PMID- 22229211 TI - Perspective on...the new PSA screening recommendations. PMID- 22229212 TI - Resection for thoracic metastases from sarcoma. AB - Sarcoma metastasizes to the lungs in 20% to 40% of patients and in most cases does not involve any other organ. Systemic chemotherapy is of unproven benefit for stage IV sarcoma. Retrospective studies have shown 5-year survival rates of 21% to 38% with wedge resection of metastatic pulmonary nodules, and up to 30% to 40% of patients survive an additional 5 years with repeated metastasectomy. In this article, we provide an extensive review of patient selection criteria and surgical approaches, as well as of controversies regarding resection for metastatic sarcoma. PMID- 22229213 TI - Resection of pulmonary metastases: a mechanical solution for a biological problem. PMID- 22229214 TI - Comments regarding lung metastasis surgery for sarcoma. PMID- 22229215 TI - Thoracic metastases from sarcoma: a commentary. PMID- 22229216 TI - AZURE subgroup analysis shows adjuvant therapy with zoledronic acid may benefit breast cancer patients postmenopausal >5 years. PMID- 22229217 TI - Phase III aflibercept-chemotherapy combination trial shows benefit in previously treated metastatic colorectal cancer patients. PMID- 22229218 TI - Veliparib plus temozolomide in metastatic melanoma trends toward increased PFS but results are not statistically significant. PMID- 22229219 TI - Geographical information systems: applications and limitations in oncology research. AB - The relationship between geography and cancer incidence and treatment is a critical area of health outcomes research. Geographical information systems (GIS) are software packages designed to store and analyze data related to geographic locations. Although more commonly associated with the social sciences and urban planning, the use of GIS software in medical research has been increasing. Moreover, since the 1999 establishment of the Geographical Informational Systems Special Interest Group (GISSIG) at the National Cancer Institute, oncology has been at the forefront of GIS-related health research. In this review, we discuss the potential applications and limitations of GIS software in oncology research. Our aims are to help clinicians and policy makers interpret studies generated using GIS, and to help clinical investigators implement GIS in future research. PMID- 22229220 TI - Examining the geography of cancer incidence and care. PMID- 22229221 TI - Oral anti-angiogenesis treatment plus chemotherapy is not more efficacious than bevacizumab plus chemotherapy in metastatic colorectal cancer. PMID- 22229222 TI - Radium-223 plus chemo shows clear OS benefit. PMID- 22229223 TI - Personalized medicine may prove faster and more effective. PMID- 22229224 TI - Could aspirin be a viable adjuvant treatment for cancer? PMID- 22229225 TI - Long-term study finds vitamin E supplements raise the risk of prostate cancer. PMID- 22229226 TI - Study finds different treatment responses between BRCA2- and BRCA1-mutated ovarian cancers. PMID- 22229227 TI - Growing number of cancer survivors among aging population as baby boomers pass the 65-year mark. PMID- 22229228 TI - Erlotinib as maintenance therapy shows PFS benefit for lung cancer patients with EGFR-mutated tumors. PMID- 22229229 TI - Flaxseed (Linum usitatissimum). PMID- 22229230 TI - Infections of the aorta and iliac arteries. Report of 20 years experience in a single centre. AB - AIM: Retrospective review of aorto-iliac infections in a single vascular surgery center. METHODS: From a retrospective review of their experience in the last 20 years, the Authors analyze a series of 12 cases of aorto-iliac infection. Prognostic factors, surgical options and results are discussed and compared with the literature. RESULTS: Infections of the aorta eventually associated with aneurysmal degeneration are uncommon (less than 3% of all aortic aneurysms) but still a life-threatening condition with high hospital mortality (25%). No statistical evaluation can be drawn from small series; however, early results are apparently influenced by emergency surgery and comorbidities affecting the immune response; in-situ reconstruction is associated with better long-term results (patency 100%, recurrent infection 0%). CONCLUSIONS: In our experience, in situ aortic grafting reconstruction associated with proper antibiotic therapy obtained satisfactory results in terms of mortality and long-term survival Endovascular treatment can be adopted in critical patients with prohibitive surgical risk. PMID- 22229231 TI - Multicentric evaluation by Verbal Rate Scale and EuroQoL-5D of early and late post-operative pain after TAPP and TEP procedures with mechanical fixation for bilateral inguinal hernias. AB - Aimed to evaluate the postoperative pain and other complications among two cohorts of patients undergone transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) laparoscopic hernia repairs with mechanical fixation, the chart of 305 TAPP and 134 TEP for bilateral not recurrent inguinal hernias were reviewed. The postoperative pain was assessed by using the Verbal Rating Scale (VRS) at one week, one month, 3 months ad six months postoperatively. A subgroup of 60 patients was also administered the QoL EQ-5D questionnaire and follow up for at least 6 months. We found a statistically significant difference in the first day (p = 0.001), in the 7th day (p = 0.002), 30th, and 90th day (p = 0.008) between patients perception of pain in TAPP group and TEP group, but after the 180th day there was not any considerable distinction. On the short term the postoperative pain seems slightly lesser in TEP group. PMID- 22229232 TI - Surgical repair of popliteal artery aneurysms remains a safe treatment option in the endovascular era: a 10-year single-center study. AB - INTRODUCTION: Endovascular popliteal artery aneurysm repair has emerged recently as a feasible alternative to standard surgical repair. However, the evidence from the literature is still limited, with only case reports, case series and one small randomized trial. Currently, the available data suggests that stent-grafts should be used in patients at very high surgical risk. The purpose of this study is to present our surgical experience in popliteal artery aneurysm repair in an endovascular era. MATERIALS AND METHODS: Data from 36 consecutive patients, who were admitted to our hospital from January 2000 to April 2010, was analyzed retrospectively. Twenty-six patients underwent surgical treatment through medial or posterior access. The posterior approach was used preferentially. The medial approach was adopted in patients with large aneurysms or aneurysms involving the superficial femoral artery. RESULTS: Twelve patients (Group A; 46.1%) were operated on via medial access followed by femoropopliteal bypass. In the remaining fourteen patients (Group B; 53.9%) an interposition graft was performed via a posterior approach. The 30-day overall mortality rate was 3.8% (1/26). The 30-day amputation rate was 0% in both groups. The primary patency rate was 83.3% in Group A at 78.8-month average follow-up (range: 18-128 months) and was 100% in Group B at 46.3-month average follow-up (range: 5-121 months). CONCLUSION: Notwithstanding the extensive use of stent-grafts worldwide, surgical repair remains the gold standard for the management of popliteal artery aneurysms. In our experience open repair using either a medial or posterior approach is associated with low mortality and morbidity rates. PMID- 22229233 TI - [Aesthetic result of thyroidectomy: evaluation of different kinds of skin suture]. AB - AIM: The aesthetic results of thyroidectomy have been evaluated in a prospective single-blinded randomized study MATERIAL OF STUDY: 140 patients undergoing thyroid surgery were randomized for skin closure into 4 groups: (1) intradermal non-absorbable suture; (2) intradermal non-absorbable double layer suture; (3) staples; (4) tissue adhesive. 136 out of the 140 patients were followed up at 3 months postoperatively. Scars were evaluated by a blinded plastic surgeon using the mVSS tool (modified Vancouver Scar Scale). Patients completed the PSAS form (Patient Scar Assessment Scale). RESULTS: Assessment of wound cosmesis with the mVSS revealed no statistical difference between group (1), (2) and (3); a statistically significant difference in the results with the group (4) (p = 0.0020) was found. The analysis of the results of PSAS showed very good subjective outcomes in all groups. However, the median values of PSAS at 3 months are better (p = 0.0001) for the group (1): follow results of group (2), (3) and (4). In some cases, the subjective rating in the group of women has been even higher than that reported by the blinded specialist. DISCUSSION: (1) still represents the gold standard in thyroidectomy. Conceptually the ideal technique should be (2): removing the suture (after two weeks from surgery) all problems related to the stimulus from foreign body are eliminated. CONCLUSIONS: The choice of suture technique to use depends on the skill and experience of the single surgeon. All four types of suture, if performed correctly, have given very attractive subjective and objective results. PMID- 22229234 TI - Efficacy and safety of ablative techniques in elderly HCC patients. AB - BACKGROUND: This study was conducted to evaluate the efficacy and safety of ablative techniques in elderly patients with hepatocellular carcinoma (HCC). METHODS: From February 2004 to February 2009, 80 elderly patients (age > or = 70 years) affected by non-resectable HCC were treated with a regional palliative approach, trans-arterial-chemo-embolization and radio-frequency-thermal-ablation (TACE, RFA). Our approach includes a first treatment of TACE and then a control CT plan after a month. A possible following RFA can be performed to ensure a complete necrosis of the lesions, and then a further contrast enhanced CT scan after 2 months. For 60 patients, the first TACE was sufficient to treat the disease at beginning. For 15 patients TACE was followed by RFA, and for 5 patients an RFA was performed directly due to nodule localization. Response to TACE is assessed every 2 to 3 months with serial AFP level and TC scan. RESULTS: Two patients died for related method's causes (2.5%): liver-renal syndrome (1 patients), and portal thrombosis with irreversible postoperative liver failure (1 patients). A total of 15 patients were lost to follow-up (18.7%): 2 (2.5%) patients had died for non-tumor-related causes, 1 due to a liver transplantation, and 12 (15%) due to failure to attend follow-up visits. All patients developed further localisation, medially after 4 months, and underwent TACE treatment for a mean of another two times. A mean follow up is 36.7 months (1-60) with a mean survival rate of 35.1 months (1-60). CONCLUSIONS: We conclude that, even in over 70-year-olds, TACE and RFA treatment should be employed to completely cure HCC, if liver function and tumor stage are acceptable. PMID- 22229235 TI - Surgical management of the glomus tumors of the fingers: a single center experience. AB - INTRODUCTION: Glomus tumors are rare neoplasms arising from the subcutaneous glomus apparatus. They account for 1 - 5% of the soft tissue tumors of the upper extremity, occurring in most cases in the nail bed. The typical clinical presentation includes paroxysmal pain and hypersensitivity to cold which limit the use of the affected hand causing practical, professional and often emotional discomfort for the patient. MATERIALS AND METHODS: Four patients with finger glomus tumor were treated in our institution in the last 30 years. Three patients had a right hand tumor (1st, 3rd and 4th finger) and one patient a left hand tumor (2nd finger). Three tumors were placed in the nail bed and one in the finger tip. In all cases duplex ultrasonography was employed preoperatively and during surgery to ensure complete resection of the tumor. All patients underwent surgical excision of the tumor with local block anesthesia. RESULTS: Intense point pain and hypersensitivity to cold was observed in all cases (100%). Two out of 4 patients (50%) presented an irradiation of the pain at the ipsilateral arm and shoulder. Surgical procedure was performed successfully in all cases, with total excision of the tumor and no intraoperative or postoperative complications. No recurrences occurred. CONCLUSIONS: Diagnosis of glomus tumors of the fingers is generally easy when manifested with the classical clinical picture and duplex ultrasonography is employed. Complete surgical excision is curative, providing immediate relief of symptoms and improvement of eventual professional or psychological discomfort. PMID- 22229236 TI - Early and late troponin T determination after elective cardiac surgery. Two different meanings. AB - AIM: Although Troponins are demonstrated to be better predictors than CK-MB in quantification of myocardial damage, the relation between cut-off values for the diagnosis of perioperative myocardial infarction (PMI) and sample time is still not clear. In the present study we sought to analyse the clinical consequence of an early and late cTnt determinations after elective cardiac surgery. MATERIAL OF STUDY: Data of 117 patients undergone elective open heart surgery between January 2006 and June 2007 were prospectively collected. PMI was detected on the basis of postoperative electrocardiography/echocardiography and hemodynamic state. RESULTS: The in-hospital mortality was 1.7%. Eight patients (6.8%) presented PMI. Receiver-operating characteristic (ROC) analyses showed a cTnt cut-off of 1.22 mg/L (CI 0.94 to 0.99, P = 0.0001, 100% sensitivity and 96% specificity) on arrival to ICU for the diagnosis of PMI. On the second post-operative day the cut off value was 2.8 mg/L (CI 95% 0.84 to 0.98, P = 0.0001) (sensitivity 66% and specificity 100%). At this time the Pearson's test revealed the best correlation to ICU (P = 0.008) and in-hospital (P = 0.01) length of stay (LOS). DISCUSSION: A better sensibility of cTnt in diagnosis of PMI in the early postoperative period has been demonstrated to be associated to an increasing specificity in the late post-operative period. CONCLUSIONS: PMI must be suspected in patients with a cTnt > 1.22 mg/L. A second later assessment on the 2nd post-operative can exclude false positives and significantly predict the ICU and the in-hospital length of stay. PMID- 22229237 TI - The effect of omega-3 fatty acid and ascorbic acid on healing of ischemic colon anastomoses. AB - PURPOSE: Many systemic and local factors contribute to gastrointestinal tract anastomoses dehiscence, which is a serious and potentially fatal postoperative complication. The aim of this study was to evaluate the effects of omega-3 fatty acid and ascorbic acid on the healing of ischemic colon anastomosis. PATIENTS AND METHODS: 40 Wistar Albino rats weighing between 180 and 220 g were divided into four groups. Groups were assigned as follows; Group 1 (control): anastomosis and no treatment, Group 2: anastomosis plus ascorbic acid, Group 3: anastomosis plus omega-3 fatty acid, and Group 4: anastomosis plus ascorbic acid and omega-3 fatty acid. Colon anastomoses was were performed in all rats. All animals were sacrificed on the 5th postoperative day. Healing of the anastomoses was assessed by measuring the burst pressures (BP) and hydroxyproline levels. RESULTS: No mortality was observed and perianastomotic abscesses were not noted in any rats. The BP was significantly higher in the ascorbic acid plus omega-3 fatty acid combination group than the other groups (p < 0.05). The hydroxyproline levels were significantly high in ascorbic acid plus omega-3 fatty acid combination group than the other groups (p < 0.05). CONCLUSION: Dietary supplementation with omega-3 fatty acid and ascorbic acid improved colonic anastomoses healing. Ascorbic acid and omega-3 fatty acid enhance the colonic wound healing process by additive action. PMID- 22229238 TI - Observations and considerations on a case of Mondor's syndrome associated with gigantomastia. AB - AIM: The study of the Mondor's syndrome as a possible complication of gigantomastia. MATERIAL AND METHOD: A 49 year old woman, with gigantomastia, came to our observation for the presence of a large superficial vein of the left breast affected by thrombophlebitis, compatible with Mondor's syndrome. RESULTS: A "Thorek" breast reduction was performed; the patient was discharged on the second postoperative day and the follow up was smooth and fee from any complications. DISCUSSION: In the case we observed, gigantomastia had a clear role in the pathogenesis of the Mondor's disease; in fact, the excessive weight of the breasts caused stretching of the mammary dorsal vein evolving in phlebitis. In literature, among the causes related to Mondor's disease the pendulous breast is described, probably with the same dynamic we have seen in this patient, but has never reported, so obviously, the correlation between the two events. It's considered as good practice in the pre-operative evaluation, to make differential diagnosis with any cancer, that, in a certain percentage, is associated with Mondor's syndrome, and once established the causes of the pathology, it is imperative to eliminate them to prevent any relapses. CONCLUSION: Among the various causes recognized as predisposing to Mondor's syndrome, there has never been described gigantomastia so far. The observation and treatment of a patient in whom the gigantomastia certainly led to the onset of Mondor's disease, has led us to consider this as one of the possible complications of gigantomastia, providing an additional cue to the treatment of this condition even at an early stage. PMID- 22229239 TI - Duplication cyst of the stomach with respiratory epithelium in adult: an uncommon finding. Report of case and review of literature. AB - Gastrointestinal duplication is a congenital rare disease entity. Duplication cyst of the stomach with pseudo stratified columnar ciliated epithelium is extremely rare. The very appearance of a gastric duplication cyst in an adult can present a diagnostic dilemma. In majority of reported cases, the diagnosis is established during surgical exploration. We report on a 34 year-old female patient suffering from repeated episodes of epigastric pain and gastroesophageal reflux. Abdominal computed tomography and endoscopic ultrasound demonstrated a intramural lesion attached to the gastric fundus, suggestive of gastrointestinal stromal tumor (GIST). At exploratory laparotomy a non-communicating cyst, was found along the greater curvature of the stomach in the esophagogastric transition. The lesion was excised along with an adjacent sleeve of the stomach and esophagus wall because shared muscular layer with the stomach and esophagus. The final pathologic examination revealed that the inner wall of the cyst was lined by a pseudostratified columnar ciliated epithelium (respiratory type) and, in part, columnar and gastric foveolar epithelium. Even though a panel of imaging modalities is available, it is still difficult to obtain a preoperative diagnosis. Duplication cyst can be mistaken for a soft tissue tumor of the gastrointestinal tract. There is no therapeutic algorithm. Surgical treatment is recommended for symptomatic cases. PMID- 22229240 TI - [Congenital dilatation of the biliary system in adult: about three clinical cases]. AB - The authors refer to three cases of congenital dilatation of the biliary system in an adult, an extremely rare pathology in the West, with no specific symptomatology, and therefore often discovered accidentally and unexpectedly The first patient had suffered from unexplained periods of fever since childhood, the second had only complained of vague abdominal pains a years before diagnosis; for the third, a Romanian woman, it was the first time she complained of a biliary colic. All the patients had an Ultrasound, a CT scan and a MRCP (magnetic resonance cholangiopancretography). Based on the Todani classification, the first and the third case belongs to type IV A, while the second is a type I. In all three patients the pathology was resolved due to an operation entailing disconnection of the biliary-pancreatic tract, with complete surgical removal of the dilated bile ducts followed by a Roux-en-Y hepatico-jejunostomy. Nevertheless the procedures undertaken are not immune to criticism: in the first and second case the diagnostic imagery had not immediately produced a clear interpretation, leading to a delay in the diagnosis and the execution in the first of a not anodyne ERCP; in the third case a colecistectomy was performed as it were as an intermediary measure; finally there was probably omitted a thorough explanation to the patient with regard to a pathology deserving of a careful follow-up for the possible recidivist of the infectious phenomena and above all the onset of the dangerous degeneration carcinomatosa. PMID- 22229241 TI - Chylous ascites following laparoscopic living donor nephrectomy. Case report. AB - Kidney transplantation is a therapeutic option of choice for patients with end stage disease. Laparoscopic living donor nephrectomy (LLDN) is a less invasive alternative to the open procedure to increase the number of renal donors. However, several studies have reported that this technique requires a long learning curve, and that the complication rate varies from 6.4% to 16.5%. Among these, chylous ascites (CA) is a severe and rare complications of LLDN. The treatment option for this condition is primarily conservative. Surgery is considered after failure of conservative treatment and its role, however, remains controversial. We report a case of CA as a complication of laparoscopic donor nephrectomy. A 44 year old woman underwent LLDN of the left kidney. There were no intraoperative or immediate postoperative complications and the patient was discharged home on postoperative day 3. Two weeks after discharge, the patient returned for a routine follow-up visit and presented with abdominal distension, discomfort, and dyspnea. A CT scan of the abdomen with oral and intravenous contrast revealed significant ascites in all four quadrants of abdomen and pelvis. An ultrasound guided paracentesis was performed, and 7 L of chyle was aspirated Conservative management with medium chain triglyceride and spironolactone was immediately initiated; the symptoms improved after paracentesis, and the CA completely resolved after 3 days of therapy. However, to prevent recurrence, the patient consumed a low-fat medium chain triglyceride diet for 6 months. CA needs to be considered as a potential severe and rare complication of LLDN, and conservative management should be proposed to all patients, reserving the surgical treatment to treatment failure. PMID- 22229242 TI - The double opposing "Y" technique for umbilical reconstruction after omphalectomy. AB - BACKGROUND: Abdominal surgical procedures, such as ventral hernia repair, may require the removal of the umbilicus, which gives an unnatural appearance to the abdomen. This situation can be corrected by umbilical reconstruction during the same operative time or at a later stage. In previous studies, we reported a versatile technique for umbilicoplasty based on a double opposing "Y" incision on the abdominal flap to create a new umbilicus. We now report the use of this technique for umbilical reconstruction in patients who underwent previous or concurrent omphalectomy. METHODS: A prospective open-label study was performed on 10 patients undergoing the double opposed "Y" umbilicoplasty after omphalectomy. Postoperative patients' satisfaction and results were evaluated during the follow up of minimum 1 year. A modified 5 ml syringe was used to assess depth and volume of umbilical stalk. Depth value variations from one month to one year after surgery were statistically compared using the Wilcoxon test. RESULTS: Complete healing of the new umbilicus was achieved in 14-21 days in nine cases. In one case, partial dehiscence of the wound occurred and complete healing was achieved in 4 weeks. Follow-up time ranged from 1 to 4 years. In all patients, a three dimensional umbilicus with satisfactory depression was created. During follow-up, no significant changes in shape, dimension and appearance were observed. All patients were pleased with the results. No cicatricial umbilical stenosis occurred. CONCLUSIONS: The double opposing "Y" technique creates a new natural umbilical scar; this technique can be easily performed for umbilical reconstruction after omphalectomy. PMID- 22229243 TI - [Squamous-cell carcinoma and pilonidal sinus disease. Case report and review of literature]. AB - Squamous-cell carcinoma arising in a pilonidal sinus is a rare occasion. Authors report the case of a 60 years old male, with a 15 years history of recurrent pilonidal sinus disease. The patient underwent incisional biopsy, staging with total body CT, and finally radical surgery. The large wound healed by secondary intention, with a complete formation of the scar in three months. After six months, no complications or signs of recurrence were observed. Authors recommend careful inspection of the pilonidal area in all chronic and longstanding inflammatory lesions to identify promptly malignant transformation. PMID- 22229244 TI - [Gastrointestinal stromal tumors]. PMID- 22229245 TI - Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients:implications for cancer therapy. AB - Patients with metastatic Colorectal Cancer (mCRC), in which primary tumors are KRAS mutated, have no response to anti-EGFR therapy. However, less than half of mCRC patients with KRAS wild-type primary tumors respond to anti-EGFR therapy. Other downstream effectors of the EGFR pathway are being analyzed to fine-tune KRAS predictive value. However, as the primary tumor is the tissue of analysis that determines the use of anti-EGFR therapy in advanced disease, a high concordance in the status of these effectors between primary tumors and related metastases is required. We analyzed the concordances of downstream EGFR effectors in tumoral pairs of primaries and related metastases in a series of KRAS wild type patients. One hundred seventeen tumoral pairs from patients with CRC were tested for KRAS mutational status. The level of concordance in the presence of KRAS mutations was 91% between the primary tumor and related metastases. The 70 pairs with KRAS wild-type primary tumors were further analyzed for BRAF and PIK3CA mutational status and for EGFR, PTEN and pAKT expression, and the number of concordant pairs was 70 (100%), 66 (94%), 43 (61%), 46 (66%) and 36 (54%), respectively. Our findings suggest that the mutational status of KRAS, BRAF and PIK3CA in the primary tumor is an adequate surrogate marker of the status in the metastatic disease. On the other hand, the immunohistochemical analysis of EGFR, PTEN and pAKT showed a much higher degree of discordance between primaries and related metastases. PMID- 22229246 TI - Clinical experience with thalidomide and lenalidomide in multiple myeloma. AB - Thal has antiangiogenic and immunomodulatory activity. Clinical research provided clear evidence that Thal belongs to the most active drugs for the treatment of multiple myeloma e.g. leading to decrease of monoclonal protein of at least 50 % in 30 % of patients with relapsed or refractory multiple myeloma. Randomized trials that were designed based on a large body of evidence from phase II trials determined that Thal significantly increases total response rate, progression free and in some studies overall survival in combination regimens (dexamethason and or chemotherapy) for relapsed as well as newly diagnosed patients and was therefore approved for first-line treatment of Multiple Myeloma. Strict guidelines apply due to the teratogenic effects of Thal and to monitor and prevent other potential adverse events as neuropathy and thrombosis has been recognized by leading organizations as part of the treatment concept for patients with relapsed or refractory disease. The success of Thal has sparked the development of Thal analogues with Lenalidomide (Len) the most advanced compound which was approved for relapsed multiple myeloma. As Len has a lower incidence of polyneuropathy, constipation and somnolence compared to Thalidomid but at least equal if not higher efficacy Len is meanwhile used more frequently in clinical routine and has advantages in combination therapies with Bortezomib. Additional randomized studies will now define the status of Thal and Len for maintenance therapy and their optimal integration in multi-agent treatment regimen. PMID- 22229247 TI - Targeting aurora kinases: a novel approach to curb the growth & chemoresistance of androgen refractory prostate cancer. AB - Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC. PMID- 22229248 TI - Genetic variants in genes involved in mechanisms of chemoresistance to anticancer drugs. AB - Refractoriness to the pharmacological treatment of cancer is dependent on the expression levels of genes involved in mechanisms of chemoresistance and on the existence of genetic variants that may affect their function. Thus, changes in genes encoding solute carriers may account for considerable inter-individual variability in drug uptake and the lack of sensitivity to the substrates of these transporters. Moreover, changes in proteins involved in drug export can affect their subcellular localization and transport ability and hence may also modify the bioavailability of antitumor agents. Regarding pro-drug activation or drug inactivation, genetic variants are responsible for changes in the activity of drug-metabolizing enzymes, which affect drug clearance and may determine the lack of response to anticancer chemotherapy. The presence of genetic variants may also decrease the sensitivity to pharmacological agents acting through molecular targets or signaling pathways. Recent investigations suggest that changes in genes involved in DNA repair may affect the response to platinum-based drugs. Since most anticancer agents activate cell death pathways, the evasion of apoptosis plays an important role in chemoresistance. Several genetic variants affecting death-receptor pathways, the mitochondrial pathway, downstream caspases and their natural modulators, and the p53 pathway, whose elements are mutated in more than half of tumors, and survival pathways, have been reported. The present review summarizes the available data regarding the role of genetic variants in the different mechanisms of chemoresistance and discusses their potential impact in clinical practice and in the development of tools to predict and overcome chemoresistance. PMID- 22229249 TI - Targeting angiogenesis for treatment of NSCLC brain metastases. AB - Lung cancer is the leading cause of cancer-related mortality worldwide, and non small cell lung cancer (NSCLC) accounts for about 85% of all new lung cancer diagnosis. The majority of people with NSCLC are unsuitable for surgery since most patients have metastatic disease at diagnosis. About 60% of brain metastases arise from lung cancer. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery, chemotherapy and new biologic agents. Angiogenesis is essential for the development and progression of cancer, and vascular endothelial growth factor (VEGF) is a critical mediator of tumour angiogenesis. One of the targeted approaches most widely studied in the treatment of NSCLC is the inhibition of angiogenesis. Bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced non squamous NSCLC patients. Patients with central nervous system (CNS) metastases have initially been excluded from bevacizumab trials for the risk of cerebral haemorrhage as a result of the treatment. Nevertheless, the available data suggest an equal risk of intracranial bleeding in patients with CNS metastases treated with or without bevacizumab therapy. Several other anti-angiogenetic drugs are being investigated in the treatment of advanced NSCLC patients, but results of their activity specifically in CNS metastases are still lacking. This review will focus on the potential role of bevacizumab and other anti angiogenetic agents in the treatment of brain metastases from NSCLC. PMID- 22229250 TI - Anti-angiogenic approaches to malignant gliomas. AB - Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant gliomas is poor. Malignant gliomas are highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Recent studies of bevacizumab, an anti-VEGF monoclonal antibody, alone or associated with chemotherapy, have demonstrated high response rates and prolongation of median and 6-month progression-free survival. Clinical evaluation of several multitarget small molecule tyrosine kinase inhibitors is ongoing. Other promising antiangiogenic compounds are cilengitide and continuous temozolomide. Toxicity is acceptable. Open issues are represented by patterns of tumor progression, resistance mechanisms and biomarkers. PMID- 22229251 TI - The blood-brain barrier: its influence in the treatment of brain tumors metastases. AB - Brain metastases represent the most common intracranial tumors in the adults. Its incidence outnumbers that of primary brain tumors by a tenfold factor. Estimated cumulative incidence is between 10 to 20% of all cancer patients, which would represent over 170 000 new cases in the US. Typically, patients with multiple brain metastases are exposed to whole brain radiation therapy, as a palliative measure. Resulting median survival improvement is modest, ranging from 3 to 5 months. This survival has not been altered despite 3 decades of clinical research aiming at improving outcome of these patients. The role of standard chemotherapy in the treatment of brain metastases has always been marginal, as the penetration of chemotherapy beyond the BBB (blood-brain barrier) is considered limited. Whereas the BBB is universally recognized as a physiological entity, its role in the treatment of brain metastases remains controversial. Metastatic lesions often depict a homogeneous intense enhancement on either CT or MRI, thus implying that the brain tumor barrier (BTB) is breached. Although there is no doubt that the BBB and BTB suffer from variable degrees of breach in integrity in the presence of malignant brain tumors, impediment to drug delivery remains, and strategy to optimize delivery must be considered if one is to really impact patient ? s outcome in the treatment of these diseases. The intended purpose of this paper is to review current data on the role of the BBB in the treatment of CNS metastatic disease. PMID- 22229252 TI - Role of EGFR inhibitors in the treatment of central nervous system metastases from non-small cell lung cancer. AB - Brain metastases (BM) are a common occurrence in patients with non-small cell lung cancer (NSCLC). Standard therapy options include whole brain radiotherapy and, in selected patients, surgery or stereotactic radiosurgery. The role of systemic treatment is controversial. There is a strong clinical rationale for the use of targeted therapies, because patients often have a poor performance status, and are not candidates for cytotoxic chemotherapy or radiotherapy, yet treatment is required to improve the extra-cranial disease. The efficacy of epidermal growth factor receptor (EGFR) inhibitors in the treatment of patients with BM from NSCLC has been reported mainly in case reports or small retrospective case series, with only a few prospective trials. Current evidence suggests that the use of EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib should be considered in patients with asymptomatic CNS involvement, when clinical characteristics suggest a high likelihood of response; these characteristics are adenocarcinoma histology, never-smoker status, female gender and East Asian ethnicity. Upfront therapy with EGFR TKIs should be strongly considered in asymptomatic patients harboring activating EGFR mutations. In symptomatic BM, radiotherapy (RT) remains the standard treatment. Based on currently available data, treatment with concurrent RT and EGFR TKIs should be investigated in experimental trials only. PMID- 22229253 TI - Over-nutrition, obesity and insulin resistance in the development of beta-cell dysfunction. AB - The incidence of type 2 diabetes mellitus (DM2) has increased dramatically over the last several decades, largely driven by equally worrisome growing rates of obesity. Chronic diabetic complications are leading causes of morbidity and mortality worldwide. Key players in the pathophysiology of DM2 are insulin resistance and beta cell dysfunction, which in turn is a result of both beta cell functional abnormality as well as reduced beta cell mass. The mechanisms implicated are multifactorial and include genetic and environmental factors related to obesity. Glucose homeostasis is critically dependent on a finely regulated balance between insulin sensitivity and output in the pancreas, and insulin resistance demands a corresponding rise in insulin output in order to maintain normal glycemia. However, this compensation is lost in individuals predisposed to DM2, resulting in overt hyperglycemia. Furthermore, insulin resistance related to excess adiposity is linked to several abnormalities which impact beta cell function and viability. These include glucotoxicity, lipotoxicity, increased oxidative stress, and inflammation. In addition, insulin signaling in the beta cell is essential to its own functionality and viability, and obesity-related abnormalities in insulin signaling are known to induce failure of insulin secretion and hyperglycemia. Insulin resistance in the beta cell arises from defects in phosphorylation/activation of insulin receptor substrates (IRS) proteins, which result in impairment in glucose sensing, glucose stimulated insulin secretion, and also in increased loss of beta cells. This review intends to provide an update on the main characteristics and mechanisms that link obesity and insulin resistance to beta cell dysfunction in the pathogenesis of DM2. PMID- 22229254 TI - Direct patterning of TiO2 using step-and-flash imprint lithography. AB - Although step-and-flash imprint lithography, or S-FIL, has brought about tremendous advancement in wafer-scale fabrication of sub-100 nm features of photopolymerizable organic and organo-silicon-based resists, it has not been successful in direct patterning of inorganic materials such as oxides because of the difficulties associated with resist formulation and its dispensing. In this paper, we demonstrate the proof-of-concept S-FIL of titanium dioxide (TiO(2)) carried by an acrylate-based formulation containing an allyl-functionalized titanium complex. The prepolymer formulation contains 48 wt % metal precursor, but it exhibits low enough viscosity (~5 mPa.s) to be dispensed by an automatic dispensing system, adheres and spreads well on the substrate, is insensitive to pattern density variations, and rapidly polymerizes when exposed to broadband UV radiation to give a yield close to 95%. Five fields, each measuring 1 cm * 1 cm, consisting of 100 nm gratings were successively imprinted. Heat-treatment of the patterned structures at 450 degrees C resulted in the loss of organics and their subsequent shrinkage without the loss of integrity or aspect ratio and converted them to TiO(2) anatase nanostructures as small as 30 nm wide. With this approach, wafer-scale direct patterning of functional oxides on a sub-100 nm scale using S FIL can become a distinct possibility. PMID- 22229256 TI - Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of aromatase inhibitor vs. gonadotrophin releasing hormone agonists in treating premenopausal women with uterine adenomyosis. DESIGN: A prospective randomized controlled study. SETTING: A university hospital and a private practice setting. POPULATION: Thirty-two patients with uterine adenomyosis. METHODS: Patients were randomly allocated to receive oral letrozole (2.5 mg/day) or a subcutaneous gonadotropin-releasing hormone agonist (goserelin, 3.6 mg) for 12 weeks. Uterine and adenomyoma volumes were determined at baseline and during treatment at four, eight and 12 weeks. OUTCOME MEASURES: Measurements were performed at baseline and during treatment at four, eight 8 and 12 weeks, and mean values were calculated. Symptoms at the start and after 12 weeks were evaluated. RESULTS: No significant differences in the total uterine size between the post treatment uterine volumes in the two groups (20.1, 15.4 and 13.0 cm(3) vs. 21.7, 15.1 and 11.7 cm(3) , at four, eight and 12 weeks, respectively). Total adenomyoma volume decreased by 8.6, 29.7 and 40.9% vs. 5.7, 34.6 and 49.1% after four, eight and 12 weeks of treatment, in group A and B, respectively. Two patients became pregnant in group A during treatment. CONCLUSIONS: Aromatase inhibitors are as effective as gonadotropin releasing hormone agonists in reducing adenomyoma volume and improving symptoms. PMID- 22229257 TI - Formulation study of directly compressible chewable polymers containing ascorbic acid. AB - The topic of this article is the compression physics of different gum bases which can be used to prepare chewing gum tablets by direct compression. Three different gum bases, Pharmagum((r)) C, M and S, were tested alone and in different combinations. The preparations were compressed with a Korsch EK0 eccentric tableting machine at compression forces of 5, 7.5, 10, 12.5 and 15 kN. The compression and breaking processes and the physical parameters of the tablets were investigated. The results revealed that increase of the compression force did not significantly change the studied parameters of the tablets. PMID- 22229258 TI - Firm, fair, and caring officer-offender relationships protect against supervision failure. AB - A growing body of research suggests that high quality dual role relationships between community corrections officers and offenders reduce risk of recidivism. This study assesses whether this finding generalizes from offenders with mental illness to their relatively healthy counterparts. More importantly, this study tests the possibility that this finding is spurious, reflecting the influence of pre-existing offender characteristics more than a promising principle of practice. In this study of 109 parolees without mental illness, the authors found that (a) firm, fair, and caring relationships protect against rearrest, and (b) do so even after accounting for offenders' pre-existing personality traits and risk for recidivism. These findings are consistent with the theoretical notion that good dual role relationships are an essential element of core correctional practice, even (or particularly) for difficult or high risk offenders. PMID- 22229259 TI - Anabolic steroids and cardiovascular risk. AB - Recent reports from needle exchange programmes and other public health initiatives have suggested growing use of anabolic steroids (AS) in the UK and other countries. Data indicate that AS use is not confined to body-builders or high-level sportsmen. Use has spread to professionals working in emergency services, casual fitness enthusiasts and subelite sportsmen and women. Although the precise health consequences of AS use is largely undefined, AS use represents a growing public health concern. Data regarding the consequences of AS use on cardiovascular health are limited to case studies and a modest number of small cohort studies. Numerous case studies have linked AS use with a variety of cardiovascular disease (CVD) events or endpoints, including myocardial infarction, stroke and death. Large-scale epidemiological studies to support these links are absent. Consequently, the impact of AS use upon known CVD risk factors has been studied in relatively small, case-series studies. Data relating AS use to elevated blood pressure, altered lipid profiles and ECG abnormalities have been reported, but are often limited in scope, and other studies have often produced equivocal outcomes. The use of AS has been linked to the appearance of concentric left ventricular hypertrophy as well as endothelial dysfunction but the data again remains controversial. The mechanisms responsible for the negative effect of AS on cardiovascular health are poorly understood, especially in humans. Possibilities include direct effects on myocytes and endothelial cells, reduced intracellular Ca2+ levels, increased release of apoptogenic factors, as well as increased collagen crosslinks between myocytes. New data relating AS use to cardiovascular health risks are emerging, as novel technologies are developed (especially in non-invasive imaging) that can assess physiological structure and function. Continued efforts to fully document the cardiovascular health consequences of AS use is important to provide a clear, accurate, public health message to the many groups now using AS for performance and image enhancement. PMID- 22229261 TI - Improving grape phenolic content and wine chromatic characteristics through the use of two different elicitors: methyl jasmonate versus benzothiadiazole. AB - Benzothiadiazole (BTH) and methyl jasmonate (MeJ) have been described as exogenous elicitors of some plant defense compounds, polyphenols among them. The objective of this study was to determine whether the application of BTH or MeJ to grape clusters at the beginning of the ripening process had any effect on the accumulation of the main flavonoid compounds in grapes (anthocyanins, flavonols, and flavanols) and the technological significance of these treatments in the resulting wines. The results obtained after a 2 year experiment indicated that both treatments increased the anthocyanin, flavonol, and proanthocyanidin content of grapes. The wines obtained from the treated grapes showed higher color intensity and total phenolic content than the wines made from control grapes. The exogenous application of these elicitors, as a complement to fungicide treatments, could be an interesting strategy for vine protection, increasing, at the same time, the phenolic content of the grapes and the resulting wines. PMID- 22229263 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry identification of Archaea: towards the universal identification of living organisms. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) identification of Archaea has been limited to some environmental extremophiles belonging to distant taxa. We developed a specific protocol for MALDI-TOF-MS identification of Archaea and applied it to seven environmental human-associated Methanobrevibacter smithii, Methanobrevibacter oralis, Methanosphaera stadtmanae, and the recently described Methanomassiliicoccus luminyensi Archaea. After mechanical lyse, we observed a unique protein profile for each organisms comprising 7-24 peaks ranging from 3,015 to 10,632 Da with a high quality score of 7.38 +/- 1.26. Profiles were reproducible over successive experiments performed at 1, 2, and 3-week growth durations and unambiguously distinguished the Archaea from all of the 3,995 bacterial spectra in the Bruker database. After the incorporation of the determined profiles into a local database, archaeal isolates were blindly identified within 10 min with an identification score of 1.9-2.3. The MALDI-TOF-MS-based clustering of these archaeal organisms was consistent with their 16S rDNA sequence-based phylogeny. These data prove that MALDI-TOF-MS profiling could be used as a first-line technique for the identification of human Archaea. In complement to previous reports for animal cells, Bacteria and giant viruses, MALDI-TOF-MS therefore appears as a universal method for the identification of living unicellular and multicellular organisms. PMID- 22229260 TI - Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. AB - AIMS: Intracellular amyloid beta (Abeta) oligomers and extracellular Abeta plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Abeta production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase Abeta generation and thereby initiate a vicious cycle further impairing mitochondrial function. RESULTS: Complex I and III dysfunction was induced in a cell model using the respiratory inhibitors rotenone and antimycin, resulting in mitochondrial dysfunction and enhanced ROS levels. Both treatments lead to elevated levels of Abeta. Presence of an antioxidant rescued mitochondrial function and reduced formation of Abeta, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Abeta showed impairment of mitochondrial function such as comprised mitochondrial respiration, strongly altered morphology, and reduced intracellular mobility of mitochondria. Again, the capability of these cells to generate Abeta was partly reduced by an antioxidant, indicating that Abeta formation was also ROS dependent. Moreover, mice with a genetic defect in complex I, or AD mice treated with a complex I inhibitor, showed enhanced Abeta levels in vivo. INNOVATION: We show for the first time that mitochondrion-derived ROS are sufficient to trigger Abeta production in vitro and in vivo. CONCLUSION: Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Abeta itself leads to mitochondrial dysfunction and increased ROS levels. We propose that starting from mitochondrial dysfunction a vicious cycle is triggered that contributes to the pathogenesis of sporadic AD. PMID- 22229264 TI - Differential effect of the expression of TGF-beta pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior. AB - The aim of our study was to investigate the expression of Smad-7 and Ski proteins in invasive breast carcinomas, to determine their clinicopathological value and their influence on carcinomas biologic behavior. Immunohistochemistry was applied on 150 invasive breast carcinomas to detect the expression of Smad-7 and Ski. Their correlation to clinicopathologic parameters and markers of metastasis was statistically processed using chi-squared test. Overall and disease-free survival was assessed using Kaplan-Meier test and log-rank statistics. Smad-7 was immunodetected in the cytoplasm of cancer cells in 60%, whereas Ski was immunodetected in the cytoplasm and nuclei in 44.5% and 17.6% of the cases, respectively. Smad-7 expression was positively correlated with tumor size, stage, matrix metalloproteinase (MMP)-9, and MMP-14. Cytoplasmic Ski expression was negatively associated with tumor size, stage, and lymph node status, and its nuclear expression was negatively related to histologic grade. Cytoplasmic Ski expression was associated with longer overall and disease-free survival. It appears that two negative regulators of the transforming growth factor-beta pathway, Smad-7 and Ski, behave differentially in invasive breast carcinomas. Smad-7 appears to be related with an aggressive phenotype, whereas Ski expression is related to a less aggressive behavior and positively influences patients' survival. PMID- 22229265 TI - Role of c-Jun N-terminal kinase and p38/activation protein-1 in interleukin-1beta mediated type I collagen synthesis in rat hepatic stellate cells. AB - Interleukin-1 (IL-1) may play a role in maintaining hepatic stellate cell (HSC) in activated state that is responsible for hepatic fibrogenesis. However, the signal transduction pathway that is stimulated by IL-1 in HSC remains to be fully elucidated. The aims of this study were to investigate the role of c-Jun N terminal kinase (JNK) and p38/activation protein (AP-1) in IL-1beta-mediated type I collagen synthesis in rat HSCs. Here, we show that IL-1beta could activate JNK and p38 in a time-dependent manner, and that inhibition of the JNK pathway could increase collagen synthesis; however, inhibition of the p38 pathway could inhibit collagen synthesis. Furthermore, IL-1beta activated AP-1 in a time-dependent manner in rat HSCs. These data demonstrate that L-1beta could promote the synthesis of type I collagen in rat HSCs, and the JNK and p38/AP-1 pathways were involved in this process. In summary, IL-1beta-induced collagen synthesis is possibly mediated by cytoplasmic JNK and p38/AP-1 pathways. Therefore, drugs that block the p38/AP-1 pathway may inhibit liver extracellular matrix synthesis and suppress liver fibrosis. PMID- 22229266 TI - Construction and characterization of three knockout mutants of the fbl gene in Staphylococcus lugdunensis. AB - Staphylococcus lugdunensis is an important human pathogen that causes infectious diseases similar to those caused by Staphylococcus aureus. In contrast to S. aureus, only a very few pathogenicity factors of S. lugdunensis have been characterized. Notably, a genetic manipulation of S. lugdunensis has not yet been described. Ours is the first report where transformation of three different plasmids (pBT2, pRB473, and pT181) into S. lugdunensis and a directed genetic manipulation of S. lugdunensis are described. We constructed fbl knockout mutants from three different strains of S. lugdunensis to show that at least in these strains, the fibrinogen binding is exclusively mediated by Fbl. PMID- 22229267 TI - Carbonic anhydrase isozymes II, IX, and XII in uterine tumors. AB - Histopathological diagnostics of gynecological malignancies continues to be challenging despite the well established criteria. For example, the morphological distinction of uterine leiomyosarcoma from certain variants of benign leiomyoma can be difficult. Herein, we investigated the expression of Carbonic anhydrase (CA) II, IX, and XII in the normal endometrium, leiomyomas, uterine sarcomas, and endometrial adenocarcinomas using immunohistochemistry. These isozymes are considered promising diagnostic markers and therapeutic targets. The normal endometrium showed high CA XII expression, whereas the signals were lower in endometrial adenocarcinoma (p < 0.004). Only sporadic CA IX staining was found in the normal endometrium, whereas the enzyme was overexpressed in most cases of endometrial adenocarcinoma (p < 0.005). CA II expression was slightly weaker in the normal endometrium than that in the adenocarcinomas (p < 0.008). Positive immunostaining reactions for CAs were observed in the uterine sarcomas, whereas all leiomyomas were negative for CA II and XII. A comparison between leiomyomas and sarcomas showed statistically significant differences for all studied isozymes (p < 0.001). Our study shows that CA isozymes could together serve as histopathological biomarkers for differential diagnosis between uterine leiomyosarcoma and leiomyoma. In addition to being found in leiomyosarcomas, CA II and IX were overexpressed in endometrial adenocarcinoma, where they might regulate the pH of the tumor microenvironment. PMID- 22229268 TI - CD73 protects kidney from ischemia-reperfusion injury through reduction of free radicals. AB - Renal ischemia-reperfusion injury (IRI) may cause severe systemic diseases. Extracellular adenosine is anti-inflammatory especially during hypoxemia. As ecto 5'-nucleotidase (CD73) is the rate-limiting enzyme for extracellular adenosine generation, it may protect renal IRI through adenosine production. In the current studies, we investigated the effects of CD73 in genetically modified mice. We found that renal IRI caused more serious histological injury, vascular permeability, and lipid peroxidation in CD73(-/-) than that in CD73(+/+) mice. In addition, AMP and free radical concentrations were much higher in CD73(-/-) than that in CD73(+/+) mice. Our data support the fact that CD73 may protect the kidney from IRI through adenosine production and a reduction of free radicals. PMID- 22229269 TI - Streptococcus mitis/human gingival fibroblasts co-culture: the best natural association in answer to the 2-hydroxyethyl methacrylate release. AB - One of the major components of dental polymerized resin-based restorative materials is 2-hydroxyethyl methacrylate (HEMA) and its release in monomeric form interferes with the oral cavity environment. This study aimed to evaluate HEMA monomeric effects on the co-culture of Streptococcus mitis and human gingival fibroblasts (HGFs). Streptococcus mitis DS12 and S. mitis ATCC 6249 were co cultivated with HGF in the presence of HEMA (3 mM), for 48 and 72 h; the amount of sessile and planktonic cells, as well as the prokaryotic and eukaryotic cell viability were analyzed in treated and untreated samples. The treatment of S. mitis/HGFs with HEMA did not produce significant effects on the bacterial adhesion and induced an increase in planktonic S. mitis ATCC 6249 population after 48 and 72 h. HEMA increased significantly the planktonic S. mitis ATCC 6249 viability when co-cultured with HGFs, while a cytotoxic effect on HGFs, without bacteria, was recorded. An increase of bacterial aggregation on HGFs was also detected with HEMA. Data obtained in this study suggest that HEMA exhibits a toxic effect mainly on eukaryotic cells and this effect can be modulated by co cultivation with the S. mitis cells which, in the presence of the monomer, enhance their aggregation rate on HGFs. PMID- 22229271 TI - Ghrelin in the fetal pancreas - a digital quantitation study. AB - Ghrelin is a hormone produced by specialized neuroendocrine cells located in the fetal pancreas. In the adult, ghrelin has multiple effects, but in the fetus the role of ghrelin and the distribution of ghrelin-producing cells is not well documented. The aim of this study was to describe and quantitate the number of ghrelin positive cells in the pancreas during gestation. The material consisted of pancreatic tissue from 19 fetuses at different gestational ages. Immunohistochemical staining was performed, and the expression was quantitated using an automated digital image analysis system. The results showed ghrelin producing cells as scattered single cells in ductular structures and acini throughout the gestation. From midgestation they were also found in the periphery of the islets as a rim of cells. A tendency towards a high ghrelin expression during early gestation and a stable expression from midgestation to term was observed. In conclusion, the effects of fetal ghrelin are not fully understood, but the varying distribution of ghrelin positive cells indicates different effects of ghrelin during development. PMID- 22229270 TI - Low-dosage metronomic chemotherapy and angiogenesis: topoisomerase inhibitors irinotecan and mitoxantrone stimulate VEGF-A-mediated angiogenesis. AB - Metronomic chemotherapy with cytotoxic agents has been shown to inhibit angiogenesis and, consequently, tumor growth by targeting vascular endothelial cells (ECs). In these regimens, anti-tumor activities additional to anti angiogenesis may operate. Moreover, chemotherapy typically generates reactive oxygen species in targeted ECs, which can affect angiogenesis. The aim of the present study was to assess the systemic effect of low-dosage metronomic treatment with either irinotecan or mitoxantrone on angiogenesis induced by VEGF A. Angiogenesis was induced in normal adult rat mesentery by intraperitoneal injection of a low dosage of VEGF-A. Thereafter, irinotecan and mitoxantrone were infused separately continuously at minimally toxic dosages for 14 consecutive days via a subcutaneous osmotic minipump. Angiogenesis was assessed in terms of objective and quantitative variables using morphologic and computerized image analyses. Irinotecan or mitoxantrone significantly stimulated angiogenesis, with ironotecan increasing angiogenesis by 104%, when compared with the vehicle treated animals. Low-dosage metronomic chemotherapy with irinotecan or mitoxantrone stimulates angiogenesis in the normal mesentery of rats, probably by inducing low-level oxidative stress in the targeted ECs. Whether or not this pertains to tumor angiogenesis may be difficult to confirm, as several anti-tumor modes may operate during low-dosage metronomic chemotherapy. PMID- 22229272 TI - Designation of subtypes of Mycobacterium tuberculosis Beijing family: an issue of priority. PMID- 22229274 TI - Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence. AB - Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ~50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence. PMID- 22229275 TI - Degradation of nuclease-stabilized RNA oligonucleotides in Mycoplasma contaminated cell culture media. AB - Artificial RNA reagents such as small interfering RNAs (siRNAs) and aptamers often must be chemically modified for optimal effectiveness in environments that include ribonucleases. Mycoplasmas are common bacterial contaminants of mammalian cell cultures that are known to produce ribonucleases. Here we describe the rapid degradation of nuclease-stabilized RNA oligonucleotides in a human embryonic kidney 293 (HEK) cell culture contaminated with Mycoplasma fermentans, a common species of mycoplasma. RNA with 2'-fluoro- or 2'-O-methyl- modified pyrimidines was readily degraded in conditioned media from this culture, but was stable in conditioned media from uncontaminated HEK cells. RNA completely modified with 2' O-methyls was not degraded in the mycoplasma-contaminated media. RNA zymogram analysis of conditioned culture media and material centrifuged from the media revealed several distinct protein bands (ranging from 30 to 68 kDa) capable of degrading RNA with 2'-fluoro- or 2'-O-methyl-modified pyrimidines. Finally, the mycoplasma-associated nuclease was detected in material centrifuged from the contaminated culture supernatants in as little as 15 minutes with an RNA oligo containing 2'-O-methyl-modified pyrimidines and labeled with a 5'-fluorescein amidite (FAM) and 3'-quencher. These results suggest that mycoplasma contamination may be a critical confounding variable for cell culture experiments involving RNA-based reagents, with particular relevance for applications involving naked RNA (e.g., aptamer-siRNA chimeras). PMID- 22229277 TI - Nutritional quality of fermented defatted soya and flaxseed flours and their effect on texture and sensory characteristics of wheat sourdough bread. AB - The use of soya and flaxseed flours fermented with Pediococcus acidilactici for wheat sourdough bread production was investigated. The protein digestibility, biogenic amine contents of soya and flaxseed sourdoughs, texture and sensory features of bread were studied. The fermentation with P. acidilactici significantly improved soya and flaxseed protein extraction and increased protein digestibility on an average by 13.5%. The concentrations of histamine (3.8 +/- 2.3 and 4.0 +/- 0.2 mg/kg), tyramine (4.6 +/- 0.7 and 19.3 +/- 1.8 mg/kg) and putrescine (66.4 +/- 1.3 and 11.3 +/- 3.0 mg/kg) do not present a health risk for consumers due to their relatively low levels in fermented plant products. The flaxseed sourdoughs influenced a 17.5% higher specific volume and a 4.6% lower crumb hardness of bread than those of soya sourdoughs, and did not disimprove sensory properties of bread. However, the fermented soya additives decreased acceptability of bread because of intensive taste and odour. PMID- 22229278 TI - Scientific problems in the regulation of red blood cell products. AB - BACKGROUND: For the past 30 years, red blood cell (RBC) storage systems have been licensed in the United States based on the demonstration that 24-hour in vivo recovery was greater than 75% and hemolysis was less than 1%. Now additional requirements for storage system licensure have being added. The meaning and value of these new requirements have been questioned. STUDY DESIGN AND METHODS: The literature regarding the performance of present and suggested new tests for RBC licensure was reviewed. RESULTS: (51) Cr 24-hr in vivo recovery has an intrinsic 4% error of measurement whereas the error in measures of hemolysis is less than 0.1%. Both measures have large donor-dependent end-of-storage variability; nevertheless, they have successfully guided RBC storage system development for six decades. Adenosine 5'-triphosphate and 2,3-diphosphoglycerate are difficult to measure accurately and international shared-sample studies suggest 6 and 11% coefficients of variation across laboratories. There is no readily available way to measure the oxygen equilibrium curve accurately. The new failure criteria provide no useful information and randomly fail good products. CONCLUSIONS: Attempts to expand the useful regulatory requirements for RBC storage system licensure are limited by poor understanding of the storage lesion and its effect of RBC performance. Measures of (51) Cr 24-hour in vivo recovery remain critical and resources for this measure are limiting. The interaction between limited testing resources and large donor variability remains a major limit on RBC storage system development. It is important that new required tests contribute meaningful information and not make development and licensure of better products more difficult. PMID- 22229305 TI - Effect of Helicobacter pylori treatment on gastroesophageal reflux disease (GERD): meta-analysis of randomized controlled trials. AB - OBJECTIVE: Gastroesophageal reflux disease (GERD) is a multifactorial disorder characterized by reflux of acidic gastric contents into the esophagus leading to tissue damage and symptoms. The role of H. pylori in the pathogenesis of GERD is controversial. Therefore, we performed a meta-analysis on the effect of H. pylori treatment on symptomatic as well as endoscopic changes associated with GERD. MATERIAL AND METHODS: Multiple medical databases were searched (4/2011). Randomized controlled trials (RCTs) comparing H. pylori treatment with no treatment on symptomatic adults with GERD were included. The effects of H. pylori eradication were analyzed by calculating pooled estimates for new onset or changes in the symptoms of GERD or endoscopic reflux esophagitis. Separate analyses were performed for each outcome by using odds ratio (OR) or weighted mean difference (WMD) by fixed and random effects models. Publication bias was assessed by funnel plots. Heterogeneity among studies was assessed by calculating I2 measure of inconsistency. RESULTS: Ten trials met the inclusion criteria. No statistically significant effect was found for symptomatic GERD (OR 0.81, 95% CI 0.56-1.17, p = 0.27) or endoscopic evidence of reflux esophagitis (OR 1.13; 95% CI: 0.72-1.78, p = 0.59) between the two groups. A subgroup analysis of eradication data revealed a statistically significant lower incidence of GERD symptoms in the eradicated group (13.8%) compared with the non-eradicated group (24.9%) (OR 0.55; 95% CI: 0.35-0.87, p = 0.01). Funnel plot revealed no publication bias. CONCLUSIONS: Treatment of H. pylori does not seem to increase GERD symptoms or reflux esophagitis. However, documented eradication of H. pylori appears to significantly improve GERD symptoms. PMID- 22229304 TI - Does consumption of two portions of salmon per week enhance the antioxidant defense system in pregnant women? AB - Salmon is a rich source of marine n-3 fatty acids, which may increase oxidative stress and, in turn, could affect the antioxidant defense system in blood plasma and erythrocytes of pregnant women. The Salmon in Pregnancy Study provided two meals of salmon per week to pregnant women from week 20 of gestation; the control group maintained their habitual diet low in oily fish. Higher selenium and retinol plasma concentrations were observed after dietary salmon supplementation. Besides, a concomitant increase in selenium and glutathione concentration as well as glutathione peroxidase and reductase activities were detected as pregnancy progressed. However, tocopherols, retinol, beta-carotene, and coenzyme Q(10) decreased in late pregnancy. Collectively, our findings lead to the hypothesis that increased farmed salmon intake may increase antioxidant defenses during pregnancy. Clinical trials identifier NCT00801502. PMID- 22229306 TI - Effects of acupuncture on LIF and IL-12 in rats of implantation failure. AB - PROBLEM: Acupuncture has a positive effect on implantation obstacle, but the mechanism is still not clear, so the aim of the experiment is to explore the possible role that acupuncture plays in implantation. METHOD OF STUDY: Early pregnant rats were randomized into normal group (N), group treated with mifepristone (M), acupuncture treatment group (A), and progestin treatment group (P). The model of blastocyst implantation obstacle in groups M, A, and P was established with mifepristone. Bilateral 'Housanli' and 'Sanyinjiao' were needled in group A. The expression of interleukin (IL)-12, leukemia inhibitory factor (LIF), LIFR protein, and mRNA in endometrium were detected. RESULTS: Positivity of the protein expression of IL-12, LIF, and LIFR in the endometrium was significantly higher in groups N, A, and P; positivity of the mRNA of IL-12 and LIF in the endometrium was significantly higher in groups N, A, and P. CONCLUSION: Acupuncture could improve the poor receptive state of endometrium by promoting LIF and IL-12 secretion to improve blastocyst implantation. PMID- 22229307 TI - Possible harmful effect of implantable cardioverter-defibrillator (ICD) lead placement on tricuspid valve function. PMID- 22229309 TI - Editorial: magic bullets and arrows: biologic approaches to treat substance use disorders. PMID- 22229308 TI - Interception of cocaine by enzyme or antibody delivered with viral gene transfer: a novel strategy for preventing relapse in recovering drug users. AB - Recent progress in enzyme engineering has led to versions of human butyrylcholinesterase (BChE) that hydrolyze cocaine efficiently in plasma, reduce concentrations reaching reward neurocircuity in the brain, and weaken behavioral responses to this drug. Along with enzyme advances, increasingly avid anti cocaine antibodies and potent anti-cocaine vaccines have also been developed. Here we review these developments and consider the potential advantages along with the risks of delivering drug-intercepting proteins via gene transfer approaches to treat cocaine addiction. PMID- 22229310 TI - Nicotine vaccines. AB - Smoking is a global healthcare problem. Current smoking cessation rates using behavioral counseling and pharmacotherapeutic interventions have had modest success, with ~1:5 smokers remaining abstinent long-term. Nicotine vaccines are a new class of immunotherapeutics under development. It is believed that anti nicotine antibodies arising from vaccination capture nicotine and prevent or reduce its entry into the brain, as the antibody-bound nicotine is too large to cross the blood-brain barrier. This in turn decreases the pleasurable effects of smoking, reducing or eliminating positive reinforcement, thereby making it easier for a smoker to quit smoking. Four vaccine candidates have advanced into clinical testing with mixed success. Proof-of-concept has been established in that individuals with higher levels of anti-nicotine antibodies were observed to have higher smoking cessation and abstinence rates. Recently, the most advanced candidate vaccine, NicVAX, failed to meet the primary endpoint in two large phase III studies, although the correlation of higher abstinence rates in subjects with higher immunity to nicotine was observed. Although the field has had setbacks, the magnitude of the tobacco epidemic and the positive pre-clinical research and observed clinical trends indicate continued research is warranted. Several avenues are being actively pursued: a) improving vaccine potency by introducing novel carriers and/or adjuvants to stimulate higher immune response b) targeting subjects who have a robust response (e.g. personalized medicine) c) combining vaccines with pharmacotherapy for maintenance of abstinence/relapse prevention. PMID- 22229312 TI - Anti-cocaine vaccine based on coupling a cocaine analog to a disrupted adenovirus. AB - The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans, we hypothesized that linking a cocaine hapten to Ad capsid proteins would elicit high-affinity, high-titer antibodies against cocaine, sufficient to sequester systemically administered cocaine and prevent access to the brain, thus suppressing cocaine induced behaviors. Based on these concepts, we developed dAd5GNE, a disrupted E1 E3- serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In pre-clinical studies, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies, and was highly effective in blocking cocaine-induced hyperactivity and cocaine self-administration behavior in rats. Future studies will be designed to expand the efficacy studies, carry out relevant toxicology studies, and test dAd5GNE in human cocaine addicts. PMID- 22229311 TI - Developing a vaccine against multiple psychoactive targets: a case study of heroin. AB - Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment. PMID- 22229313 TI - Immunotherapy for drug abuse. AB - Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use. PMID- 22229314 TI - Monoclonal antibodies as pharmacokinetic antagonists for the treatment of (+) methamphetamine addiction. AB - Developing specific medications to treat (+)-methamphetamine (METH) addiction is a difficult challenge because METH has multiple sites of action that are intertwined with normal neurological function. As a result, no small molecule medication for the treatment of METH addiction has made it through the FDA clinical trials process. With the invention of a new generation of proteinbased therapies, it is now possible to consider treating drug addiction by an entirely different approach. This new approach is based on the discovery of very high affinity anti-METH monoclonal antibodies (mAbs), which are non-addictive and antagonize METH effects from the blood stream without entering the brain. Due to a very long biological half-life, anti-METH mAbs would only need to be administered once every 2-4 weeks, aiding in patient compliance. As a relapse prevention medication, anti-METH mAbs could reduce or prevent the rewarding effects of a relapse to METH use and thereby improve a patient's probability of remaining in therapy and recovering from their addiction. In this review, we discuss the discovery process of anti-METH mAbs, with a focus on the preclinical development leading to high affinity anti-METH mAb antagonists. PMID- 22229315 TI - Amyloid and Alzheimer's disease: easing the load. PMID- 22229316 TI - Superior neuroprotective effects of cerebrolysin in nanoparticle-induced exacerbation of hyperthermia-induced brain pathology. AB - In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world's population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed. PMID- 22229317 TI - Neurotoxicity of engineered nanoparticles from metals. AB - Human exposure to metal nanoparticles such as silver (Ag), copper (Cu) or aluminum (Al) is very common at work places involving automobile, aerospace industry, gun factories or defense related explosives making. Additional sources of exposure to engineered nanoparticles affecting human health are chemical, electronics and communication industries. The nanoparticles (ca. 20 to 120 nm) easily enter the body through inhalation and are deposited into various tissues and organs including brain, where they could stay there for long periods of time. However, the pathophysiological reactions of nanoparticles in vivo on brain function are still not well known. Previous observations from our laboratory showed that engineered nanoparticles from Ag, Cu or Al (50-60 nm) when administered through systemic or intracerebral routes in rats or mice induce neurotoxicity depending on their type, dose and duration of the exposure. These nanoparticles also altered sensory, motor and cognitive functions at the time of development of brain pathologies. Thus, neuronal, glial, axonal and endothelial cell damages are most pronounced following Ag and Cu intoxication as compared to Al in identical doses that are more pronounced in mice as compared to rats of similar age group. The functional significance of these findings and the probable mechanisms of metal nanoparticle-induced neurotoxicity are discussed in this review largely based on our own investigations. PMID- 22229319 TI - Commentary (two hits with one shot: a possibility of simultaneous targeting motor neuron loss and depression in ALS by upregulating ADAR2). PMID- 22229318 TI - Nanoparticle delivery of transition-metal chelators to the brain: Oxidative stress will never see it coming! AB - The pathological lesions typical of Alzheimer disease (AD) are sites of significant and abnormal metal accumulation. Metal chelation therapy, therefore, provides a very attractive therapeutic measure for the neuronal deterioration of AD, though its institution suffers fundamental deficiencies. Namely, chelating agents, which bind to and remove excess transition metals from the body, must penetrate the blood-brain barrier to instill any real effect on the oxidative damages caused by the presence of the metals in the brain. Despite many advances in chelation administration, however, this vital requirement remains therapeutically out of reach: the most effective chelators-i.e., those that have high affinity and specificity for transition metals like iron and copper-are bulky and hydrophilic, making it difficult to reach their physiological place of action. Moreover, small, lipophilic chelators, which can pass through the brain's defensive wall, essentially suffer from their over-effectiveness. That is, they induce toxicity on proliferating cells by removing transition metals from vital RNA enzymes. Fortunately, research has provided a loophole. Nanoparticles, tiny, artificial or natural organic polymers, are capable of transporting metal chelating agents across the blood-brain barrier regardless of their size and hydrophilicity. The compounds can thereby sufficiently ameliorate the oxidative toxicity of excess metals in an AD brain without inducing any such toxicity themselves. We here discuss the current status of nanoparticle delivery systems as they relate to AD chelation therapy and elaborate on their mechanism of action. An exciting future for AD treatment lies ahead. PMID- 22229320 TI - Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy. AB - We assessed the effect of palmitoylethanolamide (PEA) on pain and nerve function in patients with chemotherapy-induced painful neuropathy, in 20 patients undergoing thalidomide and bortezomib treatment for multiple myeloma. All patients were evaluated before and after a two-month treatment with PEA 300 mg BID using pain and warmth thresholds; blinded examiners measured motor and sensory nerve fibre function and laser-evoked potentials. Although no variables returned to normal values, pain and all neurophysiological measures ? assessing Aalpha, Abeta, and Adelta fibres ? significantly improved (P < 0.05). In contrast, warmth thresholds, assessing unmyelinated afferents, remained unchanged (P > 0.50). Although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures indicate that PEA exerted a positive action on myelinated fibre groups. PEA, possibly by moderating mast cell hyperactivity, relieved conduction blocks secondary to endoneural edema. In a severe condition such as painful neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides significant restoration of nerve function. PMID- 22229321 TI - Human platelet acetylcholinesterase inhibition by cyclophosphamide: a combined experimental and computational approach. AB - Acetylcholinesterase (AChE)-inhibition is an area of priority research as various roles have been attributed to AChE in neurodegenerative disorders and cancer as well. In the present study, a comparative multiple 4 dimensional (4D)-approach was applied to analyze human platelet AChE-inhibition by cyclophosphamide (CP). AChE activity was assessed by measuring the hydrolysis of acetylthiocholine iodide (ASChI). The different perspective of analysis was based on two classical (Lineweaver-Burk as well as Dixon) plots, built-in equations of GOSA and a recently introduced graphical approach. Thus, various kinetic constants such as KI, Ks, Km, ksl, Vmao, Ki, ksli, Slmax, ?Ks, K1/2, kcat and ksp were estimated. Previous findings of AChE (from different sources) inhibition by CP were also compared. This study extends the elucidation of the kinetic approach of analysis and quantifying enzyme-substrate and enzyme-inhibitor interactions, which is crucial to bringing any drug from bench to bedside. The acyl pocket of human AChE was found to interact with CP through the amino acid residues Y70, Y121, W233, F288, F290, Y334, F408 and Y442, while the anionic sub-site of catalytic site (CAS) interacted with the ligand through residues W84, N85, G116, G117, Y121, S122, G123, L127, Y130, E198, Y334, H443 and G444. CP displayed variable docking poses with the peripheral anionic site (PAS) of human AChE. The findings of kinetic analysis were reinforced by the results of docking experiments. Both the applied approaches strongly indicate partial mixed type of inhibition pattern for the study enzyme (AChE) and its inhibitor (CP). PMID- 22229322 TI - C-peptide and its correlation to parameters of insulin resistance in the metabolic syndrome. AB - The progress of metabolic syndrome (MetS) continues with the onset of type-2 diabetes mellitus (Type-2 DM) along with linkage to other disorders such as neurodegenerative, especially Alzheimer's disease (AD), via oxidative stress and low grade systemic inflammatory process. Type-2 DM and AD are health disorders of priority research. The treatment for an individual suffering with Type- 2 DM and/or AD requires monitoring by clinicians. The aim of this study was to investigate the role of C-peptide and its correlation to insulin resistance, body mass index (BMI), beta cell function, insulin sensitivity, lipid profile and hemoglobin A1c (HbA1c). The study was designed to include 96 Type-2 DM individuals from India. 58.3% males and 41.7% females were selected and fasting blood samples were collected for estimation of fasting C-peptide, fasting blood sugar (FBS), postprandial blood sugar (PPBS), HbA1c and lipid profile. Analysis was done on Hitachi912 and Elecsys 2010 using Roche reagents and standard controls. Anthropometries to calculate BMI and beta cell function, insulin sensitivity, and insulin resistance were obtained. The statistical tool ANOVA, followed by calculation of p-value and r ? value were applied for investigating correlation of C-peptide levels to those of high density lipoprotein-C (HDL-C), low density lipoprotein-C (LDL-C), triglycerides (TGL), HbA1c, beta cell function, insulin sensitivity and insulin resistance. Highly significant positive correlations were observed in different quantiles of C-peptide levels to the studied parameters of MetS, BMI and % beta cell function. Lower HDL-C level was found to be significantly related to higher C-peptide levels. Similarly, TGL and C-peptide levels displayed a significant positive correlation. A significant negative correlation was observed between C-peptide quantiles and % sensitivity. Thus, insulin resistance showed a positive correlation until the fourth quantile. No significant correlation was observed between C-peptide and HbA1c levels. This study demonstrates that assessment of C-peptide levels is a useful tool to monitor the progress of MetS among patients suffering from Type-2 DM and AD, as these disorders are intertwined to each other by common metabolic pathways. Assessment of C-peptide levels, along with HDL-C levels, in patients can be used to monitor insulin resistance. PMID- 22229323 TI - Diabetes exacerbates nanoparticles induced brain pathology. AB - Long term exposure of nanoparticles e.g., silica dust (SiO2) from desert environments, or engineered nanoparticles from metals viz., Cu, Al or Ag from industry, ammunition, military equipment and related products may lead to adverse effects on mental health. However, it is unclear whether these nanoparticles may further adversely affect human health in cardiovascular or metabolic diseases e.g., hypertension or diabetes. It is quite likely that in diabetes or hypertension where the body immune system is already compromised there will be greater adverse effects following nanoparticles exposure on human health as compared to their exposure to healthy individuals. Previous experiments from our laboratory showed that diabetic or hypertensive animals are more susceptible to heat stress-induced neurotoxicity. Furthermore, traumatic injury to the spinal cord in SiO2 exposed rats resulted in exacerbation of cord pathology. However, whether nanoparticles such as Cu, Ag or SiO2 exposure will lead to enhanced neurotoxicity in diabetic animals are still not well investigated. Previous data from our laboratory showed that Cu or Ag intoxication (50 mg/kg, i.p. per day for 7 days) in streptozotocine induced diabetic rats exhibited enhanced neurotoxicity and exacerbation of sensory, motor and cognitive function as compared to normal animals under identical conditions. Thus the diabetic animals showed exacerbation of regional blood-brain barrier (BBB) disruption, edema formation and cell injuries along with greater reduction in the local cerebral blood flow (CBF) as compared to normal rats. These observations suggest that diabetic animals are more vulnerable to nanoparticles induced brain damage than healthy rats. The possible mechanisms and functional significance of these findings are discussed in this review largely based on our own investigations. PMID- 22229324 TI - Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals. AB - Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins and the number of injured neurons. This indicates that cerebrolysin in higher doses could be a good candidate for treating SCI cases following nanoparticle intoxication. The possible mechanisms and functional significance of these findings are discussed in this review. PMID- 22229325 TI - Nanowired drug delivery of antioxidant compound H-290/51 enhances neuroprotection in hyperthermia-induced neurotoxicity. AB - Nanoparticles from the environment or through industrial sources can induce profound alterations in human health, often leading to brain dysfunction. However, it is still unclear whether nanoparticle intoxication could also alter the physiological or pathological responses of additional brain injury, stress response or disease processes. Military personals engaged in combat or peacekeeping operations are often exposed to nanoparticles from various environmental sources, e.g., Ag, Cu, Si, C, Al. In addition, these military personals are often exposed to high environmental heat, or gun and missle explosion injury leading to head or spinal trauma. Thus it is likely that additional CNS injury or stress-induced pathophysiological processes are influenced by nanoparticle intoxication. In this situation, when a combination of nanoparticles and central nervous system (CNS) injury or stress exist together, drug therapy needed to correct these anomalies may not work as effectively as in normal situation. Previous studies from our laboratory show that nanoparticle intoxicated animals when subjected to hyperthermia resulted in exacerbation of brain pathology. In these animals, antioxidant compounds, e.g., H-290/51 that inhibits free radical formation and induces marked neuroprotection in normal rats after heat stress, failed to protect brain damage when a combination of nanoparticles and heat exposure was used. However, nanowired H-290/51 resulted in better neuroprotection in nanoparticles intoxicated animals after heat stress. Interestingly, high doses of the normal compound induced some neuroprotection in these nanoparticle-treated, heat-stressed rats. These observations suggest that a combination of nanoparticles and heat stress is dangerous and in such situations modification of drug dosage is needed to achieve comparable neuroprotection. In this review possible mechanisms of nanoparticle-induced exacerbation of heat induced neurotoxicity and brain protection achieved by nanowired drug delivery is discussed that is largely based on our own investigations. PMID- 22229326 TI - Bromazepam impairs motor response: an ERSP study. AB - This study aimed to investigate the acute modulatory effect of bromazepam, a benzodiazepine derivative drug, on alpha and beta bands (8-35Hz) in primary motor areas (M1) through event-related spectral perturbation (ERSP). Ten healthy subjects were submitted to a cross-over double-blind design. Subjects performed a visuomotor task where they had to identify rapidly the ball launched horizontally and catch it quickly, while electroencephalographic activity was acquired. We found a statistically significant difference on the time windows of 2920 ms for 13Hz in the electrodes C3 and Cz, and on the time window of 2000 ms for 18Hz in the electrodes C3, when compared the bromazepam and placebo conditions. We concluded that the acute effects of bromazepam provoked changes in information process in the left M1 represented by electrode C3 in both 13 Hz and 18 Hz. Our paradigm is relevant for a better understanding of the brain dynamics due to the information related to bromazepam effects on sensorimotor processes. We consider this report an invitation to conduct more studies in order to associate electro cortical activity and psychometric tests. PMID- 22229327 TI - Kinetic study on the effects of extremely low frequency electromagnetic field on catalase, cytochrome P450 and inducible nitric oxide synthase in human HaCaT and THP-1 cell lines. AB - Extremely low frequency electromagnetic fields (ELF-EMF) have been found to produce a variety of biological effects. These effects of ELF-EMF depend upon frequency, amplitude, and length of exposure, and are also related to intrinsic susceptibility and responsiveness of different cell types. Although the mechanism of this interaction is still obscure, ELF-EMF can influence cell proliferation, differentiation, cell cycle, apoptosis, DNA replication and protein expression. The aim of this study was to estimate various kinetic constants of catalase, cytochrome P450 and inducible nitric oxide synthase in response to ELF-EMF exposure in human HaCaT and THP-1 cell lines. In order to evaluate the effect of ELF-EMF on the modulation of cellular responses to an inflammatory stimulus, both cell lines were treated with lipopolysaccharide. To the best of our knowledge there is no available report on such type of kinetic study of selected enzymes in response to ELF-EMF in these cell lines. Therefore, the current study may reveal novel mechanism of ELFEMF biological interaction with the enzymological and hormonal systems of living organisms. These new insights may be important for ELF EMF application particularly for wound healing, tissue regeneration, Parkinson's and Alzheimer's diseases. PMID- 22229328 TI - The prevalence of epilepsy in the Nakhichevan Autonomous Republic of Azerbaijan. AB - Epilepsy is a devastating neurological disorder in which those afflicted can gain benefit from specific treatments based on their genetics and geographic location. Currently the prevalence of epilepsy is estimated at 0.5-3% of the world-wide population, and is increasing in developing countries. In order to make more accurate assessments of the prevalence of epilepsy, we applied the capture recapture method in a 12-month study of epilepsy in a population from the Sharur district of Nakhichevan Autonomous Republic, Azerbaijan with 114,451 people from sixty nine villages and towns. The following methods were applied to determine epilepsy: Door To Door (DTD) survey, Non-Medical Source (NMS), and Medical Source. Using these three techniques, 1,032 patients with epilepsy (9.02/1000) were included in our study. The DTD survey determined 627 patients with epilepsy (5.48/1000) and 247 (2.16/1000) from the NMS methods versus 158 (1.38/1000) from the Medical Source (MS) methods. Applying the capture-recapture method, NMS, and DTD methods, the number of epilepsy cases increased to 1,330 (11.62/1000) [95% CI: 10.21-13.03]. The combinations of these methods show that 887 people (7.75/1000) have a diagnosis of epilepsy. Multiple epidemiological tasks used in our study can be used to estimate clinical signs and/or markers in future applications for the determination and development of treatment strategies for this devastating disease in the third world countries such as the Nakhichevan Autonomous Republic of Azerbaijan. PMID- 22229329 TI - Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model. AB - The effects of amiodarone on ventricular electrophysiological parameters, especially the dispersion of ventricular repolarization, were investigated in a canine model of congestive heart failure (CHF). Dogs were randomized to either a control, amiodarone, CHF, or CHF+amiodarone group. Dogs in the CHF and CHF+amiodarone groups underwent 4-5 weeks of rapid ventricular pacing; dogs in the control and amiodarone groups underwent sham operation only. Amiodarone (20 mg/kg per day) was administered orally, beginning on postoperative Day 1, in the treatment groups; ventricular electrophysiological variables were evaluated 4-5 weeks after rapid pacing or sham operation. In CHF dogs, the transmural dispersion ventricular repolarization time (TDVRT) increased significantly. Amiodarone significantly decreased the TDVRT in CHF dogs. The ventricular fibrillation threshold (VFT) decreased in the CHF group. Amiodarone increased the VFT in CHF dogs. The TDVRT increased in CHF dogs, but amiodarone decreased TDVRT and increased VFT in these dogs. These results suggest a beneficial effect of amiodarone on malignant arrhythmias and may provide the basis for its use in CHF patients. PMID- 22229330 TI - Conradi-Hunermann-Happle syndrome in males vs. MEND syndrome (male EBP disorder with neurological defects). AB - BACKGROUND: There is confusion in the literature concerning disorders caused by EBP (emopamil-binding protein) mutations in males. OBJECTIVES: To study the clinical and genetic differences in males affected either with Conradi-Hunermann Happle (CHH) syndrome (X-linked dominant chondrodysplasia punctata, CDPX2) or with a nonmosaic, X-linked recessive disorder for which we propose the acronymic term MEND syndrome (male EBP disorder with neurological defects). METHODS: We report a 7-year-old boy with a history of transient scaly erythematous lesions on his limbs, trunk and scalp soon after birth. DNA was isolated from ethylenediamine tetraacetic acid-blood samples of the patient and the four coding exons of the EBP gene were amplified by polymerase chain reaction. We review all published cases of CHH syndrome in males in the literature and elaborate the clinical and genetic differences between CHH syndrome in males and MEND syndrome. RESULTS: We found at position 33 of the EBP gene the variant c.33C>A leading to the same nonsense mutation p.Y11X that had previously occurred de novo in a female with typical manifestations of CHH syndrome. When the known male cases with EBP mutations were reviewed, a striking nosological difference between the mosaic and nonmosaic phenotypes was evident. Clear-cut clinical criteria are elaborated to distinguish between CHH syndrome in males and MEND syndrome. CONCLUSIONS: Because the clinical outcome and prognosis are different it is important to distinguish between males with CHH syndrome that represents a mosaic phenotype, and those with MEND syndrome that is a nonmosaic trait. PMID- 22229331 TI - Impact factor in cytopathology journals: what does it reflect and how much does it matter? AB - B. AbdullGaffar Impact factor in cytopathology journals: what does it reflect and how much does it matter? OBJECTIVE: To study the trends of impact factor (IF) in four cytopathology journals. To investigate the factors that might influence IF in cytopathology literature and whether IF has any impact on cytopathology practice. METHODS: The IFs of four cytopathology journals were searched from 2005 to 2009. The IFs and their relationships with the types and number of publications, publishers, the official societies, readership, the quality of their contents, the topics covered and the levels of evidence were compared. RESULTS: Cancer Cytopathology (CC) had the highest IF. Acta Cytologica (AC) had the lowest IF, which appeared to be in decline. Cytopathology (C) and Diagnostic Cytopathology (DC) had a slow but steady increase in their IF. Components that might influence these differences could include the category and the society of the journal, targeted readers and certain types of publications. Publishers, the number of publications, the types of topics covered and the levels of evidence probably have no major effect on IF. CONCLUSIONS: IF has its own benefits and original applications. IF is a quantitative measure that does not reflect the levels of evidence in cytopathology journals. IF should not be abandoned because it might encourage competition between cytopathology journals, but it should not dictate their contents. PMID- 22229333 TI - Update: Complications and care related to pregnancy, labor and delivery, active component, U.S. Armed Forces, 2001-2010. AB - Diagnoses of "complications of pregnancy, childbirth, and the puerperium" (ICD-9 CM: 630-679) include both morbid complications and indications for routine care of pregnant women. During 2001-2010, U.S. service members with live births (n=156,314) had 1.16 million medical encounters with primary diagnoses of "pregnancy complications". The most frequent diagnoses were "other current conditions", "other threatened labor" (e.g., false labor), "previous cesarean delivery" and "normal delivery". The number of complication-related medical encounters per pregnancy more than doubled during 2001-2010. Diagnoses of gestational diabetes, previous cesarean delivery and advanced maternal age contributed to the largest increases in pregnancy-related medical encounters during the period. The complications that accounted for the largest increases in the percents of pregnancies affected by them were urinary tract infections, fetal heart rate/rhythm abnormalities and back pain in pregnancy. PMID- 22229334 TI - Urinary stones, active component, U.S. Armed Forces, 2001-2010. AB - Urinary stones can cause debilitating morbidity that impairs the operational effectiveness of affected members of the U.S. Armed Forces. This report describes a "gender shift," i.e., the narrowing of prevalence differences between men and women, similar to trends described in the U.S. civilian population. Rates of incident diagnoses of urinary stones increased in the active component during the past decade - particularly among females. On average, 60 service members were medically evacuated from combat zones each year during the period. Service members with a history of urinary stones should be counseled on reducing risk, particularly in the deployment setting. PMID- 22229335 TI - Uterine fibroids, active component females, U.S. Armed Forces, 2001-2010. AB - Uterine fibroids are benign tumors of the uterus that can cause significant morbidity in symptomatic women. From 2001 to 2010 there were 11,931 incident cases (incidence rate: 57.6 per 10,000 person-years) of uterine fibroids among active component females. The incidence rates were highest among black, non Hispanic females and increased with advancing age. The observed decline in the number and percentage of inpatient hysterectomies for fibroids may reflect changes in overall treatment patterns during the period. Uterine fibroids commonly affect the health and military operational effectiveness of women on active duty; research to identify causes and preventive interventions is warranted. PMID- 22229336 TI - Historical snapshot: Dr. Anna Baetjer, industrial hygiene pioneer, military occupational health advocate. PMID- 22229337 TI - Births, active component, U.S. Armed Forces, 2001-2010. PMID- 22229338 TI - Numbers and characteristics of women in the active component, U.S. Armed Forces, 2011. PMID- 22229340 TI - Implicit and explicit emotional processing in Parkinson's disease. AB - INTRODUCTION: Our study investigated the ability of nondemented Parkinson's disease (PD) patients to explicitly identify emotional words and to show implicit sensitivity to these emotions in a task that did not require emotional processing. METHODS: Twelve PD patients and 12 healthy controls, matched for age and education, performed lexical decision (LD) and emotional categorisation tasks (fear, disgust, and happiness) on the same words. RESULTS: PD patients were specifically impaired in the explicit identification of disgust with a decreased accuracy in LD. However, a slowdown in LD latency in both PD patients and the control group suggested the persistence of emotional sensitivity to disgust. CONCLUSION: Despite the persistence of an automatic capture by the emotional content of disgust, PD patients may suffer from emotional deficits in recognising both the emotional and semantic components of words, resulting in blunted emotional responses. PMID- 22229341 TI - Gist-based conceptual processing of pictures remains intact in patients with amnestic mild cognitive impairment. AB - OBJECTIVE: The picture superiority effect, better memory for pictures compared to words, has been found in young adults, healthy older adults, and, most recently, in patients with Alzheimer's disease and mild cognitive impairment. Although the picture superiority effect is widely found, there is still debate over what drives this effect. One main question is whether it is enhanced perceptual or conceptual information that leads to the advantage for pictures over words. In this experiment, we examined the picture superiority effect in healthy older adults and patients with amnestic mild cognitive impairment (MCI) to better understand the role of gist-based conceptual processing. METHOD: We had participants study three exemplars of categories as either words or pictures. In the test phase, participants were again shown pictures or words and were asked to determine whether the item was in the same category as something they had studied earlier or whether it was from a new category. RESULTS: We found that all participants demonstrated a robust picture superiority effect, better performance for pictures than for words. CONCLUSIONS: These results suggest that the gist based conceptual processing of pictures is preserved in patients with MCI. While in healthy older adults preserved recollection for pictures could lead to the picture superiority effect, in patients with MCI it is most likely that the picture superiority effect is a result of spared conceptually based familiarity for pictures, perhaps combined with their intact ability to extract and use gist information. PMID- 22229343 TI - Targeting the subtypes of breast cancer: rethinking investigational drugs. AB - INTRODUCTION: The choice of adjuvant treatments for women with breast cancer is based on several features that take into account the heterogeneity of the disease. Questions raised during the decision process include the following: i) What leads to the use of endocrine therapy? ii) What leads to the use of anti HER2 therapy? iii) What justifies the use of chemotherapy? AREAS COVERED: Choices of adjuvant treatment are based on parameters defined by molecular characterization of breast cancer subtypes or by approximations to this classification using traditional clinical-pathological features. Clinicians should consider cases within the various distinct subpopulation in order to properly select the most 'personalized' adjuvant therapeutic approach. Sensitivity to chemotherapy and/or targeted agents in subtypes of breast cancers are predictable based on gene pathway alterations and associated gene products. This review covers several clinical data on several investigational agents for early-stage breast cancer molecular subtypes. We selected from literature data prospective Phase I, II and III clinical trials of chemotherapy (weekly or daily schedules), including indicators of activity and toxicity and data on survival/mortality. EXPERT OPINION: The future of many investigational therapeutics in breast cancer is linked to our ability to identify the most druggable target in each subtype. PMID- 22229344 TI - Graphite-coated magnetic nanoparticle microarray for few-cells enrichment and detection. AB - Graphite-coated, highly magnetic FeCo core-shell nanoparticles were synthesized by a chemical vapor deposition method and solubilized in aqueous solution through a unique polymer mixture modification, which significantly improved the biocompatibility and stability of the magnetic nanoparticles (MNPs). Such functionalized MNPs were proven to be very stable in different conditions which would be significant for biological applications. Cell staining, manipulation, enrichment, and detection were developed with these MNPs. Under external magnetic manipulation, the MNP-stained cells exhibited directed motions. Moreover, MNPs were printed on substrates to modulate the magnetic field distribution on the surface. Capture and detection of sparse populations of cancer cells spiked into whole blood has been explored in a microarray fashion. Cancer cells from hundreds down to only two were able to be simply and efficiently detected from 1 mL of whole blood on the MNP microarray chips. Interestingly, the cells captured through the MNP microarray still showed viability and adhered to the MNP spots after incubation, which could be utilized for cancer cell detection, localized growth, and proliferation. PMID- 22229347 TI - Chemical interesterification of blends of palm stearin, coconut oil, and canola oil: physicochemical properties. AB - trans-Free interesterified fat was produced for possible usage as a margarine. Palm stearin, coconut oil, and canola oil were used as substrates for chemical interesterification. The main aim of the present study was to evaluate the physicochemical properties of blends of palm stearin, coconut oil, and canola oil submitted to chemical interesterification using sodium methoxide as the catalyst. The original and interesterified blends were examined for fatty acid composition, softening and melting points, solid fat content, and consistency. Chemical interesterification reduced softening and melting points, consistency, and solid fat content. The interesterified fats showed desirable physicochemical properties for possible use as a margarine. Therefore, our result suggested that the interesterified fat without trans-fatty acids could be used as an alternative to partially hydrogenated fat. PMID- 22229348 TI - Comparison of red blood cell survival in sheep determined using red blood cells labeled with either biotin at multiple densities or [14C]cyanate: validation of a model to study human physiology and disease. AB - BACKGROUND: Measurement of red blood cell (RBC) survival (RCS) is important for investigating pathophysiology and treatment of anemia. Our objective was to validate the multidensity biotin method for RCS determination in sheep, a commonly used model of RBC physiology. [(14) C]Cyanate served as the reference method for long-term RCS because the (51) Cr method (the reference method for humans) is not reliable in sheep. STUDY DESIGN AND METHODS: Aliquots of autologous RBCs from eight adult sheep were labeled with [(14) C]cyanate and four separate densities of biotin (BioRBCs) and reinfused. Short-term RCS was assessed by posttransfusion recovery at 24 hours (PTR(24) ); long-term RCS was assessed by the time to 50% survival (T(50) ) and mean potential life span (MPL). RESULTS: Values for PTR(24) of the four BioRBC densities were not different. Values for RCS as reflected by T(50) and MPL were nearly identical for [(14) C]cyanate and the two intermediate-density BioRBC populations. In contrast, the lowest-density BioRBC population survived slightly longer (p < 0.01), but with a difference of no clinical significance. The highest-density BioRBC population importantly shortened RCS (p < 0.01 compared to the two intermediate densities). CONCLUSION: This study provides evidence that BioRBCs labeled at four biotin densities can be used to independently and simultaneously measure short-term RCS and that BioRBCs labeled at the three lowest biotin densities can be used to accurately and simultaneously measure long-term RCS. Because the sheep RBC model is comparable to humans, this nonradioactive method has promise for use in RBC kinetic studies in neonates and pregnant women. PMID- 22229339 TI - Cardiac aging: from molecular mechanisms to significance in human health and disease. AB - Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several "anti-aging" strategies that treat CVDs and improve healthy cardiac aging. PMID- 22229365 TI - Thrombophylaxis and bleeding complications after cesarean section. AB - OBJECTIVE: To evaluate the safety of different regimes of thromboprophylaxis with low molecular weight heparins (LMWHs) in women undergoing cesarean section. DESIGN: Retrospective single-center cross-sectional study. SETTING: University Medical Center, The Netherlands. POPULATION: All women that delivered by cesarean section in the Erasmus Medical Center, Rotterdam, between January 2004 and December 2007 received thromboprophylaxis. We included women who received thromboprophylaxis according to the routine administration schedule at that time. METHODS: Three different consecutive regimes of thromboprophylaxis were used. In the first period, women received dalteparin 5000IU pre- and postoperatively (group A), in the second period, nadroparin 5700IU was administered pre- and postoperatively (group B), and in the third period, nadroparin 2850IU was administered not earlier than 6-12 hours postoperatively (group C). Detailed information on individual characteristics, cesarean section and postpartum period were extracted from patient files. MAIN OUTCOME MEASURES: Postoperative bleeding complications. RESULTS: A total of 1527 women were eligible and included. In group B, significantly more women experienced bleeding complications (necessitating either conservative treatment or re-laparotomy) compared with the other two groups (19/574 women in group B vs. 9/647 in group A and 1/306 in group C). After adjusting for potential confounders (maternal age, body mass index, and occurrence of preeclampsia/hemolysis, elevated liver enzymes and low platelet count) these effects remained significant (p=0.005). The incidence of thromboembolism was not different in the three groups. CONCLUSIONS: Different regimes of thromboprophylaxis in women with cesarean section influenced the occurrence of bleeding complications. PMID- 22229366 TI - Mass murder and the individual: psychoanalytic reflections on perpetrators and their victims. PMID- 22229367 TI - Personal reflections on Hugh Mullan: existential group therapist. AB - This article reviews the work of the psychiatrist Hugh Mullan, a pioneer of modern group therapy. Heavily influenced by existential philosophy, Hugh Mullan applied notions from that perspective to his innovative and unorthodox approach. Central to this was an early, indeed prescient, advocacy for the use of the therapist's personal subjectivity, striving for mutuality, and non-rational experience in the conduct of psychotherapy. This way of thinking was not in accord with prevailing theories throughout most of his life as a practitioner (1946-1986); Hugh Mullan was not considered a mainstream theorist in his time. However, contemporary relational theorists have begun to give these ideas a great deal of attention, offering validation and support for his original insights. This writer recalls, as well, his experience of Hugh Mullan as a therapist and mentor. PMID- 22229368 TI - On hostage taking (a psychoanalytic object). AB - Abstract Hostage taking is a pervasive phenomenon in human relations, in groups, and in societies. It exists literally, figuratively, and psychologically, and hence is both a phenomenon in the mind and in the outside world. A case example illustrates how group members (including the leader) hold, or may seem to hold, others hostage by their words and actions. By conceptualizing and focusing on a series of interactions as a type of object relationship, that is, a complex idea worthy of attention, the group came to understand and experience hostage taking as a "psychoanalytic object." PMID- 22229369 TI - Group therapy for refugees and torture survivors: treatment model innovations. AB - The paper discusses varieties of group therapies with refugees and torture survivors and the logic behind enhancing traditional group therapies to fit the unique experiences of refugees and torture survivors. It discusses some lessons learned from practice and from empirical research and some recommended adaptations. Finally, it discusses the Center for Torture and Trauma Survivors' therapy group model for torture survivors and describes two of its variants: The Bashal group for African and Somali women and the Bhutanese multi-family therapy group. Group therapies, in this model, extend to community healing. One of the essential and innovative features of the model is that it focuses not only on treating individual psychopathology but also extends to community healing by promoting the development of social clubs and organizations that promote the values and culture of the graduates of the therapy group and the continuation of social support. New graduates from the group join the club and become part of the social advocacy process and of group and community support and healing. This model adds an ecological dimension to the traditional group therapy. PMID- 22229370 TI - Projected fantasies and the political process: toward understanding why Hillary lost. AB - The author explores the events involved in the Democratic Party primary campaign of 2007-2008. Well before the campaign began, Senator Hillary Rodham Clinton was seen as the odds-on favorite to capture the nomination. But, that did not happen. Not only did she trail a relatively politically unknown, but she lost favor with many of those who would normally have supported her, such as advocates of gender progressivism, including many women. The author attempts to explain what happened by examining voter behavior, large group identity and its corollary of political identity, and the relation of large groups to leaders. Noting the effect of the sexual scandals during the Presidency of her husband, the author postulates that particular scenarios that have been repetitive throughout history, in art and literature, and reflected in mythology were graphed onto the perception of the Clintons. These narratives, much like Jung's archetypes, have evocative potential. Freud's early formulation of oedipal betrayal is used to explain the dynamics of infidelity and how that weakened Senator Clinton in the eyes of the public. PMID- 22229371 TI - Large-scale voter behavior. PMID- 22229372 TI - Addressing anniversary reactions of trauma through group process: the Hurricane Katrina anniversary wellness workshops. AB - Natural disasters such as Hurricane Katrina, which devastated the Gulf Coast of the United States in the summer of 2005, have highlighted the need to develop effective post-trauma psychotherapeutic intervention strategies, not only to deal with the immediate psychological aftermath of trauma, but also the long-term effects of anniversary reactions. Governmental responses to Hurricane Katrina relief were greatly criticized for disorganization and delay. Both immediately afterwards and in ensuing months, people's life needs often were not addressed. People-to-people individual and group grassroots efforts, including those provided by mental health professionals, however, did reach local communities to service immediate needs and long-term emotional reactions. The present paper describes one such effort designed to help survivors cope on the occasion of the first anniversary of Hurricane Katrina. Specifically, anniversary reaction group workshops were held to address unresolved emotional issues and to promote healing by encouraging belonging, comfort, security, and resilience. The ultimate goal of these wellness workshops was to assist participants in understanding and resolving their anniversary reactions. Preliminary quantitative and qualitative findings suggested that this workshop format helped participants face their anniversary reactions, address their related psychological sequelae, and deal with their physical displacement. Participants were then able to find the emotional strength to reattach, form new communities, and begin problem solving. These methods, with appropriate cultural modifications, were subsequently used in China, to assist Chinese mental health professionals prepare for the first anniversary of the Sichuan earthquake. PMID- 22229373 TI - On Suzanne Cohen's (2011) paper: "Coming to our senses: the application of somatic psychology to group psychotherapy". PMID- 22229375 TI - Ignoring the social elements: research of prevention-focused group programs for preadolescents and adolescents. PMID- 22229380 TI - Progress and priorities in reducing indoor air pollution in developing countries. PMID- 22229381 TI - Prediction and prenosological diagnostics of heart diseases based on energy characteristics of acupuncture points and fuzzy logic. AB - Many theories of reflexology use ancient concepts which do not coincide with the modern medical terminology of anatomy, physiology and biophysics. This substantially reduces the trust of physicians in reflexology methods. During this research, several mathematical models for the interaction of the internal and biological active points of meridian structures have been proposed. The analysis of these models allows the specification of a list of heart diseases for which reflex diagnostics and reflex therapy methods are most effective and also allows increasing the effectiveness of these procedures. It is shown that good results for the prediction and early diagnosis of diseases from the reaction energy of biologically active points (acupuncture points) are obtained using fuzzy logic decision making. PMID- 22229383 TI - Lipoxin A4 inhibits the development of endometriosis in mice: the role of anti inflammation and anti-angiogenesis. AB - PROBLEM: To evaluate the effects of the anti-inflammatory and anti-angiogenic roles of LXA4 on endometriosis in mice. METHOD OF STUDY: Endometriosis was induced in 40 mice and separated into two groups. LXA4 group was administered by LXA4 for 3 weeks. The endometriotic lesions were counted, measured, and identified by pathology. The presence of a panel of pro-inflammatory factors was assessed by real-time RT-PCR, and enzyme-linked immunoassay, the mRNA, protein levels of matrix metalloproteinase (MMPs), and vascular endothelial growth factor (VEGF) were determined by real-time RT-PCR and immunohistochemistry; the activity of MMPs was evaluated by gelatin zymography. RESULTS: Treatment with LXA4 significantly inhibited endometriotic lesion development (13.58 +/- 4.01 mm(2) in LXA4 group and 23.20 +/- 7.49 mm(2) , P = 0.0002), downregulated pro-inflammatory factors, suppressed the activity of MMP9, and reduced the VEGF levels associated with endometriosis in mice. CONCLUSION: LXA4 may inhibit the progression of endometriosis possibly by anti-inflammation and anti-angiogenesis. PMID- 22229384 TI - Potential role of green tea catechins in various disease therapies: progress and promise. AB - Green tea (from the plant Camellia sinensis), a beverage whose consumption started 5000 years ago in China, has important biological and pharmacological properties. The beneficial effects of green tea have been attributed to the presence of phenolic compounds that are powerful anti-oxidants and free iron scavengers. Of all the catechins found in green tea, namely (-)-epicatechin-3 gallate, (-)-epigallocatechin, (-)-epicatechin and (-)-epigallocatechin-3-gallate (EGCG), EGCG is the most abundant and powerful. It is widely believed that green tea may protect against death from all causes, especially cardiovascular diseases (coronary heart disease and stroke) owing to the presence of catechins associated with green tea consumption. Other health benefits include various types of cancer chemoprevention, weight loss and protective effects against neurodegenerative diseases (Alzheimer's disease and Parkinson's disease). Thus far, numerous pharmacological activities regulating disease-specific molecular targets have been reported in vitro for EGCG concentrations in the micromolar range, which are physiologically irrelevant. Although most of the studies have shown benefits with two to three cups of green tea per day, the optimal dose has not yet been established to enable any solid conclusions to be drawn regarding the various health benefits of green tea or its constituents in humans. With Phase I trials providing information on the safety profile and pharmacokinetics of EGCG, the window of opportunity is wider to undertake well-controlled long-term human studies to enable a full understanding of the protective effects of green tea catechins on various parameters in different settings. PMID- 22229385 TI - Dissection of genotype-phenotype associations in rice grains using metabolome quantitative trait loci analysis. AB - A comprehensive and large-scale metabolome quantitative trait loci (mQTL) analysis was performed to investigate the genetic backgrounds associated with metabolic phenotypes in rice grains. The metabolome dataset consisted of 759 metabolite signals obtained from the grains of 85 lines of rice (Oryza sativa, Sasanishiki * Habataki back-crossed inbred lines). Metabolome analysis was performed using four mass spectrometry pipelines to enhance detection of different classes of metabolites. This mQTL analysis of a wide range of metabolites highlighted an uneven distribution of 802 mQTLs on the rice genome, as well as different modes of metabolic trait (m-trait) control among various types of metabolites. The levels of most metabolites within rice grains were highly sensitive to environmental factors, but only weakly associated with mQTLs. Coordinated control was observed for several groups of metabolites, such as amino acids linked to the mQTL hotspot on chromosome 3. For flavonoids, m-trait variation among the experimental lines was tightly governed by genetic factors that alter the glycosylation of flavones. Many loci affecting levels of metabolites were detected by QTL analysis, and plausible gene candidates were evaluated by in silico analysis. Several mQTLs profoundly influenced metabolite levels, providing insight into the control of rice metabolism. The genomic region and genes potentially responsible for the biosynthesis of apigenin-6,8-di-C-alpha l-arabinoside are presented as an example of a critical mQTL identified by the analysis. PMID- 22229386 TI - Impact of a diabetes disease management program on diabetes control and patient quality of life. AB - The worldwide burden of diabetes is projected to be 5.4% of the adult population by the year 2025. Diabetes is associated with multiple medical complications that both decrease health-related quality of life (HR-QOL) and contribute to earlier mortality. There is growing evidence for the effectiveness of multidisciplinary disease management programs that incorporate self-management principles in improving patients' long-term outcomes. The aim of this project was to evaluate the effectiveness of this approach in improving: (1) glycemic control measured by HbA1c, and (2) HR-QOL measured by the Assessment of Quality of Life (AQOL), at enrollment and at 12-months follow-up. Between 2004 and 2008, a total of 967 patients were enrolled in the program; 545 (56%) of these patients had HbA1c data available at baseline and at 12 months. Mean HbA1c at enrollment was 8.6% (SD 1.9) versus 7.3% (SD 1.2) at 12 months (P<0.001). Overall, 68% of patients experienced improvements in HbA1c. At enrollment, patients reported "fair" HR QOL, which was significantly lower than age-adjusted population norms who reported "good" HR-QOL. At 12 months, 251 (64%) patients had improved HR-QOL, 27 (7%) had no change, and 114 (29%) deteriorated. Mean utility scores improved by 0.11 (P<0.001), which is almost twice the minimum clinically important difference for the AQOL. This study confirms that a multidisciplinary disease management program for patients with poorly controlled type 2 diabetes can improve both glycemic control and HR-QOL. PMID- 22229387 TI - Frontal fibrosing alopecia in black patients. PMID- 22229388 TI - I think I can, I think I can: examining the within-person coupling of control beliefs and cognition in older adults. AB - We examined short-term intraindividual variability in control beliefs (competence and locus of control) and cognitive performance and the extent to which the constructs travel together over time. Thirty-six older adults (M = 74 years, SD = 5.51) completed questionnaires and cognitive tests twice each day for 60 consecutive days. Results indicated that control beliefs fluctuate within people across time. Multilevel models revealed that control and competence are coupled with concurrent and subsequent performance, but the benefit of occasion-level increases in control depends on individuals' average control. These findings underscore the importance of examining constructs using a within-person approach to identify dynamic processes in cognitive aging. PMID- 22229389 TI - Age, clutter, and competitive selection. AB - Modern theory explains visual selective attention as a competition for receptive fields in the extrastriate cortex. The present study examined whether this competition contributes to older adults' difficulty in processing visual clutter. In 2 experiments, young and older adult subjects made same-different judgments of target shapes in displays with or without clutter. The target shapes were either high or low in discriminability. The spatial separation between targets varied across trials, and the effects of competitive selection were gauged through decrements in task performance that resulted as separation decreased. Both age groups showed a competition-in-clutter effect, evincing a stronger influence of target separation within cluttered displays. However, the costs of clutter in general and the strength of the competition-in-clutter effect more specifically were both substantially larger for older adults. Effects of clutter and competition also varied with stimulus discriminability; judgments of highly discriminable stimuli evinced no intertarget competition in uncluttered displays for either age group, while judgments of less discriminable stimuli showed competition whether clutter was present or not. Results suggest that clutter disproportionately degrades older adults' visual performance by forcing more careful stimulus resolution, engendering stronger competition for selection. PMID- 22229390 TI - Aging, parafoveal preview, and semantic integration in sentence processing: testing the cognitive workload of wrap-up. AB - The current study investigated the degree to which semantic-integration processes ("wrap-up") during sentence understanding demand attentional resources by examining the effects of clause and sentence wrap-up on the parafoveal preview benefit (PPB) in younger and older adults. The PPB is defined as facilitation in processing word N + 1, based on information extracted while the eyes are fixated on word N, and is known to be reduced by processing difficulty at word N. Participants read passages in which word N occurred in a sentence-internal, clause-final, or sentence-final position, and a gaze-contingent boundary-change paradigm was used to manipulate the information available in parafoveal vision for word N + 1. Wrap-up effects were found on word N for both younger and older adults. Early-pass measures (first-fixation duration and single-fixation duration) of the PPB on word N + 1 were reduced by clause wrap-up and sentence wrap-up on word N, with similar effects for younger and older adults. However, for intermediate (gaze duration) and later-pass measures (regression-path duration, and selective regression-path duration), sentence wrap-up (but not clause wrap-up) on word N differentially reduced the PPB of word N + 1 for older adults. These findings suggest that wrap-up is demanding and may be less efficient with advancing age, resulting in a greater cognitive processing load for older readers. PMID- 22229393 TI - Electroresistance effect in ferroelectric tunnel junctions with symmetric electrodes. AB - Understanding the effects that govern electronic transport in ferroelectric tunnel junctions (FTJs) is of vital importance to improve the efficiency of devices such as ferroelectric memories with nondestructive readout. However, our current knowledge (typically based on simple semiempirical models or first principles calculations restricted to the limit of zero bias) remains partial, which may hinder the development of more efficient systems. For example, nowadays it is commonly believed that the tunnel electroresistance (TER) effect exploited in such devices mandatorily requires, to be sizable, the use of two different electrodes, with related potential drawbacks concerning retention time, switching, and polarization imprint. In contrast, here we demonstrate at the first-principles level that large TER values of about 200% can be achieved under finite bias in a prototypical FTJ with symmetric electrodes. Our atomistic approach allows us to quantify the contribution of different microscopic mechanisms to the electroresistance, revealing the dominant role of the inverse piezoelectric response of the ferroelectric. On the basis of our analysis, we provide a critical discussion of the semiempirical models traditionally used to describe FTJs. PMID- 22229394 TI - Nonlinear stochastic Markov processes and modeling uncertainty in populations. AB - We consider an alternative approach to the use of nonlinear stochastic Markov processes (which have a Fokker-Planck or Forward Kolmogorov representation for density) in modeling uncertainty in populations. These alternate formulations, which involve imposing probabilistic structures on a family of deterministic dynamical systems, are shown to yield pointwise equivalent population densities. Moreover, these alternate formulations lead to fast efficient calculations in inverse problems as well as in forward simulations. Here we derive a class of stochastic formulations for which such an alternate representation is readily found. PMID- 22229395 TI - The implications of model formulation when transitioning from spatial to landscape ecology. AB - In this article we compare and contrast the predictions of some spatially explicit and implicit models in the context of a thought problem at the interface of spatial and landscape ecology. The situation we envision is a one-dimensional spatial universe of infinite extent in which there are two disjoint focal patches of a habitat type that is favorable to some specified species. We assume that neither patch is large enough by itself to sustain the species in question indefinitely, but that a single patch of size equal to the combined sizes of the two focal patches provides enough contiguous favorable habitat to sustain the given species indefinitely. When the two patches are separated by a patch of unfavorable matrix habitat, the natural expectation is that the species should persist indefinitely if the two patches are close enough to each other but should go extinct over time when the patches are far enough apart. Our focus here is to examine how different mathematical regimes may be employed to model this situation, with an eye toward exploring the trade-off between the mathematical tractability of the model on one hand and the suitability of its predictions on the other. In particular, we are interested in seeing how precisely the predictions of mathematically rich spatially explicit regimes (reaction-diffusion models, integro-difference models) can be matched by those of ostensibly mathematically simpler spatially implicit patch approximations (discrete diffusion models, average dispersal success matrix models). PMID- 22229392 TI - Brief hyperoxia increases mitochondrial oxidation and increases phosphodiesterase 5 activity in fetal pulmonary artery smooth muscle cells. AB - AIMS: Oxygen is a pulmonary vasodilator, but data suggest high O(2) concentrations impede that response. We previously reported 24 h of 100% O(2) increased phosphodiesterase 5 (PDE5) activity in fetal pulmonary artery smooth muscle cells (FPASMC) and in ventilated neonatal lambs. PDE5 degrades cyclic GMP (cGMP) and inhibits nitric oxide (NO)-mediated cGMP-dependent vasorelaxation. We sought to determine the mechanism by which hyperoxia initiates reactive oxygen species (ROS) production and regulates PDE5. RESULTS: Thirty minutes of hyperoxia increased mitochondrial ROS versus normoxia (30.3+/-1.7% vs. 21.1+/-2.8%), but had no effect on cytosolic ROS, measured by roGFP, a ratiometric protein thiol redox sensor. Hyperoxia increased PDE5 activity (220+/-39%) and decreased cGMP responsiveness to NO (37+/-17%). Mitochondrial catalase overexpression attenuated hyperoxia-induced mitochondrial roGFP oxidation, compared to FPASMC infected with empty adenoviral vector (50+/-3% of control) or mitochondrial superoxide dismutase. MitoTEMPO, mitochondrial catalase, and DT-3, a cGMP-dependent protein kinase I alpha inhibitor, decreased PDE5 activity (32+/-13%, 26+/-21%, and 63+/ 10% of control, respectively), and restored cGMP responsiveness to NO (147+/ 16%,172+/-29%, and 189+/-43% of control, respectively). C57Bl6 mice exposed to 90%-100% O(2) for 45 min+/-mechanical ventilation had increased PA PDE5 activity (206+/-39% and 235+/-75%, respectively). INNOVATION: This is the first description that hyperoxia induces ROS in the mitochondrial matrix prior to the cytosol. Our results indicate that short hyperoxia exposures can produce significant changes in critical cellular signaling pathways. CONCLUSIONS: These results indicate that mitochondrial matrix oxidant signals generated during hyperoxia, specifically H(2)O(2), activate PDE5 in a cGMP-dependent protein kinase-dependent manner in pulmonary vascular smooth muscle cells. PMID- 22229396 TI - An evaluation of dynamic outlet boundary conditions in a 1D fluid dynamics model. AB - When modeling the cardiovascular system, the use of boundary conditions that closely represent the interaction between the region of interest and the surrounding vessels and organs will result in more accurate predictions. An often overlooked feature of outlet boundary conditions is the dynamics associated with regulation of the distribution of pressure and flow. This study implements a dynamic impedance outlet boundary condition in a one-dimensional fluid dynamics model using the pulmonary vasculature and respiration (feedback mechanism) as an example of a dynamic system. The dynamic boundary condition was successfully implemented and the pressure and flow were predicted for an entire respiration cycle. The cardiac cycles at maximal expiration and inspiration were predicted with a root mean square error of 0.61 and 0.59 mm Hg, respectively. PMID- 22229397 TI - Nonlinear functional response parameter estimation in a stochastic predator-prey model. AB - Parameter estimation for the functional response of predator-prey systems is a critical methodological problem in population ecology. In this paper we consider a stochastic predator-prey system with non-linear Ivlev functional response and propose a method for model parameter estimation based on time series of field data. We tackle the problem of parameter estimation using a Bayesian approach relying on a Markov Chain Monte Carlo algorithm. The efficiency of the method is tested on a set of simulated data. Then, the method is applied to a predator-prey system of importance for Integrated Pest Management and biological control, the pest mite Tetranychus urticae and the predatory mite Phytoseiulus persimilis. The model is estimated on a dataset obtained from a field survey. Finally, the estimated model is used to forecast predator-prey dynamics in similar fields, with slightly different initial conditions. PMID- 22229398 TI - Impact of discontinuous treatments on disease dynamics in an SIR epidemic model. AB - We consider an SIR epidemic model with discontinuous treatment strategies. Under some reasonable assumptions on the discontinuous treatment function, we are able to determine the basic reproduction number R0, confirm the well-posedness of the model, describe the structure of possible equilibria as well as establish the stability/instability of the equilibria. Most interestingly, we find that in the case that an equilibrium is asymptotically stable, the convergence to the equilibrium can actually be achieved in finite time, and we can estimate this time in terms of the model parameters, initial sub-populations and the initial treatment strength. This suggests that from the view point of eliminating the disease from the host population, discontinuous treatment strategies would be superior to continuous ones. The methods we use to obtain the mathematical results are the generalized Lyapunov theory for discontinuous differential equations and some results on non-smooth analysis. PMID- 22229399 TI - Threshold dynamics for a tuberculosis model with seasonality. AB - In this paper, we investigate a SEILR tuberculosis model incorporating the effect of seasonal fluctuation, where the loss of sight class is considered. The basic reproduction number R0 is defined. It is shown that the disease-free equilibrium is globally asymptotically stable and the disease eventually disappears if R0 < 1, and there exists at least one positive periodic solution and the disease is uniformly persistent if R0 > 1. Numerical simulations are provided to illustrate analytical results. PMID- 22229400 TI - A statistical approach to the use of control entropy identifies differences in constraints of gait in highly trained versus untrained runners. AB - Control entropy (CE) is a complexity analysis suitable for dynamic, non stationary conditions which allows the inference of the control effort of a dynamical system generating the signal. These characteristics make CE a highly relevant time varying quantity relevant to the dynamic physiological responses associated with running. Using High Resolution Accelerometry (HRA) signals we evaluate here constraints of running gait, from two different groups of runners, highly trained collegiate and untrained runners. To this end,we further develop the control entropy (CE) statistic to allow for group analysis to examine the non linear characteristics of movement patterns in highly trained runners with those of untrained runners, to gain insight regarding gaits that are optimal for running. Specifically, CE develops response time series of individuals descriptive of the control effort; a group analysis of these shapes developed here uses Karhunen Loeve Analysis (KL) modes of these time series which are compared between groups by application of a Hotelling T2 test to these group response shapes. We find that differences in the shape of the CE response exist within groups, between axes for untrained runners (vertical vs anterior-posterior and mediolateral vs anterior-posterior) and trained runners (mediolateral vs anterior-posterior). Also shape differences exist between groups by axes (vertical vs mediolateral). Further, the CE, as a whole, was higher in each axis in trained vs untrained runners. These results indicate that the approach can provide unique insight regarding the differing constraints on running gait in highly trained and untrained runners when running under dynamic conditions. Further, the final point indicates trained runners are less constrained than untrained runners across all running speeds. PMID- 22229401 TI - Assessing the effect of non-pharmaceutical interventions on containing an emerging disease. AB - Non-pharmaceutical interventions, such as quarantine, isolation and entry screening, are usually the primary public health measures to control the spread of an emerging infectious disease through a human population. This paper proposes a multi-regional deterministic compartmental model to assess the effectiveness and implications of non-pharmaceutical interventions. The reproduction number is determined as the spectral radius of a nonnegative matrix product. Comparisons are made using the reproduction number, epidemic peaks and cumulative number of infections and mortality as indexes. Simulation results show that quarantine of suspected cases and isolation of cases with symptom are effective in reducing disease burden for multiple regions. Using entry screening strategy leads to a moderate time delay for epidemic peaks, but is of no help for preventing an epidemic breaking out. The study further shows that isolation strategy is always the best choice in the presence or absence of stringent hygiene precautions and should be given priority in combating an emerging epidemic. PMID- 22229402 TI - Global analysis of a delayed vector-bias model for malaria transmission with incubation period in mosquitoes. AB - A delayed vector-bias model for malaria transmission with incubation period in mosquitoes is studied. The delay t corresponds to the time necessary for a latently infected vector to become an infectious vector. We prove that the global stability is completely determined by the threshold parameter, R0(tau). If R0(tau) >= 1, the disease-free equilibrium is globally asymptotically stable. If R0(tau) > 1 a unique endemic equilibrium exists and is globally asymptotically stable. We apply our results to Ross-MacDonald malaria models with an incubation period (extrinsic or intrinsic). PMID- 22229403 TI - A quasi-lumped model for the peripheral distortion of the arterial pulse. AB - As blood circulates through the arterial tree, the flow and pressure pulse distort. Principal factors to this distortion are reflections form arterial bifurcations and the viscous character of the flow of the blood. Both of them are expounded in the literature and included in our analysis. The nonlinearities of inertial effects are usually taken into account in numerical simulations, based on Navier-Stokes like equations. Nevertheless, there isn't any qualitative, analytical formula, which examines the role of blood's inertia on the distortion of the pulse. We derive such an analytical nonlinear formula. It emanates from a generalized Bernoulli's equation for an an-harmonic, linear, viscoelastic, Maxwell fluid flow in a linear, viscoelastic, Kelvin-Voigt, thin, cylindrical vessel. We report that close to the heart, convection effects related to the change in the magnitude of the velocity of blood dominate the alteration of the shape of the pressure pulse, while at remote sites of the vascular tree, convection of vorticity, related to the change in the direction of the velocity of blood with respect to a mean axial flow, prevails. A quantitative comparison between the an-harmonic theory and related pressure measurements is also performed. PMID- 22229404 TI - Effect of branchings on blood flow in the system of human coronary arteries. AB - In this work, we investigate the behavior of the pulsatile blood flow in the system of human coronary arteries. Blood is modeled as an incompressible non Newtonian fluid. The transient phenomena of blood flow through the coronary system are simulated by solving the three dimensional unsteady state Navier Stokes equations and continuity equation. Distributions of velocity, pressure and wall shear stresses are determined in the system under pulsatile conditions on the boundaries. Effect of branching vessel on the flow problem is investigated. The numerical results show that blood pressure in the system with branching vessels of coronary arteries is lower than the one in the system with no branch. The magnitude of wall shear stresses rises at the bifurcation. PMID- 22229405 TI - MDV3100 for the treatment of prostate cancer. AB - INTRODUCTION: MDV3100 is a rationally designed androgen receptor antagonist, which has recently been shown to improve survival in men with metastatic castration-resistant prostate cancer previously treated with docetaxel chemotherapy. Drug development for advanced prostate cancer is advancing at a rapid pace with four other novel therapies (abiraterone, cabazitaxel, alpharadin and sipuleucel-T) also shown to improve overall survival in large randomised studies. AREAS COVERED: This review will cover the historical background of androgen deprivation therapy, recently approved agents for advanced prostate cancer, an overview of the clinical development of MDV3100 and an analysis of how MDV3100 may fit into future treatment protocols for this disease. EXPERT OPINION: Full analysis of safety and efficacy data is awaited; however, MDV3100 appears to be a well-tolerated addition to the expanding portfolio of effective drugs for the treatment of advanced prostate cancer. PMID- 22229406 TI - Combined salicyclic acid and ultrasound treatments for reducing the chilling injury on peach fruit. AB - The effects of salicylic acid (SA; 1 mmol L(-1)) and ultrasound treatment (40 kHz, 10 min) either separately or combined on the chilling injury (CI) in cold stored peach fruit ( Prunus persica Batsch cv. Baifeng) were investigated. The results showed that SA treatment alone alleviated CI during storage. Ultrasound alone had no influence, but when it was combined with SA, it resulted in greater inhibition of CI than SA alone. The activities of antioxidant enzymes, such as catalase, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase, were induced by a combination of SA with ultrasound. In addition, the combined treatment also increased the endogenous SA concentrations in peaches. These results suggested that the induced tolerance against CI by the combination of ultrasound and SA treatment in cold-stored peach fruit was related to the induction of antioxidant enzymes and the increase in the SA concentration. PMID- 22229409 TI - Insights from crystal structures into the opposite effects on RNA affinity caused by the S- and R-6'-methyl backbone modifications of 3'-fluoro hexitol nucleic acid. AB - Locked nucleic acid (LNA) analogues with 2',4'-bridged sugars show promise in antisense applications. S-5'-Me-LNA has high RNA affinity, and modified oligonucleotides show weakened immune stimulation in vivo. Conversely, an R-5' methyl group dramatically lowers RNA affinity. To test the effects of S- and R-6' methyl groups on 3'-fluoro hexitol nucleic acid (FHNA) stability, we synthesized S- and R-6'-Me-FHNA thymidine and incorporated them into oligo-2' deoxynucleotides. As with LNA, S-6'-Me is stabilizing whereas R-6'-Me is destabilizing. Crystal structures of 6'-Me-FHNA-modified DNAs explain the divergent consequences for stability and suggest convergent origins of these effects by S- and R-6'-Me (FHNA) [-5'-Me (LNA and RNA)] substituents. PMID- 22229410 TI - The crystal structure of the C-terminal truncated apolipoprotein A-I sheds new light on amyloid formation by the N-terminal fragment. AB - Apolipoprotein A-I (apoA-I) is the main protein of plasma high-density lipoproteins (HDL, or good cholesterol) that remove excess cell cholesterol and protect against atherosclerosis. In hereditary amyloidosis, mutations in apoA-I promote its proteolysis and the deposition of the 9-11 kDa N-terminal fragments as fibrils in vital organs such as kidney, liver, and heart, causing organ damage. All known amyloidogenic mutations in human apoA-I are clustered in two residue segments, 26-107 and 154-178. The X-ray crystal structure of the C terminal truncated human protein, Delta(185-243)apoA-I, determined to 2.2 A resolution by Mei and Atkinson, provides the structural basis for understanding apoA-I destabilization in amyloidosis. The sites of amyloidogenic mutations correspond to key positions within the largely helical four-segment bundle comprised of residues 1-120 and 144-184. Mutations in these positions disrupt the bundle structure and destabilize lipid-free apoA-I, thereby promoting its proteolysis. Moreover, many mutations place a hydrophilic or Pro group in the middle of the hydrophobic lipid-binding face of the amphipathic alpha-helices, which will likely shift the population distribution from HDL-bound to lipid poor/free apoA-I that is relatively unstable and labile to proteolysis. Notably, the crystal structure shows segment L44-S55 in an extended conformation consistent with the beta-strand-like geometry. Exposure of this segment upon destabilization of the four-segment bundle probably initiates the alpha-helix to beta-sheet conversion in amyloidosis. In summary, we propose that the amyloidogenic mutations promote apoA-I proteolysis by destabilizing the protein structure not only in the lipid-free but also in the HDL-bound form, with segment L44-S55 providing a likely template for the cross-beta-sheet conformation. PMID- 22229411 TI - Structural and kinetic isotope effect studies of nicotinamidase (Pnc1) from Saccharomyces cerevisiae. AB - Nicotinamidases catalyze the hydrolysis of nicotinamide to nicotinic acid and ammonia. Nicotinamidases are absent in mammals but function in NAD(+) salvage in many bacteria, yeast, plants, protozoa, and metazoans. We have performed structural and kinetic investigations of the nicotinamidase from Saccharomyces cerevisiae (Pnc1). Steady-state product inhibitor analysis revealed an irreversible reaction in which ammonia is the first product released, followed by nicotinic acid. A series of nicotinamide analogues acting as inhibitors or substrates were examined, revealing that the nicotinamide carbonyl oxygen and ring nitrogen are critical for binding and reactivity. X-ray structural analysis revealed a covalent adduct between nicotinaldehyde and Cys167 of Pnc1 and coordination of the nicotinamide ring nitrogen to the active-site zinc ion. Using this structure as a guide, the function of several residues was probed via mutagenesis and primary (15)N and (13)C kinetic isotope effects (KIEs) on V/K for amide bond hydrolysis. The KIE values of almost all variants were increased, indicating that C-N bond cleavage is at least partially rate limiting; however, a decreased KIE for D51N was indicative of a stronger commitment to catalysis. In addition, KIE values using slower alternate substrates indicated that C-N bond cleavage is at least partially rate limiting with nicotinamide to highly rate limiting with thionicotinamide. A detailed mechanism involving nucleophilic attack of Cys167, followed by elimination of ammonia and then hydrolysis to liberate nicotinic acid, is discussed. These results will aid in the design of mechanism-based inhibitors to target pathogens that rely on nicotinamidase activity. PMID- 22229413 TI - Applications of the photodynamic therapy to cancer,water- and vector-borne diseases. PMID- 22229412 TI - The kinase activity of the Helicobacter pylori Asp-tRNA(Asn)/Glu-tRNA(Gln) amidotransferase is sensitive to distal mutations in its putative ammonia tunnel. AB - The Helicobacter pylori (Hp) Asp-tRNA(Asn)/Glu-tRNA(Gln) amidotransferase (AdT) plays important roles in indirect aminoacylation and translational fidelity. AdT has two active sites, in two separate subunits. Kinetic studies have suggested that interdomain communication occurs between these subunits; however, this mechanism is not well understood. To explore domain-domain communication in AdT, we adapted an assay and optimized it to kinetically characterize the kinase activity of Hp AdT. This assay was applied to the analysis of a series of point mutations at conserved positions throughout the putative AdT ammonia tunnel that connects the two active sites. Several mutations that caused significant decreases in AdT's kinase activity (reduced by 55-75%) were identified. Mutations at Thr149 (37 A distal to the GatB kinase active site) and Lys89 (located at the interface of GatA and GatB) were detrimental to AdT's kinase activity, suggesting that these mutations have disrupted interdomain communication between the two active sites. Models of wild-type AdT, a valine mutation at Thr149, and an arginine mutation at Lys89 were subjected to molecular dynamics simulations. A comparison of wild-type, T149V, and K89R AdT simulation results unmasks 59 common residues that are likely involved in connecting the two active sites. PMID- 22229415 TI - Protein degradation by the ubiquitin-proteasome pathway and organ fibrosis. AB - Abnormal and exaggerated deposition of extracellular matrix proteins is the common feature of fibrotic diseases. The resulting fibrosis disrupts the normal architecture of the affected organs and finally leads to their dysfunction and failure. At present, there are no effective therapies for fibrotic diseases. Protein degradation via the ubiquitin-proteasome system is the major pathway for non-lysosomal proteolysis and controls many critical cellular functions including cell-cycle progression, deoxyribonucleic acid repair, growth and differentiation. Therefore, aberration of the system leads to dysregulation of cellular homeostasis and development of many diseases such as cancers, degenerative diseases and fibrotic diseases. Although the ubiquitin-proteasome system has mainly been investigated in the field of cancers so far and several anti-cancer drugs that modulate the activity of the system have been used clinically, the recent findings regarding the system and fibrosis can provide a rational basis for the discovery of novel therapy for fibrotic diseases. In this article, we discuss (i) the basic mechanism of the ubiquitin-proteasome system and (ii) the recent findings regarding the association between the system and pathological organ fibrosis. These examples indicate that the ubiquitin-proteasome system plays diverse roles in the progression of fibrotic diseases, and further studies of the system are expected to reveal new strategies for overcoming pathological fibrosis. PMID- 22229416 TI - Novel biomarkers assessing the calcium deposition in coronary artery disease. AB - Coronary atherosclerosis is the pathophysiologic background of coronary artery disease. Vascular calcification is an actively regulated form of calcified tissue metabolism and a common feature of coronary atherosclerotic plaques. Interestingly, systematic research has revealed that vascular mineralization, is also a strong and independent predictor of cardiovascular morbidity and mortality. Recently, several biomarkers, including osteopontin, fetuin-A, matrix carboxyglutamic acid protein, pyrophosphates, bone morphogenetic proteins, leptin, osteoprotegerin have emerged as surrogate markers of coronary calcification. Furthermore, biomarkers of vascular calcification can be used as prognostic markers of coronary artery disease and can predict future cardiovascular events and mortality. Nevertheless, there is little knowledge on the usefulness of these biomarkers in evaluating the results of treatments targeting coronary artery disease. Within this context, the present review sets out to discuss the role of new biomarkers assessing calcium deposition in coronary arteries and their role in the prognosis, progression, and treatment of cardiovascular disease. PMID- 22229414 TI - Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance. AB - Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer. PMID- 22229417 TI - The development of MetAP-2 inhibitors in cancer treatment. AB - Methionine aminopeptidases (MetAPs), which remove methionine residue from newly synthesized polypeptide chains, are a class of metalloproteases ubiquitously distributed in both eukaryotes and prokaryotes. MetAP-2 inhibition can induce G1 cell cycle arrest, cytostasis in tumor cells in vitro and inhibition of tumor growth in vivo. The discovery of fumagillin with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. Early drug discovery efforts have focused on analogs of fumagillin, which irreversibly inhibit MetAP-2 through covalent modification of an epoxide. Several fumagillin analogs, like CKD-732, TNP-470 and PPI-2458, were found to be potent selective inhibitors of MetAP-2 (proteolytic activity) and endothelial cell proliferation. Further, they have entered in clinical trials for the treatment of different types of tumors. Recently, attention has been paid to reversible human MetAP-2 inhibitors, such as bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs, which have demonstrated their potential to inhibit angiogenesis and tumor growth in vivo as well. This review article mainly discussed the development of MetAP-2 inhibitors in cancer therapy and also summarized their structure-activity relationships. PMID- 22229438 TI - Obstetric near-miss cases among women admitted to intensive care units in Italy. AB - OBJECTIVE: Maternal near-miss defines a narrow category of morbidity encompassing potentially life-threatening episodes. The purpose of this study was to detect near-miss instances among women admitted to intensive care units or coronary units, analyze associated causes, and compute absolute and specific maternal morbidity rates in six Italian regions. DESIGN: Observational retrospective study. SETTING: Six Italian regions representing 49% of all resident Italian women aged 15-49 years. POPULATION: The study population included all pregnant women aged 15-49 years admitted to intensive care units or coronary care units in the participating regions. Cases were defined as women aged 15-49 years resident in the participating regions, with one or more hospitalizations in intensive care for pregnancy or any pregnancy outcome between 2004 and 2005. METHODS: Cases were identified through the Hospital Discharge Database. Enrolled cases were diagnosed according to the 9(th) International Classification of Diseases. MAIN OUTCOME MEASURE: Maternal near-miss rate (number of women experiencing an admission to intensive care units/all women with live or stillborn babies). RESULTS: A total of 1259 near-miss cases were identified and the total maternal near-miss rate was 2.0/1000 deliveries. Seventy percent of the women were admitted to intensive care units or coronary units after a cesarean section. The leading associated risk factors were obstetric hemorrhage/disseminated intravascular coagulation (40%) and hypertensive disorders of pregnancy (29%). CONCLUSIONS: Monitoring of near miss morbidity in conjunction with mortality surveillance could help to identify effective preventive measures for potentially life-threatening episodes. PMID- 22229439 TI - Spherical nucleic acids. AB - A historical perspective of the development of spherical nucleic acid (SNA) conjugates and other three-dimensional nucleic acid nanostructures is provided. This Perspective details the synthetic methods for preparing them, followed by a discussion of their unique properties and theoretical and experimental models for understanding them. Important examples of technological advances made possible by their fundamental properties spanning the fields of chemistry, molecular diagnostics, gene regulation, medicine, and materials science are also presented. PMID- 22229441 TI - IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. AB - Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin 17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target. PMID- 22229440 TI - Patterning skin by planar cell polarity: the multi-talented hair designer. AB - In mammals, the skin can form complex global and local patterns to meet diverse functional requirements in different parts of the body. To date, the fundamental principles that underlie skin patterning remain poorly understood because of the involvement of multiple interacting processes. Genes involved in the planar cell polarity (PCP) signalling pathway, which is capable of polarizing cells within the planar plane of an epithelium, can control the orientation and differentiation of hair follicles, underlining their involvement in skin pattern formation. Here, we summarize recent progress that has been made to understand the PCP signalling pathway and its function in mammalian skin, including its role in hair follicle morphogenesis, ciliogenesis and wound healing. We argue that dissecting PCP signalling in the context of hair follicle formation might reveal many as-yet-undiscovered functions for PCP in the development, homeostasis and regeneration of skin. PMID- 22229442 TI - Involvement of RAGE, MAPK and NF-kappaB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes. AB - Advanced glycation end products (AGEs) exert divergent effects on the pathogenesis of diabetes complications. Excessive expression of matrix metalloproteinases-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. However, the effect of AGEs on MMP-9 induction in skin cells and the exact molecular mechanisms involved are still poorly understood. In this study, we investigated the effect of AGEs on the production of MMP-9 in HaCaT keratinocytes and characterized the signal transduction pathways activated by AGEs that are involved in MMP-9 regulation. We showed that AGE-BSA increased MMP-9 expression in HaCaT cells at both the protein and mRNA levels. The stimulatory effect of AGE-BSA on MMP-9 was attenuated by inhibitors of extracellular-signal-regulated kinase (ERK1/2, U0126), p38 mitogen activated protein kinase (MAPK, SB203580) and NF-kappaB, but not c-Jun N-terminal kinase. Furthermore, receptor for advanced glycation end products (RAGE) was expressed in keratinocytes, and incubation with AGE-BSA resulted in a significant upregulation of RAGE expression in a dose-dependent manner. Silencing of the RAGE gene prevented AGE-BSA-induced MMP-9 activation and the phosphorylation of ERK1/2 and p38 MAPK. We also observed the involvement of NF-kappaB in AGE-BSA-induced MMP-9 activation, which was not blocked by U0126 and SB203580. These results suggest that AGEs may play an important role in the impairment of diabetic wound healing by upregulating MMP-9 expression in keratinocytes via the RAGE, ERK1/2 and p38 MAPK pathways; activation of NF-kappaB is also involved in this process. These pathways may represent potential targets for drug interventions to improve diabetic wound healing, a process in which MMP-9 plays a critical role. PMID- 22229443 TI - Fatty acids and vitamins generate singlet oxygen under UVB irradiation. AB - UVB radiation is already known as initiator and promoter of carcinogenesis in skin. UVB is well absorbed in proteins and DNA leading to products such as cyclobutane pyrimidine dimers. In contrast, UVA radiation generates reactive oxygen species such as singlet oxygen, which can initiate a variety of cellular damages and cellular signalling. It was the goal to investigate whether and to which extent UVB radiation is additionally able to cause oxidative damages via singlet oxygen. Potential endogenous photosensitizers such as vitamin B molecules or unsaturated fatty acids were irradiated in solution using monochromatic UVB radiation at 308 nm. Singlet oxygen was directly detected and quantified by its luminescence at 1270 nm. All investigated endogenous photosensitizers showed clear singlet oxygen signals with a quantum yield ranging from 5 to 40%. UVB radiation altered the photosensitizer molecules during irradiation yielding a change of absorption in the entire ultraviolet spectrum (280-400 nm). UVB irradiation of endogenous photosensitizers produced singlet oxygen that in turn changes the absorption of those molecules. Being an important prerequisite, the changed absorption may either reduce or increase singlet oxygen production. An increase in singlet oxygen generation may initiate a vicious cycle that has the potential to amplify UVB- or UVA-mediated effects in skin cells. PMID- 22229444 TI - Effects of the re-innervation of organotypic skin explants on the epidermis. AB - The nervous system takes part in skin homeostasis and interacts with skin cells. In in vitro organotypic skin models, these interactions are lost owing to the absence of nerve endings. We have developed an in vitro organotypic skin model based on a re-innervated human skin explant using primary sensory neurons from the dorsal root ganglia of rats. After 10 days of co-culture between skin explant and neurons, a dense network of nerve fibres was observed. The epidermis and dermis presented nerve fibres associated with cellular body from sensory neurons introduced in the co-culture. Epidermal thickness, cell density and quality of re innervated skin explant were all higher when skin explants were re-innervated by sensory neurons at 10 days of culture. Proliferation of epidermal cell was not modified, but the apoptosis was significantly diminished. Hence, this innovative model of co-cultured skin explants and neurons allows better epidermal integrity and could be useful for studies concerning interactions between the skin and its peripheral nervous system. PMID- 22229445 TI - Anti-allergic effect of a chloroform-soluble extract of Cinnamomum cambodianum in bone marrow-derived mast cells. AB - Cinnamomum cambodianum has been used as a traditional medicine in Cambodia. Its effect on the bone marrow-derived mast cells (BMMCs) mediated allergic response remains unknown. In this study, a chloroform-soluble extract of C. cambodianum was evaluated for its effect on allergic mediators, including prostaglandin D2 (PGD2), leukotriene C4 (LTC4), beta-hexosaminidase and cyclooxygenase-2 (COX-2) protein, in phorbol 12-myristate 13-acetate (PMA) plus calcimycin-stimulated BMMCs. The results revealed that the chloroform-soluble extract inhibited the production of interleukin-6, PGD2 and LTC4, and the expression of COX-2 in PMA plus calcimycin-stimulated BMMCs, implying a potential benefit of C. cambodianum in the treatment of allergy. PMID- 22229447 TI - Detailed finite element modelling of deep needle insertions into a soft tissue phantom using a cohesive approach. AB - Detailed finite element modelling of needle insertions into soft tissue phantoms encounters difficulties of large deformations, high friction, contact loading and material failure. This paper demonstrates the use of cohesive elements in high resolution finite element models to overcome some of the issues associated with these factors. Experiments are presented enabling extraction of the strain energy release rate during crack formation. Using data from these experiments, cohesive elements are calibrated and then implemented in models for validation of the needle insertion process. Successful modelling enables direct comparison of finite element and experimental force-displacement plots and energy distributions. Regions of crack creation, relaxation, cutting and full penetration are identified. By closing the loop between experiments and detailed finite element modelling, a methodology is established which will enable design modifications of a soft tissue probe that steers through complex mechanical interactions with the surrounding material. PMID- 22229446 TI - Increased echocardiographic epicardial fat thickness is related to impaired diurnal blood pressure profiles. AB - OBJECTIVE: Epicardial fat has been proposed as a new cardiometabolic risk factor. Although epicardial fat thickness (EFT) is associated with hypertension, the relationship between diurnal blood pressure profiles and EFT is still unknown. The purpose of this study is to investigate the association between the echocardiographic EFT and diurnal blood pressure profiles in hypertensive patients. METHODS: After the ambulatory blood pressures of 123 patients were monitored, they were divided into three groups according to the clinical diagnoses: 41 patients (33.3%) were in the normotensive group, 40 patients (32.5%) were in the dipper hypertensive group and 42 patients (34.1%) were in the non-dipper hypertensive group. All participants underwent transthoracic echocardiography and ambulatory blood pressure monitoring to measure the EFT and blood pressure responses. RESULTS: The mean EFT measurements of the dipper group were significantly higher than the normotensive group (6.5 +/- 0.6 vs 5.8 +/- 0.6; p < 0.0001). On the other hand, the mean EFTs of the non-dipper group were also significantly higher than the dipper group (7.4 +/- 0.7 vs 6.5 +/- 0.6, p < 0.0001). An EFT of >= 7 mm predicted the non-dipper profile in hypertensive patients with 74% sensitivity and 71% specificity (receiving operator characteristic area under the curve: 0.826, 95% CI 0.738-0.913; p < 0.0001). EFT was associated with both dipper (OR 8.9, 95% CI 3.03-26.3; p < 0.0001) and non dipper blood pressure profiles (OR 12.3, 95% CI 1.75-86.31; p < 0.0001), and this relationship was also independent from all the risk factors. CONCLUSION: Echocardiographic EFT assessment is independently associated with impaired diurnal blood pressure profiles in the hypertensive individuals. Thus, the echocardiographic assessment of the EFT may be helpful in cardiometabolic risk stratification and therapeutic interventions. PMID- 22229448 TI - Evaluation of particle gel immunoassays for the detection of severe immunoglobulin A deficiency and anti-human immunoglobulin A antibodies. AB - BACKGROUND: Immunoglobulin A (IgA)-deficient patients with anti-IgA (Ab) require transfusions using blood components with less than 0.05 mg IgA/dL as they are known to be safe for these patients. Identification of severely IgA-deficient (IgA SD) donors involved preliminary screening by the Ouchterlony double immunodiffusion assay followed by confirmatory testing at the required level of sensitivity for IgA and Ab at an external reference laboratory. Two in vitro particle gel immunoassays (ID-PaGIA IgA deficiency test and anti-IgA test) were also evaluated for their suitability in identifying IgA SD individuals and determining their Ab status. STUDY DESIGN AND METHODS: Samples from 198 donors and 36 patients, subjected to confirmatory testing for IgA SD and Ab over a 2 year period, were also evaluated using the ID-PaGIA kits. RESULTS: DiaMed test sensitivity and specificity for detection of IgA SD in donors was 98% whereas for Ab, test sensitivity was 91% at a specificity of 94%. In patients, sensitivity was 94% for IgA SD and 67% for Ab, both tests at a specificity of 100%. CONCLUSIONS: The ID-PaGIA IgA deficiency test was a sensitive and specific tool for identifying IgA SD donors or patients. Sensitivity of the Ab test was high for donors but reduced for patients and of high specificity in both groups. Further studies with patients are needed to confirm this latter observation. Implementation of these tests would make it possible to supply appropriate products from IgA SD donors to prevent anaphylactic transfusion reactions in patients. PMID- 22229449 TI - Abandoned pacemaker leads are a potential risk for patients undergoing MRI. PMID- 22229451 TI - Serum sTREM-1 (soluble triggering receptor expressed on myeloid cells-1) associates negatively with embryo quality in infertility patients. AB - PROBLEM: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker of infection and inflammation. METHOD OF STUDY: We studied serum and follicular fluid sTREM-1 in infertile patients (N = 110) utilizing enzyme linked immunosorbent assay. RESULTS: Serum and follicular sTREM-1 were in good correlation (Pearson's correlation 0.56, P < 0.0001) with higher values in follicular fluid (140.4 +/- 34.4 and 115.6 +/- 35.1 pg/mL, t-test, P < 0.0001). Endometriosis associated with lower follicular and serum sTREM-1 compared with male factor infertility patients (age-adjusted r = -25.7 pg/mL, P = 0.018; r = 22.1 pg/mL, P = 0.030). No associations between follicular or serum sTREM-1 and clinical parameters were found, except higher serum sTREM-1 associated with lower embryo quality in all patients (adjusted r = -0.3%, P = 0.033), with a cutoff value between 111.5 and 113.3 pg/mL (OR = 0.38, P = 0.048; OR = 0.34, P = 0.028) predicting that more than 39% of embryos would be with good quality. CONCLUSION: Serum sTREM-1 could represent a prognostic marker for female fecundity, probably indicating impaired inflammatory reaction of immune system. PMID- 22229453 TI - Genitoperineal papular acantholytic dyskeratosis is allelic to Hailey-Hailey disease. PMID- 22229452 TI - Mechanical stretch inhibits adipogenesis and stimulates osteogenesis of adipose stem cells. AB - A reciprocal relationships between osteogenesis and adipogenesis has been observed in vitro and in vivo, and mechanical stretch has been believed to be a regulating factor of osteo-adipogenic axis differentiation of mesenchymal stem cells. In this study, rat adipose stem cells (ASCs) were isolated and cultured in adipogenic or normal medium. Their exposure to cyclic mechanical stretch (2000 MUepsilon, 1 Hz) in the presence of adipogenic medium decreased mRNA and protein level of PPAR-gamma, and increased Runx2 mRNA and protein levels as well as Pref 1 mRNA level, compared to static samples. ASCs cultured in normal medium without adipogenic induction did not show any significant change in mRNA expression of PPAR-gamma, Runx2, nor Pref-1 irrespective of mechanical loading. Stretching induced phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) during the induction period. It was concluded that mechanical stretch inhibited adipogenesis and stimulated osteogenesis of these ASCs in the presence of adipogenic medium and that ERK1/2 activation may be involved in the mechanical stress-induced trans-differentiation. PMID- 22229455 TI - The ethics of selling methods for scientific research. PMID- 22229456 TI - Differentiating the effects of status and power: a justice perspective. AB - Few empirical efforts have been devoted to differentiating status and power, and thus significant questions remain about differences in how status and power impact social encounters. We conducted 5 studies to address this gap. In particular, these studies tested the prediction that status and power would have opposing effects on justice enacted toward others. In the first 3 studies, we directly compared the effects of status and power on people's enactment of distributive (Study 1) and procedural (Studies 2 and 3) justice. In the last 2 studies, we orthogonally manipulated status and power and examined their main and interactive effects on people's enactment of distributive (Study 4) and procedural (Study 5) justice. As predicted, all 5 studies showed consistent evidence that status is positively associated with justice toward others, while power is negatively associated with justice toward others. The effects of power are moderated, however, by an individual's other orientation (Studies 2, 3, 4, and 5), and the effects of status are moderated by an individual's dispositional concern about status (Study 5). Furthermore, Studies 4 and 5 also demonstrated that status and power interact, such that the positive effect of status on justice emerges when power is low and not when power is high, providing further evidence for differential effects between power and status. Theoretical implications for the literatures on status, power, and distributive/procedural justice are discussed. PMID- 22229457 TI - Competitive victimhood as a response to accusations of ingroup harm doing. AB - Accusations of unjust harm doing by the ingroup threaten the group's moral identity. One strategy for restoring ingroup moral identity after such a threat is competitive victimhood: claiming the ingroup has suffered compared with the harmed outgroup. Men accused of harming women were more likely to claim that men are discriminated against compared with women (Study 1), and women showed the same effect when accused of discriminating against men (Study 3). Undergraduates engaged in competitive victimhood with university staff after their group was accused of harming staff (Study 2). Study 4 showed that the effect of accusations on competitive victimhood among high-status group members is mediated by perceived stigma reversal: the expectation that one should feel guilty for being in a high-status group. Exposure to a competitive victimhood claim on behalf of one's ingroup reduced stigma reversal and collective guilt after an accusation of ingroup harm doing (Study 5). PMID- 22229458 TI - The virtues of gossip: reputational information sharing as prosocial behavior. AB - Reputation systems promote cooperation and deter antisocial behavior in groups. Little is known, however, about how and why people share reputational information. Here, we seek to establish the existence and dynamics of prosocial gossip, the sharing of negative evaluative information about a target in a way that protects others from antisocial or exploitative behavior. We present a model of prosocial gossip and the results of 4 studies testing the model's claims. Results of Studies 1 through 3 demonstrate that (a) individuals who observe an antisocial act experience negative affect and are compelled to share information about the antisocial actor with a potentially vulnerable person, (b) sharing such information reduces negative affect created by observing the antisocial behavior, and (c) individuals possessing more prosocial orientations are the most motivated to engage in such gossip, even at a personal cost, and exhibit the greatest reduction in negative affect as a result. Study 4 demonstrates that prosocial gossip can effectively deter selfishness and promote cooperation. Taken together these results highlight the roles of prosocial motivations and negative affective reactions to injustice in maintaining reputational information sharing in groups. We conclude by discussing implications for reputational theories of the maintenance of cooperation in human groups. PMID- 22229459 TI - A facial expression for anxiety. AB - Anxiety and fear are often confounded in discussions of human emotions. However, studies of rodent defensive reactions under naturalistic conditions suggest anxiety is functionally distinct from fear. Unambiguous threats, such as predators, elicit flight from rodents (if an escape-route is available), whereas ambiguous threats (e.g., the odor of a predator) elicit risk assessment behavior, which is associated with anxiety as it is preferentially modulated by anti anxiety drugs. However, without human evidence, it would be premature to assume that rodent-based psychological models are valid for humans. We tested the human validity of the risk assessment explanation for anxiety by presenting 8 volunteers with emotive scenarios and asking them to pose facial expressions. Photographs and videos of these expressions were shown to 40 participants who matched them to the scenarios and labeled each expression. Scenarios describing ambiguous threats were preferentially matched to the facial expression posed in response to the same scenario type. This expression consisted of two plausible environmental-scanning behaviors (eye darts and head swivels) and was labeled as anxiety, not fear. The facial expression elicited by unambiguous threat scenarios was labeled as fear. The emotion labels generated were then presented to another 18 participants who matched them back to photographs of the facial expressions. This back-matching of labels to faces also linked anxiety to the environmental scanning face rather than fear face. Results therefore suggest that anxiety produces a distinct facial expression and that it has adaptive value in situations that are ambiguously threatening, supporting a functional, risk assessing explanation for human anxiety. PMID- 22229460 TI - Mild traumatic brain injury is associated with impaired hippocampal spatiotemporal representation in the absence of histological changes. AB - Mild traumatic brain injury (mTBI) accounts for the majority of head trauma cases. Despite some lasting cognitive, emotional, and behavioral deficits, there are frequently no overt morphological defects, suggesting that changes may result from alterations in the physiology of individual neurons. We investigated hippocampal neural activity in rats during a working memory task to determine the effect of mTBI on cellular physiology. Male Sprague-Dawley rats (300-350 g) underwent mTBI via lateral fluid percussion (1.5 atm), and were compared with sham-operated rats. The rats then underwent bilateral implantation of electrodes into the CA1 and CA3 hippocampal subfields and were trained to perform in a delayed nonmatch-to-place swim T-maze. Single-neuron activity was analyzed during task performance 30-90 days after trauma. There were no histological differences between control and mTBI rats. Stereological analysis demonstrated no neuronal loss. Nevertheless, rats subjected to mTBI demonstrated significantly poorer performance on the task with increasing delay. Examination of single-neuron spiking activity revealed no significant difference in firing rates or spike characteristics, but rats exposed to mTBI were found to have significantly fewer cells with activity spatiotemporally correlated with location in the maze ("task specific cells," p<0.05 by Fisher's exact test). Memory deficits, including disorganized patterns of hippocampal neural activity after mTBI, were seen in rats. Because it is seen in the absence of clear morphological defects, these data suggest that functional impairment after mTBI may result from alterations in the activity of individual neurons. PMID- 22229461 TI - Redox control of 20S proteasome gating. AB - The proteasome is the primary contributor in intracellular proteolysis. Oxidized or unstructured proteins can be degraded via a ubiquitin- and ATP-independent process by the free 20S proteasome (20SPT). The mechanism by which these proteins enter the catalytic chamber is not understood thus far, although the 20SPT gating conformation is considered to be an important barrier to allowing proteins free entrance. We have previously shown that S-glutathiolation of the 20SPT is a post translational modification affecting the proteasomal activities. AIMS: The goal of this work was to investigate the mechanism that regulates 20SPT activity, which includes the identification of the Cys residues prone to S-glutathiolation. RESULTS: Modulation of 20SPT activity by proteasome gating is at least partially due to the S-glutathiolation of specific Cys residues. The gate was open when the 20SPT was S-glutathiolated, whereas following treatment with high concentrations of dithiothreitol, the gate was closed. S-glutathiolated 20SPT was more effective at degrading both oxidized and partially unfolded proteins than its reduced form. Only 2 out of 28 Cys were observed to be S-glutathiolated in the proteasomal alpha5 subunit of yeast cells grown to the stationary phase in glucose-containing medium. INNOVATION: We demonstrate a redox post-translational regulatory mechanism controlling 20SPT activity. CONCLUSION: S-glutathiolation is a post translational modification that triggers gate opening and thereby activates the proteolytic activities of free 20SPT. This process appears to be an important regulatory mechanism to intensify the removal of oxidized or unstructured proteins in stressful situations by a process independent of ubiquitination and ATP consumption. Antioxid. Redox Signal. 16, 1183-1194. PMID- 22229462 TI - Photoacoustic sentinel lymph node imaging with self-assembled copper neodecanoate nanoparticles. AB - Photoacoustic tomography (PAT) is emerging as a novel, hybrid, and non-ionizing imaging modality because of its satisfactory spatial resolution and high soft tissue contrast. PAT combines the advantages of both optical and ultrasonic imaging methods. It opens up the possibilities for noninvasive staging of breast cancer and may replace sentinel lymph node (SLN) biopsy in clinic in the near future. In this work, we demonstrate for the first time that copper can be used as a contrast metal for near-infrared detection of SLN using PAT. A unique strategy is adopted to encapsulate multiple copies of Cu as organically soluble small molecule complexes within a phospholipid-entrapped nanoparticle. The nanoparticles assumed a size of 80-90 nm, which is the optimum hydrodynamic diameter for its distribution throughout the lymphatic systems. These particles provided at least 6-fold higher signal sensitivity in comparison to blood, which is a natural absorber of light. We also demonstrated that high SLN detection sensitivity with PAT can be achieved in a rodent model. This work clearly demonstrates for the first time the potential use of copper as an optical contrast agent. PMID- 22229463 TI - Editorial update on emerging drugs for cancer cachexia. AB - Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and weakness. It affects most patients with advanced cancers, reduces quality of life and accounts for more than 20% of all cancer related deaths. A number of promising therapies for cancer cachexia are in development, including appetite stimulants, anti-inflammatory drugs and those targeting catabolism. However, the multifactorial pathogenesis indicates strongly that the most effective treatments will come from drug combination approaches. Drug treatments should ideally be combined with exercise training to maximize efficacy and ultimately reduce mortality and enhance the quality of life of patients with cancer cachexia. PMID- 22229466 TI - The compact neutron spectrometer at ASDEX Upgrade. AB - The first neutron spectrometer of ASDEX Upgrade (AUG) was installed in November 2008. It is a compact neutron spectrometer (CNS) based on a BC501A liquid scintillating detector, which can simultaneously measure 2.45-MeV and 14-MeV neutrons emitted from deuterium (D) plasmas and gamma radiation. The scintillating detector is coupled to a digital pulse shape discrimination data acquisition (DPSD) system capable of count rates up to 10(6) s(-1). The DPSD system can operate in acquisition and processing mode. With the latter n-gamma discrimination is performed off-line based on the two-gate method. The paper describes the tests of the CNS and its installation at AUG. The neutron emission from the D plasma measured during a discharge with high auxiliary heating power was used to validate the CNS performance. The study of the optimal settings for the DPSD data processing to maximize the n-gamma discrimination capability of the CNS is reported. The CNS measured both 2.45-MeV and 14-MeV neutrons emitted in AUG D plasmas with a maximum count rate of 5.4 * 10(5) s(-1) (>10 times higher than similar spectrometers previously achieved) with an efficiency of 9.3 * 10( 10) events per AUG neutron. PMID- 22229473 TI - Reflex-free digital fundus photography using a simple and portable camera adaptor system. A viable alternative. AB - PURPOSE: To describe a digital single lens reflex (dSLR) camera adaptor for posterior segment photography. METHOD: A total of 30 normal canine and feline animals were imaged using a dSLR adaptor which mounts between a dSLR camera body and lens. Posterior segment viewing and imaging was performed with the aid of an indirect lens ranging from 28-90D. Coaxial illumination for viewing was provided by a single white light emitting diode (LED) within the adaptor, while illumination during exposure was provided by the pop-up flash or an accessory flash. Corneal and/or lens reflections were reduced using a pair of linear polarizers, having their azimuths perpendicular to one another. RESULTS: Quality high-resolution, reflection-free, digital images of the retina were obtained. Subjective image evaluation demonstrated the same amount of detail, as compared to a conventional fundus camera. A wide range of magnification(s) [1.2-4X] and/or field(s) of view [31-95 degrees, horizontal] were obtained by altering the indirect lens utilized. CONCLUSION: The described adaptor may provide an alternative to existing fundus camera systems. Quality images were obtained and the adapter proved to be versatile, portable and of low cost. PMID- 22229467 TI - Effective targeted gene delivery to dendritic cells via synergetic interaction of mannosylated lipid with DOPE and BCAT. AB - The efficient delivery of plasmids encoding antigenic determinants into dendritic cells (DCs) that control immune response is a promising strategy for rapid development of new vaccines. In this study, we prepared a series of targeted cationic lipoplex based on two synthetic lipid components, mannose-poly(ethylene glycol, MW3000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (Mannose-PEG3000 DSPE) and O-(2R-1,2-di-O-(1'Z-octadecenyl)-glycerol)-3-N-(bis-2-aminoethyl) carbamate (BCAT), that were formulated with 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine (DOPE) for evaluation as nonviral vectors for transgene expression in DCs. First, we optimized the N/P ratio for maximum transfection and then screened the effects of mannose targeting for further enhancement of transfection levels. Our results indicate that efficient delivery of gWIZ GFP plasmid into DCs was observed for mannose compositions of ~10%, whereas low transfection efficiencies were observed with nontargeted formulations. Mannose targeted lipofectamine complexes also showed high GFP expression levels in DCs relative to nontargeted lipofectamine controls. The best transfection performance was observed using 10 mol % Mannose-PEG3000-DSPE, 60 mol % BCAT, and 30 mol % DOPE, indicating that the most efficient delivery into DCs occurs via synergistic interaction between mannose targeting and acid-labile, fusogenic BCAT/DOPE formulations. Our data suggest that mannose-PEG3000-DSPE/BCAT/DOPE formulations may be effective gene delivery vehicles for the development of DC-based vaccines. PMID- 22229476 TI - Reversible regulation of protein binding affinity by a DNA machine. AB - We report a DNA machine that can reversibly regulate target binding affinity on the basis of distance-dependent bivalent binding. It is a tweezer-like DNA machine that can tune the spatial distance between two ligands to construct or destroy the bivalent binding. The DNA machine can strongly bind to the target protein when the ligands are placed at an appropriate distance but releases the target when the bivalent binding is disrupted by enlargement of the distance between the ligands. This "capture-release" cycle could be repeatedly driven by single-stranded DNA without changing the ligands and target protein. PMID- 22229477 TI - Combination of valproic acid and ATRA restores RARbeta2 expression and induces differentiation in cervical cancer through the PI3K/Akt pathway. AB - Epigenetic silencing of the tumor suppressor gene, RARbeta2, through histone deacetylation has been established as an important process of cervical carcinogenesis. This pivotal role has led to the suggestion that a combination of retinoids selective for RARbeta2 with histone deacetylase (HDAC) inhibitors may have therapeutic potential. Valproic acid (VPA), a HDAC inhibitor, has a critical role in the regulation of gene expression through histone acetylation and causes transformed cells to undergo growth arrest, differentiation, and apoptosis. Therefore, we hypothesized that the combination of VPA and ATRA could restore RARbeta2 expression, thus resulting in enhanced anti-neoplastic activity in cervical cancer. Here, we show that VPA combined with ATRA led to hyperacetylation of histone H3 and a significant alteration of gene expression in cervical cancer cells, including RARbeta2 gene expression, which was upregulated 50- to 90-fold. The combination therapy effectively inhibited the growth of cervical cancer cells more than the single agent treatment both in vitro and in vivo. The additive effects were associated with a significant upregulation of p21(CIP1) and p53 as well as a pronounced decrease in p-Stat3. Furthermore, the combined treatment led to cell cycle arrest predominantly at the G1 phase, and it preferentially induced cell differentiation rather than apoptosis in cervical cancer cells. The differentiation program was determined by the presence of E cadherinmediated adhesion and activation of the PI3K/Akt pathway. Taken together, these results provide new insight into the mechanisms of enhanced antitumor activity of the HDAC inhibitor and ATRA regimen, thus offering a new therapeutic strategy for cervical cancer patients. PMID- 22229478 TI - The effects of sildenafil on rectal sensitivity and tone in patients with the irritable bowel syndrome. AB - BACKGROUND: Visceral tone supposedly affects gut sensitivity in irritable bowel syndrome (IBS). Sildenafil increases nitric oxide and influences visceral compliance. AIM: To evaluate the effects of sildenafil tone inhibition on rectal sensitivity. METHODS: Eight controls and 21 IBS patients (Rome II) were enrolled in a double-blind study, after dosing with placebo or sildenafil (50 mg p.o.). Thresholds for first sensation, first desire to defecate, pain and supraliminar pain were the sensory endpoints, measured with a barostat and 600-mL rectal bag. Pain (100-mm VAS) and depression-anxiety (Hamilton questionnaire) were scored. RESULTS: Irritable bowel syndrome rectal compliance and sensory-endpoint thresholds were similar to controls. Five IBS patients had pain threshold lower than controls 95% confidence interval (hypersensitive). Depression score was greater in IBS than controls (11.9 +/- 1.3 vs. 6.3 +/- 2.5, P = 0.036). In IBS, pain intensity was nonsignificantly higher (37.6 +/- 5.3 mm vs. 23.4 +/- 8.5 mm, P = 0.064) and supraliminar pain intensity was greater (45.6 +/- 5.4 mm vs. 25.9 +/- 5.1 mm, P = 0.044) than controls. IBS rectal relaxation increased volume (155.4 +/- 41.3 mL vs. 118.8 +/- 47.7 mL, P = 0.004) and tension (193.1 +/- 118.6 mmHg mL(-1) vs. 133.2 +/- 98.1 mmHg mL(-1) , P = 0.019) for triggering first desire to defecate but not for other perceptions. Sildenafil increased volume for both first desire to defecate and pain in the hypersensitive IBS patients. Sildenafil increased rectal compliance only in diarrhoea-IBS. Mixed-IBS obtained higher anxiety (12.9 +/- 1.3 vs. 5.9 +/- 3.1, P < 0.05) and depression scores (13.9 +/- 1.9 vs. 6.3 +/- 2.5, P < 0.05) and reported more intense supraliminar pain (53.6 +/- 9.8 mm vs. 25.9 +/- 5.1 mm, P < 0.05) than controls. CONCLUSIONS: Rectal relaxation following dosing with sildenafil 50 mg increased the first desire to defecate threshold in IBS as a whole, but decreased pain only in the hypersensitive subset. Mixed-IBS presented higher supraliminar pain and anxiety depression scores. PMID- 22229479 TI - Integration of geometric separation mechanisms by implementing curved constrictions in a biochip microchannel fluidic separator. AB - This paper investigates the effectiveness of using curved constrictions in the bifurcation region of T-type fluid separators for promoting flow development in the intervals between bifurcations. A design of biofluid separator is proposed and a mathematical analysis and a numerical simulation of the blood flow in microchannels are conducted. The design is based on a modification of an existing T-shaped biochip device which consists of a main channel and a series of perpendicularly positioned side channels. By means of bifurcation effect, the blood is separated into plasma concentration flow from the side channels and blood cell concentration flow from the main channel. In this design, curved constrictions are inserted between bifurcations to replace the original straight channel section, so that the constriction and curved channel effects can be induced apart from the existing bifurcation effect. The mathematical analysis is aimed to the flow field and shear stress of the blood fluid in the microchannel geometries employed in the current design, including bifurcation, constriction and curved channel. The numerical simulation and mathematical analysis result in agreed conclusions, giving some insights into the importance of the relevant geometries in promoting biofluid separation. The main results can be summarised as follows: (i) the constrictions can largely increase the shear stress by the ratio of square of the reduction of the sections between the constriction and parent main channel. (ii) The curved channel intervals can induce centrifugal force, smoothly transit the flow field and increase the chances depleting fluid from the cell-free layer. (iii) The thickness of the boundary layer skimmed into the side channels from the main channel is decreased in this design and can be controlled, falling into the cell-free layer region by adjusting the geometry of the side channels. PMID- 22229480 TI - C-reactive protein and nitric oxide level in patients with white coat hypertension. AB - BACKGROUND: There are controversial results regarding the endothelial function in patients with white coat hypertension (WCH). The aim of this study was to assess endothelial function measuring nitric oxide (NO) and C-reactive protein (CRP) level in WCH and to compare those with essential hypertension (EH) and healthy subjects. METHODS: The 40 newly diagnosed patients with EH, 40 patients with WCH and 40 healthy volunteers were included to study. Plasma CRP levels were measured by immunonephelometery method. Plasma NO level was also detected by using the Griess method. RESULTS: Plasma CRP level was significantly higher in patients with EH when compared with those with WCH and healthy subjects (6.3 +/- 2.1 mg/l, 2.1 +/- 0.9 mg/l and 1.6 +/- 1.3 mg/l, p < 0.05, respectively). However, there was no significant difference with respect to CRP level between those with WCH and healthy subjects. NO level was significantly lower in patients with EH when compared with those with WCH and healthy subjects (4.6 +/- 1.1 umol/l, 6.9 +/- 1.2 umol/l and 8.1 +/- 1.5 umol/l, p < 0.05, respectively). There was no significant difference with respect to NO level between those with WCH and healthy subjects. Plasma CRP level was positively correlated with office, daytime, night-time and 24-h blood pressure values, whereas NO level was inversely correlated with these parameters. Plasma CRP level was also inversely correlated with NO level. CONCLUSIONS: Our data suggest that CRP concentration is significantly higher and NO level is meaningfully lower in patients with essential hypertension when compared with those with WCH and controls. This may suggest that endothelial functions are preserved in patients with WCH in contrast to essential hypertension. PMID- 22229481 TI - Rheophysical properties of fluorinated nonionic micellar phases. AB - Micellar phases can be used as templates for the preparation of mesoporous silica materials. Fluorinated and hydrogenated surfactants can provide a large variety of well-defined micellar structures: spherical and cylindrical micelles as well as more complex structures such as lamellar or sponge phases can be formed in various thermodynamic conditions. However, the preparation of ordered mesoporous materials from these organized media is not always successful for a reason not known at the moment. It thus seems of the highest importance to properly characterize the micellar solution prior to the addition of the silica precursor during the material synthesis. In this paper, we describe some rheophysical properties of the micellar phase L(1) prepared with a fluorinated surfactant, the formula of which is C(7)F(15)C(2)H(4)(OC(2)H(4))(8)OH, labeled as R(F)(7)(EO)(8). This surfactant forms micelles in water, and the direct micellar phases have been characterized in a wide range of temperatures and surfactant concentrations. The rheological properties of the L(1) phase have also been studied as a function of temperature and concentration. Under steady and dynamic flow conditions, the solutions behave like Newtonian or shear thinning fluids depending on the temperature and surfactant concentration. A crossover between G' and G" is observed in the solution at the concentration of 20 wt % and at the temperature of 10 degrees C, suggesting the presence of long entangled micelles in solution at this temperature. When subjected to the action of a shearing device, the 20 wt % solution becomes optically anisotropic and shows flow birefringence, but the average orientation of the micelles quantified by the extinction angle chi shows an unexpected behavior when the shear rate is gradually increased. PMID- 22229482 TI - The use of ranolazine to facilitate electrical cardioversion in cardioversion resistant patients: a case series. AB - BACKGROUND: Occasionally atrial fibrillation (AF) is resistant to electrical cardioversion (EC). Ranolazine (RZ) is an antianginal agent, which inhibits abnormal late Na(+) channel currents in cardiomyocytes and decreases Na(+) /Ca(++) overload. RZ is a potent inhibitor of after-depolarizations and triggered activity and prolongs atrial refractory periods. We postulated RZ could facilitate EC in patients resistant to EC. METHODS: Over a 3-year period, we identified 25 EC-resistant patients who had been administered oral RZ shortly after failing attempted EC. The anterior-posterior cardioversion approach was used and each patient had failed to be restored to sinus rhythm despite using up to the maximum output of a biphasic cardioversion device. Repeat EC was performed 3.5-4 hours after administration of 2 g of oral RZ using the same device, sedation, and lead placement. RESULTS: Sinus rhythm was successfully restored in 19 (76%) of 25 EC-resistant patients. Three patients spontaneously converted before the second attempt at EC within 4 hours of the RZ dose. Of the 22 patients undergoing another attempt at EC, 16 were successfully converted to sinus rhythm. Five of the six patients who were refractory to repeat EC despite RZ had AF of unknown duration and each is now in permanent AF. No adverse effects were noted. CONCLUSION: RZ shows promise as a safe and convenient agent to facilitate EC in EC-resistant patients. It appears to be most effective in patients whose AF duration is known to be less than 3 months. PMID- 22229483 TI - Randomized controlled trial of a lay-facilitated angina management programme. AB - AIMS: This article reports a randomized controlled trial of lay-facilitated angina management (registered trial acronym: LAMP). BACKGROUND: Previously, a nurse-facilitated angina programme was shown to reduce angina while increasing physical activity, however most people with angina do not receive a cardiac rehabilitation or self-management programme. Lay people are increasingly being trained to facilitate self-management programmes. DESIGN: A randomized controlled trial comparing a lay-facilitated angina management programme with routine care from an angina nurse specialist. METHODS: Participants with new stable angina were randomized to the angina management programme (intervention: 70 participants) or advice from an angina nurse specialist (control: 72 participants). Primary outcome was angina frequency at 6 months; secondary outcomes at 3 and 6 months included: risk factors, physical functioning, anxiety, depression, angina misconceptions and cost utility. Follow-up was complete in March 2009. Analysis was by intention-to-treat; blind to group allocation. RESULTS: There was no important difference in angina frequency at 6 months. Secondary outcomes, assessed by either linear or logistic regression models, demonstrated important differences favouring the intervention group, at 3 months for: Anxiety, angina misconceptions and for exercise report; and at 6 months for: anxiety; depression; and angina misconceptions. The intervention was considered cost-effective. CONCLUSION: The angina management programme produced some superior benefits when compared to advice from a specialist nurse. PMID- 22229484 TI - The costs of centralisation: a systematic review of the economic impact of the centralisation of cancer services. AB - While evidence suggests that within specific cancer sites centralisation of services improves outcomes and quality of care, the economic impact of centralisation is unclear. This systematic review identified 19 studies that have investigated whether or not the centralisation of cancer services results in economies of scale, or is cost-effective, or increases the costs of accessing care for patients and their carers. Evidence from 13 studies suggests that increasing surgeon volumes are associated with cost reductions, although one study suggested that this relationship is U-shaped and the evidence is not consistent for hospital volumes and costs. Only one study demonstrated that centralisation was cost-effective with an incremental cost utility ratio of $5029 (?3616) per quality-adjusted life year gained. Consistent evidence from four studies suggested that centralised services increase the costs of accessing care for patients and their carers. Current evidence on the economic impact of centralisation of cancer services is limited and of poor quality. Therefore, it remains unclear whether centralisation results in economies of scale and is cost effective. Future research should be based on a clear definition of the different components of centralisation in order to determine which aspects of centralisation are efficient and for which cancer subgroups. PMID- 22229487 TI - Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). AB - We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS. PMID- 22229486 TI - Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) manifests with cutaneous lesions consisting of yellowish papules coalescing into plaques of inelastic skin. Histopathology demonstrates accumulation of pleiomorphic elastic structures with progressive mineralization. The classic form of PXE is caused by mutations in the ABCC6 gene. OBJECTIVES: A 2-year-old patient with PXE of the neck, inguinal folds and lower abdomen, and with extensive tissue mineralization, was evaluated for the underlying mutations in candidate genes known to be involved in ectopic mineralization disorders. METHODS: The patient's genotype was studied by sequencing ABCC6, MGP and ENPP1 genes, encoding proteins which harbour mutations in ectopic mineralization disorders. RESULTS: No pathogenetic mutations were found in the ABCC6 or MGP genes. Sequencing of ENPP1 disclosed a homozygous missense mutation, p.Y513C, associated with generalized arterial calcification of infancy. CONCLUSIONS: This study demonstrates the presence of the cutaneous features of PXE in a genetically distinct disease, generalized arterial calcification of infancy, and thus expands the spectrum of PXE-related disorders. PMID- 22229488 TI - On the redox control of B lymphocyte differentiation and function. AB - SIGNIFICANCE: On the one hand, redox emerges as a key mechanism in regulating intra- and intercellular signaling and homeostatic systems. On the other hand, cells of the B lineage provide powerful systems to unravel the intra- and intercellular mechanisms that coordinate the processes of development and terminal differentiation. RECENT ADVANCES: This essay summarizes a few paradigmatic examples of redox regulation and signal modulation that emerged from, or were confirmed by, studies on the development, differentiation and function of B cells. CRITICAL ISSUES: While a role for intra- and intercellular redox signaling has been firmly established for differentiating B cells, many fundamental questions remain open, including the cellular sources of reactive oxygen species (ROS), the spatial and temporal constraints of ROS signaling, and the functional role of the antioxidant response. FUTURE DIRECTIONS: Given their robustness and biotechnological and clinical interest, cells of the B lineage continue to be fruitful goldmines from which redox biologists can dig novel mechanistic knowledge of general relevance. PMID- 22229489 TI - Multidimensional vector model of stimulus-response compatibility. AB - The present study proposes and examines the multidimensional vector (MDV) model framework as a modeling schema for choice response times. MDV extends the Thurstonian model, as well as signal detection theory, to classification tasks by taking into account the influence of response properties on stimulus discrimination. It is capable of accounting for stimulus-response compatibility, which is known to be an influential task variable determining choice-reaction performance but has not been considered in previous mathematical modeling efforts. Specific MDV models were developed for 5 experiments using the Simon task, for which stimulus location is task irrelevant, to examine the validity of model assumptions and illustrate characteristic behaviors of model parameters. The MDV models accounted for the experimental data to a remarkable degree, demonstrating the adequacy of the framework as a general schema for modeling the latency of choice performance. Some modeling issues involved in the MDV model framework are discussed. PMID- 22229490 TI - Modeling cross-situational word-referent learning: prior questions. AB - Both adults and young children possess powerful statistical computation capabilities--they can infer the referent of a word from highly ambiguous contexts involving many words and many referents by aggregating cross-situational statistical information across contexts. This ability has been explained by models of hypothesis testing and by models of associative learning. This article describes a series of simulation studies and analyses designed to understand the different learning mechanisms posited by the 2 classes of models and their relation to each other. Variants of a hypothesis-testing model and a simple or dumb associative mechanism were examined under different specifications of information selection, computation, and decision. Critically, these 3 components of the models interact in complex ways. The models illustrate a fundamental tradeoff between amount of data input and powerful computations: With the selection of more information, dumb associative models can mimic the powerful learning that is accomplished by hypothesis-testing models with fewer data. However, because of the interactions among the component parts of the models, the associative model can mimic various hypothesis-testing models, producing the same learning patterns but through different internal components. The simulations argue for the importance of a compositional approach to human statistical learning: the experimental decomposition of the processes that contribute to statistical learning in human learners and models with the internal components that can be evaluated independently and together. PMID- 22229492 TI - Using E-Z Reader to simulate eye movements in nonreading tasks: a unified framework for understanding the eye-mind link. AB - Nonreading tasks that share some (but not all) of the task demands of reading have often been used to make inferences about how cognition influences when the eyes move during reading. In this article, we use variants of the E-Z Reader model of eye-movement control in reading to simulate eye-movement behavior in several of these tasks, including z-string reading, target-word search, and visual search of Landolt Cs arranged in both linear and circular arrays. These simulations demonstrate that a single computational framework is sufficient to simulate eye movements in both reading and nonreading tasks but also suggest that there are task-specific differences in both saccadic targeting (i.e., decisions about where to move the eyes) and the coupling between saccadic programming and the movement of attention (i.e., decisions about when to move the eyes). These findings suggest that some aspects of the eye-mind link are flexible and can be configured in a manner that supports efficient task performance. PMID- 22229493 TI - The law of categorical judgment (corrected) extended: a note on Rosner and Kochanski (2009). AB - Rosner and Kochanski (2009) noticed an inconsistency in the mathematical statement of the Law of Categorical Judgment and derived "the valid equation, the Law of Categorical Judgment (Corrected)" (p. 125). The purpose of this comment is to point out that the law can be corrected in many different ways, leading to substantially different equations. The different versions have different consequences for the predicted distributions of the responses and, hence, for fitting real data. Some of these consequences are unexpected and sometimes undesirable. Researchers should be aware of the different possibilities as they may lead to pronouncedly different accounts of given data. PMID- 22229495 TI - Teaching single-cell digital analysis using droplet-based microfluidics. AB - Microfluidics allows the manipulation of small quantities of reagents in a high throughput manner and is therefore highly amenable to single cell characterization and more generally to digital analysis, with applications in fields as varied as genomics, diagnostics, directed evolution, and drug screening. The growing place of microfluidics in biology laboratories encouraged us to develop a teaching method where advanced undergraduate or first-year graduate-level students are taught to fabricate droplet-based microfluidic devices, characterize them, and finally use them to perform a digital analysis of bacterial samples based on a phenotypic marker. PMID- 22229491 TI - Goal-directed decision making as probabilistic inference: a computational framework and potential neural correlates. AB - Recent work has given rise to the view that reward-based decision making is governed by two key controllers: a habit system, which stores stimulus-response associations shaped by past reward, and a goal-oriented system that selects actions based on their anticipated outcomes. The current literature provides a rich body of computational theory addressing habit formation, centering on temporal-difference learning mechanisms. Less progress has been made toward formalizing the processes involved in goal-directed decision making. We draw on recent work in cognitive neuroscience, animal conditioning, cognitive and developmental psychology, and machine learning to outline a new theory of goal directed decision making. Our basic proposal is that the brain, within an identifiable network of cortical and subcortical structures, implements a probabilistic generative model of reward, and that goal-directed decision making is effected through Bayesian inversion of this model. We present a set of simulations implementing the account, which address benchmark behavioral and neuroscientific findings, and give rise to a set of testable predictions. We also discuss the relationship between the proposed framework and other models of decision making, including recent models of perceptual choice, to which our theory bears a direct connection. PMID- 22229496 TI - Population-based comparative epidemiological survey of hepatitis B, D, and C among Inuit migrated to Denmark and in high endemic Greenland. AB - OBJECTIVE: Infection with hepatitis B virus (HBV) is endemic among Arctic populations where it may have a benign course. However, the relation of HBV to migration to low endemic areas is unknown, as it is for hepatitis D and C, and details on the influence of delta virus at a population level are lacking. MATERIAL AND METHODS: Population-based investigation of Greenlanders living in Denmark (n = 136) and in Greenland (n = 441). We tested for HBsAg, anti-HBs, anti HBc, HBeAg, anti-HBe, HBV-DNA, HBV genotypes, anti-HDV, HDV-RNA, anti-HCV, HCV Elisa test, HCV-RNA, aspartate aminotransferase, gamma-glutamyl transferase, bilirubin, and albumin, and performed a physical examination. RESULTS: Participation rate was 52/95% in Denmark/Greenland. Half of participants in Denmark had lived more than half of their lives in Denmark, and 54.5% had been exposed to HBV. This was similar to 53% among Greenlanders living in West Greenland (p = 0.76). HBsAg was positive in 4.4% of Greenlanders in Denmark (n = 6), who all were anti-HBe positive and had low viral load. Serological signs of HBV infection associated with having both parents born in Greenland (p = 0.007) and with IV drug use (p = 0.03). We found serological signs of HDV exposure among participants in Denmark/Greenland in 0.7/1.1% (n = 1/5) and HCV exposure in 1.5/0.0% (n = 2/0). Liver biochemistry was elevated in Greenlanders exposed to HDV. CONCLUSIONS: Hepatitis B, D, and C occurrences among Greenlanders in Denmark mirrored that of Greenland. Importantly, previously undetected exposure to delta virus associated with elevated liver biochemistry, and the introduction of delta virus is a liability to Greenlanders and to Greenland. PMID- 22229497 TI - Insights into the conformational switching mechanism of the human vascular endothelial growth factor receptor type 2 kinase domain. AB - Human vascular endothelial growth factor receptor type 2 (h-VEFGR2) is a receptor tyrosine kinase involved in the angiogenesis process and regarded as an interesting target for the design of anticancer drugs. Its activation/inactivation mechanism is related to conformational changes in its cytoplasmatic kinase domain, involving first among all the alphaC-helix in N-lobe and the A-loop in C-lobe. Affinity of inhibitors for the active or inactive kinase form could dictate the open or closed conformation of the A-loop, thus making the different conformations of the kinase domain receptor (KDR) domain different drug targets in drug discovery. In this view, a detailed knowledge of the conformational landscape of KDR domain is of central relevance to rationalize the efficiency and selectivity of kinase inhibitors. Here, molecular dynamics simulations were used to gain insight into the conformational switching activity of the KDR domain and to identify intermediate conformations between the two limiting active and inactive conformations. Specific energy barriers have been selectively removed to induce, and hence highlight at the atomistic level, the regulation mechanism of the A-loop opening. The proposed strategy allowed to repeatedly observe the escape of the KDR domain from the DFG-out free energy basin and to identify rare intermediate conformations between the DFG-out and the DFG-in structures to be employed in a structure-based drug discovery process. PMID- 22229499 TI - Transparent films based on PLA and montmorillonite with tunable oxygen barrier properties. AB - Polylactide (PLA) is viewed as a potential material to replace synthetic plastics (e.g., poly(ethylene terephthalate) (PET)) in food packaging, and there have been a number of developments in this direction. However, for PLA to be competitive in more demanding uses such as the packaging of oxygen-sensitive foods, the oxygen permeability coefficient (OP) needs to be reduced by a factor of ~10. To achieve this, a layer-by-layer (Lbl) approach was used to assemble alternating layers of montmorillonite clay and chitosan on extruded PLA film surfaces. When 70 bilayers were applied, the OP was reduced by 99 and 96%, respectively, at 20 and 50% RH. These are, to our knowledge, the best improvements in oxygen barrier properties ever reported for a PLA/clay-based film. The process of assembling such multilayer structures was characterized using a quartz crystal microbalance with dissipation monitoring. Transmission electron microscopy revealed a well-ordered laminar structure in the deposited multilayer coatings, and light transmittance results demonstrated the high optical clarity of the coated PLA films. PMID- 22229501 TI - Topical nitrogen mustard therapy in patients with mycosis fungoides or parapsoriasis. AB - BACKGROUND: Topical nitrogen mustard is a chemotherapeutic agent used in treatment of mycosis fungoides (MF). OBJECTIVE: To evaluate the response and side effects in patients with MF and parapsoriasis treated with topical nitrogen mustard. METHODS: A retrospective study of treatment response in 116 patients diagnosed with MF and 71 patients with parapsoriasis and treated with topical nitrogen mustard from 1991 to 2009. RESULTS: Overall response rate and complete response (CR) rate was 91.4% and 53.4% in patients with MF and 90.1% and 40.8% in patients with parapsoriasis, respectively. Relapse following CR was observed in 67.7% in patients with MF and 62.1% in patients with parapsoriasis. Freedom-from relapse was higher in patients with T1-T2 than in T3 disease (P < 0.01). Progressive disease (PD) occurred in 25.0% and 26.8% in patients with MF and parapsoriasis, respectively. Progression-free survival was similar in patients with T1-T2 compared with T3 (P = 0.79) and T4 disease (P = 0.22) and lower in patients with parapsoriasis with <10% than >10% skin involvement (P = 0.05). CONCLUSION: The present study confirms that topical nitrogen mustard is a safe and effective therapy. The treatment response in patients with parapsoriasis was not statistically different from the response in patients with MF. This supports, that parapsoriasis is not a distinct entity, but an early stage of MF. Nitrogen mustard should therefore still be considered as an important treatment modality in patients with early stages (parapsoriasis) and later stages of MF either as monotherapy or in combination with other topical or systemic therapies. PMID- 22229502 TI - When smoke gets in your eyes. PMID- 22229503 TI - Cross-polarisation, making it practical. AB - The author investigated the use of cross-polarisation for day-to-day practice after a request from a clinician to remove specular highlights from intra-oral photographs. The paper evaluates camera and light source devices for image capture using cross-polarisation. Following this it defines ways to calibrate the camera to the correct white balance. It then develops by carrying out a series of tests to define the point of influence in regard to signal-to-noise ratio. These tests showed that the anti-aliasing filters of some cameras are more prominent than others and therefore can have a significant affect. In conclusion, when the appropriate equipment is employed, cross-polarisation is a viable and practical technique that has application within the medical, scientific, and forensic fields. PMID- 22229504 TI - No case of exercise-associated hyponatremia in male ultra-endurance mountain bikers in the 'Swiss Bike Masters'. AB - Exercise-associated hyponatremia (EAH) has mainly been investigated in runners and triathletes. In mountain bikers, EAH was studied in two multi-stage races, but not in a single stage race. The aim of this study was to investigate the prevalence of EAH in a single-stage mountain bike ultra-marathon. In the 'Swiss Bike Masters' over 120 km with a climb of ~ 5,000 m in altitude, we determined pre and post race body mass, hematocrit, plasma sodium concentration ([Na+]), and urinary specific gravity in 37 cyclists. Athletes recorded their fluid intake while racing. No athlete developed EAH. The cyclists drank on average (means +/- SD) 0.7 +/- 0.2 l/h. Fluid intake was significantly and negatively related to race time (r = -0.41, P < 0.05), but showed no association with post race plasma [Na+], the change in plasma [Na+], post race body mass, or the change in body mass. The athletes lost 1.4 kg body mass (P < 0.05), plasma [Na+] decreased by 0.7% (P < 0.05), plasma volume increased by 1.4% and urinary specific gravity increased by 0.4% (P < 0.05). The change in body mass was neither related to post race plasma [Na+] nor to the change in plasma [Na+]. The decrease in plasma [Na+] was not related to fluid intake. The change in plasma [Na+] was related to post race plasma [Na+] (r = 0.40, P < 0.01). Ad libitum fluid intake showed no case of EAH in a single-stage mountain bike ultra-marathon. In contrast to previous findings, the faster athletes drank more than the slower ones. PMID- 22229505 TI - Evaluation of gender-related differences in various oxidative stress enzymes in mice. AB - Oxidative stress caused by redundant free radical, lipid oxygen and peroxide usually results in the pathogenesis of various diseases, which can be alleviated by cellular antioxidant enzymes. According to statistics, there are different incidence rates of some diseases depending on the gender. The present study aimed to investigate potential gender-related differences of antioxidant enzymes in mice. The activities of glutamate-cysteine ligase (GCL), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) in the kidney, brain, lung and heart of both male and female mice were determined. Our results showed that GPx and GCL activities were higher in female kidney and brain than those in male. On the other hand, the activities of SOD were higher in female brain and lung than those in male. Moreover, female kidney appeared to show higher activities of CAT than the male kidney. But the activities of GCL and GPx were higher in male heart than those in female. Taken together, our results demonstrate that there are gender related differences in the activities of cellular antioxidant enzymes in various important organs in mice. Variations in such enzymes may be the explanation for some gender-related diseases. PMID- 22229506 TI - Directional effect on post-stroke motor overflow characteristics. AB - Motor overflow (MO) is an involuntary muscle activation associated with strenuous contralateral movement and may become manifested after stroke. The study was undertaken to investigate physiological correlation underlying atypical directional effect of joint movement on post-stroke MO in the affected upper limb. Thirty patients with unilateral post-stroke hemiparesis and fifteen age matched healthy controls participated in this study. According to motor function assessed with the Fugl-Meyer arm scale, the patients were categorized into two groups of equal number with better (CVA_G; n = 15) or poorer motor functions (CVA_P; n = 15). Surface electromyography (EMG) was used to record irradiated muscle activation from eight muscles of the affected upper limb when the subjects performed maximal isometric contractions in different directions with the unaffected shoulder, elbow and wrist joints. The results showed that only MO amplitude of the CVA_G and the control groups was more sensitive to variations in direction of joint movement in the unaffected arm than the CVA_P group. The CVA_G group exhibited larger amplitudes of MO than the control analog, whereas this tendency was reversed for the CVA_P group. In terms of EMG polar plots, spatial representations of post-stroke MO were insensitive to direction of contralateral movement. The spatial representations of the CVA_G and CVA_P groups were predominated by potent flexion-abduction synergy, contrary to the typical extension adduction synergy seen in the control analog. In conclusion, post stroke MO amplitude was subject to contralateral movement direction for healthy controls and stroke patients with better motor recovery. However, alterations in MO spatial pattern due to directional effect were not strictly related to the degree of motor deficits of the stroke victims. PMID- 22229507 TI - Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity. AB - An increasing number of studies has indicated that hypoxic-ischemic-induced cerebral injury is partly mediated via oxidative stress. Recent researches have focused on searching for drug and herbal manipulations to protect against hypoxic ischemic-induced oxidative cell damage. Scutellarin is a flavonoid derived from the Erigeron breviscapus (vant.) and has been reported to exhibit neuroprotective properties. However, its precise mechanism, particularly its antioxidation mechanism, remains elusive. In the present study, we investigated the neuroprotective effects of scutellarin on middle cerebral artery occlusion (MCAO) induced brain damage in rats, and oxygen-glucose deprivation (OGD)-induced toxicity in primary culture of rat cortical neurons. In vivo, intraperitoneal injections of scutellarin (20 and 60 mg/kg) improved the neurological score and diminished the percentage of brain infarct volume. At the same time, scutellarin significantly increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) level in ischemic brain tissues, enhancing endogenous antioxidant activity. Moreover, pretreatment of scutellarin (25, 50 and 100 MUM) protected neurons against lethal stimuli, decreased the percentage of apoptotic cells and inhibited reactive oxygen species (ROS) generation in OGD-induced primary cortical neurons in vitro. These results suggest that the preventive and therapeutic potential of scutellarin in cerebral injury patients is, at least in part, ascribed to augmentation of cellular antioxidant defense capacity. PMID- 22229508 TI - Resveratrol protects left ventricle by increasing adenylate kinase and isocitrate dehydrogenase activities in rats with myocardial infarction. AB - Our prior study had shown that resveratrol was a potent cardioprotective agent in rats with myocardial infarction (MI). In this study, we further evaluated the mechanism of cardioprotection of resveratrol by proteomic analysis. After permanent ligation of the left anterior descending artery under isoflurane anesthesia, surviving rats were randomly allocated to three groups and treated with resveratrol at 1 mg/kg/day (MI/R group), or vehicles (sham group and MI group) once daily for four weeks. In proteomic analysis, the MI group showed decreased expression of adenylate kinase 1 (AK1) and mitochondrial NADP+ dependent isocitrate dehydrogenase (IDPm) after MI compared with the sham group. These variations were reversed by resveratrol in the MI/R group. Validation with Western blot and immunohistochemical analyses showed similar trends in protein expression profiling. Our studies suggest that the beneficial effects of resveratrol on ventricular modeling may be due to increased expression of AK1 and IDPm, which have been known to increase myocardial energetic efficiency and reduce reactive oxygen species-mediated damage, respectively. PMID- 22229509 TI - Association between Ataxia Telangiectasia Mutated gene polymorphisms and childhood leukemia in Taiwan. AB - The ataxia telangiectasia mutated (ATM) gene plays a major role in repairing the double-strand breaks and maintaining the genome stability. In this case-control study, associations of seven ATM single-nucleotide polymorphisms (rs600931, rs189037, rs652311, rs624366, rs228589, rs227092 and rs227060) with risks in childhood leukemia in a Taiwanese population were investigated. Two hundred and sixty-six patients with childhood leukemia and 266 age-matched healthy controls recruited were genotyped and analyzed. The P-values of the distributions of the genotypic frequencies in the seven ATM polymorphisms were 0.8925, 0.2835, 0.5772, 0.8731, 0.3641, 0.9181 and 0.5071, respectively. The Pvalues of the distributions of the allelic frequencies in the seven ATM polymorphisms were 0.6158, 0.1179, 0.6971, 0.7944, 0.1887, 0.6605 and 0.2747, respectively. Although the results did not indicate that ATM polymorphism is directly associated with childhood leukemia, the gene-gene and gene-environment interactions of ATM with other factors is worthy of further investigation in the future. PMID- 22229510 TI - Involvement of nitric oxide in mesenteric vascular reactivity following intraperitoneal pancreatic juice in rats. AB - The purposes of this study were to examine the protein expressions of endothelial and inducible nitric oxide synthase (eNOS and iNOS) of the rat intestinal smooth muscle, and to elucidate the role of nitric oxide (NO) in the reactivity of the superior mesenteric artery (SMA) to vasoconstrictors following intraperitoneal (i.p.) injection of pancreatic juice. Immunohistochemistry was used to observe the protein expressions of eNOS and iNOS in the intestinal tissues 15 h after i.p. injection of pancreatic juice (1 ml/100 g body weight). To test the vascular reactiveness, SMA was isolated and perfused with Tyrode's solution at a constant flow rate of 5 ml/min. The changes in perfusion pressure as the measure of contractile responses to phenylephrine (PE) were monitored. I.P. injection of pancreatic juice induced increases of plasma levels of tumor necrosis factor alpha (TNFalpha) (P < 0.001; N = 7) and NO (P < 0.001; N = 7). Nomega-nitro-L arginine methyl ester (L-NAME) reduced the release of TNFalpha and NO. There were 8.3 +/- 1.2-fold and 11.4 +/- 2.8-fold increases in the protein expressions of eNOS and iNOS, respectively, in the intestinal tissue after pancreatic juice injection. PE (10-8 ~ 10-4 M) produced a dose-dependent vasoconstrictive effects on the SMA bed. Contractile responses to PE were attenuated in pancreatic juice treated group. Addition of L-NAME (10-4 M) resulted in full recovery of the responses to phenylephrine in SMA bed, while aminoguanidine (AG, 10-4 M) caused only partial recovery. Our results indicate that i.p. injection of pancreatic juice results in a decrease in vascular reactivity of mesenteric vessels that is dependent on both eNOS and iNOS expressions in the intestinal vascular bed. Overproduction of NO elicits intestinal low vascular reactivity. PMID- 22229511 TI - Vulnerability in simulated ischemic ventricular transmural tissues. AB - Vulnerability is an effective index to evaluate increased risk for unidirectional conduction block and reentry in hearts. Recent reports in animal experiments have indicated an opposite characteristics of the vulnerability in normal and ischemic transmural tissues. In order to clarify the differences and to investigate the mechanisms, a computer simulation method was used in this study to investigate the vulnerability relative to the premature pacing sites in normal and ischemic transmural tissues. Endo-, mid- and epi-cardial myocytes incorporating different severities of ischemia were developed across a tissue strand. The sodium channel inactivation gating variable h was calculated to provide the degree of sodium current recovery preceding the premature pacing. In the normal tissue, the measured vulnerable window was demonstrated to be wider by delivering an endocardial premature beat than that by applying an epicardial premature pacing. On the contrary, during ischemia the epicardium showed a wider vulnerable window than the endocardium. The results illustrated that during ischemia h decreased with accumulation of [K+]o, and action potential duration dispersion was obviously altered due to anoxia. In contrast, the elevated [K+]o was suggested to play an important role in the difference of the location-dependent vulnerability in normal and ischemic tissues. PMID- 22229512 TI - Effects of ulinastatin, a urinary trypsin inhibitor, on synaptic plasticity and spatial memory in a rat model of cerebral ischemia/reperfusion injury. AB - Established therapies for cerebral ischemia-reperfusion injury are currently limited. The urinary trypsin inhibitor ulinastatin (UTI) is considered cytoprotective against ischemia-reperfusion injury in internal organs through its anti-inflammatory activity. We aimed to investigate the neuroprotective effects of UTI on learning and memory of rats after cerebral ischemia-reperfusion injury. Rats were treated with UTI at 10,000 U/kg body weight, then underwent ischemia and reperfusion by the middle cerebral arterial occlusion (MCAO) method. At various times after the onset of reperfusion, we evaluated neurologic impairment scores. Brain sections underwent immunohistochemical staining for synaptophysin and calcium-binding protein S100beta. Other rats underwent the Morris water maze test to determine the effects of UTI on learning and memory. Spatial reference learning and memory were improved with UTI treatment by down-regulating S100beta positive cells and preventing the loss of neural cells. Thus, UTI has a neuroprotective role on synaptic plasticity and spatial memory with cerebral ischemia-reperfusion injury in rats. PMID- 22229513 TI - Review article: the pathophysiology and management of gastrointestinal symptoms during physical exercise, and the role of splanchnic blood flow. AB - BACKGROUND: The prevalence of exercise-induced gastrointestinal (GI) symptoms has been reported up to 70%. The pathophysiology largely remains unknown. AIM: To review the physiological and pathophysiological changes of the GI-tract during physical exercise and the management of the most common gastrointestinal symptoms. METHODS: Search of the literature published in the English and Dutch languages using the Pubmed database to review the literature that focused on the relation between splanchnic blood flow (SBF), development of ischaemia, postischaemic endotoxinemia and motility. RESULTS: During physical exercise, the increased activity of the sympathetic nervous system (SNS) redistributes blood flow from the splanchnic organs to the working muscles. With prolonged duration and/or intensity, the SBF may be decreased by 80% or more. Most studies point in the direction of increased SNS-activity as central driving force for reduction in SBF. A severely reduced SBF may frequently cause GI ischaemia. GI-ischaemia combined with reduced vagal activity probably triggers changes in GI-motility and GI absorption derangements. GI-symptoms during physical exercise may be prevented by lowering the exercise intensity, preventing dehydration and avoiding the ingestion of hypertonic fluids. CONCLUSIONS: Literature on the pathophysiology of exercise-induced GI-symptoms is scarce. Increased sympathetic nervous system activity and decreased splanchnic blood flow during physical exercise seems to be the key factor in the pathogenesis of exercise-induced GI-symptoms, and this should be the target for symptom reduction. PMID- 22229515 TI - Polymorphism near the ATP2B1 gene is associated with hypertension risk in East Asians: a meta-analysis involving 15 909 cases and 18 529 controls. AB - OBJECTIVE: Recent genome-wide association studies showed that the rs2681472 polymorphism near the ATP2B1 gene was associated with hypertension susceptibility in Europeans. Subsequently, several studies have investigated the association among East Asian populations. However, the results have been inconsistent. In this study, a meta-analysis was performed to assess the association of the ATP2B1 rs2681472 polymorphism with hypertension risk in East Asians. METHODS: Published literature from PubMed, ISI Web of Science and Embase databases were retrieved. All studies evaluating the association between rs2681472 (rs17249754 or rs11105378) and hypertension risk in East Asians were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random effects model. RESULTS: Seven studies (15 909 cases/18 529 controls) were identified. The results suggested that rs2681472 was significantly associated with hypertension risk in East Asians (OR = 1.18, 95% CI 1.10-1.27, p = 0.000). Sensitivity analysis confirmed the positive association. No publication bias was detected (Begg's test, p = 0.368; Egger's test, p = 0.346). CONCLUSIONS: The present meta-analysis confirmed the significant association of the ATP2B1 gene polymorphism with hypertension susceptibility in East Asians. Further studies that include gene-gene and gene-environment interactions should be considered to investigate the identified associations in the future. PMID- 22229516 TI - Editorial: Identification of material parameters through inverse finite element modelling. PMID- 22229517 TI - Microcapsules composed of cross-linked organoclay. AB - Polyelectrolyte-modified montmorillonite particles were used to stabilize oil-in water Pickering emulsions, which were then bound together by an oil-soluble cross linker to obtain microcapsules. It was determined how the morphology and rigidity of the microcapsules changed as polyelectrolyte and cross-linker concentrations were varied. Well-defined microcapsules could be formed by using a moderate concentration of polyelectrolyte, and the higher the cross-linker concentration, the more rigid the microcapsules. Dried microcapsules were observed using SEM, and it was shown that the clay platelets lie flat next to each other on the microcapsule surface, forming an armor-like structure. PMID- 22229518 TI - Challenges and opportunities to prevent transfusion errors: a Qualitative Evaluation for Safer Transfusion (QUEST). AB - BACKGROUND: One of the most frequent causes of transfusion-associated morbidity or mortality is the transfusion of the wrong blood to the wrong patient. This problem persists in spite of the incorporation of numerous procedures into the pretransfusion checking process in an effort to improve patient safety. A qualitative study was undertaken to understand this process from the perspective of those who administer blood products and to identify concerns and suggestions to improve safety. STUDY DESIGN AND METHODS: Twelve focus group discussions and seven individual interviews were conducted at six hospitals in five countries (n = 72 individuals). Health care professionals from a variety of clinical areas participated. Data analysis identified common themes using the constant comparison method. RESULTS: Five major themes emerged from the analysis: the pretransfusion checking process, training, policy, error, and monitoring. Findings include the following: staff were aware and appreciative of the seriousness of errors and were receptive to continuous monitoring, the focus was on checking the bag label with the paperwork rather than the bag label with the patient at the bedside, training methods varied with most perceived to have minimal effectiveness, and access to policies was challenging and keeping up to date was difficult. Other factors that could contribute to errors included high volume of workload distractions and interruptions and familiarity or lack of familiarity with patients. CONCLUSIONS: Multiple factors can contribute to errors during the pretransfusion checking limiting the effectiveness of any individual intervention designed to improve safety. Areas of further research to improve safety of blood administration were identified. PMID- 22229519 TI - Monitoring device acceptance in implantable cardioverter defibrillator patients using the Florida Patient Acceptance Survey. AB - BACKGROUND: Patient device acceptance might be essential in identifying patients at risk for adverse patient-reported outcomes following implantation of an implantable cardioverter defibrillator (ICD). We examined the validity and reliability of the Florida Patient Acceptance Scale (FPAS) and identified correlates of device acceptance in a Dutch cohort of ICD patients. METHODS: Patients with a first-time ICD (N = 272, mean age = 59.2 +/- 11.9, 82% men) recruited from the Erasmus Medical Center, Rotterdam, or the Medisch Spectrum Twente, Enschede, The Netherlands completed the FPAS, the Type D Scale, and the Hospital Anxiety and Depression Scale. RESULTS: Exploratory and confirmatory factor analyses indicated that eliminating three items from the FPAS, leaving 12 items contributing to three factors, is equivalent to the original four-factor version of the FPAS. The abbreviated FPAS had a high internal consistency both for the total scale and all subscales, with Cronbach's alphas ranging from 0.76 to 0.82. Anxiety (odds ratio [OR]: 9.75; 95% confidence interval [CI]: 2.38 39.87; P = 0.002), depression (OR: 2.96; 95% CI: 0.98-8.93; P = 0.05), and the distressed (Type D) personality (OR: 5.04; 95% CI: 1.50-16.92; P = 0.01), but not demographic and clinical factors including shocks, were significant independent correlates of poor device acceptance. CONCLUSION: A shortened 12-item, three factor version of the FPAS was shown to be a valid and internally consistent instrument to assess device acceptance in Dutch ICD patients. Psychological but not clinical factors were the primary correlates of device acceptance, which underlines the importance of taking into account the patient's psychological profile when seeking to identify patients at risk for adjustment difficulties after ICD implantation. PMID- 22229520 TI - Molecular characterization of Ephestia kuehniella (Lepidoptera: Pyralidae) transferrin and its response to parasitoid Venturia canescens (Hymenoptera: Ichneumonidae Gravenhorst). AB - In the present study, we characterized a full-length cDNA encoding a putative iron-binding protein transferrin from the lepidopteran Mediterranean flour moth (EkTrf, 2397 bp). The putative EkTrf is 683 amino acids with a molecular mass of approximately 76 kDa. The deduced amino acid sequence showed significant homology with other insect transferrins from Chilo suppressalis (76%), Galleria mellonella (75%), Plutella xylostella (72%), Manduca sexta (74%), Bombyx mori (73%), Spodoptera litura and (72%), Choristoneura fumiferana (71%). Northern blot analysis indicated that Ephestia transferrin mRNA was expressed in the last larval instars of both males and females and in the pupal developmental stages. EkTrf is expressed predominantly in the fat body and ovary tissues. Analysis of parasitized larva by the endoparasitoid Venturia canescens suggests that transferrin expression is induced following parasitoid challenge. Expression of EkTrf levels also increased upon bacterial infection at 6 h post treatment and remained high until 24 h. Similarly to other insect transferrins, EkTrf may play a role in immunity through its iron-binding capacity. PMID- 22229521 TI - Suppression of NaNO3 crystal nucleation by glycerol: micro-Raman observation on the efflorescence process of mixed glycerol/NaNO3/water droplets. AB - Although the hygroscopicity of a NaNO(3)/water microdroplet and a polyalcohol/water microdroplet, two of the most important aerosols in atmosphere, has been widely studied, little is known about the relationship between the hygroscopic behavior of mixed NaNO(3)/polyalcohol/water droplets and their structures on the molecular level. In this study, the hygroscopicity of mixed glycerol/NaNO(3)/water droplets deposited on a hydrophobic substrate was studied by micro-Raman spectroscopy with organic-to-inorganic molar ratios (OIRs) of 0.5, 1, and 2. In the mixed glycerol/NaNO(3)/water droplets, glycerol molecules tended to combine with Na(+) and NO(3)(-) ions by electrostatic interaction and hydrogen bonding, respectively. On the basis of the analyses of the changes of symmetric stretching (v(s)-CH(2)), asymmetric stretching (v(a)-CH(2)), their area ratio (Av(a)-CH(2)/Av(s)-CH(2)) of glycerol, and symmetric stretching band of NO(3)(-) (nu(1)-NO(3)(-)) with relative humidity (RH), it was found that the conformation of glycerol was transformed from alphaalpha mainly to gammagamma and partly to alphagamma with a decreasing RH in the mixed droplets, contrary to the case in the glycerol/water droplet. In addition, the glycerol with gammagamma and alphagamma conformation had strong interaction with Na(+) and NO(3)(-) respectively, which suppressed the formation of contact of ions and delayed the efflorescence relative humidity (ERH) for the mixed droplets compared to the NaNO(3)/water droplet. PMID- 22229522 TI - Using the theory of planned behaviour to predict nurses' intention to integrate research evidence into clinical decision-making. AB - AIMS: Using an extended theory of planned behaviour, this article is a report of a study to identify the factors that influence nurses' intention to integrate research evidence into their clinical decision-making. BACKGROUND: Health professionals are increasingly asked to adopt evidence-based practice. The integration of research evidence in nurses' clinical decision-making would have an important impact on the quality of care provided for patients. Despite evidence supporting this practice and the availability of high quality research in the field of nursing, the gap between research and practice is still present. DESIGN: A predictive correlational study. METHODS: A total of 336 nurses working in a university hospital participated in this research. Data were collected in February and March 2008 by means of a questionnaire based on an extension of the theory of planned behaviour. Descriptive statistics of the model variables, Pearson correlations between all the variables and multiple linear regression analysis were performed. RESULTS/FINDINGS: Nurses' intention to integrate research findings into clinical decision-making can be predicted by moral norm, normative beliefs, perceived behavioural control and past behaviour. The moral norm is the most important predictor. Overall, the final model explains 70% of the variance in nurses' intention. CONCLUSION: The present study supports the use of an extended psychosocial theory for identifying the determinants of nurses' intention to integrate research evidence into their clinical decision-making. Interventions that focus on increasing nurses' perceptions that using research is their responsibility for ensuring good patient care and providing a supportive environment could promote an evidence-based nursing practice. PMID- 22229525 TI - What other anomalies? Failure to wean post ventricular septal defect repair secondary to anomalous origin of the left coronary artery from the pulmonary artery. AB - A six week old infant underwent ventricular septal defect and atrial septal defect closure. Preoperative echocardiography showed evidence of pulmonary hypertension. The post operative course was complicated failure to wean from ventilatory and inotropic support. Echocardiography showed severe left ventricular (LV) dysfunction and suggested some fistulous drainage of the left coronary artery into the right pulmonary artery; this anomalous drainage of the left coronary artery into the right pulmonary artery (ALCAPA) was confirmed with coronary angiogram. Re-implantation of the left coronary artery into the aorta was performed. Extra-corporeal membrane oxygenation (ECMO) was required to allow time for ventricular recovery. Supports were weaned gradually, with concurrent evidence of LV recovery and the child was discharged on postoperative day 30. ALCAPA is rare and typically presents at 8 weeks of age with symptoms of heart failure, as pulmonary pressure falls leading to myocardial ischaemia due to myocardial hypoperfusion with relatively desaturated blood. In our case the pulmonary hypertension and left to right shunt preoperatively were protective, maintaining forward flow of relatively oxygenated blood. While protective to the myocardium this made the preoperative diagnosis of ALCAPA difficult, as there was no flow reversal on Doppler echocardiography. Closure of the septal defects meant this protective effect was lost, with subsequent severe myocardial ischaemia and heart failure. This case highlights the diagnostic challenges of ALCAPA, the 'protective' effects of pulmonary hypertension with ALCAPA, and the importance of early cardiac catheterization in the setting of unexplained failure to wean post cardiac surgery. PMID- 22229524 TI - Phenolic secoiridoids in extra virgin olive oil impede fibrogenic and oncogenic epithelial-to-mesenchymal transition: extra virgin olive oil as a source of novel antiaging phytochemicals. AB - The epithelial-to-mesenchymal transition (EMT) genetic program is a molecular convergence point in the life-threatening progression of organ fibrosis and cancer toward organ failure and metastasis, respectively. Here, we employed the EMT process as a functional screen for testing crude natural extracts for accelerated drug development in fibrosis and cancer. Because extra virgin olive oil (EVOO) (i.e., the juice derived from the first cold pressing of the olives without any further refining process) naturally contains high levels of phenolic compounds associated with the health benefits derived from consuming an EVOO-rich Mediterranean diet, we have tested the ability of an EVOO-derived crude phenolic extract to regulate fibrogenic and oncogenic EMT in vitro. High-performance liquid chromatography (HPLC) coupled to time-of-flight (TOF) mass spectrometry assays revealed that the EVOO phenolic extract was mainly composed (~70%) of two members of the secoiridoid family of complex polyphenols, namely oleuropein aglycone-the bitter principle of olives-and its derivative decarboxymethyl oleuropein aglycone. EVOO secoiridoids efficiently prevented loss of proteins associated with polarized epithelial phenotype (i.e., E-cadherin) as well as de novo synthesis of proteins associated with mesenchymal migratory morphology of transitioning cells (i.e., vimentin). The ability of EVOO to impede transforming growth factor-beta (TGF-beta)-induced disintegration of E-cadherin-mediated cell cell contacts apparently occurred as a consequence of the ability of EVOO phenolics to prevent the upregulation of SMAD4-a critical mediator of TGF-beta signaling-and of the SMAD transcriptional cofactor SNAIL2 (Slug)-a well recognized epithelial repressor. Indeed, EVOO phenolics efficiently prevented crucial TGF-beta-induced EMT transcriptional events, including upregulation of SNAI2, TCF4, VIM (Vimentin), FN (fibronectin), and SERPINE1 genes. While awaiting a better mechanistic understanding of how EVOO phenolics molecularly shut down the EMT differentiation process, it seems reasonable to suggest that nontoxic Oleaceae secoiridoids certainly merit to be considered for aging studies and, perhaps, for ulterior design of more pharmacologically active second-generation anti-EMT molecules. PMID- 22229527 TI - Evaluation of a ski and snowboard injury prevention program. AB - The objective was to study the effectiveness of a brochure and video at improving skiing and snowboarding knowledge. Sixty-nine Grade 7 students were randomised to an educational intervention (n = 35) or control (n = 34) group. The intervention group viewed an injury prevention video aimed at improving skiers and snowboarder's knowledge, attitudes and behaviours about ski and snowboard safety and received a brochure. The control group participated in a teaching session and had a simple question and answer session about snow sports. Pre- and post-tests were administered and injuries during four trips were documented. Pre-test scores were similar between the two groups. Compared with the control group, there was a significantly greater improvement in post-test scores among the intervention group (WMD: 2.1; 95% CI: 0.19-4.01). There was no significant difference in injury rates (RR: 0.49; 95% CI: 0.04, 3.39). All injuries were minor and did not require medical attention. The intervention aimed at youth skiers and snowboarders appears to be effective at improving knowledge, attitudes and behaviours of skiing and snowboarding safety. PMID- 22229528 TI - Identification of a novel S249C FGFR3 mutation in a keratinocytic epidermal naevus syndrome. PMID- 22229526 TI - Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats. AB - AIMS: Hypothalamic mitochondrial reactive oxygen species (mROS)-mediated signaling has been recently shown to be involved in the regulation of energy homeostasis. However, the upstream signals that control this mechanism have not yet been determined. Here, we hypothesize that glucose-induced mitochondrial fission plays a significant role in mROS-dependent hypothalamic glucose sensing. RESULTS: Glucose-triggered translocation of the fission protein dynamin-related protein 1 (DRP1) to mitochondria was first investigated in vivo in hypothalamus. Thus, we show that intracarotid glucose injection induces the recruitment of DRP1 to VMH mitochondria in vivo. Then, expression was transiently knocked down by intra-ventromedial hypothalamus (VMH) DRP1 siRNA (siDRP1) injection. 72 h post siRNA injection, brain intracarotid glucose induced insulin secretion, and VMH glucose infusion-induced refeeding decrease were measured, as well as mROS production. The SiDRP1 rats decreased mROS and impaired intracarotid glucose injection-induced insulin secretion. In addition, the VMH glucose infusion induced refeeding decrease was lost in siDRP1 rats. Finally, mitochondrial function was evaluated by oxygen consumption measurements after DRP1 knock down. Although hypothalamic mitochondrial respiration was not modified in the resting state, substrate-driven respiration was impaired in siDRP1 rats and associated with an alteration of the coupling mechanism. INNOVATION AND CONCLUSION: Collectively, our results suggest that glucose-induced DRP1-dependent mitochondrial fission is an upstream regulator for mROS signaling, and consequently, a key mechanism in hypothalamic glucose sensing. Thus, for the first time, we demonstrate the involvement of DRP1 in physiological regulation of brain glucose-induced insulin secretion and food intake inhibition. Such involvement implies DRP1-dependent mROS production. PMID- 22229529 TI - Portrait professional. AB - Most medical photographers, unless working as dedicated ophthalmic photographers or retinal screeners, will shoot portraits or publicity pictures. Many will spend a proportion of their time producing brochure shots for patient information material or their Trust's Annual Report. High-quality images of staff at work are often required by the strategic planning departments of Trusts to support bids for business from service commissioners. This "non-clinical" work is in reality commercial work - the jobs that high street portrait and general practice photographers would undertake in different settings. Medical photographers use many of the same tools as their commercial cousins. They use the same DSLR cameras and lenses. They use Adobe Photoshop to manipulate images. However, one software tool extensively used by portrait and social photographers, but possibly unfamiliar to many medical photographers, is Portrait Professional. Currently in its 10th version, it is produced by Anthropics Technology ( http://www.anthropics.com ), a London-based company specialising in image manipulation software. PMID- 22229530 TI - The personal development planning cycle. AB - This Learning and CPD sheet is designed to pull together into a framework many of the activities that have already been published. It should also help anyone planning to go for audit of their CPD or who have been requested to submit for audit. There are a number of different ways of viewing the Personal Development Planning (PDP) or CPD cycle; the one covered here is just one example and shouldn't be seen as the only way of looking at PDP. For a greater range of activities, look at the book "Skills for Success: The Personal Development Planning Handbook" by Cottrell and the companion website. PMID- 22229532 TI - Outcomes in community-acquired Clostridium difficile infection. AB - BACKGROUND: Community-acquired Clostridium difficile infection (CA-CDI) is an increasingly appreciated condition. It is being described in populations lacking traditional predisposing factors that have been previously considered at low-risk for this infection. As most studies of CDI are hospital-based, outcomes in these patients are not well known. AIM: To examine outcomes and their predictors in patients with CA-CDI. METHODS: A sub-group analysis of a population-based epidemiological study of CDI in Olmsted county, Minnesota from 1991-2005 was performed. Data regarding outcomes, including severity, treatment response, need for hospitalisation and recurrence were analysed. RESULTS: Of 157 CA-CDI cases, the median age was 50 years and 75.3% were female. Among all CA-CDI cases, 40% required hospitalisation, 20% had severe and 4.4% had severe-complicated infection, 20% had treatment failure and 28% had recurrent CDI. Patients who required hospitalisation were significantly older (64 years vs. 44 years, P < 0.001), more likely to have severe disease (33.3% vs. 11.7%, P = 0.001), and had higher mean Charlson comorbidity index scores (2.06 vs. 0.84, P = 0.001). They had similar treatment failure and recurrence rates as patients who did not require hospitalisation. CONCLUSIONS: Community-acquired Clostridium difficile infection can be associated with complications and poor outcomes, including hospitalisation and severe Clostridium difficile infection. As the incidence of community-acquired Clostridium difficile infection increases, clinicians should be aware of risk factors (increasing age, comorbid conditions and disease severity) that predict the need for hospitalisation and complications in patients with community-acquired Clostridium difficile infection. PMID- 22229533 TI - Food intake and meal pattern in IAPP knockout mice with and without infusion of exogenous IAPP. AB - OBJECTIVE: The current study used islet amyloid polypeptide (IAPP) knockout mice (KO mice) to investigate the physiological role of IAPP in the regulation of food intake (FI). MATERIAL AND METHODS: FI and body weight were measured in KO and wild-type (WT) mice for 27 weeks. In an additional short-term experiment, IAPP (25 pmol.kg(-1)min(-1)) was infused subcutaneously for 3 days in KO and WT mice, and FI, meal pattern, and body weight were analyzed. RESULTS: In the long-term experiment, no significant differences in body weight were seen between WT and KO mice at any point. FI, meal number, and meal size did not differ significantly between the groups in any of the five selected weeks that were studied. In the short-term experiment, FI decreased significantly during IAPP infusion in both WT and KO groups. FI was significantly lower in the KO mice compared with WT on days 1 and 2 (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: The data showing no differences in FI and body weight were seen between KO and WT mice, indicating that FI can be controlled in the absence of IAPP. The more marked anorectic effect seen in the KO mice during IAPP infusion suggests that IAPP receptors and/or IAPP post-receptor signaling pathways are up-regulated in mice lacking endogenous IAPP. PMID- 22229535 TI - Personal and contextual factors in the escalation of driving after drinking across the college years. AB - College students continue to drive after drinking at alarmingly high rates. Age trends suggest that driving after drinking increases from late adolescence across the college years, largely mirroring trends in binge drinking. Relatively little research, however, has examined change over time in driving after drinking among college students or tested whether some students might be at greater risk of escalations in driving after drinking. Using a sample of 1,833 nonabstaining students who completed surveys for seven semesters across the college years, we tested whether personal (i.e., age of drinking onset, gender, risk perceptions, and sensation seeking) and contextual (i.e., college residence) factors were associated with changes in driving after drinking. Using latent growth curve modeling, we found significant individual differences in rates of change in driving after drinking. Male students and students who began drinking earlier in life increased in driving after drinking more rapidly, whereas living in on campus housing was associated with time-specific decreases in driving after drinking. These results demonstrate the value of considering driving after drinking from a longitudinal perspective and suggest possible avenues toward preventing the public health consequences of intoxicated driving. PMID- 22229536 TI - Lipid profiles in untreated patients with dermatomyositis. AB - BACKGROUND AND OBJECTIVE: Altered lipid levels may occur in autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. However, serum lipid profiles in patients with dermatomyositis (DM) have not been investigated. Our aim was to identify lipid profiles in untreated DM patients, and to assess the relationship of the inflammatory condition of DM with lipid profiles. METHODS: This work was designed and conducted as a case-control study. Forty-one DM patients and 41 age- and gender-matched healthy controls were included. None of the patients had received corticosteroids or disease-modifying antirheumatic drugs prior to the study. Triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were assessed using standard techniques. RESULTS: Twenty-nine patients (70.7%) had an increase level of TG, and 41.5% had a decrease level of HDL-C. The levels of HDL-C in DM were significantly lower than in controls (P < 0.01). The levels of TG, Non- HDL cholesterol and very LDL-cholesterol (VLDL-C) were significantly higher than in controls (P < 0.001, P < 0.001 and P < 0.05 respectively). The ratios of VLDL C/LDL-C, TC/HDL-C and LDL-C/HDL-C were significantly higher than in controls (P < 0.001). Spearman's correlation test demonstrated that serum CRP levels correlated negatively with HDL-C in DM(r = -0.420, P = 0.006). CONCLUSION: Dyslipoproteinemia is a common feature in patients with DM that is characterized by an increase in TG and a decrease in HDL-C, suggesting a high risk of atherosclerosis. Inflammation might partly account for the changes of serum lipid profiles in DM. PMID- 22229537 TI - Effect of anticoagulation with citrate versus heparin on the adsorption of coagulation factors to blood purification resins with different charge. AB - In liver failure, hydrophobic toxins accumulate in the blood circulation. To support hepatic function, extracorporeal blood purification systems have been developed, in which both cationic and neutral adsorbents are used to remove albumin-bound metabolites from blood. An issue of these systems is the additional removal of coagulation factors containing negatively charged gamma carboxyglutamate (Gla) domains, which, in physiological conditions, are shielded by calcium ions. We hypothesized that complexation of calcium ions by citrate leads to exposure of negative Gla domains, resulting in their binding to the positively charged adsorbents. The data presented here confirm that the binding of coagulation factors containing Gla domains to positively charged polymers is enhanced in the presence of citrate as compared to heparin. This effect increased with increasing charge density of the polymer and has important implications for the clinical application of positively charged polymers. PMID- 22229538 TI - Determination of isocyanate specific albumin-adducts in workers exposed to toluene diisocyanates. AB - Toluene diisocyanates (2,4-TDI and 2,6-TDI) are important intermediates in the chemical industry. Among the main damages after low levels of TDI exposure are lung sensitization and asthma. It is therefore necessary to have sensitive and specific methods to monitor isocyanate exposure of workers. Urinary metabolites or protein adducts have been used as biomarkers in workers exposed to TDI. However, with these methods it was not possible to determine if the biomarkers result from exposure to TDI or to the corresponding toluene diamines (TDA). This work presents a new procedure for the determination of isocyanate-specific albumin adducts. Isotope dilution mass spectrometry was used to measure the adducts in albumin present in workers exposed to TDI. 2,4-TDI and 2,6-TDI formed adducts with lysine: N(epsilon)-[({3-amino-4-methylphenyl}amino)carbonyl]-lysine, N(epsilon)-[({5-amino-2-methylphenyl}amino)carbonyl]-lysine, and N(epsilon)- [({3 amino-2-methylphenyl}amino)carbonyl]-lysine. In future studies, this new method can be applied to measure TDI-exposures in workers. PMID- 22229539 TI - Unusual manifestation of upper rate limitation in a dual-chamber ICD. PMID- 22229540 TI - 'Straight to the GP; that would be where I would go': an analysis of male frequent attenders' constructions of their decisions to use or not use health care services in the UK. AB - An important consideration that needs adding to discussions of patient choice and whether or not men are reluctant to use primary care services is that many frequent attenders are male. The aim of this article is to explore how male frequent attenders construct decisions to use or not use health-care services. This is achieved through secondary analysis of baseline interviews with male frequent attenders from the Self Care in Primary Care study. As this was a complex study, a three-step analytic process was employed to incorporate the involvement of multiple researchers working together over a number of years. First, the interviewer summarised each interview and second, the summaries were read as a group to find themes across them. Subsequently, we returned to the interviews to add detail that would further illustrate or challenge the analysis. Participants talked of 'engaging health and avoiding ill-health', constructing themselves as embodied, health conscious and rational in a similar vein to constructions of feminine interactions with health. While participants talked of 'choosing health services' as if they were drawing upon a range of choices, the dominance of the image of the GP was such that seeing a GP was the only legitimate health choice. PMID- 22229541 TI - Increased levels of angiopoietins 1 and 2 in sputum supernatant in severe refractory asthma. AB - BACKGROUND: Airway and vascular remodeling may play a prominent role in the clinical severity of severe refractory asthma (SRA). Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas angiopoietin-2 (Ang-2) acts as its natural inhibitor. OBJECTIVE: We aimed to determine the levels of angiopoietins in sputum supernatants of patients with SRA and to investigate the possible associations with mediators and cells involved in both the inflammatory and the vascular remodeling processes. METHODS: Thirty eight patients with SRA, 35 patients with moderate asthma, and 20 healthy subjects were studied. All participants underwent lung function tests, bronchial hyperresponsiveness assessment and sputum induction for cell count identification and Ang-1, Ang-2, VEGF, TGF-beta1, Cys-LTs, MMP-2, IL-13, ECP, and IL-8 measurement in supernatants. Airway vascular permeability (AVP) index was also assessed. RESULTS: Ang-1 (ng/ml) and Ang-2 (pg/ml) levels were significantly elevated in patients with SRA compared with patients with moderate asthma and control subjects [median, interquartile ranges: 30 (17-39) vs 7.5 (5-11) vs 4.7 (3.8-5.9) respectively, P < 0.001; and 506 (400-700) vs 190 (146-236) vs 96 (89 120) respectively, P < 0.001]. Regression analysis showed a significant positive association between Ang-2 and AVP index, MMP-2, Ang-1, and VEGF in SRA. A weak association was also observed between Ang-1 and sputum eosinophils% in SRA. CONCLUSION: Our results indicate that both angiopoietins levels are higher in SRA compared with moderate asthma and healthy subjects. In SRA, Ang-2 is associated with mediators involved in both the inflammatory and the vascular remodeling processes. PMID- 22229543 TI - Topical herbal application as an adjuvant treatment for chronic kidney disease--a systematic review of randomized controlled clinical trials. AB - AIM: To report a systematic review to evaluate whether topical herbal medicine delays the progress of renal disease and improves its complications in people with chronic kidney disease. BACKGROUND: Besides dialysis or renal transplantation, patients with chronic kidney disease, especially those with insufficient renal function, are in a great need of effective conservative treatment methods. Topical application of herbal medicine, a common treatment modality in China, has been found in some clinical studies to benefit the patients with chronic kidney disease. DATA SOURCES: The English databases including CENTRAL (February 2010), Medline (1950 to February 2010), EMBASE (1980 to February 2010), and AMED (1985 to January 2010), and several Chinese databases covering the period of 1949 to February 2010 were searched for randomized controlled trials that compared external use of herbal medicine with no treatment, placebo, or conventional treatment for chronic kidney disease and its complications. REVIEW METHODS: We undertook a systematic review and meta-analysis following Cochrane processes. RESULTS: Twenty-three trials with a total of 1057 patients were included. Their results suggest that herbal paste and bathing or fuming treatment might have a beneficial effect in terms of delaying the progress of renal disease, improving kidney function, and ameliorating some kidney complications in patients with chronic kidney disease. However, the low quality and poor reporting practices of the studies covered led to no definitive conclusion. CONCLUSION: Further larger and more rigorously designed clinical trials with proper outcome measures are needed to confirm the findings. PMID- 22229544 TI - Expression analyses of caspase-1 and related activities in the midgut of Galleria mellonella during metamorphosis. AB - The cDNA encoding caspase-1, a main protease involved in apoptosis, was cloned and sequenced from the midgut of the greater wax moth, Galleria mellonella. The open reading frame contains 879 nucleotides, encodes 293 amino acids, and was registered as Gmcaspase-1. The sequence comparison showed a high homology to lepidopteran caspase-1, human caspase-3, and ced-3 of Caenorhabditis elegans. Gmcaspase-1 is predicted to contain a short prodomain, large subunit, and small subunit domain. It also exhibits all characteristics of caspase, including three conserved cleavage sites after Asp-25, Asp-192, and Asp-181, three active site residues including a highly conserved QACQG pentapeptide active-site motif, and four substrate binding sites. The expression profiles during development showed that the transcript of Gmcaspase-1 and its protein products appeared in two or more waves in the midgut during metamorphosis. Immunohistochemistry, in situ hybridization, and TUNEL analyses revealed that apoptosis occurred first at the basal, then middle and then apical regions in the midgut epithelium and the yellow body is formed in the lumen. At least three waves of mitosis and differentiation follow the apoptosis waves from the basal and middle to apical parts to form the adult epithelium. PMID- 22229545 TI - Calculation of infrared/Raman spectra and dielectric properties of various crystalline poly(lactic acid)s by density functional perturbation theory (DFPT) method. AB - We calculated infrared (IR) and Raman spectra of poly(lactic acid) (PLA) polymorphs by employing density functional perturbation theory (DFPT) and a plane wavebasis set. Significant different characteristics are found in the calculated spectra of poly(L-lactic acid) (PLLA) alpha-form and PLLA/poly(D-lactic acid) (PDLA) stereocomplex (sc) form. Particularly in the carbonyl stretching region, there is only one sharp peak in the sc-form while there are five peaks in the PLLA alpha-form. A low wavenumber (65 cm(-1)) vibration band of alpha-PLLA observed in a previous terahertz time-domain spectroscopy study was reproduced in the calculated solid-state PLLA spectra. This band could not be obtained by using DFT (B3LYP/6-31G*) simulation on a single PLA oligomer chain and had been attributed to lattice vibrations in the crystal. The permittivity and polarizability tensors of PLA single crystals were also obtained using the DFPT method and were found to be anisotropic. PMID- 22229547 TI - Use of FloSeal hemostatic matrix in a patient with severe postpartum hemorrhage. AB - FloSeal (hemostatic gelatin matrix with a human-derived thrombin component; Baxter Healthcare, Deerfield, IL, USA) hemostatic matrix is used as an adjunct to hemostasis when conventional procedures have proved ineffective. In the present case, FloSeal was used in combination with transfusions, NovoSeven (recombinant activated human factor VIIa; Novo Nordisk, Copenhagen, Denmark) and compression to achieve hemostasis in a patient with postpartum bleeding and hypofibrinogenemia due to primary acute fatty liver of pregnancy. The patient presented with signs of acute hepatic failure, modified renal failure and bleeding disorder at week 37 of pregnancy. She suffered persistent hemorrhage after a soft vacuum-assisted delivery. Local hemostasis was achieved, but not maintained and metrorrhagia resumed requiring transfusion. FloSeal was applied intrauterine and to the vaginal walls, and stable hemostasis was achieved after 2 h. At the one-month post-delivery visit, anatomic and physiological status had returned to normal, although the patient had low fibrinogen and prothrombin activity. This case demonstrates the safety and effectiveness of FloSeal in combination with conventional procedures to achieve hemostasis in postpartum bleeding in a patient with hypofibrinogenemia. PMID- 22229548 TI - Endothelial dysfunction and increased responses to renal nerve stimulation in rat kidneys during rhabdomyolysis-induced acute renal failure: role of hydroxyl radical. AB - Rhabdomyolysis is an important cause of acute renal failure (ARF) and renal vasoconstriction is the main mechanism in the pathogenesis of ARF. Lipid peroxidation due to hydroxyl radical (.OH) formation and redox cycling of myoglobin also have a role. We investigated the disturbance in renal vascular reactivity to reveal the mechanisms leading to ARF. Female Wistar rats (n = 7) were injected with glycerol (10 mL/kg, 50% in saline) intramuscularly to induce rhabdomyolysis, and then the kidneys were isolated and perfused. We investigated acetylcholine (ACh)-induced endothelium-dependent and papaverine (PAP)-induced endothelium-independent vasodilation responses and renal nerve stimulation (RNS) induced vasoconstrictions. These were also investigated both in rats which received either .OH scavenger, dimethylthiourea (DMTU: 500 mg/kg before glycerol injection and 125 mg/kg 8 h after glycerol injection, n = 7), or myoglobin redox cycling inhibitor, acetaminophen (ApAP: 100 mg/kg 2 h before glycerol injection and 100 mg/kg each 4 h, and 22 h after glycerol injection, n = 7). ACh-induced responses in glycerol group were decreased (p < 0.001), but PAP-induced vasodilation did not change. RNS-induced vasoconstriction in all kidneys was greater (p < 0.001) in glycerol group. DMTU restored both endothelium-dependent vasodilation and RNS-induced vasoconstriction. ApAP had no effect on vascular responses. Both DMTU and ApAP exerted a partial protective effect in renal histology without restoring serum creatinine and blood urea nitrogen (BUN) levels or creatinine clearance. This study showed that endothelial dysfunction and increased vasoconstriction developed during rhabdomyolysis. .OH plays an important role in the development of these vascular responses. These findings suggest that decreased endothelium-dependent vasodilation and augmented renal sympathetic tonus contribute to the development of renal vasoconstriction during rhabdomyolysis-induced ARF. PMID- 22229549 TI - Impact of lipophilic efficiency on compound quality. AB - Lipophilic efficiency indices such as LLE and LELP were suggested to support balanced optimization of potency and ADMET profile. Here we investigated the performance of LLE and LELP on multiple data sets representing different stages of drug discovery including fragment and HTS hits and leads, development candidates, phase II compounds, and launched drugs. Analyzing their impact on ADME and safety properties and binding thermodynamics, we found that both LLE and LELP help identifying better quality compounds. LLE is sensible for the development stages but does not prefer fragment-type hits, while LELP has an advantage for this class of compounds and discriminates preferred starting points effectively. Both LLE and LELP have significant impact on ADME and safety profiles; however, LELP outperforms LLE in risk assessment at least on the present data set. On the basis of the results reported here, monitoring lipophilic efficiency metrics could contribute significantly to compound quality and might improve the output of medicinal chemistry programs. PMID- 22229550 TI - Delusion of inanimate doubles: description of a case of focal retrograde amnesia. AB - This paper reports the case of a patient, M.P., who developed delusion of inanimate doubles, without Capgras syndrome, after traumatic brain injury. His delusional symptoms were studied longitudinally and the cognitive impairments associated with delusion were investigated. Data suggest that M.P. did 'perceive' the actual differences between doubles and originals rather than 'confabulate' them. The cognitive profile, characterized by retrograde episodic amnesia, but neither object processing impairment nor confabulations, supports this hypothesis. The study examines the nature of object misidentification based on Ellis' and Staton's account and proposes a new account based on concurrent unbiased retrieval of semantic memory traces and biased recollection of episodic memory traces. PMID- 22229551 TI - High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. AB - AIMS: Hydrogen sulfide (H(2)S) is a signaling molecule, which influences many physiological processes. While H(2)S is produced and degraded in many cell types, the kinetics of its turnover in different tissues has not been reported. In this study, we have assessed the rates of H(2)S production in murine liver, kidney, and brain homogenates at pH 7.4, 37 degrees C, and at physiologically relevant cysteine concentrations. We have also studied the kinetics of H(2)S clearance by liver, kidney, and brain homogenates under aerobic and anaerobic conditions. RESULTS: We find that the rate of H(2)S production by these tissue homogenates is considerably higher than background rates observed in the absence of exogenous substrates. An exponential decay of H(2)S with time is observed and, as expected, is significantly faster under aerobic conditions. The half-life for H(2)S under aerobic conditions is 2.0, 2.8, and 10.0 min with liver, kidney, and brain homogenate, respectively. Western-blot analysis of the sulfur dioxygenase, ETHE1, involved in H(2)S catabolism, demonstrates higher steady-state protein levels in liver and kidney versus brain. INNOVATION: By combining experimental and simulation approaches, we demonstrate high rates of tissue H(2)S turnover and provide estimates of steady-state H(2)S levels. CONCLUSION: Our study reveals that tissues maintain a high metabolic flux of sulfur through H(2)S, providing a rationale for how H(2)S levels can be rapidly regulated. PMID- 22229553 TI - The ovary feels fine when paracrine and autocrine networks cooperate with gonadotropins in the regulation of folliculogenesis. AB - The production of a mature oocyte is the major function of the female gonad. This process depends on highly coordinated interplay between all the components of the ovarian follicle, i.e. the oocyte surrounded by epithelial-derived granulosa cells and mesenchymal- derived theca cells. Follicular growth and oocyte maturation are dependent primarily on pituitary-derived gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). However, other bioactive molecules play an important role during this process. In fact, granulosa and theca cells as well as the oocytes are the site of synthesis and/or action of a number of locally-released factors that promote the complex regulation of follicular development. The elucidation of these factors is critical to understand ovarian physiology and pathology. PMID- 22229554 TI - Extrapituitary actions of GnRH antagonists: prospects for in vitro fertilization programs. AB - Gonadotropin-releasing hormone antagonists (GnRH-ant) are routinely used to prevent premature luteinizing hormone (LH) surges in women undergoing in vitro fertilization (IVF) programs. GnRH-ant act by competitively binding GnRH receptors (GnRHr), leading to rapid pituitary suppression. GnRH-ant can also block extrapituitary GnRHr, including those present in ovary, placenta, and endometrium. A full understanding of the functional roles played by extrapitutary GnRHr, along with a better characterization of the possible reproductive consequences of their blockage may aid the refinement of controlled ovarian stimulation (COS) protocols using GnRHant. This review summarizes current research in the area, especially focusing on the possible impact of GnRH-ant on steroidogenesis, folliculogenesis and endometrial receptivity. PMID- 22229552 TI - D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. AB - BACKGROUND AND PURPOSE: Lipoxidation-derived reactive carbonyl species (RCS) such as 4-hydroxy-2-nonenal (HNE) react with proteins to form advanced lipoxidation end products (ALEs), which have been implicated in both atherosclerosis and renal disease. L-carnosine acts as an endogenous HNE scavenger, but it is rapidly inactivated by carnosinase. This study aimed at assessing the effect of the carnosinase-resistant, D-carnosine, on HNE-induced cellular injury and of its bioavailable prodrug D-carnosine octylester on experimental atherosclerosis and renal disease. EXPERIMENTAL APPROACH: Vascular smooth muscle cells (VSMCs) were exposed to HNE or H2O2 plus D-carnosine. ApoE null mice fed a Western, pro atherogenic diet were treated with D-carnosine octylester for 12 weeks. KEY RESULTS: In vitro, D-carnosine attenuated the effect of HNE, but not of H2O2, on VSMCs. In vivo, D-carnosine octylester-treated mice showed reduced lesion area and a more stable plaque phenotype compared with untreated animals, with reduced foam cell accumulation, inflammation and apoptosis and increased clearance of apoptotic bodies and collagen deposition, resulting in decreased necrotic core formation. Likewise, renal lesions were attenuated in D-carnosine octylester treated versus untreated mice, with lower inflammation, apoptosis and fibrosis. This was associated with increased urinary levels of HNE-carnosine adducts and reduced protein carbonylation, circulating and tissue ALEs, expression of receptors for these products, and systemic and tissue oxidative stress. CONCLUSIONS AND IMPLICATIONS: These data indicate RCS quenching with a D carnosine ester was highly effective in attenuating experimental atherosclerosis and renal disease by reducing carbonyl stress and inflammation and that this may represent a promising therapeutic strategy in humans. PMID- 22229555 TI - Biomolecules of human female fertility--potential therapeutic targets for pharmaceutical design. AB - Scientists are able to advance the frontiers of human reproduction by employing a variety of molecular biological techniques to understand the biological processes intricately linked to oocyte and ovarian follicle development. Despite an abundance of knowledge concerning essential pathways which may have critical roles in oogenesis and folliculogenesis, the repertoire of medications to treat female fertility problems remains limited to a few classes of drugs involved in the induction or suppression of folliculogenesis and ovulation; many of which are not specific in their drug actions and can give rise to complications during clinical application. This paper aims to review biomolecules and pathways (e.g. PI3K, WNT, MAPK) pertinent to ovarian follicular development and active in human oocytes, including those involved in communication between somatic cells within the ovary (cumulus cells, granulosa cells and thecal cells) and the oocyte itself. These biomolecules which are involved in the nuclear and cytoplasmic maturation of oocytes and the control of ovarian folliculogenesis have potential as targets for improved ovarian stimulation, optimisation of oocyte maturation, and as biomarkers of oocyte viability assessment. PMID- 22229557 TI - Early in vivo testing to assess new therapeutic interventions in CF patients. AB - New therapeutic strategies are targeting correction of the basic defect in cystic fibrosis (CF) disease. In fact, completion of the first successful clinical drug trials now signals the start of a new era in CF therapy. Many promising drug candidates are emerging into the clinical drug pipeline. However, their translation from the bench to the bed side is challenged by the lack of accurate and reliable biomarker assays that allow testing for their clinical efficiency and safety in early clinical trials. It is surprising that despite the availability of modern equipment and technologies relatively little effort has been directed towards innovative approaches to exploit our pathophysiological understanding of CF disease for the design of novel assays that allow in vivo assessment of CFTR dysfunction as the measurable correlate of the basic defect of CF disease. This lack of adequate outcome measure is now gaining increased attention, and first studies are being initiated to screen larger CF patient cohorts for biological markers that can be used as a potential measure of drug response. This paper reviews currently available in vivo tests, highlighting new methods and their potential use as early in vivo markers for therapeutic investigations. Finally, key criteria of the validation process that needs to be addressed before new biomarker assays can be introduced into clinical trials are discussed. PMID- 22229556 TI - Identification and validation of hits from high throughput screens for CFTR modulators. AB - These are exciting times with the appearance of small molecule compounds in clinical trials which target the basic defects caused by mutation in the CFTR gene. This progress was enabled by years of basic research probing the molecular and cellular consequences caused by mutation and the development of methods by which to study the primary anion transport defect in a high-throughput manner by robotics. Future progress with the development of new, more effective corrector compounds is needed. Such discovery will require further progress in defining the molecular targets for effective intervention using a multidisciplinary approach, merging computational, molecular, proteomic and cell biological methods. There is also an urgent need to develop means to link the right therapeutic compound to the right patients given the heterogeneity of the CF patient population. We envision a time when mid to high-throughput methods will be married with stem cell biology to enable testing a compendium of compounds on cells derived from each individual patient. Given the rate of progress in this field- this scenario may exist in the not too distant future. PMID- 22229558 TI - Beta-arrestin biased agonism/antagonism at cardiovascular seven transmembrane spanning receptors. AB - Heptahelical, G protein-coupled or seven transmembrane-spanning receptors, such as the beta-adrenergic and the angiotensin II type 1 receptors, are the most diverse and therapeutically important family of receptors in the human genome, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by phosphorylation of the agonist bound receptor by the G-protein coupled receptor kinases (GRKs), followed by betaarrestin binding, which uncouples the phosphorylated receptor from the G protein and subsequently targets the receptor for internalization. As the receptor-betaarrestin complex enters the cell, betaarrestin-1 and -2, the two mammalian betaarrestin isoforms, serve as ligand-regulated scaffolds that recruit a host of intracellular proteins and signal transducers, thus promoting their own wave of signal transduction independently of G-proteins. A constantly increasing number of studies over the past several years have begun to uncover specific roles played by these ubiquitously expressed receptor adapter proteins in signal transduction of several important heptahelical receptors regulating the physiology of various organs/ systems, including the cardiovascular (CV) system. Thus, betaarrestin-dependent signaling has increasingly been implicated in CV physiology and pathology, presenting several exciting opportunities for therapeutic intervention in the treatment of CV disorders. Additionally, the discovery of this novel mode of heptahelical receptor signaling via betaarrestins has prompted a revision of classical pharmacological concepts such as receptor agonism/antagonism, as well as introduction of new terms such as "biased signaling", which refers to ligand-specific activation of selective signal transduction pathways by the very same receptor. The present review gives an overview of the current knowledge in the field of betaarrestin-dependent signaling, with a specific focus on CV heptahelical receptor betaarrestin mediated signaling and on "biased" CV heptahelical receptor ligands that promote or inhibit it. Exciting new possibilities for cardiovascular therapeutics arising from the delineation of this betaarrestin-dependent signaling are also discussed. PMID- 22229560 TI - Enkephalin degrading enzymes: metalloproteases with high potential for drug development. AB - Enkephalins play a great role in management of pain, blood pressure, hypertension and cardiovascular diseases. Enkephalins are short-lived molecules being rapidly hydrolyzed following their synaptic release by enkephalin degrading enzymes. The inhibitors of enkephalin degrading enzymes are able to prolong the duration of action of enkephalins. This review will focus on the inhibitors of enkephalin degrading enzymes as a novel therapeutic approach for cancer itself and also in cancer and neuropathic pain management with discussion on the present status and future directions for a new class of drugs. PMID- 22229561 TI - Editorial [ hot topic: new frontiers in female reproduction and fertility (executive guest editor: sandra cecconi)]. PMID- 22229562 TI - The control of cell cycle in mouse primordial germ cells: old and new players. AB - The cell cycle of primordial germ cells (PGCs), the embryonic precursors of gametes, is characterized by a mitotic phase common to both sexes and a mitotic meiotic switch in the female. In the present work, we will review the results obtained in the last decade by studies aimed to clarify intrinsic and extrinsic regulatory signals of such processes, with particular reference to mouse PGCs. Besides providing a better understanding of how the gamete population is established in mammals, information about the players controlling the PGC cycle will be useful to clarify other intriguing aspects of germ cell biology such as the origin of germ cell tumours and the mechanisms allowing the maintenance of totipotency in the germ line. PMID- 22229559 TI - Probing heterotrimeric G protein activation: applications to biased ligands. AB - Cell surface G protein-coupled receptors (GPCRs) drive numerous signaling pathways involved in the regulation of a broad range of physiologic processes. Today, they represent the largest target for modern drugs development with potential application in all clinical fields. Recently, the concept of "ligand directed trafficking" has led to a conceptual revolution in pharmacological theory, thus opening new avenues for drug discovery. Accordingly, GPCRs do not function as simple on-off switch but rather as filters capable of selecting the activation of specific signals and thus generating texture responses to ligands, a phenomenon often referred to as ligand-biased signaling. Also, one challenging task today remains optimization of pharmacological assays with increased sensitivity so to better appreciate the inherent texture of ligands. However, considering that a single receptor has pleiotropic signaling properties and that each signal can crosstalk at different levels, biased activity remains thus difficult to evaluate. One strategy to overcome these limitations would be examining the initial steps following receptor activation. Even, if some G protein independent functions have been recently described, heterotrimeric G protein activation remains a general hallmark for all GPCRs families and the first cellular event subsequent to agonist binding to the receptor. Herein, we review the different methodologies classically used or recently developed to monitor G protein activation and discussed them in the context of G protein biased-ligands. PMID- 22229563 TI - Unveiling mRNA changes during meiotic progression and pre-implantation development: help from large animal models. AB - Assisted reproductive technologies (ART) are successfully applied in several mammals, including humans, thanks to the ability of oocytes and embryos to face maturation, fertilization and first development in vitro. However, efficiency and safety of ART represent main issues. Mammalian oocytes and early embryos are transcriptionally inactive, and rely exclusively on maternal RNAs and proteins, deposited during oocyte growth, until embryonic genome activation (EGA). Such transcriptional quiescence needs complex post-transcriptional and post translational mechanisms to coordinate meiotic maturation, fertilization, and reprogramming of the nascent genome. These events are the final outcome of complex, hormonally regulated biological processes that translate into specific molecular mechanisms, which are still far from being fully understood. A deep knowledge of these early phases of development is crucial to understand the core mechanisms of life onset, and to optimize the safety and efficiency of in vitro reproductive technologies. This work focuses on meiotic progression and pre implantation development in mammals, underlining the importance of fundamental molecules stored during oocyte growth and selectively used during early embryogenic stages. Taking into account the species-specific behaviour of these pivotal molecules, this review describes the advantages of using large domestic animals for research in the reproductive field and proposes large domestic animals as models to improve human ART. PMID- 22229564 TI - Phenotypes and enviromental factors: their influence in PCOS. AB - Polycystic ovary syndrome (PCOS) is a complex syndrome of unclear etiopathogenesis characterized by heterogeneity in phenotypic manifestations. The clinical phenotype of PCOS includes reproductive and hormonal aberrations, namely anovulation and hyperandrogenism, which coexist with metabolic disturbances. Reflecting the crosstalk between the reproductive system and metabolic tissues, obesity not only deteriorates the metabolic profile but also aggravates ovulatory dysfunction and hyperandrogenism. Although the pathogenesis of PCOS remains unclear, the syndrome appears to involve environmental and genetic components. Starting from early life and extending throughout lifecycle, environmental insults may affect susceptible women who finally demonstrate the clinical phenotype of PCOS. Diet emerges as the major environmental determinant of PCOS. Overnutrition leading to obesity is widely recognized to have an aggravating impact, while another detrimental dietary factor may be the high content of food in advanced glycated end products (AGEs). Environmental exposure to industrial products, particularly Bisphenol A (BPA), may also exacerbate the clinical course of PCOS. AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome. PCOS appears to mirror the harmful influence of the modern environment on the reproductive and metabolic balance of inherently predisposed individuals. PMID- 22229565 TI - Stem cells in adult human ovaries: from female fertility to ovarian cancer. AB - The human ovary is a complex endocrine gland, which is responsible for production of different hormones and provides mature and competent oocytes for reproduction. Additionally, it produces various substances, such as growth factors and cytokines which are involved in the complex signalling pathways of folliculogenesis or oogenesis. The abnormalities of ovarian function might lead to infertility or manifestation of aggressive cancer. Therefore, stem cells in adult human ovaries are of great interest to reproductive medicine for improved understanding of the mechanisms leading to ovarian infertility or cancer formation, yet they represent a difficult scientific subject, because it is still generally accepted that they do not exist. The persisting dogma is that the end number of follicles is set up at the time of birth, and that there is no neo folliculogenesis or neo-oogenesis in the postnatal or adult ovaries. The main reason for persistence of the dogma lies in the fact that it is very difficult to perform studies on adult human ovaries; it is impossible to perform in vivo studies, and there is also a lack of ovarian tissue available for research. However, there is more and more evidence about the presence of putative stem cells in postnatal and adult mammalian ovaries. First promising experimental results were obtained in the mouse model, but have been followed also in humans. The aim of this review article is to elucidate the fast upcoming new knowledge of ovarian stem cells, and their potential implications for reproductive medicine and gynecological oncology in the future. PMID- 22229566 TI - Fertility preservation in women after the cancer. AB - Thanks to the recent advances in cancer care, more and more young women can survive but suffer from infertility as a result of cancer treatment that had to be submitted. There are a variety of methods to preserve fertility, as chemoprotection, ovariopexy, and some assisted reproductive technologies, although some of these are promising but still highly experimental techniques. Cryopreservation of embryos for example is already established, while the oocyte banking is still considered an experimental practice. Many experiments have been conducted around the world on the cryopreservation of ovarian tissue and maturation of ovarian follicles, in an attempt to demonstrate its potential use in fertility preservation. Although in recent years there has been major improvements in the preservation of ovarian tissue, there are still many unresolved technical issues related to these procedures. In this chapter we examine the recent evidence of the pathophysiology of chemotherapy / radiotherapy induced gonadal toxicity, and recent data regarding the indications and results of the techniques used to preserve fertility in women with cancer. PMID- 22229567 TI - Angiogenesis and microvasculature in the female reproductive organs: physiological and pathological implications. AB - The female reproductive organs such as ovary, uterus, and placenta are some of the few adult tissues that exhibit regular intervals of rapid growth, and are highly vascularized and have high rates of blood flow. Angiogenesis is a process of vascular growth that is mainly limited to the reproductive system in healthy adult animals. The development of new blood vessels in the ovary and uterus is essential to guarantee the necessary supply of nutrients and hormones. The genetic and molecular mechanisms that control the development of capillary blood vessels in the reproductive organs are beginning to be elucidated. Reproductive organs contain and produce angiogenic factors which may act alone or in concert to regulate the process of vasculature. Vascular endothelial growth factors (VEGFs) and fibroblast growth factor (FGFs) are key factors for vascular system in the reproductive organs. Recent numerous studies reported several roles of VEGFs and FGFs on ovarian and uterine functions. In this review, we focus on the involvement of VEGFs and FGFs as angiogenic factors on reproductive organs and vascular therapy for diseases of reproductive organs using anti-angiogenic agents. PMID- 22229568 TI - Application of RNA interference for the control of female reproductive functions. AB - RNA interference, a recently discovered new mechanism controlling gene expression via small RNAs, was shown to be involved in the characterization and control of basic ovarian cell functions. The main classes of small RNAs, as well as their expression in ovaries have been described. Furthermore, the successful application of RNA interference for the study and control of basic ovarian functions (fertility, proliferation, apoptosis, secretory activity, luteogenesis, oocyte maturation and related ovarian cell malignant transformation) and production of recombinant proteins has been demonstrated. Application of RNA interference in reproductive biology and medicine can be successful in three main areas - (1) characterization and prediction of physiological and pathological state (association between particular small RNA and physiological or pathological processes), (2) application of small RNAs for regulation of reproductive processes and (3) treatment of reproductive disorders or their particular indexes. Problems of improvement of small RNA delivery to target ovarian cells and potent RNA interference-related approaches for the treatment of ovarian disorders (especially of ovarian cancer) have been discussed. PMID- 22229569 TI - New developments in pharmaceutical treatments for cystic fibrosis. PMID- 22229570 TI - New therapies in cystic fibrosis. AB - Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to abnormalities in transepithelial ion transport in the airways of affected patients. Lung disease is the major contributor to morbidity and mortality in patients with cystic fibrosis but recommended therapeutic interventions so far have focussed on symptom control rather than treatment of the underlying causes of the disease. New therapies that are currently in pre-clinical and clinical testing include CFTR pharmacotherapy, drugs targeting other ion channels, and hydrators of the cystic fibrosis airways. The current status of these and other new developments in the treatment of cystic fibrosis are reviewed. PMID- 22229571 TI - Progress in gene and cell therapy for cystic fibrosis lung disease. AB - Although the development of gene therapy for cystic fibrosis (CF) was high priority for many groups in academia and industry in the first 10 to 15 years after cloning the gene, more recently active research into CF gene therapy is only being performed by a small number of committed, mainly academic, groups. However, despite the waning enthusiasm, which is largely due to the realisation that gene transfer into lungs is more difficult than originally thought and the fact that meaningful clinical trials are expensive and difficult to perform, gene therapy continues to hold promise for the treatment of CF lung disease. Problems related to repeat administration of adenovirus and adeno-associated virus-based vectors led to a focus on non-viral vectors in clinical trials. The UK CF Gene Therapy Consortium is currently running the only active gene therapy programme, aimed at assessing if repeated administration of a non-viral gene transfer agent can improve CF lung disease. However, the recent suggestion that lentiviral vectors may be able to evade the immune system and, thereby, allow for repeat administration and long lasting expression opens new doors for the use of viral vectors in the context of CF gene therapy. In addition, early pre-clinical studies have recently been initiated to address cell therapy-based approaches for CF. This involves systemic and topical administration of a variety of stem/progenitor cells, as well as first attempts as producing a tissue-engineered lung. Recent studies in viral and non-viral vector developments, as well as cell therapy will be discussed and an update on clinical gene therapy studies will be provided here. PMID- 22229572 TI - Modifier gene studies to identify new therapeutic targets in cystic fibrosis. AB - Since the discovery of the CFTR gene mutations which cause cystic fibrosis (CF) in 1989 the average life expectancy of CF patients has almost doubled and now exceeds 37 years. The advances in molecular diagnostics and medical treatments expanded beyond the CF patient population as some of the newest treatments are also being tested for treatment of complex diseases such as COPD and other inherited disorders. Rapid development of CF therapeutics is important for the cystic fibrosis community and is an excellent example for other nonprofit organizations, disease foundations and pharmaceutical companies alike. Better understanding of disease variability and underlying molecular mechanisms through genetic association studies aimed to identify novel CF modifier genes opens new venues for targeted drug design. Furthermore, these genetic studies allow development of molecular diagnostic tests for patient population stratification and treatment personalization, which is already being done for CF patients with specific mutations in the CFTR gene, as well as implementation of new molecular tests for reliable assessment of disease progression and severity. PMID- 22229573 TI - New developments in inhaled antibiotics for the treatment of Pseudomonas aeruginosa. AB - The field of inhaled antibiotics that target Pseudomonas aeruginosa infections has made substantial contributions to the health, disease management, and life expectancies of individuals with cystic fibrosis (CF) over the last three decades. This paper reviews some of the recent clinical developments in the field of inhaled antibiotics for CF and briefly describes formulations and ongoing developments for US and/or European regulatory approvals. Lung delivery technologies, in regards to inhaled antibiotics for CF, are also reviewed. PMID- 22229574 TI - New treatments for emerging cystic fibrosis pathogens other than Pseudomonas. AB - The development of antimicrobial treatments for respiratory pathogens in cystic fibrosis (CF) has been an integral component to the increased survival of CF patients over the past fifty years. Despite significant treatment advances, however, respiratory failure secondary to chronic bacterial pulmonary infection remains the primary cause of death in CF patients. The purpose of this review is to discuss emerging pathogens (other than Pseudomonas) in CF by describing the characteristics of the organism, their clinical significance in CF, their mechanisms of antimicrobial resistance and the current treatment approaches including newer pharmaceutical modalities. This review will focus on the following pathogens: Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus and nontuberculous mycobacteria The goal is to familiarize the reader with the challenges in treating pulmonary infections in CF caused by multi-drug resistant pathogens and to highlight some of the newer pharmaceutical treatments that are currently the focus of intense research. PMID- 22229575 TI - Nitric oxide and L-arginine deficiency in cystic fibrosis. AB - The concentrations of nitric oxide are decreased in airways of patients with cystic fibrosis. The reasons for this nitric oxide deficiency are incompletely understood but may include reduced production from nitric oxide synthases due to decreased expression, the enzymes in airway epithelial cells, reduced availability of L-arginine, the substrate for nitric oxide synthases, and the presence of endogenous inhibitors of the enzymes in the airways. As nitric oxide plays a role in a number of important physiological processes in the lung including host defense against pathogens such as Pseudomonas aeruginosa, inflammation and the regulation of vascular and broncho motor tone, the lack of nitric oxide may contribute to lung disease in cystic fibrosis patients. Therapeutic interventions aiming to correct the nitric oxide deficiency in the cystic fibrosis airways are therefore currently being explored as new therapies for these patients. PMID- 22229576 TI - The multiple layers of signaling selectivity at protease-activated receptors. AB - The Protease-Activated Receptors (PARs) are G-protein-coupled receptors (GPCRs) characterized by a unique mechanism of activation. They carry built in their extended N-terminal structure their own activating agonist, in the form of a cryptic tethered ligand, unmasked by an irreversible proteolytic cleavage. Besides, PARs display several other particular properties, that converge and create interacting and intertwined layers of molecular processes regulating receptor's selective signaling with important biological and pharmacological consequences. These include the operation of multiple proteases, co-factors and protease inhibitors expressed in many types of cells and tissues, creating a dynamic balance between activators and inhibitors of PAR function in a tissue specific way. Membrane microdomain compartmentalization and allosteric modulation through intermolecular interactions between PARs adds further complexity to the receptor signaling and desensitization. Furthermore, molecular components interacting with thrombin and PARs take on new roles. In particular, activated protein C (APC) forms a significant negative feedback loop for thrombin with anticoagulant properties. In addition, APC exerts anti-inflammatory and direct neuroprotective effects in vivo and in vitro. This has informed the pharmacological dissection of anticoagulant from the anti-inflammatory and neuroprotective actions of APC and the generation of engineered APC mutations with diminished risk of serious bleeding, while preserving the cytoprotective effects of APC on cells. Even more important, these advances have made possible a paradigm shift, away from a "neurocentric" and towards a "vasculo-neuronal inflammatory model of action", which supports novel pharmacological strategies targeting multiple disease mechanisms. PMID- 22229577 TI - The G-protein coupled receptor family: actors with many faces. AB - G-protein coupled receptors (GPCRs) comprise the largest family of proteins in our body, which have many important physiological functions and are implicated in the pathophysiology of many serious diseases. GPCRs therefore are significant targets in pharmaceutical research. GPCRs share the common architecture of seven plasma membrane-spanning segments connected to each other with three extracellular and three intracellular loops. In addition, GPCRs contain an extracellular N-terminal region and an intracellular C-terminal tail. GPCRs could stimulate different intracellular G-proteins (internal stimuli) and signaling pathways after their interaction with different ligands (external stimuli). The exceptional functional plasticity of GPCRs could be attributed to their inherent dynamic nature to adopt different active conformations, which are stabilized differentially by different stimuli as well as by several mutations. This review describes the structural changes of GPCRs associated with their activation. Understanding the dynamic nature of GPCRs could potentially contribute in the development of future structure-based approaches to design new receptor-specific, signaling-selective ligands, which will enrich the pharmaceutical armamentarium against various diseases. PMID- 22229578 TI - GRK2 inhibition in heart failure: something old, something new. AB - Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains the number one killer disease in the western world. HF is a chronic and progressive clinical syndrome mainly characterized by reduction in left ventricular ejection fraction and adverse remodeling of the myocardium. One of its hallmark molecular abnormalities is elevation of cardiac G protein-coupled receptor (GPCR) kinase (GRK)-2, originally termed beta-adrenergic receptor kinase 1 (betaARK1), a member of the GRK family of serine/threonine protein kinases which phosphorylate and desensitize GPCRs. Up-regulated GRK2 in the heart underlies the diminished contractile responsiveness of the heart to positive inotropes, as it abrogates the pro-contractile signaling of various important cardiac receptors: mainly beta-adrenergic receptors (betaARs), but also angiotensin II type 1 receptors (AT(1)Rs), etc. Thus, cardiac-specific GRK2 inhibition via various transgenic approaches is postulated to combat chronic HF symptoms by increasing cardiac function, and even be salutary in some cases by increasing survival. This has been extensively documented over the past 15 years through a vast series of preclinical studies on animals of all sizes and shapes, from small mice up to large rabbits and pigs closely resembling human physiology, and genetically manipulated to have cardiac GRK2 inhibited or deleted, transiently or permanently. However, over the past several years, it has become increasingly clear that GRK2, like other members of the GRK family, exerts additional effects that can aggravate HF, in addition to merely blunt cardiac contractility by opposing cardiac betaAR G protein-mediated signaling. One of these newly discovered cardiotoxic effects of GRK2, uncovered by our laboratory, is promotion by adrenal GRK2 of sympathetic hyperactivity of the failing heart, a significant morbidity factor in HF, targeted therapeutically nowadays by the use of beta-blockers in HF pharmacotherapy. Thus, new avenues for therapeutic exploitation of GRK2 inhibition in HF treatment might be possible in the near future. The present review gives first a brief account of what has already been documented about the benefits of cardiac GRK2 genetic manipulation in HF as a positive inotropic therapy for the disease, and then goes on to discuss in detail the intriguing new possibility that has emerged of lowering GRK2 activity in the adrenal gland, which could constitute a novel sympatholytic therapy for HF that helps relieve the devastatingly cardiotoxic sympathetic overload of the failing heart. PMID- 22229579 TI - The plasticity of the 7TMR signaling machinery and the search for pharmacological selectivity. AB - Components of 7TMR signaling machinery once considered as rigid, fixed and inflexible entities, operating in a one-dimensional way, homogeneous spatially and temporally, are now proved to be structurally plastic, flexible and dynamic in space and time. 7TMRs are thought to exist as ensembles of multiple, inter convertible, pre-existing conformations and this conformational diversity provides a structural plasticity and the molecular mechanism for the functional diversity of 7TMRs. Furthermore, 7TMRs appear to function not as monomers, but rather as higher order structures, within which allosteric mechanisms affect ligand binding, G protein selection and receptor mobility and signalling of GPCR protomers. Moreover, their function is regulated through compartmentalization of G protein receptor and effector molecules into specialized membrane microdomains, such as lipid rafts and caveolae. Different permutations of receptor localization and translocation in membrane microdomains and internalization patterns, employed by 7TMRs regulate their signalling. Finally, the previous clear distinction between cell signalling and endocytic membrane trafficking has been blurred by evidence that these processes are intertwined and bidirectionally linked. 7TMRs normally signaling from the plasma membrane can elicit signaling cascades from an intracellular location, with distinct biochemical outputs. All these developments have moved the search for selective drugs beyond the mere design of receptor subtype-selective ligands targeting their orthosteric site. Even the notion of ligand has been expanded, so as to include "superagonists" ", acting as "super" 7TMR agonists to confer sustained endosomal signaling and biased agonists targeting GPCRs signalling from intracellular sites, as well as pharmacochaperones restoring insufficiently folded or misfolded receptors. The plasticity of the 7TMR signaling machinery and its dynamics in space and time will most probably impact further on the search for 7TMR drug selectivity. PMID- 22229580 TI - GRK2 at the control shaft of cellular metabolism. AB - G protein receptor kinase 2 (GRK2) has been for years mainly considered the negative regulator of the cardiac beta adrenergic signaling. However GRK2 is a ubiquitous molecule and its kinase activity and scaffold properties brought to several investigations which have evidenced its involvement in pathophysiology of extra-cardiac diseases. Later discoveries, moreover, indicated that this molecule is also able to influence other pathways such as insulin signaling by an inhibitory role similar to what described years before on betaAR signaling. The importance of this novel function is in particular related to the possibility that this molecule can regulate the cellular metabolism, modifying the ability of cells to utilize different substrates. This hypothesis has been recently investigated in animal model of Heart Failure, evidencing that upregulation of GRK2 leads to alterations of cardiac glucose metabolism in the early stages of the disease. However GRK2 shows increased level also in the early stages of others chronic disease such as Alzheimer's Disease, indicating that these findings could be possibly applied to others cellular system and supporting the emerging idea of GRK2 as master regulator of cellular metabolism. PMID- 22229581 TI - Current opinions and perspectives on the role of immune system in the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta. To date, although a bulk of evidences suggest that the etiology of PD is multifactorial, none of the mechanisms yet proposed have been considered conclusive. Activated glia seem to play a critical role in the degeneration of nigral dopaminergic neurons in PD, by secreting a complex array of cytokines, chemokines, proteolytic enzymes, reactive oxygen/nitrogen species and complement proteins that may have deleterious effects on the dopaminergic system. Recently, it has been reported that microglia activation and immunity are key factors contributing to disease progression. Here, we review studies on the role of inflammation mediated by the innate and adaptive immune systems involved in the pathogenesis of PD and highlight some of the important areas for future investigation. PMID- 22229582 TI - Current treatment strategies for multiple sclerosis - efficacy versus neurological adverse effects. AB - Recent years have broadened the spectrum of therapeutic strategies and specific agents for treatment of multiple sclerosis (MS). While immune-modulating drugs remain the first-line agents for MS predominantly due to their benign safety profile, our growing understanding of key processes in initiation and progression of MS has pioneered development of new agents with specific targets. One concept of these novel drugs is to hamper migration of immune cells towards the affected central nervous system (CNS). The first oral drug approved for MS therapy, fingolimod inhibits egress of lymphocytes from lymph nodes; the monoclonal antibody natalizumab prevents inflammatory CNS infiltration by blocking required adhesion molecules. The second concept is to deplete T cells and/or B cells from the peripheral circulation using highly specific monoclonal antibodies such as alemtuzumab (anti-CD52) or rituximab/ocrelizumab (anti-CD20). All of these novel, highly effective agents are a substantial improvement in our therapeutic armamentarium; however, they have in common to potentially lower the abundance of immune cells within the CNS, thereby collaterally affecting immune surveillance within this well-controlled compartment. In this review, we aim to critically evaluate the risk/benefit ratio of therapeutic strategies in treatment of MS with a specific focus on infectious neurological side effects. PMID- 22229585 TI - Virtual reality haptic dissection. AB - This project aims to create a three-dimensional digital model of the human hand and wrist which can be virtually 'dissected' through a haptic interface. Tissue properties will be added to the various anatomical structures to replicate a realistic look and feel. The project will explore the role of the medical artist, and investigate cross-discipline collaborations in the field of virtual anatomy. The software will be used to train anatomy students in dissection skills, before experience on a real cadaver. The effectiveness of the software will be evaluated and assessed both quantitatively as well as qualitatively. PMID- 22229586 TI - Associative status of the training context determines the effectiveness of compound extinction. AB - Studies of extinction of a target cue in compound with another excitor have produced evidence of both deepened and attenuated extinction relative to elemental extinction. The present experiments sought to resolve this discrepancy by assessing the effect of the extinction context-unconditioned stimulus (US) association on compound extinction. In an ABC renewal situation with rats, Experiment 1 replicated the observation that enhanced extinction (i.e., reduced conditioned suppression) occurs as a result of nonreinforcement in compound with a concurrent excitor. In Experiment 2, inflation of the extinction context-US association through unsignaled, intertrial US presentations reversed the effect of a concurrent excitor (i.e., extinction with a concurrent excitor was less effective than elemental extinction). Experiment 3 compared compound extinction and second-order conditioning with respect to the effect of context inflation, and produced results incompatible with the view that second-order conditioning contributed to the results of Experiment 2. In Experiment 4, a concurrent excitor enhanced extinction in ABC renewal and attenuated extinction in AAC renewal. The present results suggest that the effect of a concurrent excitor during extinction depends on the strength of the extinction context-US association, thereby confirming predictions of the sometimes -competing retrieval model of associative acquisition and extinction. PMID- 22229588 TI - Salience modulation in serial preexposure: implications for perceptual learning. AB - In three experiments rats were given serial preexposure to two flavor stimuli. In Experiment 1, some animals were given exposure to AX followed by the presentation of BX, a forward schedule; the others were given backward preexposure (BX->AX). Conditioning and test trials with the A element showed that salience or effectiveness of A was better protected in the forward than in the backward condition. Experiments 2 and 3 assessed the relevance of this salience modulation mechanism for perceptual learning. In these experiments, generalization of a conditioned aversion from AX to BX was reduced in the forward (but not in the backward) condition only after prolonged exposure, indicating that the establishment of an inhibitory link from B to A is required for successful discrimination. However, generalization to a novel compound stimulus, NX, was reduced in the forward group both after short and long preexposure, suggesting the existence of salience modulation processes that work in parallel with associative inhibition. These results seem to support the existence of a salience modulation mechanism that seems to be beyond the scope of current theories of perceptual learning. PMID- 22229589 TI - Classical conditioning mechanisms can differentiate between seeing and doing in rats. AB - We show that the attentional-associative SLG model of classical conditioning, based on the 1996 research of Schmajuk, Lam, and Gray, correctly describes experimental results regarded as evidence of causal learning in rats: (a) interventions attenuate responding following common-cause training but do not interfere on subsequent responding during observation, and (b) interventions do not affect responding after direct-cause training or (c) causal-chain training. According to the model, responding to the weakly attended test stimulus is strongly inhibited by the intervention in the common-cause case. Instead, in the direct-cause and causal-chain cases, the strongly attended test stimulus becomes inhibitory, thereby overshadowing the inhibitory effect of interventions. Most importantly, the model predicted that with relatively few test trials (a) the 2008 results of Experiment 3 by Leising, Wong, Waldmann, and Blaisdell should be similar to those of Dwyer, Starns, and Honey's 2009 Experiment 1, showing that interventions equally affect responding after common-cause and direct-cause training; and (b) the 2006 results of Experiment 2a by Blaisdell, Sawa, Leising, and Waldmann should be similar to those of Dwyer, Starns, and Honey's 2009 Experiment 2, showing that interventions equally affect responding after common cause and causal-chain training. When those data were made available to us, we confirmed those predictions. In agreement with the SLG associative model, but not with causal model theory, this evidence supports the notion that the attenuation of responding by interventions only following common-cause training is the consequence of well-known learning processes-latent inhibition, sensory preconditioning, conditioned inhibition, protection from extinction, and overshadowing. PMID- 22229590 TI - Evidence for a magnitude effect in temporal discounting with pigeons. AB - A magnitude effect in human intertemporal choice is well established-larger rewards or outcomes are discounted over time at a lower rate than are smaller rewards. However, many recent studies have failed to find a corresponding effect in nonhuman animals. Here we report a magnitude effect in temporal discounting for pigeons' choices involving a tradeoff between reward delay and amount. Pigeons chose between a small reward (1-s access to food) after a 2-s delay, and a large reward (4.5-s access to food) after a 28-s delay. Across conditions, the delays to the small and large rewards were increased or decreased, respectively. Temporal discounting functions obtained through a value-estimation procedure showed clear evidence of a magnitude effect: The value of the large reward decreased more slowly with increasing delay than the value of the small reward. We linked this result to a nonlinear relationship between choice and the delays associated with the small and large rewards. The nonlinearity was contrary to the generalized matching law but was predicted by the contextual choice model. Our results confirm the existence of a magnitude effect in nonhuman temporal discounting, showing that this adaptation is not unique to humans. PMID- 22229591 TI - Surgical and implant-supported fixed prosthetic treatment of a patient with ectodermal dysplasia: a case report. AB - Ectodermal dysplasia (ED) is a hereditary disorder that affects ectodermal structures. The main clinical oral manifestations of ED include oligodontia and deficient alveolar ridges. This case report presents the oral rehabilitation of a 15-year-old female patient who never received an accurate diagnosis or appropriate dental care. Treatment included a combination of surgical intervention, a maxillary tooth-supported fixed detachable telescopic prosthesis, and an implant-supported mandibular fixed partial denture. The results showed a significant improvement in the esthetics, function, and psychological status of the patient. This article stresses the importance of appropriate care in providing an acceptable quality of life for patients with ED. PMID- 22229592 TI - Decrease in oral health may be associated with length of time since beginning dialysis. AB - The aim of this study was to evaluate how oral health is affected by the length of time a patient has been receiving hemodialysis (HD) treatment. Ninety-four subjects participated in this study. Demographic, periodontal parameters, and decayed missing and filled teeth (DMFT) index were recorded by a trained and calibrated examiner. The subjects were divided into two groups: Group L (subjects who had been on HD for less than 36 months), and Group M (those who had been on HD for more than 37 months). In Group M, the mean probing depth was deeper (p= 0.01) and clinical attachment loss was significantly higher (p= 0.02) than subjects in Group L. The DMFT index score was also significantly higher in Group M (p= 0.03). A moderate correlation between length of time on HD and DMFT index, probing depth, and clinical attachment loss was observed. The group of subjects who had been on HD for more than 37 months had more periodontal disease and higher DMFT index scores, suggesting that the length of time on HD could negatively impact oral health. PMID- 22229593 TI - Oral vascular malformation in a patient with hereditary hemorrhagic telangiectasia: a case report. AB - Hereditary hemorrhagic telangiectasia (HHT) is an inherited mucocutaneous disease characterized by recurrent epistaxis, lesions on skin and oral mucosa, and arteriovenous malformations of the soft tissues. This article describes the treatment of a 64-year-old woman with a bleeding nodule, which was diagnosed as an arteriovenous malformation of the gingival mucosa. She was treated using sclerotherapy. Patients with HHT can be treated in the dental office and vascular malformations of these patients can be successfully managed with sclerotherapy, which eliminates the need for invasive surgical procedures and the possibility of postsurgical complications. PMID- 22229594 TI - A review of the oro-dento-facial characteristics of hereditary sensory and autonomic neuropathy type III (familial dysautonomia). AB - The oro-dento-facial features and dysfunction of children with hereditary sensory and autonomic neuropathy type III, known as familial dysautonomia or Riley-Day syndrome, was first described in the scientific literature in 1949. They include dental trauma; dental and soft tissue self-mutilation; normal dental age; normal sequence and timing of eruption and exfoliation of teeth; smaller tooth size; different and disproportional tooth components; normal alveolar bone height; small jaws, mild crowding, and malocclusions. These persons have craniofacial morphology that is different from accepted norms but they resemble norms of their ethnic origin. The subjects can have gray, pale, shiny faces with an asymmetric suffering expression; frontal bossing, with eventual hypertelorism and narrow lips; a low-caries rate; drooling, and hypersalivation. They can have changes in salivary composition and content, which influences plaque and calculus and increases the risk of gingival and periodontal diseases. They also have difficulty in controlling oral muscles; a progressive decrease in number of tongue fungiform papillae, accompanied by lack of taste buds; and specific dysgeusia, but a normal sense of smell. PMID- 22229595 TI - Dental treatment of patients with systemic diseases compared to patients with developmental disabilities under general anesthesia. AB - The medical and dental records were examined for 46 patients with systemic diseases (SD) and 75 patients with developmental disabilities (DD) aged 2-20 years, who had received dental treatment under general anesthesia (GA). Age, gender, decayed missing and filled teeth (dmft/DMFT), dental procedures, duration of GA, and posttreatment hospitalization were recorded. Before treatment, dental disease in the primary teeth was significantly higher among the group with SD (p= 0.04). In the permanent teeth, dental disease was higher among the group with DD, though not significantly. More teeth were restored, (p= 0.015) and total dmft (p= 0.043) was significantly higher among subjects with SD. In the permanent teeth, more extracted and more restored teeth and higher DMFT were noted among subjects with DD, though not significantly. Only pulpectomies were significantly more prevalent among those with DD (p= 0.038). Six subjects needed hospitalization due to their diseases after GA. PMID- 22229596 TI - A one-year survey of inpatient dental consultations at a children's hospital. AB - This study describes dental consultations for pediatric inpatients. Records of inpatient dental consultations in 2007 were analyzed to determine consultation reasons, diagnoses, treatment, and demographics. Consultations from Hematology Oncology (Hem-Onc) and Transplant Oncology (T-Onc) were further analyzed. One hundred and fifty-five consultations were performed for 133 subjects. Hem-Onc (37%) and T-Onc (17%) were the most frequent consultations. Requests were most frequently for baseline evaluation (33%) and oral pain/discomfort (10%). Frequent dental diagnoses were soft tissue conditions (29%) and caries (23%). A dental home preexisted for 48% of subjects and in 44% of consultations with caries and 53% without caries. Caries was present in 30% of consultations where Medicaid was sole payer versus 18% with non-Medicaid payers. Subjects from the Oncology department had more baseline evaluations, frequently had soft tissue diagnoses, and more often received preventive counseling and treatment under general anesthesia. In conclusion, dentists play an important role in optimal management of certain hospital inpatients. PMID- 22229598 TI - Proximal femoral locking plate with cannulated screws for the treatment of femoral neck fractures. AB - The purpose of this study was to evaluate the efficacy and safety of the proximal femoral locking plate with cannulated screws for the treatment of femoral neck fractures. A prospective study was performed in 41 patients with femoral neck fractures treated with a proximal femoral locking plate with cannulated screws between January 2005 and December 2008. Twenty-five men and 16 women had a mean age of 47 years (range, 21-65 years). The time from injury to surgery ranged from 2 hours to 7 days. Three patients had a Garden type I fracture, 9 a type II, 18 a type III and 11 a type IV. Operative time, intraoperative blood loss, fracture healing time, Harris Hip Score for hip function, and complications were recorded to evaluate treatment effects.Mean operative time was 63.6 minutes (range, 40-90 minutes), with mean intraoperative blood loss of 84.2 mL (range, 50-200 mL). Mean time to union was 15.5 weeks (range, 12-36 weeks). Two patients (Garden type III and type IV) did not achieve union, and 4 patients (1 Garden type III and 3 type IV) had avascular necrosis of the femoral head. In patients with nonunion, 1 (Garden type III) underwent intertrochanteric osteotomy, and the other underwent total hip replacement (THR). In patients with avascular necrosis, 2 required THR and the others (1 Garden type III) required no further surgery. Twenty-six (63%) patients had excellent results, 8 (20%) had good results, 3 (7%) had moderate results, and 4 (10%) had poor results. These findings suggest that the proximal femoral locking plate with cannulated screws for the treatment of femoral neck fractures is effective and results in fewer complications, especially for Garden type I, II, and III fractures. PMID- 22229599 TI - Pseudoseptic arthritis of the shoulder following pneumococcal vaccination. AB - Pseudoseptic arthritis is primarily described in rheumatoid arthritis and other systemic inflammatory conditions. To our knowledge, only 1 case report of pseudoseptic arthritis associated with intra-articular injection of a pneumococcal polyvalent vaccine (PPV) has been published. Here, a second case is presented in which a patient presented with swelling, pain, and erythema of the affected shoulder. A 59-year-old woman presented to the emergency department with a 3-day history of severe pain and decreased mobility of her left shoulder after receiving a PPV vaccination. Her clinical and laboratory workup was suspicious for septic arthritis; however, magnetic resonance imaging of the affected shoulder with and without contrast showed only a partial thickness tear of the rotator cuff, fluid in the subacromial/subdeltoid bursa, and subcutaneous edema without evidence of an abscess. Based on the clinical and laboratory data, she underwent arthroscopic debridement. There was inflammatory tissue throughout the shoulder but no obvious purulent material. She did well postoperatively with a supervised range of motion rehabilitation protocol. Her cultures remained negative. At 12 weeks, she was discharged from follow-up. We suspect that the vaccination was inadvertently injected into the glenohumeral joint directly through the rotator cuff given the lack of a full-thickness tear and the patient's thin body habitus, which could explain her aseptic inflammatory arthritis. PMID- 22229600 TI - Hemiarthroplasty in a patient with pigmented villonodular synovitis of the shoulder. AB - We report the 2-year follow-up results of a hemiarthroplasty in a 29-year-old patient with pigmented villonodular synovitis (PVNS) with extra-articular extension and severe bony destruction. The patient presented with diffuse pain and swelling of the right shoulder for several years. Radiographs showed severe osteolytic lesions in the humeral head and neck, greater tuberosity, and a small osteolytic lesion in the glenoid neck area. Further examination with magnetic resonance imaging of the shoulder joint showed a large, lobulated soft tissue mass extending from the subdeltoid area to the chest wall invading the adjacent bony structures. The operative findings included a large, multilobulated, yellowish-brown mass extending from the subdeltoid area to the axillary pouch, subacromial space, and thoracic wall. The mass invaded the anatomical neck area of the humeral head and caused a fracture of the humeral head. We observed a complete rupture of the long head of the biceps tendon, supraspinatus tendon, and infraspinatus tendon, but the subscapularis tendon was partially ruptured. We performed the complete excision and cemented hemiarthroplasty. At 2-year follow up, no signs of local recurrence were present. The patient had no significant pain and achieved a good functional result.To the best of our knowledge, 1 report with shoulder hemiarthroplasty in PVNS of the shoulder has been published in the English literature. For PVNS of the shoulder with a large extra-articular extension and bony destruction, shoulder arthroplasty with total synovectomy produces the lowest recurrence rates because of better access and excision to the posterior location of the PVNS lesion. PMID- 22229601 TI - Proximal clavicle physeal fracture with posterior displacement: diagnosis, treatment, and prevention. AB - Posterior sternoclavicular fracture displacement can present as a posterior sternoclavicular joint dislocation and is rare in the pediatric population. This article provides an algorithm for evaluation and management.A 14-year-old boy with a previously undiagnosed posterior sternoclavicular displacement presented with persistent 7/10 shoulder pain extending into his neck after undergoing nonoperative treatment for an unconfirmed diagnosis at another emergency department. Plain radiographs revealed a displacement of the right medial clavicle, and the position of the clavicular head indicated advanced imaging. Computed tomography showed the posterior portion of the clavicular head butting against the left braciocephalic vein at its confluence with the superior vena cava. The patient underwent open reduction and internal fixation. After exposing the sternoclavicular joint, a Salter-Harris I fracture with no evidence of vascular injury was confirmed. The fracture was reduced and stabilized using figure-eight #5 Ethibond sutures (Ethicon, Somerville, New Jersey), and the patient was placed in an immobilizer for 1 week. At 1 year postoperatively, the patient regained full range of motion and was completely healed.Posterior clavicle displacements are potentially devastating injuries that are difficult to diagnose. Coordinating operative treatment with orthopedic and general surgery is indicated to manage the fracture or displacement and potential vascular injury. Due to difficulties in maintaining a closed reduction, open reduction and internal fixation is the preferred mode of treatment for the reduction of all posterior clavicular fracture displacements. PMID- 22229602 TI - Intracranial meningeal hemangiopericytoma metastatic to the scapula. AB - Meningeal hemangiopericytomas are rare vascular tumors that have a propensity for recurrence and metastasis. Intracranial hemangiopericytomas are rare vascular tumors. They account for 0.5% of primary central nervous system tumors and 2% of meningiomas. Unlike usual benign meningiomas, which rarely metastasize extracranially, meningeal hemangiopericytoma has a high rate of local recurrence and distant metastasis. The treatment paradigms for hemangiopericytomas and meningiomas differ based on their biological behaviors. Hemangiopericytomas have higher rates of recurrence and metastasis compared with meningiomas. Intracranial meningeal hemangiopericytoma is characterized by clinically repeated local recurrences at the primary site. Bone, liver, lung, central nervous system, and abdominal cavity are the most commonly reported sites of metastasis in hemangiopericytomas.This article describes a case of bone metastasis with extensive involvement of the scapula from intracranial hemangiopericytoma. Bone metastasis can be seen in a relatively late phase of the disease, with metastasis to other organs. Although radiation therapy is effective in controlling pain from bone metastases in unresectable disease and those with extensive visceral metastases, aggressive local surgical control of a solitary bone metastasis may be an option for patients with limited distant disease. The diagnosis may be initially confused with clear cell meningioma and benign meningiomas. The management of bone metastasis is not well reported in the orthopedic literature. PMID- 22229603 TI - Epithelioid hemangioma of the distal humerus with pathologic fracture. AB - Epithelioid hemangioma is a rare tumor that can have bone involvement. Its clinically and radiographically aggressive appearance mimics a malignant neoplasm. Although epitheliod hemangioma has been described as having an aggressive appearance on magnetic resonance imaging (MRI) and plain radiographs, this is the first reported case of pathologic fracture associated with this lesion to our knowledge. This article describes a case of epithelioid hemangioma involving the distal humerus, which initially presented with progressive pain and fracture of the lateral condyle. The aggressive appearance on plain radiographs and MRI suggested a malignant bone tumor. This preliminary diagnosis was confirmed due to the presence of local lymph node spread on positron emission tomography/computed tomography. After a core needle biopsy revealed nondiagnostic tissue, rather than performing a wide resection based on a presumptive malignant diagnosis, we followed the standard diagnostic algorithm and performed an open biopsy with temporary internal stabilization. The tissue sample was adequate and revealed a diagnosis of epithelioid hemangioma. Based on this finding, we were able to proceed with surgical management, including curettage of the lesion, placement of a bone graft, and internal fixation, rather than a wide resection with elbow joint replacement. This article emphasizes the need for careful adherence to the diagnostic algorithm for musculoskeletal tumors. In doing so, a definitive diagnosis was reached, and our patient was able to resume his occupation as a laborer without the restrictions that would have accompanied elbow arthroplasty. PMID- 22229604 TI - Intraosseous tophus deposits in the os trigonum. AB - High levels of uric acid cause accumulation of monosodium urate crystals. This formation of masses is called tophus. Intraosseous tophus deposits are rare, even for patients with gout. We report an unusual case of intraosseous tophus deposits in the os trigonum. The patient presented with ankle pain with no previous history of gout. On examination, tenderness on the posterior aspect of his ankle and limitation of plantarflexion was noted. Laboratory values were normal, except for an elevated serum uric acid value. Radiographs of the right ankle showed the presence of a large os trigonum with osteosclerotic changes, whereas magnetic resonance imaging showed intraosseous tophus deposits in the os trigonum. Conservative therapy failed, and the patient was admitted for an endoscopic resection of the os trigonum.Intraosseous chalky crystals were detected during endoscopic resection of the os trigonum. The histological diagnosis was tophaceous gout. The underlying pathological mechanism of intraosseous tophi is uncertain. Penetration of urate crystals from the joint due to hyperuricemia may be the mechanism of deposition in this patient.When a patient with hyperuricemia presents with posterior ankle impingement symptoms, intraosseous tophus deposits should be included in the differential diagnosis. Posterior endoscopic excision may be an option for treating intraosseous lesions of the os trigonum because of good visualization, satisfactory excision, and rapid recovery time. PMID- 22229605 TI - Life-threatening necrotizing fasciitis due to 'bath salts' injection. AB - Necrotizing fasciitis is an orthopedic emergency. The ability to quickly and accurately diagnose this rapidly spreading disease can save a patient's life and limb. However, the diagnosis is complex because necrotizing fasciitis usually manifests as a less severe cellulitis or abscess while the majority of the damages rage beneath the surface of the skin. Although the diagnosis is not new, the potential causes and vectors continually change. This article reports a new source of necrotizing fasciitis in an intramuscular injection of "bath salts," a rapidly emerging street drug that is legal in some states and evades authorities with its innocuous name. The patient presented 2 days after injection of bath salts with extensive cellulitis extending to the mid portion of her upper arm. The cellulitis initially responded to broad-spectrum intravenous antibiotics, but rapidly deteriorated 48 hours later, leading to a forequarter amputation with radical mastectomy and chest wall debridement to obtain healthy tissue margins and control the disease. The patient made a full recovery after further minor debridements, negative pressure dressings, directed antibiotic therapy, and skin grafting. The recent emerging popularity of this highly obtainable, injectable substance may lead to an increase in cases of necrotizing fasciitis. Orthopedic surgeons should be vigilant in diagnosing this process early and should perform an extensive debridement. PMID- 22229606 TI - Nocardia spinal epidural abscess: 14-year follow-up. AB - This article describes an immunocompetent patient with a spinal abscess that developed from Nocardia asteroides. Nocardia is a rare etiology for spinal abscesses, especially in immunocompetent patients. Nocardia usually affects the lungs and brain of immunocompromised individuals. Few reports of Nocardia involving bones or the spine have been published.The patient had a history of chronic back pain and had several procedures to alleviate the pain. In August 1997, the patient had an epidural block and a subsequent infection that was treated with antibiotics. In October 1997, she developed increasing back pain greater than her baseline chronic low back pain. Additional presenting symptoms were fever, chills, and nausea. On admission, magnetic resonance imaging (MRI) revealed an epidural abscess. The patient underwent irrigation and debridement. Postoperatively, the patient was initially placed on broad-spectrum antibiotics. After 38 days, the culture was identified as N asteroides, and the patient was placed on appropriate antibiotics. The patient has been followed with MRI prior to the discovery of the abscess and annually since the abscess due to her baseline chronic low back pain. No residual abscess was discovered. PMID- 22229607 TI - Mid-radial portal for operative arthroscopy of the elbow: cadaveric and clinical description of a new portal. AB - We report a previously undescribed portal on the lateral aspect of the elbow-the mid-radial portal-and discuss the safety and use of this portal in a clinical practice via cadaveric dissection and retrospective review of 61 patients. It is located midway between the proximal anterolateral and the direct lateral portals at the level of the radiocapitellar joint and serves as a second portal on the lateral side of the elbow for use anteriorly or posteriorly. The portal penetrates the common extensor origin and courses between the radial and ulnar bands of the lateral collateral ligament complex prior to penetrating the joint capsule.In the clinical series, the mid-radial portal was used in 40 (66%) of 61 cases. The most common procedures involved removal of loose bodies and debridement in the radiocapitellar joint or posterolateral gutter. Follow-up in the clinical series averaged 6 months. No major and 2 minor complications, neither of which could be directly attributed to the use of the mid-radial portal, were found. Specifically, no cases of postoperative lateral instability existed. The previously undescribed mid-radial portal is a safe, effective option for arthroscopy on the lateral aspect of the elbow. PMID- 22229608 TI - Evaluation of arthroscopic stabilization of acute acromioclavicular joint dislocation using the TightRope system. AB - The purpose of this study was to evaluate the results of the arthroscopic treatment of acute acromioclavicular dislocation using the TightRope system (Arthrex, Naples, Florida). Between January 2006 and May 2007, ten shoulders in 10 patients with acute acromioclavicular joint dislocation (Rockwood types IV and V) underwent arthroscopic acromioclavicular joint stabilization using the TightRope. Average patient age was 30 years (range, 22-42 years), and mean follow up was 24 months (range, 18-30 months). Follow-up occurred at 2 and 6 weeks, 3 months, and then every 6 months postoperatively. The shoulders were evaluated radiologically by comparing the acromioclavicular joint with the normal side and clinically by assessing the pain, function, and range of joint motion using the Constant score.Ten patients returned to work without pain 10 to 12 weeks postoperatively. Average Constant score was 96.3 (range, 94-99) at last follow up. Because of technical error, 1 patient experienced TightRope fixation failure on the coracoid side, and the acromioclavicular joint was redislocated, which was treated by an open technique. The 10 patients were satisfied with their functional results and cosmetic appearance.The arthroscopic treatment of acute acromioclavicular dislocation using the TightRope is a minimally invasive surgical technique that has been proven effective for the treatment of these lesions. It is characterized by less morbidity, less hospitalization, excellent cosmoses, and early rehabilitation. PMID- 22229609 TI - Anatomical reduction for treatment of displaced midshaft clavicular fractures: Knowles pinning vs. reconstruction plating. AB - The purpose of this study was to compare Knowles pinning and fixation with cerclage wires vs reconstruction plating and fixation with extraplate wires for the treatment of displaced midshaft clavicular fractures, with anatomical reduction serving as the objective. In this retrospective study, the records of 103 consecutive patients with complete follow-up data (minimum 12 months follow up) treated operatively for displaced midshaft clavicular fractures between 1997 and 2009 by a single surgeon were reviewed. A total of 53 patients (mean age, 35.2+/-14.5 years) received Knowles pinning and 50 patients (mean age, 39.9+/ 14.8 years) received reconstruction plating. No differences were observed between the groups with respect to type of fracture, union rate (88.7% vs. 94.0%, respectively; P=.439), and surgical complication rate (13.2% vs. 10.0%, respectively; P=.761). Wound length was significantly shorter in the Knowles pinning group (5.3+/-0.9 cm vs. 8.4+/-0.5 cm, respectively; P<.001) and implant related complications, symptomatic hardware (P<.001), visible implant (P<.001), and palpable implant (P<.015) were significantly higher in the reconstruction plating than in the pinning group. Anatomical reduction is the ultimate objective of anatomical and functional restoration when surgical intervention is indicated, and patient compliance is the major prerequisite for surgical treatment. For treatment of displaced midshaft clavicle fractures, both Knowles pinning with cerclage wires and reconstruction plating with extraplate wires provide rigid fixation and perfect union. PMID- 22229610 TI - Is it possible to train patients to limit weight bearing on a lower extremity? AB - Orthopedic patients are often instructed on how much weight to bear on an injured or postoperative extremity. Although specific weight-bearing instructions are given to a majority of lower-extremity orthopedic patients, the ability of patients to comply with these instructions is questioned in the medical literature. This study compared the effectiveness of new forms of clinical interventions designed to train patients on weight bearing, focusing on the use of biofeedback devices designed to offer real-time feedback to partial weight bearing patients. Twenty healthy patients aged 20 to 30 years completed 3 interventions: (1) verbal instructions on weight bearing, (2) training with a bathroom scale, and (3) training with a biofeedback device.Patients given touchdown weight-bearing instructions (25 lb) initially bore an average of 63.57+/-6.24 lb when given verbal instructions. This was reduced to 44.75+/-5.69 lb after training with a bathroom scale (P<.001), and was further reduced to 26.2+/-1.57 lb with biofeedback training (P=.011). Likewise, patients given partial weight-bearing instructions (75 lb) initially bore an average of 92.28+/ 7.85 lb. No improvement occurred with the use of a bathroom scale (at 75 lb), which showed an average of 90.82+/-7.19 lb (P=1.000). Training with a biofeedback device improved the average weight bearing to 69.67+/-3.18 lb (P=.014).Biofeedback training led to superior compliance with touchdown and partial weight-bearing instructions. Because partial weight-bearing instructions are commonly given to orthopedic patients, training with such a device may be appropriately considered. PMID- 22229611 TI - Association of low-energy femoral shaft fractures and bisphosphonate use. AB - The purpose of this study was to elaborate on the association between the use of bisphosphonates and low-energy femoral shaft fractures. A retrospective review was performed between January 2000 and January 2010 to identify patients older than 65 years who sustained femoral shaft diaphyseal fractures (Orthopaedic Trauma Association classification 32 A [extra-articular], B [partial articular/unicondylar], or C [complete articular/bicondylar]) using ICD-9 code 821.01. After exclusion criteria were applied, 77 patients remained for analysis. A total of 66 patients had no history of bisphosphonate therapy, and 11 patients had received bisphosphonate therapy for >2 years prior to admission. All 11 patients in the bisphosphonate group had sustained a low-energy fall from a standing height or lower. In 9 of 11 (82%) patients in the bisphosphonate group, radiographs resembled transverse shaft fractures with lateral cortical beaking that have been observed in patients on chronic bisphosphonate therapy.Our series echoes the findings of other authors, who found that bisphosphonate use is associated with lateral cortical beaking and low-energy, transverse fractures of the femoral shaft. Further research is needed to determine if specific medications and length of treatment are important risk factors. PMID- 22229612 TI - Comparative study of the proximal femoral nail antirotation versus the reconstruction nail in the treatment of comminuted proximal femoral fracture. AB - The purpose of our study was to compare the proximal femoral nail antirotation (PFNA; Synthes, Paoli, Pennsylvania) with a reconstruction nail (Recon; Zimmer, Warsaw, Indiana) in the treatment of comminuted proximal femoral fractures. Between 2003 and 2010, twenty-three consecutive patients with AO/Orthopaedic Trauma Association 31-A3 fractures combined with proximal 32 fractures who had a minimum 18-month follow-up were evaluated retrospectively. There were 10 patients (age range, 18-74 years) in the Recon nail group and 13 patients (age range, 22 90 years) in the PFNA nail group. Patients treated with Recon nails experienced a longer operation time (P=.006) and more blood loss (P=.012) than patients treated with the PFNA nail. On postoperative radiographs, the change in the neck-shaft angle was 8.8 degrees in the Recon nail group and 4.7 degrees in the PFNA nail group (P=.048). The fracture union time averaged 31.8 weeks in the Recon nail group and 21.5 weeks in the PFNA nail group (P=.148). More patients in the Recon nail group underwent major or minor reoperation (P=.038) compared with the PFNA nail group. No implant failure occurred in either group. The functional results were similar in the 2 groups. For the treatment of comminuted proximal femoral fractures, use of either the PFNA and Recon nail is clinically effective. However, the PFNA nail provides a shorter operation time, less blood loss, and better realignment ability and reduces the incidence of reoperation. Therefore, the PFNA nail can be considered a better device than the Recon nail. PMID- 22229613 TI - Use of the reamer-irrigator-aspirator may reduce tumor dissemination during intramedullary fixation of malignancies. AB - Intramedullary nail fixation is the treatment of choice for impending and pathologic fractures secondary to metastatic cancer; however, this procedure has been shown to cause systemic embolization of intramedullary contents. This article reports the use of the reamer-irrigator-aspirator (RIA) (Synthes, Paoli, Pennsylvania) instead of a standard femoral reamer to decrease tumor intravasation during femoral intramedullary nail fixation for impending or pathologic fractures.Twenty-one consecutive patients indicated for fixation of malignant femoral lesions were treated with intramedullary nail placement. The RIA was used for canal preparation, and solid reamings were collected and submitted for analysis by a single pathologist. The volume of each specimen was recorded, and representative samples were examined histologically to determine their percent tumor content. These data were then used to estimate the volume of tumor retrieved by the RIA in each case. The mean volume of reamings collected by the RIA was 75.0 cc per case (range, 23.4-196.0 cc), and the mean tumor content was 24.8% (range, 1.0%-60.0%). The mean estimated volume of tumor retrieved in each case was 16.7 cc (range, 0.35-36.0 cc). In 2 cases, the tip of the RIA dissociated from the device intraoperatively but was retrieved without adverse consequence to the patient. Use of the RIA in cases of femoral intramedullary nail fixation for pathologic lesions or fractures effectively retrieves variable amounts of intramedullary contents, including tumor. By preventing the systemic dissemination of malignant cells, this technique may reduce the risk of distant metastases. PMID- 22229614 TI - Comparison of the effects of human beta-defensin 3, vancomycin, and clindamycin on Staphylococcus aureus biofilm formation. AB - Despite improvements in surgical techniques and implant design in orthopedic surgery, implantation-associated infections are still a challenging problem for surgeons. In 2006, trace quantities of human beta-defensin 3 (hBD-3) were found in human bone tissue and bone cells. Human beta-defensin 3 is a 45-amino-acid peptide that is considered the most promising class of defensin antimicrobial peptides and may help in the prevention and treatment of implantation-associated infections. Studies of the effectiveness of hBD-3 against Staphylococcus aureus showed that hBD-3 was more potent at low concentrations than other antibiotics. The effect of hBD-3 on S aureus biofilms has not been reported. We studied the effect of hBD-3, vancomycin, and clindamycin on S aureus biofilms and on the survival of the bacteria in the biofilms.Staphylococcus aureus biofilms were examined with confocal scanning laser microscopy. Staining with LIVE/DEAD BacLight viability stain (Molecular Probes Europe BV, Leiden, The Netherlands) differentiated between live and dead bacteria within the biofilms, and extracellular polymeric substances (slime) from the biofilms was evaluated after staining with calcofluor white (Sigma Chemical Company, Rocky Hill, New Jersey). Human beta-defensin 3 and clindamycin reduced the S aureus biofilm area. Human beta-defensin 3 was significantly more effective against bacteria from the S aureus biofilms than was clindamycin. Vancomycin did not reduce the S aureus biofilm area. PMID- 22229615 TI - Autologous chondrocyte implantation for knee cartilage injuries: moderate functional outcome and performance in patients with high-impact activities. AB - Few studies have assessed the results of autologous chondrocyte implantation in patients with high-impact activities. The purpose of this study was to evaluate the early functional outcome and activity level after 2-stage autologous chondrocyte implantation in professional soldiers and athletes. Nineteen patients with an average age of 32.2 years were treated with autologous chondrocyte implantation and followed up for a minimum of 2 years. All patients except 2 had received previous arthroscopic treatment with debridement and/or microfracture. The mean size of the postdebridement defect was 6.54 cm2. Using Novocart technology (B. Braun-Tetec, Reutlingen, Germany), periosteal patch and matrix assisted autologous chondrocyte implantation was sequentially performed with no randomization. The average subjective knee evaluation score and Lysholm score improved from 39.16 and 42.42, respectively, preoperatively to 62.4 and 69.4, respectively, at latest follow-up. Median Tegner activity score was 8.8 before injury, 3.8 preoperatively, and 6.15 at latest follow-up. Second-look arthroscopy was performed in 11 patients due to persistent pain, decreased range of movement, and mechanical symptoms. Six of 19 (31.5%) patients with professional or recreational athletic activities returned to preinjury levels of athletic performance.This study shows that mid-term results with autologous chondrocyte implantation in high-performance patients are not as good as have been reported with other similar technologies. Motivational issues during prolonged rehabilitation, multiple surgical interventions before autologous chondrocyte implantation, patient age, and large defects can potentially influence the outcome and overall performance in this selected group of patients. PMID- 22229616 TI - Pedicle screw placement with O-arm and stealth navigation. AB - Various navigation systems are available to aid pedicle screw placement. The O arm replaces the need for fluoroscopy and generates a 3-dimensional volumetric dataset that can be viewed as transverse, coronal, and sagittal images of the spine, similar to computed tomography (CT) scanning. The dataset can be downloaded to the Stealth system (Medtronic Navigation, Louisville, Colorado) for real-time intraoperative navigation.The main objectives of the current study were to assess (1) accuracy of pedicle screw placement using the O-arm/Stealth system, and (2) time for draping, positioning of the O-arm, and screw placement. Of 188 screws (25 patients), 116 had adequate images for analysis. The average time for O-arm draping was 3.5 minutes. Initial O-arm positioning was 6.1 minutes, and final positioning was 4.9 minutes. Mean time for screw placement, including O-arm draping and positioning and array attachment, was 8.1 minutes per screw. Mean time for screw placement alone was 5.9 minutes per screw. Screw placements on final O-arm images were on average 3.14 mm deeper than on the snapshot navigation images. Three screws (2.6%) breached the medial cortex, and 3 screws (2.6%) were misaligned and did not follow the pilot hole trajectory.The use of the O arm/Stealth system was associated with a low rate of pedicle screw misalignment. The time to place screws was less than previously reported with CT navigation, but longer than conventional techniques. It is important to be aware of the potential discrepancy between snapshot navigation images and actual screw placement on final O-arm images. Our findings suggest that final screw positions may be deeper than awl positions appear on navigation images. PMID- 22229617 TI - Anterior reconstruction with nano-hydroxyapatite/polyamide-66 cage after thoracic and lumbar corpectomy. AB - Cages are used to regain stability of the anterior spinal column following vertebrectomy, which could prevent significant donor-site morbidity from the iliac autograft harvesting and the risk of disease transmission associated with the allograft. The hollow, porous, cylindrical nanohydroxyapatite/polyamide 66 (n HA/PA66) cage is a new nonmetallic cage device made by combining nanohydroxyapatite with polyamide 66. Few studies have examined its effectiveness and outcomes over a follow-up >2 years.We retrospectively studied 51 consecutive patients with acute traumatic thoracic or lumbar burst fracture who underwent anterior reconstruction with the n-HA/PA66 cage following single-level corpectomy. Radiologic parameters (radiographs and 3-dimensional computed tomography scans) preoperatively and at 1 week and >2 years postoperatively, as well as clinical outcome parameters (SF-36 scores), were analyzed. Mean kyphosis correction in the segment within the cage was 11.8 degrees +/-7.1 degrees , and mean loss of correction at last follow-up was 1.9 degrees +/-2.1 degrees . Osseous fusion was achieved in 90.2% of patients, and severe cage subsidence (settling >2 mm) was observed in 19.6% of patients at final follow-up. Significant differences were found in 7 of 8 health dimensions of the SF-36 between neurologically intact patients and neurologically injured patients. Our clinical results indicate that the n-HA/PA66 cage is an effective device for reconstruction after anterior thoracic and lumbar vertebral resection, resulting in a high rate of successful osseous fusion and a low proportion of severe cage subsidence. PMID- 22229618 TI - Minimally invasive thoracolumbar corpectomy and reconstruction. AB - Minimally invasive surgical approaches have been advocated to approach ventrolateral thoracolumbar pathology. This article describes our technique for performing minimally invasive surgical thoracolumbar corpectomy and reconstruction. Twenty-five consecutive patients at a single institution were treated between 2006 and 2010 for a variety of diagnoses including tumors, infections, and trauma. Treatment variables, including operating time, estimated blood loss, number of levels treated, and complications, were collected, as were visual analog scale (VAS) scores for pain.Surgical times (mean, 188.5 minutes) and blood loss (mean, 423 mL) reflect a significant improvement over standard open corpectomy procedures. More than 60% of patients did not need blood products after the corpectomy procedure because substantial blood loss encountered during an open exposure to the spine was obviated. Similarly, operative times and anesthetic load was minimal enough for >=80% of our patients to be extubated immediately after the corpectomy procedure. A 62% decrease in self-reported VAS scores was observed. No wound complications or radiographic evidence of implant subsidence or failure were observed at last follow-up.The advantages of the minimally invasive approach for corpectomies of the thoracolumbar spine were that an access surgeon was not needed; tissue dissection and surgical exposure were reduced, improving VAS scores postoperatively; and blood loss and operative times were minimized, preventing hemodynamic deterioration in these complex cases. Corpectomies may be performed in this fashion safely, with excellent pain relief and without many of the morbidities and difficulties associated with conventional open procedures. PMID- 22229619 TI - Corona mortis artery avulsion due to a stable pubic ramus fracture. AB - A 70-year-old woman with osteoporosis fell at home and presented to our emergency department with intense left hip pain. Radiographs revealed a left iliopubic rami fracture and nondisplaced right ischiopubic rami fracture. She was discharged after a 24-hour observation with no clinical changes. Seventy-two hours later, she was readmitted with a painful abdominal mass, progressive oliguria, tachycardia, hypotension, and profuse perspiration with generalized pallor. On physical examination, a painful mass in the hypogastrium and intense inflammation in the thigh and the proximal portion of left knee were found.Emergent multiphase contrast computed tomography revealed a large nonhomogeneous hematoma neighboring the fractured left iliopubic rami, and contrast extravasation indicated arterial bleeding. Selective angiography showed an active hemorrhage from the distal portion of a small branch of the left obturator artery. After embolization of the arterial vessel, the patient was hemodynamically stable. The fracture was rotationally and vertically stable.These fractures are common, especially among the elderly. This type of injury is usually treated conservatively and with active mobilization once the acute pain has subsided. Supraselective embolization after localization of the bleeding vessels by arteriography is recognized as a minimally invasive procedure with excellent outcomes in hemorrhagic complications of pelvic fractures. An apparently benign pubic rami fracture in the setting of hemodynamic instability should raise the suspicion of a corona mortis injury, especially in elderly and anticoagulated patients. PMID- 22229620 TI - Femoral neck fracture following hardware removal. AB - It is uncommon for femoral neck fractures to occur after proximal femoral hardware removal because age, osteoporosis, and technical error are often noted as the causes for this type of fracture. However, excessive alcohol consumption and failure to comply with protected weight bearing for 6 weeks increases the risk of femoral neck fractures.This article describes a case of a 57-year-old man with a high-energy ipsilateral inter-trochanteric hip fracture, comminuted distal third femoral shaft fracture, and displaced lateral tibial plateau fracture. Cephalomedullary fixation was used to fix the ipsilateral femur fractures after medical stabilization and evaluation of the patient. The patient healed clinically and radiographically at 6 months. Despite conservative treatment for painful proximal hardware, elective hip screw removal was performed 22.5 months after injury. Seven weeks later, he sustained a nontraumatic femoral neck fracture.In this case, it is unlikely that the femoral neck fracture occurred as a result of hardware removal. We assumed that, in addition to the patient's alcohol abuse and tobacco use, stress fractures may have attributed to the femoral neck fracture. We recommend using a shorter hip screw to minimize hardware prominence or possibly off-label use of an injectable bone filler, such as calcium phosphate cement. PMID- 22229621 TI - Piercing injury of the pelvis with a steel bar. AB - A piercing or penetrating injury of the pelvis by a steel bar is a rare condition compared with piercing or penetrating injuries of the extremities. We report the case of a 34-year-old woman who attempted a suicidal fall that resulted in the piercing of the pelvis with a long steel bar. The steel bar entered the pelvic cavity from the left buttock through the sciatic notch and was bent at the middle of the pelvic cavity between the bladder and rectum. At the right hip joint, the rod penetrated the posteromedial aspect of the femoral head, was bent again, and extended straight along the medial border of the femur without damaging the femoral neurovascular bundle. At the middle one-third level, the bar spanned in a posterolateral direction and then down toward the lateral aspect at the level of the mid-calf. The bar exited the lateral side of the left calf.An explorative laparotomy was performed to ensure that no intraperitoneal injury had occurred. The smaller portion of the uterus bicornis was the only organ that had been pierced. The penetrated uterus was incised to expose the bent portion of the bar. The bar was cut in half using a diamond burr, and the cutting edge was trimmed so as not to injure the surrounding organs during removal. The second bent portion of the rod, located in the right hip joint, was straightened by positional reduction, and the hip joint was abducted under fluoroscopic monitoring from outside of the operative field by grasping the end of the bar remaining in the pelvic cavity. The steel bar was safely removed and treated after careful planning and multiteam approaches with a general surgeon and orthopedic trauma specialists. PMID- 22229622 TI - Fracture of the alumina-bearing couple delta ceramic liner. AB - The fracture rate of third-generation ceramic liners is greatly reduced compared with first- and second-generation liners because of improvements in the design and manufacturing process. Fractures of the alumina-bearing couple are rare for the same reason.This article describes a case of a fracture of an alumina-bearing couple delta ceramic liner without trauma history that was treated with ceramic on-polyethylene revision total hip arthroplasty. A 57-year-old man was admitted to the hip ward because of an alumina-bearing couple delta ceramic liner fracture. He underwent hip replacement by anterior approach 18 months previously in the same center because of left hip primary osteoarthritis. He received a 54*36-mm modular press-fit cup ceramic alumina-bearing couple delta insert. Probable causes of such fractures are manufacture production failure and edge loading based on cup inclination, but in our patient, inacceptable range of motion, failure of the locking mechanism during implantation insertion, or cracking were possible causes of fracture.Although the fracture rate of third generation alumina-bearing couples is low, we believe that it may not be possible to eliminate the actual risk of alumina head fracture. Patients should be informed about the potential for this complication before receiving an alumina bearing couple. PMID- 22229623 TI - Methicillin-sensitive Staphylococcus aureus infection after steroid hip injection. AB - Infection after intra-articular steroid injection of the hip is rare, occurring in <1 of 15,000 cases. Septic arthritis following intra-articular injection is even rarer. This is the only documented case of systemic septicemia following intra-articular injection.The patient received an intra-articular steroid injection to the left hip under fluoroscopic guidance, which resulted in reduced pain and increased mobility. Two weeks after the injection, the patient noticed sharp pain in the left hip and groin and malaise. Over a 48-hour period, he became progressively ill and was hospitalized for severe groin and thigh pain, inability to extend his hip, and diaphoresis. He underwent aspiration of the hip, which revealed Gram-positive cocci in clusters.At admission, the patient underwent incision and drainage of the left hip with removal of approximately 25 cc of fluid. The patient was started on intravenous vancomycin, then converted to nafcillin as the cultures and sensitivities revealed methicillin-sensitive Staphylococcus aureus. After 6 days of intravenous methicillin, the blood cultures were negative, and the patient was discharged. The patient's laboratory findings were normal, and cultures for aerobic anaerobic bacteria were negative. The patient underwent hip resurfacing and aggressive rehabilitation and was able to return to work. Thirty months after hip resurfacing, the patient had no evidence of infection, walked without a limp, had normal laboratory findings, and was pain free. PMID- 22229624 TI - Concurrent little leaguer's elbow and shoulder in a 15-year-old baseball pitcher and football quarterback. AB - Little leaguer's elbow and Little leaguer's shoulder are overuse pathologies seen in overhead-throwing athletes. No instance of simultaneously occurring pathologies has been published. A 15-year-old baseball pitcher and football quarterback developed pain in his throwing shoulder and elbow during spring baseball, which partially resolved with several months of rest. During fall football practice, he felt a pop and pain over his medial throwing elbow. Five days after the initial injury, medial elbow tenderness, mild swelling, and decreased range of motion were noted. Radiographs revealed a Salter I avulsion fracture of the medial humeral epicondyle (Little leaguer's elbow) and a periosteal reaction along the lateral aspect of the humeral metadiaphysis with slight widening (Little leaguer's shoulder). Surgical fixation of the medial epicondyle fracture and nonoperative treatment of the shoulder pathology were performed. Two-year follow-up radiographs showed a healed medial epicondylar fracture and resolution of the periosteal reaction of the humeral metadiaphysis. The patient returned to full activity and was starting quarterback for his football team. Biomechanical forces specific to overhead-throwing activities are associated with the development of Little leaguer's elbow and shoulder. Treatments of both pathologies remain controversial, with either initial operative vs nonoperative care. In this patient, a good outcome was achieved with surgical fixation of the elbow fracture and conservative management of the shoulder pathology. Educating coaches and parents on proper throwing technique and pitching limits should be the first step in reducing the occurrence of either pathology in this population. PMID- 22229625 TI - Antenatal exercise to improve outcomes in overweight or obese women: A systematic review. AB - BACKGROUND: Women who are overweight or obese during pregnancy are at increased risk of a number of adverse pregnancy outcomes. OBJECTIVE: To review the literature systematically to assess the benefits and harms of an exercise intervention for pregnant women who are overweight or obese. SEARCH STRATEGY: A literature search of PUBMED, SCOPUS, the Cochrane Controlled Trials Register (CENTRAL) and the Australian and International Clinical Trials Registers was performed, as well as an additional hand search through bibliographies of various publications. There were no date or language restrictions. SELECTION CRITERIA: Studies included were randomized controlled trials comparing supervised antenatal exercise intervention with routine standard antenatal care in women who were overweight or obese during pregnancy. The primary outcome was maternal gestational weight gain. The quality of each study was assessed utilizing standard Cochrane systematic review methodology. Data collection and analysis. Six randomized controlled trials and one quasi-randomized trial were identified and included, involving a total of 276 women who were overweight or obese during pregnancy. RESULTS: Provision of a supervised antenatal exercise intervention was associated with lower gestational weight gain (five trials, 216 participants, mean difference of -0.36 kg, 95% confidence interval -0.64 to -0.09 kg) when compared with standard antenatal care. CONCLUSIONS: A monitored physical activity intervention appears to be successful in limiting gestational weight gain; however, the effect on maternal and infant health is less certain. PMID- 22229626 TI - Outcomes of a 5-year follow-up of patients with sessile serrated adenomas. AB - OBJECTIVE: Sessile serrated adenomas (SSAs) are precursors to colorectal cancer (CRC). The purpose of this study is to determine the occurrence of new polyps and CRC in patients with an SSA over a 5-year follow-up interval. METHODS: This study is a retrospective chart review of patients with SSAs diagnosed at colonoscopy in 2005. Abstracted information included patient demographics, colonoscopy information, and polyp characteristics. RESULTS: During 2005, 34 SSAs and 5 mixed SSAs were identified in 33 patients. The mean patient age was 66 years and 58% were female. There was a family history of CRC in 45%, prior polyps in 33%, and previous CRC in 15%. The mean SSA size was 11 mm. SSAs were located proximal to the splenic flexure in 70%. Low-grade dysplasia was present in 3% of SSAs and 80% mixed SSAs. Synchronous adenomatous and hyperplastic polyps occurred respectively in 45% and 21%. High-grade dysplasia was present in 12% of the adenomas. Twenty two patients underwent subsequent colonoscopies with 20 new SSAs and 1 mixed SSA identified. In SSAs low-grade dysplasia occurred in 10% and high-grade dysplasia in 5%. Low-grade dysplasia was present in the mixed SSA. Synchronous adenomatous and hyperplastic polyps occurred respectively in 45% and 37%. High-grade dysplasia was present in 10% of adenomas and CRC occurred in 1 (5%) patient. CONCLUSIONS: SSAs occurred more frequently in females and in the right colon. Dysplasia occurred in a small subset of SSAs. There was a high rate of prior and subsequent CRC in patients with SSAs. PMID- 22229627 TI - Morton Edward Bitterman (1921-2011). PMID- 22229628 TI - Agnes N. O'Connell (1933-2011). PMID- 22229629 TI - Darryl Bruce (1939-2011). PMID- 22229630 TI - The ever-changing meanings of retirement. PMID- 22229631 TI - Is retirement always stressful? The potential impact of creativity. PMID- 22229633 TI - Core-shell structured PEO-chitosan nanofibers by coaxial electrospinning. AB - Core-shell structured PEO-chitosan nanofibers have been produced using a coaxial electrospinning setup. PEO and chitosan solutions, both in an aqueous acetic acid solvent, were used as the inner (core) and outer (shell) layer, respectively. Uniform-sized defect-free nanofibers of 150-190 nm diameter were produced. In addition, hollow nanofibers could be obtained subsequent to PEO washing of the membranes. The core-shell nanostructure and existence of chitosan on the shell layer were confirmed by TEM images obtained before and after washing the PEO content with water. The presence of chitosan on the surface of the composite nanofibers was further supported by XPS studies. The chitosan and PEO compositions in the nanofibrous mats were determined by TGA analysis, which were similar to their ratio in the feed solutions. The local compositional homogeneity of the membranes and the efficiency of the washing step to remove PEO were also verified by FTIR. In addition, DSC and XRD were used to characterize the crystalline structure and morphology of the co-electrospun nonwoven mats. The prepared coaxial nanofibers (hollow and solid) have several potential applications due to the presence of chitosan on their outer surfaces. PMID- 22229634 TI - Scaffold tailoring by a newly detected Pictet-Spenglerase activity of strictosidine synthase: from the common tryptoline skeleton to the rare piperazino-indole framework. AB - The Pictet-Spenglerase strictosidine synthase (STR1) has been recognized as a key enzyme in the biosynthesis of some 2000 indole alkaloids in plants, some with high therapeutic value. In this study, a novel function of STR1 has been detected which allows for the first time a simple enzymatic synthesis of the strictosidine analogue 3 harboring the piperazino[1,2-a]indole (PI) scaffold and to switch from the common tryptoline (hydrogenated carboline) to the rare PI skeleton. Insight into the reaction is provided by X-ray crystal analysis and modeling of STR1 ligand complexes. STR1 presently provides exclusively access to 3 and can act as a source to generate by chemoenzymatic approaches libraries of this novel class of alkaloids which may have new biological activities. Synthetic or natural monoterpenoid alkaloids with the PI core have not been reported before. PMID- 22229635 TI - Repeated radioimmunotherapy with 177Lu-DOTA-BR96 in a syngeneic rat colon carcinoma model. AB - AIM: Fractionation is generally used as a mean to improve radioimmunotherapy (RIT). Since RIT is considered suitable for small-volume disease, the aim of the current study was to investigate whether repeated administration of (177)Lu labeled mAb BR96 was tolerated and could delay or prevent metastatic disease after complete remission of the tumor obtained by the first administration. METHODS: Immunocompetent rats bearing a syngeneic colon carcinoma were first treated with 400 MBq/kg (177)Lu-DOTA-BR96, an activity resulting in complete response in 29 of 30 animals. On day 21, two groups of rats were given an additional activity of 150 or 350 MBq/kg resulting in total administered activities corresponding to 0.9 and 1.3 times the maximal tolerated dose. RESULTS: The additional treatment resulted in tolerable myelotoxicity; however, the frequency of metastatic disease and survival were not affected. Immunohistochemistry demonstrated binding of the BR96 antibody to tissue sections of analyzed metastases. CONCLUSIONS: In our model, development of metastatic disease after treatment of the manifest tumor was not prevented by an additional treatment with the same radioimmunoconjugate. Therefore, the antibody should be labeled with a more suitable radionuclide for treatment of metastases. The repeated targeted therapy was well tolerated in aspects of myelotoxicity. PMID- 22229636 TI - Effects of isotretinoin treatment on general psychiatric symptoms, quality of life and social phobia in acne vulgaris patients. PMID- 22229637 TI - Galectin-9 induced by dietary synbiotics is involved in suppression of allergic symptoms in mice and humans. AB - BACKGROUND: Prebiotic galacto- and fructo-oligosaccharides (scGOS/lcFOS) resembling non-digestible oligosaccharides in human milk reduce the development of atopic disorders. However, the underlying mechanisms are still unclear. Galectins are soluble-type lectins recognizing beta-galactoside containing glycans. Galectin-9 has been shown to regulate mast cell degranulation and T-cell differentiation. In this study, the involvement of galectin-9 as a mechanism by which scGOS/lcFOS in combination with Bifidobacterium breve M-16V protects against acute allergic symptoms was investigated. METHODS: Mice were sensitized orally to whey, while being fed with a diet containing scGOS/lcFOS and Bifidobacterium breve M-16V (GF/Bb) or a control diet. Galectin-9 expression was determined by immunohistochemistry in the intestine and measured in the serum by ELISA. T-cell differentiation was investigated in the mesenteric lymph nodes (MLN) as well as in galectin-9-exposed peripheral blood mononuclear cells (PBMC) cultures. Sera of the mice were evaluated for the capacity to suppress mast cell degranulation using a RBL-2H3 degranulation assay. In addition, in a double blind, placebo-controlled multicenter trial, galectin-9 levels were measured in the sera of 90 infants with atopic dermatitis who received hydrolyzed formulae with or without GF/Bb. RESULTS: Galectin-9 expression by intestinal epithelial cells and serum galectin-9 levels were increased in mice and humans following dietary intervention with GF/Bb and correlated with reduced acute allergic skin reaction and mast cell degranulation. In addition, GF/Bb enhanced T(h)1- and T(reg)-cell differentiation in MLN and in PBMC cultures exposed to galectin-9. CONCLUSIONS: Dietary supplementation with GF/Bb enhances serum galectin-9 levels, which associates with the prevention of allergic symptoms. PMID- 22229638 TI - Bacteriochlorophyll excited-state quenching pathways in bacterial reaction centers with the primary donor oxidized. AB - One striking feature of bacterial reaction centers is that while they show a high degree of structural symmetry, function is entirely asymmetric: excitation of the primary electron donor, P, a bacteriochlorophyll (BChl) dimer, results almost exclusively in electron transfer along one of the two symmetric electron transfer pathways. Here another functional asymmetry of the reaction center is explored; i.e., the two monomer BChl molecules (B(A) and B(B)) have distinct interactions with P in the oxidized state, P(+). Previous work has suggested that the excited states of both B(A) and B(B) were quenched via energy transfer to P(+) within a few hundred femtoseconds. Here, it is shown that various excitation wavelengths, corresponding to different initial B(A) and B(B) excited states, result in distinct reaction pathways, and which pathway dominates depends both on the initial excited state formed and on the electronic structure of P(+). In particular, it is possible to specifically excite the Q(X) transition of B(B) by using excitation at 495 nm directly into the carotenoid S(2) state which then undergoes energy transfer to B(B). This results in the formation of a new state on the picosecond time scale that is both much longer lived and spectrally different than what one would expect for a simple excited state. Combining results from additional measurements using nonselective 600 or 800 nm excitation of both B(A) and B(B) to the Q(X) or Q(Y) states, respectively, it is found that B(B)* and B(A)* are quenched by P(+) with different kinetics and mechanisms. B(A)* formed using either Q(X) or Q(Y) excitation appears to decay rapidly (~200 fs) without a detectable intermediate. In contrast, B(B)* formed via Q(X) excitation predominantly generates the long-lived state referred to above via an electron transfer reaction from the Q(X) excited state of B(B) to P(+). This reaction is in competition with intramolecular relaxation of the Q(X) state to the lowest singlet excited state. The Q(Y) excited state of B(B) appears to undergo the electron transfer reaction seen upon Q(X) excitation only to a very limited extent and is largely quenched via energy transfer to P(+). Finally, the ability of P(+) to quench B(B)* depends on the electronic structure of P(+). The asymmetric charge distribution between the two halves of P in the native reaction center is effectively reversed in the mutant HF(L168)/LH(L131), and in this case, the rate of quenching decreases significantly. PMID- 22229639 TI - Crossing the cultural divide: issues in translation, mistrust, and cocreation of meaning in cross-cultural therapeutic assessment. AB - This article examines cross-cultural therapeutic assessment in a community mental health clinic. The first case describes the work between a Caucasian assessor and a Mexican American family. The authors explore the metaphorical and literal translation of the findings from English to Spanish and the parallel process of translation of the self, experienced by both assessor and client. The second case describes the work between a Caucasian assessor and an African American adolescent. We describe the inherent challenge between the Eurocentric "task" orientation of the evaluation and the Afrocentric "relationship" orientation. We suggest that bridging the gap between cultures and overcoming cultural mistrust lay in the building of the assessor-client relationship. Fischer's concepts of rapport and intimacy are emphasized and expanded on as we emphasize the importance of cocreated meaning in cross-cultural assessment work. PMID- 22229640 TI - Ionic crystals of {[Ni(phen)3]2Ge4S10}.xSol, showing solid-state solvatochromism and rapid solvent-induced recrystallization. AB - Thiogermanates, {[Ni(phen)(3)](2)Ge(4)S(10)}.xSol (Sol = 4MeOH.12H(2)O (1) and 24H(2)O (2)) were prepared and characterized by single-crystal structure analysis. There are large quantities of the solvent molecules that cocrystallize with the anions and cations and form a strong hydrogen bonding network (O-H...S and O...H-O-H...O). Reversible yellow-pink color change with fast speed was found for these compounds, when the crystals were immersed in alcohol solvents and water alternately. The time of the solvent-induced color change relates to the molecular size and structure of the alcohols. The smaller the molecule is, the faster the color change will be. The fastest color change was found by using the methanol solvent that took only about one second. The color change also relates to the ratio of water/alcohol. The solvatochromism phenomenon is accompanied with a rapid solvent-induced recrystallization that is verified by the XRD patterns. PMID- 22229641 TI - Subclavian venoplasty may reduce implant times and implant failures in the era of increasing device upgrades. AB - BACKGROUND: The incidence of subclavian venous occlusions (SCVOs) may be an increasing problem in the era of device upgrades, especially to cardiac resynchronization therapy. Venoplasty (VP) performed by the electrophysiologist as a way of managing SCVOs may be advantageous. METHODS: We reviewed the implantable cardioverter defibrillator (ICD) implants of the past 5 years at Montefiore Medical Center and searched for SCVOs that required intervention and compared cases where VP was performed with cases where it was not. RESULTS: Of 1,853 ICD implants, 41 SCVOs (2.2%) requiring intervention were identified. Its incidence increased seven-fold from 0.7% in 2005 to 5.2% in 2009. Twenty-seven of the 41 SCVOs were found during a device upgrade. Of these 41 SCVOs, 18 underwent VP and 23 did not. In the VP group, there was a trend towards a shorter total procedure time, 2:31 hours versus 3:28 hours (P=0.37), and the total fluoroscopy time was 30 minutes versus 27 minutes (P=0.55). VP was successful in all 18 patients. Among the non-VP group (n=23), five (21.5%) had a failed implantation because of the inability to gain venous access and 10 (42.7%) had to be implanted on the contralateral side. CONCLUSION: The incidence of SCVOs requiring intervention is increasing in the era of device upgrades. VP performed by an electrophysiologist appears to be a safe and efficient approach to manage these SCVOs. VP seems to reduce the implant time and the need to implant on the other side as well as implant failure due to the inability to gain venous access. PMID- 22229642 TI - Malassezia globosa tends to grow actively in summer conditions more than other cutaneous Malassezia species. AB - Malassezia globosa is a major pathogen of Malassezia folliculitis (MF) and the predominant species on human skin. The aim of this study was to clarify the differences between M. globosa and other cutaneous Malassezia species, M. restricta, M. dermatis, M. sympodialis and M. furfur. The optimum growth temperature, effects of compounds of sweat and free fatty acids on growth, and lipase activities of five cutaneous Malassezia species were determined. The growth of M. globosa was promoted strongly by the compounds of sweat and high temperature unlike that of other cutaneous Malassezia species. This result clarified that M. globosa tended to grow actively in summer conditions more than other cutaneous Malassezia species. Furthermore, M. globosa showed high lipase activity. We consider these characteristics of M. globosa to relate to the pathogenesis of MF. PMID- 22229643 TI - Similar risk for hemangiomas after amniocentesis and transabdominal chorionic villus sampling. AB - AIM: In an earlier study we have shown that transcervical chorionic villus sampling in excess of 90 mg increases the risk for hemangiomas of infancy three- to four-fold compared to amniocentesis. In the present study we investigated whether transabdominal chorionic villus sampling (TA-CVS), in which the samples are smaller, carries the same risk. MATERIAL AND METHODS: Retrospectively, data were analyzed from 200 consecutive TA-CVS procedures and 200 consecutive amniocentesis procedures. Forty-two TA-CVS procedures and 27 amniocentesis procedures were excluded on predefined criteria. Questionnaires were sent to the parents asking if there was any skin mark on the child: vascular, pigmented or otherwise. All hemangiomas were clinically confirmed. RESULTS: In the TA-CVS group, 118/158 questionnaires (75%), and in the amniocentesis group 134/173 questionnaires (77%) were returned. Based on the results of the questionnaire (i.e. mentioning of any skin lesion), 24 children in the TA-CVS group and 42 children in the amniocentesis group qualified for a physical examination. In the TA-CVS group 11/118 children (9%) had one or more hemangiomas. In the amniocentesis group 6/134 children (4%) had one or more hemangiomas. There was no statistical difference between the two groups (P = 0134). CONCLUSION: These results suggest that TA-CVS does not cause an increase in the prevalence of hemangioma compared to amniocentesis. A larger series is, however, necessary to confirm this. PMID- 22229644 TI - Treatment of periodontal diseases reduces chronic systemic inflammation in maintenance hemodialysis patients. AB - BACKGROUND: Evidences suggest that chronic systemic inflammation is associated with increasing mortality in maintenance hemodialysis patients due to atherosclerosis and malnutrition. Periodontal diseases are treatable sources of systemic inflammation in hemodialysis patients. We therefore evaluated the effect of periodontal treatment in maintenance hemodialysis patients. METHOD: Periodontal diseases were evaluated in 30 stable maintenance hemodialysis patients by using clinical periodontal status by plaque index (PI) and periodontal disease index (PDI). Hematologic, biochemical, nutritional, and dialysis-related parameters as well as highly sensitive C-reactive protein (hs CRP), a sensitive systemic inflammatory marker, were analyzed before and after periodontal therapy. RESULT: Maintenance hemodialysis patients had high prevalence of periodontal disease (63%). At baseline, hs-CRP positively correlated with clinical periodontal status (PI, r = 0.74, p < 0.001; PDI, r = 0.66, p < 0.001), but negatively correlated with hemoglobin (r = -0.51, p < 0.001), serum albumin (r = -0.61, p = 0.002), and normalized protein catabolic rate (r = -0.42, p = 0.043). After completion of periodontal therapy (duration 6 +/- 2 weeks), the PI and PDI significantly declined from 2.13 to 1.48 (p = 0.001) and 3.53 to 2.52 (p = 0.001), respectively, while hs-CRP significantly declined from 3.8 to 0.6 mg/L (p < 0.001). Moreover, erythropoietin dosage could be reduced from 8000 to 6000 unit/week (p = 0.03) after treatment. Pre-dialysis blood urea nitrogen increased from 66.18 to 79.54 mg/dL (p = 0.003) and serum albumin level increased from 3.15 to 3.38 mg/dL (p = 0.003), reflecting improved nutritional status of the patients after periodontal treatment. CONCLUSION: Periodontitis is an important source of chronic inflammation. Treatment of periodontal diseases can improve systemic inflammation, nutritional status, and erythropoietin responsiveness in the hemodialysis population. PMID- 22229645 TI - Topical application of disodium isostearyl 2-O-L-ascorbyl phosphate, an amphiphilic ascorbic acid derivative, reduces neuropathic hyperalgesia in rats. AB - BACKGROUND AND PURPOSE: Ca(v) 3.2 T-type calcium channels, targeted by H(2) S, are involved in neuropathic hyperalgesia in rats and ascorbic acid inhibits Ca(v) 3.2 channels. Therefore, we evaluated the effects of intraplantar (i.pl.) administration of ascorbic acid or topical application of disodium isostearyl 2-O L-ascorbyl phosphate (DI-VCP), a skin-permeable ascorbate derivative on hyperalgesia induced by NaHS, an H(2) S donor, and on neuropathic hyperalgesia. EXPERIMENTAL APPROACH: In rats mechanical hyperalgesia was evoked by i.pl. NaHS, and neuropathic hyperalgesia was induced by L5 spinal nerve cutting (L5SNC) or by repeated administration of paclitaxel, an anti-cancer drug. Dermal ascorbic acid levels were determined colorimetrically. KEY RESULTS: The NaHS-evoked Ca(v) 3.2 channel-dependent hyperalgesia was inhibited by co-administered ascorbic acid. Topical application of DI-VCP, but not ascorbic acid, prevented the NaHS-evoked hyperalgesia, and also increased dermal ascorbic acid levels. Neuropathic hyperalgesia induced by L5SNC or paclitaxel was reversed by i.pl. NNC 55-0396, a selective T-type calcium channel blocker, ascorbic acid or DI-VCP, and by topical DI-VCP, but not by topical ascorbic acid. The effects of i.pl. ascorbic acid and topical DI-VCP in the paclitaxel-treated rats were characterized by the faster onset and greater magnitude, compared with their effects in the L5SNC rats. Dermal ascorbic acid levels in the hindpaw significantly decreased after paclitaxel treatment, but not L5SNC, which was reversed by topical DI-VCP. CONCLUSIONS AND IMPLICATIONS: Ascorbic acid, known to inhibit Ca(v) 3.2 channels, suppressed neuropathic hyperalgesia. DI-VCP ointment for topical application may be of benefit in the treatment of neuropathic pain. PMID- 22229646 TI - Relatively normal repetition performance despite severe disruption of the left arcuate fasciculus. AB - The arcuate fasciculus (AF) is believed to be fundamental to the neural circuitry behind many important cognitive processes. Connecting Wernicke's and Broca's area, these fibers are thought to be especially important for repetition. In this case study we present evidence from a patient that set doubt on these assumptions. We present structural imaging, diffusion tensor imaging, and language data on a patient with a large left-sided stroke and severely damaged left AF who showed intact word repetition and relatively intact sentence repetition performance. Specifically, his sentence repetition is more fluent and grammatical, with less hesitation than spontaneous speech, and with rare omissions only during the longest sentences. These results challenge classical theories that maintain the left AF is the dominant language processing pathway or mechanism for repetition. PMID- 22229647 TI - Design, synthesis, and biological evaluation of new diaminoquinazolines as beta catenin/Tcf4 pathway inhibitors. AB - More than 50 new diaminoquinazoline derivatives have been synthesized and evaluated in a colon carcinoma cell growth inhibition assay using HCT116 and SW480 cells. Twenty compounds with good cell growth inhibitory activities (<4 MUM) were tested as inhibitors of the beta-catenin/T cell transcription factor 4 (Tcf4) signaling pathway using a HCT116 cell-based luciferase reporter assay. Results from the biological activities as well as the comparative molecular field analysis (CoMFA) of the properties of the molecules yielded a preliminary structure-activity relationship (SAR). Three potent compounds, 74, 78, and 86, showed IC(50) values <1 MUM for growth inhibition of HCT116 cells and ~1 MUM for SW480 cells, as well as IC(50) values of 1.5-2.5 MUM for HCT116 cells with the luciferase reporter assay. PMID- 22229648 TI - A novel non-canonical mechanism of regulation of MST3 (mammalian Sterile20 related kinase 3). AB - The canonical pathway of regulation of the GCK (germinal centre kinase) III subgroup member, MST3 (mammalian Sterile20-related kinase 3), involves a caspase mediated cleavage between N-terminal catalytic and C-terminal regulatory domains with possible concurrent autophosphorylation of the activation loop MST3(Thr(178)), induction of serine/threonine protein kinase activity and nuclear localization. We identified an alternative 'non-canonical' pathway of MST3 activation (regulated primarily through dephosphorylation) which may also be applicable to other GCKIII (and GCKVI) subgroup members. In the basal state, inactive MST3 co-immunoprecipitated with the Golgi protein GOLGA2/gm130 (golgin A2/Golgi matrix protein 130). Activation of MST3 by calyculin A (a protein serine/threonine phosphatase 1/2A inhibitor) stimulated (auto)phosphorylation of MST3(Thr(178)) in the catalytic domain with essentially simultaneous cis autophosphorylation of MST3(Thr(328)) in the regulatory domain, an event also requiring the MST3(341-376) sequence which acts as a putative docking domain. MST3(Thr(178)) phosphorylation increased MST3 kinase activity, but this activity was independent of MST3(Thr(328)) phosphorylation. Interestingly, MST3(Thr(328)) lies immediately C-terminal to a STRAD (Sterile20-related adaptor) pseudokinase like site identified recently as being involved in binding of GCKIII/GCKVI members to MO25 scaffolding proteins. MST3(Thr(178)/Thr(328)) phosphorylation was concurrent with dissociation of MST3 from GOLGA2/gm130 and association of MST3 with MO25, and MST3(Thr(328)) phosphorylation was necessary for formation of the activated MST3-MO25 holocomplex. PMID- 22229650 TI - Complement activation and interleukin response in major abdominal surgery. AB - The objective of this study was to evaluate whether major abdominal surgery leads to complement activation and interleukin response and whether the kind of anaesthesia influence complement activation and the release of inflammatory interleukins. The study design was prospective and randomised. Fifty patients undergoing open major colorectal surgery due to cancer disease or inflammatory bowel disease were studied. Twenty-five patients were given total intravenous anaesthesia (TIVA) with propofol and remifentanil, and 25 patients were given inhalational anaesthesia with sevoflurane and fentanyl. To determine complement activation (C3a and SC5b-9) and the release of pro- and anti-inflammatory interleukins (tumour necrosis factor-a (TNF-a)), interleukin-1b (IL-1b), IL-6, IL 8, IL-4 and IL-10), blood samples were drawn preoperatively, 60 minutes after start of surgery, 30 minutes after end of surgery and 24 hours postoperatively. Complement was activated and pro-inflammatory interleukins (IL-6 and IL-8) and anti-inflammatory interleukins (IL-10) were released during major colorectal surgery. There was no significant difference between TIVA and inhalational anaesthesia regarding complement activation and cytokine release. Major colorectal surgery leads to activation of the complement cascade and the release of both pro-inflammatory and anti-inflammatory cytokines. There are no significant differences between total intravenous anaesthesia (TIVA) with propofol and remifentanil and inhalational anaesthesia with sevoflurane and fentanyl regarding complement activation and the release of pro- and anti inflammatory interleukins. PMID- 22229649 TI - Damaged mitochondrial DNA replication system and the development of diabetic retinopathy. AB - AIM: In the pathogenesis of diabetic retinopathy, retinal mitochondria are damaged, superoxide levels are elevated, and mitochondrial DNA (mtDNA) biogenesis is impaired. mtDNA has a noncoding region, displacement loop (D-loop), which has essential transcription and replication elements, and this region is highly vulnerable to oxidative damage. The aim of this study is to investigate the effect of diabetes on the D-loop damage and the mtDNA replication machinery. RESULTS: Using retina from wild-type (WT) and mitochondrial superoxide dismutase transgenic (Tg) mice, we have investigated the effect of diabetes on retinal D loop damage and on the replication system. The results were confirmed in the isolated retinal endothelial cells in which the DNA polymerase gamma 1 (POLG1) function was genetically manipulated. Diabetes damaged retinal mtDNA, and the damage was more at the D-loop region compared with the cytochrome B region. Gene transcripts and mitochondrial accumulation of POLG1, POLG2, and mtDNA helicase, the enzymes that form replisome to bind/unwind and extend mtDNA, were also decreased in WT-diabetic mice compared with WT-normal mice. Tg-diabetic mice were protected from diabetes-induced damage to the D-loop region. Overexpression of POLG1 prevented high glucose-induced D-loop damage. This was accompanied by a decrease in mitochondrial superoxide levels. INNOVATION AND CONCLUSIONS: Integrity of the retinal D-loop region and the mtDNA replication play important roles in the mtDNA damage experienced by the retina in diabetes, and these are under the control of superoxide. Thus, the regulation of mtDNA replication/repair machinery has the potential to prevent mitochondrial dysfunction and the development of diabetic retinopathy. PMID- 22229651 TI - Improvement of neural stem cell survival in collagen hydrogels by incorporating laminin-derived cell adhesive polypeptides. AB - Cell transplantation is a potential methodology for the treatment of Parkinson's disease. However, the therapeutic effect is limited by poor viability of transplanted cells. To overcome this problem, we hypothesized that a dual step approach, whereby providing an adhesive substrate for transplanted cells and, at the same time, by preventing the infiltration of activated microglia into the site of transplantation promotes the cell survival. To establish above conditions, attempts were made to prepare 3-D matrices using collagen hydrogels that incorporated integrin-binding polypeptides derived from laminin-1. Tandem combinations of laminin globular domains as well as a single globular domain 3 were prepared using recombinant DNA technology as a fusion with hexahistidine and bound to metal chelated surfaces to screen for the adhesion and proliferation of neural stem cells (NSCs). In addition, a small peptide derived from laminin gamma1 chain was prepared and heterodimerized with the globular domain-containing chimeric proteins to evaluate for the enhancement of integrin-mediated cell adhesion. As a result, a heterodimer consisting of the globular domain 3 of the laminin alpha1 chain and the peptide from the laminin gamma1 chain was selected as the best candidate among the polypeptides studied here for the incorporation into a collagen hydrogel. It was shown that the survival of NSCs was indeed promoted in the collagen hydrogel incorporating the heterodimer compared to the pure collagen hydrogel. PMID- 22229652 TI - T-helper 17 cells mediate the osteo/odontoclastogenesis induced by excessive orthodontic forces. AB - OBJECTIVE: The aim of this study was to investigate how T-helper 17 cells (Th17 cells), interleukin (IL)-17, and interleukin-6 contribute to root resorption during orthodontic tooth movement. MATERIALS AND METHODS: Fifteen male 6-week-old Wistar rats were subjected to orthodontic force of 10 or 50 g to induce a mesially tipping movement of the upper first molars for 7 days. The expression levels of TRAP, IL-17, the IL-17 receptor (IL-17R), and IL-6 proteins were determined in periodontal ligament (PDL) by immunohistochemical analysis. Moreover, the fluorescent localization immunoassay was performed to detect Th17 cells. Furthermore, the effects of IL-17 on IL-6 release were investigated using human PDL cells in vitro. The effect of IL-17 on osteoclastogenesis was evaluated by TRAP staining, actin ring staining, and the pit formation assay. RESULTS: The immunoreactivity for Th17, IL-17, IL-17R, and IL-6 was detected in PDL tissue subjected to the orthodontic force on day 7. IL-17 increased the release of IL-6 from human periodontal ligament cells in a time-dependent manner. Moreover, IL-17 stimulated osteoclastogenesis from human osteoclast precursor cells, and these effects were partially suppressed by an anti-IL-6 antibody. CONCLUSION: These results suggest that Th17 cells may aggravate the process of orthodontically induced inflammatory root resorption. PMID- 22229653 TI - Fully enclosed microfluidic paper-based analytical devices. AB - This article introduces fully enclosed microfluidic paper-based analytical devices (microPADs) fabricated by printing toner on the top and bottom of the devices using a laser printer. Enclosing paper-based microfluidic channels protects the channels from contamination, contains and protects reagents stored on the device, contains fluids within the channels so that microPADs can be handled and operated more easily, and reduces evaporation of solutions from the channels. These benefits extend the capabilities of microPADs for applications as low-cost point-of-care diagnostic devices. PMID- 22229654 TI - A new model for magnesium chemistry in the upper atmosphere. AB - This paper describes the kinetic study of a number of gas-phase reactions involving neutral Mg-containing species, which are important for the chemistry of meteor-ablated magnesium in the upper mesosphere/lower thermosphere region. The study is motivated by the very recent observation of the global atomic Mg layer around 90 km, using satellite-born UV-visible spectroscopy. In the laboratory, Mg atoms were produced thermally in the upstream section of a fast flow tube and then converted to the molecular species MgO, MgO(2), OMgO(2), and MgCO(3) by the addition of appropriate reagents. Atomic O was added further downstream, and Mg was detected at the downstream end of the flow tube by laser-induced fluorescence. The following rate coefficients were determined at 300 K: k(MgO + O -> Mg + O(2)) = (6.2 +/- 1.1) * 10(-10); k(MgO(2) + O -> MgO + O(2)) = (8.4 +/- 2.8) * 10(-11); k(MgCO(3) + O -> MgO(2) + CO(2)) >= 4.9 * 10(-12); and k(MgO + CO -> Mg + CO(2)) = (1.1 +/- 0.3) * 10(-11) cm(3) molecule(-1) s(-1). Electronic structure calculations of the relevant potential energy surfaces combined with RRKM theory were performed to interpret the experimental results and also to explore the likely reaction pathways that convert MgCO(3) and OMgO(2) into long lived reservoir species such as Mg(OH)(2). Although no reaction was observed in the laboratory between OMgO(2) and O, this is most likely due to the rapid recombination of O(2) with the product MgO(2) to form the relatively stable O(2)MgO(2). Indeed, one significant finding is the role of O(2) in the mesosphere, where it initiates holding cycles by recombining with radical species such as MgO(2) and MgOH. A new atmospheric model was then constructed which combines these results together with recent work on magnesium ion-molecule chemistry. The model is able to reproduce satisfactorily some of the key features of the Mg and Mg(+) layers, including the heights of the layers, the seasonal variations of their column abundances, and the unusually large Mg(+)/Mg ratio. PMID- 22229656 TI - Neurofibromatosis type 1 with dural ectasia. PMID- 22229655 TI - Protein detection by nanopores equipped with aptamers. AB - Protein nanopores have been used as stochastic sensors for the detection of analytes that range from small molecules to proteins. In this approach, individual analyte molecules modulate the ionic current flowing through a single nanopore. Here, a new type of stochastic sensor based on an alphaHL pore modified with an aptamer is described. The aptamer is bound to the pore by hybridization to an oligonucleotide that is attached covalently through a disulfide bond to a single cysteine residue near a mouth of the pore. We show that the binding of thrombin to a 15-mer DNA aptamer, which forms a cation-stabilized quadruplex, alters the ionic current through the pore. The approach allows the quantification of nanomolar concentrations of thrombin, and provides association and dissociation rate constants and equilibrium dissociation constants for thrombin.aptamer interactions. Aptamer-based nanopores have the potential to be integrated into arrays for the parallel detection of multiple analytes. PMID- 22229657 TI - Adsorption of glycinin and beta-conglycinin on silica and cellulose: surface interactions as a function of denaturation, pH, and electrolytes. AB - Soybean proteins have found uses in different nonfood applications due to their interesting properties. We report on the kinetics and extent of adsorption on silica and cellulose surfaces of glycinin and beta-conglycinin, the main proteins present in soy. Quartz crystal microgravimetry (QCM) experiments indicate that soy protein adsorption is strongly affected by changes in the physicochemical environment. The affinity of glycinin and the mass adsorbed on silica and cellulose increases (by ca. 13 and 89%, respectively) with solution ionic strength (as it increases from 0 to 100 mM NaCl) due to screening of electrostatic interactions. In contrast, beta-conglycinin adsorbs on the same substrates to a lower extent and the addition of electrolyte reduces adsorption (by 25 and 57%, respectively). The addition of 10 mM 2-mercaptoethanol, a denaturing agent, reduces the adsorption of both proteins with a significant effect for glycinin. This observation is explained by the cleavage of disulfide bonds which allows unfolding of the molecules and promotes dissociation into subunits that favors more compact adsorbed layer structures. In addition, adsorption of glycinin onto cellulose decreases with lowering the pH from neutral to pH 3 due to dissociation of the macromolecules, resulting in flatter adsorbed layers. The respective adsorption isotherms fit a Langmuir model and QCM shifts in energy dissipation and frequency reveal multiple-step kinetic processes indicative of changes in adlayer structure. PMID- 22229658 TI - Extracellular matrix in airway smooth muscle is associated with dynamics of airway function in asthma. AB - BACKGROUND: Altered deposition of extracellular matrix (ECM) in the airway smooth muscle (ASM) layer as observed in asthma may influence ASM mechanical properties. We hypothesized that ECM in ASM is associated with airway function in asthma. First, we investigated the difference in ECM expression in ASM between asthma and controls. Second, we examined whether ECM expression is associated with bronchoconstriction and bronchodilation in vivo. METHODS: Our cross-sectional study comprised 19 atopic mild asthma patients, 15 atopic and 12 nonatopic healthy subjects. Spirometry, methacholine responsiveness, deep-breath-induced bronchodilation (DeltaR(rs) ) and bronchoscopy with endobronchial biopsies were performed. Positive staining of elastin, collagen I, III and IV, decorin, versican, fibronectin, laminin and tenascin in ASM was quantified as fractional area and mean density. Data were analysed using Pearson's or Spearman's correlation coefficient. RESULTS: Extracellular matrix expression in ASM was not different between asthma and controls. In asthmatics, fractional area and mean density of collagen I and III were correlated with methacholine dose-response slope and DeltaR(rs) , respectively (r = 0.71, P < 0.01; r = 0.60, P = 0.02). Furthermore, ASM collagen III and laminin in asthma were correlated with FEV(1) reversibility (r = -0.65, P = 0.01; r = -0.54, P = 0.04). CONCLUSION: In asthma, ECM in ASM is related to the dynamics of airway function in the absence of differences in ECM expression between asthma and controls. This indicates that the ASM layer in its full composition is a major structural component in determining variable airways obstruction in asthma. PMID- 22229659 TI - Mood disorders and outcome in patients receiving cardiac resynchronization therapy. AB - BACKGROUND: Mood disorders (MD) have been demonstrated to influence outcome in cardiac disease in general and specifically in chronic heart failure (HF). Little is known about their possible effect on response to cardiac resynchronization therapy (CRT). OBJECTIVE: To evaluate the influence of MD on CRT response. METHODS: We conducted a retrospective chart review of all cardiac CRT-D (CRT defibrillator) recipients (N = 153) at the Veterans Affairs Pittsburgh Healthcare System from beginning of 2004 through end of 2006. All-cause death and HF-related hospitalizations (HFH), individually and combined, were sought through 2009. RESULTS: During a mean follow-up time of 31.4 +/- 14.7 months, there were 48 (31.4%) deaths and 55 (35.9%) HFHs in HF patients having New York Heart Association class of 2.9 +/- 0.3, left ventricular ejection fraction (LVEF) of 25.8 +/- 9.1%, left ventricular end-diastolic diameter (LVEDD) of 61.6 +/- 11.6 mm, and QRS of 152 +/- 30.5 ms . A total of 65 (42.5%) patients had MD (depression, anxiety, or posttraumatic stress disorder). Compared to others, patients in the MD group were at a significantly higher risk of HFH alone (47.7% vs 27.3%, P = 0.009) or when combined with death (58.5% vs 39.8%, P = 0.022) but not death alone (35.4% vs 28.4%, P = 0.36). The significant predictive effect of MD on HFH alone and when combined with death shown in univariate analysis was not attenuated after adjustment for age, ejection fraction, etiology of cardiomyopathy, cumulative number of any shocks, smoking, and evidence of postimplantation echocardiographic improvement. CONCLUSIONS: MD in patients with advanced but stable HF receiving CRT-D therapy was a predictor of HFH alone or when combined with death but not mortality alone. PMID- 22229661 TI - 3-D germanate constructed with Ge7 cluster layers and nickel-ethanolamine linkage. AB - A Ge(7) germanate, [Ni(H(2)O)(MU-C(2)H(6)NO)(2)Ge(7)O(14)(C(2)H(7)NO)].C(2)H(5)OH (1), was prepared by the solvothermal method using ethanolamine (C(2)H(7)NO) as solvent, ligand, and structure-directing agent. Compound 1 shows an unusual GeO framework fused with transition metal complex. The 2-D layers of Ge(7) clusters are linked by a [Ni(H(2)O)(MU-C(2)H(6)NO)(2)] moiety, forming a 3-D architecture. The preparation and structure of 1 are discussed in comparison with the Ge(9) germanates decorated with metal ethylenediamine complexes. The hydroxyl group of the ethanolamine plays an important role in formation of the 3-D structure, in which the ligand ethanolamine is coordinated directly onto the Ge cluster by the hydroxyl group. It is a new type of germanates incorporated with a TM complex bridge. The proton on the flexible amine side can be exchanged by alkali metal ions. PMID- 22229660 TI - Evaluation of the clinical relevance of body composition parameters in patients with cancer metastatic to the liver treated with hepatic arterial infusion chemotherapy. AB - The association between body composition parameters and toxicity from hepatic arterial infusion (HAI) chemotherapy regimens has not been analyzed. We assessed data from patients with advanced cancer and liver metastases treated on a clinical trial of a regimen of HAI oxaliplatin combined with systemic 5 fluorouracil/leucovorin and bevacizumab. Correlations between patient characteristics, response, and toxicity and body composition data taken from CT images were analyzed. Forty-eight of 57 patients (mean age 56 yr; 60% women) had available CT scans. The most common diagnosis was colorectal cancer (22/48, 46%); 30/48 patients (63%) had body mass index (BMI) >=25 kg/m(2). Twenty (42%) of 48 patients were sarcopenic. Grade 3-4 adverse events did not differ among patients with and without sarcopenia or according to BMI. The median survival (95% C]) was 167 (128-206) days for sarcopenic and 280 (214-346) days for nonsarcopenic patients (P = 0.271). Among patients treated at the maximum tolerated dose, the median survival was 103 days for sarcopenic and 312 days for nonsarcopenic patients (P = 0.173). Sarcopenia was present in 30% (6/20) of patients with reduction in tumor size posttreatment, and in 52% (14/27) of patients with increased tumor size (P = 0.171). In conclusion, body composition was not significantly associated with toxicities or survival in our small sample. PMID- 22229662 TI - The influence of fetal head circumference on labor outcome: a population-based register study. AB - OBJECTIVE: To investigate the association between postnatal head circumference and the occurrence of the three main indications for instrumental delivery, namely prolonged labor, signs of fetal distress and maternal distress. We also studied the association between postnatal fetal head circumference and the use of vacuum extraction and emergency cesarean section. DESIGN: Population-based register study. SETTING: Nationwide study in Sweden. POPULATION: A total of 265 456 singleton neonates born to nulliparous women at term between 1999 and 2008 in Sweden. METHODS: Register study with data from the Swedish Medical Birth Register. MAIN OUTCOME MEASURES: Prolonged labor, signs of fetal distress, maternal distress, use of vacuum extraction and emergency cesarean section. RESULTS: The prevalence of each outcome increased gradually as the head circumference increased. Compared with women giving birth to a neonate with average size head circumference (35 cm), women giving birth to an infant with a very large head circumference (39-41 cm) had significantly higher odds of being diagnosed with prolonged labor [odds ratio (OR) 1.49, 95% confidence interval (CI) 1.33-1.67], signs of fetal distress (OR 1.73, 95% CI 1.49-2.03) and maternal distress (OR 2.40, 95% CI 1.96-2.95). The odds ratios for vacuum extraction and cesarean section were thereby elevated to 3.47 (95% CI 3.10-3.88) and 1.22 (95% CI 1.04-1.42), respectively. The attributable risk proportion percentages associated with vacuum extraction and cesarean section were 46 and 39%, respectively among the cases exposed to a head circumference of 37-41 cm. CONCLUSIONS: Large fetal head circumference is associated with complicated labor and is etiological to a considerable proportion of assisted vaginal births and emergency cesarean sections. PMID- 22229663 TI - Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets? AB - Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed. PMID- 22229664 TI - The spectroscopic basis of fluorescence triple correlation spectroscopy. AB - We have developed fluorescence triple correlation spectroscopy (F3CS) as an extension of the widely used fluorescence microscopy technique fluorescence correlation spectroscopy. F3CS correlates three signals at once and provides additional capabilities for the study of systems with complex stoichiometry, kinetic processes, and irreversible reactions. A general theory of F3CS was developed to describe the interplay of molecular dynamics and microscope optics, leading to an analytical function to predict experimental triple correlations of molecules that freely diffuse through the tight focus of the microscope. Experimental correlations were calculated from raw fluorescence data using triple correlation integrals that extend multiple-tau correlation theory to delay times in two dimensions. The quality of experimental data was improved by tuning specific spectroscopic parameters and employing multiple independent detectors to minimize optoelectronic artifacts. Experiments with the reversible system of freely diffusing 16S rRNA revealed that triple correlation functions contain symmetries predicted from time-reversal arguments. Irreversible systems are shown to break these symmetries, and correlation strategies were developed to detect time-reversal asymmetries in a comprehensive way with respect to two delay times, each spanning many orders of magnitude in time. The correlation strategies, experimental approaches, and theory developed here enable studies of the composition and dynamics of complex systems using F3CS. PMID- 22229665 TI - Parallel phylogeographic structure in ecologically similar sympatric sister taxa. AB - Present-day phylogeographic patterns have been shaped by the dual histories of lineages and places, producing a diversity of relationships that may challenge discovery of general rules. For example, the predicted positive correlation between dispersal ability and gene flow has been supported inconsistently, suggesting unaccounted complexity in theory or the comparative framework. Here, I extend the sympatric sister-species approach, in which variance between lineages and places is minimized, to sister clades and test a fundamental assumption of comparative genetic studies of dispersal: that taxa which evolved at the same time and in the same place will, if they have similar life histories and ecologies, have essentially the same phylogeographic structure. Phylogenetic analyses of 197 Stigmatopora pipefishes using two nuclear (creatine kinase intron 6, alpha-tropomyosin) and two mitochondrial (16S, noncoding region) loci revealed largely synchronous parallel diversification of sister clades that are codistributed from Western Australia to New Zealand, supporting the null hypothesis. Only one comparison, however, yielded a sympatric sister-species pair (the two stem species), so I also explored the potential for extant species sharing a substantial proportion of their evolutionary histories in sympatry to substitute for sister taxon comparisons. In eastern Australia, where strong environmental structure is lacking, phylogeographic differences between species that have been codistributed for ~85% of their evolutionary histories were consistent with tendencies favoured by their modest life-history differences, that is the larger, rarer species had lower genetic diversity. In contrast, in New Zealand, two species codistributed for ~70% of their evolutionary histories were both structured similarly by a strong biogeographic filter despite differences in life history. Rigorously quantifying the influence of intrinsic and extrinsic factors on phylogeographic structure may advance most efficiently through meta-analyses of contemporaneously codistributed taxa, including but not limited to sympatric sister species. PMID- 22229666 TI - Investigating the feasibility of promoting and sustaining delivery of cardiac rehabilitation in a rural community. AB - INTRODUCTION: Members of rural communities face the dual burden of high rates of cardiovascular disease and barriers to accessing cardiac rehabilitation programs (CRPs). While rural healthcare providers recognise the need for local delivery of such programs, they are constrained by funding and resource limitations. METHODS: This research sought to explore the feasibility, acceptance and support for the delivery of a secondary prevention CRP in a rural community. Eight local participants were recruited to a pilot CRP following cardiac surgery, diagnosis of cardiovascular disease and/or identification by health practitioners as being at risk of developing cardiovascular disease. The key measures of success were the ability of the team to provide a program based on self-management principles, with a local and collaborative focus. The Health Education Impact Questionnaire (HeiQ) was used to measure the effectiveness and outcomes of the CRP. Qualitative data were also used in order to enhance understandings of the efficacy of CRPs in rural settings from the participant perspective. RESULTS: The delivery of a pilot program that engaged local healthcare providers in partnerships with local residents was successful. Local provision was clearly a positive aspect of the program. Participants described the program as supportive, holistic and convenient, providing new information in a framework that supported self management. The program encouraged local collaboration that enabled continuation of the program. CONCLUSIONS: Local support from health professionals and participants provided strong motivation for attendance; however, the location of the program in a rural setting did not remove all travel barriers. Adhering to the principles of empowerment inherent in a self-management approach to rehabilitation meant accepting fluctuating attendance as individuals managed priorities in their lives. PMID- 22229668 TI - Exogenous normal lymph alleviating kidney injury by improving coagulation function in disseminated intravascular coagulation rats. AB - AIM: To investigate the effect of exogenous normal lymph on kidney injury in disseminated intravascular coagulation (DIC) rats and to probe its mechanism. METHODS: The DIC model was established by intravenous injection of Dextran 500. After 6 min, normal lymph without cell components was infused in the lymph group. After 40 min, the renal and coagulation function indices and renal histomorphology were observed. RESULTS: Serum urea and creatinine in the model group were significantly higher than in the control and lymph groups. Renal morphological study showed red blood cell silting and casts forming in the model group. The prothrombin time (PT), prothrombin time ratio (PTR), activated partial thromboplastin time (APTT), and thrombin time of lymph and model groups were higher than those in the control group, whereas fibrinogen was lower. The PT, PTR, and APTT were prolonged in the lymph group than in the model group. The platelet functions of the lymph and model groups were higher than in the control group, but platelet aggregation rate and thrombosis-forming indices were lower than in the control group; the platelet adhesive and aggregation rates and thrombosis dry weight of the lymph group were lower than those of the model group. CONCLUSION: Exogenous normal lymph could alleviate kidney injury in DIC rats, which may be related to the improving coagulation function. PMID- 22229667 TI - The importance of an asymmetric distribution of acidic lipids for synaptotagmin 1 function as a Ca2+ sensor. AB - Syt1 (synaptotagmin 1) is a major Ca2+ sensor for synaptic vesicle fusion. Although Syt1 is known to bind to SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes and to the membrane, the mechanism by which Syt1 regulates vesicle fusion is controversial. In the present study we used in vitro lipid-mixing assays to investigate the Ca2+-dependent Syt1 function in proteoliposome fusion. To study the role of acidic lipids, the concentration of negatively charged DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L serine) in the vesicle was varied. Syt1 stimulated lipid mixing by 3-10-fold without Ca2+. However, with Ca2+ there was an additional 2-5-fold enhancement. This Ca2+-dependent stimulation was observed only when there was excess PS (phosphatidylserine) on the t-SNARE (target SNARE) side. If there was equal or more PS on the v-SNARE (vesicule SNARE) side the Ca2+-dependent stimulation was not observed. We found that Ca2+ at a concentration between 10 and 50 MUM was sufficient to give rise to the maximal enhancement. The single-vesicle-fusion assay indicates that the Ca2+-dependent enhancement was mainly on docking, whereas its effect on lipid mixing was small. Thus for Syt1 to function as a Ca2+ sensor, a charge asymmetry appears to be important and this may play a role in steering Syt1 to productively trans bind to the plasma membrane. PMID- 22229669 TI - Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors. AB - In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N'-{4-[(6,7-dimethoxyquinazolin-4 yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series. PMID- 22229671 TI - Case report: a prototypical experience of 'poltergeist' activity, conspicuous quantitative electroencephalographic patterns, and sLORETA profiles - suggestions for intervention. AB - People who report objects moving in their presence, unusual sounds, glows around other people, and multiple sensed presences but do not meet the criteria for psychiatric disorders have been shown to exhibit electrical anomalies over the right temporal lobes. This article reports the striking quantitative electroencephalography, sLORETA results, and experimental elicitation of similar subjective experiences in a middle-aged woman who has been distressed by these classic phenomena that began after a head injury. She exhibited a chronic electrical anomaly over the right temporoinsular region. The rotation of a small pinwheel near her while she 'concentrated' upon it was associated with increased coherence between the left and right temporal lobes and concurrent activation of the left prefrontal region. The occurrence of the unusual phenomena and marked 'sadness' was associated with increased geomagnetic activity; she reported a similar mood when these variations were simulated experimentally. Our quantitative measurements suggest people displaying these experiences and possible anomalous energies can be viewed clinically and potentially treated. PMID- 22229672 TI - Effect of age, body mass index, and parity on Pelvic Organ Prolapse Quantification system measurements in women with symptomatic pelvic organ prolapse. AB - AIM: To evaluate the effect of age, body mass index (BMI), and parity on Pelvic Organ Prolapse Quantification (POP-Q) system measurements in women with symptomatic prolapse. MATERIAL AND METHODS: The charts of 603 women with symptomatic prolapse were reviewed. Patients with prior prolapse surgery or hysterectomy were excluded. POP-Q measurements were recorded by a single examiner. Data were analyzed using descriptive statistics, the Pearson's product moment correlation, and Wilcoxon signed rank test. RESULTS: Three hundred and eleven patients met inclusion criteria. Mean age was 63.4 years, mean parity was 2.6, and mean body mass index (BMI) was 26.6 kg/m(2) . Increasing age was correlated with worsening scores on Ba (r = 0.33, P < 0.0001), C (r = 0.14, P < 0.02), D (r = 0.14, P = 0.02) and Bp (r = 0.13, P = 0.02), while parity was only correlated with worsening scores on Aa (r = 0.12, P = 0.04). There was no correlation between BMI and any POP-Q data point. CONCLUSION: The effect of increasing parity was seen solely on point Aa in women with symptomatic prolapse. Age affected all vaginal compartments, while BMI had no impact on POP-Q data points. PMID- 22229674 TI - What's in this issue? PMID- 22229675 TI - Publication: in whose interests? PMID- 22229676 TI - Fever treatment in critical care: when available evidence does not support traditional practice. PMID- 22229673 TI - Hydrogen sulfide is a signaling molecule and a cytoprotectant. AB - SIGNIFICANCE: Accumulating evidence shows that hydrogen sulfide may function as a signaling molecule in processes such as neuromodulation in the brain and smooth muscle relaxation in the vascular system. It also has a cytoprotective effect, since it can protect neurons and cardiac muscle from oxidative stress and ischemia-reperfusion injury, respectively. Hydrogen sulfide can also modulate inflammation, insulin release, and angiogenesis. RECENT ADVANCES: The regulation of the activity of 3-mercaptopyruvate sulfur transferase (3MST) along with cysteine aminotransferase (CAT), one of the H(2)S producing pathways, has been demonstrated. The production of H(2)S by the pathway, which is regulated by Ca(2+) and facilitated by thioredoxin and dihydrolipoic acid, is also involved in H(2)S signaling as well as cytoprotection. Sulfur hydration of proteins by H(2)S has been proposed to modulate protein functions. H(2)S-sensitive fluorescent probes, which enable us to measure the localization of H(2)S in real time, have been developed. CRITICAL ISSUES: The basal concentrations of H(2)S have recently been measured and found to be much lower than those initially reported. However, the concentration of H(2)S reached in stimulated cells, as well as the regulation of H(2)S producing enzymes is not well understood. It has been proposed that some of the effects of H(2)S on the regulation of enzymes and receptors might be explained through the properties of sulfane sulfur (S(0)), another form of active sulfur. FUTURE DIRECTIONS: The determination of H(2)S concentrations in activated cells using new methods including H(2)S-sensitive fluorescent probes, as well as the investigation of the effects of H(2)S using specific inhibitors, may provide better understanding of the physiological function of this molecule. Clarifying mechanisms of H(2)S activity may also facilitate the development of new therapeutic compounds. PMID- 22229677 TI - The experience of being an 'extracorporeal membrane oxygenation' relative within the CESAR trial. AB - AIMS AND OBJECTIVES: This article reports a study exploring experiences of the relatives of adult patients receiving extracorporeal membrane oxygenation (ECMO) within the CESAR trial. BACKGROUND: Relatives of ECMO patients have undergone unique experiences which have not previously been addressed in the literature and thus may have different needs which may not be met by present practice. DESIGN AND METHODS: A grounded theory approach was adopted. In-depth unstructured interviews were conducted with family members of 10 surviving adult patients who had been randomized and received ECMO within the CESAR trial. RESULTS: Relatives have a range of needs specific to the ECMO experience, these include the depth and positivity of information. Particular areas for support were concerning a perceived self-inflicted nature of illness, personal guilt, distance from home, receiving 'the call', weaning from sedation and transfer/discharge from the ECMO unit. CONCLUSIONS: Relatives would benefit from the opportunity to talk about their 'ECMO experiences' following the patient's recovery to enable them and their families to 'move on'. RELEVANCE TO CLINICAL PRACTICE: Interventions need to be in place to follow-up relatives and patients to provide ongoing support to the family unit. PMID- 22229678 TI - Inotropic drugs and their uses in critical care. AB - The aim of this article was to provide a resource for critical care nurses wishing to further their understanding of inotropic drugs used in critical care. The physiology of cardiac output and blood pressure is examined along with an explanation of adrenergic receptors acted on by inotropes. Some common indications for inotropic therapy are discussed, along with essential patient monitoring and dose calculations to ensure safe therapeutic ranges are observed. Some of the most commonly used positive inotropes used in critical care environments are individually explored, providing indications and some of the latest research relating to their uses. Frequently, observed side effects of individual inotropes are also offered, enabling the nurse to maintain patient safety when administering these potent drugs. Some major nursing and professional issues related to inotrope therapy and medicine administration are discussed, as well as some recommended practices in renewing infusions. PMID- 22229679 TI - Continuous lateral rotation therapy - a review. AB - AIMS: This article reviews the current evidence, benefits and drawbacks for the use of continuous lateral replacement therapy in the treatment and prevention of nosocomial infections in the ventilated patient. RELEVANT TO PRACTICE: The acquisition of nosocomial infections and the development of pressure sores continue to be major issues in the care of the critically ill, ventilated patient. The use of continuous lateral rotation therapy (CLRT) as an adjunct in the prevention and treatment of pneumonia has increased in popularity in recent years. A number of institutions routinely advocate the use of CLRT in critically ill patients. CONCLUSION: While there is some data to suggest that CLRT may have an impact on prevention of and treatment for nosocomial infections acquired by ventilated patients, there still remains insufficient evidence to its inclusion as a fully validated treatment. Clearly, there is a requirement for more robust, in-depth research into the efficacy of this proposed treatment. PMID- 22229680 TI - Critical care patients' experience of the helmet continuous positive airway pressure. AB - BACKGROUND: Continuous positive airway pressure (CPAP) is a common treatment modality for acute respiratory failure (ARF) in critical care. Historically, a tight-fitting mask is used to provide respiratory support. This however is not without risks to the patient. The helmet CPAP is a new product that provides the same treatment with a different method of delivery. There is minimal evidence to date explaining the patient's experience of the new helmet modality. AIMS AND OBJECTIVES: The aim of this research study is to explore critical care patient's experience of helmet CPAP. DESIGN: A qualitative approach was taken utilizing descriptive phenomenological methodology. In order to obtain rich data, six interviews with cues provided the platform for data generation and collection. A thematic framework was utilized with emergent themes manually analysed using a constant comparative technique to express the experiences or phenomena of a particular event or experiences. FINDINGS/RESULTS: The overall experience was unique to each patient. The patients entrusted the health care team which made the experience more tolerable. Paradoxical themes were experienced during treatment. The themes included entrapment, confusion, helping me breathe, liberation, challenges, apprehension, relief, trust and endurance. The desire to survive the acute illness proved to be a driving factor. CONCLUSION: The study has provided an insight into the patient's experience of helmet CPAP in the critical care setting. The findings have provided a basis for policy and guideline development. It will also assist in developing future patient focused care. PMID- 22229681 TI - Newly qualified nurses experiences in the intensive care unit. AB - AIM: The aim of this research was to investigate newly qualified nurses (NQN) experiences of starting their career in the intensive care unit (ICU). The author also investigated the opinions of senior nurses from ICU in relation to NQN in ICU. BACKGROUND: Although not a new concept, NQN in ICU has little substantive research to support recruitment. There is a current demand to investigate this topic, because of retention of staff and a shortage of qualified nurses. METHOD: This was a comparative, qualitative study using two forms of data collection. This study was conducted over two phases. Phase I, used semi-structured interviews with eight NQN, with one participant for the pilot study. PHASE II used a focus group to interview seven senior nurses in ICU. FINDINGS: NQN experienced anxiety about time management, accountability and socialization. Senior nurses felt NQN coped well with the demanding aspects of ICU but were aware that preceptors are under a lot of pressure. They were concerned about NQN lack of hospital knowledge. The competency-based practice highlighted the importance of record keeping and its associated legal implications. CONCLUSION: NQN cope well with the complexity of ICU. Having student placements in this area seem to ease this transition and reduce some 'reality shock'. They therefore seem better equipped to deal with the steep learning curve. PMID- 22229683 TI - EfCCNa visit. PMID- 22229682 TI - Freshman committee member!! (like being a fresher at uni. ...with more cake) a reflection by Sarah Bashford. PMID- 22229688 TI - Notch signalling regulates cytokine production by CD8+ and CD4+ T cells. AB - The Notch signalling pathway regulates several aspects of cellular differentiation such as T lineage commitment and effector functions on peripheral T cells; however, there is limited information regarding Notch receptor expression on different T cell subsets and the putative role of the different receptors on T cell effector function. Here, we studied the protein expression of Notch receptors on murine T cells in vitro and in vivo and analysed the role of the Notch pathway in cytokine production by CD4+ and CD8+ T cells. We found that resting CD4+ and CD8+ T cells do not express Notch receptors, but they upregulate Notch 1 and Notch 2 shortly after in vitro and in vivo activation. Using a gamma secretase inhibitor, which blocks Notch signalling through all Notch receptors, we demonstrated that the Notch pathway regulates IL-10 production by CD4+ T cells and IFN-gamma and IL-17 production by CD8+ T cells. These results suggest that Notch 1 and 2 are expressed by CD4+ and CD8+ T cells and represent the putative Notch receptors that regulate effector functions and cytokine production by these cells. PMID- 22229689 TI - Effects of the 755-nm Alexandrite laser on fine dark facial hair: review of 90 cases. AB - Laser hair removal is a relatively effective method for thick hair. Despite the risk for induction of fine hair growth, application of laser for fine dark hair is sometimes inevitable. We investigate the effects of 755-nm Alexandrite laser on fine dark facial hair and evaluate the induction rates of fine hair growth and case satisfaction. In the present study, the thickening rate of hairs (33.33%) was found to be higher than the previously published rates. However, reduction of hair density can be obtained when the laser sessions are continued. PMID- 22229691 TI - The economy and absenteeism: a macro-level study. AB - Despite much speculation, little is known about the net effects of the economy on the employed workforce. To fill this gap, we used state-level data collected by the Bureau of Labor Statistics to examine the effects of the condition of the economy, as indicated by the unemployment rate, on incidence rates of absence reportedly due to symptoms of illness and violent acts in the workplace for 43 states from 1992 to 2009. Our results suggest that the unemployment rate is positively associated with these indicators of absenteeism, and that these effects are delayed in time. PMID- 22229690 TI - Prenatal allergen exposures prevent allergen-induced sensitization and airway inflammation in young mice. AB - BACKGROUND: Immune-modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen-induced sensitization and airway inflammation in the offspring in a murine model. METHODS: BALB/c mice were exposed to aerosolized ovalbumin (OVA) three times per week from day 7 of pregnancy until delivery (day 0). Offspring were systemically sensitized by six intraperitoneal injections with OVA between postnatal days 21 and 35, prior to airway allergen challenges on days 48, 49, and 50. Analyses were performed on day 52. To examine long-lasting effects of maternal OVA exposures some offspring were sensitized between days 115 and 129; analyses took place on day 147. RESULTS: Compared to maternal placebo exposures, maternal OVA exposures suppressed OVA-specific IgE serum levels and inhibited development of allergen-induced airway inflammation in the OVA-sensitized offspring on both days 52 and 147. This protective effect was associated with a shift from a predominant Th2 immune response toward a predominant production of the cytokines IFN-gamma and IL-10. Further, maternal OVA exposures were associated with development of CD25(+) Foxp3(+) regulatory T cells (T(regs)) in the OVA-sensitized offspring. Depletion of T(regs) or neutralization of IL-10 prior to allergen sensitization re-established OVA-induced sensitization and eosinophilic airway inflammation in the OVA-sensitized offspring. CONCLUSIONS: In our model, maternal allergen exposures during pregnancy prevented later allergen mediated sensitization and airway inflammation by allergen-specific tolerance induction in the offspring. PMID- 22229692 TI - Doing the right thing without being told: joint effects of initiative climate and general self-efficacy on employee proactive customer service performance. AB - We developed and tested a cross-level model of the antecedents and outcomes of proactive customer service performance. Results from a field study of 900 frontline service employees and their supervisors in 74 establishments of a multinational hotel chain located in Europe, the Middle East, Africa, and Asia demonstrated measurement equivalence and suggested that, after controlling for service climate, initiative climate at the establishment level and general self efficacy at the individual level predicted employee proactive customer service performance and interacted in a synergistic way. Results also showed that at the establishment level, controlling for service climate and collective general service performance, initiative climate was positively and indirectly associated with customer service satisfaction through the mediation of aggregated proactive customer service performance. We discuss important theoretical and practical implications of these findings. PMID- 22229693 TI - Job burnout and depression: unraveling their temporal relationship and considering the role of physical activity. AB - Job burnout and depression have been generally found to be correlated with one another. However, evidence regarding the job burnout-depression association is limited in that most studies are cross-sectional in nature. Moreover, little is known about factors that may influence the job burnout-depression association, other than individual or organizational factors (e.g., gender, supervisor support). The current study seeks to address these gaps by (a) unraveling the temporal relationship between job burnout and depression and (b) examining whether the job burnout-depression association may be contingent upon the degree to which employees engage in physical activity. On the basis of a full-panel 3 wave longitudinal design with a large sample of employees (N = 1,632), latent difference score modeling indicated that an increase in depression from Time 1 to Time 2 predicts an increase in job burnout from Time 2 to Time 3, and vice versa. In addition, physical activity attenuated these effects in a dose-response manner, so that the increase in job burnout and depression was strongest among employees who did not engage in physical activity and weakest to the point of nonsignificance among those engaging in high physical activity. PMID- 22229694 TI - Z-Selectivity in olefin metathesis with chelated Ru catalysts: computational studies of mechanism and selectivity. AB - The mechanism and origins of Z-selectivity in olefin metathesis with chelated Ru catalysts were explored using density functional theory. The olefin approaches from the "side" position of the chelated Ru catalysts, in contrast to reactions with previous unchelated Ru catalysts that favor the bottom-bound pathway. Steric repulsions between the substituents on the olefin and the N-substituent on the N heterocyclic carbene ligand lead to highly selective formation of the Z product. PMID- 22229695 TI - Determination of the rate constant for the NH2(X2B1) + NH2(X2B1) recombination reaction with collision partners He, Ne, Ar, and N2 at low pressures and 296 K. Part 1. AB - The recombination rate constant for the NH(2)(X(2)B(1)) + NH(2)(X(2)B(1)) -> N(2)H(4)(X(1)A(1)) reaction in He, Ne, Ar, and N(2) was measured over the pressure range 1-20 Torr at a temperature of 296 K. The NH(2) radical was produced by 193 nm laser photolysis of NH(3) dilute in the third-body gas. The production of NH(2) and the loss of NH(3) were monitored by high-resolution continuous-wave absorption spectroscopy: NH(2) on the (1)2(21) <- (1)3(31) rotational transition of the (0,7,0)A(2)A(1) <- (0,0,0) X(2)B(1) vibronic band and NH(3) on either inversion doublet of the (q)Q(3)(3) rotational transition of the nu(1) fundamental. Both species were detected simultaneously following the photolysis laser pulse. The broader Doppler width of the NH(2) spectral transition allowed temporal concentration measurements to be extended up to 20 Torr before pressure broadening effects became significant. Fall-off behavior was identified and the bimolecular rate constants for each collision partner were fit to a simple Troe form defined by the parameters, k(0), k(inf), and F(cent). This work is the first part of a two part series in which part 2 will discuss the measurements with more efficient energy transfer collision partners CH(4), C(2)H(6), CO(2), CF(4), and SF(6). The pressure range was too limited to extract any new information on k(inf), and k(inf) was taken from the theoretical calculations of Klippenstein et al. (J. Phys. Chem A 2009, 113, 10241) as k(inf) = 7.9 * 10(-11) cm(3) molecule(-1) s(-1) at 296 K. The individual Troe parameters were: He, k(0) = 2.8 * 10(-29) and F(cent) = 0.47; Ne, k(0) = 2.7 * 10(-29) and F(cent) = 0.34; Ar, k(0) = 4.4 * 10(-29) and F(cent) = 0.41; N(2), k(0) = 5.7 * 10(-29) and F(cent) = 0.61, with units cm(6) molecule(-2) s(-1) for k(0). In the case of N(2) as the third body, it was possible to measure the recombination rate constant for the NH(2) + H reaction near 20 Torr total pressure. The pure three body recombination rate constant was (2.3 +/- 0.55) * 10(-30) cm(6) molecule(-2) s(-1), where the uncertainty is the total experimental uncertainty including systematic errors at the 2sigma level of confidence. PMID- 22229696 TI - Bioinspired silicification of silica-binding peptide-silk protein chimeras: comparison of chemically and genetically produced proteins. AB - Novel protein chimeras constituted of "silk" and a silica-binding peptide (KSLSRHDHIHHH) were synthesized by genetic or chemical approaches and their influence on silica-silk based chimera composite formation evaluated. Genetic chimeras were constructed from 6 or 15 repeats of the 32 amino acid consensus sequence of Nephila clavipes spider silk ([SGRGGLGGQG AGAAAAAGGA GQGGYGGLGSQG](n)) to which one silica binding peptide was fused at the N terminus. For the chemical chimera, 28 equiv of the silica binding peptide were chemically coupled to natural Bombyx mori silk after modification of tyrosine groups by diazonium coupling and EDC/NHS activation of all acid groups. After silica formation under mild, biomaterial-compatible conditions, the effect of peptide addition on the properties of the silk and chimeric silk-silica composite materials was explored. The composite biomaterial properties could be related to the extent of silica condensation and to the higher number of silica binding sites in the chemical chimera as compared with the genetically derived variants. In all cases, the structure of the protein/chimera in solution dictated the type of composite structure that formed with the silica deposition process having little effect on the secondary structural composition of the silk-based materials. Similarly to our study of genetic silk based chimeras containing the R5 peptide (SSKKSGSYSGSKGSKRRIL), the role of the chimeras (genetic and chemical) used in the present study resided more in aggregation and scaffolding than in the catalysis of condensation. The variables of peptide identity, silk construct (number of consensus repeats or silk source), and approach to synthesis (genetic or chemical) can be used to "tune" the properties of the composite materials formed and is a general approach that can be used to prepare a range of materials for biomedical and sensor-based applications. PMID- 22229698 TI - Asymmetric siRNA: new strategy to improve specificity and reduce off-target gene expression. AB - Small interfering RNAs (siRNAs) have been used extensively in reverse genetic research, and many have made their way into clinical trials. The most widely used siRNA structure consists of double-stranded RNA with 19 base pairs and 2 nucleotide overhangs at the 3'-end of both strands (19+2). Although widely used, this symmetric structure bears inherent disadvantages in both research and clinical applications. One of the most common caveats is the off-target effect leading to adverse effects in clinical application. In the current study, using C C chemokine receptor (CCR5) as a target, we have shown that 19+2 siRNA could still cause considerable global off-target effects regardless of rational design based on its thermodynamic asymmetry. However, we demonstrated that structurally asymmetric siRNA targeting CCR5 could be adopted to improve the strand specificity and greatly reduce the off-target effects without significantly compromising its on-target effects. Data from microarray analysis suggest that an unidentified mechanism resulting in global gene down-regulation might be avoided through strand shortening. Taken together, our work suggested a promising and simple way to improve strand specificity and overcome the off-target gene expression effects without introducing more complications while retaining the efficacy of siRNA. PMID- 22229697 TI - Profiling of dihydroorotate dehydrogenase, p38 and JAK inhibitors in the rat adjuvant-induced arthritis model: a translational study. AB - BACKGROUND AND PURPOSE: Translational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients. EXPERIMENTAL APPROACH: Teriflunomide - a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 - a selective p38 MAPK inhibitor; and tofacitinib - a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion. KEY RESULTS: All three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia. CONCLUSIONS AND IMPLICATIONS: This multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA. PMID- 22229699 TI - Monoammoniate of calcium amidoborane: synthesis, structure, and hydrogen-storage properties. AB - The monoammoniate of calcium amidoborane, Ca(NH(2)BH(3))(2).NH(3), was synthesized by ball milling an equimolar mixture of CaNH and AB. Its crystal structure has been determined and was found to contain a dihydrogen-bonded network. Thermal decomposition under an open-system begins with the evolution of about 1 equivalent/formula unit (equiv.) of NH(3) at temperatures <100 degrees C followed by the decomposition of Ca(NH(2)BH(3))(2) to release hydrogen. In a closed-system thermal decomposition process, hydrogen is liberated in two stages, at about 70 and 180 degrees C, with the first stage corresponding to an exothermic process. It has been found that the presence of the coordinated NH(3) has induced the dehydrogenation to occur at low temperature. At the end of the dehydrogenation, about 6 equiv. (~ 10.2 wt %) of hydrogen can be released, giving rise to the formation of CaB(2)N(3)H. PMID- 22229700 TI - The road ends in Detroit. PMID- 22229701 TI - Evaluation of liver fibrosis by transient elastography (Fibroscan(r)) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial. AB - BACKGROUND: Methotrexate is an effective treatment for inflammatory bowel disease (IBD). However, long-term treatments have been associated with the development of liver fibrosis. FibroScan(r) is a noninvasive, safe, and effective technique to evaluate liver fibrosis. AIM: To evaluate the presence of significant liver fibrosis by transient elastography (FibroScan(r)) in IBD patients treated with methotrexate. METHODS: Cross-sectional study including IBD patients treated with methotrexate from different hospitals. Clinical and analytical data, duration of treatment, and cumulative dose of methotrexate were obtained. Liver stiffness was assessed by FibroScan(r). The cutoff value for significant liver fibrosis (according to METAVIR) was F >= 2: 7.1 kPa. Results. In the study, 46 patients were included, 30 women (65%), with a mean age of 43 +/- 10 years. 31 patients had Crohn's disease (67.4%), 13 ulcerative colitis (28.3%), and 2 indeterminate colitis (4.3%). The mean cumulative dose of methotrexate was 1242 +/- 1349 mg, with a mean treatment duration of 21 +/- 24 months. The mean value of liver stiffness was 4.7 +/- 6.9 kPa. There were 35 patients (76.1%) with F01, 8 patients (17.4%) with F = 2, and 3 patients with F >= 3 (6.5%). There were no differences in liver stiffness depending on sex, age, type of IBD, or cumulative dose of methotrexate. CONCLUSIONS: (1) Development of advanced liver fibrosis in IBD patients treated with methotrexate is exceptional. (2) There were no differences in liver stiffness depending on the type of IBD or the cumulative dose of methotrexate. (3) FibroScan(r) may be potentially useful for evaluation and follow-up of liver fibrosis in methotrexate-treated patients. PMID- 22229702 TI - Progestagen supplementation during early pregnancy does not improve embryo survival in pigs. AB - Progesterone supplementation during early pregnancy may increase embryo survival in pigs. The current study evaluated whether oral supplementation with an analogue of progesterone, altrenogest (ALT), affects embryo survival. A first experiment evaluated the effect of a daily 20-mg dosage of ALT during days 1-4 or 2-4 after onset of oestrus on embryo survival at day 42 of pregnancy. A control group (CTR1) was not treated. The time of ovulation was estimated by transrectal ultrasound at 12-h intervals. Altrenogest treatment significantly reduced pregnancy rate when start of treatment was before or at ovulation: 25% (5/20) compared to later start of treatment [85% (28/33)] and non-treated CTR1 [100% (23/23)]. Altrenogest treatment also reduced (p < 0.05) number of foetuses, from 14.6 +/- 2.6 in CTR1 to 12.5 +/- 2.5 when ALT started 1-1.5 days from ovulation and 10.7 +/- 2.9 when ALT started 0-0.5 days from ovulation. In a second experiment, sows with a weaning-to-oestrous interval (WOI) of 6, 7 or 8-14 days were given ALT [either 20 mg (ALT20; n = 49) or 10 mg (ALT10; n = 48)] at day 4 and day 6 after onset of oestrus or were not treated (CTR2; n = 49), and farrowing rate and litter size were evaluated. Weaning-to-oestrous interval did not affect farrowing rate or litter size. ALT did not affect farrowing rate (86% vs 90% in CTR2), but ALT20 tended to have a lower litter size compared with CTR2 (11.7 +/- 4.1 vs 13.3 +/- 3.1; p = 0.07) and ALT10 was intermediate (12.3 +/- 2.9). In conclusion, altrenogest supplementation too soon after ovulation reduces fertilization rate and embryo survival rate and altrenogest supplementation at 4 6 days of pregnancy reduces litter size. As a consequence, altrenogest supplementation during early pregnancy may reduce both farrowing rate and litter size and cannot be applied at this stage in practice as a remedy against low litter size. PMID- 22229703 TI - Risk of malignancy index used as a diagnostic tool in a tertiary centre for patients with a pelvic mass. AB - OBJECTIVE: Risk of malignancy index (RMI), based on a serum cancer antigen 125 level, ultrasound findings and menopausal status, is used to discriminate ovarian cancer from benign pelvic mass. In Denmark, patients with pelvic mass and RMI >=200 are referred to tertiary gynecologic oncology centers according to the national guidelines for ovarian cancer treatment. The guidelines include recalculation of RMI at the tertiary center and, if indicated, positron emission tomography/computed tomography and fast-track surgery by specialists in cancer surgery. The aim of this study was to validate the use of RMI >=200 as a tool for preoperative identification of ovarian cancer at a tertiary center. DESIGN: Prospective observational study. SETTING: A tertiary center in Copenhagen, Denmark. POPULATION: One thousand one hundred and fifty-nine women with pelvic mass. METHODS: The RMI was calculated after ultrasound examination and blood sampling for serum cancer antigen 125 analysis within two weeks before surgery. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values were calculated to evaluate the ability of RMI to distinguish between ovarian cancer and benign pelvic mass. RESULTS: There were 778 women diagnosed with benign pelvic mass, while 251 had ovarian cancer and 74 had borderline ovarian tumor. Fifty-six women were diagnosed with other forms of cancer. Sensitivity and specificity for ovarian cancer vs. benign pelvic mass for RMI >=200 were 92 and 82%, respectively. Corresponding positive and negative predictive values were 62 and 97%. CONCLUSIONS: Risk of malignancy index >=200 is a reliable tool for identifying patients with ovarian cancer pelvic masses at a tertiary centre to select patients for further preoperative examinations. PMID- 22229704 TI - Understanding and improving communication and decision-making in palliative care for Turkish and Moroccan immigrants: a multiperspective study. AB - OBJECTIVE: The aim of this study is to explore how communication and decision making in palliative care among Turkish and Moroccan patients is influenced by different styles of care management between Turkish and Moroccan families and Dutch professional care providers. Problems as well as solutions for these problems are highlighted. DESIGN: A qualitative design was used, totally interviewing 83 people (6 patients, 30 relatives and 47 care providers) covering 33 cases of incurable cancer patients receiving palliative care. Data were analysed thematically and contextually. RESULTS: The analysis reveals that problems in decision-making are partly related to differences in ethnic-cultural views on 'good care' at the end of life: Dutch palliative care providers prefer to focus on quality of life rather than on prolonging life, while Turkish and Moroccan families tend to insist on cure. Another barrier is caused by conflicting views on the role of the 'care management group': Dutch care providers see the patient as their primary discussion partner, while in Turkish and Moroccan families, relatives play a major part in the communication and decision-making. Moreover, the family's insistence on cure often leads to the inclusion of additional care providers in communication, thus complicating joint decision-making. CONCLUSION: Care providers need to understand that for Turkish and Moroccan patients, decision-making is seldom a matter of one-to-one communication. Next to acknowledging these patients' different cultural backgrounds, they must also recognise that the families of these patients often function as care management groups, with an 'equal' say in communication and decision-making. In addition, professionals should optimise communication within their own professional care management group. PMID- 22229705 TI - pH- and voltage-responsive chitosan hydrogel through covalent cross-linking with catechol. AB - A new method for covalently cross-linking chitosan is developed by chemically oxidizing catechol to o-quinone which subsequently reacts with and cross-links chitosan through Michael addition and Schiff base formation. The cross-linked chitosan film shows a pH-responsive, switchlike behavior toward the negatively charged redox probe, Fe(CN)(6)(3-/4-), and withstands harsh acidic conditions. The negative Fe(CN)(6)(3-/4-) is found to be trapped and enriched in the catechol cross-linked chitosan film under acidic conditions and released into solution by either increasing pH or applying a negative voltage. Chitosan films made with different techniques, i.e., solvent evaporation (simple deposition), electrodeposition, and covalent cross-linking, are examined using cyclic voltammetry and electrochemical impedance spectroscopy (EIS), and the results demonstrate that fabrication methods greatly affect the properties of the chitosan films. PMID- 22229706 TI - Monitoring the effective population size of a brown bear (Ursus arctos) population using new single-sample approaches. AB - The effective population size (N(e) ) could be the ideal parameter for monitoring populations of conservation concern as it conveniently summarizes both the evolutionary potential of the population and its sensitivity to genetic stochasticity. However, tracing its change through time is difficult in natural populations. We applied four new methods for estimating N(e) from a single sample of genotypes to trace temporal change in N(e) for bears in the Northern Dinaric Mountains. We genotyped 510 bears using 20 microsatellite loci and determined their age. The samples were organized into cohorts with regard to the year when the animals were born and yearly samples with age categories for every year when they were alive. We used the Estimator by Parentage Assignment (EPA) to directly estimate both N(e) and generation interval for each yearly sample. For cohorts, we estimated the effective number of breeders (N(b) ) using linkage disequilibrium, sibship assignment and approximate Bayesian computation methods and extrapolated these estimates to N(e) using the generation interval. The N(e) estimate by EPA is 276 (183-350 95% CI), meeting the inbreeding-avoidance criterion of N(e) > 50 but short of the long-term minimum viable population goal of N(e) > 500. The results obtained by the other methods are highly consistent with this result, and all indicate a rapid increase in N(e) probably in the late 1990s and early 2000s. The new single-sample approaches to the estimation of N(e) provide efficient means for including N(e) in monitoring frameworks and will be of great importance for future management and conservation. PMID- 22229707 TI - Slowing down DNA translocation through a nanopore in lithium chloride. AB - The charge of a DNA molecule is a crucial parameter in many DNA detection and manipulation schemes such as gel electrophoresis and lab-on-a-chip applications. Here, we study the partial reduction of the DNA charge due to counterion binding by means of nanopore translocation experiments and all-atom molecular dynamics (MD) simulations. Surprisingly, we find that the translocation time of a DNA molecule through a solid-state nanopore strongly increases as the counterions decrease in size from K(+) to Na(+) to Li(+), both for double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA). MD simulations elucidate the microscopic origin of this effect: Li(+) and Na(+) bind DNA stronger than K(+). These fundamental insights into the counterion binding to DNA also provide a practical method for achieving at least 10-fold enhanced resolution in nanopore applications. PMID- 22229708 TI - Brazilian green propolis extracts improve Tinea pedis interdigitalis and Tinea corporis. PMID- 22229709 TI - Finding an ally: can dogs help therapists promote communication in individuals with profound intellectual and multiple disabilities? PMID- 22229710 TI - Binding evaluation of fragment-based scaffolds for probing allosteric enzymes. AB - Fragment-based drug discovery has become a powerful method for the generation of drug leads against therapeutic targets. Beyond the identification of novel and effective starting points for drug design, fragments have emerged as reliable tools for assessing protein druggability and identifying protein hot spots. Here, we have examined fragments resulting from the deconstruction of known inhibitors from the glycogen phosphorylase enzyme, a therapeutic target against type 2 diabetes, with two motivations. First, we have analyzed the fragment binding to the multiple binding sites of the glycogen phosphorylase, and then we have investigated the use of fragments to study allosteric enzymes. The work we report illustrates the power of fragmentlike ligands not only for probing the various binding pockets of proteins, but also for uncovering cooperativity between these various binding sites. PMID- 22229711 TI - An effective environmental intervention for management of the 'mirror sign' in a case of probable Lewy body dementia. AB - The term 'mirror sign' refers to the inability to recognize the reflection of oneself in a mirror, while the ability to recognize others' faces often remains intact. In this article, we present a case of an 85-year-old woman, with probable Lewy body dementia, who stably exhibited a delusional 'mirror sign' for a period of 9 months. Following a straightforward, ecological, non-pharmacological intervention, her 'mirror sign' delusion was no longer present. PMID- 22229712 TI - Meperidine for uterine dystocia and its effect on duration of labor and neonatal acid-base status: a randomized clinical trial. AB - AIM: The aim of this study was to evaluate the effectiveness of meperidine, administered during the first stage of labor in patients with uterine dystocia, on the duration of labor and neonatal acid-base status at birth. MATERIAL AND METHODS: We randomly assigned 240 nulliparous women with a singleton pregnancy at term who were diagnosed with uterine dystocia in labor at 4-6-cm cervical dilatation to receive either a single dose of 50 mg meperidine in 10 mL of saline (slow intravenous injection over 2 min) or 10 mL of isotonic saline (control group). The primary outcome measures were duration of labor (from the time of beginning of the intervention to the time of the expulsion of the fetal head) and umbilical cord arterial acid-base status. RESULTS: The evidence revealed no statistically significant difference between the two groups in length of labor (188.2 +/- 92.3 min in the meperidine group compared to 205.4 +/- 96.1 min in the placebo group, P = 0.159). The pH of the umbilical cord arterial samples was lower in the meperidine group than in the control group, although the difference was not statistically significant (P = 0.089). CONCLUSION: Because of the absence of any beneficial effect of meperidine on uterine dystocia, its use in labor should be limited to pain relief in the absence of epidural analgesia. PMID- 22229713 TI - Reported adverse events in young women following quadrivalent human papillomavirus vaccination. AB - PURPOSE: To assess and describe young women's experiences with their first dose of quadrivalent human papillomavirus vaccine (HPV4) (Gardasil(r)) in a large managed care organization. METHODS: We collected survey and electronic medical record (EMR) data for 899 young women aged 11-26 receiving their first HPV4 injection from February through September 2008. Survey items included questions about adverse events, interactions with healthcare providers, and knowledge and attitudes toward HPV disease and HPV4. RESULTS: Six hundred ninety-six (78%) participants reported pain at the injection site. Other common reactions included injection site bruising or discoloration (n=155, 17%) or swelling (n=127, 14%) and presyncope or syncope (n=134, 15%). Overall, preteens and teens were more likely than adult participants to report vaccine adverse events. Most respondents, particularly in the adult age group, reported that their healthcare provider reviewed important information about HPV infection and about the risks and benefits of receiving the vaccine. Knowledge and attitudes about HPV and HPV4 also varied by age, with older women generally exhibiting more accurate knowledge about HPV and perceived susceptibility to cervical cancer. CONCLUSIONS: There were significant age differences in young women's experiences with their first HPV4 injection. These findings highlight the importance of age-appropriate education and provider communications about HPV disease and vaccination. PMID- 22229714 TI - Sexual desire problems in women seeking healthcare: a novel study design for ascertaining prevalence of hypoactive sexual desire disorder in clinic-based samples of U.S. women. AB - BACKGROUND: Hypoactive sexual desire disorder (HSDD) has been estimated to occur in 10%-15% of adult women in large population-representative and community-based studies. However, none of these studies have used in-person diagnostic interview assessment to rule out alternative diagnoses, nor has the impact of other health conditions or help-seeking experiences been investigated. The current study aimed to determine the prevalence of generalized acquired HSDD in women aged >=18 who attended primary care or obstetrics and gynecology clinics for nonurgent clinic visits in the United States. METHODS: A total of 701 women were enrolled at 20 clinical sites across the United States between June 11, 2010, and October 15, 2010. Participants completed a two-part self-administered questionnaire, and a validated, structured, in-person diagnostic interview, conducted by a trained health professional was used for diagnosing HSDD according to DSM-IV-TR criteria. RESULTS: Fifty-two women (7.4%) were assigned a diagnosis of generalized acquired HSDD. Prevalence was lower in minority and postmenopausal women. Level of education and other sociodemographic factors did not appear to differentiate between women with and without HSDD. A marked increase in HSDD prevalence was noted in the perimenopausal (i.e., 40-49 years) and immediate postmenopausal (i.e., 50-59) age groups. Of the women diagnosed with HSDD, 53% had sought care from a health professional for HSDD. CONCLUSIONS: In this sample of women recruited in the clinical care setting, we observed an overall prevalence rate of 7.4% of acquired, generalized HSDD, with markedly increased prevalence in midlife women. PMID- 22229715 TI - Mucous membrane pemphigoid accompanied by ovarian cancer: a case with autoantibodies solely against gamma(2) -subunit of laminin-332. PMID- 22229716 TI - MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-kappaB signalling pathways. AB - BACKGROUND: MicroRNAs (miRNAs) are known to regulate the inflammatory response in various cell types. However, the ability of miRNAs to modulate dendritic cells (DCs) function for allergen immunotherapy is unclear. OBJECTIVE: To assess the role of miR-23b in the regulation of ovalbumin (OVA)-induced DC differentiation and function and to investigate the related molecular mechanisms. METHODS: Bone marrow-derived dendritic cells (BMDCs) were generated from murine bone marrow progenitor cells and subsequently stimulated with OVA to examine the profile of miRNA expression. After transfection with miR-23b reagents, DCs were evaluated for endocytic ability, surface marker expression, cytokine secretion and CD4+ T cell differentiation. The possible roles of the Notch and NF-kappaB signalling pathways were also evaluated. Human monocyte-derived dendritic cells (MDDCs) were similarly evaluated as well. RESULTS: Significant upregulation of miR-23b was observed in BMDCs pulsed with OVA. Following miR-23b transfection, BMDCs showed decreased OVA uptake, increased IL-10 production, decreased IL-12 production and an enhanced capacity to promote FoxP3+ CD4+ T regulatory cells (Tregs) differentiation. In addition, inactivation of the Notch1 and NF-kappaB signalling pathways were observed. Conversely, inhibition of miR-23b in BMDCs resulted in the opposite effects. In human MDDCs, miRNA23b transfection similarly increased IL-10 and decreased IL-12 production, and that treated human MDDCs induced increased FoxP3+ CD4+ T cells. CONCLUSION: Our findings provide evidence that miR 23b is capable of inducing tolerogenic DC activity and Treg responses in vitro through the inhibition of the Notch1 and NF-kappaB signalling pathways; thus, miR 23b might represent a therapeutic target for the management of allergic diseases. PMID- 22229717 TI - Oxidation of 2-cys peroxiredoxins in human endothelial cells by hydrogen peroxide, hypochlorous acid, and chloramines. AB - AIMS: Reactive oxygen species released from neutrophils during vascular inflammation could contribute to endothelial dysfunction seen in diseases such as atherosclerosis. Activated neutrophils generate hydrogen peroxide (H(2)O(2)) and hypochlorous acid (HOCl), as well as chloramines that are formed when HOCl reacts with amino compounds. These oxidants preferentially target thiol groups and thiol containing proteins. The peroxiredoxins (Prxs) are thiol proteins that have high reactivity with H(2)O(2) and may also be sensitive to HOCl and chloramines. RESULTS: We have investigated human umbilical vein endothelial cells and shown that their cytoplasmic (Prx1 and Prx2) and mitochondrial (Prx3) Prxs are oxidized when they are exposed to H(2)O(2), HOCl, or cell-permeable chloramines. H(2)O(2) converted the Prxs to hyperoxidized, inactive forms, with little accumulation of disulfide-linked dimers. The oxidized Prxs were reduced over hours, presumably due to the action of endothelial sulfiredoxin. In contrast to the hyperoxidation seen with H(2)O(2), HOCl and the chloramine derivatives of glycine and ammonia converted the Prxs to disulfide-linked dimers and dimerization was reversed within 10-30 min of oxidant removal. HOCl treatment caused thioredoxin reductase (TrxR) inhibition with no reversal of dimerization. The cytotoxicity of ammonia chloramine was increased when cells were pretreated with H(2)O(2) to hyperoxidize the Prxs, or when the chloramine was added in the presence of the TrxR inhibitor, auranofin. INNOVATION: We describe the novel observation that exposure of nucleated cells to inflammatory oxidants results in the accumulation of Prxs in the dimeric form. CONCLUSIONS: Endothelial cell Prxs are sensitive targets for neutrophil-derived oxidants and may protect against their damaging effects. PMID- 22229718 TI - Prizes in an age of collaborative research. PMID- 22229721 TI - Profile of John T. Lis. Interviewed by Kristie Nybo. PMID- 22229722 TI - Leveraging the promise of chemical genomics. PMID- 22229723 TI - Native PAGE. PMID- 22229724 TI - Application of the wheat-germ cell-free translation system to produce high temperature requirement A3 (HtrA3) proteases. AB - Mammalian high temperature requirement A3 (HtrA3) is a serine protease of the HtrA family. It is an important factor for placental development and a tumor suppressor. The biochemical properties of HtrA3 are uncharacterized. One critical step in biochemical characterization is overexpressing and purifying the full length recombinant protein. However, utility of cell-based expression systems is limited for a protease because of autocleavage. The wheat-germ cell-free translation system is highly efficient at producing "difficult" eukaryotic multidomain proteins and is easily modifiable for protein synthesis at different temperatures. In this study, we evaluated the potential of the wheat-germ cell free translation system for producing human HtrA3. HtrA3 underwent autocleavage when synthesized at 17 degrees C. When the synthesis temperature was lowered to 4 degrees C, full-length HtrA3 was successfully produced and proteolytically active. Catalytic site serine substitution with alanine (S305A) stabilized HtrA3 while abolishing its protease activity. This mutant was readily synthesized and stable at 17 degrees C. When used with glutathione S-transferase (GST) pull-down assay, S305A HtrA3 was a valuable bait in searching for endogenous HtrA3 binding proteins. Thus, we demonstrated the unique utility of the wheat-germ cell-free translation system for producing and characterizing human HtrA3. These strategies will be likely applicable to a wide range of proteases. PMID- 22229725 TI - A cryohistological protocol for preparation of large plant tissue sections for screening intracellular fluorescent protein expression. AB - In this study, we have developed a robust cryohistological method that allows imaging of virtually any type of plant cell or tissue while preserving fluorescent protein signals and maintaining excellent cellular and subcellular morphology. This method involves modified fixation of plant tissues (i.e., leaves, stems, and petioles), infiltration in a sucrose gradient, freezing, and collection of cryosections directly onto a cryoadhesive tape. Using this method followed by microscopic analysis, we demonstrated a localized accumulation of green fluorescent protein (GFP) in Nicotiana benthamiana plants agroinfiltrated with the movement-incompetent tobacco mosaic virus-based vector and systemic accumulation of GFP in plants infiltrated with the movement-competent vector. Overall, this simple cryohistological procedure reduced sample preparation time and allowed processing of tissue sections for high-resolution imaging of targeted fluorescent proteins in all plant tissues. PMID- 22229726 TI - Spatial manipulation of cells and organelles using single electrode dielectrophoresis. AB - The selection, isolation, and accurate positioning of single cells in three dimensions are increasingly desirable in many areas of cell biology and tissue engineering. We describe the application of a simple and low cost dielectrophoretic device for picking out and relocating single target cells. The device consists of a single metal electrode and an AC signal generator. It does not require microfabrication technologies or sophisticated electronics. The dielectrophoretic manipulator also discriminates between live and dead cells and is capable of redistributing intracellular organelles. PMID- 22229728 TI - Generating a custom TA-cloning expression plasmid for Lactococcus lactis. AB - The growing popularity of the lactic acid bacterium Lactococcus lactis has increased demand for novel high-throughput cloning methods. Here we describe a general TA-cloning methodology and demonstrate its feasibility using the plasmid pNZ8148. PCR products were directly ligated into a linear, PCR-amplified and XcmI digested pNZ8148 derivative that was termed pNZ-T. Cloning using pNZ-T yielded a high proportion of insert-containing plasmids on transformation. Although demonstrated with L. lactis, the technique presented here is organism-independent and can be implemented in other plasmids. PMID- 22229727 TI - Visualization of cofilin-actin and Ras-Raf interactions by bimolecular fluorescence complementation assays using a new pair of split Venus fragments. AB - The bimolecular fluorescence complementation (BiFC) assay is a method for visualizing protein-protein interactions in living cells. To visualize the cofilin-actin interaction in living cells, a series of combinations of the N- and C-terminal fragments of Venus fused upstream or downstream of cofilin and actin were screened systematically. A new pair of split Venus fragments, Venus (1-210) fused upstream of cofilin and Venus (210-238) fused downstream of actin, was the most effective combination for visualizing the specific interaction between cofilin and actin in living cells. This pair of Venus fragments was also effective for detecting the active Ras-dependent interaction between H-Ras and Raf1 and the Ca(2+)-dependent interaction between calmodulin and its target M13 peptide. In vitro BiFC assays using the pair of purified BiFC probes provided the means to detect the specific interactions between cofilin and actin and between H Ras and Raf1. In vivo and in vitro BiFC assays using the newly identified pair of Venus fragments will serve as a useful tool for measuring protein-protein interactions with high specificity and low background fluorescence and could be applied to the screening of inhibitors that block protein-protein interactions. PMID- 22229729 TI - Comparison of direct and alternating current vacuum ultraviolet lamps in atmospheric pressure photoionization. AB - A direct current induced vacuum ultraviolet (dc-VUV) krypton discharge lamp and an alternating current, radio frequency (rf) induced VUV lamp that are essentially similar to lamps in commercial atmospheric pressure photoionization (APPI) ion sources were compared. The emission distributions along the diameter of the lamp exit window were measured, and they showed that the beam of the rf lamp is much wider than that of the dc lamp. Thus, the rf lamp has larger efficient ionization area, and it also emits more photons than the dc lamp. The ionization efficiencies of the lamps were compared using identical spray geometries with both lamps in microchip APPI mass spectrometry (MUAPPI-MS) and desorption atmospheric pressure photoionization-mass spectrometry (DAPPI-MS). A comprehensive view on the ionization was gained by studying six different MUAPPI solvent compositions, five DAPPI spray solvents, and completely solvent-free DAPPI. The observed reactant ions for each solvent composition were very similar with both lamps except for toluene, which showed a higher amount of solvent originating oxidation products with the rf lamp than with the dc lamp in MUAPPI. Moreover, the same analyte ions were detected with both lamps, and thus, the ionization mechanisms with both lamps are similar. The rf lamp showed a higher ionization efficiency than the dc lamp in all experiments. The difference between the lamp ionization efficiencies was greatest when high ionization energy (IE) solvent compositions (IEs above 10 eV), i.e., hexane, methanol, and methanol/water, (1:1 v:v) were used. The higher ionization efficiency of the rf lamp is likely due to the larger area of high intensity light emission, and the resulting larger efficient ionization area and higher amount of photons emitted. These result in higher solvent reactant ion production, which in turn enables more efficient analyte ion production. PMID- 22229730 TI - Children's antisocial behavior, mental health, drug use, and educational performance after parental incarceration: a systematic review and meta-analysis. AB - Unprecedented numbers of children experience parental incarceration worldwide. Families and children of prisoners can experience multiple difficulties after parental incarceration, including traumatic separation, loneliness, stigma, confused explanations to children, unstable childcare arrangements, strained parenting, reduced income, and home, school, and neighborhood moves. Children of incarcerated parents often have multiple, stressful life events before parental incarceration. Theoretically, children with incarcerated parents may be at risk for a range of adverse behavioral outcomes. A systematic review was conducted to synthesize empirical evidence on associations between parental incarceration and children's later antisocial behavior, mental health problems, drug use, and educational performance. Results from 40 studies (including 7,374 children with incarcerated parents and 37,325 comparison children in 50 samples) were pooled in a meta-analysis. The most rigorous studies showed that parental incarceration is associated with higher risk for children's antisocial behavior, but not for mental health problems, drug use, or poor educational performance. Studies that controlled for parental criminality or children's antisocial behavior before parental incarceration had a pooled effect size of OR = 1.4 (p < .01), corresponding to about 10% increased risk for antisocial behavior among children with incarcerated parents, compared with peers. Effect sizes did not decrease with number of covariates controlled. However, the methodological quality of many studies was poor. More rigorous tests of the causal effects of parental incarceration are needed, using randomized designs and prospective longitudinal studies. Criminal justice reforms and national support systems might be needed to prevent harmful consequences of parental incarceration for children. PMID- 22229731 TI - A novel mutation W388X underlying properdin deficiency in a Finnish family. AB - Properdin deficiency is a rare immunological disorder inherited as an X chromosomal recessive trait. Properdin deficiency poses a significant risk for severe meningococcal infections. About 20 mutations have been reported to underlie properdin deficiency. Here we report a large Finnish family with a novel mutation in the properdin gene (CFP). Based on the total absence of properdin activity in a 14-year-old male patient with an infection resembling meningococcal bacteraemia, the coding region and splice sites of the gene were sequenced. The mutation is located in exon 9 and changes guanine to adenine at nucleotide 1164 (c.1164G>A) that causes tryptophan to change to a premature stop codon (W388X). The mother of the patient was shown to be a carrier of the mutation. In total, the mutation was identified in six females and three young males in the family. The mutation must be inherited from the grandfather who had died of an unknown infectious disease. This is the first mutation of the properdin gene identified in Finland. PMID- 22229732 TI - Small intestinal malabsorption in chronic alcoholism: a retrospective study of alcoholic patients by the 14C-D-xylose breath test. AB - OBJECTIVE: The 14C-D-xylose breath test was used at Ulleval University Hospital in the period from 1986 TO 1995 for malabsorption testing. The objective of this retrospective study was to reveal whether patients with chronic alcoholism may have intestinal malabsorption. MATERIALS AND METHODS: The consecutive 14C-D xylose breath test database was reviewed and patients with the diagnosis of chronic alcoholism were identified. 14C-D-xylose breath test results of the alcoholic patients were compared with the results of untreated celiac patients and patient and healthy controls. In the 14C-D-xylose breath test, 14C-D-xylose was dissolved in water and given orally after overnight fast. Breath samples were taken at 30-min intervals for 210 min, and 14CO2 : 12CO2 ratios were calculated for each time point, presenting a time curve for 14C-D-xylose absorption. Urine was collected after 210 min and the fraction of the total d-xylose passed was calculated (U%). 14CO2 in breath and 14C-D-xylose in urine were analyzed using liquid scintillation. RESULTS: Both breath and urine analysis revealed a pattern of malabsorption in alcoholics comparable with untreated celiac patients, with significantly reduced absorption of d-xylose compared with patient and healthy controls. CONCLUSION: Alcoholic patients have a significantly reduced 14C-D xylose absorption, comparable with untreated celiac patients. This indicates a reduced intestinal function in chronic alcoholism. PMID- 22229733 TI - Post-protein-binding reactivity and modifications of the fac-[Re(CO)3]+ core. AB - The reactivity of the [Re(CO)(3)(H(2)O)(2)](+) complex coordinated to the His15 residue of HEW lysozyme is described. In the fully metalated protein (Lys-1), the Re ion retains its reactivity only toward selected ligands, while others induce a ligand-mediated demetalation of the enzyme. It is further shown that some of the complexes that may be "engineered" on the lysozyme do not react with the free protein even if present in solution in excess. The formation of stable metal adducts starting from Lys-1 was confirmed by X-ray crystallography. PMID- 22229734 TI - Product detection of the CH radical reaction with acetaldehyde. AB - The reaction of the methylidyne radical (CH) with acetaldehyde (CH(3)CHO) is studied at room temperature and at a pressure of 4 Torr (533.3 Pa) using a multiplexed photoionization mass spectrometer coupled to the tunable vacuum ultraviolet synchrotron radiation of the Advanced Light Source at Lawrence Berkeley National Laboratory. The CH radicals are generated by 248 nm multiphoton photolysis of CHBr(3) and react with acetaldehyde in an excess of helium and nitrogen gas flow. Five reaction exit channels are observed corresponding to elimination of methylene (CH(2)), elimination of a formyl radical (HCO), elimination of carbon monoxide (CO), elimination of a methyl radical (CH(3)), and elimination of a hydrogen atom. Analysis of the photoionization yields versus photon energy for the reaction of CH and CD radicals with acetaldehyde and CH radical with partially deuterated acetaldehyde (CD(3)CHO) provides fine details about the reaction mechanism. The CH(2) elimination channel is found to preferentially form the acetyl radical by removal of the aldehydic hydrogen. The insertion of the CH radical into a C-H bond of the methyl group of acetaldehyde is likely to lead to a C(3)H(5)O reaction intermediate that can isomerize by beta hydrogen transfer of the aldehydic hydrogen atom and dissociate to form acrolein + H or ketene + CH(3), which are observed directly. Cycloaddition of the radical onto the carbonyl group is likely to lead to the formation of the observed products, methylketene, methyleneoxirane, and acrolein. PMID- 22229735 TI - Considerations for the design and technical setup of a human whole-body exposure chamber. AB - Exposures to air contaminants, such as chemical vapors and particulate matter, pose important health hazards at workplaces. Short-term experimental exposures to chemical vapors and particles in humans are a promising attempt to investigate acute effects of such hazards. However, a significant challenge in this field is the determination of effects of co-exposures to more than one chemical or mixtures of chemical vapors and/or particles. To overcome such a challenge, studies have to be conducted under standardized exposure characterization and real time measurements, if possible. A new exposure laboratory (ExpoLab) was installed at IPA, combining sophisticated engineering designs with new analytical techniques, to fulfill these requirements. Low-dose as well as high-dose exposure scenarios are achieved by means of a calibration-gas-generator. Exposure monitoring can be carried out with a high performance real time mass spectrometer and other suitable analyzers (e.g. gas chromatograph). Numerous automated security facilities guarantee the physical integrity of the volunteers, and the waste atmosphere is removed using either charcoal filtration or catalytic post combustion. Measurements of sulfur hexafluoride, carbon dioxide, aniline and carbon black are presented to demonstrate the performance of the exposure unit with respect to the temporal and spatial stability of generated atmospheres. The variations of generated contents in the atmospheres at steady state are slightly higher than the measurement precision of the analyzers (the typical standard deviation of generated atmospheres is < 2%). The technical components of ExpoLab and its monitoring systems ensure high quality standards in validity and reliability of generating and measuring exposure atmospheres. PMID- 22229736 TI - Direct NMR observation and pKa determination of the Asp102 side chain in a serine protease. AB - The pK(a) value of aspartic acid in the catalytic triad of serine proteases has been a pivotal element in essentially every mechanism proposed for these enzymes over the past 40 years, but has, until now, eluded direct determination. Here, we have used the multinuclear 3D-NMR pulse programs HCACO and HCCH-TOCSY to directly identify and study the side-chain resonances of the aspartate and glutamate residues in uniformly (13)C-labeled alpha-lytic protease. Resonances from four of the six residues were detected and assigned, including that of Asp(102), which is notably the weakest of the four. pH titrations have shown all of the carboxylate (13)C signals to have unusually low pK(a) values: 2.0, 3.2, and 1.7 for Glu(129), Glu(174), and Glu(229), respectively, and an upper limit of 1.5 for Asp(102). The multiple H-bonds to Asp(102), long known from X-ray crystal studies, probably account for its unusually low pK(a) value through preferential stabilization of its anionic form. These H-bonds probably also contribute to the weakness of the NMR resonances of Asp(102) by restricting its mobility. The Asp(102)(13)C(gamma) atom responds to the ionization of His(57) in the resting enzyme and to the inhibitor-derived oxyanion in a chloromethyl ketone complex, observations that strongly support the assignment. The low pK(a) value of Asp(102) would appear to be incompatible with mechanisms involving strong Asp(102)-His(57) H-bonds or high pK(a) values, but is compatible with mechanisms involving normal Asp(102)-His(57) H-bonds and moving His(57) imidazole rings, such as the reaction-driven ring flip. PMID- 22229738 TI - One-step "click" method for generating vinyl sulfone groups on hydroxyl containing water-soluble polymers. PMID- 22229739 TI - Low-risk labor - outcomes after introduction of special guidelines combined with increased awareness of risk category. AB - OBJECTIVE: To study whether special guidelines for low-risk parturients combined with increased awareness of risk category affect the management of labor. DESIGN: Hospital-based registry study. SETTING: Two identical birth units in one university hospital in Oslo, Norway. POPULATION: All low-risk parturient women in the years 2001-2009; a total of 28 533 deliveries. METHODS: From September 2005, a special protocol for management of low-risk labors was introduced in one of the units. Data were obtained from standardized patient records, routinely recorded electronically. Outcomes were extracted for each year, and for the years 2006 2009 the outcomes for the two units were compared. Logistic regression was used to study factors associated with spontaneous vaginal delivery. MAIN OUTCOME MEASURES: Delivery method, use of electronic fetal monitoring, use of oxytocin, duration of labor and Apgar score at five minutes. RESULTS: For nulliparas, the unit with special guidelines had a slightly higher rate of spontaneous vaginal deliveries (76 vs. 72.5%, p=0.006), lower use of oxytocin (48.8 vs. 56.1%, p<0.001) and electronic fetal monitoring (63.8 vs. 69.4%, p<0.001) and longer duration of labor. In multiparas, there was a small difference (15.5 vs. 18.4%, p=0.003) in the use of oxytocin. In a logistic regression, spontaneous vaginal delivery in nulliparas was negatively associated with use of oxytocin and electronic fetal monitoring, but not with the birth unit. CONCLUSIONS: A special protocol to increase awareness of risk category led to a small, although statistically significant, increase in the rate of spontaneous vaginal delivery in nulliparous, but not in parous low-risk parturients. PMID- 22229740 TI - 'The worst of the Bangladeshi and the worst of the British': exploring eating patterns and practices among British Bangladeshi adolescents in east London. AB - OBJECTIVES: This article examines how aspects of a specific locality, history and set of practices interact to produce an obesogenic environment. The analysis grid for environments linked to obesity (ANGELO) framework and a biocultural approach are used to examine one obesogenic environment--that experienced by British Bangladeshi adolescents (ages 11-14 years old) in Tower Hamlets, east London. Interdisciplinary literature and methods explore how physical, economic, cultural, and political pressures in school, street, and home micro-environments influence eating patterns and practices. DESIGN: This ethnographic research included living on a council estate and working as an assistant physical education teacher in two secondary schools in Tower Hamlets. Anthropometric and socioeconomic characteristics were collected from the young people whose physical education classes I assisted (n=447). Then interviews and questionnaires were completed with a subsample of participants (n=165) drawn from the first phase of research to understand the factors that influence eating patterns. RESULTS: Among this group of adolescents, interwoven cultural and structural pressures encourage frequent consumption of energy-dense foods in their schools, streets, and homes. They were exposed to factors that have led to the widespread increase in the prevalence of overweight and obesity such as the increased availability and affordability of energy-dense foods. In addition, they faced cultural and structural pressures associated with being the adolescent children of immigrants from Bangladesh and living in an economically depressed neighborhood. CONCLUSION: To develop a comprehensive understanding of the factors that may lead to weight gain in different ethnic, geographic and socioeconomic contexts it is important to examine the pressures specific to that context that might influence the variety and frequency of food consumption. This type of research may lead to the identification of points of intervention that are specific to the pressures and sensitivities of particular environments. PMID- 22229737 TI - A novel u-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors. AB - BACKGROUND AND PURPOSE: The u-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new u-conopeptide (u-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant. EXPERIMENTAL APPROACH: u-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. u-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data. KEY RESULTS: Synthetic u-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC(50) = 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with u-SIIIA, u-SmIIIA and u-PIIIA. u-CnIIIC blocked Na(V)1.4 (IC(50) = 1.3 nM) and Na(V)1.2 channels in a long-lasting manner. Cardiac Na(V)1.5 and DRG-specific Na(V)1.8 channels were not blocked at 1 uM. u-CnIIIC also blocked the alpha3beta2 nAChR subtype (IC(50) = 450 nM) and, to a lesser extent, on the alpha7 and alpha4beta2 subtypes. Structure determination of u-CnIIIC revealed some similarities to alpha-conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS: u-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels. PMID- 22229741 TI - An approach to mimicking the sesquiterpene cyclase phase by nickel-promoted diene/alkyne cooligomerization. AB - Artificially mimicking the cyclase phase of terpene biosynthesis inspires the invention of new methodologies, since working with carbogenic frameworks containing minimal functionality limits the chemist's toolbox of synthetic strategies. For example, the construction of terpene skeletons from five-carbon building blocks would be an exciting pathway to mimic in the laboratory. Nature oligomerizes, cyclizes, and then oxidizes gamma,gamma-dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) to all of the known terpenes. Starting from isoprene, the goal of this work was to mimic Nature's approach for rapidly building molecular complexity. In principle, the controlled oligomerization of isoprene would drastically simplify the synthesis of terpenes used in the medicine, perfumery, flavor, and materials industries. This article delineates our extensive efforts to cooligomerize isoprene or butadiene with alkynes in a controlled fashion by zerovalent nickel catalysis building off the classic studies by Wilke and co-workers. PMID- 22229743 TI - Consequences of frugivore-mediated seed dispersal for the spatial and genetic structures of a neotropical palm. AB - The idiosyncratic behaviours of seed dispersers are important contributors to plant spatial associations and genetic structures. In this study, we used a combination of field, molecular and spatial studies to examine the connections between seed dispersal and the spatial and genetic structures of a dominant neotropical palm Attalea phalerata. Field observation and genetic parentage analysis both indicated that the majority of A. phalerata seeds were dispersed locally over short distances (<30 m from the maternal tree). Spatial and genetic structures between adults and seedlings were consistent with localized and short distance seed dispersal. Dispersal contributed to spatial associations among maternal sibling seedlings and strong spatial and genetic structures in both seedlings dispersed near (<10 m) and away (>10 m) from maternal palms. Seedlings were also spatially aggregated with juveniles. These patterns are probably associated with the dispersal of seeds by rodents and the survival of recruits at specific microsites or neighbourhoods over successive fruiting periods. Our cross cohort analyses found palms in older cohorts and cohort pairs were associated with a lower proportion of offspring and sibling neighbours and exhibited weaker spatial and genetic structures. Such patterns are consistent with increased distance- and density-dependent mortality over time among palms dispersed near maternal palms or siblings. The integrative approaches used for this study allowed us to infer the importance of seed dispersal activities in maintaining the aggregated distribution and significant genetic structures among A. phalerata palms. We further conclude that distance- and density-dependent mortality is a key postdispersal process regulating this palm population. PMID- 22229742 TI - Determination of the distance between the Mo(V) and Fe(III) heme centers of wild type human sulfite oxidase by pulsed EPR spectroscopy. AB - Intramolecular electron transfer (IET) between the molybdenum and heme centers of vertebrate sulfite oxidase (SO) is proposed to be a key step in the catalytic cycle of the enzyme. However, the X-ray crystallographic distance between these centers, R(MoFe) = 32.3 A, appears to be too long for the rapid IET rates observed in liquid solution. The Mo and heme domains are linked by a flexible tether, and it has been proposed that dynamic interdomain motion brings the two metal centers closer together and thereby facilitates rapid IET. To date, there have been no direct distance measurements for SO in solution that would support or contradict this model. In this work, pulsed electron-electron double resonance (ELDOR) and relaxation induced dipolar modulation enhancement (RIDME) techniques were used to obtain information about R(MoFe) in the Mo(V)Fe(III) state of wild type recombinant human SO in frozen glassy solution. Surprisingly, the data obtained suggest a fixed structure with R(MoFe) = 32 A, similar to that determined by X-ray crystallography for chicken SO, although the orientation of the R(MoFe) radius-vector with respect to the heme center was found to be somewhat different. The implications of these findings for the flexible tether model are discussed. PMID- 22229744 TI - Nanopatterning on nonplanar and fragile substrates with ice resists. AB - Electron beam (e-beam) lithography using polymer resists is an important technology that provides the spatial resolution needed for nanodevice fabrication. But it is often desirable to pattern nonplanar structures on which polymeric resists cannot be reliably applied. Furthermore, fragile substrates, such as free-standing nanotubes or thin films, cannot tolerate the vigorous mechanical scrubbing procedures required to remove all residual traces of the polymer resist. Here we demonstrate several examples where e-beam lithography using an amorphous ice resist eliminates both of these difficulties and enables the fabrication of unique nanoscale device structures in a process we call ice lithography. (1, 2) We demonstrate the fabrication of micro- and nanostructures on the tip of atomic force microscope probes, microcantilevers, transmission electron microscopy grids, and suspended single-walled carbon nanotubes. Our results show that by using amorphous water ice as an e-beam resist, a new generation of nanodevice structures can be fabricated on nonplanar or fragile substrates. PMID- 22229745 TI - Soft tissue sarcoma - a population-based, nationwide study with special emphasis on local control. AB - BACKGROUND: A prospective diagnostics and treatment protocol for extremity and trunk wall soft tissue sarcoma (STS) was introduced by the Scandinavian Sarcoma Group in 1986 and it was also widely adopted in Finland. We have updated the protocol and made it more detailed at the Helsinki University Central Hospital. We retrospectively compared diagnostics and treatment of STS in a nationwide population-based material to this protocol with special emphasis on local control. METHODS: Data for 219 patients with an STS of extremity or trunk wall diagnosed during 1998-2001 was retrieved from the nationwide Finnish Cancer Registry. Histologic review was performed. Treatment centres were divided into high-, intermediate- and low-volume centres based on the number of patients with final surgery during the study period. RESULTS: Significantly more patients were operated with a preoperative histological or cytological diagnosis at high-volume centres. No preoperative diagnosis was a strong predictor for the patient to undergo more than one operation (p < 0.0001). Wide surgical margin was achieved more often at high-volume centres, but in all centre categories a considerable percentage of patients with inadequate surgical margin did not receive adjuvant radiation therapy. Local control at five years was 82% at high-volume centres, 61% at intermediate-volume centres treating highest percentage of deep tumours and 69% at low-volume centres (p = 0.046). Local control improved as the number of patients operated (surgical volume of the centre) increased. CONCLUSION: The present quality-control study is the first nationwide population-based study to assess diagnostics and treatment of STS. When referred to a specialised sarcoma centre even patients with inadequate surgery can achieve good local control. STS is a rare cancer and its treatment should be centralised in Finland, which has 5.4 million inhabitants and approximately 100 new STSs of extremities and trunk wall annually. PMID- 22229746 TI - Squamous cell carcinoma of the lung in lung transplantation - a relation to human papilloma virus? PMID- 22229747 TI - Centralised registration of gestational trophoblastic disease and trends in incidence. PMID- 22229748 TI - Prevalence of esophageal cancer during the pretreatment of hypopharyngeal cancer patients: routinely performed esophagogastroduodenoscopy and FDG-PET/CT findings. AB - BACKGROUND: The prevalence of esophageal cancer accompanied by hypopharyngeal cancer (HPC) is high and increasing rapidly in Asia. The purpose of this prospective study was to evaluate the prevalence of esophageal cancer during the pretreatment of HPC patients who were routinely examined using esophagogastroduodenoscopy (EGD) and 18F-fluorodeoxyglucose/computed tomography (FDG-PET/CT) and to discuss the utility of these examinations. MATERIAL AND METHODS: Between September 2005 and September 2010, 33 patients with newly diagnosed HPC (all with squamous cell carcinoma) underwent EGD (after a conventional endoscopy, iodine staining was performed) and FDG-PET/CT examinations. We evaluated the prevalence of esophageal cancer among HPC patients according to the EGD findings and determined the sensitivity of FDG-PET/CT for the detection of esophageal primary tumors for each clinical T classification. RESULTS: In 17 of the 33 patients (51.5%), 29 biopsy-proven esophageal squamous cell carcinomas were diagnosed using EGD. In eight of the 17 (47.1%) patients, two or more esophageal cancer lesions were diagnosed. Twenty-four of the 29 (82.8%) lesions were superficial esophageal cancers, and the remaining five (17.2%) lesions were advanced esophageal cancers. In six of the 29 (20.7%) esophageal cancer lesions that were detected using FDG-PET/CT, only one of the 29 (3.4%) lesions was evaluated as being equivocal; the remaining 22 (75.9%) lesions were not detected. The distribution of the clinical T classifications detected using FDG-PET/CT was as follows: T1a, 0/21 (0%); T1b, 1/3 (33%); and T3, 5/5 (100%). CONCLUSIONS: The prevalence of esophageal cancer during the pretreatment of HPC patients was 51.5%; this prevalence was higher than that in previous reports. We believe that the increasing proportion of superficial lesions (82.8%) detected using iodine staining and EGD may have led to the relatively high prevalence. FDG-PET/CT detected only 20.7% of the esophageal cancers, although FDG-PET/CT is capable of detecting unexpected primary malignant tumors other than esophageal cancer. PMID- 22229749 TI - Supported lipid bilayers at skeletonized surfaces for the study of transmembrane proteins. AB - Skeletonized zirconium phosphonate surfaces are used to support planar lipid bilayers and are shown to be viable substrates for studying transmembrane proteins. The skeletonized surfaces provide space between the bilayer and the solid support to enable protein insertion and avoid denaturation. The skeletonized zirconium octadecylphosphonate surfaces were prepared using Langmuir Blodgett techniques by mixing octadecanol with octadecylphosphonic acid. After zirconation of the transferred monolayer, rinsing the coating with organic solvent removes the octadecanol, leaving holes in the film ranging from ~50 to ~500 nm in diameter, depending on the octadecanol content. Upon subsequent deposition of a lipid bilayer, either by vesicle fusion or by Langmuir Blodgett/Langmuir-Schaefer techniques, the lipid assemblies span the holes providing reservoirs beneath the bilayer. The viability of the supported bilayers as model membranes for transmembrane proteins was demonstrated by examining two approaches for incorporating the proteins. The BK channel protein inserts directly into a preformed bilayer on the skeletonized surface, in contrast to a bilayer on a nonskeletonized film, for which the protein associates only weakly. As a second approach, the integrin alpha(5)beta(1) was reconstituted in lipid vesicles, and its inclusion in supported bilayers on the skeletonized surface was achieved by vesicle fusion. The integrin retains its ability to recognize the extracellular matrix protein fibronectin when supported on the skeletonized film, again in contrast to the response if the bilayer is supported on a nonskeletonized film. PMID- 22229750 TI - Outcome of twin pregnancies after amniocentesis. AB - AIM: The aim of this study was to assess the miscarriage and fetal loss rates of twin pregnancies after amniocentesis. MATERIAL AND METHODS: The outcome of 140 twin pregnancies that had amniocentesis performed from 1997 to 2006 was reviewed. RESULTS: Among 140 twin pregnancies with amniocentesis, 35 were excluded (fetuses with structural anomalies, post-selective feticide, abnormal fetal karyotype, twin-twin transfusion syndrome [TTTS], termination of pregnancy, and unknown outcome). For the remaining 105 twin pregnancies, 102 had live births of all fetuses. One dichorionic twin had silent miscarriage of one fetus at 23 weeks. Another dichorionic twin had intrauterine death of one fetus at unknown gestation. One patient had preterm delivery at 32 weeks with neonatal death of one twin due to severe intrauterine growth restriction. The miscarriage rate (one or both fetuses) for twins before 24 weeks was 0.96% (1/105), the pregnancy loss (one or both fetuses) within 4 weeks of amniocentesis was 0.96% (1/105). The total fetal loss rate was 0.96% (2/210) for twins. CONCLUSION: Our cohort showed a low fetal loss rate after amniocentesis for uncomplicated twin pregnancies. PMID- 22229751 TI - Exogenous hydrogen sulfide (H2S) reduces blood pressure and prevents the progression of diabetic nephropathy in spontaneously hypertensive rats. AB - The coexistence of hypertension and diabetes results in the rapid development of nephropathy. Hydrogen sulfide (H2S) is claimed to control the vascular and renal functions. This study tested the hypothesis that exogenous H2S lowers the blood pressure and decreases the progression of nephropathy in spontaneously hypertensive rats (SHR) that were diabetic. Eighteen SHR were divided into three groups: SHR, SHR diabetic, and SHR diabetic treated with a group of Wistar-Kyoto rats serving as normotensive nondiabetic control. Diabetes was induced with streptozotocin (STZ) in two groups and one diabetic group received sodium hydrosulfide (NaHS), a H2S donor for 5 weeks. Blood pressure was measured in conscious and anesthetized states and renal cortical blood perfusion in acute studies. Plasma and urinary H2S levels, creatinine concentrations, and electrolytes were measured on three different occasions throughout the 35-day period. Diabetic SHR had higher blood pressure, lower plasma and urinary H2S levels, and renal dysfunction as evidenced by increased plasma creatinine, creatinine clearance, and decreased urinary sodium-to-potassium ratio and renal cortical blood perfusion. NaHS reduced blood pressure, increased H2S levels in plasma and urinary excretion, and reversed the STZ-induced renal dysfunction. The findings of this study suggest that the administration of exogenous H2S lowers the blood pressure and confers protection against the progression of STZ-induced nephropathy in SHR. PMID- 22229752 TI - Negative impact of occupational exposure on surgical outcome in patients with rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a frequent condition that is treated by functional endoscopic sinus surgery (FESS) when medical treatment fails. Endogenous as well as exogenous factors may be responsible for persisting symptoms after FESS. The role of occupational exposures on success of FESS has never been investigated. METHODS: In this case-control study, we tested the hypothesis that the outcome of FESS procedures is related to exposures at work. Questionnaires were sent to 890 patients who had undergone one or more FESS procedures and to 182 controls. Three independent experts assessed blindly the reported work exposures to inhaled agents. The relationship between exposure and the number of FESS procedures was analyzed. RESULTS: Relevant occupational exposure was reported by 25% of all responding patients undergoing FESS (n = 467) and 12% of controls (n = 69). The prevalence of occupational exposures increased linearly with the number of FESS procedures from 21% in those who had one FESS to 44% in those who had four or more FESS (chi(2) = 12.74, P < 0.001). Logistic regression analysis with adjustments for potential confounders, including smoking, atopy, and asthma, confirmed that the odds ratio (OR) for reporting occupational exposures was significantly higher in those needing more than one FESS (OR = 1.64) or more than two FESS (OR = 1.97). These results were mainly driven by exposure to low molecular weight agents. CONCLUSION: Exposure at work appears to be a risk factor for the occurrence of CRS and for its recurrence or persistence, as evidenced by the need for revision surgery. PMID- 22229753 TI - CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B cell malignancies. AB - Established cell lines are utilized extensively to study tumor biology and preclinical therapeutic development. However, they may not accurately recapitulate the heterogeneity of their corresponding primary disease. B-cell tumor cells are especially difficult to maintain under conventional culture conditions, limiting access to samples that faithfully represent this disease for preclinical studies. Here, we used primary canine diffuse large B-cell lymphoma to establish a culture system that reliably supports the growth of these cells. CD40 ligand, either expressed by feeder cells or provided as a soluble two trimeric form, was sufficient to support primary lymphoma cells in vitro. The tumor cells retained their original phenotype, clonality and known karyotypic abnormalities after extended expansion in culture. Finally, we illustrate the utility of the feeder cell-free culture system for comparable assessment of cytotoxicity using dog and human B-cell malignancies. We conclude that this system has broad applications for in vitro preclinical development for B-cell malignancies. PMID- 22229754 TI - Translation and validation of the Hindi version of the Geriatric Oral Health Assessment Index. AB - PURPOSE: To translate the original English version of the Geriatric Oral Health Assessment Index (GOHAI) into Hindi and assess its validity and reliability for use among people in India. MATERIALS AND METHOD: After translation into Hindi, a total of 385 participants aged 55+ demonstrated acceptable validity and reliability when used for people in India. Individual GOHAI items were recorded and summed as originally recommended. The questionnaire sought information about socio-demographic characteristics and self-reported perception of general and oral health. Clinical examination included assessment of periodontal status and number of decayed teeth, missing teeth, filled teeth and crowned teeth. RESULT: Mean GOHAI score was 40.9 (SD, 10.6; range, 12-60). Cronbach's alpha for the GOHAI score was 0.88, indicating a high degree of internal consistency and homogeneity between the GOHAI items. The test-retest correlation coefficient for add-GOHAI scores was 0.72, indicating good stability. Add-GOHAI scores increased with poorer perceived general and oral health. Convergent validity, construct validity and discriminant validity of the GOHAI were demonstrated. CONCLUSION: It could therefore be used as a valuable instrument for measuring oral health related quality of life for people in this region. PMID- 22229755 TI - Epigenetic manifestation of metabolic syndrome and dietary management. AB - SIGNIFICANCE: Metabolic syndrome constitutes a group of disorders such as insulin resistance, hypertension, and hypertriglyceridemia, predisposing an individual to risk factors such as cardiovascular disease, diabetes, obesity, and dyslipidemia. A majority of these diseases are influenced by the environmental factors, nutrient uptake, and genetic profile of an individual that together dysregulate gene function. These genetic and nongenetic factors are reported to introduce epigenetic cues that modulate the gene function which is inherited by the offspring. RECENT ADVANCES: Considering the epigenetic modulation of the metabolic disorders, nutrigenomics has been distinctly categorized as a branch that deals with modulatory effect of nutrients on metabolic disorders and disease progression by supplementing the individuals with key nutrient-enriched diets which are derived from plant and animal sources. CRITICAL ISSUES: Nutritional components of the diet regulate the metabolic health of an individual either by controlling the expression of some key genes related to metabolic pathways or by modulating the epigenetic events on such genes. The present article discusses various metabolic disorders in detail and the effect of nutrients on the specific genes causing those disorders. We also highlight the molecular mechanisms of some metabolic disorders through epigenetic modifications and possible therapeutic interventions. FUTURE DIRECTIONS: With the advent of high-throughput technologies and epigenetic modulation of the metabolic disorders, an altered epigenetic code that is programmed due to improper nutrients can be reverted back by supplementing the diet with various plant-derived compounds. The implication of small molecular drugs is also of utmost significance for challenging the metabolic disorders. PMID- 22229756 TI - Coupled electrochemical reactions at bipolar microelectrodes and nanoelectrodes. AB - Here we report the voltammetric study of coupled electrochemical reactions on microelectrodes and nanoelectrodes in a closed bipolar cell. We use steady-state cyclic voltammetry to discuss the overall voltammetric response of closed bipolar electrodes (BPEs) and understand its dependence on the concentration of redox species and electrode size. Much of the previous work in bipolar electroanalytical chemistry has focused on the use of an "open" cell with the BPE located in an open microchannel. A closed BPE, on the other hand, has two poles placed in separate compartments and has remained relatively unexplored in this field. In this work, we demonstrated that carbon-fiber microelectrodes when backfilled with an electrolyte to establish conductivity are closed BPEs. The coupling between the oxidation reaction, e.g., dopamine oxidation, on the carbon disk/cylinder and the reduction of oxygen on the interior fiber is likely to be responsible for the conductivity. We also demonstrated the ability to quantitatively measure voltammetric properties of both the cathodic and anodic poles in a closed bipolar cell from a single cyclic voltammetry (CV) scan. It was found that "secondary" reactions such as oxygen reduction play an important role in this process. We also described the fabrication and use of Pt bipolar nanoelectrodes which may serve as a useful platform for future advances in nanoscale bipolar electrochemistry. PMID- 22229757 TI - Avoidant coping and treatment outcome in rape-related posttraumatic stress disorder. AB - OBJECTIVE: This study investigated the impact of avoidant coping on treatment outcome in rape-related posttraumatic stress disorder (PTSD). METHOD: Adult women with rape-related PTSD (N = 62) received 9 sessions of prolonged exposure (PE) or eye movement desensitization and reprocessing (EMDR). The mean age for the sample was 34.7 years, and race or ethnicity was reported as 67.7% Caucasian, 25.8% African American, 3.2% Latina, and 3.2% other. PTSD was assessed with the PTSD Symptom Scale-Self-Report (Foa, Riggs, Dancu, & Rothbaum, 1993), and avoidant coping was assessed using the Coping Strategies Inventory-Disengagement subscale (CSI-D; Tobin, Holroyd, Reynolds, & Wigal, 1989). RESULTS: Pretreatment avoidant coping was negatively associated with posttreatment PTSD symptom severity even when controlling for initial severity of total PTSD symptoms and when removing PTSD avoidance symptoms from the analysis to account for potential overlap between avoidant coping and PTSD avoidance symptoms: DeltaR2 = .08, b* = -0.31, 95% CI [-0.17, -0.01], t(60) = -2.27, p = .028. The CSI-D pretreatment mean score of 100 predicted a 96% likelihood of experiencing clinically significant change (CSC) during treatment. A CSI-D pretreatment score of 61 was associated with a 40% likelihood of experiencing CSC. CONCLUSIONS: PE and EMDR appear to be beneficial for women who frequently engage in avoidant coping responses following rape. A small subset of women with initially low levels of avoidant coping are unlikely to experience a therapeutic response from PE or EMDR. PMID- 22229758 TI - A randomized trial adapting contingency management targets based on initial abstinence status of cocaine-dependent patients. AB - OBJECTIVE: Contingency management (CM) reduces drug use, but questions remain regarding optimal targets and magnitudes of reinforcement. We evaluated the efficacy of CM reinforcing attendance in patients who initiated treatment with cocaine-negative samples, and of higher magnitude abstinence-based CM in patients who began treatment positive. METHOD: Initially cocaine-negative patients (n = 333) were randomized to standard care (SC), SC + CM reinforcing submission of negative samples with $250 in prizes ($250Abs), or SC + CM reinforcing attendance ($250Att). Initially cocaine-positive patients (n = 109) were randomized to SC, $250Abs, or higher magnitude CM ($560Abs). RESULTS: For initially cocaine negative patients, $250Abs and $250Att were equally efficacious to SC in enhancing longest duration of abstinence (LDA); $250Att patients submitted lower proportions of negative samples when missing samples were considered missing, but these patients also attended more study sessions, provided more samples, and submitted a higher proportion of negative samples than SC patients when expected samples were analyzed, ps < .05. In initially cocaine-positive patients, both CM conditions increased proportions of negative samples relative to SC when missing samples were excluded from analyses, but only $560Abs was efficacious in increasing LDA and proportion of negative samples when expected samples were analyzed, ps < .05. Follow-ups revealed no differences among groups, but LDA was consistently associated with abstinence during follow-up, p < .05. CONCLUSIONS: High magnitude abstinence-based reinforcement improved all abstinence outcomes in patients who began treatment while using cocaine. For patients initiating treatment abstinent, both attendance- and abstinence-based CM resulted in improvements on some measures. PMID- 22229760 TI - A novel HLA-B*51:01:29 allele identified by sequence-based typing. AB - A novel HLA-B*51:01:29 allele differs from B*51:01:01 at one nucleotidic position in the exon 3. PMID- 22229761 TI - The relationship of locus of control, self-control, and acceptable noise levels for young listeners with normal hearing. AB - OBJECTIVE: Background noise acceptance while listening to speech, assessed via the acceptable noise level (ANL) measure, has been shown to be an accurate predictor of hearing-aid success. No specific listener characteristics have been identified as being related to a listener's ability to accept background noise. The purpose of this study was to determine whether or not locus of control and self-control are related to ANL. DESIGN: Correlational design. STUDY SAMPLE: Participants were seventy young adults (21 male, 49 female; aged 19 to 39 years) with normal hearing. Participants completed psychological profiles that evaluated locus of control and self-control and their ANLs were measured. RESULTS: Results revealed correlations between ANL and self-control. Listeners with higher levels of self-control accepted more background noise than listeners with lower levels of self-control. CONCLUSIONS: This research suggests that exercises aimed at strengthening a listener's auditory self-control may lead to improved background noise acceptance. Improvement in background noise acceptance could lead to improved hearing-aid success. Future research should explore these possibilities. PMID- 22229759 TI - Biochemical characterization of recombinant beta-glucosyltransferase and analysis of global 5-hydroxymethylcytosine in unique genomes. AB - 5-Hydroxymethylcytosine (5-hmC) is an enzymatic oxidative product of 5 methylcytosine (5-mC). The Ten Eleven Translocation (TET) family of enzymes catalyze the conversion of 5-mC to 5-hmC. Phage-encoded glucosyltransferases are known to glucosylate 5-hmC, which can be utilized to detect and analyze the 5-hmC as an epigenetic mark in the mammalian epigenome. Here we have performed a detailed biochemical characterization and steady-state kinetic parameter analysis of T4 phage beta-glucosyltransferase (beta-GT). Recombinant beta-GT glucosylates 5-hmC DNA in a nonprocessive manner, and binding to either 5-hmC DNA or uridine diphosphoglucose (UDP-glucose) substrates is random, with both binary complexes being catalytically competent. Product inhibition studies with beta-GT demonstrated that UDP is a competitive inhibitor with respect to UDP-glucose and a mixed inhibitor with respect to 5-hmC DNA. Similarly, the glucosylated-5-hmC (5 ghmC) DNA is a competitive inhibitor with respect to 5-hmC DNA and mixed inhibitor with respect to UDP-glucose. 5-hmC DNA binds ~10 fold stronger to the beta-GT enzyme when compared to its glucosylated product. The numbers of 5-hmC on target sequences influenced the turnover numbers for recombinant beta-GT. Furthermore, we have utilized recombinant beta-GT to estimate global 5-hmC content in a variety of genomic DNAs. Most of the genomic DNAs derived from vertebrate tissue and cell lines contained 5-hmC. DNA from mouse, human, and bovine brains displayed 0.5-0.9% of the total nucleotides as 5-hmC, which was higher compared to the levels found in other tissues. A comparison between cancer and healthy tissue genomes suggested a lower percentage of 5-hmC in cancer, which may reflect the global hypomethylation of 5-mC observed during oncogenesis. PMID- 22229762 TI - Large-balloon dilation of the sphincter of Oddi after sphincterotomy or infundibulotomy to extract large calculi or multiple common bile duct stones without using mechanical lithotripsy. AB - OBJECTIVE: Endoscopic sphincterotomy plus large-balloon dilatation (ESLBD) has an efficacy equal to or higher than that of endoscopic sphincterotomy alone for biliary lithiasis extractions. Our purpose was to evaluate the feasibility, efficacy and morbidity of large-balloon dilatation of the sphincter of Oddi after sphincterotomy or infundibulotomy for large or multiple common bile duct stones. MATERIAL AND METHODS: Retrospective analysis. RESULTS: A total of 64 ESLBD procedures were performed in 62 patients: 57 after sphincterotomy and 7 after infundibulotomy. The feasibility was 100%, and full clearance of the common bile duct was achieved in a single session without using mechanical lithotripsy in 95.3% of cases. Short-term complications were observed in 9 patients (14%). There were no perforations. The most frequent complication was delayed bleeding (7.8%). There was no significant difference of overall complications after sphincterotomy or after infundibulotomy (12.3% vs. 28.6%, p = 0.25). The incidence of acute pancreatitis was significantly higher after infundibulotomy than after sphincterotomy (28.6% vs. 0%, p = 0.01). CONCLUSIONS: ESLBD after endoscopic sphincterotomy or infundibulotomy is a simple, reproducible and effective technique, associated with a low morbidity rate and helps in avoiding mechanical lithotripsy in 95.3% of cases for the endoscopic extraction of large or multiple common bile duct stones. PMID- 22229763 TI - Persistence of Bartonella spp. stealth pathogens: from subclinical infections to vasoproliferative tumor formation. AB - Bartonella spp. are facultative intracellular bacteria that typically cause a long-lasting intraerythrocytic bacteremia in their mammalian reservoir hosts, thereby favoring transmission by blood-sucking arthropods. In most cases, natural reservoir host infections are subclinical and the relapsing intraerythrocytic bacteremia may last weeks, months, or even years. In this review, we will follow the infection cycle of Bartonella spp. in a reservoir host, which typically starts with an intradermal inoculation of bacteria that are superficially scratched into the skin from arthropod feces and terminates with the pathogen exit by the blood-sucking arthropod. The current knowledge of bacterial countermeasures against mammalian immune response will be presented for each critical step of the pathogenesis. The prevailing models of the still-enigmatic primary niche and the anatomical location where bacteria reside, persist, and are periodically seeded into the bloodstream to cause the typical relapsing Bartonella spp. bacteremia will also be critically discussed. The review will end up with a discussion of the ability of Bartonella spp., namely Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis, to induce tumor-like vascular deformations in humans having compromised immune response such as in patients with AIDS. PMID- 22229764 TI - Partial tolerance induced by transplantation of spatially separated thymuses: a cue for T cell retolerization in thymus grafts. AB - Thymus grafts made up of mixed syngeneic and xenogeneic thymus tissues could induce donor-specific tolerance to xenografts with no development of autoimmune syndrome (AIS). But the requirements for the simultaneous presentation of tissue antigens from both species in the process of T cell development in thymus grafts have not hitherto been defined. To do this, we setup a model in which xenothymus grafts from F344 rats were heterotopically implanted into BALB/c nude mice carrying syngeneic thymus grafts, and the grafts were either mixed together or spatially separately; next, we examined the induction of donor-specific tolerance, any pathological changes and the distribution of T lymphocytes. In contrast to the mixed thymus grafts, spatially separated thymus transplants could neither induce a long-term tolerance to skin grafts nor prevent AIS completely. (51) Cr-labelled cell-tracing experiments showed that mature peripheral T cells could re-enter into both kinds of thymus grafts, while the T cells isolated from the syngeneic thymus tended to concentrate in the xenothymus grafts. Hence, our data suggest that the immune tolerance induced by mixed thymus transplants could be partially reversed if the thymus tissues from donors and recipients were segregated by spatial telorism. The uneven recirculation of mature T cells might imply that T cells get retolerized within the thymus grafts. PMID- 22229765 TI - Relative rate study of the kinetics, mechanism, and thermodynamics of the reaction of chlorine atoms with CF3CF?CH2 (HFO-1234yf) in 650-950 Torr of N2 or N2/O2 diluent at 296-462 K. AB - The rate constant of the reaction Cl + CF(3)CF?CH(2) (k(1)) has been measured relative to several reference species using the relative rate technique with either gas chromatographic analysis with flame-ionization detection (GC/FID) or Fourier transform infrared (FTIR) analysis. Cl atoms were generated by UV irradiation of Cl(2)/CF(3)CF?CH(2)/reference/N(2)/O(2) mixtures. At 300-400 K in the presence of >20 Torr O(2), k(1) = 1.2 * 10(-11) e((+1100/RT)) cm(3) molecule( 1) s(-1). In N(2) diluent, k(1) has a sharp negative temperature coefficient resulting from the relatively small exothermicity of the following reactions: (1a) Cl + CF(3)CF?CH(2) <-> CF(3)CFClCH(2)(*); (1b) Cl + CF(3)CF?CH(2) <-> CF(3)CF(*)CH(2)Cl (reaction 1), which were determined in these experiments to be ~16.5 (+/-2.0) kcal mol(-1). This low exothermicity causes reaction 1 to become significantly reversible even at ambient temperature. The rate constant ratio for the reaction of the chloroalkyl radicals formed in reaction 1 with Cl(2) (k(2)) or O(2) (k(3)) was measured to be k(2)/k(3) = 0.4 e(-(3000/RT)) for 300-400 K. At 300 K, k(2)/k(3) = 0.0026. The reversibility of reaction 1 combined with the small value of k(2)/k(3) leads to a sensitive dependence of k(1) on the O(2) concentration. Products measured by GC/FID as a function of temperature are CF(3)CFClCH(2)Cl, CF(3)COF, and CH(2)Cl(2). The mechanism leading to these products is discussed. The rate constant for the reaction Cl + CF(3)CFClCH(2)Cl (k(11)) was measured as a function of temperature (300-462 K) at 760 Torr to be k(11) = 8.2 * 10(-12) e(-(4065/RT)) cm(3) molecule(-1) s(-1). Rate constants relative to CH(4) for the reactions of Cl with the reference compounds CH(3)Cl, CH(2)Cl(2), and CHCl(3) were measured at 470 K to resolve a literature discrepancy. (R = 1.986 cal K(-1) mol(-1)). PMID- 22229767 TI - Molecular and electronic structure, magnetotropicity and absorption spectra of benzene-trinuclear copper(I) and silver(I) trihalide columnar binary stacks. AB - The molecular and electronic structures, stabilities, bonding features, magnetotropicity and absorption spectra of benzene-trinuclear Cu(I) and Ag(I) trihalide columnar binary stacks with the general formula [c-M(3)(MU(2) X)(3)](n)(C(6)H(6))(m) (M = Cu, Ag; X = halide; n, m <= 2) have been investigated by means of electronic structure calculation methods. The interaction of c M(3)(MU(2)-X)(3) clusters with one and two benzene molecules yields 1:1 and 1:2 binary stacks, while benzene sandwiched 2:1 stacks are formed upon interaction of two c-M(3)(MU(2)-X)(3) clusters with one benzene molecule. In all binary stacks the plane of the alternating c-M(3)(MU(2)-X)(3) and benzene components adopts an almost parallel orientation. The separation distance between the centroids of the benzene and the proximal c-M(3)(MU(2)-X)(3) metallic cluster found in the range 2.97-3.33 A at the B97D/Def2-TZVP level is indicative of a pi...pi stacking interaction mode, for the centroid separation distance is very close to the sum of the van der Waals radii of Cu...C (3.10 A) and Ag...C (3.44 A). Energy decomposition analysis (EDA) at the SSB-D/TZP level revealed that the dominant term in the c-M(3)(MU(2)-X)(3)...C(6)H(6) interaction arises from dispersion and electrostatic forces while the covalent interactions are predicted to be negligible. On the other hand, charge decomposition analysis (CDA) illustrated very small charge transfer from C(6)H(6) toward the c-M(3)(MU(2)-X)(3) clusters, thus reflecting weak pi-base/pi-acid interactions which are further corroborated by the respective electrostatic potentials and the fact that the total dipole moment vector points to the center of the metallic ring of the c-M(3)(MU(2)-X)(3) cluster. The absorption spectra of all aromatic columnar binary stacks simulated by means of TD-DFT calculations showed strong absorptions in the UV region. The main features of the simulated absorption spectra are thoroughly analyzed, and assignments of the contributing electronic transitions are given. The magnetotropicity of the binary stacks evaluated by the NICS(zz)-scan curves indicated an enhancement of the diatropicity of the inorganic ring upon interaction with the aromatic benzene molecule. Noteworthy is the slight enhancement of the diatropicity of the benzene ring, particularly in the region between the interacting rings, probably due to the superposition (coupling) of the diamagnetic ring currents of the interacting aromatic ring systems. PMID- 22229766 TI - Global structure of a three-way junction in a phi29 packaging RNA dimer determined using site-directed spin labeling. AB - The condensation of bacteriophage phi29 genomic DNA into its preformed procapsid requires the DNA packaging motor, which is the strongest known biological motor. The packaging motor is an intricate ring-shaped protein/RNA complex, and its function requires an RNA component called packaging RNA (pRNA). Current structural information on pRNA is limited, which hinders studies of motor function. Here, we used site-directed spin labeling to map the conformation of a pRNA three-way junction that bridges binding sites for the motor ATPase and the procapsid. The studies were carried out on a pRNA dimer, which is the simplest ring-shaped pRNA complex and serves as a functional intermediate during motor assembly. Using a nucleotide-independent labeling scheme, stable nitroxide radicals were attached to eight specific pRNA sites without perturbing RNA folding and dimer formation, and a total of 17 internitroxide distances spanning the three-way junction were measured using Double Electron-Electron Resonance spectroscopy. The measured distances, together with steric chemical constraints, were used to select 3662 viable three-way junction models from a pool of 65 billion. The results reveal a similar conformation among the viable models, with two of the helices (H(T) and H(L)) adopting an acute bend. This is in contrast to a recently reported pRNA tetramer crystal structure, in which H(T) and H(L) stack onto each other linearly. The studies establish a new method for mapping global structures of complex RNA molecules, and provide information on pRNA conformation that aids investigations of phi29 packaging motor and developments of pRNA-based nanomedicine and nanomaterial. PMID- 22229768 TI - Defining synaesthesia. AB - Studies investigating developmental synaesthesia have sought to describe a number of qualities that might capture in behavioural terms the defining characteristics of this unusual phenomenon. The task of generating a definition is made more difficult by the fact that any description of synaesthesia must be broad enough to capture the 61 different variants of the condition already reported to date. Given these difficulties, the current literature now contains a number of conflicting assumptions about the nature of this condition. Here, I attempt to address several of these divisive areas from a set of contemporary definitions. I present evidence that might argue against previous claims that synaesthesia is (a) a 'merging of the senses', which (b) gives rise to consistent synaesthetic associations over time, with (c) synaesthetic associations that are spatially extended. I then investigate the possible benefits of moving from a behavioural definition to a neurobiological one and explore the ways in which this might force a rethink about the potential outermost boundaries of this fascinating condition. PMID- 22229769 TI - Synaesthesia in its protean guises. PMID- 22229770 TI - Redefining synaesthesia? AB - In a thought-provoking paper, Simner (2012) highlights and criticizes a number of assumptions concerning synaesthesia. She specifically takes issue with the following assumptions: (1) synaesthesia is strictly a sensory-perceptual phenomenon; (2) consistency of inducer-concurrent pairs is the gold standard for establishing the authenticity of an individual's synaesthesia; and (3) synaesthesia is not heterogeneous. In the wake of this critique, Simner advances a working definition of synaesthesia as a neurological hyper-association that aims to be more inclusive of its variants. We are very sympathetic to Simner's approach and believe that it raises important points that will advance our understanding of synaesthesia. Here we supplement, and sometimes challenge, some of these ideas. PMID- 22229771 TI - Defining synaesthesia: a response to two excellent commentaries. AB - This paper is an author response to two commentaries on 'Defining Synaesthesia' (Simner, 2012) by David M. Eagleman ('Synesthesia in its protean guises', 2012), and Roi Cohen Kadosh and Devin B. Terhune ('Redefining synaesthesia?', 2012). Together with these authors, I seek to more closely examine existing criteria on which definitions of synaesthesia have been based. In particular, I focus on the fact (a) that existing definitions paint synaesthesia as an overly homogenous condition, (b) synaesthesia may have multiple neurological causes, and (c) synaesthetes and non-synaesthetes may lie on a continuum. PMID- 22229772 TI - Resolving conflicting social categories: the role of age-related executive ability. AB - We investigated the effect of age-related decline in executive ability on the application of emergent features to incongruent social category conjunctions (e.g., male midwife). When forming an impression of an incongruent conjunction, older adults used more emergent attributes (attributes associated exclusively with the category conjunction and not the constituents), relative to younger adults. Moreover, this relationship was mediated by a reduction in inhibitory ability (measured using a Stroop task) and processing speed (measured using a Digit Symbol Substitution Test, DSST). These findings are consistent with the notion that executive ability is pivotal in understanding social functioning in older adults. We discuss the implications of these findings for the continuing development of models outlining the processes and stages involved in perceiving social category conjunctions. PMID- 22229773 TI - Aesthetic appraisal of product designs: independent effects of typicality and arousal. AB - Theories differ on how typicality and arousal influence aesthetic appraisal and whether these processes together interact or have independent effects on aesthetic appraisal. This research investigates the simultaneous effects of typicality and arousal on aesthetic appraisal for product designs by manipulating both processes separately: typicality by prototype deviation and arousal by colour saturation levels. We demonstrate that typicality has a curvilinear relationship with aesthetic appraisal. Additionally, arousal has a positive linear relationship with aesthetic appraisal of product designs. Moreover, arousal can influence aesthetic appraisal independent from typicality. PMID- 22229774 TI - The decline of theory of mind in old age is (partly) mediated by developmental changes in domain-general abilities. AB - Following up on existing, mixed findings in the literature on social cognition in old age different aspects of theory of mind were investigated in younger and older adults. In line with some previous findings, older participants--though matched with the younger ones on crystallized abilities--performed significantly worse both on tasks requiring the ascription of complex intentional attitudes to story protagonists and on tasks of recognizing subtle emotional expressions from video displays. Control analyses showed, however, that these deficits are partly explained by domain-general declines in processing speed and executive function. The implications of these findings for the nature of social cognition and its fate in old age are discussed. PMID- 22229775 TI - Integration of faces and voices, but not faces and names, in person recognition. AB - Recent studies on cross-modal recognition suggest that face and voice information are linked for the purpose of person identification. We tested whether congruent associations between familiarized faces and voices facilitated subsequent person recognition relative to incongruent associations. Furthermore, we investigated whether congruent face and name associations would similarly benefit person identification relative to incongruent face and name associations. Participants were familiarized with a set of talking video-images of actors, their names, and their voices. They were then tested on their recognition of either the face, voice, or name of each actor from bimodal stimuli which were either congruent or novel (incongruent) associations between the familiarized face and voice or face and name. We found that response times to familiarity decisions based on congruent face and voice stimuli were facilitated relative to incongruent associations. In contrast, we failed to find a benefit for congruent face and name pairs. Our findings suggest that faces and voices, but not faces and names, are integrated in memory for the purpose of person recognition. These findings have important implications for current models of face perception and support growing evidence for multisensory effects in face perception areas of the brain for the purpose of person recognition. PMID- 22229776 TI - Framing effects and risk-sensitive decision making. AB - Prospect theory suggests that people are risk-averse when facing gains, but risk prone when facing losses, a pattern known as the framing effect. Although framing effects have been widely demonstrated, few studies have investigated framing effects under conditions of need. Risk-sensitivity theory predicts that decision makers should prefer high-risk options in situations of high need, when lower risk options are unlikely to meet those needs. In two experiments, we examined (1) whether framing effects occurred in behavioural tasks involving risky decision making from description and decision making from experience, (2) whether participants' risky decision making conformed to the predictions of risk sensitivity theory, and (3) whether decision framing interacted with conditions of need to influence decision making under risk. The results suggest that under all circumstances, risky decision making conformed to the predictions of risk sensitivity theory. Framing effects were at least partially demonstrable under all experimental conditions. Finally, negative frames interacted with situations of high need to produce particularly elevated levels of risky choice. Together, the results suggest that risk-sensitivity theory can augment prospect theory to explain choice under conditions of need. PMID- 22229777 TI - Visuospatial over verbal demands in predicting Tower of London planning tasks. AB - The role of verbal and visuospatial information processing in Tower of London (TOL) tasks was investigated. The first part of the investigation examined the verbal and visuospatial abilities and preferred cognitive style (visualizer vs. verbalizer) of 79 participants, in an inter-individual differences approach. Visuospatial abilities significantly predicted TOL performance, but the impact of cognitive style was negligible. The second part applied a dual-task manipulation of concurrent interference of TOL planning tasks on verbal and visuospatial memory, using the same participants. Concurrent processing of the TOL tasks diminished visuospatial memory performance considerably but had no effect on verbal memory, and there was no interaction between cognitive style and memory. These findings clearly underscore the role of visuospatial information processing in TOL tasks and indicate little bearing of verbal or visual cognitive style on TOL problem solving. These results have important implications for TOL and cognitive style in clinical application and cognitive neuroimaging research. PMID- 22229778 TI - Gender-specific contribution of a visual cognition network to reading abilities. AB - Based on the assumption that boys are more likely to tackle reading based on the visual modality, we assessed reading skills, visual short-term memory (VSTM), visual long-term memory for details (VLTM-D), and general non-verbal cognitive ability in primary school children. Reading was within the normal range in both accuracy and understanding. There was no reading performance gap in favour of girls, on the contrary, in this sample boys read better. An entire array of visual, non-verbal processes was associated directly or indirectly with reading in boys, whereas this pattern was not observed for the girls. PMID- 22229779 TI - Escaping the impulse to immediate gratification: the prospect concept promotes a future-oriented mindset, prompting an inclination towards delayed gratification. AB - People's willingness to postpone receiving an immediate reward in order to gain additional benefits in the future, that is, a tendency to shallow delay discounting, is closely related to one's health, wealth, and happiness. We conducted two experiments investigating how the prospect concept can induce a future-oriented mindset and induce people to behave accordingly. We found that engaging in prospective imagery led the participants to focus on delayed utility over immediate utility in financial decisions (Experiment 1). Participants who received the prospect prime via a scrambled-sentence task decreased their desire to pursue hedonic activities for instant gratification (Experiment 2). Moreover, a state of future orientation mediated the effect of the prospect prime on measures of delayed gratification (Experiments 1 and 2). Thus, reminders of prospect may activate a mindset for future orientation by which delayed gratification is strengthened. PMID- 22229781 TI - TBAF and cellulose esters: unexpected deacylation with unexpected regioselectivity. AB - Tetrabutylammonium fluoride has been found to catalyze the deacylation of cellulose esters. More surprisingly, the deacylation is highly regioselective. Even more remarkably, in contrast with the C-6 regioselectivity of other reactions of cellulose and its derivatives, this deacylation shows substantial selectivity for the removal of the acyl groups from the esters of the secondary alcohols at C-2 and C-3, affording cellulose-6-O-esters with high regioselectivity by a simple one-step process employing no protective groups. PMID- 22229782 TI - Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: a systematic review. AB - OBJECTIVE: To evaluate the efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding. DESIGN: Systematic review. POPULATION: Women with a diagnosis of idiopathic and non-functional heavy menstrual bleeding treated with tranexamic acid. METHODS: Electronic searches were conducted in literature databases up to February 2011 by two independent reviewers. We included all trials involving the efficacy of tranexamic acid for the treatment of heavy uterine bleeding. Pregnant, postmenopausal and cancer patients were excluded. MAIN OUTCOME MEASURES: Effect of tranexamic acid treatment on objective reduction of menstrual bleeding and improvement in patient quality of life. RESULTS: A total of 10 studies met our inclusion criteria. Available evidence indicates that tranexamic acid therapy in women with idiopathic menorrhagia resulted in 34-54% reduction in menstrual blood loss. Following tranexamic acid treatment, patient's quality-of-life parameters improved by 46-83%, compared with 15-45% for norethisterone treatment. When compared with placebo, tranexamic acid use significantly decreased the blood loss by 70% in women with menorrhagia secondary to an intrauterine device (p<0.001). Limited evidence indicated potential benefit in fibroid patients with menorrhagia. No thromboembolic event was reported in all studies analyzed. CONCLUSIONS: Available evidence indicates that tranexamic acid treatment is effective and safe, and could potentially improve quality of life of patients presenting with idiopathic and non-functional heavy menstrual bleeding. Data on the therapeutic efficacy of tranexamic acid in patients with symptomatic fibroids are limited, and further studies are therefore needed. PMID- 22229783 TI - Nanoscale patterning of organosilane molecular thin films from the gas phase and its applications: fabrication of multifunctional surfaces and large area molecular templates for site-selective material deposition. AB - A simple methodology to fabricate micrometer- and nanometer-scale patterned surfaces with multiple chemical functionalities is presented. Patterns with lateral dimensions down to 110 nm were made. The fabrication process involves multistep gas-phase patterning of amine, thiol, alkyl, and fluorinated alkyl functional organosilane molecules using PDMS molds as shadow masks. Also, a combination process of channel diffused plasma etching of organosilane molecular thin films in combination with masked gas-phase deposition to fabricate multilength scale, multifunctional surfaces is demonstrated. PMID- 22229784 TI - SnCl2-catalyzed selective atom economic imino Diels-Alder reaction: synthesis of 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinolines. AB - The synthesis of 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinolines by a SnCl(2) catalyzed multicomponent reaction has been described. The reaction proceeds chemo and regioselectively in an atom-economic way, generating a library of 24 quinoline derivatives. PMID- 22229785 TI - Chromatic plasmonic polarizers for active visible color filtering and polarimetry. AB - Color filters are widely used in color displays, optical measurement devices, and imaging devices. Conventional color filters have usually only one fixed output color. However developing active color filters with controllable color output can lead to more compact and sophisticated color filter-based devices and applications. Recent progress in nanotechnology and new knowledge of the interaction of light with metal nanostructures allow us to capture and control light better than ever. Here we use it to fabricate active color filters, based on arrays of metallic optical nanoantennas that are tailored to interact with light at visible frequencies via excitation of localized surface plasmons. This interaction maps the polarization state of incident white light to visible color. Similarly, it converts unpolarized white light to chromatically polarized light. We experimentally demonstrate a wide range of applications including active color pixels, chromatically switchable and invisible tags, and polarization imaging based on these engineered colored metasurfaces. PMID- 22229786 TI - Are the cardiac dimensions spared in growth-restricted fetuses resulting from uteroplacental insufficiency? AB - AIM: The aim of this study was to investigate the effect of intrauterine growth restriction (IUGR), specifically from uteroplacental insufficiency, on fetal cardiac dimensions. MATERIAL AND METHODS: Cardiac circumference (CC) and cardiac area (CA) were measured in four-chamber view in 143 normal fetuses between 18 and 40 weeks of gestation. A study group comprised a homogeneous group of 49 IUGR fetuses with abnormal umbilical artery impedance. Multiple regression analysis was used to compare the cardiac dimensions between normal and IUGR fetuses and to determine if there were differences in cardiac measurements between those with normal and with abnormal ductus venosus Doppler. RESULTS: Fetal cardiac dimensions did not differ significantly between normal and IUGR fetuses. In IUGR fetuses, cardiac dimensions were not statistically different between those with normal and abnormal ductus venosus Doppler. CONCLUSION: Cardiac dimensions are spared and may be used for gestational age estimation in growth-restricted fetuses resulting from uteroplacental insufficiency. PMID- 22229787 TI - High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. AB - BACKGROUND: Indolent systemic mastocytosis (ISM) is a rare disease characterized by accumulation of abnormal mast cells in various tissues, including bone marrow. Symptoms are usually related to release of mast cell mediators. The aims are to establish the prevalence of osteoporotic fractures in ISM and to investigate the association with serum tryptase and the urinary histamine metabolites, methylhistamine (MH), and methylimidazole acetic acid. METHODS: The fracture prevalence in 157 patients (65 men; 92 women), mean age 54 +/- 12 years, was assessed by vertebral morphometry and data from patient records, supplemented by a questionnaire. Bone mineral density (BMD) of lumbar spine and femoral neck was measured, and tryptase and histamine metabolites were analysed. RESULTS: We registered 235 lifetime fractures in 154 patients, including 140 osteoporotic (low-energy trauma) fractures, of which 62% were vertebral, 1% hip and 36% other nonvertebral fractures. Osteoporotic fractures and osteoporosis were found in 37% and 28% of the patients, respectively. In men, the prevalence of these osteoporotic manifestations (46% <50 years; 73% >=50 years) was much higher compared with women (18% <50 years; 58% >=50 years). Older age, male gender, and higher urinary MH were independently related to the osteoporotic manifestations. CONCLUSIONS: This first publication about prevalence of fractures and osteoporosis in patients with ISM shows that the risk of osteoporotic fractures is high, especially in men. Higher urinary MH levels are associated with a higher risk of osteoporotic manifestations. Routine measurements of BMD and vertebral morphometry are warranted in these patients for early detection of osteoporosis. PMID- 22229788 TI - The cardioprotective association of average alcohol consumption and ischaemic heart disease: a systematic review and meta-analysis. AB - AIMS: Most, but not all, epidemiological studies suggest a cardioprotective association for low to moderate average alcohol consumption. The objective was to quantify the dose-response relationship between average alcohol consumption and ischaemic heart disease (IHD) stratified by sex and IHD end-point (mortality versus morbidity). METHODS: A systematic search of published studies using electronic databases (1980-2010) identified 44 observational studies (case control or cohort) reporting a relative risk measure for average alcohol intake in relation to IHD risk. Generalized least-squares trend models were used to derive the best-fitting dose-response curves in stratified continuous meta analyses. Categorical meta-analyses were used to verify uncertainty for low to moderate levels of consumption in comparison to long-term abstainers. RESULTS: The analyses used 38,627 IHD events (mortality or morbidity) among 957,684 participants. Differential risk curves were found by sex and end-point. Although some form of a cardioprotective association was confirmed in all strata, substantial heterogeneity across studies remained unexplained and confidence intervals were relatively wide, in particular for average consumption of one to two drinks/day. CONCLUSIONS: A cardioprotective association between alcohol use and ischaemic heart disease cannot be assumed for all drinkers, even at low levels of intake. More evidence on the overall benefit-risk ratio of average alcohol consumption in relation to ischaemic heart disease and other diseases is needed in order to inform the general public or physicians about safe or low-risk drinking levels. PMID- 22229789 TI - Efficient calculation of molecular configurational entropies using an information theoretic approximation. AB - Accurate computation of free energy changes upon molecular binding remains a challenging problem, and changes in configurational entropy are especially difficult due to the potentially large numbers of local minima, anharmonicity, and high-order coupling among degrees of freedom. Here we propose a new method to compute molecular entropies based on the maximum information spanning tree (MIST) approximation that we have previously developed. Estimates of high-order couplings using only low-order terms provide excellent convergence properties, and the theory is also guaranteed to bound the entropy. The theory is presented together with applications to the calculation of the entropies of a variety of small molecules and the binding entropy change for a series of HIV protease inhibitors. The MIST framework developed here is demonstrated to compare favorably with results computed using the related mutual information expansion (MIE) approach, and an analysis of similarities between the methods is presented. PMID- 22229790 TI - The effect of osteoporosis on residual ridge resorption and masticatory performance in denture wearers. AB - AIM: To compare masticatory performance, masticatory efficiency and residual ridge resorption (RRR) in osteoporotic and non-osteoporotic edentulous subjects after rehabilitation with complete dentures. METHOD: Thirty subjects fulfilling the inclusion criteria were enrolled from the patients visiting the Department of Prosthodontics for complete denture fabrication. Two groups consisting of control subjects (group I; N = 15) and osteoporotic subjects (group II; N = 15) were formed. Complete dentures satisfying certain criteria were fabricated for both groups. Masticatory performance and efficiency were measured 6 months after denture insertion. Areal measurements were taken on lateral cephalograms before and 6 months after denture fabrication. The data were then computed to analyse differences between groups I and II using SPSS statistical software version 15.0. RESULTS: Six months after denture fabrication, the masticatory performance and efficiency were significantly higher (p < 0.001) for group I, with a significant decrease in maxillary and mandibular sagittal area seen in both groups. The rate of bone loss was more in group II compared with group I. CONCLUSION: Greater masticatory function was demonstrated by the non-osteoporotic group, and the rate of RRR was more in the osteoporotic group compared with the normal group. In this pilot study, osteoporosis leads to greater RRR, decreased masticatory performance and efficiency in edentulous subjects 6 months after denture insertion. Screening for osteoporosis is suggested as a routine procedure for all edentulous subjects undergoing rehabilitation. Recall check-ups for osteoporotic patients should be more frequent, and these patients may require more frequent denture remakes. PMID- 22229791 TI - Targeting mitochondria for neuroprotection in Parkinson's disease. AB - SIGNIFICANCE: Several genetic causes of familial Parkinson's disease (PD) have now been identified and include mutations of genes encoding mitochondrial proteins. Mitochondrial complex I toxins can induce dopaminergic cell death and produce a parkinsonian state. Importantly, defects of mitochondrial function have been identified in postmortem substantia nigra from pathologically proven cases of PD. RECENT ADVANCES: These observations provide compelling evidence to support the notion that mitochondria play an important role in the pathogenesis of PD. Thus, targeting mitochondrial function to delay or prevent neuronal cell death would represent a logical means to modify the course of this disease. Several attempts have already been made in this respect, and have been tested in clinical trial. CRITICAL ISSUES: To date, there is no unequivocal evidence for an effective intervention to slow the disease. However, several novel mitochondrial targets are now emerging, including the potential to manipulate the mitochondrial pool to maintain function via biogenesis and mitophagy. FUTURE DIRECTIONS: This development in drug targets needs to be supported by a parallel improvement in clinical trial design to be able to detect a neuroprotective or disease-modifying effect over a reasonable time scale. PMID- 22229792 TI - Immunoglobulin/T-cell receptor gene rearrangements in the diagnostic paradigm of pediatric patients with T-cell acute lymphoblastic leukemia. PMID- 22229793 TI - Association of PAX2 with cell apoptosis in unilateral ureteral obstruction rats. AB - Renal interstitial fibrosis (RIF) is the final common pathway for chronic kidney disease. Cell apoptosis is a critical detrimental event that leads to renal fibrosis. Paired box 2 (PAX2) plays a major role in the development of the kidney. This study was performed to investigate whether PAX2 was associated with cell apoptosis in the progression of RIF in unilateral ureteral obstruction (UUO) rats. Eighty Wistar male rats were divided into two groups randomly: sham operation group (SHO) and model group subjected to UUO (GU), n = 40, respectively. The model was established by left ureteral ligation. Renal tissues were collected 14 and 28 days after surgery. Protein expressions of PAX2, transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin (alpha SMA), collagen-IV (Col-IV), fibronectin (FN), and caspase-3 were detected using immunohistochemical analysis; mRNA expression of PAX2 in renal tissue was detected by real-time reverse transcription polymerase chain reaction; and RIF index and cell apoptosis index in renal interstitium were also calculated. When compared with those in the SHO group, expressions of PAX2 (protein and mRNA) were markedly increased in the GU group (each p < 0.01). Protein expressions of TGF beta1, alpha-SMA, Col-IV, FN, and caspase-3 and RIF index and cell apoptosis index in the GU group were remarkably increased when compared with those in the SHO group (each p < 0.01). The protein expression of PAX2 was positively correlated with the protein expressions of TGF-beta1, alpha-SMA, Col-IV, FN, and caspase-3 and with RIF index and cell apoptosis index (all p < 0.01). The apoptotic cell in our observation was mainly derived from renal tubular epithelial cells. In conclusion, the increased expression of PAX2 is associated with cell apoptosis in the progression of RIF in UUO rats, suggesting that PAX2 is a potentially therapeutic target for prevention of RIF. Tian-Biao Zhou and Yuan-Han Qin wish it to be known that, in their opinion, they should be regarded as joint first authors. PMID- 22229794 TI - Essential role of the donor acyl carrier protein in stereoselective chain translocation to a fully reducing module of the nanchangmycin polyketide synthase. AB - Incubation of recombinant module 2 of the polyether nanchangmycin synthase (NANS), carrying an appended thioesterase domain, with the ACP-bound substrate (2RS)-2-methyl-3-ketobutyryl-NANS_ACP1 (2-ACP1) and methylmalonyl-CoA in the presence of NADPH gave diastereomerically pure (2S,4R)-2,4-dimethyl-5 ketohexanoic acid (4a). These results contrast with the previously reported weak discrimination by NANS module 2+TE between the enantiomers of the corresponding N acetylcysteamine-conjugated substrate analogue (+/-)-2-methyl-3-ketobutyryl-SNAC (2-SNAC), which resulted in formation of a 5:3 mixture of 4a and its (2S,4S) diastereomer 4b. Incubation of NANS module 2+TE with 2-ACP1 in the absence of NADPH gave unreduced 3,5,6-trimethyl-4-hydroxypyrone (3) with a k(cat) of 4.4 +/- 0.9 min-1 and a k(cat)/K(m) of 67 min-1 mM-1, corresponding to a ~2300-fold increase compared to the k(cat)/K(m) for the diffusive substrate 2-SNAC. Covalent tethering of the 2-methyl-3-ketobutyryl thioester substrate to the NANS ACP1 domain derived from the natural upstream PKS module of the nanchangmycin synthase significantly enhanced both the stereospecificity and the kinetic efficiency of the sequential polyketide chain translocation and condensation reactions catalyzed by the ketosynthase domain of NANS module 2. PMID- 22229795 TI - Axenfeld-Rieger spectrum in a patient with 45,X Turner syndrome. AB - PURPOSE: To report the presence of Axenfeld-Rieger spectrum in a case of 45,X Turner syndrome. DESIGN: Non-interventional case report. METHODS: A 13-year-old girl underwent complete genetic clinical evaluation comprising detailed family history taking with pedigree construction in addition to a thorough clinical examination and a number of investigations. A cytogenetic study, molecular testing for hidden Y-chromosome material, and a full ophthalmological assessment including slit lamp examination were also performed. RESULTS: Physical examination revealed typical features of Turner syndrome: short stature, webbing of the neck with low posterior hairline, widely spaced nipples and lack of development of secondary sexual characteristics. Abdominal and pelvic ultrasound showed a horse-shoe kidney with double ureter, a hypoplastic uterus and bilateral streak ovaries. Mitral regurgitation was diagnosed on echocardiography. Chromosomal analysis revealed a 45,X Turner syndrome karyotype while the molecular study failed to demonstrate any occult Y chromosome derivative. The ophthalmological assessment revealed sclerocornea and Axenfeld anomaly with synechia. CONCLUSION: Few reported cases in the literature describe the coexistence of Axenfeld-Rieger spectrum and Turner syndrome. Our study adds to the evidence that ocular problems occur frequently in Turner syndrome. A routine ophthalmologic examination is recommended early in Turner syndrome to diagnose and treat confirmed abnormalities. Conversely, general examination and chromosomal analysis should be indicated in patients presenting with anterior chamber dysgenesis. PMID- 22229797 TI - Production of nuclear transfer embryos by using somatic cells isolated from milk in buffalo (Bubalus bubalis). AB - Somatic cells in milk are a potential source of nuclei for nuclear transfer to produce genetically identical animals; this is especially important in animals that are susceptible to risks of bacterial infection on biopsy collection. In this study, a minimum of 10 milk samples were collected from each of the three buffaloes representing Murrah breed. All the samples were processed immediately and cell colonies were obtained. Cell colonies from one buffalo (MU-442) survived beyond 10 passages and were evaluated by fluorescence microscopy and used in nuclear transfer experiments. In culture, these cells expressed vimentin, indicating they were of fibroblast origin similar to ear cells. We compared the effectiveness of cloning using those milk-derived fibroblast (MDF) cells and fibroblast cells derived from the ear derived fibroblast (EDF). Fusion and cleavage rates of MDF-NT and EDF-NT embryos were found to be similar (92.43 +/- 1.28% vs 94.98 +/- 1.24%, and 80.27 +/- 1.75% vs 84.56 +/- 3.73%, respectively; p > 0.01); however, development to blastocyst stage and total cell number was higher for EDF-NT embryos (50.24 +/- 2.54%, 227.14 +/- 13.04, respectively, p < 0.01), than for MDF-NT embryos (16.44 +/- 0.75%, 170.57 +/- 4.50 respectively). We conclude that somatic cells from milk can be cultured effectively and used as nucleus donor to produce cloned blastocyst-stage embryos. PMID- 22229796 TI - Human T-lymphotropic virus type 1 prevalence in northeastern Iran, Sabzevar: an epidemiologic-based study and phylogenetic analysis. AB - Human T-lymphotropic virus type 1 (HTLV-I) is an important global health problem in the world mainly in the endemic areas of HTLV-I infection. It was previously reported that Mashhad, in northeastern Iran, is a new endemic region of HTLV-I. The aim of this study was to examine the prevalence and phylogenetic analysis of HTLV-I in Sabzevar, located in the southeast of Mashhad. In this cross-sectional study 1445 individuals were selected by multistage cluster sampling. Serum samples were screened for anti-HTLV-I antibody using enzyme-linked immunosorbent assay (ELISA); all of the ELISA-positive samples were confirmed by polymerase chain reaction (PCR). Long terminal repeat (LTR) sequencing was carried out to determine the type of HTLV-I in Sabzevar. In the primary screening by ELISA, 26/1445 (1.8%) of those sampled were reactive for HTLV-I antibody. Twenty-four out of 26 samples were confirmed HTLV-I infection by PCR (24/1445). The overall prevalence of HTLV-I infection in Sabzevar is 1.66%. The prevalence of the virus infection in men and women was 2.42% (11/455) and 1.31% (13/989), respectively. Seroprevalence was associated with age, increasing significantly among those older than 30 years (p=0.015), and a history of surgery (p=0.002), imprisonment (p=0.018), and hospitalization (p=0.005). Three out of 24 positive HTLV-I samples were selected for sequencing and phylogenetic analysis of LTR. The results showed that HTLV-I in Sabzevar belonged to the cosmopolitan subtype. The present study showed Sabzevar is a new endemic area for HTLV-I infection. Our study emphasizes that systemic HTLV-I screening of blood donors in Sabzevar and other cities in Khorasan province is important and should be taken into account. PMID- 22229798 TI - A threshold model of social support, adjustment, and distress after breast cancer treatment. AB - This study examined a threshold model that proposes that social support exhibits a curvilinear association with adjustment and distress, such that support in excess of a critical threshold level has decreasing incremental benefits. Women diagnosed with a first occurrence of breast cancer (N = 154) completed survey measures of perceived support (Social Provisions Scale), quality of life (Functional Living Index--Cancer), adjustment (Psychological Adjustment to Illness Scale) and psychological distress (Brief Symptom Inventory) approximately 3 weeks after surgical treatment and 8-16 months later. Consistent with a threshold model, multiple regression analyses suggested a significant curvilinear relationship between social support and distress at Time 1 and Time 2 and between social support and adjustment at Time 2. Consistent with this model, the significant bivariate correlations between social support and outcomes were accounted for almost entirely by women in the lowest quartile of support. Social support among women in the highest 3 quartiles was unrelated or only marginally related to adjustment and distress. PMID- 22229799 TI - A latent class regression analysis of men's conformity to masculine norms and psychological distress. AB - How are specific dimensions of masculinity related to psychological distress in specific groups of men? To address this question, the authors used latent class regression to assess the optimal number of latent classes that explained differential relationships between conformity to masculine norms and psychological distress in a racially diverse sample of 223 men. The authors identified a 2-class solution. Both latent classes demonstrated very different associations between conformity to masculine norms and psychological distress. In Class 1 (labeled risk avoiders; n = 133), conformity to the masculine norm of risk-taking was negatively related to psychological distress. In Class 2 (labeled detached risk-takers; n = 90), conformity to the masculine norms of playboy, self reliance, and risk-taking was positively related to psychological distress, whereas conformity to the masculine norm of violence was negatively related to psychological distress. A post hoc analysis revealed that younger men and Asian American men (compared with Latino and White American men) had significantly greater odds of being in Class 2 versus Class 1. The implications of these findings for future research and clinical practice are examined. PMID- 22229800 TI - Multi-species biofilms: living with friendly neighbors. AB - Our knowledge regarding the nature and development of microbial biofilms has grown significantly since the first report of these communities by Antonie van Leeuwenhoek in the late 1600s. Nevertheless, most biofilm studies examine mono species cultures, whereas nearly all biofilm communities in nature comprise a variety of microorganisms. The species that constitute a mixed biofilm and the interactions between these microorganisms critically influence the development and shape of the community. In this review, we focus on interactions occurring within a multi-species biofilm and their effects on the nature of the mixed community. In general, interspecies interactions involve communication, typically via quorum sensing, and metabolic cooperation or competition. Interactions among species within a biofilm can be antagonistic, such as competition over nutrients and growth inhibition, or synergistic. The latter can result in the development of several beneficial phenotypes. These include the promotion of biofilm formation by co-aggregation, metabolic cooperation where one species utilizes a metabolite produced by a neighboring species, and increased resistance to antibiotics or host immune responses compared to the mono-species biofilms. These beneficial interactions in mixed biofilms have important environmental, industrial, and clinical implications. The latter, for example, impacts the course and treatment of biofilm-related infections, such as those manifested in the lungs of cystic fibrosis patients. PMID- 22229801 TI - Bayesian approach for peak detection in two-dimensional chromatography. AB - A new method for peak detection in two-dimensional chromatography is presented. In a first step, the method starts with a conventional one-dimensional peak detection algorithm to detect modulated peaks. In a second step, a sophisticated algorithm is constructed to decide which of the individual one-dimensional peaks have been originated from the same compound and should then be arranged in a two dimensional peak. The merging algorithm is based on Bayesian inference. The user sets prior information about certain parameters (e.g., second-dimension retention time variability, first-dimension band broadening, chromatographic noise). On the basis of these priors, the algorithm calculates the probability of myriads of peak arrangements (i.e., ways of merging one-dimensional peaks), finding which of them holds the highest value. Uncertainty in each parameter can be accounted by adapting conveniently its probability distribution function, which in turn may change the final decision of the most probable peak arrangement. It has been demonstrated that the Bayesian approach presented in this paper follows the chromatographers' intuition. The algorithm has been applied and tested with LC * LC and GC * GC data and takes around 1 min to process chromatograms with several thousands of peaks. PMID- 22229802 TI - Effects of cooking using multi-ply cookware on absorption of potassium and vitamins: a randomized double-blind placebo control study. AB - This 2-week interventional study involved a randomized allocation of subjects into three groups: Group A (daily ingestion of 350 g vegetables cooked without water using multi-ply [multilayer-structured] cookware), Group B (daily ingestion of 350 g vegetables; ordinary cookware) and Group C (routine living). Before and after intervention, each subject underwent health examination with 24-h urine sampling. Blood vitamin C significantly increased after intervention from the baseline in Group A (P < 0.01) and Group B (P < 0.05). beta-Carotene levels also increased significantly after intervention in Group A (P < 0.01) and Group B (P < 0.01). Oxidized low-density lipoprotein decreased significantly after intervention in Group A (P < 0.01). In Group A, 24-h urinary potassium excretion increased significantly (P < 0.01) and 24-h urinary sodium (Na)/K ratio improved significantly (P < 0.05) after intervention. In conclusion, a cooking method modification with multi-ply cookware improved absorption of nutrients from vegetables and enhanced effective utilization of the antioxidant potentials of vegetable nutrients. PMID- 22229803 TI - Clinical application of the multigene analysis test in discriminating between ulcerative colitis and Crohn's disease: a retrospective study. AB - METHODS: The newly described--multigene analysis test (DiBiCol) identifying 7 inflammatory bowel disease (IBD)-specific genes in colonic mucosal biopsy differentiating between ulcerative colitis (UC) and Crohn's disease (CD) with active inflammation--is a new addition to existing methods with a higher stated sensitivity and specificity. Method biopsy material from 78 patients with a complicated course diagnosed as most probably UC in 38, CD in 18 and inflammatory bowel disease unclassified (IBDU) in 22 were investigated by DiBiCol. RESULTS: DiBiCol showed a pattern consistent with CD in 13 patients with UC and led to change of diagnosis in 3 patients and a strong suggestion of CD in 8 patients. A total of 2 patients remained as UC. DiBiCol showed a pattern of UC in 4 patients of 18 with CD leading to a changing of diagnosis to UC in 3 patients, but the fourth remained as CD. In 22 patients with IBDU DiBiCol showed a pattern consistent with UC in 7 cases and with CD in 13 cases. A new evaluation 1 year after the DiBiCol allowed the assessment of clinical diagnosis in 10 patients confirmed in 9 of 10 patients by DiBiCol. In patients with acute flare of colitis the clinical diagnosis corresponded in 10 of 12 UC and in 5 of 6 CD cases. SUMMARY: Adopting the DiBiCol test led to a change of the primary diagnosis in a significant number of patients with the initial diagnosis of UC and CD and suggested a clinically probable diagnosis in most of the patients with IBDU and in those with an acute flare of colitis. PMID- 22229804 TI - Enveloped virus but not bacteria block IL-13 responses in human cord blood T cells in vitro. AB - Infections that occur early in life may have a beneficial effect on the immune system and thereby reduce the risk of allergen sensitization and/or allergic disease. It is not yet clear to what extent specific virus and/or bacteria can mediate this effect. The purpose of this study was to assess the role of virus and bacteria in CD4(+) T cell-derived cytokine production in newborns. We compared the effects of five bacteria (Staphlococcus aureus, Escherichia coli, Clostridium difficile, Lactobacillus rhamnosus and Bifidobacterium bifidus) and seven virus (adenovirus, coronavirus, cytomegalovirus, herpes simplex virus, influenza virus, morbillivirus and poliovirus) on the Th1/Th2 cytokine production in mixed lymphocyte reactions using CD4(+) T cells from cord blood cocultured with allogenic myeloid or plasmacytoid dendritic cells. When comparing the baseline cytokine production prior to microbial stimulation, we observed that cord plasmacytoid DC were stronger inducers of Th2 cytokines (IL-5 and IL-13) compared with cord myeloid DC and to adult DC. When adding microbes to these cultures, bacteria and virus differed in two major respects; Firstly, all enveloped viruses, but none of the bacteria, blocked Th2 (IL-13) production by cord CD4(+) cells. Secondly, all Gram-positive bacteria, but none of the virus, induced IL-12p40 responses, but the IL-12p40 responses did not affect Th1 cytokine production (IFN-gamma). Instead, Th1 responses were correlated with the capacity to induce IFN-alpha secretion, which in cord cells were induced by S. aureus and influenza virus alone. These data imply that enveloped virus can deviate Th2 responses in human cord T cells. PMID- 22229805 TI - Isomerization and dissociation of n-butylbenzene radical cation. AB - Fragmentation mechanisms of ionized butylbenzene to give m/z 91 and m/z 92 fragment ions have been examined at the G3B3 and G3MP2B3 levels of theory. It is shown that the energetically favored pathways lead to tropylium, Tr(+), and methylene-2,4-cyclohexadiene, MCD(*+), ions. Formation of m/z 91 benzyl ions, Bz(+), by a simple bond fission (SBF) process, needs about 30 kJ/mol more energy than Tr(+). Possible formation of C(7)H(8)(*+) ions of structures different from the retro-ene rearrangement (RER) product, MCD(*+), has been also considered. Comparison with experimental data of this "thermometer" system is done through a kinetic modeling using Rice-Ramsperger-Kassel-Marcus (RRKM) and orbiting transition state (OTS) rate constant calculations on the G3MP2B3 0 K energy surface. The results agree with previous experimental observation if (i) the competitive formation of Tr(+) and Bz(+) is taken into account in the m/z 91 pathway, and (ii) the stepwise character of the RER fragmentation is introduced in the m/z 92 fragmentation route. PMID- 22229806 TI - Real-time tracking of phytochrome's orientational changes during Pr photoisomerization. AB - Photoisomerization of a protein bound chromophore is the basis of the light sensing and signaling responses of many photoreceptors. Z-to-E photoisomerization of the Pr Cph1Delta2 phytochrome has been investigated by polarization resolved femtosecond visible pump-infrared probe spectroscopy, which yields structural information on the Pr excited (Pr*), Pr ground, and lumi-R product states. By exhaustive search analysis, two photoreaction time constants of (4.7 +/- 1.4) and (30 +/- 5) ps were found. Ring D orientational change in the electronic excited state to the transition state (90 degrees twist) has been followed in real-time. Rotation of ring D takes place in the electronically excited state with a time constant of 30 +/- 5 ps. The photoisomerization is best explained by a single rotation around C(15)?C(16) methine bridge in the Pr* state and a diffusive interaction with its protein surrounding. PMID- 22229807 TI - Decaborane thiols as building blocks for self-assembled monolayers on metal surfaces. AB - Three nido-decaborane thiol cluster compounds, [1-(HS)-nido-B(10)H(13)] 1, [2 (HS)-nido-B(10)H(13)] 2, and [1,2-(HS)(2)-nido-B(10)H(12)] 3 have been characterized using NMR spectroscopy, single-crystal X-ray diffraction analysis, and quantum-chemical calculations. In the solid state, 1, 2, and 3 feature weak intermolecular hydrogen bonding between the sulfur atom and the relatively positive bridging hydrogen atoms on the open face of an adjacent cluster. Density functional theory (DFT) calculations show that the value of the interaction energy is approximately proportional to the number of hydrogen atoms involved in the interaction and that these values are consistent with a related bridging hydrogen atom interaction calculated for a B(18)H(22).C(6)H(6) solvate. Self assembled monolayers (SAMs) of 1, 2, and 3 on gold and silver surfaces have been prepared and characterized using X-ray photoelectron spectroscopy. The variations in the measured sulfur binding energies, as thiolates on the surface, correlate with the (CC2) calculated atomic charge for the relevant boron vertices and for the associated sulfur substituents for the parent B(10)H(13)(SH) compounds. The calculated charges also correlate with the measured and DFT-calculated thiol (1)H chemical shifts. Wetting-angle measurements indicate that the hydrophilic open face of the cluster is directed upward from the substrate surface, allowing the bridging hydrogen atoms to exhibit a similar reactivity to that of the bulk compound. Thus, [PtMe(2)(PMe(2)Ph)(2)] reacts with the exposed and acidic B-H-B bridging hydrogen atoms of a SAM of 1 on a gold substrate, affording the addition of the metal moiety to the cluster. The XPS-derived stoichiometry is very similar to that for a SAM produced directly from the adsorption of [1-(HS)-7,7 (PMe(2)Ph)(2)-nido-7-PtB(10)H(11)] 4. The use of reactive boron hydride SAMs as templates on which further chemistry may be carried out is unprecedented, and the principle may be extended to other binary boron hydride clusters. PMID- 22229808 TI - Harry Potter and nummular headache. PMID- 22229810 TI - Characterization of polyphenolic metabolites in the seeds of Vitis germplasm. AB - The composition and content of polyphenols in the seeds of 91 grape accessions from 17 Vitis species were characterized. Eleven compounds, including 2 gallic derivatives, 3 monomeric flavan-3-ols, 3 flavonols, resveratrol, and procyanidin B1 and B2, were identified via HPLC-MS and quantified by HPLC-DAD. In addition, seventeen dimeric and trimeric flavan-3-ols were also quantified. Tremendous variation was observed both among and within species for these compounds. Monomeric flavan-3-ols were the most abundant polyphenols in seeds, followed by dimeric and trimeric flavan-3-ols, which collectively accounted for more than 96% of the total polyphenols. V. palmata, V. vinifera, and V. vulpina had significantly higher content of total polyphenols than other species. A number of Vitis accessions with high content of various types of seed polyphenols were identified, and they can serve as potential germplasm for improving the composition and content of seed polyphenols in cultivated grapes. PMID- 22229811 TI - Building addressable libraries: amino acid derived fluorescent linkers. AB - A new amino acid derived fluorescent linker for attaching molecules to the surface of a microelectrode array has been developed. Molecules to be monitored on an array are attached to the C-terminus of the linker, the N-terminus is then used to attach the linker to the array, and the side chain is used to synthesize a fluorescent tag. The fluorescent group is made with a one-step oxidative cycloaddition reaction starting from a hydroxyindole group. The linker is compatible with site-selective Cu(I)-chemistry on the array, it allows for quality control assessment of the array itself, and it is compatible with the electrochemical impedance experiments used to monitor binding events on the surface of the array. PMID- 22229812 TI - Synthesis of bishomoinositols and an entry for construction of a substituted 3 oxabicyclo[3.3.1]nonane skeleton. AB - 1,3,3a,7a-Tetrahydro-2-benzofuran was used as key compound for the synthesis of various bishomoinositol derivatives. The diene was subjected to an epoxidation reaction for further functionalization of the diene unit. The bisepoxide obtained was submitted to a ring-opening reaction with acid in the presence of water. Various bishomoinositols were synthesized. However, when the reaction was carried out in the presence of acetic anhydride, a substituted 3-oxabicyclo[3.3.1]nonane skeleton was formed. The mechanism of the formation of the products is discussed. PMID- 22229813 TI - Plasmon bleaching dynamics in colloidal gold-iron oxide nanocrystal heterodimers. AB - Colloidal nanocrystal heterodimers composed of a plasmonic and a magnetic domain have been widely studied as potential materials for various applications in nanomedicine, biology, and photocatalysis. One of the most popular nanocrystal heterodimers is represented by a structure made of a Au domain and a iron oxide domain joined together. Understanding the nature of the interface between the two domains in such type of dimer and how this influences the energy relaxation processes is a key issue. Here, we present the first broad-band transient absorption study on gold/iron oxide nanocrystal heterodimers that explains how the energy relaxation is affected by the presence of such interface. We found faster electron-electron and electron-phonon relaxation times for the gold "nested" in the iron oxide domain in the heterodimers with respect to gold "only" nanocrystals, that is, free-standing gold nanocrystals in solution. We relate this effect to the decreased electron screening caused by spill-out of the gold electron distribution at gold/iron oxide interface. PMID- 22229814 TI - Rupture of a pregnant unscarred uterus in an early secondary trimester: a case report and brief review. AB - Rupture of a pregnant uterus in early pregnancy and an unscarred uterus are extremely rare, and some non-specific symptoms might appear before this occurrence. We report the case of a multiparous woman (gravida 3, para 2) with uterine fundal rupture in her early second trimester (17+ weeks of gestational age), who presented upper abdominal discomfort and vomiting for 3 days, and progressed into sudden acute abdomen and shock. During emergent laparotomy, the entire amniotic sac was found in the peritoneal cavity with a rupture of the uterine fundus. Although we could not confirm that the appearance of upper gastrointestinal symptoms and severe vomiting was associated with uterine rupture in this pregnant woman, abdominal symptoms or signs might be a hint or cause of severe catastrophic pregnancy-related complications. PMID- 22229815 TI - Component-resolved diagnosis of vespid venom-allergic individuals: phospholipases and antigen 5s are necessary to identify Vespula or Polistes sensitization. AB - BACKGROUND: Cross-reactivity between hymenoptera species varies according to the different allergenic components of the venom. The true source of sensitization must therefore be established to ensure the efficacy of venom immunotherapy. OBJECTIVE: In the Mediterranean region, Polistes dominulus and Vespula spp. are clinically relevant cohabitating wasps. A panel of major vespid venom allergens was used to investigate whether serum-specific IgE (sIgE) could be used to distinguish sensitization to either vespid. METHODS: Fifty-nine individuals with allergic reactions to vespid stings and positive ImmunoCAP and/or intradermal tests to vespid venoms were studied. sIgE against recombinant and natural venom components from each wasp species was determined using the ADVIA Centaur((r)) system. RESULTS: sIgE against recombinant antigen 5s sensitization to be detected in 52% of the patients tested (13/25). The sensitivity increased to 80% (20/25), when using natural antigen 5s, and to 100% with the complete panel of purified natural components, because the sIgE was positive to either the antigen 5s (Pol d 5/Ves v 5) or to the phospholipases (Pol d 1/Ves v 1) of the two vespids, or to both components at the same time. In 69% of cases, it was possible to define the most probable sensitizing insect, and in the rest, possible double sensitization could not be excluded. Vespula hyaluronidase was shown to have no additional value as regards the specificity of the assay. CONCLUSIONS: The major allergens of P. dominulus' and Vespula vulgaris' venom, namely phoshpholipases and antigen 5s, are required to discriminate the probable sensitizing species in vespid allergic patients. PMID- 22229816 TI - Interactive effects of approach motivational intensity and alcohol cues on the scope of perceptual attention. AB - AIMS: Many theoretical perspectives suggest that alcohol-related stimuli bear on attentional processes. Building upon these ideas and recent advances regarding the attention-constricting impact of approach motivational states, we predicted that mere exposure to alcohol-related images would suffice to reduce the breadth of attention among individuals who possessed a strong motivation to consume alcohol. DESIGN: Two studies exposed participants to alcohol and neutral cues prior to assessing attention structure. In both studies, measures of alcohol use, negative alcohol expectancies, trait approach motivation and alcohol-related approach motivation were assessed. SETTING AND PARTICIPANTS: Study 1 comprised 102 undergraduates and study 2 comprised 161 undergraduates. Studies were conducted at Texas A&M University, College Station, Texas. MEASUREMENTS: In both studies, participants were briefly exposed to pictures of various stimuli (alcohol versus neutral pictures). After each picture was displayed, participants completed a trial assessing attentional focus. FINDINGS: After controlling for relevant covariates, both studies demonstrated that exposure to alcohol-related pictures led to a narrowing of attentional focus among individuals who possessed a strong motivation to use alcohol. Exposure to neutral pictures, however, did not interact with alcohol-related motivation to influence attentional focus. CONCLUSIONS: Alcohol cues narrow attentional breadth for individuals who are motivated to consume alcohol, suggesting a non-pharmacological means in which alcohol produces a narrow mindset. Alcohol cues may contribute to cognitive and behavioral deficits, as well as drinking behaviors, in part, because they lead to the inability to process a broad range of information in the environment. PMID- 22229817 TI - Influence of natural and synthetic histone deacetylase inhibitors on chromatin. AB - SIGNIFICANCE: Histone deacetylase inhibitors (HDACIs) have emerged as a new class of anticancer therapeutics. The hydroxamic acid, suberoylanilide hydroxamic acid (Vorinostat, ZolinzaTM), and the cyclic peptide, depsipeptide (Romidepsin, IstodaxTM), were approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma in 2006 and 2009, respectively. At least 15 HDACIs are currently undergoing clinical trials either alone or in combination with other therapeutic modalities for the treatment of numerous hematological and solid malignancies. RECENT ADVANCES: The potential utility of HDACIs has been extended to nononcologic applications, including autoimmune disorders, inflammation, diseases of the central nervous system, and malaria. CRITICAL ISSUES: Given the promise of HDACIs, there is growing interest in the potential of dietary compounds that possess HDAC inhibition activity. This review is focused on the identification of and recent findings with HDACIs from dietary, medicinal plant, and microbial sources. We discuss the mechanisms of action and clinical potential of natural HDACIs. FUTURE DIRECTIONS: Apart from identification of further HDACI compounds from dietary sources, further research will be aimed at understanding the effects on gene regulation on lifetime exposure to these compounds. Another important issue that requires clarification. PMID- 22229818 TI - Analysis of risk factors associated with antibiotic-resistant Escherichia coli. AB - Antimicrobial-resistant bacteria represent a major threat to human and animal health. We compared equine fecal samples (n=264) from 138 horses from hospital and nonhospital (livery stable and riding school) premises in North West England to determine the prevalence of Escherichia coli, Salmonella, and Campylobacter and rates of antimicrobial-resistant E. coli strains. Campylobacter jejuni was detected only in hospitalized horses (1.1%), and no Salmonella was identified. Data analysis of the horses' management and veterinary treatments (Tx) identified risk factors associated with shedding of antimicrobial-resistant E. coli. The hospital was the major source of resistant and multi-drug-resistant (MDR) E. coli. Moreover, shedding of antimicrobial-resistant E. coli was associated significantly with hospitalization for a gastrointestinal problem (odds ratio [OR]:+/-95% confidence intervals=8.50:1.79-40.32), receipt of oral antimicrobial Tx (OR=3.52:1.11-11.10), multiple antimicrobial Tx in hospital (OR/Tx=1.05:1.01 1.09), or geldings (OR=4.62:1.23-17.46). Interestingly, intravenous antimicrobial Tx was negatively associated with shedding of antimicrobial-resistant E. coli (OR=0.18:0.04-0.76). MDR E. coli was associated with hospitalization, antimicrobial Tx in hospital (OR/Tx=3.65:1.54-8.68), and increased age (OR/year=1.11:1.03-1.19). Thus, equine hospitals in this geographic location appear to be an important source of antimicrobial-resistant and MDR E. coli strains, but unlikely reservoirs of Salmonella or Campylobacter. Thus, it is important to moderate antimicrobial Tx given to hospitalized horses to lessen exposure and fecal shedding of resistant pathogens. PMID- 22229819 TI - Proliferation as a requirement for in vitro chondrogenesis of human mesenchymal stem cells. AB - During embryonic cartilage development, proliferation and differentiation are tightly linked with a transient cell cycle arrest observed during determination and before main extracellular matrix production. Aim of this study was to address whether these steps are imitated during in vitro differentiation of mesenchymal stem cells (MSCs) and are crucial for a proper chondrogenesis. Human MSCs were expanded in distinct media and subjected to pellet culture in chondrogenic medium. Cells were labeled with 5-iodo-2'-deoxyuridin (IdU) or treated with mitomycin C at various time points during culture. Apoptosis was detected by cleaved caspase 3. Proliferation rate of expanded MSCs at start of pellet culture showed a positive correlation with chondrogenesis according to DNA content, proteoglycan deposition, collagen type II content, and final pellet size. Evenly distributed IdU signals at day 1 diminished and became restricted primarily to the periphery by day 3. Between days 10 and 21, IdU-positive cells were detected throughout coinciding with collagen type II positivity. Little IdU incorporation occurred after day 21 and in areas of strong matrix deposition. DNA content decreased and apoptosis was detected up to day 14. Irreversible growth arrest by mitomycin C fully blocked chondrogenic differentiation and seemed to arrest differentiation at the stage reached at treatment. In conclusion, chondrogenesis involved a transient proliferation phase appearing simultaneously with start of collagen type II deposition and growth was crucial for proper chondrogenesis. Growth and differentiation steps, thus, seemed closely coordinated and resembled, with respect to proliferation, stages known from embryonic cartilage development. Stimulation of proliferation and prevention of early apoptosis are attractive goals to further improve MSC chondrogenesis. PMID- 22229821 TI - Phenotypic and genetic spectrum of Danish patients with ABCA4-related retinopathy. AB - BACKGROUND: Pathogenic variations in the ABCA4 gene were originally recognized as genetic background for the autosomal recessive disorders Stargardt disease and fundus flavimaculatus, but have expanded to embrace a diversity of retinal diseases, giving rise to the new diagnostic term, ABCA4-related retinopathy. Diagnostic genotyping of ABCA4 is complicated by the large size of the gene and the existence of approximately 600 known pathogenic variations, along with numerous rare polymorphisms. A commercial diagnostic array-based assay has been developed targeting known mutations, however a conclusive genetic diagnosis must rely on a comprehensive genetic screening as the mutation spectrum of ABCA4 related retinopathies continues to expand. MATERIAL AND METHODS: Among 161 patients with a Stargardt-related phenotype previously assessed with the commercial ABCA4 mutation microarray, we analyzed the ABCA4 gene with High resolution melting (HRM) in patients in whom the array analysis identified either a heterozygous mutation (n = 50) or no mutation (n = 30). RESULTS: The HRM method detected each of the already known mutations and polymorphisms. We identified the second ABCA4 mutation in 31 of 50 heterozygous patients (62%). Several novel mutations were identified of which four were identified multiple times. The recurrent novel mutations were subsequently assessed among the 30 patients with possible ABCA4-related diseases, previously found to be negative for known ABCA4 mutations by array analysis. In total, 30 different mutations were identified of which 21 have not been described before. CONCLUSION: Scandinavian patients with ABCA4-related retinopathy appear to have a distinct mutation spectrum, which can be identified in patients of diverse clinical phenotypes. PMID- 22229822 TI - Impacted mandibular second molars. AB - OBJECTIVE: To determine the prevalence and severity of impacted permanent mandibular second molars (MdM2s) in the general population of Taiwan as well as to evaluate treatment outcomes with an innovative method for impacted MdM2s. MATERIALS AND METHODS: Dental records of 21,580 patients were retrospectively screened in this study. The impactions of MdM2s were registered. The chosen study population consisted of 96 patients with 125 impacted MdM2s who received orthodontic treatment in our clinics. Standardized periapical radiographs were taken to measure the angles and depths of the impacted MdM2s. In addition, the initial uprighting periods of the impacted MdM2s were recorded. RESULTS: The prevalence of MdM2 impaction in the Taiwanese population was 0.65%. Most of the angles and depths of the MdM2s were 31-60 degrees and 9-12 mm, respectively. The mean initial uprighting period of the impacted MdM2 was 3.6 months. There were no significant differences between genders in the initial uprighting period based on patient ages, impacted angles, or impacted depths (P > .05). Correlation analysis revealed that the impacted depth was highly and positively correlated with the initial uprighting period (r > .75). CONCLUSIONS: The prevalence of MdM2 impaction in this study was low but slightly higher than previous reports investigating whites. Although such impactions are rare, it is recommended to diagnose early for an optimal treatment time and reduction of complications. In addition, the effective molar uprighting appliance used in this study has displayed good treatment outcomes with natural improvement of the adjacent infrabony defects of the first molars. PMID- 22229823 TI - Comparative assessment of clinical performance of esthetic bracket materials. AB - OBJECTIVES: To compare the alterations in esthetic appearance and slot morphology/integrity of two main types of esthetic brackets caused after clinical use. MATERIALS AND METHODS: Sixteen ceramic (CR) and 16 plastic (PR) central incisor brackets were obtained from 16 young adult patients at the end of treatment in a prospective randomized manner. As controls, 12 ceramic (CC) and 12 plastic (PC) nonused brackets were also examined. Three representative slot width measurements were obtained through micrometric microscopy. Visual inspection of optical microscopy images, surface electron microscopy (SEM), and energy dispersive x-ray spectroscopy (EDS) were also performed. RESULTS: Intraoral exposure time varied from 5 to 20 months (mean, 12.4; P = .73). Two-way analysis of variance revealed significant differences in slot width among the different materials and a significant interaction between the material effect and its status (P < .001). Bonferroni post hoc tests on material * status effect showed significant differences between CC (95% confidence interval [CI]: 434.5, 447.0) vs PC (95% CI: 460.2, 472.8), CC vs CR (95% CI: 453.2, 464.4), and PC vs PR (95% CI: 448.8, 458.9). Interestingly, a significant difference was not detected for CR vs PR. Slot width was correlated with the time under clinical use only for plastic brackets (PR: r = -.64, P < .01). Visual inspection of the optical microscopy images did not reveal any major macroscopic morphological disfigurements or significant discolorations. However, a rough and irregular slot wall surface was evident after clinical use (also with SEM), especially in the bottom of the slot. CONCLUSIONS: Both bracket types presented adequate clinical performance at least for the time period studied and in terms of esthetic appearance and morphologic integrity. PMID- 22229824 TI - Bracket bond strength and cariostatic potential of an experimental resin adhesive system containing Portland cement. AB - OBJECTIVE: To determine if a new experimental resin-based material containing Portland cement (PC) can help prevent enamel caries while providing adequate shear bond strength (SBS). MATERIALS AND METHODS: Brackets were bonded to human premolars with experimental resin-based adhesive pastes composed of three weight rations of resin and PC powder (PC 30, 7:3; PC 50, 5:5; PC 70, 3:7; n = 7). Self-etching primer (SEP) adhesive (Transbond Plus) and resin-modified glass ionomer cement (RMGIC) adhesive (Fuji Ortho FC Automix) were used for comparison. All of the bonded teeth were subjected to alternating immersion in demineralizing (pH 4.55) and remineralizing (pH 6.8) solutions for 14 days. The SBS for each sample was examined, and the Adhesive Remnant Index (ARI) score was calculated. The hardness and elastic modulus of the enamel were determined by a nanoindenter at 20 equidistant depths from the external surface at 100 um from the bracket edge. Data were compared by one-way analysis of variance and a chi-square test. RESULTS: PC 50 and PC 70 showed significantly greater SBS than Fuji Ortho FC Automix, although Transbond Plus showed significantly greater SBS than other bonding systems. No significant difference in the ARI category was observed among the five groups. For specimens bonded with PC 50 and PC 70, the hardness and elastic modulus values in most locations were equivalent to those of Fuji Ortho FC Automix. CONCLUSIONS: Experimental resin-based bonding material containing PC provides adequate SBS and a caries-preventive effect equivalent to that of the RMGIC adhesive system. PMID- 22229825 TI - BsrG/SR4 from Bacillus subtilis--the first temperature-dependent type I toxin antitoxin system. AB - Here, we describe bsrG/SR4, a novel type I toxin-antitoxin system from the SPbeta prophage region of the Bacillus subtilis chromosome. The 294-nucleotide bsrG RNA encodes a 38-amino-acid toxin, whereas SR4 is a 180-nucleotide antisense RNA that acts as the antitoxin. Both genes overlap by 123 nucleotides. BsrG expression increases at the onset of stationary phase. The sr4 promoter is 6- to 10-fold stronger than the bsrG promoter. Deletion of sr4 stabilizes bsrG mRNA and causes cell lysis on agar plates, which is due to the BsrG peptide and not the bsrG mRNA. SR4 overexpression could compensate cell lysis caused by overexpression of bsrG. SR4 interacts with the 3' UTR of bsrG RNA, thereby promoting its degradation. RNase III cleaves the bsrG RNA/SR4 duplex at position 185 of bsrG RNA, but is not essential for the function of the toxin-antitoxin system. Endoribonuclease Y and 3'-5' exoribonuclease R participate in the degradation of both bsrG RNA and SR4, whereas PnpA processes three SR4 precursors to the mature RNA. A heat shock at 48 degrees C results in faster degradation and, therefore, significantly decreased amounts of bsrG RNA. PMID- 22229826 TI - Methicillin-resistant Staphylococcus pseudintermedius isolated from canine pyoderma in North China. AB - AIMS: To determine the prevalence of carriage of methicillin-resistant Staphylococcus pseudintermedius (MRSP) among dogs with pyoderma from two small animal hospitals in North China during a 21-month period and to characterize these isolates. METHODS AND RESULTS: Swabs were taken from 260 dogs with pyoderma, and the staphylococcal species isolated and methicillin resistance were confirmed phenotypically and genotypically. The identified MRSP isolates were characterized by multilocus sequence typing (MLST), spa typing, staphylococcal cassette chromosome (SCC) mec typing, testing for susceptibility to nine antimicrobial agents and SmaI-digested pulsed-field gel electrophoresis. Thirty three (12.7%) dogs were positive for MRSP. The most prevalent genotypes detected among MRSP were ST71(MLST)-t06(spa)-II-III(SCCmec) (n = 22, 66.7%), followed by ST5-t19 (n = 8, 24.2%), ST126-III(n = 2, 6.1%) and ST6-t02-V (3.0%). All MRSP isolates showed extended resistance to tested antimicrobial agents. Eight different SmaI patterns were observed in 21 typeable MRSP isolates. CONCLUSIONS: Clinical isolates of MSRP isolated from dogs in North China belonged to two major clonal lineages ST71 and ST5. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report on MRSP from canine pyoderma in China. Further surveillance study is needed to gain more detailed data concerning this major clinical challenge in veterinary medicine. PMID- 22229827 TI - Enhanced dissolution rate and oral bioavailability of simvastatin nanocrystal prepared by sonoprecipitation. AB - BACKGROUND: Simvastatin is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility and an acceptable permeability through biomembranes. The strategy of increasing the in vitro dissolution has the potential to enhance the oral bioavailability when using nanosized crystalline drugs. OBJECTIVE: The aim of this article was to prepare simvastatin nanocrystals to enhance its dissolution rate and bioavailability by exploiting sonoprecipitation. METHODS: Injecting 0.50% (w/v) methanol solution of simvastatin into 0.20% (w/v) water solution of F68 under sonication amplitude of 400 W and processing temperature of 3 degrees C. RESULTS: Simvastatin nanocrystal with average diameter of 360 +/- 9 nm could be obtained. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) confirmed the decreased crystallinity of nanoparticles stabilized by F68. The results of in vitro study demonstrated that the saturation solubility and dissolution rate of simvastatin nanocrystals were enhanced by 1 fold and 4 fold respectively, compared with crude simvastatin and the dissolution rate improved with the decrease in particle size. The C(max) and AUC((0-24 h)) values of simvastatin nanocrystal group were approximately 1.50-fold and 1.44-fold greater than that of simvastatin nanocrystal group, respectively. Additionally, the T(max) of simvastatin nanocrystal group was 1.99 h, comparing to 2.88 h of reference group. CONCLUSION: Sonoprecipitation method can produce small and uniform simvastatin nanocrystals with an improved saturation solubility, dissolution rate and oral bioavailability. PMID- 22229828 TI - Determining the content of lead and cadmium in infant food from the Polish market. AB - The present study aimed to analyse the toxic metals in the baby fruit and vegetable desserts, juices and dinners available on the Polish market, and find that these products a less are safe for infants. The average daily intake of cadmium and lead found in one jar of dessert, one bottle of juice and one jar of baby dinner is, respectively, 0.20 MUg (2% of PTDI) and 0.82 MUg (2.2% of PTDI), 0.15 MUg (2% of PTDI) and 4.86 MUg (13.6% of PTDI), and 0.98 MUg (10% of PTDI) and 2.36 MUg (6.7% of PTDI). It was confirmed that all the examined baby food met the requirements regarding lead and cadmium contamination, and the obtained results were lower than the maximum acceptable level of the contamination with these metals. It may be assumed that fruit and vegetable products available on the Polish market are safe for infants. However, in some products, the levels of cadmium and lead were high. PMID- 22229829 TI - Redox and acid-base chemistry of 7,7,8,8-tetracyanoquinodimethane, 7,7,8,8 tetracyanoquinodimethane radical anion, 7,7,8,8-tetracyanoquinodimethane dianion, and dihydro-7,7,8,8-tetracyanoquinodimethane in acetonitrile. AB - The chemistry and electrochemistry of TCNQ (7,7,8,8-tetracyanoquinodimethane), TCNQ(*-), TCNQ(2-), and H(2)TCNQ in acetonitrile (0.1 M Bu(4)NPF(6)) solution containing trifluoroacetic acid (TFA) has been studied by transient and steady state voltammetric methods with the interrelationship between the redox and the acid-base chemistry being supported by simulations of the cyclic voltammograms. In the absence of acid, TCNQ and its anions undergo two electrochemically and chemically reversible one-electron processes. However, in the presence of TFA, the voltammetry is considerably more complex. The TCNQ(2-) dianion is protonated to form HTCNQ(-), which is oxidized to HTCNQ(*), and H(2)TCNQ which is electroinactive over the potential range of -1.0 to +1.0 V versus Ag/Ag(+). The monoreduced TCNQ(*-) radical anion is weakly protonated to give HTCNQ(*), which disproportionates to TCNQ and H(2)TCNQ. In acetonitrile, H(2)TCNQ deprotonates slowly, whereas in N,N-dimethylformamide or tetrahydrofuran, rapid deprotonation occurs to yield HTCNQ(-) as the major species. H(2)TCNQ is fully deprotonated to the TCNQ(2-) dianion in the presence of an excess concentration of the weak base, CH(3)COOLi. Differences in the redox and acid-base chemistry relative to the fluorinated derivative TCNQF(4) are discussed in terms of structural and electronic factors. PMID- 22229830 TI - Benign recurrent intrahepatic cholestasis: review and long-term follow-up of five cases. AB - OBJECTIVE: Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive inherited disorder characterized by intermittent episodes of cholestatic jaundice. For the patients, the disease is a physical and psychological challenge. There is no curable treatment, but symptomatic relief is described following treatment with rifampicin or plasmapheresis. MATERIAL AND METHODS: Five patients suffering from BRIC followed up for 17 years by one consultant are described. Two patients were treated with rifampicin and plasmapheresis, two with rifampicin alone, and one with plasmapheresis. RESULTS: The treatments showed symptomatic relief, effect on biochemical parameters, and earlier clinical remission compared with no treatment or treatment with other substances like cholestyramine, antihistamines, and ursodeoxycholic acid. CONCLUSIONS: Both rifampicin and plasmapheresis represent important therapeutic options of acute cholestatic attacks in patients with BRIC. As a noninvasive treatment, rifampicin may be the first choice. PMID- 22229831 TI - Advances in Proteomics of Mycobacterium leprae. AB - Although Mycobacterium leprae was the first bacterial pathogen identified causing human disease, it remains one of the few that is non-cultivable. Understanding the biology of M. leprae is one of the primary challenges in current leprosy research. Genomics has been extremely valuable, nonetheless, functional proteins are ultimately responsible for controlling most aspects of cellular functions, which in turn could facilitate parasitizing the host. Furthermore, bacterial proteins provide targets for most of the vaccines and immunodiagnostic tools. Better understanding of the proteomics of M. leprae could also help in developing new drugs against M. leprae. During the past nearly 15 years, there have been several developments towards the identification of M. leprae proteins employing contemporary proteomics tools. In this review, we discuss the knowledge gained on the biology and pathogenesis of M. leprae from current proteomic studies. PMID- 22229832 TI - Photoassisted "gate-lock" fluorescence "turn-on" in a new Schiff base and coordination ability of E-Z isomers. AB - Rapid photoresponse (1.0-8.0 min) through fluorescence "turn-on" signaling displayed by a novel Schiff base (L) creating "gate lock" via intramolecular C H...N interaction in photoisomerized product (L') has been described. Coordination chemistry of pre- and postirradiated species demonstrated a drastic change in the reactivity which has been supported by NMR, HRMS, UV-vis, emission, electrochemical, and complexation studies. PMID- 22229833 TI - Completed suicide, ideation and attempts in attention deficit hyperactivity disorder. PMID- 22229834 TI - Factors limiting the synthesis of virgin olive oil volatile esters. AB - The aim of the present work was to establish the limiting factors affecting the biosynthesis of volatile esters present in virgin olive oil (VOO). Oil volatile fractions of the main Spanish olive cultivars, Arbequina and Picual, were analyzed. It was observed that acetate esters were the most abundant class of volatile esters in the oils, in concordance with the high content of acetyl-CoA found in olive fruit, and that the content of C6 alcohols is limited for the synthesis of volatile esters during the production of VOO. Thus, the increase of C6 alcohol availability during VOO production produced a significant increase of the corresponding ester in the oils in both cultivars at two different maturity stages. However, the increase of acetyl-CoA availability had no effect on the VOO volatile fraction. The low synthesis of these C6 alcohols seems not to be due to a shortage of precursors or cofactors for alcohol dehydrogenase (ADH) activity because their increase during VOO production had no effect on the C6 alcohol levels. The experimental findings are compatible with a deactivation of ADH activity during olive oil production in the cultivars under study. In this sense, a strong inhibition of olive ADH activity by compounds present in the different tissues of olive fruit has been observed. PMID- 22229835 TI - Biofuels: network analysis of the literature reveals key environmental and economic unknowns. AB - Despite rapid growth in biofuel production worldwide, it is uncertain whether decision-makers possess sufficient information to fully evaluate the impacts of the industry and avoid unintended consequences. Doing so requires rigorous peer reviewed data and analyses across the entire range of direct and indirect effects. To assess the coverage of scientific research, we analyzed over 1600 peer-reviewed articles published between 2000 and 2009 that addressed 23 biofuels related topics within four thematic areas: environment and human well-being, economics, technology, and geography. Greenhouse gases, fuel production, and feedstock production were well-represented in the literature, while trade, biodiversity, and human health were not. Gaps were especially striking across topics in the Southern Hemisphere, where the greatest potential socio-economic benefits, as well as environmental damages, may co-occur. There was strong asymmetry in the connectedness of research topics; greenhouse gases articles were twice as often connected to other topics as biodiversity articles. This could undermine the ability of scientific and economic analyses to adequately evaluate impacts and avoid significant unintended consequences. At the least, our review suggests caution in this developing industry and the need to pursue more interdisciplinary research to assess complex trade-offs and feedbacks inherent to an industry with wide-reaching potential impacts. PMID- 22229836 TI - Intriguing electrochemical behavior of free base porphyrins: effect of porphyrin meso-phenyl interaction controlled by position of substituents on meso-phenyls. AB - Electrochemical properties of substituted free base meso-tetraphenylporphyrins (H(2)T(o,o'-X)PP, H(2)T(o-X)PP, and H(2)T(p-X)PP, where X = OCH(3), CH(3), H, F, or Cl on the phenyl rings) are examined by cyclic voltammetry. When a substituent is located only at the para position of the meso-phenyl group, the difference between the first and second oxidation potentials (DeltaE(ox), i.e., E(2)(ox) - E(1)(ox)), is generally significantly smaller than those of the H(2)TPPs with bulky o,o'-substituents on the phenyl group. This trend is elucidated with density functional theory calculations and attributed mainly to the sterically controlled pi-conjugation of the meso-phenyl groups to the central porphyrin ring, rather than the often discussed deformation of porphyrin. PMID- 22229837 TI - Transdermal sumatriptan for acute treatment of migraineurs with baseline nausea. AB - OBJECTIVE: To evaluate the efficacy and safety of transdermal sumatriptan in migraine patients who have baseline nausea. BACKGROUND: Migraine-associated nausea and vomiting can limit the effectiveness of acute treatment with oral agents by causing delays, avoidance, or incomplete absorption of medication due to post-dose vomiting. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study in adult (aged 18-66 years) migraineurs, 530 patients were randomized to receive transdermal sumatriptan or a placebo patch and remained in the study until they had treated a single moderate to severe migraine attack or had gone 2 months without treatment. At baseline (before applying the study patch), patients recorded headache pain intensity and the presence or absence of migraine-associated symptoms, including nausea. The use of analgesic or anti-emetic rescue medications within 2 hours of patch activation was prohibited. Post-hoc analyses were conducted to assess the proportion of patients with nausea at baseline who experienced headache relief and who were free from nausea, photophobia, and phonophobia at 1 and 2 hours post-activation. RESULTS: A total of 454 patients were included in the intent-to-treat population for efficacy analyses. Baseline demographic and migraine headache characteristics were generally similar between the treatment groups. In the overall study population, transdermal sumatriptan was significantly superior to placebo at 1 hour post-activation for pain relief (29% vs 19%, respectively; P < .0135) and freedom from nausea (71% vs 58%, respectively; P < .05) and at 2 hours post activation for freedom from pain (18% vs 9%, respectively; P < .009), pain relief (53% vs 29%, respectively; P < .0001), freedom from nausea (84% vs 63% respectively; P < .001), freedom from photophobia (51% vs 36%, respectively; P < .0028), freedom from phonophobia (55% vs 39%, respectively; P < .0002); and freedom from migraine (16% vs 8%, respectively; P < .0135). In the post-hoc analysis, transdermal sumatriptan was markedly superior to placebo for pain relief and freedom from pain, nausea, photo-, and phonophobia at 1 and 2 hours post-activation. CONCLUSIONS: Transdermal sumatriptan is superior to oral triptans for migraine patients whose baseline nausea causes them to delay or avoid acute treatment. PMID- 22229838 TI - Variations of structures and gas sorption properties of three coordination polymers induced by fluorine atom positions in azamacrocyclic ligands. AB - Three coordination polymers of [(NiL(1))(3)(TCBA)(2)] (1), [(NiL(2))(3)(TCBA)(2)] (2), and [(NiL(3))(3)(TCBA)(2)] (3) have been constructed using azamacrocyclic Ni(II) complexes [NiL(1)](ClO(4))(2)/[NiL(2)](ClO(4))(2)/[NiL(3)](ClO(4))(2) and TCBA(3-) as building blocks (L(1) = 3,10-bis(2-fluorobenzyl)-1,3,5,8,10,12 hexaazacyclotetradecane; L(2) = 3,10-bis(3-fluorobenzyl)-1,3,5,8,10,12 hexaazacyclotetradecane; L(3) = 3,10-bis(4-fluorobenzyl)-1,3,5,8,10,12- hexaazacyclotetradecane; TCBA(3-) = tri(4-carboxy-benzyl)amine). The results of X ray diffraction analyses reveal that 1 shows a 2D Borromean structure, while 2 and 3 form 2D layer structures, and the 2D layers are further connected by the interlayer F...F interactions in 2 and C-H...F interactions in 3 to generate two 3D porous structures with 1D fluorine atoms interspersed channels. Gas sorption measurements illustrate that the desolvated 2 and 3can adsorb N(2), H(2), and CO(2) molecules. The different structures and gas sorption properties of 1 and 2/3 are mainly induced by the different positions of F atoms in azamacrocycle ligands. PMID- 22229839 TI - Social demography of alcohol-related harm to children in Australia. AB - AIMS: This study seeks to establish the prevalence alcohol-related harms to children (ARHC) that occur because of others' drinking in the general population and examine how this varies by who was reported to have harmed the child and socio-demographic factors. DESIGN AND SETTING: A randomly selected cross sectional national population telephone survey undertaken in 2008 in Australia. PARTICIPANTS: A total of 1142 adult respondents who indicated they lived with or had a parental/carer role for children. MEASUREMENTS: Questions included whether children had been negatively affected in any way, left unsupervised or in an unsafe situation, verbally abused, physically hurt or exposed to serious family violence because of others' drinking in the past year. FINDINGS: Twenty-two per cent of respondents reported children had been affected because of another's drinking in the past year; 3% reported substantial harm. Respondents most commonly reported that children were verbally abused because of others' drinking (9%). Participants in single-carer households were more likely to report ARHC than participants in households with two carers, and participants who drank weekly were more likely to report ARHC than those who did not drink. CONCLUSIONS: Almost a quarter of those with a caring role for children in Australia reported that a child or children with whom they lived or for whom they were responsible have been affected adversely by others' alcohol consumption in the past year. The problem extends across the social spectrum, but children in single-parent homes may be at higher risk. PMID- 22229840 TI - Entropic intermediates and hidden rate-limiting steps in seemingly concerted cycloadditions. Observation, prediction, and origin of an isotope effect on recrossing. AB - An unusual intramolecular kinetic isotope effect (KIE) in the reaction of dichloroketene with cis-2-butene does not fit with a simple asynchronous cycloaddition transition state, but it can be predicted from trajectory studies on a bifurcating energy surface. The origin of the KIE is related to a high propensity for transition state recrossing in this system, with heavier masses recrossing less. The KIE can also be predicted by a statistical model that treats the cycloaddition as a stepwise mechanism, the rate-limiting second step being associated with an entropic barrier for formation of the second carbon-carbon bond. The relevance of this stepwise mechanism to other asynchronous but seemingly concerted cycloadditions is suggested by examination of organocatalytic Diels-Alder reactions. PMID- 22229841 TI - NADPH oxidases as regulators of tumor angiogenesis: current and emerging concepts. AB - SIGNIFICANCE: Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and peroxynitrite are generated ubiquitously by all mammalian cells and have been understood for many decades as inflicting cell damage and as causing cancer by oxidation and nitration of macromolecules, including DNA, RNA, proteins, and lipids. RECENT ADVANCES: A current concept suggests that ROS can also promote cell signaling pathways triggered by growth factors and transcription factors that ultimately regulate cell proliferation, differentiation, and apoptosis, all of which are important hallmarks of tumor cell proliferation and angiogenesis. Moreover, an emerging concept indicates that ROS regulate the functions of immune cells that infiltrate the tumor environment and stimulate angiogenesis, such as macrophages and specific regulatory T cells. CRITICAL ISSUES: In this article, we highlight that the NADPH oxidase family of ROS-generating enzymes are the key sources of ROS and, thus, play an important role in redox signaling within tumor, endothelial, and immune cells thereby promoting tumor angiogenesis. FUTURE DIRECTIONS: Knowledge of these intricate ROS signaling pathways and identification of the culprit NADPH oxidases is likely to reveal novel therapeutic opportunities to prevent angiogenesis that occurs during cancer and which is responsible for the revascularization after current antiangiogenic treatment. PMID- 22229842 TI - The dose-response relation for the antinociceptive effect of morphine in a fish, rainbow trout. AB - There have been suggestions that analgesics be used by fish researchers. But in the absence of dose-response data for morphine, this suggestion seems imprudent. The purpose of the present study was to develop a dose-response relationship in fish using six doses of morphine. The response (movement of the fins or tail) to a noxious stimulus (electrical shock to the face region) was monitored before and after a dose of morphine intraperitoneally (i.p.). The i.p. dose of morphine ED(50) in rainbow trout was 6.7 +/- 0.8 mg/kg (n = 12 at each dose). The plasma morphine concentration EC(50) was 4.1 +/- 1.5 mg/L. In a second experiment, rainbow trout tested with equal amounts of morphine and naloxone (30 mg/kg) showed that the antinociceptive effect of morphine was blocked by naloxone. It has been suggested that stress-induced analgesia has been a confounding factor in some fish studies. However, plasma cortisol levels in our study indicated that stress was not a confounding factor in the present experiments. The ED(50) for morphine in fish was higher than that reported for humans or other mammals. Our observation showing a dose-response relation for morphine using a noxious stimulus supports arguments for its effectiveness as an antinociceptive drug in fish. PMID- 22229843 TI - Association of metabolic syndrome parameters with TT3 and FT3/FT4 ratio in obese Turkish population. AB - BACKGROUND: Obesity and metabolic syndrome are major health problems worldwide, including Turkey. Recent studies have shown an association between thyroid function tests and metabolic syndrome parameters. In this study, we aimed to determine the frequency of metabolic syndrome in an obese Turkish population and the relationship between metabolic syndrome and thyroid functions. MATERIALS AND METHOD: We recruited 211 patients (187 females/24 males; mean age, 39.7+/-11.7 years) with body mass index (BMI) >30 kg/m(2) and no other hormonal pathology that could cause obesity. Anthropometric evaluation was followed by measurement of fasting blood glucose (FBG), insulin, total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free T3 (FT3), and free T4 (FT4). Metabolic syndrome was defined according to the 2005 revision of the National Cholesterol Education Program Adult Panel III (NCEP ATP III) criteria. Insulin resistance was calculated from homeostasis model assessment of insulin resistance (HOMA-IR) formula. The TSH cutoff value was set at 2.5 mU/L. RESULTS: Metabolic syndrome was diagnosed in 122 patients (58%). Metabolic syndrome positive patients had significantly higher FBG, triglycerides, FT4, systolic (SBP) and diastolic blood pressure (DBP), and statistically lower HDL-C and FT3/FT4 ratio than metabolic syndrome negative patients. TSH decreased with age and was not related with any metabolic syndrome parameters. The FT3/FT4 ratio negatively correlated with FBG, triglycerides, SBP, and DBP (P=0.003, r=-38; P=0.02, r=-0.28; P=0.005, r=-0.35; and P=0.007, r=-0.34, respectively); TT3 positively correlated with HOMA-IR (P=0.006, r=0.40), FBG (P=0.009, r=0.38), and waist circumference (P=0.02, r=0.34). CONCLUSION: Metabolic syndrome frequency was increased in our study population compared to the general population. Metabolic syndrome parameters (except HDL) correlated with TT3, FT4, and the FT3/FT4 ratio. FT4 levels were associated with obesity and metabolic syndrome independently of insulin resistance, whereas TT3 levels were associated with both insulin resistance and metabolic syndrome. This relationship can be explained by compensatory effects of TT3, and probably FT4, on energy expenditure and thermogenesis in obese people. PMID- 22229845 TI - Transport mechanisms in capillary condensation of water at a single-asperity nanoscopic contact. AB - Transport mechanisms involved in capillary condensation of water menisci in nanoscopic gaps between hydrophilic surfaces are investigated theoretically and experimentally by atomic force microscopy (AFM) measurements of capillary force. The measurements showed an instantaneous formation of a water meniscus by coalescence of the water layers adsorbed on the AFM tip and sample surfaces, followed by a time evolution of meniscus toward a stationary state corresponding to thermodynamic equilibrium. This dynamics of the water meniscus is indicated by time evolution of the meniscus force, which increases with the contact time toward its equilibrium value. Two water transport mechanisms competing in this meniscus dynamics are considered: (1) Knudsen diffusion and condensation of water molecules in the nanoscopic gap and (2) adsorption of water molecules on the surface region around the contact and flow of the surface water toward the meniscus. For the case of very hydrophilic surfaces, the dominant role of surface water transportation on the meniscus dynamics is supported by the results of the AFM measurements of capillary force of water menisci formed at sliding tip-sample contacts. These measurements revealed that fast movement of the contact impedes on the formation of menisci at thermodynamic equilibrium because the flow of the surface water is too slow to reach the moving meniscus. PMID- 22229846 TI - Diagnosis and management of leiomyosarcoma arising from ovarian vein: case report and literature review. AB - Primary leiomyosarcomas arising from the ovarian vein are extremely rare and are associated with high morbidity. A 49-year-old nulliparous woman presented with a left lower abdominal mass. Although extremely rare, the radiological appearance is able to preoperatively identify malignant retroperitoneal masses, such as leiomyosarcomas originating from the ovarian vein; thus, the patient underwent a simple total excision of the mass-adjacent organs, as well as complete resection of the uterus, bilateral adnexae and the left ovarian vein. Adjuvant postoperative combination chemotherapy with gemcitabine and docetaxel was administered. At 22 months, she had no recurrence or metastasis. Delayed diagnosis and high metastatic potentiality are associated with the high morbidity of vascular leiomyosarcomas. The preoperative radiological appearance is useful for early diagnosis, and radical treatment with adjuvant chemotherapy consisting of gemcitabine and docetaxel may improve the poor prognosis of patients with leiomyosarcoma arising from the ovarian vein. PMID- 22229848 TI - Predictors of response to targeted therapy in renal cell carcinoma. AB - CONTEXT: The prognosis for patients with metastatic renal cell carcinoma is poor, with an average 5-year survival of approximately 10%. Use of traditional cytokine therapy, specifically high-dose interleukin 2, is limited by significant toxicity. Better understanding of the molecular pathogenesis of renal cell carcinoma has led to the development of targeted therapies to inhibit specific cellular pathways leading to tumorigenesis. These drugs provide improved survival with a more favorable toxicity profile. There is ongoing investigation of markers that predict response of an individual patient to different targeted therapies. OBJECTIVE: To explain the molecular basis for vascular endothelial growth factor inhibitor (antiangiogenic) and mammalian target of rapamycin inhibitor therapies for renal cell carcinoma, summarize the clinical trials demonstrating the effectiveness of these drugs, and describe the biomarkers shown to correlate with outcome in patients treated with targeted therapy. DATA SOURCES: All included sources are from peer-reviewed journals in PubMed (US National Library of Medicine). CONCLUSION: Emerging evidence shows promise that biomarkers will be useful for predicting an individual patient's response to targeted therapy, leading to a more personalized approach to treating renal cell carcinoma. PMID- 22229849 TI - Targeted therapies and predictive markers in epithelial malignancies of the gastrointestinal tract. AB - CONTEXT: In recent years, there has been a tremendous amount of interest in the development of targeted therapies for the treatment of human cancers. Increased understanding of the specific molecular pathways and driver mutations critical to cancer cell growth have allowed the development of these advanced therapeutics. Among these, inhibitors of the epidermal growth factor receptor and HER2/neu pathways now play a major role in the management of gastrointestinal cancers in addition to other solid malignancies. In colorectal and gastric cancers, the use of epidermal growth factor receptor inhibitors and HER2/neu inhibitors has increased the available treatment options for patients with advanced disease. OBJECTIVE: To focus on the current targeted therapies and predictors of response in malignancies of the gastrointestinal tract. DATA SOURCES: Medical literature searchable on PubMed (US National Library of Medicine) as well as older studies revealed by the literature review were used as the source of data. CONCLUSION: Gene testing of critical elements of the pathways targeted by these agents (such as KRAS mutational analysis in colorectal tumors and HER2/neu testing in gastric cancers) allows the ability to predict which patients will respond to these treatments. As the molecular profiling of tumors and our understanding of cancer genomics and epigenetic alterations continues to grow, it is expected that these personalized targeted therapies will form one of the mainstays of gastrointestinal cancer treatment. PMID- 22229850 TI - Predictors of response to targeted therapies for gastrointestinal stromal tumors. AB - CONTEXT: The inhibition of oncogenic kinase signaling is a successful strategy to treat both hematologic and solid malignancies. Patients with chronic myelogenous leukemia, lung adenocarcinoma, renal cell carcinoma, and gastrointestinal stromal tumors are experiencing tremendous clinical benefits from targeted therapies in the form of kinase inhibitors. These drugs marked a revolution in cancer treatment, not only for their safety and efficacy, but also because they continue to expand our knowledge of the pathophysiology of cancer. OBJECTIVE: To provide a summary of the biologic predictors of gastrointestinal stromal tumor behavior and response to targeted therapies that currently help guide clinical decision making. DATA SOURCES: Published articles pertaining to the diagnosis, molecular genetics, prognostication, clinical behavior, and treatment of gastrointestinal stromal tumors, as well as experiences in a multidisciplinary sarcoma clinic. CONCLUSIONS: In gastrointestinal stromal tumors, the strongest predictor of response to targeted therapies is the mutational status of KIT or PDGFRA. Patients whose tumors harbor a KIT exon 11 mutation benefit the most from imatinib mesylate therapy, in terms of response rate, progression-free survival, and overall survival. Conversely, tumors without detectable mutations in either gene ("wild-type" gastrointestinal stromal tumors) are generally not responsive to imatinib mesylate. PMID- 22229851 TI - Phenotype-genotype correlation in potential female carriers of X-linked developmental cataract (Nance-Horan syndrome). AB - PURPOSE: To correlate clinical examination with underlying genotype in asymptomatic females who are potential carriers of X-linked developmental cataract (Nance-Horan syndrome). METHODS: An ophthalmologist blind to the pedigree performed comprehensive ophthalmic examination for 16 available family members (two affected and six asymptomatic females, five affected and three asymptomatic males). Facial features were also noted. Venous blood was collected for sequencing of the gene NHS. RESULTS: All seven affected family members had congenital or infantile cataract and facial dysmorphism (long face, bulbous nose, abnormal dentition). The six asymptomatic females ranged in age from 4-35 years old. Four had posterior Y-suture centered lens opacities; these four also exhibited the facial dysmorphism of the seven affected family members. The fifth asymptomatic girl had scattered fine punctate lens opacities (not centered on the Y-suture) while the sixth had clear lenses, and neither exhibited the facial dysmorphism. A novel NHS mutation (p.Lys744AsnfsX15 [c.2232delG]) was found in the seven patients with congenital or infantile cataract. This mutation was also present in the four asymptomatic girls with Y-centered lens opacities but not in the other two asymptomatic girls or in the three asymptomatic males (who had clear lenses). CONCLUSIONS: Lens opacities centered around the posterior Y-suture in the context of certain facial features were sensitive and specific clinical signs of carrier status for NHS mutation in asymptomatic females. Lens opacities that did not have this characteristic morphology in a suspected female carrier were not a carrier sign, even in the context of her affected family members. PMID- 22229852 TI - Top-down influence in young children's linguistic ambiguity resolution. AB - Language is rife with ambiguity. Do children and adults meet this challenge in similar ways? Recent work suggests that while adults resolve syntactic ambiguities by integrating a variety of cues, children are less sensitive to top down evidence. We test whether this top-down insensitivity is specific to syntax or a general feature of children's linguistic ambiguity resolution by evaluating whether children rely largely or completely on lexical associations to resolve lexical ambiguities (e.g., the word swing primes the baseball meaning of bat) or additionally integrate top-down global plausibility. Using a picture choice task, we compared 4-year-olds' ability to resolve polysemes and homophones with a Bayesian algorithm reliant purely on lexical associations and found that the algorithm's power to predict children's choices was limited. A 2nd experiment confirmed that children override associations and integrate top-down plausibility. We discuss this with regard to models of psycholinguistic development. PMID- 22229853 TI - An examination of the impact of harsh parenting contexts on children's adaptation within an evolutionary framework. AB - The current study tests whether propositions set forth in an evolutionary model of temperament (Korte, Koolhaas, Wingfield, & McEwen, 2005) may enhance our understanding of children's differential susceptibility to unsupportive and harsh caregiving practices. Guided by this model, we examined whether children's behavioral strategies for coping with threat and challenge cohered into 2 broad, phenotypic dimensions--hawk and dove--that have been maintained by frequency dependent selection throughout our ancestral history: Hawk-like strategies are characterized by approach, dominant-negative affect, and activity, whereas dove like strategies are evidenced by avoidance, inhibition, and vulnerable affect. In turn, we examined the moderating effect of hawk or dove profile membership on children's physiological and psychological adaptation to harsh rearing environments. Participants included 201 2-year-old toddlers and their mothers. Consistent with the Korte model, latent profile analyses extracted 2 profiles that cohered into hawk and dove strategies. Children were classified within hawk or dove profiles and separately examined in a process model of harsh caregiving. As predicted, associations between harsh caregiving practices and children's basal cortisol, parasympathetic nervous system, and sympathetic nervous system activity were moderated by profile membership. In turn, basal physiological levels were differentially predictive of children's psychological adaptation over time. Collectively, findings highlight the potential value of translating the study of evolutionary models to understanding developmental outcomes associated with harsh caregiving. PMID- 22229854 TI - Multifunctional food and traditional ingredients: a competitive marriage. PMID- 22229855 TI - A model of the transmission of micro-organisms in a public setting and its correlation to pathogen infection risks. AB - AIM: Gastro-intestinal infections are widespread in the community and have considerable economic consequences. In this study, we followed chains of infection from a public toilet scenario, looking at infection risks by correlating the transmission of bacteria, fungi and viruses to our current knowledge of infectious doses. METHODS AND RESULTS: Transmission of Escherichia coli, Bacillus atrophaeus spores, Candida albicans and bacteriophage MS2 from hands to surfaces was examined in a transmission model, that is toilet brush, door handle to water tap. The load of viable pathogens was significantly reduced during transfer from hands to objects. Nevertheless, it was shown that pathogens were successfully transferred to other people in contagious doses by contact with contaminated surfaces. CONCLUSIONS: Our results suggest that infection risks are mainly dependent on current infectious doses of pathogens. For enteritic viruses or bacteria, for example Norovirus or EHEC, only a few particles or cells are sufficient for infection in public lavatories, thus bearing a high risk of infection for other persons. However, there seems to be only a low probability of becoming infected with pathogens that have a high infectious dose whilst sharing the same bathroom. SIGNIFICANCE AND IMPACT OF THE STUDY: The transmission model for micro-organisms enables a risk assessment of gastro-intestinal infections on the basis of a practical approach. PMID- 22229856 TI - Intercalating oleylamines in graphite oxide. AB - Graphite oxide has been synthesized from raw graphite particles and been treated with various mass amounts of oleylamine as intercalants to form intercalation compounds. X-ray diffraction patterns reveal that the inter-sheet distances strongly depend on the graphite oxide to oleylamine mass ratios. The equilibrium like behavior implies diffusion-dominated oleylamine adsorption on graphite oxide in solution and excluded volume intercalations among oleylamine-adsorbed graphite oxide during restacking. The intercalation compounds are soluble in organic solvents, and their applications in the fabrication of transparent and conductive coatings have been demonstrated. PMID- 22229857 TI - N-Directing group assisted rhodium-catalyzed aryl C-H addition to aryl aldehydes. AB - Direct aryl C-H addition to aryl aldehydes to produce biaryl methanols was reported via Rh catalysis with an N-containing directing group. The method is highly atom-, step-, and redox-economic. The procedure is robust, reliable, and compatible with water and air. PMID- 22229858 TI - Simultaneous on-chip DC dielectrophoretic cell separation and quantitative separation performance characterization. AB - Through integration of a MOSFET-based microfluidic Coulter counter with a dc dielectrophoretic cell sorter, we demonstrate simultaneous on-chip cell separation and sizing with three different samples including 1) binary mixtures of polystyrene beads, 2) yeast cells of continuous size distribution, and 3) mixtures of 4T1 tumor cells and murine bone marrow cells. For cells with continuous size distribution, it is found that the receiver operator characteristic analysis is an ideal method to characterize the separation performance. The characterization results indicate that dc-DEP separation performance degrades as the sorting throughput (cell sorting rate) increases, which provides insights into the design and operation of size-based microfluidic cell separation. PMID- 22229859 TI - Determination of nonprotein amino acids and betaines in vegetable oils by flow injection triple-quadrupole tandem mass spectrometry: a screening method for the detection of adulterations of olive oils. AB - A novel screening method using an automated flow injection electrospray ionization tandem mass spectrometry system is proposed for the simultaneous determination of five nonprotein amino acids (beta-alanine, alloisoleucine, ornithine, citrulline, pyroglutamic acid) and three betaines (glycine betaine, trigonelline, proline betaine) after derivatization with butanolic HCl. MS/MS experiments were carried out in a triple-quadrupole instrument using multiple reaction monitoring mode in <2 min. The proposed method provided high fingerprinting power to identify the presence of five of the studied compounds in different types of vegetable oils (soybean, sunflower, corn, olive) with LODs at parts per billion levels. The method was validated, and different mixtures of extra virgin olive oil with seed oils were analyzed, achieving the typification for the detection of adulterations in extra virgin olive oils up to 2% w/w. The nonprotein amino acid ornithine was confirmed as a marker for adulteration in the olive oils analyzed. PMID- 22229861 TI - Metal site-mediated, thermally induced structural changes in Cr6+-silicalite-2 (MEL) molecular sieves. AB - Cr(6+) ions were incorporated into the lattice sites of phase-pure silicalite-2 made using 3,5-dimethylpiperidinium as a structure-directing agent. The materials exhibited a remarkably well-resolved vibronic emission consisting of a high frequency progression of 987 cm(-1), which was assigned to the fundamental symmetric stretching mode of the (Si-O-)(2)Cr(?O)(2) group dominated by the terminal Cr?O stretch. A low frequency progression at 214 cm(-1), which was assigned to a symmetric O-Cr-O bending mode, was built on each band of the 987 cm(-1) progression. Studies of the vibronic structure of the emission spectrum as a function of temperature and Cr ion concentration reveal an abrupt change in the Franck-Condon factor of the emission at 20 K for samples with very low Cr concentrations (0.03 mol %). The change in the Franck-Condon factor is attributed to a temperature-induced structural change in the coordination sphere of the metal ion. This structural change was found to be accompanied by a concomitant structural change in the lattice structure of the silicalite-2. This structural change, as studied by temperature-dependent X-ray diffraction, did not involve a crystallographic phase change but an abrupt decrease in the unit cell volume, caused specifically by a decrease in the c-axis. This structural change was not observed in pure silicalite-2, indicating that it is not intrinsic to the silicalite lattice. Moreover, no similar structural change was observed at higher Cr loading (1 mol %). This suggests that the presence of the Cr ions and the changes in the coordination geometry they undergo at low temperature induced the observed contraction in the silicalite-2 lattice, in effect acting as a thermal switch that decreases the unit cell volume. PMID- 22229862 TI - Calprotectin in ankylosing spondylitis--frequently elevated in feces, but normal in serum. AB - OBJECTIVES: To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS) patients by assessing the levels of fecal calprotectin, to study levels of serum calprotectin in AS, and to correlate the concentrations of calprotectin in feces and serum with reported gastrointestinal symptoms, medication, and measures of disease activity. METHODS: All patients fulfilling the Modified New York criteria of AS at the study centers were invited to participate. The patients answered questionnaires concerning medication, symptoms, and disease activity. Physical examination was performed, including back mobility tests. Samples of stools and blood were collected and analyzed for fecal and serum calprotectin. RESULTS: Elevated levels of fecal calprotectin (>50 mg/kg) was found in 140 of 205 AS patients (68%). Levels of fecal calprotectin were associated with increasing age, disease duration, ESR, CRP, and serum calprotectin, but not with gastrointestinal symptoms. Fecal calprotectin was higher in patients using NSAIDs, salicylates, and proton pump inhibitors, but lower in patients using methotrexate and infliximab. Serum calprotectin levels were normal or low in 98% of AS patients and not different from the levels in healthy blood donors. Serum calprotectin levels were positively associated with ESR, CRP, WBC, and PLT. CONCLUSIONS: Two-thirds of AS patients had elevated levels of fecal calprotectin, without associated gastrointestinal symptoms. Serum calprotectin was mostly normal in AS, in contrast to various other inflammatory rheumatic diseases. We suggest that fecal calprotectin may be a marker for subclinical intestinal inflammation in AS and should be measured after stopping NSAIDs, but further endoscopic studies are needed. PMID- 22229863 TI - Is elevated gastric tissue NOX2 associated with lymphoma of mucosa-associated lymphoid tissue? AB - Abstract Helicobacter pylori infection plays a crucial role in the pathogenesis of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). However, the host response to this infection is also important in the development of the disease. In particular, NADPH oxidases (NOXs) which generate reactive oxygen species are known to induce cell damage possibly leading to carcinogenesis. We analyze for the first time NOX expression in a series of well characterized gastric MALT lymphoma (GML) patients in comparison with controls. Our observation leads to the hypothesis that NOX2 expression is significantly associated with GML. PMID- 22229864 TI - Risk and prognosis of campylobacteriosis in relation to polymorphisms of host inflammatory cytokine genes. AB - The risk of infection with Campylobacter jejuni/coli as well as complications may be related to host genetics. We assessed six single-nucleotide polymorphisms in inflammatory cytokine genes in 105 patients with Campylobacter jejuni/coli gastroenteritis. The population distribution of the genes was determined in healthy subjects. The patients responded to mailed questionnaires with regard to reactive arthritis (RA) and irritable bowel syndrome (IBS) in 6-month follow-up. The genotype INFG(+ 874A/A) was less frequent in patients than in controls (20% versus 33%; P = 0.015), whereas the distribution of the other five SNPs did not differ from controls. After 6 months, RA had developed in 15 subjects and IBS in 20 subjects. RA was significant more frequent in patients with IL-18(-137G/G) (22%) than IL-18(-137C/C) (0%), P = 0.03, with INFG(+874 T/T (32%) than INFG(+874A/A) (0%), P = 0.007, and with INFG(+2197 A/A) (22%) than INFG(+2197G/G) (0%), P = 0.02. The development of IBS was not linked to gene polymorphisms. In conclusion, the risk of acquiring clinical gastroenteritis with Campylobacter jejuni/coli is related to the INFG (+ 874A>T) of intron 1. Polymorphisms in IL-18 and INFG are linked to the risk of post-infectious reactive arthritis, but not to irritable bowel syndrome. PMID- 22229865 TI - Adaptive strategies of Parietaria diffusa (M.&K.) to calcareous habitat with limited iron availability. AB - The study of native plants growing in hostile environments is useful to understand how these species respond to stress conditions. Parietaria diffusa (M.&K.) is able to survive in highly calcareous soils and extreme environments, such as house walls, without displaying any chlorotic symptoms. Here, we have investigated the existence of Strategy I complementary/alternative mechanism(s) involved in Fe solubilization and uptake and responsible for Parietaria's extraordinary efficiency. After assessing the specific traits involved in a calcicole-behaviour in the field, we have grown plants in conditions of Fe deficiency, either direct (-Fe) or induced by the presence of bicarbonate (+FeBic). Then, the growth performance, physiological and biochemical responses of the plants were investigated. The study shows that in Parietaria+FeBic, the classical responses of Strategy I plants are activated to a lower extent than in Fe. In addition, there is a greater production of phenolics and organic acids that are both exuded and accumulated in the roots, which in turn show structures similar to 'proteoid-like roots'. We suggest that in the presence of this constraint, Parietaria undergoes some metabolic rearrangements that involve PEP consuming reactions and an enhancement of the shikimate pathway. PMID- 22229866 TI - Origin of enantioselectivity in the propargylation of aromatic aldehydes catalyzed by helical N-oxides. AB - The enantioselective propargylation of aromatic aldehydes with allenyltrichlorosilanes catalyzed by bipyridine N-oxides was explored using density functional theory. Low-lying transition states for a highly enantioselective helical bipyridine N-oxide catalyst [Org. Lett. 2011, 13, 1654] were characterized at the B97-D/TZV(2d,2p) level of theory. Predicted free energy barrier height differences are in agreement with experimental ee's for the propargylation of benzaldehyde and substituted analogues. The origin of enantioselectivity was pinpointed through distortion-interaction analyses. The stereoselectivity arises in part from through-space electrostatic interactions of the carbonyl carbon with the Cl ligands bound to Si, rather than noncovalent aryl aryl interactions between the aromatic aldehyde and the helix as previously proposed. Moreover, aryl-aryl interactions between the aldehyde and helix are predicted to favor transition states leading to the R enantiomer, and ultimately reduce the enantioselectivity of this reaction. (S)-2,2'-bipyridine N-oxide was studied as a model catalyst in order to quantify the inherent enantioselectivity arising from different chiral arrangements of ligands around the hexacoordinate silicon in the stereocontrolling transition state for these reactions. The predicted selectivities arising from different chiral octahedral silicon complexes provide guidelines for the development of transition state models for N oxide-based alkylation catalysts. PMID- 22229867 TI - Hypoglycemia at night: a cause for alarm? PMID- 22229868 TI - Silibinin potentially protects arsenic-induced oxidative hepatic dysfunction in rats. AB - Arsenic (As) compounds are reported as environmental toxicants and human carcinogens. Exposure to arsenic imposes a big health issue worldwide. Silibinin (SB) is a major flavonolignan compound of silimarin and is found in milk thistle of Silybum marianum. It has been reported that silibinin has antioxidant efficacy as metal chelators due to the orientation of its functional groups. However, it has not yet been explored in experimental animals. In view of this fact, the purpose of this study was to delineate the ameliorative role of silibinin against arsenic-induced hepatotoxicity in rats. Rats were orally treated with arsenic alone (5 mg/kg body weight (bw)/day) plus silibinin (75 mg/kg bw/day) for 4weeks. Hepatotoxicity was evaluated by the increased activities of serum hepatospecific enzymes namely aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase and total bilirubin along with increased elevation of lipid peroxidative markers, thiobarbituric acid reactive substances, lipid hydroperoxides, protein carbonyl content and conjugated dienes. The toxic effect of arsenic was also indicated by significantly decreased activities of membrane bound ATPases, enzymatic antioxidants like superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase along with nonenzymatic antioxidants like reduced glutathione, total sulfhydryl groups, vitamins C and E. Administration of silibinin exhibited a significant reversal of arsenic-induced toxicity in hepatic tissue. All these changes were supported by reduction of DNA damage in hepatocytes and histopathological observations of the liver. These results suggest that silibinin has a potential protective effect over arsenic-induced hepatotoxicity in rat. PMID- 22229870 TI - Genome-wide association of serum uric acid concentration: replication of sequence variants in an island population of the Adriatic coast of Croatia. AB - A genome-wide association study of serum uric acid (SUA) laevels was performed in a relatively isolated population of European descent from an island of the Adriatic coast of Croatia. The study sample included 532 unrelated and 768 related individuals from 235 pedigrees. Inflation due to relatedness was controlled by using genomic control. Genetic association was assessed with 2,241,249 single nucleotide polymorphisms (SNPs) in 1300 samples after adjusting for age and gender. Our study replicated four previously reported SUA loci (SLC2A9, ABCG2, RREB1, and SLC22A12). The strongest association was found with a SNP in SLC2A9 (rs13129697, P=2.33*10(-19)), which exhibited significant gender specific effects, 35.76 MUmol/L (P=2.11*10(-19)) in females and 19.58 MUmol/L (P=5.40*10(-5)) in males. Within this region of high linkage disequilibrium, we also detected a strong association with a nonsynonymous SNP, rs16890979 (P=2.24*10(-17)), a putative causal variant for SUA variation. In addition, we identified several novel loci suggestive of association with uric acid levels (SEMA5A, TMEM18, SLC28A2, and ODZ2), although the P-values (P<5*10(-6)) did not reach the threshold of genome-wide significance. Together, these findings provide further confirmation of previously reported uric-acid-related genetic variants and highlight suggestive new loci for additional investigation. PMID- 22229871 TI - Clinical laboratory assessment of the abuse liability of an electronic cigarette. AB - AIMS: To provide an initial abuse liability assessment of an electronic cigarette (EC) in current tobacco cigarette smokers. DESIGN: The first of four within-subject sessions was an EC sampling session that involved six, 10-puff bouts (30 seconds inter-puff interval), each bout separated by 30 minutes. In the remaining three sessions participants made choices between 10 EC puffs and varying amounts of money, 10 EC puffs and a varying number of own brand cigarette (OB) puffs, or 10 OB puffs and varying amounts of money using the multiple-choice procedure (MCP). The MCP was completed six times at 30-minute intervals, and one choice was reinforced randomly at each trial. SETTING: Clinical laboratory. PARTICIPANTS: Twenty current tobacco cigarette smokers. MEASUREMENTS: Sampling session outcome measures included plasma nicotine, cardiovascular response and subjective effects. Choice session outcome was the cross-over value on the MCP. FINDINGS: EC use resulted in significant nicotine delivery, tobacco abstinence symptom suppression and increased product acceptability ratings. On the MCP, participants chose to receive 10 EC puffs over an average of $1.06 or three OB puffs and chose 10 OB puffs over an average of $1.50 (P < 0.003). CONCLUSIONS: Electronic cigarettes can deliver clinically significant amounts of nicotine and reduce cigarette abstinence symptoms and appear to have lower potential for abuse relative to traditional tobacco cigarettes, at least under certain laboratory conditions. PMID- 22229872 TI - Transport of Cryptosporidium parvum oocysts in a silicon micromodel. AB - Effective removal of Cryptosporidium parvum oocysts by granular filtration requires the knowledge of oocyst transport and deposition mechanisms, which can be obtained based on real time microscopic observation of oocyst transport in porous media. Attachment of oocysts to silica surface in a radial stagnation point flow cell and in a micromodel, which has 2-dimensional (2-D) microscopic pore structures consisting of an array of cylindrical collectors, was studied and compared. Real time transport of oocysts in the micromodel was recorded to determine the attached oocyst distributions in transversal and longitudinal directions. In the micromodel, oocysts attached to the forward portion of clean collectors, where the flow velocity was lowest. After initial attachment, oocysts attached onto already attached oocysts. As a result, the collectors ripened and the region available for flow was reduced. Results of attachment and detachment experiments suggest that surface charge heterogeneity allowed for oocyst attachment. In addition to experiments, Lattice-Boltzmann simulations helped understanding the slightly nonuniform flow field and explained differences in the removal efficiency in the transversal direction. However, the hydrodynamic modeling could not explain differences in attachment in the longitudinal direction. PMID- 22229874 TI - In vitro antitumour activity of stearic acid-g-chitosan oligosaccharide polymeric micelles loading podophyllotoxin. AB - Development of successful formulations for poorly water-soluble drugs remains a longstanding critical and challenging issue in cancer therapy. The stearic acid-g chitosan oligosaccharide (CSO-SA) micelles have been presented as potential candidates for intracellular antitumour agent delivery carrier. Herein, podophyllotoxin (PPT) loaded CSO-SA micelles (CSO-SA/PPT) were prepared by a dialysis method. The drug encapsulation efficiency could reach a higher level, the micellar size and the zeta potential increased with increasing charged amounts of drug. The cumulative release percentage of PPT drug from micelles enhanced with decreasing PPT content in the micelles. The cytotoxicities of CSO SA/PPT micelles against human breast carcinoma (MCF-7) cells, human lung cancer cells (A549) and human hepatoma cell line (Bel-7402) were higher than that of free PPT formulation. The higher cytotoxicities were due to the faster PPT transport into tumour cells mediated by CSO-SA micelles. Overall, CSO-SA micelles might be a promising carrier for PPT delivery in cancer therapy. PMID- 22229875 TI - Is severe dysplasia the same lesion as carcinoma in situ? 10-Year follow-up of laryngeal precancerous lesions. AB - CONCLUSION: Our results showed that the behavior of moderate dysplasia lesions was more like that of severe dysplasia lesions, while severe dysplasia was very different from carcinoma in situ (CIS). CIS should be managed more aggressively than the other lesions. Mild dysplasia could not be viewed as a precancerous lesion of the larynx. OBJECTIVE: This study aimed to identify the possibilities of the precancerous lesions of larynx (including mild dysplasia, moderate dysplasia, severe dysplasia, and CIS) progressing to invasive carcinomas and to highlight the importance of adequate management and follow-up strategies for these patients. METHODS: A retrospective study of patients who had these preinvasive lesions in the larynx over a 10-year period was performed. RESULTS: These patients were followed for a minimum period of 2 years from the initial diagnosis. In all, 86 patients were identified the cohort. Of these, 17 (19.8%) patients developed carcinoma: 0 of 22 with mild dysplasia, 5 of 25 (20%) with moderate dysplasia, 2 of 14 (15%) with severe dysplasia, and 10 of 25 (40%) patients with CIS progressed to invasive cancers (p = 0.001). Over 50% of cases progressed 3 years after the original biopsy. Only 1 of 86 (1%) died of the disease. PMID- 22229876 TI - Connection between hyperemesis gravidarum, jaundice or liver dysfunction, and biliary sludge. AB - Jaundice in hyperemesis gravidarum may cause physicians to suspect several underlying diseases. Jaundice appeared in a woman with hyperemesis gravidarum and an ultrasound revealed biliary sludge. Hydration concomitantly ameliorated the symptoms, jaundice and the biliary sludge. Another woman with hyperemesis gravidarum showed elevated aminotransferases, with biliary sludge also being present. Hydration ameliorated the symptoms and liver dysfunction, and reduced the total bilirubin level. Biliary sludge appeared, but was ameliorated according to the symptoms of hyperemesis gravidarum. PMID- 22229877 TI - Hydrogen atom reactivity toward aqueous tert-butyl alcohol. AB - Through a combination of pulse radiolysis, purification, and analysis techniques, the rate constant for the H + (CH(3))(3)COH -> H(2) + (*)CH(2)C(CH(3))(2)OH reaction in aqueous solution is definitively determined to be (1.0 +/- 0.15) * 10(5) M(-1) s(-1), which is about half of the tabulated number and 10 times lower than the more recently suggested revision. Our value fits on the Polanyi-type, rate-enthalpy linear correlation ln(k/n) = (0.80 +/- 0.05)DeltaH + (3.2 +/- 0.8) that is found for the analogous reactions of other aqueous aliphatic alcohols with n equivalent abstractable H atoms. The existence of such a correlation and its large slope are interpreted as an indication of the mechanistic similarity of the H atom abstraction from alpha- and beta-carbon atoms in alcohols occurring through the late, product-like transition state. tert-Butyl alcohol is commonly contaminated by much more reactive secondary and primary alcohols (2-propanol, 2 butanol, ethanol, and methanol), whose content can be sufficient for nearly quantitative scavenging of the H atoms, skewing the H atom reactivity pattern, and explaining the disparity of the literature data on the H + (CH(3))(3)COH rate constant. The ubiquitous use of tert-butyl alcohol in pulse radiolysis for investigating H atom reactivity and the results of this work suggest that many other previously reported rate constants for the H atom, particularly the smaller ones, may be in jeopardy. PMID- 22229879 TI - Marital adjustment and interleukin-6 (IL-6). AB - Building on prior research that marital functioning is associated with a variety of health outcomes, we evaluated the association between marital adjustment and a marker of inflammation in a sample of married adults between the ages of 35 and 84 years old (N = 415) from the second wave of the population-based Survey of Midlife Development in the United States (MIDUS II). Specifically, we evaluated associations between positive (i.e., partner support) and negative (i.e., partner strain) dimensions of marital adjustment and interleukin-6 (IL-6) separately for men and women, and whether these associations were moderated by age. Results indicated that (a) marital adjustment was not associated with IL-6 in men, (b) age moderated the association between marital adjustment and IL-6 in women, (c) partner support and partner strain were associated with IL-6 in younger women, and (d) partner support but not partner strain was uniquely associated with IL-6 in younger women. The associations between marital adjustment and IL-6 in younger women were significant when controlling for demographic variables, health status indicators, health behaviors, depressive symptoms, and perceived stress. These findings suggest that IL-6 may be a useful biomarker for studying health-relevant biological responses within intimate relationships, and that young women, in particular, may exhibit increased inflammation when partner support is low. PMID- 22229880 TI - The effects of marriage education for army couples with a history of infidelity. AB - While existing literature has begun to explore risk factors which may predict differential response to marriage education, a history of couple infidelity has not been examined to determine whether infidelity moderates the impacts of marriage education. The current study evaluated self-report marital satisfaction and communication skills in a sample of 662 married Army couples randomly assigned to marriage education (i.e., PREP) or a no-treatment control group and assessed prior to intervention, post intervention, and at 1 year after intervention. Of these, 23.4% couples reported a history of infidelity in their marriage. Multilevel modeling analyses indicated that having a history of infidelity significantly moderated the impact of PREP for marital satisfaction, with a trend for a similar effect on communication skills. However, couples with a history of infidelity assigned to PREP did not reach the same levels of marital satisfaction after intervention seen in the group of couples without infidelity assigned to PREP, although they did show comparable scores on communication skills after intervention. Implications of these findings for relationship education with couples with a history of infidelity are discussed. PMID- 22229878 TI - An unusual feature associated with LEE1 P1 promoters in enteropathogenic Escherichia coli (EPEC). AB - Transcription start points in bacteria are influenced by the nature of the RNA polymerase.promoter interaction. For Escherichia coli RNA polymerase holoenzyme containing sigma70, it is presumed that specific sequence in one or more of the 10, extended -10 and -35 elements of the promoter guides the RNAP to select the cognate start point. Here, we investigated the promoter driving expression of the LEE1 operon in enteropathogenic E. coli and found two promoters separated by 10 bp, LEE1 P1A (+1) and LEE1 P1B (+10) using various in vitro biochemical tools. A unique feature of P1B was the presence of multiple transcription starts from five neighbouring As at the initial transcribed region. The multiple products did not arise from stuttering synthesis. Analytical software based on information theory was employed to determine promoter elements. The concentration of the NTP pool altered the preferred transcription start points, albeit the underlying mechanism is elusive. Under in vivo conditions, dominant P1B, but not P1A, was subject to regulation by IHF. PMID- 22229881 TI - Measuring the rate of weight gain and the influential role of diet in patients undergoing elective laparoscopic cholecystectomy: a 6-month follow-up study. AB - Weight gain after cholecystectomy is one of the major surgical problems consistent with morbidities and long-term mortalities. Here, we aimed to study the impact of palliative cholecystectomy on weight gain and nutritional status of the patients before and in 1, 4 and 6 months after surgery. We performed a prospective survey on a cohort of 48 patients undergoing elective cholecystectomy. The nutritional status of the patients was collected by nutrition nurse and analysed by NutriBase software. There were 13 (16%) females and 35 (84%) males with the mean age of 51.8 +/- 1.97. In 6 months after surgery, patients had higher values of BMI, daily energy expenditure, carbohydrate and lipid consumption and a decreased level of protein consumption. Weight gain after surgery was caused by an increase in fat consumption which resulted in the weight gain and worsening of lipid profile. Dietary consultation, shortly after surgery, would improve patient outcome after cholecystectomy. PMID- 22229882 TI - Mass spectrometric identification of water-soluble gold nanocluster fractions from sequential size-selective precipitation. AB - This paper presents a simple and convenient methodology to separate and characterize water-soluble gold nanocluster stabilized with penicillamine ligands (AuNC-SR) in aqueous medium by sequential size-selective precipitation (SSSP) and mass spectrometry (MS). The highly polydisperse crude AuNC-SR product with an average core diameter of 2.1 nm was initially synthesized by a one-phase solution method. AuNCs were then precipitated and separated successively from larger to smaller ones by progressively increasing the concentration of acetone in the aqueous AuNCs solution. The SSSP fractions were analyzed by UV-vis spectroscopy, matrix-assisted laser desorption/ionization time-of-flight-MS, and thermogravimetric analysis (TGA). The MS and TGA data confirmed that the fractions precipitated from 36, 54, 72, and 90% v/v acetone (F(36%), F(54%), F(72%), and F(90%)) comprised families of close core size AuNCs with average molecular formulas of Au(38)(SR)(18), Au(28)(SR)(15), Au(18)(SR)(12), and Au(11)(SR)(8), respectively. In addition, F(36%), F(54%), F(72%), and F(90%) contained also the typical magic-sized gold nanoparticles of Au(38), Au(25), Au(18), and Au(11), respectively, together with some other AuNCs. This study shed light on the potential use of SSSP for simple and large-scale preliminary separation of polydisperse water-soluble AuNCs into different fractions with a relatively narrower size distribution. PMID- 22229884 TI - Characterization of exopolysaccharides produced by Bifidobacterium longum NB667 and its cholate-resistant derivative strain IPLA B667dCo. AB - Bifidobacteria are natural members of the human intestinal microbiota and some strains are being used as probiotics. Adaptation to bile can allow them to increase survival in gastrointestinal conditions, thus improving their viability. Bifidobacterium longum NB667 and the cholate-resistant strain B. longum IPLA B667dCo produced exopolysaccharides (EPS) that were partially characterized. Analysis by size exclusion chromatography-multiangle laser light scattering indicated that the EPS crude fractions of both strains contained two polymer peaks of different molar mass. On the basis of chromatographic techniques both peaks appeared to be heteropolysaccharides. The smaller peak was mainly composed of glucose, galactose and rhamnose whose molar ratios and linkage types showed slight variations between the EPS fractions of both strains. The bigger peak consisted of glucose and galactose; the monosaccharide composition was identical in the EPS fractions of the two microorganisms, but their infrared spectra presented some differences regarding compounds other than carbohydrates that seem to be associated to the polymer. Differences in the composition of EPS fractions did not affect the capability of crude EPS from B. longum to be fermented by the human intestinal microbiota in fecal batch cultures. PMID- 22229883 TI - Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. AB - BACKGROUND AND OBJECTIVES: During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin. METHODS: Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally. RESULTS: Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived. CONCLUSIONS: Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates. PMID- 22229886 TI - Insight into the selenoproteome of the malaria parasite Plasmodium falciparum. AB - AIMS: The malaria parasite Plasmodium falciparum possesses four unique selenoproteins (PfSel1-PfSel4) which are likely to represent important components of the redox-regulatory network of this infectious agent. So far these proteins have only been characterized in silico. The aim of the present study was to gain further insight into the structural, biochemical, and functional properties of P. falciparum selenoproteins. RESULTS: Using (75)Se labeling in P. falciparum cell culture, the presence of selenoproteins in the parasite could be verified for the first time. Bioinformatic analyses indicated distant relatedness between the Plasmodium proteins and selenoproteins described in other organisms, namely between PfSel1 and SelK, PfSel2 and SelT, and between PfSel4 and SelS. For PfSel3 no remarkable similarities with proteins from other organisms were identified. All four proteins were recombinantly produced in Escherichia coli as UGA->UGU (selenocysteine->cysteine) mutants. Using green fluorescent protein (GFP)-fusion proteins and immunofluorescence, the subcellular localization of the four selenoprotein mutants was studied. PfSel1, PfSel2, and PfSel4 localized to the endoplasmic reticulum whereas PfSel3 was visualized in the nucleus and/or the apicoplast. Functional assays support the roles of PfSel1 and PfSel4 in cellular redox reactions. Transcriptional profiles of the four selenoproteins, and proteins involved in selenoprotein biosynthesis, indicate that their expression is regulated via the availability of selenium and via oxidative and nitrosative stress. INNOVATION: In this study the presence of selenoproteins in Plasmodium has been proven for the first time; the subcellular localization of the proteins and their relatedness to known selenoproteins have been systematically studied, and recombinant proteins as well as information on regulation of transcript levels have been obtained. CONCLUSION: Taken together, our data enhance our understanding of the functional role of selenoproteins in Plasmodium. PMID- 22229887 TI - Association between mental distress, gastrointestinal symptoms, and health-care utilization in functional dyspepsia: a prospective 7-year follow-up study. AB - OBJECTIVE: The association between psychosocial factors and gastrointestinal symptoms is unclear. It has been proposed that they simply drive health-care seeking of patients. We therefore aimed to study whether mental distress would increase health-care utilization in functional dyspepsia (FD). METHODS: 171 primary care FD patients completed questionnaires screening gastrointestinal symptoms, mental distress, and health-care utilization between 1993 and 2000. These included the Bowel Disease Questionnaire and 12-item General Health Questionnaire. The patients' medical records were reviewed in primary care centers, Kuopio University Hospital, local hospitals, and private clinics. RESULTS: The majority of patients revisited their general practitioner (GP), and most of them were prescribed antisecretory medication. Repeated gastroscopy and lower gastrointestinal endoscopy were performed in 26% of the patients. A radiological reinvestigation, usually upper abdominal ultrasound, was performed in one-third. Nine percent were hospitalized due to gastrointestinal reasons. A single additional bowel symptom increased the probability of repeated endoscopy by 19%, a visit to the GP by 19%, and an inpatient period by 51%. Neither an increase in the dyspepsia score nor the presence of mental distress or suspicion of serious illness increased the probability of health-care utilization. CONCLUSION: There is no association between mental distress and health-care utilization for gastrointestinal symptoms. PMID- 22229888 TI - Heptabismuthate [Bi7I24]3-: a main group element anderson-type structure and its relationships with the polyoxometalates. AB - We describe the unique structural and electronic arrangement in the heptanuclear polyiodobismuthate [Bi(7)I(24)](3-) which displays striking similarities with the Anderson-type structures found in polyoxometalates. This main group element anion is part of the complex [Bi(OAc)(2)(thf)(4)](3)[Bi(7)I(24)] (1) which has been characterized by X-ray crystallography. We investigated the structure, stability, and bonding of [Bi(7)I(24)](3-) using relativistic dispersion corrected density functional theory in combination with a quantitative energy decomposition and electron localization function analysis in order to better understand the main features of this isopolyanion. A comparative analysis of the properties of [Bi(7)I(24)](3-) and previously reported high-nuclearity [Bi(n)X(3n+m)](m-) anions, in the gas phase and in solution, has been performed, in the latter case to track the macroscopic solvent effects. [Bi(7)I(24)](3-) is the largest building block in the class of trianionic iodobismuthates and the sole heptanuclear framework in the family of iodobismuthates. PMID- 22229891 TI - IL-8 from local subcutaneous wounds regulates CD11b activation. AB - The cellular and soluble mediators of a dermal inflammation can be studied by the skin chamber technique. The aim of this study was to address the physiological effect of soluble mediators, released into the skin chamber, with special focus on neutrophil CD11b activation. Mediators released at the inflammatory site were studied by Milliplex and enzyme-linked immunosorbent assay (ELISA) and correlated with transmigration and CD11b activation in vivo and in vitro. Transmigration was studied by the skin chamber technique and by the transwell method, and expression of the CBRM1/5 epitope on activated CD11b was analysed by flow cytometry following in vivo and in vitro incubation with chamber fluid or recombinant interleukin-8 (IL-8). Leucocyte in vivo and in vitro transmigration both correlated with the concentrations of IL-1beta, tumour necrosis factor alpha (TNFalpha) and IL-8 at P < 0.05 (R > 0.7). Furthermore, CD11b was activated, in terms of exposure of the activation epitope, on neutrophils after 30 min of in vitro incubation with chamber fluid and correlated solely with the concentration of IL-8, P < 0.05 (R = 0.72). In vitro incubation with recombinant IL-8 confirmed a concentration-dependent expression of the activation epitope; however, induction of CBRM1/5 by recombinant IL-8 required a concentration that was significantly higher compared with that in chamber fluid. In addition, the CBRM1/5 epitope was analysed on in vivo extravasated neutrophils that displayed a significantly higher expression compared with circulating neutrophils, P = 0.04. We conclude that IL-8 is the major factor regulating the expression of CD11b activation epitope in neutrophils. PMID- 22229892 TI - Redox-dependent protein quality control in the endoplasmic reticulum: folding to degradation. AB - SIGNIFICANCE: Nascent polypeptides entering the endoplasmic reticulum (ER) are co and post-translationally modified by N-glycosylation and the oxidation/isomerization of cysteine residues followed by folding with the aid of molecular chaperones. Only properly folded proteins reach their final destination. The oxidative environment in the ER enables ER-resident oxidoreductases to facilitate disulfide bond formation, which stabilizes protein structures. ER oxidoreductases involve in both the productive folding of newly synthesized proteins and ER-associated degradation (ERAD) of misfolded proteins. RECENT ADVANCES: The ER luminal event of ERAD is composed of three major steps: the recognition and segregation of terminally misfolded proteins from folding intermediates, unfolding of misfolded substrates by oxidoreductases that cleave the disulfide bonds to enable the translocation of the substrates through the retrotranslocation channel, and transport of substrates to be degraded to the dislocon channel. The factors required for these three critical steps have been found to form a supramolecular complex in the ER. CRITICAL ISSUES: This complex comprises EDEM1, a lectin-like molecule that recognizes mannose-trimming and segregates the identified substrates from the productive folding pathway into the degradation pathway; ER DnaJ (ERdj)5, a reductase that resides in the ER and reduces disulfides in misfolded proteins; and immunoglobulin heavy chain binding protein (BiP), an heat shock protein (Hsp)70 family molecular chaperone that recruits substrates to the dislocon channel after dissociation from the EDEM1/ERdj5 complex coupled with ATP hydrolysis. FUTURE DIRECTIONS: The importance of disulfide bond reduction in misfolded proteins for retrotranslocation through the dislocon channel will be discussed by comparing the function of ERdj5 with that of other oxidoreductases in the ER. PMID- 22229893 TI - A 12-year-old boy with an infected ectopic ureter presenting with acute appendicitis-like symptoms and acute scrotum. AB - An ectopic ureter draining into the seminal vesicle or vas deferens in males is a very rare anomaly and is usually associated with renal dysplasia or agenesis. An ectopic ureter associated with a dysplastic kidney is not usually a suspected cause during clinical evaluation of children with abdominal pain. This report presents a rare case of an ectopic ureter associated with a dysplastic kidney with an acute infection in a previously healthy 12-year-old boy, demonstrated by magnetic resonance imaging. He presented with abdominal pain that mimicked acute appendicitis-like symptoms which was subsequently complicated by epididymitis manifesting as an acute scrotum. Clinicians should consider including an ectopic ureter in the differential diagnosis of children presenting with acute abdomen. PMID- 22229895 TI - Reflections on the Journal after 10 years at the helm--a developmental voyage. PMID- 22229896 TI - Management and education in nursing: common goals and interests. PMID- 22229897 TI - The pivotal role of nurse managers, leaders and educators in enabling excellence in nursing care. AB - AIM: The aims of this paper are to present the findings from a discursive analysis of key issues associated with providing excellence in nursing care; and to provide an exemplar framework to support excellence in nursing care and describe the potential benefits when excellence in nursing care occurs. BACKGROUND: The challenge facing the nursing profession is in ensuring that the core principles of dignity, respect, compassion and person (people) centered care become central to all aspects of nursing practice. To regain the public and professional confidence in nursing, nurse leaders, managers and educators play a pivotal role in improving the image of nursing. KEY ISSUES: Excellence in nursing care will only happen by ensuring that nurse managers, leaders and educators are able to respond to the complexity of reform and change by leading, managing, enabling, empowering, encouraging and resourcing staff to be innovative and entrepreneurial in practice. CONCLUSIONS: Creating healthcare environments that enable excellence in nursing care will not occur without the development of genuine shared working partnerships and collaborations between nurse managers, leaders and educators and their associated organizations. IMPLICATIONS FOR NURSING MANAGEMENT: The importance of adopting an authentic sustainable leadership approach to facilitating and supporting frontline staff to innovate and change is imperative in restoring and evidencing that nurses do care and are excellent at what they do. By focusing attention on what resources are required to create a healthcare environment that enables compassion, safety and excellence in nursing care and what this means would be a reasonable start on the journey to excellence in nursing. PMID- 22229890 TI - Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. AB - Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury. PMID- 22229898 TI - Managing the transition of Saudi new graduate nurses into clinical practice in the Kingdom of Saudi Arabia. AB - BACKGROUND: With the national policy of Saudization of the workforce, the numbers of Saudi new graduate nurses (NGNs) seeking employment is increasing. METHODS: A project report outlining an educational needs analysis of Saudi NGNs, and the subsequent development and expansion of a New Graduate Development Programme (NGDP) utilizing a Practise Development framework. Competence and safe practise in Saudi NGNs was evaluated using two specifically designed tools: the Final Clinical Competence Evaluation and the Clinical Challenge. RESULTS: A three-phase structured NGDP was successfully implemented resulting in NGNs developing improved confidence and competence. They were judged as being safe to practise and more patient centred, as measured against the established performance indicators. CONCLUSION: Adopting a practise Development (PD) framework provided a clear structure and direction for the NGDP. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse Managers who invest human, financial and education resources into developing new graduate nurses are likely to retain such staff longer. In the Middle Eastern context, such investment is likely to rapidly promote the goal of increasing the number of indigenous nationals working as nurses. PMID- 22229899 TI - Nursing education in China: past, present and future. AB - BACKGROUND: The development of nursing education in China is closely tied with the country's wider context, including the social, political and economic environment. EVALUATION: The source of information includes published materials accessible to the public and the authors' knowledge as content experts of the nursing situation in China. KEY ISSUES: Nursing in China is developing rapidly particularly in the last decade in quantity and quality terms. The education development of nursing is in line with the service development which aims at client-centred care adopting a holistic approach caring for clients at the preventive, curative and rehabilitative levels. CONCLUSIONS: Nursing education in China, both at the pre-registration and post-registration level, plays a key role in building a strong team of nurses to fulfil the health mission of the country. IMPLICATIONS FOR NURSING MANAGEMENT: Managers in nursing education need to continuously revise the curriculum to produce nurses who meet societal needs at present and for the future. At the same time, nurse managers in the service need to make best use of these nursing talents according to the nurses' competence and educational levels. PMID- 22229900 TI - Preferences of Israeli nursing students in choosing their future workplace. AB - AIM: To examine the decision-making process and factors influencing nursing students when choosing a workplace. BACKGROUND: In view of the global nursing shortage, nurse recruitment strategies should address multicultural factors and students' expectations, which may influence their workplace preference. METHODS: A combined study involving qualitative (focus groups) and quantitative (questionnaire survey) methods, was carried out in a University School of Nursing in Israel. RESULTS: Focus groups revealed that students focused on various aspects of job security and salary benefits. The perceived 'ideal' hospital is one with close proximity to home, offers good employment conditions and has a positive social atmosphere. Differences were found in the quantitative survey between female and male students as well as between students in the academic vs. non-academic track. CONCLUSIONS: IT is important to periodically review the considerations and motives of nursing students when choosing a workplace and responsively implement various strategies to recruit new nurses. IMPLICATIONS FOR NURSING MANAGEMENT: The hospital's image as a quality and friendly workplace should be strengthened and nursing students should be offered opportunities for professional and academic development. PMID- 22229901 TI - A South African perspective: current position and challenges in health care service management and education in nursing. AB - AIM: The present study discusses the current context of South African nurse managers' working environment, exploring the challenges of disease demographics, service change and development, and educating a nursing workforce to meet healthcare delivery demands. BACKGROUND: Post-apartheid South Africa has a legacy of inequalities in access to healthcare; increasingly poor morbidity and mortality demographics; and inadequate numbers of qualified nurses to provide a service to meet the Millennium Development Goals outlined by the Government in 2010. EVALUATION: The present study discusses the current position and developments pertaining to nursing management relating to both healthcare challenges and educating a nursing workforce. KEY ISSUES: Collaborative action by various stakeholders in the development of nursing management will ensure a nursing workforce and service environment fit-for-purpose in delivering the healthcare outcomes envisaged in the transformed South Africa in the future. CONCLUSION: Different role players are involved in critical issues regarding the management and education of nursing in South Africa. Nurse managers are central to the success of service redesign, delivery and education. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers need to influence policy decisions regarding nursing service design and delivery, and the education required to prepare the next generation of practitioners for these new services. PMID- 22229902 TI - Management and leadership in nursing: an Australian educational perspective. AB - AIM: In this article, we present an Australian perspective on issues influencing management and leadership education in nursing. BACKGROUND: Nurse leaders and managers work in a context of high pressure, uncertainty and rapid change, and face unprecedented challenges on a daily basis. EVALUATION AND KEY ISSUES: In the present paper, we reflect on the issues and challenges facing providers of management education for nursing, and consider these challenges in relationship to current trends and imperatives. CONCLUSIONS: Collaborative approaches between educational and clinical settings are needed to ensure quality, relevant educational support for managers and leaders, and enhance curriculum integrity. IMPLICATIONS FOR NURSING MANAGEMENT: There is a need for contemporaneous and relevant research to inform innovative models of collaborative education. PMID- 22229903 TI - Evaluation of a clinical leadership programme for nurse leaders. AB - AIM: This is an evaluation study of the impact of the adapted RCN Clinical Leadership Programme on the development of leadership competencies of nurse leaders in Switzerland. BACKGROUND: Transformational leadership competencies are essential for delivering high-quality care within health-care organizations. However, many countries have identified a lack of leadership skills in nurse leaders. Consequently, the development of leadership competencies is a major objective for health-care centres. METHODS: This article describes the quantitative results of a mixed methods study. A one-group pre-test-post-test quasi-experimental design was used. A convenience sample of 14 ward leaders were assessed three times using the Leadership Practices Inventory (LPI). Descriptive and inferential data analysis techniques were employed. RESULTS: In total 420 observer-assessment questionnaires and 42 self-assessment questionnaires were distributed. Our main finding was that nurse leaders following the programme, demonstrated significant improvement in two subscales of the LPI -'inspiring a shared vision' and 'challenging the process'. CONCLUSION: This study showed improvement in two leadership practices of nurse leaders following a programme that has been adapted to Swiss health care. IMPLICATIONS FOR NURSING MANAGEMENT: Findings concur with others studies that suggest that investments in educational programs to facilitate leadership skills in nurse leaders are justified. PMID- 22229904 TI - Evaluation of the Manchester clinical supervision scale: Norwegian and Swedish versions. AB - AIM: To develop Norwegian and Swedish versions of the Manchester Clinical Supervision Scale (MCSS) and to test and verify its hypothesized seven-factor structural model. BACKGROUND: Nurse managers are responsible for upholding and ensuring quality of care as well as for maintaining staff competence, thus safeguarding the standard of care. METHODS: The research process included a translation-back-translation procedure with monolingual and bilingual tests in addition to psychometric evaluation. The sample consisted of 150 student and registered nurses (RNs) from Norway and Sweden, and confirmatory factor analysis was performed. RESULTS: The translated versions did not exhibit satisfactory validity and reliability. The confirmatory factor analysis failed to show a good model fit. Low alpha-values were revealed except for factors 1, 2, 3 and 7. The most important factors of the MCSS were Trust/Rapport, Supervisor advice/Support, Improved care/Skills and Reflection. CONCLUSION: Translation of an instrument for cross-cultural nursing research is important, although there are methodological limitations associated with construct validity. IMPLICATION FOR NURSE MANAGERS: Instruments for the evaluation of nursing care are necessary in order to formulate strategies at a managerial level. Nurse managers who encourage nurses to attend supervision promote professional development and enhance patient safety. PMID- 22229905 TI - A model for a national clinical final examination in the Swedish bachelor programme in nursing. AB - AIM: To describe the development and evaluation of a model for a national clinical final examination in the bachelor nursing education. BACKGROUND: After the transfer of nursing education to the academy, concerns have been raised among nurses, nurse leaders, lecturers and researchers about the nursing students' clinical competence at the entrance to professional life. METHODS: During 2003 to 2005, a collaborative project was carried out between four universities and adjunctive health-care areas supplying clinical placements in Sweden. A two-part examination was agreed upon comprising a written theoretical test and a bedside test. An assessment tool for the bedside test was created. Nursing students, nurses and clinical lecturers participated voluntarily in the evaluation. RESULTS: The model was highly appreciated, and its relevance, usability, and validity were considered quite good for the assessment of nursing students' clinical competence at the final stage of their education. Several deficiencies were revealed, which led to further development of the model. CONCLUSIONS AND IMPLICATIONS FOR NURSING MANAGEMENT: The development and first evaluation of the model proved encouraging for further use, but it needs further evaluation. Involvement of nursing managers is necessary in order to satisfy new demands on competence and staffing of clinical nurses. PMID- 22229906 TI - Masters in nursing degrees: an evaluation of management and leadership outcomes using a retrospective pre-test design. AB - AIM: The aim of the present study was to measure the leadership and management abilities of graduates who had completed a master's degree in nursing. BACKGROUND: A number of reports have recommended that leadership competencies be integrated into education programmes for nurses at a master's level. In spite of the growth in the number of graduates from higher degrees in nursing, there is a paucity of evidence on the management and leadership outcomes that develop as a result of undertaking a master's degree. METHODS: A cross-sectional survey using a retrospective pre-test design was used to measure self-reported leadership and management outcomes from the graduates' educational programmes. RESULTS: Results found that graduates had gained significantly on their ability to change practice, communicate and work as part of a team and to problem solve as an outcome of completing a master's degree in nursing. CONCLUSION: Graduates make substantial gains in leadership and management capabilities as a consequence of their higher degree. These capabilities are necessary as nurses take the lead in many areas of healthcare. IMPLICATIONS FOR NURSING MANAGEMENT: The masters in nursing degree now has a pivotal role in providing effective continuing education to the nursing profession; especially for those who occupy or intend to occupy senior positions within clinical, management or education branches of the profession. PMID- 22229907 TI - Learning as doing: common goals and interests across management and education. AB - AIM: The aim of the present study was to evaluate approaches to learning of healthcare professionals in a postgraduate management programme. BACKGROUND: The study was carried out in a higher education institution. METHODS: An evaluation research study of an inter-professional healthcare group was carried out with students (insider stakeholders), their lecturers and an external examiner (external stakeholders). All three perspectives are presented here. Data were collected by interview, document analysis and reflection. RESULTS: The present study focused on the domain of learning as doing, as a major theme of the study, drawing variances between nurses and other healthcare professionals. The study highlights the importance of exploring approaches to learning from a pluralistic stance. CONCLUSIONS: There is a risk of adopting a narrow approach to education if management programmes are overly influenced by the immediate needs of application of knowledge to practice. Education is influenced by the needs of the students themselves in coming to the programme to acquire knowledge and skills for application to practice. IMPLICATIONS FOR NURSING MANAGEMENT: Nurses undertaking management programmes need to be facilitated to cope with the conflicting demands of completing tasks on the job, engaging deeply with learning from these demands and becoming empowered to develop professionally and personally. PMID- 22229908 TI - Strengthening the nursing and midwifery unit manager role: an interim programme evaluation. AB - AIMS: An interim evaluation was conducted on the professional development components of the New South Wales (NSW) Health 'take the lead' ('ttl') programme, an initiative aimed at enhancing nursing/midwifery unit managers' (N/MUM) skills. BACKGROUND: Previous research has highlighted the importance of strong nurse leaders, and shown that training programmes may assist in improving leadership skills. The NSW Nursing and Midwifery Office (NaMO) developed the 'ttl' programme for N/MUMs with the intention of improving hospital quality by strengthening nurse leadership. The programme had three strands, with the professional development modules a key component. METHOD: Semi-structured interviews were conducted with 17 participants who had completed components of the 'ttl' programme. The interviews explored participants' perceptions of the programme, and suggestions for improvement. Qualitative analysis was conducted on the transcribed interviews. RESULTS: The N/MUMs reported feeling increasingly empowered, knowledgeable and supported as a result of attending the 'ttl' workshops. CONCLUSIONS: The results suggest that the studied components of the 'ttl' programme may be effective in assisting nurse leaders gain new leadership skills and institute positive changes in the nursing work environment. IMPLICATIONS FOR NURSING MANAGEMENT: Leadership programmes such as 'ttl' may provide an effective tool for improving N/MUM performance and role confidence. PMID- 22229909 TI - The role of the Professional Doctorate in developing professional practice. AB - AIMS: The present study aims to reflect on, and analyse, one particular approach to the award of a Professional Doctorate. BACKGROUND: The concept of the 'Professional' Doctorate offers opportunities for the development of work-based skills which transcend professional boundaries. There is now an established basis for Professional Doctorates with many Universities offering a qualification of this nature. EVALUATIONS: It commences with a consideration of what the Professional Doctorate is, the philosophy of the Professional Doctorate and how it can impact on professional practice. KEY ISSUES: The key issues are underpinnings of the Professional Doctorate which is concerned with Mode 2 knowledge and the ways in which the Professional Doctorate can enhance and develop practice. CONCLUSIONS: Conclusions are then drawn which the authors believe will be of use to those managing, developing and studying on, Professional Doctorate programmes. IMPLICATIONS FOR NURSING MANAGEMENT: The present study then explores the issues which the authors have experienced over the past 5 years in running the scheme and highlights the potential benefits of the professional doctorate for organizations. PMID- 22229910 TI - Letter to the editor: Being a seasoned nurse in active practice. PMID- 22229912 TI - A comparison of patterns of sun protection during beach holidays and everyday outdoor activities in a population sample of young German children. AB - BACKGROUND: Reducing exposure to ultraviolet (UV) radiation is the main effective measure for preventing skin cancer. Educational campaigns targeting sun protection have been focused either on behaviour on the beach during the summer holiday alone, or during everyday outdoor activities of the children. Little is known about the comparison between these different settings. OBJECTIVES: To analyse whether parents apply similar protective measures to reduce UV exposure for their young children in different outdoor environments. METHODS: Families (n = 2619) with children aged 3-6 years (response: 64.7%) were enrolled in a population-based survey in the German city of Erlangen and its surrounding rural county. Using a self-administered standardized questionnaire parents gave information about demographic and photosensitivity data of their children, their knowledge about risk factors for skin cancer and their typical instructions given to their children when these played outside on a summer day in different outdoor environments. RESULTS: Significant discrepancies regarding the four UV protective measures (clothes, shade, sunhat, sunscreen) for children between an everyday outdoor setting and a holiday setting on the beach were observed. A high level of parental risk factor knowledge was significantly associated with a better protection for children in all four measures only on the beach. Photosensitivity and demographic characteristics had some impact on protective behaviour, too. Measures of sun protection were reduced with children's increasing age. CONCLUSIONS: Skin cancer prevention campaigns should target the encouragement of sun protection for children also in outdoor activities of daily living, not only during a summer holiday on the beach. PMID- 22229911 TI - Synthetic polymer nanoparticle-polysaccharide interactions: a systematic study. AB - The interaction between synthetic polymer nanoparticles (NPs) and biomacromolecules (e.g., proteins, lipids, and polysaccharides) can profoundly influence the NPs fate and function. Polysaccharides (e.g., heparin/heparin sulfate) are a key component of cell surfaces and the extracelluar matrix and play critical roles in many biological processes. We report a systematic investigation of the interaction between synthetic polymer nanoparticles and polysaccharides by ITC, SPR, and an anticoagulant assay to provide guidelines to engineer nanoparticles for biomedical applications. The interaction between acrylamide nanoparticles (~30 nm) and heparin is mainly enthalpy driven with submicromolar affinity. Hydrogen bonding, ionic interactions, and dehydration of polar groups are identified to be key contributions to the affinity. It has been found that high charge density and cross-linking of the NP can contribute to high affinity. The affinity and binding capacity of heparin can be significantly diminished by an increase in salt concentration while only slightly decreased with an increase of temperature. A striking difference in binding thermodynamics has been observed when the main component of a polymer nanoparticle is changed from acrylamide (enthalpy driven) to N-isopropylacryalmide (entropy driven). This change in thermodynamics leads to different responses of these two types of polymer NPs to salt concentration and temperature. Select synthetic polymer nanoparticles have also been shown to inhibit protein-heparin interactions and thus offer the potential for therapeutic applications. PMID- 22229913 TI - EXAFS and DFT investigations of uranyl arsenate complexes in aqueous solution. AB - Uranium and arsenic often co-occur in nature, for example, in acid mine drainage waters. Interaction with arsenic is thus important to understand uranium mobility in aqueous solutions. For the present study, EXAFS spectroscopy was used to investigate the formation and identify the structure of aqueous uranyl arsenate species at pH 2. The nearest U-As distance of 3.39 A, observed in shock-frozen liquid samples, was significantly shorter than that observed in solid uranyl arsenate minerals. The shorter bond length indicated that the solution contained a bidentate-coordinated species, in contrast to the monodentate coordination in solid uranyl arsenate minerals. The U-As coordination number of 1.6 implied that two uranyl arsenate species with U:As ratios of 1:1 and 1:2 formed in nearly equal proportions and that the hydrated uranyl ion was present only as a minor component. The two uranyl arsenate species could not be differentiated spectroscopically, since their U-As distances were equal. A comparison based on DFT modeling indicated for both the 1:1 and the 1:2 species, that the bidentate arsenates were bound to uranium with one of the binding oxygen atoms being protonated. Based on the present spectroscopic study, the two species that will have to be considered in acidic uranium-arsenic-rich solutions are thus UO(2)H(2)AsO(4)(+), and UO(2)(H(2)AsO(4))(2)(0). PMID- 22229914 TI - What's your diagnosis? Lateral femoral condylar shear injury. PMID- 22229915 TI - Accurate 3-dimensional preoperative planning and resection in orthopedic oncology. PMID- 22229917 TI - Use of an oblique obturator radiograph in aspiration at anterior iliac crest. AB - The purpose of this study was to evaluate the use of an oblique obturator radiograph in bone marrow aspiration. The authors retrospectively reviewed 22 patients who underwent bone marrow aspiration guided by the real-time oblique obturator radiograph while in a supine position at their institution between November 2009 and August 2010. The mean duration of bone marrow aspiration was 35+/-9 seconds. According to the visual analog scale, the postoperative pain score at the site of aspiration was an average 1.6 of 10. No complications were observed. The oblique obturator radiograph can improve the accuracy of the aspiration. PMID- 22229918 TI - Spinal cord contusions. PMID- 22229919 TI - In vitro response of human chondrocytes to a combination of growth factors and a proteinase inhibitor. AB - Degenerative disk disease is an accelerating cascade of tissue degeneration in the intervertebral disk. A harsh catabolic environment perpetuates the degeneration of the intervertebral disk. Tissue engineering-based techniques offer effective treatment to slow the progression of degenerative disk disease and regenerate intervertebral disk tissue. The purpose of this study was to assess the efficacy of a regenerative therapy for degenerative disk disease by treating human chondrocytes with anabolic growth factors and a proteinase inhibitor. The use of both proved effective in upregulating important extracellular matrix markers of human chondrocytes. These successful in vitro results have implications for the regeneration of the intervertebral disk. PMID- 22229920 TI - Effects of lumbar disk herniation on the careers of professional baseball players. AB - Outcomes after lumbar disk herniation in baseball athletes are currently unknown. It has been postulated that the repetitive torque-producing motions of a baseball player may have negative implications after a disk injury. Sixty-nine lumbar disk herniations (40 treated operatively, 29 nonoperatively) in 64 professional baseball players were identified, and important outcome measures including successful return to play, time to recovery, career longevity, and performance based on vital statistics to each position were documented. Ninety-seven percent of baseball athletes successfully returned to play at an average of 6.6 months after diagnosis. Athletes treated operatively required significantly more time to return to play than those managed nonoperatively (8.7 vs 3.6 months, respectively; P<.0001). PMID- 22229922 TI - Dupuytren's disease. AB - Dupuytren's disease is a benign contractile disorder of the hand. The condition commonly affects older men of Celtic descent. Although fibroproliferation and collagen alteration play a role in its etiology, defining a cause remains elusive. Nonoperative intervention for advanced disease has shown only short-term benefit. Therefore, open fasciectomy has become the mainstay of treatment. Associated morbidity and recurrence have prompted investigation into less invasive techniques, including needle aponeurotomy and enzymatic fasciotomy. Data from phase III studies using injectable collagenase are changing treatment algorithms. Postoperative rehabilitation includes nighttime splinting and immediate active range of motion exercises to facilitate return to function. PMID- 22229924 TI - Interevaluator reliability of a mock paramedic practical examination. AB - INTRODUCTION: Prior to graduation, paramedic students must be assessed for terminal competency and preparedness for national credentialing examinations. Although the procedures for determining competency vary, many academic programs use a practical and/or oral examination, often scored using skill sheets, for evaluating psychomotor skills. However, even with validated testing instruments, the interevaluator reliability of this process is unknown. Objective. We sought to estimate the interevaluator reliability of a subset of paramedic skills as commonly applied in terminal competency testing. METHODS: A mock examinee was videotaped performing staged examinations mimicking adult ventilatory management, oral board, and static and dynamic cardiac stations during which the examinee committed a series of prespecified errors. The videotaped performances were then evaluated by a group of qualified evaluators using standardized skill sheets. Interevaluator variability was measured by standard deviation and range, and reliability was evaluated using Krippendorff's alpha. Correlation between scores and evaluator demographics was assessed by Pearson correlation. RESULTS: Total scores and critical errors varied considerably across all evaluators and stations. The mean (+/- standard deviation) scores were 24.77 (+/-2.37) out of a possible 27 points for the adult ventilatory management station, 11.69 (+/-2.71) out of a possible 15 points for the oral board station, 7.79 (+/-3.05) out of a possible 12 points for the static cardiology station, and 22.08 (+/-1.46) out of a possible 24 points for the dynamic cardiology station. Scores ranged from 18 to 27 for adult ventilatory management, 7 to 15 for the oral board, 2 to 12 for static cardiology, and 19 to 24 for dynamic cardiology. Krippendorff's alpha coefficients were 0.30 for adult ventilatory management, 0.01 for the oral board, 0.10 for static cardiology, and 0.48 for dynamic cardiology. Critical criteria errors were assigned by 10 (38.5%) evaluators for adult ventilatory management, five (19.2%) for the oral board, and nine (34.6%) for dynamic cardiology. Total scores were not correlated with evaluator demographics. CONCLUSIONS: There was high variability and low reliability among qualified evaluators using skill sheets as a scoring tool in the evaluation of a mock terminal competency assessment. Further research is needed to determine the true overall interevaluator reliability of this commonly used approach, as well as the ideal number, training, and characteristics of prospective evaluators. PMID- 22229925 TI - Quorum-sensing non-coding small RNAs use unique pairing regions to differentially control mRNA targets. AB - Quorum sensing is a mechanism of cell-cell communication that bacteria use to control collective behaviours including bioluminescence, biofilm formation and virulence factor production. In the Vibrio harveyi and Vibrio cholerae quorum sensing circuits, multiple non-coding small regulatory RNAs called the quorum regulated small RNAs (Qrr sRNAs) function to establish the global quorum-sensing gene expression pattern by modulating translation of multiple mRNAs encoding quorum-sensing regulatory factors. Here we show that the Qrr sRNAs post transcriptionally activate production of the low cell density master regulator AphA through base pairing to aphA mRNA, and this is crucial for the accumulation of appropriate levels of AphA protein at low cell density. We find that the Qrr sRNAs use unique pairing regions to discriminate between their different targets. Qrr1 is not as effective as Qrr2-5 in activating aphA because Qrr1 lacks one of two required pairing regions. However, Qrr1 is equally effective as the other Qrr sRNAs at controlling targets like luxR and luxO because it harbours all of the required pairing regions for these targets. Sequence comparisons reveal that Vibrionaceae species possessing only qrr1 do not have the aphA gene under Qrr sRNA control. Our findings suggest co-evolving relationships between particular Qrr sRNAs and particular mRNA targets. PMID- 22229926 TI - Mycoplasma hyopneumoniae Surface proteins Mhp385 and Mhp384 bind host cilia and glycosaminoglycans and are endoproteolytically processed by proteases that recognize different cleavage motifs. AB - P97 and P102 paralogues occur as endoproteolytic cleavage fragments on the surface of Mycoplasma hyopneumoniae that bind glycosaminoglycans, plasminogen, and fibronectin and perform essential roles in colonization of ciliated epithelia. We show that the P102 paralogue Mhp384 is efficiently cleaved at an S/T-X-F?X-D/E-like site, creating P60(384) and P50(384). The P97 paralogue Mhp385 is inefficiently cleaved, with tryptic peptides from a 115 kDa protein (P115(385)) and 88 kDa (P88(385)) and 27 kDa (P27(385)) cleavage fragments identified by LC-MS/MS. This is the first time a preprotein belonging to the P97 and P102 paralogue families has been identified by mass spectrometry. The semitryptic peptide (752)IQFELEPISLNV(763) denotes the C-terminus of P88(385) and defines the novel cleavage site (761)L-N-V?A-V-S(766) in Mhp385. P115(385), P88(385), P27(385), P60(384), and P50(384) were shown to reside extracellularly, though it is unknown how the fragments remain attached to the cell surface. Heparin- and cilium-binding sites were identified within P60(384), P50(384), and P88(385). No primary function was attributed to P27(385); however, this molecule contains four tandem R1 repeats with similarity to porcine collagen type VI (alpha3 chain). P97 and P102 paralogue families are adhesins targeted by several proteases with different cleavage efficiencies, and this process generates combinatorial complexity on the surface of M. hyopneumoniae. PMID- 22229927 TI - Re-consideration of lymphadenectomy for stage Ib1 cervical cancer. AB - AIM: Because of less frequent lymph node metastasis and parametrial involvement, patients with stage Ib1 cervical cancer may benefit from a curtailment of surgery. We retrospectively investigated the distribution of lymph node metastasis in stage Ib1 patients. After comparing the data with that of higher stages and sentinel lymph node navigation (SLNN), the appropriate extent of lymphadenectomy (LA) in stage Ib1 disease was newly suggested. METHOD: A total of 303 patients underwent a radical hysterectomy with LA and the region-specific rate of node metastasis was obtained. SLNN was performed for 50 patients using (99m) Tc phytate injection into the cervix and intra-operative detection by a gamma-probe. RESULTS: The rate of node metastasis and the average number of nodes removed, respectively, were: 23/189 (12.2%), 65.2 in stage Ib1; 14/47 (29.8%), 70.1 in stage Ib2; 7/20 (35.0%), 78.2 in stage IIa; and 26/47 (55.3%), 69.1 in stage IIb. Lymph node metastasis in stage Ib1 was prevalent in the obturator (Ob) (9.5%), inter-iliac (Ii) (4.9%), superficial common iliac (Sc) (2.3%), cardinal (Cd) (2.2%) and external iliac (Ei) (1.7%) nodes. In patients with upper stage disease, lymph node metastasis could occur in all lymph nodes. In stage Ib1 patients, the sentinel nodes were assigned only to the Ob, Ii, Sc and Ei nodes, being identical with frequent metastatic sites in stage Ib1 (excluding Cd). CONCLUSION: The extent of LA can be routinely completed with the removal of Ob, Ii, Ei, Sc and Cd nodes, which may provide a higher quality of life, including the reduction of lymphedema by preventing the removal of the inguinal nodes. PMID- 22229928 TI - Social relationships and health: is feeling positive, negative, or both (ambivalent) about your social ties related to telomeres? AB - OBJECTIVES: The quality of one's personal relationships has been linked to morbidity and mortality across different diseases. As a result, it is important to examine more integrative mechanisms that might link relationships across diverse physical health outcomes. In this study, we examine associations between relationships and telomeres that predict general disease risk. These questions are pursued in the context of a more comprehensive model of relationships that highlights the importance of jointly considering positive and negative aspects of social ties. METHOD: One hundred thirty-six individuals from a community sample (ages 48 to 77 years) completed the social relationships index, which allows a determination of relationships that differ in their positive and negative substrates (i.e., ambivalent, supportive, aversive, indifferent). Telomere length was determined from peripheral blood mononuclear cells via quantitative polymerase chain reaction. RESULTS: Participants who had a higher number of ambivalent ties in their social networks evidenced shorter telomeres. These results were independent of other relationship types (e.g., supportive) and standard control variables (e.g., age, health behaviors, and medication use). Gender moderated the links between ambivalent ties and telomere length, with these associations seen primarily in women. Follow-up analyses revealed that the links between ambivalent ties and telomeres were primarily due to friendships, parents, and social acquaintances. CONCLUSION: Consistent with epidemiological findings, these data highlight a novel and integrative biological mechanism by which social ties may affect health across diseases and further suggest the importance of incorporating positivity and negativity in the study of specific relationships and physical health. PMID- 22229929 TI - Preschoolers' everyday conflict at home and diurnal cortisol patterns. AB - OBJECTIVE: Early life family conflict is associated with physical health problems later in life, but little is known about the biological pathways through which conflict at home exerts it deleterious effects on health. The goal of this study was to investigate the associations between naturalistically assessed conflict in everyday family environments and diurnal cortisol in preschool-aged children. DESIGN: Forty-four children aged 3-5 from two-parent families provided six saliva samples per day over 2 days from a Saturday morning through Sunday night. For a full day on either Saturday or Sunday, children wore a child version of the Electronically Activated Recorder, a digital voice recorder that records ambient sounds while participants go about their daily lives. Parents provided reports of child externalizing behaviors as well as daily reports of child conflicts. MAIN OUTCOME MEASURES: Diurnal salivary cortisol over the two weekend days of the study. RESULTS: Greater Electronically Activated Recorder-assessed child conflict at home was associated with children having lower cortisol at wakeup (p < .009) and flatter diurnal cortisol slopes (p < .007). These associations remained significant even after controlling for parent reports of child externalizing behaviors, parent reports of daily child conflicts, and child age and sex. CONCLUSION: These findings indicate that taking into consideration everyday conflicts at home may be key to our understanding of stress-health links in young children. PMID- 22229930 TI - A pilot study of expressive writing intervention among Chinese-speaking breast cancer survivors. AB - OBJECTIVE: Little attention has been focused on Asian American breast cancer survivor's psychological needs. No outcome-based psychosocial interventions have been reported to target at this population. Expressive writing interventions have been previously shown to improve health outcomes among non-Hispanic White breast cancer populations. This pilot study aimed to test the cultural sensitivity, feasibility, and potential health benefits of an expressive writing intervention among Chinese-speaking breast cancer survivors. METHODS: Participants (N = 19) were asked to write about their deepest thoughts and feelings, their coping efforts, and positive thoughts and feelings regarding their experience with breast cancer each week for 3 weeks. Health outcomes were assessed at baseline, 3, and 6 months after the intervention. A Community-Based Participatory Research Approach (CBPR) is used. RESULTS: Expressive writing was associated with medium and large effect sizes (eta(p)2 = 0.066~0.208) in improving multiple health outcomes (quality of life, fatigue, posttraumatic stress, intrusive thoughts, and positive affect) at follow-ups. Participants perceived the study to be valuable. The study yielded high compliance and completion rates. CONCLUSION: Expressive writing is associated with long-term improvement of health outcomes among Chinese breast cancer survivors and has the potential to be utilized as a support strategy for minority cancer survivors. In addition, CBPR is valuable in improving feasibility and cultural sensitivity of the intervention in understudied populations. Future studies employing randomized, controlled trial designs are warranted. PMID- 22229931 TI - He said, she said: work, biopsychosocial, and lifestyle contributions to coronary heart disease risk. AB - OBJECTIVE: To test a model incorporating job characteristics, biopsychosocial, lifestyle, and nonmodifiable factors as they relate to coronary heart disease (CHD). Specifically, job characteristics and nonwork social ties (NWST) were examined as predictors of biopsychosocial health (BPSH), which was, in turn, expected to predict CHD directly and indirectly through influencing lifestyle. We also examined how age and family history of premature heart disease predicted objectively measured CHD risk. Within this model, sex differences were explored. METHOD: A structural equation modeling analysis of data from a cross-sectional sample of 541 employees (317 men and 224 women) taking part in a cross organization workplace wellness program. T tests of sex differences were also conducted. RESULTS: Positive perceptions of job characteristics and NWST predicted positive BPSH. BPSH displayed no direct relationship to CHD risk, but positively predicted a healthier lifestyle. A healthier lifestyle was related to lower levels of CHD risk. Family history, but not age, was also useful in predicting CHD risk. Analyses indicated that men were significantly worse on all objective measures of CHD risk factors, but no other main effect sex differences were found. There were no differences between men and women in the relationships between variables. CONCLUSIONS: Adds to a body of literature indicating the importance of psychological components of the job in determining biopsychosocial health, and the importance of this variable in its impact on lifestyle decisions. The results support continued efforts to guide future interventions on lifestyle for both men and women. PMID- 22229932 TI - Health Psychology special series on health disparities. PMID- 22229933 TI - Race and sexual behavior predict uptake of the human papillomavirus vaccine. AB - OBJECTIVE: To identify predictors of human papillomavirus (HPV) vaccination initiation by girls at high risk for HPV infection. METHOD: Participants were 2,098 girls enrolled in the ongoing Pittsburgh Girls Study, who were between the ages of 12 and 15 years in 2008, and their primary caregivers. The study was conducted in the 2 years after the deployment of the first HPV vaccine approved by the U.S. Food and Drug Administration. Primary caregivers were asked about HPV vaccine uptake. Girls were interviewed about pubertal development and sexually intimate behavior. RESULTS: Approximately 60% of the girls had initiated the HPV vaccine in the past year. Among the hypothesized predictors of initiation, African-American race decreased the likelihood and level of sexually intimate behavior in the previous year increased the likelihood of uptake. Controlling for receipt of public assistance, African-American girls were close to 40% less likely to be vaccinated than European-American girls. CONCLUSION: Racial disparities in use of preventive interventions such as the HPV vaccine exist. Lack of information about public financing of the vaccine, timing of vaccination relative to sexual activity, and perceptions of preventive value may limit uptake among those at highest risk for infection and negative sequelae from infection. Further research to probe knowledge and attitudes toward HPV vaccination and the impact of the media on vaccine initiation and uptake may reveal specific targets of intervention. PMID- 22229934 TI - Hypoglycaemic and hypolipidaemic effects of low GI and medium GL Indian diets in type 2 diabetics for a period of 4 weeks: a prospective study. AB - This prospective study reports significant hypoglycaemic and hypolipidaemic effects in type 2 diabetic subjects who were provided the complete diet plan to be on low glycaemic index (GI) and low-medium glycaemic load (GL) Indian vegetarian snacks and mixed meals for 4 continuous weeks. Five millilitres of fasting blood sample drawn at weekly intervals for 4 weeks were analysed for blood glucose, HbA1c and lipid profile. Four weeks later mean blood glucose level of 173.6 mg% decreased to 137.8 mg%, HbA1c of 8% also decreased to 7.1% which reflected the blood glucose level during the study period and hence correlated well with the fall in blood glucose level. Triglyceride level of 244.5 mg% decreased to 164.7 mg% (p < 0.0001) and total cholesterol of 173.5 mg% decreased to 134.6 mg% (p < 0.0001). High-density lipoprotein cholesterol of 33 mg% increased to 39.8 mg% (p < 0.003), very low density lipoprotein (VLDL) cholesterol of 48.9 mg% decreased to 32.9 mg% (p < 0.0001) and low-density lipoprotein cholesterol of 90.1 mg% decreased to 64.3 (p < 0.009). This significant outcome can be improved further if compliance to low GI and low-to medium GL diet is continued. This may achieve desired glycaemic control and that's limit oxidative stress. PMID- 22229935 TI - Clinical manifestations of cutaneous metastases: a review with special emphasis on cutaneous metastases mimicking keratoacanthoma. AB - Approximately 5% of oncology patients develop cutaneous metastases, with only a small number of these patients (less than 1%) having metastatic skin lesions as the first sign of their visceral cancer. Metastases tend to occur on skin surfaces in the vicinity of the primary tumor. However, any site may be affected by cutaneous metastases. Skin metastases can present with several morphologies including, albeit rarely, keratoacanthoma-like lesions. Keratoacanthoma is a keratinous tumor that morphologically appears as a nodule with a central keratin filled crater. This article reviews the characteristics of oncology patients whose cutaneous metastases mimicked a keratoacanthoma, including illustrations from our patient, a 53-year-old Caucasian man whose metastatic esophageal adenocarcinoma not only presented with a keratoacanthoma-like tumor on his upper lip but also a forehead macule and a scalp nodule. We also report keratoacanthoma like presentations from literature cases of breast cancer, chondrosarcoma, and pulmonary malignancies. The lesions were discovered 3-24 months after diagnosis of visceral cancer and led to the discovery of unsuspected lung cancer in two patients. Most of the patients (60%) died within 2 months of discovery of the keratoacanthoma-like cutaneous metastases. We also reviewed the literature and discuss other morphologies of cutaneous metastases in patients whose primary tumors were in the breast, lung, and esophagus. In addition, we review from the literature other examples of tumors that present as metastatic nodules on the scalp. The possibility of cutaneous metastasis should be entertained and pathologic evaluation should be considered in an oncology patient with underlying visceral malignancy who develops a keratoacanthoma-like lesion. PMID- 22229937 TI - Antioxidant activity of isolated ellagitannins from red raspberries and cloudberries. AB - Ellagitannins from red raspberries (Rubus idaeus) and cloudberries (Rubus chamaemorus) were isolated by using column chromatography and preparative HPLC. The berry phenolic isolates consisted of 80% (cloudberry) and of 60% (raspberry) of ellagitannins, with raspberries also containing anthocyanins. The main ellagitannins of both raspberries and cloudberries were identified by ESI-MS to consist of the dimeric sanguiin H-6 and the trimeric lambertianin C. Monomeric ellagitannins such as casuarictin in raspberries and pedunculagin in cloudberries were also found. The antioxidant activity of the berry phenolic isolate, ellagitannin isolate (mixture), ellagitannin main fraction (dimer and trimer), and ellagic acid was studied in bulk and emulsified methyl linoleate, in human low-density lipoprotein in vitro, and the radical scavenging activity was studied in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. Cloudberry and red raspberry ellagitannins were highly effective as radical scavengers. Berry ellagitannins also showed significant antioxidant activity toward oxidation of both human LDL and methyl linoleate emulsions. However, only weak or moderate antioxidant activity was exhibited by ellagitannins toward oxidation of bulk oil. Thus, ellagitannins contribute significantly to the antioxidant capacity of cloudberries and red raspberries in lipoprotein and lipid emulsion environments, the latter being more relevant for food applications. PMID- 22229940 TI - Hepatitis E--an unexpected problem at home. PMID- 22229941 TI - The elusive 5'-deoxyadenosyl radical in coenzyme-B12-mediated reactions. AB - Vitamin B(12) and its biologically active counterparts possess the only examples of carbon-cobalt bonds in living systems. The role of such motifs as radical reservoirs has potential application in future catalytic and electronic nanodevices. To fully understand radical generation in coenzyme B(12) (dAdoCbl) dependent enzymes, however, major obstacles still need to be overcome. In this work, we have used Car-Parrinello molecular dynamics (CPMD) simulations, in a mixed quantum mechanics/molecular mechanics (QM/MM) framework, to investigate the initial stages of the methylmalonyl-CoA-mutase-catalyzed reaction. We demonstrate that the 5'-deoxyadenosyl radical (dAdo(*)) exists as a distinct entity in this reaction, consistent with the results of extensive experimental and some previous theoretical studies. We report free energy calculations and first-principles trajectories that help understand how B(12) enzymes catalyze coenzyme activation and control highly reactive radical intermediates. PMID- 22229939 TI - Lack of p53 decreases basal oxidative stress levels in the brain through upregulation of thioredoxin-1, biliverdin reductase-A, manganese superoxide dismutase, and nuclear factor kappa-B. AB - AIMS: The basal oxidative and nitrosative stress levels measured in cytosol, mitochondria, and nuclei as well as in the whole homogenate obtained from the brain of wild type (wt) and p53 knockout [p53((-/-))] mice were evaluated. We hypothesized that the loss of p53 could trigger the activation of several protective mechanisms such as those involving thioredoxin-1 (Thio-1), the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system, manganese superoxide dismutase (MnSOD), the IkB kinase type beta (IKKbeta)/nuclear factor kappa-B (NF kB), and the nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf-2). RESULTS: A decrease of protein carbonyls, protein-bound 4-hydroxy-2-nonenal (HNE), and 3-nitrotyrosine (3-NT) was observed in the brain from p53((-/-)) mice compared with wt. Furthermore, we observed a significant increase of the expression levels of Thio-1, BVR-A, MnSOD, IKKbeta, and NF-kB. Conversely a significant decrease of Nrf-2 protein levels was observed in the nuclear fraction isolated from p53((-/-)) mice. No changes were found for HO-1. INNOVATION: This is the first study of basal oxidative/nitrosative stress in in vivo conditions of brain obtained from p53((-/-)) mice. New insights into the role of p53 in oxidative stress have been gained. CONCLUSION: We demonstrated, for the first time, that the lack of p53 reduces basal oxidative stress levels in mice brain. Due to the pivotal role that p53 plays during cellular stress response our results provide new insights into novel therapeutic strategies to modulate protein oxidation and lipid peroxidation having p53 as a target. The implications of this work are profound, particularly for neurodegenerative disorders. PMID- 22229943 TI - Prognostic factors for self-rated function and perceived health in patient living at home three months after a hip fracture. AB - PURPOSE: To explore the relationship between prefracture sociodemographic and health characteristics, basic activities of daily living, instrumental activities of daily living and perceived health 3 months after a hip fracture aged 65 or older. METHODS: Age, sex, living alone or not, use of walking aids and whether they had experienced another fall during the previous 6 months, were recorded in hospital and at a three-month follow-up. A total of 277 patients were included. The Barthel Index, the Nottingham Extended ADL Index, the Short Form-12 questionnaire, and the Mini Mental State Examination were used. RESULTS: Prefracture use of a walking aid outdoors was a predictor of postfracture dependency in basic activities of daily living: odds ratio (OR) 2.0, 95% confidence intervals (CI 1.1-3.6), reduced score in instrumental activities of daily living (OR 1.8; 95% CI 1.0-3.2) and reduced perceived physical health (p = 0.04). Prefracture instrumental activity of daily living was a predictor for dependency in basic activities of daily living (OR 3.3; 95% CI 1.7-6.3). Cognitive dysfunction was a risk factor for dependency in basic activities of daily living (OR 0.1; 95% CI 0.01-0.7). CONCLUSIONS: Prefracture use of outdoor walking aids, perceived physical health, cognitive function, instrumental activity of daily living and female gender were all predictors explaining the three-month outcomes for basic activities of daily living and instrumental activity of daily living. PMID- 22229944 TI - Alloreactivity: an old puzzle revisited. AB - Alloreactivity, defined as a strong primary T cell response against allelic variants of major histocompatibility complex (MHC) molecules in the species, has been a long-standing puzzle in immunology with some of its details remaining unclear up to now. Here I shall provide a historical overview of how our understanding of alloreactivity has evolved and propose an interpretation that considers alloreactivity to be a mixture of four mechanistically distinct prototypes of T cell response, namely, self-restricted peptide specific, allorestricted peptide specific, alloreactive peptide dependent and alloreactive peptide independent. The relative contribution of each prototype to a given alloresponse is dependent on the extent of disparity (i.e. the number and nature of amino acid substitutions in the docking surface for T cell receptor) between the MHC molecule that the T cell recognizes as self and the stimulating MHC molecule. PMID- 22229945 TI - Serotypes, virulence genes, and intimin types of shiga toxin-producing Escherichia coli and enteropathogenic Escherichia coli isolated from mastitic milk relevant to human health in Egypt. AB - Some foodborne pathogens can cause mastitis, in which the organism is directly excreted into milk. Therefore, we undertook the steps to determine the prevalence and molecular characteristics of Shiga toxin-producing Escherichia coli (STEC) isolates from bovine mastitic milk in Egypt. Forty milk samples from dairy cattle showing mastitis were collected and examined for the presence of E. coli. Following enrichment and plating on selective agar, confirmation of the isolates was based on biochemical tests and the isolates were determined at the species level using cytochrome oxidase, triple sugar iron agar, urea, and indole tests as putatively E. coli. About 77.4% of the isolates belonged to four different O serogroups (O26, O86, O111, and O127). The multiplex polymerase chain reaction (PCR) found that the seven isolates revealed positive amplification of the Eagg gene from the extracted DNA of the E. coli isolates in an incidence of 100%. Also, the selected isolates were subjected to a simple PCR for the detection of 12 of the most important E. coli genes associated with virulence. Those genes detected were stx1, stx2, hylA, Flic(h7), stb, F41, K99, sta, F17, LT-I, LT-II, and eaeA. A total of seven E. coli isolates that were non-O157 isolates were investigated. Among the seven isolates, none was stx positive, and all seven lacked F41, K99, LT-I, LT-II, and Flic(h7). Of these seven isolates, three (42.85%) were enterohemorrhagic E. coli hlyA positive and two (28.57%) were eaeA positive. STEC isolates were not found in bovine mastitic milk in Egypt. Isolates from mastitic milk were potentially pathogenic for human in that they belonged to serogroups associated with diarrhea and hemolytic-uremic syndrome, and some of them were hylA, stb, sta, F17, and eaeA positive. PMID- 22229946 TI - Does hyperoxia selection cause adaptive alterations of mitochondrial electron transport chain activity leading to a reduction of superoxide production? AB - Prolonged hyperoxia exposure generates excessive reactive oxygen species (ROS) and potentially leads to oxidative injury in every organ. We have previously generated Drosophila melanogaster flies that tolerate extreme oxidative stress (90%-95% O2), a lethal condition to naive flies, through a long-term laboratory selection. We found that hyperoxia-selected (S(O2)A) flies had a significantly longer lifespan in hyperoxia and paraquat-induced oxidative stress. Prolonged hyperoxia exposure induced a significant ROS accumulation and an increased expression of oxidative stress markers, including lipid peroxidation and protein carbonyl contents in control flies, but not in S(O2)A flies. Enzymatic assays revealed that antioxidant enzyme activity in S(O2)A flies was similar to that in control flies. However, in isolated mitochondria and using electron paramagnetic resonance, we observed that S(O2)A flies displayed a decreased superoxide yield during state 3 respiration as compared to control flies and that the activity of electron transport chain complex I and III was also inhibited in S(O2)A flies. Our observations lead to the hypothesis that decreased complex activity results in a decreased ROS production, which might be a major potential adaptive mechanism of hyperoxia tolerance. PMID- 22229948 TI - Visually guided sequential pulmonary vein isolation: insights into techniques and predictors of acute success. AB - INTRODUCTION: Pulmonary vein isolation (PVI) is a challenging procedure most often requiring sophisticated technical aids such as electroanatomical mapping, double transseptal access, and the use of a circular mapping catheter. We sought to develop a PVI strategy solely based on visual guidance with a single ablation device as well as a single transseptal puncture using the endoscopic ablation system (EAS). METHODS AND RESULTS: In 35 patients with drug-refractory atrial fibrillation (18 male, mean age: 62 +/- 9 years) ablation was performed. PVI was achieved in 96 of 137 PVs (70%) purely by visually guided circular ablation. Predictors of acute isolation were the degree of PV occlusion by EAS as well as the number of catheter repositionings but not total ablation energy or the number of laser applications. Conduction gaps were detected at sites with suboptimal occlusion as well as esophageal temperature elevations. Further EAS ablation resulted in a 98% acute isolation rate. Mean procedure and fluoroscopy times were 154 +/- 38 minutes and 16 +/- 6 minutes, respectively. Between the first and last 12 cases, a reduction in procedure times (175 +/- 48 minutes vs 138 +/- 26 minutes; P = 0.05) was observed. One pericardial tamponade and 1 right-sided phrenic nerve palsy occurred. During a median follow-up of 266 days (q-q3: 218 389), 27 of 35 patients (77%) remained free of any tachyarrhythmia recurrence off antiarrhythmic drugs. CONCLUSIONS: Sequential PVI based solely on endoscopic visual information with a single device and a single transseptal puncture is feasible. Optimal PV occlusion and few controlled repositionings facilitate PVI. PMID- 22229949 TI - A new reagent for direct difluoromethylation. AB - Molecular scaffolds containing alkylfluorine substituents are desired in many areas of chemical research from materials to pharmaceuticals. Herein, we report the invention of a new reagent (Zn(SO(2)CF(2)H)(2), DFMS) for the innate difluoromethylation of organic substrates via a radical process. This mild, operationally simple, chemoselective, and scalable difluoromethylation method is compatible with a range of nitrogen-containing heteroarene substrates of varying complexity as well as select classes of conjugated pi-systems and thiols. Regiochemical comparisons suggest that the CF(2)H radical generated from the new reagent possesses nucleophilic character. PMID- 22229950 TI - CsRAV1 induces sylleptic branching in hybrid poplar. AB - * Sylleptic branching in trees may increase significantly branch number, leaf area and the general growth of the tree, particularly in its early years. Although this is a very important trait, so far little is known about the genes that control this process. * This article characterizes the Castanea sativa RAV1 gene, homologous to Arabidopsis TEM genes, by analyzing its circadian behavior and examining its winter expression in chestnut stems and buds. Transgenic hybrid poplars over-expressing CsRAV1 or showing RNA interference down-regulated PtaRAV1 and PtaRAV2 expression were produced and analyzed. * Over-expression of the CsRAV1 gene induces the early formation of sylleptic branches in hybrid poplar plantlets during the same growing season in which the lateral buds form. Only minor growth differences and no changes in wood anatomy are produced. * The possibility of generating trees with a greater biomass by manipulating the CsRAV1 gene makes CsRAV1 transgenic plants promising candidates for bioenergy production. PMID- 22229951 TI - Comparison of Skindex-29, Dermatology Life Quality Index, Psoriasis Disability Index and Medical Outcome Study Short Form 36 in patients with mild to severe psoriasis. AB - BACKGROUND: Severity assessment of patients with psoriasis is a critical issue. Classical clinical assessment has recently been combined with quality of life (QoL) scores, but several instruments are used. Moreover, studies have focused on patients with moderate to severe psoriasis. OBJECTIVES: To compare the characteristics of QoL instruments in patients with the full range of psoriasis severity attending dermatology clinics. METHODS: Observational, prospective, multicentre study. Patients completed Skindex-29 (anchor) and a second instrument randomly selected from Dermatology Life Quality Index (DLQI), Psoriasis Disability Index (PDI) and Medical Outcome Study Short Form 36 (SF-36). RESULTS: Demographic data, Psoriasis Area and Severity Index and affected body surface area were not different between the three groups. Skindex-29 showed a weak but significant correlation with clinical severity; only PDI showed similar correlation. PDI, DLQI and SF-36 showed a substantial floor effect in patients with mild to severe psoriasis. Skindex-29 showed strong correlations with the other three QoL instruments. SF-36 was more sensitive than the other instruments in detecting worse QoL in male patients. CONCLUSIONS: Skindex-29 has better sensitivity to clinical severity with minimal floor effect, and covers the main domains explored by the other three QoL instruments in patients with mild to severe psoriasis. PMID- 22229953 TI - Risk assessment of engineered nanomaterials: a review of available data and approaches from a regulatory perspective. AB - It has been largely recognised that substantial limitations and uncertainties make the conventional risk assessment (RA) of chemicals unfeasible to apply to engineered nanomaterials (ENMs) today, which leaves the regulators with little support in the near term. The aim of this paper is to discuss the state of the art in the area of the RA of nanomaterials, focusing on the available data and approaches. There is a paucity of reliable information in the online safety databases and the literature is dominated by (eco)toxicity studies, while the nano-exposure research lags behind. Most of the reviewed nano-RA approaches are designed to serve as preliminary risk screening and/or research prioritisation tools and are not intended to support regulatory decision making. In this context, we recommend to further study the possibilities to apply complementary/alternative tools for near-term RA of ENMs in order to facilitate their timely regulation, using the data that are currently available in the literature. PMID- 22229954 TI - Paramedic King Laryngeal Tube airway insertion versus endotracheal intubation in simulated pediatric respiratory arrest. AB - INTRODUCTION: Pediatric endotracheal intubation (ETI) is difficult and can have serious adverse events when performed by paramedics in the prehospital setting. Paramedics may use the King Laryngeal Tube airway (KLT) in difficult adult airways, but only limited data describe their application in pediatric patients. OBJECTIVE: To compare paramedic airway insertion speed and complications between KLT and ETI in a simulated model of pediatric respiratory arrest. METHODS: This prospective, randomized trial included paramedics and senior paramedic students with limited prior KLT experience. We provided brief training on pediatric KLT insertion. Using a random allocation protocol, participants performed both ETI and KLT on a pediatric mannequin (6-month old size) in simulated respiratory arrest. The primary outcomes were 1) elapsed time to successful airway placement (seconds), and 2) proper airway positioning. We compared airway insertion performance between KLT and ETI using the Wilcoxon signed-ranks test. Subjects also indicated their preferred airway device. RESULTS: The 25 subjects included 19 paramedics and 6 senior paramedic students. Two subjects had prior adult KLT experience. Airway insertion time was not statistically different between the KLT (median 27 secs) and ETI (median 31 secs) (p = 0.08). Esophageal intubation occurred in 2 of 25 (8%) ETI. Airway leak occurred in 3 of 25 (12%) KLT, but ventilation remained satisfactory. Eighty-four percent of the subjects preferred the KLT over ETI. CONCLUSIONS: Paramedics and paramedic students demonstrated similar airway insertion performance between KLT and ETI in simulated, pediatric respiratory arrest. Most subjects preferred KLT. KLT may provide a viable alternative to ETI in prehospital pediatric airway management. PMID- 22229955 TI - Hypopyon in the context of tuberculous uveitis. AB - An 86-year-old man presented with blurred vision and pain in the left eye. A slitlamp examination revealed anterior uveitis with hypopyon. During the investigation of the uveitis, the diagnosis of tuberculosis was confirmed. Hypopyon is a rare manifestation of uveitis due to tuberculosis. PMID- 22229956 TI - Rapidly grown congenital fetal immature gastric teratoma causing severe neonatal respiratory distress. AB - A pregnant woman in the mid-third trimester developed complications with enlarged fetal abdomen and polyhydramnios. Prenatal ultrasound visualized dilated bowel, intraperitoneal calcifications, ascites, hydroceles and polyhydramnios, giving the impression of meconium peritonitis. The fetal abdomen continued to increased in size, and maternal dyspnea due to polyhydramnios was aggravated. She underwent a cesarean section at 36 + 1 weeks' gestation. The delivery was followed by severe neonatal respiratory distress due to the huge mass in the abdomen. The tumor was successfully removed by emergency surgery and diagnosed as immature gastric teratoma. No other associated anomaly was found. The infant made a good progress after the operation. PMID- 22229957 TI - Serum vitamin B12 and folate levels in patients with non-alcoholic fatty liver disease. AB - The aim of the study was the evaluation of serum vitamin B12 and folate levels in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) and their association with the disease severity. Thirty patients with biopsy-proven NAFLD and 24 healthy controls matched for gender, age, body mass index and waist circumference were recruited. Blood samples for vitamin B12, folate, insulin and standard biochemical tests were obtained after overnight fasting. Homeostatic model of assessment-insulin resistance was calculated. There was no difference in serum vitamin B12 and folate levels between groups. Neither vitamin B12 nor folate levels were significantly different within any histological category, including steatosis grade, fibrosis stage, lobular inflammation, portal inflammation and ballooning. In conclusion, similar vitamin B12 and folate levels were observed in non-alcoholic steatohepatitis and non-alcoholic fatty liver patients, and controls. Furthermore, vitamin B12 and folate levels were not associated with either insulin resistance or the severity of liver disease. PMID- 22229960 TI - Discrimination against South African adolescents orphaned by AIDS. AB - This article describes the discrimination against adolescents orphaned by AIDS. A qualitative phenomenological approach using reflective diaries was used to extract how this population is discriminated on. Fifteen adolescents ages 14 to 18 living in an urban area in South Africa participated in the study. Data were collected as part of a larger study in which a peer-based mental health intervention was designed for use with adolescents orphaned by AIDS. Colaizzi's seven stages were used to analyze the data from the reflective diaries. Analysis revealed that adolescents orphaned by AIDS experienced physical, social, and institutional expressions of stigma leading to discrimination. Adolescents were discriminated on by peers, caregivers, and teachers. The results of this study show that adolescents orphaned by AIDS face discrimination; further studies on the topic with a larger sample are needed to verify these findings. PMID- 22229958 TI - Delayed transanal repair of persistent coloanal anastomotic leak in diverted patients after resection for rectal cancer. AB - AIM: Anastomotic leakage is a feared complication of colorectal surgery and can be devastating in low pelvic anastomosis. With the advent of nonoperative treatments for leakage, the question of management of persistent low colorectal and coloanal anastomosis arises. A review of patients who have undergone transanal repair of anastomotic leakage is presented. METHOD: A review of all anastomoses performed in the Division of Colorectal surgery at two institutions, from January 2000 to June 2008, was performed. Anastomotic leakage was defined as the finding at reoperation of a dehiscence, or radiographic findings of extravasation from the anastomosis, or the identification of intra-abdominal abscess formation at the site of the anastomosis, enterocutaneous fistula or rectovaginal fistula. Patients who underwent transanal repair of the leakage were identified. RESULTS: There were 663 low anterior resections performed during the study period. Of these, 36 experienced leakage of a low colorectal or coloanal anastomosis. Of these 36 patients, five underwent transanal repair of the anastomotic leak. All had had a low anterior resection for rectal cancer (coloanal=4; low colorectal anastomosis=1). Four had had prior chemoradiation and ileostomy defunctioning at the initial operation. The fifth had an ileostomy created to treat a leak. Six transanal repairs were performed, including endorectal advancement flap (n=3), dermal flap (n=1), direct suture repair (n=1) and debridement of an infected cavity (n=1). At the time of the present assessment, four patients had undergone reversal of ileostomy after radiographic evidence of complete healing and the fifth patient has a persistent leak. CONCLUSION: Transanal repair of a persistent low colorectal or coloanal anastomotic leakage is feasible in selected cases, even when chemoradiation has been performed. PMID- 22229961 TI - Disrupted by disaster: shared experiences of student registered nurse anesthetists affected by hurricane Katrina. AB - The purpose of this focused ethnography was to describe the shared experiences of student registered nurse anesthetists (SRNAs) whose senior year of education and training was disrupted by Hurricane Katrina, as well as to determine the storm's psychosocial impact on them. A convenience sample of 10 former SRNAs participated in focus groups that were audiorecorded, transcribed, and qualitatively analyzed. Three major themes emerged from the study: Seriousness of Urgency, Managing Uncertainty, and Stability Equaled Relief. The themes represented how the SRNAs appraised and coped with the stressful events surrounding Hurricane Katrina. The psychosocial impact of Hurricane Katrina on the SRNAs resulted mainly in temporary increased alcohol consumption and short-term anxiety. One person started smoking. The results of this study should serve as a guide to formulate policies regarding the education of SRNAs during and immediately after a disaster and to provide a framework for future disaster studies regarding SRNAs. PMID- 22229962 TI - Chronic pain in older adults. AB - Despite the sophisticated pharmaceutical agents and technologies available today, many people, including older adults, continue to experience chronic pain. Inadequately treated chronic pain can seriously affect one's quality of life. Health care providers are only beginning to understand the structural and functional changes that occur in older adults with chronic pain, but recent research suggests that nurses and other health professionals need to become aware of the unique needs of older adults who live with chronic pain. When health professionals lack specific knowledge of pain management in older adults, patients may suffer needlessly. PMID- 22229963 TI - Now take a deep breath: inhaled loxapine for the treatment of acute agitation. AB - Acute agitation in patients with schizophrenia or bipolar disorder is an important clinical management problem. Liquid concentrates, orally disintegrating tablets, and/or intramuscular formulations of several second-generation atypical antipsychotic drugs are available for treating acute agitation. Loxapine is an older first-generation antipsychotic drug that is approved for the treatment of schizophrenia. Staccato((r)) loxapine is an investigational device system using a loxapine-coated heat source to administer loxapine by inhalation. Three multicenter, randomized, double-blind, placebo-controlled efficacy and safety studies of Staccato loxapine have been conducted in patients with acute agitation associated with schizophrenia or bipolar disorder. These studies found that inhaled loxapine was rapidly effective and generally well tolerated, although there are potential concerns about adverse pulmonary effects. PMID- 22229964 TI - Rootstock-regulated gene expression patterns associated with fire blight resistance in apple. AB - BACKGROUND: Desirable apple varieties are clonally propagated by grafting vegetative scions onto rootstocks. Rootstocks influence many phenotypic traits of the scion, including resistance to pathogens such as Erwinia amylovora, which causes fire blight, the most serious bacterial disease of apple. The purpose of the present study was to quantify rootstock-mediated differences in scion fire blight susceptibility and to identify transcripts in the scion whose expression levels correlated with this response. RESULTS: Rootstock influence on scion fire blight resistance was quantified by inoculating three-year old, orchard-grown apple trees, consisting of 'Gala' scions grafted to a range of rootstocks, with E. amylovora. Disease severity was measured by the extent of shoot necrosis over time. 'Gala' scions grafted to G.30 or MM.111 rootstocks showed the lowest rates of necrosis, while 'Gala' on M.27 and B.9 showed the highest rates of necrosis. 'Gala' scions on M.7, S.4 or M.9F56 had intermediate necrosis rates. Using an apple DNA microarray representing 55,230 unique transcripts, gene expression patterns were compared in healthy, un-inoculated, greenhouse-grown 'Gala' scions on the same series of rootstocks. We identified 690 transcripts whose steady state expression levels correlated with the degree of fire blight susceptibility of the scion/rootstock combinations. Transcripts known to be differentially expressed during E. amylovora infection were disproportionately represented among these transcripts. A second-generation apple microarray representing 26,000 transcripts was developed and was used to test these correlations in an orchard grown population of trees segregating for fire blight resistance. Of the 690 transcripts originally identified using the first-generation array, 39 had expression levels that correlated with fire blight resistance in the breeding population. CONCLUSIONS: Rootstocks had significant effects on the fire blight susceptibility of 'Gala' scions, and rootstock-regulated gene expression patterns could be correlated with differences in susceptibility. The results suggest a relationship between rootstock-regulated fire blight susceptibility and sorbitol dehydrogenase, phenylpropanoid metabolism, protein processing in the endoplasmic reticulum, and endocytosis, among others. This study illustrates the utility of our rootstock-regulated gene expression data sets for candidate trait-associated gene data mining. PMID- 22229965 TI - Primary health care staff's perceptions of childhood tuberculosis: a qualitative study from Tanzania. AB - BACKGROUND: Diagnosing tuberculosis in children remains a great challenge in developing countries. Health staff working in the front line of the health service delivery system has a major responsibility for timely identification and referral of suspected cases of childhood tuberculosis. This study explored primary health care staff's perception, challenges and needs pertaining to the identification of children with tuberculosis in Muheza district in Tanzania. METHODS: We conducted a qualitative study that included 13 semi-structured interviews and 3 focus group discussions with a total of 29 health staff purposively sampled from primary health care facilities. Analysis was performed in accordance with the principles of a phenomenological analysis. RESULTS: Primary health care staff perceived childhood tuberculosis to be uncommon in the society and tuberculosis was rarely considered as a likely differential diagnosis. Long duration and severe signs of disease together with known exposure to tuberculosis were decisive for the staff to suspect tuberculosis in children and refer them to hospital. None of the staff felt equipped to identify cases of childhood tuberculosis and they experienced lack of knowledge, applicable tools and guidelines as the main challenges. They expressed the need for more training, supervision and referral feedback to improving case identification. CONCLUSIONS: Inadequate awareness of the burden of childhood tuberculosis, limited knowledge of the wide spectrum of clinical presentation and lack of clinical decision support strategies is detrimental to the health staff's central responsibility of suspecting and referring children with tuberculosis especially in the early disease stages. Activities to improve case identification should focus on skills required by primary health care staff to fulfil their responsibility and reflect primary health care level capacities and challenges. PMID- 22229966 TI - Prevalence of colonic neoplasia and advanced lesions in the normal population: a prospective population-based colonoscopy study. AB - OBJECTIVE: There are few prospective studies of the prevalence of colonic neoplasia in the normal population. In order to properly evaluate screening protocols for colorectal cancer in risk groups (e.g., older subjects or those with a family history), it is essential to know the prevalence of adenomas and cancer in the normal population. METHODS: A prospective population-based colonoscopy study on 745 individuals born in Sweden aged 19-70 years was conducted (mean age 51.1 years). All polyps seen were retrieved and examined. RESULTS: Out of the 745 individuals 27% had polyps, regardless of kind. Adenomas were found in 10% of the individuals and finding of adenomas was positively correlated to higher age. Men had adenomas in 15% and women in 6% of the cases. Women had a right-sided dominance of adenomas. Hyperplastic polyps were seen in 21% of the individuals. The presence of hyperplastic polyps was significantly positively correlated to the presence of adenomas. Advanced adenomas were seen in 2.8% of the study participants, but no cancers were detected. CONCLUSION: One in 10 healthy subjects had an adenoma but advanced adenomas were uncommon. Men and women have a different adenoma prevalence and localization. The results provide baseline European data for evaluating colonoscopy screening-protocols for colorectal cancer risk groups, and the findings may have implications for colon cancer screening in the normal, otherwise-healthy population. PMID- 22229967 TI - Association studies of gene polymorphisms in toll-like receptors 2 and 4 in Croatian patients with acute myocardial infarction. AB - The aim of the study was to assess the frequency of SNP896A/G in the Toll-like receptor (TLR) 4 gene and SNP1350T/C in the TLR2 gene in patients with acute myocardial infarction (AMI) and to analyse the association of these SNPs with risk factors for atherosclerosis and clinical aspects of AMI in a sample of the Croatian population. We included 240 participants in the study: 120 AMI patients and 120 sex- and age-matched healthy blood donor controls. The SNP1350T/C variant in the TLR2 gene showed a lower frequency in the AMI patient group than in the control group (P = 0.033). The frequency of SNP896A/G variants in the TLR4 gene between the patients and the controls did not differ (P = 0.286). Significantly, fewer people had SNP1350T/C in the TLR2 gene (P = 0.003) among the participants with arterial hypertension than those without it. The frequency of SNP896A/G in TLR4 was the same in hypertensive patients compared with normotensive subjects (P = 0.088). SNP1350T/C in TLR2 was less frequent in the AMI patients and in those with hypertension. Thus, SNP1350T/C in TLR2 might play a protective role against AMI and arterial hypertension. The frequency of SNP896A/G in the TLR4 gene was not associated with AMI and arterial hypertension. Other risk factors for atherosclerosis and clinical aspects of myocardial infarction were not associated with the genotype distribution of the examined genes. PMID- 22229968 TI - Alkyne-functionalized ruthenium nanoparticles: ruthenium-vinylidene bonds at the metal-ligand interface. AB - Stable ruthenium nanoparticles were prepared by the self-assembly of 1-dodecyne onto the "bare" Ru colloid surface. The formation of a Ru-vinylidene (Ru?C?CH-R) interfacial bonding linkage was confirmed by the specific reactivity of the nanoparticles with imine derivatives to form a heterocyclic complex at the metal ligand interface, as manifested in (1)H and (13)C NMR, photoluminescence, and electrochemical measurements in which a ferrocenyl imine was used as the labeling probe. Notably, the resulting nanoparticles could also undergo olefin metathesis reactions with vinyl-terminated molecules, as exemplified by the functionalization of the nanoparticles with 1-vinylpyrene. In sharp contrast, no reactvity was observed with 1-dodecynide-stabilized ruthenium nanoparticles with either imine or vinyl derivatives, indicating that these (deprotonated) nanoparticles were stabilized instead by the formation of a Ru-C= dpi bond at the metal-ligand interface. PMID- 22229969 TI - Effects of inhaled nitric oxide on hemostasis in healthy adults treated with heparin: a randomized, controlled, blinded crossover study. AB - BACKGROUND: Effects of nitric oxide (NO) on hemostasis have been studied in various investigational settings, but data regarding inhaled NO on bleeding and platelet function are conflicting. It is not known if inhaled NO has an effect when administered with drugs that influence hemostasis. This trial evaluated effects of inhaled NO on hemostasis in the presence of heparin using aspirin as a positive control. PATIENTS/METHODS: Twelve healthy adult males were enrolled in a single-center, randomized, single-blind, four-way crossover trial. Subjects received 80 ppm NO or medical air (placebo) inhalation for 30 min with simultaneous injection of placebo or heparin. Aspirin capsules were used as a positive control. Parameters of hemostasis were measured before treatment and at post-treatment intervals. RESULTS: Activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased only in groups that received heparin. Areas under the curve for ACT in heparin groups receiving inhaled NO were judged to be equivalent to those receiving medical air for both 0- to 4-h (ratio: 1.00; 90% CI, 0.90-1.11) and 0- to 24-h time intervals (ratio: 1.01; 90% CI, 0.92-1.12). Changes in bleeding time and platelet aggregation were observed only in aspirin groups. No clinically significant changes in hemoglobin, red blood cell counts or haematocrit were observed in any group. CONCLUSIONS: Inhaled NO, when administered with heparin, exhibited no significant additive effects on ACT, PT, aPTT, bleeding time or platelet aggregation. PMID- 22229970 TI - The use of an antibody drug conjugate, glembatumumab vedotin (CDX-011), for the treatment of breast cancer. AB - INTRODUCTION: Breast cancer (BC) is the most common malignancy in women in the USA. Despite the multi-modality treatments that are currently available, advanced BC has a persistent and unacceptable mortality rate. The need for new therapeutic strategies is extremely high. Experimental approaches with targeted therapies such as antibody drug conjugates provide hope for future treatment possibilities. AREAS COVERED: The development status and the possible role of antibody-mediated cytotoxic therapy are discussed in the setting of advanced BC. An overview of, mechanism of action, preclinical and Phase I/II results of glembatumumab vedotin (CDX-011) are discussed. EXPERT OPINION: The evidence that the glycoprotein NBM (GPNMB) target is a relevant target in BC, along with data showing that CDX-011 is safe and active in patients with advanced BC, provide a strong rationale to continue to explore this drug in patients with GPNMB-expressing breast tumors. PMID- 22229971 TI - Biology and pathogenesis of Acanthamoeba. AB - Acanthamoeba is a free-living protist pathogen, capable of causing a blinding keratitis and fatal granulomatous encephalitis. The factors that contribute to Acanthamoeba infections include parasite biology, genetic diversity, environmental spread and host susceptibility, and are highlighted together with potential therapeutic and preventative measures. The use of Acanthamoeba in the study of cellular differentiation mechanisms, motility and phagocytosis, bacterial pathogenesis and evolutionary processes makes it an attractive model organism. There is a significant emphasis on Acanthamoeba as a Trojan horse of other microbes including viral, bacterial, protists and yeast pathogens. PMID- 22229973 TI - Factor VIII/von Willebrand factor concentrate therapy for ventricular assist device-associated acquired von Willebrand disease. AB - BACKGROUND: Acquired von Willebrand disease (aVWD) can lead to a propensity to bleed, and many different modalities have been used to treat this condition. The efficacy of these agents in patients with aVWD secondary to cardiac assist devices is not fully understood. STUDY DESIGN AND METHODS: A case is reported of a patient with two risk factors for aVWD, multiple myeloma and ventricular assist device (VAD), who was successfully treated with von Willebrand factor (VWF)/Factor VIII concentrate (Humate-P, CSL Behring) during the bridge to VAD replacement. RESULTS: Although continued absence of high-molecular-weight VWF persisted after VWF replacement with Humate-P, the patient's VWF antigen and activity increased and clinical hemostasis was achieved. The VAD clotted on a few occasions, despite a continuous heparin infusion; however, these events were resolved with temporarily holding the Humate-P. A VAD exchange was performed and the patient was successfully bridged to heart transplant. CONCLUSION: The treatment of VAD-associated aVWD may be augmented with Humate-P, and successful treatment can allow a bridge to heart transplantation. However, careful monitoring for thrombosis in the VAD circuit must be undertaken. PMID- 22229974 TI - Treatment of severe hidradenitis suppurativa with infliximab in combination with surgical interventions. PMID- 22229972 TI - Mitral isthmus ablation with and without temporary spot occlusion of the coronary sinus: a randomized clinical comparison of acute outcomes. AB - OBJECTIVE: To evaluate the safety and outcomes of mitral isthmus (MI) linear ablation with temporary spot occlusion of the coronary sinus (CS). BACKGROUND: CS blood flow cools local tissue precluding transmurality and bidirectional block across MI lesion. METHODS: In a randomized, controlled trial (CS-occlusion = 20, Control = 22), MI ablation was performed during continuous CS pacing to monitor the moment of block. CS was occluded at the ablation site using 1 cm spherical balloon, Swan-Ganz catheter with angiographic confirmation. Ablation was started at posterior mitral annulus and continued up to left inferior pulmonary vein (LIPV) ostium using an irrigated-tip catheter. If block was achieved, balloon was deflated and linear block confirmed. If not, additional ablation was performed epicardially (power <=25 W). Ablation was abandoned after ~30 minutes, if block was not achieved. RESULTS: CS occlusion (mean duration -27 +/- 9 minutes) was achieved in all cases. Complete MI block was achieved in 13/20 (65%) and 15/22 (68%) patients in the CS-occlusion and control arms, respectively, P = 0.76. Block was achieved with significantly small number (0.5 +/- 0.8 vs 1.9 +/- 1.1, P = 0.0008) and duration (1.2 +/- 1.7 vs 4.2 +/- 3.5 minutes, P = 0.009) of epicardial radiofrequency (RF) applications and significantly lower amount of epicardial energy (1.3 +/- 2.4 vs 6.3 +/- 5.7 kJ, P = 0.006) in the CS-occlusion versus control arm, respectively. There was no difference in total RF (22 +/- 9 vs 23 +/- 11 minutes, P = 0.76), procedural (36 +/- 16 vs 39 +/- 20 minutes, P = 0.57), and fluoroscopic (13 +/- 7 vs 15 +/- 10 minutes, P = 0.46) durations for MI ablation between the 2 arms. Clinically uneventful CS dissection occurred in 1 patient CONCLUSIONS: Temporary spot occlusion of CS is safe and significantly reduces the requirement of epicardial ablation to achieve MI block. It does not improve overall procedural success rate and procedural duration. Tissue cooling by CS blood flow is just one of the several challenges in MI ablation. PMID- 22230006 TI - Linking the evidence: intermediate outcomes in medical test assessments. AB - OBJECTIVES: The aim of this study is to review how health technology assessments (HTA) of medical tests incorporate intermediate outcomes in conclusions about the effectiveness of tests on improving health outcomes. METHODS: Systematic review of English-language test assessments in the HTA database from January 2005 to February 2010, supplemented by a search of the Web sites of International Network of Agencies for Health Technology Assessment (INAHTA) members. RESULTS: A total of 149 HTAs from eight countries were assessed. Half evaluated tests for screening or diagnosis, a third for disease classification (including staging, prognosis, monitoring), and a fifth for multiple purposes. In seventy-one HTAs (48 percent) only diagnostic accuracy was reported, while in seventeen (11 percent) evidence of health outcomes was reported in addition to accuracy. Intermediate outcomes, mainly the impact of test results on patient management, were considered in sixty-one HTAs (41 percent). Of these, forty-seven identified randomized trials or observational studies reporting intermediate outcomes. The validity of these intermediate outcomes as a surrogate for health outcomes was not consistently discussed; nor was the quality appraisal of this evidence. Clear conclusions about whether the test was effective were included in approximately 60 percent of HTAs. CONCLUSIONS: Intermediate outcomes are frequently assessed in medical test HTAs, but interpretation of this evidence is inconsistently reported. We recommend that reviewers explain the rationale for using intermediate outcomes, identify the assumptions required to link intermediate outcomes and patient benefits and harms, and assess the quality of included studies. PMID- 22230007 TI - Tennis racket cells in severe dyskaryosis in hyperchromatic crowded cell groups of SurePath(TM) cervical samples. PMID- 22230008 TI - Bridging the gap between PCR detection of Mycobacterium tuberculosis complex and tuberculosis diagnosis. AB - The growing demand for rapid diagnosis of tuberculosis (TB) has led to the incorporation of nucleic acid amplification (NAA) tests in case definitions. The objective of this study was to evaluate the contribution of a real-time polymerase chain reaction (PCR) assay in providing a result predictive of a confirmed TB case. Respiratory and extra-pulmonary specimens (n = 308) were subjected to NAA, culture and smear microscopy. Qualitative PCR assessment, translated by an increase in NAA cycles, disregarding template copy number, resulted in an increase in confirmed cases, helping to bridge the gap between the test's analytical performance and its actual performance in TB diagnosis. PMID- 22230011 TI - Mucinous borderline-like tumor of the gastrointestinal type arising from mature cystic teratoma of the ovary and its immunohistochemical cytokeratin and mucin phenotype. AB - Malignant transformation is rarely seen in the disease course of mature cystic teratoma (MCT) of the ovary. Adenocarcinoma arising from MCT is especially rare. We herein present the case of a premenopausal woman with a mucinous borderline like tumor arising from a MCT. Based on the histological transition between the borderline-like tumor and gastrointestinal elements of the MCT, we consider that the tumor derived from teratomatous gastrointestinal epithelium. Immunohistochemistry showed that the proliferating mucinous cells were diffusely positive for cytokeratin 20 and partially positive for cytokeratin 7. MUC5AC was partially positive, whereas MUC2 and MUC6 were positive in a small number of tumor cells. The immunophenotype of cytokeratins and mucins in the present case was compatible with malignant transformation of the teratomatous gastrointestinal epithelium. PMID- 22230015 TI - Measurement of 222Rn diffusion through sandy soil with solar cells photodiodes as the detector. AB - An experimental system was developed to study the diffusion rate of radon (222Rn) gas through porous media as a function of soil porosity/grain size and soil water content. Columns with different grain sizes, soil water content and soil depths were used. The system used solar cells photodiodes as alpha (alpha) detectors. This new detector is highly efficient and low cost compared to other known detectors. Soil water content was found to be the most dominant factor affecting the 222Rn diffusion rate. A maximum diffusion rate value of (6.5 +/- 0.07) * 10-6 m2/s was found in dry conditions. The minimum diffusion value of less than (3.9 +/- 0.14) * 10-7 m2/s was found in 2% soil water content. The experimental results were compared with theoretical calculations done with the "GREEN equation". Two discrepancies were observed: the time to equilibrium state in the measurements was longer compare to the calculated values and the alpha count rates were lower in the experiment compared with the theoretical calculations. These results can be explained by the differences in the system geometry. PMID- 22230016 TI - Applicability of health physics lessons learned from the Three Mile Island Unit 2 accident to the Fukushima Daiichi accident. AB - The TMI-2 and Fukushima Daiichi accidents appear to be dissimilar because they involve different reactor types. However, the health physics related lessons learned from TMI-2 are applicable, and can enhance the Fukushima Daiichi recovery effort. PMID- 22230017 TI - Natural radioactivity in building materials in the European Union: a database and an estimate of radiological significance. AB - The authors set up a database of activity concentration measurements of natural radionuclides (226Ra, 232Th and 40K) in building material. It contains about 10,000 samples of both bulk material (bricks, concrete, cement, natural- and phosphogypsum, sedimentary and igneous bulk stones) and superficial material (igneous and metamorphic stones) used in the construction industry in most European Union Member States. The database allowed the authors to calculate the activity concentration index I--suggested by a European technical guidance document and recently used as a basis for elaborating the draft Euratom Basic Safety Standards Directive--for bricks, concrete and phosphogypsum used in the European Union. Moreover, the percentage could be assessed of materials possibly subject to restrictions, if either of the two dose criteria proposed by the technical guidance were to be adopted. PMID- 22230018 TI - Developments in real-time radon monitoring at Stromboli volcano. AB - We present the results of one year of continuous radon monitoring at Stromboli volcano collected at two automated real-time stations. These were deployed on the NE flank (at 520 m a.s.l.) and within the summit area (900 m a.s.l.). Higher daily emissions at the lower station approached 4,200 Bq/m3, with bulk averages around 1,800 (+/-980) Bq/m3; whereas the summit station reached peak values of 23,000 Bq/m3 and bulk averages of 12,500 Bq/m3 (+/-4,000). Negative correlations are observed between radon emissions, soil temperature and, to a lesser extent, atmospheric pressure. In contrast, increases in radon concentrations were observed during periods of higher rainfall conditions. Therefore, trends in radon concentrations may be decoupled from those of other geochemical parameters (CO2 fluxes and CO2/SO2 plume ratios) during periods of heavy to moderate rainfalls. Multiple Linear Regression statistics (including the effects of soil temperature, atmospheric pressure and tidal forces) led us to compute the residuals given by the difference of measured and calculated 222Rn concentrations. The cross-check between the daily measured radon activities and the absolute variations in radon residuals, for the data collected at the summit station, give us the opportunity to suggest a methodological approach that can be used in the attempt of predicting some major changes in volcanic activity. PMID- 22230019 TI - Assessment of natural radioactivity levels and their relationship with soil characteristics in undisturbed soils of the northeast of Buenos Aires province, Argentina. AB - Surface and depth profile concentrations (down to 50 cm) of 232Th chain, 226Ra, and 40K radionuclides were determined in undisturbed coastal and inland soils of La Plata city region, Argentina, through their gamma-ray activity using a high purity Ge detector spectrometer. These results were compared with superficial activities determined in soils from the surroundings of the Centro Atomico Ezeiza (Ezeiza Atomic Center) located in Ezeiza, Buenos Aires Province, Argentina. The hyperfine and magnetic Fe phase's properties of soil profiles were characterized by Mossbauer spectroscopy, magnetic hysteresis loops and AC magnetic susceptibility. No dependence of the activity of the 232Th natural chain on depth was found, whereas variations for 226Ra and 40K activities were observed. Positive correlations, determined by the Pearson correlation coefficients, were established between 40K, 226Ra and 232Th activity concentrations for the whole set of soil samples. The annual external equivalent dose for adults was similar for La Plata and Ezeiza regions, with average values of 0.08 +/- 0.01 mSv and 0.06 +/- 0.02 mSv, respectively. The thermal dependence of the AC magnetic susceptibility revealed the existence of magnetite and hematite. The Mossbauer spectra of all soils were made up of signals associated with alpha-Fe2O3, a paramagnetic relaxation component, and Fe3+ and Fe2+ doublets. In addition, the spectra of inland soils revealed the presence of Fe3O4. A negative correlation was found between the activity concentrations and the alpha-Fe2O3 and Fe3O4 relative fractions, whereas a positive correlation was found between the Fe3+ relative fraction and the 40K activity. PMID- 22230020 TI - The removal of U(VI) from aqueous solution by oxidized multiwalled carbon nanotubes. AB - Multiwalled carbon nanotubes (MWCNTs) have exhibited high sorption capacity for radionuclides due to the unique hollow structure and large surface area. In this study, surface properties of oxidized MWCNTs were characterized by using XRD, SEM, FTIR and potentiometric acid-base titration. The sorption of U(VI) on oxidized MWCNTs as a function of contact time, U(VI) concentration, pH, ionic strength, humic acid/fulvic acid (HA/FA) and carbonate was investigated by using batch technique. The removal of U(VI) by oxidized MWCNTs was strongly dependent on pH and ionic strength. The presence of HA/FA enhanced U(VI) removal on oxidized MWCNTs at low pH while inhibited U(VI) sorption at high pH. The mechanism of U(VI) sorption on oxidized MWCNTs was assumed to be cation exchange/outer-sphere surface complexation in acidic pH and to form precipitation under circum neutral conditions. The oxidized MWCNTs exhibit higher sorption capacity and stronger chemical affinity than pristine MWCNTs. PMID- 22230021 TI - TOCATTA: a dynamic transfer model of 14C from the atmosphere to soil-plant systems. AB - Many nuclear facilities release 14C into the environment, mostly as 14CO2, which mixes readily with stable CO2. This complete isotopic mixing (equilibrium) is often used as the basis for dose assessment models. In this paper, a dynamic compartment model (TOCATTA) has been investigated to describe 14C transfer in agricultural systems exposed to atmospheric 14C releases from nuclear facilities under normal operating or accidental conditions. The TOCATTA model belongs to the larger framework of the SYMBIOSE modelling and simulation platform that aims to assess the fate and transport of a wide range of radionuclides in various environmental systems. In this context, the conceptual and mathematical models of TOCATTA have been designed to be relatively simple, minimizing the number of compartments and input parameters required, appropriate to its use in an operational mode. This paper describes in detail 14C transfer in agricultural plants exposed to time-varying concentrations of atmospheric 14C, with a consideration also of the transfer pathways of 14C in soil. The model was tested against in situ data for 14C activity concentration measured over two years on a grass field plot located 2 km downwind of the AREVA NC La Hague nuclear reprocessing plant. The first results showed that the model roughly reproduced the observed month-to-month variability in grass 14C activity, but under estimated (by about 33%) most of the observed peaks in the 14C activity concentration of grass. This tends to prove that it is not suitable to simulate intra-monthly variability, and a fortiori, the response of vegetation to accidental releases that may occur during the day. The need to increase the temporal resolution of the model has been identified in order to simulate the impact of intermittent 14C releases occurring either the day or night, such as those recorded by the AREVA NC plant. PMID- 22230022 TI - Numerical modeling of the radionuclide water pathway with HYDRUS and comparison with the IAEA model of SR 44. AB - This study depicts a theoretical experiment in which the radionuclide transport through the porous material of a landfill consisting of concrete rubble (e.g., from the decommissioning of nuclear power plants) and the subsequent migration through the vadose zone and aquifer to a model well is calculated by means of the software HYDRUS-1D (Simunek et al., 2008). The radionuclides originally contained within the rubble become dissolved due to leaching caused by infiltrated rainwater. The resulting well-water contamination (in Bq/L) is calculated numerically as a function of time and location and compared with the outcome of a simplified analytic model for the groundwater pathway published by the IAEA (2005). Identical model parameters are considered. The main objective of the present work is to evaluate the predictive capacity of the more simple IAEA model using HYDRUS-1D as a reference. For most of the radionuclides considered (e.g., 129I, and 239Pu), results from applying the IAEA model were found to be comparable to results from the more elaborate HYDRUS modeling, provided the underlying parameter values are comparable. However, the IAEA model appears to underestimate the effects resulting from, for example, high nuclide mobility, short half-life, or short-term variations in the water infiltration. The present results indicate that the IAEA model is suited for screening calculations and general recommendation purposes. However, the analysis of a specific site should be accompanied by detailed HYDRUS computer simulations. In all models considered, the calculation outcome largely depends on the choice of the sorption parameter K(d). PMID- 22230023 TI - Characterization of local soils and study the migration behavior of radionuclide from disposal site of LILW. AB - Migration behavior of radionuclide is one of the most important factors to be considered for the long-term safety assessment of a radioactive waste disposal facility in a wet geological formation. In the present study, laboratory based column experiments have been carried out to assess the radionuclide migration behavior of 137Cs and 60Co and to evaluate the retardation factor through a clay soil layers using gamma spectrometry. Investigation was performed for a range of particle sizes and fixed column lengths to determine an appropriate value of migration rate of 137Cs and 60Co. The distribution pattern of particle size in soil samples were measured by sieved method. Two different particle sizes (<= 90 MUm and mixed size) were used in the column experiments. The migration rate in the clay type soil layer of particle size <= 90 MUm was found by the order of 60Co > 137Cs. The maximum migration length of 60Co in the soil layer was found to be 0-25 cm, however in the case of 137Cs it was found at a maximum length of 0-10 cm. The distribution coefficient of 60Co was found nearly same as that of 137Cs. The retardation factor was found to be 1.79 and 1.94 for 60Co and 137Cs, respectively. The experimental breakthrough from this study indicates that the amount of radioactive cesium and cobalt released depends upon the composition of the soils. PMID- 22230024 TI - Is chorioamnionitis harmful for the brain of preterm infants? A clinical overview. AB - BACKGROUND: Chorioamnionitis is an important risk factor underlying preterm delivery, and it has also been suggested that it is associated with brain lesions and deviant neurological development in prematurely born infants. OBJECTIVE: To evaluate the possible effects of chorioamnionitis on the brain of preterm infants. DESIGN: A systematic review. METHODS: A systematic database search was performed to identify all original articles published until 5 October 2011 evaluating the association between histological and/or clinical chorioamnionitis and brain lesions and/or neurological development in preterm infants. Altogether, 609 potentially relevant articles were identified, of which 84 original articles were included. RESULTS: The majority of the articles do not support the hypothesis that chorioamnionitis poses a direct risk on the central nervous system of preterm infants. The full course of antenatal steroids seems to further reduce the adverse effects of inflammation on the developing nervous system. CONCLUSIONS: It seems that there are both benefits and risks with regard to the effects of chorioamnionitis on the brain development of preterm infants. It is plausible that inflammation enhances maturation of the preterm infant and therefore has protective effects balancing its potential harmful effects. We conclude that chorioamnionitis does not carry higher risks for the brain of preterm infants than other underlying pathologies behind preterm delivery. PMID- 22230025 TI - Incidental appendectomy--standard or unnecessary additional trauma in surgery for colorectal cancer? A retrospective analysis of histological findings in 380 specimens. AB - BACKGROUND: Incidental appendectomy is a frequent but non-standard procedure during surgery for colorectal cancer. Incidental appendectomy during colorectal resections is performed at the discretion of the operating surgeon. METHOD: This retrospective study used data from 1352 consecutive patients who underwent surgery for colorectal cancer between 1993 and 2009 at the Medical University of Vienna. The authors evaluated histopathological results of appendices removed incidentally. In addition, complications and costs of the additional intervention were analyzed. RESULTS: Appendectomy had been performed in 314 (23.22%) patients because of appendicitis. Incidental appendectomy had been performed in 380 (28.11%) patients: 86 (22.63%) had a histologically completely normal appendix, a pathologic alteration was found in 289 (76.05%) and a neoplasm was found in seven (1.84%). No complications occurred from the additional surgical procedure. The costs and time effort were negligible. CONCLUSION: Incidental appendectomy is a safe procedure and can be integrated into surgery for colorectal carcinoma to avoid future complications. Pathological findings of the appendix, including neoplasm, are frequent but the clinical relevance remains questionable. PMID- 22230026 TI - Microsatellite typing and population structuring of Trypanosoma evansi in Mindanao, Philippines. AB - Trypanosoma evansi, a blood-borne protozoan parasite with an extensive geographical range is the causative agent of the livestock disease known as surra. A total of 140 out of 179 T. evansi isolates collected between 2006 and 2007 from 44 villages (comprising of 16 reported surra outbreaks) in 3 provinces (Agusan del Sur (ADS), Surigao del Sur (SDS) and Agusan del Norte (ADN)) in Mindanao, Philippines were each successfully genotyped using a suite of 7 polymorphic microsatellites. The study identified 16 multi locus genotypes (MLG) within the T. evansi isolates and evidence of the spread of surra outbreaks from one village to another, most likely due to the movement of infected animals. Genotyping provided evidence of population sub-structuring with 3 populations (I, II and III (only 1 isolate)) identified. The most abundant population was II, which was the predominant population in ADS and SDS (p=0.022). In addition, buffalo mortality was statistically higher in outbreak areas associated with isolates from population I (13.6%) than with isolates from population II (6.9%) (p=0.047). The present study has highlighted the utility of microsatellite loci to improve understanding of the epidemiology of T. evansi and in tracking surra outbreaks. PMID- 22230027 TI - Evaluation of pulmonary function variables by using plethysmography in cats with respiratory disease associated to Dirofilaria immitis. AB - Heartworm Associated Respiratory Disease (HARD) is a pulmonary syndrome that results from the vascular and parenchymal inflammatory response associated with the arrival and death of Dirofilaria immitis in the distal pulmonary arteries. Barometric whole-body plethysmography (BWBP) is a non-invasive pulmonary function test (PFT) that allows a dynamic study of breathing patterns and is useful to study airway disease and the response to different treatments. The aim of this prospective non-blinded study was to compare respiratory function variables between healthy cats and HARD cats (seropositive to D. immitis) by use of BWBP. Twenty-five healthy cats and six HARD cats were put into the plethysmograph chamber and different respiratory variables were measured. The results were analyzed and compared between the two groups of animals. There were significant differences for bronchoconstriction index variables Pause (P-value<0.001) and enhanced pause (P-value<0.001), minute volume (P-value<0.05) and tidal volume (P value<0.05) between healthy and HARD cats. There were no significant differences in respiratory rate and inspiratory and expiratory times between both groups of animals. The results obtained in our study support that HARD cats show significant differences in pulmonary function variables obtained by BWBP due to an acute inflammatory response at bronchial, vascular and parenchymal level. This PFT could be a useful method to facilitate the diagnosis of pathological states of bronchoconstriction in HARD cats. PMID- 22230028 TI - Emphysematous osteomyelitis: a case report and review of the literature. AB - We report the case of a 15-year-old girl with pelvic and sacral emphysematous osteomyelitis caused by Fusobacterium necrophorum. This infection was cured following four surgical procedures and 4 weeks of intravenous then 4 weeks of oral antibiotics. We review our case alongside the 24 previously reported cases of emphysematous osteomyelitis in the literature. The 25 cases include 15 monomicrobial and 10 polymicrobial infections. The causative organism(s) in all but three cases included an anaerobe or a member of the Enterobacteriaceae family. A significant underlying comorbidity was reported in 18 cases. At least 15 cases required one or more surgical procedures. There was a significant associated mortality with eight (32%) patients dying in hospital at 7 to 56 days after the diagnosis of emphysematous osteomyelitis. PMID- 22230029 TI - Concurrent speciation in the eastern woodland salamanders (Genus Plethodon): DNA sequences of the complete albumin nuclear and partial mitochondrial 12s genes. AB - Salamanders of the North American plethodontid genus Plethodon are important model organisms in a variety of studies that depend on a phylogenetic framework (e.g., chemical communication, ecological competition, life histories, hybridization, and speciation), and consequently their systematics has been intensively investigated over several decades. Nevertheless, we lack a synthesis of relationships among the species. In the analyses reported here we use new DNA sequence data from the complete nuclear albumin gene (1818 bp) and the 12s mitochondrial gene (355 bp), as well as published data for four other genes (Wiens et al., 2006), up to a total of 6989 bp, to infer relationships. We relate these results to past systematic work based on morphology, allozymes, and DNA sequences. Although basal relationships show a strong consensus across studies, many terminal relationships remain in flux despite substantial sequencing and other molecular and morphological studies. This systematic instability appears to be a consequence of contemporaneous bursts of speciation in the late Miocene and Pliocene, yielding many closely related extant species in each of the four eastern species groups. Therefore we conclude that many relationships are likely to remain poorly resolved in the face of additional sequencing efforts. On the other hand, the current classification of the 45 eastern species into four species groups is supported. The Plethodon cinereus group (10 species) is the sister group to the clade comprising the other three groups, but these latter groups (Plethodon glutinosus [28 species], Plethodon welleri [5 species], and Plethodon wehrlei [2 species]) probably diverged from each other at approximately the same time. PMID- 22230030 TI - Distinct Bradyrhizobium [corrected] communities nodulate legumes native to temperate and tropical monsoon Australia. AB - Geographic isolation and growing climate aridity played major roles in the evolution of Australian legumes. It is likely that these two factors also impacted on the evolution of their root-nodule bacteria. To investigate this issue, we applied a multilocus sequence analysis (MLSA) approach to examine Bradyrhizobium isolates originating from temperate areas of Western Australia (WA) and the tropical-monsoon area of the Northern Territory (NT). The isolates were mostly collected from the nodules of legumes belonging to tribes, genera and species endemic or native to Australia. Phylogenetic analyses of sequences for the housekeeping atpD, dnaK, glnII, gyrB, recA and 16S rRNA genes and nodulation nodA gene revealed that most isolates belonged to groups that are distinct from non-Australian Bradyrhizobium isolates, which is in line with earlier studies based on 16S rRNA gene sequence analyses. Phylogenetic analysis of the nodA data allowed identification of five major Clades among the WA and NT isolates. All WA isolates grouped in a subgroup I.1 of Clade I with strains originating from temperate eastern Australia. In contrast, the NT isolates formed part of Clades I (subgroup I.2), III (subgroup III.3), IV, V and X. Of these nodA clades, Clade I, Clade IV, Clade X presumably have an Australian origin. Overall, these data demonstrate that the impact of geographic isolation of the Australian landmass is manifested by the presence of numerous unique clusters in housekeeping and nodulation gene trees. In addition, the intrinsic climate characteristics of temperate WA and tropical-monsoon NT were responsible for the formation of distinct legume communities selecting for unrelated Bradyrhizobium groups. PMID- 22230031 TI - Fine needle aspiration cytology of nodular fasciitis presenting as a mass in the male breast: report of an unusual case. PMID- 22230032 TI - Extended transpelvic deep inferior epigastric myocutanaeous rectus abdominis flap for posterior vaginal wall reconstruction in advanced pelvic malignancy. PMID- 22230033 TI - A minimally invasive approach for the correction of a traumatic buttock deformity via wire subcision and volume replacement. PMID- 22230034 TI - Evaluation of care and surveillance of cardiovascular disease: can we trust medico-administrative hospital data? AB - BACKGROUND: The evaluation of care and the surveillance of disease are important in respect to cardiovascular disease because it is prevalent and costly. In Canada, medico-administrative hospital data are readily available, continuously updated, and offer comprehensive coverage of the patient population. However, there is concern about the quality of the information. METHODS: The reliability and predictive capability of comorbidity data contained within Quebec's hospital discharge database were assessed in comparison with data collected by clinical medical record reabstraction in a sample of 1989 patients hospitalized from 2002 to 2006 in a mix of 13 hospitals. Patients either had a principal diagnosis of myocardial infarction or underwent angioplasty or bypass surgery. Twenty-one comorbidities included in the Charlson comorbidity index or known to be associated with mortality were validated via medical record reabstraction. RESULTS: Of 14 comorbidities with > 2% prevalence, 8 had excellent agreement with medical record review (kappa > 0.8) while 6 had substantial agreement (kappa > 0.6). In general, positive predictive values were high, while measures of sensitivity were more variable. Univariate associations between comorbidities and 30-day and 1-year mortality were generally similar in the 2 data sources. Comorbidities retained in the final multivariate stepwise regression models from each data source were almost identical, as were the 2 models' abilities to predict mortality. CONCLUSIONS: Hospital discharge data in Quebec are, in general, reliably coded and compare favourably with clinical medical record review in their ability to predict mortality. It appears sufficiently reliable to provide useful information about clinical outcomes of cardiac care and to identify problems that warrant investigation. PMID- 22230036 TI - Erythrocytes as carriers for drugs: the transition from the laboratory to the clinic is approaching. AB - Erythrocytes have been suggested to be smart carriers for drugs, biologics and other therapeutic agents, and a paper in the present issue of the journal confirms the wide interest and the expectations the technology has generated. In this Editorial, I briefly summarize the advances in the field and try to figure out the process that will take this technology to the clinic. The conclusion is that, after several years of basic research, the time is fast approaching since two companies in Europe are actively engaged in industrializing the process and searching approval for treatments with structured clinical trials. PMID- 22230035 TI - Bacillus anthracis-derived edema toxin (ET) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway. AB - BACKGROUND: A common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (PMNs) in infected tissues in the face of abundant circulating PMNs. A major virulence determinant of anthrax is edema toxin (ET), which is formed by the combination of two proteins produced by the organism, edema factor (EF), which is an adenyl cyclase, and protective antigen (PA). Since cAMP, a product of adenyl cyclase, is known to enhance endothelial barrier integrity, we asked whether ET might decrease extravasation of PMNs into tissues through closure of the paracellular pathway through which PMNs traverse. RESULTS: Pretreatment of human microvascular endothelial cell(EC)s of the lung (HMVEC-L) with ET decreased interleukin (IL)-8-driven transendothelial migration (TEM) of PMNs with a maximal reduction of nearly 60%. This effect required the presence of both EF and PA. Conversely, ET did not diminish PMN chemotaxis in an EC-free system. Pretreatment of subconfluent HMVEC-Ls decreased transendothelial 14 C-albumin flux by ~ 50% compared to medium controls. Coadministration of ET with either tumor necrosis factor-alpha or bacterial lipopolysaccharide, each at 100 ng/mL, attenuated the increase of transendothelial 14 C-albumin flux caused by either agent alone. The inhibitory effect of ET on TEM paralleled increases in protein kinase A (PKA) activity, but could not be blocked by inhibition of PKA with either H-89 or KT-5720. Finally, we were unable to replicate the ET effect with either forskolin or 3-isobutyl-1-methylxanthine, two agents known to increase cAMP. CONCLUSIONS: We conclude that ET decreases IL-8-driven TEM of PMNs across HMVEC-L monolayers independent of cAMP/PKA activity. PMID- 22230037 TI - Challenges scoring radiation pneumonitis in patients irradiated for lung cancer. AB - BACKGROUND AND PURPOSE: To quantify uncertainties in scoring radiation pneumonitis. MATERIALS AND METHODS: Records of 434 patients irradiated for lung cancer from 2000 to 2010 were retrospectively reviewed; IRB-approved study. From these, 121 received >= 60 Gy for non-small cell lung cancer (NSCLC) with >= 6 months follow-up. Patients where the physicians were uncertain of the diagnosis due to confounding factors were deemed "hard to score". Subgroups were defined based on lung dosimetric parameters, and frequencies in different subgroups were compared via Fisher's exact test. RESULTS: 21/121 of patients were considered to have pneumonitis; median follow 17 months. Of these, 10/21 were "hard to score"; reasons including acute COPD exacerbation, infection, and tumor progression. "Hard to score" pneumonitis was slightly more common in patients with a COPD history (15%) vs. without COPD (4%) (p=0.05); and with a pre-RT FEV1<1.7 L (16%) vs. >=1.7 L (4%) (p=0.09). Rates of "unambiguous" pneumonitis trended to be non significantly slightly higher in patients higher mean lung doses, V5, and V30. CONCLUSION: Radiation pneumonitis occurred in 17% of patients undergoing RT for NSCLC; with diagnostic uncertainty in 48% of these. Poor pre-RT pulmonary function increases the rate of "hard to score" pneumonitis. Dosimetric parameters are slightly better related to "unambiguous" than "hard to score" pneumonitis, as expected. PMID- 22230038 TI - How do we monitor hospital transfusion practice using an end-to-end electronic transfusion management system? PMID- 22230039 TI - Effects of lexicality and word frequency on brain activation in dyslexic readers. AB - We investigated the neural basis of lexical access to written stimuli in adult dyslexics and normal readers via the Lexicality effect (pseudowords>words) and the Frequency effect (low>high frequent words). The participants read aloud German words (with low or high lexical frequency) or pseudowords while being scanned. In both groups, both Lexicality effect and Frequency effect involved Broca's region (areas 44 and 45). Whereas the effects were stronger for dyslexic than normal readers in area 44, area 45 showed the reverse pattern. These findings mimic recent results from an fMRI study on dyslexic primary school children, indicating that lexical access to written stimuli poses increased and enduring difficulties on dyslexic readers, at least in a language with a transparent orthography. Additionally, data from four compensated adult dyslexics are reported and discussed, which hint at the importance of both Broca's and Wernicke's region for recovery from childhood dyslexia. PMID- 22230040 TI - Stimulation of the AT2 receptor reduced atherogenesis in ApoE(-/-)/AT1A(-/-) double knock out mice. AB - AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE(-/-)) mice and in ApoE/AT1A receptor double knockout mice (ApoE(-/-)/AT1A( /-)). ApoE(-/-) mice and ApoE(-/-)/AT1A(-/-) mice were fed cholesterol-rich diet for 7 weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoE(-/-) mice, but were markedly reduced in ApoE(-/-)/AT1A(-/-) mice. Concomitant treatment of ApoE(-/ )/AT1A(-/-) mice with either telmisartan or ramipril had no additional effect on blood pressure, vascular oxidative stress, AT2 receptor expression, and endothelial function. Remarkably, atherosclerotic lesion formation was increased in ramipril treated ApoE(-/-)/AT1A(-/-) mice compared to untreated ApoE(-/ )/AT1A(-/-) mice whereas pharmacological AT1 receptor inhibition with telmisartan had no additional effect on atherogenesis. Moreover, chronic AT2 receptor inhibition with PD123,319 significantly increased plaque development in ApoE(-/ )/AT1A(-/-) mice. In additional experiments, direct AT2 receptor stimulation reduced atherogenesis in ApoE(-/-)/AT1A(-/-) mice. Taken together, our data demonstrate a relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice and provide novel insight in RAS-physiology. PMID- 22230041 TI - The health and economic burden of chickenpox and herpes zoster in Belgium. AB - Varicella-zoster virus causes chickenpox (CP) and after reactivation herpes zoster (HZ). Vaccines are available against both diseases warranting an assessment of the pre-vaccination burden of disease. We collected data from relevant Belgian databases and performed five surveys of CP and HZ patients. The rates at which a general practitioner is visited at least once for CP and HZ are 346 and 378/100 000 person-years, respectively. The average CP and HZ hospitalization rates are 5.3 and 14.2/100 000 person-years respectively. The direct medical cost for HZ is about twice as large as the direct medical cost for CP. The quality-adjusted life years lost for ambulatory CP patients consulting a physician is more than double that of those not consulting a physician (0.010 vs. 0.004). In conclusion, both diseases cause a substantial burden in Belgium. PMID- 22230042 TI - SMTP (Stachybotrys microspora triprenyl phenol) enhances clot clearance in a pulmonary embolism model in rats. AB - BACKGROUND: Stachybotrys microspora triprenyl phenols (SMTPs) are a novel family of small molecules that enhance both activation and fibrin-binding of plasminogen. While their effects on fibrinolysis have been characterized in vitro, little is known about their activity in vivo with respect to plasminogen activation and blood clot clearance. RESULTS: To select a potent SMTP congener for the evaluation of its action in vitro and in vivo, we tested several SMTP congeners with distinct structural properties for their effects on plasminogen activation. As a result, SMTP-7 (orniplabin) was found to have distinguished activity. Several lines of biochemical evidence supported the idea that SMTP-7 acted as a plasminogen modulator. SMTP-7 elevated plasma level of plasmin-alpha2 antiplasmin complex, an index of plasmin formation in vivo, 1.5-fold in mice after the intravenous injections at doses of 5 and 10 mg kg-1. In a rat pulmonary embolism model, SMTP-7 (5 mg kg-1) enhanced the rate of clot clearance ~3-fold in the absence of exogenous plasminogen activator. Clot clearance was enhanced further by 5 mg kg-1 of SMTP-7 in combination with single-chain urokinase-type plasminogen activator. CONCLUSIONS: Our results show that SMTP-7 is a superior plasminogen modulator among the SMTP family compounds and suggest that the agent enhances plasmin generation in vivo, leading to clearance of thrombi in a model of pulmonary embolism. PMID- 22230043 TI - Parent-reported health care expenditures associated with autism spectrum disorders in Heilongjiang province, China. AB - BACKGROUND: The aim of this study was to determine the health expenses incurred by families with children with autism spectrum disorder (ASD) and those expenses' relation to total household income and expenditures. METHODS: In this cross sectional study, health care expenditure data were collected through face-to-face interviews. Expenses included annual costs for clinic visits, medication, behavioral therapy, transportation, and accommodations. Health care costs as a percentage of total household income and expenditures were also determined. The participants included 290 families with ASD children who were treated at the Children Development and Behavior Research Center, Harbin Medical University, China. RESULTS: Families with ASD children from urban and rural areas had higher per-capita household expenditures by 60.8% and 74.7%, respectively, compared with provincial statistics for 2007. Behavioral therapy accounted for the largest proportion of health expenses (54.3%) for ASD children. In 19.9% of urban and 38.2% of rural families, health care costs exceeded the total annual household income. Most families (89.3% of urban families; 88.1% of rural families) in that province reported higher health care expenditures than the provincial household average. CONCLUSION: For families with ASD children, the economic burden of health care is substantially higher than the provincial average. PMID- 22230044 TI - Role of calcineurin in inhibiting disadvantageous associations. AB - Calcineurin is an important calcium-dependent phosphatase that is evolutionarily conserved in all studied species, and has been implicated in the consolidation and maintenance of new memories. However, recent evidence has extended the role of calcineurin. In contrast to learning tasks that require behavioral acquisition, extinction tasks that require behavioral inhibition have been shown to be reliant on calcineurin. In the present study, using a Morris water maze, we have demonstrated that pharmacological inhibition of calcineurin causes augmentation of spatial learning and perseveration of spatial reversal-learning in a dose-dependent manner. Direct infusions of a specific calcineurin inhibitor, cyclosporine A, into the dorsal hippocampi bilaterally, prior to spatial learning, led to increased learning, whereas similar injections of cyclosporine A following a spatial learning task and prior to a spatial reversal-learning task resulted in perseveration of reversal-learning. Our results indicate that injections of cyclosporin A resulted in decreased calcineurin activity in the dorsal hippocampus and increased difficulty in switching to new task demands, in a dose-dependent manner, despite evidence indicating no deficit in ability to learn new information. Therefore, calcineurin activity contributes to the inhibition of previously learned but unwanted behavioral responses during competitive spatial learning. Involvement of calcineurin in extinction of fear memory has recently been demonstrated. Our results also indicate that calcineurin activity plays a role in memory extinction in spatial memory tasks, and therefore, suggest that calcineurin might be an important molecule in mediating behavioral flexibility in general. PMID- 22230045 TI - Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse models. AB - Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial function, to reduce reactive oxygen species, to clear aggregates of toxic proteins, and to act as a nitric oxide synthase inhibitor. These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP 43(G348C) mice. Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS. The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score, and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A) mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP 43(G348C) mice. PMID- 22230047 TI - Expression of an antiviral protein from Lonomia obliqua hemolymph in baculovirus/insect cell system. AB - The control of viral infections, mainly those caused by influenza viruses, is of great interest in Public Health. Several studies have shown the presence of active properties in the hemolymph of arthropods, some of which are of interest for the development of new pharmacological drugs. Recently, we have demonstrated the existence of a potent antiviral property in the hemolymph of Lonomia obliqua caterpillars. The aim of this study was to produce an antiviral protein in a baculovirus/Sf9 cell system. The resulting bacmid contains the sequence coding for the antiviral protein previously described by our group. Total RNA from L. obliqua caterpillars was extracted with Trizol and used in the reverse transcription assay with oligo(d)T primer followed by polymerase chain reactions (RT-PCR) with specific primers for the cDNA coding for the antiviral protein, based on the sequence deposited in the GenBank database. Restriction sites were inserted in the cDNA for ligation in the donor plasmid pFastBac1TM. The recombinant plasmid was selected in Escherichia coli DH5alpha and subsequently used in the transformation of E. coli DH10Bac for the construction of the recombinant bacmid. This bacmid was used for the expression of the antiviral protein in the baculovirus/Sf9 cell system. After identifying the protein by western blot, activity tests were performed, showing that the purified recombinant protein was able to significantly reduce viral replication (about 4 logs). Studies on the optimization of the expression system for the production of this antiviral protein in insect cells are in progress. PMID- 22230046 TI - Enhancers and silencers: an integrated and simple model for their function. AB - Regulatory DNA elements such as enhancers, silencers and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Herein we discuss some examples and a parsimonious model for their function is proposed. All are transcription units that tether their target promoters close to, or distant from, transcriptional hot spots (or 'factories'). PMID- 22230048 TI - An efficient synthesis of highly functionalized novel chromeno[4,3-b]pyrroles and indolizino[6,7-b]indoles as potent antimicrobial and antioxidant agents. AB - A facile and efficient synthesis of novel chromeno[4,3-b]pyrroles has been accomplished by intramolecular 1,3-dipolar cycloaddition which on subsequent Pictet-Spengler cyclisation in presence of p-toluenesulfonic acid yielded indolizino[6,7-b]indoles. The synthesized chromenopyrroles and indolizinoindoles were evaluated for their antimicrobial and antioxidant activities. Compounds 7b, 7e, 7a and 7d exhibited respectively, good antibacterial and antifungal activities against tested pathogens when compared to reference control. PMID- 22230049 TI - Novel dendrimeric lipopeptides with antifungal activity. AB - A series of new cationic lipopeptides containing branched, amphiphilic polar head derived from (Lys)Lys(Lys) dendron and C(8) or C(12) chain at C-end were designed, synthesized and characterized. Antimicrobial in vitro activity expressed as minimal inhibitory concentration (MIC) was evaluated against Gram positive and Gram-negative bacteria and yeasts from the Candida genus. A significant enhancement of antimicrobial potency along with increased selectivity against Candida reference strains was detected for derivatives with the C(12) residue. Several compounds were characterized by a low hemotoxicity. The antifungal activity of branched lipopeptides is multimodal and concentration dependent. Several compounds, studied in detail, induced potassium leakage from fungal cells, caused morphological alterations of fungal cells and inhibited activity of candidal beta(1,3)-glucan synthase. PMID- 22230050 TI - Synthesis and carbonic anhydrase inhibitory properties of novel cyclohexanonyl bromophenol derivatives. AB - The Naturally occurring novel cyclohexanonyl bromophenol 2(R)-2-(2,3,6-tribromo 4,5-dihydroxybenzyl)cyclohexanone (4) was synthesized as a racemic compound. Cyclohexylphenyl methane derivatives (10-17) with Br, OMe, CO, and OH were also obtained. Inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I, II, IV, and VI, with compounds 2-4, 8, and 10-26 was investigated. These compounds were found to be promising carbonic anhydrase inhibitors and some of them showed interesting inhibitory activity. Some of the compounds investigated here showed effective hCA inhibitory activity, and might be used as leads for generating novel carbonic anhydrase inhibitors which are valuable drug candidates for the treatment of glaucoma, epilepsy, gastric and duodenal ulcers, neurological disorders, and osteoporosis. PMID- 22230051 TI - Impact of the Gen-Probe Amplified MTD(r) Test on tuberculosis diagnosis in children. AB - OBJECTIVE: To evaluate the performance of the Gen-Probe Amplified MTD(r) Test (AMTD) for childhood tuberculosis (TB) diagnosis compared to conventional culture. DESIGN: We retrospectively studied 121 childhood cases (73 males; median age 7 years, range 1-16). Pulmonary samples (104/152, 68%) included gastric aspirates (n = 53), induced sputum samples (n = 43), bronchial aspirates and bronchoalveolar lavage (n = 8). Extra-pulmonary samples (48/152, 32%) included lymph nodes (n = 34) and other sterile fluids (n = 14). Specimens were examined using acid-fast bacilli (AFB) microscopy, AMTD and bacterial culture using BACTECTM MGITTM 960 and Lowenstein-Jensen (LJ) media. RESULTS: A clinical diagnosis of TB was made in 50/121 (41%) children (43/50 pulmonary disease). AFB microscopy was positive in 6%; Mycobacterium tuberculosis was recovered by culture from 16/50 (32%) and AMTD was positive in 29/50 (58%). AMTD sensitivity, specificity, positive predictive value and negative predictive value compared to culture were respectively 100%, 85%, 50% and 100%. For pulmonary vs. extra pulmonary disease, the performance of AMTD compared to culture was respectively 100%, 77%, 46% and 100% vs. 100%, 97.5%, 75% and 100%. CONCLUSIONS: Nucleic acid amplification tests are more sensitive and very specific methods for the rapid detection of M. tuberculosis. The AMTD technique increases TB detection in children compared to conventional culture. PMID- 22230057 TI - Custom vs conventional PRK: a prospective, randomized, contralateral eye comparison of postoperative visual function. AB - PURPOSE: To determine whether VISX S4 (VISX Inc) custom photorefractive keratectomy (PRK) results in better visual outcomes than VISX S4 conventional PRK. METHODS: Photorefractive keratectomy was performed on 80 eyes from 40 patients in this randomized, prospective, contralateral eye study. Dominant eyes were randomized to one group with the fellow eye receiving the alternate treatment. Primary outcome measures included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), contrast sensitivity, and root mean-square (RMS) higher order aberrations. RESULTS: Mean UDVA was -0.023+/-0.099 (20/19) in the custom group and -0.044+/-0.080 (20/18) in the conventional group 6 months after surgery (P=.293). Mean CDVA was -0.073+/-0.067 (20/17) in the custom group and -0.079+/-0.071 (20/17) in the conventional group 6 months after surgery (P=.659). Total higher order aberration RMS and spherical aberration increased in both groups compared to preoperative values (P<.05). Coma increased in the conventional group (P<.05) whereas it was similar to preoperative values in the custom group. No significant differences were noted in induction of trefoil. CONCLUSIONS: Custom and conventional PRK were shown to be safe and effective with excellent visual acuity and contrast sensitivity performance at 6 and 12 months. Conventional PRK induced more coma than custom PRK; however, this did not seem to correlate with clinical outcomes. PMID- 22230058 TI - Effect of basic fibroblast growth factor on corneal epithelial healing after photorefractive keratectomy. AB - PURPOSE: To evaluate the effect of basic fibroblast growth factor (bFGF) eye drops on corneal epithelial healing after photorefractive keratectomy (PRK). METHODS: One hundred patients treated with PRK for myopia were enrolled in this prospective, randomized study. Fifty patients were treated postoperatively with standard topical therapy and bFGF eye drops and 50 patients, used as controls, received standard postoperative therapy plus placebo (saline drops). Postoperatively, patients were examined daily until the epithelium healed. The velocity of resurfacing was recorded. Corneal clarity, visual acuity, and refraction were evaluated during the 3-month postoperative period. RESULTS: Complete epithelial healing was observed starting at postoperative day 3 in 46% of eyes in the bFGF group and 14% of eyes in the control group. At day 4, 98% and 72% of eyes in the bFGF and control groups, respectively, had healed. Five days after PRK, 100% of eyes treated with bFGF and 92% of control eyes achieved complete epithelial healing. In the control group, 98% of eyes healed at day 6 and all eyes completed healing at day 7. The difference in healing time was statistically significant (P<.001). No statistically significant differences were noted for haze prevalence, uncorrected distance visual acuity, and spherical equivalent refraction after treatment between groups (P>.05). No side or toxic effects were reported during the study. CONCLUSIONS: Basic fibroblast growth factor accelerates epithelial healing after PRK and could be used as additional treatment in circumstances of delayed healing. PMID- 22230059 TI - Improved keratoconus detection by ocular response analyzer testing after consideration of corneal thickness as a confounding factor. AB - PURPOSE: To compare corneal hysteresis (CH) and corneal resistance factor (CRF) between normal eyes and eyes with keratoconus correcting for the effect of central corneal thickness (CCT) and to estimate keratoconus detection sensitivity and specificity of these parameters. METHODS: Observational case series of 102 normal eyes (control group) and 77 eyes with keratoconus (keratoconus group). Examination included corneal topography, tomography, and biomechanical testing with the Ocular Response Analyzer (Reichert Technologies). The confounding effect of CCT was controlled by stratification (20-MUm CCT intervals) and linear transformation. Receiver operating characteristic curves were used to identify optimal CH and CRF cutoff points for keratoconus detection. Main outcome measures were CCT, CH, CRF, and diagnostic performance of CH and CRF. RESULTS: Corneal hysteresis and CRF were positively correlated to CCT in both groups. In the control versus keratoconus group, CH was 9.79 +/- 1.51 vs 8.49 +/- 1.48 (P<.0001) and CRF was 9.55 +/- 1.64 vs 7.24 +/- 1.43 (P<.0001), respectively. Only CRF remained significantly lower in eyes with keratoconus after CCT stratification in 20-MUm intervals, and keratoconus grade influenced CH and CRF. Transformed CH and CRF data confirmed these results. Sensitivity and specificity of CRF cutoff points ranged between 83% and 94% and 69% and 83%, respectively. True positive rate for CRF in eyes with keratoconus with normal topography was 84%. CONCLUSIONS: Corneal resistance factor was better than CH for detecting keratoconic corneas once the effect of CCT on ORA measurements was considered, even for topographically unaffected fellow eyes of patients with keratoconus. The CCT-corrected CRF cutoff values and transformed indices may be of clinical use. PMID- 22230060 TI - First evidence on different transportation modes of arsenic and phosphorus in arsenic hyperaccumulator Pteris vittata. AB - Arsenic (As) reduction and translocation are key processes for As hyperaccumulation by the hyperaccumulator Pteris vittata L. Micro-X-ray adsorption spectroscopy of P. vittata's rhizoid tissues revealed that As reduction mainly occurred in endodermis during translocation from epidermis to vascular bundle. Prior to reduction, arsenate (As (V)) translocation was an active process requiring energy and employing a phosphate (P) transporter. Use of a synchrotron X-ray microprobe showed that As (V) and P were cotransported and that this process could be enhanced by As (V) exposure or P deficiency but restrained by energy release inhibition caused by 2,4-dinitrophenol or sodium orthovanadate. In contrast, after As reduction, As(III) translocation differed from P translocation and was more efficient, appearing free from the apparent endodermal blockage. The results here revealed the role of the P transporter on As translocation as well as the key role of As reduction in As hyperaccumulation by P. vittata. PMID- 22230061 TI - Formation of halogenated C-, N-DBPs from chlor(am)ination and UV irradiation of tyrosine in drinking water. AB - The formation of regulated and emerging halogenated carbonaceous (C-) and nitrogenous disinfection by-products (N-DBPs) from the chlor(am)ination and UV irradiation of tyrosine (Tyr) was investigated. Increased chlorine contact time and/or Cl(2)/Tyr ratio increased the formation of most C-DBPs, with the exception of 4-chlorophenol, dichloroacetonitrile, and dichloroacetamideChloroform and dichloroacetic acid increased with increasing pH, dichloroacetonitrile first increased and then decreased, and other DBPs had maximum yields at pH 7 or 8. The addition of ammonia significantly reduced the formation of most C-DBPs but increased 4-chlorophenol, dichloroacetonitrile, dichloroacetamide, and trichloroacetonitrile yields for short prechlorination contact times before dosing ammonia. When UV irradiation and chlorination were performed simultaneously, the concentrations of the relatively stable C-DBPs increased, and the concentrations of dichloroacetonitrile, dichloroacetamide, and 4-chlorophenol decreased with increasing UV dose. This information was used to develop a mechanistic model for the formation of intermediate DBPs and end products from the interaction of disinfectants with tyrosine. PMID- 22230062 TI - Enhanced phytoextraction of chromium by the aquatic macrophyte Potamogeton pusillus in presence of copper. AB - The aquatic macrophyte, Potamogeton pusillus was evaluated for the removal of Cu(2+) and Cr(+6) from aqueous solutions during 15 days phytoextraction experiments. Results show that P. pusillus is capable of accumulating substantial amount of Cu and Cr from individual solutions (either Cu(2+) or Cr(+6)). Significant correlations between metal removal and bioaccumulation were obtained. Roots and leaves accumulated the highest amount of Cu and Cr followed by stems. The bioaccumulation of Cr was significantly enhanced in the presence of Cu, showing a synergic effect on Cr(+6) removal, presenting a good alternative for the removal of these metals from polluted aquifers. To the extent of our knowledge, this is the first report on both enhanced phytoextraction of Cr(+6) in presence of Cu(+2) and bioaccumulation of these heavy metals by P. pusillus. PMID- 22230063 TI - In situ sorption of hydrophobic organic compounds to sediment amended with activated carbon. AB - Contaminated sediments can be remediated by adding carbonaceous materials (CM), e.g. activated carbons (AC). Here, we analyze published datasets from AC amendment trials to identify variation in the effectiveness of AC in reducing porewater concentrations of hydrophobic organic contaminants (HOCs). The analysis uses a model that separates the contribution of HOC sorption to AC by parameterzing the sorption contributions by amorphous organic matter and black carbon (BC). It appears that sorption to BC increased with LogK(OW), whereas sorption to AC showed a relatively narrow range of affinity properties with a median Freundlich LogK(F,)(AC) value of 7.2 (MUg/kg(AC))/(MUg/L)(n) (IQR = 7.0 7.5) for polychlorinated biphenyls (PCBs) and 8.6 (IQR = 8.3-8.8) for polycyclic aromatic hydrocarbons (PAHs). Estimated Freundlich exponents were n(F,)(AC) = 0.74 for PCBs and 0.82 for PAH. Sorption to AC was stronger than to BC for chemicals below LogK(OW) = 6.3-6.6. For HOC risk reduction this is favorable, because chemicals with low K(OW) show generally higher bioavailable concentrations. PMID- 22230064 TI - Removal of the antiviral agent oseltamivir and its biological activity by oxidative processes. AB - The antiviral agent oseltamivir acid (OA, the active metabolite of Tamiflu((r))) may occur at high concentrations in wastewater during pandemic influenza events. To eliminate OA and its antiviral activity from wastewater, ozonation and advanced oxidation processes were investigated. For circumneutral pH, kinetic measurements yielded second-order rate constants of 1.7 +/- 0.1 * 10(5) and 4.7 +/- 0.2 * 10(9) M(-1) s(-1) for the reaction of OA with ozone and hydroxyl radical, respectively. During the degradation of OA by both oxidants, the antiviral activity of the treated aqueous solutions was measured by inhibition of neuraminidase activity of two different viral strains. A transient, moderate (two fold) increase in antiviral activity was observed in solutions treated up to a level of 50% OA transformation, while for higher degrees of transformation the activity corresponded to that caused exclusively by OA. OA was efficiently removed by ozonation in a wastewater treatment plant effluent, suggesting that ozonation can be applied to remove OA from wastewater. PMID- 22230065 TI - Vegetative cover and PAHs accumulation in soils of urban green space. AB - We investigated how urban land uses influence soil accumulation of polycyclic aromatic hydrocarbons (PAHs) in the urban green spaces composed of different vegetative cover. How did soil properties, urbanization history, and population density affect the outcomes were also considered. Soils examined were obtained at 97 green spaces inside the Beijing metropolis. PAH contents of the soils were influenced most significantly by their proximity to point source of industries such as the coal combustion installations. Beyond the influence circle of industrial emissions, land use classifications had no significant effect on the extent of PAH accumulation in soils. Instead, the nature of vegetative covers affected PAH contents of the soils. Tree-shrub-herb and woodland settings trapped more airborne PAH and soils under these vegetative patterns accumulated more PAHs than those of the grassland. Urbanization history, population density and soil properties had no apparent impact on PAHs accumulations in soils of urban green space. PMID- 22230066 TI - Use of a Bayesian isotope mixing model to estimate proportional contributions of multiple nitrate sources in surface water. AB - To identify different NO(3)(-) sources in surface water and to estimate their proportional contribution to the nitrate mixture in surface water, a dual isotope and a Bayesian isotope mixing model have been applied for six different surface waters affected by agriculture, greenhouses in an agricultural area, and households. Annual mean delta(15)N-NO(3)(-) were between 8.0 and 19.40/00, while annual mean delta(18)O-NO(3)(-) were given by 4.5-30.70/00. SIAR was used to estimate the proportional contribution of five potential NO(3)(-) sources (NO(3)( ) in precipitation, NO(3)(-) fertilizer, NH(4)(+) in fertilizer and rain, soil N, and manure and sewage). SIAR showed that "manure and sewage" contributed highest, "soil N", "NO(3)(-) fertilizer" and "NH(4)(+) in fertilizer and rain" contributed middle, and "NO(3)(-) in precipitation" contributed least. The SIAR output can be considered as a "fingerprint" for the NO(3)(-) source contributions. However, the wide range of isotope values observed in surface water and of the NO(3)(-) sources limit its applicability. PMID- 22230067 TI - A contribution towards the risk assessment of soils from the Sao Domingos Mine (Portugal): chemical, microbial and ecotoxicological indicators. AB - This study is a contribution towards a risk assessment of the Sao Domingos Mine area (Portugal), integrating information from: soil physicochemical characteristics, pseudo-total and bioavailable trace elements (As, Cd, Cr, Cu, Ni, Pb and Zn), ecotoxicological evaluation, and microbial indicators. The bioassays using soil eluates (seed germination, luminescent inhibition of Vibrio fischeri and Daphnia magna immobilization) confirmed the soil toxicity categorization obtained with the bioassays using soil (plant growth tests, Eisenia fetida mortality and avoidance behaviour). However, the soil identified as the most toxic using bioassays, was different from the expected when considering the results from pseudo-total and effective bioavailable trace elements. Taking in consideration the observations, it is highly recommended to complement the results from environmental chemistry with results from bioassays, in order to provide a more complete and relevant information on the bioavailability of contaminants and to characterize the risk of contaminated soils. PMID- 22230068 TI - Soil invertebrates as bioindicators of urban soil quality. AB - This study aimed at relating the abundance and diversity of invertebrate communities of urban soils to chemical and physical soil characteristics and to identify the taxa most sensitive or tolerant to soil stressors. The invertebrate community of five urban soils in Naples, Italy, was sampled. To assess soil quality invertebrate community indices (Shannon, Simpson, Menhinick and Pielou indices), Acarina/Collembola ratios, and the soil biological quality index (QBS) were calculated. The chemical and physical characteristics of the soils strongly differed. Abundance rather than taxa richness of invertebrates were more affected by soil characteristics. The community was more abundant and diverse in the soils with high organic matter and water content and low metal (Cu, Pb, Zn) concentrations. The taxa more resistant to the urban environment included Acarina, Enchytraeids, Collembola and Nematoda. Collembolans appeared particularly sensitive to changing soil properties. Among the investigated indices, QBS seems most appropriate for soil quality assessment. PMID- 22230069 TI - Inflammatory effects on human lung epithelial cells after exposure to diesel exhaust micron sub particles (PM1.0) and pollen allergens. AB - Asthma is currently defined as a chronic inflammatory disease of the airway. Several evidence indicate that vehicle emissions in cities is correlated with the allergic respiratory diseases. In the present study, we evaluated in the A549 cells the production and release of IL-4, IL-5 and IL-13 after treatment with sub micron PM(1.0) particles (PM(1.0)), Parietaria officinalis (ALL), and PM(1.0) + ALL together. Our data demonstrated that PM(1.0) + ALL together exhibited the greatest capacity to induce A549 cells to enhance the expression of IL-4 and IL-5 compared with the only PM(1.0) or ALL treatment. Interestingly, IL-13 that is necessary for allergen-induced airway hyper responsiveness, is increased in cells treated with PM(1.0) + ALL together, but is higher expressed when the cells are treated only with the allergen. Our data support the hypothesis that the urban environment damage the acinar lung units and activates cells of the immune system. PMID- 22230070 TI - Long-term biological monitoring of environmental quality around a solid waste landfill assessed with lichens. AB - The diversity of epiphytic lichens and the accumulation of selected trace elements in the lichen Flavoparmelia caperata L. (Hale) were used as indicators of pollution around a landfill in central Italy along 14 years of waste management. Lichens revealed an increased deposition for some elements (i.e., Cd, Cr, Fe and Ni) and a decrease of the lichen diversity at sites facing the landfill after an enlargement of the dumping area. However, the results allowed to exclude a significant increase in heavy metal depositions in the surrounding area and suggested that successful waste management may be associated with environmental quality. It is concluded that lichen monitoring might provide essential information to enhance the implementation of ecological impact assessment, supporting industrial regulatory procedures, also when waste management is concerned. PMID- 22230071 TI - The opposite impacts of Cu and Mg cations on dissolved organic matter-ofloxacin interaction. AB - Dialysis equilibrium system was applied to investigate the roles of Cu(II) and Mg(II) on DOM-ofloxacin (OFL) interaction. The binding behavior of both cations and OFL were studied. The introduction of Cu(II) increased DOM-OFL interaction, while Mg(II) decreased DOM-OFL binding. Cu(II) binding to DOM was also increased by OFL, while Mg(II) binding was decreased by OFL. The change in OFL binding amount in the absence and presence of cations (DeltaC(b)) was calculated and compared with cation binding (C(b)(m)). DeltaC(b)/C(b)(m) was in the range of 1-3 for Cu(II) depending on the applied Cu concentration. Two ternary complexes of DOM-OFL-Cu and DOM-Cu-OFL were proposed. For Mg(II), DeltaC(b)/C(b)(m) was around -1 at Mg(II) concentrations lower than 1 mM, but decreased up to -5 with increasing Mg(II) concentration. The competitive effect of Mg(II) to OFL was thus proposed. FTIR spectra were collected for mechanistic discussion. PMID- 22230072 TI - Presence and biological effects of emerging contaminants in Llobregat River basin: a review. AB - Llobregat River (North-East Spain) is the most important drinking water source for Barcelona and its surrounding area. As one of the only water sources in the area the river water have been overexploited and effluents from more than 30 urban wastewater treatment plants, industries and agriculture runoffs have been discharged into the river. This article reviews the presence of emerging contaminants published during the last decades, emphasizing on the observed effects on ecosystems caused by the contamination. Pesticides, surfactants, estrogens, pharmaceuticals and personal care products and even abuse drugs are the main groups detected in different studies, reporting alterations in species composition, abundance or biomass and endocrine disruption measured by alterations in enzymatic activity or specific protein production. The information available provides an overview of the river status according to the Water Framework Directive. PMID- 22230073 TI - Long term trends in PBDE concentrations in gannet (Morus bassanus) eggs from two UK colonies. AB - We used the eggs of an avian sentinel, the Northern gannet (Morus bassanus), to determine long-term (1977-2007) trends in PBDE contamination in Western Atlantic (Ailsa Craig colony) and North Sea (Bass Rock colony) waters around the UK. BDEs 47, 49, 99, 100, 153, 154 were the most abundant and were found in all eggs. Individual congener and SigmaPBDE concentrations in eggs from both colonies increased mainly from the late 1980s, peaked in 1994, and then rapidly declined so that concentrations in 2002 were similar to or lower than those in the 1970s and 1980s. The PBDE congener profile and temporal variation in PBDE concentrations suggests that the Penta-BDE technical formula was the main source of PBDE contamination. However, contributions of heavier BDE congeners to SigmaPBDE concentrations have increased over time, suggesting other sources are becoming more important. PBDEs had no measurable effect on egg volume or eggshell index. PMID- 22230074 TI - Distribution of PCBs and PBDEs in soils along the altitudinal gradients of Balang Mountain, the east edge of the Tibetan Plateau. AB - Surface soils were collected in Balang Mountain to explore the environmental process of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) during air transport. The average concentrations of ?(25)PCBs and ?(13)PBDEs in soils were 163 pg/g and 26 pg/g, respectively. The significant correlations between the concentrations of pollutants and total organic carbon (TOC) indicated the importance of TOC in accumulation potential of POPs. The slopes from fitted curves of PCBs were highly related with logK(oa), demonstrating that TOC dominates the soil-air exchange of PCBs. The TOC normalized concentrations of contaminants in samples from below-treeline were higher than those from alpine meadow, probably due to the forest filter effect. The increasing trends of the concentrations with altitude from the alpine meadow samples, could be attributed to the mountain cold-trapping effect. And the weak cold-trapping effect of POPs might be due to the less precipitation in 2008 when comparing with those in 2006. PMID- 22230075 TI - Can the integration of multiple biomarkers and sediment geochemistry aid solving the complexity of sediment risk assessment? A case study with a benthic fish. AB - Surveying toxicity of complex geochemical media as aquatic sediments often yields results that are either difficult to interpret or even contradictory to acknowledged theory. Multi-level biomarkers were investigated in a benthic fish exposed to estuarine sediments through laboratory and in situ bioassays, to evaluate their employment either in ecological risk assessment or in more mechanistic approaches to assess sediment-bound toxicity. Biomarkers reflecting lesions (such as genotoxicity or histopathology), regardless of their low or absent specificity to contaminants, are efficient in segregating exposure to contaminated from uncontaminated sediments even when classical biomarkers like CYP1A and metallothionein induction are inconclusive. Conversely, proteomics and gene transcription analyses provided information on the mechanics of toxicity and aided explaining response variation as a function of metabolic imbalance and impairment of defences against insult. In situ bioassays, although less expedite and more affected by confounding factors, produced data better correlated to overall sediment contamination. PMID- 22230076 TI - Influence of black carbon addition on phenanthrene dissipation and microbial community structure in soil. AB - Biodegradation processes and changes in microbial community structure were investigated in black carbon (BC) amended soils in a laboratory experiment using two soils (black soil and red soil). We applied different percentages of charcoal as BC (0%, 0.5% and 1% by weight) with 100 mg kg(-1) of phenanthrene. Soil samples were collected at different incubation times (0, 7, 15, 30, 60, 120 d). The amendment with BC caused a marked decrease in the dissipation (ascribed to mainly degradation and/or sequestration) of phenanthrene residues from soil. Extracted phenanthrene in black soil with 1% BC were higher, oppositely in red soil, 0.5% BC amendments were higher. There were significant changes in the PLFA pattern in phenanthrene-spiked soils with time but BC had little effect on the microbial community structure of phenanthrene-spiked soils, as indicated by principal component analysis (PCA) of the PLFA signatures. PMID- 22230077 TI - Distribution and toxicity of current-use insecticides in sediment of a lake receiving waters from areas in transition to urbanization. AB - Current-use insecticides including organophosphate (OPs) and synthetic pyrethroid (SPs) insecticides were analyzed in 35 sediment samples collected from Chaohu Lake in China, where a transition from a traditional agricultural to a modern urbanized society is ongoing. Total concentrations of five OPs and eight SPs ranged from 0.029 to 0.681 ng/g dry weight and 0.016-301 ng/g dry weight, respectively. Toxic unit analysis showed that 13% of the sediment samples likely produced over 50% of the mortality for benthic invertebrates. Analysis also showed that cypermethrin was the principal contributor to the toxicity. Spatial distribution evaluation implied that OPs were mainly from non-point sources associated with agricultural activities. Conversely, SPs may have been derived from runoff of inflowing rivers through urban regions, as their concentrations were well-correlated with concentrations of other urban-oriented contaminants. PMID- 22230078 TI - Persistent organic pollutants in four bivalve species from Svalbard waters. AB - Organochlorine compounds (OC) were determined in Arctic bivalves (Mya truncata, Serripes groenlandicus, Hiatella arctica and Chlamys islandica) from Svalbard with regard to differences in geographic location, species and variations related to their size and age. Higher chlorinated polychlorinated biphenyls (PCB 101-PCB 194), chlordanes and alpha-hexachlorocyclohexane (alpha-HCH) were consistently detected in the bivalves and PCBs dominated the OC load in the organisms. OC concentrations were highest in Mya truncata and the lowest in Serripes groenlandicus. Species-specific OC levels were likely related to differences in the species' food source, as indicated by the delta(13)C results, rather than size and age. Higher OC concentrations were observed in bivalves from Kongsfjorden compared to the northern sampling locations Liefdefjorden and Sjuoyane. The spatial differences might be related to different water masses influencing Kongsfjorden (Atlantic) and the northern locations (Arctic), with differing phytoplankton bloom situations. PMID- 22230079 TI - Formation and stability of Pb-, Zn- & Cu-PO4 phases at low temperatures: implications for heavy metal fixation in polar environments. AB - Low temperatures and frequent soil freeze-thaw in polar environments present challenges for the immobilisation of metals. To address these challenges we investigated the chemical forms of Pb, Zn and Cu in an Antarctic landfill, examined in vitro reaction kinetics of these metals and orthophosphate at 2 and 22 degrees C for up to 185 days, and subjected the products to freeze-thaw. Reaction products at both temperatures were similar, but the rate of production varied, with Cu-PO(4) phases forming faster, and the Zn- and Pb-PO(4) phases slower at 2 degrees C. All metal-orthophosphate phases produced were stable during a 2.5 h freeze-thaw cycle to -30 degrees C. Metal immobilisation using orthophosphate can be successful in polar regions, but treatments will need to consider differing mineral stabilities and reaction rates at low temperatures. PMID- 22230080 TI - Atmospheric concentrations of halogenated flame retardants at two remote locations: the Canadian High Arctic and the Tibetan Plateau. AB - Atmospheric concentrations of halogenated flame retardants (FRs) were monitored for approximately one year at two remote stations, namely Nam Co on the Tibetan Plateau and Alert in the Canadian High Arctic. BDE-47 and 99 were the dominant polybrominated diphenyl ether (PBDE) congeners at both sites. Atmospheric PBDE concentrations in Nam Co were generally lower than those at Alert. While significant seasonal variations were observed for PBDEs at Alert, the FR concentrations at Nam Co showed no significant seasonality, even though air masses originated from distinctly different regions during different seasons. This suggests that FRs in Tibet do not have regional sources, but are reflective of truly global background contamination. Three new FRs, namely 1,2-bis(2,4,6 tribromophenoxy)ethane (BTBPE), 2-ethyl-1-hexyl-2,3,4,5-tetrabromobenzoate (EHTeBB) and bis(2-ethyl-1-hexyl)tetrabromophthalate (TBPH) were detected at relatively high concentrations at both sites. This is the first report of these FRs in the remote global atmosphere and suggests significant potential for long range atmospheric transport. PMID- 22230081 TI - Spatial distribution of per- and polyfluoroalkyl compounds in coastal waters from the East to South China Sea. AB - The spatial distribution of per- and polyfluoroalkyl compounds (PFCs) were investigated in coastal waters collected onboard research vessel Snow Dragon from the East to South China Sea in 2010. All samples were prepared by solid-phase extraction and analyzed using high performance liquid chromatography/negative electrospray ionization-tandem mass spectrometry (HPLC/(-)ESI-MS/MS). Concentrations of 9 PFCs, including C(4) and C(8) (PFBS, PFOS) perfluoroalkyl sulfonate (PFSAs), C(5)-C(9) and C(13) (PFPA, PFHxA, PFHpA, PFOA, PFNA, PFTriDA) perfluoroalkyl carboxylates (PFCAs), and N-ethyl perfluorooctane sulfonamide (EtFOSA) were quantified. The SigmaPFC concentrations ranged from 133 pg/L to 3320 pg/L, with PFOA (37.5-1541 pg/L), PFBS (23.0-941 pg/L) and PFHpA (0-422 pg/L) as dominant compounds. Concentrations of PFCs were greater in coastal waters along Shanghai, Ningbo, Taizhou, Xiamen and along coastal cities of the Guangdong province compared to less populated areas along the east Chinese coast. Additionally, the comparison with other seawater PFC measurements showed lower levels in this study. PMID- 22230082 TI - Coal fly ash basins as an attractive nuisance to birds: parental provisioning exposes nestlings to harmful trace elements. AB - Birds attracted to nest around coal ash settling basins may expose their young to contaminants by provisioning them with contaminated food. Diet and tissues of Common Grackle (Quiscalus quiscala) nestlings were analyzed for trace elements to determine if nestlings were accumulating elements via dietary exposure and if feather growth limits elemental accumulation in other tissues. Arsenic, cadmium, and selenium concentrations in ash basin diets were 5* higher than reference diets. Arsenic, cadmium, and selenium concentrations were elevated in feather, liver, and carcass, but only liver Se concentrations approached levels of concern. Approximately 15% of the total body burden of Se, As, and Cd was sequestered in feathers of older (>5 days) nestlings, whereas only 1% of the total body burden of Sr was sequestered in feathers. Feather concentrations of only three elements (As, Se, and Sr) were correlated with liver concentrations, indicating their value as non-lethal indicators of exposure. PMID- 22230083 TI - Seasonal variation in mercury and food web biomagnification in Lake Ontario, Canada. AB - Seasonal variation in mercury (Hg) concentrations and food web structure was assessed for eastern Lake Ontario. Hg concentrations, measured in 6 species of invertebrates and 8 species of fishes, tended to be highest in the spring and lowest in the summer for most biota. Yellow perch (Perca flavescens) exhibited significant ontogenetic shifts in diet and Hg, although such patterns were not evident for other species. Food web structure, as indicated by stable isotope values (delta(15)N, delta(13)C) was not static. Log-transformed Hg data were strongly and consistently correlated with delta(15)N values for the whole food web in each of the three seasons (slopes, 0.17-0.24) and across the entire year (slope, 0.2). While significantly different between seasons, the regression slope values are still consistent with published global Hg biomagnification rates. Our results indicate that the assessment of Hg trends in Great Lakes must take into account seasonal patterns and time of sampling. PMID- 22230084 TI - Characterizing the emission of chlorinated/brominated dibenzo-p-dioxins and furans from low-temperature thermal processing of waste printed circuit board. AB - This study focuses primarily on the inventory of PCDD/Fs and PBDD/Fs associated with the low-temperature thermal processing of scrap printed circuit boards (PCBs). Twelve 2,3,7,8-substituted PBDD/Fs congeners were found in various sample outputs, with a total content of 60,000 ng TEQ/kg at 250 degrees C under air atmosphere. A rapid increase of PBDD/Fs was produced with 160,000 ng TEQ/kg, at 275 degrees C-about twice that under the N(2) atmosphere. At 275 degrees C, the total contents of PCDD/Fs were only 170 and 770 ng TEQ/kg under an N(2) and air atmospheres respectively. The results reveal that a large contribution of PBDD/Fs emission may be expected from the dismantling or any other thermal processing of PCB scrap. PCDD/Fs, however, are formed and released into the environment in a variety of ways. Additional research is required to look for the causal factors that affect emissions. PMID- 22230085 TI - Quantitative identification of dynamic and static quenching of ofloxacin by dissolved organic matter using temperature-dependent kinetic approach. AB - Ofloxacin (OFL) was used as a model antibiotic and the quenching of OFL fluorescence by DOM was examined with an emphasis on temperature-dependent quenching kinetics. OFL fluorescence intensity was corrected for inner filter and temperature effects. The kinetics data were fitted well using a two-compartment pseudo first-order kinetics model. Three quenching compartments were identified using this model, namely, a very fast quenching compartment (q(0)) and two pseudo first-order quenching compartments (q(1) + q(2)). The q(0) values had a positive relationship with temperature, while (q(1) + q(2)) were negatively related with temperature. In addition, OFL-DOM binding quantified by (q(1) + q(2)) was consistent with binding result obtained from dialysis equilibrium system. We concluded that q(0) was resulted from dynamic quenching, while (q(1) + q(2)) was attributed to static quenching. The dynamic quenching of OFL by DOM accounted for 30-90% to the overall quenching and thus was very significant. PMID- 22230086 TI - Enhanced dissipation of polycyclic aromatic hydrocarbons in the presence of fresh plant residues and their extracts. AB - The feasibility of using fresh plant residues and their extracts to stimulate the bio-dissipation of polycyclic aromatic hydrocarbons (PAHs) were highlighted. Wood chip, bamboo leave, orange peel and their water-extractable organic matter (WEOM) were chosen as amendment materials. Effect of WEOM on bio-dissipation (bioaccumulation and biodegradation) of phenanthrene and pyrene from water by two bacteria were investigated. Orange peel extract demonstrated the highest efficiency for stimulating PAHs removal by bacterium B1 (Pseudomonas putida), while bamboo leave extract was the best one to enhance PAHs bio-dissipation by bacterium B2 (unidentified bacterium isolated from PAHs-contaminated soil). Amended the actual contaminated soil with 1% plant residues, PAHs dissipation were increased by 15-20%, 20-39%, 14-24%, 12-23% and 17-26%, respectively, for 2 , 3-, 4-, 5- and 6-ring PAHs via stimulating indigenous microbial degradation activity. Bamboo leave exhibited the most effective one to stimulate dissipation of PAHs in contaminated soil. PMID- 22230087 TI - Toxicokinetic of benzo[a]pyrene and fipronil in female green frogs (Pelophylax kl. esculentus). AB - A general consensus that an increased logK(ow) led to an increase in xenobiotic uptake and bioaccumulation is accepted. In this study we compared the toxicokinetics of two chemically different xenobiotics, i.e. benzo[a]pyrene and fipronil in female green frogs. Surprisingly, the uptake rates and the bioconcentration factors (BCF) of the two contaminants were not predicted by their logK(ow). The uptake rates obtained were of the same order of magnitude for the two contaminants and the BCFs measured for fipronil were about 3-fold higher than those obtained for benzo[a]pyrene. Fipronil appeared to be more recalcitrant than benzo[a]pyrene to detoxification processes leading to the accumulation of sulfone-fipronil especially in the ovaries. This phenomenon may explain reproductive influence of this contaminant described in other studies. Detoxification processes, including metabolism and the excretion of pollutants, are of importance when considering their persistence in aquatic organisms and trying to quantify their risks. PMID- 22230088 TI - Chemical characteristics of size-resolved PM2.5 at a roadside environment in Beijing, China. AB - Size-resolved particulate matter in the three size ranges (0.2-0.5 MUm, 0.5-1.0 MUm, and 1.0-2.5 MUm) were collected at a roadside site in Beijing during and after the 2008 Olympic Games. The concentrations of PM mass, 14 elements, 3 major inorganic ions, and carbonaceous species were determined. The main contributors to PM(2.5) were crustal sources, vehicle emissions, secondary aerosol formation along with coal combustion, biomass from burning, and industrial processes, with vehicle emissions contributing more to roadside PM(2.5) than in the urban areas. The peaks at 0.5-1.0 MUm in summer for PM mass and inorganic ions were most likely due to secondary aerosol formation, whereas the peaks at 0.2-0.5 MUm in winter for PM mass and some elements were probably attributed to combustion from heating sources. The temporary control measures applied during the Olympics showed different effects on various emission sources and chemical species. PMID- 22230089 TI - Spatial distribution of chlordanes and PCB congeners in soil in Cedar Rapids, Iowa, USA. AB - Residential soils from Cedar Rapids, Iowa, USA were collected and analyzed for chlordanes and polychlorinated biphenyls (PCBs). This study is one of the very few urban soil investigations in the USA. The chlordanes concentrations ranged from 0 to 7500 ng g(-1) dry weight (d.w.), with a mean and standard deviation of 130 +/- 920 ng g(-1) d.w., which is about 1000 times larger than background levels. SigmaPCB concentrations ranged from 3 to 1200 ng g(-1) d.w., with a mean and standard deviation of 56 +/- 160 ng g(-1) d.w. and are about 10 times higher than world-wide background levels. Both groups exhibit considerable variability in chemical patterns and site-to-site concentrations. Although no measurements of dioxins were carried out, the potential toxicity due to the 12 dioxin-like PCBs found in the soil is in the same order of magnitude of the provisional threshold recommended by USEPA to perform soil remediation. PMID- 22230090 TI - PBDEs in Italian sewage sludge and environmental risk of using sewage sludge for land application. AB - Polybrominated diphenyl ethers (PBDEs) were determined in sewage sludge samples collected from eight Italian wastewater treatment plants (WWTPs) between June 2009 and March 2010. Total PBDE concentrations ranged from 158.3 to 9427 ng g(-1) dw, while deca-BDE (BDE-209) (concentrations ranging from 130.6 to 9411 ng g(-1) dw) dominated the congener profile in all the samples, contributing between 77% and 99.8% of total PBDE. The suitability of using a magnetic particle enzyme linked immunoassay (ELISA) to analyse PBDEs in sewage sludge was also tested. The ELISA results, expressed as BDE-47 equivalents, were well correlated with those obtained by GC-NCI-MS, with correlation coefficients (r(2)) of 0.899 and 0.959, depending on the extraction procedure adopted. The risk assessment of PBDEs in sewage sludge addressed to land application was calculated. PEC(soil) values compared to the relative PNEC(soil) for penta and deca-BDE suggests that there is a low risk to the soil environment. PMID- 22230091 TI - A GIS technology based potential eco-risk assessment of metals in urban soils in Beijing, China. AB - Ecological risks of heavy metals in urban soils were evaluated using Beijing, China as an example. Cadmium, Cu, Zn, Pb, Cr and Ni contents of 233 surface soils sampled by 1 min latitude * 1 min longitude grid were used to identify their spatial distribution patterns and potential emission sources. Throughout the city, longer the duration of urbanization greater was the accumulations of heavy metals especially, Cd, Cu, Pb, and Zn. The soil Zn mainly came from the wears of vehicular tires. Point source emissions of heavy metals were few and far in the downwind south-east quadrant of Beijing. The calculated risk indices showed potential median eco-risks in the ancient central city. No potential high eco risk due to soil-borne heavy metals was found. The potential medium eco-risk areas in Beijing would expand from the initial 24 to 110 km(2) if soil pH were to reduce by 0.5 units in anticipation. PMID- 22230092 TI - Guidelines for the identification and management of patients with familial hypercholesterolaemia (FH): are we coming to a consensus? PMID- 22230093 TI - BH3 profiling--measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. AB - Apoptosis is a form of programmed cell death that is controlled at the mitochondrion by the BCL-2 family of proteins. While much has been learned about the structure and function of these proteins over the past two decades, the important goal of predicting cell fate decisions in response to toxic stimuli is largely unrealized. BH3 profiling is a functional approach that can be used to predict cellular responses to stimuli based on measuring the response of mitochondria to perturbation by a panel of BH3 domain peptides. BH3 profiling has proven useful in identifying and understanding cellular dependence on individual anti-apoptotic proteins like BCL-2 or MCL-1. Consequently, it can also be used to predict cellular response to chemotherapy agents such as ABT-737 that target these individual proteins. PMID- 22230094 TI - Octogenarians: an increasing challenge for acute care and colorectal surgeons. An outcomes analysis of emergency colorectal surgery in the elderly. AB - AIM: Emergency surgery is associated with higher mortality rates, especially in elderly patients presenting with emergent colorectal disease. The aim of this study was to determine the outcomes in elderly patients following emergency colorectal resection, with particular focus on octogenarians who presented a sixfold higher mortality rate with respect to other patients. METHOD: This study examined 355 patients who underwent surgery at an Emergency Department for complications of colorectal disease between January 2007 and December 2009. Morbidity and mortality were analyzed on the basis of patients' characteristics and presentation. Univariate and logistic regression analyses were performed on morbidity and mortality risk factors. RESULTS: Two-hundred and fifteen patients of > 65 years of age were included, 93 of whom were >= 80 years of age. The global mortality rate was 16%. In patients >= 80 years of age the mortality rate was 30%. The difference in mortality rate between patients < 80 years of age vs patients >= 80 years of age was 24%. In resected patients >= 80 years of age, American Society of Anesthesiology grade, colonic ischaemia, neurological comorbidity and anastomotic dehiscence were identified as independent risk factors in both univariate and logistic regression analyses. The morbidity rate was approximately 17%, and no significant difference in morbidity was found between the two groups. CONCLUSION: The results of this study show that fitness status and micro vascular impairment impact significantly on mortality in the elderly, particularly in octogenarians. Although the outcomes observed were compatible with the literature, the six fold higher mortality rate observed in the most elderly patients identifies a group for which death prevention is best achieved with aggressive resuscitation and intensive postoperative care, rather than timing of surgery. PMID- 22230095 TI - Coding of procedures documented by general practitioners in Swedish primary care an explorative study using two procedure coding systems. AB - BACKGROUND: Procedures documented by general practitioners in primary care have not been studied in relation to procedure coding systems. We aimed to describe procedures documented by Swedish general practitioners in electronic patient records and to compare them to the Swedish Classification of Health Interventions (KVA) and SNOMED CT. METHODS: Procedures in 200 record entries were identified, coded, assessed in relation to two procedure coding systems and analysed. RESULTS: 417 procedures found in the 200 electronic patient record entries were coded with 36 different Classification of Health Interventions categories and 148 different SNOMED CT concepts. 22.8% of the procedures could not be coded with any Classification of Health Interventions category and 4.3% could not be coded with any SNOMED CT concept. 206 procedure-concept/category pairs were assessed as a complete match in SNOMED CT compared to 10 in the Classification of Health Interventions. CONCLUSIONS: Procedures documented by general practitioners were present in nearly all electronic patient record entries. Almost all procedures could be coded using SNOMED CT.Classification of Health Interventions covered the procedures to a lesser extent and with a much lower degree of concordance. SNOMED CT is a more flexible terminology system that can be used for different purposes for procedure coding in primary care. PMID- 22230096 TI - ProFASTA: a pipeline web server for fungal protein scanning with integration of cell surface prediction software. AB - Surface proteins, such as those located in the cell wall of fungi, play an important role in the interaction with the surrounding environment. For instance, they mediate primary host-pathogen interactions and are crucial to the establishment of biofilms and fungal infections. Surface localization of proteins is determined by specific sequence features and can be predicted by combining different freely available web servers. However, user-friendly tools that allow rapid analysis of large datasets (whole proteomes or larger) in subsequent analyses were not yet available. Here, we present the web tool ProFASTA, which integrates multiple tools for rapid scanning of protein sequence properties in large datasets and returns sequences in FASTA format. ProFASTA also allows for pipeline filtering of proteins with cell surface characteristics by analysis of the output created with SignalP, TMHMM and big-PI. In addition, it provides keyword, iso-electric point, composition and pattern scanning. Furthermore, ProFASTA contains all fungal protein sequences present in the NCBI Protein database. As the full fungal NCBI Taxonomy is included, sequence subsets can be selected by supplying a taxon name. The usefulness of ProFASTA is demonstrated here with a few examples; in the recent past, ProFASTA has already been applied successfully to the annotation of covalently-bound fungal wall proteins as part of community-wide genome annotation programs. ProFASTA is available at: http://www.bioinformatics.nl/tools/profasta/. PMID- 22230098 TI - Echocardiographic findings of iatrogenic septal defect during TA-AVI. PMID- 22230097 TI - Do obese children with diabetic ketoacidosis have type 1 or type 2 diabetes? AB - OBJECTIVE: Many obese children with unprovoked diabetic ketoacidosis (DKA) display clinical features of type 2 diabetes during follow up. We describe the clinical presentation, autoimmune markers and the long-term course of obese and lean children with DKA. RESEARCH DESIGN AND METHODS: We reviewed the medical records on the initial acute hospitalization and outpatient follow-up care of 21 newly diagnosed obese and 20 lean children with unprovoked DKA at Emory University affiliated children's hospitals between 1/2003 and 12/2006. RESULTS: Obese children with DKA were older and predominantly male, had acanthosis nigricans, and had lower prevalence of autoantibodies to islet cells and glutamic acid decarboxylase than lean children. Half of the obese, but none of the lean children with DKA achieve near-normoglycemia remission and discontinued insulin therapy during follow-up. Time to achieve remission was 2.2+/-2.3 months. There were no differences on clinical presentation between obese children who achieved near-normoglycemia remission versus those who did not. The addition of metformin to insulin therapy shortly after resolution of DKA resulted in lower hemoglobin A1c (HbA1c) levels, higher rates of near-normoglycemia remission, and lower frequency of DKA recurrence. Near-normoglycemia remission, however, was of short duration and the majority of obese patients required reinstitution of insulin treatment within 15 months of follow-up. CONCLUSION: In contrast to lean children with DKA, many obese children with unprovoked DKA display clinical and immunologic features of type 2 diabetes during follow-up. The addition of metformin to insulin therapy shortly after resolution of DKA improves glycemic control, facilitates achieving near-normoglycemia remission and prevents DKA recurrence in obese children with DKA. PMID- 22230099 TI - [Right atrial thrombus: a rare presentation of plasminogen activator inhibitor deficiency]. AB - Free-floating right atrial thrombi are rare but associated with high mortality. Although advances in echocardiography have improved diagnosis, their management is still the subject of debate. A 24-year-old woman with a history of smoking, obesity and oral contraceptive use presented to the emergency department with dyspnea, cough and hemoptysis. Transthoracic echocardiography revealed a large free-floating cardiac mass occupying the right atrial chamber and restricting tricuspid valve opening. In view of recurrent pulmonary embolism, she was referred for cardiac surgery and the cardiac mass was excised. Anatomopathological analysis revealed an organized and calcified thrombus. Genetic study showed her to be homozygous for the 4G/4G allelic variant of plasminogen activator inhibitor-1 and heterozygous for the allelic variant A1298C of 5,10-methylenetetrahydrofolate reductase. PMID- 22230100 TI - Sonochemical synthesis, photocatalytic activity and optical properties of silica coated ZnO nanoparticles. AB - In this paper, we report the synthesis of silica coated ZnO nanoparticles by ultrasound irradiation of a mixture of dispersion of ZnO, tetraethoxysilane (TEOS), and ammonia in an ethanol-water solution medium. The silica coating layer formed at the initial TEOS/ZnO loading of 0.8 for 60 min ultrasonic irradiation was uniform and extended up to 3 nm from the ZnO surface as revealed from HR-TEM images. Silica coated ZnO nanoparticles demonstrated a significant inhibition of photocatalytic activity against photodegradation of methylene blue dye in aqueous solution. The effects of silica coating on the UV blocking property of ZnO nanoparticles were also studied. PMID- 22230101 TI - Ultrasound promoted efficient and green synthesis of beta-amino carbonyl compounds in aqueous hydrotropic medium. AB - Ultrasound promoted synthesis of beta-amino carbonyl compounds in aqueous hydrotropic medium at ambient temperature is reported. The remarkable features of the new procedure are shorter reaction time, excellent yields in aqueous medium, cleaner reaction profile and simple experimental and work-up procedure. PMID- 22230102 TI - Prevalence survey of healthcare-associated infections in Argentina; comparison with England, Wales, Northern Ireland and South Africa. AB - BACKGROUND: Prevalence surveillance methodology is the systematic observation of the occurrence and distribution of healthcare-associated infections (HCAIs) so that appropriate actions can be taken. AIM: The objectives of a prevalence survey with an international validated methodology were to determine the prevalence of HCAIs for the first time in Argentina, and to provide data which could be used for international benchmarking. METHODS: In 2008, an HCAI prevalence survey was carried out in 39 hospitals in seven of 23 provinces in Argentina, with methodology identical to that employed by the Hospital Infection Society in the third prevalence survey of HCAIs in acute hospitals in the British Isles. Data collected were processed and analysed at the Northern Ireland Healthcare Associated Infection Surveillance Centre at Belfast. FINDINGS: A total of 4249 patients were surveyed; 480 of these had at least one HCAI, resulting in a prevalence of 11.3% of patients. Male prevalence was 13.6% and female 9.0%. The most common HCAIs were pneumonia (3.3%), urinary tract infection (3.1%), surgical site infection (2.9%), primary bloodstream infection (1.5%), and soft tissue infections (1.2%). Among the 1027 patients who underwent surgery, the prevalence of surgical site infection was 10.2%. The prevalence of meticillin-resistant Staphylococcus aureus was 1.1%, accounting for 10.0% of all HCAI isolates. The results for Argentina show higher HCAI rates compared with corresponding findings for England, Wales, Northern Ireland and South Africa. CONCLUSION: This survey will contribute to the prioritization of resources and help to inform Departments of Health and hospitals in the continuing effort to reduce HCAIs. PMID- 22230103 TI - Outcome of central venous catheter-related bacteraemia according to compliance with guidelines: experience with 91 episodes. AB - BACKGROUND: Infection is a major complication associated with the use of central venous catheters. Guidelines for medical management of catheter-related bacteraemia have been published, but no study has assessed the appropriateness of physician practices. AIM: To assess medical practices in cases of central venous catheter-related bacteraemia (CRB) in a university hospital. METHODS: Cases were recorded over a period of 12 months and their management was evaluated. All cases of positive blood cultures based on central venous catheter sampling were analysed, and episodes of CRB were determined in this group of patients. Medical management and patient outcome were analysed independently by two physicians. FINDINGS: In all, 187 cases of positive blood culture were recorded and 91 cases of CRB were analysed. Systemic antimicrobial therapy was optimal in 56% of the episodes. In 51 episodes, catheter salvage was attempted, for 29 with an indication in agreement with the guidelines but without antibiotic-lock therapy in 20 episodes. The overall medical management was appropriate in 41.8% of the episodes. The overall cure rate was 72.5%. CRB-related death occurred in 5.5% of the episodes. Cure was associated with guideline compliance (P = 0.03) and with adaptation of systemic antimicrobial therapy (P < 0.01). Conservative treatment success was associated with compliance with the guidelines for the indication (P = 0.01). CONCLUSION: Medical management of CRB did not closely adhere to international guidelines. CRB outcome was associated with the appropriateness of this management, particularly when conservative treatment was attempted. PMID- 22230105 TI - The foot posture index, ankle lunge test, Beighton scale and the lower limb assessment score in healthy children: a reliability study. AB - BACKGROUND: Outcome measures are important when evaluating treatments and physiological progress in paediatric populations. Reliable, relevant measures of foot posture are important for such assessments to be accurate over time. The aim of the study was to assess the intra- and inter-rater reliability of common outcome measures for paediatric foot conditions. METHODS: A repeated measures, same-subject design assessed the intra- and inter-rater reliability of measures of foot posture, joint hypermobility and ankle range: the Foot Posture Index (FPI 6), the ankle lunge test, the Beighton scale and the lower limb assessment scale (LLAS), used by two examiners in 30 healthy children (aged 7 to 15 years). The Oxford Ankle Foot Questionnaire (OxAFQ-C) was completed by participants and a parent, to assess the extent of foot and ankle problems. RESULTS: The OxAFQ-C demonstrated a mean (SD) score of 6 (6) in adults and 7(5) for children, showing good agreement between parents and children, and which indicates mid-range (transient) disability. Intra-rater reliability was good for the FPI-6 (ICC = 0.93 - 0.94), ankle lunge test (ICC = 0.85-0.95), Beighton scale (ICC = 0.96 0.98) and LLAS (ICC = 0.90-0.98). Inter-rater reliability was largely good for each of the: FPI-6 (ICC = 0.79), ankle lunge test (ICC = 0.83), Beighton scale (ICC = 0.73) and LLAS (ICC = 0.78). CONCLUSION: The four measures investigated demonstrated adequate intra-rater and inter-rater reliability in this paediatric sample, which further justifies their use in clinical practice. PMID- 22230104 TI - Ramipril-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes (ADaPT) study. AB - BACKGROUND: Previous randomized controlled trials demonstrated a protective effect of renin angiotensin system blocking agents for the development of type-2 diabetes in patients with pre-diabetes. However, there are no real-world data available to illustrate the relevance for clinical practice. METHODS: Open, prospective, parallel group study comparing patients with an ACE inhibitor versus a diuretic based treatment. The principal aim was to document the first manifestation of type-2 diabetes in either group. RESULTS: A total of 2,011 patients were enrolled (mean age 69.1+/-10.3 years; 51.6% female). 1,507 patients were available for the per-protocol analysis (1,029 ramipril, 478 diuretic group). New-onset diabetes was less frequent in the ramipril than in the diuretic group over 4 years. Differences were statistically different at a median duration of 3 years (24.4% vs 29.5%; p<0.05). Both treatments were equally effective in reducing BP (14.7+/-18.0/8.5+/-8.2 mmHg and 12.7+/-18.1/7.0+/-8.3 mmHg) at the 4 year follow-up (p<0.001 vs. baseline; p=n.s. between groups). In 38.6% and 39.7% of patients BP was below 130/80 mmHg (median time-to-target 3 months). There was a significant reduction of cardiovascular morbidity and mortality in favour of ramipril (p=0.033). No significant differences were found for a change in HbA1c as well as for fasting blood glucose levels during follow-up. The rate of adverse events was higher in diuretic treated patients (SAE 15.4 vs. 12.4%; p<0.05; AE 26.6 vs. 25.6%; p=n.s). CONCLUSIONS: Ramipril treatment is preferable over diuretic based treatment regimens for the treatment of hypertension in pre diabetic patients, because new-onset diabetes is delayed. PMID- 22230106 TI - Analysis of the interdiffusion of resin monomers into pre-polymerized fiber reinforced composites. AB - OBJECTIVES: The aim of the study was to analyze the dissolving depth of adhesive resin monomers into pre-polymerized fiber-reinforced composites (FRC) with either a semi-interpenetrating polymer network (semi-IPN) or a cross-linked polymer (CLP) matrix. METHODS: Five unidirectional FRCs were tested, including one semi IPN FRC (everStick((r)) C&B, StickTech, (ES)) and four CLP-FRCs (GrandTec((r)), VOCO, (GT); Dentapreg((r)), ADM, (DP); TenderFiber((r)), Micerium, (TF); Splint It((r)), Pentron Clinical Technologies, (SI)). The FRCs were light-polymerized following manufacturers' instructions: the oxygen inhibition layers were removed and the adhesive resin (Optibond-FL((r)), KerrHawe) was labeled with a fluorescent dye (Rhodamine-B-isothiocyanate), which was then applied to the FRCs (5 min) and light-polymerized (40s). Specimens were then prepared for confocal laser scanning microscopy. Three FRC strands per group were sectioned orthogonally to the direction of fibers, thus forming nine slices in each group. Four images were taken from each slice and the depths of adhesive penetration were measured in four sites per image (n=144 measurements per group). SIGNIFICANCE: Dissolving depths were 17.28 (3.04) MUm (ES), 12.58 (2.94) MUm (SI), 7.57 (1.91) MUm (TF), 3.27 (0.73) MUm (DP) and 2.55 (0.63) MUm (GT). Samples were normally distributed. Differences between groups were analyzed by ANOVA (PostHoc Scheffe) showing four subgroups (p=0.05). The infiltration layers detected were either continuous/homogenous (ES, TF, DP GT) or discontinuous/insular (SI). CONCLUSION: The adhesive resin monomers were able to diffuse significantly deeper into pre-polymerized semi-IPN specimens than into CLP materials. Semi-IPN specimens showed a homogenous and comparatively deeper layer of infiltration. The diffusion capabilities of secondary-IPN formation might increase the opportunity to establish a good bond between pre-polymerized FRC and new resin. PMID- 22230108 TI - Blood natural killer cell cytotoxicity enhancement correlates with an increased activity in brain motor structures following chronic stimulation of the bed nucleus of the stria terminalis in rats. AB - The present study indicates that a chronic 14 day electrical stimulation of the bed nucleus of the stria terminalis (BST) increased blood but not spleen natural killer cell (NK) cytotoxicity and a large granular lymphocyte (LGL) number. These immune changes positively correlated with the increased activity in brain cortical and subcortical motor structures that influence the BST stimulation induced behavioral response. No significant changes in blood and spleen leukocyte population numbers and plasma corticosterone concentration after the stimulation were found. The obtained results suggest that this immunoenhancing effect on blood NK cell function and number is dependent on the behavioral outcome of the BST stimulation rather than endocrine response. PMID- 22230107 TI - Resin composite blocks via high-pressure high-temperature polymerization. AB - OBJECTIVES: The aim of this study was to thermo-polymerize under high pressure four commercially available dental resin composites to obtain and characterize composite blocks suitable for CAD/CAM procedures. METHODS: Gradia (GC, Japan), Vita VM LC (Vita Zahnfabrik, Germany), Grandio (VOCO, Germany), and EsthetX (Dentsply, Germany), were selected for this study. Paradigm (3 M ESPE, USA), a CAD/CAM composite block, was included for comparison. Composite blocks were obtained through polymerization at high-temperature high-pressure (HT/HP). Samples for mechanical/physical characterizations were cut from Paradigm and HT/HP composite blocks while control samples were obtained by photo-polymerizing (PP) the materials in molds. Flexural strength (sigma(f)), fracture toughness (K(IC)), hardness, and density (rho) were determined and compared by pairwise t tests (alpha=0.05). Fractured surfaces were characterized under a scanning electron microscope. RESULTS: The results have shown that HT/HP polymerization resulted in a significant (p<0.05) increase in sigma(f), hardness, and rho for all composites investigated. Even if K(IC) of all materials was increased by HT/HP polymerization, significant increases were detected only for Gradia and EsthetX. The Weibull modulus of HT/HP polymerized composites was higher than that of PP counterparts. HT/HP materials had higher sigma(f), Weibull modulus, and K(IC) compared to Paradigm. The most significant SEM observation of fractured K(IC) specimens from all the materials tested was the presence of fewer and smaller voids in HT/HP polymerized composites. SIGNIFICANCE: The results of this study suggest that HT/HP polymerization could be used to obtain dental resin composite blocks with superior mechanical properties, suitable for CAD/CAM processing. PMID- 22230109 TI - 186th ENMC international workshop: congenital myasthenic syndromes 24-26 June 2011, Naarden, The Netherlands. PMID- 22230110 TI - Gastroenteritis in older people living in the community: results of two Australian surveys. AB - We analysed two large national surveys conducted in 2001 and 2008 to examine incidence and outcomes of gastroenteritis in older Australians. A case was someone reporting >=3 loose stools or >=1 episode of vomiting in 24 h, excluding non-infectious causes. We compared cases arising in the elderly (>=65 years) and in other adults (20-64 years). Elderly people experienced 0.33 [95% confidence interval (CI) 0.24-0.42] episodes of gastroenteritis/person per year, compared to 0.95 (95% CI 0.74-1.15) in other adults. Elderly cases reported less stomach cramps, fever and myalgia than younger cases, and were more likely to be hospitalized, although this was not statistically significant. In multivariable analysis, gastroenteritis in elderly people was associated with travelling within the state (odds ratio 1.35, 95% CI 1.07-1.71). Elderly people were less concerned about food safety than other adults. Older Australians were less likely to report gastroenteritis and experienced different symptoms and outcomes from other adults. PMID- 22230111 TI - A method for quantitative characterization of growth in the 3-D structure of rat pulmonary arteries. AB - Understanding mechanisms causing pulmonary vascular disease (PVD) frequently requires a thorough understanding of the underlying structural changes in the pulmonary circulation. Animal models have been used extensively to study different forms of PVD but conventional experimental techniques are limited in their ability to allow the study of the whole pulmonary vasculature at once. In this study, we introduce novel techniques of arterial casting, high-resolution imaging and tree analysis to study the pulmonary circulation in rodent models. Male Sprague-Dawley rats were used at 20, 36, 52, 100 and 160 days of age. A technique involving arterial casting with Microfil silicone polymer, high resolution micro-computed tomography (micro-CT) at 12.5 MUm resolution and image data analysis involving segmentation and skeletonization was developed to both qualitatively and quantitatively describe the changes in the pulmonary vasculature with increasing age. Parameters identified to affect the quality of pulmonary arterial casting included polymer flow rate, total injected volume, polymer viscosity and polymerization time. By optimizing these parameters, we successfully created arterial casts of the pulmonary circulation in rats of different ages and demonstrated the feasibility of quantitatively characterizing the changes in the number of vessels with postnatal growth. These preliminary data suggest that the number of vessels with lumen diameters of 50-200 MUm increases rapidly in both lungs between 52 and 100 days of age. With this new technique, the pulmonary vasculature can now be studied in a whole lung animal model to better understand the global effects of disease on vascular structure. PMID- 22230112 TI - Expression of vascular endothelial growth factor (VEGF) and its soluble receptor 1 in endometriosis. AB - The aim of this study is to evaluate the expression of vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) in peritoneal fluid (PF), peritoneal endometriotic lesions and eutopic endometrial tissues of patients with endometriosis. Peritoneal fluid, peritoneal endometriotic lesions and eutopic endometrial samples from patients with endometriosis, and peritoneal fluid, peritoneal tissue and endometrial samples from patients without endometriosis were obtained during an operative laparoscopy. The mean PF concentrations of VEGF and sFlt-1 were significantly higher in patients with endometriosis than in the controls. In the peritoneal tissue, the expressions of VEGF and sFlt-1 were significantly higher, where the expression of sFlt-1 in endometrium was significantly lower in patients with endometriosis. These findings indicate that not only abnormal expressions of angiogenic factors, but also aberrant expressions of antiangiogenic factors in the peritoneal and endometrial environment seem to be involved in the pathogenesis of endometriosis. PMID- 22230113 TI - Reproducibility of LDF blood flow measurements: dynamical characterization versus averaging. A response to the letter from Stefanovska. PMID- 22230114 TI - An investigation of whether there are sex differences in certain behavioural and neurochemical parameters in the rat. AB - In clinical populations, sex differences in disease prevalence, symptoms and outcome have been established. Despite this, female rats are frequently omitted from preclinical research; growing preclinical evidence, however, illustrates meaningful sex differences in behavioural, neurochemical and neuroanatomical endpoints. This review outlines the effects of sex on tests of depression- and anxiety-like symptoms, learning and memory, and responses to stress in rats. In addition, sexual dimorphisms in monoamine neurotransmitter and neurotrophic factor levels, neurogenesis and plasticity, and responsiveness to drugs of abuse are reviewed. Female rats display greater baseline activity levels compared to males, test-specific sex differences also exist in learning and memory protocols as females respond more actively in conditioning paradigms and are somewhat impaired in tests of spatial memory compared to males. Differential baseline and stress-induced hypothalamic-pituitary-adrenal axis responses between male and female rats depend on the nature of the stressor. Females are more responsive to the effects of psychomotor stimulant drugs; sexual dimorphisms in response to psychotropic drugs are likely mediated by neurochemical differences between male and female rats. Differences exist in neurotransmitter activity, transporter and receptor expression between the sexes. Studies of ovariectomised and intact female rats demonstrate a potent impact of elevated estrogen during the estrous cycle on behaviour, neurochemistry, dendritic growth and drug response. Sex differences in baseline behaviours and the methodological procedures employed can influence behavioural pharmacology result interpretation. In addition, the inclusion of both male and female rats in studies investigating neurochemistry and neuromorphology may enhance the validity of drug or rehabilitative treatments. PMID- 22230115 TI - Human memory manipulated: dissociating factors contributing to MTL activity, an fMRI study. AB - Memory processes are mainly studied with subjective rating procedures. We used a morphing procedure to objectively manipulate the similarity of target stimuli. While undergoing functional magnetic resonance imaging, nineteen subjects performed a encoding and recognition task on face and scene stimuli, varying the degree of manipulation of previously studied targets at 0%, 20%, 40% or 60%. Analyses were performed with parametric modulations for objective stimulus status (morphing level), subjective memory (confidence rating), and reaction times (RTs). Results showed that medial temporal lobe (MTL) activity can be best explained by a combination of subjective and objective factors. Memory success is associated with activity modulation in the hippocampus both for faces and for scenes. Memory failures correlated with lower hippocampal activity for scenes, but not for faces. Activity changed during retrieval on similar areas activated during encoding. There was a considerable impact of RTs on memory-related areas. Objective perceptual identity correlated with activity in the left MTL, while subjective memory experience correlated with activity in the right MTL for both types of material. Overall, the results indicate that MTL activity is heterogeneous, showing both linear and non-linear activity, depending on the factor analyzed. PMID- 22230116 TI - Bramwell-Hill modeling for local aortic pulse wave velocity estimation: a validation study with velocity-encoded cardiovascular magnetic resonance and invasive pressure assessment. AB - BACKGROUND: The Bramwell-Hill model describes the relation between vascular wall stiffness expressed in aortic distensibility and the pulse wave velocity (PWV), which is the propagation speed of the systolic pressure wave through the aorta. The main objective of this study was to test the validity of this model locally in the aorta by using PWV-assessments based on in-plane velocity-encoded cardiovascular magnetic resonance (CMR), with invasive pressure measurements serving as the gold standard. METHODS: Seventeen patients (14 male, 3 female, mean age +/- standard deviation = 57 +/- 9 years) awaiting cardiac catheterization were prospectively included. During catheterization, intra arterial pressure measurements were obtained in the aorta at multiple locations 5.8 cm apart. PWV was determined regionally over the aortic arch and locally in the proximal descending aorta. Subsequently, patients underwent a CMR examination to measure aortic PWV and aortic distention. Distensibility was determined locally from the aortic distension at the proximal descending aorta and the pulse pressure measured invasively during catheterization and non-invasively from brachial cuff-assessment. PWV was determined regionally in the aortic arch using through-plane and in-plane velocity-encoded CMR, and locally at the proximal descending aorta using in-plane velocity-encoded CMR. Validity of the Bramwell Hill model was tested by evaluating associations between distensibility and PWV. Also, theoretical PWV was calculated from distensibility measurements and compared with pressure-assessed PWV. RESULTS: In-plane velocity-encoded CMR provides stronger correlation (p = 0.02) between CMR and pressure-assessed PWV than through-plane velocity-encoded CMR (r = 0.69 versus r = 0.26), with a non significant mean error of 0.2 +/- 1.6 m/s for in-plane versus a significant (p = 0.006) error of 1.3 +/- 1.7 m/s for through-plane velocity-encoded CMR. The Bramwell-Hill model shows a significantly (p = 0.01) stronger association between distensibility and PWV for local assessment (r = 0.8) than for regional assessment (r = 0.7), both for CMR and for pressure-assessed PWV. Theoretical PWV is strongly correlated (r = 0.8) with pressure-assessed PWV, with a statistically significant (p = 0.04) mean underestimation of 0.6 +/- 1.1 m/s. This theoretical PWV-estimation is more accurate when invasively-assessed pulse pressure is used instead of brachial cuff-assessment (p = 0.03). CONCLUSIONS: CMR with in-plane velocity-encoding is the optimal approach for studying Bramwell-Hill associations between local PWV and aortic distensibility. This approach enables non-invasive estimation of local pulse pressure and distensibility. PMID- 22230117 TI - [Rare diseases. Introduction]. PMID- 22230118 TI - Gaucher's disease: the changing paradigm of a lysosomal disorder. AB - Gaucher's disease (GD) is the most common lysosomal storage disease with a frequency of approximately 1:50,000 people. It is the result of the deficiency of the lysosomal enzyme beta-glucocerebrosidase. The deficiency of the enzyme results in the accumulation of the substrate, glucosyl-ceramide, in the organs. Substitutive enzymatic treatment has been available since almost 20 years. This brief overview highlights some of the most important milestones and the treatments for this disease. The study of this rare disorder is beginning to provide information on the pathogenesis of common diseases such as Parkinson's disease or cancer. Individuals with GD are at greater risk of developing cancer in general, especially hepatobiliary and hematologic (multiple myeloma and B-cell neoplasms). This association has been attributed to the immunologic abnormalities associated with abnormal expression of cytokines such as interleukin-6. Alternative and complementary, some recently marketed and licensed, are providing options for patients throughout Europe and the world. PMID- 22230119 TI - [Clinical characteristics of the neurological forms of Gaucher's disease]. AB - Gaucher's disease is the most prevalent disease of accumulation of glycosphingolipids. Neurological involvement is used to classify the different types of the disease. Type 1 affects approximately 90% of patients, and visceral manifestations and bone marrow, without affecting the nervous system. Type 2 is considered a severe form of disease with severe nervous system and death within two years. Type 3 is late, slowly progressive neurological symptoms and survival until the third decade. Besides these classical syndromes, the best knowledge of the disease related to the existence of national registries, the increased survival of patients resulting from replacement therapy, and demonstration of the behavior of glucocerebrosidase mutations as a risk factor of neurodegenerative diseases, has expanded the clinical phenotype and altered the traditional classification of the disease. PMID- 22230120 TI - [Diagnosis, biomarkers and biochemical alterations in Gaucher's disease]. AB - Gaucher's disease (GD) is an inherited metabolic disease due to lack of activity of the enzyme betaglucocerebrosidase. The diagnosis of GD is usually performed by fluorimetric analysis of the enzyme betaglucocerebrosidase. It can also be done by measuring the activity of tandem mass spectrometry. This enzyme can be analyzed in different samples such as leukocytes, fibroblasts, blood dried on paper and in case of prenatal diagnosis in chorionic villi or culture of amniocytes. Various biomarkers have been described for monitoring GD once diagnosed, to evaluate the response to potential treatments. Chitotriosidase activity is the most widely used biomarker for the assessment of GD, and for patients homozygous for the null CHIT1 gene variants, in general, is replaced by the analysis of the biomarker CCL18. PMID- 22230121 TI - [Genetics of Gaucher's disease. Genotype-phenotype correlation]. AB - Gaucher's disease (GD) results from a deficiency of the lysosomal enzyme glucocerebrosidase and, in very rare occasions, a deficiency of its activator, the saposin C. The complexity of identification and characterization of mutations in the gene of glucocerebrosidase (GBA1) is caused by a great amount of mutated alleles, the existence of a highly homologous pseudogene and its location in a very rich zone in genes, which promotes the presence of complex alleles. Although genotype-phenotype correlations in EG are not completely established, there are a series of generalities, as the mutation c.1226A>G (N370S) is often associated with a certain degree of neuroprotection and the homozygosity for the c.1448T>C (L444P) mutation presents with neurological symptoms. PMID- 22230122 TI - [Bone disease in Gaucher's disease]. AB - The exposition aims, is to review the pathophysiological mechanisms of bone marrow involvement and the patterns of marrow infiltration by Gaucher cells. We have reviewed the different methods of assessment of bone marrow infiltration and its temporal development. Qualitative methods include simple radiography, magnetic resonance imaging (MRI), computed tomography (CT) and radioisotope. The simple radiography is the basic element, but its sensitivity is limited and only allows for assessing changes and trabecular bone remodeling MRI allows us to appreciate the bone marrow infiltration, detection of complications and response to therapy. Radioisotopes can contribute to the differential diagnosis of osteomyelitis and bone crises. Among the quantitative methods are the QCSI (quantitative chemical shift imaging) and the dual-energy X-ray absorptiometry (DEXA), as well as new quantitative techniques of CT, MRI and ultrasound densitometry. The QCSI performed an assessment of fat content of bone marrow in the spine. DEXA quantifies bone density by measuring the attenuation coefficient. The semiquantitative methods have various "scores" to establish criteria for generalized bone disease endpoints of disease progression and response to therapy. PMID- 22230123 TI - [Molecular basis of treatment in Gaucher's disease]. AB - In Gaucher's disease (GD) there is an imbalance in the monocyte-macrophage system between the rate of formation and degradation of glucosylceramide due to low activity of the lysosomal enzyme betaglucorebrosidase. Therapeutic approaches are aimed to reduce the synthesis of glucosylceramide by inhibiting ceramide glucosyltransferase or increasing the degradation of glucosylceramide using a recombinant beta-glucorebrosidase or recovering the residual activity of mutant enzymes with pharmacological chaperones. Inhibitory molecules of ceramide glucosyltransferase used mimic glucose or ceramide. All recombinant enzymes used in GD enzyme replacement therapy have similar kinetic parameters, but differ in their amino acid sequence, as well as, in the exposed mannose oligosaccharide chains. The mannose content and localization in the oligosaccharide chains are essential for cell uptake. Velaglucerase alpha have a high content of mannoses in their oligosaccharide chains. PMID- 22230124 TI - [Safety of use of velaglucerase in 2 patients with type 1 Gaucher's disease]. AB - The incidence of immunologic reactions in patients with Gaucher's disease (GD) on enzymatic replacement therapy with imiglucerase is about 17% and related with the presence of non-neutralizing immunoglobulin G antibodies. The clinical trials with a new enzyme obtained in human cells (GA-GCB-velaglucerase) have demonstrated absence of immune reactions and no antibodies against the enzyme in spite of some patients had previous developed antibodies against imiglucerase. We present 2 clinical cases of patients diagnosed with EG in childhood and who developed antibodies and important imiglucerase immunoallergic adverse reaction during the imiglucerase perfusion, indicating systematic administration of steroids and antihistamines prior to each perfusion and perfusion time > 4h. PMID- 22230125 TI - [Clinical outcomes of 2 pediatric patients with Gaucher's disease in enzyme replacement therapy for 9 years]. AB - We report two cases of type 1 Gaucher's disease in childhood and their outcomes after 9 years of enzyme replacement therapy. The first case concerns a 6-year-old boy who was diagnosed with Gaucher's disease after developing petechial exanthema, thrombocytopenia, anemia and hepatosplenomegaly, coinciding with chickenpox. The second case involves a 9-year-old girl who was referred to our unit. She had hepatosplenomegaly since 4-month-old and subsequently developed thrombocytopenia. Both patients have the N370S/L444P mutation. Enzyme replacement therapy was started with 60 U/kg imiglucerase every 2 weeks at the age of 6 and 9 years, respectively. In both patients, the therapeutic goals were achieved and maintained throughout treatment with a dose of 30 U/kg. PMID- 22230126 TI - [Therapeutic targets in Gaucher's disease]. AB - Gaucher's disease (GD) occurs because of deficiency of the enzyme beta glucocerebrosidase that results in accumulation of this glycolipid compound in the cells of the macrophage-monocyte system. There are 3 types: type 1 is non neuronopathic with primarily visceral signs and symptoms which range tremendously in severity; infantile-onset type 2 and later-onset type 3 involve the central nervous system. More than 300 mutations have been described in the gene, partially explaining phenotypic heterogeneity. Commercialization in 1991 of the first enzyme replacement therapy, alglucerase, resulted in a revolution in the management of patients with symptomatic GD (i.e., by improving the hematological and visceral signs and symptoms). Within the first 5 years of alglucerase, its safety and efficacy in improving hemoglobin levels and platelet counts, and in reducing splenic and hepatic enlargement were confirmed albeit recognizing its inability to impact neurological symptoms and signs because of its large molecular size. Recombinant imiglucerase soon replaced alglucerase as the standard of care for GD. The therapeutic targets recently defined as treatment goals were: normalization of cell counts; reduction of liver and spleen volume; elimination of the infiltration in the bone marrow to prevent the complications, and improvement in surrogate biomarkers. PMID- 22230127 TI - [Current treatment for Gaucher's disease and new prospects]. AB - Two new useful enzymes have recently undergone clinical trials for the treatment of Gaucher's disease (GD): velaglucerase alpha and taliglucerase alpha were both approved for early access programs as of the June 2009 shortage in Imiglucerase supply. Velaglucerase has been approved by both, Food and Drug Administration and European Medicines Agency. The Phase I/II trial of velaglucerase is in its 8th year: There were no drug-related serious adverse events or withdrawals, and no antibodies. Statistically significant improvements (p<0.004) were noted in mean percent change from baseline to nine months and baseline to 48 months for hemoglobin (19.2% and 21.7%, respectively), platelet counts (67.6% and 157.8%, respectively), normalized liver volume (<18.2% and <42.8%, respectively), and normalized spleen volume (<49.5% and <79.3%, respectively). Within 2 years of initiation of therapy, all patients achieved normalization of hemoglobin level, all but one patient achieved platelet counts of greater than 100*10(9)/L, all patients achieved near normalization in liver volumes, and all patients but one exhibited a reduction of more than 50% in spleen volume. At present, velaglucerase alpha is indicated in type 1 GD symptomatic patients (children or adults) and is accepted as an orphan drug by the EMA with similar cost to imiglucerase. Taliglucerasa alpha, obtained from transfected plant cell cultures, is pending to approval. PMID- 22230128 TI - [Guidelines for type 1 Gaucher's disease]. AB - Gaucher's disease (GD) is an inborn error of metabolism of the lysosomal enzyme beta-glucosidase, which induces the deposition of undegraded glycolipid material in organs rich in mononuclear macrophage system including liver, spleen and bone marrow. Beta-glucosidase is suspected in patients with evidence of liver and/or spleen enlargement, anemia and/or thrombocytopenia not attributable to other causes, or bone crisis especially in children. In scarce cases GD is associated with neurological involvement. The diagnosis confirmation is performed by analysis of beta-glucosidase activity in peripheral blood leukocytes or fibroblasts. It is necessary to identify genetic mutations that cause GD. It is also advisable to identify biomarkers including chitotriosidase activity and plasma CCL-18/PARC concentration. The use of a protocol for assessing the intensity of the deposit is mandatory to establish the indication for treatment, especially in rare diseases. Nowadays there are several options for treatment of GD: enzyme replacement therapy and substrate reduction therapy. Regular assessments are needed to establish the response and the degree of achievement of the therapeutic goals recommended through expert consensus. PMID- 22230129 TI - The mesocolon: a prospective observational study. AB - AIM: The aim of this study was to characterize formally the mesocolic anatomy during and following total mesocolic excision. Total mesocolic excision may improve survival in patients with colon cancer. Although this requires a detailed knowledge of normal and variant mesocolic anatomy, the latter is poorly characterized. No studies have prospectively characterized the anatomy of the entire mesocolon. METHOD: Total mesocolic excision was performed in 109 patients undergoing total abdominal colectomy. The mesocolon was maintained intact thereby permitting a precise anatomical characterization from ileocaecal to mesorectal levels. Two- and three-dimensional schematic reconstructions were generated to illustrate in situ conformation. RESULTS: Several previously undocumented findings emerged, including: (i) the mesocolon was continuous from ileocaecal to rectosigmoid level; (ii) a mesenteric confluence occurred at the ileocaecal and rectosigmoid junction as well as at the hepatic and splenic flexures; (iii) each flexure (and ileocaecal junction) was a complex of peritoneal and omental attachments to the colon centred on a mesenteric confluence; (iv) the proximal rectum originated at the confluence of the mesorectum and mesosigmoid; and (v) a plane occupied by Toldt's fascia separated the entire apposed mesocolon from the retroperitoneum. CONCLUSION: When the mesocolon is fully mobilized during a total mesocolic excision of the colon, several anatomical findings that have not been previously documented emerge. These findings provide a rationalization of the surgical, embryological and anatomical approaches to the mesocolon. This has implications for all related sciences. PMID- 22230130 TI - Evaluation of color Doppler ultrasonography in diagnosing hepatic alveolar echinococcosis. AB - To assess the accuracy of color Doppler ultrasonography in diagnosing hepatic alveolar echinococcosis, 129 patients were examined at the First Affiliated Hospital of Xinjiang Medical University between July 2004 and June 2010. Those patients suspected of having hepatic alveolar echinococcosis were examined and diagnosed by color Doppler ultrasound. All the cases were compared with the gold standard. The findings of their sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and 95% confidence interval were recorded. Sensitivity: 95% (95% confidence interval: 90.7%-99.3%); specificity: 20.7% (95% confidence interval: 6.0%-35.4%); positive predictive value: 80.5%; negative predictive value: 54.5%; positive likelihood ratio: 1.2: negative likelihood ratio: 0.2. Our study indicates that color Doppler ultrasonography, when used in diagnosing hepatic alveolar echinococcosis, has high sensitivity although specificity is low. Color Doppler ultrasound is, thus, considered to be an efficient means for diagnosing hepatic alveolar echinococcosis. PMID- 22230131 TI - Mapping of superficial extremity veins: normal diameters and trends in a vascular patient-population. AB - Ultrasonic measurement of superficial extremity veins is a common procedure. To establish normal values for vein-size in a population of vascular patients and to assess if measurements remain unchanged over time, we analyzed a database with results of 28,130 measurements in 2420 separate saphenous and 3206 cephalic veins. Mean size of the great saphenous vein ranges from 2.3 mm to 4.4 mm but did not follow a tapering pattern as is often assumed. The distal calf segment is smaller than the ankle segment. The mean cephalic vein size in the upper arm (2.4 mm) was smaller than at the antecubital level (2.7 mm). A decrease in vein diameter over time was noted in many locations and this reached statistical significance (p < 0.005 for the thigh segment). The clinical significance of this is a need to repeat ultrasonic vein-mapping if more than a year elapses between ultrasound and surgical vein harvest. PMID- 22230132 TI - Color Doppler ultrasonography evaluation for chemotherapy treatment response of osteogenic sarcoma. AB - The aim of this study was to evaluate the vascular parameters of the proximal peripheral arteries of limbs by color Doppler ultrasonography (CDUS) in individuals with osteogenic sarcoma (OGS) after neoadjuvant chemotherapy and their relation to the tumor necrosis rate. We recruited 50 individuals with osteogenic sarcoma who were scheduled for neoadjuvant chemotherapy before elective surgery from 2003 to 2010. Once enrolled, we evaluated these 50 subjects using color Doppler sonography to identify vascular parameters of tumor vessels before and after neoadjuvant therapy. The vascular parameters of the proximal peripheral arteries of limbs (peak systolic velocity [PSV], end-diastolic velocity [EDV], resistive index [RI]) and tumor neovascularity were compared before and after neoadjuvant chemotherapy using CDUS. Before chemotherapy, the PSV, EDV and RI differed significantly between the diseased and contralateral normal limbs (p < 0.001). Among the factors relating to the tumor necrosis rate before chemotherapy, the EDV of the diseased limb (p = 0.047) and tumor neovascularity (p = 0.027) showed significant differences. After chemotherapy, the PSV of the diseased limb (p = 0.022) and the difference in PSV between the diseased and contralateral limbs (p = 0.003) showed significant differences. The vascular parameters of the proximal peripheral arteries of limbs owing to tumor burden differ significantly between the diseased and contralateral normal limbs. For individuals with osteogenic sarcoma who still have a higher difference in PSV between the diseased and contralateral limbs after chemotherapy, another course of chemotherapy after surgery and close follow-up should be considered. PMID- 22230133 TI - Low-intensity pulsed ultrasound (LIPUS) may prevent polyethylene induced periprosthetic osteolysis in vivo. AB - We investigated the effect of local low-intensity pulsed ultrasound (LIPUS) on polyethylene debris induced periprosthetic osteolysis. The periprosthetic osteolysis model was made by injecting endotoxin-free pure polyethylene particles into the distal part of the femur canal and inserting a stainless steel plug into this femur. The effects of polyethylene and LIPUS were assessed histologically and by the shear strength test and periprosthetic bone mineral density (BMD) test. Sixteen rabbits received a stainless steel plug on one side and both polyethylene and a stainless steel plug on the other side. Three months later, the side that received polyethylene showed periprosthetic osteolysis. Subsequently, another 16 rabbits received polyethylene plus local LIPUS (200 mW/cm(2) for 20 min daily) on one side and polyethylene alone on the other side. Three months later, LIPUS effectively prevented the periprosthetic osteolysis caused by polyethylene in this rabbit model. PMID- 22230134 TI - Completely automated segmentation approach for breast ultrasound images using multiple-domain features. AB - Lesion segmentation is a challenging task for computer aided diagnosis systems. In this article, we propose a novel and fully automated segmentation approach for breast ultrasound (BUS) images. The major contributions of this work are: an efficient region-of-interest (ROI) generation method is developed and new features to characterize lesion boundaries are proposed. After a ROI is located automatically, two newly proposed lesion features (phase in max-energy orientation and radial distance), combined with a traditional intensity-and texture feature, are utilized to detect the lesion by a trained artificial neural network. The proposed features are tested on a database of 120 images and the experimental results prove their strong distinguishing ability. Compared with other breast ultrasound segmentation methods, the proposed method improves the TP rate from 84.9% to 92.8%, similarity rate from 79.0% to 83.1% and reduces the FP rate from 14.1% to 12.0%, using the same database. In addition, sensitivity analysis demonstrates the robustness of the proposed method. PMID- 22230135 TI - Speckle noise reduction in ultrasound biomedical B-scan images using discrete topological derivative. AB - Over three decades, several despeckling techniques have been developed by researchers to reduce the speckle noise inherently present in ultrasound B-scan images without losing the diagnostic information. The topological derivative (TD) is the recently adopted technique in the area of biomedical image processing. In this work, we computed the topological derivative for an appropriate function associated to the ultrasound B-scan image gradient by assigning a diffusion factor k, which indicates the cost endowed to that particular image. In this article, a novel image denoising approach, called discrete topological derivative (DTD) has been implemented. The algorithm has been developed in MATLAB7.1 and tested over 200 ultrasound B-scan images of several organs such as the liver, kidney, gall bladder and pancreas. Further, the performance of the DTD algorithm has been estimated by calculating important performance metrics. A comparative study was carried out between the DTD and the traditional despeckling techniques. The calculated peak signal-to-noise ratio (PSNR) (the ratio between the maximum possible power of a signal and the power of corrupting noise that affects the fidelity of its representation) value of the DTD despeckled liver image is found to be 28 which is comparable with the outperformed speckle reducing anisotropic diffusion (SRAD) filter. SRAD filter is an edge-sensitive diffusion method for speckled images of ultrasonic and radar imaging applications. Canny edge detection and visual inspection of DTD filtered images by the trained radiologist found that the DTD algorithm preserves the hypoechoic and hyperechoic regions resulting in improved diagnosis as well as tissue characterization. PMID- 22230136 TI - Evaluation of the accuracy of articular cartilage thickness measurement by B-mode ultrasonography with conventional imaging and real-time spatial compound ultrasonography imaging. AB - The present study aimed to quantify the thickness of articular cartilage (Tc) in vitro using both conventional and real-time spatial compound B-mode ultrasonography (US) with a clinically used transducer and to evaluate the accuracy of measurement by comparing the results with values obtained microscopically. Femoral condyle samples were obtained from a 6-month-old pig and a 3-year-old pig. B-mode US images with conventional imaging and real-time spatial compound imaging (RTSCI) of osteochondral blocks were acquired. Tc determined using US (Tc-US) was measured from line data parallel to US beam direction acquired from B-mode images with an objective method for determining cartilage surface and bone-cartilage interfaces at the peak brightness values. Tc was also determined under microscopy (Tc-optical) using the corresponding points from US measurement. Tc-US was compared with Tc-optical to assess accuracy. Tc-US correlated significantly with Tc in both conventional imaging and RTSCI (r = 0.961, 0.976, respectively). Bland-Altman plots showed mean differences between Tc-optical and Tc-US were -0.0073 mm and 0.0139 mm with standard deviations of 0.171 mm and 0.131 mm for conventional imaging and RTSCI, respectively. Our results show that Tc-US measurement using B-mode US allows accurate measurement of Tc. Considering correlation coefficients between Tc-US and Tc-optical, RTSCI US may offer higher accuracy for measuring Tc than conventional methods when an objective tissue border determination algorithm is used, even though both showed good accuracy in our study. PMID- 22230137 TI - Left ventricular assist devices: physiologic assessment using echocardiography for management and optimization. AB - Left ventricular assist devices (LVAD) are being deployed increasingly in patients with severe left ventricular dysfunction and medically refractory congestive heart failure of any etiology. The United States Food and Drug Administration (FDA) recently approved the use of the Thoratec Heartmate II (Thoratec Corporation, Pleasanton, CA, USA) for outpatient use. Echocardiography is fundamental during each stage of patient management, pre-LVAD placement, during LVAD placement, for postoperative LVAD optimization and long-term follow up. We present a pragmatic and systematic echocardiographic approach that serves as a guide for the management of left ventricular assist devices. PMID- 22230142 TI - Reconstruction of oomycete genome evolution identifies differences in evolutionary trajectories leading to present-day large gene families. AB - The taxonomic class of oomycetes contains numerous pathogens of plants and animals but is related to nonpathogenic diatoms and brown algae. Oomycetes have flexible genomes comprising large gene families that play roles in pathogenicity. The evolutionary processes that shaped the gene content have not yet been studied by applying systematic tree reconciliation of the phylome of these species. We analyzed evolutionary dynamics of ten Stramenopiles. Gene gains, duplications, and losses were inferred by tree reconciliation of 18,459 gene trees constituting the phylome with a highly supported species phylogeny. We reconstructed a strikingly large last common ancestor of the Stramenopiles that contained ~10,000 genes. Throughout evolution, the genomes of pathogenic oomycetes have constantly gained and lost genes, though gene gains through duplications outnumber the losses. The branch leading to the plant pathogenic Phytophthora genus was identified as a major transition point characterized by increased frequency of duplication events that has likely driven the speciation within this genus. Large gene families encoding different classes of enzymes associated with pathogenicity such as glycoside hydrolases are formed by complex and distinct patterns of duplications and losses leading to their expansion in extant oomycetes. This study unveils the large-scale evolutionary dynamics that shaped the genomes of pathogenic oomycetes. By the application of phylogenetic based analyses methods, it provides additional insights that shed light on the complex history of oomycete genome evolution and the emergence of large gene families characteristic for this important class of pathogens. PMID- 22230144 TI - The retrograde technique for recanalization of chronic total occlusions: a step by-step approach. AB - Chronic total occlusion recanalization still represents the final frontier in percutaneous coronary intervention. Retrograde chronic total occlusion recanalization has recently become an essential complement to the classical antegrade approach. In experienced hands, the retrograde technique currently has a high success rate with a low complication profile, despite frequent utilization in the most anatomically and clinically complex patients. Since its initial description, important changes have occurred that make the technique faster and more successful. We propose a step-by-step approach of the technique as practiced at experienced centers in North America. Because the technique can vary substantially, we describe the different alternatives to each step and offer what we perceived to be the most efficient techniques. PMID- 22230143 TI - Isoniazid preventive therapy and 4-year incidence of pulmonary tuberculosis among HIV-infected Thai patients. AB - SETTING: Human immunodeficiency virus (HIV) clinics at two Thai tertiary care medical centres. OBJECTIVES: To evaluate the efficacy of tuberculin skin test (TST) guided isoniazid preventive therapy (IPT) in combination with antiretroviral therapy (ART) in the prevention of tuberculosis (TB). DESIGN: A 4 year prospective comparative study of patients at two HIV clinics: one performed TST at enrolment and, if positive, prescribed IPT (IPT group), while the other did not perform TST (non-IPT group). RESULTS: There were 200 patients included in each group. Baseline characteristics and drop-out rates were similar in both groups. The incidence of pulmonary TB over 4 years was not significantly different between the IPT and non-IPT groups (0.80 cases vs. 1.76 per 100 person years [py], P = 0.13). However, the incidence of pulmonary TB in the non-IPT group was significantly higher during the first 6 months (8.60 vs. 0 cases/100 py, P = 0.01) and among patients with initial CD4 < 200 cells/l (9.41 vs. 0 cases/100 py, P = 0.02). The survival analyses demonstrated a protective effect of IPT (x(2) = 3.66, P = 0.04) for early TB. CONCLUSIONS: Benefit of IPT plus ART was evident only in the first 6 months of care. These findings suggest that TST guided IPT should be routinely provided for HIV-infected patients after initial entry into medical care. PMID- 22230145 TI - Examination of the in vivo mechanisms of late drug-eluting stent thrombosis: findings from optical coherence tomography and intravascular ultrasound imaging. AB - OBJECTIVES: This study investigated the role of uncovered stent struts on late stent thrombosis (LST) after drug-eluting stent (DES) implantation with optical coherence tomography (OCT). BACKGROUND: Autopsy studies have identified delayed healing and lack of endothelialization of DES struts as the hallmarks of LST. DES strut coverage has not previously been examined in vivo in patients with LST. METHODS: We studied 54 patients, including 18 with DES LST (median 615 days after implant) undergoing emergent percutaneous coronary interventions and 36 matched DES control subjects undergoing routine repeat OCT and intravascular ultrasound (IVUS) who did not experience LST for >=3 years. Thrombus aspiration was performed during emergent percutaneous coronary intervention before OCT and IVUS assessment. RESULTS: By OCT, patients with LST--compared with control subjects- had a higher percentage of uncovered (median [interquartile range]) (12.27 [5.50 to 23.33] vs. 4.14 [3.00 to 6.22], p < 0.001) and malapposed (4.60 [1.85 to 7.19] vs. 1.81 [0.00 to 2.99], p < 0.001) struts. The mean neointimal thickness was similar in the 2 groups (0.23 +/- 0.17 mm vs. 0.17 +/- 0.09 mm, p = 0.28). By IVUS, stent expansion was comparable in the 2 groups, although positive remodeling was increased in patients with LST (mean vessel cross-section area 19.4 +/- 5.8 mm(2) vs. 15.1 +/- 4.6 mm(2), p = 0.003). Thrombus aspiration demonstrated neutrophils and eosinophils in most cases. By multivariable analysis, the length of segment with uncovered stent struts by OCT and the remodeling index by IVUS were independent predictors of LST. CONCLUSIONS: In this in vivo case-controlled study, the presence of uncovered stent struts as assessed by OCT and positive vessel remodeling as imaged by IVUS were associated with LST after DES. PMID- 22230146 TI - Do we know what causes very late drug-eluting stent thrombosis? PMID- 22230147 TI - Transradial versus transfemoral intervention for acute myocardial infarction: a propensity score-adjusted and -matched analysis from the REAL (REgistro regionale AngiopLastiche dell'Emilia-Romagna) multicenter registry. AB - OBJECTIVES: This study sought to assess whether transradial intervention, by minimizing access-site bleeding and vascular events, improves outcomes in patients with ST-segment elevation myocardial infarction compared with the transfemoral approach. BACKGROUND: Bleeding and consequent blood product transfusions have been causally associated with a higher mortality rate in patients with myocardial infarction undergoing coronary angioplasty. METHODS: We identified all adults undergoing percutaneous intervention for acute myocardial infarction in Emilia-Romagna, a region in the north of Italy of 4 million residents, between January 1, 2003, and July 30, 2009, at 12 referral hospitals using a region-mandated database of percutaneous coronary intervention procedures. Differences in the risk of death at 2 years between patients undergoing transfemoral versus transradial intervention, assessed on an intention to-treat basis, were determined from vital statistics records and compared based on propensity score adjustment and matching. RESULTS: A total of 11,068 patients were treated for acute myocardial infarction (8,000 via transfemoral and 3,068 via transradial route). According to analysis of matched pairs, the 2-year, risk adjusted mortality rates were lower for the transradial than for the transfemoral group (8.8% vs. 11.4%; p = 0.0250). The rate of vascular complications requiring surgery or need for blood transfusion were also significantly decreased in the transradial group (1.1% vs. 2.5%, p = 0.0052). CONCLUSIONS: In patients undergoing angioplasty for acute myocardial infarction, transradial treatment is associated with decreased 2-year mortality rates and a reduction in the need for vascular surgery and/or blood transfusion compared with transfemoral intervention. PMID- 22230148 TI - The Leipzig prospective vascular ultrasound registry in radial artery catheterization: impact of sheath size on vascular complications. AB - OBJECTIVES: This study investigated the impact of sheath size on the rate of radial artery occlusions (RAO) (primary objective) and other access site complications (hemorrhage, pseudoaneurysm, arteriovenous fistula) as secondary objectives after transradial coronary catheterization. BACKGROUND: The number of vascular access complications in the published data ranges from 5% to 38% after transradial catheterization. METHODS: Between November 2009 and August 2010, 455 patients 65.3 +/- 10.9 years of age (62.2% male) with transradial access with 5-F (n = 153) or 6-F (n = 302) arterial sheaths were prospectively recruited. Duplex sonography was obtained in each patient before discharge. Patients with symptomatic RAO were treated with low-molecular-weight heparin (LMWH), and a follow-up was performed. RESULTS: The incidence of access site complications was 14.4% with 5-F sheaths compared with 33.1% with 6-F sheaths (p < 0.001). Radial artery occlusion occurred in 13.7% with 5-F sheaths compared with 30.5% with 6-F sheaths (p < 0.001). There was no difference between groups with regard to hemorrhage, pseudoaneurysms, or arteriovenous fistulas. Female sex, larger sheath size, peripheral arterial occlusive disease, and younger age independently predicted RAO in multivariate analysis. In total, 42.5% of patients with RAO were immediately symptomatic; another 7% became symptomatic within a mean of 4 days. Of patients with RAO, 59% were treated with LMWH. The recanalization rates were significantly higher in patients receiving LMWH compared with conventional therapy (55.6% vs. 13.5%, p < 0.001) after a mean of 14 days. CONCLUSIONS: The incidence of RAO by vascular ultrasound was higher than expected from previous data, especially in patients who underwent the procedure with larger sheaths. PMID- 22230149 TI - Observations from a transradial registry: our remedies oft in ourselves do lie. PMID- 22230150 TI - Kissing balloon or sequential dilation of the side branch and main vessel for provisional stenting of bifurcations: lessons from micro-computed tomography and computational simulations. AB - OBJECTIVES: This study sought to evaluate post-dilation strategies in bifurcation stenting. BACKGROUND: In bifurcation stenting practice, it is still controversial how post-dilation should be performed and whether the kissing balloon (KB) technique is mandatory when only the main vessel (MV) receives a stent. METHODS: A series of drug-eluting stents (DES) (n = 26) were deployed in a coronary bifurcation model following a provisional approach. After the deployment of the stent in the MV, post-dilation with the KB technique was compared with a 2-step, sequential post-dilation of the side branch (SB) and MV without kissing. RESULTS: The percentage of the SB lumen area free of stent struts was similar after KB (79.1 +/- 8.7%) and after the 2-step sequence (74.4 +/- 11.6%, p = 0.25), a considerable improvement compared with MV stenting only without dilation of the stent at the SB ostium (30.8 +/- 7.8%, p < 0.0001). The rate of strut malapposition in the ostium was 21.3 +/- 9.2% after KB and 24.9 +/- 10.4% after the 2-step sequence, respectively, a significant reduction compared with a simple SB dilation (55.3 +/- 16.8%, p < 0.0001) or MV stenting only (47.0 +/- 8.5%, p < 0.0005). KB created a significant elliptical overexpansion of the MV lumen, inducing higher stress concentration proximal to the SB. KB also led to a higher risk of incomplete stent apposition at the proximal stent edge (30.7 +/- 26.4% vs. 2.8 +/- 9.6% for 2-step, p = 0.0016). CONCLUSIONS: Sequential 2-step post dilation of the SB and MV may offer a simpler and more efficient alternative to final KB technique for provisional stenting of bifurcations. PMID- 22230151 TI - Angiographic stent thrombosis at coronary bifurcations: short- and long-term prognosis. AB - OBJECTIVES: This study sought to describe the presentation, management, and outcomes of patients presenting with angiographic definite stent thrombosis (ST) at coronary bifurcations. BACKGROUND: The development of drug-eluting stents has made it increasingly feasible to treat bifurcation lesions percutaneously. However, ST at coronary bifurcations may be associated with greater mortality than ST elsewhere. METHODS: We analyzed a multicenter California registry comprising all cases of angiographic definite ST at 5 academic hospitals from 2005 to 2010. Stenting was defined as occurring at a bifurcation if the main vessel stent crossed a side branch >=2.0 mm in diameter (provisional single-stent approach), or if there was a prior 2-stent bifurcation approach. RESULTS: Among 173 cases of angiographic definite ST, we identified 20 cases of ST at coronary bifurcations. Nine of 20 bifurcation ST (45%) occurred with a stent present in both the parent and branch vessel. Eight cases had thrombus present in both the parent and side branch vessels. In-hospital mortality was much higher for subjects with bifurcation ST than ST at a nonbifurcation site (20% vs. 2%, p < 0.0001). During a median follow-up of 2.3 years, ST at a coronary bifurcation was associated with increased long-term mortality (hazard ratio [HR]: 3.3, 95% confidence interval [CI]: 1.4 to 7.7, p = 0.007) and a significantly higher risk for major adverse cardiovascular events (HR: 2.2, 95% CI: 1.04 to 4.8, p = 0.04) relative to ST at a nonbifurcation site. CONCLUSIONS: ST at coronary bifurcations is associated with a higher in-hospital and long-term mortality than ST at nonbifurcation lesions. (Stent Thrombus in Acute Coronary Syndromes; NCT00931502). PMID- 22230153 TI - Quantifying the learning curve in the use of a novel vascular closure device: an analysis of the NCDR (National Cardiovascular Data Registry) CathPCI registry. AB - OBJECTIVES: This study sought to quantify the learning curve for the safety and effectiveness of a newly introduced vascular closure device through evaluation of the NCDR (National Cardiovascular Data Registry) CathPCI clinical outcomes registry. BACKGROUND: The impact of learning on the clinical outcomes complicates the assessment of the safety and efficacy during the early experience with newly introduced medical devices. METHODS: We performed a retrospective analysis of the relationship between cumulative institutional experience and clinical device success, defined as device deployment success and freedom from any vascular complications, for the StarClose vascular closure device (Abbott Vascular, Redwood City, California). Generalized estimating equation modeling was used to develop risk-adjusted clinical success predictions that were analyzed to quantify learning curve rates. RESULTS: A total of 107,710 procedures used at least 1 StarClose deployment, between January 1, 2006, and December 31, 2007, with overall clinical success increasing from 93% to 97% during the study period. The learning curve was triphasic, with an initial rapid learning phase, followed by a period of declining rates of success, followed finally by a recovery to a steady state rate of improved device success. The rates of learning were influenced positively by diagnostic (vs. percutaneous coronary intervention) procedure use and teaching status and were affected inversely by annual institutional volume. CONCLUSIONS: An institutional-level learning curve for the initial national experience of StarClose was triphasic, likely indicating changes in patient selection and expansion of number of operators during the initial phases of device adoption. The rate of learning was influenced by several institutional factors, including overall procedural volume, utilization for percutaneous coronary intervention procedures, and teaching status. PMID- 22230154 TI - Prevention of contrast nephropathy by furosemide with matched hydration: the MYTHOS (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention) trial. AB - OBJECTIVES: This study investigated the effect of furosemide-forced diuresis and intravenous saline infusion matched with urine output, using a novel dedicated device designed for contrast-induced nephropathy (CIN) prevention. BACKGROUND: CIN is a frequent cause of acute kidney injury associated with increased morbidity and mortality. METHODS: A total of 170 consecutive patients with chronic kidney disease (CKD) undergoing coronary procedures were randomized to either furosemide with matched hydration (FMH group, n = 87) or to standard intravenous isotonic saline hydration (control group; n = 83). The FMH group received an initial 250-ml intravenous bolus of normal saline over 30 min followed by an intravenous bolus (0.5 mg/kg) of furosemide. Hydration infusion rate was automatically adjusted to precisely replace the patient's urine output. When a urine output rate >300 ml/h was obtained, patients underwent the coronary procedure. Matched fluid replacement was maintained during the procedure and for 4 h post-treatment. The definition of CIN was a >=25% or >=0.5 mg/dl rise in serum creatinine over baseline. RESULTS: In the FMH group, no device- or therapy related complications were observed. Four (4.6%) patients in the FMH group developed CIN versus 15 (18%) controls (p = 0.005). A lower incidence of cumulative in-hospital clinical complications was also observed in FMH-treated patients than in controls (8% vs. 18%; p = 0.052). CONCLUSIONS: In patients with CKD undergoing coronary procedures, furosemide-induced high urine output with matched hydration significantly reduces the risk of CIN and may be associated with improved in-hospital outcome. (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention [MYTHOS]; NCT00702728). PMID- 22230155 TI - Contemporary use and effectiveness of N-acetylcysteine in preventing contrast induced nephropathy among patients undergoing percutaneous coronary intervention. AB - OBJECTIVES: The aim of this study was to examine the use of and outcomes associated with use of N-acetylcysteine (NAC) in real-world practice. BACKGROUND: The role of NAC in the prevention of contrast-induced nephropathy (CIN) is controversial, leading to widely varying recommendations for its use. METHODS: Use of NAC was assessed in consecutive patients undergoing nonemergent percutaneous coronary intervention from 2006 to 2009 in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium, a large multicenter quality improvement collaborative. We examined the overall prevalence of NAC use in these patients and then used propensity matching to link its use with clinical outcomes, including CIN, nephropathy-requiring dialysis, and death. RESULTS: Of the 90,578 percutaneous coronary interventions performed during the study period, NAC was used in 10,574 (11.6%) procedures, with its use steadily increasing over the study period. Patients treated with NAC were slightly older and more likely to have baseline renal insufficiency and other comorbidities. In propensity matched, risk-adjusted models, we found no differences in outcomes between patients treated with NAC and those not receiving NAC for CIN (5.5% vs. 5.5%, p = 0.99), nephropathy-requiring dialysis (0.6% vs. 0.6%, p = 0.69), or death (0.6% vs. 0.8%, p = 0.15). These findings were consistent across many prespecified subgroups. CONCLUSIONS: Use of NAC is common and has steadily increased over the study period but does not seem to be associated with improved clinical outcomes in real-world practice. PMID- 22230156 TI - Percutaneous edge-to-edge mitral valve repair in high-surgical-risk patients: do we hit the target? AB - OBJECTIVES: This study sought to assess the feasibility and safety of percutaneous edge-to-edge mitral valve (MV) repair in patients with an unacceptably high operative risk. BACKGROUND: MV repair for mitral regurgitation (MR) can be accomplished by use of a clip that approximates the free edges of the mitral leaflets. METHODS: All patients were declined for surgery because of a high logistic EuroSCORE (>20%) or the presence of other specific surgical risk factors. Transthoracic echocardiography was performed before and 6 months after the procedure. Differences in New York Heart Association (NYHA) functional class, quality of life (QoL) using the Minnesota questionnaire, and 6-min walk test (6 MWT) distances were reported. RESULTS: Fifty-five procedures were performed in 52 patients (69.2% male, age 73.2 +/- 10.1 years, logistic EuroSCORE 27.1 +/- 17.0%). In 3 patients, partial clip detachment occurred; a second clip was placed successfully. One patient experienced cardiac tamponade. Two patients developed inguinal bleeding, of whom 1 needed surgery. Six patients (11.5%) died during 6 month follow-up (5 patients as a result of progressive heart failure and 1 noncardiac death). The MR grade before repair was >=3 in 100%; after 6 months, a reduction in MR grade to <=2 was present in 79% of the patients. Left ventricular (LV) end-diastolic diameter, LV ejection fraction, and systolic pulmonary artery pressure improved significantly. Accompanied improvements in NYHA functional class, QoL index, 6-MWT distances, and log N-terminal pro-B-type natriuretic peptide were observed. CONCLUSIONS: In a high-risk population, MR reduction can be achieved by percutaneous edge-to-edge valve repair, resulting in LV remodeling with improvement of functional capacity after 6 months. PMID- 22230157 TI - Stiff coronary stenosis in a young female with pseudoxanthoma elasticum. PMID- 22230159 TI - Very high perforation rate in patients undergoing unsuccessful percutaneous coronary interventions of chronic total occlusions could explain worse outcome in these patients and not chronically occluded artery. PMID- 22230158 TI - First successful management of aortic valve insufficiency associated with HeartMate II left ventricular assist device support by transfemoral CoreValve implantation: the Columbus's egg? PMID- 22230152 TI - The sirolimus-eluting Cypher Select coronary stent for the treatment of bare metal and drug-eluting stent restenosis: insights from the e-SELECT (Multicenter Post-Market Surveillance) registry. AB - OBJECTIVES: This study sought to compare the 1-year safety and efficacy of Cypher Select or Cypher Select Plus (Cordis Corporation, Bridgewater, New Jersey) sirolimus-eluting stents (SES) with the treatment of bare-metal stents (BMS) and drug-eluting stent (DES) in-stent restenosis (ISR) in nonselected, real-world patients. BACKGROUND: There is paucity of consistent data on DES for the treatment of ISR, especially, DES ISR. METHODS: The e-SELECT (Multicenter Post Market Surveillance) registry is a Web-based, multicenter and international registry encompassing virtually all subsets of patients and lesions treated with at least 1 SES during the period from 2006 to 2008. We enrolled in this pre specified subanalysis all patients with at least 1 clinically relevant BMS or DES ISR treated with SES. Primary endpoint was major adverse cardiac events and stent thrombosis rate at 1 year. RESULTS: Of 15,147 patients enrolled, 1,590 (10.5%) presented at least 1 ISR (BMS group, n = 1,235, DES group, n = 355). Patients with DES ISR had higher incidence of diabetes (39.4% vs. 26.9%, p < 0.001), renal insufficiency (5.8% vs. 2.3%, p = 0.003), and prior coronary artery bypass graft (20.5% vs. 11.8%, p < 0.001). At 1 year, death (1.4% for BMS vs. 2.1% for DES, p = 0.3) and myocardial infarction (2.4% for BMS and 3.3% for DES, p = 0.3) rates were similar, whereas ischemia-driven target lesion revascularization and definite/probable late stent thrombosis were higher in patients with DES ISR (6.9% vs. 3.1%, p = 0.003, and 1.8% vs. 0.5%, p = 0.04, respectively). CONCLUSIONS: Use of SES for either BMS or DES ISR treatment is safe and associated with low target lesion revascularization recurrence and no apparent safety concern. PMID- 22230160 TI - Chronic total occlusion recanalization: a call for a randomized trial. PMID- 22230162 TI - Use the ingredients that are in season. PMID- 22230163 TI - Overcoming limited depth penetration of optical coherence tomography with wire bias. PMID- 22230164 TI - Diabetic gastroparesis: myth or reality? PMID- 22230165 TI - Liver invasion of the duodenum due to hepatocellular carcinoma. PMID- 22230166 TI - Ectopic thyroid presenting as a liver mass. PMID- 22230167 TI - Helicobacter pylori infection is strongly associated with gastric and duodenal ulcers in a large prospective study. AB - BACKGROUND & AIMS: Infection with Helicobacter pylori (H pylori) is a risk factor for peptic ulcer disease (PUD), but there are limited longitudinal data on the associations between infection and incident gastric or duodenal ulcers. METHODS: Information on potential risk factors, lifetime history of PUD, and serologic measurements of H pylori infection were obtained from a German cohort of 9953 adults, 50 to 74 years old at baseline (2000-2002). The incidence of ulcers was determined by questionnaires sent to study participants and general practitioners 2 and 5 years later, and was validated by medical records. RESULTS: A lifetime history of PUD was reported by 1030 participants, and during the follow-up period 48 had a first gastric and 22 had a first duodenal ulcer. Infection with H pylori strains that express cytotoxin-associated gene A (cagA) was significantly associated with a lifetime history of PUD (odds ratio, 1.75; 95% confidence interval [CI], 1.50-2.04). Based on longitudinal analyses with physician validated end points, the adjusted hazard ratios for incident gastric and duodenal ulcer disease were 2.9 (95% CI, 1.5-5.5) and 18.4 (95% CI, 4.2-79.9), respectively, among patients infected with cagA-positive strains of H pylori. CONCLUSIONS: In cross-sectional analysis, infection with cagA-positive strains of H pylori was associated with a 1.75-fold increased risk of peptic ulcer disease. Longitudinal analyses revealed an 18.4- and 2.9-fold increased risk for duodenal ulcer and gastric ulcer, respectively. The proportion of PUD that is attributable to H pylori infection might be larger than previously believed. PMID- 22230168 TI - Involvement of upper torso stress amplification, tissue compression and distortion in the pathogenesis of keloids. AB - Keloids are benign tumours composed of fibrous tissue produced during excessive tissue repair triggered by minor injury, trauma or surgical incision. Although it is recognized that keloids have a propensity to form in the upper torso of the body, the predisposing factors responsible for this have not been investigated. It is crucial that the aetiopathoical factors implicated in keloid formation be established to provide guidelines for well-informed more successful treatment. We compared keloid-prone and keloid-protected skin, identified pertinent morphological differences and explored how inherent structural characteristics and intrinsic factors may promote keloid formation. It was determined that keloid prone areas were covered with high tension skin that had low stretch and a low elastic modulus when compared with skin in keloid protected areas where the skin was lax with a high elastic modulus and low pre-stress level. Factors contributing to elevated internal stress in keloid susceptible skin were the protrusion of hard connective tissue such as bony prominences or cartilage into the dermis of skin as well as inherent skin characteristics such as the bundled arrangement of collagen in the reticular dermis, the existent high tension, the low elastic modulus, low stretch ability, contractile forces exerted by wound healing fibroblastic cells and external forces. Stress promotes keloid formation by causing dermal distortion and compression which subsequently stimulate proliferation and enhanced protein synthesis in wound healing fibroblastic cells. The strain caused by stress also compresses and occludes microvessels causing ischaemic effects and reperfusion injury which stimulate growth when blood rich in growth factors returns to the tissue. The growth promoting effects of increased internal stress, primarily, and growth factors released by reperfusing blood, manifest in keloid formation. Other inherent skin characteristics promoting keloid growth during the late stages of wound healing in the upper torso are the thinner epidermis, the presence of vellus hairs, the absence of protective immunoglobulin A (IgA), and the thick fragile quality of upper torso skin. As it is not known why there is a predilection for keloids to form in the upper torso of the body, this hypothesis implicating and associating inherent morphological characteristics and elevated stress in the aetiopathogenesis of keloids is of potential value in terms of prevention, management and treatment of these enigmatic tumours. PMID- 22230169 TI - A high-resolution 3D ultrasonic system for rapid evaluation of the anterior and posterior segment. AB - BACKGROUND AND OBJECTIVE: Traditional ultrasound imaging systems for ophthalmology employ slow, mechanical scanning of a single-element ultrasound transducer. The goal was to demonstrate rapid examination of the anterior and posterior segment with a three-dimensional (3D) commercial ultrasound system incorporating high-resolution linear probe arrays. MATERIALS AND METHODS: The 3D images of the porcine eye were generated in approximately 10 seconds by scanning one of two commercial linear arrays (25- and 50-MHz). Healthy enucleated pig eyes were compared with those with induced injury or placement of a foreign material (eg, metal). Rapid, volumetric imaging was also demonstrated in one human eye in vivo. RESULTS: The 50-MHz probe provided exquisite volumetric images of the anterior segment at a depth up to 15 mm and axial resolution of 30 MUm. The 25 MHz probe provided a larger field of view (lateral X depth: 20 * 30 mm), sufficient for capturing the entire anterior and posterior segments of the pig eye, at a resolution of 60 MUm. A 50-MHz scan through the human eyelid illustrated detailed structures of the Meibomian glands, cilia, cornea, and anterior segment back to the posterior capsule. CONCLUSION: The 3D system with its high-frequency ultrasound arrays, fast data acquisition, and volume rendering capability shows promise for investigating anterior and posterior structures of the eye. PMID- 22230170 TI - Working range of stimulus flux transduction determines dendrite size and relative number of pheromone component receptor neurons in moths. AB - We are proposing that the "relative" abundances of the differently tuned pheromone-component-responsive olfactory receptor neurons (ORNs) on insect antennae are not a result of natural selection working to maximize absolute sensitivity to individual pheromone components. Rather, relative abundances are a result of specifically tuned sensillum-plus-ORN units having been selected to accurately transduce and report to the antennal lobe the maximal ranges of molecular flux imparted by each pheromone component in every plume strand. To not reach saturating stimulus flux levels from the most concentrated plume strands of a pheromone blend, the dendritic surface area of the ORN type that is tuned to the most abundant component of a pheromone blend is increased in dendritic diameter in order to express a greater number of major pheromone component specific odorant receptors. The increased ability of these enlarged dendrite, major component-tuned ORNs to accurately report very high flux of its component results in a larger working range of stimulus flux able to be accurately transduced by that type of ORN. However, the larger dendrite size and possibly other high-flux adjustments in titers of pheromone-binding proteins and degrading enzymes cause a decrease in absolute sensitivity to lower flux levels of the major component in lower concentration strands of the pheromone blend. In order to restore the ability of the whole-antenna major pheromone component-specific channel to accurately report to its glomerulus the abundance of the major component in lower concentration strands, the number of major component ORNs over the entire antenna is adjusted upward, creating a greater proportion of major component-tuned ORNs than those tuned to minor components. Pheromone blend balance reported by the whole-antennal major and minor component channels in low plume-flux strands is now restored, and the relative fluxes of the 2 components occurring in both low- and high-flux strands are thereby accurately reported to the component-specific glomeruli. Thus, we suggest that the 2 phenomena, dendrite size and relative numbers of differentially tuned ORNs are linked, and both are related to wide disparities in molecular flux ranges occurring for the more abundant and less abundant components in the pheromone blend plume strands. PMID- 22230171 TI - Slow breathing and emotions associated with odor-induced autobiographical memories. AB - An important feature of olfactory perception is its dependence on respiratory activity. By inspiration, olfactory information ascends directly to olfactory related limbic structures. Therefore, every breath with odor molecules activates these limbic areas associated with emotional experience and memory retrieval. We tested whether odors associated with autobiographical memories can trigger pleasant emotional experiences and whether respiration changes during stimulation with these odors. During presentation of odors related to autobiographical memories and control odors, we measured minute ventilation, tidal volume, respiratory frequency, O2 consumption, and end tidal CO2 concentration. Findings showed that autobiographical memory retrieval was associated with increasing tidal volume and decreasing respiratory frequency more than during presentation of control odors. Subjective feelings such as emotional arousal during retrieval of the memory, arousal level of the memory itself, or pleasantness and familiarity toward the odor evoked by autobiographical memory were more specific emotional responses compared with those related to control odors. In addition, high trait anxiety subjects responded with a stronger feeling of being taken back in time and had high arousal levels with tidal volume increases. We discussed assumptions regarding how deep and slow breathing is related to pleasantness and comfortableness of an autobiographical memory. PMID- 22230172 TI - Effects of resin ligand density on yield and impurity clearance in preparative cation exchange chromatography. I. Mechanistic evaluation. AB - The effects of resin ligand density on cation exchange chromatography performance in preparative monoclonal antibody purification processes were evaluated. A set of agarose-based cation exchange resins spanning a relatively wide range of ligand densities was tested using three different monoclonal antibodies with unique impurity profiles. Experiments were performed in bind-and-elute mode using gradient elution at both intermediate protein loadings and near saturation capacity. Ligand density did not affect clearance of high molecular weight variants under any of the conditions tested; however, ligand density did affect resolution of a basic charge variant in one case and changed host cell protein clearance in another instance. In general, the results indicate that the relationships between ligand density, retention, and resolution are affected by both characteristic charge and protein surface charge distribution. PMID- 22230173 TI - Picogram per liter level determination of hydroxylated polybrominated diphenyl ethers in water by liquid chromatography-electrospray tandem mass spectrometry. AB - Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have obtained increasing attention; however, few analytical methods are available for sensitive identification of these compounds in water. In this paper, we developed a highly sensitive method for simultaneous determination of nine OH-PBDEs in water by using hydrophilic-lipophilic balanced cartridge extraction, silica cartridge purification, and the combination of derivatization with liquid chromatography electrospray tandem mass spectrometry. The effective sample pretreatment process and greatly increased instrumental sensitivity by derivatization allow for the quantification of nine OH-PBDEs at a method detection limit of 0.04-3.5 pg/L with 1-L wastewater treatment plant effluent or river water. This method was applied to wastewater effluent and river water samples collected in Beijing, China, where two OH-tetraPBDEs were detected at concentrations ranging from 0.63 to 1.0 pg/L (5-OH-BDE-47) and from 0.92 to 1.3 pg/L (6-OH-BDE-47). PMID- 22230174 TI - Predictors of second language acquisition in Latino children with specific language impairment. AB - PURPOSE: This study evaluated the extent to which the language of intervention, the child's development in Spanish, and the effects of English vocabulary, use, proficiency, and exposure predict differences in the rates of acquisition of English in Latino children with specific language impairment (SLI). METHOD: In this randomized controlled trial, 188 Latino preschoolers with SLI participated in a small-group academic enrichment program for 12 weeks and were followed up 3 and 5 months later. Children were randomly assigned to either a bilingual or an English-only program. Predictors of English growth included measures of Spanish language skills and English vocabulary, use, proficiency, and exposure. Performance on English outcomes (i.e., picture description and narrative sample) was assessed over time. A series of longitudinal models were tested via multilevel modeling with baseline and posttreatment measures nested within child. RESULTS: Children demonstrated growth on the English outcomes over time. The language of intervention, Spanish skills, English vocabulary, and English use significantly predicted differences in rates of growth across children for specific measures of English development. CONCLUSIONS: This study underscores the role of the child's first language skills, the child's level of English vocabulary development, and level of English use for predicting differences in English acquisition in Latino preschoolers with SLI. These factors should be carefully considered in making clinical decisions. PMID- 22230175 TI - Model choice and sample size in item response theory analysis of aphasia tests. AB - PURPOSE: The purpose of this study was to identify the most appropriate item response theory (IRT) measurement model for aphasia tests requiring 2-choice responses and to determine whether small samples are adequate for estimating such models. METHOD: Pyramids and Palm Trees (Howard & Patterson, 1992) test data that had been collected from individuals with aphasia were analyzed, and the resulting item and person estimates were used to develop simulated test data for 3 sample size conditions. The simulated data were analyzed using a standard 1-parameter logistic (1-PL) model and 3 models that accounted for the influence of guessing: augmented 1-PL and 2-PL models and a 3-PL model. The model estimates obtained from the simulated data were compared to their known true values. RESULTS: With small and medium sample sizes, an augmented 1-PL model was the most accurate at recovering the known item and person parameters; however, no model performed well at any sample size. Follow-up simulations confirmed that the large influence of guessing and the extreme easiness of the items contributed substantially to the poor estimation of item difficulty and person ability. CONCLUSION: Incorporating the assumption of guessing into IRT models improves parameter estimation accuracy, even for small samples. However, caution should be exercised in interpreting scores obtained from easy 2-choice tests, regardless of whether IRT modeling or percentage correct scoring is used. PMID- 22230176 TI - Relationships between vocabulary size, working memory, and phonological awareness in Spanish-speaking English language learners. AB - PURPOSE: The goals of this study were to evaluate the impact of short-term phonological awareness (PA) instruction presented in children's first language (L1; Spanish) on gains in their L1 and second language (L2; English) and to determine whether relationships exist between vocabulary size, verbal working memory, and PA in Spanish-speaking English language learners (ELLs). METHOD: Participants included 25 kindergartners who received PA instruction and 10 controls. A 2-way within-subjects repeated measures multivariate analysis of variance (MANOVA) was conducted to evaluate gains. Relationships between PA gains, Spanish and English vocabulary, and memory, as measured using nonword repetition and experimental working memory tasks, were analyzed using correlation and regression analyses. RESULTS: Results indicated significant and equivalent gains in both languages of children in the experimental group and no gains in the control group. Spanish vocabulary size was significantly related to PA gains in both languages and was more strongly related to English gains than was English vocabulary size. The memory tasks predicted gains in each language in distinct ways. CONCLUSION: Results support the conclusion that PA instruction and strong vocabulary skills in an individual's L1 benefit PA development in both the L1 and L2. Results also indicate that dynamic relationships exist between vocabulary size, storage and processing components of working memory, and PA development in both languages of ELLs. PMID- 22230177 TI - Acquired apraxia of speech: the effects of repeated practice and rate/rhythm control treatments on sound production accuracy. AB - PURPOSE: This investigation was designed to elucidate the effects of repeated practice treatment on sound production accuracy in individuals with apraxia of speech (AOS) and aphasia. A secondary purpose was to determine if the addition of rate/rhythm control to treatment provided further benefits beyond those achieved with repeated practice. METHOD: A single-subject design was employed with 10 speakers with chronic AOS and aphasia. Articulation accuracy served as the dependent measure. Participants received repeated practice treatment until a plateau in performance was observed or high levels of accuracy were achieved. If performance criterion was not reached, rate/rhythm control was added to the treatment to determine if additional gains would be made. RESULTS: For 8 of the participants, improvements were evident for all applications of repeated practice treatment, and positive response generalization was observed in most cases. When rate/rhythm control treatment was applied, modest additional gains were apparent for the majority of the applications. The 2 participants who did not benefit from repeated practice treatment also did not show improvements with rate/rhythm control treatment. CONCLUSIONS: Repeated practice treatment resulted in improved articulation for the majority of participants. The amount of improvement varied within and across participants. Rate/rhythm control appeared to have limited additional benefits for some participants. PMID- 22230178 TI - Changing nonmainstream American English use and early reading achievement from kindergarten to first grade. AB - PURPOSE: This study had 2 principal aims: (a) to examine whether children who spoke Nonmainstream American English (NMAE) frequently in school at the end of kindergarten increased their production of Mainstream American English (MAE) forms by the end of first grade, and (b) to examine concurrent and predictive relations between children's NMAE use and reading skills. METHOD: A longitudinal design was implemented with 49 children who varied in their spoken NMAE production in kindergarten. Word reading, phonological awareness, and receptive vocabulary skills were measured at both time points. RESULTS: Analyses indicated that most children significantly increased their production of MAE forms between the 2 time points; however, this change was not associated with change in letter word reading and phonological awareness skills. Regression analyses showed that NMAE use in kindergarten contributed significantly and independently to the variance in word reading in first grade, even after accounting for phonological awareness (although word reading in kindergarten was the best predictor of word reading in first grade). CONCLUSIONS: The findings extend previous reports of a significant relation between NMAE use and reading among young children. Theoretical, research, and educational implications of the findings are discussed. PMID- 22230179 TI - Attention and other cognitive deficits in aphasia: presence and relation to language and communication measures. AB - PURPOSE: This study was designed to further elucidate the relationship between cognition and aphasia, with a focus on attention. It was hypothesized that individuals with aphasia would display variable deficit patterns on tests of attention and other cognitive functions and that their attention deficits, particularly those of complex attention functions, would be related to their language and communication status. METHOD: A group of individuals with varying types and severity of aphasia and a group of age- and education-matched adults with no brain damage completed tests of attention, short-term and working memory, and executive functioning. RESULTS: Overall, the group with aphasia performed significantly more poorly than the control group on the cognitive measures but displayed variability in the presence, types, and severity of their attention and other cognitive deficits. Correlational and regression analyses yielded significant relations between participants' attention deficits and their language and communication status. CONCLUSION: The findings accorded well with prior research identifying (a) attention and other cognitive deficits in most but not all individuals with aphasia; (b) heterogeneity in the types and severity of attention and other cognitive symptoms among individuals with cognitive impairments; and (c) potent associations among attention, language, and other cognitive domains. Implications for clinical practice and future research are discussed. PMID- 22230180 TI - Miranda rights comprehension in young adults with specific language impairment. AB - PURPOSE: The purpose of this study was to determine whether citizens with language impairment understand legal rights as conveyed in Miranda warnings. METHOD: Grisso's Instruments for Assessing Understanding and Appreciation of Miranda Rights (1998) was administered to 34 young adults, half of whom met the diagnostic criteria for specific language impairment (SLI). A correlational analysis of the relationship between language scores and Miranda rights comprehension was conducted, as were tests of differences between individuals with SLI (n = 17) and individuals without SLI. RESULTS: Language ability was positively correlated with overall performance on the Miranda measure. As a group, individuals with SLI were significantly poorer than their peers with normal language at defining Miranda vocabulary and applying Miranda rights in hypothetical situations. The group with SLI was also marginally less able to paraphrase Miranda sentences. CONCLUSION: Language impairment limits comprehension of Miranda warnings. As a result, citizens with language impairment are at risk of being denied their constitutional rights. PMID- 22230181 TI - Facilitating emergent literacy: efficacy of a model that partners speech-language pathologists and educators. AB - PURPOSE: This study examined the efficacy of a professional development program for early childhood educators that facilitated emergent literacy skills in preschoolers. The program, led by a speech-language pathologist, focused on teaching alphabet knowledge, print concepts, sound awareness, and decontextualized oral language within naturally occurring classroom interactions. METHOD: Twenty educators were randomly assigned to experimental and control groups. Educators each recruited 3 to 4 children from their classrooms to participate. The experimental group participated in 18 hr of group training and 3 individual coaching sessions with a speech-language pathologist. The effects of intervention were examined in 30 min of videotaped interaction, including storybook reading and a post-story writing activity. RESULTS: At posttest, educators in the experimental group used a higher rate of utterances that included print/sound references and decontextualized language than the control group. Similarly, the children in the experimental group used a significantly higher rate of utterances that included print/sound references and decontextualized language compared to the control group. CONCLUSION: These findings suggest that professional development provided by a speech-language pathologist can yield short-term changes in the facilitation of emergent literacy skills in early childhood settings. Future research is needed to determine the impact of this program on the children's long-term development of conventional literacy skills. PMID- 22230182 TI - The role of experience in the perception of phonetic detail in children's speech: a comparison between speech-language pathologists and clinically untrained listeners. AB - PURPOSE: This study examined whether experienced speech-language pathologists (SLPs) differ from inexperienced people in their perception of phonetic detail in children's speech. METHOD: Twenty-one experienced SLPs and 21 inexperienced listeners participated in a series of tasks in which they used a visual-analog scale (VAS) to rate children's natural productions of target /s/-/theta/, /t/ /k/, and /d/-// in word-initial position. Listeners rated the perceived distance between individual productions and ideal productions. RESULTS: The experienced listeners' ratings differed from the inexperienced listeners' ratings in four ways: They had higher intrarater reliability, showed less bias toward a more frequent sound, and were more closely related to the acoustic characteristics of the children's speech. In addition, the experienced listeners' responses were related to a different set of predictor variables. CONCLUSION: Results suggest that experience working as an SLP leads to better perception of phonetic detail in children's speech. Limitations and future research are discussed. PMID- 22230183 TI - The effect of feedback and practice on the acquisition of novel speech behaviors. AB - PURPOSE: This study examined the effect of manipulating several parameters of motor learning theory on participants' phonetic acquisition and retention of utterances in a foreign language (Korean). METHOD: Thirty-two native English speaking participants naive to the Korean language were each given 10 Korean sentences to practice and learn. The independent variables in the study were the number of practice trials and the feedback schedule. The participants listened to sentences delivered by a native speaker and received feedback according to the schedule. Participant responses were then judged by a panel of native Korean speakers in terms of their intelligibility, naturalness, and precision. RESULTS: The combination of 20% feedback and 100 practice trials was more effective than other combinations of feedback and practice trial schedule for the retention of novel phonetic productions of Korean phrases both 1 day after training and 1 week later. CONCLUSIONS: These findings are in agreement with previously reported applications of motor learning-guided principles on the acquisition of motoric skills. These findings may have direct implications for both second-language learning and the treatment of neuromotor speech disorders such as apraxia of speech. PMID- 22230184 TI - Effect of meal size on the specific dynamic action of the juvenile snakehead (Channa argus). AB - The effect of meal size on the specific dynamic action (SDA) of the juvenile snakehead (Channa argus) was assessed at 25 degrees C. The fish were fed with test diets at meal sizes of 0.5, 1, 2, 3, 4, and 5% body mass and the postprandial oxygen consumption rate was determined at 1-h intervals until it returned to the pre-prandial level. The peak metabolic rate increased from 237.4 to 283.2 mg O(2) kg(-1) h(-1) as the relative meal size increased from 0.5% to 3% and leveled off at 4% and 5%. Factorial metabolic scope increased from 1.53 to 1.99 and SDA duration increased from 11.7 to 32.3h as the relative meal size increased from 0.5% to 5%. The relationship between SDA duration (D) and relative meal size (M) was described as: D=4.28 M+10.62 (r(2)=0.752, P<0.05, n=50). The energy expended on SDA increased while the SDA coefficient decreased with increasing meal size. The results of the present study suggest that the snakehead may adopt different feeding strategies when taking in different amounts of food. PMID- 22230185 TI - Methionine sulfoxide reductases and methionine sulfoxide in the subterranean mole rat (Spalax): characterization of expression under various oxygen conditions. AB - The blind subterranean mole rat (Spalax ehrenbergi) exhibits a relatively long life span, which is attributed to an efficient antioxidant defense affording protection against accumulation of oxidative modifications of proteins. Methionine residues can be oxidized to methionine sulfoxide (MetO) and then enzymatically reduced by the methionine sulfoxide reductase (Msr) system. In the current study we have isolated the cDNA sequences of the Spalax Msr genes as well as 23 additional selenoproteins and monitored the activities of Msr enzymes in liver and brain of rat (Rattus norvegicus), Spalax galili, and Spalax judaei under normoxia, hypoxia, and hyperoxia. Under normoxia, the Msr activity was lower in S. galili in comparison to S. judaei and R. norvegicus especially in the brain. The pattern of Msr activity of the three species was similar throughout the tested conditions. However, exposure of the animals to hypoxia caused a significant enhancement of Msr activity, especially in S. galili. Hyperoxic exposure showed a highly significant induction of Msr activity compared with normoxic conditions for R. norvegicus and S. galili brain. It was concluded that among all species examined, S. galili appears to be more responsive to oxygen tension changes and that the Msr system is upregulated mainly by severe hypoxia. PMID- 22230186 TI - High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells. AB - BACKGROUND: Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal beta-cell line, INS 1E. METHODS: The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed. RESULTS: Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 MUM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction. CONCLUSIONS: Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity. PMID- 22230187 TI - Effectiveness of part C early intervention physical, occupational, and speech therapy services for preterm or low birth weight infants in Wisconsin, United States. AB - OBJECTIVE: To determine the effectiveness of policy-driven therapy (ie, Part C early intervention [EI]) in the context of varying maternal supports among preterm infants in Wisconsin. METHODS: A longitudinal study of mother-infant dyads recruited from 3 newborn intensive care units in southeastern Wisconsin. Participation in EI-based therapy was collected at 36 months via parent-report. Cognitive function was measured at 16 months by use of the Bayley Scales of Infant Development (Mental Developmental Index), 2nd edition and at 24 and 36 months postterm via use of the Stanford-Binet Intelligence scale, 5th edition. Maternal support was measured at 4 months with the Maternal Support Scale. Propensity score matching was used to reduce selection bias. Latent growth models of matched pairs estimated the effect of EI therapy on cognitive function trajectories. Ordinary least squares regression estimated the differential effect of EI therapy on cognitive function at 16, 24, and 36 months postterm for mothers reporting more maternal supports. RESULTS: Of the 128 infants, 41 received EI therapy and, of those, 32 (78%) were successfully matched with controls. The results of the matched analysis (n = 64) reveal that 1) receipt of therapy is inversely associated with cognitive function baseline (P = .04) and positively associated with trajectories (P = .03), 2) the number of maternal supports is positively associated with cognitive function for families receiving Part C early intervention, at 16 months (P = .05), 24 months (P < .01), and 36 months (P = .05) postterm. CONCLUSIONS: Participation in EI therapy may be associated with more optimal cognitive function trajectories. Among preterm children whose mothers have more supports, receiving therapy appears particularly beneficial. PMID- 22230189 TI - The possible benefits of reduced errors in the motor skills acquisition of children. AB - An implicit approach to motor learning suggests that relatively complex movement skills may be better acquired in environments that constrain errors during the initial stages of practice. This current concept paper proposes that reducing the number of errors committed during motor learning leads to stable performance when attention demands are increased by concurrent cognitive tasks. While it appears that this approach to practice may be beneficial for motor learning, further studies are needed to both confirm this advantage and better understand the underlying mechanisms. An approach involving error minimization during early learning may have important applications in paediatric rehabilitation. PMID- 22230190 TI - The costs of parental pressure to express emotions: conditional regard and autonomy support as predictors of emotion regulation and intimacy. AB - This research focuses on offspring's perceptions of their parents' usage of conditional regard and autonomy-supportive practices in response to the offspring's experiences of negative emotion. Participants were 174 college students (60% were females). As predicted from self-determination theory (Ryan & Deci, 2000), students' perceptions of parents as hinging their regard on students' expression or suppression of negative emotions predicted a maladaptive pattern of emotion regulation and intimacy capacity. In contrast, autonomy supportive parenting predicted more adaptive emotion regulation and intimacy patterns. Also as predicted, emotion-regulation mode mediated the relations between parental practices and intimacy capacity. The innovative aspect of the study is the finding that parents who use conditional regard to encourage children's expression (sharing) of negative emotions may actually undermine their children's socioemotional capacities. PMID- 22230188 TI - Engineered Trx2p industrial yeast strain protects glycolysis and fermentation proteins from oxidative carbonylation during biomass propagation. AB - BACKGROUND: In the yeast biomass production process, protein carbonylation has severe adverse effects since it diminishes biomass yield and profitability of industrial production plants. However, this significant detriment of yeast performance can be alleviated by increasing thioredoxins levels. Thioredoxins are important antioxidant defenses implicated in many functions in cells, and their primordial functions include scavenging of reactive oxygen species that produce dramatic and irreversible alterations such as protein carbonylation. RESULTS: In this work we have found several proteins specifically protected by yeast Thioredoxin 2 (Trx2p). Bidimensional electrophoresis and carbonylated protein identification from TRX-deficient and TRX-overexpressing cells revealed that glycolysis and fermentation-related proteins are specific targets of Trx2p protection. Indeed, the TRX2 overexpressing strain presented increased activity of the central carbon metabolism enzymes. Interestingly, Trx2p specifically preserved alcohol dehydrogenase I (Adh1p) from carbonylation, decreased oligomer aggregates and increased its enzymatic activity. CONCLUSIONS: The identified proteins suggest that the fermentative capacity detriment observed under industrial conditions in T73 wine commercial strain results from the oxidative carbonylation of specific glycolytic and fermentation enzymes. Indeed, increased thioredoxin levels enhance the performance of key fermentation enzymes such as Adh1p, which consequently increases fermentative capacity. PMID- 22230191 TI - Evidence that AMP-activated protein kinase can negatively modulate ornithine decarboxylase activity in cardiac myoblasts. AB - The responses of AMP-activated protein kinase (AMPK) and Ornithine decarboxylase (ODC) to isoproterenol have been examined in H9c2 cardiomyoblasts, AMPK represents the link between cell growth and energy availability whereas ODC, the key enzyme in polyamine biosynthesis, is essential for all growth processes and it is thought to have a role in the development of cardiac hypertrophy. Isoproterenol rapidly induced ODC activity in H9c2 cardiomyoblasts by promoting the synthesis of the enzyme protein and this effect was counteracted by inhibitors of the PI3K/Akt pathway. The increase in enzyme activity became significant between 15 and 30min after the treatment. At the same time, isoproterenol stimulated the phosphorylation of AMPKalpha catalytic subunits (Thr172), that was associated to an increase in acetyl coenzyme A carboxylase (Ser72) phosphorylation. Downregulation of both alpha1 and alpha2 isoforms of the AMPK catalytic subunit by siRNA to knockdown AMPK enzymatic activity, led to superinduction of ODC in isoproterenol-treated cardiomyoblasts. Downregulation of AMPKalpha increased ODC activity even in cells treated with other adrenergic agonists and in control cells. Analogue results were obtained in SH-SY5Y neuroblastoma cells transfected with a shRNA construct against AMPKalpha. In conclusion, isoproterenol quickly activates in H9c2 cardiomyoblasts two events that seem to contrast one another. The first one, an increase in ODC activity, is linked to cell growth, whereas the second, AMPK activation, is a homeostatic mechanism that negatively modulates the first. The modulation of ODC activity by AMPK represents a mechanism that may contribute to control cell growth processes. PMID- 22230192 TI - Regulation of SGLT expression and localization through Epac/PKA-dependent caveolin-1 and F-actin activation in renal proximal tubule cells. AB - This study demonstrated that exchange proteins directly activated by cAMP (Epac) and protein kinase A (PKA) by 8-bromo (8-Br)-adenosine 3',5'-cyclic monophosphate (cAMP) stimulated [(14)C]-alpha-methyl-D-glucopyranoside (alpha-MG) uptake through increased sodium-glucose cotransporters (SGLTs) expression and translocation to lipid rafts in renal proximal tubule cells (PTCs). In PTCs, SGLTs were colocalized with lipid raft caveolin-1 (cav-1), disrupted by methyl beta-cyclodextrin (MbetaCD). Selective activators of Epac or PKA, 8-Br-cAMP, and forskolin stimulated expressions of SGLTs and alpha-MG uptake in PTCs. In addition, 8-Br-cAMP-induced PKA and Epac activation increased phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB), which were involved in expressions of SGLTs. Furthermore, 8-Br-cAMP stimulated SGLTs translocation to lipid rafts via filamentous actin (F-actin) organization, which was blocked by cytochalasin D. In addition, cav-1 and SGLTs stimulated by 8-Br-cAMP were detected in lipid rafts, which were blocked by cytochalasin D. Furthermore, 8-Br cAMP-induced SGLTs translocation and alpha-MG uptake were attenuated by inhibition of cav-1 activation with cav-1 small interfering RNA (siRNA) and inhibition of F-actin organization with TRIO and F-actin binding protein (TRIOBP). In conclusion, 8-Br-cAMP stimulated alpha-MG uptake via Epac and PKA dependent SGLTs expression and trafficking through cav-1 and F-actin in PTCs. PMID- 22230193 TI - New cholinesterase inhibiting bisbenzylisoquinoline alkaloids from Abuta grandifolia. AB - The phytochemical study of the stem bark and wood of Abuta grandifolia (Mart.) Sandwith led to the identification of four bisbenzylisoquinoline alkaloids (BBIQs), namely (R,S)-2 N-norberbamunine (1), (R,R)-isochondodendrine (2), (S-S) O4"-methyl, Nb-nor-O6'-demethyl-(+)-curine (3), and (S-S)-O4"-methyl, O6' demethyl-(+)-curine (4), together with the aporphine alkaloid R-nornuciferine (5), all obtained by countercurrent distribution separation (CCD) and identified on the basis of their spectroscopic data. Alkaloids 3 and 4 were new. All the isolated compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. 1 was the most active against AChE, whereas 3 and 4 were the most potent against BChE. Interestingly, all tested alkaloids are more potent against BChE than against AChE. This selectivity of cholinesterase (ChE) inhibition could be important in order to speculate on their potential therapeutic relevance. PMID- 22230194 TI - Isolation and identification of C-19 fatty acids with anti-tumor activity from the spores of Ganoderma lucidum (reishi mushroom). AB - We previously showed that ethanolic extracts of spores of Ganoderma lucidum inhibit tumor cell proliferation and induce apoptosis of HL-60 cells. The active constituents appeared to be long-chain fatty acids, particularly carbon-19 (C-19) fatty acids which have not been reported in spores of Ganoderma lucidum. In the present study, two of these C-19 fatty acids which are key compounds in the activities, were identified as their 2-naphthyl ester derivatives after esterification of a mixture of fatty acids obtained from the spores. The active compounds were determines as nonadecanoic acid and cis-9-nonadecenoic acid. The location of the double bond of cis-9-nonadecenoic acid was demonstrated by GC-MS analysis, based on the fragmentation pattern of the adduct prepared from the fatty acid and dimethyl disulfide. PMID- 22230195 TI - Bleomycin induces delayed instability of interstitial telomeric sequences in Chinese hamster ovary cells. AB - We analyzed the behavior of interstitial telomeric sequences (ITSs) in the progeny of Chinese Hamster Ovary (CHO) cells exposed to the radiomimetic compound bleomycin (BLM) in order to determine if ITSs play some role in the long-term clastogenic effect of this antibiotic. To this end, CHO cells were treated with a single concentration of BLM (2.5MUg/ml), and the frequency of unstable chromosomal aberrations was determined at several times after treatment (18h, and 6, 15 and 34/36 days) by using PNA-FISH with a pan-telomeric probe [(TTAGGG)n repeats]. Cytogenetic analysis revealed a higher frequency of aberrations at 18h and 6 days after treatment in BLM-exposed cultures vs. untreated cultures, although the yield of BLM-induced aberrations decreased on average five times 6 days after treatment compared with the one induced 18h after treatment. Moreover, no significant differences in the frequency of aberrations were observed between untreated and BLM-exposed cells at 15 or 34/36 days after treatment. These data indicate that, in terms of unstable aberrations, the in vitro clastogenic effect of BLM on CHO cells persists for at least 6 days but less than 15 days after exposure. In addition, we found that BLM induces ITSs instability, cytogenetically detectable as acentric fragments (18h after treatment) or additional (new) FISH signals (6 days after treatment). We propose that the delayed effect of BLM on ITSs mainly results from breakage of heterochromatic ITSs blocks and further insertion of these sequences at the sites of monochromatid breaks occurring at G2 phase of the cell cycle, since most of the additional FISH signals were present as single dots and located at interstitial sites of the involved chromosomes. PMID- 22230196 TI - Bystander apoptosis in human cells mediated by irradiated blood plasma. AB - Following exposure to high doses of ionizing radiation, due to an accident or during radiotherapy, bystander signalling poses a potential hazard to unirradiated cells and tissues. This process can be mediated by factors circulating in blood plasma. Thus, we assessed the ability of plasma taken from in vitro irradiated human blood to produce a direct cytotoxic effect, by inducing apoptosis in primary human peripheral blood mononuclear cells (PBM), which mainly comprised G(0)-stage lymphocytes. Plasma was collected from healthy donors' blood irradiated in vitro to 0-40Gy acute gamma-rays. Reporter PBM were separated from unirradiated blood with Histopaque and held in medium with the test plasma for 24h at 37 degrees C. Additionally, plasma from in vitro irradiated and unirradiated blood was tested against PBM collected from blood given 4Gy. Apoptosis in reporter PBM was measured by the Annexin V test using flow cytometry. Plasma collected from unirradiated and irradiated blood did not produce any apoptotic response above the control level in unirradiated reporter PBM. Surprisingly, plasma from irradiated blood caused a dose-dependent reduction of apoptosis in irradiated reporter PBM. The yields of radiation-induced cell death in irradiated reporter PBM (after subtracting the respective values in unirradiated reporter PBM) were 22.2+/-1.8% in plasma-free cultures, 21.6+/-1.1% in cultures treated with plasma from unirradiated blood, 20.2+/-1.4% in cultures with plasma from blood given 2-4Gy and 16.7+/-3.2% in cultures with plasma from blood given 6-10Gy. These results suggested that irradiated blood plasma did not cause a radiation-induced bystander cell-killing effect. Instead, a reduction of apoptosis in irradiated reporter cells cultured with irradiated blood plasma has implications concerning oncogenic risk from mutated cells surviving after high dose in vivo irradiation (e.g. radiotherapy) and requires further study. PMID- 22230197 TI - Characterization of oocyte-expressed GDF9 gene in buffalo and mapping of its TSS and putative regulatory elements. AB - Summary In spite of emerging evidence about the vital role of GDF9 in determination of oocyte competence, there is insufficient information about its regulation of oocyte-specific expression, particularly in livestock animals. Because of the distinct prominence of buffalo as a dairy animal, the present study was undertaken to isolate and characterize GDF9 cDNA using orthologous primers based on the bovine GDF9 sequence. GDF9 transcripts were found to be expressed in oocytes irrespective of their follicular origin, and shared a single transcription start site (TSS) at -57 base pairs (bp) upstream of ATG. Assignment of the TSS is consistent with the presence of a TATA element at -23 of the TSS mapped in this study. Localization of a buffalo-specific minimal promoter within 320 bp upstream of ATG was consolidated by identification of an E-box element at 113bp. Presence of putative transcription factor binding sites and other cis regulatory elements were analyzed at ~5 kb upstream of TSS. Various germ cell specific cis-acting regulatory elements (BNCF, BRNF, NR2F, SORY, Foxh1, OCT1, LHXF etc.) have been identified in the 5' flanking region of the buffalo GDF9 gene, including NOBOX DNA binding elements and consensuses E-boxes (CANNTG). Presence of two conserved E-boxes found on buffalo sequence at -520 and -718 positions deserves attention in view of its sequence deviation from other species. Two NOBOX binding elements (NBE) were detected at the -3471 and -203 positions. The fall of the NBE within the putative minimal promoter territory of buffalo GDF9 and its unique non-core binding sequence could have a possible role in the control of the core promoter activity. PMID- 22230198 TI - Characterization of a 1,4-disubstituted 1,2,3-triazole binding to T box antiterminator RNA. AB - The T box riboswitch regulates the transcription of many bacterial genes by structurally responding to cognate non-aminoacylated (uncharged) tRNA. The riboswitch contains multiple conserved RNA elements including a key structural element, the antiterminator, which binds the tRNA acceptor end nucleotides. Previous studies identified a lead 1,4-disubstituted 1,2,3-triazole, GHB-7, that disrupted formation of a tRNA-antiterminator RNA model complex. The affinity and molecular interactions of GHB-7 binding to antiterminator model RNA were characterized as part of a comprehensive T box antiterminator RNA-targeted drug discovery project. In-line probing, UV-monitored thermal denaturation and docking studies all consistently indicated that GHB-7 likely binds to the bulge region of the antiterminator, reduces the flexibility of the bulge nucleotides and, overall, stabilizes the RNA secondary structure. These results begin to elucidate possible mechanisms for ligand-induced inhibition of tRNA binding to T box antiterminator RNA and contribute to the knowledge of how small molecules bind relatively simple RNA structural elements such as bulges. PMID- 22230199 TI - Unbiased binding assays for discovering small-molecule probes and drugs. AB - 2011 marks the 10-year anniversary of milestone manuscripts describing drafts of the human genome sequence. Over the past decade, a number of new proteins have been linked to disease-many of which fall into classes that have been historically considered challenging from the perspective of drug discovery. Several of these newly associated proteins lack structural information or strong annotation with regard to function, making development of conventional in vitro functional assays difficult. A recent resurgence in the popularity of simple small molecule binding assays has led to new approaches that do not require knowledge of protein structure or function in advance. Here we briefly review selected methods for executing binding assays that have been used successfully to discover small-molecule probes or drug candidates. PMID- 22230200 TI - Assessment of MRI issues at 3-Tesla for metallic surgical implants: findings applied to 61 additional skin closure staples and vessel ligation clips. AB - PURPOSE: Metallic skin closure staples and vessel ligation clips should be tested at 3-Tesla to characterize MRI issues in order to ensure patient safety. Therefore, metallic surgical implants were assessed at 3-Tesla for magnetic field interactions, MRI-related heating, and artifacts. METHODS: A skin closure staple (Visistat Skin Stapler, staple, Polytetrafluoroethylene, PTFE, coated 316L/316LVM stainless steel; Teleflex Medical, Durham, NC) and a vessel ligation clip (Hemoclip Traditional, stainless steel; Teleflex Medical, Durham, NC) that represented the largest metallic sizes made from materials with the highest magnetic susceptibilities (i.e., based on material information) among 61 other surgical implants (52 metallic implants, 9 nonmetallic implants) underwent evaluation for magnetic field interactions, MRI-related heating, and artifacts using standardized techniques. MRI-related heating was assessed by placing each implant in a gelled-saline-filled phantom with MRI performed using a transmit/receive RF body coil at an MR system reported, whole body averaged SAR of 2.9-W/kg for 15-min. Artifacts were characterized using T1-weighted, SE and GRE pulse sequences. RESULTS: Each surgical implant showed minor magnetic field interactions (20- and 27-degrees, which is acceptable from a safety consideration). Heating was not substantial (highest temperature change, <= 1.6 degrees C). Artifacts may create issues if the area of interest is in the same area or close to the respective surgical implant. CONCLUSIONS: The results demonstrated that it would be acceptable for patients with these metallic surgical implants to undergo MRI at 3-Tesla or less. Because of the materials and dimensions of the surgical implants that underwent testing, these findings pertain to 61 additional similar implants. PMID- 22230201 TI - Gratitude for new beginnings and for those who serve Nursing Outlook. PMID- 22230202 TI - Are we evidence-based when we like the evidence? PMID- 22230203 TI - An exploratory randomized controlled trial comparing telephone and hospital follow-up after treatment for colorectal cancer. AB - AIM: Following treatment for colorectal cancer it is common practice for patients to attend hospital clinics at regular intervals for routine monitoring, although debate persists on the benefits of this approach. Nurse-led telephone follow-up is effective in meeting information and psycho-social needs in other patient groups. We explored the potential benefits of nurse-led telephone follow-up for colorectal cancer patients. METHOD: Sixty-five patients were randomized to either telephone or hospital follow-up in an exploratory randomized trial. RESULTS: The telephone intervention was deliverable in clinical practice and acceptable to patients and health professionals. Seventy-five per cent of eligible patients agreed to randomization. High levels of satisfaction were evident in both study groups. Appointments in the hospital group were shorter (median 14.0 min, range 2.3-58.0) than appointments in the telephone group (median 28.9 min, range 6.1 48.3). Patients in the telephone arm were more likely to raise concerns during consultations. CONCLUSION: Historical approaches to follow-up unsupported by evidence of effectiveness and efficiency are not sustainable. Telephone follow-up by specialist nurses may be a feasible option. A main trial comparing hospital and telephone follow-up is justified, although consideration needs to be given to trial design and practical issues related to the availability of specialist nurses at study locations. PMID- 22230213 TI - UGT1A1 polymorphisms associated with risk of induced liver disorders by anti tuberculosis medications. AB - First-line drug treatment for tuberculosis (TB) is frequently associated with liver toxicity. The goal of this study was to examine the association between UDP glucuronosyl-transferase 1A1 (UGT1A1) genetic variations and anti-tuberculosis drug-induced hepatotoxicity (ATDH). A total of 98 patients, including 17 patients with ATDH, were enrolled; compound UGT1A1*27 and UGT1A1*28 were associated with an increased risk for developing ATDH after adjusting for age (OR 13.859; 95%CI 1.085-177.056). These findings require confirmation. However, screening for genetic variations prior to TB treatment may reduce the incidence of ATDH and improve treatment adherence. PMID- 22230214 TI - Synthesis of porphyrinoids with silane anchors and their covalent self-assembling and metallation on solid surface. AB - We have synthesized a set of porphyrin and phthalocyanine compounds with two different silane anchors. Syntheses of the anchor-substituted chromophores have been carried out via hydrosilylation of alkene derivatives, catalyzed by platinum complexes. The reduction side-process was suppressed using specific anchor/catalyst pairs, and the silane-containing compounds were successfully isolated from hydrogenated by-products in pure form with good yields. The target porphyrinoids having stable reactive silane anchors possess the ability to self assemble on metal oxides and quartz surfaces and optical fibers. Covalent attachment is done in one-step, which makes the bonding process fast and easy. Immobilized chromophores were further converted by on-surface reactions into Zn(II) and Mg(II) metal complexes. The metallation time was found to be as fast as 1 min for Zn ion. Bonding densities calculated from the absorbances of the deposited layers give rough estimations for packing of the molecules on various substrates and evidence for monomolecular layers formation. PMID- 22230216 TI - Effects of conjugated linoleic acid isomers on monocyte, macrophage and foam cell phenotype in atherosclerosis. AB - Conjugated linoleic acid (CLA) is a generic term denoting a group of naturally occurring isomers of linoleic acid (18:2, n6) that differ in the position or geometry (i.e. cis or trans) of their double bonds. The predominant isomers in ruminant fats are cis-9,trans-11 CLA (c9,t11-CLA), and trans-10,cis-12 CLA (t10,c12-CLA). The biological activities of CLA have received considerable attention because of its protective effects in cancer, immune function, obesity and atherosclerosis. Importantly, dietary administration of a blend of the two most abundant isomers of CLA, has been shown to inhibit the progression and induce the regression of pre-established atherosclerosis in the ApoE-/- murine model. Studies investigating the mechanisms involved in CLA induced protective effects are continually emerging with results from both in vitro and in vivo models yielding confounding and often inconsistent results depending on both the isomer of CLA and the species under investigation. The purpose of this review is to comprehensively discuss the effects of CLA on monocyte/macrophage function in atherosclerosis. This review also discusses the possible mechanisms through which CLA mediates its atheroprotective effects with a particular emphasis on the migratory capacity of the monocyte and the inflammatory and cholesterol homeostasis of the macrophage. PMID- 22230215 TI - Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study. AB - BACKGROUND: The aim of this study was to explore the associations between common potential functional promoter polymorphisms in pro-/anti-inflammatory cytokine genes and kidney function/chronic kidney disease (CKD) prevalence in a large Japanese population. METHODS: A total of 3,323 subjects aged 35-69 were genotyped for all 10 single nucleotide polymorphisms (SNPs) in the promoter regions of candidate genes with minor allele frequencies of > 0.100 in Japanese populations. The estimated glomerular filtration rate (eGFR) and CKD prevalence (eGFR < 60 ml/min/1.73 m2) of the subjects were compared among the genotypes. RESULTS: A higher eGFR and lower prevalence of CKD were observed for the homozygous variants of IL4 -33CC (high IL-4 [anti-inflammatory cytokine]-producing genotype) and IL6 572GG (low IL-6 [pro-inflammatory cytokine]-producing genotype). Subjects with IL4 CC + IL6 GG showed the highest mean eGFR (79.1 ml/min/1.73 m2) and lowest CKD prevalence (0.0%), while subjects carrying IL4 TT + IL6 CC showed the lowest mean eGFR (73.4 ml/min/1.73 m2) and highest CKD prevalence (17.9%). CONCLUSIONS: The functional promoter polymorphisms IL4 T-33C (rs2070874) and IL6 C-572G (rs1800796), which are the only SNPs that affect the IL-4 and IL-6 levels in Japanese subjects, were associated with kidney function and CKD prevalence in a large Japanese population. PMID- 22230217 TI - Reactive lymphoid hyperplasia of the liver and pancreas. A report of two cases and a comprehensive review of the literature. AB - BACKGROUND: Reactive lymphoid hyperplasia (RLH) is a rare non-neoplastic extranodal pathology with exceedingly rare occurrence in the liver and pancreas. We present two cases of hepatic RLH, one which had coinciding pancreatic involvement. To the best of our knowledge, concomitant hepatic and pancreatic RLH has not been previously reported. We also present a comprehensive review of the literature on hepatic and pancreatic RLH. METHODS: An extensive literature search for all published reports on hepatic or pancreatic RLH was conducted. Data on clinical, radiographic and histopathological features were extracted in addition to therapeutic options and outcomes. RESULTS: Forty-two hepatic and three pancreatic cases of RLH were described in the literature. The mean age of hepatic cases was 58 years, with a male-to-female ratio of above 1:7. Almost 25% of cases were associated with internal malignancy. Four hepatic cases were managed through active observation. The remainder (84%) underwent surgical resection. Due to their small number, no meaningful analysis could be made on the pancreatic cases. No recurrences were identified in any of the reported cases. CONCLUSION: RLH should be considered in the diagnosis of hepatic nodules where biopsies fail to demonstrate malignant cells. Confirmed RLH lesions should be managed by active observation. Investigation and treatment of any potential source of lymphoid reactivity should be undertaken. More reports on pancreatic RLH need to be studied prior to drawing any useful recommendations on its management. PMID- 22230218 TI - Plasma thrombin-activatable fibrinolysis inhibitor as an indicator of inflammation and disease severity in acute pancreatitis. AB - AIM: In addition to suppressing fibrinolysis, thrombin activatable fibrinolysis inhibitor (TAFI) was suggested to be involved in inflammation. To date, no study has been published that reports the role of TAFI in acute pancreatitis (AP). Therefore, the objective of the present study was to investigate the role of plasma TAFI as an indicator of inflammation in AP, and its association with disease severity. METHODS: Plasma TAFI antigen levels quantitatively determined by using ELISA kits in 21 AP patients at onset and remission and 17 healthy controls. Associations of TAFI with inflammatory markers to determine AP and disease severity were assessed. To predict the severity of AP, modified Glasgow prognostic score (mGPS) and computerized tomography severity index (CTSI) were used for each subject. RESULTS: Plasma TAFI levels was higher in AP patients at onset of the disease compared with healthy controls. The disease severity according to mGPS was significantly correlated with TAFI levels. Overall, accuracy of TAFI in determining AP was 83.3% with a sensitivity, specificity, NPV and PPV of 80.9%, 85.7%, 81.8%, and 85% respectively (AUC: 0.915). CONCLUSIONS: The present study for the first time demonstrated that TAFI is elevated in AP. The appraisal of TAFI levels in patients with AP in conjunction with other markers of inflammation may provide additional information in estimating AP severity. PMID- 22230219 TI - Effect of prostaglandin E2 injection on the structural properties of the rat patellar tendon. AB - BACKGROUND: Increased tendon production of the inflammatory mediator prostaglandin E2 (PGE2) has been suggested to be a potential etiologic agent in the development of tendinopathy. Repeated injection of PGE2 into tendon has been proposed as a potential animal model for studying treatments for tendinopathy. In contrast, nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit PGE2 production and are commonly prescribed in treating tendinopathy have been shown to impair the healing of tendon after acute injury in animal models. The contradictory literature suggests the need to better define the functional effects of PGE2 on tendon. Our objective was to characterize the effects of PGE2 injection on the biomechanical and biochemical properties of tendon and the activity of the animals. Our hypothesis was that weekly PGE2 injection to the rat patellar tendon would lead to inferior biomechanical properties. METHODS: Forty rats were divided equally into four groups. Three groups were followed for 4 weeks with the following peritendinous injection procedures: No injection (control), 4 weekly injections of saline (saline), 4 weekly injections of 800 ng PGE2 (PGE2-4 wks). The fourth group received 4 weekly injections of 800 ng PGE2 initially and was followed for a total of 8 weeks. All animals were injected bilaterally. The main outcome measurements included: the structural and material properties of the patellar tendon under tensile loading to failure, tendon collagen content, and weekly animal activity scores. RESULTS: The ultimate load of PGE2-4 wks tendons at 4 weeks was significantly greater than control or saline group tendons. The stiffness and elastic modulus of the PGE2 injected tendons at 8 weeks was significantly greater than the control or saline tendons. No differences in animal activity, collagen content, or mean fibril diameter were observed between groups. CONCLUSIONS: Four weekly peritendinous injections of PGE2 to the rat patellar tendon were not found to be an effective model of clinical tendinopathy. In contrast, improved structural and material properties of the patellar tendon were found after PGE2 injection. While PGE2 has been thought to have a contributory role in the development of tendinopathy and anti inflammatory medications remain a common treatment, our results suggest a positive role of PGE2 in tendon remodeling in some circumstances. PMID- 22230220 TI - Towards a post-traumatic subtype of obsessive-compulsive disorder. AB - We evaluated whether traumatic events are associated with a distinctive pattern of socio-demographic and clinical features of obsessive-compulsive disorder (OCD). We compared socio-demographic and clinical features of 106 patients developing OCD after post-traumatic stress disorder (PTSD; termed post-traumatic OCD), 41 patients developing OCD before PTSD (pre-traumatic OCD), and 810 OCD patients without any history of PTSD (non-traumatic OCD) using multinomial logistic regression analysis. A later age at onset of OCD, self-mutilation disorder, history of suicide plans, panic disorder with agoraphobia, and compulsive buying disorder were independently related to post-traumatic OCD. In contrast, earlier age at OCD onset, alcohol-related disorders, contamination washing symptoms, and self-mutilation disorder were all independently associated with pre-traumatic OCD. In addition, patients with post-traumatic OCD without a previous history of obsessive-compulsive symptoms (OCS) showed lower educational levels, greater rates of contamination-washing symptoms, and more severe miscellaneous symptoms as compared to post-traumatic OCD patients with a history of OCS. PMID- 22230221 TI - Novel strategies lead to pre-elimination of malaria in previously high-risk areas in Suriname, South America. AB - BACKGROUND: Suriname was a high malaria risk country before the introduction of a new five-year malaria control program in 2005, the Medical Mission Malaria Programme (MM-MP). Malaria was endemic in the forested interior, where especially the stabile village communities were affected. CASE DESCRIPTION: The interventions of the MM-MP included new strategies for prevention, vector control, case management, behavioral change communication (BCC)/information, education and communication (IEC), and strengthening of the health system (surveillance, monitoring and evaluation and epidemic detection system). After a slow first year with non-satisfying scores for the performance indicators, the MM MP truly engaged in its intervention activities in 2006 and kept its performance up until the end of 2009. A total of 69,994 long-lasting insecticide-treated nets were distributed and more than 15,000 nets re-impregnated. In high-risk areas, this was complemented with residual spraying of insecticides. Over 10,000 people were screened with active case detection in outbreak and high-risk areas. Additional notification points were established and the national health system was strengthened. DISCUSSION AND EVALUATION: In the current paper, the MM-MP is evaluated both on account of the targets established within the programme and on account of its impact on the malaria situation in Suriname. Malaria vector populations, monitored in sentinel sites, collapsed after 2006 and concurrently the number of national malaria cases decreased from 8,618 in 2005 to 1,509 in 2009. Malaria transmission risk shifted from the stabile village communities to the mobile gold mining communities, especially those along the French Guiana border. CONCLUSIONS: The novel strategies for malaria control introduced in Suriname within the MM-MP have led to a significant decrease in the national malaria burden. The challenge is to further reduce malaria using the available strategies as appropriate in the affected areas and populations. Elimination of malaria in the country will require a thorough understanding of transmission dynamics and a dedicated investment in key effective interventions. PMID- 22230222 TI - The effect of chitosan on transcellular and paracellular mechanisms in the intestinal epithelial barrier. AB - Chitosan is employed as an absorption enhancer for drug delivery strategies. Aim of this study was to investigate the rapid effects on barrier properties of the intestinal epithelial cell model HT-29/B6. Chitosan (0.005%) induced a fast decrease in transepithelial resistance (R(t)) which was completely reversible after wash-out. Two-path impedance spectroscopy revealed that chitosan affects both, the paracellular (R(para)) and the transcellular (R(trans)) resistance. pH dependence and inhibition of both effects by negatively charged heparin indicated a chitosan action only in the protonated form. The decrease in R(trans) was mediated by activation of a chloride-bicarbonate exchanger involved in intracellular pH regulation. This activation was coupled to the decrease in R(para) which was associated with an increase in ion permeability and permeability for paracellular flux markers up to 10 kDa. No effects on expression and subcellular distribution of tight junction (TJ) proteins or the actin cytoskeleton were observed. Accordingly, inhibition of actin-myosin interaction, Ca(2+)-dependent intracellular signaling, PKC, PI3K/Akt, MAP kinase p38, and endocytosis pathways did not impair the chitosan effect. These results suggest that the rapid and reversible absorption-enhancing chitosan effect is due to changes in intracellular pH caused by the activation of a chloride-bicarbonate exchanger resulting in the opening of the TJ. PMID- 22230223 TI - Multifunctional gold nanorod theragnostics probed by multi-photon imaging. AB - This study exhibits the fabrication of target-specific Gold nanorods (GNRs) coupled with an anti-tumorigenic apoptotic drug and provides tracking of the labeled particles as they migrate through cells and release their drug-load to targeted cancer cells. We utilize the photoluminescence property of GNRs and their ability to be conjugated with multiple agents to transform facile rods to a targeted drug delivery vehicle. GNRs of aspect ratio 2.8 were conjugated with a targeting ligand, folic acid and an anthracycline drug, Doxorubicin. The multifunctional nanorods were then used to target folate receptor expressing cancers cells for the delivery of a concentration dependent dosage of Doxorubicin (DOX). By utilizing the photoluminescence of GNRs and the innate fluorescence of DOX, multi-photon fluorescence lifetime imaging was utilized to monitor the uptake of functionalized nanorods, the release of the drug and its localization in living cells. We show that these nano-vehicles successfully targeted cancer cells over expressing folate receptors and showed low toxicity to control cell lines. Release of DOX was observed in the cytoplasmic region and after 16 h was found to be redistributed in the nucleus resulting in cell death. Our theragnostic approach demonstrates the fabrication of multifunctional GNRs for targeted drug delivery and monitoring of the drug and the vehicle by multi-photon microscopy using fluorescence intensity and lifetime imaging. PMID- 22230224 TI - Embryo production by parthenogenetic activation and fertilization of in vitro matured oocytes from Cebus apella. AB - The efficiency of in vitro fertilization (IVF) depends on the viability of spermatozoa. For capuchin monkeys (Cebus apella), in vitro capacitation of spermatozoa is challenging because of their unique seminal coagulum. Motile spermatozoa can be obtained after liquefaction of the semen coagulum in coconut water-based solution. The objective of the present study was to establish an optimal in vitro maturation (IVM) protocol for capuchin monkeys and to observe the effect of follicle stimulating hormone (FSH) and luteinising hormone (LH) on IVF and parthenogenetic activation (PA) of oocytes collected from unstimulated females. We assessed spermatozoa quality after recovery from seminal coagulum using the solution ACP-118(r) as an extender. Oocytes were matured in vitro for 36 or 40 h and subjected to IVF or PA by applying ionomycin combined either with 6-dimethylaminopurine (6-DMAP) or roscovitine. In total, 87% of oocytes reached metaphase II (MII) after 40 IVM and 4-cell embryo production was obtained after IVF and parthenogenesis using ionomycin/6-DMAP. ACP-118(r) was used successfully to harvest viable spermatozoa from semen coagulum and in the preservation of spermatozoa, which were able to fertilize oocytes in vitro. PMID- 22230225 TI - Recombinant lactoferrin (Lf) of Vechur cow, the critical breed of Bos indicus and the Lf gene variants. AB - Vechur cow, categorized as a critically maintained breed by the FAO, is a unique breed of Bos indicus due to its extremely small size, less fodder intake, adaptability, easy domestication and traditional medicinal property of the milk. Lactoferrin (Lf) is an iron-binding glycoprotein that is found predominantly in the milk of mammals. The full coding region of Lf gene of Vechur cow was cloned, sequenced and expressed in a prokaryotic system. Antibacterial activity of the recombinant Lf showed suppression of bacterial growth. To the best of our knowledge this is the first time that the full coding region of Lf gene of B. indicus Vechur breed is sequenced, successfully expressed in a prokaryotic system and characterized. Comparative analysis of Lf gene sequence of five Vechur cows with B. taurus revealed 15 SNPs in the exon region associated with 11 amino acid substitutions. The amino acid arginine was noticed as a pronounced substitution and the tertiary structure analysis of the BLfV protein confirmed the positions of arginine in the beta sheet region, random coil and helix region 1. Based on the recent reports on the nutritional therapies of arginine supplementation for wound healing and for cardiovascular diseases, the higher level of arginine in the lactoferrin protein of Vechur cow milk provides enormous scope for further therapeutic studies. PMID- 22230226 TI - Functional analysis of cus operon promoter of Klebsiella pneumoniae using E. coli lacZ assay. AB - The transcriptional fusion of reporter lacZ gene with cusRS regulatory promoter of cus operon of Klebsiella pneumoniae enabled us to analyze the inductive effect of copper on promoter via lacZ assay. The stimulus response curve of promoter to a range of copper metal concentrations indicated a normal sigmoidal response profile with apparent Hill coefficient 1.0. There was a positive correlation of promoter response to the increasing concentration of copper in the medium. AC(50) value of copper was calculated to be 1mM, whereas the promoter response was exponential beyond 1mM and up to 2.5mM concentration. The promoter activity did not increase exponentially in copper concentration higher than 2.5mM. The promoter PcusRS requires two chromosomally encoded regulatory proteins, CusS and CusR, in trans for maximal in vitro activation. The PcusRS regulatory promoter sequence also contained regulatory -10 and -35 boxes along with CusR binding motif. The results supported the concept of cus operon regulation as an essential mechanism for maintaining the cellular homeostasis at very high (e.g. 3mM), and even toxic copper concentrations. PMID- 22230227 TI - Closing-in behaviour and motor distractibility. AB - This study relates two behaviours, each well documented within its own literature but not previously considered together: closing-in behaviour (CIB) and the effect of visual distractors on reaching. CIB is common in typically developing children, and in adults with dementia, and classically manifests as the tendency to perform graphic copying tasks very close to, or on the top of the model. The effect of visual distractors on reaching has been studied extensively in normal adults. Distractors induce characteristic deviations of the reach, usually away from the distractor, which imply that a competing response towards the distractor is automatically primed, and actively suppressed. It is possible that CIB reflects a failure to inhibit motor distraction, such that the acting hand is attracted automatically to a salient stimulus (the model, during copying tasks). This hypothesis predicts that CIB should be associated with distractor effects during reaching, characterised by veering towards, rather than away from the distractor. We tested this prediction in groups of pre-school children with and without CIB, and in young adults, using task-relevant and task-irrelevant distractors. Both groups of children showed greater veering towards distractors than did adults, implying a lower capacity to inhibit automatic responses. Crucially, this effect was stronger in children with CIB than without CIB when a task-irrelevant distractor was presented. These findings support the idea that CIB reflects a failure to inhibit automatically primed actions towards salient stimuli. PMID- 22230229 TI - Plasticity of lateralization: schooling predicts hand preference but not hand skill asymmetry in a non-industrial society. AB - Considerable variation in the frequency of left-handedness between cultures has been reported, ranging from 0.5 to 24%. This variation in hand preference may have evolved under natural or cultural selection. It has been suggested that schooling affects handedness but as in most human societies only a selected and minor part of the population does not attend school this is difficult to test. We investigated to what extent schooling affects both hand preference and asymmetry in hand skill in a non-industrial population in the highlands of New Guinea. This provided unique opportunities because of the relatively recent establishment of a primary school in this population, and where people still live a non-industrial traditional life reflecting conditions in which handedness may have evolved. We interviewed 620 inhabitants (aged 5-70 y) to collect demographic data and school history, tested hand preference on 10 ecologically relevant activities, and measured performance of each hand on three tasks (pegboard, grip force, ball throwing). Schooled individuals were overall faster in fine motor performance, had greater grip strength and greater throwing accuracy. This suggests that there is implicit selection on the fitter part of the population to enter school. Schooling is associated with hand preference, as schooled individuals were more likely to be extremely right-handed and less likely to be strongly right-handed, but not with asymmetry of hand skill (controlled for sex and age). Developmental plasticity in hand preference but not skill asymmetry, and the weak correlations between hand preference and hand skill asymmetry indicate that they represent different aspects of brain lateralization. Furthermore, the weak correlations between hand preference and hand skill asymmetry leave room for moderating factors such as schooling, sex and age to have a differential effect on hand preference and hand skill, and each needs to be studied in its own right. PMID- 22230230 TI - Event related potentials elicited by violations of auditory regularities in patients with impaired consciousness. AB - Improving our ability to detect conscious processing in non communicating patients remains a major goal of clinical cognitive neurosciences. In this perspective, several functional brain imaging tools are currently under development. Bedside cognitive event-related potentials (ERPs) derived from the EEG signal are a good candidate to explore consciousness in these patients because: (1) they have an optimal time resolution within the millisecond range able to monitor the stream of consciousness, (2) they are fully non-invasive and relatively cheap, (3) they can be recorded continuously on dedicated individual systems to monitor consciousness and to communicate with patients, (4) and they can be used to enrich patients' autonomy through brain-computer interfaces. We recently designed an original auditory rule extraction ERP test that evaluates cerebral responses to violations of temporal regularities that are either local in time or global across several seconds. Local violations led to an early response in auditory cortex, independent of attention or the presence of a concurrent visual task, while global violations led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations. In the present work, we report the results of this test in 65 successive recordings obtained at bedside from 49 non-communicating patients affected with various acute or chronic neurological disorders. At the individual level, we confirm the high specificity of the 'global effect': only conscious patients presented this proposed neural signature of conscious processing. Here, we also describe in details the respective neural responses elicited by violations of local and global auditory regularities, and we report two additional ERP effects related to stimuli expectancy and to task learning, and we discuss their relations to consciousness. PMID- 22230228 TI - Medial prefrontal functional connectivity--relation to memory self-appraisal accuracy in older adults with and without memory disorders. AB - It is tentatively estimated that 25% of people with early Alzheimer's disease (AD) show impaired awareness of disease-related changes in their own cognition. Research examining both normative self-awareness and altered awareness resulting from brain disease or injury points to the central role of the medial prefrontal cortex (MPFC) in generating accurate self-appraisals. The current project builds on this work - examining changes in MPFC functional connectivity that correspond to impaired self-appraisal accuracy early in the AD time course. Our behavioral focus was self-appraisal accuracy for everyday memory function, and this was measured using the Memory Function Scale of the Memory Awareness Rating Scale - an instrument psychometrically validated for this purpose. Using regression analysis of data from people with healthy memory (n=12) and people with impaired memory due to amnestic mild cognitive impairment or early AD (n=12), we tested the hypothesis that altered MPFC functional connectivity - particularly with other cortical midline structures and dorsolateral prefrontal cortex - explains variation in memory self-appraisal accuracy. We spatially constrained (i.e., explicitly masked) our regression analyses to those regions that work in conjunction with the MPFC to evoke self-appraisals in a normative group. This empirically derived explicit mask was generated from the result of a psychophysiological interaction analysis of fMRI self-appraisal task data in a separate, large group of cognitively healthy individuals. Results of our primary analysis (i.e., the regression of memory self-appraisal accuracy on MPFC functional connectivity) were generally consistent with our hypothesis: people who were less accurate in making memory self-appraisals showed attenuated functional connectivity between the MPFC seed region and proximal areas within the MPFC (including subgenual anterior cingulate cortex), bilateral dorsolateral prefrontal cortex, bilateral caudate, and left posterior hippocampus. Contrary to our expectations, MPFC functional connectivity with the posterior cingulate was not significantly related to accuracy of memory self-appraisals. Results reported here corroborate findings of variable memory self-appraisal accuracy during the earliest emergence of AD symptoms and reveal alterations in MPFC functional connectivity that correspond to impaired memory self-appraisal. PMID- 22230231 TI - Neglect severity after left and right brain damage. AB - While unilateral spatial neglect after left brain damage is undoubtedly less common than spatial neglect after a right hemisphere lesion, it is also assumed to be less severe. Here we directly test this latter hypothesis using a continuous measure of neglect severity: the so-called Center of Cancellation (CoC). Rorden and Karnath (2010) recently validated this index for right brain damaged neglect patients. A first aim of the present study was to evaluate this new measure for spatial neglect after left brain damage. In a group of 48 left sided stroke patients with and without neglect, a score greater than -0.086 on the Bells Test and greater than -0.024 on the Letter Cancellation Task turned out to indicate neglect behavior for acute left brain damaged patients. A second aim was to directly compare the severity of spatial neglect after left versus right brain injury by using the new CoC measure. While neglect is less frequent following left than right hemisphere injury, we found that when this symptom occurs it is of similar severity in acute left brain injury as in patients after acute right brain injury. PMID- 22230232 TI - Gamma-ray energies in the decay of 38Cl. AB - In order to resolve a long-standing discrepancy of some 30 standard deviations between the two most precise previously reported values of the gamma-ray energies in the (38)Cl decays, we have undertaken a new precision measurement of the decay energies using a variety of different sources for energy calibration. The deduced energies from the present work are 1642.668 +/- 0.010 and 2167.395 +/- 0.010 keV. These results agree very well with one of the previous reports and disagree with the other. PMID- 22230233 TI - Fluorometric estimation of surface associated microbial abundance. AB - Surface associated microbes have historically been difficult to accurately and effectively enumerate. In the current study, we propose a rapid and simple method for estimating abundance of surface associated microbial cells by fluorescence of SYBRGreen stained bacteria and in vivo chlorophyll a fluorescence of benthic diatoms in 24 and 48-well microtiter plates. The effectiveness of this high throughput technique is demonstrated by assessing sensitivity of a clinical strain of Vibrio cholerae, a benthic bacterial isolate and the benthic microalgae Cylindrotheca closterium to three antibiotics--tylosin, lincomycin and ciproflaxacin. We report on the significant linear relationships between spectral chl a fluorescence and cell abundance and between microalgal growth rates derived from cell counts and fluorescence. Additionally, we provide a simplified and improved method for preparation of a silica gel matrix (SGM), which is an ideal plating media for fluorescence applications. These findings indicate that spectrofluorometry is an inexpensive tool for rapidly estimating abundance of surface associated microbiota and can be employed for assessing antibiotic sensitivity. PMID- 22230234 TI - A simple defined medium for growth and maintenance of the mixotrophic protist Ochromonas danica. AB - A simple-defined medium was formulated that allows robust axenic-growth of the model mixotrophic protist Ochromonas danica at a neutral pH. This new defined medium, with a minimum number of constituents, facilitates more highly controlled studies of mixotrophic metabolism and nutrient regeneration than have previously been possible. PMID- 22230235 TI - Development of a rotor-gene real-time PCR assay for the detection and quantification of Mycoplasma genitalium. AB - We developed and validated a real-time quantitative polymerase chain reaction (qPCR) assay to determine Mycoplasma genitalium bacterial load in endocervical swabs, based on amplification of the pdhD gene which encodes dihydrolipoamide dehydrogenase, using the Rotor-Gene platform. We first determined the qPCR assay sensitivity, limit of detection, reproducibility and specificity, and then determined the ability of the qPCR assay to quantify M. genitalium in stored endocervical specimens collected from Zimbabwean women participating in clinical research undertaken between 1999 and 2007. The qPCR assay had a detection limit of 300 genome copies/mL and demonstrated low intra- and inter-assay variability. The assay was specific for M. genitalium DNA and did not amplify the DNA from other mycoplasma and ureaplasma species. We quantified M. genitalium in 119 of 1600 endocervical swabs that tested positive for M. genitalium using the commercial Sacace M. genitalium real-time PCR, as well as 156 randomly selected swabs that were negative for M. genitalium by the same assay. The M. genitalium loads ranged between <300 and 3,240,000 copies/mL. Overall, the qPCR assay demonstrated good range of detection, reproducibility and specificity and can be used for both qualitative and quantitative analyses of M. genitalium in endocervical specimens and potentially other genital specimens. PMID- 22230236 TI - Structural characterization and electrochemical properties of Co3O4 anode materials synthesized by a hydrothermal method. AB - Cobalt oxide [Co3O4] anode materials were synthesized by a simple hydrothermal process, and the reaction conditions were optimized to provide good electrochemical properties. The effect of various synthetic reaction and heat treatment conditions on the structure and electrochemical properties of Co3O4 powder was also studied. Physical characterizations of Co3O4 are investigated by X-ray diffraction, scanning electron microscopy, and Brunauer-Emmett-Teller [BET] method. The BET surface area decreased with values at 131.8 m2/g, 76.1 m2/g, and 55.2 m2/g with the increasing calcination temperature at 200 degrees C, 300 degrees C, and 400 degrees C, respectively. The Co3O4 particle calcinated at 200 degrees C for 3 h has a higher surface area and uniform particle size distribution which may result in better sites to accommodate Li+ and electrical contact and to give a good electrochemical property. The cell composed of Super P as a carbon conductor shows better electrochemical properties than that composed of acetylene black. Among the samples prepared under different reaction conditions, Co3O4 prepared at 200 degrees C for 10 h showed a better cycling performance than the other samples. It gave an initial discharge capacity of 1,330 mAh/g, decreased to 779 mAh/g after 10 cycles, and then showed a steady discharge capacity of 606 mAh/g after 60 cycles. PMID- 22230237 TI - Psycholinguistic abilities of children with Williams syndrome. AB - The objective of this study was to investigate the psycholinguistic abilities of children with Williams syndrome (WS) and typically developing children using the Illinois Test of Psycholinguistic Abilities (ITPA). Performance on the ITPA was analysed in a group with WS (N=20, mean age=8.5 years, SD=1.62) and two typically developing groups, matched in mental (MA, N=20, mean age=4.92 years, SD=1.14) and chronological age (CA, N=19, mean age=8.35 years, SD=3.07). Overall, within-group analyses showed that individuals with WS displayed higher scalar scores on the visual reception and visual association subtests. When groups were compared, we observed inferior performance of the WS group on all ITPA subtests when compared with typically developing groups. Moreover, an interaction between reception and group was found, only the WS group demonstrated superior performance on the visual reception subtest when compared to the auditory reception subtest. Evidence from this study offers relevant contributions to the development of educational intervention programs for children with WS. PMID- 22230238 TI - Executive dysfunctions among boys with Attention Deficit Hyperactivity Disorder (ADHD): performance-based test and parents report. AB - Difficulty in executive functions (EF) is a core symptom of ADHD. Yet, the EF assessments are still in controversy. It is still unclear whether the everyday implementation of EF can be assessed under laboratory conditions. Therefore, the purposes of the present study are: (a) to examine EF among boys with ADHD both in everyday behavior (as reported by parents) and in a performance-based test. (b) To examine correlations between the two tests. Both the Behavior Assessment of Dysexecutive Functions for Children (BADS-C) and the Behavior Rating Inventory of Executive Functions (BRIEF) were independently applied to 25 boys aged 8-11 years with ADHD and 25 age-matched typical boys. Results of the two assessments were compared between the two groups to indicate differences in EF. Correlations between the two assessments for all participants were evaluated. Overall, significant differences in EF were found between the two groups on both assessments. Significant correlations were found between BADS-C and BRIEF, specifically in metacognition but not in behavioral regulation. Findings indicate that poor EF manifests itself in everyday behavior. These difficulties are found in metacognitive and behavioral regulation components. Nevertheless, applying a valid ecological assessment of behavior regulation merits future research. PMID- 22230240 TI - Xanthine oxidase-generated hydrogen peroxide is a consequence, not a mediator of cell death. AB - Oxidative stress has been associated with a wide range of diseases including atherosclerosis, cancer and Alzheimer's disease. When present in excessive concentrations, reactive oxygen species (ROS) can cause deleterious effects. This has led to the notion that the anticancer effects of various chemotherapeutics may be mediated, at least in part, by an increase in ROS. To investigate the role of xanthine oxidase (XO), a source of hydrogen peroxide, in cell death, MCF7, HeLa and 293T cells were treated with various cell-death-inducing drugs in the presence and absence of allopurinol, a specific inhibitor of XO. In the absence of allopurinol, each drug led to a time- and concentration-dependent increase in percent DNA fragmentation and ROS levels, regardless of the mechanism of cell death incurred, i.e. caspase dependent and caspase independent. By contrast, pretreatment with allopurinol led to dramatically lower ROS levels in all cases, suggesting that XO is a major contributor to oxidative stress. However, allopurinol did not exhibit a protective effect against cell death. Similarly, the administration of siRNA against XO also did not exhibit a protective effect against cell death. The level of oxidative stress was recorded using the ROS sensor CM-H(2) DCFDA and a ratiometric bioluminescent assay that takes advantage of the increased sensitivity of Firefly luciferase to hydrogen peroxide, compared with a stable variant of Renilla luciferase (RLuc), RLuc8. Overall, these findings suggest that XO-generated hydrogen peroxide, and perhaps hydrogen peroxide in general, is a consequence, but not a mediator of cell death. PMID- 22230243 TI - Associations of serum aflatoxin B1-lysine adduct level with socio-demographic factors and aflatoxins intake from nuts and related nut products in Malaysia. AB - Aflatoxins are one of the major risk factors in the multi-factorial etiology of human hepatocellular carcinoma. Therefore, the information on aflatoxins exposure is very important in the intervention planning in order to reduce the dietary intake of aflatoxins, especially among the children. This study investigated the relationship between aflatoxin B(1) (AFB(1)) lysine adduct levers in serum and socio-demographic factors and dietary intake of aflatoxins from nuts and nut products in Penang, Malaysia. A cross-sectional field study was conducted in five districts of Penang. A survey on socio-demographic characteristics was administered to 364 healthy adults from the three main ethnic groups (Malay, Chinese and Indian). A total of 170 blood samples were successfully collected and tested for the level of AFB(1)-lysine adduct. 97% of the samples contained AFB(1) lysine adduct above the detection limit of 0.4 pg/mg albumin and ranged from 0.20 to 23.16 pg/mg albumin (mean+/-standard deviation=7.67+/-4.54 pg/mg albumin; median=7.12 pg/mg albumin). There was no significant association between AFB(1) lysine adduct levels with gender, district, education level, household number and occupation when these socio-demographic characteristics were examined according to high or low levels of AFB(1)-lysine. However, participants in the age group of 31-50 years were 3.08 times more likely to have high AFB(1) levels compared to those aged between 18 and 30 years (P=0.026). Significant difference (P=0.000) was found among different ethnic groups. Chinese and Indian participants were 3.05 and 2.35 times more likely to have high AFB(1) levels than Malay. The result of AFB(1)-lysine adduct suggested that Penang adult population is likely to be exposed to AFB(1) but at a level of less than that needed to cause direct acute illness or death. PMID- 22230244 TI - Google Flu Trends: correlation with emergency department influenza rates and crowding metrics. AB - BACKGROUND: Google Flu Trends (GFT) is a novel Internet-based influenza surveillance system that uses search engine query data to estimate influenza activity and is available in near real time. This study assesses the temporal correlation of city GFT data to cases of influenza and standard crowding indices from an inner-city emergency department (ED). METHODS: This study was performed during a 21-month period (from January 2009 through October 2010) at an urban academic hospital with physically and administratively separate adult and pediatric EDs. We collected weekly data from GFT for Baltimore, Maryland; ED Centers for Disease Control and Prevention-reported standardized influenzalike illness (ILI) data; laboratory-confirmed influenza data; and ED crowding indices (patient volume, number of patients who left without being seen, waiting room time, and length of stay for admitted and discharged patients). Pediatric and adult data were analyzed separately using cross-correlation with GFT. RESULTS: GFT correlated with both number of positive influenza test results (adult ED, r = 0.876; pediatric ED, r = 0.718) and number of ED patients presenting with ILI (adult ED, r = 0.885; pediatric ED, r = 0.652). Pediatric but not adult crowding measures, such as total ED volume (r = 0.649) and leaving without being seen (r = 0.641), also had good correlation with GFT. Adult crowding measures for low acuity patients, such as waiting room time (r = 0.421) and length of stay for discharged patients (r = 0.548), had moderate correlation with GFT. CONCLUSIONS: City-level GFT shows strong correlation with influenza cases and ED ILI visits, validating its use as an ED surveillance tool. GFT correlated with several pediatric ED crowding measures and those for low-acuity adult patients. PMID- 22230245 TI - Poor birth weight recovery among low birth weight/preterm infants following hospital discharge in Kampala, Uganda. AB - BACKGROUND: Healthy infants typically regain their birth weight by 21 days of age; however, failure to do so may be due to medical, nutritional or environmental factors. Globally, the incidence of low birth weight deliveries is high, but few studies have assessed the postnatal weight changes in this category of infants, especially in Africa. The aim was to determine what proportion of LBW infants had not regained their birth weight by 21 days of age after discharge from the Special Care Unit of Mulago hospital, Kampala. METHODS: A cross sectional study was conducted assessing weight recovery of 235 LBW infants attending the Kangaroo Clinic in the Special Care Unit of Mulago Hospital between January and April 2010. Infants aged 21 days with a documented birth weight and whose mothers gave consent to participate were included in the study. Baseline information was collected on demographic characteristics, history on pregnancy, delivery and postnatal outcome through interviews. Pertinent infant information like gestation age, diagnosis and management was obtained from the medical records and summarized in the case report forms. RESULTS: Of the 235 LBW infants, 113 (48.1%) had not regained their birth weight by 21 days. Duration of hospitalization for more than 7 days (AOR: 4.2; 95% CI: 2.3 - 7.6; p value < 0.001) and initiation of the first feed after 48 hours (AOR: 1.9; 95% CI 1.1 - 3.4 p value 0.034) were independently associated with failure to regain birth weight. Maternal factors and the infant's physical examination findings were not significantly associated with failure to regain birth weight by 21 days of age. CONCLUSION: Failure to regain birth weight among LBW infants by 21 days of age is a common problem in Mulago Hospital occurring in almost half of the neonates attending the Kangaroo clinic. Currently, the burden of morbidity in this group of high-risk infants is undetected and unaddressed in many developing countries. Measures for consideration to improve care of these infants would include; discharge after regaining birth weight and use of total parenteral nutrition. However, due to the pressure of space, keeping the baby and mother is not feasible at the moment hence the need for a strong community system to boost care of the infant. Close networking with support groups within the child's environment could help alleviate this problem. PMID- 22230246 TI - Expression profile of immune response genes during acute myopathy induced by chikungunya virus in a mouse model. AB - During the recent re-emergence of chikungunya, clinical complications and deaths were recorded. Persistent musculoskeletal pain, arthralgia, arthritis were among the most common complications. To understand pathogenesis of CHIKV induced disease, we developed suckling, outbred mouse model presenting with severe myopathology. Histopathology, dynamics of viral load, IgG antibodies/isotypes, serum cytokines by cytometric bead array and mRNA expression levels of immune response genes in the target tissue by Taqman Low Density Array were studied. Peak viral load was associated with peak serum levels of CCL-2,KC, CCL-4, RANTES, IL-6, IL-10, CSF-3, and locally very high mRNA expression of CCL-2, CXCL-10, CXCL 11 and concomitant IFNgamma, IL-10, STAT-1, SOCS-1 and CSF-3 suggesting strong IFNgamma program. Symptomatic phase correlated with peak serum levels of IL-2, IFNgamma, IL-17, CCL-3, IL-1beta, eotaxin, IL-9 and CSF-2 and locally with peak mRNA expression of macrophage induced pro inflammatory cytokines and immune infiltration biased towards Th1. IgG antibodies were detected on day 6PI, reaching high titres by day 11PI. IgG2a was the predominant isotype, indicating Th1 bias. This is the first report of comprehensive analysis of immune response genes expression in target tissue of CHIKV mouse model. The data would contribute significantly in understanding pathogenesis of CHIKV disease and viral myopathies. PMID- 22230247 TI - Effect of the Japanese herbal medicine, Boiogito, on the osteoarthritis of the knee with joint effusion. AB - BACKGROUND: Boiogito (Japanese herbal medicine, Tsumura Co. Tokyo, Japan) contains sinomenin which inhibits inflammatory reactions. Since sinomenine is a principle component of the Boiogito, there is a possibility of it being effective on osteoarthritis (OA) of the knee with joint effusion. However, there is no report concerning the effectiveness of Boiogito on knee OA. The objective of the present study is to investigate the therapeutic effect of Boiogito on OA of the knee associated with joint effusion in a comparative study among randomly assigned groups. METHODS: Study was performed using 50 patients who were diagnosed with primary osteoarthritis of the knee with joint effusion. The patients were randomly assigned to two groups: one group (25 patients) using both loxoprofen (2-{4-[(2-oxocyclopentyl) methyl]} propanoic acid) and Boiogito and the other group (25 patients) using loxoprofen, and were evaluated during a 12 week observation period. The assessment parameters including knee scores in the Knee Society Rating System including Knee score and Functional scores, amount of joint effusion by joint puncture in clinically detected cases, the 36-items short form of the Medical Outcome Study Questionnaire (SF-36) as a measurement of health related quality of life were used. RESULTS: The knee scores based on the Knee Society Rating System were improved in both groups. The staircase climbing up and down ability in the Knee society rating system functional score was significantly improved in the group using Boiogito and loxoprofen compared to the loxoprofen group. In the evaluation using SF-36, significant improvements were found in the scores in both groups in physical functioning after 12 weeks. The amount of joint fluid was significantly decreased at 4, 8 and 12 weeks compared to pre-administration baseline in the group using Boiogito and loxoprofen. A side effect of Boiogito, dry mouth, was found in one case. The symptom was mild and improved immediately after discontinuation of administration. CONCLUSION: The results indicated that Boiogito have a possibility for a treatment modality for joint effusion with osteoarthritis of the knee. PMID- 22230248 TI - Platelet-derived growth factor C deficiency in C57BL/6 mice leads to abnormal cerebral vascularization, loss of neuroependymal integrity, and ventricular abnormalities. AB - Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) are known to play important roles during development of the lungs, central nervous system (CNS), and skeleton and in several diseases. PDGF-C is a ligand for the tyrosine kinase receptor PDGFRalpha. Mutations in the gene encoding PDGF-C have been linked to clefts of the lip and/or palate in humans, and ablation of PDGF-C in 129/Sv background mice results in death during the perinatal period. In this study, we report that ablation of PDGF-C in C57BL/6 mice results in a milder phenotype than in 129/Sv mice, and we present a phenotypic characterization of PDGF-C deficiency in the adult murine CNS. Multiple congenital defects were observed in the CNS of PDGF-C-null C57BL/6 mice, including cerebral vascular abnormalities with abnormal vascular smooth muscle cell coverage. In vivo imaging of mice deficient in PDGF-C also revealed cerebral ventricular abnormalities, such as asymmetry of the lateral ventricles and hypoplasia of the septum, reminiscent of cavum septum pellucidum in humans. We further noted that PDGF-C-deficient mice displayed a distorted ependymal lining of the lateral ventricles, and we found evidence of misplaced neurons in the ventricular lining. We conclude that PDGF-C plays a critical role in the development of normal cerebral ventricles and neuroependymal integrity as well as in normal cerebral vascularization. PMID- 22230249 TI - VEGF-mediated STAT3 activation inhibits retinal vascularization by down regulating local erythropoietin expression. AB - Avascular, hypoxic retina has been postulated to be a source of angiogenic factors that cause aberrant angiogenesis and intravitreal neovascularization (IVNV) in retinopathy of prematurity. Vascular endothelial growth factor (VEGF) is an important factor involved. However, VEGF is also required for normal retinal vascular development, which raises concerns about inhibiting its activity to treat IVNV in retinopathy of prematurity. Therefore, understanding the effects that VEGF has on other factors in the development of avascular retina is important to prevent aberrant angiogenesis and IVNV. Here, we show that STAT3 was activated by increased retinal VEGF in the rat 50/10 oxygen-induced retinopathy model. Phospho-STAT3 colocalized with glutamine synthetase-labeled Muller cells. Inhibition of STAT3 reduced avascular retina and increased retinal erythropoietin (Epo) expression. Epo administered exogenously also reduced avascular retina in the model. In an in vitro study, hypoxia-induced VEGF inhibited Epo gene expression by STAT3 activation in rat Muller cells. The mechanism by which activated STAT3 regulated Epo was by inhibition of Epo promoter activity. Together, these findings show that increased retinal VEGF contributes to avascular retina by regulating retinal Epo expression through Janus kinase/STAT signaling. Our results suggest that rescuing Epo expression in the retina before the development of IVNV may promote normal developmental angiogenesis and, therefore, reduce the stimulus for later pathologic IVNV. PMID- 22230250 TI - Validation study on the accuracy of echocardiographic measurements of right ventricular systolic function in pulmonary hypertension. AB - BACKGROUND: The accuracy of echocardiographic parameters of right ventricular (RV) function has not been sufficiently validated in patients with pulmonary hypertension (PH). The aim of this study was to evaluate whether echocardiographic measurements reliably reflect RV systolic function in PH using cardiac magnetic resonance imaging (CMRI)-derived RV ejection fraction (RVEF) as a gold standard. METHODS: A total of 37 consecutive patients with PH, 20 with pulmonary arterial hypertension, 12 with chronic thromboembolic PH, and five others, were prospectively studied. All patients underwent echocardiography, CMRI, and right-heart catheterization within a 1-week interval. Associations between five echocardiography-derived parameters of RV systolic function and CMRI derived RVEF were evaluated. RESULTS: All five echocardiography-derived parameters were significantly correlated with CMRI-derived RVEF (percentage RV fractional shortening: r = 0.48, P = .0011; percentage RV area change: r = 0.40, P = .0083; tricuspid annular plane systolic excursion [TAPSE]: r = 0.86, P < .0001; RV myocardial performance index: r = -0.59, P < .0001; and systolic lateral tricuspid annular motion velocity: r = 0.63, P < .0001). Compared with the other indices, TAPSE exhibited the highest correlation coefficient. Of the five echocardiographic measurements, only TAPSE significantly predicted CMRI derived RVEF in multiple regression analysis (P < .0001). Intraobserver and interobserver reproducibility was favorable for all five indices and was particularly high for TAPSE and systolic lateral tricuspid annular motion velocity. CONCLUSIONS: Echocardiographic measurements are promising noninvasive indices of RV systolic function in patients with PH. In particular, TAPSE is superior to other indices in accuracy. PMID- 22230251 TI - The characterization of fibrocyte-like cells: a novel fibroblastic cell of the placenta. AB - The placenta is a highly vascularized organ thus angiogenesis is a key process in placental development. The contribution that different cells in the villous stroma play in placental angiogenesis is largely unknown. In this study we identified a novel stromal cell type in sections of term placenta which is morphologically fibroblastic and expressing the fibroblast marker TE-7 but also positive for the monocytic markers CD115 and CD14 and designated these cells as fibrocyte-like cells. Populations of fibrocyte-like cells from the placenta were isolated by two methods: culture of adherence-selected placental cells and, for higher purity, by CD45 fluorescence activated cell sorting (FACS). Fibrocyte-like cell conditioned medium increased endothelial tubule-like structure formation 2 fold versus control medium. Both pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) and the anti-angiogenic factor soluble-Flt were found in the conditioned medium. Neutralizing antibodies against VEGF and b-FGF reduced endothelial cell tubule like structures to control levels. These data suggests that fibrocyte-like cells, a previously unidentified cell of the villous stroma, may play an important role in the regulation of placental angiogenesis. PMID- 22230252 TI - Strength of the relationships between three self-reported dietary intake instruments and serum carotenoids: the Observing Energy and Protein Nutrition (OPEN) Study. AB - OBJECTIVE: To assess the strength of the relationships between serum carotenoids and three self-reported dietary intake instruments often used to characterize carotenoid intake in studies of diet and disease. DESIGN: Participants completed a Diet History Questionnaire (DHQ), two 24 h dietary recalls (24HR), a fruit and vegetable screener and a fasting blood draw. We derived dietary intake estimates of alpha-carotene, beta-carotene, cryptoxanthin, lutein, zeaxanthin and lycopene from each diet instrument and calculated sex-specific multivariate correlations between dietary intake estimates and their corresponding serum values. SETTING: Montgomery County, Maryland, USA. SUBJECTS: Four hundred and seventy women and men aged 40-69 years in the National Cancer Institute's Observing Protein and Energy Nutrition (OPEN) Study. RESULTS: Serum carotenoids correlated more strongly with the DHQ (r = 0.34-0.54 for women; r = 0.38-0.56 for men) than with the average of two recalls (r = 0.26-0.47 for women; r = 0.26-0.40 for men) with the exception of zeaxanthin, for which the correlations using recalls were higher. With adjustment for within-person variation, correlations between serum carotenoids and recalls were greatly improved (r = 0.38-0.83 for women; r = 0.42 0.74 for men). In most cases, correlations between serum carotenoids and the fruit and vegetable screener resembled serum-DHQ correlations. CONCLUSIONS: Evidence from the study provides support for the use of the DHQ, a fruit and vegetable screener and deattenuated recalls for estimating carotenoid status in studies without serum measures, and draws attention to the importance of adjusting for intra-individual variability when using recalls to estimate carotenoid values. PMID- 22230253 TI - Dopamine and food reward: effects of acute tyrosine/phenylalanine depletion on appetite. AB - It has been suggested that obese individuals over-eat in order to compensate for deficits in the dopaminergic reward system. The current study used acute tyrosine/phenylalanine depletion (ATPD) to investigate the effect of reduced dopamine function on appetite and the reward value of food in healthy volunteers. The compensatory-eating hypothesis would predict an increase in the reward value and consumption of food following depletion by this method. In a double-blind, counterbalanced, crossover study, 17 male participants (mean age=29.2 (SEM=2.7) years; mean body mass index=24.4 (SEM=0.6) kg/m(2)) were administered with a tyrosine/phenylalanine-free mixture (TYR/PHE-free; depletion condition) and a balanced amino acid mixture (BAL; control). Plasma amino acid levels were measured at baseline and peak depletion (300 min). Appetite, willingness to pay for food, liking, desired portion size and ad libitum food intake were also assessed. The TYR/PHE-free mixture was associated with significant decreases in tyrosine, phenylalanine, and the ratio of tyrosine+phenylalanine to the other large neutral amino acids (all p<.001). There were no effects on our measures of willingness to pay for food or liking. However, in the TYR/PHE-free condition, participants reported significantly lower levels of hunger following a fixed-test meal relative to the BAL condition. In conclusion, we found no evidence for compensatory eating following ATPD. Our results also provide support for the role of dopamine in motivational components of eating. PMID- 22230254 TI - Chorda tympani nerve modulates the rat's avoidance of calcium chloride. AB - Calcium intake depends on orosensory factors, implying the presence of a mechanism for calcium detection in the mouth. To better understand how information about oral calcium is conveyed to the brain, we examined the effects of chorda tympani nerve transection on calcium chloride (CaCl(2)) taste preferences and thresholds in male Wistar rats. The rats were given bilateral transections of the chorda tympani nerve (CTX) or control surgery. After recovery, they received 48-h two-bottle tests with an ascending concentration series of CaCl(2). Whereas control rats avoided CaCl(2) at concentrations of 0.1mM and higher, rats with CTX were indifferent to CaCl(2) concentrations up to 10mM. Rats with CTX had significantly higher preference scores for 0.316 and 3.16 mM CaCl(2) than did control rats. The results imply that the chorda tympani nerve is required for the normal avoidance of CaCl(2) solution. PMID- 22230256 TI - The mode of administration of total parenteral nutrition and nature of lipid content influence the generation of peroxides and aldehydes. AB - BACKGROUND & AIMS: The absence of light protection of neonatal total parenteral nutrition (PN) contributes to the generation of 4-hydroxynonenal and peroxides. 4 Hydroxynonenal is suspected to be involved in PN-related liver complications. AIMS: To find a practical modality to reduce 4-hydroxynonenal in PN and assess in vivo the impact of PN containing low 4-hydroxynonenal concentration. METHODS: Six modalities of delivering PN were compared for the in vitro generation of peroxides and 4-hydroxynonenal: 1) MV-AA-L: light-protected (-L) solution containing multivitamin (MV) mixed with amino acids + dextrose (AA); 2) MV-AA+L: MV-AA without photo-protection (+L); 3) MV-LIP+L: MV mixed with lipid emulsion (LIP). LIP was a) Intralipid20%((r)) or b) Omegaven((r)). Hepatic markers of oxidative stress (glutathione, F(2alpha)-isoprostanes, GS-HNE) and inflammation (mRNA of TNF-alpha and IL-1) were measured in newborn guinea pigs infused during 4-days with MV-AA+L compounded with Intralipid20%((r)) or Omegaven((r)). RESULTS: Hydroperoxides and 4-hydroxynonenal were the lowest in MV-AA-L and the highest in MV-LIP+L. MV-AA+L with Omegaven((r)) was associated with the lowest levels of markers of oxidative stress and inflammation. CONCLUSION: Compared to Intralipid20%((r)), Omegaven((r)) reduces oxidative stress associated with PN and prevents liver inflammation. These findings offer an alternative strategy to light protection of PN, which in the clinical setting is a cumbersome modality. PMID- 22230255 TI - A review of malaria vaccine clinical projects based on the WHO rainbow table. AB - Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below. PMID- 22230257 TI - Risk factors for prolonged treatment of lymph node tuberculosis. AB - Lymph node tuberculosis (LNTB) is the most frequent form of extra-pulmonary tuberculosis (TB). Randomised, controlled trials have convincingly demonstrated that 6 months of chemotherapy is sufficient for most drug-susceptible LNTB. We performed a retrospective, multicentric study from 1997 to 2010 to describe factors associated with prolonged anti-tuberculosis treatment in patients with LNTB. Of 126 patients diagnosed with LNTB, 22 (17.5%) were human immunodeficiency virus (HIV) infected. The median treatment duration was 9 months (interquartile range, 6-12). Treatment was significantly longer in patients with HIV (P < 0.01), additional sites of TB (P < 0.01) or weight loss (P = 0.04). Factors independently associated with excessively lengthy treatment were HIV co-infection and the presence of other TB foci. PMID- 22230258 TI - Targeted therapies in the treatment of germ cell tumors: the need for new approaches against "orphan" tumors. AB - Germ cell tumors (GCTs) are a heterogeneous group of tumors that are highly clinically relevant to oncologists. GCTs are generally highly sensitive to cisplatin-based chemotherapy and represent a model for curable neoplasms. Cisplatin-based combination therapy followed by surgical resection of the residual tumor is the cornerstone for GCTs treatment. Although the overall cure rate is high for patients with GCTs, patients with a poor prognosis according to International Consensus Criteria or with chemoresistant disease remain a major clinical challenge. Currently, between 15% and 20% of patients with metastatic disease still progress and will die as a consequence of the disease. Therefore, the discovery of new treatment strategies or new drugs based on translational oncology remains a priority for the treatment of patients with cisplatin refractory disease and those with a poor prognosis. Clinical trials with new targeted therapies are ongoing for the treatment of GCTs. In this article, we review some of the new targeted biologic therapies that act on the most relevant oncogenesis pathways and are in clinical development for the treatment of GCTs. PMID- 22230259 TI - Hafnium metallocene compounds used as cathode interfacial layers for enhanced electron transfer in organic solar cells. AB - We have used hafnium metallocene compounds as cathode interfacial layers for organic solar cells [OSCs]. A metallocene compound consists of a transition metal and two cyclopentadienyl ligands coordinated in a sandwich structure. For the fabrication of the OSCs, poly[3,4-ethylenedioxythiophene]:poly(styrene sulfonate), poly(3-hexylthiophene-2,5-diyl) + 66-phenyl C61 butyric acid methyl ester, bis-(ethylcyclopentadienyl)hafnium(IV) dichloride, and aluminum were deposited as a hole transport layer, an active layer, a cathode interfacial layer, and a cathode, respectively. The hafnium metallocene compound cathode interfacial layer improved the performance of OSCs compared to that of OSCs without the interfacial layer. The current density-voltage characteristics of OSCs with an interfacial layer thickness of 0.7 nm and of those without an interfacial layer showed power conversion efficiency [PCE] values of 2.96% and 2.34%, respectively, under an illumination condition of 100 mW/cm2 (AM 1.5). It is thought that a cathode interfacial layer of an appropriate thickness enhances the electron transfer between the active layer and the cathode, and thus increases the PCE of the OSCs. PMID- 22230260 TI - Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice. AB - Inorganic arsenic, an early life carcinogen in humans and mice, can initiate lesions promotable by other agents in later life. The biomethylation product of arsenic, dimethylarsinic acid (DMA), is a multi-site tumor promoter. Thus, pregnant CD1 mice were given drinking water (0 ppm or 85 ppm arsenic) from gestation day 8 to 18 and after weaning male offspring received DMA (0 ppm or 200 ppm; drinking water) for up to 2 years. No renal tumors occurred in controls or DMA alone treated mice while gestational arsenic exposure plus later DMA induced a significant renal tumor incidence of 17% (primarily renal cell carcinoma). Arsenic plus DMA or arsenic alone also increased renal hyperplasia over control but DMA alone did not. Arsenic alone, DMA alone and arsenic plus DMA all induced urinary bladder hyperplasia (33-35%) versus control (2%). Compared to control (6%), arsenic alone tripled hepatocellular carcinoma (20%), and arsenic plus DMA doubled this rate again (43%), but DMA alone had no effect. DMA alone, arsenic alone, and arsenic plus DMA increased lung adenocarcinomas and adrenal adenomas versus control. Overall, DMA in adulthood promoted tumors/lesions initiated by prenatal arsenic in the kidney and liver, but acted independently in the urinary bladder, lung and adrenal. PMID- 22230261 TI - ERK and p38 MAPK signaling pathways are involved in ochratoxin A-induced G2 phase arrest in human gastric epithelium cells. AB - Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic, and immunotoxic effects. Recent work from our laboratory found that OTA evoked G2 phase arrest in GES-1 cells in vitro by modulating the key factors Cdc25C, Cdc2 and cyclinB1, which were critical to the G2/M phase transmission, suggested that OTA-induced G2 arrest mediate at least in part OTA toxicity effect. However, the molecular mechanism of this effect is currently unclear. In the present study, we showed that treatment of GES-1 cells with OTA could induce the activation of MAPK family members ERK and p38. ERK inhibitor PD98059 and p38 inhibitor SB203580 significantly reversed the depression of Cdc25C/p-Cdc25C, Cdc2/p-Cdc2, cyclinB1 as well as the cyclinB1-Cdc2 complex, thereby, abolished the delay in G2 phase. In addition, silencing ERK and p38 expression with siRNA significantly inhibited OTA-induced G2 arrest in GES-1 cells as well. Collectively, these data suggest that the ERK and p38 MAPK signaling pathways play important roles in the regulation of OTA-induced G2 arrest in GES-1 cells. PMID- 22230262 TI - Comparative kinetics of organophosphates and oximes with erythrocyte, muscle and brain acetylcholinesterase. AB - There is an ongoing debate whether oximes can effectively counteract the effects of organophosphorus compounds (OP) on brain acetylcholinesterase (AChE) activity and whether there are differences in the kinetic properties of brain and erythrocyte AChE. In order to investigate the kinetics of AChE from different tissues and species the well established dynamically working in vitro model with real-time determination of membrane-bound AChE activity was adapted for use with brain AChE. The enzyme reactor, that was loaded with brain, erythrocyte or muscle AChE, was continuously perfused with substrate and chromogen while AChE activity was on-line analyzed in a flow-through detector. It was possible to determine the Michaelis-Menten constants of human erythrocyte, muscle and brain AChE which were almost identical. In addition, the inhibition kinetics of sarin and paraoxon as well as the reactivation kinetics of obidoxime and HI 6 were determined with human, swine and guinea pig brain and erythrocyte AChE. It was found that the inhibition and reactivation kinetics of brain and erythrocyte AChE were highly comparable in all tested species. These data support the view that AChE from different tissue has similar kinetic properties and that brain AChE is comparably susceptible toward reactivation by oximes. PMID- 22230263 TI - Differential expression of ADAM15 and ADAM17 metalloproteases in the rat brain after severe hypobaric hypoxia and hypoxic preconditioning. AB - The ADAMs (a disintegrin and metalloprotease) are a family of membrane-anchored glycoproteins capable of shedding a multitude of proteins from the cell surface. Although ADAMs are being considered as crucial modulators of physiological and pathophysiological processes, their roles in neuronal death/survival are largely unexplored. In the present study, changes in brain expression of ADAM15 and ADAM17 (TACE) have been quantitatively examined in rats in response to injurious severe hypoxia (SH) and in animals which acquired hypoxic tolerance through preconditioning to mild hypoxia prior SH. SH persistently up-regulated ADAM15 mRNA and protein levels in hippocampus and neocortex but not in thalamus or hypothalamus. This effect was not observed in the preconditioned rats tolerant to SH. In contrast, hippocampal levels of ADAM17 mRNA and neocortical levels of ADAM17 mRNA and protein were largely reduced following SH in non-preconditioned rats. Hypoxic preconditioning prevented down-regulation of the adam17 gene and considerably enhanced ADAM17 protein expression in hippocampus and neocortex in response to SH. The present findings implicate ADAM15 in the processes of neuronal hypoxic injury. On the other hand, these results also provide evidence for a pro-survival neuroprotective role of ADAM17 and its engagement in the process of preconditioning-induced hypoxic tolerance. The analysis of the protein levels of soluble and membrane-bound forms of APP in the neocortex and hippocampus of rats subjected to SH and SH with preconditioning has demonstrated that an increased ADAM17 expression in preconditioned animals 24h after hypoxia corresponded to a higher level of soluble form of APP and a reduction of the membrane bound fraction which reflects the role of ADAM17 in APP shedding. PMID- 22230265 TI - The virtuous cycle. PMID- 22230264 TI - Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation. AB - Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and theta burst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous D-serine. Chronic treatment with L NAC, but not acute application of the reducing agent, restored potent D-serine dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in D-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the D-serine dependent pathway. PMID- 22230267 TI - Rationale for a 39-week elective delivery policy. PMID- 22230268 TI - Comprehensive medical school rural programs produce rural family physicians. PMID- 22230269 TI - Cirrhosis: diagnosis, management, and prevention. AB - Cirrhosis is the 12th leading cause of death in the United States. It accounted for 29,165 deaths in 2007, with a mortality rate of 9.7 per 100,000 persons. Alcohol abuse and viral hepatitis are the most common causes of cirrhosis, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary care physicians share responsibility with specialists in managing the most common complications of the disease, screening for hepatocellular carcinoma, and preparing patients for referral to a transplant center. Patients with cirrhosis should be screened for hepatocellular carcinoma with imaging studies every six to 12 months. Causes of hepatic encephalopathy include constipation, infection, gastrointestinal bleeding, certain medications, electrolyte imbalances, and noncompliance with medical therapy. These should be sought and managed before instituting the use of lactulose or rifaximin, which is aimed at reducing serum ammonia levels. Ascites should be treated initially with salt restriction and diuresis. Patients with acute episodes of gastrointestinal bleeding should be monitored in an intensive care unit, and should have endoscopy performed within 24 hours. Physicians should also be vigilant for spontaneous bacterial peritonitis. Treating alcohol abuse, screening for viral hepatitis, and controlling risk factors for nonalcoholic fatty liver disease are mechanisms by which the primary care physician can reduce the incidence of cirrhosis. PMID- 22230270 TI - Cirrhosis and liver damage. PMID- 22230271 TI - Diagnosis and management of Crohn's disease. AB - Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract at any point from the mouth to the rectum. Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia. Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum. Acute phase reactants, such as C-reactive protein level and erythrocyte sedimentation rate, are often increased with inflammation and may correlate with disease activity. Levels of vitamin B12, folate, albumin, prealbumin, and vitamin D can help assess nutritional status. Colonoscopy with ileoscopy, capsule endoscopy, computed tomography enterography, and small bowel follow-through are often used to diagnose Crohn's disease. Ultrasonography, computed axial tomography, scintigraphy, and magnetic resonance imaging can assess for extraintestinal manifestations or complications (e.g., abscess, perforation). Mesalamine products are often used for the medical management of mild to moderate colonic Crohn's disease. Antibiotics (e.g., metronidazole, fluoroquinolones) are often used for treatment. Patients with moderate to severe Crohn's disease are treated with corticosteroids, azathioprine, 6-mercaptopurine, or anti-tumor necrosis factor agents (e.g., infliximab, adalimumab). Severe disease may require emergent hospitalization and a multidisciplinary approach with a family physician, gastroenterologist, and surgeon. PMID- 22230272 TI - Crohn's disease. PMID- 22230273 TI - Subacute management of ischemic stroke. AB - Ischemic stroke is the third leading cause of death in the United States and a common reason for hospitalization. The subacute period after a stroke refers to the time when the decision to not employ thrombolytics is made up until two weeks after the stroke occurred. Family physicians are often involved in the subacute management of ischemic stroke. All patients with an ischemic stroke should be admitted to the hospital in the subacute period for cardiac and neurologic monitoring. Imaging studies, including magnetic resonance angiography, carotid artery ultrasonography, and/or echocardiography, may be indicated to determine the cause of the stroke. Evaluation for aspiration risk, including a swallowing assessment, should be performed, and nutritional, physical, occupational, and speech therapy should be initiated. Significant causes of morbidity and mortality following ischemic stroke include venous thromboembolism, pressure sores, infection, and delirium, and measures should be taken to prevent these complications. For secondary prevention of future strokes, antiplatelet therapy with aspirin should be initiated within 24 hours of ischemic stroke in all patients without contraindications, and one of several antiplatelet regimens should be continued long-term. Statin therapy should also be given in most situations. Although permissive hypertension is initially warranted, antihypertensive therapy should begin within 24 hours. Diabetes mellitus should be controlled and patients counseled about lifestyle modifications to reduce stroke risk. Rehabilitative therapy following hospitalization improves outcomes and should be considered. PMID- 22230274 TI - Common cold. PMID- 22230276 TI - Arcuate, red plaques with pustules on the trunk. PMID- 22230277 TI - FPIN's clinical inquiries: antibody testing for systemic lupus erythematosus. PMID- 22230281 TI - The light-sensitive photoprotein berovin from the bioluminescent ctenophore Beroe abyssicola: a novel type of Ca(2+) -regulated photoprotein. AB - Light-sensitive Ca(2+) -regulated photoproteins are responsible for the bright bioluminescence of ctenophores. Using functional screening, four full-size cDNA genes encoding the same 208-amino-acid polypeptide were isolated from two independent cDNA libraries prepared from two Beroe abyssicola specimens. Sequence analysis revealed three canonical EF-hand calcium-binding sites characteristic of Ca(2+) -regulated photoproteins, but a very low degree of sequence identity (27 29%) with aequorin-type photoproteins, despite functional similarities. Recombinant berovin was expressed in Escherichia coli cells, purified, converted to active photoprotein and characterized. Active berovin has absorption maxima at 280 and 437 nm. The Ca(2+) -discharged protein loses visible absorption, but exhibits a new absorption maximum at 335 nm. The berovin bioluminescence is blue (lambda(max) = 491 nm) and a change in pH over the range 6.0-9.5 has no significant effect on the light emission spectrum. By contrast, the fluorescence of Ca(2+) -discharged protein (lambda(ex) = 350 nm) is pH sensitive: at neutral pH the maximum is at 420 nm and at alkaline pH there are two maxima at 410 and 485 nm. Like native ctenophore photoproteins, recombinant berovin is also inactivated by light. The Ca(2+) concentration-effect curve is a sigmoid with a slope on a log-log plot of ~ 2.5. Although this curve for berovin is very similar to those obtained for obelin and aequorin, there are evident distinctions: berovin responds to calcium changes at lower concentrations than jellyfish photoproteins and its Ca(2+) -independent luminescence is low. Recombinant berovin was successfully expressed in mammalian cells, thereby demonstrating potential for monitoring intracellular calcium. Database The nucleotide sequences have been deposited in the GenBankTM/EBI Data Bank with accession numbers: apoberovin cDNA genes, JN673813 (BA1), JN673814 (BA2), JN673815 (BA3), JN673816 (BA4); fragment 18S rRNA, JN673817 (BA-rRNA5). PMID- 22230282 TI - Analytical expressions for the homotropic binding of ligand to protein dimers and trimers. AB - Cooperative binding of a ligand to multiple subsites on a protein is a common theme among enzymes and receptors. The analysis of cooperative binding data (either positive or negative) often relies on the assumption that free ligand concentration, L, can be approximated by the total ligand concentration, L(T). When this approximation does not hold, such analyses result in inaccurate estimates of dissociation constants. Presented here are exact analytical expressions for equilibrium concentrations of all enzyme and ligand species (in terms of K(d) values and total concentrations of protein and ligand) for homotropic dimeric and trimeric protein-ligand systems. These equations circumvent the need to approximate L and are provided in Excel worksheets suitable for simulation and least-squares fitting. The equations and worksheets are expanded to treat cases where binding signals vary with distinct site occupancy. PMID- 22230283 TI - Signal-enhanced electrochemiluminescence immunosensor based on synergistic catalysis of nicotinamide adenine dinucleotide hydride and silver nanoparticles. AB - A new metal-organic nanocomposite with synergistic catalysis function was prepared and developed to construct an electrochemiluminescence (ECL) immunosensor for ultrasensitive detection of tumor biomarker CA125. Silver nanoparticles (AgNPs) and nicotinamide adenine dinucleotide hydride (NADH) that can participate and catalyze the ECL reaction of Ru(bpy)(3)(2+) were employed as the metal component and the organic component to synthesize the metal-organic nanocomposite of NADH-AgNPs (NA). The novel ECL immunosensor was assembled via Ru(bpy)(3)(2+)-doped silica nanoparticles (Ru-SiO(2)) modified electrode with the NA as immune labels. First, the chitosan-suspended Ru-SiO(2) nanoparticles were cast on the gold electrode surface to immobilize the ECL probes of Ru(bpy)(3)(2+) and link gold nanoparticles. Then, the primary antibodies were loaded onto the modified electrode via the gold sulfhydryl covalent binding. After immunobinding the analytes of antigen, NA-attached secondary antibodies could be captured as a sandwich type on the electrode. Finally, based on the circularly synergistic catalysis by the silver and NADH for the solid-phase ECL of Ru(bpy)(3)(2+), the proposed immunosensor sensed the concentration of antigen. The synergistic ECL catalysis of metal-organic nanocomposite amplified response signal and pushed the detection limit down to 0.03 U ml(-1), which initiated a new ECL labeling field and has great significance for ECL immunoassays. PMID- 22230284 TI - One-pot fusion polymerase chain reaction for combinatorial synthesis of DNA from several cassettes. AB - The fusion of DNA fragments is becoming increasingly more important. The ability to work without being constrained by restriction sites enables DNA fusion to be applied to a much broader range of fragments. Therefore, we describe a simplified polymerase chain reaction (PCR)-based method for fusion of DNA fragments in one step. In a single PCR, two templates, an overlapping primer, and template specific forward and reverse primers are used. After a few cycles, the fusion DNA is assembled and is amplified. The ratio of overlapping primer to forward/reverse primers and template DNA is essential for the success of the reaction. PMID- 22230286 TI - An electrophoretic mobility shift assay for methionine sulfoxide in proteins. AB - Study of the posttranslational modification of methionine to its sulfoxide has been receiving increasing attention because of its implication in regulation of protein activity, but techniques for the detection of this modification remain limited. In particular, there has been no method to detect the oxidation of methionine on polyacrylamide gels. Here we demonstrate that alkylation of methionine introduces a charge change that shifts the mobility of the protein on an acidic gel relative to the alkylation-resistant sulfoxide form. PMID- 22230285 TI - A quantitative continuous enzyme assay of intramolecularly quenched fluorogenic phospholipase substrates for molecular imaging. AB - There has been recent growth in the development of activatable near-infrared (NIR) fluorescent probes for molecular imaging, generally designed by placing fluorochromes on a cleavable substrate in close proximity to one another, such that they self-quench, but fluoresce on separation via enzymatic cleavage of the substrate. Although these probes offer excellent contrast, the detection of enzyme activity has largely only been described qualitatively. In order to assess the effectiveness of a probe, it is useful to have a quantitative measure, such as the enzyme-substrate kinetic parameters. We have developed an assay to determine kinetic parameters and applied it to an intramolecularly quenched molecule, Pyro-PtdEtn-BHQ, a NIR fluorescent probe specific to phosphatidylcholine-specific phospholipase C. The development of this assay includes corrections for intermolecular quenching, calibration, optimization of reaction mixtures, and determination of kinetic and inhibition parameters. This assay can easily be extended to analyze and compare the efficiency of other fluorescent activatable phospholipase probes as suitable molecular imaging agents. PMID- 22230287 TI - Allowance for effects of thermodynamic nonideality in sedimentation equilibrium distributions reflecting protein dimerization. AB - This reexamination of a high-speed sedimentation equilibrium distribution for alpha-chymotrypsin under slightly acidic conditions (pH 4.1, I(M) 0.05) has provided experimental support for the adequacy of nearest-neighbor considerations in the allowance for effects of thermodynamic nonideality in the characterization of protein self-association over a moderate concentration range (up to 8 mg/mL). A widely held but previously untested notion about allowance for thermodynamic nonideality effects is thereby verified experimentally. However, it has also been shown that a greater obstacle to better characterization of protein self association is likely to be the lack of a reliable estimate of monomer net charge, a parameter that has a far more profound effect on the magnitude of the measured equilibrium constant than any deficiency in current procedures for incorporating the effects of thermodynamic nonideality into the analysis of sedimentation equilibrium distributions reflecting reversible protein self association. PMID- 22230288 TI - Clinicopathological features of salivary and non-salivary adenoid cystic carcinomas. AB - Adenoid cystic carcinoma (ACC), commonly from salivary glands, is known for its insidious local growth and usually protracted clinical course. ACC developing from non-salivary glands (i.e., non-salivary ACC) is heterogeneous, and its clinicopathological features remain poorly defined. Patients treated for ACC in a single institution between 1995 and 2007 were included in this study. Immunohistochemical evaluation of Ki-67, E-cadherin, p16, and cyclinD1 was performed. The prognostic significance of clinical and immunophenotypic markers was evaluated. 83 cases of salivary ACC and 24 cases of non-salivary ACC were included. The expression levels of Ki-67 (54.8%), E-cadherin (90.4%), p16 (32.9%), and cyclinD1 (19.2%) between ACCs present at various sites were not different. Sinonasal, lacrimal, and tracheobronchial ACCs had significantly worse outcomes than those of ACC of the major salivary glands. Postoperative radiotherapy reduced the recurrence rate of patients with a negative resection margin (P=0.028). Older age (age >60 years), advanced stage, positive resection margin, high histological grade, and high expression of Ki-67 were significantly correlated with poor prognosis. In conclusion, the site of origin plays a role in the prognosis of ACC, in which positive resection margin and advanced stage are possible factors underlying the differences in outcomes. PMID- 22230289 TI - Serum ferritin levels associated with increased risk for developing CHD in a low income urban population. AB - OBJECTIVE: The present study examined the association of serum ferritin with CHD risk using the Framingham Heart Study's 10-year risk algorithm. DESIGN: Ordinal logistic regression modelling was used to interpret risk. Proportional odds modelling assessed four divisions of ranked CHD risk (4, high; 3, increased; 2, slight; 1, minimal), separately by sex. SETTING: Baltimore, MD, USA. SUBJECTS: African-American and white participants (n 1823) from baseline of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, aged 30 64 years. RESULTS: For men, there was a 0.5 % increase in risk for every 10-unit rise in serum ferritin (pmol/l). Other significant predictors included increased BMI, white race, unemployment and C-reactive protein >=9.5 mg/l. For women, there was a 1.5 % [corrected] increase in risk per 10-unit rise in serum ferritin (pmol/l). Other significant predictors included increased BMI, lower education, unemployment and C-reactive protein >=9.5 mg/l. CONCLUSIONS: Serum ferritin is a significant predictor of 10-year hard CHD risk for HANDLS study participants, a low-income, urban population. Serum ferritin, independent of elevated C-reactive protein, was associated with increased 10-year CHD risk for HANDLS participants. To our knowledge, these data provide the first evidence of the role of serum ferritin as a risk factor for hard CHD in African-American and white postmenopausal women in the USA. Future research on cardiovascular events from this prospective study may confirm the association. PMID- 22230293 TI - Inhibition of microRNA function by antimiR oligonucleotides. AB - MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression in many developmental and cellular processes. Moreover, there is now ample evidence that perturbations in the levels of individual or entire families of miRNAs are strongly associated with the pathogenesis of a wide range of human diseases. Indeed, disease-associated miRNAs represent a new class of targets for the development of miRNA-based therapeutic modalities, which may yield patient benefits unobtainable by other therapeutic approaches. The recent explosion in miRNA research has accelerated the development of several computational and experimental approaches for probing miRNA functions in cell culture and in vivo. In this review, we focus on the use of antisense oligonucleotides (antimiRs) in miRNA inhibition for loss-of-function studies. We provide an overview of the currently employed antisense chemistries and their utility in designing antimiR oligonucleotides. Furthermore, we describe the most commonly used in vivo delivery strategies and discuss different approaches for assessment of miRNA inhibition and potential off-target effects. Finally, we summarize recent progress in antimiR mediated pharmacological inhibition of disease-associated miRNAs, which shows great promise in the development of novel miRNA-based therapeutics. PMID- 22230295 TI - Cocaine use during pregnancy assessed by hair analysis in a Canary Islands cohort. AB - BACKGROUND: Drug use during pregnancy is difficult to ascertain, and maternal reports are likely to be inaccurate. The aim of this study was to estimate the prevalence of illicit drug use among pregnant women by using maternal hair analysis. METHODS: A toxicological analysis of hair was used to detect chronic recreational drug use during pregnancy. In 2007, 347 mother-infant dyads were included from the Hospital La Candelaria, Santa Cruz de Tenerife, Canary Islands (Spain). Data on socioeconomic characteristics and on substance misuse during pregnancy were collected using a structured questionnaire. Drugs of abuse: opiates, cocaine, cannabinoids and amphetamines were detected in maternal hair by immunoassay followed by gas chromatography-mass spectrometry for confirmation and quantitation. RESULTS: Hair analysis revealed 2.6% positivity for cocaine and its metabolites. Use of cocaine during pregnancy was associated with unusual behaviour with potentially harmful effects on the baby. CONCLUSIONS: The results of the study demonstrate significant cocaine use by pregnant women in Canary Islands. The data should be used for the purpose of preventive health and policy strategies aimed to detect and possibly to avoid in the future prenatal exposure to drugs of abuse. PMID- 22230294 TI - Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature. AB - The resurgence of the malaria eradication agenda and the increasing number of severe manifestation reports has contributed to a renewed interested in the Plasmodium vivax infection. It is the most geographically widespread parasite causing human malaria, with around 2.85 billion people living under risk of infection. The Brazilian Amazon region reports more than 50% of the malaria cases in Latin America and since 1990 there is a marked predominance of this species, responsible for 85% of cases in 2009. However, only a few complicated cases of P. vivax have been reported from this region. A systematic review of the Brazilian indexed and non-indexed literature on complicated cases of vivax malaria was performed including published articles, masters' dissertations, doctoral theses and national congresses' abstracts. The following information was retrieved: patient characteristics (demographic, presence of co-morbidities and, whenever possible, associated genetic disorders); description of each major clinical manifestation. As a result, 27 articles, 28 abstracts from scientific events' annals and 13 theses/dissertations were found, only after 1987. Most of the reported information was described in small case series and case reports of patients from all the Amazonian states, and also in travellers from Brazilian non endemic areas. The more relevant clinical complications were anaemia, thrombocytopaenia, jaundice and acute respiratory distress syndrome, present in all age groups, in addition to other more rare clinical pictures. Complications in pregnant women were also reported. Acute and chronic co-morbidities were frequent, however death was occasional. Clinical atypical cases of malaria are more frequent than published in the indexed literature, probably due to a publication bias. In the Brazilian Amazon (considered to be a low to moderate intensity area of transmission), clinical data are in accordance with the recent findings of severity described in diverse P. vivax endemic areas (especially anaemia in Southeast Asia), however in this region both children and adults are affected. Finally, gaps of knowledge and areas for future research are opportunely pointed out. PMID- 22230296 TI - Estrogen- and xenoestrogen-induced ERK signaling in pituitary tumor cells involves estrogen receptor-alpha interactions with G protein-alphai and caveolin I. AB - Multiple physiologic estrogens (estradiol, estriol, and estrone), as well as xenoestrogenic compounds (including alkylphenols and bisphenol A), can act via nongenomic signaling initiated by liganding of the plasma membrane estrogen receptor-alpha (mERalpha). We examined heterotrimeric G protein involvement leading to extracellular-regulated kinase (ERK) activation in GH3/B6/F10 rat anterior pituitary tumor cells that express abundant mERalpha, and smaller amounts of mERbeta and GPR30. A combination of microarrays, immunoblots, and quantitative immunoassays demonstrated the expression of members of all alpha, beta, and gamma G protein classes in these cells. Use of selective inhibitors showed that the G(alphai) subtype was the primary initiator of downstream ERK signaling. Using antibodies against the GTP-bound form of G(alpha) protein subtypes i and s, we showed that xenoestrogens (bisphenol A, nonylphenol) activated G(alphai) at 15-30s; all alkylphenols examined subsequently suppressed activation by 5min. GTP-activation of G(alphai) for all estrogens was enhanced by irreversible cumulative binding to GTPgammaS. In contrast, G(alphas) was neither activated nor deactivated by these treatments with estrogens. ERalpha and G(alphai) co-localized outside nuclei and could be immuno-captured together. Interactions of ERalpha with G(alphai) and caveolin I were demonstrated by epitope proximity ligation assays. An ERalpha/beta antagonist (ICI182780) and a selective disruptor of caveolar structures (nystatin) blocked estrogen-induced ERK activation. CONCLUSIONS: Xenoestrogens, like physiologic estrogens, can evoke downstream kinase signaling involving selective interactions of ERalpha with G(alphai) and caveolin I, but with some different characteristics, which could explain their disruptive actions. PMID- 22230297 TI - PDS5A, a novel translocation partner of MLL in acute myeloid leukemia. PMID- 22230298 TI - Proteomic analysis identifies differentially expressed proteins in AML1/ETO acute myeloid leukemia cells treated with DNMT inhibitors azacitidine and decitabine. AB - Azacitidine and decitabine are DNA methyltransferase inhibitors used to treat myelodysplastic syndromes and acute myeloid leukemias. To further characterize different mechanisms between these two agents, cellular extracts from leukemic cells untreated or treated with either drug were analyzed using 2D electrophoresis. Numerous differentially expressed proteins were identified with MALDI-TOF/TOF-MS. Cyclophilin A, Catalase, Nucleophosmin and PCNA were decreased exclusively by azacitidine, TCP1 and hnRNP A2/B1 by both drugs; alpha-Enolase and Peroxiredoxin-1 by decitabine. Interestingly, the expression of the proinflammatory protein Cyclophilin A, also suggested as marker of cell necrosis, was stimulated by decitabine. Finally, a comprehensive pathway analysis of data highlighted a relationship between the identified proteins and potential effectors. PMID- 22230299 TI - Incidence of the BRAF V600E mutation in chronic lymphocytic leukaemia and prolymphocytic leukaemia. AB - The spectrum of underlying molecular abnormalities of clinically and biologically heterogeneous chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) has yet to be identified. While whole genome sequencing has identified several genes implicated in the pathogenesis and progression of CLL, the molecular lesions in a substantial proportion of patients remain to be elucidated. The incidence of the BRAF V600E mutation, widely implicated in solid tumours and other B-cell malignancies, was sought in a cohort of patients with CLL and related disorders. One CLL patient and one patient with B-prolymphocytic leukaemia (PLL) were found to harbour this mutation. Although present at a low frequency, the finding of BRAF V600E has biological and clinical implications for CLL and PLL. PMID- 22230300 TI - Hypomethylating therapy and autoimmunity in MDS: an enigmatic relationship. PMID- 22230301 TI - Features and serotypes of chlamydial conjunctivitis. PMID- 22230303 TI - Antidepressants for agitation and psychosis in patients with dementia. PMID- 22230304 TI - Outpatient burns: prevention and care. AB - Most burn injuries can be managed on an outpatient basis by primary care physicians. Prevention efforts can significantly lower the incidence of burns, especially in children. Burns should be managed in the same manner as any other trauma, including a primary and secondary survey. Superficial burns can be treated with topical application of lotions, honey, aloe vera, or antibiotic ointment. Partial-thickness burns should be treated with a topical antimicrobial agent or an absorptive occlusive dressing to help reduce pain, promote healing, and prevent wound desiccation. Topical silver sulfadiazine is the standard treatment; however, newer occlusive dressings can provide faster healing and are often more cost-effective. Physicians must reevaluate patients frequently after a burn injury and be aware of the indications for referral to a burn specialist. PMID- 22230305 TI - Caring for minor burns. PMID- 22230306 TI - Evaluation and management of abnormal uterine bleeding in premenopausal women. AB - Up to 14 percent of women experience irregular or excessively heavy menstrual bleeding. This abnormal uterine bleeding generally can be divided into anovulatory and ovulatory patterns. Chronic anovulation can lead to irregular bleeding, prolonged unopposed estrogen stimulation of the endometrium, and increased risk of endometrial cancer. Causes include polycystic ovary syndrome, uncontrolled diabetes mellitus, thyroid dysfunction, hyperprolactinemia, and use of antipsychotics or antiepileptics. Women 35 years or older with recurrent anovulation, women younger than 35 years with risk factors for endometrial cancer, and women with excessive bleeding unresponsive to medical therapy should undergo endometrial biopsy. Treatment with combination oral contraceptives or progestins may regulate menstrual cycles. Histologic findings of hyperplasia without atypia may be treated with cyclic or continuous progestin. Women who have hyperplasia with atypia or adenocarcinoma should be referred to a gynecologist or gynecologic oncologist, respectively. Ovulatory abnormal uterine bleeding, or menorrhagia, may be caused by thyroid dysfunction, coagulation defects (most commonly von Willebrand disease), endometrial polyps, and submucosal fibroids. Transvaginal ultrasonography or saline infusion sonohysterography may be used to evaluate menorrhagia. The levonorgestrel-releasing intrauterine system is an effective treatment for menorrhagia. Oral progesterone for 21 days per month and nonsteroidal anti-inflammatory drugs are also effective. Tranexamic acid is approved by the U.S. Food and Drug Administration for the treatment of ovulatory bleeding, but is expensive. When clear structural causes are identified or medical management is ineffective, polypectomy, fibroidectomy, uterine artery embolization, and endometrial ablation may be considered. Hysterectomy is the most definitive treatment. PMID- 22230307 TI - Abnormal bleeding during your period. PMID- 22230308 TI - Osteoarthritis: diagnosis and treatment. AB - Osteoarthritis is a common degenerative disorder of the articular cartilage associated with hypertrophic bone changes. Risk factors include genetics, female sex, past trauma, advancing age, and obesity. The diagnosis is based on a history of joint pain worsened by movement, which can lead to disability in activities of daily living. Plain radiography may help in the diagnosis, but laboratory testing usually does not. Pharmacologic treatment should begin with acetaminophen and step up to nonsteroidal anti-inflammatory drugs. Exercise is a useful adjunct to treatment and has been shown to reduce pain and disability. The supplements glucosamine and chondroitin can be used for moderate to severe osteoarthritis when taken in combination. Corticosteroid injections provide inexpensive, short term (four to eight weeks) relief of osteoarthritic flare-ups of the knee, whereas hyaluronic acid injections are more expensive but can maintain symptom improvement for longer periods. Total joint replacement of the hip, knee, or shoulder is recommended for patients with chronic pain and disability despite maximal medical therapy. PMID- 22230309 TI - What you should know about osteoarthritis. PMID- 22230310 TI - Refocusing geriatricians' role in training to improve care for older adults. PMID- 22230311 TI - Persistent cough. PMID- 22230313 TI - Tritimovirus P1 functions as a suppressor of RNA silencing and an enhancer of disease symptoms. AB - Wheat streak mosaic virus (WSMV) is an eriophyid mite-transmitted virus of the genus Tritimovirus, family Potyviridae. Complete deletion of helper component proteinase (HC-Pro) has no effect on WSMV virulence or disease synergism, suggesting that a different viral protein suppresses RNA silencing. RNA silencing suppression assays using Nicotiana benthamiana 16C plants expressing GFP were conducted with each WSMV protein; only P1 suppressed RNA silencing. Accumulation of GFP siRNAs was markedly reduced in leaves infiltrated with WSMV P1 at both 3 and 6 days post infiltration relative to WSMV HC-Pro and the empty vector control. On the other hand, helper component-proteinase (HC-Pro) of two species in the mite-transmitted genus Rymovirus, family Potyviridae was demonstrated to be a suppressor of RNA silencing. Symptom enhancement assays were conducted by inoculating Potato virus X (PVX) onto transgenic N. benthamiana. Symptoms produced by PVX were more severe on transgenic plants expressing WSMV P1 or potyvirus HC-Pro compared to transgenic plants expressing GFP or WSMV HC-Pro. PMID- 22230314 TI - Complete nucleotide sequence of Cherry leaf roll virus (CLRV), a subgroup C nepovirus. AB - The complete nucleotide sequence of both genomic (+)ss RNAs of a rhubarb isolate of Cherry leaf roll virus (CLRV) was determined. The larger RNA1 is 7918 nucleotides and the shorter RNA2 6360 nucleotides in size, each genome component comprising a single open reading frame (ORF). The RNA1-encoded polyprotein (P1) is 2112 amino acids long (235.6 kDa) containing domains characteristic for a proteinase-cofactor (PCo), nucleotide-binding helicase (Hel), genome-linked protein (VPg), proteinase (Pro), and an RNA-dependent RNA polymerase (Pol). The RNA2-encoded polyprotein (P2) has a molecular mass of 174.9 kDa (1589 aa) encoding the putative movement protein (MP) and the coat protein (CP) of CLRV. The genome region upstream of the MP has a coding capacity of 77 kDa, however processing of P2 by the putative virus-encoded proteinase and protein-function encoded by this region is unknown. Furthermore, it could be demonstrated that the 5'-termini including the N-terminal region (208 aa) of P1 and P2 of the rhubarb isolate of CLRV are nearly identical among the two genome segments. The taxonomic position of CLRV as member of the genus Nepovirus was confirmed by phylogenetic analyses employing the amino acid sequences of the conserved Pro-Pol region of RNA1, the complete P2, and the CP. However, clustering of Nepovirus-species according to allocated subgroups was inconsistent and depended on the compared genome fragment. PMID- 22230315 TI - Cell culture-adapted IBDV uses endocytosis for entry in DF-1 chicken embryonic fibroblasts. AB - Although membrane perforation was suggested as the means of penetration mediated by IBDV, the cellular mechanism being hijacked to facilitate its entry is largely unknown. In this study, the entry pathway of cell culture adapted IBDV (caIBDV) was characterized in DF-1 chicken embryonic fibroblasts. We observed that the entry of caIBDV was inhibited by bafilomycin A1 and CaEGTA which interfere with the function of vacuolar H(+)-ATPase (V-ATPase) and retain endosomal Ca(2+). This result suggests that the intact caIBDV particle was transported to the V-ATPase positive vesicles for uncoating and implicates an essential role of endocytosis during the viral entry. The IBDV-mediated endocytosis was demonstrated to be clathrin-independent. Instead, the entry of caIBDV in DF-1 was reduced under the inhibitions or depletions of lipid raft, c-Src tyrosine kinase, dynamin and actin polymerization. In summary, this study confirmed the role of endocytosis in caIBDV entry and characterized the route of its endocytosis. PMID- 22230316 TI - Human papillomavirus 8 E6 disrupts terminal skin differentiation and prevents pro Caspase-14 cleavage. AB - Expression of the betapapillomavirus (betaPV) E6/E7 genes has been shown to impair both keratinocyte differentiation and apoptosis. Especially late-terminal keratinocyte differentiation shares certain aspects with apoptosis, such as fragmentation of DNA and activation of caspases. Here we investigated the disruption of keratinocyte differentiation in organotypic skin (raft) cultures of primary (PHK) and immortalized (N/TERT) human keratinocytes, in particular by human papillomavirus (HPV)8. Immunohistochemical analysis of HPV5 and HPV8 E6/E7 expressing PHK revealed thickening of the rafts and complete absence of stratum corneum formation, even after 18 days of culture. This phenotype was confirmed in N/TERT raft cultures. When expressed separately, the aberrant morphology was observed only in rafts expressing E6, not E7. Immunofluorescence analysis of HPV8 E6 PHK rafts showed an increase in number and size of Filaggrin- and Caspase-14 positive cells in the granular layer. In raft lysates analyzed by western-blot, the presence of pro-Caspase-14 in the differentiated keratinocytes was confirmed, but in the HPV8 E6 rafts none of the Caspase-14 subunits were detected. In conclusion, in the raft system, HPV8 E6 prevented late-terminal keratinocyte differentiation resulting in an accumulation of Filaggrin and pro-Caspase-14 positive cells in the absence of stratification. This differentiation arrest was accompanied by the failure to express Caspase-14 subunits, suggesting absence of Caspase-14 activation and probable abrogation of Filaggrin maturation in HPV8 E6 expressing keratinocytes. PMID- 22230317 TI - A role for Epstein-Barr viral BALF1 in facilitating tumor formation and metastasis potential. AB - Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that triggers transformation and tumorigenesis of latently infected B cells in vitro. BALF1, a Bcl-2-like EBV gene expressed in both latent and lytic stages, was recently characterized in EBV-infected cells; however, the role and function of BALF1 has remained elusive. Here, we demonstrate that BALF1 expression alters cellular morphology. Importantly, BALF1 promotes cellular transformation, with tumorigenicity assays showing larger and substantially greater numbers of tumors in BALF1 transfectant-injected mice compared to mice injected with pcDNA control transfectants. In addition, BALF1 expression increases cell survival under low serum conditions, an effect that is attributable to suppression of apoptosis, not to promotion of cell-cycle progression. Furthermore, BALF1 transfectants exhibit markedly increased tumor metastasis in vitro and in vivo. Taken together, these findings suggest that BALF1 may be a new tumor marker for EBV diagnosis and provide a new direction for research on treatments of EBV-associated tumors. PMID- 22230318 TI - Donor vigilance: what are we doing about it? AB - Donor vigilance is the systematic monitoring of adverse reactions and incidents in blood donor care with a view to improving quality and safety for blood donors. Standard international definitions are available for surveillance purposes. In recent years advances have been made in determining risk factors for vasovagal and other adverse reactions to blood donation as well as in evaluating preventive measures. Blood establishments should record all adverse reactions in blood donors. Besides its use for individual donor care, this information can be reviewed within and between organisations to guide policy decisions and research for improving donor care. PMID- 22230321 TI - Synthesis, characterization and evaluation of computationally designed nanoparticles of molecular imprinted polymers as drug delivery systems. AB - The aim of the present study was to prepare nanoparticles of molecular imprinted polymers (MIPs) with high loading capacity for naltrexone as template drug. To achieve this goal, a computational protocol was employed to select the most appropriate monomer for MIP preparation. Density functional theory (DFT) method at the B3LYP level of theory in conjugate with the 6-31+G(d) basis set was used to evaluate the extent of interaction between naltrexone and a small library of frequently used vinylic monomers. The results revealed that acrylic acid (AA) and methacrylic acid (MAA) can be considered as suitable monomers. To select the best monomer, two MIPs with AA and MAA monomer were synthesized and their loading capacity, selectivity and release profile were evaluated. The experimental results showed that the MIPs synthesized using AA (MIP-AA) exhibited a surprisingly high loading capacity to naltrexone (75mg of drug/g of MIP) compared to MIP-MAA (34mg of drug/g of MIP). In vitro release dynamics of the drug from MIPs was also investigated and modeled. It was found that non-Fickian-type diffusion mechanism was responsible for drug release. The results can lead to the conclusion that MIPs designed by computational approach can be considered as promising candidates for drug delivery systems. PMID- 22230322 TI - Highly pathogenic avian influenza virus H5N1 controls type I IFN induction in chicken macrophage HD-11 cells: a polygenic trait that involves NS1 and the polymerase complex. AB - BACKGROUND: Influenza A viruses are well characterized to antagonize type I IFN induction in infected mammalian cells. However, limited information is available for avian cells. It was hypothesised that avian influenza viruses (AIV) with distinct virulence may interact differently with the avian innate immune system. Therefore, the type I IFN responses induced by highly virulent and low virulent H5N1 AIV and reassortants thereof were analysed in chicken cells. RESULTS: The highly pathogenic (HP) AIV A/chicken/Yamaguchi/7/04 (H5N1) (Yama) did not induce type I IFN in infected chicken HD-11 macrophage-like cells. This contrasted with an NS1 mutant Yama virus (Yama-NS1(A144V)) and with the attenuated H5N1 AIV A/duck/Hokkaido/Vac-1/04 (Vac) carrying the haemagglutinin (HA) of the Yama virus (Vac-Yama/HA), that both induced type I IFN in these cells. The substitution of the NS segment from Yama with that from Vac in the Yama backbone resulted in induction of type I IFN secretion in HD-11 cells. However, vice versa, the Yama NS segment did not prevent type I IFN induction by the Vac-Yama/HA virus. This was different with the PB1/PB2/PA segment reassortant Yama and Vac-Yama/HA viruses. Whereas the Yama virus with the Vac PB1/PB2/PA segments induced type I IFN in HD-11 cells, the Vac-Yama/HA virus with the Yama PB1/PB2/PA segments did not. As reported for mammalian cells, the expression of H5N1 PB2 inhibited the activation of the IFN-beta promoter in chicken DF-1 fibroblast cells. Importantly, the Yama PB2 was more potent at inhibiting the IFN-beta promoter than the Vac PB2. CONCLUSIONS: The present study demonstrates that the NS1 protein and the polymerase complex of the HPAIV Yama act in concert to antagonize chicken type I IFN secretion in HD-11 cells. PB2 alone can also exert a partial inhibitory effect on type I IFN induction. In conclusion, the control of type I IFN induction by H5N1 HPAIV represents a complex phenotype that involves a particular viral gene constellation rather than a single viral protein. Collectively, these findings contribute to understand the high virulence of HPAIV H5N1 viruses observed in the chicken host. PMID- 22230323 TI - Pharmacogenetic determinants of statin-induced reductions in C-reactive protein. AB - BACKGROUND: In randomized trials, statins reduce plasma levels of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C), and the magnitude of event reduction relates to on-treatment levels of both. However, whether different mechanisms underlie statin-induced CRP and LDL-C reduction is unknown. METHODS AND RESULTS: We performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6766 participants of European ancestry randomly allocated to 20 mg/d of rosuvastatin or placebo in the JUPITER trial. Among 3386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy (P<0.001 for both) and essentially uncorrelated (r(2)<0.03). No variants in the 3 genes (ABCG2, LPA, and APOE) that previously showed genome-wide association with LDL-C reduction in this cohort and none of the candidate single-nucleotide polymorphisms associated with LDL-C reduction were associated with rosuvastatin induced CRP change after multiple testing correction. Among candidate single nucleotide polymorphisms selected from prior genetic analyses of baseline CRP, CRP reduction was associated with rs2794520 in CRP (mean, -3.5% [SE, 2.0%] change in CRP per minor allele; P=6.4*10(-4)) and with rs2847281 in PTPN2 (mean, 3.7% [SE, 1.9%] change in CRP per minor allele; P=7.4*10(-4)). These associations remained significant after multiple testing correction but were not significant in a formal test of interaction. Neither variant was associated with rosuvastatin induced LDL-C reduction or with CRP reduction among 3380 placebo-allocated JUPITER participants. CONCLUSIONS: The genetic determinants of rosuvastatin induced CRP reduction differ from, and are largely independent of, the major pharmacogenetic determinants of rosuvastatin-induced LDL-C reduction. This supports the hypothesis that differing pathways may mediate the anti-inflammatory and lipid-lowering properties of statin therapy. PMID- 22230324 TI - Rather than interleukin-27, interleukin-6 expresses positive correlation with liver severity in naive hepatitis B infection patients. AB - AIMS: Effective cytokines can drive the commitment of naive T cells to regulate immune response after antigen-mediated activation. Aims are to elucidate the clinical role of serum IL-27 and IL-6 in the different stages of naive hepatitis B virus (HBV)-infected patients. METHODS: Samples with well-characterized clinical profiles were assessed from 395 HBV-infected patients including chronic hepatitis B (CHB) group in 291 patients, liver cirrhosis (LC) group in 57 patients, hepatocellular carcinoma (HCC) group in 47 patients. Another 139 non HBV infected individuals were enrolled as control group (CG) including 104 with normal liver function (NF) and 35 with liver dysfunction (LD). RESULTS: The HBV infected group and separated groups presented significantly higher IL-27 and IL-6 expression than the CG or subgroups of CG. In contrast to IL-27, IL-6 showed significant differences with deteriorating liver condition compared with LC or HCC with CHB groups. Furthermore, IL-6, rather than IL-27, showed significant statistical differences in patients with advanced liver disease compared with those of mild or moderate to severe liver disease and in patients with terminal stage HCC compared with those of early to intermediate or advanced stage HCC. The data associated with liver function, including Albumin, Bilirubin, INR, Platelet and AFP levels, were significantly correlated to IL-6 expression, but had weak correlation to IL-27 expression in HBV patients. CONCLUSION: Serum IL-27 can trigger immune response to prevent hepatic injury in different clinical pathologic stages of HBV-infected patients earlier, but IL-6 may play an extremely important role to determine the liver progression. PMID- 22230325 TI - Host susceptibility to tuberculosis: insights from a longitudinal study of gene expression in diabetes. AB - Tuberculosis (TB) remains a major global disease, and diabetes, which is documented to increase susceptibility to TB threefold, is also becoming pandemic. This susceptibility has been attracting extensive research interest. The increased risk of TB in diabetes may serve as a unique model to understand host susceptibility to specific pathogens in humans. To examine this rationale, we investigated the expression of reported TB candidate genes in a longitudinal diabetes study. Two genes, HK2 and CD28, emerged as potential culprits in diabetes-increased TB susceptibility. PMID- 22230326 TI - The many roles of PTK7: a versatile regulator of cell-cell communication. AB - PTK7 (protein tyrosine kinase 7) is an evolutionarily conserved transmembrane receptor with functions in various processes ranging from embryonic morphogenesis to epidermal wound repair. Here, we review recent findings indicating that PTK7 is a versatile co-receptor that functions as a molecular switch in Wnt, Semaphorin/Plexin and VEGF signaling pathways. We focus in particular on the role of PTK7 in Wnt signaling, as recent data indicate that PTK7 acts as a Wnt co receptor, which activates the planar cell polarity pathway, but inhibits canonical Wnt signaling. PMID- 22230328 TI - Role of connexin 43 in the mechanism of action of alendronate: dissociation of anti-apoptotic and proliferative signaling pathways. AB - Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [(3)H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na(3)VO(4) increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents. PMID- 22230327 TI - Recent advances in our understanding of 1,25-dihydroxyvitamin D(3) regulation of intestinal calcium absorption. AB - Calcium is required for many cellular processes including muscle contraction, nerve pulse transmission, stimulus secretion coupling and bone formation. The principal source of new calcium to meet these essential functions is from the diet. Intestinal absorption of calcium occurs by an active transcellular path and by a non-saturable paracellular path. The major factor influencing intestinal calcium absorption is vitamin D and more specifically the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). This article emphasizes studies that have provided new insight related to the mechanisms involved in the intestinal actions of 1,25(OH)(2)D(3). The following are discussed: recent studies, including those using knock out mice, that suggest that 1,25(OH)(2)D(3) mediated calcium absorption is more complex than the traditional transcellular model; evidence for 1,25(OH)(2)D(3) mediated active transport of calcium by distal as well as proximal segments of the intestine; 1,25(OH)(2)D(3) regulation of paracellular calcium transport and the role of 1,25(OH)(2)D(3) in protection against mucosal injury. PMID- 22230329 TI - Secretion from bacterial versus mammalian cells yields a recombinant scFv with variable folding properties. AB - Escherichia coli (E. coli) is the most commonly used organism for expressing antibody fragments such as single chain antibody Fvs (scFvs). Previously, we have utilized E. coli to express well-folded scFvs for characterization and engineering purposes with the goal of using these engineered proteins as building blocks for generating IgG-like bispecific antibodies (BsAbs). In the study, described here, we observed a significant difference in the secondary structure of an scFv produced in E. coli and the same scFv expressed and secreted from chinese hamster ovary (CHO) cells as part of a BsAb. We devised a proteolytic procedure to separate the CHO-derived scFv from its antibody-fusion partner and compared its properties with those of the E. coli-derived scFv. In comparison to the CHO-derived scFv, the E. coli-derived scFv was found trapped in a misfolded, but monomeric state that was stable for months at 4 degrees C. The misfolded state bound antigen in a heterogeneous fashion that included non-specific binding, which made functional characterization challenging. This odd incidence of obtaining a misfolded scFv from bacteria suggests careful characterization of the folded properties of bacterially expressed scFvs is warranted if anomalous issues with antigen-binding or non-specificity occur during an engineering campaign. Additionally, our proteolytic methodology for obtaining significant levels of intact scFvs from highly expressed IgG-like antibody proteins serves as a robust method for producing scFvs in CHO without the use of designed cleavage motifs. PMID- 22230330 TI - Current status of establishing a venous line in CPA patients by Emergency Life Saving Technicians in the prehospital setting in Japan and a proposal for intraosseous infusion. AB - INTRODUCTION: It is important to have a venous line in cardiopulmonary arrest (CPA) patients as an emergency treatment measure in prehospital settings, but establishment of a peripheral venous line is difficult in such patients. This study aimed to investigate the current status of intravenous infusion (IVI) in CPA patients by Emergency Life-Saving Technicians (ELSTs) in Japan. We also considered alternative measures in case IVI was difficult or impossible. METHODS: We investigated a nationwide database between 1 January 2005 and 31 December 2008. From a total of 431,968 CPA cases, we calculated the IVI success rate and related parameters.The Bone Injection Gun (BIG) and simulator legs (adult, pediatric, and infant) were used by 100 ELSTs selected for the study to measure the time required and the success rate for intraosseous infusion (IOI). RESULTS: The number of CPA patients, IVI, adrenaline administration, and the IVI success rate in adult CPA patients increased every year. However, the IVI success rate in pediatric CPA patients did not increase. Although adrenaline administration elevated the ROSC rate, there was no improvement in the 1-month survival rate. The time required for IOI with BIG was not different among the leg models. The success rates of IOI with BIG were 93%, 94%, and 84% (p < 0.05 vs. adult and pediatric) in adult, pediatric, and infant models, respectively. CONCLUSIONS: The rate of success of IVI in adult CPA patients has been increased yearly in Japan. However, as establishing a peripheral venous line in pediatric patients (1-7 years old) by ELSTs is extremely difficult in prehospital settings, there was no increase in the IVI success rate in such patients. As the study findings indicated IOI with BIG was easy and rapid, it may be necessary to consider IOI with BIG as an alternative option in case IVI is difficult or impossible in adult and pediatric patients. PMID- 22230331 TI - A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. AB - Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone +/- linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone +/- linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrials.gov identifier: NCT00326287]. PMID- 22230332 TI - Intracellular concentrations of micafungin in different cellular compartments of the peripheral blood. AB - Whilst micafungin serum concentrations are well studied, little is known about its concentrations within cellular compartments of the peripheral blood. Hence, in this study blood samples were collected from patients receiving micafungin (n=26). These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. Intracellular concentrations within the obtained cells, i.e. peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs) and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Within PBMCs and PMNs, the intracellular micafungin concentration was significantly increased compared with the concentration in plasma (P<0.001). The intracellular concentration within RBCs did not significantly differ from the plasma concentration. Micafungin reaches high concentrations in human PBMCs and PMNs and is present in RBCs. In vitro data showed that intracellular uptake of micafungin by PBMCs depends on the albumin concentration of the surrounding medium, but only at non-physiological protein concentrations. PMID- 22230333 TI - Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. AB - This article reviews recent findings on the global epidemiology of healthcare acquired/associated (HA), community-acquired/associated (CA) and livestock associated (LA) meticillin-resistant Staphylococcus aureus (MRSA) and aims to reach a consensus regarding the harmonisation of typing methods for MRSA. MRSA rates continue to increase rapidly in many regions and there is a dynamic spread of strains across the globe. HA-MRSA is currently endemic in hospitals in most regions. CA-MRSA clones have been spreading rapidly in the community and also infiltrating healthcare in many regions worldwide. To date, LA-MRSA is only prevalent in certain high-risk groups of workers in direct contact with live animals. CA-MRSA and LA-MRSA have become a challenge for countries that have so far maintained low rates of MRSA. These evolutionary changes have resulted in MRSA continuing to be a major threat to public health. Continuous efforts to understand the changing epidemiology of S. aureus infection in humans and animals are therefore necessary, not only for appropriate antimicrobial treatment and effective infection control but also to monitor the evolution of the species. The group made several consensus decisions with regard to harmonisation of typing methods. A stratified, three-level organisation of testing laboratories was proposed: local; regional; and national. The functions of, and testing methodology used by, each laboratory were defined. The group consensus was to recommend spa and staphylococcal cassette chromosome mec (SCCmec) typing as the preferred methods. Both are informative in defining particular strain characteristics and utilise standardised nomenclatures, making them applicable globally. Effective communication between each of the different levels and between national centres was viewed as being crucial to inform and monitor the molecular epidemiology of MRSA at national and international levels. PMID- 22230334 TI - Comparative Activity of Carbapenem Testing (COMPACT) study in Germany. AB - The aim of this study was to determine the current susceptibility of hospital isolates of contemporary Gram-negative pathogens to the carbapenems doripenem, imipenem and meropenem. Between May and October 2008, seven centres in Germany were invited to collect and submit Pseudomonas aeruginosa, Enterobacteriaceae and other Gram-negative bacterial Intensive Care Unit (ICU)/non-ICU isolates from patients with complicated intra-abdominal infections (cIAIs), bloodstream infections (BSIs) or nosocomial pneumonia (NP). Susceptibility was determined at each centre by Etest. A central laboratory performed species confirmation as well as limited susceptibility and quality control testing. In total, 363 isolates were collected, comprising 46.0% Enterobacteriaceae, 45.2% P. aeruginosa, 4.7% Acinetobacter spp. and 4.1% other Gram-negatives. Most isolates (47.9%) were collected from NP, 32.8% were from cIAIs and 19.3% from BSIs; 57.3% were obtained from ICU patients. The MIC(90) values (minimum inhibitory concentration for 90% of the isolates) for doripenem, meropenem and imipenem were, respectively, 4, 16 and 32 mg/L against P. aeruginosa, 0.06, 0.06 and 0.5mg/L against Enterobacteriaceae and >= 64 mg/L for each carbapenem against other Gram-negative isolates. Using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 81.1%, 75.6% and 79.3% of P. aeruginosa were susceptible to doripenem, imipenem and meropenem, respectively. Against all pathogens combined, MIC(90) values for ICU versus non-ICU isolates, respectively, were 4 mg/L vs. 1mg/L for doripenem, 8 mg/L vs. 1mg/L for meropenem and >= 64 mg/L vs. 8 mg/L for imipenem. Doripenem showed comparable activity against P. aeruginosa from patients with BSIs, cIAIs or NP. Similar findings were observed for Enterobacteriaceae and other Gram-negatives, including Acinetobacter spp. Doripenem generally showed similar or slightly better activity than meropenem and better activity than imipenem against Gram-negative pathogens collected in Germany. PMID- 22230335 TI - Effect on risk of anencephaly of gene-nutrient interactions between methylenetetrahydrofolate reductase C677T polymorphism and maternal folate, vitamin B12 and homocysteine profile. AB - OBJECTIVE: To evaluate the effects on anencephaly risk of the interaction between the maternal profile of folate, vitamin B12 and homocysteine and the 677C->T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR). DESIGN: Case-control study paired (1:1) on maternity clinic, date of birth and state of residence. Cases of anencephaly were identified using the Registry of the Mexican Neural Tube Defect Epidemiological Surveillance System. Case and control mothers were selected from the same maternity departments. All mothers completed a structured questionnaire and blood samples were obtained to determine the MTHFR 677C->T polymorphism and biochemical profile. SETTING: Mexico, Puebla and Guerrero states, Mexico. SUBJECTS: A total of 151 mothers of cases and controls were enrolled from March 2000 to February 2001. We had complete information on biochemical profile and MTHFR C677T polymorphism for ninety-eight mothers of cases and ninety-one mothers of controls. RESULTS: The adjusted models show that the risk of anencephaly in mothers with 677TT genotype was reduced by 18 % (OR = 0.82; 95 % CI 0.72, 0.94) for each 1 ng/ml increment in serum folate. In terms of tertiles, mothers with 677TT genotype with serum folate levels in the upper tertile (>14.1 ng/ml) had a 95 % lower risk to have a child with anencephaly than mothers with serum folate levels in the first and second tertiles (P trend = 0.012). CONCLUSIONS: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C->T polymorphism and folate status. We observed a protective effect on anencephaly risk only in mothers with 677TT genotype as serum folate levels increased. PMID- 22230336 TI - Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. AB - We have analyzed transcriptomic, proteomic and metabolomic profiles of hepatoma cells cultivated inside a microfluidic biochip with or without acetaminophen (APAP). Without APAP, the results show an adaptive cellular response to the microfluidic environment, leading to the induction of anti-oxidative stress and cytoprotective pathways. In presence of APAP, calcium homeostasis perturbation, lipid peroxidation and cell death are observed. These effects can be attributed to APAP metabolism into its highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). That toxicity pathway was confirmed by the detection of GSH-APAP, the large production of 2-hydroxybutyrate and 3-hydroxybutyrate, and methionine, cystine, and histidine consumption in the treated biochips. Those metabolites have been reported as specific biomarkers of hepatotoxicity and glutathione depletion in the literature. In addition, the integration of the metabolomic, transcriptomic and proteomic collected profiles allowed a more complete reconstruction of the APAP injury pathways. To our knowledge, this work is the first example of a global integration of microfluidic biochip data in toxicity assessment. Our results demonstrate the potential of that new approach to predictive toxicology. PMID- 22230338 TI - The effect of DDT and its metabolite (DDE) on prostaglandin secretion from epithelial cells and on contractions of the smooth muscle of the bovine oviduct in vitro. AB - The insecticide DDT and its metabolite (DDE), due to their lipolytic nature and resistance to biodegradation, are accumulated in the living tissues. In cows, DDT and DDE were found to affect prostaglandin (PG) secretion from the endometrium and contractions of the myometrium. In this study, the impact of both xenobiotics (0.1, 1, 10 or 100ng/ml) on the function of epithelial cells and muscle strips of bovine oviducts from 1 to 5day of the oestrous cycle was examined. Therefore the concentration of PGE2 and PGFM (a metabolite of PGF2alpha) in culture media, mRNA expression of genes involved in PGs synthesis in epithelial cells and the force and amplitude of strips contractions were measured after 2 and 24 or 48h of incubation. Neither DDT nor DDE affected the viability of cells after 48h (P>0.05). Both DDT and DDE increased the concentrations of PGFM in culture medium and secretion of PGE2 after only 2h of cell culture (P<0.05). Similar effects were seen for the influence of DDE on amount of PGFM after 48h, while DDT decreased secretion of PGE2 (P<0.05). DDT after 2h increased (P<0.05) mRNA expression of PGF2alpha synthase (PGFS), while both xenobiotics decreased (P<0.05) mRNA expression of cyclooxygenase-2 (COX-2) after 24h. DTT also increased the force of isthmus contractions after 2h, as did both xenobiotics after 48h (P<0.05). Moreover, after 2 and 48h, DDE stimulated the amplitude of contractions of the isthmus as well as the ampulla, (P<0.05). The effect of both compounds on oviduct contractions was diminished by indomethacin, which blocks PG synthesis. We conclude that oviductal secretion of prostaglandins is affected, by DDT and DDE. The influence of these xenobiotics on PGF2alpha and PGE2 secretion and ratio may be part of the mechanism by which both DDT and its metabolite disturb the contractions of oviductal muscle. PMID- 22230337 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment alters eicosanoid levels in several organs of the mouse in an aryl hydrocarbon receptor-dependent fashion. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) adversely affects many mammalian organs and tissues. These effects are mediated by the aryl hydrocarbon receptor (AHR). CYP1A1, CYP1A2 and CYP1B1 are upregulated by the liganded AHR. These (and other) cytochromes P450 can metabolize arachidonic acid into a variety of bioactive eicosanoids. Towards investigating a potential role of eicosanoids in TCDD toxicity, arachidonic acid, two other unsaturated long-chain fatty acids, and up to twenty-five eicosanoids were measured in five organs/tissues of male and female wild-type and Ahr null mice treated or untreated with TCDD. TCDD generally increased the levels of the four dihydroxyeicosatrienoic acids (DHETs) and (where measured) 5,6-epoxyeicosatrienoic acid and 18-, 19- and 20 hydroxyeicosatrienoic acids (HETEs) in the serum, liver, spleen and lungs, but not the heart, of both sexes, and increased the levels in the serum, liver and spleen of several metabolites that are usually considered products of lipoxygenase activity, but which may also be generated by cytochromes P450. TCDD also increased the levels of the esterified forms of these eicosanoids in the liver in parallel with the corresponding free forms. The levels of prostanoids were generally not affected by TCDD. The above changes did not occur in Ahr null mice, and are therefore mediated by the AHR. TCDD increased the mRNA levels of Cyp1a1, Cyp1a2, Cyp1b1 and the Pla2g12a form of phospholipase A(2) to varying degrees in the different organs, and these increases correlated with some but not all the changes in eicosanoids levels in the organs, suggesting that other enzymes may also be involved. PMID- 22230339 TI - Limiting the caesarean section rate in low risk pregnancies is key to lowering the trend of increased abdominal deliveries: an observational study. AB - BACKGROUND: As the rate of Caesarean sections (CS) continues to rise in Western countries, it is important to analyze the reasons for this trend and to unravel the underlying motives to perform CS. This research aims to assess the incidence and trend of CS in a population-based birth register in order to identify patient groups with an increasing risk for CS. METHODS: Data from the Flemish birth register 'Study Centre for Perinatal Epidemiology' (SPE) were used for this historic control comparison. Caesarean sections (CS) from the year 2000 (N = 10540) were compared with those from the year 2008 (N = 14016). By means of the Robson classification, births by Caesarean section were ordered in 10 groups according to mother - and delivery characteristics. RESULTS: Over a period of eight years, the CS rise is most prominent in women with previous sections and in nulliparous women with a term cephalic in spontaneous labor. The proportion of inductions of labor decreases in favor of elective CS, while the ongoing inductions of labor more often end in non-elective CS. CONCLUSIONS: In order to turn back the current CS trend, we should focus on low-risk primiparae. Avoiding unnecessary abdominal deliveries in this group will also have a long-term effect, in that the number of repeat CS will be reduced in the future. For the purpose of self-evaluation, peer discussion on the necessity of CS, as well as accurate registration of the main indication for CS are recommended. PMID- 22230340 TI - Distribution of enteroviruses in hospitalized children with hand, foot and mouth disease and relationship between pathogens and nervous system complications. AB - BACKGROUND: To explore the relationship between enteroviruses and hospitalized children with hand, foot and mouth disease (HFMD) complicated with nervous system disease. 234 hospitalized HFMD patients treated in Shengjing Hospital, Liaoning Province were analyzed retrospectively. Based on the presence and severity of nervous system disease, the patients were grouped as follows: general patients, severely ill patients, critically ill patients and fatal patients. Based on the detected pathogen, the patients were grouped as follows: Enterovirus 71 (EV71) infection, coxsackie A16 (CA16) infection and other enterovirus (OE) infection. RESULTS: Of the 423 hospitalized patients, most were admitted in July 2010(129/423, 30.5%). Enteroviruses were detected in 177(41.8%). 272/423 patients were male (64.3%), and fatal patients had the greatest proportion of male patients (p < 0.05). EV71 infection was found in 89/423 patients (21%). CA16 infection was detected in 8/423 patients (16.1%). Compared to group CA16, patients in group EV71 were hospitalized earlier, and the duration of hospitalization was longer (p < 0.05). Of the 92 patients with nervous system damage, 65 were infected with EV71 and 19 were infected with CA16. Among these CA16 infected patients, 2 had brainstem encephalitis and 1 had AFP. There were more patients with nervous system dysfunction in group EV71 than in groups CA16 or OE (p < 0.05). The 5 fatalities all occurred in group EV71 patients (p < 0.05). Infection with EV71 was most likely to cause neurogenic pulmonary edema (p < 0.05). Patients in group EV71 had a higher rate of suffering from coma and limb movement disorder than patients in groups CA16 or OE (p < 0.05). CONCLUSION: The disease progresses faster in EV71-infected HFMD patients. These patients are more likely to suffer nervous system damage, neurogenic pulmonary edema, severe sequelae or death. CA16 and other enteroviruses can also cause HFMD with severe nervous system complications. PMID- 22230342 TI - Altering the immune response with lipid-based nanoparticles. AB - Lipid-based nanoparticles (LNPs) hold great promise as delivery vectors in the treatment of cancer, inflammation, and infections and are already used in clinical practice. Numerous strategies based on LNPs are being developed to carry drugs into specific target sites. The common denominator for all of these LNPs based platforms is to improve the payloads' pharmacokinetics, biodistribution, stability and therapeutic benefit, and to reduce to minimal adverse effects. In addition, the delivery system must be biocompatible and non-toxic and avoid undesirable interactions with the immune system. In order to achieve optimal benefits from these delivery strategies, interactions with the immune system must be thoroughly investigated. This report will center on the interactions of LNPs with different subsets of leukocytes and will detail representative examples of suppression or activation of the immune system by these carriers. By understanding the interactions of LNPs with the innate and the adaptive arms of the immune system it might be possible to attain improved therapeutic benefits and to avoid immune toxicity. PMID- 22230343 TI - Demonstrating the importance of polymer-conjugate conformation in solution on its therapeutic output: Diethylstilbestrol (DES)-polyacetals as prostate cancer treatment. AB - The design of improved polymeric carriers to be used in the next generation of polymer therapeutics is an ongoing challenge. Biodegradable systems present potential advantages regarding safety benefit apart from the possibility to use higher molecular weight (Mw) carriers allowing PK optimization, by exploiting the enhanced permeability and retention (EPR)-mediated tumor targeting. Within this context, we previously designed pH-responsive polyacetalic systems, tert polymers, where a drug with the adequate diol-functionality was incorporated within the polymer mainchain. The synthetic, non-steroidal estrogen, diethylstilboestrol (DES) clinically used for the treatment of advanced prostate cancer was chosen as drug. In order to improve the properties of this tert polymer, novel polyacetalic systems as block-co-polymers, with more defined structure have been obtained. This second generation polyacetals allowed higher drug capacity than the tert-polymer, a biphasic DES release profile at acidic pH and due to its controlled amphiphilic character readily formed micelle-like structures in solution. These features result in an enhancement of conjugate therapeutic value in selected prostate cancer cell models. Exhaustive physico chemical characterization focusing on nanoconjugate solution behavior and using advanced techniques, such as, pulsed-gradient spin-echo NMR (PGSE-NMR) and small angle neutron scattering (SANS), has been carried out in order to demonstrate this hypothesis. Clear evidence of significantly different conformation in solution has been obtained for both polyacetals. These results demonstrate that an adequate control on molecular or supramolecular conformation in solution with polymer therapeutics is crucial in order to achieve the desired therapeutic output. PMID- 22230341 TI - Combination radiofrequency (RF) ablation and IV liposomal heat shock protein suppression: reduced tumor growth and increased animal endpoint survival in a small animal tumor model. AB - BACKGROUND: To investigate the effect of IV liposomal quercetin (a known down regulator of heat shock proteins) alone and with liposomal doxorubicin on tumor growth and end-point survival when combined with radiofrequency (RF) tumor ablation in a rat tumor model. METHODS: Solitary subcutaneous R3230 mammary adenocarcinoma tumors (1.3-1.5 cm) were implanted in 48 female Fischer rats. Initially, 32 tumors (n=8, each group) were randomized into four experimental groups: (a) conventional monopolar RF alone (70 degrees C for 5 min), (b) IV liposomal quercetin alone (1 mg/kg), (c) IV liposomal quercetin followed 24hr later with RF, and (d) no treatment. Next, 16 additional tumors were randomized into two groups (n=8, each) that received a combined RF and liposomal doxorubicin (15 min post-RF, 8 mg/kg) either with or without liposomal quercetin. Kaplan Meier survival analysis was performed using a tumor diameter of 3.0 cm as the defined survival endpoint. RESULTS: Differences in endpoint survival and tumor doubling time among the groups were highly significant (P<0.001). Endpoint survivals were 12.5+/-2.2 days for the control group, 16.6+/-2.9 days for tumors treated with RF alone, 15.5+/-2.1 days for tumors treated with liposomal quercetin alone, and 22.0+/-3.9 days with combined RF and quercetin. Additionally, combination quercetin/RF/doxorubicin therapy resulted in the longest survival (48.3+/-20.4 days), followed by RF/doxorubicin (29.9+/-3.8 days). CONCLUSIONS: IV liposomal quercetin in combination with RF ablation reduces tumor growth rates and improves animal endpoint survival. Further increases in endpoint survival can be seen by adding an additional anti-tumor adjuvant agent liposomal doxorubicin. This suggests that targeting several post ablation processes with multi-drug nanotherapies can increase overall ablation efficacy. PMID- 22230344 TI - The Swiss Early Psychosis Project SWEPP: a national network. AB - AIM: The study aims to describe the activities of the Swiss Early Psychosis Project (SWEPP) which was founded in 1999 as a national network to further and disseminate knowledge on early psychosis (EP) and to enhance collaboration between healthcare groups. METHODS: The present paper is a detailed account of the initiation and the development of the Swiss network. We describe all activities such as the several educational campaigns that were addressed to primary and secondary care groups since the early days. We also provide an overview of the current status of EP services throughout the country. RESULTS: Today, most regions in Switzerland provide specialized EP inpatient and/or outpatient services with a clinical or combined clinical research approach that targets at-risk and/or first-episode populations. Some more recently initiated EP services have been launched as collaborative models between several local or regional psychiatric services. CONCLUSIONS: The increasing number of EP services and experts in Switzerland may mirror the catalyzing contribution of the Swiss Early Psychosis Project in this important field of health care. The country's small size and the increasing density of specialized services provide excellent bases for larger-scale networking activities in the future, both in clinical and research areas. PMID- 22230345 TI - Balancing harms and benefits of service mammography screening programs: a cohort study. AB - INTRODUCTION: The use of screening mammography is still under debate within the medical community. The aim of this study is to define a balance sheet of benefits (breast cancer mortality reduction) and harms (overdiagnosis) for mammography screening programs. METHODS: We compared breast cancer incidence and mortality in two cohorts of women, defined as 'attenders' or 'non-attenders' on the basis of the individual attitudes towards screening, who were invited to the first round of the Florentine screening program. The effects of screening exposure on breast cancer incidence and mortality were evaluated by fitting Poisson regression models adjusted for age at entry, marital status and deprivation index. We performed a sensitivity analysis excluding 34 women not responding to the invitation with a breast cancer diagnosis in the following six months. RESULTS: In total, we included 51,096 women aged 50 to 69 years invited at the first screening round (1991 to 1993) and followed-up for breast cancer incidence and mortality until 31 December 2007 and 31 December 2008, respectively The estimate of mortality reduction varies from 45% among 50 to 59 year-old women up to 51% among 60 to 69 year-old women. The estimate of overdiagnosis, according to the cumulative-incidence method, is an additional 10% of all breast cancer cases among 60 to 69 year-old women screened. CONCLUSIONS: Comparing the breast cancer mortality and breast cancer incidence between attenders and non-attenders, we have determined that the overall cost to save one life corresponds to no more than one over-diagnosed tumor (from 0.6 to 1 depending on the selection criteria of the cohort), even if a residual self-selection bias cannot be excluded. PMID- 22230347 TI - If you stock it, will they buy it? Healthy food availability and customer purchasing behaviour within corner stores in Hartford, CT, USA. AB - OBJECTIVE: Literature on food environments has expanded rapidly, yet most research focuses on stores and community characteristics without integrating customer-level data. The present study combines customer shopping behaviour with store food inventory data. DESIGN: Face-to-face interviews were conducted with customers shopping in corner stores to measure food shopping behaviour, household food security and demographics. Store inventories were conducted to measure availability of healthy food in corner stores. Multilevel logistic regression models estimated the probability of customers purchasing a food item given the availability of that item in the store. SETTING: Nineteen corner stores in Hartford, CT, USA, average size 669 ft(2) (62.15 m(2)). SUBJECTS: Sample of 372 customers. RESULTS: The majority of customers were Black or Hispanic (54 % and 40 %, respectively) and 61 % experienced food insecurity. For each additional type of fruits or vegetables available in the store, the estimated odds of a customer purchasing fruits increased by 12 % (P = 0.03) and the odds for purchasing vegetables increased by 15 % (P = 0.01). Customers receiving the Supplemental Nutrition Assistance Program (SNAP) were 1.7 times as likely to purchase fruit as those not receiving SNAP (P = 0.04). Greater availability of reduced-fat milk was not associated with increased likelihood of customers purchasing reduced-fat milk. CONCLUSIONS: There is a positive association between fruit and vegetable variety and the probability that a customer purchases fruits and vegetables. Increasing the selection of produce in corner stores may increase their consumption by food-insecure and low-income residents at risk for health disparities. These findings have implications for future store interventions and food policies. PMID- 22230349 TI - Predicting the effect of steroids on membrane biophysical properties based on the molecular structure. AB - The relationship between sterol structure and the resulting effects on membrane physical properties is still unclear, owing to the conflicting results found in the current literature. This study presents a multivariate analysis describing the physical properties of 83 steroid membranes. This first structure-activity analysis supports the generally accepted physical effects of sterols in lipid bilayers. The sterol chemical substituents and the sterol/phospholipid membrane physical properties were encoded by defining binary variables for the presence/absence of those chemical substituents in the polycyclic ring system and physical parameters obtained from phospholipid mixtures containing those sterols. Utilizing Principal Coordinates Analysis, the steroid population was grouped into five well-defined clusters according to their chemical structures. An examination of the membrane activity of each sterol structural cluster revealed that a hydroxyl group at C3 and an 8-10 carbon isoalkyl side-chain at C17 are mainly present in membrane active sterols having rigidifying, molecular ordering/condensing effects and/or a raft promoting ability. In contrast, sterol chemical structures containing a keto group at C3, a C4-C5-double bond, and polar groups or a short alkyl side-chain at C17 (3 to 7 atoms) are mostly found in sterols having opposite effects. Using combined multivariate approaches, it was concluded that the most important structural determinants influencing the physical properties of sterol-containing mixtures were the presence of an 8-10 carbon C17 isoalkyl side-chain, followed by a hydroxyl group at C3 and a C5-C6 double bond. Finally, a simple Logistic Regression model predicting the dependence of membrane activity on sterol chemical structure is proposed. PMID- 22230348 TI - S4(13)-PV cell-penetrating peptide induces physical and morphological changes in membrane-mimetic lipid systems and cell membranes: implications for cell internalization. AB - The present work aims to gain insights into the role of peptide-lipid interactions in the mechanisms of cellular internalization and endosomal escape of the S4(13)-PV cell-penetrating peptide, which has been successfully used in our laboratory as a nucleic acid delivery system. A S4(13)-PV analogue, S4(13) PVscr, displaying a scrambled amino acid sequence, deficient cell internalization and drug delivery inability, was used in this study for comparative purposes. Differential scanning calorimetry, fluorescence polarization and X-ray diffraction at small and wide angles techniques showed that both peptides interacted with anionic membranes composed of phosphatidylglycerol or a mixture of this lipid with phosphatidylethanolamine, increasing the lipid order, shifting the phase transition to higher temperatures and raising the correlation length between the bilayers. However, S4(13)-PVscr, in contrast to the wild-type peptide, did not promote lipid domain segregation and induced the formation of an inverted hexagonal lipid phase instead of a cubic phase in the lipid systems assayed. Electron microscopy showed that, as opposed to S4(13)-PVscr, the wild type peptide induced the formation of a non-lamellar organization in membranes of HeLa cells. We concluded that lateral phase separation and destabilization of membrane lamellar structure without compromising membrane integrity are on the basis of the lipid-driven and receptor-independent mechanism of cell entry of S4(13)-PV peptide. Overall, our results can contribute to a better understanding of the role of peptide-lipid interactions in the mechanisms of cell-penetrating peptide membrane translocation, helping in the future design of more efficient cell-penetrating peptide-based drug delivery systems. PMID- 22230350 TI - A calcium-permeable non-selective cation channel in the thick ascending limb apical membrane of the mouse kidney. AB - Non-selective cation channels have been described in the basolateral membrane of the renal tubule, but little is known about functional channels on the apical side. Apical membranes of microdissected fragments of mouse cortical thick ascending limbs were searched for ion channels using the cell-free configuration of the patch-clamp technique. A cation channel with a linear current-voltage relationship (19pS) that was permeable both to monovalent cations [P(NH4)(1.7)>P(Na) (1.0)=P(K) (1.0)] and to Ca(2+) (P(Ca)/P(Na)~0.3) was detected. Unlike the basolateral TRPM4 Ca(2+)-impermeable non-selective cation channel, this non-selective cation channel was insensitive to internal Ca(2+), pH and ATP. The channel was already active after patch excision, and its activity increased after reduced pressure was applied via the pipette. External gadolinium (10(-5)M) decreased the channel-open probability by 70% in outside-out patches, whereas external amiloride (10(-4)M) had no effect. Internal flufenamic acid (10( 4)M) inhibited the channel in inside-out patches. Its properties suggest that the current might be supported by the TRPM7 protein that is expressed in the loop of Henle. The conduction properties of the channel suggest that it could be involved in Ca(2+) signaling. PMID- 22230352 TI - Histopathological changes induced by Hemiscorpius lepturus scorpion venom in mice. AB - Envenomation by Hemiscorpius lepturus (H. lepturus) is associated with local necrosis, followed by systemic manifestations. In this work the LD50 of H. lepturus venom were determined by subcutaneous (SC) injection in white Balb/c mice (5 mg/kg). Histopathological alterations in organs such as kidney, heart, liver, lungs, stomach and intestine were determined in 3, 6, 12 and 24 h following experimental (SC) envenoming injection of one LD 50 of the venom in Balb/c mice. Histological studies showed degenerative changes in the kidney with disorganized glomeruli and necrotic tubular in 3 h and reached to its climax in 6 h. Myocardium showed massive myocytolysis with interstitial necrosis in 3 h and reached to its peak after 6 h past envenoming. Bowels showed edema of lamina propria and slight villous necrosis. The enzymatic activities of creatine kinase (CK) and lactate dehydrogenase (LDH) were significantly increased in the serum in 9 h. No necrotic lesion observed in lungs and liver. The results indicate that the venom of H. lepturus is a highly cytotoxic, and induces massive tissue damages in specific organs, starting from the heart and kidney as the first target in 3 h and ends to the bowels in 6 h post envenomation. PMID- 22230351 TI - Novel histone-derived antimicrobial peptides use different antimicrobial mechanisms. AB - The increase in multidrug resistant bacteria has sparked an interest in the development of novel antibiotics. Antimicrobial peptides that operate by crossing the cell membrane may also have the potential to deliver drugs to intracellular targets. Buforin 2 (BF2) is an antimicrobial peptide that shares sequence identity with a fragment of histone subunit H2A and whose bactericidal mechanism depends on membrane translocation and DNA binding. Previously, novel histone derived antimicrobial peptides (HDAPs) were designed based on properties of BF2, and DesHDAP1 and DesHDAP3 showed significant antibacterial activity. In this study, their DNA binding, permeabilization, and translocation abilities were assessed independently and compared to antibacterial activity to determine whether they share a mechanism with BF2. To investigate the importance of proline in determining the peptides' mechanisms of action, proline to alanine mutants of the novel peptides were generated. DesHDAP1, which shows significant similarities to BF2 in terms of secondary structure, translocates effectively across lipid vesicle and bacterial membranes, while the DesHDAP1 proline mutant shows reduced translocation abilities and antimicrobial potency. In contrast, both DesHDAP3 and its proline mutant translocate poorly, though the DesHDAP3 proline mutant is more potent. Our findings suggest that a proline hinge can promote membrane translocation in some peptides, but that the extent of its effect on permeabilization depends on the peptide's amphipathic properties. Our results also highlight the different antimicrobial mechanisms exhibited by histone derived peptides and suggest that histones may serve as a source of novel antimicrobial peptides with varied properties. PMID- 22230353 TI - Influence of carbohydrate supplementation on skill performance during a soccer match simulation. AB - OBJECTIVES: This study investigated the influence of carbohydrate supplementation on skill performance throughout exercise that replicates soccer match-play. DESIGN: Experimentation was conducted in a randomised, double-blind and cross over study design. METHODS: After familiarization, 15 professional academy soccer players completed a soccer match simulation incorporating passing, dribbling and shooting on two separate occasions. Participants received a 6% carbohydrate electrolyte solution (CHO) or electrolyte solution (PL). Precision, success rate, ball speed and an overall index (speed-precision-success; SPS) were determined for all skills. Blood samples were taken at rest, immediately before exercise, every 15 min during exercise (first half: 15, 30 and 45 min; second half: 60, 75 and 90 min), and 10 min into the half time (half-time). RESULTS: Carbohydrate supplementation influenced shooting (time*treatment interaction: p<0.05), where CHO attenuated the decline in shot speed and SPS index. Supplementation did not affect passing or dribbling. Blood glucose responses to exercise were influenced by supplementation (time*treatment interaction: p<0.05), where concentrations were higher at 45 min and during half-time in CHO compared with PL. Blood glucose concentrations reduced by 30+/-1% between half-time and 60 min in CHO. CONCLUSIONS: Carbohydrate supplementation attenuated decrements in shooting performance during simulated soccer match-play; however, further research is warranted to optimise carbohydrate supplementation regimes for high-intensity intermittent sports. PMID- 22230354 TI - The birth of convulsive therapy revisited: a reappraisal of Laszlo Meduna's first cohort of patients. AB - BACKGROUND: The introduction of convulsive therapy (COT) was undoubtedly one of the milestones in the history of psychiatry. Its originator, Laszlo Meduna, has become one of the founding fathers of biological psychiatry. METHODS: In his first major publication on COT, Meduna described the short-term treatment outcome of the first 26 schizophrenia patients who underwent camphor- or cardiazol induced COT; 10 improved significantly, 3 appeared slightly improved, and 13 were unimproved. The original medical notes of 23 of the 26 patients were recently recovered and the patients re-diagnosed by the authors employing ICD-10 criteria. RESULTS: The diagnosis of schizophrenia was confirmed in 15 cases (all but two of them involving prominent catatonic symptomatology), while 2 cases met diagnostic criteria for schizoaffective disorder, 3 for Bipolar Affective Disorder (BAD) with psychotic features, 1 for psychotic depression, and 1 for Acute and Transient Psychotic Disorder (ATPD). In a final case, the most probable diagnosis was schizophrenia. Scrutiny of the notes revealed that 4 schizophrenia patients evidenced slight improvement on COT and in one case the improvement was only transient. A limitation of this study is that the quality of the original files varied considerably and the re-evaluation was done retrospectively. CONCLUSIONS: A very broad concept of schizophrenia in the 1930s explains the discrepancy between the original and the revised results. In line with the current views on the effectiveness of electroconvulsive therapy, catatonic symptoms, but not the core schizophrenic process, showed some improvement while all ATPD, BAD and depressed patients responded to COT. PMID- 22230355 TI - Malaria control in Bhutan: case study of a country embarking on elimination. AB - BACKGROUND: Bhutan has achieved a major reduction in malaria incidence amid multiple challenges. This case study seeks to characterize the Bhutan malaria control programme over the last 10 years. METHODS: A review of the malaria epidemiology, control strategies, and elimination strategies employed in Bhutan was carried out through a literature review of peer-reviewed and grey national and international literature with the addition of reviewing the surveillance and vector control records of the Bhutan Vector-Borne Disease Control Programme (VDCP). Data triangulation was used to identify trends in epidemiology and key strategies and interventions through analysis of the VDCP surveillance and programme records and the literature review. Enabling and challenging factors were identified through analysis of socio-economic and health indicators, corroborated through a review of national and international reports and peer review articles. FINDINGS: Confirmed malaria cases in Bhutan declined by 98.7% from 1994 to 2010. The majority of indigenous cases were due to Plasmodium vivax (59.9%) and adult males are most at-risk of malaria. Imported cases, or those in foreign nationals, varied over the years, reaching 21.8% of all confirmed cases in 2006. Strategies implemented by the VDCP are likely to be related to the decline in cases over the last 10 years. Access to malaria diagnosis in treatment was expanded throughout the country and evidence-based case management, including the introduction of artemisinin-based combination therapy (ACT) for P. falciparum, increasing coverage of high risk areas with Indoor Residual Spraying, insecticide-treated bed nets, and long-lasting insecticidal nets are likely to have contributed to the decline alongside enabling factors such as economic development and increasing access to health services. CONCLUSION: Bhutan has made significant strides towards elimination and has adopted a goal of national elimination. A major challenge in the future will be prevention and management of imported malaria infections from neighbouring Indian states. Bhutan plans to implement screening at border points to prevent importation of malaria and to targeted prevention and surveillance efforts towards at-risk Bhutanese and migrant workers in construction sites. PMID- 22230356 TI - Investigating the interaction between schizotypy, divergent thinking and cannabis use. AB - Cannabis acutely increases schizotypy and chronic use is associated with elevated rates of psychosis. Creative individuals have higher levels of schizotypy, however links between cannabis use, schizotypy and creativity have not been investigated. We investigated the effects of cannabis smoked naturalistically on schizotypy and divergent thinking, a measure of creativity. One hundred and sixty cannabis users were tested on 1 day when sober and another day when intoxicated with cannabis. State and trait measures of both schizotypy and creativity were administered. Quartile splits compared those lowest (n=47) and highest (n=43) in trait creativity. Cannabis increased verbal fluency in low creatives to the same level as that of high creatives. Cannabis increased state psychosis-like symptoms in both groups and the high creativity group were significantly higher in trait schizotypy, but this does not appear to be linked to the verbal fluency change. Acute cannabis use increases divergent thinking as indexed by verbal fluency in low creatives. PMID- 22230357 TI - Non-visual consciousness and visual images in blindsight. AB - In a recent response paper to Brogaard (2011a), Morten Overgaard and Thor Grunbaum argue that my case for the claim that blindsight subjects are not visually conscious of the stimuli they correctly identify rests on a mistaken necessary criterion for determining whether a conscious experience is visual or non-visual. Here I elaborate on the earlier argument while conceding that the question of whether blindsight subjects are visually conscious of the visual stimuli they correctly identify largely is an empirical question. I conclude by sketching a method for testing whether blindsight subjects have visual consciousness of stimuli presented to them in their blind field. PMID- 22230358 TI - Preparation, characterization and adsorption behavior of tannin-modified poly(glycidylmethacrylate)-grafted zirconium oxide-densified cellulose for the selective separation of bovine serum albumin. AB - Bovine serum albumin (BSA) is one of the major constituents of blood plasma and its recovery is a significantly useful subject for biomedical applications. In this study, a novel adsorbent, tannin-modified poly(glycidylmethacrylate)-grafted zirconium oxide-densified cellulose (TMPGZDC) was synthesized by graft copolymerization reaction of glycidylmethacrylate onto zirconium oxide-densified cellulose (ZDC) in the presence of N,N'-methylenebisacrylamide as cross-linker followed by tannin immobilization. The adsorbent was characterized using TG, XRD, SEM/EDS, FTIR and fluorescence analyses. The efficiency of the TMPGZDC to adsorb BSA from aqueous solutions was studied at different optimized conditions. The optimum pH for maximum adsorption was found to be 4.8 with the adsorption percentage of 97.8% for an initial concentration of 100 mg/L. Equilibrium was achieved within 30 min. The kinetic data were found to follow pseudo-first-order model which is based on solid capacity. The well agreement of equilibrium data with Langmuir isotherm and Redlich-Peterson isotherm models confirms the monolayer coverage of BSA onto TMPGZDC surface and the maximum adsorption capacity at 30 degrees C was found to be 93.11 mg/g. Thermodynamic study revealed an exothermic adsorption process. TMPGZDC was found to be efficient in the selective adsorption of proteins. Spent adsorbent was effectively regenerated [correction of degenerated] with 0.1 M NaCl. The present investigation shows that TMPGZDC is a promising adsorbent for the recovery of BSA from aqueous solutions and protein mixtures. PMID- 22230359 TI - Patterned poly(lactic acid) films support growth and spontaneous multilineage gene expression of adipose-derived stem cells. AB - Conventional culture surfaces do not provide optimal environmental cues for expansion or differentiation of adult stem cells. Aiming to increase the efficiency of the in vitro culture conditions, biocompatible and biodegradable biomaterials such as poly(lactic acid) (PLA) have been proposed to engineer the stem cell microenvironment. In this study, we explored the feasibility of using PLA substrates to control the responses of adipose-derived stem cells (ASCs). The substrates consisted of flat and patterned PLA films fabricated by casting a chloroform-PLA solution on a glass surface. Patterning was achieved through the condensation of nano-sized water droplets during chloroform evaporation, which resulted in films displaying irregularly distributed circular indentations with a mean diameter of 248+/-65 nm. Both types of PLA substrates were assessed for protein adsorption using fibronectin and in vitro cell culturing. Tissue-culture polystyrene (TCPS) plates were used as control surfaces. The experiments demonstrated that the patterned PLA substrates had a significantly higher fibronectin adsorption capacity when compared with the flat counterparts. For the entire duration of the culture period, there was no significant difference in cell growth rate on the PLA surfaces with respect to TCPS despite signs of reduced adhesion. In addition, the semi-quantitative real-time RT-PCR analysis of a set of 14 lineage-specific genes revealed that the PLA-related transcriptional activity significantly surpassed that of TCPS. Remarkably, when assessing the effect of patterning, the patterned films proved superior regarding the activation of genes involved in the skeletal myogenic, cardiomyogenic, chondrogenic, and adipogenic pathways. Taken together, our data provide evidence that the surface patterning can exert such an influence on the stem cell microenvironment that the differentiation process can be effectively modulated. Consequently, the patterned PLA surfaces could potentially be used as a platform for localized delivery and engraftment of stem cells. PMID- 22230360 TI - Human Mycobacterium bovis infection in Buenos Aires: epidemiology, microbiology and clinical presentation. AB - We performed a retrospective study of clinical, epidemiological and microbiological characteristics of patients with confirmed Mycobacterium bovis infection treated at Francisco Muniz Hospital, Buenos Aires, Argentina, between 1996 and 2008. A total of 39 patients were included, accounting for 0.4% of tuberculosis cases in our hospital. Of these, 93% had at least one risk factor for M. bovis; the most frequent was occupational exposure (65%), followed by history of living in a rural area (31%) and consumption of unpasteurised milk (4%). Pulmonary disease was the most frequent clinical presentation. Rifampicin resistance and multidrug resistance were seen in two patients, both of whom had human immunodeficiency virus infection. PMID- 22230362 TI - The contribution of the two hemispheres to lexical decision in different languages. AB - BACKGROUND: Both reading words and text in Arabic is slower than in other languages, even among skilled native Arabic speakers Previously we have shown that the right hemisphere (RH) had difficulty in matching Arabic letters, and suggested that it cannot contribute to word recognition in Arabic. In this study we tested this finding directly. METHOD: We used the Divided Visual Field (DVF) lexical decision (LD) paradigm to assess hemispheric function during reading. The experiment had two conditions (unilateral and bilateral). In the unilateral condition, the target stimulus was presented unilaterally to the left or the right visual field. In the bilateral condition two stimuli were presented simultaneously, and participants were cued as to which one was the target. Three groups of participants were tested: Arabic speakers, Hebrew speakers, and English speakers. Each group was tested in their native language. RESULTS: For Hebrew and English speakers, performance in both visual fields was significantly better in the unilateral than in the bilateral condition. For Arabic speakers, performance in the right visual field (RVF, where stimuli are presented directly to the left hemisphere) did not change in the two conditions. Performance in the LVF (when stimuli are presented directly to the right hemisphere) was at chance level in the bilateral condition, but not in the unilateral condition. CONCLUSION: We interpret these data as supporting the hypothesis that in English and Hebrew, both hemispheres are involved in LD, whereas in Arabic, the right hemisphere is not involved in word recognition. PMID- 22230361 TI - Detection of group A Streptococcus in tonsils from pediatric patients reveals high rate of asymptomatic streptococcal carriage. AB - BACKGROUND: Group A Streptococcus (GAS) causes acute tonsillopharyngitis in children, and approximately 20% of this population are chronic carriers of GAS. Antibacterial therapy has previously been shown to be insufficient at clearing GAS carriage. Bacterial biofilms are a surface-attached bacterial community that is encased in a matrix of extracellular polymeric substances. Biofilms have been shown to provide a protective niche against the immune response and antibiotic treatments, and are often associated with recurrent or chronic bacterial infections. The objective of this study was to test the hypothesis that GAS is present within tonsil tissue at the time of tonsillectomy. METHODS: Blinded immunofluorescent and histological methods were employed to evaluate palatine tonsils from children undergoing routine tonsillectomy for adenotonsillar hypertrophy or recurrent GAS tonsillopharyngitis. RESULTS: Immunofluorescence analysis using anti-GAS antibody was positive in 11/30 (37%) children who had tonsillectomy for adenotonsillar hypertrophy and in 10/30 (33%) children who had tonsillectomy for recurrent GAS pharyngitis. Fluorescent microscopy with anti-GAS and anti-cytokeratin 8 & 18 antibodies revealed GAS was localized to the tonsillar reticulated crypts. Scanning electron microscopy identified 3 dimensional communities of cocci similar in size and morphology to GAS. The characteristics of these communities are similar to GAS biofilms from in vivo animal models. CONCLUSION: Our study revealed the presence of GAS within the tonsillar reticulated crypts of approximately one-third of children who underwent tonsillectomy for either adenotonsillar hypertrophy or recurrent GAS tonsillopharyngitis at the Wake Forest School of Medicine. TRIAL REGISTRATION: The tissue collected was normally discarded tissue and no patient identifiers were collected. Thus, no subjects were formally enrolled. PMID- 22230363 TI - Trends in incidence and detection of advanced breast cancer at biennial screening mammography in The Netherlands: a population based study. AB - INTRODUCTION: The aims of this study were to determine trends in the incidence of advanced breast cancer at screening mammography and the potential of screening to reduce it. METHODS: We included a consecutive series of 351,009 screening mammograms of 85,274 women aged 50-75 years, who underwent biennial screening at a Dutch breast screening region in the period 1997-2008. Two screening radiologists reviewed the screening mammograms of all advanced screen detected and advanced interval cancers and determined whether the advanced cancer (tumor > 20 mm and/or lymph node positive tumor) had been visible at a previous screen. Interval cancers were breast cancers diagnosed in women after a negative screening examination (defined as no recommendation for referral) and before any subsequent screen. Patient and tumor characteristics were compared between women with advanced cancer and women with non-advanced cancer, including ductal carcinoma in situ. RESULTS: A total of 1,771 screen detected cancers and 669 interval cancers were diagnosed in 2,440 women. Rates of advanced cancer remained stable over the 12-year period; the incidence of advanced screen-detected cancers fluctuated between 1.5 - 1.9 per 1,000 screened women (mean 1.6 per 1,000) and of advanced interval cancers between 0.8 - 1.6 per 1,000 screened women (mean 1.2 per 1,000). Of the 570 advanced screen-detected cancers, 106 (18.6%) were detected at initial screening; 265 (46.5%) cancers detected at subsequent screening had been radiologically occult at the previous screening mammogram, 88 (15.4%) had shown a minimal sign, and 111 (19.5%) had been missed. Corresponding figures for advanced interval cancers were 50.9% (216/424), 24.3% (103/424) and 25.1% (105/424), respectively. At multivariate analysis, women with a >= 30 months interval between the latest two screens had an increased risk of screen detected advanced breast cancer (OR 1.63, 95%CI: 1.07-2.48) and hormone replacement therapy increased the risk of advanced disease among interval cancers (OR 3.04, 95%CI: 1.22-7.53). CONCLUSION: We observed no decline in the risk of advanced breast cancer during 12 years of biennial screening mammography. The majority of these cancers could not have been prevented through earlier detection at screening. PMID- 22230364 TI - BMI and obesity in US blood donors: a potential public health role for the blood centre. AB - OBJECTIVE: According to the 2007-2008 National Health and Nutrition Examination Survey, the prevalence of obesity in the US population was 33.8 %; 34.3 % and 38.2 %, respectively, in middle-aged men and women. We asked whether available blood donor data could be used for obesity surveillance. DESIGN: Cross-sectional study of BMI and obesity, defined as BMI >= 30.0 kg/m2. Adjusted odds ratios (aOR) were calculated with logistic regression. SETTING: A network of six US blood centres. SUBJECTS: Existing data on self-reported height and weight from blood donors, excluding persons deferred for very low body weight. RESULTS: Among 1 042 817 donors between January 2007 and December 2008, the prevalence of obesity was 25.1 %; 25.7 % in men and 24.4 % in women. Obesity was associated with middle age (age 50-59 years v. <20 years: aOR = 1.92 for men and 1.81 for women), black (aOR = 1.57 for men and 2.35 for women) and Hispanic (aOR = 1.47 for men and 1.49 for women) race/ethnicity compared with white race/ethnicity, and inversely associated with higher educational attainment (college degree v. high school or lower: aOR = 0.56 for men and 0.48 for women) and double red cell donation and platelet donation. CONCLUSIONS: Obesity is common among US blood donors, although of modestly lower prevalence than in the general population, and is associated with recognized demographic factors. Blood donors with higher BMI are specifically recruited for certain blood collection procedures. Blood centres can play a public health role in obesity surveillance and interventions. PMID- 22230365 TI - A review of post-operative feeding in patients undergoing resection and reconstruction for oral malignancy and presentation of a pre-operative scoring system. AB - Percutaneous endoscopic gastrostomy (PEG) and nasogastric tubes (NGT) are routine after resection and reconstruction of oral cancer. The selection of the most appropriate method of feeding can be challenging, as both methods carry morbidity. This makes correct selection paramount. The objectives of this retrospective review were to identify the benefits and complications of feeding with PEG and NGT in patients with oral malignancy. We retrospectively reviewed 144 patients who had undergone oral cancer resection and reconstruction, to compare PEG and NGT feeding and to identify the key factors that aid selection of the most appropriate feeding method. We used these factors to develop the Key to Appropriate Replacement Enteral Nutrition (KAREN) scoring system. One hundred and twenty of the 144 patients were managed with PEG, and of these, 9 used it for less than 28 days. The mean (range) duration of use was 13 (5-63) days, and 1.9 (1-5) tubes/patient were used. The KAREN scoring system assigned the correct method of feeding in 92% of cases. The scoring system requires prospective validation but could provide clinicians with a tool to assist in a sometimes difficult decision. PMID- 22230366 TI - Thioredoxin-1 and protein disulfide isomerase catalyze the reduction of similar disulfides in HIV gp120. AB - HIV-1 enters cells via interaction of the viral glycoprotein gp120, the host cell surface receptor CD4 and the co-receptors CCR5 or CXCR4. For entry, gp120 undergoes conformational changes that depend on the reduction of one or more disulfides. Previous studies indicate that protein disulfide isomerase (PDI), thioredoxin-1 (Trx1), and glutaredoxin-1 (Grx1) catalyze gp120 reduction, but their specific disulfide targets are not known. Here, it was demonstrated that PDI and Trx1 have similar gp120 disulfide targets as determined by labeling after reduction, but with some pattern differences, including overall stronger labeling with Trx1 than with PDI. Furthermore, uneven labeling of the residues of a disulfide may reflect altered accessibility by conformational changes upon the reduction process. Since both PDI and Trx1 may be involved in viral entry, compounds that target the host redox system or the viral gp120 were tested in vitro to investigate whether redox regulation is a target for anti-HIV therapy. Carbohydrate binding agents (CBAs), previously shown to bind gp120 and inhibit HIV entry, were now demonstrated to inhibit gp120 disulfide reduction. Auranofin, an inhibitor of thioredoxin reductase 1 (TrxR1), also showed inhibitory activity towards HIV infection, although close to its cytotoxic concentration. Our results demonstrate that both the host redox system and the viral surface glycoproteins are of interest for the development of new generations of anti-HIV therapeutics. PMID- 22230367 TI - Bax inhibitor-1 regulates the expression of P450 2E1 through enhanced lysosome activity. AB - In this study, we explored the role of Bax inhibitor-1 (BI-1) on the expression of P450 2E1 and related ROS production. P450 2E1 protein, not mRNA, was expressed at relatively low levels in BI-1 plasmid-transfected cells (BI-1 cells) compared with neomycin-resistant vector-transfected cells (Neo cells). When exposed to ER stress, P450 2E1 expression and activity and ER membrane lipid peroxidation increased in both Neo cells and BI-1 cells, but to a lesser degree in BI-1 cells. This observation correlated with the lower level of ER stress in BI-1 cells than Neo cells. To examine the BI-1-associated P450 2E1 degradation mechanism, cells were treated with the lysosome inhibitor, bafilomycin and the proteasome inhibitor, MG132. Bafilomycin recovered the reduced P450 2E1 expression in BI-1 cells, but did not affect P450 2E1 expression in Neo cells. Next, proteosomal and lysosomal activities in Neo cells were compared to those in BI-1 cells. Although proteosomal activity was similar between Neo and BI-1 cells, LysoTracker and acridine orange labeling, lysosomal V-ATPase activity, and lysosomal cathepsin B expression were higher in BI-1 cells than in Neo cells. In the presence of ER stress, lysosomal activities decreased in Neo cells but did not change in BI-1 cells. P450 2E1 expression and ER membrane lipid peroxidation were greater in the hepatocytes and livers of BI-1 knock-out mice than in BI-1 wild-type cells and mice. Our results suggest that the BI-1-mediated enhancement of lysosomal activity regulates P450 2E1 expression and resultant ROS accumulation. PMID- 22230368 TI - Cellular retinol-binding protein 1 (CRBP-1) regulates osteogenenesis and adipogenesis of mesenchymal stem cells through inhibiting RXRalpha-induced beta catenin degradation. AB - Mesenchymal stem cells (MSCs) are multipotent adult stem cells that can differentiate into osteoblasts, chondrocytes and adipocytes, providing a potential source for musculoskeletal tissue engineering. Retinoid signaling plays very important roles in skeletal development. CRBP1 (cellular retinol binding protein 1), a key component of retinoid signaling pathway, is known to take part in vitamin A metabolism and intracellular transporting of retinoids. However, the role of CRBP1 in MSCs remains still obscure. In this study, we investigated the cellular effects of CRBP1 on osteogenic and adipogenic differentiation of bone marrow derived MSCs in vitro and in vivo. Our results showed that CRBP1 overexpression promoted osteogenic differentiation of bone marrow derived MSCs, while inhibited their adipogenic differentiation. We also demonstrated that the possible underlying mechanism for CRBP1 promoting osteogenic differentiation of MSCs was by inhibiting RXRalpha-induced beta-catenin degradation, maintaining beta-catenin and pERK1/2 at higher levels. These findings reveal a potential role of CRBP1 in the regulation of beta-catenin turnover which can greatly affect the process of osteogenesis and adipogenesis of MSCs. PMID- 22230369 TI - Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth. AB - Ceramides are known to be key players in intracellular signaling and are involved in apoptosis, cell senescence, proliferation, cell growth and differentiation. They are synthesized by ceramide synthases (CerS). So far, six different mammalian CerS (CerS1-6) have been described. Recently, we demonstrated that human breast cancer tissue displays increased activity of CerS2, 4, and 6, together with enhanced generation of their products, ceramides C(16:0), C(24:0), and C(24:1). Moreover, these increases were significantly associated with tumor dignity. To clarify the impact of this observation, we manipulated cellular ceramide levels by overexpressing ceramide synthases 2, 4 or 6 in MCF-7 (breast cancer) and HCT-116 (colon cancer) cells, respectively. Overexpression of ceramide synthases 4 and 6 elevated generation of short chain ceramides C(16:0), C(18:0) and C(20:0), while overexpression of ceramide synthase 2 had no effect on ceramide production in vivo, presumably due to limited substrate availability, because external addition of very long chain acyl-CoAs resulted in a significant upregulation of very long chain ceramides. We also demonstrated that upregulation of CerS4 and 6 led to the inhibition of cell proliferation and induction of apoptosis, whereas upregulation of CerS2 increased cell proliferation. On the basis of our data, we propose that a disequilibrium between ceramides of various chain length is crucial for cancer progression, while normal cells require an equilibrium between very long and long chain ceramides for normal physiology. PMID- 22230370 TI - Reducing current spread using current focusing in cochlear implant users. AB - Cochlear implant performance in difficult listening situations is limited by channel interactions. It is known that partial tripolar (PTP) stimulation reduces the spread of excitation (SOE). However, the greater the degree of current focusing, the greater the absolute current required to maintain a fixed loudness. As current increases, so does SOE. In experiment 1, the SOE for equally loud stimuli with different degrees of current focusing is measured via a forward masking procedure. Results suggest that at a fixed loudness, some but not all patients have a reduced SOE with PTP stimulation. Therefore, it seems likely that a PTP speech processing strategy could improve spectral resolution for only those patients with a reduced SOE. In experiment 2, the ability to discriminate different levels of current focusing was measured. In experiment 3, patients subjectively scaled verbal descriptors of stimuli of various levels of current focusing. Both discrimination and scaling of verbal descriptors correlated well with SOE reduction, suggesting that either technique have the potential to be used clinically to quickly predict which patients would receive benefit from a current focusing strategy. PMID- 22230371 TI - Allele frequency covariance among cohorts and its use in estimating effective size of age-structured populations. AB - A general expression for the covariance of allele frequencies among cohorts in age-structured populations is derived. The expression is used to extend the so called temporal method for estimating effective population size from allele frequency shifts among samples from cohorts born any number of years apart. Computer simulations are used to check on the accuracy and precision of the method, and an application to coastal Atlantic cod is presented. PMID- 22230378 TI - Ultrasound-guided hip joint injections: a new scanning routine for easy methodical training. PMID- 22230379 TI - Re: Pergolizzi et al. 2011: Exposure to potential CYP450 pharmacokinetic drug drug interactions. PMID- 22230380 TI - The term of functional somatic syndrome should be changed to the term of central sensitivity syndrome. PMID- 22230381 TI - Contrast normalization contributes to a biologically-plausible model of receptive field development in primary visual cortex (V1). AB - Neuronal populations in the primary visual cortex (V1) of mammals exhibit contrast normalization. Neurons that respond strongly to simple visual stimuli - such as sinusoidal gratings - respond less well to the same stimuli when they are presented as part of a more complex stimulus which also excites other, neighboring neurons. This phenomenon is generally attributed to generalized patterns of inhibitory connections between nearby V1 neurons. The Bienenstock, Cooper and Munro (BCM) rule is a neural network learning rule that, when trained on natural images, produces model neurons which, individually, have many tuning properties in common with real V1 neurons. However, when viewed as a population, a BCM network is very different from V1 - each member of the BCM population tends to respond to the same dominant features of visual input, producing an incomplete, highly redundant code for visual information. Here, we demonstrate that, by adding contrast normalization into the BCM rule, we arrive at a neurally plausible Hebbian learning rule that can learn an efficient sparse, overcomplete representation that is a better model for stimulus selectivity in V1. This suggests that one role of contrast normalization in V1 is to guide the neonatal development of receptive fields, so that neurons respond to different features of visual input. PMID- 22230382 TI - A dual role for genetically modified lymphocytes in cancer immunotherapy. AB - T cells as the ultimate effectors of adaptive immune responses are currently used to treat patients affected by infectious diseases and certain tumors. Recently, T cells have been manipulated ex vivo with viral vectors coding for chimeric antigen receptors, exogenous T cell receptors, or 'suicide' genes to potentiate their efficacy and minimize possible side effects. However, the introduction of exogenous genes into T lymphocytes, particularly bacterial or viral transgene products, has occasionally produced immune-mediated elimination of transduced lymphocytes. This immune effect has recently been exploited in a trial of active immunotherapy in melanoma patients. In this opinion article, we discuss the therapeutic possibilities presented by the dual aspects of genetically modified lymphocytes used to treat cancer patients. PMID- 22230383 TI - PEG-tethered guanosine acetal conjugates for the enzymatic synthesis of modified RNA. AB - A short and efficient synthetic route to guanosine monophosphate conjugates connected to a protected aldehyde group via a flexible polydisperse polyethylene glycol linker is described. These conjugates are enzymatically incorporated into RNA transcripts with 52% yield. The resulting aldehyde-modified RNA gave full conversion in the reaction with biotin hydrazide, demonstrating the utility of the method. PMID- 22230385 TI - Widespread expression of SAA and Hp RNA in bovine tissues after evaluation of suitable reference genes. AB - The serum amyloid A (SAA) and haptoglobin (Hp) are the most prominent acute phase proteins (APPs) in cow. Liver mainly produces APPs, but extra hepatic expression has also been demonstrated in some tissues. The major aim of the present study was to assess the constitutive SAA and Hp mRNA expression by quantitative PCR (qPCR) in a wide panel of 33 bovine tissues, including gastrointestinal tract, respiratory system, urogenital system, mammary gland, hematopoietic system, central nervous system, eye, thyroid and heart. Normalization of gene expression in different samples requires reference genes, which are stably expressed. Therefore, seven reference genes were investigated (ACTB, GAPDH, HMBS, SDHA, YWHAZ, SF3A1, EEF1A2) and three genes, namely SF3A1, HMBS and ACTB, were selected after assessing their stability with geNormTM and NormFinder((c)) softwares. The qPCR analysis confirmed liver as the principal source of SAA and Hp, but also identified both APPs' mRNA in almost all tissues. The highest expression rate of SAA was found in thyroid, followed by pancreas and submandibulary gland. Hp mRNA expression was detected at high concentration in pancreas and submandibulary gland. The present data indicated a widespread expression of SAA and Hp also in non pathological conditions, thus envisaging a possible role as immunomodulatory and protective molecules. To understand where SAA and Hp come from is the prerequisite to their utilization as Acute Phase Reaction biomarkers. PMID- 22230386 TI - Rearrangement patterns of the canine TCRgamma locus in a distinct group of T cell lymphomas. AB - The T cell antigen receptor chains are assembled through a rearrangement process that combines variable (V), diversity (D) and joining (J) region genes. Recently, the entire canine T cell receptor gamma (TRG) locus was described. It is arranged in 8 cassettes with up to 3 V genes, 2 J genes and 1 C gene each. However, no data is available beyond the level of sequence analysis. The objective of this study was to identify rearranged genes of the canine TRG locus through experimental analysis and to assess gene usage and patterns of rearrangement in a series of canine T cell lymphomas. Rearranged genes were identified through computational analysis of recombination signal sequences (RSSs), a gene's potential to generate a polyclonal smear, and through sequencing of clonal rearrangements in a series of T cell lymphomas. Out of a total of 32 Vgamma and Jgamma genes, 21 genes were found to rearrange, 8 genes were considered not rearranged and 3 genes were suspected to rearrange but their status could not be determined definitely. Rearrangements of the canine TRG locus were assessed in a group of canine T cell lymphomas as well as 3 neoplastic T cell lines. An average of 4.6 rearrangements per lymphoma was found suggesting that canine T cells routinely rearrange multiple cassettes per allele. The most commonly rearranged Vgamma genes belonged to subgroups Vgamma2, Vgamma3, and Vgamma7. Genes in cassettes 2 and 3 preferentially rearranged within their respective cassettes, while Vgamma genes in cassette 7 rearranged to a Jgamma gene in cassette 8. There was a strong preference for Vgamma2 genes to rearrange to a 3' Jgamma gene and for Vgamma3 and Vgamma7 genes to rearrange to a 5' Jgamma gene. This rearrangement pattern coincided with the conservation of the spacer sequence between V and J gene subgroups rather than the topologic location of genes. These data show that highly divergent spacer sequences allow for equally efficient recombination and suggest that spacer sequences can mediate compatibility between V and J genes. PMID- 22230384 TI - MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults. AB - BACKGROUND: This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults. METHODS: A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks. RESULTS: After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989). CONCLUSIONS: This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation. PMID- 22230387 TI - Ecomorphology, differentiated habitat use, and nocturnal activities of Rhinolophus and Hipposideros species in East Asian tropical forests. AB - We investigated the wing morphology and foraging distributions of sympatric Rhinolophus and Hipposideros species by acoustic sampling, measuring wing parameters, and observing bats in different settings of tropical East Asian forests, to evaluate their flexibility in habitat use and edge sensitivity. R. formosae and H. terasensis were more abundant at edges/in open habitats and shared the highest overlap, with R. formosae displaying the greatest breadth in habitat use, whereas R. monoceros had a higher abundance and feeding efficiency in forest interiors with a continuous canopy. H. terasensis was significantly larger and had higher wing loading and aspect ratio than R. formosae and R. monoceros, while R. formosae had higher wing loading but a lower aspect ratio than the smaller-sized R. monoceros. Shrubs and herbs were higher at sites where bats were captured than at those without bat captures, and R. monoceros and R. formosae were associated with greater canopy and ground coverage, respectively. R. monoceros always foraged while flying at lower heights close to the herb/shrub layers, while H. terasensis and R. formosae used perching to different extents, with R. formosae preferably using fly-catching techniques and appearing farther from the path in open forests rather than in forest interiors. Our results indicate that differences in wing parameters account for the different degrees of flexibility in habitat use, yet the deviations of call frequency from the expected values in R. formosae and H. terasensis suggest additional adaptations accounting for their flexibility in exploring habitats. PMID- 22230388 TI - Posttraumatic stress symptoms and health-related quality of life: a two year follow up study of injury treated at the emergency department. AB - BACKGROUND: Among injury victims relatively high prevalence rates of posttraumatic stress disorder (PTSD) have been found. PTSD is associated with functional impairments and decreased health-related quality of life (HRQoL). Previous studies that addressed the latter were restricted to injuries at the higher end of the severity spectrum. This study examined the association between PTSD symptoms and health-related quality of life (HRQoL) in a comprehensive population of injury patients of all severity levels and external causes. METHODS: We conducted a self-assessment survey which included items regarding demographics of the patient, accident type, sustained injuries, EuroQol health classification system (EQ-5D) and Health Utilities Index (HUI) to measure functional outcome and HRQoL, and the Impact of Event Scale (IES) to measure PTSD symptoms. An IES-score of 35 or higher was used as indication for the presence of PTSD. The survey was completed by 1,781 injury patients two years after they were treated at the Emergency Department (ED), followed by either hospital admission or direct discharge to the home environment. RESULTS: Symptoms indicative of PTSD were associated with more problems on all EQ-5D and HUI3 domains of functional outcome and a considerable utility loss in both hospitalized (0.23-0.24) and non hospitalized (0.32-0.33) patients. Differences in reported problems between patients with IES scores higher or lower than 35 were largest for EQ-5D health domains pain/discomfort (82% versus 28%) and anxiety/depression (53% versus 11%) and HUI domains emotion (92% versus 33%) and pain (84% versus 38%). After adjusting for potential confounders, PTSD remained strongly associated with adverse HRQoL. CONCLUSIONS: Among patients treated at an ED posttraumatic stress symptoms indicative of PTSD were associated with a considerable decrease in HRQoL in both hospitalized and non-hospitalized patients. PTSD symptoms may therefore raise a major barrier for full recovery of injury patients of even minor levels of severity. PMID- 22230389 TI - Atherosclerosis: a classic inflammatory disease. AB - Atherosclerosis is an inflammatory disease due to a diet high in saturated fat, hypercholesterolemia, obesity, hypoglycemia, etc. mainly mediated by the infiltration of macrophage and T cells into the vascular wall. Once the endothelial is damaged monocytes penetrate the tissue and are transformed in scavenger cells. Upon stimulation of Th1 cells, a group of cytokines is released and contributes to the inflammatory response of atherosclerotic tissue. When macrophages proliferate they amplify inflammatory response through the secretion of growth factors and cytokines such as TNF and IL-1. In addition, chemokines such as RANTES and other C-C chemokines are generated, and matrix metalloprotinease 9 (MMP-9) are produced by activated monocytes. However, the immune system in atherosclerosis still remains unclear. Here, in this study we revisited the inter-relationship between atherosclerosis and inflammation. PMID- 22230390 TI - Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes. AB - Cryopyrin-associated periodic syndromes are categorized as a spectrum of three autoinflammatory diseases, namely familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome. All are caused by mutations in the NLRP3 gene coding for cryopyrin and result in active interleukin-1 release: their rarity and shared clinical indicators involving skin, joints, central nervous system and eyes often mean that correct diagnosis is delayed. Onset occurs early in childhood, and life-long therapy with interleukin-1 blocking agents usually leads to tangible clinical remission and inflammatory marker normalization in a large number of patients, justifying the need to facilitate early diagnosis and thus avoid irreversible negative consequences for tissues and organs. PMID- 22230392 TI - Identification of differentially-expressed proteins between early submucosal non invasive and invasive colorectal cancer using 2D-DIGE and mass spectrometry. AB - Early detection and diagnosis of colorectal cancer (CRC) are closely related to a better therapeutic outcome, and the five-year survival rate of early CRC is over 90 percent. Though endoscopic minimally invasive treatment has become a quick and effective therapy for early CRC, endoscopic biopsies are usually not deep enough to obtain tissues from the submucosal layer and it is difficult to determine whether early CRC has infiltrated into the submucosa. Therefore, in the present study, we constructed tumor models of early submucosal non-invasive CRC (SNICRC) and submucosal invasive CRC (SICRC) in Fischer-344 rats induced by N-methyl-N nitrosourea (MNU). The differentially-expressed proteins were analyzed and identified in SNICRC, SICRC and normal control (NC) tissues using highly sensitive two dimensional differential gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS). Proteomic data revealed 132 protein spots between SNICRC and SICRC, 162 protein spots between SICRC and NC and 154 protein spots between SNICRC and NC which were found differentially expressed. These differential spots were picked, in-gel digested and peptide mass fingerprints were obtained by MALDITOF-MS/MS. Finally, five differentially-expressed proteins in SNICRC, SICRC and NC were identified, and increases in Transgelin, peptidylprolyl isomerase A (PPIA) and tropomyosin alpha isoform d were observed, while decreases in carbonic anhydrase 2 (CAII) and an unnamed protein were detected in SICRC compared with SNICRC and NC. Furthermore, Fluorescence-based quantitative polymerase chain reaction (FQ-PCR), Western blotting and immunohistochemistry assays also revealed significant upregulation of Transgelin expression and down-regulation of CAII expression in SICRC tissues. In conclusion, 2D-DIGE is confirmed to be an efficient strategy that enables us to identify differentially expressed proteins between early SNICRC and SICRC. The potential biomarkers such as Transgelin and CAII may be used for the detection of early SICRC. PMID- 22230391 TI - Effects of subchronic inhalation exposure to ethyl tertiary butyl ether on splenocytes in mice. AB - Ethyl tertiary-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. The current use of ETBE in gasoline or petrol is modest but increasing. To investigate the effects of ETBE on splenocytes, mice were exposed to 0 (control), 500 ppm, 1750 ppm, or 5000 ppm of ETBE by inhalation for 6 h/day for 5 days/wk over a 6- or 13-week period. Splenocytes were harvested from the control and exposed mice, and the following cell phenotypes were quantified by flow cytometry: (1) B cells (PerCP-Cy5.5-CD45R/B220), (2) T cells (PerCP-Cy5-CD3e), (3) T cell subsets (FITC-CD4 and PE-CD8a), (4) natural killer (NK) cells (PE NK1.1), and (5) macrophages (FITC-CD11b). Body weight and the weight of the spleen were also examined. ETBE-exposure did not affect the weight of the spleen or body weight, while it transiently increased the number of RBC and the Hb concentration. The numbers of splenic CD3+, CD4+, and CD8+ T cells, the percentage of CD4+ T cells and the CD4+/CD8+ T cell ratio in the ETBE-exposed groups were significantly decreased in a dose-dependent manner. However, ETBE exposure did not affect the numbers of splenic NK cells, B cells, or macrophages or the total number of splenocytes. The above findings indicate that ETBE selectively affects the number of splenic T cells in mice. PMID- 22230393 TI - Effects of paraquat and capsaicin on the expression of genes related to inflammatory, immune responses and cell death in immortalized human HaCat keratinocytes. AB - The present experiments were aimed to characterize in immortalized human HaCat keratinocytes the gene expression induced by paraquat and capsaicin, two agents known to induce cell death or to affect inflammatory and pain pathways, respectively. In particular, the following set of genes were analysed by qRealtime PCR: CXCL10,CXCL11, IL-10 (inflammatory and immune responses), TP73, BCL2, (apoptotic and anti-apoptotic genes), MMP9 (proteolysis), SOD-1, BAK-1 and CAT (peroxysomal and microsomal oxidation pathways). In this way, we were able to differentiate the two toxins since they had a different profile of gene expression. In fact, paraquata was found to activate set of genes involved in inflammatory (CXL10,CXL11 and IL-10), and cell death (BCL2, BAK-1, MMP9) pathways. Another specific site of action of paraquat was represented by an activation of the gene involved in SOD-1 transcription. On the contrary, capsaicin was found to produce only an up-regulation of BCL2, an anti-apoptotic gene and MMP9, whereas no significant changes were reported in genes involved in inflammatory and immune responses. Finally, in comparison to previous experiments carried out with TNF-alpha and IL-1beta, we have shown that paraquat produced a similar pattern of activation of set of genes involved both in inflammation and apoptosis. PMID- 22230394 TI - Time-related dynamics of variation in core clock gene expression levels in tissues relevant to the immune system. AB - Immune parameters show rhythmic changes with a 24-h periodicity driven by an internal circadian timing system that relies on clock genes (CGs). CGs form interlocked transcription-translation feedback loops to generate and maintain 24 h mRNA and protein oscillations. In this study we evaluate and compare the profiles and the dynamics of variation of CG expression in peripheral blood, and two lymphoid tissues of mice. Expression levels of seven recognized key CGs (mBmal1, mClock, mPer1, mPer2, mCry1, mCry2, and Rev-erbalpha) were evaluated by quantitative RT- PCR in spleen, thymus and peripheral blood of C57BL/6 male mice housed on a 12-h light (L)-dark (D) cycle and sacrificed every 4 h for 24 h (3-4 mice/time point). We found a statistically significant time-effect in spleen (S), thymus (T) and blood (B) for the original values of expression level of mBmal1 (S), mClock (T, B), mPer1 (S, B), mPer2 (S), mCry1 (S), mCry2 (B) and mRev Erbalpha (S, T, B) and for the fractional variation calculated between single time-point expression value of mBmal1 (B), mPer2 (T), mCry2 (B) and mRev-Erbalpha (S). A significant 24-h rhythm was validated for five CGs in blood (mClock, mPer1, mPer2, mCry2, mRev-Erbalpha), for four CGs in the spleen (mBmal1, mPer1, mPer2, mRev-Erbalpha), and for three CGs in the thymus (mClock, mPer2, mRev Erbalpha). The original values of acrophases for mBmal1, mClock, mPer1, mPer2, mCry1 and mCry2 were very similar for spleen and thymus and advanced by several hours for peripheral blood compared to the lymphoid tissues, whereas the phases of mRev-Erbalpha were coincident for all three tissues. In conclusion, central and peripheral lymphoid tissues in the mouse show different sequences of activation of clock gene expression compared to peripheral blood. These differences may underlie the compartmental pattern of web functioning in the immune system. PMID- 22230395 TI - Lactobacillus paracasei Lp6 favors immune modulation induced by allergoid treatment in ragweed sensitized mice. AB - It has been hypothesized that lactic acid bacteria (LAB) could be used as adjuvant for specific immunotherapy (SIT), as various studies conducted on humans and animals converge to define LAB as anti-Th2 modulators and Treg inducers. In the present study we evaluated the effects of LAB, in particular Lactobacillus paracasei Lp6 (Lp6), in a mouse model of ragweed (RW) allergy. Groups of Balb/c mice, experimentally sensitized towards ragweed, were treated by viable Lp6 or by RWallergoid with or without co-administration of Lp6. A control group was sham sensitized with PBS and sham-treated with water and a group was sensitized with RW and treated with water. Serum IgE, RW-induced release of IFN-gamma, IL-4 and IL-10 from splenocytes and the frequency of CD4CD25 regulatory T cells (Tregs) expressing Foxp3 or IL-10 were evaluated in various groups. RW-allergoid treatment induced a reduction of serum IgE, with a decrease in RW-induced release of IL-4, and an increase in IL-10 and IFN-gamma, along with a significant change in the frequency of Tregs, both CD25+ and -. The joint RWallergoid+ Lp6 treatment induced the highest degree of suppression of allergen-driven IL-4, the greatest reduction of IL-4/IFN-gamma and IL-4/IL-10 ratios and the most significant increase of Foxp3 and IL-10 expressing Tregs. The study shows that Lp6 strengthens the immune modulation induced by allergoid-SIT in RW-sensitized mice, essentially characterized by a differential induction of Tregs associated to a reduction of IL-4; data converge to define a role of SIT adjuvant for Lp6. PMID- 22230396 TI - Stimulation of TH1 response by Helicobacter pylori neutrophil activating protein decreases the protective role of IgE and eosinophils in experimental trichinellosis. AB - Th2 responses seem to play an important role in defence against Trichinella spiralis (Ts). The neutrophil Activating protein of Helicobacter pylori (HP-NAP), that induces IL-12, and IL-23 expression and shifts to Th1 allergen-specific Th2 cells in vitro was used as an anti-Th2 agent in BALB/c mice infected with T. spiralis. The muscle larvae (ML) burden was lower (p < 0.02) in untreated infected animals than those infected treated with HP-NAP. In both groups there was an inverse relationship between ML burden of each animal and total IgE level (controls: r -0.617, p = 0.0013 and HP-NAP-treated: r -0.678, p = 0.0001) or eosinophil count, evaluated in the same mouse on day 42 (r -0.390, p = 0.0592 and r -0.803, p = 0.0001, respectively). Inflammatory response around the nurse cell parasite complex was significantly higher in HP-NAP-treated infected animals than in those untreated infected, on the contrary the number of eosinophils, counted around each complex was significantly lower in the first animal group. This study provides evidence of a powerful anti-Th2 activity in vivo by HP-NAP and for the partial protective effect of Th2 responses in T. spiralis infection. PMID- 22230397 TI - Galectin-3 plasma levels and coronary artery disease: a new possible biomarker of acute coronary syndrome. AB - Inflammation plays a key role in atherosclerosis. Galectin-3 is a macrophage- and endothelium-derived mediator actively involved in the regulation of many aspects of inflammatory cell behaviour. The aim of this study is to quantify plasma Galectin-3 in patients with coronary artery disease (CAD) and different clinical manifestation at the moment of observation in order to verify whether Galectin-3 could be a useful biomarker of atherosclerotic state. We enrolled 125 patients affected by CAD, angiographically documented (70 stable, 55 unstable). They underwent accurate examinations and anamnestic data was collected. The most important traditional risk factors, such as age, hypertension, and body mass index, were reported. Plasma Galectin-3 was quantified using an ELISA kit. Unstable patients (n = 55) had a higher plasma Galectin-3 levels in respect to the stable subjects (27.75 ng/mL (19.27-39.09) vs 6.48 ng/ml (4.88-8.83), p<0.001. A trend in correlation between plasma Galectin-3 levels and number of vessels compromised seems to be present: CAD patients with three-vessel disease had higher levels of Galectin-3 than patients with one-or two-vessel disease (17.39 ng/ml (10.75-29.82) vs 9.18 ng/ml (5.56-23.22), p= 0.058. The significantly higher plasma Galectin-3 levels in patients with unstable angina in respect to the stable angina confirm the involvement of Galectin-3 in promoting macrophage activation and monocyte attraction. Despite the distribution of CAD in patients with acute and chronic coronary disease being similar, we may hypothesize that Galectin-3 could be a useful biomarker of atherosclerotic plaque and in particular of its destabilization. PMID- 22230398 TI - Circulating regulatory T cells in "clinical" monoclonal B-cell lymphocytosis. AB - Regulatory T-cells (Tregs) constitute a small subset of cells involved in antitumour immunity and are generally increased in patients with chronic lymphocytic leukemia (CLL). No data is available on Tregs in monoclonal B-cell lymphocytosis (MBL), a disease entity characterized by less than 5000/microL circulating clonal B-cells in absence of other features of lymphoproliferative disorders. We used multicolour flow cytometry to evaluate the number of circulating Tregs in 56 patients with "clinical" MBL, 74 patients with previously untreated CLL and 40 healthy subjects. MBL patients showed a lower absolute number of Tregs, compared to CLL patients, but slightly higher than controls. Moreover, the absolute cell number of Tregs directly correlated both with more advanced Rai/Binet clinical stages and peripheral blood B-cell lymphocytosis. Of note, the absolute number of Tregs was found lower in MBL patients than in CLL patients staged as 0/A Rai/Binet. The study showed that Treg increase gradually from normal subjects to "clinical" MBL patients and are significantly higher in CLL patients as compared to MBL patients. Moreover, a significant direct relationship was found between higher Treg values and a higher tumor burden expressed by B-lymphocytosis or more advanced clinical stages. In light of this data, MBL seems to be a preliminary phase preceding CLL. The progressive increase of Treg numbers might contribute both to the clinical evolution of MBL to overt CLL and to CLL progression. PMID- 22230399 TI - KMUP-1 inhibits H441 lung epithelial cell growth, migration and proinflammation via increased NO/CGMP and inhibited RHO kinase/VEGF signaling pathways. AB - This study investigates whether KMUP-1 protects soluble guanylate cyclase (sGC) and inhibits vascular endothelial growth factor (VEGF) expression in lung epithelial cells in hypoxia, therapeutically targeting epithelial proinflammation. H441 cells were used as a representative epithelial cell line to examine the role of sGC and VEGF in hypoxia and the anti-proinflammatory activity of KMUP-1 in normoxia. Human H441 cells were grown in hypoxia for 24-72 h. KMUP-1 (1, 10, 100 microM) arrested cells at the G0/G1 phase of the cell cycle, reduced cell survival and migration, increased p21/p27, restored eNOS, increased soluble guanylate cyclase (sGC) and PKG and inhibited Rho kinase II (ROCK-II). KMUP-1 (0.001-0.1 microM) concentration dependently increased eNOS in normoxia and did not inhibit phosphodiesterase-5A (PDE-5A) in hypoxic cells. Hypoxia-induced factor-1alpha (HIF-1alpha) and VEGF were suppressed by KMUP-1 but not by L-NAME (100 microM). The PKG inhibitor Rp-8-CPT-cGMPS (10 microM) blunted the inhibition of ROCK-II by KMUP-1. KMUP-1 inhibited thromboxane A2-mimetic agonist U46619 induced PDE-5A, TNF-alpha (100 ng/ml)-induced iNOS, and ROCK-II and associated phospho-p38 MAPK, suggesting multiple anti-proinflammatory activities. In addition, increased p21/p27 by KMUP-1 at higher concentrations might contribute to an increased Bax/Bcl-2 and active caspase-3/procaspase-3 ratio, concomitantly causing apoptosis. KMUP-1 inhibited ROCK-II/VEGF in hypoxia, indicating its anti neoplastic and anti-inflammatory properties. KMUP-1 inhibited TNF-alpha-induced iNOS and U46619-induced PDE-5A and phospho-p38 MAPK in normoxia, confirming its anti-proinflammatory action. KMUP-1 could be used as an anti-proinflammatory to reduce epithelial inflammation. PMID- 22230400 TI - Activation of human monocyte-derived dendritic cells in vitro by the biological response modifier arabinoxylan rice bran (MGN-3/Biobran). AB - Arabinoxylan rice bran (MGN-3/Biobran) is a potent biological response modifier (BRM) that activates natural killer (NK) cells, T cells and monocytes. Currently, little is known regarding the effects of MGN-3 on dendritic cells (DCs), the cell type that bridges innate and adaptive immunity. Therefore, we examined the stimulatory effects of MGN-3 on DCs. Human monocyte-derived DCs were treated with MGN-3 at different concentrations (5-20 microg/ml) for 24 hours in vitro. Activation of DCs was determined by assessing the expression of co-stimulatory and maturation markers (CD40, CD80, CD83, CD86 and HLA-DR) by flow cytometry, and production of cytokines by ELISA. DC function was determined by assessing their ability to activate naive T cells. Activation of T cells was assessed by measuring cell proliferation and cytokine production. MGN-3 treatment, in a dose dependent manner, resulted in: 1) up-regulation of the surface expression of CD83 and CD86, on DCs; 2) an increase in the production of pro-inflammatory and immuno regulatory cytokines (IL-1beta, IL-6, IL-10, TNF-alpha, IL-12p40 and low levels of IL-12p70 and IL-2) by DCs; and 3) MGN-3 stimulated DC induced CD4+T cell proliferation and their production of cytokines, IFN-gamma, IL-10, IL-17. Results suggest that MGN-3 functions as a natural adjuvant for DC activation and thus may be used in DC-based vaccine strategies against infections and cancer. PMID- 22230401 TI - 2B4 (CD244) is involved in eosinophil adhesion and chemotaxis, and its surface expression is increased in allergic rhinitis after challenge. AB - A role for the subtypes of CD2 Ig superfamily receptors has been recently demonstrated in eosinophilic inflammation in experimental asthma and atopic asthmatics. We investigated the functions of 2B4 (CD244) molecules in eosinophil adhesion and chemotaxis, and correlated the results to the pathophysiology of allergic rhinitis (AR). Herein, we show that agonistic stimulation of 2B4 by C1.7, the anti-human 2B4 functional grade purified antibody, resulted in significant increase of eosinophils and eosinophil cell line (Eol-1 cells) adhesion to collagen type IV, and random migration. These functions were associated with tyrosine kinase phosphorylation of several protein residues of low molecular weight. Flow cytometry (FACS) experiments demonstrated that Eol-1 cells, normal peripheral blood eosinophils and eosinophils from AR patients, express surface 2B4 molecules. In vitro AR model demonstrated that the CC chemokine receptor CCR3 stimulation by eotaxin induced significant increase in the expression of surface 2B4 in eosinophils and Eol-1 cells. Immunofluorescence confocal microscopy images showed that eotaxin induces also redistribution of 2B4 molecules towards the pseudopods in eosinophils and Eol-1 cells, changing their shape. Blocking of 2B4 molecules by the corresponding neutralizing antibody inhibited eotaxin induced Eol-1-adhesion, chemotaxis and the cytoskeleton changes. Pretreatment of Eol-1 cells with 1 microM genistein blocked eotaxin induced Eol-1 adhesion, chemotaxis and 2B4 up-regulated expression. In vivo correlation demonstrated the expression of 2B4 molecules in eosinophils from AR patients to be significantly increased, after nasal provocation challenge. These results identify a novel role for 2B4 molecules in eosinophil functional migratory response and may point to a novel tyrosine kinase-mediated ligation between CCR3 receptor and 2B4 co-receptor in eosinophil chemotaxis. If so, then 2B4 molecules would be a novel target for therapeutic modalities in diseases characterized by eosinophilia such as AR. PMID- 22230402 TI - Expression of IL-23, VEGF and TLR2/TLR4 on mononuclear cells after exposure to Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative, aerobic bacillus causing infections of the respiratory and other organ systems in susceptible hosts. Although it does not cause pulmonary infections in immunocompetent individuals, P. aeruginosa causes chronic lung infection in individuals with cystic fibrosis and nosocomial pneumonia resulting in significant morbidity and mortality. Exogenous administration of an important P. aeruginosa virulence factor, lipase, present in P. aeruginosa culture supernatant, induces potent mononuclear cell activation leading to the production of numerous proinflammatory cytokines. In particular, P. aeruginosa culture supernatant stimulated increased proliferation of THP-1 cells and monocytes (MN). The addition of culture supernatant to THP-1 cells and MN also induced Interleukin (IL)-23 and vascular endothelial growth factor (VEGF) release in a time-dependent manner. To investigate whether any compounds present in the supernatant lipase contributed to releasing IL-23 and VEGF, the culture supernatant from P. aeruginosa containing lipase was treated with hexadecylsulfonylfluoride (AMSF). The AMSF-treated culture supernatant (CS) did not show any induction on the IL-23 and VEGF release compared to the cells treated with CS without AMSF. We also showed that Toll-like receptors (TLR)2/TLR4 are expressed in THP-1 cells and MN treated with P. aeruginosa CS in a time dependent fashion. Flow cytometry analysis revealed a higher TLR4 and a lower TLR2 expression at 48 and 72 h of treatment. The treatment of cells with TLR4 neutralizing antibody, and to a lesser extent with TLR2 neutralizing antibody, resulted in a decrease in P. aeruginosa CS-induced IL-23 and VEGF production. PMID- 22230403 TI - Magnesium content in daily food portions and the influence of supplementation. AB - Magnesium is one of the most important cations for an organism. The aim of our study is to evaluate whether the use of a magnesium formulation as a diet supplement or medical treatment is necessary. The 24-hour recall method was used to obtain information regarding the daily magnesium consumption of 949 people. The results were compared with the Estimated Average Requirement (EAR) and Recommended Daily Allowance (RDA) values. The average daily requirement for magnesium was exceeded by 292 (183 women and 109 men) of the 949 respondents. This research confirmed excessive magnesium intake by both men and women that exceeded both the EAR and the RDA. Uncontrolled, excessive dietary supplementation or medical treatment with magnesium by this group may constitute a health threat. PMID- 22230404 TI - Hyper-IgM, neutropenia, mild infections and low response to polyclonal stimulation: hyper-IgM syndrome or common variable immunodeficiency? AB - A young woman presenting respiratory infections, polyarthritis, severe neutropenia, and increased serum IgM was treated with intravenous immunoglobulin (IVIG) with good clinical and laboratory outcome followed by a loss of efficacy. The increased serum IgM associated to recurrent infections and autoimmune manifestations suggested the diagnosis of a hyper-IgM syndrome (HIGMs). The frequency of peripheral T cells, the expression of CD40 on the patients' B cells and CD40L on T cells and the activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) at mRNA level was comparable to controls. In contrast, the frequency of B cells was one half of the healthy control and all cells showed an atypical phenotype. Although AID and UNG were normal, class switch recombination was not very efficient because circulating switched memory were reduced and, once stimulated with CpG, generated less antibody-secreting cells than controls. An increase in serum B Lymphocytes stimulator (BLyS) was also found. The patient presented a peculiar clinical and immunological phenotype fitting for many aspects of both HIGM4 and Common Variable Immunodeficiency (CVID). These findings underline the need to better explore the complex link between these two diseases. PMID- 22230405 TI - Micro opioid receptor A118G polymorphism and post-operative pain: opioids' effects on heterozygous patients. AB - The single-nucleotide-polymorphism (SNP) 118A>G in the micro-1 opioid receptor gene (OPRM1) is associated with a decrease in the analgesic effects of opioids. The aim of this study is to assess whether 118A >G polymorphism could influence the analgesic response to opioid-based postoperative pain (POP) therapy. The study consisted of two parts: section alpha, observational, included 199 subjects undergoing scheduled surgical procedures with pain management standardized on surgery invasiveness and on expected level of postoperative pain; section beta, randomized, included 41 women undergoing scheduled caesarean delivery with continuous intra-operative epidural anesthesia and post-operative analgesia (CEA). In both sections, POP was measured over 48 h (T6h-T24h-T48h) by the visual analogue scale (VAS). In section beta we also tested the responsiveness of hypothalamic-pituitary-adrenal axis (HPA) expressed by cortisol levels. In section alpha, with cluster analysis, subjects were analyzed according to their genotype: a group (no. 1) of 34 patients reporting VAS score >3 at every time lapse was identified and included only A118G carriers, while wild-type (A118A - absence of 118A>G polymorphism) patients were unevenly distributed between those with cluster no. 2 (VAS score <3 at every study steps) and those with cluster no. 3 (VAS score progressively reducing from T6h). In section beta, A118G carriers receiving epidural sufentanil had the lowest VAS scores at T24h; also in these patients, cortisol levels remained more stable, with a mild decrease at T6h. This study shows that the OPRM1 118A>G polymorphism affects postoperative pain response in heterozygous patients: they have a different postoperative pain response than patients with wild-type genes, which may affect the efficacy of the analgesic therapy. PMID- 22230406 TI - Neo-adjuvant chemo/immunotherapy in the treatment of stage III (N2) non-small cell lung cancer: a phase I/II pilot study. AB - In a previous randomized study, we showed that adjuvant immunotherapy with tumor infiltrating lymphocytes and recombinant interleukin-2 (rIL-2) significantly improved survival in resected N2-non small cell lung cancer (NSCLC) patients. The present study assesses feasibility, safety and potential efficacy of combined neo adjuvant chemotherapy and immunotherapy with peripheral blood mononuclear cells (PBMC) and rIL-2 in resectable N2-NSCLC patients. Eighty-two consecutive N2-NSCLC patients underwent neo-adjuvant chemotherapy with cisplatin and gemcitabine. Out of the 82 patients, 23 were also subjected to leukapheresis prior to neo-adjuvant chemotherapy while the remaining 59 did not. Collected PBMC were analyzed for viability and phenotype and then stored frozen in liquid nitrogen. Thawed PBMC were infused intravenously, 5 days before surgery. After the infusion, rIL-2 was administered subcutaneously until surgery. Only patients with a partial or complete response to neoadjuvant chemotherapy underwent surgery: 13 patients in the experimental immunotherapy group (A) and 32 in the reference group (B). The two groups were homogeneous for all major prognostic factors. Median leukapheresis yield was 10 billion PBMC, (range 3-24 billions). Two to six billion PBMC were infused. The phenotypic analysis showed that similar proportions of CD4 and CD8 cells were present in leukapheresis products, and thawed PBMC, as well as in T lymphocytes isolated from the removed tumours. No severe adverse effects were observed following immunotherapy. No significant differences in overall survival (OS) and event-free survival (EFS) were seen between the two groups. However, the 5-year OS in group A was almost twice as much compared to group B (59 percent vs 32 percent). After adjustment for major prognostic factors, a statistically significant 66 percent reduction in the hazard of death was seen in patients receiving immunotherapy. The OS benefit was more evident in patients with adenocarcinoma than in those with squamous cell carcinoma. This study supports the favorable toxicity profile and potential efficacy of combining neo-adjuvant chemotherapy and immunotherapy with PBMC and rIL-2 in the treatment of N2-NSCLC patients. PMID- 22230407 TI - Psychophysical distress and alexithymic traits in chronic fatigue syndrome with and without comorbid depression. AB - Patients with chronic fatigue syndrome (CFS) often report a comorbid depressive disorder. Comorbid depression may negatively influence the long-term outcome of CFS therefore it must be correctly diagnosed and treated. The aim of the present study is to provide a clinical and psychometric assessment of CFS patients with and without depressive features. A comparative analysis between 57 CFS subjects (CDC, 1994), 17 of whom with a comorbid depression, and 55 matched healthy volunteers was assessed to evaluate the presence of any psychophysical distress and alexithymic traits, by means of Symptom Checklist-90-R (SCL-90R) and Toronto Alexithymia Scale (TAS-20). The severity of fatigue was also assessed in all CFS patients using the Fatigue Impact Scale (FIS). With regard to psychiatric comorbidity, the SCL-90R scores showed higher levels of somatic complaints in CFS patients than in healthy subjects, whereas augmented depressive and obsessive compulsive symptoms were observed only in the depressed CFS subgroup. When comparing the TAS-20 scores, we observed a selective impairment in the capacity to identify feelings and emotions, as measured by the Difficulty in Identifying Feelings subscale (DIF), non-depressed CFS patients showing an intermediate score between depressed CFS and healthy controls. Finally, in terms of FIS scores, a statistical trend versus a higher fatigue severity in depressed CFS patients, with respect to non-depressed ones, was observed. In conclusion, comorbid depression in CFS significantly increased the level of psychophysical distress and the severity of alexithymic traits. These findings suggest an urgent need to address and treat depressive disorders in the clinical care of CFS cases, to improve social functioning and quality of life in such patients. PMID- 22230408 TI - Modulation of biofilm of strains isolated from patients with chronic obstructive pulmonary disease by levofloxacin, moxifloxacin, ciprofloxacin, amoxicillin/clavulanic acid and ceftriaxone. AB - The ability of levofloxacin, moxifloxacin, ciprofloxacin, amoxicillin/clavulanic acid and ceftriaxone to interfere on biofilm produced by Pseudomonas aeruginosa, Haemophilus influenzae and Streptococcus pneumoniae isolated from patients with chronic obstructive pulmonary disease was evaluated. The effects of antibiotics were evaluated on formation of biofilm (at 1/2, 1/4 and 1/8 X MIC) and on preformed biofilm (at epithelial lining fluid peak concentrations) by means of a spectrophotometric method. Levofloxacin was the most active compound followed by ciprofloxacin, moxifloxacin and amoxicillin/clavulanic acid and ceftriaxone. Levofloxacin may contribute to clear the reservoir of pathogens involved in chronic obstructive pulmonary disease, thus leading to decreased occurrence of acute exacerbations. PMID- 22230409 TI - Effects of Lactobacillus salivarius LS01 (DSM 22775) treatment on adult atopic dermatitis: a randomized placebo-controlled study. AB - Atopic dermatitis (AD) is a common inflammatory skin disease characterized by xerosis, pruritus and eczema. The role of probiotics in the prevention and the treatment of AD have been extensively studied in children with controversial results while there are few studies on an adult population. The aim of this randomized, double-blind, placebo-controlled study is to evaluate the clinical efficacy of the intake of a probiotic strain (Lactobacillus salivarius LS01) in the treatment of adult patients with AD. A group of 38 patients was treated with probiotics or placebo (maltodextrin) for 16 weeks. The study was performed from January (T0) to May, 2009 (T16). The assessment of efficacy was based on change in SCORAD (SCORing Atopic Dermatitis) index, dermatology life quality index (DLQI) improvement, cytokine production by PBMCs and ability to modify faecal microbial flora. No significant adverse events were recorded during the study. Patients treated with probiotics showed a statistically improvement of both clinical parameters (SCORAD p<0.0001 and DLQI p= 0.021) at the end of treatment (T16) compared with the placebo group. Furthermore, after four months of treatment there was a significant reduction of Th1 cytokines (IL-12+IFNgamma) (p= 0.03) and Th1/Th2 ratio (IL-12+IFNgamma/IL-4+IL-5) (p= 0.019) only in placebo treated patients. A statistically relevant decrease of staphylococci in faeces of the probiotictreated group was also observed at the end of treatment. In our study, the administration of L. salivarius LS01 was well tolerated and was associated with a significant improvement of clinical manifestation and QoL. This probiotic strain could have an important role in modulating Th1/Th2 cytokine profiles and could be considered as an important adjunctive therapy in the treatment of adult AD. PMID- 22230410 TI - A comparison between IgE and IgG4 as markers of allergy in children: an experimental trial in a model of natural antigen avoidance. AB - IgG4 have been hypothesized to act as blocking antibodies capable of preventing IgE-mediated effector cell triggering. This study aims to evaluate the changes in IgG4 in children during a period of natural antigen avoidance. Serum IgE and IgG4 were evaluated in a group of asthmatic children, aged between 7 and 17 years, admitted to the residential house Istituto Pio XII (Misurina, BL, Italy), located at 1,756 m, in a natural model of antigen avoidance. All the patients were skin prick test positive to at least two of the following allergens: Dermatophagoides pteronissynus, Dermatophagoides farinae, cat epithelium, timothy grass pollen and Parietaria pollen. During the 180 days of hospitalization, serum specific IgE and IgG4 were measured six times. A significant decrease (p≤0.05) in serum specific IgE to house dust mite and pollen allergens was observed; by contrast, no significant variations were shown by IgG4 and IgG4/IgE ratio. No significant relationship was found between serum specific IgE, IgG4 and IgG4/IgE ratio variations and the re-exposure to house dust mite allergens during the Christmas holidays. A positive correlation between specific IgE and specific IgG4 was observed at each considered time (T0: r=0.57, p=0.08; T1: r=0.85, p=0.001; T3: r=0.76, p=0.01). The positive correlation between specific IgE and specific IgG4, enduring throughout the entire time of study, suggests a relationship between these classes of immunoglobulins. PMID- 22230411 TI - Lactoferrin decreases inflammatory response by cystic fibrosis bronchial cells invaded with Burkholderia cenocepacia iron-modulated biofilm. AB - In cystic fibrosis (CF) high iron concentration in airway secretion plays a pivotal role in bacterial multiplication and biofilm formation as well as in inflammatory response. Burkholderia cenocepacia, an opportunistic facultative pathogen responsible for chronic lung infections and cepacia syndrome, recurrently infects CF patients. Lactoferrin (Lf), an iron binding multifunctional glycoprotein synthesized by exocrine glands and neutrophils, has been found at higher concentration in the airway secretions of infected CF patients than in healthy subjects. Here the influence of milk derivative bovine lactoferrin (bLf), an emerging important regulator of iron and inflammatory homeostasis, on invasiveness of B. cenocepacia iron-modulated biofilm, as well as on inflammatory response by infected CF bronchial (IB3-1) cells, is reported. bLf did not significantly affect invasion efficacy by biofilmforming B. cenocepacia clinical strains. Conversely, the addition of bLf to cell monolayers during infection significantly decreased the pro-inflammatory Interleukin (IL)-1beta and increased the anti-inflammatory IL-11 expression compared to that observed in cells infected in the absence of bLf. The bLf ability to modulate genes expressed following B. cenocepacia infection seems related to its localization to the nucleus of infected IB3-1 cells. These results provide evidence for a role of bLf in the protection of infected CF cells from inflammation-related damage, thus extending the therapeutic potential of this multifunctional natural protein. PMID- 22230413 TI - Anetoderma: evidence of the relationship with autoimmune disease and a possible role of macrophages in the etiopathogenesis. AB - Anetoderma is a benign condition characterized by round or oval macular lesions with focal loss of dermal elastic tissue resulting in localized areas of flaccid or herniated saclike skin. Often, the anetoderma is associated with immuno mediated pathogenetic mechanism. In this article, we describe the association between anetoderma and autoimmune diseases, by underlining the role and the action of macrophages as a possible etiopathogenesis. PMID- 22230412 TI - Evaluation of bronchial hyperreactivity with mannitol dry powder challenge test in a paediatric population with intermittent allergic asthma or allergic rhinitis. AB - We evaluated the bronchial hyperreactivity (BHR) with a new bronchial challenge test, mannitol dry powder, in a paediatric population with intermittent allergic asthma or allergic rhinitis who did not respond to an exercise challenge test. We selected 50 children, aged 9-16 years, with intermittent allergic bronchial asthma (Group 1) or allergic rhinitis without clinical manifestation of asthma for at least 12 months (Group 2). All patients performed the following tests in three different days (≥ 48 hours apart): Day 1: exhaled nitric oxide (FeNO) determination followed by baseline spirometry and reversibility to inhaled beta2-agonists; Day 2: exercise challenge test followed by FeNO determination; Day 3: mannitol challenge test followed by FeNO determination. Forty children completed the study. Eighteen subjects of Group 1 (90 percent) and 5 subjects of Group 2 (25 percent) resulted positive to the mannitol test. Positive mannitol challenge subjects showed no statistically significant differences compared to negative subjects as regard baseline spirometry, reversibility to salbutamol and response to the exercise challenge test, but they had significantly higher FeNO values. In conclusion, the mannitol challenge test can be a diagnostic tool more useful than the exercise challenge test to identify BHR in a paediatric population with intermittent allergic asthma or allergic rhinitis because it is better reproducible, quick and easy to perform and well tolerated. PMID- 22230414 TI - Churg-Strauss and montelukast. AB - Churg-Strauss syndrome (CSS) is a systemic small vessel vasculitis involving lungs, skin, heart, gastrointestinal tract and peripheral nerves. We report the case of a 36-year-old woman with a necrotic lesion on the left foot of two months duration, associated with hypereosinophilia, patchy lung infiltrates, cardiac damage and a mononeuritis. The personal history was remarkable only for an asthma, treated with Montelukast, a leukotriene receptor antagonist (LRA). Clinical symptoms, laboratory exams and instrumental examinations led us to the diagnosis of CSS. In recent years several studies have reported the possible relationship between use of leukotriene receptor antagonist (LRA) and CSS expression. We report this case to underline the possible relationship between LRA and CSS and its etiopathogenetic mechanism. PMID- 22230415 TI - Aggressive large B-cell lymphoma in a systemic lupus erythematosus patient with chronic active Epstein-Barr virus infection: a case report. AB - A link between Epstein-Barr Virus (EBV) infection, systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL) has been recently reported in literature. Here we report a case of diffuse large B-cell lymphoma (DLBCL) with a particularly aggressive clinical course in an SLE patient with EBV infection. A 49-year-old woman with a long history of SLE was admitted to the Department of Experimental and Clinical Medicine and dramatically died a few hours later. The autopsy described no evidence of active lymphoproliferative disorder. Instead, histological examination demonstrated an atypical lymphocitic proliferation in lymph node, kidneys, pericardium and uterus. Immunoistochemically, the lymphomatous cells were positive with CD19, CD20, CD22 and CD79a, which was consistent with a DLBCL. The cells were also reactive to EBV markers, indicating the possible role of previous EBV infection in DLBCL pathogenesis. PMID- 22230416 TI - Videocapillaroscopic pattern of alopecia areata before and after diphenylciclopropenone treatment. AB - Alopecia areata (AA) is an inflammatory skin disease the most effective therapy for which is diphenylcyclopropenone (DPCP). Videodermatoscopy and intra-vital capillaroscopy (IVCP) are two non-invasive techniques that help in the differential diagnosis of alopecias. It is known that, after DPCP therapy, there is a histologically proven significant increase of VEGF in hair follicle keratinocytes and a consequent increase in capillary vessels in the dermis of the same follicles. The aim of our study is to emphasize any clinical and videodermatoscopic-videocapillaroscopic changes after DPCP treatment in 20 patients affected by alopecia areata. Videodermatoscopic images and an intravital videocapillaroscopic analysis were performed at T0, T12 and T24 to emphasize clinical modifications and microscopic changes in vascular pattern before and after DPCP treatment. At T0, videodermatoscopy showed the presence of exclamation point hairs, hair follicles filled with hyperkeratotic plugs (yellow dots), hair follicles containing cadaverized hairs (black dots) and broken hairs. IVCP highlighted a pale scalp, and vessels were not visible. At 24 weeks (T24), videodermatoscopy revealed the disappearance or a statistically significant reduction of AA hallmarks and an increase of number of vellus hairs. Videocapillaroscopy showed a statistically significant increase of new vessels and, where neoangiogenesis were more marked, a major hair regrowth was evident. Our study emphasizes that, after DPCP therapy, neoangiogenesis is detectable by videocapillaroscopy and these new capillaries could be considered an initial positive attempt to compensate capillary loss of T0 alopecia areata images. PMID- 22230417 TI - Severe necrotizing pneumonia complicating influenza A (H1N1): the role of immunologic interaction. AB - This report describes the successful management of a documented necrotizing pneumonia due to Streptococcus pneumoniae in a child with pandemic influenza A (H1N1). The importance of early recognition of bacterial superinfection in patients with influenza and the immunologic interactive mechanisms between viruses and bacteria in determining respiratory diseases are highlighted. The role of modern molecular techniques in improving diagnostic microbiology sensitivity and informing consequent clinical care is emphasized. PMID- 22230418 TI - Rheumatoid arthritis: a complication of aromatase inhibitor therapy? AB - We report the case of a 56-year-old woman treated with aromatase inhibitors for a breast cancer. Following one year of such therapy, the patient presented with widespread osteoarthrealgia. The clinical picture worsened 3 years later when the pain became more severe with swelling and stiffness involving several joints in a symmetric fashion. Biochemical analysis showed an increase of ESR, CRP and rheumatoid factor, as well as of anti-CCP antibodies. The x-ray was compatible with a diagnosis of rheumatoid arthritis (RA). Therapy with methotrexate, prednisol one, bisphosphonates and vitamin D was started, achieving a quick clinical remission. Aromatase inhibitors have been shown to alter the distribution of Th1/Th2 lymphocytes and increase the level of RANKL. A possible role of aromatase inhibitors in RA development has been further addressed. PMID- 22230419 TI - Effectiveness of Ischia thermal water nasal aerosol in children with seasonal allergic rhinitis: a randomized and controlled study. AB - Allergic rhinitis is characterized by local inflammation. Nasal lavage may be a useful treatment, however, there are few studies on this topic. This study aims to evaluate the effects of Ischia thermal water nasal irrigation on allergic rhinitis symptoms and airway inflammation during the period of natural exposure to Parietaria pollen in children with allergic rhinitis and intermittent asthma. Forty allergic children were randomly divided into two groups: the first group (Group 1) practiced crenotherapy with thermal water aerosol for 15 days per month, for three consecutive months, the control group (Group 2) was treated with 0.9% NaCl (isotonic) solution. In addition, all children were treated with cetirizine (0.5 gtt./kg/day once daily). Nasal symptom assessment, including Total Symptom Score (TSS), spirometry, and exhaled nitric oxide (FeNO) were considered before the treatment (T0), at the end of the treatment (T1) and again 2 weeks after the end of the treatment (T2). The study was registered in the Clinical Trials.gov (NCT01326247). Thermal water significantly reduced both TSS and FeNO levels and there was a significant relationship between reduction of nasal symptoms and FeNO values at the end of treatment with thermal water. In conclusion, this study shows that nasal crenotherapy with the hypermineral chloride-sodium water of Ischia was effective in children with seasonal allergic rhinitis based on the sensitivity to Parietaria. These results demonstrate that this natural treatment may be effective in a common and debilitating disease such as the allergic rhinitis. PMID- 22230420 TI - Contact allergic dermatitis to gold in a tattoo: a case report. AB - The art of tattooing has increasing in recent decades. Allergic sensitivity to one of the pigments is the most frequent cause of dermatological reactions at the site of the tattoo. Gold is a new pigment used in tattooing, because of its bright yellow color and luster. Allergy to this metal is uncommon. To our knowledge, this is the first reported case of allergic contact dermatitis to gold in a tattoo. PMID- 22230421 TI - Acquired angioedema with C1 inhibitor deficiency associated with anticardiolipin antibodies. AB - Acquired angioedema (AAE) with C1 inhibitor deficiency is often associated to B cell lymphoproliferative disorders or autoimmune diseases. We report a case of AAE associated with IgM anti-cardiolipin antibodies, with frequent edematous attacks, that disappeared completely after a slight immunosuppression and danazol therapy. PMID- 22230422 TI - Exhaled nitric oxide as a marker of lung involvement in Crohn's disease. AB - Crohn's disease is an inflammatory bowel disease associated with a variety of systemic manifestations, including large and small airway involvement. The latter is most often a subclinical one, and requires expensive and invasive diagnostic approaches. Nitric oxide (NO) can be detected non-invasively in the exhaled air (eNO) and be considered as a surrogate marker of airway inflammation. eNO tested at multiple expiratory flows can be used to distinguish the alveolar concentration of NO (CalvNO) from the total amount of fractional eNO (FeNO). The aim of our study is to compare FeNO and concentration of alveolar nitric oxide (CalvNO) levels and to assess their relationship with pulmonary involvement in Crohn's patients differing in clinical stage and therapeutic regimens versus a group of healthy subjects. Thirty Crohn's patients not showing clinical evidence of pulmonary diseases and 21 non-smoking, non-atopic healthy controls were enrolled. FeNO (14.9+/-10.2 ppb vs 10.1+/-6.3 ppb, p=0.049) and CalvNO (4.4+/-2.2 ppb vs 2.6+/-1.9; p=0.006) values were found to be significantly higher in Crohn's patients than in healthy controls. Both FeNO and CalvNO correlated positively with the Crohn's Disease Activity Index. In conclusion, our results for FeNO and CalvNO confirm the presence of subclinical pulmonary involvement in Crohn's disease. eNO measurement may be of clinical value in the follow-up of Crohn's patients. PMID- 22230423 TI - Lupus mastitis in systemic lupus erythematosus: a rare condition requiring a minimally invasive diagnostic approach. AB - Breast involvement is a rare event in SLE patients. The most frequent presentation is lupus panniculitis with skin erythema, tenderness, and parenchymal nodules. However, when breast masses are detected in SLE patients without significant superficial inflammation, it is mandatory to rule out breast carcinoma. Here, we report the case of a 47-year-old woman with an 18-year-long history of SLE, who presented with a suspicious breast mass. Since surgical trauma has been reported to be able to exacerbate breast inflammation in lupus mastitis, an ultrasound-guided minimally invasive Mammotome biopsy was performed to obtain tissue samples for histological and immunohistochemical examinations. Histology was consistent with lupus mastitis. The patient was already on mycophenolate mofetil and hydroxychloroquine. At the latest follow-up visit 6 years later, no progression of the breast lesion was observed. PMID- 22230425 TI - Perceived quality and availability of fruit and vegetables are associated with perceptions of fruit and vegetable affordability among socio-economically disadvantaged women. AB - OBJECTIVE: Perceptions that fruit and vegetables are expensive have been found to be associated with lower consumption of fruit and vegetables among disadvantaged women; however, the determinants of these perceptions are relatively unknown. The purpose of the current paper is to examine whether perceived availability and quality of fruit and vegetables, and social support for healthy eating, are associated with perceptions of fruit and vegetable affordability among women residing in disadvantaged neighbourhoods. DESIGN: Cross-sectional self-report survey. SETTING: The study was conducted in Melbourne, Australia. SUBJECTS: An Australian sample of 4131 women, aged 18-45 years, residing in neighbourhoods ranked in the lowest Victorian tertile of relative disadvantage by the Australian Bureau of Statistics, an index that considers aspects of disadvantage such as residents' income, education, motor vehicle access and employment. RESULTS: Results showed that irrespective of education, income and other key covariates, women who perceived poor availability and quality of fruit and vegetables in their local neighbourhood were more likely to perceive fruit and vegetables as expensive. CONCLUSIONS: Our results suggest that perceptions of fruit and vegetable affordability are not driven exclusively by lack of financial or knowledge-related resources, but also by women's psychological response and interpretation of their local nutrition environment. PMID- 22230426 TI - Functional capacity, muscle strength and falls in women with fibromyalgia. AB - BACKGROUND: Patients with fibromyalgia have difficulty with activities of daily living, they exhibit reduced muscle strength and high incidence of reported falls. The objective of this study was to evaluate the functional performance and lower limb muscle strength in women with fibromyalgia and determine the relationship between muscle strength and falls. METHODS: Sixteen females with fibromyalgia and 16 healthy women participated in the study. Pain intensity, fibromyalgia impact on quality of life, physical activity level and fall prevalence were assessed. The peak torque and the rate of torque development were determined in maximal voluntary isometric contraction (hip, knee and ankle joints) using a load cell. The 30s chair stand, 8 ft up and go, sit and reach, and functional reach tests were used to characterize functional performance. FINDINGS: Women with fibromyalgia showed deficits in lower limb muscle strength, balance and agility and exhibited decreased knee extension peak torque and rate of torque development. In addition, they showed lower hip adduction and extension peak torque in comparison to the control group (P>0.05). Hip extension rate of torque development, duration of fibromyalgia symptoms, overall pain, knee pain, and fibromyalgia impact were strong predictors of the number of falls in patients with fibromyalgia (R2=0.86; P<0.05), when considered collectively. INTERPRETATION: Women with fibromyalgia showed reduced functional performance and lower limb muscle strength, mostly explained by pain. There was a high prevalence of falls in this population, as explained by hip extensors rate of torque development, duration of fibromyalgia symptoms and pain. PMID- 22230424 TI - On the molecular mechanism of GC content variation among eubacterial genomes. AB - BACKGROUND: As a key parameter of genome sequence variation, the GC content of bacterial genomes has been investigated for over half a century, and many hypotheses have been put forward to explain this GC content variation and its relationship to other fundamental processes. Previously, we classified eubacteria into dnaE-based groups (the dimeric combination of DNA polymerase III alpha subunits), according to a hypothesis where GC content variation is essentially governed by genome replication and DNA repair mechanisms. Further investigation led to the discovery that two major mutator genes, polC and dnaE2, may be responsible for genomic GC content variation. Consequently, an in-depth analysis was conducted to evaluate various potential intrinsic and extrinsic factors in association with GC content variation among eubacterial genomes. RESULTS: Mutator genes, especially those with dominant effects on the mutation spectra, are biased towards either GC or AT richness, and they alter genomic GC content in the two opposite directions. Increased bacterial genome size (or gene number) appears to rely on increased genomic GC content; however, it is unclear whether the changes are directly related to certain environmental pressures. Certain environmental and bacteriological features are related to GC content variation, but their trends are more obvious when analyzed under the dnaE-based grouping scheme. Most terrestrial, plant-associated, and nitrogen-fixing bacteria are members of the dnaE1|dnaE2 group, whereas most pathogenic or symbiotic bacteria in insects, and those dwelling in aquatic environments, are largely members of the dnaE1|polV group. CONCLUSION: Our studies provide several lines of evidence indicating that DNA polymerase III alpha subunit and its isoforms participating in either replication (such as polC) or SOS mutagenesis/translesion synthesis (such as dnaE2), play dominant roles in determining GC variability. Other environmental or bacteriological factors, such as genome size, temperature, oxygen requirement, and habitat, either play subsidiary roles or rely indirectly on different mutator genes to fine-tune the GC content. These results provide a comprehensive insight into mechanisms of GC content variation and the robustness of eubacterial genomes in adapting their ever-changing environments over billions of years. PMID- 22230427 TI - Nitric oxide exacerbates Al-induced inhibition of root elongation in rice bean by affecting cell wall and plasma membrane properties. AB - Aluminum (Al) toxicity is one of the most widespread problems for crop production on acid soils, and nitric oxide (NO) is a key signaling molecule involved in the mediation of various biotic and abiotic stresses in plants. Here we found that exogenous application of the NO donor sodium nitroprusside (SNP) exacerbated the inhibition of Al-induced root growth in rice bean [Vigna umbellata (Thunb.) Ohwi & Ohashi 'Jiangnan', Fabaceae]. This was accompanied by an increased accumulation of Al in the root apex. However, Al treatments had no effect on endogenous NO concentrations in root apices. These results indicate that a change in NO concentration is not the cause of Al-induced root growth inhibition and the adverse effect of SNP on Al-induced root growth inhibition should result from increased Al accumulation. Al could significantly induce citrate efflux but SNP had no effects on citrate efflux either in the absence or presence of Al. On the other hand, SNP pretreatment significantly increased Al-induced malondialdehyde accumulation and Evans Blue staining, indicating an intensification of the disruption of plasma membrane integrity. Furthermore, SNP pretreatment also caused greater induction of pectin methylesterase activity by Al, which could be the cause of the increased Al accumulation. Taken together, it is concluded that NO exacerbates Al-induced root growth inhibition by affecting cell wall and plasma membrane properties. PMID- 22230428 TI - Rodent cell transformation assays-a brief historical perspective. AB - In vitro cell transformation is a process characterized by a series of progressive distinctive events that often emulate manifestations occurring in vivo and which are associated with neoplasia. Attendant cellular and sub-cellular alterations include, among others: cellular immortality, phenotypic changes, aneuploidy, genetic variability, cellular disarray, anchorage-independent growth, and tumorigenicity in vivo. Early chemically induced neoplastic transformation studies involved the use of normal diploid (Syrian) hamster embryo (SHE) cells and monitored the formation of morphologically altered colonies. Later investigations employed primarily two established mouse cell lines, i.e. the BALB/c 3T3 A31 cell line and the C3H 10T 1/2 cell line, and monitored the induction of morphologically aberrant foci. In either case, such transformed cellular clusters (colonies and foci) could induce tumors upon inoculation in vivo. Some subsequent noteworthy advancements using these systems included pH adjustments, metabolic supplementation, amplification of expression of formerly latent transformed foci, concurrent detection of mutagenesis and transformation, and use of a Bhas 42 cell line (v-Ha-ras transfected BALB/c 3T3 cells) to detect both tumor initiators and promoters. Over time, such transformation assay systems have been found useful in academic, industry and regulatory laboratories, generally for research purposes, but also occasionally as screening tools for potential chemical carcinogens. Nevertheless, to date, use of these assays for decision-making purposes in the regulatory arena remains elusive and will require comprehensive validation to gain universal acceptance. PMID- 22230430 TI - Merging nano-genotoxicology with eco-genotoxicology: an integrated approach to determine interactive genotoxic and sub-lethal toxic effects of C(60) fullerenes and fluoranthene in marine mussels, Mytilus sp. AB - Whilst there is growing concern over the potential detrimental impact of engineered nanoparticles (ENPs) on the natural environment, little is known about their interactions with other contaminants. In the present study, marine mussels (Mytilus sp.) were exposed for 3 days to C(60) fullerenes (C(60); 0.10-1 mg l( 1)) and a model polycyclic aromatic hydrocarbon (PAH), fluoranthene (32-100 MUg l(-1)), either alone or in combination. The first two experiments were conducted by exposing the organisms to different concentrations of C(60) and fluoranthene alone, in order to determine the effects on total glutathione levels (as a measure of generic oxidative stress), genotoxicity (DNA strand breaks using Comet assay in haemocytes), DNA adduct analyses (using (32)P-postlabelling method) in different organs, histopathological changes in different tissues (i.e. adductor muscle, digestive gland and gills) and physiological effects (feeding or clearance rate). Subsequently, in the third experiment, a combined exposure of C(60) plus fluoranthene (0.10 mg l(-1) and 32 MUg l(-1), respectively) was carried out to evaluate all endpoints mentioned above. Both fluoranthene and C(60) on their own caused concentration-dependent increases in DNA strand breaks as determined by the Comet assay. Formation of DNA adducts however could not be detected for any exposure conditions. Combined exposure to C(60) and fluoranthene additively enhanced the levels of DNA strand breaks along with a 2-fold increase in the total glutathione content. In addition, significant accumulation of C(60) was observed in all organs, with highest levels in digestive gland (24.90 +/- 4.91MUg C(60) g(-1) ww). Interestingly, clear signs of abnormalities in adductor muscle, digestive gland and gills were observed by histopathology. Clearance rates indicated significant differences compared to the control with exposure to C(60), and C(60)/fluoranthene combined treatments, but not after fluoranthene exposure alone. This study demonstrated that at the selected concentrations, both C(60) and fluoranthene evoke toxic responses and genetic damage. The combined exposure produced enhanced damage with additive rather than synergistic effects. PMID- 22230431 TI - Epidemiology of primary central nervous system tumors. PMID- 22230429 TI - Sources of variance in baseline gene expression in the rodent liver. AB - The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver. PMID- 22230432 TI - Molecular biology of brain tumors. AB - Much progress has been made in understanding the molecular genetics of brain tumors, especially gliomas.The development and use of high-throughput platforms that can interrogate molecular lesions on a variety of platforms will increase our ability to identify molecular subclasses of these tumors. Future challenges will include the development of methods to integrate these data among different platforms in order to identify optimal biomarkers and robust subclasses. The ultimate challenge, however, remains the translation of this biological knowledge into improved therapies for patients. PMID- 22230433 TI - Angiogenesis and invasion in cancer. PMID- 22230434 TI - Immunology of brain tumors. AB - Brain tumors of different origin, but notably malignant gliomas, are characterized by their immunosuppressive properties which allow them to escape the host's immune surveillance. The activating immune cell ligands that are expressed by tumor cells, together with potentially immunogenic antigens, are overridden by numerous immune inhibitory signals, with TGF-3 as the master immunosuppressive molecule (Figure 4.1).The ongoing investigation of mechanisms of tumor-derived immunosuppression allows for an increasing understanding of brain tumor immunology. Targeting different mechanisms of tumor-derived immunosuppression, such as inhibition of TGF-[, may represent a promising strategy for future immunotherapeutic approaches. PMID- 22230435 TI - Blood-brain barrier and brain edema. PMID- 22230436 TI - Stem cells in gliomas. PMID- 22230437 TI - Diagnostic neuropathology of tumors of the central nervous system. PMID- 22230438 TI - Neuroimaging. PMID- 22230439 TI - Functional imaging in brain surgery. PMID- 22230440 TI - Imaging brain tumors with PET, SPECT, and ultrasonography. PMID- 22230441 TI - CSF and laboratory analysis (tumor markers). PMID- 22230442 TI - Electrophysiology and intraoperative neurophysiological monitoring. PMID- 22230443 TI - Evaluation and monitoring of peripheral nerve function. PMID- 22230444 TI - Evaluation of cognitive functions and quality of life. PMID- 22230445 TI - Principles of brain tumor surgery. PMID- 22230446 TI - Radiotherapy. PMID- 22230447 TI - Chemotherapy with cytotoxic and cytostatic agents in brain cancer. PMID- 22230448 TI - Molecularly targeted therapy in neuro-oncology. PMID- 22230449 TI - Inhibiting angiogenesis in malignant gliomas. PMID- 22230450 TI - Immunotherapy of brain tumors. PMID- 22230451 TI - Gene therapy. PMID- 22230452 TI - Chemotherapy for brain tumors with polymer drug delivery. PMID- 22230453 TI - Convection-enhanced delivery of therapeutic agents into the brain. AB - CED of therapeutic agents remains a promising strategy for treating malignant gliomas and non-neoplastic neurological diseases. Although initial clinical trials have failed to show survival benefit for new agents delivered via this approach, multiple earlier stage trials have addressed only a fraction of the myriad of technical and technological issues that surround this novel approach. Development of CED has been limited by the fact that both new technologies and novel therapeutic agents are being developed simultaneously.New trials are being planned to investigate agents that can be coinfused with radiographic tracers, as well as novel catheters that avoid problems with backflow and potentially will provide more reliable drug distribution. PMID- 22230454 TI - Management of cognitive deficits and mood disturbance. PMID- 22230455 TI - Steroids and brain tumors. PMID- 22230456 TI - Seizure control in brain tumors. PMID- 22230457 TI - Cancer pain management and palliative care. PMID- 22230458 TI - Clinical trials in neuro-oncology. PMID- 22230461 TI - Molecular mechanisms of Staphylococcus aureus nasopharyngeal colonization. AB - Staphylococcus aureus is responsible for a wide range of different infections ranging in severity from mild to fatal. However, it primarily exists as a commensal organism in a number of different anatomical sites including the nasopharynx. Although colonization itself is a harmless state, colonized individuals are at risk of endogenous infection when S. aureus enters otherwise sterile sites via wounds or indwelling medical devices. As such, studies of colonization may identify important targets for vaccines or other prophylactic approaches. Colonization is a dynamic process; S. aureus must attach to host surfaces, overcome immune components and compete with other commensal microbes. This occurs via a number of surface-attached and secreted proteins and other factors such as wall teichoic acid. In addition, colonizing S. aureus must constantly replicate to maintain its niche and exclude other strains. These myriad interactions provide a strong selective pressure for the maintenance or enhancement of mechanisms of adhesion, invasion and immune evasion. The evolutionary implications of this may explain why S. aureus is such a capable pathogen because many of the proteins involved in colonization have also been identified as virulence factors. This review describes the diverse molecular mechanisms used by S. aureus to colonize the host and discusses how the pressures that have selected for these may have led to its virulence. PMID- 22230462 TI - Sialic acid, periodontal pathogens and Tannerella forsythia: stick around and enjoy the feast! AB - Periodontal pathogens, like any other human commensal or pathogenic bacterium, must possess both the ability to acquire the necessary growth factors and the means to adhere to surfaces or reside and survive in their environmental niche. Recent evidence has suggested that sialic acid containing host molecules may provide both of these requirements in vivo for several periodontal pathogens but most notably for the red complex organism Tannerella forsythia. Several other periodontal pathogens also possess sialic acid scavenging enzymes - sialidases, which can also expose adhesive epitopes, but might also act as adhesins in their own right. In addition, recent experimental work coupled with the release of several genome sequences has revealed that periodontal bacteria have a range of sialic acid uptake and utilization systems while others may also use sialic acid as a cloaking device on their surface to mimic host and avoid immune recognition. This review will focus on these systems in a range of periodontal bacteria with a focus on Ta. forsythia. PMID- 22230463 TI - Signaling transduction analysis in gingival epithelial cells after infection with Aggregatibacter actinomycetemcomitans. AB - Periodontal diseases result from the interaction of bacterial pathogens with the host's gingival tissue. Gingival epithelial cells are constantly challenged by microbial cells and respond by altering their transcription profiles, inducing the production of inflammatory mediators. Different transcription profiles are induced by oral bacteria and little is known about how the gingival epithelium responds after interaction with the periodontopathogenic organism Aggregatibacter actinomycetemcomitans. In the present study, we examined the transcription of genes involved in signaling transduction pathways in gingival epithelial cells exposed to viable A. actinomycetemcomitans. Immortalized gingival epithelial cells (OBA-9) were infected with A. actinomycetemcomitans JP2 for 24 h and the transcription profile of genes encoding human signal transduction pathways was determined. Functional analysis of inflammatory mediators positively transcribed was performed by ELISA in culture supernatant and in gingival tissues. Fifteen of 84 genes on the array were over-expressed (P < 0.01) after 24 h of infection with viable A. actinomycetemcomitans. Over-expressed genes included those implicated in tissue remodeling and bone resorption, such as CSF2, genes encoding components of the LDL pathway, nuclear factor-kappaB-dependent genes and other cytokines. The ELISA data confirmed that granulocyte-macrophage colony-stimulating factor/colony-stimulating factor 2, tumor necrosis factor-alpha and intercellular adhesion molecule-1 were highly expressed by infected gingival cells when compared with control non-infected cells, and presented higher concentrations in tissues from patients with aggressive and chronic periodontitis than in tissues from healthy controls. The induction in epithelial cells of factors such as the pro-inflammatory cytokine CSF2, which is involved in osteoclastogenesis, may help to explain the outcomes of A. actinomycetemcomitans infection. PMID- 22230464 TI - Metabolism of sugars by genetically diverse species of oral Leptotrichia. AB - Leptotrichia buccalis ATCC 14201 is a gram-negative, anaerobic rod-shaped bacterium resident in oral biofilm at the tooth surface. The sequenced genome of this organism reveals three contiguous genes at loci: Lebu_1525, Lebu_1526 and Lebu_1527. The translation products of these genes exhibit significant homology with phospho-alpha-glucosidase (Pagl), a regulatory protein (GntR) and a phosphoenol pyruvate-dependent sugar transport protein (EIICB), respectively. In non-oral bacterial species, these genes comprise the sim operon that facilitates sucrose isomer metabolism. Growth studies showed that L. buccalis fermented a wide variety of carbohydrates, including four of the five isomers of sucrose. Growth on the isomeric disaccharides elicited expression of a 50-kDa polypeptide comparable in size to that encoded by Lebu_1525. The latter gene was cloned, and the expressed protein was purified to homogeneity from Escherichia coli TOP10 cells. In the presence of two cofactors, NAD(+) and Mn(2+) ions, the enzyme readily hydrolyzed p-nitrophenyl-alpha-glucopyranoside 6-phosphate (pNPalphaG6P), a chromogenic analogue of the phosphorylated isomers of sucrose. By comparative sequence alignment, immunoreactivity and signature motifs, the enzyme can be assigned to the phospho-alpha-glucosidase (Pagl) clade of Family 4 of the glycosyl hydrolase super family. We suggest that the products of Lebu_1527 and Lebu_1525, catalyze the phosphorylative translocation and hydrolysis of sucrose isomers in L. buccalis, respectively. Four genetically diverse, but 16S rDNA related, species of Leptotrichia have recently been described: L. goodfellowii, L. hofstadii, L. shahii and L. wadei. The phenotypic traits of these new species, with respect to carbohydrate utilization, have also been determined. PMID- 22230466 TI - Therapy switching, augmentation, and discontinuation in patients with osteoarthritis and chronic low back pain. AB - BACKGROUND: Recommended pain treatments for osteoarthritis (OA) and chronic low back pain (CLBP) are suboptimal, and limited information is available regarding patterns of pharmacotherapy among patients with these conditions. AIMS: Evaluate patterns of therapy switching, augmentation, and discontinuation after treatment initiation with select pain medications in patients with OA and CLBP. METHODS: Using the U.K. The Health Improvement Network (THIN) database, OA and CLBP patients newly prescribed (index-event) nonselective nonsteroidal anti inflammatory drugs (NS-NSAIDs), cyclooxygenase-2 inhibitors (Cox-2s), acetaminophen, tramadol and weak or strong opioids were selected. Descriptive statistics, Kaplan-Meier analyses, and COX proportional hazards models were used to evaluate patterns of changes in pharmacotherapy during the 12-month postindex period. RESULTS: Rates of therapy switching, augmentation, and discontinuation, respectively, were significantly different (all P values<0.0001) across the evaluated medication cohorts for both OA and CLBP patients. Discontinuation rates in OA patients were 91.9% (NS-NSAIDs), 86.9% (Cox-2s), 91.4% (acetaminophen), 89.7% (tramadol), 93.2% (weak opioids), and 84.3% (strong opioids); and in CLBP patients were 97.2% (NS-NSAIDs), 94.0% (Cox-2s), 95.0% (acetaminophen), 92.8% (tramadol), 97.0% (weak opioids), and 86.8% (strong opioids). The rates of switching (range 30.0% to 59.6%) and augmentation (range 7.5% to 15.2%) were lower. Estimated probability evaluations suggested that two-thirds of patients who switched, augmented, or discontinued therapy did so within the first couple of months, and a majority did so within 6-months of treatment initiation. CONCLUSIONS: This study demonstrates that therapy switching and discontinuation of select pain medications were common among OA and CLBP patients in the U.K. and may result from inadequate pain relief or undesirable side effects. PMID- 22230465 TI - Periodontal pathogens affect the level of protease inhibitors in gingival crevicular fluid. AB - In periodontitis, an effective host-response is primarily related to neutrophils loaded with serine proteases, including elastase (NE) and protease 3 (PR3), the extracellular activity of which is tightly controlled by endogenous inhibitors. In vitro these inhibitors are degraded by gingipains, cysteine proteases produced by Porphyromonas gingivalis. The purpose of this study was to determine the level of selected protease inhibitors in gingival crevicular fluid (GCF) in relation to periodontal infection. The GCF collected from 31 subjects (nine healthy controls, seven with gingivitis, five with aggressive periodontitis and 10 with chronic periodontitis) was analyzed for the levels of elafin and secretory leukocyte protease inhibitor (SLPI), two main tissue-derived inhibitors of neutrophil serine proteases. In parallel, activity of NE, PR3 and arginine-specific gingipains (Rgps) in GCF was measured. Finally loads of P. gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola were determined. The highest values of elafin were found in aggressive periodontitis and the lowest in controls. The quantity of elafin correlated positively with the load of P. gingivalis, Ta. forsythia and Tr. denticola, as well as with Rgps activity. In addition, NE activity was positively associated with the counts of those bacterial species, but not with the amount of elafin. In contrast, the highest concentrations of SLPI were found in periodontally healthy subjects whereas amounts of this inhibitor were significantly decreased in patients infected with P. gingivalis. Periodontopathogenic bacteria stimulate the release of NE and PR3, which activities escape the control through degradation of locally produced inhibitors (SLPI and elafin) by host-derived and bacteria derived proteases. PMID- 22230470 TI - Dangkwisoo-san, an herbal medicinal formula, ameliorates acute lung inflammation via activation of Nrf2 and suppression of NF-kappaB. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dangkwisoo-san (DS), an herbal medicinal formula, has long been used in Korea for the treatment of inflammatory complications caused by physical trauma. Although the therapeutic effect of DS is likely associated with anti-inflammatory activity, the precise underlying mechanisms are largely unknown. Here we sought to elucidate the possible mechanisms of anti inflammatory activity of DS. MATERIALS AND METHODS: The water extract of DS was orally fed to C57BL/6 mice for 14 days prior to LPS intranasal instillation for lung inflammation. The effects of DS on lung inflammation were determined by differential cell counting, lung histology, and semi-quantitative RT-PCR of lung sections. The effects of DS on the activities of Nrf2 and NF-kappaB were assessed by western blotting, semi-quantitative RT-PCR, and luciferase reporter assays in RAW 264.7, an NF-kappaB reporter cell line, and HEK 293 transfected with an NF kappaB reporter construct. RESULTS: Mice that were treated with a water extract of DS showed significant attenuation of lung inflammation induced by intranasal lipopolysaccharide (LPS) compared to control mice treated with vehicle. In vitro experiments show that DS activated Nrf2, an anti-oxidant transcription factor that protects from various inflammatory diseases, and induced Nrf2-regulated genes including GCLC, NQO-1 and HO-1. In addition, DS suppressed NF-kappaB activity and reduced the production of pro-inflammatory cytokines. Transfection experiment indicates that inhibition of NF-kappaB likely occurred upstream of IKK complex. Furthermore, DS enhanced the expression of HO-1 and suppressed that of IL-1beta and TNF-alpha in inflamed mouse lungs. CONCLUSIONS: These results suggest that the therapeutic effects of DS are related with suppression of inflammation, which is, at least in part, mediated by activation of anti inflammatory factor Nrf2 and inhibition of pro-inflammatory factor NF-kappaB. PMID- 22230471 TI - Involvement of the L-arginine-nitric oxide pathway in the antinociception caused by fruits of Prosopis strombulifera (Lam.) Benth. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Prosopis strombulifera (Lam.) Benth. is a rhizomatous shrub that grows in the north and central zone of Argentina. In folk medicine, the fruits of this plant have been used as an astringent, anti inflammatory and odontalgic agent and anti-diarrheic. AIM OF THE STUDY: To investigate the antinociceptive effect of ethanol (EE), chloroform (CE) and ethyl acetate (EtOAcE) extracts of Prosopis strombulifera fruits and the involvement of the l-arginine-nitric oxide pathway in this effect. MATERIALS AND METHODS: The antinociceptive effects of the EE, CE and EtOAcE of Prosopis strombulifera fruits were evaluated in vivo using the formalin-induced pain test in mice with aspirin and morphine as reference antinociceptive compounds. The participation of the l arginine-nitric oxide pathway in the antinociceptive effect was investigated in the same animal model using l-arginine as a nitric oxide (NO) precursor. The in vitro inhibitory effect of the extracts on LPS-induced nitric oxide production and iNOS expression was investigated in a J774A.1 macrophage-derived cell line. RESULTS: CE (300mg/kg), in contrast to EE and EtOAcE, caused significant inhibition (p<0.05) of the in vivo nociceptive response. Moreover, CE (100 1000mg/kg, p.o.) produced a dose-dependent inhibition of the neurogenic and the inflammatory phases of the formalin test with inhibition values (at 600mg/kg) of 42+/-7% and 62+/-7%, respectively. CE inhibition was more potent in the inflammatory phase, with an ID(50) of 400.1 (252.2-634.8)mg/kg. The antinociception caused by CE (600mg/kg, p.o.) was significantly attenuated (p<0.05) by i.p. treatment of mice with l-arginine (600mg/kg). In addition, CE (100MUg/mL) produced significant in vitro inhibition (p<0.001) of LPS-induced NO production, which was not observed with EE and EtOAcE at the same concentration. The inhibition of NO production by CE (10-100MUg/mL) was dose-dependent, with an IC(50) of 39.8 (34.4-46.1)MUg/mL, and CE significantly inhibited LPS-induced iNOS expression in J774A.1 cells. CONCLUSIONS: This study supports, in part, the ethnomedical use of Prosopis strombulifera fruits by showing that its CE produces moderate antinociception in vivo. The findings also provide scientific information for understanding the molecular mechanism involved in the analgesic effect of this plant. PMID- 22230472 TI - Structure guided understanding of NAD+ recognition in bacterial DNA ligases. AB - NAD(+)-dependent DNA ligases (LigA) are essential bacterial enzymes that catalyze phosphodiester bond formation during DNA replication and repair processes. Phosphodiester bond formation proceeds through a 3-step reaction mechanism. In the first step, the LigA adenylation domain interacts with NAD(+) to form a covalent enzyme-AMP complex. Although it is well established that the specificity for binding of NAD(+) resides within the adenylation domain, the precise recognition elements for the initial binding event remain unclear. We report here the structure of the adenylation domain from Haemophilus influenzae LigA. This structure is a first snapshot of a LigA-AMP intermediate with NAD(+) bound to domain 1a in its open conformation. The binding affinities of NAD(+) for adenylated and nonadenylated forms of the H. influenzae LigA adenylation domain were similar. The combined crystallographic and NAD(+)-binding data suggest that the initial recognition of NAD(+) is via the NMN binding region in domain 1a of LigA. PMID- 22230473 TI - Parent-reported social support for child's fruit and vegetable intake: validity of measures. AB - OBJECTIVE: To develop and validate measures of parental social support to increase their child's fruit and vegetable (FV) consumption. DESIGN: Cross sectional study design. SETTING: School and home. PARTICIPANTS: Two hundred three parents with at least 1 elementary school-aged child. MAIN OUTCOME MEASURE: Parents completed a questionnaire that included instrumental social support scale (ISSPS), emotional social support scale (ESSPS), household FV availability and accessibility index, and demographics. ANALYSIS: Exploratory factor analysis with promax rotation was conducted to obtain the psychometric properties of ISSPS and ESSPS. Internal consistency and test-retest reliabilities were also assessed. RESULTS: Factor analysis indicated a 4-factor model for ESSPS: positive encouragement, negative role modeling, discouragement, and an item cluster called reinforcement. Psychometric properties indicated that ISSPS performed best as independent single scales with alpha = .87. Internal consistency reliabilities were acceptable, and test-retest reliabilities ranged from low to acceptable. Correlations between scales, subscales, and item clusters were significant (P < .05). In addition, ISSPS and the positive encouragement subscale were significantly correlated with household FV availability. CONCLUSIONS AND IMPLICATIONS: The ISSPS and ESSPS subscales demonstrated good internal consistency reliability and are suitable for impact assessment of an intervention designed to target parents to help their children eat more fruit and vegetables. PMID- 22230474 TI - The bioavailability of ergothioneine from mushrooms (Agaricus bisporus) and the acute effects on antioxidant capacity and biomarkers of inflammation. AB - BACKGROUND: Ergothioneine (ET) is a sulfur containing amino acid that functions as an antioxidant. Mushrooms are a primary source of ET containing from 0.4 to 2.0mg/g (dry-weight). The bioavailability of ET from mushrooms in humans remains unclear. OBJECTIVE: We evaluated the bioavailability of ET in healthy men (n=10) in a pilot study, using a randomized, cross-over, dose-response, postprandial time-course design, conducted at the General Clinical Research Center at Pennsylvania State University in 2009. METHOD: ET was administered through a mushroom test meal containing 8 g and 16 g of mushroom powder. Postprandial red blood cell concentrations of ET were measured. Plasma glucose, triglycerides, HDL, LDL and total cholesterol also were monitored. Biomarkers of inflammation and oxidative stress were evaluated using C-reactive protein and ORAC(total). RESULTS: ET was bioavailable after consuming mushrooms and a trend in the postprandial triglyceride response indicated that there was a blunting effect after both the 8 g and 16 g ET doses were compared with the 0 g dose. Despite ET's antioxidant properties, ORAC(total) values decreased after the 8 g and 16 g mushroom meal. CONCLUSIONS: Ergothioneine from A. bisporus mushrooms is bioavailable as assessed by red blood cell uptake postprandially, and consumption is associated with an attenuated postprandial TG response. PMID- 22230475 TI - Are Bombax buonopozense and Bombax malabaricum possible nutraceuticals for age management? AB - Human longevity and healthy ageing though controversial require extended investigations. Some studies have shown that ageing can be managed by reducing the amounts of free radicals the cells are exposed to. Oxidative stress has been shown to be combated by antioxidants and plant sources are known to generate antioxidants that are efficacious and low in toxicity. This review aims to enlighten on antioxidants from Bombax buonopozense and Bombax malabaricum for prevention, reversal or delay of age-related diseases. Furthermore, it advocates for more studies to enable the shift from research to commercial applications of the antioxidants as nutraceuticals in age management. PMID- 22230476 TI - Neighborhood level risk factors for type 1 diabetes in youth: the SEARCH case control study. AB - BACKGROUND: European ecologic studies suggest higher socioeconomic status is associated with higher incidence of type 1 diabetes. Using data from a case control study of diabetes among racially/ethnically diverse youth in the United States (U.S.), we aimed to evaluate the independent impact of neighborhood characteristics on type 1 diabetes risk. Data were available for 507 youth with type 1 diabetes and 208 healthy controls aged 10-22 years recruited in South Carolina and Colorado in 2003-2006. Home addresses were used to identify Census tracts of residence. Neighborhood-level variables were obtained from 2000 U.S. Census. Multivariate generalized linear mixed models were applied. RESULTS: Controlling for individual risk factors (age, gender, race/ethnicity, infant feeding, birth weight, maternal age, number of household residents, parental education, income, state), higher neighborhood household income (p = 0.005), proportion of population in managerial jobs (p = 0.02), with at least high school education (p = 0.005), working outside the county (p = 0.04) and vehicle ownership (p = 0.03) were each independently associated with increased odds of type 1 diabetes. Conversely, higher percent minority population (p = 0.0003), income from social security (p = 0.002), proportion of crowded households (0.0497) and poverty (p = 0.008) were associated with a decreased odds. CONCLUSIONS: Our study suggests that neighborhood characteristics related to greater affluence, occupation, and education are associated with higher type 1 diabetes risk. Further research is needed to understand mechanisms underlying the influence of neighborhood context. PMID- 22230477 TI - The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. AB - Exosomes are bioactive vesicles derived from the cell's endosomal membrane system and secreted into surrounding body fluids. Exosomes contain cell and cell-state specific cargos of protein, mRNA and miRNA. Exosome formation, cargo content, and delivery to surrounding cells is of immense biological interest considering the role that exosomes are believed to play in various pathological conditions. They aid antigen presentation by immune cells and can exhibit either anti-inflammatory or pro-inflammatory properties depending on the parent antigen-presenting cell's conditioning. Viruses can hijack a host cell's exosomal machinery to evade host defense systems aiding in the trans-infection of viruses. Tumor derived exosomes may help establish an oncogenic niche systemically via delivery of protein, mRNA, and miRNA that can aid angiogenesis, cell proliferation, and cell survival. Exosomes have also been implicated in the spread of neurodegenerative diseases. Studies have shown that exosomes are selectively taken up by cells distal from their release. They can reprogram the recipient cells due to their active molecular cargo. Cell-lineage and state-specific exosomes imply that they may therefore harbor body fluid-based biomarkers of unparalleled accuracy, particularly for tissues that are difficult or impossible to access. Exosome specific membrane proteins provide markers enabling exosome identity and selection, while cell type and cell condition-specific protein, mRNA and miRNA cargo provide a rich potential source of biomarkers. This review serves to provide an overview of the current state of the science in the burgeoning field of exosome biology. PMID- 22230478 TI - Knockdown of HURP inhibits the proliferation of hepacellular carcinoma cells via downregulation of gankyrin and accumulation of p53. AB - We determined earlier that the hepatoma upregulated protein (HURP) is overexpressed in hepatocellular carcinoma (HCC), but the role of this protein during cancer development and progression remains unknown. Here, we observed that the overexpression of HURP in HEK293 cells promoted the ubiquitination of p53 and its degradation by the proteasome. In contrast, HURP knockdown using short hairpin RNA reversed these effects. Knockdown of HURP promoted the accumulation of p53 in SK-Hep-1 cells (p53+/-), and these cells showed reduced proliferation, while the p53-mutant Mahlavu cells were not affected. HURP knockdown did not affect the proliferation of H1299 lung carcinoma cells and Hep3B HCC cells which lack p53. Knockdown of HURP also sensitized SK-Hep-1 cells to cisplatin. On the other hand, the expression of exogenous p53 in H1299 and Hep3B cells was decreased following overexpression of HURP, and these cells showed decreased sensitivity to cisplatin-induced apoptosis. Importantly, overexpression of HURP promoted the proliferation of HEK293 cells in an anchorage-independent manner, and inoculation of SK-Hep-1 cancer cells that expressed short-hairpin RNA to knockdown HURP resulted in smaller tumors in nude mice. Gankyrin, a positive regulator of the E3 ubiquitin ligase MDM2, was found to be upregulated following HURP expression, and gankyrin knockdown decreased the HURP-mediated downregulation of p53. Notably, we detected a positive correlation between elevated HURP and gankyrin protein levels in HCC patients (r(2) = 0.778; N = 9). Taken together, these results indicate that HURP represents an oncogene that may play a role in HCC progression and chemoresistance. PMID- 22230479 TI - Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. AB - Hepatocellular carcinoma (HCC) often displays resistance to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Dovitinib, a multiple tyrosine kinase inhibitor, and tigatuzumab, a novel humanized anti-human death receptor 5 (DR5) agonistic antibody, are both under clinical investigations in HCC. Here, we report that dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through inhibition of signal transducers and activators of transcription 3 (STAT3). Our data indicate that HCC cells showed significant resistance to TRAIL- and tigatuzumab-induced apoptosis. The combination of dovitinib and tigatuzumab restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced apoptosis. Dovitinib down-regulated phospho-STAT3 (Tyr705) (p-STAT3) and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in TRAIL-treated HCC cells. Knockdown of STAT3 by RNA interference overcame apoptotic resistance to TRAIL in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of dovitinib on TRAIL-induced apoptosis. Importantly, silencing SHP-1 by RNA-interference reduced the effects of dovitinib and TRAIL on p-STAT3 and apoptosis, whereas co-treatment of TRAIL and dovitinib increased the activity of SHP-1. Moreover, in vivo the combination of tigatuzumab and dovitinib inhibited Huh-7 xenograft tumor growth. In conclusion, dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab induced apoptosis through a novel machinery: SHP-1 dependent STAT3 inhibition. PMID- 22230480 TI - Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer. AB - Apo 2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), is a member of the TNF family of cytokines, which can induce apoptotic cell death in cells expressing at least one of their specific death receptors, DR4 (TRAIL-R1) or DR5 (TRAIL-R2). In the last decade, the Apo2L/TRAIL system of apoptosis has attracted significant interest as a potential drug targeting pathway for human therapy, due to the ability of that cytokine to trigger apoptosis in various types of cancer cells while displaying low or no toxicity to normal cells. Recent results suggest that manipulating the Apo2L/TRAIL system may be also useful for the treatment of inflammatory disorders such as rheumatoid arthritis. For its possible therapeutic use, a number of receptor-specific Apo2L/TRAIL molecular variants and agonistic monoclonal antibodies have been developed, and some of them are in clinical trials. In addition, Apo2L/TRAIL-resistant tumors can be sensitized to Apo2L/TRAIL by selected novel or classical chemotherapeutic agents, opening new possibilities for combined therapies. We will briefly review the current status of Apo2L/TRAIL based therapies for human disease, their promises and limitations. PMID- 22230481 TI - Risk of acute myocardial infarction after the death of a significant person in one's life: the Determinants of Myocardial Infarction Onset Study. AB - BACKGROUND: Acute psychological stress is associated with an abrupt increase in the risk of cardiovascular events. Intense grief in the days after the death of a significant person may trigger the onset of acute myocardial infarction (MI), but this relationship has not been systematically studied. METHODS AND RESULTS: We conducted a case-crossover analysis of 1985 participants from the multicenter Determinants of Myocardial Infarction Onset Study interviewed during index hospitalization for an acute MI between 1989 and 1994. We compared the observed number of deaths in the days preceding MI symptom onset with its expected frequency based on each patient's control information, defined as the occurrence of deaths in the period from 1 to 6 months before infarction. Among the 1985 subjects, 270 (13.6%) experienced the loss of a significant person in the prior 6 months, including 19 within 1 day of their MI. The incidence rate of acute MI onset was elevated 21.1-fold (95% confidence interval, 13.1-34.1) within 24 hours of the death of a significant person and declined steadily on each subsequent day. The absolute risk of MI within 1 week of the death of a significant person is 1 excess MI per 1394 exposed individuals at low (5%) 10-year MI risk and 1 per 320 among individuals at high (20%) 10-year risk. CONCLUSIONS: Grief over the death of a significant person was associated with an acutely increased risk of MI in the subsequent days. The impact may be greatest among individuals at high cardiovascular risk. PMID- 22230482 TI - Emergency medical service dispatch cardiopulmonary resuscitation prearrival instructions to improve survival from out-of-hospital cardiac arrest: a scientific statement from the American Heart Association. PMID- 22230483 TI - Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes. AB - BACKGROUND: Secretory phospholipase A2 (sPLA(2)) and lipoprotein-associated phospholipase A2 (Lp-PLA(2)) are enzyme biomarkers of increased cardiovascular risk and targets of emerging therapeutic agents. Their relationship to cardiovascular events in the setting of high-dose statin therapy compared with placebo in patients with acute coronary syndrome is not known. METHODS AND RESULTS: sPLA(2) and Lp-PLA(2) mass and activity were measured in 2587 patients in the Myocardial Ischemia Reduction With Acute Cholesterol Lowering (MIRACL) trial at baseline and after 16 weeks of treatment with atorvastatin 80 mg/d or placebo. Baseline levels of sPLA(2) and Lp-PLA(2) mass and activity were not associated with the primary efficacy measure of the trial of death, myocardial infarction, or unstable angina. However, in the overall cohort, baseline sPLA(2) mass predicted risk of death after multivariable adjustment (hazard ratio for 2 fold increase, 1.30; 95% confidence interval, 1.09-1.56; P=0.004). This association remained significant when examined separately in the placebo group but not in the atorvastatin group. Compared with placebo, atorvastatin reduced median sPLA(2) mass (-32.1% versus -23.1%), sPLA(2) activity (-29.5% versus 19.2%), Lp-PLA(2) mass (-35.8% versus -6.2%), and Lp-PLA(2) activity (-24.3% versus 5.4%; P<0.001 for all). Atorvastatin reduced the hazard of death associated with elevated sPLA(2) mass and activity by ~50%. CONCLUSIONS: sPLA(2) mass independently predicts death during a 16-week period after acute coronary syndrome. High-dose atorvastatin significantly reduces sPLA(2) and Lp-PLA(2) mass and activity after acute coronary syndrome and mitigates the risk of death associated with sPLA(2) mass. Atorvastatin may exert antiinflammatory effects on phospholipases that contribute to its therapeutic benefit after acute coronary syndrome. PMID- 22230484 TI - Retrospective analysis of surgery versus endovascular intervention in Takayasu arteritis: a multicenter experience. AB - BACKGROUND: With recent advances in endovascular treatment, percutaneous endoluminal angioplasty has become particularly attractive for arterial lesions of Takayasu arteritis. However, data came from case reports or small series, and the long-term outcome has not been reported. The incidence of potential vascular complications after surgery or endovascular treatment is still to be determined. METHODS AND RESULTS: This retrospective multicenter study analyzed the results and outcomes of 79 consecutive patients with Takayasu arteritis (median age, 39 years; interquartile range [IQR], 25-50 years; 63 women [79.7%]) who underwent 166 vascular procedures (surgery, 104 [62.7%]; endovascular repair, 62 [37.3%]) for the management of arterial complications. After a follow-up of 6.5 years (IQR, 2.2-11.5 years), 70 complications were observed, including restenosis (n=53), thrombosis (n=7), bleeding (n=6), and stroke (n=4). The overall 1-, 3-, 5 , and 10-year arterial complication-free survival rates were 78% (IQR, 69%-88%), 67% (IQR, 57%-78%), 56% (IQR, 46%-70%), and 45% (IQR, 34%-60%), respectively. Among the 104 surgical procedures, 39 (37.5%) presented a complication compared with 31 of the 62 (50%) with endovascular repair. In multivariate analysis, biological inflammation at the time of revascularization (odds ratio, 7.48; 95% confidence interval, 1.42-39.39; P=0.04) was independently associated with the occurrence of arterial complications after the vascular procedure. Patients who experienced complications had higher erythrocyte sedimentation rates (P<0.001) and C-reactive protein (P<0.001) and fibrinogen (P<0.005) serum levels compared with those without complications. CONCLUSIONS: The overall 5-year arterial complication rate was 44%. Biological inflammation increased the likelihood of complications after revascularization in patients with Takayasu arteritis. PMID- 22230485 TI - Serum levels of interleukin (IL)-18, IL-23 and IL-17 in Chinese patients with multiple sclerosis. AB - It has been reported that cytokines play an important role in the pathogenesis of multiple sclerosis (MS). The aim of this study was to evaluate the serum levels of interleukin (IL)-18, IL-23 and IL-17 in Chinese patients with MS. We compared the serum concentrations of pro-inflammatory cytokines IL-18, IL-23 and IL-17 in 39 patients with MS and 39 healthy controls matched with sex and age. Serum cytokines were measured by FlowCytomix, a kind of cytometric bead-based assay. Correlations between the serum levels of the three cytokines and disability (expanded disability status scale, EDSS), disease duration, current age and age at onset were examined. Serum concentrations of all IL-18, IL-23 and IL-17 were significantly higher in MS patients than healthy controls. There were no significant differences of the three cytokines' levels between female and male healthy controls, while the serum IL-18 level was observed significantly higher (P=0.049) in male MS patients than female MS patients. No significant correlations were observed between any of the three cytokines' levels and EDSS, disease duration and current age. However, IL-23 was found negatively correlated with age at onset in male MS patients (r(s)=-0.775, P=0.041). Our data suggest that all IL-18, IL-23 and IL-17 may be involved in the pathogenesis of MS. However, the relationships of the three cytokines and clinical characteristics of MS need to be further investigated in the future. PMID- 22230486 TI - Schisandra chinensis reverses visceral hypersensitivity in a neonatal-maternal separated rat model. AB - Visceral hypersensitivity is an important characteristic feature of functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). This study evaluated the effect of Schisandra chinensis on visceral hyperalgesia induced by neonatal maternal separation (NMS) in an IBS rat model. The visceromotor responses to colorectal balloon distension (CRD) were measured by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activities. NMS control rats (receiving vehicle) underwent aggravated visceral pain in response to CRD as compared to normal rats, evidenced by the reduced pain threshold, enhanced AWR scores and EMG responses. Treatment with a 70% ethanol extract of S. chinensis (0.3g/kg and 1.5g/kg/day) for 7 days resulted in an increase in the pain threshold (NMS control: 19.1+/-1.0mmHg vs low-dose: 24.8+/-1.3mmHg and high-dose: 25.2+/-1.8mmHg, p<0.01), and abolished the elevated AWR and EMG responses to CRD in NMS rats (AUC values of EMG response curve were: 1952+/-202 in NMS control group vs 1074+/-90 in low-dose group and 1145+/-92 in high-dose group, p<0.001), indicating that S. chinensis could reverse the visceral hypersensitivity induced by early-life stress event. The result of ELSA measurement shows that the elevated serotonin (5-HT) level in the distal colon of NMS rats returned to normal level after treatment with S. chinensis. Moreover, the increase in pain threshold in rats treated with S. chinensis was associated with a decline of the mRNA level of 5-HT(3) receptor in the distal colon. All available results demonstrate that S. chinensis can reverse visceral hypersensitivity induced by neonatal-maternal separation, and the effect may be mediated through colonic 5-HT pathway in the rat. PMID- 22230488 TI - Effect of age on exercise-induced alterations in cognitive executive function: relationship to cerebral perfusion. AB - Regular exercise improves the age-related decline in cerebral blood flow (CBF) and is associated with improved cognitive function; however, less is known about the direct relationship between CBF and cognitive function. We examined the influence of healthy aging on the capability of acute exercise to improve cognition, and whether exercise-induced improvements in cognition are related to CBF and cortical hemodynamics. Middle cerebral artery blood flow velocity (MCAv; Doppler) and cortical hemodynamics (NIRS) were measured in 13 young (24+/-5 y) and 9 older (62+/-3 y) participants at rest and during cycling at 30% and 70% of heart rate range (HRR). Cognitive performance was assessed using a computer adapted Stroop task (i.e., test of executive function cognition) at rest and during exercise. Average response times on the Stroop task were slower for the older compared to younger group for both simple and difficult tasks (P<0.01). Independent of age, difficult-task response times improved during exercise (P<0.01), with the improvement greater at 70% HRR exercise (P=0.04 vs. 30% HRR). Higher MCAv was correlated with faster response times for simple and difficult tasks at rest (R(2)=0.47 and R(2)=0.47, respectively), but this relation uncoupled progressively during exercise. Exercise-induced increases in MCAv were similar and unaltered during cognitive tasks for both age groups. In contrast, prefrontal cortical hemodynamic NIRS measures [oxyhemoglobin (O(2)Hb) and total hemoglobin (tHb)] were differentially affected by exercise intensity, age and cognitive task; e.g., there were smaller increases in [O(2)Hb] and [tHb] in the older group between exercise intensities (P<0.05). These data indicate that: 1) Regardless of age, cognitive (executive) function is improved while exercising; 2) while MCAv is strongly related to cognition at rest, this relation becomes uncoupled during exercise, and 3) there is dissociation between global CBF and regional cortical oxygenation and NIRS blood volume markers during exercise and engagement of prefrontal cognition. PMID- 22230487 TI - Elevated levels of serum IL-5 are associated with an increased likelihood of major depressive disorder. AB - BACKGROUND: Inflammatory mediators in both the peripheral circulation and central nervous system (CNS) are dysregulated in major depressive disorder (MDD). Nevertheless, relatively little is known about the role of the T-helper (Th)-2 effector cytokines interleukin (IL)-5 and IL-13 in MDD. METHODS: We examined the serum levels of these cytokines and a Th-1 comparison cytokine, interferon (IFN) gamma, in 116 individuals (MDD, n = 58; controls, n = 58). RESULTS: In our basic multivariate model controlling for the effects of potential confounders on the associations between MDD and the examined cytokines, each 1-unit increase in the serum IL-5 level increased the likelihood of belonging to the MDD group by 76% (OR 1.76, 95% CI 1.03-2.99, p = 0.04; model covariates: age, gender, marital status, daily smoking and alcohol use). The likelihood further increased in models additionally controlling for the effects of the use of antidepressants and NSAIDS, and a diagnosis of asthma. No such associations were detected with regard to IL-13 (OR 1.08, 95% CI 0.96-1.22, p = 0.22) or IFN-gamma (OR 1.02, 95% CI 0.99 1.05, p = 0.23). CONCLUSIONS: Elevated levels of IL-5, which uses the neural plasticity-related RAS GTPase-extracellular signal-regulated kinase (Ras-ERK) pathway to mediate its actions in the central nervous system (CNS), could be one of the factors underlying the depression-related changes in CNS plasticity. PMID- 22230489 TI - Does the oxidative stress theory of aging explain longevity differences in birds? II. Antioxidant systems and oxidative damage. AB - The oxidative damage hypothesis of aging posits that the accumulation of oxidative damage is a determinant of an animal species' maximum lifespan potential (MLSP). Recent findings in extremely long-living mammal species such as naked mole-rats challenge this proposition. Among birds, parrots are exceptionally long-living with an average MLSP of 25 years, and with some species living more than 70 years. By contrast, quail are among the shortest living bird species, averaging about 5-fold lower MLSP than parrots. To test if parrots have correspondingly (i) superior antioxidant protection and (ii) lower levels of oxidative damage compared to similar-sized quail, we measured (i) total antioxidant capacity, uric acid and reduced glutathione (GSH) levels, as well as the activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase and catalase), and (ii) markers of mitochondrial DNA damage (8-OHdG), protein damage (protein carbonyls) and lipid peroxidation (lipid hydroperoxides and TBARS) in three species of long-living parrots and compared these results to corresponding measures in two species of short-living quails (average MLSP=5.5 years). All birds were fed the same diet to exclude differences in dietary antioxidant levels. Tissue antioxidants and oxidative damage were determined both 'per mg protein' and 'per g tissue'. Only glutathione peroxidase was consistently higher in tissues of the long-living parrots and suggests higher protection against the harmful effects of hydroperoxides, which might be important for parrot longevity. The levels of oxidative damage were mostly statistically indistinguishable between parrots and quails (67%), occasionally higher (25%), but rarely lower (8%) in the parrots. Despite indications of higher protection against some aspects of oxidative stress in the parrots, the pronounced longevity of parrots appears to be independent of their antioxidant mechanisms and their accumulation of oxidative damage. PMID- 22230490 TI - Is maternal nutrition knowledge more strongly associated with the diets of mothers or their school-aged children? AB - OBJECTIVE: Maternal nutrition knowledge has frequently been identified as an important target for nutrition promotion interventions. The aim of the present study was to investigate whether maternal nutrition knowledge is more strongly associated with the mother's own diet or that of her child. DESIGN: Cross sectional multivariate linear regression with interactions analyses of survey data. SETTING: Socio-economically disadvantaged neighbourhoods in Victoria, Australia. SUBJECTS: Five hundred and twenty-three mothers and their children who participated in the Resilience for Eating and Physical Activity Despite Inequality (READI) study, a cross-sectional survey study conducted in 2009 among women and their children residing in socio-economically disadvantaged neighbourhoods. RESULTS: In adjusted models, for three (vegetable, chocolate/lollies and soft drink consumption) out of the seven dietary outcomes assessed, there was a significant association between maternal nutrition knowledge and maternal diet, whereas for the children's diets none of the seven outcomes were associated with maternal nutrition knowledge. Statistical comparison of regression coefficients showed no difference between the maternal nutrition knowledge-maternal diet association and the maternal nutrition knowledge-child diet association. CONCLUSIONS: Promoting maternal nutrition knowledge may represent an important avenue for improving diet in mothers from socio-economically disadvantaged neighbourhoods, but more information is needed on how and when this knowledge is translated to benefits for their children's diet. PMID- 22230491 TI - Does cognitive impairment influence quality of life among nursing home residents? AB - PURPOSE: We investigated the relationship between cognitive status and quality of life (QOL) of Minnesota nursing home (NH) residents and the relationship between conventional or Alzheimer's special care unit (SCU) placement and QOL. The study may inform development of dementia-specific quality measures. DESIGN AND METHODS: Data for analyses came from face-to-face interviews with a representative sample of 13,130 Minnesota NH residents collected through the 2007 Minnesota NH Resident Quality of Life and Consumer Satisfaction survey. We examined 7 QOL domains: comfort, meaningful activities, privacy, environment, individuality, autonomy, relationships, and a positive mood scale. We applied multilevel models (resident and facility) to examine the relationship between the resident's score on each QOL domain and the resident's cognitive impairment (CI) level and SCU placement after controlling for covariates, such as activities of daily living dependency, pain, depression or psychiatric diagnosis, and length of stay. RESULTS: Residents with more severe CI reported higher QOL in the domains of comfort and environment and lower QOL in activities, individuality, privacy and meaningful relationships, and the mood scale. Residents on SCU reported higher QOL in the meaningful activities, comfort, environment, and autonomy domains but had lower mood scores. IMPLICATIONS: Our findings point to QOL domains that show significant variation by CI and thus may be of greatest interest to consumers, providers, advocacy groups, and other stakeholders committed to improving dementia care. Findings are particularly applicable to the development of NH quality indicators that more accurately represent the QOL of NH residents with CI. PMID- 22230493 TI - Forget me not: dementia in prison. AB - The number of older adults with dementia in U.S. prisons is rapidly rising. Yet, the vast majority of this marginalized subgroup of the aging population is left neglected behind bars without access to adequate medical and mental health care services. We assert that proactive, interdisciplinary collaborative efforts to improve practice, policy, and research and to develop a high-quality evidence based continuum of care for this aging population are urgently needed. The overarching goals of this paper are to raise awareness of the life and experiences of persons with dementia in prison and to stimulate discussion, research, and advocacy efforts for this forgotten subgroup of older Americans. We describe the growing number of older adults with dementia in U.S. prisons, high risk factors for dementia present in the prison population, and the life and experience of persons with dementia in the culture and environment of prison that is primarily not designed for them. We review the current state of services and programs for dementia in prison. We conclude by proposing practice, policy, and research-related priority areas and strategies for interdisciplinary gerontological responses. PMID- 22230492 TI - Rural-urban differences in end-of-life nursing home care: facility and environmental factors. AB - PURPOSE OF THE STUDY: This study examines urban-rural differences in end-of-life (EOL) quality of care provided to nursing home (NH) residents. DATA AND METHODS: We constructed 3 risk-adjusted EOL quality measures (QMs) for long-term decedent residents: in-hospital death, hospice referral before death, and presence of severe pain. We used CY2005-2007 100% Minimum Data Set, Medicare beneficiary file, and inpatient and hospice claims. Logistic regression models were estimated to predict the probability of each outcome conditional on decedents' risk factors. For each facility, QMs were calculated as the difference between the actual and the expected risk-adjusted outcome rates. We fit multivariate linear regression models, with fixed state effects, for each QM to assess the association with urban-rural location. RESULTS: We found urban-rural differences for in-hospital death and hospice QMs, but not for pain. Compared with NHs located in urban areas, facilities in smaller towns and in isolated rural areas have significantly (p < .001) worse EOL quality for in-hospital death and hospice use. Whereas the differences in these QMs are statistically significant between facilities located in large versus small towns, they are not statistically significant between facilities located in small towns and isolated rural areas. IMPLICATIONS: This study provides empirical evidence for urban-rural differences in EOL quality of care using a national sample of NHs. Identifying differences is a necessary first step toward improving care for dying NH residents and for bridging the urban-rural gap. PMID- 22230494 TI - [Effects of ginkgolide B on proliferation, phagocytosis, NO and ROS production of murine peritoneal macrophages in vitro]. AB - AIM: To explore the potential immunomodulatory effects and related mechanisms of ginkgolide B (GB), a known potent antagonist of platelet-activating factor receptor, we investigated the proliferation, phagocytosis, NO and ROS production of macrophage. METHODS: After murine peritoneal macrophages (PMs) preparation, PMs were treated with different concentrations of GB before culture time and then activated by LPS. Drug toxicology and PM proliferation were measured by MTT assays. Fluorescent beads ingestion and flow cytometry were used to assess phagocytosis of LPS-activated PMs. Griess reagent system was used to determine the amount of LPS-induced NO production. H2DCFDA labeling and flow cytometry were used to trace ROS level of both rest and LPS-activated PMs. RESULTS: In a dose-dependent manner, GB (5, 10, and 20 MUmol/L) significantly suppressed the phagocytosis as well as NO and ROS production at 24 h and inhibited cell proliferation at 48 h after LPS stimulation. CONCLUSION: According to these interesting effects of GB on macrophage behaving and functioning, it's quite reasonable to do further studies of GB as a nature occurring immunomodulator candidate. PMID- 22230495 TI - [Transcriptional regulatory properties of DNA sequence upstream of the human ezrin gene promoter in nasopharyngeal carcinoma cells]. AB - AIM: To investigate transcriptional regulatory properties of DNA sequence upstream of the ezrin gene promoter in nasopharyngeal carcinoma CNE2 cells. METHODS: A series of reporter gene expression vectors carrying ezrin-1541/-706 sequence were constructed. In forward or reverse orientation, the ezrin -1541/ 706 segment was located upstream of the luc gene in pGL3-Basic, upstream of the ezrin promoter or SV40 promoter, or downstream of the luc gene controlled by ezrin promoter or SV40 promoter. These plasmids were transfected into CNE2 cells for luciferase assay. RESULTS: In CNE2 cells, when the ezrin -1541/-706 was located upstream of luc gene in pGL3-Basic in the forward orientation, it exhibited transcriptional activation about 50% of ezrin promoter; while this transactivation nearly abolished when this segment was reversed. When this segment was located upstream of the ezrin promoter or SV40 promoter in the forward orientation, it dramatically increased luciferase expression. However, the transcriptional enhancement disappeared when this segment was located upstream of promoters in the reverse orientation, or downstream of reporter genes in the forward or reverse orientation. CONCLUSION: In CNE2 cells, the DNA sequence upstream of the ezrin promoter could exhibit transcriptional activation and enhancement, in a position- and orientation-dependent manner. PMID- 22230496 TI - [Quercetin affects leptin and its receptor in human gastric cancer MGC-803 cells and JAK-STAT pathway]. AB - AIM: Quercetin affects the expressions of leptin and its receptor in human gastric cancer MGC-803 cells and JAK-STAT pathway. METHODS: The cultured MGC-803 cells were divided into three groups: CONTROL GROUP: the cultured cells without quercetin, and Quercetin group: the cultured cells with quercetin(40 MUmol/L), and AG490group: the cultured cells with AG490(40 MUmol/L)The expressions of Leptin, Leptin receptor and P-STAT3 were detected in protein level by immunocytochemical and Western bloting method respectively. The expressions of Leptin, Leptin receptor were detected in mRNA level by RT-PCR method. MGC-803 cell cycle was arrest by flow cytometry (FCM); MGC-803 cell apoptosis ratio by apoptotic marker An-necxinV. RESULTS: The protein expression of Leptin, Leptin receptor, P-STAT3 and the the mRNA expression of Leptin and Leptin receptor were significantly increased (P<0.05), compared with the control group.There was the rectilinear correlation relationship not only between Leptin and P-STAT3 protein(r=0.741, P<0.05) but also between Leptin receptor and P-STAT3 protein(r=0.693, P<0.05). FCM analysis showed that quercetin arrested MGC-803 cells at the G2/M phase, The ratio of apoptotic and necrosic cells increased with added quercetin concentration. CONCLUSION: Quercetin could inhibit the Proliferation of MGC-803 cells. It is probably relevant to the down regulation the expressions of Leptin and Leptin receptor protein, Leptin mRNA and Leptin receptor mRNA by JAK-STAT pathway. PMID- 22230497 TI - [The effect of human placenta-derived mesenchymal stem cells on cord blood CD8(+);T cells activation, cellcycle and secretion of IL-17]. AB - AIM: To study the effect of human placenta-derived mesenchymal stem cells (hPMSCs) on cord blood CD8(+);T cell activation, cell cycle and secretion of IL 17, and to provide the theoretical basis for it application in the cell-based therapies. METHODS: hPMSCs were isolated from mature placenta by the method of digestion. Then hPMSCs were cultured, expanded in vitro, and were used in test after the third passage. CD8(+);T cells were sorted from cord blood with immunomagetic beads. FCM was used to analyze the expression of early activation phenotype, cell cycle of cord blood CD8(+);T cells and cytokine secretion. RESULTS: CD8(+);T cells stimulated by PHA in the presence of hPMSCs were arrested at G0/G1 phase. The expression of the early activation marker CD25 and CD69 of cord blood CD8(+);T cells was inhibited in the presence of hPMSCs. While, IL 17secretion of cord blood CD8(+);T cells stimulated by PMA was increased. CONCLUSION: hPMSCs can suppress the activation of cord blood CD8(+);T cells by altering T cell cycle; up-regulate the level of IL-17 secreted by cord blood CD8(+);T cells. PMID- 22230498 TI - [mTOR/p70s6k signaling pathway is involved in megakaryocyte polyploidization]. AB - AIM: To investigate the mechanisms of megakaryocyte polyploid cell cycle control. METHODS: The expression and phosphorylation of mTOR/p70s6k pathway proteins was detected by western blot. Double-labeling techniques were used to investigate in which of the phase of the polyploid cell cycle S6K1 at Thr421/Ser424 are phosphorylated. RESULTS: Nocodazole induced a relatively synchronized polyploidization in Dami cells. The expression of mTOR and the phosphorylation of mTOR at Ser2448 increased when Dami cells begin to progress from G1 to S-phase in cell cycle. Analysis of flow cytometry showed that phosphorylation of S6K1 at Thr421/Ser424 increased at G2/M-phase. CONCLUSION: mTOR/S6K1 pathway is involved in megakaryocyte polyploid cell cycle control. PMID- 22230499 TI - [The efficacy of enhancing murine zona pellucid 3 DNA vaccine immunized through intranasal vaccination by IL-15]. AB - AIM: To observe the efficacy of enhancing murine zona pellucid 3(mZP3) DNA vaccine immunized through intranasal vaccination by IL-15 as adjuvant and chitosan as delivery vactor. METHODS: C57BL/6 mice were delivered with chitosan loaded mZP3 DNA vaccine or IL-15+pcD-mZP3 vaccine by intranasal route, and to detect specific IgG in serum and sIgA in vaginal fluid by indirect ELISA, and to perform fertility experiment that all female C57BL/6 mice were mated(one male for each female) with normal males of similar age. To do histology analysis of immunized mice ovary and lungs for morphology of ovary. RESULTS: The results of ELISA showed IL-15 can promote IgG antibody level of immunized mice, and the fertility rate was decreased to some degrees. CONCLUSION: IL-15 and chitosan can enhance the antibody levels induced by mZP3 DNA vaccine, and reduce murine fertility rate to a certain extent. PMID- 22230500 TI - [Effects and molecular mechanisms of inhibiting FOXM1 expression on ovarian cancer cell line SKOV3 by Lentiviral vector]. AB - AIM: To investigate the effects and possible molecular mechanisms of inhibiting FOXM1 expression on SKOV3 cells by lentiviral vector targeting FOXM1 shRNA. METHODS: SKOV3 cells were infected by lentiviral vector targeting FOXM1 shRNA with a multiplicity of infection (MOI) of 20, then growth curve of SKOV3 cells was determined by MTT assay, cell cycle was analysed by flow cytometry(FCM), and the expression of mRNA and protein of FOXM1, Cyclin D1, PLK1 by Real time PCR and Western blot. RESULTS: Lentiviral vector targeting FOXM1 shRNA with a multiplicity of infection (MOI) of 20 could significantly inhibit the growth of SKOV3 cells. After infected by lentiviral vector targeting FOXM1 shRNA, the G(0);/G(1); phase cells increased and the S-phase cells decreased, and the expression of mRNA and protein of FOXM1, Cyclin D1, PLK1 of SKOV3 cells were significantly down-regulated. CONCLUSION: Inhibiting FOXM1 expression has a significantly effect of inhibiting proliferation on SKOV3 cells. Blocking SKOV3 cells in the G(0);/G(1); phase by down-regulating the expression of Cyclin D1, PLK1 protein may be its mechanism. PMID- 22230501 TI - [Effects on proliferation and apoptosis of serum-induced rabbit VSMCs by adenovirus-mediated transfer of the Gax gene]. AB - AIM: To investigate the effect of a recombinant replication-incompetent Ad5-hGax vector on the proliferation and apoptosis of serum-induced rabbit vascular smooth muscle cells (VSMCs) in vitro, and to provide an important support that Gax would be an optimal gene for gene therapy in vein graft failure. METHODS: The Ad5 hGax vector was infected into rabbit VSMCs, then the protein level of rabbit VSMCs was detected at 1 d, 3 d, 5 d by Western blot, respectively. MTT was applied to observe the inhibitory effects of overexpressed hGax on serum-induced rabbit VSMCs. the apoptosis of serum-induced rabbit VSMCs was measured by using flow cytometry in 72 h after transfection. RESULTS: The protein expression of human Gax in the Ad5-hGax transfected cells on 1st day, 3rd day, 5th day was determined; MTT showed that the proliferation of serum-induced rabbit VSMCs was significantly inhibited in Ad5-hGax group at 48 h, 72 h and 96 h (P<0.05, respectively); After transfecting for 72 h, flow cytometry analysis showed that the number of the apoptosis cells was increased in serum-induced Rabbit VSMCs of Ad5-hGax group (P<0.05). CONCLUSION: Overexpressed hGax could inhibit the proliferation of serum-induced Rabbit VSMCs and induce their apoptosis. These findings carry significant implications for adenovirus vector-based Gax gene therapies for vein graft failure. PMID- 22230502 TI - [Preparation and identification of monoclonal antibody against human GCRG213]. AB - AIM: To prepare and characterize the monoclonal antibody against human GCRG213. METHODS: The HIS-GCRG213 fusion protein was expressed in E.coli. Mice were immunized with the purified HIS-GCRG213 protein. Hybridoma cell lines secreting monoclonal antibodies against GCRG213 were screened by regular cell fusion and subcloning approach. The titer and specificity of the antibody was characterized by ELISA and Western blot, respectively. The expression of GCRG213 was determined using immunohistochemistry technique on paraffin-embedded tissue sections from normal gastric mucosal tissues and advanced gastric cancer. RESULTS: The HIS-GCRG213 fusion protein with relative molecular mass of 20 800 was over expressed in E.coli. Two hybridoma cell lines which secreted monoclonal antibody specifically against human GCRG213 fusion protein were successfully obtained. The ascite titers of this monoclonal antibody reached 1:10(6);. Western blot analysis showed that the monoclonal antibody could bind to the recombinant HIS-GCRG213 protein specifically.The immunohistochemistry showed that GCRG213 were expressed higher in gastric cancer tissues than in normal ones. CONCLUSION: The monoclonal antibody against human GCRG213 with high titer and specificity has been successfully prepared, which could be utilized as a useful reagent for further studying the biological function of the GCRG213. PMID- 22230503 TI - [Cloning and identification of the variable region gene of mouse anti-human BAFF mAb]. AB - AIM: To obtain the variable region gene sequence of heavy and light chain of mouse anti-human BAFF monoclonal antibody (mAb) on base of BAFF mAb which was cloned in our laboratory. METHODS: The total RNA was extracted from mouse anti human BAFF mAb hybridoma cell line FMMUB(4);, and then the RNA was reverse transcribed into cDNA. Specific primers were designed to amplify the targeted gene. The targeted gene fragments were inserted into vectors to construct the clone vectors. The gene sequences were analyzed after identified by positive clones screening and restrictive enzyme digestion. RESULTS: The variable region gene sequences of mouse anti-human BAFF mAb were obtained. CONCLUSION: The variable region gene sequences of mouse anti-human BAFF mAb will provide experimental basis for further study on constructing engineered antibodies. PMID- 22230504 TI - [Preparation and property study of the recombinant Camel anti-SpaA-N single domain antibodies]. AB - AIM: In order to obtain single domain antibody against surface protective antigen A (SpaA)of Erysipelothrix rhusiopathiae. METHODS: The SpaA-N recombinant protein was used to screen binders from Bactrian camel VHH phage display library. After sequencing, the interested VHH gene fragments were subcloned into pET-30a vector to overexpress the protein in E.coli BL21. The binding specificity of the recombinant VHH with SpaA-N was determined by Western blotting. The thermal stability of single-domain antibody was evaluated by ELISA. RESULTS: By enrichment of screening, 2 clones were selected. Recombinant single domain antibodies purified by Ni-ion affinity chromatography showed a single band at M(r); 29 000, 23 000 on SDS-PAGE. ELISA results showed that VHH can bind its antigen specifically. After thermal denaturation, VHH can restore the antigen binding ability after refolding. Western blotting results showed that the recombinant VHH specific bind surface protective antigen of Erysipelothrix rhusiopathiae at M(r); 66 000. Two VHH single domain antibodies with high thermal stability and good antigen binding specificity were identified by screening Bactrian camel VHH phage display library. CONCLUSION: Two single domain antibodies that specifically aggulated SpaA-N is obtained, which provide the basis for further study in the immune role of single domain antibody against Erysipelothrix rhusiopathiae infection. PMID- 22230505 TI - [The expression and clinical significance of Annexin II in clear-cell renal cell carcinoma]. AB - AIM: To discuss the difference of annexinII expression between the Clear-Cell Renal Cell Carcinoma(ccRCC) and the corresponding normal renal tissues, and to reveal the clinical significance of Annexin II expression in ccRCC. METHODS: Western blotting was used to detect the expression of Annexin II in 29 samples of fresh ccRCC and the corresponding normal renal tissues. Annexin II expression was examined in 120 samples of paraffin-embedding ccRCC and the corresponding normal renal tissues using immunohistochemistry. Correlations with Annexin IIexpression and clinic-pathological parameters were analyzed. RESULTS: There was expression of Annexin II in both ccRCC and the corresponding normal renal tissues. In ccRCC tissues, the total levels of Annexin II proteins were significantly higher than that in the corresponding normal renal tissues (P<0.01). The positive rate of AnnexinII expression in immunohistochemistry was 67.5% in the ccRCC tissues, existing significant difference compared with the corresponding normal renal tissues (P<0.01). Expression of Annexin II in ccRCC mainly showed membranous staining. Annexin II expression level was positively correlated with TNM stage (P<0.05), histology grade (P<0.05), renal capsule infiltration (P<0.01) and distant metastasis (P<0.01) of ccRCC. Moreover, Annexin II expression level was significantly correlated with ccRCC patients'5 years survival rate(P<0.01). CONCLUSION: Overexpression of AnnexinII in the ccRCC is closely correlated with the ccRCC development. It may play an important role in the process of ccRCC invasion and metastasis. PMID- 22230506 TI - [The research on the expression and localization of multiple myeloma associated antigen MMSA-1]. AB - AIM: To study the expression profile of multiple myeloma associated gene (MMSA 1), explore the relationship between its expression level and MM cells' proliferation as well as its celluler localization. METHODS: The mRNA levels of MMSA-1 and DKK1 genes were detected by RT-PCR in patients with MM, leukemia, non-tumor diseases and in the healthy donors, respectively. Then, their correlation was analyzed. The effects of Ibandronate Sodium on the cell cycle and early apoptosis of 8226 cells were analyzed by flow cytometry, and the effect on its protein expression was analyzed by immunohistochemistry. Construct MMSA-1 eukaryotic expression vector pCMV-Myc-MMSA-1, and antibody immunohistochemistry was applied to study the cellular localization of the protein. RESULTS: MMSA-1 gene was expressed in all of the specimens described above, and the mRNA level in MM was much higher than that in the others, just like DKK1 gene. More than that, their expression exhibited a significant positive correlation. Ibandronate Sodium could inhibit cell proliferation by a cell-cycle arrest in S-phase. By reducing cell maturation promoting factor release, it stopped the cell cycle, promoted their early apoptosis and decreased the protein expression of MMSA-1. MMSA-1 protein principally distributed on cell membranes, however, there are a small quantity in cytalplasm. CONCLUSION: These results revealed that MMSA-1 may play a pivotal role in MM proliferation and osteolysis destruction, which lay the foundation for the further study of biological function and immunotherapy based on MMSA-1. PMID- 22230507 TI - [Effect of HIF-1alpha and its mechanism on invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo]. AB - AIM: To investigate the effects of HIF-1alpha by RNAi on invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo, in order to explore its probable mechanism. METHODS: CoCl(2); was used to mimic tumor hypoxic microenvironment. mRNA and protein levels of HIF-1alpha, E-cadherin and MMP-2 under hypoxia were detected by RT-PCR and immunohistochemistry. The effects of silencing HIF-1alpha by RNAi on HIF-1alpha, E-cadherin and MMP-2 mRNA were detected by RT-PCR. The effect of RNAi on invasion and metastasis were tested by cell scratch assay and transwell chambers. The Eca109-implanted nude mouse model was established, and the effects of HIF-1alphaon tumor growth and lymphoid node metastasis were observed. The expressions of HIF-1alpha, E-cadherin and MMP-2 in transplanted tumors were detected by Western blot, and the effects of HIF-1alpha on tumor growth, invasion and metastasis in vitro and in vivo were analyzed. RESULTS: Hypoxia up-regulated HIF-1alpha protein, mRNA and protein levels of E cadherin down-regulated, and MMP-2 up-regulated, while had no effect on HIF 1alpha mRNA . RNAi could silencing HIF-1alpha effectively, and inhibited E cadherin or MMP-2 decreased or increased, respectively. The migration and the number of invading cells decreased (P<0.05) after silencing HIF-1alpha by RNAi. The tumor volume was much smaller, lymph node metastasis rate lower as well in vivo (P<0.05). CONCLUSION: Via its effects on E-cadherin and MMP-2, HIF-1alpha regulate the growth, invasion and metastasis of Eca109 cells in vitro and in vivo. PMID- 22230508 TI - [Construction of eukaryotic expression vector and package of lentivirus vector encoding human leukocyte antigen-G5]. AB - AIM: To construct a lentiviral expression vector carrying HLA-G5. METHODS: The CDs region of HLA-G5 gene was cloned into the lentiviral vector by restriction endonuclease Nhe I/Not I digestion and T4DNA ligase ligation. After transformation into completent E.coli cells, the candidate clones were identified by PCR and kidney cell line 293T cells by lipofectamine 2000 to produce the lentiviral particles, and the viral titer was determined. RESULTS: The lentiviral vector pCDH-CMV-MCS-EF1-copGFP Vector for HLA-G5 was constructed successfully, and the virus in the supernatant reached a titer of TU/mL. CONCLUSION: This research completed the package of lentivirus vector encoding HLA G5 as a tool for further study. PMID- 22230509 TI - [Establishment of a sandwich ELISA for testing serum sB7-H3 and detection of sB7 H3 levels in liver disease]. AB - AIM: To establish quantitative ELISA for soluble sB7-H3 and evaluate its clinical application. METHODS: Two mAbs of mouse anti-human sB7-H3(4H7 and 2E6)established by our lab were used. The mAb 4H7 was used as coating antibody and the 2E6 as a sandwich antibody, which recognized a different epitope and was labeled by biotin. The serum sB7-H3 levels of healthy volunteers and patients were measured by this method. RESULTS: Sandwich ELISA was established with the linear range covering from 8.192 ng/L to 2 000 ng/L. The outcomes of repeatability test, recovery test, stability test and specificity test were quite good. The increased levels of sB7-H3 were found in schistosomiasis cirrhosis, the reduced levels in severe hepatitis and the difference in both situations showed significance. CONCLUSION: A specific and sensitive sandwich ELISA is developed, the detection in liver disease indicates that the ELISA kit provides a potential tool in the clinical application. PMID- 22230510 TI - Infant feeding practices in Bhaktapur, Nepal: a cross-sectional, health facility based survey. AB - BACKGROUND: Promotion of proper breastfeeding practices for the first six months of life is the most cost-effective intervention for reducing childhood morbidity and mortality. However, the adherence to breastfeeding recommendations in many developing countries is not satisfactory. The aims of the study were to determine breastfeeding and infant feeding patterns at nine months of age and to assess factors influencing exclusive breastfeeding practices. METHODS: In Bhaktapur, Nepal, we carried out a cross-sectional survey of 325 infants who came for measles vaccination at the age of nine months. Mothers were interviewed on details regarding feeding of their child and health since birth. RESULTS: Three quarters of all mothers reported that they did not receive any information on breastfeeding during the antenatal visit. Two hundred and ninety five (91%) mothers gave colostrum and 185 (57%) initiated breastfeeding within one hour of delivery. The prevalence of exclusively breastfeeding at 1, 3 and 6 months were 240 (74%), 78 (24%) and 29 (9%), and partial feeding was initiated in 49 (15%), 124 (38%) and 257 (79%) babies, respectively. The main reason, according to the mother, for introducing other foods before six months of age was insufficient breast milk. In logistic regression analyses, mother's knowledge on how long child should be given only breast milk and not living in joint families were associated positively with exclusive or predominant breastfeeding for four months or beyond. CONCLUSIONS: Despite the high proportion of mothers who initiated breastfeeding immediately after birth, continuation of exclusive breastfeeding for up to six months was not common. Very few mothers received any information on breastfeeding during the antenatal visit, indicating a need for counseling on exclusive breastfeeding. Possible options for this counseling could be during antenatal visits and at regular clinic visits for vaccination. PMID- 22230511 TI - Low-grade gliomas. PMID- 22230512 TI - Anaplastic astrocytomas. PMID- 22230513 TI - Anaplastic oligodendroglial tumors. PMID- 22230514 TI - Glioblastoma. PMID- 22230515 TI - Gliomatosis cerebri. PMID- 22230516 TI - Primary central nervous system lymphoma. PMID- 22230517 TI - Medulloblastoma and primitive neuroectodermal tumors. AB - Medulloblastomas and sPNETs remain highly problematic tumors to treat. Prognosis has improved over the past two decades, but many children who survive treatment have significant long-term sequelae. The improvements in outcome have been due to advances in surgical techniques, the wider use of chemotherapy, and the more judicious use of radiotherapy. For further improvements,the recent impressive discoveries concerning molecular mechanisms of embryonal tumor origin, development,and growth will need to be translated into molecularly based, risk adapted therapy. PMID- 22230518 TI - Ependymomas, neuronal and mixed neuronal-glial tumors, dysembroblastic neuroepithelial tumors, pleomorphic xanthoastrocytomas, and pilocytic astrocytomas. PMID- 22230519 TI - Neurofibromatosis and other genetic syndromes. PMID- 22230520 TI - Brainstem tumors. PMID- 22230521 TI - Optic, hypothalamic, and thalamic tumors. PMID- 22230522 TI - Pineal parenchymal tumors, embryonal tumors, and germ cell tumors. PMID- 22230523 TI - Tumors of the cerebellopontine angle. PMID- 22230524 TI - Tumors of the meninges. PMID- 22230525 TI - The management of skull base tumors. PMID- 22230526 TI - Peripheral nerve tumors. PMID- 22230527 TI - General oncology and neurological complications. PMID- 22230528 TI - Neurological complications of solid tumors. PMID- 22230529 TI - Neurological complications of leukemia and lymphoma. PMID- 22230530 TI - Neurological complications in plasma cell dyscrasias. PMID- 22230531 TI - Brain metastases. PMID- 22230532 TI - Neoplastic meningitis. PMID- 22230533 TI - Spinal cord involvement. PMID- 22230534 TI - Neuromuscular complications. AB - Although direct neoplastic involvement of muscle tis-sue is surprisingly rare, considering the large amount of body mass that is represented by muscle tissue, the most important and unresolved muscle effect is muscle cachexia.Other associations, such as inflammatory, paraneo-plastic, toxic, and several extremely rare associations,have been described. Drug-induced toxicity and radiation recall syndrome need to be taken into consideration when muscle symptoms appear in patients with cancer. PMID- 22230535 TI - Neurovascular complications of solid tumors and hematological neoplasms. PMID- 22230536 TI - Infectious, metabolic, and endocrine complications. PMID- 22230537 TI - Central nervous system paraneoplastic disease. PMID- 22230538 TI - Paraneoplastic disorders of the peripheral nervous system. PMID- 22230539 TI - Complications of chemotherapy in neuro-oncology. PMID- 22230540 TI - Complications of radiotherapy to the central nervous system. PMID- 22230541 TI - Neurological complications of chemotherapy to the central nervous system. AB - One of the most common complications of chemotherapeutic drugs is toxicity to the central nervous system (CNS). This toxicity can manifest in many ways, including encephalopathy syndromes and confusional states, seizure activity, headache, cerebrovascular complications and stroke, visual loss, cerebellar dysfunction, and spinal cord damage with myelopathy. For many drugs, the toxicity is related to route of administration and cumulative dose, and can vary from brief, transient episodes to more severe, chronic sequelae. However, the neurotoxicity can be idiosyncratic and unpredictable in some cases. Among the antimetabolite drugs, methotrexate, 5-fluorouracil, and cytosine arabinoside are most likely to cause CNS toxicity. Of the alkylating agent chemotherapeutic drugs, the nitrosoureas (e.g., BCNU) and cisplatin most frequently cause toxicity to the CNS, especially when given via the intra-arterial route. Ifosfamide is also likely to cause neurotoxicity at high intravenous doses. Other alkylating agents, such as busulfan, cyclophosphamide, procarbazine, and temozolomide, are better tolerated by the CNS at moderate doses. The retinoid drugs are known to cause severe headaches at high doses. l-Asparaginase can induce an encephalopathy syndrome, as well as cerebrovascular complications such as stroke. PMID- 22230542 TI - Neurological complications of chemotherapy to the peripheral nervous system. PMID- 22230543 TI - General and neurological complications of targeted therapy. PMID- 22230547 TI - ATM and DNA-PKcs make a complementary couple in DNA double strand break repair. AB - The interplay between ATM and DNA-PKcs kinases during double strand breaks (DSBs) resolution is still a matter of debate. ATM and DNA-PKcs participate differently in the DNA damage response pathway (DDR), but important common aspects are indeed found: both of them are activated when faced with DSBs, they share common targets in the DDR and the absence of either kinase results in faulty DSB repair. Absence of ATM translates into timely repair that, nevertheless, is incomplete. On the other hand, DNA-PKcs absence translates into slower repair, which in turn gives rise to the accumulation of simple and complex reorganizations. These outcomes confirm that the function of both protein kinases is essential to guarantee genome integrity. Interestingly, V(D)J and CSR recombination events provide a powerful tool to study the interplay between both kinases in DSB repair. Although the physiological DSBs generated during V(D)J and CSR recombination are resolved by the non-homologous end-joining (NHEJ) repair pathway, ATM absence during these events translates into chromosome translocations. These results suggest that NHEJ accuracy is threatened in the absence of ATM, which may play a role in avoiding illegitimate repair by favouring the joining of the correct DNA ends. Indeed, simultaneous DNA-PKcs and ATM deficiency during V(D)J and CSR recombination translates into a synergistic increase in potentially dangerous chromosomal translocations and deletions. Although the exact nature of their interaction remains elusive, the evidence indicates that ATM and DNA-PKcs play complementary roles that allow complete and legitimate DSB repair to be reached. Faithful repair can only be achieved by the presence and correct functioning of both kinases: while DNA-PKcs ensures fast rejoining, ATM guarantees complete repair. PMID- 22230548 TI - BiP mRNA expression is upregulated by dehydration in vasopressin neurons in the hypothalamus in mice. AB - The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone that facilitates the proper folding of newly synthesized secretory and transmembrane proteins. Here we report that BiP mRNA was expressed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in wild-type mice under basal conditions. Dual in situ hybridization in the SON and PVN demonstrated that BiP mRNA was expressed in almost all the neurons of arginine vasopressin (AVP), an antidiuretic hormone. BiP mRNA expression levels were increased in proportion to AVP mRNA expression in the SON and PVN under dehydration. These data suggest that BiP is involved in the homeostasis of ER function in the AVP neurons in the SON and PVN. PMID- 22230549 TI - Identification and molecular characterization of three new K+-channel specific toxins from the Chinese scorpion Mesobuthus martensii Karsch revealing intronic number polymorphism and alternative splicing in duplicated genes. AB - K(+)-channel specific toxins from scorpions are powerful probes used in the structural and functional characterization of different subfamilies of K(+) channels which are thought to be the most diverse ion channels. However, only a limited number of K(+)-channel toxins have been identified from scorpions so far; moreover, little is known about the mechanisms for the generation of a combinatorial peptide library in a venom gland of a scorpion. Here, we identified and characterized three new K(+)-channel toxin-like peptides from the scorpion Mesobuthus martensii Karsch, which were referred to as BmKcug1, BmKcug2 and BmKcugx, respectively. BmKcug1 and BmKcug2 are two new members of alpha-KTx1 subfamily, and have been classified as alpha-KTx1.14 and alpha-KTx1.15, respectively. BmKcugx represents a new subfamily of K(+)-channel specific toxins which was classified into alpha-KTx22. BmKcugx was thus classified as alpha KTx22.1. Genomic analysis demonstrated that BmKcugx gene has two exons interrupted by an intron inserted in the signal peptide encoding region, whereas BmKcug1a (a close homologue of BmKcug1)/BmKcug2 gene was interrupted by two introns, located within the 5'UTR of the gene and in the signal peptide encoding region, respectively. Transcriptomic analysis for the venom glands of M. martensii Karsch indicated that the abundances of the transcripts of BmKcug1a and BmKcug2 are much higher than that of BmKcugx; it suggests that the intron in 5'UTR could markedly increase the expression level of the K(+)-channel toxins. Alignment of the genomic sequences of BmKcug1a and BmKcug2 revealed that an alternative splicing event occurred at the intron 1-exon 2 junction in the 5'UTR of BmKcug2 transcript. PMID- 22230553 TI - [Treatment of lung lesions by stereotactic body radiation therapy after computed tomography guided placement of a Visicoil((r)) marker: initial experience]. AB - OBJECTIVE: To describe the technique of stereotactic body radiation therapy (SBRT) of lung lesions after the computed tomography (CT) guided placement of an internal fiducial marker and to assess the results, complications and secondary effects of these procedures. MATERIAL AND METHOD: A series of 39 lesions (8 primary and 31 metastases) in 25 patients treated using this procedure were analysed. A CT-guided percutaneous transthoracic puncture was performed for placing the internal marker in the lesion or near to it. The procedure did not require sedation. The marker serves as a guide for the treatment of the lesion using SBRT with respiratory synchronism, which allows the movement of the tumour to be controlled and to decrease the radiation volume, giving high doses with precision to the tumour, and minimal to the surrounding healthy tissue. RESULTS: The only complication of the percutaneous fiducial placement was a pneumothorax in 6 (24%) patients. A pleural drain had to be placed in 3 patients. Local control was achieved in 96.7% of the lesions. The radiation produced a grade 1 asthenia in 1 patient, a grade 2 pneumonitis in one patient and a grade 1 pneumonitis in the remainder. CONCLUSIONS: The CT-guided placement of internal markers in lung lesions is a safe technique that may be performed as ambulatory procedure. SBRT with respiratory synchronism allows the dose to the tumour to be increased, and reduces the volume of healthy lung treated, with few secondary effects. PMID- 22230554 TI - [Computed tomography characteristics of isolated caecal ischaemia]. AB - OBJECTIVE: The aims of this review are to describe the main characteristics for the CT diagnosis of isolated caecal ischaemia (ICA) and give details of the differential diagnosis with other conditions with a similar clinical picture. MATERIAL AND METHODS: A retrospective study was conducted to review the CT findings of 4 patients diagnosed with ICA in our hospital. The parameters recorded to analyse their characteristics in the CT were: maximum thickness of the caecum wall, the appearance of the peri-caecum fat, presence of free fluid, signs of caecal or portal pneumatosis, the appearance of the caecal appendix, and general signs of the presence of vasculopathy. RESULTS: In all cases it was recorded that there was a thickening of the walls of the blind loop with an abrupt transition between the caecal wall and the walls of the ascending colon wall. In all cases the caecal thickening had a characteristic image in the central area. Signs of caecal pneumatosis were observed in two cases. All of them had an appendix with normal characteristics. CONCLUSIONS: The combination of caecal wall thickening with oedematous characteristics, with no changes in the appendix, ileum and colon, suggest the diagnosis of caecal ischaemia, particularly with the presence of pneumatosis. PMID- 22230555 TI - Human serum albumin: from bench to bedside. AB - Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multi-domain macromolecule, representing the main determinant of plasma oncotic pressure and the main modulator of fluid distribution between body compartments. HSA displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds. Indeed, HSA represents the main carrier for fatty acids, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays (pseudo-)enzymatic properties. HSA is a valuable biomarker of many diseases, including cancer, rheumatoid arthritis, ischemia, post-menopausal obesity, severe acute graft-versus-host disease, and diseases that need monitoring of the glycemic control. Moreover, HSA is widely used clinically to treat several diseases, including hypovolemia, shock, burns, surgical blood loss, trauma, hemorrhage, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, nutrition support, resuscitation, and hypoalbuminemia. Recently, biotechnological applications of HSA, including implantable biomaterials, surgical adhesives and sealants, biochromatography, ligand trapping, and fusion proteins, have been reported. Here, genetic, biochemical, biomedical, and biotechnological aspects of HSA are reviewed. PMID- 22230556 TI - Transient troponin elevations in the blood of healthy young children. AB - AIMS: Whilst cardiac troponin is considered to be indicative of cardiac necrosis, the advent of new high sensitivity assays for troponin suggests that troponin may be present in the blood of healthy persons. We have examined a cohort of healthy children and measured TnT in their blood. METHODS AND RESULTS: In this community based prospective study, we collected blood samples from a large cohort of healthy children at ages 8, 10 and 12 years and measured hs-TnT on these samples. 727 children had at least one blood sample collected and of these 28.6% had at least one sample in which troponin was detected. The number of samples with a positive troponin at each period of blood collection varied between 14.0% and 20.3%. Statistical analysis showed that the prevalence of positive TnT varied between schools and the between school pattern was different in different years. CONCLUSIONS: Low concentrations of troponin may be seen transiently in healthy children with no evidence of cardiac injury. This between-school by year variation is highly significant and is suggestive of a transient infective agent. PMID- 22230557 TI - Assessment of urinary gamma-glutamyltransferase in type 2 diabetic patients with glomerular hyperfiltration. PMID- 22230558 TI - Increased LDL susceptibility to oxidation accelerates future carotid artery atherosclerosis. AB - BACKGROUND: We analyzed the causal relationship between LDL susceptibility to oxidation and the development of new carotid artery atherosclerosis over a period of 5 years. We previously described the determinants related to a risk of cardiovascular changes determined in a Japanese population participating in the Niigata Study, which is an ongoing epidemiological investigation of the prevention of cardiovascular diseases. METHODS: We selected 394 individuals (169 males and 225 females) who underwent a second carotid artery ultrasonographic examination in 2001 - 2002 for the present study. The susceptibility of LDL to oxidation was determined as the photometric absorbance and electrophoretic mobility of samples that had been collected in 1996 - 1997. The measurements were compared with ultrasonographic findings obtained in 2001 - 2002. RESULTS: The multivariate-adjusted model showed that age (odds ratio (OR), 1.034; 95% confidence interval (95%CI), 1.010 - 1.059), HbA1c (OR, 1.477; 95%CI, 0.980 - 2.225), and photometric O/N (OR, 2.012; 95%CI, 1.000 - 4.051) were significant variables that could independently predict the risk of new carotid artery atherosclerosis. CONCLUSION: The susceptibility of LDL to oxidation was a significant parameter that could predict new carotid artery atherosclerosis over a 5-year period, and higher susceptibility was associated with a higher incidence of new carotid artery atherosclerosis. PMID- 22230559 TI - Pre- and post-palatoplasty Eustachian tube function in infants with cleft palate. AB - OBJECTIVE: One past study conducted in 1986 reported Eustachian tube dilation with swallowing during the forced response test (FRT) in a very high percentage (>80%) of cleft palate patients both before and after palatoplasty. The present study was designed to determine the reproducibility of those results. METHODS: The FRT was used to evaluate Eustachian tube function in a cohort of cleft palate children before and after palatoplasty. Pre-palatoplasty FRT data were available for 25 ears and post-palatoplasty data were available for 31 ears; 14 ears had paired pre-post palatoplasty test data. The results for the FRT tests were compared between the pre- and post-palatoplasty groups for the cross-sectional data and for the paired subset of ears. RESULTS: The 3 passive function measures of the FRT, the opening pressure, closing pressure and passive resistance were not different before and after palatoplasty for either data set. Similarly, 2 of the 3 active function measures, active resistance and dilatory efficiency, were not different pre- and post-palatoplasty, but the percent of ears evidencing tubal dilation for the cross-sectional data was 39% and 62% (p=NS) and for the paired subset was 33% and 83% (p=0.04) at the pre- and post-palatoplasty tests. CONCLUSION: Palatoplasty had no effect on most measures of the FRT, but may have had a positive effect on the ability to dilate the Eustachian tube during swallowing. The high frequency of ears with tubal dilation before palatoplasty reported in the 1986 study was not reproduced but that frequency after palatoplasty was similar. PMID- 22230560 TI - Association of congenital microtia with environmental risk factors in South Korea. AB - BACKGROUND: Though there are reports regarding congenital microtia in various populations, few studies have focused on patients in South Korea. The objectives of the present study were to investigate the characteristics of microtia in South Korea and demonstrate the contribution of environmental risk factors to the occurrence of microtia. PATIENTS AND METHODS: We performed a retrospective chart review of congenital microtia patients who presented to our institution between January 2002 and December 2010. A case-control study was performed in 169 microtia patients and 128 controls to investigate the impact of environmental and prenatal factors on the development of congenital microtia. The data were gathered by personal interviews and detailed questionnaires filled out by the patients' parents. RESULTS: A total of 374 microtia patients were included in the present study. Most cases were sporadic, and most were male. Unilateral microtia was more common, especially on the right side, while bilateral microtia occurred in only 25 patients. Two hundred forty-three patients had isolated microtia with no other congenital anomalies. In subgroups divided by type, lobule-type microtia was more common than concha-type microtia, and patients with anotia were the least common. Risk factors analyzed using multivariate regression models between groups, resident area during pregnancy, threatened abortion history, rubella vaccination, medication history during the first trimester, and alcohol consumption during the first trimester had significant impacts on the development of isolated microtia. CONCLUSIONS: The characteristics of congenital microtia in South Korea are similar to those in other populations, including the predominance of sporadic occurrence, male gender, lobule type, and isolated microtia. Several environmental risk factors can have significant impacts on the development of microtia. PMID- 22230562 TI - The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster. AB - Methylmercury (MeHg) is a ubiquitous toxicant that targets the developing fetal nervous system. MeHg interacts with the Notch signaling pathway, a highly conserved intercellular signaling mechanism required for normal development. Notch signaling is conveyed by activation of the genes in the enhancer of split (E(spl)) locus in Drosophila. We have previously shown that acute high doses of MeHg upregulate several E(spl) genes in Drosophila neural-derived C6 cells. Furthermore, MeHg induction of E(spl) can occur independent of the Notch receptor itself. We now show that MeHg, unlike inorganic mercury (HgCl2), preferentially upregulates E(spl)mdelta and E(spl)mgamma in Drosophila C6 cells. This is distinct from Delta ligand-induced Notch signaling in which no induction of E(spl)mdelta is seen. MeHg is also seen to specifically upregulate E(spl)mdelta in Drosophila embryos where HgCl2 showed no such effect. Additionally, treatment of embryos with MeHg caused a consistent failure in axonal outgrowth of the intersegmental nerve (ISN). This ISN phenotype was partially replicated by genetic activation of the Notch pathway, but was not replicated by increasing expression of E(spl)mdelta. These data suggest a role for Notch signaling and the E(spl)mdelta target gene in MeHg toxicity, however, the site of action for E(spl)mdelta in this system remains to be elucidated. PMID- 22230561 TI - Transcriptional regulation in the innate immune system. AB - In cells of the innate immune system, the transcriptional response to a microbial stimulus is tailored to both the stimulus and cell type, suggesting the existence of highly sophisticated regulatory mechanisms. Early studies suggested that specificity is dictated by sets of differentially induced transcription factors that synergistically activate target genes containing their binding sites. However, recent studies have revealed additional interrelated regulatory layers, which are the topic of this article. In particular, individual transcription factors may require different post-translational modifications and coregulatory interactions to regulate different target genes. Furthermore, competence for induction is programmed at an early stage of development by factors involved in lineage commitment, and the architecture and chromatin structure of each promoter play critical roles in transcriptional specificity. PMID- 22230563 TI - Stapled peptides for intracellular drug targets. AB - Proteins that engage in intracellular interactions with other proteins are widely considered among the most biologically appealing yet chemically intractable targets for drug discovery. The critical interaction surfaces of these proteins typically lack the deep hydrophobic involutions that enable potent, selective targeting by small organic molecules, and their localization within the cell puts them beyond the reach of protein therapeutics. Considerable interest has therefore arisen in next-generation targeting molecules that combine the broad target recognition capabilities of protein therapeutics with the robust cell penetrating ability of small molecules. One type that has shown promise in early stage studies is hydrocarbon-stapled alpha-helical peptides, a novel class of synthetic miniproteins locked into their bioactive alpha-helical fold through the site-specific introduction of a chemical brace, an all-hydrocarbon staple. Stapling can greatly improve the pharmacologic performance of peptides, increasing their target affinity, proteolytic resistance, and serum half-life while conferring on them high levels of cell penetration through endocytic vesicle trafficking. Here, we discuss considerations crucial to the successful design and evaluation of potent stapled peptide interactions, our intention being to facilitate the broad application of this technology to intractable targets of both basic biologic interest and potential therapeutic value. PMID- 22230564 TI - Mapping of vascular ZIP codes by phage display. AB - Each organ and pathology has a unique vascular ZIP code that can be targeted with affinity ligands. In vivo peptide phage display can be used for unbiased mapping of the vascular diversity. Remarkably, some of the peptides identified by such screens not only bind to target vessels but also elicit biological responses. Recently identified tissue-penetrating CendR peptides trigger vascular exit and parenchymal spread of a wide range of conjugated and coadministered payloads. This review is designed to serve as a practical guide for researchers interested in setting up ex vivo and in vivo phage display technology. We focus on T7 coliphage platform that our lab prefers to use due to its versatility, physical resemblance of phage particles to clinical nanoparticles, and ease of manipulation. PMID- 22230565 TI - Engineering cyclic peptide toxins. AB - Peptide-based toxins have attracted much attention in recent years for their exciting potential applications in drug design and development. This interest has arisen because toxins are highly potent and selectively target a range of physiologically important receptors. However, peptides suffer from a number of disadvantages, including poor in vivo stability and poor bioavailability. A number of naturally occurring cyclic peptides have been discovered in plants, animals, and bacteria that have exceptional stability and potentially ameliorate these disadvantages. The lessons learned from studies of the structures, stabilities, and biological activities of these cyclic peptides can be applied to the reengineering of toxins that are not naturally cyclic but are amenable to cyclization. In this chapter, we describe solid-phase chemical synthetic methods for the reengineering of peptide toxins to improve their suitability as therapeutic, diagnostic, or imaging agents. The focus is on small disulfide-rich peptides from the venoms of cone snails and scorpions, but the technology is potentially widely applicable to a number of other peptide-based toxins. PMID- 22230566 TI - Peptide discovery using bacterial display and flow cytometry. AB - Peptides are increasingly used as therapeutic and diagnostic agents. The combination of bacterial cell-surface display peptide libraries with magnetic- and fluorescence-activated cell sorting technologies provides an efficient and highly effective methodology to identify and engineer peptides for a growing number of molecular recognition applications. Here, detailed protocols for both the generation and screening of bacterial display peptide libraries are presented. The methods described enable the discovery and evolutionary optimization of protein-binding peptides, cell-specific peptides, and enzyme substrates for diverse biotechnology applications. PMID- 22230567 TI - Designed ankyrin repeat proteins (DARPins) from research to therapy. AB - Designed ankyrin repeat proteins (DARPins) have been developed into a robust and versatile scaffold for binding proteins. High-affinity binders are routinely selected by ribosome display and phage display. DARPins have entered clinical trials and have found numerous uses in research, due to their high stability and robust folding, allowing many new molecular formats. We summarize the DARPin properties and highlight some biomedical applications. Protocols are given for labeling with dyes and polyethylene glycol, for quantitatively measuring binding to cell surface receptors by kinetics and thermodynamics, and for exploiting new engineering opportunities from using "click chemistry" with nonnatural amino acids. PMID- 22230568 TI - Target-binding proteins based on the 10th human fibronectin type III domain (10Fn3). AB - We describe concepts and methods for generating a family of engineered target binding proteins designed on the scaffold of the 10th human fibronectin type III domain ((10)Fn3), an extremely stable, single-domain protein with an immunoglobulin-like fold but lacking disulfide bonds. Large libraries of possible target-binding proteins can be constructed on the (10)Fn3 scaffold by diversifying the sequence and length of its surface loops, which are structurally analogous to antibody complementarity-determining regions. Target-binding proteins with high affinity and specificity are selected from (10)Fn3-based libraries using in vitro evolution technologies such as phage display, mRNA display, or yeast-surface display. (10)Fn3-based target-binding proteins have binding properties comparable to those of antibodies, but they are smaller, simpler in architecture, and more user-friendly; as a consequence, these proteins are excellent building blocks for the construction of multidomain, multifunctional chains. The ease of engineering and robust properties of (10)Fn3 based target-binding proteins have been validated by multiple independent academic and industrial groups. In addition to performing well as specific in vitro detection reagents and research tools, (10)Fn3-based binding proteins are being developed as therapeutics, with the most advanced candidate currently in Phase II clinical trials. PMID- 22230569 TI - Anticalins small engineered binding proteins based on the lipocalin scaffold. AB - Anticalins are a novel class of small, robust proteins with designed ligand binding properties derived from the natural lipocalin scaffold. Due to their compact molecular architecture, comprising a single polypeptide chain, they provide several benefits as protein therapeutics, such as high target specificity, good tissue penetration, low immunogenicity, tunable plasma half life, efficient Escherichia coli expression, and suitability for furnishing with additional effector functions via genetic fusion or chemical conjugation. The lipocalins are a widespread family of proteins that naturally serve in many organisms, including humans, for the transport, storage, or sequestration of small biological compounds like vitamins and hormones. Their fold is dominated by an eight-stranded antiparallel beta-barrel, which is open to the solvent at one end. There, four loops connect the beta-strands in a pairwise manner and, altogether, they form the entry to a ligand-binding site. This loop region can be engineered via site-directed random mutagenesis in combination with genetic library selection techniques to yield "Anticalins" with exquisite specificities and down to picomolar affinities-for prescribed molecular targets of either hapten or antigen type. Several Anticalins directed against medically relevant disease targets have been successfully engineered and can be applied, for example, for the blocking of soluble signaling factors or cell surface receptors or for tissue-specific drug targeting. While natural lipocalins were already subject to clinical studies in the past, a first Anticalin has completed Phase I trials in 2011, thus paving the way for the broad application of Anticalins as a promising novel class of biopharmaceuticals. PMID- 22230570 TI - T cell receptor engineering. AB - T lymphocytes express on their surface a heterodimeric alphabeta receptor, called the T cell receptor (TCR), which recognizes foreign antigens. Unlike antibodies, the recognition requires both an antigenic peptide epitope and a protein encoded by the major histocompatibility complex (MHC). In contrast to conventional antibody-directed target antigens, antigens recognized by the TCR can include the entire array of potential intracellular proteins, which are processed and delivered to the cell surface as a peptide/MHC complex. In the past 10 years, there have been significant efforts to engineer TCRs in various formats, which would allow improved recognition and destruction of virus-infected cells or cancer. The proposed therapeutic approaches involve either the use of engineered, high-affinity TCRs in soluble forms, analogous to antibody-directed therapies, or the use of engineered TCRs whose genes are reintroduced into autologous T cells and transferred back into patients (T cell adoptive therapies). This chapter describes three methods associated with the engineering of TCRs for these therapeutic purposes: (1) use of a yeast display system to engineer higher affinity single-chain ValphaVbeta TCRs, called scTv; (2) use of a T cell display system to engineer higher affinity full-length TCRs; and (3) expression, purification, and characterization of soluble TCRs in an Escherichia coli system. PMID- 22230571 TI - Engineering knottins as novel binding agents. AB - Cystine-knot miniproteins, also known as knottins, contain a conserved core of three tightly woven disulfide bonds which impart extraordinary thermal and proteolytic stability. Interspersed between their conserved cysteine residues are constrained loops that possess high levels of sequence diversity among knottin family members. Together these attributes make knottins promising molecular scaffolds for protein engineering and translational applications. While naturally occurring knottins have shown potential as both diagnostic agents and therapeutics, protein engineering is playing an important and increasing role in creating designer molecules that bind to a myriad of biomedical targets. Toward this goal, rational and combinatorial approaches have been used to engineer knottins with novel molecular recognition properties. Here, methods are described for creating and screening knottin libraries using yeast surface display and fluorescence-activated cell sorting. Protocols are also provided for producing knottins by synthetic and recombinant methods, and for measuring the binding affinity of knottins to target proteins expressed on the cell surface. PMID- 22230572 TI - Practical theoretic guidance for the design of tumor-targeting agents. AB - Theoretical analyses of targeting agent pharmacokinetics provides specific guidance with respect to desirable design objectives such as agent size, affinity, and target antigen. These analyses suggest that IgG-sized macromolecular constructs exhibit the most favorable balance between systemic clearance and vascular extravasation, resulting in maximal tumor uptake. Quantitative predictions of the effects of dose and binding affinity on tumor uptake and penetration are also provided. The single bolus dose required for saturation of xenografted tumors in mice can be predicted from knowledge of antigen expression level and metabolic half-life. The role of high binding affinity in tumor uptake can be summarized as: essential for small peptides, less important for antibodies, and negligible for nanoparticles. PMID- 22230573 TI - Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. AB - Recombinant protein therapeutics cannot enter brain drug development because these large molecule drugs do not cross the blood-brain barrier (BBB). However, recombinant proteins can be reengineered as BBB-penetrating IgG fusion proteins, where the IgG part is a genetically engineered monoclonal antibody (MAb) against an endogenous BBB receptor, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The IgG binds the endogenous insulin receptor or TfR to trigger transport across the BBB and acts as a molecular Trojan horse (MTH) to ferry into brain the fused protein therapeutic. The most potent MTH to date is a MAb against the HIR, designated the HIRMAb, which is active in humans and Old World primates, such as the Rhesus monkey. There is no known MAb against the mouse insulin receptor. For drug delivery in the mouse, protein therapeutics are fused to a chimeric MAb against the mouse TfR, designated the cTfRMAb. The HIRMAb or cTfRMAb Trojan horses have been engineered and expressed as fusion proteins with multiple classes of protein therapeutics, including lysosomal enzymes, neurotrophins, decoy receptors, single chain Fv therapeutic antibodies, and avidin. The pharmacokinetic (PK) properties of the IgG fusion proteins differ from that of typical MAb drugs and resemble the PK profiles of small molecules due to rapid uptake by peripheral tissues, as well as brain. The brain uptake of the IgG fusion proteins, 2-3% of injected dose/brain, is comparable to the brain uptake of small molecules. The IgG fusion proteins have been administered chronically in mouse models, and the immune response is low titer and has no effect on the fusion protein clearance from blood or brain uptake in vivo. The BBB MTH technology enables the reengineering of a wide spectrum of recombinant protein therapeutics for targeted drug delivery to the brain. PMID- 22230574 TI - Engineering and identifying supercharged proteins for macromolecule delivery into mammalian cells. AB - Supercharged proteins are a class of engineered or naturally occurring proteins with unusually high positive or negative net theoretical charge. Both supernegatively and superpositively charged proteins exhibit a remarkable ability to withstand thermally or chemically induced aggregation. Superpositively charged proteins are also able to penetrate mammalian cells. Associating cargo with these proteins, such as plasmid DNA, siRNA, or other proteins, can enable the functional delivery of these macromolecules into mammalian cells both in vitro and in vivo. The potency of functional delivery in some cases can exceed that of other current methods for macromolecule delivery, including the use of cell penetrating peptides such as Tat and adenoviral delivery vectors. This chapter summarizes methods for engineering supercharged proteins, optimizing cell penetration, identifying naturally occurring supercharged proteins, and using these proteins for macromolecule delivery into mammalian cells. PMID- 22230575 TI - Protein engineering for therapeutics, part B. Preface. PMID- 22230576 TI - Acceptance of health-promoting Brassica vegetables: the influence of taste perception, information and attitudes. AB - OBJECTIVE: To investigate the relative importance of specific health knowledge and taste on acceptance of Brassica vegetables (broccoli, red and green cabbages, broccolini, cauliflower, Brussels sprouts). DESIGN: In a sample of adults all reporting medium-high physical activity (as a marker/control of health behaviour) and reporting either low (<=2 portions/d) or high (>=3 portions/d) vegetable intake, half of those with low vegetable consumption (Li group) and half of those with high vegetable consumption (Hi group) received cancer protection information, while the other half did not (Ln and Hn groups), before hedonic (9 point), perceived taste and flavour impact responses (100 mm scales) to samples of six Brassica vegetables were elicited. Additionally, attitudes towards foods for health, pleasure and reward, sociodemographics, intentions to consume the vegetables in the near future and recall of health information were also measured. SUBJECTS: Adult males and females (n 200) aged 18-55 years. SETTING: Central location testing, Adelaide, Australia. RESULTS: Information groups Li and Hi reported specific cancer protection information knowledge, in contrast to Ln and Hn groups (P < 0.000). Information independently influenced responses to (the least liked) Brussels sprouts only. Multivariate regression analysis found sensory perception tended to predict liking and intentions to consume Brassica vegetables. For example, broccoli hedonics (adjusted R 2 = 0.37) were predicted (P < 0.05) by bitterness (beta = -0.38), flavour (beta = 0.31), sweetness (beta = 0.17) and female gender (beta = 0.19) and intentions to consume (adjusted R 2 = 0.20) were predicted (P < 0.05) by bitterness (beta = -0.38), flavour (beta = 0.24), female gender (beta = 0.20) and vegetable intake (beta = 0.14). CONCLUSIONS: Addressing taste dimensions (while retaining healthy compounds) may be more important than promoting health information in order to increase the popularity of Brassica vegetables. PMID- 22230577 TI - A national cohort study of parental socioeconomic status and non-fatal suicidal behaviour--the mediating role of school performance. AB - BACKGROUND: A link between low parental socioeconomic status and mental health problems in offspring is well established in previous research. The mechanisms that explain this link are largely unknown. The present study investigated whether school performance was a mediating and/or moderating factor in the path between parental socioeconomic status and the risk of hospital admission for non fatal suicidal behaviour. METHODS: A national cohort of 447 929 children born during 1973-1977 was followed prospectively in the National Patient Discharge Register from the end of their ninth and final year of compulsory school until 2001. Multivariate Cox proportional hazards and linear regression analyses were performed to test whether the association between parental socioeconomic status and non-fatal suicidal behaviour was mediated or moderated by school performance. RESULTS: The results of a series of multiple regression analyses, adjusted for demographic variables, revealed that school performance was as an important mediator in the relationship between parental socioeconomic status and risk of non-fatal suicidal behaviour, accounting for 60% of the variance. The hypothesized moderation of parental socioeconomic status-non-fatal suicidal behaviour relationship by school performance was not supported. CONCLUSIONS: School performance is an important mediator through which parental socioeconomic status translates into a risk for non-fatal suicidal behaviour. Prevention efforts aimed to reduce socioeconomic inequalities in non-fatal suicidal behaviour among young people will need to consider socioeconomic inequalities in school performance. PMID- 22230578 TI - The challenge of post-implementation surveillance for novel meningococcal vaccines. AB - Novel serogroup B meningococcal vaccines are currently in late stage development and may be used in mass immunisation campaigns over the coming years. This represents an exciting development in the prevention of childhood meningitis, however monitoring the impact of these vaccines on meningococcal disease epidemiology will provide significant challenges. Although designed to prevent serogroup B meningococcal disease the vaccine antigens are not serogroup specific, creating the potential for multiple definitions of vaccine effectiveness and vaccine failure. PMID- 22230579 TI - Cloned cDNA of A/swine/Iowa/15/1930 internal genes as a candidate backbone for reverse genetics vaccine against influenza A viruses. AB - Reverse genetics viruses for influenza vaccine production usually utilize the internal genes of the egg-adapted A/Puerto Rico/8/34 (PR8) strain. This egg adapted strain provides high production yield in embryonated eggs but does not necessarily give the best yield in mammalian cell culture. In order to generate a reverse genetics viral backbone that is well-adapted to high growth in mammalian cell culture, a swine influenza isolate A/swine/Iowa/15/30 (H1N1) (rg1930) that was shown to give high yield in Madin-Darby canine kidney (MDCK) cells was used as the internal gene donor for reverse genetics plasmids. In this report, the internal genes from rg1930 were used for construction of reverse genetics viruses carrying a cleavage site-modified hemagglutinin (HA) gene and neuraminidase (NA) gene from a highly pathogenic H5N1 virus. The resulting virus (rg1930H5N1) was low pathogenic in vivo. Inactivated rg1930H5N1 vaccine completely protected chickens from morbidity and mortality after challenge with highly pathogenic H5N1. Protective immunity was obtained when chickens were immunized with an inactivated vaccine consisting of at least 2(9) HA units of the rg1930H5N1 virus. In comparison to the PR8-based reverse genetics viruses carrying the same HA and NA genes from an H5N1 virus, rg1930 based viruses yielded higher viral titers in MDCK and Vero cells. In addition, the reverse genetics derived H3N2 and H5N2 viruses with the rg1930 backbone replicated in MDCK cells better than the cognate viruses with the rgPR8 backbone. It is concluded that this newly established reverse genetics backbone system could serve as a candidate for a master donor strain for development of inactivated influenza vaccines in cell-based systems. PMID- 22230580 TI - Antibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency. AB - Prevalence of non-typeable Haemophilus influenzae (NTHi) in the etiology of invasive infections in immunocompromised individuals is increasing. Serum IgG antibody levels to H. influenzae protein D (PD) were significantly lower in adults suffering from chronic conditions causing secondary immunodeficiency (COPD, cancer, chronic renal failure, and diabetes) compared to age-matched healthy controls. A lack of naturally acquired antibody against this highly conserved antigen may contribute to an increased susceptibility to invasive NTHi disease. As COPD patients frequently infected with NTHi during disease exacerbations were unable to develop antibody response to PD, such defect could potentially contribute to the pathogenesis. Considering that pediatric PD containing vaccines show protective effect against NTHi-caused otitis media, our data suggest the possibility of improving the defense against NTHi in COPD patients using immunization against PD. Although more research on the role of anti-PD antibody in protection against invasive NTHi disease is warranted, development of adult formulations of PD-based vaccines may be advantageous for prevention of severe infections in immunocompromised individuals. PMID- 22230581 TI - Measles control in Sub-Saharan Africa: South Africa as a case study. AB - BACKGROUND: Due to intensified measles immunization efforts, measles mortality has decreased substantially worldwide, particularly in Sub-Saharan Africa (SSA). The World Health Organization (WHO) estimated a 92% decrease in measles-related deaths in the WHO AFRO region for the period 2000-2008. Recently, the AFRO region established a measles pre-elimination goal and experts have suggested engaging in a measles eradication campaign at the global level. However, recent large-scale outbreaks in many Sub-Saharan African countries present a challenge to measles control efforts. This paper examines measles immunization and the impact of measles supplemental immunization activities (SIAs) on routine immunization coverage in South Africa (SA). METHODS: We reported on immunization coverage trends in SA for the period 2001-2010 at the province and district levels. The data included routine immunization for 1st and 2nd doses of measles vaccine (MCV1, MCV2), SIAs, 1st dose of Bacille Calmette-Guerin vaccine, 1st and 3rd doses of oral polio vaccine (OPV1, OPV3), 3rd dose of Diphtheria-Tetanus Pertussis-Haemophilus-influenzae-B vaccine (DTP-Hib3), and the number of under one-year-olds having completed a primary course of immunization (Imm1). A regression model looked at the SIA impact on routine coverage. RESULTS: Over the past decade, MCV1 and MCV2 coverage have increased nationally from 68% and 57% in 2001 to 95% and 83% in 2010, respectively. SIA coverage has remained at high levels, around 90%, over the same period. Substantial heterogeneity in MCV1 and MCV2 coverage is present across SA districts, with differences in coverage of 56% (MCV1) and 51% (MCV2) in 2010. In any given year, occurrence of SIAs was associated with a decrease in routine immunization coverage of MCV1, MCV2, OPV1, OPV3, DTP-Hib3, and Imm1, at the district level. CONCLUSIONS: The heterogeneity in measles vaccination coverage across SA districts challenges the goal of measles elimination in SA and SSA. The reduction in routine immunization coverage associated with the occurrence of SIAs raises the legitimate concern that SIAs may negatively impact health systems' functioning. PMID- 22230582 TI - Antigen-specific responses assessment for the evaluation of Bordetella pertussis T cell immunity in humans. AB - Measurement of antigen-specific T cell responses is an adjunctive parameter to evaluate protection induced by a previous Bordetella pertussis infection or vaccination. The assessment of T cell responses is technically complex and usually performed on fresh peripheral blood mononuclear cells (PBMC). The objective of this study was to identify simplified methods to assess pertussis specific T cell responses and verify if these assays could be performed using frozen/thawed (frozen) PBMC. Three read-outs to measure proliferation were compared: the fluorescent dye 5,6-carboxylfluorescein diacetate succinimidyl ester (CFSE) dilution test, the number of blast cells defined by physical parameters, and the incorporation of (3)H-thymidine. The results of pertussis specific assays performed on fresh PBMC were compared to the results on frozen PBMC from the same donor. High concordance was obtained when the results of CFSE and blast read-outs were compared, an encouraging result since blast analysis allows the identification of proliferating cells and does not require any use of radioactive tracer as well as any staining. The results obtained using fresh and frozen PBMC from the same donor in the different T cell assays, including IFNgamma and TNFalpha cytokine production, did not show significant differences, suggesting that a careful cryopreservation process of PBMC would not significantly influence T cell response evaluation. Adopting blast analysis and frozen PBMC, the possibility to test T cell responses is simplified and might be applied in population studies, providing for new instruments to better define correlates of protection still elusive in pertussis. PMID- 22230583 TI - Vaccination of healthy and diseased koalas (Phascolarctos cinereus) with a Chlamydia pecorum multi-subunit vaccine: evaluation of immunity and pathology. AB - Chlamydial infections represent a major threat to the long-term survival of the koala and a successful vaccine would provide a valuable management tool. Vaccination however has the potential to enhance inflammatory disease in animals exposed to a natural infection prior to vaccination, a finding in early human and primate trials of whole cell vaccines to prevent trachoma. In the present study, we vaccinated both healthy koalas as well as clinically diseased koalas with a multi-subunit vaccine consisting of Chlamydia pecorum MOMP and NrdB mixed with immune stimulating complex as adjuvant. Following vaccination, there was no increase in inflammatory pathological changes in animals previously infected with Chlamydia. Strong antibody (including neutralizing antibodies) and lymphocyte proliferation responses were recorded in all vaccinated koalas, both healthy and clinically diseased. Vaccine induced antibodies specific for both vaccine antigens were observed not only in plasma but also in ocular secretions. Our data shows that an experimental chlamydial vaccine is safe to use in previously infected koalas, in that it does not worsen infection-associated lesions. Furthermore, the prototype vaccine is effective, as demonstrated by strong levels of neutralizing antibody and lymphocyte proliferation responses in both healthy and clinically diseased koalas. Collectively, this work illustrates the feasibility of developing a safe and effective Chlamydia vaccine as a tool for management of disease in wild koalas. PMID- 22230584 TI - Adverse events following immunization during mass vaccination campaigns at first introduction of a meningococcal A conjugate vaccine in Burkina Faso, 2010. AB - MenAfriVacTM is a new meningococcal A conjugate vaccine developed to prevent meningitis outbreaks in Africa. It was first introduced during the last quarter of 2010 in three West African countries. We report on the monitoring of adverse events following immunization (AEFI) in Burkina Faso where more than 11 million people aged 1-29 years were vaccinated. Vaccine pharmacovigilance relied on stimulated passive AEFI surveillance countrywide and active surveillance for 12 clinical conditions in one sentinel district (Ziniare) with 97,715 people eligible for vaccination. All AEFI occurring during the 10 days of mass campaign or the 42 subsequent days were to be notified. Serious AEFI were submitted to a national expert committee (NEC) for causality assessment. A total of 11,466,950 people were vaccinated with 1471 vaccinees reported to have experienced at least one AEFI (12.83 cases per 100,000). 1444 AEFI were minor; the most common of which were fever, headache, gastro-intestinal disorders and local reactions (2-7 cases per 100,000). Of 27 serious AEFI reported, four cases were classified by the NEC as related to vaccine (1 case per 3 million vaccinated) including one case each of exanthematous pustulosis, angioedema, bronchospasm and severe vomiting. Active surveillance identified 71 cases of the 12 conditions of interest. Convulsions, urticaria and bronchospasm were more frequently reported. Attack rates for those conditions were similar to the baseline rates recorded in the same population, over the same time period, a year earlier. With the exception of convulsions in the days following vaccination the distribution of time intervals between vaccination and the occurrence of symptoms did not reveal any temporal clustering. The monitoring of AEFI of MenAfriVacTM in Burkina Faso did not suggest special concern regarding the vaccine safety. However, reported possible hypersensitivity reactions to vaccine components would require further review to rule out any anaphylactic reaction. PMID- 22230585 TI - Impaired production of TNF-alpha by dendritic cells of older adults leads to a lower CD8+ T cell response against influenza. AB - Seasonal influenza causes more morbidity and mortality in older adults than in young adults, apparently because of a decline in immune function with increasing age, known as immunosenescence. In this study, we compared the capacity of dendritic cells (DCs) from healthy older adults (>=65 years) with DCs from healthy young adults (20-40 years) to initiate a T cell response against influenza. DCs from older adults were impaired in the induction of influenza specific CD8+ T cells as compared to DCs from young adults, which was demonstrated by a decreased proliferation, an impaired production of IFN-gamma and a reduced expression of the degranulation marker CD107a by CD8+ T cells. Importantly, DCs from older adults produced significantly less TNF-alpha, showed a decreased expression of HLA class I and had a lower maturation state after influenza virus infection. Supplementing TNF-alpha increased the expression of HLA class I and of maturation markers and enhanced the induction of the influenza specific CD8+ T cell response. Together, these findings indicate that the impaired influenza-specific CD8+ T cell response in older adults is associated with a reduced production of TNF-alpha and with a lower DC maturation. We suggest that the production of TNF-alpha is a determining factor in the DC-mediated CD8+ T cell response against influenza. PMID- 22230586 TI - A genomics-based approach to assessment of vaccine safety and immunogenicity in children. AB - Immune responses to vaccines in infants and young children are typically Th2 biased, giving rise to concerns regarding potential atopy-like side effects, and antagonism of Th1-associated sterilising immunity. Conventional immunological methodology has limited capacity to effectively address these problems because of the inherent complexity of the immune responses involved. In the present study, we sought to develop an unbiased systems biology approach to elucidate superficially similar Th2-associated responses to paediatric vaccines and allergens, and to differentiate between them via gene coexpression network analysis. We demonstrate below that in immune responses to the diptheria/acellular pertussis/tetanus and pneumococcal polysaccharide conjugate vaccines, potentially antagonistic Th1-/IFN-associated and Th2-associated gene networks coexist in an apparent state of dynamic equilibrium, whereas in Th2 dominant allergen-specific responses of atopics the Th1 and IFN networks are respectively disrupted and downregulated. Capacity to detect and interpret these covert differences between responses to vaccines and allergens relies on the use of sophisticated algorithms that underpin coexpression network analysis, which identify genes that function co-ordinately in complex pathways. This methodology has significant potential to identify covert interactions between inflammatory pathways triggered by vaccination, and as such may be a useful tool in prediction of vaccine safety/efficacy. PMID- 22230588 TI - Antigen delivery for cross priming via the emulsion vaccine adjuvants. AB - The function of emulsion adjuvants in vaccine antigen delivery remains unclear. To investigate the roles of emulsion adjuvants in cross presentation of exogenous antigens, a series of emulsions were prepared for both in vitro and in vivo studies. Bone marrow-derived dendritic cells (BMDCs) were treated with the adjuvants and analyzed by flow cytometry for the expression of costimulatory molecules. The activation of antigen-specific T cells in vitro was determined with B3Z cells. Antibody secretion in the draining lymph nodes of emulsion adjuvant-treated animals was measured by enzyme-linked immuno-spot (ELISPOT) assays, and antigen-specific proliferation of cells was conducted to examine the roles of emulsion adjuvants in antigen delivery. Data on phagocytosis of adjuvant treated cells correlated well with the degree of cell death induced by the emulsion adjuvants. Significant inflammatory infiltration and cell death were observed in vivo at the adjuvant injection sites, as demonstrated by hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Ovalbumin (OVA)-based ELISPOT assays showed that L121 adjuvant, containing Pluronic L121, induced the most significant cell death also stimulated the strongest antibody-producing response in the draining lymph nodes, consistent with the data on the proliferation of antigen-specific T cells and activation of B3Z cells in vitro. Results presented in this study have demonstrated the roles of emulsion adjuvants in induction of cell death and delivery of exogenous antigens for cross-priming, leading to stimulation of antigen-specific immune responses. PMID- 22230587 TI - Geographic differentiation of polymorphism in the Plasmodium falciparum malaria vaccine candidate gene SERA5. AB - SERA5 is regarded as a promising malaria vaccine candidate of the most virulent human malaria parasite Plasmodium falciparum. SERA5 is a 120 kDa abundantly expressed blood-stage protein containing a papain-like protease. Since substantial polymorphism in blood-stage vaccine candidates may potentially limit their efficacy, it is imperative to fully investigate polymorphism of the SERA5 gene (sera5). In this study, we performed evolutionary and population genetic analysis of sera5. The level of inter-species divergence (kS=0.076) between P. falciparum and Plasmodium reichenowi, a closely related chimpanzee malaria parasite is comparable to that of housekeeping protein genes. A signature of purifying selection was detected in the proenzyme and enzyme domains. Analysis of 445 near full-length P. falciparum sera5 sequences from nine countries in Africa, Southeast Asia, Oceania and South America revealed extensive variations in the number of octamer repeat (OR) and serine repeat (SR) regions as well as substantial level of single nucleotide polymorphism (SNP) in non-repeat regions (2562 bp). Remarkably, a 14 amino acid sequence of SERA5 (amino acids 59-72) that is known to be the in vitro target of parasite growth inhibitory antibodies was found to be perfectly conserved in all 445 worldwide isolates of P. falciparum evaluated. Unlike other major vaccine target antigen genes such as merozoite surface protein-1, apical membrane antigen-1 or circumsporozoite protein, no strong evidence for positive selection was detected for SNPs in the non-repeat regions of sera5. A biased geographical distribution was observed in SNPs as well as in the haplotypes of the sera5 OR and SR regions. In Africa, OR- and SR haplotypes with low frequency (<5%) and SNPs with minor allele frequency (<5%) were abundant and were mostly continent-specific. Consistently, significant genetic differentiation, assessed by the Wright's fixation index (Fst) of inter population variance in allele frequencies, was detected for SNPs and both OR- and SR-haplotypes among almost all parasite populations. The exception was parasite populations between Tanzania and Ghana, suggesting frequent gene flow in Africa. The present study points to the importance of investigating whether biased geographical distribution for SNPs and repeat variants in the OR and SR regions affect the reactivity of human serum antibodies to variants. PMID- 22230589 TI - Mucosal vaccination increases local chemokine production attracting immune cells to the stomach mucosa of Helicobacter pylori infected mice. AB - BACKGROUND: Vaccination is an attractive approach for the prevention of Helicobacter pylori infection and disease. In a mouse model, infection induces an accumulation of dendritic cells, macrophages, granulocytes, and B- and T cells to the stomach mucosa, which is further heightened when the infection is preceded by a mucosal immunization. We have studied the chemokines and chemokine receptors guiding infection- and vaccination-induced immune cells to the stomach and their relation to protection against H. pylori infection in mice. MATERIALS AND METHODS: C57BL/6 mice were immunized sublingually with H. pylori lysate antigens and cholera toxin adjuvant or left unimmunized, and then challenged with live H. pylori bacteria. Stomach tissue was taken at 3, 7, 14 and 21 days after challenge and bacterial colonization, chemokine and chemokine receptor gene expression, and influx of cells into the stomach mucosa were evaluated. RESULTS: RT-PCR array screening revealed differential expression of a broad range of chemokine and chemokine receptor genes between immunized and unimmunized mice. A significant upregulation of chemokines known to attract, among other cells, eosinophils (CCL8), T cells (CXCL10, CXCL11) and neutrophils (CXCL2, CXCL5) and of their cognate receptors CCR3, CXCR3 and CXCR2, preceded or coincided with vaccine induced protection, which was first evident 7 days after infection and was then sustained at the later time-points. Consistent with the increase in chemokines and chemokine receptors flow cytometric analysis indicated a sequential accumulation of CD4(+) T cells, eosinophils, neutrophils and CD103(+) dendritic cells in the gastric lamina propria of immunized mice. CONCLUSIONS: This study provides insights into vaccination-induced chemokines that guide the influx of protective immune cells into the stomach of H. pylori infected mice. PMID- 22230590 TI - U.K. parents' decision-making about measles-mumps-rubella (MMR) vaccine 10 years after the MMR-autism controversy: a qualitative analysis. AB - BACKGROUND AND OBJECTIVES: Public concern about an unsubstantiated link between MMR vaccine and autism stemmed from a 1998 paper by Dr Andrew Wakefield and colleagues, and the substantial media coverage which that work attracted. Though the Wakefield paper is now discredited and an MMR-autism link has never been demonstrated empirically, this concern has manifested in over a decade of suboptimal MMR uptake. Few qualitative studies have explored parents' MMR decision-making since uptake began to improve in 2004. This study updates and adds methodological rigour to the evidence base. METHODS: 24 mothers planning to accept, postpone or decline the first MMR dose (MMR1) for their 11-36 month-old children, described their decision-making in semi-structured interviews. Mothers were recruited via General Practice, parents' groups/online forums, and chain referral. MMR1 status was obtained from General Practice records 6 months post interview. Interview transcripts were coded and interpreted using a modified Grounded Theory approach. RESULTS: Five themes were identified: MMR vaccine and controversy; Social and personal consequences of MMR decision; Health professionals and policy; Severity and prevalence of measles, mumps and rubella infections; Information about MMR and alternatives. Results indicated that MMR1 acceptors were sympathetic toward Wakefield as a person, but universally rejected his study which sparked the controversy; parents opting for single vaccines expressed the sense that immune overload is not a consideration but that not all three components of MMR are warranted by disease severity; and MMR1 rejectors openly criticised other parents' MMR decisions and decision-making. CONCLUSIONS: This study corroborated some previous qualitative work but indicated that the shrinking group of parents now rejecting MMR comprises mainly those with more extreme and complex anti-immunisation views, whilst parents opting for single vaccines may use second-hand information about the controversy. In response, policymakers and practitioners should revise their expectations of today's MMR decision-makers, and their methods for supporting them. PMID- 22230591 TI - Health-related quality of life in the Anthrax Vaccination Program for workers in the Laboratory Response Network. AB - BACKGROUND: In 2002 CDC initiated the Anthrax Vaccination Program (AVP) to provide voluntary pre-exposure vaccination with Anthrax Vaccine Adsorbed (AVA) for persons at high risk of exposure to Bacillus anthracis spores. There has been concern that AVA could be associated with long term impairment of physical and/or mental health. OBJECTIVES: To ascertain whether physical and mental functional status, as measured by the SF-36v2 health survey (Medical Outcomes Trust, Boston, MA), of AVA recipients and controls changed differently over time. METHODS: We enrolled 437 exposed (received AVA) and 139 control subjects. The exposed group received AVA under then-current Advisory Committee on Immunization Practices (ACIP) recommendations. SF-36v2 surveys were completed at 0, 12, and 30 months. SF-36v2 physical and mental scores both range from 0 to 100 with an estimated national average of 50 points. RESULTS: For physical scores, the average change from baseline was -0.53 for exposed vs. -0.67 for controls at 12 months (p=0.80) and -1.09 for exposed vs. -1.97 for controls at 30 months (p=0.23). For mental scores, the average change from baseline was -1.50 for exposed vs. -1.64 for controls at 12 months (p=0.86) and -2.11 for exposed vs. -0.24 for controls at 30 months (p=0.06). In multivariable analysis, the difference in mental score change between exposed vs. controls at 30 months was less pronounced (p=0.37) but other findings were similar to univariate analyses. CONCLUSIONS: These results do not favor an association between receipt of AVA and an altered health related quality of life over a 30-month period. PMID- 22230592 TI - Clinical study of transcutaneous vaccination using a hydrogel patch for tetanus and diphtheria. AB - Transcutaneous immunization (TCI) is a non-invasive and easy-to-use vaccination method. We demonstrated the efficacy and safety of a transcutaneous vaccine formulation using a hydrogel patch in animal experiments. In the present study, we performed a clinical study to apply our TCI formulation for vaccination against tetanus and diphtheria in human. The TCI device was a hydrogel patch (antigen-free) applied to the left brachial medial skin of 22 healthy volunteers for 48 h. Next, the hydrogel patch, containing 2mg tetanus toxoid (TT) and 2mg diphtheria toxoid (DT) as the TCI formulation, was applied to 27 healthy volunteers for 24h and some volunteers were vaccinated again by TCI formulation. For safety assessment, the patch application site was observed to assess local adverse events, and systemic adverse events were determined by a blood test. The antigen-free hydrogel patch and TCI formulation containing TT and DT did not induce local or systemic severe adverse events. For vaccine efficacy estimation, toxoid-specific serum antibody titers were determined by ELISA and the toxin neutralizing activity of the induced antibody was evaluated in a passive challenge experiment. The anti-TT IgG titer and the anti-DT IgG titer increased, and a significant effect was detected by paired t-test. The antibody titers were maintained at higher level than that before vaccination for at least 1 year. Moreover, toxoid-specific antibodies were produced by the second vaccination in some subjects. Antibodies induced by application of the TCI formulation neutralized the toxin and prevented toxic death in mice. In addition, changes in the skin condition due to application of the TCI formulation were observed under in vivo confocal Raman spectroscopy. The amount of water and patch components in the stratum corneum increased after application of the TCI formulation, suggesting that the change in the skin condition was related to antigen penetration. These data indicate that this easy-to-use TCI system induces an immune response without severe adverse reactions in humans. This easy-to-use and safe TCI formulation enables mass treatment in an outbreak setting and increased vaccination rates in developing countries, and will greatly contribute to worldwide countermeasures against infectious diseases. PMID- 22230593 TI - Characterizing providers' immunization communication practices during health supervision visits with vaccine-hesitant parents: a pilot study. AB - OBJECTIVE: To determine the feasibility of using direct observation of provider parent immunization discussions and to characterize provider communication practices with vaccine-hesitant parents. METHODS: Over a 6 month period in 2010, we videotaped immunization discussions between pediatric providers and vaccine hesitant parents during health supervision visits involving children 2-15 months old (N=24) in the Seattle area, Washington, USA. Videotapes were analyzed using the qualitative method of conversation analysis. RESULTS: We approached 96 parents seen by 9 different providers. Of those who were eligible (N=56), we enrolled 43% (N=24). Four videotaped visits were excluded from analysis for failure to obtain parental HIPAA authorization. Of the remaining 20 visits, there were >=2 visits each that involved children aged 2, 4, 6, 9, 12, and 15 months, and all videotaped visits contained at least a brief immunization discussion. We identified 6 communication practices and several behavior types within each practice relevant to immunization: Practice 1, providers' initiations of the topic of vaccination; Types: participatory or presumptive format; Practice 2, parents' responses to providers' topic initiations; Types: strong or weak acceptance or resistance; Practice 3, providers' follow-ups to parent's responses; Types: no, immediate, or delayed pursuit; Practice 4, parents' vaccine related questions or statements; Types: fact- or concern-based; Practice 5, providers' explicit solicitations of parent's questions/concerns; Types: designed to discourage or encourage discussion; and Practice 6, parents' responses to providers' solicitations of questions/concerns; Types: no question or fact- or concern-based inquiry. CONCLUSION: Direct observation of immunization discussions in the primary care pediatric setting is feasible and yields insight into several provider-parent immunization communication practices that are worthy of further study to determine which are effective at improving parental acceptance of immunization. PMID- 22230594 TI - Factors associated with the impact of quality improvement collaboratives in mental healthcare: an exploratory study. AB - BACKGROUND: Quality improvement collaboratives (QICs) bring together groups of healthcare professionals to work in a structured manner to improve the quality of healthcare delivery within particular domains. We explored which characteristics of the composition, participation, functioning, and organization of these collaboratives related to changes in the healthcare for patients with anxiety disorders, dual diagnosis, or schizophrenia. METHODS: We studied three QICs involving 29 quality improvement (QI) teams representing a number of mental healthcare organizations in the Netherlands. The aims of the three QICs were the implementation of multidisciplinary practice guidelines in the domains of anxiety disorders, dual diagnosis, and schizophrenia, respectively. We used eight performance indicators to assess the impact of the QI teams on self-reported patient outcomes and process of care outcomes for 1,346 patients. The QI team members completed a questionnaire on the characteristics of the composition, participation in a national program, functioning, and organizational context for their teams. It was expected that an association would be found between these team characteristics and the quality of care for patients with anxiety disorders, dual diagnosis, and schizophrenia. RESULTS: No consistent patterns of association emerged. Theory-based factors did not perform better than practice-based factors. However, QI teams that received support from their management and both active and inspirational team leadership showed better results. Rather surprisingly, a lower average level of education among the team members was associated with better results, although less consistently than the management and leadership characteristics. Team views with regard to the QI goals of the team and attitudes towards multidisciplinary practice guidelines did not correlate with team success. CONCLUSIONS: No general conclusions about the impact of the characteristics of QI teams on the quality of healthcare can be drawn, but support of the management and active, inspirational team leadership appear to be important. Not only patient outcomes but also the performance indicators of monitoring and screening/assessment showed improvement in many but not all of the QI teams with such characteristics. More studies are needed to identify factors associated with the impact of multidisciplinary practice guidelines in mental healthcare. PMID- 22230595 TI - Age- and gender-related variations in hematology, clinical biochemistry, and hormones in Spanish fillies and colts. AB - In order to assess which laboratorial parameters need specific age- and/or gender related reference values, hematological and biochemical profiles (including hormones) were performed in 205 Spanish foals of 5 groups: A (1-2 months; 20 fillies, 10 colts), B (2-3 months; 24 fillies, 18 colts), C (3-6 months; 25 fillies, 16 colts), D (6-9 months; 20 fillies, 23 colts) and E (9-12 months; 25 fillies, 15 colts). Additionally, 120 adult horses were sampled in order to establish baseline data for this breed in our laboratory. Group E had lower red blood cell number and mean cell volume than B, C and D, and neutrophil count was lower in A. Albumin was lower in A than in D, lactate was higher in B, C and D, CK, AST and K were higher in C. In D and E, cortisol was lower and adrenaline was higher. Urea progressively increases, whereas ALP decreases with age. Packed cell volume was higher in fillies of group A, creatinine was higher in colts of group E and fillies of groups B, C, and D had higher aldosterone than colts. In comparison to Spanish adult horses, mean cell volume, albumin, urea, CK, AST, LDH, and ALP requires specific ranges for foals. PMID- 22230596 TI - Lipid-dependent protein sorting at the trans-Golgi network. AB - In eukaryotic cells, the trans-Golgi network serves as a sorting station for post Golgi traffic. In addition to coat- and adaptor-mediated mechanisms, studies in mammalian epithelial cells and yeast have provided evidence for lipid-dependent protein sorting as a major delivery mechanism for cargo sorting to the cell surface. The mechanism for lipid-mediated sorting is the generation of raft platforms of sphingolipids, sterols and specific sets of cargo proteins by phase segregation in the TGN. Here, we review the evidence for such lipid-raft-based sorting at the TGN, as well as their involvement in the formation of TGN-to-PM transport carriers. This article is part of a Special Issue entitled Lipids and Vesicular Transport. PMID- 22230597 TI - Comments regarding 'Assessment of the accuracy of AortaScan for detection of abdominal aortic aneurysm (AAA)'. PMID- 22230598 TI - Nurr1 haplotypes are associated with femoropopliteal restenosis/re-occlusion after percutaneous transluminal angioplasty. AB - Restenosis/re-occlusion remains a frequent complication in the first year after percutaneous transluminal angioplasty (PTA). In this study, association of nuclear receptor related 1 protein (Nurr1) haplotypes to the restenosis/re occlusion rate after femoropopliteal PTA was investigated. Patients (n = 142) with disabling claudication or critical limb ischaemia, who had undergone technically successful femoropopliteal PTA, were prospectively followed up by vascular ultrasound imaging 12 months after the procedure. Nurr1 haplotypes 2 and 3 were associated significantly with the restenosis/re-occlusion rate (adjusted odds ratio 1.6, 95% confidence interval (CI) 1.1-2.3 and 2.0, 1.3-2.8, respectively) on univariate analysis. PMID- 22230599 TI - Prospective randomised comparative study of visual foam sclerotherapy alone or in combination with ultrasound-guided foam sclerotherapy for treatment of superficial venous insufficiency: preliminary report. AB - OBJECTIVE: The aim of the study is to compare ultrasound-guided foam sclerotherapy (UGFS: injection of foam sclerosant under ultrasound guidance) of the great saphenous vein (GSV) combined with visual foam sclerotherapy (VFS: injection of foam sclerosant under visual control) for varicose tributary veins and VFS alone in the treatment of GSV reflux. DESIGN AND METHODS: A total of 133 limbs in 97 patients with GSV reflux were randomised to receive either VFS alone or VFS combined with UGFS. In both groups, 1% polidocanol foam was used. Assessments included duplex ultrasonography, evaluation of Venous Clinical Severity Scores (VCSS) and CEAP (clinical, etiologic, anatomic, and pathophysiologic) scores. Ultrasonographic inspection of the foam in the GSV was carried out during 5 min before compression was applied. The primary 'end' point of the study was obliteration of the GSV at 6 months. RESULTS: A total of 51 limbs in 48 patients were treated with UGFS + VFS and the remaining 52 limbs in 49 patients were treated with VFS alone. There were no significant inter-group differences in patient age, male: female ratio, height, weight, body mass index, CEAP clinical scores or VCSS. The GSV diameter was 6.0 +/- 1.7 mm (median +/- interquartile range) in the UGFS + VFS group and 5.7 +/- 1.6 mm in the VFS group (p = 0.419). The mean injected volume of foam for varicose tributary veins was 4 +/- 2 ml in the UGFS + VFS group and 6 +/- 2 ml in the VFS group, a significantly higher amount of foam being used in the latter (p < 0.001). However, the mean total amount of foam was greater in limbs treated with UFGS + VFS than in those treated with VFS alone (p = 0.017). Ultrasonographic inspection revealed complete vasospasm of the GSV in 37 (72.5%) limbs in the UGFS + VFS group and 29 (55.8%) in the VFS group during sclerotherapy (p = 0.097). At 6-month follow-up, complete occlusion was found in 23 limbs (45.1%) treated with UGFS + VFS and in 22 limbs (42.3%) treated with VFS. The difference between the two groups was not significant (p = 0.775). Reflux was absent in 30 limbs (58.8%) treated with UGFS + VFS and in 37 (71.2%) treated with VFS (p = 0.190). There was no inter-group difference in post-treatment VCSS (p = 0.223). CONCLUSIONS: These results show that UGFS + VFS and VFS are equally effective for the treatment of GSV reflux, despite the lower volume of foam used for VFS alone. PMID- 22230600 TI - Outcomes after open surgery and endovascular aneurysm repair for abdominal aortic aneurysm in patients with massive neck atheroma. AB - OBJECTIVE: We retrospectively analysed surgically treated abdominal aortic aneurysm (AAA) in patients with massive atheroma in the aneurysmal neck and compared the outcomes of endovascular aneurysm repair (EVAR) and open surgery (OS) to determine an appropriate strategy for massive neck atheroma cases. METHODS: A retrospective study was performed in 326 consecutive patients who underwent EVAR and in 247 patients who underwent OS. We defined massive neck atheromas if the following characteristics were observed: (1) thickness >= 5 mm; (2) the circumference of the infrarenal aorta >= 75%; and (3) length >= 5 mm. Twenty-eight patients (8.5%) in the EVAR group and 22 (8.9%) in the OS group met these criteria. We modified the previously published reporting standards on the basis of the selection of systemic and embolisation-related complications. RESULTS: Patients in the EVAR group had less intra-operative blood loss, shorter operation time, and shorter hospital stays after the operation (P < 0.01). No perioperative deaths were observed in either group. Major complications were categorised as early (in-hospital) or late (outpatient, within 6 months). Five and three patients in the OS and EVAR groups had early complications, but the difference was not statistically significant. In contrast, 7 patients in the EVAR group had late complications, compared to no patients in the OS group (P = 0.01). Kaplan-Meier analysis revealed a significantly higher survival rate in the OS group (P = 0.011). Two of the 4 patients with suprarenal clamping developed major complications. Mild eosinophilia was observed in 10 patients in the EVAR group. Proteinuria occurred or worsened in 5 EVAR patients and 1 OS patient. CONCLUSION: Compared to OS patients, EVAR patients with massive neck atheroma tend to develop late-phase complications possibly related to cholesterol crystal embolisation. The clinical features of massive neck atheroma patients receiving EVAR should be carefully monitored even after hospital discharge. PMID- 22230601 TI - Re-engineering health systems: the U.S. experience. PMID- 22230608 TI - The role of indoleamine 2, 3 dioxygenase in regulating host immunity to leishmania infection. AB - Pathogen persistence in immune-competent hosts represents an immunological paradox. Increasing evidence suggests that some pathogens, such as, Leishmania major (L. major) have evolved strategies and mechanisms that actively suppress host adaptive immunity. If this notion is correct conventional vaccination therapies may be ineffective in enhancing host immunity, unless natural processes that suppress host immunity are also targeted therapeutically. The key problem is that the basis of pathogen persistence in immune-competent individuals is unknown, despite decades of intense research. This fact, coupled with poor health care and a dearth of effective treatments means that these diseases will remain a scourge on humans unless a better understanding of why the immune system tolerates such infections emerges from research. Indoleamine 2,3-dioxygenase (IDO) has been shown to act as a molecular switch regulating host responses, and IDO inhibitor drugs shown to possess potential in enhancing host immunity to established leishmania infections. It is hoped that this review will help stimulate and help generate critical new knowledge pertaining to the IDO mechanism and how to exploit it to suppress T cell mediated immunity, thus offer an innovative approach to studying the basis of chronic leishmania infection in mice. PMID- 22230609 TI - Fish oil improves hemodynamic stabilization and inflammation after resuscitation in a rat model of hemorrhagic shock. AB - BACKGROUND: Hemorrhagic shock followed by resuscitation stimulates an inflammatory response. This study tests the hypothesis that treatment with fish oil will attenuate inflammatory responses and stabilize hemodynamics. METHODS: Male SD rats (n = 48; 250~300 g) were randomly divided into 4 groups: SHAM, hemorrhagic shock (HS), hemorrhagic shock/resuscitation (HS/R) and fish oil (FO). Shock was induced, and a mean arterial pressure (MAP) was maintained at 35 to 40 mmHg for 60 minutes. Resuscitation was carried out by returning half of the shed blood and Ringer's lactate solution to the animal. In FO group, fish oil (0.2 g/Kg) was infused through caudal vena at 30 minutes after shock. Half of each group was killed at 30 minutes and at 4 hours after resuscitation. Then several kinds of inflammation and oxidative stress indicators such as IL-6, MPO and GSH were tested. RESULT: FO group required less resuscitative fluid and had higher urinary output at the recovery periods from hemorrhagic shock than HS/R group(p < 0.001). After resuscitation, the MAP of HS/R group markedly declined than FO group (p < 0.001). The inflammatory indexes of FO group were lower than HS group and HS/R group and the same as sham group. But the level of endotoxin in FO group was significantly higher than sham group at 4 hours. CONCLUSION: Fish oil pretreatment before fluid resuscitation showed a beneficial effect to the hemodynamic stabilization and inflammation reduction in HS/R rat model. PMID- 22230610 TI - Antioxidant activities potential of tea polysaccharide fractions obtained by ultra filtration. AB - Three polysaccharide fractions (TPS1, TPS2 and TPS3) with different molecular weights were obtained using ultra filtration membranes from crude tea polysaccharide (CTPS) extracted from abandoned lower grade tea leaves. Each fraction contained different contents of neutral sugar, uronic acid, protein, and total polyphenols. These differences provided basis for the antioxidant and free radical scavenging activity of these polysaccharide fractions. The molecular weights of TPS1, TPS2, and TPS3 were around 2.40*10(5) Da, 2.14*10(4) Da, and 2.46*10(3) Da, respectively. In general, TPS1 and CTPS had stronger antioxidant activity, TPS2 and TPS3 had lower antioxidant activity. TPS1 had higher activity for DPPH and lipid per oxidation inhibition. But it had lower capacity for reducing power and metal chelating. This might be due to its higher content of hexuronic acid and larger molecular weight. The order of inhibition activity of lipid per oxidation of various polysaccharide fractions was the same as DPPH radical scavenging activity, as well as the order of metal chelating activity of various polysaccharide fractions similar to hydroxyl radical scavenging activity, which demonstrated that hydroxyl radical scavenging activity of polysaccharide relied heavily on the Fe(2+) metal chelating to decrease the generation of hydroxyl radical. PMID- 22230611 TI - Design and characterization of antitumor drug paclitaxel-loaded chitosan nanoparticles by W/O emulsions. AB - Chitosan nanoparticles and paclitaxel loaded chitosan nanoparticles were prepared by emulsification-crosslinking method in a W/O emulsion system, using glutaraldehyde as crosslinking agent. The mean diameter of chitosan nanoparticles decreased with increase of pH value of the reaction system from 4.5 to 6.5, and increased when the pH exceeded 6.5. Ultraviolet spectrum analysis showed that the largest loading efficiency and encapsulation efficiency could be 8.55% and 94.01%, respectively. In vitro drug release profile was also determined by ultraviolet spectrometry. MTT assays revealed that the blank chitosan nanoparticles had almost none toxicity, and cell culture was carried out accordingly. PMID- 22230612 TI - Immobilization of beta-d-galactosidase from Kluyveromyces lactis on functionalized silicon dioxide nanoparticles: characterization and lactose hydrolysis. AB - beta-D-Galactosidase (BGAL) from Kluyveromyces lactis was covalently immobilized to functionalized silicon dioxide nanoparticles (10-20 nm). The binding of the enzyme to the nanoparticles was confirmed by Fourier transform-infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Functionalized nanoparticles showed 87% immobilization yield. Soluble and immobilized enzyme preparation exhibited pH-optima at pH 6.5 and 7.0, respectively, with temperature optima at 35 and 40 degrees C, respectively. Michaelis constant (K(m)) was 4.77 and 8.4mM for free and immobilized BGAL, respectively. V(max) for the soluble and immobilized enzyme was 12.25 and 13.51 U/ml, respectively. Nanoparticle immobilized BGAL demonstrated improved stability after favoring multipoint covalent attachment. Thermal stability of the immobilized enzyme was enhanced at 40, 50 and 65 degrees C. Immobilized nanoparticle-enzyme conjugate retained more than 50% enzyme activity up to the eleventh cycle. Maximum lactose hydrolysis by immobilized BGAL was achieved at 8h. PMID- 22230613 TI - Potential biosorbent based on sugarcane bagasse modified with tetraethylenepentamine for removal of eosin Y. AB - Tetraethylenepentamine (TEPA) modified sugarcane bagasse (SB), a novel biosorbent (TEPA-MSB), was proved to be an effective adsorbent for anionic dyes due to the introduced functional amino groups. FTIR, TG and DSC analysis were employed to characterize the sorbent. The effects of pH, temperature, contact time and initial concentration of dye on the adsorption of eosin Y were investigated. The experimental data fit very well to the Langmuir model, giving a maximum sorption capacity of 399.04 mg/g at 25 degrees C. And the kinetic data were well described by the pseudo-second-order kinetic model. pH 6 was the optimal pH for eosin Y adsorption, and the maximum adsorption capacity of TEPA-MSB calculated by Langmuir model was 18 times higher than that of SB. PMID- 22230615 TI - Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice. AB - During lymphangiogenesis in the mammalian embryo, a subset of vascular endothelial cells in the cardinal veins is reprogrammed to adopt a lymphatic endothelial fate. The prevailing model of lymphangiogenesis contends that these lymphatic precursor cells migrate away from the cardinal veins and reassemble peripherally as lymph sacs from which a lymphatic vasculature is generated. However, this model fails to account for a number of observations that, as a result, have remained anecdotal. Here, we use optical projection tomography, confocal microscopy and in vivo live imaging to uncover three key stages of lymphatic vascular morphogenesis in the mouse embryo at high resolution. First, we define territories or "pre-lymphatic clusters" of Prox1-positive lymphatic endothelial progenitor cells along the antero-posterior axis of the cardinal veins. Second, these pre-lymphatic clusters undergo progressive extrusion ("ballooning") to generate primitive lymph sacs. Third, lymphatic vessels emerge by a combination of mechanisms including sprouting from the lymph sacs and direct delamination of streams of cells from the cardinal veins. Our data support a new model for lymphatic vascular patterning and morphogenesis, as a basis for identifying the molecular cues governing these processes. PMID- 22230614 TI - Lamellipodia-based migrations of larval epithelial cells are required for normal closure of the adult epidermis of Drosophila. AB - Cell migrations are an important feature of animal development. They are, furthermore, essential to wound healing and tumour progression. Despite recent progress, it is still mysterious how cell migration is spatially and temporally regulated during morphogenesis and how cell migration is coordinated with other cellular behaviours to shape tissues and organs. The formation of the abdominal epithelium of Drosophila during metamorphosis provides an attractive system to study morphogenesis. Here, the diploid adult histoblasts replace the polyploid larval epithelial cells (LECs). Using in vivo 4D microscopy, I show that, besides apical constriction and apoptosis, the LECs undergo extensive coordinated migrations. The migrations follow a transition from a stationary (epithelial) to a migratory mode. The migratory behaviour is stimulated by autocrine Dpp signalling. Directed apical lamellipodia-like protrusions propel the cells. Initially, planar cell polarity determines the orientation of LEC migration. While LECs are migrating they also constrict apically, and changes in activity of the small GTPase Rho1 can favour one behaviour over the other. This study shows that the LECs play a more active role in morphogenesis than previously thought, with their migrations contributing to abdominal closure. It furthermore provides insights into how the migratory behaviour of cells is regulated during morphogenesis. PMID- 22230617 TI - Development and evolution of the neural crest: an overview. AB - The neural crest is a multipotent and migratory cell type that forms transiently in the developing vertebrate embryo. These cells emerge from the central nervous system, migrate extensively and give rise to diverse cell lineages including melanocytes, craniofacial cartilage and bone, peripheral and enteric neurons and glia, and smooth muscle. A vertebrate innovation, the gene regulatory network underlying neural crest formation appears to be highly conserved, even to the base of vertebrates. Here, we present an overview of important concepts in the neural crest field dating from its discovery 150 years ago to open questions that will motivate future research. PMID- 22230616 TI - EGFR signaling is required for regenerative proliferation in the cochlea: conservation in birds and mammals. AB - Proliferation and transdifferentiaton of supporting cells in the damaged auditory organ of birds lead to robust regeneration of sensory hair cells. In contrast, regeneration of lost auditory hair cells does not occur in deafened mammals, resulting in permanent hearing loss. In spite of this failure of regeneration in mammals, we have previously shown that the perinatal mouse supporting cells harbor a latent potential for cell division. Here we show that in a subset of supporting cells marked by p75, EGFR signaling is required for proliferation, and this requirement is conserved between birds and mammals. Purified p75+ mouse supporting cells express receptors and ligands for the EGF signaling pathway, and their proliferation in culture can be blocked with the EGFR inhibitor AG1478. Similarly, in cultured chicken basilar papillae, supporting cell proliferation in response to hair cell ablation requires EGFR signaling. In addition, we show that EGFR signaling in p75+ mouse supporting cells is required for the down-regulation of the cell cycle inhibitor p27(Kip1) (CDKN1b) to enable cell cycle re-entry. Taken together, our data suggest that a conserved mechanism involving EGFR signaling governs proliferation of auditory supporting cells in birds and mammals and may represent a target for future hair cell regeneration strategies. PMID- 22230618 TI - Opioid substitution treatment in a public health setting: a collaboration between hospitals and NGOs in the Punjab. PMID- 22230619 TI - Vegetarian diets and blood pressure among white subjects: results from the Adventist Health Study-2 (AHS-2). AB - OBJECTIVE: Previous work studying vegetarians has often found that they have lower blood pressure (BP). Reasons may include their lower BMI and higher intake levels of fruit and vegetables. Here we seek to extend this evidence in a geographically diverse population containing vegans, lacto-ovo vegetarians and omnivores. DESIGN: Data are analysed from a calibration sub-study of the Adventist Health Study-2 (AHS-2) cohort who attended clinics and provided validated FFQ. Criteria were established for vegan, lacto-ovo vegetarian, partial vegetarian and omnivorous dietary patterns. SETTING: Clinics were conducted at churches across the USA and Canada. Dietary data were gathered by mailed questionnaire. SUBJECTS: Five hundred white subjects representing the AHS-2 cohort. RESULTS: Covariate-adjusted regression analyses demonstrated that the vegan vegetarians had lower systolic and diastolic BP (mmHg) than omnivorous Adventists (beta = -6.8, P < 0.05 and beta = -6.9, P < 0.001). Findings for lacto ovo vegetarians (beta = -9.1, P < 0.001 and beta = -5.8, P < 0.001) were similar. The vegetarians (mainly the vegans) were also less likely to be using antihypertensive medications. Defining hypertension as systolic BP > 139 mmHg or diastolic BP > 89 mmHg or use of antihypertensive medications, the odds ratio of hypertension compared with omnivores was 0.37 (95 % CI 0.19, 0.74), 0.57 (95 % CI 0.36, 0.92) and 0.92 (95 % CI 0.50, 1.70), respectively, for vegans, lacto-ovo vegetarians and partial vegetarians. Effects were reduced after adjustment for BMI. CONCLUSIONS: We conclude from this relatively large study that vegetarians, especially vegans, with otherwise diverse characteristics but stable diets, do have lower systolic and diastolic BP and less hypertension than omnivores. This is only partly due to their lower body mass. PMID- 22230620 TI - From tetrapods to primates: conserved developmental mechanisms in diverging ecological adaptations. AB - Primates are endowed with a brain about twice the size that of a mammal with the same body size, and humans have the largest brain relative to body size of all animals. This increase in brain size may be related to the acquisition of higher cognitive skills that permitted more complex social interactions, the evolution of culture, and the eventual ability to manipulate the environment. Nevertheless, in its internal structure, the primate brain shares a very conserved design with other mammals, being covered by a six-layered neocortex that, although expands disproportionately to other brain components, it does so following relatively well-defined allometric trends. Thus, the most fundamental events generating the basic design of the primate and human brain took place before the appearance of the first primate-like animal. Presumably, the earliest mammals already displayed a brain morphology radically different from that of their ancestors and that of their sister group, the reptiles, being characterized by the presence of an incipient neocortex that underwent an explosive growth in subsequent mammal evolution. In this chapter, we propose an integrative hypothesis for the origin of the mammalian neocortex, by considering the developmental modifications, functional networks, and ecological adaptations involved in the generation of this structure during the cretaceous period. Subsequently, the expansion of the primate brain is proposed to have relied on the amplification of the same, or very similar, developmental mechanisms as those involved in its primary origins, even in different ecological settings. PMID- 22230622 TI - Cerebral cortical development in rodents and primates. AB - Rodents and primates both show considerable variation in the overall size, the radial and tangential dimensions, folding and subdivisions into distinct areas of their cerebral cortex. Our current understanding of brain development is based on a handful of model systems. A detailed comparative analysis of the cellular and molecular mechanisms that regulate neural progenitor production, cell migration, and circuit assembly can provide much needed insights into the working of neocortical evolution. From the limited comparative data currently available, it is apparent that the emergence and variation of the neuronal progenitor cells have led to the production of increased neuronal populations and the evolution of the cortex. Further diversification and compartmentalization of the germinal zone together with changing proportions of radial glia in the ventricular zone and various intermediate progenitors in the subventricular zone may have been the driving force behind increased cell numbers in larger brains both in rodents and primates. Radial and tangential migratory patterns are both present in rodents and primates, but in different proportions. There are apparent differences between mouse and human in the generation and elaboration of the interneuronal subtypes and also in gene expression patterns associated with the appearance of distinct cortical areas. The increased cortical dimensions and the formation of a more elaborate cortical architecture in primates require a larger and more compartmentalized transient subplate zone during development. More comparative analysis in rodent and primate species with large, small, and smooth and folded brains is needed to reveal the biological significance of the alterations in these cortical developmental programs. PMID- 22230621 TI - Genetic correlates of the evolving primate brain. AB - The tremendous shifts in the size, structure, and function of the brain during primate evolution are ultimately caused by changes at the genetic level. Understanding what these changes are and how they effect the phenotypic changes observed lies at the heart of understanding evolutionary change. This chapter focuses on understanding the genetic basis of primate brain evolution, considering the substrates and mechanisms through which genetic change occurs. It also discusses the implications that our current understandings and tools have for what we have already discovered and where our studies will head in the future. While genetic and genomic studies have identified many regions undergoing positive selection during primate evolution, the findings are certainly not exhaustive and functional relevance remains to be confirmed. Nevertheless, a strong foundation has been built upon which future studies will emerge. PMID- 22230623 TI - Embracing covariation in brain evolution: large brains, extended development, and flexible primate social systems. AB - Brain size, body size, developmental length, life span, costs of raising offspring, behavioral complexity, and social structures are correlated in mammals due to intrinsic life-history requirements. Dissecting variation and direction of causation in this web of relationships often draw attention away from the factors that correlate with basic life parameters. We consider the "social brain hypothesis," which postulates that overall brain and the isocortex are selectively enlarged to confer social abilities in primates, as an example of this enterprise and pitfalls. We consider patterns of brain scaling, modularity, flexibility of brain organization, the "leverage," and direction of selection on proposed dimensions. We conclude that the evidence supporting selective changes in isocortex or brain size for the isolated ability to manage social relationships is poor. Strong covariation in size and developmental duration coupled with flexible brains allow organisms to adapt in variable social and ecological environments across the life span and in evolution. PMID- 22230625 TI - Lateralization of the human brain. AB - It is often suggested that cerebral asymmetry, when a consistent direction of asymmetry prevails, is unique to humans. We now know that many other species exhibit directionally consistent cerebral and behavioral asymmetries. Nevertheless, the predominance of left-cerebral dominance for language and manual functions may have played a special role in human evolution, even though precursors may be found in other animals-and especially in the great apes. I argue that the common cerebral asymmetry for these functions derives from the origins of language in manual gestures. These, in turn, may originate in specialized circuits for grasping that have been identified in primates, and lateralization may have been progressively introduced as praxic and linguistic functions became more complex. PMID- 22230624 TI - The evolution of neocortex in primates. AB - We can learn about the evolution of neocortex in primates through comparative studies of cortical organization in primates and those mammals that are the closest living relatives of primates, in conjunction with brain features revealed by the skull endocasts of fossil archaic primates. Such studies suggest that early primates had acquired a number of features of neocortex that now distinguish modern primates. Most notably, early primates had an array of new visual areas, and those visual areas widely shared with other mammals had been modified. Posterior parietal cortex was greatly expanded with sensorimotor modules for reaching, grasping, and personal defense. Motor cortex had become more specialized for hand use, and the functions of primary motor cortex were enhanced by the addition and development of premotor and cingulate motor areas. Cortical architecture became more varied, and cortical neuron populations became denser overall than in nonprimate ancestors. Primary visual cortex had the densest population of neurons, and this became more pronounced in the anthropoid radiation. Within the primate clade, considerable variability in cortical size, numbers of areas, and architecture evolved. PMID- 22230626 TI - The insular cortex: a review. AB - The human insular cortex forms a distinct, but entirely hidden lobe, situated in the depth of the Sylvian fissure. Here, we first review the recent literature on the connectivity and the functions of this structure. It appears that this small lobe, taking up less than 2% of the total cortical surface area, receives afferents from some sensory thalamic nuclei, is (mostly reciprocally) connected with the amygdala and with many limbic and association cortical areas, and is implicated in an astonishingly large number of widely different functions, ranging from pain perception and speech production to the processing of social emotions. Next, we embark on a long, adventurous journey through the voluminous literature on the structural organization of the insular cortex. This journey yielded the following take-home messages: (1) The meticulous, but mostly neglected publications of Rose (1928) and Brockhaus (1940) are still invaluable for our understanding of the architecture of the mammalian insular cortex. (2) The relation of the insular cortex to the adjacent claustrum is neither ontogenetical nor functional, but purely topographical. (3) The insular cortex has passed through a spectacular progressive differentiation during hominoid evolution, but the assumption of Craig (2009) that the human anterior insula has no homologue in the rhesus monkey is untenable. (4) The concept of Mesulam and Mufson (1985), that the primate insula is essentially composed of three concentrically arranged zones, agranular, dysgranular, and granular, is presumably correct, but there is at present much confusion concerning the more detailed architecture of the anterior insular cortex. (5) The large spindle shaped cells in the fifth layer of the insular cortex, currently known as von Economo neurons (VENs), are not only confined to large-brained mammals, such as whales, elephants, apes, and humans, but also occur in monkeys and prosimians, as well as in the pygmy hippopotamus, the Atlantic walrus, and Florida manatee. Finally, we point out that the human insula presents a unique opportunity for performing an in-depth comparative analysis of the relations between structure and function in a typical sensory and a typical cognitive cortical domain. PMID- 22230627 TI - The missing link: evolution of the primate cerebellum. AB - The cerebellum has too often been seen as the "little brain," subservient to the "big brain," the cerebrum. That is changing, as neuroimaging uncovers the cerebellum as the "missing link" in the neurological underpinnings of many cognitive domains. Connections between the neocortex and the cerebellum are now more precisely defined, with functionally localized areas of cerebellar cortex understood for cognitive tasks in humans. Comparative volumetric studies of the primate cerebellum have isolated some elements of circuitry, and our field is moving toward a better integration with the neurosciences in a systematic comparative framework. The next decade may show great advances, as relatively noninvasive techniques of neuroimaging have the potential to build a comparative model of the evolution of primate neurocircuitry. PMID- 22230628 TI - Human prefrontal cortex: evolution, development, and pathology. AB - The prefrontal cortex is critical to many cognitive abilities that are considered particularly human, and forms a large part of a neural system crucial for normal socio-emotional and executive functioning in humans and other primates. In this chapter, we survey the literature regarding prefrontal development and pathology in humans as well as comparative studies of the region in humans and closely related primate species. The prefrontal cortex matures later in development than more caudal regions, and some of its neuronal subpopulations exhibit more complex dendritic arborizations. Comparative work suggests that the human prefrontal cortex differs from that of closely related primate species less in relative size than it does in organization. Specific reorganizational events in neural circuitry may have taken place either as a consequence of adjusting to increases in size or as adaptive responses to specific selection pressures. Living in complex environments has been recognized as a considerable factor in the evolution of primate cognition. Normal frontal lobe development and function are also compromised in several neurological and psychiatric disorders. A phylogenetically recent reorganization of frontal cortical circuitry may have been critical to the emergence of human-specific executive and social-emotional functions, and developmental pathology in these same systems underlies many psychiatric and neurological disorders, including autism and schizophrenia. PMID- 22230629 TI - Minicolumn size and human cortex. AB - Minicolumns in primates are small when compared with those of other mammals, both in absolute and relative terms. The data suggest that minicolumns in the earliest primates were especially narrow and increased in accordance with encephalization so that the largest minicolumns in this mammalian order are found in apes and humans. Among the evolutionary strategies that led to the successful human brain was a combination of enhanced cortical volume based on increases in the number of ontogenetic units, along with enlargement of the individual minicolumns. However, continued encephalization of the large human brain presents serious problems that may limit future growth. When further increases in brain size can no longer be sustained, the alternative for further adaptations will have to be done at the level of brain organization. A downsizing of minicolumns may be among those responses. This has the advantage of permitting increases in the number of processing units without adding surface area. However, it is argued that narrow minicolumns process information differently, which raises questions about the relation between minicolumn size and behavior. There is evidence that minicolumns may be smaller in extant humans within selected populations, and the implications of this are briefly considered. PMID- 22230630 TI - Human brain evolution writ large and small. AB - Human evolution was marked by an extraordinary increase in total brain size relative to body size. While it is certain that increased encephalization is an important factor contributing to the origin of our species-specific cognitive abilities, it is difficult to disentangle which aspects of human neural structure and function are correlated by-products of brain size expansion from those that are specifically related to particular psychological specializations, such as language and enhanced "mentalizing" abilities. In this chapter, we review evidence from allometric scaling studies demonstrating that much of human neocortical organization can be understood as a product of brain enlargement. Defining extra-allometric specializations in humans is often hampered by a severe lack of comparative data from the same neuroanatomical variables across a broad range of primates. When possible, we highlight evidence for features of human neocortical architecture and function that cannot be easily explained as correlates of brain size and, hence, might be more directly associated with the evolution of uniquely human cognitive capacities. PMID- 22230631 TI - Hominin paleoneurology: where are we now? AB - Hominin paleoneurology is the subfield of paleoanthropology that investigates brain evolution in human ancestors. For over a century, paleoneurologists have focused on analyses of cranial capacities (as surrogates for brain size) and endocranial casts (endocasts), which are prepared from the interiors of fossilized braincases and reproduce details of external brain morphology. This review discusses recent improvements in our understanding of hominin brain evolution in terms of brain size, sulcal patterns, and cortical shape features. To the extent possible, the evolution of neurological reorganization is assessed in light of findings from paleoneurology. In order to make inferences about cognitive evolution, paleoneurologists interpret their data within a framework that incorporates behavioral information from comparative primatological studies and findings from comparative neuroanatomical and medical imaging investigations. Advances in our knowledge about the evolution of the prefrontal cortex (Brodmann's area 10) provide an example of a productive synthesis of comparative neuroanatomical and behavioral research with investigations of the fossil record of hominin endocasts. PMID- 22230632 TI - Evolution of hominin cranial ontogeny. AB - Hominin evolution is characterized by two main trends, transition to bipedality and increase in brain size. Fossil evidence shows that both trends had a major impact on the structure and function of the hominin skull. This chapter asks how evolutionary modification of the cranial ontogenetic program led to morphological reorganization of the hominin skull and ultimately to hominin cranial diversity. Three major mechanisms of evolutionary developmental reorganization are proposed: modified prenatal development of the cranial base and face reflects adaptation to bipedality; high rates of neurocranial growth during early postnatal ontogeny are essential to attain large brain sizes; taxon-specific modification of facial development reflects dietary adaptation and-in the genus Homo-a general trend toward neoteny. PMID- 22230633 TI - Hominins and the emergence of the modern human brain. AB - Evidence used to reconstruct the morphology and function of the brain (and the rest of the central nervous system) in fossil hominin species comes from the fossil and archeological records. Although the details provided about human brain evolution are scarce, they benefit from interpretations informed by interspecific comparative studies and, in particular, human pathology studies. In recent years, new information has come to light about fossil DNA and ontogenetic trajectories, for which pathology research has significant implications. We briefly describe and summarize data from the paleoarcheological and paleoneurological records about the evolution of fossil hominin brains, including behavioral data most relevant to brain research. These findings are brought together to characterize fossil hominin taxa in terms of brain structure and function and to summarize brain evolution in the human lineage. PMID- 22230634 TI - Neuronal scaling rules for primate brains: the primate advantage. AB - In what concerns cognitive abilities, primates usually outrank other mammals of similar, or even larger, brain size, as illustrated by comparisons between a macaque monkey and a capybara; a chimpanzee and a cow; or a human and a dolphin, whale, or elephant. Such a cognitive advantage is inconsistent with the traditional view of brain scaling in mammalian evolution as a homogeneous phenomenon regarding numbers of neurons and neuronal density, with brains of different sizes viewed as similarly scaled-up or scaled-down versions of a shared basic plan. Here, I will argue, instead, that different neuronal scaling rules apply to different mammalian orders and that the particular rules that apply to primates are such that endow us with an advantage over other mammals that is likely to have important cognitive consequences: a larger number of neurons concentrated per volume in the brain. PMID- 22230635 TI - Self-organization and interareal networks in the primate cortex. AB - Variability of gene expression of cortical precursors may partially reflect the operation of the gene regulatory network and determines the boundaries of the state space within which self-organization of the cortex can unfold. In primates, including humans, the outer subventricular zone, a primate-specific germinal zone, generates a large contingent of the projection neurons participating in the interareal network. The number of projection neurons in individual pathways largely determines the network properties as well as the hierarchical organization of the cortex. Mathematical modeling of cell-cycle kinetics of cortical precursors in the germinal zones reveals how multiple control loops ensure the generation of precise numbers of different categories of projection neurons and allow partial simulation of cortical self-organization. We show that molecular manipulation of the cell cycle of cortical precursors shifts the trajectory of the cortical precursor within its state space, increases the diversity in the cortical lineage tree, and explores changes in phylogenetic complexity. These results explore how self-organization underlies the complexity of the cortex and suggest evolutionary mechanisms. PMID- 22230636 TI - Neural wiring optimization. AB - Combinatorial network optimization theory concerns minimization of connection costs among interconnected components in systems such as electronic circuits. As an organization principle, similar wiring minimization can be observed at various levels of nervous systems, invertebrate and vertebrate, including primate, from placement of the entire brain in the body down to the subcellular level of neuron arbor geometry. In some cases, the minimization appears either perfect, or as good as can be detected with current methods. One question such best-of-all possible-brains results raise is, what is the map of such optimization, does it have a distinct neural domain? PMID- 22230637 TI - Design principles of the human brain: an evolutionary perspective. AB - The evolution of the brain in mammals has been accompanied by a reorganization of the brain as a result of differential growth of certain brain regions. Consequently, the geometry of the brain, and especially the size and shape of the cerebral cortex, has changed notably during evolution. Comparative studies of the cerebral cortex suggest that there are general architectural principles governing its growth and evolutionary development and that the primate neocortex is uniformly organized and composed of neural processing units. We are beginning to understand the geometric, biophysical, and energy constraints that have governed the evolution of these neuronal networks. In this review, some of the design principles and operational modes will be explored that underlie the information processing capacity of the cerebral cortex in primates, and it will be argued that with the evolution of the human brain we have nearly reached the limits of biological intelligence. PMID- 22230638 TI - Primate encephalization. AB - Encephalization is a concept that implies an increase in brain or neocortex size relative to body size, size of lower brain areas, and/or evolutionary time. Here, I review 26 large-scale comparative studies that provide robust evidence for five lifestyle correlates of encephalization (group living, a large home range, a high quality diet, a strong reliance on vision, arboreal and forest dwelling), six cognitive correlates (better performance in captive tests, more tactical deception, innovation, tool use, social learning, all subsumed in part by general intelligence), one life history correlate (a longer lifespan), two evolutionary correlates (a high rate of change in microcephaly genes, an increase in brain size over macroevolutionary time), as well as three trade-offs (a slower juvenile development, a higher metabolic rate, sexually selected dimorphism). Of the 26 different encephalization measures used in these studies, corrected neocortex size, either with a ratio or a residual, is the most popular structural correlate of the functional variables, while residual brain size is the measure associated with the greatest number of them. Controversies remain on corrected or absolute measures of neural structure size, concerted versus mosaic evolution of brain parts and specialized versus domain-general brain structures and cognitive processes. PMID- 22230639 TI - Evolution of the brain and intelligence in primates. AB - Primates are, on average, more intelligent than other mammals, with great apes and finally humans on top. They generally have larger brains and cortices, and because of higher relative cortex volume and neuron packing density (NPD), they have much more cortical neurons than other mammalian taxa with the same brain size. Likewise, information processing capacity is generally higher in primates due to short interneuronal distance and high axonal conduction velocity. Across primate taxa, differences in intelligence correlate best with differences in number of cortical neurons and synapses plus information processing speed. The human brain stands out by having a large cortical volume with relatively high NPD, high conduction velocity, and high cortical parcellation. All aspects of human intelligence are present at least in rudimentary form in nonhuman primates or some mammals or vertebrates except syntactical language. The latter can be regarded as a very potent "intelligence amplifier." PMID- 22230641 TI - Evolution of brain and language. AB - In this chapter evolutionary changes in the human brain that are relevant to language are reviewed. Most of what is known involves assessments of the relative sizes of brain regions. Overall brain size is associated with some key behavioral features relevant to language, including complexity of the social environment and the degree of conceptual complexity. Prefrontal cortical and temporal lobe areas relevant to language appear to have increased disproportionately. Areas relevant to language production and perception have changed less dramatically. The extent to which these changes were a consequence specifically of language versus other behavioral adaptations is a good question, but the process may best be viewed as a complex adaptive system, whereby cultural learning interacts with biology iteratively over time to produce language. Overall, language appears to have adapted to the human brain more so than the reverse. PMID- 22230640 TI - Evolution of human emotion: a view through fear. AB - Basic tendencies to detect and respond to significant events are present in the simplest single cell organisms and persist throughout all invertebrates and vertebrates. Within vertebrates, the overall brain plan is highly conserved, though differences in size and complexity also exist. The forebrain differs the most between mammals and other vertebrates. The classic notion that the evolution of mammals led to radical changes such that new forebrain structures (limbic system and neocortex) were added has not held up nor has the idea that so-called limbic areas are primarily involved in emotion. Modern efforts have focused on specific emotion systems, like the fear or defense system, rather than on the search for a general purpose emotion systems. Such studies have found that fear circuits are conserved in mammals, including humans. Animal work has been especially successful in determining how the brain detects and responds to danger. Caution should be exercised when attempting to discuss other aspects of emotion, namely subjective feelings, in animals since there are no scientific ways of verifying and measuring such states except in humans. PMID- 22230642 TI - Evolution of the primate brain. Preface. PMID- 22230644 TI - Impairment on sperm quality and fertility of adult rats after antiandrogen exposure during prepuberty. AB - This study evaluated the effects of antiandrogen exposure during the prepubertal period on reproductive development and reproductive competence in adults. Male rats were divided into two groups: flutamide, receiving 25 mg/kg/day of flutamide by oral gavage and control, receiving vehicle daily. Dosing continued from PND 21 to 44, and animals were killed on PND 50 or PND 75-80. The epididymis, prostate, vas deferens and seminal vesicle weights were lower in Flutamide group on PND 50, while on PND 80 only seminal vesicle weight was reduced. Fertility assessed by IUI revealed a decrease in the fertility potential in the flutamide-treated adults. Flutamide accelerated sperm transit time through the epididymis, impairing sperm motility and storage. A quantitative analysis of the cauda sperm membrane proteome revealed a few significant changes in protein expression. Thus, exposure to flutamide during the prepubertal period compromises the function of the epididymis along with epididymal sperm quality at adulthood. PMID- 22230643 TI - Unevenly distributed: a systematic review of the health literature about socioeconomic inequalities in adult obesity in the United Kingdom. AB - BACKGROUND: There is a growing literature documenting socioeconomic inequalities in obesity risk among adults in the UK, with poorer groups suffering higher risk. METHODS: In this systematic review, we summarize and appraise the extant peer reviewed literature about socioeconomic inequalities in adult obesity risk in the UK published between 1980 and 2010. Only studies featuring empirical assessments of relations between socioeconomic indicators and measures of obesity among adults in the UK were included. RESULTS: A total of 35 articles met inclusion criteria, and were reviewed here. CONCLUSION: Socioeconomic indicators of low socioeconomic position (SEP), including occupational social class of the head-of household at birth and during childhood, earlier adulthood occupational social class, contemporaneous occupational social class, educational attainment, and area-level deprivation were generally inversely associated with adult obesity risk in the UK. Measures of SEP were more predictive of obesity among women than among men. We outline important methodological limitations to the literature and recommend avenues for future research. PMID- 22230645 TI - Exposures that may affect sperm DNA integrity: two decades of follow-up in a pregnancy cohort. AB - Prenatal lifestyle exposures are linked to alterations in conventional semen characteristics. Sperm DNA integrity is another marker of semen quality shown to be altered in mice prenatally exposed to chemicals. From a Danish pregnancy cohort established in 1984-1987, sons were selected for a follow-up study in 2005 2006. We examined associations between prenatal and current lifestyle exposures and DNA fragmentation index (DFI) among 337 men. Sons of overweight mothers had 22% (95% CI: -3; 52) higher DFI than sons of normal weight mothers and sons of parents with a TTP >12 months had 14% (95% CI: -4; 34) higher DFI than sons of parents with a TTP of 0-6 months. Abstinence time was positively associated with DFI (p<0.005). Overweight men had higher DFI compared to normal weight men, however, statistically insignificantly. In conclusion, results indicate that DFI is affected by prenatal exposures, but confidence limits are wide and results statistically insignificant. PMID- 22230647 TI - Effects of lithium therapy on Na+-K+-ATPase activity and lipid peroxidation in bipolar disorder. AB - OBJECTIVES: Oxidative stress induced lipid peroxidation along with a reduced Na(+)-K(+)-ATPase activity has been implicated in the pathophysiology of bipolar disorders (BPD). Although, lithium therapy results in significant improvement in the symptoms of the disease, studies regarding its effect on the altered sodium pump activity and lipid peroxidation status have come out with conflicting results. The present study was undertaken to evaluate the status of lipid peroxidation and analyze the role of lithium and Na(+)-K(+)-ATPase activity in its regulation in BPD patients in our region. METHOD: We measured RBC membrane Na(+)-K(+)-ATPase activity and serum thiobarbituric acid reacting substances (TBARS) level in 73 BPD patients and serum lithium, in addition, in 48 patients receiving lithium therapy among them. RESULTS: Na(+)-K(+)-ATPase activity and serum TBARS level were significantly decreased and increased respectively in all BPD patients compared to age and sex matched healthy controls. Same trend was observed in the BPD patients stabilized on lithium therapy compared to the lithium naive ones. Although, the enzyme activity showed a reciprocal relationship with TBARS in all patients of BPD, a significant positive correlation and dependence of the enzyme activity was evident with serum lithium level only in the lithium stabilized BPD group. CONCLUSIONS: BPD patients showed significantly compromised Na(+)-K(+)-ATPase activity and increased lipid peroxidation. Lithium induced improvement in the enzyme activity was associated with significant reduction in lipid peroxidation. Enhancement of the Na(+)-K(+) ATPase activity by optimum dosage of lithium may be a potential contributing factor for reducing oxidative stress in BPD patients. PMID- 22230646 TI - Auditory orienting and inhibition of return in schizophrenia: a functional magnetic resonance imaging study. AB - Patients with schizophrenia (SP) exhibit deficits in both attentional reorienting and inhibition of return (IOR) during visual tasks. However, it is currently unknown whether these deficits are supramodal in nature and how these deficits relate to other domains of cognitive dysfunction. In addition, the neuronal correlates of this pathological orienting response have not been investigated in either the visual or auditory modality. Therefore, 30 SP and 30 healthy controls (HC) were evaluated with an extensive clinical protocol and functional magnetic resonance imaging (fMRI) during an auditory cuing paradigm. SP exhibited both increased costs and delayed IOR during auditory orienting, suggesting a prolonged interval for attentional disengagement from cued locations. Moreover, a delay in the development of IOR was associated with cognitive deficits on formal neuropsychological testing in the domains of attention/inhibition and working memory. Event-related fMRI showed the characteristic activation of a frontoparietal network (invalid trials>valid trials), but there were no differences in functional activation between patients and HC during either attentional reorienting or IOR. Current results suggest that orienting deficits are supramodal in nature in SP, and are related to higher-order cognitive deficits that directly interfere with day-to-day functioning. PMID- 22230648 TI - Rivastigmine reduces "Likely to use methamphetamine" in methamphetamine-dependent volunteers. AB - We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3mg, PO for 5days) significantly attenuated "Desire for METH". Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30mg), but not saline, increased several positive subjective effects, including "Any Drug Effect", "High", "Stimulated", "Desire METH", and "Likely to Use METH" (all p's<0.0001). In addition, during self administration sessions, participants were significantly more likely to choose METH over saline (p<0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce "Desire METH" (p=0.27), and rivastigmine significantly attenuated "Likely to Use METH" (p=0.01). These effects were most prominent for rivastigmine 6mg when participants were exposed to the low dose (15mg, IV), but not high dose (30mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence. PMID- 22230649 TI - A comparison of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour. AB - Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5ms) is a very effective treatment for severe depression but is associated with cognitive side effects. It has been proposed that ultrabrief pulse (UBP; pulse width 0.25 0.30ms) ECT may be as effective as BP ECT but have less cognitive effects because it is a more physiological form of neuronal stimulation. To investigate this further, we treated normal rats with a 10 session course of either BP (0.5ms), UBP (0.3ms), or sham electroconvulsive stimulation (ECS) and measured antidepressant-related changes in dentate gyrus cell proliferation and hippocampal BDNF protein levels as well as hippocampal-dependant spatial reference memory using the water plus maze and immobility time on the forced swim test. Both BP and UBP ECS induced very similar types of motor seizures. However, BP ECS but not UBP ECS treatment led to a significant, near 3-fold, increase in cell proliferation (p=0.026) and BDNF levels (p=0.01). In the forced swim test, only BP ECS treated animals had a significantly lower immobility time (p=0.046). There was a trend for similarly reduced hippocampal-dependent memory function in both BP and UBP groups but overall there was not a significant difference between treatment and control animals when tested 10 days after completing allocated treatment. These findings show that, even though both forms of ECS elicited similar motor seizures, UBP ECS was less efficient than BP ECS in inducing antidepressant-related molecular, cellular and behavioural changes. PMID- 22230650 TI - Serum lipids, metabolic syndrome and lifetime suicide attempts in patients with bipolar disorder. AB - OBJECTIVE: Bipolar disorder is associated with a high risk of suicide. Many clinical characteristics and, recently, biomarkers have been studied with the aim to find useful predictors of suicidality. The role of serum lipids has also been explored albeit with conflicting results; however, few studies have been focused on patients with bipolar disorder. Aim of our study is to investigate whether serum cholesterol, triglycerides, HDL-c and metabolic syndrome are associated with lifetime suicide attempts in a large naturalistic sample of patients with bipolar disorder. METHODS: 220 patients with bipolar disorder were included. History of lifetime suicide attempts was systematically and retrospectively assessed for each patient. Blood exams testing total cholesterol, triglycerides, and HDL-c levels were performed, and metabolic syndrome was diagnosed according to NCEP ATP-III modified criteria. Serum lipid levels and metabolic syndrome were compared in patients with or without history of suicide attempt. According to a theory that links impulsivity and violence with low cholesterol, the association between lipid levels and violent suicidal behavior was also assessed. RESULTS: Lifetime suicide attempts rate was 32.3%. There were no statistically significant differences between patients with and without lifetime suicide attempts in cholesterol, triglycerides, HDL-c levels, and the prevalence of metabolic syndrome. No differences in the same variables were found in violent suicide attempters compared with nonviolent ones. Clinical characteristics such as gender, low education, higher number of manic and depressive episodes, and taking more medications for bipolar disorder were associated with lifetime suicide attempts. CONCLUSIONS: Our results do not support the hypothesis of a strong association between serum lipid levels and suicide in patients with bipolar disorder. PMID- 22230651 TI - Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. AB - In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean+/-SD age, 48.8+/-13.8years; male [N=14]; Asians [N=23], Caucasians [N=12]; risperidone [N=20] at 3.2+/-2.3mg/day, and olanzapine [N=15] at 9.2+/-4.9mg/day) between September and December 2010. 48.6% (N=17) did not achieve a continuous blockade of >=65%. Moreover, 11.4% (N=4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of >=65%. The results suggest that sustained D2 receptor occupancy levels of >=65% may not always be necessary for the maintenance treatment of schizophrenia. PMID- 22230653 TI - Hole transport materials with low glass transition temperatures and high solubility for application in solid-state dye-sensitized solar cells. AB - We present the synthesis and device characterization of new hole transport materials (HTMs) for application in solid-state dye-sensitized solar cells (ssDSSCs). In addition to possessing electrical properties well suited for ssDSSCs, these new HTMs have low glass transition temperatures, low melting points, and high solubility, which make them promising candidates for increased pore filling into mesoporous titania films. Using standard device fabrication methods and Z907 as the sensitizing dye, power conversion efficiencies (PCE) of 2.94% in 2-MUm-thick cells were achieved, rivaling the PCE obtained by control devices using the state-of-the-art HTM spiro-OMeTAD. In 6-MUm-thick cells, the device performance is shown to be higher than that obtained using spiro-OMeTAD, making these new HTMs promising for preparing high-efficiency ssDSSCs. PMID- 22230652 TI - Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. AB - BACKGROUND: Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice. RESULTS: Our analysis of LRRK2-/- kidneys at multiple ages, such as 1, 4, 7, and 20 months, revealed unique age-dependent development of a variety of molecular, cellular, and ultrastructural changes. Gross morphological abnormalities of the kidney, including altered size, weight, texture, and color, are evident in LRRK2 /- mice at 3-4 months of age, along with increased accumulation of autofluorescent granules in proximal renal tubules. The ratio of kidney/body weight in LRRK2-/- mice is increased at 1, 4, and 7 months of age (-10% at 1 month, and -20% at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (-50%). While kidney filtration function evaluated by levels of blood urea nitrogen and serum creatinine is not significantly affected in LRRK2-/ mice at 12-14 months of age, expression of kidney injury molecule-1, a sensitive and specific biomarker for epithelial cell injury of proximal renal tubules, is up-regulated (-10-fold). Surprisingly, loss of LRRK2 causes age-dependent bi phasic alterations of the autophagic activity in LRRK2-/- kidneys, which is unchanged at 1 month of age, enhanced at 7 months but reduced at 20 months, as evidenced by corresponding changes in the levels of LC3-I/II, a reliable autophagy marker, and p62, an autophagy substrate. Levels of alpha-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in LRRK2 /- kidneys at 7 months of age but increased at 20 months. Interestingly, the age dependent bi-phasic alterations in autophagic activity in LRRK2-/- kidneys is accompanied by increased levels of lysosomal proteins and proteases at 1, 7, and 20 months of age as well as progressive accumulation of autolysosomes and lipofuscin granules at 4, 7-10, and 20 months of age. CONCLUSIONS: LRRK2 is important for the dynamic regulation of autophagy function in vivo. PMID- 22230657 TI - Factors affecting calf mortality in Iranian Holstein dairy herds. AB - The objective of this study was to document mortality reasons and risk factors for mortality in dairy calves in the northeast of Iran. This was a prospective cohort study of calves born on ten commercial dairy herds from 21 March 2009 to 20 March 2010. A total of 4097 live calves were followed for 90 days after birth. For each calf details of sex, parity of the dam, type of parturition and season of birth were recorded. The interval (in days) from the date of birth to the date of death and the reason for death was recorded for those calves that died before 90 days of age. A Cox proportional hazards model, including a frailty term to account for unmeasured herd-level effects was developed to quantify the effect of factors associated with time to death. Two hundred and sixty-six (6.5%, 95% CI: 5.8-7.3%) of the 4097 live-born calves died or were euthanised before 90 days of age. The most important reasons for death were digestive tract disorders (58% of all deaths, 95% CI: 52-64%) followed by respiratory diseases (13% of all deaths, 95% CI: 9-17%). Calves exposed to dystocia at birth had 2.09 (95% CI: 1.49-2.92) times the daily hazard of death compared with calves born from a normal calving. The daily hazard of death for calves born in the summer was 1.93 (95% CI: 1.41 2.64) times greater than the hazard for those calves born in the autumn. Inclusion of the herd-level frailty term had a significant effect on hazard estimates indicating that the study herds were heterogeneous in the distribution of unmeasured herd-level factors influencing calf survival. Our results show that diarrhoea is the most important cause of calf mortality in dairy herds in this area of Iran and that environmental and management factors affect calf mortality rate. PMID- 22230658 TI - Implementing a probabilistic definition of freedom from infection to facilitate trade of livestock: putting theory into praxis for the example of bovine herpes virus-1. AB - International trade of livestock and livestock products poses a significant potential threat for spread of diseases, and importing countries therefore often require that imported animals and products are free from certain pathogens. However, absolute freedom from infection cannot be documented, since all test protocols are imperfect and can lead to false-negative results. It is possible instead to estimate the "probability of freedom from infection" and its opposite, the probability of infection despite having a negative test result. These probabilities can be estimated based on a pre-defined target prevalence, known surveillance efforts in the target population and known test characteristics of any pre-export test. Here, calculations are demonstrated using the example of bovine herpes virus-1 (BoHV-1). In a population that recently became free of BoHV 1 without using vaccination, the probability of being infected of an animal randomly selected for trade is 800 per 1 million and this probability is reduced to 64 (95% probability interval PI 6-161) per 1 million when this animal is tested negatively prior to export with a gB-ELISA. In a population that recently became free of BoHV-1 using vaccination, the probability of being infected of an animal randomly selected for trade is 200 per 1 million, and this probability can be reduced to 63 (95% PI 42-87) when this animal is tested negatively prior to export with a gE-ELISA. Similar estimations can be made on a herd level when assumptions are made about the herd size and the intensity of the surveillance efforts. Subsequently, the overall probability for an importing country of importing at least 1 infected animal can be assessed by taking into account the trade volume. Definition of the acceptable level of risk, including the probability of false-negative results to occur, is part of risk management. Internationally harmonized target prevalence levels for the declaration of freedom from infection from selected pathogens provide a significant contribution to the facilitation of international trade of livestock and livestock products by allowing exporting countries to design tailor-made output-based surveillance programs, while providing equivalent guarantees regarding the probability of freedom from infection of the population. Combining this with an approach to assess the overall probability of introducing at least 1 infected animal into an importing country during a defined time interval will help importing countries to achieve their desired level of acceptable risk and will help to assess the equivalence of animal health and food safety standards between trading partners. PMID- 22230654 TI - Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines. AB - BACKGROUND: S100A7 is an antimicrobial peptide involved in several inflammatory diseases. The aim of the present study was to explore the expression and regulation of S100A7 in seasonal allergic rhinitis (SAR). METHODS: Nasal lavage (NAL) fluid was obtained from healthy controls before and after lipopolysaccharide (LPS) provocation, from SAR patients before and after allergen challenge, and from SAR patients having completed allergen-specific immunotherapy (ASIT). Nasal biopsies, nasal epithelial cells and blood were acquired from healthy donors. The airway epithelial cell line FaDu was used for in vitro experiments. Real-time RT-PCR and immunohistochemistry were used to determine S100A7 expression in nasal tissue and cells. Release of S100A7 in NAL and culture supernatants was measured by ELISA. The function of recombinant S100A7 was explored in epithelial cells, neutrophils and peripheral blood mononuclear cells (PBMC). RESULTS: Nasal administration of LPS induced S100A7 release in healthy non-allergic subjects. The level of S100A7 was lower in NAL from SAR patients than from healthy controls, and it was further reduced in the SAR group 6 h post allergen provocation. In contrast, ASIT patients displayed higher levels after completed treatment. S100A7 was expressed in the nasal epithelium and in glands, and it was secreted by cultured epithelial cells. Stimulation with IL-4 and histamine repressed the epithelial S100A7 release. Further, recombinant S100A7 induced activation of neutrophils and PBMC. CONCLUSIONS: The present study shows an epithelial expression and excretion of S100A7 in the nose after microbial stimulation. The levels are diminished in rhinitis patients and in the presence of an allergic cytokine milieu, suggesting that the antimicrobial defense is compromised in patients with SAR. PMID- 22230659 TI - Pyrolysis of polyethylene mixed with paper and wood: Interaction effects on tar, char and gas yields. AB - In the present study the interactions between the main constituents of the refuse derived fuel (plastics, paper, and wood) during pyrolysis were studied. Binary mixtures of polyethylene-paper and polyethylene/sawdust have been transformed into pellets and pyrolyzed. Various mixtures with different composition were analyzed and pyrolysis products (tar, gas, and char) were collected. The mixtures of wood/PE and paper/PE have a different behavior. The wood/PE mixtures showed a much reduced interaction of the various compounds because the yields of pyrolysis products of the mixture can be predicted as linear combination of those of the pure components. On the contrary, a strong char yield increase was found at a low heating rate for paper/PE mixtures. In order to explain the results, the ability of wood and paper char to adsorb and convert the products of PE pyrolysis into was studied. Adsorption and desorption tests were performed on the char obtained by paper and wood by using n-hexadecane as a model compound for the heavy products of PE pyrolysis. PMID- 22230660 TI - Life cycle assessment of biogas upgrading technologies. AB - This article evaluates the life cycle assessment (LCA) of three biogas upgrading technologies. An in-depth study and evaluation was conducted on high pressure water scrubbing (HPWS), as well as alkaline with regeneration (AwR) and bottom ash upgrading (BABIU), which additionally offer carbon storage. AwR and BABIU are two novel technologies that utilize waste from municipal solid waste incinerators - namely bottom ash (BA) and air pollution control residues (APC) - and are able to store CO(2) from biogas through accelerated carbonation processes. These are compared to high pressure water scrubbing (HPWS) which is a widely used technology in Europe. The AwR uses an alkaline solution to remove the CO(2) and then the solution - rich in carbonate and bicarbonate ions - is regenerated through carbonation of APC. The BABIU process directly exposes the gas to the BA to remove and immediately store the CO(2), again by carbonation. It was determined that the AwR process had an 84% higher impact in all LCA categories largely due to the energy intensive production of the alkaline reactants. The BABIU process had the lowest impact in most categories even when compared to five other CO(2) capture technologies on the market. AwR and BABIU have a particularly low impact in the global warming potential category as a result of the immediate storage of the CO(2). For AwR, it was determined that using NaOH instead of KOH improves its environmental performance by 34%. For the BABIU process the use of renewable energies would improve its impact since accounts for 55% of the impact. PMID- 22230662 TI - Canadian society of allergy and clinical immunology annual scientific meeting 2011 quebec, Canada. 20-23 october 2011. Abstracts. PMID- 22230661 TI - Identification of troponin I and actin, alpha cardiac muscle 1 as potential biomarkers for hearts of electrically stimulated chickens. AB - METHODS: In this study, proteomics methods have been used to study the effects of different currents and voltages used to stun chickens. Protein profiles of chicken hearts were constructed to detect differences in protein expression and modification. The different voltages studied were 10 V, 40 V and 70 V, while the currents examined were 0.25 A, 0.5 A, and 0.75 A. The profiles obtained from these stunning conditions were compared to the non-stunned (0 A, 0 V) sample. RESULTS: Proteomics analyses using 2D Platinum ImageMaster 6.0 and Matrix assisted laser desorption/ionization with time-of-flight mass spectrometry (MALDI TOF) identified troponin I and alpha cardiac muscle actin 1 in the electrically stimulated heart samples. The overexpression of the proteins was further confirmed at the transcriptional level by Real Time PCR. CONCLUSION: The results from MALDI-TOF and Real Time PCR agreed; therefore, this method for identifying biomarkers of electrically stimulated chicken hearts provides a novel approach for differentiation the hearts of increased electrically stimulated chickens from those of non-stunned chickens. PMID- 22230663 TI - Review of hot flash diaries. AB - Currently, there is only 1 published hot flash diary. This diary rates hot flash severity according to 4 categories: mild, moderate, severe, and very severe. The descriptions of these 4 severity categories are located on a separate form from the main data form. For each 24-h period, subjects record the number of hot flashes experienced for each of the 4 severity categories either by recollection or from a separate data source on which hot flashes have been tallied. This diary has been validated but does not conform to the FDA and EMEA guidance for industry. After we observed a high percentage of subjects reporting confusion when using this 4-category diary, we constructed and used a hot flash diary containing 3 severity categories that offered real-time recording of hot flashes, contained all severity definitions on the principle data form and also conformed to the FDA and EMEA guidance for industry. We compare these 2 diaries here and provide a sample of the 3-category diary, which has not been formally validated but is considered valid by the FDA and EMEA in support of drug approval. Either diary is acceptable for use in clinical trials. PMID- 22230664 TI - New cloning and expression vector derived from Escherichia coli plasmid pIGWZ12; a potential vector for a two-plasmid expression system. AB - We constructed pIGPZ, a new cloning and expression vector derived from Escherichia coli plasmid pIGWZ12::Kan. pIGPZ contains a kanamycin resistance marker, a multiple-cloning-site (MCS) region, and a promoter for constitutive expression of cloned genes. pIGPZ has the same high level of stability as the original plasmid, even in the absence of antibiotic selection. Furthermore, we show that pIGPZ is compatible with ColE1-based plasmids and a pSC101-like plasmid. All the characteristic elements of theta-replicating plasmids were found in the pIGPZ putative origin of replication. Finally, we demonstrate that pIGPZ can be used in a double-plasmid expression system by co-expressing UBP1 protease from pIGPZ with ubi-interferon alpha (IFNA13; GenBank Accession No. NM_006900.3) or ubi-human growth hormone (ubi-hGH; patent No. WO 2005/066208 A2) cloned in another plasmid. In this system, both ubi-interferon alpha and ubi-human growth hormone were deubiquitinated efficiently in E. coli cells. PMID- 22230665 TI - Mesenchymal stem cells and glioma cells form a structural as well as a functional syncytium in vitro. AB - The interaction of human mesenchymal stem cells (hMSCs) and tumor cells has been investigated in various contexts. HMSCs are considered as cellular treatment vectors based on their capacity to migrate towards a malignant lesion. However, concerns about unpredictable behavior of transplanted hMSCs are accumulating. In malignant gliomas, the recruitment mechanism is driven by glioma-secreted factors which lead to accumulation of both, tissue specific stem cells as well as bone marrow derived hMSCs within the tumor. The aim of the present work was to study specific cellular interactions between hMSCs and glioma cells in vitro. We show, that glioma cells as well as hMSCs differentially express connexins, and that they interact via gap-junctional coupling. Besides this so-called functional syncytium formation, we also provide evidence of cell fusion events (structural syncytium). These complex cellular interactions led to an enhanced migration and altered proliferation of both, tumor and mesenchymal stem cell types in vitro. The presented work shows that glioma cells display signs of functional as well as structural syncytium formation with hMSCs in vitro. The described cellular phenomena provide new insight into the complexity of interaction patterns between tumor cells and host cells. Based on these findings, further studies are warranted to define the impact of a functional or structural syncytium formation on malignant tumors and cell based therapies in vivo. PMID- 22230666 TI - Protective action of NDP-MSH in experimental subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) is still a major cause of morbidity and mortality. alpha-Melanocyte stimulating hormone (alpha-MSH) and other melanocortin peptides exert potent neuroprotective action and they might modulate key molecules involved in SAH-induced vasospasm. The aim of this research was to determine whether treatment with the alpha-MSH analog Nle4,DPhe7-alpha-MSH (NDP-MSH) exerts protective effects in experimental SAH in the rat. Initial experiments examined effects of NDP-MSH on the basilar artery phenotype in the absence of injury. In these tests intrathecal injection of small concentrations (10ng) of the peptide induced a tolerant phenotype similar to that observed after ischemic preconditioning. Then the effect of systemic treatment with NDP-MSH (100MUg i.v.) on experimental SAH was evaluated. SAH was induced by a single-blood injection into the cisterna magna. The basilar artery phenotype was examined at 4h and the artery caliber at 5days following SAH. Expression of 96 genes was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) using Custom Taqman Low-Density Arrays. Four hours after SAH, the transcriptional profile of the basilar artery was deeply disrupted. Transcript alteration included genes involved in inflammation, stress response, apoptosis, and vascular remodeling. Treatment with NDP-MSH prevented most of these transcription changes and decreased phosphorylation of extracellular-signal-regulated kinases (ERK1/2) and inhibitor protein IkappaBalpha. Vasospasm on day 5 was significantly reduced by NDP-MSH administration. These results combine with others on CNS inflammation to suggest that the melanocortins could be safe and effective therapeutic candidates to treat SAH-related complications. PMID- 22230667 TI - A new alternative NF-kappaB pathway mediated the neuroprotection of GDNF on 6 OHDA-induced DA neurons neurotoxicity. AB - Glial cell line-derived neurotrophic factor (GDNF) is a potent protective factor for dopaminergic (DA) neurons, but the signaling mechanisms underlying the effect of GDNF on these neurons remain obscure. Here, both our in vivo and in vitro studies demonstrate that the majority of DA neurons express the NF-kappaB inducing kinase (NIK), which is the essential kinase for mediating activation of the new alternative NF-kappaB signaling pathway. Additionally, we also show that GDNF induced the time/dose-dependent phosphorylation of IkappaB kinase alpha (IKKalpha) and p100, facilitated the processing of p100 to p52 and accelerated the translocation of NF-kappaB dimmers into the nuclei of DA neurons. We furtherly found that the dimmer which translocate into the nucleus was RelA/p52 not RelB/p52. Meanwhile, the attenuation of 6-OHDA-induced DA neuronal apoptosis due to GDNF was reversed subsequent to the inhibition of p100 expression by RNAi while the neuroprotective effect of GDNF on injured DA neurons was strengthened by the overexpression of p100. Our data, therefore, indicate that a new alternative NF-kappaB signaling pathway, which was not the classic pathway but different from the non-canonical pathway, exists in DA neurons and mediates the neuroprotective effect of GDNF on these neurons. PMID- 22230668 TI - Neuronal damage in hippocampal subregions induced by various durations of transient cerebral ischemia in gerbils using Fluoro-Jade B histofluorescence. AB - Although there are many studies on ischemic brain damage in the gerbil, which is a good model of transient cerebral ischemia, studies on neuronal damage according to the duration of ischemia-reperfusion (I-R) time are limited. We carried out neuronal damage in the gerbil hippocampus after various durations of I-R (5, 10, 15 and 20 min) using Fluoro-Jade B (F-J B, a maker for neuronal degeneration) histofluorescence as well as cresyl violet (CV) staining. The changes of CV positive ((+)) neurons were well detected in the hippocampal CA1 region, not in the other regions. F-J B histofluorescence staining showed apparent neuronal damage in all the hippocampal subregions. In the CA1, most of the pyramidal neurons of the stratum pyramidale (SP) were stained with F-J B (about 100/mm(2) in a section), and F-J B(+) neurons in the other ischemia-groups were not changed. In the CA2, a few F-J B(+) neurons were detected in the SP of the 5 min ischemia-group, and F-J B(+) neurons were gradually increased with the longer time of ischemia: in the 20 min ischemia-group, the mean number of F-J B(+) neurons was about 85/mm(2) in a section. In the CA3, some F-J B(+) neurons were observed only in the SP of the 20 min ischemia-group. In the dentate gyrus, some F-J B positive neurons were detected only in the polymorphic layer (PL) of the 5 min ischemia-group, and the number of F-J B(+) neurons were gradually increased with the longer ischemic time. Our findings indicate that F-J B histofluorescence showed a very high quality of neuronal damage in all the hippocampal subregions. PMID- 22230669 TI - Finding centre: ocular and fMRI investigations of bisection and landmark task performance. AB - The line bisection task is used as a bedside test of spatial neglect patients who typically bisect lines to the right of true centre. To disambiguate the contribution of perceptual from motor biases in bisection, previous research has used the landmark task in which participants determine whether a transection mark is left or right of centre. One recent study using stimuli that reliably leads to leftward perceptual biases in healthy individuals, found that ocular judgements of centre were biased to the right of centre, whereas manual bisections were biased leftwards. Here we used behavioural measures and functional MRI in healthy individuals to investigate ocular and perceptual judgements of centre. Ocular judgements were made by having participants fixate the centre of a horizontal bar that was dark at one end and light at the other (i.e., a 'greyscale' stimulus), whereas perceptual responses were made by having participants indicate whether a transection mark on the greyscales stimuli was to the left or right of centre. Behavioural data indicated a leftward bias in the first, second and longest fixations for bisection. Moreover, greyscale orientation (i.e., dark extremity to the right or to the left), and stimulus position modulated fixations. In contrast, for the landmark task, initial fixations were attracted towards the transection mark, whereas subsequent fixations were closer to veridical centre. Imaging data showed a large bilateral network, including superior parietal and lingual cortex, that was active for bisection. The landmark task activated a predominantly right hemisphere network including superior and inferior parietal cortices. Taken together these results indicate that very different strategies and underlying neural networks are invoked by the bisection and landmark tasks. PMID- 22230670 TI - The enhanced processing of visual novel events in females: ERP correlates from two modified three-stimulus oddball tasks. AB - The ability to detect and cope with unpredictable novel events is fundamental for adapting to a rapidly changing environment and ensuring the survival of the organism. Despite knowledge of gender differences in emotional processing, little is currently known about the impact of gender on neural processing of emotion irrelevant, novel stimuli. Using two modified three-stimulus oddball tasks and event-related potentials (ERPs), the present study investigated the impact of sex on brain processing of novel events and the associated neurophysiological correlates. With novel and non-novel control stimuli used as task-irrelevant distracters, Experiment 1 showed higher novelty rating scores and larger size of novelty effects in brain potentials at 200-300 ms and 300-430 ms time intervals in females compared to males. After excluding the contribution of stimulus probability, Experiment 2 continued to display significant novelty effects in the response times and the amplitudes of the 130-500 ms time windows. Most importantly, females displayed a sustained novelty effect in the late positive component (LPC) amplitudes of the 500-600 ms interval, which was not observed in males. Therefore, Experiment 1 and 2 demonstrated that females are equipped with enhanced brain processing of emotion-irrelevant, novel stimuli. This phenomenon is independent of the established gender difference in infrequent stimulus processing. We suggest that our findings reflect the differential adaptive demands on females and males during evolution. PMID- 22230671 TI - Aortic graft infections: current perspectives. Introduction. PMID- 22230672 TI - Current role of imaging in diagnosing aortic graft infections. AB - Vascular prosthetic graft infection is a rare but serious complication after aortic graft replacement, with high morbidity and mortality rates. Therefore, adequate diagnostics are needed to detect and treat these infections as early as possible. Several imaging modalities provide different diagnostic values for detecting prosthetic graft infection. Previous studies reported on the diagnostic value of ultrasound, computed tomography imaging, magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography, and single-photon emission computed tomography. In addition, adjunctive studies on new and promising techniques to detect prosthetic graft infection (eg, bio-optical imaging and target imaging with nuclear techniques) have also been investigated. This review provides a summary of noninvasive imaging modalities and their diagnostic values in order to evaluate and treat possible vascular graft infections as early as possible. PMID- 22230673 TI - Antibiotic therapy of aortic graft infection: treatment and prevention recommendations. AB - Surgical site infection (SSI) after aortic intervention, an uncommon but serious vascular condition, requires patient-specific antibiotic therapy. Effective treatment and prevention requires the vascular surgeon to be cognizant of changing SSI microbiology, advances in antibiotic delivery, and patient characteristics. The majority of aortic graft infections are caused by Gram positive bacteria, with methicillin-resistant Staphylococcus aureus now the prevalent pathogen. Nasal carriage of methicillin-sensitive or methicillin resistant S aureus strains, diabetes mellitus, recent hospitalization, a failed arterial reconstruction, and the presence of a groin incision are important SSI risk factors. Overall, the aortic SSI rate is higher than predicted by the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance risk category system; ranging from 5% after open or endovascular aortic interventions to as high as 10% to 15% after aortofemoral bypass or uni aortoiliac grafting with femorofemoral bypass. Perioperative measures to reduce S aureus nares and skin colonization, administration of antibiotic prophylaxis, meticulous wound closure/care, and therapy directed to optimize patient host defense regulation mechanisms (eg, temperature, oxygenation, blood sugar) can minimize SSI occurrence. Antibiotic therapy for aortic graft infection should utilize bactericidal drugs that penetrate bacteria biofilms and can be delivered to the surgical site both parenterally and locally in the form of antibiotic impregnated beads or prosthetic grafts. PMID- 22230674 TI - Conservative treatment of aortic graft infection. AB - Conservative, nonresectional management of aortic graft infections is the optimal management for selected patients with aortic graft infections. The best candidates are those patients who have significant comorbidities, or where the existing aortic graft is in a location that precludes excision without causing a high likelihood of morbidity and/or mortality, such as thoracoabdominal and aortic arch grafts. When considering the conservative approach, computed tomographic angiography, supplemented by Indium(111) leukocyte scanning, is the best combination of diagnostic tests. Contraindications to a conservative approach are infected anastomotic aneurysms, graft-enteric fistulas, and suture line hemorrhage. Needle aspiration of perigraft fluid or phlegmon, under ultrasound or computed tomography guidance, is useful to both culture the infection and provide drainage. A conservative approach should not be considered when the graft infection is due to invasive Gram-negative organisms, such as Pseudomonas or Salmonella species. Once a conservative approach is selected as the best treatment option, drainage of an infected perigraft space is critical to success, and can be performed either percutaneously or with open surgery, whether an endograft or surgically placed graft is in place. If open drainage is required, the perigraft space should be debrided and catheters placed for long term antibiotic irrigation. With continuous antibiotic irrigation until the cultures are negative, followed by life-long oral antibiotics, there are multiple case reports and small series of long-term survivors. Whether the aortic graft infection is cured or controlled is debated, but outcomes for high-risk patients and those with grafts in critical vascular beds are often superior to a high-risk surgical graft resection. PMID- 22230675 TI - Aortic graft infections: is there still a role for axillobifemoral reconstruction? AB - Infection of an aortic prosthesis is a severe condition with high morbidity and mortality rates. Surgical treatment of an infected aortic graft focuses on treatment of the infection and maintaining or restoring perfusion of the lower limbs. Traditionally, this is done by removing the graft, extensive debridement, and constructing an extra-anatomic bypass, usually an axillobifemoral bypass (AXBF). The disappointing early results of these extra-anatomic bypass reconstructions prompted various surgeons to develop new surgical treatment options to secure lower limb perfusion. With the upcoming role of in situ reconstructions, AXBF is being scrutinized. Patients with an infected aortic graft are often critically ill, and the interplay of patient fitness and seriousness of the disease must lead to a tailor-made treatment strategy. Most in situ reconstructions have surpassed AXBF in almost every aspect. After having held the position of gold standard for years, AXBF is now part of a wide array of treatment options with limited indications. PMID- 22230676 TI - Antibiotic-impregnated grafts for aortic reconstruction. AB - An infected aorta, or aortic graft, is a challenge to manage. Extra-anatomical bypass followed by resection of the infected aorta has been considered standard practice. Outcomes are far from ideal and anatomical constraints make this impossible at the visceral and thoracic aorta. In situ aortic repair is an alternative and can be accomplished in most cases. Use of this technique has been tempered by concerns of graft durability and reinfection. In vitro and in vivo laboratory experiments have demonstrated antibiotics can be bound to polytetrafluoroethylene and Dacron aortic grafts. In animal models, antibiotic soaked grafts were resistant to infection when seeded with an intravenous bacteria challenge. Purulent, infected aortic grafts created in animal models by direct bacteria inoculation could be successfully replaced in situ with infection resistant antibiotic-soaked Dacron grafts. The antibiotic of choice is rifampin, which readily binds to commercially available, off-the-shelf gelatin- or collagen impregnated Dacron. In humans, rifampin-soaked Dacron has not only been used to reconstruct the aorta in the face of infection, but also in elective aortic reconstruction as a prophylaxis against future infection. Outcomes from case series are difficult to interpret because of the heterogeneous nature of patients presenting with aortic infections. Thirty-day mortality ranges from 7% to 21% and morbidity from 2% to 60%. Amputations are rarely seen in these cases, but are common in extra-anatomical bypass from graft occlusion. Reinfection of the rifampin grafts are seen in 4% to 22% of patients, and 5-year survival is near 50%. In the future, the utility of rifampin-soaked Dacron will have to be tested against the emergence of antibiotic-resistant bacteria. Improvements in alternative conduits, such as cryopreserved aortic grafts, may diminish the use of antibiotic-soaked grafts, but it will remain a useful tool in the vascular surgeon's armamentarium. PMID- 22230677 TI - Neoaortoiliac System (NAIS) procedure for the treatment of the infected aortic graft. AB - We aim to provide a thorough and current summary highlighting the use of autologous vein grafts during reconstruction of infected aortic grafts. Aortic graft infections, while rare, remain one of the most difficult problems that a vascular surgeon can encounter. Optimal management of patients with aortic graft infections requires a full understanding of all potential therapeutic interventions available. Reconstruction with autologous vein grafts is a technique that has evolved and has been refined during the past 2 decades, representing a major advance in the treatment of aortic graft infections. Thirty day operative mortality is <= 10%, with 5-year mortality rates of 30% to 50%. Thirty-day major amputation rates range from 2% to 7.4%, with 5-year limb-salvage rates ranging between 89% and 96%. Early occlusion of the grafts are rare, with <4% undergoing thrombosis within the first 30 days; 5-year primary patency ranges from 75% to 91%, with secondary patency approaching 91% at 5 years. Recurrent infection is very rare, occurring in <2% of patients. Venous morbidity is similarly low, with fasciotomy rates of 12%, and only 15% of patients experiencing chronic venous insufficiency at 5 years. Aneurysmal degeneration is also exceptionally rare. Use of autologous vein grafts for in situ reconstruction of infected aortic grafts represents the standard of care in the treatment of aortic graft infections. With appropriate patient selection, centers with sufficient resources should be able to comparable outcomes. PMID- 22230678 TI - Arterial allografts in treating aortic graft infections: something old, something new. AB - Surgical treatment of major aortic infection remains the most demanding challenge in aortic surgery. Excellent results with cryopreserved allograft heart valves in the treatment of acute infectious endocarditis prompted the use of allografts for in situ replacement of mycotic aortic aneurysms and prosthetic aortic graft infection. This review summarizes the indications for use of allografts in the management of major aortic infection, describes technical pitfalls at the time of implantation, presents clinical results, and analyzes the findings in explanted segments of failed allografts. In addition, the current status of the use of allografts will be compared with competitive techniques for treatment of vascular infections. PMID- 22230679 TI - Antimicrobial silver grafts for prevention and treatment of vascular graft infection. AB - In vascular surgery, graft infection remains a serious limb-threatening and often life-threatening complication, despite progress in the last several decades. During the past 3 decades, prevention of surgical site infection predominantly relied on availability of effective perioperative antibiotic prophylaxis or the use of systemic antibiotics for treatment of infections after their clinical manifestation. However, evidence for the prophylactic effect of systemic antibiotics exists only for patients with vein grafts, who are at a lower risk of infection compared to patients receiving prosthetic material. Furthermore, because of the changed epidemiology of bacterial susceptibility against antibiotics today, reliance on the efficacy of systemic antibiotic prophylaxis must be done with caution. The outlook of current trends indicates that maximum effort is needed to maintain the current balance. Simply looking for new antibiotics will not lead to an additional decrease in the rate of infection in vascular surgery. Because of the consequences of infection in vascular surgery and the increasing resistance of causative micro-organisms, the future strategy to deal with infection needs to shift from reliance on systemic antibiotics and treatment of manifest infection to a strong focus on primary prevention of infection, particularly for surgical procedures involving prosthetic materials. This article summarizes current strategies for prevention of surgical site infection in vascular surgery and reviews current literature on antimicrobial vascular grafts using antiseptic agents instead of antibiotics to achieve antimicrobial efficacy. Specific emphasis is put on silver and its use in antimicrobial vascular grafts for prevention and treatment of vascular surgical infection. PMID- 22230680 TI - Endografts for the treatment of aortic infection. AB - Aortic infection is an uncommon but life-threatening condition. Conservative medical treatment is insufficient in many cases because of the high risk of persistent infection, aortic rupture, and death. Conventional open surgical treatment consists of extensive tissue debridement, complete removal of the infected prosthetic material, and arterial reconstruction with anatomical or extra-anatomical bypass. This treatment is associated with significant morbidity and mortality; in order to avoid these, minimally invasive options with endovascular aneurysm repair have been attempted. Endovascular repair is minimally invasive and provides rapid aneurysm exclusion and prompt control of bleeding in the face of hemodynamic instability. Despite this, a major concern is the risk associated with endograft placement in an infected bed, leading to controversy about the wisdom of using endovascular aneurysm repair in this setting for mid- and long-term periods. The rate of recurrent infection is unclear because the majority of information exists in exceptional single cases or short-term series, while unsuccessful results with this approach are less likely to be reported. This review aims to assess the role of endovascular therapy for aortic infections, including its applicability as definitive or bridge repair in mycotic aneurysm, aortobronchial, aortoesophageal, and aortoenteric fistulas, in terms of both primary and secondary outcomes (ie, after previous open or endovascular aneurysm repair). PMID- 22230681 TI - WEBCAM: Western evidence-based complementary and alternative medicine. PMID- 22230682 TI - What can we learn from Steve Jobs about complementary and alternative therapies? PMID- 22230683 TI - Opposite effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) over expression and knockdown on colorectal liver metastases. AB - BACKGROUND: Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed. METHODS: To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that over-expression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect. RESULTS: In concordance with the earlier results, TIMP-1 over-expression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 over-expression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden. CONCLUSION: These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model. PMID- 22230684 TI - Human and rat hepatocyte toxicity and protein phosphatase 1 and 2A inhibitory activity of naturally occurring desmethyl-microcystins and nodularins. AB - Contamination of water, foods and food supplements by various genera of cyanobacteria is a serious health problem worldwide for humans and animals, largely due to the toxic effects of microcystins (MCs) and nodularin (NOD), a group of hepatotoxic cyclic peptides. The toxins occur in variable structures resulting in more than 90 different MCs and 8 different NODs, many of them not having been investigated for their toxic potency. Potent MCs such as MC-LR have been shown to elicit their hepatotoxic potency via inhibition of hepatic protein phosphatases (PP) 1 and 2A leading to over-phosphorylation of vital cellular proteins. This mechanism of action is also thought to be responsible for the long term tumor promoting action of certain MCs and NOD in the liver. Here, we report on the isolation of certain MCs and NOD as well as a number of their desmethylated derivatives from algae bloom. Subsequently, we determined the cytotoxicity of these compounds in isolated primary human and rat hepatocytes in culture. In parallel experiments, we analyzed the inhibitory potency of these congeners on PP1 and 2A using commercially available enzymes. We found in primary rat hepatocytes that MC-LR, -YR and NOD were cytotoxic, namely in the 10 to >50 nM range, while MC-RR was not. The desmethylated congeners of MC-LR, -YR, and NOD were equally or more-toxic as/than their fully methylated counterparts. In primary human hepatocytes we could show that MC-LR, NOD and the desmethylated variants [3Asp]MC-LR, [7Dha]MC-LR and [1Asp]NOD were cytotoxic in the 20 to >600 nM range. Inhibition data with human, bovine and rabbit protein phosphatases 1 and 2A were roughly in accordance with the cytotoxicity findings in human and rat hepatocytes, i.e. desmethylation had no pronounced effects on the inhibitory potencies. Thus, a variety of naturally occurring desmethylated MC and NOD congeners have to be considered as being at least as toxic as the corresponding fully methylated derivatives. PMID- 22230686 TI - Deep subwavelength spatial characterization of angular emission from single crystal Au plasmonic ridge nanoantennas. AB - We use spatially and angle-resolved cathodoluminescence imaging spectroscopy to study, with deep subwavelength resolution, the radiation mechanism of single plasmonic ridge antennas with lengths ranging from 100 to 2000 nm. We measure the antenna's standing wave resonances up to the fifth order and measure the dispersion of the strongly confined guided plasmon mode. By directly detecting the emitted antenna radiation with a 2D CCD camera, we are able to measure the angular emission patterns associated with each individual antenna resonance. We demonstrate that the shortest ridges can be modeled as a single point-dipole emitter oriented either upward (m = 0) or in-plane (m = 1). The far-field emission pattern for longer antennas (m > 2) is well described by two interfering in-plane point dipoles at the end facets, giving rise to an angular fringe pattern, where the number of fringes increases as the antenna becomes longer. Taking advantage of the deep subwavelength excitation resolution of the cathodoluminescence technique, we are able to determine the antenna radiation pattern as a function of excitation position. By including the phase of the radiating dipoles into our simple dipole model, we completely reproduce this effect. This work demonstrates how angle-resolved cathodoluminescence spectroscopy can be used to fully determine the emission properties of subwavelength ridge antennas, which ultimately can be used for the design of more complex and efficient antenna structures. PMID- 22230685 TI - Up-to-date on mortality in COPD - report from the OLIN COPD study. AB - BACKGROUND: The poor recognition and related underdiagnosis of COPD contributes to an underestimation of mortality in subjects with COPD. Data derived from population studies can advance our understanding of the true burden of COPD. The objective of this report was to evaluate the impact of COPD on mortality and its predictors in a cohort of subjects with and without COPD recruited during the twenty first century. METHODS: All subjects with COPD (n = 993) defined according to the GOLD spirometric criteria, FEV1/FVC < 0.70, and gender- and age-matched subjects without airway obstruction, non-COPD (n = 993), were identified in a clinical follow-up survey of the Obstructive Lung Disease in Northern Sweden (OLIN) Studies cohorts in 2002-2004. Mortality was observed until the end of year 2007. Baseline data from examination at recruitment were used in the risk factor analyses; age, smoking status, lung function (FEV1 % predicted) and reported heart disease. RESULTS: The mortality was significantly higher among subjects with COPD, 10.9%, compared to subjects without COPD, 5.8% (p < 0.001). Mortality was associated with higher age, being a current smoker, male gender, and COPD. Replacing COPD with FEV1 % predicted in the multivariate model resulted in the decreasing level of FEV1 being a significant risk factor for death, while heart disease was not a significant risk factor for death in any of the models. CONCLUSIONS: In this cohort COPD and decreased FEV1 were significant risk factors for death when adjusted for age, gender, smoking habits and reported heart disease. PMID- 22230688 TI - A new D2 dopamine receptor agonist allosterically modulates A(2A) adenosine receptor signalling by interacting with the A(2A)/D2 receptor heteromer. AB - The structural and functional interaction between D2 dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D2DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D2DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D2DR co-transfected cells, these receptors exist as homo- and hetero dimers. The classical D2DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D2DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D2 dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1 yl)ethyl)piperidine (compound 1), full agonist of D2DR and modulator of A(2A)-D2 receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D2R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D2DR homomers and heteromers and induced A(2A)AR/D2DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D2 DR heteromers. PMID- 22230687 TI - Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up regulation. AB - Patulin is a fungal mycotoxin of Aspergilus and Penicillium that is commonly found in rotting fruits and exerts its potential toxic effect mainly by reactive oxygen species (ROS) generation. However, the effect of patulin on cancer cells as well as its intracellular mechanism has been controversial and not clearly defined yet. In this study, patulin was found to induce G1/S accumulation and cell growth arrest accompanied by caspase-3 activation, PARP cleavage and ATF3 expression in human colon cancer cell line HCT116. Ser/Thr phosphorylation of a transcription factor, EGR-1, was increased while its expression did not change upon patulin treatment to the cells. Knockdown of ATF3 and EGR-1 using their respective siRNAs showed EGR-1 dependent ATF3 expression. Moreover, treatment of the cells with antioxidants N-acetylcysteine (NAC) and glutathione (GSH) revealed that patulin induced ATF3 expression and apoptosis were dependent on ROS generation. ATF3 expression was also increased by patulin in other colorectal cancer cell types, Caco2 and SW620. Collectively, our data present a new anti cancer molecular mechanism of patulin, suggesting EGR-1 and ATF3 as critical targets for the development of anti-cancer chemotherapeutics. In this regard, patulin could be a candidate for the treatment of colorectal cancers. PMID- 22230689 TI - Ceramide kinase regulates TNFalpha-stimulated NADPH oxidase activity and eicosanoid biosynthesis in neuroblastoma cells. AB - A persistent inflammatory reaction is a hallmark of chronic and acute pathologies in the central nervous system (CNS) and greatly exacerbates neuronal degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) plays a pivotal role in the initiation and progression of inflammatory processes provoking oxidative stress, eicosanoid biosynthesis, and the production of bioactive lipids. We established in neuronal cells that TNFalpha exposure dramatically increased Mg(2+)-dependent neutral sphingomyelinase (nSMase) activity thus generating the bioactive lipid mediator ceramide essential for subsequent NADPH oxidase (NOX) activation and oxidative stress. Since many of the pleiotropic effects of ceramide are attributable to its metabolites, we examined whether ceramide kinase (CerK), converting ceramide to ceramide-1-phosphate, is implicated both in NOX activation and enhanced eicosanoid production in neuronal cells. In the present study, we demonstrated that TNFalpha exposure of human SH SY5Y neuroblastoma caused a profound increase in CerK activity. Depleting CerK activity using either siRNA or pharmacology completely negated NOX activation and eicosanoid biosynthesis yet, more importantly, rescued neuronal viability in the presence of TNFalpha. These findings provided evidence for a critical function of ceramide-1-phospate and thus CerK activity in directly linking sphingolipid metabolism to oxidative stress. This vital role of CerK in CNS inflammation could provide a novel therapeutic approach to intervene with the adverse consequences of a progressive CNS inflammation. PMID- 22230694 TI - Amperometric acetylcholine biosensor based on self-assembly of gold nanoparticles and acetylcholinesterase on the sol-gel/multi-walled carbon nanotubes/choline oxidase composite-modified platinum electrode. AB - A novel acetylcholinesterase (AChE)/choline oxidase (ChOx) bienzyme amperometric acetylcholine biosensor based on gold nanoparticles (AuNPs) and multi-walled carbon nanotubes (MWCNTs) has been successfully developed by self-assembly process in combination of sol-gel technique. A thiolated aqueous silica sol containing MWCNTs and ChOx was first dropped on the surface of a cleaned Pt electrode, and then AuNPs were assembled with the thiolated sol-gel network. Finally, the alternate deposition of poly (diallyldimethylammonium chloride) (PDDA) and AChE was repeated to assemble different layers of PDDA-AChE on the electrode for optimizing AChE loading. Among the resulting biosensors, the biosensor based on two layers of PDDA-AChE multilayer films showed the best performance. It exhibited a wide linear range, high sensitivity and fast amperometric response, which were 0.005-0.4mM, 3.395 MUA/mM, and within 15s, respectively. The biosensor showed long-term stability and acceptable reproducibility. More importantly, this study could provide a simple and effective multienzyme immobilization platform for meeting the demand of the effective immobilization enzyme on the electrode surface. PMID- 22230690 TI - Transcriptome changes during fruit development and ripening of sweet orange (Citrus sinensis). AB - BACKGROUND: The transcriptome of the fruit pulp of the sweet orange variety Anliu (WT) and that of its red fleshed mutant Hong Anliu (MT) were compared to understand the dynamics and differential expression of genes expressed during fruit development and ripening. RESULTS: The transcriptomes of WT and MT were sampled at four developmental stages using an Illumina sequencing platform. A total of 19,440 and 18,829 genes were detected in MT and WT, respectively. Hierarchical clustering analysis revealed 24 expression patterns for the set of all genes detected, of which 20 were in common between MT and WT. Over 89% of the genes showed differential expression during fruit development and ripening in the WT. Functional categorization of the differentially expressed genes revealed that cell wall biosynthesis, carbohydrate and citric acid metabolism, carotenoid metabolism, and the response to stress were the most differentially regulated processes occurring during fruit development and ripening. CONCLUSION: A description of the transcriptomic changes occurring during fruit development and ripening was obtained in sweet orange, along with a dynamic view of the gene expression differences between the wild type and a red fleshed mutant. PMID- 22230695 TI - Dielectrophoresis and shear-enhanced sensitivity and selectivity of DNA hybridization for the rapid discrimination of Candida species. AB - We present a dielectrophoresis (DEP)-based microfluidic chip that is capable of enhancing the sensitivity and selectivity of DNA hybridization using an AC electric field and hydrodynamic shear in a continuous through-flow. Molecular DEP was employed to rapidly trap ssDNA molecules in a flowing solution to a cusp shaped nanocolloid assembly on a microfluidic chip with a locally amplified AC electric field gradient. The detection time can be accelerated to sub-minute periods, and the sensitivity can reach the pico-molar level due to the AC DEP enhanced molecule concentration (at an optimal AC frequency of 900 kHz) in a small region (~100 MUm(2)) instead of the broad area used in a tank reactor (~10(6) MUm(2)). Continuous flow in a microchannel provides a constant and high shear rate that can shear off most non-specific target-probe binding to promote the discriminating selectivity. On-chip multi-target discrimination of Candida species can be achieved within a few minutes under optimal conditions. PMID- 22230696 TI - Low potential detection of NADH based on Fe3O4 nanoparticles/multiwalled carbon nanotubes composite: fabrication of integrated dehydrogenase-based lactate biosensor. AB - Fe(3)O(4) magnetic nanoparticles were in situ loaded on the surface of multiwalled carbon nanotubes (MWCNTs) by a simple coprecipitation procedure. The resulting Fe(3)O(4)/MWCNTs nanocomposite brings new capabilities for electrochemical sensing by combining the advantages of Fe(3)O(4) magnetic nanoparticles and MWCNTs. It was found that Fe(3)O(4) has redox properties similar to those of frequently used mediators used for electron transfer between NADH and electrode. The cyclic voltammetric results indicated the ability of Fe(3)O(4)/MWCNTs modified GC electrode to catalyze the oxidation of NADH at a very low potential (0.0 mV vs. Ag/AgCl) and subsequently, a substantial decrease in the overpotential by about 650 mV compared with the bare GC electrode. The catalytic oxidation current allows the stable and selective amperometric detection of NADH at an applied potential of 0.0 mV (Ag/AgCl) with a detection limit of 0.3 MUM and linear response up to 300 MUM. This modified electrode can be used as an efficient transducer in the design of biosensors based on coupled dehydrogenase enzymes. Lactate dehydrogenase (LDH) and NAD(+) were subsequently immobilized onto the Fe(3)O(4)/MWCNTs nanocomposite film by covalent bond formation between the amine groups of enzyme or NAD(+) and the carboxylic acid groups of the Fe(3)O(4)/MWCNT film. Differential pulse voltammetric detection of lactate on Fe(3)O(4)/MWCNT/LDH/NAD(+) modified GC electrode gives linear responses over the concentration range of 50-500 MUM with the detection limit of 5 MUM and sensitivity of 7.67 MUA mM(-1). Furthermore, the applicability of the sensor for the analysis of lactate concentration in human serum samples has been successfully demonstrated. PMID- 22230697 TI - Automated portable array biosensor for multisample microcystin analysis in freshwater samples. AB - An automated array biosensor based on evanescent-wave excitation has been developed for the detection of microcystins (MCs) in freshwater samples. The sensing surface consisted of microcystin-leucine-arginine (MCLR) covalently immobilized onto a planar waveguide (microscope slide). The binding of anti-MCLR monoclonal antibodies, spiked in the sample, to the immobilized MCLR was competitively inhibited by MCLR in solution and the amount of antibody bound to the patterned antigens was revealed using Cy5-labeled rabbit anti-mouse IgG. Surface chemistry has been optimized to improve biosensor performance in terms of sensitivity, regeneration ability and to avoid non specific binding for further application to environmental monitoring. The optimized biosensor assay presents an IC(50) value of 0.34 +/- 0.01 MUg/L, a detection limit of 16 +/- 3 ng/L and a dynamic range from 0.06 to 1.5 MUg/L MCLR, improving the performance of previously reported devices. Cross-reactivity to other related MCs, such as microcystin-RR (MCRR, 90%), microcystin-RR desmethylated (dm-MCRR, 95%) and microcystin-YR (MCYR, 91%), was also evaluated. The automated microarray can assay up to six different samples in parallel, with a total analysis time of about 60 min. The sensing surface was regenerated with 50mM NaOH and each chip was reused for, at least, 15 assay-regeneration cycles without significant binding capacity loss. The immunosensor has been successfully applied to the direct analysis of MCs in surface water samples and the results were in close agreement with those provided by LC-MS/MS. PMID- 22230698 TI - Amperometric immunosensor for the determination of IgA deficiency in human serum samples. AB - An electrochemical immunosensor for the detection of human IgA deficiency in real human blood serum has been developed. The performance of the immunosensor presents a large but sensitive dynamic range that allows the determination of non deficient IgA levels (>70 MUg/mL) as well as of severe IgA deficiencies (0.5-5.0 MUg/mL). The assay architecture involves the immobilisation of a coating antibody on an electrode surface using carboxylic-ended bipodal alkane-thiol self assembled monolayers (SAMs). The long chain bipodal SAM presents intercalated poly(ethylenglycol) groups that confer the immunosensor the ability to retain its optimum performance in very complex matrices and serum with negligible non specific adsorption phenomena. Amperometric optimisation of the assay resulted in limits of detection of 142 ng/mL in just 30 min total assay time. Real patients' serum samples were analysed using the developed electrochemical immunosensor demonstrating an excellent correlation in terms of sensitivity and reproducibility compared with standard enzyme linked immunosorbent assays (ELISA). PMID- 22230700 TI - Segmental configuration and putative origin of the reassortant orbivirus, epizootic hemorrhagic disease virus serotype 6, strain Indiana. AB - In 2006, an exotic reassortant orbivirus, epizootic hemorrhagic disease virus serotype 6 (EHDV-6) [strain (Indiana)], was first detected in the United States. To characterize the reassortment configuration of this virus and to conclusively determine the parental virus of each RNA segment, the complete genome of EHDV-6 (Indiana) was sequenced, in addition to the genomes of representative EHDV-6 and EHDV-2 isolates. Based on genomic comparisons to all other EHDV serotypes, we determined that EHDV-6 (Indiana) originated from a reassortment event between the Australian prototype strain of EHDV-6 (CSIRO 753) and the North American topotype of EHDV-2 (Alberta). Additionally, phylogenetic analysis of all EHDV-6 (Indiana) isolates detected in the United States from 2006 to 2010 suggests that the virus may be undergoing continual reassortment with EHDV-2 (Alberta). In 2010, EHDV-6 (CSIRO 753) was detected in Guadeloupe, demonstrating that the parental virus of the reassortment event is circulating in the Caribbean. PMID- 22230699 TI - Prediction and characterization of protein-protein interaction networks in swine. AB - BACKGROUND: Studying the large-scale protein-protein interaction (PPI) network is important in understanding biological processes. The current research presents the first PPI map of swine, which aims to give new insights into understanding their biological processes. RESULTS: We used three methods, Interolog-based prediction of porcine PPI network, domain-motif interactions from structural topology-based prediction of porcine PPI network and motif-motif interactions from structural topology-based prediction of porcine PPI network, to predict porcine protein interactions among 25,767 porcine proteins. We predicted 20,213, 331,484, and 218,705 porcine PPIs respectively, merged the three results into 567,441 PPIs, constructed four PPI networks, and analyzed the topological properties of the porcine PPI networks. Our predictions were validated with Pfam domain annotations and GO annotations. Averages of 70, 10,495, and 863 interactions were related to the Pfam domain-interacting pairs in iPfam database. For comparison, randomized networks were generated, and averages of only 4.24, 66.79, and 44.26 interactions were associated with Pfam domain-interacting pairs in iPfam database. In GO annotations, we found 52.68%, 75.54%, 27.20% of the predicted PPIs sharing GO terms respectively. However, the number of PPI pairs sharing GO terms in the 10,000 randomized networks reached 52.68%, 75.54%, 27.20% is 0. Finally, we determined the accuracy and precision of the methods. The methods yielded accuracies of 0.92, 0.53, and 0.50 at precisions of about 0.93, 0.74, and 0.75, respectively. CONCLUSION: The results reveal that the predicted PPI networks are considerably reliable. The present research is an important pioneering work on protein function research. The porcine PPI data set, the confidence score of each interaction and a list of related data are available at (http://pppid.biositemap.com/). PMID- 22230701 TI - Divergent ancestral lineages of newfound hantaviruses harbored by phylogenetically related crocidurine shrew species in Korea. AB - Spurred by the recent isolation of a novel hantavirus, named Imjin virus (MJNV), from the Ussuri white-toothed shrew (Crocidura lasiura), targeted trapping was conducted for the phylogenetically related Asian lesser white-toothed shrew (Crocidura shantungensis). Pair-wise alignment and comparison of the S, M and L segments of a newfound hantavirus, designated Jeju virus (JJUV), indicated remarkably low nucleotide and amino acid sequence similarity with MJNV. Phylogenetic analyses, using maximum likelihood and Bayesian methods, showed divergent ancestral lineages for JJUV and MJNV, despite the close phylogenetic relationship of their reservoir soricid hosts. Also, no evidence of host switching was apparent in tanglegrams, generated by TreeMap 2.0beta. PMID- 22230702 TI - NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders. AB - N-methyl-D-aspartate receptors (NMDARs) are key components of neural signaling, playing roles in synaptic transmission and in the synaptic plasticity thought to underlie learning and memory. NMDAR activation can also have neurotoxic consequences contributing to several forms of neurodegeneration. Additionally, NMDARs can modulate neuronal function and regulate the ability of synapses to undergo synaptic plasticity. Evidence gathered over the past 20 years strongly supports the idea that untimely activation of NMDARs impairs the induction of long-term potentiation (LTP) by a form of metaplasticity. This metaplasticity can be triggered by multiple stimuli including physiological receptor activation, and metabolic and behavioral stressors. These latter findings raise the possibility that NMDARs contribute to cognitive dysfunction associated with neuropsychiatric disorders. This paper examines NMDAR metaplasticity and its potential role in cognition. Recent studies using NMDAR antagonists for therapeutic purposes also raise the possibility that metaplasticity may contribute to clinical effects of certain drugs. PMID- 22230705 TI - Degrees of separation: a quantitative neuroimaging meta-analysis investigating self-specificity and shared neural activation between self- and other-reflection. AB - In functional neuroimaging studies, self-specificity has been investigated by contrasting other-relevant processing against the self. Our meta-analysis investigates self-specificity with respect to degrees of self-relatedness (SR) of the other (i.e. close and public other). Literature suggests a dorsal-ventral component of self- and other-reflection within the MPFC, which has yet to be analyzed according to varying SR, nor has it been quantified statistically. In the present meta-analysis, we pursued three main objectives. First, we conducted whole-brain ALE meta-analyses using contemporary literature analyzing self>close other and self>public other contrasts to determine self-specific regions sensitive to SR. Next, we conducted ALE and conjunction analyses of studies employing self>control, close other>control, or public other>control contrasts to determine shared regions of activation. Third, we conducted post hoc analyses to quantify any observed dorsal-ventral distinction, employing novel methodology using a surface-based coordinates system. We observed significant activation in the dACC and vACC for self>close other and self>public other, whereas anterior insula was observed only for self>public other. An MPFC dorsal-ventral distinction was observed and quantified whereby public other>control was significantly more dorsal than self>control and close other>control. Our results are discussed with regards to SR. Prospective avenues of research exploiting our methodology are proposed. PMID- 22230703 TI - The use of a running wheel to measure activity in rodents: relationship to energy balance, general activity, and reward. AB - Running wheels are commonly employed to measure rodent physical activity in a variety of contexts, including studies of energy balance and obesity. There is no consensus on the nature of wheel-running activity or its underlying causes, however. Here, we will begin by systematically reviewing how running wheel availability affects physical activity and other aspects of energy balance in laboratory rodents. While wheel running and physical activity in the absence of a wheel commonly correlate in a general sense, in many specific aspects the two do not correspond. In fact, the presence of running wheels alters several aspects of energy balance, including body weight and composition, food intake, and energy expenditure of activity. We contend that wheel-running activity should be considered a behavior in and of itself, reflecting several underlying behavioral processes in addition to a rodent's general, spontaneous activity. These behavioral processes include defensive behavior, predatory aggression, and depression- and anxiety-like behaviors. As it relates to energy balance, wheel running engages several brain systems-including those related to the stress response, mood, and reward, and those responsive to growth factors-that influence energy balance indirectly. We contend that wheel-running behavior represents factors in addition to rodents' tendency to be physically active, engaging additional neural and physiological mechanisms which can then independently alter energy balance and behavior. Given the impact of wheel-running behavior on numerous overlapping systems that influence behavior and physiology, this review outlines the need for careful design and interpretation of studies that utilize running wheels as a means for exercise or as a measurement of general physical activity. PMID- 22230706 TI - The name Cryptosporidium tyzzeri Ren, Zhao, Zhang, Ning, Jian, Wang, Lv, Wang, Arrowood and Xiao, 2012 is permanently invalid. PMID- 22230707 TI - Cryptosporidium tyzzeri and Cryptosporidium pestis: which name is valid? AB - The dispute on the validity of Cryptosporidium pestis and Cryptosporidium tyzzeri origins from the uncertainty on the identity of Cryptosporidium parvum described by Tyzzer in 1912 and the interpretation of the Principal of Priority of the International Code of Zoological Nomenclature (ICZN). Using a rigid interpretation of the Principal of Priority, one researcher proposed to rename C. parvum as C. pestis and retain C. parvum for Cryptosporidium mouse genotype I on the basis that Tyzzer was probably describing mouse genotype I. However, the ICZN clearly states that the Principle of Priority is to be used to promote stability and is not intended to upset a long-accepted name. Because mice are known to be naturally infected with C. parvum, and the 1985 taxonomic re-description of C. parvum for bovine and human isolates is accepted by almost all Cryptosporidium researchers, the prevailing name C. parvum for the species infective to calves and humans must be retained to avoid confusion. The designation of C. tyzzeri for the mouse genotype I brings further clarity to the taxonomy of Cryptosporidium spp. in humans, cattle, and domestic mice. PMID- 22230708 TI - Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart. AB - Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an alpha(2)-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with dexmedetomidine before ischemia. The alpha(2)-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of alpha(2)-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of alpha(2) adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac alpha(2)-adrenergic receptor stimulation. PMID- 22230709 TI - Isolation of nuclear proteins from flax (Linum usitatissimum L.) seed coats for gene expression regulation studies. AB - BACKGROUND: While seed biology is well characterized and numerous studies have focused on this subject over the past years, the regulation of seed coat development and metabolism is for the most part still non-elucidated. It is well known that the seed coat has an essential role in seed development and its features are associated with important agronomical traits. It also constitutes a rich source of valuable compounds such as pharmaceuticals. Most of the cell genetic material is contained in the nucleus; therefore nuclear proteins constitute a major actor for gene expression regulation. Isolation of nuclear proteins responsible for specific seed coat expression is an important prerequisite for understanding seed coat metabolism and development. The extraction of nuclear proteins may be problematic due to the presence of specific components that can interfere with the extraction process. The seed coat is a rich source of mucilage and phenolics, which are good examples of these hindering compounds. FINDINGS: In the present study, we propose an optimized nuclear protein extraction protocol able to provide nuclear proteins from flax seed coat without contaminants and sufficient yield and quality for their use in transcriptional gene expression regulation by gel shift experiments. CONCLUSIONS: Routinely, around 250 MUg of nuclear proteins per gram of fresh weight were extracted from immature flax seed coats. The isolation protocol described hereafter may serve as an effective tool for gene expression regulation and seed coat-focused proteomics studies. PMID- 22230710 TI - Predominance of rotavirus genotype G6P[11] in diarrhoeic lambs. AB - Out of 500 faecal samples from lambs with diarrhoea in Jammu and Kashmir, India, 66 (13.2%) were positive for group A rotavirus (GARV) by the latex agglutination test (LAT). Electropherotyping by RNA-polyacrylamide gel electrophoresis revealed the typical GARV 4-2-3-2 migration pattern in 49/66 (74.2%) samples. Fifty-two samples (10.4%) were positive by reverse transcription-PCR. G6 was the predominant G genotype (25/52; 48.07%), followed by G10 (19/52; 36.54%) whereas, the predominant P genotype was P[11] (46/52; 88.46%). G6P[11] is the prevalent strain of group A rotavirus in sheep in Jammu and Kashmir, India. PMID- 22230711 TI - Structure of a polysaccharide from Providencia rustigianii O11 containing a novel amide of 2-acetamido-2-deoxygalacturonic acid with L-glutamyl-L-alanine. AB - An acidic polysaccharide was isolated from Providencia rustigianii O11 by the phenol-water extraction. The polysaccharide was cleaved by solvolysis with triflic acid to yield disaccharides with uronic acid derivatives at the non reducing end. The polysaccharide and the disaccharides were studied by chemical analyses, high-resolution ESI MS, and 2D (1)H and (13)C NMR spectroscopy, and the following structure of the tetrasaccharide repeating unit of the polysaccharide was established: where GalNAcA stands for 2-acetamido-2-deoxygalacturonic acid, GalNAcA6GluAla for N-(2-acetamido-2-deoxygalacturonoyl)-l-glutam-1-yl-l-alanine, QuiNAc4NAcyl for 2-acetamido-4-[(S)-3-hydroxybutanoylamino]-2,4,6-trideoxyglucose (~75%) or 2,4-diacetamido-2,4,6-trideoxyglucose (~25%); the d configuration of GalNA and QuiN4N was ascribed tentatively. To the best of our knowledge, this is for the first time that an amide of uronic acid with a dipeptide is found in bacterial polysaccharides. PMID- 22230712 TI - Remarks about remarkable surgical outcomes. PMID- 22230713 TI - Anatomic grading of nerve sparing during robot-assisted radical prostatectomy. AB - BACKGROUND: Because of the lack of intraoperative visual cues, the amount of nerve sparing (NS) intended by the surgeon does not always correspond to what is actually performed during surgery. OBJECTIVE: Describe a standardized NS grading system based on intraoperative visual cues. DESIGN, SETTING, AND PARTICIPANTS: A total of 133 consecutive patients who underwent robot-assisted radical prostatectomy (RARP) by a single surgeon were evaluated. The surgeon intraoperatively graded the NS independently for either side as follows: 1=no NS; 2=<50% NS; 3=50% NS; 4=75% NS; 5= >= 95% NS. SURGICAL PROCEDURE: RARP; detailed description of a five-point NS grading system. MEASUREMENTS: The area of residual nerve tissue on prostatectomy specimens was compared with the intraoperative NS score (NSS). The rate of positive surgical margins (PSMs) according to the NSS is also reported. RESULTS AND LIMITATIONS: In all, 52.6% of operated sides (140 of 266 sides) had NSS 5, 30.1% (80 of 266) had NSS 4, 2.3% (6 of 266) had NSS 3, 13.2% (35 of 266) had NSS 2, and 1.9% (5 of 266) had NSS 1. The area of residual nerve tissue was significantly different among the different NSSs: median area (interquartile range) for NSS 5: 0.5 (0-2) mm(2); for NSS 4: 3 (0-8) mm(2); for NSS 3: 13 (7-23) mm(2); for NSS 2: 14 (8-24) mm(2); and for NSS 1: 57 (56-165) mm(2) (p<0.001). Overall, 9.02% of the patients (12 of 133 patients) had a PSM, with 8.3% (9 of 108) for pT2 and 12% (3 of 25) for pT3. Side-specific PSMs according to NSS were 3.6% (5 of 140) for NSS 5, 7.5% (6 of 80) for NSS 4, 16.7% (1 of 6) for NSS 3, 5.7% (2 of 35) for NSS 2, and 0% (0 of 5) for NSS 1. A limitation of our study is that the key anatomic landmarks are not recognizable in every case, and this technique might not be easy to perform during the early learning curve. CONCLUSIONS: We believe that the visual cues exposed in this article will help surgeons achieve more consistent NS during RARP. PMID- 22230714 TI - Resolving the contributions of fatigue-induced migration and scapular reorientation on the subacromial space: an orthopaedic geometric simulation analysis. AB - Subacromial impingement occurs when tissues interposed between the humeral head and the acromion become compressed between the bones. Two fatigue-related mechanisms are suggested to contribute to this impingement: superior humeral head migration and scapular reorientation, specifically downward rotation, anterior tilt and protraction. Although both mechanisms have received attention, controversy exists regarding their relative contributions to reducing subacromial space width. This simulation study presents a three-dimensional orthopedic model for assessing the spatial relationship between the humerus and the scapula. Through incorporating empirically generated fatigue data as inputs, changes in the subacromial space associated with each mechanism acting independently and in combination were quantified. These changes were examined for three scenarios (average, impingement sparing, impingement causing) and at three humeral elevation angles (0 degrees , 45 degrees and 90 degrees ) in a total of 36 unique simulations. Humeral head migration generally decreased the subacromial space and scapular reorientation generally increased the space across scenarios. This strongly implies that superior humeral migration is the dominant fatigue related mechanism associated with increasing the likelihood of impingement. The results suggest that future research should target efforts to reduce migration in industry, primarily through avoidance or modification of situations known to induce rotator cuff fatigue, such as overhead work. PMID- 22230704 TI - Neural and cellular mechanisms of fear and extinction memory formation. AB - Over the course of natural history, countless animal species have evolved adaptive behavioral systems to cope with dangerous situations and promote survival. Emotional memories are central to these defense systems because they are rapidly acquired and prepare organisms for future threat. Unfortunately, the persistence and intrusion of memories of fearful experiences are quite common and can lead to pathogenic conditions, such as anxiety and phobias. Over the course of the last 30 years, neuroscientists and psychologists alike have attempted to understand the mechanisms by which the brain encodes and maintains these aversive memories. Of equal interest, though, is the neurobiology of extinction memory formation as this may shape current therapeutic techniques. Here we review the extant literature on the neurobiology of fear and extinction memory formation, with a strong focus on the cellular and molecular mechanisms underlying these processes. PMID- 22230715 TI - Anticipatory phase correction in sensorimotor synchronization. AB - Studies of phase correction in sensorimotor synchronization often introduce timing perturbations that are unpredictable with regard to direction, magnitude, and position in the stimulus sequence. If participants knew any or all of these parameters in advance, would they be able to anticipate perturbations and thus regain synchrony more quickly? In Experiment 1, we asked musically trained participants to tap in synchrony with short isochronous tone sequences containing a phase shift (PS) of -100, -40, 40, or 100 ms and provided advance information about its direction, position, or both (but not about its magnitude). The first two conditions had little effect, but in the third condition participants shifted their tap in anticipation of the PS, though only by about +/-40 ms on average. The phase correction response to the residual PS was also enhanced. In Experiment 2, we provided complete advance information about PSs of various magnitudes either at the time of the immediately preceding tone ("late") or at the time of the tone one position back ("early") while also varying sequence tempo. Anticipatory phase correction was generally conservative and was impeded by fast tempo in the "late" condition. At fast tempi in both conditions, advancing a tap was more difficult than delaying a tap. The results indicate that temporal constraints on anticipatory phase correction resemble those on reactive phase correction. While the latter is usually automatic, this study shows that phase correction can also be controlled consciously for anticipatory purposes. PMID- 22230718 TI - Mass spectrometry based methods for the discrimination and typing of mycobacteria. AB - Identification and typing of mycobacteria is very important for epidemiology, susceptibility testing and diagnostic purposes. This paper describes the development and validation of the alternative methods for species identification and typing of mycobacteria based on a matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-ToF MS). Altogether there were 383 clinical isolates analyzed which include 348 strains of Mycobacterium tuberculosis complex (MTBC) (342 strains of M. tuberculosis and 6 strains of M. bovis) and 35 strains of nontuberculous mycobacteria (NTM) represented by 16 different species. Direct bacterial profiling (DBP) by means of MALDI-ToF MS was carried out. Cluster analysis of DBP mass spectra divided them into two large separate groups corresponding to MTBC and NTM, and also demonstrated the possibility of isolate identification at the species level. Spoligotyping protocol based on mass spectrometry was developed and validated, it matched completely to classical spoligotyping data. Our results suggest that MALDI-ToF MS has potential as a rapid and reproducible platform for the identification and typing of Mycobacterium species. PMID- 22230721 TI - Exonuclease 1 (EXO1) gene variation and melanoma risk. AB - OBJECTIVE: DNA repair pathway genes play an important role in maintaining genomic integrity and protecting against cancer development. This study aimed to identify novel SNPs in the DNA repair-related genes associated with melanoma risk from a genome-wide association study (GWAS). METHODS: A total of 8422 SNPs from the 165 DNA repair-related genes were extracted from a GWAS of melanoma risk, including 494 cases and 5628 controls from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We further replicated the top SNPs in a GWAS of melanoma risk from the MD Anderson Cancer Center (1804 cases and 1026 controls). RESULTS: A total of 3 SNPs with P value <0.001 were selected for in silico replication. One SNP was replicated: rs3902093 [A] in EXO1 promoter region (P(discovery)=6.6 * 10-4, P(replication)=0.039, P(joint)=2.5 * 10-4; OR(joint)=0.80, 95% CI: 0.71, 0.90). This SNP was associated with the expression of the EXO1; carriers of the A allele showed lower expression (P=0.002). CONCLUSION: Our study found that a promoter region SNP in the editing and processing nucleases gene EXO1 was associated with decreased expression of EXO1 and decreased melanoma risk. Further studies are warranted to validate this association and to investigate the potential mechanisms. PMID- 22230723 TI - IADT guidelines for treatment of traumatic dental injuries. PMID- 22230722 TI - Fluoride bioavailability in saliva and plaque. AB - BACKGROUND: Different fluoride formulations may have different effects on caries prevention. It was the aim of this clinical study to assess the fluoride content, provided by NaF compared to amine fluoride, in saliva and plaque. METHODS: Eight trained volunteers brushed their teeth in the morning for 3 minutes with either NaF or amine fluoride, and saliva and 3-day-plaque-regrowth was collected at 5 time intervals during 6 hours after tooth brushing. The amount of collected saliva and plaque was measured, and the fluoride content was analysed using a fluoride sensitive electrode. All subjects repeated all study cycles 5 times, and 3 cycles per subject underwent statistical analysis using the Wilcoxon-Mann Whitney test. RESULTS: Immediately after brushing the fluoride concentration in saliva increased rapidly and dropped to the baseline level after 360 minutes. No difference was found between NaF and amine fluoride. All plaque fluoride levels were elevated after 30 minutes until 120 minutes after tooth brushing, and decreasing after 360 minutes to baseline. According to the highly individual profile of fluoride in saliva and plaque, both levels of bioavailability correlated for the first 30 minutes, and the fluoride content of saliva and plaque was back to baseline after 6 hours. CONCLUSIONS: Fluoride levels in saliva and plaque are interindividually highly variable. However, no significant difference in bioavailability between NaF and amine fluoride, in saliva, or in plaque was found. PMID- 22230724 TI - International Association of Dental Traumatology guidelines for the management of traumatic dental injuries: 1. Fractures and luxations of permanent teeth. AB - Traumatic dental injuries (TDIs) of permanent teeth occur frequently in children and young adults. Crown fractures and luxations are the most commonly occurring of all dental injuries. Proper diagnosis, treatment planning and followup are important for improving a favorable outcome. Guidelines should assist dentists and patients in decision making and for providing the best care effectively and efficiently. The International Association of Dental Traumatology (IADT) has developed a consensus statement after a review of the dental literature and group discussions. Experienced researchers and clinicians from various specialties were included in the group. In cases where the data did not appear conclusive, recommendations were based on the consensus opinion of the IADT board members. The guidelines represent the best current evidence based on literature search and professional opinion. The primary goal of these guidelines is to delineate an approach for the immediate or urgent care of TDIs. In this first article, the IADT Guidelines for management of fractures and luxations of permanent teeth will be presented. PMID- 22230725 TI - Intracanal dressing and root canal filling materials in tooth replantation: a literature review. AB - The prognosis of tooth replantation is usually related to the need of endodontic treatment, which has a direct relationship with the occurrence of root resorptions. Several studies have been undertaken in an attempt to prevent, delay, or treat these complications, which are the main causes of loss of replanted teeth. This literature review examines research evidence on intracanal dressings and root canal filling materials used in cases of tooth replantation. A comprehensive search was performed in the Medline/Pubmed, Bireme and Scielo full text electronic journal databases to retrieve English-language articles referring to these topics that had been published between 1964 and 2010. Calcium hydroxide (CH) remains the usually recommended choice as an intracanal medicament in replanted teeth; however, there is evidence to support the initial use of a corticosteroid-antibiotic combination such as Ledermix paste to control potential early resorption, prior to the introduction of CH where the beneficial effect in the treatment of progressive root resorption has been well proven. Regarding root filling materials, CH-containing sealers are a good option because of their biological properties. Accurate diagnosis and adequate treatment plan may constitute very complex tasks, particularly in tooth avulsion because several variables are involved. In addition to the technical knowledge and clinical experience directed toward the quality of treatment, patient education may favorably influence the survival of replanted teeth. PMID- 22230726 TI - Sorption influenced transport of ionizable pharmaceuticals onto a natural sandy aquifer sediment at different pH. AB - The pH-dependent transport of eight selected ionizable pharmaceuticals was investigated by using saturated column experiments. Seventy-eight different breakthrough curves on a natural sandy aquifer material were produced and compared for three different pH levels at otherwise constant conditions. The experimentally obtained K(OC) data were compared with calculated K(OC) values derived from two different logK(OW)-logK(OC) correlation approaches. A significant pH-dependence on sorption was observed for all compounds with pK(a) in the considered pH range. Strong retardation was measured for several compounds despite their hydrophilic character. Besides an overall underestimation of K(OC), the comparison between calculated and measured values only yields meaningful results for the acidic and neutral compounds. Basic compounds retarded much stronger than expected, particularly at low pH when their cationic species dominated. This is caused by additional ionic interactions, such as cation exchange processes, which are insufficiently considered in the applied K(OC) correlations. PMID- 22230727 TI - Comparison of the cytotoxic responses of Escherichia coli (E. coli) AMC 198 to different fullerene suspensions (nC60). AB - Fullerenes are set to be produced on an industrial scale in anticipation of their wide applications. This calls for research on their environmental and health impacts. This study investigates and compares the cell toxicity of different aqueous fullerene aggregates. Popular C(60) dispersal methods were used to prepare four types of nC(60) aggregates. These aggregates were tested against the indicator species Escherichia coli (E. coli) AMC 198. With aggregates of around 150 nm in diameter, the THF/nC(60) suspension was very toxic and gave rise to a half maximal effective concentration (EC(50)) of 0.54 mg L(-1) in E. coli. By contrast, the Tol/nC(60) suspension exhibited a cytoprotective role while the Aqu N(2)/nC(60) and Aqu-O(2)/nC(60) suspensions enhanced the metabolism of E. coli. Although some toxicants, such as THF and THF-peroxide, were introduced into the THF/nC(60) suspension during the dispersion, the toxicity of nC(60) itself cannot be neglected. PMID- 22230728 TI - Analytical model for site-specific isotope fractionation in 13C during sorption: determination by isotopic 13C NMR spectrometry with vanillin as model compound. AB - The aim of this study was to conceive a reactive transport model capable of providing quantitative site-specific enrichment factors for fractionation in (13)C isotopic content during sorption. As test compound the model treats vanillin, for which the (13)C isotopic content at natural abundance at each of the 8 carbon positions can be measured by quantitative (13)C nuclear magnetic resonance spectrometry. This technique determines the isotope ratios with a resolution better than +/-10/00 (0.1%) at each carbon position. Site-specific isotope fractionations were recorded in chromatography column experiments with silica RP-18 as stationary phase. The one dimensional reactive transport model accounted for the sorption/desorption behavior of 8 individual (13)C-isotopomers and one (12)C-isotopomer of vanillin and reproduced satisfactorily the bulk (average over the whole compound) fractionation observed during elution. After model calibration, the enrichment factors were fitted for each carbon site where a significant fractionation was recorded. To show the interest of such a transport model for environmental studies, the model, extended to three dimensions, was exploited to simulate reactive transport in an aquifer. These results show that significant (13)C isotope fractionation is expected for 4 out of 8 (13)C-isotopomers in vanillin, and illustrate that bulk isotope ratios measured by conventional compound specific isotope analysis and mass spectrometry would hardly document significant isotope fractionations in vanillin. It is concluded that modeling of site-specific isotope ratios in molecules is a priori feasible and may help to quantify unknown processes in the environment. PMID- 22230729 TI - Gonad differential proteins revealed with proteomics in oyster (Saccostrea cucullata) using alga as food contaminated with cadmium. AB - As mercury and lead, cadmium (Cd) is one of the highly toxic metals in both the ocean and land environments, but its toxicological mechanism in organisms including human is still unclear because of the complex toxicological pathways in vivo. Here, the alga Chlorella vulgaris were cultivated at room temperature under the stress of cadmium (1 mg L(-1)) to obtain a toxic food, and then the contaminated food were directly supplied to oyster (Saccostrea cucullata) in seawater. After feeding with C. vulgaris contaminated with Cd (C. vulgaris-Cd), the differential proteins in the oyster gonad (OG) were effectively separated and identified with proteomic approaches. Eleven protein spots were observed to be significantly changed in the OG feeding with C. vulgaris-Cd, which seven spots of these differential proteins were down-regulated while four spots were up regulated. These altered spots were further excised in gels and identified by a combined technique of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and database searching. A portion of these differential proteins were further proofed by real-time PCR and Western blotting. The results indicate that the major functions of these differential proteins were described as follows: binding, protein translocation, catalysis, regulation of energy metabolism, reproductive function and skeleton structure. These differential proteins in part may effectively provide a few novel biomarkers for the evaluation of Cd pollution level via a food pathway for harming halobios, mammal and human health, and for understanding the complex mechanisms of Cd toxicity in vivo. PMID- 22230730 TI - Gene expression profiles in the testis associated with testis-ova in adult Japanese medaka (Oryziaslatipes) exposed to 17alpha-ethinylestradiol. AB - The occurrence of oocytes in the testis (testis-ova) of several fish species is often associated with exposure of estrogenic chemicals. However, induction mechanisms of the testis-ova remain to be elucidated. To develop marker genes for detecting testis-ova in the testis, adult male medaka were exposed to nominal concentration of 100 ng L(-1) of 17alpha-ethinylestradiol (EE2) for 3-5 weeks, and 800 ng estradiol benzoate (EB) for 3 weeks (experiment I), and a measured concentration of 20 ng L(-1) EE2 for 1-6 weeks (experiment II). Histological analysis was performed for the testis, and microarray analyses were performed for the testis, liver and brain. Microarray analysis in the estrogen-exposed medaka liver showed vitellogenin and choriogenin as estrogen responsive genes. Testis ova were induced in the testis after 4 weeks of exposure to 100 ng L(-1) EE2, 3 weeks of exposure to 800 ng EB, and 6 weeks of exposure to 20 ng L(-1) EE2. Microarray analysis of estrogen-exposed testes revealed up-regulation of genes related to zona pellucida (ZP) and the oocytes marker gene, 42Sp50. Using quantitative RT-PCR we confirmed that Zpc5 gene can be used as a marker for the detection of testis-ova in male medaka. PMID- 22230731 TI - The validity and precision of the Leicester Cough Questionnaire in COPD patients with chronic cough. AB - BACKGROUND: A validated instrument to assess the effects of chronic cough on health status in patients with chronic obstructive pulmonary disease (COPD) is currently not available. The Leicester Cough Questionnaire (LCQ) is a cough specific health status questionnaire which is originally validated for a population of general patients presenting with chronic cough. We examined the psychometric performance of the LCQ in patients with COPD and chronic productive cough. METHODS: Concurrent validity, internal consistency, reproducibility and responsiveness were determined. The St. George's Respiratory Questionnaire (SGRQ) and the Short Form-36 (SF-36) were used as external criteria. Questionnaires were completed at the start of the study. After 2 and 12 weeks the LCQ was repeated, together with a global rating of change. RESULTS: In total 54 patients were included. Concurrent validity analysis showed significant correlations between corresponding domains of the LCQ and the SGRQ (r(s) -0.31 to -0.60). Corresponding domains of the LCQ and the SF-36 showed weaker correlations (r(s) 0.04 to 0.41). Internal consistency was adequate for two of the three domains (Cronbach's alpha 0.74 - 0.86). Test-retest reliability in stable patients was high (intraclass correlation coefficients 0.79 - 0.93). The mean difference after two weeks was 0.73 (+/- 1.75). Responsiveness analysis indicated that the LCQ was able to detect changes after 12 weeks. CONCLUSION: The LCQ is a valid, reliable, responsive instrument to measure health status in COPD patients with chronic productive cough. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01071161. PMID- 22230733 TI - Predictors of 5-year mortality in pulmonary Mycobacterium avium-intracellulare complex disease. AB - SETTING: Kyoto, Japan. OBJECTIVE: To determine predictors of 5-year mortality in pulmonary Mycobacterium avium-intracellulare complex (MAC) disease. DESIGN: Retrospective study of 164 patients diagnosed with pulmonary MAC disease between 1999 and 2005 and followed for 5 years. RESULTS: Overall 5-year mortality was 28.0%. Among 117 patients with microbiological outcomes, 54 were treated (treated MAC patients) and 24 were not treated and did not experience sputum culture conversion during follow-up (untreated chronic MAC patients); 39 patients were not treated and experienced sputum culture conversion. Five-year all-cause overall mortality among the 78 patients with definite MAC disease (including treated and untreated chronic MAC patients) was 25.6%. The mortality rate was 33.3% for untreated chronic MAC patients only vs. 22.2% for treated MAC patients (P = 0.30). After adjustment for clinical, microbiological and radiological confounders, independent factors for 5-year mortality were a high Charlson comorbidity index in cases with definite MAC disease (hazard ratio [HR] 1.76) and untreated chronic MAC (HR 3.08), and presence of cavitary lesions in cases with definite MAC disease (HR 1.82) and treated MAC patients (HR 3.91). CONCLUSION: Patients with cavitary lesions require immediate treatment for sputum culture conversion and to improve their chances of survival. PMID- 22230732 TI - Tumor associated antigen specific T-cell populations identified in ex vivo expanded TIL cultures. AB - Ex vivo expanded tumor infiltrating lymphocytes (TILs) from malignant melanoma (MM) and head & neck squamous cell carcinoma (HNSCC) share a similar oligoclonal composition of T effector memory cells, with HLA class I restricted lysis of tumor cell lines. In this study we show that ex vivo expanded TILs from MM and HNSCC demonstrate a heterogeneous composition in frequency and magnitude of tumor associated antigen specific populations by Elispot IFNgamma quantitation. TILs from MM and HNSCC shared reactivity towards NY ESO-1, cyclin B1 and Bcl-x derived peptides. Additionally we show that dominating T-cell clones and functionality persists through out expansion among an oligoclonal composition of T-cells. Our findings mirror prior results on the oligoclonal composition of TIL cultures, further indicating a potential for a broader repertoire of specific effector cells recognizing the heterogeneous tumors upon adoptive transfer; increasing the probability of tumor control by minimizing immune evasion by tumor cell escape variants. PMID- 22230734 TI - The mammalian red nucleus and its role in motor systems, including the emergence of bipedalism and language. AB - The human red nucleus consists of the well-developed parvicellular red nucleus (pNr) and the rudimentary magnocellular red nucleus (mNr). It is believed that the human pNr is separated from the nucleus accessorius medialis of Bechterew (NB), which, generally speaking, is located in the ventral central gray. It was initially suggested that the "rolled sheet" model of the human pNr that we proposed included the view that the human NB does not occupy the ventral central gray but is placed in the dorsomedial part of the red nucleus. It is perhaps more appropriate to state that the NB, the origin of the medial tegmental tract (MTT), over time became displaced from the ventral central gray and was in part shifted to the adjacent reticular formation. The majority of the MTT tract however remained in its established location. Evolutionarily speaking, this separation of the NB and the nucleus of Darkschewitsch (ND), and the translocation of the position of the NB just referred to, might have begun within the lineage of the apes prior to the emergence of man. Furthermore it is generally believed that the human mNr consists of a scattered few groups of giant-to-large neurons situated among the fiber bundles of the superior cerebellar peduncle at the level of the oculomotor nerve fibers. It has long been considered impossible to clearly draw an outline of the human mNr such that it could be seen as a self-contained structural entity. However, we now demonstrate just such an outline of the rudimentary human adult mNr through employment of the concepts of the so-called "Mannen's closed nucleus" and "Ogawa's human mNr": descriptions that exclude the associated area that contains neurons which possess melanin pigment. Interestingly, recent studies have shown that the human fetus and newborns have a well-developed semilunar mNr, and this observation raises the possibility that the associated transient but well-developed rubrospinal tract seen in the perinatal state might have had an important role for the development of upright bipedalism in hominids. The well-developed human prefrontal-NB-olivo-lateral cerebellar circuit might possibly have resulted in the emergence of language. PMID- 22230736 TI - Recurrent Mycobacterium avium infection after seven years of latency in a HIV infected patient receiving efficient antiretroviral therapy. AB - We report the first case of Mycobacterium avium reactivation, after prolonged latency, in a HIV-infected patient receiving highly active antiretroviral therapy with undetectable viral replication and normal CD4 cell count. The patient presented with a painful swollen shoulder seven years after initial M. avium bacteriaemia. Articular puncture grew M. avium. The isolates of the first and second infection were identical using repetitive-sequence-based Polymerase Chain Reaction analyses. PMID- 22230738 TI - An ultrasensitive tool exploiting hydration dynamics to decipher weak lipid membrane-polymer interactions. AB - We introduce a newly developed tool, (1)H Overhauser Dynamic Nuclear Polarization (ODNP), to sensitively explore weak macromolecular interactions by site specifically probing the modulation of the translational dynamics of hydration water at the interaction interface, in the full presence of bulk water. Here, ODNP is employed on an illustrative example of a membrane-active triblock copolymer, poloxamer 188 (P188), which is known to restore the integrity of structurally compromised cell membranes. We observe a distinct change in the translational dynamics of the hydration layer interacting with the lipid membrane surface and the bilayer-interior as P188 is added to a solution of lipid vesicles, but no measurable changes in the dynamics or structure of the lipid membranes. This study shows that hydration water is an integral constituent of a lipid membrane system, and demonstrates for the first time that the modulation of its translational diffusivity can sensitively report on weak polymer-membrane interactions, as well as mediate essential lipid membrane functions. ODNP holds much promise as a unique tool to unravel molecular interactions at interfaces even in the presence of bulk water under ambient conditions. PMID- 22230740 TI - Percutanenous therapies for mitral regurgitation. AB - Percutaneous therapies for the treatment of mitral regurgitation have emerged rapidly over the past several years. Most of the percutaneous approaches are modifications of existing surgical approaches to mitral annuloplasty or leaflet repair. Most of the percutaneous devices are based on surgical approaches. Catheter-based leaflet repair with the MitraClip is accomplished using an implantable clip to mimic the surgical edge-to-edge technique. Percutaneous annuloplasty can be achieved indirectly via the coronary sinus, or directly from retrograde left ventricular access. Several of these percutaneous approaches have been successfully used in trials or are in the early stages of use in practice. PMID- 22230741 TI - Quantitative determination of odanacatib in human plasma using liquid-liquid extraction followed by liquid chromatography-tandem mass spectrometry analysis. AB - Odanacatib (ODN, MK-0822) is an investigational drug under development for the treatment of osteoporosis. A quantitative LC/MS-MS methodology was developed and validated to determine ODN concentrations in human plasma, with a linear calibration range from 0.500 to 500ng/mL. Stable isotope (13)C(6)-labeled ODN was employed as the internal standard (IS). Sample preparation was based on liquid liquid extraction of basified plasma with methyl t-butyl ether in a 96-well plate format. The extracted samples were analyzed on a liquid chromatography-tandem mass spectrometry system equipped with a turbo ion spray source. Chromatographic separation of the analyte and IS was achieved on a Phenomenex Luna C18 (50mm*2.0mm, 5MUm) column. Ion pairs m/z 526->313 for the analyte and m/z 532 >319 for the IS were monitored in positive ionization mode for MS detection. This methodology has been fully validated and proved to be rugged and reproducible. Intra- and inter-run variability was within 5.88%, with accuracy between 95.6 and 106% of the nominal concentrations. Analyte stability was evaluated under various sample preparation, analysis and storage conditions. This assay has been utilized to analyze human plasma samples obtained from phase I to III clinical trials. PMID- 22230737 TI - Sculpting the maturation, softening and ethylene pathway: the influences of microRNAs on tomato fruits. AB - BACKGROUND: MicroRNAs (miRNAs), a ubiquitous class of short RNAs, play vital roles in physiological and biochemical processes in plants by mediating gene silencing at post-transcriptional (PTGS) level. Tomato is a model system to study molecular basis of fleshy fruit ripening and senescence, ethylene biosynthesis and signal transduction owing to its genetic and molecular tractability. To study the functions of miRNAs in tomato fruit ripening and senescence, and their possible roles in ethylene response, the next generation sequencing method was employed to identify miRNAs in tomato fruit. Bioinformatics and molecular biology approaches were combined to profile the miRNAs expression patterns at three different fruit ripening stages and by exogenous ethylene treatment. RESULTS: In addition to 7 novel miRNA families, 103 conserved miRNAs belonging to 24 families and 10 non-conserved miRNAs matching 9 families were identified in our libraries. The targets of many these miRNAs were predicted to be transcriptional factors. Other targets are known to play roles in the regulation of metabolic processes. Interestingly, some targets were predicted to be involved in fruit ripening and softening, such as Pectate Lyase, beta-galactosidase, while a few others were predicted to be involved in ethylene biosynthesis and signaling pathway, such as ACS, EIN2 and CTR1. The expression patterns of a number of such miRNAs at three ripening stages were confirmed by stem-loop RT-PCR, which showed a strong negative correlation with that of their targets. The regulation of exogenous ethylene on miRNAs expression profiles were analyzed simultaneously, and 3 down regulated, 5 up-regulated miRNAs were found in this study. CONCLUSIONS: A combination of high throughput sequencing and molecular biology approaches was used to explore the involvement of miRNAs during fruit ripening. Several miRNAs showed differential expression profiles during fruit ripening, and a number of miRNAs were influenced by ethylene treatment. The results suggest the importance of miRNAs in fruit ripening and ethylene response. PMID- 22230742 TI - Simultaneous determination of fluoroquinolones in foods of animal origin by a high performance liquid chromatography and a liquid chromatography tandem mass spectrometry with accelerated solvent extraction. AB - A confirmatory and quantitative method based on a high performance liquid chromatography UV detector (HPLC-UV) and a liquid chromatography tandem mass spectrometry (LC-MS/MS) with an extraction procedure of accelerated solvent extraction (ASE) has been developed for simultaneous determination of 15 kinds of fluoroquinolones in various animal origin food samples. The sample preparation procedures consist of an extraction step with acetonitrile and a cleaning-up step with Oasis HLB cartridge. Parameters for extraction pressure and temperature, cycle of ASE, clean-up, and analysis procedure have been optimized systematically. The recoveries of FQNs spiked in the tissues as the muscle, liver, kidney of swine, bovine, chicken and fish at a concentration range of 10 800MUg/kg were found between 70.6% and 111.1% with relative standard deviations (RSD) less than 15% in HPLC. The LOD and LOQ of the HPLC for the 15 FQNs were 3MUg/kg and 10MUg/kg, respectively, and those of the LC-MS/MS were 0.3 and 1MUg/kg, respectively. These rapid and reliable methods can be used to efficiently separate, characterize and quantify the residues of 15 FQNs (Marbofloxacin, Enoxacin, Fleroxacin, Ofloxacin, Pefloxacin, Lomefloxacin, Danofloxacin, Enrofloxacin, Orbifloxacin, Cinoxacin, Gatifloxacin, Sarafloxacin, Difloxacin, Nalidixic Acid, Flumequine) in food of animal origin. PMID- 22230745 TI - Measuring the value of older people's production: a diary study. AB - BACKGROUND: The productive capacity of retired people is usually not valued. However, some retirees produce much more than we might expect. This diary-based study identifies the activities of older people, and suggests some value mechanisms. One question raised is whether it is possible to scale up this diary study into a larger representative study. METHODS: Diaries kept for one week were collected among 23 older people in the north of Sweden. The texts were analysed with a grounded theory approach; an interplay between ideas and empirical data. RESULTS: Some productive activities of older people must be valued as the opportunity cost of time or according to the market value, and others must be valued with the replacement cost. In order to make the choice between these methods, it is important to consider the societal entitlement. When there is no societal entitlement, the first or second method must be used; and when it exists, the third must be used. CONCLUSIONS: An explicit investigation of the content of the entitlement is needed to justify the choice of valuation method for each activity. In a questionnaire addressing older people's production, each question must be adjusted to the type of production. In order to fully understand this production, it is important to consider the degree of free choice to conduct an activity, as well as health-related quality of life. PMID- 22230746 TI - Inspiratory-activated and inspiratory-inhibited airway vagal preganglionic neurons in the ventrolateral medulla of neonatal rat are different in intrinsic electrophysiological properties. AB - This study investigates the firing properties of the inspiratory-activated and inspiratory-inhibited airway vagal preganglionic neurons located in the external formation of the nucleus ambiguus. The results showed that inspiratory-activated and inspiratory-inhibited neurons are distributed with different density and site preference in this area. Inspiratory-inhibited neurons exhibit significantly more positive resting membrane potential, more negative voltage threshold and lower minimal current required to evoke an action potential under current clamp. The afterhyperpolarization in inspiratory-activated neurons was blocked by apamin, a blocker of the small-conductance Ca(2+)-activated K(+) channels; and that in inspiratory-inhibited neurons by charybdotoxin, a blocker of the large conductance Ca(2+)-activated K(+) channels. Under voltage clamp, depolarizing voltage steps evoked tetrodotoxin-sensitive rapid inward sodium currents, 4 aminopyridine-sensitive outward potassium transients and lasting outward potassium currents. 4-Aminopyridine partially blocked the lasting outward potassium currents of inspiratory-activated neurons but was ineffective on those of inspiratory-inhibited neurons. These findings suggest that inspiratory activated and inspiratory-inhibited neurons are differentially organized and express different types of voltage-gated ion channels. PMID- 22230747 TI - Allergy-associated symptoms in relation to childhood non-Hodgkin's as contrasted to Hodgkin's lymphomas: a case-control study in Greece and meta-analysis. AB - An increase of the prevalence of childhood allergic diseases and the incidence of childhood Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL) were reported in the late 20th century. Among adults, several studies point to an inverse association with lymphoma; it remains to be confirmed whether allergy is also related to childhood lymphomas and whether the association, if any, is of an aetiologic nature. Between 1996 and 2008, 277 children (aged 0-14 years) with HL (N = 111) or NHL (N = 166) were enrolled in Nationwide Registry for Childhood Hematological Malignancies (NARECHEM), a Greek hospital-based-registry of childhood hematological malignancies. Hospital controls were individually matched to cases on age and sex. Multivariate conditional logistic regression was used to estimate odds ratios (ORs) with 95%confidence intervals (CIs) for associations of allergic diseases and other covariates with childhood HL or NHL risk. Subsequently, we combined our results with those of a French case-control study in a meta-analysis amounting to a total of 330 NHL cases/1478 controls and 239 HL cases/959 controls. After controlling for sociodemographic, perinatal and environmental factors, childhood NHL was less prevalent among children with allergy-associated symptoms overall (OR:0.50, 95%CI:0.27-0.92) or a history of asthma (OR:0.43, 95%CI:0.21-0.88). By contrast, allergy did not seem to be associated with childhood HL risk, although statistical power was limited. Fewer seaside holidays and higher birth weight were also associated with increased childhood NHL risk. The combined OR of the two studies for the association of asthma with NHL risk was: 0.52, 95%CI:0.32-0.84, whereas for HL: 0.86, 95%CI:0.51-1.45. Allergy seems to be strongly and inversely associated with childhood NHL. It remains to be elucidated in future investigations comprising larger populations, focusing on specific disease subtypes and employing more pertinent study-designs, whether this association is genuinely protective. PMID- 22230748 TI - Tumour-derived IL-10 within tumour microenvironment represses the antitumour immunity of Socs1-silenced and sustained antigen expressing DCs. AB - It has been shown that silencing of suppressor of cytokine signalling 1 (Socs1) or stably expressing transgenic protein Ags in antigen-presenting dentritic cells (DCs) strongly enhances antigen-specific anti-tumour immunity. However, whether the strong and long-lasting T cell responses induced by the modified DCs could modulate the immunosuppressive tumour microenvironment has not been clarified. In this study, we explored the anti-tumour immunity of DCs modified by Socs1-shRNA lentiviral transduction combined with sustained expression of TRP2 in different tumour models. We showed that transfer Socs1-silenced or tumour antigen TRP2 persistent expressed DCs, or DCs modified by combination of Socs1-silencing and sustaining TRP2 expression prior to inoculation of tumour cells delayed B16 tumour cell growth, prolonged mouse survival and increased the ratio of CD8+ T/Treg as well as the CTL activity in tumours. However, there was no significant effect on tumour growth and mouse survival rate upon tumour established. Further, we showed that tumour cell secreted IL-10 counteracted the immunity of modified DCs in established tumour model, injection of Socs1-shRNA and TRP2 antigen modified significantly inhibited growth of the established B16-IL-10(-/-) tumours. These data indicated that the high level of IL-10 within tumour microenvironment is one of factors that compromise DC vaccine functions. PMID- 22230749 TI - [Laparoscopic treatment of common bile duct calculi. Is there still controversy?]. PMID- 22230751 TI - Fate maps of ventral and dorsal pancreatic progenitor cells in early somite stage mouse embryos. AB - The origins of liver progenitor cells have been extensively studied, but evidence on the origin of pancreatic precursor cells is currently limited. Pancreatic and duodenal homeobox gene 1 (Pdx1) is one of the earliest known markers for the pancreas. A transgenic mouse line expressing green fluorescent protein (GFP) under the control of the Pdx1 promoter showed that Pdx1/GFP expression was first observed in the mid-region of the anterior intestinal portal (AIP) lip at embryonic day (E) 8.5 at the 5-6 somite stage (ss). The liver progenitors were confirmed to originate from separate domains at the lateral endoderm and the inner part of the medial AIP as previously reported (Tremblay and Zaret, 2005), which turned out to lie caudally to the Pdx1/GFP-expressing domain. To confirm if the early Pdx1/GFP-positive cells give rise to the pancreatic bud, we labeled the cells on the lip of the AIP using the carbocyanine dye CM-DiI and traced their fates in 1-4 ss, 5-6 ss and 7-9 ss E8.5 embryos using an ex utero whole embryo culture method. At 1 ss, the ventral pancreas progenitors were observed in the lateral endoderm, not yet being segregated from the liver or gut progenitors. Cells that contributed solely to the ventral pancreas first appeared at the AIP lip from 5 ss. At 5-6 ss, cells from the medial of the AIP lip contributed to the ventral pancreas. The pancreas fate region become narrower as development progresses. At 7-9 ss, the cells contributing to the ventral pancreas resided in a narrow region of the AIP lip. From 5 ss, the right flanking region contributes to the posterior gut, and the left flanking region contributes to the anterior gut. Dorsal pancreatic progenitors originate from the dorsal endoderm at the 3-6 somite level at 7-9 ss, though they have not yet diverged from the dorsal gut progenitors at this stage. PMID- 22230750 TI - Correlation between promoter methylation of p14(ARF), TMS1/ASC, and DAPK, and p53 mutation with prognosis in cholangiocarcinoma. AB - BACKGROUND: To study the methylation status of genes that play a role in the p53 Bax mitochondrial apoptosis pathway and its clinical significance in cholangiocarcinoma. PATIENTS AND METHODS: Out of 36 cases cholangiocarcinoma patients from April 2000 to May 2005 were collected.Promoter hypermethylation of DAPK, p14(ARF), and ASC were detected by methylation-specific PCR on cholangiocarcinoma and normal adjacent tissues samples. Mutation of the p53 gene was examined by automated sequencing. Correlation between methylation of these genes and/or p53 mutation status with clinical characteristics of patients was investigated by statistical analysis. RESULTS: We found 66.7% of 36 cholangiocarcinoma patients had methylation of at least one of the tumor suppressor genes analyzed. p53 gene mutation was found in 22 of 36 patients (61.1%). Combined p53 mutation and DAPK, p14(ARF), and/or ASC methylation was detected in 14 cases (38.9%). There were statistically significant differences in the extent of pathologic biology, differentiation, and invasion between patients with combined p53 mutation and DAPK, p14(ARF), and/or ASC methylation compared to those without (P < 0.05). The survival rate of patients with combined DAPK, p14(ARF), and ASC methylation and p53 mutation was poorer than other patients (P < 0.05). CONCLUSION: Our study indicates that methylation of DAPK, p14(ARF), and ASC in cholangiocarcinoma is a common event. Furthermore, p53 mutation combined with DAPK, p14(ARF), and/or ASC methylation correlates with malignancy and poor prognosis. PMID- 22230752 TI - Controlling pesticide release via structuring agropolymer and nanoclays based materials. AB - The potential use of nanoclays for modulating transfer properties of active agents in bio-sourced polymers was explored. For this purpose, new pesticide formulations were designed by combining wheat gluten, ethofumesate (model pesticide) and three montmorillonites (MMT) using a bi-vis extrusion process. Controlled release properties, evaluated through release experiments in water, were discussed in relation to the material formulations and their resulting structure. Partition coefficients were calculated from experimental data and diffusivity values were identified with a Fick's second law mechanistic model. The effect of temperature on release pattern was also evaluated and the activation energy of diffusion was determined. Ethofumesate release was slowed down for all wheat gluten based-formulations as compared to the commercial product. This slow release effect was increased in the presence of hydrophobic MMTs, due to a higher affinity for ethofumesate than for wheat gluten. Contrarily, hydrophilic MMT, displaying a greater affinity for wheat gluten than for ethofumesate seemed ineffective to slow down its release despite the tortuous pathway achieved through a well-exfoliated structure. To conclude, the release mechanisms would be rather governed by pesticide/MMT interactions than MMT/polymer matrix in the case of a hydrophobic pesticide such as ethofumesate and a hydrophilic matrix such as wheat gluten. PMID- 22230753 TI - Assessment of by-products of chlorination and photoelectrocatalytic chlorination of an azo dye. AB - The present work describes a more efficient methodology for the chlorination of water containing disperse dyes, where the chlorinated byproducts identified by mass spectra are compared. For this investigation, we tested the degradation of CI Disperse Blue 291 dye, 2-[(2-Bromo-4,6-dinitrophenyl)azo]-5-(diethylamino)-4 methoxyacetanilide) a commercial azo dye with mutagenic properties. The present work evaluates the photoelectrocatalytic efficiency of removing the CI Disperse Blue 291 dye from a wastewater of the textile industry. We employed NaCl as a supporting electrolyte. It should be noted that photoelectrocatalytic techniques are non-conventional method of generating chlorine radicals. The by-products formed in this process were analyzed using spectrophotometry, liquid chromatography, dissolved organic carbon, mass spectral analysis and mutagenicity assays. The process efficiency was compared with the conventional chlorination process adopted during sewage and effluents treatment processes. This conventional chlorination process is less efficient in removing color, total organic carbon than the photoelectrochemistry technique. Furthermore, we shall demonstrate that the mutagenicity of the generated by-products obtained using photoelectrocatalysis is completely different from that obtained by the conventional oxidation of chloride ions in the drinking water treatment process. PMID- 22230754 TI - Determination of trace element concentrations and stable lead, uranium and thorium isotope ratios by quadrupole-ICP-MS in NORM and NORM-polluted sample leachates. AB - This work focuses on the monitoring of the potential pollution in scenarios that involve NORM-related industrial activities (environmental or in-door scenarios). The objective was to develop a method to determine extent and origin of the contamination, suitable for monitoring (i.e. simple, fast and economical) and avoiding the use of too many different instruments. It is presented a radiochemical method that allows the determination of trace element concentrations and 206Pb/207Pb/208Pb, 238U/234U and 232Th/230Th isotope ratios using a single sample aliquot and a single instrument (ICP-QMS). Eichrom UTEVA(r) extraction chromatography minicolumns were used to separate uranium and thorium in sample leachates. Independent ICP-MS determinations of uranium and thorium isotope ratios were carried out afterwards. Previously a small aliquot of the leachate was used for the determination of trace element concentrations and lead isotope ratios. Several radiochemical arrangements were tested to get maximum performances and simplicity of the method. The performances of the method were studied in terms of chemical yields of uranium and thorium and removal of the potentially interfering elements. The established method was applied to samples from a chemical industry and sediments collected in a NORM-polluted scenario. The results obtained from our method allowed us to infer not only the extent, but also the sources of the contamination in the area. PMID- 22230755 TI - Changes in the chemical characteristics of water-extracted organic matter from vermicomposting of sewage sludge and cow dung. AB - The chemical changes of water-extractable organic matter (WEOM) from five different substrates of sewage sludge enriched with different proportions of cow dung after vermicomposting with Eisenia fetida were investigated using various analytical approaches. Results showed that dissolved organic carbon, chemical oxygen demand, and C/N ratio of the substrates decreased significantly after vermicomposting process. The aromaticity of WEOM from the substrates enhanced considerably, and the amount of volatile fatty acids declined markedly, especially for the cow dung substrate. Gel filtration chromatography analysis showed that the molecular weight fraction between 10(3) and 10(6) Da became the main part of WEOM in the final product. 1H nuclear magnetic resonance spectra revealed that the proportion of H moieties in the area of 0.00-3.00 ppm decreased, while increasing at 3.00-4.25 ppm after vermicomposting. Fluorescence spectra indicated that vermicomposting caused the degradation of protein-like groups, and the formation of fulvic and humic acid-like compounds in the WEOM of the substrates. Overall results indicate clearly that vermicomposting promoted the degradation and transformation of liable WEOM into biological stable substances in sewage sludge and cow dung alone, as well as in mixtures of both materials, and testing the WEOM might be an effective way to evaluate the biological maturity and chemical stability of vermicompost. PMID- 22230757 TI - Chromium (VI) and zinc (II) waste water co-treatment by forming layered double hydroxides: mechanism discussion via two different processes and application in real plating water. AB - Two processes, adsorption after synthesis (AAS) and adsorption during synthesis (ADS) were compared in CrO4(2-) and Zn2+/CrO4(2-) removal. Kinetic results showed that ADS was a better method than AAS, since Cr content was 0.65/0.81 mmol/g in Cr-ADS/ZnCr-ADS, but it was only 0.37/0.56 mmol/g in Cr-AAS/ZnCr-AAS. Then, a low cost mixture was proposed to function as ADS raw materials in treating real plating waters. This mixture first got an isothermal saturation of 1.1 mmol/g in simulated CrO4(2-) water. When Zn2+ was co-treated, it was increased to 1.3 mmol/g. At the same time, a Zn2+ removal of 1.5 mmol/g was attained. Furthermore, real plating water co-treatment reached equilibrium in 6h and obtained 1.4/0.9 mmol/g for Zn2+/CrO4(2-), respectively. According to XRD analysis, this co treatment enhancement resulted from the formation of Zn and Cr contained layered double hydroxide. PMID- 22230756 TI - Deep extractive and oxidative desulfurization of dibenzothiophene with C5H9NO.SnCl2 coordinated ionic liquid. AB - A new C5H9NO.SnCl2 coordinated ionic liquid (IL) was prepared by reacting N methyl-pyrrolidone with anhydrous SnCl2. Desulfurization of dibenzothiophene (DBT) via extraction and oxidation with C5H9NO.SnCl2 IL as extractant, H2O2 and equal mol of CH3COOH as oxidants was investigated. The Nernst partition coefficients k(N) of C5H9NO.SnCl2 IL for the DBT in n-octane was above 5.0, showing its excellent extraction ability. During the oxidative desulfurization process, the optimal molar ratio of H2O2/DBT was six. Sulfur removal of DBT in n octane was 94.8% in 30 min at 30 degrees C under the conditions of H2O2/DBT molar ratio of six and V (IL):V (oil)=1:3. Moreover, the sulfur removal increased with increasing temperature because of the high reaction rate constant, low viscosity, and high solubility of dibenzothiophene-sulfone in the IL. The kinetics of oxidative desulfurization of DBT was also investigated, and the apparent activation energy was found to be 32.5 kJ/mol. The IL could be recycled six times without a significant decrease in activity. PMID- 22230758 TI - Cardiovascular reactivity of younger and older adults to positive-, negative-, and mixed-emotion cognitive challenge. AB - Although aging is associated with progressive increases in blood pressure level, previous research has been inconsistent as to whether older adults show greater or lesser cardiovascular reactivity (CVR) to emotion than do younger adults. There is reason to believe that these inconsistencies could be clarified by examining age-related differences in hemodynamic profile revealed by measuring the pattern of cardiac output and total peripheral resistance associated with changes in blood pressure reactivity. Accordingly, the present study examined the performance, CVR, and hemodynamic profile of younger and older adults during encoding and recognition of word pairs involving four valence types: positive, negative, mixed (positive/negative), and neutral word pairs. Results revealed higher baseline blood pressure, increased CVR characterized by a vascular hemodynamic profile, and more rapid recovery (especially during encoding) for older than for younger participants. Results are discussed in light of research and theory on the relationship between aging and cardiovascular health. PMID- 22230762 TI - Newly described components and regulatory mechanisms of circadian clock function in Arabidopsis thaliana. AB - The circadian clock temporally coordinates plant growth and metabolism in close synchronization with the diurnal and seasonal environmental changes. Research over the last decade has identified a number of clock components and a variety of regulatory mechanisms responsible for the rhythmic oscillations in metabolic and physiological activities. At the core of the clock, transcriptional/translational feedback loops modulate the expression of a significant proportion of the genome. In this article, we briefly describe some of the very recent advances that have improved our understanding of clock organization and function in Arabidopsis thaliana. The new studies illustrate the role of clock protein complex formation on circadian gating of plant growth and identify alternative splicing as a new regulatory mechanism for clock function. Examination of key clock properties such as temperature compensation has also opened new avenues for functional research within the plant clockwork. The emerging connections between the circadian clock and metabolism, hormone signaling and response to biotic and abiotic stress also add new layers of complexity to the clock network and underscore the significance of the circadian clock regulating the daily life of plants. PMID- 22230763 TI - Quantitative Interactor Screening with next-generation Sequencing (QIS-Seq) identifies Arabidopsis thaliana MLO2 as a target of the Pseudomonas syringae type III effector HopZ2. AB - BACKGROUND: Identification of protein-protein interactions is a fundamental aspect of understanding protein function. A commonly used method for identifying protein interactions is the yeast two-hybrid system. RESULTS: Here we describe the application of next-generation sequencing to yeast two-hybrid interaction screens and develop Quantitative Interactor Screen Sequencing (QIS-Seq). QIS-Seq provides a quantitative measurement of enrichment for each interactor relative to its frequency in the library as well as its general stickiness (non-specific binding). The QIS-Seq approach is scalable and can be used with any yeast two hybrid screen and with any next-generation sequencing platform. The quantitative nature of QIS-Seq data make it amenable to statistical evaluation, and importantly, facilitates the standardization of experimental design, data collection, and data analysis. We applied QIS-Seq to identify the Arabidopsis thaliana MLO2 protein as a target of the Pseudomonas syringae type III secreted effector protein HopZ2. We validate the interaction between HopZ2 and MLO2 in planta and show that the interaction is required for HopZ2-associated virulence. CONCLUSIONS: We demonstrate that QIS-Seq is a high-throughput quantitative interactor screen and validate MLO2 as an interactor and novel virulence target of the P. syringae type III secreted effector HopZ2. PMID- 22230764 TI - Mycobacterium tuberculosis transmission over an 11-year period in a low incidence, urban setting. AB - SETTING: Montreal, Canada, has a mean annual tuberculosis (TB) incidence of 9 per 100,000 population, 1996-2007. OBJECTIVE: To characterise potential Mycobacterium tuberculosis transmission by patient subgroups defined by age, sex, birthplace, smear and human immunodeficiency virus status, and to estimate the proportion of cases that resulted from transmission between these patient subgroups. DESIGN: Retrospective study using DNA fingerprinting techniques, with clinical and demographic information from the public health department. Among cases with matching fingerprints, a pulmonary index case was identified. The transmission index was defined as the average number of subsequent TB cases generated directly or indirectly from an index case, and was compared among subgroups, including Haitian immigrants. RESULTS: Compared to non-Haitian foreign-born index cases, Canadian-born index cases were associated with 2.38 times as many (95%CI 1.24 4.58) subsequent cases, while Haitian-born index cases were associated with 3.58 times as many (95%CI 1.74-7.36). Smear-positive index cases were not independently associated with increased transmission. However, middle-aged Canadian-born index patients were associated with a disproportionate number of subsequent cases. CONCLUSION: In Montreal, index patients from several high-risk groups are associated with subsequent transmission. This approach can be applied to other low-incidence settings to identify where targeted interventions could potentially further reduce transmission. PMID- 22230765 TI - Detection of fingermarks by colloidal gold (MMD/SMD)--beyond the pH 3 limit. AB - This work is part of a continuing goal to improve the multimetal deposition technique (MMD), as well as the single-metal deposition (SMD), to make them more robust, more user-friendly, and less labour-intensive. Indeed, two major limitations of the MMD/SMD were identified: (1) the synthesis of colloidal gold, which is quite labour-intensive, and (2) the sharp decrease in efficiency observed when the pH of the working solution is increased above pH 3. About the synthesis protocol, it has been simplified so that there is no more need to monitor the temperature during the synthesis. The efficiency has also been improved by adding aspartic acid, conjointly with sodium citrate, during the synthesis of colloidal gold. This extends the range of pH for which it is possible to detect fingermarks in the frame of the MMD/SMD. The operational range is now extended from 2 to 6.7, compared to 2-3 for the previous formulations. The increased robustness of the working solution may improve the ability of the technique to process substrates that tend to increase the pH of the solution after their immersion. PMID- 22230766 TI - Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb. AB - PURPOSE: Glioma stem cells (GSC) are a critical therapeutic target of glioblastoma multiforme (GBM). EXPERIMENTAL DESIGN: The effects of a G-quadruplex ligand, telomestatin, were evaluated using patient-derived GSCs, non-stem tumor cells (non-GSC), and normal fetal neural precursors in vitro and in vivo. The molecular targets of telomestatin were determined by immunofluorescence in situ hybridization (iFISH) and cDNA microarray. The data were then validated by in vitro and in vivo functional assays, as well as by immunohistochemistry against 90 clinical samples. RESULTS: Telomestatin impaired the maintenance of GSC stem cell state by inducing apoptosis in vitro and in vivo. The migration potential of GSCs was also impaired by telomestatin treatment. In contrast, both normal neural precursors and non-GSCs were relatively resistant to telomestatin. Treatment of GSC-derived mouse intracranial tumors reduced tumor sizes in vivo without a noticeable cell death in normal brains. iFISH revealed both telomeric and non telomeric DNA damage by telomestatin in GSCs but not in non-GSCs. cDNA microarray identified a proto-oncogene, c-Myb, as a novel molecular target of telomestatin in GSCs, and pharmacodynamic analysis in telomestatin-treated tumor-bearing mouse brains showed a reduction of c-Myb in tumors in vivo. Knockdown of c-Myb phenocopied telomestatin-treated GSCs both in vitro and in vivo, and restoring c Myb by overexpression partially rescued the phenotype. Finally, c-Myb expression was markedly elevated in surgical specimens of GBMs compared with normal tissues. CONCLUSIONS: These data indicate that telomestatin potently eradicates GSCs through telomere disruption and c-Myb inhibition, and this study suggests a novel GSC-directed therapeutic strategy for GBMs. PMID- 22230767 TI - Sex and species differences in plasma testosterone and in counts of androgen receptor-positive cells in key brain regions of Sceloporus lizard species that differ in aggression. AB - We studied neuroendocrine correlates of aggression differences in adults of two Sceloporus lizard species. These species differ in the degree of sex difference in aggressive color signals (belly patches) and in aggression: Sceloporus undulatus (males blue, high aggression; females white, low aggression) and Sceloporus virgatus (both sexes white, lower aggression). We measured plasma testosterone and counted cells expressing androgen receptor-like immunoreactivity to the affinity-purified polyclonal AR antibody, PG-21, in three brain regions of breeding season adults. Male S. undulatus had the highest mean plasma testosterone and differed significantly from conspecific females. In contrast, there was no sex difference in plasma testosterone concentrations in S. virgatus. Male S. undulatus also had the highest mean number of AR-positive cells in the preoptic area: the sexes differed in S. undulatus but not in S. virgatus, and females of the two species did not differ. In the ventral medial hypothalamus, S. undulatus males had higher mean AR cell counts compared to females, but again there was no sex difference in S. virgatus. In the habenula, a control brain region, the sexes did not differ, and although the sex by species interaction significant was not significant, there was a trend (p=0.050) for S. virgatus to have higher mean AR cell counts than S. undulatus. Thus hypothalamic AR cell counts paralleled sex and species differences in aggression, as did mean plasma testosterone levels in these breeding-season animals. PMID- 22230768 TI - Extracellular diffusion in laminar brain structures exemplified by hippocampus. AB - Numerous brain structures are composed of distinct layers and such stratification has a profound effect on extracellular diffusion transport in these structures. We have derived a more general form of diffusion equation incorporating inhomogeneities in both the extracellular volume fraction (alpha) and diffusion permeability (theta). A numerical solution of this equation for a special case of layered environment was employed to analyze diffusion in the CA1 region of hippocampus where stratum pyramidale occupied by the bodies of principal neurons is flanked by stratum radiatum and stratum oriens. Extracellular diffusion in the CA1 region was measured in vitro by real-time iontophoretic and real-time pressure methods, and numerical analysis found that stratum pyramidale had a significantly smaller extracellular volume fraction (alpha=0.127) and lower diffusion permeability (theta=0.327) than the other two layers (alpha=0.218, theta=0.447). Stratum pyramidale thus functioned as a diffusion barrier for molecules attempting to cross it. We also demonstrate that unless the detailed properties of all layers are taken into account when diffusion experiments are interpreted, the extracted apparent parameters of the extracellular space lose their physical meaning and capacity to describe any individual layer. Such apparent parameters depend on diffusion distance and direction, giving a false impression of microscopic anisotropy and non-Gaussian behavior. This finding has implications for all diffusion mediated physiological processes as well as for other diffusion methods including integrative optical imaging and diffusion weighted magnetic resonance imaging. PMID- 22230769 TI - High resolution 3T fMRI in anesthetized monkeys. AB - Although there are numerous 3T MRI research devices all over the world, only a few functional studies at 3T have been done in anesthetized monkeys. In the past, anesthetized preparations were reported to be misleading when exploring cortical brain regions outside the primary sensory areas. Nonetheless, a great improvement has been achieved in the limited effect of anesthetic agents on the reactivity of the brain. Here, we re-address the feasibility and potential applications of the brain oxygen level dependent (BOLD) fMRI signal in Macaca mulatta monkeys that have been lightly anesthetized with sevoflurane and curarized. The monkeys were studied with commercially available coils and sequences using a 3T clinical magnet. We obtained sagittal T1 scout images, gray matter double inversion recovery, standard gradient echo sequences and gradient echo functional imaging sequences. Given that fMRI signals are most readily identified in the cerebral cortices, we optimized Echo Planar Imaging sequences to reproduce significant changes in the BOLD signal subsequent to a visual stimulation paradigm. Our results provide a satisfactory signal to noise ratio with a limited standard deviation range, when compared with studies on alert macaques. We suggest that the 3T magnet remains a valuable tool to analyze neural pathways in the macaque brain under light anesthesia and report the use of spatially resolved fMRI in higher visual areas of anesthetized monkeys. This methodology avoids the need for time-consuming training of awake monkeys, is stable over many hours, provides reproducible data and could be applied successfully to future functional studies. PMID- 22230770 TI - Estimation of the total number of hippocampal CA1 pyramidal neurons: new methodology applied to helpless rats. AB - We have recently reported that in the learned helplessness model of depression, the less hippocampal spine synapses rats have, the more helpless they become. It remains unclear, however, whether the observed synaptic changes are associated with the loss of CA1 pyramidal cells. Cell bodies in the CA1 pyramidal layer are very densely packed, making cell counting difficult in this hippocampal subregion. To address this issue, we developed a new approach that (1) yields excellent preservation of the three-dimensional tissue structure; (2) utilizes osmium tetroxide to unambiguously label nucleoli; and (3) facilitates and accelerates unbiased, reliable counting of densely packed cell bodies. Our method provides an improved tool for studies aiming to evaluate hippocampal atrophy and cell loss, the most characteristic features in many neurodegenerative diseases, such as Alzheimer's disease, temporal lobe epilepsy and ischemia, as well as in several psychiatric disorders. Using this new method, we demonstrated no significant changes in the number of CA1 pyramidal cells in the rat learned helplessness paradigm. In addition, volumes of the CA1 pyramidal cell layer and the entire CA1 subfield remained unchanged among treatment groups. We conclude that previously observed synaptic alterations in helpless rats are not associated with CA1 pyramidal cell loss. This finding suggests that behavioral outcome in the learned helplessness paradigm is related to plastic events at the synaptic level, rather than at the level of principal cells. PMID- 22230772 TI - [Kearns-Sayre syndrome]. PMID- 22230773 TI - Efficient lipase purification using reverse micellar extraction. AB - Reverse micellar extraction (RME) of enzyme provides an attractive option for conventional method with the potential to achieve purification and concentration in a single step with high yield. This study presents a methodology for optimization of RME with Pseudomonas lipase as model system. Fold-purification, percent recovery and extraction time were the objective functions while the type and concentration of surfactant, contact time, pH, ionic strength, and the ratio of organic to aqueous phase were the decision variables. Under optimized conditions, the AOT (Aerosol OT (bis 2-ethylhexyl) sodium sulfosuccinate) isooctane system gave a 15-fold purification, 80% recovery and 2.5-fold concentration of the Pseudomonas lipase with process time of 45 min. PMID- 22230774 TI - Role and significance of extracellular polymeric substances on the property of aerobic granule. AB - Because of the important role of extracellular polymeric substances (EPS) in microbial aggregates, the relationship of the EPS and physico-chemical properties of aerobic granule was studied in two sequencing airlift bioreactors (SABR) using two kinds of substrates, acetate+glucose and 4-chloroaniline (4-ClA). Higher amounts of the exopolymeric protein (PN) and lower polysaccharides (PS) and DNA level were extracted from aerobic granules in the SABRs, and the variations in the PN and PN/PS of aerobic granules were higher (770% and 360%) in the SABR using 4-ClA as substrate than that in the other reactor. At the same time, suitable operating parameters (surface gas velocity at about 2.4 cm s(-1) and settling time at 5-10 min) favored EPS production and sludge granulation. Furthermore, the minimal settling velocity, hydrophobicity, surface charge increased in accordance with PN content increase, and a negative correlation between the sludge volume index (SVI) and PN content was observed. PMID- 22230771 TI - Assessment of nursing home residents in Europe: the Services and Health for Elderly in Long TERm care (SHELTER) study. AB - BACKGROUND: Aims of the present study are the following: 1. to describe the rationale and methodology of the Services and Health for Elderly in Long TERm care (SHELTER) study, a project funded by the European Union, aimed at implementing the interRAI instrument for Long Term Care Facilities (interRAI LTCF) as a tool to assess and gather uniform information about nursing home (NH) residents across different health systems in European countries; 2. to present the results about the test-retest and inter-rater reliability of the interRAI LTCF instrument translated into the languages of participating countries; 3 to illustrate the characteristics of NH residents at study entry. METHODS: A 12 months prospective cohort study was conducted in 57 NH in 7 EU countries (Czech Republic, England, Finland, France, Germany, Italy, The Netherlands) and 1 non EU country (Israel). Weighted kappa coefficients were used to evaluate the reliability of interRAI LTCF items. RESULTS: Mean age of 4156 residents entering the study was 83.4 +/- 9.4 years, 73% were female. ADL disability and cognitive impairment was observed in 81.3% and 68.0% of residents, respectively. Clinical complexity of residents was confirmed by a high prevalence of behavioral symptoms (27.5% of residents), falls (18.6%), pressure ulcers (10.4%), pain (36.0%) and urinary incontinence (73.5%). Overall, 197 of the 198 the items tested met or exceeded standard cut-offs for acceptable test-retest and inter-rater reliability after translation into the target languages. CONCLUSION: The interRAI LTCF appears to be a reliable instrument. It enables the creation of databases that can be used to govern the provision of long-term care across different health systems in Europe, to answer relevant research and policy questions and to compare characteristics of NH residents across countries, languages and cultures. PMID- 22230775 TI - Integrated green algal technology for bioremediation and biofuel. AB - Sustainable non-food energy biomass and cost-effective ways to produce renewable energy technologies from this biomass are continuously emerging. Algae are capable of producing lipids and hydrocarbons quickly and their photosynthetic abilities make them a promising candidate for an alternative energy source. In addition, their favorable carbon life cycle and a renewed focus on rural economic development are attractive factors. In this review the focus is mainly on the integrated approach of algae culture for bioremediation and oil-based biofuel production with mention of possible other value-added benefits of using algae for those purposes. PMID- 22230776 TI - Novel modular endo-beta-1,4-xylanase with transglycosylation activity from Cellulosimicrobium sp. strain HY-13 that is homologous to inverting GH family 6 enzymes. AB - The gene (2304-bp) encoding a novel xylanolytic enzyme (XylK2) with a catalytic domain, which is 70% identical to that of Cellulomonas flavigena DSM 20109 GH6 beta-1,4-cellobiohydrolase, was identified from an earthworm (Eisenia fetida) symbiotic bacterium, Cellulosimicrobium sp. strain HY-13. The enzyme consisted of an N-terminal catalytic GH6-like domain, a fibronectin type 3 (Fn3) domain, and a C-terminal carbohydrate-binding module 2 (CBM 2). XylK2DeltaFn3-CBM 2 displayed high transferase activity (788.3 IU mg(-1)) toward p-nitrophenyl (PNP) cellobioside, but did not degrade xylobiose, glucose-based materials, or other PNP-sugar derivatives. Birchwood xylan was degraded by XylK2DeltaFn3-CBM 2 to xylobiose (59.2%) and xylotriose (40.8%). The transglycosylation activity of the enzyme, which enabled the formation of xylobiose (33.6%) and xylotriose (66.4%) from the hydrolysis of xylotriose, indicates that it is not an inverting enzyme but a retaining enzyme. The endo-beta-1,4-xylanase activity of XylK2DeltaFn3-CBM 2 increased significantly by approximately 2.0-fold in the presence of 50mM xylobiose. PMID- 22230777 TI - Production of 2,3-butanediol from acid hydrolysates of Jatropha hulls with Klebsiella oxytoca. AB - Jatropha hulls were successfully for the first time used as raw materials for the production of 2,3-butanediol via dilute sulfuric acid hydrolysis and fermentation with Klebsiella oxytoca. Two-step hydrolysis was used to effectively hydrolyze the hulls at 150 degrees C after pretreatment. In the first-step, hemicellulose was hydrolyzed under mild conditions (0.5h, 1.5% acid) to avoid secondary decomposition. The remained cellulose was further hydrolyzed in the second-step under severer conditions (1h, 4% acid). After hydrolysis, total hydrolysis yield was 64%, which was much higher than that (37%) from the first-step. Maximum yields of 2,3-butanediol and acetoin in flask experiments were 35.6% and 41.4% from the hydrolysates of the first- and second-step hydrolysis, equivalent to 71.2% and 82.8% of the theoretical values, respectively. Similar yields were obtained in a controlled bioreactor but with higher productivities. Jatropha hulls are attractive raw materials for the production of 2,3-butanediol with high yield. PMID- 22230778 TI - Dewatering and granulation of sewage sludge by biophysical drying and thermo degradation performance of prepared sludge particles during succedent fast pyrolysis. AB - A novel two-step technology, fast biophysical drying (BPD) coupling with fast pyrolysis (FP), was investigated for moisture removal and energy recovery from sewage sludge. For BPD, combined operations of extreme thermophilic amendment (with accelerated increasing and controllable maintenance of substrate temperature) and enhanced convective evaporation were conducted, both beneficial for moisture removal (moisture content reaching 23.1% for 7d) and organic preservation. Biophysical-dried sludge (BPDS) was characterized by homogeneous fine-particle morphology and well-developed porous microstructure. The synthesized BPDS particle preserved most organic components (92% volatile matters and 79% HHV of traditional thermal-dried sludge [TTDS]) attributable to the inhibitory effect of BPD adjustment, presenting considerable capacity for subsequent residue-derived energy. For FP, the distribution of products from BPDS pyrolysis indicated that syngas and char yields were higher than those of TTDS. The syngas from BPDS is a type of hydrogen-rich gas composed of 42.6 vol.% H(2) at 900 degrees C. PMID- 22230779 TI - Industrial biotransformations in the synthesis of building blocks leading to enantiopure drugs. AB - Due to the growing demand of enantiomerically pure compounds, as well as the increasing strict safety, quality and environmentally requirements of industrial synthetic processes, the development of more sustainable, healthy and economically attractive strategies for the synthesis of chiral biologically active molecules is still an open challenge in the pharmaceutical industry. In this context, the biotransformations field has emerged as a real alternative to traditional synthetic routes, because of the exquisite chemo-, regio- and enantioselectivities commonly displayed by enzymes; thus, biocatalysis is becoming a widespread methodology for the synthesis of chiral compounds, not only at laboratory scale, but also at industrial scale. As hydrolases and oxido reductases are the most employed enzymes, this review is focused on describing several industrial processes based on the use of these enzymes for obtaining chiral compounds useful for the pharmaceutical industry. PMID- 22230780 TI - Application of the distributed activation energy model to the kinetic study of pyrolysis of the fresh water algae Chlorococcum humicola. AB - Apart from capturing carbon dioxide, fresh water algae can be used to produce biofuel. To assess the energy potential of Chlorococcum humicola, the alga's pyrolytic behavior was studied at heating rates of 5-20K/min in a thermobalance. To model the weight loss characteristics, an algorithm was developed based on the distributed activation energy model and applied to experimental data to extract the kinetics of the decomposition process. When the kinetic parameters estimated by this method were applied to another set of experimental data which were not used to estimate the parameters, the model was capable of predicting the pyrolysis behavior, in the new set of data with a R(2) value of 0.999479. The slow weight loss, that took place at the end of the pyrolysis process, was also accounted for by the proposed algorithm which is capable of predicting the pyrolysis kinetics of C. humicola at different heating rates. PMID- 22230781 TI - Impact of herbicide Ametryn on microbial communities in mixed liquor of a membrane bioreactor (MBR). AB - Ametryn, which is a second generation herbicide, was introduced to a lab-scale MBR at a concentration of 1mg/L and a 20-40% removal was observed at HRT ranging from 7.8 to 15.6h for an average influent Ametryn concentration of 0.8 mg/L. Components of EPS (protein and carbohydrates) increased in the bioreactor and the observed biomass production reduced after the addition of Ametryn. In a batch study, GAC was added to MBR mixed liquor and removal of Ametryn via biodegradation and adsorption were measured. Five common bacterial colony types (Gram negative and positive bacilli and Gram negative cocci) were identified and three of these were resistant to Ametryn up to 5mg/L. GAC was found to be a very effective Ametryn adsorption medium and in some occasions Ametryn may have acted as a nutrient source for bacteria. PMID- 22230782 TI - Population structure and genetic diversity analysis in Gynaikothrips uzeli (Zimerman, 1909) (Thysanoptera: Phlaeothripidae) by RAPD markers. AB - Thrips are small insects (0.5-3.0 mm) with distinct habits and life histories characterized by haplodiploid sex determination. In general, low levels of genetic diversity have been reported in haplodiploid insects, although most reports focus on the order Hymenoptera. Therefore, we used RAPD markers to evaluate the structure and both inter- and intra-population genetic variability of Gynaikothrips uzeli (Thysanoptera: Phlaeothripidae). Six populations, three from Parana state, southern Brazil, and three from Bahia, northeastern Brazil, were studied. Similarly to other haplodiploid insects, the genetic diversity of G. uzeli was reduced. This result is putatively related to the haplodiploid sex determination system, which yields little genetic variation, and to ecological traits of the studied species, such as the low dispersal abilities and life mode in leaf galls. All individuals were homogeneously clustered in their respective collection sites, forming two main groups in which populations from similar environments were more closely related. The analyzed populations were highly structured, and the genetic variation was higher among than within populations. PMID- 22230783 TI - Making sense of postoperative CT imaging following laparoscopic partial nephrectomy. AB - The increasing popularity of laparoscopic partial nephrectomy (LPN) necessitates radiologists to become familiar with the operative techniques as well as normal and abnormal postoperative findings. Due to the varying presentation of abnormal changes following LPN and their similarities with other disease entities, radiologists should be cognizant of common pitfalls to avoid inadvertent misdiagnosis. A few common pitfalls discussed in this paper are the identification of laparoscopic port placement issues, recognizing a myriad of post-surgical materials, differentiating haemostatic materials from postoperative abscess and infection, non-absorbable suture material mimicking rim calcifications, as well as hints for differentiating exuberant granulation tissue from tumour recurrence. PMID- 22230784 TI - Guidelines for the clinical use of 24 hour ambulatory blood pressure monitoring (ABPM) (JCS 2010): - digest version -. PMID- 22230785 TI - [Clinical safety plan in a university hospital complex. Initial diagnosis: study of adverse events]. AB - OBJECTIVES: To establish the incidence of adverse events (AEs) and incidence of patients with AEs in the University Hospital Complex of Albacete (CHUA); to identify and define the AEs which are linked to health care; to analyse avoidable AE and determine their impact; to plan improvement actions. METHOD: . DESIGN: Retrospective cohort study. SAMPLE: Patients registered from 5 November to 19 November, 2007. CASE DEFINITION: Any accident or incident reported in the medical record which injured or may have injured the patient. MATERIAL: Adverse Events Screening Guide, adapted from the Harvard study. Spanish version of the Modular Review Form (MRF2) for retrospective case record review. STATISTICAL ANALYSIS: Univariate and bivariate analysis and logistic regression model. RESULTS: The incidence of patients with AEs linked to hospital care was 6.8%. The incidence was significantly different depending on: age, presence of intrinsic or extrinsic risk factors (excluding peripheral venous catheter); 8.2% of AE was linked to care; 14.3% to medication; 26.5% to nosocomial infections; 35.7% to technical problems in procedures; 11.2% to diagnosis, and the remaining 4.1% to other types of AEs. In these incidences, 12.2% were considered mild, 78.6% moderate and 8.2% serious. Half (50%) of AEs caused an increase in hospital stay, and in 34.7% cases determined hospitalisation. A total of 63.3% of AEs were considered avoidable. CONCLUSIONS: The study of AEs in the CHUA represents an improvement within the hospital quality program. Incidences of patients with AEs and those related to health care fall within the range of those found in the studies where the objective was quality improvement. PMID- 22230786 TI - Functional characterization and oligomerization of a recombinant xyloglucan specific endo-beta-1,4-glucanase (GH12) from Aspergillus niveus. AB - Xyloglucan is a major structural polysaccharide of the primary (growing) cell wall of higher plants. It consists of a cellulosic backbone (beta-1,4-linked glucosyl residues) that is frequently substituted with side chains. This report describes Aspergillus nidulans strain A773 recombinant secretion of a dimeric xyloglucan-specific endo-beta-1,4-glucanohydrolase (XegA) cloned from Aspergillus niveus. The ORF of the A. niveus xegA gene is comprised of 714 nucleotides, and encodes a 238 amino acid protein with a calculated molecular weight of 23.5kDa and isoelectric point of 4.38. The optimal pH and temperature were 6.0 and 60 degrees C, respectively. XegA generated a xyloglucan-oligosaccharides (XGOs) pattern similar to that observed for cellulases from family GH12, i.e., demonstrating that its mode of action includes hydrolysis of the glycosidic linkages between glucosyl residues that are not branched with xylose. In contrast to commercial lichenase, mixed linkage beta-glucan (lichenan) was not digested by XegA, indicating that the enzyme did not cleave glucan beta-1,3 or beta-1,6 bonds. The far-UV CD spectrum of the purified enzyme indicated a protein rich in beta-sheet structures as expected for GH12 xyloglucanases. Thermal unfolding studies displayed two transitions with mid-point temperatures of 51.3 degrees C and 81.3 degrees C respectively, and dynamic light scattering studies indicated that the first transition involves a change in oligomeric state from a dimeric to a monomeric form. Since the enzyme is a predominantly a monomer at 60 degrees C, the enzymatic assays demonstrated that XegA is more active in its monomeric state. PMID- 22230787 TI - Facial nerve palsy in childhood. PMID- 22230788 TI - Identification and characterization of protein glycosylation using specific endo- and exoglycosidases. AB - Glycosylation, the addition of covalently linked sugars, is a major post translational modification of proteins that can significantly affect processes such as cell adhesion, molecular trafficking, clearance, and signal transduction. In eukaryotes, the most common glycosylation modifications in the secretory pathway are additions at consensus asparagine residues (N-linked); or at serine or threonine residues (O-linked) (Figure 1). Initiation of N-glycan synthesis is highly conserved in eukaryotes, while the end products can vary greatly among different species, tissues, or proteins. Some glycans remain unmodified ("high mannose N-glycans") or are further processed in the Golgi ("complex N-glycans"). Greater diversity is found for O-glycans, which start with a common N Acetylgalactosamine (GalNAc) residue in animal cells but differ in lower organisms. The detailed analysis of the glycosylation of proteins is a field unto itself and requires extensive resources and expertise to execute properly. However a variety of available enzymes that remove sugars (glycosidases) makes possible to have a general idea of the glycosylation status of a protein in a standard laboratory setting. Here we illustrate the use of glycosidases for the analysis of a model glycoprotein: recombinant human chorionic gonadotropin beta (hCGbeta), which carries two N-glycans and four O-glycans. The technique requires only simple instrumentation and typical consumables, and it can be readily adapted to the analysis of multiple glycoprotein samples. Several enzymes can be used in parallel to study a glycoprotein. PNGase F is able to remove almost all types of N-linked glycans. For O-glycans, there is no available enzyme that can cleave an intact oligosaccharide from the protein backbone. Instead, O-glycans are trimmed by exoglycosidases to a short core, which is then easily removed by O Glycosidase. The Protein Deglycosylation Mix contains PNGase F, O-Glycosidase, Neuraminidase (sialidase), beta1-4 Galactosidase, and beta-N Acetylglucosaminidase. It is used to simultaneously remove N-glycans and some O glycans. Finally, the Deglycosylation Mix was supplemented with a mixture of other exoglycosidases (alpha-N-Acetylgalactosaminidase, alpha1-2 Fucosidase, alpha1-3,6 Galactosidase, and beta1-3 Galactosidase), which help remove otherwise resistant monosaccharides that could be present in certain O-glycans. SDS PAGE/Coomasie blue is used to visualize differences in protein migration before and after glycosidase treatment. In addition, a sugar-specific staining method, ProQ Emerald-300, shows diminished signal as glycans are successively removed. This protocol is designed for the analysis of small amounts of glycoprotein (0.5 to 2 MUg), although enzymatic deglycosylation can be scaled up to accommodate larger quantities of protein as needed. PMID- 22230789 TI - Treatment of Paget's disease of bone. AB - Paget's disease of bone is the paradigm of bone focal distortion with accelerated bone turnover. Over the years, a number of different drugs have been used to control its activity but, since biphosphonates were introduced for the treatment of the disease, they have become the preferred treatment. This review will update the therapeutic indications, available drugs and therapeutic response monitoring. PMID- 22230794 TI - Aberrant anatomy of the hypoglossal nerve. AB - OBJECTIVE: Variant anatomy of the hypoglossal nerve is very rare. We report an unusual intra-operative finding of an aberrant branch of the hypoglossal nerve, encountered during a facial reanimation procedure. CASE REPORT: A 50-year-old man was referred to the head and neck surgery department by the neurosurgeons for hypoglossal-facial nerve anastomosis to treat his facial paralysis, which had occurred following the removal of an intracranial neoplasm. During surgery, we identified an aberrant branch of the hypoglossal nerve, which took a more ventral and superior course in the carotid triangle, prior to entering the base of the tongue. Following further dissection, we found the main trunk of the 'true' hypoglossal nerve. Several interconnecting strands were seen in the proximal aspect of both the aberrant branch and the main trunk of the hypoglossal nerve. These interconnecting fibres appeared to have tethered the main trunk into an abnormal anatomical position. CONCLUSION: As far as we can ascertain, this is the first report of an aberrant branch of the hypoglossal nerve. Although this variant would appear to be extremely rare, surgeons must consider all variations of this nerve during head and neck procedures, in order to minimise iatrogenic complications. PMID- 22230793 TI - Molecular basis of essential amino acid transport from studies of insect nutrient amino acid transporters of the SLC6 family (NAT-SLC6). AB - Two protein families that represent major components of essential amino acid transport in insects have been identified. They are annotated as the SLC6 and SLC7 families of transporters according to phylogenetic proximity to characterized amino acid transporters (HUGO nomenclature). Members of these families have been identified as important apical and basolateral parts of transepithelial essential amino acid absorption in the metazoan alimentary canal. Synergistically, they play critical physiological roles as essential substrate providers to diverse metabolic processes, including generic protein synthesis. This review briefly clarifies the requirements for amino acid transport and a variety of amino acid transport mechanisms, including the aforementioned families. Further it focuses on the large group of Nutrient Amino acid Transporters (NATs), which comprise a recently identified subfamily of the Neurotransmitter Sodium Symporter family (NSS or SLC6). The first insect NAT, cloned from the caterpillar gut, has a broad substrate spectrum similar to mammalian B(0) transporters. Several new NAT-SLC6 members have been characterized in an effort to explore mechanisms for the essential amino acid absorption in model dipteran insects. The identification and functional characterization of new B(0)-like and narrow specificity transporters of essential amino acids in fruit fly and mosquitoes leads to a fundamentally important insight: that NATs evolved and act together as the integrated active core of a transport network that mediates active alimentary absorption and systemic distribution of essential amino acids. This role of NATs is projected from the most primitive prokaryotes to the most complex metazoan organisms, and represents an interesting platform for unraveling the molecular evolution of amino acid transport and modeling amino acid transport disorders. The comparative study of NATs elucidates important adaptive differences between essential amino acid transportomes of invertebrate and vertebrate organisms, outlining a new possibility for selective targeting of essential amino acid absorption mechanisms to control medically and economically important arthropods and other invertebrate organisms. PMID- 22230795 TI - Androgen receptor signalling in Vascular Endothelial cells is dispensable for spermatogenesis and male fertility. AB - BACKGROUND: Androgen signalling is essential both for male development and function of the male reproductive system in adulthood. Within the adult testis, Germ cells (GC) do not express androgen receptor (AR) suggesting androgen mediated promotion of spermatogenesis must act via AR-expressing somatic cell types. Several recent studies have exploited the Cre/lox system of conditional gene-targeting to ablate AR function from key somatic cell-types in order to establish the cell-specific role of AR in promotion of male fertility. In this study, we have used a similar approach to specifically ablate AR-signalling from Vascular Endothelial (VE) cells, with a view to defining the significance of androgen signalling within this cell-type on spermatogenesis. FINDINGS: AR expression in VE cells of the testicular vasculature was confirmed using an antibody against AR. A Cre-inducible fluorescent reporter line was used to empirically establish the utility of a mouse line expressing Cre Recombinase driven by the Tie2-Promoter, for targeting VE cells. Immunofluorescent detection revealed expression of YFP (and therefore Cre Recombinase function) limited to VE cells and an interstitial population of cells, believed to be macrophages, that did not express AR. Mating of Tie2-Cre males to females carrying a floxed AR gene produced Vascular Endothelial Androgen Receptor Knockout (VEARKO) mice and littermate controls. Ablation of AR from all VE cells was confirmed; however, no significant differences in bodyweight or reproductive tissue weights could be detected in VEARKO animals and spermatogenesis and fertility was unaffected. CONCLUSIONS: We demonstrate the successful generation and empirical validation of a cell-specific knockout of AR from VE cells, and conclude that AR expression in VE cells is not essential for spermatogenesis or male fertility. PMID- 22230796 TI - Use of ChIP-Seq data for the design of a multiple promoter-alignment method. AB - We address the challenge of regulatory sequence alignment with a new method, Pro Coffee, a multiple aligner specifically designed for homologous promoter regions. Pro-Coffee uses a dinucleotide substitution matrix estimated on alignments of functional binding sites from TRANSFAC. We designed a validation framework using several thousand families of orthologous promoters. This dataset was used to evaluate the accuracy for predicting true human orthologs among their paralogs. We found that whereas other methods achieve on average 73.5% accuracy, and 77.6% when trained on that same dataset, the figure goes up to 80.4% for Pro-Coffee. We then applied a novel validation procedure based on multi-species ChIP-seq data. Trained and untrained methods were tested for their capacity to correctly align experimentally detected binding sites. Whereas the average number of correctly aligned sites for two transcription factors is 284 for default methods and 316 for trained methods, Pro-Coffee achieves 331, 16.5% above the default average. We find a high correlation between a method's performance when classifying orthologs and its ability to correctly align proven binding sites. Not only has this interesting biological consequences, it also allows us to conclude that any method that is trained on the ortholog data set will result in functionally more informative alignments. PMID- 22230797 TI - New oral solid dosage form for furosemide oral administration. AB - Furosemide (FURO) is a drug labeled in class IV of the Biopharmaceutics Classification System (BCS) as it is both poor soluble and poor permeable. The aim of this work was to improve FURO biopharmaceutical properties by its formulation in a new solid oral dosage form. It consists in the realization of the composite MgAl-HTlc-FURO, obtained by FURO intercalation into the inorganic matrix hydrotalcite (MgAl-HTlc), and its successive formulation in tablets intended to be swallowed whole and to disintegrate rapidly in the stomach. These formulations were prepared by direct compression of a simple powder mixture constituted by MgAl-HTlc-FURO, a super disintegrant (Explotab, PolyplasdoneXL, PolyplasdoneXL-10, PolyplasdoneINF 10 or L-HPCLH-21) and a filler. The prepared formulations were submitted to disintegration time tests, and only those displaying the lowest disintegration time in gastric medium were submitted to in vitro release studies. Drug dissolution profiles from MgAl-HTlc-FURO tablets were compared with those containing crystalline FURO alone or physically mixed to MgAl HTlc instead of MgAl-HTlc-FURO. The results revealed that tablets containing MgAl HTlc-FURO give the best dissolution profile and that L-HPCLH-21 is able to promote the highest drug release in gastric medium, resulting in the most suitable super disintegrant in comparison with the other tested. PMID- 22230798 TI - Mechanistic modelling of the drying behaviour of single pharmaceutical granules. AB - The trend to move towards continuous production processes in pharmaceutical applications enhances the necessity to develop mechanistic models to understand and control these processes. This work focuses on the drying behaviour of a single wet granule before tabletting, using a six-segmented fluidised bed drying system, which is part of a fully continuous from-powder-to-tablet manufacturing line. The drying model is based on a model described by Mezhericher et al. and consists of two submodels. In the first drying phase (submodel 1), the surface water evaporates, while in the second drying phase (submodel 2), the water inside the granule evaporates. The second submodel contains an empirical power coefficient, beta. A sensitivity analysis was performed to study the influence of parameters on the moisture content of single pharmaceutical granules, which clearly points towards the importance of beta on the drying behaviour. Experimental data with the six-segmented fluidised bed dryer were collected to calibrate beta. An exponential dependence on the drying air temperature was found. Independent experiments were done for the validation of the drying model. PMID- 22230799 TI - Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies. AB - Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest. PMID- 22230801 TI - Mindfulness, body image, and drive for muscularity in men. AB - Studies have shown that dispositional mindfulness, a construct characterized by awareness and attention to present moment experiences, is associated with body image constructs in women. However, little is known about the relationship between dispositional mindfulness and body image among men. Therefore, this study examined the unique associations between dispositional mindfulness and three body image variables in men: overall appearance evaluation, satisfaction with distinct body areas, and drive for muscularity. Undergraduate men (N=296) completed the Multidimensional Body Self-Relations Questionnaire-Appearance Scales, the Drive for Muscularity Scale, the Mindful Attention Awareness Scale, and the Positive and Negative Affect Schedule. A series of hierarchical regression analyses revealed that mindfulness was uniquely associated with all three body image variables after accounting for body mass index and negative affect. Results are discussed with regard to the potential role of dispositional mindfulness in body dissatisfaction among men. PMID- 22230800 TI - Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia. AB - Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naive patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naive patients with Ph+ ALL. PMID- 22230802 TI - Assessment of the stereoselective fungal biotransformation of albendazole and its analysis by HPLC in polar organic mode. AB - A high-performance liquid chromatographic method using polar organic mode was developed to analyze albendazole (ABZ), albendazole sulfone (ABZSO(2)) and the chiral and active metabolite albendazole sulfoxide (ABZSOX, ricobendazole) that was further applied in stereoselective fungal biotransformation studies. The chromatographic separation was performed on a Chiralpak AS column using acetonitrile:ethanol (97:3, v/v) plus 0.2% triethylamine and 0.2% acetic acid as the mobile phase at a flow rate of 0.5 mL min(-1). The present study employed hollow fiber liquid-phase microextraction as sample preparation. The method showed to be linear over the concentration range of 25-5000 ng mL(-1) for each ABZSOX enantiomer, 200-10,000 ng mL(-1) for ABZ and 50-1000 ng mL(-1) for ABZSO(2) metabolite with correlation coefficient (r)>0.9934. The mean recoveries for ABZ, rac-ABZSOX and ABZSO(2) were, respectively, 9%, 33% and 20% with relative standard deviation below 10%. Within-day and between-day precision and accuracy assays for these analytes were studied at three concentration levels and were lower than 15%. This study opens the door regarding the possibility of using fungi in obtaining of the active metabolite ricobendazole. Nigrospora sphaerica (Sacc.) E. W. Mason (SS67), Pestalotiopsis foedans (VR8), Papulaspora immersa Hotson (SS13) and Mucor rouxii were able to stereoselectively metabolize ABZ into its chiral metabolite. Among them, the fungus Mucor rouxii was the most efficient in the production of (+)-ABZSOX. PMID- 22230803 TI - Selection of Plasmodium falciparum parasites for cytoadhesion to human brain endothelial cells. AB - Most human malaria deaths are caused by blood-stage Plasmodium falciparum parasites. Cerebral malaria, the most life-threatening complication of the disease, is characterised by an accumulation of Plasmodium falciparum infected red blood cells (iRBC) at pigmented trophozoite stage in the microvasculature of the brain(2-4). This microvessel obstruction (sequestration) leads to acidosis, hypoxia and harmful inflammatory cytokines (reviewed in (5)). Sequestration is also found in most microvascular tissues of the human body(2, 3). The mechanism by which iRBC attach to the blood vessel walls is still poorly understood. The immortalized Human Brain microvascular Endothelial Cell line (HBEC-5i) has been used as an in vitro model of the blood-brain barrier(6). However, Plasmodium falciparum iRBC attach only poorly to HBEC-5i in vitro, unlike the dense sequestration that occurs in cerebral malaria cases. We therefore developed a panning assay to select (enrich) various P. falciparum strains for adhesion to HBEC-5i in order to obtain populations of high-binding parasites, more representative of what occurs in vivo. A sample of a parasite culture (mixture of iRBC and uninfected RBC) at the pigmented trophozoite stage is washed and incubated on a layer of HBEC-5i grown on a Petri dish. After incubation, the dish is gently washed free from uRBC and unbound iRBC. Fresh uRBC are added to the few iRBC attached to HBEC-5i and incubated overnight. As schizont stage parasites burst, merozoites reinvade RBC and these ring stage parasites are harvested the following day. Parasites are cultured until enough material is obtained (typically 2 to 4 weeks) and a new round of selection can be performed. Depending on the P. falciparum strain, 4 to 7 rounds of selection are needed in order to get a population where most parasites bind to HBEC-5i. The binding phenotype is progressively lost after a few weeks, indicating a switch in variant surface antigen gene expression, thus regular selection on HBEC-5i is required to maintain the phenotype. In summary, we developed a selection assay rendering P. falciparum parasites a more "cerebral malaria adhesive" phenotype. We were able to select 3 out of 4 P. falciparum strains on HBEC-5i. This assay has also successfully been used to select parasites for binding to human dermal and pulmonary endothelial cells. Importantly, this method can be used to select tissue-specific parasite populations in order to identify candidate parasite ligands for binding to brain endothelium. Moreover, this assay can be used to screen for putative anti-sequestration drugs(7). PMID- 22230804 TI - Opioids added to local anesthetics for single-shot intrathecal anesthesia in patients undergoing minor surgery: a meta-analysis of randomized trials. AB - Opioids are widely used as additives to local anesthetics for intrathecal anesthesia. Benefit and risk remain unclear. We systematically searched databases and bibliographies to February 2011 for full reports of randomized comparisons of any opioid added to any intrathecal local anesthetic with the local anesthetic alone in adults undergoing surgery (except cesarean section) and receiving single shot intrathecal anesthesia without general anesthesia. We included 65 trials (3338 patients, 1932 of whom received opioids) published between 1983 and 2010. Morphine (0.05-2mg) and fentanyl (10-50 MUg) added to bupivacaine were the most frequently tested. Duration of postoperative analgesia was prolonged with morphine (weighted mean difference 503 min; 95% confidence interval [CI] 315 to 641) and fentanyl (weighted mean difference 114 min; 95% CI 60 to 168). Morphine decreased the number of patients needing opioid analgesia after surgery and decreased pain intensity to the 12th postoperative hour. Morphine increased the risk of nausea (number needed to harm [NNH] 9.9), vomiting (NNH 10), urinary retention (NNH 6.5), and pruritus (NNH 4.4). Fentanyl increased the risk of pruritus (NNH 3.3). With morphine 0.05 to 0.5mg, the NNH for respiratory depression varied between 38 and 59 depending on the definition of respiratory depression chosen. With fentanyl 10 to 40 MUg, the risk of respiratory depression was not significantly increased. For none of these effects, beneficial or harmful, was there evidence of dose-responsiveness. Consequently, minimal effective doses of intrathecal morphine and fentanyl should be sought. For intrathecal buprenorphine, diamorphine, hydromorphone, meperidine, methadone, pentazocine, sufentanil, and tramadol, there were not enough data to allow for meaningful conclusions. PMID- 22230805 TI - Neural correlates of fear of movement in high and low fear-avoidant chronic low back pain patients: an event-related fMRI study. AB - The fear-avoidance model postulates that in chronic low back pain (CLBP) a fear of movement is acquired in the acute phase, which leads to subsequent avoidance of physical activity and contributes to the pain syndrome's becoming chronic. In the present event-related functional magnetic resonance imaging (fMRI) study of the neural correlates of the fear of movement, 60 women (30 CLBP patients, 15 healthy controls, and 15 women with spider phobia; mean age 46.8+/-9.8 years) participated. The CLBP patients were divided into a high and low fear-avoidant group on the basis of the Tampa Scale of Kinesiophobia. The participants viewed photographs depicting neutral and aversive (back-stressing) movements, generally fear-inducing and neutral pictures from the International Affective Picture System, and pictures of spiders while fMRI data were acquired. It was hypothesized that the high fear-avoidant CLBP patients would show fear-related activations when viewing the aversive movements and that they would differ from CLBP patients with low fear-avoidance and controls in this regard. No such activations were found for high or low fear-avoidant CLBP patients. The random effects analysis showed no differences between high and low fear-avoidant CLBP patients or high fear-avoidant CLBP patients and controls. Normal fear-related activations were present in the high fear-avoidant CLBP patients for the generally fear-inducing pictures, demonstrating the validity of the stimulation paradigm and a generally unimpaired fear processing of the high fear-avoidant CLBP patients. Our findings do not support the fear component of the fear avoidance model. PMID- 22230806 TI - Proteomic characterization in the hippocampus of prenatally stressed rats. AB - Rats exposed to early life stress are considered as a valuable model for the study of epigenetic programming leading to mood disorders and anxiety in the adult life. Rats submitted to prenatal restraint stress (PRS) are characterized by an anxious/depressive phenotype associated with neuroadaptive changes in the hippocampus. We used the model of PRS to identify proteins that are specifically affected by early life stress. We therefore performed a proteomic analysis in the hippocampus of adult male PRS rats. We found that PRS induced changes in the expression profile of a number of proteins, involved in the regulation of signal transduction, synaptic vesicles, protein synthesis, cytoskeleton dynamics, and energetic metabolism. Immunoblot analysis showed significant changes in the expression of proteins, such as LASP-1, fascin, and prohibitin, which may lie at the core of the developmental programming triggered by early life stress. PMID- 22230807 TI - Increased expression and phosphorylation of the two S100A9 isoforms in mononuclear cells from patients with systemic lupus erythematosus: a proteomic signature for circulating low-density granulocytes. AB - Proteins differentially expressed in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients versus Normal controls were identified by 2-DE and MALDI-MS. Thus, S100A9 expression was significantly increased in SLE PBMCs relative to Normal PBMCs at both mRNA and protein levels. Increased S100A9 levels in SLE PBMCs correlated positively with the abnormal presence of low-density granulocytes (LDGs) detected by flow-cytometry in the mononuclear cell fractions. Another set of proteins that were differentially expressed in SLE PBMCs formed S100A9-independent clusters, suggesting that these differences in protein expression are in fact reflecting changes in the abundance of specific cell types. In SLE PBMCs spots of the two S100A9 isoforms, S100A9-l and S100A9-s, and their phosphorylated counterparts were identified and confirmed to be phosphorylated at Thr(113) by MS/MS analyses. In addition, the phorbol ester PMA alone or in combination with ionomycin induced a stronger increase in threonine phosphorylation of S100A9 in SLE than in Normal PBMCs, while the same stimuli caused the opposite effect on phosphorylation and activation of Erk1/2, suggesting the existence of an abnormal S100A9 signaling in SLE PBMCs. Therefore, the expansion and activation of LDGs in SLE seems to underlie this prominent S100A9 signature. PMID- 22230808 TI - Ginger Rogers? No, Ginger Ale and its invisible proteome. AB - The trace proteome of a Ginger drink, stated to be produced with a ginger root extract, has been investigated via capture with combinatorial peptide ligand libraries (ProteoMiner). Although in traces, we could confirm the presence of five grape proteins and one apple protein, but not even the faintest trace of any ginger root proteins. The first two findings are correct, as the producer stated that this beverage had been reinforced with 12% grape juice and 6% apple juice, but the absence of even traces of ginger proteins does not permit the classification of this beverage as a ginger extract on a proteomics scale. However, organoleptic tasting has confirmed the presence of a ginger extract, due to its piquant and tongue-biting taste. Nevertheless, any ginger root extract must be considered as a minor component as compared to the presence of grape and apple juice. At the light of these findings, it is hoped that the competent authorities will in the future make compulsory the proper labelling also of beverages so that all amounts of compounds utilized will be clearly stated in the label, including the presumptive main component. PMID- 22230809 TI - Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity. AB - Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI >= 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 +/- 0.32% to 6.97 +/- 0.20%; from 147.4 +/- 7.3mg/dL to 127.0 +/- 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and DeltaHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, DeltaCA and DeltaCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of beta cell function, i.e. HOMA-beta, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced beta cell activity rather than improved insulin resistance. PMID- 22230810 TI - Three single nucleotide variants of the SIRT1 gene are associated with overweight in a Chinese population: a case control study. AB - We aimed to explore whether common allelic variations in the SIRT1 gene were associated with excess body weight in a Chinese cohort. Using standard molecular techniques 820 non-diabetic individuals, some of who were classified as overweight (> 23 Kg/m(2)), were genotyped for four haplotype-tagged single nucleotide polymorphisms. The rs10509291AA and rs10823116GG genotypes were associated with high body mass index (BMI) > 23 Kg/m(2), and the rs7894483TT genotype was associated with lower BMI (< 23 Kg/m(2)). The rs10509291AT genotype was associated with a modestly higher risk of being overweight, consistent with the presence of an rs10509291A being a dominant or semi-dominant allele. The ATAA (rs7894483/rs10823116) and ATAG haplotypes were associated with a higher risk of being overweight (OR: 17.11 and 5.12) compared with the AAAG haplotype (P <0.01). Thus, the rs10509291, rs7894483, and rs10823116 alleles were associated with a high BMI (> 23 Kg/m(2)) and with overweight in this non-diabetic Chinese population. PMID- 22230811 TI - Resting energy expenditure in short-stature children. AB - It is not clear what dietary intake standards should be used for children with abnormal body size. To investigate the energy requirements of short-stature children with no underlying diseases, their resting energy requirements (REE) were measured by indirect calorimetry. The short-stature group consisted of 30 prepubertal children with short stature and with no underlying diseases (age 6y+/ 2) and the control group consisted of 13 age-matched children with standard stature. Fasting REE and the respiration quotient (RQ) with subjects in the supine position were measured by canopy indirect calorimetry. Actual measurements and body-size-adjusted REEs were compared between the groups. Also, REE measurements were compared with the basal metabolic rate (BMR) calculated using the Dietary Reference Intakes for Japanese (Dietary Reference Intakes). REE in the control group was significantly higher than that in the short-stature group. However, body-size-adjusted REEs were significantly higher for the short stature group. When the actual REE was compared with the calculated BMR within both the control group and the short-stature group, which was acquired using the Dietary Reference Intakes, there was no difference within the control group but the actual REE measurements were significantly higher than the calculated BMR in the short-stature group. The same pattern was seen within the short-stature group when subjects were matched for height. There were no significant differences in RQ between the two groups. PMID- 22230812 TI - State-of-the-art vitamin D assays: a comparison of automated immunoassays with liquid chromatography-tandem mass spectrometry methods. AB - BACKGROUND: Vitamin D testing is increasing worldwide. Recently several diagnostic manufacturers including Abbott and Siemens have launched automated 25 hydroxy vitamin D (25OH-D) immunoassays. Furthermore, preexisting assays from DiaSorin and Roche have recently been modified. We compared the performance of 5 automated immunoassays, an RIA and 2 liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. METHODS: Aliquots of 170 randomly selected patient samples were prepared and 25OH-D was measured by 2 LC-MS/MS methods, an RIA (DiaSorin), and automated immunoassays from Abbott (Architect), DiaSorin (LIAISON), IDS (ISYS), Roche (E170, monoclonal 25OH-D(3) assay), and Siemens (Centaur). Within-run and between-run imprecision were evaluated by measurement of 5 replicates of 2 serum pools on 5 consecutive days. RESULTS: The LC-MS/MS methods agreed, with a concordance correlation coefficient (CCC) of 0.99 and bias of 0.56 MUg/L (1.4 nmol/L). The RIA assay showed a performance comparable to LC MS/MS, with a CCC of 0.97 and a mean bias of 1.1 MUg/L (2.7 nmo/L). All immunoassays measured total 25OH-D (including D(3) and D(2)), with the exception of the Roche assay (D(3) only). Among the immunoassays detecting total 25OH-D, the CCCs varied between 0.85 (Abbott) to 0.95 (LIAISON). The mean bias ranged between 0.2 MUg/L (0.5 nmol/L) (LIAISON) and 4.56 MUg/L (11.4 nmol/L) (Abbott). The Roche 25OH-D(3) assay demonstrated small mean bias [-2.7 MUg/L (-6.7 nmol/L)] [-2.7 MUg/L (-6.7 nmol/L)] but a low CCC of just 0.66. Most assays demonstrated good intra- and interassay precision, with CV <10%. CONCLUSIONS: Automated immunoassays demonstrated variable performance and not all tests met our minimum performance goals. It is important that laboratories be aware of the limitations of their assay. PMID- 22230813 TI - Development and laboratory evaluation of two lateral flow devices for the detection of vesicular stomatitis virus in clinical samples. AB - Two lateral flow devices (LFD) for the detection of vesicular stomatitis (VS) virus (VSV), types Indiana (VSV-IND) and New Jersey (VSV-NJ) were developed using monoclonal antibodies C1 and F25VSVNJ-45 to the respective VSV serotypes. The performance of the LFDs was evaluated in the laboratory on suspensions of vesicular epithelia and cell culture passage derived supernatants of VSV. The collection of test samples included 105 positive for VSV-IND (92 vesicular epithelial suspensions and 13 cell culture antigens; encompassing 93 samples of subtype 1 [VSV-IND-1], 9 of subtype 2 [VSV-IND-2] and 3 of subtype 3 [VSV-IND-3]) and 189 positive for VSV-NJ (162 vesicular epithelial suspensions and 27 cell culture antigens) from suspected cases of vesicular disease in cattle and horses collected from 11 countries between 1937 and 2008 or else were derived from experimental infection and 777 samples that were either shown to be positive or negative for foot-and-mouth disease (FMD) virus (FMDV) and swine vesicular disease virus (SVDV) or else collected from healthy cattle or pigs and collected from 68 countries between 1965 and 2011. The diagnostic sensitivity of the VSV IND (for reaction with VSV-IND-1) and VSV-NJ LFDs was either similar or identical at 94.6% (VSV-IND) and 97.4% (VSV-NJ) compared to 92.5% and 97.4% obtained by the reference method of antigen ELISA. The VSV-IND LFD failed to react with viruses of VSV-IND-2 and 3, while the VSV-NJ device recognized all VSV-NJ virus strains. The diagnostic specificities of the VSV-IND and VSV-NJ LFDs were 99.1% and 100, respectively, compared to 99.6% and 99.8% for the ELISA. Reactions with FMDV which can produce indistinguishable syndromes clinically in cattle, pigs and sheep and SVDV (vesicular disease in pigs) did not occur. These data illustrate the potential for the LFDs to be used next to the animal for providing rapid and objective support to veterinarians in their clinical judgment of vesicular disease and for the subtype (VSV-IND-1) and type-specific (VSV-NJ) pen-side diagnosis of VS and differential diagnosis from FMD. PMID- 22230814 TI - DNA polymorphisms of the KiSS1 3' untranslated region interfere with the folding of a G-rich sequence into G-quadruplex. AB - KISS1R and its ligand, the kisspeptins, are key hypothalamic factors that regulate GnRH hypothalamic secretion and therefore the pubertal timing. During studies analysing KiSS1 as a candidate gene in pubertal onset disorders, two SNP and one nucleotide insertion were observed in a 23 nucleotides G-rich sequence located 65 nucleotides downstream of the stop codon. The polymorphisms formed four haplotypes. Biophysical experiments revealed the ability of this G-rich sequence to fold into G-quadruplex structures and demonstrated that the three DNA polymorphisms did not perturb the folding into G-quadruplex but affected G quadruplex conformation. A functional luciferase reporter-based assay revealed functional differences between 3'UTR haplotypes. These data show that polymorphisms in a G-rich sequence of the 3'UTR of KISS1, able to fold into G quadruplex structures, can modulate gene expression. They highlight the potential role of this G-quadruplex in the regulation of KISS1 expression and in the timing of pubertal onset. PMID- 22230815 TI - Impact of estradiol, ER subtype specific agonists and genistein on energy homeostasis in a rat model of nutrition induced obesity. AB - Estrogens are known to be involved in the control of energy homeostasis. Here we investigated the role of ER alpha and ER beta in a model of nutrition induced obesity. Ovariectomized Wistar rats were fed a high fat diet and received either vehicle, E2, ER subtype selective agonists (Alpha and Beta) or genistein. After 10 weeks, body weight, visceral fat, serum leptin, blood lipids, and in the soleus muscle anabolic markers were determined. Treatment with E2 and Alpha decreased body weight, total cholesterol and VLDL. Visceral fat mass, adipocyte size, and serum leptin were reduced by E2, Alpha and Beta. In the soleus muscle, treatment with E2 and Beta modulated Igf1 and Pax7 gene expression and resulted in larger muscle fibers. Our data indicate that blood lipids are affected via ER alpha, whereas activation of ER beta results in an increase of soleus muscle mass. Adipose tissue homeostasis seems to be affected via both ERs. PMID- 22230816 TI - RNA stability: Remember your driver. PMID- 22230818 TI - Small RNAs: Little transgressions. PMID- 22230817 TI - Computer simulations: tools for population and evolutionary genetics. AB - Computer simulations are excellent tools for understanding the evolutionary and genetic consequences of complex processes whose interactions cannot be analytically predicted. Simulations have traditionally been used in population genetics by a fairly small community with programming expertise, but the recent availability of dozens of sophisticated, customizable software packages for simulation now makes simulation an accessible option for researchers in many fields. The in silico genetic data produced by simulations, along with greater availability of population-genomics data, are transforming genetic epidemiology, anthropology, evolutionary and population genetics and conservation. In this Review of the state-of-the-art of simulation software, we identify applications of simulations, evaluate simulator capabilities, provide a guide for their use and summarize future directions. PMID- 22230819 TI - Awareness of vitamin D deficiency among at-risk patients. AB - BACKGROUND: Vitamin D deficiency is a significant problem for a growing proportion of the UK population. Individuals with dark or covered skin are at particularly high risk due to ethno-cultural, environmental and genetic factors. We assessed the level of awareness of vitamin D deficiency among at-risk patients in order to identify groups most in need of education. FINDINGS: A cross sectional survey using a piloted questionnaire was conducted among consecutive at risk patients without a diagnosis of Vitamin D deficiency arriving at a large inner city general practice in the North West of England over a five day period. The survey was completed by 221 patients. The mean age was 35 years. 28% of them (n = 61) had never heard about vitamin D. Older patients (p = 0.003) were less likely to have heard about vitamin D. 54% of participants were unaware of the commonest symptoms of vitamin D deficiency. 34% did not expose their skin other than their face in the last one year, and 11% did not include vitamin D rich foods in their diet. CONCLUSION: The majority of at-risk patients are aware of vitamin D; nevertheless, there is a significant lack of knowledge among older people, who have higher morbidity. A programme of targeted education of the at risk population is recommended. PMID- 22230824 TI - Simplifying care for complex patients. PMID- 22230825 TI - Treatment adjustment and medication adherence for complex patients with diabetes, heart disease, and depression: a randomized controlled trial. AB - PURPOSE: Medication nonadherence, inconsistent patient self-monitoring, and inadequate treatment adjustment exacerbate poor disease control. In a collaborative, team-based, care management program for complex patients (TEAMcare), we assessed patient and physician behaviors (medication adherence, self-monitoring, and treatment adjustment) in achieving better outcomes for diabetes, coronary heart disease, and depression. METHODS: A randomized controlled trial was conducted (2007-2009) in 14 primary care clinics among 214 patients with poorly controlled diabetes (glycated hemoglobin [HbA(1c)] >=8.5%) or coronary heart disease (blood pressure >140/90 mm Hg or low-density lipoprotein cholesterol >130 mg/dL) with coexisting depression (Patient Health Questionnaire-9 score >=10). In the TEAMcare program, a nurse care manager collaborated closely with primary care physicians, patients, and consultants to deliver a treat-to-target approach across multiple conditions. Measures included medication initiation, adjustment, adherence, and disease self-monitoring. RESULTS: Pharmacotherapy initiation and adjustment rates were sixfold higher for antidepressants (relative rate [RR] = 6.20; P <.001), threefold higher for insulin (RR = 2.97; P <.001), and nearly twofold higher for antihypertensive medications (RR = 1.86, P <.001) among TEAMcare relative to usual care patients. Medication adherence did not differ between the 2 groups in any of the 5 therapeutic classes examined at 12 months. TEAMcare patients monitored blood pressure (RR = 3.20; P <.001) and glucose more frequently (RR = 1.28; P = .006). CONCLUSIONS: Frequent and timely treatment adjustment by primary care physicians, along with increased patient self-monitoring, improved control of diabetes, depression, and heart disease, with no change in medication adherence rates. High baseline adherence rates may have exerted a ceiling effect on potential improvements in medication adherence. PMID- 22230826 TI - Integrated management of type 2 diabetes mellitus and depression treatment to improve medication adherence: a randomized controlled trial. AB - PURPOSE: Depression commonly accompanies diabetes, resulting in reduced adherence to medications and increased risk for morbidity and mortality. The objective of this study was to examine whether a simple, brief integrated approach to depression and type 2 diabetes mellitus (type 2 diabetes) treatment improved adherence to oral hypoglycemic agents and antidepressant medications, glycemic control, and depression among primary care patients. METHODS: We undertook a randomized controlled trial conducted from April 2010 through April 2011 of 180 patients prescribed pharmacotherapy for type 2 diabetes and depression in primary care. Patients were randomly assigned to an integrated care intervention or usual care. Integrated care managers collaborated with physicians to offer education and guideline-based treatment recommendations and to monitor adherence and clinical status. Adherence was assessed using the Medication Event Monitoring System (MEMS). We used glycated hemoglobin (HbA(1c)) assays to measure glycemic control and the 9-item Patient Health Questionnaire (PHQ-9) to assess depression. RESULTS: Intervention and usual care groups did not differ statistically on baseline measures. Patients who received the intervention were more likely to achieve HbA(1c) levels of less than 7% (intervention 60.9% vs. usual care 35.7%; P < .001) and remission of depression (PHQ-9 score of less than 5: intervention 58.7% vs. usual care 30.7%; P < .001) in comparison with patients in the usual care group at 12 weeks. CONCLUSIONS: A randomized controlled trial of a simple, brief intervention integrating treatment of type 2 diabetes and depression was successful in improving outcomes in primary care. An integrated approach to depression and type 2 diabetes treatment may facilitate its deployment in real world practices with competing demands for limited resources. PMID- 22230828 TI - Primary care attributes and mortality: a national person-level study. AB - PURPOSE: Research demonstrates an association between the geographic concentration of primary care clinicians and mortality in the area, but there is limited evidence of a mortality benefit of primary care at the individual patient level. We examined whether patient-reported access to selected primary care attributes, including some emphasized in the medical home literature, is associated with lower individual mortality risk. METHODS: We analyzed data from 2000-2005 Medical Expenditure Panel Survey respondents aged 18 to 90 years (N = 52,241), linked to the National Death Index through 2006. A score was constructed from 5 yes/no items assessing whether the respondent's usual source of care had 3 attributes: comprehensiveness, patient-centeredness, and enhanced access. Scores ranged from 0 to 1 (higher scores = more attributes). We examined the association between the primary care attributes score and mortality during up to 6 years of follow-up using Cox survival analysis, adjusted for social, demographic, and health-related characteristics. RESULTS: Racial/ethnic minorities, poorer and less educated persons, individuals without private insurance, healthier persons, and residents of regions other than the Northeast reported less access to primary care attributes than others. The primary care attributes score was inversely associated with mortality (adjusted hazard ratio = 0.79; 95% confidence interval, 0.64-0.98; P = .03); supplementary analyses showed mortality decreased linearly with increasing score. CONCLUSIONS: Greater reported patient access to selected primary care attributes was associated with lower mortality. The findings support the current interest in ensuring that patients have access to a medical home encompassing these attributes. PMID- 22230829 TI - Reimbursement restriction and moderate decrease in benzodiazepine use in general practice. AB - PURPOSE: To limit misuse and save costs, on January 1, 2009, benzodiazepines were excluded from the Dutch reimbursement list when used as anxiolytic, hypnotic, or sedative. This study aims to assess the impact of this reimbursement restriction on benzodiazepine use in patients with newly diagnosed anxiety or sleeping disorder in general practice. METHODS: Was conducted a retrospective observational database study deriving data on diagnoses and prescriptions from the electronic health records-based Netherlands Information Network of General Practice (LINH). We looked for patients aged 18 years and older with an incident diagnosis of sleeping disturbance (International Classification of Primary Care code: P06) or anxiety (P74, P01) between January 2008 and December 2009. Incidence of these diagnoses, benzodiazepine use, and initiation of selective serotonin reuptake inhibitor (SSRI) treatment was compared between 2008 and 2009. RESULTS: In total, we identified 13,596 patients with an incident diagnosis of anxiety (3,769 in 2008 and 3,710 in 2009) or sleeping disorder (3,254 in 2008 and 2,863 in 2009). The proportion of patients being prescribed a benzodiazepine after a diagnosis was lower in 2009 than in 2008 for both anxiety (30.1% vs. 33.7% P < .05) and sleeping disorder (59.1% vs. 67.0%, P < .05), as was the proportion of patients with more than 1 benzodiazepine prescription for both anxiety (36.4% vs. 42.6%, P < .05) and sleeping disorder (35.0% vs. 42.6%, P < .05). We found no increase in the use of alternative treatment for anxiety with SSRIs. CONCLUSIONS: The reimbursement restriction has led to a moderate decrease in the number of incident diagnoses and initiation of benzodiazepine use in patients with newly diagnosed anxiety or sleeping disorder. This finding indicates that in settings where no such reimbursement opportunities exist, physicians have room to reduce benzodiazepine prescribing. PMID- 22230827 TI - Depression treatment in patients with general medical conditions: results from the CO-MED trial. AB - PURPOSE: We studied the effect of 3 antidepressant treatments on outcomes (depressive severity, medication tolerability, and psychosocial functioning) in depressed patients having comorbid general medical conditions in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. METHODS: Adult outpatients who had chronic and/or recurrent major depressive disorder (MDD) with and without general medical conditions were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram plus placebo, (2) bupropion-SR plus escitalopram, or (3) venlafaxine XR plus mirtazapine. At weeks 12 and 28, we compared response and tolerability between participants with 0, 1, 2, and 3 or more general medical conditions. RESULTS: Of the 665 evaluable patients, 49.5% reported having no treated general medical conditions, 23.8% reported having 1, 14.8% reported having 2, and 11.9% reported having at least 3. We found only minimal differences in antidepressant treatment response between these groups having different numbers of conditions; patients with 3 or more conditions reported higher rates of impairment in social and occupational functioning at week 12 but not at week 28. Additionally, we found no significant differences between the 3 antidepressant treatments across these groups. CONCLUSIONS: Patients with general medical conditions can be safely and effectively treated for MDD with antidepressants with no additional adverse effect or tolerability burden relative to their counterparts without such conditions. Combination therapy is not associated with an increased treatment response beyond that found with traditional monotherapy in patients with MDD, regardless of the presence and number of general medical conditions. PMID- 22230830 TI - Chlamydia trachomatis testing sensitivity in midstream compared with first-void urine specimens. AB - PURPOSE: Traditionally first-void urine specimens are used to test for Chlamydia trachomatis. In contrast, midstream urine specimens are traditionally recommended for microscopy and culture of presumptive bacterial urinary tract infections. The ability to test for both C trachomatis and urinary tract infection on a single midstream urine specimen would greatly aid clinical practice, as an urinary tract infection is an extremely common complaint in primary care. This study set out to determine how well positive C trachomatis results obtained on first-void specimens would correlate with positive findings in matched midstream specimens. METHODS: One hundred women with a first-void urine specimen positive for C trachomatis also provided midstream specimens for comparison. All specimens had C trachomatis testing performed using a DNA detection method. RESULTS: Of the 100 eligible participants with a first-void specimen positive for C trachomatis, 96 (96%) also had a positive midstream specimen (95% exact confidence limits, 90.1%, 98.9%). CONCLUSIONS: These results suggest that by using newer nucleic acid amplification techniques (NAATs), timing of specimen collection is not so important in testing for C trachomatis as previously thought. The sensitivity of NAAT testing on midstream urine specimens in women is sufficiently equivalent to testing on first-void specimens to consider in clinical practice and research settings where first-void specimens have formerly been collected. PMID- 22230831 TI - Envisioning a learning health care system: the electronic primary care research network, a case study. AB - PURPOSE: The learning health care system refers to the cycle of turning health care data into knowledge, translating that knowledge into practice, and creating new data by means of advanced information technology. The electronic Primary Care Research Network (ePCRN) was a project, funded by the U.S. National Institutes of Health, with the aim to facilitate clinical research using primary care electronic health records (EHRs). METHODS: We identified the requirements necessary to deliver clinical studies via a distributed electronic network linked to EHRs. After we explored a variety of informatics solutions, we constructed a functional prototype of the software. We then explored the barriers to adoption of the prototype software within U.S. practice-based research networks. RESULTS: We developed a system to assist in the identification of eligible cohorts from EHR data. To preserve privacy, counts and flagging were performed remotely, and no data were transferred out of the EHR. A lack of batch export facilities from EHR systems and ambiguities in the coding of clinical data, such as blood pressure, have so far prevented a full-scale deployment. We created an international consortium and a model for sharing further ePCRN development across a variety of ongoing projects in the United States and Europe. CONCLUSIONS: A means of accessing health care data for research is not sufficient in itself to deliver a learning health care system. EHR systems need to use sophisticated tools to capture and preserve rich clinical context in coded data, and business models need to be developed that incentivize all stakeholders from clinicians to vendors to participate in the system. PMID- 22230832 TI - Organizing care for complex patients in the patient-centered medical home. PMID- 22230833 TI - Systematic review and meta-analysis of practice facilitation within primary care settings. AB - PURPOSE: This study was a systematic review with a quantitative synthesis of the literature examining the overall effect size of practice facilitation and possible moderating factors. The primary outcome was the change in evidence-based practice behavior calculated as a standardized mean difference. METHODS: In this systematic review, we searched 4 electronic databases and the reference lists of published literature reviews to find practice facilitation studies that identified evidence-based guideline implementation within primary care practices as the outcome. We included randomized and nonrandomized controlled trials and prospective cohort studies published from 1966 to December 2010 in English language only peer-reviewed journals. Reviews of each study were conducted and assessed for quality; data were abstracted, and standardized mean difference estimates and 95% confidence intervals (CIs) were calculated using a random effects model. Publication bias, influence, subgroup, and meta-regression analyses were also conducted. RESULTS: Twenty-three studies contributed to the analysis for a total of 1,398 participating practices: 697 practice facilitation intervention and 701 control group practices. The degree of variability between studies was consistent with what would be expected to occur by chance alone (I2 = 20%). An overall effect size of 0.56 (95% CI, 0.43-0.68) favored practice facilitation (z = 8.76; P <.001), and publication bias was evident. Primary care practices are 2.76 (95% CI, 2.18-3.43) times more likely to adopt evidence-based guidelines through practice facilitation. Meta-regression analysis indicated that tailoring (P = .05), the intensity of the intervention (P = .03), and the number of intervention practices per facilitator (P = .004) modified evidence-based guideline adoption. CONCLUSION: Practice facilitation has a moderately robust effect on evidence-based guideline adoption within primary care. Implementation fidelity factors, such as tailoring, the number of practices per facilitator, and the intensity of the intervention, have important resource implications. PMID- 22230834 TI - Indication. AB - Should the indications for therapies differ from one nation to the next? What are the reasons behind controversial therapeutic variations? What roles do cultural history and authoritarian conflict among clinicians play in the adoption of therapies? When I worked at a rural hospital in Kenya, a woman experiencing obstructed labor made me ponder many questions-but only after our emergency ended in the death of her newborn son. In recounting and learning from this episode, I listened to the disparate Kenyan voices of the patient, the hospital's director, the consultant obstetrician, and to the even more controversial voices of evidence-based medicine. In reflecting on this process, I have learned at least 3 lessons-about the transmissibility of arrogance, the role of guests in other countries, and the nature of science. PMID- 22230835 TI - Shaping health-related policy in the United States: 1 family physician at a time. PMID- 22230836 TI - Investments in medical home model starting to pay dividends. PMID- 22230837 TI - Understanding the "sum of subtest to overall score discrepancy" on the MC-FP examination. PMID- 22230838 TI - New web site helps departments and programs effectively train and support preceptors. PMID- 22230839 TI - The Council of Academic Family Medicine (CAFM): where academic family medicine speaks and acts as one. PMID- 22230842 TI - Evolution of building facade road traffic noise levels in Flanders. AB - The evolution of daytime facade noise levels by road traffic at 250 dwellings in Flanders is assessed. Three identical man-operated measurement campaigns have been conducted in the years 1996, 2001 and 2009, during fall. A practical methodology has been developed, based on short time noise measurements and context observations at these locations. The uncertainty introduced by short-term sampling has been quantified as a function of the noise level. Furthermore, a correction is proposed for measuring at a random moment during daytime. Analysis of the data showed that road traffic noise levels hardly changed globally over this period of 13 years. The distribution of changes in noise level at corresponding measurement locations is nevertheless rather wide-all improvements are equally compensated by increases in noise levels at other locations. The percentage of the dwelling facades exposed to daytime noise levels above 65 dBA has increased slightly between 1996 and 2001, but seems to stagnate in 2009. In spite of the increased interest and actions of policy makers during the past decades, noise exposure caused by road traffic at dwelling facades is a persistent problem. PMID- 22230843 TI - Identification and characterization of IL-1 receptor-associated kinase-4 (IRAK-4) in half-smooth tongue sole Cynoglossus semilaevis. AB - As a crucial component in TLR/IL-1R signaling pathways, IRAK-4 plays a central role in innate and adaptive immunity. In the present study, the cDNA of IRAK-4 was cloned for the first time from half-smooth tongue sole (Cynoglossus semilaevis). The full-length cDNA of csIRAK-4 was 2149 bp and contained a 168 bp 5' UTR, a 580 bp 3' UTR and a 1401 bp CDS. The predicted protein sequence of csIRAK-4 had two typical domains, a death domain (DD) at the N terminus and a serine/threonine/tyrosine protein kinase domain (STYKc) at the C terminus. RT-PCR showed that csIRAK-4 mRNA was detected in all tested tissues, especially in immune-related organs, gonads and brain. After injected with inactivated Vibrio anguillarum, the expressions of csIRAK-4 were up-regulated significantly (P<0.05) in spleen and head kidney. During development, csIRAK-4 was expressed at all selected stages and low-level expression was detected at metamorphosis. Taken together, the present study indicated that csIRAK-4 played a crucial role in immune responses and might be involved in the process of development. PMID- 22230844 TI - A protocol for detecting and scavenging gas-phase free radicals in mainstream cigarette smoke. AB - Cigarette smoking is associated with human cancers. It has been reported that most of the lung cancer deaths are caused by cigarette smoking (5,6,7,12). Although tobacco tars and related products in the particle phase of cigarette smoke are major causes of carcinogenic and mutagenic related diseases, cigarette smoke contains significant amounts of free radicals that are also considered as an important group of carcinogens(9,10). Free radicals attack cell constituents by damaging protein structure, lipids and DNA sequences and increase the risks of developing various types of cancers. Inhaled radicals produce adducts that contribute to many of the negative health effects of tobacco smoke in the lung(3). Studies have been conducted to reduce free radicals in cigarette smoke to decrease risks of the smoking-induced damage. It has been reported that haemoglobin and heme-containing compounds could partially scavenge nitric oxide, reactive oxidants and carcinogenic volatile nitrosocompounds of cigarette smoke(4). A 'bio-filter' consisted of haemoglobin and activated carbon was used to scavenge the free radicals and to remove up to 90% of the free radicals from cigarette smoke(14). However, due to the cost-ineffectiveness, it has not been successfully commercialized. Another study showed good scavenging efficiency of shikonin, a component of Chinese herbal medicine(8). In the present study, we report a protocol for introducing common natural antioxidant extracts into the cigarette filter for scavenging gas phase free radicals in cigarette smoke and measurement of the scavenge effect on gas phase free radicals in mainstream cigarette smoke (MCS) using spin-trapping Electron Spin Resonance (ESR) Spectroscopy(1,2,14). We showed high scavenging capacity of lycopene and grape seed extract which could point to their future application in cigarette filters. An important advantage of these prospective scavengers is that they can be obtained in large quantities from byproducts of tomato or wine industry respectively(11,13). PMID- 22230845 TI - A method for the removal of tungsten carbide rings. AB - BACKGROUND: The removal of metal rings from fingers is a well-described process that often employs a toothed cutting wheel or bolt cutters to sever the ring and allow it to be pried open. However, tungsten carbide (TC) rings are impervious to these traditional ring-cutting devices. STUDY OBJECTIVES: We sought to describe a method for removal of TC rings from cadaveric fingers and characterize potential complications of the technique. METHODS: On cadaveric fingers, we placed TC rings and created a snug fit by injecting a fluorescein and saline solution. The rings were removed by a controlled crushing technique using a pair of locking pliers. Fingers were inspected under magnification and using an LED (light-emitting diode) black light, and X-ray studies of each finger were obtained. Injuries were characterized. RESULTS: Six rings were applied and successfully removed from six cadaveric fingers through controlled ring shatter. After ring removal, two fingers demonstrated superficial (<1 mm deep) lacerations, one of which had residual debris within the wound. No phalangeal fractures were identified. CONCLUSION: Removal of a TC ring can be performed through controlled crushing using locking pliers. Superficial lacerations and retained debris are potential complications. PMID- 22230846 TI - Assessing the pharmacodynamic profile of intravenous antibiotics against prevalent Gram-negative organisms collected in Colombia. AB - OBJECTIVES: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. METHODS: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40% of the dosing interval. RESULTS: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90% cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20% lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90% CFR against bloodstream and respiratory isolates of K. pneumoniae. CONCLUSIONS: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials. PMID- 22230847 TI - Diversity of genotypes in CTX-M-producing Klebsiella pneumoniae isolated in different hospitals in Brazil. AB - OBJECTIVE: The present study was undertaken to characterize CTX-M ESBL-producing Klebsiella pneumoniae collected from hospitals in different cities of Brazil. MATERIAL AND METHODS: Eighty-five K. pneumoniae strains isolated from hospitalized patients in six different hospitals of three cities of Brazil were analyzed. ESBL production was confirmed by the standard double-disk synergy test and the Etest(r). The MIC50 and MIC90 for ESBL-producing isolates were determined by the Etest(r) method. The antimicrobial susceptibilities of bacterial isolates were determined using the agar diffusion method according to the CLSI. Screening for blaTEM, blaSHV, blaCTX-M genes and class 1 integron was performed by PCR amplification. To determine the genomic diversity of CTX-M-producers, isolates were analyzed by macrorestriction profile analysis following PFGE. RESULTS AND DISCUSSION: Seventy-one K. pneumoniae isolates were ESBL-producing. PCR and sequencing experiments detected 38 CTX-M-producing K. pneumoniae belonged to groups CTX-M 1, CTX-M 2, CTX-M 8 and CTX-M 9. The association of different types ESBL (CTX-M, SHV and TEM) was frequent. All K. pneumoniae isolates carried class 1 integron. PFGE analysis revealed thirty-one clonal types among CTX-M-producing isolates. The data presented herein illustrate the diversity of genotypes of CTX M producing K. pneumoniae among Brazilians hospitals. PMID- 22230848 TI - Length of exposure to the hospital environment is more important than antibiotic exposure in healthcare associated infections by methicillin-resistant Staphylococcus aureus: a comparative study. AB - OBJECTIVES: Both total antimicrobial use and specific antimicrobials have been implicated as risk factors for healthcare-associated methicillin-resistant Staphylococcus aureus (HCA-MRSA) infection. The aims of this study were: (I) to explore predictors of a new HCA-MRSA infection in comparison with a new healthcare-associated methicillin-sensitive Staphylococcus aureus (HCA-MSSA); (II) to thoroughly assess the role of recent antibiotic use qualitatively and quantitatively. METHODS: The time-period for our study was from October 1997 through September 2001. Through applying strict criteria, we identified two groups of inpatients, one with a new HCA-MRSA infection and one with a new HCA MSSA infection. We recorded demographic, clinical and antibiotic use-related data up to 30 days before the positive culture date. RESULTS: We identified 127 and 70 patients for each group, respectively. Two logistic regression models were carried out to assess the role of antimicrobial use (qualitatively and quantitatively). In model I, duration of hospital stay, presence of chronic wounds, aminoglycoside and fluoroquinolone use retained statistical significance. In model II, duration of hospital stay and history of intubation during the last month stood out as the only significant predictors of a subsequent HCA-MRSA infection. No significant differences in outcome were noted. CONCLUSIONS: The length of exposure to the hospital environment may be the best predictor of a new HCA-MRSA infection. Use of aminoglycosides and fluoroquinolones may also stand independently along with presence of chronic ulcers and surgical procedures. No independent association between quantitative antibiotic use and subsequent HCA MRSA infection was documented. PMID- 22230849 TI - Molecular identification and typing of Mycobacterium massiliense isolated from postsurgical infections in Brazil. AB - OBJECTIVE: One hundred thirty-one cases of postsurgical infections were reported in Southern Region of Brazil between August 2007 and January 2008. Thirty-nine (29.8%) cases were studied; this report describes epidemiological findings, species identification, antimicrobial susceptibility and clonal diversity of rapidly growing mycobacteria isolated in this outbreak. METHODS: All 39 isolates were analyzed by Ziehl-Nielsen stained smear, bacterial culture and submitted to rpoB partial gene sequencing for identification. The isolates were also evaluated for their susceptibility to amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, tobramycin and sulfamethoxazole. RESULTS: Thirty-six isolates out of the confirmed cases were identified as Mycobacterium massiliense and the remaining three were identified as Mycobacterium abscessus, Mycobacterium chelonae and Mycobacterium fortuitum. All M. massiliense isolates were susceptible to amikacin (MIC90 = 8 ug/mL) and clarithromycin (MIC90 = 0.25 ug/mL) but resistant to cefoxitin, ciprofloxacin, doxycycline, tobramycin and sulfamethoxazole. Molecular analysis by pulsed-field gel electrophoresis clustered all 36 M. massiliense isolates and showed the same pattern (BRA 100) observed in three other outbreaks previously reported in Brazil. CONCLUSIONS: These findings suggest a common source of infection for all patients and reinforce the hypotheses of spread of M. massiliense BRA100 in Brazilian hospital surgical environment in recent years. PMID- 22230850 TI - Miltefosine induces metacaspase and PARP genes expression in Leishmania infantum. AB - OBJECTIVES: Apoptosis is the process of programmed cell death (PCD) that occurs in both animal and plant cells. Protozoan parasites possess metacaspase and these caspase-related proteases could be involved in the PCD pathways in these organisms. Therefore we analyzed the activities of metacaspase and PARP genes in Leishmania infantum (MCAN/IR/96/LON49) treated with miltefosine. MATERIALS AND METHODS: Anti-leishmania activity of miltefosine was studied by treatment of cultured promastigotes with various concentration of miltefosine. MTT assay and Annexin-V FLUOS staining by using FACS flow cytometry methods were used. Cytotoxic potential of HePC on the amastigots of L.infantum was evaluated in J774 cell line. In addition, metacaspase and PARP genes expression of treated L. infantum were studied. RESULTS: Miltefosine led to dose-dependent death of L. infantum with features compatible with apoptosis. Over expression of metacaspase and PARP was seen 6 hr after treatment. CONCLUSIONS: Our study showed that miltefosine exerts cytotoxic effect on L. infantum via an apoptotic-related mechanism. PMID- 22230851 TI - Virus C genotype predisposes to primary hypothyroidism during interferon-alpha treatment for chronic hepatitis C. AB - OBJECTIVE: The treatment of the chronic hepatitis C (HCV) with alpha-interferon is associated with thyroid dysfunction (TD). The aim of this study was to evaluate thyroid function outcome among patients with chronic HCV under treatment with conventional interferon (IFN) or peguilated interferon (PEG-IFN) in association with ribavirin. PATIENTS AND METHODS: We studied 293 patients with chronic HCV, submitted to drug therapy for 24 or 48 weeks. Initially, we evaluated FT4, TSH, TPOAb, TgAb, and continued to monitor FT4 and TSH every three months during therapy and six months thereafter. RESULTS: At baseline, TD prevalence was 6.82% (n = 20); 6.14% hypothyroidism; 0.68% hyperthyroidism. TPOAb was present in 5.46% of euthyroid patients. Out of 273 euthyroid patients at baseline, 19% developed TD: 17.2% hypothyroidism; 1.8% hyperthyroidism; 5.1% destructive thyroiditis (DT). 90% of TPOAb-positive patients at baseline developed hypothyroidism vs 14.5% of TPOAb-negative patients (p < 0.001). On average, TD occurred after 25.8 +/- 15.5 weeks of treatment. 87.2% of patients who developed hypothyroidism did so during the first therapeutic cycle (p = 0.004; OR = 3.52; 95% CI = 1.36-9.65). Patients infected with genotype 1 virus were 2.13 times more likely to develop hypothyroidism (p = 0.036; 95% CI = 1.04 4.38). Hypothyroid and DT patients presented higher TSH levels before-treatment than patients who had remained euthyroid (p < 0.001; p = 0.002, respectively). DT patients presented lower qALT (p = 0.012) than euthyroid patients. CONCLUSION: Hypothyroidism was the most frequent TD, especially during the first cycle of alpha-interferon. Genotype 1 virus was associated with a risk two times higher for developing the illness. There was no need to interrupt or to change HCV treatment. Therefore, approximately 34% of TD was transient. PMID- 22230852 TI - Study of the relationship between socio-demographic characteristics and new influenza A (H1N1). AB - OBJECTIVE: The pandemic of new influenza A (H1N1) has spread rapidly throughout the world, characterized by high transmissibility, but low pathogenicity and virulence. The aim of this study was to understand the pandemic event and available technologies for disease surveillance, prevention, control and management. METHODS: In this retrospective study, we used data from patients in the State of Parana who had been diagnosed with the disease during the 2009 pandemic. Data were collected from the disease notification form and the study only included patients with confirmed laboratory diagnosis by RT-PCR. RESULTS: We present the epidemiological profile of 4,740 patients that met the inclusion criteria. The variables age, level of schooling and gestational age were shown to be associated with mortality due to the infection. Gender and race/ethnicity were not associated with the outcome of the infection. CONCLUSION: These results underscore the importance of knowing the variables associated with unfavorable outcomes of pandemic influenza infection in order to minimize the health related consequences. Attention should be given to its forms of transmission and to the frailty of certain age groups that have no cross-immunity. PMID- 22230854 TI - Human papillomavirus detection and typing using a nested-PCR-RFLP assay. AB - BACKGROUND: It is clinically important to detect and type human papillomavirus (HPV) in a sensitive and specific manner. OBJECTIVES: Development of a nested polymerase chain reaction-restriction fragment length polymorphism (nested-PCR RFLP) assay to detect and type HPV based on the analysis of L1 gene. METHODS: Analysis of published DNA sequence of mucosal HPV types to select sequences of new primers. Design of an original nested-PCR assay using the new primers pair selected and classical MY09/11 primers. HPV detection and typing in cervical samples using the nested-PCR-RFLP assay. RESULTS: The nested-PCR-RFLP assay detected and typed HPV in cervical samples. Of the total of 128 clinical samples submitted to simple PCR and nested-PCR for detection of HPV, 37 (28.9%) were positive for the virus by both methods and 25 samples were positive only by nested-PCR (67.5% increase in detection rate compared with single PCR). All HPV positive samples were effectively typed by RFLP assay. CONCLUSION: The method of nested-PCR proved to be an effective diagnostic tool for HPV detection and typing. PMID- 22230853 TI - Spatial exploration of Streptococcus pneumoniae clonal clustering in Sao Paulo, Brazil. AB - OBJECTIVES: To examine the spatial distribution of Streptococcus pneumoniae and its clonal patterns collected between 2002 and 2006 in Sao Paulo, Brazil. METHODS: As part of an observational study in Sao Paulo city, Brazil, S. pneumoniae isolates routinely cultured from blood, respiratory specimens, or cerebrospinal and other profound fluids were selected. Additionally, only isolates with either penicillin (PEN) intermediate (I) or resistant (R) status on routine antibiogram were included, in order to obtain a higher probability of clonal isolates. A single I/R S. pneumoniae isolate per patient was included and submitted to genotypic determination by pulsed field gel electrophoresis (PFGE). Minimum inhibitory concentrations (MICs) were determined for the isolates by Etest(r) to PEN and other antimicrobials. Each isolate was geocoded in a digital map. The Kernel function and ratio methods between total isolates vs. clones were used in order to explore possible cluster formations. RESULTS: Seventy-eight (78) S. pneumoniae community isolates from two major outpatient centers in Sao Paulo, Brazil, were selected from the databank according to their penicillin susceptibility profile, i.e. R or I to penicillin assessed by oxacillin disc diffusion. Of these, 69 were submitted to PFGE, 65 to MIC determination, and 48 to spatial analytical procedures. Preliminary spatial analysis method showed two possible cluster formation located in southwest and southeast regions of the city. CONCLUSION: Further analyses are required for precisely determining the existence of S. pneumoniae clusters and their related risk factors. Apparently there is a specific transmission pattern of S. pneumoniae clones within certain regions and populations. GIS and spatial methods can be applied to better understand epidemiological patterns and to identify target areas for public health interventions. PMID- 22230855 TI - HPV infection and intraepithelial lesions from the anal region: how to diagnose? AB - In the last years, the prevalence of HPV infection in the anal region has increased, especially in some groups like homosexual and HIV-positive people. Since this infection can be associated with the development of squamous anal cancer due to its progression from HPV infection to anal intraepithelial neoplasia (AIN) and finally to cancer, the screening and evaluation of these conditions are important. Anal cytology and high resolution anoscopy are good methods that are available and can be used. Although useful, these methods should be performed correctly and not indiscriminately in all patients. Patients for whom anal cytology screening is recommended are: HIV-infected patients, homosexuals, women who present with high-grade vulvar squamous intraepithelial neoplasia, vulvar cancer or cervical cancer. An abnormal anal cytology should be further evaluated with high resolution anoscopy. PMID- 22230856 TI - Detection of SPM and IMP metallo-beta-lactamases in clinical specimens of Pseudomonas aeruginosa from a Brazilian public tertiary hospital. AB - Phenotypic and genotypic SPM and IMP metallo-beta-lactamases (MBL) detection and also the determination of minimal inhibitory concentrations (MIC) to imipenem, meropenem and ceftazidime were evaluated in 47 multidrug-resistant Pseudomonas aeruginosa isolates from clinical specimens. Polymerase chain reaction detected 14 positive samples to either blaSPM or blaIMP genes, while the best phenotypic assay (ceftazidime substrate and mercaptopropionic acid inhibitor) detected 13 of these samples. Imipenem, meropenem and ceftazidime MICs were higher for MBL positive compared to MBL negative isolates. We describe here the SPM and IMP MBL findings in clinical specimens of P. aeruginosa from the University Hospital of Botucatu Medical School, Sao Paulo, Brazil, that reinforce local studies showing the high spreading of blaSPM and blaIMP genes among brazilian clinical isolates. PMID- 22230857 TI - Adult Reye-like syndrome associated with serologic evidence of acute parvovirus B19 infection. AB - Reye's syndrome is an infrequently diagnosed medical condition affecting mainly children. The etiology, epidemiology and natural history of Reye's syndrome have been cloudily written in footnotes of medical books and exotic papers since the initial description in early 1950s. We report here a case of adult Reye's syndrome associated with serologic evidence of parvovirus B19 infection. PMID- 22230858 TI - Cutaneous cytomegalovirus infection in a child with hyper IgE and specific defects in antibody response to protein vaccines. AB - Cytomegalovirus (CMV) infection is a common opportunistic systemic infection in immunocompromised patients, but skin involvement is rare. Herein, we report a 10 year-old girl from consanguineous parents who was referred to our center because of disseminated maculopapular rash. She had history of upper and lower respiratory tract infections. In immunological studies, increased serum IgE level and decreased responses to tetanus and diphtheria were detected. Polymerase chain reaction (PCR) examination of bronchoalveolar lavage and serum sample revealed the presence of CMV. Early diagnosis of cutaneous CMV and appropriate treatment are the key actions in management of patients with underlying immunodeficiencies to avoid further complications. PMID- 22230859 TI - Successful treatment of pulmonary Nocardia farcinica infection with linezolid: case report and literature review. AB - Nocardia infection is rare but potentially fatal. Therapy of Nocardia infection remains difficult. Linezolid, a novel oxazolidinone antibiotic, has proven to be effective, but clinical data are limited. Here we describe a case of a 45-year old man with pulmonary N. farcinica infection following a liver transplantation. The initial therapy was trimethoprim-sulfamethoxazole, which showed no effect. According to susceptibility test, linezolid was administered with clearly improving the patient's condition. The treatment was stopped for anemia as drug related adverse event, and the therapy lasted for as long as 5 months. At the end of treatment clinical cure was confirmed and anemia reversed after discontinuation of linezolid. We also analyzed the clinical data of previously published reports by literature review, focusing on the efficacy and safety of linezolid treatment for Nocardia infection. PMID- 22230860 TI - Dengue hemorrhagic fever complicated by pancreatitis. AB - Acute pancreatitis is an atypical complication of dengue fever and is rarely described. We are reporting a case of dengue hemorrhagic fever complicated by acute pancreatitis in a patient with history of diabetes mellitus type 1 and end stage renal disease on hemodialysis. PMID- 22230861 TI - Leptospirosis presenting as ascending progressive leg weakness and complicating with acute pancreatitis. AB - Leptospirosis is a spirochetal bacterial infection of great public health importance. It has a broad spectrum of clinical manifestations which goes from subclinical infection and self-limited anicteric febrile illness (80-90% of all cases) to icteric leptospiropirosis known as Weil's disease. This is a severe disease characterized by hemorrhage, acute renal failure and jaundice. It is uncommon for leptospirosis to present itself as a primary neurological disease. Additionally, acute pancreatitis is an unusual gastrointestinal manifestation. We report a case of leptospirosis presenting as ascending progressive leg weakness and complicating with acute pancreatitis in an adult patient treated at Hospital Universitario, Universidade Federal de Santa Catarina. The diagnosis was confirmed through ELISA-IgM antibody testing positive for leptospirosis. After antibiotic therapy and support treatment for a few weeks, total resolution of severe manifestations was achieved. Rare and unusual presentations of leptospirosis should be kept in mind in relevant epidemiological scenario. PMID- 22230862 TI - A reduced dose of darunavir/ritonavir is effective in PI-experienced HIV-infected patients. AB - Darunavir (DRV) is an HIV-1 protease inhibitor that is used together with a low boosting dose of ritonavir as part of an antiretroviral therapy (ART) regimen in treatment-experienced and naive HIV-positive patients. In naive and experienced patients with no DRV-mutations, DRV is licensed at the dose of 800 mg plus 100 mg of ritonavir once daily. We report our results in seven ART-experienced HIV infected patients, in whom a reduced dose of darunavir/ritonavir (600/100 mg once daily) successfully controlled viral replication. PMID- 22230863 TI - Risk factors for mortality in Acinetobacter bacteremia. PMID- 22230864 TI - Disseminated tuberculosis and human immunodeficiency virus infection. PMID- 22230865 TI - Seven years of experience with zygomycosis in Iran: a seasonal disease. PMID- 22230866 TI - Nosocomial outbreak of carbapenem-resistant Pseudomonas aeruginosa carrying blaVIM-2 in burn wards, China. PMID- 22230868 TI - Uncover the immune biomarkers underlying hepatitis B e antigen (HBeAg) seroconversion: a need for more translational study. PMID- 22230869 TI - Bacterial resistance in cirrhotic patients: an emerging reality. PMID- 22230871 TI - Interaction between IL28B and PNPLA3 genotypes in the pathogenesis of steatosis in chronic hepatitis C non genotype-3 patients. PMID- 22230872 TI - Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: why is it different? PMID- 22230873 TI - [Hydrogen sulfide: production, release, and functions]. PMID- 22230874 TI - [Role of hydrogen sulfide in duodenal HCO3(-) secretion]. PMID- 22230875 TI - [Production of hydrogen sulfide and its protective role in the pancreatic B cell]. PMID- 22230876 TI - [Role of hydrogen sulfide in chronic kidney disease and diabetic nephropathy]. PMID- 22230877 TI - [Multi regional clinical trials in Japan]. PMID- 22230878 TI - [Pharmacological profile and clinical results of the rivastigmine patch as a new therapeutic agent for Alzheimer's disease]. PMID- 22230879 TI - [Pharmacological properties and clinical efficacy of pentetate calcium trisodium and pentetate zinc trisodium, antidotes for transuranium elements]. PMID- 22230880 TI - Diversity in the later Paleogene proboscidean radiation: a small barytheriid from the Oligocene of Dhofar Governorate, Sultanate of Oman. AB - Despite significant recent improvements to our understanding of the early evolution of the Order Proboscidea (elephants and their extinct relatives), geographic sampling of the group's Paleogene fossil record remains strongly biased, with the first ~30 million years of proboscidean evolution documented solely in near-coastal deposits of northern Africa. The considerable morphological disparity that is observable among the late Eocene and early Oligocene proboscideans of northern Africa suggests that other, as yet unsampled, parts of Afro-Arabia might have served as important centers for the early diversification of major proboscidean clades. Here we describe the oldest taxonomically diagnostic remains of a fossil proboscidean from the Arabian Peninsula, a partial mandible of Omanitherium dhofarensis (new genus and species), from near the base of the early Oligocene Shizar Member of the Ashawq Formation, in the Dhofar Governorate of the Sultanate of Oman. The molars and premolars of Omanitherium are morphologically intermediate between those of Arcanotherium and Barytherium from northern Africa, but its specialized lower incisors are unlike those of other known Paleogene proboscideans in being greatly enlarged, high-crowned, conical, and tusk-like. Omanitherium is consistently placed close to late Eocene Barytherium in our phylogenetic analyses, and we place the new genus in the Family Barytheriidae. Some features of Omanitherium, such as tusk-like lower second incisors, the possible loss of the lower central incisors, an enlarged anterior mental foramen, and inferred elongate mandibular symphysis and diminutive P(2), suggest a possible phylogenetic link with Deinotheriidae, an extinct family of proboscideans whose origins have long been mysterious. PMID- 22230882 TI - Machine learning and data mining: strategies for hypothesis generation. AB - Strategies for generating knowledge in medicine have included observation of associations in clinical or research settings and more recently, development of pathophysiological models based on molecular biology. Although critically important, they limit hypothesis generation to an incremental pace. Machine learning and data mining are alternative approaches to identifying new vistas to pursue, as is already evident in the literature. In concert with these analytic strategies, novel approaches to data collection can enhance the hypothesis pipeline as well. In data farming, data are obtained in an 'organic' way, in the sense that it is entered by patients themselves and available for harvesting. In contrast, in evidence farming (EF), it is the provider who enters medical data about individual patients. EF differs from regular electronic medical record systems because frontline providers can use it to learn from their own past experience. In addition to the possibility of generating large databases with farming approaches, it is likely that we can further harness the power of large data sets collected using either farming or more standard techniques through implementation of data-mining and machine-learning strategies. Exploiting large databases to develop new hypotheses regarding neurobiological and genetic underpinnings of psychiatric illness is useful in itself, but also affords the opportunity to identify novel mechanisms to be targeted in drug discovery and development. PMID- 22230881 TI - The dappled nature of causes of psychiatric illness: replacing the organic functional/hardware-software dichotomy with empirically based pluralism. AB - Our tendency to see the world of psychiatric illness in dichotomous and opposing terms has three major sources: the philosophy of Descartes, the state of neuropathology in late nineteenth century Europe (when disorders were divided into those with and without demonstrable pathology and labeled, respectively, organic and functional), and the influential concept of computer functionalism wherein the computer is viewed as a model for the human mind-brain system (brain=hardware, mind=software). These mutually re-enforcing dichotomies, which have had a pernicious influence on our field, make a clear prediction about how 'difference-makers' (aka causal risk factors) for psychiatric disorders should be distributed in nature. In particular, are psychiatric disorders like our laptops, which when they dysfunction, can be cleanly divided into those with software versus hardware problems? I propose 11 categories of difference-makers for psychiatric illness from molecular genetics through culture and review their distribution in schizophrenia, major depression and alcohol dependence. In no case do these distributions resemble that predicted by the organic functional/hardware-software dichotomy. Instead, the causes of psychiatric illness are dappled, distributed widely across multiple categories. We should abandon Cartesian and computer-functionalism-based dichotomies as scientifically inadequate and an impediment to our ability to integrate the diverse information about psychiatric illness our research has produced. Empirically based pluralism provides a rigorous but dappled view of the etiology of psychiatric illness. Critically, it is based not on how we wish the world to be but how the difference makers for psychiatric illness are in fact distributed. PMID- 22230883 TI - Cerebral folate receptor autoantibodies in autism spectrum disorder. AB - Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted. PMID- 22230884 TI - Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. AB - Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Here, we describe the first characterization and neuronal differentiation of induced pluripotent stem (iPS) cells derived from Mecp2-deficient mice. Fully reprogrammed wild-type (WT) and heterozygous female iPS cells express endogenous pluripotency markers, reactivate the X-chromosome and differentiate into the three germ layers. We directed iPS cells to produce glutamatergic neurons, which generated action potentials and formed functional excitatory synapses. iPS cell-derived neurons from heterozygous Mecp2(308) mice showed defects in the generation of evoked action potentials and glutamatergic synaptic transmission, as previously reported in brain slices. Further, we examined electrophysiology features not yet studied with the RTT iPS cell system and discovered that MeCP2-deficient neurons fired fewer action potentials, and displayed decreased action potential amplitude, diminished peak inward currents and higher input resistance relative to WT iPS derived neurons. Deficiencies in action potential firing and inward currents suggest that disturbed Na(+) channel function may contribute to the dysfunctional RTT neuronal network. These phenotypes were additionally confirmed in neurons derived from independent WT and hemizygous mutant iPS cell lines, indicating that these reproducible deficits are attributable to MeCP2 deficiency. Taken together, these results demonstrate that neuronally differentiated MeCP2-deficient iPS cells recapitulate deficits observed previously in primary neurons, and these identified phenotypes further illustrate the requirement of MeCP2 in neuronal development and/or in the maintenance of normal function. By validating the use of iPS cells to delineate mechanisms underlying RTT pathogenesis, we identify deficiencies that can be targeted for in vitro translational screens. PMID- 22230886 TI - Effects of microinjections of apomorphine and haloperidol into the inferior colliculus on prepulse inhibition of the acoustic startle reflex in rat. AB - Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in schizophrenia patients and in rats with central dopamine (DA) activation. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The aim of this study was to elucidate the role of DA transmission of the IC on the development of acoustic PPI. Bilateral microinjections of apomorphine (9.0 MUg/0.5 MUL), an agonist of D(2) receptors, into the IC disrupted PPI while microinjections of haloperidol (0.5 MUg/0.5 MUL), an antagonist of D(2) receptors, into this structure did not alter PPI. These results suggest that dopamine-mediated mechanisms of the IC are involved in the expression of PPI in rodents. PMID- 22230885 TI - Cannabinoid receptor expression at the MNTB-LSO synapse in developing rats. AB - The organization of developing auditory circuits depends on the elimination of aberrant connections and strengthening of appropriate ones. Endocannabinoid mediated plasticity is a proposed mechanism for this refinement. Here we investigated for the anatomical presence of cannabinoid receptors (CB1R) in the lateral superior olive (LSO) and medial nucleus of the trapezoid body (MNTB) of developing rats. We found that CB1R is present within the LSO and that it colocalized with vesicular glutamate transporter (VGLUT3), a presynaptic marker for MTNB terminals. Both before (P5) and around hearing onset (P12), the expression levels of CB1R were higher in the lateral limb of the LSO than in the medial limb. These results suggest that endocannabinoid signaling can modulate the strength of the developing MNTB-LSO synapse. PMID- 22230887 TI - Distribution of the purinegic receptors P2X(4) and P2X(6) during rat gut development. AB - The purinergic receptors P2X(4) and P2X(6) are ion channels activated by ATP. These receptors are present in the gastrointestinal tract, and they are involved in synaptic transmission, taste sensation, and pain, among other functions. In this work, we studied the distribution of P2X(4) and P2X(6) receptors in proximal and distal regions of the gut newborn and adult rats. Using immunohistochemistry, purinergic receptors were found in gut epithelial cells and capillary vessels. In both proximal and distal regions of newborn rats, we observed P2X(4) signal in epithelial cells, whereas P2X(6) was present in capillary vessels in the proximal region and to a lesser extent in the distal region. In both regions of adult gut, we observed P2X(4) and P2X(6) immunostain in the capillary vessels. Semi quantification indicated a significant difference in the amount of P2X(4) between proximal regions, whereas the P2X(6) content of both newborn regions differed from that in adult proximal gut. We conclude that P2X(4) and P2X(6) purinoreceptors are present in the gut from birth and that they are differentially distributed among regions. PMID- 22230888 TI - Early brain amyloidosis in APP/PS1 mice with serum insulin-like growth factor-I deficiency. AB - The influence of insulin-like growth factor I (IGF-I) on the progression of Alzheimer's disease (AD) is discussed controversially. To help clarify the role of this circulating neurotrophic factor in brain amyloidosis, the major pathological trait in AD, we analyzed plaque formation in a mouse model of AD transgenic for human APP and PS1 mutations with reduced serum IGF-I levels (LIDAD mice). We found that brain amyloidosis in LIDAD mice appeared earlier than in AD mice, at 2 months of age, while attained comparable levels at 6 months. In parallel, early microgliosis was observed in LIDAD mice also at 2 months and remained exacerbated at 6 months. Collectively, these observations suggest a role of serum IGF-I in delaying early brain amyloidosis. PMID- 22230890 TI - Selective attention deficits in early and moderate stage Parkinson's disease. AB - Patients with Parkinson's disease (PD) often show impaired performance on visuospatial attentional tasks. The objective of the study was to examine the attentional function of PD patients performing the attentional network test (ANT). We used the ANT to compare PD patients with healthy controls with respect to the efficiency of 3 anatomically defined attentional networks: the alerting, orienting, and executive control networks. We found that PD patients showed a selective abnormality in the orienting network. Although the alerting and executive control networks apparently remained unaffected, the efficiencies of these networks in patients with PD negatively correlated with the Hoehn-Yahr stage. The results supported the idea that the orienting processes may be more dynamic in PD than in non-PD individuals. PMID- 22230889 TI - Bolus injection of hypertonic solutions for cerebral edema in rats: challenge of homeostasis of healthy brain. AB - Hypertonic solutions are mainstay of osmotherapy to cerebral edema. How hypertonic solutions affect healthy brain homeostasis, however, is not fully understood. Using rat model of cerebral edema induced by local cryoinjury, we found with immunohistochemistry that less microglial activation in healthy hemishere 24 h after hypertonic saline (HS, 3% NaCl) administration, compared to mannitol (20%, the same osmotic concentration of 3% NaCl) while dehydrating the brain tissue. To see whether blood-brain barrier (BBB) or aquaporin-4 (AQP4) contribute to this difference, HS or mannitol was intra-arterially injected to normal rats, and BBB opening, ultrastructure and AQP4 immunoreactivity were examined. Evans blue extravasation indicated that BBB was opened much lighter in HS group than mannitol group at the same time points. Electron microscopy also showed edema around the capillaries slightly lighter in HS than mannitol group 24 h after injection. Meanwhile, HS injection led to AQP4 down regulation in expression similarly as mannitol, compared with NS group. These data suggested that bolus injection of hypertonic agents may lead to microglia activation in healthy brain in different extent, due to BBB compromise, instead of water movement or AQP4 expression. Hence in clinical application, BBB of healthy brain should be considered in perspective to maintain the brain homeostasis. PMID- 22230891 TI - Heparan sulfate niche for cell proliferation in the adult brain. AB - In adulthood, new neurons and glial cells are generated from stem cells in restricted zones of the brain, namely the olfactory bulb (OB), rostral migratory stream (RMS), subventricular zone (SVZ) of the lateral ventricle, sub-callosum zone (SCZ) and sub-granular layer (SGL) of the dentate gyrus. What makes these zones germinal? We previously reported that N-sulfated heparan sulfates (N sulfated HS) present in specialized extracellular matrix structures (fractones) and vascular basement membranes bind the neurogenic factor FGF-2 (fibroblast growth factor-2) next to stem cells in the anterior SVZ of the lateral ventricle, the most neurogenic zone in adulthood. To determine to which extent cell proliferation is associated with N-sulfated HS, we mapped N-sulfated HS and proliferating cells by immunohistochemistry throughout the adult mouse brain. We found that cell proliferation is associated with N-sulfated HS in the OB, RMS, the whole germinal SVZ, and the SCZ. Cell proliferation was weakly associated with N-sulfated HS in the SGL, but the SGL was directly connected to a sub cortical N-sulfated HS+ extension of the meninges. The NS-sulfated HS+ structures were blood vessels in the OB, RMS and SCZ, and primarily fractones in the SVZ. N sulfated HS+ fractones, blood vessels and meninges formed a continuum that coursed along the OB, SVZ, RMS, SCZ and SGL, challenging the view that these structures are independent germinal entities. These results support the possibility that a single anatomical system might be globally responsible for mitogenesis and ultimately the production of new neurons and glial cells in the adult brain. PMID- 22230892 TI - zVLL-CHO at low concentrations acts as a calpain inhibitor to protect neurons against okadaic acid-induced neurodegeneration. AB - There is evidence that beta-secretase and amyloid precursor protein beta-C terminal fragments (APP-CTF) are involved in the pathogenesis of Alzheimer's disease (AD). Previously, we have reported that N-benzyloxycarbonyl-Val-Leu leucinal (zVLL-CHO) reduced APP beta-CTF accumulation in axonal swellings of degenerating neurons. Here, in an effort to discover more effective neuroprotective agents, we examined the effects of the beta-secretase inhibitors, H-KTEEISEVN-stat-VAEF-OH (VAEF) and H-EVNstatineVAEF-NH2 (GL-189) as well as zVLL CHO on OA (okadaic acid)-induced neurodegeneration. Unexpectedly, we found that pretreatment with zVLL-CHO (1 MUM) protected neurons after OA treatment, whereas both VAEF and GL-189 lacked neuroprotective effects. Interestingly, 1 MUM zVLL CHO did not inhibit beta-secretase. We previously reported that calpain is activated by OA treatment and calpain inhibitors protect against OA-induced neurodegeneration. The data presented here show that pretreatment with 1 MUM zVLL CHO decreased the levels of calpain-cleaved alpha-spectrin with a concomitant decrease in LDH release and an increase in average dendritic branch length compared to neurons treated with OA alone. These findings suggest that zVLL-CHO protects against OA-induced neurodegeneration via calpain inactivation. PMID- 22230893 TI - Effects of low and high frequency repetitive transcranial magnetic stimulation of the primary motor cortex on contingent negative variations in normal subjects. AB - The state of primary motor cortex (M1) excitability is crucial for the processing of voluntary movement. We aimed to test the modulation induced by 1 Hz and 5 Hz repetitive transcranial magnetic stimulation (rTMS) of M1 on both early and late components of the contingent negative variation (CNV) and on the motor reaction in normal subjects. The CNV was evaluated in basal, and after 15 min of real or sham 1 Hz and 5 Hz stimulation of the left motor cortex in 7 right handed volunteers. Inhibition of motor cortex, due to rTMS stimulation, resulted in an amplitude increase of early and late components of CNV, and a slight reducing effect on motor reaction times, while 5 Hz stimulation did not change CNV amplitude. In normal subjects transient inhibition of motor cortex causes an increase of cortical events preceding external-cued voluntary movements, as a probable compensatory phenomena able to maintain an efficient motor performance. PMID- 22230894 TI - Glucocorticoids impair maternal anxiolysis during lactation. AB - Lactating female rats show a maternal anxiolysis signal, which is part of the behavioral pattern that develops post-partum and seems to be related to hormonal changes during lactation. Assuming that glucocorticoids modulate prolactin and oxytocin secretion, we evaluated the effect of dexamethasone on behavior responses of fear and anxiety in lactating rats. For this study, the non lactating and lactating rats were submitted to an elevated T-maze and open field tests. In the elevated T-maze, the lactating rats showed a decrease in inhibitory avoidance and an increase in the escape time when compared with the non-lactating group. The lactating rats that had been treated with dexamethasone showed increased initial avoidance latency when compared with lactating rats treated with vehicle. The same result was found in the subsequent repetitions (avoidance 1 and 2). In addition, there was a reduction in one-way escape time for the lactating rats that were treated with dexamethasone. The lactating rats treated with vehicle had increase of number central entries, and consequently, the anti thigmotactic effect increased relative to non-lactating rats. Thus, lactating rats showed a reduced emotional responsiveness as evaluated by elevated T-maze and open field tests, which characterizes maternal anxiolysis. In addition, it could be concluded that the dexamethasone impairs maternal anxiolysis in lactating female rats. PMID- 22230895 TI - Establishment of retinal progenitor cell clones by transfection with Pax6 gene of mouse induced pluripotent stem (iPS) cells. AB - We previously reported that transfection of Pax6 gene which regulated early events in eye development into mouse ES cells brought about their differentiation into retinal progenitors. Here, we attempted to establish cloned retinal progenitors which had ability to further differentiate into photoreceptor like cells by transfecting mouse induced pluripotent stem (iPS) cells with Pax6 gene. Undifferentiated iPS cells were transfected with Pax6 cDNA, followed by selection with G418. After limiting dilution culture, we selected cloned Pax6-transfected cells, which simultaneously expressed mRNAs of Nestin, Musashi1, Six3 and Chx10 for further characterization. We obtained totally 8 clonally expanding Pax6 transfected cells. They started to express mRNAs of Brn3b, Cone-rod homeobox (Crx), pkc, CD73, rhodopsin and the gamma-subunit of rod cGMP phosphodiesterase (PDEgamma). Flow cytometric analysis revealed that almost half of the cells were CD73+, a marker of photoreceptor precursors. Western blotting confirmed cytoplasmic protein expression of rhodopsin. High KCl stimulation increased free Ca influx into the cells on Ca(2+) imaging. iPS cells transfected with Pax6 gene, followed by subsequent limiting dilution culture became retinal progenitors including photoreceptor like cells. The cloned cell lines may be useful for analyzing differentiation requirement of retinal progenitors. PMID- 22230896 TI - Direct visualization of retinoic acid in the rat hypothalamus: an immunohistochemical study. AB - In order to increase our knowledge about the distribution of vitamins in the mammalian brain, we have developed a highly specific antiserum directed against retinoic acid with good affinity (10(-8) M), as evaluated by ELISA tests. In the rat brain, no immunoreactive fibers containing retinoic acid were detected. Cell bodies containing retinoic acid were only found in the hypothalamus. This work reports the first visualization and the morphological characteristics of cell bodies containing retinoic acid in the mammalian paraventricular hypothalamic nucleus and in the dorsal perifornical region, using an indirect immunoperoxidase technique. The restricted distribution of retinoic acid in the rat brain suggests that this vitamin could be involved in very specific physiological mechanisms. PMID- 22230897 TI - Adiponectin activates endothelial nitric oxide synthase through AMPK signaling after subarachnoid hemorrhage. AB - Adiponectin is produced from fatty tissue and has been reported to be involved with metabolic syndrome. Recently, adiponectin has been demonstrated to play a neuroprotective role against cerebral ischemia. In this study, we explored the time-course serial expression changes of adiponectin in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH) and the effects of adiponectin on cerebral arteries. The concentrations of adiponectin were measured serially until day 14 in CSF of 8 patients with SAH. The CSF samples obtained from 6 patients suffering from an unruptured aneurysm were used as controls. Serum samples were collected from 6 healthy adult volunteers. Rat cerebral arteries were incubated with adiponectin (2MUg/ml). Western blot analysis using AMP-activated protein kinase alpha (AMPKalpha), phosphorylated (p)-AMPKalpha at Thr(172), endothelial nitric oxide synthase (eNOS), p-eNOS at Ser(1177) and actin antibodies was then performed. The adiponectin concentrations in serum and control CSF were 17,670+/ 3748ng/ml and 9.2+/-3.0ng/ml, respectively. After SAH, the concentration of adiponectin in the CSF significantly increased on the first post-SAH day and gradually decreased thereafter. Adiponectin significantly phosphorylated both the AMPKalpha and eNOS of the cerebral arteries. Our findings suggest that adiponectin is significantly increased in the CSF after SAH, resulting in the activation of AMPKalpha and eNOS. Adiponectin plays an important role against cerebral vasospasm via the AMPK/eNOS signaling pathway. PMID- 22230898 TI - The costs of changing an intended action: movement planning, but not execution, interferes with verbal working memory. AB - How much cognitive effort does it take to change a movement plan? In previous studies, it has been shown that humans plan and represent actions in advance, but it remains unclear whether or not action planning and verbal working memory share cognitive resources. Using a novel experimental paradigm, we combined in two experiments a grasp-to-place task with a verbal working memory task. Participants planned a placing movement toward one of two target positions and subsequently encoded and maintained visually presented letters. Both experiments revealed that re-planning the intended action reduced letter recall performance; execution time, however, was not influenced by action modifications. The results of Experiment 2 suggest that the action's interference with verbal working memory arose during the planning rather than the execution phase of the movement. Together, our results strongly suggest that movement planning and verbal working memory share common cognitive resources. PMID- 22230901 TI - Hepatocellular carcinoma in 2011: Genomics in hepatocellular carcinoma--a big step forward. PMID- 22230900 TI - Management of low back pain with facet joint injections and nerve root blocks under computed tomography guidance. A prospective study. AB - OBJECTIVES: The aim of this work was to assess the performance of facet joint and nerve root infiltrations under computed tomography guidance for the management of low back pain and to investigate the complications and patient tolerance. MATERIALS AND METHODS: The study was board-certified and informed consent was obtained from all patients. In 1 year, 86 consecutive patients (47 male, 39 female, age range 47-87 years, mean age 63) with low back pain for more than 2 years were included. All patients were clinically examined and had cross sectional imaging performed before the procedure. Fifty-five facet joint infiltrations and 31 nerve blocks were performed under computed tomography guidance. All patients completed two valid pain questionnaires before and 3 months after the procedures. At the same time, they were clinically examined by the referring Orthopaedic Surgeon. The pain response was assessed by comparing the scores of the questionnaires. The improvement in clinical examination findings was assessed as well. RESULTS: In patients who underwent facet joint infiltrations, long-term pain improvement was achieved in 79% and in those with nerve blocks in 85%. Immediate pain relief was demonstrated in 83% of patients with nerve infiltrations. No complications were observed. All procedures were very well tolerated by patients. CONCLUSIONS: Facet joint and nerve infiltrations under computed tomography guidance constitute an accurate and safe method that could be used to relieve low back pain and minimize the risk of disability. PMID- 22230902 TI - Pediatrics: An oligosaccharide can prevent necrotizing enterocolitis in rats. PMID- 22230905 TI - IBD in 2011: Advances in IBD management--towards a tailored approach. PMID- 22230903 TI - Diagnosis and management of nonvariceal upper gastrointestinal bleeding. AB - Nonvariceal upper gastrointestinal bleeding (UGIB) is a major cause of morbidity and mortality worldwide. Despite the improvements in the management of this condition in western countries, mortality rates have remained at 5-10% over the past decade. This article presents the main recommendations for the management of UGIB. Pre-endoscopic management (including use of scoring scales, nasogastric tube placement and blood pressure stabilization) is crucial for triage and optimal resuscitation of patients, and should include a multidisciplinary approach at an early stage. Unless the patient has specific comorbidities, transfusion should only be considered if their hemoglobin level is <=70 g/l. Endoscopic therapy, the cornerstone of therapeutic management of high-risk lesions, should not be delayed for more than 24 h following admission. Several endoscopic techniques, mostly using clips or thermal methods, are available and new approaches are emerging. When endoscopy fails, surgery or arterial embolization should be considered. Although the efficacy of prokinetics and high dose intravenous PPI prior to endoscopy is controversial, the use of an intravenous PPI following endoscopy is strongly recommended. Antiplatelet therapy should be suspended and resumed in 3-5 days. Finally, all patients should be tested for Helicobacter pylori by serology in the acute setting. PMID- 22230909 TI - Enhancing the predictability of complex rehabilitation with a removable CAD/CAM fabricated long-term provisional prosthesis: a clinical report. AB - Implementing any definitive prosthetic treatment of the residual edentulous ridge involves several risks. The patient's expectations may not be completely fulfilled as such treatment procedures include major changes in function and esthetics. Innovative materials, such as high-density polymers based on a highly cross-linked polymethylmetacrylate (PMMA) or composite resin for CAD/CAM manufacturing are an alternative treatment option. They enhance the predictability of complex rehabilitations, especially in situations where the prognosis of the residual ridge behavior over time is challenging. This article describes an innovative approach of an extended pretreatment phase by using intraoral scanning and CAD/CAM technology for the fabrication of a long-term provisional removable dental prosthesis made of high-density polymer. PMID- 22230910 TI - Management of interproximal soft tissue with a resin-bonded prosthesis after immediate implant placement: a clinical report. AB - This report describes immediate implant placement after the extraction of a vertically fractured tooth. During the healing phase, a resin-bonded prosthesis was inserted as a provisional restoration. After the creation of the optimal emergence profile and papillae with the provisional restoration, the definitive metal ceramic crown was fabricated. PMID- 22230911 TI - Comparison of the anatomic crown width/length ratios of unworn and worn maxillary teeth in Asian and white subjects. AB - STATEMENT OF PROBLEM: Various aspects of anatomic tooth dimensions have been examined in a number of studies where data are primarily based on the measurements obtained from white subjects. Additional factors such as ethnicity should be considered to produce a more comprehensive analysis. PURPOSE: The purpose of this study is to compare the anatomic crown dimensions of extracted maxillary teeth in Asian and white populations. MATERIAL AND METHODS: The width/length ratio (%) was calculated with standardized digital images of extracted maxillary anterior teeth from 157 Asian and 142 white subjects. Statistical analysis was performed to compare the 4 tooth groups (central incisiors, lateral incisiors, canines, and premolars) of the 2 ethnicities. The distribution of the outcome variables were examined for normality with the Kolmigorov-Smirnov test. Independent sample t tests were used to examine differences in outcomes in Asian and white subjects. RESULTS: There was a significant difference (P<.05) in the width/length ratios of all maxillary anterior teeth in Asian and white subjects. In addition, there was a significant difference in the width of unworn central incisors and the length of worn lateral incisors and canines. CONCLUSIONS: Ethnicity influences width/length ratios for all 4 anterior maxillary teeth. Anterior maxillary teeth in Asian subjects appear to be more slender when compared with those in white subjects. PMID- 22230912 TI - The effect of multiple firings on the marginal integrity of pressable ceramic single crowns. AB - STATEMENT OF PROBLEM: The marginal adaptation of metal ceramic crowns is affected by firing cycles for veneering porcelain application. The effect of multiple firings on the marginal integrity of pressable ceramic core crowns is unknown. PURPOSE: The purpose of this in vitro study was to evaluate the effect of repeated firing cycles on the marginal discrepancy of veneered (layered) pressable ceramic anterior crowns with 2 different finish line configurations. MATERIAL AND METHODS: Forty pressable ceramic single anterior complete crowns were fabricated from 2 systems (IPS Empress Esthetic and IPS e.max Press) with 2 finish line designs (shoulder, chamfer) on epoxy resin dies. Specimens were divided into 4 groups of 10, and measurements were made after pressing (control) and after 5 veneer firing stages: 1) wash, 2) first incisal, 3) second incisal, 4) characterization and glazing, and 5) corrective. The change in vertical marginal discrepancy was measured with a light microscope at 4 locations: facial (F), mesial (M), lingual (L), and distal (D) surfaces. One-way ANOVA (alpha-=.05) was used to evaluate the marginal change. A Student-Newman-Keuls test was also used for comparison among the groups. RESULTS: There were no significant changes in the vertical marginal integrity related to ceramic type and marginal location and their interactions. However, there was a significant marginal integrity change during the characterization and glazing firing stage. (P<.05) CONCLUSIONS: The marginal gap increased for both systems during veneer application and decreased during the characterization and glazing firing cycle. The total marginal fit change after 5 firings was 0.33 MUm for IPS e.max Press, and 0.27 MUm for IPS Empress Esthetic. PMID- 22230913 TI - Influence of recasting different types of dental alloys on gingival fibroblast cytotoxicity. AB - STATEMENT OF PROBLEM: Surplus alloy from the initial casting is commonly reused with the addition of new alloy. This recasting procedure could affect the cytotoxicity of dental alloys. PURPOSE: The purpose of this in vitro study was to evaluate the effect of repeated casting of high-noble and base metal alloys on gingival fibroblast cytotoxicity. MATERIAL AND METHODS: Disk-shaped specimens (5 * 2 mm, n=60) of a high-noble (Au-Pt) and 2 base metal (Ni-Cr and Cr-Co, n=20) alloys were prepared with 100% new alloy and 50%, 65%, and 100% once recast alloy. The elemental composition of specimens was analyzed with X-ray energy dispersive spectroscopy. Five specimens from each group were conditioned in saline with 3% fetal bovine serum albumin. The conditioning media were analyzed for elemental release with atomic absorption spectroscopy. Cytotoxic effects were assessed on human gingival fibroblast with a 3-(4.5-dimethylthiazol-2-yl)-2.5 diphenyl tetrazolium bromide (MTT) colorimetric assay. The data were analyzed with 1-way and 2-way ANOVA and Tukey's HSD multiple comparison test (alpha-=.05). RESULTS: Elemental compositions of Co-Cr and Au-Pt alloys were significantly different among casting protocols. Elemental release of Co-Cr and Ni-Cr alloys was significantly different between new and recast specimens (P<.001). Nickel release increased with recast alloy addition. The 2-way ANOVA showed a significant effect of the casting procedure (P<.001) alloy group (P<.001) and their interaction for cytotoxicity (P<.001). The Ni-Cr alloy groups with 65% and 100% recast alloy had lower cellular activity than all other specimens (P<.001). CONCLUSIONS: The results of this study indicated that alloys containing nickel have increased cytotoxic effects and that composition of the alloys affected the cytotoxicity. Furthermore, recasting nickel-containing alloys with 65% surplus metal addition significantly increased the cytotoxic activity. PMID- 22230914 TI - CAD/CAM fabricated complete dentures: concepts and clinical methods of obtaining required morphological data. AB - The clinical impression procedures described in this article provide a method of recording the morphology of the intaglio and cameo surfaces of complete denture bases and also identify muscular and phonetic locations for the prosthetic teeth. When the CAD/CAM technology for fabricating complete dentures becomes commercially available, it will be possible to scan the denture base morphology and tooth positions recorded with this technique and import those data into a virtual tooth arrangement program where teeth can be articulated and then export the data to a milling device for the fabrication of the complete dentures. A prototype 3-D tooth arrangement program is described in this article that serves as an example of the type of program than can be used to arrange prosthetic teeth virtually as part of the overall CAD/CAM fabrication of complete dentures. PMID- 22230915 TI - The influence of different registration techniques on condyle displacement and electromyographic activity in stomatognathically healthy subjects: a prospective study. AB - STATEMENT OF PROBLEM: It is unclear whether different intermaxillary registration techniques are related to a physiological condylar position that permits neuromuscular equilibrium. PURPOSE: This study analyzes and quantifies the effects of different registration techniques on the condyle position and how the registration technique modulates bilateral masseter and anterior temporalis muscle electromyographic activity. MATERIAL AND METHODS: Three-dimensional electronic condylar position analysis (EPA) with an ultrasound-based jaw-tracking system and surface electromyographic activity (sEMG) was recorded during the registration of a manually guided centric relation (CR), maximal intercuspation (MI), and Gothic arch tracing guided centric relation (DIR method). Participants were 26 stomatognathically healthy volunteers (mean age, 30.6 +/-9.5 years). Data were analyzed by 1-way ANOVA and post hoc Bonferroni correction (alpha=.05). RESULTS: EPA showed significant differences (P<.001) for CR, MI, and DIR in the vertical, sagittal, and horizontal axes. The condyle position during DIR was found to be significantly more anteriorly and inferiorly located than with CR (P<.001) and MI (P<.04). There were no significant differences in the mean muscle activity among CR, MI, and DIR. Muscular symmetry ranged from 63.87 to 81.47%. Significantly higher symmetry for the anterior temporalis (P=.03) and the masseter (P=.03) was found during the DIR than with CR. Torque coefficients (potential laterodeviating effect) were between 88.02% (CR) and 89.94% (MI). CONCLUSIONS: Registration technique significantly influenced the condyle position, while mean muscular activity was minimally affected. With respect to muscular balance and activation, the DIR position proved to be capable of inducing the greatest motor unit activity when compared with manually guided CR and MI. PMID- 22230916 TI - Use of transparent vinyl polysiloxane in a minimally invasive approach for creating composite resin undercuts for partial removable dental prostheses. AB - A technique using a transparent vinyl polysiloxane material developed for use with light-polymerized composite resin and that does not require a lubricant is presented for creating composite resin undercuts for partial removable dental prosthesis clasps. With a surveyor, the undercut is waxed on the diagnostic cast according to the intended path of insertion. The transparent vinyl polysiloxane is used to fabricate a template for the undercut. The template is used intraorally to create the undercut in composite resin on the abutment tooth. PMID- 22230917 TI - Trial insertion procedure for milled lithium disilicate restorations in the precrystallized state. AB - A treatment protocol with lithium disilicate restorations and a computer-aided design and computer-aided manufacturing (CAD/CAM) fabrication process is proposed for the restoration of teeth in the esthetic zone. The technique involves trial insertion of restorations at the precrystallized stage, allowing verification of the marginal fit and evaluation of the internal adaptation and overall esthetic plan to ensure an optimal clinical result for the definitive restorations. Furthermore, this procedure allows most adjustments to the lithium disilicate ceramic to be made before crystallization and minimizes potential surface and subsurface damage to the definitive restorations. PMID- 22230918 TI - Effects of 29-h total sleep deprivation on local cold tolerance in humans. AB - To study the effects of a 29-h total sleep deprivation (TSD) on local cold tolerance, 10 healthy men immersed their right hand for 30 min in a 5 degrees C water bath (CWI) after a 30-min rest period in a thermoneutral environment (Control), after a normal night (NN) and after a 29-h TSD. CWI was followed by a 30-min passive rewarming (Recovery). Finger 2 and 4 skin temperatures (Tfi2, Tfi4) and finger 2 cutaneous vascular conductance (CVC) were monitored to study cold-induced vasodilation (CIVD). Rectal temperature (Tre), mean skin temperature ([Formula: see text]), heart rate (HR) and blood pressure (BP) were also measured. Blood samples were collected at the end of the Control, at the lower and at the first maximal Tfi2 values during CWI and at Recovery. Tfi2, Tfi4 and CVC did not differ after TSD at Control, whereas they were reduced during CWI ( 2.6 +/- 0.7 degrees C for Tfi2; -2 +/- 0.8 degrees C for Tfi4, -79 +/- 25% for relative CVC, P < 0.05) as during Recovery (-4.9 +/- 1.9 degrees C for Tfi2, -2.6 +/- 1.8 degrees C for Tfi4, -70 +/- 22% for relative CVC, P < 0.05). After TSD, the lower CVC values appeared earlier during CWI (-59 +/- 19.6 s, P < 0.05). After TSD at Control and CWI, plasma endothelin levels were higher and negatively correlated with Tfi2, Tfi4 and CVC. However, no effect of TSD was found on the number and amplitude of CIVD and in Tre, HR, BP and catecholamines, for all periods. We concluded that TSD induced thermal and vascular changes in the hand which impair the local cold tolerance, suggesting that TSD increases the risk of local cold injuries. PMID- 22230919 TI - Observations on saliva osmolality during progressive dehydration and partial rehydration. AB - A need exists to identify dehydrated individuals under stressful settings beyond the laboratory. A predictive index based on changes in saliva osmolality has been proposed, and its efficacy and sensitivity was appraised across mass (water) losses from 1 to 7%. Twelve euhydrated males [serum osmolality: 286.1 mOsm kg(-1) H(2)O (SD 4.3)] completed three exercise- and heat-induced dehydration trials (35.6 degrees C, 56% relative humidity): 7% dehydration (6.15 h), 3% dehydration (with 60% fluid replacement: 2.37 h), repeat 7% dehydration (5.27 h). Expectorated saliva osmolality, measured at baseline and at each 1% mass change, was used to predict instantaneous hydration state relative to mass losses of 3 and 6%. Saliva osmolality increased linearly with dehydration, although its basal osmolality and its rate of change varied among and within subjects across trials. Receiver operating characteristic curves indicated a good predictive power for saliva osmolality when used with two, single-threshold cutoffs to differentiate between hydrated and dehydrated individuals (area under curve: 3% cutoff = 0.868, 6% cutoff = 0.831). However, when analysed using a double-threshold detection technique (3 and 6%), as might be used in a field-based monitor, <50% of the osmolality data could correctly identify individuals who exceeded 3% dehydration. Indeed, within the 3-6% dehydration range, its sensitivity was 64%, while beyond 6% dehydration, this fell to 42%. Therefore, while expectorated saliva osmolality tracked mass losses within individuals, its large intra- and inter-individual variability limited its predictive power and sensitivity, rendering its utility questionable within a universal dehydration monitor. PMID- 22230920 TI - Does long-term swimming participation have a deleterious effect on the adult female skeleton? AB - Swimming is a popular activity for Australian women with proven cardiovascular benefits yet lacks the features thought necessary to stimulate positive adaptive changes in bone. Given that peak bone mass is attained close to the end of the second decade, we asked whether swimming was negatively associated with bone mineral density in premenopausal women beyond this age. Bone mass and retrospective physical activity data were gathered from 43 female swimmers and 44 controls (mean ages 40.4 and 43.8 years, respectively). Swimmers were recruited from the Australian Union of Senior Swimmers International while controls were healthy community dwellers with similar lean mass, fat mass, height, weight and body mass index. None of the participants had a history of medical complaints nor use of medications known to affect bone. Dual energy X-ray absorptiometry was used to determine areal bone mineral density at total body, lumbar spine, proximal femur, distal radius and tibia while self-administered questionnaires were used to approximate historical and recent physical activity and calcium intake. Swimmers had averaged over 2 hours of swimming per week for the past 5 years and 1.45 h/week over lifetime with no systematic swimming exposure for controls. Lifetime exposure to weight bearing and impact exercise were similar. There were no intergroup differences for bone mass at any site though controls had higher incidence of low bone mass/osteoporosis. No differences in bone mass were detected between swimmers in the upper and lower quartiles for swim participation for any period. Long-term swim participation did not compromise areal bone mineral density. PMID- 22230924 TI - Effect of enterocin 4231 in Slovak fermented salami Puchov after its experimental inoculation with Listeria innocua Li1. AB - BACKGROUND: Enteroccocci occur and may compete well in fermented sausages and Enterococcus faecium represents that species of the lactic acid bacteria which can be found in the fermented sausages. The representatives of this species can produce bacteriocins with predominant anti-listerial effect. Therefore, the effect of enterocin (Ent) 4231 produced by Enterococcus faecium CCM 4231 strain with probiotic properties was tested in a dry fermented salami Puchov (Slovak product) experimentally inoculated with L. innocua Li1 strain (10(7) cfu/ml). MATERIAL AND METHODS: The bulk salami mixture was prepared in the pilot plant and 2.5 kg for each of three trials were transferred to the laboratory for the experiments. Three independent trials were conducted, each comprising then five salami samples (0.500 g). Trial A (reference control) involved only untreated salami mixture. Trial B represented salami mixture inoculated with Listeria innocua Li1 (10(7) cfu/ml). For trial C, Ent 4231 possessing activity 6400 AU/ml was added into the salami mixture inoculated with L. innocua Li1 (Li/Ent). The mixtures were stuffed into collagen casings and the flat shape salamis were transferred back to the pilot plant and treated according to conditions typical for this product and stored for 4 weeks. RESULTS: The initial number of L. innocua Li1 in the inoculated salami mixture was 10(4) cfu/ml.After Ent 4231 addition, the count of Listeria detected in the salami samples inoculated with Li1 and treated with Ent 4231 was 3.64+/-0.14 cfu/ml; difference 0.40 logarithmic cycles was noted between Li samples and Li/Ent samples. On day 2, the difference 1.86 log cycles was noted between Li1 and Li/Ent samples. Although, in weeks 3 and 4, slight increase in Li1 cells was determined in Li salamis, the difference in the detection of Li1 cells in Li salamis and Li/Ent samples was even higher than that immedially after Ent addition (difference 2.30; 2.48 log cycles). Bacteriocin activity itself was not recovered from Li/Ent salamis. The pH of the all salamis was almost at the same level. Water activity and water content were not influenced. CONCLUSION: Addition of Ent 4231 during processing of salami Puchov experimentally inoculated with L. innocua Li1 has lead to decrease of Li1 cell growth, although the bacteriocin activity of Ent itself was not possible to detect in salami samples. The pH value, water activity, as well as sensory character of the final products were not negatively influenced. PMID- 22230921 TI - Effect of acute and short-term oral salbutamol treatments on maximal power output in non-asthmatic athletes. AB - This study aimed to clarify the controversial effects of acute and short-term salbutamol (SAL) intake on sprint performance in healthy athletes. Based on the results of previous studies, an anabolic effect for the short-term treatment and increased glycolysis in both treatments were hypothesized. Eight male recreational athletes completed force-velocity exercise tests after administration of placebo (gelatin), acute oral SAL (6 mg) or short-term oral SAL (12 mg day(-1) for 3 weeks), using a double-blind and randomized protocol. A friction-loaded cycle ergometer fitted with a strain gauge, and an incremental encoder ensured accurate measurement of the force-velocity relationship during sprints. Mechanical data were averaged during each pedal downstroke. Compared with placebo after both acute and 3 weeks of continuous treatment, the force velocity relationship shifted to the right with power output gains of 14 and 8% (p < 0.001), respectively. This effect was less marked for 3 weeks of continuous treatment compared with acute administration (p < 0.001), suggesting a down regulation in adrenoceptors. Our first hypothesis thus seems rejected. Significantly higher end-of-exercise and recovery blood lactate concentrations were found under SAL compared with placebo (p < 0.001), supporting our second hypothesis. In conclusion, these data indicate that oral administration of SAL is an effective ergogenic aid for sprint exercise in non-asthmatic athletes. Moreover, an acute treatment seems to be more effective than 3 weeks of continuous treatment. PMID- 22230925 TI - The content of protein and of amino acids in Jerusalem artichoke tubers (Helianthus tuberosus L.) of red variety Rote Zonenkugel. AB - INTRODUCTION: Jerusalem artichoke (Helianthus tuberosus L.) is grown primarily for its edible tubers, which were first cultivated by native Americans before the arrival of the Europeans. Unlike most tubers, but in common with other members of the Asteraceae, the tubers store fructans instead of starch. Fructans are non digestible carbohydrates considered functional food ingredients because they affect body processes in ways that result in better health and in many diseases prevention. However, the Jerusalem artichoke deserves attention not only because of the content of fructans, recent studies also indicate a high protein content, including essential amino acids. MATERIAL AND METHODS: The aim of the work was to establish the content of protein and amino acids in Jerusalem artichoke tubers (Helianthus tuberosus L.) of red variety--Rote Zonenkugel. The content of protein was estimated by Dumas method. The amino acids composition was analysed with ion change chromatography with postcolumn derivatisation and detection of ninhydryn reaction with automatic amino acids analyser. RESULTS: The assessed liophylisate was characterised by high protein content (6.36%) in comparison to chicory (which is the main industrial source of fructans) and to commonly consumed potatoes. There was shown a few times higher content of essential amino acids (also of methionine) in comparison to chicory and potato. The examined essential amino acids were present in very advantagenous proportions. CONCLUSIONS: In Jerusalem artichoke tubers of Rote Zonenkugel variety of the high content of protein was established in comparison to other plant sources. The high content was found of amino acids with special stress on essential amino acids (esp. sulphur ones). PMID- 22230926 TI - Antioxidant activity of apples--an impact of maturity stage and fruit part. AB - BACKGROUND: Recently, many studies have been oriented towards improving methods and efficiency of antioxidants recovery from different fruit and their wastes.The aim of the study was to evaluate antioxidant potential of apple seeds and peel, which constitute the fruit industry wastes, and compare it to apple flesh. Antioxidant activity of apples at different maturity and storage stage were analysed too. MATERIAL AND METHODS: The Idared and the Sampion cultivars of apples were used in the study. Antioxidant activity was estimated using ABTS and DPPH assays, and polyphenols profile was determined by HPLC method. RESULTS: Seeds of analysed apple cultivars were characterised by a significantly higher antioxidant capacity and by higher concentrations of polyphenols analysed when compared to their peel and flesh. There were present two predominant compounds: phloridzin in seeds (84% and 72%) and quercetin glycosides in peels (54% and 38%, Idared and Sampion cultivars, respectively). No quercetin glycosides in seeds were found. The capacity to scavenge an ABTS radical, but not DPPH, decreased during ripening of apples, while cold storage resulted in enhanced antioxidant potential. CONCLUSION: It can be concluded that unripe apples together with apple seeds and peel (fruit industry wastes) constitute a valuable source of polyphenols. PMID- 22230927 TI - The influence of selected prebiotics on the growth of lactic acid bacteria for bio-yoghurt production. AB - BACKGROUND: Prebiotics are a category of nutritional com-pounds grouped together, not necessarily by structural similarities, but by ability to promote the growth of spe-cific beneficial (probiotic) gut bacteria. Fructooligosaccharides (FOS) and inulin are among the most famous prebiotic compounds. In order to improve viability of probiotic bacteria during storage, fermented food should be supplemented with prebiotics. MATERIAL AND METHODS: Yoghurts were produced from skimmed milk powder and prebiotics (FOS, inulin or resistant starch), which were added at concentrations of 1%, 2% and 3%. Yoghurts were stored in +4 degrees C for three weeks. Every week each kind of fermented drink was examined in order to check the growth of lactic acid bacteria. Apparent viscosity and texture of bio yoghurt were determinated during refrigerated storage. RESULTS: The FOS and inulin addition to yoghurt caused an increase in the numbers of all bacteria in comparison to control yoghurt obtained without addition of prebiotics. The viable counts of Str. thermophilus, Lb. acidophilus and Bifidobacterium sp. when 1% of FOS was added to yoghurt were about 9 log cfu/g, 7.8 log cfu/g and 7.7 log cfu/g, respectively. In the presence of 1% of inulin, streptococci and bifidobacteria reached the growth at the level 8.8 log cfu/g and 7.5 respectively. Hardness and adhesiveness of yoghurt obtained with addition resistant starch increased systematically during 21 days of refrigerated storage. CONCLUSIONS: The numbers of lactic acid bacteria in obtained bio-yoghurts were sufficient in 97% of samples (10(6)-10(9) cfu/g) according to FAO/WHO protocols. Generally, viability of bacteria was sufficient for 14 days and then their numbers decreased but usually not below 10(6) cfu/g. Prebiotics as FOS and inulin added to bio-yoghurt exhibited stimulatory effect on growth Lb. acidophilus and Bifidobacterium sp. Addition of prebiotics caused an increase in apparent viscosity and hardness (in case of FOS) and decrease in syneresis of obtained bio-yoghurts. PMID- 22230928 TI - Reduction of water consumption in bioethanol production from triticale by recycling the stillage liquid phase. AB - BACKGROUND: The distillery stillage is a major and arduous byproduct generated during ethanol production in distilleries. The aim of this study was to evaluate the possibility of the stillage recirculation in the mashing process of triticale for non-byproducts production and reducing the fresh water consumption. The number of recirculation cycles which can be applied without disturbances in the ethanol fermentation process was investigated. MATERIAL AND METHODS: Winter triticale BOGO and "Ethanol Red" Saccharomyces cerevisiae yeast were used in the experiments. The method of non-pressure cooking was used for gelatinizingthe triticale, commercial alpha-amylase SPEZYME ETHYL and glucoamylase FERMENZYME L 400 were applied for starch liquefaction and saccharification. The process was conducted at 30 degrees C for 72 h, next after distillation the stillage was centrifuged and the liquid fraction was used instead of 75% of process water. RESULTS: Ethanol yield from triticale fermentations during 40 cycles ranged between 82% and 95% of theoretical yield preserving yeast vitality and quantity on the same level. The obtained distillates were characterized with enhanced volatile compounds (fusel oil, esters, aldehydes, methanol) as well as protein and potassium concentrations. CONCLUSIONS: The liquid part of stillage was proved that can be reused instead of water in bioethanol production from triticale, without disturbing the fermentation process. This investigated solution of distillery byproducts utilization (liquid phase of stillage) constitutes the way which could significantly decrease the bioethanol production costs by reducing the water consumption, as well as wastewater production. PMID- 22230929 TI - Evaluation of the effect of pretreatment and preservation on macro- and microelements retention in flageolet (Phaseolus vulgaris L.) bean seeds. AB - BACKGROUND: Legume seeds, including beans, are a good source of mineral constituents. The level of these compounds depends among other factors, on the species, cultivar and the methods of processing applied. However, there are no studies in the literature which deal with the content of mineral constituents in physiologically immature bean seeds. MATERIAL AND METHODS: The aim of this study was to evaluate the retention of ash and 13 mineral constituents in immature seeds of three bean cultivars. The investigation included raw, blanched and cooked seeds and three products prepared for consumption after 12-month storage: a frozen product obtained using the traditional method (blanching-freezing-frozen storage-cooking); a frozen product obtained using the modified method (cooking freezing-frozen storage-defrosting and heating in a microwave oven); and a sterilized canned product. RESULTS: The application of technological processes; the storage of frozen and sterilized products; and the preparation of frozen products for consumption had an effect on minerals content in finished products. The frozen product obtained using the modified method retained greater amounts of the investigated elements (apart from calcium, lead and cadmium) than the traditional frozen product. Canned bean seeds retained less ash, phosphorus, potassium, calcium, magnesium, sodium and iron than the products of the two ways of freezing, while the retention of the remaining constituents depended on the cultivar. CONCLUSIONS: Modified method of freezing of immature bean seeds resulted in greater retention of the investigated components in products prepared for consumption than the traditional method of freezing or canning. PMID- 22230930 TI - Evaluation of the mineral composition of breadstuff and frequency its consumption. AB - BACKGROUND: The aim of the study was to assess some selected minerals (Ca, Mg, Na, K, P, Fe, Zn, Cu, Mn) in different types of breadstuff. Moreover, the frequency of breadstuff consumption was determined in a selected group of students at one of Lublin universities. MATERIAL AND METHODS: The material for the study was breadstuff available on the consumer market, produced from wheat and rye flour, of varied degree of grinding. In the samples the content of dry matter, crude ash and minerals (Ca, Mg, Na, K, P, Mn, Cu, Fe and Zn) was determined. A questionnaire investigation was performed in a group of 100 university students in Lublin. The questionnaire included questions which were helpful in determining the frequency of the consumed breadstuff. RESULTS: The content of mineral elements in breadstuff depended on its recipe's composition and their higher share was noted in rye and mixed-flour bread. Whole wheat bread was richer in minerals in comparison with white bread. Assuming that a statistical Pole consumes daily 166 g of bread, it may be calculated that the men consumes daily with bread 512 mg of P (73% of RDA) and 0.7 mg of Cu (ca. 78% of RDA), ca. 20 mg of Ca (1.6-2.0% of AI), 93 mg of Mg (ca. 22-30% of RDA), 602 mg of Na (40-50% of AI), 183 mg of K (3.9% of AI), 4.5 mg of Fe (25-45% of RDA) and 3 mg of Zn (29-40% of RDA). CONCLUSION: Bread is an important source of minerals, especially phosphorus and copper. Among students an excessive consumption of white bread should be noted contrasting with a low intake of whole wheat or whole meal bread. PMID- 22230931 TI - Effect of diet composition and mixture of selected food additives on the erythrocytic system and iron metabolism in peripheral blood of male rats. AB - BACKGROUND: Metabolic processes of food additives which are "exogenous xenobiotics" are catalysed, primarily, by enzymes located in microsomes of hepatocytes affiliated to P-450 cytochrome superfamily, containing iron. The aim of the study was to investigate the effect of diet composition and selected food additives on the erythrocyte system and iron metabolism in peripheral blood of male rats. MATERIAL AND METHODS: The experiment was carried out on 30 male rats sorted into three equinumerous groups. For drinking animals received pure, settled tap water, animals from group III were receiving additionally an aqueous solution of sodium (nitrate), potassium nitrite, benzoic acid, sorbic acid and monosodium glutamate. RESULTS: Ascertained a significant effect of changes in diet composition on the increase in hematocrit marker value and the count of red blood cells in blood of animals examined. Used food additives diminished hemoglobin concentration, hematocrit value and red blood cell count, diminishing also iron concentration in serum, the total iron binding capacity and transferrin saturation with iron. CONCLUSIONS: Analysis of the results allowed ascertain adverse changes in values of the erythrocytic system markers, occurring under the influence of the applied mixture of food additives. Used food additives change the iron metabolism, most likely from the necessity of applied xenobiotics biotransformation by heme-containing monoxygenases of P-450 cytochrome. PMID- 22230932 TI - The influence of selected hypotensive drugs on the bioavailability of minerals from buckwheat groats in vitro enzymatic digestion. AB - BACKGROUND: The mineral status in hypertensive patients may be affected by hypotensive drugs. The aim of this study was to estimate the influence of hypotensive drugs (angiotensine converting enzyme inhibitors (ACE-I), beta blockers, Ca-antagonists, diuretics) on the potential bioavailability of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion. MATERIAL AND METHODS: The degree of release of magnesium, iron, zinc and copper from buckwheat groats was determined with and without (the control sample) an addition of hypotensive drugs. Four antihypertensive drugs in one dose (one tablet per sample) were analysed: metocard (a beta-blocker), cardilopin (a Ca-antagonist), apo-perindox (ACE-I) and indapen (a diuretic). The samples were subjected to enzymatic digestion under in vitro conditions. The content of minerals in buckwheat groats before and after enzymatic digestion was determined by flame atomic absorption spectrometry (AAS). RESULTS: It was found that cardilopin (amlodipine) and indapen (indapamide) significantly increased the release of zinc from groats. The degree of release of magnesium was higher and the release of iron was lower in samples with apo-perindox (perindopril) than in the control group. The release of copper was significantly decreased by indapen (indapamid). CONCLUSIONS: Amlodipine, perindopril and indapamide affected the release of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion. PMID- 22230933 TI - Comparison of DNA extraction methodologies used for assessing fungal diversity via ITS sequencing. AB - Traditional methods of assessing fungal exposure have been confounded by a number of limiting variables. The recent utilization of molecular methods such as internal transcribed spacer (ITS) sequencing of ribosomal RNA genes has provided improved insight into the diversity of fungal bioaerosols in indoor, outdoor and occupational environments. However, ITS analyses may also be confounded by a number of methodological limitations. In this study, we have optimized this technology for use in occupational or environmental studies. Three commonly used DNA extraction methodologies (UltraClean Soil kit, High Pure PCR Template kit, and EluQuik/DNeasy kit) were compared in terms of sensitivity and susceptibility to PCR inhibitors in dust for three common fungal bioaerosols, Aspergillus versicolor, Rhizopus microsporus and Wallemia sebi. Environmental dust samples were then studied using each extraction methodology and results were compared to viable culture data. The extraction methods differed in terms of their ability to efficiently extract DNA from particular species of fungi (e.g. Aspergillus versicolor). In addition, the ability to remove PCR inhibitors from dust samples was most effective using the soil DNA extraction kit. The species composition varied greatly between ITS clone libraries generated with the different DNA extraction kits. However, compared to viable culture data, ITS clone libraries included additional fungal species that are incapable of growth on solid culture medium. Collectively, our data indicated that DNA extraction methodologies used in ITS sequencing studies of occupational or environmental dust samples can greatly influence the fungal species that are detected. PMID- 22230934 TI - Simultaneous development of adenocarcinoma and gastrointestinal stromal tumor (GIST) in the stomach: case report. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) and adenocarcinoma are distinct neoplasms originating from different cell layers. Approximately 20% of patients with GIST develop other cancers. CASE PRESENTATION: We report a case of the coexistence of adenocarcinoma and gastrointestinal stromal tumor (GIST). Gastric endoscopy showed the ulcerated tumor with bleeding along the lesser curvature of the proximal stomach and a submucosal nodule that measured about 3 cm in diameter in the lower part of the stomach body. Their pathological examination showed gastric cancer (poorly differentiated diffuse adenocarcinoma) and GIST (low-risk category). Further, immunohistochemical staining for C-kit and CD34 was positive, while that for SMA and S-100 was negative. CONCLUSION: Although it is not easy to speculate on the coexistence of adenocarcinoma and GIST, pre-and post-operative diagnoses may be essential, and such cancer development is not considered to be unusual. PMID- 22230935 TI - Database for crude drugs and Kampo medicine. AB - A wiki-based repository for crude drugs and Kampo medicine is introduced. It provides taxonomic and chemical information for 158 crude drugs and 348 prescriptions of the traditional Kampo medicine in Japan, which is a variation of ancient Chinese medicine. The system is built on MediaWiki with extensions for inline page search and for sending user-input elements to the server. These functions together realize implementation of word checks and data integration at the user-level. In this scheme, any user can participate in creating an integrated database with controlled vocabularies on the wiki system. Our implementation and data are accessible at http://metabolomics.jp/wiki/. PMID- 22230936 TI - Mechanism of cell cycle disruption by multiple p53 pulses. AB - When the DNA damage is generated, the tumor suppressor gene p53 is activated and selects the cell fate such as the cell cycle arrest, the DNA repair and the induction of apoptosis. Recently, the p53 oscillation was observed in MCF7 cell line. However, the biological meaning of p53 oscillation was still unclear. Here, we constructed a novel mathematical model of cell cycle regulatory system with p53 signaling network to investigate the relationship between the p53 oscillation and the cell cycle progression. First, the simulated result without DNA damage agreed with the biological findings. Next, the simulations with DNA damage realized both the p53 oscillation and the cell cycle arrest, and indicated that the generation of multiple p53 pulses disrupted the cell cycle progression. Moreover, the simulated results showed that the cell cycle disruption was caused by the catastrophe of M phase in the cell cycle, which resulted from the decline in cyclin A/cyclin-dependent kinase 2. The results in this study suggested that the generation of multiple p53 pulses against DNA damage may be used as a marker of cell cycle disruption. PMID- 22230937 TI - Docking-calculation-based method for predicting protein-RNA interactions. AB - Elucidating protein-RNA interactions (PRIs) is important for understanding many cellular systems. We developed a PRI prediction method by using a rigid-body protein-RNA docking calculation with tertiary structure data. We evaluated this method by using 78 protein-RNA complex structures from the Protein Data Bank. We predicted the interactions for pairs in 78*78 combinations. Of these, 78 original complexes were defined as positive pairs, and the other 6,006 complexes were defined as negative pairs; then an F-measure value of 0.465 was obtained with our prediction system. PMID- 22230938 TI - Sign: large-scale gene network estimation environment for high performance computing. AB - Our research group is currently developing software for estimating large-scale gene networks from gene expression data. The software, called SiGN, is specifically designed for the Japanese flagship supercomputer "K computer" which is planned to achieve 10 petaflops in 2012, and other high performance computing environments including Human Genome Center (HGC) supercomputer system. SiGN is a collection of gene network estimation software with three different sub-programs: SiGN-BN, SiGN-SSM and SiGN-L1. In these three programs, five different models are available: static and dynamic nonparametric Bayesian networks, state space models, graphical Gaussian models, and vector autoregressive models. All these models require a huge amount of computational resources for estimating large scale gene networks and therefore are designed to be able to exploit the speed of 10 petaflops. The software will be available freely for "K computer" and HGC supercomputer system users. The estimated networks can be viewed and analyzed by Cell Illustrator Online and SBiP (Systems Biology integrative Pipeline). The software project web site is available at http://sign.hgc.jp/ . PMID- 22230939 TI - Linear regression models predicting strength of transcriptional activity of promoters. AB - We developed linear regression models which predict strength of transcriptional activity of promoters from their sequences. Intrinsic transcriptional strength data of 451 human promoter sequences in three cell lines (HEK293, MCF7 and 3T3), which were measured by systematic luciferase reporter gene assays, were used to build the models. The models sum up contributions of CG dinucleotide content and transcription factor binding sites (TFBSs) to transcriptional strength. We evaluated prediction accuracies of the models by cross validation tests and found that they have adequate ability for predicting transcriptional strength of promoters in spite of their simple formalization. We also evaluated statistical significance of the contributions and proposed a picture of regulatory code hidden in promoter sequences. That is, CG dinucleotide content and TFBSs mainly determine strength of transcriptional activity under ubiquitous and specific environments, respectively. PMID- 22230941 TI - Resuscitation science: a role for observation? PMID- 22230942 TI - Effects of variation in temperature management on cerebral performance category scores in patients who received therapeutic hypothermia post cardiac arrest. AB - AIM: To assess differences in cerebral performance category (CPC) in patients who received therapeutic hypothermia post cardiac arrest by time to initiation, time to target temperature, and duration of therapeutic hypothermia (TH). METHODS: A secondary data analysis was conducted using hospital-specific data from the international cardiac arrest registry (INTCAR) database. The analytic sample included 172 adult patients who experienced an out-of-hospital cardiac arrest and were treated in one Midwestern hospital. Measures included time from arrest to ROSC, arrest to TH, arrest to target temperature, and length of time target temperature was maintained. CPC was assessed at three points: transfer from ICU, discharge from hospital, and post discharge follow-up. RESULTS: Average age was 63.6 years and 74.4% of subjects were male. Subjects had TH initiation a mean of 94.4 min (SD 81.6) after cardiac arrest and reached target temperature after 309.0 min (SD 151.0). In adjusted models, the odds of a poor neurological outcome increased with each 5 min delay in initiating TH at transfer from ICU (OR=1.06, 95% C.I. 1.02-1.10). Similar results were seen for neurological outcomes at hospital discharge (OR=1.06, 95% C.I. 1.02-1.11) and post-discharge follow-up (OR=1.08, 95% C.I. 1.03-1.13). Additionally the odds of a poor neurological outcome increased for every 30 min delay in time to target temperature at post discharge follow-up (OR=1.17, 95% C.I. 1.01-1.36). CONCLUSION: In adults undergoing TH post cardiac arrest, delay in initiation of TH and reaching target temperature differentiated poor versus good neurologic outcomes. Randomized trials assessing the range of current recommended guidelines for TH should be conducted to establish optimal treatment protocols. PMID- 22230943 TI - Compartmental differences of circulating tumor cells in colorectal cancer. AB - BACKGROUND: The prognostic role of circulating tumor cells (CTCs) has been established for colorectal cancer (CRC). We investigated the qualitative and quantitative detection of CTC in the central (CVBC) and mesenteric (MVBC) venous blood compartments to elucidate the patterns of hematogenous tumor cell dissemination in patients with CRC. METHODS: A total of 200 patients were enrolled prospectively. Blood samples were collected from the tumor-draining vein and via a central venous line. CTCs were detected and quantified by using the CellSearch system. Factors associated with CTC detection in both compartments were analyzed by using univariate and multivariate analyses. RESULTS: CTC analyses were performed in the CVBC and MVBC in 200 and 80 patients, respectively. CTCs were found at a higher rate (P=0.01) and at a higher count (P=0.006) in the MVBC compared with the CVBC. On multivariate analyses, stage IV disease (odds ratio, 3.83; 95% confidence interval, 1.42-10.35) and increased preoperative carbohydrate antigen 19-9 level (odds ratio, 3.57; 1.30-9.79) were associated with CTC detection in the CVBC. CTCs were detected more frequently (P=0.05) and at higher numbers (P=0.05) in the CVBC of patients with low compared with mid or high rectal tumors. CONCLUSIONS: The qualitative and quantitative detection of CTCs is higher in the MVBC compared with the CVBC of patients with CRC. PMID- 22230944 TI - Micrometastases in sentinel lymph nodes: not getting lost in translation. PMID- 22230945 TI - How to measure cortical folding from MR images: a step-by-step tutorial to compute local gyrification index. AB - Cortical folding (gyrification) is determined during the first months of life, so that adverse events occurring during this period leave traces that will be identifiable at any age. As recently reviewed by Mangin and colleagues(2), several methods exist to quantify different characteristics of gyrification. For instance, sulcal morphometry can be used to measure shape descriptors such as the depth, length or indices of inter-hemispheric asymmetry(3). These geometrical properties have the advantage of being easy to interpret. However, sulcal morphometry tightly relies on the accurate identification of a given set of sulci and hence provides a fragmented description of gyrification. A more fine-grained quantification of gyrification can be achieved with curvature-based measurements, where smoothed absolute mean curvature is typically computed at thousands of points over the cortical surface(4). The curvature is however not straightforward to comprehend, as it remains unclear if there is any direct relationship between the curvedness and a biologically meaningful correlate such as cortical volume or surface. To address the diverse issues raised by the measurement of cortical folding, we previously developed an algorithm to quantify local gyrification with an exquisite spatial resolution and of simple interpretation. Our method is inspired of the Gyrification Index(5), a method originally used in comparative neuroanatomy to evaluate the cortical folding differences across species. In our implementation, which we name local Gyrification Index (lGI(1)), we measure the amount of cortex buried within the sulcal folds as compared with the amount of visible cortex in circular regions of interest. Given that the cortex grows primarily through radial expansion(6), our method was specifically designed to identify early defects of cortical development. In this article, we detail the computation of local Gyrification Index, which is now freely distributed as a part of the FreeSurfer Software (http://surfer.nmr.mgh.harvard.edu/, Martinos Center for Biomedical Imaging, Massachusetts General Hospital). FreeSurfer provides a set of automated reconstruction tools of the brain's cortical surface from structural MRI data. The cortical surface extracted in the native space of the images with sub-millimeter accuracy is then further used for the creation of an outer surface, which will serve as a basis for the lGI calculation. A circular region of interest is then delineated on the outer surface, and its corresponding region of interest on the cortical surface is identified using a matching algorithm as described in our validation study(1). This process is repeatedly iterated with largely overlapping regions of interest, resulting in cortical maps of gyrification for subsequent statistical comparisons (Fig. 1). Of note, another measurement of local gyrification with a similar inspiration was proposed by Toro and colleagues(7), where the folding index at each point is computed as the ratio of the cortical area contained in a sphere divided by the area of a disc with the same radius. The two implementations differ in that the one by Toro et al. is based on Euclidian distances and thus considers discontinuous patches of cortical area, whereas ours uses a strict geodesic algorithm and include only the continuous patch of cortical area opening at the brain surface in a circular region of interest. PMID- 22230946 TI - Fighting food temptations: the modulating effects of short-term cognitive reappraisal, suppression and up-regulation on mesocorticolimbic activity related to appetitive motivation. AB - The premise of cognitive therapy is that one can overcome the irresistible temptation of highly palatable foods by actively restructuring the way one thinks about food. Testing this idea, participants in the present study were instructed to passively view foods, up-regulate food palatability thoughts, apply cognitive reappraisal (e.g., thinking about health consequences), or suppress food palatability thoughts and cravings. We examined whether these strategies affect self-reported food craving and mesocorticolimbic activity as assessed by functional magnetic resonance imaging. It was hypothesized that cognitive reappraisal would most effectively inhibit the mesocorticolimbic activity and associated food craving as compared to suppression. In addition, it was hypothesized that suppression would lead to more prefrontal cortex activity, reflecting the use of more control resources, as compared to cognitive reappraisal. Self-report results indicated that up-regulation increased food craving compared to the other two conditions, but that there was no difference in craving between the suppression and cognitive reappraisal strategy. Corroborating self-report results, the neuroimaging results showed that up-regulation increased activity in important regions of the mesocorticolimbic circuitry, including the ventral tegmental area, ventral striatum, operculum, posterior insular gyrus, medial orbitofrontal cortex and ventromedial prefrontal cortex. Contrary to our hypothesis, suppression more effectively decreased activity in the core of the mesocorticolimbic circuitry (i.e., ventral tegmental area and ventral striatum) compared to cognitive reappraisal. Overall, the results support the contention that appetitive motivation can be modulated by the application of short-term cognitive control strategies. PMID- 22230947 TI - Neural systems for guilt from actions affecting self versus others. AB - Guilt is a core emotion governing social behavior by promoting compliance with social norms or self-imposed standards. The goal of this study was to contrast guilty responses to actions that affect self versus others, since actions with social consequences are hypothesized to yield greater guilty feelings due to adopting the perspective and subjective emotional experience of others. Sixteen participants were presented with brief hypothetical scenarios in which the participant's actions resulted in harmful consequences to self (guilt-self) or to others (guilt-other) during functional MRI. Participants felt more intense guilt for guilt-other than guilt-self and guilt-neutral scenarios. Guilt scenarios revealed distinct regions of activity correlated with intensity of guilt, social consequences of actions, and the interaction of guilt by social consequence. Guilt intensity was associated with activation of the dorsomedial PFC, superior frontal gyrus, supramarginal gyrus, and anterior inferior frontal gyrus. Guilt accompanied by social consequences was associated with greater activation than without social consequences in the ventromedial and dorsomedial PFC, precuneus, posterior cingulate, and posterior superior temporal sulcus. Finally, the interaction analysis highlighted select regions that were more strongly correlated with guilt intensity as a function of social consequence, including the left anterior inferior frontal gyrus, left ventromedial PFC, and left anterior inferior parietal cortex. Our results suggest these regions intensify guilt where harm to others may incur a greater social cost. PMID- 22230949 TI - At the rhythm of language: brain bases of language-related frequency perception in children. AB - What neural mechanisms underlie language and reading acquisition? Slow rhythmic modulations in the linguistic stream (below 8 Hz) mark syllable and word boundaries in the continuous linguistic stream, potentially helping children master the words and structures of their language. Converging evidence across language and reading research suggests that children's sensitivity to these slow rhythmic modulations is important for language and reading acquisition. In infancy, children produce rhythmically alternating syllables, or babbles, at a slow frequency of ~1.5 Hz or 660 ms (Petitto et al., 2001). In early grades, children's sensitivity to slow rhythmic modulations correlates with their reading ability (Goswami, 2011). We used functional Near Infrared (fNIRS) imaging to investigate the brain bases of "language rhythm" in beginning readers (ages 6-9). Right hemisphere showed an overall greater activation toward the slow rhythmic stimuli, and left hemisphere showed greater activation toward 1.5 Hz, relative to faster and slower frequencies. The findings suggest that while right hemisphere might have an overall better ability to process rhythmic sensitivity, left hemisphere might have a select sensitivity to a preferred range of slow rhythmic modulations-a range that might be particularly salient to brain mechanisms responsible for cross-modal language processing and reading acquisition. PMID- 22230948 TI - Species-specific response to human infant faces in the premotor cortex. AB - The human infant face represents an essential source of communicative signals on the basis of which adults modulate their interactions with infants. Behavioral studies demonstrate that infants' faces activate sensitive and attuned responses in adults through their gaze, face expression, voice, and gesture. In this study we aimed to identify brain responses that underlie adults' general propensity to respond to infant faces. We recorded fMRI during adults' (non-parents) processing of unfamiliar infant faces compared to carefully matched adult faces and infrahuman mammal infant and adult faces. Human infant faces activated several brain systems including the lateral premotor cortex, supplementary motor area, cingulate cortex, anterior insula and the thalamus. Activation of these brain circuits suggests adults' preparation for communicative behavior with infants as well as attachment and caregiving. The same brain regions preferentially responded to human infant faces when compared to animal infant faces, indicating species-specific adult brain responses. Moreover, results of support vector machine based classification analysis indicated that these regions allowed above chance-level prediction of brain state during perception of human infant faces. The complex of brain responses to human infant faces appears to include biological mechanisms that underlie responsiveness and a caring inclination toward young children which appear to transcend adult's biological relationship to the baby. PMID- 22230952 TI - Bacterial pathogenesis: a balancing act for LLO and PLC. PMID- 22230950 TI - Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. AB - Some individuals who are infected with HIV rapidly deteriorate shortly after starting antiretroviral therapy, despite effective viral suppression. This reaction, referred to as immune reconstitution inflammatory syndrome (IRIS), is characterized by tissue-destructive inflammation and arises as CD4(+) T cells re emerge. It has been proposed that IRIS is caused by a dysregulation of the expanding population of CD4(+) T cells specific for a co-infecting opportunistic pathogen. Here, we argue that IRIS instead results from hyper-responsiveness of the innate immune system to T cell help, a mechanism that may be shared by the many manifestations of IRIS that occur following the reversal of other types of immunosuppression in pathogen-infected hosts. PMID- 22230951 TI - Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. AB - In little more than 30 years, Lyme disease, which is caused by the spirochaete Borrelia burgdorferi, has risen from relative obscurity to become a global public health problem and a prototype of an emerging infection. During this period, there has been an extraordinary accumulation of knowledge on the phylogenetic diversity, molecular biology, genetics and host interactions of B. burgdorferi. In this Review, we integrate this large body of information into a cohesive picture of the molecular and cellular events that transpire as Lyme disease spirochaetes transit between their arthropod and vertebrate hosts during the enzootic cycle. PMID- 22230953 TI - BC047440 antisense eukaryotic expression vectors inhibited HepG2 cell proliferation and suppressed xenograft tumorigenicity. AB - The biological functions of the BC047440 gene highly expressed by hepatocellular carcinoma (HCC) are unknown. The objective of this study was to reconstruct antisense eukaryotic expression vectors of the gene for inhibiting HepG(2) cell proliferation and suppressing their xenograft tumorigenicity. The full-length BC047440 cDNA was cloned from human primary HCC by RT-PCR. BC047440 gene fragments were ligated with pMD18-T simple vectors and subsequent pcDNA3.1(+) plasmids to construct the recombinant antisense eukaryotic vector pcDNA3.1(+)BC047440AS. The endogenous BC047440 mRNA abundance in target gene transfected, vector-transfected and naive HepG(2) cells was semiquantitatively analyzed by RT-PCR and cell proliferation was measured by the MTT assay. Cell cycle distribution and apoptosis were profiled by flow cytometry. The in vivo xenograft experiment was performed on nude mice to examine the effects of antisense vector on tumorigenicity. BC047440 cDNA fragments were reversely inserted into pcDNA3.1(+) plasmids. The antisense vector significantly reduced the endogenous BC047440 mRNA abundance by 41% in HepG(2) cells and inhibited their proliferation in vitro (P < 0.01). More cells were arrested by the antisense vector at the G(1) phase in an apoptosis-independent manner (P = 0.014). Additionally, transfection with pcDNA3.1(+)BC047440AS significantly reduced the xenograft tumorigenicity in nude mice. As a novel cell cycle regulator associated with HCC, the BC047440 gene was involved in cell proliferation in vitro and xenograft tumorigenicity in vivo through apoptosis independent mechanisms. PMID- 22230954 TI - Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. AB - Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule--D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P(4))--acting as an 'intermolecular glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P(4), which may act as a regulator--potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities. PMID- 22230955 TI - X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. AB - Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GABA (gamma-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes the extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain 1a and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances. PMID- 22230956 TI - Evolution of increased complexity in a molecular machine. AB - Many cellular processes are carried out by molecular 'machines'-assemblies of multiple differentiated proteins that physically interact to execute biological functions. Despite much speculation, strong evidence of the mechanisms by which these assemblies evolved is lacking. Here we use ancestral gene resurrection and manipulative genetic experiments to determine how the complexity of an essential molecular machine--the hexameric transmembrane ring of the eukaryotic V-ATPase proton pump--increased hundreds of millions of years ago. We show that the ring of Fungi, which is composed of three paralogous proteins, evolved from a more ancient two-paralogue complex because of a gene duplication that was followed by loss in each daughter copy of specific interfaces by which it interacts with other ring proteins. These losses were complementary, so both copies became obligate components with restricted spatial roles in the complex. Reintroducing a single historical mutation from each paralogue lineage into the resurrected ancestral proteins is sufficient to recapitulate their asymmetric degeneration and trigger the requirement for the more elaborate three-component ring. Our experiments show that increased complexity in an essential molecular machine evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes. PMID- 22230958 TI - Evolutionary biology: A ratchet for protein complexity. PMID- 22230957 TI - Cysteinyl leukotriene type I receptor desensitization sustains Ca2+-dependent gene expression. AB - Receptor desensitization is a universal mechanism to turn off a biological response; in this process, the ability of a physiological trigger to activate a cell is lost despite the continued presence of the stimulus. Receptor desensitization of G-protein-coupled receptors involves uncoupling of the receptor from its G-protein or second-messenger pathway followed by receptor internalization. G-protein-coupled cysteinyl leukotriene type I (CysLT1) receptors regulate immune-cell function and CysLT1 receptors are an established therapeutic target for allergies, including asthma. Desensitization of CysLT1 receptors arises predominantly from protein-kinase-C-dependent phosphorylation of three serine residues in the receptor carboxy terminus. Physiological concentrations of the receptor agonist leukotriene C(4) (LTC(4)) evoke repetitive cytoplasmic Ca(2+) oscillations, reflecting regenerative Ca(2+) release from stores, which is sustained by Ca(2+) entry through store-operated calcium-release activated calcium (CRAC) channels. CRAC channels are tightly linked to expression of the transcription factor c-fos, a regulator of numerous genes important to cell growth and development. Here we show that abolishing leukotriene receptor desensitization suppresses agonist-driven gene expression in a rat cell line. Mechanistically, stimulation of non-desensitizing receptors evoked prolonged inositol-trisphosphate-mediated Ca(2+) release, which led to accelerated Ca(2+) dependent slow inactivation of CRAC channels and a subsequent loss of excitation transcription coupling. Hence, rather than serving to turn off a biological response, reversible desensitization of a Ca(2+) mobilizing receptor acts as an 'on' switch, sustaining long-term signalling in the immune system. PMID- 22230959 TI - Structure of the carboxy-terminal region of a KCNH channel. AB - The KCNH family of ion channels, comprising ether-a-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K(+)-channel subfamilies, is crucial for repolarization of the cardiac action potential, regulation of neuronal excitability and proliferation of tumour cells. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family. However, despite the importance of the C-linker/CNBHD for the function of KCNH channels, the structural basis of ion-channel regulation by the C-linker/CNBHD is unknown. Here we report the crystal structure of the C-linker/CNBHD of zebrafish ELK channels at 2.2-A resolution. Although the overall structure of the C-linker/CNBHD of ELK channels is similar to the cyclic-nucleotide-binding domain (CNBD) structure of the related hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels, there are marked differences. Unlike the CNBD of HCN, the CNBHD of ELK displays a negatively charged electrostatic profile that explains the lack of binding and regulation of KCNH channels by cyclic nucleotides. Instead of cyclic nucleotide, the binding pocket is occupied by a short beta-strand. Mutations of the beta-strand shift the voltage dependence of activation to more depolarized voltages, implicating the beta-strand as an intrinsic ligand for the CNBHD of ELK channels. In both ELK and HCN channels the C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. However, in the zebrafish ELK structure there is a reorientation in the C-linker so that the subunits form dimers instead of tetramers, as observed in HCN channels. These results provide a structural framework for understanding the regulation of ion channels in the KCNH family by the C-linker/CNBHD and may guide the design of specific drugs. PMID- 22230960 TI - Molecular recognition of a single sphingolipid species by a protein's transmembrane domain. AB - Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids. PMID- 22230961 TI - Maternal and paternal age are jointly associated with childhood autism in Jamaica. AB - Several studies have reported maternal and paternal age as risk factors for having a child with Autism Spectrum Disorder (ASD), yet the results remain inconsistent. We used data for 68 age- and sex-matched case-control pairs collected from Jamaica. Using Multivariate General Linear Models (MGLM) and controlling for parity, gestational age, and parental education, we found a significant (p < 0.0001) joint effect of parental ages on having children with ASD indicating an adjusted mean paternal age difference between cases and controls of [5.9 years; 95% CI (2.6, 9.1)] and a difference for maternal age of [6.5 years; 95% CI (4.0, 8.9)]. To avoid multicollinearity in logistic regression, we recommend joint modeling of parental ages as a vector of outcome variables using MGLM. PMID- 22230962 TI - Thyroid cancer surgery in Germany: an analysis of the nationwide DRG statistics 2005-2006. AB - PURPOSE: In 2004, a Diagnosis Related Groups (DRG)-based hospital reimbursement system became mandatory in Germany. The aim of this study was to provide nationwide data on the surgery of thyroid cancer by analyzing DRG statistics of the years 2005 and 2006. METHODS: The unit of analysis was hospital admission with a diagnosis of thyroid cancer. We assessed the influence of age, sex and region on the relative frequency of thyroid cancer-related hospitalisations with surgery of the thyroid and we measured the association between hospitalisation rates and incidence rates of thyroid cancer among the Federal States of Germany. RESULTS: Over the period 2005 to 2006, 11,107 thyroid cancer-associated hospitalisations included surgical treatment of the thyroid. The age-standardised DRG-based hospitalisation rates and the corresponding cancer registry-based incidences of thyroid cancer were positively associated. Overall, 68% of the hospitalisations with thyroid surgery included a total thyroidectomy. The percentage of surgery of the thyroid with a total thyroidectomy was nearly identical among men and women, decreased among men aged over 60 and varied considerably by region (minimum, 48% in Saarland; maximum, 78% in Saxony-Anhalt). CONCLUSIONS: Our analyses of DRG statistics provide for the first time representative population-based data of the surgical management of thyroid cancer patients in Germany. Despite an identical health care system all over Germany and existing guidelines for surgical treatment of thyroid cancer, we observed a considerable regional variation in the proportion of total thyroidectomies performed in Germany. PMID- 22230963 TI - The safety of energy-based devices in open thyroidectomy: a prospective, randomised study comparing the LigaSureTM (LF1212) and the Harmonic(r) FOCUS. AB - PURPOSE: The options for haemostasis and dissection during modern thyroid surgery include the use of a bipolar vessel sealing system and ultrasonic technology. The aim of this study was to compare these energy-based devices (EBDs) with respect to their use in open thyroidectomy. METHODS: The FOCUS Shear (F) and LigaSure LF1212 (L) were evaluated. A total of 182 consecutive patients scheduled for open thyroidectomy were prospectively randomised into two similarly sized groups. The parameters of operative time, morbidity, incision length, postoperative pain and hospital stay were analysed. RESULTS: The main clinically primary endpoints of the two devices were identical in the study as the rate of nerve lesions, bleeding, drainage, operative time and postoperative calcium concentration with no significant differences with respect to the instrument utilised. The mean length of the incision was greater in the F group (p < 0.05). Patients in the F group were more likely to complain of pain while swallowing (p < 0.001). Early postoperative measurements of intact parathyroid hormone plasma levels revealed that although the levels were within the reference range, they were significantly lower in the F group (p < 0.001). Oral calcium supplementation was significantly higher and more prolonged in the F group. CONCLUSIONS: The present study demonstrated no significant difference in the rates of postoperative morbidity associated with these two different EBDs used. Differences in clinically less significant were founded and focused on. PMID- 22230964 TI - Sense of coherence as an independent predictor of health-related quality of life among coronary heart disease patients. AB - PURPOSE: The aim of this study was to determine whether sense of coherence (SOC) at baseline predicts health-related quality of life (HRQoL) at 12-28-month follow up among patients with coronary heart disease when controlled for sociodemographic and medical variables. METHODS: A total of 179 consecutive patients (58.28 +/- 6.52 years, 16.8% women) scheduled for coronary angiography (CAG) were interviewed before CAG and 12-28 months after. SOC was measured with the 13-item Orientation to Life Questionnaire. HRQoL was measured using the Short Form Health Survey 36 (SF-36), from which the mental and physical component summaries (MCS, PCS) were calculated. The relationship between SOC and HRQoL was examined using regression analyses. RESULTS: SOC proved to be a significant predictor of the MCS-score (B = 0.29; 95% CI = 0.17-0.41) and PCS-score (B = 0.18; 95% CI = 0.06-0.31) when not adjusted for possible confounding sociodemographic and medical variables. After adjustment for sociodemographic and medical variables, SOC remained a predictor of the MCS-score (B = 0.26; 95% CI = 0.14-0.39). SOC also remained a predictor of the PCS-score when controlled for gender, age and family income; however, the association disappeared after adjustment for functional status (B = 0.07; 95% CI = -0.05 to 0.19). CONCLUSIONS: SOC is a predictor of mental and physical HRQoL at 12-28-month follow-up, crude and also after adjustment. Patients undergoing CAG with low SOC thus deserve particular attention in regard to the maintenance and improvement of their HRQoL. PMID- 22230965 TI - Satisfaction with care as a quality-of-life predictor for stroke patients and their caregivers. AB - PURPOSE: We sought to identify indicators associated with the quality of life (QoL) of stroke patients and caregivers. METHODS: The cross-sectional study was conducted at nine Dutch stroke service facilities involving 251 stroke patients and their caregivers. We used the EuroQol (EQ-5D) and Satisfaction with Stroke Care questionnaires, and included the variables (1) disability at hospital admission, (2) length of hospital stay, (3) demographic data, and (4) caregivers' relationship with stroke patients. The Actor-Partner (patient-caregiver) Interdependence Model (APIM) was used to examine dependence between patients' and caregivers' QoL scores through dyad membership. RESULTS: Patients' age was significantly related to their QoL, and caregivers' age and educational level were significantly related to their QoL. Patients' disability on hospital admission and length of stay were associated with patients' QoL, and their disability on admission was related to caregivers' QoL. No relationship was found between length of stay and caregivers' QoL. Satisfaction with care was associated with both patients' and caregivers' QoL. CONCLUSIONS: The APIM distinguished the different roles of patients and caregivers while acknowledging the interdependence of their QoL scores. Satisfaction with care was identified as important indicator of stroke patients' and caregivers' QoL. PMID- 22230966 TI - [Thiamine, pyridoxine and cobalamine. From myths to pharmacology and clinical practice]. AB - Vitamins are not uncommonly uncritically prescribed by neurologists and other medical professions. The effects of vitamins are, however, often pharmacologically and biochemically well-defined. This offers the opportunity for a rational scientific approach to treatment. In this article the biochemical and pharmacological mode of action of vitamins B1 (thiamine), B6 (pyridoxine) and B12 (cobalamine) will be discussed and modern approaches to the diagnosis and treatment of clinical states of hypervitaminoses (B6) and vitamin deficiencies (B1, B6, and B12) will be presented. PMID- 22230967 TI - Characterization of changes to the mechanical properties of arteries due to cold storage using nanoindentation tests. AB - Understanding the effect of cold storage on arterial tissues is essential in various clinical and experimental practices. Cold storage techniques could significantly affect the post-cryosurgical or post-cryopreservation mechanical behavior of arteries. Previously, arteries were considered homogenous and elastic and the changes in material properties due to cold storage were inconclusive. In this study, using a custom-made nanoindentation device, changes to the local viscoelastic properties of porcine thoracic aorta wall due to three common storage temperatures (+4, -20, and -80 degrees C) within 24 h, 48 h, 1 week, and 3 weeks were characterized. The changes to both elastic and relaxation behaviors were investigated considering the multilayer, heterogeneous nature of the aortic wall. The results showed that the average instantaneous Young's modulus (E) of +4 degrees C storage samples decreased while their permanent average relaxation amplitude (G (infinity)) increased and after 48 h these changes became significant (10 and 13% for E and G (infinity), respectively). Generally, in freezer storage, E increased and G (infinity) showed no significant change. In prolonged preservation (>1 week), the results of -20 degrees C showed significant increase in E (20% after 3 weeks) while this increase for -80 degrees C was not significant, making it a better choice for tissue cold storage applications. PMID- 22230968 TI - A Cre-Lox P recombination approach for the detection of cell fusion in vivo. AB - The ability of two or more cells of the same type to fuse has been utilized in metazoans throughout evolution to form many complex organs, including skeletal muscle, bone and placenta. Contemporary studies demonstrate fusion of cells of the same type confers enhanced function. For example, when the trophoblast cells of the placenta fuse to form the syncytiotrophoblast, the syncytiotrophoblast is better able to transport nutrients and hormones across the maternal-fetal barrier than unfused trophoblasts(1-4). More recent studies demonstrate fusion of cells of different types can direct cell fate. The "reversion" or modification of cell fate by fusion was once thought to be limited to cell culture systems. But the advent of stem cell transplantation led to the discovery by us and others that stem cells can fuse with somatic cells in vivo and that fusion facilitates stem cell differentiation(5-7). Thus, cell fusion is a regulated process capable of promoting cell survival and differentiation and thus could be of central importance for development, repair of tissues and even the pathogenesis of disease. Limiting the study of cell fusion, is lack of appropriate technology to 1) accurately identify fusion products and to 2) track fusion products over time. Here we present a novel approach to address both limitations via induction of bioluminescence upon fusion (Figure 1); bioluminescence can be detected with high sensitivity in vivo(8-15). We utilize a construct encoding the firefly luciferase (Photinus pyralis) gene placed adjacent to a stop codon flanked by LoxP sequences. When cells expressing this gene fuse with cells expressing the Cre recombinase protein, the LoxP sites are cleaved and the stop signal is excised allowing transcription of luciferase. Because the signal is inducible, the incidence of false-positive signals is very low. Unlike existing methods which utilize the Cre/LoxP system(16, 17), we have incorporated a "living" detection signal and thereby afford for the first time the opportunity to track the kinetics of cell fusion in vivo. To demonstrate the approach, mice ubiquitously expressing Cre recombinase served as recipients of stem cells transfected with a construct to express luciferase downstream of a floxed stop codon. Stem cells were transplanted via intramyocardial injection and after transplantation intravital image analysis was conducted to track the presence of fusion products in the heart and surrounding tissues over time. This approach could be adapted to analyze cell fusion in any tissue type at any stage of development, disease or adult tissue repair. PMID- 22230969 TI - Quantitative and dynamic assay of single cell chemotaxis. AB - We have developed a single-cell assay platform that allows quantitative analysis of single cell chemotaxis by dynamic morphogenetic gradients, subcellular microscopic imaging and automated image analysis, and have applied these to measure cellular polarization of budding yeast. The computer-controlled microfluidic device regulates the gradient profile at any given time, and allows quantitative monitoring of cell morphology and the localization and expression of specific marker proteins during the dynamic polarization process. With this integrated experimental system, we compare the polarized signaling response of wild-type and far1-H7 mutant cells, which express a truncated Far1 protein unable to interact with Cdc24. Our results confirm that Far1 functions as an adaptor that recruits polarity establishment proteins to the site of extracellular signaling. Moreover, by changing the gradient profile and estimating the number of bound surface receptors, we quantitatively address why surprisingly small differences in pheromone concentration across yeast cells can be amplified into a robust polarity axis. This integrated single cell experimental platform thus opens the possibility to quantitatively investigate the molecular regulatory mechanism of chemotaxis in yeast, which serves as a paradigm to understand the fundamental processes involved in cancer metastasis, angiogenesis and axon generation. PMID- 22230970 TI - Review on the application of nanobiosensors in food analysis. AB - Nano-biosensors could be defined as biosensors, which are combined with nanotechnology by using several techniques. This strategy could be seen as a key to yielding device which exhibits rapid responses combined with very high sensitivities. In recent years as consumer demand traceability and legislators and account- ability in the food chain distribution has increased, the need for rapid and verifiable methods of food quality assurance has grown rapidly. Sensing technologies for food analysis including optical, chromatographic, colorimetric, etc. are employed. Biosensors allow the detection of analyte's wide spectrum in complex sample matrices, and have shown great promise in areas such as food analysis, environmental monitoring and bioprocess. Biosensors can be divided into six groups which depend on the method of signal transduction: magnetic, optical, electrochemical, mass, thermal and micromechanical sensors. The aim of this paper is to present the directions of the development of nano-biosensors and their useability to detect a range of biological and chemical compounds in the food industry market. PMID- 22230971 TI - Application of fast liquid chromatography for antioxidants analysis. AB - BACKGROUND: An intensive development of the Fast Liquid Chromatography (FLC) has been recently observed. It makes possible to reduce time analysis and improve resolution as well as sensitivity. The aim of this study was to separate the chosen antioxidants optimization using the FLC method. MATERIAL AND METHODS: The three various procedures for antioxidants analysis were compared. Mobile phases containing aqueous solution of formic acid, acetic acid, acetonitrile, and methanol were tested. Limit of detection (LOD), limit of quantification (LOQ), linearity and repeatability of each procedures were determined. RESULTS: Developed procedure enabled to separate all analytes and allowed to get low LOD levels and good repeatability. This procedure was used for antioxidants analysis in buckwheat and buckwheat products. CONCLUSION: Fast Liquid Chromatography allows to reduce time analysis and obtain good validation parameters. PMID- 22230972 TI - The effect of an addition of sodium chloride and sodium triphosphate on fat oxidation products in cold stored beef. AB - INTRODUCTION: Meat and processed meats, depending on the animal species and anatomical element from which they were obtained, exhibit a varied fat content (most typically from 10% to 80% dry matter). Fats are relatively unstable food components. The aim of this study was to determine the effect of an addition of model brines on lipid oxidation rate in the selected beef element stored under aerobic conditions and in vacuum at a temperature of 5 degrees C. MATERIAL AND METHODS: Material for analyses comprised beef: rump cut (R) and the heel of round (L). Meat was cured (at 20% in relation to raw material weight) with brine A, containing 1% NaCl in total weight and brine B, containing 1% NaCl and 0.3% sodium tripolyphosphate E 451i (including 56% P2O5 ). Meat after being massaged was stored under aerobic conditions (T) and in vacuum (P) at a temperature of 5 degrees C for 15 days. During storage of samples changes were determined in peroxide value (PV), contents of secondary fat decomposition products using the TBARS test as well as changes in pH value. RESULTS: It was observed that with an extension of sample storage time peroxide value was growing gradually, but the dynamics of this growth varied. Samples coming from the rump cut muscle, stored in the atmosphere with unlimited access of oxygen, were characterised by slightly, but statistically significantly higher peroxide values in comparison to the other tested samples. The highest increase in the TBARS test value was observed in samples stored under aerobic conditions and coming from the heel of round muscle, irrespective of the type of applied brine. Conducted analyses showed that vacuum packaging of meat, in comparison to the storage of samples at unlimited access of oxygen, effectively slowed down the increase in the content of secondary oxidation products determined by the TBARS test. The greatest effect of vacuum packaging was observed for the heel of round in brine A. CONCLUSIONS: Vacuum packaging, in comparison to storage of experimental samples under aerobic conditions, delayed the increase in peroxide value and effectively slowed down the increase in contents of secondary lipid oxidation products. Statistically significant changes in pH values were observed in the heel of round, irrespective of the type of applied brine, stored under aerobic conditions. PMID- 22230973 TI - Shelf life determination of the brined golden mullet Liza aurata during vacuum refrigerated storage using some quality aspect. AB - BACKGROUND: Salted fi sh products are popular in many countries around the world. Salting is one of the oldest techniques for fi sh preservation, and is essentially intended to increase the shelf-life of the product depressing water activity by means of dehydration and salt uptake by the fi sh muscle. However, the current demand for salted fi sh is driven more by the flavour of the product than for preservation purposes. Vacuum-packaging represents a static form of hypobaric storage. It is widely used in the food industry because of its effectiveness in reducing oxidative reactions in the product at relatively low cost. Low temperature storage is one of the primary methods to maintain fi sh quality, based on the reduction in the rates of microbiological, chemical and biochemical changes. MATERIAL AND METHODS: Fresh Golden mullets were rapidly beheaded, scaled, gutted and immediately washed with tap water then, samples were taken to the laboratory in ice box for chemical and microbial analysis of fresh fish, other samples were put in the brine (6 liter water and 2160 g salt was used for brine solution). After 14 days of brining, fish were taken out of brine solution and drained, then they were Vacuum Packed and labelled (each pack contained two fish about 1500 g weight). All the packs were stored in a refrigerator 4 degrees C. Some quality aspects including Total Volatile Nitrogen (TVN), Peroxide Value (PV), Thiobarbituric Acid (TBA), Total Viable Count (TVC), Halophilic Bacteria (HB) and presence of Clostridium Botulinum were determined in fresh mullets, fresh brined mullets after 14 days of brining, and in (Vacuum Packed) VP samples stored at 4 degrees C at intervals of 30, 60 and 90 days. RESULTS: TVN increased from ten mg/100 g in fresh brined after 14 days to 30.80 mg/100 g in VP brined Golden mullet after 90 days of storage at 4 degrees C, PV increased after brining from 1.50 meq/kg in fresh brined to 28.90 meq/kg in VP brined Golden mullet after 90 days of storage at 4 degrees C, TBA increased from 0.07 mg MDA/kg in fresh brined to 0.10 after 60 days and then, decreased to 0.09 mg MDA/kg in VP brined Golden mullet after 90 days of storage and TVC decreased from 4.70 log CFU/gr in fresh brined to 4.40 log CFU/ gr after 30 days and then, increased to 5.70 log CFU/gr in VP brined Golden mullet after 90 days of storage at 4 degrees C, HB increased from 4.55 log CFU/gr in fresh brined to 6.30 log CFU/gr after 90 days of storage period at 4 degrees C and exceeded the permissible level. Clostridium botulinum toxin was not detected in any of the samples throughout the storage. CONCLUSIONS: The results from this study clearly suggested that a combination of brining, vacuum packaging and storage at refrigerated temperature prolongs the shelf-life of Golden mullet to a great extent. Our findings revealed that the longest shelf-life was for VP brined Golden mullet stored at 4 degrees C is 30 days. PMID- 22230974 TI - Effect of hydrothermal processing on phenolic acids and flavonols contents in selected brassica vegetables. AB - BACKGROUND: Commonly occurring diseases can have the origin in oxidative processes ongoing in the human body. Vegetables of Brassicaceae family are the essential sources of natural antioxidants, especially phenolic compounds, in the human diet. The research was aimed to estimate the content of phenolic compounds in selected vegetables and their quantity changes during hydrothermal processes. MATERIAL AND METHODS: The vegetables subjected to analysis were: kale, broccoli, Brussels sprouts, and white and green cauliflower. The fresh and processed (blanched, cooked, frozen, cooked after freezing) vegetables were freeze-dried. The levels of phenolic acids and flavonols by HPLC method were estimated. RESULTS: The presence of derivatives of hydroxycinnamic acid, mainly of caffeic acid, p-coumaric acid, sinapic acid and of flavonols - kaempferol, and in smaller amounts of quercetin was found. The largest amounts of above components were present in kale (total 94.4 mg*100 g-1 of fresh matter), whereas the smallest amounts were found in white and green cauliflower - 3.6 mg*100 g-1 f.m. and 3.03 mg*100 g-1 f.m., respectively. The applied technological processes contributed to lover amounts of all tested compounds depending on the process and the vegetable kind. The biggest loses, up to 70-80%, took place during cooking of raw and previously frozen vegetables. CONCLUSIONS: Analysed Brassicaceae were characterized by high contents of the investigated flavonoids. The best source of those compounds was kale whereas the smallest amounts of searched components were presented in cauliflowers. The used hydrothermal processes led to losses of searched compounds. PMID- 22230975 TI - Enzymatic hydrolysis of potato pulp. AB - BACKGROUND: Potato pulp constitutes a complicated system of four types of polysaccharides: cellulose, hemicellulose, pectin and starch. Its composition makes it a potential and attractive raw material for the production of the second generation bioethanol. The aim of this research project was to assess the usefulness of commercial enzymatic preparations for the hydrolysis of potato pulp and to evaluate the effectiveness of hydrolysates obtained in this way as raw materials for ethanol fermentation. MATERIAL AND METHODS: Sterilised potato pulp was subjected to hydrolysis with commercial enzymatic preparations. The effectiveness of the preparations declared as active towards only one fraction of potato pulp (separate amylase, pectinase and cellulase activity) and mixtures of these preparations was analysed. The monomers content in hydrolysates was determined using HPLC method. RESULTS: The application of amylolytic enzymes for potato pulp hydrolysis resulted in the release of only 18% of raw material with glucose as the dominant (77%) constituent of the formed product. In addition, 16% galactose was also determined in it. The hydrolysis of the cellulose fraction yielded up to 35% raw material and the main constituents of the obtained hydrolysate were glucose (46%) and arabinose (40%). Simultaneous application of amylolytic, cellulolytic and pectinolytic enzymes turned out to be the most effective way of carrying out the process as its efficiency in this case reached 90%. The obtained hydrolysate contained 63% glucose, 25% arabinose and 12% other simple substances. CONCLUSION: The application of commercial enzymatic preparations made it possible to perform potato pulp hydrolysis with 90% effectiveness. This was achieved by the application of a complex of amylolytic, cellulolytic and pectinolytic enzymes and the hydrolysate obtained in this way contained, primarily, glucose making it a viable substrate for ethanol fermentation. PMID- 22230976 TI - Antibacterial and antioxidant activities of three endemic plants from Algerian Sahara. AB - BACKGROUND: Saharan plants are known by their high content of antioxidant products like phenolic compounds due to the extreme climatic conditions. They constitute the basis of treatments used by local population for various diseases. The purposes of this study were to measure the total phenolic compounds and total fl avonoid compounds, to determine antioxidant capacity, and to evaluate the antibacterial activity of three wild Saharan medicinal plants. MATERIAL AND METHODS: Hexane and ethyl acetate fractions of ethanol:water extract and the residu of the extracted aqueous layer of Ferula vesceritensis fruits, Genista saharae aerial parts and Zilla macropterae fruits were assayed to determine their antibacterial activity using the disc diffusion method against: Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923) and Pseudomonas aeruginosa (ATCC 27853). In addition, the total phenolic compounds and total flavonoids and antioxydant activity using DPPH test of ethyl acetate fractions (EAF) of plant parts studied were investigated. Gallic acid, quercetin and vitamin C were used for these parameters. RESULTS: Among the extracts tested, ethyl acetate fractions of all plants and hexane fraction of F. vesceritensis showed activity against S. aureus. Good activity was shown by EAF of G. saharae. According to the results, it is observed that Z. macropterae fruits possess a good antioxidant activity. CONCLUSION: The results indicate that the ethyl acetate fraction of G. sahara Aerial parts possesses a good antibacterial activity against S. aureus, which justifies its use in traditional medicine for treating respiratory diseases. Furthermore, evaluation of in vitro antioxidant capacity of Ethyl acetate fractions of these plants, particular Z. macroptera fruits, has also provided interesting results. Zilla macroptera fruits may therefore be a good source of antioxidants. PMID- 22230977 TI - Critical issues related to transfersomes - novel vesicular system. AB - It has become increasingly apparent that vesicular drug delivery elicits modest possessions in drug targeting. Transfersomes are a form of elastic or deformable vesicle, which were first introduced in the early 1990s. Elasticity can be achieved by using an edge activator in the lipid bilayer structure. Molecules greater than 500 Da normally do not cross the skin. This prevents epicutaneous delivery of the high molecular weight therapeutics as well as non-invasive transcutaneous immunisation. Transdermal route will always remain a lucrative area for drug delivery. With the advent of new categories of drugs like peptides this route has captured more focus to combat the problems related to their delivery through oral route. But the transdermal route is equally filled with the hopes and disappointments as the transport of drug through this route faces many problems especially for the large molecules. To answer this problem many approaches were adopted. One of the very recent approaches is the use of ultra deformable carrier systems (transfersomes). They have been used as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. Transfersomes penetrate through the pores of stratum corneum which are smaller than its size and get into the underlying viable skin in intact form. This is because of its deformable nature. The aim of this article is explanation the formation of micelle and vesicles, various types of vesicles, specifically focusing on transfersomes. PMID- 22230978 TI - A comparison of ABTS and DPPH methods for assessing the total antioxidant capacity of human milk. AB - INTRODUCTION: The Total Antioxidant Capacity (TAC) of human milk reflects the concentration and the activity of many components which prevent oxidative degradation of fats and proteins. This study compares the effectiveness of ABTS and DPPH tests with regard to the recovery, precision and sensitivity (detection and quantification limit) of (TAC) values in human milk. MATERIAL AND METHODS: TAC values were determined in twenty five samples of human milk obtained from healthy mothers, residents of Gdansk, on the 14th day postpartum. RESULTS: The average TAC of human milk determined by ABTS assay was 19.61 +/-3.311 mg TE (Trolox Equivalents)/100 cm3, the average values obtained by the DPPH assay reached 9.95 +/-4.36 mg TE/100 cm3. For each milk sample the TAC determined by the ABTS test was significantly higher than the values pro- duced by the DPPH test. The above findings can be attributed to the presence of substances whose spectra overlap with DPPH* spectra. ABTS test was characterised by a higher sensitivity and repeatability of the determination of TAC in human milk compared to the DPPH test. CONCLUSIONS: Comparing the calculated values for the validation parameters of both methods and taking into account the solubility of DPPH only in polar matrices, slower reaction of selected antioxidants with DPPH radical, and the presence in human milk constituents absorbing electromagnetic radiation in the absorption of DPPH be assumed that the ABTS test is more appropriate method of determining of TAC in breast milk. PMID- 22230979 TI - Somatic cells count in cow's bulk tank milk. AB - The objective of this study was therefore to present factors affecting somatic cell counts in bovine bulk milk as a result of intramammary infections as well as non-infectious factors. The paper presents also the impact of on-farm management practices on the level of bulk milk somatic cell counts and presents quality indicators in bulk tank milk. At the farm level bulk milk bacterial infection takes place through three main sources: bacterial contamination from the external surface of the udder and teats, from the surface of the milking equipment, and from mastitis microorganisms within the udder. The threshold of 200,000 cells/ml identifies bacteriological negative quarters of the udder. The counts of mammary pathogens in bulk tank milk are relatively low, on average not exceeding 1,000 cfu/ml. Environmental pathogens predominate in bulk tank milk samples with somatic cells count <300 * 10(3) ml. PMID- 22230980 TI - Pathological classification of canine mammary tumor based on quantifying mRNA levels of hormonal receptors, SATB1, and Snail in tissue and fine needle biopsy samples. AB - Cytological diagnosis is not generally conclusive enough to identify histopathological malignancy in canine mammary tumors (CMTs). To establish cytological examination using fine needle biopsy (FNB) samples, gene expressions of hormonal receptors, human epidermal growth factor receptor 2 (HER2), and transcription regulators (Special AT-rich binding protein 1: SATB1 and Snail) were investigated in both tissue and FNB samples of CMTs. In tissue samples of malignant CMTs, especially invasive ones, low expressions of hormonal receptors and high expressions of SATB1 and Snail were detected. On discriminant analysis of tissue samples, 73.2% of CMTs were correctly classified according to histopathological examinations. In FNB samples of malignant CMTs, low expressions of hormonal receptors were detected. On discriminant analysis of FNB samples, 74.2% of CMTs were correctly classified according to histopathological examination. In conclusion, FNB gene expressions had a utility for diagnosis of CMTs malignancy in some degree. By researching more sensitive genes for malignant CMTs, the gene examination of FNB samples from CMTs will become a useful diagnostic tool that can be performed easily without anesthesia and could predict tumor malignancy and invasion prior to surgical removal. PMID- 22230981 TI - Seasonal changes in spermatogenesis and peripheral testosterone concentration in raccoons (Procyon lotor) in Hokkaido. AB - Feral raccoons (Procyon lotor) have been increasing in number since 1979 and are currently subject to pest control in Hokkaido. One of the reasons for the increase in numbers is thought to be the high reproductive potential of raccoons, but little is known about their reproduction. The main aim of this study was to clarify seasonal changes in spermatogenesis and peripheral testosterone concentration of raccoons in Hokkaido. In the present study, external characteristics and histology of the testis and epididymis and the plasma testosterone concentration were investigated in 68 feral, male raccoons culled for pest control and once a month in one live, captive male. The feral males exhibited seasonal changes in spermatogenesis, showing active spermatogenesis in autumn, winter and spring (October-June) with noted spermatogenesis and inactive spermatogenesis in summer (July-September) with lower mean levels of spermatozoa in the cauda epididymis. Even in the inactive period, spermatozoa were observed in about half of the individuals (14/26); therefore, individuals producing spermatozoa existed every month throughout the year. Testosterone concentrations were significantly high in the winter mating season. In the captive male, the testosterone concentrations were low from June to August, and spermatozoa could not be observed from July to September. These results suggest that raccoons exhibit seasonality of reproduction, but the time and duration of spermatogenetic decline varies widely among individuals. This individual variation in the inactive period is a feature of male raccoon reproduction and is unique among seasonally breeding mammals. PMID- 22230982 TI - Transglutaminase 2: a novel autoantigen in canine idiopathic central nervous system inflammatory diseases. AB - Necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE) and granulomatous meningoencephalomyelitis (GME) are common idiopathic inflammatory central nervous system (CNS) diseases with unknown etiology in dogs. We previously showed that IgG autoantibodies in the cerebrospinal fluid (CSF) of NME cases reacted to unknown brain proteins as well as to glial fibrillary acidic protein (GFAP). In the present report, we evaluated the autoantibodies against transglutaminase2 (TG2) in the canine CNS diseases. CSF samples obtained from dogs with NME (n=19), NLE (n=7), GME (n=11) and miscellaneous CNS diseases (n=12) were subjected. CSFs from 20 healthy dogs were used as controls. Indirect fluorescent antibody test on the canine cerebrum revealed astrocyte-binding IgG in the CSF of NME. After absorption of the CSF with bovine GFAP, the CSF still possessed the reactivity to astrocytes. Double-color staining showed clear colocalization of the autoantibodies and anti-human TG2 rabbit polyclonal IgG. An immunoblot assay against human recombinant TG2 revealed anti-TG2 IgG in the CSF from dogs with NME, NLE and GME. The CSF of canine idiopathic encephalitis cases, notably of NME, tended to show high ELISA OD values against human recombinant TG2 compared to healthy controls. The presence of anti-TG2 autoantibodies in the CSF may contribute to the elucidation of the etiology of canine NME, NLE and GME. PMID- 22230983 TI - Mitigation of pyrexia by a Th-1-biased IgG subclass response after infection with equine herpesvirus type 1 in horses pre-immunized with inactivated vaccine. AB - The immunoglobulin G (IgG) subclass response was investigated in horses with or without pyrexia after natural infection with equine herpesvirus type 1 (EHV-1) in the field. All horses were kept at the training centers of the Japan Racing Association and were immunized with an inactivated EHV-1 vaccine before EHV-1 infection. An IgG subclass response dominated by IgGa and IgGb was induced in horses without pyrexia after EHV-1 infection. In contrast, horses that developed pyrexia showed increased IgGc and IgG (T) subclass production in addition to IgGa and IgGb. Although inactivated EHV-1 vaccines are considered to induce a mainly Th-2-biased response, these results indicated that the responses in horses inoculated with inactivated EHV-1 vaccine were not uniform, and that horses with a Th-1-biased response were likely to be protected from pyrexia. PMID- 22230985 TI - High width variability during spiral drawing: further evidence of cerebellar dysfunction in essential tremor. AB - Essential tremor (ET) is among the most prevalent neurological diseases, yet the location of the primary disease substrate continues to be a matter of debate. The presence of intention tremor and mild gait ataxia suggests an underlying abnormality of the cerebellum and/or cerebellar pathways. Uncovering additional signs of cerebellar dysfunction would further substantiate the proposition that ET is a disease of the cerebellar system. We evaluated 145 ET cases and 34 normal controls clinically and by computerized spiral analysis. Spiral analysis is a program that objectively characterizes kinematic and physiologic features of hand drawn spirals using specific calculated spiral indices that correlate with spiral shape and motor execution. We used the spiral width variability index (SWVI), a measure of loop-to-loop spiral width variation with the influence of tremor removed, as a metric of drawing ataxia. The SWVI was higher in cases than controls (0.91 +/- 1.94, median=0.46 vs. 0.40 +/- 0.29, median=0.30, p<0.001). Cases with higher SWVI also had greater intention tremor during the finger-nose finger maneuver, r=0.27, p=0.001), and cases with intention tremor of the head had the highest SWVI (1.57 +/- 3.44, median=0.51, p<0.001). There was a modest association between SWVI and number of missteps during tandem gait (r=0.16, p=0.06). The primary anatomical substrate for ET continues to be a matter of speculation, yet these and other clinical data lend support to the notion that there is an underlying abnormality of the cerebellum and/or its pathways. PMID- 22230986 TI - Instruments to assess the oral language of children fitted with a cochlear implant: a systematic review. AB - The oral language development depends on the effective development of the hearing system. In cases of children presenting with hearing loss, a cochlear implant is an electronic device indicated to (re)habilitate the hearing function. Thus, it is of paramount importance to assess and follow the oral language development of children fitted with a cochlear implant (CI) to measure the effectiveness of the electronic device and support the therapeutic planning of these children. Questions are currently being raised about the instruments to assess the oral language of children using a CI, and, seeking the answers, this systematic review aimed at surveying these instruments. Searches were performed in three different databases utilizing six different descriptors to select articles published from 2004 to 2009 that performed an oral language assessment of children with a CI. Initially, 373 articles were found, and, after the application of inclusion criteria, 47 articles were analyzed, resulting in a survey of 74 instruments for oral language assessment, including tests, questionnaires and inventories. In analyzing the articles, it was realized that the studies included in this systematic review presented varied methodologies and low levels of evidence, with a greater concentration of instruments assessing receptive and expressive language, emphasizing the survey of the child's vocabulary and questionnaires. Thus, it can be verified that other linguistic skills, such as morphosyntactic, semantic, and narrative-pragmatic ones that are important in structuring speech and language for the effectiveness of the child's speech, are not being focused on. Just one of the instruments cited, a questionnaire, was specific for the oral language assessment of children with cochlear implants. PMID- 22230987 TI - Adequacy of human milk viscosity to respond to infants with dysphagia: experimental study. AB - Neonatal nutrition is an important subject in health in the short, medium and long term. In preterm newborns, nutrition assumes a predominant role for the child's overall development. Babies with uncoordinated swallowing or respiration may not have the necessary oral abilities to suck the mother's breast and will need to implement different feeding practices; one of them is changing the consistency of the milk offered. OBJECTIVES: Determine viscosity variations of untreated human and pasteurized milk without and with thickening to adapt the diet to the needs of dysphagic infants hospitalized in the Neonatal Intensive Cara Unit (NICU). MATERIAL AND METHODS: The authors altered the viscosity of natural infant powdered milk and, after thickening, determined and adopted a thickening standard for human milk. Untreated human and pasteurized milk was thickened in concentrations of 2%, 3%, 5% and 7% and the viscosity were determined every 20 minutes for a period of 60 minutes at a temperature of 37oC. RESULTS: The infant lactose formula thickened at concentrations of 2% and 3% produced viscosities of 8.97cP and 27.73 cP, respectively. The increases were significantly different after 1 hour. Inversely, untreated human milk at 2%, 3%, 5% and 7% produced diminished viscosity over time; the changes were more accentuated in the first 20 minutes. In pasteurized human milk, the 2% concentration had no variation in viscosity, but with the 3%, 5% and 7% concentrations, there was a significant decrease in the first 20 minutes with stability observed in the subsequent times. CONCLUSION: In powdered milk, the viscosity increases over time; the viscosity in human milk diminishes. The results point out the importance not only of considering the concentration of the thickener but also the time being administered after its addition to effectively treat dysphagic infants. PMID- 22230988 TI - Development of a CD-ROM on written language for the continuing education of elementary school teachers. AB - Distance education has emerged to minimize the anxiety of many professionals who need to update their knowledge, but do not have the time and opportunity to travel to educational centers. OBJECTIVES: To describe the development of a CD ROM to provide distance continuing education to basic school teachers that addresses issues related to written language. MATERIAL AND METHODS: Previously, a script was developed with themes related to the acquisition and development of written language. Subsequently, a technical team transformed the texts in multimedia language. RESULTS: The titles of each content area addressed are available on buttons and links. The files can be viewed in a linear sequence, allowing the teacher to start learning at the desired moment and go straight to the file that he or she wants to access. Videos that show practical applications of the concepts available in text are included. CONCLUSIONS: Brazil is a developing country. The use of technologies for education reduces cultural isolation among education professionals. It is necessary to focus on making teaching materials for distance education. In order to provide an effective learning environment, the learners reality should be considered. A multidisciplinary team should prepare the materials. The development of educational material for distance education on the acquisition and development of written language seems not only appropriate, but also warranted to provide professional growth opportunity for teachers who need time flexibility and/or live far away from academic centers. PMID- 22230989 TI - Oral and vocal fold diadochokinesis in dysphonic women. AB - The evaluation of oral and vocal fold diadochokinesis (DDK) in individuals with voice disorders may contribute to the understanding of factors that affect the balanced vocal production. Scientific studies that make use of this assessment tool support the knowledge advance of this area, reflecting the development of more appropriate therapeutic planning. OBJECTIVE: To compare the results of oral and vocal fold DDK in dysphonic women and in women without vocal disorders. MATERIAL AND METHODS: For this study, 28 voice recordings of women from 19 to 54 years old, diagnosed with dysphonia and submitted to a voice assessment from speech pathologist and otorhinolaryngologist, were used. The control group included 30 nondysphonic women evaluated in prior research from normal adults. The analysis parameters like number and duration of emissions, as well as the regularity of the repetition of syllables "pa", "ta", "ka" and the vowels "a" and "i," were provided by the Advanced Motor Speech Profile program (MSP) Model-5141, version-2.5.2 (KayPentax). The DDK sequence "pataka" was analyzed quantitatively through the Sound Forge 7.0 program, as well as manually with the audio-visual help of sound waves. Average values of oral and vocal fold DDK dysphonic and nondysphonic women were compared using the "t Student" test and were considered significant when p<0.05. RESULTS: The findings showed no significant differences between populations; however, the coefficient of variation of period (CvP) and jitter of period (JittP) average of the "ka," "a" and "i" emissions, respectively, were higher in dysphonic women (CvP=10.42%, 12.79%, 12.05%; JittP=2.05%, 6.05%, 3.63%) compared to the control group (CvP=8.86%; 10.95%, 11.20%; JittP=1.82%, 2.98%, 3.15%). CONCLUSION: Although the results do not indicate any difficulties in oral and laryngeal motor control in the dysphonic group, the largest instability in vocal fold DDK in the experimental group should be considered, and studies of this ability in individuals with communication disorders must be intensified. PMID- 22230990 TI - Psychometric assessments of life quality and voice for teachers within the municipal system, in Bauru, SP, Brazil. AB - Studies show a high prevalence of vocal alterations among teachers. One of the criteria for the establishment of the prevalence of vocal alteration is based on teachers' self-perception. OBJECTIVE: This study aimed at comparing voice disordered quality of life measures between a group of teachers who reported vocal alteration and a group of teachers who did not, by verifying the teachers' perception regarding the impact of vocal alteration in the different dimensions of voice quality of life. MATERIAL AND METHODS: Ninety-seven (97) teachers answered three psychometric protocols of voice quality of life: Voice Handicap Index (VHI), Voice-Related Quality of Life (V-RQOL), and the Voice Activity Participation Profile (VAPP), in addition to a questionnaire for characterization of the sample. RESULTS: The results were that 39.8% of the teachers reported vocal alteration. When comparing voice measures between the groups (with and without vocal alteration), statistically significant differences were observed: the total score of VHI, total score of V-RQOL and total score of VAAP and its dimensions. It was also verified that the physical dimension of VHI has a greater impact among the dimensions of this protocol. For VRQOL, the most striking dimension was the physical functioning domain, both indicating the laryngeal discomfort and the impact of voice on communication, in teachers with and without complaints. As for VAAP, no domain prevailed over the others in the group with no complaints. For teachers with complaints, three domains, i.e., daily communication, work, and emotions have a greater impact than social communication. The limitation and restriction scores were calculated as well, and it was observed the limitation of activities is greater than the restriction of activities, both in the group with and the group without complaints. CONCLUSION: One may conclude that the teachers who reported vocal alterations better realize the impact of voice in different dimensions of voice quality of life. PMID- 22230991 TI - Occurrence of consonant production errors in liquid phonemes in children with operated cleft lip and palate. AB - Information about the prevalence of consonant production errors, including compensatory articulations (CA), in individuals with cleft lip and palate (CLP) who speak Brazilian Portuguese is limited, particularly regarding liquid sounds. The literature primarily reports the occurrence of CA for plosive and fricative sounds, since occurrence of CAs in sounds that require higher amounts of oral air pressure is expected. While the use of CA during liquid sound production is not expected, clinical experience suggests that individuals with CLP present with inadequate backing, elevation, and anteriorization of the tongue as well as tongue clicks during production of /r/ and /l/. OBJECTIVES: Describe the occurrence of consonant error productions during liquid sounds for children with CLP; compare the occurrence between children operated with the Furlow and von Langenbeck techniques for palatoplasty; and compare the occurrence between children operated between 9-12 months and 15-18 months of age at primary palatoplasty. MATERIAL AND METHODS: A sample of 397 children (237 males and 160 females) with operated unilateral CLP was studied. In this group, 163 underwent palatoplasty with the Furlow procedure and 234 with the modified von Langenbeck procedure. Age at palatoplasty was between 9 and 12 months for 189 children and between 15 and 18 months for 208 children. Data about production of /l/, /r/, /R/, /lambda/ and consonant clusters /l/ and /r/ were obtained from speech pathology records. Speech pathologists registered the speech findings after an auditory-perceptual evaluation of the participants at the sixth year of age. RESULTS: The use of middorsum palatal place (MDP) of production was identified for 2% of the sample. Tongue anteriorization of the /l/ production was observed for 55% of the children. No significant difference was found related to surgical technique, but children operated earlier developed the use of the consonant cluster /r/ sooner than children operated later (p=0.040). CONCLUSION: We found a low occurrence of use of cleft related CA during attempts of production of liquid phonemes, and the variable age at primary palatoplasty significantly interfered with the acquisition of consonant cluster /r/. PMID- 22230992 TI - Translation and adaptation of functional auditory performance indicators (FAPI). AB - Work with deaf children has gained new attention since the expectation and goal of therapy has expanded to language development and subsequent language learning. Many clinical tests were developed for evaluation of speech sound perception in young children in response to the need for accurate assessment of hearing skills that developed from the use of individual hearing aids or cochlear implants. These tests also allow the evaluation of the rehabilitation program. However, few of these tests are available in Portuguese. Evaluation with the Functional Auditory Performance Indicators (FAPI) generates a child's functional auditory skills profile, which lists auditory skills in an integrated and hierarchical order. It has seven hierarchical categories, including sound awareness, meaningful sound, auditory feedback, sound source localizing, auditory discrimination, short-term auditory memory, and linguistic auditory processing. FAPI evaluation allows the therapist to map the child's hearing profile performance, determine the target for increasing the hearing abilities, and develop an effective therapeutic plan. OBJECTIVE: Since the FAPI is an American test, the inventory was adapted for application in the Brazilian population. MATERIAL AND METHODS: The translation was done following the steps of translation and back translation, and reproducibility was evaluated. Four translated versions (two originals and two back-translated) were compared, and revisions were done to ensure language adaptation and grammatical and idiomatic equivalence. RESULTS: The inventory was duly translated and adapted. CONCLUSION: Further studies about the application of the translated FAPI are necessary to make the test practicable in Brazilian clinical use. PMID- 22230993 TI - Bauru School of Dentistry Tele-Health League: an educational strategy applied to research, teaching and extension among applications in tele-health. AB - Tele-health is more than an innovative alternative; it is an excellent tool that enables access to health and education in health, making it possible to minimize distances, optimize time and reduce costs. Based on these advantages, some Brazilian Universities have used these actions in strategies of education, research and extension, aiming at the application of Tele-health in Brazil. In that way, the Bauru School of Dentistry - University of Sao Paulo (FOB-USP) has applied the use of information and communication technologies in health by means of a "Tele-Health League" (TL), in order to diagnose, prevent and treat diseases, in addition to educate the population and health services. OBJECTIVE: The present study aims to introduce the characteristics of the Tele-Health League of FOB-USP, as well as the development of its projects. MATERIAL AND METHODS: The Tele-Health League consisted as a Diffusion Course approved by the Provost of Culture and Academic Extension of the University of Sao Paulo. It is composed as a large group enclosing professoriate coordinator, academician principal, contributing professors and league members, those, diversified between undergraduates students, graduated, health employees, technology and information areas. The participant members are evaluated by the presence frequency (minimum of 85%), and by the performance of tests and paperwork about the theoretical content provided. RESULTS: In four years of activities, the TLFOB-USP obtained a high satisfaction index (90%), an increased number of vacancies due to the interest to become a member, more commitment of the professors of the University and the accomplishment of association with other Brazilian leagues. It is emphasized that the approval percentage of the course results in approval from approximately half of its members. Also, it is important to identify and repair the causes related to the quitting of some members. CONCLUSIONS: The results showed that the TLFOB USP members, adjoining to the professor's participants, develop projects in Tele helth, in Tele-aid and Tele-education areas, thus resulting in the involvement of the University and the community. PMID- 22230994 TI - Histomorphometric assessment of bone necrosis produced by two cryosurgery protocols using liquid nitrogen: an experimental study on rat femurs. AB - OBJECTIVE: The aim of this study was to evaluate the effects of liquid nitrogen cryosurgery on the femoral diaphysis of rats. MATERIAL AND METHODS: The femoral diaphyses of 42 Wistar rats were exposed to three local and sequential applications of liquid nitrogen for 1 or 2 min, intercalated with periods of 5 min of passive thawing. The animals were sacrificed after 1, 2, 4 and 12 weeks and the specimens obtained were processed and analyzed histomorphometrically. RESULTS: The depth and extent of peak bone necrosis were 124.509 um and 2087.094 um for the 1-min protocol, respectively, and 436.424 um and 12046.426 um for the 2-min protocol. Peak necrosis was observed in the second experimental week with both cryotherapy protocols. CONCLUSIONS: The present results indicate that the 2 min protocol produced more marked bone necrosis than the 1-min protocol. Although our results cannot be entirely extrapolated to clinical practice, they contribute to the understanding of the behavior of bone tissue submitted to different cycles of liquid nitrogen freezing and may serve as a basis for new studies. PMID- 22230995 TI - Effect of axial loads on implant-supported partial fixed prostheses by strain gauge analysis. AB - OBJECTIVES: The present study used strain gauge analysis to perform an in vitro evaluation of the effect of axial loading on 3 elements of implant-supported partial fixed prostheses, varying the type of prosthetic cylinder and the loading points. MATERIAL AND METHODS: Three internal hexagon implants were linearly embedded in a polyurethane block. Microunit abutments were connected to the implants applying a torque of 20 Ncm, and prefabricated Co-Cr cylinders and plastic prosthetic cylinders were screwed onto the abutments, which received standard patterns cast in Co-Cr alloy (n=5). Four strain gauges (SG) were bonded onto the surface of the block tangentially to the implants, SG 01 mesially to implant 1, SG 02 and SG 03 mesially and distally to implant 2, respectively, and SG 04 distally to implant 3. Each metallic structure was screwed onto the abutments with a 10 Ncm torque and an axial load of 30 kg was applied at five predetermined points (A, B, C, D, E). The data obtained from the strain gauge analyses were analyzed statistically by RM ANOVA and Tukey's test, with a level of significance of p<0.05. RESULTS: There was a significant difference for the loading point (p=0.0001), with point B generating the smallest microdeformation (239.49 uepsilon) and point D the highest (442.77 uepsilon). No significant difference was found for the cylinder type (p=0.748). CONCLUSIONS: It was concluded that the type of cylinder did not affect in the magnitude of microdeformation, but the axial loading location influenced this magnitude. PMID- 22230996 TI - Nasalance and nasality at experimental velopharyngeal openings in palatal prosthesis: a case study. AB - The use of prosthetic devices for correction of velopharyngeal insufficiency (VPI) is an alternative treatment for patients with conditions that preclude surgery and for those individuals with a hypofunctional velopharynx (HV) with a poor prognosis for the surgical repair of VPI. Understanding the role and measuring the outcome of prosthetic treatment of velopharyngeal dysfunction requires the use of tools that allow for documenting pre- and post-treatment outcomes. Experimental openings in speech bulbs have been used for simulating VPI in studies documenting changes in aerodynamic, acoustic and kinematics aspects of speech associated with the use of palatal prosthetic devices. The use of nasometry to document changes in speech associated with experimental openings in speech bulbs, however, has not been described in the literature. OBJECTIVE: This single-subject study investigated nasalance and nasality at the presence of experimental openings drilled through the speech bulb of a patient with HV. MATERIAL AND METHODS: Nasometric recordings of the word "pato" were obtained under 4 velopharyngeal conditions: no-opening (control condition), no speech bulb, speech bulb with a 20 mm2 opening, and speech bulb with 30 mm2 opening. Five speech-language pathologists performed auditory-perceptual ratings while the subject read an oral passage under all conditions. RESULTS: Kruskal-Wallis test showed significant difference among conditions (p=0.0002), with Scheffe post hoc test indicating difference from the no-opening condition. CONCLUSION: The changes in nasalance observed after drilling holes of known sizes in a speech bulb suggest that nasometry reflect changes in transfer of sound energy related to different sizes of velopharyngeal opening. PMID- 22230997 TI - Effect of repeated immersion solution cycles on the color stability of denture tooth acrylic resins. AB - OBJECTIVE: Chemical solutions have been widely used for disinfection of dentures, but their effect on color stability of denture tooth acrylic resins after repeated procedures is still unclear. The aim of this in vitro study was to evaluate whether repeated cycles of chemical disinfectants affected the color stability of two denture tooth acrylic resins. MATERIAL AND METHODS: Sixty disc shaped specimens (40 mm x 3 mm) were fabricated from two different brands (Artiplus and Trilux) of denture tooth acrylic resin. The specimens from each brand (n=30) were randomly divided into 6 groups (n=5) and immersed in the following solutions: distilled water (control group) and 5 disinfecting solutions (1% sodium hypochlorite, 2% sodium hypochlorite, 5.25% sodium hypochlorite, 2% glutaraldehyde, and 4% chlorhexidine gluconate). Tooth color measurements were made by spectrophotometry. Before disinfection, the initial color of each tooth was recorded. Further color measurements were determined after subjecting the specimens to 7, 21, 30, 45, 60, and 90 immersion cycles in each tested solution. Color differences (DeltaE*) were determined using the CIE L*a*b* color system. Data were analyzed using two-way repeated measures analysis of variance (ANOVA) followed by Tukey tests. The significance level was set at 5%. RESULTS: There were statistically significant differences in DeltaE* among the 5 disinfectants and water during the 90 cycles of immersion for both denture tooth acrylic resins. Distilled water promoted the greatest color change in both denture tooth acrylic resins, nevertheless none of tested disinfectants promoted DeltaE* values higher than 1.0 on these acrylic materials during the 90 cycles of disinfection. CONCLUSIONS: Repeated immersion cycles in disinfecting solutions alter DeltaE* values, however these values do not compromise the color of the tested denture tooth acrylic resins because they are imperceptible to the human eye. PMID- 22230998 TI - Effects of sulfur-based hemostatic agents and gingival retraction cords handled with latex gloves on the polymerization of polyvinyl siloxane impression materials. AB - OBJECTIVES: This study investigated the possible interactions between three addition silicone materials (Express(r), Aquasil Ultra(r) and Adsil(r)), three hemostatic agents (ferric sulfate, StatGel FS(r); aluminum sulfate, GelCord(r); and aluminum chloride, Hemostop(r)) and gingival retraction cords previously handled with latex gloves to determine whether direct contact with medicaments or indirect contamination by latex in conditions similar to those found in clinical practice inhibit or affect the setting of the impression materials. MATERIAL AND METHODS: A portable device for the simultaneous test of several specimens was specifically developed for this study. Polymerization inhibition was analyzed by examination of the impressions and the molded surface. Ten trials were performed for each addition silicone material used in the study, at a total of 240 study samples. RESULTS: All the samples tested (N=240) were nonreactive regardless of the type of combination used. CONCLUSIONS: Aluminum sulfate, ferric sulfate and aluminum chloride hemostatic solutions did not show any inhibitory potential on the addition silicone samples under study, and there were no changes in polymerization as a result of contact between addition silicone and retraction cords handled with latex gloves. PMID- 22230999 TI - Treatment effects of R-appliance and anterior inclined bite plate in class II, division I malocclusion. AB - OBJECTIVES: The purpose of this study was to compare the effects of a differently designed functional appliance (R-appliance) and the Anterior Inclined Bite Plate (AIBP) in Class II Division I (Cl II Div I) cases. MATERIAL AND METHODS: Fifty patients (28 girls, 22 boys) were chosen for the study: 25 patients (13 girls, 12 boys) with mean age of 10.4+/-0.8 years were treated with R-appliance for 11+/-2 months, the other 25 patients (15 girls, 10 boys) with mean age of 9+/-1.2 years were treated with AIBP for 10+/-2 months. All patients had Cl II Div I malocclusion due to mandibular deficiency. Lateral cephalograms were analyzed at the beginning (T1, T 1) and end of the study (T2, T 2). RESULTS: Paired T-test showed that SNB had a significant increase in both groups. The same test revealed that IMPA was reduced in R-appliance for 3.1+/-4.7 (p<0.01), but it was increased for 0.1+/-5.1 (p<0.9) in AIBP group. T-test showed that the inter-group difference of IMPA was statistically significant (p<0.05). SNA showed an increase in both groups (p<0.9). Ar-B and Ar-Pog showed an increase in both groups and the differences between them were statistically significant. CONCLUSIONS: Mandibular advancement was achieved in both groups, but R-appliance achieved this result without lingual tipping of lower incisors. PMID- 22231000 TI - A comparative scanning electron microscopy evaluation of smear layer removal with apple vinegar and sodium hypochlorite associated with EDTA. AB - OBJECTIVE: The purpose of this study was to evaluate by scanning electron microscopy (SEM) the removal of smear layer from the middle and apical root thirds after use of different irrigating solutions. MATERIAL AND METHODS: Forty roots of permanent human teeth had their canals instrumented and were randomly assigned to 4 groups (n=10), according to the irrigating solution: apple vinegar (group A), apple vinegar finished with 17% ethylenediaminetetraacetic acid (EDTA) (group B), 1% sodium hypochlorite (NaOCl) finished with 17% EDTA (group C) and saline (group D - control). After chemomechanical preparation, the roots were cleaved longitudinally and their middle and apical thirds were examined by SEM at *1,000 magnification. Two calibrated examiners (kappa=0.92) analyzed the SEM micrographs qualitatively attributing scores that indicated the efficacy of the solutions in removing the smear layer from the surface of the dentin tubules (1 - poor, 2 - good and 3 - excellent). Data from the control and experimental groups were analyzed by the Kruskal-Wallis and Dunn's test, while the Wilcoxon test was used to compare the middle and apical thirds of the canals within the same group (a=0.05). RESULTS: The middle third presented less amount of smear layer than the apical third, regardless of the irrigant. There was statistically significant difference (p=0.0402) among the groups in the middle third. In the apical third, the apple vinegar/EDTA group showed the greatest removal of smear layer (p=0.0373). CONCLUSION: Apple vinegar associated or not with EDTA was effective in removing smear layer when used as an endodontic irrigant. PMID- 22231001 TI - Bond strength of different endodontic sealers to dentin: push-out test. AB - OBJECTIVE: The aim of this in vitro study was to evaluate the bond strength of different root canal sealers to dentin. MATERIAL AND METHODS: Forty extracted single-rooted human teeth were examined and the coronal and middle thirds of the canals were prepared with a 1.50 mm post drill (FibreKor Post System, Pentron). The teeth were allocated in two experimental groups, irrigated with 2.5% NaOCl+17% EDTA or saline solution (control group) and instrumented using Race rotary files (FKG) to a size #40 at the working length. Then, the groups were divided into four subgroups and filled with Epiphany sealer (Group 1), EndoREZ (Group 2), AH26 (Group 3) and Grossman's Sealer (Group 4). After 2 weeks of storage in 100% humidity at 37oC, all teeth were sectioned transversally into 2 mm-thick discs. Push-out tests were performed at a cross-head speed of 1 mm/min using a universal testing machine. The maximum load at failure was recorded and expressed in MPa. RESULTS: Means (+/-SD) in root canals irrigated with 2.5% NaOCl and 17% EDTA were: G1 (21.6+/-6.0), G2 (15.2+/-3.7), G3 (14.6+/-4.5) and G4 (11.7+/-4.1).Two-way ANOVA and Tukey's test showed the highest bond strength for the Epiphany's group (p< 0.01) when compared to the other tested sealers. Saline solution decreased the values of bond-strength (p<0.05) for all sealers. CONCLUSION: Epiphany sealer presented higher bond strength values to dentin in both irrigating protocols, and the use of 2.5% NaOCl and 17% EDTA increased the bond strength values for all sealers. PMID- 22231002 TI - Resistance to compression of weakened roots subjected to different root reconstruction protocols. AB - OBJECTIVE: This study evaluated, in vitro, the fracture resistance of human non vital teeth restored with different reconstruction protocols. MATERIAL AND METHODS: Forty human anterior roots of similar shape and dimensions were assigned to four groups (n=10), according to the root reconstruction protocol: Group I (control): non-weakened roots with glass fiber post; Group II: roots with composite resin by incremental technique and glass fiber post; Group III: roots with accessory glass fiber posts and glass fiber post; and Group IV: roots with anatomic glass fiber post technique. Following post cementation and core reconstruction, the roots were embedded in chemically activated acrylic resin and submitted to fracture resistance testing, with a compressive load at an angle of 45o in relation to the long axis of the root at a speed of 0.5 mm/min until fracture. All data were statistically analyzed with bilateral Dunnett's test (alpha=0.05). RESULTS: Group I presented higher mean values of fracture resistance when compared with the three experimental groups, which, in turn, presented similar resistance to fracture among each other. None of the techniques of root reconstruction with intraradicular posts improved root strength, and the incremental technique was suggested as being the most recommendable, since the type of fracture that occurred allowed the remaining dental structure to be repaired. CONCLUSION: The results of this in vitro study suggest that the healthy remaining radicular dentin is more important to increase fracture resistance than the root reconstruction protocol. PMID- 22231003 TI - Stress analysis of a fixed implant-supported denture by the finite element method (FEM) when varying the number of teeth used as abutments. AB - OBJECTIVES: In some clinical situations, dentists come across partially edentulous patients, and it might be necessary to connect teeth to implants. The aim of this study was to evaluate a metal-ceramic fixed tooth/implant-supported denture with a straight segment, located in the posterior region of the maxilla, when varying the number of teeth used as abutments. MATERIAL AND METHODS: A three element fixed denture composed of one tooth and one implant (Model 1), and a four element fixed denture composed of two teeth and one implant (Model 2) were modeled. A 100 N load was applied, distributed uniformly on the entire set, simulating functional mastication, for further analysis of the SEQV (Von Mises) principal stresses, which were compared with the flow limit of the materials. RESULTS: In a quantitative analysis, it may be observed that in the denture with one tooth, the maximum SEQV stress was 47.84 MPa, whereas for the denture with two teeth the maximum SEQV stress was 35.82 MPa, both located in the region between the pontic and the tooth. CONCLUSION: Lower stresses were observed in the denture with an additional tooth. Based on the flow limit of the materials, porcelain showed values below the limit of functional mastication. PMID- 22231004 TI - Corrosion in Haas expanders with and without use of an antimicrobial agent: an in situ study. AB - OBJECTIVES: The purpose of this study was to evaluate in situ the occurrence of corrosion in the soldering point areas between the wire, silver brazing and band in Haas expanders. MATERIAL AND METHODS: Thirty-four 7-12-year-old patients who needed maxillary expansion with a Haas expander were randomly assigned to two groups of 17 individuals each, according to the oral hygiene protocol adopted during the orthodontic treatment: Group I (control), toothbrushing with a fluoride dentifrice and Group II (experimental), toothbrushing with the same dentifrice plus 0.12% chlorhexidine gluconate (Periogard(r)) mouthrinses twice a week. The appliances were removed after approximately 4 months. Fragments of the appliances containing a metallic band with a soldered wire were sectioned at random for examination by stereomicroscopy, scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDS). Data were analyzed statistically by Fisher's test at 5% significance level. RESULTS: The analysis by optical microscopy revealed areas with color change suggestive of corrosion in the soldering point areas joining the band and the wire in all specimens of both groups, with no statistically significant difference between the groups (p=1). The peaks of chemical elements (Ni, Fe, Cr, O, C and P) revealed by EDS were also similar in both groups. CONCLUSION: Color changes and peaks of chemical elements suggestive of corrosion were observed in the soldering point areas between the wire, silver brazing and band in both control and experimental groups, which indicate that the 0.12% chlorhexidine gluconate mouthrinses did not influence the occurrence of corrosion in situ. PMID- 22231006 TI - Attitudes of a group of Brazilian orthodontists towards the diagnosis and management of primary headache (migraine): an electronic-based survey. AB - OBJECTIVES: The aim of this study was to investigate the knowledge and attitudes of orthodontists in the diagnosis and management of migraine without aura. MATERIAL AND METHODS: Participants were dentists, recruited among members of the Brazilian Association of Orthodontics and Facial Orthopedics (ABOR). An e-mail was sent to all ABOR members, with a link to a website, especially prepared for this research. Dentists were presented to a report of a fictional patient fulfilling diagnostic criteria for a primary headache disorder, known as migraine without aura. Participants were asked to describe how they would relieve the patient's pain. Professional procedures were classified as "adequate" or "inadequate" according to the answers given. RESULTS: 161 valid answers were received (18.8% response rate). Of them, 36% of the actions were considered to be "adequate" procedures, while 64% were "inadequate". The results yielded 12 main procedures, based on common characteristics. Eighty-two orthodontists suggested orthodontic treatment with or without orthognathic surgery, and some suggested using stabilization appliances prior to the orthodontic treatment. CONCLUSIONS: The majority of participants proposed inadequate therapies, and 51% suggested orthodontic correction of occlusion, including orthognathic surgery. Educational activities on migraine should also target orthodontists. PMID- 22231005 TI - The effectiveness of chemical denture cleansers and ultrasonic device in biofilm removal from complete dentures. AB - Adequate denture hygiene can prevent and treat infection in edentulous patients. They are usually elderly and have difficulty for brushing their teeth. OBJECTIVE: This study evaluated the efficacy of complete denture biofilm removal using chemical (alkaline peroxide-effervescent tablets), mechanical (ultrasonic) and combined (association of the effervescent and ultrasonic) methods. MATERIAL AND METHODS: Eighty complete denture wearers participated in the experiment for 21 days. They were distributed into 4 groups (n=20): (1) Brushing with water (Control); (2) Effervescent tablets (Corega Tabs); (3) Ultrasonic device (Ultrasonic Cleaner, model 2840 D); (4) Association of effervescent tablets and ultrasonic device. All groups brushed their dentures with a specific brush (Bitufo) and water, 3 times a day, before applying their treatments. Denture biofilm was collected at baseline and after 21 days. To quantify the biofilm, the internal surfaces of the maxillary complete dentures were stained and photographed at 45o. The photographs were processed and the areas (total internal surface stained with biofilm) quantified (Image Tool 2.02). The percentage of the biofilm was calculated by the ratio between the biofilm area multiplied by 100 and the total area of the internal surface of the maxillary complete denture. RESULTS: The Kruskal-Wallis test was used for comparison among groups followed by the Dunn multiple-comparison test. All tests were performed respecting a significance level of 0.05. Significant difference was found among the treatments (KW=21.18; P<0.001), the mean ranks for the treatments and results for Dunn multiple comparison test were: Control (60.9); Chemical (37.2); Mechanical (35.2) and Combined (29.1). CONCLUSION: The experimental methods were equally effective regarding the ability to remove biofilm and were superior to the control method (brushing with water). Immersion in alkaline peroxide and ultrasonic vibration can be used as auxiliary agents for cleaning complete dentures. PMID- 22231007 TI - Speech therapy for compensatory articulations and velopharyngeal function: a case report. AB - The objective of this study was to describe the process of intensive speech therapy for a 6-year-old child using compensatory articulations while presenting with velopharyngeal insufficiency (VPI) and a history of cleft lip and palate. The correction of VPI was temporarily done with a pharyngeal obturator since the child presented with very little movement of the pharyngeal walls during speech, compromising the outcome of a possible pharyngeal flap procedure (pharyngoplasty). The program of intensive speech therapy involved 3 phases, each for duration of 2 weeks incorporating 2 daily sessions of 50 minutes of therapy. A total of 60 sessions of intervention were done with the initial goal of eliminating the use of compensatory articulations. Evaluation before the program indicated the use of co-productions (coarticulations) of voiceless plosive and fricative sounds with glottal stops (simultaneous production of 2 places of productions), along with weak intraoral pressure and hypernasality, all compromising speech intelligibility. To address place of articulation, strategies to increase intraoral air pressure were used along with visual, auditory and tactile feedback, emphasizing the therapy target and the air pressure and airflow during plosive and fricative sound productions. After the first two phases of the program, oral place of articulation of the targets were achieved consistently. During the third phase, velopharyngeal closure during speech was systematically addressed using a bulb reduction program with the objective of achieving velopharyngeal closure during speech consistently. After the intensive speech therapy program involving the use of a pharyngeal obturator, we observed absence of hypernasality and compensatory articulation with improved speech intelligibility. PMID- 22231009 TI - Characterization of major lipid droplet proteins from Dunaliella. AB - Many green algal species can accumulate large amounts of triacylglycerides (TAG) under nutrient deprivation, making them a potential source for production of biodiesel. TAG are organized in cytoplasmic lipid bodies, which contain a major lipid droplet protein termed MLDP. Green algae MLDP differ in sequence from plant oleosins and from animal perilipins, and their structure and function are not clear. In this study, we describe the isolation of MLDP from three species of the extreme halotolerant green algae Dunaliella. Sequence alignment with other green algae MLDP proteins identified a conserved 4-proline domain that may be considered as a signature domain of Volvocales green algae MLDP. Gold immunolabeling localized MLDP at the surface of lipid droplets in D. salina. The induction of MLDP by nitrogen deprivation is kinetically correlated with TAG accumulation, and inhibition of TAG biosynthesis impairs MLDP accumulation suggesting that MLDP induction is co-regulated with TAG accumulation. These results can lead to a better understanding of the structure and function of Volvocales green algae MLDP proteins. PMID- 22231012 TI - The effect of alpha lipoic acid on the developmental competence of mouse isolated preantral follicles. AB - PURPOSE: This study was designed to investigate the effect of alpha-lipoic acid (ALA) on reactive oxygen species (ROS) production, total antioxidant capacity (TAC) and developmental competence of cultured pre-antral follicles derived from mouse ovarian tissue. METHODS: Pre-antral follicles were isolated from immature mouse ovaries and were cultured in alpha- minimal essential medium supplemented with different concentrations (0, 50, 100, 250 and 500 uM) of ALA. Follicular growth, oocyte maturation and embryo development were evaluated. Separately, ROS and TAC were measured after 0, 24, 48, 72 and 96 h of culture with spectrofluorometery and ferric reducing/antioxidant power (FRAP) assay, respectively. RESULTS: In the presence of 100 uM ALA, developmental rates of follicles, oocytes and embryos were significantly higher than other groups (p < 0.05). At 96 h after culture, a decrease in ROS and an increase in TAC were observed in ALA group compared to control group (p < 0.05). CONCLUSION: ALA (100 uM) improves the in vitro development of follicles. This effect may be mediated by decreasing ROS concentration and increasing follicular TAC level during the culture period. PMID- 22231013 TI - Comparison of cabergoline and intravenous albumin in the prevention of ovarian hyperstimulation syndrome: a randomized clinical trial. AB - PURPOSE: To compare the efficacy of cabergoline (Cb2) and intravenous human albumin (HA) in the prevention of ovarian hyperstimulation syndrome. METHODS: In this randomized controlled trial study, 138 women who were at high risk for developing OHSS were randomly allocated into two groups. In Group one, 20 gr of HA 20% was infused over 1 h. Group two received 0.5 mg per day of Cb2 orally for 7 days, starting on oocyte pickup day. All patients were visited seven and 14 days after oocyte retrieval to determine early clinical or ultrasound evidence of OHSS. RESULTS: Moderate OHSS was observed in 33 versus 14 cases in the HA and Cb2 groups, respectively, which was significantly different. The number of severe OHSS cases in the HA group was significantly higher than in the Cb2 group (P < 0.001). CONCLUSIONS: Prophylactic oral low dose cabergoline was more effective and less costly than intravenous human albumin in the prevention of OHSS in high risk patients. PMID- 22231014 TI - Role of spatial ionic distribution on the energetics of hydrophobic assembly and properties of the water/hydrophobe interface. AB - We present results from all-atom molecular dynamics simulations of large-scale hydrophobic plates solvated in NaCl and NaI salt solutions. As observed in studies of ions at the air-water interface, the density of iodide near the water plate interface is significantly enhanced relative to chloride and in the bulk. This allows for the partial hydration of iodide while chloride remains more fully hydrated. In 1 M solutions, iodide directly pushes the hydrophobes together (contributing -2.51 kcal mol(-1)) to the PMF. Chloride, however, strengthens the water-induced contribution to the PMF by ~-2.84 kcal mol(-1). These observations are enhanced in 3 M solutions, consistent with the increased ion density in the vicinity of the hydrophobes. The different salt solutions influence changes in the critical hydrophobe separation distance and characteristic wetting/dewetting transitions. These differences are largely influenced by the ion-specific expulsion of iodide from bulk water. Results of this study are of general interest to the study of ions at interfaces and may lend insight to the mechanisms underlying the Hofmeister series. PMID- 22231015 TI - Minimally invasive input function for 2-18F-fluoro-A-85380 brain PET studies. AB - PURPOSE: Quantitative neuroreceptor positron emission tomography (PET) studies often require arterial cannulation to measure input function. While population based input function (PBIF) would be a less invasive alternative, it has only rarely been used in conjunction with neuroreceptor PET tracers. The aims of this study were (1) to validate the use of PBIF for 2-(18)F-fluoro-A-85380, a tracer for nicotinic receptors; (2) to compare the accuracy of measures obtained via PBIF to those obtained via blood-scaled image-derived input function (IDIF) from carotid arteries; and (3) to explore the possibility of using venous instead of arterial samples for both PBIF and IDIF. METHODS: Ten healthy volunteers underwent a dynamic 2-(18)F-fluoro-A-85380 brain PET scan with arterial and, in seven subjects, concurrent venous serial blood sampling. PBIF was obtained by averaging the normalized metabolite-corrected arterial input function and subsequently scaling each curve with individual blood samples. IDIF was obtained from the carotid arteries using a blood-scaling method. Estimated Logan distribution volume (V(T)) values were compared to the reference values obtained from arterial cannulation. RESULTS: For all subjects, PBIF curves scaled with arterial samples were similar in shape and magnitude to the reference arterial input function. The Logan V(T) ratio was 1.00 +/- 0.05; all subjects had an estimation error <10%. IDIF gave slightly less accurate results (V(T) ratio 1.03 +/- 0.07; eight of ten subjects had an error <10%). PBIF scaled with venous samples yielded inaccurate results (V(T) ratio 1.13 +/- 0.13; only three of seven subjects had an error <10%). Due to arteriovenous differences at early time points, IDIF could not be calculated using venous samples. CONCLUSION: PBIF scaled with arterial samples accurately estimates Logan V(T) for 2-(18)F-fluoro-A 85380. Results obtained with PBIF were slightly better than those obtained with IDIF. Due to arteriovenous concentration differences, venous samples cannot be substituted for arterial samples. PMID- 22231017 TI - Novel electrophilic synthesis of 6-[18F]fluorodopamine and comprehensive biological evaluation. AB - PURPOSE: 6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2 diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/MUmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs. METHODS: 6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6 [(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs. RESULTS: 6-[(18)F]FDA was synthesised with 2.6 +/- 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 +/- 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 +/- 2.7 GBq/MUmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects. CONCLUSION: 6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6 [(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved. PMID- 22231016 TI - Influence of PSA, PSA velocity and PSA doubling time on contrast-enhanced 18F choline PET/CT detection rate in patients with rising PSA after radical prostatectomy. AB - PURPOSE: To evaluate the accuracy of contrast-enhanced (18)F-choline PET/CT in restaging patients with prostate cancer after radical prostatectomy in relation to PSA, PSA velocity (PSAve) and PSA doubling time (PSAdt). METHODS: PET/CT was performed in 49 patients (age range 58-87 years) with rising PSA (mean 4.13 ng/ml) who were divided in four groups according to PSA level: <=1 ng/ml, 1 to <=2 ng/ml, 2 to <=4 ng/ml, and >4 ng/ml. PSAve and PSAdt were measured. PET and CT scans were interpreted separately and then together. RESULTS: PET/CT diagnosed relapse in 33 of the 49 patients (67%). The detection rates were 20%, 55%, 80% and 87% in the PSA groups <=1, 1 to <=2, 2 to <=4 and >4 ng/ml, respectively. PET/CT was positive in 7 of 18 patients (38.9%) with a PSA <=2 ng/ml, and in 26 of 31 (83.9%) with a PSA >2 ng/ml. PET/CT was positive in 7 of 25 patients (84%) with PSAdt <=6 months, and in 12 of 24 patients (50%) with PSAdt >6 months, and was positive in 26 of 30 patients (86%) with a PSAve >2 ng/ml per year, and in 7 of 19 patients (36.8%) with PSAve <=2 ng/ml per year. PET alone was positive in 31 of 49 patients (63.3%), and of these 31 patients, CT was negative in 14 but diagnosed bone lesions in 2 patients in whom PET alone was negative. CT with the administration of intravenous contrast medium did not provide any further information. CONCLUSION: Detection rate of (18)F-choline imaging is closely related to PSA and PSA kinetics. In particular, (18)F-choline PET/CT is recommended in patients with PSA >2 ng/ml, PSAdt <=6 months and PSAve >2 ng/ml per year. CT is useful for detecting bone metastases that are not (18)F-choline avid. The use of intravenous contrast agent seems unnecessary. PMID- 22231019 TI - Major causes of mastitis and associated risk factors in smallholder dairy farms in and around Hawassa, Southern Ethiopia. AB - A cross-sectional study was carried out from October 2008 to May 2009 in smallholder dairy farms in and around Hawassa to estimate the prevalence of mastitis, to isolate and characterize major bacterial pathogens, and to identify possible associated factors. The study involved a total of 201 milking cows randomly drawn from smallholder farms. The prevalence of clinical and subclinical mastitis was determined through clinical examination of the udder and using mastitis indicator paper (Bovivet indicator paper, Kruuse, Denmark). The prevalence of mastitis at cow and quarter level was 30.3 (61/201) and 10.3 (79/766), respectively. Subclinical mastitis was 25.4% and 5.0% was clinical. Stage of lactation significantly affected (P < 0.05) the prevalence of mastitis, with the highest prevalence observed in the late stage of lactation (41.3%) as compared to early (25.0%) and mid (22.1%) stages of lactation. Floor type and bedding had association (P < 0.05) with mastitis prevalence. Cows housed in concrete-floored houses had lower prevalence (19.0%) of mastitis compared to cows kept in soil-floored houses (47.6%). Mastitis prevalence was low in farms which do not use bedding (23.5%) as compared to farms using hay/straw bedding (37.4%). However, age, parity, and history of mastitis had no association (P > 0.05) on the prevalence of mastitis. The pathogens isolated from mastitic cows were Staphylococcus aureus (48.6%), other staphylococci species (15.7%), Streptococcus agalactiae (11.4%), other streptococci (17.1%), Bacillus species (2.9%), and coliforms (Escherichia coli and Klebsiella species) (4.3%). Strict hygienic measure of housing and bedding should be considered, in reducing the prevalence of mastitis. PMID- 22231020 TI - Effects of level of concentrate supplementation on growth performance of Arsi Bale and Boer * Arsi-Bale male goats consuming low-quality grass hay. AB - Eighteen Arsi-Bale (local) and 18 Boer * Arsi-Bale (crossbred) male goats, initially approximately 10 months of age, were used in a 12-week experiment to investigate potential interactions between genotype and nutritional plane in growth performance, carcass and skin characteristics, and mass of non-carcass components. Grass hay (6.7% crude protein and 71.9% neutral detergent fiber) was consumed ad libitum supplemented with 150, 300, or 450 g/day (dry matter; low, moderate, and high, respectively) of a concentrate mixture (50% wheat bran, 49% noug seed cake, and 1% salt). Initial body weight was 20.7 and 14.0 kg for crossbred and local goats, respectively (SE = 0.36). Hay dry matter intake was greater (P < 0.05) for crossbred vs. local goats (461 and 429 g/day) and similar among concentrate levels (438, 444, and 451 g/day for high, moderate, and low, respectively; SE = 4.7). Average daily gain was greater (P < 0.05) for crossbred than for local goats (36.6 and 20.8 g) and differed (P < 0.05) among each level of concentrate (43.7, 29.6, and 12.8 g for high, moderate, and low, respectively). Dressing percentage was similar between genotypes (41.1% and 41.1% live body weight for crossbred and local goats, respectively; SE = 0.59) and greater (P < 0.05) for high vs. low (43.5% vs. 38.7% live body weight). Carcass weight differed (P < 0.05) between genotypes (9.23 and 6.23 kg for crossbred and local goats, respectively) and high and low (8.80 and 6.66 kg, respectively). Carcass concentrations of physically dissectible lean and fat were similar between genotypes and high and low concentrate levels. There were few differences between genotypes or concentrate levels in other carcass characteristics such as color and skin properties. Relative to empty body weight, the mass of most non carcass tissues and organs did not differ between genotypes. However, the low concentrate-level mass of omental-mesenteric fat was greater (P < 0.05) for local vs. crossbred goats (1.06% vs. 0.54% empty body weight, respectively). In conclusion, growth performance and carcass weight advantages from crossing Boer and Arsi-Bale goats were similar with a low-quality basal grass hay diet regardless of level of supplemental concentrate. PMID- 22231021 TI - Effect of estrus synchronization protocols on plasma progesterone profile and fertility in postpartum anestrous Kankrej cows. AB - The study was aimed at induction/synchronization of estrus in postpartum anestrous Kankrej cows of zebu cattle maintained at an organized farm. The study included use of different hormone protocols, viz., Ovsynch, CIDR (controlled internal drug release), Ovsynch plus CIDR, and Heatsynch with estimation of plasma progesterone on days 0, 7, 9/11 (artificial insemination--AI) and on day 20 post-AI following fixed time insemination. Thirty selected anestrous animals were divided into five equal groups (four treatment and one control), and the findings were compared with the normal cyclic control group of six cows. All the protocols were initiated in cows with postpartum anestrous period of more than 4 months, considering the day of first GnRH injection or CIDR insertion as day 0. The animals were bred by fixed time artificial insemination. Pregnancy was confirmed per rectum on day 60 post-AI in non-return cases. The conception rates at induced/first heat in Ovsynch, CIDR, Ovsynch + CIDR, and Heatsynch protocols were 33.33, 66.66, 50.00 and 16.67%, respectively. The corresponding overall conception rates of three cycles post-treatment were 50.00% (3/6), 100.00% (6/6), 66.66% (4/6), and 50.00% (3/6). In normal cyclic and anestrous control groups, the pooled pregnancy rates were 83.33% (5/6) and 16.67% (1/6), respectively. The pooled mean plasma progesterone (nanograms per milliliter) concentrations were significantly (P < 0.05) higher on day 7 in Ovsynch (5.727 +/- 1.26), CIDR (4.37 +/- 0.66), Ovsynch plus CIDR (3.55 +/- 0.34), and Heatsynch (5.92 +/- 1.11) protocols as compared with their corresponding values obtained on days 0, 9/11 (AI), and on day 20 post-AI. In anestrous control group, the mean progesterone concentration at the beginning of experiment was 0.67 +/- 0.33 ng/ml, which was at par with values of all other groups. The overall plasma progesterone levels on the day of initiating treatment were low in all groups, with smooth small inactive ovaries palpated per rectum twice at 10 days interval, suggesting that most of the animals used in the study were in anestrous phase. Mean (+/- SE) values of plasma progesterone (nanograms per milliliter) on day 20 post-AI were higher in conceived cows than the non-conceived cows of all the groups, but differed significantly (P < 0.05) only in normal cyclic group. These results suggest that use of different hormone protocols particularly Ovsynch, CIDR, and Ovsynch + CIDR may serve as an excellent tool for induction and synchronization of estrus and improvement of conception rate in postpartum anestrous Kankrej cows. PMID- 22231022 TI - Perception of cancer recurrence risk: more information is better. AB - OBJECTIVE: Breast cancer is the most common cancer among women worldwide. Given the advances in extending survival, the number of recently diagnosed breast cancer patients and longer-term breast cancer survivors is growing. The goals of this study were to better understand (1) perceptions of provider cancer recurrence risk communication, (2) perceived risk of breast cancer recurrence in cancer patients and survivors, and (3) accuracy of perceived risk. METHODS: A survey was conducted on women with a prior breast cancer (n=141). RESULTS: Approximately 40% of women perceived that providers had not talked about their breast cancer recurrence risk; although only 1 person reported not wanting a physician to talk to her about her risk. Women were largely inaccurate in their assessments of risk. Greater worry, living in a rural area, and longer time since diagnosis were associated with greater inaccuracy. Women tended to think about distal recurrence of cancer as often of local recurrence. CONCLUSIONS: Perceived risk of breast cancer recurrence was inaccurate, and patients desired more communication about recurrence risk. PRACTICE IMPLICATIONS: Consistent with findings from other studies, greater efforts are needed to improve the communication of cancer recurrence risk to patients. Attention should be paid to those from rural areas and to distal cancer recurrence in women with a previous history of breast cancer. PMID- 22231023 TI - Quantitative imaging of cartilage and bone morphology, reactive oxygen species, and vascularization in a rodent model of osteoarthritis. AB - OBJECTIVE: To assess temporal changes in cartilage and bone morphology, reactive oxygen species (ROS), and vascularization in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA), using advanced imaging methodologies. METHODS: Right knees of 8-week-old male Wistar rats were injected with 1 mg MIA in 50 MUl saline and left knees were injected with 50 MUl saline as controls. After 1, 2, and 3 weeks (n = 5 at each time point), changes in cartilage morphology and composition were quantified using equilibrium partitioning of an ionic contrast agent microfocal computed tomography (MUCT), and changes in subchondral and trabecular bone were assessed by standard MUCT. ROS were characterized by in vivo fluorescence imaging at 1, 11, and 21 days (n = 5 at each time point). Three weeks following fluorescence imaging, alterations in knee joint vascularity were quantified with MUCT after perfusion of a vascular contrast agent. RESULTS: Femoral cartilage volume, thickness, and proteoglycan content were significantly decreased in MIA-injected knees compared with control knees, accompanied by loss of trabecular bone and erosion of subchondral bone surface. ROS quantities were significantly increased 1 day after MIA injection and subsequently decreased gradually, having returned to normal by 21 days. Vascularity in whole knees and distal femora was significantly increased at 21 days after MIA injection. CONCLUSION: Contrast-enhanced MUCT and fluorescence imaging were combined to characterize articular cartilage, subchondral bone, vascularization, and ROS, providing unprecedented 3-dimensional joint imaging and quantification in multiple tissues during OA progression. These advanced imaging techniques have the potential to become standardized methods for comprehensive evaluation of articular joint degeneration and evaluation of therapeutic efficacy. PMID- 22231024 TI - Prevalence of Puroindoline D1 and Puroindoline b-2 variants in U.S. Pacific Northwest wheat breeding germplasm pools, and their association with kernel texture. AB - Kernel texture is a major factor influencing the classification and end use properties of wheat (Triticum aestivum L.), and is mainly controlled by the Puroindoline a (Pina) and Puroindoline b (Pinb) genes. Recently, a new puroindoline gene, Puroindoline b-2 (Pin b-2), was identified. In this study, 388 wheat cultivars and advanced breeding lines from the U.S. Pacific Northwest were investigated for frequencies of Puroindoline D1 alleles and Pinb-2 variants 2 and 3. Results indicated that Pinb-D1b (74.0%) was the predominant genotype among hard wheats (N = 196), the only other hard allele encountered was Pina-D1b (26.0%). Across all varieties, Pinb-2v3 was the predominant genotype (84.5%) compared with Pinb-2v2 (15.5%). However, among 240 winter wheat varieties (124 soft white, 15 club, 68 hard red and 33 hard white varieties), all carried Pinb 2v3. Among spring wheats, Pinb-2v2 and Pinb-2v3 frequencies were more variable (soft white 25.0:75.0, hard red 58.2:41.8 and hard white 40.0:60.0, respectively). Kernel texture variation was analyzed using 247 of the 388 wheat varieties grown in multi-location factorial trials in up to 7 crop years. The range of variety means among the four groups, soft winter, soft spring, hard winter and hard spring, was on the order of 15-25 single kernel characterization system (SKCS) Hardness Index. The least significant difference for each of these trials ranged from 2.8 to 5.6 SKCS Hardness Index. Observations lead to the conclusion that Pinb-2 variants do not exert a prominent effect on kernel texture, however, Pinb-2 variants do identify features of wheat germ plasm structure in the U.S. Pacific Northwest. PMID- 22231025 TI - Risk factors associated with recurrence after nipple-sparing mastectomy for invasive and intraepithelial neoplasia. AB - BACKGROUND: To identify risk factors of recurrence in a large series of patients with breast cancer who underwent a nipple-sparing mastectomy (NSM). PATIENTS AND METHODS: Breast-related recurrences and local recurrences (LR) in the breast and the nipple areola complex (NAC) were studied. Cumulative incidences of events were estimated through competing risk analysis. Multivariate Cox regression models were also applied. RESULTS: We identified 934 consecutive NSM patients during 2002-2007. Median follow-up was 50 months. In 772 invasive carcinoma patients, the rate of LR in the breast and in the NAC was 3.6% and 0.8%, respectively. In the 162 patients with intraepithelial neoplasia, the rate of LR in the breast and in the NAC was 4.9% and 2.9%, respectively. The significant risk factors of LR in the breast for the group A were grade, overexpression/amplification of HER2/neu and breast cancer molecular subtype Luminal B. In group B, the risk factors of LR in the breast and in the NAC were age (<45 years), absence of estrogen receptors, grade, HER2/neu overexpression and high Ki-67. CONCLUSIONS: The LR rate after NSM in our series was low. Biological features of disease and young age should be taken into account when considering NSM in breast cancer patients. PMID- 22231026 TI - History of cholelithiasis and cancer risk in a network of case-control studies. AB - BACKGROUND: We analyzed the relationship between cholelithiasis and cancer risk in a network of case-control studies conducted in Italy and Switzerland in 1982 2009. METHODS: The analyses included 1997 oropharyngeal, 917 esophageal, 999 gastric, 23 small intestinal, 3726 colorectal, 684 liver, 688 pancreatic, 1240 laryngeal, 6447 breast, 1458 endometrial, 2002 ovarian, 1582 prostate, 1125 renal cell, 741 bladder cancers, and 21 284 controls. The odds ratios (ORs) were estimated by multiple logistic regression models. RESULTS: The ORs for subjects with history of cholelithiasis compared with those without were significantly elevated for small intestinal (OR=3.96), prostate (OR=1.36), and kidney cancers (OR=1.57). These positive associations were observed >=10 years after diagnosis of cholelithiasis and were consistent across strata of age, sex, and body mass index. No relation was found with the other selected cancers. A meta-analysis including this and three other studies on the relation of cholelithiasis with small intestinal cancer gave a pooled relative risk of 2.35 [95% confidence interval (CI) 1.82-3.03]. CONCLUSION: In subjects with cholelithiasis, we showed an appreciably increased risk of small intestinal cancer and suggested a moderate increased risk of prostate and kidney cancers. We found no material association with the other cancers considered. PMID- 22231027 TI - Rapid prototyping of three-dimensional microfluidic mixers in glass by femtosecond laser direct writing. AB - The creation of complex three-dimensional (3D) microfluidic systems has attracted significant attention from both scientific and applied research communities. However, it is still a formidable challenge to build 3D microfluidic structures with arbitrary configurations using conventional planar lithographic fabrication methods. Here, we demonstrate rapid fabrication of high-aspect-ratio microfluidic channels with various 3D configurations in glass substrates by femtosecond laser direct writing. Based on this approach, we demonstrate a 3D passive microfluidic mixer and characterize its functionalities. This technology will enable rapid construction of complex 3D microfluidic devices for a wide array of lab-on-a-chip applications. PMID- 22231028 TI - Therapeutic gene delivery and transfection in human pancreatic cancer cells using epidermal growth factor receptor-targeted gelatin nanoparticles. AB - More than 32,000 patients are diagnosed with pancreatic cancer in the United States per year and the disease is associated with very high mortality (1). Urgent need exists to develop novel clinically-translatable therapeutic strategies that can improve on the dismal survival statistics of pancreatic cancer patients. Although gene therapy in cancer has shown a tremendous promise, the major challenge is in the development of safe and effective delivery system, which can lead to sustained transgene expression. Gelatin is one of the most versatile natural biopolymer, widely used in food and pharmaceutical products. Previous studies from our laboratory have shown that type B gelatin could physical encapsulate DNA, which preserved the supercoiled structure of the plasmid and improved transfection efficiency upon intracellular delivery. By thiolation of gelatin, the sulfhydryl groups could be introduced into the polymer and would form disulfide bond within nanoparticles, which stabilizes the whole complex and once disulfide bond is broken due to the presence of glutathione in cytosol, payload would be released (2-5). Poly(ethylene glycol) (PEG)-modified GENS, when administered into the systemic circulation, provides long-circulation times and preferentially targets to the tumor mass due to the hyper-permeability of the neovasculature by the enhanced permeability and retention effect (6). Studies have shown over-expression of the epidermal growth factor receptor (EGFR) on Panc-1 human pancreatic adenocarcinoma cells (7). In order to actively target pancreatic cancer cell line, EGFR specific peptide was conjugated on the particle surface through a PEG spacer.(8) Most anti-tumor gene therapies are focused on administration of the tumor suppressor genes, such as wild-type p53 (wt-p53), to restore the pro-apoptotic function in the cells (9). The p53 mechanism functions as a critical signaling pathway in cell growth, which regulates apoptosis, cell cycle arrest, metabolism and other processes (10). In pancreatic cancer, most cells have mutations in p53 protein, causing the loss of apoptotic activity. With the introduction of wt-p53, the apoptosis could be repaired and further triggers cell death in cancer cells (11). Based on the above rationale, we have designed EGFR targeting peptide-modified thiolated gelatin nanoparticles for wt-p53 gene delivery and evaluated delivery efficiency and transfection in Panc-1 cells. PMID- 22231029 TI - Perioperative change in peripheral blood monocyte count may predict prognosis in patients with colorectal liver metastasis after hepatic resection. AB - BACKGROUND: Prognostic value of perioperative change in peripheral blood leukocyte subset count of cancer patients have not been fully investigated. Therefore, we retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease-free as well as overall survival after hepatic resection for colorectal liver metastasis (CRLM). METHODS: The subjects were 64 patients who underwent hepatic resection for CRLM between January 2000 and December 2008. We retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease-free as well as overall survival. RESULTS: In multivariate analysis, more than four lymph node metastases (P = 0.0298) and extrahepatic disease (P = 0.0423) were significant predictors of disease-free survival, while significant predictor of overall survival were more than four lymph node metastases (P = 0.0011), bilobar disease (P = 0.0024), and increase in perioperative monocyte less than twice (P = 0.0029). Morover, increase in perioperative monocyte of less than twice positively correlated with intraoperative blood transfusion. CONCLUSIONS: Perioperative change in peripheral blood monocyte count is an independent risk factor for overall survival after hepatic resection for CRLM, and may reflect immunosuppressive state. PMID- 22231030 TI - Detection of fetomaternal hemorrhage. AB - The prevention of Rhesus D alloimmunization through Rh immune globulin (RhIg) administration is the major indication for the accurate detection and quantification of fetomaternal hemorrhage (FMH). In the setting of D incompatibility, D-positive fetal cells can sensitize the D-negative mother, resulting in maternal anti-D alloantibody production. These anti-D alloantibodies may lead to undesirable sequelae such as hemolytic disease of the newborn (HDN). Since the widespread adoption of FMH screening and RhIg immunoprophylaxis, the overall risk of Rh alloimmunization and infant mortality from HDN has substantially decreased. The rosette screen, the initial test of choice, is highly sensitive in qualitatively detecting 10 mL of fetal whole blood in the maternal circulation. As the screen is reliant on the presence of the D antigen to distinguish fetal from maternal cells, it cannot be used to detect FMH in D positive mothers or in D-negative mothers carrying a D-negative fetus. The Kleihauer-Betke acid-elution test, the most widely used confirmatory test for quantifying FMH, relies on the principle that fetal RBCs contain mostly fetal hemoglobin (HbF), which is resistant to acid-elution whereas adult hemoglobin is acid-sensitive. Although the Kleihauer-Betke test is inexpensive and requires no special equipment, it lacks standardization and precision, and may not be accurate in conditions with elevated F-cells. Anti-HbF flow cytometry is a promising alternative, although its use is limited by equipment and staffing costs. Hematology analyzers with flow cytometry capabilities may be adapted for fetal cell detection, thus giving clinical laboratories a potentially attractive automated alternative for quantifying FMH. PMID- 22231031 TI - Immune reconstitution in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is associated with a profound immune defect, which results in increased susceptibility to recurrent infections as well as a failure to mount effective antitumor immune responses. Current chemotherapy-based regimens are not curative and often worsen this immune suppression, so their usefulness is limited, particularly in the frail and elderly. This article reviews the immune defect in CLL and discusses strategies aimed at repairing or circumventing this defect. In particular, it focuses on recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors. PMID- 22231032 TI - Do albuminuria and hs-CRP add to the International Diabetes Federation definition of the metabolic syndrome in predicting outcome? AB - BACKGROUND: To investigate the added value of elevated urinary albumin excretion (UAE) and high high-sensitive C-reactive protein (hs-CRP) in predicting new-onset type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and chronic kidney disease (CKD) in addition to the present metabolic syndrome (MetS) defining criteria. METHODS: The PREVEND Study is a prospective population-based cohort study in the Netherlands, including 8592 participants. The MetS was defined according to the 2004 International Diabetes Federation criteria, elevated UAE as albuminuria >= 30 mg/24 h and high hs-CRP as >= 3 mg/L. RESULTS: At follow-up, subjects without MetS when compared to subjects with MetS had a lower incidence of T2DM, CVD as well as CKD (2.5 versus 15.5; 4.1 versus 10.3 and 5.8 versus 11.2%, all P < 0.001). In subjects with MetS, the incidence of all three outcomes was higher among subjects with elevated albuminuria versus subjects with normoalbuminuria (all P < 0.01). The incidence of all outcomes was also higher among subjects with high hs-CRP versus subjects without elevated hs-CRP but only significant for CKD (P = 0.002). Multivariate analysis including elevated UAE, hs CRP and the variables defining the MetS showed that elevated albuminuria was independently associated with the risk for new-onset T2DM, CVD and CKD, whereas high hs-CRP was only independently associated with new-onset CVD and CKD. CONCLUSION: Our data show that elevated UAE has added value to the present MetS defining variables in predicting new-onset T2DM, CVD and CKD, whereas hs-CRP adds to predicting new-onset CVD and CKD, but not T2DM. PMID- 22231033 TI - Selectively increasing the clearance of protein-bound uremic solutes. AB - BACKGROUND: The toxicity of bound solutes could be better evaluated if we could adjust the clearance of such solutes independent of unbound solutes. This study assessed whether bound solute clearances can be increased while maintaining urea clearance constant during the extended hours of nocturnal dialysis. METHODS: Nine patients on thrice-weekly nocturnal dialysis underwent two experimental dialysis treatments 1 week apart. The experimental treatments were designed to provide the same urea clearance while providing widely different bound solute clearance. One treatment employed a large dialyzer and high dialyzate flow rate (Qd) of 800 mL/min while blood flow (Qb) was 270 mL/min. The other treatment employed a smaller dialyzer and Qd of 300 mL/min while Qb was 350 mL/min. RESULTS: Treatment with the large dialyzer and higher Qd greatly increased the clearances of the bound solutes p-cresol sulfate (PCS: 27+/-9 versus 14+/-6 mL/min) and indoxyl sulfate (IS: 26+/-8 versus 14+/-5 mL/min) without altering the clearance of urea (204+/-20 versus 193+/-16 mL/min). Increasing PCS and IS clearances increased the removal of these solutes (PCS: 375+/-200 versus 207+/-86 mg/session; IS: 201+/ 137 versus 153+/-74 mg/session), while urea removal was not different. CONCLUSIONS: The removal of bound solutes can thus be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/V(urea) during extended treatment. Selectively increasing the clearance of bound solutes provides a potential means to test their toxicity. PMID- 22231034 TI - Renal replacement therapy in critically ill patients with acute kidney injury- when to start. AB - BACKGROUND: Despite the frequent use of renal replacement therapy (RRT) for patients with acute kidney injury (AKI) in the intensive care unit (ICU), there is no accepted consensus on the optimal indications and timing. METHODS: The aim of this paper is to identify optimal triggers for RRT in critically ill patients with AKI. RESULTS: We examined data from 2 randomized controlled trials, 2 prospective studies and 13 retrospective trials and found large variation in the different parameters and cut-offs for initiation of RRT. No single biochemical parameter was adequate to define the optimal indication and time to commence RRT. Degree of fluid overload, oliguria and associated non-renal organ failure appeared to be more appropriate parameters for initiation of RRT. We propose a clinical algorithm based on regular assessment of the patient's condition and trends in these parameters. It is intended to aid the process of deciding when to start RRT in critically ill adult patients with AKI. CONCLUSION: Available evidence suggests that the decision when to start RRT in critically ill patients with AKI should be based on trends in the patient's severity of illness, presence of oliguria and fluid overload and associated non-renal organ failure rather than specific serum creatinine or urea values. PMID- 22231035 TI - Renal biopsy criterion in children with asymptomatic constant isolated proteinuria. AB - BACKGROUND: The criterion of a renal biopsy in children with asymptomatic persistent isolated proteinuria is controversial. METHODS: To determine an adequate renal biopsy criterion in children with asymptomatic constant isolated proteinuria, the optimal cutoff maximum urinary protein/creatinine ratio (uP/Cr) to separate minor glomerular abnormalities (MGA) and other significant glomerular changes was obtained by receiver operating characteristic analysis in 44 children with asymptomatic constant isolated proteinuria (uP/Cr >= 0.2 g/g) screened from 1167 patients who underwent a renal biopsy between September 2000 and April 2010. Patients were divided into two groups according to the cutoff value to verify its validity. RESULTS: The optimal uP/Cr was 0.5 g/g. In Group 1 (uP/Cr <0.5 g/g, n = 15), only one patient (6.7%) showed focal segmental glomerulosclerosis (FSGS) and the other 14 patients (93.3%) had MGA. In Group 2 (uP/Cr >= 0.5 g/g at least once before biopsy, n = 29), 5 patients showed FSGS and 7 patients had nephritis such as IgA nephropathy (41.4%, n = 12) and the other 17 patients (58.6%) showed MGA. These findings indicated that the ratio of non-MGA/MGA was significantly higher in Group 2 than that in Group 1 (P = 0.016) and that if renal biopsies were performed with a criterion of a maximum uP/Cr >= 0.5 g/g (criterion for Group 2), renal biopsies could be avoided in 45.2% of patients with MGA. One patient with FSGS in Group 1 showed proteinuria with uP/Cr >= 0.5 g/g in the clinical course. CONCLUSIONS: An adequate renal biopsy criterion in children with asymptomatic constant isolated proteinuria is uP/Cr >= 0.5 g/g. PMID- 22231036 TI - PET measurement of adenosine stimulated absolute myocardial blood flow for physiological assessment of the coronary circulation. AB - Considerable awareness has been raised of late of the need to reduce radiation exposure and control costs of x-ray and radionuclide imaging procedures. PET/CT cameras are now widely available and in conjunction with appropriate radionuclides and commercially available software make quantitative measurement of absolute MBF feasible for routine clinical practice. Quantitative measurement of absolute MBF under condition of coronary vasodilation permits independent assessment of the functional status of each of the three major coronary perfusion zones and so obviates the need for rest MBF determination in the great majority of cases. Coronary microvascular function also may be assessed in this same way. Thus, the stress-only protocol with quantitative PET measurement of MBF provides essential information required for clinical decision making related to need for catheterization and intervention for patients with known or suspected ischemic heart disease. Moreover, the single PET determination of maximal MBF in contrast to the usual rest/stress procedure addresses both safety and cost concerns. The present review focuses on: (1) quantitative PET measurements of myocardial blood flow for physiological assessment of the coronary circulation and (2) the value and potential limitations of performing stress only imaging in the clinical context. PMID- 22231037 TI - Some unsettled problems in behavioral neuroscience research. AB - The goal of behavioral neuroscience is to map psychological concepts onto physiological and anatomical concepts and vice versa. The present paper reflects on some of the hidden obstacles that have to be overcome in order to find unique psychophysiological relationships. These are, among others: (1) the different status of concepts which are defined in the two domains (ontological subjectivity in psychology and ontological objectivity in physiology); (2) the distinct hierarchical levels to which concepts from the two domains may belong; (3) ambiguity of concepts, because-due to limited measurement resolution or definitional shortcomings-they sometimes do not cover unique states or processes; (4) ignored context dependencies. Moreover, it is argued that due to the gigantic number of states and state changes, which are possible in a nervous system, it seems unlikely that neuroscience can provide exact causal explanations and predictions of behavior. Rather, as in statistical thermodynamics the transition from the microlevel of explanations to the macrolevel is only possible with probabilistic uncertainty. PMID- 22231038 TI - Oncotype DX test on unequivocally HER2-positive cases: potential for harm. PMID- 22231039 TI - Non-uremic calcific arteriolopathy (calciphylaxis) in relapsed/refractory Hodgkin's lymphoma: a previously unreported association. PMID- 22231040 TI - Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. AB - PURPOSE: Complete remission (CR) is uncommon during treatment for metastatic renal cell carcinoma (mRCC) with tyrosine kinase inhibitors (TKIs), but it may occur in some patients. It remains a matter of debate whether therapy should be continued after CR. METHODS: A multicenter, retrospective analysis of a series of patients with mRCC who obtained CR during treatment with TKIs (sunitinib or sorafenib), either alone or with local treatment (surgery, radiotherapy, or radiofrequency ablation), was performed. RESULTS: CR was identified in 64 patients; 36 patients had received TKI treatment alone and 28 had also received local treatment. Most patients had clear cell histology (60 of 64 patients), and all had undergone previous nephrectomy. The majority of patients were favorable or intermediate risk; however, three patients were poor risk. Most patients developed CR during sunitinib treatment (59 of 64 patients). Among the 36 patients who achieved CR with TKI alone, eight continued TKI treatment after CR, whereas 28 stopped treatment. Seventeen patients who stopped treatment (61%) are still in CR, with a median follow-up of 255 days. Among the 28 patients in CR after TKI plus local treatment, 25 patients stopped treatment, and 12 of these patients (48%) are still in CR, with a median follow-up of 322 days. CONCLUSION: CR can occur after TKI treatment alone or when combined with local treatment. CR was observed at every metastatic site and in every prognostic group. PMID- 22231041 TI - Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. AB - PURPOSE: Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels. RESULTS: Targeted for 124 patients with a planned 5 year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status. CONCLUSION: When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group. PMID- 22231043 TI - Multiple cytokine-producing plasmablastic solitary plasmacytoma of bone with polyneuropathy, organomegaly, endocrinology, monoclonal protein, and skin changes syndrome. PMID- 22231044 TI - Are we ready for online tools in decision making for BRCA1/2 mutation carriers? PMID- 22231042 TI - Online tool to guide decisions for BRCA1/2 mutation carriers. AB - PURPOSE: Women with BRCA1 or BRCA2 (BRCA1/2) mutations must choose between prophylactic surgeries and screening to manage their high risks of breast and ovarian cancer, comparing options in terms of cancer incidence, survival, and quality of life. A clinical decision tool could guide these complex choices. METHODS: We built a Monte Carlo model for BRCA1/2 mutation carriers, simulating breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years and prophylactic mastectomy (PM) and/or prophylactic oophorectomy (PO) at various ages. Modeled outcomes were cancer incidence, tumor features that shape treatment recommendations, overall survival, and cause specific mortality. We adapted the model into an online tool to support shared decision making. RESULTS: We compared strategies on cancer incidence and survival to age 70 years; for example, PO plus PM at age 25 years optimizes both outcomes (incidence, 4% to 11%; survival, 80% to 83%), whereas PO at age 40 years plus MRI screening offers less effective prevention, yet similar survival (incidence, 36% to 57%; survival, 74% to 80%). To characterize patients' treatment and survivorship experiences, we reported the tumor features and treatments associated with risk-reducing interventions; for example, in most BRCA2 mutation carriers (81%), MRI screening diagnoses stage I, hormone receptor-positive breast cancers, which may not require chemotherapy. CONCLUSION: Cancer risk-reducing options for BRCA1/2 mutation carriers vary in their impact on cancer incidence, recommended treatments, quality of life, and survival. To guide decisions informed by multiple health outcomes, we provide an online tool for joint use by patients with their physicians (http://brcatool.stanford.edu). PMID- 22231045 TI - Bone scan index: a quantitative treatment response biomarker for castration resistant metastatic prostate cancer. AB - PURPOSE: There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure. PATIENTS AND METHODS: We retrospectively examined serial bone scans from patients with castration resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival. RESULTS: Eighty eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic. CONCLUSION: These data furnish early evidence that on treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC. PMID- 22231047 TI - Microsatellite instability status is critical to analysis of survival in stage II colon cancer. PMID- 22231046 TI - Ovarian suppression for prevention of premature menopause and infertility: empty promise or effective therapy? PMID- 22231048 TI - Severe anemia during rituximab maintenance therapy for follicular lymphoma. PMID- 22231049 TI - Impact of call center work in subjective voice symptoms and complaints--an analytic study. AB - PURPOSE: To estimate the prevalence of vocal symptoms, occupational risk factors, associated symptoms and their impact on the professional activity of the telemarketers. METHODS: Cross-section analytical study with 124 telemarketers and 109 administrative workers (control group) selected from a random sample stratified by gender. The subjects answered an anonymous self-administered questionnaire involving issues related to the presence of vocal symptoms, potential risk factors for dysphonia, and vocal impact of symptoms in professional activity. The presence of one or more voice symptoms that occurred daily or weekly was considered positive for the presence of vocal symptoms. RESULTS: The prevalence of vocal symptoms was found in 33% of telemarketers and in 21% of the control group, indicating an association between vocal symptoms and the activity of the telemarketer. When adjusted for confounders, this association remained in the sense of risk. In telemarketers, the sensation of dry air, ambient noise, and lack of vocal rest were the most frequently reported complaints reported by those presenting vocal symptoms. Almost 70% of telemarketers with vocal symptoms reported that these symptoms interfere with their professional activity. The rate of absenteeism by vocal symptoms in this group was 29%. CONCLUSION: Vocal symptoms are common in most telemarketers when compared to their peer controls, and significantly affect their job performance. PMID- 22231050 TI - Hard palate dimensions in nasal and mouth breathers from different etiologies. AB - PURPOSE: To compare the hard palate dimensions of nasal-breathing children, mouth breathers from obstructive etiology, and habitual mouth breathers. METHODS: The sample comprised 76 children, 37 boys and 39 girls, with mean age of 9.32+/-1.16 years, distributed according to the diagnosis of breathing mode and to the etiology of mouth breathing. Plaster cast models of the subjects' superior dental arch were obtained in order to measure the hard palate with a digital caliper. Measurements of transverse, vertical and anteroposterior palatal length were taken. The hard palate measures were compared among the groups through statistical analysis. RESULTS: The comparison of hard palate dimensions observed in nasal and mouth breathers showed differences regarding the distance and depth of second premolars, and the distance of first molars. Differences were also found between the groups of mouth breathers regarding the hard palate depth at the level of canines. CONCLUSION: Mouth breathers showed narrower hard palate at the level of second premolars and first molars, and deeper palate in the level of second premolars, when compared to nasal breathers. It is evidenced that habitual mouth breathers presented deeper hard palate at the level of canines, when compared to mouth breathers from obstructive etiology. PMID- 22231051 TI - Facial type and head posture of nasal and mouth-breathing children. AB - PURPOSE: To verify the facial type and the head posture of nasal and mouth breathing children from habitual and obstructive etiologies, as well as to correlate the morphological facial index to the head angulation position in the sagittal plane. METHODS: Participants were 59 children with ages between 8 years and 11 years and 10 months. All subjects were undergone to speech-language pathology screening, otorhinolaryngologic evaluation, and nasopharyngoscopy, allowing the constitution of three groups: nasal breathers--15 children; mouth breathers from obstructive etiology--22 children; and habitual mouth breathers- 22 children. In order to determine facial type and morphological facial index, the height and the width of the face were measured using a digital caliper. The head posture was assessed through physical examination and computerized photogrammetry. RESULTS: It was verified the predominance of short face in nasal breathers, and long face in mouth breathers. There was an association among facial type and breathing mode/mouth breathing etiology: the brachyfacial type was more frequent among nasal breathers, and less frequent in subjects with obstructive nasal breathing. Head posture was similar in all three groups. No correlation was found between morphological facial index and head posture. CONCLUSION: The brachyfacial type favors the nasal-breathing mode and the head posture is not influenced by breathing mode and by the etiology of mouth breathing, as well as it is not related to facial type. PMID- 22231052 TI - Quality of life of parents/caregivers of children and adolescents with Down syndrome. AB - PURPOSE: To assess the quality of life (LQ) of parents/caregivers of children and adolescents with Down syndrome (DS), as well as the influence of socio demographic aspects on the results obtained. METHODS: Participants were 31 parents/caregivers of children and adolescents with DS, divided into three groups: G1, caregivers of ten preschoolers (ages between 1 year and 5 years and 11 months); G2, caregivers of 11 school-aged children (ages between 6 years and 10 years and 11 months); and, G3, caregivers of ten pre-teens and adolescents (ages between 11 years and 15 years and 11 months). Parents/caregivers characterization: most of them were between 40 and 49 years old; high-school was the most common education level, followed by incomplete elementary school and college education; concerning the socio-economic class, most of them were from classes C and B2. The QL WHOQOL- bref protocol was administered. RESULTS: Eighty four percent of the parents/caregivers rated their QL as "good", and 55% reported to be "satisfied" with their health. The lowest average score was found for the Environment domain, which was found to be correlated with socio-demographic variables "education degree" and "socio-economic level". No difference was found between groups when age ranges were compared. CONCLUSION: The results suggest that the studied population consider their QL as "good", and is "satisfied" with their health. The Environment domain and the socio-demographic variables "education degree" and "socio-economic level" are the aspects that influence their quality of life. PMID- 22231053 TI - Psycholinguistic and scholastic abilities in children with myelomeningocele. AB - PURPOSE: To describe the performance of individuals with myelomeningocele regarding psycholinguistic and scholastic abilities. METHODS: Participants were five individuals with myelomeningocele and lumbar sacral abnormalities, and chronological age between 9 years and 10 months and 11 years and 7 months (Group 1 - G1); five subjects with typical development (Group 2 - G2), matched to G1 for age, gender, and educational level. The evaluation consisted of interview with parents/caregivers, and application of the following tests: Illinois Test of Psycholinguistic Abilities (ITPA); School Performance Test; Speed Reading Test; and Rapid Automatized Naming Test. RESULTS: The between-groups comparison in the ITPA subtests showed that the maximum values obtained by G1 corresponded approximately to the minimum values obtained by G2, confirming the difference between the groups, except for the auditory closure subtest. In the Scholastic Performance Test, significant alterations were observed on the performance of G1 in all tasks. In the Speed Reading and Rapid Automatized Naming tests, individuals in G1 also presented considerable deficits, making more mistakes and spending more time than G2 to perform the same tasks. CONCLUSION: Individuals with myelomeningocele present deficits in psycholinguistic abilities, school performance, reading speed, and rapid automatized naming. PMID- 22231054 TI - Fluency and reading comprehension in students with reading difficulties. AB - PURPOSE: To characterize the performance of students with reading difficulties in decoding and reading comprehension tasks as well as to investigate the possible correlations between them. METHODS: Sixty students (29 girls) from 3rd to 5th grades of public Elementary Schools were evaluated. Thirty students (Research Group - RG), ten from each grade, were nominated by their teachers as presenting evidences of learning disabilities. The other thirty students were indicated as good readers, and were matched by gender, age and grade to the RG, composing the Comparison Group (CG). All subjects were assessed regarding the parameters of reading fluency (rate and accuracy in words, pseudowords and text reading) and reading comprehension (reading level, number and type of ideas identified, and correct responses on multiple choice questions). RESULTS: The RG presented significantly lower scores than the CG in fluency and reading comprehension. Different patterns of positive and negative correlations, from weak to excellent, among the decoding and comprehension parameters were found in both groups. In the RG, low values of reading rate and accuracy were observed, which were correlated to low scores in comprehension and improvement in decoding, but not in comprehension, with grade increase. In CG, correlation was found between different fluency parameters, but none of them was correlated to the reading comprehension variables. CONCLUSION: Students with reading and writing difficulties show lower values of reading fluency and comprehension than good readers. Fluency and comprehension are correlated in the group with difficulties, showing that deficits in decoding influence reading comprehension, which does not improve with age increase. PMID- 22231055 TI - Speech disorders in students in Belo Horizonte. AB - PURPOSE: To describe speech disorders in students from 1st to 4th grades, and to investigate possible associations between these disorders and stomatognathic system and auditory processing disorders. METHODS: Cross-sectional study with stratified random sample composed of 288 students, calculated based on an universe of 1,189 children enrolled in public schools from the area covered by a health center in Belo Horizonte. The median age was 8.9 years, and 49.7% were male. Assessment used a stomatognathic system protocol adapted from the Myofunctional Evaluation Guidelines, the Phonology task of the ABFW - Child Language Test, and a simplified auditory processing evaluation. Data were statistically analyzed. RESULTS: From the subjects studied, 31.9% had speech disorder. From these, 18% presented phonetic deviation, 9.7% phonological deviation, and 4.2% phonetic and phonological deviation. Linguistic variation was observed in 38.5% of the children. There was a higher proportion of children with phonetic deviation in 1st grade, and a higher proportion of children younger than 8 years old with both phonetic and phonological deviations. Phonetic deviation was associated to stomatognathic system disorder, and phonological deviation was associated to auditory processing disorder. CONCLUSION: The prevalence of speech disorders in 1st to 4th grade students is considered high. Moreover, these disorders are associated to other Speech-Language Pathology and Audiology alterations, which suggest that one disorder may be a consequence of the other, indicating the need for early diagnosis and intervention. PMID- 22231056 TI - Fine motor, sensory and perceptive function of students with attention deficit disorder with hyperactivity. AB - PURPOSE: To characterize and compare the fine motor, sensory and perceptive functions of students with Attention Deficit Disorder with Hyperactivity (ADHD) and students with good academic performance, without behavior alteration. METHODS: Participants were 22 male students from Elementary School distributed into: GI - 11 children with ADHD; and GII - 11 students with good academic performance and no behavior alteration. Students were submitted to the Protocol for Evaluation of Fine Motor, Sensory and Perceptual Function, and to the Dysgraphia Scale. RESULTS: There were differences between GI and GII in tasks concerning fine motor function, sensory function, and perceptual function, with lower performance from GI. All students in GI presented dysgraphia. CONCLUSION: Students with Attention Deficit Disorder with Hyperactivity present lower performance regarding fine motor, sensory and perception functions in relation to students with good academic performance. These difficulties can cause significant impact on academic performance, impairing the development of written language and causing dysgraphia in these students. PMID- 22231057 TI - Function of the medial olivocochlear system in children with phonological disorders. AB - PURPOSE: To verify whether children with phonological disorders present alterations in the medial olivocochlear system. METHODS: This is a prospective cross-sectional study in which 19 normal hearing children of both genders, with ages between 4 and 7 years, were divided into two groups: 11 children without phonological disorders (control group) and eight with phonological disorders (study group). The auditory condition was verified by visual examination of the external ear canal, pure tone audiometry, and tympanometry. The study included only children with hearing thresholds below or equal to 15 dB, type A tympanometry, and presence of acoustic reflexes. To evaluate the function of the medial olivocochlear system, it was carried out the evaluation of transient evoked otoacoustic emissions (TEOAE) with and without contralateral white noise at 60 dBHL. Data were statistically analyzed. RESULTS: The occurrence and average values of TEOAE suppression in right and left ears did not present differences in the frequencies of 1, 2, 3 and 4 kHz within groups. In the comparison of the mean and the occurrence of the suppressive effect of TEOAE between control and study groups, there was also no difference in the frequencies analyzed. CONCLUSION: Children with phonological disorders do not present alterations in the medial olivocochlear system, as evidenced by the occurrence of the suppressive effect of transient evoked otoacoustic emissions. PMID- 22231058 TI - Gaps-in-Noise test: gap detection thresholds in 9-year-old normal-hearing children. AB - PURPOSE: To establish the standard criteria for the Gaps-in-Noise (GIN) test in 9 year-old normal-hearing children; to obtain the mean gap detection thresholds; and to verify the influence of the variables gender and ear on the gap detection thresholds. METHODS: Forty normal-hearing individuals, 20 male and 20 female, with ages ranging from 9 years to 9 years and 11 months, were evaluated. The procedures performed were: anamnesis, audiological evaluation, acoustic immittance measures (tympanometry and acoustic reflex), Dichotic Digits Test, and GIN test. The results obtained were statistically analyzed. RESULTS: The results revealed similar performance of right and left ears in the population studied. There was also no difference regarding the variable gender. In the subjects evaluated, the mean gap detection thresholds were 4.4 ms for the right ear, and 4.2 ms for the left ear. CONCLUSION: The values obtained for right and left ear, as well as their standard deviations, can be used as standard criteria for 9-year old children, regardless of ear or gender. PMID- 22231059 TI - Translation and adaptation of the ABEL: Auditory Behavior in Everyday Life questionnaire into Brazilian Portuguese. AB - PURPOSE: To translate and adapt the ABEL--Auditory Behavior in Everyday Life- questionnaire into Brazilian Portuguese, and to establish the profile of auditory behavior in a group of children who use hearing aids. METHODS: The ABEL questionnaire was translated and back translated. This version was compared to the original version regarding semantic equivalence, generating a new version in Portuguese. After that, 31 parents of children fitted with hearing aids answered an anamnesis and the Portuguese version of the ABEL questionnaire. The scores obtained were related to the variables investigated in the anamnesis. RESULTS: Differences were found in the analysis of the aural-oral score for the variables degree of hearing loss and time of daily use of the hearing aid: children with milder degrees of hearing loss and/or children who use the hearing aid for longer periods showed better performances. There were also differences in total and auditory awareness scores for the variable time of daily use of the hearing aid, indicating that children who user their hearing aids for longer periods daily showed better performances. CONCLUSION: There was consistency between the versions generated during the translation of the questionnaire, allowing the formulation of its final version in Portuguese. Children with lower degrees of hearing loss and/or who use their hearing aids for longer periods have their daily activities less affected by the hearing loss. The ABEL questionnaire is an appropriate instrument to detail the development of auditory behaviors in children who use hearing aids. PMID- 22231060 TI - Newborn hearing screening in infants born to HIV-seropositive mothers. AB - PURPOSE: To analyze the otoacoustic emissions (OAE) of the newborn hearing screening of infants born to HIV-seropositive mothers. METHODS: It was carried out the Transient-Evoked OAE and the research of cochleopalpebral reflex in 247 full-term newborns with no risk factors for hearing. The Control Group (CG) comprised 167 infants, and the Research Group (RG), 80 infants that had been exposed to HIV during gestation. It was considered "failure" when the newborn had absence of TOAE in at least one ear. Data were statistically analyzed. RESULTS: In the, Eight infants (10%) from the Research Group and seven (4.2%) from the Control Group failed in the newborn hearing screening (p=0.09). Retest of the infants who failed showed persistence of the absence of OAE in one subject (12.5%) from the Research Group and two (28.6%) from the Control Group (p=0.6). Cochleopalpebral reflex was present in all subjects. CONCLUSION: There was no association between the absence of TOAE and the newborn's HIV exposure during gestation. PMID- 22231061 TI - Auditory processing in unilateral hearing loss: case report. AB - Unilateral hearing loss represents great risk to academic backwardness, communication, social development, and also to auditory processing. Thus, the aim of this study was to evaluate the auditory abilities of localization, closing, figure-ground, temporal resolution, and simple temporal ordering in a male 17 year-old individual diagnosed with profound unilateral sensorineural hearing loss of idiopathic etiology, without other alterations. The evaluation process consisted on the application of a checklist, and the conduction of conventional clinical audiological evaluation (pure-tone audiometry, logoaudiometry, and tympanometry), and of monotic (ipsilateral SSI, Filtered speech test) and diotic (Sound localization, Auditory memory for verbal and non-verbal sounds, AFT-R) auditory processing test. Results showed alteration only in the sound localization test. No complaints were reported regarding the abilities of sound localization, attention, discrimination, and comprehension. In this case study, the profound unilateral sensorineural hearing loss did not seem to restrict the development of the auditory processing abilities evaluated, except for the localization of the sound source. PMID- 22231062 TI - Dysphagia and cerebrovascular accident: relationship between severity degree and level of neurological impairment. AB - The aim of this case study was to verify the occurrence of dysphagia in acute ischemic stroke within 48 hours after the onset of the first symptoms, in order to establish a possible relationship between the level of neurologic impairment and the severity degree of dysphagia. After emergency hospital admission, three patients underwent neurological clinical evaluation (general physical examination, neurological examination, and application of the National Institute of Health Stroke Scale - NIHSS), and clinical assessment of swallowing using the Protocolo Fonoaudiologico de Avaliacao do Risco para Disfagia (PARD--Speech Language Pathology Protocol for Risk Evaluation for Dysphagia). One of the patients presented functional swallowing (NIHSS score 11), while the other two had mild and moderate oropharyngeal dysphagia (NIHSS scores 15 and 19, respectively). The service flow and the delay on the patients' search for medical care determined the small sample. The findings corroborate literature data regarding the severity of the neurological condition and the manifestation of dysphagia. PMID- 22231063 TI - Speech-Language Pathology production regarding voice in popular singing. AB - PURPOSE: To present a literature review about the Brazilian scientific production in Speech-Language Pathology and Audiology regarding voice in popular singing in the last decade, as for number of publications, musical styles studied, focus of the researches, and instruments used for data collection. RESEARCH STRATEGY: Cross-sectional descriptive study carried out in two stages: search in databases and publications encompassing the last decade of researches in this area in Brazil, and reading of the material obtained for posterior categorization. SELECTION CRITERIA: The databases LILACS and SciELO, the Databasis of Dissertations and Theses organized by CAPES, the online version of Acta ORL, and the online version of OPUS were searched, using the following uniterms: voice, professional voice, singing voice, dysphonia, voice disorders, voice training, music, dysodia. Articles published between the years 2000 and 2010 were selected. DATA ANALYSIS: The researches found were classified and categorized after reading their abstracts and, when necessary, the whole study. RESULTS: Twenty researches within the proposed theme were selected, all of which were descriptive, involving several musical styles. Twelve studies focused on the evaluation of the popular singer's voice, and the most frequently used data collection instrument was the auditory-perceptual evaluation. The results of the publications found corroborate the objectives proposed by the authors and the different methodologies. CONCLUSION: The number of studies published is still restricted when compared to the diversity of musical genres and the uniqueness of popular singer. PMID- 22231064 TI - Cross-cultural adaptation of the Brazilian version of the Voice Symptom Scale: VoiSS. AB - PURPOSE: To present the cultural equivalence of the Brazilian version of the Voice Symptom Scale - VoiSS. METHODS: The questionnaire was translated into Portuguese by two Brazilian bilingual speech-language pathologists, who were informed about the purpose of this research. The back translation was performed by a third bilingual Brazilian speech-language pathologist, who was also an English teacher, and had not participated in the previous stage. After the comparison of translations, a final version of the questionnaire was produced and called Escala de Sintomas Vocais--ESV, which was administered to 15 individuals with vocal complaint. The inclusion criterion was the presence of dysphonia, regardless of type or degree. The option "not applicable" was added to each item of the protocol. RESULTS: During the process of translation and cultural adaptation, no item was changed and/or eliminated from the questions. The ESV kept the same structure as the original British version with 30 questions, 15 regarding the impairment domain (functionality), eight the emotional domain (psychological effect), and seven the physical domain (organic symptoms). CONCLUSION: The cultural equivalence of the Brazilian version of the VoiSS, entitled ESV, was demonstrated. The ESV validation is currently being concluded. PMID- 22231065 TI - Scientific writing and the quality of papers: towards a higher impact. AB - Given the latent concern of scientists and editors on the quality of scientific writing, the aim of this paper was to present topics on the recommended structure of peer-reviewed papers. We described the key points of common sections of original papers and proposed two additional materials that may be useful for scientific writing: one particular guide to help the organization of the main ideas of the paper; and a table with examples of non desirable and desirable structures in scientific writing. PMID- 22231068 TI - Direct SERS detection of contaminants in a complex mixture: rapid, single step screening for melamine in liquid infant formula. AB - Melamine can be detected in infant formula without the need for additional sample preparation or purification using a simple galvanic displacement reaction to fabricate portable silver SERS substrates. The reaction is rapid, inexpensive, and robust enough to perform well on highly heterogeneous common metal objects such as tape and coins. PMID- 22231069 TI - Are predefined decoy sets of ligand poses able to quantify scoring function accuracy? AB - Due to the large number of different docking programs and scoring functions available, researchers are faced with the problem of selecting the most suitable one when starting a structure-based drug discovery project. To guide the decision process, several studies comparing different docking and scoring approaches have been published. In the context of comparing scoring function performance, it is common practice to use a predefined, computer-generated set of ligand poses (decoys) and to reevaluate their score using the set of scoring functions to be compared. But are predefined decoy sets able to unambiguously evaluate and rank different scoring functions with respect to pose prediction performance? This question arose when the pose prediction performance of our piecewise linear potential derived scoring functions (Korb et al. in J Chem Inf Model 49:84-96, 2009) was assessed on a standard decoy set (Cheng et al. in J Chem Inf Model 49:1079-1093, 2009). While they showed excellent pose identification performance when they were used for rescoring of the predefined decoy conformations, a pronounced degradation in performance could be observed when they were directly applied in docking calculations using the same test set. This implies that on a discrete set of ligand poses only the rescoring performance can be evaluated. For comparing the pose prediction performance in a more rigorous manner, the search space of each scoring function has to be sampled extensively as done in the docking calculations performed here. We were able to identify relative strengths and weaknesses of three scoring functions (ChemPLP, GoldScore, and Astex Statistical Potential) by analyzing the performance for subsets of the complexes grouped by different properties of the active site. However, reasons for the overall poor performance of all three functions on this test set compared to other test sets of similar size could not be identified. PMID- 22231070 TI - What happened to personalized medicine? PMID- 22231071 TI - Incyte comes of age with JAK inhibitor approval. PMID- 22231078 TI - Russian fund steps up investments in innovative biotechs. PMID- 22231075 TI - Safety profiles come to fore as more drugs approach MS market. PMID- 22231080 TI - Monsanto to face biopiracy charges in India. PMID- 22231081 TI - Embryonic stem cell pioneer Geron exits field, cuts losses. PMID- 22231083 TI - Foundation medicine. PMID- 22231084 TI - Drug pipeline: Q411. PMID- 22231085 TI - The NIH's role in accelerating translational sciences. PMID- 22231086 TI - Building stem-cell genomics in California and beyond. PMID- 22231087 TI - Approval on a knife edge. PMID- 22231088 TI - Bringing business risk into sharp focus. PMID- 22231089 TI - Big data in small places. PMID- 22231090 TI - Exploiting host molecules to augment mycoinsecticide virulence. PMID- 22231091 TI - European discussion forum on transgenic tree biosafety. PMID- 22231092 TI - Factors influencing agbiotech adoption and development in sub-Saharan Africa. PMID- 22231093 TI - Reinventing clinical trials. PMID- 22231094 TI - Maintaining patents protecting biologics or small-molecule drugs. PMID- 22231096 TI - Parallel genome universes. PMID- 22231097 TI - Dopaminergic neurons for Parkinson's therapy. PMID- 22231098 TI - New competition in RNA regulation. PMID- 22231104 TI - The discovery and development of belimumab: the anti-BLyS-lupus connection. AB - For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta), is a human monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). The approval of belimumab combined a pioneering approach to genomics-based gene discovery, an astute appreciation of translational medicine, a disciplined clinical strategy, a willingness to take calculated risks, a devoted cadre of patients and physicians and a healthy dose of serendipity. Collectively, these efforts have provided a model for the development of a new generation of drugs to treat the broad manifestations of SLE. However, as a substantial percentage of SLE patients do not respond to belimumab, further research is needed to better characterize the pathogenetic mechanisms of SLE, identify additional therapeutic targets, and develop effective and nontoxic novel agents against these targets. PMID- 22231111 TI - Broadening PhD curricula. PMID- 22231114 TI - The unexpected traits associated with core promoter elements. AB - The core promoter of eukaryotic coding and non-coding genes that are transcribed by RNA polymerase II (RNAP II) is composed of DNA elements surrounding the transcription start site. These elements serve as the docking site of the basal transcription machinery and have an important role in determining the position and directing the rate of transcription initiation. This review summarizes the current knowledge about core promoter elements and focuses on several unexpected links between core promoter structure and certain gene features. These include the association between the presence or absence of a TATA-box and gene length, gene structure, gene function, evolution rate and transcription elongation. PMID- 22231115 TI - Effects of the MDM2 promoter SNP285 and SNP309 on Sp1 transcription factor binding and cancer risk. AB - The proto-oncogene MDM2 inhibits p53 and plays a key role in cell growth control and apoptosis. Identification of two antagonizing MDM2 polymorphisms, SNP285 and SNP309, affecting cancer risk through modulation of Sp1 transcription factor binding, shed new light on the biological activity and phylogeny of this gene. PMID- 22231116 TI - Transcriptional regulation of Rho GTPase signaling. AB - Signaling through the Rho family of small GTPases regulates a variety of cellular processes via changes in the actin cytoskeleton. Here we discuss recent findings that show the transcription factor p53 regulates the expression of several Rho pathway signaling molecules, and how mutation of p53 in cancer dramatically alters signaling output through this pathway. PMID- 22231117 TI - Transcription and splicing: when the twain meet. AB - Splicing can occur co-transcriptionally. What happens when the splicing reaction lags after the completed transcriptional process? We found that elongation rates are independent of ongoing splicing on the examined genes and suggest that when transcription has completed but splicing has not, the splicing machinery is retained at the site of transcription, independently of the polymerase. PMID- 22231118 TI - The RNA polymerase C-terminal domain: a new role in spliceosome assembly. AB - Work over the last two decades has provided a wealth of data indicating that the RNA polymerase II transcriptional machinery can play an important role in facilitating the splicing of its transcripts. In particular, the C-terminal domain of the RNA polymerase II large subunit (CTD) is central in the coupling of transcription and splicing. While this has long been assumed to involve physical interactions between splicing factors and the CTD, few functional connections between the CTD and such factors have been established. We recently used a biochemical approach to identify a splicing factor that interacts directly with the CTD to activate splicing and, in doing so, may play a role in the process of spliceosome assembly. PMID- 22231119 TI - Enhancers: multi-dimensional signal integrators. AB - Enhancers play a critical role in regulating tissue-specific gene expression, but their molecular mechanisms of function have not been fully characterized. It is now increasingly clear that enhancers associate with specific protein factors and chromatin modifications and also produce non-coding RNAs known as eRNAs. These predictive signatures have facilitated genomic identification of enhancers and helped characterize tissue-specific gene expression mechanisms. Herein we review recent studies investigating enhancers in mammalian cells, and propose that enhancers function as a central platform integrating lineage-specific transcription factors and epigenetic states with ubiquitous yet signal-dependent transcriptional inputs, culminating in highly specific gene expression programs. PMID- 22231120 TI - The TIF1alpha-related TRIM cofactors couple chromatin modifications to transcriptional regulation, signaling and tumor suppression. AB - TRIM24 (TIF1alpha), TRIM28 (TIF1beta) and TRIM33 (TIF1gamma) are related cofactors defining a subgroup of the tripartite motif (TRIM) superfamily comprising an N-terminal RING finger E3 ligase and a C-terminal PHD-Bromodomain chromatin interacting module. Increasing evidence highlights the important roles of these proteins as modulators of multiple signaling pathways during normal development and as tumor suppressors. The finding that they interact to form a multiprotein complex suggests new mechanisms to integrate multiple signaling pathways for tumor suppression. PMID- 22231121 TI - Control of the RNA polymerase II phosphorylation state in promoter regions by CTD interaction domain-containing proteins RPRD1A and RPRD1B. AB - RNA polymerase II (RNAP II) C-terminal domain (CTD) phosphorylation is important for various transcription-related processes. Here, we identify by affinity purification and mass spectrometry three previously uncharacterized human CTD interaction domain (CID)-containing proteins, RPRD1A, RPRD1B and RPRD2, which co purify with RNAP II and three other RNAP II-associated proteins, RPAP2, GRINL1A and RECQL5, but not with the Mediator complex. RPRD1A and RPRD1B can accompany RNAP II from promoter regions to 3'-untranslated regions during transcription in vivo, predominantly interact with phosphorylated RNAP II, and can reduce CTD S5- and S7-phosphorylated RNAP II at target gene promoters. Thus, the RPRD proteins are likely to have multiple important roles in transcription. PMID- 22231125 TI - Detection of impaired glucose regulation and/or type 2 diabetes mellitus, using primary care electronic data, in a multiethnic UK community setting. AB - AIMS/HYPOTHESIS: The aim of this study was to develop and validate a score for detecting the glycaemic categories of impaired glucose regulation (IGR) and type 2 diabetes using the WHO 2011 diagnostic criteria. METHODS: We used data from 6,390 individuals aged 40-75 years from a multiethnic population based screening study. We developed a logistic regression model for predicting IGR and type 2 diabetes (diagnosed using OGTT or HbA(1c) >= 6.5% [48 mmol/mol]) from data which are routinely stored in primary care. We developed the score by summing the beta coefficients. We externally validated the score using data from 3,225 participants aged 40-75 years screened as part of another study. RESULTS: The score includes age, ethnicity, sex, family history of diabetes, antihypertensive therapy and BMI. Fifty per cent of a population would need to be invited for testing to detect type 2 diabetes mellitus on OGTT with 80% sensitivity; this is slightly raised to 54% that need to be invited if using HbA(1c). Inviting the top 10% for testing, 9% of these would have type 2 diabetes mellitus using an OGTT (positive predictive value [PPV] 8.9% [95% CI 5.8%,12.8%]), 26% would have IGR (PPV 25.9% [95% CI 20.9%, 31.4%]). Using HbA(1c) increases the PPV to 19% for type 2 diabetes mellitus (PPV 18.6% [95% CI 14.2%, 23.7%]) and 28% for an HbA(1c) between 6.0% and 6.4% (PPV 28.3% [95% CI 23.1%, 34.0%]). CONCLUSIONS: The score can be used to reliably identify those with undiagnosed IGR and type 2 diabetes in multiethnic populations. This is the first score developed taking into account HbA(1c) in the diagnosis of type 2 diabetes. PMID- 22231124 TI - The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3 kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways. AB - AIMS/HYPOTHESIS: Pancreatic islet microendothelium exhibits unique features in interdependent relationship with beta cells. Gastrointestinal products of the ghrelin gene, acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (Ob), and the incretin, glucagon-like peptide-1 (GLP-1), prevent apoptosis of pancreatic beta cells. We investigated whether the ghrelin gene products and the GLP-1 receptor agonist exendin-4 (Ex-4) display survival effects in human pancreatic islet microendothelial cells (MECs) exposed to chronic hyperglycaemia. METHODS: Islet MECs were cultured in high glucose concentration and treated with AG, UAG, Ob or Ex-4. Apoptosis was assessed by DNA fragmentation, Hoechst staining of the nuclei and caspase-3 activity. Western blot analyses and pharmacological inhibition of protein kinase B (Akt) and extracellular signal related kinase (ERK)1/2 pathways, detection of intracellular cAMP levels and blockade of adenylyl cyclase (AC)/cAMP/protein kinase A (PKA) signalling were performed. Levels of NO, IL-1beta and vascular endothelial growth factor (VEGF)-A in cell culture supernatant fractions were measured. RESULTS: Islet MECs express the ghrelin receptor GHS-R1A as well as GLP-1R. Treatment with AG, UAG, Ob and Ex 4 promoted cell survival and significantly inhibited glucose-induced apoptosis, through activation of PI3K/Akt, ERK1/2 phosphorylation and intracellular cAMP increase. Moreover, peptides upregulated B cell lymphoma 2 (BCL-2) and downregulated BCL-2-associated X protein (BAX) and CD40 ligand (CD40L) production, and significantly reduced the secretion of NO, IL-1beta and VEGF-A. CONCLUSIONS/INTERPRETATION: The ghrelin gene-derived peptides and Ex-4 exert cytoprotective effects in islet MECs. The anti-apoptotic effects involve phosphoinositide 3-kinase (PI3K)/Akt, ERK1/2 and cAMP/PKA pathways. These peptides could therefore represent a potential tool to improve islet vascularisation and, indirectly, islet cell function. PMID- 22231126 TI - The association between prior infection with five serotypes of Coxsackievirus B and incident type 2 diabetes mellitus in the EPIC-Norfolk study. AB - AIMS/HYPOTHESIS: Infections with Coxsackieviruses have been linked to beta cell dysfunction. Given the importance of beta cell dysfunction in the aetiology of type 2 diabetes, we hypothesised that prior infection with Coxsackieviruses B would increase the risk of type 2 diabetes. The aims of the study were to estimate cross-sectional associations between potential predictors of previous infection and seropositivity for Coxsackievirus B serotypes 1-5 (CBV1-5), and then to assess the association between seropositivity and incident type 2 diabetes. METHODS: Using a case-cohort design nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk study, we ascertained n = 603 cases of incident type 2 diabetes. From within the entire cohort we identified a random subcohort of n = 835, without diabetes at baseline. The presence of Coxsackievirus B neutralising antibodies against serotypes 1-5 was assessed using a plaque neutralisation assay. Weighted Cox regression was used to examine the association between presence of antibodies to CBV1-5 and the development of type 2 diabetes. RESULTS: Seropositivity in the subcohort for CBV1-5 was 50%, 67%, 66%, 75% and 45%, respectively. After adjustment for age, sex, BMI, physical activity and family history of diabetes, the presence of antibodies against CBV1 5 was not associated with incident type 2 diabetes, over a mean follow-up of 5.7 years (HR [95% CIs] 0.94 [0.72,1.25], 0.92 [0.68, 1.23], 1.33 [0.98,1.81], 1.16 [0.83,1.61] and 1.03 [0.77,1.39] for CBV1-5, respectively). CONCLUSIONS/INTERPRETATION: The presence of antibodies against any of five serotypes of Coxsackievirus B was not associated with incident type 2 diabetes. PMID- 22231127 TI - Radioguided occult lesion localization plus sentinel node biopsy (SNOLL) versus wire-guided localization plus sentinel node detection: a case control study of 129 unifocal pure invasive non-palpable breast cancers. AB - AIMS: We compared histological patterns after lumpectomy for non-palpable breast cancers preoperatively localized by radioguided occult lesion localization plus sentinel node localization (SNOLL) versus wire-guided localization. METHODS: To ensure a homogeneously treated cohort and rigorous comparisons, only patients with invasive cancer and measurable opacity by imaging were included. Exclusion criteria were one or more parameters that could interfere with localization and/or the surgical procedure. Forty-three SNOLL were compared with 86 WGL plus sentinel node (SN) localization. Cancer localization effectiveness was based on careful assessment of histological data from only the first resected glandular specimen, as any additional resection specimens were guided by intraoperative histological examination. RESULTS: Reexcisions to ensure free tissue margins were performed during the same procedure in 13.9% of SNOLL versus 31.3% of WGL; p = 0.02. Significantly more women in SNOLL (53.4%) also had free nearest margins of >9 mm after the first procedure compared with WGL (33.7%); p = 0.03. The median centricity ratio after the first procedure was better in SNOLL (2.8, range 1.3 14) than WGL (5, range 1-50); p = 0.008. The median number of SN detected by lymphoscintigraphy was the same in SNOLL and WGL (1, range 0-9, vs. 1, range 0 8). Intraoperative SN detection by blue dye and/or gamma probe was successful for 97.6% of SNOLL versus 93% of WGL. CONCLUSION: In this study, SNOLL was effective and safe, and this procedure significantly improved the rate of negative margins in the first specimen and the rate of reexcision for positive margins compared with WGL. PMID- 22231128 TI - Efficacy of lower-body shielding in computed tomography fluoroscopy-guided interventions. AB - PURPOSE: Computed tomography (CT) fluoroscopy-guided interventions pose relevant radiation exposure to the interventionalist. The goal of this study was to analyze the efficacy of lower-body shielding as a simple structural method for decreasing radiation dose to the interventionalist without limiting access to the patient. MATERIAL AND METHODS: All examinations were performed with a 128-slice dual source CT scanner (12 * 1.2-mm collimation; 120 kV; and 20, 40, 60, and 80 mAs) and an Alderson-Rando phantom. Scatter radiation was measured with an ionization chamber and a digital dosimeter at standardized positions and heights with and without a lower-body lead shield (0.5-mm lead equivalent; Kenex, Harlow, UK). Dose decreases were computed for the different points of measurement. RESULTS: On average, lower-body shielding decreased scatter radiation by 38.2% within a 150-cm radius around the shielding. This decrease is most significant close to the gantry opening and at low heights of 50 and 100 cm above the floor with a maximum decrease of scatter radiation of 95.9% close to the scanner's isocentre. With increasing distance to the gantry opening, the effect decreased. There is almost no dose decrease effect at >=150 above the floor. Scatter radiation and its decrease were linearly correlated with the tube current-time product (r (2) = 0.99), whereas percent scatter radiation decrease was independent of the tube current-time product. CONCLUSION: Lower-body shielding is an effective way to decrease radiation exposure to the interventionalist and should routinely be used in CT fluoroscopy-guided interventions. PMID- 22231129 TI - Severity of nephrotic IgA nephropathy according to the Oxford classification. AB - BACKGROUND: IgA nephropathy with nephrotic syndrome (nephrotic IgAN) is a rare form of IgAN. Its prognosis and response to steroid therapy are still controversial because the differential diagnosis between nephrotic IgAN and minimal change nephrotic syndrome with IgA depositions is sometimes confused. METHODS: In this retrospective cohort analysis, we accurately diagnosed 42 cases of nephrotic IgAN (4.4%) from 954 IgAN patients, according to the Oxford classification. We analyzed the clinical and histological data, prognosis, and response to steroid therapy. RESULTS: In nephrotic IgAN, mean estimated glomerular filtration rate (eGFR) was 51.1 +/- 24.6 ml/min, proteinuria was 5.71 +/- 2.56 g/day, and urinary red blood cells were 51.0 +/- 37.8 high power field. Both active and chronic histological lesions were observed. Cumulative renal survival rate was significantly lower in nephrotic IgAN than in non-nephrotic IgAN (the control group consisted of 47 non-nephrotic IgAN patients diagnosed between 1995 and 1996) (log-rank test: P < 0.0001). The cases with steroid therapy significantly improved their prognosis, though their male-to-female ratio and blood pressure level measured at renal biopsy were significantly lower than in the cases without steroid therapy. Steroid therapy was particularly effective in cases with low-grade tubular atrophy and interstitial fibrosis (T-grade in Oxford classification). Without steroid therapy, lower eGFR and higher T-grade were independent risk factors for severe outcome by multivariate Cox regression. CONCLUSION: Nephrotic IgAN is a very severe form of IgAN, with renal dysfunction, massive hematuria, and active and chronic histopathological lesions. Renal outcome is severe; however, steroid therapy can improve prognosis in cases with higher eGFR and lower T-grade, according to the Oxford classification. PMID- 22231132 TI - Alport syndrome: ACEIs delay RRT and increase lifespan in Alport syndrome. PMID- 22231133 TI - Progression of renal disease: High salt intake blunts the benefit of ACE inhibitors and accelerates renal function decline. PMID- 22231130 TI - Clinical role of the renal transplant biopsy. AB - Percutaneous needle core biopsy is the definitive procedure by which essential diagnostic and prognostic information on acute and chronic renal allograft dysfunction is obtained. The diagnostic value of the information so obtained has endured for over three decades and has proven crucially important in shaping strategies for therapeutic intervention. This Review provides a broad outline of the utility of performing kidney graft biopsies after transplantation, highlighting the relevance of biopsy findings in the immediate and early post transplant period (from days to weeks after implantation), the first post transplant year, and the late period (beyond the first year). We focus on how biopsy findings change over time, and the wide variety of pathological features that characterize the major clinical diagnoses facing the clinician. This article also includes a discussion of acute cellular and humoral rejection, the toxic effects of calcineurin inhibitors, and the widely varying etiologies and characteristics of chronic lesions. Emerging technologies based on gene expression analyses and proteomics, the in situ detection of functionally relevant molecules, and new bioinformatic approaches that hold the promise of improving diagnostic precision and developing new, refined molecular pathways for therapeutic intervention are also presented. PMID- 22231139 TI - Vasculitis: Renal involvement in granulomatosis with polyangiitis-role of ANCA isotype and Fc receptor genotype. PMID- 22231140 TI - Acute kidney injury: Timing of biomarker increases in acute kidney injury. PMID- 22231144 TI - Natural products as kinase inhibitors. AB - Natural products have been widely used to dissect the basic mechanisms of fundamental life science and as clinical therapeutics. Recently, there has been significant interest in discovering new chemical pharmacophores in natural products to fulfil the vast demand for novel kinase inhibitors and address critical unmet medical needs with respect to signal transduction pathways. In this review, we summarize the history of several different classes of natural product-derived kinase inhibitors, discuss their kinome-wide target profiles and examine their structural binding modes based on available 3D X-ray structures. In particular, their origin, target activity, selectivity, scope and potential therapeutic development are highlighted against the backdrop of medicinal chemistry. PMID- 22231143 TI - Detection of toxin translocation into the host cytosol by surface plasmon resonance. AB - AB toxins consist of an enzymatic A subunit and a cell-binding B subunit(1). These toxins are secreted into the extracellular milieu, but they act upon targets within the eukaryotic cytosol. Some AB toxins travel by vesicle carriers from the cell surface to the endoplasmic reticulum (ER) before entering the cytosol(2-4). In the ER, the catalytic A chain dissociates from the rest of the toxin and moves through a protein-conducting channel to reach its cytosolic target(5). The translocated, cytosolic A chain is difficult to detect because toxin trafficking to the ER is an extremely inefficient process: most internalized toxin is routed to the lysosomes for degradation, so only a small fraction of surface-bound toxin reaches the Golgi apparatus and ER(6-12). To monitor toxin translocation from the ER to the cytosol in cultured cells, we combined a subcellular fractionation protocol with the highly sensitive detection method of surface plasmon resonance (SPR)(13-15). The plasma membrane of toxin treated cells is selectively permeabilized with digitonin, allowing collection of a cytosolic fraction which is subsequently perfused over an SPR sensor coated with an anti-toxin A chain antibody. The antibody-coated sensor can capture and detect pg/mL quantities of cytosolic toxin. With this protocol, it is possible to follow the kinetics of toxin entry into the cytosol and to characterize inhibitory effects on the translocation event. The concentration of cytosolic toxin can also be calculated from a standard curve generated with known quantities of A chain standards that have been perfused over the sensor. Our method represents a rapid, sensitive, and quantitative detection system that does not require radiolabeling or other modifications to the target toxin. PMID- 22231145 TI - Heme oxygenase 1 attenuates interleukin-1beta-induced cytosolic phospholipase A2 expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts. AB - OBJECTIVE: Reactive oxygen species (ROS) produced by cytokines induce the expression of inflammatory mediators in rheumatoid arthritis (RA). Heme oxygenase 1 (HO-1) exerts an antiinflammatory effect. The aim of this study was to examine the mechanisms underlying interleukin-1beta (IL-1beta)-induced cytosolic phospholipase A2 (cPLA2) expression through ROS generation as modulated by HO-1 in RA synovial fibroblasts (RASFs). METHODS: IL-1beta-induced ROS generation was determined by flow cytometry. The involvement of MAPKs and NADPH oxidase (NOX)/ROS in IL-1beta-induced cPLA2 expression was investigated using pharmacologic inhibitors and transfection with small interfering RNAs (siRNAs) and was analyzed by Western blotting and promoter assay. Overexpression of HO-1 was performed by transfection of RASFs with a recombinant adenovirus containing human HO-1 plasmid. SCID mice with inflammation caused by IL-1beta were infected with adenovirus containing HO-1. Histologic characterization of joint inflammation and local expression of cPLA2 were evaluated after treatment. RESULTS: IL-1beta-induced cPLA2 expression was mediated through NOX activation/ROS production, which was attenuated by N-acetylcysteine (NAC; a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK-1/2 (U0126), and JNK-1/2 (SP600125), transfection with the respective siRNAs, and the overexpression of HO-1 in RASFs. IL-1beta-induced cPLA2 expression was mediated through recruitment of activator protein 1 (AP-1) to the cPLA2 promoter region, which was attenuated by NAC and overexpression of HO-1. Furthermore, HO-1 overexpression inhibited IL-1beta-mediated cPLA2 expression in SCID mice. CONCLUSION: In RASFs, IL-1beta induced cPLA2 expression via activation of p42/p44 MAPK and JNK-1/2, leading to p47phox phosphorylation, ROS production, and AP-1 activation. The induction of HO-1 exerted protective effects on the pathogenesis of RA. PMID- 22231147 TI - Assurance of energy efficiency and data security for ECG transmission in BASNs. AB - With the technological advancement in body area sensor networks (BASNs), low cost high quality electrocardiographic (ECG) diagnosis systems have become important equipment for healthcare service providers. However, energy consumption and data security with ECG systems in BASNs are still two major challenges to tackle. In this study, we investigate the properties of compressed ECG data for energy saving as an effort to devise a selective encryption mechanism and a two-rate unequal error protection (UEP) scheme. The proposed selective encryption mechanism provides a simple and yet effective security solution for an ECG sensor based communication platform, where only one percent of data is encrypted without compromising ECG data security. This part of the encrypted data is essential to ECG data quality due to its unequally important contribution to distortion reduction. The two-rate UEP scheme achieves a significant additional energy saving due to its unequal investment of communication energy to the outcomes of the selective encryption, and thus, it maintains a high ECG data transmission quality. Our results show the improvements in communication energy saving of about 40%, and demonstrate a higher transmission quality and security measured in terms of wavelet-based weighted percent root-mean-squared difference. PMID- 22231146 TI - Automatic bifurcation detection in coronary IVUS sequences. AB - In this paper, we present a fully automatic method which identifies every bifurcation in an intravascular ultrasound (IVUS) sequence, the corresponding frames, the angular orientation with respect to the IVUS acquisition, and the extension. This goal is reached using a two-level classification scheme: first, a classifier is applied to a set of textural features extracted from each image of a sequence. A comparison among three state-of-the-art discriminative classifiers (AdaBoost, random forest, and support vector machine) is performed to identify the most suitable method for the branching detection task. Second, the results are improved by exploiting contextual information using a multiscale stacked sequential learning scheme. The results are then successively refined using a priori information about branching dimensions and geometry. The proposed approach provides a robust tool for the quick review of pullback sequences, facilitating the evaluation of the lesion at bifurcation sites. The proposed method reaches an F-Measure score of 86.35%, while the F-Measure scores for inter- and intraobserver variability are 71.63% and 76.18%, respectively. The obtained results are positive. Especially, considering the branching detection task is very challenging, due to high variability in bifurcation dimensions and appearance. PMID- 22231148 TI - Controlled aspiration and positioning of biological cells in a micropipette. AB - Manipulating single cells with a micropipette is the oldest, yet still a widely used technique. This paper discusses the aspiration of a single cell into a micropipette and positioning the cell accurately to a target position inside the micropipette. Due to the small volume of a single cell (picoliter) and nonlinear dynamics involved, these tasks have high skill requirements and are labor intensive in manual operation that is solely based on trial and error and has high failure rates. We present automated techniques in this paper for achieving these tasks via computer vision microscopy and closed-loop motion control. Computer vision algorithms were developed to detect and track a single cell outside and inside a micropipette for automated single-cell aspiration. A closed loop robust controller integrating the dynamics of cell motion was designed to accurately and efficiently position the cell to a target position inside the micropipette. The system achieved high success rates of 98% for cell detection and 97% for cell tracking (n = 100). The automated system also demonstrated its capability of aspirating a single cell into a micropipette within 2 s (versus 10 s by highly skilled operators) and accurately positioning the cell inside the micropipette within 8 s (versus 25 s by highly skilled operators). PMID- 22231149 TI - Overexpression of thrombospondin-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. AB - BACKGROUND AND OBJECTIVES: The roles of thrombospondin-1 (THBS-1) in tumor growth and metastasis are complicated and its function as a cancer inhibitor or promoter remains controversial. This clinical study investigated the functional roles of THBS-1 in gastric carcinoma by examining the expression patterns of THBS-1 protein and mRNA levels during gastric cancer development. METHODS: Eighty-two gastric carcinomas were included in this study. THBS-1, alpha-smooth muscle actin, and CD34 proteins were localized by immunohistochemical staining, and the levels of THBS-1 mRNA were quantified by real-time polymerase chain reaction. RESULTS: THBS-1 mRNA expression in gastric carcinoma tissues was significantly higher than in adjacent non-cancerous stomach tissues (P = 0.03). Tumor THBS-1 mRNA expression level was significantly related to lymph node metastasis (P = 0.031), tumor size (P = 0.021) and patient age (P = 0.005). THBS-1 protein was mainly located in stromal myofibroblasts, and was undetectable in tumor cells. Myofibroblasts may be mainly derived from stromal fibroblasts in gastric cancer. The abundance of myofibroblasts was positively correlated with tumor growth and nodal metastasis in gastric carcinoma (P = 0.03, P = 0.0008, respectively). CONCLUSIONS: This clinical study revealed that overexpression of THBS-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. THBS-1 may activate latent transforming growth factor-beta1 to stimulate fibroblasts to differentiate into myofibroblasts, though further studies are needed to validate this hypothesis. These results suggest that THBS-1 and myofibroblasts may serve as novel targets for strategies aimed at protection against and treatment of gastric carcinoma. PMID- 22231151 TI - Integration of data from remote monitoring systems and programmers into the hospital electronic health record system based on international standards. AB - Remote follow-up of implanted ICDs may offer a solution to the problem of overcrowded outpatient clinics. All major device companies have developed a remote follow-up solution. Data obtained from the remote follow-up systems are stored in a central database system, operated and owned by the device company and accessible for the physician or technician. However, the problem now arises that part of the patient's clinical information is stored in the local electronic health record (EHR) system in the hospital, while another part is only available in the remote monitoring database. This may potentially result in patient safety issues. Ideally all information should become available in the EHR system. IHE (Integrating the Healthcare Enterprise) is an initiative to improve the way computer systems in healthcare share information. To address the requirement of integrating remote monitoring data in the local EHR, the IHE Implantable Device Cardiac Observation (IDCO) profile has been developed. In our hospital, we have implemented the IHE IDCO profile to import data from the remote databases from two device vendors into the departmental Cardiology Information System. Data are exchanged via an HL7/XML communication protocol, as defined in the IHE IDCO profile. PMID- 22231150 TI - Inpatient management of sickle cell pain: a 'snapshot' of current practice. AB - The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. While PROACTIVE was not designed to assess pain management and was terminated early due to inadequate patient accrual, collection of clinical data allowed a "snapshot" of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain. PMID- 22231152 TI - Percutaneous left atrial appendage closure for stroke prevention in atrial fibrillation. AB - BACKGROUND: Percutaneous left atrial appendage (LAA) closure can be an alternative to coumadin treatment in patients with atrial fibrillation (AF) at high risk for thromboembolic events and/or bleeding complications. We report the initial experience with this new technique. METHODS: Patients were eligible if they had AF with a high stroke risk (CHADS(2) score >1), and/or contraindication for coumadin therapy. The procedure was performed under general anaesthesia, using biplane fluoroscopy and (3D) transoesophageal echocardiography (TEE) guidance. Patients were discharged on coumadin until a TEE was repeated at 45 days after closure to evaluate LAA occlusion. If LAA occlusion was achieved, oral anticoagulation was discontinued and aspirin started. RESULTS: Percutaneous LAA closure was performed in 10 patients (50% male, age 61.6 +/- 9.6 years). The median CHADS(2) score was 3 (range 2-4), median CHA(2)DS(2)-VASc score 3.5 (range 2-6) and HAS-BLED score 1.5 (range 1-4). Nine patients had a history of stroke and 2 patients had a history of major bleeding while on coumadin. Concomitant pulmonary vein isolation was performed in 9 patients. The device was successfully placed in all patients within a median of 56 min (38-137 min). Asymptomatic catheter thrombus occurred in one patient. At 45-day follow-up, no thromboembolic events occurred, TEE showed minimal residual flow in the LAA in three patients. In one patient the LAA device was dislocated, requiring successful percutaneous retrieval. CONCLUSION: Device closure of the LAA may provide an alternative strategy to chronic coumadin therapy in patients with AF and high risk of stroke and/or bleeding complications using coumadin. PMID- 22231153 TI - Different anthropometric adiposity measures and their association with cardiovascular disease risk factors: a meta-analysis. AB - OBJECTIVES: To investigate which anthropometric adiposity measure has the strongest association with cardiovascular disease (CVD) risk factors in Caucasian men and women without a history of CVD. DESIGN: Systematic review and meta analysis. METHODS: We searched databases for studies reporting correlations between anthropometric adiposity measures and CVD risk factors in Caucasian subjects without a history of CVD. Body mass index (BMI), waist circumference, waist-to-hip ratio, waist-to-height ratio and body fat percentage were considered the anthropometric adiposity measures. Primary CVD risk factors were: systolic blood pressure, diastolic blood pressure, high density lipoprotein (HDL) cholesterol, triglycerides and fasting glucose. Two independent reviewers performed abstract, full text and data selection. RESULTS: Twenty articles were included describing 21,618 males and 24,139 females. Waist circumference had the strongest correlation with all CVD risk factors for both men and women, except for HDL and LDL in men. When comparing BMI with waist circumference, the latter showed significantly better correlations to CVD risk factors, except for diastolic blood pressure in women and HDL and total cholesterol in men. CONCLUSIONS: We recommend the use of waist circumference in clinical and research studies above other anthropometric adiposity measures, especially compared with BMI, when evaluating CVD risk factors. PMID- 22231154 TI - Remote care: bidding our ICD patients a fond farewell? AB - Remote follow-up has proven its safety and efficacy in the literature, and indeed in daily use. It saves the patient time and travel, allows earlier detection of events, and reduces inappropriate shocks. At the same time, it is not infallible and definitely not a universal substitute for in-office visits, as the 5 cases below demonstrate. It saves time, but also takes some time, with problems and challenges we were hitherto not familiar with. Hopes for the future include uniform definitions regarding policy and responsibilities, reimbursement, even better connectivity, better alert management and remote programmability. To end on a more utopic note, it would be a huge step forward if devices and leads were so reliable that we did not need remote care to detect malfunctions. PMID- 22231155 TI - Potential cardiovascular consequences of switching from atorvastatin to generic simvastatin in the Netherlands. AB - BACKGROUND: The statin authorisation form implemented in the Netherlands in January 2009 has led to significant switching of patients from atorvastatin to generic simvastatin, but often to less than equipotent doses. We sought to assess the potential consequences of this. METHODS: A modelling analysis was undertaken using data from a pharmacy database covering the majority of drug prescriptions in the Netherlands. Recent meta-analyses provided data on the dose-specific, lipid-modifying potencies of atorvastatin and simvastatin, and the relationship between reduction in low-density lipoprotein cholesterol (LDL-C) achieved by statin therapy and relative reduction in risk of cardiovascular disease (CVD). RESULTS: In the first quarter of 2009, 33.7%, 47.2% and 19.1% of Dutch patients initially on atorvastatin were switched to less potent, equipotent and more potent doses of simvastatin, respectively. The net effect was estimated to be a 6.8% increase in LDL-C. Assuming a pre-switch LDL-C of 2 mmol/L, the predicted relative increases (95%CI) in the risks of all-cause mortality and major cardiovascular events were 1.7% (0.9%-2.6%) and 2.8% (1.6%-4.1%), respectively. CONCLUSIONS: In the Netherlands, policy-driven switching from atorvastatin to generic simvastatin led overall to less potent doses being used, with possible significant clinical implications. PMID- 22231156 TI - Virchows Archiv: quo vadis? PMID- 22231157 TI - Feasibility and efficacy of minimally invasive stand-alone surgical ablation of atrial fibrillation. A single-center experience. AB - PURPOSE: Minimally invasive surgical ablation for atrial fibrillation (AF) has shown good results and low complications incidence. Our objective was to evaluate feasibility and efficacy of this technique in our center. METHODS: The procedure included pulmonary vein isolation, ganglionic plexi ablation, ligament of Marshall resection, and left atrial appendage exclusion through beating heart minimally invasive bilateral thoracotomies. Patients were monitored daily by telemedicine during the first 4 months and then by quarterly 24-h Holter monitoring or by implantable cardiac monitor. Ablation success was defined as freedom from any atrial tachyarrhythmia recurrence lasting more than 30 s and from antiarrhythmic drugs. All patients were followed up for a minimum of 12 months. RESULTS: Twenty-two consecutive patients with AF, paroxysmal in 27% and persistent in 73%, were treated. Mean age was 63 +/- 10 years, 86% were men. Seventy-three percent of patients had previously undergone to one or more catheter ablations. Median follow-up period was 22 months (25 degrees -75 degrees percentile, 20-27). Patients free from any arrhythmia recurrence for at least 6 consecutive months discontinued antiarrhythmic therapy. Ablation was successful in 73% of patients at 12 months. Freedom from AF recurrences independently from antiarrhythmic therapy status was 91% at 12 months. Results were consistent in patients that reached 24 months follow-up. There were no deaths. Complications were: one conversion to sternotomy owing to thoracic adherences, one pacemaker implant, and one postoperative hemothorax requiring surgical revision. CONCLUSIONS: Our results show that minimally invasive surgical ablation was feasible and gave satisfactory results at long-term term follow-up in patients with AF. PMID- 22231158 TI - Experimental study on malfunction of pacemakers due to exposure to different external magnetic fields. AB - PURPOSE: Cardiac pacemaker malfunction due to exposure to magnetic fields may cause serious problems in some work environments for workers having cardiac pacemakers. The aim of this study was to find the magnetic field interference thresholds for several commonly used pacemaker models. METHODS: We investigated 16 pacemakers from three different manufacturers with the frequency range of 2 to 1,000 Hz, using sinusoidal, pulse, ramp, and square waveforms. The magnetic fields were produced by a computer-controlled Helmholtz coil system. RESULTS: Pacemaker malfunction occurred in six of 16 pacemakers. Interaction developed almost immediately after high-intensity magnetic field exposure started. With each waveform, at least two pacemakers exhibited interference. In most exposure settings, there was no interference at magnetic field levels below the international occupational safety limits. Nevertheless, some frequencies using ramp or square waveforms interfered with pacemakers even at levels below public exposure limits. The occurrence of interference depended greatly on the waveform, frequency, magnetic field intensity, and the sensing configuration of the pacemaker. Unipolar configurations were more susceptible for interference than the bipolar ones. In addition, magnetic fields perpendicular to the pacemaker loops were more likely to cause interference than parallel fields. CONCLUSION: There is a need for further investigations on pacemaker interference caused by different external magnetic fields to ensure safe working environment to workers with a pacemaker. PMID- 22231159 TI - [Maternal mortality in Brazil: the need for strengthening health systems]. PMID- 22231160 TI - [Assessment of fetal well-being in pregnancies complicated by maternal moderate to severe thrombocytopenia]. AB - PURPOSE: To analyze the results of assessment of fetal well-being in pregnancies complicated by moderate or severe maternal thrombocytopenia. METHODS: Data from April 2001 to July 2011 of 96 women with a diagnosis of thrombocytopenia in pregnancy were retrospectively analyzed. We analyzed the following tests performed during the antepartum period for fetal assessment: cardiotocography, fetal biophysical profile, amniotic fluid index and umbilical artery Doppler velocimetry. RESULTS: A total of 96 pregnancies with the following diagnoses were analyzed: gestational thrombocytopenia (n=37, 38.5%) hypersplenism (n=32, 33.3%), immune thrombocytopenic purpura (ITP, n=14, 14.6%), secondary immune thrombocytopenia (n=6, 6.3%), bone marrow aplasia (n=3, 3.1%), and others (n=4, 4.1%). Cardiotocography showed normal results in 94% of cases, a fetal biophysical profile with an index of 8 or 10 in 96.9% and an amniotic fluid index >5.0 cm in 89.6%. Doppler umbilical artery velocimetry showed normal results in 96.9% of cases. In the analysis of the major groups of thrombocytopenia, the diagnosis of oligohydramnios was found to be significantly more frequent in the group with ITP (28.6%) compared to the other groups (gestational thrombocytopenia: 5.4% and hypersplenism: 9.4%, p=0.04). CONCLUSIONS: This study indicates that in pregnancies complicated by moderate or severe maternal thrombocytopenia, even though the fetal well-being remains preserved in most cases, fetal surveillance is important in pregnant women with ITP, with emphasis on amniotic fluid volume evaluation due to its association with oligohydramnios. PMID- 22231161 TI - [Factors associated with low birth weight among adolescents in the Brazil Southeast region]. AB - PURPOSES: To determine the rate of low birth weight and some of the risk factors associated with this event among adolescents. METHODS: A cross-sectional study conducted between October 1994 and December 2009 at a maternity in Campinas, in Brazil, using information generated from the computerized obstetric form. After selection of adolescents who delivered at this hospital, two groups were created, with and without low birth weight, respectively. Relative risk and 95% confidence interval for all independent variables (risk factors) and the Chi2 test for some perinatal results were performed. The level of significance was set at 5%. RESULTS: During the study period, 24,000 births occurred at CAISM. Of these, 2,404 occurred among 2,357 teenagers (10.02%) and the frequency of low birth weight was 15.1%. Adolescent pregnancy recurred in 294 (8.2%). Age less than 15 years-old, anemia, smoking, and hypertension were not significantly associated with low birth weight. Antecedent of miscarriage and association with systemic lupus erythematosus increased the risk of low birth weight. Cesarean section and an Apgar score below seven were more prevalent among adolescents with low birth weight, and 85% of all adolescents had less than six prenatal visits. CONCLUSIONS: The prevalence of low birth weight is higher among adolescents than among adult women, and there was a large number of adolescents with less than six prenatal visits. The antecedent of miscarriage and the presence of systemic lupus erythematosus were risk factors associated with the occurrence of low birth weight among adolescents. PMID- 22231162 TI - [Manual vacuum aspiration uterine treatment of incomplete abortion to 12 gestational weeks: an alternative to curettage]. AB - PURPOSE: To analyze the effectiveness and occurrence of complications, in addition to hospitalization time and blood losses. METHODS: Thirty patients were assigned alternatively and consecutively to one of two groups (15 to the Curettage Group and 15 to the Manual Vacuum Aspiration Group). The following variables were analyzed: effectiveness of the method, occurrence of complications, time before the procedure, time of execution of the procedure, time after the procedure, and total time of hospital permanence, in addition to hematocrit and hemoglobin, which were measured before and after the procedure. Patients were evaluated clinically 10 to 14 days after the procedure. Parametric and nonparametric tests were used for statistical analysis, with the level of significance set at p>0.05. RESULTS: Both methods were efficient and no complications were recorded. Blood losses were similar in the two groups, but the hospitalization time was significantly shorter for the Manual Vacuum Aspiration Group (p=0.03). CONCLUSION: Manual vacuum aspiration is as efficient and safe as uterine curettage, with the advantage of requiring shorter hospitalization, which increases the resolution of the method, improving the quality of care for these patients. PMID- 22231163 TI - [Evaluation of the quality of care for normal delivery]. AB - PURPOSE: To evaluate the quality of health care assistance during childbirth in the hospitals of Goiania, in Brazil. METHODS: Thirteen hospitals were appraised from April to December 2007, and a random sample of 404 normal births was studied. Data were obtained from interviews with mothers after delivery and by consulting their medical records. The quality of assistance at birth was evaluated by using the Bologna score and by comparing the procedures used in those hospitals to standard recommended practices. RESULTS: The Bologna score presented an average value of 1.04 (95%CI=0.9-1.1). The elective caesarian rate was 30%, the emergency caesarian rate was 10%, and the rate of induced childbirth was 1.6% The percentage of childbirths attended by health care professionals was 100%, but pediatricians in the delivery room were present only in 30% of the time. During labor, half of the women had no evaluation of the uterine dynamics and 29% had no auscultation fetal monitoring. The partogram was used for only 28.5% of the women, whereas the use of oxytocin was 45.8%. CONCLUSIONS: The results indicate a poor quality of childbirth care with low values of the Bologna score, high elective and emergency caesarians rates, a high number of unnecessary and potentially harmful interventions, and an insufficient frequency of beneficial interventions. PMID- 22231164 TI - [Micronuclei in uterine cervical cells of women HIV+ according to immunocompetence markers]. AB - PURPOSE: to investigate the micronucleation (MN) of exfoliated cells from the uterine cervix of HIV+ women according to immunocompetence status. We investigated the clinical conditions of immunocompetence by analyzing the levels of CD4+ lymphocytes and viral count for HIV (VC). METHODS: biological material was collected from 23 HIV+ patients whose cervical oncologic cytology results were negative. They were patients from the STD/AIDS-FCMS-PUCSP who underwent a cytobrush collection in the squamous columnar junction. Similar material was obtained from 19 healthy control women. The material, about 2000 cells per patient, was processed for cytology using light microscopy and an immersion objective. To analyze the immunological status of HIV+ patients we used CD4+ count and VC. Statistical analysis was performed using the Chi2 and Kolmorogov Smirnov tests. RESULTS: twenty-three patients composed the group of HIV+ women and 19 composed the control group. We found micronuclei (MN) in all HIV+ patients and in 84.2% of the control group. In 17 73.9% of the HIV+ patients and in 5.2% of the control group we found more than 7 MN cells. MN tended to occur more among women with poorer immunological status in the HIV+ group. CONCLUSIONS: HIV+ patients in the AIDS phase have a higher prevalence of micronucleated cells, as opposed to a control group. Also, the frequency of MN was associated with worse conditions of immunosuppression. PMID- 22231165 TI - [Impact of hormone replacement therapy on body weight]. AB - PURPOSE: to evaluate the effect of hormone replacement therapy (HT) on the weight on perimenopausal women as well as the effect of different treatment regimens on this parameter. METHODS: a retrospective study of 139 women with menopause for less than 2 years, who were monitored with periodical visits in our department. We compared two groups: women who started HT (n=89) with women who had no hormonal treatment (n=50) and in the two groups, we evaluated the changes in body weight over a 1-year period. In the first group, we assessed the same parameter as a function of different treatment regimens: estrogen alone versus estrogen combined with progestin and standard dose versus low dose. The SPSS(r) program was used for statistical analysis, with the level of significance set at p<0.05. RESULTS: the groups were similar with respect to demographic and baseline characteristics; weight gain was higher in the untreated group (434 vs 76 g), but the difference observed was not significant (p = 0.406); among HT users, those taking estrogen alone had an increased weight gain compared to women taking estrogen with progestin (775 vs 24 g), although no statistically significant difference was observed and the same applied when comparing the dose initially prescribed (92 vs 49 g). CONCLUSIONS: despite the common belief about weight gain associated with HT, the results of the present study seem to contradict this point, with no additional weight gain beyond that normally associated with this period in a woman's life. PMID- 22231166 TI - [Prevalence of human papillomavirus genotypes: comparison between three detection methods in patients of Pernambuco, Brazil]. AB - PURPOSE: to compare three methods for the detection of HPV infection and to determine the prevalence of the genotypes found. METHODS: a total of 120 cervical scrape samples from patients with cervical intraepithelial neoplasia were analyzed by the conventional polymerase chain reaction using the MY09/11 and GP05+/06+ primers, and by the Nested polymerase chain reaction. The samples were subjected to DNA amplification with the GH20 and PC04 primers (beta-globin) to verify DNA quality and also by polymerase chain reaction and Nested polymerase chain reaction. The amplicons were visualized in 1.2% agarose gel stained with Blue Green Loading Dye I. Positive samples also were sequenced using the automatic DNA sequencer "MegaBACE 1000". The Chi2 and Fisher tests were used for statistical analysis with the level of significance set at 5%. RESULTS: fifteen samples were eliminated from the study because they failed to amplify the beta globin gene. Of the remaining samples, 40% (42/105) were positive using primers MY09/11, 98% (103/105) using primers GP05+/06+, and 92% (97/105) using Nested PCR. With the MY09/11 and GP05+/06+ techniques, it was possible to obtain 100% HPV-positive samples. In this study, the prevalence of the genotypes found was 57, 23, 5, 4 and 3% for HPV genotypes 16, 18, 31, 33 and 56, respectively. HPVs 67 and 83 were present in 2%, and genotypes 6, 11, 58 and candHPV85 were present in 1% each. The prevalence of the more common genotypes (HPV 16 and 18) in this study agrees with that reported worldwide (IC95%=0.4657-0.8976). CONCLUSIONS: to obtain more reliable results, it is necessary the use of more than one primer system to detect HPV infections. We believe that the three techniques studied are important and suitable for the clinical diagnosis of HPV, when they are appropriately combined. PMID- 22231167 TI - Reversible electrochemical modulation of fluorescence and selective sensing of ascorbic acid using a DCIP-CA-CdTe QD system. AB - The reversible electrochemical modulation of fluorescence and selective sensing of ascorbic acid has been achieved using a DCIP-CA-CdTe QD system. Ascorbic acid could be detected over a linear range from 2.33 MUM to 56.49 MUM, with a detection limit of 0.50 MUM. PMID- 22231170 TI - Accuracy of the morphology enabled dipole inversion (MEDI) algorithm for quantitative susceptibility mapping in MRI. AB - Determining the susceptibility distribution from the magnetic field measured in a magnetic resonance (MR) scanner is an ill-posed inverse problem, because of the presence of zeroes in the convolution kernel in the forward problem. An algorithm called morphology enabled dipole inversion (MEDI), which incorporates spatial prior information, has been proposed to generate a quantitative susceptibility map (QSM). The accuracy of QSM can be validated experimentally. However, there is not yet a rigorous mathematical demonstration of accuracy for a general regularized approach or for MEDI specifically. The error in the susceptibility map reconstructed by MEDI is expressed in terms of the acquisition noise and the error in the spatial prior information. A detailed analysis demonstrates that the error in the susceptibility map reconstructed by MEDI is bounded by a linear function of these two error sources. Numerical analysis confirms that the error of the susceptibility map reconstructed by MEDI is on the same order of the noise in the original MRI data, and comprehensive edge detection will lead to reduced model error in MEDI. Additional phantom validation and human brain imaging demonstrated the practicality of the MEDI method. PMID- 22231171 TI - Alignment of 3-D optical coherence tomography scans to correct eye movement using a particle filtering. AB - Eye movement artifacts occurring during 3-D optical coherence tomography (OCT) scanning is a well-recognized problem that may adversely affect image analysis and interpretation. A particle filtering algorithm is presented in this paper to correct motion in a 3-D dataset by considering eye movement as a target tracking problem in a dynamic system. The proposed particle filtering algorithm is an independent 3-D alignment approach, which does not rely on any reference image. 3 D OCT data is considered as a dynamic system, while the location of each A-scan is represented by the state space. A particle set is used to approximate the probability density of the state in the dynamic system. The state of the system is updated frame by frame to detect A-scan movement. The proposed method was applied on both simulated data for objective evaluation and experimental data for subjective evaluation. The sensitivity and specificity of the x-movement detection were 98.85% and 99.43%, respectively, in the simulated data. For the experimental data (74 3-D OCT images), all the images were improved after z alignment, while 81.1% images were improved after x-alignment. The proposed algorithm is an efficient way to align 3-D OCT volume data and correct the eye movement without using references. PMID- 22231168 TI - Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. AB - Multiciliate cells function prominently in the respiratory system, brain ependyma and female reproductive tract to produce vigorous fluid flow along epithelial surfaces. These specialized cells form during development when epithelial progenitors undergo an unusual form of ciliogenesis, in which they assemble and project hundreds of motile cilia. Notch inhibits multiciliate cell formation in diverse epithelia, but how progenitors overcome lateral inhibition and initiate multiciliate cell differentiation is unknown. Here we identify a coiled-coil protein, termed multicilin, which is regulated by Notch and highly expressed in developing epithelia where multiciliate cells form. Inhibiting multicilin function specifically blocks multiciliate cell formation in Xenopus skin and kidney, whereas ectopic expression induces the differentiation of multiciliate cells in ectopic locations. Multicilin localizes to the nucleus, where it directly activates the expression of genes required for multiciliate cell formation, including foxj1 and genes mediating centriole assembly. Multicilin is also necessary and sufficient to promote multiciliate cell differentiation in mouse airway epithelial cultures. These findings indicate that multicilin initiates multiciliate cell differentiation in diverse tissues, by coordinately promoting the transcriptional changes required for motile ciliogenesis and centriole assembly. PMID- 22231169 TI - Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B. AB - Activation of Toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation. However, despite increased levels of phosphorylated eIF2alpha (p-eIF2alpha), a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis and translational suppression of critical proteins. As p-eIF2alpha decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signalling activates eIF2B GEF activity to counteract the effects of p-eIF2alpha. We now show that TLR-TRIF signalling activates eIF2B GEF through PP2A-mediated serine dephosphorylation of the eIF2B E-subunit. PP2A itself is activated by decreased Src-family-kinase induced tyrosine phosphorylation of its catalytic subunit. Each of these processes is required for TLR-TRIF-mediated CHOP suppression in ER-stressed cells in vitro and in vivo. Thus, in the setting of prolonged, physiologic ER stress, a unique TLR-TRIF-dependent translational control pathway enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis while still benefiting from the protective arms of the UPR. PMID- 22231172 TI - Differential role of calmodulin and calcium ions in the stabilization of the catalytic domain of adenyl cyclase CyaA from Bordetella pertussis. AB - The catalytic adenyl cyclase (AC) domain of the protein CyaA from Bordetella pertussis is activated by interaction with the C terminal lobe of calmodulin (C CaM). The AC/C-CaM complex displays an elongated shape, but hydrodynamics measurements on the isolated AC domain allowed to characterize the shape of the protein as spherical. Here, we study by molecular dynamics simulations the complexes between AC and the apo and Ca(2+)-loaded C-CaM, as well as the isolated AC, to characterize the features of AC conformational variability and of AC/C-CaM interaction. The removal of calcium ions from C-CaM increases the AC flexibility, but the removal of C-CaM induces a dramatic drift of the AC conformation. Isolated AC conformations show a general tendency to become less elongated, as the two protein extremities (regions SA and CB) tend to get closer. An analysis of the energetic influences between the C-CaM and the AC regions shows a simple influence scheme, in agreement with the high affinity of AC to CaM. In this scheme, a single influence is observed from C-CaM to the region CA of the AC domain. This influence is correlated to the presence of hydrogen bonds involving residues from C-CaM, and from regions CA, C-terminal tail, and catalytic loop of AC. This study reveals a C-CaM/AC interaction picture where C-CaM stabilizes AC by a steric hindrance on the conformational drift of SA, whereas the Ca(2+) ions allow further stabilization by the establishment of a hydrogen bond network extending from C-CaM to the AC catalytic loop. PMID- 22231173 TI - Use of expiratory change in bladder pressure to assess expiratory muscle activity in patients with large respiratory excursions in central venous pressure. AB - BACKGROUND: Expiratory muscle activity may cause the end-expiratory central venous pressure (CVP) to greatly overestimate right atrial transmural pressure. METHODS: We recorded CVP and expiratory change in intra-abdominal pressure (DeltaIAP) in 39 patients who had a respiratory excursion in CVP from end expiration to end-inspiration (CVP(ee)-CVP(ei)) >= 8 mmHg. Uncorrected CVP was measured at end-expiration, and corrected CVP was calculated as uncorrected CVP DeltaIAP. In 13 patients measurements were repeated during relaxed breathing. RESULTS: The CVP(ee)-CVP(ei) was 15.2 +/- 6.3 mmHg (range 8-34 mmHg), and DeltaIAP was 7.4 +/- 6.0 mmHg (range 0-30 mmHg). Uncorrected CVP was 18.3 +/- 6.1 mmHg, and corrected CVP was 10.9 +/- 3.9 mmHg. There was a significant positive correlation between CVP(ee)-CVP(ei) and DeltaIAP (r = 0.814). However, some patients with a large CVP(ee)-CVP(ei) had negligible DeltaIAP. In a subset of 13 patients with active expiration who had a relaxed CVP tracing available for comparison, the difference between uncorrected CVP and relaxed CVP was much greater than the difference between corrected CVP and relaxed CVP (7.3 +/- 3.0 vs. 1.1 +/- 0.7 mmHg, p < 0.001). CONCLUSION: Patients with large respiratory excursions in CVP often have significant expiratory muscle activity that will cause their CVP to overestimate transmural right atrial pressure. The magnitude of expiratory muscle activity can be assessed by measuring DeltaIAP. Subtracting DeltaIAP from the end-expiratory CVP usually provides a reasonable estimate of the CVP that would be obtained if exhalation were passive. PMID- 22231174 TI - Standard subcutaneous dosing of unfractionated heparin for venous thromboembolism prophylaxis in surgical ICU patients leads to subtherapeutic factor Xa inhibition. AB - PURPOSE: To assess coagulation status and factor Xa inhibition in surgical intensive care unit (ICU) patients administered prophylactic unfractionated heparin for venous thromboembolism (VTE) prophylaxis. METHODS: We conducted a randomized, single-blind study at a tertiary academic medical center. Included were patients 18 years and older admitted to the surgical ICU directly after major abdominal surgery. Exclusion criteria included significant bleeding risk, preoperative anticoagulation, or history of heparin-induced thrombocytopenia. Patients were randomized to two regimens for VTE prophylaxis: standard of care unfractionated heparin, 5,000 units subcutaneously three times daily (SQH) versus unfractionated heparin via intravenous infusion, titrated to an activated partial thromboplastin time of 40-45 s (IVH). Blood samples were taken prior to surgical incision on day 0 and daily for 5 days after surgery. Samples were analyzed for factor Xa inhibition and viscoelastic whole blood clotting parameters (Sonoclot analyzer). RESULTS: A total of 50 patients were randomized to either SQH or IVH. The majority of patients had cancer. Patients in the SQH group had no detectable peak anti-factor Xa (aFXa) activity for 5 days after surgery, while patients in the IVH group had statistically elevated levels compared to the SQH group on days 3-5. SQH patients demonstrated a hypercoagulable profile on Sonoclot, while IVH patients displayed a normal profile. CONCLUSIONS: Standard of care subcutaneous dosing of unfractionated heparin for VTE prophylaxis in surgical ICU patients leads to subtherapeutic levels of factor Xa inhibition. PMID- 22231175 TI - Directional lapped orthogonal transform: theory and design. AB - This paper proposes a directional design method of 2-D nonseparable linear-phase paraunitary filter banks. The proposed method is based on a lattice structure consisting of the 2-D separable DCT block and nonseparable support extension processes. Because of the nonseparability, the bases are allowed to be directional with the critically fixed subsampling, overlapping, orthogonal, symmetric, real-valued, and compact support properties. First, a novel vanishing moment (VM) condition is introduced as a suitable directional constraint, where the moment is referred to as the trend VM. The condition forces wavelet filters, i.e., high-pass and bandpass filters, to annihilate trend-surface components. Second, some theoretical properties of TVMs are discussed for general 2-D paraunitary systems, and then, the properties are applied to the lattice parameters. In order to verify the significance, several design examples are shown, the trend-surface annihilation properties are numerically confirmed, and the denoising capability is evaluated for images through shrinkage. It is shown that our proposed transforms yield perceptually preferable results. PMID- 22231176 TI - Adaptive online performance evaluation of video trackers. AB - We propose an adaptive framework to estimate the quality of video tracking algorithms without ground-truth data. The framework is divided into two main stages, namely, the estimation of the tracker condition to identify temporal segments during which a target is lost and the measurement of the quality of the estimated track when the tracker is successful. A key novelty of the proposed framework is the capability of evaluating video trackers with multiple failures and recoveries over long sequences. Successful tracking is identified by analyzing the uncertainty of the tracker, whereas track recovery from errors is determined based on the time-reversibility constraint. The proposed approach is demonstrated on a particle filter tracker over a heterogeneous data set. Experimental results show the effectiveness and robustness of the proposed framework that improves state-of-the-art approaches in the presence of tracking challenges such as occlusions, illumination changes, and clutter and on sequences containing multiple tracking errors and recoveries. PMID- 22231177 TI - Real-time probabilistic covariance tracking with efficient model update. AB - The recently proposed covariance region descriptor has been proven robust and versatile for a modest computational cost. The covariance matrix enables efficient fusion of different types of features, where the spatial and statistical properties, as well as their correlation, are characterized. The similarity between two covariance descriptors is measured on Riemannian manifolds. Based on the same metric but with a probabilistic framework, we propose a novel tracking approach on Riemannian manifolds with a novel incremental covariance tensor learning (ICTL). To address the appearance variations, ICTL incrementally learns a low-dimensional covariance tensor representation and efficiently adapts online to appearance changes of the target with only O(1) computational complexity, resulting in a real-time performance. The covariance-based representation and the ICTL are then combined with the particle filter framework to allow better handling of background clutter, as well as the temporary occlusions. We test the proposed probabilistic ICTL tracker on numerous benchmark sequences involving different types of challenges including occlusions and variations in illumination, scale, and pose. The proposed approach demonstrates excellent real-time performance, both qualitatively and quantitatively, in comparison with several previously proposed trackers. PMID- 22231178 TI - A direct approach toward global minimization for multiphase labeling and segmentation problems. AB - This paper intends to extend the minimization algorithm developed by Bae, Yuan and Tai [IJCV, 2011] in several directions. First, we propose a new primal-dual approach for global minimization of the continuous Potts model with applications to the piecewise constant Mumford-Shah model for multiphase image segmentation. Different from the existing methods, we work directly with the binary setting without using convex relaxation, which is thereby termed as a direct approach. Second, we provide the sufficient and necessary conditions to guarantee a global optimum. Moreover, we provide efficient algorithms based on a reduction in the intermediate unknowns from the augmented Lagrangian formulation. As a result, the underlying algorithms involve significantly fewer parameters and unknowns than the naive use of augmented Lagrangian-based methods; hence, they are fast and easy to implement. Furthermore, they can produce global optimums under mild conditions. PMID- 22231191 TI - Voting among virtually generated versions of a classification problem. AB - A classifier combining strategy, virtual voting by random projection (VVRP), is presented. VVRP takes advantage from the bounded distortion incurred by random projection in order to improve accuracies of stable classifiers like discriminant analysis (DA) where existing classifier combining strategies are known to be failed. It uses the distortion to virtually generate different training sets from the total available training samples in a way that does not have the potential for overfitting. Then, a majority voting combines the base learners trained on these versions of the original problem. VVRP is very simple and just needs determining a proper dimensionality for the versions, an often very easy task. It is shown to be stable in a very large region of the hyperplane constructed by the dimensionality and the number of the versions. VVRP improves the best state-of the-art DA algorithms in both small and large sample size problems in various classification fields. PMID- 22231192 TI - Stroke in 2011: Major advances across the spectrum of stroke care. PMID- 22231194 TI - Movement disorders: Genetic and epigenetic factors determine the clinical course in Friedreich ataxia. PMID- 22231193 TI - Multiple sclerosis in 2011: Advances in therapy, imaging and risk factors in MS. PMID- 22231195 TI - Dementia in 2011: Microbleeds in dementia--singing a different ARIA. PMID- 22231196 TI - Headache. Diagnosing subarachnoid hemorrhage: are CT scans enough? AB - Subarachnoid hemorrhage is a rare but potentially fatal cause of headache. According to results from a recent study, CT scans enable clinicians to identify patients with subarachnoid hemorrhage, with a high sensitivity. Does CT imaging rule out the need for lumbar puncture in patients who present with headache? PMID- 22231197 TI - Epilepsy in 2011: Insights into epilepsy treatments and biomarkers. PMID- 22231198 TI - Assessment of tremor activity in the Parkinson's disease using a set of wearable sensors. AB - Tremor is the most common motor disorder of Parkinson's disease (PD) and consequently its detection plays a crucial role in the management and treatment of PD patients. The current diagnosis procedure is based on subject-dependent clinical assessment, which has a difficulty in capturing subtle tremor features. In this paper, an automated method for both resting and action/postural tremor assessment is proposed using a set of accelerometers mounted on different patient's body segments. The estimation of tremor type (resting/action postural) and severity is based on features extracted from the acquired signals and hidden Markov models. The method is evaluated using data collected from 23 subjects (18 PD patients and 5 control subjects). The obtained results verified that the proposed method successfully: 1) quantifies tremor severity with 87 % accuracy, 2) discriminates resting from postural tremor, and 3) discriminates tremor from other Parkinsonian motor symptoms during daily activities. PMID- 22231199 TI - ASIL1 is required for proper timing of seed filling in Arabidopsis. AB - In flowering plants, seed development and seed filling are intricate genetically programmed processes that correlate with changes in metabolite levels and that are spatially and temporally regulated by a complex signaling network mediated mainly by sugars and hormones. ASIL1, a member of the plant-specific trihelix family of DNA-binding transcription factors, was isolated based on its interaction with the GT-element of the Arabidopsis thaliana 2S albumin At2S3 promoter. Mutation of ASIL1 derepressed expression of a subset of embryonic genes resulting in accumulation of 2S albumin and embryo-specific lipids in leaves. It was recently reported that mutation of ASIL1 led to early embryo development in Arabidopsis. In this study, we demonstrated that ASIL1 acts as a temporal regulator of seed filling. In developing siliques, mutation of ASIL1 led to earlier expression of master regulatory genes LEC2, FUS3 and ABI3 as well as genes for seed storage reserves. Moreover, the 12S globulin accumulated to a much higher level in the developing seeds of asil1-1 compared to wild type. To our knowledge, this is the first evidence that ASIL1 not only functions as a negative regulator of embryonic traits in seedlings but also contributes to the maintenance of precise temporal control of seed filling. Thus, ASIL1 represents a novel component of the regulatory framework controlling embryonic gene expression in Arabidopsis. PMID- 22231200 TI - Ascorbate peroxidase-related (APx-R) is not a duplicable gene. AB - Phylogenetic, genomic and functional analyses have allowed the identification of a new class of putative heme peroxidases, so called APx-R (APx-Related). These new class, mainly present in the green lineage (including green algae and land plants), can also be detected in other unicellular chloroplastic organisms. Except for recent polyploid organisms, only single-copy of APx-R gene was detected in each genome, suggesting that the majority of the APx-R extra-copies were lost after chromosomal or segmental duplications. In a similar way, most APx R co-expressed genes in Arabidopsis genome do not have conserved extra-copies after chromosomal duplications and are predicted to be localized in organelles, as are the APx-R. The member of this gene network can be considered as unique gene, well conserved through the evolution due to a strong negative selection pressure and a low evolution rate. PMID- 22231201 TI - Plants on the move: towards common mechanisms governing mechanically-induced plant movements. AB - One may think that plants seem relatively immobile. Nevertheless, plants not only produce movement but these movements can be quite rapid such as the closing traps of carnivorous plants, the folding up of leaflets in some Leguminosae species and the movement of floral organs in order to increase cross pollination. We focus this review on thigmotropic and thigmonastic movements, both in vegetative and reproductive parts of higher plants. Ultrastructural studies revealed that most thigmotropic and thigmonastic movements are caused by differentially changing cell turgor within a given tissue. Auxin has emerged as a key molecule that modulates proton extrusion and thus causing changes in cell turgor by enhancing the activity of H(+)ATPase in cell membranes. Finding conserved molecules and/or operational molecular modules among diverse types of movements would help us to find universal mechanisms controlling movements in plants and thus improve our understanding about the evolution of such phenomena. PMID- 22231203 TI - BCR-ABL1 kinase domain mutations: methodology and clinical evaluation. AB - The introduction of tyrosine kinase inhibitors (TKIs), starting with imatinib and followed by second and third generation TKIs, has significantly changed the clinical management of patients with chronic myeloid leukemia (CML). Despite their unprecedented clinical success, a proportion of patients fail to achieve complete cytogenetic remission by 12 months of treatment (primary resistance) while others experience progressive resistance after an initial response (secondary resistance). BCR-ABL1 kinase domain (KD) mutations have been detected in a proportion of patients at the time of treatment failure, and therefore their identification and monitoring plays an important role in therapeutic decisions particularly when switching TKIs. When monitoring KD mutations in a clinical laboratory, the choice of method should take into account turnaround time, cost, sensitivity, specificity, and ability to accurately quantify the size of the mutant clone. In this article, we describe in a "manual" style the methods most widely used in our laboratory to monitor KD mutations in patients with CML including direct sequencing, D-HPLC, and pyrosequencing. Advantages, disadvantages, interpretation of results, and their clinical applications are reviewed for each method. PMID- 22231204 TI - Electric field standing wave artefacts in FTIR micro-spectroscopy of biological materials. AB - FTIR absorption micro-spectroscopy is a widely used, powerful technique for analysing biological materials. In principle it is a straightforward linear absorption spectroscopy, but it can be affected by artefacts that complicate the interpretation of the data. In this article, artefacts produced by the electric field standing-wave (EFSW) in micro-reflection-absorption (transflection) spectroscopy are investigated. An EFSW is present at reflective metallic surfaces due to the interference of incident and reflected light. The period of this standing wave is dependent on the wavelength of the radiation and can produce non linear changes in absorbance with increasing sample thickness (non-Beer-Lambert like behaviour). A protein micro-structure was produced as a simple experimental model for a biological cell and used to evaluate the differences between FTIR spectra collected in transmission and transflection. By varying the thickness of the protein samples, the relationship between the absorbance and sample thickness in transflection was determined, and shown to be consistent with optical interference due to the EFSW coupled with internal reflection from the sample top surface. FTIR spectral image data from MCF 7 breast adenocarcinoma cells was then analysed to determine the severity of the EFSW artefact in data from a real sample. The results from these measurements confirmed that the EFSW artefact has a profound effect on transflection spectra, and in this case the main spectral variations were related to the sample thickness rather than any biochemical differences. PMID- 22231205 TI - An opposed matched field IMRT technique for prostate cancer patients with bilateral prosthetic hips. AB - Intensity-modulated radiation therapy (IMRT) has gained wide-spread use for treating patients with prostate cancer, yet developing a plan for patients with bi-lateral metal hip prostheses implants may be challenging. The high atomic number of the metallic hips not only gives rise to streak artifacts that obscure anatomy but also attenuates laterally directed fields by a significant amount that cannot be reliably ascertained from the CT dataset. A common approach to planning directs five IMRT fields such that incidence through the metal hips is avoided. While this technique generally gives adequate PTV coverage, it may escalate the rectal dose if beams, which would otherwise be incident from a lateral direction, are angled toward a posterior direction in order to avoid the prosthesis. In this work, we propose and investigate a new technique which alleviates this problem by introducing asymmetric opposed fields that are edge matched along a plane that is tangent to the metal prostheses. With this approach, a posterior oblique field is oriented closer to the lateral direction but does not irradiate the ipsilateral prosthesis. The portion of the target eclipsed by the prosthesis is irradiated by the opposed matched anterior oblique field which, again, avoids the corresponding ipsilateral prosthesis. While the proposed technique may improve rectal sparing and PTV coverage, the dose along the match plane is sensitive to intrafraction motion. In the worse case of intrafraction motion perpendicular to the plane occurring in the time interval between the deliveries of successive fields of the opposed matched pair, the induced error is typically about 5 cGy per mm of target motion for a 200 cGy fraction. To reduce the induced error, several approaches to broadening the penumbra at the match plane were investigated and compared to conventional IMRT plans for three patients. Phantom measurements were performed to evaluate the effectiveness of these approaches. Match-plane shifts of 4 mm in a single step, in two 2 mm steps, and in four 1 mm steps, were effective in reducing the worse case induced error to 2.8 cGy per mm. Imposing match-plane shifts precludes the use of intensity modulation for the opposed matched field pairs. Therefore, we favor an approach whereby the opposed matched fields overlap by 4 mm. Since both fields contribute fluence to the overlap region, the worse case induced error was observed to be typically within 2.9 cGy per mm. In conclusion, the use of this technique should be considered for patients with bilateral metal hip implants who do not meet dose-volume criteria by conventional IMRT techniques. PMID- 22231206 TI - Dose to craniofacial region through portal imaging of pediatric brain tumors. AB - The purpose of this study was to determine dose to the planning target volume (PTV) and organs at risk (OARs) from portal imaging (PI) of the craniofacial region in pediatric brain tumor patients treated with intensity-modulated radiation therapy (IMRT). Twenty pediatric brain tumor patients were retrospectively studied. Each received portal imaging of treatment fields and orthogonal setup fields in the craniofacial region. The number of PI and monitor units used for PI were documented for each patient. Dose distributions and dose volume histograms were generated to quantify the maximum, minimum, and mean dose to the PTV, and the mean dose to OARs through PI acquisition. The doses resulting from PI are reported as percentage of prescribed dose. The average maximum, minimum, and mean doses to PTV from PI were 2.9 +/- 0.7%, 2.2 +/- 1.0%, and 2.5 +/- 0.7%, respectively. The mean dose to the OARs from PI were brainstem 2.8 +/- 1.1%, optic nerves/chiasm 2.6 +/- 0.9%, cochlea 2.6 +/- 0.9%, hypothalamus/pituitary 2.4 +/- 0.6%, temporal lobes 2.3 +/- 0.6%, thyroid 1.6 +/- 0.8%, and eyes 2.6 +/- 0.9%. The mean number of portal images and the mean number of PI monitor units per patient were 58.8 and 173.3, respectively. The dose from PI while treating pediatric brain tumors using IMRT is significant (2%-3% of the prescribed dose). This may result in exceeding the tolerance limit of many critical structures and lead to unwanted late complications and secondary malignancies. Dose contributions from PI should be considered in the final documented dose. Attempts must be made in PI practices to lower the imaging dose when feasible. PMID- 22231207 TI - Image intensifier distortion correction for fluoroscopic RSA: the need for independent accuracy assessment. AB - Fluoroscopic images suffer from multiple modes of image distortion. Therefore, the purpose of this study was to compare the effects of correction using a range of two-dimensional polynomials and a global approach. The primary measure of interest was the average error in the distances between four beads of an accuracy phantom, as measured using RSA. Secondary measures of interest were the root mean squared errors of the fit of the chosen polynomial to the grid of beads used for correction, and the errors in the corrected distances between the points of the grid in a second position. Based upon the two-dimensional measures, a polynomial of order three in the axis of correction and two in the perpendicular axis was preferred. However, based upon the RSA reconstruction, a polynomial of order three in the axis of correction and one in the perpendicular axis was preferred. The use of a calibration frame for these three-dimensional applications most likely tempers the effects of distortion. This study suggests that distortion correction should be validated for each of its applications with an independent "gold standard" phantom. PMID- 22231208 TI - Establishing the quality management baseline in the use of computed tomography machines in Kenya. AB - The objective of this study was to assess the level of compliance to quality assurance and image quality standards in computed tomography facilities in Kenyan hospitals. A quality assurance inspection and physical image quality assessment in eighteen representative computed tomography facilities were completed. A quantitative method was developed and used to score the results obtained from the physical image quality measurements using the American Association of Physicists in Medicine (AAPM) water phantom. Inspection was done in order to establish the level of compliance with internationally recognized standards such as those stipulated in the European Guidelines Quality Criteria for Computed Tomography and the International Basic Safety Standards for Protection against Ionizing Radiation. The overall findings placed the national quality management performance at 50 +/- 3%, while image quality and quality assurance performance were 61 +/- 3% and 37 +/- 3%, respectively. The quality assurance assessment benchmarked the country's level of quality management system compliance in diagnostic radiology. During accreditation appraisal, the scrutiny of scores from each stage in the medical imaging chain per facility will encourage continual implementation of the quality improvement process. PMID- 22231209 TI - 4D CT image acquisition errors in SBRT of liver identified using correlation. AB - In the AAPM Report 80, the imaging modality of 4D CT and respiration-correlated CT was declared a "promising solution for obtaining high-quality CT data in the presence of respiratory motion". To gather anatomically correct data over time, the existence of correlation between the internal organ movement and an external surrogate has to be assumed. For the in-house evaluation of such correlation, we retrospectively analyzed 21 four-dimensional computer tomography (4D CT) scans of five patients, out of which the artifacts experienced in three patients are shown here. To provide context and a baseline for the analysis of patient motion, a real-tissue liver phantom was used with a solid water block and liver tissue. The superior-inferior motion of fiducials in phantom and patients was correlated to the recorded anterior-posterior motion of an external surrogate marker on the chest. The use of a solid water block yielded a measurable correlation coefficient of 0.98 or better using a sinusoidal animation pattern. With sinusoidally-animated liver tissue, the minimum correlation observed was 0.96. Comparing this to retrospective patient data, we found three cases of a change in the correlation coefficient, or simply a low correlation. The source of this low correlation was investigated by careful examination of the breathing traces and the CT-phase assignments used to reconstruct the datasets. Consequences of nonregular breathing are elaborated on. We demonstrate the impact of wrong phase assignments and missing image information in the 4D CT phase sampling processes. We also show how daily patient-based correlation analysis can indicate changes in breathing traces, which can be significant enough to decrease, or completely eliminate, previously existing correlation. PMID- 22231210 TI - A quality assurance tool for helical tomotherapy using a step-wedge phantom and the on-board MVCT detector. AB - The purpose of this study was to develop and evaluate filmless quality assurance (QA) tools for helical tomotherapy by using the signals from the on-board megavoltage computed tomography (MVCT) detector and applying a dedicated step wedge phantom. The step-wedge phantom is a 15 cm long step-like aluminum block positioned on the couch. The phantom was moved through the slit beam and MVCT detector signals were analyzed. Two QA procedures were developed, with gantry fixed at 0 degrees : 1) step-wedge procedure: to check beam energy consistency, field width, laser alignment with respect to the virtual isocenter, couch movement, and couch velocity; and 2) completion procedure: to check the accuracy of a field abutment made by the tomotherapy system after a treatment interruption. The procedures were designed as constancy tool and were validated by measurement of deliberately induced variations and comparison with a reference method. Two Hi-Art II machines were monitored over a period of three years using the step-wedge procedures. The data acquisition takes 5 minutes. The analysis is fully automated and results are available directly after acquisition. Couch speed deviations up to 2% were induced. The mean absolute difference between expected and measured couch speed was 0.2% +/- 0.2% (1 standard deviation SD). Field width was varied around the 10 mm nominal size, between 9.7 and 11.1 mm, in steps of 0.2 mm. Mean difference between the step-wedge analysis and the reference method was < 0.01 mm +/- 0.03 mm (1 SD). Laser (mis)alignment relative to a reference situation was detected with 0.3 mm precision (1SD). The step-wedge profile was fitted to a PDD in water. The PDD ratio D20/D10, measured at depths of 20 cm and 10 cm, was used to check beam energy consistency. Beam energy variations were induced. Mean difference between step-wedge and water PDD ratios was 0.2% +/- 0.3% (1SD). The completion procedure was able to reveal abutment mismatches with a mean error of -0.6 mm +/- 0.2 mm (1SD). The trending data over a period of three years showed a mean deviation of 0.4% +/- 0.1% (1 SD) in couch speed. The spread in field width was 0.15 mm (1 SD). The sagittal and transverse lasers showed a variation of 0.5 mm (1 SD). Beam energy varied 1.0% (1 SD). A mean abutment mismatch was found of -0.4 mm +/- 0.2 mm (1 SD) between interrupted treatments. The on-board MVCT detector, in combination with the step-wedge phantom, is a suitable tool for a QA program for helical tomotherapy. The method allowed frequent monitoring of machine behavior for the past three years. PMID- 22231211 TI - Image quality of an investigational imaging panel for use with the imaging beam line cone-beam CT. AB - The purpose of this study was to measure and compare the contrast-to-noise ratio (CNR) as a function of dose for the cone-beam CT (CBCT) produced by the imaging beam line (IBL) for the standard and an investigational imaging panel. Two Siemens Artiste linear accelerators were modified at our institution such that the MV-CBCT would operate under an investigational IBL. The imaging panel from one of the machines was replaced with an investigational imaging panel. After the modification, a set of CBCT for a large and small phantom consisting of eight tissue-equivalent inserts was acquired for the standard imager and for the investigational imager with and without the standard copper plate. Ten dose settings for each phantom using the IBL in combination with the standard and investigational imaging panel were acquired. The CNR for each tissue-equivalent insert was calculated. Resolution measurements in line pairs per mm (lp/mm) of the CBCT for the various imaging panel setups were made. In addition, CBCT images of two patients that were imaged with each panel configuration were displayed for a group of physicians and therapists who were asked to identify the best and worst CBCT for each patient. This was used as a qualitative judge of practical image quality. The CNR of the muscle insert for the large phantom with 1.5 cGy at isocenter was 1.3 for the standard imager, 1.5 for the investigational imager with the copper plate, and 1.9 without the plate. Under the same conditions, the CNR of the trabecular bone insert was 5.9, 7.3, and 9.7, respectively. For the small phantom with the same dose to isocenter, the CNR for muscle was 1.7, 2.1, and 3.3, respectively. For the trabecular bone, the CNR was 8.1, 9.6, and 12.1 respectively. The resolution for 1 cGy at isocenter was 0.37 lp/mm for the standard imager, 0.32 and 0.33 for the investigational imager with and without the copper plate. The qualitative test ranked the CBCT of the investigational imager without the copper plate to be the best image, and the standard imager to be the worst. The investigational imaging panel improves image quality as compared to the standard imager for IBL CBCTs. A 1 cGy IBL CBCT, no matter which imager is used, is sufficient for bony anatomy localization. The investigational imager without the copper plate was judged clinically to produce the best IBL CBCT. PMID- 22231212 TI - Dosimetric characteristics of the small diameter BrainLabTM cones used for stereotactic radiosurgery. AB - The purpose was to study the dosimetric characteristics of the small diameter (<= 10.0 mm) BrainLAB cones used for stereotactic radiosurgery (SRS) treatments in conjunction with a Varian Trilogy accelerator. Required accuracy and precision in dose delivery during SRS can be achieved only when the geometric and dosimetric characteristics of the small radiation fields is completely understood. Although a number of investigators have published the dosimetric characteristics of SRS cones, to our knowledge, there is no generally accepted value for the relative output factor (ROF) for the 5.0 mm diameter cone. Therefore, we have investigated the dosimetric properties of the small (<= 10.0 mm) diameter BrainLAB SRS cones used in conjunction with the iPlan TPS and a Trilogy linear accelerator with a SRS beam mode. Percentage depth dose (PDD), off-axis ratios (OAR), and ROF were measured using a SRS diode and verified with Monte Carlo (MC) simulations. The dependence of ROF on detector material response was studied. The dependence of PDD, OAR, and ROF on the alignment of the beam CAX with the detector motion line was also investigated using MC simulations. An agreement of 1% and 1 mm was observed between measurements and MC for PDD and OAR. The calculated ROF for the 5.0 mm diameter cone was 0.692 +/- 0.008--in good agreement with the measured value of 0.683 +/- 0.007 after the diode response was corrected. Simulations of the misalignment between the beam axis and detector motion axis for angles between 0.5 degrees -1.0 degrees have shown a deviation > 2% in PDD beyond a certain depth. We have also provided a full set of dosimetric data for BrainLAB SRS cones. Monte Carlo calculated ROF values for cones with diameters less than 10.0 mm agrees with measured values to within 1.8%. Care should be exercised when measuring PDD and OAR for small cones. We recommend the use of MC to confirm the measurement under these conditions. PMID- 22231213 TI - Effects of dose scaling on delivery quality assurance in tomotherapy. AB - Delivery quality assurance (DQA) of tomotherapy plans is routinely performed with silver halide film which has a limited range due to the effects of saturation. DQA plans with dose values exceeding this limit require the dose of the entire plan to be scaled downward if film is used, to evaluate the dose distribution in two dimensions. The potential loss of fidelity between scaled and unscaled DQA plans as a function of dose scaling is investigated. Three treatment plans for 12 Gy fractions designed for SBRT of the lung were used to create DQA procedures that were scaled between 100% and 10%. The dose was measured with an ionization chamber array and compared to values from the tomotherapy treatment planning system. Film and cylindrical ion chamber measurements were also made for one patient for scaling factors of 50% to 10% to compare with the ionization chamber array measurements. The array results show the average gamma pass rate is >= 99% from 100% to 30% scaling. The average gamma pass rate falls to 93.6% and 51.1% at 20% and 10% scaling, respectively. Film analysis yields similar pass rates. Cylindrical ion chambers did not exhibit significant variation with dose scaling, but only represent points in the low gradient region of the dose distribution. Scaling the dose changes the mechanics of the radiation delivery, as well as the signal-to-noise ratio. Treatment plans which exhibit parameters that differ significantly from those common to DQA plans studied in this paper may exhibit different behavior. Dose scaling should be limited to the smallest degree possible. Planar information, such as that from film or a detector array, is required. The results show that it is not necessary to perform both a scaled and unscaled DQA plan for the treatment plans considered here. PMID- 22231214 TI - A study of segment weight optimization with the CMS XiO step-and-shoot IMRT technique for prostate cancer. AB - The aim of this study was to compare IMRT optimization in the CMS XiO radiotherapy treatment planning system, with and without segment weight optimization. Twenty-one prostate cancer patients were selected for this study. All patients were initially planned with step-and-shoot IMRT (S-IMRT). A new plan was then created for each patient by applying the segment weight optimization tool (SWO-IMRT). Analysis was performed on the (SWO-IMRT) and (S-IMRT) plans by comparing the total number of segments, monitor units, rectal and bladder dose. The study showed a statistically significant reduction in the total number of segments (mean: 25.3%; range: 16.8%-31.1%) with SWO-IMRT as compared to S-IMRT (p < 0.0001). Similarly, a mean reduction of 3.8% (range: 0.4%-7.7%) in the total MU was observed with SWO-IMRT (p < 0.0001). The study showed an average rectal dose decrease of 13.7% (range: 7.9%-21.4%) with SWO-IMRT (p < 0.0001). We also observed a statistically significant reduction of 26.7% (range: 16.0%-41.4%; p < 0.0001) in the mean dose to the posterior one-third rectum and an overall reduction in mean bladder dose of 2.2% (range: 0.1%-6.1%) for SWO-IMRT (p < 0.0001). This study shows that the segment weight optimization method significantly reduces the total number of segments and the dose to the rectum for IMRT prostate cancer. It also resulted in fewer monitor units for most of the prostate cases observed in this study. PMID- 22231216 TI - Anatomy driven optimization strategy for total marrow irradiation with a volumetric modulated arc therapy technique. AB - The purpose of this study was to evaluate the possibility of dose distribution optimization for total marrow irradiation (TMI) employing volumetric-modulated arc therapy (VMAT) with RapidArc (RA) technology setting isocenter's positions and jaw's apertures according to patient's anatomical features. Plans for five patients were generated with the RA engine (PROIII): eight arcs were distributed along four isocenters and simultaneously optimized with collimator set to 90 degrees . Two models were investigated for geometrical settings of arcs: (1) in the "symmetric" model, isocenters were equispaced and field apertures were set the same for all arcs to uniformly cover the entire target length; (2) in the "anatomy driven" model, both field sizes and isocenter positions were optimized in order to minimize the target volume near the field edges (i.e., to maximize the freedom of motion of MLC leaves inside the field aperture (for example, avoiding arcs with ribs and iliac wings in the same BEV)). All body bones from the cranium to mid of the femurs were defined as PTV; the maximum length achieved in this study was 130 cm. Twelve (12) Gy in 2 Gy/fractions were prescribed in order to obtain the covering of 85% of the PTV by 100% of the prescribed dose. For all organs at risk (including brain, optical structures, oral and neck structures, lungs, heart, liver, kidneys, spleen, bowels, bladder, rectum, genitals), planning strategy aimed to maximize sparing according to ALARA principles, looking to reach a mean dose lower than 6 Gy (i.e., 50% of the prescribed dose). Mean MU/fraction resulted 3184 +/- 354 and 2939 +/- 264 for the two strategies, corresponding to a reduction of 7% (range -2% to 13%) for (1) and (2). Target homogeneity, defined as D(2%)-D(98%) was 18% better for (2). Mean dose to the healthy tissue, defined as body minus PTV, had 10% better reduction with (2). The isocenter's position and the jaw's apertures are significant parameters in the optimization of the TMI with RA technique, giving the medical physicist a crucial role in driving the optimization and thus obtaining the best plan. A clinical protocol started in our department in October 2010. PMID- 22231215 TI - Influence of acquisition parameters on MV-CBCT image quality. AB - The production of high quality pretreatment images plays an increasing role in image-guided radiotherapy (IGRT) and adaptive radiation therapy (ART). Megavoltage cone-beam computed tomography (MV-CBCT) is the simplest solution of all the commercially available volumetric imaging systems for localization. It also suffers the most from relatively poor contrast due to the energy range of the imaging photons. Several avenues can be investigated to improve MV-CBCT image quality while maintaining an acceptable patient exposure: beam generation, detector technology, reconstruction parameters, and acquisition parameters. This article presents a study of the effects of the acquisition scan length and number of projections of a Siemens Artiste MV-CBCT system on image quality within the range provided by the manufacturer. It also discusses other aspects not related to image quality one should consider when selecting an acquisition protocol. Noise and uniformity were measured on the image of a cylindrical water phantom. Spatial resolution was measured using the same phantom half filled with water to provide a sharp water/air interface to derive the modulation transfer function (MTF). Contrast-to-noise ratio (CNR) was measured on a pelvis-shaped phantom with four inserts of different electron densities relative to water (1.043, 1.117, 1.513, and 0.459). Uniformity was independent of acquisition protocol. Noise decreased from 1.96% to 1.64% when the total number of projections was increased from 100 to 600 for a total exposure of 13.5 MU. The CNR showed a +/- 5% dependence on the number of projections and 10% dependence on the scan length. However, these variations were not statistically significant. The spatial resolution was unaffected by the arc length or the sampling rate. Acquisition parameters have little to no effect on the image quality of the MV-CBCT system within the range of parameters available on the system. Considerations other than image quality, such as memory storage, acquisition speed, and individual projection image quality, speak in favor of the use of a coarse sampling rate on the short scan. PMID- 22231217 TI - Radiochromic film dosimetry of rectal inhomogeneity and applicator attenuation in high dose rate brachytherapy of uterine cervix. AB - Heterogeneities existing in the patient during treatment are neglected, as the treated subject is considered homogeneous in most of the commercially-available treatment planning systems (TPSs) used for high dose rate (HDR) brachytherapy. The choice of a suitable dosimeter for experimental dosimetry near the HDR source is crucial, mainly due to existence of steep dose gradients. The present work aimed to assess the effect of rectal air heterogeneity and applicator attenuation in the HDR Ir-192 brachytherapy treatment of carcinoma uterine cervix by utilizing GAFCHROMIC EBT2 film dosimetry. The dose to rectal walls under the condition of rectal air heterogeneity was measured experimentally using EBT2 film in a rectal phantom, and the measurements were validated by the Monte Carlo (MC) simulations. The applicator attenuation was measured by EBT2 film for a commonly used stainless steel uterine tube in a homogeneous water equivalent phantom. The measured doses were compared with the TPS calculated values. In case of the air cavity, the measured dose at the closest rectal surface was 12.8% less than the TPS calculated value due to lack of back scattering, whereas at the farthest rectal surface, it was higher by 24.5% due to no attenuation. The magnitude of attenuation due to the metal applicator was measured as high as 2% when compared with the TPS calculation. The dose reduction at the nearest rectal surface due to the effect of rectal air has indicated a clinically favorable dose distribution within the rectum, whereas the shielding effect posed by the metallic applicator was found to be less significant. Mutual agreement of the measured doses with the MC calculated dose values confirmed the suitability of EBT2 film for clinical dosimetry in HDR brachytherapy. PMID- 22231218 TI - Sensitivity of a helical diode array device to delivery errors in IMRT treatment and establishment of tolerance level for pretreatment QA. AB - The aim of this study is to determine the gantry angle and multileaf collimator (MLC) gap error-detection threshold of a diode helical array with an inserted micro-ionization chamber in order to use this device for the pretreatment quality assurance (QA) of intensity-modulated radiation therapy (IMRT) treatments. Implications on the dose-volume histograms (DVHs) of the patient treatments will also be considered for the establishment of a QA protocol with a reasonable tolerance level. Three dynamic IMRT HN (head and neck) and prostate treatments were studied. Random and systematic variations of gantry angle and systematic errors in MLC gap width of the clinical treatments were analyzed in order to establish the detection sensitivity of the array. The associated clinical significance was studied introducing the same errors in the treatment plan based on the patients' computed tomography (CT) and calculating the corresponding DVHs. The Gamma (3%/3 mm) presented a 4% variation in failure rate for a rotation error of 1 degrees for both types of treatment. Both systematic and random errors in gantry rotation angle have little effect on the patients' DVHs. MLC gap width errors of 1 mm and 2 mm in the prostate treatments imply a mean variation in isocenter-measured absorbed dose of 2.1% and 4.1%, respectively. In the case of HN, these errors entail a change in measured isocenter dose of 4.7% and 8.6%, respectively. The variation observed in the DVHs of the patients was, basically, a global displacement of the curves proportional to the isocenter dose variation caused by the gap width error. According to the array sensitivity to the analyzed errors and its implication in patient DVHs, a tolerance of 95% point passing rate for the gamma criterion 3%/2 mm and an agreement of 2% in isocenter absolute dose have been established as tolerance criteria for our pretreatment IMRT QA protocol. PMID- 22231219 TI - Skyshine photon doses from 6 and 10 MV medical linear accelerators. AB - The skyshine radiation phenomenon consists of the scattering of primary photon beams in the atmosphere above the roof of a medical linear accelerator facility, generating an additional dose at ground level in the vicinity of the treatment room. Thus, with respect to radioprotection, this situation plays an important role when the roof is designed with little shielding and there are buildings next to the radiotherapy treatment room. In literature, there are few reported skyshine-measured doses and these contain poor agreement with empirical calculations. In this work, we carried out measurements of skyshine photon dose rates produced from eight different 6 and 10 MV medical accelerators. Each measurement was performed outside the room facility, with the beam positioned in the upward direction, at a horizontal distance from the target and for a 40 cm * 40 cm maximum photon field size at the accelerator isocenter. Measured dose equivalent rates results were compared with calculations obtained by an empirical expression, and differences between them deviated in one or more order of magnitude. PMID- 22231220 TI - Calculating the peak skin dose resulting from fluoroscopically-guided interventions. Part II: case studies. AB - Part II of this review article presents four case studies for which peak skin doses are calculated following the methods outlined in Part I of this review. The data available in the cases ranges from proprietary dose reports to fluoroscopy time and number of digital acquisition frames only. Flowcharts are provided for each case. These flowcharts outline the calculation steps and data sources used to estimate the peak skin dose. The accuracy that can be achieved using these methods depends on several factors, including the calibration accuracy of dosimetric equipment, accuracy of information reported in the DICOM header and proprietary dose reports, accuracy of quantities measured by the medical physicist, and procedural factors such as rotation of the C-arm during a fluoroscopically-guided procedure. PMID- 22231221 TI - A "rolling average" multiple adaptive planning method to compensate for target volume changes in image-guided radiotherapy of prostate cancer. AB - For prostate cancer radiotherapy, the interfractional organ motion can have several forms: changes in position, shape, and volume. The interfractional motion can be managed through either online or offline image guidance (IG). The position changes are commonly corrected through online IG by correcting couch position at each treatment fraction, while the shape and volume changes, or target deformation, can be compensated by margins in offline adaptive planning. In this study, we proposed and evaluated a rolling-average (RA) adaptive replanning method to account for the target volume variations. A total of 448 repeated helical computed tomography (HCT) scans from 28 patients were included in the study. Both low-risk patients (LRP, CTV = prostate) and intermediate-risk patients (IRP, CTV = prostate + seminal vesicles) were simulated. The benefit of RA strategy was evaluated geometrically and compared with the standard online IG only method and a single replanning adaptive hybrid strategy. A new geometric index, cumulative index of target volume (CITV), was used for the evaluation. Two extreme scenarios of target volume changes, Type Ascending and Descending, were simulated by sorting the CTV volumes of actual patient data in order to have a better evaluation of the methods. Modest target volume variations were observed in our patient group. The prostate volume change was -0.14 +/- 0.11 cc/day (or 0.30% +/- 0.26% per day). It is found that RA is superior to the online IG and hybrid techniques. However, the magnitude of improvement depends on how significantly and rapidly the target volume changes. On the issue of planning complexity, the hybrid is more complex than online IG only, requiring one offline replanning, and RA is significantly more complex, with multiple replanning. In clinical implementation of RA, the effectiveness and efficiency should be balanced. The effectiveness is dependent on the patient population. For low-risk patients, RA is beneficial if there is significant time trend in target volume during the treatment course of radiotherapy. The optimal number of fractions necessary for the internal target volume (ITV) construction is 2 for LRP and 3 for IRP for RA strategy. PMID- 22231222 TI - Investigation of the feasibility of a simple method for verifying the motion of a binary multileaf collimator synchronized with the rotation of the gantry for helical tomotherapy. AB - In this paper, we suggest a new method for verifying the motion of a binary multileaf collimator (MLC) in helical tomotherapy. For this we used a combination of a cylindrical scintillator and a general-purpose camcorder. The camcorder records the light from the scintillator following photon irradiation, which we use to track the motion of the binary MLC. The purpose of this study is to demonstrate the feasibility of this method as a binary MLC quality assurance (QA) tool. First, the verification was performed using a simple binary MLC pattern with a constant leaf open time; secondly, verification using the binary MLC pattern used in a clinical setting was also performed. Sinograms of simple binary MLC patterns, in which leaves that were open were detected as "open" from the measured light, define the sensitivity which, in this case, was 1.000. On the other hand, the specificity, which gives the fraction of closed leaves detected as "closed", was 0.919. The leaf open error identified by our method was -1.3 +/- 7.5%. The 68.6% of observed leaves were performed within +/- 3% relative error. The leaf open error was expressed by the relative errors calculated on the sinogram. In the clinical binary MLC pattern, the sensitivity and specificity were 0.994 and 0.997, respectively. The measurement could be performed with -3.4 +/- 8.0% leaf open error. The 77.5% of observed leaves were performed within +/- 3% relative error. With this method, we can easily verify the motion of the binary MLC, and the measurement unit developed was found to be an effective QA tool. PMID- 22231223 TI - Medical physics staffing for radiation oncology: a decade of experience in Ontario, Canada. AB - The January 2010 articles in The New York Times generated intense focus on patient safety in radiation treatment, with physics staffing identified frequently as a critical factor for consistent quality assurance. The purpose of this work is to review our experience with medical physics staffing, and to propose a transparent and flexible staffing algorithm for general use. Guided by documented times required per routine procedure, we have developed a robust algorithm to estimate physics staffing needs according to center-specific workload for medical physicists and associated support staff, in a manner we believe is adaptable to an evolving radiotherapy practice. We calculate requirements for each staffing type based on caseload, equipment inventory, quality assurance, educational programs, and administration. Average per-case staffing ratios were also determined for larger-scale human resource planning and used to model staffing needs for Ontario, Canada over the next 10 years. The workload specific algorithm was tested through a survey of Canadian cancer centers. For center-specific human resource planning, we propose a grid of coefficients addressing specific workload factors for each staff group. For larger scale forecasting of human resource requirements, values of 260, 700, 300, 600, 1200, and 2000 treated cases per full-time equivalent (FTE) were determined for medical physicists, physics assistants, dosimetrists, electronics technologists, mechanical technologists, and information technology specialists, respectively. PMID- 22231225 TI - Radiological emergencies and the medical physicist. PMID- 22231226 TI - Distance-dependent atomic knowledge-based force in protein fold recognition. AB - We have recently introduced a novel model for discriminating the correctly folded proteins from well-designed decoy structures using mechanical interatomic forces. In the model, we considered a protein as a collection of springs and the force imposed to each atom was calculated by using the relation between the potential energy and the force. A mean force potential function is obtained from statistical contact preferences within the known protein structures. In this article, the interatomic forces are calculated by numerical derivation of the potential function. For assessing the knowledge-based force function we consider an optimal structure and define a score function on the 3D structure of a protein. We compare the force imposed to each atom of a protein with the corresponding atom in the optimum structure. Afterwards we assign larger scores to those atoms with the lower forces. The total score is the sum of partial scores of atoms. The optimal structure is assumed to be the one with the highest score in the dataset. Finally, several decoy sets are applied in order to evaluate the performance of our model. PMID- 22231227 TI - Simple copper/TEMPO catalyzed aerobic dehydrogenation of benzylic amines and anilines. AB - CuBr(2) with 2,2,6,6-tetramethylpiperidyl-1-oxy (TEMPO) has been successfully employed for the aerobic oxidation of primary and secondary benzyl amines in aqueous acetonitrile. Such catalytic systems have previously been used extensively in alcohol oxidation reactions. The same catalyst system was also used for oxidative cross-couplings of benzylamines with anilines. The electronic and steric properties of the aniline partner were found to be of crucial importance in determining reactivity or lack thereof. A mechanism for these reactions is proposed based on the data obtained to date. In the absence of benzyl amines, electron-rich anilines were found to undergo dehydrogenative coupling and yields of the resulting azo products could be increased by replacing CuBr(2) with CuBr. No ligand (e.g. pyridine) is required for either reaction to proceed and presumably water and acetonitrile solvate the copper-containing intermediates. PMID- 22231228 TI - Superior molecularly altered influenza virus hemagglutinin peptide 308-317 inhibits collagen-induced arthritis by inducing CD4+ Treg cell expansion. AB - OBJECTIVE: To investigate the inhibitory effect and possible mechanism of a novel influenza virus hemagglutinin 308-317 peptide (altered HA308-317 peptide) in collagen-induced arthritis (CIA). METHODS: CIA was induced in DBA/1 mice by immunization with type II collagen (CII). Altered HA308-317 peptide, wild HA308 317 peptide, wild CII263-272 peptide, and irrelevant peptide were administered intranasally beginning at arthritis onset. Clinical and histologic scores were assessed, and cytokine levels were determined in the serum or in supernatants from splenocytes. Characteristics of T cell subsets in response to different peptides were analyzed both in vivo and in vitro. RESULTS: Intranasal administration of wild CII263-272 peptide, wild HA308-317 peptide, or altered HA308-317 peptide could significantly ameliorate CIA, but altered HA308-317 peptide showed greater therapeutic effects than wild CII263-272 peptide and wild HA308-317 peptide. The effect of altered HA308-317 peptide was associated with a substantial decrease in production of interleukin-17 (IL-17) and interferon-gamma (IFNgamma) and with a marked increase in production of IL-10 and transforming growth factor beta, both in serum and in supernatants from splenocytes treated with altered HA308-317 peptide. Both the number and function of CD4+ Treg cells were significantly up-regulated by altered HA308-317 peptide, with a decreased induction of Th1 cells (CD4+IFNgamma+) and Th17 cells (CD4+IL-17+). Adoptive transfer of CD4+CD25+ T cells from altered HA308-317 peptide-treated mice resulted in greater suppressive capacity in ameliorating CIA severity than did adoptive transfer of CD4+CD25+ T cells from wild HA308-317 peptide-treated, wild CII263-272 peptide-treated, or irrelevant peptide-treated mice. CONCLUSION: Intranasal administration of altered HA308-317 peptide potently suppressed the severity of CIA by increasing the number and function of CD4+ Treg cells, suggesting that altered HA308-317 peptide might be a promising candidate for treatment of rheumatoid arthritis. PMID- 22231229 TI - Effects of high hydrostatic pressure on color of spinach puree and related properties. AB - BACKGROUND: Changes in instrumental color parameters, chlorophyll a and b, activity of chlorophyllase, Mg-dechelatase, peroxidase and polyphenol oxidase, total phenolic compounds and pH of spinach puree were assessed after high hydrostatic pressure (HHP) (200, 400 and 600 MPa for 5, 15 and 25 min) treatments at room temperature. RESULTS: HHP treatments induced a better retention of visual green color (-a* and L* values) and chlorophyll contents of spinach puree. As for chlorophyll degradation-related enzymes, the results indicated that chlorophyllase activity decreased at all pressures; however, Mg-dechelatase activity was dramatically activated after HHP treatment at 400 and 600 MPa. Peroxidase exhibited higher resistance to HHP; however, polyphenol oxidase, which is responsible for enzymatic browning, was suppressed progressively with increase in pressure level from 200 to 600 MPa. In addition, the pH value of HHP-treated spinach puree was increased to be close to neutral pH, which could effectively inhibit chlorophyll degradation. No significant differences (P > 0.05) were found after extending the treatment times at the same level of pressure. CONCLUSION: HHP treatments effectively prevent chlorophyll degradation and enzymatic browning in spinach puree and retain a better original fresh green color of spinach compared with conventional thermal treatment. PMID- 22231230 TI - Vasculitis in 2011: the renaissance of granulomatous inflammation in AAV. AB - In 2011, the year that subtypes of ANCA-associated vasculitis (AAV) were officially renamed according to key pathological characteristics, important progress was made not only in differentiating these subtypes, but also in understanding-and treating-their eponymous manifestations. PMID- 22231232 TI - RA in 2011: Advances in diagnosis, treatment and definition of remission. AB - Evidence presented in 2011 suggests that rheumatoid arthritis might comprise two separate diseases-each with different etiological underpinnings-and that kinase inhibitors could soon be added to the therapeutic armamentarium. Together with new definitions of remission, these advances could aid the development of personalized, treat-to-target strategies. PMID- 22231231 TI - Mechanisms of joint damage in gout: evidence from cellular and imaging studies. AB - The clinical course of gout is initially characterized by acute self-limited joint inflammation, but long-standing disease is often associated with chronic inflammation followed by the development of erosive joint damage, which can result in long-term functional impairment. Preventing joint damage is now a major focus of therapeutic intervention in gout. New light has been shed on the mechanisms leading to cartilage and bone damage in patients with this disease. Here, we discuss basic science studies focusing on the cellular immunology of bone and cartilage in gout and the effects of monosodium urate crystals on signaling pathways, cytokine release and the function of osteoclasts, osteoblasts and chondrocytes. We then explore the use of advanced imaging modalities (including MRI, ultrasonography, CT and dual-energy CT) to investigate pathology in gout, as they provide new ways to visualize joint tissues. These modalities vary in their ability to detect the various pathological features of gout and have different clinical applications. Imaging provides information about the inflammatory nature of the joint lesion, position and size of tophaceous deposits, and extent of bone and cartilage damage. Imaging is also increasingly being used to monitor the progression of joint damage and regression of tophi with effective urate-lowering therapy. PMID- 22231233 TI - SLE in 2011: Deciphering the role of NETs and networks in SLE. AB - From neutrophil extracellular traps to genetic networks that underlie the disease and new targeted therapies, important advances in 2011 improve our understanding of the pathogenesis of systemic lupus erythematosus and mark the beginning of our ability to treat it effectively. PMID- 22231234 TI - Vasculitis syndromes: Insights into the role of IL-21 in GCA. PMID- 22231235 TI - SSc in 2011: From mechanisms to medicines. AB - Findings from ongoing studies of imatinib in systemic sclerosis (SSc) were eagerly awaited in 2011, but results from these clinical trials have so far been disappointing. However, progress in the understanding of the mechanisms that underlie SSc pathogenesis could provide clues to novel targets for 2012 and beyond. PMID- 22231236 TI - JIA in 2011: New takes on categorization and treatment. AB - In 2011, new treatment recommendations for juvenile idiopathic arthritis (JIA) were proposed, inroads were made towards understanding the heterogeneity of this disease, and data were presented demonstrating the potential efficacy of DMARD combination therapies for JIA treatment. These advances hold promise for improved management of JIA in 2012 and beyond. PMID- 22231238 TI - OA in 2011: Age-related OA--a concept emerging from infancy? AB - That primary osteoarthritis (OA) is an age-related disorder is undoubted, but how aging contributes to OA is poorly understood. New insights from 2011 offer potential explanations, novel models for study, and the suggestion that a deeper understanding of what 'aging' actually is might pave the way to everlasting joints. PMID- 22231237 TI - Etiology of osteoarthritis: genetics and synovial joint development. AB - Osteoarthritis (OA) has a considerable hereditary component and is considered to be a polygenic disease. Data derived from genetic analyses and genome-wide screening of individuals with this disease have revealed a surprising trend: genes associated with OA tend to be related to the process of synovial joint development. Mutations in these genes might directly cause OA. In addition, they could also determine the age at which OA becomes apparent, the joint sites involved, the severity of the disease and how rapidly it progresses. In this Review, I propose that genetic mutations associated with OA can be placed on a continuum. Early-onset OA is caused by mutations in matrix molecules often associated with chondrodysplasias, whereas less destructive structural abnormalities or mutations confer increased susceptibility to injury or malalignment that can result in middle-age onset. Finally, mutations in molecules that regulate subtle aspects of joint development and structure lead to late onset OA. In this Review, I discuss the genetics of OA in general, but focus on the potential effect of genetic mutations associated with OA on joint structure, the role of joint structure in the development of OA--using hip abnormalities as a model--and how understanding the etiology of the disease could influence treatment. PMID- 22231239 TI - Quantification of HIV-1 viral RNA in the blood in needles used for venous puncture in HIV-infected individuals. AB - INTRODUCTION: Occupational HIV infection among healthcare workers is an important issue in exposures involving blood and body fluids. There are few data in the literature regarding the potential and the duration of infectivity of HIV type 1 (HIV-1) in contaminated material under adverse conditions. METHODS: We quantified HIV-1 viral RNA in 25*8mm calibre hollow-bore needles, after punctures, in 25 HIV 1-infected patients selected during the sample collection. All of the patients selected were between the ages of 18 and 55. Five samples were collected from 16 patients: one sample for the immediate quantification of HIV-1 RNA in the plasma and blood samples from the interior of 4 needles to be analyzed at 0 h, 6 h, 24 h, and 72 h after collection. In nine patients, another test was carried out in the blood from one additional needle, in which HIV-1 RNA was assessed 168 h after blood collection. The method used to assess HIV-1 RNA was nucleic acid sequence based amplification. RESULTS: Up to 7 days after collection, HIV-1 RNA was detected in all of the needles. The viral RNA remained stable up to 168 h, and there were no statistically significant differences among the needle samples. CONCLUSIONS: Although the infectivity of the viral material in the needles is unknown, the data indicate the need to re-evaluate the practices in cases of occupational accidents in which the source is not identified. PMID- 22231240 TI - Epidemiological aspects of dengue in Aracaju, State of Sergipe, Brazil. AB - INTRODUCTION: The dengue fever remains to be a disease of serious public health concern, and its incidence has increased in the past decades. This study aimed to characterize the epidemiological incidence of dengue in the period 2001-2010. METHODS: This is an epidemiological study of dengue in the municipality of Aracaju, state of Sergipe, in the period between 2001 and 2010, whose data were obtained from the Information System of Diseases Notifications. A descriptive analysis of the number of confirmed cases of dengue, according to year, semester, sanitary district, age, and sex, was performed. RESULTS: There were 16,462 confirmed cases, especially in 2008, which obtained the highest incidence of the disease, with 10,485 confirmed cases. The first semester obtained the highest registration of cases during the years of research; this was predominated by females between 15 and 49 years old. With regard to the territorial distribution, the second district of the municipality obtained the highest number of cases. CONCLUSIONS: In 2008, in the City of Aracaju, SE, a significant increase in the proportion of dengue cases compared with other years was verified. However, a fast decline in the other years was observed, possibly because of the intensification of preventive actions to combat the mosquito that transmits the dengue virus. PMID- 22231241 TI - Molecular characterization of rabies virus isolated from non-haematophagous bats in Brazil. AB - INTRODUCTION: Rabies is an important zoonosis that causes thousands of deaths worldwide each year. Although the terrestrial cycle, mainly transmitted by dogs, is controlled in Brazil, the aerial cycle remains a serious public health issue, besides the economic problem. In the aerial cycle, the haematophagous bat Desmodus rotundus is the main source of infection, where several different species of non-haematophagous bats can be infected and can transmit the virus. METHODS: The aim of this work was to study the epidemiological pattern of rabies using antigenic characterization with monoclonal antibodies and genetic characterization by reverse-transcriptase polymerase chain reaction followed by sequencing and phylogenetic analysis of non-haematophagous bats' and herbivorous animals' central nervous system samples from the western region of the State of Sao Paulo, Brazil. RESULTS: From 27 samples, 3 antigenic variants were identified: AgV-3, AgV-4, and AgV-6; and from 29 samples, 5 different clusters were identified, all belonging to the rabies virus species. CONCLUSIONS: Although only non-haematophagous bats were evaluated in the studied region, the majority of samples were from antigenic and genetic variants related to haematophagous bats Desmodus rotundus. Samples from the same antigenic variant were segregated in more than one genetic cluster. This study demonstrated the diversity of rabies virus genetic lineages presented and circulating in non-haematophagous bats in the studied region. PMID- 22231242 TI - Prevalence of Trypanosoma cruzi antibodies and inflammatory markers in uncompensated heart failure. AB - INTRODUCTION: Heart failure (HF) represents the final stage of chronic chagasic cardiomyopathy (CChC). The diagnosis of CChC is based on the demonstration of anti-Trypanosoma cruzi antibodies (aTcAg) and clinical and epidemiological data. In Venezuela, there are no data about the prevalence of chagasic HF. The aim of this study was to determine the epidemiological, clinical, and inflammatory risk factors associated with seronegative or seropositive HF patients. METHODS: We performed a cross-sectional study in the Venezuelan central-west states among a healthy rural population and in patients admitted to the emergency room with uncompensated HF. RESULTS: The seroprevalence rates of Trypanosoma cruzi antibodies were 11.2% and 40.1% in the healthy population and in HF patients, respectively. Seropositivity in healthy individuals was associated with age, knowledge on triatomine vectors, and having seen wild reservoirs in the house; in HF patients, with contact with the vector and previous clinical diagnosis of Chagas' disease; and in both groups taken together, with age, knowledge on triatomines, and HF. Seropositive patients had prolonged QRS, decreased ejection fraction, and high serum magnesium, all significant as compared with HF seronegative cases. Left atrium enlargement and ventricular hypertrophy were most frequently observed in HF seronegative patients. CRP, IL6, ILbeta1, IL2, and FNTalpha were elevated in 94.5%, 48%, 17.8%, 13.7%, and 6.9% of HF patients, respectively, but only IL2 levels were associated with chagasic HF. CONCLUSIONS: There is a high prevalence of aTcAg in HF patients from the central-west region of Venezuela, and their epidemiological, clinical, and inflammatory features are discreetly different as compared with those of seronegative cases. PMID- 22231243 TI - Serological survey for Chagas disease in the rural areas of Manaus, Coari, and Tefe in the Western Brazilian Amazon. AB - INTRODUCTION: Deforestation, uncontrolled forest, human population migration from endemic areas, and the large number of reservoirs and wild vectors naturally infected by Trypanosoma cruzi promote the endemicity of Chagas disease in the Amazon region. METHODS: We conducted an initial serological survey (ELISA) in a sample of 1,263 persons; 1,095 (86.7%) were natives of the State of Amazonas, 666 (52.7%) were male, and 948 (75.1%) were over 20 years old. Serum samples that were found to be reactive, indeterminate, or inconclusive by indirect immunofluorescence (IFI) or positive with low titer by IFA were tested by Western blot (WB). Serologically confirmed patients (WB) were evaluated in terms of epidemiological, clinical, ECG, and echocardiography characteristics. RESULTS: Fifteen patients had serologically confirmed T. cruzi infection, and 12 of them were autochthonous to the state of Amazonas, for an overall seroprevalence of 1.2% and 0.9% for the state of Amazonas. Five of the 15 cases were males, and the average age was 47 years old; most were farmers with low education. One patient who was not autochthonous, having originated from Alagoas, showed right bundle branch block, bundle branch block, and anterosuperior left ventricular systolic dysfunction with an ejection fraction of 54%. CONCLUSIONS: The results of this study ratify the importance of monitoring CD cases in Amazonia, particularly in the state of Amazonas. PMID- 22231244 TI - Study on Chagas disease occurrence in the municipality of Monte Negro, State of Rondonia, Brazilian Amazon. AB - INTRODUCTION: Studies on Chagas disease deal with the perspective of its occurrence in the Amazon region, which is directly correlated to the population growth and the spread of the bug biotope. The state of Rondonia has an immense source of vectors (Triatomine) and reservoirs of Trypanosoma cruzi. Environmental changes brought forth by the deforestation in the region may cause vector behavior changes and bring these vectors to a closer contact with humans, increasing the probability of vector infection. METHODS: This study was carried out to check the occurrence of Chagas disease in the municipality of Monte Negro, Rondonia, Brazil, based on a random sampling of the farms and people wherein blood collection from the population and capturing triatomines were done. The blood samples were submitted to serologic tests to detect antibodies of the IgG class against T. cruzi. The triatomines that were collected had their digestive tract checked for the presence of trypanosomatidae with morphology resembling that of the T. cruzi. RESULTS: The population examined was mostly from other states. From the 322 bugs examined on the microscope, 50% showed parasites with morphology compatible with T. cruzi. From the serology of 344 random samples of human blood, 1.2% was found positive, 6% showed inconclusive results, and 92.8% were negative. CONCLUSIONS: Monte Negro shows low prevalence of human infection by T. cruzi and none active vector transmission; however, preventive and surveying measures, which are not performed until now, shall be taken due to the abundance of vectors infected by trypanosomatidae. PMID- 22231245 TI - Relationship between rainfall and temperature: observations on the cases of visceral leishmaniasis in Sao Luis Island, State of Maranhao, Brazil. AB - INTRODUCTION: Visceral leishmaniasis is a serious public health problem that requires global control strategies, especially with respect to factors that may intervene in reducing the incidence of endemicity. In this work, rainfall density and temperature were correlated with the incidence of human cases in an area endemic for leishmaniasis in Sao Luis do Maranhao, Northeastern Brazil. METHODS: Notification of human cases by the National Health Foundation/Regional Coordination of Maranhao (FUNASA/COREMA) from 2002 to 2010 was used. Ecological data (mean temperature and rainfall density) were provided by the Meteorological Office of State. RESULTS: A significant association was verified between the number of VL cases and rainfall rate but not in the analysis concerning mean temperatures. CONCLUSIONS: These data suggest that the control actions in visceral leishmaniasis should be performed during rainy season in the State of Maranhao, which is in the first half of the year. PMID- 22231246 TI - Molecular characterization of clinical multiresistant isolates of Acinetobacter sp. from hospitals in Porto Alegre, State of Rio Grande do Sul, Brazil. AB - INTRODUCTION: Hospitals around the world have presented multiresistant Acinetobacter sp. outbreaks. The spread of these isolates that harbor an increasing variety of resistance genes makes the treatment of these infections and their control within the hospital environment more difficult. This study aimed to evaluate the occurrence and dissemination of Acinetobacter sp. multiresistant isolates and to identify acquired resistance genes. METHODS: We analyzed 274 clinical isolates of Acinetobacter sp. from five hospitals in Porto Alegre, RS, Brazil. We evaluated the susceptibility to antimicrobial, acquired resistance genes from Ambler's classes B and D, and performed molecular typing of the isolates using enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) technique. RESULTS: A high (68%) percentage of multiresistant isolates of Acinetobacter sp. was observed, and 69% were resistant to carbapenems. We identified 84% of isolates belonging to species A. baumannii because they presented the gene blaOXA-51. The gene blaOXA-23 was detected in 62% of the isolates, and among these, 98% were resistant to carbapenems. Using the ERIC-PCR technique, we identified clones of Acinetobacter sp. spread among the four hospitals analyzed during the sampling period. CONCLUSIONS: The data indicate the dissemination of Acinetobacter sp. isolates among hospitals and their permanence in the hospital after one year. PMID- 22231247 TI - Reduction of catheter-associated bloodstream infections through procedures in newborn babies admitted in a university hospital intensive care unit in Brazil. AB - INTRODUCTION: Catheter-associated bloodstream infection (CA-BSI) is the most common nosocomial infection in neonatal intensive care units. There is evidence that care bundles to reduce CA-BSI are effective in the adult literature. The aim of this study was to reduce CA-BSI in a Brazilian neonatal intensive care unit by means of a care bundle including few strategies or procedures of prevention and control of these infections. METHODS: An intervention designed to reduce CA-BSI with five evidence-based procedures was conducted. RESULTS: A total of sixty seven (26.7%) CA-BSIs were observed. There were 46 (32%) episodes of culture proven sepsis in group preintervention (24.1 per 1,000 catheter days [CVC days]). Neonates in the group after implementation of the intervention had 21 (19.6%) episodes of CA-BSI (14.9 per 1,000 CVC days). The incidence of CA-BSI decreased significantly after the intervention from the group preintervention and postintervention (32% to 19.6%, 24.1 per 1,000 CVC days to 14.9 per 1,000 CVC days, p=0.04). In the multiple logistic regression analysis, the use of more than 3 antibiotics and length of stay >8 days were independent risk factors for BSI. CONCLUSIONS: A stepwise introduction of evidence-based intervention and intensive and continuous education of all healthcare workers are effective in reducing CA BSI. PMID- 22231248 TI - Validation of a case definition for leptospirosis diagnosis in patients with acute severe febrile disease admitted in reference hospitals at the State of Pernambuco, Brazil. AB - INTRODUCTION: Leptospirosis is often mistaken for other acute febrile illnesses because of its nonspecific presentation. Bacteriologic, serologic, and molecular methods have several limitations for early diagnosis: technical complexity, low availability, low sensitivity in early disease, or high cost. This study aimed to validate a case definition, based on simple clinical and laboratory tests, that is intended for bedside diagnosis of leptospirosis among hospitalized patients. METHODS: Adult patients, admitted to two reference hospitals in Recife, Brazil, with a febrile illness of less than 21 days and with a clinical suspicion of leptospirosis, were included to test a case definition comprising ten clinical and laboratory criteria. Leptospirosis was confirmed or excluded by a composite reference standard (microscopic agglutination test, ELISA, and blood culture). Test properties were determined for each cutoff number of the criteria from the case definition. RESULTS: Ninety seven patients were included; 75 had confirmed leptospirosis and 22 did not. Mean number of criteria from the case definition that were fulfilled was 7.8+/-1.2 for confirmed leptospirosis and 5.9+/-1.5 for non-leptospirosis patients (p<0.0001). Best sensitivity (85.3%) and specificity (68.2%) combination was found with a cutoff of 7 or more criteria, reaching positive and negative predictive values of 90.1% and 57.7%, respectively; accuracy was 81.4%. CONCLUSIONS: The case definition, for a cutoff of at least 7 criteria, reached average sensitivity and specificity, but with a high positive predictive value. Its simplicity and low cost make it useful for rapid bedside leptospirosis diagnosis in Brazilian hospitalized patients with acute severe febrile disease. PMID- 22231249 TI - Use of Poisson spatiotemporal regression models for the Brazilian Amazon Forest: malaria count data. AB - INTRODUCTION: Malaria is a serious problem in the Brazilian Amazon region, and the detection of possible risk factors could be of great interest for public health authorities. The objective of this article was to investigate the association between environmental variables and the yearly registers of malaria in the Amazon region using bayesian spatiotemporal methods. METHODS: We used Poisson spatiotemporal regression models to analyze the Brazilian Amazon forest malaria count for the period from 1999 to 2008. In this study, we included some covariates that could be important in the yearly prediction of malaria, such as deforestation rate. We obtained the inferences using a bayesian approach and Markov Chain Monte Carlo (MCMC) methods to simulate samples for the joint posterior distribution of interest. The discrimination of different models was also discussed. RESULTS: The model proposed here suggests that deforestation rate, the number of inhabitants per km2, and the human development index (HDI) are important in the prediction of malaria cases. CONCLUSIONS: It is possible to conclude that human development, population growth, deforestation, and their associated ecological alterations are conducive to increasing malaria risk. We conclude that the use of Poisson regression models that capture the spatial and temporal effects under the bayesian paradigm is a good strategy for modeling malaria counts. PMID- 22231250 TI - Africanized honeybee stings: how to treat them. AB - INTRODUCTION: In 1956, Africanized honeybees (AHB) migrated from Brazil to other regions of the Western Hemisphere, including South, Central, and North America, except for Canada. Despite being productive, they are highly aggressive and cause fatal accidents. This study aimed to evaluate patients at the Clinical Hospital of Botucatu Medical School (HC-FMB) and to propose treatment guidelines. METHODS: From 2005 to 2006, the clinical and laboratorial aspects of 11 patients (7 male and 4 female) and the anatomopathological aspects of one patient who had died in 2003 were analyzed. RESULTS: The age of the surviving patients varied from 5 to 87 years, with a mean of 42.5 years. The majority of accidents occurred in the afternoon, and the number of stings ranged from 20 to 500. The principal signs and symptoms were pain and local inflammatory signs, nausea, tachycardia, and vomiting. Biochemical findings presented increased levels of creatine phosphokinase, lactate dehydrogenase, and aspartate/alanine aminotransferase. An 11-year-old male patient died upon entering the attic of a two-story building where he was attacked by a swarm, receiving more than 1,000 stings. He was sent to HC-FMB where he was treated, but he died 24h later. Observed at the autopsy were erythematous-purpuric skin lesions besides necrosis at the sting locations, rhabdomyolysis, focal myocardial necrosis, tubular hydropic degeneration and focal tubular acute necrosis of the kidneys, myoglobinuria, and centrolobular necrosis in the liver. CONCLUSIONS: Accidents caused by multiple AHB stings always constitute a medical emergency. As there is no specific antivenom, we have developed guidelines, including first aid, drugs, and the proper removal of stingers. PMID- 22231251 TI - Co-infection Trypanosoma cruzi/HIV: systematic review (1980-2010). AB - INTRODUCTION: The co-infection Trypanosoma cruzi/HIV has been described as a clinical event of great relevance. The objective of this study was to describe clinical and epidemiological aspects published in literature. METHODS: It is a systematic review of a descriptive nature from the databases Medline, Lilacs, SciELO, Scopus, from 1980 to 2010. RESULTS: There were 83 articles (2.8 articles/year) with a total of 291 cases. The co-infection was described in 1980 and this situation has become the defining AIDS clinical event in Brazil. This is the country with the highest number of publication (51.8%) followed by Argentina (27.7%). The majority of cases are amongst adult men (65.3%) native or from endemic regions with serological diagnosis in the chronic stage (97.9%) and indeterminate form (50.8%). Both diseases follow the normal course, but in 41% the reactivation of the Chagas disease occurs. The most severe form is the meningoencephalitis, with 100% of mortality without specific and early treatment of the T. cruzi. The medication of choice was the benznidazole on doses and duration normally used for the acute phase. The high parasitemia detected by direct or indirect quantitative methods indicated reactivation and its elevation is the most important predictive factor. The lower survival rate was related to the reactivation of the Chagas disease and the natural complications of both diseases. The role of the antiretroviral treatment on the co-infection cannot yet be defined by the knowledge currently existent. CONCLUSIONS: Despite the relevance of this clinical event there are still gaps to be filled. PMID- 22231252 TI - Characterization of Leishmania infantum species in dogs from the urban area of Cuiaba, State of Mato Grosso, Brazil. AB - INTRODUCTION: Visceral leishmaniasis presents urban behavior in some Brazilian cities, with domestic dogs as the main infection source. In Cuiaba, MT, canine visceral leishmaniasis was diagnosed and characterized as recommended by the Ministry of Health. METHODS: Biological samples from suspected canine carriers were analyzed by the isoenzyme electrophoresis technique. The 6PGDH enzyme and reference strain IOC/L0566 (MHOM/BR/1975/M2903) of Leishmania (Leishmania) infantum was used as one of the controls. RESULTS: Electrophoresis analysis revealed that the canine isolates belonged to the species L. (L.) infantum. CONCLUSIONS: The authors emphasize the importance of species characterization, particularly in areas of mixed infection like Cuiaba. PMID- 22231253 TI - Capture of Triatoma arthurneivai (Hemiptera: Reduviidae) using a new luminous trap in Southeast Brazil. AB - INTRODUCTION: Triatomine bug captures in the wild are laborious and time consuming. Some traps may assist in this task. We report a new trap design and the capture of a specimen of a triatomine rarely found. METHODS: Two luminous traps were installed in the city of Diamantina, State of Minas Gerais, and surveyed weekly for a year. RESULTS: A Triatoma arthurneivai female and other triatomine bugs were caught. CONCLUSIONS: A new trap design may be used in triatomine bugs field captures, mainly in low density areas. We assume the center of endemism of Triatoma arthurneivai is the Espinhaco Mountain range. PMID- 22231254 TI - In vitro antifungal activity of fatty acid methyl esters of the seeds of Annona cornifolia A.St.-Hil. (Annonaceae) against pathogenic fungus Paracoccidioides brasiliensis. AB - INTRODUCTION: Fatty acids are abundant in vegetable oils. They are known to have antibacterial and antifungal properties. METHODS: Antifungal susceptibility was evaluated by broth microdilution assay following CLSI (formerly the NCCLS) guidelines against 16 fungal strains of clinical interest. RESULTS: In this work, fatty acid methyl esters (FAME) was able to inhibit 12 clinical strains of the pathogenic fungus Paracoccidioides brasiliensis and were also active in the bioautographic assay against Cladosporium sphaerospermum. CONCLUSIONS: FAME was a more potent antifungal than trimethoprim-sulfamethoxazole against P. brasiliensis under the experimental conditions tested. PMID- 22231255 TI - Acetylcholinesterase inhibition starting from extracts of Bauhinia variegata L., Bauhinia var. candida (Aiton) Buch.-Ham., and Bauhinia ungulata L. AB - INTRODUCTION: A treatment to the Alzheimer's disease consists inhibition of the acetylcholinesterase, which is responsible for the acetylcholine control in the synapses. METHODS: We have investigated the potential of inhibition of the acetylcholinesterase produced by hexane extracts of leaves, branches, and flowers from three Bauhinia specimens, which is based on the technique of thin layer chromatography and on identifying the organ of the plant that possesses larger concentration of inhibitors. RESULTS: Retention factor analysis shows values of 0.31aA, 0.31aA, and 0.46aB for flowers B. variegata, B. var. candida, and B. ungulata, respectively. CONCLUSIONS: The flower extract of B. ungulata is the most suitable for further studies on this inhibition. PMID- 22231256 TI - Acute meningoencephalomyelitis due to varicella-zoster virus in an AIDS patient: report of a case and review of the literature. AB - Varicella-zoster virus (VZV) meningoencephalomyelitis is a rare but severe neurological complication of VZV reactivation in immunocompromised patients. We report the case of an HIV-infected individual who developed an acute and severe meningoencephalomyelitis accompanied by a disseminated cutaneous eruption due to VZV. The presence of VZV DNA in cerebrospinal fluid was confirmed by polymerase chain reaction (PCR) technique. The patient started undergoing an intravenous acyclovir therapy with a mild recovery of neurological manifestations. Varicella zoster virus should be included as a cause of acute meningoencephalomyelitis in patients with AIDS. Early diagnosis followed by specific therapy should modify the rapid and fulminant course for this kind of patients. PMID- 22231257 TI - Postmalaria neurological syndrome: a case report. AB - Described here is a case of postmalaria neurological syndrome in a patient who presented infection by Plasmodium falciparum two months earlier. The patient received empiric use of acyclovir for herpetic meningoencephalitis, but neuropsychiatric symptoms improved only after administration of methylprednisolone. PMID- 22231258 TI - Accident caused by Centruroides testaceus (DeGeer, 1778) (Scorpiones, Buthidae), native to the Caribbean, in Brazilian airport. AB - Describes the case of a 6-year-old girl who was stung by a Centruroides testaceus, a scorpion native to the Lesser Antilles, in the Guarulhos International Airport, Sao Paulo, Brazil, as she disembarked from a flight coming from the Caribbean. The patient presented only local symptoms (a small area of erythema and pain at the sting site), which were resolved after a few hours with analgesics, without the need for antivenom. Physicians who treat patients stung by scorpions should be alert to the possibility of such accidents being caused by non native species, especially those cases that occur near airports or ports. PMID- 22231259 TI - Pseudothrombocytopenia in schistosomiasis mansoni. PMID- 22231260 TI - Comparison among homemade repellents made with cloves, picaridin, andiroba, and soybean oil against Aedes aegypti bites. PMID- 22231261 TI - Hantavirus infection in suspected dengue cases from State of Ceara, Brazil. PMID- 22231262 TI - Secondary amyloidosis associated with tuberculosis in renal biopsy. PMID- 22231263 TI - Acanthamoeba castellanii: in vitro UAH-T17c3 trophozoite growth study in different culture media. AB - Acanthamoeba is one of the most common free-living amoebae. It is widespread in the environment and can infect humans, causing diseases such as keratitis and encephalitis. In this study, we used a strain of Acanthamoeba castellanii (UAH T17c3) isolated from cooling towers, and we evaluated the efficiency of three different culture media in its growth, with the aim of selecting one which allowed better growth, was easier to prepare, and was able to keep the trophozoites by long periods of time. We compared the growth of A. castellanii in peptone-yeast extract-glucose (PYG, the most commonly used medium to grow this strain) to the growth in PYG-Bactocasitone (PYG with 2% Bactocasitone) and brain heart infusion broth (BHI is a standard microbiological medium rarely used in the culture of amoebae). Flow cytometry and cell count results showed all three media allowed the growth of trophozoites. PYG-Bactocasitone was shown to be the best for long-term culture. The BHI and PYG-Bactocasitone media have not been used for Acanthamoeba spp. trophozoite growth. In view of the results, we can affirm that these media are adequate to grow the above-mentioned strain for in vitro screening assays. PMID- 22231264 TI - In vitro activity of a serine protease from Monacrosporium thaumasium fungus against first-stage larvae of Angiostrongylus vasorum. AB - A serine protease from the nematophagous fungus Monacrosporium thaumasium (NF34a) was purified, partially characterized and tested in vitro in control of the first larval stage of Angiostrongylus vasorum. NF34a grew in liquid culture medium, producing its crude extract that was purified by ion exchange chromatography. The fractions with high protease activity were collected in a pool, and elution of proteases was monitored by enzymatic assay and protein content. Purification steps were monitored by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Protease activity was determined under different pH and temperature conditions, and the inhibitor effects of metal ions and phenylmethylsulfonyl fluoride (PMSF) were assessed. In an experimental test, the infection process of NF34a on first-stage larvae of A. vasorum was investigated. A purified serine protease (Mt1) was identified, with an approximate molecular mass of 40 kDa and apparent homogeneity in SDS-PAGE, having optimal activity at pH 7.0 to 8.0 and temperature of 60 degrees C. Mg(2+) and Zn(2+) partially inhibited the activity of Mt1 while PMSF inhibited it completely. Mt1 production was observed when NF34a was grown using first-stage larvae of A. vasorum as the only source of carbon and nitrogen. These results show that the enzyme may have a possible role in the infection process of the larvae. In the in vitro test of applicability against A. vasorum L(1), we observed a reduction in the number of larvae of 23.9% (p < 0.05) in the group treated with Mt1 compared with the control group. However, even this low reduction demonstrates that the Mt1 is important in the infection process. PMID- 22231265 TI - Larvicidal and ovicidal properties of leaf and seed extracts of Delonix elata (L.) Gamble (family: Fabaceae) against malaria (Anopheles stephensi Liston) and dengue (Aedes aegypti Linn.) (Diptera: Culicidae) vector mosquitoes. AB - Mosquito-borne diseases with an economic impact create loss in commercial and labor outputs, particularly in countries with tropical and subtropical climates. Mosquito control is facing a threat because of the emergence of resistance to synthetic insecticides. Extracts from plants may be alternative sources of mosquito control agents because they constitute a rich source of bioactive compounds that are biodegradable into nontoxic products and potentially suitable for use to control mosquitoes. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. In view of the recently increased interest in developing plant origin insecticides as an alternative to chemical insecticide, this study was undertaken to assess the larvicidal and ovicidal potential of the crude hexane, benzene, chloroform, ethyl acetate, and methanol solvent extracts from the medicinal plant Delonix elata against the medically important mosquito vectors, Anopheles stephensi and Aedes aegypti (Diptera: Culicidae). The larval mortality was observed after 24 h of exposure. All extracts showed moderate larvicidal effects; however, the highest larval mortality was found in methanol extract of leaf of D. elata against the larvae of A. stephensi and A. aegypti with the LC(50) and LC(90) values being 93.59 and 111.83, and 163.69 and 202.77 ppm, respectively. Compared to leaf extracts, seeds have low potency against two mosquitoes with the LC(50) and LC(90) values being 115.28 and 139.04, and 225.07 and 273.03 ppm, respectively. The mean percent hatchability of the eggs was observed after 48 h post-treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. All the five solvent extracts showed moderate ovicidal activity; however, the methanol extract showed the highest ovicidal activity. One hundred percent mortality was observed at 300 ppm for leaf methanol extract and 500 ppm for seed methanol extract of D. elata against A. stephensi and A. aegypti, respectively. These results suggest that the leaf and seed extracts have the potential to be used as an ideal ecofriendly approach for the control of mosquitoes. This is the first report on the mosquito larvicidal and ovicidal activities of the reported D. elata plant. PMID- 22231266 TI - A study on ovine tick-borne hemoprotozoan parasites (Theileria and Babesia) in the East Black Sea Region of Turkey. AB - In this study, the frequency of Theileria and Babesia species was assessed via reverse line blotting and blood smear-based diagnostic methods in small ruminants. A total of 201 apparently healthy animals from 26 randomly selected herds located in 4 locations (Artvin, Giresun, Gumushane, and Tokat) of East Black Sea Region of Turkey were investigated for the blood protozoans. In a polymerase chain reaction (PCR), the hypervariable V4 region of the 18S ribosomal RNA gene was amplified with a set of general primers specific for all Theileria and Babesia species. The PCR products were hybridized against catchall and species-specific (Theileria spp., Theileria lestoquardi, Theileria ovis, Theileria sp. OT1, Theileria sp., OT3, Theileria sp., MK, Theileria luwenshuni, Theileria uilenbergi, Babesia spp., Babesia ovis, Babesia motasi, and Babesia crassa) probes. Theileria piroplasms were identified in nine (4.47%) samples by microscopic examination. Reverse line blotting (RLB) detected the infection in 19.90% of the samples. The infection rate of sheep (28.90%) was higher than goats (4.10%). T. ovis, Theileria sp., MK, and Theileria sp. OT3 were detected by RLB. The most prevalent Theileria species was T. ovis (18.90%) followed by Theileria sp. MK (0.99%). Theileria sp. OT3 was detected in one sample (0.43%). A single animal was infected as mix with T. ovis and Theileria sp. MK. The other Theileria (T. lestoquardi, Theileria sp. OT1, T. luwenshuni, and T. uilenbergi) and Babesia (B. ovis, B. motasi, and B. crassa) species were not detected. This study is the first molecular survey on ovine tick-borne protozoans in East Black Sea Region of Turkey. PMID- 22231267 TI - Epidemiological implications of the use of various methods for the diagnosis of canine leishmaniasis in dogs with different characteristics and in differing prevalence scenarios. AB - Our aim was to establish the influence on the prevalence of canine leishmaniasis (CanL) of the following: (1) the use of different diagnostic techniques; (2) different positivity thresholds; (3) selection of animals either at random from a population or focused on symptomatic individuals, (4) the function which the dog performs; and (5) scenarios with differing epidemiological characteristic. Three groups of dogs were analysed (416 sampled at random from an endemic area, 71 with symptomatology compatible with CanL and 15 from a non-endemic area) using three serological techniques (indirect fluorescence antibody test (IFAT), Kalazar Detect(TM) and Q Letitest ELISA) and a PCR-ELISA. The diagnostic technique had a considerable influence on the CanL prevalence value obtained. Uncertain antibody titres were more representative in dogs sampled at random and with the IFAT technique. Although employing different capture antigens, correlation of results was higher between the two commercial techniques in the group of dogs with symptomatology compatible with CanL. The sensitivity and specificity values of the different diagnostic techniques were affected by the epidemiological characteristic of the area under study, the presence of clinical signs and the function which the dog performs. This must be taken into account when comparing endemicity in different geographical areas, such as in studies carried out for the construction of risk maps. Using more than one technique, and adopting the criterion of considering an animal to be positive only when it has been diagnosed as such by more than one technique, considerably raises the prevalence values but maintains the differences between areas with different characteristics. PMID- 22231268 TI - Larvicidal efficacy of the Citrus limetta peel extracts against Indian strains of Anopheles stephensi Liston and Aedes aegypti L. AB - The extracts from the peels of Citrus limetta were prepared using hexane and petroleum ether as the solvents. The larvicidal potential of each extract was assessed against dengue fever vector, Aedes aegypti, and malarial vector, Anopheles stephensi, by evaluating the toxicity effects on early fourth instars. Both the extracts were found effective against both the species. The bioassay with hexane extracts resulted in LC(50) values of 132.45 and 96.15 ppm against A. stephensi and A. aegypti, respectively; while the petroleum ether extracts from the C. limetta peels showed LC(50) values of 244.59 and 145.50 ppm, respectively. It revealed that the hexane extracts possessed 1.9-fold more larvicidal potential against A. stephensi and 1.5-fold more efficacy against A. aegypti as compared to the extracts obtained using petroleum ether as solvent. The data further revealed that the extracts were 1.4-1.7 times more effective against A. aegypti as compared to A. stephensi. The qualitative phytochemical study of the extracts showed the presence of terpenoids and flavonoids as the common phytochemical constituents in the extracts suggesting their possible role in the toxicity. Other constituents tested were not detected except alkaloids which were found to be present only in the petroleum ether extract. Further studies are needed to isolate and identify the active principles involved, their mode of action, formulated preparations for enhancing potency and stability, toxicity, and effects on non-target organisms and the environment. This could help in formulating efficient strategies for mosquito control. PMID- 22231269 TI - Objective evaluation of anterior knee laxity; comparison of the KT-1000 and GNRB(r) arthrometers. AB - PURPOSE: Accurate measurement of laxity after anterior cruciate ligament (ACL) rupture is usually performed with the KT-1000 arthrometer, and reproducibility and reliability are discussed. A new arthrometer, the GNRB((r)), has been recently developed in an attempt to improve intra- and inter-examiner reproducibility. The aim of this diagnostic study was to evaluate the intra- and inter-examiner reproducibility of the GNRB((r)) and the KT-1000. METHODS: Three protocols were designed to evaluate and compare the two arthrometers. Fifteen physiotherapists conducted tests on 15 subjects with healthy knees. The intra- and inter-reproducibility of the two tests were compared by analysis of variance and the F-test. RESULTS: Measure reproducibility was significantly worst with the KT-1000 than with the GNRB((r)) (machine effect, P < 0.001) regardless of operator experience. There was no significant difference between experienced and inexperienced examiners with the GNRB((r)) (no 'examiners effect'). Regardless of the machine, there was a 'side effect' with healthy knees. CONCLUSION: This clinical study demonstrates the superior intra- and inter-examiner reproducibility of the GNRB((r)) over the KT-1000. There appears to be some technological advantages to using the GNRB((r)) including pressure control of the patella, accuracy of the displacement transducer, control of the load on the calf, and control of hamstring activity. LEVEL OF EVIDENCE: Diagnostic study, Level I. PMID- 22231270 TI - Injectable silk fibroin/polyurethane composite hydrogel for nucleus pulposus replacement. AB - In degenerative disc disease, an injectable hydrogel can fill a degenerate area completely, reduce the risk of implant migration and subsequent loss of height of the intervertebral disc, and minimise surgical defects. Here, we propose a method of preparing an injectable silk fibroin/polyurethane (SF/PU) composite hydrogel by chemical cross-linking under physiological conditions. Mechanical testing was used to determine the mechanical strength of the hydrogel. The impact of hydrogel height on the biomechanical properties was discussed to estimate the working capacity of the hydrogel for further clinical application. Rheological properties were also examined to assess the practical ability of the hydrogel for clinical application. Hydrogel injection and cell assessment is also of interest for clinical application. An SF/PU composite hydrogel can be injected through a small incision. A cell proliferation assay using bone marrow stromal cells showed positive cell viability and increased proliferation over a seven-day period in culture. Importantly, the hydrogel can be monitored in real-time using X-ray fluoroscopy during and after surgery according to the results of X-ray fluoroscopy examination, and shows good visibility based on X-ray assays. In particular, the hydrogel offers the clinically important advantage of visibility in CT and T2-weighted magnetic resonance imaging. Based on the results of the current study, the SF/AU composite hydrogel may offer several advantages for future application in nucleus pulposus replacement. PMID- 22231271 TI - Disease-specific non-reducing end carbohydrate biomarkers for mucopolysaccharidoses. AB - A considerable need exists for improved biomarkers for differential diagnosis, prognosis and monitoring of therapeutic interventions for mucopolysaccharidoses (MPS), inherited metabolic disorders that involve lysosomal storage of glycosaminoglycans. Here we report a simple, reliable method based on the detection of abundant nonreducing ends of the glycosaminoglycans that accumulate in cells, blood and urine of individuals with MPS. In this method, glycosaminoglycans are enzymatically depolymerized, releasing unique mono-, di- or trisaccharides from the nonreducing ends of the chains. The composition of the released mono- and oligosaccharides depends on the nature of the lysosomal enzyme deficiency, and therefore they serve as diagnostic biomarkers. Analysis by LC/MS allowed qualitative and quantitative assessment of the biomarkers in biological samples. We provide a simple conceptual scheme for diagnosing MPS in uncharacterized samples and a method to monitor efficacy of enzyme replacement therapy or other forms of treatment. PMID- 22231272 TI - Timing facilitated site transfer of an enzyme on DNA. AB - Many enzymes that react with specific sites in DNA have the property of facilitated diffusion, in which the DNA chain is used as a conduit to accelerate site location. Despite the importance of such mechanisms in gene regulation and DNA repair, there have been few viable approaches to elucidate the microscopic process of facilitated diffusion. Here we describe a new method in which a small molecule trap (uracil) is used to clock a DNA repair enzyme as it hops and slides between damaged sites in DNA. The 'molecular clock' provides unprecedented information: the mean length for DNA sliding, the one-dimensional diffusion constant, the maximum hopping radius and the time frame for DNA hopping events. In addition, the data establish that the DNA phosphate backbone is a sufficient requirement for DNA sliding. PMID- 22231273 TI - Oxysterols are allosteric activators of the oncoprotein Smoothened. AB - Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S) hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. We present several lines of evidence that this protein target is the seven-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing sterol signaling mechanisms. PMID- 22231275 TI - Predictors of ethylene glycol ingestion cases called into a regional poison center. AB - Poison center consultations for potential toxic alcohol poisonings are challenging because blood levels are typically not immediately available. The primary objective of this study was to determine whether readily obtainable laboratory values can be used to accurately and rapidly diagnose these poisonings. Over a 15-month period, patients with a history of toxic alcohol ingestion or a metabolic acidemia (pH <= 7.30 or serum bicarbonate <= 18 mEq/L) that prompted a poison center consultation were enrolled. A predictive logistic regression model was used to assess the combined ability of serum pH, calcium, osmolar gap, and anion gap levels to predict a final diagnosis of toxic alcohol poisoning. There were 102 subjects included in the analysis. A total of 44% (45/102) patients had a final diagnosis of ethylene glycol (EG) poisoning. Higher levels of calcium, osmolar gap, and anion gap were independently associated with statistically significant or marginally significant increases in the odds of a final diagnosis of EG poisoning. The c-index was estimated at 0.81, indicating that the model showed a reasonable ability to discriminate EG cases from others. The final model had a sensitivity and specificity of 78% and 89%, respectively, and positive and negative predictive values of 84% and 83% respectively. The combination of elevated calcium, osmolar gap, and anion gap is associated with a high likelihood of EG poisoning, but clinician gestalt is still essential for its diagnosis. Further refinement of the model is needed. PMID- 22231274 TI - Pediatric vasculitis. AB - The primary systemic vasculitides in childhood are quite rare except for Henoch Schonlein purpura and Kawasaki disease. These are usually self-limited diseases. The etiopathogenesis for most of them is not clearly understood. However, it is usually thought that environmental triggers (mostly infectious) evoke an aggravated inflammatory response in susceptible individuals. The classification criteria for most of them were recently validated for children. Clinical manifestations are determined by the organs affected, reflecting the involved vessels on a background of constitutional symptoms. For treatment, the main data are adapted from adult studies, especially for rarer vasculitides in childhood. In this review, the recent classification criteria, current pathophysiologic pathways, and treatment protocols are summarized. PMID- 22231278 TI - Current treatment strategies for epistaxis: a multidisciplinary approach. AB - Epistaxis is a common clinical complaint with a spectrum of severity ranging from spontaneous cessation to unrelenting, life threatening hemorrhage requiring surgical treatment. Both otolaryngologic and neurointerventional techniques are discussed to provide a comprehensive paradigm to treat patients with epistaxis. An exhaustive review of the anatomic basis for the two main subtypes of epistaxis is provided as well as a graduated approach to appropriate clinical management. PMID- 22231277 TI - Positron emission tomography of 64Cu-DOTA-Rituximab in a transgenic mouse model expressing human CD20 for clinical translation to image NHL. AB - PURPOSE: This study aims to evaluate (64)Cu-DOTA-rituximab (PETRIT) in a preclinical transgenic mouse model expressing human CD20 for potential clinical translation. PROCEDURES: (64)Cu was chelated to DOTA-rituximab. Multiple radiolabeling, quality assurance, and imaging experiments were performed. The human CD20 antigen was expressed in B cells of transgenic mice (CD20TM). The mice groups studied were: (a) control (nude mice, n = 3) that received 7.4 MBq/dose, (b) with pre-dose (CD20TM, n = 6) received 2 mg/kg pre-dose of cold rituximab prior to PETRIT of 7.4 MBq/dose, and (c) without pre-dose (CD20TM, n = 6) PETRIT alone received 7.4 MBq/dose. Small animal PET was used to image mice at various time points (0, 1, 2, 4, 24, 48, and 72 h). The OLINDA/EXM software was used to determine the human equivalent dose for individual organs. RESULTS: PETRIT was obtained with a specific activity of 545 +/- 38.91 MBq/nmole, radiochemical purity >95%, and immunoreactivity >75%. At 24 h, spleenic uptake of PETRIT%ID/g (mean +/- STD) with and without pre-dose was 1.76 +/- 0.43% and 16.5 +/- 0.45%, respectively (P value = 0.01). Liver uptake with and without pre-dose was 0.41 +/ 0.51% and 0.52 +/- 0.17% (P value = 0.86), respectively. The human equivalents of highest dose organs with and without pre-dose are osteogenic cells at 30.8 +/- 0.4 MUSv/MBq and the spleen at 99 +/- 4 MUSv/MBq, respectively. CONCLUSIONS: PET imaging with PETRIT in huCD20 transgenic mice provided human dosimetry data for eventual applications in non-Hodgkins lymphoma patients. PMID- 22231279 TI - Double-barrel entanglement of intracranial Enterprise stents resulting from undetected incomplete stent apposition. AB - OBJECTIVE: Although intracranial stents have expanded the spectrum of aneurysms amenable to coiling, closed cell design variants can be prone to incomplete stent apposition around tightly curved arterial bends. A case is presented illustrating the technical ramifications of this phenomenon during subsequent treatment. CLINICAL PRESENTATION: A 49-year-old woman who had previously undergone Enterprise (closed cell design) stent mediated coiling of a wide necked ophthalmic carotid artery aneurysm was noted to harbor residual central filling on follow-up imaging, and was scheduled for additional embolization. INTERVENTION: During retreatment, performed with a second concentrically placed Enterprise and further coil packing using the jailing technique, the proximal portion of the second Enterprise stent failed to expand as expected. C-arm cone beam CT (CBCT) revealed the second stent to have been navigated into and out of the orphaned lumen created by the incompletely apposed first Enterprise stent at the carotid siphon. This stent entanglement resulted in the formation of a trapped proximal double-barrel lumen in the curved segment and resolution to a single barrel lumen in the distal straight segment of the parent vessel facing the aneurysm neck. CONCLUSION: Caution is urged when navigating around curved vessel segments through previously deployed intracranial stents, which may be incompletely apposed to the vessel wall, to avoid deleterious and potentially catastrophic entanglement. CBCT imaging may be helpful in delineating the spatial relationship of previously deployed intracranial stents during subsequent endovascular navigation. PMID- 22231280 TI - The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma. AB - Single-agent bortezomib, a potent, selective, and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the MCL patients; however, complete remission rates are low and duration of response proved to be relatively short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Rational combination treatment and schedules require profound knowledge of underlying molecular mechanisms. Here we show that single-agent bortezomib treatment of MCL cell lines leads to G2/M arrest and induction of apoptosis accompanied by downregulation of EIF4E and CCND1 mRNA but upregulation of p15(INK4B) and p21 mRNA. We further present synergistic efficacy of bortezomib combined with cytarabine in MCL cell lines. Interestingly this sequence-dependent synergistic effect was seen almost exclusively in combination with AraC, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach. PMID- 22231281 TI - Imatinib trough plasma levels do not correlate with the response to therapy in patients with chronic myeloid leukemia in routine clinical setting. AB - Association of trough imatinib plasma levels (IPL) with cytogenetic or molecular response to treatment in patients with chronic myeloid leukemia (CML) was repeatedly reported. We analyzed their value in the routine clinical setting in 131 patients with chronic phase CML in whom imatinib was applied as first- or second-line treatment. A total of 1,118 measurements were obtained by ultra performance liquid chromatography-tandem mass spectrometry assay in patients treated with daily dose of imatinib ranging from 100 to 800 mg. Samples were obtained from 1 to 96 h after drug ingestion. High inter (36%) and intraindividual variability (9-33%) of IPL was observed. For analysis of correlation of IPL with treatment response, two sets of samples were selected according to the European LeukemiaNet (ELN) criteria. The first set consisted of 241 samples taken 24 +/- 2 h after dosing in 54 patients, and the second one consisted of 329 samples taken 24 +/- 4 h after imatinib ingestion in 84 patients. In both sets, only patients treated with 400 mg imatinib once daily for at least 18 months were included. From multiple measurements in individual patients, mean IPL were used. In both sets, we were not able to demonstrate a statistically significant correlation between IPL and response to treatment according to the ELN. We believe that this was due to the differences in patients' compliance, leukemia biology, and other variables that are difficult to eliminate in the routine clinical practice. The use of IPL for prognostic estimation in CML treatment outside the clinical trials is probably limited. PMID- 22231282 TI - BRI1 activity in the root meristem involves post-transcriptional regulation of PIN auxin efflux carriers. AB - Spatiotemporal coordination between multiple hormonal pathways is a key determinant of plant growth. This coordination can be mediated by distribution of the auxin network via the action of PIN auxin efflux carriers. We showed that brassinosteroids (BRs) promote cell proliferation and cell expansion of meristematic cells. Hence, roots with high epidermal expression of the BR receptor BRI1 have enlarged meristem whereas bri1 mutant has a reduced meristem size. Because the extent of mitotic activity and differentiation is tightly linked to auxin gradient we further asked how the BR pathway integrates with current proposed models for PIN regulation. We showed that the small meristem of BR deficient plants does not involve transcriptional modulation of PIN 1, 3 and 7 genes. Here, we found that PIN2 and PIN4 are under transcriptional regulation. However, their accumulation in the epidermis/cortex and columella respectively was also determined by BRs in a post-transcriptional manner. Thus, BRs impinge on auxin distribution through distinct regulatory modes and the self-organizing auxin system represents at least one mechanism that contributes to BR-mediated growth. PMID- 22231284 TI - Elastic properties of freely suspended MoS2 nanosheets. PMID- 22231283 TI - Predictors of prolonged survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma. AB - A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with myeloablative (MAC; n = 38) or reduced-intensity conditioning (RIC; n = 110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28-70) years with a followup time of 28.5 (3-164) months. The 100-day and 5-year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative incidence of Grade II-IV acute graft-versus-host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo-HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18-0.67) and OS (HR 0.29; 95% CI 0.15-0.55), while absence of high-risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37-0.95). We observe that TRM has decreased with the use of RIC regimens, and long-term disease control can be expected in a subset of MM patients undergoing allo-HCT. Further studies should be conducted in carefully designed clinical trials in this patient population. PMID- 22231285 TI - Direct amination of alpha-substituted nitroacetates using di-tert-butyl azodicarboxylate catalyzed by Hatakeyama's catalyst beta-ICD. AB - We report the first example of catalytic asymmetric direct amination of alpha monosubstituted nitroacetates using di-tert-butyl azodicarboxylate. The simple and easily available Hatakeyama's catalyst beta-ICD 11 was found to be a highly enantioselective catalyst for this reaction. PMID- 22231286 TI - Microfluidic extraction and stretching of chromosomal DNA from single cell nuclei for DNA fluorescence in situ hybridization. AB - We have developed a novel method for genetic characterization of single cells by integrating microfluidic stretching of chromosomal DNA and fiber fluorescence in situ hybridization (FISH). In this method, individually isolated cell nuclei were immobilized in a microchannel. Chromosomal DNA was released from the nuclei and stretched by a pressure-driven flow. We analyzed and optimized flow conditions to generate a millimeter-long band of stretched DNA from each nucleus. Telomere fiber FISH was successfully performed on the stretched chromosomal DNA. Individual telomere fiber FISH signals from single cells could be resolved and their lengths measured, demonstrating the ability of the method to quantify genetic features at the level of single cells. PMID- 22231287 TI - A two-step ICT process for solvatochromic betaine pyridinium revealed by ultrafast spectroscopy, multivariate curve resolution, and TDDFT calculations. AB - This work deals with the photophysics of a pyridinium betaine, 2-pyridin-1-yl-1H benzimidazole (SBPa), based on a combination of steady-state, femtosecond photoionization (gas phase) and femtosecond transient absorption (solution) spectroscopic measurements, supported by (LR)-PCM-(TD)DFT calculations. Preliminary and new electrochemical results have revealed a strongly negative solvatochromic charge transfer (CT) absorption due to a S(0) -> S(2) vertical transition and a weakly-solvatochromic emission due to S(1) -> S(0) transition. Advanced TDDFT optimizations of the Franck-Condon states S(2)(FC) and S(1)(FC) led to two additional CT levels with planar geometry, S(2)(CT) and S(1)(CT), respectively, allowing prediction of a two-step photoinduced ICT process, i.e., S(0) -> S(2)(FC) and S(2)(CT) -> S(1)(CT), separated by a S(2)(FC) -> S(2)(CT) back charge transfer relaxation. While the pyridinium ring is the acceptor group in both steps, two different donor groups, the benzene ring and the imidazole bridge, are involved in the excitation and internal conversion processes, respectively. Femtosecond transient absorption experiments supported by MCR-ALS decomposition confirmed indeed the contribution of two distinct CT states in the photophysics of SBPa: following excitation to the S(2)(CT) state, ultrafast production of the emissive S(1) state (the only channel observable in the gas phase) was observed to occur in competition with a further ICT process toward the S(1)(CT) state, with a time constant ranging from 300 fs to 20 ps depending on the solvent. While in aprotic media this ICT process was found to be purely solvent controlled (double polarity and viscosity dependency), in protic solvents, the influence of the hydrogen bond network has to be taken into account. Comparison with data obtained for a pre-twisted SBPa analogue led us to exclude the presence of any large-amplitude geometrical change during ICT. Analyzing the solvent dependency using the power law approach, we concluded that the S(1)(CT) state decays essentially through IC in the 3-40 ps time range whereas the emissive S(1) state decays within 130-260 ps via IC, ISC and fluorescence. PMID- 22231288 TI - Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the juvenile arthritis disease activity score. AB - OBJECTIVE: To determine cutoff values for defining remission, minimal disease activity, and parent and child acceptable symptom state in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: For the selection of cutoff values, data from a clinical database including 609 children with JIA were used. Optimal cutoff values were determined against external criteria by calculating the 75th percentile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria included formal definitions of inactive disease and minimal disease activity, subjective rating of remission by physicians, parents, and children, and rating of acceptable symptom state by parents and children. The choice of cutoffs was made based on clinical and statistical grounds. Cross validation was performed using 4 JIA patient samples that included a total of 1,323 patients, and was based on assessment of construct, discriminant, and predictive validity. RESULTS: With all versions of the JADAS, the cutoff score for classifying a patient as having inactive disease was 1, whereas the cutoff for classification of minimal disease activity was 2 for oligoarticular JIA and 3.8 for polyarticular JIA. Cutoffs for physicians', parents', and children's subjective rating of remission ranged from 2 to 2.3. Cutoffs for acceptable symptom state ranged from 3.2 to 5.4 for parents and from 3 to 4.5 for children. Results of cross-validation analyses strongly supported the selected cutoff values. CONCLUSION: Cutoff values for classifying various disease states in JIA using the JADAS were developed. In cross-validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome. PMID- 22231289 TI - Sexual dysfunction in 2011: advances in epidemiology, pathophysiology and treatment. PMID- 22231290 TI - Predictive models for the practical management of renal cell carcinoma. AB - The expanding availability of multiple therapeutic strategies and sequencing options for patients with renal cell carcinoma (RCC) has increased the importance of skilled individualized outcome estimation for patients. This need has driven the development of statistical models to guide patient management in a variety of common clinical settings, including the management of small renal masses, identification of patients with high-risk localized RCC requiring systemic therapy and selection of suitable targeted therapies in metastatic disease. With an increasing number of different predictive models described in the literature, identifying those models most relevant for practical use is challenging. In addition to statistical models based on clinical data, there has also been an evolution towards incorporation of molecular markers into predictive algorithms. These models also serve as important benchmarks for the researchers developing novel prognostic and predictive molecular biomarkers. PMID- 22231292 TI - Prostate cancer: cardiovascular risk and androgen deprivation therapy. PMID- 22231291 TI - XMRV and prostate cancer--a 'final' perspective. AB - XMRV was first described in 2006, when it was identified in samples isolated from prostate cancer tissues. However, studies have since shown that XMRV arose in the laboratory and was formed by genetic recombination between two viral genomes carried in the germline DNA of mice used during serial transplantation of the CWR22 prostate cancer xenograft. These new findings strongly imply that XMRV does not circulate in humans, but is only present in the laboratory. Thus, there is no reason to believe that it has any role in the etiology of prostate cancer or other diseases. PMID- 22231293 TI - Mathematically modelling and controlling prostate cancer under intermittent hormone therapy. AB - In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer (PCa). Although hormone therapy for PCa shows remarkable results at the beginning of treatment, cancer cells frequently acquire the ability to grow without androgens during long-term therapy, resulting in an eventual relapse. To circumvent hormone resistance, intermittent androgen suppression was investigated as an alternative treatment option. However, at the present time, it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient. In addition, clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others. To resolve these two problems, we have developed mathematical models for PCa under intermittent androgen suppression. The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods. PMID- 22231294 TI - Effects of Melandrium firmum methanolic extract on testosterone-induced benign prostatic hyperplasia in Wistar rats. AB - Benign prostatic hyperplasia (BPH) is an age-related disease of unknown aetiology characterized by prostatic enlargement coincident with distinct alterations in tissue histomorphology. Instead of therapeutic agents that can cause severe side effects, plant extracts are frequently used to treat BPH. In this study, we investigated whether the Melandrium firmum methanolic extract (MFME) improves BPH, using the testosterone propionate (TP)-induced BPH rat model. Castration was performed via the scrotal route under sodium pentobarbital anaesthesia. BPH in castrated rats was generated via daily subcutaneous injections of TP (3 mg kg( 1)) dissolved in corn oil, for 4 weeks. MFME was administered daily by oral gavage at a dose of 200 mg kg(-1) for 4 weeks, along with the TP injections. The control group received injections of corn oil subcutaneously. At the scheduled termination of the experiment, all rats were killed and their prostates weighed; the relative prostate weight (prostate/body weight ratio) was calculated, and histomorphological changes in the prostate were examined. Additionally, we measured the levels of testosterone and dihydrotestosterone (DHT) in the serum and the prostate. Experimentally induced BPH led to marked decreases in the relative prostate weight and the DHT levels in the serum and the prostate. Histologically, BPH was evident in the ventral lobe of the prostate, and MFME treatment suppressed the severity of the lesions. These results indicate that MFME effectively inhibits the development of BPH induced by testosterone in a rat model. Further studies will be needed to identify the compound(s) responsibility for inducing the protective effect against BPH and determine its mechanism of action. PMID- 22231295 TI - Thulium:YAG VapoEnucleation of the prostate in large glands: a prospective comparison using 70- and 120-W 2-um lasers. AB - This study compared the efficacy of 70- and 120-w 2-um thulium:YAG VapoEnucleation of the prostate (ThuVEP) for patients with benign prostatic obstruction (BPO). A prospective analysis of 84 patients with symptomatic BPO and prostatic enlargement (>=60 ml) who underwent either 70-w (n=44) or 120-w ThuVEP (n=40) non-randomly was carried out. Patient demographics and perioperative and 12-month follow-up data were analysed. The mean prostate volume was 79.90+/-27.49 ml in patients who had received 70-w ThuVEP, which was less than in those who had received 120-w ThuVEP (88.53+/-25.10; P=0.033). The mean enucleation (resected weight/laser time, 2.16+/-1.21 g min(-1) vs. 1.23+/-0.60 g min(-1); P=0.013), operation efficiency (resected weight/total operation time, 0.76+/-0.35 g min(-1) vs. 0.42+/-0.27 g min(-1); P=0.000) and percentage of resected tissue (66.93%+/ 22.79% vs. 45.41%+/-23.33%; P=0.000) were higher with 120-w treatment compared to 70-w ThuVEP. One patient (1.2% of total patients) (in the 120-w group) required a blood transfusion postoperatively. Sixty-one patients (73%) were available for review at the 12-month follow-up time point. The quality of life (QoL), International Prostate Symptom Score (IPSS), maximum urinary flow rate (Q(max)), postvoiding residual urine (PVR) and prostate volume improved significantly after treatment (P<=0.035) and were not significantly different between those treated with the different devices (70- and 120-w). The median prostate volume reduction was 81.70% and 82.19% with 70- and 120-w ThuVEP, respectively. The incidence of complications was low and did not differ between groups treated with the different devices. Two patients (2.4%) (one per group) had a bladder neck contracture at the follow-up. ThuVEP is a safe and efficacious procedure for the treatment of symptomatic BPO. The incidence of complications was low with both devices. The 120-w thulium:YAG device enhances the effectiveness of ThuVEP with regard to the percentage of resected tissue and the enucleation/operation efficiency. PMID- 22231296 TI - Quality of life issues in men undergoing androgen deprivation therapy: a review. AB - Androgen deprivation therapy (ADT) has been an essential treatment option for treating prostate cancer (PCa). The role for hormonal treatment initially was restricted to men with metastatic and inoperable, locally advanced disease. Now it has been extended to neoadjuvant or adjuvant therapy for surgery and radiotherapy, for biochemical relapse after surgery or radiation, and even as primary therapy for non-metastatic disease. Fifty percent of PCa patients treated will receive ADT at some point. There is growing concern about the adverse effects and costs associated with more widespread ADT use. The adverse effects on quality of life (QoL), including physical, social and psychological well-being when men are androgen-deprived, may be considerable. This review examines the QoL issues in the following areas: body feminisation, sexual changes, relationship changes, cognitive and affective symptoms, fatigue, sleep disturbance, depression and physical effects. Further suggestions for therapeutic approaches to reduce these alterations are suggested. PMID- 22231297 TI - Amniotic fluid stem cell-based models to study the effects of gene mutations and toxicants on male germ cell formation. AB - Male infertility is a major public health issue predominantly caused by defects in germ cell development. In the past, studies on the genetic regulation of spermatogenesis as well as on negative environmental impacts have been hampered by the fact that human germ cell development is intractable to direct analysis in vivo. Compared with model organisms including mice, there are fundamental differences in the molecular processes of human germ cell development. Therefore, an in vitro model mimicking human sperm formation would be an extremely valuable research tool. In the recent past, both human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have been reported to harbour the potential to differentiate into primordial germ cells and gametes. We here discuss the possibility to use human amniotic fluid stem (AFS) cells as a biological model. Since their discovery in 2003, AFS cells have been characterized to differentiate into cells of all three germ layers, to be genomically stable, to have a high proliferative potential and to be non-tumourigenic. In addition, AFS cells are not subject of ethical concerns. In contrast to iPS cells, AFSs cells do not need ectopic induction of pluripotency, which is often associated with only imperfectly cleared epigenetic memory of the source cells. Since AFS cells can be derived from amniocentesis with disease-causing mutations and can be transfected with high efficiency, they could be used in probing gene functions for spermatogenesis and in screening for male reproductive toxicity. PMID- 22231298 TI - Impact of androgen deprivation therapy on sexual function. AB - Many patients with prostate cancer for whom androgen deprivation therapy (ADT) is indicated are young and desire to remain sexually active. In such patients, the side effects of androgen therapy on sexual function can be a source of serious reduction in overall quality of life. Providing the appropriate treatment options in this patient population is therefore essential. Nevertheless, treating such patients is challenging and an understanding of the underlying mechanisms of sexual physiology and pathophysiology is crucial to optimal patient care. In this paper, we reviewed what was known regarding the effects of ADT on sexual function in animal models and we also provided a detailed review on the effects of ADT on sexual health in humans and its treatment. PMID- 22231299 TI - Use of androgen deprivation therapy in prostate cancer: indications and prevalence. AB - Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies. PMID- 22231301 TI - Pregnancy outcome after intracytoplasmic sperm injection with strontium oocyte activation in a globozoospermic patient. PMID- 22231300 TI - Hematological changes during androgen deprivation therapy. AB - Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the well-described actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies. PMID- 22231302 TI - Effects of genotype, soil type, year and fertilisation on sensory and morphological attributes of carrots (Daucus carota L.). AB - BACKGROUND: The aim of the study was to investigate the effects of variety, soil type and fertilisation, and the interactions between these factors, on yield and quality traits of carrots. RESULTS: Optimum fertilisation levels for yield and quality of grade one roots were found to be between 80 and 160 kg ha(-1) for nitrogen and between 0 and 120 kg ha(-1) for potassium depending on soil type and precipitation. Carrots grown in peat soil had the highest score for sweetness and the lowest scores for negatively associated characteristics such as bitterness, earthy flavour, terpene flavour and firmness. Nitrate content and the amounts of splitted and forked roots were lowest on sandy soil. Variety significantly affected number of grade 1 roots, dry matter, nitrate content and most of the sensory attributes tested. Interactions between variety, soil type and nitrogen fertilisation were found for most of the tested quality characteristics. CONCLUSION: The investigations showed that year and variety had the highest impact on the carrot quality attributes studied, whereas soil type and fertilisation had less influence. Peat soil and moderate fertilisation with N and K gave optimal sensory quality while sand soil gave optimal quality as regards morphological characters like splitting and forking of roots as well as nitrate content. PMID- 22231303 TI - A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. AB - A female offspring of consanguineous parents, showed features of Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema, thrombocytopenia, defective T cell proliferation and chemotaxis, and impaired natural killer cell function. Cells from this patient had undetectable WAS protein (WASP), but normal WAS sequence and messenger RNA levels. WASP interacting protein (WIP), which stabilizes WASP, was also undetectable. A homozygous c.1301C>G stop codon mutation was found in the WIPF1 gene, which encodes WIP. Introduction of WIP into the patient's T cells restored WASP expression. These findings indicate that WIP deficiency should be suspected in patients with features of WAS in whom WAS sequence and mRNA levels are normal. PMID- 22231306 TI - Central pontine myelinolysis: a metabolic disorder of myelin. PMID- 22231304 TI - Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. AB - Dendritic cells (DCs) and macrophages (MPs) are important for immunological homeostasis in the colon. We found that F4/80(hi)CX3CR1(hi) (CD11b(+)CD103(-)) cells account for 80% of mouse colonic lamina propria MHC-II(hi) cells. Both CD11c(+) and CD11c(-) cells within this population were identified as MPs based on multiple criteria, including an MP transcriptome revealed by microarray analysis. These MPs constitutively released high levels of IL-10 at least partially in response to the microbiota via an MyD88-independent mechanism. In contrast, cells expressing low to intermediate levels of F4/80 and CX3CR1 were identified as DCs based on phenotypic and functional analysis and comprise three separate CD11c(hi) cell populations: CD103(+)CX3CR1(-)CD11b(-) DCs, CD103(+)CX3CR1(-)CD11b(+) DCs, and CD103(-)CX3CR1(int)CD11b(+) DCs. In noninflammatory conditions, Ly6C(hi) monocytes (MOs) differentiated primarily into CD11c(+) but not CD11c(-) MPs. In contrast, during colitis, Ly6C(hi) MOs massively invaded the colon and differentiated into proinflammatory CD103( )CX3CR1(int)CD11b(+) DCs, which produced high levels of IL-12, IL-23, iNOS, and TNF. These findings demonstrate the dual capacity of Ly6C(hi) blood MOs to differentiate into either regulatory MPs or inflammatory DCs in the colon and that the balance of these immunologically antagonistic cell types is dictated by microenvironmental conditions. PMID- 22231307 TI - What does epilepsy tell us about the neural correlates of consciousness? AB - Epilepsy and consciousness are intimately related. Epileptic seizures can cause impairment of consciousness, and the study of how this occurs has informed us about the neural mechanisms that underlie normal consciousness. Moreover, loss of consciousness during seizures increases injury risk and worsens health-related quality of life. The present review describes the current understanding of consciousness and its alterations during ictal events, with implications for the clinical management of patients with epilepsy and relevant neuro-philosophical issues. PMID- 22231308 TI - Hashimoto's encephalopathy: systematic review of the literature and an additional case. AB - Hashimoto's encephalopathy, first described in 1966, is still problematic in terms of its pathophysiology, diagnosis, and treatment. The syndrome is more common in women, and is associated with autoimmune antithyroid antibodies. Presentation varies considerably; there may be episodes of cerebral ischemia, seizure, or psychosis, or there may be depression, cognitive decline, and periods of fluctuating consciousness. Because the symptoms respond so well to immunosuppressive treatment, prompt diagnosis and management are important. Here, the authors present a representative case report, along with a comprehensive review of current literature. PMID- 22231305 TI - A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. AB - The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies. PMID- 22231309 TI - Neurocognitive functioning in youth with pediatric autoimmune neuropsychiatric disorders associated with streptococcus. AB - This study evaluated neurocognitive functioning in 26 youth with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and primarily obsessive-compulsive disorder (OCD) symptoms. Marked impairment in visuospatial recall memory (as assessed using the Rey-Osterrieth Complex Figure Test) was observed in spite of average to above-average performance on academic and other neurocognitive measures. Group A beta-hemolytic Streptococcus titer elevations were associated with worse performance on tasks of neurocognitive and executive ability (Stroop Color-Word Interference Test), visuospatial memory, and fine motor speed (finger tapping) as well as elevated obsessive-compulsive symptom severity. PMID- 22231310 TI - Discriminant analysis of Beck Depression Inventory and Hamilton Rating Scale for Depression in Huntington's disease. AB - Depression is common in Huntington's disease, but standard rating scales have doubtful validity in this population. Using data from the European Huntington's Disease REGISTRY study, the authors examined the discriminant value of items on the Beck Depression Inventory (N=843) and the Hamilton Rating Scale for Depression (N=768). Good discriminators of depression, apart from "depressed mood," were "guilt," "loss of interest," and "suicidality." Items that discriminated poorly were "weight loss," "sleep disturbance," "loss of appetite," "psychomotor retardation," "agitation," and "irritability." These findings highlight the limited usefulness of these scales within the area of Huntington's disease. PMID- 22231311 TI - Evidence for involvement of central noradrenergic activity in crying proneness. AB - Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior. PMID- 22231312 TI - Neurological soft signs in OCD patients with early age at onset, versus patients with schizophrenia and healthy subjects. AB - Compelling evidence suggests that both schizophrenia and obsessive compulsive disorder (OCD) are related to deviant neurodevelopment. Neurological soft signs (NSS) have been proposed to be a marker of abnormal brain development in schizophrenia. The purpose of this study is to examine whether NSS are also a marker in patients with OCD, in particular, in early-onset OCD. The authors included 162 subjects and compared patients with OCD, patients with schizophrenia (SCZ), and healthy control subjects. They were all examined for NSS (Krebs' Scale), extrapyramidal symptoms (Simpson-Angus Scale), and were rated on the Abnormal Involuntary Movements Scale (AIMS). The authors found no differences between NSS total scores and subscores in OCD versus controls, whereas total NSS, motor coordination, and motor integration were significantly lower in OCD than in SCZ. OCD patients with early-onset (before age 13) did not differ from those with later-onset OCD. These results support the idea that NSS, as determined by current scales, is relatively specific to schizophrenia, although they do not preclude the existence of a neurological dysfunction in OCD. Further studies are required to determine the type of neurological signs that could be useful trait markers in the phenotypic characterization of subtype OCD. PMID- 22231313 TI - Familial aggregation of panic disturbances in Parkinson's disease. AB - Panic disorder has an elevated prevalence in Parkinson's disease (PD). To explore the basis for this co-occurrence, the familial aggregation of panic disorder was examined in patients with PD. Probands and relatives of patients with PD and panic disorder (PD-PANIC; N=20, N=115) and control probands with PD and no active psychiatric illness (PD-NA; N=17, N=108) were interviewed by phone, using a structured interview to determine panic status. Lifetime prevalence of panic and "panic-like" disorders was higher in PD-PANIC than in PD-NA relatives. Panic and "panic-like" disorders are familial disorders in PD. PMID- 22231314 TI - Psychiatric manifestations of voltage-gated potassium-channel complex autoimmunity. AB - The authors describe the neuropsychiatric spectrum of voltage-gated potassium channel complex (VGKC) autoimmunity among 67 seropositive patients; 2 had initially been assigned a primary psychiatric diagnosis. Diverse manifestations were recorded, often affective-predominant. Symptoms for 24 patients with florid presentations included confusion, 92%; memory impairment, 75%; personality change, 58%; depression, 33%; and anxiety, 29%. Of 15 who received immunotherapy, 67% improved. Forty-three patients with milder presentations or low positive VGKC complex Ab values are also described. Neuropsychiatric presentations were significantly associated with higher autoantibody values. Improvements were most evident in patients treated early, which emphasizes the need for early diagnosis and immunotherapy initiation. PMID- 22231315 TI - Incidence, course, and predictors of apathy in Huntington's disease: a two-year prospective study. AB - This study examined the incidence and course of apathy in subjects with Huntington's disease (HD). Our results showed that at follow-up 14% of the subjects free of apathy at baseline had developed apathy. In these subjects, a lower baseline Mini-Mental State Exam score predicted incidence of apathy. Of the 34 subjects with apathy at baseline, 14 subjects were no longer apathetic at follow-up. Twenty subjects had persistent apathy, with a low baseline Symbol Digits Modalities Test as the only predictor. These results showed that apathy in HD is most closely linked to global and executive cognitive performance. PMID- 22231316 TI - Increase in interleukin-6 levels is related to depressive phenomena in the acute (relapsing) phase of multiple sclerosis. AB - The aim of the present study was to investigate the possible connection between interleukin-6, the acute phase (relapse) of multiple sclerosis (MS), and depression. The authors determined and statistically evaluated the levels of interleukin-6 and its soluble receptor in the serum of 28 MS patients in relapsing, 14 MS patients in remission, and 20 control subjects, as well as the presence of depression among these individuals. The results of our study indicate that depression is not only very common during relapses of MS, but also that the levels of IL-6 increase during the acute phase of the disease, especially when depression is detected. PMID- 22231317 TI - Clock-drawing performance predicts inpatient rehabilitation outcomes after traumatic brain injury. AB - The authors used clock-drawing performance to assess cognition and predict inpatient rehabilitation outcomes among persons with traumatic brain injury. Clock-drawing performance, as assessed with the Clock Drawing Interpretation Scale, predicts rehabilitation length of stay as well as Functional Independence Measure scores at the time of neurobehavioral assessment and rehabilitation discharge. PMID- 22231318 TI - PTSD, attention bias, and heart rate after severe brain injury. AB - Does "partial" posttraumatic stress disorder (PTSD) occur after head injury? The authors found that attention bias to trauma-related threat stimuli and higher heart rate during trauma interview were not associated with PTSD symptom severity in 42 participants with severe head injury. They found no evidence for "partial" PTSD. PMID- 22231323 TI - Psychogenic myasthenia gravis. PMID- 22231319 TI - Disorganized symptoms and executive functioning predict impaired social functioning in subjects at risk for psychosis. AB - Predictors of social functioning deficits were assessed in 22 individuals "at risk" for psychosis. Disorganized symptoms and executive functioning predicted social functioning at follow-up. Early intervention efforts that focus on social and cognitive skills are indicated in this vulnerable population. PMID- 22231324 TI - Rumination syndrome in a patient with Hashimoto's encephalopathy. PMID- 22231325 TI - Obsessive-compulsive disorder after right temporal-lobe hemorrhage. PMID- 22231326 TI - Visual and auditory hallucinations during normal use of paroxetine for treatment of major depressive disorder. PMID- 22231327 TI - Emergence of neuroleptic malignant syndrome while switching between risperidone and paliperidone. PMID- 22231328 TI - Mirtazapine relieves limb paralysis of unknown etiology: a three-year case follow up. PMID- 22231329 TI - Neutropenia during risperidone treatment. PMID- 22231331 TI - Pramipexole-induced peripheral edema in a patient with bipolar depression. PMID- 22231330 TI - Anti-NMDA receptor encephalitis suspected as cause of drug-induced psychosis. PMID- 22231332 TI - Reversible carbamazapine encephalopathy with frontal intermittent rhythmic delta activity. PMID- 22231333 TI - Automatic focal seizure suppression system: an application of optogenetic gene silencing. PMID- 22231334 TI - First-onset psychotic disorder concurrent with a first-onset seizure disorder. PMID- 22231335 TI - Nonconvulsive status epilepticus in schizophrenia: focus on early detection. PMID- 22231336 TI - Acute, non-lethal Marchiafava-Bignami disease with reversible posterior leucoencephalopathy and split-brain syndrome. PMID- 22231337 TI - Jealous delusions and dysfunction of the right parietal lobe in early-onset Alzheimer's disease. PMID- 22231338 TI - Malapropisms, or "the Archie Bunker syndrome," and frontotemporal dementia. PMID- 22231339 TI - Is there really an acute alcohol-related axonal polyneuropathy? PMID- 22231340 TI - Suicide without depression after withdrawal of a dopamine agonist in a patient with Parkinson's disease. PMID- 22231341 TI - Sexual side effects of milnacipran. PMID- 22231342 TI - The role of cerebellar rehabilitation in improvement of ADHD imbalance. PMID- 22231343 TI - Tardive Tourette-like syndrome in a patient treated with paliperidone. PMID- 22231345 TI - Visual hallucinations in Charles Bonnet syndrome can be seen in fluorodeoxyglucose-PET. PMID- 22231344 TI - Opioid withdrawal delirium. PMID- 22231346 TI - Assessing neuropsychiatric disturbances associated with post-stroke aphasia. PMID- 22231347 TI - Falling (or ascending) into oblivion: transient global amnesia with paragliding. PMID- 22231348 TI - Neurosyphilis as a cause of cognitive decline and psychiatric symptoms at younger age. PMID- 22231349 TI - Brain tumor presenting with psychiatric symptoms. PMID- 22231350 TI - Charles Bonnet syndrome-induced psychosis? Visual hallucinations with paranoid delusions in a visually-impaired man. PMID- 22231351 TI - Personality disorder related to an acute orbitofrontal lesion in multiple sclerosis. PMID- 22231352 TI - Brief manic episode after rituximab treatment of limbic encephalitis. PMID- 22231353 TI - Fahr-type calcification and neuropsychiatric symptoms with M-proteinemia. PMID- 22231354 TI - The role of Pbx1 in T cells. AB - Tissue and organ differentiation is tightly controlled to ensure proper development and function of the growing embryo as well as cells such as lymphocytes that differentiate throughout the adult stage. Therefore it is vital that the genes and the protein they encode that are involved in these processes function accurately. Hence, any mutation or error that occurs along the way can result in extensive damage, which is expressed in various ways in the embryo and can result in immune pathogenesis, including immunodeficiency and autoimmune diseases, when lymphocyte development is altered. A number of studies have been carried out to look at the genes regulating transcription in tissue differentiation, including the transcription factors Pbx1. This gene is of particular interest to us as we have identified that it is associated with systemic lupus erythematosus susceptibility (Cuda et al., in press). This perspective summarizes the known roles of Pbx1 in tissue differentiation as well as our recent findings associating genetic variations in Pbx1 to lupus susceptibility, and we will speculate on how this gene controls the maintenance of immune tolerance in T cells. PMID- 22231355 TI - Protein-protein complexation in bioluminescence. AB - In this review we summarize the progress made towards understanding the role of protein-protein interactions in the function of various bioluminescence systems of marine organisms, including bacteria, jellyfish and soft corals, with particular focus on methodology used to detect and characterize these interactions. In some bioluminescence systems, protein-protein interactions involve an "accessory protein" whereby a stored substrate is efficiently delivered to the bioluminescent enzyme luciferase. Other types of complexation mediate energy transfer to an "antenna protein" altering the color and quantum yield of a bioluminescence reaction. Spatial structures of the complexes reveal an important role of electrostatic forces in governing the corresponding weak interactions and define the nature of the interaction surfaces. The most reliable structural model is available for the protein-protein complex of the Ca(2+) regulated photoprotein clytin and green-fluorescent protein (GFP) from the jellyfish Clytia gregaria, solved by means of Xray crystallography, NMR mapping and molecular docking. This provides an example of the potential strategies in studying the transient complexes involved in bioluminescence. It is emphasized that structural studies such as these can provide valuable insight into the detailed mechanism of bioluminescence. PMID- 22231357 TI - Structural vaccinology: structure-based design of influenza A virus hemagglutinin subtype-specific subunit vaccines. AB - There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs. The main component of the current split influenza A virus vaccine is viral hemagglutinin (HA) which induces a strong antibody-mediated immune response. To develop a modern vaccine against influenza A viruses, the current research has been focused on the universal vaccines targeting viral M2, NP and HA proteins. Crystallographic studies have shown that HA forms a trimer embedded on the viral envelope surface, and each monomer consists of a globular head (HA1) and a "rod-like" stalk region (HA2), the latter being more conserved among different HA subtypes and being the primary target for universal vaccines. In this study, we rationally designed the HA head based on the crystal structure of the 2009-pandemic influenza A (H1N1) virus HA as a model, tested its immunogenicity in mice, solved its crystal structure and further examined its immunological characteristics. The results show that the HA globular head can be easily prepared by in vitro refolding in an E. coli expression system, which maintains its intact structure and allows for the stimulation of a strong immune response. Together with recent reports on some similar HA globular head preparations we conclude that structure-based rational design of the HA globular head can be used for subtype-specific vaccines against influenza viruses. PMID- 22231356 TI - Gene therapy: light is finally in the tunnel. AB - After two decades of ups and downs, gene therapy has recently achieved a milestone in treating patients with Leber's congenital amaurosis (LCA). LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy. Mutations in several genes, including RPE65, cause the disease. Using adeno-associated virus as a vector, three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects. However, considering the whole field of gene therapy, there are still major obstacles to clinical applications for other diseases. These obstacles include innate and immune barriers to vector delivery, toxicity of vectors and the lack of sustained therapeutic gene expression. Therefore, new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy. In this article, we shall review the major advancements over the past two decades and, using lung gene therapy as an example, discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research. PMID- 22231359 TI - Developing an algorithm for pulse oximetry derived respiratory rate (RR(oxi)): a healthy volunteer study. AB - OBJECTIVE: The presence of respiratory information within the pulse oximeter signal (PPG) is a well-documented phenomenon. However, extracting this information for the purpose of continuously monitoring respiratory rate requires: (1) the recognition of the multi-faceted manifestations of respiratory modulation components within the PPG and the complex interactions among them; (2) the implementation of appropriate advanced signal processing techniques to take full advantage of this information; and (3) the post-processing infrastructure to deliver a clinically useful reported respiratory rate to the end user. A holistic algorithmic approach to the problem is therefore required. We have developed the RR(OXI) algorithm based on this principle and its performance on healthy subject trial data is described herein. METHODS: Finger PPGs were collected from a cohort of 139 healthy adult volunteers monitored during free breathing over an 8-min period. These were subsequently processed using a novel in-house algorithm based on continuous wavelet transform technology within an infrastructure incorporating weighted averaging and logical decision making processes. The computed oximeter respiratory rates (RR(oxi)) were then compared to an end-tidal CO2 reference rate RR(ETCO2). RESULTS: RR(ETCO2) ranged from a lowest recorded value of 2.97 breaths per min (br/min) to a highest value of 28.02 br/min. The mean rate was 14.49 br/min with standard deviation of 4.36 br/min. Excellent agreement was found between RR(oxi) and RR(ETCO2), with a mean difference of -0.23 br/min and standard deviation of 1.14 br/min. The two measures are tightly spread around the line of agreement with a strong correlation observable between them (R2 = 0.93). CONCLUSIONS: These data indicate that RR(oxi) represents a viable technology for the measurement of respiratory rate of healthy individuals. PMID- 22231358 TI - Engineering a zinc binding site into the de novo designed protein DS119 with a betaalphabeta structure. AB - Functional proteins designed de novo have potential application in chemical engineering, agriculture and healthcare. Metal binding sites are commonly used to incorporate functions. Based on a de novo designed protein DS119 with a betaalphabeta structure, we have computationally engineered zinc binding sites into it using a home-made searching program. Seven out of the eight designed sequences tested were shown to bind Zn(2+) with micromolar affinity, and one of them bound Zn(2+) with 1:1 stoichiometry. This is the first time that metalloproteins with an alpha, beta mixed structure have been designed from scratch. PMID- 22231370 TI - Toxicology of isoproturon to the food crop wheat as affected by salicylic acid. AB - PURPOSE: Isoproturon, a herbicide belonging to the phenylurea family, is widely used to kill weeds in soils. Recent study indicated that isoproturon has become a contaminant in ecosystems due to its intensive use, thus bringing environmental risks to crop production safety. Salicylic acid (SA) is one of the components in plant defense signaling pathways and regulates diverse physiological responses to biotic and environmental stresses. The purpose of the study is to help to understand how SA mediates the biological process in wheat under isoproturon stress. METHODS: Wheat seeds (Triticum aestivum, cv. Yangmai 13) were surface sterilized and placed on moist filter paper for germination. After 24 h, the germinating seeds were placed on a plastic pot (1 L) containing 1,120 g soil mixed with isoproturon at 4 mg kg(-1) soil. After 4 days, wheat leaves were sprayed with 5 mg L(-1) SA. The SA treatment was undertaken once a day and lasted for 6 days, when the third true leaf was well developed. For control seedlings, only water was sprayed. Seedlings were grown under a light intensity of 300 umol m(-2) s(-1) with a light/dark cycle of 12/12 h at 25 degrees C, and watered to keep 70% relative water content in soils. RESULTS AND DISCUSSION: We investigated the role of SA in alleviating isoproturon-induced toxicity in the food crop wheat (T. aestivum). Plants exposed to 4 mg kg(-1) isoproturon showed growth stunt and oxidative damage, but concomitant treatment with 5 mg L(-1) SA was able to attenuate the toxic effect. Isoproturon in soils was readily accumulated by wheat, but such accumulation can be blocked significantly by SA application. Treatment with SA decreased the abundance of O(2) (.-) and H(2)O(2), as well as activities of antioxidant enzymes, and increased activities of catalase in isoproturon-exposed plants. The enzyme activities were confirmed by the native polyacrylamide gel electrophoresis. Further, an RT-PCR-based assay was performed to show that several transcripts coding antioxidant enzymes were increased with isoproturon but decreased by SA. CONCLUSION: The present results indicate that exogenous SA is able to improve the wheat tolerance to isoproturon toxicity. PMID- 22231371 TI - Radiative effects of aerosols over Indo-Gangetic plain: environmental (urban vs. rural) and seasonal variations. AB - Aerosol radiative effects over two environmentally distinct locations, Kanpur (urban site) and Gandhi College (rural location) in the Indo-Gangetic plain (IGP), a regional aerosol hot spot, utilizing the measured optical and physical characteristics of aerosols, an aerosol optical properties model and a radiative transfer model, are examined. Shortwave aerosol radiative forcing (ARF) at the top of the atmosphere (TOA) is < -12 W m( - 2) over Kanpur and Gandhi College. ARF at the surface is >= -30 W m( - 2). Atmospheric warming is maximum during premonsoon (>30 W m( - 2)). Shortwave atmospheric heating due to aerosols is >0.4 K/day over IGP and peaks during premonsoon at >0.6 K/day due to lower single scattering albedo (SSA) and higher surface albedo. TOA forcing is always less negative over Kanpur when compared to Gandhi College due to lower surface albedo except in postmonsoon owing to higher SSA. This happens as TOA forcing depends on SSA and surface albedo in addition to aerosol optical depth. The magnitude of longwave forcing and atmospheric cooling in an absolute sense is significantly small and contributes only about 20% or less to the net (shortwave + longwave) forcing. Aerosol radiative effects over these two locations, despite differences in aerosol characteristics, are similar, thus confirming that aerosols and their radiative influence get transported due to circulation. ARF over Kanpur and Gandhi College is an order of magnitude higher when compared to greenhouse gas forcing. A large reduction in surface reaching solar irradiance accompanied by large atmospheric warming can have implications on precipitation and hydrological cycle, and these aerosol radiative effects should be included while performing regional-scale aerosol climate assessments. PMID- 22231372 TI - Cellular and molecular damage of Phanerochaete chrysosporium by the oxidation hair dyes. AB - INTRODUCTION: The toxic effect of the oxidation hair dyes on Phanerochaete chrysosporium was investigated by exposure of this fungus in a nitrogen-limited culture medium to various concentrations of the oxidation hair dyes. RESULTS: The results showed that both the size and the dry weight of the mycelial pellets of P. chrysosporium could be reduced when the concentration of the oxidation hair dyes was higher than 300 mg/L. By using the AFLP analysis and the UPGMA dendrogram, the DNA damage of P. chrysosporium by the oxidation hair dyes was also detected. Comparing with that in the control, the percent polymorphism under different concentrations of the oxidation hair dyes increased. In the meantime, the DNA similarity was decreased, which meant that the DNA damage was aggravated with an increase in the concentrations of the oxidation hair dyes. CONCLUSION: Thus, as an environmental pollutant, the oxidation hair dyes have a toxic effect on P. chrysosporium at both cellular and molecular levels. PMID- 22231373 TI - Standardizing the double-observer survey method for estimating mountain ungulate prey of the endangered snow leopard. AB - Mountain ungulates around the world have been threatened by illegal hunting, habitat modification, increased livestock grazing, disease and development. Mountain ungulates play an important functional role in grasslands as primary consumers and as prey for wild carnivores, and monitoring of their populations is important for conservation purposes. However, most of the several currently available methods of estimating wild ungulate abundance are either difficult to implement or too expensive for mountainous terrain. A rigorous method of sampling ungulate abundance in mountainous areas that can allow for some measure of sampling error is therefore much needed. To this end, we used a combination of field data and computer simulations to test the critical assumptions associated with double-observer technique based on capture-recapture theory. The technique was modified and adapted to estimate the populations of bharal (Pseudois nayaur) and ibex (Capra sibirica) at five different sites. Conducting the two double observer surveys simultaneously led to underestimation of the population by 15%. We therefore recommend separating the surveys in space or time. The overall detection probability for the two observers was 0.74 and 0.79. Our surveys estimated mountain ungulate populations (+/- 95% confidence interval) of 735 (+/- 44), 580 (+/- 46), 509 (+/- 53), 184 (+/- 40) and 30 (+/- 14) individuals at the five sites, respectively. A detection probability of 0.75 was found to be sufficient to detect a change of 20% in populations of >420 individuals. Based on these results, we believe that this method is sufficiently precise for scientific and conservation purposes and therefore recommend the use of the double-observer approach (with the two surveys separated in time or space) for the estimation and monitoring of mountain ungulate populations. PMID- 22231374 TI - Testing the directed dispersal hypothesis: are native ant mounds (Formica sp.) favorable microhabitats for an invasive plant? AB - Ant-mediated seed dispersal may be a form of directed dispersal if collected seeds are placed in a favorable microhabitat (e.g., in or near an ant nest) that increases plant establishment, growth, and/or reproduction relative to random locations. We investigated whether the native ant community interacts with invasive leafy spurge (Euphorbia esula) in a manner consistent with predictions of the directed dispersal hypothesis. Resident ants quickly located and dispersed 60% of experimentally offered E. esula seeds. Additionally, 40% of seeds whose final deposition site was observed were either brought inside or placed on top of an ant nest. Seed removal was 100% when seeds were placed experimentally on foraging trails of mound-building Formica obscuripes, although the deposition site of these seeds is unknown. Natural density and above-ground biomass of E. esula were greater on Formica mound edges compared to random locations. However, seedling recruitment and establishment from experimentally planted E. esula seeds was not greater on mound edges than random locations 3 m from the mound. Soil from Formica mound edges was greater in available nitrogen and available phosphorus relative to random soil locations 3 m from the mound. These results suggest Formica ant mounds are favorable microhabitats for E. esula growth following seedling establishment, a likely consequence of nutrient limitation during plant growth. The results also indicate positive species interactions may play an important role in biological invasions. PMID- 22231375 TI - Complex knee ligament surgery: editorial comment. PMID- 22231376 TI - Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial. AB - PURPOSE: As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p 4E-BP1) or S6, two downstream markers of mTOR activity. METHODS: 32 patients (pts) were dosed intravenously with ridaforolimus once daily for 5 consecutive days (QD * 5) every 2 weeks. The pharmacodynamic activity of ridaforolimus was assessed in peripheral blood mononuclear cells (PBMCs; 32 pts), skin (28 pts), and tumor specimens (3 pts) collected before and after dosing by measuring levels of p-4E-BP1 by immunoblot analysis or pS6 by immunohistochemistry. Levels of these markers were assessed in up to 19, 5, and 2 pre- and post-dose time points in PBMC, skin, and tumor specimens, respectively. RESULTS: In preclinical models, ridaforolimus induced a dose-dependent inhibition of p-4E-BP1 in PBMCs that was associated with antitumor activity. Rapid and potent inhibition of mTOR was observed in PBMCs from all 32 pts dosed, with a median level of inhibition of 96% observed within 1 h after the first dose. Inhibition of mTOR (>90%) was sustained during the entire QD * 5 dosing period, and substantial inhibition was still observed after the 9-day holiday between dosing courses. Evidence of mTOR inhibition was also obtained in skin in pts from all dose cohorts, although it did not persist through the break between courses. After two to three doses of ridaforolimus, inhibition of mTOR was detected in the tumor from one of three pts analyzed. CONCLUSIONS: Ridaforolimus was shown to inhibit its intended target, mTOR, in PBMCs, skin, and tumors. In PBMCs and skin, inhibition was observed at all dose levels tested, thus supporting but not driving the selection of a recommended phase 2 dose. PMID- 22231378 TI - Yeast complementation is sufficiently sensitive to detect the residual activity of ASL alleles associated with mild forms of argininosuccinic aciduria. PMID- 22231379 TI - Intellectual and neurological functioning in Morquio syndrome (MPS IVa). AB - Mucopolysaccharidosis type IVa (MPS IVa, Morquio syndrome OMIM #253000) is a lysosomal storage disease caused by deficiency in N-acetylgalactosamine-6 sulfatase (GALNS, EC 3.1.6.4; encoded by GALNS gene at 16q24.3). Unlike other MPS disorders involving excessive heparan and dermatan sulfate, Morquio syndrome has not been associated with neurological involvement nor with intellectual impairment as this disorder of keratan sulfate has been described as a purely visceral and skeletal disorder. Neurocognitive assessment was undertaken of MPS IVa patients with age appropriate intellectual tests as well as a Child Behaviour Checklist as part of clinical follow up. Available neuroimaging studies (MRI and MR spectroscopy) were reviewed. Whilst more than half of the overall IQ scores fell in the average range, scores for 3/8 children fell below average. A number of behavioural problems were highlighted, including anxiety/depression, attention and somatic complaints. Subtle neuroimaging abnormalities were demonstrated in over half of the children. These findings present a challenge to existing assumptions about the nature of Morquio A syndrome. A hypothesis regarding the potential role of calcium signalling is explored. PMID- 22231377 TI - Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities. PMID- 22231381 TI - Newborn screening for lysosomal diseases: current status and potential interface with population medical genetics in Latin America. AB - The aim of newborn screening (NBS) programs is to detect a condition in a presymptomatic baby and provide management measures which could significantly improve the natural history of the disease. NBS programs for metabolic diseases were first introduced in North America and Europe and in the 1960s for phenylketonuria, expanded a few years later to include congenital hypothyroidism, and have been growing steadily in terms of number of conditions tested for and number of countries and births covered. Lysosomal storage diseases (LSDs) are a group of around 50 genetic conditions in which a defect in a lysosomal function occurs. LSDs are progressive conditions, being usually asymptomatic at birth, but with clinical features becoming apparent in childhood, with severe manifestations in most instances, high morbidity and shortened life span. Although individually rare, the prevalence of LSDs is significant when the group is considered as a whole (around 1:4,000-1:9,000 live births). Several management techniques, including bone marrow transplantation, enzyme replacement therapy, substrate inhibition therapy, pharmacological chaperones and many other approaches are transforming the LSDs into treatable conditions. However, lack of awareness and lack of access to tests cause a significant delay between onset of symptoms and diagnosis. Several lines of evidence showing that the earlier introduction of therapy may provide a better outcome, are bringing support to the idea of including LSDs in NBS programs. Due to advances in technology, high-throughput multiplex methods are now available for mass screening of several LSDs. Pilot projects were already developed in many countries for some LSDs, with interesting results. Although some NBS in Latin America has been carried out since the 1970s, it has so far been incorporated as a public health program in only a few countries in the region. It will probably take many years before NBS is implemented in most Latin American countries with a comprehensive coverage in terms of number of diseases and number of births. Population medical genetics is the area of medical genetics that aims at the study and medical care of the population, and not of the family, which is the case for clinical or medical genetics itself. It combines different aspects of genetics: clinical genetics; human population genetics, which investigates populations according to micro evolutionary parameters; epidemiological genetics, traditionally involved in the study of common chronic diseases of polygenic etiology, except for Mendelian diseases; and sanitary or community genetics, which stands at the interface with public health, giving support to preventive health measures. Taking into account that several LSDs were identified in a higher frequency in selected areas and/or populations, the population medical genetics approach could help to introduce the NBS for LSDs in the region, with identification of areas with higher risk for selected diseases and design of customized screening program to address specific needs. As an example of the potential of this approach, a pilot program of NBS for MPS VI was implemented in a community from North East Brazil where 13 cases of MPS VI were identified in an area with 50,000 inhabitants. This program, which will enable not only identification and early treatment of affected newborns but also carrier detection, and which would allow genetic counseling for at-risk couples, could be an alternative model for a customized NBS of LSDs to be carried out in selected regions. PMID- 22231380 TI - Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). AB - Riboflavin and ubiquinone (Coenzyme Q(10), CoQ(10)) deficiencies are heterogeneous groups of autosomal recessive conditions affecting both children and adults. Riboflavin (vitamin B(2))-derived cofactors are essential for the function of numerous dehydrogenases. Genetic defects of the riboflavin transport have been detected in Brown-Vialetto-Van Laere and Fazio-Londe syndromes (C20orf54), and haploinsufficiency of GPR172B has been proposed in one patient to cause persistent riboflavin deficiency. Mutations in the electron tranferring fravoprotein genes (ETFA/ETFB) and its dehydrogenase (ETFDH) are causative for multiple acyl-CoA dehydrogenase deficiency. Mutations in ACAD9, encoding the acyl CoA dehydrogenase 9 protein were recently reported in mitochondrial disease with respiratory chain complex I deficiency. All these conditions may respond to riboflavin therapy. CoQ(10) is a lipid-soluble component of the cell membranes, where it functions as a mobile electron and proton carrier, but also participates in other cellular processes as a potent antioxidant, and by influencing pyrimidine metabolism. The increasing number of molecular defects in enzymes of the CoQ(10) biosynthetic pathways (PDSS1, PDSS2, COQ2, COQ6, COQ9, CABC1/ADCK3) underlies the importance of these conditions. The clinical heterogeneity may reflect blocks at different levels in the complex biosynthetic pathway. Despite the identification of several primary CoQ(10) deficiency genes, the number of reported patients is still low, and no true genotype-phenotype correlations are known which makes the genetic diagnosis still difficult. Additionally to primary CoQ(10) deficiencies, where the mutation impairs a protein directly involved in CoQ(10) biosynthesis, we can differentiate secondary deficiencies. CoQ(10) supplementation may be beneficial in both primary and secondary deficiencies and therefore the early recognition of these diseases is of utmost importance. PMID- 22231382 TI - Heterozygosity for an in-frame deletion causes glutaryl-CoA dehydrogenase deficiency in a patient detected by newborn screening: investigation of the effect of the mutant allele. AB - A patient with suspected glutaric aciduria type 1 (GA-1) was detected by newborn screening. GA-1 is known as an autosomal recessively inherited disease due to defects in the gene coding for glutaryl-CoA dehydrogenase (GCDH), a mitochondrial enzyme involved in the catabolism of the amino acids hydroxylysine, lysine and tryptophan. DNA and cDNA sequencing revealed a 18 bp deletion (c.553_570del18) resulting in deletion of six amino acids (p.Gly185_Ser190del) in one allele and no sequence changes in the other allele. Confirmatory biochemical analysis of blood, urine and cultured fibroblasts from the proband were consistent with a mild biochemical GA-1 phenotype. Recombinant expression of the mutant variant in E. coli showed that the GCDH-(p.Gly185_Ser190del) protein displayed severely decreased assembly into tetramers and enzyme activity. To discover a potential dominant negative effect of the mutant protein, we engineered a prokaryotic expression system in which expression of a wild type and a mutant GCDH allele is controlled by separately inducible promoters. These cells displayed decreased levels of GCDH tetramer and enzyme activity when expressing both the wild type and the mutant GCDH variant protein compared to the situation when only the wild type allele was expressed. Further experiments suggest that the major impact of the GCDH-(p.Gly185_Ser190del) protein in heterozygous cells consists of hampering the assembly of wild type GCDH into tetramers. Our experimental data are consistent with the hypothesis that heterozygosity for this mutation confers a dominant negative effect resulting in a GCDH enzyme activity that is significantly lower than the expected 50%. PMID- 22231383 TI - Endothelial function in children and adolescents with mucopolysaccharidosis. AB - BACKGROUND: Although coronary artery pathology is a prominent feature of mucopolysaccharidosis (MPS), it may be underestimated by coronary angiography because of its diffuse nature. It is also generally assumed that cardiovascular risk is increased in MPS and reduced following hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT), but this has never been formally evaluated. Non-invasive methods of assessing vascular endothelial function may provide a measure of cardiovascular risk in MPS. We evaluated endothelial function, using digital reactive hyperemia, in youth with MPS and in healthy controls. METHODS: Digital reactive hyperemic index (RHI) was measured in 12 children and adolescents (age 10.3 +/- 3.9 years old; 11 boys) with treated MPS and nine age- and gender-matched (11.4 +/- 4.0; 8 boys) healthy controls. An independent t-test was used to compare RHI between individuals with MPS and controls. RESULTS: Children and adolescents with MPS (MPS type II: N = 5; type I: N = 4; type VI: N = 3) whether treated by HSCT (N = 4) or ERT (N = 8) had significantly lower RHI compared to controls (MPS 1.22 +/- 0.19 vs. controls 1.46 +/- 0.32, p < 0.05). CONCLUSION: These preliminary findings suggest that children and adolescents with treated MPS have significantly poorer endothelial function when compared to healthy controls. Further investigation into the utility of endothelial function for risk stratification and the long term implications of reduced endothelial function in MPS is warranted. PMID- 22231384 TI - Decreased functional brain connectivity in individuals with early-treated phenylketonuria: evidence from resting state fMRI. AB - Previous histological and neuroimaging studies have documented structural abnormalities in the white matter of the brain in individuals with early-treated phenylketonuria (ETPKU). It remains unclear, however, the extent to which the function of the brain's interconnections are impacted by this condition. Presently, we utilized functional magnetic resonance imaging (fMRI) to evaluate the synchronization of neural signals (i.e., functional connectivity) among brain regions comprising the default mode network (DMN) in a sample of 11 individuals with ETPKU and 11 age- and gender-matched neurologically intact controls. The DMN is a group of interconnected brain regions that are known to be generally more active during rest than during task performance. Data analysis revealed decreased functional connectivity among DMN regions for the ETPKU group compared with the control group. Within the PKU group, we also found a significant relationship between blood phenylalanine (phe) levels and the functional connectivity between select regions of the DMN. In conjunction with findings from another recent fMRI study (Christ, Moffitt et al. 2010), the present results suggest that ETPKU related deficiencies in functional connectivity are pervasive. The current findings also provide initial evidence that the extent of such impairment may be moderated in part by blood phe levels. PMID- 22231385 TI - Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. AB - INTRODUCTION: Mitochondrial disorders (MD) may manifest in neonates, but early diagnosis is difficult. In this study, clinical and laboratory data were analyzed in 129 patients with neonatal onset of MD to identify any association between specific mitochondrial diseases and their symptoms with the aim of optimizing diagnosis. MATERIALS AND METHODS: Retrospective clinical and laboratory data were evaluated in 461 patients (331 families) with confirmed MD. RESULTS: The neonatal onset of MD was reported in 28% of the patients. Prematurity, intrauterine growth retardation and hypotonia necessitating ventilatory support were present in one third, cardiomyopathy in 40%, neonatal seizures in 16%, Leigh syndrome in 15%, and elevated lactate level in 87%. Hyperammonemia was observed in 22 out of 52 neonates. Complex I deficiency was identified in 15, complex III in one, complex IV in 23, complex V in 31, combined deficiency of several complexes in 53, and PDH complex deficiency was identified in six patients. Molecular diagnosis was confirmed in 49 cases, including a newborn with a 9134A>G mutation in the MTATP6 gene, which has not been described previously. CONCLUSION: The most significant finding is the high incidence of neonatal cardiomyopathy and hyperammonemia. Based on our experience, we propose a diagnostic flowchart applicable to critically ill neonates suspicious for MD. This tool will allow for the use of direct molecular genetic analyses without the need for muscle biopsies in neonates with Alpers, Barth, MILS and Pearson syndromes, SCO1, SCO2, TMEM70, ATP5E, SUCLG1 gene mutations and PDH complex deficiency. PMID- 22231388 TI - Delayed gastric emptying determined using the 13C-octanoic acid breath test in patients with systemic sclerosis. AB - OBJECTIVE: To determine the prevalence of delayed gastric emptying using the 13C octanoic acid breath test in unselected patients with systemic sclerosis (SSc), to evaluate whether findings of the 13C-octanoic acid breath test are associated with clinical digestive manifestations, gastric mucosal abnormalities detected by gastroscopy, motor activity dysfunction detected by antroduodenal manometry, and esophageal motor impairment and extradigestive manifestations of SSc, and to develop a risk prediction score of gastric emptying in SSc. METHODS: Consecutive patients with SSc (n=57) underwent the 13C-octanoic acid breath test. All of the patients with SSc completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated. RESULTS: The prevalence of delayed gastric emptying was 47.4% in patients with SSc. A marked correlation was observed between a GSS of digestive symptoms>=5 and the presence of delayed gastric emptying (P<0.00001). The sensitivity of a GSS>=5 for predicting delayed gastric emptying was as high as 0.93, while the specificity was 0.73. Moreover, a GSS>=5, mucosal gastric abnormalities, severe esophageal motor impairment, and interstitial lung disease were factors that were independently associated with the presence of delayed gastric emptying, and these variables were used to create a risk prediction score. The area under the receiver operating characteristic curve for the risk prediction score was 0.90; the sensitivity of this score for the prediction of delayed gastric emptying was 0.93, while the specificity was 0.77. CONCLUSION: The results indicate that delayed gastric emptying occurs often in patients with SSc. Interestingly, using risk models with routine clinical characteristics, a simple risk prediction score can be calculated, allowing prediction of the occurrence of delayed gastric emptying in patients with SSc. PMID- 22231386 TI - Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. AB - Hyperinsulinaemic hypoglycaemia (HH) is due to the unregulated secretion of insulin from pancreatic beta-cells. A rapid diagnosis and appropriate management of these patients is essential to prevent the potentially associated complications like epilepsy, cerebral palsy and neurological impairment. The molecular basis of HH involves defects in key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) which regulate insulin secretion. The most severe forms of HH are due to loss of function mutations in ABCC8/KCNJ11 which encode the SUR1 and KIR6.2 components respectively of the pancreatic beta-cell K(ATP) channel. At a histological level there are two major forms (diffuse and focal) each with a different genetic aetiology. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The focal form can now be accurately localised pre-operatively using a specialised positron emission tomography scan with the isotope Fluroine-18L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET). Focal lesionectomy can provide cure from the hypoglycaemia. However the diffuse form is managed medically or by near total pancreatectomy (with high risk of diabetes mellitus). Recent advances in molecular genetics, imaging with 18F-DOPA-PET/CT and novel surgical techniques have changed the clinical approach to patients with HH. PMID- 22231389 TI - Al2O3(1120) surface as a template for the ordered growth of Ni and Co nanoclusters. AB - The morphology and thermal stability of Ni and Co nanoclusters grown by physical vapour deposition on a reconstructed (1120) surface of alpha-Al(2)O(3) is investigated using non-contact atomic force microscopy (NC-AFM). NC-AFM images reveal that the clean alpha-Al(2)O(3)(1120) substrate adopts a characteristic (12 * 4) reconstruction when prepared in vacuum at high temperature. Subsequent deposition of Ni and Co onto this substrate at room temperature facilitates the growth of well-ordered metal nanocluster arrays with a preferred inter-cluster distance determined by the (12 * 4) periodicity of the substrate surface. The order in the cluster arrangement remains intact even upon annealing the system to temperatures up to 500 degrees C indicating a high resistance against sintering. The reconstructed alpha-Al(2)O(3)(1120) surface can, therefore, serve as an appropriate insulating template for studies of size-dependent magnetic or catalytic effects in a well-defined ensemble of metallic nanoclusters. PMID- 22231391 TI - Radiosensitization induced by the anti-epidermal growth factor receptor monoclonal antibodies cetuximab and nimotuzumab in A431 cells. AB - Epidermal growth factor receptors (EGFR) are overexpressed in a wide range of malignancies including head and neck, colon, and breast cancers. It has been identified that carcinomas with high expression levels of EGFR are more resistant to radiotherapy. Therefore, inhibiting nuclear translocation of EGFR to increase the radiosensitivity of malignant cells expressing EGFR offers the potential for increasing the therapeutic index of radiotherapy. The purpose of the present study was to quantify and to compare the radiosensitizing properties of the well known anti-EGFR antibodies, cetuximab and nimotuzumab in human epidermoid A431 overexpressing EGFR cells. Cells were treated with two concentrations of the antibodies and then irradiated with a single dose of 4 Gy. The results indicated that the two antibodies induced radiosensitization increasing the percentage of dead/dying cells and the yield of gamma-H2AX foci 24 h after irradiation. Whereas cetuximab exhibited a significant increase in radiosensitization at the highest concentration, the effects of nimotuzumab were more modest. A correlation between gamma-H2AX foci signals and dead/dying cells was observed. The disparity in modulation of radiation-induced DNA damage by the two antibodies could be associated with the level of their respective intrinsic cytotoxic properties. Overall, the findings highlight the potential therapeutic benefit of combination therapy with anti-EGFR antibodies and radiotherapy for relevant carcinomas. PMID- 22231390 TI - Identification of mammary epithelial cells subject to chronic oxidative stress in mammary epithelium of young women and teenagers living in USA: implication for breast carcinogenesis. AB - Current knowledge of changes in the mammary epithelium relevant to breast carcinogenesis is limited to when histological changes are already present because of a lack of biomarkers needed to identify where such molecular changes might be ongoing at earlier during the of decades-long latent stages of breast carcinogenesis. Breast reduction tissues from young women and teenagers, representative of USA's high breast cancer incidence population, were studies using immunocytochemistry and targeted PCR arrays in order to learn whether a marker of chronic oxidative-stress [protein adducts of 4-hydroxy-2-nonenal (4HNE)] can identify where molecular changes relevant to carcinogenesis might be taking place prior to any histological changes. 4HNE-immunopositive (4HNE+) mammary epithelial cell-clusters were identified in breast tissue sections from most women and from many teenagers (ages 14-30 y) and, in tissues from women ages 17-27 y with many vs. few 4HNE+ cells, the expression of 30 of 84 oxidative stress associated genes was decreased and only one was increased > 2-fold. This is in contrast to increased expression of many of these genes known to be elicited by acute oxidative-stress. The findings validate using 4HNE-adducts to identify where molecular changes of potential relevance to carcinogenesis are taking place in histologically normal mammary epithelium and highlight differences between responses to acute vs. chronic oxidative-stress. We posit that the altered gene expression in 4HNE+ tissues reflect adaptive responses to chronic oxidative-stress that enable some cells to evade mechanisms that have evolved to prevent propagation of cells with oxidatively-damaged DNA and to accrue heritable changes needed to establish a cancer. PMID- 22231392 TI - Towards mesostructured zinc imidazolate frameworks. AB - The transfer of supramolecular templating to the realm of metal-organic frameworks opens up new avenues to the design of novel hierarchically structured materials. We demonstrate the first synthesis of mesostructured zinc imidazolates in the presence of the cationic surfactant cetyltrimethylammonium bromide (CTAB), which acts as a template giving rise to ordered lamellar hybrid materials. A high degree of order spanning the atomic and mesoscale was ascertained by powder X-ray diffraction, electron diffraction, as well as solid-state NMR and IR spectroscopy. The metrics of the unit cells obtained for the zinc methylimidazolate and imidazolate species are a=(11.43+/-0.45), b=(9.55+/-0.35), c=(27.19+/-0.34) A, and a=(10.98+/-0.90), b=(8.95+/-0.95), c=(26.33+/-0.34) A, respectively, assuming orthorhombic symmetry. The derived structure model is consistent with a mesolamellar structure composed of bromine-terminated zinc (methyl)imidazolate chains interleaved with motionally rigid cationic surfactant molecules in an all-trans conformation. The hybrid materials exhibit unusually high thermal stability up to 300 degrees C, at which point CTAB is lost and evidence for a thermally induced transformation into poorly crystalline mesostructures with larger feature sizes is obtained. Treatment with ethanol effects the extraction of CTAB from the material, followed by facile transformation into pure microporous ZIF-8 nanoparticles within minutes, thus demonstrating a unique transition from a mesostructure into a microporous zinc imidazolate. PMID- 22231393 TI - A new and convenient approach for the preparation of beta-cyanoethyl protected trinucleotide phosphoramidites. AB - Herein we report a convenient approach for the preparation of fully protected trinucleotide synthons to be used for the synthesis of gene libraries. The trinucleotide synthons bear beta-cyanoethyl groups at the phosphate residues, and thus can be used in standard oligonucleotide synthesis without additional steps for deprotection and work-up. PMID- 22231394 TI - Novel agents inhibit human leukemic cells. PMID- 22231395 TI - Plumbagin inhibits cell growth and potentiates apoptosis in human gastric cancer cells in vitro through the NF-kappaB signaling pathway. AB - AIM: To investigate the effects and underlying mechanisms of plumbagin, a naphthoquinone derived from medicinal plant Plumbago zeylanica, on human gastric cancer (GC) cells. METHODS: Human gastric cancer cell lines SGC-7901, MKN-28, and AGS were used. The cell viability was examined using CCK-8 viability assay. Cell proliferation rate was determined using both clonogenic assay and EdU incorporation assay. Apoptosis was detected via Annexin V/propidium iodide double labeled flow cytometry. Western blotting was used to assess the expression of both NF-kappaB-regulated gene products and TNF-alpha-induced activation of p65, IkappaBalpha, and IKK. The intracellular location of NF-kappaB p65 was detected using confocal microscopy. RESULTS: Plumbagin (2.5-40 MUmol/L) concentration dependently reduced the viability of the GC cells. The IC(50) value of plumbagin in SGC-7901, MKN-28, and AGS cells was 19.12, 13.64, and 10.12 MUmol/L, respectively. The compound (5-20 MUmol/L) concentration-dependently induced apoptosis of SGC-7901 cells, and potentiated the sensitivity of SGC-7901 cells to chemotherapeutic agents TNF-alphaand cisplatin. The compound (10 MUmol/L) downregulated the expression of NF-kappaB-regulated gene products, including IAP1, XIAP, Bcl-2, Bcl-xL, tumor factor (TF), and VEGF. In addition to inhibition of NF-kappaB p65 nuclear translocation, the compound also suppressed TNF-alpha induced phosphorylation of p65 and IKK, and the degradation of IkappaBalpha. CONCLUSION: Plumbagin inhibits cell growth and potentiates apoptosis in human GC cells through the NF-kappaB pathway. PMID- 22231396 TI - Novel targeted therapy for acute myeloid leukemia with a dual FLT3 and JAK2 inhibitor. PMID- 22231397 TI - Thiazolidione derivatives targeting the histidine kinase YycG are effective against both planktonic and biofilm-associated Staphylococcus epidermidis. AB - AIM: To evaluate the efficacies of six derivatives of Compound 2, a novel YycG histidine kinase inhibitor with the thiazolidione core structure in the treatment of medical device-related biofilm infections. METHODS: The minimal inhibitory concentration (MIC) of the derivatives was determined using the macrodilution broth method, and the minimal bactericidal concentration (MBC) was obtained via sub-culturing 100 MUL from each negative tube from the MIC assay onto drug-free Mueller-Hinton agar plates. Biofilm-killing effect for immature (6 h-old) biofilms was examined using a semiquantitative plate assay, and the effect on mature (24 h-old) biofilms was observed under a confocal laser scanning microscope (CLSM). RESULTS: The derivatives potently suppressed the growth of Staphylococcus epidermidis. The MIC values of the derivatives H2-10, H2-12, H2 20, H2-29, H2-27, and H2-28 on S epidermidis ATCC 35984 were 24.3, 6.5, 6.2, 3.3, 3.1, and 1.5 MUg/mL, respectively. The MBC values of these derivatives were 48.6, 52.2, 12.4, 52.6, 12.4, and 6.2 MUg/mL, respectively. The derivatives killed all bacteria in immature (6 h-old) biofilms and eliminated the biofilm proliferation. The derivatives also displayed strong bactericidal activities toward cells in mature (24 h-old) biofilms, whereas they showed low cytotoxicity and hemolytic activity toward Vero cells and human erythrocytes. CONCLUSION: The bactericidal and biofilm-killing activities of the new anti-YycG compounds were significantly better than the parent Compound 2. PMID- 22231398 TI - A conserved PUF-Ago-eEF1A complex attenuates translation elongation. AB - PUF (Pumilio/FBF) RNA-binding proteins and Argonaute (Ago) miRNA-binding proteins regulate mRNAs post-transcriptionally, each acting through similar, yet distinct, mechanisms. Here, we report that PUF and Ago proteins can also function together in a complex with a core translation elongation factor, eEF1A, to repress translation elongation. Both nematode (Caenorhabditis elegans) and mammalian PUF Ago-eEF1A complexes were identified, using coimmunoprecipitation and recombinant protein assays. Nematode CSR-1 (Ago) promoted repression of FBF (PUF) target mRNAs in in vivo assays, and the FBF-1-CSR-1 heterodimer inhibited EFT-3 (eEF1A) GTPase activity in vitro. Mammalian PUM2-Ago-eEF1A inhibited translation of nonadenylated and polyadenylated reporter mRNAs in vitro. This repression occurred after translation initiation and led to ribosome accumulation within the open reading frame, roughly at the site where the nascent polypeptide emerged from the ribosomal exit tunnel. Together, these data suggest that a conserved PUF Ago-eEF1A complex attenuates translation elongation. PMID- 22231399 TI - Structure of a KirBac potassium channel with an open bundle crossing indicates a mechanism of channel gating. AB - KirBac channels are prokaryotic homologs of mammalian inwardly rectifying (Kir) potassium channels, and recent crystal structures of both Kir and KirBac channels have provided major insight into their unique structural architecture. However, all of the available structures are closed at the helix bundle crossing, and therefore the structural mechanisms that control opening of their primary activation gate remain unknown. In this study, we engineered the inner pore lining helix (TM2) of KirBac3.1 to trap the bundle crossing in an apparently open conformation and determined the crystal structure of this mutant channel to 3.05 A resolution. Contrary to previous speculation, this new structure suggests a mechanistic model in which rotational 'twist' of the cytoplasmic domain is coupled to opening of the bundle-crossing gate through a network of inter- and intrasubunit interactions that involve the TM2 C-linker, slide helix, G-loop and the CD loop. PMID- 22231400 TI - Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. AB - The asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) acts as a repressive mark that antagonizes trimethylation of H3 lysine 4. Here we report that H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and present in euchromatic regions. Profiling of H3-tail interactors by SILAC MS revealed that H3R2me2s excludes binding of RBBP7, a central component of co repressor complexes Sin3a, NURD and PRC2. Conversely H3R2me2s enhances binding of WDR5, a common component of the coactivator complexes MLL, SET1A, SET1B, NLS1 and ATAC. The interaction of histone H3 with WDR5 distinguishes H3R2me2s from H3R2me2a, which impedes the recruitment of WDR5 to chromatin. The crystallographic structure of WDR5 and the H3R2me2s peptide elucidates the molecular determinants of this high affinity interaction. Our findings identify H3R2me2s as a previously unknown mark that keeps genes poised in euchromatin for transcriptional activation upon cell-cycle withdrawal and differentiation in human cells. PMID- 22231402 TI - Chromodomains read the arginine code of post-translational targeting. AB - Chromodomains typically recruit protein complexes to chromatin and read the epigenetic histone code by recognizing lysine methylation in histone tails. We report the crystal structure of the chloroplast signal recognition particle (cpSRP) core from Arabidopsis thaliana, with the cpSRP54 tail comprising an arginine-rich motif bound to the second chromodomain of cpSRP43. A twinned aromatic cage reads out two neighboring nonmethylated arginines and adapts chromodomains to a non-nuclear function in post-translational targeting. PMID- 22231401 TI - Dynein achieves processive motion using both stochastic and coordinated stepping. AB - Processivity, the ability of single molecules to move continuously along a track, is a fundamental requirement of cargo-transporting molecular motors. Here, we investigate how cytoplasmic dynein, a homodimeric, microtubule-based motor, achieves processive motion. To do this, we developed a versatile method for assembling Saccharomyces cerevisiae dynein heterodimers, using complementary DNA oligonucleotides covalently linked to dynein monomers labeled with different organic fluorophores. Using two-color, single-molecule microscopy and high precision, two-dimensional tracking, we find that dynein has a highly variable stepping pattern that is distinct from all other processive cytoskeletal motors, which use 'hand-over-hand' mechanisms. Uniquely, dynein stepping is stochastic when its two motor domains are close together. However, coordination emerges as the distance between motor domains increases, implying that a tension-based mechanism governs these steps. This plasticity may allow tuning of dynein for its diverse cellular functions. PMID- 22231404 TI - Non-destructive evaluation of ripening and quality traits in apples using a multiparametric fluorescence sensor. AB - BACKGROUND: The detection of pigments and colourless flavonoids in apples can provide a useful indication of fruit quality. Optical methods are preferable because they are fast and non-destructive. In this study, a fluorescence-based portable sensor was used in order to non-invasively determine the content of chlorophylls, anthocyanins and flavonols in Fuji, Granny Smith and Golden Delicious apple cultivars. The aim was to define new non-destructive optical indices of apple quality. RESULTS: The anthocyanin index (ANTH) in Fuji was higher in the sunny (i.e. sun-exposed) side of the fruit compared to the shady side. For all cultivars, the flavonol index (FLAV) was higher in the sunny side compared with the shady side. The chlorophyll index (CHL) for the shady sides of Granny Smith and Golden Delicious was significantly higher than for the sunny sides. Fine linear regressions were found between the ANTH, FLAV and CHL indices and the actual anthocyanin, flavonol and chlorophyll concentrations, respectively, which were determined destructively on the apple peel extracts. A negative correlation was found between the apple sugar content and the chlorophyll fluorescence in the far-red spectral band. CONCLUSION: Our results indicate that a single multiparametric fluorescence-based sensor can provide valuable non-destructive markers of ripening and quality in apples. PMID- 22231403 TI - Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2. AB - Homologous recombination facilitates accurate repair of DNA double-strand breaks (DSBs) during the S and G2 phases of the cell cycle by using intact sister chromatids as sequence templates. Homologous recombination capacity is maximized in S and G2 by cyclin-dependent kinase (CDK) phosphorylation of CtIP, which subsequently interacts with BRCA1 and the Mre11-Rad50-NBS1 (MRN) complex. Here we show that, in human and mouse, Mre11 controls these events through a direct interaction with CDK2 that is required for CtIP phosphorylation and BRCA1 interaction in normally dividing cells. CDK2 binds the C terminus of Mre11, which is absent in an inherited allele causing ataxia telangiectasia-like disorder. This newly uncovered role for Mre11 does not require ATM activation or nuclease activities. Therefore, functions of MRN are not restricted to DNA damage responses but include regulating homologous recombination capacity during the normal mammalian cell cycle. PMID- 22231405 TI - Anaplastic oligodendroglioma with ganglioglioma-like maturation. AB - Neuronal differentiation of oligodendroglioma has been demonstrated by immunohistochemical and ultrastructural examinations in recent studies. However, oligodendrogliomas displaying a complete neurocytic morphology or even gangliocytic differentiation are rare. We describe a case of anaplastic oligodendroglioma that was characterized by the presence of ganglion cells in a 40-year-old-male. Histologically, the tumor was mainly composed of classical oligodendroglioma cells. The most exceptional finding of this tumor was the presence of ganglion cells and intermediate-sized ganglioid cells. Immunohistochemical analysis revealed that these cells were positive for Olig2 and negative for glial fibrillary acid protein (GFAP). Synaptophysin and microtubule-associated protein 2 (MAP2) were mainly detected in the ganglion cells. Fluorescence in situ hybridization analysis (FISH) revealed the deletion of the 1p and 19q chromosome arms in both the oligodendroglioma cells and ganglion cells. The R132H mutated isocitrate dehydrogenase 1 (IDH1) protein was detected by immunohistochemistry and direct DNA sequencing. The morphological, immunohistochemical, and genetic features of the tumor suggested a diagnosis of anaplastic oligodendroglioma, and this tumor was considered to be a rare form of oligodendroglioma displaying ganglioglioma-like maturation. FISH and mutant IDH1 examinations are useful diagnostic tools for the differential diagnosis of this tumor, i.e., ganglioglioma with anaplastic oligodendroglial features. PMID- 22231406 TI - Dioscin induces cancer cell apoptosis through elevated oxidative stress mediated by downregulation of peroxiredoxins. AB - Dioscin has been shown to promote anticancer activity against several forms of cancers. However, its detailed molecular mechanisms have not been clearly clarified.In this study, we demonstrate that dioscin induces apoptosis in cancer cells through the induction of oxidative stress. Treatment with cancer cells in vitro with dioscin resulted in rapid generation of reactive oxygen species (ROS) and the induction of mitochondrial pathway apoptosis in human esophageal cancer cell line Kyse510. Inhibition of oxidative stress by the antioxidant N acetylcysteine blocked the induction of apoptosis by dioscin, indicating that ROS generation is the primary mechanism responsible for the proapoptotic activity of dioscin. Proteomic analysis and protein gel blotting further revealed peroxiredoxins 1 and 6 (PRDX 1 and 6), which are implicated in ROS metabolism and apoptosis, were associated with the anticancer effects of dioscin. Meanwhile, overexpression of PRDX 1 and 6 significantly blocked the elevated ROS and apoptosis induced by dioscin. In conclusion, we suggest that PRDX1 and PRDX6 are key targets in the process of dioscin-induced apoptosis that involves intracellular elevated ROS. PMID- 22231407 TI - Dietary calcium supplementation enhances efficacy but also toxicity of EGFR inhibitor therapy for colon cancer. AB - The inverse correlation between levels of dietary calcium and colorectal cancer (CRC) incidence has been extensively investigated. However, the impact of supplemental calcium on cancer therapy remains unknown. We used four models of CRC, Caco-2 and HCT116 human cancer cell lines and Apc (Min/+) and azoxymethane carcinogen-induced mouse models, to investigate the impact of a western-style diet low in calcium (0.05%) vs. a similar diet but supplemented with calcium (5%) on therapeutic targeting of the epidermal growth factor receptor (EGFR). We found that calcium supplementation combined with pharmacologic blockade of EGFR results in an additive effect on tumor growth inhibition in all models. Unexpectedly, the combined use of dietary calcium supplementation and EGFR inhibitors also resulted in elevated toxicity suggesting that careful consideration be given when combining dietary supplements with prescribed cancer therapies. PMID- 22231408 TI - The percutaneous trampoline platysmaplasty: technique and experience with 105 consecutive patients. AB - BACKGROUND: Controversy persists regarding the optimal procedure to rejuvenate the aging neck. More invasive procedures carry increased risks of complications, whereas less invasive approaches may deliver marginal results. The challenge is selecting the appropriate procedure for delivering consistent, durable results meeting both the patient's and surgeon's expectations. OBJECTIVES: The authors describe their trampoline platysmaplasty (TPP) approach, a percutaneous suture suspension necklift that constitutes a less invasive approach for neck rejuvenation. METHODS: A retrospective study was conducted of 105 consecutive patients who underwent TPP. Age, sex, procedure(s) performed, complications, and patient satisfaction were recorded. Cadaver studies were conducted to compare the tensile strength of the ligaments that anchor the TPP to the tensile strength of the sutures placed to approximate the medial platysma borders. In addition, the accuracy of light transillumination to determine depth of travel of the light emitting diode (LED) lighted rod was evaluated. RESULTS: Patients underwent either TPP alone (18 women, 24 men) or TPP with a facelift (35 women, 28 men) between October 2007 and June 2009. The average age of the patients was 52 years, and average length of follow-up was 33 months. Patient satisfaction was high. Three early patients underwent immediate revision to improve results secondary to the suture matrix being too loose. Six additional patients had recurrent banding around one year postoperatively, but correction was achieved in all six by replacing the matrix with the help of the lighted rod. The results of the cadaver study revealed that the tensile strength of the retaining ligaments was statistically identical to the medial platysma borders, and the light transillumination feedback was accurate with regard to the depth of travel of the illuminated rod tip. CONCLUSIONS: The TPP approach for neck rejuvenation is effective and durable in properly-selected patients. It works well as a stand alone procedure and in conjunction with facelift procedures. It also offers younger patients a less-invasive option to improve neck contours inherited through genetics. After nearly three years of follow-up of the patients in this report, the results appear to be long-lasting. PMID- 22231409 TI - Commentary on: "The percutaneous trampoline platysmaplasty: technique and experience with 105 consecutive patients". PMID- 22231410 TI - Intranasal surgical approach for malar alloplastic augmentation. AB - BACKGROUND: Alloplastic malar augmentation is becoming an increasingly common procedure for enhancement of the midface and an adjunct method of improving the effects of other rejuvenation procedures. OBJECTIVES: The authors present a new surgical approach for placement of malar implants by means of an intranasal incision, which they believe has several advantages over traditional techniques. They also propose a new classification for regions of the midface to assist in augmentation planning. METHODS: Between 1990 and 2010, the authors treated 20 patients with an intranasal approach for alloplastic malar augmentation. Patients were preoperatively divided into three groups: Type 1 included those with adequate nostril opening, including good elasticity of the internal nasal mucosa, allowing a good exposure of the piriform aperture through the nasal speculum; Type 2a included those with inadequate nostril opening; and Type 2b included those who required an alar base correction. Implants were selected according to these classifications and placed with the authors' technique. RESULTS: Of the 20 patients treated, 18 were female and two were male. Ages ranged from 15 to 65 years. Average follow-up was 10 years, and all patients experienced favorable results. There were no major complications, no nerve or vascular supply compromise, and no cases of implant malposition. One patient requested removal of the implant at one year postoperatively despite her good postoperative outcome; overall patient satisfaction was 95%. CONCLUSIONS: The intranasal approach for alloplastic malar augmentation has shown good results for midface enhancement in the authors' hands. In this patient series, results showed excellent overall patient satisfaction and a very low (nearly 0%) complication rate. PMID- 22231411 TI - Facelift and patterns of lymphatic drainage. AB - BACKGROUND: It has commonly been assumed that deeper facelift dissection causes greater and more prolonged swelling. OBJECTIVES: In this preliminary report, the authors compare the lymphatic reconstitution after multiple techniques of rhytidectomy by means of dynamic lymphoscintigraphy. METHODS: Three patients were enrolled in this study. All three were female, were similar in age, and exhibited similar signs and degrees of facial aging. Each woman underwent a facelift with a different technique: (1) subcutaneous dissection with superficial musculoaponeurotic system (SMAS) plication, (2) subcutaneous dissection with SMASectomy, and (3) a "high SMAS" composite facelift. Postoperatively, (99m)Tc sulfur colloid was injected into a standardized infraorbital location in each patient to compare patterns of lymphatic drainage using lymphoscintigraphy. Postoperative scans at two weeks, six weeks, three months, six months, and one year were compared to the preoperative scans taken seven days prior to surgery. RESULTS: All rhytidectomy techniques appeared to temporarily create a significant and similar degree of interruption in lymphatic drainage. There was a subtotal recovery of lymphatic pathways within three months and complete return to baseline drainage pattern after six months, regardless of surgical technique. CONCLUSIONS: Based on the results of this study, it appears that the extent of facial dissection, rather than the depth, is the most significant factor in postoperative edema. PMID- 22231412 TI - A three-dimensional construct of the aging eyebrow: the illusion of volume loss. AB - BACKGROUND: The eyebrows and eyebrow fat pads, key structures in upper facial aesthetics, are particularly vulnerable to age-related changes. OBJECTIVES: In this study, the authors compare the impact of aging on the eyebrows and eyebrow fat pad volume in men and women through three-dimensional (3D) volumetric analysis. METHODS: Electronic medical records of patients seen at the Jules Stein Eye Institute in the Division of Orbital and Ophthalmic Plastic Surgery between 2005 and 2010 were reviewed. Patients were included if they had undergone investigative imaging of the orbit for unilateral pathology. Computed tomography (CT) scans of patients with Graves disease diagnosis, extensive orbital trauma, and/or previous eyebrow surgery were excluded. A total of 52 CT scans (24 men and 28 women) were retained for analysis. A 3D reconstruction software was used to analyze the scans and calculate volumes of the retroorbicularis oculi fat (ROOF), galeal fat (ROOF and subcutaneous fat), and soft tissue muscles. RESULTS: Galeal and brow fat volumes showed a significant positive trend toward enlargement in women (P values of .01 and .05, respectively). Although men showed a tendency toward fat enlargement with age, this was not statistically significant. Soft tissue-muscle volume decreased significantly in aging women (9.32 mm(3)/y) (P = .02). Data indicated that soft tissue volume in men tended to increase with age (3.92 mm(3)/y) but not significantly (P = .36). Neither total volume nor brow thickness appeared to change significantly in women (P = .56, P = .73). In men, total volume and brow thickness showed weak evidence of increasing with age (P = .12, P = .22). Linear regressions of Hertel measurements with and without sex interaction showed no statistically significant trend between the amount of proptosis and the galeal or brow fat. CONCLUSIONS: Although overall eyebrow volume does not change with age, the relative contribution of fat and soft tissue to the total volume does seem to change. This pattern also differs between males and females. As women age, the fat volume increases and the soft tissue volume decreases. In men, the shift from soft tissue volume to fat volume is less pronounced. Although many clinicians have been drawn to the concept of fat volume deflation as a key element of facial aging, this study does not support this perspective in the eyebrow fat pad. An increasingly refined understanding of the dynamics of facial aging is mandatory for clinical diagnosis and will likely provide the framework from which to develop more innovative treatment options. PMID- 22231413 TI - Broken heart syndrome: a risk of teenage rhinoplasty. AB - "Broken heart" syndrome is a rare phenomenon characterized by transient ballooning of the left ventricle and chronic heart failure, usually presenting in postmenopausal women. It is formally known as acute stress-induced cardiomyopathy and, although described in the cardiology literature, it has not been previously described in plastic surgery patients. It is thought to occur secondary to increased catecholamine levels. This case report outlines two instances of the syndrome occurring in teenage girls undergoing cosmetic rhinoplasty. PMID- 22231414 TI - Evaluating the role of postoperative prophylactic antibiotics in primary and secondary breast augmentation: a retrospective review. AB - BACKGROUND: The use of postoperative prophylactic antibiotics following augmentation mammaplasty remains a controversial topic, with many surgeons opting for extended prophylaxis. OBJECTIVES: The authors evaluate the role of postoperative prophylactic antibiotics in both primary and secondary cosmetic breast augmentation. METHODS: A five-year retrospective chart review was performed on all patients undergoing cosmetic breast augmentation at a single institution from January 2005 to December 2009. The four attending physicians in this study utilized similar perioperative protocol and implant materials. Patients were divided into two cohorts: those who had received three days of postoperative antibiotics (primarily cephalosporins) and those who had not. End points of particular interest included infection, capsular contracture (CC), and local wound complications. The mean follow-up time was 3.8 years. RESULTS: A total of 605 implants were included over the five-year study period. The overall infection rate was 0.66%. For primary augmentation, 493 implants were studied, with 52% of those patients having received postoperative antibiotics. There was no statistically significant reduction in infection, CC, or total complication rate for those receiving postoperative antibiotics. Similarly, 112 implants were studied for secondary augmentation, and again, postoperative antibiotics were not associated with a reduction in complications. CONCLUSIONS: The data suggest that there was no reduction in the overall rate of total complications, infection, or CC with postoperative prophylactic antibiotics for either primary or secondary cosmetic breast augmentation. This study provides Level 3 evidence in support of discontinuing prophylactic postoperative antibiotics following cosmetic breast augmentation. PMID- 22231415 TI - Poland syndrome and breast tumor: a case report and review of the literature. AB - Poland syndrome is a rare congenital malformation. Hypoplasia of the sternocostal portion of the pectoralis major muscle is the most significant feature and is most frequently associated with homolateral breast hypoplasia. In this article, the authors present a case of bilateral phyllodes tumors in a 28-year-old woman with Poland syndrome and discuss (1) the relationship between the condition and breast cancer, (2) the modes of surveillance in patients with Poland syndrome, and (3) its impact on breast reconstruction. PMID- 22231416 TI - Improving outcomes in upper arm liposuction: adding radiofrequency-assisted liposuction to induce skin contraction. AB - BACKGROUND: Brachioplasty is frequently recommended for patients with more skin laxity than subcutaneous fat. However, many patients are reluctant to accept a visible scar that will affect the activity of the upper arm or clothing choices. Traditional liposuction is effective when minimal skin laxity is present, but the dual problems of postoperative residual skin laxity and unsatisfactory contour irregularities are common when upper arm skin laxity is the chief complaint. OBJECTIVES: The author investigates the degree of skin contraction resulting from treatment with radiofrequency-assisted liposuction (RFAL) and attempts to determine whether, after long-term follow-up, the classification of upper arm deformities and their corresponding treatment protocols can be refined to offer patients with prominent skin laxity an alternative to traditional brachioplasty. METHODS: A prospective, institutional review board-approved pilot study was planned with 12 consecutive patients who presented to the author's private clinic for treatment of upper arm laxity. Patients were included only if they were categorized as Stage 2b, 3, or 4 according to the El Khatib and Teimourian system. Based on the "pinch" test and the vertical measurement of skin distal to the bicipital groove as described by El Khatib, a novel caliper was devised to quantify the shortening of the pendulous volar skin. Treatment regions were tattooed prior to surgery and measurements from a Vectra system (Canfield Scientific, Inc., Fairfield, New Jersey) confirmed the preoperative surface area. All patients were treated with the BodyTite device (Invasix, Inc., Yokneam, Israel). No patient underwent skin resection in the volar treatment region. Skin contraction was measured at one year posttreatment. Statistical analysis was conducted with a paired t-test. RESULTS One year after treatment with RFAL, the mean surface area reduction in the volar upper arm region was 33.5% bilaterally. The mean degree of pendulous vertical "hang" shortening was 50% bilaterally. Statistical analysis showed a P value of >.001 for both measurements. CONCLUSIONS: Treatment with RFAL achieved statistically significant skin contraction in the upper arm region. Patients in categories 2b and 4 were successfully treated with RFAL instead of traditional brachioplasty (which is recommended by the current classification system). Category 3 patients, however, did require a short-scar brachioplasty procedure to obtain satisfactory results. PMID- 22231417 TI - Prospective randomized comparison of onabotulinumtoxinA (Botox) and abobotulinumtoxinA (Dysport) in the treatment of forehead, glabellar, and periorbital wrinkles. AB - BACKGROUND: There are several commercially available neurotoxins to improve facial aesthetics, but few prospective, randomized trials have been conducted without commercial support to compare these agents. OBJECTIVES: The authors present the results of a study examining and comparing the effects of onabotulinumtoxinA (BoNT-ONA; Botox, Allergan, Inc., Irvine, California) and abobotulinumtoxinA (BoNT-ABO; Dysport, Ipsen Ltd, Slough, UK). METHODS: The authors enrolled 53 patients in a prospective, randomized trial in which each patient received a dose of BoNT-ONA on one side of the upper face and BoNT-ABO on the other. The effects of each agent were monitored and recorded over 150 days according to each patient's ability to elevate the brow, wrinkle count (as measured by the Visia system; Canfield Imaging Systems, Fairfield, New Jersey), and assessment of Fitzpatrick wrinkle scale rankings by blinded graders. RESULTS: Results showed no statistically significant differences between the two agents. Both agents yielded measurable improvements on wrinkles of the upper face at 150 days. CONCLUSIONS: At the current pricing of the agents, BoNT-ABO offers a significant cost savings over BoNT-ONA, with a comparable efficacy. The effect of both drugs appears to be more prolonged than indicated in the current manufacturer guidelines. PMID- 22231418 TI - Why evidence-based medicine matters to aesthetic surgery. PMID- 22231419 TI - Quantitative analysis of aesthetic results: introducing a new paradigm. PMID- 22231420 TI - Intraoperative ultrasonography to guide intramuscular buttock implants. PMID- 22231421 TI - Higher expression of androgen receptor is a significant predictor for better endocrine-responsiveness in estrogen receptor-positive breast cancers. AB - The aim was to investigate the implications of androgen receptor (AR) expression levels on outcomes for estrogen receptor (ER)-positive tumors. Immunohistochemically AR levels were determined from tissue microarrays of 614 ER positive patients who received adjuvant endocrine with or without chemotherapy between November 1999 and August 2005. Characteristics and survival were analyzed using a Chi-square test, Kaplan-Meier methods, and Cox's models. AR levels were categorized into 3 subgroups as follows: low, AR < 10%; intermediate, 10% <= AR < 50%; high, AR >= 50%. Low, intermediate, and high AR levels were observed in 29.0, 44.0, and 27.0% of patients, respectively. High AR was associated with smaller size, nodal uninvolvement, grade I/II tumor, higher progesterone receptor expression, and lower proliferation index. With a median follow-up of 70.9 months, the high AR subgroup showed better survival, and these associations were maintained in 119 patients who received endocrine therapy alone [hazard ratio (HR), 0.111; 95% CI, 0.013-0.961 for disease-free survival (DFS); HR, 0.135; 95% CI, 0.015-1.208 for overall survival (OS)]. No significant benefits from chemotherapy were demonstrated in the high AR subgroup; however, the benefit from chemotherapy was significant among 448 AR-intermediate or -low patients (HR, 2.679; 95% CI, 1.452-4.944 for DFS; HR, 3.371; 95% CI, 1.611-7.052 for OS). High AR is an independent prognostic factor and a significant predictor for better endocrine-responsiveness in ER-positive tumors. AR-low or -intermediate levels could give an additional indication for use of chemotherapy in ER-positive tumors. PMID- 22231422 TI - Stress, coping and cognitive deficits in women after surgery for breast cancer. AB - Research on neuropsychological difficulties among cancer patients has focused on chemotherapy as a primary cause, yet several studies have now shown that some patients evidence cognitive weaknesses prior to chemotherapy. As an alternative to the 'chemo-brain' theory, this study examined the hypothesis that stress and coping style may be associated with observed neuropsychological difficulties among female cancer patients. Thirty-six women completed neuropsychological testing and psychological questionnaires following surgery for breast cancer and prior to any subsequent treatments. Twenty-seven percent of participants evidenced deficits on at least one measure of verbal fluency, and 14% of participants were impaired on at least one memory measure. Self-reported stress was correlated with deficits in memory, verbal fluency, and attention. Subsequent mediational analyses indicated that use of passive coping styles may underlie this relationship between stress and neuropsychological deficits. These findings highlight the potential relevance of psychological mechanisms, such as coping style, in cancer patients' experience of neuropsychological deficits. PMID- 22231424 TI - A systematic review of the global prevalence of low back pain. AB - OBJECTIVE: To perform a systematic review of the global prevalence of low back pain, and to examine the influence that case definition, prevalence period, and other variables have on prevalence. METHODS: We conducted a new systematic review of the global prevalence of low back pain that included general population studies published between 1980 and 2009. A total of 165 studies from 54 countries were identified. Of these, 64% had been published since the last comparable review. RESULTS: Low back pain was shown to be a major problem throughout the world, with the highest prevalence among female individuals and those aged 40-80 years. After adjusting for methodologic variation, the mean +/- SEM point prevalence was estimated to be 11.9 +/- 2.0%, and the 1-month prevalence was estimated to be 23.2 +/- 2.9%. CONCLUSION: As the population ages, the global number of individuals with low back pain is likely to increase substantially over the coming decades. Investigators are encouraged to adopt recent recommendations for a standard definition of low back pain and to consult a recently developed tool for assessing the risk of bias of prevalence studies. PMID- 22231423 TI - Associations between positive and negative affect and 12-month physical disorders in a national sample. AB - Associations between positive and negative affect and a range of 12-month physical disorders were investigated in the Midlife Development in the United States Survey, a nationally representative sample of 3,032 adults ages 25-74. These associations were examined, controlling for relevant sociodemographic and psychiatric covariates. High positive affect was associated with decreased risk of physical disorders, whereas high negative affect was associated with increased risk. However, associations between positive affect and physical disorders were partially attenuated following adjustment for concurrent negative affect. Additionally, high affect balance was associated with decreased risk of physical disorders before and after adjustments. These findings underscore the relevance of affective disposition in health status, suggesting that both positive and negative affect may serve as viable health risk parameters. PMID- 22231425 TI - Saccade-confounded image statistics explain visual crowding. AB - Processing of shape information in human peripheral visual fields is impeded beyond what can be expected by poor spatial resolution. Visual crowding, the inability to identify objects in clutter, has been shown to be the primary factor limiting shape perception in peripheral vision. Despite the well-documented effects of crowding, its underlying causes remain poorly understood. Given that spatial attention both facilitates learning of image statistics and directs saccadic eye movements, we propose that the acquisition of image statistics in peripheral visual fields is confounded by eye-movement artifacts. Specifically, the image statistics acquired under a peripherally deployed spotlight of attention are systematically biased by saccade-induced image displacements. These erroneously represented image statistics lead to inappropriate contextual interactions in the periphery and cause crowding. PMID- 22231426 TI - SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance. AB - Endocannabinoids (eCBs) regulate neuronal activity in the dorso-lateral striatum (DLS), a brain region that is involved in habitual behaviors. How synaptic eCB signaling contributes to habitual behaviors under physiological and pathological conditions remains unclear. Using a mouse model of cannabinoid tolerance, we found that persistent activation of the eCB pathway impaired eCB-mediated long term depression (LTD) and synaptic depotentiation in the DLS. The loss of eCB LTD, occurring preferentially at cortical connections to striatopallidal neurons, was associated with a shift in behavioral control from goal-directed action to habitual responding. eCB LTD and behavioral alterations were rescued by in vivo modulation of small-conductance calcium activated potassium channel (SK channel) activity in the DLS, which potentiates eCB signaling. Our results reveal a direct relationship between drug tolerance and changes in control of instrumental performance by establishing a central role for eCB LTD in habit expression. In addition, SK channels emerge as molecular targets to fine tune the eCB pathway under pathological conditions. PMID- 22231427 TI - NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins. AB - During synaptogenesis, macromolecular protein complexes assemble at the pre- and postsynaptic membrane. Extensive literature identifies many transmembrane molecules sufficient to induce synapse formation and several intracellular scaffolding molecules responsible for assembling active zones and recruiting synaptic vesicles. However, little is known about the molecular mechanisms coupling membrane receptors to active zone molecules during development. Using Caenorhabditis elegans, we identify an F-actin network present at nascent presynaptic terminals and required for presynaptic assembly. We unravel a sequence of events whereby specificity-determining adhesion molecules define the location of developing synapses and locally assemble F-actin. Next, the adaptor protein NAB-1 (neurabin) binds to F-actin and recruits active zone proteins SYD-1 and SYD-2 (liprin-alpha) by forming a tripartite complex. NAB-1 localizes transiently to synapses during development and is required for presynaptic assembly. Altogether, we identify a role for the actin cytoskeleton during presynaptic development and characterize a molecular pathway whereby NAB-1 links synaptic partner recognition to active zone assembly. PMID- 22231428 TI - Emergence of a 'visual number sense' in hierarchical generative models. AB - Numerosity estimation is phylogenetically ancient and foundational to human mathematical learning, but its computational bases remain controversial. Here we show that visual numerosity emerges as a statistical property of images in 'deep networks' that learn a hierarchical generative model of the sensory input. Emergent numerosity detectors had response profiles resembling those of monkey parietal neurons and supported numerosity estimation with the same behavioral signature shown by humans and animals. PMID- 22231429 TI - Mechanisms underlying cortical activity during value-guided choice. AB - When choosing between two options, correlates of their value are represented in neural activity throughout the brain. Whether these representations reflect activity that is fundamental to the computational process of value comparison, as opposed to other computations covarying with value, is unknown. We investigated activity in a biophysically plausible network model that transforms inputs relating to value into categorical choices. A set of characteristic time-varying signals emerged that reflect value comparison. We tested these model predictions using magnetoencephalography data recorded from human subjects performing value guided decisions. Parietal and prefrontal signals matched closely with model predictions. These results provide a mechanistic explanation of neural signals recorded during value-guided choice and a means of distinguishing computational roles of different cortical regions whose activity covaries with value. PMID- 22231430 TI - Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications. AB - Here we report 41 novel mutations in the TCIRG1 gene that is responsible for the disease in more than 50% of ARO patients. The characterisation of mutations in this gene might be useful in the process of drug design for osteoporosis treatment. INTRODUCTION: Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder due to reduced bone resorption by osteoclasts. In this process, a crucial role is played by the proton pump V-ATPase. Biallelic mutations in the TCIRG1 gene, encoding for the a3 subunit of this pump, are responsible for more than one half of ARO patients. METHODS: Patients with a clinical diagnosis of ARO have been collected for 7 years and mutation analysis of the TCIRG1 gene was performed using direct DNA sequencing of PCR-amplified exons according to both a standard protocol and a modified one. RESULTS: We report here 41 novel mutations identified in 67 unpublished patients, all with biallelic mutations. In particular, we describe two novel large genomic deletions and two splice site mutations in the 5' UTR of the TCIRG1 gene, in patients previously classified as mono-allelic. CONCLUSIONS: Our data highlights the importance of two large genomic deletions and mutations in the 5' UTR with respect to patient management and, more critically, to prenatal diagnosis. With the present work, we strongly contribute to the molecular dissection of TCIRG1 deficient ARO and identify several protein residues which are fundamental for proton pump function and could thus be the target of future drugs designed to inhibit osteoclast resorptive activity. PMID- 22231431 TI - Relationship between p53 overexpression, human papillomavirus infection, and lifestyle in Indian patients with head and neck cancers. AB - Exposure to pollutants in the environment, tobacco and alcohol consumption, poor oral hygiene and opportunistic viral infections are important aetiological factors in head and neck cancers. In this study, we evaluate the complex interrelationships between these factors and molecular events such as p53 overexpression in causation of head and neck cancers. Tissue samples from 110 patients with histopathologically confirmed carcinoma of head and neck were analyzed from our tissue biorepository with patient consent. Data pertaining to their dietary habits, tobacco and alcohol consumption were abstracted. P53 overexpression was analysed by immunohistochemistry and HPV (high-risk genotype) were studied by Chromogenic in situ Hybridization using an ultra sensitive DNA probe. Chi-square analysis was done to determine relationships between proportions of dependent and independent variables. Bivariate relationships were determined between these variables using Spearman's rank correlation. Linear regression analysis was used to determine the best predictor variable influencing p53 expression. Tobacco consumption especially smoking cigarettes and all forms of tobacco consumption put together and HPV infection significantly influenced p53 overexpression. Forty-five percent of the studied cohort was positive for HPV. Regression analysis showed interaction between tobacco and HPV infection to be a primary predictor (beta = 0.31, p = 0.02) for p53 expression. Tobacco in any form: chewing, smoking and snuffing, along with HPV infection is significantly associated with p53 overexpression. There is a high prevalence of HPV infection (45%) in Indian patients suggesting its possible role in the aetiology of head and neck cancer. PMID- 22231432 TI - Prognostic value of plasmatic tumor M2 pyruvate kinase and carcinoembryonic antigen in the survival of colorectal cancer patients. AB - Colorectal cancer (CRC) can be cured in most cases if diagnosed at an early stage. Carcinoembryonic antigen (CEA) remains the most widely used cancer marker for determining prognosis of CRC. Previous studies have shown that plasmatic tumor M2 pyruvate kinase (Tu M2-PK) is highly sensitive in CRC detection at an early stage and equally as good as the results for established tumor markers with clinical potential for cancer prognosis and monitoring. The aim of this study was to assess the prognostic value of Tu M2-PK in plasma using a survival analysis in combination with CEA in serum in patients newly diagnosed with CRC. The initial study included 183 patients who had a complete diagnostic colonoscopy. This cohort study was designed to evaluate the survival in patients with histologically confirmed gastrointestinal cancers (n = 41). Tu M2-PK concentrations in EDTA plasma were determined immunologically using an ELISA assay. Plasma Tu M2-PK levels were significantly higher in patients with distant metastases, stage IV for TNM score, and advanced stage (C+D) subgroups of Dukes than other subgroups. The univariate Cox's analysis showed that CEA and Tu M2-PK gave high hazard ratios for risk of death (odds ratio CEA = 3.57 and odds ratioTu M2-PK = 2.23) and comparable values in average survival time. The results for both biomarkers did not overlap. These findings suggest that plasmatic Tu M2-PK levels of more than 20 U/mL may be a predictor of death risk. PMID- 22231433 TI - Vascular endothelial growth factor A gene (VEGFA) polymorphisms and expression of VEGFA gene in lung cancer patients of Kashmir Valley (India). AB - The vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. Polymorphisms in the VEGF gene may regulate VEGF production. In this case-control study, we investigated whether functional polymorphisms (+405 C > G and +936 C > T) in the VEGF gene are associated with the risk of lung cancer. Genomic DNA was isolated from the blood of 100 lung cancer patients and 150 healthy controls, and total RNA was isolated from 48 tumor tissues and adjacent normal lung tissues. Two DNA polymorphisms (+405 C > G and +936 C > T) in the 3'-untranslated regions (3'-UTR) and 5' untranslated regions (5'-UTR) of vascular endothelial growth factor A (VEGFA) were studied using PCR-RFLP method, and mRNA expression of VEGFA was studied by quantitative real-time PCR. Polymorphisms in the 5'-UTR (+405 C > G) and 3'-UTR (+936 C > T) did not show significant difference between lung cancer cases and control samples (P = 0.11 and P = 0.09, respectively). VEGF +405 CG and GG are significantly more in age group >50 years old, in all grades, and in early pathological stages (P = 0.04, P = 0.03, and P = 0.006, respectively). Also, increased expression of VEGFA mRNA was noted in tumorous compared to non-tumorous tissue (P < 0.0001). Overexpression of the gene was considered at DeltaC (T) > 6.0. Within the group of patients with conventional tumor, those with histology other than squamous cell carcinoma (SCC) had a higher level of VEGFA mRNA expression than SCC patients (P = 0.04). Overexpression of VEGFA mRNA was noted in lung cancer and more so in lung cancer with adenocarcinoma and large cell carcinoma histology and in pathological stages III and IV. VEGFA +405 C > G SNP showed an association with age, pathological grade, and stage. PMID- 22231434 TI - Genetic polymorphisms of ALDH2 and ADH2 are not associated with risk of hepatocellular carcinoma among East Asians. AB - The aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 2 (ADH2) genes have been implicated in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, we performed a meta analysis to clarify the associations between polymorphisms of ALDH2 and ADH2 genes and HCC. Published literatures from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Ten studies including 1,231 HCC cases and 1,849 controls were included in the meta-analysis of the association between ALDH2 polymorphism and HCC risk. The results indicated that ALDH2 polymorphism was not significantly associated with risk of HCC (homogeneous co-dominant model: OR = 0.99, 95% CI 0.72-1.34; heterogeneous co-dominant model: OR = 0.90, 95% CI 0.75 1.08; dominant model: OR = 0.91, 95% CI 0.70-1.18; recessive model: OR = 1.11, 95% CI 0.66-1.87). In addition, four studies including 518 cases and 607 controls were included in the meta-analysis of the association between ADH2 polymorphism and HCC risk. There was no association between ADH2 polymorphism and HCC risk (homogeneous co-dominant model: OR = 0.93, 95% CI 0.58-1.51; heterogeneous co dominant model: OR = 1.39, 95% CI 0.87-2.23; dominant model: OR = 1.19, 95% CI 0.76-1.88; recessive model: OR = 0.91, 95% CI 0.54-1.54). Further analysis suggested that the ALDH2 polymorphism-alcohol interaction was marginally associated with HCC risk under the dominant model (OR = 2.05, 95% CI 1.01-4.17). However, the result was not robust by sensitivity analysis. The results from the present meta-analysis indicated that there was no significant association between ALDH2 polymorphism, ADH2 polymorphism, or ALDH2 polymorphism-alcohol intake interaction and HCC risk in the East Asians. PMID- 22231435 TI - Aldehyde and xanthine oxidase activities in tissues of streptozotocin-induced diabetic rats: effects of vitamin E and selenium supplementation. AB - Effects of vitamin E and selenium supplementation on aldehyde oxidase (AO) and xanthine oxidase (XO) activities and antioxidant status in liver, kidney, and heart of streptozotocin (STZ)-induced diabetic rats were examined. AO and XO activities increased significantly after induction of diabetes in rats. Following oral vitamin E (300 mg/kg) and sodium selenite (0.5 mg/kg) intake once a day for 4 weeks, XO activity decreased significantly. AO activity decreased significantly in liver, but remained unchanged in kidney and heart of vitamin E- and selenium treated rats compared to the diabetic rats. Total antioxidants status, paraoxonase-1 (PON1) and erythrocyte superoxide dismutase activities significantly decreased in the diabetic rats compared to the controls, while a higher fasting plasma glucose level was observed in the diabetic animals. The glutathione peroxidase activity remained statistically unchanged. Malondialdehyde and oxidized low-density lipoprotein levels were higher in the diabetic animals; however, these values were significantly reduced following vitamin E and selenium supplementation. In summary, both AO and XO activities increase in STZ-induced diabetic rats, and vitamin E and selenium supplementation can reduce these activities. The results also indicate that administration of vitamin E and selenium has hypolipidemic, hypoglycemic, and antioxidative effects. It decreases tissue damages in diabetic rats, too. PMID- 22231436 TI - The effect of age on 12 chemical element contents in the intact prostate of adult men investigated by inductively coupled plasma atomic emission spectrometry. AB - The effect of age on 12 chemical element contents in intact prostate of 64 apparently healthy, 13-60-year-old men (mean age 36.5 years) was investigated by inductively coupled plasma atomic emission spectrometry. Mean values (M +/- SEpsilonMU) for mass fraction (milligrams/kilogram, on dry weight basis) of Ba, Ca, Cu, Fe, K, Mg, Na, P, S, Sr, and Zn were: Ba 1.18 +/- 0.12, Ca 2,178 +/- 160, Cu 10.7 +/- 0.9, Fe 122 +/- 5, K 12,530 +/- 360, Mg 1,100 +/- 70, Na 10,470 +/- 320, P 7,580 +/- 300, S 8,720 +/- 180, Sr 1.85 +/- 0.28, and Zn 782 +/- 97, respectively. The upper limit of mean content of V was <=0.22 mg/kg. A tendency of age-related increase in Ca, Fe, Na, and Zn mass fraction as well an increase in Zn/Ba, Zn/Ca, Zn/Cu, Zn/Fe, Zn/K, Zn/Mg, Zn/Na, Zn/P, Zn/S, and Zn/Sr ratios in prostate was observed. A significant positive correlation was seen between the prostatic zinc and Ca, Cu, Fe, Mg, Na, and P contents. PMID- 22231437 TI - Influence of phosvitin and calcium gluconate concentration on permeation and intestinal absorption of calcium ions. AB - The effect of egg yolk phosvitin on the permeation and absorption of calcium was investigated in vitro in relation to calcium gluconate concentration. Obtained results indicate that phosvitin significantly reduces the intestinal calcium absorption from 1 and 10 mM of calcium gluconate solution. It is associated with the formation of the complex of Ca (II) ions with phosvitin. The process of calcium permeation increases under phosvitin influence when calcium gluconate concentrations rise up to 10 mM. At a higher concentration of calcium gluconate (20 mM), no effect of phosvitin was seen on permeation of calcium ions. PMID- 22231438 TI - The increasing incidence of initial steroid resistance in childhood nephrotic syndrome. AB - BACKGROUND: Recently, a number of reports have highlighted changes in the histopathology and response to corticosteroid treatment in childhood nephrotic syndrome; however, these involved ethnically mixed populations. For comparison, the purpose of our research was to search for changes in the characteristics of nephrotic syndrome in a homogeneous population of Caucasian children over two consecutive decades. METHODS: Chart analysis was performed to identify children with new-onset nephrotic syndrome. The children were admitted to the Division of Pediatric Nephrology, Zabrze, during two periods: 1986-1995 (76 patients) and 1996-2005 (102 patients). Specifically, a comparison of clinical characteristics and morphology of nephrotic syndrome between the two groups was performed. Steroid resistance was defined as no remission within 8 weeks of corticosteroid treatment. Histopathology was available in 36.8% and 43.1% of patients respectively. RESULTS: There was a significant increase in primary steroid resistance in the latter decade: 15.8% vs 31.4% (P = 0.017). Changes in the histopathology did not reach the level of statistical significance: minimal change nephrotic syndrome 25% vs 9% (P = 0.095), mesangial proliferative glomerulonephritis 46.4% vs 61.3% (P = 0.21), focal segmental glomerulosclerosis 17.9% vs 20.4% (P = 0.78), membranoproliferative glomerulonephritis 7.1% vs 6.8% (P = 1.0), membranous glomerulonephritis 3.6% vs 0% (P = 0.39). CONCLUSIONS: Our results show the increasing incidence of primary steroid resistance in childhood nephrotic syndrome. PMID- 22231439 TI - Semi-synthesis of unusual chondroitin sulfate polysaccharides containing GlcA(3-O sulfate) or GlcA(2,3-di-O-sulfate) units. AB - The extraction from natural sources of Chondroitin sulfate (CS), a polysaccharide used for management of osteoarthritis, leads to very complex mixtures. The synthesis of CS by chemical modification of other polysaccharides has seldom been reported due to the intrinsic complexity that arises from fine chemical modifications of the polysaccharide structure. In view of the growing interest in expanding the application of CS to pharmacological fields other than osteoarthritis treatment, we launched a program to find new sources of known or even unprecedented CS polysaccharides. As part of this program, we report herein on an investigation of the use of a cyclic orthoester group to selectively protect the 4,6-diol of N-acetyl-galactosamine residues in chondroitin (obtained from a microbial source), thereby facilitating its transformation into CSs. In particular, three CS polysaccharides were obtained and demonstrated to possess rare or hitherto unprecedented sulfation patterns by 2D NMR spectroscopy characterization. Two of them contained disaccharide subunits characterized by glucuronic acid residues selectively sulfated at position 3 (GlcA(3S)), the biological functions of which are known but have yet to be fully investigated. This first semi-synthetic access to GlcA(3S)-containing CS could greatly expedite such studies, since it can easily furnish considerable amounts of these polysaccharides, which are usually isolated with difficulty and in very low quantity from natural sources. PMID- 22231440 TI - Immune senescence in old and very old rhesus monkeys: reduced antibody response to influenza vaccination. AB - The health of old monkeys usually begins to deteriorate by 20 years of age, coinciding with the onset of a slowly progressing immune senescence. Changes in lymphocyte subsets and responses to several antigens have been characterized in geriatric primates, but systematic research has not been conducted on vaccination against influenza virus, a topic of considerable clinical concern for elderly humans. Antibody responses were significantly reduced to primary immunizations in old monkeys, but by administering a second vaccine at 1 month, it was possible to boost antibody titers up to the level found in young adults during their primary phase. The immune competence of unusually long-lived animals (26-37 years) was also compared to more typical aged monkeys (19-25 years). Antibody responses were low overall, although some monkeys in both age groups did respond to immunization. Among the oldest animals, the leukocytes of the responders with higher antibody titers were found to release more interleukin-2 following in vitro stimulation with an anti-CD3/anti-CD28 cocktail relative to their cellular reactions to staphylococcal enterotoxin B. The general decline in immune vigor, and the marked individual variation in how old monkeys age, provides a useful animal model for investigating factors associated with immunosenescence. PMID- 22231441 TI - First-principles investigation of transition metal atom M (M = Cu, Ag, Au) adsorption on CeO2(110). AB - Transition metal atom M (M = Cu, Ag, Au) adsorption on CeO(2)(110), a technologically important catalytic support surface, is investigated with density functional theory within the DFT+U formalism. A set of model configurations was generated by placing M at three surface sites, viz., on top of an O, an O bridge site, and a Ce bridge site. Prior to DFT optimization, small distortions in selected Ce-O distances were imposed to explore the energetics associated with reduction of Ce(4+) to Ce(3+) due to charge transfer to Ce during M adsorption. Charge redistribution is confirmed with spin density isosurfaces and site projected density of states. We demonstrate that Cu and Au atoms can be oxidized to Cu(2+) and Au(2+), although the adsorption energy, E(ads), of Au(2+) is less favorable and, unlike Cu(2+), it has not been experimentally observed. Oxidation of Ag always results in Ag(+). For M adsorption at an O bridge site, E(ads)(2NN) > E(ads)(3NN) > E(ads)(1NN) where NN denotes the nearest neighbor Ce(3+) site relative to M. Alternatively, for M adsorption at a Ce bridge site, E(ads)(3NN) > E(ads)(2NN) > E(ads)(1NN). The adsorption behavior of M on CeO(2) (110) is compared with M adsorption on CeO(2)(111). PMID- 22231442 TI - Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer. AB - Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERalpha and ERbeta, transcription factors that display functional antagonism with each other, with ERbeta acting as oncosuppressor and interfering with the effects of ERalpha on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERalpha+ BC cells often lack ERbeta, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERbeta might influence BC cell behavior via miRNAs, we compared miRNome expression in ERbeta+ vs ERbeta- hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERbeta in BC cells, clearly distinguishes ERbeta+, node-negative, from ERbeta-, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERbeta+ in BC cell nuclei. In particular, ERbeta downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERalpha on pri-miR maturation by the p68/DDX5 Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERbeta in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor. PMID- 22231444 TI - RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells. AB - Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream beta-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3 binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused beta-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer. PMID- 22231443 TI - Ikaros represses and activates PU.1 cell-type-specifically through the multifunctional Sfpi1 URE and a myeloid specific enhancer. AB - Generation of myeloid and lymphoid cells from progenitors involves dynamic changes in transcription factor expression and use, and disruption of hematopoietic transcription factor function and expression can contribute to leukemic transformation. PU.1 and Ikaros are pivotal factors whose expression and utilization are dynamically altered during hematopoietic development. Here, we demonstrate that expression of PU.1, encoded by the Sfpi1 gene, is divergently regulated by Ikaros in distinct cell type-specific contexts. Chromatin immune precipitation analysis and functional perturbations revealed that Ikaros can directly repress or activate Sfpi1 transcription via different PU.1 cis-elements, with PU.1 and Ikaros collaborating at myeloid-specific elements but not at other elements. Our results thus shed light on how PU.1 and Ikaros can act as lineage competency factors to facilitate both myeloid and lymphoid developmental programs. PMID- 22231445 TI - STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. AB - In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein 2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular-signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones. PMID- 22231446 TI - Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer. AB - MicroRNAs (miRNAs) are small non-coding RNAs of ~20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located ~2 kb upstream of the 5' stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers. PMID- 22231447 TI - Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. AB - Epidermal growth factor receptor (EGFR)-mediated cell signaling is critical for mammary epithelial cell growth and survival; however, targeting EGFR has shown no or only minimal therapeutic benefit in patients with breast cancer. Here, we report a novel regulatory mechanism of EGFR signaling that may explain the low response rates. We found that breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. We demonstrate that Brk inhibits ligand-induced EGFR degradation through uncoupling activated EGFR from casitas B-lineage lymphoma-mediated EGFR ubiquitination. In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity. Experimental elevation of Brk conferred resistance of breast cancer cells to cetuximab (an EGFR-blocking antibody)-induced inhibition of cell signaling and proliferation, whereas knockdown of Brk sensitized the cells to cetuximab by inducing apoptosis. Our findings reveal a previously unknown role of Brk in EGFR-targeted therapy. PMID- 22231450 TI - Metabolic reprogramming of the tumor. AB - Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed. PMID- 22231449 TI - CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling. AB - While Ras is well-known to function on the plasma membrane (PM) to mediate growth factor signaling, increasing evidence suggests that Ras has complex roles in the cytoplasm. To uncover these roles, we screened a cDNA library and isolated H-Ras binding proteins that also influence Ras functions. Many isolated proteins regulate trafficking involving endosomes; CHMP6/VPS20 and VPS4A, which interact with ESCRT-III (Endosomal Sorting Complex Required for Transport-III), were chosen for further study. We showed that the binding is direct and occurs in endosomes. Furthermore, the binding is most efficient when H-Ras has a functional effector-binding loop, and is GTP-bound and ubiquitylated. CHMP6 and VPS4A also bound to N-Ras but not K-Ras. Repressing CHMP6 and VPS4A blocked Ras-induced transformation, which correlated with inefficient Ras localization to the PM as measured by cell fractionation and photobleaching. Moreover, silencing CHMP6 and VPS4A also blocked epidermal growth factor receptor (EGFR) recycling. These data suggest that Ras interacts with key ESCRT-III components to promote recycling of itself and EGFR back to the PM to create a positive feedback loop to enhance growth factor signaling. PMID- 22231448 TI - Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart. AB - Chk1 both arrests replication forks and enhances repair of DNA damage by phosphorylating downstream effectors. Although there has been a concerted effort to identify effectors of Chk1 activity, underlying mechanisms of effector action are still being identified. Metnase (also called SETMAR) is a SET and transposase domain protein that promotes both DNA double-strand break (DSB) repair and restart of stalled replication forks. In this study, we show that Metnase is phosphorylated only on Ser495 (S495) in vivo in response to DNA damage by ionizing radiation. Chk1 is the major mediator of this phosphorylation event. We had previously shown that wild-type (wt) Metnase associates with chromatin near DSBs and methylates histone H3 Lys36. Here we show that a Ser495Ala (S495A) Metnase mutant, which is not phosphorylated by Chk1, is defective in DSB-induced chromatin association. The S495A mutant also fails to enhance repair of an induced DSB when compared with wt Metnase. Interestingly, the S495A mutant demonstrated increased restart of stalled replication forks compared with wt Metnase. Thus, phosphorylation of Metnase S495 differentiates between these two functions, enhancing DSB repair and repressing replication fork restart. In summary, these data lend insight into the mechanism by which Chk1 enhances repair of DNA damage while at the same time repressing stalled replication fork restart. PMID- 22231451 TI - The relationship between current and former shift work and the metabolic syndrome. AB - OBJECTIVE: The occurrence of possible health hazards among former shift workers is not well-known. We studied associations of former and current shift work with the metabolic syndrome (MetS). METHODS: Participants were 1811 full-time employees of a large airline company (1009 men). Working times were categorized into five groups: day worker [N=297 (the reference group)], former shift worker (N=341), 2-shift worker (N=418), night-shift worker (N=283), and in-flight worker (N=472). MetS was measured by the International Diabetes Federation (IDF) criteria and the National Institute of Health Adult Treatment Panel III (NCEP) guideline. The prevalence of the syndrome in the study population was 28.5% and 20.8%, respectively. RESULTS: Among male former shift workers, MetS was more prevalent compared to male day workers [IDF: age-adjusted odds ratio (OR) 2.13, 95% confidence interval (95% CI) 1.35-3.37; NCEP: OR 1.83, 95% CI 1.13-2.96]. Associations did not change after additional adjustments for education, smoking, physical activity, alcohol consumption, and insomnia symptoms (IDF: OR 2.00, 95% CI 1.26-3.19; NCEP: 1.67, 95% CI 1.02-2.72). Male 2-shift workers also had an elevated risk of IDF-defined MetS (OR 1.64, 95% CI 1.06-2.55) but the association weakened in the fully adjusted analyses (OR 1.48, 95% CI 0.93-2.24). Prevalence of the MetS was marginally significantly higher among night-shift work (IDF: OR 1.51, 95% CI 0.95-2.34) and was attenuated further with additional adjustments (OR 1.37, 95% CI 0.84-2.22). Among women, no significant differences in prevalence of the MetS between day work and shift work were observed. CONCLUSION: Findings of the cross-sectional study suggest that MetS diagnosed by standardized criteria is more prevalent among former male shift workers than current day workers who have never worked in shifts. PMID- 22231452 TI - Arctic actinomycetes as potential inhibitors of Vibrio cholerae biofilm. AB - The aim of this study was to identify novel biofilm inhibitors from actinomycetes isolated from the Arctic against Vibrio cholerae, the causative agent of cholera. The biofilm inhibitory activity of actinomycetes was assessed using biofilm assay and was confirmed using air-liquid interphase coverslip assay. The potential isolates were identified using 16S rRNA gene sequencing. Of all, three isolates showed significant biofilm inhibition against V. cholerae. The results showed that 20% of the actinomycetes culture supernatant could inhibit up to 80% of the biofilm formation. When different extracted fractions were assessed, significant biofilm inhibition activity was only seen in the diethyl ether fraction of A745. At 200 MUg ml(-1) of diethyl ether fraction, 60% inhibition of V. cholerae biofilm was observed. The two potential isolates were found to be Streptomyces sp. and one isolate belonged to Nocardiopsis sp. This is the first report showing a Streptomyces sp. and Nocardiopsis sp. isolated from the Arctic having a biofilm inhibitory activity against V. cholerae. The spread of drug resistant V. cholerae strains is a major clinical problem and the ineffectiveness in antibiotic treatment necessitates finding new modes of prevention and containment of the disease, cholera. The formation of biofilms during the proliferation of V. cholerae is linked to its pathogenesis. Hence, the bioactive compound from the culture supernatant of the isolates identified in this study may be a promising source for the development of a potential quorum sensing inhibitors against V. cholerae. PMID- 22231453 TI - Evidence for two putative holin-like peptides encoding genes of Bacillus pumilus strain WAPB4. AB - An open reading frame encoding a 71-amino acid BhlA bacteriocin-related holin like peptide was present upstream of 86-amino acid holin-like peptide, xhlB, encoding gene in the genome of Bacillus pumilus strain WAPB4. Analysis of BhlA using TMHMM server suggested one putative transmembrane domain at the N-terminal part and a number of highly charged amino acid residues at the C-terminal part. XhlB of B. pumilus strain WAPB4 composed of two putative transmembrane domains separated by a beta-turn, and numerous charged residues in the C-terminus. The dual start motifs were found in both BhlA and XhlB. Structural analysis of their sequence revealed features characteristic for holin. To analyze the effect of BhlA on bacteria cell, its ORF was cloned and expressed in Escherichia coli BL21(DE3). Expression of holin-like peptide, BhlA, was found to be toxic to the host cell. The site of action of BhlA is on the cell membrane and caused bacterial death by cell membrane disruption as clearly demonstrated by transmission electron microscopy or TEM. PMID- 22231454 TI - Synergistic effect between two bacteriocin-like inhibitory substances produced by Lactobacilli Strains with inhibitory activity for Streptococcus agalactiae. AB - Group B streptococci (GBS) are bacterial species that colonize the vagina in pregnant women and as such may cause serious infections in neonates that passed through the birth channel. The objective of this work was to study the inhibitory activities produced by each bacteriocin-like inhibitory substance (BLIS) of Lactobacillus rhamnosus L60 and Lactobacillus fermentum L23, and the effects of the combined BLIS-es of these lactobacilli on GBS. The interactions between the BLIS-es were assessed by qualitative and quantitative methods on agar plates. The minimum inhibitory concentrations (MICs) and fractional inhibitory concentrations (FICs) were determined by a modification of the broth microdilution and checkerboard methods, respectively. Antibiotic susceptibilities of all S. agalactiae strains were assayed and the results of these tests were evaluated for statistical significance. A 7.5% of GBS isolates were recovered from 760 pregnant women and 91% of those strains were susceptible to each BLIS produced by L. fermentum, L. rhamnosus, and also to a mixture of them. The comparisons among the BLIS-es showed statistically significant differences, with a combination of the BLIS-es from the two Lactobacillus species being better than the BLIS of each one alone (P < 0.05) as GBS growth inhibitors. Synergistic activities between the BLIS-es were found on 100% of susceptible GBS strains, MICs ranges of BLIS of L23 and L60 were 80-160 and 160-320 UA ml(-1), respectively. By the checkerboard method, the BLIS-es combination showed synergistic effect on all sensitive strains tested, with values of FICs ranging from 0.131 to 0.218. The BLIS-es produced by these lactobacilli of vaginal origin were able to inhibit S. agalactiae isolates. The results indicate that these strains may have probiotic potential for the control of GBS in women and may consequently prevent GBS infections in newborns. PMID- 22231456 TI - Efficient synthesis of multicyclic spirooxindoles via a cascade Michael/Michael/oxa-Michael reaction of curcumins and isatylidene malononitriles. AB - A cascade Michael/Michael/oxa-Michael reaction between curcumins and isatylidene malononitriles has been developed. Multicyclic spirooxindoles were prepared in excellent yields and diastereoselectivities. DMAP was found to catalyze this transformation efficiently under mild reaction conditions. PMID- 22231455 TI - Assessment of in vitro antioxidant, antibacterial and immune activation potentials of aqueous and ethanol extracts of Phyllanthus niruri. AB - BACKGROUND: Recently much attention has been paid to biologically active plants because of their low production cost and fewer adverse effects compared with chemical drugs. In the present investigation the bioactivity of Phyllanthus niruri ethanol and aqueous extracts was evaluated in vitro. RESULTS: The ethanol extract of P. niruri showed a high level of flavonoid content (123.9 +/- 0.002 mg g-1), while the aqueous extract showed the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH; IC50 6.85 +/- 1.80 umol L-1) and 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS; 46.44 +/- 0.53 umol L-1) free radical scavenging activities with high phenol content (376 +/- 0.02 mg g-1) and elevated levels of ferric reducing antioxidant power (FRAP; 23 883 +/- 0.019 mmol g-1) with excellent antibacterial activity against Staphylococcus aureus (20 mm inhibition zone) and Streptococcus agalactiae (12 mm inhibition zone), respectively, in addition to the best immune activation potential of human peripheral blood mononuclear cells (450.5%). CONCLUSIONS: It is clear from our results that both extracts of P. niruri has excellent bioactivity roles via elevated levels of antibacterial, antioxidant and percentage of peripheral blood mononuclear cell proliferation, which could lead to the development of medications for clinical use. PMID- 22231457 TI - Influence of pregnancy on the adipocytokine and peroxisome proliferator-activated receptor pathways in peripheral blood mononuclear cells from healthy donors and rheumatoid arthritis patients. AB - OBJECTIVE: To identify candidate genes that are regulated by human pregnancy and have the potential to modulate rheumatoid arthritis (RA) disease activity. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy pregnant volunteers were analyzed using Affymetrix GeneChips at 4 time points (during the first, second, and third trimesters and 6 weeks postpartum). Based on the GeneChip data, target genes were further analyzed via real-time quantitative polymerase chain reaction (qPCR) using PBMCs from healthy controls and RA patients. In order to determine the cellular source of the candidate gene messenger RNA (mRNA), monocytes and lymphocytes from healthy controls and RA patients were positively selected using magnetic beads, and their mRNA was analyzed by qPCR. RESULTS: One-way analysis of variance identified 1,286 mRNAs that were differentially expressed with regard to the 4 time points. The changes became more pronounced as pregnancy progressed, and they were reversed postpartum. A subsequent pathway analysis suggested a regulatory role of pregnancy on the adipocytokine pathway as well as on the peroxisome proliferator activated receptor (PPAR) signaling pathway. Of 19 preselected candidate genes, AKT3, SOCS3, FADS2, STAT1, and CD36 proved to be differentially regulated by pregnancy. In samples from RA patients, the differences were concordant with those in healthy controls but more pronounced. Both T lymphocytes and monocytes contributed to the regulated expression of these genes. CONCLUSION: Our findings indicate that normal human pregnancy leads to changes in the expression of several molecular pathways in PBMCs, which are reversed postpartum. Changes in RA patients, although concordant, exceed the levels observed in healthy controls. Genes of the adipocytokine and PPAR signaling pathways qualify as candidates for the modulation of RA disease activity during pregnancy. PMID- 22231458 TI - A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT. AB - An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT. PMID- 22231459 TI - Patients receiving HLA-haploidentical/partially matched related allo-HSCT can achieve desirable health-related QoL that is comparable to that of patients receiving HLA-identical sibling allo-HSCT. AB - To investigate the health-related quality of life (HRQoL) of patients receiving allogeneic hematopoietic SCT (allo-HSCT) from HLA-haploidentical/partially matched related donors (HID/PMRD) and to compare this value with that of patients receiving allo-HSCT from HLA-identical sibling donor (ISD), a total of 350 patients receiving allo-HSCT were enrolled in a study (ISD: 173; HID/PMRD: 177). HRQoL post transplantation was evaluated by an SF-36 questionnaire. The effect of various factors on the HRQoL was analyzed through COX regression. Compared with the ISD group, patients in the HID/PMRD group had higher scores in physical functioning, general health, bodily pain, vitality and emotional role functioning, and these patients functioned significantly better on the physical and mental component summaries. Also, long-term survivors exhibit better HRQoL. Measured by multivariate analysis, extensive chronic GVHD was observed to have a strongly negative impact on patients' HRQoL, while male gender status, lower age when receiving allo-HSCT and returning to work or school were associated with positive impacts on at least one subscale. These results showed that the HRQoL of patients receiving HID/PMRD hematopoietic SCT (HSCT) is comparable to that of patients receiving ISD HSCT, and HLA disparity is not the factor affecting the HRQoL. PMID- 22231460 TI - Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT. AB - CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160-200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17-114% IIV and 12-103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9*2 explained a significant portion of the IIV in the clearance (P<0.002) and thus the area under the concentration curve (P<0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established. PMID- 22231461 TI - ECIL-3 classical diagnostic procedures for the diagnosis of invasive fungal diseases in patients with leukaemia. AB - Invasive fungal diseases (IFDs) continue to cause considerable morbidity and mortality in patients with haematological malignancy. Diagnosis of IFD is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often reported to be low, which may at least in part be due to sub-optimal sampling or subsequent handling in the routine microbiological laboratory. Therefore, a working group of the European Conference in Infections in Leukaemia was convened in 2009 with the task of reviewing the classical diagnostic procedures and providing recommendations for their optimal use. The recommendations were presented and approved at the ECIL-3 conference in September 2009. Although new serological and molecular tests are examined in separate papers, this review focuses on sample types, microscopy and culture procedures, antifungal susceptibility testing and imaging. The performance and limitations of these procedures are discussed and recommendations are provided on when and how to use them and how to interpret the results. PMID- 22231462 TI - Long-term follow-up after autologous stem cell transplantation for light- and heavy-chain deposition disease. PMID- 22231463 TI - Graft vs GIST? PMID- 22231464 TI - The role of HLA antibodies in allogeneic SCT: is the 'type-and-screen' strategy necessary not only for blood type but also for HLA? AB - The role of HLA antibodies in SCT has drawn increasing attention because of the significantly increased number of patients who receive HLA-mismatched SCT, including cord blood transplantation, haploidentical SCT and unrelated SCT. Technical advancements in the methods of HLA Ab testing have realized rapid, accurate and objective identification, as well as quantification of specific HLA antibodies. Recent clinical studies have suggested that the presence of donor specific HLA antibodies (DSA) in patients is associated with graft failure in HLA mismatched SCT when the above-listed stem cell sources are used and results in different impacts. Of note, most of the 'HLA-matched' unrelated SCT actually involve HLA mismatches in HLA-DP and the presence of antibodies against this locus has been reported to be associated with graft failure. Thus, HLA Ab should be examined as a work-up for all patients who undergo SCT from 'alternative donors.' The simplest route for preventing HLA Ab-mediated graft failure in Ab positive patients is to avoid donors who possess the target Ag of HLA antibodies. If SCT from such donors must be performed, treatment for DSA before SCT may improve the chances of successful donor engraftment. PMID- 22231465 TI - Successful use of second cord blood transplantation to achieve long-term remission in cord blood donor cell-derived AML harboring a FLT3-ITD and an NPM1 mutation. PMID- 22231466 TI - Enteral nutrition: a first option for nutritional support of children following allo-SCT? AB - Parenteral nutrition (PN) is the treatment of choice for nutritional support of patients undergoing allo-SCT following myeloablative conditioning (MAC). Here we prospectively assessed the outcomes of early enteral nutrition (EN) in a paediatric cohort. From 2003 to 2010, all 65 consecutive children undergoing MAC allo-SCT at our referral centre began EN the day after transplantation. Post transplant and nutritional outcomes of patients receiving only EN (EN group, n=50) were compared with those of patients requiring additional PN (EN-PN group, n=15). In the EN group time to platelet recovery (P=0.01) and length of hospitalisation (P<0.001) were shorter, while in the EN-PN group the proportion of unrelated donors (P=0.02) and the frequency of severe acute GVHD (aGVHD; P=0.004) were higher. All patients were alive at day 100. PN was started 14 days after transplant because of poor digestive tolerance to EN or severe gut aGVHD. The body mass index Z-score in the EN-PN group decreased from transplant to discharge (P=0.02). In only 23% of cases was PN required for severely ill patients. Our results suggest that EN might be considered to be an option for nutritional support in children undergoing MAC allo-SCT, while PN should be used only as a rescue option, possibly in combination with EN. PMID- 22231467 TI - Temporal changes of strain parameters in the progress of chronic ischemia: with comparison to transmural infarction. AB - The aim of this study was to reveal the temporal and spatial changes of strain parameters during the progression of chronic coronary ischemia. Fourteen pigs received occluder implantation to create gradual ischemia (CI), while six pigs underwent a sham surgery (Control). Six pigs after myocardial infarction were also studied (MI). Strain analysis was performed using a speckle-tracking algorithm. Eleven of the 14 animals with occluder implantation had total occlusion of the left anterior descending artery with collaterals at 1 month (early occlusion group), whereas three pigs had occlusion at 3 months (late occlusion group). Both radial strain (RS) and circumferential strain (CS) of ischemic area deteriorated at 1 month in the early occlusion group and remained at the same level throughout the remaining 2 months of the experiment. In the late occlusion group, RS gradually declined, while CS took the same course as Control until the 2 month time point. Thereafter, both metrics reached the same level as the early occlusion group at the time of occlusion. Interestingly, RS in the remote area decreased moderately, whereas CS remained normal in CI pigs. The comparison between CI and MI revealed preserved CS at the ischemic area in CI pigs. Both RS and CS deteriorate by the time total coronary occlusion was established and remain at the same level thereafter. Altered RS in the remote area may be an indicator of remodeling in the non-ischemic area, whereas CS may be useful for distinguishing between transmural and non-transmural scar. PMID- 22231468 TI - Applicability, limitations and downstream impact of echocardiography utilization based on the Appropriateness Use Criteria for transthoracic and transesophageal echocardiography. AB - To evaluate impact of echocardiography on patient management based on published transthoracic echocardiography (TTE) Appropriate Use Criteria (AUC). A prospective analysis of 170 consecutive outpatients who underwent TTE over a period of 2 months. Echo studies were classified into appropriate (A), inappropriate (I), or uncertain (U) based on the 2007/2011 AUC. A fourth group of studies which were not addressed by the 2007 AUC and therefore have unclassifiable category (UC) were also included in the analysis. The impact of AUC categorized echo results on patient management were evaluated by review of patient records in the ensuing 2 months. Based on 2007 AUC, 77% (131/170) were A, 9% were I, and 14% were UC category. Echo studies classified as A were more likely to be associated with new and major findings, (P = 0.034) and (P = 0.028) respectively when compared to all other studies. Furthermore, patient care intervention as defined in the study protocol was significantly associated with A studies as opposed to I and UC studies (P = 0.004). A studies were also more likely to have an impact on patient management when compared to other studies (P = 0.022). When studies were re-evaluated based on the 2011 AUC, all prior UC studies were now included in the U group in the new AUC of 2011, and there was no change in A or I study classification. This study demonstrates that the 2007/2011 AUC are helpful in evaluating practice patterns in a majority of outpatients undergoing TTE. Implementing AUC have a direct clinical impact as A studies are significantly more likely to reveal new and major findings, and more likely to result in a patient care intervention based on the echo findings. PMID- 22231469 TI - Intracranial dural metastasis from uterine leiomyosarcoma with orbital extension. AB - Intracranial metastases from uterine leiomyosarcoma are very rare and have been found mainly in the brain (17 cases); on the other hand, metastases to the skull, dura and orbit are really exceptional. The authors report the case of a 57-year old woman who presented with a 6-week history of right proptosis, left hemiparesis, intracranial hypertension and torpor 8 months after surgery for uterine leiomyosarcoma. CT scan showed a very large right frontal tumor with both intracranial and intraorbital extension. At operation the tumor was found to arise from the dura of the right anterior cranial fossa; complete removal of the intracranial tumor mass and partial removal of the intraorbital component were performed. However, early tumor regrowth was observed 45 days after operation and death occurred 2 months later. Pathologic examination showed a high-grade sarcoma with smooth muscle differentiation and high mitotic activity. Immunohistochemical staining revealed positivity for actin and vimentin and negativity for S-100 protein, cytocheratin and desmin. This is the first reported case of uterine leiomyosarcoma metastatic to the dura of the anterior cranial fossa with intracranial and intraorbital extension. An aggressive surgical resection is the best treatment of intracranial metastatic leiomyosarcoma, because of the scarce response to radiotherapy and chemotherapy. However, the outcome is poor, with early recurrence. PMID- 22231470 TI - Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia. AB - Our previous studies have showed that ginsenoside (GS)-Rd, a mono-compound isolated from traditional Chinese herb panax ginseng, has the neuroprotective effects following ischemic stroke. However, the underlying mechanisms are still largely unknown. Our latest study showed that GS-Rd could block calcium influx in cultured cortical neurons after excitotoxic injury, indicating that GS-Rd may act on cation channels. To explore this possibility, in this study, we used a rat middle cerebral artery occlusion (MCAO) model to examine the effects of GS-Rd on the expression of non-selective cation channels, including transient receptor potential melastatin (TRPM) and acid sensing ion channels (ASIC), and cation channels, including N-methyl-D-aspartate (NMDA) receptors, which all play essential roles in ischemic stroke. Our results showed that both TRPM and ASIC channels were expressed in the brain. At 24 h following MCAO insult, mRNA and protein expression levels of TRPM7, ASIC1a and ASIC2a were significantly increased. Pretreatment of 10 mg/kg GS-Rd attenuated MCAO-induced expression of TRPM7 and ASIC1a but promoted that of ASIC2a. In contrast, GS-Rd had no significant effects on the expression of NMDA receptors. Thus, our results suggest that GS-Rd neuroprotection following cerebral ischemia may be at least due to its effects on the expression of TRPM7, ASIC1a and ASIC2a. PMID- 22231471 TI - Exercise improves motor deficits and alters striatal GFAP expression in a 6-OHDA induced rat model of Parkinson's disease. AB - Astrocytic changes have been demonstrated in several neurodegenerative diseases, showing that these cells play an important role in functional recovery/maintenance against brain damage. Physical exercise is known to contribute to this process; however, the cellular mechanisms involved are not fully understood. This study investigated the effects of physical exercise on motor deficits and the expression of glial fibrillary acidic protein (GFAP) in a model of Parkinson's disease (PD). Rats were divided into four groups: sham sedentary (SS) and sham trained (ST); lesioned sedentary (LS) and lesioned trained (LT). 6-OHDA was infused unilaterally into the medial forebrain bundle. Behavioral tasks were applied to evaluate motor abilities. Tyrosine hydroxylase (TH-in substantia nigra) and GFAP (in striatum) immunoreactivities (ir) were semi quantified using optical density. The animals submitted to treadmill training completed fewer pharmacological-induced rotations when compared with sedentary animals and they also showed ameliorated motor impairments. Interestingly, although no change in TH-ir, the exercise led to restored striatal GFAP expression in the LT group while there was no effect in the ST group. This study is the first study to show data indicating the recovery of GFAP expression post exercise in this model and further research is necessary to determine the precise action mechanisms of exercise on astrocytes in the PD. PMID- 22231472 TI - Anti-N-methyl-D-aspartate receptor encephalitis with minimal cortical impairment. AB - Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been recently identified as a fulminant encephalopathy, presenting with a variety of symptoms including behavioral change, amnesia and seizures suggesting cortical gray matter involvement. A 42-year-old woman presented with acute-onset clinical and magnetic resonance imaging (MRI) findings indicating brainstem and diencephalon involvement. Her neuropsychological examination revealed mild frontal dysfunction with no memory impairment. Detailed diagnostic workup proved negative except for serum/cerebrospinal fluid (CSF) NMDAR-antibodies and increased activity in inguinal and pelvic lymph nodes on positron-emission tomography (PET) examination. The symptoms and MRI findings completely resolved following steroid treatment. A 38-year-old woman presented with migraine-type headache and episodes of forgetfulness. Her brain MRI and neuropsychological examination were normal and diagnostic workup was unremarkable. N-methyl-D-aspartate receptor antibodies were identified in her sera and her symptoms spontaneously resolved within few months. Our cases suggest that anti-NMDAR encephalitis might present with minimal cognitive impairment, no apparent cortical gray matter involvement, a mild clinical course and without the classical clinical features of the disease. PMID- 22231473 TI - Pheromonal mediation of intraseasonal declines in the attractivity of female red sided garter snakes, Thamnophis sirtalis parietalis. AB - During the breeding season, female red-sided garter snakes (Thamnophis sirtalis parietalis) produce and express a sexual attractiveness pheromone that elicits male courtship behavior. Composed of a homologous series of saturated and monounsaturated methyl ketones, this pheromone is expressed in female skin lipids. Recent studies have shown that the sexual attractivity of unmated female garter snakes declines as the breeding season progresses. Here, we investigated whether temporal changes in the quantity and/or quality of the female sexual attractiveness pheromone are responsible for the observed loss of attractivity. Female red-sided garter snakes were collected immediately following spring emergence and held under natural conditions for the duration of the breeding season. Behavioral experiments confirmed that unmated females become significantly less attractive to males within two weeks of emergence from hibernation. Additionally, these females had lower estradiol concentrations at two weeks post-emergence. Subsequent chemical analyses revealed qualitative variation between the pheromone profiles of newly emerged females and those of females at two weeks post-emergence. Together, these results support the hypothesis that changes in the female sexual attractiveness pheromone are responsible for declining post-emergence female attractivity in garter snakes. PMID- 22231474 TI - Chemical ecology of astigmatid mites LXXXVII. S-(+)-isopiperitenone: re identification of the alarm pheromone as the female sex pheromone in Tyrophagus similis (Acari: Acaridae). AB - Behavioral analysis revealed that S-(+)-isopiperitenone [(S)-3-methyl-6 isopropenyl-2-cyclohexen-1-one], previously identified as an alarm pheromone, is also the female sex pheromone of Tyrophagus similis (Astigmata: Acaridae), showing maximum male attraction at a dose of 0.1 female equivalent. Although the antipode, R-(-)-isopiperitenone, was not detectable in the mite extract, this synthetic optical isomer (80% e.e.) also induced activity at a dose of 100 ng, a response indicative of S-(+)-isopiperitenone being the active compound. The average content was determined to be 38.5 ng per female and 19.8 ng per male. This is the first example of an astigmatid mite species possessing a compound that functions as an alarm as well as a sex pheromone. PMID- 22231475 TI - Limonene: electronic state spectroscopy by high-resolution vacuum ultraviolet photoabsorption, electron scattering, He(I) photoelectron spectroscopy and ab initio calculations. AB - Electronic state spectroscopy of limonene has been investigated using vacuum ultraviolet photoabsorption spectroscopy in the energy range 5.0-10.8 eV. The availability of a high resolution photon beam (~0.075 nm) enabled detailed analysis of the vibrational progressions and allowed us to propose, for the first time, new assignments for several Rydberg series. Excited states located in the 7.5-8.4 eV region have been studied for the first time. A He(I) photoelectron spectrum has also been recorded from 8.2 to 9.5 eV and compared to previous low resolution works. A new value of 8.521 +/- 0.002 eV for the ground ionic state adiabatic ionisation energy is proposed. Absolute photoabsorption cross sections were derived in the 10-26 eV range from electron scattering data. All spectra presented in this paper represent the highest resolution data yet reported for limonene. These experiments are complemented by new ab initio calculations performed for the three most abundant conformational isomers of limonene, which we then used in the assignment of the spectral bands. PMID- 22231476 TI - Biochemical characterisation of the chlamydial MurF ligase, and possible sequence of the chlamydial peptidoglycan pentapeptide stem. AB - Chlamydiaceae are obligate intracellular bacteria that do not synthesise detectable peptidoglycan although they possess an almost complete arsenal of genes encoding peptidoglycan biosynthetic activities. In this paper, the murF gene from Chlamydia trachomatis was shown to be capable of complementing a conditional Escherichia coli mutant impaired in UDP-MurNAc-tripeptide:D-Ala-D-Ala ligase activity. Recombinant MurF from C. trachomatis was overproduced and purified from E. coli. It exhibited ATP-dependent UDP-MurNAc-X-gamma-D-Glu-meso A(2)pm:D-Ala-D-Ala ligase activity in vitro. No significant difference of kinetic parameters was seen when X was L-Ala, L-Ser or Gly. The L-Lys-containing UDP MurNAc-tripeptide was a poorer substrate as compared to the meso-A(2)pm containing one. Based on the respective substrate specificities of the chlamydial MurC, MurE, MurF and Ddl enzymes, a sequence L-Ala/L-Ser/Gly-gamma-D-Glu-meso A(2)pm-D-Ala-D-Ala is expected for the chlamydial pentapeptide stem, with Gly at position 1 being less likely. PMID- 22231477 TI - Characterization of Edwardsiella tarda rpoN: roles in sigma(70) family regulation, growth, stress adaption and virulence toward fish. AB - Edwardsiella tarda EIB202, a Gram-negative pathogen with strong virulence, is an opportunistic pathogen capable of causing edwardsiellosis with high mortality to fish. Alternative sigma factor 54 (RpoN) is an important regulator of virulence and stress resistance genes in many bacterial species and mainly responsible for transcription of genes in nitrogen utilization. In this study, the in-frame rpoN deletion mutant was constructed to analyze the function of RpoN in Edwardsiella tarda firstly. Compared to the wild-type and complemented strain rpoN (+), the DeltarpoN was impaired in terms of the ability to survive under oxidative stress, osmotic stress and acid resistance, as well as the growth in Luria-Bertani medium, demonstrating essential roles of RpoN in stress resistance and nitrogen utilization. In addition, the DeltarpoN displayed markedly decreased biofilm formation and chondroitinase activity and was attenuated in virulence reflected in the increased median lethal dose value and extended infection cycle. Real-time polymerase chain reaction revealed that the expression levels of sigma(70) class changed in varying degrees in the rpoN mutant. Especially, the expression levels of rpoS and fliA were down-regulated 4.1-fold and 7.9-fold in stationary phase in comparison with the wild type, respectively. Furthermore, two differential expression genes, znuA and flhC, were detected in the wild type and DeltarpoN using the method of differential display reverse transcription PCR. PMID- 22231478 TI - A case of caffeine-induced coronary artery vasospasm of a 17-year-old male. AB - The intentional consumption and use of stimulants, such as caffeine, are known to have numerous interactions with the human cardiovascular system. Ex vivo studies have shown caffeine-induced vasoconstriction of coronary arteries (Forman et al. in Ann Emerg Med 29:178-180, 1997). We report on a case of a 17-year-old male who presented with angina and an abnormal electrocardiogram (ECG) concerning for ST elevation myocardial infarct. He was found to have diffuse ECG changes and markedly elevated cardiac enzymes. A transthoracic echocardiogram revealed a reduced left ventricular (LV) systolic function as well as segmental wall motion abnormalities consistent with an ischemic insult. The patient admitted to consuming near lethal doses of caffeine immediately preceding his angina. He was diagnosed with coronary vasospasms as a result of stimulant use. During hospitalization, ECG changes resolved, cardiac enzymes started trending downward, and LV systolic function returned to normal, all consistent with stunned myocardium that fully recovered. This case strongly suggests that overuse of stimulants, such as caffeine, should be considered in patients presenting with coronary vasospasms, particularly in teenagers and young adults. PMID- 22231479 TI - Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. AB - OBJECTIVE: To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids. METHODS: Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end point was renal response status at week 52. RESULTS: Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving rituximab (P = 0.18); partial responses accounted for most of the difference. The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti-double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group. CONCLUSION: Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals. PMID- 22231480 TI - Scope of symptoms and self-management strategies for chemotherapy-induced peripheral neuropathy in breast cancer patients. AB - PURPOSE: This study explored the self-management strategies utilized by female breast cancer patients to cope with the impact of chemotherapy-induced peripheral neuropathy (CIPN) symptoms. We also examined the variety of taxane-related side effects in women with and without CIPN in order to discriminate the CIPN symptom experience. METHODS: A purposive sample of 25 patients treated with docetaxel or paclitaxel were recruited, half with and half without CIPN. Semistructured interviews and patient level data were utilized for this exploratory, descriptive study. Interview data were analyzed with the constant comparative method; patient level data were abstracted from the electronic medical record. RESULTS: Participants were aged 24-60 years, were currently receiving chemotherapy or within 6 months of having completed treatment, and 14 had CIPN. CIPN impacted routine activities, functions, and behaviors in the areas of domestic, work, and social/leisure life. Multiple self-management and coping strategies to minimize the impact of CIPN symptoms were reported; the focus was on movement to reduce symptoms, attitude awareness, logistics to simplify demands, and environmental change. Women with and without CIPN were similar in the quantity and type of other reported side effects. CONCLUSIONS: CIPN affects breast cancer patients' routine activities, functions, and behaviors, but they develop management strategies to reduce the impact. The management strategies reported in this study suggest breast cancer patients may adopt interventions that focus on exercise, mindfulness, occupational therapy, and environmental planning toward the goal of reducing the impact of CIPN symptoms on their lives. PMID- 22231481 TI - Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. AB - Genomic duplications spanning Xq28 are associated with a spectrum of phenotypes, including anxiety and autism. The minimal region shared among affected individuals includes MECP2 and IRAK1, although it is unclear which gene when overexpressed causes anxiety and social behavior deficits. We report that doubling MECP2 levels causes heightened anxiety and autism-like features in mice and alters the expression of genes that influence anxiety and social behavior, such as Crh and Oprm1. To test the hypothesis that alterations in these two genes contribute to heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) that have reduced Crh and Oprm1 expression. In MECP2 TG1 animals, reducing the levels of Crh or its receptor, Crhr1, suppressed anxiety-like behavior; in contrast, reducing Oprm1 expression improved abnormal social behavior. These data indicate that increased MeCP2 levels affect molecular pathways underlying anxiety and social behavior and provide new insight into potential therapies for MECP2-related disorders. PMID- 22231482 TI - Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint. AB - Exogenous double-stranded RNA (dsRNA) has been shown to exert homology-dependent effects at the level of both target mRNA stability and chromatin structure. Using C. elegans undergoing RNAi as an animal model, we have investigated the generality, scope and longevity of dsRNA-targeted chromatin effects and their dependence on components of the RNAi machinery. Using high-resolution genome-wide chromatin profiling, we found that a diverse set of genes can be induced to acquire locus-specific enrichment of histone H3 lysine 9 trimethylation (H3K9me3), with modification footprints extending several kilobases from the site of dsRNA homology and with locus specificity sufficient to distinguish the targeted locus from the other 20,000 genes in the C. elegans genome. Genetic analysis of the response indicated that factors responsible for secondary siRNA production during RNAi were required for effective targeting of chromatin. Temporal analysis revealed that H3K9me3, once triggered by dsRNA, can be maintained in the absence of dsRNA for at least two generations before being lost. These results implicate dsRNA-triggered chromatin modification in C. elegans as a programmable and locus-specific response defining a metastable state that can persist through generational boundaries. PMID- 22231483 TI - De novo assembly and genotyping of variants using colored de Bruijn graphs. AB - Detecting genetic variants that are highly divergent from a reference sequence remains a major challenge in genome sequencing. We introduce de novo assembly algorithms using colored de Bruijn graphs for detecting and genotyping simple and complex genetic variants in an individual or population. We provide an efficient software implementation, Cortex, the first de novo assembler capable of assembling multiple eukaryotic genomes simultaneously. Four applications of Cortex are presented. First, we detect and validate both simple and complex structural variations in a high-coverage human genome. Second, we identify more than 3 Mb of sequence absent from the human reference genome, in pooled low coverage population sequence data from the 1000 Genomes Project. Third, we show how population information from ten chimpanzees enables accurate variant calls without a reference sequence. Last, we estimate classical human leukocyte antigen (HLA) genotypes at HLA-B, the most variable gene in the human genome. PMID- 22231484 TI - Genome-wide patterns of genetic variation in worldwide Arabidopsis thaliana accessions from the RegMap panel. AB - Arabidopsis thaliana is native to Eurasia and is naturalized across the world. Its ability to be easily propagated and its high phenotypic variability make it an ideal model system for functional, ecological and evolutionary genetics. To date, analyses of the natural genetic variation of A. thaliana have involved small numbers of individual plants or genetic markers. Here we genotype 1,307 worldwide accessions, including several regional samples, using a 250K SNP chip. This allowed us to produce a high-resolution description of the global pattern of genetic variation. We applied three complementary selection tests and identified new targets of selection. Further, we characterized the pattern of historical recombination in A. thaliana and observed an enrichment of hotspots in its intergenic regions and repetitive DNA, which is consistent with the pattern that is observed for humans but which is strikingly different from that observed in other plant species. We have made the seeds we used to produce this Regional Mapping (RegMap) panel publicly available. This panel comprises one of the largest genomic mapping resources currently available for global natural isolates of a non-human species. PMID- 22231486 TI - DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. AB - OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up-regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc. METHODS: CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real-time reverse transcription-polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region. RESULTS: CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated. CONCLUSION: Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc. PMID- 22231485 TI - Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. AB - Chromatin modifications are associated with many aspects of gene expression, yet their role in cellular transitions during development remains elusive. Here, we use a new approach to obtain cell type-specific information on chromatin state and RNA polymerase II (Pol II) occupancy within the multicellular Drosophila melanogaster embryo. We directly assessed the relationship between chromatin modifications and the spatio-temporal activity of enhancers. Rather than having a unique chromatin state, active developmental enhancers show heterogeneous histone modifications and Pol II occupancy. Despite this complexity, combined chromatin signatures and Pol II presence are sufficient to predict enhancer activity de novo. Pol II recruitment is highly predictive of the timing of enhancer activity and seems dependent on the timing and location of transcription factor binding. Chromatin modifications typically demarcate large regulatory regions encompassing multiple enhancers, whereas local changes in nucleosome positioning and Pol II occupancy delineate single active enhancers. This cell type-specific view identifies dynamic enhancer usage, an essential step in deciphering developmental networks. PMID- 22231487 TI - Internal consistency, concurrent validity, and discriminant validity of a measure of public support for policies for active living in transportation (PAL-T) in a population-based sample of adults. AB - Active living is a broad conceptualization of physical activity that incorporates domains of exercise; recreational, household, and occupational activities; and active transportation. Policy makers develop and implement a variety of transportation policies that can influence choices about how to travel from one location to another. In making such decisions, policy makers act in part in response to public opinion or support for proposed policies. Measures of the public's support for policies aimed at promoting active transportation can inform researchers and policy makers. This study examined the internal consistency, and concurrent and discriminant validity of a newly developed measure of the public's support for policies for active living in transportation (PAL-T). A series of 17 items representing potential policies for promoting active transportation was generated. Two samples of participants (n = 2,001 and n = 2,502) from Montreal, Canada, were recruited via random digit dialling. Analyses were conducted on the combined data set (n = 4,503). Participants were aged 18 through 94 years (58% female). The concurrent and discriminant validity of the PAL-T was assessed by examining relationships with physical activity and smoking. To explore the usability of the PAL-T, predicted scale scores were compared to the summed values of responses. Results showed that the internal consistency of the PAL-T was 0.70. Multilevel regression demonstrated no relationship between the PAL-T and smoking status (p > 0.05) but significant relationships with utilitarian walking (p < 0.05) and cycling (p < 0.01) for at least 30 minutes on 5 days/week. The PAL-T has acceptable internal consistency and good concurrent and discriminant validity. Measuring public opinion can inform policy makers and support advocacy efforts aimed at making built environments more suitable for active transportation while allowing researchers to examine the antecedents and consequences of public support for policies. PMID- 22231488 TI - Injection drug users' perspectives on placing HIV prevention and other clinical services in pharmacy settings. AB - In their role as a source of sterile syringes, pharmacies are ideally situated to provide additional services to injection drug users (IDUs). Expanding pharmacy services to IDUs may address the low utilization rates of healthcare services among this population. This qualitative study of active IDUs in San Francisco explored perspectives on proposed health services and interventions offered in pharmacy settings, as well as facilitators and barriers to service delivery. Eleven active IDUs participated in one-on-one semistructured interviews at a community field site and at a local syringe exchange site between February and May 2010. Results revealed that most had reservations about expanding services to pharmacy settings, with reasons ranging from concerns about anonymity to feeling that San Francisco already offers the proposed services in other venues. Of the proposed health services, this group of IDUs prioritized syringe access and disposal, clinical testing and vaccinations, and provision of methadone. Pharmacists' and pharmacy staff's attitudes were identified as a major barrier to IDUs' comfort with accessing services. The findings suggest that although IDUs would like to see some additional services offered within pharmacy settings, this is contingent upon pharmacists and their staff receiving professional development trainings that cultivate sensitivity towards the needs and experiences of IDUs. PMID- 22231489 TI - The importance of stereochemically active lone pairs for influencing Pb(II) and As(III) protein binding. AB - The toxicity of heavy metals, which is associated with the high affinity of the metals for thiolate rich proteins, constitutes a problem worldwide. However, despite this tremendous toxicity concern, the binding mode of As(III) and Pb(II) to proteins is poorly understood. To clarify the requirements for toxic metal binding to metalloregulatory sensor proteins such as As(III) in ArsR/ArsD and Pb(II) in PbrR or replacing Zn(II) in delta-aminolevulinc acid dehydratase (ALAD), we have employed computational and experimental methods examining the binding of these heavy metals to designed peptide models. The computational results show that the mode of coordination of As(III) and Pb(II) is greatly influenced by the steric bulk within the second coordination environment of the metal. The proposed basis of this selectivity is the large size of the ion and, most important, the influence of the stereochemically active lone pair in hemidirected complexes of the metal ion as being crucial. The experimental data show that switching a bulky leucine layer above the metal binding site by a smaller alanine residue enhances the Pb(II) binding affinity by a factor of five, thus supporting experimentally the hypothesis of lone pair steric hindrance. These complementary approaches demonstrate the potential importance of a stereochemically active lone pair as a metal recognition mode in proteins and, specifically, how the second coordination sphere environment affects the affinity and selectivity of protein targets by certain toxic ions. PMID- 22231490 TI - ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer--a comparative study of two monoclonal antibodies. AB - BACKGROUND: Overexpression of the ERG protein is highly prevalent in prostate cancer (PCa) and commonly results from gene fusions involving the ERG gene. Recently, N-terminal epitope-targeted mouse and a C-terminal epitope-targeted rabbit monoclonal anti-ERG antibody (ERG-MAbs) have been introduced for the detection of the ERG protein. Independent studies reported that immunohistochemistry (IHC) with both ERG-MAbs highly correlates with the underlying ERG gene rearrangement status. However, comparative studies of both antibodies are lacking. Here, we are among the first to compare the mouse ERG-MAb with the rabbit ERG-MAb for their concordance on the same PCa cohort. Furthermore, we assessed whether the ERG protein expression is conserved in lymph node and distant PCa metastases. METHODS: We evaluated tissue microarrays of 278 specimens containing 265 localized PCa, 29 lymph node, 30 distant metastases and 13 normal prostatic tissues. We correlated ERG protein expression with ERG rearrangement status using an ERG break-apart fluorescence in-situ hybridization assay and IHC of both ERG-MAbs. RESULTS: ERG expression and ERG rearrangement status were highly concordant regardless of whether the mouse or rabbit ERG-MAb was used (97.8% versus 98.6%, respectively). Of interest, both ERG antibodies reliably detected the ERG expression in lymph node and distant PCa metastases, of which a subset underwent decalcification. Lymphocytes only revealed immunoreactivity using the rabbit ERG-MAb. If ERG protein expression was present in localized PCa, we observed the same pattern in the corresponding lymph node metastases. CONCLUSIONS: By demonstrating a broad applicability of IHC to study ERG protein expression using either antibody, this study adds an important step toward a facilitated routine clinical application. Further, we demonstrate that the clonal nature of the ERG rearrangement is not restricted to the genomic level, but proceeds in the proteome. Together, our results simplify future efforts to further eliucidate the biological role of ERG in PCa. PMID- 22231491 TI - The effect of hydration on the UV absorption coefficient of intact melanosomes. AB - The physical properties of melanosomes have been shown to depend on water content. Herein, the ultraviolet absorption coefficient at lambda = 244 nm for intact bovine choroidal melanosomes is determined from photoemission electron microscopy images recorded as a function of vacuum exposure. The dehydration of the melanosome under ultra-high vacuum manifests itself by a decrease in the absorption coefficient to about 60% of its initial value, and a concomitant increase in its image brightness. This change in the absorption of the melanosome is consistent with the influence of solvent polarity on the UV absorption coefficient of model systems for the pigment eumelanin, the predominant UV absorber contained in the choroid melanosomes. PMID- 22231492 TI - Aberrant I-123 MIBG uptake in a gastrointestinal stromal tumour. PMID- 22231493 TI - The influence of ripening stage and cultivation system on the total antioxidant activity and total phenolic compounds of yellow passion fruit pulp. AB - BACKGROUND: This work aimed to investigate the influence of both ripening stage and cultivation system on the total phenolic compounds (TPC) and total antioxidant activity (TAA) of passion fruit pulp. TPC extraction was optimized using a 23 central composed design. The variables were fruit pulp volume, methanol volume and extraction solution volume. TPC was determined using the Folin-Ciocalteu reaction, and TAA using the ABTS radical reaction. RESULTS: The conditions to extract TPC were 2 mL passion fruit pulp and 9 mL extraction solution containing 40% methanol:water (v/v). TPC values increased in the passion fruit pulp during ripening for both cultivation systems, ranging from 281.8 to 361.9 mg gallic acid L-1 (P <= 0.05) for the organic pulp and from 291.0 to 338.6 mg gallic acid L-1 (P <= 0.05) for the conventional pulp. CONCLUSION: TPC values increased during ripening for both organic and conventional passion fruit. The same was true for TAA values for conventional passion fruit. For organic passion fruit, however, TAA values were highest at the initial ripening stages. These results suggest that antioxidant compounds exert strong influence on the initial ripening stages for organic passion fruit, when TPC still did not reach its maximum level. PMID- 22231494 TI - A facile solvent free Claisen-Schmidt reaction: synthesis of alpha,alpha'-bis (substituted-benzylidene)cycloalkanones and alpha,alpha'-bis-(substituted alkylidene)cycloalkanones. AB - Solvent-free Claisen-Schmidt reactions of cycloalkanones with various substituted benzaldehydes (aryl aldehydes) using solid NaOH (20 mol%) and applying a grinding technique were studied. Quantitative yields (96-98%) of alpha,alpha'-bis (substituted-benzylidene)cycloalkanones were obtained. Aliphatic aldehydes also provided alpha,alpha'-bis-(substituted-alkylidene)cycloalkanones in very good yields with minor amounts of a-(substituted-alkylidene)cycloalkanones. The catalytic performance of solid NaOH was examined. The molar ratio of NaOH was optimized. The catalytic effect of solid NaOH was also evaluated by comparing it with KOH, NaOAc, and NH(4)OAc and it turns out that 20 mol% of solid NaOH was good enough to catalyze the Claisen-Schmidt reactions of cycloalkanones with various substituted benzaldehydes. Additionally, the regioselectivity of the Claisen-Schmidt reaction of acetone with benzaldehyde was examined. Using the same method, we could synthesize the corresponding bis-benzylidene- and mono benzylideneacetone separately in 98% and 96% yields, respectively. PMID- 22231495 TI - Mixed biopolymer systems based on starch. AB - A binary mixture of starch-starch or starch with other biopolymers such as protein and non-starch polysaccharides could provide a new approach in producing starch-based food products. In the context of food processing, a specific adjustment in the rheological properties plays an important role in regulating production processing and optimizing the applicability, stability, and sensory of the final food products. This review examines various biopolymer mixtures based on starch and the influence of their interaction on physicochemical and rheological properties of the starch-based foods. It is evident that the physicochemical and rheological characteristics of the biopolymers mixture are highly dependent on the type of starch and other biopolymers that make them up mixing ratios, mixing procedure and presence of other food ingredients in the mixture. Understanding these properties will lead to improve the formulation of starch-based foods and minimize the need to resort to chemically modified starch. PMID- 22231496 TI - Daphnoretin induces cell cycle arrest and apoptosis in human osteosarcoma (HOS) cells. AB - In this study antiproliferation, cell cycle arrest and apoptosis induced by daphnoretin in human osteosarcoma (HOS) cells were investigated. Antiproliferative activity was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The IC(50) value of daphnoretin was 3.89 MUM after 72 h treatment. Induction of apoptosis was evidenced by apoptotic body appearance and Annexin V-FITC/PI apoptosis detection kit. Flow cytometric analysis indicated daphnoretin arrested the cell cycle in the G2/M phase. Western blot assay showed that the G2/M phase arrest was accompanied by down-regulation of cdc2, cyclin A and cyclin B1. Moreover, daphnoretin inhibited Bcl-2 expression and induced Bax expression to desintegrate the outer mitochondrial membrane and causing cytochrome c release. Mitochondrial cytochrome c release was associated with the activation of caspase-9 and caspase-3 cascade. Our results demonstrated that daphnoretin caused death of HOS cells by blocking cells successively in G2/M phases and activating the caspase-3 pathway. PMID- 22231497 TI - Genomic analyses of modern dog breeds. AB - A rose may be a rose by any other name, but when you call a dog a poodle it becomes a very different animal than if you call it a bulldog. Both the poodle and the bulldog are examples of dog breeds of which there are >400 recognized worldwide. Breed creation has played a significant role in shaping the modern dog from the length of his leg to the cadence of his bark. The selection and line breeding required to maintain a breed has also reshaped the genome of the dog, resulting in a unique genetic pattern for each breed. The breed-based population structure combined with extensive morphologic variation and shared human environments have made the dog a popular model for mapping both simple and complex traits and diseases. In order to obtain the most benefit from the dog as a genetic system, it is necessary to understand the effect structured breeding has had on the genome of the species. That is best achieved by looking at genomic analyses of the breeds, their histories, and their relationships to each other. PMID- 22231498 TI - Comparison of non-invasive fibrosis markers and classical liver biopsy in chronic hepatitis C. AB - The aim of this study was to compare the results of nine non-invasive serum biomarkers with liver biopsies to predict liver fibrosis stage. HCV-RNA-positive, HCV genotype 1, treatment-naive patients with chronic HCV infections were included from 14 centers (n=77). The platelet count, AST/ALT ratio (AAR), cirrhosis discriminate score (CDS), FIB4, AST/platelet ratio index (APRI), age platelet (AP) index, Goteborg University cirrhosis index (GUCI), FibroTest, and ActiTest were calculated and compared to histologic findings. All serum biomarkers, except AAR, were weakly or moderately correlated with liver biopsy results (ISHAK fibrosis score). The mean scores of FibroTest, FIB4, APRI, and AP index were significantly different between F0-F2 and F3-F4 groups and the negative predictive values (NPVs) of the F3-F4 group were 95%, 85%, 85%, and 83%, respectively, for these serum biomarkers. Our study suggests that serum biomarkers may help to diagnose significant fibrosis but inadequate to detect fibrosis in early stages. Although liver biopsy is still the gold standard to diagnose liver fibrosis, FibroTest, FIB4, APRI, or AP index may be used to exclude significant fibrosis with >80% NPV. PMID- 22231499 TI - Immuno-PCR for the early serological diagnosis of acute infectious diseases: the Q fever paradigm. AB - To reduce the delay in diagnosis of Q fever, we have adapted the ultrasensitive immuno-PCR method for the detection of Phase II IgM anti-Coxiella burnetii. We compared its performance to ELISA, IFA and PCR using 31 acute Q fever sera and 50 control sera. The best sensitivity was obtained by iPCR (27 out of 31) followed by PCR (18 out of 31), ELISA (12 out of 31) and IFA (10 out of 31). A specificity of 92% was found by iPCR (3 false positive out of 40), 92% for ELISA (3 false positive out of 40) whereas PCR and IFA exhibited a specificity of 100%. Among the 31 Q fever sera, we compared the four methods for the detection of the early sera sampled during the two first weeks after the onset of symptoms and found a sensitivity of 90% by iPCR, 55% for PCR, 35% for ELISA and 25% for IFA. The results presented in this study suggest that iPCR is a promising, sensitive and specific method that can be used for the early diagnosis of acute Q fever and more generally for acute infections where traditional methods lack sensitivity. PMID- 22231500 TI - Post-translational control of tetrapyrrole biosynthesis in plants, algae, and cyanobacteria. AB - The tetrapyrrole biosynthetic pathway provides the vital cofactors and pigments for photoautotrophic growth (chlorophyll), several essential redox reactions in electron transport chains (haem), N- and S-assimilation (sirohaem), and photomorphogenic processes (phytochromobilin). While the biochemistry of the pathway is well understood and almost all genes encoding enzymes of tetrapyrrole biosynthesis have been identified in plants, the post-translational control and organization of the pathway remains to be clarified. Post-translational mechanisms controlling metabolic activities are of particular interest since tetrapyrrole biosynthesis needs adaptation to environmental challenges. This review surveys post-translational mechanisms that have been reported to modulate metabolic activities and organization of the tetrapyrrole biosynthesis pathway. PMID- 22231501 TI - Exploring NUE in crops and in Arabidopsis ideotypes to improve yield and seed quality. AB - There is evidence that crop yields are showing a trend of stagnation in many countries. This review aims to make an inventory of the last decade's crop productions and the associated economic and environmental challenges. Manipulating nitrogen use efficiency in crops appears to be the best way to conciliate global food security, respecting environmental policies, and the need to produce biofuels. In such a context, the specifications of ideal plants for the future are discussed with regards to human needs and taking into account current physiological and genetic knowledge. The approaches undertaken so far to design an ideal crop and to find suitable new germplasms are discussed. The interest in using model plants in agronomic research is illustrated through the recent data provided by studies exploring natural variation in Arabidopsis thaliana. Efficient Arabidopsis ideotypes are proposed and discussed. PMID- 22231502 TI - Resuscitating supplementary information: is the solution a two-for-one offer? PMID- 22231503 TI - The frequency of heterologous synapsis increases with aging in Robertsonian heterozygous male mice. AB - The house mouse is characterised by highly variable chromosome number due to the presence of Robertsonian (Rb) chromosomes. During meiosis in Rb heterozygotes, intricated chromosomal figures are produced, and many unsynapsed regions are present during the first prophase, triggering a meiotic silencing of unsynapsed chromatin (MSUC) in a similar mode to the sex chromosome inactivation. The presence of unsynapsed chromosome regions is associated with impaired spermatogenesis. Interestingly, in male mice carrying multiple Rb trivalents, the frequency of germ cell death, defective tubules, and altered sperm morphology decreases during aging. Here, we studied whether synapsis of trivalent chromosomes and MSUC are involved in this improvement. By immunocytochemistry, we analysed the frequency of unsynapsed chromosomes and of those positive to gammaH2AX (a marker of MSUC) labelling in spermatocytes of 3-, 5- and 7-month-old Rb heterozygotes. With aging, we observed a decrease of the frequency of unsynapsed chromosomes, of spermatocytes bearing them and of trivalents carrying gammaH2AX-negative unsynapsed regions. Our quantitative results show that both synapsis and MSUC processes are better accomplished during male aging, partially accounting for the improvement of spermatogenesis. PMID- 22231504 TI - Theory of electron localization and its application to blue-shifting hydrogen bonds. AB - We propose a theory of electron localization or stabilization by electron localization through the interactions between occupied (i) and vacant (j*) orbitals under certain conditions, which have been believed so far to cause only electron delocalization. Electrons localize when the electrons redistributed by the interaction are more stable in the i-th occupied orbital than in the overlap region: h(ij*) > s(ij*)h(ii) for s(ij*) > 0. Electron delocalization occurs when h(ij*) < s(ij*)h(ii) for s(ij*) > 0. The h(ij*) and s(ij*)h(ii) terms represent the energy of the electrons in the overlap region and the energy of the redistributed electrons in the occupied orbital, respectively. The theory of electron localization is substantiated by the correlation of the C-H bond lengths of fluorinated methanes H(4-n)CF(n) (n = 1, 2, 3) to the electron population of the sigma(CH) bonding orbital, and successfully applied to understanding blue shifting hydrogen bonds in F(3)CH...X (X = CO, N(2), OC, Ne, OC(CH(3))(2)) and designing some proton donors, HCO(2)CH(3) and hypervalent molecules HPF(4) and HSF(5), for blue-shifting hydrogen bonds. PMID- 22231507 TI - Sensitive determination of prohibited drugs in dried blood spots (DBS) for doping controls by means of a benchtop quadrupole/Orbitrap mass spectrometer. AB - In the present study, a new type of mass spectrometer combining a quadrupole mass filter, a higher collision dissociation (HCD) cell and an Orbitrap detector, was evaluated for the analysis of dried blood spots (DBS) in doping controls. DBS analysis is characterized by the necessity to detect prohibited compounds in sub nanogram-per-milliliter levels with high identification capacity. After extraction of DBS with an organic solvent and liquid chromatographic separation (using a regular C18-RP-analytical UHPLC-column) of target analytes, mass spectrometry is performed with a high-resolution full scan in positive and negative mode by means of electrospray ionisation. Single-product ion mass spectra are acquired using the data-dependent analysis mode (employing an inclusion list) for previously selected precursors of known prohibited compounds with fixed retention time ranges. Besides, a sensitive screening in a targeted approach, non-targeted analysis for retrospective data evaluation is thus possible. The chosen experimental design enables the determination of various drugs from different classes with one generic sample preparation which is shown for 26 selected model compounds (Delta(9)-tetrahydrocannabinol (THC), tetrahydrocannabinol-9-carboxylic acid (THC-COOH), methylhexaneamine, methylphenidate, cocaine, nikethamide, 3,4-methylenedioxyamphetamine, N-methyl 3,4-methylenedioxyamphetamine, strychnine, mesocarb, salbutamol, formoterol, clenbuterol, metandienone, stanozolol, bisoprolol, propranolol, metoprolol, anastrazole, clomiphene, exemestane, dexamethasone, budesonide, selective androgen receptor modulator (SARM) S4 (andarine), SARM S1, hydrochlorothiazide). Generally, only qualitative result interpretation was focussed upon, but for target analytes with deuterium-labelled internal standards (salbutamol, clenbuterol, cocaine, dexamethasone, THC-COOH and THC) quantitative analysis was also possible. Especially the most challenging analytes, THC and its carboxy metabolite, were detected in DBS at relevant concentrations (<0.5 ng/mL) using targeted HCD experiments. The method was validated for the parameters: specificity, linearity (0-20 ng/mL), precision (<25%), recovery (mean 60%), limit of detection/quantification, ion suppression, stability and accuracy (80-120%). Six isotope-labelled analogues used as internal standards facilitate a quantitative result interpretation which is of utmost importance especially for in-competition drug sports testing. PMID- 22231508 TI - Simultaneous quantitation of urinary cotinine and acrylonitrile-derived mercapturic acids with ultraperformance liquid chromatography-tandem mass spectrometry. AB - Acrylonitrile (AN), a widely used industrial chemical also found in tobacco smoke, has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer. AN can be detoxified by glutathione S-transferase (GST) to form glutathione (GSH) conjugates in vivo. It can be metabolically activated by cytochrome P450 2E1 to form 2-cyanoethylene oxide, which can also be detoxified by GST to generate GSH conjugates. The GSH conjugates can be further metabolized to mercapturic acids (MAs), namely, N acetyl-S-(2-cyanoethyl)cysteine (CEMA), N-acetyl-S-(2-hydroxyethyl)cysteine (HEMA), and N-acetyl-S-(1-cyano-2-hydroxyethyl)cysteine (CHEMA). This study developed an ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method to quantitatively profile the major AN urinary metabolites (CEMA, HEMA, and CHEMA) to assess AN exposure, as well as analyze urinary cotinine (COT) as an indicator for tobacco smoke exposure. The limits of quantitation were 0.1, 0.1, 1.0, and 0.05 MUg/L for HEMA, CEMA, CHEMA, and COT, respectively. This method was applied to analyze the three AN-derived MAs in 36 volunteers with no prior occupational AN exposure. Data analysis showed significant correlations between the level of COT and the levels of these MAs, suggesting them as biomarkers for exposure to low levels of AN. The results demonstrate that a highly specific and sensitive UPLC-MS/MS method has been successfully developed to quantitatively profile the major urinary metabolites of AN in humans to assess low AN exposure. PMID- 22231509 TI - Characterization of a mixed-mode reversed-phase/cation-exchange stationary phase prepared by thermal immobilization of poly(dimethylsiloxane) onto the surface of silica. AB - A novel stationary phase prepared by the thermal immobilization of poly(dimethylsiloxane) onto the surface of silica (PDMS-SiO(2)) has been described, evaluated and compared with 229 commercially available RP-LC stationary phases using the Tanaka column classification protocol. The phase exhibited many unique chromatographic properties and, based on the phases in the database, was most similar to the fluoroalkylated phases (aside from the obvious lack of fluoro selectivity imposed by the C-F dipole). The phase exhibited classic reversed-phase behaviour in acid mobile phase conditions and mixed-mode reversed-phase/cation-exchange retention behaviour in neutral mobile phase conditions. The phase exhibited acceptable stability at both low and intermediate pH, conditions which should impart optimum chromatographic selectivity to the phase. Retention of basic analytes was shown to occur by a "three site model" as proposed by Neue. This new PDMS-SiO(2) stationary phase is extremely interesting in that the dominancy of its hydrophobic and ion-exchange interactions can be controlled by the influence of mobile phase pH, buffer type and concentration. The PDMS-SiO(2) stationary phase may provide a complementary tool to reversed phase and HILIC stationary phases. The present results highlight the fact that the type of buffer, its concentration and pH can not only affect peak shape but also retention, selectivity and hence chromatographic resolution. Therefore, in method development and optimization strategies it is suggested that more emphasis should be given to the evaluation of these mobile phase operating parameters especially when basic solutes are involved. PMID- 22231510 TI - Generation of metabolites by an automated online metabolism method using human liver microsomes with subsequent identification by LC-MS(n), and metabolism of 11 cathinones. AB - Human liver microsomes (HLMs) are used to simulate human xenobiotic metabolism in vitro. In forensic and clinical toxicology, HLMs are popularly used to study the metabolism of new designer drugs for example. In this work, we present an automated online extraction system we developed for HLM experiments, which was compared to a classical offline approach. Furthermore, we present studies on the metabolism of 11 cathinones; for eight of these, the metabolism has not previously been reported. Metabolites were identified based on MS(2) and MS(3) scans. Fifty-three substances encompassing various classes of drugs were employed to compare the established offline and the new online methods. The metabolism of each of the following 11 cathinones was studied using the new method: 3,4 methylenedioxy-N-benzylcathinone, benzedrone, butylone, dimethylcathinone, ethylone, flephedrone, methedrone, methylone, methylethylcathinone, naphyrone, and pentylone. The agreement between the offline and the online methods was good; a total of 158 metabolites were identified. Using only the offline method, 156 (98.7%) metabolites were identified, while 151 (95.6%) were identified using only the online method. The metabolic pathways identified for the 11 cathinones included the reduction of the keto group, desalkylation, hydroxylation, and desmethylenation in cathinones containing a methylenedioxy moiety. Our method provides a straightforward approach to identifying metabolites which can then be added to the library utilized by our clinical toxicological screening method. The performance of our method compares well with that of an established offline HLM procedure, but is as automated as possible. PMID- 22231511 TI - Physico-chemical characterization of protein-pigment interactions in tempera paint reconstructions: casein/cinnabar and albumin/cinnabar. AB - In this work, we characterized paint reconstructions using ovalbumin and casein as binders, and cinnabar (HgS) as a pigment, before and after artificial ageing. Egg and casein are common paint binders that were used historically in the technique of tempera painting. Despite extensive research on the identification of proteinaceous binders in paintings, there is a substantial lack of knowledge regarding the ageing pathway of their protein content, and their chemical interaction with inorganic pigments. Thermogravimetric analysis, infrared spectroscopy and size-exclusion chromatography (SEC) were used to reveal the physico-chemical processes involved in the ageing of proteins in paintings. Taken together, the three techniques highlighted that proteins are subject to both cross-linking and hydrolysis upon ageing, and to a lesser extent, to oxidation of the side chains. Mercury-protein interactions were also revealed using a cold vapour generation atomic fluorescence spectrometer mercury-specific detector coupled to SEC. The study clearly showed that HgS forms stable complexes with proteins and acts as a sensitizer in cross-linking, hydrolysis and oxidation. PMID- 22231512 TI - Study of beta endorphin metabolism in inflamed tissue, serum and trypsin solution by liquid chromatography-tandem mass spectrometric analysis. AB - Beta endorphin (beta-END) is recognised as one of the most significant endogenous neuropeptides, responsible for a wide range of biological activities in the body. However, within the body beta-END is exposed to hydrolysis by a variety of enzymes. In this study, we investigated the metabolism and fragmentation pattern of beta-END in rat inflamed tissue, in rat serum and in trypsin solution. beta END (1-31)-rat was incubated at 37 degrees C in each matrix for different incubation times. The resultant fragments were separated using a C4 column and detected by mass spectrometry using total ion current mode. Structural information for the fragments was elucidated using tandem mass spectrometry. Incubation of beta-END (1-31)-rat in trypsin solution and in rat serum resulted in 8 and 13 fragments, respectively. Incubation in inflamed rat paw tissue resulted in 22 fragments at pH 7.4 and 26 fragments at pH 5.5. Some of these fragments were common to both pH values. The degradation of beta-END (1-31)-rat in inflamed tissue at pH 5.5 was faster than that at pH 7.4. Secondary fragmentation of some larger primary fragments was also observed in this study. PMID- 22231513 TI - Arginine-rich coconut kernel diet influences nitric oxide synthase activity in alloxandiabetic rats. AB - BACKGROUND: Coconut kernel protein (CKP) has been reported to contain significant amounts of L-arginine. Its potential effect on glucose homeostasis, possibly through the nitric oxide synthase (NO) pathway, was therefore investigated in alloxan-induced diabetic rats. Diabetes was induced by a single intraperitoneal dose of alloxan (150 mg kg-1 body weight). Experimental rats were grouped as follows: Group I, normal control; Group II, diabetic control; Group III, diabetic + CKP; Group IV, diabetic + L-arginine; Group V, diabetic + L-arginine + L-N(G) Nitroarginine methyl ester (L-NAME). Purified CKP isolated from dried coconut kernel and L-arginine was administered to rats along with a semi-synthetic diet for 45 days. L-NAME (0.5 mg kg-1 body weight) was given to Group V animals. After the experimental period, serum glucose, insulin, activities of liver nitric oxide synthase and arginase, liver glycogen levels and histopathology of the pancreas were evaluated. RESULTS: Serum glucose, insulin and antioxidant enzyme activities and liver glycogen levels were found to be restored to basal levels in CKP-fed rats. Decreased arginase and increased nitric oxide synthase (NOS) activities were found in CKP- and arginine-fed rats. L-NAME treatment showed a partial effect on these parameters. Histopathology revealed that CKP and L-arginine feeding reduced the diabetes-related pancreatic damage in treated rats compared to the diabetic control. CONCLUSION: The results observed in this study indicate that the potential antidiabetic activity of CKP may be through an arginine-NO pathway leading to pancreatic beta cell regeneration. PMID- 22231514 TI - The role of vitamin B6 as an antioxidant in the presence of vitamin B2 photogenerated reactive oxygen species. A kinetic and mechanistic study. AB - We report on the photostability of a mixture of vitamins B6 and B2 (riboflavin, Rf) upon visible light irradiation and on the possible role of the vitamin B6 family (B6D) as deactivators of reactive oxygen species (ROS). The work is a systematic kinetic and mechanistic study under conditions in which only Rf absorbs photoirradiation. Pyridoxine, pyridoxal hydrochloride, pyridoxal phosphate and pyridoxamine dihydrochloride were studied as representative members of the vitamin B6 family. The visible light irradiation of dissolved Rf and B6D in pH 7.4 aqueous medium under aerobic conditions induces photoprocesses that mainly produce B6D degradation. The overall oxidative mechanism involves the participation of ROS. Photogenerated (3)Rf* is quenched either by oxygen, giving rise to O(2)((1)Delta(g)) by electronic energy transfer to dissolved ground state oxygen, or by B6D yielding, through an electron transfer process, the neutral radical RfH, and O(2)(-) in an subsequent step. B6D act as quenchers of O(2)((1)Delta(g)) and O(2)(-), the former in a totally reactive event that also inhibits Rf photoconsumption. The common chromophoric moiety of B6D represented by 3-hydroxypyridine, constitutes an excellent model that mimics the kinetic behavior of the vitamin as an antioxidant towards Rf-generated ROS. The protein lysozyme, taken as an O(2)((1)Delta(g))-mediated oxidizable biological target, is photoprotected by B6D from Rf-sensitized photodegradation through the quenching of electronically excited triplet state of the pigment, in a process that competes with O(2)((1)Delta(g)) generation. PMID- 22231515 TI - Perturbation of nuclear lamin A causes cell death in chondrocytes. AB - OBJECTIVE: Mutations in LMNA encoding the A-type lamins cause several diseases, including those with features of premature aging and skeletal abnormalities. The aim of this study was to examine the expression of lamin A in cartilage from patients with osteoarthritis (OA) and the effects of its overexpression on chondrocyte senescence and apoptosis. METHODS: Human chondrocyte-like cells (SW 1353) were used. RNA isolated from human OA and non-OA cartilage was used for profiling messenger RNA expression, using Affymetrix microarray analysis. The effects of lamin A overexpression on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, and cytochrome c release, and with a TUNEL assay. Western blotting was performed to determine protein expression. RESULTS: Lamin A expression was markedly elevated in OA cartilage samples compared with non-OA control samples. Western blot analysis confirmed increased expression of lamin A in OA compared with non-OA cartilage. Interleukin-1beta treatment inhibited lamin A accumulation, whereas treatment with prostaglandin E(2) (PGE(2) ) caused a marked increase in lamin A accumulation. These effects of exogenous PGE(2) on lamin A expression were mediated via the EP(2) /EP(4) receptors. Transfected chondrocytes that expressed lamin A displayed markers of early senescence/apoptosis. CONCLUSION: The results of this study suggest that lamin A is up-regulated in OA chondrocytes, and that increased nuclear accumulation of lamin A in response to catabolic stress may account for the premature aging phenotype and apoptosis of OA chondrocytes. PMID- 22231516 TI - Type I interferons: beneficial in Th1 and detrimental in Th17 autoimmunity. AB - In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-beta are the most prescribed treatment for this disease. However, within the RRMS population, 30 50% of MS patients are nonresponsive to this treatment, and it consistently worsens neuromyelitis optica (NMO), a disease once considered to be a form of RRMS. In contrast to RRMS, type I IFNs have been shown to have properties that drive the inflammatory pathologies in many other autoimmune diseases. These diseases include Sjogren's syndrome, system lupus erythematosus (SLE), neuromyelitis optica (NMO), rheumatoid arthritis (RA) and psoriasis. Historically, autoimmune diseases were thought to be driven by a TH1 response to auto-antigens. However, since the discovery of the TH17 in experimental autoimmune encephalomyelitis (EAE), it is now generally thought that TH17 plays an important role in MS and all other autoimmune diseases. In this article, we will discuss recent clinical and basic research advances in the field of autoimmunity and argue that IFN-beta and other type I IFNs are immuno-modulatory in diseases driven predominantly by TH1 but in contrast are inflammatory in diseases that have a predominant Th17 response. PMID- 22231517 TI - NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells. AB - Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-gamma (IFN-gamma) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8alpha(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL 18) and IL-1beta, only IL-18 was required for IFN-gamma production by memory CD8(+) T cells. Conversely, only the release of IL-1beta, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity. PMID- 22231518 TI - Signaling via the kinase p38alpha programs dendritic cells to drive TH17 differentiation and autoimmune inflammation. AB - Dendritic cells (DCs) bridge innate and adaptive immunity, but how DC-derived signals regulate T cell lineage choices remains unclear. We report here that the mitogen-activated protein kinase p38alpha programmed DCs to drive the differentiation of the T(H)17 subset of helper T cells. Deletion of p38alpha in DCs protected mice from T(H)17 cell-mediated autoimmune neuroinflammation, but deletion of p38alpha in macrophages or T cells did not. We also found that p38alpha orchestrated the expression of cytokines and costimulatory molecules in DCs and further 'imprinted' signaling via the receptor for interleukin 23 (IL 23R) in responding T cells to promote T(H)17 differentiation. Moreover, p38alpha was required for tissue-infiltrating DCs to sustain T(H)17 responses. This activity of p38alpha was conserved in mouse and human DCs and was dynamically regulated by pattern recognition and fungal infection. Our results identify p38alpha signaling as a central pathway for the integration of instructive signals in DCs for T(H)17 differentiation and inflammation. PMID- 22231520 TI - The Alzheimer's disease related tau protein as a new target for chemical protein engineering. PMID- 22231519 TI - The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. AB - Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic inflammation, remain unknown. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin 1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation. PMID- 22231521 TI - Mathematical model for two germline stem cells competing for niche occupancy. AB - In the Drosophila germline stem cell ovary niche, two stem cells compete with each other for niche occupancy to maintain stem cell quality by ensuring that differentiated stem cells are rapidly pushed out the niche and replenished by normal ones (Jin et al. in Cell Stem Cell 2:39-49, 2008). To gain a deeper understanding of this biological phenomenon, we have derived a mathematical model for explaining the physical interactions between two stem cells. The model is a system of two nonlinear first order and one second order differential equations coupled with E-cadherins expression levels. The model can explain the dynamics of the competition process of two germline stem cells and may help to reveal missing information obtained from experimental results. The model predicts several qualitative features in the competition process, which may help to design rational experiments for a better understanding of the stem cell competition process. PMID- 22231522 TI - Metabolic engineering of thermophilic Bacillus licheniformis for chiral pure D 2,3-butanediol production. AB - 2,3-Butanediol is an important compound that can be used in many areas, especially as a platform chemical and liquid fuel. But traditional 2,3-butanediol producing microorganisms, such as Klebsiella pneumonia and K. xoytoca, are pathogens and they can only ferment sugars at 37 degrees C. Here, we reported a newly developed Bacillus licheniformis. A protoplast transformation system was developed and optimized for this organism. With this transformation method, a marker-less gene deletion protocol was successfully used to knock out the ldh gene of B. licheniformis BL1 and BL3. BL1 was isolated earlier from soil for lactate production and it was further evolved to BL3 for xylose utilization. Combined with pH and aeration control, ldh mutant BL5 and BL8 can efficiently ferment glucose and xylose to D-(-) 2,3-butanediol at 50 degrees C, pH 5.0. For glucose and xylose, the specific 2,3-butanediol productivities are 29.4 and 26.1 mM/h, respectively. The yield is 0.73 mol/mol for BL8 in xylose and 0.9 mol/mol for BL5 and BL8 in glucose. The D-(-) 2,3-butanediol optical purity is more than 98%. As far as we know, this is the first reported high temperature butanediol producer to match the simultaneous saccharification and fermentation conditions. Therefore, it has potential to further lower butanediol producing cost with low cost lignocellulosic biomass in the near future. PMID- 22231523 TI - New developments in diabetic limb salvage. PMID- 22231524 TI - The challenging topic of diabetic foot revascularization: does the angiosome guided angioplasty may improve outcome. AB - The angiosome model was first pioneered by Jan Taylor in 1987 by his influential anatomical works in the plastic reconstructive surgery field. The concept depicts the human body into three-dimensional blocks of tissue, fed by specific arterial and venous irrigation sources, the "angiosomes". Adjacent angiosomes are linked by a vast compensatory collateral web "the choke vessels". This collateral network provides a remarkable "rescue system" in non-atherosclerotic and non diabetic patients. However, it could be dramatically damaged in chronic limb ischemia (CLI) subjects witnessing miscellaneous systemic arterial disease. The angiosome concept may provide useful information on the human vascular anatomy and related pathology, with specific applications in surgical and vascular interventional therapies. This knowledge may become particularly beneficial in CLI while treating advanced atherosclerotic disease that adds extended collateral depletion. The concept may allow to deliberately focus arterial flow reconstruction in specific limb ischemic areas that exhibit tissue loss and fluctuating "rescue-vessels" supply. The implementation of angiosome-derived strategies in Rutherford grade III CLI presentations, may afford encouraging wound healing and limb preservation rates for both, bypass or endovascular techniques. The present paper proposes a parallel review of the main contemporary publications that share this theory in dedicated CLI literature, with practical considerations for its daily use. Recent applications of the angiosome concept in current CLI revascularization seem to evince benefic results in tissue cicatrization, although comparative and prospective data are further mandatory to cast any pertinent clinical validation. PMID- 22231525 TI - How paclitaxel can improve results in diabetics. AB - Despite advances in endovascular techniques, the success of these revascularization procedures is limited by neointimal hyperplasia and subsequent restenosis or occlusion. Infrainguinal interventions have higher rates of restenosis after intervention in comparison to other vascular beds, and this is likely due to a host of anatomic, mechanical, biological and rheological factors that create a relatively hostile environment for the restoration of lower extremity perfusion through endovascular means. In addition, outcomes in the diabetic subpopulation are even worse, with a higher risk of amputation, re interventions, and failed procedures in critical limb ischemia. Novel techniques for antiproliferative drug release into the vessel wall at the site of endovascular intervention have shown promising results in combating restenosis in the coronary arteries and data are accumulating to suggest promise in the infrainguinal arteries as well. The application of paclitaxel, delivered either through drug coated balloons or drug-eluting stents, has demonstrated benefit in enhanced durability of lower extremity endovascular procedures, and may be of particular advantage concerning diabetic limb salvage. This review presents an overview of the current literature and ongoing trials with the use of paclitaxel in diabetic lower extremity occlusive disease. PMID- 22231526 TI - Integrated surgical protocol for the treatment of the infected diabetic foot. AB - Diabetes is a chronic disease with a worldwide increasing trend. Feet complication, closely related to neuropathy and obstructive peripheral vascular disease, are responsible for more than 1 million of leg amputations every year. Foot infection can dramatically improve the risk of amputation. Although many ulcer classification systems have been proposed to stratify the severity of infectious process the problem of the definition of a correct therapeutic approach to different clinical pictures still remains unresolved. A diabetic foot triage and an integrated surgical protocol are proposed to try identifying a diagnostic flowchart and a step-by-step surgical protocol that can be applied in the treatment of diabetic foot infection. Goals and technical aspects of emergent and elective surgical procedures in diabetic foot are analysed to evaluate critical aspects and to suggest proper surgical choices. PMID- 22231527 TI - Endovascular procedures and new insights in diabetic limb salvage. AB - Critical limb ischemia (CLI) is affecting an increasing number of patients, mainly due to an ageing population and the growing number of diabetics. Clinically, CLI is characterized by rest pain, non-healing foot wounds and gangrene, due to insufficient arterial blood supply. Limb preservation should be the goal in patients with diabetic foot due to tibial occlusive disease. As surgery is associated with considerable morbidity and mortality rates, endovascular therapy can offer a valuable alternative. Small-diameter below-the knee arteries that were previously unamenable to surgical methods, can now be reached and treated. Currently, many endovascular techniques are available, from regular PTA and bare metal stents to drug-coated balloons and drug-eluting stents. In our opinion the results of endovascular therapy for below-the-knee vessels will be further improved by the continuous technical evolution and new material developments. In the light of the current evolution towards minimally invasive techniques, an increasing number of experienced centers will be able to treat the vast majority of all below-the-knee arterial pathology by endovascular means. PMID- 22231528 TI - Pharmacological interventions on critical limb ischemia in diabetic patients. AB - Peripheral arterial disease is highly prevalent in patients with diabetes mellitus. Critical limb ischemia is an important component of this disease entity. Early diagnosis, identification of risk factors, and appropriate therapeutic management strategies are needed to aggresively treat this disease. This paper reviews risk factors for critical limb ischemia and discusses updates on pharmacologic therapies with a specific focus on the diabetic population. PMID- 22231529 TI - Lesion characteristics of patients with chronic critical limb ischemia that determine choice of treatment modality. AB - This paper will review the literature in order to define lesion characteristics that determine decision for surgical or endovascular therapy in patients with chronic critical limb ischemia (CLI). The typical pattern of disease is multilevel, infrainguinal disease. The great majority of patients with CLI can be treated by endovascular means, and the pathoanatomical pattern of disease dictates the choice of treatment modality. Long iliac artery occlusions, in particular, if associated with common femoral artery pathology and long superficial femoral artery occlusions crossing the knee joint so far remain a domain of surgery. However, there is an ongoing shift from surgery to endovascular treatment. PMID- 22231530 TI - Primary amputation: is there still a place for it? AB - Diabetic foot (DF) continues to present a significant challenge to the vascular surgeon. Despite great advances in the treatment of DF, including open revascularization and endovascular techniques, significant numbers of amputations are still performed. The effect of aggressive revascularization on ultimate limb salvage rates continues to be debated. In the US the amputation rate has increased from 19 to 30 per 100000 persons years over the last two decades primarily due to an increase in diabetes and advancing age. Despite advances in cardiovascular treatment, in patients over 85 year of age an amputation rate of 140 per 100000 persons/year has been reported with a primary amputation (PA) still carrying an excessively high mortality rate of 13-17%. Amputation has been historically regarded as a life saving therapeutic measure. At the time the advances of surgical techniques in revascularization, diagnostic modalities and effectiveness in antimicrobial agents have unintentionally designated amputation to be the last treatment option. Nowadays we have a variety of therapeutic options to correct, modify, or circumvent the obstructive vascular pathology, such as angioplasty, atherectomy, stenting, stent graft and the traditional open surgical approach using endarterectomy, patch angioplasty, or bypass revascularization and even sympathectomy to enhance cutaneous perfusion to the toes. However it is understandable that many older patients who have received multiple limb preservation procedures have spent most of the remaining days of their lives in and out of the hospital or in a long-term care facility where high technical and sophisticated wound care techniques can be provided. PMID- 22231531 TI - Is digital arteries recanalization useful to preserve the foot functionality and avoid toes amputation, after pedal recanalization? Clinical results. AB - AIM: The authors aimed to assess clinical results following percutaneous transluminal angioplasty (PTA) of pedal arteries and digital branches in order to avoid minor amputations or support surgical skin incisions, in patients with CLI and distal wounds on the toes. METHODS: Baseline, procedural and mid-term outcome data of all consecutive patients with CLI and ulcerative lesion on the toes, in which endovascular treatment of the foot arteries and digital branches was attempted, were prospectively collected between January 2010 and January 2011. The primary end-point was acute success (i.e. technical, angiographic and procedural success). Secondary end-points included limb, foot and toes salvage rates, minor amputations, reocclusion/restenosis and repeat treatment. RESULTS: 1057 consecutive patients with CLI were treated and in 24 cases (2.3%), after tibial and foot arteries PTA, related to the presence of arterial lesion (stenosis/occlusion) in the digital branches, the recanalization of the target vessel was performed. Acute technical success was achieved in 100% of cases, with adequate angiographic results without peri-procedural complications. Clinical improvement was obtained and maintained after an average of 9 months. Amputation was avoided in 9 patients (37.5%), in 8 patients (29.6%) amputation involved only a distal phalange, in 5 patients (20.8%) toe amputations was necessary, in 2 patients (8.4%) trans-metatarsal amputation was performed. No below the ankle (BTA) or major amputations were performed. CONCLUSION: Endovascular recanalization of digital branches in patients with CLI and distal wounds on the toes is feasible and safe; represent a support to avoid minor amputations or surgical skin lesion healing. PMID- 22231532 TI - The management of ruptured abdominal aortic aneurysms: screening for abdominal aortic aneurysm and incidence of rupture. AB - Twenty-five years have passed since the first randomised controlled trial began its recruitment for screening for abdominal aortic aneurysm (AAA) in men aged 65 and above. Since this and other randomised trials, all launched in the late 80s and 90s of the last century, the epidemiologic profile of abdominal aortic aneurysm may have changed. The trials reported an AAA prevalence in the range of 4-7% for men aged 65 years or more. AAA-related mortality was significantly improved by screening, and after 13 years, the largest trial showed a benefit for all-cause mortality. Screening also was shown to be cost-effective. Today, there are studies showing a substantial decrease of AAA prevalence to sometimes less than 2% in men aged >= 65 years and there is evidence that the incidence of ruptured aneurysm and mortality from AAA is also declining. This decline preceded the implementation of screening programmes but may be due to a change in risk factor management. The prevalence of smoking has decreased and there has been improvement in the control of hypertension and a rising use of statins for cardiovascular risk prevention. Additionally, there is a shift of the burden to the older age group of >= 75 years. Such radical changes may influence screening policy and it is worth reflecting on the optimum age of screening - it might be better to screen at ages >65 years - or rescreening 5 to 10 years after the first screen. PMID- 22231533 TI - Systematic approach to ruptured abdominal aortic aneurysm in the endovascular era: Intention-to-treat eEVAR protocol. AB - Emergency endovascular aneurysm repair (eEVAR) for ruptured abdominal aortic aneurysms (rAAA) is still a relatively new treatment option. A pre-defined strategy of an eEVAR first approach for rAAA is associated with improved mortality rates. After establishing and implementing the Intention-to-treat eEVAR protocol for rAAAs the mortality and morbidity rates improved significantly. The presented Intention-to-treat eEVAR protocol starts at the first telephone call to the ambulance department and lasts until the post-operative care unit. The protocol involves the close collaboration between the ambulance department, vascular surgeon, emergency department physicians, anaesthesiologists, operating room staff and, radiology technicians. The availability of a variety of off-the shelf stent-grafts, and an operating room that is adequately equipped to perform endovascular procedures is crucial in obtaining better outcomes. High volume centres that offer open surgical repair as well as eEVAR for rAAA show that the Intention-to-treat eEVAR protocol is achievable and appears to be associated with favorable mortality over open repair with appropriate case selection. Unstable or older patients with rAAA may particularly benefit by eEVAR. PMID- 22231534 TI - Endovascular treatment of ruptured abdominal aortic aneurysm: is there a long term benefit at follow-up? AB - AIM: Several studies have shown the feasibility of endovascular repair of ruptured abdominal aortic aneurysms (rEVAR). However, the role and value of rEVAR remains controversial due to selection bias and lack of long-term results. In the present study we describe our short- and long-term results of treating patients with rEVAR irrespective of hemodynamic condition and challenging anatomy. METHODS: In April 2006 we started the single centre prospective non-randomised Ruptured Aneurysm Study (RASA). During a four year enrolment period all consecutive patients presenting with infrarenal ruptured AAA (rAAA, N.=117) were assessed for preferential rEVAR treatment. A rAAA was defined as extravasation of blood or hematoma outside the AAA due to transmural tear in the infrarenal abdominal aorta wall documented by preoperative computed tomography (CT) angiography examination or during open repair. Patients with challenging anatomy (infrarenal neck length below 15 mm and neck angulation above 60 degrees) were included as part of a damage control concept. Complication and mortality rates were studied at 30 days and yearly afterwards. RESULTS: Thirty-five patients (33% of all admitted rAAA) were treated with rEVAR and 42% of them were considered hemodynamically unstable (systolic blood pressure <100 mmHg) and 30% had challenging AAA anatomy. The mortality rate at 30 days in the rEVAR group was 17%, in the open repair group 31%, and in the entire rAAA group (including abstained patients) 36%. During the first 30 days, 18 rEVAR patients experienced complications with nine re-interventions as a result. Long-term mortality of the rEVAR patients was 34% after a median follow-up of 3.4 years. All deaths after one year follow-up were non-AAA related. Multivariate analysis shows that Hardman index, presence of peripheral arterial obstructive disease and lowest systolic blood pressure during surgery are independently associated with long-term survival. Challenging rAAA anatomy was not associated with impaired survival. CONCLUSION: Our study shows that rEVAR is feasible irrespective of hemodynamic condition and that it is associated with relative low mortality rates. Challenging rAAA anatomy may not affect overall long-term survival, but six out of ten patients remain unsuitable for rEVAR because of inappropriate anatomy. PMID- 22231535 TI - Tibial microdissection for diabetic wounds. AB - Few data are available focusing on controlled blunt microdissection during below the-knee interventions as sole or synchronous technique coupled to subintimal angioplasty, particularly in the management of diabetic critical-ischemic foot wounds. We present two cases of targeted recanalizations in the tibial and pedal trunks for plantar and forefoot diabetic ischemic tissue defects, following an angiosome-model for perfusion. PMID- 22231536 TI - Influence of temperature management on neurocognitive function in biological aortic valve replacement. A prospective randomized trial. AB - AIM: Aim of this study was to elucidate if postoperative neurocognitive function after biological aortic valve replacement (AVR) can be influenced by temperature management during cardiopulmonary bypass (CPB). METHODS: In this prospective randomized study, we measured the effect of mild hypothermic (32 degrees C, N.=30) vs. normothermic (37 degrees C, N.=30) CPB on neurocognitive function. All patients underwent elective isolated biological AVR (mean age 67 +/- 8 years, mean additional EuroSCORE 5.6 +/- 2.4). Neurocognitive function was objectively measured by means of objective P300 auditory-evoked potentials before surgery, one week and four months after surgery. Clinical data and outcome were monitored. RESULTS: P300 evoked potentials were comparable between patients operated with mild hypothermic (370 +/- 30 ms) and normothermic CPB (373 +/- 32 ms) before surgery (P=0.85). P300 peak latencies were prolonged (=impaired) in patients operated with normothermic (402 +/- 29, P<0.0001) as well as with mild hypothermic CPB (405 +/- 30 ms, P<0.0001) one week after surgery. Even four months after surgery, still impairment of P300 peak latencies could be documented in either patients operated with normothermic (394 +/- 28 ms) and mild hypothermic CPB (400 +/- 33 ms,) in repeated measures analysis of variance (P=0.042). Group comparison revealed no difference between patients operated with normothermic and mild hypothermic CPB at one week (P=0.54) and four months (P=0.67) after surgery. Clinical data as well as postoperative adverse events were comparable between the two groups. CONCLUSION: Normothermic temperature management during CPB is non-inferior to hypothermic in means of neuroprotection. Since patients after biological aortic valve replacement show a subclinical but measurable cognitive deficit up to four months after surgery, other factors have to be addressed to add further benefit to the extremely good results of open biological AVR. PMID- 22231537 TI - Superiority of topical negative pressure over closed irrigation therapy of deep sternal wound infection in cardiac surgery. AB - AIM: We sought to compare clinical outcomes, in-hospital mortality and 1-year survival of two different treatment modalities of deep sternal wound infection, topical negative pressure and the closed irrigation therapy. METHODS: Retrospective analysis of 66 consecutive patients treated for deep sternal infection at our institution. A total of 28 patients (February 2002 through September 2004) underwent primarily closed irrigation therapy, and 34 patients (November 2004 through December 2007) had the application of topical negative pressure. Four patients (July 2004 through December 2004) who underwent a combination of both strategies were excluded from the study. Clinical and wound care outcomes were compared, focusing on therapeutic failure rate, in-hospital stay and the 1-year mortality of both treatment strategies. RESULTS: Topical negative pressure was associated with a significantly lower failure rate of the primary therapy (P<0.05), shortening of the intensive care unit stay (P<0.001), a particular decrease in the in-hospital stay (P<0.05) and the 1-year mortality (P<0.05) in comparison with closed irrigation therapy. Comparable overall length of the therapy, in-hospital stay and the risk of wire-related fistulas after chest reconstruction were found. CONCLUSION: Topical negative pressure is a superior method of treatment for deep sternal wound infection, which is based on lower therapeutic failure rate, significant decrease in-hospital stay, and the decrease of the 1-year mortality rate, compared with primarily applied closed irrigation. PMID- 22231538 TI - Sternal neoangiogenesis following internal mammary artery devascularization: an experimental model. AB - AIM: The use of bilateral internal thoracic arteries (BIMA) for coronary artery revascularization is associated with better long-term survival and longer freedom from reoperation. Concerns of deep sternal wound infections and mediastinitis have constantly emerged with the utilization of BIMA grafts on a routine basis, especially in diabetic patients. METHODS: We performed a quantitative evaluation of sternal bone healing and angiogenesis after left (LIMA) or bilateral internal mammary artery (BIMA) ligation two and four weeks after sternotomy in normal and diabetic Sprague-Dawley rats. RESULTS: The BIMA group showed a significant increase in neoangiogenesis two weeks after surgery compared to LIMA and control groups (control: 38.3 +/- 5.1 vessels/mm2, LIMA: 31.4 +/- 3.6 vessels/mm2, BIMA: 81.6 +/- 7.7 vessels/mm2; P=0.047 and P=0.04, respectively). Four weeks after the procedure, bilateral devascularization was associated with lower microvessel formation when compared to LIMA or control groups (control: 50.4 +/- 5.2 vessels/mm2, LIMA: 64.6 +/- 4.9 vessels/mm2; BIMA: 31.5 +/- 4.4 vessels/mm2; P=0.006 and P=0.02, respectively). Diabetic animals showed similar results with lower four weeks microvessel formation. However, there were no significant differences when animals with induced diabetes were compared to the normal euglycemic groups for each procedure performed. CONCLUSION: BIMA ligation promotes an early increase in neoangiogenesis. Progressive sternal consolidation is associated with a significant lower level of capillaries and arterioles in the BIMA group four weeks after ligation. Diabetes did not influence the extent of neoangiogenesis between groups with similar procedures. More important clinical determinants could explain the increase incidence of sternal infection in this specific population. PMID- 22231539 TI - Novel mechanism of conjoined gene formation in the human genome. AB - Recently, conjoined genes (CGs) have emerged as important genetic factors necessary for understanding the human genome. However, their formation mechanism and precise structures have remained mysterious. Based on a detailed structural analysis of 57 human CG transcript variants (CGTVs, discovered in this study) and all (833) known CGs in the human genome, we discovered that the poly(A) signal site from the upstream parent gene region is completely removed via the skipping or truncation of the final exon; consequently, CG transcription is terminated at the poly(A) signal site of the downstream parent gene. This result led us to propose a novel mechanism of CG formation: the complete removal of the poly(A) signal site from the upstream parent gene is a prerequisite for the CG transcriptional machinery to continue transcribing uninterrupted into the intergenic region and downstream parent gene. The removal of the poly(A) signal sequence from the upstream gene region appears to be caused by a deletion or truncation mutation in the human genome rather than post-transcriptional trans splicing events. With respect to the characteristics of CG sequence structures, we found that intergenic regions are hot spots for novel exon creation during CGTV formation and that exons farther from the intergenic regions are more highly conserved in the CGTVs. Interestingly, many novel exons newly created within the intergenic and intragenic regions originated from transposable element sequences. Additionally, the CGTVs showed tumor tissue-biased expression. In conclusion, our study provides novel insights into the CG formation mechanism and expands the present concepts of the genetic structural landscape, gene regulation, and gene formation mechanisms in the human genome. PMID- 22231540 TI - Hyperthermia by bathing in a hot spring improves cardiovascular functions and reduces the production of inflammatory cytokines in patients with chronic heart failure. AB - Balneotherapy has been shown to reduce systemic blood pressure in healthy volunteers. Hyperthermia might ameliorate the inflammatory status in heart failure through improving cardiac function. The purpose of this study was to examine the beneficial effects of balneotherapy in patients with chronic heart failure (CHF). Thirty-two patients with systolic CHF classified as New York Heart Association functional status II or III were randomized to divide either a balneotherapy group or a control group. The patients in the balneotherapy group were immersed in a hot spring at 40 degrees C for 10 min daily for 2 weeks; the control group patients took a shower daily. The left ventricular ejection fraction (EF) and cardiothoracic ratio (CTR) were evaluated and plasma brain natriuretic peptide (BNP), high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels were measured. The clinical symptoms improved after 2 weeks of hot spring therapy. Although the heart rate did not change, clinical symptoms, CTR, EF, and BNP were significantly improved. Moreover, the inflammatory responses, including hsCRP, TNF-alpha and IL-6 decreased significantly after balneotherapy. The improvement of BNP correlates with the changes in inflammatory biomarkers. Repeated hyperthermia by bathing in a hot spring is therefore considered to improve the cardiac and inflammatory status in patients with CHF. PMID- 22231541 TI - Stability of predictors of mortality after spinal cord injury. AB - STUDY DESIGN: Cohort study. OBJECTIVES: To identify the stability of socio environmental, behavioral and health predictors of mortality over an 8-year time frame. SETTING: Data were analyzed at a large medical university in the Southeast United States of America (USA). METHODS: Adults with residual impairment from a spinal cord injury (SCI) who were at least 1-year post-injury at assessment were recruited through a large specialty hospital in the Southeast USA. A total of 1209 participants were included in the final analysis. A piecewise exponential model with two equal time intervals (8 years total) was used to assess the stability of the hazard and the predictors over time. RESULTS: The hazard did significantly change over time, where the hazard in the first time interval was significantly lower than the second. There were no interactions between the socio environmental, behavior or health factors and time, although there was a significant interaction between age at injury (a demographic variable) and time. CONCLUSION: These results suggest there is stability in the association between the predictors and mortality, even over an 8-year time period. Results reinforce the use of historic variables for prediction of mortality in persons with SCI. PMID- 22231542 TI - Sport, free time and hobbies in people with spinal cord injury. AB - STUDY DESIGN: Prospective, multicenter follow-up (F-U) observational study. OBJECTIVES: To investigate the changes in participation and sports practice of people after spinal cord injury (SCI) and their impact on perceived quality of life (QoL). METHODS: The questionnaire investigated the health status and management of clinical conditions and attendance of social integration, occupation, autonomy, car driving, sentimental relationships and perceived QoL in a SCI population 4 years after the first rehabilitation hospitalization. RESULTS: Respondents were 403, 83.4% male; 39% was tetraplegic. At F-U, 42.1% worked and studied, 42.2% still held their jobs or studies, and 69% drove the car. In all, 77.2% had bowel continence and 40.4% urinary continence. The results showed that for the 68.2% of respondents, the attendance of friends, relatives and colleagues during their free time was the same or increased compared with the time before the injury, whereas 31.8% showed a decrease. The amount of time the 52.1% of respondents left home was the same or increased compared with before the trauma, whereas 50.6% of the respondents said that the time they were engaged in hobbies was either the same or increased. CONCLUSION: SCI people who perceived their QoL as being higher, and whose attendance, autonomy and time was increased in respect to hobbies, were mainly men with an age range between 36 and 40 years, unmarried, paraplegic and with A-B Asia Score. Regarding the amount of time dedicated to practicing sports, the only difference was the most of that respondents, who indicated a decrease, were women. PMID- 22231543 TI - Acute effect of electrical stimulation of the dorsal genital nerve on rectal capacity in patients with spinal cord injury. AB - BACKGROUND: Constipation and fecal incontinence are considerable problems for most individuals with spinal cord injury (SCI). Neurogenic bowel symptoms are caused by several factors including abnormal rectal wall properties. Stimulation of the dorsal genital nerve (DGN) can inhibit bladder contractions and because of common innervation inhibitory effects are anticipated in the rectum too. Therefore, DNG could have a future role in the treatment of neurogenic fecal incontinence. AIM: To study the effect of acute DGN stimulation on the rectal cross sectional area (CSA) in SCI patients. METHODS: Seven patients with complete supraconal SCI (median age 50 years) were included. Stimulation was applied via plaster-electrodes using an amplitude of twice the genito-anal reflex threshold (pulse width: 200 MUs; pulse rate: 20 Hz). A pressure controlled phasic (10, 20 and 30 cmH(2)O) rectal distension protocol was repeated four times with subjects randomized to stimulation during 1st and 3rd distension series or 2nd and 4th distension series. The rectal CSA and pressure were measured using impedance planimetry and manometry. RESULTS: All patients completed the investigation. Median stimulation amplitude was 51 mA (range 30-64). CSA was smaller during stimulation and differences reached statistical significance at distension pressures of 20 cmH(2)O (average decrease 9%; P = 0.02) and 30 cmH(2)O (average decrease 4%; P = 0.03) above resting rectal pressure. Accordingly, rectal pressure-CSA relation was significantly reduced during stimulation at 20 (P=0.03) and 30 cmH(2)O distension (P=0.02). CONCLUSION: DGN Stimulation in patients with supraconal SCI results in an acute decrease of rectal CSA and the rectal pressure CSA relation. PMID- 22231544 TI - The effect of semiconditional dorsal penile nerve electrical stimulation on capacity and compliance of the bladder with deformity in spinal cord injury patients: a pilot study. AB - STUDY DESIGN: Bladder capacity, bladder compliance, the volume of the first overactive contraction, maximal volume during cystometry (CMG) and the vesicoureteral reflux, bladder wall deformity before and after semiconditional stimulation on DPN. OBJECTIVES: To evaluate the effect of the semiconditional electrical stimulation on dorsal penile nerve (DPN) to improve the complicated bladder function in male with spinal cord injury (SCI). SETTING: Semiconditional stimulation system and urodynamic laboratory in a university hospital. PARTICIPANTS: Six men (age, 33-59 years) with SCI incurred from 38 to 156 months before this study. INTERVENTION: semiconditional stimulation parameters were set during CMG and semiconditional stimulation on DPN by surface electrodes via Empi Focus stimulator was applied from 14 to 28 days, at home. Parameters about bladder function were measured before and after stimulation applied. RESULT: All parameters for bladder after semiconditional stimulation were increased. Also, the vesicoureteral reflux and bladder wall deformity was improved in five of six patients. CONCLUSION: Semiconditional electrical stimulation on DPN effectively suppresses neurogenic detrusor overactivity and distend the bladder physiologically in the SCI patient with a complicated bladder. The bladder capacity and compliance as well as the bladder wall deformity were improved as a result of this treatment. PMID- 22231545 TI - Maximum voluntary ventilation as a sensitive measure to monitor the ventilatory function in cervical spondylotic myelopathy. AB - STUDY DESIGN: A prospective clinical cohort study. OBJECTIVES: To test if maximum voluntary ventilation (MVV), which is currently underutilized in diseases, serves for assessing subclinical ventilatory impairment in cervical spondylotic myelopathy (CSM). SETTING: Kochi Medical School, Japan. METHODS: We studied ventilatory function in 49 CSM patients and 20 age- and sex-matched control patients with either lumbar stenosis or lower limb osteoarthritis. All patients underwent ventilatory function studies consisting of flow volume curves, vital capacity (VC) and the MVV in 12 s before and after surgery. Tetraparesis was assessed by the functional scale of the Japanese Orthopaedic Association (JOA). RESULTS: The CSM group had significantly smaller %forced VC , %peak expiratory flow rate (%PEFR) and %MVV than the control group preoperatively. In contrast to the control group, the CSM group showed a significant increase in %MVV from 74.9+/-18.7% preoperatively to 80.3+/-19.0% postoperatively (P<0.005), but not in any other ventilatory measures. This postoperative increase in %MVV significantly correlated with the JOA score (r=0.493; P<0.001). As a possible effect of diaphragmatic recovery, the %PEFR significantly increased postoperatively only in patients with the primary site of involvement at or rostral to C3-4. CONCLUSION: Of the various ventilatory measurements, MVV was most sensitive to changes in tetraparesis in CSM, presumably because MVV, unlike the other ventilatory measures, reflects the coordination in addition to the strength of respiratory muscles. PMID- 22231546 TI - Response to 'technology for mobility in SCI ten years from now'. PMID- 22231547 TI - Priapism in acute spinal cord injury. PMID- 22231548 TI - Evaluator agreement in placement recommendations for insanity acquittees. AB - Research has examined differences between psychologists and psychiatrists in opinions on trial competency and criminal responsibility, but there is little research on such differences in risk assessment. This study examined the impact of disciplinary affiliation on opinions regarding whether new insanity acquittees should be hospitalized or released, and the risk factors given the most weight by each discipline. There was no significant difference between disciplines in the frequency of recommendations for hospitalization versus release. However, the concordance rate at the individual case level was only moderate when controlling for chance, which raises questions about the reliability and validity of forensic risk assessments in real-world settings. A number of variables emerged as significant in the decision-making of each discipline, with some differences noted. PMID- 22231549 TI - Photo-orientation of axial molecules. AB - We examine the photo-orientation of molecules in a linearly polarized field and the ensuing optical anisotropy of a sample. We propose a theoretical model that considers both photoinduced reorientation and rotational diffusion, for the case of linear or axial molecules not interacting among them, as in dilute solutions in viscous media. We perform numerical simulations to highlight the dependence on the parameters of the molecular reorientation processes, on the intensity of the exciting light, and on the use of cross polarized pulses. As a realistic example we simulate the photo-orientation of azobenzene in ethylene glycol. PMID- 22231550 TI - [Outpatient rehabilitation after myocardial infarction or for heart failure]. AB - Reducing cardiac mortality and improving quality of life are the main objectives of cardiac rehabilitation. In recent years, outpatient rehabilitation within easy patient reach has achieved the same status as inpatient rehabilitation. Outpatient rehabilitation permits close involvement of the patient's family and social environment, thus easing reintegration into everyday life. However, the health care system is not yet utilizing outpatient rehabilitation to its full potential. This contribution illustrates the principles of rehabilitation following myocardial infarction or for heart failure in an outpatient setting, as well as its potential and future development. PMID- 22231551 TI - Severe meningo-radiculo-neuritis associated with ipilimumab. AB - PURPOSE: Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) to promote antitumoural immunity. In phase III trials, ipilimumab was shown to be the first agent to improve survival in advanced melanoma patients, regardless of previous treatment. We report a case of severe neurologic disease after ipilimumab treatment. PATIENT AND METHODS: Neurologic symptoms including facial diplegia, tetraplegia, areflexia progressed with time a few days after the fourth monthly ipilimumab infusion. Analysis of the cerebro-spinal fluid showed elevated proteinorachy and lymphocytic meningitis. Despite high doses of steroids and symptomatic treatment, the symptoms worsened. RESULTS: Veinoglobulins were then infused and the patient began to improve and recovered almost normal activity two years later. CONCLUSION: The adverse event profile associated with ipilimumab was primarily immune-related. This is the first case in which such a severe event has been reported. PMID- 22231553 TI - Immune receptor signaling: from ubiquitination to NF-kappaB activation. PMID- 22231552 TI - Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy. AB - Acute-on-chronic liver failure (ACLF) is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells (mDCs) and the efficacy of methylprednisolone (MP) treatment for hepatitis B virus (HBV)-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at 10-day intervals; 26 patients received conservative medical (CM) management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients. PMID- 22231554 TI - Salmeterol attenuates the inflammatory response in asthma and decreases the pro inflammatory cytokine secretion of dendritic cells. AB - Salmeterol is a long-acting beta2-agonist that activates adenylate cyclase, causing long-lasting bronchodilation and has been used for many years to control asthma. However, little information is available about the immunoregulatory effects of salmeterol. We found that salmeterol decreases the production of pro inflammatory cytokines in a model of allergen-challenged mice that expressed tumor-necrosis factor-alpha, interleukin-1 and interleukin-6. Dendritic cells (DCs) are antigen-presenting cells and act as sentinels in the airway. We found that salmeterol (10(-5) mol/l) reduced the inflammation caused by lipopolysaccharide (0.1 ug/ml) in activated murine bone marrow-derived DCs. Moreover, western blots demonstrated that this protective effect was mediated partially by inhibiting signaling through the nuclear factor-kappa B (NF-kappaB), mitogen-activated protein kinase (MAPK) pathways and dramatically decreased levels of p-ERK. We suggest that salmeterol regulates the inflammation of allergen-induced asthma by modulating DCs. In conclusion, we provide evidence that DCs are the target immune cells responsible for the action of salmeterol against asthma. PMID- 22231555 TI - Identification of novel HLA-A*0201-restricted epitopes from anterior gradient-2 as a tumor-associated antigen against colorectal cancer. AB - Anterior gradient-2 (AGR2) promotes tumor growth, cell migration and cellular transformation and its enhanced expression is almost completely restricted to malignant tissues, thus making AGR2 an interesting target for the development of immunotherapeutic strategies. We investigated whether the AGR2 molecule comprises human leukocyte antigen (HLA)-A*0201-binding epitopes recognized by human cytotoxic T lymphocytes (CTLs), which could be targeted in dendritic cell (DC) based cancer immunotherapy against colorectal cancer (CRC). We reviewed the sequence of AGR2 for peptides that could potentially bind to HLA-A*0201 with the aid of a computer-based program. Five candidate peptides with different binding scores were synthesized and tested. These peptides were then assessed for their immunogenicity to elicit specific immune responses mediated by CTLs in vitro by means of enzyme-linked immunospot assays and CTL assays. AGR2 was highly expressed in several CRC cell lines, including DK01, DLD1, KM12C, HCT-8 and HT 29. DCs pulsed with AGR2-P2 (aa 11-19; LLVALSYTL) or AGR2-P4 (aa 127-135; RIMFVDPSL) generated potent CTLs that could lyse T2 cells pulsed with AGR2-P2 or AGR2-P4 and HLA-A0201(+) AGR2-positive CRC cell lines in a strong dose-dependent and HLA-A*0201-restricted manner. In conclusion, these novel epitopes derived from AGR2 protein may be attractive candidates for DC-based immunotherapy for CRC. PMID- 22231556 TI - AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. AB - Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that is associated with malignant hyperthermia in humans, die when exposed to short periods of temperature elevation (>=37 degrees C). We show here that treatment with 5-aminoimidazole-4 carboxamide ribonucleoside (AICAR) prevents this heat-induced sudden death in this mouse model. The protection by AICAR is independent of AMP-activated protein kinase (AMPK) activation and results from a newly identified action of the compound on mutant Ryr1 to reduce Ca(2+) leak from the sarcoplasmic reticulum to the sarcoplasm. AICAR thus prevents Ca(2+)-dependent increases in the amount of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) that act to further increase resting Ca(2+) concentrations. If unchecked, the temperature driven increases in resting Ca(2+) concentrations and the amounts of ROS and RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents heat-induced death in vivo. Our findings suggest that AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations. PMID- 22231557 TI - Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. AB - Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ~170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent. PMID- 22231559 TI - Perineal reconstruction after abdominoperineal excision using inferior gluteal artery perforator flaps. AB - BACKGROUND: Perineal wound complications following abdominoperineal excision (APE) for low rectal tumours remain an important cause of morbidity and prolonged hospital stay, particularly after chemoradiotherapy. The aim was to assess outcomes after using inferior gluteal artery perforator (IGAP) flaps for immediate perineal reconstruction, and to compare these with the authors' previous experience and published literature on myocutaneous flaps. METHODS: A series of patients who underwent immediate IGAP flap reconstruction after APE between April 2008 and December 2010 were examined retrospectively to determine patient demographics, length of operation, complications (perineal wound and general) and length of hospital stay. RESULTS: Forty patients with rectal adenocarcinoma (33 primary and 7 recurrent disease) underwent immediate IGAP flap reconstruction following APE. Median follow-up was 9 months. Neoadjuvant chemoradiotherapy was received by 98 per cent of the patients. Thirty-two patients underwent APE plus IGAP flaps (25 open, 7 laparoscopic), with a median operating time of 402 min, and eight patients had multivisceral resection (MVR) plus IGAP flaps (7 total pelvic exenteration (TPE), 1 abdominosacral resection), with a median duration of surgery of 561 min. There was one death (fatal stroke) and four major flap complications (10 per cent) (1 enteroperineal fistula, and 3 deep wound infections). Median length of hospital stay was 13 days after APE plus IGAP flaps and 27 days following MVR plus IGAP flaps. Late complications occurred in two patients who had vaginal reconstruction and developed perineal hernias requiring revisional surgery. CONCLUSION: Although operating times are long, the IGAP flap is robust, with no flap necrosis observed in this series. PMID- 22231558 TI - A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. AB - In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here we show that genomic ablation of Smad ubiquitin regulatory factor 2 (Smurf2), a HECT-domain E3 ubiquitin ligase, results in dysregulation of both the DNA damage response and genomic stability, culminating in increased susceptibility to various types of cancers in aged mice. We show that Smurf2 regulates the monoubiquitination of histone H2B as well as the trimethylation of histone H3 at Lys4 and Lys79 by targeting ring finger protein 20 (RNF20) for proteasomal degradation in both mouse and human cells. We also show that Smurf2 and RNF20 are colocalized at the gamma-H2AX foci of double stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20. PMID- 22231560 TI - In the absence of physical practice, observation and imagery do not result in updating of internal models for aiming. AB - The presence of after-effects in adaptation tasks implies that an existing internal model has been updated. Previously, we showed that although observers adapted to a visuomotor perturbation, they did not show after-effects. In this experiment, we tested 2 further observer groups and an actor group. Observers were now actively engaged in watching (encouraged through imagery and movement estimation), with one group physically practising for 25% of the trials (mixed). Participants estimated the hand movements that produced various cursor trajectories and/or their own hand movement from a preceding trial. These trials also allowed us to assess the development of explicit knowledge as a function of the three practice conditions. The pure observation group did not show after effects, whereas the actor and mixed groups did. The pure observation group improved their ability to estimate hand movement of the video model. Although the actor and mixed groups improved in actual reaching accuracy, they did not improve in explicit estimation. The mixed group was more accurate in reaching during adaptation and showed larger after-effects than the actors. We suggest that observation encourages an explicit mode of learning, enabling performance benefits without corresponding changes to an internal model of the mapping between output and sensory input. However, some physical practice interspersed with observation can change the manner with which learning is achieved, encouraging implicit learning and the updating of an existing internal model. PMID- 22231561 TI - Antioxidant, antimicrobial and anticancer activities of three Parmelia species. AB - BACKGROUND: Lichens are symbiotic organisms consisting of algae and fungi. They are used for human and animal nutrition and in the production of colours, perfumes and alcohol. Lichens have also been used in traditional medicine to treat diseases such as jaundice, pulmonary, stomach and cranial diseases. In this study the acetone extracts of three lichens, Parmelia caperata, Parmelia sulcata and Parmelia saxatilis, were tested for their antioxidant, antimicrobial and anticancer potential. RESULTS: Of the lichens tested, P. saxatilis had the highest free radical-scavenging activity (55.3% inhibition). Moreover, all tested extracts showed effective reducing power and superoxide anion radical scavenging. Strong relationships between total phenolic and flavonoid contents and antioxidant effects of the tested extracts were observed. The extract of P. sulcata was most active in terms of antimicrobial ability, with minimum inhibitory concentration values ranging from 0.78 to 12.5 mg L-1. All extracts were found to have strong anticancer activity, with IC50 values ranging from 9.55 to 22.95 ug mL-1. CONCLUSION: The present study showed that the tested lichen extracts exhibited strong antioxidant, antimicrobial and anticancer effects. This suggests that lichens may be used as possible natural antioxidant, antimicrobial and anticancer agents. PMID- 22231563 TI - Identification of epithelialization in high transsphincteric fistulas. AB - BACKGROUND: At present, transanal advancement flap repair (TAFR) is the treatment of choice for transsphincteric fistulas passing through the upper and middle third of the external anal sphincter. It has been suggested that epithelialization of the fistula tract contributes to the failure of the treatment. The aim of this study was to assess the prevalence of epithelialization of the fistula tract and to study its effect on the outcome of TAFR and TAFR combined with ligation of the intersphincteric fistula tract (LIFT). METHODS: Forty-four patients with a high transsphincteric fistula of cryptoglandular origin underwent TAFR. Nine of these patients underwent a combined procedure of TAFR with LIFT. In all patients the fistula tract was excised from the external opening up to the outer border of the external anal sphincter. In patients undergoing TAFR combined with LIFT an additional central part of the intersphincteric fistula tract was excised. A total of 53 specimens were submitted. Histopathological examination of the specimens was carried out by a pathologist, blinded for clinical data. RESULTS: Epithelialization of the distal and intersphincteric fistula tract was observed in only 25 and 22% of fistulas, respectively. There was no difference in outcome between fistulas with or without epithelialization. CONCLUSIONS: Epithelialization of high transsphincteric fistulas is rare and does not affect the outcome of TAFR and TAFR combined with LIFT. PMID- 22231564 TI - Alphaherpesvirus latency. PMID- 22231566 TI - Clinical and economic challenges facing pharmacogenomics. AB - In this paper, we examine the clinical and economic challenges that face developers of and payers for personalized drugs and companion diagnostics. We review and summarize clinical, regulatory and reimbursement issues with respect to eight, high profile personalized medicines and their companion diagnostics. Subsequently, we determine Medicare parts B and D reimbursement of the eight drugs from publicly available databases. Finally, we utilize surveys-each tailored to three key stakeholders; payers, drug and diagnostic developers, and pharmacogenomic expert analysts-to assess reimbursement of diagnostics, analyze the role that different kinds of evidence have in informing prescribing and reimbursement decisions, as well as the specific clinical, regulatory and economic challenges that confront pharmacogenomics as it moves forward. We found that Medicare beneficiary access to physician-administered (Medicare part B) drugs is relatively unfettered, with a fixed patient co-insurance percentage of 20%. More reimbursement restrictions are placed on self-administered (Medicare part D) drugs, which translates into higher and more variable cost sharing, more use of prior authorization and quantity limits. There is a lack of comprehensive reimbursement of companion diagnostics, even in cases in which the diagnostic is on the label and recommended or required by the Food and Drug Administration. Lack of evidence linking diagnostic tests to health outcomes has caused payers to be skeptical about the clinical usefulness of tests. Expert analysts foresee moderate growth in post-hoc development of companion diagnostics to personalize already approved drugs, and limited growth in the concurrent co-development of companion diagnostics and personalized medicines. Lack of clinically useful diagnostics as well as an evidence gap in terms of knowledge of drug and diagnostic clinical effectiveness appear to be hindering growth in personalized medicine. An increase in comparative effectiveness research may help to close the evidence gap. PMID- 22231565 TI - Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy. AB - Recent studies suggest CD133, a surface protein widely used for isolation of colon cancer stem cells, to be associated with tumor angiogenesis and recurrence. We hypothesized that gene expression levels and germline variations in CD133 will predict clinical outcome in patients with metastatic colorectal cancer (mCRC), treated in first-line setting with 5-fluorouracil, oxaliplatin and bevacizumab (BV), and we investigated whether there is a correlation with gene expression levels of CD133, vascular endothelial growth factor (VEGF) and its receptors. We evaluated intra-tumoral gene expression levels by quantitative real-time (RT) PCR from 54 patients and three germline variants of the CD133 gene by PCR-restriction fragment length polymorphism from 91 patients with genomic DNA. High gene expression levels of CD133 (>7.76) conferred a significantly greater tumor response (RR=86%) than patients with low expression levels (?7.76, RR=38%, adjusted P=0.003), independent of VEGF or its receptor gene expression levels. Gene expression levels of CD133 were significantly associated with VEGF and its receptors messenger RNA levels (VEGFR-1 (P<0.01), -2 and -3, P<0.05). Combined analyses of two polymorphisms showed a significant association with progression free survival (PFS) (18.5 months vs 9.8 months, P=0.004) in a multivariate analysis as an independent prognostic factor for PFS (adjusted P=0.002). These results suggest that CD133 is a predictive marker for standard first-line BV based treatment in mCRC. PMID- 22231567 TI - Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3. AB - Human organic cation transporter 3 (OCT3 and SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer, and is markedly underexpressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g. 81G>delGA (rs60515630) (minor allele frequency 11.5% in African American) and g. 2G>A (rs555754) (minor allele frequency>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor-binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 messenger RNA expression levels were significantly higher in Asian (P<0.001) and Caucasian (P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer. PMID- 22231569 TI - Craniovertebral junction abnormality in a case of Joubert syndrome. PMID- 22231570 TI - Acute epidural spinal hemorrhage from vasculitis: resolution with immunosuppression. AB - BACKGROUND: Angiographic vasculitis affecting the spine has been rarely described. The use of immunosuppression as a primary treatment and a review of the literature is presented. METHODS: Case report. RESULTS: A 61-year-old female presented with sudden onset back pain and headache. The patient was found to have acute spinal epidural hemorrhage and subsequent work-up demonstrated angiographic spinal vasculitis. Immunosuppression with cyclophosphamide resulted in clinical and radiographic improvement. CONCLUSIONS: Immunomodulating therapy should be considered in the management of select patients with spinal vasculitis which may lead to improved clinical outcome and potentially disease resolution. PMID- 22231571 TI - Effect of splinting and exercise on intraneural edema of the median nerve in carpal tunnel syndrome--an MRI study to reveal therapeutic mechanisms. AB - Splinting and nerve and tendon gliding exercises are commonly used to treat carpal tunnel syndrome (CTS). It has been postulated that both modalities reduce intraneural edema. To test this hypothesis, 20 patients with mild to moderate CTS were randomly allocated to either night splinting or a home program of nerve and tendon gliding exercises. Magnetic resonance images of the wrist were taken at baseline, immediately after 10 min of splinting or exercise, and following 1 week of intervention. Primary outcome measures were signal intensity of the median nerve at the wrist as a measure of intraneural edema and palmar bowing of the carpal ligament. Secondary outcome measures were changes in symptom severity and function. Following 1 week of intervention, but not immediately after 10 min, signal intensity of the median nerve was reduced by ~ 11% at the radioulnar level for both interventions (p = 0.03). This was accompanied by a mild improvement in symptoms and function (p < 0.004). A similar reduction in signal intensity is not observed in patients who only receive advice to remain active. No changes in signal intensity were identified further distally (p > 0.28). Ligament bowing remained unchanged (p > 0.08). Intraneural edema reduction is a likely therapeutic mechanism of splinting and exercise. PMID- 22231572 TI - Ultrasound-guided Hartmann's solution enema: first-choice procedure for reducing idiopathic intussusception. AB - PURPOSE: This study was undertaken to compare the effectiveness of ultrasound guided Hartmann's solution enema (US-E) and radiological liquid enema (RX-E) in reducing idiopathic ileocecocolic intussusceptions in relation to patient age and symptom duration. MATERIALS AND METHODS: The study group consisted of 42 patients with idiopathic ileocecocolic intussusception treated with US-E (20 patients) or RX-E (23 patients), with one patient undergoing both procedures owing to recurrence. Patients were divided into subgroups according to age (<6 months, 6 12 months, >12 months) and symptom duration (<12 h, 12-24 h, >24 h). RESULTS: Complete reduction was achieved in 15/20 patients treated with US-E (75%) and in 10/23 treated with RX-E (43.5%) (p=ns). Recurrence was observed in 1/20 US-E and 0/23 RX-E (p=ns) patients. No complications were encountered. US-E had a significantly higher success rate than RX-E in patients >12 months (p=0.0063) and with symptom duration >24 h (p=0.0361). No differences were found in the other subgroups (p=ns). CONCLUSIONS: US-E and RX-E are procedures of comparable value and safety in reducing idiopathic intussusception. US-E seems to be more effective in patients >12 months or with symptom duration >24 h. As US-E avoids radiation exposure, it should be considered the first-choice procedure for reducing idiopathic ileocecocolic intussusception, particularly in these two subgroups of patients. PMID- 22231573 TI - Magnetic resonance imaging in women with pelvic pain from gynaecological causes: a pictorial review. AB - This article illustrates causes of pelvic pain in girls and women that may be inadequately diagnosed by ultrasound (US) and more adequately assessed by magnetic resonance imaging (MRI). We describe MRI features necessary for detecting disease and helpful in differential diagnosis. Special attention is paid to correlating age and pathology by subdividing the population into four categories: girls up to prepubertal age, pubertal girls, women of reproductive age and postmenopausal women. US is the first-line imaging modality in children and women with pelvic pain, and computed tomography (CT) is usually requested, especially in emergency settings, in patients in whom US is inadequate for diagnosis. However, MRI should be considered at least in urgent, if not in emergent, care given the wide range of female pelvic disorders that can be correctly assessed thanks to the excellent soft-tissue contrast, high spatial resolution and ability to depict blood products. Moreover, MRI should be preferred in children and women of reproductive age because of the absence of radiation exposure. PMID- 22231568 TI - Evaluation of TRAF6 in a large multiancestral lupus cohort. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. METHODS: Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 * 10(-5) and P = 4.73 * 10( 5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 * 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 * 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. CONCLUSION: Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity. PMID- 22231574 TI - Quantitative MRCP assessment of pancreatic exocrine reserve and its correlation with faecal elastase-1 in patients with chronic pancreatitis. AB - PURPOSE: This retrospective study was done to correlate a quantitative assessment of the pancreatic exocrine reserve by dynamic secretin magnetic resonance cholangiopancreatography (MRCPQ) with the faecal elastase-1 (FE-1) test in patients with chronic pancreatitis. MATERIALS AND METHODS: Thirty-five patients with a clinical diagnosis of chronic (CP) or acute recurrent (ARP) pancreatitis were enrolled. FE-1 was indicative of the pancreatic exocrine reserve. Subsequently, the patient population was subdivided into two groups according to a clinical threshold value of 200 MUg/g. All patients underwent MRCP examination during secretin administration. Duodenal filling volume was calculated on T2 weigthed rapid acquisition with relaxation enhancement (RARE) MRCP images obtained 10 min after secretin injection. Duodenal filling volumes were compared with FE-1 values. Scatter plots, Pearson correlation coefficient and the Mann Whitney U test were performed. RESULTS: Thirty-five paired MRCPQ-FE1 data sets were analysed. MRCPQ was significantly different (p=0.007) between patients with impaired and preserved pancreatic function; median and interquartile range (IQR) were 150.7 ml (137.3-205.5 ml; n=9) and 332.4 ml (190.6-506.9 ml; n=26). Both Pearson correlation coefficient (p<0.001) and the Mann-Whitney U test (p=0.007) were significant. CONCLUSIONS: MRCPQ significantly correlates with FE-1 values. It is possible to discriminate impaired and preserved pancreatic exocrine function using MRCPQ. PMID- 22231576 TI - A rare case of supraclinoid internal carotid artery (ICA) fenestration in combination with duplication of the middle cerebral artery (MCA) originating from the ICA fenestration and an associated aneurysm. AB - Fenestrations and duplications of the cervical and intracranial arteries are rare anatomic variants, reported to be associated with aneurysms or other vascular anomalies. We here present a patient with a supraclinoid ICA fenestration in combination with a duplication of the MCA originating from the ICA fenestration and an associated aneurysm. PMID- 22231577 TI - Monitoring the multi-faceted problem of youth violence: the Asian/Pacific Islander Youth Violence Prevention Center's surveillance system. AB - Youth violence (YV) is a complex public health issue that spans geographic, ethnic, and socioeconomic lines. The Asian/Pacific Islander Youth Violence Prevention Center conducts qualitative and quantitative research on YV in Hawai'i. A critical element in YV prevention involves measuring YV and its risk protective factors to determine the scope of the problem and to monitor changes across time. Under the Asian/Pacific Islander Youth Violence Prevention Center's (APIYVPC's) surveillance umbrella, a variety of methodologies are utilized. The major forms of active surveillance are a School-Wide Survey for youth, and a Safe Community Household Survey for adults. A variety of secondary data sources are accessed, such as the Centers for Disease Control and Prevention (Youth Risk Behavior Surveillance System), the Hawai'i State Department of the Attorney General, the Hawai'i State Department of Education, and the Hawai'i State Department of Health. State data are especially important for the Center, because most of these sources disaggregate ethnicity data for Asian Americans/Pacific Islanders. This paper details the surveillance methodologies utilized by the APIYVPC to monitor YV in one specific community and in Hawai'i, in comparison to the rest of the State and nation. Empirical results demonstrate the utility of each methodology and how they complement one another. Individually, each data source lends valuable information to the field of YV prevention; however, collectively, the APIYVPC's surveillance methods help to paint a more complete picture regarding violence rates and the relationship between YV and its risk protective factors, particularly for minority communities. PMID- 22231578 TI - Characterizing sexual health resources on college campuses. AB - This observational study describes the development of the college resources and sexual health inventory, the profile of sexual health promotion resources at participating colleges, and comparisons of resources across several college characteristics. 28 diverse college campuses in one Midwestern state participated. 10 domains were assessed, including characteristics of campus health services (e.g. convenience), condom programs, sexual health information, communication about resources, sexual violence resources and gay/lesbian/bisexual student resources. Scores for each measure reflected the presence or extent of each resource. Summary scores were created for the overall level of sexual health resources and for each domain. T tests and ANOVAs were used to compare resources at 2-year versus 4-year colleges, public versus private sectors, metro versus non metro locations, and across enrollment size. Inventory scores ranged from 6 to 53. 4-year colleges offered significantly more resources than 2-year; resource levels were statistically similar across location and enrollment size. Subsequent analyses comparing campuses with and without a health center indicated that several resources which were not inherently tied to a clinic nonetheless differed significantly with having a health center. Colleges without this resource could position sexual health resources in other offices or departments or provide referrals to sexual health resources in the broader community. PMID- 22231575 TI - Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection. AB - BACKGROUND: Nucleotide analogues have recently been approved for the treatment of patients with hepatitis B virus (HBV) infection. However, it is still controversial whether the decrease of HBV-DNA amount induced by treatment with nucleotide analogues can reduce the risk of hepatocellular carcinoma (HCC) development in HBV patients. METHODS: A total of 293 HBV patients without HCC who were treated with lamivudine (LAM) were enrolled in a multicenter trial. The incidence of HCC was examined after the start of LAM therapy, and the risk factors for liver carcinogenesis were analyzed. The mean follow-up period was 67.6 +/- 27.4 months. RESULTS: On multivariate analysis for HCC development in all patients, age >=50 years, platelet count <14.0 * 10(4)/mm(3), cirrhosis, and median HBV-DNA levels of >=4.0 log copies/ml during LAM treatment were significant risk factors. The cumulative carcinogenesis rate at 5 years was 3% in patients with chronic hepatitis and 30% in those with cirrhosis. For the chronic hepatitis patients, the log-rank test showed the significant risk factors related to HCC development to be age >=50 years, platelet count <14.0 * 10(4)/mm(3), and hepatitis B e antigen negativity, but median HBV-DNA levels of <4.0 log copies/ml (maintained viral response, MVR) did not significantly suppress the development of HCC. In cirrhosis patients, however, the attainment of MVR during LAM treatment was revealed to reduce the risk of HCC development. CONCLUSIONS: These results suggest that the incidence of HCC in HBV patients with cirrhosis can be reduced in those with an MVR induced by consecutive LAM treatment. PMID- 22231579 TI - Imaging of therapy response in oncology. PMID- 22231580 TI - Response assessment in oncology: limitations of anatomic response criteria in the era of tailored treatments. AB - Evaluation of tumor response is a vital element in clinical oncology research, particularly in the development of new drugs. Tumor response also plays a significant role in treatment decisions made by clinicians in practice. The underlying concept of tumor response, however, was developed as a result of limited understanding of tumor biology coupled with restricted availability of both effective treatments and imaging modalities. In recent years, impressive advances have been made in the treatment of cancer. Groundbreaking advances in our understanding of the molecular biology of tumor growth and proliferation have been made. New biologic agents have been approved for the treatment of several malignancies and, in many cases, biomarkers have been identified that can help predict those patients who will benefit. Pre-operative chemotherapy is now established for a number of tumor types. Modern imaging technologies allowing functional characterization of tumors have been introduced into clinical practice. In this new therapeutic landscape, the existing concept of tumor response risks becoming an anachronism, and revision of the criteria used to define tumor response is warranted. In this paper, we critically review the limitations of the classic criteria for tumor response assessment, and briefly discuss the potential role of alternative methodologies in providing a new, functional definition of tumor response. PMID- 22231581 TI - CT and MRI in monitoring response: state-of-the-art and future developments. AB - The present review is aimed at updating the reader with the current role of computed tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of tumor response, contextualizing the imaging methods advantages and limitations. CT has been the most frequent and widely adopted diagnostic tool. The main advantages of such method include wide availability, high reproducibility, capability to contemporarily evaluate soft tissues, bone and lung parenchyma, besides being easy to perform. Its main limitation is related to the use of ionizing radiation. MRI has emerged as a feasible alternative to CT, particularly in patients with contraindications to the use of iodinated contrast agents, with advantages related to its high soft tissues contrast. The disadvantages are based on its operational complexity and the many technical variables involved which may influence and compromise the reproducibility and broad implementation of the method. New criteria for evaluation of tumor response have recently been proposed, contemplating lately developed drugs and therapeutic strategies that demand the utilization of functional parameters. In this context, the technological developments incorporated in the CT and MRI imaging techniques, such as perfusion analysis, diffusion studies (DW-RM) and MR spectroscopy (MRS), among others, have provided relevant information regarding the tumor response to targeted therapies, anticipating dimensional alterations and guiding physicians in the course of the treatment. Despite such developments, further efforts are needed to establish reproducible protocols, functional response criteria and time intervals for response evaluation in order to allow a definitive incorporation of these new technologies in the assessment of tumor response. PMID- 22231582 TI - (18)F-FDG-PET/CT in evaluating response to therapy in solid tumors: where we are and where we can go. AB - In the past, enormous public and private investments have been made to reduce cancer incidence and mortality. Despite some improvements over the last 10 years, the overall outcome of the "war on cancer" has been disappointing. Among the reasons for this limited success is our inability to determine, whether the therapeutic target is present, and whether the target is reached by the drug. A further important issue is our limited ability to correctly assess response to treatment early after start of therapy which would allow for more individualized treatment approaches. PET and PET/CT with the glucose analogue 2'-[(18)F]-fluoro 2'-deoxy-D-glucose (FDG) are increasingly used to assess response to therapy in patients, and a converging large body of evidence is emerging that suggests that changes in glucose utilization during therapy can be used to predict clinical outcome. In this article we provide an overview of the utility of (18)F-FDG PET/CT imaging for early monitoring of cancer therapy and address current and future challenges for its more widespread adoption. First, we discuss general requirements that any imaging modality must meet to provide valid and valuable treatment response assessment. We will then review the strengths and limitations of CT (RECIST) and PET based response criteria. Finally, we will examine the role of FDG-PET/(CT) imaging for response assessments in solid tumors. PMID- 22231583 TI - Use of PET/CT to evaluate response to therapy in lymphoma. AB - (18)F-FDG-PET is a well established standard procedure for most lymphoma subtypes. In particular the advantage of metabolic imaging stands in its strong predictivity in response. Indeed PET scan has been incorporated into revised response criteria for aggressive lymphomas and recommended to be performed at baseline and after therapy. At the same time, several ongoing clinical trials are investigating the value of treatment adaptation based on interim PET (PETi) results for Hodgkin Lymphoma (HL) and aggressive Non-Hodgkin Lymphoma (NHL). On the other hand, scientific literature provides limited detailed information regarding the numerous non aggressive NHL subtypes. Usually indolent NHL are typically less FDG avid, furthermore their long natural history and high incidence of recurrence decreases the clinical impact of a potential risk-adapted or response-adapted approach. We reviewed, from a nuclear medicine point of view and a clinical point of interest, evidence for the use of FDG-PET in monitoring early and end treatment response. PMID- 22231585 TI - Development of molecular techniques for imaging and treatment of tumors. AB - With the advances in molecular biology and biochemistry new imaging and treatment modalities based on the biological properties of tissues have been developed. In oncology, the major progress has been achieved using peptide and antibody targeting vectors. Besides the identification of new target structures, progress in molecular biology also made new techniques for the development of new biomolecules. This relies on the identification of lead compounds and on the screening of various derivatives of these compounds one at a time. The principle of high-troughput methods for the identification of novel high affinity binders is to generate a vast library of possible variants of the molecule of interest and screen the population for the few variants that show the property of interest. The attracting feature of the concept arises from the huge number of candidate molecules that can be used for further evaluation. After the characterization of the structure-function relationships for the lead compounds found in this process further improvement by rational design of analogs can be performed. PMID- 22231584 TI - Therapy response assessment in radiotherapy of lung cancer. AB - Radiotherapy represents an important therapeutic modality in the treatment of lung cancer. Treatment response assessment after high-dose radiotherapy with or without concurrent chemotherapy using conventional imaging methods is limited since normal tissue appearance might resemble tumour recurrence very close. Positron emission tomography (PET) based imaging has been introduced in this situation with great enthusiasm and provides useful additional information on the biologic characteristics of the irradiated region, be it tumour or healthy lung tissue, provided some marginal conditions are taken into account. Furthermore, biologic imaging seems highly appealing for treatment guidance especially during treatment protocols including multimodality approaches with neoadjuvant intent. Treatment response might not only serve as a surrogate marker for pathological remission but for overall prognosis as well. Within this context, the optimal time point and the best parameter to evaluate remain issues of continuing debate. This review is aimed to give an overview of the current state of the scientific knowledge. PMID- 22231586 TI - Integrative care for adolescent mood problems: brief report from a Pediatric Second Opinion Clinic. PMID- 22231587 TI - Blistering skin disorders in the neonate. PMID- 22231588 TI - Isothermal titration calorimetry and molecular dynamics study of ion-selectivity in mixtures of hydrophobic polyelectrolytes with sodium halides in water. AB - Aliphatic x,y-ionenes are polyelectrolytes in which x and y denote the numbers of methylene groups separating quaternary ammonium ions. They represent useful model substances for studying hydrophobic and charge effects in aqueous solutions. We used isothermal titration calorimetry to measure the enthalpies of mixing, DeltaH(mix), of 3,3- and 6,6-ionene fluorides and bromides with low molecular weight salts (NaF, NaCl, NaBr, and NaI) at 298 K in water. The signs and magnitudes of the measured enthalpies depend on the hydrophobicity of the ionene and on the nature of the added salt. For example, addition of sodium fluoride to solutions of 3,3- and 6,6-ionene fluorides produced endothermic effects, while addition of sodium bromide to 3,3-ionene bromide resulted in a strong exothermic effect. Interestingly, mixing of 6,6-ionene bromide and NaBr solutions in water gave a small exothermic heat effect. Polyelectrolyte theories, based on continuum solvent models, predict enthalpies of mixing to be positive (endothermic) for all the solutions examined in this work. The ion-specific effect is more strongly expressed in ionene solutions with higher charge density (3,3-ionene). The most important result of this work is the finding that the enthalpy of mixing of 3,3- (and of 6,6-ionene) fluorides with sodium halides can be expressed as a linear function of the enthalpy of hydration of the halide counterions. The experimental results were complemented with an explicit water molecular dynamics simulation of solutions of oligoions modelling 3,3- and 6,6-ionenes. The computer simulation results for various nitrogen-counterion pair distribution functions were in most cases consistent with the enthalpy measurements. PMID- 22231589 TI - Assessment of trace metal contamination in a historical freshwater canal (Buckingham Canal), Chennai, India. AB - The present study was done to assess the sources and the major processes controlling the trace metal distribution in sediments of Buckingham Canal. Based on the observed geochemical variations, the sediments are grouped as South Buckingham Canal and North Buckingham Canal sediments (SBC and NBC, respectively). SBC sediments show enrichment in Fe, Ti, Mn, Cr, V, Mo, and As concentrations, while NBC sediments show enrichment in Sn, Cu, Pb, Zn, Ni, and Hg. The calculated Chemical Index of Alteration and Chemical Index of Weathering values for all the sediments are relatively higher than the North American Shale Composite and Upper Continental Crust but similar to Post-Archaean Average Shale, and suggest a source area with moderate weathering. Overall, SBC sediments are highly enriched in Mo, Zn, Cu, and Hg (geoaccumulation index (I(geo)) class 4-6), whereas NBC sediments are enriched in Sn, Cu, Zn, and Hg (I(geo) class 4-6). Cu, Ni, and Cr show higher than Effects-Range Median values and hence the biological adverse effect of these metals is 20%; Zn, which accounts for 50%, in the NBC sediments, has a more biological adverse effect than other metals found in these sediments. The calculated I(geo), Enrichment Factor, and Contamination Factor values indicate that Mo, Hg, Sn, Cu, and Zn are highly enriched in the Buckingham Canal sediments, suggesting the rapid urban and industrial development of Chennai Metropolitan City have negatively influenced on the surrounding aquatic ecosystem. PMID- 22231591 TI - A minimal solution for the extrinsic calibration of a camera and a laser rangefinder. AB - This paper presents a new algorithm for the extrinsic calibration of a perspective camera and an invisible 2D laser-rangefinder (LRF). The calibration is achieved by freely moving a checkerboard pattern in order to obtain plane poses in camera coordinates and depth readings in the LRF reference frame. The problem of estimating the rigid displacement between the two sensors is formulated as one of registering a set of planes and lines in the 3D space. It is proven for the first time that the alignment of three plane-line correspondences has at most eight solutions that can be determined by solving a standard p3p problem and a linear system of equations. This leads to a minimal closed-form solution for the extrinsic calibration that can be used as hypothesis generator in a RANSAC paradigm. Our calibration approach is validated through simulation and real experiments that show the superiority with respect to the current state of-the-art method requiring a minimum of five input planes. PMID- 22231590 TI - Assessment of the levels of DDT and DDE in soil and blood samples from Tabasco, Mexico. AB - In Mexico, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) was used until the year 2000, principally in agriculture and anti-paludal program health campaigns. The southeastern region of Mexico was an important area of malaria, and from 1957 DDT was applied indoors every 6 months, with a coverage of 2 g/m(2). The current study was performed in Tabasco, a Mexican state located in the southeastern region of Mexico. DDT and 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (DDE) were analyzed by gas chromatography/mass spectrometry. In general, low levels were found in household outdoor samples; the levels of DDT ranged from not detectable to 0.048 mg/kg, and of DDE from 0.001 to 0.068 mg/kg. An important finding was that, in all communities where DDT in blood was analyzed, exposure to DDT was found, indicating both past and present exposure. Although the levels found in this study were lower than other studies in Mexico, there is a need to evaluate whether the people living in the study area are at risk. PMID- 22231592 TI - Embedding retrieval of articulated geometry models. AB - Due to the popularity of computer games and animation, research on 3D articulated geometry model retrieval has attracted a lot of attention in recent years. However, most existing works extract high-dimensional features to represent models and suffer from practical limitations. First, misalignment in high dimensional features may produce unreliable euclidean distances and affect retrieval accuracy. Second, the curse of dimensionality also degrades efficiency. In this paper, we propose an embedding retrieval framework to improve the practicability of these methods. It is based on a manifold learning technique, the Diffusion Map (DM). We project all pairwise distances onto a low-dimensional space. This improves retrieval accuracy because intercluster distances are exaggerated. Then we adapt the Density-Weighted Nystrom extension and further propose a novel step to locally align the Nystrom embedding to the eigensolver embedding so as to reduce extension error and preserve retrieval accuracy. Finally, we propose a heuristic to handle disconnected manifolds by augmenting the kernel matrix with multiple similarity measures and shortcut edges, and further discuss the choice of DM parameters. We have incorporated two existing matching algorithms for testing. Our experimental results show improvement in precision at high recalls and in speed. Our work provides a robust retrieval framework for the matching of multimedia data that lie on manifolds. PMID- 22231594 TI - A blur-robust descriptor with applications to face recognition. AB - Understanding the effect of blur is an important problem in unconstrained visual analysis. We address this problem in the context of image-based recognition by a fusion of image-formation models and differential geometric tools. First, we discuss the space spanned by blurred versions of an image and then, under certain assumptions, provide a differential geometric analysis of that space. More specifically, we create a subspace resulting from convolution of an image with a complete set of orthonormal basis functions of a prespecified maximum size (that can represent an arbitrary blur kernel within that size), and show that the corresponding subspaces created from a clean image and its blurred versions are equal under the ideal case of zero noise and some assumptions on the properties of blur kernels. We then study the practical utility of this subspace representation for the problem of direct recognition of blurred faces by viewing the subspaces as points on the Grassmann manifold and present methods to perform recognition for cases where the blur is both homogenous and spatially varying. We empirically analyze the effect of noise, as well as the presence of other facial variations between the gallery and probe images, and provide comparisons with existing approaches on standard data sets. PMID- 22231595 TI - Charged nanoparticles as supramolecular surfactants for controlling the growth and stability of microcrystals. AB - Microcrystals of desired sizes are important in a range of processes and materials, including controlled drug release, production of pharmaceutics and food, bio- and photocatalysis, thin-film solar cells and antibacterial fabrics. The growth of microcrystals can be controlled by a variety of agents, such as multivalent ions, charged small molecules, mixed cationic-anionic surfactants, polyelectrolytes and other polymers, micropatterned self-assembled monolayers, proteins and also biological organisms during biomineralization. However, the chief limitation of current approaches is that the growth-modifying agents are typically specific to the crystalizing material. Here, we show that oppositely charged nanoparticles can function as universal surfactants that control the growth and stability of microcrystals of monovalent or multivalent inorganic salts, and of charged organic molecules. We also show that the solubility of the microcrystals can be further tuned by varying the thickness of the nanoparticle surfactant layers and by reinforcing these layers with dithiol crosslinks. PMID- 22231596 TI - A new class of doped nanobulk high-figure-of-merit thermoelectrics by scalable bottom-up assembly. AB - Obtaining thermoelectric materials with high figure of merit ZT is an exacting challenge because it requires the independent control of electrical conductivity, thermal conductivity and Seebeck coefficient, which are often unfavourably coupled. Recent works have devised strategies based on nanostructuring and alloying to address this challenge in thin films, and to obtain bulk p-type alloys with ZT>1. Here, we demonstrate a new class of both p- and n-type bulk nanomaterials with room-temperature ZT as high as 1.1 using a combination of sub atomic-per-cent doping and nanostructuring. Our nanomaterials were fabricated by bottom-up assembly of sulphur-doped pnictogen chalcogenide nanoplates sculpted by a scalable microwave-stimulated wet-chemical method. Bulk nanomaterials from single-component assemblies or nanoplate mixtures of different materials exhibit 25-250% higher ZT than their non-nanostructured bulk counterparts and state-of the-art alloys. Adapting our synthesis and assembly approach should enable nanobulk thermoelectrics with further increases in ZT for transforming thermoelectric refrigeration and power harvesting technologies. PMID- 22231597 TI - Destruction of the Kondo effect in the cubic heavy-fermion compound Ce3Pd20Si6. AB - How ground states of quantum matter transform between one another reveals deep insights into the mechanisms stabilizing them. Correspondingly, quantum phase transitions are explored in numerous materials classes, with heavy-fermion compounds being among the most prominent ones. Recent studies in an anisotropic heavy-fermion compound have shown that different types of transitions are induced by variations of chemical or external pressure, raising the question of the extent to which heavy-fermion quantum criticality is universal. To make progress, it is essential to broaden both the materials basis and the microscopic parameter variety. Here, we identify a cubic heavy-fermion material as exhibiting a field induced quantum phase transition, and show how the material can be used to explore one extreme of the dimensionality axis. The transition between two different ordered phases is accompanied by an abrupt change of Fermi surface, reminiscent of what happens across the field-induced antiferromagnetic to paramagnetic transition in the anisotropic YbRh2Si2. This finding leads to a materials-based global phase diagram--a precondition for a unified theoretical description. PMID- 22231598 TI - Thermal conductivity of isotopically modified graphene. AB - In addition to its exotic electronic properties graphene exhibits unusually high intrinsic thermal conductivity. The physics of phonons--the main heat carriers in graphene--has been shown to be substantially different in two-dimensional (2D) crystals, such as graphene, from in three-dimensional (3D) graphite. Here, we report our experimental study of the isotope effects on the thermal properties of graphene. Isotopically modified graphene containing various percentages of 13C were synthesized by chemical vapour deposition (CVD). The regions of different isotopic compositions were parts of the same graphene sheet to ensure uniformity in material parameters. The thermal conductivity, K, of isotopically pure 12C (0.01% 13C) graphene determined by the optothermal Raman technique, was higher than 4,000 W mK(-1) at the measured temperature T(m)~320 K, and more than a factor of two higher than the value of K in graphene sheets composed of a 50:50 mixture of 12C and 13C. The experimental data agree well with our molecular dynamics (MD) simulations, corrected for the long-wavelength phonon contributions by means of the Klemens model. The experimental results are expected to stimulate further studies aimed at a better understanding of thermal phenomena in 2D crystals. PMID- 22231599 TI - Metastable structures and isotope exchange reactions in polyoxometalate ions provide a molecular view of oxide dissolution. AB - Reactions involving minerals and glasses in water are slow and difficult to probe spectroscopically but are fundamental to the performance of oxide materials in green technologies such as automotive thermoelectric power generation, CO2 capture and storage and water-oxidation catalysis; these must be made from geochemically common elements and operate in hydrous environments. Polyoxometalate ions (POMs) have structures similar to condensed oxide phases and can be used as molecular models of the oxide/water interface. Oxygen atoms in POM exchange isotopes at different rates, but, at present, there is no basis for predicting how the coordination environment and metal substitution influences rates and mechanisms. Here we identify low-energy metastable configurations that form from the breaking of weak bonds between metals and underlying highly coordinated oxygen atoms, followed by facile hydroxide, hydronium or water addition. The mediation of oxygen exchange by these stuffed structures suggests a new view of the relationship between structure and reactivity at the oxide/solution interface. PMID- 22231601 TI - Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis. AB - Voriconazole (VRCZ) reportedly possesses a broad spectrum of antifungal activity against Aspergillus spp. and Candida spp., and the blood concentration of VRCZ is correlated with both the efficacy and the adverse effects of this drug. Monitoring of the blood concentration target level of VRCZ has not yet been widely adopted in the medical field, and no evidence concerning this target level has been reported. Accordingly, we used a meta-analysis to investigate the optimal blood concentration of VRCZ. Using data from 12 reports, we found that the success rate for fungal infection treatment increased significantly at VRCZ levels greater than 1.0 MUg/ml when a graded cutoff value within the range of 1.0 3.0 MUg/ml was used as the VRCZ trough blood concentration [odds ratio (OR) 7.23, 95% confidence interval (CI) 2.84-18.37, P < 0.0001]. Concerning the safety evaluation, the incidence of adverse neurological effects increased significantly at a cutoff value of 4.0 MUg/ml when a graded cutoff value within the range of 3.0-6.0 MUg/ml was used (OR 2.23, 95% CI 1.12-4.46, P = 0.02). However, in all 12 literature sources, an increasing incidence of liver dysfunction was reported at higher blood concentrations, and no accurate cutoff values were obtained. Consequently, a VRCZ trough blood concentration more than 1.0 MUg/ml from the perspective of efficacy and less than 4.0 MUg/ml from the perspective of safety is recommended. PMID- 22231602 TI - Unusual presentation of neurobrucellosis: a solitary intracranial mass lesion mimicking a cerebral tumor : a case of encephalitis caused by Brucella melitensis. AB - Among the diverse presentations of neurobrucellosis, solitary intracranial mass lesions are extremely rare. To the best of our knowledge, we describe here the second case of neurobrucellosis mimicking a cerebral tumor caused by Brucella melitensis. The mass lesion was clinically and radiologically indistinguishable from a brain tumor. The diagnosis was established by isolating Brucella melitensis in a blood culture and a positive Wright's agglutination test on the cerebrospinal fluid at 1:320 titers. Paraffin sections of the cerebral mass showed nongranulomatous encephalitis. We suggest that patients with an isolated intraparenchymal mass lesion with nongranulomatous encephalitis should also be studied for brucellosis in endemic areas. PMID- 22231603 TI - Risk factors for postoperative bleeding after thyroid surgery. AB - BACKGROUND: Postoperative bleeding after thyroid surgery is a feared and life threatening complication. The aim of the study was to identify risk factors for postoperative bleeding, with special emphasis on the impact of the individual surgeon and the time to diagnosis of the complication. METHODS: Data on consecutive thyroid operations were collected prospectively in a database over 30 years and analysed retrospectively for potential risk factors for postoperative bleeding. RESULTS: There were 30,142 operations and postoperative bleeding occurred in 519 patients (1.7 per cent). Risk factors identified were older age (odds ratio (OR) 1.03 per year), male sex (OR 1.64), extent of resection (OR up to 1.41), bilateral procedure (OR 1.99) and operation for recurrent disease (OR 1.54). The risk of complications among individual surgeons differed by up to sevenfold. Postoperative bleeding occurred in 336 (80.6 per cent) of 417 patients within the first 6 h after surgery. Postoperative bleeding was diagnosed after 24 h in ten patients (2.4 per cent), all of whom had bilateral procedures. Nine patients required urgent tracheostomy. Three patients died, giving a mortality rate of 0.01 per cent overall and 0.6 per cent among patients who had surgery for postoperative bleeding. CONCLUSION: Observation for up to 24 h is recommended for the majority of patients undergoing bilateral thyroid surgery in an endemic goitre area. Same-day discharge is feasible in selected patients, especially after a unilateral procedure. Quality improvement by continuous outcome monitoring and retraining of individual surgeons is suggested. PMID- 22231604 TI - Local-to-global form interference in biological motion perception. AB - Point-light walkers have been useful to study the contribution of form and motion to biological motion perception by manipulating the lifetime, number, or spatial distribution of the light points. Recent studies have also manipulated the light points themselves, replacing them with small images of objects. This manipulation degraded the recognizability of biological motion, particularly for local images of human bodies. This result suggests an interference of body form information in the local images with the body form analysis necessary for global biological motion recognition at the global level. We further explored this interference with respect to its selectivity for body orientation and motion. Participants had to either discriminate the facing direction (left/right) or the walking direction (forward/backward) of a global walker composed of local stick figures that could face left or right and either stand still or walk forward or backward. Local stick figures interfered stronger with the facing direction task if they were facing in the same direction as the global walker. Walking (forward/backward/static) of the stick figures influenced neither the facing direction task nor the walking direction task. We conclude that the interference is highly specific since it concerns not only the category (human form), but even the facing direction. PMID- 22231605 TI - Pupil-BLAH-metry: cognitive effort in speech planning reflected by pupil dilation. AB - In reading research, a longstanding question is whether any stages of lexical processing require central attention, and whether such potential demands are frequency-sensitive. In the present study, we examined the allocation of cognitive effort in lexical processing by examining pupil dilations and naming latencies in a modified delayed naming procedure. In this dual-task/change procedure, participants read words and waited for various delays before being signaled to issue a response. On most trials (80%), participants issued a standard naming response. On the remaining trials, they were cued to abandon the original speech plan, saying "blah" instead, thereby equating production across different words. Using feature-matched low- and high-frequency words, we observed the differences in pupil dilations as a function of word frequency. Indeed, frequency-sensitive cognitive demands were seen in word processing, even after naming responses were issued. The results suggest that word perception and/or speech planning requires the frequency-sensitive allocation of cognitive resources. PMID- 22231606 TI - Influence of category identity on letter matching: conceptual penetration of visual processing or response competition? AB - Participants performed same-different matching tasks, with physical-identity instructions, on letter pairs composed from the letters B, b, and p. The letters in a pair were presented simultaneously or sequentially, with the experiments differing in whether (1) the letters could appear in two or four positions, (2) two or five SOAs were used, (3) the font was Arial or one in which the two loops of the letter B were of the same size, and (4) p did or did not occur in same pairs. With sequential presentation, different RTs were longer when the letters had the same name (Bb; within-category pair) than when they did not (Bp; between category pair), replicating a finding by Lupyan et al. (2010). However, unlike in their study, this category effect was also significant with simultaneous presentation, tending to be nonsignificantly smaller for RTs but larger for accuracy than that obtained with sequential presentation. A similar pattern was observed when we removed a bias to respond different whenever the letter p was detected in the experiments in which p did not appear in same pairs. The presence of a category effect with simultaneous presentation is predicted by a response competition account, but not by Lupyan et al.'s conceptual-penetration-of-visual processing account. PMID- 22231607 TI - Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. AB - BACKGROUND: This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Women's Health Initiative (WHI). METHODS: The WHI recruited 161,808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification. RESULTS: This investigation included 153,840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10,242 incident cases of self-reported DM over 1,004,466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self reported DM with longitudinal measures of statin use in 125,575 women confirmed these findings. CONCLUSIONS: Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new onset DM in this population. PMID- 22231608 TI - Aspirin therapy in primary prevention: comment on "effect of aspirin on vascular and nonvascular outcomes". PMID- 22231609 TI - Importance of more judicious catheter use. PMID- 22231610 TI - Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. AB - BACKGROUND: The net benefit of aspirin in prevention of CVD and nonvascular events remains unclear. Our objective was to assess the impact (and safety) of aspirin on vascular and nonvascular outcomes in primary prevention. DATA SOURCES: MEDLINE, Cochrane Library of Clinical Trials (up to June 2011) and unpublished trial data from investigators. STUDY SELECTION: Nine randomized placebo controlled trials with at least 1000 participants each, reporting on cardiovascular disease (CVD), nonvascular outcomes, or death were included. DATA EXTRACTION: Three authors abstracted data. Study-specific odds ratios (ORs) were combined using random-effects meta-analysis. Risks vs benefits were evaluated by comparing CVD risk reductions with increases in bleeding. RESULTS: During a mean (SD) follow-up of 6.0 (2.1) years involving over 100, 000 participants, aspirin treatment reduced total CVD events by 10% (OR, 0.90; 95% CI, 0.85-0.96; number needed to treat, 120), driven primarily by reduction in nonfatal MI (OR, 0.80; 95% CI, 0.67-0.96; number needed to treat, 162). There was no significant reduction in CVD death (OR, 0.99; 95% CI, 0.85-1.15) or cancer mortality (OR, 0.93; 95% CI, 0.84-1.03), and there was increased risk of nontrivial bleeding events (OR, 1.31; 95% CI, 1.14-1.50; number needed to harm, 73). Significant heterogeneity was observed for coronary heart disease and bleeding outcomes, which could not be accounted for by major demographic or participant characteristics. CONCLUSIONS: Despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis. PMID- 22231611 TI - Reducing inappropriate urinary catheter use: a statewide effort. AB - BACKGROUND: Indwelling urinary catheters may lead to both infectious and noninfectious complications and are often used in the hospital setting without an appropriate indication. The objective of this study was to evaluate the results of a statewide quality improvement effort to reduce inappropriate urinary catheter use. METHODS: Retrospective analysis of data collected between 2007 and 2010 as part of a statewide collaborative initiative before, during, and after an educational intervention promoting adherence to appropriate urinary catheter indications. The data were collected from 163 inpatient units in 71 participating Michigan hospitals. The intervention consisted of educating clinicians about the appropriate indications for urinary catheter use and promoting the daily assessment of urinary catheter necessity during daily nursing rounds. The main outcome measures were change in prevalence of urinary catheter use and adherence to appropriate indications. We used flexible generalized estimating equation (GEE) and multilevel methods to estimate rates over time while accounting for the clustering of patients within hospital units. RESULTS: The urinary catheter use rate decreased from 18.1% (95% CI, 16.8%-19.6%) at baseline to 13.8% (95% CI, 12.9%-14.8%) at end of year 2 (P < .001). The proportion of catheterized patients with appropriate indications increased from 44.3% (95% CI, 40.3%-48.4%) to 57.6% (95% CI, 51.7%-63.4%) by the end of year 2 (P = .005). CONCLUSIONS: A statewide effort to reduce inappropriate urinary catheter use was associated with a significant reduction in catheter use and improved compliance with appropriate use. The effect of the intervention was sustained for at least 2 years. PMID- 22231612 TI - Improving use of the "other" catheter: comment on "reducing inappropriate urinary catheter use". PMID- 22231613 TI - Increased diabetes mellitus risk with statin use: comment on "statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative". PMID- 22231614 TI - Supplemental oxygen therapy in medical emergencies: more harm than benefit? PMID- 22231615 TI - Important data after drug approval: comment on "Dabigatran association with higher risk of acute coronary events". PMID- 22231616 TI - Dabigatran: do we have sufficient data?: comment on "Dabigatran association with higher risk of acute coronary events". PMID- 22231617 TI - Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. AB - BACKGROUND: The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial suggested a small increased risk of myocardial infarction (MI) with the use of dabigatran etexilate vs warfarin in patients with atrial fibrillation. We systematically evaluated the risk of MI or acute coronary syndrome (ACS) with the use of dabigatran. METHODS: We searched PubMed, Scopus, and the Web of Science for randomized controlled trials of dabigatran that reported on MI or ACS as secondary outcomes. The fixed-effects Mantel-Haenszel (M H) test was used to evaluate the effect of dabigatran on MI or ACS. We expressed the associations as odds ratios (ORs) and their 95% CIs. RESULTS: Seven trials were selected (N = 30,514), including 2 studies of stroke prophylaxis in atrial fibrillation, 1 in acute venous thromboembolism, 1 in ACS, and 3 of short-term prophylaxis of deep venous thrombosis. Control arms included warfarin, enoxaparin, or placebo administration. Dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group (dabigatran, 237 of 20,000 [1.19%] vs control, 83 of 10,514 [0.79%]; OR(M H), 1.33; 95% CI, 1.03-1.71; P = .03). The risk of MI or ACS was similar when using revised RE-LY trial results (OR(M-H), 1.27; 95% CI, 1.00-1.61; P = .05) or after exclusion of short-term trials (OR(M-H), 1.33; 95% CI, 1.03-1.72; P = .03). Risks were not heterogeneous for all analyses (I(2) = 0%; P >= .30) and were consistent using different methods and measures of association. CONCLUSIONS: Dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls. Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran. PMID- 22231618 TI - The landscape after LUNAR: rituximab's crater-filled path. PMID- 22231619 TI - Detecting brown adipose tissue activity with BOLD MRI in mice. AB - The recent discovery of active brown adipose tissue (BAT) in adult humans and the correlation found between the activity of this tissue and resting metabolic rate strongly suggest that this tissue may be implicated in the development of obesity in humans, as it is in rodents. Despite the possible physiological role of this tissue in the onset of human obesity, few noninvasive imaging techniques to detect BAT activity in humans exist. The scope of this work is to investigate the possibility of detecting BAT activity using blood-oxygen-level-dependent MRI. Our results show that the strong increase in oxygen consumption and consequent increase in blood deoxyhemoglobin levels following BAT activation lead to a well localized signal drop in BAT. This strongly suggests the possibility to use blood oxygen-level-dependent MRI for the noninvasive detection of BAT activity. PMID- 22231620 TI - The use of infliximab in the prevention of postsurgical recurrence in polysurgery Crohn's disease patients: a pilot open-labeled prospective study. AB - PURPOSE: Crohn's disease (CD) commonly recurs after surgery, and a number of patients need repeated surgery, especially smokers and those with repeated surgeries or penetrating disease. Whether infliximab prevents postsurgical recurrence in high-risk CD remains unknown. In the present pilot open-labeled study, we investigated the safety and efficacy of scheduled infliximab, which was started early after surgery, in maintaining remission of CD patients who have undergone multiple surgeries due to penetrating disease. METHODS: Eleven patients (nine male, two female; age range, 26-48 years) who had undergone repeated surgeries (median, 4; range, 2-5) for penetrating disease were enrolled. Two to 4 weeks after surgery, the patients were started on intravenous infliximab (5 mg/kg) at an 8-week interval. The primary end points were the proportion of patients in clinical remission at the end of the study, the rate of endoscopic/radiologic remission at 24 months, and the rate of adverse effects. RESULTS: One patient dropped out due to non-compliance, and ten patients were eligible for analysis. Clinical remission was maintained in six of ten patients (60.0%) at the end of the study. At 24 months, four out of ten patients were in endoscopic or radiological remission (40.0%). Two patients experienced adverse effects (18.2%), one of whom elected to withdraw from the study. CONCLUSION: The findings of no major safety concern and possible clinical benefit in our study suggest that further investigation of infliximab as a treatment for prevention of postsurgical recurrence in high-risk CD is warranted. PMID- 22231621 TI - Linoleic acid and colorectal cancer cell growth suppression: is the deregulation of mitochondrial survivin the key factor? PMID- 22231622 TI - The Kernel of Maximum Agreement Subtrees. AB - A Maximum Agreement SubTree (MAST) is a largest subtree common to a set of trees and serves as a summary of common substructure in the trees. A single MAST can be misleading, however, since there can be an exponential number of MASTs, and two MASTs for the same tree set do not even necessarily share any leaves. In this paper, we introduce the notion of the Kernel Agreement SubTree (KAST), which is the summary of the common substructure in all MASTs, and show that it can be calculated in polynomial time (for trees with bounded degree). Suppose the input trees represent competing hypotheses for a particular phylogeny. We explore the utility of the KAST as a method to discern the common structure of confidence, and as a measure of how confident we are in a given tree set. We also show the trend of the KAST, as compared to other consensus methods, on the set of all trees visited during a Bayesian analysis of flatworm genomes. PMID- 22231623 TI - A biologically inspired validity measure for comparison of clustering methods over metabolic data sets. AB - In the biological domain, clustering is based on the assumption that genes or metabolites involved in a common biological process are coexpressed/coaccumulated under the control of the same regulatory network. Thus, a detailed inspection of the grouped patterns to verify their memberships to well-known metabolic pathways could be very useful for the evaluation of clusters from a biological perspective. The aim of this work is to propose a novel approach for the comparison of clustering methods over metabolic data sets, including prior biological knowledge about the relation among elements that constitute the clusters. A way of measuring the biological significance of clustering solutions is proposed. This is addressed from the perspective of the usefulness of the clusters to identify those patterns that change in coordination and belong to common pathways of metabolic regulation. The measure summarizes in a compact way the objective analysis of clustering methods, which respects coherence and clusters distribution. It also evaluates the biological internal connections of such clusters considering common pathways. The proposed measure was tested in two biological databases using three clustering methods. PMID- 22231624 TI - Comparison of morphological and molecular genetic quantification of relative abundance of arbuscular mycorrhizal fungi within roots. AB - Nested PCR amplicons of ribosomal RNA genes have been used to identify individuals within assemblages of arbuscular mycorrhizal (AM) fungi in roots and to estimate their relative abundance. Microscopy has also been used to identify their relative abundance in roots, but only at low resolution, usually the genus level. We evaluated the robustness of using nested PCR amplicons of ribosomal RNA genes to estimate the relative abundance of undefined AM fungi in uniformly aged roots in comparison to visual estimates. The relative abundance of AM fungi was assessed as per cent root length colonised by morphotypes and relative sequence type abundance in clone libraries. Plants were grown in coastal soil to obtain assemblages of unknown AM fungi at two times (spring and autumn). Relative abundance of dominant genera of AM fungi in roots (Archaeospora and Glomus) based on an analysis of ribosomal RNA genes did not consistently correspond with relative abundance of morphotypes. This microscopic vs. molecular genetic comparison supports previous conclusions that there can be limitations in using nested PCR amplicons for quantifying the relative abundance of AM fungi in roots, with a sampling bias likely to be of significance. Both molecular genetic and morphological methods are used to estimate relative abundance of AM fungi as a precursor to understanding mycorrhizal function in field soils, but they are rarely verified using alternative approaches although this may be necessary. PMID- 22231625 TI - An international workshop: mycorrhiza, a biological tool for sustainable development in Africa. PMID- 22231626 TI - Clinical significance and prognostic value of PAX3 expression in human glioma. AB - The paired box 3 (PAX3), a crucial transcription factor, is normally expressed during embryonic development and is absent in normal adult human tissues. Deregulated expression of PAX3 has been observed in tumors like rhabdomyosarcoma and melanomas. To assess deregulated PAX3 expression in patients with gliomas, these samples from 57 glioma patients (13 grade I, 16 grade II, 14 grade III, and 14 grade IV tumors) and 10 normal brain specimens acquired from 10 patients undergoing surgery for epilepsy as control were obtained. PAX3 expression was measured by RT-PCR, Western blot, and immunohistochemistry. Survival analyses were performed using the Kaplan-Meier method. Association between PAX3 expression, clinicopathological characteristics, and patients' survival were analyzed by using SPSS 17.0. We found that the expression of PAX3 was upregulated in high-grade glioma tissues compared with that in low-grade and normal brain tissues, and increased with ascending tumor World Health Organization (WHO) grades (P = 0.001). The increased PAX3 expression in gliomas was significantly associated with higher WHO grade (P = 0.021) and poorer disease-specific survival of patients (P = 0.001). Our results suggested that PAX3 might be an intrinsic regulator of progression in glioma cells and it might serve as a prognostic factor for this dismal disease. PMID- 22231627 TI - Biochemical and biophysical characterization of purified thermophilic xylanase isoforms in Cereus pterogonus plant spp. AB - Two thermostable xylanase isoforms T60 and T80 were purified to homogeneity from the cladodes of the xerophytic Cereus pterogonus plant species. After three consecutive purification steps, the specific activity of T60 and T80 isoforms were found to be 178.6 and 216.2 U mg-1 respectively. The molecular mass of both isoforms was determined to be 80 kDa. The optimum temperature for T60 and T80 xylanase isoforms were 60 and 80 degrees C respectively. The pH was 5.0 for both isoforms. The presence of divalent metal ions (10 mM Co2+) showed stimulatory effects of both catalytic activities, where as in the presence of Hg2+, Cd2+, Cu2+ showed inhibitory effect on these activities at all concentrations studied. The thermodynamic analysis of xylanase activity using denaturation kinetics and the presence divalent cations at 30-100 degrees C, showed lower DeltaH, DeltaS, and DeltaG values at all the temperatures investigated. The melting temperature of purified T80 xylanase isoform as determined by TG/DTA analysis and it showed the unfolding temperature was 80 degrees C. The g value and hyperfine (A) value purified xylanase T80 isoform was 2.017 and 10.80 respectively. Immunoblot analysis with antiserum raised against the purified T80 xylanase isoforms revealed single immunolgically related polypeptides of 80 kDa, identical with the polypeptide band produced on SDS-PAGE. The results of double immunodiffusion against the T80 isoforms showed a single precipitin line indicating that the serum used was specific to these xylanase isoforms. The kinetic and thermodynamic properties suggested that xylanase from C. pterogonus may have a potential usage in various industries. PMID- 22231628 TI - Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30. PMID- 22231629 TI - Microglial migration mediated by ATP-induced ATP release from lysosomes. AB - Microglia are highly motile cells that act as the main form of active immune defense in the central nervous system. Attracted by factors released from damaged cells, microglia are recruited towards the damaged or infected site, where they are involved in degenerative and regenerative responses and phagocytotic clearance of cell debris. ATP release from damaged neural tissues has been suggested to mediate the rapid extension of microglial process towards the site of injury. However, the mechanisms of the long-range migration of microglia remain to be clarified. Here, we found that lysosomes in microglia contain abundant ATP and exhibit Ca(2+)-dependent exocytosis in response to various stimuli. By establishing an efficient in vitro chemotaxis assay, we demonstrated that endogenously-released ATP from microglia triggered by local microinjection of ATPgammaS is critical for the long-range chemotaxis of microglia, a response that was significantly inhibited in microglia treated with an agent inducing lysosome osmodialysis or in cells derived from mice deficient in Rab 27a (ashen mice), a small GTPase required for the trafficking and exocytosis of secretory lysosomes. These results suggest that microglia respond to extracellular ATP by releasing ATP themselves through lysosomal exocytosis, thereby providing a positive feedback mechanism to generate a long-range extracellular signal for attracting distant microglia to migrate towards and accumulate at the site of injury. PMID- 22231631 TI - How to counter the problem of R1 resection in duodenopancreatectomy for pancreatic cancer? AB - OBJECTIVE: Although duodenopancreatectomy has been standardized for many years, the pathological examination of the specimen was re-described in the last years. In methodical pathological studies up to 85% had an R1 margin.1,2 These mainly involved the posterior und medial resection margin.3 As a consequence we need to optimize and standardize the pathological workup of the specimen and to extend the surgical resection, where possible without risk for the patient. METHOD AND RESULT: In an instructive video we show the technique of duodenopancreatectomy with emphasis on the dorsal and medial resection margin. Furthermore we show the standardized pathological workup of the specimen, involving the reporting of all the resection margins. CONCLUSION: To accurately determine R1 status at the posterior and medial resection margin, a close collaboration between pathologist and surgeon is crucial. Pathologists do a standardized workup of the resected specimen with staining of the surfaces and systematic analysis of all the resection margins. Surgeons need to extend the resection of the pancreatic head to the superior mesenteric artery by dorsal dissection. PMID- 22231632 TI - High-resolution manometry patterns of lower esophageal sphincter complex in symptomatic post-fundoplication patients. AB - INTRODUCTION: There has been an increase in the number of patients seeking treatment after an anti-reflux surgical procedure. The objective of this study is to describe high-resolution manometry (HRM) topography as it relates to the post fundoplication anatomy. METHODS: Retrospective review of a prospectively maintained database was conducted to identify patients who underwent esophagogastroduodenoscopy and HRM at Creighton University Medical Center (CUMC) between November 2008 and October 2010, for symptoms after a previous fundoplication. Patients were categorized as having intact, intrathoracic, disruptured, twisted, or slipped fundoplication based on endoscopic findings. RESULTS: Sixty-one patients {intact, 17(28%), disrupted, 2(3%), twisted, 3(5%), intra-thoracic, 18(30%), slipped, 21(34%)} are included in this study. A double high-pressure zone (HPZ) configuration was identified in both intra-thoracic and slipped fundoplication. This was not noted in appropriately positioned fundoplications. In intra-thoracic fundoplications, the HPZ below the fundoplication was lower pressure and showed respiratory variations. In slipped fundoplication, the higher HPZ had lower pressure and no respiratory variations. In appropriately positioned fundoplication, the lower esophageal sphincter (LES) pressure and extent of relaxation in the single HPZ correlated with intact (normal pressure and good relaxation), disrupted (low pressure and good relaxation), and twisted (high pressure with incomplete relaxation) fundoplication. Patients with only a recurrent para-esophageal hernia had characteristics of an appropriately positioned fundoplication. CONCLUSION: LES complex HRM findings correlate well with anatomical status of the fundoplication. PMID- 22231630 TI - Neural crest stem cells: discovery, properties and potential for therapy. AB - Neural crest (NC) cells are a migratory cell population synonymous with vertebrate evolution. They generate a wide variety of cell and tissue types during embryonic and adult development including cartilage and bone, connective tissue, pigment and endocrine cells as well as neurons and glia amongst many others. Such incredible lineage potential combined with a limited capacity for self-renewal, which persists even into adult life, demonstrates that NC cells bear the key hallmarks of stem and progenitor cells. In this review, we describe the identification, characterization and isolation of NC stem and progenitor cells from different tissues in both embryo and adult organisms. We discuss their specific properties and their potential application in cell-based tissue and disease-specific repair. PMID- 22231633 TI - Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors. AB - BACKGROUND: The purpose of the present study was to investigate outcome after whole brain radiotherapy (WBRT) alone as a palliative treatment without concomitant chemotherapy for intracranial leptomeningeal carcinomatosis (LMC). PATIENTS AND METHODS: Overall survival and treatment response were retrospectively analyzed in 27 consecutive patients with LMC from breast and lung cancer. All patients had evidence of intracranial manifestations of LMC. Seven potential prognostic factors were evaluated. RESULTS: Median overall survival (OS) for the entire group was 8.1 weeks. OS rates after 6 and 12 months were 26% and 15%, respectively. Improvement of neurological deficits was observed in 3 patients. In 3 of 4 patients with follow-up MRI studies, a decreased size of contrast-enhanced lesions was observed. Prognostic factors for improved OS on univariate analysis were absence of cranial nerve dysfunction, Karnofsky Performance Score (KPS) > 60%, and time interval > 35 months between the initial diagnosis of malignant disease and development of LMC. On multivariate analysis, absence of cranial nerve dysfunction remained the only significant prognosticator for OS (median 3.7 vs. 19.4 weeks, p < 0.001). CONCLUSION: WBRT alone is an effective palliative treatment for patients unfit/unsuitable for chemotherapy and low performance status suffering from intracranial LMC. However, prognostic factors should be considered in order to identify patients who are likely to benefit from WBRT. PMID- 22231635 TI - [Lymph nodes, tumour deposits, and TNM: are we getting better? 7th edition of UICC 2010 TNM classification of malignant tumors]. PMID- 22231634 TI - Radiotherapy with and without temozolomide in elderly patients with glioblastoma. AB - BACKGROUND AND PURPOSE: The optimal treatment for elderly patients (age >= 70 years) with glioblastoma (GBM) remains controversial. We conducted a retrospective analysis in 43 consecutive elderly patients with glioblastoma who either underwent radiotherapy (RT) or radiotherapy plus concomitant temozolomide (TMZ). PATIENTS AND METHODS: A total of 43 patients (>= 70 years of age, median age 75.8 years) with newly diagnosed glioblastoma and a Karnofsky performance status (KPS) >= 70 were treated with RT alone (median 60 Gy in 2 Gy single fractions) or RT plus TMZ at a dose of 75 mg/m(2) per day. The two groups were well-balanced; univariate (log-rank test) and multivariate Cox proportional hazards analysis were used to identify relevant prognostic factors. RESULTS: The median overall survival (mOS) of the entire patient cohort was 264 days (8.8 months) and the median progression-free survival (PFS) was 192 days (6.4 months). The factors age, sex, previous surgery, KPS, and concomitant use of TMZ had no significant influence on OS/PFS; multivariate analysis was performed to obtain adjusted hazard ratios. TMZ use resulted in a trend toward poorer overall survival when applied concomitantly (314 days compared to 192 days within the TMZ group, p = 0.106). The subgroup analysis revealed that TMZ use resulted in significantly worse survival rates in patients with KPS70 (p = 0.027), but for patients with KPS80 this difference was not detectable. CONCLUSION: TMZ should only be used carefully in elderly patients with unfavorable KPS. In this patient cohort, radiotherapy alone is a reasonable option. Standard RT plus concomitant TMZ may be an advantageous treatment option for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors. PMID- 22231636 TI - Quantifying agonist activity at G protein-coupled receptors. AB - When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors. Receptors behave as quantal switches that alternate between active and inactive states (Figure 1). The active state interacts with specific G proteins or other signaling partners. In the absence of ligands, the inactive state predominates. The binding of agonist increases the probability that the receptor will switch into the active state because its affinity constant for the active state (K(b)) is much greater than that for the inactive state (K(a)). The summation of the random outputs of all of the receptors in the population yields a constant level of receptor activation in time. The reciprocal of the concentration of agonist eliciting half-maximal receptor activation is equivalent to the observed affinity constant (K(obs)), and the fraction of agonist-receptor complexes in the active state is defined as efficacy (epsilon) (Figure 2). Methods for analyzing the downstream responses of GPCRs have been developed that enable the estimation of the K(obs) and relative efficacy of an agonist. In this report, we show how to modify this analysis to estimate the agonist K(b) value relative to that of another agonist. For assays that exhibit constitutive activity, we show how to estimate K(b) in absolute units of M(-1). Our method of analyzing agonist concentration-response curves consists of global nonlinear regression using the operational model. We describe a procedure using the software application, Prism (GraphPad Software, Inc., San Diego, CA). The analysis yields an estimate of the product of K(obs) and a parameter proportional to efficacy (tau). The estimate of tauK(obs) of one agonist, divided by that of another, is a relative measure of K(b) (RA(i)). For any receptor exhibiting constitutive activity, it is possible to estimate a parameter proportional to the efficacy of the free receptor complex (tau(sys)). In this case, the K(b) value of an agonist is equivalent to tauK(obs)/tau(sys). Our method is useful for determining the selectivity of an agonist for receptor subtypes and for quantifying agonist-receptor signaling through different G proteins. PMID- 22231637 TI - Anti-epidermal growth factor receptor therapy for advanced head and neck squamous cell carcinoma: a meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of anti-epidermal growth factor receptor (EGFR) therapy versus non-anti-EGFR therapy for advanced head and neck squamous cell carcinoma (HNSCC). METHODS: The Cochrane Central Register of Controlled Trials, Medline, and Embase databases were searched for relevant reports. Quantitative analysis was carried out to evaluate the overall response rate (ORR), overall survival (OS), progression free survival (PFS), and grade 3-4 adverse effects. RESULTS: Ten reports involving 2,396 patients were included. Primary meta-analysis indicated that anti-EGFR therapy could improve ORR [relative risk (RR) 1.36, 95% confidence interval (CI) 1.12-1.67] and PFS [hazard ratio (HR) 0.63, 95% CI 0.55-0.71), but failed to improve OS (HR 0.88, 95% CI 0.74-1.03). In subgroup analyses, we found that monoclonal antibodies (Mabs) could improve ORR, OS, and PFS for both locoregionally advanced (LA) (ORR: 1.21, 1.08-1.37; OS: 0.72, 0.59-0.89; PFS: 0.66, 0.53-0.83) and recurrent/metastatic (RM) HNSCC (ORR: 1.88, 1.40-2.54; OS: 0.79, 0.67-0.94; PFS: 0.61, 0.52-0.71), while tyrosine kinase inhibitors (TKIs) did not improve any of these in patients with either LA (ORR: 1.09, 0.91-1.32; OS: 0.7, 0.31-1.63; PFS: 0.71, 0.34-1.52) or RM (ORR: 1.65, 0.84-3.24; OS: 1.13, 0.97-1.31; PFS: not available) HNSCC. Analysis of adverse effects demonstrated that rash (RR 14.34, 95% CI 5.02-41.02), diarrhea (2.36, 1.15-4.87), and anorexia (2.49, 1.11-5.56) were significantly associated with anti-EGFR therapy. CONCLUSIONS: Anti-EGFR Mabs are effective for both LA and RM HNSCC. In contrast, TKIs were unsuitable for treatment of advanced HNSCC. During anti-EGFR therapy, rash and some gastrointestinal reactions, such as diarrhea and anorexia, should be carefully monitored. PMID- 22231639 TI - Ethylene polymerization on a SiH4-modified Phillips catalyst: detection of in situ produced alpha-olefins by operando FT-IR spectroscopy. AB - Ethylene polymerization on a model Cr(II)/SiO(2) Phillips catalyst modified with gas phase SiH(4) leads to a waxy product containing a bimodal MW distribution of alpha-olefins (M(w) < 3000 g mol(-1)) and a highly branched polyethylene, LLDPE (M(w) ~ 10(5) g mol(-1), T(m) = 123 degrees C), contrary to the unmodified catalyst which gives a linear and more dense PE, HDPE (M(w) = 86,000 g mol(-1) (PDI = 7), T(m) = 134 degrees C). Pressure and temperature resolved FT-IR spectroscopy under operando conditions (T = 130-230 K) allows us to detect alpha olefins, and in particular 1-hexene and 1-butene (characteristic IR absorption bands at 3581-3574, 1638 and 1598 cm(-1)) as intermediate species before their incorporation in the polymer chains. The polymerization rate is estimated, using time resolved FT-IR spectroscopy, to be 7 times higher on the SiH(4)-modified Phillips catalyst with respect to the unmodified one. PMID- 22231638 TI - Proteomic profiling following immunoaffinity capture of high-density lipoprotein: association of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis. AB - OBJECTIVE: To identify protein biomarkers associated with proinflammatory high density lipoprotein (HDL) in patients with active rheumatoid arthritis (RA) by proteomic analysis. METHODS: Liquid chromatography tandem mass spectrometry (LC MS/MS) was used to analyze proteins associated with immunoaffinity-purified HDL from plasma obtained from 2 sets of RA patients, 1 with antiinflammatory HDL and 1 with proinflammatory HDL. Proteins were fractionated by Offgel electrophoresis and analyzed using an LC-MS/MS system equipped with a high-capacity high performance liquid chromatography chip incorporating C18 reverse-phase trapping and analytical columns. Sandwich enzyme-linked immunosorbent assays were used to validate the association between select proteins and proinflammatory HDL in a second cohort of RA patients. RESULTS: Seventy-eight proteins were identified in the HDL complexes. The levels of 12 proteins were significantly increased in RA patients with proinflammatory HDL compared to RA patients with antiinflammatory HDL. These proteins included the acute-phase proteins apolipoprotein J, fibrinogen, haptoglobin, serum amyloid A, and complement factors (B, C3, and C9). The associations between proinflammatory HDL and 4 of the proteins were validated in a second RA cohort. CONCLUSION: Our findings indicate that proinflammatory HDL in patients with RA contains a significantly altered proteome, including increased amounts of acute-phase proteins and proteins involved in the complement cascade. These findings suggest that HDL is significantly altered in the setting of chronic inflammation in active RA, with resultant loss of its antiinflammatory function. The characterization of the biomarkers described herein may identify novel molecular connections that contribute to the higher risk of cardiovascular disease in RA patients. PMID- 22231640 TI - Blotting protein complexes from native gels to electron microscopy grids. AB - We report a simple and generic method for the direct transfer of protein complexes separated by native gel electrophoresis to electron microscopy grids. After transfer, sufficient material remains in the gel for identification and characterization by mass spectrometry. The method should facilitate higher throughput single-particle analysis by substantially reducing the time needed for protein purification, as demonstrated for three complexes from Thermoplasma acidophilum. PMID- 22231641 TI - Fast two-photon in vivo imaging with three-dimensional random-access scanning in large tissue volumes. AB - The understanding of brain computations requires methods that read out neural activity on different spatial and temporal scales. Following signal propagation and integration across a neuron and recording the concerted activity of hundreds of neurons pose distinct challenges, and the design of imaging systems has been mostly focused on tackling one of the two operations. We developed a high resolution, acousto-optic two-photon microscope with continuous three-dimensional (3D) trajectory and random-access scanning modes that reaches near-cubic millimeter scan range and can be adapted to imaging different spatial scales. We performed 3D calcium imaging of action potential backpropagation and dendritic spike forward propagation at sub-millisecond temporal resolution in mouse brain slices. We also performed volumetric random-access scanning calcium imaging of spontaneous and visual stimulation-evoked activity in hundreds of neurons of the mouse visual cortex in vivo. These experiments demonstrate the subcellular and network-scale imaging capabilities of our system. PMID- 22231642 TI - Dual-objective STORM reveals three-dimensional filament organization in the actin cytoskeleton. AB - By combining astigmatism imaging with a dual-objective scheme, we improved the image resolution of stochastic optical reconstruction microscopy (STORM) and obtained <10-nm lateral resolution and <20-nm axial resolution when imaging biological specimens. Using this approach, we resolved individual actin filaments in cells and revealed three-dimensional ultrastructure of the actin cytoskeleton. We observed two vertically separated layers of actin networks with distinct structural organizations in sheet-like cell protrusions. PMID- 22231643 TI - Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. AB - AIM: Several clinical trials have demonstrated the antianginal and anti-ischemic efficacy of ivabradine in combination with beta-blocker in patients with stable angina pectoris. The ADDITIONS (PrActical Daily efficacy anD safety of Procoralan((r)) In combinaTION with betablockerS) study evaluated the efficacy, safety, and tolerability of ivabradine added to beta-blocker, and its effect on angina symptoms and quality of life in routine clinical practice. METHODS: This non-interventional, multicenter, prospective study included 2,330 patients with stable angina pectoris treated with a flexible dose of ivabradine twice daily in addition to beta-blocker for 4 months. The parameters recorded included heart rate, number of angina attacks, nitrate consumption, tolerance, and quality of life. RESULTS: After 4 months ivabradine (mean dose 12.37 +/- 2.95 mg/day) reduced heart rate by 19.4 +/- 11.4 to 65.6 +/- 8.2 bpm (p < 0.0001). The number of angina attacks was reduced by 1.4 +/- 1.9 per week (p < 0.0001), and nitrate consumption by 1.9 +/- 2.9 U per week (p < 0.0001). At baseline (i.e., on beta blocker), half of the patients (51%) were classified as Canadian Cardiovascular Society (CCS) grade II; 29% were CCS grade I. After 4 months' treatment with ivabradine, most of the patients were CCS grade I (68%). The EQ-5D index improved by 0.17 +/- 0.23 (p < 0.0001). The overall efficacy of ivabradine was considered by the physicians as "very good" (61%) or "good" (36%) in most patients. Suspected adverse drug reactions were documented in 14 patients; none were severe. CONCLUSION: In daily clinical practice, combining ivabradine with beta blocker not only reduces heart rate, number of angina attacks, and nitrate consumption, but also improves the quality of life in patients with stable angina pectoris. PMID- 22231644 TI - Dual- versus single-coil implantable defibrillator leads: review of the literature. AB - The preferred use of dual-coil implantable defibrillator lead systems in current implantable defibrillator therapy is likely based on data showing statistically lower defibrillation thresholds with dual-coil defibrillator lead systems. The following review will summarize the clinical data for dual- versus single-coil defibrillator leads in the left and right pectoral implant locations, and will then discuss the clinical implications of single- versus dual-coil usage for atrial defibrillation, venous complications, and the risks associated with lead extraction. It will be noted that there are no comparative clinical studies on the use and outcomes of single- versus dual-coil lead systems in implantable defibrillator therapy over a long-term follow-up. The limited long-term reliability of defibrillator leads is a major concern in implantable defibrillator and cardiac resynchronization therapy. A simpler single-coil defibrillator lead system may improve the long-term performance of implanted leads. Furthermore, the superior vena cava coil is suspected to increase interventional risk in transvenous lead extraction. Therefore, the need for objective data on extractions and complications will be emphasized. PMID- 22231645 TI - HMGB1 is an independent predictor of death and heart transplantation in heart failure. AB - BACKGROUND: High-Mobility-Group Box 1 (HMGB1) has been established as an important mediator of myocardial inflammation and associated with progression of heart failure (HF). The aim of this study was to analyze the prognostic value of systemic HMGB1 levels in HF patients with ischemic and non-ischemic cardiomyopathy. METHODS AND RESULTS: We conducted an analysis (median follow-up time 2.5 years) of HMGB1 plasma concentration in 154 patients with systolic HF and correlated the results with disease severity and prognosis. HMGB1 in HF patients with severe symptoms (NYHA III/IV; 5.35 ng/ml; interquartile range (IQR) = 3.48-8.42 ng/ml) was significantly elevated compared with that in patients with mild symptoms (NYHA I/II; 3.37 ng/ml, IQR = 2.31-5.22 ng/ml, p < 0.0001) and with controls (3.25 ng/ml, IQR = 3.04-3.67 ng/ml, p < 0.0001). HMGB1 levels correlated with other markers of heart failure indicating an association of HMGB1 with disease severity in HF. In a univariate cox regression model for the combined endpoint of death and heart transplantation, HMGB1 proved to be a predictor at cut-off values based on HMGB1 terciles of either 3.4 or 6.1 ng/ml (p = 0.001 and p < 0.0001, respectively). In a multivariate cox regression model, which included NT-proBNP, creatinine, age, NYHA class, white blood cell count, anemia, and age, HMGB1 remained an independent predictor of the combined endpoint (hazard ratio (HR) = 2.48, 95% confidence interval (CI) = 1.06-5.83, p = 0.037 and HR = 2.48, 95% CI = 1.31-4.71, p = 0.005, respectively). CONCLUSION: Our findings demonstrate that HMGB1 plasma concentration is elevated in HF and correlates with disease severity and that is an independent predictor of the combined endpoint death and heart transplantation in HF patients. PMID- 22231646 TI - Cochlear kainate receptors. AB - Synaptic transmission between the cochlear hair cell and its afferent fiber is mediated by glutamate receptors. While kainate receptors are known to be present in the spiral ganglion, little is known of their distribution or functional role. We have detected all five kainate receptor subunits in the mouse cochlea with quantitative RT-PCR and with immunohistochemistry. We observed kainate receptors on afferent terminals co-localized with alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA: ) receptors at the afferent synapse. Individual terminals innervating a single hair cell varied in their ratios of AMPA: to kainate receptor immunoreactivity. Infusion of the mouse cochlea via the scala tympani with UBP296, a recently developed antagonist with high specificity for the GluK1 kainate receptor (compared to the AMPA: receptor), reduced the compound action potential and elevated auditory neural thresholds without affecting the distortion product otoacoustic emission thresholds. Thus, the pharmacological evidence suggests that kainate receptors may contribute to the response to transmitter released from the hair cell during acoustic stimulation. It is plausible that afferent transmission at this synapse is mediated by a mix of AMPA: and kainate receptors. PMID- 22231647 TI - A specific absorption rate prediction concept for parallel transmission MR. AB - The specific absorption rate (SAR) is a limiting factor in high-field MR. SAR estimation is typically performed by numerical simulations using generic human body models. However, SAR concepts for single-channel radiofrequency transmission cannot be directly applied to multichannel systems. In this study, a novel and comprehensive SAR prediction concept for parallel radiofrequency transmission MRI is presented, based on precalculated magnetic and electric fields obtained from electromagnetic simulations of numerical body models. The application of so called Q-matrices and further computational optimizations allow for a real-time estimation of the SAR prior to scanning. This SAR estimation method was fully integrated into an eight-channel whole body MRI system, and it facilitated the selection of different body models and body positions. Experimental validation of the global SAR in phantoms demonstrated a good qualitative and quantitative agreement with the predictions. An initial in vivo validation showed good qualitative agreement between simulated and measured amplitude of (excitation) radiofrequency field. The feasibility and practicability of this SAR prediction concept was shown paving the way for safe parallel radiofrequency transmission in high-field MR. PMID- 22231648 TI - Intensity modulated radiation therapy with field rotation--a time-varying fractionation study. AB - This paper proposes a novel mathematical approach to the beam selection problem in intensity modulated radiation therapy (IMRT) planning. The approach allows more beams to be used over the course of therapy while limiting the number of beams required in any one session. In the proposed field rotation method, several sets of beams are interchanged throughout the treatment to allow a wider selection of beam angles than would be possible with fixed beam orientations. The choice of beamlet intensities and the number of identical fractions for each set are determined by a mixed integer linear program that controls jointly for the distribution per fraction and the cumulative dose distribution delivered to targets and critical structures. Trials showed the method allowed substantial increases in the dose objective and/or sparing of normal tissues while maintaining cumulative and fraction size limits. Trials for a head and neck site showed gains of 25%-35% in the objective (average tumor dose) and for a thoracic site gains were 7%-13%, depending on how strict the fraction size limits were set. The objective did not rise for a prostate site significantly, but the tolerance limits on normal tissues could be strengthened with the use of multiple beam sets. PMID- 22231649 TI - Scoring system to predict the risk of surgical-site infection after colorectal resection. AB - BACKGROUND: There is no dedicated scoring system for predicting the risk of surgical-site infection (SSI) after resection of the colon or rectum. Generic scores, such as the National Nosocomial Infections Surveillance index, are not used by colorectal surgeons. METHODS: Multivariable analysis of risk factors for SSI was performed in patients who underwent resection of the colon or rectum, and were followed during the first month after operation. A logistic regression model was used to identify determinant variables and construct a predictive score. RESULTS: There were 534 patients of whom 114 (21.3 per cent) developed SSI. In multivariable analysis, four parameters correlated with an increased risk of SSI: obesity (odds ratio (OR) 2.93, 95 per cent confidence interval 1.71 to 5.03), contamination class 3-4 (OR 3.33, 2.08 to 5.32), American Society of Anesthesiologists grade III-IV (OR 1.82, 1.14 to 2.90) and open surgery (OR 2.22, 1.01 to 4.88). Each of these contributed 1 point to the risk score. The observed risk of SSI was 5 per cent for a score of 0, 12.0 per cent for a score of 1 point, 18.7 per cent for 2 points, 44 per cent for 3 points and 68 per cent for 4 points. The area under the receiver operating characteristic curve for the score was 0.729. CONCLUSION: A simple clinical score based on four preoperative variables was clinically useful in predicting the risk of SSI in patients undergoing colorectal surgery. PMID- 22231651 TI - The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance. AB - Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis. PMID- 22231652 TI - Phenotype and functions of conventional dendritic cells are not compromised in aged mice. AB - Aging has profound effects on the immune system, including thymic involution, reduced diversity of the T cell receptor repertoire, reduced effector T cell and B cell function and chronic increase of proinflammatory cytokine production by innate immune cells. The precise effects of aging on conventional dendritic cells (cDC), the main antigen presenting cells of the immune system, however, are not well understood. We found that in aged mice the number of cDC in the spleen and lymph nodes remained stable, whereas the number of cDC in the lungs increased with age. Whereas cDC in mice showed similar cycling kinetics in all organs tested, cDC reconstitution by aged bone marrow precursors was relatively higher than that of their young counterparts. With the exception of CD86, young and aged cDC did not differ in their expression of co-stimulatory molecules at steady state. Most toll-like receptor (TLR) ligands induced comparable upregulation of co-stimulatory molecules CD40, CD86 and B7H1 on young and aged cDC, whereas TLR2 and TLR5 stimulation resulted in reduced upregulation of CD80 and CD86 on aged cDC in vitro. In vivo, influenza infection-induced upregulation of CD86, but not other co-stimulatory molecules, was lower in aged DC. Young and aged DC were equally capable of direct and cross presentation of antigens in vitro. Transcriptome analysis did not reveal any significant difference between young and aged cDC. These data show that unlike T and B cells, the maintenance of cDC throughout the life of a healthy animal is relatively robust during the aging process. PMID- 22231653 TI - BAFF and innate immunity: new therapeutic targets for systemic lupus erythematosus. AB - Recently, the B cell has emerged as a cornerstone of systemic lupus erythematosus (SLE) pathogenesis. This has been highlighted by studies of the cytokine B-cell activating factor of the tumour necrosis factor (TNF) family (BAFF), a crucial factor regulating B-cell maturation, survival and function. Overexpression of BAFF in mice leads to the development of an SLE-like disease, independent of T cells but instead relying on innate immunity mechanisms. Moreover, BAFF has been shown to be elevated in the serum of patients suffering from autoimmune conditions, especially SLE, and may correlate with disease activity. These findings challenge the previous notion that T:B-cell collaboration is the sole driver of SLE. In recent years, controlled trials have for the first time tested targeted therapeutics for SLE. However, agents designed to target B cells failed to meet primary endpoints in clinical trials in SLE, suggesting that a more complex role for B cells in SLE awaited elucidation. By contrast, on 9 March 2011, the US Food and Drug Administration approved belimumab, a fully human anti BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. This article will review over 10 years of research on the BAFF system, key findings that led to this recent positive clinical outcome and propose a model potentially explaining why this B-cell-specific therapy has yielded positive results in clinical trials. We will also review promising therapies presently in clinical trials targeting innate immunity, which are likely to revolutionize SLE management towards a personalized and targeted therapy approach. PMID- 22231654 TI - Cellulolytic enzyme production and enzymatic hydrolysis for second-generation bioethanol production. AB - Second-generation bioethanol made from lignocellulosic biomass is considered one of the most promising biofuels. However, the enzymatic hydrolysis of the cellulose component to liberate glucose for ethanol fermentation is one of the major barriers for the process to be economically competitive because of the recalcitrance of feedstock. In this chapter, the progress on the understanding of the mechanisms of lignocellulose degradation, as well as the identification and optimization of fungal cellulases, cellulolytic strains, and cellulase production is reviewed. The physiologic functions and enzymatic mechanisms of two groups of enzymes involved in lignocellulose degradation, cellulases and hemicellulases, are discussed, and the synergism of the cellulase components during lignocellulose degradation is addressed. Furthermore, the methods for screening filamentous fungal strains capable of degrading lignocellulose are evaluated and the production of cellulases by these fungal strains is discussed. Aside from traditional mutagenesis for improving the secretion level and enzymatic activities of cellulases from filamentous fungal species, genetic engineering of strains and protein engineering on cellulase molecules are also highlighted. PMID- 22231655 TI - Single cell transcriptional profiling of adult mouse cardiomyocytes. AB - While numerous studies have examined gene expression changes from homogenates of heart tissue, this prevents studying the inherent stochastic variation between cells within a tissue. Isolation of pure cardiomyocyte populations through a collagenase perfusion of mouse hearts facilitates the generation of single cell microarrays for whole transcriptome gene expression, or qPCR of specific targets using nanofluidic arrays. We describe here a procedure to examine single cell gene expression profiles of cardiomyocytes isolated from the heart. This paradigm allows for the evaluation of metrics of interest which are not reliant on the mean (for example variance between cells within a tissue) which is not possible when using conventional whole tissue workflows for the evaluation of gene expression (Figure 1). We have achieved robust amplification of the single cell transcriptome yielding micrograms of double stranded cDNA that facilitates the use of microarrays on individual cells. In the procedure we describe the use of NimbleGen arrays which were selected for their ease of use and ability to customize their design. Alternatively, a reverse transcriptase - specific target amplification (RT-STA) reaction, allows for qPCR of hundreds of targets by nanofluidic PCR. Using either of these approaches, it is possible to examine the variability of expression between cells, as well as examining expression profiles of rare cell types from within a tissue. Overall, the single cell gene expression approach allows for the generation of data that can potentially identify idiosyncratic expression profiles that are typically averaged out when examining expression of millions of cells from typical homogenates generated from whole tissues. PMID- 22231656 TI - Wire grill brush bristle as an unusual foreign body: report of two pediatric cases. AB - Wire grill brushes are commonly used for cleaning grill grates. Accidental ingestion of a wire bristle from a grill-cleaning brush is a rarely reported foreign body, with only three prior case reports. Although scarce in the literature, we encountered two pediatric cases at the regional children's hospital within 1 year. By presenting these two cases, our goal was to raise awareness of this potentially hazardous foreign body. Additionally, we raise a consumer safety issue associated with the use of wire grill-cleaning brushes as there are currently no ingestion hazard warnings on these products. Laryngoscope,, 2011. PMID- 22231658 TI - Making transparency matter. PMID- 22231659 TI - Risk factors for suicidal ideation in Korean middle-aged adults: the role of socio-demographic status. AB - BACKGROUND: The investigations of the risk factors for suicidal ideation among middle-aged adults may be especially important for predicting suicidal actions, given the steep increase in suicide among Koreans aged 45-54. Few studies have sought to investigate the effect of socio-demographic status on suicidal ideation among middle-aged adults. OBJECTIVE: This study investigated the influence of socio-demographic status on suicidal ideation among middle-aged adults in South Korea. METHODS: The sample consisted of middle-aged men (n = 3,214) and middle aged women (n = 4,087) aged 40-64 years who had participated in the 2005 cross sectional Seoul Citizens Health and Social Indicators Survey. Using multiple logistic regression analysis, we examined the effect of socio-demographic status, health behaviours and health status on suicidal ideation in middle-aged adults. RESULTS: The outstanding finding was that suicidal ideation was most prevalent among middle-aged women who engaged in manual labour (i.e. blue-collar workers) (OR = 2.77, 95% CI = 1.20-6.42). The absence of a spouse was significantly associated with suicidal ideation among middle-aged men (OR = 2.10, 95% CI = 1.30 3.40). CONCLUSIONS: The effect of enhanced security related to stable employment was strongest among middle-aged women in blue-collar jobs, and the effect of intensive counselling services was strongest among divorced or widowed middle aged men. PMID- 22231657 TI - How much time do low-income patients and primary care physicians actually spend discussing pain? A direct observation study. AB - BACKGROUND: We know little about how much time low-income patients and physicians spend discussing pain during primary care visits. OBJECTIVE: To measure the frequency and duration of pain-related discussions at a primary care clinic serving mostly low-income black patients; to investigate variables associated with these discussions. DESIGN: We measured the frequency and duration of pain related discussions using video-recorded primary care visits; we used multiple regression to evaluate associations between discussions and patient self-report variables. PARTICIPANTS: A total of 133 patients presenting to a primary care clinic for any reason; 17 family medicine residents. MAIN MEASURES: Independent variables were pain severity, health status, physical function, chief complaint, and whether the patient and physician had met previously. Dependent variables were presence of pain-related discussions and percent of total visit time spent discussing pain. KEY RESULTS: Sixty-nine percent of visits included pain-related discussions with a mean duration of 5.9 min (34% of total visit time). Increasing pain severity [OR 1.69, 95% CI (1.18, 2.41)] and pain-related chief complaints [OR 4.10, 95% CI (1.39, 12.12)] were positively associated with the probability of discussing pain. When patients discussed pain, they spent 4.5% more [95% CI (0.60, 8.37)] total visit time discussing pain for every one-point increase in pain severity. Better physical function was negatively associated with the probability of discussing pain [OR 0.65, 95% CI (0.48, 0.86)], but positively associated with the percent of total visit time spent discussing pain [3% increase; 95% CI (0.32, 5.75)] for every one-point increase in physical function). Patients and physicians who had met previously spent 11% less [95% CI (-21.65, -0.55)] total visit time discussing pain. Pain severity was positively associated with time spent discussing pain only when patients and physicians had not met previously. CONCLUSIONS: Pain-related discussions comprise a substantial proportion of time during primary care visits. Future research should evaluate the relationship between time spent discussing pain and the quality of primary care pain management. PMID- 22231660 TI - Increased numbers of CD5+ B lymphocytes with a regulatory phenotype in spondylarthritis. AB - OBJECTIVE: Whether and how B lymphocytes contribute to the pathogenesis of spondylarthritis (SpA), a seronegative arthritis associated with gut inflammation, remains unknown. Because innate-like CD5+ B lymphocytes with regulatory functions have been identified in colitis models, we undertook the present study to analyze the presence and function of CD5+ B cells in human SpA. METHODS: Peripheral blood B cells from patients with SpA, patients with rheumatoid arthritis (RA), and healthy controls were analyzed by flow cytometry. Synovial biopsy samples were evaluated by immunohistochemistry analysis. Sorted CD5+ and CD5- B cells were analyzed for somatic hypermutation, expression of costimulatory molecules, and cytokine production. RESULTS: The naive, marginal zone-like, and to a lesser extent memory B cell compartments in patients with SpA exhibited a clear and specific increase of CD5+ B cells, which was not found in patients with RA. This increase was not due to either B cell activation or preferential migration of CD5- B cells to the inflamed synovium. Consistent with their phenotype and the low-affinity polyreactive immunoglobulins produced by their murine counterpart cells, CD5+ B cells from patients with SpA showed low levels of somatic hypermutation. With regard to antigen presentation, CD5+ B cells expressed slightly increased HLA-DR levels but low CD80 and CD86 levels. In vitro activation failed to up-regulate these costimulatory molecules but induced significant production of interleukin-10 and interleukin-6 by CD5+ B cells. CONCLUSION: CD5+ B cells are specifically increased in SpA. Analysis of somatic hypermutation, expression of antigen-presenting and costimulatory molecules, and cytokine production indicates that this B cell subset has regulatory capacities. Further investigation of the potential role of CD5+ cells in SpA is warranted. PMID- 22231661 TI - Comparison of bioaccumulation and biomarker responses in Dreissena polymorpha and D. bugensis after exposure to resuspended sediments. AB - The zebra mussel Dreissena polymorpha is widely used as sentinel organism for the assessment of environmental contamination in freshwater environments. However, in the River Rhine (Germany), the D. polymorpha population is declining, whereas the closely related quagga mussel D. bugensis is found in high numbers at some sites. In the present laboratory study, D. polymorpha and D. bugensis were exposed to resuspended native sediments for <=2 weeks. Wet sediments (<63 MUm, 100 mg l(-1) dry weight) were used as surrogate suspended particulate matter to mimic one of the mussels' main uptake route for chemicals. The sediments were sampled in (1) the River Elbe in Dessau, a site known to be highly polluted with, e.g., organochlorine (OC) pesticides and (2) at a relatively unpolluted site in Havelberg in the River Havel, one of the Elbe's tributaries. Chemical analysis of persistent OC compounds (seven polychlorinated biphenyls [PCBs], DDT and its metabolites (DDX), hexachlorocylohexanes [HCHs], and hexachlorobenzene [HCB]) in soft tissue of mussels showed significantly greater values of PCBs 101, 118, 153, 138, 180, the sum of seven PCBs, and p,p'-DDD in D. bugensis compared with D. polymorpha. Fourteen days of exposure to Dessau sediment increased the concentration of p,p'-DDE and p,p'-DDD, as well as the sum of DDX, in both species compared with Havelberg sediment. Interspecific differences were less pronounced when regarding chemical concentrations with lipid content instead of dry-weight of tissue because D. bugensis had greater levels of total lipid than D. polymorpha. DNA damage in gills, as measured with the comet assay, was greater in D. bugensis compared with D. polymorpha. Simultaneously, the content of heat shock protein (hsp70) in gills was greater in D. polymorpha than in D. bugensis. DNA damage and hsp70 were not induced by exposure time or sediment type. This study shows that D. bugensis and D. polymorpha may differ in their bioaccumulation potential of OC pesticides as well as their levels of DNA damage and hsp70. Therefore, more investigations are needed before quagga mussel can be used as alternative test organism for the zebra mussel. PMID- 22231662 TI - Covalent bond orders and atomic anisotropies from iterated stockholder atoms. AB - Iterated stockholder atoms are produced by dividing molecular electron densities into sums of overlapping, near-spherical atomic densities. It is shown that there exists a good correlation between the overlap of the densities of two atoms and the order of the covalent bond between the atoms (as given by simple valence rules). Furthermore, iterated stockholder atoms minimise a functional of the charge density, and this functional can be expressed as a sum of atomic contributions, which are related to the deviation of the atomic densities from spherical symmetry. Since iterated stockholder atoms can be obtained uniquely from the electron density, this work gives an orbital-free method for predicting bond orders and atomic anisotropies from experimental or theoretical charge density data. PMID- 22231663 TI - Probing and repairing damaged surfaces with nanoparticle-containing microcapsules. AB - Nanoparticles have useful properties, but it is often important that they only start working after they are placed in a desired location. The encapsulation of nanoparticles allows their function to be preserved until they are released at a specific time or location, and this has been exploited in the development of self healing materials and in applications such as drug delivery. Encapsulation has also been used to stabilize and control the release of substances, including flavours, fragrances and pesticides. We recently proposed a new technique for the repair of surfaces called 'repair-and-go'. In this approach, a flexible microcapsule filled with a solution of nanoparticles rolls across a surface that has been damaged, stopping to repair any defects it encounters by releasing nanoparticles into them, then moving on to the next defect. Here, we experimentally demonstrate the repair-and-go approach using droplets of oil that are stabilized with a polymer surfactant and contain CdSe nanoparticles. We show that these microcapsules can find the cracks on a surface and selectively deliver the nanoparticle contents into the crack, before moving on to find the next crack. Although the microcapsules are too large to enter the cracks, their flexible walls allow them to probe and adhere temporarily to the interior of the cracks. The release of nanoparticles is made possible by the thin microcapsule wall (comparable to the diameter of the nanoparticles) and by the favourable (hydrophobic-hydrophobic) interactions between the nanoparticle and the cracked surface. PMID- 22231664 TI - Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits. AB - Deciphering the neuronal code--the rules by which neuronal circuits store and process information--is a major scientific challenge. Currently, these efforts are impeded by a lack of experimental tools that are sensitive enough to quantify the strength of individual synaptic connections and also scalable enough to simultaneously measure and control a large number of mammalian neurons with single-cell resolution. Here, we report a scalable intracellular electrode platform based on vertical nanowires that allows parallel electrical interfacing to multiple mammalian neurons. Specifically, we show that our vertical nanowire electrode arrays can intracellularly record and stimulate neuronal activity in dissociated cultures of rat cortical neurons and can also be used to map multiple individual synaptic connections. The scalability of this platform, combined with its compatibility with silicon nanofabrication techniques, provides a clear path towards simultaneous, high-fidelity interfacing with hundreds of individual neurons. PMID- 22231665 TI - Photoluminescence imaging of electronic-impurity-induced exciton quenching in single-walled carbon nanotubes. AB - The electronic properties of single-walled carbon nanotubes can be altered by surface adsorption of electronic impurities or dopants. However, fully understanding the influence of these impurities is difficult because of the inherent complexity of the solution-based colloidal chemistry of nanotubes, and because of a lack of techniques for directly imaging dynamic processes involving these impurities. Here, we show that photoluminescence microscopy can be used to image exciton quenching in semiconducting single-walled carbon nanotubes during the early stages of chemical doping with two different species. The addition of AuCl(3) leads to localized exciton-quenching sites, which are attributed to a mid gap electronic impurity level, and the adsorbed species are also found sometimes to be mobile on the surface of the nanotubes. The addition of H(2)O(2) leads to delocalized exciton-quenching hole states, which are responsible for long-range photoluminescence blinking, and are also mobile. PMID- 22231666 TI - Hematuria due to congenital arteriovenous fistula treated with embolization. AB - OBJECTIVE: To report a rare case that supposed an emergency. It is a case of hematuria caused by an arteriovenous fistula. METHODS: We describe the background, clinical exploration, complementary exams and their results, as well as the treatment applied in an adolescent with hematuria. RESULTS: Congenital arteriovenous fistula was diagnosed and treated by percutaneous embolization, with immediate stop of the hematuria. CONCLUSION: Non-traumatic renal arteriovenous fistulae are infrequent and even more if they appear with gross hematuria. We present the case of an emergency caused by one of them which was treated by percutaneous embolization, avoiding surgery. PMID- 22231667 TI - Conditions for worm-robot locomotion in a flexible environment: theory and experiments. AB - Biological vessels are characterized by their substantial compliance and low friction that present a major challenge for crawling robots for minimally invasive medical procedures. Quite a number of studies considered the design and construction of crawling robots; however, very few focused on the interaction between the robots and the flexible environment. In a previous study, we derived the analytical efficiency of worm locomotion as a function of the number of cells, friction coefficients, normal forces, and local (contact) tangential compliance. In this paper, we introduce the structural effects of environment compliance, generalize our previous analysis to include dynamic and static coefficients of friction, determine the conditions of locomotion as function of the external resisting forces, and experimentally validate our previous and newly obtained theoretical results. Our experimental setup consists of worm robot prototypes, flexible interfaces with known compliance and a Vicon motion capture system to measure the robot positioning. Separate experiments were conducted to measure the tangential compliance of the contact interface that is required for computing the analytical efficiency. The validation experiments were performed for both types of compliant conditions, local and structural, and the results are shown to be in clear match with the theoretical predictions. Specifically, the convergence of the tangential deflections to an arithmetic series and the partial and overall loss of locomotion verify the theoretical predictions. PMID- 22231668 TI - Electromechanical design and construction of a rotating radio-frequency coil system for applications in magnetic resonance. AB - While recent studies have shown that rotating a single radio-frequency (RF) coil during the acquisition of magnetic resonance (MR) images provides a number of hardware advantages (i.e., requires only one RF channel, avoids coil-coil coupling and facilitates large-scale multinuclear imaging), they did not describe in detail how to build a rotating RF coil system. This paper presents detailed engineering information on the electromechanical design and construction of a MR compatible RRFC system for human head imaging at 2 T. A custom-made (bladeless) pneumatic Tesla turbine was used to rotate the RF coil at a constant velocity, while an infrared optical encoder measured the selected frequency of rotation. Once the rotating structure was mechanically balanced and the compressed air supply suitably regulated, the maximum frequency of rotation measured ~14.5 Hz with a 2.4% frequency variation over time. MR images of a water phantom and human head were obtained using the rotating RF head coil system. PMID- 22231669 TI - Experimental characterization and numerical modeling of tissue electrical conductivity during pulsed electric fields for irreversible electroporation treatment planning. AB - Irreversible electroporation is a new technique to kill cells in targeted tissue, such as tumors, through a nonthermal mechanism using electric pulses to irrecoverably disrupt the cell membrane. Treatment effects relate to the tissue electric field distribution, which can be predicted with numerical modeling for therapy planning. Pulse effects will change the cell and tissue properties through thermal and electroporation (EP)-based processes. This investigation characterizes these changes by measuring the electrical conductivity and temperature of ex vivo renal porcine tissue within a single pulse and for a 200 pulse protocol. These changes are incorporated into an equivalent circuit model for cells and tissue with a variable EP-based resistance, providing a potential method to estimate conductivity as a function of electric field and pulse length for other tissues. Finally, a numerical model using a human kidney volumetric mesh evaluated how treatment predictions vary when EP- and temperature-based electrical conductivity changes are incorporated. We conclude that significant changes in predicted outcomes will occur when the experimental results are applied to the numerical model, where the direction and degree of change varies with the electric field considered. PMID- 22231670 TI - Three-dimensional rotation of mouse embryos. AB - Research and clinical applications, such as microinjection and polar-body biopsy involve 3-D rotation of mammalian oocytes/embryos. In these cell manipulation tasks, the polar body of an embryo/oocyte must be made visible and properly oriented under optical microscopy. Cell rotation in conventional manual operation by skilled professionals is based on trial and error, such as through repeated vacuum aspiration and release. The randomness of this manual procedure, its poor reproducibility, and inconsistency across operators entail a systematic technique for automated, noninvasive, 3-D rotational control of single cells. This paper reports a system that tracks the polar body of mouse embryos in real time and controls multiple motion control devices to conduct automated 3-D rotational control of mouse embryos. Experimental results demonstrated the system's capability for polar-body orientation with a high success rate of 90%, an accuracy of 1.9 degrees , and an average speed of 22.8 s/cell (versus averagely 40 s/cell in manual operation). PMID- 22231671 TI - Increased preoperative C-reactive protein levels are associated with inhospital death after coronary artery bypass surgery. AB - Increased C-reactive protein (CRP) is a predictor of cardiovascular risk, but its influence on outcomes after coronary artery bypass grafting surgery (CABG) is still incompletely studied. We studied the association between preoperative CRP and inhospital death after CABG. Patients with acute or chronic infectious or inflammatory disorders, autoimmune diseases, cancer, and prior cardiac surgery were excluded. Seventy-six patients were studied [27.6% with elevated CRP (>3 mg/l)]. Elevated CRP was more frequently found in patients who died than in those who survived (83.3% vs 17.1%, p = 0.003); mean CRP levels were, respectively, 6.5 +/- 3.4 vs 2.4 +/- 3.5 mg/l (p = 0.03). The hazard ratio of death was 11.7 for elevated CRP, and the ROC curve for the discrimination of death with CRP had an area under the curve of 0.82. An improvement to mortality risk prediction following CABG may be offered by the preoperative analysis of CRP. PMID- 22231672 TI - Intervention-based multidimensional phase unwrapping using recursive orthogonal referring. AB - We present a new intervention-based phase unwrapping algorithm, which solves the inherent integration-path-dependent problem (typically resulting in streaks), by using a 2D recursive orthogonal referring (PUROR) approach. The streaks were removed by three consecutive procedures: intra-image phase unwrapping, inter image cross-referring a "good-strip," and cross-referring line segments. The application of these procedures results in streak-free 2D phase images. The phase inconsistencies across slices in a 3D image were removed using a hybrid 3D PUROR algorithm: the two step approach involves stacking the individual slices, by using the mean phase values of each slice, then applying the 2D PUROR algorithm to reformatted 2D images that include the slice direction. The described approach was tested with in vivo multislice phase images acquired in the axial, sagittal, and coronal orientation. The results of the unwrapped phase volume recovered using the PUROR algorithm have equivalent quality to that achieved by using established methods, but the PUROR algorithm is about two orders of magnitude faster (between 1 and 5 s per 256*256 slice; independent of slice orientation and echo time). PMID- 22231673 TI - Biomechanics of meniscus cells: regional variation and comparison to articular chondrocytes and ligament cells. AB - Central to understanding mechanotransduction in the knee meniscus is the characterization of meniscus cell mechanics. In addition to biochemical and geometric differences, the inner and outer regions of the meniscus contain cells that are distinct in morphology and phenotype. This study investigated the regional variation in meniscus cell mechanics in comparison with articular chondrocytes and ligament cells. It was found that the meniscus contains two biomechanically distinct cell populations, with outer meniscus cells being stiffer (1.59 +/- 0.19 kPa) than inner meniscus cells (1.07 +/- 0.14 kPa). Additionally, it was found that both outer and inner meniscus cell stiffnesses were similar to ligament cells (1.32 +/- 0.20 kPa), and articular chondrocytes showed the highest stiffness overall (2.51 +/- 0.20 kPa). Comparison of compressibility characteristics of the cells showed similarities between articular chondrocytes and inner meniscus cells, as well as between outer meniscus cells and ligament cells. These results show that cellular biomechanics vary regionally in the knee meniscus and that meniscus cells are biomechanically similar to ligament cells. The mechanical properties of musculoskeletal cells determined in this study may be useful for the development of mathematical models or the design of experiments studying mechanotransduction in a variety of soft tissues. PMID- 22231674 TI - Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. AB - We have previously shown that remote ischemic preconditioning by limb ischemia (rIPC) or intra-arterial adenosine releases a dialyzable cardioprotective circulating factor(s), the release of which requires an intact neural connection to the limb and is blocked by pretreatment with S-nitroso-N-acetylpenicillamine (SNAP). Remote cardioprotection can be induced by other forms of peripheral stimulation including topical capsaicin, but the mechanisms of their signal transduction are incompletely understood. Rabbits were anesthetized by intravenous pentobarbital, intubated and ventilated, then randomized (4-7 animals in each group) to receive sham procedure, rIPC (4 cycles of 5 min lower limb ischemia, 5 min reperfusion), direct femoral nerve stimulation, topical capsaicin, pretreatment with intra-arterial SNAP + capsaicin, pretreatment with topical DMSO (a sensory nerve blocker) + topical capsaicin, or pretreatment with intra-arterial SNAP + femoral nerve stimulation, topical DMSO alone, or intra arterial SNAP alone. Blood was then rapidly drawn from the carotid artery to produce the plasma dialysate which was used to perfuse a naive heart from an untreated donor rabbit. The infarct size and recovery of LV-developed pressure and end-diastolic pressure were measured after 30 min of global ischemia and 120 min of reperfusion. Compared to sham, dialysate from rIPC, femoral nerve stimulation, and topical capsaicin groups all produced significant cardioprotection with significantly reduced infarct size, and improved the post ischemic cardiac performance. Cardioprotection was not seen in the topical DMSO capsaicin, SNAP + capsaicin, and SNAP + FNS groups. These results confirm the central role of peripheral nerves in the local signal transduction of remote cardioprotection. Direct electrical or peripheral neural stimulation evokes the release of cardioprotective substances into the bloodstream, with comparable effects to that of rIPC induced by limb ischemia. PMID- 22231676 TI - The role of acupuncture in the treatment of migraine. PMID- 22231675 TI - Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia. AB - Ossabaw miniswine have been naturally selected to efficiently store large amounts of lipids offering them a survival advantage. Our goal was to evaluate the myocardial response to chronic ischemia of the Ossabaw consuming a hypercaloric, high-fat/cholesterol diet with and without metformin supplementation. At 6 weeks of age animals were fed either a regular diet (OC, n = 9), a hypercaloric high fat/cholesterol diet (OHC, n = 9), or a hypercaloric high-fat/cholesterol diet supplemented with metformin (OHCM, n = 8). At 9 weeks, all animals underwent ameroid constrictor placement to the left circumflex coronary artery to simulate chronic ischemia. Seven weeks after ameroid placement, all animals underwent hemodynamic and functional measurements followed by cardiac harvest. Both OHC and OHCM animals developed significantly greater weight gain, total cholesterol, and LDL:HDL ratio compared to OC controls. Metformin administration reversed diet induced hypertension and glucose intolerance. There were no differences in global and regional contractility, myocardial perfusion, capillary and arteriolar density, or total protein oxidation between groups. Myocardial protein expression of VEGF, PPAR-alpha, gamma, and delta was significantly increased in the OHC and OHCM groups. Microvessel reactivity was improved in the OHC and OHCM groups compared to controls, and correlated with increased p-eNOS expression. Overfed Ossabaw miniswine develop several components of metabolic syndrome. However, impairments of myocardial function, neovascularization and perfusion were not present, and microvessel reactivity was paradoxically improved in hypercholesterolemic animals. The observed cardioprotection despite metabolic derangements may be due to lipid-dependant upregulation of the PPAR pathway which is anti-inflammatory and governs myocardial fatty acid metabolism. PMID- 22231677 TI - Fixed drug eruption due to fluconazole. PMID- 22231678 TI - Universal health coverage still rare in Africa. PMID- 22231679 TI - Quality-improvement interventions for osteoporosis: when are the results worth the effort? PMID- 22231680 TI - A proactive approach to migraine in primary care: a pragmatic randomized controlled trial. AB - BACKGROUND: Migraine is a common, disabling headache disorder that leads to lost quality of life and productivity. We investigated whether a proactive approach to patients with migraine, including an educational intervention for general practitioners, led to a decrease in headache and associated costs. METHODS: We conducted a pragmatic randomized controlled trial. Participants were randomized to one of two groups: practices receiving the intervention and control practices. Participants were prescribed two or more doses of triptan per month. General practitioners in the intervention group received training on treating migraine and invited participating patients for a consultation and evaluation of the therapy they were receiving. Physicians in the control group continued with usual care. Our primary outcome was patients' scores on the Headache Impact Test (HIT 6) at six months. We considered a reduction in score of 2.3 points to be clinically relevant. We used the Kessler Psychological Distress Scale (K10) questionnaire to determine if such distress was a possible effect modifier. We also examined the interventions' cost-effectiveness. RESULTS: We enrolled 490 patients in the trial (233 to the intervention group and 257 to the control group). Of the 233 patients in the intervention group, 192 (82.4%) attended the consultation to evaluate the treatment of their migraines. Of these patients, 43 (22.3%) started prophylaxis. The difference in change in score on the HIT-6 between the intervention and control groups was 0.81 (p = 0.07, calculated from modelling using generalized estimating equations). For patients with low levels of psychological distress (baseline score on the K10 <= 20) this change was -1.51 (p = 0.008), compared with a change of 0.16 (p = 0.494) for patients with greater psychological distress. For patients who were not using prophylaxis at baseline and had two or more migraines per month, the mean HIT-6 score improved by 1.37 points compared with controls (p = 0.04). We did not find the intervention to be cost-effective. INTERPRETATION: An educational intervention for general practitioners and a proactive approach to patients with migraine did not result in a clinically relevant improvement of symptoms. Psychological distress was an important confounder of success. (Current Controlled Trials registration no. ISRCTN72421511.). PMID- 22231681 TI - Enhancing the clinical utility of depression screening. PMID- 22231682 TI - Reducing the "pill burden". PMID- 22231684 TI - Research on drug use goes down the toilet. PMID- 22231685 TI - Public health fallout from Japanese quake. PMID- 22231686 TI - Stem cell tourism poses risks. PMID- 22231687 TI - Prices gone wild: grey market 'scalpers' scoring windfall in American drug market. PMID- 22231688 TI - Crowdfunding for medical expenses. PMID- 22231689 TI - Promise of nano revolution hasn't materialized. PMID- 22231690 TI - Scombroid poisoning. PMID- 22231692 TI - Impact of participation in randomized trials on outcome following surgery for gastro-oesophageal reflux. AB - BACKGROUND: Patients may be unwilling to participate in clinical trials if they perceive risks. Outcomes were evaluated following surgery for gastro-oesophageal reflux in patients recruited to randomized trials compared with patients not in trials. METHODS: This study compared outcomes of patients who had surgery for reflux within or outside randomized trials between 1994 and 2009. The choice of procedure outside each trial was according to surgeon or patient preference. Clinical outcomes were determined 1 and 5 years after surgery using a standardized questionnaire, with analogue scales to assess heartburn, dysphagia and overall satisfaction. Subgroup analysis was undertaken for those aged less than 75 years undergoing laparoscopic Nissen fundoplication. RESULTS: Some 417 patients entered six randomized trials evaluating surgery for reflux and 981 underwent surgery outside the trials. The trial group contained a higher proportion of men and younger patients, and patients in trials were more likely to have undergone Nissen fundoplication. At 1 year, patients in the trials had slightly lower heartburn scores and less abdominal bloating, but otherwise similar outcomes to those not in the trials. At 5 years there were no differences, except for a slightly higher dysphagia score for liquids in the trial group. For the subgroup analysis, demographic data were similar for both groups. There were no differences at 1 year, but at 5 years patients enrolled in the trials had higher scores for dysphagia for liquids and heartburn. All of the statistically significant differences were thought unlikely to be clinically relevant. CONCLUSION: Participation in a randomized trial assessing surgery for reflux did not influence outcomes. PMID- 22231693 TI - A graphical method for determining the in-plane rotation angle in geometric calibration of circular cone-beam CT systems. AB - It is well known that seven parameters completely describe a circular cone-beam geometry in either flat-panel X-ray computed tomography (CT) or single pinhole SPECT imaging. This paper considers the problem of determining one of the seven parameters only, the detector in-plane rotation or twist angle eta. We describe a graphical procedure that can determine eta independently of all other six parameters from a geometric calibration scan of point objects. Our method is exact in the ideal noise-free case and is general in that the other two out-of plane detector rotation angles theta and phi can be nonzero. The calibration scan typically needs at least two point objects and an even number of projection views over a full 360 degrees data acquisition. Under certain conditions, projection data truncation or a short scan acquisition of 180 degrees + fan angle can be accommodated without affecting the accuracy of the calibration result. The graphical method is equally applicable to rotational multipinhole SPECT geometry. In this case, the final result is averaged from the individual estimates considering each pinhole separately. We use computer simulations and a multipinhole SPECT experiment to demonstrate the accuracy and precision of the proposed method. PMID- 22231691 TI - Acupuncture for migraine prophylaxis: a randomized controlled trial. AB - BACKGROUND: Acupuncture is commonly used to treat migraine. We assessed the efficacy of acupuncture at migraine-specific acupuncture points compared with other acupuncture points and sham acupuncture. METHODS: We performed a multicentre, single-blind randomized controlled trial. In total, 480 patients with migraine were randomly assigned to one of four groups (Shaoyang-specific acupuncture, Shaoyang-nonspecific acupuncture, Yangming-specific acupuncture or sham acupuncture [control]). All groups received 20 treatments, which included electrical stimulation, over a period of four weeks. The primary outcome was the number of days with a migraine experienced during weeks 5-8 after randomization. Our secondary outcomes included the frequency of migraine attack, migraine intensity and migraine-specific quality of life. RESULTS: Compared with patients in the control group, patients in the acupuncture groups reported fewer days with a migraine during weeks 5-8, however the differences between treatments were not significant (p > 0.05). There was a significant reduction in the number of days with a migraine during weeks 13-16 in all acupuncture groups compared with control (Shaoyang-specific acupuncture v. control: difference -1.06 [95% confidence interval (CI) -1.77 to -0.5], p = 0.003; Shaoyang-nonspecific acupuncture v. control: difference -1.22 [95% CI -1.92 to -0.52], p < 0.001; Yangming-specific acupuncture v. control: difference -0.91 [95% CI -1.61 to 0.21], p = 0.011). We found that there was a significant, but not clinically relevant, benefit for almost all secondary outcomes in the three acupuncture groups compared with the control group. We found no relevant differences between the three acupuncture groups. INTERPRETATION: Acupuncture tested appeared to have a clinically minor effect on migraine prophylaxis compared with sham acupuncture. TRIAL REGISTRATION: Clinicaltrials.gov NCT00599586. PMID- 22231695 TI - [Cancer pain in palliative medicine]. AB - During the course of cancer progression up to 90% of the patients suffer from pain of nociceptive, neuropathic or mixed nociceptive/neuropathic origin. Psychological, social or existential factors may additionally affect the intensity of pain (concept of "total pain"). The WHO "analgesic ladder" provides a large variety of effective drugs that can be used according to the specific pain type. Parenteral or peridural opioid therapy as well as neurodestructive methods can effectively support the analgesic treatment in selected cases. PMID- 22231694 TI - [Albuminuria : prognostic marker or therapeutic goal?]. AB - Microalbuminuria has most often been linked with renal disease in diabetic patients. However, accumulating data demonstrate that the development of albuminuria is closely associated with cardiovascular and renal disease in both diabetic and non-diabetic patients. The role of albuminuria in the pathogenesis of these clinical conditions remains controversial. While reductions in albuminuria have been associated with improved outcomes, the evidence for lower levels of albuminuria (microalbuminuria and normoalbuminuria) is inconclusive. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have demonstrated some success in treating or delaying the onset of microalbuminuria. However, it remains to be established whether these effects result in meaningful reductions in clinical renal or cardiovascular events. PMID- 22231696 TI - [Gastroenteropancreatic neuroendocrine tumors: diagnosis and therapy in nuclear medicine]. AB - The over expression of somatostatin receptors (SSTR) in neuroendocrine tumors (NET) enables diagnosis and targeted therapy using radio-labelled somatostatin analogues. PET with (68)Ga-DOTATATE or (68)Ga-DOTATOC, both with a high affinity to the SSTR subtype 2, enables diagnosis of NET with a very high sensitivity and has a significant influence on the therapeutic management of patients with NET. In particular, therapy with (177)Lu-DOTATATE, which offers a considerably lower nephrotoxicity as compared to (90)Y-DOTATOC, has only few side effects and is usually well tolerated. Up to 46% of patients suffering from GEP-NET show a response to this therapy, which is able to mitigate tumour-related symptoms and significantly improve quality of life. PMID- 22231697 TI - Tumor necrosis factor-alpha receptor expression correlates with mucosal changes and biofilm presence in chronic rhinosinusitis with nasal polyposis. AB - OBJECTIVES/HYPOTHESIS: Biofilms might play a potential role in the pathogenesis and high recurrence rate of chronic rhinosinusitis with nasal polyposis (CRSwNP). Biofilm persistence has been thought to correlate with epithelial damage, subepithelial inflammatory cell infiltration, and tumor necrosis factor-alpha receptor (TNFR) expression in CRSwNP. STUDY DESIGN: Case-control experimental study. METHODS: A total of 36 patients with CRSwNP undergoing endoscopic sinus surgery were analyzed. The negative control group consisted of eight patients undergoing septoplasty for nasal obstruction without CRSwNP. The nasal polyps and inferior turbinate mucosa samples applied as negative controls were processed by hematoxylin-eosin (HE) and Gram staining and TNFR-I and TNFR-II-specific immunofluorescent assay. RESULTS: Biofilm was detected in 29 of 36 patients with CRSwNP and in none of the eight negative controls. Staining by HE showed strong correlation with the results of Gram staining protocol. In the biofilm-positive cases, TNFR-I and TNFR-II displayed homogeneous pattern of significantly increased epithelial expression compared to the biofilm-negative nasal polyps. In cases of biofilm absence, the expression pattern of TNF-alpha receptors was characterized by increased TNFR-II-specific immunoreaction. It was found that biofilm detectability corresponded to the integrity of nasal epithelium and to the dominant inflammatory cell type of the subepithelial layer. CONCLUSIONS: Persisting biofilms might increase the epithelial sensitivity against TNF-alpha that result in epithelium destruction. Coexistence of biofilms and increased TNFR expression might explain the inflammatory mucosal changes, functional disorders, and therapy resistance featuring CRSwNP. PMID- 22231698 TI - Human NK Cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. AB - Polymorphonuclear neutrophils (PMN) are potent inflammatory effector cells essential to host defense, but at the same time they may cause significant tissue damage. Thus, timely induction of neutrophil apoptosis is crucial to avoid tissue damage and induce resolution of inflammation. NK cells have been reported to influence innate and adaptive immune responses by multiple mechanisms including cytotoxicity against other immune cells. In this study, we analyzed the effect of the interaction between NK cells and neutrophils. Coculture experiments revealed that human NK cells could trigger caspase-dependent neutrophil apoptosis in vitro. This event was dependent on cell-cell contact, and experiments using blocking Abs indicated that the effect was mediated by the activating NK cell receptor NKp46 and the Fas pathway. CD56-depleted lymphocytes had minimal effects on neutrophil survival, suggesting that the ability to induce neutrophil apoptosis is specific to NK cells. Our findings provide evidence that NK cells may accelerate neutrophil apoptosis, and that this interaction may be involved in the resolution of acute inflammation. PMID- 22231699 TI - TRAIL(+) human plasmacytoid dendritic cells kill tumor cells in vitro: mechanisms of imiquimod- and IFN-alpha-mediated antitumor reactivity. AB - Dendritic cells (DCs) not only exhibit the unique capacity to evoke primary immune responses, but may also acquire TLR-triggered cytotoxic activity. We and others have previously shown that TLR7/8- and TLR9-stimulated plasmacytoid DCs (pDCs) isolated from human peripheral blood express the effector molecule TRAIL. The exact mechanisms through which pDCs acquire and elicit their cytotoxic activity are still not clear. We now show that in the absence of costimulators, TRAIL induction on pDCs occurs with agonists to intracellular TLRs only and is accompanied by a phenotypic as well as functional maturation, as evidenced by a comparatively superior MLR stimulatory capacity. pDCs acquired TRAIL in an IFN alpha/beta-dependent fashion and, notably, TRAIL expression on pDCs could be induced by IFN-alpha stimulation alone. At a functional level, both TLR7/8- (imiquimod [IMQ]) and TLR9-stimulated (CpG2216) pDCs lysed Jurkat T cells in a TRAIL- and cell contact-dependent fashion. More importantly, IFN-alpha-activated pDCs acquired similar cytotoxic properties, independent of TLR stimulation and maturation. Both IMQ- and IFN-alpha-activated pDCs could also lyse certain melanoma cell lines in a TRAIL-dependent fashion. Interestingly, suboptimal doses of IMQ and IFN-alpha exhibited synergistic action, leading to optimal TRAIL expression and melanoma cell lysis by pDCs. Our data imply that tumor immunity in patients receiving adjuvant IMQ and/or IFN-alpha may involve the active participation of cytotoxic pDCs. PMID- 22231700 TI - Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. AB - Immunostimulatory CpG oligonucleotides (ODN) activate cells that express TLR9 and have been shown to improve the host's response to tumor Ags. Unfortunately, the immunosuppressive microenvironment that surrounds many cancers inhibits Ag specific cellular responses and thus interferes with CpG-mediated immunotherapy. Myeloid-derived suppressor cells (MDSC) represent an important constituent of this immunosuppressive milieu. Large numbers of MDSC are present in and near tumor sites where they inhibit the activity of Ag-specific T and NK cells. Current studies indicate that the delivery of CpG ODN directly into the tumor bed reduces the immunosuppressive activity of monocytic (CD11b(+), Ly6G(-), Ly6C(high)) MDSC. Monocytic MDSC express TLR9 and respond to CpG stimulation by 1) losing their ability to suppress T cell function, 2) producing Th1 cytokines, and 3) differentiating into macrophages with tumoricidal capability. These findings provide insight into a novel mechanism by which CpG ODN contribute to tumor regression, and they support intratumoral injection as the optimal route for their delivery. PMID- 22231701 TI - Murine regulatory T cells contain hyperproliferative and death-prone subsets with differential ICOS expression. AB - Regulatory T cells (Treg) are crucial for self-tolerance. It has been an enigma that Treg exhibit an anergic phenotype reflected by hypoproliferation in vitro after TCR stimulation but undergo vigorous proliferation in vivo. We report in this study that murine Treg are prone to death but hyperproliferative in vitro and in vivo, which is different from conventional CD4(+)Foxp3(-) T cells (Tcon). During in vitro culture, most Treg die with or without TCR stimulation, correlated with constitutive activation of the intrinsic death pathway. However, a small portion of the Treg population is more sensitive to TCR stimulation, particularly weak stimulation, proliferates more vigorously than CD4(+) Tcon, and is resistant to activation-induced cell death. Treg proliferation is enhanced by IL-2 but is less dependent on CD28-mediated costimulation than that of Tcon. We demonstrate further that the surviving and proliferative Treg are ICOS(+) whereas the death-prone Treg are ICOS(-). Moreover, ICOS(+) Treg contain much stronger suppressive activity than that of ICOS(-) Treg. Our data indicate that massive death contributes to the anergic phenotype of Treg in vitro and suggest modulation of Treg survival as a therapeutic strategy for treatment of autoimmune diseases and cancer. PMID- 22231704 TI - Chinese integrative medicine: translation toward person-centered and balanced medicine. AB - Chinese integrative medicine (CIM) focuses on the integration of conventional medicine (biomedicine) with Chinese medicine (CM). Although the CIM field has witnessed several advancements, the definition and classification of CIM is not quite clear, given that an independent theory system has not yet been established in this field. Therefore, future research and studies should focus on the following objectives: (1) emphasizing CM features, (2) improving CIM positioning, and (3) establishing CIM standards. These concerted efforts will help CIM be at par with international standards and criteria. With the development of CIM, the world will embrace a new medical system providing person-centered treatment with a balanced medicine approach. PMID- 22231702 TI - IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice. AB - MRL/MpJ-Fas(lpr/lpr)/J (MRL(lpr)) mice develop lupus-like disease manifestations in an IL-21-dependent manner. IL-21 is a pleiotropic cytokine that can influence the activation, differentiation, and expansion of B and T cell effector subsets. Notably, autoreactive CD4(+) T and B cells spontaneously accumulate in MRL(lpr) mice and mediate disease pathogenesis. We sought to identify the particular lymphocyte effector subsets regulated by IL-21 in the context of systemic autoimmunity and, thus, generated MRL(lpr) mice deficient in IL-21R (MRL(lpr).IL 21R(-/-)). Lymphadenopathy and splenomegaly, which are characteristic traits of the MRL(lpr) model were significantly reduced in the absence of IL-21R, suggesting that immune activation was likewise decreased. Indeed, spontaneous germinal center formation and plasma cell accumulation were absent in IL-21R deficient MRL(lpr) mice. Correspondingly, we observed a significant reduction in autoantibody titers. Activated CD4(+) CD44(+) CD62L(lo) T cells also failed to accumulate, and CD4(+) Th cell differentiation was impaired, as evidenced by a significant reduction in CD4(+) T cells that produced the pronephritogenic cytokine IFN-gamma. T extrafollicular helper cells are a recently described subset of activated CD4(+) T cells that function as the primary inducers of autoantibody production in MRL(lpr) mice. Importantly, we demonstrated that T extrafollicular helper cells are dependent on IL-21R for their generation. Together, our data highlighted the novel observation that IL-21 is a critical regulator of multiple pathogenic B and T cell effector subsets in MRL(lpr) mice. PMID- 22231705 TI - Efficacy of ursodeoxycholic acid combined with Tongdan Decoction () on immunological indices and histopathological changes in primary biliary cirrhosis patients. AB - OBJECTIVE: To observe the efficacy of ursodeoxycholic acid (UDCA) combined with Tongdan: Decoction () on immunological indices and histopathological changes in patients with primary biliary cirrhosis (PBC) of IIor III histological stage. METHODS: Sixty PBC patients were assigned randomly and equally: to the control group treated with UDCA alone and the treatment group treated with UDCA combined with Tongdan Decoction. The immunological indices and histopathological changes were detected before and after 24-week treatment, and the follow-up lasted for 1 3 years. RESULTS: After 24-week treatment, CD4(+)CD28(-) in the peripheral blood was lowered and CD4(+)CD25(+) was increased in both groups, and better effect was shown in the treatment group (P<0.01). The levels of IgM, IgG, and IgA decreased markedly after 96-week treatment in the treatment group (P< 0.05, P< 0.01), while in the control group, only the latter two showed significant decrease after 148 week (all P<0.05). At the end of the 3-year follow-up, the medians of histopathological 1.0 min-1. Sensitivity to diagnose malignant SPNs at a cutoff of k(ep) = 1.0 min-1 was 76%, specificity was 100%, positive predictive value was 100%, negative predictive value was 45%, and accuracy was 80%. Of all indices studied, k(ep) was the most significant in differentiating malignant from benign SPNs. PMID- 22231731 TI - Effect of prostaglandin I2 analogs on cytokine expression in human myeloid dendritic cells via epigenetic regulation. AB - Prostaglandin I(2) (PGI(2)) analog is regarded as a potential candidate for treating asthma. Human myeloid dendritic cells (mDCs) play a critical role in the pathogenesis of asthma. However, the effects of PGI(2) analog on human mDCs are unknown. In the present study, circulating mDCs were isolated from six healthy subjects. The effects of PGI(2) analogs iloprost and treprostinil on cytokine production, maturation and T-cell stimulatory function of human mDCs were investigated. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay. The expression of costimulatory molecules was investigated by flow cytometry. T-cell stimulatory function was investigated by measuring interferon (IFN)-gamma, IL-13 and IL-10 production by T cells cocultured with iloprost-treated mDCs. Intracellular signaling was investigated by Western blot and chromatin immunoprecipitation. We found that iloprost and treprostinil induced IL-10, but suppressed TNF-alpha production in polyinosinic-polycytidylic acid (poly I:C)-stimulated mDCs. This effect was reversed by the I-prostanoid (IP), E-prostanoid (EP) receptor antagonists or intracellular free calcium (Ca(2+)) chelator. Forskolin, an adenyl cyclase activator, conferred a similar effect. Iloprost and treprostinil increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, and iloprost also increased intracellular Ca(2+). Iloprost suppressed poly I:C-induced mitogen activated protein kinase (MAPK) phospho-p38 and phospho-activating transcription factor (ATF)2 expression. Iloprost downregulated poly I:C-induced histone H3K4 trimethylation in the TNFA gene promoter region via suppressing translocation of histone 3 lysine 4 (H3K4)-specific methyltransferases MLL (mixed lineage leukemia) and WDR5 (WD repeat domain 5). Iloprost-treated mDCs inhibited IL-13, IFN-gamma and IL-10 production by T cells. In conclusion, PGI(2) analogs enhance IL-10 and suppress TNF-alpha expression through the IP/EP2/EP4 receptors-cAMP and EP1 receptor-Ca(2+) pathway. Iloprost suppressed TNF-alpha expression via the MAPK-p38-ATF2 pathway and epigenetic regulation by downregulation of histone H3K4 trimethylation. PMID- 22231732 TI - Effect of nuclear factor kappaB inhibition on serotype 9 adeno-associated viral (AAV9) minidystrophin gene transfer to the mdx mouse. AB - Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-kappaB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-kappaB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-kappaB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD because of vector tropism to cardiac and skeletal muscle. In quadriceps of C57BL/10ScSn-Dmd(mdx)/J (mdx) mice, the addition of octalysine (8K)-NF-kappaB essential modulator (NEMO)-binding domain (8K-NBD) peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, high-level transgene expression was achieved with AAV9 minidystoophin gene delivery alone; therefore, improvements in histological and physiological indices were comparable in the two treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer, which may be highly significant for clinical applications of muscle gene delivery. PMID- 22231734 TI - Effectiveness of cevimeline to improve oral health in patients with postradiation xerostomia. AB - BACKGROUND: We assessed the effectiveness of cevimeline 30 mg 3 times daily in patient-reported oral health (Oral Health Impact Profile [OHIP-49]) and quality of life (QOL) in patients with xerostomia. METHODS: In our investigator initiated, multicenter, randomized, double-blind, placebo-controlled study, patients who received >40 Gy of radiation therapy to the head and neck including at least 3 major salivary glands were randomized to cevimeline 30 mg or placebo orally 3 times daily for 6 weeks. Patients had to have grade 1 or 2 xerostomia and be >16 weeks posttreatment. Clinical data were collected and questionnaires administered at baseline and week 6. The primary outcome was change in OHIP-49 total score from baseline to week 6. RESULTS: No statistically significant differences in oral health or QOL were observed. During the 6 weeks of the study, the severity of xerostomia decreased from baseline. CONCLUSIONS: Xerostomia is a significant sequela of treatment of head and neck cancer that may improve with time. The role of oral parasympathetic muscarinic secretogogues in alleviating patient symptoms and complaints remains unclear. PMID- 22231733 TI - Expression of interleukin-8 receptor CXCR2 and suppressor of cytokine signaling-3 in astrocytic tumors. AB - The aim was to expand recently published information regarding the significance of the interleukin (IL)-8/p-STAT-3 (signal transducer and activator of transcription) pathway in astrocytomas, focusing on the IL-8 receptor, chemokine (C-X-C motif) receptor 2 (CXCR2), and the STAT-3 inhibitor SOCS-3 (suppressors of cytokine signaling). A total of 91 paraffin-embedded human astrocytoma tissues (grades II-IV) were investigated for the association of SOCS-3 and CXCR2 expression with clinicopathologic and morphometric microvascular characteristics, vascular endothelial growth factor (VEGF), IL-8 and p-STAT-3 expression and patient survival. Peripheral IL-8 secretion levels were assessed by enzyme-linked immunosorbent spot (ELISPOT). SOCS-3, p-STAT-3 and CXCR2 protein levels were also quantified by Western immunoblotting in six cases, and the protein levels of SOCS 3 and CXCR2 were correlated with the immunohistochemical expression of the respective proteins. All CXCR2-positive cases by Western immunoblotting displayed increased peripheral IL-8 secretion levels. Treatment of primary glioblastoma cell cultures with exogenous IL-8 enhanced proliferation, and this effect was inhibited by treatment with a neutralizing anti-CXCR2 antibody. SOCS-3 and CXCR2 were expressed by neoplastic astrocytes in 92.4% and 48.78% of cases, respectively, with their levels increasing with histological grade and extent of necrosis. VEGF expression and microvessel density, CXCR2 and IL-8 levels were interrelated. SOCS-3 and p-STAT-3 were co-expressed in 85.7% of cases, although they were not interrelated. In univariate survival analysis, increased SOCS-3 expression and the presence of CXCR2 adversely affected survival, whereas in multivariate analysis, only CXCR2 remained significant. The prognostic significance of CXCR2 was validated in an independent set of 63 patients. Our data implicate IL-8/CXCR2 signaling pathway in the progression and regulation of angiogenesis in astrocytomas and provide a rationale for CXCR2 therapeutic exploitation in these tumors. PMID- 22231735 TI - Sox4 functions as a positive regulator of beta-catenin signaling through upregulation of TCF4 during morular differentiation of endometrial carcinomas. AB - Sox factors function as either activators or repressors of beta-catenin/TCF transcription depending on the cellular context and associated interacting proteins. Our previous study provided evidence that alteration in beta-catenin signaling is an essential event during transdifferentiation toward the morular phenotype of endometrial carcinomas (Em Cas). Here, we focused on related functional roles of Sox factors. Of eight Sox factors investigated, Sox4 could enhance beta-catenin/TCF4 transcription, through upregulation of TCF4 at the transcription level, without any direct beta-catenin association. Cells stably overexpressing Sox4 showed significant decreases in proliferation rate, along with increases in expression of p21(WAF1), as well as TCF4, in contrast to increased cell growth observed with knockdown. Of these factors, only Sox7 could transcriptionally upregulate Sox4 expression, but it also resulted in not only inhibition of Sox4-meditated activation of beta-catenin/TCF4-driven transcription, but also repression of its own promoter activity, indicating the existence of very complex feedback loop for Sox-mediated signal cascades. Finally, Sox4 immunoreactivity was frequently pronounced in morular lesions of Em Cas, the expression being positively correlated with status of beta-catenin, TCF4, and Sox7, and inversely with cell proliferation. These data therefore suggest that Sox4 may serve as a positive regulator of beta-catenin signaling through alteration in TCF4 expression during morular differentiation of Em Ca cells, leading to inhibition of cell proliferation. In addition, Sox7 may also participate in the process, having complex roles in modulation of signaling. PMID- 22231736 TI - Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease. AB - Indoxyl sulfate (IS), one of the uremic toxins, is regarded to have a substantial role in the progression of chronic kidney disease (CKD). Epithelial-to mesenchymal transition (EMT) and apoptosis of renal tubular cells are known to be the critical mechanisms of the development and aggravation of CKD. We investigated the effect of IS on EMT and apoptosis in renal proximal tubular cells, NRK-52E cells. IS significantly inhibited cell proliferation and induced cell migration with a morphological transition from cuboidal epithelial cells to spindle-shaped scattered fibroblast-like cells. IS downregulated the expressions of zonula occluden-1 and E-cadherin, whereas upregulated alpha-SMA expression at 48 h, which was blocked by a pretreatment of the organic anion transporter, probenecid. IS also induced apoptosis of NRK cells from a concentration of 25 MUg/ml with an activation of ERK1/2 and p38 MAP kinase (MAPK). Pretreatment of ERK1/2 or p38 MAPK inhibitors, PD98059 or SB203580, resulted in no significant effect on IS-induced EMT, whereas it ameliorated IS-induced apoptosis of NRK cells. These findings suggested phenotypic transition and apoptosis as potential mechanisms of IS-induced renal damage and the differential role of MAPK activation in IS-induced EMT and apoptosis of renal tubular cells. PMID- 22231737 TI - Application of a partial-thickness human ex vivo skin culture model in cutaneous wound healing study. AB - A number of in vivo and ex vivo skin models have been applied to human wound healing studies. A reliable skin model, which recapitulates the features of human wound repair, is essential for the clinical and mechanical investigation of human cutaneous wound healing. Full-skin ex vivo culture systems have been used in wound healing studies. However, important structures of the skin, such as the differentiation of keratinocytes and epidermis-dermis junction, are poorly characterized in this model. This study aims to develop an optimized partial thickness human ex vivo skin culture (HESC) model to maintain human skin characteristics in vitro. During our culture, the basal layer, suprabasal layer, and stratum granulosum layer of epidermis were preserved until day 8. Analyses of hemidesmosome proteins, bullous pemphigoid antigen 1 (BP180) and 2 (BP230), showed that the integrity of the basement membrane of the epidermis was well preserved in the HESC model. In contrast, an organotypic culture with human keratinocytes and fibroblasts failed to show an integrated basement membrane. Maintenance of skin structure by histological analysis and proliferation of epidermal keratinocytes by Ki67 staining were observed in our model for 12 days. Complete re-epithelialization of the wounding area was observed at day 6 post wounding when a superficial incisional wound was created. The expression of Ki-67 and keratin 6, indicators of activated keratinocytes in epidermis, was significantly upregulated and new collagen synthesis was found in the dermis during the wound healing process. As control, we also used organotypic culture in studying the differentiation of the keratinocyte layers and incisional wound repair. It turned out that our model has advantage in these study fields. The results suggest that our HESC model retains important elements of in vivo skin and has significant advantages for the wound healing studies in vitro. PMID- 22231739 TI - Mapping of ghrelin gene expression and cell distribution in the stomach of morbidly obese patients--a possible guide for efficient sleeve gastrectomy construction. AB - BACKGROUND: Ghrelin is secreted mainly in the stomach and plays a role in food intake regulation. Morbidly obese (MO) individuals report a decline in appetite after sleeve gastrectomy (SG), presumably due, in part, to ghrelin cell removal. Ghrelin cell distribution and expression were determined in three areas of resected stomach specimens from MO patients subjected to SG. METHODS: Resected stomach specimens from 20 MO patients undergoing SG were analyzed. Real-time polymerase chain reaction of ghrelin mRNA and immunohistostaining for ghrelin cells in three stomach regions (fundus, body, and pre-antral areas) were performed. Body mass index (BMI) and total plasma ghrelin levels were obtained before and 3 months postoperatively. RESULTS: Ghrelin mRNA was detected throughout the stomach, its expression decreasing from the fundus towards the antrum. The relative quantification for ghrelin mRNA expression was 0.043, 0.026, and 0.015 at the fundus, body, and pre-antral region, respectively (P = 0.05, fundus vs. pre-antral region). Average ghrelin cell counts declined from 60 +/- 40 to 45 +/- 20 and 39 +/- 13 cells/high power fields in the fundus, body, and pre-antral region, respectively. Three months after surgery, total plasma ghrelin levels decreased from 1,676 +/- 470 to 1,179 +/- 188 pg/ml (P < 0.00001) and BMI dropped from 46 +/- 6 to 38 +/- 5 kg/m2 (P < 0.00001). CONCLUSIONS: Distribution and expression of ghrelin-secreting cells throughout the stomach were defined, emphasizing the importance of meticulous resection of the fundus during SG for maximal ghrelin cell removal. PMID- 22231740 TI - Prevalence of cytomegalovirus infection in steroid-refractory Crohn's disease. PMID- 22231738 TI - Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjogren's syndrome. AB - Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjogren's syndrome (SS)-associated SQM, we identified CD4(+) T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4(+) T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4(+) T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4(+) T cells. In the eye, IL 1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4(+) T-cell infiltration was only observed in the presence of IL 1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4(+) T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4(+) T cells, we observed SQM hallmarks in local tissues-corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4(+) T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study indicated a central role for IL-1 in orchestrating a functional interplay between immune cells and resident cells of SS-targeted tissues in the pathogenesis of SQM. PMID- 22231741 TI - Two types of assays for detecting frog sperm chemoattraction. AB - Sperm chemoattraction in invertebrates can be sufficiently robust that one can place a pipette containing the attractive peptide into a sperm suspension and microscopically visualize sperm accumulation around the pipette. Sperm chemoattraction in vertebrates such as frogs, rodents and humans is more difficult to detect and requires quantitative assays. Such assays are of two major types - assays that quantitate sperm movement to a source of chemoattractant, so-called sperm accumulation assays, and assays that actually track the swimming trajectories of individual sperm. Sperm accumulation assays are relatively rapid allowing tens or hundreds of assays to be done in a single day, thereby allowing dose response curves and time courses to be carried out relatively rapidly. These types of assays have been used extensively to characterize many well established chemoattraction systems - for example, neutrophil chemotaxis to bacterial peptides and sperm chemotaxis to follicular fluid. Sperm tracking assays can be more labor intensive but offer additional data on how chemoattractancts actually alter the swimming paths that sperm take. This type of assay is needed to demonstrate the orientation of sperm movement relative to the chemoattrractant gradient axis and to visualize characteristic turns or changes in orientation that bring the sperm closer to the egg. Here we describe methods used for each of these two types of assays. The sperm accumulation assay utilized is called a "two-chamber" assay. Amphibian sperm are placed in a tissue culture plate insert with a polycarbonate filter floor having 12 MUm diameter pores. Inserts with sperm are placed into tissue culture plate wells containing buffer and a chemoatttractant carefully pipetted into the bottom well where the floor meets the wall (see Fig. 1). After incubation, the top insert containing the sperm reservoir is carefully removed, and sperm in the bottom chamber that have passed through the membrane are removed, pelleted and then counted by hemocytometer or flow cytometer. The sperm tracking assay utilizes a Zigmond chamber originally developed for observing neutrophil chemotaxis and modified for observation of sperm by Giojalas and coworkers. The chamber consists of a thick glass slide into which two vertical troughs have been machined. These are separated by a 1 mm wide observation platform. After application of a cover glass, sperm are loaded into one trough, the chemoattractant agent into the other and movement of individual sperm visualized by video microscopy. Video footage is then analyzed using software to identify two-dimensional cell movements in the x-y plane as a function of time (xyt data sets) that form the trajectory of each sperm. PMID- 22231743 TI - Retraction Note to: Direct renin inhibition: clinical pharmacology. AB - Retraction to: J Mol Med 86(6): 647-54DOI 10.1007/s00109-008-0329-z. The Editors of the Journal of Molecular Medicine in agreement with the author and the publisher hereby retract this article. The article is retracted due to copyright issues that cannot be resolved. PMID- 22231742 TI - IL-17 producing T cells in mouse models of multiple sclerosis and rheumatoid arthritis. AB - Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) are amongst the most common autoimmune diseases in the northern hemisphere. There is mounting evidence that in both afflictions, not only environmental and genetic factors influence disease, but cellular components such as autoreactive T cells also contribute to pathology. Animal models are key in the study and subsequent therapeutic development for human autoimmune diseases. As patient material is often difficult to obtain and in some cases--as in MS, where the central nervous system (CNS) is concerned--even not accessible, animal models provide a multifaceted tool to explore disease-underlying mechanisms. The pro-inflammatory T cell cytokine IL-17 has recently moved to center stage due to its crucial role in autoimmune diseases including MS and RA. A plethora of studies in animal models has sustained the relevance of this cytokine pathway for the development of autoimmunity and shed light on its cellular sources and patho-mechanisms. This review addresses the role of IL-17 producing T lymphocytes, in particular CD4(+) and gammadelta T cells, in three commonly used mouse models for MS and RA, namely experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and antigen induced arthritis (AIA). Comparing and combining knowledge gained from different animal models will broaden our understanding of the IL-17 biology and facilitate the translation to the human diseases. PMID- 22231744 TI - Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. AB - Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b+ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 alpha-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor. PMID- 22231745 TI - Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. AB - Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARgamma-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms. PMID- 22231747 TI - Nerve growth factor receptor expression in lymphocytes: comment on the article by Raychaudhuri et al. PMID- 22231746 TI - A new, powerful player in lipoprotein metabolism: brown adipose tissue. AB - Important causes for modern epidemics such as obesity, diabetes, and cardiovascular disease are over- and malnutrition. Dietary as well as endogenous lipids are transported through the bloodstream in lipoproteins, and disturbances in lipoprotein metabolism are associated with atherosclerosis, heart disease, and diabetes. Recent findings reveal biological principles-how lipoproteins, in particular triglyceride-rich lipoproteins, are metabolized and what factors regulate their processing. The fate of triglycerides delivered by lipoproteins is quite simple: either they can be stored or they can be utilized for combustion or biosynthetic pathways. In the healthy state, fatty acids derived from triglycerides can be burned in the heart, muscle, and other organs for actual work load, or they can be stored in white adipose tissue. The combination of storage and combustion is realized in brown adipose tissue (BAT), a peripheral organ that was long thought to be only of relevance in small mammals: Recent data however prove that BAT plays an important role in human adults. Here, we will review recent insights on how BAT controls triglyceride clearance and the possible implications for the treatment of chronic diseases caused by lipid mishandling. PMID- 22231748 TI - [Postoperative vaginal brachytherapy in endometrial cancer]. AB - Several randomized studies published in recent years have greatly changed the management of postoperative endometrial cancer, especially for lesions of intermediate prognosis. Vaginal brachytherapy is now standard treatment for these lesions at the expense of external beam radiation, which, despite an improvement in locoregional control, has no impact on overall survival. This review aims to take stock of new indications for vaginal brachytherapy detailing the trials that led to change standards or care. PMID- 22231749 TI - Eculizumab treatment of paroxysmal nocturnal hemoglobinuria presenting as moyamoya syndrome in a 9-year-old male. PMID- 22231751 TI - Breast cancer: Fast, positive data from neosphere. PMID- 22231753 TI - Equipoise: asking the right questions for clinical trial design. AB - Randomized controlled trials (RCTs) are central to evidence-based clinical and health-policy decisions. However, RCTs highlight the tension between the therapeutic obligations of the physician and the scientific obligations of the investigator. Clinical equipoise, defined as honest professional disagreement among expert clinicians about the preferred treatment, is often cited as the solution to this RCT dilemma. Nevertheless, there are numerous practical and conceptual problems with the notion of equipoise. These problems include its mistaken imposition of therapeutic norms on the scientific enterprise of research, the difficulty of knowing when a state of equipoise exists, the susceptibility of expert judgment to bias and weak evidence, and its inability to support evidence necessary for health-policy decisions. An alternate approach to risk-benefit assessment that is congruent with the scientific purpose of RCTs can better guide ethical evaluation of these trials, as discussed in this Perspective. PMID- 22231754 TI - Hematological cancer in 2011: New therapeutic targets and treatment strategies. AB - 2011 saw improvements in our understanding of B-cell malignancies: insights into the genomic basis of chronic lymphocytic leukemia were achieved; reduced treatment intensity caused fewer toxic effects in early-stage Hodgkin lymphoma; first-line rituximab maintenance therapy improved outcome in follicular lymphoma; and selected patients with diffuse large-cell lymphoma benefited from the addition of bortezomib. PMID- 22231756 TI - Gastrointestinal cancer: Not all CRC subtypes are created equal. PMID- 22231757 TI - Urological cancer: Heart facts rehabilitate ADT. PMID- 22231759 TI - Denosumab in patients with cancer-a surgical strike against the osteoclast. AB - Elucidation of the molecular pathways underlying bone turnover has revealed potential therapeutic targets, including receptor activator of nuclear factor kappaB ligand (RANKL), which is a mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKL. This agent has been developed for use in patients with early stage and advanced-stage cancer, as well as for the treatment of osteoporosis, and can prevent bone loss and reduce fragility fractures in both types of disease. In the bone metastasis setting, several large phase III studies have shown that denosumab is more effective than bisphosphonates, namely zoledronic acid, in reducing skeletal morbidity arising from a wide range of tumors. In addition, a remarkable activity of denosumab has been demonstrated in giant-cell tumors of the bone. Subsequent studies of denosumab have demonstrated that it can delay bone metastasis in patients with castration-resistant prostate cancer; adjuvant studies in patients with breast cancer are in progress. This Review critically explores the emerging role of denosumab in maintaining bone health in the oncology setting, and discusses the factors that are likely to influence the choice between bisphosphonates and denosumab in clinical practice. PMID- 22231760 TI - Prostate cancer in 2011: Hitting old targets better and identifying new targets. AB - Options to treat late-stage castration-resistant prostate cancer continued to increase in 2011, as three agents with different mechanisms of action prolonged life and a fourth reduced the morbidity of skeletal metastases. These outcomes contrasted with the heightened controversy generated by the recommendation against PSA screening and other early detection strategies. PMID- 22231761 TI - Genetics: United colors of glioblastoma. PMID- 22231762 TI - Melanoma in 2011: a new paradigm tumor for drug development. AB - Melanoma has emerged as the paradigm tumor for drug development through mutation targeted therapies (inhibitors targeting BRAF, MEK, and c-KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will require scientific rationale and the cooperation of the pharmaceutical industry. But, with these challenges comes another opportunity to change the paradigms in drug development. PMID- 22231764 TI - Patient satisfaction and postoperative pain with different postoperative therapy regimens after standardized cataract surgery: a randomized intraindividual comparison. AB - The purpose of this study was to evaluate if administration of artificial tears of high or low-viscosity improve cataract patients' satisfaction and postoperative pain after cataract surgery. Thirty consecutive patients undergoing bilateral cataract surgery under topical anesthesia were enrolled prospectively. Administration of the following postoperative therapies was randomized: for all participants, one eye was treated with "instant vision" (IV) therapy alone (IV alone), i.e., this eye remained uncovered. In group 1 (n = 11), the second eye received IV therapy with Hylo-Comod((r)) (HC) eye drops; in group 2 (n = 9), IV with Vidisic((r)) (VS) eye drops; in group 3 (n = 10), an ointment bandage (OB). Postoperative satisfaction, pain scores, visual acuity, intraocular pressure, tear break-up time and postoperative corneal changes were compared. Group 1: No clear preference was observed for any of the methods concerning subjective satisfaction. Group 2: 100% of patients preferred IV + VS therapy. Group 3: Patients' postoperative satisfaction with OB therapy was 89%. Concerning postoperative pain perception, no significant differences were found between IV therapy alone and the IV-combination therapies. Significant differences in pain perception (P < 0.042) were measured between IV and OB in the first 8 h postoperatively. Ten hours postoperatively and beyond, there were no significant differences in pain scores (P > 0.05). Pain perception was significantly lower with OB when compared to IV-alone or IV-combination therapies using artificial tears. This result was verified by OB's 89% patient satisfaction level. Low viscosity artificial tears showed no significant subjective benefits for the patients; patient satisfaction was greatest (100%) with a high-viscosity tear substitute. PMID- 22231763 TI - When parents disclose BRCA1/2 test results: their communication and perceptions of offspring response. AB - BACKGROUND: BRCA1/2 testing is not recommended for children, as risk reduction measures and screening are not generally recommended before 25 years old (YO). Little is known about the prevalence and predictors of parent communication to offspring and how offspring respond to this communication. METHODS: Semi structured interviews were conducted with parents who had BRCA1/2 testing and at least 1 child <25 YO. Logistic regressions were utilized to evaluate associations with communication. Framework analysis was utilized to analyze open-ended responses. RESULTS: A total of 253 parents completed interviews (61% response rate), reporting on 505 offspring. Twenty-nine percent of parents were BRCA1/2 mutation carriers. Three hundred thirty-four (66%) offspring learned of their parent's test result. Older offspring age (P <= .01), offspring gender (female, P = .05), parents' negative test result (P = .03), and parents' education (high school only, P = .02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). Thirteen percent of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent's BRCA1/2 positive or variant of uncertain significance result. CONCLUSIONS: Many parents communicate their BRCA1/2 test results to young offspring. Parents' perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk life span. PMID- 22231766 TI - Kearns Sayre Syndrome--case report with review of literature. AB - Kearns-Sayre Syndrome is form of rare mitochondrial cytopathy, first described by Thomas P. Kearns and George Pomeroy Sayre in 1958 and is characterized by progressive external opthalmoplegia, cardiac conduction block, pigmentary retinal degeneration, variable number of red ragged fibers on muscle biopsy. It presents before the child reaches the age of twenty. Kearns-Sayre syndrome may affect many organ systems and additional features may include myopathy, dystonia, bulbar symptoms in the form of dysarthria and nasal regurgitation and bilateral facial weakness. Endocrine abnormalities (e.g., diabetes, growth retardation/short stature, and hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis, skeletal muscle weakness (proximal more than distal) and exercise intolerance are additional features. Kearns Sayre Syndrome occurs as a result of large-scale single deletions (or rearrangements) of mitochondrial DNA (mtDNA), which is usually not inherited but occurs spontaneously, probably at the germ-cell level or very early in embryonic development. No disease-modifying therapy is available for Kearns-Sayre syndrome (KSS). Management is supportive vigilance for detection of associated problems. In the future, potential treatment in patients with Kearns-Sayre syndrome may attempt to inhibit mutant mtDNA replication or encourage replication of wild-type mtDNA. PMID- 22231767 TI - Need of excluding immunodeficiency and related challenges in management of a child with acute lymphoblastic leukemia. PMID- 22231768 TI - Umbilical signs of peritoneal tuberculosis in children. AB - OBJECTIVES: To report the observation of involvement of the umbilicus with alteration of its morphology in association with peritoneal tuberculosis. METHODS: This is a retrospective observational case series of abdominal tuberculosis (ATB) in children, treated in the department of pediatric surgery of a tertiary-care children's hospital in the period from January 2004 through April 2010. RESULTS: Out of a total of 38 cases of ATB in children, 22(57.9%) were of the peritoneal type, 14(36.8%) were of the intestinal type, and 2(5.3%) involved the mesenteric lymph nodes. Of the patients manifesting with peritoneal tuberculosis, 11 cases (50%) had involvement of the umbilicus with changes in the umbilical shape and appearance. In seven cases the umbilicus was found retracted and transversely oriented (a slit-like "smiling" appearance) with loss of the umbilical hollow. In two cases there was puckering of the umbilicus. Other findings included umbilical erythema with inflammation in one patient and a fecal fistula at the umbilicus in another patient. While seven cases responded to treatment with antituberculous therapy (ATT), four cases underwent surgery (two laparotomy and two laparoscopy). Findings were similar in all four patients, consisting of adhered dilated bowel loops studded with tubercles which also covered the parietal peritoneum and the falciform ligament. All four cases responded to postoperative ATT. CONCLUSIONS: Morphological changes of the umbilicus can provide an additional clue to the diagnosis of peritoneal tuberculosis in children. PMID- 22231769 TI - Response letter to the article: recurrent femur neck fracture and response to bisphosphonates in polyostotic fibrous dysplasia: a novel molecular mechanism. PMID- 22231770 TI - Left ventricular failure due to a rare variant of congenital adrenal hyperplasia. AB - "Hypertensive" variant of congenital adrenal hyperplasia is rare. The authors describe an interesting case of a 6-y-old boy who presented with an acute respiratory illness and progressive breathlessness since 1 y. Genital hyperpigmentation was noticed since 2 y of age; the onset of pubarche and increasing penile size at 4 y. He was admitted in congestive cardiac failure with a blood pressure of 150/100 mm Hg. Facial acne; slight facial, pubic hair and penile enlargement were additionally noted. Chest radiograph revealed cardiomegaly. Basal ACTH and 17-OHP levels were high. A diagnosis of congenital adrenal hyperplasia (11beta-hydroxylase deficiency) was made due to hypertension with virilized genitalia. Cardiac failure was controlled with fluid restriction and diuretics; he was started on prednisolone, spironolactone and nifedipine. This case is presented for its rarity where hypertension can cause complication of cardiac failure, if diagnosis is delayed despite early features of pseudoprecocious puberty. PMID- 22231771 TI - Visceral fat assessment in over nourished children by ultrasonography and its relation to anthropometry. AB - OBJECTIVE: To measure visceral fat (VF) in over nourished children (6-15 y) by ultrasonography (USG) and to find relation between anthropometric measurements (AM) and VF in these children. This case series included 113 children of 6-15 y with Body Mass Index (BMI) >85th centile who attended the nutrition clinic of a tertiary care centre in rural Kerala from January 2009 through June 2010. METHODS: After recording the base line demographic parameters and anthropometric measurements, VF was assessed by USG. Relation between VF and anthropometric measurements were assessed by correlation. Measurements which showed significant positive correlation were further analyzed by linear regression. RESULTS: The mean total VF was 145.63 (SD = 25.37) mm. Total VF increased with age. Significant positive correlation was found for weight, height, BMI, hip circumference (HC) and waist circumferences (WC). WC showed maximum correlation. The best predictor of VF was WC. CONCLUSIONS: The total VF in over nourished children increases with age. Even though the most important predictor of visceral fat is WC, it has a low predictive power. PMID- 22231772 TI - Management of a massive pediatric cerebral infarct with mass effect. AB - A preschool child presented with a large middle cerebral artery (MCA) infarct with midline shift, overt signs of raised intracranial pressure and hemodynamic instability. Aggressive management including ventilatory support was instrumental in the successful outcome. Raising awareness of pediatric stroke is crucial to improving overall care of these children. PMID- 22231773 TI - First case report of Moraxella osloensis diarrhea in a hemolytic uremic syndrome/acute renal failure child from rural coastal India-Manipal, Karnataka. AB - The authors report a rare case of diarrhea caused by Moraxella osloensis in a pediatric child with Hemolytic Uremic Syndrome/Acute Renal Failure (HUS/ARF). A 6 y-old boy was referred to the Pediatric Unit with a 3 d history of bloody diarrhea with mucus and fever and decreased urine output for 6 d. Microbiological investigations were done as per CLSI guidelines. His diarrhea, and the subsequent renal failure resolved with appropriate treatment. To the best of authors' knowledge and pubmed search, this is the first case of M. osloensis causing diarrhea in a HUS/ARF pediatric patient reported from India-Manipal. PMID- 22231774 TI - The efficacy of hypothermia in hypoxic-ischemic encephalopathy at 18 mo or more. AB - OBJECTIVE: To evaluate the efficacy of hypothermia in the treatment of hypoxic ischemic encephalopathy (HIE) in neonates at 18 mo of age or more. Also to examine whether the severity of encephalopathy affects the efficacy of hypothermia on mortality and neurodevelopmental disability. METHODS: The authors recruited the trials that assessed the efficacy of therapeutic hypothermia in the treatment of HIE in neonates at 18 mo of age or older up to April 2011. The meta- analysis was performed using a fixed effect model. RESULTS: Hypothermia significantly reduced the combined rate of death or neurodevelopmental disability (RR = 0.74, 95% CI: 0.67 to 0.82; RD = -0.13, 95% CI: -0.18 to -0.08; NNT = 7, 95% CI: 6 to 9) among infants at 18 mo of age or older. Hypothermia reduced the rate of death (RR = 0.75, 95% CI: 0.64 to 0.88), neurodevelopmental disability (RR = 0.65, 95% CI: 0.54 to 0.79), cerebral palsy (RR = 0.65, 95% CI: 0.53 to 0.80), developmental delay (RR = 0.72, 95% CI: 0.57 to 0.92), neuromotor delay (RR = 0.78, 95% CI: 0.61 to 0.99) and visual deficit (RR = 0.59, 95% CI: 0.36 to 0.99). Analysis of the severity of disease showed that hypothermia reduced the combined rate of death or neurodevelopmental disability not only in moderate encephalopathy infants (RR = 0.63, 95% CI: 0.53 to 0.76) but also in severe encephalopathy infants (RR = 0.82, 95% CI: 0.74 to 0.92). CONCLUSIONS: Hypothermia has a beneficial effect in the treatment of HIE in neonates at 18 mo of age or older. PMID- 22231776 TI - Kuppuswamy's socioeconomic status scale--revision for 2011 and formula for real time updating. PMID- 22231775 TI - Unusual association of epidemic dropsy with brachial neuritis and palatal palsy. AB - Epidemic dropsy (ED) results from accidental ingestion of adulterated mustard oil with argemone oil. Chief organs involved in this disease are heart, subcutaneous tissue, eyes and kidneys. Nervous system involvement is very rare. Objective manifestation of neurological involvement is even rarer. The authors report two cases from the same family, who were victims of epidemic dropsy along with their parents. One of them showed objective neurologic involvement in the form of brachial neuritis and another showed palatal palsy. PMID- 22231777 TI - Survival and complications following gamma knife radiosurgery or enucleation for ocular melanoma: a 20-year experience. AB - BACKGROUND: We present our experience in treating ocular melanoma at the National Centre for Stereotactic Radiosurgery in Sheffield, UK over the last 20 years. METHOD: We analysed 170 patients treated with Gamma Knife radiosurgery, recorded the evolution of visual acuity and complication rates, and compared their survival with 620 patients treated with eye enucleation. Different peripheral doses (using the 50% therapeutic isodose) were employed: 50-70 Gy for 24 patients, 45 Gy for 71 patients, 35 Gy for 62 patients. FINDINGS: There was no significant difference in survival between the 35-Gy, 45-Gy and 50- to 70-Gy groups when compared between themselves (p = 0.168) and with the enucleation group (p = 0.454). The 5-year survival rates were: 64% for 35 Gy, 62.71% for 45 Gy, 63.6% for 50-70 Gy and 65.2% for enucleated patients. Clinical variables influencing survival for radiosurgery patients were tumour volume (p = 0.014) and location (median 66.4 vs 37.36 months for juxtapapillary vs peripheral tumours, respectively; p = 0.001), while age and gender did not prove significant. Regarding complications, using 35 Gy led to more than a 50% decrease, when compared with the 45-Gy dose, in the incidence of cataract, glaucoma and retinal detachment. Retinopathy, optic neuropathy and vitreous haemorrhage were not significantly influenced. Blindness decreased dramatically from 83.7% for 45 Gy to 31.4% for 35 Gy (p = 0.006), as well as post-radiosurgery enucleation: 23.9% for 45 Gy vs 6.45% for 35 Gy (p = 0.018). Visual acuity, recorded up to 5 years post-radiosurgery, was significantly better preserved for 35 Gy than for 45 Gy (p = 0.0003). CONCLUSIONS: Using 35 Gy led to a dramatic decrease in complications, vision loss and salvage enucleation, while not compromising patient survival. PMID- 22231778 TI - Side-to-side neurorrhaphy for high-level peripheral nerve injuries. AB - BACKGROUND: The results of peripheral nerve repair, especially for high-level peripheral nerve injuries, have been unsatisfactory. The method of side-to-side neurorrhaphy was developed in our laboratory from 1994 to 2002. This method involves suturing the injured nerve to a nearby donor nerve in a side-to-side manner. This study was performed to assess the clinical results of side-to-side neurorrhaphy in patients with high-level peripheral nerve injuries. METHODS: Twenty-five patients with various types of high-level peripheral nerve injuries who underwent side-to-side neurorrhaphy were studied. The British Medical Research Council (BMRC) scale was used to assess recovery of nerve function. RESULTS: Average follow-up duration was 3.2 years. Before surgery the patients had a nerve function of M0/S0 to M1/S1. After side-to-side neurorrhaphy, 7 patients had a score of M3/S4, 8 patients a score of M3/S3 and 10 patients a score of M2/S3. The total useful recovery rate (BMRC grade >=3) was 60% for motor function and 100% for sensory function. Side-to-side neurorrhaphy did not result in any significant loss of donor nerve function. There was significant correlation between both the type of injury and the time interval between injury and surgery and motor nerve function. Age, gender and location of the injured nerve did not correlate with sensory or motor nerve function. CONCLUSION: Side-to side neurorrhaphy appears to be promising as a feasible method for repair of high level peripheral nerve injuries. PMID- 22231779 TI - Extended transsphenoidal approach for tuberculum sellae meningioma--what are the optimum and critical indications? AB - BACKGROUND: Recent advances in minimally invasive surgery have allowed extended transsphenoidal approaches to treat large and complex lesions beyond the sella turcica including basal meningiomas, but the inclusion criteria and limitations of this approach remain unclear. METHODS: Retrospective review of 19 consecutive patients (5 males and 14 females aged from 43 to 79 years) with tuberculum sellae meningioma with a maximum diameter of less than 30 mm surgically treated between December 2006 and August 2011 by a single surgeon. Operative outcomes and limitation-based indications were investigated. FINDINGS: Total removal was achieved in 15 cases including Simpson's grade 1 in 2 cases (78.9%). All tumor remnants were located in the lateral portion of the internal carotid artery (ICA), as indicated by preoperative magnetic resonance (MR) imaging. Additional oblique imaging along the longitudinal axis of the C1-2 portion of the ICA revealed a paradoxical presence of tumor in between both sides of the ICA in some patients, even in the case with lateral extension over the ICA on coronal MR imaging. Total removal could be achieved in these patients, and after the introduction of additional preoperative oblique MR imaging, total removal was achieved in all patients. Visual outcomes of eyes showed improvement in 23, remained steady in 11, and showed deterioration in 4, and 89.5% eyes recovered to a good state. Deterioration was caused by injury of a small vein in one patient and previous disruption of the arachnoidal sheath in the remaining three. One patient suffered cerebrospinal fluid leakage and required re-operation. None of the patients developed endocrinological deficits or required prolonged hormonal supplementation. CONCLUSIONS: The extended transsphenoidal approach has equivalent potential to transcranial surgery for tuberculum sellae meningiomas with a maximum diameter of less than 30 mm. The tumors with lateral extension over the ICA have fewer chances of total removal. ICA-oriented simulation and surgical planning are important. PMID- 22231780 TI - On the calculation of the structure of charge-stabilized colloidal dispersions using density-dependent potentials. AB - The structure of charge-stabilized colloidal dispersions has been studied through a one-component model using a Yukawa potential with density-dependent parameters examined with integral equation theory and Monte Carlo simulations. Partial thermodynamic consistency was guaranteed by considering the osmotic pressure of the dispersion from the approximate mean-field renormalized jellium and Poisson Boltzmann cell models. The colloidal structures could be accurately described by the Ornstein-Zernike equation with the Rogers-Young closure by using the osmotic pressure from the renormalized jellium model. Although we explicitly show that the correct effective pair-potential obtained from the inverse Monte Carlo method deviates from the Yukawa shape, the osmotic pressure constraint allows us to have a good description of the colloidal structure without losing information on the system thermodynamics. Our findings are corroborated by primitive model simulations of salt-free colloidal dispersions. PMID- 22231781 TI - Regional ventilation mapping of the rat lung using hyperpolarized 129Xe magnetic resonance imaging. AB - Lung ventilation was mapped in seven healthy male Sprague-Dawley rats (433 +/- 24 g) using hyperpolarized 129Xe magnetic resonance imaging (MRI) at 3.0 T, and validated with hyperpolarized 3He MRI under similar ventilator conditions. Ventilation maps were obtained using flip angle variation for offset of RF and relaxation (FAVOR) which is a multiple breath imaging technique that extracts the fractional ventilation parameter, r, on a pixel-by-pixel basis from the dynamic signal enhancement. r is defined as the fractional refreshment of gas per breath. Under the ventilator conditions used in this work, whole-lung measurements of fractional ventilation obtained using hyperpolarized 129Xe were not significantly different from those obtained using hyperpolarized 3He (p = 0.8125 by a Wilcoxon matched pairs test). Fractional ventilation gradients calculated in the superior/inferior (S/I) and anterior/posterior (A/P) directions obtained using hyperpolarized 129Xe were not significantly different from those obtained using hyperpolarized 3He (p = 0.9375 and p = 0.1563, for the S/I and A/P directions, respectively). Following baseline fractional ventilation measurements, one representative rat was challenged with methacholine and fractional ventilation measurements were performed over a time course of 10 min. A reduction and subsequent recovery in whole-lung r values were detected using the FAVOR method. PMID- 22231782 TI - Blind detection of vascular sources and territories using random vessel encoded arterial spin labeling. AB - OBJECT: The goal of this work is to use vessel encoded arterial spin labeling (VEASL) methods to detect feeding arteries without prior knowledge of their positions, and map the vascular territory of each. MATERIALS AND METHODS: Five healthy subjects were scanned, each with four different tagging planes. The VEASL tagging method was modified to use 60 different pairs of encoding steps with random orientation and spacing. A signal model was developed to calculate the theoretical ASL signal resulting from a vessel in any position in the tagging plane. For each voxel, the location of the feeding vessel was estimated by finding the theoretical signal that correlates most closely with the data. RESULTS: The main intracranial arteries, including carotid, vertebral, basilar, and cerebral arteries above the Circle of Willis were identified and localized from the ASL data in all subjects. In addition, external carotid branches were detected in all subjects. CONCLUSIONS: Randomly encoded VEASL provides data that allows for blind detection of source vessels. This method simplifies the VEASL prescription process and allows for efficient detection of atypical or collateral circulation. PMID- 22231783 TI - Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes. AB - Little is known about the effects of altering sphingolipid (SL) acyl chain structure and composition on the biophysical properties of biological membranes. We explored the biophysical consequences of depleting very long acyl chain (VLC) SLs in membranes prepared from lipid fractions isolated from a ceramide synthase 2 (CerS2)-null mouse, which is unable to synthesize C22-C24 ceramides. We demonstrate that ablation of CerS2 has different effects on liver and brain, causing a significant alteration in the fluidity of the membrane and affecting the type and/or extent of the phases present in the membrane. These changes are a consequence of the depletion of VLC and unsaturated SLs, which occurs to a different extent in liver and brain. In addition, ablation of CerS2 causes changes in intrinsic membrane curvature, leading to strong morphological alterations that promote vesicle adhesion, membrane fusion, and tubule formation. Together, these results show that depletion of VLC-SLs strongly affects membrane biophysical properties, which may compromise cellular processes that critically depend on membrane structure, such as trafficking and sorting. PMID- 22231785 TI - Risk prediction of cardiovascular surgery in Japanese patients. PMID- 22231784 TI - Liver Patt1 deficiency protects male mice from age-associated but not high-fat diet-induced hepatic steatosis. AB - Patt1 is a newly identified protein acetyltransferase that is highly expressed in liver. However, the role of Patt1 in liver is still unclear. We generated Patt1 liver-specific knockout (LKO) mice and mainly measured the effect of hepatic Patt1 deficiency on lipid metabolism. Hepatic Patt1 deficiency in male mice markedly decreases fat mass and dramatically alleviates age-associated accumulation of lipid droplets in liver. Moreover, hepatic Patt1 abrogation in male mice significantly reduces the liver triglyceride and free fatty acid levels, but it has no effect on liver cholesterol level, liver weight, and liver function. Consistently, primary cultured Patt1-deficient hepatocytes are resistant to palmitic acid-induced lipid accumulation, but hepatic Patt1 deficiency fails to protect male mice from high-fat diet-induced hepatic steatosis. Further studies show that hepatic Patt1 deficiency decreases fatty acid uptake, reduces lipid synthesis, and enhances fatty acid oxidation, which may contribute to the attenuated hepatic steatosis in Patt1 LKO mice. These results demonstrate that Patt1 plays an important role in hepatic lipid metabolism and have implications toward resolving age-associated hepatic steatosis. PMID- 22231786 TI - Validation of the JapanSCORE versus the logistic EuroSCORE for predicting operative mortality of cardiovascular surgery in Yamaguchi University Hospital. AB - PURPOSE: Recent studies have shown that the European System for Cardiac Operative Risk Evaluation (Euro-SCORE) is a reliable risk model in cardiac surgery. In Japan, the JapanSCORE has been devised as the Japanese original risk model for cardiovascular surgery. We evaluated the validity of the JapanSCORE, especially in comparison with the logistic EuroSCORE METHODS: We calculated the predicted mortality according to two risk models for 523 consecutive patients who underwent cardiovascular surgery within a 6-year period (July 2003 to June 2009) at Yamaguchi University Hospital. We assessed the scores' validity by calculating the area under the receiver operating characteristics curve (C-index) and by the chi-squared test or Fisher's exact test. RESULTS: The C-indexes were 0.688 with the logistic EuroSCORE and 0.770 with the JapanSCORE (P = 0.053). Although the difference was not significant, the JapanSCORE tended to be more accurate. The C indexes limited to isolated coronary artery bypass grafting (CABG) were 0.564 with the logistic EuroSCORE and 0.790 with the JapanSCORE (P = 0.001). The Japan SCORE was significantly more valid than the logistic EuroSCORE for isolated CABG. The actual mortality was 4.0%; the mean predictive mortality was 5.6% with the JapanSCORE and 15.1% with the logistic Euro-SCORE. The mortality predicted by the JapanSCORE was closer to the observed mortality. There was a significant difference between the observed mortality and the logistic EuroSCORE (P < 0.0001). CONCLUSION: The JapanSCORE seems to be a more reliable risk model than the logistic EuroSCORE for patients undergoing cardiac or thoracic aortic surgery at Yamaguchi University Hospital. PMID- 22231787 TI - Prognostic implication of lymphatic vessel invasion in stage IB (pT2aN0M0) non small cell lung cancer. AB - PURPOSE: To clarify the prognostic factors for recently revised stage IB non small cell lung cancer. METHODS: Twenty-six specimens of completely resected stage IB (pT2aN0M0) non-small cell lung cancer were studied. Clinicopathological profiles of the 26 patients, including age, sex, smoking status, tumor size, histology, pleural invasion, and lymphatic and blood vessel invasion, were assessed. Correlation between tumor recurrence and these factors was assessed by statistical analysis. RESULTS: Lymphatic vessel invasion was the only statistically significant factor for postoperative tumor recurrence as assessed by multivariate analysis. Kaplan-Meier survival curves showed a 5-year recurrence free rate of 77.8% in 26 patients with no lymphatic vessel invasion compared with 28.6% in those with lymphatic vessel invasion. CONCLUSION: Lymphatic vessel invasion of cancer cells was indicated as an independent prognostic factor in revised stage IB non-small cell lung cancer. PMID- 22231788 TI - Successful surgical treatment of intravascular ultrasonography catheter entrapment. AB - Coronary angiography (CAG) was performed in a 77-year-old woman who presented with chest discomfort. The CAG showed two diseased vessels. For treatment, the patient underwent angioplasty and stenting. During intravascular ultrasonography (IVUS) following stent deployment, the IVUS catheter became entrapped in the left anterior descending coronary artery, causing ischemic changes in the anterolateral wall, which were apparent on the electrocardiogram. The patient underwent emergency coronary artery bypass grafting and removal of the entrapped IVUS catheter. PMID- 22231789 TI - Floating thrombus originating from an almost normal thoracic aorta. AB - We present a case of floating thrombus originating from an almost normal thoracic aorta in a 54-year-old man who presented with acute arterial occlusion of his left leg. Transesophageal echocardiography (TEE), computed tomography, and magnetic resonance imaging showed two masses in an almost normal aorta after embolectomy for the acute arterial occlusion. Although the embolus was thrombus histologically, malignant tumors could not be ruled out. The masses did not decrease in size after 7 days of anticoagulant therapy, so they were extirpated under cardiopulmonary bypass (CPB) and TEE guidance. Frozen section examination during CPB indicated that there was no evidence of malignancy in the removed mass. TEE played an important role in the diagnosis and surgery of this condition, and it was useful when deciding on a surgical strategy. Because the treatment strategy for this disease remains controversial, further studies are needed. PMID- 22231790 TI - Successful treatment of lung adenocarcinoma in an 18-year-old man. AB - Primary lung cancer is an extremely rare neoplasm in young adults. We report a case of a primary lung adenocarcinoma in an 18-year-old man who presented for examination of a solitary nodule located in the right lower lobe of the lung. A right lower lobectomy was performed with an incomplete resection because of pleural dissemination (pT4N2M0 stage IIIB adenocarcinoma). Intrathoracic chemotherapy (cisplatin, 50 mg/body) was administered initially, followed by systemic chemotherapy (carboplatin + paclitaxel). A bronchopleural fistula occurred 2 months postoperatively and was successfully treated with conservative therapy, including thoracic drainage, intrathoracic fibrin glue administration, and transbronchial superglue administration. Thereafter, a total of five courses of systemic chemotherapy with minor changes in the administration regimen were performed. The patient was alive and with no evidence of recurrence at his 5-year follow-up. PMID- 22231791 TI - Thoracoscopic resection of a mesenchymal cystic hamartoma of the lung. AB - Mesenchymal cystic hamartomas are uncommon tumors originating from nodules of primitive mesenchymal cells, and their occurrence in the lung is extremely rare. We present a case of surgically resected mesenchymal cystic hamartoma of the lung in a 49-year old woman who presented without any symptoms. Chest computed tomography showed a solitary cystic lesion in the right lower lobe. The patient underwent preoperative marking by 0.2 ml lipiodol 4 days before surgery. Thoracoscopic partial resection of the right lower lobe was performed. The histological picture and immunohistochemical profile were compatible with this tumor. PMID- 22231792 TI - A case of an elderly patient treated for descending necrotizing mediastinitis. AB - We report a case of descending necrotizing mediastinitis (DNM). DNM is a serious infection, and preventing death requires early diagnosis and draining of the infection focus. An 84-year-old man was admitted to our hospital complaining of a swollen neck and pain when swallowing. He had had a tooth extracted at a neighboring dental clinic 2 days previously. Cervicothoracic computed tomography (CT) scan demonstrated gas bubbles and unencapsulated abscesses in the cervical spaces and anterosuperior and posterior mediastinum, extending below the carina. He was diagnosed as DNM caused by odontogenic infection. Cervical drainage was performed, in addition to mediastinal drainage using video-assisted thoracic surgery (VATS). Complications were sepsis, disseminated intravascular coagulation (DIC), and heart failure after surgery, but he recovered following intensive care. This was a lifesaving case of DNM for which mediastinal drainage was performed with VATS. PMID- 22231793 TI - Successfully treated postbronchoplasty bronchial stenosis using short-interval repeated endobronchial balloon dilation. AB - A 63-year-old man with a history of lung cancer underwent lobectomy of the right upper lobe and bronchoplasty. At the 2-month follow-up, bronchial stenosis due to a granuloma was observed. Endoscopic debridement and balloon dilation were performed. At 1 month after the dilation, atelectasis occurred owing to cicatricial stenosis. We repeated balloon dilation, but the patient suffered from cicatricial restenosis. After a failed stent placement, balloon dilation was then performed every 2 weeks under local anesthesia; the stenosis was resolved after performing dilation 7 times. Short-term repeated balloon dilation was effective in this case. PMID- 22231794 TI - Combined subsegmentectomy for S(2)(b) (horizontal subsegment of the posterior segment) and S(3)(a) (lateral subsegment of the anterior segment) in the right upper pulmonary lobe. AB - A technique for combined resection of S(2)(b) (horizontal subsegment of the posterior segment) and S(3)(a) (lateral subsegment of the anterior segment) of the right upper lobe of the lung is presented. Although both the S(2)(b) and S(3)(a) should be resected from the interlobar fissure, an approach for the artery and bronchus of S(3)(a) (A(3)(a) and B(3)(a), respectively) is easier from the ventral side of the hilum rather than from the interlobar fissure, because B(3) runs in back of V(2) at the interlobar fissure. To resolve this contradiction, we devised a procedure as follows: (1) A(2)(b) and B(2)(b) are cut at the interlobar fissure; (2) A(3)(a) and B(3)(a) are cut from the ventral side of hilum; (3) the peripheral stumps of A(3)(a) and B(3)(a) are transferred to the interlobar fissure; and (4) subsegments of S(3)(a) and S(2)(b) are resected with the peripheral stumps of A(2)(b), B(2)(b), A(3)(a), and B(3)(a) from the side of the interlobar fissure. We believe this procedure makes the combined resection of S(2)(b) and S(3)(a) easy. PMID- 22231795 TI - Thoracic and cardiovascular surgery in Japan during 2009: annual report by the Japanese Association for Thoracic Surgery. PMID- 22231796 TI - Delayed hypersensitivity reaction with infliximab: unusual to occur after initial dose. PMID- 22231797 TI - Evaluation of overall tumor cellularity after neoadjuvant chemotherapy in patient with locally advanced hypopharyngeal cancer. AB - The aim of this study is to clarify the prognostic value of the pathological overall tumor cellularity after neoadjuvant chemotherapy for locally advanced hypopharyngeal cancer. In consecutive series of 45 operable patients with locally advanced hypopharyngeal cancer, neoadjuvant chemotherapy by cisplatin and 5 fluorouracil was administered. Pathological image analysis was performed in 30 patients using the large cross-section specimen after total resection to evaluate the overall tumor cellularity. The chemotherapeutic responses were classified according to the pathological grading scale by dividing into four categories; more than 70% overall tumor cellularity in Grade 1, between an estimated 10 and 70% in Grade 2, less than 10% in Grade 3, and no identifiable malignant tumor cells in Grade 4. The pathological grades were taken into account for analysis of the survival. In 30 available patients, 40% had Grade 1 pathological response, 30% had Grade 2, and 30% had Grade 3. There was no Grade 4 patient. The overall 5 year survival rate for these 30 patients was 53.33%. The survival rate (61.66%) for patients with Grade 2 and 3 responses was significantly higher than that (27.78%) for patients with Grade 1 response (p = 0.009). Cox regression analysis revealed that the increasing pathological grade was an independent predictor of a better survival in patients undergoing neoadjuvant chemotherapy. We have shown that the prognosis of patients with locally advanced hypopharyngeal cancer, who had been treated by neoadjuvant chemotherapy followed by total resection, can be predicted by evaluation of pathological overall tumor cellularity from the large section specimen. PMID- 22231798 TI - Assessment of nasal septoplasty using NOSE and RhinoQoL questionnaires. AB - The objective was to assess outcomes of nasal septoplasty without turbinectomy using validated subjective instruments and to correlate results with patient satisfaction. The prospective observational study was conducted in a tertiary referral center. The method included the use of NOSE and RhinoQoL questionnaires to assess patients before and 6 months after Cottle septoplasty without turbinectomy. Patient satisfaction was measured on a visual analog scale. Data were compared by the non-parametric Wilcoxon test. Minimal Clinically Important Differences (MCIDs) were calculated. Correlations between post-operative scores and patient satisfaction were assessed using the Spearman test. Univariate analysis was performed to assess predictors of improvement. One hundred patients were enrolled. Their mean age was 43.4 years and 28% had allergic rhinitis. There was a highly significant improvement in each score at 6 months (p < 0.00001). The MCID for the NOSE was comprised between 5 and 7.5, whereas the mean change was 35.2 points. They ranged from 3.8 to 6.1 for RhinoQoL scores, whereas mean changes were comprised between 12.6 and 20.9. Allergic rhinitis was a predictive factor of less improvement (NOSE p = 0.04-RhinoQoL p = 0.0001). Mean patient satisfaction was 8.2 +/- 1.8. Post-operative NOSE and RhinoQoL frequency scores were moderately correlated (r = 0.380; r = 0.356, respectively) whereas bothersomeness and impact scores were highly correlated with patient satisfaction (r = 0.459; r = 0.443, p < 0.00001, respectively). This study shows that the NOSE and RhinoQoL questionnaires can be used in English- and French-speaking populations to perform pre- and post-therapeutic assessment. These validated instruments show that septoplasty without turbinectomy allows management of nasal obstruction and its burden. PMID- 22231799 TI - Long-term efficacy of submucosal uvulopalatopharyngoplasty for obstructive sleep apnea syndrome. AB - The objective of the study was the assessment of the long-term efficacy of submucosal uvulopalatopharyngoplasty in patients with obstructive sleep apnea syndrome. Thirty-two of 156 patients who underwent UPPP between January 2001 and March 2007 with a follow-up period of 36-96 months (mean, 56 months) were included in the study conducted at the university affiliated center. Preoperative and postoperative snoring evaluation forms and Epworth Sleepiness Scale (ESC) scores were used for subjective analysis. Preoperative and postoperative respiratory distress index (RDI) levels were evaluated objectively. Patients who had 50% or more reduction in RDI levels postoperatively were named as responders to the procedure. The other patients were named as non-responders. Body mass index (BMI) was also analyzed preoperatively and postoperatively. Snoring disappeared in 83% of the patients, did not change in 13% and deteriorated in 4% of the patients (p < 0.001). Excessive daytime sleepiness decreased in 22 patients (68%) and ESC values decreased from 14.6 +/- 3.7 to 6.5 +/- 3.9 (p = 0.0001). RDI decreased by more than 50% of the preoperative values in 15 (46.9%) of 32 patients forming the responders and the mean RDI decreased from 33.3 +/- 22.9 to 23.7 +/- 22.8 (p = 0.027). BMI increased over years (p = 0.0001) evidencing a preponderance in non-responder patients. Submucosal uvulopalatopharyngoplasty is an effective tool in treating patient's subjective symptoms of OSAS. Objective findings suggest that smUPPP is inadequate in treating OSAS. It cannot abolish OSAS, though it can decrease the intensity of the condition in nearly half of the patients. Weight gain decreases the success of the procedure over the years. PMID- 22231800 TI - Health-related quality of life of pediatric intensive care survivors. AB - OBJECTIVE: To assess the health-related quality of life (HRQoL) of children surviving to pediatric intensive care discharge. METHODS: A prospective evaluation of HRQoL at admission and 6 months later was carried out with children aged 6 years or more, admitted to three tertiary pediatric intensive care units (PICUs) from May 2002 to June 2004. HRQoL was measured with the Health Utilities Index Mark 3 (HUI3) questionnaire, administered to a child's proxy. RESULTS: From the 517 eligible admissions, 44 children died in the PICU (8.5%) and 320 cases were evaluated at admission; among those, follow-up data were available in 252 cases. There were no statistically significant differences between preadmission and follow-up HUI3 global scores (medians [interquartile range] of 0.86 [0.42 1.00] and 0.83 [0.45-1.00]; p = 0.674, respectively). At the individual level, 21% of children had their HRQoL unchanged, improvement was seen in 40% and deterioration in 38% of the cases. Severe disability before admission (HUI3 global score < 0.70) was present in 36% of the cases, with improvement at the 6 month follow-up in 60% of them. Among those with deterioration of HRQoL at follow up, 45% were trauma victims. CONCLUSIONS: Although the HRQoL was globally similar in both evaluations, several differences were found at the individual level. Children with low preadmission HRQoL (severe disability) may benefit from pediatric intensive care, since many of these children improved their HRQoL compared to preadmission status. PMID- 22231802 TI - In vivo electroporation of morpholinos into the adult zebrafish retina. AB - Many devastating inherited eye diseases result in progressive and irreversible blindness because humans cannot regenerate dying or diseased retinal neurons. In contrast, the adult zebrafish retina possesses the robust ability to spontaneously regenerate any neuronal class that is lost in a variety of different retinal damage models, including retinal puncture, chemical ablation, concentrated high temperature, and intense light treatment. Our lab extensively characterized regeneration of photoreceptors following constant intense light treatment and inner retinal neurons after intravitreal ouabain injection. In all cases, resident Muller glia re-enter the cell cycle to produce neuronal progenitors, which continue to proliferate and migrate to the proper retinal layer, where they differentiate into the deficient neurons. We characterized five different stages during regeneration of the light-damaged retina that were highlighted by specific cellular responses. We identified several differentially expressed genes at each stage of retinal regeneration by mRNA microarray analysis. Many of these genes are also critical for ocular development. To test the role of each candidate gene/protein during retinal regeneration, we needed to develop a method to conditionally limit the expression of a candidate protein only at times during regeneration of the adult retina. Morpholino oligos are widely used to study loss of function of specific proteins during the development of zebrafish, Xenopus, chick, mouse, and tumors in human xenografts. These modified oligos basepair with complementary RNA sequence to either block the splicing or translation of the target RNA. Morpholinos are stable in the cell and can eliminate or "knockdown" protein expression for three to five days. Here, we describe a method to efficiently knockdown target protein expression in the adult zebrafish retina. This method employs lissamine-tagged antisense morpholinos that are injected into the vitreous of the adult zebrafish eye. Using electrode forceps, the morpholino is then electroporated into all the cell types of the dorsal and central retina. Lissamine provides the charge on the morpholino for electroporation and can be visualized to assess the presence of the morpholino in the retinal cells. Conditional knockdown in the retina can be used to examine the role of specific proteins at different times during regeneration. Additionally, this approach can be used to study the role of specific proteins in the undamaged retina, in such processes as visual transduction and visual processing in second order neurons. PMID- 22231801 TI - Item difficulty in the evaluation of computer-based instruction: an example from neuroanatomy. AB - This article reports large item effects in a study of computer-based learning of neuroanatomy. Outcome measures of the efficiency of learning, transfer of learning, and generalization of knowledge diverged by a wide margin across test items, with certain sets of items emerging as particularly difficult to master. In addition, the outcomes of comparisons between instructional methods changed with the difficulty of the items to be learned. More challenging items better differentiated between instructional methods. This set of results is important for two reasons. First, it suggests that instruction may be more efficient if sets of consistently difficult items are the targets of instructional methods particularly suited to them. Second, there is wide variation in the published literature regarding the outcomes of empirical evaluations of computer-based instruction. As a consequence, many questions arise as to the factors that may affect such evaluations. The present article demonstrates that the level of challenge in the material that is presented to learners is an important factor to consider in the evaluation of a computer-based instructional system. PMID- 22231803 TI - Sex difference in stress-induced enhancement of hippocampal CA1 long-term depression during puberty. AB - Females and males react differently to stress. Our previous studies revealed that acute stress facilitates the induction of long-term depression (LTD) in hippocampal CA1 region. However, it remains unknown whether sex difference exists in the effect of stress on LTD. Using an acute unpredictable and inescapable restraint-tailshock stress paradigm, we report here that hippocampal slices from stressed male rats expressed larger LTD by low-frequency stimulation (LFS) than controls, whereas such effect was not observed in female rats during puberty. The facilitatory effect of stress on LTD was prevented when animals were submitted to bilateral adrenalectomy. However, no sex difference in the magnitudes of LTD induced by direct application of N-methy-D-aspartate or a combination of LFS with the glutamate uptake inhibitor D,L-threo-beta-benzyloxyaspartate was observed in slices from naive rats. Female rats exhibited significantly higher basal but not stress-evoked levels of plasma corticosterone than male rats. In addition, the expression levels of glucocorticoid receptors in hippocampal CA1 region were significantly lower in female than male rats. Moreover, female rats showed less responsiveness to stress- or dexamethasone-induced suppression of glutamate uptake in hippocampal synaptosomal preparations than male rats. Importantly, female rats that were masculinized with testosterone at birth responded to stress like male rats did, demonstrating an enhancement of LTD. In contrast, ovariectomized female rats failed to restore the ability of stress to facilitate LTD. These results reveal an obvious sex difference in stress-induced modification of hippocampal synaptic plasticity, which depends on organizational effect of testosterone during early development. PMID- 22231806 TI - Qualitative versus quantitative methods in psychiatric research. AB - Qualitative studies are gaining their credibility after a period of being misinterpreted as "not being quantitative." Qualitative method is a broad umbrella term for research methodologies that describe and explain individuals' experiences, behaviors, interactions, and social contexts. In-depth interview, focus groups, and participant observation are among the qualitative methods of inquiry commonly used in psychiatry. Researchers measure the frequency of occurring events using quantitative methods; however, qualitative methods provide a broader understanding and a more thorough reasoning behind the event. Hence, it is considered to be of special importance in psychiatry. Besides hypothesis generation in earlier phases of the research, qualitative methods can be employed in questionnaire design, diagnostic criteria establishment, feasibility studies, as well as studies of attitude and beliefs. Animal models are another area that qualitative methods can be employed, especially when naturalistic observation of animal behavior is important. However, since qualitative results can be researcher's own view, they need to be statistically confirmed, quantitative methods. The tendency to combine both qualitative and quantitative methods as complementary methods has emerged over recent years. By applying both methods of research, scientists can take advantage of interpretative characteristics of qualitative methods as well as experimental dimensions of quantitative methods. PMID- 22231807 TI - Animal models of self-injurious behaviour: an overview. AB - Self-injurious behaviour is highly prevalent in neurodevelopmental disorders. Interestingly, it is not restricted to any individual diagnostic group. Rather, it is exhibited in various forms across patient groups with distinct genetic defects and classifications of disorders. This suggests that there may be shared neuropathology that confers vulnerability. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key culprit. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury, and highlights the convergence in findings between these models and expression of self-injury in humans. PMID- 22231805 TI - Experimental psychiatric illness and drug abuse models: from human to animal, an overview. AB - Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development. PMID- 22231804 TI - New frontiers in animal research of psychiatric illness. AB - Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness. PMID- 22231808 TI - Rodent models of adaptive decision making. AB - Adaptive decision making affords the animal the ability to respond quickly to changes in a dynamic environment: one in which attentional demands, cost or effort to procure the reward, and reward contingencies change frequently. The more flexible the organism is in adapting choice behavior, the more command and success the organism has in navigating its environment. Maladaptive decision making is at the heart of much neuropsychiatric disease, including addiction. Thus, a better understanding of the mechanisms that underlie normal, adaptive decision making helps achieve a better understanding of certain diseases that incorporate maladaptive decision making as a core feature. This chapter presents three general domains of methods that the experimenter can manipulate in animal decision-making tasks: attention, effort, and reward contingency. Here, we present detailed methods of rodent tasks frequently employed within these domains: the Attentional Set-Shift Task, Effortful T-maze Task, and Visual Discrimination Reversal Learning. These tasks all recruit regions within the frontal cortex and the striatum, and performance is heavily modulated by the neurotransmitter dopamine, making these assays highly valid measures in the study of psychostimulant addiction. PMID- 22231809 TI - Animal models of depression and neuroplasticity: assessing drug action in relation to behavior and neurogenesis. AB - Depression is among the most prevalent forms of mental illness and a major cause of morbidity worldwide. Diagnosis of depression is mainly based on symptomatic criteria, and the heterogeneity of the disease suggests that multiple different biological mechanisms may underlie its etiology. Animal models have been important for recent advances in experimental neuroscience, including modeling of human mood disorders, such as depression and anxiety. Over the past few decades, a number of stress and neurobiochemical models have been developed as primary efficacy measures in depression trials, which are paving the way for the discovery of novel therapeutic targets. Recent data indicates that stress-related mood disorders have influence on neuroplasticity and adult neurogenesis. In this chapter, several currently available animal models are presented as powerful tools for both mechanistic studies into the neurobiology of the antidepressant response and for drug discovery. PMID- 22231810 TI - Modeling depression in animal models. AB - Animal models and preclinical tests have played large roles in the development of antidepressant drugs and are likely to continue to play important roles. In the present communication, the main animal models of depression have been described and reviewed. These models include the Flinders sensitive line (FSL) rat, the Wistar Kyoto (WKY) rat, the fawn-hooded (FH) rat, and the learned helpless (LH) rat. In addition, the materials used to assess the behavior of these rats, including swim tanks, drinking tubes, and an open field apparatus, have been discussed. Finally, the methods used in collecting the relevant behaviors in the animal models are described. These include the procedures used in the forced swim test and chronic mild stress protocols, including the sucrose preference test. It is concluded that the behavioral tests used to infer depressed-like behavior in rats will continue to provide useful data if the appropriate animals and proper methods are used. PMID- 22231811 TI - Behavioral model for assessing cognitive decline. AB - The water maze task can be used to assess sensory motor and cognitive function in rodents. When properly employed, this task can behaviorally assess acquisition of a spatial search strategy, as well as working and reference memory. The following section uses research on age-related, cognitive decline to illustrate the methods employed and highlight areas that can, if not properly controlled, confound a study. PMID- 22231812 TI - The pemoline model of self-injurious behaviour. AB - Traditional models of neuropsychiatric disorders consist of attempts to replicate the broad spectrum of behavioural and neurochemical sequelae that characterize a specific disorder. However, these disorders comprise complex constellations of symptoms, including emotional instability, perseverative thoughts, and aberrant behaviours. Close examination often reveals heterogeneity of symptom expression within patient groups and homogeneity in expression of specific symptoms across diagnostic categories. Accordingly, it may not be possible to model the entire spectrum of characteristics for any one of these disorders in any single animal model. A focus on one or more specific behavioural characteristics (e.g. self injury) may be a more fruitful strategy. Development of behaviourally focused models yields increased understanding of the genetic basis and biochemical abnormalities that underlie specific psychiatric dysfunctions. Furthermore, by revealing pathophysiology that underlies specific disease characteristics, behaviourally focused models improve translational power and help to identify targets for effective pharmacotherapies. One such behaviourally focused animal model is the pemoline model of self-injurious behaviour. PMID- 22231813 TI - Modeling risky decision making in rodents. AB - Excessive risk taking is a hallmark of various psychopathological disorders. We have developed a task that models such risky decision making in rats. In this task, rats are given choices between small, safe rewards and large rewards accompanied by a risk of punishment (footshock). The risk of punishment increases throughout the test session, which allows the quantification of risky decision making at different degrees of risk for each subject. Importantly, this task yields a consistently wide degree of reliable individual variability, allowing the characterization of rats as "risk taking" or "risk averse." This task has been demonstrated to be effective for testing the effects of pharmacological agents on risk taking, and the individual variability (which mimics the human population) allows assessment of neurobiological distinctions between subjects based on risk-taking profile. PMID- 22231814 TI - Open space anxiety test in rodents: the elevated platform with steep slopes. AB - This report describes a behavioral test protocol for assessing anxiety in mice and rats in single or multiple sessions. The test is based on exposure of animals to an open-space elevated platform with suspended steep slopes attached on two opposite sides. In this test, all animals cross frequently onto and spend more time in the areas adjacent to slopes than in the areas adjacent to a void space. Balb/c mice (albinos) were shown consistently to be more anxious than CD-1 mice (albinos), c57/Bl6J and c57/Bl6N (pigmented) mice; they do not cross onto the slopes. When Balb/c mice are treated with amphetamine or diazepam, the number of crossings on the platform is significantly increased but only diazepam-treated mice do cross onto the slopes. In the presence of a protected space on the platform, the behavior of c57/Bl6J compares to that of Balb/c mice; they stop crossings onto the slopes and demonstrate avoidance response. Unlike the current existing tests, the present open-space anxiety test demonstrates reliable and consistent results with strong construct and discriminant validity. It provides unequivocal measures of fear-induced anxiety, which are not confounded with measures of fear-induced escape/avoidance responses, hyperactivity or impulsive responses. PMID- 22231815 TI - An animal model to study the molecular basis of tardive dyskinesia. AB - Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects. This limitation presents a marked therapeutic challenge. The present method (21 days administration of haloperidol, 5 mg/kg, i.p.) has been established to gain deeper insight into the molecular etiology (inflammation and apoptosis) of haloperidol-induced cellular death. In the present model, besides the corresponding increase in the vacuous chewing movements (VCMs), enhanced oxidative stress, there was a significant increase in cellular markers of inflammation and apoptotic protein (caspase-3), leading to cellular death. We also suggest that this model will be effective in preclinical testing of new chemical entities for the treatment of haloperidol induced tardive dyskinesia and related symptoms. PMID- 22231816 TI - Models of chronic alcohol exposure and dependence. AB - Alcoholism is a chronic treatment-resistant disorder typically presenting with recurrent/cyclic periods of abusive drinking, withdrawal, abstinence, and relapse. Various strategies that attempt to model these processes in animals have been developed to elucidate the behavioral and neural processes underlying alcoholism. Many of these have involved chronic ethanol exposure and withdrawal with the most widely employed methods involving mice or rats. Prominent features of these methods include alcohol vapor or intragastric forced exposure, cyclic or intermittent periods of alcohol availability with various lengths of forced abstinence, voluntary consumption, the use of genetically alcohol-preferring animals, and inclusion of various pharmacological or environmental challenges to worsen or mitigate symptoms. This chapter emphasizes alcohol exposure and withdrawal and discusses representative metrics used to monitor the consequences of employing these methods. These include but are not limited to intensity and pattern of alcohol exposure, seizure sensitivity during withdrawal, and emotional responding. PMID- 22231817 TI - Rat models of prenatal and adolescent cannabis exposure. AB - Marijuana (Cannabis sativa) is the illicit drug most commonly used by two vulnerable populations relevant to neurodevelopment-pregnant women and teenagers. Human longitudinal studies have linked prenatal and adolescent cannabis exposure with long-term behavioral abnormalities as well as increased vulnerability to neuropsychiatric disorders in adulthood. Animal models provide a means of studying the neurobiological mechanisms underlying these long-term effects. This chapter provides an overview of the animal models we have used to study the developmental impact of cannabis. PMID- 22231818 TI - Modeling nicotine addiction in rats. AB - Among the human population, 15% of drug users develop a pathological drug addiction. This figure increases substantially with nicotine, whereby more than 30% of those who try smoking develop a nicotine addiction. Drug addiction is characterized by compulsive drug-seeking and drug-taking behaviors (craving), and loss of control over intake despite impairment in health, social, and occupational functions. This behavior can be accurately modeled in the rat using an intravenous self-administration (IVSA) paradigm. Initial attempts at establishing nicotine self-administration had been problematic, yet in recent times increasingly reliable models of nicotine self-administration have been developed. The present article reviews different characteristics of the nicotine IVSA model that has been developed to examine nicotine reinforcing and motivational properties in rats. PMID- 22231819 TI - Animal models of nicotine withdrawal: intracranial self-stimulation and somatic signs of withdrawal. AB - Tobacco addiction is one of the leading causes of preventable death worldwide. Despite the negative health outcomes of tobacco use and a desire to quit, there is a low success rate of maintaining abstinence. Nicotine, the main psychoactive component of tobacco smoke, is mildly rewarding and maintains smoking behavior. Nicotine withdrawal induces somatic symptoms that may contribute to smoking behavior. However, it has been hypothesized that the negative affective signs are of greater motivational significance in contributing to relapse and continued tobacco use than the somatic symptoms of nicotine withdrawal (Markou and Koob (Eds.) Intracranial self-stimulation thresholds as a measure of reward, Vol. 2, Oxford University Press, New York, 1993; Koob et al. Semin Neurosci 5: 351-358, 1993). Intracranial self-stimulation (ICSS) has been established as a method to assess the bivalent properties of nicotine exposure and withdrawal from acute and chronic nicotine administration. Thus, ICSS provides a means to measure the negative affective aspects of nicotine withdrawal in animal models and may contribute to the understanding of the neurobiological bases of nicotine dependence and the development of effective treatment strategies to facilitate nicotine abstinence. PMID- 22231821 TI - Cocaine self-administration in rats: hold-down procedures. AB - For decades, researchers have used animal self-administration models to examine the effects drugs of abuse have on physiology and behavior. Sophisticated self administration procedures have been developed to model many different aspects of drug addiction. The hold-down procedure provides animals with control over the amount of each injection. Holding the lever down turns the syringe pump on and subsequently releasing the lever turns the pump off. In this way, animals can hold the lever down for any duration of time thereby self-administering any dose on a continuous spectrum. This procedure eliminates some of the ambiguity in translating results from effects only observed at one unit dose and allows examination of which dose the animal "prefers" at different times. PMID- 22231820 TI - Methods in drug abuse models: comparison of different models of methamphetamine paradigms. AB - Methamphetamine (METH) is a widely abused psychomotor stimulant. Investigating the effects of METH use on the brain has been applied in different animal models, including rats, mice, and nonhuman primates. Human abuse of METH occurs in different paradigms ranging from episodes of binge abuse to chronic abuse over years; different animal models have been established to replicate these various patterns of human behavior. In this chapter, we discuss the different models of METH abuse, including the acute model which assesses the immediate effects of METH on the brain and chronic exposure model which simulates the more common long term use observed in humans; additionally, two other relevant models, escalating dose paradigm and METH self-administration, are examined. In comparing the models, this chapter briefly considers the METH-induced neurotoxic effects associated with each METH administration paradigm and the behavioral changes observed. PMID- 22231822 TI - Cocaine self-administration in rats: discrete trials procedures. AB - A discrete trials procedure involves splitting up a self-administration session so that there are multiple distinct trials and inter-trial-intervals. This schedule is well suited to be used over 24 h periods which allows insight into diurnal variability in self-administration behavior. DT is also well suited for investigations using pretreatments for increasing or decreasing both high and low probability behavior. PMID- 22231823 TI - Cocaine self-administration in rats: threshold procedures. AB - Cocaine self-administration provides a methodology allowing researchers to study changes in distinct aspects of drug-taking behavior that model behaviors observed in drug addicts. Traditionally, self-administration schedules were designed to independently study changes in drug-taking behaviors (e.g., rate of responding, reinforcing efficacy, etc.). The threshold self-administration procedure was developed to measure two distinct dependent measures within the same experimental session that are important in the study of drug addiction: the maximal price an animal expends to self-administer cocaine and an animal's preferred level of cocaine consumption when available at a low behavioral cost. PMID- 22231824 TI - Assessing locomotor-stimulating effects of cocaine in rodents. AB - Locomotor activity procedures are useful for characterizing the behavioral effects of a drug, the influence of pharmacological, neurobiological, and environmental manipulations on drug sensitivity, and changes in activity following repeated administration (e.g., tolerance or sensitization) are thought to be related to the development of an addiction-like behavioral phenotype. The effects of cocaine on locomotor activity have been relatively extensively characterized. Many of the published studies use between-subject experimental designs, even though changes in sensitivity within a particular individual due to experimental manipulations, or behavioral and pharmacological histories is potentially the most important outcome as these changes may relate to differential development of an addiction-like phenotype in some, but not all, animals (including humans). The two behavioral protocols described herein allow extensive within-subject analyses. The first protocol uses daily locomotor activity levels as a stable baseline to assess the effects of experimental manipulations, and the second uses a pre- versus post-session experimental design to demonstrate the importance of drug-environment interactions in determining the behavioral effects of cocaine. PMID- 22231825 TI - Methods in tobacco abuse: proteomic changes following second-hand smoke exposure. AB - Smoking is one of the leading preventable causes of disease, disability, and death in the USA and leads to more than 400,000 preventable deaths per year. Nicotine is the major alkaloid present in tobacco smoke, and many of the negative effects of smoking are attributed to nicotine. Nicotine is not only the addictive component of tobacco smoke, but also highly associated with carcinogenesis and induces oxidative stress. Furthermore, the administration of nicotine via subcutaneous mini-osmotic pumps or by injection is an established method in preclinical studies for this area of research. Thus, preclinical research on the negative effects of tobacco smoke and tobacco addiction has focused primarily on the effects of nicotine. However, there are over 4,500 components found in tobacco smoke, many of which are highly toxic. Other components may also contribute to the addictive properties of tobacco smoke. Furthermore, the negative effects of tobacco smoke are not isolated to the smoker but can have negative effects to those exposed to the secondhand smoke (SHS) stream. SHS exposure is the third leading cause of preventable death. Approximately 38,000 deaths per year are attributed to SHS exposure in the USA. SHS exposure increases the risk of heart disease by approximately 30% and is associated with increased risk of stroke, cancer, type II diabetes, as well as pulmonary disease. Thus, methods of administering tobacco smoke in a controlled environment will further our understanding of tobacco addiction and the role tobacco smoke in other disease states. Moreover, combining smoke exposure with proteomics can lead to the discovery of biomarkers that can be potentially useful tools in screening, early diagnosis, prevention, and treatment of diseases caused by SHS. PMID- 22231826 TI - Animal models of sugar and fat bingeing: relationship to food addiction and increased body weight. AB - Binge eating is a behavior that occurs in some eating disorders, as well as in obesity and in nonclinical populations. Both sugars and fats are readily consumed by human beings and are common components of binges. This chapter describes animal models of sugar and fat bingeing, which allow for a detailed analysis of these behaviors and their concomitant physiological effects. The model of sugar bingeing has been used successfully to elicit behavioral and neurochemical signs of dependence in rats; e.g., indices of opiate-like withdrawal, increased intake after abstinence, cross-sensitization with drugs of abuse, and the repeated release of dopamine in the nucleus accumbens following repeated bingeing. Studies using the model of fat bingeing suggest that it can produce some, but not all, of the signs of dependence that are seen with sugar binge eating, as well as increase body weight, potentially leading to obesity. PMID- 22231827 TI - Animal models of overeating. AB - Obesity has become a major health and economic burden, and the development of new treatments is urgently needed. Initially, such treatments involve use of animal models, and the purpose of this chapter is to describe some of the most useful models, why one might be chosen over another to address a particular question, and any procedural pitfalls. I restrict the discussion to rats and mice, used in the overwhelming majority of preclinical studies, and more specifically to protocols of diet-induced obesity and those that emulate binge eating. PMID- 22231828 TI - The activity-based anorexia mouse model. AB - Animals housed with running wheels and subjected to daily food restriction show paradoxical reductions in food intake and increases in running wheel activity. This phenomenon, known as activity-based anorexia (ABA), leads to marked reductions in body weight that can ultimately lead to death. Recently, ABA has been proposed as a model of anorexia nervosa (AN). AN affects about 8 per 100,000 females and has the highest mortality rate among all psychiatric illnesses. Given the reductions in quality of life, high mortality rate, and the lack of pharmacological treatments for AN, a better understanding of the mechanisms underlying AN-like behavior is greatly needed. This chapter provides basic guidelines for conducting ABA experiments using mice. The ABA mouse model provides an important tool for investigating the neurobiological underpinnings of AN-like behavior and identifying novel treatments. PMID- 22231829 TI - Dissociating behavioral, autonomic, and neuroendocrine effects of androgen steroids in animal models. AB - Developments in behavioral assessment, autonomic and/or baseline reactivity, psychopharmacology, and genetics, have contributed significantly to the assessment of performance-enhancing drugs in animal models. Particular classes of steroid hormones: androgenic steroids are of interest. Anecdotally, the performance enhancing effects of androgens are attributed to anabolic events. However, there is a discrepancy between anecdotal evidence and investigative data. While some androgen steroids may promote muscle growth (myogenesis), effects of androgens on performance enhancement are not always seen. Indeed, some effects of androgens on performance may be attributable to their psychological and cardiovascular effects. As such, we consider androgen effects in terms of their behavioral, autonomic, and neuroendocrine components. Techniques are discussed in this chapter, some of which are well established, while others have been more recently developed to study androgen action. Androgens may be considered for their positive impact, negative consequence, or psychotropic properties. Thus, this review aims to elucidate some of the effects and/or mechanisms of androgens on behavioral, autonomic, and/or neuroendocrine assessment that may underlie their controversial performance enhancing effects. PMID- 22231830 TI - Interleukin-2 and the septohippocampal system: intrinsic actions and autoimmune processes relevant to neuropsychiatric disorders. AB - The effects of IL-2 on brain development, function, and disease are the result of IL-2's actions in the peripheral immune system and its intrinsic actions in the central nervous system (CNS). Determining whether, and under what circumstances (e.g., development, acute injury), these different actions of IL-2 are operative in the brain is essential to make significant advances in understanding the multifaceted affects of IL-2 on CNS function and disease, including psychiatric disorders. For several decades, there has been a great deal of speculation about the role of autoimmunity in brain disease. More recently, we have learned a great deal about the role of cytokines on neurobiological processes, and there have been many studies that have found peripheral immune alterations in patients with neurological and neuropsychiatric diseases. Despite a plethora of published literature, almost all of this data in humans is correlative and much of the basic research has understandably relied on simpler models (e.g., in vitro models). Good animal models such as our IL-2 knockout mouse model could provide valuable new insight into understanding how the complex biology of a cytokine such as IL-2 can have simultaneous, dynamic effects on multiple systems (e.g., regulating homeostasis in the brain and immune system, autoimmunity that can affect both systems). Animal models can also provide much needed new data elucidating neuroimmunological and autoimmune processes involved in brain development and disease. Such information may ultimately provide critical new insight into the role of brain cytokines and autoimmunity in prominent neurological and neuropsychiatric diseases (e.g., Alzheimer's disease, autism, multiple sclerosis, schizophrenia). PMID- 22231831 TI - Experimental schizophrenia models in rodents established with inflammatory agents and cytokines. AB - Immune inflammatory processes in prenatal and perinatal stages are suggested to play crucial roles in the vulnerability to schizophrenia. Based upon this immune inflammatory hypothesis for schizophrenia, we have established animal models for this illness by subcutaneously administering cytokines or proinflammatory agents to rodent neonates. These models exhibit various schizophrenia-like behavioral abnormalities after puberty, most of which are sensitive to various antipsychotics. The experimental procedures are all simple and easily utilized by researchers unfamiliar with these models. The behavioral changes are reproducible and remarkable but do not accompany learning deficits. The molecular and cellular targets of these agents have also been investigated and partially characterized, such as the cortical GABAergic system, midbrain dopaminergic system and hippocampal glutamate system. In this chapter, we introduce the details of the procedure and discuss the potential application of these animal models to drug development for schizophrenia. PMID- 22231832 TI - P11: a potential biomarker for posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder that occurs after a traumatic event. It is associated with an increased risk of suicide and marked deficits in social and occupational functioning. Currently, the diagnosis for PTSD is established on the basis of a patient's clinical history, mental status examination, duration of symptoms, and clinician administered symptom checklist or patient self-report. However, there are no available laboratory biomarker tests for PTSD. To begin intervention at the earliest possible time, priority must be given to developing objective approaches to determine the presence of PTSD. Thus, using cutting-edge technology and skill to develop a simple blood test or a biomarker to detect PTSD at its earliest and most treatable stage would benefit both physician and patient. Several technologies and skills have been used in the identification biomarker research. We discuss three major methods in this chapter (blood RNA and DNA purification, chromatin immunoprecipitation, and Western blot), which have been used in our study to determine whether p11 is a potential biomarker for PTSD. Using these procedures will not only enhance the study of the molecular mechanisms of PTSD but also help the translation of basic science to a clinical setting. PMID- 22231833 TI - Investigation of age-specific behavioral and proteomic changes in an animal model of chronic ethanol exposure. AB - Alcohol use during adolescence represents a major health concern given that this is a period in which the brain continues to undergo critical developmental changes. Much behavioral research has been conducted in animal models of alcohol exposure, and a vulnerable period in adolescence has been identified that suggests lasting effects of ethanol exposure during adolescence. However, identification of molecular changes underlying the behavioral outcomes observed as a result from exposure to ethanol during adolescence remains a major technical challenge. In this chapter, we describe a method that allows for assessment of the effects of chronic ethanol exposure during adolescence relative to adulthood through global-scale analysis of protein expression as well as evaluation of behavioral responsivity in adolescent and adult rats. Results from this type of analysis can facilitate identification of age-specific molecular markers associated with behavioral changes following treatment with ethanol or in other animal models of drug abuse. PMID- 22231834 TI - Quantitative peptidomics to measure neuropeptide levels in animal models relevant to psychiatric disorders. AB - Neuropeptides play many important roles in cell-cell signaling and are involved in the control of anxiety, depression, pain, reward pathways, and many other processes that are relevant to psychiatric disorders. Mass spectrometry-based peptidomics techniques can identify the precise forms of peptides that are present in a given tissue. Utilizing this technique, peptides with any posttranslational modifications can be identified, and the exact sequence of the peptides can be determined. Unlike radioimmunoassays, which are limited by specific antibodies and often cannot discriminate between different lengths of peptides from the same precursor, peptidomics reveals the precise sequence and allows for the identification of both known and novel peptides. The use of isotopic labels allows for quantitative peptidomics, which results in the ability to compare peptide levels between differently treated samples. These tags can be synthesized in five different isotopic forms, permitting multivariate analysis of up to five different groups of tissue extracts in a single liquid chromatography/mass spectrometry run; this is ideal for measuring changes in neuropeptides in animals subjected to drug treatments, or in comparing animal models of psychiatric disorders. PMID- 22231835 TI - ADHD animal model characterization: transcriptomics and proteomics analyses. AB - Mechanisms underlying behavioral abnormalities of patients with attention-deficit hyperactivity disorder (ADHD) disorder are still unknown. It is worth clarifying alterations in the brain of animal models for ADHD. The animals with neonatal treatment with 6-hydroxydopamine (6-OHDA) and congenic wiggling (Wig) rats show motor hyperactivities during a period of darkness at 4 weeks of age. In rats with 6-OHDA lesions, subcutaneous injection of methamphetamine attenuates hyperactivity, the reverse of its effect in Wig rats. To understand mechanisms underlying such behavioral abnormalities, transcriptomics and proteomics analyses may provide novel information in brain research. The expression of genes and proteins in brain regions can be measured by DNA microarray and two-dimensional gel electrophoresis, respectively. We have shown different expressions of genes and proteins in brains of rats with neonatal 6-OHDA lesions and Wig rats. PMID- 22231836 TI - Psychiatric disorder biomarker discovery using quantitative proteomics. AB - To date, no molecular biomarker exists for any psychiatric disorder. To identify phenotype-specific biomarkers and investigate the molecular underpinnings of anxiety pathophysiology, we interrogated the well-established mouse model of high (HAB), normal (NAB) and low (LAB) anxiety-related behavior by in vivo (15)N metabolic labeling and quantitative proteomics. The (15)N metabolic labeling approach enables accurate quantification due to the early mixing of the labeled and unlabeled samples under comparison, thus avoiding the biased experimental error introduction during handling. Differentially expressed proteins between HAB and LAB mice can be validated with non-mass-spectrometry-based methods. In silico pathway analysis enables identification of protein networks implicated in anxiety neural circuits. The presented workflow provides a precise and non-hypothesis driven tool for identifying candidate biomarkers using animal models of psychiatric disorders. PMID- 22231837 TI - Gene profiling of laser-microdissected brain regions and individual cells in drug abuse and schizophrenia research. AB - Application of transcriptomics approaches to accurately dissected anatomically defined brain regions and individual neuronal populations remains a central focus of current neurobiological investigations. A vast selection of methods and commercial products are currently available that allow one to implement routine gene quantitation and profiling from laser-microdissected brain regions, subregions, and neuronal populations. The present chapter reviews laser microdissection strategies for gene expression analyses, strategies for RNA extraction, reverse transcriptase-coupled PCR (RT-PCR), and target preparation for microarray analyses that are in use in our labs. PMID- 22231838 TI - Stable isotope labeling with amino acids in cell culture-based proteomic analysis of ethanol-induced protein expression profiles in microglia. AB - Ethanol exposure causes neurotoxicity, where neuroinflammation has been proposed to contribute to ethanol neurotoxicity. In addition to astroglia, microglia, as resident immune cells in the central nervous system, have been implicated as a key contributor to the neuroimmune and inflammatory processes. However, little is known regarding the role of microglia in alcohol-induced neuronal dysfunction. In this chapter, we describe a method that provides an effective and unbiased global scale analysis for relative quantitation of protein expression in microglial cells to elucidate the molecular mechanisms underlying microglial activation after ethanol exposure. The approach involves stable isotope labeling with amino acids in cell culture followed by mass spectrometric analysis of stable isotope labeled proteins derived from cultured microglial cells and represents a powerful tool that can be used for general assessment of microglial response at the protein level. PMID- 22231839 TI - Systems biology in psychiatric research: from complex data sets over wiring diagrams to computer simulations. AB - The classification of psychiatric disorders has always been a problem in clinical settings. The present debate about the major systems in clinical practice, DSM-IV and ICD-10, has resulted in attempts to improve and replace those schemes by some that include more endophenotypic and molecular features. However, these disorders not only require more precise diagnostic tools, but also have to be viewed more extensively in their dynamic behaviors, which require more precise data sets related to their origins and developments. This enormous challenge in brain research has to be approached on different levels of the biological system by new methods, including improvements in electroencephalography, brain imaging, and molecular biology. All these methods entail accumulations of large data sets that become more and more difficult to interpret. In particular, on the molecular level, there is an apparent need to use highly sophisticated computer programs to tackle these problems. Evidently, only interdisciplinary work among mathematicians, physicists, biologists, and clinicians can further improve our understanding of complex diseases of the brain. PMID- 22231840 TI - Data mining in psychiatric research. AB - Mathematical sciences and computational methods have found new applications in fields like medicine over the last few decades. Modern data acquisition and data analysis protocols have been of great assistance to medical researchers and clinical scientists. Especially in psychiatry, technology and science have made new computational methods available to assist the development of predictive modeling and to identify diseases more accurately. Data mining (or knowledge discovery) aims to extract information from large datasets and solve challenging tasks, like patient assessment, early mental disease diagnosis, and drug efficacy assessment. Accurate and fast data analysis methods are very important, especially when dealing with severe psychiatric diseases like schizophrenia. In this paper, we focus on computational methods related to data analysis and more specifically to data mining. Then, we discuss some related research in the field of psychiatry. PMID- 22231841 TI - The development of whisker control in rats in relation to locomotion. AB - Adult rats sweep their large facial whiskers (macrovibrissae) back and forth in a rhythmic pattern known as "whisking". Here we examine how these whisker movements develop in relation to other aspects of exploratory behavior, particularly locomotion. We analyzed 963 high-speed video recordings of neonatal rats, from P1 (Post-natal day 1) to P21, and measured the emergence of whisker control and of head, body, and limb movements. Prior to P11, whisker movements were largely limited to unilateral retractions accompanying head turns. Between P11 and P13 bilateral whisking emerged alongside increased forward locomotion and improved control of the head. Contact-induced modulations of whisking symmetry, synchrony, and whisker spread emerge shortly thereafter but continue to develop until at least P18, coinciding with the emergence of adult-like locomotion patterns such as rearing. Overall, whisking develops alongside increasing locomotor competence indicating that active vibrissal sensing plays an important role in the exploratory behavior of the developing animal. PMID- 22231842 TI - Activation of transcriptional activity of HSE by a novel mouse zinc finger protein ZNFD specifically expressed in testis. AB - Zinc finger proteins (ZFPs) that contain multiple cysteine and/or histidine residues perform important roles in various cellular functions, including transcriptional regulation, cell proliferation, differentiation, and apoptosis. The Cys-Cys-His-His (C(2)H(2)) type of ZFPs are the well-defined members of this super family and are the largest and most complex proteins in eukaryotic genomes. In this study, we identified a novel C(2)H(2) type of zinc finger gene ZNFD from mice which has a 1,002 bp open reading frame and encodes a protein with 333 amino acid residues. The predicted 37.4 kDa protein contains a C(2)H(2) zinc finger domain. ZNFD gene is located on chromosome 18qD1. RT-PCR analysis revealed that the ZNFD gene was specifically expressed in mouse testis but not in other tissues. Subcellular localization analysis demonstrated that ZNFD was localized in the nucleus. Reporter gene assays showed that overexpression of ZNFD in the COS7 cells activates the transcriptional activities of heat shock element (HSE). Overall, these results suggest that ZNFD is a member of the zinc finger transcription factor family and it participates in the transcriptional regulation of HSE. Many heat shock proteins regulated by HSE are involved in testicular development. Therefore, our results suggest that ZNFD may probably participate in the development of mouse testis and function as a transcription activator in HSE mediated gene expression and signaling pathways. PMID- 22231843 TI - A novel kynurenic acid analog (SZR104) inhibits pentylenetetrazole-induced epileptiform seizures. An electrophysiological study : special issue related to kynurenine. AB - The concentration of kynurenic acid (KYNA) in the cerebrospinal fluid, which is in the nanomolar range, is known to decrease in epilepsy. The experimental data suggest that treatment with L: -KYN dose dependently increases the concentration of the neuroprotective KYNA in the brain, which itself hardly crosses the blood brain barrier. However, it is suggested that new synthetic KYNA analogs may readily cross the blood-brain barrier. In this study, we tested the hypothesis that a new KYNA analog administered systemically in a sufficient dose results in a decreased population spike activity recorded from the pyramidal layer of area CA1 of the hippocampus, and also provides protection against pentylenetetrazole induced epileptiform seizures. PMID- 22231844 TI - Changes of hand preference in Parkinson's disease. AB - This study focused on the difference between pre-morbid and current hand preference of patients with Parkinson's disease (PD). A survey instrument comprised items measuring pre-morbid and current hand preference and question related to the side of occurrence of initial symptoms. These questions were administered to 471 PD patients. The results show a significant change of pre morbid right hand preference toward using the left when the side of PD onset was on the right hand and vice versa. Disease duration does not predict the amount of hand preference shift. PMID- 22231845 TI - Development of Parkinson's disease in patients with Narcolepsy. AB - Although amphetamine drugs can damage dopaminergic axons, it is unknown whether chronic treatment with amphetamine increases the risk of developing Parkinson's disease (PD). Of 1,152 consecutive PD patients, 3 had a prior diagnosis of narcolepsy. This rate is five times higher than expected (p = 0.02). These patients had typical onset of narcolepsy and underwent treatment with amphetamine. Although preliminary, this observation raises the possibility that some factors intrinsic to narcolepsy or its treatment may be a risk factor for PD. PMID- 22231846 TI - Botulinum toxin in hemifacial spasm: the challenge to assess the effect of treatment. AB - Hemifacial spasm is characterized by intermittent tonic or clonic contractions of the muscles supplied by the facial nerve. Although vision is less impaired than in patients with blepharospasm, the disease can impose significant psychosocial burden on patient's life. Botulinum toxin (BoNT) is the well-established pharmacotherapy of choice, but evidence from controlled clinical trials is sparse. There is a broad variety of rating scales used in clinical studies with BoNT and obviously no consensus has been reached how to assess treatment outcome in hemifacial spasm. Clinical rating scales focusing on objective function were used in a couple of controlled studies with BoNT and were appropriate to discriminate between BoNTA and placebo. But it has not been shown that they would be sensitive enough to detect minor differences between several BoNT formulations. Although most of the clinical scales consist of a five-point rating, the descriptors for the ordinal numbers are not necessarily the same so that the results of different clinical studies are not comparable to each other. The main disadvantage of clinical scales is that they do not take into account patient's perspective of disability and impact on daily life. For this reason some clinical studies applied health-related quality of life (HRQoL) questionnaires to assess efficacy, and one research group worked on the development of disease-specific tools. Although these HRQoL questionnaires have been validated and a good correlation to disease severity could be demonstrated, they are far from having become an established variable for efficacy assessment in hemifacial spasm trials. The challenge remains to establish tools which are appropriate to rate BoNT treatment effects in hemifacial spasm. Currently, it is virtually impossible to identify one rating scale which can cover all relevant aspects of the disorder. In consequence we recommend the implementation of a combination of different rating scales which address functional impairment as well as those issues which are most important to patients. Further research is needed to standardize and validate rating scales for hemifacial spasm in clinical studies. PMID- 22231850 TI - Diabetes: A closer look at the mechanisms of action of colesevelam in humans. PMID- 22231852 TI - Thyroid function: Autoimmunity in pregnancy and ADHD. PMID- 22231848 TI - Anti-Mullerian hormone: an ovarian reserve marker in primary ovarian insufficiency. AB - Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a disorder of infertility characterized by amenorrhoea, low estrogen levels and increased gonadotropin levels in women aged <40 years. POI is the result of premature exhaustion of the follicle pool or can be attributed to follicular dysfunction, for example, owing to mutations in the follicle-stimulating hormone receptor or steroidogenic cell autoimmunity. Moreover, advances in cancer therapeutics over the past decades have led to increasing survival rates for both paediatric and adult malignancies. Given the gonadotoxic effect of many cancer treatments, more women develop POI. A marker that predicts whether women are at risk of POI would, therefore, aid in early diagnosis and fertility counselling. Anti-Mullerian hormone (AMH), a growth factor produced solely by small, growing follicles in the ovary, might constitute such a marker, as serum levels of this hormone correlate strongly with the number of growing follicles. In addition, AMH could potentially help assess the progression of ovarian senescence, as serum AMH levels are independent of hypothalamic-pituitary-gonadal axis function and decrease to undetectable levels at menopause. In cancer survivors, serum AMH levels correlate with the extent of gonadal damage. In this Review, we provide an overview of the current studies that have measured AMH in women with POI of various aetiologies and discuss its possible application as a marker to determine ovarian reserve. PMID- 22231853 TI - Thyroid function: Outcome of salt iodisation in India. PMID- 22231854 TI - Metabolism: Mitochondrial pathways in NAFLD. PMID- 22231856 TI - Geometry- and rate-dependent adhesive failure of micropatterned surfaces. AB - The dynamic nature of adhesive interface failure remains poorly understood, especially when the contact between the two surfaces is localized in microscopic points of adhesion. Here, we explore the dynamic failure of adhesive interfaces composed of a large number of micron-sized pillars against glass. Surprisingly, we find a large influence of the microcontact geometry; ordered arrays of these pillars exhibit significantly stronger adhesive properties than equivalent surfaces in which the pillars are disordered. This can be understood with a simple geometric argument that accounts for the number of adhesive bonds that needs to be broken simultaneously to propagate the crack front. Moreover, the adhesive strength in both cases depends largely on the velocity with which the surfaces are separated. This rate dependence is explained on the basis of a semi phenomenological model that describes macroscopic failure as a consequence of microscopic bond-rupture events. Our results suggest that the dynamics of adhesive failure, in the limit explored here, is predominantly stress-driven and highly sensitive to local geometry effects. PMID- 22231857 TI - Importance of recognizing and preventing blindness from juvenile idiopathic arthritis-associated uveitis. PMID- 22231858 TI - Vascular endothelial growth factor serum levels in children with newly diagnosed rhabdomyosarcoma. AB - BACKGROUND: The adverse prognostic impact of elevated levels of circulating Vascular Endothelial Growth Factor (VEGF) is described in several malignancies. However, no information is available in childhood rhabdomyosarcoma (RMS). In the present study, serum VEGF-A (sVEGF-A) was measured at diagnosis in a series of patients with RMS. PROCEDURE: sVEGF-A was assessed retrospectively in 17 newly diagnosed RMS patients. sVEGF-A concentrations were determined by quantitative enzyme-linked immunoabsorbent ELISA kit and their possible associations with age at diagnosis, gender, histology, primary site, primary size, Intergroup Rhabdomyosarcoma Study (IRS) post-surgical group, and outcome were investigated. RESULTS: sVEGF-A median value in patients with RMS was significantly higher than in controls: 499.0 pg/ml, range: 2,648.0 versus 301.5 pg/ml, range: 716.0 (P = 0.013). Although not statistically significant probably due to the limited number of patients, sVEGF-A median levels resulted higher in unfavorable primary sites (277.0 vs. 539.0 pg/ml; P = 0.31), and advanced groups (390.0 vs. 715.0; P = 0.29). Patients with shorter 5-year overall survival (OS) and 5-year progression free survival (PFS) times also had higher sVEGF-A levels, although again the difference was not statistically significant (P = 0.18 and P = 0.22, respectively). CONCLUSIONS: Circulating VEGF is significantly increased in pediatric patients with newly diagnosed RMS. Further studies in larger series of RMS patients are needed to understand whether measurements of circulating VEGF might have a role in assessing prognosis and modulating treatment. PMID- 22231859 TI - Isotropic submillimeter fMRI in the human brain at 7 T: combining reduced field of-view imaging and partially parallel acquisitions. AB - Echo-planar imaging is the most widely used imaging sequence for functional magnetic resonance imaging (fMRI) due to its fast acquisition. However, it is prone to local distortions, image blurring, and signal voids. As these effects scale with echo train length and field strength, it is essential for high resolution echo-planar imaging at ultrahigh field to address these problems. Partially parallel acquisition methods can be used to improve the image quality of echo-planar imaging. However, partially parallel acquisition can be affected by aliasing artifacts and noise enhancement. Another way to shorten the echo train length is to reduce the field-of-view (FOV) while maintaining the same spatial resolution. However, to achieve significant acceleration, the resulting FOV becomes very small. Another problem occurs when FOV selection is incomplete such that there is remaining signal aliased from the region outside the reduced FOV. In this article, a novel approach, a combination of reduced FOV imaging with partially parallel acquisition, is presented. This approach can address the problems described above of each individual method, enabling high-quality single shot echo-planar imaging acquisition, with submillimeter isotropic resolution and good signal-to-noise ratio, for fMRI at ultrahigh field strength. This is demonstrated in fMRI of human brain at 7T with an isotropic resolution of 650 MUm. PMID- 22231861 TI - Modifying the pores of an inverse opal scaffold with chitosan microstructures for truly three-dimensional cell culture. AB - Inverse opal scaffolds have recently emerged as a novel class of scaffolds with uniform and controllable pore sizes for tissue engineering to provide better nutrient transport, a uniform cell distribution, and an adjustable microenvironment for cell differentiation. However, when the pore size of the scaffold is much larger than the dimension of a cell, the cell actually encounters a local 2D environment and the void space associated with the pore can not be efficiently utilized. Here, we demonstrate that a truly 3D microenvironment can be created inside a pore by further functionalizing the as prepared inverse opal scaffold with a second polymer by freeze-drying. The resultant inverse opal scaffold with hierarchically structured pores can enhance both cell proliferation and tissue infiltration. PMID- 22231862 TI - Diversity, emergence, resilience: guides for a new generation of ecohealth research and practice. PMID- 22231860 TI - Hot or not? Discovery and characterization of a thermostable alditol oxidase from Acidothermus cellulolyticus 11B. AB - We describe the discovery, isolation and characterization of a highly thermostable alditol oxidase from Acidothermus cellulolyticus 11B. This protein was identified by searching the genomes of known thermophiles for enzymes homologous to Streptomyces coelicolor A3(2) alditol oxidase (AldO). A gene (sharing 48% protein sequence identity to AldO) was identified, cloned and expressed in Escherichia coli. Following 6xHis tag purification, characterization revealed the protein to be a covalent flavoprotein of 47 kDa with a remarkably similar reactivity and substrate specificity to that of AldO. A steady-state kinetic analysis with a number of different polyol substrates revealed lower catalytic rates but slightly altered substrate specificity when compared to AldO. Thermostability measurements revealed that the novel AldO is a highly thermostable enzyme with an unfolding temperature of 84 degrees C and an activity half-life at 75 degrees C of 112 min, prompting the name HotAldO. Inspired by earlier studies, we attempted a straightforward, exploratory approach to improve the thermostability of AldO by replacing residues with high B-factors with corresponding residues from HotAldO. None of these mutations resulted in a more thermostable oxidase; a fact that was corroborated by in silico analysis. PMID- 22231863 TI - Density of Trematocranus placodon (Pisces: Cichlidae): a predictor of density of the schistosome intermediate host, Bulinus nyassanus (Gastropoda: Planorbidae), in Lake Malawi. AB - From the mid-1980s, we recorded a significant increase in urinary schistosomiasis infection rate and transmission among inhabitants of lakeshore communities in the southern part of Lake Malawi, particularly on Nankumba peninsula in Mangochi District. We suggested that the increase was due to over-fishing, which reduced the density of snail-eating fishes, thereby allowing schistosome intermediate host snails to increase to higher densities. In this article, we collected data to test this hypothesis. The density of both Bulinus nyassanus, the intermediate host of Schistosoma haematobium, and Melanoides spp. was negatively related to density of Trematocranus placodon, the most common of the snail-eating fishes in the shallow water of Lake Malawi. Both these snails are consumed by T. placodon. Transmission of S. haematobium through B. nyassanus only occurs in the southern part of the lake and only at villages where high density of the intermediate host is found relatively close to the shore. Thus, we believe that implementation of an effective fish ban up to 100-m offshore along these specific shorelines in front of villages would allow populations of T. placodon to increase in density and this would lead to reduced density of B. nyassanus and possibly schistosome transmission. To reduce dependence on natural fish populations in the lake and still maintain a source of high quality food, culture of indigenous fishes may be a viable alternative. PMID- 22231864 TI - Social, societal, and economic burden of mal de debarquement syndrome. AB - Mal de debarquement syndrome (MdDS) is a disorder of phantom perception of self motion of unknown cause. The purpose of this work was to describe the quality of life (QOL) of patients with MdDS and to estimate the economic costs associated with this disorder. A modified version of a QOL survey used for another neurological disease (multiple sclerosis; MSQOL-54) was used to assess the impact of MdDS on QOL in 101 patients. The estimated economic costs were based on self reported direct and indirect costs of individuals living in the United States using Medicare reimbursement payment rates for 2011 in 79 patients. Patients with MdDS reported a poor overall QOL as indicated by a mean composite QOL score of 59.26 +/- 1.89 (out of 100). The subcategories having the lowest QOL rating were role limitations due to physical problems (18.32 +/- 3.20), energy (34.24 +/- 1.47), and emotional problems (36.30 +/- 4.00). The overall physical health composite score including balance was 49.40 +/- 1.69, and the overall mental health composite score was 52.40 +/- 1.83. The cost to obtain a diagnosis was $2,997 +/- 337, which included requiring an average of 19 physician visits per patient. The direct cost of MdDS medical care was $826 +/- 140 per patient per year, which mainly included diagnostic imaging and physician visits. The indirect costs (i.e., lost wages) were $9,781 +/- 2,347 per patient per year. Among 65 patients who were gainfully employed when they acquired MdDS, the indirect costs were $11,888 +/- 2,786 per patient per year. Thus, the total annual cost of the disorder ranged from $11,493 +/- 2,341 to $13,561 +/- 2,778 per patient per year depending on employment status prior to developing MdDS. MdDS negatively and dramatically impacts QOL, and also imposes a substantial economic burden on MdDS patients. These findings underscore the need for further basic and clinical research on MdDS. PMID- 22231865 TI - How to identify stroke mimics in patients eligible for intravenous thrombolysis? AB - Since decision-making for thrombolysis in acute stroke settings is restricted to a limited time window and based on clinical assessment and CT findings only, thrombolysis is sometimes applied to patients with a final diagnosis other than a stroke. From a prospectively collected stroke/MRI data bank (2004-2010) with 648 suspected ischemic stroke patients treated with rtPA, we identified patients without evidence of acute infarction on follow-up MRI and a final diagnosis other than a stroke or acute cerebrovascular event. We compared demographics, symptoms, complications, and outcome of patients with stroke mimics (SM) to those with acute infarction. In 42 patients, an SM was diagnosed: seizures in 20, conversion disorder in seven, dementia in six, migraine in three, brain tumor in two, and others in four patients. Patients with SM less often had typical stroke symptoms like dysarthria (p < 0.01), facial palsy (p < 0.001), hemiparesis (p < 0.001), horizontal gaze palsy (p < 0.001), and visuospatial neglect (p = 0.03), while aphasia (p = 0.004) and accompanying convulsions (p = 0.01) occurred more often. Independent predictors of SM were known cognitive impairment, aphasia, and accompanying convulsions. Thrombolysis-related complications (orolingual angioedema) occurred in one SM patient and none of the SM patients deteriorated clinically. Stroke mimics comprise neurological/psychiatric disorders and differ from ischemic stroke patients with regard to the clinical presentation at onset. This might be helpful in deciding which patients should undergo acute stroke MRI to rule out SM, facilitate treatment decisions, and reduce the risk of unnecessary therapy. PMID- 22231866 TI - Muscle imaging findings in GNE myopathy. AB - GNE myopathy (MIM 600737) is an autosomal recessive muscle disease caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Besides the typical phenotype, characterized by the initial involvement of the distal leg muscles that eventually spreads proximally with sparing of the quadriceps, uncommon presentations with a non-canonical clinical phenotype, unusual muscle biopsy findings or both are increasingly recognized. The aim of our study was to characterize the imaging pattern of pelvic and lower limb muscles in GNE myopathy, thus providing additional diagnostic clues useful in the identification of patients with atypical features. We retrospectively evaluated muscle MRI and CT scans of a cohort of 13 patients heterogeneous for GNE mutations and degree of clinical severity. We found that severe involvement of the biceps femoris short head and, to a lesser extent, of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis was consistently present even in patients with early or atypical disease. The vastus lateralis, not the entire quadriceps, was the only muscle spared in advanced stages, while the rectus femoris, vastus intermedius and medialis showed variable signs of fatty replacement. Younger patients showed hyperintensities on T2-weighted sequences in muscles with a normal or, more often, abnormal T1-weighted signal. Our results define a pattern of muscle involvement that appears peculiar to GNE myopathy. Although these findings need to be further validated in a larger cohort, we believe that the recognition of this pattern may be instrumental in the initial clinical assessment of patients with possible GNE myopathy. PMID- 22231867 TI - Does fingolimod in multiple sclerosis patients cause macular edema? AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system and is the common cause of optic neuritis. Fingolimod, an immunosuppressive agent, is used in MS to prevent acute exacerbations. We report a case of relapsing-remitting MS treated with fingolimod. The patient presented with an acute decrease in vision in the left eye. Eye examination showed clinical macular edema (ME) in the left eye, which was confirmed on fluorescein angiogram and optical coherence tomography (OCT). After discontinuation of fingolimod and treatment with topical corticosteroid medication, there was complete resolution of the ME. The ME as a side-effect of fingolimod is reversible after discontinuing, which was seen on OCT. PMID- 22231868 TI - Genotype and phenotype study of 34 Spanish patients diagnosed with oculopharyngeal muscular dystrophy. AB - Oculopharyngeal muscular dystrophy is an autosomal dominant adult-onset disease with several clinical features. The genetic cause is an expanded (GCN)n mutation coding for polyalanine. Severity and the age of onset are variable and may depend on the size of the unstable triplet. Our objectives were to correlate the genotypic and phenotypic features in 34 affected patients, and to complete the molecular analysis for a control Spanish population in order to confirm the (GCN)n polymorphism frequency observed in other populations. We found a correlation between impaired CPK levels and sex. No statistical differences were found when comparing the length in triplet expansion and other variables. The (GCN)n polymorphism's frequency observed in other countries could not be proven in ours. Moreover, no correlation was observed amongst the size of the mutation, the age of onset, and the phenotype. This fact suggests that other conditions apart from the already known genotype could influence the age of onset and the severity of the symptoms. PMID- 22231869 TI - Growth-differentiation factor-15 and functional outcome after acute ischemic stroke. AB - Blood biomarkers may improve the performance in predicting early stroke outcome beyond well-established clinical factors. We investigated the value of growth differentiation factor-15 (GDF-15) to predict functional outcome after 90 days in a prospectively collected patient cohort with symptoms of acute ischemic stroke. Two hundred eighty-one patients with symptoms of acute ischemic stroke were prospectively investigated. Serial blood samples for GDF-15 analysis were obtained after the admission of the patient, after 6 and 24 h. Primary outcome was the dichotomized modified ranking scale (MRS) 90 days after the initial clinical event. Within the final study population (264 patients, mean age 70.3 +/ 12.7 years, 55.3% male), National Institutes of Health Stroke Scale (NIH-SS) [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.141-1.412, p < 0.001] and initial GDF-15 levels (OR 1.029, 95% CI 1.007-1.053, p = 0.011) were independently associated with a MRS >= 2 after day 90 after multiple regression analysis. Growth-differentiation factor-15 levels increase with higher NIH-SS tertiles (p = 0.005). Receiver-operator characteristic curves demonstrated a discriminatory accuracy to predict unfavourable stroke outcome of 0.629 (95% CI 0.558-0.699), 0.753 (95% CI 0.693-812) and 0.774 (95% CI 0.717-0.832) for GDF-15, NIH-SS and the combination of these variables. The additional use of GDF-15 to NIH-SS ameliorates the model with a net reclassification index of 0.044 (p = 0.541) and integrated discrimination improvement of 0.034 (p = 0.443). Growth differentiation factor-15 as an acute stroke biomarker independently predicts unfavourable functional 90 day stroke outcome. Discriminatory value in addition to NIH-SS is only modestly distinct. PMID- 22231871 TI - Causes of coma and their evolution in the medical intensive care unit. PMID- 22231870 TI - REM sleep behavior disorder in Japanese patients with Parkinson's disease: a multicenter study using the REM sleep behavior disorder screening questionnaire. AB - REM sleep behavior disorder (RBD) is known to be observed more frequently in patients with an alpha-synucleinopathy such as Parkinson's disease (PD) than in the general population. The precise prevalence of RBD in Japanese PD patients is not known. Therefore, we investigated the prevalence and the clinical characteristics of patients with RBD in a large population of Japanese patients with PD. We investigated various clinical features and employed the Japanese version of the RBD screening questionnaire on 469 non-demented Japanese PD patients in this multicenter study. Probable or possible RBD was detected in 146 patients (31.1%) and was significantly associated with longer PD duration, higher Hoehn and Yahr stage, higher Unified Parkinson's Disease Rating Scale part III subscale (7 items), more motor fluctuations, and a higher levodopa-equivalent daily dose (p < 0.01). As to the major autonomic dysfunctions, severe constipation was significantly more frequent in PD patients with RBD than in those without it (p < 0.01). The RBD symptoms of 53 patients (39.0%) preceded the onset of PD motor symptoms. The median interval from the onset of RBD symptoms to PD motor symptoms was 17.5 years, and 3 patients had intervals of over 50 years. This large-scale multicenter study revealed that RBD is a frequent non-motor symptom in Japanese patients with PD, which may precede the onset of motor symptoms. Moreover, RBD that increases with the duration and severity of PD may be associated with autonomic dysfunction. PMID- 22231872 TI - Semantic dementia associated with corticobasal syndrome: a further variant of frontotemporal lobe degeneration? PMID- 22231873 TI - Temporal trend of amyotrophic lateral sclerosis incidence in southern Europe: a population study in the health district of Ferrara, Italy. AB - Data about the temporal trend of amyotrophic lateral sclerosis (ALS) incidence in southern Europe are scarce. Incidence studies on ALS have been carried out in the health district of Ferrara, Italy, since 1960s. We expanded the previous studies from 1964 to 2009. The study was prospective with a subsequent retrospective intensive survey of multiple sources of case ascertainment. All patients with a definite and probable ALS according to the original El Escorial criteria were selected. There were 130 incident cases in the years 1964-2009 giving an average annual crude incidence of 1.82 per 100,000 population (95% CI 1.53-2.17). An incidence increase during the study period was estimated in women (chi(2) test for trend = 7.19, p < 0.01) and in the elderly (chi(2) test for trend = 7.803, p < 0.01). The age-adjusted incidence was stable over time in both women (1.19 per 100,000, 95% CI 0.90-1.52) and men (1.45 per 100,000, 95% CI 0.12-1.84). The annual number of new ALS cases in the study population followed the Poisson distribution in both sexes as well as in the elderly group of the population. The present findings suggest that ALS incidence is nearly stable over time. The crude incidence increase we estimated over time among women is mainly explained by population ageing. The increasing incidence in the elderly population was likely the consequence of an increasing precision in ALS diagnosis in the elderly since the increasing attention and care over time of neurologic elderly patients that likely concern elderly women more than previous time periods rather than better case ascertainment of diagnosed patients. The present findings do not support the role of specific environmental factors in ALS pathogenesis. PMID- 22231874 TI - Relating kindergarten attention to subsequent developmental pathways of classroom engagement in elementary school. AB - We examine the relationship between children's kindergarten attention skills and developmental patterns of classroom engagement throughout elementary school in disadvantaged urban neighbourhoods. Kindergarten measures include teacher ratings of classroom behavior, direct assessments of number knowledge and receptive vocabulary, and parent-reported family characteristics. From grades 1 through 6, teachers also rated children's classroom engagement. Semi-parametric mixture modeling generated three distinct trajectories of classroom engagement (n = 1369, 50% boys). Higher levels of kindergarten attention were proportionately associated with greater chances of belonging to better classroom engagement trajectories compared to the lowest classroom engagement trajectory. In fact, improvements in kindergarten attention reliably increased the likelihood of belonging to more productive classroom engagement trajectories throughout elementary school, above and beyond confounding child and family factors. Measuring the development of classroom productivity is pertinent because such dispositions represent precursors to mental health, task-orientation, and persistence in high school and workplace behavior in adulthood. PMID- 22231875 TI - Pathology of endometrioid carcinoma. AB - Endometrioid carcinoma is the third most frequent cancer among women in France. They are divided in two groups: type I and type II. This article describes anatomopathological and molecular features of this disease. Type I carcinoma, the most frequent, develops in a context of hyperoestrogenia. Endometrial glandular hyperplasia is the precursor lesion. The histological type is an endometrioid carcinoma. Its prognosis is good. Type II carcinoma is less frequent. It occurs on an atrophic mucosa. It is usually a more aggressive tumor like serous adenocarcinoma, clear cells carcinoma or carcinosarcoma with a poor prognosis. Type I and type II carcinoma also present different molecular pathways. PTEN inactivation, an early event in carcinogenesis, is the most frequent abnormality in type I carcinoma. An average of 28% of type I carcinoma also acquire PI3K mutations. On the contrary, P53 mutation is involved in 90% of type II carcinoma. Identifying and understanding these two types of endometrial carcinoma led to various therapeutic management. PMID- 22231876 TI - [Neurocutaneous melanosis. Case report and literature review]. AB - Neurocutaneous melanosis is characterized by an increased number of melanocytes and melanin deposit in central nervous system associated with giant melanocytic congenital nevi. Patients with multiple satellite nevi or giant cutaneous melanocytic nevus in a midline location (overlying the back, neck or head) have more likelihood of having neurocutaneous melanosis. In most patients, the neurocutaneous melanosis is asymptomatic, only detectable by MRI; nevertheless, those patients with clinical manifestations have a poor prognosis, dying within 3 years of initial neurological manifestations. We present a patient with giant melanocytic congenital nevi and multiple satellite nevi associated with asymptomatic neurocutaneous melanosis. We emphazise the importance of multidisciplinary evaluation in order to detect early neurological symptoms and/or melanoma. PMID- 22231877 TI - [Rifaximin for hepatic encephalopathy in children. Case report]. AB - Rifaximin is an antibiotic recently approved for the treatment of hepatic encephalopathy in adults. In children more than 12 year-old, it has been approved for travelers' diarrhea and it is also widely used in inflammatory bowel disease. We report, to our knowledge, the first case of a pediatric patient who received rifaximin for hepatic encephalopathy with good clinical outcome. PMID- 22231878 TI - [Pilomatrixoma: unusual clinical presentation]. AB - Pilomatrixoma is a rare, benign neoplasm that is derived from hair matrix cells. It is more frequent during childhood, especially between the ages of 5 and 15 years. Pilomatrixoma is usually a hard, well circumscribed, solitary lesion, and can be located on any part of the body, except palms and soles, with a predilection for maxillofacial region. Multiple pilomatrixomas are rare and they have been associated with various systemic syndromes, of which myotonic dystrophy has been the most described. The diagnosis of pilomatrixoma is fundamentally clinical. Complementary studies such as ultrasound can be useful to confirm the diagnosis. Excisional surgery is the standard curative treatment. We present a 17 year-old female patient with an extremely uncommon clinical presentation of pilomatrixoma: multiple lesions, anetodermic, and rapid growth. PMID- 22231879 TI - [Intracranial hemorrhage as initial presentation of biliary atresia: two cases report]. AB - Biliary atresia in infants occasionally presents as intracranial, nasal or gastrointestinal bleeding, instead of the classical triad of jaundice, acholia and choluria. We present two female infants aged four and two months, who were hospitalized with convulsive episode, cephalohematoma and drowsiness. Computed tomography findings were subdural hemorrhage in one patient and intraventricular and parenchymal bleeding in the other one. At admission they have history, clinical and laboratory signs of cholestasis of unknown etiology. The patient with subdural hemorrhage required surgical drainage. The other girl with intraventricular and parenchymal bleeding received vitamin K and no surgery. Biliary atresia was diagnosed and treated in both girls. At six months both had an adequate neurological outcome and required liver transplantation at one year old. Biliary atresia should be considered in all infants with sudden acute bleeding and cholestasis. PMID- 22231880 TI - [Intestinal malrotation with volvulus associated with severe stress hyperglycemia]. AB - A 2-year-old boy was admitted with diagnosis of diabetes debut, with blood glucose of 500 mg% on admission, without ketosis or metabolic acidosis. He also presented bilious vomiting and brownish bloody stools. He was operated with a presumptive diagnosis of acute intestinal obstruction. The final diagnosis was volvulus, secondary to congenital malrotation. After surgery, he normalized blood sugar levels. The clinical setting was assumed as hyperglycemia without ketosis, with characteristic of severity caused by stress, secondary to volvulus in malrotation. This association has not yet been described. PMID- 22231881 TI - [Hibernoma: brown fat retroperitoneal tumor. Report of a pediatric case]. AB - Hibernoma is a rare benign tumor of soft tissue, composed of brown fat. This tissue is predominant in hibernating animals and hence its name. Because of its rarity in Pediatrics and difficult diagnosis, we report a 3 month-old patient with a diagnosis consistent with an abdominal tumor. Ultrasound and computed tomography exams showed an infiltrative retroperitoneal tumor, with hypervascular and lipomatous features. After tumor excision, histopathological exam confirmed the diagnosis of hibernoma or brown fat tumor. This presentation describes the characteristics of this type of tumor, rare in children, and reviews the fatty tumors, according to their frequency in pediatric patients. PMID- 22231882 TI - [The dissatisfaction in medical practice]. PMID- 22231883 TI - [Advantages and risks associated with the use of electronic medical records]. PMID- 22231884 TI - [Audiologic and molecular screening for hearing loss by 35delG mutation in connexin 26 gene and congenital cytomegalovirus infection]. AB - INTRODUCTION: Hearing loss may be attributed to genetic and environmental factors. Mutations in the gene of the CX26 protein (connexin 26), are responsible for 30-80% of all cases of non-syndromic profound hearing loss. The 35delG is the most frequent variant in the caucasian population. As to environmental factors, the cytomegalovirus (CMV) is the main cause of congenital infection. OBJECTIVES: To determine the prevalence of congenital CMV infection and the frequency of the 35delG mutation in newborns. To identify those at risk of suffering hearing loss in order to do an audiologic follow-up of detected cases. MATERIALS AND METHODS: One thousand and twenty samples of dry blood spots corresponding to newborns were tested using conventional and real time PCR. Audiologic screening was performed to all newborns before hospital discharge. RESULTS: Fifteen out of 1020 subjects were heterozygous for the mutation. No homozygous patients were found. Six out of the samples tested positive for CMV (confirmed by a urine sample), out of which only one newborn was symptomatic. The auditory brainstem response was recorded in all these children. Hearing loss was found in three children with congenital CMV infection and two with 35delG mutation. CONCLUSION: The frecuency of 35delG mutation carriers in our population was 1.3% and the CMV congenital infection prevalence was 0.6%. Audiologic monitoring of these two populations allowed detection of hearing loss of late onset. PMID- 22231885 TI - [Growth, development, social integration and parenting practices on children living with their mothers in prison]. AB - Prisons are considered a very high risk environment, but there is very scarce scientific information on the growth and development of children who live there. OBJECTIVE: With the purpose of evaluating growth and development of children living with their mothers in prison, a cross sectional survey was performed in 68 children aged 0-3 years in Unit 31, a prison for mothers with children located at 30 km from Buenos Aires. METHODS: Weight, supine length, and developmental quotient (Cats Clams) was measured, PRUNAPE, and SQE-SE test were administered (screening tests for detecting developmental and emotional disorders, respectively). Mothers' child rearing practices were assessed with a previously standardized questionnaire. RESULTS: Age range of mothers was 18-46 years, median 23.5 yr. Duration of stay in prison of children was 0.05-35 months. Mean +/- standard error of "Z" score for height was -0.30 +/- 0.12, weight 0.40 +/- 0.12; body mass index 0.91 +/- 0.18; head circumference 0.19 +/- 0.14; and developmental quotient 92.4 +/- 1.7. There were only 7 children out of 67 who failed the PRUNAPE. Mean Cats Clams developmental score was 91.3. ASQ-SE test showed high prevalence (39%) of emotional and social integration problems. Mothers' knowledge about child rearing practices was poorer than that found in a normal urban local population. There were no trends for results to be related to the length of stay in prison. CONCLUSION: Children are shorter and with higher BMI than reference. Emotional disorders are frequent (39%). Mothers' knowledge about child care was poorer than that found in a near population. A program for longitudinal surveillance for all prisons in the country was proposed to the authorities. PMID- 22231886 TI - [Assessment of competence in pediatric postgraduate education: implementation of a pediatric version of the Mini-Cex]. AB - AIMS: Faced with the increased challenge of assessing competences in young doctors, the purpose of the study was to evaluate the implementation of a pediatric version of the Mini-Cex in pediatric trainees as well as the level of satisfaction of teachers and students with the new assessment tool. METHODS AND RESULTS: From July 2007 to August 2009, 54 pediatric trainees were periodically monitored in a variety of clinical settings by 50 teachers. The competences evaluated included medical interviewing, physical examination and counseling skills, humanistic qualities/ professionalism, clinical judgment, organization and overall clinical competence. The feasibility of this study was defined as an average 4 observations per participant, and observations in all clinical rotations. During the study, 388 observations were carried over 54 students (average of 7.18 observations per student); 57% took place in ambulatory settings, 60% were of low complexity and 85% involved healthy children programmed consultations. The ratings for specific competences had little variation; the focus related to the setting. CONCLUSIONS: Used in a variety of settings, with different patient problems, the method was well accepted by both students and teachers. PMID- 22231887 TI - [Validation of a simplified prediction rule to identify etiology in children with pneumonia]. AB - INTRODUCTION: Identifying on admission those children with bacterial pneumonia could reduce inappropriate antibiotic use. The BPS (Bacterial Pneumonia Score) is a clinical prediction rule that accurately identifies children with bacterial pneumonia. Because the interpretation of chest X-ray included in this model could be considered difficult, a simplified version was developed, but this version has not yet been validated in a different population. OBJECTIVE: To validate a simplified clinical prediction rule to identify children with an increased risk of having bacterial pneumonia. METHODS: Children aged under 5 years, hospitalized for pneumonia (viral or bacterial) were included. On admission, axillary temperature, age, absolute neutrophil count, bands, and chest radiograph were evaluated. RESULTS: We included 168 patients (23 with bacterial pneumonia and 145 with viral pneumonia). Those with bacterial pneumonia showed a score higher than those with viral pneumonia (5.3 +/- 2.5 vs. 2.6 +/- 2.02; p <0.001). A score =3 points was identified as the optimum cutoff value to predict bacterial pneumonia (aucROC= 0.79; 95% IC: 0.68-0.90), and was more frequent among patients with bacterial than viral pneumonia (19/23 vs. 42/145, p= 0.003; OR: 4.8; CI95%: 1.4 17.6), achieving 82.6% sensitivity, 50.3% specificity, 20.9% positive predictive value, 94.8% negative predictive value, 1.66 positive likelihood ratio and 0.35 negative likelihood ratio. CONCLUSIONS: The evaluated simplified prediction rule showed a limited diagnostic accuracy on identifying children with bacterial pneumonia, being less accurate than the BPS. PMID- 22231888 TI - [A holistic view of pediatrics]. PMID- 22231889 TI - [Drug use safety in paediatrics]. AB - Many studies have reported increased pediatric susceptibility to the development of errors; children are more vulnerable, so it is very important to guarantee the best therapeutic results at the lowest risk. There are many studies related to prescription of drugs in pediatrics under conditions other than those authorized. Studies show that approximately 50% of the drugs used in children are off label or unlicensed, and in about 70% of pediatric patients at least one drug is prescribed under those conditions. PMID- 22231890 TI - [The prognosis for children of mothers with preeclampsia. Part 2: long-term effects]. AB - Preeclampsia affects between 4% to 8% of all human pregnancies. It compromised both mothers and offspring beyond perinatal period. This is the second of two papers devoted to show the available evidence about the effect of preeclampsia on offsprings beyond perinatal period from cohort studies, some over 60-years follow up. From this perspective, these children are at great risk to develop cardiovascular disorders as hypertension, as well as other disorders, as cancer or neuropsychiatric ones. PMID- 22231892 TI - [Reducing asthma treatment: is it as simple as it seems?]. PMID- 22231891 TI - [Influenza A H1N1 respiratory infection: radiologic findings and correlation with clinical outcome in pediatric inpatients. A pediatric hospital experience]. AB - INTRODUCTION: In the year 2009, the World Health Organization declared the Influenza A H1N1 virus as a pandemic. It has been reported that the radiographic pattern in chest x-ray may predict the clinical outcome in patients affected. OBJECTIVE: To describe the chest x-ray findings in pediatrics patients with confirmed diagnosis of Influenza H1N1 respiratory infection and its correlation with clinical evolution. POPULATION AND METHODS: A retrospective, analytic and descriptive study of 47 pediatric inpatients with confirmed diagnosis of H1N1 influenza who had available chest x-ray was performed. Medical records were reviewed for underlying medical conditions and patient's outcome. RESULTS: 94% of patients had abnormal x-ray. Consolidation and ground-glass opacities had significantly higher frequency in patients who needed more days of oxygen supplement. Initial chest x-ray with lobar consolidation was observed in patients with greater risk of Intensive care unit admission. CONCLUSION: The most frequent radiological patterns found were ground-glass opacities and peribronchial markings. Lobar consolidation and ground-glass opacities are associated with adverse outcome. PMID- 22231893 TI - [Recommendations in Neonatal Resuscitation 2011: 2nd part: Oxygen administration. Ventilatory strategies. Chest compressions]. PMID- 22231894 TI - [Description of a case presented in the previous issue. Patent ductus arteriosus]. PMID- 22231898 TI - Hypothalamic-pituitary-adrenocortical axis function in attention-deficit hyperactivity disorder. AB - The hypothalamic-pituitary-adrenocortical axis plays a critical role in mediating the physiological response to the imposition of stress. There are theoretical reasons to expect reduced basal cortisol secretion and cortisol hyporeactivity in hyperactive/impulsive or combined type attention-deficit hyperactivity disorder (ADHD). Early studies reported profound abnormalities in the diurnal rhythm of cortisol secretion or the cortisol response to stress in children with severe or persistent ADHD. However, subsequent work using larger samples or improved methods has not provided convincing evidence for changes in basal cortisol secretion in non-comorbid forms of ADHD. In contrast, children with ADHD and comorbid oppositional defiant disorder show lower basal cortisol concentrations and a blunted cortisol awakening response. With respect to cortisol reactivity to stress in ADHD, recent evidence has been mixed, with some studies reporting normal cortisol responses and others showing blunted cortisol responses in non comorbid ADHD. Again, it appears important to consider whether comorbid disorders are present, because children with ADHD and comorbid disruptive behavior disorders exhibit blunted cortisol responses, whereas those with comorbid anxiety disorders show enhanced cortisol responses to stress. Longitudinal studies are required to investigate whether abnormalities in cortisol secretion play a causal role in the etiology of ADHD and related disruptive behavior disorders. PMID- 22231897 TI - Magnetic resonance enterography with and without biphasic contrast agent enema compared to conventional ileocolonoscopy in patients with Crohn's disease. AB - BACKGROUND: Magnetic resonance imaging (MRI) of the bowel is a valuable diagnostic tool for assessing disease activity in patients with inflammatory bowel disease (IBD). We compared magnetic resonance enterography (MRE) with and without water enema to conventional ileocolonoscopy to evaluate the advantage of a water enema for MRI diagnostics of Crohn's disease (CD). METHODS: We prospectively evaluated 50 patients with known CD. MRE with enema was performed in 23 cases, whereas 27 patients received an MRE without enema. All patients underwent conventional ileocolonoscopy. We assessed the degree of inflammation in both modalities, evaluating up to seven bowel segments in each patient. We compared MRE with and without rectal enema to each other and to conventional ileocolonoscopy. RESULTS: MRE achieved a sensitivity and specificity of 100% and 74%, respectively, for detection of inflammation in the terminal ileum with enema and a sensitivity and specificity of 72% and 87%, respectively, without enema. Considering the colon, MRE with enema had a sensitivity of 79% (specificity 96%), while the examination without enema showed a sensitivity of 38% (specificity 99%). MRE with enema proved statistically superior to MRE without enema in detecting inflammation in the terminal ileum, ascending colon, and rectum (P < 0.05). CONCLUSIONS: MRE with enema is a valuable diagnostic tool for assessing inflammation in CD patients. Water enema is well tolerated and significantly improves detection of inflammation in the terminal ileum. Water enema should therefore be included in MRE protocols for CD patients. PMID- 22231899 TI - Valvular heart disease in patients exposed to pergolide: insights from the clinical presentation. AB - PURPOSE: The aim of this study was to determine whether the presence of symptoms would aid in the detection of valvular heart disease (VHD) in those exposed to pergolide. METHODS: Utilizing a prospective, cross-sectional study design, patients with an exposure to pergolide were asked regarding the presence or absence of chest pain, shortness of breath or lower extremity edema through a questionnaire. Echocardiograms were obtained on the same day as the questionnaire and were blinded to all staff involved in the study. The sensitivity, specificity, positive and negative predictive value of the reported symptoms towards the outcome moderate or severe valvular regurgitation were obtained. Using the area under the receiver-operating characteristic curve, we also ascertained whether a relationship existed between symptoms, pergolide dose and presence of VHD. To understand the associations between symptoms and echocardiographic covariates, a logistic regression analysis was performed adjusted for age and gender. RESULTS: The sensitivity, specificity, positive and negative predictive value of symptom presentation and total dose was sufficiently low that it did not aid in the determination whether significant valvular regurgitation was present. Multivariable analysis noted a significant association with indexed left atrial volume (p = 0.011), estimated pulmonary artery pressure (p = 0.047) and shortness of breath. CONCLUSIONS: The presence or absence of symptoms does not help guide whether valvular regurgitation is present or absent in individuals exposed to pergolide. Therefore, echocardiography is needed to confirm or refute pergolide-associated VHD. PMID- 22231901 TI - Acute intestinal failure in surgical patients: an audit of incidence, management and outcomes in an irish hospital, and compliance with ASGBI guidelines. AB - BACKGROUND: Acute intestinal failure (AIF) is defined as an inability to tolerate 80% of nutritional requirements delivered enterally for a minimum of 48 h. In surgical patients it commonly relates to abdominal sepsis, intestinal obstruction, or ileus. The prevalence of AIF in surgical units in Ireland has not previously been studied. METHODS: We retrospectively audited the general surgical and ICU departments in St James's Hospital over a 3-month period to identify patients with AIF and followed their management and outcomes focusing on the need for artificial nutrition and surgical intervention. RESULTS: Fifty-four surgical patients (11.4% of surgical emergency admissions) were diagnosed with AIF over the 3-month period. Of these, 30 (55.6%) required nutritional support; 26 (48.2%) had surgical +/- radiological intervention and 6 (11.1%) had radiological intervention alone. Abdominal sepsis was present in 17 (31.5%) patients, a group that required significantly longer parenteral (14.6 vs. 6.7 days, p 0.029) and enteral (13.9 vs. 2.2 days, p 0.005) nutrition than AIF patients without abdominal sepsis. AIF also took longer to resolve in (5.8 vs. 4.2 days, p 0.024) in sepsis versus nonsepsis patients. The majority of patients (n = 43, 80%) were referred to clinical nutrition teams early after having symptoms for 3.77 days (range 1-21) and 72% had complete nutritional assessment clearly documented. CONCLUSION: AIF is common, and can often be treated conservatively. Early linkage with nutrition services is recommended. Early diagnosis of abdominal sepsis is important as this cohort of patients can be particularly difficult to manage. PMID- 22231902 TI - Cannabis, possible cardiac deaths and the coroner in Ireland. AB - BACKGROUND: The elevated risk of triggering a myocardial infarction by smoking cannabis is limited to the first 2 h after smoking. AIM: To examine the possible role of cannabis in cardiac deaths. CASES AND RESULTS: From 3,193 coroners' cases over 2 years, there were 13 cases where the clinical information was compatible with a primary cardiac cause of death. An inquest was held in three cases. Myocardial infarction was the primary cause of death in 54%. Other causes were sudden adult death syndrome, sudden death in epilepsy, and poisoning by alcohol and diazepam. Cannabis was mentioned once only on a death certificate, but not as a cause of death. Blood delta9-tetrahydrocannabinol-carboxylic acid was recorded in one case and in no case was plasma tetrahydrocannabinol (THC) measured. CONCLUSIONS: To attribute sudden cardiac death to cannabis, plasma THC should be measured in the toxicology screen in coroners' cases where urine cannabinoids are positive. A positive urine cannabinoids immunoassay alone is insufficient evidence in the linkage of acute cardiac death and cannabis. PMID- 22231900 TI - Mass spectrometry-based proteomics: qualitative identification to activity-based protein profiling. AB - Mass spectrometry has become the method of choice for proteome characterization, including multicomponent protein complexes (typically tens to hundreds of proteins) and total protein expression (up to tens of thousands of proteins), in biological samples. Qualitative sequence assignment based on MS/MS spectra is relatively well-defined, while statistical metrics for relative quantification have not completely stabilized. Nonetheless, proteomics studies have progressed to the point whereby various gene-, pathway-, or network-oriented computational frameworks may be used to place mass spectrometry data into biological context. Despite this progress, the dynamic range of protein expression remains a significant hurdle, and impedes comprehensive proteome analysis. Methods designed to enrich specific protein classes have emerged as an effective means to characterize enzymes or other catalytically active proteins that are otherwise difficult to detect in typical discovery mode proteomics experiments. Collectively, these approaches will facilitate identification of biomarkers and pathways relevant to diagnosis and treatment of human disease. PMID- 22231903 TI - Lead (Pb)-induced biochemical and ultrastructural changes in wheat (Triticum aestivum) roots. AB - The focus of the present study was to explore lead (Pb)-induced metabolic alterations vis-a-vis ultrastructural changes in wheat roots to establish Pb toxicity syndrome at a structural level. Pb (50-500 MUM) enhanced malondialdehyde (an indicator of lipid peroxidation) and hydrogen peroxide content, and electrolyte leakage, thereby suggesting reactive oxygen species-induced disruption of membrane integrity and oxidative stress in wheat roots. The activities of superoxide dismutases and catalases enhanced upon Pb exposure, whereas those of ascorbate and guaiacol peroxidases declined. Pb-induced metabolic disruption was manifested in significant alterations in wheat root ultrastructure as analyzed by transmission electron microscopy. Pb caused thinning of cell wall (at 50 MUM), formation of amoeboid protrusions and folds and intercellular spaces, and appearance of lesions and nicks/breaks (at >= 250 MUM Pb). Pb was deposited along the cell walls as dark precipitates. At <= 250 MUM Pb, the number of mitochondria increased significantly, whereas structural damage in terms of change of shape and disintegration was observed at >= 250 MUM Pb. Pb reduced the size of nucleoli and induced puff formation (at 250 MUM), resulting in complete disintegration/disappearance of nucleolus at 500 MUM. The study concludes that Pb inhibited wheat root growth involving an ROS-mediated oxidative damage vis-a-vis the ultrastructural alterations in cell membrane and disruption of mitochondrial and nuclear integrity. PMID- 22231904 TI - Predicting future response to certolizumab pegol in rheumatoid arthritis patients: features at 12 weeks associated with low disease activity at 1 year. AB - OBJECTIVE: To determine the prognostic significance of data collected early after starting certolizumab pegol (CZP) to predict low disease activity (LDA) at week 52. METHODS: Data from 703 CZP-treated patients in the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) trial through week 12 were used as variables to predict LDA (Disease Activity Score in 28 joints-erythrocyte sedimentation rate <=3.2) at week 52. We identified variables, developed prediction models using classification trees, and tested performance using training and testing data sets. Additional prediction models were constructed using the Clinical Disease Activity Index (CDAI) and an alternate outcome definition (composite of LDA or American College of Rheumatology criteria for 50% improvement [ACR50]). RESULTS: Using week 6 and 12 data and across several different prediction models, response (LDA) and nonresponse at 1 year were predicted with relatively high accuracy (70-90%) for most patients. The best performing model predicting nonresponse by 12 weeks was 90% accurate and applied to 46% of the population. Model accuracy for predicted responders (30% of the RAPID 1 population) was 74%. The area under the receiver operating curve was 0.76. Depending on the desired certainty of prediction at 12 weeks, ~12-25% of patients required >12 weeks of treatment to be accurately classified. CDAI-based models and those evaluating the composite outcome (LDA or ACR50) achieved comparable accuracy. CONCLUSION: We could accurately predict within 12 weeks of starting CZP whether most established rheumatoid arthritis (RA) patients with high baseline disease activity would likely achieve/not achieve LDA at 1 year. Decision trees may be useful to guide prospective management for RA patients treated with CZP and other biologics. PMID- 22231905 TI - Long-term graft-versus-tumor effect following reduced intensity hematopoietic stem cell transplantation in a child with metastatic renal cell carcinoma. AB - Pediatric renal cell carcinoma (RCC) is rare and different from adult RCC. Although target agents have recently been introduced, allogeneic hematopoietic stem cell transplantation exploiting graft-versus-tumor effect still remains an important treatment option for metastatic RCC. A 2-year-old male with RCC developed hepatic metastases 6 months following radical nephrectomy and subsequent cytokine therapy. Allogeneic reduced-intensity stem cell transplantation (RIST) with early withdrawal of immunosuppression and delayed donor lymphocyte infusions was performed. A second transplantation was undertaken following marrow aplasia. Now he remains progression-free with regression of hepatic metastases 5.7 years after RIST, along with complete donor chimerism. PMID- 22231906 TI - Circulating microRNAs involved in multiple sclerosis. AB - Multiple sclerosis (MS) is an immune-mediated, demyelinating and neurodegenerative disease of the central nervous system. After traumatic brain injury, it is the leading cause of neurology disability in young adults. Considerable advances have been made in identifying genes involved in MS but the genetic and phenotypic complexity associated with this disease significantly hinders any progress. A novel class of small RNA molecules, microRNAs (miRNAs) has acquired much attention because they regulate the expression of up to 30% of protein-coding genes and may play a pivotal role in the development of many, if not all, complex diseases. Seven published studies investigated miRNAs from peripheral blood mononuclear cells, CD4+, CD8+ T cell, B lymphocytes, peripheral blood leukocytes, whole blood and brain astrocytes with MS risk. The absence of MS studies investigating plasma miRNA prompted the current investigation of identifying a circulating miRNA signature in MS. We conducted a microarray analysis of over 900 known miRNA transcripts from plasma samples collected from four MS individuals and four sex-aged and ethnicity matched healthy controls. We identified six plasma miRNA (miR-614, miR-572, miR-648, miR-1826, miR-422a and miR-22) that were significantly up-regulated and one plasma miRNA (miR-1979) that was significantly down-regulated in MS individuals. Both miR-422a and miR-22 have previously been implicated in MS. The present study is the first to show a circulating miRNA signature involved in MS that could serve as a potential prognostic and diagnostic biomarker for MS. PMID- 22231907 TI - Steady state dynamics of a moving model cell. AB - Crawling cell motility results due to treadmilling of a polymerized actin network at the leading edge. Steady state dynamics of a moving cell are governed by actin concentration profiles across the cell. Branching of new filaments implicating Arp2/3 and capping of existing filaments with capZ or Gelsolin are central to the robust functioning of the actin network. Using computer simulations, steady state concentration profiles of globular actin (G actin) and filamentous actin (F actin) are computed. The profiles are in agreement with experimentally observed ones. Simulations unveil that there is an optimal capping and branching rate for which the velocity of the model cell is maximum. Our simulations also indicate that the capping of actin filaments results in an increase in nucleation of new filaments by Arp2/3-induced branching and is in agreement with a recently observed monomer gating model. We observe that Arp2/3 and capping protein exhibit a functional antagonism with respect to the actin network treadmilling. PMID- 22231908 TI - Prevalence of pain in Parkinson's disease: a systematic review using the modified QUADAS tool. AB - Pain has been studied more intensely as a symptom of Parkinson's disease (PD) in recent years. However, studies on the characteristics and prevalence of pain in PD have yielded conflicting results, prompting us to do a systematic review of the literature. A systematic review of the literature was conducted, using different databases. The last inclusion date was March 15, 2011. The modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used, which is especially designed for judging prevalence studies on their methodological quality. Only articles that met the predefined criteria were used in this review. We found 18 articles, of which only 8 met the methodological criteria. Prevalence frequency ranges from 40% to 85% with a mean of 67.6%. Pain is most frequently located in the lower limbs, with almost one-half of all PD patients complaining about musculoskeletal pain (46.4%). The pain fluctuates with on-off periods. Surprisingly, only 52.4% of PD patients with pain used analgesics, most often nonopioids. PD patients seem to be predisposed to develop pain and physicians should be aware of pain as a common feature of PD. As many as one-half of PD patients with pain may be missing out on a potentially useful treatment, and proper treatment could increase quality of life in PD patients. PMID- 22231909 TI - Live monitoring of cargo release from peptide-based hybrid nanocapsules induced by enzyme cleavage. AB - The miniemulsion process is used as a new route for the preparation of enzyme responsive nanocapsules with payload-release properties. Peptide-based hybrid nanocapsules are prepared via interfacial polyaddition containing a water-soluble dye that is efficiently encapsulated inside. The influence of the synthetic parameters as the functionality of the peptide and the nature of the dispersed phase on the structure of the nanocapsules were investigated. After redispersion in water, the enzymatic cleavage of the peptide sequence and the release of the fluorescent dye are both monitored in real time. This is evidenced because of the quenching FRET system framing the recognition site in the peptide sequence, and the fluorescence recovery of the self-quenched encapsulated dye respectively. PMID- 22231910 TI - Residents' corner November 2011. Residents' editorial choice. PMID- 22231911 TI - Residents' corner November 2011. (Carpe)DIEM - dermatological indications for electron microscopy: Ehlers Danlos syndrome. PMID- 22231912 TI - Odontogenic ameloblast-associated and amelotin are novel basal lamina components. AB - Odontogenic ameloblast-associated (ODAM) and amelotin (AMTN) are secreted by maturation stage ameloblasts and accumulate at the interface with enamel where an atypical basal lamina (BL) is present. This study aimed at determining and quantifying the ultrastructural distribution of ODAM and AMTN at the cell-tooth interface. Ultrathin sections of enamel organs from the early to mid- and late maturation stage of amelogenesis were processed for immunogold labeling with antibodies against ODAM, AMTN or with the lectins wheat germ agglutinin, Helix pomatia agglutinin (HPA) and Ricinus communis I agglutinin. Immunolabeling showed that both ODAM and AMTN localized to the BL. Quantitative analyses indicated that at the beginning of maturation there is a concentration of ODAM on the cell side of the BL while AMTN appears more concentrated on the enamel side. In the late maturation stage, such differential distribution is no longer apparent. All three lectins are bound to the BL. Competitive incubation with native lectins did not affect the binding efficiency of ODAM; however, AMTN binding was significantly reduced after incubation with HPA. In conclusion, ODAM and AMTN are bona fide components of the BL associated with maturation stage ameloblasts and they organize into different subdomains during the early maturation stage. The data also suggest that the BL is a dynamic structure that rearranges its organization as enamel maturation advances. Finally, the abrogation of AMTN antibody labeling by HPA supports the presence of O-linked sugars in the molecule and/or its close association with other O-glycosylated molecules. PMID- 22231914 TI - Effect of golimumab combined with methotrexate on radiographic progression in rheumatoid arthritis: comment on the article by Emery et al. PMID- 22231913 TI - Lim1/LIM1 is expressed in developing and adult mouse and human endometrium. AB - Lim1 encodes a homeodomain transcription factor required for head, kidney and female reproductive tract development in the murine embryo. Recently, Lim1 expression was documented in several adult murine and human organs. In the developing female reproductive tract, Lim1 expression was first detected in the Mullerian ducts. Using immunofluorescence, we detected LIM1 expression in a developmental model of human female reproductive tract which was established by recombination of neonatal uterine mesenchyme with human embryonic stem cells. In addition, we report a dynamic expression of Lim1/LIM1 in neonatal and adult mouse, and adult human endometrial epithelium and stroma as revealed by immunofluorescence and quantitative real-time polymerase chain reaction. LIM1 expression was also observed in several endometrial epithelial cancer cell lines (ECC-1, Ishikawa, and HEC1A). Furthermore, we found that Activin A significantly upregulated LIM1 mRNA expression in ECC-1 cells. These studies demonstrate previously unreported Lim1/LIM1 expression in neonatal, adult mouse and human endometrium suggesting Lim1/LIM1 may have a role in endometrial development and remodelling. PMID- 22231915 TI - Resveratrol causes antiatherogenic effects in an animal model of atherosclerosis. AB - BACKGROUND: Resveratrol protects the cardiovascular system by a number of mechanisms, including antioxidant and anti-platelet activities. OBJECTIVE: To assess the potential anti-inflammatory and antiatherogenic effects of resveratrol using rabbits fed a hypercholesterolemic diet (1% cholesterol). METHODS: Twenty white male rabbits were selected and divided into two groups: control group (CG), 10 rabbits; and resveratrol group (RG), 10 rabbits. The animals were fed a hypercholesterolemic diet for 56 days. For the RG diet, resveratrol (2 mg/kg weight/day) was added from days 33-56. RESULTS: There was no significant difference in the total serum cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides between the groups. Of the CG, 70% had advanced aortic atherosclerotic lesions (types III, IV, V, or VI). All animals from the RG had mild aortic atherosclerotic lesions (types I or II, or no lesions). The intima area and the intima/media layer area ratio was significantly lower in the RG as compared to the CG (p<0.001). Positive areas for VCAM-1 molecules were lower in the RG (p=0.007). The MCP-1 and IL-6 concentrations were lower in the RG than the CG (p=0.039 and p=0.015, respectively). CONCLUSION: Resveratrol had significant anti-atherogenic and anti-inflammatory effects in an animal model with rabbits fed a hypercholesterolemic diet (1% cholesterol). PMID- 22231916 TI - Anthropometric measures as predictors of cardiovascular disease risk factors in the urban population of Iran. AB - BACKGROUND: Overweight and obesity are an important public health problem in society, due to their association with various chronic diseases. OBJECTIVE: The purpose of this study is to determine the prevalence and distribution of overweight and obesity, using different anthropometric measurements and to identify the best anthropometric indicator which is most closely related to cardiovascular disease (CVD) risk factors in an Iranian urban population. METHODS: This cross-sectional study was conducted with 991 men and 1188 women aged 15 to 64 years. Body mass index (BMI), waist circumference (WC), waist-to hip ratio (WHR), waist-to-height ratio (WHtR) and percentage of body fat were measured. A fasting blood specimen was obtained. CVD risk factors, including fasting blood glucose, triglycerides, total cholesterol (Tchol), low-density (LDL C) and high-density-lipoprotein cholesterol (HDL-C) were assessed. RESULTS: Based on BMI, more than 49% of men and 53% of women were either overweight or obese with 10.2% of men and 18.6% of women being obese. In both men and women, the prevalence of overweight was greater among 40-49 year olds and the prevalence of obesity was greater among those 50+ years. Using the multiple regression analysis, BMI, WHtR and WHR explained the highest percentage of variation of triglycerides, Tchol/HDL-C ratio and LDL-C in men, respectively, whereas WHR explained the highest percentage of variation of triglycerides and WC explained the highest percentage of variation of Tchol/HDL-C ratio and LDL-C in women. CONCLUSION: Our data indicated that WHR and WHtR were the anthropometric indicators that best predicted CVD risk factors in men and WHR and WC in women. PMID- 22231917 TI - Prevalence and predictors of pulmonary embolism in patients with acutely decompensated heart failure. AB - BACKGROUND: The prevalence of pulmonary embolism (PE) has not been reported in patients hospitalized due to classical findings of decompensated heart failure (HF). OBJECTIVE: To describe the prevalence of PE and to assess the diagnostic accuracy of the Wells and Geneva scores in patients hospitalized due to HF. METHODS: Patients hospitalized primarily due to HF underwent systematic ventilation-perfusion lung scan, and PE was defined by a result of high probability. Aiming at interpreting, low clinical probability of PE was defined as prevalence < 5%, according to the literature. When calculating the sample size, 49 patients were required to provide a 95% confidence interval with +/-10% accuracy, estimating an a priori prevalence of 15%. RESULTS: Of 51 patients studied, six had a high probability of PE on lung scan, resulting in 12% prevalence (95% CI = 5% - 23%). The Wells and Geneva scores had an area under the ROC curve of 0.53 (95% CI = 0.27 - 0.80; p = 0.80) and 0.43 (95% CI = 0.13 - 0.73; p = 0.56), respectively, indicating lack of accuracy for the diagnosis of PE. Alternatively, variables related to HF showed a tendency towards association with PE, and an exploratory model formed by that type of variable showed diagnostic accuracy for PE (ROC = 0.81; 95% CI = 0.66 - 0.96; p = 0.01). CONCLUSION: (1) Despite the lack of primary suspicion, patients admitted with HF have intermediate clinical probability of concomitant PE; (2) the scores usually used to estimate the clinical probability of PE do not apply to the population with HF, and future predictive models should consider variables related to that syndrome. PMID- 22231918 TI - Stochastic gene expression stabilization as a new therapeutic strategy for cancer. AB - Current differentiation therapies for cancer may not be effective because it might not be enough to only use molecules targeting chromatin remodelers. It may also be necessary to stabilize the re-expressed genes to convert malignant cells into benign ones. PMID- 22231919 TI - Stereochemistry of benzylic carbon substitution coupled with ring modification of 2-nitrobenzyl groups as key determinants for fast-cleaving reversible terminators. PMID- 22231920 TI - Less advanced stages of colon cancer in patients with type 2 diabetes mellitus: an unexpected finding? AB - INTRODUCTION: Epidemiological studies have found an increased risk for colon cancer and faster disease progression in patients with type 2 diabetes mellitus (T2DM). We aimed to determine whether patients with T2DM are diagnosed with more advanced stages of colorectal cancer, i. e., metastasized disease (UICC III and IV), at the time of diagnosis, since such a finding may have an impact on future guidelines for patients with T2DM. MATERIALS AND METHODS: A cross-sectional analysis of colorectal cancer patients was performed. Stages at diagnosis in patients with (18.0%) or without (82%) T2DM were compared using logistic regression analysis to correct for confounders. RESULTS: Patients with T2DM were older, more obese, and more often male (each p<0.05). Unexpectedly, patients with T2DM had a lower risk for metastasized disease at diagnosis (p=0.023). Correction for age, gender, BMI, smoking and aspirin intake in a multiple logistic regression analysis did not change the result (OR=0.57, p=0.037). When looking at individual cancer stages rather than collapsed categories, there was a trend for less advanced stages in patients with T2DM (p=0.093). Excluding stage I because of potential screening bias due to the introduction of (insurance-covered) colonoscopy screening improved model fit, and confirmed less advanced cancer stages (p=0.0246). CONCLUSIONS: Possibly because of earlier detection, patients with T2DM may be at lower risk for advanced stages of colon cancer at diagnosis. Further studies are warranted to confirm our results and to investigate the impact of closer medical surveillance in patients with type 2 diabetes mellitus. PMID- 22231921 TI - Increased DNA-glycation in type 2 diabetic patients: the effect of thiamine and pyridoxine therapy. AB - BACKGROUND: It is well known that advanced glycation plays an important role in the progression of diabetic complications. Although several studies have been done on protein glycation, studies related to DNA glycation is limited. The aim of this study is primarily to investigate DNA glycation in diabetes mellitus and secondarily to observe the effects of vitamins B(1) and B(6). MATERIALS AND METHODS: Patients with diabetes (n=31) were divided into 2 groups as patients with nephropathy (n=17) and without nephro-pathy (n=14). The control group was recruited from age and sex matched healthy individuals (n=30). In the experimental groups, DNA glycation was measured in DNA isolated from leukocytes. HbA(1c), thiamine pyrophosphate (TPP) and pyridoxal 5-phosphate (PLP) levels were determined in whole blood; glucose and insulin levels in plasma. Patients with nephropathy were further divided into 2 groups and were administered either vitamins B(1) + B(6) (n=6) or B(6) (n=11), for 5 months. All the measurements were performed both before and after the vitamin administration period. RESULTS: AGE-DNA levels were found significantly higher in diabetic patients (p<0.05) than the healthy controls. AGE-DNA and PLP levels were negatively correlated in control patients (r= - 0.361, p<0.05). The combined administration of B(1) and B(6) caused a significant decrease in AGE-DNA values (p<0.05). CONCLUSION: This study shows that the combined administration of vitamins B(1) and B(6) to diabetic nephropathy patients causes a decrease in DNA glycation in leukocytes. Importantly the administration of vitamin B(6) alone did not have such an effect. To our knowledge, these are the first reported findings related to glycation of leukocyte nuclear DNA in diabetic nephropathy. PMID- 22231922 TI - Expression and significance of lipin1 and AMPKalpha in hepatic insulin resistance in diet-induced insulin resistance rats. AB - BACKGROUND: Lipin1, a lately indentified adipokine, may link obesity with insulin resistance and diabetes. The present study aimed to investigate the changes and significance of lipin1 expression and lipin1-AMPK signaling in diet-induced hepatic insulin resistance. METHODS: 24 4-week-old Male Wistar rats were randomly divided into 2 groups: (1) control group (CO), (2) high-fat diet group (HF). Insulin sensitivity was evaluated by hyperinsulinemic-euglycemic clamp technique. The mRNA levels of alpha1 and alpha2 subunit of AMPKalpha as well as Lipin1 were measured using Real-time RT-PCR. The activities of AMPKalpha and Akt were evaluated by detection of p-AMPKalpha (Thr-172) and p-Akt (ser473) by Western blot. RESULTS: After treatment of 4 months, HF group showed significantly increased levels of body weight, fasting plasma glucose and insulin levels; Plasma and liver total cholesterol (TC), triglycerides (TG) levels were also markedly elevated; Lipin1 expression at both mRNA and protein levels were significantly deceased. Compared with CO group, the mRNA and protein levels of AMPKalpha1 and AMPKalpha2 were not changed, whereas the p-AMPK (Thr-172) and p AKT (ser473) levels in liver were significantly decreased in HF group. CONCLUSIONS: These findings indicated that the decrease in lipin1 expression and AMPKalpha activation may contribute to hepatic insulin resistance in diet-induced obese rats. PMID- 22231923 TI - The control of hyperglycemia in alloxan treated diabetic mice through the stimulation of hepatic insulin synthesis due to the production of nitric oxide. AB - OBJECTIVE: The hepatocytes from the adult mice when stimulated by glucose had been reported to synthesize and secrete insulin. The feasibility of controlling hyperglycemia in alloxan induced diabetic mice through hepatic synthesis of insulin was studied. MATERIALS AND METHODS: Insulin synthesis was determined by in vitro translation of mRNA and by immunohistochemistry of the hepatocytes and assayed by enzyme linked immunosorbent assay (ELISA). Dermcidin isoform 2 (dermcidin) was measured by ELISA. Nitric oxide was measured by methemoglobin method. Insulin synthesis was quantitated by immunoblot technique and the expression of proinsulin genes I and II in the hepatocytes was quantitated by cDNA synthesis. RESULTS: It was found that in contrast to normal hepatocytes, the hepatocytes from the diabetic mice showed impaired insulin synthesis in the presence of glucose that was related to the inhibition of nitric oxide synthesis through the synthesis of dermcidin, a potent competitive inhibitor of nitric oxide synthase. The increase of systemic NO synthesis either by oral use of 0.7 mM acetyl salicylic acid (aspirin) or by dermal application of 0.28 mmol sodium nitroprusside in saline soaked in cotton pad was found to decrease blood glucose level from 600 mg/dL to 120 mg/dL with concomitant increase of plasma insulin level from 5 uunits/dL to 38 uunits/dL. And subsequently normalized dermcidin level from 80 nM to 4.5 nM within 24 h (p<0.001; n=10). CONCLUSION: Our studies suggested the possibility of controlling hyperglycemia in alloxan induced diabetic mice by the stimulation of the hepatic insulin synthesis through the systemic stimulation of NO production in the hepatocytes. PMID- 22231924 TI - Availability of self-recorded axillary temperature for assessment of thermic effects of food: relationship between HDL-cholesterol level and postprandial thermoregulation in type 2 diabetic patients. AB - AIMS: The present study was performed to develop a simple procedure for assessment of body temperature and to determine whether postprandial thermoregulation is related to metabolic regulation in diabetic patients. METHODS: We examined 101 male and female subjects with diabetes. Axillary temperature was measured prior to and after all meals (3 meals per day) and self recorded for 1 week. The averages were calculated. Positive postprandial thermoregulation (PPT) was defined as a pattern in which each of 3 average postprandial temperatures was higher than the corresponding 3 preprandial temperatures. Negative postprandial thermoregulation (NPT) was defined as the pattern except for PPT. RESULTS: A significant increase in postprandial temperature was observed. With the exception of high-density lipoprotein (HDL) cholesterol levels, there were no relationships between the categorized postprandial thermoregulation and other factors, including age, sex, body mass index, thyroid function, HbA1c, diabetic complications, lipid metabolism, and calorie intake. Logistic analysis indicated an independent positive relation between HDL-cholesterol and PPT. CONCLUSION: A simple method for measurement of body temperature indicated that HDL-cholesterol level was predominantly associated with thermic effects of food in diabetic patients, while other metabolic factors showed no such relations. HDL-cholesterol may affect the postprandial regulation of body temperature in diabetic patients. PMID- 22231925 TI - Metabolic syndrome indicators and target organ damage in urban active coping African and Caucasian men: the SABPA study. AB - Psychosocial stress relating to an urban environment or acculturation increases the prevalence of metabolic syndrome (MetS). The objectives of this study were firstly to indicate and compare differences regarding appraisal of stress or active coping responses in urban African (n=88) and Caucasian (n=101) male teachers of South Africa, in accord with the prevalence of MetS indicators. And secondly to investigate the extent to which utilisation of active coping responses, together with MetS indicators, predict target organ damage, in these men. The Coping Strategy Indicator determined high and low active coping responses in male teachers from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. SABPA inclusion and exclusion criteria were used. Additionally, diabetic medication users (n=8), and participants with renal impairment (n=2) or HIV positive (n=13), were excluded. MetS indicators included glucose, triglyceride, high-density lipoprotein cholesterol, blood pressure, and waist circumference, independent of confounders (age, physical activity, gamma glutamyl transferase). Microalbuminuria and carotid intima-media thickness indicated target organ damage. More MetS indicators exceeded the IDF cut-off points in high active coping African men (14.71%) than in their Caucasian counterparts (3.33%), as determined from chi2 analyses. Furthermore, stepwise regressions indicated that more MetS indicators predicted endothelial dysfunction, especially in the high active coping African men. High active coping African men showed more manifestation of MetS, compared to their Caucasian counterparts, and revealed progress towards endothelial dysfunction. PMID- 22231926 TI - The role of TG2 in ECV304-related vasculogenic mimicry. AB - Tumour vasculogenesis can occur by a process referred to as vasculogenic mimicry, whereby the vascular structures are derived from the tumour itself. These tumours are highly aggressive and do not respond well to anti-angiogenic therapy. Here, we use the well characterised ECV304 cell line, now known as the bladder cancer epithelial cell line T24/83 which shows both epithelial and endothelial characteristics, as a model of in vitro vasculogenic mimicry. Using optimised ratios of co-cultures of ECV304 and C378 human fibroblasts, tubular structures were identifiable after 8 days. The tubular structures showed high levels of TG2 antigen and TG in situ activity. Tubular structures and in situ activity could be blocked either by site-directed irreversible inhibitors of TG2 or by silencing the ECV304 TG2 by antisense transfection. In situ activity for TG2 showed co localisation with both fibronectin and collagen IV. Deposition of these proteins into the extracellular matrix could be reduced by inclusion of non-cell penetrating TG inhibitors when analysed by Western blotting suggesting that the contribution of TG2 to tube formation is extracellular. Incubation of ECV304 cells with these same irreversible inhibitors reduced cell migration which paralleled a loss in focal adhesion assembly, actin cytoskeleton formation and fibronectin deposition. TG2 appears essential for ECV304 tube formation, thus representing a potential novel therapeutic target in the inhibition of vasculogenic mimicry. PMID- 22231927 TI - Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis? AB - OBJECTIVE: Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome-wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants. METHODS: Overall, 502 AS patients were examined, consisting of 312 patients who had first-degree relatives (FDRs) with AS (familial) and 190 patients who had no FDRs with AS or spondylarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York criteria for AS. The patients were recruited from 2 US cohorts (the North American Spondylitis Consortium and the Prospective Study of Outcomes in Ankylosing Spondylitis) and from the UK-Oxford cohort. The frequencies of AS susceptibility loci in IL-23R, IL1R2, ANTXR2, ERAP 1, 2 intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag single-nucleotide polymorphism (SNP) rs4349859 were compared between familial and sporadic cases of AS. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size. RESULTS: HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (odds ratio 4.44 [95% confidence interval 2.06, 9.55], P = 0.0001). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend toward higher frequency in the multiplex cases (P = 0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined. CONCLUSION: HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-major histocompatibility complex susceptibility loci is not markedly different between the sporadic and familial cases of AS. PMID- 22231929 TI - Antibiotic prescribing trends in a paediatric sub-population in Ireland. AB - PURPOSE: Little is known about antibiotic prescribing in Irish children. This study aims to examine antibiotic prescribing patterns in Irish children and associated costs and to compare this with European findings. METHODS: A retrospective analysis of the Irish Health Services Executive (HSE) pharmacy claims database 2004-2009 for the General Medical Services (GMS) scheme for dispensed medications. This represents 28% of Irish children but over-represents lower socio-economic groups. Overall prescribing rates were reported over time (2004-2009), age (0-4, 5-11, 12-15 years) and gender. Statistical comparison is made using negative binomial regression. Overall prescribing rates for the most commonly prescribed drugs were calculated. Associated cost of prescribing also was calculated. European prescribing data were retrieved from the literature. RESULTS: Rates remained stable from 2004 (631/1000 GMS population; 95%CI 628-634) to 2009 (621/1000; 95%CI 618-624). An interaction effect emerged between gender and age. Rates were generally higher for girls, except for the boys aged 0-4 years. The preferred choice of agents changed across years, with co-amoxiclav becoming the most prescribed drug in 2009 (308/1000; 95%CI 306-310). The total cost of antibiotics increased from ?4.4 million in 2004 to ?6.0 million in 2009. Higher overall rates of antibiotic prescribing emerged compared with available European data. Differences were observed between prescribing of some first-line and second-line drugs. CONCLUSIONS: Age and gender trends are consistent with international literature. However, Ireland has higher overall prescribing rates relative to some European countries. This suggests that a quality improvement in prescribing intervention is warranted. PMID- 22231928 TI - Recent advances in stealth coating of nanoparticle drug delivery systems. AB - Modifying surfaces of nanoparticles (NPs) with polyethylene glycol (PEG), the so called PEGylation, is the most commonly used method for reducing premature clearance of NPs from the circulation. However, several reports point out that PEGylation may negatively influence the performance of NPs as a drug carrier. Alternative surface modification strategies, including substitute polymers, conditional removal of PEG, and biomimetic surface modification, may provide solutions for the limitations of PEG. PMID- 22231930 TI - Multimodality imaging for assessment of myocardial viability: nuclear, echocardiography, MR, and CT. AB - The assessment of myocardial viability may be an important component of the evaluation of patients with coronary artery disease and left ventricular dysfunction. The primary goal of viability assessment in such patients is to guide therapeutic decisions by determining which patients would most likely benefit from revascularization. In patients with chronic coronary artery disease, left ventricular dysfunction may be a consequence of prior myocardium infarction, which is an irreversible condition, or reversible ischemic states such as stunning and hibernation. Imaging techniques utilize several methods to assess myocardial viability: left ventricular function, morphology, perfusion, and metabolism. Each technique (echocardiography, nuclear imaging, magnetic resonance imaging, and x-ray computed tomography) has the ability to assess one or more of these parameters. This article describes how each of these imaging modalities can be used to assess myocardial viability, and reviews the relative strengths and limitations of each technique. PMID- 22231931 TI - Tests of linkage and allelic association between markers in the 1p36 PRKCZ (protein kinase C zeta) gene region and bipolar affective disorder. AB - Three linkage studies of families with multiple cases of bipolar disorder and/or unipolar affective disorder have confirmed the involvement of the chromosome 1p36 region in the etiology of affective disorders with LOD scores of 2.7, 3.6, and 3.97. We investigated the protein kinase C zeta gene (PRKCZ) as a susceptibility locus for bipolar disorder because it is highly brain expressed and is localized close to the marker D1S243 which was linked to affective disorder in a single large UCL bipolar disorder family with a LOD of 3.1. PRKCZ encodes an unusual type of protein kinase which affects axonal differentiation through Wnt signaling. We genotyped four microsatellite markers and nine single nucleotide polymorphism (SNP) markers within or near the PRKCZ gene in the UCL case-control sample of 600 bipolar disorder patients and up to 605 supernormal controls. Markers D1S243 and rs3128396 were significantly associated with bipolar disorder (empirical P = 0.037 and P = 0.040, respectively). We also included data from eight SNPs which were genotyped as part of our GWA study on bipolar disorder for association analysis. Tests of haplotypic association found that a haplotype block comprising markers rs3128296, rs2503706, and rs3128309 was associated with bipolar disorder (empirical P = 0.004). A previous linkage study had shown greater evidence for linkage within female cases compared to males. Therefore, to assess if the association was sex-specific, we performed a female-only allelic association analysis, which resulted in SNPs rs3128296 and rs3128309 becoming associated with bipolar disorder (P = 0.004 and P = 0.016, respectively). PRKCZ may play a role in susceptibility to bipolar affective disorder. PMID- 22231932 TI - An experimental xenograft mouse model of diffuse pontine glioma designed for therapeutic testing. AB - The prognosis for diffuse infiltrating pontine gliomas (DIPG) remains extremely poor, with the majority of patients surviving less than 2 years. Here, we have adapted standard xenograft techniques to study glioma growth in the mouse brainstem, and have utilized the mouse model for studying a relevant therapeutic for treating DIPGs. bioluminescence imaging monitoring revealed a progressive increase in signal following the injection of either of two tumor cell types into the brainstem. Mice with orthotopic GS2 tumors, and receiving a single 100 mg/kg dose of temozolomide showed a lengthy period of decreased tumor luminescence, with substantially increased survival relative to untreated mice (P < 0.001). A small molecule inhibitor that targets cdk4/6 was used to test AM-38 brainstem xenograft response to treatment. Drug treatment resulted in delayed tumor growth, and significantly extended survival. Our results demonstrate the feasibility of using an orthotopic brainstem tumor model in athymic mice, and for application to testing therapeutic agents in treating DIPG. PMID- 22231933 TI - Abnormal expression of E-cadherin in tumor cells is associated with poor prognosis of gastric carcinoma. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to clarify the relationship of hepatocyte growth factor (HGF), c-Met, and E-cadherin with clinicopathological parameters and prognosis in gastric carcinoma (GC). METHODS: 114 specimens were collected from GC patients and expression of HGF, c-Met, and E cadherin in tissue microarray was evaluated by immunohistochemical staining. Correlation between immunostainings and clinicopathological parameters, follow-up data of patients, was analyzed statistically. RESULTS: Abnormal E-cadherin expression was found in 60.5% (69/114) and associated with tumor depth (P = 0.003), lymph node metastasis (P = 0.001) and advanced clinical stage (P = 0.001). High-expression of HGF and c-Met were found in 64.0% (73/114) and 82.4% (94/114), respectively. High c-Met expression was significantly associated with advanced clinical stage (P = 0.001) and lymph node metastasis (P = 0.011) of GC. In univariate survival analysis, high-expression of HGF and c-Met, and abnormal E cadherin were significantly associated with poor prognosis of GC patients. However, only abnormal E-cadherin expression (P = 0.001) and tumor depth (P = 0.010) emerged as strong independent prognostic factors for overall survival of GC patients. CONCLUSION: We found significant correlation among HGF/c-Met, E cadherin expression and worse prognosis of patients with GC. Abnormal E-cadherin expression may serve as an independent predictive factor for prognosis of GC patients. PMID- 22231934 TI - Crystal structure of hypothetical protein TTHB210, controlled by the sigma(E) /anti-sigma(E) regulatory system in Thermus thermophilus HB8, reveals a novel homodecamer. PMID- 22231935 TI - Non-viral transfection of goat germline stem cells by nucleofection results in production of transgenic sperm after germ cell transplantation. AB - Germline stem cells (GSCs) can be used for large animal transgenesis, in which GSCs that are genetically manipulated in vitro are transplanted into a recipient testis to generate donor-derived transgenic sperm. The objectives of this study were to explore a non-viral approach for transgene delivery into goat GSCs and to investigate the efficiency of nucleofection in producing transgenic sperm. Four recipient goats received fractionated irradiation at 8 weeks of age to deplete endogenous GSCs. Germ cell transplantations were performed 8-9 weeks post irradiation. Donor cells were collected from testes of 9-week-old goats, enriched for GSCs by Staput velocity sedimentation, and transfected by nucleofection with a transgene construct harboring the human growth hormone gene under the control of the goat beta-casein promoter (GBC) and a chicken beta-globin insulator (CBGI) sequence upstream of the promoter. For each recipient, transfected cells from 10 nucleofection reactions were pooled, mixed with non-transfected cells to a total of 1.5 * 10(8) cells in 3 ml, and transplanted into one testis (n = 4 recipients) by ultrasound-guided cannulation of the rete testis. The second testis of each recipient was removed. Semen was collected, starting at 9 months after transplantation, for a period of over a year (a total of 62 ejaculates from four recipients). Nested genomic PCR for hGH and CBGI sequences demonstrated that 31.3% +/- 12.6% of ejaculates were positive for both hGH and CBGI. This study provides proof-of-concept that non-viral transfection (nucleofection) of primary goat germ cells followed by germ cell transplantation results in transgene transmission to sperm in recipient goats. PMID- 22231936 TI - Hypertension in type 1 diabetic patients-the influence of body composition and body mass index: an observational study. AB - OBJECTIVE: To estimate the influence of body composition and body mass index on blood pressure in type 1 diabetic patients. METHODS: This cross-sectional, observational study included 45 type 1 diabetic patients and 30 age and sex matched healthy volunteers. Blood pressure, anthropometric measurements, and body composition by dual X-ray absorptiometry (DXA) were done for all patients and controls. T-test, one way ANOVA and multiple regressions were used for statistical analyses. RESULTS: Twenty diabetic patients (44.4%) had hypertension. Hypertensive diabetic patients had the highest total fat mass %, soft tissue fat mass %, abdomen fat % and fat/lean ratio followed by non hypertensives and the least was the controls (p=0.0001). Abdominal fat % was the only parameter significantly associated with mean arterial blood pressure (beta-5.8, 95% CI: 3.7 8.0, p=0.0001) and systolic blood pressure (beta-8.6, 95% CI: 5.4-11.9, p=0.0001) by stepwise multiple regression analysis in the diabetic patients. In the contrary, abdominal fat % (beta-2.7, 95% CI: 0.9-4.5, p=0.006), duration of diabetes (beta-2.5, 95% CI: 1.4-3.5, p=0.0001) and fat/ lean ratio (beta-11.7, 95% CI: 1.5-21.9, p=0.03) were related to diastolic blood pressure. CONCLUSION: Diabetes is associated with an increase in body fat especially abdominal, which leads to an increase in insulin resistance and decrease in lean mass. In type 1 diabetic patients, blood pressure depends on body mass index SDS and fat mass. Abdominal fat is the only factor related to mean arterial blood pressure and systolic blood pressure. PMID- 22231937 TI - Can quantitative regional myocardial dynamics contribute to the differential diagnosis of acute stress cardiomyopathy? AB - Acute stress-induced cardiomyopathy has excessive sympathetic stimulation, microvascular dysfunction similar to hypertension. Regional prominence of left ventricular (LV) septal base and stress-induced LV hypercontractility are the particular features of both acute and chronic stress-related conditions. Novel imaging methods have shown that stress-induced cavity dilation and myocardial wall abnormalities can be a reflection of underlying previous exaggerated hypertensive episodes due to sympathetic overdrive, which results in microvascular dysfunction. Hypertension-mediated chronic stress due to increased after load episodes is possibly the main reason for blunted LV myocardial wall motion capability in patients with stress-related exaggerated hypertension. In this short report, we discussed the interrelation of myocardial dynamics and stress-induced exaggerated hypertension episodes. In addition, quantitative echocardiographic methods which previously were used for description of particular features including LV regional dynamics in hypertensive heart disease can be an option in differential diagnosis of potential cases of acute stress induced cardiomyopathy. PMID- 22231938 TI - Transcatheter treatment of interrupted arcus aorta in two adolescents. PMID- 22231939 TI - Catheter ablation of atrial fibrillation in a patient with unusual pulmonary vein anatomy involving right upper pulmonary vein. PMID- 22231940 TI - Changes of high-sensitive troponin level in a patient with paroxysmal supraventricular tachycardia. PMID- 22231941 TI - [Valve-sparing operation for aortic coaptation/valve-sparing operation for ascending aorta aneurysm]. PMID- 22231942 TI - Percutaneous renal denervation in patients with resistant hypertension-first experiences in Turkey. PMID- 22231943 TI - [Impact factors of cardiovascular journals and ethics in 2010]. PMID- 22231944 TI - Risk factors among coronary heart disease patients in the context of the Albanian paradox. PMID- 22231945 TI - [Reposition of the coronary sinus lead transvenously via femoral vein]. PMID- 22231946 TI - Pre-operative use of anti-aggregants may reduce atrial fibrillation development rate during coronary bypass surgery. PMID- 22231947 TI - [Endovascular stent graft repair of abdominal and thoracic aortic aneurysms]. PMID- 22231948 TI - A cyst within a cyst. PMID- 22231949 TI - A giant mediastinal carcinoid tumor that compresses the pulmonary artery and vein. PMID- 22231950 TI - Giant pulmonary artery aneurysm due to chronic pulmonary embolus associated with pulmonary hypertension. PMID- 22231951 TI - Resolution of obstructive prosthetic valve thrombosis after coronary embolism. PMID- 22231952 TI - Role of cardiovascular magnetic resonance in the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia with left ventricular involvement. PMID- 22231953 TI - [Change of flag in the Anatolian Journal of Cardiology, which has newly become a 10-year-old]. PMID- 22231955 TI - Inhibiting calcineurin activity under physiologic tonicity elevates anabolic but suppresses catabolic chondrocyte markers. AB - OBJECTIVE: The physiologic interstitial tonicity of healthy articular cartilage (350-480 mOsm) is lowered to 280-350 mOsm in osteoarthritis (OA). This results in loss of tissue prestress, altered compressive behavior, and, thus, inferior tissue properties. This study was undertaken to determine whether physiologic tonicity in combination with the inhibition of calcineurin (Cn) activity by FK 506 has synergistic effects on human articular chondrocytes and explants in vitro. METHODS: OA chondrocytes and explants and non-OA chondrocytes were cultured in cytokine-free medium of 280 mOsm or 380 mOsm with or without Cn inhibition by FK-506. Chondrogenic, hypertrophic, and catabolic marker expression was evaluated at the messenger RNA (mRNA), protein, and activity levels. RESULTS: Compared to OA chondrocytes cultured at 280 mOsm, those cultured at 380 mOsm had increased expression of mRNA for chondrogenic markers (e.g., ~13 fold for COL2; P < 0.001), and decreased COL1 expression (~0.5 fold, P < 0.01). Inhibiting Cn activity under physiologic tonicity further enhanced the expression of anabolic markers at the mRNA level (~50 fold for COL2; P < 0.001, ~2 fold for AGC1; P < 0.001, and ~3.5 fold for SOX9; P < 0.001) and at the protein level (~6 fold for type II collagen; P < 0.001). Cn inhibition suppressed relevant collagenases as well as hypertropic and mineralization markers at the mRNA and activity levels. Expression of aggrecanase 1 and aggrecanase 2 was not influenced by tonicity or FK-506 alone, but the combination suppressed both, by ~50% (P < 0.05) and ~40% (P < 0.001), respectively. Generally, similar anabolic and antihypertrophic effects were observed in ex vivo cartilage explant cultures and non-OA chondrocytes. CONCLUSION: Our findings indicate that Cn at physiologic tonicity exerts a superior effect compared to physiologic tonicity or FK-506 alone, increasing anabolic markers while suppressing hypertrophic and catabolic markers. Our data may aid in the development of improved cell-based chondral repair and OA treatment strategies. PMID- 22231956 TI - Age dependent switching role of cyclin D1 in breast cancer. AB - BACKGROUND: Cyclin D1 gene (CCND1) plays pivotal roles in the development of several human cancers, including breast cancer, functioning as an oncogene. The aim of this study was to better understand the molecular dynamics of ductal carcinomas with regard to proliferation and the ageing process. METHODS: 130 cases of ductal breast cancer in postmenopausal women, aged 52-96 in 3 age classes were selected. Tumoral tissues preserved in formaldehyde solution and subsequently embedded in paraffin were subjected to analysis Fluorescence in situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT- PCR) and immuno-histochemical tests. The molecular variables studied were estimated in relation to the patients' age. RESULTS: The results obtained suggest that the increment of the levels of cyclin D1 in intra-ductal breast tumors in older woman that we have examined is significantly associated with a lower proliferation rate. CONCLUSION: Cyclin D1, which characterizes tumor in young women as molecular director involved in strengthening tumoral proliferation mechanisms, may be seen as a potential blocking molecular switch in corresponding tumours in old women. PMID- 22231958 TI - Hip resurfacing: not your average hip replacement. AB - Hip resurfacing (HR) has become a widely used surgical intervention for younger patients requiring hip joint arthroplasty. While case reports have been published describing rehabilitation programs following HR, there has yet to be established rehabilitation guidelines. Through experience and clinical reasoning, the following guidelines have been developed based on the patients at the Hospital for Special Surgery. The demographics of the typical HR patient, along with the surgical process are described. Current published literature reporting rehabilitation for patients with arthritic hip pathologies has been incorporated into the guidelines and is presented. The guidelines are divided into three phases, with goals for each phase explained. A progression through phases by way of reaching certain milestones and goals is advocated. PMID- 22231957 TI - Hip osteoarthritis and the active patient: will I run again? AB - The popularity of running as a recreational sport for health gains has steadily increased. Runners may acquire several types of injuries including hip osteoarthritis (OA). Running is possible with mild forms of OA if proper joint mechanics, neuromuscular control, and technique are present. Recent literature will be discussed that builds upon previously published articles regarding forces encountered at the hip joint during running. This article will outline the biomechanics and necessary muscle forces during running, and theories regarding strengthening and neuromuscular control. Perspectives on treatment, based on known evidence and our clinical reasoning are presented. PMID- 22231959 TI - Highly efficient Narasaka-Heck cyclizations mediated by P(3,5-(CF3)2C6H3)3: facile access to N-heterobicyclic scaffolds. PMID- 22231960 TI - [Nanomedicine in otorhinolaryngology--future prospects]. AB - BACKGROUND: Nanotechnology becomes more and more important in the world of today. Equally, it does generally in medicine and of course specifically in otorhinolaryngology. Essentially, there are the following fields: Diagnostics, new therapies and agents, drug delivery and medical implants. MATERIAL AND METHODS: An extensive literature research on nanomedicine in otorhinolaryngology was carried out in the standard online medical reference databases "PubMed/Medline" and "Web of Science". Furthermore, we are giving an overview of the work of the Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), University Hospital Erlangen. RESULTS: A lot of new and innovative studies on nanotechnology in diagnostics and therapy were recovered. Depending on the variety in otorhinolaryngology, there are numerous versatile approaches, according to the different areas. The main part is engaged in drug delivery. CONCLUSIONS: The efforts to exploit the potential of nanotechnology in otorhinolaryngology are multifaceted, innovative and seminal. The best perspective of success is attributed to nanoparticulate drug delivery systems. PMID- 22231962 TI - [Austrian Tonsil Study 2009 - 2010]. PMID- 22231963 TI - [The Austrian tonsil study 2010--part 1: statistical overview]. AB - BACKGROUND: Tonsillectomy (TE), tonsillotomy (TO) and adenoidectomy (AE) are surgeries performed routinely by otorhinolaryngologists. There were 5 cases of fatal postoperative bleeding in Austria during the years 2006 and 2007, all in children under 6 years of age. The intensive discussion following these sad events resulted in a Consensus Paper of the Austrian Society of ORL, H&NS with the Austrian Society of Pediatrics with modified recommendations towards indications and surgical techniques in different age groups; in addition, the prospective study presented here was initiated. In Austria for the first time a full census could be performed assessing all TE, TO and AE with standardized definitions. MATERIAL AND METHODS: Within the study period of 9 months' from October 1, 2009, to June 30, 2010, data on patients' characteristics, indication for surgery, surgical technique and postoperative haemorrhage were prospectively collected. Postoperative haemorrhage was defined as any bleeding after extubation regardless of whether or not a surgical intervention was required. Postoperative bleeding events were categorised into 7 grades depending on severity. RESULTS: More than one million data of 9,405 patients from 32 ENT-departments in Austria were collected and analysed. One third were children younger than 6 years (n=3,474; 37%) and one third were adults (n=3,507, 37%). A TE +/-AE was performed in 48.8% (n=4,594), an AE in 37.1% (n=3,492) and a TO in 14.0% (n=1, 319). For the indication "recurrent tonsillitis and tonsilar hypertrophy" 70% of children had a TO but 95% of adults had a TE (p<0.001). Adults with OSAS had a TE whereas in children aged younger than 6 with the same indication a TO was preferably performed in 90% (p<0.001). For TO the Colorado-needle and the Coblation technique were most commonly used. The Adenotome by La Force and the Adenoid curette by Beckmann, with or without endoscopic control, were most frequently used for AE. CONCLUSIONS: For the first time a prospective full survey could be performed in one country assessing all tonsil and adenoid surgeries along standardized criteria. The study gives an overview about the types of surgery, the indications, the operation techniques and the frequency of postoperative haemorrhage. The latter, because of its clinical importance, is dealt with and described in detail in the second part of this publication. PMID- 22231964 TI - [Direct recording from cochlear nerve via a ball-electrode in transtemporal acoustic neuroma surgery]. AB - BACKGROUND: Intraoperative monitoring (IOM) of the cochlear nerve function during acoustic neuroma surgery is employed to assist in preserving hearing. So far, Auditory Brain-stem Response (ABR) is considered to be an optimal method for intraoperative monitoring in transtemporal approach. The aim of this study was to perform direct recording of the cochlear nerve action potential after resection of the tumor by using a ball-electrode and to evaluate the use of this method in predicting the postoperative hearing. The obtained data were compared to the simultaneous ABR results and to the postoperative hearing. MATERIAL AND METHODS: In 2009, 38 patients have undergone acoustic Neuroma Surgery at the ENT University hospital, Wuerzburg. In 33 patients an intraoperative ABR as well as a direct measurement from the cochlear nerve using a ball electrode were performed. In 5 patients the postoperative hearing was predicted using the direct measurement at the cochlear nerve only. RESULTS: The direct recording from the cochlear nerve gave very robust responses. Even in cases where ABR recording was not possible, the identification of clear cochlear nerve action potential could still be reached. Using the direct recordings from the cochlear nerve to predict the post operative hearing turned out to have a sensitivity of 100% and a specificity of 70%. CONCLUSIONS: These results show that intraoperative monitoring with direct recording from the cochlear nerve via a ball-electrode in transtemporal approaches offers a valuable method to predict the postoperative hearing. Further investigation will be made to provide additional information. PMID- 22231965 TI - [First experiences with ultrasound guided subclavian vein port placement in ENT]. AB - BACKGROUND: Description of ultrasound guided port placement in the subclavian vein in ENT and discussion of clinical advantages and disadvantages. MATERIALS AND METHODS: 50 Patients underwent ultrasound guided port placement. The catheter tip was placed over subclavian vein or jugular vein between the superior vena cava and the right atrium. Correct placement was confirmed radiographically. All patients received ports prior to chemotherapy and were followed up in our institution. RESULTS: Port placement was successful in all 50 cases. In 2 cases the suclavian vein could not be punctured. The internal and external jugular veins were used as alternatives in one case each. Subcutaneous hematoma was observed in 4 cases, in 2 cases revision was required. In one case a discrete pneumothorax was observed in radiographic imaging. However, further treatment was not required. During the application of chemotherapy one case of catheter infection was observed and one case of catheter thrombosis. Thrombosis followed incorrect use of the catheter in an external department. In both cases the port catheter was removed. In one further case removal of the catheter was performed after completion of the chemotherapy. In total 3 different port catheter systems were used. CONCLUSION: Ultrasound guided placement of port catheters in the subclavian vein is a simple procedure for ENT settings. Complication rates were very low, application of chemotherapy is simple and quality of life for the oncologic patient is increased. PMID- 22231966 TI - [Of the expert office: expert evaluation of benign paroxysmal positional vertigo (BPPV) to current criteria]. PMID- 22231967 TI - [Avoidance and therapy of post-operative infections]. PMID- 22231968 TI - [Growth hormone in children and adolescents with cystic fibrosis]. AB - The recombinant human growth hormone (rhGH) can improve weight gain, physical growth, clinical and lung in cystic fibrosis (CF). However, the routine use, although promising, is not established in the literature. The objective of this study was to assess the benefits of rhGH in children and adolescents with CF. We conducted a systematic review in the database PubMed, Lilacs, SciELO and Cochrane, in the period 2000-2010, using the keywords: "cystic fibrosis", "growth hormone", "children" and "adolescents". We found 77 articles and included 11 randomized controlled trials, with 290 children and adolescents with CF. The short-term use (1-24 months) of rhGH improved the height, weight, growth rate, bone mineral content and components of pulmonary function. Adverse effects, like diabetes, were not observed in the studies. The short-term use of rhGH improved growth and body composition in patients with CF. PMID- 22231969 TI - The role of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 in diabetic nephropathy. AB - The increased prevalence of diabetes mellitus has caused a rise in the occurrence of its chronic complications, such as diabetic nephropathy (DN), which is associated with elevated morbidity and mortality. Familial aggregation studies have demonstrated that besides the known environmental risk factors, DN has a major genetic component. Therefore, it is necessary to identify genes associated with risk for or protection against DN. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. Increased levels of ENPP1 expression inhibit tyrosine kinase activity of the insulin receptor in several cell types, leading to insulin resistance. K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. The elucidation of genetic factors and their associations will provide better understanding of the pathogenesis of DN and, may consequently, lead to a more effective approach to prevention and treatment. PMID- 22231970 TI - Economic evaluation of outpatients with type 2 diabetes mellitus assisted by a pharmaceutical care service. AB - OBJECTIVE: To analyze the costs related to visits and drug prescription in outpatients with type 2 diabetes mellitus assisted by a pharmaceutical care service. SUBJECTS AND METHODS: A prospective and experimental study was carried out. Seventy one patients were divided into two groups: control and pharmaceutical care. Patients in the pharmaceutical care group were followed up monthly by a single clinical pharmacist. RESULTS: The pharmaceutical care group had a statistically significant reduction in costs of metformin and emergency department visits, and increased costs with their family physicians. On the other hand, the control group had a statistically significant increase of 21.3% in the general costs of treatment and visits. CONCLUSION: The pharmaceutical care group maintained the same costs related to drugs and visits, while the control group showed a significant increase in general costs. PMID- 22231971 TI - Treatment of mild to moderate Graves' ophthalmopathy with sodium diclofenac: a pilot study. AB - OBJECTIVE: To report the use of sodium diclofenac, an antagonist of PPAR-gamma and cyclooxigenase-2 (COX-2) inhibitor in the treatment of mild to moderate Graves' ophthalmopathy. SUBJECTS AND METHODS: Thirteen patients with clinical activity score (CAS) 2 to 7 were treated during a period ranging from 3 to 12 months (mean 7.8 +/- 3.4) with oral sodium diclofenac, 50 mg every 12 hours. RESULTS: Extra-ocular muscle restriction and CAS improved significantly, p = 0.003 and = 0.004, respectively. Ocular pain and diplopia disappeared, except for one patient who reported improvement of these symptoms. No recurrence was found after interruption of treatment. CONCLUSIONS: Treatment of moderate Graves' ophthalmopathy with oral sodium diclofenac is a good, safe and less expensive therapeutic option. Like others new treatment trials, findings must be confirmed in a greater number of patients in a controlled study. PMID- 22231972 TI - [Correlation between thyroid volume determined either by ultrasound or by scintigraphy and its implications in dosimetric radioiodine calculations in Graves disease treatment]. AB - INTRODUCTION: Graves disease (GD) is the most common cause of hiperthyroidism, and the most common treatment options are surgery, antithyroid drugs and radioiodine therapy. In radiodosimetric calculations to determine radioiodine dosage it is possible to use thyroid volume estimatives based on ultrasound or scintigraphy. OBJECTIVE: The present study aimed to correlate these methodologies emphasizing volume estimatives and dosimetric implications. SUBJECTS AND METHODS: Were included 103 patients with GD diagnosis and indication of radioiodine treatment. They were submitted to thyroid ultrasound and thyroid scintigraphy. RESULTS AND CONCLUSIONS: Good correlation between both methods was observed, although scintigraphy systematically obtained greater volumes than ultrasound implying in lower estimatives of absorbed dose when scintigraphy is used. PMID- 22231973 TI - Parameters of glycemic control and their relationship with zinc concentrations in blood and with superoxide dismutase enzyme activity in type 2 diabetes patients. AB - OBJECTIVE: This study assessed the relationship between the parameters of glycemic control, and zinc concentrations in blood and superoxide dismutase enzyme activity in type 2 diabetes patients. SUBJECTS AND METHODS: Seventy-three individuals, aged between 25 and 59 years, were divided into the experimental group (type 2 diabetes patients, n = 36) and control group (n = 37). Plasma and erythrocyte zinc concentrations, superoxide dismutase activity, and parameters of glycemic control were analyzed. RESULTS: Mean plasma zinc concentration was 74.1 +/- 10.7 ug/dL and 68.8 +/- 9.6 ug/dL, erythrocyte zinc concentration was 48.1 +/ 9.5 ug/gHb and 41.2 +/- 8.0 ug/gHb, and superoxide dismutase activity was 2248.9 +/- 300.0 U/gHb and 2059.6 +/- 285.4 U/gHb, in the experimental group and the control group, respectively (p < 0.05). CONCLUSION: Type 2 diabetes patients showed a positive response to oxidative stress due to adequate zinc concentration in blood and increased activity of superoxide dismutase, and the enzyme was influenced by serum insulin. PMID- 22231974 TI - [Analysis of factors associated with changes in the oral glucose tolerance test, regardless of the values of fasting glucose]. AB - OBJECTIVE: To identify factors associated with changes in oral glucose tolerance test (OGTT), regardless of fasting glucose (FG). SUBJECTS AND METHODS: 377 patients (53.8 +/- 15.2 years, 77.7% women and BMI = 31.4 +/- 5.9 kg/m2) with no history of diabetes mellitus(DM), underwent OGTT and compared according to the results: normal (NGT), impaired (IGT) and DM. RESULTS: 202 patients (53.6%) had altered glucose tolerance: 69 with DM (18.3%) and 133 with IGT (35.3%). In multivariate analysis, factors regardless of FG that were associated (P < 0.05) with changes in the OGTT were age (DM = 58.7 +/- 12.9; IGT = 56.7 +/- 14.3; NGT = 49.6 +/- 15.6 years), hypertension (DM = 69.6%; IGT = 63.9%; NGT = 43.4%), FG (DM = 111.9 +/- 9.2; IGT = 103.5 +/- 10.3; NGT = 96.6 +/- 11.1 mg/dL), HbA1C (DM = 6.1 +/- 0.7%; IGT = 6.1 +/- 0.5%; NGT = 5.8 +/- 0.4%), triglycerides (DM = 179.3 +/- 169.9; IGT = 154.2 +/- 84.1; NGT = 129.1 +/- 71.9 mg/dL), HDL-c (DM =44.7 +/- 9.2; IGT = 47.5 +/- 12.3; NGT = 50.6 +/- 13.4 mg/dL) and uric acid in women (DM = 5.3 +/- 1.5; IGT = 5.3 +/- 1.3; NGT = 4.7 +/- 1.3 mg/dL). CONCLUSION: Age, hypertension, elevated triglycerides, HbA1C, uric acid (in women) and low HDL-C are associated with changes in the OGTT patients with overweight / obesity, irrespective of FG. PMID- 22231975 TI - Diabetes mellitus in a cohort of patients with acromegaly. AB - OBJECTIVES: To evaluate the presence of diabetes mellitus (DM) in a cohort of patients with acromegaly. METHODS: This was a cross sectional study. RESULTS: Fifty-eight acromegalic patients were assessed. Only 29% met the criteria for cure, and 27% had the disease controlled. Twenty-two had DM; HbA1c was equal to 7.34 +/- 2.2%. Most of the diabetic patients (18 out of 22, 82%) did not meet criteria for cure. They were more often hypertensive [16/22 (73%) vs. 17/36 (46%), p = 0.04], and used statins more frequently [14/22 (64%) vs. 8/36 (21%), p = 0.004]. After regression analysis, hypertension was associated with diabetes [odds ratio (OR): 9.28 (95% CI: 1.59 - 54.00), p = 0.01], and cured/ controlled acromegaly was associated with protection against the presence of diabetes [OR: 0.17 (95% CI: 0.03 - 0.78), p = 0.02]. CONCLUSIONS: The presence of DM was associated with active acromegaly and presence of hypertension. However, absolute levels of GH and IGF-1 did not differ between patients with and without diabetes. PMID- 22231976 TI - Diabetes mellitus and spinal epidural abscess: clinical or surgical treatment? AB - Spinal epidural abscess (SEA) is an uncommon condition and its most important predisposing factor is diabetes mellitus. Although the treatment of choice is prompt surgical abscess evacuation, followed by antibiotic therapy, successful conservative treatment of SEA has been reported in some cases. We describe a SEA case in a 23-year old white woman with diabetes for 14 years, who was successfully treated only with antibiotics, and achieved full recovery at the fourth month of follow-up. PMID- 22231977 TI - [Laboratory diagnosis of acromegaly]. PMID- 22231978 TI - [Recommendations of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism for diagnosis and treatment of acromegaly in Brazil]. PMID- 22231979 TI - Insulin resistance and chronic hepatitis C in non-diabetic patients. PMID- 22231981 TI - Height and cognitive function at older ages: is height a useful summary measure of early childhood experiences? AB - Previous research using US data suggests that height, as a marker for early investments in health, is associated with better cognitive functioning in later life, but this association disappears once education is controlled for. Using an English cohort of men and women older than 50 years, we find that the association between height and cognitive outcomes remains significant after controlling for education suggesting that height affects cognitive functioning not simply via higher educational attainment. Furthermore, the significant association between height and cognitive function remains even after controls for early life indicators have been included. PMID- 22231982 TI - Planar pi-aromatic C3h B6H(3)(+) and pi-antiaromatic C2h B8H2: boron hydride analogues of D3h C3H(3)(+) and D2h C4H4. AB - Based upon extensive density functional theory and wave function theory calculations performed in this work, we predict the existence of the perfectly planar triangle C(3h) B(6)H(3)(+) (1, (1)A') and the double-chain stripe C(2h) B(8)H(2) (9, (1)A(g)) which are the ground states of the systems and the inorganic analogues of cyclopropene cation D(3h) C(3)H (3) (+) and cyclobutadiene D(2h) C(4)H(4), respectively. Detailed adaptive natural density partitioning (AdNDP) analyses indicate that C(3h) B(6)H (3) (+) is pi plus sigma doubly aromatic with two delocalized pi-electrons and six delocalized sigma-electrons formally conforming to the 4n + 2 aromatic rule, while C(2h) B(8)H(2) is pi antiaromatic and sigma aromatic with four delocalized pi-electrons and ten delocalized sigma-electrons. The perfectly planar C(2h) B(8)H(4) (5, (1)A(g)) also proves to be pi antiaromatic analogous to D(2h) C(4)H(4), but it appears to be a local minimum about 50 kJ mol(-1) less stable than the three dimensional C(s) B(8)H(4)(6, (1)A'). AdNDP, nucleus independent chemical shifts (NICS) and electron localization function (ELF) analyses indicate that these boron hydride clusters form islands of both sigma- and pi-aromaticities and are overall aromatic in nature in ELF aromatic criteria. PMID- 22231983 TI - Ordered and disordered proteins as nanomaterial building blocks. AB - Proteins possess a number of attractive properties that have contributed to their recent emergence as nanoscale building blocks for biomaterials and bioinspired materials. For instance, the amino acid sequence of a protein can be precisely controlled and manipulated via recombinant DNA technology, and proteins can be biosynthesized with very high purity and virtually perfect monodispersity. Most importantly, protein-based biomaterials offer the possibility of technologically harnessing the vast array of functions that these biopolymers serve in nature. In this review, we discuss recent progress in the field of protein-based biomaterials, with an overall theme of relating protein structure to material properties. We begin by discussing materials based on proteins that have well defined three-dimensional structures, focusing specifically on elastin- and silk like peptides. We then explore the newer field of materials based on intrinsically disordered proteins, using nucleoporin and neurofilament proteins as case studies. A key theme throughout the review is that specific environmental stimuli can trigger protein conformational changes, which in turn can alter macroscopic material properties and function. PMID- 22231984 TI - Identification of magnetic nanoparticles for combined positioning and lentiviral transduction of endothelial cells. AB - PURPOSE: The combination of magnetic nanoparticles (MNPs) with a magnetic field is a powerful approach to enable cell positioning and/or local gene therapy. Because physical requirements for MNPs differ between these two applications we have explored whether the use of different MNPs can provide site-specific positioning combined with efficient viral transduction of endothelial cells (ECs). METHODS: A variety of MNPs was screened for magnetic cell labeling and lentivirus binding. Then two different MNPs were chosen and their combined application was evaluated regarding EC magnetization and transduction efficiency. RESULTS: The combined use of PEI-Mag2 and NDT-Mag1 particles provided both efficient lentiviral transduction and high magnetic responsiveness of ECs that could be even retained within the vascular wall under flow conditions. The use of these MNPs did not affect biological characteristics of ECs like surface marker expression and vascular network formation. Importantly, with this method we could achieve an efficient functional overexpression of endothelial nitric oxide synthase in ECs. CONCLUSIONS: The application of two different MNPs provides optimal results for magnetic labeling of ECs in combination with viral transduction. This novel approach could be very useful for targeted gene therapy ex vivo and site-specific cell replacement in the vascular system. PMID- 22231987 TI - Targeted delivery of proteins into the central nervous system mediated by rabies virus glycoprotein-derived peptide. AB - PURPOSE: Delivery of therapeutic proteins across the blood-brain barrier (BBB) is severely limited by their size and biochemical properties. Here we showed that a 39-amino acid peptide derived from the rabies virus glycoprotein (RDP) was exploited as an efficient protein carrier for brain-targeting delivery. METHODS: Three proteins with different molecular weight and pI, beta-galactosidase (beta Gal), luciferase (Luc) and brain-derived neurotrophic factor (BDNF), were fused to RDP and intravenously injected into the mice respectively. The slices of different tissues with X-Gal staining were used to examine whether RDP could deliver beta-Gal targeted into the CNS. The time-course relationship of RDP-Luc was studied to confirm the transport efficiency of RDP. The neuroprotective function of RDP-BDNF was examined in mouse experimental stroke to explore the pharmacological effect of RDP fusion protein. RESULTS: The results showed that the fusion proteins rapidly and specific entered the nerve cells in 15 min, and the t(1/2) was about 1 hr. Furthermore, RDP-BDNF fusion protein showed the neuroprotective properties in mouse experimental stroke including reduction of stroke volume and neural deficit. CONCLUSIONS: RDP provides an effective approach for the targeted delivery of biological active proteins into the central nervous system. PMID- 22231988 TI - Longitudinal study of the bidirectional association between pain and depressive symptoms in patients with psoriatic arthritis. AB - OBJECTIVE: To test the bidirectional hypothesis that depressive symptoms influence changes in pain over time, and pain influences changes in depressive symptoms. METHODS: A total of 394 patients attending the University of Toronto Psoriatic Arthritis clinic were followed over a mean period of 7.5 years with annual assessments, including number of swollen joints (SJC), Health Assessment Questionnaire (HAQ), and the Medical Outcomes Survey Short Form 36 (SF-36). Linear mixed-effects models were used to examine the cross- and lagged associations between the changes in HAQ pain and in the SF-36 mental component summary (MCS) score, adjusting for SJC and other covariates. RESULTS: The strongest predictors of changes in pain, SJC, and depressive symptoms between visits were scores of the corresponding variables at the previous visit, with standardized regression coefficients exceeding 0.75 in absolute value. There was, however, evidence of a small, but consequential, bidirectional relationship (i.e., standardized regression coefficients <0.3) between depressive symptoms and pain. Both previous MCS scores and change in MCS scores were associated with change in pain between visits; conversely, previous pain scores and change in pain scores were associated with change in depressive symptoms between visits. CONCLUSION: Even though cross-variable associations between pain and depressive symptoms exist, changes in pain and depressive symptoms appear to be strongly driven by their measurements at the previous visit. To optimize patient outcomes, a clinical approach that assesses and treats clinically significant depressive symptoms, as well as pain, is required. PMID- 22231989 TI - Distribution, crypticity, stability, and localization of alpha-L-fucosidase of mouse cauda epididymal sperm. AB - Sperm-associated and semen-specific isoforms of alpha-L-fucosidase are thought to function in fertilization in numerous organisms. Here, we report the localization, distribution, crypticity, and stability of this enzyme in mouse cauda epididymal sperm and cauda fluid. Western analysis revealed that the sperm associated alpha-L-fucosidase is present as two isoforms (Mr ~49 and 56 kDa), whereas the cauda fluid alpha-L-fucosidase shows a single band at 50 kDa. alpha-L Fucosidase activity was detected using the fluorogenic substrate 4-MU-FUC. Of the total alpha-L-fucosidase activity recovered in the cauda epididymal contents, 74% was found in the cell-free cauda fluid and about 7% was found in sperm cells. During capacitation or permeabilization, cryptic intracellular stores of soluble enzyme were released to the supernatant, while leaving bound enzyme concentrated within the small volume of sperm. Moreover, membrane-associated enzyme activity was still detectable in acrosome-reacted cells. Immunofluorescence studies support the presence of alpha-L-fucosidase (originally localizing at the acrosomal area) at the equatorial segment after the acrosome reaction. alpha-L Fucosidase activity of both cauda fluid and sperm at 37 degrees C, 5% CO(2) was relatively stable and detectable up to 72 hr. The stability and appearance of mouse sperm-associated alpha-L-fucosidase in the equatorial segment after the acrosome reaction suggest that alpha-L-fucosidase may be involved in sperm-egg interaction. PMID- 22231990 TI - Beyond the patient: the broader impact of genetic discrimination among individuals at risk of Huntington disease. AB - We aimed to address gaps in current understanding of the scope and impact of discrimination, by examining a cohort of individuals at-risk for Huntington disease (HD), to describe the prevalence of concern for oneself and one's family in multiple domains; strategies used to mitigate discrimination; and the extent to which concerns relate to experiences. We conducted a cross-sectional survey of 293 individuals at-risk for HD (80% response rate); 167 respondents were genetically tested and 66 were not. Fear of discrimination was widespread (86%), particularly in the insurance, family and social settings. Approximately half of concerned individuals experienced discrimination (40-62%, depending on genetic status). Concern was associated with "keeping quiet" about one's risk of HD or "taking action to avoid" discrimination. Importantly, concern was highly distressing for some respondents (21% for oneself; 32% for relatives). Overall, concerned respondents with high education levels, who discovered their family history at a younger age, and those who were mutation-positive were more likely to report experiences of discrimination than others who were concerned. Concerns were rarely attributed to genetic test results alone. Concern about genetic discrimination is frequent among individuals at-risk of HD and spans many settings. It influences behavioral patterns and can result in high levels of self rated distress, highlighting the need for practice and policy interventions. (c) 2012 Wiley Periodicals, Inc. PMID- 22231991 TI - Perioperative mortality in patients with myelodysplastic syndrome. AB - INTRODUCTION: Myelodysplastic syndrome (MDS) is a conglomerate of diseases in which bone marrow-derived cells die before or shortly after entering circulation. We sought to define the perioperative mortality in MDS patients. METHODS: We reviewed our experience of all persons treated for MDS at our institution over the past 15 years. Demographic and survival information were collected, and those who underwent any procedure requiring general anesthesia were defined as the operative subgroup. RESULTS: Of 169 patients identified, 39 (23%) were in the operative subgroup. The median survival was 17.8 months. The mortality rate for the operative group was 23% (N = 9) and 30.8% (N = 12) at 30 and 60 days post procedure. Twenty-three patients (59%) had an urgent/emergent indication for operation, which was associated with higher 60-day mortality (N = 12, 48%) compared to those with elective indications (N = 1, 7%) (P = 0.037, Chi-square). Several other factors (age, gender, International Prognostic Score, MDACC score, and major/minor procedure type) were not associated with perioperative mortality. CONCLUSION: Outcomes in MDS patients are poor with expected survival less than 2 years and high postoperative mortality in the setting of urgent/emergent operations. While maybe not prohibitive, we believe it is an imperative part of the informed consent process particularly for urgent/emergent procedures. PMID- 22231992 TI - Guest editorial: introduction of Progress in Hematology in this issue. PMID- 22231993 TI - Evaluation of organically acceptable insecticides as stand-alone treatments and in rotation for managing yellowmargined leaf beetle, Microtheca ochroloma (Coleoptera: Chrysomelidae), in organic crucifer production. AB - BACKGROUND: Yellowmargined leaf beetle, Microtheca ochroloma, is the most damaging pest of organic crucifer crops in the southern United States. Experiments were conducted over four growing seasons (2007-2010) in Alabama to evaluate some botanical and microbial insecticides approved by the Organic Materials Review Institute (OMRI) against M. ochroloma in organically grown crucifer crops. Insecticides evaluated included PyGanic((r)) (pyrethrum), Aza Direct((r)) (azadiractin), Entrust((r)) (spinosad), Mycotrol O((r)) (Beauveria bassiana strain GHA) and NOFLY((r)) [Isaria ( = Paecilomyces) fumosoroseus strain FE 9901]. Two experimental organic formulations, Tick-Ex (Metarhizium anisopliae strain F52) and MBI-203 (Chromobacterium subtsugae), and one non-OMRI-listed formulation, Novodor((r)) (Bacillus thuringiensis subspecies tenebrionis), were also evaluated. The insecticides were applied as stand-alone treatments at recommended field rates on a weekly schedule. In 2010, some of the treatments were also evaluated in rotation/alternation with Entrust((r)) . Insecticide efficacy was determined by comparing densities of M. ochroloma larvae and adults and crop damage ratings in treated versus untreated turnip plots. RESULTS: Entrust((r)) consistently performed well in suppressing M. ochroloma adults, larvae and crop damage. PyGanic((r)) was the second best treatment. PyGanic((r)) or NOFLY(TM) can be applied in rotation with Entrust((r)) for effective management of M. ochroloma. CONCLUSION: Entrust((r)) applied weekly or in alternation with PyGanic((r)) or NOFLY(TM) provided acceptable control of M. ochroloma in organic crucifer production. PMID- 22231994 TI - Thermal burns and scalds: clinical complications in the elderly. AB - Burns are categorized as superficial, superficial partial thickness, deep partial thickness, and full thickness. Superficial burns heal spontaneously; more serious burns require treatment. Elders are disproportionately affected, and advanced age is associated with poorer outcomes, partially because of thin skin and preexisting conditions. Clinical complications are common in elderly burn victims. Treatment's two stages, acute care and follow-up care, are discussed. Severe burns can result in significant scarring and painful contractures, and victims are at increased risk for depression and related psychiatric problems. The majority of elders suffering from severe burns are transferred to long-term care and rehabilitation facilities for follow-up care. Most burns are preventable, and burns occurring in long-term care facilities require investigation. PMID- 22231995 TI - The PACE program: home-based long-term care. AB - Programs of All-Inclusive Care for the Elderly (PACE) provide comprehensive care within the framework of a medical home model for the frail elderly living in the community. Participants must be at least 55 years of age, qualify for nursing facility level of care, and reside safely in the community at the time of enrollment. Often referred to as "nursing homes without walls," PACE programs provide all services covered by Medicare and Medicaid including primary care, medical specialties, adult day health centers, home care, prescription and over the-counter medications, social work, dietitians, and any other service deemed necessary by the interdisciplinary team. PACE programs offer a multitude of opportunities for pharmacists who specialize in geriatrics, including medication reviews, medication therapy management, therapeutic drug monitoring, fall prevention, quality assurance initiatives, chronic disease management, anticoagulation services, drug information resources, education and inservice programs, medication dispensing and distribution, drug utilization reviews, infection control, and many other services. Senior care pharmacists are uniquely qualified to promote their services to PACE programs and provide quality care to both the interdisciplinary team and participants of the program. PMID- 22231996 TI - Milt Moskowitz: finding your passion. PMID- 22231997 TI - Impact of geriatric consultation on the number of medications in hospitalized older patients. AB - OBJECTIVE: This study aims to determine the impact of the geriatric consultation on the number of medications in hospitalized older adults and the corresponding financial impact. DESIGN: Retrospective chart review of patients seen by geriatric consultants. SETTING: Tertiary-care teaching hospital. MAIN OUTCOME MEASURES: The number of medications prescribed before hospitalization, at time of consult, and at discharge, and the number and category of medications adjusted by the geriatrician. The monthly cost of the pharmaceutical interventions was computed based on the drugstore.com cost of acquisition of drugs. RESULTS: A cohort of 62 patients was reviewed with a mean age of 84.6 (+/- 7.3) years; 79% were women. The patients presented with an average of 5.6 (+/- 2.1) comorbidities of which hypertension, dementia, and musculoskeletal disorders were the most common. The most common reasons for geriatric consultations were neuropsychiatric, nutritional, and gait-related issues. The geriatric consultant identified 2.96 (+/- 1.5) additional diagnoses, of which debility, delirium, and pain were the most prevalent. The average number of medications on admission was 7.7 (+/- 3.7) and at discharge was 9.5 (+/- 2.12). The average number of medications adjusted by the geriatric consultant was 2.96 (+/- 2.12). The most common classes of adjusted medications were pain medications (22%), nutrition (13%), bowel regimens (8.5%), antipsychotics (8%), and osteoporosis (8%). The cost impact of the pharmaceutical intervention ranged between -$343 and $2,607, with an average increase of $102 (+/- 368). CONCLUSION: Geriatric consultations increased the total number of medications and the cost of medications used by elderly patients. PMID- 22231998 TI - A pharmacist's contribution to an ambulatory neurology clinic. AB - OBJECTIVE: Identify and categorize recommendations made by a consultant pharmacist in a neurology clinic, and document patient satisfaction with consultations provided by the pharmacist. DESIGN: Prospective, case series. SETTING: Ambulatory neurology clinic located in eastern Washington state. PATIENTS: Participants were referred to the consultant pharmacist by the neurologist or neurology nurse practitioner or self-referral. The pharmacist saw 56 patients, for a total of 66 encounters. INTERVENTIONS: A medication review was completed, and the patient and pharmacist met for consultation, assessment, and patient counseling. The pharmacist made pharmacotherapeutic recommendations and referrals to other health care providers. Printed surveys were distributed to patients regarding their satisfaction with the pharmacy consultation. MAIN OUTCOME MEASURE(S): The number and types of recommendations made by the pharmacist. Patient satisfaction with the pharmacist and pharmacy consultation, reported in a written survey provided after the consultation. RESULTS: The pharmacist spent an average of 38 minutes with each patient. A total of 192 pharmacotherapeutic recommendations were made: 55 (29%) to discontinue a medication, 46 (24%) to add a medication, 45 (23%) to change a dose, 39 (20%) therapeutic substitutions, and 7 (4%) for therapeutic monitoring. Survey respondents indicated they were very satisfied (97%), and all (100%) had a better understanding of how to take their medications after meeting with the pharmacist. CONCLUSION: Pharmacist involvement in a neurology clinic increases patient pharmacist contact time and patient understanding regarding medications. The pharmacist offers numerous recommendations to health care providers, potentially improving the patient's pharmacotherapy. PMID- 22231999 TI - Cranberry and warfarin interaction: a case report and review of the literature. AB - This case reports on a patient whose International Normalized Ratio (INR) increased after ingestion of cranberry sauce while stabilized on warfarin. It is followed by a review of the published literature on the potential interaction between the two.An 85-year-old woman on chronic warfarin therapy for atrial fibrillation experienced INR elevations of two- to three-fold after two separate ingestions of cranberry sauce. In each case, her INR values decreased after withholding three to four doses and resuming a similar maintenance dose of warfarin. Although the majority of the pharmacokinetic and pharmacodynamic studies did not find a significant interaction between cranberry and warfarin, several case reports indicate that cranberry products may increase INR values in patients on warfarin. Practitioners should consider cranberry usage as a potential contributor in the evaluation of supratherapeutic INR values in patients on warfarin. PMID- 22232000 TI - Clusterin mRNA and protein in Alzheimer's disease. AB - Clusterin, a multifunctional lipoprotein is expressed in a number of tissues but expression is particularly high in the brain, where it binds to amyloid-beta (Abeta), possibly facilitating Abeta transport into the bloodstream. Its concentration in peripheral blood was identified as a potential biomarker for Alzheimer's disease (AD) and predicted retention of (11)C-Pittsburgh Compound B in the temporal lobe. Single-nucleotide polymorphisms in the clusterin gene, CLU, are associated with the risk of developing AD. We measured clusterin mRNA levels in control and AD brains and investigated the relationship of the clusterin protein to soluble, insoluble, and plaque-associated Abeta. Clusterin mRNA levels were unchanged when normalized to GAPDH but modestly increased in the frontal and temporal cortex in AD in relation to NSE and MAP-2. Levels of NSE and MAP-2 mRNA were reduced in the AD frontal cortex. Clusterin protein concentration was unchanged and did not correlate with the amount of Abeta present. In the frontal cortex, clusterin concentration was higher in APOE epsilon4-negative brains but no effect of APOE was detected in the temporal cortex or thalamus. Overall clusterin mRNA and protein levels are unaltered in the neocortex in AD and clusterin concentration does not reflect Abeta content. The increase in clusterin noted in peripheral blood in AD may reflect increased passage of this chaperone protein across the blood-brain barrier but further work is needed to determine how CLU variants influence the development of AD. PMID- 22232001 TI - Amyloid-beta protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau. AB - Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-beta protein precursor (AbetaPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-beta peptides from AbetaPP is the primary event that subsequently induces abnormal tau phosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AbetaPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AbetaPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons. PMID- 22232002 TI - Molecules of the quinoline family block tau self-aggregation: implications toward a therapeutic approach for Alzheimer's disease. AB - The neurofibrillary tangles (NFTs) generated by self-aggregation of anomalous forms of tau represent a neuropathological hallmark of Alzheimer's disease (AD). These lesions begin to form long before the clinical manifestation of AD, and its severity is correlated with cognitive impairment in patients. We focused on the search for molecules that interact with aggregated tau of the Alzheimer's type and that may block its aggregation before the formation of NFTs. We show that molecules from a family of quinolines interact specifically with oligomeric forms of tau, inhibiting their assembly into AD filaments. The quinolines 2-(4 methylphenyl)-6-methyl quinoline (THQ-4S) and 2-(4-aminophenyl)-6-methylquinoline (THQ-55) inhibited in vitro aggregation of heparin-induced polymers of purified brain tau and aggregates of human recombinant tau. They also interact with paired helical filaments (PHFs) purified from AD postmortem brains. In vitro studies indicated a significantly lower inhibitory effect of amyloid-beta42 on the aggregation, suggesting that tau aggregates are specific targets for quinoline interactions. These compounds showed highly lipophilic properties as corroborated with the analysis of total polar surface areas, and evaluation of their molecular properties. Moreover, these quinolines exhibit physical chemical properties similar to drugs able to penetrate the human brain blood barrier. Docking studies based on tau modeling, as a structural approach to the analysis of the interaction of tau-binding ligands, indicated that a C-terminal tau moiety, involved in the formation of PHFs, seems to be a site for binding of quinolines. Studies suggest the potential clinical use of these quinolines and of their derivatives to inhibit tau aggregation and possible therapeutic routes for AD. PMID- 22232003 TI - Increased 5S rRNA oxidation in Alzheimer's disease. AB - It is widely accepted that oxidative stress is involved in neurodegenerative disorders such as Alzheimer's disease (AD). Ribosomal RNA (rRNA) is one of the most abundant molecules in most cells and is affected by oxidative stress in the human brain. Previous data have indicated that total rRNA levels were decreased in the brains of subjects with AD and mild cognitive impairment concomitant with an increase in rRNA oxidation. In addition, level of 5S rRNA, one of the essential components of the ribosome complex, was significantly lower in the inferior parietal lobule (IP) brain area of subjects with AD compared with control subjects. To further evaluate the alteration of 5S rRNA in neurodegenerative human brains, multiple brain regions from both AD and age matched control subjects were used in this study, including IP, superior and middle temporal gyro, temporal pole, and cerebellum. Different molecular pools including 5S rRNA integrated into ribosome complexes, free 5S rRNA, cytoplasmic 5S rRNA, and nuclear 5S rRNA were studied. Free 5S rRNA levels were significantly decreased in the temporal pole region of AD subjects and the oxidation of ribosome-integrated and free 5S rRNA was significantly increased in multiple brain regions in AD subjects compared with controls. Moreover, a greater amount of oxidized 5S rRNA was detected in the cytoplasm and nucleus of AD subjects compared with controls. These results suggest that the increased oxidation of 5S rRNA, especially the oxidation of free 5S rRNA, may be involved in the neurodegeneration observed in AD. PMID- 22232004 TI - Hippocampal GABAergic neurons are susceptible to amyloid-beta toxicity in vitro and are decreased in number in the Alzheimer's disease TgCRND8 mouse model. AB - The relevance of gamma-amino-butyric acid (GABA)-ergic dysfunctions in the pathology of Alzheimer's disease (AD) remains a matter of debate. In the present study, we characterized the toxicity of amyloid-beta (Abeta) on hippocampal GABAergic neurons both in vivo and in vitro. In the TgCRND8 mouse model of AD, we found a significant decrease in the number of hippocampal neurons immunoreactive for glutamate decarboxylase 67 (GAD67), the enzyme synthesizing GABA. This decrease, which was specific for hippocampal CA1-3 fields, was observed at 6 months of age, long after the overproduction of soluble Abeta42 (between 2 and 4 months) and accumulation of insoluble Abeta into amyloid plaques (between 4 and 6 months). In vitro, neurotoxicity was observed in primary hippocampal cultures 72 h following the addition of Abeta42 solutions containing a mixture of soluble oligomers. Taken together, our results suggest that when cultured and exposed to Abeta in vitro, GABAergic neurons are susceptible to Abeta42 neurotoxicity. However, in TgCRND8 mice, the number of GABAergic neurons is not altered up to 6 months, in spite of the massive Abeta load. Combined with the previously reported increased sensitivity to seizures observed in younger (1.5-2 month-old) TgCRND8 mice, it is likely that Abeta toxicity leads to GABAergic neuron dysfunction prior to their losses at a later stage. PMID- 22232005 TI - Therapeutic albumin binding to remove amyloid-beta. AB - Clearance of plasma amyloid-beta (Abeta) through plasma exchange and replacement with therapeutic albumin to facilitate net Abeta efflux from the brain to plasma is a novel approach for the treatment of Alzheimer's disease. Therefore, thorough characterization of the capacity of therapeutic albumin to bind Abeta is warranted. In this study, Abeta40 and Abeta42 were quantified by commercial ELISA or Araclon ABtest(r) in samples of Grifols' therapeutic albumin (Albutein(r)) 5%, 20%, and 25%. The capacity of Albutein(r) to bind Abeta was assessed by: a) ELISA in serially diluted therapeutic albumin (0-45 mg/ml protein concentration) to which 80 pg/ml of synthetic Abeta peptide (sAbeta40 or sAbeta42) were added; b) ELISA in samples of the therapeutic albumin containing serially diluted sAbeta40 or sAbeta42 (60-400 pg/ml); and c) surface plasmon resonance (SPR) for sAbeta42 binding. The Abeta content in Albutein(r) was below the quantification threshold of the ELISA tests (<25 to <62.5 pg/ml) and ABtest(r) (<3.125 pg/ml). Quantification of exogenously added sAbeta42 decreased in parallel with increasing protein concentration (59-78% at 45 mg/ml albumin). Recovery of sAbeta serially diluted in Albutein(r) was ~60% for sAbeta40 and ~70% for sAbeta42, but was ~100% in control samples without albumin. The KD by SPR analysis for sAbeta42 interaction with Albutein(r) was 1.72 +/- 0.24 * 10-6 M. In conclusion, Grifols' therapeutic albumin has undetectable content of Abeta40 and Abeta42. Moreover, Grifols' therapeutic albumin consistently binds peptides containing the primary sequence of human Abeta. PMID- 22232006 TI - Performance of abeta1-40, abeta1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment. AB - Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid beta 1-42 (Abeta1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Abeta1-40, Abeta1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Abeta1-42 levels were significantly lower in AD and MCI-AD than in MCI MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Abeta1-42/Abeta1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Abeta1-42/t-tau and Abeta1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Abeta1-42/p-tau ratio was the best parameter for discriminating MCI AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Abeta1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Abeta1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Abeta1-42 and p-tau reliably predict conversion to AD in MCI patients. PMID- 22232007 TI - Antibody 9D5 recognizes oligomeric pyroglutamate amyloid-beta in a fraction of amyloid-beta deposits in Alzheimer's disease without cross-reactivity with other protein aggregates. AB - Recent evidence suggests that soluble oligomeric amyloid-beta (Abeta) assemblies are critically involved in the pathogenesis of Alzheimer's disease (AD). We have generated a conformation-dependent monoclonal antibody (9D5) that selectively recognizes low-molecular weight AbetapE3 oligomers, and demonstrated its diagnostic and therapeutic potential. Here, we further characterize the specificity of this antibody by evaluating a spectrum of neurodegeneration related protein deposits for cross-reactivity, and by comparing the staining pattern of 9D5 with a generic Abeta antibody that targets a linear epitope (mAb NT244), and with another conformation-dependent Abeta antibody that selectively labels amyloid fibrils of various molecular weights (pAb OC). The 9D5 antibody does not cross-react with other aggregated protein deposits in brains of progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal lobar degeneration or amyotrophic lateral sclerosis with TDP-43 inclusions, Creutzfeldt-Jakob disease, and vessel changes in Binswanger encephalopathy, demonstrating the specificity of 9D5 for Abeta deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only approximately 15% of the total Abeta plaque load in the entorhinal cortex, the CA1 region, and the temporal neocortex. Our study further supports a possible therapeutic advantage of 9D5 by the highly specific recognition of an epitope found only in oligomeric assemblies of AbetapE3 of AD patients. Moreover, selective binding to only a pathogenetically relevant fraction of Abeta deposits serves as rationale for passive immunization with 9D5-derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits. PMID- 22232009 TI - Lipids and adipokines as risk factors for Alzheimer's disease. AB - To determine if measures of adipokines and other blood lipids differentiate between normal controls and persons with Alzheimer's disease (AD), we examined levels of leptin, adiponectin, total cholesterol, high density lipoproteins (HDL), calculated low density lipoproteins (LDL), triglycerides and apolipoprotein E allele status in 148 early AD subjects and 198 normal controls. We were unable to demonstrate a significant difference between leptin and adiponectin levels between normal controls and AD subjects. We were able to confirm observations of lower HDL and higher total and LDL cholesterol concentration in AD subjects than in controls. As expected, the presence of the apolipoprotein E4 allele distinguished between the two groups. PMID- 22232010 TI - Identification of putative molecular imaging probes for BACE-1 by accounting for protein flexibility in virtual screening. AB - beta-secretase (BACE-1), an enzyme critical in the process of amyloid-beta (Abeta) peptides deposition in human brain, is closely associated with the onset and progression of Alzheimer's disease (AD). A strong need exists, therefore, to identify molecular imaging probes homing at BACE-1 for use with positron emission tomography (PET) that is recognized as an effective tool for detecting AD. Through this imaging, an early diagnosis of AD could be made. Herein, to identify suitable molecular probes for use with PET, we searched the Molecular Imaging and Contrast Agent Database (MICAD), an online database warehousing scientific information regarding molecular imaging and contrast agents, and applied a virtual screening approach against the different confirmations of BACE-1 obtained from the World Wide Protein Database. The lack of considering receptor flexibility is a key drawback in virtual screening for drug discovery. Therefore, we incorporated protein flexibility into the virtual screening by using an ensemble of 143 experimental BACE-1 structures derived from the Protein Data Bank. Finally, the best performing affinity was recorded and used in the ranking of each ligand. To the best of our knowledge, this is the first virtual screening approach used to identify four new molecular probes that could target BACE-1 with favorable affinity, a discovery that can lead to the development of new PET probes for the early detection and therapy of AD. However, the actual utility of these probes can only be ascertained after in vitro and in vivo investigations. PMID- 22232011 TI - Non-native language use and risk of incident dementia in the elderly. AB - Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer's disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0-16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76-2.09; p = 0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with >= 16 years of education (HR 3.97; 95% CI 1.62 9.75; p = 0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner. PMID- 22232012 TI - Cholesterol increases ventricular volume in a rabbit model of Alzheimer's disease. AB - One of the hallmarks of Alzheimer's disease is a significant increase in ventricular volume. To date we and others have shown that a cholesterol-fed rabbit model of Alzheimer's disease displays as many as fourteen different pathological markers of Alzheimer's disease including amyloid-beta accumulation, thioflavin-S staining, blood brain barrier breach, microglia activation, cerebrovasculature changes, and alterations in learning and memory. Using structural magnetic resonance imaging at 3T, we now report that cholesterol-fed rabbits also show a significant increase in ventricular volume following 10 weeks on a diet of 2% cholesterol. The increase in volume is attributable in large part to increases in the size of the third ventricle. These changes are accompanied by significant increases in the number of amyloid-beta immuno-positive cells in the cortex and hippocampus. Increases in the number of amyloid-beta neurons in the cortex also occurred with the addition of 0.24 ppm copper to the drinking water. Together with a list of other pathological markers, the current results add further validity to the value of the cholesterol-fed rabbit as a non-transgenic animal model of Alzheimer's disease. PMID- 22232013 TI - Altered serum iron and copper homeostasis predicts cognitive decline in mild cognitive impairment. AB - Alzheimer's disease (AD) brain is marked by severe neuronal death which has been partly attributed to increased oxidative stress. The pathophysiology accounting for this free radical injury is not well-delineated at this point, but one hypothesis is that a derangement in transition metal metabolism contributes to the process. We tested the hypothesis that peripheral derangement of transition metal metabolism is present early in the dementing process. We analyzed non-heme iron and copper levels in serum from subjects with normal cognition, mild cognitive impairment, and early stage senile dementia and followed these subjects over 5 years. An increase in the ratio of serum copper to non-heme iron levels predicted which subjects with mild cognitive impairment would progress to dementia versus those that would remain cognitively stable. This increase did not correlate with changes in expression of iron regulatory protein 2 or selected downstream targets in peripheral lymphocytes. A cDNA-based microarray (IronChip) containing genes relevant to iron and copper metabolism was used to assess transition metal metabolism in circulating lymphocytes from cognitively normal and demented subjects. No gene was identified as being dysregulated more than 2 fold, and verification using quantitative RT-PCR demonstrated no significant changes in expression for ALAS2, FOS, and CTR1. The increased ratio of serum copper to serum iron prior to dementia has potential as a biomarker for cognitive decline and mirrors other changes in serum previously reported by others, but iron and copper metabolism pathways appear to be broadly unaffected in peripheral blood in AD. PMID- 22232015 TI - Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of AbetaPP/Ps1 mice. AB - Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer's disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in AbetaPP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the cerebral cortex from VEGF microcapsules-treated AbetaPP/PS1 mice at 1, 3 and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate gyrus (DG). The number of neuronal precursors in VEGF microcapsules-treated AbetaPP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells also stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of AbetaPP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD. PMID- 22232014 TI - Characterization of insulin degrading enzyme and other amyloid-beta degrading proteases in human serum: a role in Alzheimer's disease? AB - Sporadic Alzheimer's disease (AD) patients have low amyloid-beta peptide (Abeta) clearance in the central nervous system. The peripheral Abeta clearance may also be important but its role in AD remains unclear. We aimed to study the Abeta degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Abeta. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Abeta degradation may be important for the AD pathogenesis. More studies are needed to specify each Abeta degrading protease in blood as a useful biomarker and a possible treatment target for AD. PMID- 22232016 TI - Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. AB - Elevated total plasma homocysteine has been linked to the development of cognitive impairment and dementia in later life and this can be reliably lowered by the daily supplementation of vitamin B6, B12, and folic acid. We performed a systematic review and meta-analysis of 19 English language randomized, placebo controlled trials of homocysteine lowering B-vitamin supplementation of individuals with and without cognitive impairment at the time of study entry. We standardized scores to facilitate comparison between studies and to enable us to complete a meta-analysis of randomized trials. In addition, we stratified our analyses according to the folate status of the country of origin. B-vitamin supplementation did not show an improvement in cognitive function for individuals with (SMD = 0.10, 95%CI -0.08 to 0.28) or without (SMD = -0.03, 95%CI -0.1 to 0.04) significant cognitive impairment. This was irrespective of study duration (SMD = 0.05, 95%CI -0.10 to 0.20 and SMD = 0, 95%CI -0.08 to 0.08), study size (SMD = 0.05, 95%CI -0.09 to 0.19 and SMD = -0.02, 95%CI -0.10 to 0.05), and whether participants came from countries with low folate status (SMD = 0.14, 95%CI -0.12 to 0.40 and SMD = -0.10, 95%CI -0.23 to 0.04). Supplementation of vitamins B12, B6, and folic acid alone or in combination does not appear to improve cognitive function in individuals with or without existing cognitive impairment. It remains to be established if prolonged treatment with B-vitamins can reduce the risk of dementia in later life. PMID- 22232017 TI - Systematic review of meaning in life assessment instruments. AB - BACKGROUND: The construct of "meaning in life" (MiL) has raised the interest of clinicians working in psycho-oncology and end-of-life care. It has become a topic of scientific investigation where diverse assessment approaches have been applied. AIMS: We present a comprehensive systematic review of existing MiL assessment instruments. METHODS: Electronic searches of articles published in English peer-reviewed journals were performed in Psycinfo, Medline, Embase and Cinahl. Instruments are appraised with regard to ten measurement properties. RESULTS: In total, 59 nomothetic and idiographic MiL instruments were identified. Most instruments were developed in North America and meet basic psychometric criteria. They assess presence of and search for MiL, crisis and sources of MiL, meaning making, meaningful activity, MiL in the context of illness, breadth, depth, and other structural indicators. These aspects are largely consistent with existing MiL definitions. Nine out of 59 instruments included cancer populations in test development. CONCLUSIONS: This overview of available instruments underscores the complexity of the construct and might assist researchers to select an appropriate instrument for their research needs. Finally, it points to the need for more integrative theorizing and research on MiL. PMID- 22232018 TI - Effects of a universal parenting program for highly adherent parents: a propensity score matching approach. AB - This paper examines the effectiveness of a group-based universal parent training program as a strategy to improve parenting practices and prevent child problem behavior. In a dissemination trial, 56 schools were first selected through a stratified sampling procedure, and then randomly allocated to treatment conditions. 819 parents of year 1 primary school children in 28 schools were offered Triple P. 856 families in 28 schools were allocated to the control condition. Teacher, primary caregiver and child self-report data were collected at baseline, post, and two follow-up assessments. Analyses were constrained to highly adherent parents who completed all four units of the parenting program. A propensity score matching approach was used to compare parents fully exposed to the intervention with parents in the control condition, who were matched on 54 baseline characteristics. Results suggest that the intervention had no consistent effects on either five dimensions of parenting practices or five dimensions of child problem behavior, assessed by three different informants. These findings diverge from findings reported by program developers and distributors. Potential explanations for the discrepancy and implications for future research are discussed. PMID- 22232019 TI - Effects of quinestrol and levonorgestrel on populations of plateau pikas, Ochotona curzoniae, in the Qinghai-Tibetan Plateau. AB - BACKGROUND: Plateau pikas (Ochotona curzoniae, Hodgson, 1858) are viewed as a pest in the Tibetan Plateau meadow ecosystem when their population densities are high. Traditional culling using rodenticides often poses a high risk to non target species and even to humans. In this study, an investigation was made of the infertility effects of quinestrol (E), levonorgestrel (P) and a combination of the two (EP, ratio E:P = 1:2) on plateau pikas during 2007 and 2008. RESULTS: Treatment with E or EP significantly decreased the pregnancy rate of female pikas in 2007. In 2008, there was a cross-year effect that still suppressed male reproduction in treated groups. Treatment with E obviously reduced the reproduction of pikas but not their population abundance in 2007; the reduction in population size was significant in 2008. CONCLUSIONS: Single baiting of quinestrol in early breeding season reduced the reproduction and population size of pikas throughout 2007. The effect of infertility lasted into the next breeding season through a cross-year effect, which resulted in a significant reduction of population size in 2008. Quinestrol is a very promising non-lethal approach to managing pika populations; however, several factors need to be investigated further to improve the practicality of this method. PMID- 22232020 TI - Improvement of tablet coating uniformity using a quality by design approach. AB - A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design (QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate, pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard deviation of tablet averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by more than half. PMID- 22232021 TI - The influence of the polar head and the hydrophobic chain on the skin penetration enhancement effect of poly(ethylene glycol) derivatives. AB - The effect of a homologue series of nonionic surfactants, namely poly(ethylene glycol) (PEG) fatty acid esters, differing in oxyethylene (PEG 8, PEG 12, and PEG 40) and fatty acid (stearate, mono and di-laurate, and mono and di-oleate) chain lengths, on in vitro skin permeability of ketoprofen (KTP) vehicled in plasters was investigated. The drug diffusion through hairless mouse skin as well as the effect of the surfactant type and strength was studied by Franz diffusion cells and ATR-FTIR spectroscopy. The use of PEG stearate series revealed that the surfactant with the largest polar head, namely PEG 40, was ineffective in enhancing the skin permeation of KTP, independently of the plaster concentrations. The effect of the hydrophobic chain was investigated only by using the shortest oxyethylene chains. The experimental results revealed that the oxyethylene chain length of surfactants appeared to be more influent than the alkyl chain. The prediction of the absorption enhancing capability of these PEG derivatives appeared related to the vehicle other than the proper combination of the number of ethylene oxide groups and alkyl groups. PMID- 22232022 TI - Rice germ oil as multifunctional excipient in preparation of self microemulsifying drug delivery system (SMEDDS) of tacrolimus. AB - Surmounting the constraints of limited solubilization efficiency and prime requisite of antioxidant for conventional lipid formulations, the research work explores an edge over formulation utilizing potential applicability of rice germ oil (RGO) as a multifunctional excipient. Self-microemulsifying drug delivery system (SMEDDS) of tacrolimus (TAC) was formulated with RGO, an indigenous source of gamma-oryzanol. Being the same biological source, RGO and rice bran oil (RBO) were compared and it was found that RGO have more solubilization potential for TAC (2.2-fold) as well as higher antioxidant activity (8.06-fold) than the RBO. TAC-SMEDDS was prepared using RGO/Capmul PG8 (2:3) as an oil phase, Cremophore EL as a surfactant, and Transcutol P as a cosurfactant. The approximate particle size of TAC-SMEDDS was found to be 38 nm by dynamic light scattering and 12 nm by small angle neutron scattering. The in vitro dissolution studies showed complete and rapid drug release in 30 min compared to a plain drug (<5%) and marketed capsule (<50%). AUC and C(max) were found to be 45.05 +/- 15.64 ng h/ml and 3.91 +/- 1.2 ng/ml for TAC-SMEDDS, 12.59 +/- 5.54 ng h/ml and 0.48 +/- 0.12 ng/ml for plain TAC, and 30.23 +/- 10.34 ng h/ml and 2.31 +/- 0.68 ng/ml for marketed formulation, respectively. The improved pharmacokinetic profile of TAC-SMEDDS is correlating to the dissolution results. Thus, gamma-oryzanol-enriched RGO acts as a potential multifunctional excipient for lipid formulations. PMID- 22232023 TI - Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers. AB - Smoking is associated with a wide variety of adverse health outcomes including cancer, chronic obstructive pulmonary disease, diabetes, depression, and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in these processes, we examined the relationship of smoking to genome wide methylation and gene expression using biomaterial from two independent samples, lymphoblast DNA and RNA (n = 119) and lung alveolar macrophage DNA (n = 19). We found that in both samples current smoking status was associated with significant changes in DNA methylation, in particular at the aryl hydrocarbon receptor repressor (AHRR), a known tumor suppressor. Both baseline DNA methylation and smoker associated DNA methylation signatures at AHRR were highly correlated (r = 0.94 and 0.45, respectively). DNA methylation at the most differentially methylated AHRR CpG residue in both samples, cg0557592, was significantly associated with AHRR gene expression. Pathway analysis of lymphoblast data (genes with most significant methylation changes) demonstrated enrichment in protein kinase C pathways and in TGF beta signaling pathways. For alveolar macrophages, pathway analysis demonstrated alterations in inflammation related processes. We conclude that smoking is associated with functionally significant genome wide changes in DNA methylation in both lymphoblasts and pulmonary macrophages and that further integrated investigations of these epigenetic effects of smoking on carcinogenesis and other related co-morbidities are indicated. PMID- 22232024 TI - A case of esophageal stricture after iodine 131 ablation. AB - OBJECTIVE: To report the first case of esophageal stricture as a complication of radioiodine (131I) ablation therapy. METHODS: We review the medical and surgical history of this patient and discuss various potential causes of the esophageal stricture. RESULTS: A 79-year-old woman presented with increasing dysphagia and weight loss of about 4.5 kg after recent 131I therapy for thyroid cancer remnant ablation. Her pertinent history included gastroesophageal reflux disease, an anterior midcervical esophageal web, and a distal esophageal stricture. She also had a history of radiation therapy to her chest for breast cancer about 28 years previously. On the day of 131I therapy, the 5.5-GBq 131I capsule lodged accidentally in her midcervical area for approximately 2.5 hours. The resulting radiation dose to the proximal esophagus was estimated to be 7.86 Gy from gamma radiation and possibly as high as several thousand grays from beta radiation. During this time, the esophagus had possible direct exposure to the sodium phosphate dibasic that was used as filler in the sodium iodide capsule. Because of the worsening dysphagia, an esophagogastroduodenoscopy was performed 4 weeks after the 131I therapy, which showed a new proximal esophageal stricture. CONCLUSION: We believe that the additional localized radiation and sodium phosphate exposure from the lodging of the 131I capsule may have contributed to the development of a proximal esophageal stricture. To our knowledge, such an occurrence has not previously been described in the medical literature. For prevention of such an occurrence, we recommend a careful swallowing evaluation of patients with any history of esophageal radiation exposure, dysphagia, or esophageal strictures before administration of 131I in capsule form. Alternative methods of 131I delivery, if available, should be considered. PMID- 22232025 TI - Chorea--an unusual manifestation in a woman recovering from myxedema coma. AB - OBJECTIVE: To report a case of reversible chorea in a woman with myxedema coma. METHODS: We describe the clinical course, imaging findings, and laboratory test results of a patient who initially presented with myxedema coma and then developed reversible chorea upon treatment. RESULTS: A 33-year-old woman with a known history of primary hypothyroidism presented with a 3-week history of lethargy, progressing to a precipitous decline in consciousness that required intubation. Physical examination revealed concurrent hypothermia and bradycardia. Laboratory investigations demonstrated a thyrotropin concentration greater than 100 mIU/L, a free triiodothyronine concentration of 1.9 pg/mL, and a free thyroxine concentration of 0.24 ng/dL, but no other metabolic abnormalities. She was treated with intravenous levothyroxine therapy on the first 2 days of hospital admission (200 mcg and 250 mcg, respectively). On day 2, she was obeying commands and she was extubated. She began exhibiting choreiform movements. Thyroid function test results revealed a normal free thyroxine concentration (1.10 ng/dL), but an elevated thyrotropin concentration (40.98 mIU/L) and a low free triiodothyronine concentration (1.9 pg/mL). Findings from computed tomography and magnetic resonance imaging of her brain and analysis of cerebrospinal fluid were normal. Her regimen was transitioned to oral levothyroxine, 88 mcg daily, and by day 4, her choreiform movements ceased. CONCLUSIONS: Neurologic manifestations of hypothyroidism include psychomotor slowing, memory deficits, and dementia, with myxedema coma at the extreme of this spectrum. Although chorea is a rare manifestation of hyperthyroidism, this is the first report of a patient with acquired, reversible choreiform movement disorder while still being severely hypothyroid and treated with levothyroxine. PMID- 22232026 TI - Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications. AB - OBJECTIVE: To discuss the unusual occurrence of both familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism in the same patient and to explore potential mechanisms of association and issues related to clinical management. METHODS: We discuss the diagnosis, compare the clinical presentations of FHH and primary hyperparathyroidism, review the literature regarding patients who have presented with both disorders, and discuss management considerations. We also describe 2 patients who have both FHH (confirmed by genetic testing for a mutation in the gene encoding the calcium-sensing receptor [CASR]) and primary hyperparathyroidism. RESULTS: The occurrence of both FHH and primary hyperparathyroidism in the same patient has been reported in a few cases, including 2 patients described here, one of whom was documented to have a novel CASR mutation. In those with clinical sequelae of hyperparathyroidism, parathyroidectomy has led to reduction, but not normalization, of serum calcium levels. CONCLUSIONS: The coexistence of FHH and primary hyperparathyroidism should be considered in patients with hypercalcemia, hypophosphatemia, frankly elevated parathyroid hormone levels, and low urinary calcium excretion. Genetic testing for inactivating CASR gene mutations can confirm the diagnosis of FHH. Although surgical intervention does not resolve hypercalcemia, it may be beneficial by reducing the degree of hypercalcemia, alleviating the symptoms, and preventing potential complications of hyperparathyroidism. PMID- 22232027 TI - Insulin glargine or neutral protamine Hagedorn in patients with severe insulin resistance: Is there a benefit? AB - OBJECTIVE: To determine the benefit of neutral protamine Hagedorn (NPH) insulin compared with insulin glargine in a patient with type 2 diabetes mellitus and severe insulin resistance. METHODS: We describe the patient's clinical findings and treatment course. RESULTS: A 52-year-old man with a 3-year history of type 2 diabetes mellitus did not achieve adequate glucose control despite escalation of his treatment regimen to insulin glargine, 80 units twice daily; insulin lispro, 60 units before each meal; and metformin. Dietary and lifestyle changes were emphasized and implemented while medication adherence with appropriate insulin technique was reviewed at each visit. Insulin glargine was replaced with the same dosage of NPH insulin. After 3 months, a significant drop in hemoglobin A1c was noted, from 9.5% to 6.1%, consistent with the improved capillary glucose measurements. The effect was maintained over the following year, without any major hypoglycemic events. CONCLUSION: NPH insulin might be superior to the long acting analogue insulin glargine in cases of severe insulin resistance, but randomized studies are needed to confirm our finding and clarify the involved mechanisms. PMID- 22232030 TI - Fear of recurrence and disease progression in long-term (>= 5 years) cancer survivors--a systematic review of quantitative studies. AB - BACKGROUND: Increasing proportions of patients diagnosed with cancer will become long-term survivors (>= 5 years post-diagnosis). However, survivors may continue to experience negative effects of cancer and/or treatment, including fear of recurrence (FoR). This review aims to provide an overview of current knowledge on FoR, including determinants and consequences in long-term cancer survivors, and to outline methodological and conceptual challenges that should be addressed in future research. METHODS: Multiple databases including PUBMED, EMBASE, and PsycINFO were searched to identify relevant articles. Seventeen articles were included. Data were extracted by two reviewers and summarized following a systematic scheme. RESULTS: Even years after initial diagnosis, cancer survivors suffer from FoR. Most studies report low or moderate mean FoR scores, suggesting that FoR is experienced in modest intensity by most survivors. Studies including long-term and short-term survivors indicate no significant change of FoR over time. Lower level of education, lower level of optimism, and being Hispanic or White/Caucasian were found to be associated with higher levels of FoR. Significant negative associations were reported between FoR and quality of life as well as psychosocial well-being. All but three studies were conducted in the USA. General cut-offs for severity/clinical significance have not been defined yet. CONCLUSIONS: FoR at modest intensity is experienced by most long-term cancer survivors. Future studies should address determinants and consequences of FoR in more detail. Validated instruments providing cut-offs for severity/clinical significance of FoR should be developed and utilized. Efficient interventions should be implemented to reduce detrimental effects of FoR. PMID- 22232031 TI - Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: a pilot study. AB - PURPOSE: To determine whether intrathecal administration of cultured autologous bone marrow stromal cells (BMSCs) is safe and feasible for treatment of subacute spinal injury. METHODS: Five patients with complete tetraplegia due to cervical spinal injury on admission were included. A small amount of bone marrow was obtained during surgery for spinal fusion. BMSCs were cultured, reaching 107-108 cells. The properties and functional efficacy of the BMSCs were verified with surface marker analysis and a neurite extension test. BMSCs were administered by lumbar puncture. The patients were closely observed for 6 months, and the Committee on Effectiveness and Safety of Clinical Treatment (CESCT) evaluated safety. RESULTS: No adverse responses were observed in biochemical and radiographic examinations. The CESCT did not recognize any harmful effects of the transplantation, and concluded it was safe for treatment. The patients were further followed up for 1 to 4 years with no adverse responses. The recovery of American Spinal Injury Association Impairment Scale (AIS) B and C patients at transplantation was rapid and remarkable, but gradual or limited in AIS A patients. CONCLUSION: This study demonstrated that intrathecal administration of cultured autologous BMSCs is safe and feasible for treatment of spinal cord injury. PMID- 22232032 TI - Progesterone treatment alters neurotrophin/proneurotrophin balance and receptor expression in rats with traumatic brain injury. AB - PURPOSE: The neuroactive steroid progesterone (PROG) has been shown to be an effective treatment for traumatic brain injury (TBI) both in animal models and in humans, but the signaling pathways involved have not yet been fully described. Here we characterize the protein expression of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and their pro-proteins and receptors following PROG treatment for TBI. METHODS: To evaluate whether PROG treatment given after TBI alters mature and proneurotrophin protein balance and the expression of receptors involved in apoptotic and cell survival signaling, we used Western blots in tissue obtained 24 h, 72 h, and 7 days after injury from rats with bilateral frontal cortical contusions. RESULTS: Compared to controls, PROG reduced levels of pro-apoptotic NGF precursor (proNGF) at 24 h and 7 days post-injury, reduced levels of pro-apoptotic BDNF precursor (proBDNF) and the BDNF receptor TrkB at all time points, and increased levels of mature NGF at 72 h. Levels of mature BDNF were decreased at 24 and 72 h. These observations were associated with reduced markers of apoptosis and improved behavioral parameters in PROG-treated rats. CONCLUSIONS: Some of PROG's protective effects after TBI are mediated, in part, by simultaneous induction of pro-survival neurotrophin signaling and inhibition of apoptotic proneurotrophin signaling. PMID- 22232033 TI - Rationale for a natural products approach to herbicide discovery. AB - Weeds continue to evolve resistance to all the known modes of herbicidal action, but no herbicide with a new target site has been commercialized in nearly 20 years. The so-called 'new chemistries' are simply molecules belonging to new chemical classes that have the same mechanisms of action as older herbicides (e.g. the protoporphyrinogen-oxidase-inhibiting pyrimidinedione saflufenacil or the very-long-chain fatty acid elongase targeting sulfonylisoxazoline herbicide pyroxasulfone). Therefore, the number of tools to manage weeds, and in particular those that can control herbicide-resistant weeds, is diminishing rapidly. There is an imminent need for truly innovative classes of herbicides that explore chemical spaces and interact with target sites not previously exploited by older active ingredients. This review proposes a rationale for a natural-products centered approach to herbicide discovery that capitalizes on the structural diversity and ingenuity afforded by these biologically active compounds. The natural process of extended-throughput screening (high number of compounds tested on many potential target sites over long periods of times) that has shaped the evolution of natural products tends to generate molecules tailored to interact with specific target sites. As this review shows, there is generally little overlap between the mode of action of natural and synthetic phytotoxins, and more emphasis should be placed on applying methods that have proved beneficial to the pharmaceutical industry to solve problems in the agrochemical industry. PMID- 22232034 TI - Hydrogel nanoparticles with covalently linked coomassie blue for brain tumor delineation visible to the surgeon. AB - Delineation of tumor margins is a critical and challenging objective during brain cancer surgery. A tumor-targeting deep-blue nanoparticle-based visible contrast agent is described, which, for the first time, offers in vivo tumor-specific visible color staining. This technology thus enables color-guided tumor resection in real time, with no need for extra equipment or special lighting conditions. The visual contrast agent consists of polyacrylamide nanoparticles covalently linked to Coomassie Blue molecules (for nonleachable blue color contrast), which are surface-conjugated with polyethylene glycol and F3 peptides for efficient in vivo circulation and tumor targeting, respectively. PMID- 22232035 TI - Hypothermia strategies: where is the evidence in your practice? PMID- 22232036 TI - Disaster preparedness: emergency planning in the NICU. AB - Hospital emergency management has evolved beyond satisfying regulatory requirements. Although tools and resources have been developed to support hospitals in emergency planning, there appears to be a scarcity of resources to guide hospital departments. To ensure that standards of care are maintained and to minimize the impact on the hospital and/ or a nursing unit, Good Samaritan Hospital has developed a mobile emergency system and an Emergency Operations Plan (EOP) template to assist other nursing units in their planning efforts. This article focuses on the development of emergency bedside backpacks, mobile disaster boxes, disaster documentation and forms go-kits, and guidelines for creating such a plan. The ongoing equipment testing, inventory rotation, staff training, and exercising response protocols are all crucial to test the effectiveness of the program in place. All these activities require a multidisciplinary approach to ensure integration with hospital-wide emergency planning efforts. PMID- 22232037 TI - Narratives and embodied knowing in the NICU. AB - The author draws on narratives as an illustration of embodied knowledge and argues for the importance of using embodied knowing to inform ethical decisions in the neonatal setting. Nurses have a unique perspective of the complex care associated with neonatal intensive care (NIC). NIC nurses listen to parent's stories and share their own practice stories, leading to an intimate appreciation of a family's particular response to their health care experience. These narratives can deepen understanding of how nurses go about doing their everyday work, describe experiences in everyday practice, and help the writer come to terms with traumatic events. Moreover, nurses' narratives provide a voice, an expression of their embodied knowledge. By telling and listening to nurses' stories, we can better understand how embodied knowledge supports families in crisis. The narratives in this article are examples of the challenges neonatal nurses face in using embodied knowing to enhance relationships with families. These narratives may help nurses to reflect on their practice and cultivate relationships with families in the NICU. PMID- 22232038 TI - Pain management, morphine administration, and outcomes in preterm infants: a review of the literature. AB - Infants in the Neonatal Intensive Care Unit may experience a myriad of painful procedures and stressful experiences. Pain management for infants requiring mechanical ventilation is complex and challenging especially in the preterm population. Many infants may not receive analgesia, primarily due to the unknown long-term neurodevelopmental effects of morphine exposure on the developing brain. Currently, there is no consensus on how to treat pain related to mechanical ventilation due to conflicting scientific evidence lacks clarity and certainty about the role of morphine in pain in preterm infants. The Advance Practice Neonatal Nurse must make the best use of available information about morphine analgesia for the preterm infant, and use it to guide policy and practice for infants. The Advance Practice Neonatal Nurse must use his/her clinical expertise to judicially balance the risks and benefits of morphine analgesia, when used, and tailor the treatment plan to each infant's specific needs. PMID- 22232039 TI - Breastfeeding the infant with congenital diaphragmatic hernia post extracorporeal membrane oxygenation. AB - Infants born with congenital diaphragmatic hernia (CDH) often require extracorporeal membrane oxygenation (ECMO). Infants on ECMO may experience a long period of being nothing by mouth (NPO) while receiving parenteral nutrition. Once the infant with CDH is repaired and off ECMO, human milk should be used to initiate enteral feedings. Human milk provides immunologic, developmental, and nutritional protection for these highrisk infants and may be crucial in decreasing morbidities commonly associated with post-ECMO survivors. These mother infant dyads require extensive lactation support to ensure maintenance of milk supply and successful transition to direct breastfeeding. Three case studies are presented as exemplars to demonstrate how breastfeeding success can be achieved even in the most vulnerable infants. PMID- 22232040 TI - Toolkit for NICU nurse preceptors. PMID- 22232041 TI - Glucose-6-phosphatase and glucose-6-phosphate dehydrogenase deficiency: how are they different? PMID- 22232042 TI - Effect of therapeutic hypothermia on drug metabolism. PMID- 22232043 TI - Preemie parent frustration: dealing with insensitive comments. PMID- 22232047 TI - The Mini Questionnaire of Personal Organization (MQPO): preliminary validation of a new post-rationalist personality questionnaire. AB - BACKGROUND: The Mini Questionnaire of Personal Organization (MQPO) has been constructed in order to comply with the inward/outward Personal Meaning Organization's (PMO) theory. According to Nardi's Adaptive Post-Rationalist approach, predictable and invariable caregivers' behaviours allow inward focus and a physical sight of reciprocity; non-predictable and variable caregivers' behaviours allow outward focus and a semantic sight of reciprocity. METHODS: The 20 items of MQPO have been selected from 29 intermediate (n = 160) and 40 initial items (n = 204). Psychometric validation has been conducted (n = 296), including Internal Validity (Item-Total Correlation; Factor Analysis), Internal Coherence by Factor Analysis, two analyses in Discriminant Validity (n = 132 and n = 80) and Reliability by Test-Retest Analysis (n = 49). All subjects have been given their written informed consent before beginning the test. RESULTS: The validation of the MQPO shows that the ultimate version is consistent with its post rationalist paradigm. Four different factors have been found, one for each PMO. Validity of the construct and the internal reliability index are satisfying (Alpha = 0.73). Moreover, the results obtained are constant (from r = 0.80 to r = 0.89). There is an adequate agreement between the MQPO scales and the clinical evaluations (72.5%), as well as an excellent agreement (80.0%) between the scores of the MQPO and those of the Personal Meaning Questionnaire. CONCLUSION: The MQPO is a tool able to study personality as a process by focusing on the relationships between personality and developmental process axes, which are the bases of the PMO's theory, according to the APR approach. PMID- 22232048 TI - Psychotherapy across cultures: the form-content dichotomy. AB - The diversity of patients, problems, beliefs and cultures mandates the need to educate, match, negotiate and integrate psychological interventions. This is necessary in all cultures and in every setting. Many schools of psychotherapy offer specific theories and particular techniques, yet they share many common approaches. Their individual techniques allow therapists form and structure to treat different clinical problems, discuss diverse content and use them in varied settings and among people with assorted cultural backgrounds. The heterogeneity within cultures, regions and populations demands that therapists understand the local and individual reality. The apparent contradictions between standard psychological therapies and their use across cultures, when viewed through a form content framework, allow for matching strategies for specific individuals and their distress, and for choosing the best treatment options from a diverse therapeutic armamentarium. Psychotherapies are at their weakest when they attempt to provide explanations across cultures and are at their strongest when they are used as vehicles for engagement with patients. The challenge is to find a common psychotherapeutic language, which attempts to bridge the divide between the issues facing the patient and the armamentarium of the therapist. The form content paradigm at least partly explains the complexity of the issues within psychotherapy. It also allows the therapist to move from the therapy-centric orientation of Western approaches to the patient-centric orientations required for success in psychological therapies. PMID- 22232049 TI - Multiple comparisons to both a negative and a positive control. AB - This paper addresses multiple comparisons in the presence of both a negative and a positive control. The methodology of the three-arm trial is extended to the case of many experimental treatment arms or different doses of a compound. In contrast to the classic three-arm trial, the focus is on the family-wise error type I. Normally distributed data with either homogeneous or heterogeneous group variances are considered. Explicit criteria for an optimal allocation are proposed. Depending on the pattern of heterogeneity, remarkably unbalanced designs are power-optimal. As an example, the method will be applied to a toxicological experiment. PMID- 22232051 TI - Creation of the European Academy of Neurology. PMID- 22232050 TI - Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. AB - OBJECTIVE: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI). METHODS: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings. RESULTS: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent. CONCLUSION: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI. PMID- 22232052 TI - Chiasmal visual loss after retinal detachment. PMID- 22232053 TI - Association of alzheimer disease pathology with abnormal lipid metabolism: the Hisayama study. PMID- 22232054 TI - Longitudinal assessment of oxaliplatin-induced neuropathy. PMID- 22232055 TI - Normal pressure hydrocephalus: how often does the diagnosis hold water? PMID- 22232056 TI - Teaching NeuroImages: Bilateral pedicular fractures in severe lumbar dural ectasia. PMID- 22232057 TI - Clinical reasoning: an unusual lung mass causing focal weakness. PMID- 22232058 TI - Pearls & Oy-sters: Bifocal germinoma of the brain: review of systems is key to the diagnosis. PMID- 22232060 TI - Exact sample-size determination in testing non-inferiority under a simple crossover trial. AB - For testing the non-inferiority (or equivalence) of an experimental treatment to a standard treatment, the odds ratio (OR) of patient response rates has been recommended to measure the relative treatment efficacy. On the basis of an exact test procedure proposed elsewhere for a simple crossover design, we develop an exact sample-size calculation procedure with respect to the OR of patient response rates for a desired power of detecting non-inferiority at a given nominal type I error. We note that the sample size calculated for a desired power based on an asymptotic test procedure can be much smaller than that based on the exact test procedure under a given situation. We further discuss the advantage and disadvantage of sample-size calculation using the exact test and the asymptotic test procedures. We employ an example by studying two inhalation devices for asthmatics to illustrate the use of sample-size calculation procedure developed here. PMID- 22232059 TI - Role of microRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells. AB - MicroRNAs (miRNAs) are short noncoding RNAs, which post-transcriptionally regulate gene expression. miRNAs are transcribed as precursors and matured to active forms by a series of enzymes, including Dicer. miRNAs are important in governing cell differentiation, development, and disease. We have recently developed a feeder- and serum-free protocol for direct derivation of endothelial cells (ECs) from human embryonic stem cells (hESCs) and provided evidence of increases in angiogenesis-associated miRNAs (miR-126 and -210) during the process. However, the functional role of miRNAs in hESC differentiation to vascular EC remains to be fully interrogated. Here, we show that the reduction of miRNA maturation induced by Dicer knockdown suppressed hES-EC differentiation. A miRNA microarray was performed to quantify hES-EC miRNA profiles during defined stages of endothelial differentiation. miR-99b, -181a, and -181b were identified as increasing in a time- and differentiation-dependent manner to peak in mature hESC-ECs and adult ECs. Augmentation of miR-99b, -181a, and -181b levels by lentiviral-mediated transfer potentiated the mRNA and protein expression of EC specific markers, Pecam1 and VE Cadherin, increased nitric oxide production, and improved hES-EC-induced therapeutic neovascularization in vivo. Conversely, knockdown did not impact endothelial differentiation. Our results suggest that miR-99b, -181a, and -181b comprise a component of an endothelial-miRNA signature and are capable of potentiating EC differentiation from pluripotent hESCs. PMID- 22232061 TI - A direct method and ICER tables for the estimation of the cost-effectiveness of smoking cessation interventions in general populations: application to a new cytisine trial and other examples. AB - INTRODUCTION: The popularity of smoking cost-effectiveness (CE) analysis has grown rapidly. Differences in models and inputs mean results may not be comparable, and researchers may have to take them on trust because the methods are beyond their expertise and not always transparent. We describe a direct method and tables of results for researchers without specialist knowledge. METHODS: We estimate the health benefit to an individual attributed to an intervention and compute tables of incremental cost-effectiveness ratios (ICERs) for interventions with varying incremental intervention effects and costs. Estimates of life years gained come from the longest epidemiological study. After discounting, adjustments are made for future cessation and relapse. The method is described in simple steps, and conservative inputs are used throughout. RESULTS: To look up an ICER, the user needs only to know the cost of the intervention per smoker and the effect as measured by the percentage of ex-smokers attributable to the intervention at either 6- or 12-month follow-up. Reanalysis of authoritative reports indicates that these ICERs are comparable to those from decision-analytic simulation models. CONCLUSIONS: Researchers can now obtain immediate estimates of the CE of interventions in general populations. The method is easily programmed in a spreadsheet. ICERs are from the payer perspective and exclude offset and societal costs. Interventions in subpopulations will require inputs specific to those populations. Readers who wish to include an adjustment for quality of life can easily do so. The tables might promote a standard approach, with interventions compared on a consistent and transparent basis. PMID- 22232062 TI - Supramolecular cellular filament systems: how and why do they form? AB - All cells, from simple bacteria to complex human tissues, rely on extensive networks of protein fibers to help maintain their proper form and function. These filament systems usually do not operate as single filaments, but form complex suprastructures, which are essential for specific cellular functions. Here, we describe the progress in determining the architectures of molecular filamentous suprastructures, the principles leading to their formation, and the mechanisms by which they may facilitate function. The complex eukaryotic cytoskeleton is tightly regulated by a large number of actin- or microtubule-associated proteins. In contrast, recently discovered bacterial actins and tubulins have few associated regulatory proteins. Hence, the quest to find basic principles that govern the formation of filamentous suprastructures is simplified in bacteria. Three common principles, which have been probed extensively during evolution, can be identified that lead to suprastructures formation: cationic counterion fluctuations; self-association into liquid crystals; and molecular crowding. The underlying physics of these processes will be discussed with respect to physiological circumstance. PMID- 22232063 TI - Operating characteristics of a Simon two-stage phase II clinical trial design incorporating continuous toxicity monitoring. AB - Phase II clinical trials are usually designed to measure efficacy, but safety is also an important end point. Previous authors recommended a method to monitor toxic events after each patient is enrolled, which is also known as continuously monitoring the toxicity. In this work, we investigate combining the usual Simon two-stage design to monitor response with the continuous toxicity monitoring methodology. Theoretical justification is given for the nominal size, probability of early termination, and average sample size under the null hypothesis of the combined testing procedure. A series of simulations are performed to investigate the performance of the combined procedure. PMID- 22232065 TI - Self-perceived health and return to work following work-related hand injury. AB - BACKGROUND: Return to work is an important outcome following traumatic work related hand injuries. It is unclear how psychosocial factors affect the time to return to work following traumatic work-related hand injury. AIMS: To investigate the relationships between hand injury severity, self-perceived health, demographics and time off work (TOW) following traumatic work-related hand injuries and the influence of psychosocial factors on the readiness of return to work. METHODS: Data from 120 traumatic work-related hand injured patients were gathered. The Modified Hand Injury Severity Score (MHISS) and Short Form Health Survey (SF-36) were used to assess the severity of hand trauma and self-perceived health, respectively. The relationships between MHISS, SF-36, demographics and TOW were analysed by multiple regression analysis. RESULTS: Mean duration of TOW was 127 days for patients with a mild MHISS, 108 days for a moderate score, 160 days for a severe score and 236 days for those with a major score. A positive correlation between MHISS and duration of TOW was identified. Self-perceived physical functioning was found to have a negative correlation with TOW, whereas self-perceived mental health was positively correlated with TOW. CONCLUSIONS: This study highlights the importance of self-perceived health in considering return to work following traumatic work-related hand injury. PMID- 22232064 TI - Concise review: applying stem cell biology to vascular structures. AB - The vasculature, an organ that penetrates every other organ, is ideally poised to be the site where pools of stem cells are placed, to be deployed and committed in response to feedback regulation, and to respond to demands for new vascular structures. These pools of multipotent cells are often under the regulation of various members of the transforming growth factor-beta superfamily, including the bone morphogenetic proteins and their antagonists. Regulation of stem cell populations affects their recruitment, differentiation, spatial organization, and their coordination with host tissue. Loss and dysregulation of feedback control cause a variety of diseases that involve ectopic tissue formation, including atherosclerotic lesion formation and calcification, diabetic vasculopathies, and arteriovenous malformations. PMID- 22232066 TI - The in vivo response of stem and other undifferentiated spermatogonia to the reversible inhibition of glial cell line-derived neurotrophic factor signaling in the adult. AB - Maintaining adequate numbers of spermatogonial stem cells is required for the production of the millions of sperm required for male fertility. To date, however, the mechanisms that regulate the size of this pool in the adult are poorly defined. Glial cell line-derived neurotrophic factor (GDNF) is required for establishing this pool in the prepubertal animal, but its in vivo function in the normal adult testis has never been examined directly. We used a chemical genetic approach to address this issue. We generated mice carrying a single amino acid mutation (V805A) in Ret, the kinase subunit of the GDNF receptor. This mutation does not affect normal GDNF signaling but renders it susceptible to inhibition by the ATP competitive inhibitor, NA-PP1. When GDNF signaling was blocked in adults for 11 days, only a few cells remained that expressed the stem spermatogonial markers, Gfralpha1 and Zbtb16, and testicular Ret mRNA content was reduced markedly. These decreases were associated with depletion of functional stem spermatogonia; some were lost when GDNF signaling was inhibited for only 2 days while others survived for up to 11 days. However, when signaling was restored, the remaining stem cells proliferated, initiating tissue restoration. In conclusion, these results provide the first direct proof that GDNF acutely regulates the number of spermatogonial stem cells in the normal adult testis. Additionally, these results demonstrate different sensitivities among subpopulation of these stem cells to inhibition of GDNF signaling. PMID- 22232067 TI - An examination of the relative impact of type I and type II error rates in phase II drug screening trial queues. AB - In this note, we highlight the fact that the choice of type I and type II error rates should not simply be set at traditional levels in the phase II clinical trial setting when considering the relative success rate of previous trials in a given disease setting. For diseases in which it is rare that a new compound is active, we argue that more stringent type I error rates in the phase II setting may be more important relative to relaxing the type II error rates. The paper itself is more of a 'thought' experiment on this topic such that specific clinical trial settings will require specific applications of this approach. This is due in part to the fact that the real-world setting is more complex relative to overall decision process in terms of moving from phase II to phase III trials than our basic illustrative model. PMID- 22232068 TI - Neighborhood disadvantage, individual-level socioeconomic position, and self reported chronic arthritis: a cross-sectional multilevel study. AB - OBJECTIVE: To examine the association between individual- and neighborhood-level disadvantage and self-reported arthritis. METHODS: We used data from a population based cross-sectional study conducted in 2007 among 10,757 men and women ages 40 65 years, selected from 200 neighborhoods in Brisbane, Queensland, Australia using a stratified 2-stage cluster design. Data were collected using a mail survey (68.5% response). Neighborhood disadvantage was measured using a census based composite index, and individual disadvantage was measured using self reported education, household income, and occupation. Arthritis was indicated by self-report. Data were analyzed using multilevel modeling. RESULTS: The overall rate of self-reported arthritis was 23% (95% confidence interval [95% CI] 22-24). After adjustment for sociodemographic factors, arthritis prevalence was greatest for women (odds ratio [OR] 1.5, 95% CI 1.4-1.7) and in those ages 60-65 years (OR 4.4, 95% CI 3.7-5.2), those with a diploma/associate diploma (OR 1.3, 95% CI 1.1 1.6), those who were permanently unable to work (OR 4.0, 95% CI 3.1-5.3), and those with a household income <$25,999 (OR 2.1, 95% CI 1.7-2.6). Independent of individual-level factors, residents of the most disadvantaged neighborhoods were 42% (OR 1.4, 95% CI 1.2-1.7) more likely than those in the least disadvantaged neighborhoods to self-report arthritis. Cross-level interactions between neighborhood disadvantage and education, occupation, and household income were not significant. CONCLUSION: Arthritis prevalence is greater in more socially disadvantaged neighborhoods. These are the first multilevel data to examine the relationship between individual- and neighborhood-level disadvantage upon arthritis and have important implications for policy, health promotion, and other intervention strategies designed to reduce the rates of arthritis, indicating that intervention efforts may need to focus on both people and places. PMID- 22232069 TI - A facile and versatile approach to efficient luminescent materials for applications in organic light-emitting diodes. PMID- 22232071 TI - Admissible two-stage designs for phase II cancer clinical trials that incorporate the expected sample size under the alternative hypothesis. AB - Two-stage studies may be chosen optimally by minimising a single characteristic like the maximum sample size. However, given that an investigator will initially select a null treatment effect and the clinically relevant difference, it is better to choose a design that also considers the expected sample size for each of these values. The maximum sample size and the two expected sample sizes are here combined to produce an expected loss function to find designs that are admissible. Given the prior odds of success and the importance of the total sample size, minimising the expected loss gives the optimal design for this situation. A novel triangular graph to represent the admissible designs helps guide the decision-making process. The H0-optimal, H1-optimal, H0-minimax and H1 minimax designs are all particular cases of admissible designs. The commonly used H0-optimal design is rarely good when allowing stopping for efficacy. Additionally, the delta-minimax design, which minimises the maximum expected sample size, is sometimes admissible under the loss function. However, the results can be varied and each situation will require the evaluation of all the admissible designs. Software to do this is provided. PMID- 22232070 TI - Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and hippo pathway effectors by Notch1. AB - The Notch pathway plays a pivotal role in regulating cell fate decisions in many stem cell systems. However, the full repertoire of Notch target genes in vivo and the mechanisms through which this pathway activity is integrated with other signaling pathways are largely unknown. Here, we report a transgenic mouse in which the activation of the Notch pathway massively expands the neural stem cell (NSC) pool in a cell context-dependent manner. Using this in vivo system, we identify direct targets of RBPJ/N1ICD in cortical NSCs at a genome-wide level through combined ChIP-Seq and transcriptome analyses. Through a highly conservative analysis of these datasets, we identified 98 genes that are directly regulated by N1ICD/RPBJ in vivo. These include many transcription factors that are known to be critical for NSC self-renewal (Sox2, Pax6, Tlx, and Id4) and the transcriptional effectors of the Wnt, SHH, and Hippo pathways, TCF4, Gli2, Gli3, Yap1, and Tead2. Since little is known about the function of the Hippo-Yap pathway in NSCs, we analyzed Yap1 expression and function in NSCs. We show that Yap1 expression is restricted to the stem cell compartment in the developing forebrain and that its expression is sufficient to rescue Notch pathway inhibition in NSC self-renewal assays. Together, results of this study reveal a previously underappreciated complexity and breadth of Notch1 targets in vivo and show direct interaction between Notch and Hippo-Yap pathways in NSCs. PMID- 22232073 TI - Hyperspectral imaging of mucosal surfaces in patients. AB - The aim of this study was to proof applicability of hyperspectral imaging for the analysis and classification of human mucosal surfaces in vivo. The larynx as a prototypical anatomically well-defined surgical test area was analyzed by microlaryngoscopy with a polychromatic lightsource and a synchronous triggered monochromatic CCD-camera. Image stacks (5 benign, 7 malignant tumors) were analyzed by established software (principal component analysis PCA, hyperspectral classification, spectral profiles). Hyperspectral image datacubes were analyzed and classified by conventional software. In PCA, images at 590-680 nm loaded most onto the first PC which typically contained 95% of the total information. Hyperspectral classification clustered the data highlighting altered mucosa. The spectral profiles clearly differed between the different groups. Hyperspectral imaging can be applied to mucosal surfaces. This approach opens the way to analyze spectral characteristics of histologically different lesions in order to build up a spectral library and to allow non-touch optical biopsy. PMID- 22232074 TI - Colorectal cancer stem cells. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed and lethal cancers worldwide. It is a multistep process that requires the accumulation of genetic/epigenetic aberrations. There are several issues concerning colorectal carcinogenesis that remain unanswered, such as the cell of origin and the type of cells that propagate the tumor after its initiation. There are two models of carcinogenesis: the stochastic and the cancer stem cell (CSC) model. According to the stochastic model, any kind of cell is capable of initiating and promoting cancer development, whereas the CSC model suggests that tumors are hierarchically organized and only CSCs possess cancer-promoting potential. Moreover, various molecular pathways, such as Wingless/Int (Wnt) and Notch, as well as the complex crosstalk network between microenvironment and CSCs, are involved in CRC. Identification of CSCs remains controversial due to the lack of widely accepted specific molecular markers. CSCs are responsible for tumor relapse, because conventional drugs fail to eliminate the CSC reservoir. Therefore, the design of CSC-targeted interventions is a rational target, which will enhance responsiveness to traditional therapeutic strategies and reduce local recurrence and metastasis. This review discusses the implications of the newly introduced CSC model in CRC, the markers used up to now for CSC identification, and its potential implications in the design of novel therapeutic approaches. PMID- 22232075 TI - A new tool for the assessment of satisfaction with iron chelation therapy (ICT Sat) for patients with beta-thalassemia major. AB - BACKGROUND: High satisfaction with iron chelation is a major determinant for adherence to ICT in beta-thalassaemia major (beta-TM) patients. In this study, a new tool to assess different domains of satisfaction for available forms of ICT was developed and validated. The impact of patients' satisfaction with ICT has been tested. METHODS: Items were generated via focus groups and a preliminary version with 24 items (ICT-Sat) with an additional item for treatment preference and a knowledge questionnaire (KQ) was developed. 170 beta-TM patients from three Thalassaemia centers in Egypt, aged 2-32 years received three questionnaires to fill in; the new ICT-Sat, a KQ, and a previously validated tool for satisfaction with ICT (SICT) and retested 4-6 weeks later to ensure re-test reliability. Type of chelation, drug related adverse events, compliance with ICT, and serum ferritin level (SF) during the year prior to the study as well as available cardiac T2*data were recorded. RESULTS: One hundred and fifty two beta-TM patients completed all questionnaires; median age was 12 years. The final 15 remaining ICT-Sat items, yielding to four domain scores, explained 70.6% of the total variance. The "perceived effectiveness" and "fear and worries" domains of the ICT-Sat correlated significantly with the domains "perceived effectiveness" and "acceptance" of the SICT. Patients treated with oral ICT were more satisfied with perceived effectiveness, and their side effects. CONCLUSIONS: A new clinically based ICT-Sat tool was developed and revealed good psychometric characteristics. Adherence to ICT was better correlated with "perceived effectiveness" and SF level. PMID- 22232076 TI - Muscle-tendon tissue properties in the hypermobility type of Ehlers-Danlos syndrome. AB - OBJECTIVE: To investigate the passive properties of the plantar flexors muscle tendon tissue in patients with the hypermobility type of Ehlers-Danlos syndrome (EDS-HT). METHODS: Twenty-five women with EDS-HT and 25 sex- and age-matched healthy control subjects participated in the study. Passive resistive torque (PRT) of the plantar flexors was measured with an isokinetic dynamometer during 2 standardized stretch protocols to obtain the passive muscle tension. Protocol 1 consisted of 4 continuous cycles to a predetermined angle of 10 degrees dorsiflexion. Protocol 2 consisted of a slow stretch to the onset of pain. Torque, angle, and electromyography were simultaneously recorded during the tests. To take muscle thickness into account, muscle cross-sectional area (MCSA) was obtained with peripheral quantitative computed tomography. Stiffness of the Achilles tendon was assessed using a dynamometer in combination with ultrasonography. RESULTS: The results demonstrate a significantly larger maximal joint angle in the EDS-HT patients accompanied by a similar PRT compared to the control subjects (protocol 2), indicating a lower passive muscle tension in the patient group. PRT for the predetermined angle (protocol 1) was the same for both groups and there was no difference in MSCA. Furthermore, a significantly lower Achilles tendon stiffness was seen in the patient group than in the control group. CONCLUSION: This study is the first to provide evidence for altered passive properties of the muscle-tendon unit in EDS-HT patients. These changes are thought to be associated with structural modifications in connective tissue. PMID- 22232077 TI - Molecular classification of breast carcinomas with particular emphasis on "basal like" carcinoma: a critical review. AB - During the last 11 years, 5 molecular subtypes of breast carcinoma (luminal A, luminal B, Her2-positive, basal-like, and normal breast-like) have been characterized and intensively studied. As genomic research evolves, further subtypes of breast cancers into new "molecular entities" are expected to occur. For example, a new and rare breast cancer subtype, known as claudin-low, has been recently found in human carcinomas and in breast cancer cell lines. There is no doubt that global gene expression analyses using high-throughput biotechnologies have drastically improved our understanding of breast cancer as a heterogeneous disease. The main question is, however, whether new molecular techniques such as gene expression profiling (or signature) should be regarded as the gold standard for identifying breast cancer subtypes. A critical review of the literature clearly shows major problems with current molecular techniques and classification including poor definitions, lack of reproducibility, and lack of quality control. Therefore, the current molecular approaches cannot be incorporated into routine clinical practice and treatment decision making as they are immature or even can be misleading. This review particularly focuses on the "basal-like" breast cancer subtype that represents one of the most popular breast cancer "entities". It critically shows major problems and misconceptions with and about this subtype and challenges the common claim that it represents a "distinct entity". It concludes that the term "basal-like" is misleading and states that there is no evidence that expression of basal-type cytokeratins in a given breast cancer, regardless of other established prognostic factors, does have any impact on clinical outcome. PMID- 22232079 TI - Malignant melanoma as second malignant neoplasm in long-term childhood cancer survivors: a systematic review. AB - This systematic review provides information on malignant melanoma as second malignant neoplasm (SMN) after childhood cancer and evaluates its risk factors. Study reports describing incidences of SMN and malignant melanoma as SMN in a population of childhood cancer survivors (CCS) were included. Of 151,575 CCS, 4,010 (2.6%) children developed an SMN, 212 of which were melanoma (5.3% or 0.14% of all CCS). The following risk factors for malignant melanoma as SMN were identified: radiotherapy, or the combination alkylating agents and anti-mitotic drugs. Melanomas are most frequently observed after Hodgkin disease, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors. PMID- 22232078 TI - Transcription factor TCF4 maintains the properties of human corneal epithelial stem cells. AB - TCF4, a key transcription factor of Wnt signaling system, has been recently found to be essential for maintaining stem cells. However, its signaling pathway is not well elucidated. This study was to explore the functional roles and signaling pathway of TCF4 in maintaining adult stem cell properties using human corneal epithelial stem cells as a model. With immunofluorescent staining and real-time polymerase chain reaction, we observed that TCF4 was exclusively expressed in the basal layer of human limbal epithelium where corneal epithelial stem cells reside. TCF4 was found to be well colocalized with ABCG2 and p63, two recognized epithelial stem/progenitor cell markers. Using in vitro culture models of primary human corneal epithelial cells, we revealed that TCF4 mRNA and protein were upregulated by cells in exponential growth stage, and RNA interference by small interfering RNA-TCF4 (10-50 nM) transfection blocked TCF4 signaling and suppressed cell proliferation as measured by WST-1 assay. TCF4 silence was found to be accompanied by downregulated proliferation-associated factors p63 and survivin, as well as upregulated cyclin-dependent kinase inhibitor 1C (p57). By creating a wound healing model in vitro, we identified upregulation and activation of beta-catenin/TCF4 with their protein translocation from cytoplasm to nuclei, as evaluated by reverse transcription-quantitative real-time polymerase chain reaction, immunostaining, and Western blotting. Upregulated p63/survivin and downregulated p57 were further identified to be TCF4 downstream molecules that promote cell migration and proliferation in wound healing process. These findings demonstrate that transcription factor TCF4 plays an important role in determining or maintaining the phenotype and functional properties of human corneal epithelial stem cells. PMID- 22232080 TI - Clinical tool to identify patients who are most likely to achieve long-term improvement in physical function after total hip arthroplasty. AB - OBJECTIVE: To develop a clinical risk prediction tool to identify patients most likely to experience long-term clinically meaningful functional improvement following total hip arthroplasty (THA). METHODS: We studied 282 patients from 2 health districts in England (Portsmouth and North Staffordshire) who were >=45 years of age and undergoing THA for primary osteoarthritis. Baseline data on age, sex, comorbidity, body mass index (BMI), functional status (Short Form 36 [SF 36]), and preoperative radiographic severity were collected by interview and examination. The outcome was a clinically significant (30-point) improvement in SF-36 physical function score assessed ~8 years after THA. Logistic regression modeling was used to identify predictors of functional improvement. RESULTS: Improvement in physical function was less likely in patients with better preoperative functioning (odds ratio [OR] 0.73 [95% confidence interval (95% CI) 0.60, 0.89]), older people (OR 0.94 [95% CI 0.90, 0.98]), women (OR 0.37 [95% CI 0.19, 0.72]), those with a previous hip injury (OR 0.14 [95% CI 0.03, 0.74]), and those with a greater number of painful joint sites (OR 0.61 [95% CI 0.46, 0.80]). Patients with worse radiographic grades were most likely to improve (OR 2.15 [95% CI 1.17, 3.93]). We found no influence of BMI or patient comorbidity on functional outcome. Predictors of good outcomes were the same as those of bad outcomes, acting in the opposite direction. A clinical risk prediction tool was developed to identify patients who are most likely to receive functional improvement following THA. CONCLUSION: This prediction tool has the potential to inform health care professionals and patients about functional improvement following THA (as distinct from driving rationing or commissioning decisions regarding who should have surgery); it requires introduction into clinical practice under research conditions to investigate its impact on decisions made by patients and clinicians. PMID- 22232081 TI - CRAFT: Multimodality confocal skin imaging for early cancer diagnosis. AB - Although histological analysis serves as a gold standard to cancer diagnosis, its application on skin cancer detection is largely prohibited due to its invasive nature. To obtain both the structural and pathological information in situ, a Confocal Reflectance/Auto-Fluorescence Tomography (CRAFT) system was established to examine the skin sites in vivo with both reflectance and autofluorescence modes simultaneously. Nude mice skin with cancerous sites and normal skin sites were imaged and compared with the system. The cellular density and reflective intensity in cancerous sites reflects the structural change of the tissue. With the decay coefficient analysis, the corresponding NAD(P)H decay index for cancerous sites is 1.65-fold that of normal sites, leading to a 97.8% of sensitivity and specificity for early cancer diagnosis. The results are verified by the followed histological analysis. Therefore, CRAFT may provide a novel method for the in vivo, non-invasive diagnosis of early cancer. PMID- 22232082 TI - Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. AB - Background Fanconi anaemia (FA) is a group of disorders characterised by progressive bone marrow failure and a characteristic but variable craniofacial and skeletal involvement. Recessive mutations in any of 15 genes linked to FA lead to the pathognomonic increased susceptibility to double-strand DNA breaks. Methods Autozygome and exome analysis of a patient with classic FA phenotype Results The authors identified a novel truncating mutation in XRCC2. Consistent with the proposed causal link to FA, this gene is an essential non-redundant component of the RAD51 family of homologous repair proteins and its deficiency in a murine model has been shown to lead to a highly similar phenotype to that of this patient both at the cellular and organismal level. Conclusion This study implicates XRCC2 in the pathogenesis of FA and calls for further investigation of the potential contribution of XRCC2 mutations to the overall mutational load of FA. PMID- 22232083 TI - Horner syndrome in a newly diagnosed patient with high risk precursor B-cell acute lymphoblastic leukemia. PMID- 22232084 TI - miR-290 cluster modulates pluripotency by repressing canonical NF-kappaB signaling. AB - Embryonic stem cell (ESC)-specific microRNAs (miRNAs) play a critical role in the maintenance of pluripotency and self-renewal but the complete network between these miRNAs and their broad range of target genes still remains elusive. Here we demonstrate that miR-290 cluster, the most abundant miRNA family in ESCs, targets the NF-kappaB subunit p65 (also known as RelA) by repressing its translation. Forced expression of p65 causes loss of pluripotency, promotes differentiation of ESCs, and leads to an epithelial to mesenchymal transition. These data define p65 as a novel target gene of miR-290 cluster and provide new insight into the function of ESC-specific miRNAs. PMID- 22232085 TI - Effect of pregabalin on sleep in patients with fibromyalgia and sleep maintenance disturbance: a randomized, placebo-controlled, 2-way crossover polysomnography study. AB - OBJECTIVE: To assess the effect of pregabalin on polysomnographic (PSG) measures of sleep and patient-rated sleep, tiredness, and pain in fibromyalgia patients. METHODS: We performed a randomized, double-blind, placebo-controlled, 2-period crossover PSG study. Patients ages >=18 years with fibromyalgia satisfied subjective and objective sleep disturbance criteria prior to randomization. Eligible patients were randomized (1:1) to pregabalin (300-450 mg/day) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-adjustment and dose-maintenance phase, with a 2-week taper/washout between periods. In-laboratory PSGs were recorded during 2 consecutive nights at screening and at the end of each crossover period. The primary end point was the difference in sleep maintenance defined by PSG-recorded wake after sleep onset (WASO; minutes) between 4 weeks of treatment with pregabalin and with placebo. Other PSG measures; patient-rated sleep, tiredness, and pain; and tolerability were assessed. RESULTS: Of 119 patients randomized (103 women [86.6%], mean age 48.4 years), 102 (85.7%) completed both periods. Patients treated with pregabalin showed a reduction in PSG-determined WASO versus treatment with placebo (week 4 difference: -19.2 minutes [95% confidence interval (95% CI) -26.7, -11.6]; P < 0.0001). Pain score improved (decreased) with pregabalin versus placebo treatment at all 4 weeks (week 4 difference: -0.52 [95% CI -0.90, -0.14]; P = 0.0084). Modest (rho = <0.3) but significant correlations were found between PSG sleep assessments and ratings of pain and sleep quality. Frequently reported all-causality adverse events (pregabalin versus placebo) were: dizziness (30.4% versus 9.9%), somnolence (20.5% versus 4.5%), and headache (8.9% versus 8.1%). CONCLUSION: Patients with fibromyalgia treated with pregabalin had statistically significant and meaningful improvements in sleep, as assessed by PSG. Patients with fibromyalgia also reported decreased daily pain. Pregabalin was well tolerated. PMID- 22232086 TI - Anatomists provide the foundation for learning pathophysiology. AB - The need for interdisciplinary graduate training programs which prepare students to conceptualize the application of their research in clinical settings continues to grow. Though several programs have been cultivated to address this need, demand still outweighs supply. The following describes a curriculum developed with the intent of incorporating medical knowledge into a PhD graduate training program. Development of this Molecular Medicine program by the Cleveland Clinic Lerner College of Medicine in collaboration with Case Western Reserve University was funded by the Howard Hughes Medical Institute "Med into Grad" initiative. The core curriculum of this program begins with a foundation in Human Physiology and Disease course in which anatomy faculty introduce students to a basic overview of gross anatomy structure and function. This course is followed by five fundamental basic science courses, a composite course focusing on principles of clinical and translation research, a course on laboratory techniques and three, 12-week research rotations. In the second year of the program, students begin their dissertation research, complete their qualifying examination, and partake in an individually tailored Clinical Experience course. Interdisciplinary graduate programs like this provide another venue for faculty in anatomical sciences to help aspiring translational scientists relate basic science knowledge to human pathophysiology and health. PMID- 22232087 TI - It's time to halt the unacceptable toll of diabetes. PMID- 22232088 TI - Health reform gets its day in court--the Supreme one. PMID- 22232089 TI - Confronting the urgent challenge of diabetes: an overview. AB - The rising tide of diabetes has an unacceptable human and societal toll. Rates of all major forms of diabetes are increasing at enormous individual and societal cost: 8.3 percent of the US population is afflicted today, and financial costs reached $174 billion for 2007. A major cause of blindness, renal failure, amputation, and cardiovascular disease, diabetes also increases the risk of cancer and dementia and more than doubles individual health care costs. Control of glucose, blood pressure, and lipids improves outcomes. Yet diabetes management is nonetheless suboptimal, particularly in disproportionately affected poor and minority populations. Safer, less burdensome, and more personalized approaches to therapy are needed. People at high risk for type 2 diabetes must be identified if society is to realize the benefits of therapies proven to delay or prevent the disease. We have many of the tools we need to address this challenge, and we must apply them now. PMID- 22232090 TI - Effective interventions for stemming the growing crisis of diabetes and prediabetes: a national payer's perspective. AB - Between a fifth and a third of US adults will have diabetes by midcentury, up from one in ten now, according to a government estimate. We project that over the next decade, around 40 million adults could have diabetes and 100 million could be diagnosed with its clinical precursor, prediabetes. Related health care spending could reach $512 billion annually in 2021. Evidence-based interventions can curb diabetes and its clinical complications, but little has been done to implement them on a wide scale. What's needed, among other measures, are new risk assessment methods to identify subpopulations that will benefit most; the enrollment of consumers in new care models that support and encourage lifestyle change; partnerships with pharmacists, nurses, and health coaches; and new programs in Medicare and Medicaid that encourage patient engagement and lifestyle change. PMID- 22232091 TI - Diabetes's 'health shock' to schooling and earnings: increased dropout rates and lower wages and employment in young adults. AB - Despite a growing diabetes crisis, the nonmedical implications for young adults have gone virtually unexplored. We investigated the effects of diabetes on two key outcomes for this age group-schooling and earnings-and found that it delivers an increasingly common "health shock" to both. We identified effects in several measures of educational attainment, including a high school dropout rate that was six percentage points higher than among young adults without the disease. We also found lower employment and wages: A person with diabetes can conservatively expect to lose more than $160,000 over his or her working life, compared to a peer without the disease. For young adults with diabetes, having a parent with diabetes also leads to poorer outcomes than if one more parents do not have the disease-for example, reducing the likelihood of attending college by four to six percentage points, even after the child's health status is controlled for. These results highlight the urgency of attacking this growing health problem, as well as the need for measures such as in-school screening for whether diabetes's impact on individual learning and performance begins before the classic manifestations of clinical diabetes appear. PMID- 22232092 TI - Analysis & commentary: The US Preventive Services Task Force should consider a broader evidence base in updating its diabetes screening guidelines. AB - Diabetes, especially type 2 diabetes, is on the rise throughout the United States. Several national health organizations and professional medical societies advocate screening people in high-risk groups for diabetes. However, the US Preventive Services Task Force recommends screening only adults with hypertension. We examined evidence supporting screening high-risk adults, including studies using intermediate outcomes and modeling studies. We found a broad range of evidence of practical relevance to diabetes screening that merits consideration in developing new screening guidelines. This evidence could inform recommendations to expand coverage to screening of other high-risk groups and could facilitate the prevention and early treatment of diabetes. We recommend that the US Preventive Services Task Force consider these expanded sources of evidence and revise its recommendations accordingly. PMID- 22232093 TI - 'Personalized medicine' to identify genetic risks for type 2 diabetes and focus prevention: can it fulfill its promise? AB - Public health measures are required to address the worldwide increase in type 2 diabetes. Proponents of personalized medicine predict a future in which disease treatment and, more important, prevention will be tailored to high-risk individuals rather than populations and will be based on genetic and other new biomarker tests. Accurate biomarker tests to identify people at risk for diabetes could allow more-targeted and perhaps individualized prevention efforts. DNA variants conferring higher risk for type 2 diabetes have been identified. However, these account for only a small fraction of genetic risk, which limits their practical predictive value. Nor has identification of these variants yet led to new, individualized prevention methods. Further research is needed to identify genomic and other types of biomarkers that could accurately predict risk and facilitate targeted prevention. PMID- 22232094 TI - A nationwide community-based lifestyle program could delay or prevent type 2 diabetes cases and save $5.7 billion in 25 years. AB - The increasing health and economic burden of diabetes has made preventing the disease a public health priority. But investing in such chronic disease prevention programs requires a long-term horizon because many years may be required for the downstream savings to fully offset the up-front intervention cost. Using a simulation model, we projected the costs and benefits of a nationwide community-based lifestyle intervention program for preventing type 2 diabetes. Accounting for all costs to the US health care system, our results indicate that the program would break even in fourteen years. Within twenty-five years, the program would prevent or delay about 885,000 cases of type 2 diabetes in the United States and produce savings of $5.7 billion nationwide. If restricted to people ages 65-84, the program would save $2.4 billion. Thus, implementing such a program nationwide would be an efficient use of health care resources, although it might be necessary for all health insurers to participate to share prevention costs. Our results also indicate that although a prevention program would lead to cost savings in both younger and older people, it would achieve greater health and economic gains if it were directed at people under age sixty-five. PMID- 22232095 TI - Analysis & commentary: The Affordable Care Act lays the groundwork for a national diabetes prevention and treatment strategy. AB - The Affordable Care Act includes several provisions that could create a comprehensive approach to preventing and treating diabetes and other chronic health conditions. The current prevention and treatment system is an unconnected, silo-based approach, which reduces the effectiveness and increases the cost of health care. This article presents a three-part proposal: expand the Diabetes Prevention Program nationally; build care coordination through health teams into the traditional Medicare program; and use these teams to connect public health, prevention, and treatment. Enrollment in evidence-based lifestyle modification programs-specifically, those focused on excess weight-should be added as a covered benefit under Medicare with no cost sharing. Funding for the Medicare component could be provided through the budget of the Center for Medicare and Medicaid Innovation. The proposal in its totality has the potential for improving health outcomes and reducing costs. PMID- 22232096 TI - How effective were lifestyle interventions in real-world settings that were modeled on the Diabetes Prevention Program? AB - We conducted a systematic review and meta-analysis of twenty-eight US-based studies applying the findings of the Diabetes Prevention Program, a clinical trial that tested the effects of a lifestyle intervention for people at high risk for diabetes, in real-world settings. The average weight change at twelve months after the intervention was a loss of about 4 percent from participants' baseline weight. Change in weight was similar regardless of whether the intervention was delivered by clinically trained professionals or lay educators. Additional analyses limited to seventeen studies with a nine-month or greater follow-up assessment showed similar weight change. With every additional lifestyle session attended, weight loss increased by 0.26 percentage point. We conclude that costs associated with diabetes prevention can be lowered without sacrificing effectiveness, using nonmedical personnel and motivating higher attendance at program sessions. PMID- 22232097 TI - Reducing the impact of diabetes: is prevention feasible today, or should we aim for better treatment? AB - Type 2 diabetes prevention studies have shown that the onset of the disease can be delayed or prevented, chiefly by weight loss. But the current efforts to establish community-based lifestyle modification programs will not be very effective in preventing diabetes, largely because most overweight or obese people cannot maintain weight loss over time. A complex environment is driving greater food consumption along with less energy expenditure, making maintenance of weight loss extremely difficult. To improve the likelihood of achieving populationwide success in reducing the obesity pandemic, we need a better understanding of the biological processes that underlie the balance between intake and expenditure of energy. In the meantime, once diabetes develops, we can greatly reduce the likelihood of serious complications through early detection and proper medical management. PMID- 22232098 TI - Analysis & commentary: Global prevention and control of type 2 diabetes will require paradigm shifts in policies within and among countries. AB - Continued increases in the prevalence of and disproportionate health spending associated with type 2 diabetes argue for policies focused on preventing that condition and treating it appropriately, even as we strive to improve coordination of care for coexisting chronic diseases. This article argues that four policy paradigm shifts will be necessary to achieve that specific emphasis on type 2 diabetes: conceptually integrating primary and secondary prevention along a clinical continuum; recognizing the central importance of early detection of prediabetes and undiagnosed diabetes in implementing cost-effective prevention and control; integrating community and clinical expertise, and resources, within organized and affordable service delivery systems; and sharing and adopting evidence-based policies at the global level. PMID- 22232099 TI - A pay-for-performance program in Taiwan improved care for some diabetes patients, but doctors may have excluded sicker ones. AB - Many countries have implemented pay-for-performance programs to improve the quality of care. The structure of these programs, however, can have perverse consequences beyond improving care for patients. To investigate this possibility, we studied the pattern of enrollment of patients with diabetes in the first five years of a pay-for-performance program in Taiwan's National Health Insurance Program from 2001 through 2005. Taiwan's program did sharply improve quality of care for enrolled patients, producing 100 percent or nearly 100 percent adherence to all process measures. But at the same time, only a minority of the nation's patients with diabetes were enrolled, because the program's design encouraged physicians not to enroll their most complicated patients. By "cherry-picking" the healthiest patients most likely to perform well on selected measures, physicians were able to game the system and potentially reap the rewards of higher pay-for performance payments without actually improving the care of all of their diabetic patients. Our study provides a cautionary tale, emphasizing the importance of proper program design so that quality is improved on the broadest scale. PMID- 22232100 TI - Group visits hold great potential for improving diabetes care and outcomes, but best practices must be developed. AB - A diagnosis of diabetes can require multiple changes in a person's behavior, diet, and lifestyle. Efforts to sustain these changes and manage this complex chronic disease can be difficult. Group visits, in which several patients meet together with a primary care provider and transdisciplinary team, have tremendous potential to improve health care quality, cost, and access. When group-based diabetes self-management education and a primary care visit occur within a single appointment, people with the disease can address multiple needs in one visit and take advantage of peer groups for support and motivation. A review of the literature demonstrates that the efficacy of group visits has a promising evidence base-but more needs to be learned about optimal group size and aspects of the model that should be standardized. An important first step is introducing a procedural code for group visits, so that providers and researchers can better track the efficacy of the group-visit model and develop best practices before the model is adopted systemwide. PMID- 22232101 TI - Medicare Advantage Chronic Special Needs Plan boosted primary care, reduced hospital use among diabetes patients. AB - The Affordable Care Act of 2010 authorized the continued availability of Medicare Advantage Chronic Condition Special Needs Plans (C-SNPs). This case study examines the model of care used by the largest such plan, Care Improvement Plus, and compares utilization rates among its diabetes patients with those of other beneficiaries enrolled in fee-for-service Medicare in the same five states. This special-needs plan emphasizes direct contacts with patients to help identify gaps in care and promote primary and preventive health care. The comparative analysis indicates that people with diabetes in the special-needs plan-particularly nonwhite beneficiaries-had lower rates of hospitalization and readmission than their peers in fee-for-service Medicare. For example, risk-adjusted hospital days per enrollee among special-needs plan participants were 19 percent lower than for fee-for-service Medicare enrollees (27 percent lower for nonwhite enrollees). Risk-adjusted physician office visits were 7 percent higher among C-SNP enrollees than among comparable fee-for-service enrollees (26 percent higher for nonwhite enrollees). Although this study does not include a cost analysis, we believe that savings from reduced hospitalizations are likely to more than offset the additional costs of enhanced primary care programs. Our study suggests that the Centers for Medicare and Medicaid Services may be able to adapt methods used by the C-SNP program to improve care and outcomes for beneficiaries with a broad range of chronic diseases. PMID- 22232102 TI - An integrated pharmacy-based program improved medication prescription and adherence rates in diabetes patients. AB - A substantial threat to the overall health of the American public is nonadherence to medications used to treat diabetes, as well as physicians' failure to initiate patients' use of those medications. To address this problem, we evaluated an integrated, pharmacy-based program to improve patients' adherence and physicians' initiation rates. The study included 5,123 patients with diabetes in the intervention group and 24,124 matched patients with diabetes in the control group. The intervention consisted of outreach from both mail-order and retail pharmacists who had specific information from the pharmacy benefit management company on patients' adherence to medications and use of concomitant therapies. The interventions improved patients' medication adherence rates by 2.1 percent and increased physicians' initiation rates by 38 percent, compared to the control group. The benefits were greater in patients who received counseling in the retail setting than in those who received phone calls from pharmacists based in mail-order pharmacies. This suggests that the in-person interaction between the retail pharmacist and patient contributed to improved behavior. The interventions were cost-effective, with a return on investment of approximately $3 for every $1 spent. These findings highlight the central role that pharmacists can play in promoting the appropriate initiation of and adherence to therapy for chronic diseases. PMID- 22232104 TI - Physicians' actions and influence, such as aggressive blood pressure control, greatly improve the health of diabetes patients. AB - Managing diabetes and preventing its associated morbidities require active partnerships between physicians and patients. Studies to date lack the level of detail to quantify the degree to which interventions that are more controlled by physicians influence outcomes versus those that are more controlled by patients. Using the Archimedes model, we simulated a thirty-year clinical trial and compared the effects of three sets of interventions over which physicians have progressively less control: compliance with process-of-care standards, such as conducting foot and retinal exams and screening for signs of early kidney disease; control of biomarkers, such as hemoglobin A1c and blood pressure; and lifestyle modifications, such as patients' switching to healthier diets and losing weight. We found that if all US adults diagnosed with type 2 diabetes met quality targets in all of these areas, they would experience a nearly 16 percent increase in quality-adjusted life-years and a nearly 23 percent reduction in fifteen-year mortality over the thirty-year simulation period. Meeting aggressive biomarker targets yielded the most benefit. Meeting conservative biomarker targets came next, followed closely by meeting process-of-care standards. The incremental benefits of complying fully with diet and smoking cessation yielded the least benefit. Thus, through measures more readily within their control, and through collaboration with their patients, physicians have a substantial opportunity to improve outcomes. These findings can inform policy makers' rational resource allocation decisions and the design of programs to improve diabetes care. PMID- 22232103 TI - Peer support for self-management of diabetes improved outcomes in international settings. AB - Self-management of diabetes is essential to reducing the risks of associated disabilities. But effective self-management is often short-lived. Peers can provide the kind of ongoing support that is needed for sustained self-management of diabetes. In this context, peers are nonprofessionals who have diabetes or close familiarity with its management. Key functions of effective peer support include assistance in daily management, social and emotional support, linkage to clinical care, and ongoing availability of support. Using these four functions as a template of peer support, project teams in Cameroon, South Africa, Thailand, and Uganda developed and then evaluated peer support interventions for adults with diabetes. Our initial assessment found improvements in symptom management, diet, blood pressure, body mass index, and blood sugar levels for many of those taking part in the programs. For policy makers, the broader message is that by emphasizing the four key peer support functions, diabetes management programs can be successfully introduced across varied cultural settings and within diverse health systems. PMID- 22232105 TI - Gaps in quality of diabetes care in internal medicine residency clinics suggest the need for better ambulatory care training. AB - To ensure that medical residents will be prepared to deliver consistently high quality care, they should be trained in settings that provide such care. Residents in internal medicine, particularly, need to learn good care habits in order to meet the needs of patients with diabetes and other common chronic and high-impact illnesses. To assess the strength of such training, we compared the quality of medical care provided in sixty-seven US internal medicine residency ambulatory clinics with the quality of care provided by 703 practicing general internists. We found significant quality gaps in process, intermediate outcome, and patient-experience measures. These inadequacies in ambulatory training for internal medicine residents must be addressed by policy makers and educators-for example, by accelerating the movement toward new residency curricula that emphasize competency-based training. PMID- 22232106 TI - Medicaid expansion under health reform may increase service use and improve access for low-income adults with diabetes. AB - Medicaid's key role in financing diabetes care will grow when many low-income uninsured people with diabetes gain eligibility to the program in 2014 under the Affordable Care Act. Using a national data set to describe current health care use and spending among the nonelderly, low-income adult population, we found that adult Medicaid beneficiaries with diabetes had total annual per capita health expenditures more than three times higher ($14,229 versus $4,568) than those of adult beneficiaries without diabetes. At the same time, Medicaid facilitates financial protection and care access among beneficiaries with diabetes. Low income adults with diabetes who were uninsured used fewer services, spent more out of pocket, and reported worse access than did their peers who were covered by Medicaid. Uninsured adults with diabetes who gain Medicaid coverage under health reform are likely to enter the program with unmet needs, and coverage is likely to result in both improved access and increased use of health care. PMID- 22232107 TI - Diabetes management for low-income patients in Los Angeles: two strategies improved disease control in the short term. AB - Health care providers serving vulnerable patients in Los Angeles have developed programs intended to increase diabetes control through more-intensive patient education and engagement. We examined two programs, the first using a short-term intensive intervention by a care team including nurses and a specialist, and the second integrating case management and clinical pharmacy programs into primary care in a community clinic. We show evidence that both models improved short-term disease control, as measured by reductions in HbA1c and low-density lipoprotein (sometimes referred to as "bad" cholesterol). However, integrating case management and clinical pharmacy programs into a primary care setting was less labor-intensive and potentially less expensive than the care team intervention. The challenge is to understand the essential aspects of these interventions; refine their design so that they are more cost-effective and fiscally feasible; and identify long-term health and cost effects. PMID- 22232108 TI - Early lessons from an initiative on Chicago's South Side to reduce disparities in diabetes care and outcomes. AB - Interventions to improve health outcomes among patients with diabetes, especially racial or ethnic minorities, must address the multiple factors that make this disease so pernicious. We describe an intervention on the South Side of Chicago-a largely low-income, African American community-that integrates the strengths of health systems, patients, and communities to reduce disparities in diabetes care and outcomes. We report preliminary findings, such as improved diabetes care and diabetes control, and we discuss lessons learned to date. Our initiative neatly aligns with, and can inform the implementation of, the accountable care organization-a delivery system reform in which groups of providers take responsibility for improving the health of a defined population. PMID- 22232110 TI - State Medicaid programs did not make use of prior authorization to promote safer prescribing after rosiglitazone warning. AB - State Medicaid programs use preferred drug lists to help limit prescribing of high-cost drugs and, at the same time, to free providers from having to obtain prior authorization for a given prescription. We examined the impact of the Food and Drug Administration's May 2007 safety warning regarding rosiglitazone (Avandia), a diabetes drug found to raise the risk of heart attacks, on the drug's availability on state Medicaid preferred drug lists and on the prescribing of diabetes medications more generally for Medicaid beneficiaries. Nearly all state Medicaid programs covered rosiglitazone as a preferred drug, requiring no prior authorization, with minimal change after the safety warning. At the same time, the safety warning was associated with a greater-than-expected decline in rosiglitazone prescribing among states providing coverage as a preferred drug. This suggests that providers reacted to the safety warning by reducing prescriptions. However, Medicaid programs that did provide coverage of rosiglitazone as a preferred drug still exhibited prescribing rates that were three to five times greater than rates in programs that did not provide coverage without prior authorization. We conclude that state Medicaid programs missed important opportunities to promote safer, more effective prescribing in the wake of the 2007 safety warning about rosiglitazone by making full use of preferred drug lists and prior authorization programs. PMID- 22232111 TI - A penny-per-ounce tax on sugar-sweetened beverages would cut health and cost burdens of diabetes. AB - Sugar-sweetened beverages are a major contributor to the US obesity and diabetes epidemics. Using the Coronary Heart Disease Policy Model, we examined the potential impact on health and health spending of a nationwide penny-per-ounce excise tax on these beverages. We found that the tax would reduce consumption of these beverages by 15 percent among adults ages 25-64. Over the period 2010-20, the tax was estimated to prevent 2.4 million diabetes person-years, 95,000 coronary heart events, 8,000 strokes, and 26,000 premature deaths, while avoiding more than $17 billion in medical costs. In addition to generating approximately $13 billion in annual tax revenue, a modest tax on sugar-sweetened beverages could reduce the adverse health and cost burdens of obesity, diabetes, and cardiovascular diseases. PMID- 22232112 TI - Growth in US health spending remained slow in 2010; health share of gross domestic product was unchanged from 2009. AB - Medical goods and services are generally viewed as necessities. Even so, the latest recession had a dramatic effect on their utilization. US health spending grew more slowly in 2009 and 2010-at rates of 3.8 percent and 3.9 percent, respectively-than in any other years during the fifty-one-year history of the National Health Expenditure Accounts. In 2010 extraordinarily slow growth in the use and intensity of services led to slower growth in spending for personal health care. The rates of growth in overall US gross domestic product (GDP) and in health spending began to converge in 2010. As a result, the health spending share of GDP stabilized at 17.9 percent. PMID- 22232113 TI - On our own: why we who struggle to live with diabetes could use a helping hand. PMID- 22232114 TI - Grantwatch profile: New York State Health Foundation's diabetes campaign is influencing practices to improve care. PMID- 22232116 TI - Value-based purchasing for hospitals. PMID- 22232118 TI - Too few patients medicated for alcohol dependence. PMID- 22232120 TI - No rewards for efficiency. PMID- 22232121 TI - The Affordable Care Act without the mandate. PMID- 22232123 TI - Hope for African children with cancer: African Pediatric Oncology Group. PMID- 22232125 TI - Computer visualizations: factors that influence spatial anatomy comprehension. AB - Computer visualizations are increasingly common in education across a range of subject disciplines, including anatomy. Despite optimism about their educational potential, students sometime have difficulty learning from these visualizations. The purpose of this study was to explore a range of factors that influence spatial anatomy comprehension before and after instruction with different computer visualizations. Three major factors were considered: (1) visualization ability (VZ) of learners, (2) dynamism of the visual display, and (3) interactivity of the system. Participants (N = 60) of differing VZs (high, low) studied a group of anatomical structures in one of three visual conditions (control, static, dynamic) and one of two interactive conditions (interactive, non-interactive). Before and after the study phase, participants' comprehension of spatial anatomical information was assessed using a multiple-choice spatial anatomy task (SAT) involving the mental rotation of the anatomical structures, identification of the structures in 2D cross-sections, and localization of planes corresponding to given cross-sections. Results indicate that VZ had a positive influence on SAT performance but instruction with different computer visualizations could modulate the effect of VZ on task performance. PMID- 22232126 TI - Long-term outcome of lupus nephritis in Asian Indians. AB - OBJECTIVE: There are sparse data on outcome of lupus nephritis from developing countries. This study looks at outcome in Asian Indians. METHODS: This retrospective study included patients at a single center over 20 years. Patients were treated as per standard protocols. The primary outcome measure was chronic renal failure or death; the secondary outcome was end-stage renal disease or death. The worst-case scenario was also calculated, considering those lost to followup in the first year as events. Kaplan-Meier survival curves and the log rank test were used for survival analysis. Data are shown as the mean +/- SD. RESULTS: We included 188 patients with lupus nephritis, with a female:male ratio of 11:1, a mean +/- SD age at onset of 23.6 +/- 10.5 years, and a median followup time of 6 years (interquartile range 3-9 years). Of 136 patients with a biopsy sample, the distribution was as follows: class II in 22, class III in 36, class IV in 61, class V in 16, and class VI in 1. Survival with normal renal function was 84%, 69%, and 57% at 5, 10, and 15 years, respectively; in the worst-case scenario, survival was 77%, 63%, and 51%, respectively. There was no difference in survival by histologic class; however, nonbiopsied patients had lower survival. Renal survival was 91%, 81%, and 76% at 5, 10, and 15 years, respectively; in the worst-case scenario, survival was 79%, 70%, and 66%, respectively. Risk factors for poor outcome were low C3, hematuria, hypertension, creatinine, lack of remission, and occurrence of major infection. There was a high rate of major infections of 42.3%, with tuberculosis at 11.5%. Infections caused one-half of all deaths. CONCLUSION: The outcome of lupus nephritis in Asian Indians with standard immunosuppressive regimens is reasonable, but immunosuppression is associated with a high rate of infection. PMID- 22232127 TI - The use of electronic media to develop transferable skills in science students studying anatomy. AB - Transferable skills such as team working, communication, information gathering, critical thinking, and peer assessment are essential for graduates seeking employment in the competitive jobs market. Use of online discussion boards have grown to allow students to communicate with each other at a time and location of their choosing. This study aimed to develop transferable skills using specially developed online components supported by discussion boards and chat rooms. Students enrolled in the Human Anatomy and Histology module at the University of Manchester were put into groups of six or seven students (26 groups in total). Two e-learning components were constructed to develop transferable skills. Each group had a discussion board and chat room available to assist communication in completion of the components. Peer marking was also done on this media. Data collected showed the discussion boards were heavily utilized (average number of posts per group was 48). Eighty-three percent of students found the discussion boards useful to complete the tasks. Students felt their team building and critical analysis skills had improved. Peer assessment was well received by students. Using online discussion boards proved an excellent way to develop transferable skills in a large group of science students. PMID- 22232128 TI - Ultrasound evaluation of fluid in knee recesses at varying degrees of flexion. AB - OBJECTIVE: Various methods are utilized in daily practice to obtain optimal information on effusion in the knee. Our aim is to investigate which scanning position provides the best information about synovial fluid in the knee by using ultrasound and to evaluate the magnitude of difference for measuring synovial fluid in 3 major recesses (suprapatellar, medial parapatellar, and lateral parapatellar) of the knee according to various degrees of flexion. METHODS: Sonographers in 14 European centers documented bilateral knee joint ultrasound examinations on a total of 148 knee joints. The largest sagittal diameter of fluid was measured in scans corresponding to the 3 major recesses at different (0 degrees , 15 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees ) degrees of flexion of the knee. The difference of measurement of effusion according to transducer position, knee position, and the interaction between them was investigated by analysis of variance followed by Tukey's test. RESULTS: No correlation was noted between patient characteristics and ultrasound detection of effusion. The sagittal diameter of synovial fluid in all 3 recesses was greatest at 30 degrees flexion. Analysis of variance and Tukey's test revealed that the suprapatellar scan and 30 degrees flexion is the best combination for detecting effusion as confirmed by receiver operator characteristic curve analysis. CONCLUSION: The suprapatellar scan of the knee in 30 degrees flexion was the most sensitive position to detect fluid in knee joints. Sagittal diameter of fluid in all 3 recesses increased with the knee in the 30 degrees flexed position as compared to the extended position. PMID- 22232129 TI - Pertubation with lignocaine as a new treatment of dysmenorrhea due to endometriosis: a randomized controlled trial. AB - BACKGROUND: Endometriosis is a chronic inflammatory disease of unknown aetiology that can cause severe dysmenorrhea. Lignocaine has anti-inflammatory properties and exerts effects on nerve endings and intra-peritoneal macrophages. The objective of this study was to evaluate the effect of pertubation with Ringer Lignocaine on dysmenorrhea in women with endometriosis. METHODS: A double-blind randomized controlled trial (RCT) was carried out at three sites in Stockholm, Sweden. Eligible patients had endometriosis as diagnosed by laparoscopy, dysmenorrhoic pain >VAS 50 mm (visual analogue scale) and patent Fallopian tubes. The study patients were randomized sequentially to preovulatory pertubations with placebo (n= 18) or study treatment (n= 24) during three consecutive menstrual cycles. The pertubation procedure comprised passing study solution through the uterine cavity and the Fallopian tubes via an intra-cervical balloon catheter. The effect on pain was evaluated with VAS scales before and after the treatments and up to nine menstrual cycles after the last pertubation. Success was defined as a reduction of >= 50% on the VAS scale after the third pertubation. The success rate between the treatment and the placebo group was compared with Fisher's exact test. RESULTS: In the intention-to-treat analysis, the success rate was 41.7% (10 of 24) in the treatment group compared with 16.7% (3 of 18) in the placebo group (P= 0.10, 95% CI -7.3 to 36.2%). In the per protocol analysis, the success rate in the treatment group was 45% (9 of 20) compared with 7.1% (1 of 14) in the placebo group (P= 0.024, 95% CI -2.6 to 44.8%). Of the nine patients in the lignocaine group who fulfilled the criteria for success after three pertubations, 4 (44%) had an effect persisting after nine months. The treatments were well tolerated. CONCLUSIONS: This small RCT indicates that pertubation with lignocaine is a non-hormonal treatment option for patients with dysmenorrhea and endometriosis. ClinicalTrials.gov identifier: NCT01329796. PMID- 22232130 TI - The use of power Doppler colour scoring to predict successful expectant management in women with an incomplete miscarriage. AB - OBJECTIVE: To evaluate whether the use of power Doppler to confirm the presence or absence of blood flow within retained products of conception (RPC) in women with an incomplete miscarriage can predict subsequent successful expectant management. METHODS: Prospective observational study in the Acute Gynaecology and Early Pregnancy Unit (AGEPU) at Nepean Hospital from November 2006 to February 2009. Incomplete miscarriage was defined by the presence of a measurable focus of hyperechoeic material, in three planes, within the endometrial cavity using two dimensional greyscale transvaginal ultrasound (TVS). Subjective qualitative power Doppler colour scoring (PDCS) of the RPC was performed. The vascularization of the RPC was scored using the colour scoring system of the International Ovarian Tumour Analysis (IOTA) group. PDCS 1 meant absence of vascularity, PCDS 2 represented minimal vascularity, PDCS 3 rather strong vascularity and PDCS 4 very strong vascularity. The correlation between the PDCS and successful expectant management of miscarriage was analysed. The volume of RPC was calculated using the ellipsoid formula and then compared with both the PDCS and the outcome of expectant management. Successful expectant management was defined as the resolution of symptoms and the absence of RPC on follow-up TVS. RESULTS: A total of 1395 consecutive pregnant women underwent TVS. Of them, 198 women were diagnosed with an incomplete miscarriage; 172 were managed expectantly. Complete data were available on 158 cases. In total 84.8% (134/158) were managed successfully whilst 15.2% (24/158) failed expectant management. Of the total, 89% (121/136) of women with a PDCS 1 had successful expectant management compared with 57.1 (8/14) with PDCS 2 and 62.5% (5/8) with PDCS 3. Comparing absence of flow (PDCS 1) to presence of flow (PDCS 2 or more), the rate of success was significantly higher in the first group (89 versus 60.9%, Fisher's exact test P= 0.00136). In the prediction of success, the absence of flow showed a sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio of 90.3, 37.5, 89, 40.9% and 1.445 (95% confidence interval: 1.055-1.979), respectively. There was no correlation between the volume of RPC and the PDCS; and there was no relationship between the volume of RPC and the success of expectant management. CONCLUSIONS: PDCS can predict the likelihood of successful expectant management of incomplete miscarriage. The absence of flow on power Doppler is associated with a significant improvement in the rate of successful expectant management. This new approach may be helpful in quantifying the chances of successful expectant management in those women with an incomplete miscarriage at the primary scan. PMID- 22232131 TI - Re: Epidemiological study of anti-HPV-16/18 seropositivity and subsequent risk of HPV-16 and -18 infections. PMID- 22232132 TI - Interdisciplinary critique of sipuleucel-T as immunotherapy in castration resistant prostate cancer. AB - Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results. PMID- 22232133 TI - Estrogen metabolism and risk of breast cancer in postmenopausal women. AB - BACKGROUND: Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites. METHODS: We conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C 2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. CONCLUSIONS: More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer. PMID- 22232136 TI - Brain death or brain dying? PMID- 22232135 TI - Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. AB - Overactivation of the mineralocorticoid receptor signaling is implicated in cardiovascular disease, including hypertensive heart disease. Oxidative stress is suggested to augment mineralocorticoid receptor signal transduction, but the precise mechanisms remain unclear. Mineralocorticoid receptor activity is regulated by multiple factors, in addition to plasma ligand levels. We previously identified Rac1 GTPase as a modulator of mineralocorticoid receptor activity. Here we show that oxidative stress induces mineralocorticoid receptor activation in a ligand-independent, Rac1-depenent manner in cardiomyocytes. Oxidant stress was induced in rat cultured cardiomyocytes (H9c2) by l-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. BSO depleted intracellular glutathione and concomitantly increased reactive oxygen species (199%; P<0.01). BSO significantly enhanced the corticosterone-induced, mineralocorticoid receptor dependent luciferase reporter activity (186%; P<0.01) and basal luciferase activity without ligand stimulation. These effects were inhibited by the antioxidant N-acetylcysteine. The ligand independency of BSO action was indicated using a mutant mineralocorticoid receptor that does not bind ligands. With this mutant mineralocorticoid receptor, BSO-evoked mineralocorticoid receptor activation remained intact, whereas ligand-induced mineralocorticoid receptor activation was abolished. We next examined the involvement of Rac1. BSO increased active Rac1 in a redox-dependent fashion, and Rac inhibition suppressed the enhancing effect of BSO. Constitutively active Rac1, indeed, potentiated mineralocorticoid receptor transactivation. Furthermore, mineralocorticoid receptor transactivation by BSO was accompanied by enhanced nuclear accumulation of mineralocorticoid receptor. We conclude that alteration of redox state modulates mineralocorticoid receptor-dependent transcriptional activity via Rac1 in the heart. This redox-sensitive, ligand-independent mineralocorticoid receptor activation may contribute to the processes by which oxidant stress promotes cardiac injury. PMID- 22232141 TI - Glutamate dehydrogenase, insulin secretion, and type 2 diabetes: a new means to protect the pancreatic beta-cell? AB - In this issue of Journal of Endocrinology, Dr Han and colleagues report a protective effect of the glutamate dehydrogenase activator 2-aminobicyclo-(2,2,1) heptane-2-carboxylic acid (BCH) under diabetes-like conditions that impair beta cell function in both a pancreatic beta-cell line and db/db mice. Based on these observations, the authors suggest that BCH could serve as a novel treatment modality in type 2 diabetes. The present commentary discusses the importance of the findings. Some additional questions are raised, which may be addressed in future investigations, as there is some concern regarding the BCH treatment of beta-cell failure. PMID- 22232142 TI - Chipping resistance of graded zirconia ceramics for dental crowns. AB - A serious drawback of veneering porcelains is a pronounced susceptibility to chipping. Glass-infiltrated dense zirconia structures can now be produced with esthetic quality, making them an attractive alternative. In this study, we examined the hypothesis that such infiltrated structures are much more chip resistant than conventional porcelains, and at least as chip-resistant as non infiltrated zirconia. A sharp indenter was used to produce chips in flat and anatomically correct glass-infiltrated zirconia crown materials, and critical loads were measured as a function of distance from the specimen edge (flat) or side wall (crown). Control data were obtained on zirconia specimens without infiltration and on crowns veneered with porcelains. The results confirmed that the resistance to chipping in graded zirconia is more than 4 times higher than that of porcelain-veneered zirconia and is at least as high as that of non veneered zirconia. PMID- 22232134 TI - Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study. AB - It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66-1.40]; P=0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06-0.69]; P=0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group. PMID- 22232144 TI - The potential impact of the medical home on job satisfaction in primary care. PMID- 22232143 TI - Patient-centered medical home characteristics and staff morale in safety net clinics. AB - BACKGROUND: We sought to determine whether perceived patient-centered medical home (PCMH) characteristics are associated with staff morale, job satisfaction, and burnout in safety net clinics. METHODS: Self-administered survey among 391 providers and 382 clinical staff across 65 safety net clinics in 5 states in 2010. The following 5 subscales measured respondents' perceptions of PCMH characteristics on a scale of 0 to 100 (0 indicates worst and 100 indicates best): access to care and communication with patients, communication with other providers, tracking data, care management, and quality improvement. The PCMH subscale scores were averaged to create a total PCMH score. RESULTS: Six hundred three persons (78.0%) responded. In multivariate generalized estimating equation models, a 10% increase in the quality improvement subscale score was associated with higher morale (provider odds ratio [OR], 2.64; 95% CI, 1.47-4.75; staff OR, 3.62; 95% CI, 1.84-7.09), greater job satisfaction (provider OR, 2.45; 95% CI, 1.42-4.23; staff OR, 2.55; 95% CI 1.42-4.57), and freedom from burnout (staff OR, 2.32; 95% CI, 1.31-4.12). The total PCMH score was associated with higher staff morale (OR, 2.63; 95% CI, 1.47-4.71) and with lower provider freedom from burnout (OR, 0.48; 95% CI, 0.30-0.77). A separate work environment covariate correlated highly with the quality improvement subscale score and the total PCMH score, and PCMH characteristics had attenuated associations with morale and job satisfaction when included in models. CONCLUSIONS: Providers and staff who perceived more PCMH characteristics in their clinics were more likely to have higher morale, but the providers had less freedom from burnout. Among the PCMH subscales, the quality improvement subscale score particularly correlated with higher morale, greater job satisfaction, and freedom from burnout. PMID- 22232137 TI - Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants. AB - Whether intraventricular hemorrhage increases the risk of adverse developmental outcome among premature infants is controversial. Using brain ultrasound, we identified intraventricular hemorrhage and white matter abnormalities among 1064 infants born before 28 weeks' gestation. We identified adverse developmental outcomes at 24 months of age using a standardized neurologic examination and the Bayley Scales of Infant Development Mental and Motor Scales. In logistic regression models that adjusted for gestational age, sex, and public insurance, isolated intraventricular hemorrhage was associated with visual fixation difficulty but no other adverse outcome. Infants who had a white matter lesion unaccompanied by intraventricular hemorrhage were at increased risk of cerebral palsy, low Mental and Motor Scores, and visual and hearing impairments. Except when accompanied or followed by a white matter lesion, intraventricular hemorrhage is associated with no more than a modest increase (and possibly no increase) in the risk of adverse developmental outcome during infancy. PMID- 22232145 TI - Overtreatment of enterococcal bacteriuria. AB - BACKGROUND: The purposes of this study were to investigate the clinical outcomes of enterococcal bacteriuria and to determine whether current management is adherent to Infectious Diseases Society of America guidelines. METHODS: We conducted a retrospective medical record review of patients from 2 academic teaching hospitals for 3 months (September 1 through November 30, 2009). Patients were classified as having urinary tract infection (UTI) or asymptomatic bacteriuria (ABU) by applying the guidelines. Antibiotic use was deemed appropriate in patients with UTI and inappropriate in ABU. Medical records were reviewed for Enterococcus cultured from another sterile site within 30 days. RESULTS: A total of 375 urine cultures growing Enterococcus were reviewed, with 339 cultures meeting inclusion criteria. Of these 339 episodes, 183 (54.0%) were classified as ABU and 156 (46.0%) as UTI. In 289 episodes accompanied by urinalysis, pyuria was associated with UTI in 98 of 140 episodes (70.0%) compared with 63 of 149 episodes of ABU (42.3%) (odds ratio, 3.19; 95% CI, 1.96-5.18). Providers inappropriately treated 60 of 183 episodes of ABU (32.8%) with antibiotics. In multivariate analysis, only pyuria was associated with the inappropriate use of antibiotics (odds ratio, 3.27; 95% CI, 1.49-7.18). Only 7 subsequent infections with Enterococcus occurred in the 339 episodes of bacteriuria overall (2.1%), with 2 of the 183 cases of ABU (1.1%) having distant infection. CONCLUSIONS: Providers often overtreat enterococcal ABU with antibiotics, particularly in patients with pyuria. Given the low incidence of infectious complications, efforts should be made to optimize the use of antibiotics in enterococcal bacteriuria. PMID- 22232146 TI - Enhancing the safety of hospitalized patients: who is minding the antimicrobials? PMID- 22232148 TI - The effect of herbal medications on thyroid hormone economy and estrogen sensitive hepatic proteins in a patient with prostate cancer. PMID- 22232147 TI - Blood pressure components and end-stage renal disease in persons with chronic kidney disease: the Kidney Early Evaluation Program (KEEP). AB - BACKGROUND: Treatment of hypertension is difficult in chronic kidney disease (CKD), and blood pressure goals remain controversial. The association between each blood pressure component and end-stage renal disease (ESRD) risk is less well known. METHODS: We studied associations of systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse pressure (PP) with ESRD risk among 16,129 Kidney Early Evaluation Program (KEEP) participants with an estimated glomerular filtration rate of 60 mL/min/1.73 m(2) using Cox proportional hazards. We estimated the prevalence and characteristics associated with uncontrolled hypertension (SBP >= 150 or DBP >= 90 mm Hg). RESULTS: The mean (SD) age of participants was 69 (12) years; 25% were black, 6% were Hispanic, and 43% had diabetes mellitus. Over 2.87 years, there were 320 ESRD events. Higher SBP was associated with higher ESRD risk, starting at SBP of 140 mm Hg or higher. After sex and age adjustment, compared with SBP lower than 130 mm Hg, hazard ratios (HRs) were 1.08 (95% CI, 0.74-1.59) for SBP of 130 to 139 mm Hg, 1.72 (95% CI, 1.21-2.45) for SBP of 140 to 149 mm Hg, and 3.36 (95% CI, 2.51-4.49) for SBP of 150 mm Hg or greater. After full adjustment, HRs for ESRD were 1.27 (95% CI, 0.88 1.83) for SBP of 140 to 149 mm Hg and 1.36 (95% CI, 1.02-1.85) for SBP of 150 mm Hg or higher. Persons with DBP of 90 mm Hg or higher were at higher risk for ESRD compared with persons with DBP of 60 to 74 mm Hg (HR, 1.81; 95% CI, 1.33-2.45). Higher PP was also associated with higher ESRD risk (HR, 1.44 [95% CI, 1.00-2.07] for PP >= 80 mm Hg compared with PP < 50 mm Hg). Adjustment for SBP attenuated this association. More than 33% of participants had uncontrolled hypertension (SBP >= 150 mm Hg or DBP >= 90 mm Hg), mostly due to isolated systolic hypertension (54%). CONCLUSIONS: In this large, diverse, community-based sample, we found that high SBP seemed to account for most of the risk of progression to ESRD. This risk started at SBP of 140 mm Hg rather than the currently recommended goal of less than 130 mm Hg, and it was highest among those with SBP of at least 150 mm Hg. Treatment strategies that preferentially lower SBP may be required to improve BP control in CKD. PMID- 22232149 TI - Older patient experiences in the mammography decision-making process. PMID- 22232152 TI - A comparison of authorship policies at top-ranked peer-reviewed biomedical journals. PMID- 22232151 TI - Noise and sleep among adult medical inpatients: far from a quiet night. PMID- 22232153 TI - Impact of electronic health records on racial and ethnic disparities in blood pressure control at US primary care visits. PMID- 22232154 TI - Primary health care providers' attitudes and counseling behaviors related to dietary sodium reduction. PMID- 22232155 TI - The FDA and new safety warnings. PMID- 22232156 TI - Interventions to improve recognition of delirium: a sine qua non for successful transitional care programs. PMID- 22232157 TI - The transitionalist: optimizing inpatient-to-outpatient transitions of care. PMID- 22232158 TI - Prophylaxis for recurrent urinary tract infections: nitrofurantoin, not trimethoprim-sulfamethoxazole or cranberry juice. PMID- 22232159 TI - Physical activity, vascular health, and cognitive impairment. PMID- 22232160 TI - Crystals on the cover 2012. PMID- 22232161 TI - Structural insights into RipC, a putative citrate lyase beta subunit from a Yersinia pestis virulence operon. AB - Yersinia pestis remains a threat, with outbreaks of plague occurring in rural areas and its emergence as a weapon of bioterrorism; thus, an improved understanding of its various pathogenicity pathways is warranted. The rip (required for intracellular proliferation) virulence operon is required for Y. pestis survival in interferon-gamma-treated macrophages and has been implicated in lowering macrophage-produced nitric oxide levels. RipC, one of three gene products from the rip operon, is annotated as a citrate lyase beta subunit. Furthermore, the Y. pestis genome lacks genes that encode citrate lyase alpha and gamma subunits, suggesting a unique functional role of RipC in the Y. pestis rip mediated survival pathway. Here, the 2.45 A resolution crystal structure of RipC revealed a homotrimer in which each monomer consists of a (beta/alpha)(8) TIM barrel fold. Furthermore, the trimeric state was confirmed in solution by size exclusion chromatography. Through sequence and structure comparisons with homologous proteins, it is proposed that RipC is a putative CoA- or CoA derivative binding protein. PMID- 22232162 TI - Structure of CBM3b of the major cellulosomal scaffoldin subunit ScaA from Acetivibrio cellulolyticus. AB - The carbohydrate-binding module (CBM) of the major scaffoldin subunit ScaA of the cellulosome of Acetivibrio cellulolyticus is classified as a family 3b CBM and binds strongly to cellulose. The CBM3b was overexpressed, purified and crystallized, and its three-dimensional structure was determined. The structure contained a nickel-binding site located at the N-terminal region in addition to a 'classical' CBM3b calcium-binding site. The structure was also determined independently by the SAD method using data collected at the Ni-absorption wavelength of 1.48395 A and even at a wavelength of 0.97625 A in a favourable case. The new scaffoldin-borne CBM3 structure reported here provides clear evidence for the proposition that a family 3b CBM may be accommodated in scaffoldin subunits and functions as the major substrate-binding entity of the cellulosome assembly. PMID- 22232163 TI - Structure of N-formylglycinamide ribonucleotide amidotransferase II (PurL) from Thermus thermophilus HB8. AB - The crystal structure of PurL from Thermus thermophilus HB8 (TtPurL; TTHA1519) was determined in complex with an adenine nucleotide, PO(4)(3-) and Mg(2+) at 2.35 A resolution. TtPurL consists of 29 alpha-helices and 28 beta-strands, and one loop is disordered. TtPurL consists of four domains, A1, A2, B1 and B2, and the structures of the A1-B1 and A2-B2 domains were almost identical to each other. Although the sequence identity between TtPurL and PurL from Thermotoga maritima (TmPurL) is higher than that between TtPurL and the PurL domain of the large PurL from Salmonella typhimurium (StPurL), the secondary structure of TtPurL is much more similar to that of StPurL than to that of TmPurL. PMID- 22232164 TI - Expression, refolding and preliminary X-ray crystallographic analysis of equine MHC class I molecule complexed with an EIAV-Env CTL epitope. AB - In order to clarify the structure and the peptide-presentation characteristics of the equine major histocompatibility complex (MHC) class I molecule, a complex of equine MHC class I molecule (ELA-A1 haplotype, 7-6 allele) with mouse beta(2) microglobulin and the cytotoxic T lymphocyte (CTL) epitope Env-RW12 (RVEDVTNTAEYW) derived from equine infectious anaemia virus (EIAV) envelope protein (residues 195-206) was refolded and crystallized. The crystal, which belonged to space group P2(1), diffracted to 2.3 A resolution and had unit-cell parameters a = 82.5, b = 71.4, c = 99.8 A, beta = 102.9 degrees . The crystal structure contained two molecules in the asymmetric unit. These results should help to determine the first equine MHC class I molecule structure presenting an EIAV CTL epitope. PMID- 22232165 TI - Activation of legumain involves proteolytic and conformational events, resulting in a context- and substrate-dependent activity profile. AB - Localized mainly to endo/lysosomes, legumain plays an important role in exogenous antigen processing and presentation. The cysteine protease legumain, also known as asparaginyl endopepetidase AEP, is synthesized as a zymogen and is known to undergo pH-dependent autoproteolytic activation whereby N-terminal and C-terminal propeptides are released. However, important mechanistic details of this pH dependent activation as well as the characteristic pH activity profile remain unclear. Here, it is shown that all but one of the autocatalytic cleavage events occur in trans, with only the release of the C-terminal propeptide being relevant to enzymatic activity. An intriguing super-activation event that appears to be exclusively conformational in nature and enhances the enzymatic activity of proteolytically fully processed legumain by about twofold was also found. Accepting asparagines and, to lesser extent, aspartic acid in P1, super-activated legumain exhibits a marked pH dependence that is governed by the P1 residue of its substrate and conformationally stabilizing factors such as temperature or ligands. The crystallization and preliminary diffraction data analysis of active legumain are presented, which form an important basis for further studies that should clarify fundamental aspects of activation, activity and inactivation of legumain, which is a key target in (auto-)immunity and cancer. PMID- 22232166 TI - Molecular cloning, overexpression, purification, crystallization and preliminary X-ray diffraction studies of histidinol phosphate aminotransferase (HisC2) from Mycobacterium tuberculosis. AB - HisC2 from Mycobacterium tuberculosis was overexpressed in M. smegmatis and purified to homogeneity using nickel-nitrilotriacetic acid metal-affinity and gel filtration chromatography. Diffraction-quality crystals were grown using the hanging-drop vapour-diffusion technique from a condition consisting of 7 mg ml( 1) HisC2 (in 20 mM Tris pH 8.8, 50 mM NaCl and 5% glycerol), 1 M succinic acid pH 7.0, 0.1 M HEPES pH 7.0 and 1%(w/v) polyethylene glycol monomethyl ether 2000. The crystals belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 255.98, b=77.09, c = 117.97 A. X-ray diffraction data were recorded to 2.45 A resolution from a single crystal using the in-house X-ray facility. PMID- 22232167 TI - Crystallization and preliminary X-ray crystallographic analysis of the membrane binding haemprotein nitrophorin 7 from Rhodnius prolixus. AB - Nitrophorins (nitric oxide transport proteins) are haemproteins originating from the blood-feeding insect Rhodnius prolixus. They consist of an eight-stranded beta-barrel, which classifies them into the lipocalin family. Nitrophorin 7 (NP7) and the E27V mutant protein NP7(E27V) were crystallized at 277 K using the vapour diffusion method with PEG as the precipitating agent. Data sets for wild-type NP7 and NP7(E27V) were collected to 1.80 A resolution from single crystals at 100 K using synchrotron radiation. The crystals belonged to space group P2(1), with unit-cell parameters a = 38, b = 67, c = 39 A, beta = 117 degrees . The crystal contained one molecule per asymmetric unit, with a Matthews coefficient (V(M)) of 2.11 A(3) Da(-1); the solvent content was estimated to be 41.8%. PMID- 22232168 TI - Protein expression, crystallization and preliminary X-ray crystallographic analysis of chicken interferon-gamma receptor alpha chain. AB - The activity of interferon-gamma (IFN-gamma) relies on signal transduction, which is triggered by combination with the receptors interferon-gamma receptor alpha chain (IFNGR1) and beta chain (IFNGR2). Native recombinant chicken IFNGR1 (chIFNGR1; residues 25-237) was overexpressed in Escherichia coli, purified by refolding and crystallized using the vapour-diffusion technique. The crystals belonged to space group P6(5)22, with unit-cell parameters a = b = 64.1, c = 216.3 A, alpha = beta = 90, gamma = 120 degrees . The Matthews coefficient and solvent content were calculated as 2.67 A(3) Da(-1) and 53.97%, respectively. X ray diffraction data for chIFNGR1 were collected to 2.0 A resolution at a synchrotron source. PMID- 22232169 TI - Overproduction, purification, crystallization and preliminary X-ray diffraction analysis of Cockayne syndrome protein A in complex with DNA damage-binding protein 1. AB - Cockayne syndrome protein A is one of the main components in mammalian transcription coupled repair. Here, the overproduction, purification and crystallization of human Cockayne syndrome protein A in complex with its interacting partner DNA damage binding protein 1 are reported. The complex was coproduced in insect cells, copurified and crystallized using sitting drops with PEG 3350 and sodium citrate as crystallizing agents. The crystals had unit-cell parameters a = b = 142.03, c = 250.19 A and diffracted to 2.9 A resolution on beamline ID14-1 at the European Synchrotron Radiation Facility. PMID- 22232170 TI - Crystallization and preliminary neutron diffraction studies of ADP-ribose pyrophosphatase-I from Thermus thermophilus HB8. AB - ADP-ribose pyrophosphatase-I from Thermus thermophilus HB8 (TtADPRase-I) prevents the intracellular accumulation of ADP-ribose by hydrolyzing it to AMP and ribose 5'-phosphate. To understand the catalytic mechanism of TtADPRase-I, it is necessary to investigate the role of glutamates and metal ions as well as the coordination of water molecules located at the active site. A macroseeding method was developed in order to obtain a large TtADPRase-I crystal which was suitable for a neutron diffraction study to provide structural information. Neutron and X ray diffraction experiments were performed at room temperature using the same crystal. The crystal diffracted to 2.1 and 1.5 A resolution in the neutron and X ray diffraction experiments, respectively. The crystal belonged to the primitive space group P3(2)21, with unit-cell parameters a = b = 50.7, c = 119 A. PMID- 22232171 TI - Crystallization and preliminary X-ray crystallographic studies of the outer membrane cytochrome OmcA from Shewanella oneidensis MR-1. AB - The outer membrane cytochrome OmcA functions as a terminal metal reductase in the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1. The ten-heme centers shuttle electrons from the transmembrane donor complex to extracellular electron acceptors. Here, the crystallization and preliminary crystallographic analysis of OmcA are reported. Crystals of OmcA were grown by the sitting-drop vapor-diffusion method using PEG 20,000 as a precipitant. The OmcA crystals belonged to space group P2(1), with unit-cell parameters a = 93.0, b = 246.0, c = 136.6 A, alpha = 90, beta = 97.8, gamma = 90 degrees . X-ray diffraction data were collected to a maximum resolution of 3.25 A. PMID- 22232172 TI - Crystallization and preliminary X-ray crystallographic analysis of the beta-N acetylglucosaminidase CbsA from Thermotoga neapolitana. AB - The beta-N-acetylglucosaminidase CbsA was cloned from the thermophilic Gram negative bacterium Thermotoga neapolitana. Although CbsA contains a family 3 glycoside hydrolase-type (GH3-type) catalytic domain, it can be distinguished from other GH3-type beta-N-acetylglucosaminidases by its high activity towards chitobiose. The homodimeric CbsA contains a unique domain at the C-terminus for which the three-dimensional structure is not yet known. In this study, CbsA was overexpressed and the recombinant protein was purified using Ni-NTA affinity and gel-filtration chromatography. The purified CbsA protein was crystallized using the vapour-diffusion method. A diffraction data set was collected to a resolution of 2.0 A at 100 K. The crystal belonged to space group R32. To obtain initial phases, the crystallization of selenomethionyl-substituted protein and the production of heavy-atom derivative crystals are in progress. PMID- 22232173 TI - Purification, crystallization and preliminary crystallographic analysis of human dihydrodipicolinate synthase-like protein (DHDPSL). AB - Human dihydrodipicolinate synthase-like protein (DHDPSL) is a gene product of unknown function. It is homologous to bacterial pyruvate-dependent aldolases such as dihydrodipicolinate synthase (DHDPS), which functions in lysine biosynthesis. However, it cannot have this function and instead is implicated in a genetic disorder that leads to excessive production of oxalate and kidney-stone formation. In order to better understand its function, DHDPSL was expressed as an MBP-fusion protein and crystallized using an in situ proteolysis protocol. Two crystal forms were obtained, both of which diffracted X-rays to approximately 2.0 A resolution. One of these, belonging to space group P6(2)22 or P6(4)22 with unit cell parameters a = b = 142.9, c = 109.8 A, alpha = beta = 90, gamma = 120 degrees , was highly reproducible and suitable for structure determination by X ray crystallography. PMID- 22232174 TI - Expression, purification, crystallization and preliminary X-ray crystallographic analysis of L-lactate dehydrogenase and its H171C mutant from Bacillus subtilis. AB - L-Lactate dehydrogenase (LDH) is an important enzyme involved in the last step of glycolysis that catalyzes the reversible conversion of pyruvate to L-lactate with the simultaneous oxidation of NADH to NAD(+). In this study, wild-type LDH from Bacillus subtilis (BsLDH-WT) and the H171C mutant (BsLDH-H171C) were expressed in Escherichia coli and purified to near-homogeneity. BsLDH-WT was crystallized in the presence of fructose 1,6-bisphosphate (FBP) and NAD(+) and the crystal diffracted to 2.38 A resolution. The crystal belonged to space group P3, with unit-cell parameters a = b = 171.04, c = 96.27 A. BsLDH-H171C was also crystallized as the apoenzyme and in complex with NAD(+), and data sets were collected to 2.20 and 2.49 A resolution, respectively. Both BsLDH-H171C crystals belonged to space group P3, with unit-cell parameters a = b = 133.41, c = 99.34 A and a = b = 133.43, c = 99.09 A, respectively. Tetramers were observed in the asymmetric units of all three crystals. PMID- 22232175 TI - Crystallization and preliminary X-ray analysis of pyridoxine 4-oxidase, the first enzyme in pyridoxine degradation pathway I. AB - Vitamin B(6)-degradation pathway I has recently been identified in Mesorhizobium loti MAFF303099. Pyridoxine 4-oxidase, an FAD-dependent enzyme, is the first enzyme in this pathway and catalyzes the irreversible oxidation of pyridoxine to pyridoxal. The enzyme was overexpressed in Escherichia coli with a His(6) tag and purified. The recombinant enzyme was crystallized at 277 K by the sitting-drop vapour-diffusion method using PEG 4000 as the precipitant. The crystal, which belonged to space group P2(1)2(1)2(1) with unit-cell parameters a = 62.38, b = 79.44, c = 136.43 A, diffracted to 2.2 A resolution. The calculated V(M) value (3.19 A(3) Da(-1)) suggested that the asymmetric unit contained one molecule. PMID- 22232176 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of Arabidopsis thaliana dynamin-related protein 1A GTPase-GED fusion protein. AB - Plant-specific dynamin-related proteins play crucial roles in cell-plate formation, endocytosis or exocytosis, protein sorting to the vacuole and plasma membrane and the division of mitochondria and chloroplasts. In order to determine the crystal structure and thus to obtain a better understanding of the biological functions and mechanisms of dynamin-related proteins in plant cells, the GTPase domain of Arabidopsis thaliana dynamin-related protein 1A (AtDRP1A) fused to its GTPase effector domain (GED) was crystallized in a nucleotide-associated form using polyethylene glycol 3350 as precipitant. The hexagonal crystals (space group P6(1)) had unit-cell parameters a = b = 146.2, c = 204.3 A, and diffraction data were collected to 3.6 A resolution using synchrotron radiation. Four molecules, comprising two functional dimers, are assumed per asymmetric unit, corresponding to a Matthews coefficient of 3.9 A(3) Da(-1) according to the molecular weight of 39 kDa. PMID- 22232177 TI - Expression, purification, crystallization and preliminary X-ray crystallographic analysis of human beta-galactosidase. AB - beta-D-Galactosidase (beta-Gal) is an exoglycosidase that cleaves beta galactosides from glycoproteins, sphingolipids and keratan sulfate. This study reports the expression, purification, crystallization and preliminary X-ray crystallographic analysis of human lysosomal beta-Gal. The sitting-drop vapour diffusion method was used to crystallize beta-Gal in complexes with its product galactose and with the inhibitor 1-deoxygalactonojirimycin. The resulting crystals were isomorphous and belonged to space group P2(1). The crystals of the beta-Gal-galactose and the beta-Gal-inhibitor complexes had unit-cell parameters a = 94.8, b = 116.1, c = 140.3 A, beta = 92.2 degrees and a = 94.8, b = 116.0, c = 140.3 A, beta = 92.2 degrees , respectively. Diffraction data were collected to 1.8 A resolution for both crystals. PMID- 22232178 TI - Crystallization and preliminary X-ray crystallographic studies of a new class of enoyl-(acyl-carrier protein) reductase, FabV, from Vibrio fischeri. AB - Enoyl-(acyl-carrier protein) reductase (ENR) catalyzes the last step of the fatty acid elongation cycle of the bacterial fatty-acid biosynthesis (FAS II) pathway. Recently, a new class of ENR has been identified from Vibrio cholerae and was named FabV. In order to understand the molecular mechanism of the new class of ENR at the structural level, FabV from V. fischeri was overexpressed, purified and crystallized. Diffraction data were collected to 2.7 A resolution from a native crystal. The crystal belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 123.53, b = 164.14, c = 97.07 A. The presence of four molecules of FabV in the asymmetric unit gave a V(M) value of 2.81 A(3) Da( 1), with a corresponding solvent content of 54.5%. PMID- 22232179 TI - Expression, purification and preliminary structural analysis of the head domain of Deinococcus radiodurans RecN. AB - Deinococcus radiodurans is well known for its extreme tolerance to harsh conditions and for its extraordinary ability to repair DNA. Double-strand breaks (DSBs) are the most hazardous lesions that can be induced by ionizing radiation, and homologous recombination (HR) is the principal mechanism by which the integrity of the DNA is restored. In D. radiodurans the RecFOR complex is the main actor in HR and the RecN protein is believed to play an important role in DSB recognition. Here, SAXS and preliminary X-ray diffraction studies are presented of the head domain, which is the globular region formed upon interaction of the N- and C-terminal domains of RecN. The crystal structure of this domain was solved using the single-wavelength anomalous dispersion method. Model building and refinement are in progress. PMID- 22232180 TI - Crystallization and preliminary X-ray crystallographic analysis of the plant defensin NaD1. AB - Plant defensins are small (~5 kDa) basic cysteine-rich proteins that are being explored in important agricultural crops for their ability to confer enhanced disease resistance against fungal pathogens. NaD1, isolated from the flowers of the ornamental tobacco (Nicotiana alata), is a particularly well characterized antifungal defensin. Here, the crystallization and preliminary X-ray crystallographic analysis of NaD1 is reported. Crystals of NaD1 were crystallized using the sitting-drop vapour-diffusion method at 291 K. Data were collected from two crystal forms to 1.4 and 1.6 A resolution, respectively. The crystals of form A belonged to the monoclinic space group P2(1), with unit-cell parameters a = 32.697, b = 32.685, c = 41.977 A, alpha = 90, beta = 100.828, gamma = 90 degrees , whereas crystals of form B belonged to the trigonal space group P3(2)21, with unit-cell parameters a = b = 33.091, c = 128.77 A, alpha = beta = 90, gamma = 120 degrees . PMID- 22232181 TI - Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex. AB - Interleukin-20 (IL-20) is an IL-10-family cytokine that regulates innate and adaptive immunity in skin and other tissues. In addition to protecting the host from various external pathogens, dysregulated IL-20 signaling has been shown to contribute to the pathogenesis of human psoriasis. IL-20 signals through two cell surface receptor heterodimers, IL-20R1-IL-20R2 and IL-22R1-IL-20R2. In this report, crystals of the IL-20-IL-20R1-IL-20R2 ternary complex have been grown from polyethylene glycol solutions. The crystals belonged to space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = 111, c = 135 A, and diffracted X-rays to 3 A resolution. The crystallographic asymmetric unit contains one IL-20-IL-20R1-IL-20R2 complex, corresponding to a solvent content of approximately 54%. PMID- 22232182 TI - Expression, purification and preliminary crystallographic studies of NahF, a salicylaldehyde dehydrogenase from Pseudomonas putida G7 involved in naphthalene degradation. AB - Pseudomonas putida G7 is one of the most studied naphthalene-degrading species. The nah operon in P. putida, which is present on the 83 kb metabolic plasmid NAH7, codes for enzymes involved in the conversion of naphthalene to salicylate. The enzyme NahF (salicylaldehyde dehydrogenase) catalyzes the last reaction in this pathway. The nahF gene was subcloned into the pET28a(TEV) vector and the recombinant protein was overexpressed in Escherichia coli Arctic Express at 285 K. The soluble protein was purified by affinity chromatography followed by gel filtration. Crystals of recombinant NahF (6*His-NahF) were obtained at 291 K and diffracted to 2.42 A resolution. They belonged to the hexagonal space group P6(4)22, with unit-cell parameters a = b = 169.47, c = 157.94 A. The asymmetric unit contained a monomer and a crystallographic twofold axis generated the dimeric biological unit. PMID- 22232183 TI - Overexpression, crystallization and preliminary X-ray crystallographic analysis of the RNA polymerase domain of primase from Streptococcus mutans strain UA159. AB - Primase is the enzyme that synthesizes RNA primers on single-stranded DNA during normal DNA replication. In this study, the catalytic core domain of primase from Streptococcus mutans UA159 was overexpressed in Escherichia coli, purified and crystallized. Diffraction data were collected to 1.60 A resolution using a synchrotron-radiation source. The crystal belonged to space group P4(1) or P4(3), with unit-cell parameters a = b = 52.63, c = 110.31 A. The asymmetric unit is likely to contain one molecule, with a corresponding V(M) of 1.77 A(3) Da(-1) and a solvent content of 30.7%. PMID- 22232184 TI - Crystallization and preliminary X-ray data analysis of a DJ-1 homologue from Arabidopsis thaliana (AtDJ-1D). AB - A DJ-1 homologue protein from Arabidopsis thaliana (AtDJ-1D) belongs to the DJ 1/ThiJ/Pfpl superfamily and contains two tandem arrays of DJ-1-like sequences, but no structural information is available to date for this protein. AtDJ-1D was expressed in Escherichia coli, purified and crystallized for structural analysis. A crystal of AtDJ-1D was obtained by the hanging-drop vapour-diffusion method using 0.22 M NaCl, 0.1 M bis-tris pH 6.5, 21% polyethylene glycol 3350. AtDJ-1D crystals belonged to the monoclinic space group P2(1), with unit-cell parameters a = 56.78, b = 75.21, c = 141.68 A, beta = 96.87 degrees , and contained a trimer in the asymmetric unit. Diffraction data were collected to 2.05 A resolution. The structure of AtDJ-1D has been determined using the multiple-wavelength anomalous dispersion (MAD) method. PMID- 22232185 TI - Improving the diffraction of apoA-IV crystals through extreme dehydration. AB - Apolipoproteins are the protein component of high-density lipoproteins (HDL), which are necessary for mobilizing lipid-like molecules throughout the body. Apolipoproteins undergo self-association, especially at higher concentrations, making them difficult to crystallize. Here, the crystallization and diffraction of the core fragment of apolipoprotein A-IV (apoA-IV), consisting of residues 64 335, is presented. ApoA-IV(64-335) crystallized readily in a variety of hexagonal (P6) morphologies with similar unit-cell parameters, all containing a long axis of nearly 550 A in length. Preliminary diffraction experiments with the different crystal morphologies all resulted in limited streaky diffraction to 3.5 A resolution. Crystal dehydration was applied to the different morphologies with variable success and was also used as a quality indicator of crystal-growth conditions. The results show that the morphologies that withstood the most extreme dehydration conditions showed the greatest improvement in diffraction. One morphology in particular was able to withstand dehydration in 60% PEG 3350 for over 12 h, which resulted in well defined intensities to 2.7 A resolution. These results suggest that the approach of integrating dehydration with variation in crystal-growth conditions might be a general technique to optimize diffraction. PMID- 22232186 TI - Measurement of the equilibrium relative humidity for common precipitant concentrations: facilitating controlled dehydration experiments. AB - The dehydration of crystals of macromolecules has long been known to have the potential to increase their diffraction quality. A number of methods exist to change the relative humidity that surrounds crystals, but for reproducible results, with complete characterization of the changes induced, a precise humidity-control device coupled with an X-ray source is required. The first step in these experiments is to define the relative humidity in equilibrium with the mother liquor of the system under study; this can often be quite time-consuming. In order to reduce the time spent on this stage of the experiment, the equilibrium relative humidity for a range of concentrations of the most commonly used precipitants has been measured. The relationship between the precipitant solution and equilibrium relative humidity is explained by Raoult's law for the equilibrium vapour pressure of water above a solution. The results also have implications for the choice of cryoprotectant and solutions used to dehydrate crystals. For the most commonly used precipitants (10-30% PEG 2000-8000), the starting point will be a relative humidity of 99.5%. PMID- 22232187 TI - Mild Plasmodium falciparum malaria following an episode of severe malaria is associated with induction of the interferon pathway in Malawian children. AB - Infection with Plasmodium falciparum can lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Students t test, P < 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due to P. falciparum infection. PMID- 22232188 TI - Role of acinetobactin-mediated iron acquisition functions in the interaction of Acinetobacter baumannii strain ATCC 19606T with human lung epithelial cells, Galleria mellonella caterpillars, and mice. AB - Acinetobacter baumannii, which causes serious infections in immunocompromised patients, expresses high-affinity iron acquisition functions needed for growth under iron-limiting laboratory conditions. In this study, we determined that the initial interaction of the ATCC 19606(T) type strain with A549 human alveolar epithelial cells is independent of the production of BasD and BauA, proteins needed for acinetobactin biosynthesis and transport, respectively. In contrast, these proteins are required for this strain to persist within epithelial cells and cause their apoptotic death. Infection assays using Galleria mellonella larvae showed that impairment of acinetobactin biosynthesis and transport functions significantly reduces the ability of ATCC 19606(T) cells to persist and kill this host, a defect that was corrected by adding inorganic iron to the inocula. The results obtained with these ex vivo and in vivo approaches were validated using a mouse sepsis model, which showed that expression of the acinetobactin-mediated iron acquisition system is critical for ATCC 19606(T) to establish an infection and kill this vertebrate host. These observations demonstrate that the virulence of the ATCC 19606(T) strain depends on the expression of a fully active acinetobactin-mediated system. Interestingly, the three models also showed that impairment of BasD production results in an intermediate virulence phenotype compared to those of the parental strain and the BauA mutant. This observation suggests that acinetobactin intermediates or precursors play a virulence role, although their contribution to iron acquisition is less relevant than that of mature acinetobactin. PMID- 22232191 TI - Isolation by the 5' anchored PCR technique and characterization of eighteen microsatellite loci in horseshoe crab (Tachypleus gigas). PMID- 22232190 TI - A double, long polar fimbria mutant of Escherichia coli O157:H7 expresses Curli and exhibits reduced in vivo colonization. AB - Escherichia coli O157:H7 causes food and waterborne enteric infections that can result in hemorrhagic colitis and life-threatening hemolytic uremic syndrome. Intimate adherence of the bacteria to intestinal epithelial cells is mediated by intimin, but E. coli O157:H7 also possess several other putative adhesins, including curli and two operons that encode long polar fimbriae (Lpf). To assess the importance of Lpf for intestinal colonization, we performed competition experiments between E. coli O157:H7 and an isogenic DeltalpfA1 DeltalpfA2 double mutant in the infant rabbit model. The mutant was outcompeted in the ileum, cecum, and midcolon, suggesting that Lpf contributes to intestinal colonization. In contrast, the DeltalpfA1 DeltalpfA2 mutant showed increased adherence to colonic epithelial cells in vitro. Transmission electron microscopy revealed curli-like structures on the surface of the DeltalpfA1 DeltalpfA2 mutant, and the presence of curli was confirmed by Congo red binding, immunogold-labeling electron microscopy, immunoblotting, and quantitative real-time reverse transcription-PCR (qRT-PCR) measuring csgA expression. However, deletion of csgA, which encodes the major curli subunit, does not appear to affect intestinal colonization. In addition to suggesting that Lpf can contribute to EHEC intestinal colonization, our observations indicate that the regulatory pathways governing the expression of Lpf and curli are interdependent. PMID- 22232189 TI - Hemin binding protein C is found in outer membrane vesicles and protects Bartonella henselae against toxic concentrations of hemin. AB - Bartonella species are gram-negative, emerging bacterial pathogens found in two distinct environments. In the gut of the obligately hematophagous arthropod vector, bartonellae are exposed to concentrations of heme that are toxic to other bacteria. In the bloodstream of the mammalian host, access to heme and iron is severely restricted. Bartonellae have unusually high requirements for heme, which is their only utilizable source of iron. Although heme is essential for Bartonella survival, little is known about genes involved in heme acquisition and detoxification. We developed a strategy for high-efficiency transposon mutagenesis to screen for genes in B. henselae heme binding and uptake pathways. We identified a B. henselae transposon mutant that constitutively expresses the hemin binding protein C (hbpC) gene. In the wild-type strain, transcription of B. henselae hbpC was upregulated at arthropod temperature (28 degrees C), compared to mammalian temperature (37 degrees C). In the mutant strain, temperature dependent regulation was absent. We demonstrated that HbpC binds hemin and localizes to the B. henselae outer membrane and outer membrane vesicles. Overexpression of hbpC in B. henselae increased resistance to heme toxicity, implicating HbpC in protection of B. henselae from the toxic levels of heme present in the gut of the arthropod vector. Experimental inoculation of cats with B. henselae strains demonstrated that both constitutive expression and deletion of hbpC affect the ability of B. henselae to infect the cat host. Modulation of hbpC expression appears to be a strategy employed by B. henselae to survive in the arthropod vector and the mammalian host. PMID- 22232192 TI - Polymorphism of angiotensin converting enzyme (insertion/deletion) and endothelial nitric oxide synthase (intron 4ab) genes in a population from northeast India. PMID- 22232193 TI - Characterization of microsatellites in white croaker (Pennahia argentata) through cross species amplification of Miichthys miiuy. PMID- 22232194 TI - Polymorphisms of seven genes involved in lipid metabolism in an unselected Mexican population. PMID- 22232195 TI - New microsatellite markers classifying nontoxic and toxic Jatropha curcas. PMID- 22232196 TI - Fourteen polymorphic microsatellite markers isolated from big-head croaker (Collichthys lucidus). PMID- 22232197 TI - Isolation and characterization of fifteen microsatellite loci in the Tibetan fox (Vulpes ferrilata). PMID- 22232198 TI - Eighteen polymorphic microsatellites for domestic pigeon Columba livia var. domestica developed by cross species amplification of chicken markers. PMID- 22232199 TI - Distribution of MN blood group types in local populations in Philippines. PMID- 22232200 TI - Molecular diversity and phylogeny in geographical collection of chickpea (Cicer sp.) accessions. PMID- 22232201 TI - Thrombocytopenia in the intensive care unit. AB - Thrombocytopenia is a common laboratory finding in critically ill patients admitted to the intensive care unit. Potential etiologies of thrombocytopenia are myriad, ranging from acute disease processes and concomitant conditions to exposures and drugs. The mechanism of decreased platelet counts can also be varied: laboratory measurement may be spurious, platelet production may be decreased, or platelet destruction or sequestration may be increased. In addition to evaluation for the cause of thrombocytopenia, the clinician must also guard against spontaneous bleeding due to thrombocytopenia, prophylax against bleeding resulting from an invasive procedure performed in the setting of thrombocytopenia, and treat active bleeding related to thrombocytopenia. PMID- 22232202 TI - Pain in the ICU: a psychiatric perspective. AB - Pain is abundant in the intensive care unit (ICU). Successful analgesia demands a comprehensive appreciation for the etiologies of pain, vigilant clinical assessment, and personalized treatments. For the critically ill, frequent threats to mental and bodily integrity magnify the experience of pain, challenging clinicians to respond swiftly and thoughtfully. Because pain is difficult to predict and physiologic correlates are not specific, self-report remains the gold standard assessment. When communication is limited by intubation or cognitive deficits, behavioral pain scales prove useful. Patient-tailored analgesia aspires to mitigate suffering while optimizing alertness and cognitive capacity. Mindfulness of the neuropsychiatric features of pain helps the ICU clinician to clarify limits of traditional analgesia and identify alternative approaches to care. Armed with empirical data and clinical practice recommendations to better conceptualize, identify, and treat pain and its neuropsychiatric comorbidities, the authors (psychiatric consultants, by trade) reinforce holistic approaches to pain management in the ICU. After all, without attempts to understand and relieve suffering on all fronts, pain will remain undertreated. PMID- 22232203 TI - A case of severe heatstroke and review of pathophysiology, clinical presentation, and treatment. AB - Heatstroke is life-threatening condition characterized by hyperthermia and central nervous system disturbances. It can also be classified as a form of systemic inflammatory response syndrome with multiple organ dysfunction and in many ways resembles sepsis. Like sepsis, most patients with heatstroke demonstrate a hyperdynamic hemodynamic response. In contrast to sepsis, rhabdomyolysis may complicate management and initial fluid resuscitation is not well defined. We present an illustrative case report and review of literature. PMID- 22232204 TI - Toxic inhalational exposures. AB - Respirable toxicants are a spectrum of irritant and nonirritant gases, vapors, fumes, and airborne particles that can be entrained into the body through the respiratory tract, resulting in exposures that cause pulmonary injury and/or systemic disease. Sources of respirable toxicants include structural fires, industrial accidents, domestic mishaps, and intentional releases of injurious agents on the battleground (warfare) or in civilian settings (acts of terrorism). Acute toxic inhalational exposures may result in respiratory failure, multisystem organ dysfunction, and death. Management of victims includes assessment and protection of the airway, monitoring and treatment of systemic toxicity, and delivery of exposure-specific and nonspecific therapies that improve outcomes. Treatments may include antidotes, hyperbaric oxygen, and other nonspecific life supporting interventions. PMID- 22232205 TI - Human Metapneumovirus in the Cerebrospinal Fluid of a Patient With Acute Encephalitis. AB - OBJECTIVE: To report, to our knowledge, the first case of detection of human metapneumovirus in the cerebrospinal fluid of a patient during acute encephalitis. DESIGN: Case report. SETTING: University hospital. PATIENT: A 10 year-old girl with acute encephalitis. RESULTS: Human metapneumovirus was detected in cerebrospinal fluid and nasal-wash specimens during the initial phase of mild encephalitis. Abrupt clinical deterioration was associated with the presence of multiple areas of demyelination and cortical abnormalities. Demyelinated areas improved after immunomodulatory therapy, but cortical lesions spread in both hemispheres. Surprisingly, clinical worsening occurred when the virus became undetectable in cerebrospinal fluid. CONCLUSIONS: The detection of human metapneumovirus in cerebrospinal fluid strongly suggests its causative role in acute encephalitis. The evolution of the clinical and radiological features provided insight into the pathogenesis of human metapneumovirus encephalitis. PMID- 22232206 TI - Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. AB - OBJECTIVE: APOE epsilon4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. SETTING: Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri. PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants. RESULTS: APOE epsilon4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower CSF Abeta42 levels (P<.001) than did noncarriers. Our previous findings of higher [(11)C]PiB binding (P=.005) and lower CSF Abeta42 levels (P=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such that a more sedentary lifestyle was significantly associated with higher [(11)C]PiB binding for epsilon4 carriers (P=.013) but not for noncarriers (P=.20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments. CONCLUSION: Collectively, these results suggest that cognitively normal sedentary APOE epsilon4-positive individuals may be at augmented risk for cerebral amyloid deposition. PMID- 22232207 TI - A Unique Manifestation of Pupillary Fatigue in Autoimmune Autonomic Ganglionopathy. AB - OBJECTIVE: To demonstrate a unique abnormality of the pupillary light reflex in patients with autoimmune autonomic ganglionopathy (AAG). DESIGN: Case series. SETTING: Autonomic clinics at 2 university hospitals (University of Texas Southwestern Medical Center and Beth Israel Deaconess Medical Center). PARTICIPANTS: Seven patients with antibody-positive AAG. INTERVENTIONS: All patients with AAG underwent either monocular or binocular infrared pupillometry using a standard 2-second light stimulus at a defined intensity. Findings were compared with those from healthy control subjects and patients with other autonomic disorders. The light stimulus used in this study was selected to eliminate the normal phenomenon of pupil escape. MAIN OUTCOME MEASURES: The time to onset of redilation as well as other indices of pupillary constriction to light stimulus. RESULTS: Patients with AAG exhibited premature pupillary redilation (mean [SD], 1.02[0.20] seconds) compared with healthy control subjects (mean [SD], 2.24 [0.10] seconds) and other patients with autonomic disorders (mean [SD], 2.30 [0.12] seconds) (P.001). In healthy control subjects and patients with other autonomic disorders, pupillary redilation always followed the termination of the light stimulus; in patients with AAG, redilation consistently occurred during the light stimulus. In 1 patient, serial repetitive light stimulation further decreased the time to onset of redilation. CONCLUSIONS: Premature redilation of the pupil is a unique physiological feature seen only in patients with AAG. This phenomenon appears to be a manifestation of pupillary fatigue, a clinical correlate of defective synaptic transmission at the level of autonomic ganglia in antibody-positive AAG. PMID- 22232208 TI - The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin associated hemolytic uremic syndrome in humans and mice. AB - Hemolytic uremic syndrome (HUS) is a potentially life-threatening condition. It often occurs after gastrointestinal infection with E. coli O157:H7, which produces Shiga toxins (Stx) that cause hemolytic anemia, thrombocytopenia, and renal injury. Stx-mediated changes in endothelial phenotype have been linked to the pathogenesis of HUS. Here we report our studies investigating Stx-induced changes in gene expression and their contribution to the pathogenesis of HUS. Stx function by inactivating host ribosomes but can also alter gene expression at concentrations that minimally affect global protein synthesis. Gene expression profiling of human microvascular endothelium treated with Stx implicated a role for activation of CXCR4 and CXCR7 by their shared cognate chemokine ligand (stromal cell-derived factor-1 [SDF-1]) in Stx-mediated pathophysiology. The changes in gene expression required a catalytically active Stx A subunit and were mediated by enhanced transcription and mRNA stability. Stx also enhanced the association of CXCR4, CXCR7, and SDF1 mRNAs with ribosomes. In a mouse model of Stx-mediated pathology, we noted changes in plasma and tissue content of CXCR4, CXCR7, and SDF-1 after Stx exposure. Furthermore, inhibition of the CXCR4/SDF-1 interaction decreased endothelial activation and organ injury and improved animal survival. Finally, in children infected with E. coli O157:H7, plasma SDF-1 levels were elevated in individuals who progressed to HUS. Collectively, these data implicate the CXCR4/CXCR7/SDF-1 pathway in Stx-mediated pathogenesis and suggest novel therapeutic strategies for prevention and/or treatment of complications associated with E. coli O157:H7 infection. PMID- 22232209 TI - Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. AB - Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of KrasG12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that KrasG12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial KrasG12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting KrasG12D, or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer. PMID- 22232210 TI - Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. AB - Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks. PMID- 22232211 TI - Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. AB - Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP. PMID- 22232212 TI - RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. AB - RASA1 (also known as p120 RasGAP) is a Ras GTPase-activating protein that functions as a regulator of blood vessel growth in adult mice and humans. In humans, RASA1 mutations cause capillary malformation-arteriovenous malformation (CM-AVM); whether it also functions as a regulator of the lymphatic vasculature is unknown. We investigated this issue using mice in which Rasa1 could be inducibly deleted by administration of tamoxifen. Systemic loss of RASA1 resulted in a lymphatic vessel disorder characterized by extensive lymphatic vessel hyperplasia and leakage and early lethality caused by chylothorax (lymphatic fluid accumulation in the pleural cavity). Lymphatic vessel hyperplasia was a consequence of increased proliferation of lymphatic endothelial cells (LECs) and was also observed in mice in which induced deletion of Rasa1 was restricted to LECs. RASA1-deficient LECs showed evidence of constitutive activation of Ras in situ. Furthermore, in isolated RASA1-deficient LECs, activation of the Ras signaling pathway was prolonged and cellular proliferation was enhanced after ligand binding to different growth factor receptors, including VEGFR-3. Blockade of VEGFR-3 was sufficient to inhibit the development of lymphatic vessel hyperplasia after loss of RASA1 in vivo. These findings reveal a role for RASA1 as a physiological negative regulator of LEC growth that maintains the lymphatic vasculature in a quiescent functional state through its ability to inhibit Ras signal transduction initiated through LEC-expressed growth factor receptors such as VEGFR-3. PMID- 22232216 TI - Recent applications of AC electrokinetics in biomolecular analysis on microfluidic devices. AB - AC electrokinetics is a generic term that refers to an induced motion of particles and fluids under nonuniform AC electric fields. The AC electric fields are formed by application of AC voltages to microelectrodes, which can be easily integrated into microfluidic devices by standard microfabrication techniques. Moreover, the magnitude of the motion is large enough to control the mass transfer on the devices. These advantages are attractive for biomolecular analysis on the microfluidic devices, in which the characteristics of small space and microfluidics have been mainly employed. In this review, I describe recent applications of AC electrokinetics in biomolecular analysis on microfluidic devices. The applications include fluid pumping and mixing by AC electrokinetic flow, and manipulation of biomolecules such as DNA and proteins by various AC electrokinetic techniques. Future prospects for highly functional biomolecular analysis on microfluidic devices with the aid of AC electrokinetics are also discussed. PMID- 22232213 TI - The alphavbeta6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. AB - Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking alphavbeta6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in beta6 deficient mice. These findings were most likely explained by loss of TGF-beta activation, since the epithelial integrin alphavbeta6 is a critical activator of latent TGF-beta, and in vitro-differentiated mast cells showed TGF-beta-dependent expression of mMCP-1 and suppression of mMCP-4 and -6. In vitro, mMCP-1 increased contractility of murine tracheal rings, an effect that depended on intact airway epithelium, whereas mMCP-4 inhibited IL-13-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-beta by the alphavbeta6 integrin regulates airway responsiveness by modulating mast cell protease expression and that these proteases and their proteolytic substrates could be novel targets for improved treatment of allergic asthma. PMID- 22232217 TI - Shape of the liquid-liquid interface in micro counter-current flows. AB - We investigated the shape of the liquid-liquid interface in micro counter-current flows formed within microchannels. The pressure balance at the interface was calculated based on the interface geometry. Although the shape should be an arc under laminar flow, a large deformation near the center of the microchannel was observed. In the center of the microchannel, Laplace pressure (171 - 450 Pa) was induced toward the aqueous phase. In contrast, near both sidewalls, Laplace pressure (81 - 166 Pa) was induced toward the organic phase. This result suggests that opposing flow occurs in the adjacent phases near the interface, with spiral like flow generation. PMID- 22232214 TI - CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression. AB - Chronic myelogenous leukemia (CML) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein. Clinically, CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis. A CML-specific immune response is thought to contribute to the control of disease. Whether the immune system can also promote disease progression is not known. In the present study, we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells (LSCs) and mediates effects of the immune system on CML. In a mouse model of CML, BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27. Binding of CD27 by its ligand, CD70, increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active beta catenin and TRAF2- and NCK-interacting kinase (TNIK). This resulted in increased proliferation and differentiation of LSCs. Blocking CD27 signaling in LSCs delayed disease progression and prolonged survival. Furthermore, CD27 was expressed on CML stem/progenitor cells in the bone marrow of CML patients, and CD27 signaling promoted growth of BCR/ABL+ human leukemia cells by activating the Wnt pathway. Since expression of CD70 is limited to activated lymphocytes and dendritic cells, our results reveal a mechanism by which adaptive immunity contributes to leukemia progression. In addition, targeting CD27 on LSCs may represent an attractive therapeutic approach to blocking the Wnt/beta-catenin pathway in CML. PMID- 22232218 TI - An sp2 and sp3 hybrid nanocrystalline carbon film electrode for anodic stripping voltammetry and its application for electrochemical immunoassay. AB - A hybridized nanocrystalline carbon film electrode consisting of sp(2) and sp(3) bonds was investigated to reveal the reduction properties of Cd(2+) and for application as a highly sensitive and reliable electrochemical immunoassay. Conductive nanocrystalline carbon film consisting of about 60% sp(2) and 40% sp(3) bonds was fabricated using electron cyclotron resonance (ECR) sputtering equipment, and then the Cd(2+) concentrations were measured with an ECR sputtered carbon (ECR nano-carbon) electrode by employing an anodic stripping voltammetry (ASV) technique. The preconcentrated Cd was analyzed with Kelvin probe force microscopy and energy dispersive X-ray spectroscopy while observing the morphology change with an atomic force microscope and a scanning electron microscope. The preconcentrated Cd on the ECR nano-carbon electrode was revealed to be a thin sheet structure, which was significantly different from the Cd on a conventional carbon material that grows with a coralloid structure. The background current during an ASV measurement maintains a low level equivalent to that found with boron-doped diamond because the surface of the ECR nano-carbon is robust and angstrom-level flat. The carbon-electrode performance for ASV was improved by controlling its structure at a nanometer scale without any metal doping or coating. Finally, the ECR nano-carbon was used for biomolecular determination by electrochemical immunoassay with a CdSe nanoparticle label. Electrochemical immunoassay results were successfully obtained with the ECR nano carbon, and they correlated well with fluorescence results obtained for CdSe nanoparticles. PMID- 22232219 TI - A new dual immunoassay for tumor markers based on chemiluminescence signal amplification by magnetic mesoporous silica and enzyme modified gold nanoparticles. AB - A sensitive dual immunoassay was proposed for the determination of carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) based on signal amplification. Monoclonal antibodies immobilized on magnetic mesoporous silica particles (Fe(3)O(4)/SiO(2)) were prepared as the primary probe. Horseradish peroxidase (HRP) labeled antibodies co-coated with HRP on gold nanoparticles (AuNPs) were used as the secondary probe to achieve signal amplification. HRP tags were retained in the flow cells after a sandwich immunoassay. By controlling two switches on the two channels, chemiluminescent substrates were injected orderly man way, and then signals for CEA and AFP were sequentially detected by HRP-luminol-H(2)O(2). Due to the increased amount of HRP on AuNPs and the increased amount of monoclonal antibodies on Fe(3)O(4)/SiO(2), the signals were largely amplified. Under the optimal conditions, CEA and AFP could be detected in the linear ranges of 1.0 - 80 and 1.0 - 75 ng mL(-1) with detection limits of 0.25 and 0.5 ng mL(-1), respectively. PMID- 22232220 TI - Separation of progressive motile sperm from mouse semen using on-chip chemotaxis. AB - We present a novel method for the separation of progressive motile sperm from non progressive motile and immotile sperm. This separation was accomplished by inducing chemotaxis along a longitudinal chemical gradient in a microchip composed of a biocompatible polydimethysiloxane layer and a glass substrate. In a preliminary experiment using fluorescent rhodamine B as a marker, we verified that a chemical gradient was generated by diffusion within the microchannel. We used acetylcholine as a chemoattractant to evaluate the chemotactic response of sperm. We tested the response to a 1/2 to 1/64 dilution series of acetylcholine. The results of a mouse sperm chemotaxis assay showed that progressive motile sperm swam predominantly toward the outlet at an optimal chemical gradient of 0.625 (mg/ml)/mm of acetylcholine. This device provides a convenient, disposable, and high-throughput platform that could function as a progressive motile sperm sorter for potential use in intracytoplasmic sperm injection. PMID- 22232222 TI - Modification of the glass surface property in PDMS-glass hybrid microfluidic devices. AB - This paper presents a simple method to change the hydrophilic nature of the glass surface in a poly(dimethylsiloxane) (PDMS)-glass hybrid microfluidic device to hydrophobic by an extra-heating step during the fabrication process. Glass substrates bonded to a native or oxygen plasma-treated PDMS chip having microchambers (12.5 mm diameter, 110 um height) were heated at 200 degrees C for 3 h, and then the hydrophobicity of the glass surfaces on the substrate was evaluated by measuring the contact angle of water. By the extra-heating process, the glass surfaces became hydrophobic, and its contact angle was around 109 degrees , which is nearly the same as native PDMS surfaces. To demonstrate the usefulness of this surface modification method, a PDMS-glass hybrid microfluidic device equipped with microcapillary vent structures for pneumatic manipulation of droplets was fabricated. The feasibility of the microcapillary vent structures on the device with the hydrophobic glass surfaces are confirmed in practical use through leakage tests of the vent structures and liquid handling for the electrophoretic separation of DNA molecules. PMID- 22232221 TI - Development of a N-acetyl-beta-D-glucosaminidase (NAG) assay on a centrifugal lab on-a-compact-disc (Lab-CD) platform. AB - A centrifugal microfluidic platform, which is also known as lab-on-a-compact-disc (Lab-CD), was developed for use as a urinary N-acetyl-beta-D-glucosaminidase (NAG) activity assay. In this work, Lab-CD design, centrifugal operations and analytical procedures were established. Automated liquid handling on Lab-CD processes, such as fluid transport, sample metering, mixing, and fluorescence detection are accomplished using a portable Lab-CD system. The linearity of the NAG assay using 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide (4-MU-GlcNAc) was found to be acceptable in the range of 2.5 to 20 U L(-1); the relative standard deviations for the fluorescence intensity of eight samples (7.5 U L(-1)) was 6.4%. Clinical diagnostics is one of the most promising applications for Lab CD technologies. All the benefits of miniaturization, such as reduced sample requirement, reduced reagent consumption and automation, are realized in this investigation. PMID- 22232223 TI - Influence of inhalation anesthetics on ion transport across a planar bilayer lipid membrane. AB - Ion transport from one aqueous phase (W1) to another (W2) across a planar bilayer lipid membrane (BLM) in the presence of inhalation anesthetics was electrochemically investigated. In the absence of inhalation anesthetics in the BLM system, no ion transport current flowed between W1 and W2 across the BLM. When inhalation anesthetics such as halothane, chloroform, diethyl ether and trichloroethylene were added to the two aqueous phases or the BLM, the ion transport current quite clearly appeared. When the ratio of the concentration of KCl or NaCl in W1 to that in W2 was varied, the zero current potential across the BLM was shifted. By considering the magnitude of the potential shift, we concluded that the ion transport current can be predominantly ascribed to the transport of Cl(-) across the BLM. Since the dielectric constants of these anesthetics are larger than that of the inner hydrophobic domain of the BLM, the concentration of hydrophilic electrolyte ions in the BLM increases with the increase in the dielectric constant of the inner hydrophobic domain caused by addition of these anesthetics. These situations lead to an increase in the ion permeability coefficient. PMID- 22232224 TI - Single-step sandwich immunoreaction in a square glass capillary immobilizing capture and enzyme-linked antibodies for simplified enzyme-linked immunosorbent assay. AB - To simplify the complicated operation steps and to minimize sample and reagent amounts for enzyme-linked immunosorbent assays (ELISA), we developed a square glass capillary immunosensor containing both covalently immobilized capture antibodies and physically adsorbed enzyme-linked antibodies. The immobilization of capture antibodies (anti-human IgG) was carried out by the treatment of 3 aminopropyltriethoxy silane, glutaraldehyde, and protein-A, followed by affinity capture of the antibody. In contrast, the enzyme-linked antibodies (alkaline phosphatase (ALP)-linked anti-human IgG) were physically adsorbed on the four corners of the capillary with the aid of polyethylene glycol (PEG) acting as a scaffold. A nanoliter volume of antigen (human IgG)-containing sample solution was introduced via capillary action. This addition resulted in the release and diffusion of ALP-linked anti-human IgG into the bulk solution. This event led to a 20-min single-step sandwich immunoreaction at the inner wall of capillary; the reaction was detected through the reaction with fluorescein diphosphate (FDP) which generated a fluorescent product, fluorescein. Using this technique, we obtained an intra-capillary precision with a coefficient of variation of 9.7%. In addition, the specificity study showed that the human IgG capillary immunosensor did not respond to rabbit IgG. Quantitative analysis was possible within the response range of 10 - 5000 ng mL(-1) anti-human IgG. This capillary immunosensor can act as a single analytical unit or can be integrated into a capillary array for multiple bioanalysis. PMID- 22232225 TI - Confocal microscopic evaluation of mixing performance for three-dimensional microfluidic mixer. AB - We developed a confocal microscopic method for a quantitative evaluation of the mixing performance of a three-dimensional microfluidic mixer. We fabricated a microfluidic baker's transformation (MBT) mixer as a three-dimensional passive type mixer for the efficient mixing of solutions. Although the MBT mixer is one type of ideal mixers, it is hard to evaluate its mixing performance, since the MBT mixer is based on several cycles of complicated three-dimensional microchannel structures. We applied the method developed here to evaluate the mixing of water and a fluorescein isothiocyanate (FITC; diffusion coefficient, 4.9 * 10(-10) m(2) s(-1)) solution by the MBT mixer. This method enables us to capture vertical section images for the fluid distributions of FITC and water at different three-dimensional microchannel structures of the MBT device. These images are in good agreement with those of mixing images based on numerical simulations. The mixing ratio could be calculated by the fluorescence intensity at each pixel of the vertical section image; complete mixing is recognized by a mixing ratio of more than 90%. The mixing ratios are measured at different cycles of the MBT mixer by changing the flow rate; the mixing performance is evaluated by comparisons with the mixing ratio of the straight microchannel without the MBT mixer. PMID- 22232226 TI - Gold nanoparticles as localization markers for direct and live imaging of particle absorption through a Caco-2 cell monolayer using dark-field microscopy. AB - Recently, efforts have been made to reduce the size of food particles containing functional ingredients, since reducing the size is expected to improve intestinal absorption. However, the absorption mechanisms have yet to be fully clarified. Therefore, a microscopy-based method for studying interactions between the particles and intestinal cells is required. We optimized the experimental conditions for observing gold nanoparticles (AuNPs) on the surface of an unfixed Caco-2 cell using dark-field microscopy (DFM). Tight junctions were clearly visible with AuNPs on the cells, producing intense scattered light under DFM. This suggests that AuNPs could be used as localization markers to visualize particle absorption through Caco-2 cells. PMID- 22232227 TI - X-ray diffraction of protein crystal grown in a nano-liter scale droplet in a microchannel and evaluation of its applicability. AB - We describe the technical aspects of the in-situ X-ray diffraction of a protein crystal prepared by a nanodroplet-based crystallization method. We were able to obtain diffraction patterns from a crystal grown in a capillary without any manipulation. Especially in our experimental approach, the crystals that moved to the nanodroplet interface were fixed strongly enough to carry out X-ray diffraction measurements that could be attributed to the high surface tension of the nanodroplet. The crystal was damaged by an indirect action of the X-rays because our in-situ X-ray diffraction measurement was carried out in the liquid phase without freezing the crystal; however, the obtained several diffraction patterns were of sufficiently fine quality for the crystal structure factors to be generated. We consider the technical examination presented in this paper to represent a seamless coupling of crystallization to X-ray analysis. PMID- 22232228 TI - Microfluidic devices for electrochemical measurement of photosynthetic activity of cyanobacteria microcystis cells. AB - A microfluidic device with analytical chambers for electrochemical measurements has been employed to detect photosynthetic activity at single cell level. The flowing cells (Microcystis viridis) in a main channel are individually guided to the chamber with microelectrodes by an electrophoretic manipulation. The reduction current of oxygen was continuously monitored to determine the photosynthetic activity upon light irradiation. The average rates for oxygen generation were estimated and found to be 10(-18) mol/s level. PMID- 22232229 TI - Naked-eye detection of amyloid aggregates using gold nanoparticles modified with amyloid beta antibody. AB - We developed a rapid method for estimating the amyloid beta (Abeta)-conformation state related with Alzheimer's disease. We prepared gold nanoparticle (AuNP) Abeta antibody conjugates treated with bovine serum albumin to stabilize their dispersibility in a buffer. The prepared AuNPs were precipitated in the presence of Abeta aggregates, such as oligomers and fibrils. Abeta monomers did not precipitate AuNPs. The formation of AuNP precipitates by Abeta aggregates could be confirmed by the naked eye within 1 h. PMID- 22232230 TI - Multiplexed assay for proteins based on sequestration electrochemistry using the protein binding electroactive magnetic microbeads. AB - The paramagnetic microbead-based electrochemical binding assay was demonstrated for detecting two kinds of protein simultaneously. The principle of this assay is based on the sequestration electrochemistry. The protein binding electroactive magnetic microbeads which are conjugated with an electroactive compound and a ligand to bind specifically with a target protein were prepared. The avidin biotin and soybean agglutinin (SBA)-galactosamine were chosen as model protein ligand systems. The avidin binding electroactive magnetic microbead (ABEMMb) and SBA binding electroactive magnetic microbead (SBEMMb) are constructed by biotin/thionine and galactosamine/ferrocene modified on paramagnetic microbeads. The voltammetric response for these functionalized microbeads was measured by the Nd-Fe-B magnet-incorporating carbon paste rotating disk electrode. The measurements were performed in a microliter droplet using a rotating disk electrode system. Avidin and SBA were simultaneously detected by the decrease in the current responses from the reduction of ABEMMb and SBEMMb that was caused by the binding with target proteins. The limits of detection for avidin and SBA were 4 * 10(-10) and 2 * 10(-10) M, respectively. PMID- 22232231 TI - Right ventricular outflow tract aneurysm with thrombus. AB - Right ventricular outflow tract (RVOT) aneurysm is a known complication of tetralogy of Fallot repair when a ventriculotomy is done. It leads to RV dysfunction and may require re-operation. We describe a rare instance of a patient who developed an RVOT aneurysm after trans-ventricular repair of tetralogy of Fallot, which was complicated with the formation of a thrombus in the aneurysm sac. The patient underwent re-operation with thrombectomy, excision of the RVOT aneurysm and pulmonary valve replacement. To the best of our knowledge, the occurrence of this combination and its implications have not been reported. PMID- 22232232 TI - It sometimes happens: late tracheal rupture after total thyroidectomy. AB - Thyroidectomy is a safe procedure often performed either for benign or malignant thyroid diseases. Complication rate is low and tracheal injury associated with thyroidectomy is rarely described. The trachea may be perforated or lacerated intraoperatively; nevertheless, damage is usually recognized and directly repaired with reduced patient morbidity. We review a case of a 45-year-old male with a history of non-invasive thyroid cancer who underwent a total thyroidectomy with a tracheal necrosis and a subsequent rupture presenting 4 days following surgical operation. At home, while coughing, the patient experienced rapid swelling of neck, face and upper part of the chest. Computed tomography scan images demonstrated extensive subcutaneous emphysema and a defect in cervical trachea, confirmed also by bronchoscopy. The patient, without delay, underwent an exploration of the neck with a debridement of laceration. In view of the fact that a local infection was present, only a right pre-thyroid muscle flap was stitched on the defect. The patients recovered uneventfully. PMID- 22232233 TI - Transapical transcatheter aortic valve replacement in patients with cardiogenic shock. AB - Transcatheter aortic valve implantation (TAVI) has been introduced to treat patients at high risk for conventional surgery; however, cardiogenic shock is considered a contraindication for TAVI. The aim of the present study was to evaluate early and intermediate mortality of patients in cardiogenic shock undergoing TAVI as a rescue procedure. Patients in cardiogenic shock underwent transapical TAVI with Edwards SAPIEN (Edwards Lifesciences, Irvine, CA, USA) prosthetic valves. Preoperative, perioperative and 1-year follow-up data were analysed. Analysis included 358 patients. Preoperative cardiogenic shock was present in 21 (5.9%) patients. EuroSCORE (cardiogenic shock 73.1 +/- 18.9% vs. non-cardiogenic shock 36.0 +/- 18.7%; P < 0.0001) and Society of Thoracic Surgeons score (cardiogenic shock 50.8 +/- 28.1% vs. non-cardiogenic shock 16.7 +/- 12.2%; P < 0.0001) were significantly higher in the cardiogenic shock group, and left ventricular ejection fraction (cardiogenic shock 26.0 +/- 13.1% vs. no cardiogenic shock 51.4 +/- 13.0%; P < 0.0001) was significantly lower. Thirty-day mortality was significantly higher in the cardiogenic shock group (cardiogenic shock 19% vs. non-cardiogenic shock 5%; P = 0.02) and 1-year survival significantly lower (cardiogenic shock 46% vs. no-cardiogenic shock 83%; P < 0.0001). At Cox regression, EuroSCORE was the sole determinant for follow-up mortality (odds ratio = 1.02; P = 0.04). TAVI in patients who are in cardiogenic shock is feasible. Although the early and late outcomes are encouraging, a structured strategy should be developed and further experience is needed. PMID- 22232235 TI - Structural and molecular genetic analyses of the bacterial carbazole degradation system. AB - Carbazole degradation by several bacterial strains, including Pseudomonas resinovorans CA10, has been investigated over the last two decades. As the initial reaction in degradation pathways, carbazole is commonly oxygenated at angular (C9a) and adjacent (C1) carbons as two hydroxyl groups in a cis configuration. This type of dioxygenation is termed "angular dioxygenation," and is catalyzed by carbazole 1,9a-dioxygenase (CARDO), consisting of terminal oxygenase, ferredoxin, and ferredoxin reductase components. The crystal structures of all components and the electron transfer complex between terminal oxygenase and ferredoxin indicate substrate recognition mechanisms suitable for angular dioxygenation and specific electron transfer among the three components. In contrast, the carbazole degradative car operon of CA10 is located on IncP-7 conjugative plasmid pCAR1. Together with conventional molecular genetic and biochemical investigations, recent genome sequencing and RNA mapping studies have clarified that transcriptional cross-regulation via nucleoid-associated proteins is established between pCAR1 and the host chromosome. PMID- 22232234 TI - Combined elective percutaneous coronary intervention and transapical transcatheter aortic valve implantation. AB - There is no established strategy of how and when to treat coronary artery disease (CAD) in patients referred for transcatheter aortic valve implantation (TAVI). Simultaneous, single-stage treatment of both pathologies is a possible solution. We report our initial results of simultaneously performed transapical TAVI and elective percutaneous coronary interventions (PCI) in high-risk patients with severe aortic valve stenosis. Between April 2008 and July 2011, a total of 419 patients underwent transapical TAVI. Combined elective PCI and TAVI were performed in 46 (11%) patients. Only the most significant coronary lesion or lesions were treated. Technical success of the combined approach was 100%. The mean count of implanted stents per patient was 1.6 +/- 1.0 (range, 1-5 stents). The 30-day mortality rates in the PCI and TAVI group was 4.3%. Survival at 12, 24 and 36 months of the PCI and TAVI group 87.1 +/- 5.5, 69.7 +/- 10.3 and 69.7 +/- 10.3%, respectively. The results showed that the single-stage approach with combined elective PCI and TAVI is feasible and safe. It has become our primary choice for treatment of high-risk patients with severe aortic valve stenosis and CAD. PMID- 22232236 TI - Effects of lactic acid-fermented soymilk on lipid metabolism-related gene expression in rat liver. AB - We examined the effects of lactic acid fermentation of soymilk on the lipid profile and lipid metabolism-related gene expression in rat liver. Male Sprague Dawley rats aged 7 weeks were fed a control diet (AIN-93), soymilk diet, or fermented soymilk diet for 1 week or 5 weeks. The hepatic triglyceride and cholesterol contents in the soymilk (SM) group and the fermented soymilk (FSM) group were significantly lower than those in the control group after 5 weeks, but these changes had not become apparent until after 1 week. The fatty acid synthesis-related genes were more markedly down-regulated after 1 week than after 5 weeks, whereas the cytochrome p450 family 7 subfamily a polypeptide 1 (CYP7al) gene related to cholesterol catabolism was more markedly up-regulated after 5 weeks than after 1 week. This up-regulation was higher in the FSM group than in the SM group. It is assumed that the bioactive components produced by lactic acid fermentation induced the up-regulation of CYP7a1. PMID- 22232237 TI - Production and characterization of a bacteriocin from ruminal bacterium Ruminococcus albus 7. AB - The characteristics of a bacteriocin from Ruminococcus albus 7 and its potential as an antibiotic alternative were examined in this study. The addition of 3 uM 3 phenylpropanoic acid (PPA) and 0.2% Tween 80 to the culturing medium improved bacteriocin production by 2.5-fold. Native polyacrylamide gel electrophoresis of the antagonistically active gel filtration fraction established that the molecular weight of the R. albus 7 bacteriocin was approximately 36 kDa. The bacteriocin was sensitive to pepsin, protease, and pancreatin, and was inactivated by heating at 65 degrees C for 1 h. Simulating in vitro avian digestion decreased the antagonistic activity by 74.7%, but the addition of 1% bovin serum albumin restored 13% of the lost antagonistic activity. Following ion exchange purification, the bacteriocin had sufficient antagonistic activity against five tested pathogenic strains, but the addition of a protectant is necessary for utilization of bacteriocin of R. albus 7 as an antibiotic alternative in animal feed. PMID- 22232238 TI - Purification, characterization, and molecular cloning of lectin from winter buds of Lysichiton camtschatcensis (L.) Schott. AB - A novel lectin was purified to homogeneity from winter buds of Lysichiton camtschatcensis (L.) Schott of the Araceae family. It was a tetramer composed of two non-covalently associated polypeptides with small subunits (11 kDa) and large subunits (12 kDa). Sequencing of both subunits yielded unique N-terminal sequences. A cDNA encoding the lectin was cloned. The isolated cDNA contained an open reading frame that encoded 267 amino acids. It encoded both subunits, indicating that the lectin is synthesized as a single precursor protein that is post-translationally processed into two different subunits with 45% sequence identity. Each subunit contained a mannose-binding motif known to be conserved in monocot mannose-binding lectins, but its activity was not inhibited by monosaccharides, including methyl alpha-mannoside. Asialofetuin and yeast invertase were potent inhibitors. Lectin activity was detected in the buds formed during the winter season but not in the expanded leaves. PMID- 22232239 TI - Suppressive effect of peach leaf extract on glucose absorption from the small intestine of mice. AB - The crude extract of peach leaves dose-dependently suppressed the postprandial elevation in the blood glucose level after an oral administration of soluble starch to mice. This study examines the mechanism for this suppressive effect in vivo. An oral carbohydrate-loading test on mice showed that the peach leaf extract suppressed the glucose-induced increase in the blood level of glucose, but without affecting the insulin level. An enteral soluble starch and glucose loading test on mice also showed that the crude extract (1,000 mg/kg) significantly suppressed the postprandial elevation of the blood glucose level and increased the amount of glucose that remained in the intestine to within the same range as that with phloridzin (500 mg/kg), a natural sodium-dependent glucose transporter (SGLT)-specific inhibitor. In contrast, the extract did not suppress the postprandial elevation of the blood triglyceride and cholesterol levels in mice, and did not affect the normal blood glucose level in a feeding test for 21 d. These results reveal that the extract of peach leaves suppressed the postprandial elevation of blood glucose level by inhibiting the absorption of glucose in the small intestine of mice. PMID- 22232240 TI - Cloning and expression of the isocitrate lyase gene from a nitrogen-fixing bacterium, Azotobacter vinelandii, and functional analysis of the enzyme by site directed mutagenesis. AB - The gene encoding isocitrate lyase (ICL) from a nitrogen-fixing mesophilic bacterium, Azotobacter vinelandii strain IAM1078, was cloned, and the gene expression was examined. When sodium acetate or glucose was used as carbon source, similar growth was observed in this bacterium, but the ICL activity of cells grown with the former source was 43-hold higher than those with the latter. In addition, northern blot analysis revealed that expression of the ICL gene was induced by acetate. Based on a comparison of the amino acid sequences of the ICLs of various organisms, the ICL of this bacterium was found to be classifiable into subfamily 3, one of two phylogenetic groups of eubacteial ICLs. Replacement of the Ile504 in the ICL by Met, which is conserved in the corresponding position of cold-adapted ICLs of psychrophlic bacteria, resulted in decreased thermostability of activity, indicating that this amino acid residue is involved in thermal properties of this enzyme. PMID- 22232241 TI - Complementation of a defect in the asparagine-linked glycosylation of a mouse FM3A mutant G258 cell line by spheroplast fusion of a human mega YAC clone 923f5. AB - Mouse G258 mutant stopped both cell growth and the synthesis of lipid-linked oligosaccharide at the Man(3)GlcNAc(2)-P-P-Dolichol at a restricted temperature with a single gene mutation. To clarify the lesion in the G258 mutant, we isolated human genomic DNA transformants of the G258 mutant, which recovered from both defects by way of cell hybridization with X-ray irradiated HeLa cells. We detected a common 1.3-kb product by inter-human specific sequence in the L1 (L1Hs) PCR in the transformants (Kataoka et al., Somat. Cell Mol. Genet., 24, 235 243 (1998)). In the present study, we screened a human mega yeast artificial chromosome (YAC) library by PCR with primers designed according to the 1.3-kb DNA, and selected YAC clone 923f5. Moreover, we found by spheroplast fusion that YAC clone 923f5 complemented both defects of the G258 mutant. Since the human counterpart of the yeast ALG11 gene is localized in the region, the G258 mutant might have a defect in the mouse ALG11 gene. PMID- 22232242 TI - Effects of hydrostatic high pressure on the structure and antibacterial activity of recombinant human lactoferrin from transgenic rice. AB - High pressure was applied to recombinant human lactoferrin obtained from rice (rhLF) and its effect was evaluated on the structure and activity of the protein. Treatments of 400, 500, and 650 MPa for 15 min (20 degrees C), were applied to rhLF at 2 mg/mL in three iron-saturation forms. The structural characteristics of the treated proteins were analyzed by differential scanning calorimetry (DSC) and by fluorometric analysis, and immunoreactivity by ELISA. Iron retention and binding properties and antibacterial activity against Escherichia coli O157:H7 were also studied. The results obtained indicate that the treatments at 400 and 500 MPa did not greatly modifiy the conformation of lactoferrin, meanwhile treatment at 650 MPa affected in different degrees the three forms of rhLF. With respect to antibacterial activity, only apo rhLF showed antibacterial activity against E. coli, activity that was maintained after treatment at 400 MPa, while holo and AsIs rhLF did not inhibit the growth of E. coli. PMID- 22232243 TI - Inhibitory effects of water-soluble low-molecular-weight beta-(1,3-1,6) D-glucan isolated from Aureobasidium pullulans 1A1 strain black yeast on mast cell degranulation and passive cutaneous anaphylaxis. AB - We investigated the effects of water-soluble low-molecular-weight beta-(1,3-1,6) D-glucan isolated from Aureobasidium pullulans 1A1 strain black yeast (LMW-beta glucan) on mast cell-mediated anaphylactic reactions. Although it is known that LMW-beta-glucan has anti-tumor, anti-metastatic and anti-stress effects, the roles of LMW-beta-glucan in immediate-type allergic reactions have not been fully investigated. We examined whether LMW-beta-glucan could inhibit mast cell degranulation and passive cutaneous anaphylaxis (PCA). LMW-beta-glucan dose dependently inhibited the degranulation of both rat basophilic leukemia (RBL-2H3) and cultured mast cells (CMCs) activated by calcium ionophore A23187 or IgE. However, LMW-beta-glucan had no cytotoxicity towards RBL-2H3 cells and CMCs. Furthermore, orally administered LMW-beta-glucan inhibited the IgE-induced PCA reaction in mice. These results show LMW-beta-glucan to be a possible compound for the effective therapeutic treatment of allergic diseases. PMID- 22232244 TI - Changes in microbiota population during fermentation of narezushi as revealed by pyrosequencing analysis. AB - Modern Japanese sushi is derived from an archetype, narezushi, which is made by the fermentation of salted fish with rice. Several studies have demonstrated that lactic acid bacteria are dominantly present in narezushi, but no studies have addressed how microbial composition changes during fermentation. In this study, we examined changes in the microbial population in aji (horse mackerel)-narezushi during fermentation by pyrosequencing the 16S ribosomal RNA gene (rDNA). Ribosomal Database Project Classifier analysis revealed that among the 53 genera present, the Lactobacillus population drastically increased during fermentation, while the populations of other bacteria remained unchanged. Basic Local Alignment Search Tool analysis revealed that L. plantarum and L. brevis were the major species. Comparison with other fermented food microbiota indicated high product dependency of the bacterial composition, which might have been due to the starter free fermentation process. PMID- 22232245 TI - Stabilization of bovine intestine alkaline phosphatase by sugars. AB - Bovine intestine alkaline phosphatase (BIALP) is widely used as a signaling enzyme in sensitive assays such as enzyme immunoassay. In this study, we evaluated the effects of sugars on the kinetic stability of BIALP in the hydrolysis of p-nitrophenylphosphate (pNPP). The temperatures reducing initial activity by 50% in a 30-min incubation, T(50), of BIALP with 1.0 M disaccharide (sucrose and trehalose) or 2.0 M monosaccharide (glucose and fructose) were 55.0 55.5 degrees C, 4.7-5.2 degrees C higher than without sugar (50.3+/-0.1 degrees C). The T(50) of BIALP increased to 58.4+/-0.3 degrees C when the trehalose concentration was from 1.0 to 1.5 M, but did not change when the glucose concentration was from 2.0 to 3.0 M. Thermodynamic analysis revealed that the stabilization of BIALP by sugars was driven by the increase in the enthalpy change of activation for thermal inactivation of BIALP. No sugars affected the k(cat) of BIALP in the hydrolysis of pNPP. These results suggest that not only trehalose, which is considered the most effective stabilizer of enzymes, but also sucrose, glucose, and fructose can be used as stabilizers of BIALP. PMID- 22232246 TI - ROCK cooperated with ET-1 to induce epithelial to mesenchymal transition through SLUG in human ovarian cancer cells. AB - The Rho-associated serine-threonine protein kinase (ROCK) is a downstream effector of Rho GTPases that is frequently activated in the epithelial to mesenchymal transition (EMT) of human ovarian cancer cells. On the other hand, endothelin-1 (ET-1) and its receptor endothelin A receptor (ET(A)R) are overexpressed in primary and metastatic ovarian carcinoma, which suggests that ET 1 promotes tumor dissemination. Hence, two human ovarian carcinoma cell lines, SK OV-3 and CaOV3, were chosen to study the effects of ET-1/ET(A)R and ROCK in promoting EMT of ovarian cancer cells. We found that ET-1 exposure induced EMT of SK-OV-3 and CaOV3 by monitoring cells morphology, enhanced fibronectin, and reduced E-cadherin protein. At the same time, ET-1/ET(A)R enhanced the level of transcription of SLUG a transcriptional repressor of E-cadherin. More importantly, a constitutively active mutant of ROCK enhanced the transcription of SLUG by stimulating SLUG promoter activity. Furthermore, ROCK inhibitor Y27632 reversed the increase in fibronectin induced by ET-1/ET(A)R. Our data suggest that ROCK cooperated with ET-1/ET(A)R to promote EMT of human ovarian carcinoma cells through upregulation of SLUG mRNA. PMID- 22232247 TI - Antiangiogenic effect of carnosic acid and carnosol, neuroprotective compounds in rosemary leaves. AB - Carnosic acid, a diterpene in rosemary, is considered to be beneficial in the prevention of chronic neurodegenerative diseases. Recently, it has been found that drugs with antiangiogenic activity lower the risk of neurodegenerative diseases. Thus it is of interest whether carnosic acid has antiangiogenic activity. In this study, carnosic acid suppressed microvessel outgrowth on ex vivo angiogenesis assay using a rat aortic ring at higher than 10 uM. The antiangiogenic effect of carnosic acid was found in angiogenesis models using human umbilical vein endothelial cells with regard to tube formation on reconstituted basement membrane, chemotaxis and proliferation. Although the carnosol in rosemary also suppressed angiogenesis, its effect was not more potent than that of carnosic acid in the ex vivo model. These results suggest that carnosic acid and rosemary extract can be useful in the prevention of disorders due to angiogenesis, and that their antiangiogenic effect can contribute to a neuroprotective effect. PMID- 22232248 TI - Cardioprotective effects of 3-phosphoinositide-dependent protein kinase-1 on hypoxic injury in cultured neonatal rat cardiomyocytes and myocardium in a rat myocardial infarct model. AB - 3-Phosphoinositide-dependent protein kinase-1 (PDK1) is involved in numerous cellular responses. In this study, we investigated the protective effects of PDK1 gene expression against hypoxic conditions in cultured rat CMCs (rCMCs) and in a rat myocardial infarction (MI) model using the lentiviral vector (LeV) system. LeV-PDK1 transfer effectively reduced the apoptotic cell death caused by hypoxic injury as compared to LeV-GFP transfer in rCMCs the expression of survival proteins increased in the LeV-PDK1 group, whereas apoptosis signaling decreased in the rCMCs and in infarcted hearts treated with LeV-PDK1. LeV-PDK1 transfer also reduced apoptosis and infarct size and attenuated myocardial wall thinning and ventricular remodeling in a rat MI model. These findings suggest that PDK1 has a protective role in the injured ischemic myocardium via overexpression of the cell survival pathway in CMCs. Hence PDK1 can be used as a treatment strategy for myocardial salvage inin hypoxic injury. PMID- 22232249 TI - Characterization and isolation of mutants producing increased amounts of isoamyl acetate derived from hygromycin B-resistant sake yeast. AB - Hygromycin B is an aminoglycoside antibiotic that inhibits protein synthesis in prokaryotes and eukaryotes. Twenty-four hygromycin B-resistants mutants were isolated from sake yeast, and were divided into three different degrees of strength according to hygromycin B resistance. Three of four hygromycin B strongly resistant mutants produced increased amounts of isoamyl acetate in sake brewing test, although isoamyl alcohol levels remained unchanged. Many hygromycin B-resistants mutants showed higher E/A ratios than K-701 in culture with koji extract medium. Strain HMR-18 produced the largest amount of isoamyl acetate, and its alcohol acetyltransferase (AATFase) activity was 1.3-fold that of K-701. DNA microarray analysis showed that many genes overexpressed in HMR-18 were involved in stress responses (heat shock, low pH, and so on) but HMR-18 showed thermo- and acid-sensitivity. It was strongly resistant to hygromycin B and another aminoglycoside antibiotic, G418. PMID- 22232250 TI - An environmental fate study of methoxychlor using water-sediment model system. AB - Agricultural waste water containing pesticides can reach the sea via rivers and estuaries, including brackish lakes. We studied the metabolic fate of methoxychlor [MXC; 1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] in a model system consisting of sediment and associated water collected from two sampling sites: a brackish lake and a freshwater river. MXC degraded rapidly and was finally mineralized in both sediment systems. The first step of degradation was dechlorination to yield 1,1-dichloro-2,2-bis(4-methoxyphenyl)ethane [de-Cl-MXC] or CN-replacement to yield 2,2-bis(4-methoxyphenyl)acetonitrile [MXC-CN], followed by O-demethylation. Although the metabolites were common to the two sediments, the dynamics of the metabolites over time were clearly distinct. In the brackish lake sediment, de-Cl-MXC accumulated transiently, whereas in the river sediment, it was rapidly converted to its demethylated metabolite. We also found that dechlorination and CN-replacement proceeded in autoclave-sterilized river sediment. In the river sediment, the abiotic reaction mediated by abundant humic acid and low oxygen level also appeared to contribute to the overall MXC metabolism. PMID- 22232251 TI - Species composition of Bacteroidales order bacteria in the feces of healthy people of various ages. AB - A study of species distribution of numerically predominant Bacteroidales order isolates in feces of healthy people aged 1-33 years was accomplished using a combination of amplified ribosomal DNA restriction analysis (ARDRA) and 16S ribosomal DNA (rDNA) sequencing. It was found that the majority of isolates in all age groups belonged to species B. xylanisolvens, B. vulgatus, and B. uniformis. Members of genera Alistipes, Parabacteroides, Odoribacter, Barnesiella, and Prevotella were also detected frequently. PMID- 22232252 TI - Genetic organization of the hrp gene cluster in Acidovorax avenae strain N1141 and a novel effector protein that elicits immune responses in rice (Oryza sativa L.). AB - The immune system of plants consists of two main arms, pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI). The multiple effectors that trigger ETI are translocated into plant cells by the type III secretion system (T3SS) of pathogenic bacteria. The rice avirulent N1141 strain of Acidovorax avenae causes ETI in rice, including hypersensitive response (HR) cell death. Sequence analysis indicated that the N1141 genome contains the hrp gene cluster (35.3 kb), including genes encoding the T3SS apparatus. The T3SS-defective N1141 mutant (NDeltaT3SS) did not cause HR cell death, suggesting that ETI is caused by translocation of effector proteins into rice cells via T3SS. Computational sequence analysis predicted that Lrp, HrpW, and HrpY are secreted by T3SS. The hrpY deletion mutant (NDeltahrpY) did not cause ETI, suggesting that HrpY is an important effector of ETI in the interaction between A. avenae N1141 and rice. PMID- 22232253 TI - A comparative analysis of the molecular characteristics of the Arabidopsis CoA pyrophosphohydrolases AtNUDX11, 15, and 15a. AB - Coenzyme A (CoA) is an essential, ubiquitous cofactor in all biological systems, where it acts as the major acyl group carrier in various central metabolic reactions. Although much is known about CoA biosynthesis, it is unclear how the CoA pool is regulated the various cellular compartments. It has been found that the nucleoside diphosphates linked to some moiety X (Nudix) hydrolases, AtNUDX11 and 15, have pyrophosphohydrolase activity toward CoA and its derivatives. In this study we identified two alternatively spliced variants, AtNUDX15 and 15a, produced from the AtNUDX15 gene, and carried out comparative studies of the gene regulation, the kinetic parameters, and the intracellular localization of AtNUDX11, 15, and 15a. The present findings indicate that AtNUDX11 and AtNUDX15(a) function in the hydrolysis of malonyl-CoA in cytosol and succinyl-CoA in the mitochondria, respectively, suggesting their impact not only on CoA biosynthesis but also on various CoA-related pathways such as the TCA cycle. PMID- 22232254 TI - Kinetic analysis for the degradation of glycyl-L-leucine and L-leucyl-glycine in subcritical water. AB - Two dipeptides, glycyl-L-leucine (G-L) and L-leucyl-glycine (L-G), the concentrations of which were 10 mmol/L, were degraded in subcritical water in order to understand fully the phenomena occurring during treatment. Treatment was administered in a stainless steel tubular reactor, which was connected to an HPLC pump and immersed in an oil bath at 200-240 degrees C, with residence times of 10-180 s. When G-L and L-G were treated, L-G and G-L significantly formed, respectively, and then they gradually decreased at every temperature. Irrespective of the kind of substrate, ring formation occurred, and cyclo-(glycyl L-leucine) was one of the final products. The reaction rate constants related to degradation were estimated under the assumption that all the reactions obeyed first-order kinetics, and the simulated results corresponded well with the experimental ones in every case. PMID- 22232255 TI - Enhancement of endothelial progenitor cell numbers and migration by H1152, a Rho kinase specific inhibitor. AB - Endothelial progenitor cells (EPCs) are applied in the treatment of ischemic diseases. In ex vivo culture of human cord-blood derived EPCs, H1152, (S)-(+)-2 methyl-1-[(4-methyl-5-iso-quinolinyl) sulfonyl]-homopiperazine, markedly increased the number of EPCs. It also induced EPC migration, stimulated the phosphorylation of AKT, and reduced the expression of p27 in the EPCs. Thus H1152 can be used effectively in ex vivo expansion of EPCs. PMID- 22232257 TI - Sequential insertion of multiple I-SceI recognition sites at designed loci of the Bacillus subtilis 168 genome. AB - Bacillus subtilis 168 is the only bacterium-based host serving for the cloning of giant DNA above 1.000 kbp. As rapid verification of the genome structure is crucial during the cloning process, six of 18-base sequence recognized by endonuclease I-SceI were sequentially created in the B. subtilis 168 genome. The established method and materials should be of use for other B. subtilis derivatives. PMID- 22232256 TI - Effects of inorganic nitrogen sources on the production of PP-V [(10Z)-12 carboxyl-monascorubramine] and the Expression of the nitrate assimilation gene cluster by Penicillium sp. AZ. AB - A fungal strain, Penicillium sp. AZ, produced the azaphilone Monascus pigment homolog when cultured in a medium composed of soluble starch, ammonium nitrate, yeast extract, and citrate buffer, pH 5.0. One of the typical features of violet pigment PP-V [(10Z)-12-carboxyl-monascorubramine] is that pyranoid oxygen is replaced with nitrogen. In this study, we found that ammonia and nitrate nitrogen are available for PP-V biosynthesis, and that ammonia nitrogen was much more effective than nitrate nitrogen. Further, we isolated nitrate assimilation gene cluster, niaD, niiA, and crnA, and analyzed the expression of these genes. The expression levels of all these genes increased with sodium nitrate addition to the culture medium. The results obtained here strongly suggest that Penicillium sp. AZ produced PP-V using nitrate in the form of ammonium reduced from nitrate through a bioprocess assimilatory reaction. PMID- 22232258 TI - Active suppression of EndoPG IV by ligation of the pro-sequence from Stereum purpureum Pro-EndoPG I. AB - We attempted to inactivate endopolygaolacturonase from Stereum purpureum (EndoPG) IV of identical origin by linking the pro-sequence of S. purpureum Pro-EndoPG I to the C-terminus. The recombinant Pro-EndoPG IV, expressed in Escherichia coli, had no polygalacturonase (PG) activity, but activity was acquired after partial degradation of the pro-sequence with V8 protease, as was the case for Pro-EndoPG I. These results indicate that the pro-sequence of Pro-EndoPG I can suppress the PG activity of EndoPG IV. PMID- 22232259 TI - Comparison of fructooligosaccharide utilization by Lactobacillus and Bacteroides species. AB - The utilization of 1-kestose (GF(2)) and nystose (GF(3)), the main components of fructooligosaccharides (FOS), by Lactobacillus and Bacteroides species was examined. Of seven Lactobacillus and five Bacteroides strains that utilized FOS, L. salivarius, L. rhamnosus, L. casei, and L. gasseri utilized only GF(2), whereas L. acidophilus and all the Bacteroides strains utilized both GF(2) and GF(3). Only the strains able to utilize both GF(2) and GF(3) had beta fructosidase activity in the culture supernatants. The culture supernatants of the Lactobacillus strains had higher beta-fructosidase activity for GF(2) than for GF(3), whereas those of the Bacteroides strains had higher activity for GF(3) than for GF(2). Furthermore, beta-fructosidase activity of the culture supernatants of the Lactobacillus cells grown in the GF(3) medium was much higher than that of the cells grown in the GF(2) medium, whereas the activity of the culture supernatants of the Bacteroides cells grown in the GF(3) medium was almost the same as that of the cells grown in the GF(2) medium. These results indicate that Lactobacillus species metabolize FOS in a different way from that of Bacteroides species. PMID- 22232260 TI - Lupeol supplementation improves blood pressure and lipid metabolism parameters in stroke-prone spontaneously hypertensive rats. AB - Supplementation with lupeol (0.67 g.kg(-1)) of the AIN-93M-based diet fed for 7 weeks to stroke-prone spontaneously hypertensive rats caused significantly decreased blood pressure as compared with a control group. Urinary 8-hydroxy-2' deoxyguanosine was significantly lower in the lupeol group. Finally, lupeol suppressed the hepatic mRNA expression levels of the genes involved in triglyceride and cholesterol synthesis. PMID- 22232261 TI - Suppressive effects by leaves of the Dypsis lutescens palm on fat accumulation in 3T3-L1 cells and fat absorption in mice. AB - The methanol extract of Dypsis lutescens leaves showed inhibitory effects on lipase activity in vitro and on triglyceride accumulation in 3T3-L1 pre adipocytes. Further experiments using the extract on mice demonstrated a suppressive effect on the postprandial elevation of blood triglyceride level and an anti-obesity effect on obese mice induced by a high-fat diet. D. lutescens will accordingly be useful for preventing obesity. PMID- 22232262 TI - Cloning and characterization of a gene coding for a major extracellular chitosanase from the koji mold Aspergillus oryzae. AB - A gene coding for a major extracellular chitosanase was isolated from Aspergillus oryzae IAM2660. It had a multi-domain structure composed of a signal peptide, a catalytic domain, Thr- and Pro-rich linkers, and repeated peptides (the R3 domain) from the N-terminus. The R3 domain bound to insoluble powder chitosan, but it did not promote the hydrolysis rate of the chitosanase to any extent. PMID- 22232263 TI - The urinary excretory ratio of nicotinamide catabolites was associated with the conversion ratio of tryptophan to nicotinamide in growing rats fed a niacin-free 20% casein diet. AB - Weaning rats were fed a niacin-free 20% casein diet. Twenty-four-h-urine samples were collected, and nicotinamide and its catabolites were measured. A correlation was found between the urinary excretory ratio of nicotinamide catabolites (N(1) methyl-2-pyridone-5-carboxamide + N(1)-methyl-4-pyridone-3-carboxamide)/N(1) methylnicotinamide and the tryptophan-nicotinamide conversion ratio during growing period of the rats. This indicates the possibility that the conversion ratio can be deduced from the excretory ratio. PMID- 22232264 TI - The fate of mycotoxins during the distillation process of barley shochu, a distilled alcoholic beverage. AB - Mycotoxins are frequent contaminants of grains and critical risk substances for brewers. Fermented barley mash contaminated artificially with 13 representative mycotoxins was distilled with small-scale apparatuses to elucidate the possibility of mycotoxin transfer from mash to distillates. None of these were detected in the distillates. The distillation process can effectively reduce the contamination risk posed by mycotoxins in distilled alcoholic beverages. PMID- 22232265 TI - A novel function of the human chaperonin CCT epsilon subunit in yeast. AB - A malfunction in the yeast HAC1 causes the unfolding-protein response in the endoplasmic reticulum, resulting in stress-sensitive and inositol auxotrophic phenotypes. Chaperonin-containing TCP1 (CCT) is necessary for the folding of actin and tubulin in the cytosol. The introduction of the truncated human CCT epsilon subunit into yeast cells of which hac1 was disrupted clearly suppressed not only its inositol auxotrophic phenotype but also its stress-sensitive phenotype. PMID- 22232266 TI - Pyrrolysine analogs as substrates for bacterial pyrrolysyl-tRNA synthetase in vitro and in vivo. AB - Pyrrolysine-tRNA(Pyl) complex is produced by pyrrolysyl-tRNA synthetase (PylRS). In this study, we investigated the substrate specificity of Desulfitobacterium hafnience PylRS. PylRS incorporated various L-lysine derivatives into tRNA(Pyl) in vitro. In addition, the PylRS/tRNA(Pyl) pair introduced these lysine derivatives into the recombinant protein by the Escherichia coli expression system, indicating that this PylRS/tRNA(Pyl) pair can be used in protein engineering technology. PMID- 22232267 TI - Lignin is linked to ethyl-carbamate formation in ume (Prunus mume) liqueur. AB - Ethyl carbamate concentrations in oak barrel-aged ume (Prunus mume) liqueurs were measured, and possible explanations for elevated levels were examined. The average concentration was 0.30 mg/L, significantly higher than in ume liqueurs not aged in oak (0.08 mg/L). Oak powder extracts were prepared from both untoasted and toasted oak powder by extraction with aqueous ethanol, and these were used to make ume liqueurs. Relative to a no-oak control, the ethyl carbamate concentrations were 3.8 and 11 times higher in the ume liqueur made with the untoasted and toasted oak powder extracts respectively. The extracts were loaded onto a C18 column, washed with water, and eluted with methanol. The (13)C-NMR spectra for the main constituents of the methanol elution fractions were consistent with those for lignin or fragments thereof. The methanol fractions were added to ume liqueur which was stored for 3 months. Relative to a control, the ethyl carbamate concentrations in the 3-month old liqueurs were found to be 1.2 and 4.6 higher for the untoasted oak-powder and the toasted oak-powder respectively. Ethyl carbamate was formed when lignin was added to a 40% aqueous ethanol solution that contained potassium cyanide. These observations suggest that lignin or fragments thereof promote the formation of ethyl carbamate. PMID- 22232268 TI - Identification of interaction site of propeptide toward mature carboxypeptidase Y (mCPY) based on the similarity between propeptide and CPY inhibitor (IC). AB - Both the propeptide in the precursor carboxypeptidase Y (proCPY) and the mature CPY (mCPY)-specific endogenous inhibitor (I(C)) inhibit CPY activity. The N terminal inhibitory reactive site of I(C) (the N-terminal seven amino acids of I(C)) binds to the substrate-binding site of mCPY and is essential for mCPY inhibition, but the mechanism of mCPY inhibition by the propeptide is poorly understood. In this study, sequence alignment between I(C) and proCPY indicated that a sequence similar to the N-terminal region of I(C) was present in proCPY. In particular, a region including the C-terminus of the propeptide was similar to the N-terminal seven amino acids of I(C). In the presence of peptides identical to the N-terminus of I(C) and the C-terminus of the propeptide, CPY activity was competitively inhibited. The C-terminal region of the propeptide might bind to the substrate-binding site of mCPY. PMID- 22232269 TI - Molecular cloning, expression, purification, and functional characterization of palustrin-2CE, an antimicrobial peptide of Rana chensinensis. AB - Antimicrobial peptides are effector molecules of the innate immunity of amphibians. Here, one antimicrobial peptide cDNA precursor, prepropalustrin-2CE3, from the tadpole of the Chinese brown frog Rana chensinensis was cloned. The coding sequence corresponding to the mature palustrin-2CE peptide was subcloned into pGEX-6p-1. The soluble GST-palustrin-2CE fusion protein was successfully expressed in the BL21(DE3)pLysS strain at 16 degrees C, and the proportion of the fusion protein reached 35%-39% of the total cellular protein. After removal of the GST-fusion tag, the purity of the palustrin-2CE obtained by Sephadex G50 chromatography was about 97%. Moreover, the purified palustrin-2CE displayed obviously inhibitory activities against the sensitive bacteria Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, and multi-drug resistant S. aureus and E. coli. These findings suggest that the tadpole of the Chinese brown frog is a unique source of antimicrobial peptides and indicates the therapeutic potential of the palustrin-2CE peptide. PMID- 22232270 TI - A secreted placental alkaline phosphatase-based reporter assay system for screening of compounds acting at an octopamine receptor stably expressed in a mammalian cell line. AB - Octopamine receptors are attractive insecticide targets. To screen compounds acting at octopamine receptors simply and rapidly, we constructed a chemiluminescent reporter gene assay system that detects secreted placental alkaline phosphatase transcriptionally regulated by the cAMP response element for a silkworm octopamine receptor. This system proved useful in high-throughput screening to develop octopamine receptor-specific insecticides. PMID- 22232271 TI - Depressive effects on the central nervous system and underlying mechanism of the enzymatic extract and its phlorotannin-rich fraction from Ecklonia cava edible brown seaweed. AB - Marine plants have been reported to possess various pharmacological properties; however, there have been few reports on their neuropharmacological effects. Terrestrial plants have depressive effects on the central nervous system (CNS) because of their polyphenols which make them effective as anticonvulsants and sleep inducers. We investigated in this study the depressive effects of the polyphenol-rich brown seaweed, Ecklonia cava (EC), on CNS. An EC enzymatic extract (ECEE) showed significant anticonvulsive (>500 mg/kg) and sleep-inducing (>500 mg/kg) effects on the respective mice seizure induced by picrotoxin and on the mice sleep induced by pentobarbital. The phlorotannin-rich fraction (PTRF) from ECEE significantly potentiated the pentobarbital-induced sleep at >50 mg/kg. PTRF had binding activity to the gamma aminobutyric acid type A (GABA(A)) benzodiazepine (BZD) receptors. The sleep-inducing effects of diazepam (DZP, a well-known GABA(A)-BZD agonist), ECEE, and PTRF were completely blocked by flumazenil, a well-known antagonist of GABA(A)-BZD receptors. These results imply that ECEE produced depressive effects on CNS by positive allosteric modulation of its phlorotannins on GABA(A)-BZD receptors like DZP. Our study proposes EC as a candidate for the effective treatment of neuropsychiatric disorders such as anxiety and insomnia. PMID- 22232272 TI - The antioxidative effect of fullerenes during the peroxidation of methyl linoleate in toluene. AB - The antioxidative effect of fullerenes C(60) and C(70) was examined by measuring the inhibition of methyl linoleate (MeL) peroxidation in toluene initiated by 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). The fullerenes retarded the formation of MeL hydroperoxides and lowered the rate of propagation. The reaction rates of fullerenes with AMVN-derived peroxyl radicals were much higher than that of MeL. These results indicate that fullerenes can act as retarders of lipid peroxidation, though their activity is low compared with that of alpha tocopherol. PMID- 22232273 TI - Mechanisms of action of escapin, a bactericidal agent in the ink secretion of the sea hare Aplysia californica: rapid and long-lasting DNA condensation and involvement of the OxyR-regulated oxidative stress pathway. AB - The marine snail Aplysia californica produces escapin, an L-amino acid oxidase, in its defensive ink. Escapin uses L-lysine to produce diverse products called escapin intermediate products of L-lysine (EIP-K), including alpha-amino-epsilon caproic acid, Delta1-piperidine-2-carboxylic acid, and Delta2-piperidine-2 carboxylic acid. EIP-K and H2O2 together, but neither alone, is a powerful bactericide. Here, we report bactericidal mechanisms of escapin products on Escherichia coli. We show that EIP-K and H2O2 together cause rapid and long lasting DNA condensation: 2-min treatment causes significant DNA condensation and killing, and 10-min treatment causes maximal effect, lasting at least 70 h. We isolated two mutants resistant to EIP-K plus H2O2, both having a single missense mutation in the oxidation regulatory gene, oxyR. A complementation assay showed that the mutated gene, oxyR(A233V), renders resistance to EIP-K plus H2O2, and a gene dosage effect leads to reduction of resistance for strains carrying wild type oxyR. Temperature stress with EIP-K does not produce the bactericidal effect, suggesting the effect is due to a specific response to oxidative stress. The null mutant for any single DNA-binding protein--Dps, H-NS, Hup, Him, or MukB- was not resistant to EIP-K plus H2O2, suggesting that no single DNA-binding protein is necessary to mediate this bactericidal effect, but allowing for the possibility that EIP-K plus H2O2 could function through a combination of DNA binding proteins. The bactericidal effect of EIP-K plus H2O2 was eliminated by the ferrous ion chelator 1,10-phenanthroline, and it was reduced by the hydroxyl radical scavenger thiourea, suggesting hydroxyl radicals mediate the effects of EIP-K plus H2O2. PMID- 22232274 TI - A novel membrane protein, VanJ, conferring resistance to teicoplanin. AB - Bacterial resistance to the glycopeptide antibiotic teicoplanin shows some important differences from the closely related compound vancomycin. They are currently poorly understood but may reflect significant differences in the mode of action of each antibiotic. Streptomyces coelicolor possesses a vanRSJKHAX gene cluster that when expressed confers resistance to both vancomycin and teicoplanin. The resistance to vancomycin is mediated by the enzymes encoded by vanKHAX, but not by vanJ. vanHAX effect a reprogramming of peptidoglycan biosynthesis, which is considered to be generic, conferring resistance to all glycopeptide antibiotics. Here, we show that vanKHAX are not in fact required for teicoplanin resistance in S. coelicolor, which instead is mediated solely by vanJ. vanJ is shown to encode a membrane protein oriented with its C-terminal active site exposed to the extracytoplasmic space. VanJ also confers resistance to the teicoplanin-like antibiotics ristocetin and A47934 and to a broad range of semisynthetic teicoplanin derivatives, but not generally to antibiotics or semisynthetic derivatives with vancomycin-like structures. vanJ homologues are found ubiquitously in streptomycetes and include staP from the Streptomyces toyocaensis A47934 biosynthetic gene cluster. While overexpression of staP also conferred resistance to teicoplanin, similar expression of other vanJ homologues (SCO2255, SCO7017, and SAV5946) did not. The vanJ and staP orthologues, therefore, appear to represent a subset of a larger protein family whose members have acquired specialist roles in antibiotic resistance. Future characterization of the divergent enzymatic activity within this new family will contribute to defining the molecular mechanisms important for teicoplanin activity and resistance. PMID- 22232275 TI - Functional and genetic characterization of the tap efflux pump in Mycobacterium bovis BCG. AB - Efflux pumps extrude a wide variety of chemically unrelated compounds conferring multidrug resistance and participating in numerous physiological processes. Mycobacterium tuberculosis possesses many efflux pumps, and their roles in drug resistance and physiology are actively investigated. In this work we found that tap mutant cells showed changes in morphology and a progressive loss of viability upon subcultivation in liquid medium. Transcriptome analysis in Mycobacterium bovis BCG revealed that disruption of the Rv1258c gene, encoding the Tap efflux pump, led to an extensive change in gene expression patterns during stationary phase, with no changes during exponential growth. In stationary phase, Tap inactivation triggered a general stress response and led to a general repression of genes involved in cell wall biosynthesis, in particular the formation of the peptidoglycan; this suggested the accumulation of an unknown Tap substrate that reaches toxic concentrations during stationary phase. We also found that both disruption and overexpression of tap altered susceptibility to many clinically approved antibiotics in M. bovis BCG. Acriflavine and tetracycline accumulation assays and carbonyl cyanide m-chlorophenylhydrazone (CCCP) potentiation experiments demonstrated that this phenotype was due to an active efflux mechanism. These findings emphasize the important role of the Tap efflux pump in bacterial physiology and intrinsic drug resistance. PMID- 22232276 TI - Determinants of quinolone versus trimethoprim-sulfamethoxazole use for outpatient urinary tract infection. AB - Quinolones are increasingly favored over trimethoprim-sulfamethoxazole (TMP-SMX) for empirical treatment of uncomplicated urinary tract infection (UTI). This is associated with increasing resistance toward this broad-spectrum group of antibiotics. Our objective is to describe the prescribing patterns and identify determinants of the choice between TMP-SMX and quinolones for outpatient UTI treatment in Switzerland. An ongoing national Sentinel surveillance system was used to study 11,799 antibiotic prescriptions for UTI in adult outpatients and associated physician and patient factors between 2006 and 2008, to compare the prescription of quinolones versus that of TMP-SMX for treatment of UTI. Most UTI episodes were diagnosed as cystitis (90%). TMP-SMX was prescribed for one-fifth (22%) of UTIs. Independent predictors for prescribing quinolones were pyelonephritis and physicians with low thresholds for prescribing antibiotics for upper respiratory tract infections ("high prescribers"), whereas female patients were more likely to receive TMP-SMX. High-prescribing physicians also more often cared for patients who themselves favor antibiotic treatment (P < 0.001). Quinolones are commonly prescribed to outpatients with UTI. Nonclinical factors influence the choice of quinolones versus TMP-SMX, which may provide opportunities for interventions to improve prescribing patterns and control quinolone resistance. PMID- 22232277 TI - Myxobacterium-produced antibiotic TA (myxovirescin) inhibits type II signal peptidase. AB - Antibiotic TA is a macrocyclic secondary metabolite produced by myxobacteria that has broad-spectrum bactericidal activity. The structure of TA is unique, and its molecular target is unknown. Here, we sought to elucidate TA's mode of action (MOA) through two parallel genetic approaches. First, chromosomal Escherichia coli TA-resistant mutants were isolated. One mutant that showed specific resistance toward TA was mapped and resulted from an IS4 insertion in the lpp gene, which encodes an abundant outer membrane (Braun's) lipoprotein. In a second approach, the comprehensive E. coli ASKA plasmid library was screened for overexpressing clones that conferred TA(r). This effort resulted in the isolation of the lspA gene, which encodes the type II signal peptidase that cleaves signal sequences from prolipoproteins. In whole cells, TA was shown to inhibit Lpp prolipoprotein processing, similar to the known LspA inhibitor globomycin. Based on genetic evidence and prior globomycin studies, a block in Lpp expression or prevention of Lpp covalent cell wall attachment confers TA(r) by alleviating a toxic buildup of mislocalized pro-Lpp. Taken together, these data argue that LspA is the molecular target of TA. Strikingly, the giant ta biosynthetic gene cluster encodes two lspA paralogs that we hypothesize play a role in producer strain resistance. PMID- 22232278 TI - Synergistic activity of ceftobiprole and vancomycin in a rat model of infective endocarditis caused by methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus. AB - The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 MUg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 MUg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log(10) CFU/g MRSA or 6 log(10) CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation. PMID- 22232279 TI - Temporal interplay between efflux pumps and target mutations in development of antibiotic resistance in Escherichia coli. AB - The emergence of resistance presents a debilitating change in the management of infectious diseases. Currently, the temporal relationship and interplay between various mechanisms of drug resistance are not well understood. A thorough understanding of the resistance development process is needed to facilitate rational design of countermeasure strategies. Using an in vitro hollow-fiber infection model that simulates human drug treatment, we examined the appearance of efflux pump (acrAB) overexpression and target topoisomerase gene (gyrA and parC) mutations over time in the emergence of quinolone resistance in Escherichia coli. Drug-resistant isolates recovered early (24 h) had 2- to 8-fold elevation in the MIC due to acrAB overexpression, but no point mutations were noted. In contrast, high-level (>= 64* MIC) resistant isolates with target site mutations (gyrA S83L with or without parC E84K) were selected more readily after 120 h, and regression of acrAB overexpression was observed at 240 h. Using a similar dosing selection pressure, the emergence of levofloxacin resistance was delayed in a strain with acrAB deleted compared to the isogenic parent. The role of efflux pumps in bacterial resistance development may have been underappreciated. Our data revealed the interplay between two mechanisms of quinolone resistance and provided a new mechanistic framework in the development of high-level resistance. Early low-level levofloxacin resistance conferred by acrAB overexpression preceded and facilitated high-level resistance development mediated by target site mutation(s). If this interpretation is correct, then these findings represent a paradigm shift in the way quinolone resistance is thought to develop. PMID- 22232280 TI - Discordant temporal evolution of Pfcrt and Pfmdr1 genotypes and Plasmodium falciparum in vitro drug susceptibility to 4-aminoquinolines after drug policy change in French Guiana. AB - Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r = 0.64 and 0.47, respectively, n = 547); its temporal changes paralleled changes in in vitro mefloquine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area. PMID- 22232281 TI - Hydrolysis spectrum extension of CMY-2-like beta-lactamases resulting from structural alteration in the Y-X-N loop. AB - The Citrobacter freundii isolate CHA, which was responsible for postoperative peritonitis after 10 days of cefepime therapy, displayed a phenotype of resistance consistent with extended-spectrum AmpC (ESAC) beta-lactamase. The chromosome-borne bla(AmpC-CHA) gene was amplified and sequenced, revealing five amino acid substitutions, I125V, R148H, Q196H, V305A, and V348A, in the product compared to the sequence of native AmpC. A cloning experiment yielded the Escherichia coli TOP10(pAmpC-CHA) strain, which was resistant to all extended spectrum cephalosporins (ESCs), including cefepime. To ascertain whether the R148H substitution accounted for the hydrolysis spectrum extension, it was reverted by site-directed mutagenesis. The resulting E. coli TOP10(pAmpC-CHA H148R) strain was fully susceptible to cefepime, thus confirming that the Arg-148 replacement was mandatory for substrate profile enlargement. To further characterize the phenotypical and biochemical effects induced by the R148H change, it was introduced by site-directed mutagenesis into the CMY-2 beta lactamase, which is structurally related to the chromosome-borne cephalosporinase of C. freundii. The CMY-2-R148H variant conferred increased MICs of ESCs, whereas those of carbapenems were unchanged even in a porin-deficient E. coli strain. Moreover, it exhibited increased catalytic efficiency (k(cat)/K(m)) toward ceftazidime (100-fold) due to an enhanced hydrolysis rate (k(cat)), whereas the enzymatic parameters toward imipenem were unchanged. The structural analysis of the AmpC variant showed that the R148H replacement occurred in the loop containing the Y-X-N motif, which is the counterpart of the SDN loop in class A beta-lactamases. This study shows that the Y-X-N loop is a novel hot spot for mutations accounting for hydrolysis spectrum extension in CMY-2-type enzymes. PMID- 22232282 TI - First national survey of antibiotic susceptibility of the Bacteroides fragilis group: emerging resistance to carbapenems in Argentina. AB - The antibiotic susceptibility rates of 363 clinical Bacteroides fragilis group isolates collected from 17 centers in Argentina during the period from 2006 to 2009 were as follows: piperacillin-tazobactam, 99%; ampicillin-sulbactam, 92%; cefoxitin, 72%; tigecycline, 100%; moxifloxacin, 91%; and clindamycin, 52%. No metronidazole resistance was detected in these isolates during this time period. Resistance to imipenem, doripenem, and ertapenem was observed in 1.1%, 1.6%, and 2.3% of B. fragilis group strains, respectively. B. fragilis species showed a resistance profile of 1.5% to imipenem, 1.9% to doripenem, and 2.4% to ertapenem. This is the first report of carbapenem resistance in Argentina. The cfiA gene was present in 8 out of 23 isolates, all of them belonging to the B. fragilis species and displaying reduced susceptibility or resistance to carbapenems (MICs >= 4 MUg/ml). Three out of eight cfiA-positive isolates were fully resistant to carbapenems, while 5 out of 8 isolates showed low-level resistance (MICs, 4 to 8 MUg/ml). The inhibition by EDTA was a good predictor of the presence of metallo beta-lactamases in the fully resistant B. fragilis strains, but discrepant results were observed for low-level resistant isolates. B. fragilis was more susceptible to antimicrobial agents than other Bacteroides species. Bacteroides vulgatus species was the most resistant to ampicillin-sulbactam and piperacillin tazobactam, and B. thetaiotaomicron/ovatus strains showed the highest level of resistance to carbapenems, with an unknown resistance mechanism. B. vulgatus and the uncommon non-Bacteroides fragilis species were the most resistant to moxifloxacin, showing an overall resistance rate of 15.1%. PMID- 22232283 TI - In vitro potential of equine DEFA1 and eCATH1 as alternative antimicrobial drugs in rhodococcosis treatment. AB - Rhodococcus equi, the causal agent of rhodococcosis, is a severe pathogen of foals but also of immunodeficient humans, causing bronchopneumonia. The pathogen is often found together with Klebsiella pneumoniae or Streptococcus zooepidemicus in foals. Of great concern is the fact that some R. equi strains are already resistant to commonly used antibiotics. In the present study, we evaluated the in vitro potential of two equine antimicrobial peptides (AMPs), eCATH1 and DEFA1, as new drugs against R. equi and its associated pathogens. The peptides led to growth inhibition and death of R. equi and S. zooepidemicus at low micromolar concentrations. Moreover, eCATH1 was able to inhibit growth of K. pneumoniae. Both peptides caused rapid disruption of the R. equi membrane, leading to cell lysis. Interestingly, eCATH1 had a synergic effect together with rifampin. Furthermore, eCATH1 was not cytotoxic against mammalian cells at bacteriolytic concentrations and maintained its high killing activity even at physiological salt concentrations. Our data suggest that equine AMPs, especially eCATH1, may be promising candidates for alternative drugs to control R. equi in mono- and coinfections. PMID- 22232284 TI - Fosfomycin enhances the active transport of tobramycin in Pseudomonas aeruginosa. AB - Elevated levels of mucins present in bronchiectatic airways predispose patients to bacterial infections and reduce the effectiveness of antibiotic therapies by directly inactivating antibiotics. Consequently, new antibiotics that are not inhibited by mucins are needed to treat chronic respiratory infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. In these studies, we demonstrate that fosfomycin synergistically enhances the activity of tobramycin in the presence of mucin. The bactericidal killing of a novel 4:1 (wt/wt) combination of fosfomycin-tobramycin (FTI) is superior (>9 log(10) CFU/ml) relative to its individual components fosfomycin and tobramycin. Additionally, FTI has a mutation frequency resulting in an antibiotic resistance >3 log(10) lower than for fosfomycin and 4 log(10) lower than for tobramycin for P. aeruginosa. Mechanistic studies revealed that chemical adducts are not formed, suggesting that the beneficial effects of the combination are not due to molecular modification of the components. FTI displayed time-kill kinetics similar to tobramycin and killed in a concentration-dependent fashion. The bactericidal effect resulted from inhibition of protein biosynthesis rather than cell wall biosynthesis. Studies using radiolabeled antibiotics demonstrated that tobramycin uptake was energy dependent and that fosfomycin enhanced the uptake of tobramycin in P. aeruginosa in a dose-dependent manner. Lastly, mutants resistant to fosfomycin and tobramycin were auxotrophic for specific carbohydrates and amino acids, suggesting that the resistance arises from mutations in specific active transport mechanisms. Overall, these data demonstrate that fosfomycin enhances the uptake of tobramycin, resulting in increased inhibition of protein synthesis and ultimately bacterial killing. PMID- 22232286 TI - Microbiologically and clinically diagnosed vertebral osteomyelitis: impact of prior antibiotic exposure. AB - We retrospectively reviewed medical records to identify the factors that affect the results of culture in patients with pyogenic vertebral osteomyelitis. In multivariate analysis, the presence of paravertebral abscess was associated with positive results of microbiologic culture. Prior antibiotic exposure, especially of longer duration, was strongly associated with negative results. PMID- 22232288 TI - New statistical technique for analyzing MIC-based susceptibility data. AB - Seventeen laboratories participated in a cooperative study to validate the regional susceptibility testing of Neisseria gonorrhoeae in The Netherlands. International reference strains were distributed. Each laboratory determined the MICs of ciprofloxacin, penicillin, and tetracycline, for each strain by Etest. To explore a more transparent assessment of quality and comparability, a statistical regression model was fitted to the data that accounted for the censoring of the MICs. The mean MICs found by all of the laboratories except three were closer than one 2-fold dilution step to the overall mean, and the mean MICs of each antimicrobial agent were close to the MICs for the international reference strains. This approach provided an efficient tool to analyze the performance of the Dutch decentralized gonococcal resistance monitoring system and confirmed good and comparable standards. PMID- 22232287 TI - ENT1, a ribavirin transporter, plays a pivotal role in antiviral efficacy of ribavirin in a hepatitis C virus replication cell system. AB - We previously showed that equilibrative nucleoside transporter 1 (ENT1) is a primary ribavirin transporter in human hepatocytes. However, because the role of this transporter in the antiviral mechanism of the drug remains unclear, the present study aimed to elucidate the role of ENT1 in ribavirin antiviral action. OR6 cells, a hepatitis C virus (HCV) replication system, were used to evaluate both ribavirin uptake and efficacy. The ribavirin transporter in OR6 cells was identified by mRNA expression analyses and transport assays. Nitrobenzylmercaptopurine riboside (NBMPR) and micro-RNA targeted to ENT1 mRNA (miR-ENT1) were used to reduce the ribavirin uptake level in OR6 cells. Our results showed that ribavirin antiviral activity was associated with its accumulation in OR6 cells, which was also closely associated with the uptake of the drug. It was found that the primary ribavirin transporter in OR6 cells was ENT1 and that inhibition of ENT1-mediated ribavirin uptake by NBMPR significantly attenuated the antiviral activity of the drug as well as its accumulation in OR6 cells. The results also showed that even a small reduction in the ENT1-mediated ribavirin uptake, achieved in this case using miR-ENT1, caused a significant decrease in its antiviral activity, thus indicating that the ENT1-mediated ribavirin uptake level determined its antiviral activity level in OR6 cells. In conclusion, our results show that by facilitating its uptake and accumulation in OR6 cells, ENT1 plays a pivotal role in the antiviral effectiveness of ribavirin and therefore provides an important insight into the efficacy of the drug in anti HCV therapy. PMID- 22232285 TI - Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. AB - Antimicrobial resistance in Streptococcus pneumoniae remains a serious concern worldwide, particularly in Asian countries, despite the introduction of heptavalent pneumococcal conjugate vaccine (PCV7). The Asian Network for Surveillance of Resistant Pathogens (ANSORP) performed a prospective surveillance study of 2,184 S. pneumoniae isolates collected from patients with pneumococcal infections from 60 hospitals in 11 Asian countries from 2008 to 2009. Among nonmeningeal isolates, the prevalence rate of penicillin-nonsusceptible pneumococci (MIC, >= 4 MUg/ml) was 4.6% and penicillin resistance (MIC, >= 8 MUg/ml) was extremely rare (0.7%). Resistance to erythromycin was very prevalent in the region (72.7%); the highest rates were in China (96.4%), Taiwan (84.9%), and Vietnam (80.7%). Multidrug resistance (MDR) was observed in 59.3% of isolates from Asian countries. Major serotypes were 19F (23.5%), 23F (10.0%), 19A (8.2%), 14 (7.3%), and 6B (7.3%). Overall, 52.5% of isolates showed PCV7 serotypes, ranging from 16.1% in Philippines to 75.1% in Vietnam. Serotypes 19A (8.2%), 3 (6.2%), and 6A (4.2%) were the most prominent non-PCV7 serotypes in the Asian region. Among isolates with serotype 19A, 86.0% and 79.8% showed erythromycin resistance and MDR, respectively. The most remarkable findings about the epidemiology of S. pneumoniae in Asian countries after the introduction of PCV7 were the high prevalence of macrolide resistance and MDR and distinctive increases in serotype 19A. PMID- 22232289 TI - Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. AB - BC-3781 is a novel semisynthetic pleuromutilin antimicrobial agent developed as an intravenous and oral therapy for acute bacterial skin and skin structure infections (ABSSSI) and respiratory tract infections (RTI). BC-3781 and comparator agents were tested by the broth microdilution method against 1,893 clinical Gram-positive organisms predominantly causing ABSSSI. BC-3781 exhibited potent activity against methicillin-resistant Staphylococcus aureus (MIC(50/90), 0.12/0.25 MUg/ml), coagulase-negative staphylococci (MIC(50/90), 0.06/0.12 MUg/ml), beta-hemolytic streptococci (MIC(50/90), 0.03/0.06 MUg/ml), viridans group streptococci (MIC(50/90), 0.12/0.5 MUg/ml), and Enterococcus faecium (including vancomycin-nonsusceptible strains) (MIC(50/90), 0.12/2 MUg/ml). Compared with other antibiotics in use for the treatment of ABSSSI, BC-3781 displayed the lowest MICs and only a minimal potential for cross-resistance with other antimicrobial classes. PMID- 22232290 TI - Dissemination of the fosfomycin resistance gene fosA3 with CTX-M beta-lactamase genes and rmtB carried on IncFII plasmids among Escherichia coli isolates from pets in China. AB - The presence and characterization of plasmid-mediated fosfomycin resistance determinants among Escherichia coli isolates collected from pets in China between 2006 and 2010 were investigated. Twenty-nine isolates (9.0%) were positive for fosA3, and all of them were CTX-M producers. The fosA3 genes were flanked by IS26 and were localized on F2:A-:B- plasmids or on very similar F33:A-:B- plasmids carrying both bla(CTX-M-65) and rmtB. These findings indicate that the fosA3 gene may be coselected by antimicrobials other than fosfomycin. PMID- 22232292 TI - Nonthermal atmospheric plasma rapidly disinfects multidrug-resistant microbes by inducing cell surface damage. AB - Plasma, a unique state of matter with properties similar to those of ionized gas, is an effective biological disinfectant. However, the mechanism through which nonthermal or "cold" plasma inactivates microbes on surfaces is poorly understood, due in part to challenges associated with processing and analyzing live cells on surfaces rather than in aqueous solution. Here, we employ membrane adsorption techniques to visualize the cellular effects of plasma on representative clinical isolates of drug-resistant microbes. Through direct fluorescent imaging, we demonstrate that plasma rapidly inactivates planktonic cultures, with >5 log(10) kill in 30 s by damaging the cell surface in a time dependent manner, resulting in a loss of membrane integrity, leakage of intracellular components (nucleic acid, protein, ATP), and ultimately focal dissolution of the cell surface with longer exposure time. This occurred with similar kinetic rates among methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Candida albicans. We observed no correlative evidence that plasma induced widespread genomic damage or oxidative protein modification prior to the onset of membrane damage. Consistent with the notion that plasma is superficial, plasma-mediated sterilization was dramatically reduced when microbial cells were enveloped in aqueous buffer prior to treatment. These results support the use of nonthermal plasmas for disinfecting multidrug resistant microbes in environmental settings and substantiate ongoing clinical applications for plasma devices. PMID- 22232293 TI - Effect of pH on in vitro susceptibility of Candida glabrata and Candida albicans to 11 antifungal agents and implications for clinical use. AB - The treatment of vulvovaginal candidiasis (VVC) due to Candida glabrata is challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite of in vitro susceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on the in vitro activity of 11 antifungal agents against 40 C. glabrata isolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibility C. albicans strains. In vitro susceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH, C. glabrata isolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC(90) for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7, C. albicans strains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitive C. albicans isolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrent C. glabrata vaginitis, clinicians should recognize the limitations of in vitro susceptibility testing utilizing pH 7.0. PMID- 22232294 TI - Qualitative research with small connected communities: generating new knowledge while upholding research ethics. AB - Qualitative researchers have a dual mission: to generate knowledge through rigorous research and to uphold ethical standards and principles. Qualitative researchers often conduct studies with small connected communities in which relationships exist among community members. When engaging such communities, researchers might face ethical issues in upholding confidentiality standards while they work to achieve their dual mandate. Qualitative scholars have paid little attention to the ethical challenges that might arise in this context. Drawing on our experiences conducting studies with such communities, we expand the dialogue concerning qualitative research ethics by making explicit conceptual and practical tensions that emerge at various stages of the research process; articulating our respective reflective processes; and exploring issues associated with strategies for upholding confidentiality. We conclude with lessons learned to guide researchers who might face similar challenges. PMID- 22232295 TI - Methadone as social control: institutionalized stigma and the prospect of recovery. AB - Methadone maintenance treatment (MMT) is an intervention used to treat opioid (heroin) dependence. Several investigators have found that MMT is effective in reducing heroin use and other behaviors; however, a disproportionate number of MMT clients leave treatment prematurely. Moreover, MMT outcome variables are often limited in terms of their measurement. Utilizing an integrated theoretical framework of social control and stigma, we focused on the experiences of methadone maintenance from the perspective of clients. We pooled interview data from four qualitative studies in two jurisdictions and found linkages between social control and institutional stigma that serve to reinforce "addict" identities, expose undeserving customers to the public gaze, and encourage clients to be passive recipients of treatment. We discuss the implications for recovery and suggest recommendations for change. PMID- 22232291 TI - Trimethoprim-sulfamethoxazole prophylaxis and antibiotic nonsusceptibility in invasive pneumococcal disease. AB - Among 5,043 invasive pneumococcal disease (IPD) isolates identified through South African national surveillance from 2003 to 2007, we estimated the effect of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis on antimicrobial resistance. Patients on TMP-SMX prophylaxis were more likely to have a pneumococcal isolate nonsusceptible to TMP-SMX, penicillin, and rifampin. TMP-SMX nonsusceptibility was associated with nonsusceptibility to penicillin, erythromycin, and rifampin and multidrug resistance. This study informs empirical treatment of suspected IPD in patients with a history of TMP-SMX use. PMID- 22232296 TI - Antenatal care services in rural Uganda: missed opportunities for good-quality care. AB - Experience from countries that have achieved low maternal mortality suggests that access to good-quality maternity services is critical to improve maternal health. In this article we appraise the quality of antenatal care (ANC) services in a rural district of Uganda. We used a mixed methods approach, relying on a combination of semistructured interviews with both clients and providers, structured observations of provider-patient interactions, and infrastructure assessment of selected health facilities. We found several bottlenecks in health service delivery, including ineffective organization of educational sessions; selective omission of certain services; lack of explanation of important clinical and laboratory procedures; failure to link the performed procedures with preventive information; and occasional lack of respect for clients. The policy implications of these findings are discussed in relation to the need to (a) ensure an adequate supply of medical equipment and drugs, (b) enhance health workers' compliance with ANC guidelines, and (c) combine medical procedures with educational messages. PMID- 22232297 TI - Parent-adolescent communication about sex in rural India: U.S.-India collaboration to prevent adolescent HIV. AB - In this article, we examine parent-adolescent communication about sex among rural Indian youth and their parents. We conducted in-depth interviews (N = 40) with mothers, fathers, and adolescent boys and girls aged 14 to 18 years in a rural community in Maharashtra, India. In the context of key cultural factors, including gender-related norms, we explore issues of sexual health and critically assess widely held beliefs that Indian parents are unwilling or unable to discuss sex-related topics with their children. Our findings suggest that despite communication barriers, e.g., lack of knowledge and cultural proscriptions, Indian families are interested in and willing to communicate about sex-related topics. Future research should seek to determine the viability of family-based HIV prevention interventions for Indian adolescents. PMID- 22232298 TI - Cultural mechanisms in the exchange of social support among Puerto Ricans after a natural disaster. AB - In this study, I uncovered the dynamics involved in the exchange (or lack) of social support among a group of Puerto Ricans who experienced a natural disaster. I coded and analyzed 12 semistructured qualitative interviews. My analysis of the interviews revealed that a reported high degree of need was not associated with any type of help seeking from the respondents' social support networks. Relevant issues that arose in explaining the lack of social support exchanges were level of comfort in help seeking and cultural issues. My findings point to the importance of culture in shaping patterns of help-seeking behavior in the aftermath of a disaster. Two of the most salient cultural explanations as to why disaster victims were reluctant to ask for help from family and friends were the issues of confianza (trust) and pena (embarrassment). I discuss the results with reference to how they might help in planning and establishing programs to maximize help seeking among Latinos/as in an emergency situation. PMID- 22232299 TI - OxLDL up-regulates Niemann-Pick type C1 expression through ERK1/2/COX-2/PPARalpha signaling pathway in macrophages. AB - The Niemann-Pick type C1 (NPC1) is located mainly in the membranes of the late endosome/lysosome and controls the intracellular cholesterol trafficking from the late endosome/lysosome to the plasma membrane. It has been reported that oxidized low-density lipoprotein (oxLDL) can up-regulate NPC1 expression. However, the detailed mechanisms are not fully understood. In this study, we investigated the effect of oxLDL stimulation on NPC1 expression in THP-1 macrophages. Our results showed that oxLDL up-regulated NPC1 expression at both mRNA and protein levels in a dose-dependent and time-dependent manner. In addition, oxLDL also induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Treatment with oxLDL significantly increased cyclooxygenase-2 (COX-2) mRNA and protein expression in the macrophages, and these increases were suppressed by the ERK1/2 inhibitor PD98059 or ERK1/2 small interfering RNA (siRNA) treatment. OxLDL up regulated the expression of peroxisome proliferator-activated receptor alpha (PPARalpha) at the mRNA and protein levels, which could be abolished by COX-2 siRNA or COX-2 inhibitor NS398 treatment in these macrophages. OxLDL dramatically elevated cellular cholesterol efflux, which was abrogated by inhibiting ERK1/2 and/or COX-2. In addition, oxLDL-induced NPC1 expression and cellular cholesterol efflux were reversed by PPARalpha siRNA or GW6471, an antagonist of PPARalpha. Taken together, these results provide the evidence that oxLDL can up-regulate the expression of the NPC1 through ERK1/2/COX-2/PPARalpha-signaling pathway in macrophages. PMID- 22232300 TI - Tissue factor pathway inhibitor-2 may interact with nuclear protein RASSF1C. PMID- 22232301 TI - Some common errors of experimental design, interpretation and inference in agreement studies. AB - We signal and discuss common methodological errors in agreement studies and the use of kappa indices, as found in publications in the medical and behavioural sciences. Our analysis is based on a proposed statistical model that is in line with the typical models employed in metrology and measurement theory. A first cluster of errors is related to nonrandom sampling, which results in a potentially substantial bias in the estimated agreement. Second, when class prevalences are strongly nonuniform, the use of the kappa index becomes precarious, as its large partial derivatives result in typically large standard errors of the estimates. In addition, the index reflects rather one-sidedly in such cases the consistency of the most prevalent class, or the class prevalences themselves. A final cluster of errors concerns interpretation pitfalls, which may lead to incorrect conclusions based on agreement studies. These interpretation issues are clarified on the basis of the proposed statistical modelling. The signalled errors are illustrated from actual studies published in prestigious journals. The analysis results in a number of guidelines and recommendations for agreement studies, including the recommendation to use alternatives to the kappa index in certain situations. PMID- 22232302 TI - Osteoporosis and vertebral fractures in men aged 60-74 years. AB - BACKGROUND: limited information on the prevalence of osteoporosis and VFxs in men in high-risk populations is available. The choice of reference values for dual X ray absorptiometry (DXA) is debated. We evaluated the prevalence of osteoporosis and vertebral deformities in a population-based sample of men. METHODS: bone mineral density (BMD) was measured and vertebral deformities assessed using DXA and VFx assessment (VFA), respectively, in a random sample of 600 Danish men aged 60-74 years. Osteoporosis was defined as a T-score of -2.5 or less. RESULTS: the study population was comparable with the background population with regard to age, body mass index and co-morbidity. Osteoporosis was diagnosed in less than 1% of the participants at inclusion. Using Danish and NHANES III reference data, 10.2 and 11.5% of the study population had osteoporosis, respectively. In all, 6.3% participants had at least one VFx. BMD was significantly lower in participants with vertebral deformities, but only 24% of these cases had osteoporosis. CONCLUSIONS: osteoporosis and VFxs are prevalent in men aged 60-74 years. Although the majority of deformities were present in individuals without osteoporosis, BMD was lower in patients with VFxs at all sites investigated. Male osteoporosis was markedly underdiagnosed. PMID- 22232303 TI - The sudden unexpected infant death case registry: a method to improve surveillance. AB - This article describes a multistate population-based surveillance system for monitoring sudden unexpected infant deaths (SUIDs) known as the SUID Case Registry pilot program. The pilot program represents collaboration between the Centers for Disease Control and Prevention and the National Center for Child Death Review (NCCDR), which is funded by the Health Resources and Services Administration. The SUID Case Registry builds on existing child death review system activities and protocols. The objectives of the SUID Case Registry are to collect accurate and consistent population-based data about the circumstances and events associated with SUID cases, to improve the completeness and quality of SUID case investigations, and to use a decision-making algorithm with standardized definitions to categorize SUID cases. States who participate in the pilot program commit to review all SUID cases in their state by using their multidisciplinary state and local child death review teams. These teams request and review data from death scene investigators, medical examiners and coroners, law enforcement, social services, pediatric and obstetric providers, and public health per usual, but as part of the pilot program, supplement their SUID case reviews by discussing additional medical, environmental, and behavioral factors, and entering this data using the NCCDR Web-based Case Reporting System. This new surveillance system aims to improve knowledge of factors surrounding SUID events and improve investigation practices. The surveillance system will allow researchers and program planners to create prevention strategies and interventions, ultimately reducing SUIDs and injury-related infant deaths. PMID- 22232304 TI - Social-emotional screening for infants and toddlers in primary care. AB - BACKGROUND AND OBJECTIVES: Recommendations in pediatrics call for general developmental screening of young children; however, research suggests social emotional development, in particular, is important as an initial indicator of general well-being versus risk. We aim to describe a program designed to identify the social-emotional status of young children in the pediatric setting by using the Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) as a universal screening tool, and to assess the effect of interventions by a colocated psychologist on changes in ASQ:SE scores over time. METHODS: In a prospective cohort design we analyzed scores on ASQ:SE surveys completed on children 6 to 36 months of age, to determine if children were at risk for problems in social emotional development. The probability of remaining at risk over time was then compared between subjects receiving intervention by the psychologist, and those who declined intervention. Logit specifications were used in multivariate comparisons to control for a set of covariates. RESULTS: Three thousand one hundred and sixty-nine children were screened; 711 (22.4%) scored at or above the risk cutoff. Among the 711 at-risk children, 170 were rescreened. At the time of rescreening, those children who received intervention from the psychologist showed significant improvement on ASQ:SE scores compared with those who declined intervention (P = .01). CONCLUSIONS: Universal social-emotional screening in a busy pediatric practice is challenging. Significant percentages of children can be identified as being at risk for social-emotional problems, and colocation of a psychologist promotes the ability to effectively address young children's social emotional development within their medical home. PMID- 22232305 TI - Oral sucrose and "facilitated tucking" for repeated pain relief in preterms: a randomized controlled trial. AB - OBJECTIVES: To test the comparative effectiveness of 2 nonpharmacologic pain relieving interventions administered alone or in combination across time for repeated heel sticks in preterm infants. METHODS: A multicenter randomized controlled trial in 3 NICUs in Switzerland compared the effectiveness of oral sucrose, facilitated tucking (FT), and a combination of both interventions in preterm infants between 24 and 32 weeks of gestation. Data were collected during the first 14 days of their NICU stay. Three phases (baseline, heel stick, recovery) of 5 heel stick procedures were videotaped for each infant. Four independent experienced nurses blinded to the heel stick phase rated 1055 video sequences presented in random order by using the Bernese Pain Scale for Neonates, a validated pain tool. RESULTS: Seventy-one infants were included in the study. Interrater reliability was high for the total Bernese Pain Scale for Neonates score (Cronbach's alpha: 0.90-0.95). FT alone was significantly less effective in relieving repeated procedural pain (P < .002) than sucrose (0.2 mL/kg). FT in combination with sucrose seemed to have added value in the recovery phase with lower pain scores (P = .003) compared with both the single-treatment groups. There were no significant differences in pain responses across gestational ages. CONCLUSIONS: Sucrose with and without FT had pain-relieving effects even in preterm infants of <32 weeks of gestation having repeated pain exposures. These interventions remained effective during repeated heel sticks across time. FT was not as effective and cannot be recommended as a nonpharmacologic pain relief intervention for repeated pain exposure. PMID- 22232306 TI - Improving the quality of immunization delivery to an at-risk population: a comprehensive approach. AB - OBJECTIVE: Immunization quality improvement (QI) interventions are rarely tested as multicomponent interventions within the context of a theoretical framework proven to improve outcomes. Our goal was to study a comprehensive QI program to increase immunization rates for underserved children that relied on recommendations from the Centers for Disease Control and Prevention's Task Force on Community Preventive Services and the framework of the Chronic Care Model. METHODS: QI activities occurred from September 2007 to May 2008 at 6 health centers serving a low-income, minority population in Washington, DC. Interventions included family reminders, education, expanding immunization access, reminders and feedback for providers, and coordination of activities with community stakeholders. We determined project effectiveness in improving the 4:3:1:3:3:1:3 vaccination series (4 diphtheria-tetanus-pertussis vaccines, 3 poliovirus vaccines, 1 measles-mumps-rubella vaccine, 3 Haemophilus influenzae type b vaccines, 3 hepatitis B vaccines, 1 varicella vaccine, and three 7-valent pneumococcal conjugate vaccines) compliance. RESULTS: We found a 16% increase in immunization rates overall and a 14% increase in on-time immunization by 24 months of age. Improvement was achieved at all 6 health centers and maintained beyond 18 months. CONCLUSION: We were able to implement a comprehensive immunization QI program that was sustainable over time. PMID- 22232307 TI - Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. AB - OBJECTIVE: Patients with pediatric intestinal failure (IF) depend on parenteral nutrition for growth and survival, but are at risk for complications, such as catheter-related bloodstream infections (CRBSIs). CRBSI prevention is crucial, as sepsis is an important cause of IF-associated liver disease and mortality. We aim to estimate the pooled effectiveness and safety of ethanol locks (ELs) in comparison with heparin locks (HLs) with regard to CRBSI rate and catheter replacements for pediatric IF patients with chronic parenteral nutrition dependence. METHODS: A systematic review without language restriction was performed on Medline (1948-2010), Embase (1980-2010), and conference programs and trial registries up to December 2010. Search terms included "Catheter-Related Infections," "Catheter," "Catheters, Indwelling," "alcohol," "ethanol," and "lock." Two authors identified 4 retrospective studies for the pediatric IF population. Double, independent data extraction using predefined data fields and risk of bias assessment (Newcastle-Ottawa scale) was performed. RESULTS: In comparison with HLs, ELs reduced the CRBSI-rate per 1000 catheter days by 7.67 events and catheter replacements by 5.07. EL therapy decreased the CRBSI rate by 81% and replacements by 72%. One hundred eight to 150 catheter days of EL exposure were necessary to prevent 1 CRBSI and 122 to 689 days of exposure avoided 1 catheter replacement. Adverse events were rare and included thrombotic events. CONCLUSIONS: In pediatric patients with IF, EL is a more effective alternative to HL. Adverse events include thrombotic events. PMID- 22232308 TI - The risk of immune thrombocytopenic purpura after vaccination in children and adolescents. AB - BACKGROUND: The risk of immune thrombocytopenic purpura (ITP) after childhood vaccines other than measles-mumps-rubella vaccine (MMR) is unknown. METHODS: Using data from 5 managed care organizations for 2000 to 2009, we identified a cohort of 1.8 million children ages 6 weeks to 17 years. Potential ITP cases were identified by using diagnostic codes and platelet counts. All cases were verified by chart review. Incidence rate ratios were calculated comparing the risk of ITP in risk (1 to 42 days after vaccination) and control periods. RESULTS: There were 197 chart-confirmed ITP cases out of 1.8 million children in the cohort. There was no elevated risk of ITP after any vaccine in early childhood other than MMR in the 12- to 19-month age group. There was a significantly elevated risk of ITP after hepatitis A vaccine at 7 to 17 years of age, and for varicella vaccine and tetanus-diphtheria-acellular pertussis vaccine at 11 to 17 years of age. For hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines, elevated risks were based on one to two vaccine-exposed cases. Most cases were acute and mild with no long-term sequelae. CONCLUSIONS: ITP is unlikely after early childhood vaccines other than MMR. Because of the small number of exposed cases and potential confounding, the possible association of ITP with hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines in older children requires further investigation. PMID- 22232309 TI - Panhypopituitarism presenting as life-threatening heart failure caused by an inherited microdeletion in 1q25 including LHX4. AB - Clinical presentation of hypopituitarism in the neonate may be variable, ranging from absent to severe nonspecific symptoms and may be life-threatening in patients with adrenocorticotropic hormone deficiency. The LIM homeobox gene 4 (LHX4) transcription factor regulates early embryonic development of the anterior pituitary gland. Autosomal dominant mutations in LHX4 cause congenital hypopituitarism with variable combined pituitary hormone deficiency (CPHD). We report on a neonate with unexplained heart failure and minor physical anomalies, suggesting a midline defect. She was diagnosed with complete CPHD. Cardiac function was rescued by replacement with hydrocortisone and thyroxine; hypoglycaemia stopped under growth hormone therapy. Magnetic resonance imaging revealed a dysgenetic pituitary gland suggesting an early developmental defect. Array comparative genomic hybridization showed a maternally inherited 1.5 megabase microdeletion in 1q25.2q25.3, including the LHX4 gene. Haploinsufficiency of LHX4 likely explains the predominant pituitary phenotype in the proposita and we suggest variable intrafamilial penetrance of the inherited microdeletion. To the best of our knowledge, we are the first to report on heart failure as a rare nonspecific symptom of treatable CPHD in the newborn. Variably penetrant pituitary insufficiency, including this severe and atypical presentation, can be correlated with LHX4 insufficiency and highlights the role of LHX4 for pituitary development. PMID- 22232310 TI - Association of center volume with mortality and complications in pediatric heart surgery. AB - OBJECTIVE: Previous analyses have suggested center volume is associated with outcome in children undergoing heart surgery. However, data are limited regarding potential mediating factors, including the relationship of center volume with postoperative complications and mortality in those who suffer a complication. We examined this association in a large multicenter cohort. METHODS: Children 0 to 18 years undergoing heart surgery at centers participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2006-2009) were included. In multivariable analysis, we evaluated outcomes associated with annual center volume, adjusting for patient factors and surgical risk category. RESULTS: A total of 35 776 patients (68 centers) were included. Overall, 40.6% of patients had >=1 complication, and the in-hospital mortality rate was 3.9%. The mortality rate in those patients with a complication was 9.0%. In multivariable analysis, lower center volume was significantly associated with higher in-hospital mortality. There was no association of center volume with the rate of postoperative complications, but lower center volume was significantly associated with higher mortality in those with a complication (P = .03 when volume examined as a continuous variable; odds ratio in centers with <150 vs >350 cases per year = 1.59 [95% confidence interval: 1.16-2.18]). This association was most prominent in the higher surgical risk categories. CONCLUSIONS: These data suggest that the higher mortality observed at lower volume centers in children undergoing heart surgery may be related to a higher rate of mortality in those with postoperative complications, rather than a higher rate of complications alone. PMID- 22232311 TI - Bronchoscopic findings in children with chronic wet cough. AB - OBJECTIVES: Protracted bacterial bronchitis is defined as the presence of more than 4 weeks of chronic wet cough that resolves with appropriate antibiotic therapy, in the absence of alternative diagnoses. The diagnosis of protracted bacterial bronchitis is not readily accepted within the pediatric community, however, and data on the incidence of bacterial bronchitis in children are deficient. The objective of this study was to determine the frequency of bacterial bronchitis in children with chronic wet cough and to analyze their bronchoscopic findings. METHODS: We performed a retrospective review of charts of children who presented with chronic wet cough, unresponsive to therapy, before referral to the pediatric pulmonary clinic. RESULTS: A total of 197 charts and bronchoscopy reports were analyzed. Of 109 children who were 0 to 3 years of age, 33 (30.3%) had laryngomalacia and/or tracheomalacia. The bronchoscopy showed purulent bronchitis in 56% (110) cases and nonpurulent bronchitis in 44% (87). The bronchoalveolar lavage bacterial cultures were positive in 46% (91) of the children and showed nontypable Haemophilus influenzae (49%), Streptococcus pneumoniae (20%), Moraxella catarrhalis (17%), Staphylococcus aureus (12%), and Klebsiella pneumoniae in 1 patient. The chi(2) analysis demonstrated that positive bacterial cultures occurred more frequently in children with purulent bronchitis (74, 69.8%) than in children with nonpurulent bronchitis (19, 19.8%) (P < .001). CONCLUSIONS: Children who present with chronic wet cough are often found to have evidence of purulent bronchitis on bronchoscopy. This finding is often indicative of a bacterial lower airway infection in these children. PMID- 22232312 TI - The diet factor in attention-deficit/hyperactivity disorder. AB - This article is intended to provide a comprehensive overview of the role of dietary methods for treatment of children with attention-deficit/hyperactivity disorder (ADHD) when pharmacotherapy has proven unsatisfactory or unacceptable. Results of recent research and controlled studies, based on a PubMed search, are emphasized and compared with earlier reports. The recent increase of interest in this form of therapy for ADHD, and especially in the use of omega supplements, significance of iron deficiency, and the avoidance of the "Western pattern" diet, make the discussion timely. Diets to reduce symptoms associated with ADHD include sugar-restricted, additive/preservative-free, oligoantigenic/elimination, and fatty acid supplements. Omega-3 supplement is the latest dietary treatment with positive reports of efficacy, and interest in the additive-free diet of the 1970s is occasionally revived. A provocative report draws attention to the ADHD associated "Western-style" diet, high in fat and refined sugars, and the ADHD free "healthy" diet, containing fiber, folate, and omega-3 fatty acids. The literature on diets and ADHD, listed by PubMed, is reviewed with emphasis on recent controlled studies. Recommendations for the use of diets are based on current opinion of published reports and our practice experience. Indications for dietary therapy include medication failure, parental or patient preference, iron deficiency, and, when appropriate, change from an ADHD-linked Western diet to an ADHD-free healthy diet. Foods associated with ADHD to be avoided and those not linked with ADHD and preferred are listed. In practice, additive-free and oligoantigenic/elimination diets are time-consuming and disruptive to the household; they are indicated only in selected patients. Iron and zinc are supplemented in patients with known deficiencies; they may also enhance the effectiveness of stimulant therapy. In patients failing to respond or with parents opposed to medication, omega-3 supplements may warrant a trial. A greater attention to the education of parents and children in a healthy dietary pattern, omitting items shown to predispose to ADHD, is perhaps the most promising and practical complementary or alternative treatment of ADHD. PMID- 22232314 TI - The anatomical location of the flexor hallucis brevis as it pertains to implant arthroplasty. AB - BACKGROUND: Hallux limitus/rigidus is a painful arthritic condition affecting the first metatarsophalangeal joint that can be treated by implant arthroplasty, which, ultimately, may cause loss of the anatomical insertion points of the flexor hallucis brevis muscle. Preparation of the base involves resection of bone, thus compromising the insertion of the flexor hallucis brevis muscle. METHODS: We dissected 54 fresh-frozen cadaveric specimens and quantitatively measured the distalmost insertion point of the medial and lateral heads of the flexor hallucis brevis muscle. These measurements were performed for both heads. The measurements were performed three times by three separate examiners. In addition, taking into consideration the anatomical construct of the articular surface of the base of the proximal phalanx of the hallux, another measurement was performed to note the concavity using 44 of the specimens. Again, these measurements were performed three times by three separate investigators. RESULTS: The mean length from the base of the proximal phalanx to the distalmost insertion of the medial and lateral heads of the flexor hallucis brevis muscle was found to be 7 mm. CONCLUSIONS: This study provides precise anatomical data that can be used by foot and ankle surgeons when considering the use of implant arthroplasty for the treatment of hallux limitus/rigidus and the ability to maintain the insertion point of the flexor hallucis brevis muscle. PMID- 22232313 TI - I-pass, a mnemonic to standardize verbal handoffs. PMID- 22232315 TI - Consequences of pediatric obesity on the foot and ankle complex. AB - BACKGROUND: Anthropometric status can influence gait biomechanics, but there is relatively little published research regarding foot and ankle characteristics in the obese pediatric population. We sought to compare the structural and functional characteristics of the foot and ankle complex in obese and non-obese children. METHODS: Twenty healthy children (ten obese and ten normal weight) were recruited for a cross-sectional research study. Anthropometric parameters were measured to evaluate active ankle dorsiflexion, arch height (arch height index, arch rigidity index ratio, and arch drop), foot alignment (resting calcaneal stance position and forefoot-rearfoot alignment in unloaded and loaded positions), and foot type (malleolar valgus index). Independent t tests determined significant differences between groups for all assessed parameters. Statistical significance was set at P < .0125. RESULTS: Compared with non-obese participants, obese participants had significantly greater arch drop (mean +/- SD: 5.10 +/- 2.13 mm versus 2.90 +/- 1.20 mm; P =.011) and a trend toward lower arch rigidity index ratios (mean +/- SD: 0.92 +/- 0.03 versus 0.95 +/- 0.02; P = .013). In addition, obese participants had significantly less active ankle dorsiflexion at 90 degrees of knee flexion versus non-obese participants (mean +/- SD: 19.57 +/- 5.17 versus 29.07 +/- 3.06; P < .001). No significant differences existed between groups for any other anthropometric measurements. CONCLUSIONS: The decreased active ankle dorsiflexion in the obese group can increase foot contact for a longer period of the stance phase of gait. Obese participants also presented with a more flexible foot when bearing weight. PMID- 22232316 TI - Arthrodesis of the first metatarsophalangeal joint: comparison of three techniques. AB - BACKGROUND: There are cadaveric and biomechanical studies comparing different methods of fixation for achieving arthrodesis in hallux rigidus. However, there are no comparative clinical studies. We compared the clinical and radiologic outcomes of first metatarsophalangeal joint fusion using three different techniques: lag screw, lag screw and circlage wire, and Memory staples. METHODS: This was a retrospective study of 46 patients who underwent first metatarsophalangeal joint fusion. All of the operations were performed by experienced surgeons. Each patient had clinical and radiologic assessments postoperatively. RESULTS: The three groups were matching in terms of demographic features and comorbidity. Intraobserver and interobserver reliability for radiographic metatarsophalangeal joint fusion was excellent. The mean time to clinical and radiologic union in the Memory staples group was earlier (7.6 weeks) than that of the other two techniques (8.0 and 8.1 weeks). The Memory staples group also had the lowest incidence of nonunion (1 of 15 compared with 4 of 15 in the single lag screw fixation group and 3 of 16 in the lag screw and circlage wire fixation group) and no hardware-related problems. CONCLUSIONS: Our experience corroborates the advantages of Memory staples as described in the literature, including good approximation of bone fragments, technically easy application with fewer steps than an AO-applied screw, and an adequate source of internal fixation to achieve metatarsophalangeal joint fusion. There is also a suggestion that the time to achieve fusion is shorter. PMID- 22232317 TI - Effect of a metatarsal pad on the forefoot during gait. AB - BACKGROUND: Metatarsal pads are frequently prescribed for patients with metatarsalgia to reduce pain under the distal metatarsal heads. Several studies showed reduced pain and reduced plantar pressure just distal to the metatarsal pad. However, only part of the pain reduction could be explained by the decrease in plantar pressure under the forefoot. Therefore, an alternative hypothesis is proposed that pain relief is related to a widening of the foot and the creation of extra space between the metatarsal heads. This study focused on the effect of a metatarsal pad on the geometry of the forefoot by studying forefoot width and the height of the second metatarsal head. METHODS: Using a motion analysis system, 16 primary metatarsalgia feet and 12 control feet were measured when walking with and without a metatarsal pad. RESULTS: A significant mean increase of 0.60 mm in forefoot width during the stance phase was found when a metatarsal pad was worn. During midstance, the mean increase in forefoot width was 0.74 mm. In addition, walking with a metatarsal pad revealed an increase in the height of the second metatarsal head (mean, 0.62 mm). No differences were found between patients and controls. CONCLUSIONS: The combination of increased forefoot width and the height of the second metatarsal head produced by the metatarsal pad results in an increase in space between the metatarsal heads. This extra space could play a role in pain reduction produced by a metatarsal pad. PMID- 22232318 TI - Influence of turnout on foot posture and its relationship to overuse musculoskeletal injury in professional contemporary dancers: a preliminary investigation. AB - BACKGROUND: The angle of turnout is thought to predispose professional dancers to overuse musculoskeletal injuries of the lower limb; yet, the influence of angle of turnout on foot posture is currently unknown. METHODS: Twelve professional contemporary dancers (five women and seven men; mean age, 26.8 years) were recruited. The angle of gait and angle of turnout were measured using a quasi static clinical tracing method. Foot posture was assessed in the base of gait and angle of turnout using the Foot Posture Index. Each dancer completed a dance history and injury questionnaire. RESULTS: The results show a tendency toward a pronated foot posture (mean, 9 degrees ) in the angle of turnout position. A significant relationship was noted between the Foot Posture Index and angle of turnout (rho = 0.933-0.968, P < .01) and between the number of reported injuries and change in foot posture in the angle of turnout (rho = 0.789, P < .01) (right foot only). Twenty-eight injuries were reported; male dancers experienced a mean of 2.8 injuries and females a mean of 1.6 injuries. An inverse relationship was noted between age at training initiation and total reported injuries (r =-0.867, P < .01). All of the dancers reported a history of injury to the spine or lower limb, and 9 of the 12 reported an injury within the previous 12 months. CONCLUSIONS: Turnout is one of the most fundamental aspects of dance technique. This study suggests a trend toward pronation in angle of turnout and a link to lower-limb musculoskeletal injury. PMID- 22232319 TI - Navicula drop test ad modum Brody: does it show how the foot moves under dynamic conditions? AB - BACKGROUND: Understanding foot motion and function during activity is essential for clinicians because different foot types may require different treatment or rehabilitation strategies. Brody introduced the static navicular drop (ND) test, which was meant as a quick clinical test to estimate foot pronation during dynamic conditions. However, how well static ND predicts dynamic ND during walking has never been investigated. The purpose of this study was to investigate how well static ND corresponds to dynamic measures of ND during treadmill walking. METHODS: A custom video analysis system was used to assess dynamic ND during treadmill walking. The ND test ad modum Brody was used to evaluate static ND. RESULTS: Static ND showed a significant correlation with dynamic ND (r = 0.357, r(2) = 0.127, P < .001). Navicular height at heel strike demonstrated a significant correlation with navicular height at the start position of static ND (r = 0.756, r(2) = 0.571 P < .001). Minimal navicular height during walking was significantly correlated with the end position of static ND (r = 0.951, r(2) = 0.904, P < .001). CONCLUSIONS: This study of asymptomatic individuals did not confirm that static ND can be used to individually predict dynamic ND during treadmill walking. It was demonstrated that the start position of Brody's test is not well correlated with navicular height at heel strike, with this being the main reason for the weak relationship between static and dynamic ND measures. PMID- 22232320 TI - Transformative learning: empathy and multicultural awareness in podiatric medical education. AB - BACKGROUND: Short-term medical missions are common in medical educational settings and could possibly affect student learning. Little research has been conducted about the potential of these missions on students' transformative learning, in particular as it relates to empathy and multicultural awareness. METHODS: Eight podiatric medical students who participated in short-term medical missions in 2008 and 2009 completed an electronic survey to investigate the effect of their experience as it relates to their learning. The empathy and multicultural awareness impact of the mission experience was emphasized. Qualitative questions in the survey were coded, themed, and triangulated with the quantitative responses. RESULTS: Six students (75%) "strongly agreed" that participating in the medical mission was a significant positive experience in their podiatric medical training. Six students felt that their experiences in serving these communities increased their personal awareness of multicultural/diversity needs in general. All of the students agreed that they will become better podiatric physicians because of their experiences in the medical missions. The qualitative data also indicate that the experience had an effect on the students' views of health care and increased empathy toward their patients. CONCLUSIONS: Short-term medical missions could play a significant role in the transformative learning experience in podiatric medical education. This could affect the empathy and multicultural awareness of podiatric medical students. Further and more extensive evaluations of the potential impact of short term medical missions in podiatric medical education should be explored because it could influence curriculum and global health in the field of podiatric medicine. PMID- 22232321 TI - Hallux interphalangeal joint range of motion in feet with and without limited first metatarsophalangeal joint dorsiflexion. AB - BACKGROUND: This work was designed to assess the degree of correlation between hallux interphalangeal joint and first metatarsophalangeal joint dorsiflexion and to compare the mobility of the hallux interphalangeal joint between participants with and without limited first metatarsophalangeal joint dorsiflexion (hallux limitus). METHODS: Dorsiflexion of the hallux interphalangeal joint was measured in 60 normal feet and in 60 feet with hallux limitus to find correlations with first metatarsophalangeal joint dorsiflexion with the Spearman correlation coefficient and a simple linear regression equation. In addition, movement of the hallux interphalangeal joint was compared between normal and hallux limitus feet with the Mann-Whitney U test. RESULTS: Significant differences were found between the groups in mean +/- SD interphalangeal joint dorsiflexion (control group: 1.17 degrees +/- 2.50 degrees ; hallux limitus group: 10.65 degrees +/- 8.24 degrees ; P < .001). A significant inverse correlation was found between first metatarsophalangeal joint dorsiflexion and hallux interphalangeal joint dorsiflexion (rho = -0.766, P < .001), and the regression equation from which predictions could be made is the following: hallux interphalangeal joint dorsiflexion = 27.17 - 0.381 * first metatarsophalangeal joint dorsiflexion. CONCLUSIONS: Hallux interphalangeal joint dorsiflexion was greater in feet with hallux limitus than in normal feet. There was a strong inverse correlation between first metatarsophalangeal joint dorsiflexion and hallux interphalangeal joint dorsiflexion. PMID- 22232322 TI - Podiatric health needs of homeless populations as a public health concern. AB - BACKGROUND: Foot and ankle health among the homeless is an important public health concern. There are limited studies done thus far on foot and ankle conditions and the podiatric medical needs of homeless populations. A literature review was undertaken to evaluate any studies published about the lower-extremity health needs among the homeless. METHODS: We did a literature search through PubMed, the US National Library of Medicine's database of biomedical citations and abstracts for relevant publications from 1988 through 2008. We also searched the references cited in the articles found for any studies relevant to podiatric needs for homeless populations. RESULTS: We found three relevant articles that addressed the needs of podiatric care for the homeless. The articles highlighted the community health importance of foot care for homeless populations, especially in helping prevent potentially limb-threatening pathologies. CONCLUSIONS: The small number of studies published so far all emphasize the major public health need for podiatric care among homeless populations. More studies are needed to help address this important public health concern. PMID- 22232324 TI - Normal genetic variation of the human foot: part 1: the paradox of normal anatomical alignment in an evolutionary epigenetic context. AB - Molecular genetics is changing our understanding of the developmental translation of genotype to phenotype between and within different phylogenetic groups. Together with a growing understanding of our own evolutionary relationships to common ancestors, the epigenetic processes involved enforce a reexamination of what is regarded as a normal foot structure. A revised populationist approach is proposed and supported by paleoanthropologic evidence that reflects a picture of emerging suitability for bipedalism that is driven by natural genetic divergence. PMID- 22232323 TI - Comparative analysis of moral distress and values of the work organization between American and Spanish podiatric physicians. AB - BACKGROUND: Moral distress is a stress symptom arising from situations that involve ethical dimensions where the health-care provider believes that he or she is unable to preserve all interests and values at stake. The aims of this study were to evaluate the impact of, and identify possible differences in, moral distress in podiatric physicians in the United States and Spain and to determine the ethical principles most closely related to moral distress. METHODS: A 2008 e mail survey of 93 US podiatric physicians and 93 Spanish podiatric physicians (N = 186) presented statements about different ethical dilemmas, values, and goals in the workplace. RESULTS: Although moral distress is strongly present across the sample for all of the questions, the US sample shows higher levels of any kind of moral distress concerning questions about patients' treatment and economic constraints, overload of paperwork, and acting against one's conscience. In the US sample, 91.4% of physicians agreed mostly or completely with the statement that they often had to compromise their own values to cope with the demands of the workplace; 89.25% of US podiatric physicians indicated that their own professional values were congruent with the values of the organization; and a similar percentage (77.5%) reported a strong identification with the goals and framework of their work organization. The Spanish sample had similar results. CONCLUSIONS: The results underline the significance of moral distress for both samples, mainly related to time constraints and organizational aspects concerning patients and lack of resources. PMID- 22232325 TI - Dislocation of the fifth metatarsal base following partial fourth and fifth ray amputation: a case report. AB - This case report presents a rare postoperative dislocation of the fifth metatarsal base following a healed open partial fourth and fifth ray amputation of a 62-year-old male veteran with poorly controlled diabetes mellitus. The dislocated fifth metatarsal base subsequently created a chronic ulceration and an inhibition of normal gait. The patient was taken to the operating room where the fifth metatarsal base was resected with transfer of the peroneus brevis tendon to the cuboid to maintain biomechanical stability. PMID- 22232326 TI - Entrapment involving the lateral calcaneal branch of the sural nerve: a case study. AB - Sural nerve impingement is frequently reported and often arises from localized trauma but much less understood are its mechanical etiologies. This case report describes the effects of local traction on the lateral calcaneal branch of the sural nerve. The association is confirmed anatomically and symptoms are alleviated with a heel lift. PMID- 22232327 TI - Pseudarthrosis after percutaneous distal osteotomy in hallux valgus surgery: a case report. AB - Nonunion of the first metatarsal after hallux valgus surgery is a rare complication that often results in significant pain and disability requiring surgical management. We report the case of a 42-year-old woman who developed a pseudarthrosis of the first metatarsal after percutaneous retrocapital distal osteotomy of the first metatarsal for a mild hallux valgus deformity. The operative treatment consisted of debridement of fibrous nonunion with plating followed by application of pulsed electromagnetic fields (PEMF) with an external device. PMID- 22232328 TI - Comparison between local and general anesthesia for carotid endarterectomy: early and late results. AB - BACKGROUND: The aim of this retrospective study was to compare the results between general and local anesthesia (LA) for carotid endarterectomy (CEA). METHODS: Three hundred and twenty-nine patients in whom 365 CEA procedures were performed between January 1990 and September 2001, were included in this study. RESULTS: Operation time, shunt usage rates, hospitalization time (P < .0001), and permanent stroke rates (P < .05) were significantly lower in group with LA. For long-term period (121.3 +/- 37.45 vs 98.6 +/- 28.98 months), no significant difference was observed in these 2 group with respect to restenosis rates, neurological events, and deaths. CONCLUSIONS: Despite the lack of significant difference between LA and general anesthesia in terms of restenosis, neurological events, and death in the long-term period; LA is more preferable due its associated advantages including availability of testing the consciousness of the patients by direct contact, reduced use of shunts, shorter hospitalization periods, and less prevalence of permanent stroke in the short-term period. PMID- 22232329 TI - Results of a new human recombinant thrombin for the treatment of arterial pseudoaneurysm. AB - OBJECTIVE: To evaluate the results of a new thrombin sealant (Recothrom) for the treatment of arterial pseudoaneurysms (PDAs). METHODS: We reviewed 47 consecutive patients prospectively entered in a dedicated data set who underwent ultrasound guided percutaneous thrombin injection to treat PDA. End points were PDA recurrence, need for reintervention, and related complications such as limb ischemia or allergic reactions. RESULTS: Twenty-six patients were females (55%) and the median age of the entire group was 71 years (range, 45-87). The mean size of the PDA was 2.3 +/- 0.9 cm. The mean injected volume was 2.4 +/- 1.4 mL containing 500 +/- 320 units. Recurrence of the PDA occurred in 4 (8.5%) patients and was not related to anticoagulation status, body habitus, platelets levels, or use of antiplatelets. All recurred PDAs were successfully sealed with a second (n = 3) and a third injection (n = 1). There was no distal embolization or allergic reactions and no surgical intervention was required. CONCLUSION: The new human recombinant thrombin (Recothrom) is a safer nonimmunogenic option with similar success rates of other fibrin glue sealants. PMID- 22232330 TI - Endovascular repair for left common iliac artery occlusion following blunt trauma without associated bony injury: image in vascular surgery. AB - Common iliac artery injury (CIAI), commonly associated with pelvic fractures may present with a potentially fatal combination of haemorrhage and limb ischaemia. We report a case of isolated CIAI from blunt trauma without bony injury treated successfully using endovascular repair. PMID- 22232331 TI - Do we need sinks? PMID- 22232334 TI - Opioids and chronic pain. PMID- 22232335 TI - Opioids and chronic pain. PMID- 22232336 TI - Opioids and chronic pain. PMID- 22232337 TI - Centralized electronic health records benefit emergency medicine. PMID- 22232338 TI - Helicobacter pylori and immigrant health. PMID- 22232339 TI - Canada's low-risk drinking guidelines. PMID- 22232340 TI - When patient and doctor disagree. PMID- 22232341 TI - Conclusions about specialties don't match evidence. PMID- 22232342 TI - Military metaphors and friendly fire. PMID- 22232343 TI - Ultraconserved elements anchor thousands of genetic markers spanning multiple evolutionary timescales. AB - Although massively parallel sequencing has facilitated large-scale DNA sequencing, comparisons among distantly related species rely upon small portions of the genome that are easily aligned. Methods are needed to efficiently obtain comparable DNA fragments prior to massively parallel sequencing, particularly for biologists working with non-model organisms. We introduce a new class of molecular marker, anchored by ultraconserved genomic elements (UCEs), that universally enable target enrichment and sequencing of thousands of orthologous loci across species separated by hundreds of millions of years of evolution. Our analyses here focus on use of UCE markers in Amniota because UCEs and phylogenetic relationships are well-known in some amniotes. We perform an in silico experiment to demonstrate that sequence flanking 2030 UCEs contains information sufficient to enable unambiguous recovery of the established primate phylogeny. We extend this experiment by performing an in vitro enrichment of 2386 UCE-anchored loci from nine, non-model avian species. We then use alignments of 854 of these loci to unambiguously recover the established evolutionary relationships within and among three ancient bird lineages. Because many organismal lineages have UCEs, this type of genetic marker and the analytical framework we outline can be applied across the tree of life, potentially reshaping our understanding of phylogeny at many taxonomic levels. PMID- 22232344 TI - Outcome measures used in pediatric stroke studies: a systematic review. AB - Because no gold-standard outcome measure or measures exist to allow comparison of pediatric stroke study outcomes in clinical trials, we designed a systematic review of the literature to survey the current use of pediatric stroke outcome measures. Studies that used at least 1 standardized measure to assess the outcome of children with ischemic or hemorrhagic stroke, from full-term newborn to age 18 years, were included. Although 34 studies were included, an additional 36 studies could not be included because ad hoc, author-generated outcome measures were used. Excluding those measures in neuropsychological batteries, 38 unique outcome measures were used. The Wechsler Intelligence Scales, Pediatric Stroke Outcome Measure, and Bayley Scales of Infant Development were among the most used, but 79% of outcome measures were used by no more than 2 studies. Although many measures used have been validated for use in children with other medical conditions or for adults with stroke, only 1 measure has been specifically validated for use in pediatric ischemic stroke. To maximize comparability of future clinical trial results, agreement regarding a preferred pediatric stroke outcome scale or battery of measures is paramount; these measures should be reliable, responsive to change, and specifically validated for use in children with stroke. PMID- 22232345 TI - 11C-PiB imaging of human immunodeficiency virus-associated neurocognitive disorder. AB - OBJECTIVE: To evaluate whether the amyloid-binding agent carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) could differentiate Alzheimer disease (AD) from human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in middle-aged HIV-positive participants. DESIGN: (11)C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. Both chi(2) and t tests assessed differences in clinical and demographic variables between HIV-positive participants and community-living individuals observed at the Knight Alzheimer's Disease Research Center (ADRC). Analysis of variance assessed for regional differences in amyloid-beta protein 1-42 (Abeta42) using (11)C-PiB. SETTING: An ADRC and HIV clinic. PARTICIPANTS: Sixteen HIV-positive participants (11 cognitively normal and 5 with HAND) and 19 ADRC participants (8 cognitively normal and 11 with symptomatic AD). MAIN OUTCOME MEASURES: Mean and regional (11)C-PiB binding potentials. RESULTS: Participants with symptomatic AD were older (P < .001), had lower CSF Abeta42 levels (P < .001), and had higher CSF tau levels (P < .001) than other groups. Regardless of degree of impairment, HIV positive participants did not have increased (11)C-PiB levels. Mean and regional binding potentials were elevated for symptomatic AD participants (P < .001). CONCLUSIONS: Middle-aged HIV-positive participants, even with HAND, do not exhibit increased (11)C-PiB levels, whereas symptomatic AD individuals have increased fibrillar Abeta42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Abeta42 metabolism. (11)C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV-positive participants. Future cross sectional and longitudinal studies are required to assess the utility of (11)C PiB in older individuals with HAND. PMID- 22232346 TI - Daclizumab use in patients with pediatric multiple sclerosis. AB - BACKGROUND: Daclizumab, a humanized monoclonal antibody specific for the interleukin 2 receptor alpha chain, reduces clinical and magnetic resonance imaging disease activity in patients with adult-onset multiple sclerosis (MS) as monotherapy or add-on therapy with interferon. OBJECTIVE: To report the use of daclizumab in pediatric-onset MS. DESIGN: Case series. SETTING: Two comprehensive pediatric MS centers. PATIENTS: Seven patients with pediatric-onset MS with clinical and magnetic resonance imaging disease activity despite first-line disease-modifying therapy. INTERVENTION: Intravenous daclizumab, 1 mg/kg monthly. MAIN OUTCOME MEASURES: Annualized relapse rates, Expanded Disability Status Scale scores, contrast-enhancing lesions, and adverse effects. RESULTS: Treatment with daclizumab, primarily combined with interferon, was associated with reductions in annualized relapse rates and contrast-enhancing lesions and with reduction or stabilization of Expanded Disability Status Scale scores in each patient. However, 4 patients had relapses and new contrast-enhancing lesions during daclizumab treatment. No significant adverse effects occurred. CONCLUSION: Daclizumab may be a safe and at least partially effective treatment option for patients with pediatric-onset MS with disease activity despite first-line disease modifying therapy. PMID- 22232347 TI - Impact of inflammation on brain volume in multiple sclerosis. AB - OBJECTIVE: To study changes in brain volume measured monthly in patients treated for relapsing multiple sclerosis due to loss of tissue and the appearance of inflammation. DESIGN AND PATIENTS: The results from T2/fluid-attenuated inversion recovery axial images from 13 consecutive monthly 3-T brain magnetic resonance imaging tests conducted on 74 patients diagnosed with relapsing multiple sclerosis in the BECOME study were used to calculate whole brain volumes using automated software analysis tools. The patients had been randomized to receive treatment with interferon beta-1b or glatiramer acetate. Ongoing inflammation was studied by counting the number of combined active lesions and measuring the volume of gadolinium enhancement. A mixed-effects model was used to analyze brain volumes over time. RESULTS: There was a significant decrease in brain volume over time but there was no difference in its rate of change by age, sex, frequency of ongoing inflammation, multiple sclerosis type, or randomized treatment assignment. The mean rate of brain volume change per month from multivariable models was -1.1 cm(3) (95% CI, -1.5 to -0.6) and during times of magnetic resonance imaging activity, it increased transiently by an average of 1.2 cm(3)/lesion (95% CI, 0.7 to 1.7) and 7.1 cm(3)/1 cm(3 )of gadolinium volume. In a model with both measures, combined active lesions were independent predictors of brain volume but gadolinium volume was not. CONCLUSION: Two major changes in brain volume occur in patients with relapsing multiple sclerosis, a steady decrease likely due to tissue loss with overlapping transient increases due to the appearance of inflammation. PMID- 22232348 TI - Large, nonplateauing relationship between clinical disability and cerebral white matter lesion load in patients with multiple sclerosis. AB - OBJECTIVE: To better characterize the relationship between cerebral white matter lesion load (CWM-LL) and clinical disability by (1) covering the entire range of the Kurtzke Expanded Disability Status Scale (EDSS), (2) minimizing nonbiological sources of variability, and (3) increasing pathologic specificity by studying CWM lesions that are hypointense on T1-weighted magnetic resonance imaging. DESIGN: Cross-sectional, retrospective study. SETTING: Hospital-based multiple sclerosis (MS) clinic. Patients A total of 110 patients with untreated MS were recruited and studied from June 1, 1997, through June 30, 2003. MAIN OUTCOME MEASURES: Cube rooted CWM-LL and EDSS-measured clinical disability scores. RESULTS: We found a large, nonplateauing relationship between cube-rooted CWM-LL and concurrent EDSS scores, more so for T1-hypointense than T2-hyperintense lesions (r = 0.619 vs 0.548). Correlations between the EDSS scores and CWM-LL diminished when, as typically done in clinical trials, only those patients with EDSS scores of 0 to 6.0 were studied (n = 92; r = 0.523 for T1-hypointense lesions and r = 0.457 for T2-hyperintense lesions); more important, a series of boot-strapped correlations suggested that this decrease was not simply due to smaller sample size, and these relationships remained even after correcting for disease duration. CONCLUSION: A large, nonplateauing relationship exists between CWM-LL and EDSS-measured clinical disability when patients with MS are studied to examine the entire range of disability, minimize nonbiological sources of variability, and increase pathologic specificity. PMID- 22232350 TI - Association of sequence alterations in the putative promoter of RAB7L1 with a reduced parkinson disease risk. AB - OBJECTIVE: To examine whether PARK16, which was recently identified as a protective locus for Parkinson disease (PD) in Asian, white, and South American populations, is also associated with PD in the genetically homogeneous Ashkenazi Jewish population. DESIGN: Case-control study. SETTING: A medical center affiliated with a university. Subjects Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin. MAIN OUTCOME MEASURES: Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs. RESULTS: All tested SNPs were significantly associated with PD (odds ratios = 0.64-0.76; P = .0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations altered the predicted transcription factor binding sites of CdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P = 5 * 10(-5)). This SNP was included in a haplotype that reduced the risk for PD by 10- to 12-fold (P = .002-.01) in all patients with PD and in a subgroup of patients who do not carry the Ashkenazi founder mutations in the GBA or LRRK2 genes. CONCLUSIONS: Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out. PMID- 22232349 TI - Proteomic changes in cerebrospinal fluid of presymptomatic and affected persons carrying familial Alzheimer disease mutations. AB - OBJECTIVE: To identify cerebrospinal fluid (CSF) protein changes in persons who will develop familial Alzheimer disease (FAD) due to PSEN1 and APP mutations, using unbiased proteomics. DESIGN: We compared proteomic profiles of CSF from individuals with FAD who were mutation carriers (MCs) and related noncarriers (NCs). Abundant proteins were depleted and samples were analyzed using liquid chromatography-electrospray ionization-mass spectrometry on a high-resolution time-of-flight instrument. Tryptic peptides were identified by tandem mass spectrometry. Proteins differing in concentration between the MCs and NCs were identified. SETTING: A tertiary dementia referral center and a proteomic biomarker discovery laboratory. PARTICIPANTS: Fourteen FAD MCs (mean age, 34.2 years; 10 are asymptomatic, 12 have presenilin-1 [PSEN1 ] gene mutations, and 2 have amyloid precursor protein [APP ] gene mutations) and 5 related NCs (mean age, 37.6 years). RESULTS: Fifty-six proteins were identified, represented by multiple tryptic peptides showing significant differences between MCs and NCs (46 upregulated and 10 downregulated); 40 of these proteins differed when the analysis was restricted to asymptomatic individuals. Fourteen proteins have been reported in prior proteomic studies in late-onset AD, including amyloid precursor protein, transferrin, alpha(1)beta-glycoprotein, complement components, afamin precursor, spondin 1, plasminogen, hemopexin, and neuronal pentraxin receptor. Many other proteins were unique to our study, including calsyntenin 3, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 4 glutamate receptor, CD99 antigen, di- N-acetyl-chitobiase, and secreted phosphoprotein 1. CONCLUSIONS: We found much overlap in CSF protein changes between individuals with presymptomatic and symptomatic FAD and those with late-onset AD. Our results are consistent with inflammation and synaptic loss early in FAD and suggest new presymptomatic biomarkers of potential usefulness in drug development. PMID- 22232352 TI - To sleep, perchance to delay dementia. PMID- 22232351 TI - Fulminant postpartum cerebral vasoconstriction syndrome. AB - OBJECTIVE: To raise awareness of the potentially adverse consequences of postpartum cerebral vasoconstriction, which is typically considered benign and self-limiting, by describing 4 fulminantly fatal cases. DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Four postpartum women aged 15 to 33 years developed acute neurologic deficits 1 to 8 days after uncomplicated deliveries. One had a history of migraine headaches and 2 had histories of spontaneous abortion. Two of the patients had uneventful pregnancies and 2 had preeclampsia, 1 of whom had acute hepatic failure. Presenting symptoms included severe headache (n=3), focal deficit (n=1), seizure (n=1), and encephalopathy (n=1). Initial brain imaging results demonstrated cortical ischemia and global edema in 2 patients, lobar hemorrhage in 1, and normal findings in 1. All had rapid clinical deterioration from hours to days with multiterritorial infarctions and global brain edema on imaging. All had angiographic findings of diffuse, severe, segmental multifocal arterial narrowings. INTERVENTIONS: Aggressive treatment was attempted with most patients including intravenous magnesium sulfate, corticosteroids, calcium channel blockers, balloon angioplasty, vasopressors, and osmotic agents. Two patients underwent serial angiography, with results showing severe, recurrent proximal vasoconstriction involving all major intracranial vessels. RESULTS: All patients had fulminant, accelerating courses leading to their deaths within 8 to 24 days after delivery. CONCLUSIONS: Postpartum vasoconstriction can be fatal, with rapid progression of vasoconstriction, ischemia, and brain edema. Clinicians need to be aware of the potential consequences of this condition. Postpartum women with acute neurologic symptoms require prompt investigation with noninvasive cerebrovascular imaging and close monitoring for possible secondary deterioration. PMID- 22232353 TI - Association between paroxysmal tonic spasms and neuromyelitis optica. AB - OBJECTIVE: To determine the frequency of the association between tonic spasms and neuromyelitis optica (NMO) at our center. DESIGN: An institutional review board approved retrospective study of clinical, serological, and radiographic characteristics of patients with NMO. SETTING: Multiple sclerosis center. PATIENTS: Patients with NMO treated at our center between 1990 and 2008. MAIN OUTCOME MEASURE: Records were examined for documentation of tonic spasms. RESULTS: Of 110 patients with International Classification of Diseases code 341, 57 patients met diagnostic criteria for NMO. Of these, 8 patients (14%) had documented typical tonic spasms (median age at onset, 39.5 years; range, 13.8 54.2 years). Of those patients, 4 were African American, 3 were Hispanic, and 1 was white. Only 1 was male. The NMO-IgG antibody was found in 1 of 6 patients tested. Tonic spasms appeared after a mean of 24.6 months (range, 0-91 months). In 2 of 57 patients meeting NMO criteria, tonic spasms accompanied their initial episodes. Seven of 8 patients who had tonic spasms responded to treatment with carbamazepine within 1 week. CONCLUSION: Tonic spasms are associated with NMO more commonly than with multiple sclerosis and may be a presenting sign in both diseases. PMID- 22232354 TI - Novel hypomyelinating leukoencephalopathy affecting early myelinating structures. AB - OBJECTIVE: To describe 4 children with a novel hypomyelinating leukoencephalopathy, defined by a distinct pattern of magnetic resonance imaging (MRI) abnormalities. DESIGN: In our ongoing study on leukoencephalopathies of unknown origin, MRIs of patients are rated in a standardized manner. Patients are grouped according to their MRI abnormalities. The clinical and laboratory data are retrospectively reviewed. SUBJECTS: The MRIs of approximately 3000 patients with a leukoencephalopathy of unknown origin were initially evaluated. Four unrelated patients (all male, aged 1.8-7.4 years) displayed similar MRI alterations. RESULTS: Patients displayed mild T2 hyperintensity of the medulla oblongata, caudal part of the pons, hilus of the dentate nucleus, peridentate white matter, subcortical cerebellar white matter, optic radiation, and frontoparietal periventricular white matter. The posterior limb of the internal capsule showed alternating T2 hyperintense-hypointense-hyperintense stripes in 3 patients. The T1-weighted images showed hyperintensity, isointensity, or mild hypointensity of T2 hyperintense structures. The thalamus had a neonatal appearance with a mildly hyperintense signal except for a darker lateral part. Clinically, patients presented with nystagmus between ages 6 and 20 months. Over time, cerebellar ataxia and mild spasticity developed. All achieved unsupported walking. Cognition and language were normal. Known causes of hypomyelination were excluded. CONCLUSIONS: The patients share a striking pattern of MRI abnormalities and have a similar clinical picture, suggesting that they have the same disorder. The hypomyelination in this disorder specifically occurs in structures that normally myelinate early. We hypothesize that the disease is caused by a defect in a gene involved in early myelination. PMID- 22232355 TI - Severe hypercalcemia following vitamin d supplementation in a patient with multiple sclerosis: a note of caution. AB - OBJECTIVE: To describe a patient with multiple sclerosis (MS) who developed severe hypercalcemia, attributed to the additive effect of 5500 IU of cholecalciferol and 2020 mg of calcium daily. DESIGN: Case report. SETTING: University hospital. PATIENT: A 58-year-old woman with MS and osteoporosis presenting with acute-onset tremors and confusion. MAIN OUTCOME MEASURES: Serum calcium and 25-hydroxyvitamin D levels. RESULTS: The patient's corrected serum calcium level was 15.2 mg/dL (reference range, 8.7-10.1 mg/dL; to convert to millimoles per liter, multiply by 0.25), and her 25-hydroxyvitamin D level was 103 ng/mL (to convert to nanomoles per liter, multiply by 2.496). The results of extensive laboratory tests to rule out hyperparathyroidism, malignant neoplasms, and other causes of hypercalcemia were unrevealing. CONCLUSIONS: It is common practice to prescribe high-dose cholecalciferol to MS patients for its possible role in immunomodulation and relapse-rate reduction. Nevertheless, cholecalciferol may increase serum calcium, and there seems to be an additive effect when patients simultaneously use calcium supplements. This case underscores the need for physicians to be attentive to the possibility of hypercalcemia in patients treated with both high-dose cholecalciferol and calcium. PMID- 22232356 TI - Topiramate effect in opsoclonus-myoclonus-ataxia syndrome. PMID- 22232357 TI - Multiple cranial neuropathies evolving over a decade from occult perineural Basal cell carcinoma. PMID- 22232358 TI - Central nervous system epidermoid cyst rupture. PMID- 22232359 TI - Paradoxical worsening of brain tuberculomas during treatment. PMID- 22232361 TI - Methodological issues with the risk of relapse study in patients with multiple sclerosis after yellow fever vaccination. PMID- 22232360 TI - Varicella-zoster virus expression in the cerebral arteries of diabetic subjects. PMID- 22232362 TI - Daytime polysomnography recording in LIG1 --related limbic encephalitis. PMID- 22232363 TI - Genotyping in primary ciliary dyskinesia: ready for prime time, or a fringe benefit? PMID- 22232364 TI - In vivo evaluation of focal lamina cribrosa defects in glaucoma. AB - OBJECTIVES: To assess focal lamina cribrosa (LC) defects in glaucoma using enhanced depth imaging optical coherence tomography and to investigate their spatial relationships with neuroretinal rim and visual field loss. METHODS: Serial horizontal and vertical enhanced depth imaging optical coherence tomographic images of the optic nerve head were obtained from healthy subjects and those with glaucoma. Focal LC defects defined as anterior laminar surface irregularity (diameter, >100 MUm;depth, >30 MUm) that violates the normal smooth curvilinear contour were investigated regarding their configurations and locations. Spatial consistency was evaluated among focal LC defects, neuroretinal rim thinning/notching, and visual field defects. RESULTS: Forty-six healthy subjects (92 eyes) and 31 subjects with glaucoma (45 eyes) were included. Ninety eight focal LC defects representing various patterns and severity of laminar tissue loss were found in 34 eyes with glaucoma vs none in the healthy eyes. Seven of 11 eyes with glaucoma with no visible focal LC defect had a deeply excavated optic disc with poor LC visibility. Eleven focal LC defects presented clinically as an acquired pit of the optic nerve, and the others as neuroretinal rim thinning/notching. Focal LC defects preferably occurred in the inferior/inferotemporal far periphery of the LC including its insertion. Eyes with focal LC defects limited to the inferior half of the optic disc had greater sensitivity loss in the superior visual hemifield and vice versa. CONCLUSIONS: Mechanisms of LC deformation in glaucoma include focal loss of laminar beams, which may cause an acquired pit of the optic nerve in extreme cases.Focal LC defects occur in tandem with neuroretinal rim and visual field loss. PMID- 22232365 TI - A prospective pilot study of treatment outcomes for amblyopia associated with myopic anisometropia. AB - OBJECTIVES: To determine the efficacy of refractive correction alone and patching treatment with near activities on amblyopia associated with myopic anisometropia in children aged 4 to less than 14 years. The associations of visual acuity (VA) improvement with age,degree of anisometropia, patching compliance, presence of strabismus, and presence of eccentric fixation were also investigated. METHODS: Seventeen amblyopic children were recruited(range of VA in the amblyopic eye, 20/80 to 20/400). Visual acuity was assessed at 4, 8, 12, and 16 weeks while participants wore spectacles and/or contact lenses for full refractive correction. Patching treatment was initiate dat the 16-week visit. The primary outcome was VA after 16 weeks of refractive correction alone and final VA after 16 weeks of patching. RESULTS: The mean (SD) baseline VA in the amblyopiceye was 0.96 (0.27) logMAR, which improved to a mean(SD) of 0.84 (0.24) logMAR with refractive correction and to a mean (SD) of 0.71 (0.30) logMAR after the addition of patching (P.001). Comparing the final VA with the baseline VA, we found that VA improvement averaged 2.59 lines. The final VA in the amblyopic eye was associated with the baseline VA in the amblyopic eye(P.001), the magnitude of anisometropia (P.001),and the level of patching compliance (P=.04). The improvement in VA with patching was inversely associated with participants' age (P=.03) and presence of eccentric fixation (P=.02). CONCLUSION: Both refractive correction and patching significantly improved the VA of the amblyopic eye associated with myopic anisometropia, with 88% of participants' eyes improving 2 lines or more. Further improvement in VA was observed when patching plus near activities was added to refractive correction and patients were followed for 16 more weeks. We recommend that clinicians treat myopic anisometropic amblyopia with refractive correction and patching plus near activities. PMID- 22232366 TI - Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity. AB - OBJECTIVE: To investigate whether the severity of cystoid macular edema (CME) in neonates who were 31 to 36 weeks' postmenstrual age, as viewed by spectral-domain optical coherence tomography (SD-OCT)imaging, predicts the severity of retinopathy of prematurity(ROP) or is related to systemic health. DESIGN: Of 62 prematurely born neonates in a prospective institutional review board-approved study, 42 met the following inclusion criteria: at least 1 SD-OCT imaging session prior to 37 weeks' postmenstrual age and prior to ROP laser treatment, if a laser treatment was performed,and an ophthalmic ROP examination at or after 41 weeks' postmenstrual age, evidence of complete retinal vascularization in zone III, or documentation through telephone report of such information after transfer of care.Measures of CME severity, including central foveal thickness,retinal layer thicknesses, and foveal-to-parafoveal thickness ratio in 1 eye per subject, were compared with ROP outcomes: laser treatment, maximum plus disease,and maximum ROP stage. Systemic health factors were also correlated. RESULTS: Cystoid macular edema was present in 50% of neonates. Multiple elongated cystoid structures within the inner nuclear layer were most common. The presence of CME was not associated with ROP outcomes. The central foveal thickness, the thickness of the inner retinal layers, and the foveal-to-parafoveal thickness ratio were higher in eyes that required laser treatment or that developed plus disease or ROP stage 3. Cystoid macular edema was not clearly associated with systemic factors. CONCLUSIONS: Cystoid macular edema is common in premature infants screened for ROP before 37 weeks' postmenstrual age, with the most common SD-OCT phenotype ofa bulging fovea from multiple elongated cystoid spaces. Detection of CME is not associated with ROP severity; however,tomographic thickness measurements could potentially predict a higher risk of requiring laser treatment or developing plus disease or ROP stage 3. Systemic health factors are probably not related to the development of CME. PMID- 22232367 TI - The cost-effectiveness of Welcome to Medicare visual acuity screening and a possible alternative welcome to medicare eye evaluation among persons without diagnosed diabetes mellitus. AB - OBJECTIVE: To estimate the cost-effectiveness of visual acuity screening performed in primary care settings and of dilated eye evaluations performed by an eye care professional among new Medicare enrollees with no diagnosed eye disorders. Medicare currently reimburses visual acuity screening for new enrollees during their initial preventive primary care health check, but dilated eye evaluations may be a more cost-effective policy. DESIGN: Monte Carlo cost effectiveness simulation model with a total of 50 000 simulated patients with demographic characteristics matched to persons 65 years of age in the US population. RESULTS: Compared with no screening policy, dilated eye evaluations increased quality-adjusted life-years(QALYs) by 0.008 (95% credible interval [CrI], 0.005-0.011) and increased costs by $94 (95% CrI, -$35 to$222). A visual acuity screening increased QALYs in less than 95% of the simulations (0.001 [95% CrI, -0.002 to 0.004) and increased total costs by $32 (95% CrI, -$97 to $159) per person. The incremental cost-effectiveness ratio of a visual acuity screening and an eye examination compared with no screening were $29 000 and$12 000 per QALY gained, respectively. At a willingness-to-pay value of $15 000 or more per QALY gained, a dilated eye evaluation was the policy option most likely to be cost-effective. CONCLUSIONS: The currently recommended visual acuity screening showed limited efficacy and cost-effectiveness compared with no screening. In contrast, anew policy of reimbursement for Welcome to Medicare dilated eye evaluations was highly cost-effective. PMID- 22232368 TI - Lack of thrombospondin 1 and exacerbation of choroidal neovascularization. AB - OBJECTIVES: To assess the impact of thrombospondin 1(TSP1) deficiency on choroidal neovascularization (CNV)and to determine whether administration of a TSP1 antiangiogenic mimetic peptide attenuates CNV. METHODS: The impact of TSP1 deficiency on laser induced CNV was assessed using wild-type (TSP1 +/+) and TSP1 deficient (TSP1 -/-) mice. Three laser burns were placed in each eye of TSP1 +/+ and TSP1 -/- mice to induce CNV. Intravitreal injection of the TSP1 mimetic peptide was performed on days 1 and 7 postlaser in the mice.For quantitative measurements of neovascularization, intercellular adhesion molecule 2 staining was performed at 14 days postlaser of the choroidal-sclera flat mounts. The recruitment of macrophages to the sites of damage was investigated by immunohistochemistry. The CNV area was measured by intercellular adhesion molecule 2 staining and use of ImageJ software. RESULTS: The TSP1 -/- mice exhibited significantly larger areas of neovascularization on choroidal flat mounts compared with TSP1 +/ mice. This was consistent with enhanced recruitment of macrophages in TSP1 -/- mice compared with TSP1 +/+ mice 3 days postlaser. The development of CNV was significantly attenuated in mice receiving the TSP1 antiangiogenic mimetic peptide compared with those receiving vehicle alone. CONCLUSIONS: Deficiency of TSP1 contributes to enhanced choroidal neovascularization. This is consistent with the anti-inflammatory and antiangiogenic activity of TSP1. The TSP1 antiangiogenic peptide was effective in attenuation of CNV. CLINICAL RELEVANCE: Intravitreal injection of TSP1 antiangiogenic mimetic peptides may provide alternative treatment for CNV. PMID- 22232370 TI - Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. AB - Stenotrophomonas maltophilia is an emerging multidrug-resistant global opportunistic pathogen. The increasing incidence of nosocomial and community acquired S. maltophilia infections is of particular concern for immunocompromised individuals, as this bacterial pathogen is associated with a significant fatality/case ratio. S. maltophilia is an environmental bacterium found in aqueous habitats, including plant rhizospheres, animals, foods, and water sources. Infections of S. maltophilia can occur in a range of organs and tissues; the organism is commonly found in respiratory tract infections. This review summarizes the current literature and presents S. maltophilia as an organism with various molecular mechanisms used for colonization and infection. S. maltophilia can be recovered from polymicrobial infections, most notably from the respiratory tract of cystic fibrosis patients, as a cocolonizer with Pseudomonas aeruginosa. Recent evidence of cell-cell communication between these pathogens has implications for the development of novel pharmacological therapies. Animal models of S. maltophilia infection have provided useful information about the type of host immune response induced by this opportunistic pathogen. Current and emerging treatments for patients infected with S. maltophilia are discussed. PMID- 22232372 TI - Myiasis. AB - Myiasis is defined as the infestation of live vertebrates (humans and/or animals) with dipterous larvae. In mammals (including humans), dipterous larvae can feed on the host's living or dead tissue, liquid body substance, or ingested food and cause a broad range of infestations depending on the body location and the relationship of the larvae with the host. In this review, we deeply discuss myiasis as a worldwide infestation with different agents and with its broad scenario of clinical manifestations as well as diagnosis techniques and treatment. PMID- 22232371 TI - Intruders below the radar: molecular pathogenesis of Bartonella spp. AB - Bartonella spp. are facultative intracellular pathogens that employ a unique stealth infection strategy comprising immune evasion and modulation, intimate interaction with nucleated cells, and intraerythrocytic persistence. Infections with Bartonella are ubiquitous among mammals, and many species can infect humans either as their natural host or incidentally as zoonotic pathogens. Upon inoculation into a naive host, the bartonellae first colonize a primary niche that is widely accepted to involve the manipulation of nucleated host cells, e.g., in the microvasculature. Consistently, in vitro research showed that Bartonella harbors an ample arsenal of virulence factors to modulate the response of such cells, gain entrance, and establish an intracellular niche. Subsequently, the bacteria are seeded into the bloodstream where they invade erythrocytes and give rise to a typically asymptomatic intraerythrocytic bacteremia. While this course of infection is characteristic for natural hosts, zoonotic infections or the infection of immunocompromised patients may alter the path of Bartonella and result in considerable morbidity. In this review we compile current knowledge on the molecular processes underlying both the infection strategy and pathogenesis of Bartonella and discuss their connection to the clinical presentation of human patients, which ranges from minor complaints to life-threatening disease. PMID- 22232373 TI - The Malassezia genus in skin and systemic diseases. AB - In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur, M. pachydermatis, M. sympodialis, M. globosa, M. obtusa, M. restricta, and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae, M. equina, and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia-synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation induced carcinogenesis. PMID- 22232377 TI - Clinical efficacy and safety of once-weekly glucagon-like peptide-1 agonists in development for treatment of type 2 diabetes mellitus in adults. AB - OBJECTIVE: To review pharmacologic, pharmacokinetic, efficacy, and safety data of once-weekly glucagon-like peptide-1 (GLP-1) agonists exenatide long-acting release (LAR), albiglutide, and taspoglutide in treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: A MEDLINE search (1966-August 2011) was conducted using the following key words: type 2 diabetes mellitus, glucagon-like peptide-1 agonists once weekly, glucagon-like peptide-1 agonists, exenatide LAR, albiglutide, and taspoglutide. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated, prioritizing randomized controlled trials with human data. The references of published articles identified were examined for additional studies appropriate for the review. DATA SYNTHESIS: Native GLP-1 increases glucose-dependent insulin secretion, decreases glucagon secretion, and slows gastric emptying in healthy individuals, but these effects may be blunted in patients with T2DM. Because native GLP-1 is rapidly degraded by dipeptidyl peptidase-IV, it is not a practical treatment option. Currently, 2 GLP-1 receptor agonists have been approved by the Food and Drug Administration: exenatide twice daily and liraglutide once daily. Several additional GLP-1 agonists, including exenatide LAR, albiglutide, and taspoglutide, are in various stages of clinical trials and have been modified to increase their half-lives. These agents have shown significant improvements in hemoglobin A(1c), fasting plasma glucose, and postprandial plasma glucose, as well as improvements in body weight, blood pressure, and lipid parameters. These agents allow for less-frequent dosing schedules, improved glycemic control throughout the day, and improved treatment satisfaction compared to some available agents. GLP-1 agonists have been well tolerated, with the most common adverse effects being gastrointestinal related, which occurred early in therapy but typically resolved after 4-8 weeks. The incidence of hypoglycemia was infrequent and mild during therapy. CONCLUSIONS: Once-weekly GLP-1 agonists provide similar glycemic control with weight reduction, as well as overall higher treatment satisfaction for patients because of their ease of use and need for less-frequent dosing compared to some available agents. PMID- 22232375 TI - Bed bugs: clinical relevance and control options. AB - Since the late 1990s, bed bugs of the species Cimex lectularius and Cimex hemipterus have undergone a worldwide resurgence. These bed bugs are blood sucking insects that readily bite humans. Cutaneous reactions may occur and can start out as small macular lesions that can develop into distinctive wheals of around 5 cm in diameter, which are accompanied by intense itching. Occasionally, bullous eruptions may result. If bed bugs are numerous, the patient can present with widespread urticaria or eythematous rashes. Often, bites occur in lines along the limbs. Over 40 pathogens have been detected in bed bugs, but there is no definitive evidence that they transmit any disease-causing organisms to humans. Anemia may result when bed bugs are numerous, and their allergens can trigger asthmatic reactions. The misuse of chemicals and other technologies for controlling bed bugs has the potential to have a deleterious impact on human health, while the insect itself can be the cause of significant psychological trauma. The control of bed bugs is challenging and should encompass a multidisciplinary approach utilizing nonchemical means of control and the judicious use of insecticides. For accommodation providers, risk management procedures should be implemented to reduce the potential of bed bug infestations. PMID- 22232374 TI - Molecular mechanisms underlying occult hepatitis B virus infection. AB - Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section. PMID- 22232379 TI - eComment. Vacuum-assisted closure therapy in cardiac surgery. PMID- 22232380 TI - eComment. Surgical management of coronary-to-pulmonary artery fistulas. PMID- 22232381 TI - eComment. Extra-anatomic aortic valve bypass. PMID- 22232376 TI - Polymicrobial interactions: impact on pathogenesis and human disease. AB - Microorganisms coexist in a complex milieu of bacteria, fungi, archaea, and viruses on or within the human body, often as multifaceted polymicrobial biofilm communities at mucosal sites and on abiotic surfaces. Only recently have we begun to appreciate the complicated biofilm phenotype during infection; moreover, even less is known about the interactions that occur between microorganisms during polymicrobial growth and their implications in human disease. Therefore, this review focuses on polymicrobial biofilm-mediated infections and examines the contribution of bacterial-bacterial, bacterial-fungal, and bacterial-viral interactions during human infection and potential strategies for protection against such diseases. PMID- 22232382 TI - eComment. The origin of the right vertebral artery? PMID- 22232383 TI - Regulatory functions of SnRK1 in stress-responsive gene expression and in plant growth and development. AB - Sucrose-nonfermentation1-related protein kinase1 (SnRK1) is an evolutionarily conserved energy sensor protein that regulates gene expression in response to energy depletion in plants. Efforts to elucidate the functions and mechanisms of this protein kinase are hampered, however, by inherent growth defects of snrk1 null mutant plants. To overcome these limitations and study SnRK1 functions in vivo, we applied a method combining transient expression in leaf mesophyll protoplasts and stable expression in transgenic plants. We found that both rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) SnRK1 activities critically influence stress-inducible gene expression and the induction of stress tolerance. Genetic, molecular, and chromatin immunoprecipitation analyses further revealed that the nuclear SnRK1 modulated target gene transcription in a submergence dependent manner. From early seedling development through late senescence, SnRK1 activities appeared to modulate developmental processes in the plants. Our findings offer insight into the regulatory functions of plant SnRK1 in stress responsive gene regulation and in plant growth and development throughout the life cycle. PMID- 22232384 TI - The Arabidopsis tetratricopeptide thioredoxin-like gene family is required for osmotic stress tolerance and male sporogenesis. AB - TETRATRICOPEPTIDE THIOREDOXIN-LIKE (TTL) proteins are characterized by the presence of six tetratricopeptide repeats in conserved positions and a carboxyl terminal region known as the thioredoxin-like domain with homology to thioredoxins. In Arabidopsis (Arabidopsis thaliana), the TTL gene family is composed by four members, and the founder member, TTL1, is required for osmotic stress tolerance. Analysis of sequenced genomes indicates that TTL genes are specific to land plants. In this study, we report the expression profiles of Arabidopsis TTL genes using data mining and promoter-reporter beta-glucuronidase fusions. Our results show that TTL1, TTL3, and TTL4 display ubiquitous expression in normal growing conditions but differential expression patterns in response to osmotic and NaCl stresses. TTL2 shows a very different expression pattern, being specific to pollen grains. Consistent with the expression data, ttl1, ttl3, and ttl4 mutants show reduced root growth under osmotic stress, and the analysis of double and triple mutants indicates that TTL1, TTL3, and TTL4 have partially overlapping yet specific functions in abiotic stress tolerance while TTL2 is involved in male gametophytic transmission. PMID- 22232385 TI - Wuschel-related homeobox5 gene expression and interaction of CLE peptides with components of the systemic control add two pieces to the puzzle of autoregulation of nodulation. AB - In legumes, the symbiotic nodules are formed as a result of dedifferentiation and reactivation of cortical root cells. A shoot-acting receptor complex, similar to the Arabidopsis (Arabidopsis thaliana) CLAVATA1 (CLV1)/CLV2 receptor, regulating development of the shoot apical meristem, is involved in autoregulation of nodulation (AON), a mechanism that systemically controls nodule number. The targets of CLV1/CLV2 in the shoot apical meristem, the WUSCHEL (WUS)-RELATED HOMEOBOX (WOX) family transcription factors, have been proposed to be important regulators of apical meristem maintenance and to be expressed in apical meristem "organizers." Here, we focus on the role of the WOX5 transcription factor upon nodulation in Medicago truncatula and pea (Pisum sativum) that form indeterminate nodules. Analysis of temporal WOX5 expression during nodulation with quantitative reverse transcription-polymerase chain reaction and promoter-reporter fusion revealed that the WOX5 gene was expressed during nodule organogenesis, suggesting that WOX genes are common regulators of cell proliferation in different systems. Furthermore, in nodules of supernodulating mutants, defective in AON, WOX5 expression was higher than that in wild-type nodules. Hence, a conserved WUS/WOX CLV regulatory system might control cell proliferation and differentiation not only in the root and shoot apical meristems but also in nodule meristems. In addition, the link between nodule-derived CLE peptides activating AON in different legumes and components of the AON system was investigated. We demonstrate that the identified AON component, NODULATION3 of pea, might act downstream from or beside the CLE peptides during AON. PMID- 22232386 TI - Effects of sampling context on spontaneous expressive language in males with fragile X syndrome or Down syndrome. AB - PURPOSE: In this study, the authors examined the impact of sampling context on multiple aspects of expressive language in male participants with fragile X syndrome in comparison to male participants with Down syndrome or typical development. METHOD: Participants with fragile X syndrome ( n = 27), ages 10-17 years, were matched groupwise on nonverbal mental age to adolescents with Down syndrome ( n = 15) and typically developing 3- to 6-year-olds ( n = 15). Language sampling contexts were an interview-style conversation and narration of a wordless book, with scripted examiner behavior. Language was assessed in terms of amount of talk, mean length of communication unit (MLCU), lexical diversity, fluency, and intelligibility. RESULTS: Participants with fragile X syndrome had lower MLCU and lexical diversity than did participants with typical development. Participants with Down syndrome produced yet lower MLCU. A differential effect of context among those with fragile X syndrome, Down syndrome, and typical development emerged for the number of attempts per minute, MLCU, and fluency. For participants with fragile X syndrome, autism symptom severity related to the number of utterances produced in conversation. Aspects of examiner behavior related to participant performance. CONCLUSION: Sampling context characteristics should be considered when assessing expressive language in individuals with neurodevelopmental disabilities. PMID- 22232387 TI - Contribution of family environment to pediatric cochlear implant users' speech and language outcomes: some preliminary findings. AB - PURPOSE: To evaluate the family environments of children with cochlear implants and to examine relationships between family environment and postimplant language development and executive function. METHOD: Forty-five families of children with cochlear implants completed a self-report family environment questionnaire (Family Environment Scale--Fourth Edition; Moos & Moos, 2009) and an inventory of executive function (Behavior Rating Inventory of Executive Function [Gioia, Isquith, Guy, & Kenworthy, 2000] or Behavior Rating Inventory of Executive Function--Preschool Version [Gioia, Espy, & Isquith, 2003]). The authors also evaluated children's receptive vocabulary (Peabody Picture Vocabulary Test- Fourth Edition; Dunn & Dunn, 2007) and global language skills (Preschool Language Scale--Fourth Edition [Zimmerman, Steiner, & Pond, 2002] and Clinical Evaluation of Language Fundamentals--Fourth Edition [Semel, Wiig, & Secord, 2003]). RESULTS: The family environments of children with cochlear implants differed from those of normal-hearing children but not in clinically significant ways. Language development and executive function were found to be atypical but not uncharacteristic of this clinical population. Families with higher levels of self reported control had children with smaller vocabularies. Families reporting a higher emphasis on achievement had children with fewer executive function and working memory problems. Finally, families reporting a higher emphasis on organization had children with fewer problems related to inhibition. CONCLUSION: Some of the variability in cochlear implantation outcomes that have protracted periods of development is related to family environment. Because family environment can be modified and enhanced by therapy or education, these preliminary findings hold promise for future work in helping families to create robust language-learning environments that can maximize their child's potential with a cochlear implant. PMID- 22232389 TI - Sequence and system in the acquisition of tense and agreement. AB - PURPOSE: The relatedness of tense morphemes in the language of children younger than 3 years of age is a matter of controversy. Generativist accounts predict that the morphemes will be related, whereas usage-based accounts predict the absence of relationships. This study focused on the increasing productivity of the 5 morphemes in the tense productivity score (copula BE, third-person singular present - 3s, past - ed, auxiliary DO, auxiliary BE; Hadley & Short, 2005) and their relationship to one another. METHOD: Twenty typically developing children were observed longitudinally from 21 to 33 months of age. One hour of naturalistic caregiver-child interaction sampled every 3 months was analyzed. RESULTS: Copula BE was more productive than all other morphemes from age 27 months onward. Auxiliary BE was significantly less productive than - 3s, - ed, and DO from age 27 months onward. Evaluation of third-person singular tense morphemes at age 33 months revealed that the productivity scores of copula is, 3s, and does were all correlated. CONCLUSIONS: There is sequence and simultaneity in development that no prior framework has fully explained, as well as evidence of cross-morpheme relationships. In this article, the authors interpret these findings as support for the gradual morphosyntactic learning hypothesis ( Rispoli & Hadley, 2011; Rispoli, Hadley, & Holt, 2009). PMID- 22232388 TI - Use of telehealth for research and clinical measures in cochlear implant recipients: a validation study. AB - PURPOSE: The goal of this study was to compare clinical and research-based cochlear implant (CI) measures using telehealth versus traditional methods. METHOD: This prospective study used an ABA design (A = laboratory, B = remote site). All measures were made twice per visit for the purpose of assessing within session variability. Twenty-nine adult and pediatric CI recipients participated. Measures included electrode impedance, electrically evoked compound action potential thresholds, psychophysical thresholds using an adaptive procedure, map thresholds and upper comfort levels, and speech perception. Subjects completed a questionnaire at the end of the study. RESULTS: Results for all electrode specific measures revealed no statistically significant differences between traditional and remote conditions. Speech perception was significantly poorer in the remote condition, which was likely due to the lack of a sound booth. In general, subjects indicated that they would take advantage of telehealth options at least some of the time, if such options were available. CONCLUSIONS: Results from this study demonstrate that telehealth is a viable option for research and clinical measures. Additional studies are needed to investigate ways to improve speech perception at remote locations that lack sound booths and to validate the use of telehealth for pediatric services (e.g., play audiometry), sound-field threshold testing, and troubleshooting equipment. PMID- 22232390 TI - Application of classification models to pharyngeal high-resolution manometry. AB - PURPOSE: The authors present 3 methods of performing pattern recognition on spatiotemporal plots produced by pharyngeal high-resolution manometry (HRM). METHOD: Classification models, including the artificial neural networks (ANNs) multilayer perceptron (MLP) and learning vector quantization (LVQ), as well as support vector machines (SVM), were evaluated for their ability to identify disordered swallowing. Data were collected from 12 control subjects and 13 subjects with swallowing disorders; for this experiment, these subjects swallowed 5-ml water boluses. Following extraction of relevant parameters, a subset of the data was used to train the models, and the remaining swallows were then independently classified by the networks. RESULTS: All methods produced high average classification accuracies, with MLP, SVM, and LVQ achieving accuracies of 96.44%, 91.03%, and 85.39%, respectively. When evaluating the individual contributions of each parameter and groups of parameters to the classification accuracy, parameters pertaining to the upper esophageal sphincter were most valuable. CONCLUSION: Classification models show high accuracy in segregating HRM data sets and represent 1 method of facilitating application of HRM to the clinical setting by eliminating the time required for some aspects of data extraction and interpretation. PMID- 22232391 TI - Shared-reading dynamics: mothers' question use and the verbal participation of children with specific language impairment. AB - PURPOSE: In this study, the authors used sequential analysis to explore bidirectional and dynamic dependencies between mothers' question use and children's verbal participation during shared reading. METHOD: The sample was composed of mothers and their preschool-age children with specific language impairment (SLI; n = 14). Each mother and child extratextual utterance was transcribed and coded. Mother utterances were coded as "questions" or "other"; in turn, questions were coded for cognitive challenge and topic directiveness. Child utterances were coded as "verbal participation" (related to the book) or "other"; utterances designated as verbal participation were also coded for level of production (minimal, low, high) on the basis of their mean length of utterance. RESULTS: Descriptive data show variability in mothers' question use and some variability in the level of children's verbal participation during shared reading. However, mothers' question use did not facilitate higher levels of verbal participation by children. Furthermore, the level of children's verbal participation did not influence the cognitive challenge and topic directiveness of mothers' question use. CONCLUSIONS: The findings were contrary to hypotheses and collectively suggest potentially unique and challenging verbal dynamics between mothers and their young children with SLI during shared-reading experiences. Future directions for research are discussed. PMID- 22232392 TI - The efficiency of attentional networks in children who stutter. AB - PURPOSE: The purpose of this study was to evaluate whether previously reported questionnaire-based differences in self-regulatory behaviors (Eggers, De Nil, & Van den Bergh, 2009, 2010) between children who stutter (CWS) and children who do not stutter (CWNS) would also be reflected in their underlying attentional networks. METHOD: Participants consisted of 41 CWS (mean age = 6;09; years;months) and 41 CWNS (mean age = 6;09) ranging in age from 4;00 to 9;00. Participants were matched on age and gender. The efficiency of the attentional networks was assessed by using the computerized Attention Network Test (Fan, McCandliss, Sommer, Raz, & Posner, 2002). RESULTS: Primary results indicated that CWS had a significantly lower efficiency of the orienting network compared with CWNS, whereas no differences were found on the alerting or executive control network. CONCLUSION: Current findings corroborate previously found differences in self-regulatory behavior and were taken to suggest a possible role for attentional processes in developmental stuttering. PMID- 22232393 TI - An examination of the associations among multiple memory systems, past tense, and vocabulary in typically developing 5-year-old children. AB - PURPOSE: Considerable research has investigated the role of verbal working memory in language development in children with and without language problems. Much less is currently known about the relationship between language and the declarative and procedural memory systems. This study examined whether these 2 memory systems were related to typically developing children's past tense and lexical knowledge. METHOD: Fifty-eight typically developing children approximately 5 years of age completed a battery of linguistic and nonlinguistic tasks, including tests of vocabulary, past tense production, and procedural and declarative memory. RESULTS: The results showed that declarative and procedural memory were not correlated with either regular or irregular past tense use. A significant correlation was observed between declarative memory and vocabulary. CONCLUSIONS: The results of the study were not consistent with the view that the declarative and procedural memory systems support children's use of the regular and irregular past tense. However, evidence was found suggesting that declarative memory supports vocabulary in this age group. PMID- 22232394 TI - Asymmetries in the processing of vowel height. AB - PURPOSE: Speech perception can be described as the transformation of continuous acoustic information into discrete memory representations. Therefore, research on neural representations of speech sounds is particularly important for a better understanding of this transformation. Speech perception models make specific assumptions regarding the representation of mid vowels (e.g., [epsilon]) that are articulated with a neutral position in regard to height. One hypothesis is that their representation is less specific than the representation of vowels with a more specific position (e.g., [ae]). METHOD: In a magnetoencephalography study, we tested the underspecification of mid vowel in American English. Using a mismatch negativity (MMN) paradigm, mid and low lax vowels ([epsilon]/[ae]), and high and low lax vowels ([i]/[ae]), were opposed, and M100/N1 dipole source parameters as well as MMN latency and amplitude were examined. RESULTS: Larger MMNs occurred when the mid vowel [epsilon] was a deviant to the standard [ae], a result consistent with less specific representations for mid vowels. MMNs of equal magnitude were elicited in the high-low comparison, consistent with more specific representations for both high and low vowels. M100 dipole locations support early vowel categorization on the basis of linguistically relevant acoustic-phonetic features. CONCLUSION: We take our results to reflect an abstract long-term representation of vowels that do not include redundant specifications at very early stages of processing the speech signal. Moreover, the dipole locations indicate extraction of distinctive features and their mapping onto representationally faithful cortical locations (i.e., a feature map). PMID- 22232397 TI - Vocal function in introverts and extraverts during a psychological stress reactivity protocol. AB - PURPOSE: To examine the proposal that introversion predictably influences extralaryngeal and vocal behavior in vocally healthy individuals compared with individuals with extraversion and whether differences are of a nature that may support a risk hypothesis for primary muscle tension dysphonia. METHOD: Fifty four vocally healthy female adults between the ages of 18 and 35 years were divided into 2 groups: introversion (n = 27) and extraversion (n = 27). All participants completed a psychological stress reactivity experiment. Before, during, and after the stressor (public speaking), participants were assessed on extralaryngeal muscle activity (surface electromyography: submental, infrahyoid; control site: tibialis anterior), perceived vocal effort, and vocal acoustics (fundamental frequency and intensity). RESULTS: Participants in the introversion group exhibited significantly greater infrahyoid muscle activity throughout the protocol and during perceived stress than participants in the extraversion group. For both groups, perceived vocal effort significantly increased during stress, and acoustic measures significantly decreased. Infrahyoid muscle activity during the stress phase was significantly correlated with introversion and Voice Handicap Index scores but not with vocal effort scores. CONCLUSIONS: The data provided evidence of distinct differences in extralaryngeal behavior between introverts and extraverts. The findings are consistent with the trait theory of voice disorders (Roy & Bless, 2000). PMID- 22232395 TI - The effect of tongue exercise on serotonergic input to the hypoglossal nucleus in young and old rats. AB - PURPOSE: Breathing and swallowing problems affect elderly people and may be related to age-associated tongue dysfunction. Hypoglossal motoneurons that innervate the tongue receive a robust, excitatory serotonergic (5HT) input and may be affected by aging. We used a rat model of aging and progressive resistance tongue exercise to determine whether age-related alterations in 5HT inputs to the hypoglossal nucleus can be modified. We hypothesized that tongue forces would increase with exercise, 5HT input to the tongue would decrease with age, and tongue exercise would augment 5HT input to the hypoglossal nucleus. METHOD: Young (9-10 months), middle-aged (24-25 months), and old (32-33 months) male F344/BN rats received tongue exercise for 8 weeks. Immunoreactivity for 5HT was measured in digital images of sections through the hypoglossal nucleus using ImageJ software. RESULTS: Tongue exercise resulted in increased maximum tongue forces at all ages. There was a statistically significant increase in 5HT immunoreactivity in the hypoglossal nucleus in exercised, young rats but only in the caudal third of the nucleus and primarily in the ventral half. CONCLUSION: Specificity found in serotonergic input following exercise may reflect the topographic organization of motoneurons in the hypoglossal nucleus and the tongue muscles engaged in the exercise paradigm. PMID- 22232396 TI - Perceptual measures of speech from individuals with Parkinson's disease and multiple sclerosis: intelligibility and beyond. AB - PURPOSE: The primary purpose of this study was to compare percent correct word and sentence intelligibility scores for individuals with multiple sclerosis (MS) and Parkinson's disease (PD) with scaled estimates of speech severity obtained for a reading passage. METHOD: Speech samples for 78 talkers were judged, including 30 speakers with MS, 16 speakers with PD, and 32 healthy control speakers. Fifty-two naive listeners performed forced-choice word identification, sentence transcription, or visual analog scaling of speech severity for the Grandfather Passage (Duffy, 2005). Three expert listeners also scaled speech severity for the Grandfather Passage. RESULTS: Percent correct word and sentence intelligibility scores did not cleanly differentiate speakers with MS, PD, or control speakers. In contrast, both naive and expert listener groups judged reading passages produced by speakers with MS and PD to be more severely impaired than reading passages produced by control talkers. CONCLUSION: Scaled estimates of speech severity appear to be sensitive to aspects of speech impairment in MS and PD not captured by word or sentence intelligibility scores. One implication is that scaled estimates of speech severity might prove useful for documenting speech changes related to disease progression or even treatment for individuals with MS and PD with minimal reduction in intelligibility. PMID- 22232398 TI - The impact of sound-field systems on learning and attention in elementary school classrooms. AB - PURPOSE: The authors evaluated the installation and use of sound-field systems to investigate the impact of these systems on teaching and learning in elementary school classrooms. Methods The evaluation included acoustic surveys of classrooms, questionnaire surveys of students and teachers, and experimental testing of students with and without the use of sound-field systems. In this article, the authors report students' perceptions of classroom environments and objective data evaluating change in performance on cognitive and academic assessments with amplification over a 6-month period. RESULTS: Teachers were positive about the use of sound-field systems in improving children's listening and attention to verbal instructions. Over time, students in amplified classrooms did not differ from those in nonamplified classrooms in their reports of listening conditions, nor did their performance differ in measures of numeracy, reading, or spelling. Use of sound-field systems in the classrooms resulted in significantly larger gains in performance in the number of correct items on the nonverbal measure of speed of processing and the measure of listening comprehension. Analysis controlling for classroom acoustics indicated that students' listening comprehension scores improved significantly in amplified classrooms with poorer acoustics but not in amplified classrooms with better acoustics. CONCLUSIONS: Both teacher ratings and student performance on standardized tests indicated that sound-field systems improved performance on children's understanding of spoken language. However, academic attainments showed no benefits from the use of sound-field systems. Classroom acoustics were a significant factor influencing the efficacy of sound-field systems; children in classes with poorer acoustics benefited in listening comprehension, whereas there was no additional benefit for children in classrooms with better acoustics. PMID- 22232399 TI - Psychometric evaluation of children with auditory processing disorder (APD): comparison with normal-hearing and clinical non-APD groups. AB - PURPOSE: To investigate the clinical utility of the Children's Auditory Processing Performance Scale (CHAPPS; Smoski, Brunt, & Tannahill, 1992) to evaluate listening ability in 12-year-old children referred for auditory processing assessment. METHOD: This was a prospective case control study of 97 children (age range = 11;4 [years;months] to 12;7). Auditory processing disorder (APD) was diagnosed based on findings of deficits on at least 1 nonverbal test and on at least 2 tests of an auditory processing test battery. Clinically referred children were grouped as APD (n = 38) or non-APD (n = 20). RESULTS: The study found that (a) the APD group performed lower than the non-APD group on the Quiet, Ideal, Memory (p < .0001), and Attention (p < .05) subscales of the CHAPPS; (b) the non-APD group performed lower than the group with normal hearing on the Noise, Multiple Inputs, and Attention subscales (p < .0001); and (c) there were significant moderate-to-strong correlations (Spearman's rho > .04) between Dichotic Digits, Duration Pattern tests, and the CHAPPS Attention, Memory, and total scores. CONCLUSION: The CHAPPS may be a clinically useful tool to evaluate listening ability in 12-year-old children suspected of having APD. Restricting use of the CHAPPS to older children may help address its limitations as reported by other studies. PMID- 22232400 TI - Lingual propulsive pressures across consistencies generated by the anteromedian and posteromedian tongue by healthy young adults. AB - PURPOSE: In the present study, the authors investigated lingual propulsive pressures generated in the normal swallow by the anterior and posterior lingual segments for various consistencies and maximum isometric tasks. METHOD: Lingual pressures for saliva, thin, and honey-thick liquid boluses were measured via the Iowa Oral Performance Instrument (IOPI Medical, Carnation, WA) at both anteromedian and posteromedian lingual segments of 62 healthy participants, ages 18-34 years (30 men, 32 women). RESULTS: A repeated-measures analysis of variance revealed that all lingual swallowing pressures were significantly greater at the anteromedian segment than at the posteromedian segment. Gender was not a significant factor; however, women exhibited greater swallowing pressures across all conditions. Lingual pressures increased as bolus viscosity increased. No significant interactions existed. Analysis of a subset of 30 participants revealed that men exhibited greater maximal isometric pressure at the anteromedian segment than women, with no significant gender difference at the posteromedian segment. A significantly higher percentage of maximum isometric tongue pressure was exerted by the posteromedian tongue than by the anteromedian tongue. CONCLUSION: Findings suggest that greater amplitudes of lingual pressures are generated during normal swallowing at the anteromedian lingual segment; however, a greater percentage of maximum isometric tongue pressure was exerted by the posteromedian lingual segment, suggesting increased effort by the posterior tongue during bolus propulsion. PMID- 22232402 TI - Syntactic structural assignment in Brazilian Portuguese-speaking children with specific language impairment. AB - PURPOSE: In this study, the authors examined the comprehension of sentences with predicates and reflexives that are linked to a nonadjacent noun as a test of the hierarchical ordering deficit (HOD) hypothesis. That hypothesis and more modern versions posit that children with specific language impairment (SLI) have difficulty in establishing nonadjacent (hierarchical) relations among elements of a sentence. The authors also tested whether additional working memory demands in constructions containing reflexives affected the extent to which children with SLI incorrectly structure sentences as indicated by their picture-pointing comprehension responses. METHOD: Sixteen Brazilian Portuguese-speaking children (8;4-10;6 [years;months]) with SLI and 16 children with typical language development (TLD) matched for age (+/- 3 months), gender, and socioeconomic status participated in 2 experiments (predicate and reflexive interpretation). In the reflexive experiment, the authors also manipulated working memory demands. Each experiment involved a 4-choice picture selection sentence comprehension task. RESULTS: Children with SLI were significantly less accurate on all conditions. Both groups made more hierarchical syntactic construction errors in the long working memory condition than in the short working memory condition. CONCLUSION: The HOD hypothesis was not confirmed. For both groups, syntactic factors (structural assignment) were more vulnerable than lexical factors (prepositions) to working memory effects in sentence miscomprehension. PMID- 22232401 TI - Application of the envelope difference index to spectrally sparse speech. AB - PURPOSE: Amplitude compression is a common hearing aid processing strategy that can improve speech audibility and loudness comfort but also has the potential to alter important cues carried by the speech envelope. In previous work, a measure of envelope change, the Envelope Difference Index (EDI; Fortune, Woodruff, & Preves, 1994), was moderately related to recognition of spectrally robust consonants. This follow-up study investigated the relationship between the EDI and recognition of spectrally sparse consonants. METHOD: Stimuli were vowel consonant-vowel tokens processed to reduce spectral cues. Compression parameters were chosen to achieve a range of EDI values. Recognition was measured for 20 listeners with normal hearing. RESULTS: Both overall recognition and perception of consonant features were reduced at higher EDI values. Similar effects were noted with noise-vocoded and sine-vocoded processing and regardless of whether periodicity cues were available. CONCLUSION: The data provide information about the acceptable limits of envelope distortion under constrained conditions. These limits can be used to consider the impact of envelope distortions in situations where other cues are available to varying extents. PMID- 22232403 TI - Intelligibility of 4-year-old children with and without cerebral palsy. AB - PURPOSE: The authors examined speech intelligibility in typically developing (TD) children and 3 groups of children with cerebral palsy (CP) who were classified into speech/language profile groups following Hustad, Gorton, and Lee (2010). Questions addressed differences in transcription intelligibility scores among groups, the effects of utterance length on intelligibility, the relationship between ordinal ratings of intelligibility and orthographic transcription intelligibility scores, and the difference between parent and naive listener ordinal ratings. METHOD: Speech samples varying in length from 1 to 7 words were elicited from 23 children with CP ( M (age) = 54.3 months) and 20 TD children ( M (age) = 55.1 months). Two hundred fifteen naive listeners made orthographic transcriptions and ordinal ratings of intelligibility. Parent ordinal ratings of intelligibility were obtained from a previous study (Hustad et al., 2010). RESULTS: Intelligibility varied with speech/language profile group and utterance length, with different patterns observed by profile group. Ratings of intelligibility by parents and naive listeners did not differ, and both were highly correlated with transcription intelligibility scores. CONCLUSION: Intelligibility was reduced for all groups of children with CP relative to TD children, suggesting the importance of speech-language intervention and the need for research investigating variables associated with changes in intelligibility in children. PMID- 22232404 TI - Effect of speaker age on speech recognition and perceived listening effort in older adults with hearing loss. AB - PURPOSE: Older adults exhibit difficulty understanding speech that has been experimentally degraded. Age-related changes to the speech mechanism lead to natural degradations in signal quality. We tested the hypothesis that older adults with hearing loss would exhibit declines in speech recognition when listening to the speech of older adults, compared with the speech of younger adults, and would report greater amounts of listening effort in this task. METHOD: Nineteen individuals with age-related hearing loss completed speech recognition and listening effort scaling tasks. Both were conducted in quiet, when listening to high- and low-predictability phrases produced by younger and older speakers, respectively. RESULTS: No significant difference in speech recognition existed when stimuli were derived from younger or older speakers. However, perceived effort was significantly higher when listening to speech from older adults, as compared with younger adults. CONCLUSIONS: For older individuals with hearing loss, natural degradations in signal quality may require greater listening effort. However, they do not interfere with speech recognition-at least in quiet. Follow-up investigation of the effect of speaker age on speech recognition and listening effort under more challenging noise conditions appears warranted. PMID- 22232405 TI - Linking outcomes from peabody picture vocabulary test forms using item response models. AB - PURPOSE: The present work describes how vocabulary ability as assessed by 3 different forms of the Peabody Picture Vocabulary Test (PPVT; Dunn & Dunn, 1997) can be placed on a common latent metric through item response theory (IRT) modeling, by which valid comparisons of ability between samples or over time can then be made. METHOD: Responses from 2,625 cases in a longitudinal study of 697 persons for 459 unique PPVT items (175 items from Peabody Picture Vocabulary Test -Revised [PPVT-R] Form M [Dunn & Dunn, 1981], 201 items from Peabody Picture Vocabulary Test--3 [PPVT-3] Form A [Dunn & Dunn, 1997], and 83 items from PPVT-3 Form B [Dunn & Dunn, 1997]) were analyzed using a 2-parameter logistic IRT model. RESULTS: The test forms each covered approximately +/- 3 SDs of vocabulary ability with high reliability. Some differences between item sets in item difficulty and discrimination were found between the PPVT-3 Forms A and B. CONCLUSIONS: Comparable estimates of vocabulary ability obtained from different test forms can be created through IRT modeling. The authors have also written a freely available SAS program that uses the obtained item parameters to provide IRT ability estimates given item responses to any of the 3 forms. This scoring resource will allow others with existing PPVT data to benefit from this work as well. PMID- 22232406 TI - Longitudinal stability in genetic effects on children's conversational language productivity. AB - PURPOSE: The authors examined the longitudinal stability of genetic and environmental influences on children's productive language sample measures during the early school-age years. METHOD: Twin study methodology with structural equation modeling was used to derive univariate estimates of additive genetic (A), shared environmental (C), and nonshared environmental (E) effects on language measures at each of 2 time points, based on 487 twins at the 1st-grade time point and 387 twins at the 2nd-grade time point. To address questions of stability over time, the authors used longitudinal latent factor analysis. RESULTS: Stability in the Conversational Language factor was accounted for almost entirely by shared genetic effects between 1st and 2nd grade, meaning no new genetic effects were observed at the 2nd time point. In contrast, nonshared environmental effects were entirely time point specific, meaning whatever nonshared environmental influences were operating at the first time point were not influencing individual variation in the language factor at the second time point. CONCLUSION: The discussion in this article centers on possible candidates for both genetic and nonshared environmental effects as well as implications for clinical practice and future research. PMID- 22232407 TI - Intensive voice treatment (LSVT LOUD) for children with spastic cerebral palsy and dysarthria. AB - PURPOSE: The purpose of this study was to examine the effects of an intensive voice treatment (Lee Silverman Voice Treatment, commonly known as LSVT LOUD) for children with spastic cerebral palsy (CP) and dysarthria. METHOD: A nonconcurrent multiple baseline single-subject design with replication across 5 children with spastic CP was used. Auditory-perceptual analysis of speech, acoustic measures of vocal functioning, and perceptual ratings by parents of participants were obtained at baseline, posttreatment, and 6-week follow-up recording sessions. RESULTS: Listeners consistently preferred the speech samples taken immediately posttreatment over those taken during the baseline phase for most perceptual characteristics rated in this study. Changes in acoustic measures of vocal functioning were not consistent across participants and occurred more frequently for maximum performance tasks as opposed to speech. Although parents of the treated participants reported an improved perception of vocal loudness immediately following treatment, maintenance of changes at 6-week follow-up varied across the participants. No changes were observed in the 5th participant, who did not receive treatment. CONCLUSIONS: These findings provide some preliminary observations that the children with spastic CP in this study not only tolerated intensive voice treatment but also showed improvement on select aspects of vocal functioning. These outcomes warrant further research through Phase 2 treatment studies. PMID- 22232408 TI - Aging and the 4-kHz air-bone gap. AB - PURPOSE: In this study, the authors assessed age- and sex-related patterns in the prevalence and 10-year incidence of 4-kHz air-bone gaps and associated factors. METHOD: Data were obtained as part of the longitudinal, population-based Epidemiology of Hearing Loss Study (Cruickshanks et al., 1998). An air-bone gap at 4 kHz was defined as an air-conduction threshold >= 15 dB higher than the bone conduction threshold in the right ear. RESULTS: Among 3,553 participants ages 48 92 years at baseline (1993-1995), 3.4% had a 4-kHz air-bone gap in the right ear. The prevalence increased with age. Among the 120 participants with an air-bone gap, 60.0% did not have a flat tympanogram or an air-bone gap at 0.5 kHz. Ten years later, the authors assessed 2,093 participants who did not have a 4-kHz air bone gap at baseline; 9.2% had developed a 4-kHz air-bone gap in the right ear. The incidence increased with age. Among the 192 participants who had developed an air-bone gap, 60.9% did not have a flat tympanogram or air-bone gaps at other frequencies. CONCLUSION: These results suggest that a finding of a 4-kHz air-bone gap may reflect a combination of aging and other factors and not necessarily exclusively abnormal middle-ear function. PMID- 22232409 TI - Development of phonological processing skills in children with specific language impairment with and without literacy delay: a 3-year longitudinal study. AB - PURPOSE: To compare the development of phonological skills in children with specific language impairment (SLI) with and without literacy delay and to examine whether kindergarten phonological skills could discriminate these 2 groups. METHOD: In a longitudinal study, 8 children with SLI and literacy delay, 10 children with SLI and normal literacy, and 14 typically developing children were studied from the last year of kindergarten to the start of Grade 3. A wide range of phonological tasks (phonological awareness [PA], verbal short-term memory [vSTM], and rapid automatized naming [RAN]) were administered yearly. RESULTS: The SLI group with literacy delay scored significantly lower than the typically developing children on almost all phonological tasks in all grades, whereas the SLI group with normal literacy scored significantly lower only on demanding PA and vSTM tasks. A combination of kindergarten PA and RAN skills could correctly classify 75% of the children with SLI. By including vSTM, the discriminatory value did not increase. CONCLUSIONS: Children with SLI and normal literacy at age 8;1 [years;months] continued to have difficulties with demanding PA and vSTM tasks. Children with SLI and poor PA and RAN in kindergarten were at high risk of developing literacy problems in a transparent orthography. PMID- 22232411 TI - Tackling the combined effects of reverberation and masking noise using ideal channel selection. AB - PURPOSE: In this article, a new signal-processing algorithm is proposed and evaluated for the suppression of the combined effects of reverberation and noise. METHOD: The proposed algorithm decomposes, on a short-term basis (every 20 ms), the reverberant stimuli into a number of channels and retains only a subset of the channels satisfying a signal-to-reverberant ratio (SRR) criterion. The construction of this criterion assumes access to a priori knowledge of the target (anechoic) signal, and the aim of this study was to assess the full potential of the proposed channel-selection algorithm, assuming that this criterion could be estimated accurately. Listening tests with normal-hearing listeners were conducted to assess the performance of the proposed algorithm in highly reverberant conditions (T(60) = 1.0 s), which included additive noise at 0 and 5 dB signal-to-noise ratios (SNRs). RESULTS: A substantial gain in intelligibility was obtained in both reverberant and combined reverberant and noise conditions. The mean intelligibility scores improved by 44 and 33 percentage points at 0 and 5 dB SNR reverberation + noise conditions. Feature analysis of the consonant confusion matrices revealed that the transmission of voicing information was most negatively affected, followed by manner and place of articulation. CONCLUSIONS: The proposed algorithm produced substantial gains in intelligibility, and this benefit was attributed to the ability of the proposed SRR criterion to detect accurately voiced or unvoiced boundaries. It was postulated that detection of those boundaries is critical for better perception of voicing information and manner of articulation. PMID- 22232412 TI - Surface electromyography for speech and swallowing systems: measurement, analysis, and interpretation. AB - PURPOSE: Applying surface electromyography (sEMG) to the study of voice, speech, and swallowing is becoming increasingly popular. An improved understanding of sEMG and building a consensus as to appropriate methodology will improve future research and clinical applications. METHOD: An updated review of the theory behind recording sEMG for the speech and swallowing systems is provided. Several factors that are known to affect the content of the sEMG signal are discussed, and practical guidelines for sEMG recording and analysis are presented, focusing on special considerations within the context of the speech and swallowing anatomy. RESULTS: Unique challenges are seen in application of sEMG to the speech and swallowing musculature owing to the small size of the muscles in relation to the sEMG detection volume and the present lack of knowledge about innervation zone locations. CONCLUSIONS: Despite the challenges discussed, application of sEMG to speech and swallowing has potential as a clinical and research tool when used correctly and is specifically suited to noninvasive clinical studies using between-condition or between-group comparisons for which detection of specific isolated muscle activities is not necessary. PMID- 22232410 TI - Functional brain activation differences in school-age children with speech sound errors: speech and print processing. AB - PURPOSE: To examine neural response to spoken and printed language in children with speech sound errors (SSE). METHOD: Functional magnetic resonance imaging was used to compare processing of auditorily and visually presented words and pseudowords in 17 children with SSE, ages 8;6[years;months] through 10;10, with 17 matched controls. RESULTS: When processing spoken words and pseudowords, the SSE group showed less activation than typically speaking controls in left middle temporal gyrus. They also showed greater activation than controls in several cortical and subcortical regions (e.g., left superior temporal gyrus, globus pallidus, insula, fusiform, and bilateral parietal regions). In response to printed words and pseudowords, children with SSE had greater activation than controls in regions including bilateral fusiform and anterior cingulate. Some differences were found in both speech and print processing that that may be associated with children with SSE failing to show common patterns of task-induced deactivation and/or attentional resource allocation. CONCLUSION: Compared with controls, children with SSE appear to rely more on several dorsal speech perception regions and less on ventral speech perception regions. When processing print, numerous regions were observed to be activated more for the SSE group than for controls. PMID- 22232413 TI - Enhancement in informational masking. AB - PURPOSE: The ability to detect a tone added to a random masker improves when a preview of the masker is provided. In 2 experiments, the authors explored the role that perceptual organization plays in this release from masking. METHOD: Detection thresholds were measured in informational masking studies. The maskers were drawn at random prior to each trial. Masker or signal-plus-masker precursors preceded the detection interval, and the time between the precursor and the detection interval was systematically altered. In Experiment 1, the signal frequency was either fixed or random. In Experiment 2, the random masker was composed of harmonics of a common fundamental frequency (F (0)), and the randomly chosen signal frequency was either harmonically related to, or mistuned from, the masker's F (0). RESULTS: For a masker precursor, the release from informational masking withstood longer precursor-detection interval delays (a) when the signal frequency was fixed versus random and (b) when the signal was mistuned relative to a harmonic of the masker's F (0). CONCLUSION: These results suggest that listeners' ability to attend to the signal may contribute to the long-lived release from masking with a masker precursor. PMID- 22232414 TI - Developmental trajectories of early communication skills. AB - PURPOSE: This study focused on developmental trajectories of prelinguistic communication skills and their connections to later parent-reported language difficulties. METHOD: The participants represent a subset of a community-based sample of 508 children. Data include parent reports of prelinguistic communication skills at 12, 15, 18, and 21 months and language difficulties at age 4;7 (years;months). The authors used latent profile analysis to identify groups of children with differing developmental trajectories of prelinguistic communication skills ( n = 271). The relations among these groups and follow-up data of parent-reported concerns of language development ( n = 187), as well as the role of gender, were examined. RESULTS: Six meaningful prelinguistic communication groups were identified with the latent profile analysis, and these groups showed connections to later parent-reported concerns of language difficulties. Delayed early expressive language and a minor delay of overall performance, together with symbolic difficulties, appeared as predictors of later language difficulties. Nearly 80% of the children whose parents reported language related concerns at the follow-up stage could already be identified before their 2nd birthday. CONCLUSION: The results support the potential of early screening in identifying children at risk of developing language difficulties, particularly when screening includes repeated surveillance of more than one area of communication skills. PMID- 22232415 TI - Fundamental approaches in molecular biology for communication sciences and disorders. AB - PURPOSE: This contemporary tutorial will introduce general principles of molecular biology, common deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein assays and their relevance in the field of communication sciences and disorders. METHOD: Over the past 2 decades, knowledge of the molecular pathophysiology of human disease has increased at a remarkable pace. Most of this progress can be attributed to concomitant advances in basic molecular biology and, specifically, the development of an ever-expanding armamentarium of technologies for analysis of DNA, RNA, and protein structure and function. Details of these methodologies, their limitations, and examples from the communication sciences and disorders literature are presented. Results/Conclusions The use of molecular biology techniques in the fields of speech, language, and hearing sciences is increasing, facilitating the need for an understanding of molecular biology fundamentals and common experimental assays. PMID- 22232417 TI - Why public opinion changes: the implications for health and health policy. AB - Research on stasis or change in public opinion toward health, health policy, and medical care tends to focus on short-term dynamics and to emphasize the impact of discrete messages communicated by individual speakers in particular situations. This focus on what we term "situational framing," though valuable in some respects, is poorly equipped to assess changes that may occur over the longer term. We focus, instead, on "structural framing" to understand how institutionalized public health and health care policies impact public opinion and behavior over time. Understanding the dynamics of public opinion over time is especially helpful in tracking the political effects of the Patient Protection and Affordable Care Act of 2010 as it moves from the debate over its passage to its implementation and operation. PMID- 22232416 TI - Histamine modulates multiple functional activities of monocyte-derived dendritic cell subsets via histamine receptor 2. AB - Expression of CD1a proteins in human monocyte-derived dendritic cells (DCs) specifies functionally distinct subsets with different inflammatory properties. Histamine is recognized as an inflammatory mediator released by various cell types including DCs. The diverse biological effects of histamine are mediated by G-protein-coupled histamine receptors (HRs), which are able to modulate the functional activities of DC subsets. The goal of the present study was to compare the expression and activity of HRs in the CD1a(-) and CD1a(+) monocyte-derived DC subsets and to test the effects of histamine on the differentiation, activation and functional activities of these subsets. We show that H2R is present at high levels in both DC subsets, whereas H1R and H4R are expressed in a subset-specific manner. Histamine shifts DC differentiation to the development of CD1a(-) DCs and modulates DC activation through its inhibitory effect on CD1a(+) DC differentiation. Histamine-induced reduction of CD1a(+) DCs is associated with increased secretion of IL-6 and IL-10, up-regulation of a typical combination of chemokines, expression C5aR1 by the CD1a(-) DC subset and enhanced migration of both activated DC subsets supported by the production of MMP-9 and MMP-12 enzymes. All these effects were shown to be mediated in a H2R-specific manner as revealed by the specific antagonist of the receptor. As H2R is expressed at high levels in both DC subsets, we propose that it may dominate the regulation of multiple DC functions. In contrast, H1R and H4R with opposing subset-related expression may have a regulatory or fine-tuning role in histamine-induced functional activities. PMID- 22232418 TI - Motivated reasoning and public opinion. AB - Citizens, especially those who are knowledgeable and care the most about politics, are motivated to defend their beliefs and attitudes in the face of discrepant information. These motivated biases strongly influence the way people think about health care policies and the politicians and parties that propose or attack these contentious policies. Three cognitive mechanisms are identified: a prior belief effect, confirmation bias, and disconfirmation bias. Together, these information processes conspire to produce persistence and polarization of opinion on health care policies. PMID- 22232419 TI - The dynamics of health care opinion, 2008-2010: partisanship, self-interest, and racial resentment. AB - Recent debate over the Patient Protection and Affordable Care Act highlights the extent of party polarization in Washington. While the partisan divide on this issue is stark among political elites, it is less clear how the mass electorate has responded to this divisive conflict. In this article we examine individual level dynamics in health care attitudes between 2008 and 2010. We find partisan attachments and self-interests strongly predict change in health care attitudes, with Republicans growing more opposed to universal health insurance between 2008 and 2010, and those personally worried about medical expenses less likely to abandon support. We find, however, that the effect of partisanship is moderated by self-interest, with strong Republicans significantly less likely to switch to opposition if they were personally worried about medical expenses. Finally, we find that health care policy preferences, already tinged with racial attitudes in 2008, became increasingly so by 2010. PMID- 22232420 TI - Policy feedbacks and the impact of policy designs on public opinion. AB - A recently developed analytic approach--policy feedback effects--provides health policy analysts with a crucial new tool for understanding the politics of health policy. Three cases--senior citizens' opposition to the Obama health care reform, tax breaks for employer-provided health insurance, and the Medicare Part D prescription drug program--demonstrate how policy designs affect subsequent policy outcomes. To differing degrees, the three cases show how public policies can create constituencies with particular understandings of their benefits who attempt to thwart reform; can highlight or reduce the visibility of the government role in health care, shaping attitudes about the worth of government action; and can provide half solutions that fail to maximize beneficiary welfare but that deflate momentum for policy improvements. The cases illustrate a general pattern revealed by wide-ranging research on policy feedback effects: the designs of public policies influence preferences and alter patterns of political mobilization, effects that feed back into the political system, shaping the political environment and the possibilities for future policy making. PMID- 22232421 TI - Missing voices: polling and health care. AB - Examining data on the recent health care legislation, we demonstrate that public opinion polls on health care should be treated with caution because of item nonresponse--or "don't know" answers--on survey questions. Far from being the great equalizer, opinion polls can actually misrepresent the attitudes of the population. First, we show that respondents with lower levels of socioeconomic resources are systematically more likely to give a "don't know" response when asked their opinion about health care legislation. Second, these same individuals are more likely to back health care reform. The result is an incomplete portrait of public opinion on the issue of health care in the United States. PMID- 22232423 TI - Webcam delivery of the Camperdown Program for adolescents who stutter: a phase I trial. AB - PURPOSE: This Phase I clinical trial explored the viability of webcam Internet delivery of the Camperdown Program for adolescents who stutter. Method and Procedure Participants were 3 adolescents ages 13, 15, and 16 years, with moderate-severe stuttering. Each was treated with the Camperdown Program delivered by webcam with no clinic attendance. Primary outcome measures were percentage of syllables stuttered and number of treatment sessions to maintenance. Secondary outcome measures were speech naturalness, situation avoidance, self-reported stuttering severity, and parent and adolescent satisfaction. Data were collected pre treatment and at 1 day, 6 months, and 12 months post entry to maintenance. RESULTS: Participants entered maintenance after means of 18 sessions and 11 clinician hours. Group mean reduction of stuttering from pre treatment to entry to maintenance was 83%, from pre treatment to 6 months post entry to maintenance was 93%, and from pre treatment to 12 months post entry to maintenance was 74%. Self-reported stuttering severity ratings confirmed these results. Post entry to maintenance speech naturalness for participants fell within the range of that of 3 matched controls. However, avoidance of speech situations showed no corresponding improvements for 2 of the participants. CONCLUSION: The service delivery model was efficacious and efficient. All of the participants and their parents also found it appealing. Results justify a Phase II trial of the delivery model. PMID- 22232424 TI - The narrative language performance of three types of at-risk first-grade readers. AB - PURPOSE: This study investigated the narrative language performance of 3 types of readers who had been identified as being at risk through code-based response-to intervention (RTI) procedures. METHOD: In a retrospective group comparison, 32 at risk 1st-grade readers were identified: children who resolved without intervention (early resolvers, n = 11), children who met criterion following 4 weeks of intervention (good responders, n = 8), and children who failed to meet criterion following 4 weeks of intervention (poor responders, n = 13). A narrative retell and a norm-referenced language test were obtained before intervention. RESULTS: There were no significant differences between the 3 learner types on the language test. However, the narratives of the good responders were significantly higher than the narratives of the other 2 groups on total number of words, number of different words, and number of communication units. The narratives of early resolvers and good responders differed significantly on the productivity index, number of coordinating conjunctions, and number of episodic elements. There were no other significant differences. CONCLUSION: Types of learners distinguished by a code-based RTI model showed differences in their narrative language. First graders who responded well to code based reading intervention retold stories that contained more language and better story grammar than first graders who did not respond well to intervention. These results indicate the need to evaluate narrative language performance within RTI, especially for early resolvers. PMID- 22232425 TI - The effect of test presentation on children with autism spectrum disorders and neurotypical peers. AB - PURPOSE: The purpose of this experiment was to determine if there is alternate forms reliability for paper- and computer-administered standardized vocabulary tests. Another purpose was to determine whether the behavioral ratings of children with autism spectrum disorders (ASDs) would improve during the computer administered testing sessions secondary to a decreased need for social interaction. METHOD: Thirty-six school-age children (half with ASDs, half neurotypical [NT]) took 2 versions (i.e., paper vs. computer) of the Expressive One-Word Picture Vocabulary Test (EOWPVT-2000; Brownell, 2000a) and the Receptive One-Word Picture Vocabulary Test (ROWPVT-2000; Brownell, 2000b). Order of presentation was counterbalanced across participants. Test sessions were videotaped, and randomly selected 1-min intervals were rated for behaviors. Standardized test scores and behavior ratings were compared for equivalence across the test presentation methods. RESULTS: Standard scores for both versions of the tests were not significantly different for both groups of participants. There were no differences in behavioral ratings between the two methods of test presentation. CONCLUSION: Alternate forms reliability was found, thus expanding the options for testing for school-age populations. The use of computers had no effect on the behaviors of the children with ASDs. The ramifications of this finding for assessment and intervention for children with ASDs are discussed. PMID- 22232426 TI - In silico and in vitro identification of microRNAs that regulate hepatic nuclear factor 4alpha expression. AB - Hepatic nuclear factor 4alpha (HNF4A) is a nuclear transcription factor that regulates the expression of many genes involved in drug disposition. To identify additional molecular mechanisms that regulate HNF4A, we identified microRNAs (miRNAs) that target HNF4A expression. In silico analyses suggested that HNF4A is targeted by many miRNAs. We conducted in vitro studies to validate several of these predictions. With use of an HNF4A 3'-untranslated region (UTR) luciferase reporter assay, five of six miRNAs tested significantly down-regulated (~20-40%) the luciferase activity. In HepG2 cells, miR-34a and miR-449a also down-regulated the expression of both the HNF4A protein and an HNF4A target gene, PXR (~30-40%). This regulation appeared without reduction in HNF4A mRNA expression, suggesting that they must be blocking HNF4A translation. Using additional bioinformatic algorithms, we identified polymorphisms that are predicted to alter the miRNA targeting of HNF4A. Luciferase assays indicated that miR-34a and miR-449a were less effective in regulating a variant (rs11574744) than the wild-type HNF4A 3' UTR. In vivo, subjects with the variant HNF4A had lower CYP2D6 enzyme activity, although this result was not statistically significant (p = 0.16). In conclusion, our findings demonstrate strong evidence for a role of miRNAs in the regulation of HNF4A. PMID- 22232427 TI - Effects of the CYP2B6*6 allele on catalytic properties and inhibition of CYP2B6 in vitro: implication for the mechanism of reduced efavirenz metabolism and other CYP2B6 substrates in vivo. AB - The mechanism by which CYP2B6*6 allele alters drug metabolism in vitro and in vivo is not fully understood. To test the hypothesis that altered substrate binding and/or catalytic properties contribute to its functional consequences, efavirenz 8-hydroxylation and bupropion 4-hydroxylation were determined in CYP2B6.1 and CYP2B6.6 proteins expressed without and with cytochrome b5 (Cyt b5) and in human liver microsomes (HLMs) obtained from liver tissues genotyped for the CYP2B6*6 allele. The susceptibility of the variant protein to inhibition was also tested in HLMs. Significantly higher V(max) and K(m) values for 8 hydroxyefavirenz formation and ~2-fold lower intrinsic clearance (Cl(int)) were noted in expressed CYP2B6.6 protein (-b5) compared with that of CYP2B6.1 protein (-b5); this effect was abolished by Cyt b5. The V(max) and Cl(int) values for 4 hydroxybupropion formation were significantly higher in CYP2B6.6 than in CYP2B6.1 protein, with no difference in K(m), whereas coexpression with Cyt b5 reversed the genetic effect on these kinetic parameters. In HLMs, CYP2B6*6/*6 genotype was associated with markedly lower V(max) (and moderate increase in K(m)) and thus lower Cl(int) values for efavirenz and bupropion metabolism, but no difference in catalytic properties was noted between CYP2B6*1/*1 and CYP2B6*1/*6 genotypes. Inhibition of efavirenz 8-hydroxylation by voriconazole was significantly greater in HLMs with the CYP2B6*6 allele (K(i) = 1.6 +/- 0.8 MUM) than HLMs with CYP2B6*1/*1 genotype (K(i) = 3.0 +/- 1.1 MUM). In conclusion, our data suggest the CYP2B6*6 allele influences metabolic activity by altering substrate binding and catalytic activity in a substrate- and Cyt b5-dependent manner. It may also confer susceptibility to inhibition. PMID- 22232428 TI - Lower risk of stent thrombosis and restenosis with unrestricted use of 'new generation' drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). AB - AIMS: To compare the long-term outcome after percutaneous coronary intervention with 'new-generation' drug-eluting stents (n-DES) to 'older generation' DES (o DES), and bare-metal stents (BMS) in a real-world population. METHODS AND RESULTS: We evaluated 94 384 consecutive stent implantations (BMS, n = 64 631; o DES, n = 19 202; n-DES, n = 10 551) in Sweden from November 2006 to October 2010. All cases of definite stent thrombosis (ST) and restenosis were documented in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Older generation DES were classified as: Cypher and Cypher Select (Cordis Corporation, Miami, FL, USA), Taxus Express and Taxus Liberte (Boston Scientific Corporation), and Endeavor (Medtronic Inc.) and n-DES as: Endeavor Resolute (Medtronic Inc.), XienceV, Xience Prime (Abbott Laboratories) and Promus, Promus Element (Boston Scientific Corporation). The Cox regression analyses unadjusted and adjusted for clinical and angiographic covariates showed a statistically significant lower risk of restenosis in n-DES compared with BMS [adjusted hazard ratio (HR) 0.29; 95% confidence interval (CI): 0.25-0.33] and o-DES (HR 0.62; 95% CI: 0.53-0.72). A lower risk of definite ST was found in n-DES compared with BMS (HR 0.38; 95% CI: 0.28-0.52) and o-DES (HR, 0.57; 95% CI: 0.41-0.79). The risk of death was significantly lower in n-DES compared with o-DES (adjusted HR: 0.77; 95% CI: 0.63 0.95) and BMS (adjusted HR: 0.55; 95% CI: 0.46-0.67). CONCLUSION: Percutaneous coronary intervention with n-DES is associated with a 38% lower risk of clinically meaningful restenosis, a 43% lower risk of definite ST, and a 23% lower risk of death compared with o-DES in this observational study from a large real-world population. PMID- 22232429 TI - RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors. AB - Pancreas development is initiated by the specification and expansion of a small group of endodermal cells. Several transcription factors are crucial for progenitor maintenance and expansion, but their interactions and the downstream targets mediating their activity are poorly understood. Among those factors, PTF1a, a basic helix-loop-helix (bHLH) transcription factor which controls pancreas exocrine cell differentiation, maintenance, and functionality, is also needed for the early specification of pancreas progenitors. We used RNA profiling and chromatin immunoprecipitation (ChIP) sequencing to identify a set of targets in pancreas progenitors. We demonstrate that Mnx1, a gene that is absolutely required in pancreas progenitors, is a major direct target of PTF1a and is regulated by a distant enhancer element. Pdx1, Nkx6.1, and Onecut1 are also direct PTF1a targets whose expression is promoted by PTF1a. These proteins, most of which were previously shown to be necessary for pancreas bud maintenance or formation, form a transcription factor network that allows the maintenance of pancreas progenitors. In addition, we identify Bmp7, Nr5a2, RhoV, and P2rx1 as new targets of PTF1a in pancreas progenitors. PMID- 22232430 TI - Partial rescue of retinal function in chronically hypoglycemic mice. AB - PURPOSE: Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr-/- mice. METHODS: Gcgr-/- mice were administered a carbohydrate-rich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry. RESULTS: Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr-/- mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to bipolar cell synapses. Gcgr-/- retinas have 20% fewer synaptic pairings than Gcgr+/- retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts. CONCLUSIONS: Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss. PMID- 22232431 TI - Substratum topography modulates corneal fibroblast to myofibroblast transformation. AB - PURPOSE: The transition of corneal fibroblasts to the myofibroblast phenotype is known to be important in wound healing. The purpose of this study was to determine the effect of topographic cues on TGFbeta-induced myofibroblast transformation of corneal cells. METHODS: Rabbit corneal fibroblasts were cultured on nanopatterned surfaces having topographic features of varying sizes. Cells were cultured in media containing TGFbeta at concentrations ranging from 0 to 10 ng/mL. RNA and protein were collected from cells cultured on topographically patterned and planar substrates and analyzed for the myofibroblast marker alpha-smooth muscle actin (alphaSMA) and Smad7 expression by quantitative real time PCR. Western blot and immunocytochemistry analysis for alphaSMA were also performed. RESULTS: Cells grown on patterned surfaces demonstrated significantly reduced levels of alphaSMA (P < 0.002) compared with planar surfaces when exposed to TGFbeta; the greatest reduction was seen on the 1400 nm surface. Smad7 mRNA expression was significantly greater on all patterned surfaces exposed to TGFbeta (P < 0.002), whereas cells grown on planar surfaces showed equal or reduced levels of Smad7. Western blot analysis and alphaSMA immunocytochemical staining demonstrated reduced transition to the myofibroblast phenotype on the 1400 nm surface when compared with cells on a planar surface. CONCLUSIONS: These data demonstrate that nanoscale topographic features modulate TGFbeta-induced myofibroblast differentiation and alphaSMA expression, possibly through upregulation of Smad7. It is therefore proposed that in the wound environment, native nanotopographic cues assist in stabilizing the keratocyte/fibroblast phenotype while pathologic microenvironmental alterations may be permissive for increased myofibroblast differentiation and the development of fibrosis and corneal haze. PMID- 22232432 TI - Significance of C2/CFB variants in age-related macular degeneration and polypoidal choroidal vasculopathy in a Japanese population. AB - PURPOSE: To determine whether genetic variants in the complement component 2 and factor B gene (C2/CFB) locus are associated with the risk for typical age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV) in a Japanese population. METHODS: Four single nucleotide polymorphisms (SNPs) were genotyped across the C2/CFB locus of patients with typical AMD (n = 455) or PCV (n = 581) and of 865 controls. Differences in the observed genotypic distribution between the case and control groups were tested by logistic regression analysis for age and sex adjustments. Significant associations were confirmed using a second control group of 336 cataract patients. A further model adjusting for age related maculopathy susceptibility 2 (ARMS2) A69S, complement factor H (CFH) I62V, age, sex and smoking status was performed, to confirm their independent association from other covariates. RESULTS: C2 rs547154 and CFB rs541862 were significantly associated with typical AMD and PCV in this Japanese sample (P < 0.05). These two SNPs were also significantly associated with typical AMD and PCV in evaluation of the second control cohort (P < 0.05). Furthermore, an independent association of C2/CFB variants was found for both typical AMD and PCV with age, sex, smoking, and genetic background of ARMS2 A69S and CFH I62V (vs. typical AMD: P = 0.0073, odds ratio [OR] = 0.47; vs. PCV: P = 0.0083, OR = 0.53). CONCLUSIONS: C2/CFB variants play a protective role in the risk of developing neovascular AMD and PCV in the Japanese. PMID- 22232433 TI - Topographic variation and interocular symmetry of macular choroidal thickness using enhanced depth imaging optical coherence tomography. AB - PURPOSE: To report and analyze factors influencing topographical and interocular variations in choroidal thickness (CT) in a healthy adult population. METHODS: One hundred eyes of 50 healthy subjects underwent visual acuity and axial length measurements and optical coherence tomography (OCT) with enhanced depth imaging (EDI). CTs at the fovea and at 3 mm nasal, temporal, superior, and inferior to the fovea were measured manually. Topographic variation, relative interocular differences in CT and predictors of CT were analyzed. The relationships between interocular differences in CT and differences in age and interocular axial length were explored. RESULTS: The mean (SD) foveal CT in the right and left eyes were 334 (95) and 333 (90) MUm, respectively. For foveal CT, there was a high correlation between the two eyes (r = 0.90) with a relative interocular 95% limits of agreement of -80 to +83, and a median (range) absolute difference of 21 (0.4-135). There was no significant variation in the relative and absolute interocular differences in CT. Axial length was the main predictor of CT for nasal and foveal CT. Symmetry in CT in the horizontal and vertical meridians was seen in eyes with axial length shorter than 23.50 mm (P < 0.05). CONCLUSIONS: There was no significant relative interocular difference in CT. Axial length contributes to some of the variances in CT but has a significant influence on the CT profile. Although relative interocular difference is not significant, absolute interocular differences in CT may reach 85 MUm. PMID- 22232434 TI - Dependence of corneal stem/progenitor cells on ocular surface innervation. AB - PURPOSE: Neurotrophic keratopathy (NK) is a corneal degeneration associated with corneal nerve dysfunction. It can cause corneal epithelial defects, stromal thinning, and perforation. However, it is not clear if and to which extent epithelial stem cells are affected in NK. The purpose of this study was to identify the relationship between corneolimbal epithelial progenitor/stem cells and sensory nerves using a denervated mouse model of NK. METHODS: NK was induced in mice by electrocoagulation of the ophthalmic branch of the trigeminal nerve. The absence of corneal nerves was confirmed with beta-III tubulin immunostaining and blink reflex test after 7 days. ATP-binding cassette subfamily G member 2 (ABCG2), p63, and hairy enhancer of split 1 (Hes1) were chosen as corneolimbal stem/progenitor cell markers and assessed in denervated mice versus controls by immunofluorescent microscopy and real-time PCR. In addition, corneolimbal stem/progenitor cells were detected as side population cells using flow cytometry, and colony-forming efficiency assay was performed to assess their function. RESULTS: ABCG2, p63, and Hes1 immunostaining were significantly decreased in denervated eyes after 7 days. Similarly, the expression levels of ABCG2, p63, K15, Hes1, and N-cadherin transcripts were also significantly decreased in denervated eyes. Stem/progenitor cells measured as side population from NK mice were decreased by approximately 75% compared with normals. In addition, the authors found a significant (P = 0.038) reduction in colony-forming efficiency of stem/progenitor cells harvested from denervated eyes. CONCLUSIONS: Corneolimbal stem/progenitor cells are significantly reduced after depletion of sensory nerves. The data suggest a critical role of innervation in maintaining stem cells and/or the stem cell niche. PMID- 22232436 TI - Variable expression of human Beta defensins 3 and 9 at the human ocular surface in infectious keratitis. AB - PURPOSE: The authors have previously reported the presence of the antimicrobial peptides human beta defensin (hBD) 3 and hBD9 on the ocular surface (OS). These play an important role in infection and inflammation. In the present study, the authors studied the gene expression levels of hBD3 and hBD9 in healthy subjects and during and after healing of infectious keratitis. METHODS: Human OS specimens were obtained by impression cytology from healthy controls and patients with Acanthamoeba and Gram-negative and -positive bacterial keratitis (BK), both during active infection and after healing. The gene expression levels of hBD3 and hBD9 were determined using quantitative real-time polymerase chain reaction (RT PCR). RESULTS: hBD3 and hBD9 were constitutively expressed in all healthy controls. During acute Acanthamoeba keratitis (AK), hBD3 levels were markedly increased and then returned close to normal levels after healing. In BK, hBD3 gene expression was moderately increased and then decreased after healing. In contrast to hBD3, hBD9 was significantly downregulated in both AK and Gram positive BK, whereas it showed an insignificant decrease in Gram-negative BK. After healing, the expression showed upregulation except in Gram-positive BK, where it continued to decline. CONCLUSIONS: This is the first study that demonstrates the gene expression of hBD3 and hBD9 in response to infection. It illustrates that not all antimicrobial peptides (AMPs) behave in a similar manner. Some are upregulated and some are downregulated, suggesting a diverse role of AMP in infection and inflammation. The results point to a role of AMP mediated host defense in Acanthamoeba keratitis as well. PMID- 22232437 TI - Cutaneous disseminated paracoccidioidomycosis. PMID- 22232435 TI - Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. AB - PURPOSE: Mesenchymal stem/progenitor cells (MSCs) have regenerative and immunomodulatory properties, exerted by cell-cell contact and in a paracrine fashion. Part of their immunosuppressive activity has been ascribed to their ability to promote the induction of CD4+CD25+FoxP3+ T lymphocytes with regulatory functions (Treg). Here the authors studied the effect of MSCs on the induction of Treg and on the development of autoimmunity, and they examined the possibility that MSC-mediated Treg induction could be attributed to the secretion of soluble factors. METHODS: The authors induced experimental autoimmune uveitis (EAU) in mice by immunization with the 1-20 peptide of the intraphotoreceptor binding protein. At the same time, some of the animals were treated intraperitoneally with syngeneic MSCs. The authors checked T-cell responses and in vitro Treg conversion by cell proliferation and blocking assays, in cell-cell contact and transwell settings. TGFbeta and TGFbeta receptor gene expression analyses were performed by real-time PCR. RESULTS: The authors found that a single intraperitoneal injection of MSCs was able to significantly attenuate EAU and that a significantly higher percentage of adaptive Treg was present in MSC treated mice than in MSC-untreated animals. In vitro blocking of antigen presentation by major histocompatibility complex class II precluded priming and clonal expansion of antigen-specific Treg, whereas blockade of TGFbeta impaired the expression of FoxP3, preventing the conversion of CD4+ T cells into functionally active Treg. CONCLUSIONS: The authors demonstrated that MSCs can inhibit EAU and that their immunomodulatory function is due at least in part to the induction of antigen-specific Treg in a paracrine fashion by secreting TGFbeta. PMID- 22232438 TI - Lung nodules, fever, and eosinophilia in a traveler returning from Madagascar. PMID- 22232441 TI - Cholera in Haiti: the equity agenda and the future of tropical medicine. PMID- 22232440 TI - Perspectives on Haiti two years after the earthquake. PMID- 22232442 TI - The increase of imported malaria acquired in Haiti among US travelers in 2010. AB - From 2004 to 2009, the number of malaria cases reported in Haiti increased nearly fivefold. The effect of the 2010 earthquake and its aftermath on malaria transmission in Haiti is not known. Imported malaria cases in the United States acquired in Haiti tripled from 2009 to 2010, likely reflecting both the increased number of travelers arriving from Haiti and the increased risk of acquiring malaria infection in Haiti. The demographics of travelers and the proportion of severe cases are similar to those statistics reported in previous years. Non adherence to malaria chemoprophylaxis remains a nearly universal modifiable risk factor among these cases. PMID- 22232443 TI - Infectious diseases seen in a primary care clinic in Leogane, Haiti. AB - All diseases diagnosed in a primary healthcare clinic situated in Leogane, Haiti, were recorded prospectively during a 7-month period. Among the patients in this cohort, 2,821 of 6,631 (42.6%) presented with an infectious disease. The three most common syndromes among the patients presenting with infections were respiratory tract infections (33.5%), suspected sexually transmitted diseases- mostly among females with recurrent disease (18.1%)--and skin and soft tissue infections, including multiple cases of tinea capitis (12.8%). Of the 255 patients presenting with undifferentiated fever, 76 (29.8%) were diagnosed with falciparum malaria. Other vector-borne diseases included 13 cases of filariasis and 6 cases of dengue fever. Human immunodeficiency virus infection was diagnosed in 19 patients. Four cases of mumps were detected among unimmunized children. A large proportion of these infections are preventable. Concerted efforts should be made to create large-scale preventive medicine programs for various infectious diseases. PMID- 22232444 TI - A cluster of dengue cases in American missionaries returning from Haiti, 2010. AB - Dengue is an acute febrile illness caused by four mosquito-borne dengue viruses (DENV-1 to -4) that are endemic throughout the tropics. After returning from a 1 week missionary trip to Haiti in October of 2010, 5 of 28 (18%) travelers were hospitalized for dengue-like illness. All travelers were invited to submit serum specimens and complete questionnaires on pre-travel preparations, mosquito avoidance practices, and activities during travel. DENV infection was confirmed in seven (25%) travelers, including all travelers that were hospitalized. Viral sequencing revealed closest homology to a 2007 DENV-1 isolate from the Dominican Republic. Although most (88%) travelers had a pre-travel healthcare visit, only one-quarter knew that dengue is a risk in Haiti, and one-quarter regularly used insect repellent. This report confirms recent DENV transmission in Haiti. Travelers to DENV-endemic areas should receive dengue education during pre-travel health consultations, follow mosquito avoidance recommendations, and seek medical care for febrile illness during or after travel. PMID- 22232446 TI - Malaria survey in post-earthquake Haiti--2010. AB - Haiti's Ministry of Public Health and Population collaborated with global partners to enhance malaria surveillance in two disaster-affected areas within 3 months of the January 2010 earthquake. Data were collected between March 4 and April 9, 2010 by mobile medical teams. Malaria rapid diagnostic tests (RDTs) were used for case confirmation. A convenience sample of 1,629 consecutive suspected malaria patients was included. Of these patients, 1,564 (96%) patients had malaria RDTs performed, and 317 (20.3%) patients were positive. Of the 317 case patients with a positive RDT, 278 (87.7%) received chloroquine, 8 (2.5%) received quinine, and 31 (9.8%) had no antimalarial treatment recorded. Our experience shows that mobile medical teams trained in the use of malaria RDTs had a high rate of testing suspected malaria cases and that the majority of patients with positive RDTs received appropriate antimalarial treatment. Malaria RDTs were useful in the post-disaster setting where logistical and technical constraints limited the use of microscopy. PMID- 22232447 TI - The response of academic medical centers to the 2010 Haiti earthquake: the Mount Sinai School of Medicine experience. AB - On January 12, 2010, Haiti was struck by a 7.0 earthquake which left the country in a state of devastation. In the aftermath, there was an enormous relief effort in which academic medical centers (AMC) played an important role. We offer a retrospective on the AMC response through the Mount Sinai School of Medicine (MSSM) experience. Over the course of the year that followed the Earthquake, MSSM conducted five service trips in conjunction with two well-established groups which have provided service to the Haitian people for over 15 years. MSSM volunteer personnel included nurses, resident and attending physicians, and specialty fellows who provided expertise in critical care, emergency medicine, wound care, infectious diseases and chronic disease management of adults and children. Challenges faced included stressful and potentially hazardous working conditions, provision of care with limited resources and cultural and language barriers. The success of the MSSM response was due largely to the strength of its human resources and the relationship forged with effective relief organizations. These service missions fulfilled the institution's commitment to social responsibility and provided a valuable training opportunity in advocacy. For other AMCs seeking to respond in future emergencies, we suggest early identification of a partner with field experience, recruitment of administrative and faculty support across the institution, significant pre-departure orientation and utilization of volunteers to fundraise and advocate. Through this process, AMCs can play an important role in disaster response. PMID- 22232445 TI - Characteristics and spectrum of disease among ill returned travelers from pre- and post-earthquake Haiti: The GeoSentinel experience. AB - To describe patient characteristics and disease spectrum among foreign visitors to Haiti before and after the 2010 earthquake, we used GeoSentinel Global Surveillance Network data and compared 1 year post-earthquake versus 3 years pre earthquake. Post-earthquake travelers were younger, predominantly from the United States, more frequently international assistance workers, and more often medically counseled before their trip than pre-earthquake travelers. Work-related stress and upper respiratory tract infections were more frequent post-earthquake; acute diarrhea, dengue, and Plasmodium falciparum malaria were important contributors of morbidity both pre- and post-earthquake. These data highlight the importance of providing destination- and disaster-specific pre-travel counseling and post-travel evaluation and medical management to persons traveling to or returning from a disaster location, and evaluations should include attention to the psychological wellbeing of these travelers. For travel to Haiti, focus should be on mosquito-borne illnesses (dengue and P. falciparum malaria) and travelers' diarrhea. PMID- 22232448 TI - The "first" case of cholera in Haiti: lessons for global health. AB - Cholera is an acute watery diarrheal disease caused by infection with Vibrio cholerae. The disease has a high fatality rate when untreated and outbreaks of cholera have been increasing globally in the past decade, most recently in Haiti. We present the case of a 28-year-old Haitian male with a history of severe untreated mental health disorder that developed acute fatal watery diarrhea in mid-October 2010 in central Haiti after drinking from the local river. We believe he is the first or among the first cases of cholera in Haiti during the current epidemic. By reviewing his case, we extracted lessons for global health on the importance of mental health for overall health, the globalization of diseases in small communities, and the importance of a comprehensive approach to the health of communities when planning services in resource-poor settings. PMID- 22232449 TI - Social and news media enable estimation of epidemiological patterns early in the 2010 Haitian cholera outbreak. AB - During infectious disease outbreaks, data collected through health institutions and official reporting structures may not be available for weeks, hindering early epidemiologic assessment. By contrast, data from informal media are typically available in near real-time and could provide earlier estimates of epidemic dynamics. We assessed correlation of volume of cholera-related HealthMap news media reports, Twitter postings, and government cholera cases reported in the first 100 days of the 2010 Haitian cholera outbreak. Trends in volume of informal sources significantly correlated in time with official case data and was available up to 2 weeks earlier. Estimates of the reproductive number ranged from 1.54 to 6.89 (informal sources) and 1.27 to 3.72 (official sources) during the initial outbreak growth period, and 1.04 to 1.51 (informal) and 1.06 to 1.73 (official) when Hurricane Tomas afflicted Haiti. Informal data can be used complementarily with official data in an outbreak setting to get timely estimates of disease dynamics. PMID- 22232450 TI - Etiology of acute, non-malaria, febrile illnesses in Jayapura, northeastern Papua, Indonesia. AB - We conducted a prospective, inpatient fever study in malaria-endemic Papua, Indonesia to determine non-malaria fever etiologies. Investigations included malaria blood films, blood culture, paired serologic samples analysis for dengue, Japanese encephalitis, leptospirosis, scrub typhus, murine typhus, and spotted fever group rickettsia. During 1997-2000, 226 patients (127 males and 99 females) 1-80 years of age (median age = 25 years) were enrolled. Positive blood cultures (n = 34, 15%) were obtained for Salmonella Typhi (n = 13), Escherichia coli (n = 8), Streptococcus pneumoniae (n = 6), Staphylococcus aureus (n = 5), Streptococcus pyogenes (n = 1), and Klebsiella pneumoniae (n = 1). Twenty (8.8%) patients were positive for leptospirosis by polymerase chain reaction. Eighty (35.4%) of 226 patients had >= 1 positive serology, diagnostic for 15 rickettsial and 9 dengue cases. Acid-fast bacilli-positive sputum was obtained from three patients. Most common confirmed (81 of 226, 35.8%)/suspected diagnoses were typhoid fever (n = 41), pneumonia (n = 29), leptospirosis (n = 28), urinary tract infections (n = 20), rickettsioses (n = 19), dengue (n = 17), and meningitis/encephalitis (n = 15). There were 17 deaths, 7 (46.7%) were caused by meningitis/encephalitis. Multiple positive serologic results and few confirmed diagnoses indicate the need for improved diagnostics. PMID- 22232451 TI - Towards universal coverage: examining costs of illness, payment, and coping strategies to different population groups in southeast Nigeria. AB - This study investigated the costs of illness to households in different socio economic status (SES) groups and geographic places of abode in addition to the mechanisms that the different population groups used to pay for health services and cope with payments. A cross-sectional descriptive study of 3,200 households selected from six communities in two states was conducted using interviewer administered pre-tested questionnaires. An SES index was used to divide the households into quartiles, and chi(2) analysis was used to determine the relationship of SES and geographic abode of households with cost of illness, payment mechanism, and coping strategies. The results show that malaria was the illness that most people had. The average cost of transportation for malaria was 86 Naira ($0.6 US), and the total cost of treatment was 2,819.9 Naira ($20 US); of this cost, drug costs alone contributed more than 90%. Out of pocket was the main method of payment. Treatment costs differed by geographic location and socio economic status. Policy measures should establish targeted mechanisms to protect the general population, especially rural dwellers and poorer households, against the financial burden of direct healthcare payments. PMID- 22232452 TI - Hospital-based prevalence of malaria and dengue in febrile patients in Bangladesh. AB - We conducted a nationwide study at six tertiary hospitals from December 2008 through November 2009 to investigate etiologies of febrile illnesses in Bangladesh. Febrile patients meeting a clinical case definition were enrolled from inpatient and outpatient medicine and pediatric units. We assessed 720 febrile patients over 12 months; 69 (9.6%) were positive for IgM antibodies against dengue virus by enzyme-linked immunosorbent assay, and four malaria patients (0.56%) were confirmed with immuno-chromatography and microscopic slide tests. We identified dengue cases throughout the year from rural (49%) and urban areas (51%). We followed-up 55 accessible dengue-infected patients two months after their initial enrollment: 45 (82%) patients had fully recovered, 9 (16%) reported ongoing jaundice, fever and/or joint pain, and one died. Dengue infection is widespread across Bangladesh, but malaria is sufficiently uncommon that it should not be assumed as the cause of fever without laboratory confirmation. PMID- 22232453 TI - First Universities Allied for Essential Medicines (UAEM) Neglected Diseases and Innovation Symposium. AB - Universities Allied for Essential Medicines organized its first Neglected Diseases and Innovation Symposium to address expanding roles of public sector research institutions in innovation in research and development of biomedical technologies for treatment of diseases, particularly neglected tropical diseases. Universities and other public research institutions are increasingly integrated into the pharmaceutical innovation system. Academic entities now routinely undertake robust high-throughput screening and medicinal chemistry research programs to identify lead compounds for small molecule drugs and novel drug targets. Furthermore, product development partnerships are emerging between academic institutions, non-profit entities, and biotechnology and pharmaceutical companies to create diagnostics, therapies, and vaccines for diseases of the poor. With not for profit mission statements, open access publishing standards, open source platforms for data sharing and collaboration, and a shift in focus to more translational research, universities and other public research institutions are well-placed to accelerate development of medical technologies, particularly for neglected tropical diseases. PMID- 22232454 TI - Randomized, prospective, three-arm study to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombian patients with uncomplicated Plasmodium falciparum malaria. AB - The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine (N = 159), atovaquone proguanil (N = 53), or artesunate-mefloquine (N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is >= 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% (P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria. PMID- 22232455 TI - Development and optimization of a novel 384-well anti-malarial imaging assay validated for high-throughput screening. AB - With the increasing occurrence of drug resistance in the malaria parasite, Plasmodium falciparum, there is a great need for new and novel anti-malarial drugs. We have developed a 384-well, high-throughput imaging assay for the detection of new anti-malarial compounds, which was initially validated by screening a marine natural product library, and subsequently used to screen more than 3 million data points from a variety of compound sources. Founded on another fluorescence-based P. falciparum growth inhibition assay, the DNA-intercalating dye 4',6-diamidino-2-phenylindole, was used to monitor changes in parasite number. Fluorescent images were acquired on the PerkinElmer Opera High Throughput confocal imaging system and analyzed with a spot detection algorithm using the Acapella data processing software. Further optimization of this assay sought to increase throughput, assay stability, and compatibility with our high-throughput screening equipment platforms. The assay typically yielded Z'-factor values of 0.5-0.6, with signal-to-noise ratios of 12. PMID- 22232456 TI - Performance of a histidine-rich protein 2 rapid diagnostic test, Paracheck Pf(r), for detection of malaria infections in Ugandan pregnant women. AB - Improved laboratory diagnosis is critical to reduce the burden of malaria in pregnancy. Peripheral blood smears appear less sensitive than Plasmodium falciparum histidine-rich protein 2-based rapid diagnostic tests (RDTs) for placental malaria infections in studies conducted at delivery. In this study, 81 women in Uganda in the second or third trimester of pregnancy were followed-up until delivery. At each visit, peripheral blood was tested by blood smear, RDT, and nested species-specific polymerase chain reaction (PCR). Sensitivity and specificity of the tests was calculated with PCR, which detected 22 infections of P. falciparum, as the gold standard. The sensitivity and specificity of blood smears were 36.4% (95% confidence interval [CI] = 18.0-59.2%) and 99.6% (95% CI = 97.7-100%), respectively. The corresponding values for RDT were 31.8% (95% CI = 14.7-54.9%) and 100% (95% CI = 98.3-100%). The RDTs could replace blood smears for diagnosis of malaria in pregnancy by virtue of their relative ease of use. Field-based sensitive tests for malaria in pregnancy are urgently needed. PMID- 22232457 TI - Rolling Malaria Indicator Surveys (rMIS): a potential district-level malaria monitoring and evaluation (M&E) tool for program managers. AB - Novel malaria monitoring and evaluation (M&E) tools are urgently needed to complement the current "gold standard" Malaria Indicator Surveys (MIS). Rapid up scaling of malaria control efforts is resulting in substantial reductions in malaria burden across sub-Saharan Africa. As transmission goes down, timely, accurate, sub-national, and district level burden estimates are needed to guide increasingly targeted control efforts in remaining hotspot areas. To test a novel district level M&E tool, we have conducted a continuous ("rolling") MIS (rMIS) since May 2010 covering 50 villages in Chikhwawa district in southern Malawi, essentially adapting an existing cross-sectional evaluation tool into a continuous monitoring tool. Here, we report on our experience after completing the first full year of monthly data collection focusing on the methods, operational aspects, and estimated costs of rMIS in a programmatic setting. The potential applicability of this promising M&E approach for district-level program managers and control efforts is discussed. PMID- 22232458 TI - Leishmania infantum chagasi in northeastern Brazil: asymptomatic infection at the urban perimeter. AB - Visceral leishmaniasis (VL) is endemic in large cities in Brazil, including Natal. We determined the prevalence of asymptomatic human infection with Leishmania infantum chagasi and associated environmental risks around Natal. Infection was detected by Leishmania skin test (LST) and anti-leishmanial antibodies in humans and anti-leishmanial antibodies in dogs. Amongst 345 humans, 24.6% were seropositive, and 38.6% were LST-positive. Prevalence of positive serology was similar in both sexes and across all ages. However, positive LST responses increased with age, suggesting that LST is long-lasting and cumulative. Multinomial logistic analysis showed that LST response varied with location (P = 0.007) and that males were more frequently LST-positive (P = 0.027). Indicators of lower socioeconomic status associated significantly with human infection. Furthermore, there was geographic coincidence of seropositive humans and dogs (r = 0.7926, P = 0.011). These data suggest that dog and human L. i. chagasi infection are intimately interrelated in environmental conditions associated with low income. PMID- 22232459 TI - American visceral leishmaniasis in Chiapas, Mexico. AB - We report the results of a study conducted during 1990-2006 with 89 cases of American visceral leishmaniasis in Chiapas State in southeastern Mexico and a seroprevalence study performed with 726 persons and 224 dogs that lived near cases of American visceral leishmaniasis. Clinical aspects, epidemiologic profiles, and risk factors are described. Most cases were in children <= 5 years of age, the prevalence of seropositive persons was 77%. The main risk factors associated with this disease were having 1-3 rooms in a house compared with >= 4 rooms, having a roof that was not made of cement, and having domestic animals. In contrast, only 19% of dogs were seropositive, suggesting that this species is not important in the transmission cycle of Leishmania. These data indicate that active transmission is taking place in the central valley of Chiapas State, Mexico, in communities located < 1,000 meters above sea level near the Grijalva River. PMID- 22232460 TI - Epidemiology of imported cutaneous leishmaniasis at the Hospital for Tropical Diseases, London, United Kingdom: use of polymerase chain reaction to identify the species. AB - This study reviewed all patients diagnosed with imported cutaneous leishmaniasis (CL) at the Hospital for Tropical Diseases in London, United Kingdom, over an 11 year period. Diagnostic and epidemiologic information was collected prospectively for all patients with imported CL to this hospital during 1998-2009. A total of 223 patients were given a diagnosis of CL. Ninety patients were diagnosed with Old World CL, which was caused most commonly by Leishmania donovani complex (n = 20). A total of 71% were tourists to the Mediterranean region, 36% were migrants or visiting friends and relatives, and 17% were soldiers. One hundred thirty three patients were given a diagnosis of New World CL. The Leishmania subgenus Viannia caused 97 of these cases; 44% of these were in backpackers and 29% were in soldiers. Polymerase chain reaction was more sensitive and faster for detecting Leishmania DNA (86% for Old World CL and 96% for New World CL) than culture. This is the largest study of imported leishmaniasis, and demonstrates that tourists to the Mediterranean and backpackers in Central and South America are at risk for this disease. PMID- 22232461 TI - Evaluation of serum procalcitonin levels for diagnosis of secondary bacterial infections in visceral leishmaniasis patients. AB - Abstract. Secondary bacterial infections are a major complication and cause of death in children with visceral Leishmaniasis (VL). Thus, early diagnosis of bacterial infections is an important step in the treatment of patients with VL. The goal of this study was to determine if serum procalcitonin (PCT) could be used as a diagnostic marker of secondary bacterial infections in VL patients. Serum PCT was measured in 35 hospitalized patients with VL before treatment and after defervescence. The level was higher than normal (> 0.5 ng/mL) in 72% (25) of the patients. Twelve (34%) of 35 patients had secondary bacterial infections with PCT levels ranging from 0.1 to 12.29 ng/mL, and those without secondary bacterial infections (23) had PCT levels ranging from 0.1 to 14.58 ng/mL. The results suggest that PCT levels increase significantly in most VL patients but are not correlated with the presence of secondary bacterial infections. PMID- 22232462 TI - The effect of a high-fat breakfast on the pharmacokinetics of moxidectin in healthy male subjects: a randomized phase I trial. AB - The objective of this study was to assess the effect of a high-fat meal on the pharmacokinetics of moxidectin. Healthy male subjects were randomized to receive single oral 8 mg doses of moxidectin after an overnight fast or high-fat breakfast. In fasted subjects (N = 27), mean [SD] parameters were C(max): 58.9 [12.5] ng/mL; t(max): 3.7 [1.5] h; area under concentration-time curve (AUC): 3,387 [1,328] ng/h/mL; Vlambda(z)/F: 2,829 [1,267] L; CL/F: 2.76 [1.28] L/h; and t(1/2): 784 [347] h. Compared with fasted subjects, fed subjects (N = 27) exhibited a 34% increase in C(max), delay in t(max) to 5.3 [2.1] h, 44% increase in AUC, 40% decrease in Vlambda(z)/F, and a 35% decrease in CL/F. There was no significant change in t(1/2). The changes are consistent with an increase in moxidectin bioavailability following administration with food. There were no clinically relevant changes in vital signs, laboratory tests, or electrocardiograms. PMID- 22232463 TI - Capillaria philippinensis in Upper Egypt: has it become endemic? AB - The goal of this study was to present an overview of human infections with Capillaria philippinensis, a new emerging parasite in Upper Egypt. The study included 21 inpatients who had been admitted to the Assiut University Hospital. Patients suffered from intermittent abdominal pain, borborygmi, chronic diarrhea lasting for several weeks, and marked weight loss. Hypoalbuminemia and low serum levels of potassium, calcium, and sodium were detected in most patients. A stool examination was performed using direct smears and the formalin-ether concentration method. Intact adult worms and/or eggs were evaluated using a light microscope and processed for scanning electron microscopy. The examination by light microscopy illustrated the general morphology of different stages. Using scanning electron microscopy, intestinal villi were found partially covering the cuticle of the adult worms, which provided evidence for the invasion of adult worms into the jejunal mucosa. Two distinct types of eggs, thick-shelled and thin shelled, were identified and measured. PMID- 22232464 TI - Horizontal and vertical transmission of West Nile virus genotype NY99 by Culex salinarius and genotypes NY99 and WN02 by Culex tarsalis. AB - Culex tarsalis is a superior horizontal and vertical vector of West Nile virus (WNV) compared with Culex salinarius. Culex salinarius transmitted WNV genotype NY99 (CT 2741-99 strain) horizontally to suckling mice at significantly lower rates than Cx. tarsalis on Days 8, 9, 10, and 12 post-infection, and Cx. salinarius transmitted WNV genotype NY99 to offspring at a lower vertical transmission infection rate than Cx. tarsalis. Culex tarsalis transmitted WNV genotypes NY99 and WN02 (CT S0084-08 strain) with equal efficiency. Daily percent horizontal transmission of genotype NY99 by Cx. tarsalis-infected per os and by intra-thoracic infection was not significantly different from daily transmission of genotype WN02 from Days 5-23 and Days 2-9 post-infection, respectively. Our findings do not support the previously published hypothesis that genotype NY99 was replaced in the New World by WN02 because of a shorter extrinsic incubation of WN02. PMID- 22232466 TI - Trends in clinical diagnoses of Rocky Mountain spotted fever among American Indians, 2001-2008. AB - American Indians are at greater risk for Rocky Mountain spotted fever (RMSF) than the general U.S. population. The epidemiology of RMSF among American Indians was examined by using Indian Health Service inpatient and outpatient records with an RMSF International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis. For 2001-2008, 958 American Indian patients with clinical diagnoses of RMSF were reported. The average annual RMSF incidence was 94.6 per 1,000,000 persons, with a significant increasing incidence trend from 24.2 in 2001 to 139.4 in 2008 (P = 0.006). Most (89%) RMSF hospital visits occurred in the Southern Plains and Southwest regions, where the average annual incidence rates were 277.2 and 49.4, respectively. Only the Southwest region had a significant increasing incidence trend (P = 0.005), likely linked to the emergence of brown dog ticks as an RMSF vector in eastern Arizona. It is important to continue monitoring RMSF infection to inform public health interventions that target RMSF reduction in high-risk populations. PMID- 22232465 TI - Multiplex assay for species identification and monitoring of insecticide resistance in Anopheles punctulatus group populations of Papua New Guinea. AB - Anopheles punctulatus sibling species (An. punctulatus s.s., Anopheles koliensis, and Anopheles farauti species complex [eight cryptic species]) are principal vectors of malaria and filariasis in the Southwest Pacific. Given significant effort to reduce malaria and filariasis transmission through insecticide-treated net distribution in the region, effective strategies to monitor evolution of insecticide resistance among An. punctulatus sibling species is essential. Mutations in the voltage-gated sodium channel (VGSC) gene have been associated with knock-down resistance (kdr) to pyrethroids and DDT in malarious regions. By examining VGSC sequence polymorphism we developed a multiplex assay to differentiate wild-type versus kdr alleles and query intron-based polymorphisms that enable simultaneous species identification. A survey including mosquitoes from seven Papua New Guinea Provinces detected no kdr alleles in any An. punctulatus species. Absence of VGSC sequence introgression between species and evidence of geographic separation within species suggests that kdr must be monitored in each An. punctulatus species independently. PMID- 22232467 TI - Virological surveillance of dengue in Saint Martin and Saint Barthelemy, French West Indies, using blood samples on filter paper. AB - To strengthen active dengue surveillance in Saint Martin and Saint Barthelemy, two French Caribbean islands, we evaluated the epidemiological usefulness of collecting blood samples from NS1-positive dengue patients on filter paper to identify the dengue serotypes circulating in these regions during a 27-month period. This approach allowed dengue serotypes to be identified by reverse transcriptase-polymerase chain reaction in 90.1% of the total set of 666 samples analyzed and, in 95.5% of the samples collected during the acute phase of the disease. This prospective virological surveillance using blood samples absorbed onto filter paper, which were stored at 4 degrees C and shipped at ambient temperature to a specialized laboratory for analysis, allowed us to avoid the logistic and financial costs associated with shipping frozen venous blood samples. This surveillance system offers a low-cost alternative for reinforcing dengue prevention in areas where specialized laboratories do not exist, notably by facilitating the early detection of potentially new dengue serotypes. PMID- 22232468 TI - Evaluation of the 2009 WHO dengue case classification in an Indonesian pediatric cohort. AB - The classification of dengue virus-infected patients continues to be a challenge to researchers and clinicians in the field. The accuracy of the 1997 World Health Organization (WHO) dengue case definition has been debated for a decade, because the definition was very stringent, for instance, several researchers showed that apparently severe cases were misclassified as not severe. Therefore the WHO issued revised guidelines in 2009. Here, we retrospectively compared the performance of the WHO case definition of 2009 with the WHO case definition of 1997 in a detailed documented pediatric cohort from Indonesia. Intensive treatment intervention was used as an indicator of severity of disease. In line with our expectations, the 2009 WHO case classification proved to be significantly more specific, albeit less sensitive than the WHO case classification of 1997. We conclude that the revised classification is promising both from research and clinical perspectives, but validation of the classification criteria still needs to be addressed. PMID- 22232469 TI - Chikungunya and dengue fever among hospitalized febrile patients in northern Tanzania. AB - Consecutive febrile admissions were enrolled at two hospitals in Moshi, Tanzania. Confirmed acute Chikungunya virus (CHIKV), Dengue virus (DENV), and flavivirus infection were defined as a positive polymerase chain reaction (PCR) result. Presumptive acute DENV infection was defined as a positive anti-DENV immunoglobulin M (IgM) enzyme-linked immunsorbent assay (ELISA) result, and prior flavivirus exposure was defined as a positive anti-DENV IgG ELISA result. Among 870 participants, PCR testing was performed on 700 (80.5%). Of these, 55 (7.9%) had confirmed acute CHIKV infection, whereas no participants had confirmed acute DENV or flavivirus infection. Anti-DENV IgM serologic testing was performed for 747 (85.9%) participants, and of these 71 (9.5%) had presumptive acute DENV infection. Anti-DENV IgG serologic testing was performed for 751 (86.3%) participants, and of these 80 (10.7%) had prior flavivirus exposure. CHIKV infection was more common among infants and children than adults and adolescents (odds ratio [OR] 1.9, P = 0.026) and among HIV-infected patients with severe immunosuppression (OR 10.5, P = 0.007). CHIKV infection is an important but unrecognized cause of febrile illness in northern Tanzania. DENV or other closely related flaviviruses are likely also circulating. PMID- 22232470 TI - Persistence of viral RNA in chikungunya virus-infected Aedes aegypti (Diptera: Culicidae) mosquitoes after prolonged storage at 28 degrees C. AB - Experiments were conducted to determine the persistence of chikungunya viral (CHIKV) RNA in experimentally infected Aedes aegypti mosquitoes stored for prolonged periods at 28 degrees C. Intra-thoracically inoculated mosquitoes with confirmed positivity were killed by quick freezing at -80 degrees C, applied to sticky tape, and stored at 28 degrees C with 80 +/- 5% relative humidity (RH). At weekly intervals, five mosquitoes were removed from the tape randomly and assayed individually for detection of viral RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). CHIKV RNA was detected up to 12 weeks in dry mosquitoes by RT PCR. Virus could not be isolated either in cell culture or in the suckling Swiss albino mouse system at any stage. This study demonstrated the persistence of CHIKV viral RNA up to 12 weeks when stored at 28 degrees C with RH 80 +/- 5%. This finding will have significance in CHIKV surveillance programs in mosquito populations or field-based studies in countries where maintenance of a cold chain is a concern. PMID- 22232472 TI - Emergency department eye care in Florida: a study of principal payer sources 2005 through 2009. AB - OBJECTIVE: To describe trends in health insurance coverage for emergency department (ED) eye care in Florida from January 1, 2005, through December 31, 2009. METHODS: The Florida Agency for Health Care Administration ED data sets for ED outpatient visits and ED admissions for eye care were analyzed for type of insurance coverage and stratified according to age younger than 18 years and 18 years or older. Negative binomial regression models were used to measure the percentage of change in payer distribution for each 1-year increase in calendar year. RESULTS: During the 5-year study period, commercial insurance was the most frequent payer of ED outpatient services (31.1%), followed by self-pay (26.2%) and Medicaid (22.0%). For persons younger than 18 years, Medicaid and self payment made up 67.7% of principal payers. For outpatient ED visits, the percentage of change in Medicaid increased 5.9% for each calendar year (P < .001) and commercial coverage declined 4.5% (P < .001 ). The proportion of Florida residents receiving Medicaid during the study period was less than the national average. CONCLUSIONS: A substantial proportion of ED eye care in Florida is reimbursed through Medicaid or is paid for out of pocket. How the Patient Protection and Affordable Care Act of 2010 and the national economic recovery will affect safety-net institutions such as EDs and hospital staff is speculative, but the effect could be substantial. PMID- 22232473 TI - Postoperative visual acuity in patients with fuchs dystrophy undergoing descemet membrane-stripping automated endothelial keratoplasty: correlation with the severity of histologic changes. AB - OBJECTIVE: To investigate a correlation between the severity of histologic changes of the Descemet membrane in patients with Fuchs endothelial dystrophy and the best-corrected visual acuity (VA) after Descemet membrane-stripping automated endothelial keratoplasty (DSAEK). METHODS: In a retrospective study design, we created a histologic grading system based on common characteristics observed histologically among 92 DSAEK specimens sent to the University of Wisconsin Eye Pathology Laboratory with a clinical diagnosis of Fuchs dystrophy from 3 separate corneal surgeons. Cases were graded as mild, moderate, or severe on the basis of guttae dispersion, presence of a laminated Descemet membrane, presence of embedded guttae, and density of guttae. Regression models were built to study the relationship among preoperative VA, histologic findings, and best-corrected VA 6 months and 1 and 2 years after DSAEK. RESULTS: No correlation was found between the severity of histologic changes of Descemet membrane and preoperative VA. However, a correlation was noted between the preoperative and final VA. Cases with a laminated Descemet membrane but no embedded guttae (n = 8) appeared to be less responsive to DSAEK. Otherwise, the severity of histologic changes of Descemet membrane observed in patients with Fuchs corneal dystrophy after DSAEK did not show a statistically significant correlation with final VA. CONCLUSIONS: Our analysis fails to show an inverse relationship between the severity of histologic changes of the Descemet membrane and the best-corrected VA of at least 20/40 after DSAEK for Fuchs endothelial dystrophy. However, in a subset of patients with Fuchs dystrophy who develop a laminated Descemet membrane without embedded guttae, the visual recovery after DSAEK is less than expected. The laminated architecture of Descemet membrane without embedded guttae may facilitate separation between the membrane layers and, thus, incomplete removal of the recipient's Descemet membrane during DSAEK, which may then limit the postoperative visual outcome. PMID- 22232474 TI - New grading system to improve the surgical outcome of multirecurrent pterygia. AB - OBJECTIVE: To report a new grading system and surgical outcome by sealing the gap between the conjunctiva and Tenon capsule. METHODS: A total of 32 eyes of 30 patients with pterygia were managed at the Ocular Surface Center from January 1, 2002, through December 31, 2010. The eyes were consecutively operated on by recession; sealing of the gap; covering of exposed medial rectus muscle by amniotic membrane, conjunctival autograft, or oral mucosal graft (OMG); and covering of the bare sclera with amniotic membrane. Main outcome measures were recurrence, diplopia, and caruncle morphological characteristics. RESULTS: Caruncle grading strongly correlated with residual conjunctiva (P = .01), severity of diplopia (P = .001), and overall success rate (P = .05). Amniotic membrane transplantation alone was successful in 23 eyes with residual conjunctiva of 27.8 (10.1) mm, which was significantly longer than those in 6 cases in which amniotic membrane transplantation failed (13.1 [11.4] mm, P = .007) and those in 8 cases in which amniotic membrane transplantation was successful but that required an additional conjunctival autograft or oral mucosal graft (10.9 [10.4] mm, P = .001). During mean (SD) follow-up of 27.5 (20.5) months, 30 of 32 eyes (94%) achieved total success without recurrence and diplopia and normal caruncle in 17 of 21 eyes (81%) with abnormal caruncle before surgery. One eye (3%) developed corneal recurrence and was lost to follow-up, and 1 eye (3%) was left with a depressed caruncle and residual diplopia on adduction. CONCLUSIONS: Caruncle morphological characteristics and residual conjunctiva measurement help grade the severity of recurrent pterygium, guide surgical techniques, and predict outcomes. Sealing of the gap is important to create a strong barrier for preventing recurrence, restoring caruncle morphological characteristics, and regaining full motility in multirecurrent pterygia. PMID- 22232475 TI - Multimodality diagnostic imaging in unilateral acute idiopathic maculopathy. AB - OBJECTIVE: To describe the clinical features and imaging characteristics in unilateral acute idiopathic maculopathy. METHODS: Retrospective review of 4 patients with a diagnosis of unilateral acute idiopathic maculopathy. Clinical characteristics (age, symptoms, Snellen visual acuity, and funduscopic features) and images from spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography were analyzed. RESULTS: The median (range) age at presentation was 31 (27-52) years. The median (range) interval between symptom onset and presentation was 4 (1-20) weeks. Associated systemic findings included a viral prodrome (50%), orchitis (50%), hand-foot-mouth disease (25%), and positive coxsackievirus titers (50%). The median (range) visual acuity at initial examination was 20/400 (20/70 to 1/400), which improved to 20/30 (20/20 to 20/60) at final follow-up. The median (range) follow-up time was 8 (8-13) weeks. Early in the disease course, the central macula developed irregular, circular areas of white-gray discoloration. Following recovery, the macula had a stippled retinal pigment epithelium characterized by rarefaction and hyperplasia. Fluorescein angiography demonstrated irregular early hyperfluorescence and late subretinal hyperfluorescence. Spectral-domain optical coherence tomography showed a partially reversible disruption of the outer photoreceptor layer. Fundus autofluorescence initially revealed stippled autofluorescence that eventually became more hypoautofluorescent. Indocyanine green angiography showed "moth eaten"-appearing choroidal vasculature, suggestive of choroidal inflammation. CONCLUSIONS: The imaging characteristics highlight the structural changes during the active and resolution phases of unilateral acute idiopathic maculopathy. The visual recovery correlates with structural changes and suggests that the pathogenesis involves inflammation of the inner choroid, retinal pigment epithelium, and outer photoreceptor complex that is partially reversible. PMID- 22232477 TI - Capsule membrane suture fixation of decentered sulcus intraocular lenses. AB - Different surgical methods are used to fixate the subluxated sulcus intraocular lens (IOL) in the absence of in-bag fixation, ranging from iris and scleral suturing to optic capture of the IOL. A new technique, which we have termed capsule membrane suture fixation, provides an additional method for securing a subluxated or decentered sulcus-based IOL to the remnant capsule or a capsular membrane. This method can also be used in secondary surgery for fixation, repositioning, or removal and replacement of IOLs. In this technique, the IOL haptics are sutured to the fibrotic elements of the capsular membrane to center and secure the IOL to the capsular membrane and prevent complications associated with uveal touch. PMID- 22232478 TI - Emergency department use for eye care services and future directions in care. PMID- 22232476 TI - Dry eye disease: an immune-mediated ocular surface disorder. AB - Dry eye disease is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully understood, it is recognized that inflammation has a prominent role in the development and propagation of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle. Herein, we review the fundamental links between inflammation and dry eye disease and discuss the clinical implications of inflammation in disease management. PMID- 22232479 TI - The role of antiviral therapy after the resolution of acute herpes simplex keratitis or acute herpes zoster ophthalmicus. PMID- 22232480 TI - Interview with Thaddeus P. Dryja, MD. Interviewed by George B. Bartley. PMID- 22232482 TI - Population differences in genetic risk for age-related macular degeneration and implications for genetic testing. PMID- 22232481 TI - Polymerase chain reaction-based ganciclovir resistance testing of ocular fluids for cytomegalovirus retinitis. PMID- 22232483 TI - beta-Blocking and racial variation in the severity of retinopathy of prematurity. PMID- 22232484 TI - Epithelial downgrowth after type 1 Boston keratoprosthesis manifesting as tractional retinal detachment and epiretinal membrane. PMID- 22232485 TI - Bilateral uveal effusion and angle-closure glaucoma associated with bupropion use. PMID- 22232486 TI - Small dose of rituximab for graves orbitopathy: new insights into the mechanism of action. PMID- 22232487 TI - Risks of adverse events with therapies for age-related macular degeneration: a response. PMID- 22232489 TI - External needle drainage device. PMID- 22232490 TI - Restricting fermentative potential by proteome remodeling: an adaptive strategy evidenced in Bacillus cereus. AB - Pathogenesis hinges on successful colonization of the gastrointestinal (GI) tract by pathogenic facultative anaerobes. The GI tract is a carbohydrate-limited environment with varying oxygen availability and oxidoreduction potential (ORP). How pathogenic bacteria are able to adapt and grow in these varying conditions remains a key fundamental question. Here, we designed a system biology-inspired approach to pinpoint the key regulators allowing Bacillus cereus to survive and grow efficiently under low ORP anoxic conditions mimicking those encountered in the intestinal lumen. We assessed the proteome components using high throughput nanoLC-MS/MS techniques, reconstituted the main metabolic circuits, constructed DeltaohrA and DeltaohrR mutants, and analyzed the impacts of ohrA and ohrR disruptions by a novel round of shotgun proteomics. Our study revealed that OhrR and OhrA are crucial to the successful adaptation of B. cereus to the GI tract environment. Specifically, we showed that B. cereus restricts its fermentative growth under low ORP anaerobiosis and sustains efficient aerobic respiratory metabolism, motility, and stress response via OhrRA-dependent proteome remodeling. Finally, our results introduced a new adaptive strategy where facultative anaerobes prefer to restrict their fermentative potential for a long term benefit. PMID- 22232492 TI - Emergency lung transplantation contributes to knock down mortality on the waiting list. PMID- 22232491 TI - Proteome analyses of hydrogen-producing hyperthermophilic archaeon Thermococcus onnurineus NA1 in different one-carbon substrate culture conditions. AB - Thermococcus onnurineus NA1, a sulfur-reducing hyperthermophilic archaeon, is capable of H(2)-producing growth, considered to be hydrogenogenic carboxydotrophy. Utilization of formate as a sole energy source has been well studied in T. onnurineus NA1. However, whether formate can be used as its carbon source remains unknown. To obtain a global view of the metabolic characteristics of H(2)-producing growth, a quantitative proteome analysis of T. onnurineus NA1 grown on formate, CO, and starch was performed by combining one-dimensional SDS PAGE with nano UPLC-MS(E). A total of 587 proteins corresponding to 29.7% of the encoding genes were identified, and the major metabolic pathways (especially energy metabolism) were characterized at the protein level. Expression of glycolytic enzymes was common but more highly induced in starch-grown cells. In contrast, enzymes involved in key steps of the gluconeogenesis and pentose phosphate pathways were strongly up-regulated in formate-grown cells, suggesting that formate could be utilized as a carbon source by T. onnurineus NA1. In accordance with the genomic analysis, comprehensive proteomic analysis also revealed a number of hydrogenase clusters apparently associated with formate metabolism. On the other hand, CODH and CO-induced hydrogenases belonging to the Hyg4-II cluster, as well as sulfhydrogenase-I and Mbx, were prominently expressed during CO culture. Our data suggest that CO can be utilized as a sole energy source for H(2) production via an electron transport mechanism and that CO(2) produced from catabolism or CO oxidation by CODH and CO-induced hydrogenases may subsequently be assimilated into the organic carbon. Overall, proteomic comparison of formate- and CO-grown cells with starch-grown cells revealed that a single carbon compound, such as formate and CO, can be utilized as an efficient substrate to provide cellular carbon and/or energy by T. onnurineus NA1. PMID- 22232493 TI - Traversing the learning curve in minimally invasive heart valve surgery: a cumulative analysis of an individual surgeon's experience with a right minithoracotomy approach for aortic valve replacement. AB - OBJECTIVE: Cumulative sum (CUSUM) analysis, first developed to assess industrial quality control, was then used to monitor cardiac surgery performance more than 10 years ago. This analysis may be more sensitive than the standard statistical tools to analyse surgical results. The aim of this study is to assess a single surgeon's learning curve with right anterior minithoracotomy (RAMT) for aortic valve replacement (AVR) using risk-adjusted CUSUM curves and to compare the short and medium-term results of these patients with a propensity-matched cohort of patients who had standard AVR (SAVR). METHODS: The first 100 patients who underwent RAMT by a single surgeon were analysed, using risk-adjusted CUSUM curves. Predicted risks of failure for individual patients were derived from our institutional database, using logistic regression modelling. Perioperative death or one or more of 10 adverse events constituted failure. Finally, RAMT patients were matched to 100 SAVR patients operated by the same surgeon in the same period, using a propensity score analysis. RESULTS: The author's RAMT experience was associated with a low risk of cumulative failures from the outset, and no learning curve effect was observed. A cluster of surgical failure was individuated at the end of the CUSUM curve (between patients 90 and 100). The predicted risk of failure for the study population constantly increased over the time. After propensity score matching, no baseline differences were observed between RAMT and SAVR patients. The mortality rate was similar between groups (P = 0.8). However, the RAMT group had a lower need for mechanical-assisted ventilation (P = 0.02), transfusion requirements (P = 0.001), post-operative atrial fibrillation (P = 0.01) and post-operative intensive care unit and hospital stay (P = 0.001). Three-year survival was similar between groups (RAMT 94.5% vs. SAVR 92.8%). CONCLUSIONS: AVR can be safely performed through an RAMT with results comparable with the standard sternotomy technique. Patients undergoing this technique are not exposed to an increased operative risk also during the surgeon's initial experience. CUSUM analysis is a valuable tool to assess the learning curve of new surgical techniques and to implement continuous performance monitoring. PMID- 22232495 TI - Correct assessment of unusual hiatus hernia with magnetic resonance imaging. PMID- 22232496 TI - School playground facilities as a determinant of children's daily activity: a cross-sectional study of Danish primary school children. AB - BACKGROUND: This study investigates the influence of school playground facilities on children's daily physical activity. METHODS: Participants were 594 school children measured at preschool (age 6 to 7 years) and 3 years later in third grade (518 children age 9 to 10 years) from 18 schools in 2 suburban municipalities in Denmark. Physical activity data were obtained using accelerometers. These were related to the number of permanent play facilities in school grounds and the school playground area (m2). RESULTS: The number of play facilities in the school grounds was positively associated with all measures of children's activity. In preschool every 10 additional play facilities the children had access to was associated with an increase in the average accelerometer counts of 14% (r = .273, P < .001) in school time and 6.9% (r = .195, P < .001) overall. For the children in third grade, access to 10 additional play facilities was associated with an increase in school time activity level of 26% (r = .364, P < .001) and an increase in overall activity level of 9.4% (r = .211, P < .001). School playground area did not affect activity levels independently of the number of permanent play facilities. CONCLUSION: Increasing the number of play facilities in primary school playgrounds may increase the level of children's daily physical activity. PMID- 22232497 TI - Effect of urbanization on objectively measured physical activity levels, sedentary time, and indices of adiposity in Kenyan adolescents. AB - BACKGROUND: Urbanization affects lifestyles in the developing world but no studies have assessed the impact on objectively measured physical activity in children and adolescents from sub-Saharan Africa. PURPOSE: To compare objectively measured habitual physical activity, sedentary time, and indices of adiposity in adolescents from rural and urban areas of Kenya. METHODS: Physical activity and sedentary time were assessed by accelerometry for 5 consecutive days in 97 (50 female and 47 male) rural and 103 (52 female and 51 male) urban adolescents (mean age 13 +/- 1 years). Body Mass Index (BMI) and BMI z-scores were used to assess adiposity. RESULTS: Rural males spent more time in moderate-to-vigorous intensity physical activity (MVPA) compared with urban males (68 +/- 22 vs. 50 +/- 17 min, respectively; P < .001). Similarly, Rural females spent more time in MVPA compared with urban females (62 +/- 20 vs. 37 +/- 20 min, respectively; P < .001). Furthermore, there were significant differences in daily sedentary time between rural and urban subjects. Residence (rural vs. urban) significantly (P < .001) influenced BMI z-score (R(2) = .46). CONCLUSION: Rural Kenyan adolescents are significantly more physically active (and less sedentary) and have lower indices of adiposity compared with urban adolescents and this is a likely reflection of the impact of urbanization on lifestyle in Kenya. PMID- 22232498 TI - Preliminary evidence for school-based physical activity policy needs in Washington, DC. AB - BACKGROUND: The school setting could be a primary venue for promoting physical activity among inner-city children due to the structured natured of the school day. We examined differences in step counts between structured school days (SSD) and weekend days (WED) among a sample of public school children in Washington, DC. METHODS: Subjects (N = 29) were third- to sixth-grade students enrolled in government-funded, extended-day enrichment programs. Step counts were measured using a pedometer (Bodytronics) over 2 SSD and 2 WED. Differences in mean step counts between SSD and WED were determined using multivariable linear regression, with adjustments for age, sex, and reported distance between house and school (miles). RESULTS: Recorded step counts were low on both SSD and WED (7735 +/- 3540 and 8339 +/- 5314 steps/day). Boys tended to record more steps on SSD compared with girls (8080 +/- 3141 vs. 7491 +/- 3872 steps/day, respectively), whereas girls recorded more steps on the WED compared with boys (9292 +/- 6381 vs. 7194 +/- 3669 steps/day). Parameter estimates from the regression modeling suggest distance from school (P < .01) to be the strongest predictor of daily step counts, independent of day (SSD/WED), sex, and age. CONCLUSION: Among inner city school children, a safe walking route to and from school may provide an important opportunity for daily physical activity. PMID- 22232499 TI - Correlates of children's moderate and vigorous physical activity during weekdays and weekends. AB - BACKGROUND: Vigorous-intensity physical activity (VPA) may confer superior health benefits for children compared to moderate-intensity physical activity (MPA), but the correlates of MPA and VPA may differ. The study purpose was to investigate associations between selected enabling, predisposing, and demographic physical activity correlates, and MPA and VPA during weekdays and at weekends. METHODS: Data were gathered from 175 children (aged 10 to 11 years). MPA and VPA were assessed using accelerometers. Correlates were measured at child and school levels. Multilevel analyses identified correlates that significantly predicted MPA and VPA. RESULTS: Gender significantly predicted weekday MPA (P < .001), and weekend MPA (P = .022) and VPA (P = .035). Weekday VPA was predicted by gender (P < .001), indices of multiple deprivation score (P < .003), BMI (P = .018), and school playground area (P = .046). CONCLUSIONS: Gender was the most significant correlate of MPA and VPA. Children most likely to engage in weekday VPA were boys with lower deprivation scores and BMI values, with access to larger playground areas. PMID- 22232500 TI - Effects of an autonomy-supportive exercise instructing style on exercise motivation, psychological well-being, and exercise attendance in middle-age women. AB - BACKGROUND: The present study evaluated the effectiveness of an autonomy supportive intervention based on self-determination theory in influencing perceptions of autonomy support, basic psychological needs, behavioral regulations, subjective vitality, and exercise behavior. METHODS: 35 female exercise participants age 30 to 58 years who enrolled to an 8-week exercise program attended 24 exercise classes that were taught using either an autonomy supportive (n = 19) or a lack of autonomy support (n = 16) instructing style. RESULTS: The experimental group reported an increase in perceived autonomy support, the fulfillment of the needs for autonomy and competence, identified regulation, intrinsic motivation, and subjective vitality. They also reported higher attendance rates during the program and greater participation to moderate and/or mild nonstructured exercise during 5 weeks after the end of the program. The control group reported a decrease in perceived autonomy support, the needs for autonomy and competence, intrinsic motivation, and subjective vitality. CONCLUSION: The results supported tenets of self-determination theory and highlighted the motivational and psychological benefits of an autonomy-supportive exercise instructing style among middle-age women. PMID- 22232501 TI - Objectively assessing treadmill walking during the second and third pregnancy trimesters. AB - BACKGROUND: To effectively promote physical activity (PA) and quantify the effects of PA interventions for pregnant women, PA measurement during pregnancy needs improvement. The purpose of this study was to assess PA monitor output during a controlled, treadmill walking protocol among pregnant women at 20- and 32-weeks gestation. METHODS: Women (N = 43) wore an Actigraph accelerometer, NL1000, and Yamax pedometer during a 20-minute treadmill walking test [5-minute periods at 4 different speeds (54, 67, 80, and 94 m.min(-1))] at 20- and 32-weeks gestation. RESULTS: Repeated-measures ANOVAs indicated that Actigraph total counts/minute and minutes of moderate-vigorous PA (MVPA), NL1000 steps and minutes MVPA, and Yamax steps decreased from 20- to 32-weeks gestation (P <= .05), while body girth circumference and activity monitor tilt increased (P <= .05). Repeated measures ANCOVAs, controlling for changes in body girth and monitor tilt, yielded no significant differences in any outcome measures from 20- to 32-weeks gestation. CONCLUSIONS: Preliminary results suggest physical changes during pregnancy impact activity monitor output in controlled settings. Accurately measuring and statistically controlling for changes in body girth at monitor placement site and monitor tilt may improve the accuracy of activity monitors for use with pregnant populations. PMID- 22232502 TI - Response Conversion for improving comparability of International Physical Activity data. AB - BACKGROUND: Many questionnaires for measuring physical activity (PA) exist. This complicates the comparison of outcomes. METHODS: In 8 European countries, PA was measured in random samples of 600 persons, using the IPAQ as a 'bridge' to historical sets of country-specific questions. We assume that a unidimensional scale of PA ability exists on which items and respondents can be placed, irrespective of country, culture, background factors, or measurement instrument. Response Conversion (RC) based on Item Response Theory (IRT) was used to estimate such a common PA scale, to compare PA levels between countries, and to create a conversion key. Comparisons were made with Eurobarometer (IPAQ) data. RESULTS: Appropriateness of IRT was supported by the existence of a strong first dimension established by principal component analysis. The IRT analysis resulted in 1 common PA scale with a reasonable fit and face validity. However, evidence for cultural bias (Differential Item Functioning, DIF) was found in all IPAQ items. This result made actual comparison between countries difficult. CONCLUSIONS: Response Conversion can improve comparability in the field of PA. RC needs common items that are culturally unbiased. Wide-scale use of RC awaits measures that are more culturally invariant (such as international accelerometer data). PMID- 22232503 TI - Farming activities and carrying and lifting: the Agricultural Health Study. AB - BACKGROUND: Heavy carrying and lifting (HCL) is a common activity among farmers that may be related to health. The aim of this study was to examine HCL as a proxy for occupational physical activity (PA) among farm residents. The secondary objective was to evaluate PA based on HCL. METHODS: Data from 21,296 farmers and 30,951 spouses in the Agricultural Health Study examined the relationship between HCL and farm activities and individual/farm characteristics. HCL was categorized as >= 1 or < 1 hours per day. The association between HCL and farm activities (15 for farmers; 16 for spouses) and individual/farm characteristics was examined using adjusted logistic regression. To evaluate PA, we created a PA activity index using metabolic equivalents for HCL, and compared PA weekly averages with national guidelines. RESULTS: In adjusted results, most farm activities were significantly associated with HCL. Based on HCL, farmers had a median of 1.5 hours and spouses 0.5 hours of vigorous or muscle-strengthening PA per day. Most farmers (94%) and about 60% of spouses meet or exceed 2008 national guidelines for vigorous or muscle-strengthening PA. CONCLUSION: Findings suggest the HCL measure may be useful as a PA metric in future studies of occupational PA among farm residents. PMID- 22232504 TI - Active for a day: predictors of relapse among previously active mass event participants. AB - BACKGROUND: To promote maintenance of sufficient physical activity (PA), better understanding of factors associated with behavioral relapse is needed. PURPOSE: To identify PA relapsers and predictors of this state in a large community sample of women who participated in 2 mass 10-km events in Ireland. METHODS: Relapsers to 'low active' were identified at 3-month follow-up, and factors associated with relapse investigated. RESULTS: 11% of the sample decreased their participation by at least 60 minutes of moderate-intensity PA per week and regressed to 'insufficiently active.' Adjusted analysis indicated relapse was associated with walking the event (OR = 1.40; 95% CI = 1.05-1.85) and not achieving tertiary education (OR = 1.49; 95% CI = 1.18-1.88). Normal-range BMI, training continuously, urban residence, and increases in self efficacy and positive perceptions of the physical environment were related to lower incidence of relapse. CONCLUSION: Education, living in an urban area, BMI, walking the event, training, and self efficacy are all associated with relapse and while mass events are a useful motivator for PA, strategies are required following events to maintain participation levels and generate a lasting public health impact. PMID- 22232505 TI - Self-Reported and objectively measured physical activity among a cohort of postpartum women: the PIN Postpartum Study. AB - BACKGROUND: Few studies measure physical activity objectively or at multiple time points during postpartum. We describe physical activity at 3- and 12-months postpartum among a cohort of women using both self-reported and objective measures. METHODS: In total, 181 women completed the 3-month postpartum measures, and 204 women completed the 12-month postpartum measures. Participants wore an ActiGraph accelerometer for 1 week and completed in-home interviews that included questions on physical activity. A cohort of 80 women participated at both time points. Poisson regression models were used to determine whether physical activity differed over time for the cohort. RESULTS: For the cohort, average counts/minute were 364 at 3-months postpartum and 394 at 12-months postpartum. At both time periods for the cohort, vigorous activity averaged 1 to 3 minutes/day, and moderate activity averaged 16 minutes/day. Sedentary time averaged 9.3 hours at 3-months postpartum and 8.8 hours at 12-months postpartum, out of a 19-hour day. Average counts/minute increased and sedentary behavior declined from 3- to 12-months postpartum. CONCLUSION: Interventions are needed to help women integrate more moderate to vigorous physical activity and to capitalize on the improvements in sedentary behavior that occur during postpartum. PMID- 22232507 TI - A comparison of engagement strategies for encouraging outdoor walking. AB - BACKGROUND: This study investigated the effectiveness of enhanced cognitive awareness as a means of encouraging outdoor walking. An intervention using engagement-based strategies was compared with a more traditional walking intervention focused on developing and committing to a personalized walking schedule. METHODS: 117 adults were randomly assigned to 1 of 2 treatments Standard Care (schedule setting, commitment) or Engagement (awareness plans)-and asked to take at least 3, 30 minute outdoor walks each week for 2 weeks. During the study period, self-report and objective measures were used to collect data on walking behavior. RESULTS: Individuals in both treatment conditions reported significant increases (P < .05) in walking behavior. Participants in both treatments failed to sustain these increases at a follow-up measure 4 weeks later. However, the Engagement condition was particularly effective for those individuals who had less prior experience maintaining a walking routine. CONCLUSION: Overall, the findings suggest it may be beneficial to incorporate engagement-based strategies into existing walking interventions. Results of this study also raise the possibility that efforts to encourage cognitive awareness may make the outdoor walking experience more interesting and enjoyable. PMID- 22232506 TI - Patterns of yoga practice and physical activity following a yoga intervention for adults with or at risk for type 2 diabetes. AB - BACKGROUND: The current study described patterns of yoga practice and examined differences in physical activity over time between individuals with or at risk for type 2 diabetes who completed an 8-week yoga intervention compared with controls. METHODS: A longitudinal comparative design measured the effect of a yoga intervention on yoga practice and physical activity, using data at baseline and postintervention months 3, 6, and 15. RESULTS: Disparate patterns of yoga practice occurred between intervention and control participants over time, but the subjective definition of yoga practice limits interpretation. Multilevel model estimates indicated that treatment group did not have a significant influence in the rate of change in physical activity over the study period. While age and education were not significant individual predictors, the inclusion of these variables in the model did improve fit. CONCLUSIONS: Findings indicate that an 8-week yoga intervention had little effect on physical activity over time. Further research is necessary to explore the influence of yoga on behavioral health outcomes among individuals with or at risk for type 2 diabetes. PMID- 22232508 TI - Pedometer-determined step-count guidelines for afterschool programs. AB - BACKGROUND: Policies to require afterschool programs (ASPs, 3 PM to 6 PM) to provide children a minimum of 30 minutes of moderate-to-vigorous physical activity (MVPA) exist. With few low-cost, easy-to-use measures of MVPA available to the general public, ASP providers are limited in their ability to track progress toward achieving this policy-goal. Pedometers may fill this gap, yet there are no step-count guidelines for ASPs linked to 30 minutes of MVPA. METHODS: Steps and accelerometer estimates of MVPA were collected concurrently over multiple days on 245 children (8.2 years, 48% boys, BMI-percentile 68.2) attending 3 community-based ASPs. Random intercept logit models and receiver operating characteristic (ROC) analyses were used to identify a threshold of steps that corresponded with attaining 30 minutes of MVPA. RESULTS: Children accumulated an average of 2876 steps (standard error [SE] 79) and 16.1 minutes (SE0.5) of MVPA over 111 minutes (SE1.3) during the ASP. A threshold of 4600 steps provided high specificity (0.967) and adequate sensitivity (0.646) for discriminating children who achieved the 30 minutes of MVPA; 93% of the children were correctly classified. The total area under the curve was 0.919. Children accumulating 4600 steps were 25times more likely to accumulate 30 minutes of MVPA. CONCLUSIONS: This step threshold will provide ASP leaders with an objective, low-cost, easy-to-use tool to monitor progress toward policy-related goals. PMID- 22232510 TI - Maturity associated variance in physical activity and health-related quality of life in adolescent females: a mediated effects model. AB - BACKGROUND: This study tested a mediated effects model of psychological and behavioral adaptation to puberty within the context of physical activity (PA). METHODS: Biological maturity status, physical self-concept, PA, and health related quality of life (HRQoL) were assessed in 222 female British year 7 to 9 pupils (mean age = 12.7 years, SD = .8). RESULTS: Structural equation modeling using maximum likelihood estimation and bootstrapping procedures supported the hypothesized model. Maturation status was inversely related to perceptions of sport competence, body attractiveness, and physical condition; and indirectly and inversely related to physical self-worth, PA, and HRQoL. Examination of the bootstrap-generated bias-corrected confidence intervals representing the direct and indirect paths between suggested that physical self-concept partially mediated the relations between maturity status and PA, and maturity status and HRQoL. CONCLUSIONS: Evidence supports the contention that perceptions of the physical self partially mediate relations maturity, PA, and HRQoL in adolescent females. PMID- 22232509 TI - Comparison of 3 measures of physical activity and associations with blood pressure, HDL, and body composition in a sample of adolescents. AB - BACKGROUND: The association of physical activity (PA), measured 3 ways, and biomarkers were compared in a sample of adolescents. METHODS: PA data were collected on 2 cohorts of adolescents (N = 700) in the Twin Cities, Minnesota, 2007-2008. PA was measured using 2 survey questions [Modified Activity Questionnaire (MAQ)], the 3-Day Physical Activity Recall (3DPAR), and accelerometers. Biomarkers included systolic (SBP) and diastolic blood pressure (DBP), lipids, percent body fat (%BF), and body mass index (BMI) percentile. Bivariate relationships among PA measures and biomarkers were examined followed by generalized estimating equations for multivariate analysis. RESULTS: The 3 measures were significantly correlated with each other (r = .22-.36, P < .001). Controlling for study, puberty, age, and gender, all 3 PA measures were associated with %BF (MAQ = -1.93, P < .001; 3DPAR = -1.64, P < .001; accelerometer = -1.06, P = .001). The MAQ and accelerometers were negatively associated with BMI percentile. None of the 3 PA measures were significantly associated with SBP or lipids. The percentage of adolescents meeting the national PA recommendations varied by instrument. CONCLUSIONS: All 3 instruments demonstrated consistent findings when estimating associations with %BF, but were different for prevalence estimates. Researchers must carefully consider the intended use of PA data when choosing a measurement instrument. PMID- 22232511 TI - Impact of a high body mass index on lower extremity injury in marathon/half marathon participants. AB - BACKGROUND: To evaluate whether a high body mass index (BMI) predisposes marathon/half-marathon participants to lower extremity injuries. METHODS: Consenting adult participants at the 2008 National Marathon to Fight Breast Cancer were enrolled in this observational study. The primary outcome measure was prevalence of self-reported lower extremity injury, during both training and race participation, with respect to BMI. RESULTS: There were 194 subjects with complete data: 139 females (72%) and 55 males. Forty-six percent of females and 51% of males ran the full marathon (P = .63). Median BMI was 23.7 kg/m(2) for females and 26.2 kg/m(2) for males (P = .001). Eleven (24%) females in BMI tertile 1 (T1) suffered a training injury, while 9 (18%) from T2 and 4 (9%) from T3 suffered injuries (P = .072; OR 0.89; 95% CI 0.78 to 1.01). Twenty-six (19%) females suffered an injury during the race. Females in T1 were more likely to suffer a race-related injury (P = .038; OR 0.87; 95% CI 0.77 to 0.99). Females were 13% less likely to suffer a race-related injury with each 1-unit increase in BMI. Rates of injury did not differ by BMI tertile in males. CONCLUSIONS: A high BMI did not impart an increased risk of lower extremity injury during training or race participation. PMID- 22232512 TI - Predicting bacterial fitness cost associated with drug resistance. AB - OBJECTIVES: It has been proposed that antimicrobial resistance could be associated with a fitness cost in bacteria, which is often determined by competition experiments between isogenic strains (wild-type and mutant). However, this conventional approach is time consuming and labour intensive. An alternative method was developed to assess the fitness cost in drug-resistant bacteria. METHODS: Time-growth studies were performed with approximately 1 * 10(5) cfu/mL of Acinetobacter baumannii or Pseudomonas aeruginosa at baseline. Serial samples were obtained to quantify the bacterial burden over 24 h. The growth rates (K(g)) of isogenic strains (antibiotic susceptible and resistant) were determined individually and used to predict their relative abundance in a co-culture over an extended period of time. The predicted difference between the two strains was subsequently validated by in vitro growth competition experiments. RESULTS: The growth rates of A. baumannii were not significantly different in different strengths of growth medium. The difference in bacterial burden observed in competition studies was in general agreement with the predicted difference based on K(g) values, suggesting good predicting ability of the mathematical model. CONCLUSIONS: The proposed mathematical model was found to be reasonable in characterizing bacterial growth and predicting the fitness cost of resistance. This simple method appears robust in the assessment of fitness cost associated with drug resistance and warrants further investigations. PMID- 22232513 TI - Prospective study of severity assessment and management of acute medical admissions with skin and soft tissue infection. AB - BACKGROUND: Several severity scoring systems have been proposed for skin and soft tissue infections (SSTIs), but none has been tested prospectively. METHODS: We prospectively enrolled adult, acute medical admissions with SSTI between April 2009 and June 2010. Severity was assessed using two proposed SSTI scoring systems, one based on a generic sepsis definition. Antimicrobial prescribing was compared with guideline recommendations. RESULTS: We enrolled 79 patients. One of the scoring systems classified 47% into class I (no sepsis or comorbidity), 5% into class II (no sepsis, but comorbidity), 34% into class III [sepsis, but standardized early warning system (SEWS) <4], and 14% into class IV (sepsis with SEWS >= 4). The other system classified 39% as mild and 61% as moderate/severe. There were significant discrepancies between the two scoring systems. Using the worst clinical observations in the first 24 h, 19% of patients had more severe disease than was apparent on admission. Under-treatment of patients with sepsis occurred in 13% of patients according to admission observations, increasing to 22% according to the worst observations. Seventy-nine percent of patients with sepsis received antibiotics within 4 h of admission. This was associated with fewer adverse outcomes (P = 0.05). CONCLUSIONS: There is significant room for improvement in the management of SSTIs presenting to acute medical units. The added value of specific SSTI severity scores over generic sepsis assessment requires validation in a larger prospective study. We have changed our antibiotics policy for SSTI to use generic sepsis scores, and we emphasize the need to reassess patients on the day of admission. PMID- 22232514 TI - Comment on: Prosthetic hip joint infection with a Streptococcus agalactiae isolate not susceptible to penicillin G and ceftriaxone. PMID- 22232515 TI - Photodynamic medicine and infection control. AB - Given the problem of increasing antimicrobial--especially antibacterial--drug resistance and the paucity of new agents, it is sensible to consider alternative approaches to infection control to aid in conservation. Photoantimicrobials are highly active agents, regardless of the conventional drug resistance status of the intended organism. Their use in infection control, via topical or local treatment protocols, has thus far received far from proper assessment and requires a wider audience. PMID- 22232516 TI - Rapid detection of carbapenemase genes by multiplex real-time PCR. AB - OBJECTIVES: To develop a single multiplex real-time PCR assay to detect six different genetic types of carbapenemases already identified in Enterobacteriaceae (KPC, GES, NDM, IMP, VIM and OXA-48). METHODS: A total of 58 bacterial isolates were tested. Thirty were previously characterized as resistant to carbapenems and documented by PCR and sequencing analysis to carry the following genes: bla(KPC) type, bla(GES) type, bla(IMP) type, bla(VIM) type, bla(OXA-48) and bla(NDM-1). These positive strains included 21 Enterobacteriaceae, 1 Acinetobacter baumannii and 8 Pseudomonas aeruginosa isolates. The remaining 28 isolates previously tested susceptible to carbapenems and were negative for these genes. Bacterial DNA was extracted using the easyMag extractor (bioMerieux, France). The real-time PCR was performed using the Rotor Gene 6000 instrument (Corbett Life Science, Australia) and specific primers for each carbapenemase target were designed using the DNAStar software (Madison, WI, USA). RESULTS: Each one of the six carbapenemase genes tested presented a different melting curve after PCR amplification. The melting temperature (T(m)) analysis of the amplicons identified was as follows: bla(IMP) type (T(m) 80.1 degrees C), bla(OXA-48) (T(m) 81.6 degrees C), bla(NDM-1) (T(m) 84 degrees C), bla(GES) type (T(m) 88.6 degrees C), bla(VIM) type (T(m) 90.3 degrees C) and bla(KPC) type (T(m) 91.6 degrees C). No amplification was detected among the negative samples. The results showed 100% concordance with the genotypes previously identified. CONCLUSIONS: The new assay was able to detect the presence of six different carbapenemase gene types in a single 3 h PCR. PMID- 22232517 TI - Metabolic syndrome among HIV-infected Taiwanese patients in the era of highly active antiretroviral therapy: prevalence and associated factors. AB - OBJECTIVES: Metabolic complications related to antiretroviral therapy are rarely investigated among HIV-infected patients in Asian countries. We investigated the prevalence of and factors associated with metabolic syndrome among HIV-infected patients who are ethnic Chinese in the era of highly active antiretroviral therapy (HAART). METHODS: A cross-sectional survey was performed to collect information on the demographic and clinical characteristics and antiretroviral therapy prescribed in 877 HIV-infected patients at a university hospital in Taiwan from May 2008 to April 2009. The modified Adult Treatment Panel III criteria were used to define metabolic syndrome after adjusting for the waist circumference criteria for Asians. RESULTS: Of the 877 patients, 75.3% were male homosexuals, 80.7% were receiving HAART and 88.7% had CD4 counts >= 200 cells/mm(3). Metabolic syndrome was diagnosed in 210 patients (26.2%). After adjusting for age, gender, smoking status, family history of diabetes mellitus, cardiovascular disease and hypertension, and baseline CD4 and plasma HIV RNA load, use of protease inhibitors (PIs) was significantly associated with the presence of metabolic syndrome (OR 1.63; 95% CI 1.10-2.43). In addition, exposure to PI for >= 3 years, to HAART for >= 6 years and to nucleoside reverse transcriptase inhibitor(s) for >= 6 years was significantly associated with the presence of metabolic syndrome with an adjusted OR of 1.96 (95% CI 1.13-3.42), 1.78 (95% CI 1.03-3.07), and 1.91 (95% CI 1.11-3.30), respectively. CONCLUSIONS: Approximately one-fourth of HIV-infected Taiwanese patients developed metabolic syndrome in the HAART era. Receipt of HAART and prolonged exposure to PI and nucleoside reverse transcriptase inhibitor(s) were associated with metabolic syndrome. PMID- 22232519 TI - In situ analysis of mutant EGFRs prevalent in glioblastoma multiforme reveals aberrant dimerization, activation, and differential response to anti-EGFR targeted therapy. AB - Aberrations in epidermal growth factor receptor (EGFR/ErbB1) are the most common oncogenic alterations in glioblastoma multiforme (GBM), the most common primary brain tumor. Interactions between wild-type (wt) and mutant EGFRs and their subsequent activation are of biologic and potential therapeutic importance in GBMs. We recently showed that in situ proximity ligation assay (PLA) allows for quantitative evaluation of EGFR dimerization and activation in intact cells. Using this in situ platform, we show the aberrant homo-/heterodimeric properties of EGFRvIII and EGFRc958 mutants, the two most common EGFR mutants in GBMs. In addition, dimer phosphoactivation status could be detected by PLA with superior signal-noise ratio (>17-fold) and sensitivity (>16-fold) than immunofluorescence based phospho-EGFR measurements. Dimer activation analysis indicated quantitative activation differences of mutant dimers. These aberrant features were not overexpression dependent but appeared independent of cellular expression levels, suggesting inherent properties of the mutant receptors. Moreover, we observed in situ detection of EGFRwt-EGFRvIII heterodimerization in GBM specimens, supporting our cell line observations. Notably, currently used anti-EGFR therapeutics, such as cetuximab, matuzumab, and panitumumab, could effectively block EGFRwt dimerization and activation but did not equally impair EGFRvIII homodimers, EGFRwt-EGFRvIII, or EGFRvIII-EGFRc958 heterodimers. EGFRvIII appears to have intrinsic phosphoactivation independent of dimerization as matuzumab blockade of homodimerization had no effect on receptor phosphorylation levels. These data suggest differences in the dimerization-blocking efficacy of EGFR monoclonal antibodies as mutant EGFR dimer configurations prevalent in GBMs can evade blockade by anti-EGFR treatments. Further studies are warranted to evaluate whether this evasion contributes to poor therapeutic response or resistance. PMID- 22232520 TI - [Neuropsychoanalysis: the science of the unconscious in the 21st century: definition and scientific roots]. AB - The article is the first part of a two-part-study which attempts to introduce a new interdisciplinary trend called neuropsychoanalysis. Neuropsychoanalysis aspires to integrate the knowledge of psychoanalysis, neuroscience, psychology and psychiatry. The article introduces the definition and scientific connections of neuropsychoanalysis, the role of the neuroscientific knowledge of the 19th century in the formation of psychoanalytic thought, then looks over the changes in the history of psychoanalysis and cognitive sciences which resulted in the approximation of the two fields and the birth of neuropsychoanalysis. PMID- 22232518 TI - WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. AB - Abnormal activation the WNT/beta-catenin signaling pathway has been associated with ovarian carcinomas, but a specific WNT ligand and pertinent downstream mechanisms are not fully understood. In this study, we found abundant WNT7A in the epithelium of serous ovarian carcinomas, but not detected in borderline and benign tumors, normal ovary, or endometrioid carcinomas. To characterize the role of WNT7A in ovarian tumor growth and progression, nude mice were injected either intraperitoneally or subcutaneously with WNT7A knocked down SKOV3.ip1 and overexpressed SKOV3 cells. In the intraperitoneal group, mice receiving SKOV3.ip1 cells with reduced WNT7A expression developed significantly fewer tumor lesions. Gross and histologic examination revealed greatly reduced invasion of WNT7A knockdown cells into intestinal mesentery and serosa compared with the control cells. Tumor growth was regulated by loss or overexpression of WNT7A in mice receiving subcutaneous injection as well. In vitro analysis of cell function revealed that cell proliferation, adhesion, and invasion were regulated by WNT7A. The activity of the T-cell factor/lymphoid enhancer factor (TCF/LEF) reporter was stimulated by overexpression of WNT7A in ovarian cancer cells. Cotransfection with WNT7A and FZD5 receptor further increased activity, and this effect was inhibited by cotransfection with SFRP2 or dominant negative TCF4. Overexpression of WNT7A stimulated matrix metalloproteinase 7 (MMP7) promoter, and mutation of TCF-binding sites in MMP7 promoter confirmed that activation of MMP7 promoter by WNT7A was mediated by beta-catenin/TCF signaling. Collectively, these results suggest that reexpression of WNT7A during malignant transformation of ovarian epithelial cells plays a critical role in ovarian cancer progression mediated by WNT/beta-catenin signaling pathway. PMID- 22232521 TI - [Sandor Ferenczi. Notes on a house purchase. 1930, 2011]. AB - In 1983, just before his death, as the last official act of Pal Juhasz, the president of the Hungarian Psychiatric Association, placed a plaque to commemorate Sandor Ferenczi, the Hungarian psychiatrist and psychotherapist. In 2011 the Sandor Ferenczi Society, initiating an international collaboration, bought Sandor Ferenczi's original consulting office in his own villa, to establish a workplace, archive, and research centre there. The consulting office has been a significant station in the life work of the mature Ferenczi; his clinical and scientific work there had a significant influence on his colleagues and the development of modern psychoanalysis. We follow the vicissitudes of the purchase of the villa, the existential circumstances of the first psychoanalysts in their various historical phases, Ferenczi's invitations abroad, their impact on his relationships to Freud and colleagues. We follow Ferenczi's popularity in the International Psychoanalytic Association, in the light of his presidential candidacy, and the role of the villa in the fulfillment of Ferenczi's life work. PMID- 22232522 TI - [Psychological aspects of induced abortion]. AB - The present paper, based on the results of international studies, is focused on the reconsideration of the psychological aspects of induced abortion. By presenting a narrow cross-section of the Hungarian demographic data, we would like to emphasise the necessity and the significance of a deeper understanding of the subject. Factors behind the decision-making, short- and long term outcomes of the intervention influencing primarily the mental health of women and partner relationship aspects are discussed in details. While acknowledging the complexity of the subject deriving from the legal, ethical, moral, religious, medical, social and sociological concerns, our aim is to call attention to the psychological aspects of induced abortion and the importance of psychological care of women undergoing surgical operation. PMID- 22232523 TI - [Changes in the subjective perception of the quality of life. Retrospective study of patients treated at the Thalassa House]. AB - INTRODUCTION: Quality of life and psychosocial functioning are considered important factors both in psychiatric and psychotherapeutic rehabilitation; similarly they are useful outcome measures in prospective studies. In this paper we present a retrospective study conducted with patients treated in Thalassa Haz Psychiatric and Psychotherapeutic Rehabilitation Center (TH). METHOD: 1. Non systematic review of the literature concerning quality of life and social functioning measures 2. Patients discharged form TH between 01. 01. 2008 and 31. 12. 2008 were included in the study. A semi-structured, patient reported instrument was used to assess psychosocial functioning, including single questions and an open-ended questions. Statistical analysis and manual content analysis were performed. RESULTS: 208 patients were contacted, 84 completed questionnaires were sent back and analysed. Less than 31% of the patients were rehospitalized within six months with the same problem. Subjective evaluation showed that 72% of the patients suffer less from the problem, with which they were treated in TH. The majority reported positive effect on interpersonal relations (67%) and autonomy (70%) due to the treatment. There is a significant correlation between treatment satisfaction and duration of treatment. The content analysis revealed significant negative correlation between generalisational content frequencies and treatment satisfaction. CONCLUSIONS: Psychosocial functioning improved after treatment in the TH. Correlation was identified between treatment satisfaction and satisfaction with life, thus quality of life and duration of treatment. Combination of objective and subjective methods, as well as content analysis are useful measures in the effectiveness studies of therapeutic communities. PMID- 22232524 TI - cAMP-specific phosphodiesterases 8A and 8B, essential regulators of Leydig cell steroidogenesis. AB - Phosphodiesterase (PDE) 8A and PDE8B are high-affinity, cAMP-specific phosphodiesterases that are highly expressed in Leydig cells. PDE8A is largely associated with mitochondria, whereas PDE8B is broadly distributed in the cytosol. We used a new, PDE8-selective inhibitor, PF-04957325, and genetically ablated PDE8A(-/-), PDE8B(-/-) and PDE8A(-/-)/B(-/-) mice to determine roles for these PDEs in the regulation of testosterone production. PF-04957325 treatment of WT Leydig cells or MA10 cells increased steroid production but had no effect in PDE8A (-/-)/B(-/-) double-knockout cells, confirming the selectivity of the drug. Moreover, under basal conditions, cotreatment with PF-04957325 plus rolipram, a PDE4-selective inhibitor, synergistically potentiated steroid production. These results suggest that the pool(s) of cAMP regulating androgen production are controlled by PDE8s working in conjunction with PDE4. Likewise, PDE8A (-/-)/B(-/ ) cells had higher testosterone production than cells from either PDE8A(-/-) or PDE8B(-/-) mice, suggesting that both PDE8s work in concert to regulate steroid production. We further demonstrate that combined inhibition of PDE8s and PDE4 greatly increased PKA activity including phosphorylation of cholesterol-ester hydrolase (CEH)/hormone-sensitive lipase (HSL). CEH/HSL phosphorylation also was increased in PDE8A(-/-)/B(-/-) cells compared with WT cells. Finally, combined inhibition of PDE8s and PDE4 increased the expression of steroidogenic acute regulatory (StAR) protein. Together these findings suggest that both PDE8A and PDE8B play essential roles to maintain low cAMP levels, thereby suppressing resting steroidogenesis by keeping CEH/HSL inactive and StAR protein expression low. They also suggest that in order for PDE inhibitor therapy to be an effective stimulator of steroidogenesis, both PDE8 isozymes and PDE4 need to be simultaneously targeted. PMID- 22232525 TI - Influence of glycosidases addition on selected monoterpenes contents in musts and white wines from two grape varieties grown in Poland. AB - BACKGROUND: Amount of monoterpene alcohol and their glycoside precursors in grapes is determined by the type of grapes, and the availability of specific hydrolytic enzymes during the manufacturing process. Addition of these enzymes, hydrolysing beta-glycosidic bond, to the grape can be used to increase the potential of aromatic raw material, releasing odoriferous aglycons from non volatile glycosides and in consequence to enhance the flavour of white wines. In this study complex enzyme preparations AR2000 and Rapidase X-Press were used as a supplement to the musts. MATERIAL AND METHODS: Two white grape varieties (Nachodka and Perla Zali) grown in Golesz vineyard in Jaslo were used for winemaking. Aglycone analysis was conducted on the basis of fast acid hydrolysis and solid phase extraction (SPE-C18) with subsequent GC-MS analysis. Wines treated with enzymes and without enzyme treatment were prepared. Dominating terpenes (linalool, nerol, geraniol, beta-citronelol, alpha-terpineol) were quantified in this study. RESULTS: Amount of free terpenes was comparable in musts of both varieties (42.7 MUg/L for Perla Zali, 46.3 MUg/L for Nachodka), however Nachodka had 228.9 MUg/L of bound terpenes, compared to 88.8 MUg/L in Perla Zali. Addition of glycosidases to musts resulted in an approximately 50 MUg/L increase in investigated monoterpenes in Perla Zali and appr. 100 MUg/L in Nachodka. Total amount of monoterpenes decreased after 6 months storage, however their levels in enzyme treated wines were significantly higher than in control samples. Enzyme treated wines were evaluated by sensory panel and perceived different from control samples with more pronounced selected notes mainly fruity and floral. CONCLUSION: Addition of enzymes can be used to improve the flavour of white wines produced from the average quality of raw material, influencing the increase in aromatic terpene alcohols. However, one must keep in mind that the changes in amount of released flavour compounds caused by the addition of enzymes may not always have a positive effect. PMID- 22232526 TI - Changes in the phenolic acid content during wort boiling and whirlpool. AB - BACKGROUND: Phenolic acids were repeatedly pointed out as powerful antioxidants. The studies in the past prove the differences in the phenolic acids content in malts and worts. In this work, the influence of wort boiling and whirlpool separation on the phenolic acid content was studied. MATERIAL AND METHODS: Worts were produced in the local brewery by the infusion method using pale pilsner-type barley malt. Samples were analysed at the beginning of the boil, after the boil and after whirlpool separation (5 and 30 min). Free and total alkali extractable phenolic acids contents were analysed using HPLC-DAD. RESULTS: The main phenolic acid in all worts was ferulic acid in the free (35.47 +/-3.28-117.51 +/-4.40 mg.dm(-3)) as well as total alkali extractable form (193.49 +/-4.84-294.72 +/ 2.65 mg.dm(-3)). With both forms no decrease was seen after boiling of wort (80 min at 100-100.5 degrees C) followed by wort separation in the whirlpool. Similarly, no significant changes in the free and total form of p-coumaric acid content were seen. CONCLUSIONS: It can be concluded that an elevated temperature during wort boiling and separation in whirlpool had no significant influence on the content of phenolic acids (at least in the case of the specific mashing program applied in this brewery: equipment, enzyme preparations, mashing, time temperature parameters etc.). The differences in the phenolic acids levels could be rather attributed to different supplies of malt used for the production. PMID- 22232527 TI - Application of immobilized cell preparation obtained from biomass of Gluconacetobacter xylinus bacteria in biotransformation of glycerol to dihydroxyacetone. AB - INTRODUCTION: Dihydroxyacetone (DHA), being a product of glycerol oxidation by acetic acid bacteria, is an important compound widely applied in the cosmetic, food, and pharmaceutical industry, as well as in medicine. Biotransformation of glycerol to DHA is catalyzed by glycerol dehydrogenase (GlyDH, EC 1.1.1.6) bound with the cytoplasmic membrane of bacteria. An attempt was undertaken in this study to conduct glycerol biotransformation with immobilized fractions of a cell preparation with GlyDH activity. The content of dihydroxyacetone obtained with the cell preparation was compared with its content achieved in the reaction with immobilized viable cells of G. xylinus. MATERIAL AND METHODS: Cell walls of Gluconacetobacter xylinus bacteria were disintegrated enzymatically. The resultant preparation was immobilized on calcium alginate or first separated into two fractions (precipitate and supernatant) by centrifugation and then immobilized. DHA content was determined colorimetrically after the reaction with 3,5-dinitrosalicilic acid. Glycerol content was assayed with the refractometric method. RESULTS: After 20 days of the process, the concentration of DHA obtained with immobilized whole cells reached 25 g/l. In turn, the content of DHA obtained in the same period with immobilized fractions of the cell preparation accounted for 16.9 g/l and 8.95 g/l (depending on the fraction applied). CONCLUSIONS: DHA may be obtained in the process independent of G. xylinus metabolic activity using a preparation which displays the catalytic activity of glycerol dehydrogenase and obtained as a result of disintegration of live bacterial cells. The application of such a preparation may in the future eliminate technological problems posed by the presence of bacterial cells and their metabolites in the culture medium. PMID- 22232528 TI - Content of bioactive compounds and antioxidant capacity of pumpkin puree enriched with japanese quince, cornelian cherry, strawberry and apples. AB - BACKGROUND: When evaluated in terms of taste, smell or active ingredients, pumpkin in itself is not very attractive as a raw material. Hence, it is recommended to blend pumpkin with other fruits, which are aromatic, have a defined taste, and contain a large quantity of active ingredients and organic acids to improve its palatibility. MATERIAL AND METHODS: The pumpkin chosen for the experiments was of the variety Karowita, of species Cucurbita maxima. Ten different of compositions were prepared for the purpose of the study: 10, 20 and 30% (w/w) of Japanese quince and cornelian cherry each, or 20 and 30% (w/w) of strawberry and apple each. The puree was then analysed for dry matter, extract, viscosity, colour, vitamin C, total polyphenols, carotenoids and DPPH. RESULTS: The highest content of vitamin C, which was in direct proportion to the quantity of the supplement added (17.88 to 23.43 mg.100 g(-1)), was detected in the quince enriched puree. The lowest vitamin C content was determined in apple-enriched samples (1.36 to 1.6 mg.100 g(-1)). A similar pattern was observed with total polyphenols: the highest values were measured in quince-enriched puree, and the lowest in the puree supplemented with apple. CONCLUSION: Taking into account antioxidant properties of the samples, quince-enriched pumpkin puree was found to be the most attractive, and apple-enriched pumpkin puree the least attractive one. The results suggest a wide range of application for pumpkin puree enriched with various additives. PMID- 22232529 TI - Evaluation of the antiradical potential of fruit and vegetable snacks. AB - BACKGROUND: The use of plant origin polyphenols as food ingredients, supplements or antioxidants is very promising as a future trend for human health and food stability. Free radical activity, responsible for human ageing and food deterioration could be delayed by the use of antioxidants present in fruit and vegetables. The aim of the present research was to evaluate and compare the antiradical activity of selected fruits and vegetable snacks as a new promising kind of functional foods. MATERIAL AND METHODS: In the present study, seven commercial plant food snacks were analysed for the total polyphenol content and antioxidant activity evaluated according to the DPPH(*) and ABTS(*+) radical scavenging methods. RESULTS: The highest total polyphenol content was evaluated in chokeberry and blackcurrant chips extracts, apple chips contained significantly lower amount among all snacks. Chokeberry extract exhibited the highest antiradical activity when determined by the DPPH(*) and ABTS(*+) radical scavenging methods, while the apple and carrot chips extracts showed the lowest antiradical activity. DPPH(*) and ABTS(*+) gave comparable results and were highly correlated (r = 0.83, p < 0.05). CONCLUSIONS: Results obtained indicate that selection of plant matrices for snack production would be very important for consumer's health, as they are potential sources of dietary antioxidants. PMID- 22232530 TI - Characterisation of five potato cultivars according to their nutritional and pro health components. AB - INTRODUCTION: Potatoes are very popular vegetables in Poland, not only in terms that they are easy to prepare, but also by the fact that they combine the wholesomeness of cereals and delicacy and characteristic chemical composition of vegetables, so it is important that they find their place in our diet. Nutritional value of potatoes is determined by the content of nutrients such as protein, starch, fat, minerals, and absence of toxins, as well as by a significant content of bioactive components from the group of polyphenols, which guarantee proper antioxidant activity of this vegetable. The study was performed in order to analyse 5 Polish potato cultivars, according to nutritional components, i.e.: proteins, fat, starch, carbohydrates, ash and biologically active compounds: such as polyphenols, flavonoids, as well as dietary fibre. At the same time antioxidant activity of the cultivars was determined by means of two independent methods. MATERIAL AND METHODS: The material for the study consisted of five varieties of potatoes: Saturna, Hermes, Raja, Rosalind, Courage, which were analysed for the content of nutrients i.e. protein, fat, starch, carbohydrate, ash and biologically active compounds: polyphenols, flavonoids, and fiber. Antioxidant activity of the examined potato varieties was determined by two independent methods. RESULTS: It was shown, taking into account the nutrients, that the potato variety Raja was characterised by the lowest content of carbohydrate and ash, and high amounts of protein and fat. The highest content of insoluble dietary fibre was determined for Raja, and its soluble fraction for Saturna. The amounts of insoluble fibre were three times as much as the content of soluble fibre in the analysed potato cultivars. The highest total polyphenol content was measured for Saturna, and the lowest for Rosalind. Other cultivars revealed similar amounts of these components (3 mg catechin/g d.m.). The contents of flavonols and flavonoids was not proportional to total polyphenol content in the analysed potato cultivars. Antioxidant activity determined by two independant methods was proportional to total polyphenol content in the analysed plant material. CONCLUSIONS: It was shown that the content of pro-health ingredients such as: dietary fiber, total polyphenols and antioxidant activity was preferable for two of the five examined varieties of potatoes: Saturna and Raja. PMID- 22232531 TI - Comparison of quality attributes of buffalo meat curry at different storage temperature. AB - BACKGROUND: The product quality of curry is determined by the food animal source, raw materials and the method of processing. Moreover the scientific information on processing and quality of traditional buffalo meat curry from different groups of buffaloes is not available. This study was undertaken to develop processed curry from different buffalo groups and to compare its quality during storage at ambient and refrigeration temperature. MATERIAL AND METHODS: The meat samples were collected from the longissimus dorsi muscle of the carcasses from each group of buffaloes slaughtered according to the traditional halal method. Buffalo meat curry was prepared in a pressure cooker with the standardized formulation. This final product was subjected to evaluation of quality and shelf life. RESULTS: To evaluate the effect of different groups of meat samples on the quality of curry, product yield, pH, proximate composition, water activity (aw), thiobarbituric acid reactive substances (TBARS), calorific value, sensory attributes and microbiological assay were determined The energy of meat curry from young buffaloes was significantly lower than the meat curry from spent animal groups. The overall acceptability of curry decreased significantly during 3 days ambient storage compared to refrigeration storage. CONCLUSIONS: Scientific processing by adopting good manufacturing practices and suitable packaging helped greatly to improve the shelf life of the ambient temperature stored buffalo meat curry. Buffalo meat curry from young male group showed better product characteristics and overall acceptability scores than spent buffalo group. PMID- 22232532 TI - Evaluation of the effect of diet composition and B-group vitamins supplementation on selected calcium metabolism parameters in female rats. AB - BACKGROUND: The aim of the study was to observe the effects of a modified diet, in which whole grains of cereals had been isocalorically substituted with wheat flour (type "500") and saccharose, and supplementation with B-group vitamins, on selected calcium metabolism parameters in female rats. MATERIAL AND METHODS: The experiment was carried out on 36 female rats aged 6 months. Animals were fed two different diets. Groups I and II received clean tap water to drink, while group III had water solution of group-B vitamins. RESULTS: An analysis of the outcomes of the diet modifications allowed concluding that the females fed on the modified feed, either supplemented or non-supplemented, excreted more calcium with urine and exhibited its lower concentrations in blood plasma, as compared with the females fed on the standard feed. No significant differences, however, were observed in plasma ionized calcium concentrations in the studied animals, which implies that the regulation mechanism of its bio-active form concentrations is preserved. It has been found that the applied supplementation of the modified diet promoted bone calcium release inducing plasma alkaline phosphatase activity in this group of animals. Supplementation was also accompanied by a shift in calcium distribution manifested by its increased concentrations in erythrocytes. CONCLUSIONS: Change in diet composition and supplementation were found to significantly affect calcium metabolism of the rats examined. Observed intracellular calcium accumulation may have been an underlying cause of an increased adipose tissue accumulation in B-group vitamin supplemented animals, which had been observed in previous studies. PMID- 22232533 TI - Appreciation of concentration of lipoproteins and apolipoproteins in serum of male rats under the influence of diet change composition and its supplementation with group B vitamins. AB - BACKGROUND: This study was aimed at exploring, on animal model, how the diet changes, which results in exceeding 5 times the amount of deficit of group B vitamins after diet change, which up to a certain extent imitates supplementation method in people, influences the concentration of apolipoprotein A-I and apolipoprotein B - the components of lipoprotein HDL-C and LDL-C. MATERIAL AND METHODS: The research was conducted on 24 WISTAR male rats, aged ca 5 months. The animals were divided into 3 feeding groups: I was fed with basic compound which contained among others full wheat grain and corn grain, group II and III with modified compound in which part of the full wheat grain, from basic compound, was substituted for wheat flour, and 50% of corn with saccharose. Group I and II animals were drinking pure tap water which was left to stand for some time beforehand, group III animals vitamins dissolved in water: B(1), B(2), B(6), and PP - five times exceeded the difference between the amount of basic and modified feed, which in a certain way imitated the supplementation in human food. After one week of animals conditioning, the experiment was conducted for 6 weeks. In their blood serum were determined concentration of glucose (GL), triacyloglycerols (TG), total cholesterol (TC), fraction of HDL-cholesterol (HDLC), fraction of LDL-cholesterol (LDL-C) and apolipoproteins A-I (apo A-I) and apolipoproteins B (apoB). In the dissected muscles and in the animals' livers the amount of fat was determined with Soxhlet's method. The obtained results were analysed with one factor variance by use of statistic computer program Statistica(r) with application of Duncan test. RESULTS: Analysing the influence of diet change and its supplementation with chosen group B vitamins on the amount of consumed feed, it was ascertained that in spite of the same calorific value of the used feed, significantly less, compared to other groups, was consumed by the animals from the supplemented group. However, there was no significant gain of body mass in male rats and higher accumulation of pericardial and periintestinal fat tissue. Significantly lower amount of fat, in comparison to animals fed with basic feed, was observed in muscles of animals fed with modified and supplemented feed, however significantly higher amount of fat was found in liver. In animals fed with modified feed compared with animals fed with basic feed higher GL, TG, TC its LDL-C fraction and apoB and decrease of fraction HDL-C concentration was noticed. The applied supplementation with group B vitamins statistically significantly lowered concentration of GL, TG, LDL-C fraction, apoB and increased concentration of TC. Observed decrease concentration of HDL-C fraction, apoA-I, apoB and increased TC in serum of supplemented animals it was statistically insignificant. CONCLUSIONS: Analysis of the obtained results allowed stating that supplementation of diet with chosen group B vitamins in which full grains were exchanged for wheat flour and saccharose, was favourable to returning to original state of disadvantageous effects brought by change of diet content. It was demonstrated by decrease of glucose, triacyloglycerols, lipoprotein LDL-C and apoB concentration while lipoproteins HDL-C and apoA-I were decreased and increase of total cholesterol in blood of rats under research, although not all changes were statistically significant. PMID- 22232534 TI - Optimising prostate biopsy. PMID- 22232535 TI - Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study. AB - OBJECTIVES: To measure the effect of the adverse events within 35 days of transrectal ultrasound guided biopsy from the perspective of asymptomatic men having prostate specific antigen (PSA) testing; to assess early attitude to re biopsy; to estimate healthcare resource use associated with adverse events due to biopsy; and to develop a classification scheme for reporting adverse events after prostate biopsy. DESIGN: Prospective cohort study (Prostate Biopsy Effects: ProBE) nested within Prostate Testing for Cancer and Treatment (ProtecT) study. Participants Between 1999 and 2008, 227,000 community dwelling men aged 50-69 years were identified at 352 practices and invited to counselling about PSA testing. 111,148 attended a nurse led clinic in the community, and 10,297 with PSA concentrations of 3-20 ng/mL were offered biopsy within ProtecT. Between February 2006 and May 2008, 1147/1753 (65%) eligible men (mean age 62.1 years, mean PSA 5.4 ng/mL) having 10 core transrectal ultrasound guided biopsy under antibiotic cover in the context of ProtecT were recruited to the ProBE study. OUTCOME MEASURES: Purpose designed questionnaire administered at biopsy and 7 and 35 days after the procedure to measure frequency and effect of symptoms related to pain, infection, and bleeding; patients' attitude to repeat biopsy assessed immediately after biopsy and 7 days later; participants' healthcare resource use within 35 days of biopsy evaluated by questionnaire, telephone follow-up, and medical note review; each man's adverse event profile graded according to symptoms and healthcare use. RESULTS: Pain was reported by 429/984 (43.6%), fever by 172/985 (17.5%), haematuria by 642/976 (65.8%), haematochezia by 356/967 (36.8%), and haemoejaculate by 605/653 (92.6%) men during the 35 days after biopsy. Fewer men rated these symptoms as a major/moderate problem-71/977 (7.3%) for pain, 54/981 (5.5%) for fever, 59/958 (6.2%) for haematuria, 24/951 (2.5%) for haematochezia, and 172/646 (26.6%) for haemoejaculate. Immediately after biopsy, 124/1142 (10.9%, 95% confidence interval 9.2 to 12.8) men reported that they would consider further biopsy a major or moderate problem: seven days after biopsy, this proportion had increased to 213/1085 (19.6%, 17.4% to 22.1%). A negative attitude to repeat biopsy was associated with unfavourable experience after the first biopsy, particularly pain at biopsy (odds ratio 8.2, P<0.001) and symptoms related to infection (7.9, P<0.001) and bleeding (4.2, P<0.001); differences were evident between centres (P<0.001). 119/1147 (10.4%, 8.7% to 12.3%) men reported consultation with a healthcare professional (usually their general practitioner), most commonly for infective symptoms. Complete data for all index symptoms at all time points were available in 851 participants. Symptoms and healthcare use could be used to grade these men as follows: grade 0 (no symptoms/contact) 18 (2.1%, 1.3% to 3.3%); grade 1 (minor problem/no contact) 550 (64.6%, 61.4% to 67.8%); grade 2 (moderate/major problem or contact) 271 (31.8%, 28.8% to 35.1%); grade 3 (hospital admission) 12 (1.4%, 0.8% to 2.4%); and grade 4 (death) 0. Grade of adverse event was associated with an unfavourable attitude to repeat biopsy (Kendall's tau-b ordinal by ordinal 0.29, P<0.001). CONCLUSION: This study with a high response rate of 89% at 35 days in men undergoing biopsy in the context of a randomised controlled trial has shown that although prostate biopsy is well tolerated by most men, it is associated with significant symptoms in a minority and affects attitudes to repeat biopsy and primary care resource use. These findings will inform men who seek PSA testing for detection of prostate cancer and assist their physicians during counselling about the potential risks and effect of biopsy. Variability in the adverse event profile between centres suggests that patients' outcomes could be improved and healthcare use reduced with more effective administration of local anaesthetic and antibiotics. Trial registration Current Controlled Trials ISRCTN20141297. PMID- 22232536 TI - A restless night's sleep. PMID- 22232537 TI - Exercise boosts immunity--up to a point. PMID- 22232538 TI - MPs call for review of alcohol guidelines. PMID- 22232540 TI - Transformative mutation specific pharmacotherapy for cystic fibrosis. PMID- 22232539 TI - The effect of combination treatment with aliskiren and blockers of the renin angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. AB - OBJECTIVE: To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011. STUDY SELECTION: Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes. RESULTS: 10 randomised controlled studies (4814 participants) were included in the analysis. Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89). CONCLUSION: Use of aliskerin in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. The combined use of these agents warrants careful monitoring of serum potassium levels. PMID- 22232541 TI - Risks of aspirin outweigh benefits in people without cardiovascular disease, shows analysis. PMID- 22232542 TI - Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide for malignant neuroendocrine tumours. PMID- 22232543 TI - Chaos theory and a career in medicine. PMID- 22232544 TI - ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs). AB - We are in the midst of a rapidly evolving era of technology-assisted medicine. The field of telemedicine provides the opportunity for highly individualized medical management in a way that has never been possible before. Evolving medical technologies using cardiac implantable devices (CIEDs) with capabilities for remote monitoring permit evaluation of multiple parameters of cardiovascular physiology and risk, including cardiac rhythm, device function, blood pressure values, the presence of myocardial ischaemia, and the degree of compensation of congestive heart failure. Cardiac risk, device status, and response to therapies can now be assessed with these electronic systems of detection and reporting. This document reflects the extensive experience from investigators and innovators around the world who are shaping the evolution of this rapidly expanding field, focusing in particular on implantable pacemakers (IPGs), implantable cardioverter defibrillators (ICDs), devices for cardiac resynchronization therapy (CRT) (both, with and without defibrillation properties), loop recorders, and haemodynamic monitoring devices. This document covers the basic methodologies, guidelines for their use, experience with existing applications, and the legal and reimbursement aspects associated with their use. To adequately cover this important emerging topic, the International Society for Holter and Noninvasive Electrocardiology (ISHNE) and the European Heart Rhythm Association (EHRA) combined their expertise in this field. We hope that the development of this field can contribute to improve care of our cardiovascular patients. PMID- 22232545 TI - Nine in 10 Chinese are covered by medical insurance, but access to treatment remains a problem. PMID- 22232546 TI - Government puts pressure on private sector to pay for removal of PIP breast implants. PMID- 22232547 TI - Nursing home residents' psychological barriers to sleeping well: a qualitative study. AB - BACKGROUND: Sleep disorders are a relevant problem in the nursing home and difficult to treat for the residents' GPs. No intervention has yet addressed psychological factors contributing to nursing home residents' sleep disorders. OBJECTIVE: To explore what nursing home residents perceive as psychological barriers to sleeping well. METHODS: A qualitative research design. We conducted episodic interviews with 30 nursing home residents. Data were analysed by thematic coding. We constructed a typology of residents regarding their perceived barriers to sleeping well. RESULTS: The interviewed residents perceived traumatic memories, family problems, worries about their situation and future, disturbing events during the day, appointments the next day, anxiety and dreams and nightmares as psychological barriers to sleeping well. The residents could be allocated into three types: residents of Type I identified only non-psychological barriers, residents of Type II worried mainly about their current situation and residents of Type III suffered from traumatic memories and were easily disturbed by any type of psychological distress. CONCLUSIONS: Our results show the high importance of psychological factors for sleep disorders of the elderly. Future research should address nursing home residents' psychological barriers to sleeping well and the presented typology should be operationalized and tested quantitatively. PMID- 22232548 TI - Tyrosine-phosphorylated galectin-3 protein is resistant to prostate-specific antigen (PSA) cleavage. AB - Galectin-3 is a chimeric carbohydrate-binding protein, which interacts with cell surface carbohydrate-containing molecules and extracellular matrix glycoproteins and has been implicated in various biological processes such as cell growth, angiogenesis, motility, and metastasis. It is expressed in a wide range of tumor cells and is associated with tumor progression. The functions of galectin-3 are dependent on its localization and post-translational modifications such as cleavage and phosphorylation. Recently, we showed that galectin-3 Tyr-107 is phosphorylated by c-Abl; concomitantly, it was also shown that galectin-3 can be cleaved at this site by prostate-specific antigen (PSA), a chymotrypsin-like serine protease, after Tyr-107, resulting in loss of galectin-3 multivalency while preserving its carbohydrate binding activity. Galectin-3 is largely a monomer in solution but may form a homodimer by self-association through its carbohydrate recognition domain, whereas, in the presence of a ligand, galectin-3 polymerizes up to pentamers utilizing its N-terminal domain. Oligomerization is a unique feature of secreted galectin-3, which allows its function by forming ordered galectin-glycan structures, i.e. lattices, on the cell surface or through direct engagement of specific cell surface glycoconjugates by traditional ligand receptor binding. We questioned whether Tyr-107 phosphorylation by c-Abl affects galectin-3 cleavage by PSA. The data suggest a role for galectin-3 in prostate cells associated with increased activity of c-Abl kinase and loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity. In addition, the ratio of phosphorylated/dephosphorylated galectin-3 might be used as a complementary value to that of PSA for prognosis of prostate cancer and a novel therapeutic target for the treatment of prostate cancer. PMID- 22232549 TI - Ca2+-dependent GTPase, extra-large G protein 2 (XLG2), promotes activation of DNA binding protein related to vernalization 1 (RTV1), leading to activation of floral integrator genes and early flowering in Arabidopsis. AB - Heterotrimeric G proteins, consisting of Galpha, Gbeta, and Ggamma subunits, play important roles in plant development and cell signaling. In Arabidopsis, in addition to one prototypical G protein alpha subunit, GPA1, there are three extra large G proteins, XLG1, XLG2, and XLG3, of largely unknown function. Each extra large G (XLG) protein has a C-terminal Galpha-like region and a ~400 amino acid N terminal extension. Here we show that the three XLG proteins specifically bind and hydrolyze GTP, despite the fact that these plant-specific proteins lack key conserved amino acid residues important for GTP binding and hydrolysis of GTP in mammalian Galpha proteins. Moreover, unlike other known Galpha proteins, these activities require Ca(2+) instead of Mg(2+) as a cofactor. Yeast two-hybrid library screening and in vitro protein pull-down assays revealed that XLG2 interacts with the nuclear protein RTV1 (related to vernalization 1). Electrophoretic mobility shift assays show that RTV1 binds to DNA in vitro in a non-sequence-specific manner and that GTP-bound XLG2 promotes the DNA binding activity of RTV1. Overexpression of RTV1 results in early flowering. Combined overexpression of XLG2 and RTV1 enhances this early flowering phenotype and elevates expression of the floral pathway integrator genes, FT and SOC1, but does not repress expression of the floral repressor, FLC. Chromatin immunoprecipitation assays show that XLG2 increases RTV1 binding to FT and SOC1 promoters. Thus, a Ca(2+)-dependent G protein, XLG2, promotes RTV1 DNA binding activity for a subset of floral integrator genes and contributes to floral transition. PMID- 22232550 TI - Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice. AB - Altered regulation of the serotonin-1A (5-HT1A) receptor gene is implicated in major depression and mood disorders. The functional human 5-HT1A C(-1019)G promoter polymorphism (rs6295), which prevents the binding of Deaf-1/NUDR leading to dysregulation of the receptor, has been associated with major depression. In cell models Deaf-1 displays dual activity, repressing 5-HT1A autoreceptor expression in serotonergic raphe cells while enhancing postsynaptic 5-HT1A heteroreceptor expression in nonserotonergic neurons. A functional Deaf-1 binding site on the mouse 5-HT1A promoter was recognized by Deaf-1 in vitro and in vivo and mediated dual activity of Deaf-1 on 5-HT1A gene transcription. To address regulation by Deaf-1 in vivo, Deaf-1 knock-out mice bred to a C57BL/6 background were compared with wild-type siblings for changes in 5-HT1A RNA and protein by quantitative RT-PCR, in situ hybridization, and immunofluorescence. In the dorsal raphe, Deaf-1 knock-out mice displayed increased 5-HT1A mRNA, protein, and 5-HT1A positive cell counts but reduced 5-HT levels, whereas other serotonergic markers, such as tryptophan hydroxylase (TPH)- or 5-HT-positive cells and TPH2 RNA levels, were unchanged. By contrast, 5-HT1A mRNA and 5-HT1A-positive cells were reduced in the frontal cortex of Deaf-1-null mice, with no significant change in hippocampal 5-HT1A RNA, protein, or cell counts. The region-specific alterations of brain 5-HT1A gene expression and reduced raphe 5-HT content in Deaf-1(-/-) mice indicate the importance of Deaf-1 in regulation of 5-HT1A gene expression and provide insight into the role of the 5-HT1A G(-1019) allele in reducing serotonergic neurotransmission by derepression of 5-HT1A autoreceptors. PMID- 22232551 TI - Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span. AB - Transactive response DNA-binding protein (TARDBP/TDP-43), a heterogeneous nuclear ribonucleoprotein (hnRNP) with diverse activities, is a common denominator in several neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Orthologs of TDP-43 exist in animals ranging from mammals to invertebrates. Here, we systematically studied mutant Caenorhabditis elegans lacking the nematode TDP-43 ortholog, TDP-1. Heterologous expression of human TDP-43 rescued the defects in C. elegans lacking TDP-1, suggesting their functions are conserved. Although the tdp-1 mutants exhibited deficits in fertility, growth, and locomotion, loss of tdp-1 attenuated defects in several C. elegans models of proteotoxicity. Loss of tdp-1 suppressed defects in transgenic C. elegans expressing TDP-43 or CuZn superoxide dismutase, both of which are associated with proteotoxicity in neurodegenerative diseases. Loss of tdp-1 also reduced defects in mutant animals lacking the heat shock factor HSF-1. Transcriptional profiling demonstrated that the loss of TDP-1 altered expression of genes functioning in RNA processing and protein folding. Furthermore, the absence of tdp-1 extended the life span in C. elegans. The life span extension required a FOXO transcriptional factor DAF-16 but not HSF-1. These results suggest that the C. elegans TDP-1 has a role in the regulation of protein homeostasis and aging. PMID- 22232552 TI - Mutation of Glu521 or Glu535 in cytoplasmic loop 5 causes differential misfolding in multiple domains of multidrug and organic anion transporter MRP1 (ABCC1). AB - The polytopic 5-domain multidrug resistance protein 1 (MRP1/ABCC1) extrudes a variety of drugs and organic anions across the plasma membrane. Four charged residues in the fifth cytoplasmic loop (CL5) connecting transmembrane helix 9 (TM9) to TM10 are critical for stable expression of MRP1 at the plasma membrane. Thus Ala substitution of Lys(513), Lys(516), Glu(521), and Glu(535) all cause misfolding of MRP1 and target the protein for proteasome-mediated degradation. Of four chemical chaperones tested, 4-phenylbutyric acid (4-PBA) was the most effective at restoring expression of MRP1 mutants K513A, K516A, E521A, and E535A. However, although 4-PBA treatment of K513A resulted in wild-type protein levels (and activity), the same treatment had little or no effect on the expression of K516A. On the other hand, 4-PBA treatment allowed both E521A and E535A to exit the endoplasmic reticulum and be stably expressed at the plasma membrane. However, the 4-PBA-rescued E535A mutant exhibited decreased transport activity associated with reduced substrate affinity and conformational changes in both halves of the transporter. By contrast, E521A exhibited reduced transport activity associated with alterations in the mutant interactions with ATP as well as a distinct conformational change in the COOH-proximal half of MRP1. These findings illustrate the critical and complex role of CL5 for stable expression of MRP1 at the plasma membrane and more specifically show the differential importance of Glu(521) and Glu(535) in interdomain interactions required for proper folding and assembly of MRP1 into a fully transport competent native structure. PMID- 22232553 TI - Low density lipoprotein (LDL) receptor-related protein 6 (LRP6) regulates body fat and glucose homeostasis by modulating nutrient sensing pathways and mitochondrial energy expenditure. AB - Body fat, insulin resistance, and type 2 diabetes are often linked together, but the molecular mechanisms that unify their association are poorly understood. Wnt signaling regulates adipogenesis, and its altered activity has been implicated in the pathogenesis of type 2 diabetes and metabolic syndrome. LRP6(+/-) mice on a high fat diet were protected against diet-induced obesity and hepatic and adipose tissue insulin resistance compared with their wild-type (WT) littermates. Brown adipose tissue insulin sensitivity and reduced adiposity of LRP6(+/-) mice were accounted for by diminished Wnt-dependent mTORC1 activity and enhanced expression of brown adipose tissue PGC1-alpha and UCP1. LRP6(+/-) mice also exhibited reduced endogenous hepatic glucose output, which was due to diminished FoxO1 dependent expression of the key gluconeogenic enzyme glucose-6-phosphatase (G6pase). In addition, in vivo and in vitro studies showed that loss of LRP6 allele is associated with increased leptin receptor expression, which is a likely cause of hepatic insulin sensitivity in LRP6(+/-) mice. Our study identifies LRP6 as a nutrient-sensitive regulator of body weight and glucose metabolism and as a potential target for pharmacological interventions in obesity and diabetes. PMID- 22232554 TI - Non-viral expression of mouse Oct4, Sox2, and Klf4 transcription factors efficiently reprograms tadpole muscle fibers in vivo. AB - Adult mammalian cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by a limited combination of transcription factors. To date, most current iPSC generation protocols rely on viral vector usage in vitro, using cells removed from their physiological context. Such protocols are hindered by low derivation efficiency and risks associated with genome modifications of reprogrammed cells. Here, we reprogrammed cells in an in vivo context using non viral somatic transgenesis in Xenopus tadpole tail muscle, a setting that provides long term expression of non-integrated transgenes in vivo. Expression of mouse mOct4, mSox2, and mKlf4 (OSK) led rapidly and reliably to formation of proliferating cell clusters. These clusters displayed the principal hallmarks of pluripotency: alkaline phosphatase activity, up-regulation of key epigenetic and chromatin remodeling markers, and reexpression of endogenous pluripotent markers. Furthermore, these clusters were capable of differentiating into derivatives of the three germ layers in vitro and into neurons and muscle fibers in vivo. As in situ reprogramming occurs along with muscle tissue repair, the data provide a link between these two processes and suggest that they act synergistically. Notably, every OSK injection resulted in cluster formation. We conclude that reprogramming is achievable in an anamniote model and propose that in vivo approaches could provide rapid and efficient alternative for non-viral iPSC production. The work opens new perspectives in basic stem cell research and in the longer term prospect of regenerative medicine protocols development. PMID- 22232555 TI - Interplay between beta1-integrin and Rho signaling regulates differential scattering and motility of pancreatic cancer cells by snail and Slug proteins. AB - The Snail family of transcription factors has been implicated in pancreatic cancer progression. We recently showed that Snail (Snai1) promotes membrane-type 1 matrix metalloproteinase (MT1-MMP)- and ERK1/2-dependent scattering of pancreatic cancer cells in three-dimensional type I collagen. In this study, we examine the role of Slug (Snai2) in regulating pancreatic cancer cell scattering in three-dimensional type I collagen. Although Slug increased MT1-MMP expression and ERK1/2 activity, Slug-expressing cells failed to scatter in three-dimensional collagen. Moreover, in contrast to Snail-expressing cells, Slug-expressing cells did not demonstrate increased collagen I binding, collagen I-driven motility, or alpha2beta1-integrin expression. Significantly, inhibiting beta1-integrin function decreased migration and scattering of Snail-expressing cells in three dimensional collagen. As Rho GTPases have been implicated in invasion and migration, we also analyzed the contribution of Rac1 and Rho signaling to the differential migration and scattering of pancreatic cancer cells. Snail-induced migration and scattering were attenuated by Rac1 inhibition. In contrast, inhibiting Rho-associated kinase ROCK1/2 increased migration and scattering of Slug-expressing cells in three-dimensional collagen and thus phenocopied the effects of Snail in pancreatic cancer cells. Additionally, the increased migration and scattering in three-dimensional collagen of Slug-expressing cells following ROCK1/2 inhibition was dependent on beta1-integrin function. Overall, these results demonstrate differential effects of Snail and Slug in pancreatic cancer and identify the interplay between Rho signaling and beta1-integrin that functions to regulate the differential scattering and migration of Snail- and Slug-expressing pancreatic cancer cells. PMID- 22232556 TI - Protein kinase C (PKC)zeta-mediated Galphaq stimulation of ERK5 protein pathway in cardiomyocytes and cardiac fibroblasts. AB - Gq-coupled G protein-coupled receptors (GPCRs) mediate the actions of a variety of messengers that are key regulators of cardiovascular function. Enhanced Galpha(q)-mediated signaling plays an important role in cardiac hypertrophy and in the transition to heart failure. We have recently described that Galpha(q) acts as an adaptor protein that facilitates PKCzeta-mediated activation of ERK5 in epithelial cells. Because the ERK5 cascade is known to be involved in cardiac hypertrophy, we have investigated the potential relevance of this pathway in cardiovascular Gq-dependent signaling using both cultured cardiac cell types and chronic administration of angiotensin II in mice. We find that PKCzeta is required for the activation of the ERK5 pathway by Gq-coupled GPCR in neonatal and adult murine cardiomyocyte cultures and in cardiac fibroblasts. Stimulation of ERK5 by angiotensin II is blocked upon pharmacological inhibition or siRNA mediated silencing of PKCzeta in primary cultures of cardiac cells and in neonatal cardiomyocytes isolated from PKCzeta-deficient mice. Moreover, upon chronic challenge with angiotensin II, these mice fail to promote the changes in the ERK5 pathway, in gene expression patterns, and in hypertrophic markers observed in wild-type animals. Taken together, our results show that PKCzeta is essential for Gq-dependent ERK5 activation in cardiomyocytes and cardiac fibroblasts and indicate a key cardiac physiological role for the Galpha(q)/PKCzeta/ERK5 signaling axis. PMID- 22232557 TI - Flotillin-1/reggie-2 protein plays dual role in activation of receptor-tyrosine kinase/mitogen-activated protein kinase signaling. AB - Our previous work has shown that the membrane microdomain-associated flotillin proteins are potentially involved in epidermal growth factor (EGF) receptor signaling. Here we show that knockdown of flotillin-1/reggie-2 results in reduced EGF-induced phosphorylation of specific tyrosines in the EGF receptor (EGFR) and in inefficient activation of the downstream mitogen-activated protein (MAP) kinase and Akt signaling. Although flotillin-1 has been implicated in endocytosis, its depletion affects neither the endocytosis nor the ubiquitination of the EGFR. However, EGF-induced clustering of EGFR at the cell surface is altered in cells lacking flotillin-1. Furthermore, we show that flotillins form molecular complexes with EGFR in an EGF/EGFR kinase-independent manner. However, knockdown of flotillin-1 appears to affect the activation of the downstream MAP kinase signaling more directly. We here show that flotillin-1 forms a complex with CRAF, MEK1, ERK, and KSR1 (kinase suppressor of RAS) and that flotillin-1 knockdown leads to a direct inactivation of ERK1/2. Thus, flotillin-1 plays a direct role during both the early phase (activation of the receptor) and late (activation of MAP kinases) phase of growth factor signaling. Our results here unveil a novel role for flotillin-1 as a scaffolding factor in the regulation of classical MAP kinase signaling. Furthermore, our results imply that other receptor-tyrosine kinases may also rely on flotillin-1 upon activation, thus suggesting a general role for flotillin-1 as a novel factor in receptor-tyrosine kinase/MAP kinase signaling. PMID- 22232558 TI - Conserved Ser/Arg-rich motif in PPZ orthologs from fungi is important for its role in cation tolerance. AB - PPZ1 orthologs, novel members of a phosphoprotein phosphatase family of phosphatases, are found only in fungi. They regulate diverse physiological processes in fungi e.g. ion homeostasis, cell size, cell integrity, etc. Although they are an important determinant of salt tolerance in fungi, their physiological role remained unexplored in any halotolerant species. In this context we report here molecular and functional characterization of DhPPZ1 from Debaryomyces hansenii, which is one of the most halotolerant and osmotolerant species of yeast. Our results showed that DhPPZ1 knock-out strain displayed higher tolerance to toxic cations, and unlike in Saccharomyces cerevisiae, Na(+)/H(+) antiporter appeared to have an important role in this process. Besides salt tolerance, DhPPZ1 also had role in cell wall integrity and growth in D. hansenii. We have also identified a short, serine-arginine-rich sequence motif in DhPpz1p that is essential for its role in salt tolerance but not in other physiological processes. Taken together, these results underscore a distinct role of DhPpz1p in D. hansenii and illustrate an example of how organisms utilize the same molecular tool box differently to garner adaptive fitness for their respective ecological niches. PMID- 22232559 TI - Phosphorylation of alpha-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans. AB - alpha-Synuclein is causative for autosomal dominant familial Parkinson disease and dementia with Lewy bodies, and the phosphorylation of alpha-synuclein at residue Ser-129 is a key posttranslational modification detected in Parkinson disease/dementia with Lewy bodies lesions. However, the role of Ser-129 phosphorylation on the pathogenesis of Parkinson disease/dementia with Lewy bodies remains unclear. Here we investigated the neurotoxicity of Ser-129 substituted alpha-synuclein in the transgenic Caenorhabditis elegans (Tg worm) model of synucleinopathy. Tg worms pan-neuronally overexpressing nonphosphorylatable (S129A) alpha-synuclein showed severe defects including motor dysfunction, growth retardation, and synaptic abnormalities. In contrast, Tg worms expressing phosphorylation mimic (S129D) alpha-synuclein exhibited nearly normal phenotypes. Biochemical fractionation revealed that the level of membrane bound alpha-synuclein was significantly increased in S129A-alpha-synuclein Tg worms, whereas S129D- as well as A30P-alpha-synuclein displayed lower membrane binding properties. Furthermore, A30P/S129A double mutant alpha-synuclein did not cause neuronal dysfunction and displayed low membrane binding property. In human neuroblastoma SH-SY5Y cells, localization of S129A-alpha-synuclein to membranes was significantly increased. Finally, gene expression profiling of S129A-Tg worms revealed a dramatic up-regulation of Daf-16/FOXO pathway genes, which likely act against the dysfunction caused by S129A-alpha-synuclein. These results imply a role of Ser-129 phosphorylation of alpha-synuclein in the attenuation of alpha synuclein-induced neuronal dysfunction and downstream stress response by lowering the membrane binding property. PMID- 22232561 TI - Reaction Kinetics and Reduced Shrinkage Stress of Thiol-Yne-Methacrylate and Thiol-Yne-Acrylate Ternary Systems. AB - Thiol-yne-methacrylate and thiol-yne-acrylate ternary systems were investigated for polymerization kinetics and material properties and compared to the analogous pure thiol-yne and (meth)acrylate systems. Both thiol-yne-methacrylate and thiol yne-acrylate systems were demonstrated to reduce polymerization induced shrinkage stress while simultaneously achieving high glass transition temperatures (T(g)) and modulius. Formulations with 70 wt% methacrylate increased the T(g) from 51 +/ 2 to 75 +/- 1 degrees C and the modulus from 1800 +/- 100 to 3200 +/- 400 MPa (44% increase) over the pure thiol-yne system. Additionally, the shrinkage stress was 1.2 +/- 0.2 MPa, which is lower than that of the pure methacrylate, binary thiol-yne and thiol-ene-methacrylate control systems which are all > 2 MPa. Interestingly, with increasing methacrylate or acrylate concentration, a decrease and subsequent increase in the shrinkage stress values were observed. A minimum shrinkage stress value (1.0 +/- 0.2 MPa) was observed in the 50 wt% methacrylate and 70 wt% acrylate systems. This tunable behavior results from the competitive reaction kinetics of the methacrylate or acrylate homopolymerization versus chain transfer to thiol and the accompanying thiol-yne step-growth polymerization. The crosslinking density of the networks and the amount of volumetric shrinkage that occurs prior to gelation relative to the total volumetric shrinkage were determined as two key factors that control the final shrinkage stress of the ternary systems. PMID- 22232560 TI - Identification of a small molecule that modulates platelet glycoprotein Ib-von Willebrand factor interaction. AB - The von Willebrand factor (VWF) A1-glycoprotein (GP) Ibalpha interaction is of major importance during thrombosis mainly at sites of high shear stress. Inhibitors of this interaction prevent platelet-dependent thrombus formation in vivo, without major bleeding complications. However, the size and/or protein nature of the inhibitors currently in development limit oral bioavailability and clinical development. We therefore aimed to search for a small molecule protein protein interaction inhibitor interfering with the VWF-GPIbalpha binding. After determination of putative small molecule binding pockets on the surface of VWF-A1 and GPIbalpha using site-finding algorithms and molecular dynamics, high throughput molecular docking was performed on both binding partners. A selection of compounds showing good in silico docking scores into the predicted pockets was retained for testing their in vitro effect on VWF-GPIbalpha complex formation, by which we identified a compound that surprisingly stimulated the VWF-GPIbalpha binding in a ristocetin cofactor ELISA and increased platelet adhesion in whole blood to collagen under arterial shear rate but in contrast inhibited ristocetin induced platelet aggregation. The selected compound adhering to the predicted binding partner GPIbalpha could be confirmed by saturation transfer difference NMR spectroscopy. We thus clearly identified a small molecule that modulates VWF GPIbalpha binding and that will now serve as a starting point for further studies and chemical modifications to fully characterize the interaction and to manipulate specific activity of the compound. PMID- 22232562 TI - Exploratory Bi-factor Analysis. AB - Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger. The bi-factor model has a general factor and a number of group factors. The purpose of this paper is to introduce an exploratory form of bi-factor analysis. An advantage of using exploratory bi-factor analysis is that one need not provide a specific bi-factor model a priori. The result of an exploratory bi-factor analysis, however, can be used as an aid in defining a specific bi-factor model. Our exploratory bi-factor analysis is simply exploratory factor analysis using a bi-factor rotation criterion. This is a criterion designed to produce perfect cluster structure in all but the first column of a rotated loading matrix. Examples are given to show how exploratory bi factor analysis can be used with ideal and real data. The relation of exploratory bi-factor analysis to the Schmid-Leiman method is discussed. PMID- 22232563 TI - Effects of bevacizumab on the neovascular membrane of proliferative diabetic retinopathy: reduction of endothelial cells and expressions of VEGF and HIF 1alpha. AB - PURPOSE: Anti-vascular endothelial growth factor (VEGF) agents have recently been used intravitreally during the perioperative period for proliferative diabetic retinopathy (PDR). However, the mechanism of theraputic effects of the agents remains unclear. This study aimed to investigate the effects of intravitreal bevacizumab (IVB) on retinal vascular endothelial cells and expressions of VEGF and hypoxia inducible factor-1alpha (HIF-1alpha) in PDR. METHODS: Twenty-four patients with PDR were enrolled and randomized to two groups. Twelve eyes of 12 patients of each group received either an intravitreal injection of 1.25 mg bevacizumab or a sham injection 6 days before vitrectomy. Neovascular membranes (NVMs) were collected during pars plana vitrectomy. The numbers of vascular endothelial cells in the NVMs were counted after staining with hematoxylin and eosin and von Willebrand. The expressions of VEGF and HIF-1alpha in the NVMs were detected through immunohistochemistry. Ten epiretinal membrane specimens from patients with proliferative vitreoretinopathy (PVR) without IVB treatment were set as an additional control. RESULTS: The number of vascular endothelial cells in NVMs of the IVB pretreated group was significantly lower than that of the sham group (21.5+/-3.94 versus 41.33+/-7.44, p=0.003). The IVB pretreated group also showed significantly lower levels of VEGF and HIF-1alpha in NVMs than those of the sham group (P(HIF-1alpha)=0.02, P(VEGF)<0.001). A stepwise regression analysis showed that IVB was a significant negative predictor for the numbers of vascular endothelial cells (beta=-0.89, p<0.001) and the expressions of VEGF (beta=-0.85, p<0.001) and HIF-1alpha (beta=-0.64, p=0.001) in PDR patients. Epiretinal membranes of the PVR group showed negative staining of VEGF and HIF 1alpha. CONCLUSIONS: Pretreatment with IVB in patients with PDR significantly decreased vascular endothelial cells and expressions of VEGF and HIF-1alpha, which further supports preoperative use of IVB in such patients. PMID- 22232564 TI - Evaluation of bleb characteristics after implantation of the EX-PRESSTM glaucoma filtration device. AB - PURPOSE: To compare bleb survival and histology after implantation of the EX PRESSTM glaucoma filtration device versus silicone tubes in a rabbit model of filtration surgery. METHODS: Glaucoma filtration surgery was performed on one eye each of twelve New Zealand white rabbits. Eyes were randomized to implantation with the EX-PRESSTM filtration device (n=6) or a silicone tube (n=6). Bleb vascularity was evaluated at three and six weeks using a standard scale. At 6 weeks, eyes were enucleated and a histologic analysis was performed. Bleb survival was also recorded for the two groups. RESULTS: Histologically, a thin capsule consisting of mild fibroblast proliferation associated with intercellular collagen was present around both implants. Both groups demonstrated a mild infiltration of plasma cells and polymorphonuclear leukocytes. Bleb vascularity was similar between both groups at three and six weeks post-operatively. Bleb survival between the two groups was not significantly different. CONCLUSIONS: Similar outcomes were noted after glaucoma filtration surgery using either silicone tubes or the EX-PRESSTM glaucoma filtration device in this rabbit model. Both implants appear to be relatively inert with little difference in biocompatibility and bleb survival. PMID- 22232565 TI - Efficient expression and purification of recombinant human m-calpain using an Escherichia coli expression system at low temperature. AB - Calpain belongs to the superfamily of Ca(2+)-regulated cysteine proteases, which are indispensable to the regulation of various cellular functions. Of the 15 mammalian calpain isoforms, u- and m-calpains are the best characterized. Both u- and m-calpain are ubiquitously expressed and exist as heterodimers, containing a distinct 80-kDa catalytic subunit (CAPN1 and CAPN2, respectively) and the common, 30-kDa regulatory subunit (CAPNS1). To date, various expression systems have been developed for producing recombinant calpains for use in structural and physiological studies, however Escherichia coli systems have proven incompatible with large-scale preparation of calpain, with the exception of rat m-calpain. Here, we have established a highly efficient method to purify active recombinant human m-calpain using an E. coli expression system at low temperature (22 degrees C). This was achieved by co-expressing CAPN2 with a C-terminal histidine-tag, and CAPNS1, lacking the first Gly-repeated region at the N-terminal. After three sequential passes through a chromatographic column, ~5 mg of human m-calpain was homogenously purified from 1 l of E. coli culture. Proteins were stable for several months. This is the first report of efficient, large-scale purification of recombinant human m-calpain using an E. coli expression system. PMID- 22232566 TI - Changing patterns in iatrogenic ureteral injuries. AB - Advances in laparoscopic and endoscopic surgery over the past 25 years have changed the preferred methods for performing many operations. We previously reported an increase in the number of patients treated for ureteral injury at our institution that paralleled the introduction of minimally invasive techniques. Since that report, more advanced endoscopic procedures have been introduced. We sought to determine whether the latter influenced the number of ureteral injuries managed at our institution. Reported here are the results of our retrospective study, which sought to determine if the rate of treatment of major iatrogenic ureteral injuries has changed. PMID- 22232567 TI - Fertility and the aging male. AB - In the United States since 1980, the birth rate in women aged > 35 years has increased by nearly 60%, whereas the birth rate for women aged 20 to 34 years has increased by only 10%. The trend in parenthood at an older age has also been seen in men. Since 1980, the fertility rate for men in their 30s has increased by 21% and for men aged 40 years and older, the rate has increased nearly 30%. In contrast, the fertility rate in men younger than age 30 years has decreased by 15%. Age-related infertility will continue to be a problem. A basic understanding of the issues is critical for health care professionals so that they can effectively counsel patients who are considering a delay in childbearing for social reasons or for those seeking fertility treatments. This review details the changes in fertility seen in the aging male. PMID- 22232568 TI - Review of the literature: PCA3 for prostate cancer risk assessment and prognostication. AB - Prostate cancer antigen 3 (PCA3) is a novel urine-based prostate cancer biomarker that has recently been studied extensively for the prediction of prostate biopsy results and treatment outcomes. Numerous studies have demonstrated that urinary PCA3 scores are predictive of prostate cancer detection on both initial and repeat biopsy. There is conflicting evidence on the relationship between PCA3 with aggressive tumor features and treatment outcomes. This article reviews the current evidence on PCA3 as a marker for prostate cancer detection and prognosis. PMID- 22232569 TI - A review of focal therapy techniques in prostate cancer: clinical results for high-intensity focused ultrasound and focal cryoablation. AB - The advancement of focal therapy technology for the treatment of prostate cancer (PCa) is emerging as an option for a middle ground between radical therapies and active surveillance for individuals identified with localized, low-grade PCa. Two promising techniques are high-intensity focused ultrasound (HIFU) and focal cryoablation. Both focal cryoablation and HIFU show promise, but additional prospective trials are necessary before any definitive conclusions can be made on either method's viability. PMID- 22232570 TI - Benign paratesticular fibrous pseudotumor with malignant clinical features. AB - Paratesticular tumors are rare intrascrotal masses that grow mainly in structures containing connective tissue around the testis, epididymis, or spermatic cord. We report here on a case of a 55-year-old man with a mass in the hemiscrotum that was found to be a paratesticular fibrous pseudotumor in the orchiectomy specimen pathologic examination. From this case report and literature review, a diagnostic and therapeutic strategy is demonstrated for the management of this uncommon lesion. PMID- 22232571 TI - The influence of eating rate on satiety and intake among participants exhibiting high dietary restraint. AB - BACKGROUND: Studies show inconsistent results with regards to whether eating slower can enhance satiety and reduce intake in a meal. Some methodological differences are apparent and could potentially explain why results are not consistent across studies. OBJECTIVE: To determine whether eating slower can enhance satiety and reduce intake when rate of eating is manipulated and not manipulated in a kitchen setting using a sample of participants who exhibit high dietary restraint (HDR). DESIGN: Two samples of college students who exhibit HDR, which is a group likely to use behavioral strategies to manage intake, were selected in a prescreening session. Participants were told how fast or slow to eat (Variation 1) or allowed to eat at their own pace (Variation 2). Self reported satiety during the meal and amount consumed was recorded. The types of foods, macronutrient intakes, weights of foods, order of food intakes, and the dimensions of foods were held constant between groups to control for group differences in the sensory and hedonic qualities of the meals. RESULTS: Eating slower enhanced mid-meal satiety ratings, but only when instructions were given to eat fast or slow (Variation 1). In both variations, eating slower did not reduce amount consumed in the meal, although each variation had sufficient power to detect differences. CONCLUSION: Eating slower is not likely to be an effective strategy to control intake in a meal among those exhibiting HDR. PMID- 22232572 TI - Pieron's Law and Optimal Behavior in Perceptual Decision-Making. AB - Pieron's Law is a psychophysical regularity in signal detection tasks that states that mean response times decrease as a power function of stimulus intensity. In this article, we extend Pieron's Law to perceptual two-choice decision-making tasks, and demonstrate that the law holds as the discriminability between two competing choices is manipulated, even though the stimulus intensity remains constant. This result is consistent with predictions from a Bayesian ideal observer model. The model assumes that in order to respond optimally in a two choice decision-making task, participants continually update the posterior probability of each response alternative, until the probability of one alternative crosses a criterion value. In addition to predictions for two-choice decision-making tasks, we extend the ideal observer model to predict Pieron's Law in signal detection tasks. We conclude that Pieron's Law is a general phenomenon that may be caused by optimality constraints. PMID- 22232573 TI - Age-based differences in strategy use in choice tasks. AB - We incorporated behavioral and computational modeling techniques to examine age based differences in strategy use in two four-choice decision-making tasks. Healthy older (aged 60-82 years) and younger adults (aged 18-23 years) performed one of two decision-making tasks that differed in the degree to which rewards for each option depended on the choices made on previous trials. In the choice independent task rewards for each choice were not affected by the sequence of previous choices that had been made. In contrast, in the choice-dependent task rewards for each option were based on how often each option had been chosen in the past. We compared the fits of a model that assumes the use of a win-stay-lose shift (WSLS) heuristic to make decisions, to the fits of a reinforcement-learning (RL) model that compared expected reward values for each option to make decisions. Younger adults were best fit by the RL model, while older adults showed significantly more evidence of being best fit by the WSLS heuristic model. This led older adults to perform worse than younger adults in the choice independent task, but better in the choice-dependent task. These results coincide with previous work in our labs that also found better performance for older adults in choice-dependent tasks (Worthy et al., 2011), and the present results suggest that qualitative age-based differences in the strategies used in choice tasks may underlie older adults' advantage in choice-dependent tasks. We discuss possible factors behind these differences such as neurobiological changes associated with aging, and increased use of heuristics by older adults. PMID- 22232574 TI - Frontiers in molecular neuroscience - resume and perspective. PMID- 22232575 TI - Domain architecture of a calcium-permeable AMPA receptor in a ligand-free conformation. AB - Ligand-gated ion channels couple the free energy of agonist binding to the gating of selective transmembrane ion pores, permitting cells to regulate ion flux in response to external chemical stimuli. However, the stereochemical mechanisms responsible for this coupling remain obscure. In the case of the ionotropic glutamate receptors (iGluRs), the modular nature of receptor subunits has facilitated structural analysis of the N-terminal domain (NTD), and of multiple conformations of the ligand-binding domain (LBD). Recently, the crystallographic structure of an antagonist-bound form of the receptor was determined. However, disulfide trapping of this conformation blocks channel opening, suggesting that channel activation involves additional quaternary packing arrangements. To explore the conformational space available to iGluR channels, we report here a second, clearly distinct domain architecture of homotetrameric, calcium-permeable AMPA receptors, determined by single-particle electron microscopy of untagged and fluorescently tagged constructs in a ligand-free state. It reveals a novel packing of NTD dimers, and a separation of LBD dimers across a central vestibule. In this arrangement, which reconciles diverse functional observations, agonist induced cleft closure across LBD dimers can be converted into a twisting motion that provides a basis for receptor activation. PMID- 22232576 TI - Organization of Anti-Phase Synchronization Pattern in Neural Networks: What are the Key Factors? AB - Anti-phase oscillation has been widely observed in cortical neural network. Elucidating the mechanism underlying the organization of anti-phase pattern is of significance for better understanding more complicated pattern formations in brain networks. In dynamical systems theory, the organization of anti-phase oscillation pattern has usually been considered to relate to time delay in coupling. This is consistent to conduction delays in real neural networks in the brain due to finite propagation velocity of action potentials. However, other structural factors in cortical neural network, such as modular organization (connection density) and the coupling types (excitatory or inhibitory), could also play an important role. In this work, we investigate the anti-phase oscillation pattern organized on a two-module network of either neuronal cell model or neural mass model, and analyze the impact of the conduction delay times, the connection densities, and coupling types. Our results show that delay times and coupling types can play key roles in this organization. The connection densities may have an influence on the stability if an anti-phase pattern exists due to the other factors. Furthermore, we show that anti-phase synchronization of slow oscillations can be achieved with small delay times if there is interaction between slow and fast oscillations. These results are significant for further understanding more realistic spatiotemporal dynamics of cortico-cortical communications. PMID- 22232577 TI - An electroencephalographic investigation of the filled-duration illusion. AB - The study investigated how the brain activity changed when participants were engaged in a temporal production task known as the "filled-duration illusion." Twelve right-handed participants were asked to memorize and reproduce the duration of time intervals (600 or 800 ms) bounded by two flashes. Random trials contained auditory stimuli in the form of three 20 ms sounds between the flashes. In one session, the participants were asked to ignore the presence of the sounds, and in the other, they were instructed to pay attention to sounds. The behavioral results showed that duration reproduction was clearly affected by the presence of the sounds and the duration of time intervals. The filled-duration illusion occurred when there were sounds; the participants overestimated the interval in the 600-ms interval condition with sounds. On the other hand, the participants underestimated the 800-ms interval condition without sounds. During the presentation of the interval to be encoded, the contingent negative variation (CNV) appeared around the prefrontal scalp site, and P300 appeared around the parieto-central scalp site. The CNV grew larger when the intervals contained the sounds, whereas the P300 grew larger when the intervals were 800 ms and did not contain the sounds. During the reproduction of the interval to be presented, the Bereitschaftspotential (BP) appeared over the fronto-central scalp site from 1000 ms before the participants' response. The BP could refer to the decision making process associated with the duration reproduction. The occurrence of three event related potentials (ERPs), the P300, CNV, and BP, suggests that the fronto parietal area, together with supplementary motor area (SMA), is associated with timing and time perception, and magnitude of these potentials is modulted by the "filled-duration illusion". PMID- 22232578 TI - Conditioned place preference for social interaction in rats: contribution of sensory components. AB - A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. We previously developed a rat experimental model based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male Sprague Dawley rat (1) reversed CPP from cocaine to social interaction despite continuing cocaine training and (2) prevented the reinstatement of cocaine CPP. In the present study, we investigated which of the sensory modalities of the composite stimulus "social interaction" contributes most to the rats' preference for it. If touch was limited by steel bars spaced at a distance of 2 cm and running across the whole length of a partitioning, CPP was still acquired, albeit to a lesser degree. If both rats were placed on the same side of a partitioning, rats did not develop CPP for social interaction. Thus, decreasing the available area for social interaction from 750 to 375 cm(2) prevented the acquisition of CPP to social interaction despite the fact that animals could touch each other more intensely than through the bars of the partitioning. When touch was fully restricted by a glass screen dividing the conditioning chambers, and the only sensory modalities left were visual and olfactory cues, place preference shifted to place aversion. Overall, our findings indicate that the major rewarding sensory component of the composite stimulus "social interaction" is touch (taction). PMID- 22232579 TI - ERK pathway activation bidirectionally affects visual recognition memory and synaptic plasticity in the perirhinal cortex. AB - ERK 1,2 pathway mediates experience-dependent gene transcription in neurons and several studies have identified its pivotal role in experience-dependent synaptic plasticity and in forms of long term memory involving hippocampus, amygdala, or striatum. The perirhinal cortex (PRHC) plays an essential role in familiarity based object recognition memory. It is still unknown whether ERK activation in PRHC is necessary for recognition memory consolidation. Most important, it is unknown whether by modulating the gain of the ERK pathway it is possible to bidirectionally affect visual recognition memory and PRHC synaptic plasticity. We have first pharmacologically blocked ERK activation in the PRHC of adult mice and found that this was sufficient to impair long term recognition memory in a familiarity-based task, the object recognition task (ORT). We have then tested performance in the ORT in Ras-GRF1 knock-out (KO) mice, which exhibit a reduced activation of ERK by neuronal activity, and in ERK1 KO mice, which have an increased activation of ERK2 and exhibit enhanced striatal plasticity and striatal mediated memory. We found that Ras-GRF1 KO mice have normal short term memory but display a long term memory deficit; memory reconsolidation is also impaired. On the contrary, ERK1 KO mice exhibit a better performance than WT mice at 72 h retention interval, suggesting a longer lasting recognition memory. In parallel with behavioral data, LTD was strongly reduced and LTP was significantly smaller in PRHC slices from Ras-GRF1 KO than in WT mice while enhanced LTP and LTD were found in PRHC slices from ERK1 KO mice. PMID- 22232580 TI - Cellular correlates of enhanced anxiety caused by acute treatment with the selective serotonin reuptake inhibitor fluoxetine in rats. AB - Selective serotonin reuptake inhibitors (SSRIs) are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze 1 h after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA), a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment. PMID- 22232581 TI - Time-Frequency and ERP Analyses of EEG to Characterize Anticipatory Postural Adjustments in a Bimanual Load-Lifting Task. AB - Anticipatory postural adjustments (APAs) compensate in advance for the destabilizing effect of a movement. This study investigated the specific involvement of each primary motor cortex (M1) during a bimanual load-lifting task in which subjects were required to maintain a stable forearm position during voluntary unloading. Kinematics, electromyographic, and electroencephalographic (EEG) data were recorded in eight right-handed healthy subjects lifting a load placed on their left forearm. Two EEG analyses were performed: a time-frequency (TF) analysis and an event-related potential (ERP) analysis. The TF analysis revealed a mean power decrease in the mu rhythm over the left and right M1 concomitant with lifting onset. Each decrease showed specific features: over the right M1, contralateral to the postural forearm, there was a steeper slope and a greater amplitude than over the left M1. Although a mu rhythm desynchronization has until now been the signature of cortical activity related to a motor component, we show that it can also be related to postural stabilization. We discuss the involvement of the mu rhythm desynchronization over the postural M1 in the high temporal precision enabling efficient APAs. ERP analysis showed a negative wave over the left M1 and a concomitant positive wave over the right M1. While the negative wave classically reflects M1 recruitment related to the forthcoming lifting, the novelty here is that the positive wave reflects the transmission of inhibitory commands toward the postural forearm. PMID- 22232582 TI - Practice of contemporary dance promotes stochastic postural control in aging. AB - As society ages and the frequency of falls increases, counteracting gait and posture decline is a challenging issue for countries of the developed world. Previous studies have shown that exercise and hazard management help to improve balance and/or decrease the risks for falling in normal aging. Motor activity based on motor-skill learning, particularly dance, can also benefit balance and decreases falls with age. Recent studies have suggested that older dancers have better balance, posture, or gait than non-dancers. Additionally, clinical or laboratory measures have shown improvements in some aspects of balance after dance interventions in elderly trainees. This study examined the impact of contemporary dance (CD) and of fall prevention (FP) programs on postural control of older adults. Posturography of quiet upright stance was performed in 41 participants aged 59-86 years before and after 4.4-month training in either CD or FP once a week. Though classical statistic scores failed to show any effect, dynamic analyses of the center-of-pressure displacements revealed significant changes after training. Specifically, practice of CD enhanced the critical time interval in diffusion analysis, and reduced recurrence and mathematical stability in recurrence quantification analysis, whereas practice of FP induced or tended to induce the reverse patterns. Such effects were obtained only in the eyes open condition. We suggest that CD training based on motor improvisation favored stochastic posture inducing plasticity in motor control, while FP training based on more stereotyped behaviors did not. PMID- 22232583 TI - Periodic and aperiodic synchronization in skilled action. AB - Synchronized action is considered as a manifestation of shared skill. Most synchronized behaviors in humans and other animals are based on periodic repetition. Aperiodic synchronization of complex action is found in the experimental task of synchronous speaking, in which naive subjects read a common text in lock step. The demonstration of synchronized behavior without a periodic basis is presented as a challenge for theoretical understanding. A unified treatment of periodic and aperiodic synchronization is suggested by replacing the sequential processing model of cognitivist approaches with the more local notion of a task-specific sensorimotor coordination. On this view, skilled action is the imposition of constraints on the co-variation of movement and sensory flux such that the boundary conditions that define the skill are met. This non-cognitivist approach originates in the work of John Dewey. It allows a unification of the treatment of sensorimotor synchronization in simple rhythmic behavior and in complex skilled behavior and it suggests that skill sharing is a uniquely human trait of considerable import. PMID- 22232584 TI - Do artists see their retinas? AB - Our perception starts with the image that falls on our retina and on this retinal image, distant objects are small and shadowed surfaces are dark. But this is not what we see. Visual constancies correct for distance so that, for example, a person approaching us does not appear to become a larger person. Interestingly, an artist, when rendering a scene realistically, must undo all these corrections, making distant objects again small. To determine whether years of art training and practice have conferred any specialized visual expertise, we compared the perceptual abilities of artists to those of non-artists in three tasks. We first asked them to adjust either the size or the brightness of a target to match it to a standard that was presented on a perspective grid or within a cast shadow. We instructed them to ignore the context, judging size, for example, by imagining the separation between their fingers if they were to pick up the test object from the display screen. In the third task, we tested the speed with which artists access visual representations. Subjects searched for an L-shape in contact with a circle; the target was an L-shape, but because of visual completion, it appeared to be a square occluded behind a circle, camouflaging the L-shape that is explicit on the retinal image. Surprisingly, artists were as affected by context as non-artists in all three tests. Moreover, artists took, on average, significantly more time to make their judgments, implying that they were doing their best to demonstrate the special skills that we, and they, believed they had acquired. Our data therefore support the proposal from Gombrich that artists do not have special perceptual expertise to undo the effects of constancies. Instead, once the context is present in their drawing, they need only compare the drawing to the scene to match the effect of constancies in both. PMID- 22232585 TI - A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control. AB - The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing. PMID- 22232586 TI - The riddle of style changes in the visual arts after interference with the right brain. AB - We here analyze the paintings and films of several visual artists, who suffered from a well-defined neuropsychological deficit, visuo-spatial hemineglect, following vascular stroke to the right brain. In our analysis we focus in particular on the oeuvre of Lovis Corinth and Luchino Visconti as both major artists continued to be highly productive over many years after their right brain damage. We analyzed their post-stroke paintings and films, indicate several aspects that differ from their pre-stroke work (omissions, use of color, perseveration, deformation), and propose-although both artists come from different times, countries, genres, and styles-that their post-stroke oeuvre reveals important similarities in style. We argue that these changes may be associated with visuo-spatial hemineglect and the right brain. We discuss future avenues of how the neuropsychological investigation of visual artists with and without neglect may allow us to investigate the relationship between brain and art. PMID- 22232587 TI - Misdirection - past, present, and the future. AB - Misdirection refers to the magician's ability to manipulate people's attention, thoughts, and memory. It has been argued that some of the techniques used by magicians to orchestrate people's attention and awareness may provide valuable insights into human cognition. In this paper we review the scientific, as well as some of the magic literature on misdirection. We focus on four main points: (1) the magician's concept of misdirection, (2) the paradigms used to study misdirection scientifically, (3) review of the current scientific findings, and (4) future directions. PMID- 22232588 TI - An artistic exploration of inattention blindness. AB - An experiment about inattention blindness was conducted within the context of an art exhibition as opposed to a laboratory context in order to investigate the potential of art as a vehicle to study attention and its disorders. The project utilized a flash animation, Stealing Attention, that was modeled after the movie by Simons and Chabris (1999) but with significant experimental differences, involving context and staging, the emotional salience of the objects depicted, and the prior art viewing experience of participants. The study involved two components: observing if viewers watching an animation in a gallery could be distracted from noticing the disappearance of stolen museum antiquities (the targets) by the overlaid flashing images of a card game (the distractors) and then observing whether repetition of the depicted targets throughout the gallery installation could facilitate a re-direction of attention that allowed viewers to perceive the targets not initially noted in the animation. My findings were that, after viewing the entire installation and then re-viewing the animation, 64% of the viewers who did not initially remark on the targets in the animation were then able to see them. The discussion elaborates on these findings and then considers ways in which the implications of inattention blindness paradigms might be more fully rendered by uniting insights from the two disciplines of art and neuroscience than by either alone. PMID- 22232589 TI - Revisiting hydrocephalus as a model to study brain resilience. AB - Hydrocephalus is an entity which embraces a variety of diseases whose final result is the enlarged size of cerebral ventricular system, partially or completely. The physiopathology of hydrocephalus lies in the dynamics of circulation of cerebrospinal fluid (CSF). The consequent CSF stasis in hydrocephalus interferes with cerebral and ventricular system development. Children and adults who sustain congenital or acquired brain injury typically experience a diffuse insult that impacts many areas of the brain. Development and recovery after such injuries reflects both restoration and reorganization of cognitive functions. Classic examples were already reported in literature. This suggests the presence of biological mechanisms associated with resilient adaptation of brain networks. We will settle a link between the notable modifications to neurophysiology secondary to hydrocephalus and the ability of neuronal tissue to reassume and reorganize its functions. PMID- 22232590 TI - Fair and Open Evaluation May Call for Temporarily Hidden Authorship, Caution When Counting the Votes, and Transparency of the Full Pre-publication Procedure. PMID- 22232591 TI - Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism. AB - The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress 'task irrelevant' distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects. PMID- 22232592 TI - Visual activation of auditory cortex reflects maladaptive plasticity in cochlear implant users. AB - Cross-modal reorganization in the auditory cortex has been reported in deaf individuals. However, it is not well understood whether this compensatory reorganization induced by auditory deprivation recedes once the sensation of hearing is partially restored through a cochlear implant. The current study used electroencephalography source localization to examine cross-modal reorganization in the auditory cortex of post-lingually deafened cochlear implant users. We analysed visual-evoked potentials to parametrically modulated reversing chequerboard images between cochlear implant users (n = 11) and normal-hearing listeners (n = 11). The results revealed smaller P100 amplitudes and reduced visual cortex activation in cochlear implant users compared with normal-hearing listeners. At the P100 latency, cochlear implant users also showed activation in the right auditory cortex, which was inversely related to speech recognition ability with the cochlear implant. These results confirm a visual take-over in the auditory cortex of cochlear implant users. Incomplete reversal of this deafness-induced cortical reorganization might limit clinical benefit from a cochlear implant and help explain the high inter-subject variability in auditory speech comprehension. PMID- 22232593 TI - Theory of mind impairments in patients with semantic dementia. AB - Semantic dementia is characterized by semantic deficits and behavioural abnormalities that occur in the wake of bilateral inferolateral and predominantly left-sided anterior temporal lobe atrophy. The temporal poles have been shown to be involved in theory of mind, namely the ability to ascribe cognitive and affective mental states to others that regulates social interactions by predicting and interpreting human behaviour. However, very few studies have examined theory of mind in semantic dementia. In this study, we investigated both cognitive and affective theory of mind in a group of patients with semantic dementia, using separate objective and subjective assessment tasks. Results provided objective evidence of an impact of semantic dementia on cognitive and affective theory of mind, consistent with the patients' atrophy in the left temporal lobe and hypometabolism in the temporal lobes and the medial frontal cortex. However, the subjective assessment of theory of mind suggested that awareness of the affective but not cognitive theory of mind deficit persists into the moderate stage of the disease. PMID- 22232594 TI - Increased capillaries in mitochondrial myopathy: implications for the regulation of oxygen delivery. AB - Human skeletal muscle respiratory chain defects restrict the ability of working muscle to extract oxygen from blood, and result in a hyperkinetic circulation during exercise in which oxygen delivery is excessive relative to oxygen uptake and oxygen levels within contracting muscle are abnormally high. To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis, we assessed muscle oxidative capacity during cycle exercise and determined capillary levels and distribution and vascular endothelial growth factor expression in quadriceps muscle biopsies in patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutations. We found that in patients with mitochondrial myopathy, muscle capillary levels were twice that of sedentary healthy subjects (3.0 +/- 0.9% compared with 1.4 +/- 0.3%, P < 0.001) despite the fact that oxygen utilization during peak cycle exercise was half that of control subjects (11.1 +/- 4.0 ml/kg/min compared with 20.7 +/- 7.9 ml/kg/min, P < 0.01); that capillary area was greatest in patients with the most severe muscle oxidative defects and was more than two times higher around muscle fibre segments with defective (i.e. cytochrome oxidase negative/succinic dehydrogenase-positive or 'ragged-red' fibres) compared with more preserved respiratory chain function; and that vascular endothelial growth factor expression paralleled capillary distribution. The increased muscle capillary levels in patients correlated directly (r(2) = 0.68, P < 0.05) with the severity of the mismatch between systemic oxygen delivery (cardiac output) and oxygen utilization during cycle exercise. Our results suggest that capillary growth is increased as a result of impaired muscle oxidative phosphorylation in mitochondrial myopathy, thus promoting increased blood flow to respiration-incompetent muscle fibres and a mismatch between oxygen delivery and utilization during exercise. Furthermore, the finding of high capillary levels despite elevated tissue oxygen levels during exercise in respiration-deficient muscle fibres implies that mitochondrial metabolism activates angiogenesis in skeletal muscle by a mechanism that is independent of hypoxia. PMID- 22232596 TI - Automated real-time behavioral and physiological data acquisition and display integrated with stimulus presentation for FMRI. AB - Functional magnetic resonance imaging (fMRI) is based on correlating blood oxygen level dependent (BOLD) signal fluctuations in the brain with other time-varying signals. Although the most common reference for correlation is the timing of a behavioral task performed during the scan, many other behavioral and physiological variables can also influence fMRI signals. Variations in cardiac and respiratory functions in particular are known to contribute significant BOLD signal fluctuations. Variables such as skin conduction, eye movements, and other measures that may be relevant to task performance can also be correlated with BOLD signals and can therefore be used in image analysis to differentiate multiple components in complex brain activity signals. Combining real-time recording and data management of multiple behavioral and physiological signals in a way that can be routinely used with any task stimulus paradigm is a non-trivial software design problem. Here we discuss software methods that allow users control of paradigm-specific audio-visual or other task stimuli combined with automated simultaneous recording of multi-channel behavioral and physiological response variables, all synchronized with sub-millisecond temporal accuracy. We also discuss the implementation and importance of real-time display feedback to ensure data quality of all recorded variables. Finally, we discuss standards and formats for storage of temporal covariate data and its integration into fMRI image analysis. These neuroinformatics methods have been adopted for behavioral task control at all sites in the Functional Biomedical Informatics Research Network (FBIRN) multi-center fMRI study. PMID- 22232597 TI - High-resolution fiber tract reconstruction in the human brain by means of three dimensional polarized light imaging. AB - Functional interactions between different brain regions require connecting fiber tracts, the structural basis of the human connectome. To assemble a comprehensive structural understanding of neural network elements from the microscopic to the macroscopic dimensions, a multimodal and multiscale approach has to be envisaged. However, the integration of results from complementary neuroimaging techniques poses a particular challenge. In this paper, we describe a steadily evolving neuroimaging technique referred to as three-dimensional polarized light imaging (3D-PLI). It is based on the birefringence of the myelin sheaths surrounding axons, and enables the high-resolution analysis of myelinated axons constituting the fiber tracts. 3D-PLI provides the mapping of spatial fiber architecture in the postmortem human brain at a sub-millimeter resolution, i.e., at the mesoscale. The fundamental data structure gained by 3D-PLI is a comprehensive 3D vector field description of fibers and fiber tract orientations - the basis for subsequent tractography. To demonstrate how 3D-PLI can contribute to unravel and assemble the human connectome, a multiscale approach with the same technology was pursued. Two complementary state-of-the-art polarimeters providing different sampling grids (pixel sizes of 100 and 1.6 MUm) were used. To exemplarily highlight the potential of this approach, fiber orientation maps and 3D fiber models were reconstructed in selected regions of the brain (e.g., Corpus callosum, Internal capsule, Pons). The results demonstrate that 3D-PLI is an ideal tool to serve as an interface between the microscopic and macroscopic levels of organization of the human connectome. PMID- 22232595 TI - Parietofrontal integrity determines neural modulation associated with grasping imagery after stroke. AB - Chronic stroke patients with heterogeneous lesions, but no direct damage to the primary sensorimotor cortex, are capable of longitudinally acquiring the ability to modulate sensorimotor rhythms using grasping imagery of the affected hand. Volitional modulation of neural activity can be used to drive grasping functions of the paralyzed hand through a brain-computer interface. The neural substrates underlying this skill are not known. Here, we investigated the impact of individual patient's lesion pathology on functional and structural network integrity related to this volitional skill. Magnetoencephalography data acquired throughout training was used to derive functional networks. Structural network models and local estimates of extralesional white matter microstructure were constructed using T(1)-weighted and diffusion-weighted magnetic resonance imaging data. We employed a graph theoretical approach to characterize emergent properties of distributed interactions between nodal brain regions of these networks. We report that interindividual variability in patients' lesions led to differential impairment of functional and structural network characteristics related to successful post-training sensorimotor rhythm modulation skill. Patients displaying greater magnetoencephalography global cost-efficiency, a measure of information integration within the distributed functional network, achieved greater levels of skill. Analysis of lesion damage to structural network connectivity revealed that the impact on nodal betweenness centrality of the ipsilesional primary motor cortex, a measure that characterizes the importance of a brain region for integrating visuomotor information between frontal and parietal cortical regions and related thalamic nuclei, correlated with skill. Edge betweenness centrality, an analogous measure, which assesses the role of specific white matter fibre pathways in network integration, showed a similar relationship between skill and a portion of the ipsilesional superior longitudinal fascicle connecting premotor and posterior parietal visuomotor regions known to be crucially involved in normal grasping behaviour. Finally, estimated white matter microstructure integrity in regions of the contralesional superior longitudinal fascicle adjacent to primary sensorimotor and posterior parietal cortex, as well as grey matter volume co-localized to these specific regions, positively correlated with sensorimotor rhythm modulation leading to successful brain-computer interface control. Thus, volitional modulation of ipsilesional neural activity leading to control of paralyzed hand grasping function through a brain-computer interface after longitudinal training relies on structural and functional connectivity in both ipsilesional and contralesional parietofrontal pathways involved in visuomotor information processing. Extant integrity of this structural network may serve as a future predictor of response to longitudinal therapeutic interventions geared towards training sensorimotor rhythms in the lesioned brain, secondarily improving grasping function through brain-computer interface applications. PMID- 22232598 TI - Channelpedia: an integrative and interactive database for ion channels. AB - Ion channels are membrane proteins that selectively conduct ions across the cell membrane. The flux of ions through ion channels drives electrical and biochemical processes in cells and plays a critical role in shaping the electrical properties of neurons. During the past three decades, extensive research has been carried out to characterize the molecular, structural, and biophysical properties of ion channels. This research has begun to elucidate the role of ion channels in neuronal function and has subsequently led to the development of computational models of ion channel function. Although there have been substantial efforts to consolidate these findings into easily accessible and coherent online resources, a single comprehensive resource is still lacking. The success of these initiatives has been hindered by the sheer diversity of approaches and the variety in data formats. Here, we present "Channelpedia" (http://channelpedia.net), which is designed to store information related to ion channels and models and is characterized by an efficient information management framework. Composed of a combination of a database and a wiki-like discussion platform Channelpedia allows researchers to collaborate and synthesize ion channel information from literature. Equipped to automatically update references, Channelpedia integrates and highlights recent publications with relevant information in the database. It is web based, freely accessible and currently contains 187 annotated ion channels with 45 Hodgkin-Huxley models. PMID- 22232599 TI - Critical state of energy metabolism in brain slices: the principal role of oxygen delivery and energy substrates in shaping neuronal activity. AB - The interactive vasculo-neuro-glial system controlling energy supply in the brain is absent in vitro where energy provision is determined by experimental conditions. Despite the fact that neuronal activity is extremely energy demanding, little has been reported on the state of energy metabolism in submerged brain slices. Without this information, the arbitrarily chosen oxygenation and metabolic provisions make questionable the efficient oxidative metabolism in slices. We show that in mouse hippocampal slices (postnatal day 19 44), evoked neuronal discharges, spontaneous network activity (initiated by 4 aminopyridine), and synaptic stimulation-induced NAD(P)H autofluorescence depend strongly on the oxygen availability. Only the rate of perfusion as high as ~15 ml/min (95% O(2)) provided appropriate oxygenation of a slice. Lower oxygenation resulted in the decrease of both local field potentials and spontaneous network activity as well as in significant modulation of short-term synaptic plasticity. The reduced oxygen supply considerably inhibited the oxidation phase of NAD(P)H signaling indicating that the changes in neuronal activity were paralleled by the decrease in aerobic energy metabolism. Interestingly, the dependence of neuronal activity on oxygen tension was clearly shifted toward considerably larger pO(2) values in slices when compared to in vivo conditions. With sufficient pO(2) provided by a high perfusion rate, partial substitution of glucose in ACSF for beta-hydroxybutyrate, pyruvate, or lactate enhanced both oxidative metabolism and synaptic function. This suggests that the high pO(2) in brain slices is compulsory for maintaining oxidative metabolism, and glucose alone is not sufficient in fulfilling energy requirements during neuronal activity. Altogether, our results demonstrate that energy metabolism determines the functional state of neuronal network, highlighting the need for the adequate metabolic support to be insured in the in vitro experiments. PMID- 22232600 TI - Smoking attenuates transforming growth factor-beta-mediated tumor suppression function through downregulation of Smad3 in lung cancer. AB - Epidemiologic studies have shown that most cases of lung cancers (85%-90%) are directly attributable to cigarette smoking. Although much information has been gained about the effects of cigarette smoking on various signaling pathways causing lung cancer, nothing is known about the effect of cigarette smoking on the TGF-beta-induced tumor suppressor function in lung cancer. To address this issue, lung adenocarcinoma A549 and immortalized bronchial epithelial HPL1A cells were chronically treated with cigarette smoke condensate (CSC) and dimethyl sulfoxide (as a control) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-beta-mediated transcription due to reduced expression of Smad3. Long-term CSC treatment reduced apoptosis, increased cell viability, decreased TGF-beta-mediated growth inhibition, and enhanced tumorigenicity. The decrease in apoptosis is due to the upregulation of Bcl-2, which is a downstream target of Smad3. Re-expression of Smad3 in the CSC-treated cells restored TGF-beta signaling, increased apoptosis, and decreased cell viability and tumorigenicity. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability, and increased TGF beta-mediated growth inhibition. Expression of Smad3 is lower in lung tumors of current smokers than that observed in never-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-beta-mediated growth inhibition and apoptosis by reducing expression of Smad3. PMID- 22232601 TI - Parallel representation of stimulus identity and intensity in a dual pathway model inspired by the olfactory system of the honeybee. AB - The honeybee Apis mellifera has a remarkable ability to detect and locate food sources during foraging, and to associate odor cues with food rewards. In the honeybee's olfactory system, sensory input is first processed in the antennal lobe (AL) network. Uniglomerular projection neurons (PNs) convey the sensory code from the AL to higher brain regions via two parallel but anatomically distinct pathways, the lateral and the medial antenno-cerebral tract (l- and m-ACT). Neurons innervating either tract show characteristic differences in odor selectivity, concentration dependence, and representation of mixtures. It is still unknown how this differential stimulus representation is achieved within the AL network. In this contribution, we use a computational network model to demonstrate that the experimentally observed features of odor coding in PNs can be reproduced by varying lateral inhibition and gain control in an otherwise unchanged AL network. We show that odor coding in the l-ACT supports detection and accurate identification of weak odor traces at the expense of concentration sensitivity, while odor coding in the m-ACT provides the basis for the computation and following of concentration gradients but provides weaker discrimination power. Both coding strategies are mutually exclusive, which creates a tradeoff between detection accuracy and sensitivity. The development of two parallel systems may thus reflect an evolutionary solution to this problem that enables honeybees to achieve both tasks during bee foraging in their natural environment, and which could inspire the development of artificial chemosensory devices for odor-guided navigation in robots. PMID- 22232602 TI - Phorbol 12,13-dibutyrate-induced, protein kinase C-mediated contraction of rabbit bladder smooth muscle. AB - Contraction of bladder smooth muscle is predominantly initiated by M(3) muscarinic receptor-mediated activation of the G(q/11)-phospholipase C beta protein kinase C (PKC) and the G(12/13)-RhoGEF-Rho kinase (ROCK) pathways. However, these pathways and their downstream effectors are not well understood in bladder smooth muscle. We used phorbol 12,13-dibutyrate (PDBu), and 1,2 dioctanoyl-sn-glycerol (DOG), activators of PKC, in this investigation. We were interested in dissecting the role(s) of PKC and to clarify the signaling pathways in bladder smooth muscle contraction, especially the potential cross-talk with ROCK and their downstream effectors in regulating myosin light chain phosphatase activity and force. To achieve this goal, the study was performed in the presence or absence of the PKC inhibitor bisindolylmaleimide-1 (Bis) or the ROCK inhibitor H-1152. Phosphorylation levels of Thr(38)-CPI-17 and Thr(696)/Thr(850) myosin phosphatase target subunit (MYPT1) were measured during PDBu or DOG stimulation using site specific antibodies. PDBu-induced contraction in bladder smooth muscle involved both activation of PKC and PKC-dependent activation of ROCK. CPI-17 as a major downstream effector, is phosphorylated by PKC and ROCK during PDBu and DOG stimulation. Our results suggest that Thr(696) and Thr(850)-MYPT1 phosphorylation are not involved in the regulation of a PDBu-induced contraction. The results also demonstrate that bladder smooth muscle contains a constitutively active isoform of ROCK that may play an important role in the regulation of bladder smooth muscle basal tone. Together with the results from our previous study, we developed a working model to describe the complex signaling pathways that regulate contraction of bladder smooth muscle. PMID- 22232603 TI - Differential Modulation of Thresholds for Intracranial Self-Stimulation by mGlu5 Positive and Negative Allosteric Modulators: Implications for Effects on Drug Self-Administration. AB - Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5) receptor alters various addiction related behaviors such as drug self administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively) on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS). In addition, when acute effects were observed, we examined changes in ICSS thresholds following repeated administration. Male Sprague-Dawley rats were implanted with bipolar electrodes into the medial forebrain bundle and trained to respond for ICSS, followed by assessment of effects of mGlu5 ligands on ICSS thresholds using a discrete trials current-intensity threshold determination procedure. Acute administration of the selective mGlu5 NAMs MTEP (0, 0.3, 1, or 3 mg/kg) and fenobam (0, 3, 10, or 30 mg/kg) dose-dependently increased ICSS thresholds (~70% at the highest dose tested), suggesting a deficit in brain reward function. Acute administration of the mGlu5 PAMs CDPPB (0, 10, 30, and 60 mg/kg) or ADX47273 (0, 10, 30, and 60 mg/kg) was without effect at any dose tested. When administered once daily for five consecutive days, the development of tolerance to the ability of threshold elevating doses of MTEP and fenobam to increase ICSS thresholds was observed. We conclude that mGlu5 PAMs and NAMs differentially affect brain reward function, and that tolerance to the ability of mGlu5 NAMs to reduce brain reward function develops with repeated administration. These brain reward deficits should be taken into consideration when interpreting acute effects of mGlu5 NAMs on drug self-administration, and repeated administration of these ligands may be an effective method to reduce these deficits. PMID- 22232604 TI - Genotype-Phenotype Map Characteristics of an In silico Heart Cell. AB - Understanding the causal chain from genotypic to phenotypic variation is a tremendous challenge with huge implications for personalized medicine. Here we argue that linking computational physiology to genetic concepts, methodology, and data provides a new framework for this endeavor. We exemplify this causally cohesive genotype-phenotype (cGP) modeling approach using a detailed mathematical model of a heart cell. In silico genetic variation is mapped to parametric variation, which propagates through the physiological model to generate multivariate phenotypes for the action potential and calcium transient under regular pacing, and ion currents under voltage clamping. The resulting genotype to-phenotype map is characterized using standard quantitative genetic methods and novel applications of high-dimensional data analysis. These analyses reveal many well-known genetic phenomena like intralocus dominance, interlocus epistasis, and varying degrees of phenotypic correlation. In particular, we observe penetrance features such as the masking/release of genetic variation, so that without any change in the regulatory anatomy of the model, traits may appear monogenic, oligogenic, or polygenic depending on which genotypic variation is actually present in the data. The results suggest that a cGP modeling approach may pave the way for a computational physiological genomics capable of generating biological insight about the genotype-phenotype relation in ways that statistical genetic approaches cannot. PMID- 22232605 TI - Contribution of stretch to the change of activation properties of muscle fibers in the diaphragm at the transition from fetal to neonatal life. AB - The transition from fetal to postnatal life involves clearance of liquid from the lung and airways, and rapid formation of a functional residual capacity. Despite the importance of the diaphragm in this process, the impact of birth on the mechanical and functional activity of its muscle fibers is not known. This study determined the contractile characteristics of individual "skinned" diaphragm fibers from 70 days (0.47) gestation to after birth in sheep. Based on differential sensitivity to the divalent ions calcium (Ca(2+)) and strontium (Sr(2+)), all fibers in the fetal diaphragm were classified as "fast," whereas fibers from the adult sheep diaphragm exhibited a "hybrid" phenotype where both "fast" and "slow" characteristics were present within each single fiber. Transition to the hybrid phenotype occurred at birth, was evident after only 40 min of spontaneous breathing, and could be induced by simple mechanical stretch of diaphragm fibers from near-term fetuses (~147 days gestation). Both physical stretch of isolated fibers, and mechanical ventilation of the fetal diaphragm in situ, significantly increased sensitivity to Ca(2+) and Sr(2+), maximum force generating capacity, and decreased passive tension in near-term and preterm fetuses; however, only fibers from near-term fetuses showed a complete transition to a "hybrid" activation profile. These findings suggest that stretch associated with the transition from a liquid to air-filled lung at birth induces physical changes of proteins determining the activation and elastic properties of the diaphragm. These changes may allow the diaphragm to meet the increased mechanical demands of breathing immediately after birth. PMID- 22232607 TI - Is There a Relationship between DNA Methylation and Phenotypic Plasticity in Invertebrates? AB - There is a significant amount of variation in DNA methylation characteristics across organisms. Likewise, the biological role of DNA methylation varies across taxonomic lineages. The complexity of DNA methylation patterns in invertebrates has only recently begun to be characterized in-depth. In some invertebrate species that have been examined to date, methylated DNA is found primarily within coding regions and patterning is closely associated with gene function. Here we provide a perspective on the potential role of DNA methylation in these invertebrates with a focus on how limited methylation may contribute to increased phenotypic plasticity in highly fluctuating environments. Specifically, limited methylation could facilitate a variety of transcriptional opportunities including access to alternative transcription start sites, increasing sequence mutations, exon skipping, and transient methylation. PMID- 22232606 TI - The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. AB - Glycogen is the storage form of carbohydrates in mammals. In humans the majority of glycogen is stored in skeletal muscles (~500 g) and the liver (~100 g). Food is supplied in larger meals, but the blood glucose concentration has to be kept within narrow limits to survive and stay healthy. Therefore, the body has to cope with periods of excess carbohydrates and periods without supplementation. Healthy persons remove blood glucose rapidly when glucose is in excess, but insulin stimulated glucose disposal is reduced in insulin resistant and type 2 diabetic subjects. During a hyperinsulinemic euglycemic clamp, 70-90% of glucose disposal will be stored as muscle glycogen in healthy subjects. The glycogen stores in skeletal muscles are limited because an efficient feedback-mediated inhibition of glycogen synthase prevents accumulation. De novo lipid synthesis can contribute to glucose disposal when glycogen stores are filled. Exercise physiologists normally consider glycogen's main function as energy substrate. Glycogen is the main energy substrate during exercise intensity above 70% of maximal oxygen uptake ([Formula: see text]) and fatigue develops when the glycogen stores are depleted in the active muscles. After exercise, the rate of glycogen synthesis is increased to replete glycogen stores, and blood glucose is the substrate. Indeed insulin-stimulated glucose uptake and glycogen synthesis is elevated after exercise, which, from an evolutional point of view, will favor glycogen repletion and preparation for new "fight or flight" events. In the modern society, the reduced glycogen stores in skeletal muscles after exercise allows carbohydrates to be stored as muscle glycogen and prevents that glucose is channeled to de novo lipid synthesis, which over time will causes ectopic fat accumulation and insulin resistance. The reduction of skeletal muscle glycogen after exercise allows a healthy storage of carbohydrates after meals and prevents development of type 2 diabetes. PMID- 22232609 TI - Activation of the GABA(B) Receptor Prevents Nicotine-Induced Locomotor Stimulation in Mice. AB - Recent studies demonstrated that activation of the GABA(B) receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs), inhibited different nicotine-related behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABA(B) receptor agonist, baclofen, and GABA(B) PAMs, CGP7930, and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofen (0, 1.25, and 2.5 mg/kg, i.p.), CGP7930 (0, 25, and 50 mg/kg, i.g.), or GS39783 (0, 25, and 50 mg/kg, i.g.), then treated with nicotine (0 and 0.05 mg/kg, s.c.), and finally exposed to an automated apparatus for recording of locomotor activity. Pretreatment with doses of baclofen, CGP7930, or GS39783 that did not alter locomotor activity when given with nicotine vehicle fully prevented hyperlocomotion induced by 0.05 mg/kg nicotine. These data extend to nicotine stimulant effects the capacity of baclofen and GABA(B) PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABA(B) receptor may represent a potentially useful, anti-smoking therapeutic strategy. PMID- 22232608 TI - Caveolae, caveolins, cavins, and endothelial cell function: new insights. AB - Caveolae are cholesterol and glycosphingolipid-rich flask-shaped invaginations of the plasma membrane which are particularly abundant in vascular endothelium and present in all other cell types of the cardiovascular system, including vascular smooth-muscle cells, macrophages, cardiac myocytes, and fibroblasts. Caveolins and the more recently discovered cavins are the major protein components of caveolae. When caveolae were discovered, their functional role was believed to be limited to transport across the endothelial cell barrier. Since then, however, a large body of evidence has accumulated, suggesting that these microdomains are very important in regulating many other important endothelial cell functions, mostly due to their ability to concentrate and compartmentalize various signaling molecules. Over the course of several years, multiple studies involving knockout mouse and small interfering RNA approaches have considerably enhanced our understanding of the role of caveolae and caveolin-1 in regulating many cardiovascular functions. New findings have been reported implicating other caveolar protein components in endothelial cell signaling and function, such as the understudied caveolin-2 and newly discovered cavin proteins. The aim of this review is to focus primarily on molecular and cellular aspects of the role of caveolae, caveolins, and cavins in endothelial cell signaling and function. In addition, where appropriate, the possible implications for the cardiovascular and pulmonary physiology and pathophysiology will be discussed. PMID- 22232610 TI - Bilingual picture-word studies constrain theories of lexical selection. AB - Whether lexical selection is by competition is the subject of current debate in studies of monolingual language production. Here, I consider whether extant data from bilinguals can inform this debate. In bilinguals, theories that accept the notion of lexical selection by competition are divided between those positing competition among all lexical nodes vs. those that restrict competition to nodes in the target language only. An alternative view rejects selection by competition altogether, putting the locus of selection in a phonological output buffer, where some potential responses are easier to exclude than others. These theories make contrasting predictions about how quickly bilinguals should name pictures when non-target responses are activated. In Part 1, I establish the empirical facts for which any successful theory must account. In Part 2, I evaluate how well each theory accounts for the data. I argue that the data do not support theories that reject lexical selection by competition, and that although theories where competition for selection is restricted to the target language can be altered to fit the data, doing so would fundamentally undermine the distinctness of their position. Theories where selection is by competition throughout both target and non-target language lexicons must also be modified to account for the data, but these modifications are relatively peripheral to the theoretical impetus of the model. Throughout, I identify areas where our empirical facts are sparse, weak, or absent, and propose additional experiments that should help to further establish how lexical selection works, in both monolinguals and bilinguals. PMID- 22232611 TI - Do dolphins rehearse show-stimuli when at rest? Delayed matching of auditory memory. AB - The mechanisms underlying vocal mimicry in animals remain an open question. Delphinidae are able to copy sounds from their environment that are not produced by conspecifics. Usually, these mimicries occur associated with the context in which they were learned. No reports address the question of separation between auditory memory formation and spontaneous vocal copying although the sensory and motor phases of vocal learning are separated in a variety of songbirds. Here we show that captive bottlenose dolphins produce, during their nighttime resting periods, non-dolphin sounds that they heard during performance shows. Generally, in the middle of the night, these animals produced vocal copies of whale sounds that had been broadcast during daily public shows. As their life history was fully known, we know that these captive dolphins had never had the opportunity to hear whale sounds before then. Moreover, recordings made before the whale sounds started being broadcast revealed that they had never emitted such sounds before. This is to our knowledge the first evidence for a separation between formation of auditory memories and the process of learning to produce calls that match these memories in a marine mammal. One hypothesis is that dolphins may rehearse some special events heard during the daytime and that they then express vocally what could be conceived as a more global memory. These results open the way for broader views on how animals might rehearse life events while resting or maybe dreaming. PMID- 22232612 TI - Attention as a process of selection, perception as a process of representation, and phenomenal experience as the resulting process of perception being modulated by a dedicated consciousness mechanism. AB - Equivalence of attention and consciousness is disputed and necessity of attentional effects for conscious experience has become questioned. However, the conceptual landscape and interpretations of empirical evidence as related to this issue have remained controversial. Here I present some conceptual distinctions and research strategies potentially useful for moving forward when tackling this issue. Specifically, it is argued that we should carefully differentiate between pre-conscious processes and the processes resulting in phenomenal experience, move the emphasis from studying the effects of attention on the modality-specific and feature-specific perception to studying attentional effects on panmodal universal attributes of whatever conscious experience may be the case, and acknowledge that there is a specialized mechanism for leading to conscious experience of the pre-consciously represented contents autonomous from the mechanisms of perception, attention, memory, and cognitive control. PMID- 22232613 TI - Auditory motion capturing ambiguous visual motion. AB - In this study, it is demonstrated that moving sounds have an effect on the direction in which one sees visual stimuli move. During the main experiment sounds were presented consecutively at four speaker locations inducing left or rightward auditory apparent motion. On the path of auditory apparent motion, visual apparent motion stimuli were presented with a high degree of directional ambiguity. The main outcome of this experiment is that our participants perceived visual apparent motion stimuli that were ambiguous (equally likely to be perceived as moving left or rightward) more often as moving in the same direction than in the opposite direction of auditory apparent motion. During the control experiment we replicated this finding and found no effect of sound motion direction on eye movements. This indicates that auditory motion can capture our visual motion percept when visual motion direction is insufficiently determinate without affecting eye movements. PMID- 22232614 TI - Music, neuroscience, and the psychology of well-being: a precis. AB - In Flourish, the positive psychologist Seligman (2011) identifies five commonly recognized factors that are characteristic of human flourishing or well-being: (1) "positive emotion," (2) "relationships," (3) "engagement," (4) "achievement," and (5) "meaning" (p. 24). Although there is no settled set of necessary and sufficient conditions neatly circumscribing the bounds of human flourishing (Seligman, 2011), we would mostly likely consider a person that possessed high levels of these five factors as paradigmatic or prototypical of human flourishing. Accordingly, if we wanted to go about the practical task of actually increasing our level of well-being, we ought to do so by focusing on practically increasing the levels of the five factors that are characteristic of well-being. If, for instance, an activity such as musical engagement can be shown to positively influence each or all of these five factors, this would be compelling evidence that an activity such as musical engagement can positively contribute to one's living a flourishing life. I am of the belief that psychological research can and should be used, not only to identify and diagnose maladaptive psychological states, but identify and promote adaptive psychological states as well. In this article I advance the hypothesis and provide supporting evidence for the claim that musical engagement can positively contribute to one's living a flourishing life. Since there has not yet been a substantive and up-to-date investigation of the possible role of music in contributing to one's living a flourishing life, the purpose of this article is to conduct this investigation, thereby bridging the gap and stimulating discussion between the psychology of music and the psychology of well-being. PMID- 22232615 TI - Variable initial swing side and prolonged double limb support represent abnormalities of the first three steps of gait initiation in patients with Parkinson's disease with freezing of gait. AB - This study investigated abnormalities of the first three steps of gait initiation in patients with Parkinson's disease without freezing of gait (PD - FOG) and investigated which abnormalities are related to FOG. Seven PD - FOG and seven age matched healthy controls performed self-generated or cue-triggered gait initiation. Data for PD patients with FOG (PD + FOG) were cited from a previous study using a procedure similar to that used in the present study. Gait initiation was abnormal, and external cue normalized some abnormalities in PD - FOG. The initial swing side was fairly consistent among the trials in both PD - FOG and in healthy controls, although the initial swing side was inconsistent in PD + FOG. The duration of the first double limb support (DLS) was the only parameter that depends on FOG severity and that was abnormal in PD + FOG but was not abnormal in PD - FOG. The variability of the initial swing side and prolonged first DLS are abnormalities specifically related to FOG. PMID- 22232616 TI - The case for an elderly targeted stroke management. AB - Stroke is a leading cause of death and disability worldwide. The elderly, in whom atrial fibrillation (AF) is most prevalent, carry the greatest risk, undergoing more recurrent, deadlier strokes, with bigger deficits, slower recoveries, and more comorbidities. Evidence-based data on advanced age stroke management are scarce. Age-related cerebral changes might undermine the benefit of established stroke treatments. Nevertheless, the elderly should probably also undergo thrombolysis for ischemic stroke: they do not bleed more, and die not because of hemorrhage but of concomitant illnesses. Beyond natural bleeding risks, AF in advanced age has a high embolic potential if not anticoagulated. Standard or lower intensity warfarin anticoagulation prevents embolic stroke in the elderly with a hemorrhage risk even lower than aspirin. In fact, adverse effects seem to occur more often with aspirin. Excess anticoagulation hazards are prevented with lower starting doses, stricter corrections, more frequent International Normalized Ratio monitoring, and longer adjustment intervals. Validated prognostic scores such as CHADS(2) help minimize bleeds. Direct inhibitors have recently shown a benefit similar to warfarin with fewer hemorrhages. Carefully tailoring antithrombotics to this age group is therefore useful. Antihypertensives probably help 80-plus stroke patients as well, but the risk/benefit of lowering blood pressure in secondary stroke prevention at that age is uncertain. Evidence-based data on diabetes management and use of lipid lowering drugs are still lacking in this age group. In summary, emerging data suggest that stroke management should be specifically targeted to the elderly to better prevent its devastating consequences in the population at the highest risk. PMID- 22232617 TI - Two Strains of Crocosphaera watsonii with Highly Conserved Genomes are Distinguished by Strain-Specific Features. AB - Unicellular nitrogen-fixing cyanobacteria are important components of marine phytoplankton. Although non-nitrogen-fixing marine phytoplankton generally exhibit high gene sequence and genomic diversity, gene sequences of natural populations and isolated strains of Crocosphaerawatsonii, one of the two most abundant open ocean unicellular cyanobacteria groups, have been shown to be 98 100% identical. The low sequence diversity in Crocosphaera is a dramatic contrast to sympatric species of Prochlorococcus and Synechococcus, and raises the question of how genome differences can explain observed phenotypic diversity among Crocosphaera strains. Here we show, through whole genome comparisons of two phenotypically different strains, that there are strain-specific sequences in each genome, and numerous genome rearrangements, despite exceptionally low sequence diversity in shared genomic regions. Some of the strain-specific sequences encode functions that explain observed phenotypic differences, such as exopolysaccharide biosynthesis. The pattern of strain-specific sequences distributed throughout the genomes, along with rearrangements in shared sequences is evidence of significant genetic mobility that may be attributed to the hundreds of transposase genes found in both strains. Furthermore, such genetic mobility appears to be the main mechanism of strain divergence in Crocosphaera which do not accumulate DNA microheterogeneity over the vast majority of their genomes. The strain-specific sequences found in this study provide tools for future physiological studies, as well as genetic markers to help determine the relative abundance of phenotypes in natural populations. PMID- 22232619 TI - Metagenomic evidence for h(2) oxidation and h(2) production by serpentinite hosted subsurface microbial communities. AB - Ultramafic rocks in the Earth's mantle represent a tremendous reservoir of carbon and reducing power. Upon tectonic uplift and exposure to fluid flow, serpentinization of these materials generates copious energy, sustains abiogenic synthesis of organic molecules, and releases hydrogen gas (H(2)). In order to assess the potential for microbial H(2) utilization fueled by serpentinization, we conducted metagenomic surveys of a marine serpentinite-hosted hydrothermal chimney (at the Lost City hydrothermal field) and two continental serpentinite hosted alkaline seeps (at the Tablelands Ophiolite, Newfoundland). Novel [NiFe] hydrogenase sequences were identified at both the marine and continental sites, and in both cases, phylogenetic analyses indicated aerobic, potentially autotrophic Betaproteobacteria belonging to order Burkholderiales as the most likely H(2)-oxidizers. Both sites also yielded metagenomic evidence for microbial H(2) production catalyzed by [FeFe]-hydrogenases in anaerobic Gram-positive bacteria belonging to order Clostridiales. In addition, we present metagenomic evidence at both sites for aerobic carbon monoxide utilization and anaerobic carbon fixation via the Wood-Ljungdahl pathway. In general, our results point to H(2)-oxidizing Betaproteobacteria thriving in shallow, oxic-anoxic transition zones and the anaerobic Clostridia thriving in anoxic, deep subsurface habitats. These data demonstrate the feasibility of metagenomic investigations into novel subsurface habitats via surface-exposed seeps and indicate the potential for H(2) powered primary production in serpentinite-hosted subsurface habitats. PMID- 22232620 TI - Current health issues in Korean adolescents. AB - During the adolescent period, they experience rapid physical, emotional, cognitive developments while they establish their lifestyle and habitual routines that strongly influence adult health and life. Recent rapid economic growth in Korea, and the earlier onset of physical, sexual, and psychological maturation of adolescents, has resulted in changes in the health status of adolescents from many years ago. Risk-taking behaviors such as drinking alcohol, smoking, and sexual experiences are critical issues that affect the health of, adolescents. Therefore, it is important for pediatricians to note the that risk-taking behaviors of adolescents in Korea that are caused by individual psychosocial factors. This review article illustrates the current health status of Korean adolescents and provides an overview of risk-taking behaviors, to inform pediatricians about some of the key issues. PMID- 22232618 TI - Structural dynamics of retroviral genome and the packaging. AB - Retroviruses can cause diseases such as AIDS, leukemia, and tumors, but are also used as vectors for human gene therapy. All retroviruses, except foamy viruses, package two copies of unspliced genomic RNA into their progeny viruses. Understanding the molecular mechanisms of retroviral genome packaging will aid the design of new anti-retroviral drugs targeting the packaging process and improve the efficacy of retroviral vectors. Retroviral genomes have to be specifically recognized by the cognate nucleocapsid domain of the Gag polyprotein from among an excess of cellular and spliced viral mRNA. Extensive virological and structural studies have revealed how retroviral genomic RNA is selectively packaged into the viral particles. The genomic area responsible for the packaging is generally located in the 5' untranslated region (5' UTR), and contains dimerization site(s). Recent studies have shown that retroviral genome packaging is modulated by structural changes of RNA at the 5' UTR accompanied by the dimerization. In this review, we focus on three representative retroviruses, Moloney murine leukemia virus, human immunodeficiency virus type 1 and 2, and describe the molecular mechanism of retroviral genome packaging. PMID- 22232621 TI - Smoking and adolescent health. AB - With the Westernization and opening of our society, adolescents' smoking is increasing and being popularized. Many adolescents start smoking at an early age out of curiosity and venturesomeness, and earlier start of smoking makes it more difficult to quit smoking. Adolescents' habitual smoking not only becomes a gateway to all kinds of substance abuse but also causes various health problems including upper respiratory infection, immature lung development, reduced maximum vital capacity, and lung cancer. Therefore, it is quite important to prevent adolescents from smoking. The lowering of adolescents' smoking rate cannot be achieved only through social restrictions such as stereotyped education on the harms of smoking and ID checking. In order to lower adolescents' smoking rate substantially, each area of society should develop standardized programs and make related efforts. As adolescents' smoking is highly influenced by home environment or school life, it is necessary to make efforts in effective education and social reinforcement in school, to establish related norms, and to execute preventive education using peer groups. When these efforts are spread throughout society in cooperation with homes and communities, they will be helpful to protect adolescents' health and improve their quality of life. PMID- 22232623 TI - Clinical features of Epstein-Barr virus-associated infectious mononucleosis in hospitalized Korean children. AB - PURPOSE: Few studies have been conducted on the recent status of infectious mononucleosis (IM) in Korean children. The aim of this study was to evaluate the recent trend in the clinical manifestations of Epstein-Barr virus (EBV) associated IM as well as the clinical differences according to age. METHODS: A retrospective study was performed on 81 children hospitalized with EBV-associated IM who fulfilled the serological criteria for the diagnosis of EBV infection (viral capsid antigen immunoglobulin M positive). The patients were divided into 3 age groups: <5 years, 5 to 9 years, and >=10 years. We evaluated the recent trend in clinical manifestations and the differences in clinical and laboratory findings among the 3 age groups. RESULTS: Thirty (37%) children were under 5 years of age, 38 (46.9%) were 5 to 9 years of age, and 13 (16%) were 10 years of age or older. The differences in the symptoms and signs among the 3 age groups were not statistically significant, except for headache. The mean duration of fever was 7.7 days (range, 0 to 18 days). A comparison of liver enzyme elevation among the age groups showed an association with advancing age (26.6%, 63.1%, and 76.9%, respectively, P=0.04) CONCLUSION: This study showed that EBV-associated IM in Korean children continues to occur mostly in children under 10 years of age. In children with EBV-associated IM, the incidence of headache and liver enzyme elevation, the duration of fever, and the proportion of females to males were all positively associated with advancing age. PMID- 22232622 TI - Clinical characteristics of 2009 pandemic influenza A (H1N1) infection in children and the performance of rapid antigen test. AB - PURPOSE: In autumn 2009, the swine-origin influenza A (H1N1) virus spread throughout South Korea. The aims of this study were to determine the clinical characteristics of children infected by the 2009 H1N1 influenza A virus, and to compare the rapid antigen and real-time polymerase chain reaction (PCR) tests. METHODS: We conducted a retrospective review of patients >=18 years of age who presented to Soonchunhyang University Hospital in Seoul with respiratory symptoms, including fever, between September 2009 and January 2010. A real-time PCR test was used to definitively diagnose 2009 H1N1 influenza A infection. Medical records of confirmed cases were reviewed for sex, age, and the time of infection. The decision to perform rapid antigen testing was not influenced by clinical conditions, but by individual factors such as economic conditions. Its sensitivity and specificity were evaluated compared to real-time PCR test results. RESULTS: In total, 934 patients tested positive for H1N1 by real-time PCR. The highest number of patients (48.9%) was diagnosed in November. Most patients (48.2%) were aged between 6 and 10 years. Compared with the H1N1 real time PCR test results, the rapid antigen test showed 22% sensitivity and 83% specificity. Seventy-eight patients were hospitalized for H1N1 influenza A virus infection, and fever was the most common symptom (97.4%). CONCLUSION: For diagnosis of 2009 H1N1 influenza A virus infection, the rapid antigen test was inferior to the real-time PCR test in both sensitivity and specificity. This outcome suggests that the rapid antigen test is inappropriate for screening. PMID- 22232624 TI - Identification of major rice allergen and their clinical significance in children. AB - PURPOSE: Recently, an increase in the number of patients sensitized to rice allergen with or without clinical symptoms has been reported. This study was designed to determine the major allergens in rice and their clinical significance. METHODS: Twenty-four children (15 boys and 9 girls; mean age, 16.3 months) with allergic disease, who were sensitized to rice antigen (by UniCAP) in the Pediatric Allergy Respiratory Center at Soonchunhyang University Hospital, were enrolled in this study. The allergenicity of various types of rice (raw, cooked, and heat-treated, simulated gastric fluid [SGF], and simulated intestinal fluid [SIF]) was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoglobulin E (IgE) immunoblots. The patients' medical records, including laboratory data and allergy symptoms after ingestion of rice were reviewed. RESULTS: Patients were sensitized to an average of 13.5 food antigens and their mean total IgE was 6,888.7 kU/L. In SDS-PAGE, more than 16 protein bands were observed in the raw rice, whereas only 14-16 kDa and 31-35 kDa protein bands were observed in cooked rice. The common SDS-PAGE protein bands observed in SGF-, SIF-, and heat-treated rice were 9, 14, and 31 kDa. In a heated rice IgE immunoblot, protein bands of 9, 14, and 31-33 kDa were found in 27.8%, 38.9%, and 38.9% of all sera, respectively, and in 50%, 50%, and 75%, of ser a from the 4 symptomatic patients, respectively. CONCLUSION: The 9-, 14-, and 31 kDa protein bands appeared to be the major allergens responsible for rice allergy symptoms. PMID- 22232625 TI - An adverse event following 2009 H1N1 influenza vaccination: a case of acute disseminated encephalomyelitis. AB - Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that typically follows an infection or vaccination and has a favorable long-term prognosis. We describe the first reported case of ADEM after vaccination against novel influenza A (H1N1). A previously healthy 34-month-old boy who developed ADEM presented with a seizure and left-sided weakness 5 days after vaccination against novel influenza A (H1N1). Cerebrospinal fluid examination revealed elevated cell counts. T2 weighted images and fluid-attenuated inversion recovery images revealed multiple patchy hyperintense lesions in the frontal and parietal subcortical white matter and the left thalamus. After the administration of intravenous corticosteroid, the patient's clinical symptoms improved and he recovered completely without neurologic sequelae. PMID- 22232626 TI - Acute treatment of hyperammonemia by continuous renal replacement therapy in a newborn patient with ornithine transcarbamylase deficiency. AB - Ornithine transcarbamylase (OTC) deficiency is well known as the most common inherited disorder of the urea cycle, and 1 of the most common causes of hyperammonemia in newborns. We experienced a case of a 3-day-old boy with OTC deficiency who appeared healthy in the first 2 days of life but developed lethargy and seizure soon afterwards. His serum ammonia level was measured as >1700 ug/dL (range, 0 to 45 ug/dL). Continuous renal replacement therapy (CRRT) in the mode of continuous venovenous hemodiafiltration was immediately applied to correct the raised ammonia level. No seizure occurred after the elevated ammonia level was reduced. Therefore, CRRT should be included as 1 of the treatment modalities for newborns with inborn errors of metabolism, especially hyperammonemia. Here, we report 1 case of successful treatment of hyperammonemia by CRRT in a neonate with OTC deficiency. PMID- 22232627 TI - Optimal oxygen saturation in premature infants. AB - There is a delicate balance between too little and too much supplemental oxygen exposure in premature infants. Since underuse and overuse of supplemental oxygen can harm premature infants, oxygen saturation levels must be monitored and kept at less than 95% to prevent reactive oxygen species-related diseases, such as retinopathy of prematurity and bronchopulmonary dysplasia. At the same time, desaturation below 80 to 85% must be avoided to prevent adverse consequences, such as cerebral palsy. It is still unclear what range of oxygen saturation is appropriate for premature infants; however, until the results of further studies are available, a reasonable target for pulse oxygen saturation (SpO(2)) is 90 to 93% with an intermittent review of the correlation between SpO(2) and the partial pressure of arterial oxygen tension (PaO(2)). Because optimal oxygenation depends on individuals at the bedside making ongoing adjustments, each unit must define an optimal target range and set alarm limits according to their own equipment or conditions. All staff must be aware of these values and adjust the concentration of supplemental oxygen frequently. PMID- 22232628 TI - Catheter-related bloodstream infections in neonatal intensive care units. AB - Central venous catheters (CVCs) are regularly used in intensive care units, and catheter-related bloodstream infection (CRBSI) remains a leading cause of healthcare-associated infections, particularly in preterm infants. Increased survival rate of extremely-low-birth-weight infants can be partly attributed to routine practice of CVC placement. The most common types of CVCs used in neonatal intensive care units (NICUs) include umbilical venous catheters, peripherally inserted central catheters, and tunneled catheters. CRBSI is defined as a laboratory-confirmed bloodstream infection (BSI) with either a positive catheter tip culture or a positive blood culture drawn from the CVC. BSIs most frequently result from pathogens such as gram-positive cocci, coagulase-negative staphylococci, and sometimes gram-negative organisms. CRBSIs are usually associated with several risk factors, including prolonged catheter placement, femoral access, low birth weight, and young gestational age. Most NICUs have a strategy for catheter insertion and maintenance designed to decrease CRBSIs. Specific interventions slightly differ between NICUs, particularly with regard to the types of disinfectants used for hand hygiene and appropriate skin care for the infant. In conclusion, infection rates can be reduced by the application of strict protocols for the placement and maintenance of CVCs and the education of NICU physicians and nurses. PMID- 22232629 TI - An update on necrotizing enterocolitis: pathogenesis and preventive strategies. AB - Necrotizing enterocolitis (NEC) is one of the most critical morbidities in preterm infants. The incidence of NEC is 7% in very-low-birth-weight infants, and its mortality is 15 to 30%. Infants who survive NEC have various complications, such as nosocomial infection, malnutrition, growth failure, bronchopulmonary dysplasia, retinopathy of prematurity, and neurodevelopmental delays. The most important etiology in the pathogenesis of NEC is structural and immunological intestinal immaturity. In preterm infants with immature gastrointestinal tracts, development of NEC may be associated with a variety of factors, such as colonization with pathogenic bacteria, secondary ischemia, genetic polymorphisms conferring NEC susceptibility, anemia with red blood cell transfusion, and sensitization to cow milk proteins. To date, a variety of preventive strategies has been accepted or attempted in clinical practice with regard to the pathogenesis of NEC. These strategies include the use of breast feeding, various feeding strategies, probiotics, prebiotics, glutamine and arginine, and lactoferrin. There is substantial evidence for the efficacy of breast feeding and the use of probiotics in infants with birth weights above 1,000 g, and these strategies are commonly used in clinical practice. Other preventive strategies, however, require further research to establish their effect on NEC. PMID- 22232630 TI - Hu.4-1BB-Fc fusion protein inhibits allergic inflammation and airway hyperresponsiveness in a murine model of asthma. AB - PURPOSE: 4-1BB (CD 137) is a costimulatory molecule expressed on activated T cells. Repression by 4-1BB is thought to attenuate Th2-mediated allergic reactions. The aim of this study was to investigate the effect of 4-1BB on allergic airway inflammation in a murine asthma model. METHODS: BALB/c mice were sensitized to and challenged with ovalbumin (OVA). Hu.4-1BB-Fc was administered 1 day before the first OVA sensitization or 1 day after the second OVA sensitization. Following antigen challenge, airway responsiveness to methacholine was assessed and bronchoalveolar lavage (BAL) fluid was analyzed. Total immunoglobulin (Ig) E, OVA-specific IgE, IgG(1), and IgG(2a) levels in sera were measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. RESULTS: In mice treated with Hu.4-1BB-Fc before the first OVA sensitization, there was a marked decrease in airway hyperresponsiveness, total cell count, and eosinophil count in the BAL fluid. In addition, Hu.4-1BB-Fc treatment decreased serum OVA-specific IgG(1) levels and increased serum IgG(2a) level significantly compared with the corresponding levels in mice sensitized to and challenged with OVA. Hu.4-1BB-Fc-treated mice also showed suppressed peribronchial and perivascular inflammatory cell infiltration. In contrast, treatment with Hu.4-1BB Fc 1 day after sensitization had no effect on airway hyperresponsiveness and showed less suppression of inflammation in lung tissue. CONCLUSION: Administration of Hu.4-1BB-Fc can attenuate airway inflammation and hyperreactivity in a mouse model of allergic airway inflammation. In addition, administration before sensitization may be more effective. These findings suggest that 4-1BB may be a useful therapeutic molecule against asthma. PMID- 22232631 TI - Short term outcomes of topiramate monotherapy as a first-line treatment in newly diagnosed West syndrome. AB - PURPOSE: To investigate the efficacy of topiramate monotherapy in West syndrome prospectively. METHODS: The study population included 28 patients (15 male and 13 female children aged 2 to 18 months) diagnosed with West syndrome. After a 2-week baseline period for documentation of the frequency of spasms, topiramate was initiated at 2 mg/kg/day. The dose was increased by 2 mg/kg every week to a maximum of 12 mg/kg/day. Clinical assessment was based on the parents' report and a neurological examination every 2 weeks for the first 2 months of treatment. The baseline electroencephalograms (EEGs) were compared with the post-treatment EEGs at 2 weeks and 1 month. RESULTS: West syndrome was considered to be cryptogenic in 7 of the 28 patients and symptomatic in 21 patients. After treatment, 11 patients (39%) became spasm-free, 6 (21%) had more than 50% spasmsreduction, 3 (11%) showed less than 50% reduction, and 8 (29%) did not respond. The effective daily dose for achieving more than 50% reduction in spasm frequency, including becoming spasm-free, was found to be 5.8+/-1.1 mg/kg/day. Nine patients (32%) showed complete disappearance of spasms and hypsarrhythmia, and 11 (39%) showed improved EEG results. Despite adverse events (4 instances of irritability, 3 of drowsiness, and 1 of decreased feeding), no patients discontinued the medication. CONCLUSION: Topiramate monotherapy seems to be effective and well tolerated as a first line therapy for West syndrome and is not associated with serious adverse effects. PMID- 22232632 TI - Candida tropicalis arthritis of the elbow in a patient with Ewing's sarcoma that successfully responded to itraconazole. AB - Fungal infections are rarely responsible for arthritis. Few cases of fungal arthritis have been reported, even in immunocompromised hosts susceptible to low virulence organisms. Herein, the authors report the first case of Candida tropicalis arthritis in a child with a solid tumor. A 13-year-old boy with Ewing's sarcoma developed arthritis in his elbow during the neutropenic period after chemotherapy. Despite treatment with broad-spectrum antibiotics, his condition did not improve and serial blood cultures failed to reveal any causative organisms. After surgical drainage, culture of the joint fluid revealed the presence of C. tropicalis. Itraconazole treatment was started and after 3 months of therapy, the patient completely recovered full elbow function. PMID- 22232633 TI - Transient asymptomatic white matter lesions following Epstein-Barr virus encephalitis. AB - We present the case of a patient with Epstein-Barr virus (EBV) encephalitis who developed abnormal white matter lesions during the chronic phases of the infection. A 2-year-old-boy was admitted for a 2 day history of decreased activity with ataxic gait. The results of the physical examination were unremarkable except for generalized lethargy and enlarged tonsils with exudates. Brain magnetic resonance imaging (MRI) at admission showed multiple high signal intensities in both basal ganglia and thalami. The result of EBV polymerase chain reaction (PCR) of the cerebral spinal fluid was positive, and a serological test showed acute EBV infection. The patient was diagnosed with EBV encephalitis and recovered fully without any residual neurologic complications. Subsequently, follow-up MRI at 5 weeks revealed extensive periventricular white matter lesions. Since the patient remained clinically stable and asymptomatic during the follow up period, no additional studies were performed and no additional treatments were provided. At the 1-year follow-up, cranial MRI showed complete disappearance of the abnormal high signal intensities previously seen in the white matter. The patient continued to remain healthy with no focal neurologic deficits on examination. This is the first case of asymptomatic self-limited white matter lesions seen in serial MRI studies in a Korean boy with EBV encephalitis. PMID- 22232635 TI - Effects of Ficus carica paste on constipation induced by a high-protein feed and movement restriction in beagles. AB - Constipation is one of the most common functional digestive complaints worldwide. We investigated the laxative effects of figs (Ficus carica L) in a beagle model of constipation induced by high protein diet and movement restriction. The experiments were consecutively conducted over 9 weeks divided into 3 periods of 3 weeks each. All 15 beagles were subjected to a non-treatment (control) period, a constipation induction period, and a fig paste treatment period. We administered fig paste (12 g/kg daily, by gavage) for 3 weeks following a 3-week period of constipation induction in dogs. Segmental colonic transit time (CTT) was measured by counting radiopaque markers (Kolomark) using a radiograph performed every 6 h after feeding Kolomark capsules, until capsules were no longer observed. Fig paste significantly increased fecal quantity in constipated dogs, and segmental CTT was also reduced following fig paste administration. There were no significant differences in feed intake, water intake, body weight, or blood test results, between the constipation and fig paste administration periods. Our results demonstrate that fig is an effective treatment for constipation in beagles. Specifically, stool weight increased and segmental CTT decreased. Fig pastes may be useful as a complementary medicine in humans suffering from chronic constipation. PMID- 22232634 TI - Diverse animal models to examine potential role(s) and mechanism of endocrine disrupting chemicals on the tumor progression and prevention: Do they have tumorigenic or anti-tumorigenic property? AB - Acting as hormone mimics or antagonists in the interaction with hormone receptors, endocrine disrupting chemicals (EDCs) have the potentials of disturbing the endocrine system in sex steroid hormone-controlled organs and tissues. These effects may lead to the disruption of major regulatory mechanisms, the onset of developmental disorders, and carcinogenesis. Especially, among diverse EDCs, xenoestrogens such as bisphenol A, dioxins, and di(2 ethylhexyl)phthalate, have been shown to activate estrogen receptors (ERs) and to modulate cellular functions induced by ERs. Furthermore, they appear to be closely related with carcinogenicity in estrogen-dependant cancers, including breast, ovary, and prostate cancers. In in vivo animal models, prenatal exposure to xenoestrogens changed the development of the mouse reproductive organs and increased the susceptibility to further carcinogenic exposure and tumor occurence in adults. Unlike EDCs, which are chemically synthesized, several phytoestrogens such as genistein and resveratrol showed chemopreventive effects on specific cancers by contending with ER binding and regulating normal ER action in target tissues of mice. These results support the notion that a diet containing high levels of phytoestrogens can have protective effects on estrogen-related diseases. In spite of the diverse evidences of EDCs and phytoestrogens on causation and prevention of estrogen-dependant cancers provided in this article, there are still disputable questions about the dose-response effect of EDCs or chemopreventive potentials of phytoestrogens. As a wide range of EDCs including phytoestrogens have been remarkably increasing in the environment with the rapid growth in our industrial society and more closely affecting human and wildlife, the potential risks of EDCs in endocrine disruption and carcinogenesis are important issues and needed to be verified in detail. PMID- 22232636 TI - Basic data on the hematology, serum biochemistry, urology, and organ weights of beagle dogs. AB - This study was conducted to provide basic data on physiological and hematological characteristics, and organ weights of beagle dogs. A total of 237 beagle dogs were used to determine differences in physiological and hematological parameters, and organ weights depending on sex and age. The respiratory rate of both sexes tended to increase as they grew older and the female heart rate was slightly higher than that of males. Male and female body weights increased rapidly to 33 weeks old followed by a gradual increase to 41-weeks-old. The relative weight of the brain was negatively correlated with body weight, whereas the weight of reproductive organs was positively correlated with body weight. The platelet count of female dogs was slightly higher than that of males. The red blood cell, hemoglobin, and hematocrit of both sexes increased non-significantly with age. In the leukocyte differential count, the neutrophils, and eosinophils of both sexes tended to increase as they grew older, whereas basophils, lymphocytes, and monocytes decreased. In the serum biochemical profiles, alkaline phosphatase was slightly higher in males than females, while the total cholesterol of female dogs at 9-months-old was higher than that of males at the same age. Other biochemical components, including alanine aminotransferase, blood urea nitrogen, creatinine, triglyceride, and total protein increased non-significantly with age in both sexes. To conclude, we observe no significant physiological or hematological differences with sex or age, although decreasing and increasing trends were detected with some parameters. These data provide valuable reference indices of the normal physiological and hematological characteristics of beagle dogs, which should prove useful in toxicological and pharmacological studies. PMID- 22232637 TI - Peroxiredoxin I regulates the component expression of gamma-secretase complex causing the Alzheimer's disease. AB - Peroxiredoxin I (Prx I) is a member of the peroxiredoxins (Prxs) family, which are antioxidant enzymes that regulate various cellular process via intracellular oxidative signal pathways. In order to investigate the correlation between Prx I and the gamma-secretase complex, which causes Alzheimer's disease (AD), the expression level of Prx I was firstly evaluated in an animal model for AD. NSE/hPen-2 transgenic (Tg) mice, which were used as animal model in this study, showed a high level of Pen-2 expression and accumulation of Abeta-42 peptides in the hippocampus of brain. The expression level of Prx I was significantly higher on the mRNA and protein level in the brain of this model, while not change in Prx VI expression was observed. Furthermore, to verify the effect of Prx I on the gamma-secretase components in vitro, the expression level of these components was analyzed in the Prx I transfectants. Of the components of the gamma-secretase complex, the expression of PS-2 and Pen-2 was lower in the transfectants overexpressing Prx I compared to the vector transfectants. However, the expression of APP, NCT and APH-1 did not change in Prx I transfectants. Therefore, these results suggested that the expression of Prx I may be induced by the accumulation of Abeta-42 peptides and the overexpression of Prx I in neuroblastoma cells may regulate the expression of gamma-secretase components. PMID- 22232638 TI - Effects of Sigma Anti-bonding Molecule Calcium Carbonate on bone turnover and calcium balance in ovariectomized rats. AB - This study was conducted to evaluate the effect of Sigma Anti-bonding Molecule Calcium Carbonate (SAC) as therapy for ovariectomy-induced osteoporosis in rats. Three weeks after surgery, fifteen ovariectomized Sprague-Dawley rats were divided randomly into 3 groups: sham-operated group (sham), ovariectomized group (OVX) and SAC-treatment group (OVX+SAC). The OVX+SAC group was given drinking water containing 0.0012% SAC for 12 weeks. Bone breaking force and mineralization as well as blood parameters related to the bone metabolism were analyzed. In OVX animals, blood concentration of 17beta-estradiol decreased significantly, while osteocalcin and type I collagen C-terminal telopeptides (CTx) increased. Breaking force, bone mineral density (BMD), calcium and phosphorus in femurs, as well as uterine and vaginal weights, decreased significantly following OVX. However, SAC treatment (0.0012% in drinking water) not only remarkably restored the decreased 17beta-estradiol and increased osteocalcin and CTx concentrations, but also recovered decreased femoral breaking force, BMD, calcium and phosphorus, although it did not reversed reproductive organ weights. It is suggested that SAC effectively improve bone density by preventing bone turnover mediated osteocalcin, CTx and minerals, and that it could be a potential candidate for therapy or prevention of postmenopausal osteoporosis. PMID- 22232639 TI - Magnetic resonance imaging evaluation of Yukatan minipig brains for neurotherapy applications. AB - Magnetic resonance imaging (MRI) of six Yukatan minipig brains was performed. The animals were placed in stereotaxic conditions currently used in experiments. To allow for correctpositioning of the animal in the MRI instrument, landmarks were previously traced on the snout of the pig. To avoid movements, animal were anesthetized. The animals were placed in a prone position in a Siemens Magnetom Avanto 1.5 System with a head coil. Axial T2-weighted and sagittal T1-weighted MRI images were obtained from each pig. Afterwards, the brains of the pigs were fixed and cut into axial sections. Histologic and MR images were compared. The usefulness of this technique is discussed. PMID- 22232640 TI - Inhibitory effect of Suaeda asparagoides (Miq.) extract on the motility of rat gastric antrum is mediated by beta-adrenoceptor. AB - Suaeda asparagoides (Miq.) has long been used as a Korean folk herbal medicine for the treatment of functional gastrointestinal disorders. However, reports on its pharmacological activity on gastrointestinal motility are scarce. The present study investigated the effects of Suaeda asparagoides water fraction of the extract (SAWF) on antral motility in vitro. Muscle strips from rat gastric antrum were set up in an organ bath in a circular orientation. SAWF (100 ug/mL) inhibited the spontaneous contraction of antral circular muscle strips. These inhibitory effects were not significantly affected by tetrodotoxin (1 uM), N(omega)-Nitro-L-arginine methyl ester hydrochloride (100 uM), 1H (1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 uM), ryanodine (10 uM) and phentolamine (10 uM). SAWF-induced inhibition was mostly restored by cyclopiazonic acid (10 uM). Furthermore, the beta-adrenergic receptor antagonist, propranolol (10 uM), abolished SAWF-induced inhibition. These results suggest that SAWF may exert its activity on gastrointestinal smooth muscle via a adrenergic receptors and sarcoplasmic reticulum Ca(2+) ATPase. PMID- 22232641 TI - High glucose stimulates glutamate uptakes in pancreatic beta-cells. AB - Pancreatic beta-cells are major cells responsible for glucose metabolism in the body. Hyperglycemia is known to be a primary factor in the induction of diabetes mellitus. Glutamate is also an excitatory neurotransmitter in diverse organs. Oxidative stress also plays a pivotal role in the development of diabetes mellitus. However, the effect of hyperglycemia in glutamate uptake in the pancreas is not clear. Furthermore, the relationship between high glucose-induced glutamate uptake and oxidative stress has not been investigated. Therefore, this study was conducted to investigate the effect of high glucose on glutamate uptake in pancreatic beta-cells. In the present study, 25 mM glucose stimulated the glutamate uptake in HIT-15 cells of hamster pancreatic beta-cells. The treatment of 25 mM glucose and 1 mM glutamate also decreased the cell viability in HIT-15 cells. In addition, the treatment of 25 mM glucose induced an increase of lipid peroxide formation. High glucose-induced increase of LPO formation was prevented by the treatment of antioxidants such as N-acetyl-L-cysteine and quercetin. Furthermore, high glucose-induced stimulation of glutamate uptake and decrease of cell viability were also blocked by the treatment of N-acetyl-L-cysteine and quercetin. In conclusion, high glucose stimulated glutamate uptake via oxidative stress in pancreatic beta-cells. PMID- 22232642 TI - Inhibitor of DNA-binding 4 contributes to the maintenance and expansion of cancer stem cells in 4T1 mouse mammary cancer cell line. AB - The cancer stem cell (CSC) hypothesis proposes that CSCs are the root of cancer. CSC-targeted therapies may prevent cancer relapse and provide more effective treatment. The expression of aldehyde dehydrogenase 1, as assessed by the Aldefluor assay, has been recognized as a marker of CSCs in breast cancer. Inhibitors of DNA-binding proteins (IDs) have an important role in stem cell differentiation. In this study, we examined IDs necessary for the regulation of stem properties in Aldefluor(pos) 4T1 cells. When the expression profile of IDs in Aldefluor(neg) and Aldefluor(pos) 4T1 cells was compared, qRT-PCR analysis showed that ID4 expression was highly upregulated in Aldefluor(pos) 4T1 cells. In addition, knockdown of ID4 expression suppressed the properties of CSCs, including their sphere-forming ability and side population phenotype. The findings suggest that ID4 may be a therapeutic target for the treatment of advanced breast cancer. PMID- 22232643 TI - Subcellular localization of the transmembrane inner ear (Tmie) protein in a stable Tmie-expressing cell line. AB - Mutations in the transmembrane inner ear (Tmie) gene, which encodes the Tmie protein, have been attributed to deafness autosomal recessive 6 (DFNB6), an autosomal nonsyndromic recessive hearing loss disorder. Although the Tmie gene was identified a few years ago, little is known about subcellular localization of the Tmie protein. In order to address this, we developed a stable cell line expressing Tmie protein. The expression of Myc-tagged Tmie protein was confirmed by Western blot analysis using an anti-Myc antibody and localization of the Tmie protein was confirmed by immunostaining, using the anti-Myc antibody as well as the anti-tmie antibody. Our study demonstrates that the Tmie protein is localized mostly in the cellular membrane and to a lesser extent in cytoplasm. These results suggest that our Tmie expressing stable cell line provides a suitable in vitro model to explore Tmie synthesis and functions. PMID- 22232644 TI - Shigella flexneri infection in a newly acquired rhesus macaque (Macaca mulatta). AB - A 3.4 year-old rhesus macaque weighing 4.5 kg, was suffering from anorexia, acute mucous and bloody diarrhea. On physical examination, the monkey showed a loss of activity, hunched posture, abdominal pain, dehydration, mild gingivitis and unclean anus with discharge. Whole blood was collected for the examination of electrolytes, hematology and serum chemistry; fresh stool was also collected for bacterial culture. Blood profiles showed leukocytosis (14.5 K/uL) and neutrophilia (11.0 K/uL) on complete blood cell count and imbalanced electrolytes associated with diarrhea. As a result of bacterial culture, Shigella flexneri was identified through Mac/SS, IMVIC test, TCBS and VITEK II. Based on these results, this monkey was diagnosed as having acute enteritis caused by Shigella flexneri. Treatment was performed with enrofloxacin prior to the isolation of Shigella flexneri to prevent the transmission of disease. Fortunately, mucus and bloody diarrhea did not persist and general conditions fully recovered. Our results show that the use of enrofloxacin is effective in controlling Shigella flexneri infection in newly acquired rhesus monkeys. PMID- 22232645 TI - Uterine adenocarcinoma with feline leukemia virus infection. AB - Feline endometrial adenocarcinomas are uncommon malignant neoplasms that have been poorly characterized to date. In this study, we describe a uterine adenocarcinoma in a Persian cat with feline leukemia virus infection. At the time of presentation, the cat, a female Persian chinchilla, was 2 years old. The cat underwent surgical ovariohystectomy. A cross-section of the uterine wall revealed a thickened uterine horn. The cat tested positive for feline leukemia virus as detected by polymerase chain reaction. Histopathological examination revealed uterine adenocarcinoma that had metastasized to the omentum, resulting in thickening and the formation of inflammatory lesions. Based on the histopathological findings, this case was diagnosed as a uterine adenocarcinoma with abdominal metastasis. To the best of our knowledge, this is the first report of a uterine adenocarcinoma with feline leukemia virus infection. PMID- 22232646 TI - Angiotropic metastatic malignant melanoma in a canine mammary gland. AB - An eleven-year-old spayed female Yorkshire Terrier presented with a sublumbar mass and upon ultrasonographic examination, was revealed to have a mammary gland tumor. Black to reddish colored masses, located in the visceral peritoneum of the sublumbar region was observed on laparotomy with masectomy of the right side. In the laparotomy, we observed reddish masses multifocally located in the serosal membrane of the large intestine. Histopathologic examination of the intestinal and abdominal mass showed highly invasiveness into the muscle and metastasis of melanocytic tumor cells through the blood vessels. The mammary glands showed abnormal hyperplasia of melanocytes, destruction of the normal glands by tumor cells and infiltration of some lymphocytes in the pool of melanocytic cells. We have identified a malignant melanoma containing an angiotumoral complex in which tumor cells occupied a pericytic location along the microvessels with intravasation determined by immunohistochemistry for S100 protein and protein kinase C-alpha. Histologic findings in this dog lead to a diagnosis of an angiotropic metastatic malignant melanoma. PMID- 22232647 TI - Detection of sarcocystic infection in a wild rodent (Apodemus agrarius chejuensis) captured on Jeju island. AB - Sarcocystis spp is a causative agent of sarcocystosis. They have a characteristic life cycle infecting both prey and predator. Sarcocystis can cause myositis, atrophy of the adjacent cells and abortion in cattle. In mice, sarcocystosis causes mild cellular reactions without clinical disease. Severe haemorrhage and abortion were also reported. For monitoring the disease in wild rodents of the Korean peninsula, we captured Apodemus agrarius chejuensis on Jeju island and examined the specimen histopathologically. Intramuscular cysts were found and diagnosed as Sarcocystis. Sarcocystic infection has been reported in worldwide. There have been many reported infections in cattle and pigs in Korea. To our knowledge, this is the first report of Sarcocystis in Apodemus agrarius chejuensis captured in Korea. PMID- 22232648 TI - Canine hemangiosarcoma in a female Jindo dog. AB - A fourteen-year female Jindo dog showing signs of hemoperitoneum was diagnosed with hemangiosarcoma through abdominal radiography and histopathological examination. In the abdominal radiographs, a circular mass was observed on the posterior of the spleen. When the splenic mass was removed via laparotomy, it was spherical, poorly circumscribed, and showed signs of necrosis, with white spots present on the outer side of the mass. Microscopically, the mass showed that hemorrhage was widespread and extensive infiltration of neoplastic cells was found throughout. There was hypercellularity, including occasional pleomorphic cells and mitotic figures. Inflammation at the edge of the mass, along with necrosis, was also found. In this report, we describe the gross and histopathological findings of a case of canine hemangiosarcoma. PMID- 22232649 TI - Antioxidative and aldose reductase-inhibitory effects of a fermentation filtrate of Rubus coreanus. AB - Antioxidative and aldose reductase (AR)-inhibitory effects of a fermentation filtrate of Rubus coreanus (FRC) were investigated using corneal/retinal homogenate and lens cytosol, respectively. Rat corneal/retinal homogenate was treated with 50 uM FeCl(3) in the presence of FRC (3.2-100 ug/mL) for 30 min at 37C, and thiobarbituric acid-reactive substances (TBARS) was quantified as a lipid peroxidation parameter. FRC markedly suppressed the TBARS production in a concentration-dependent manner, leading to 50% (IC(50)) and 100% (IC(100)) inhibitory concentrations of 20 and 95 ug/mL, respectively, which was similar to the effect of butylated hydroxyanisole. Activity of AR from rat lens was assayed in the presence of FRC (1-31.6 ug/mL) at 25C using glyceraldehyde as a substrate. FRC inhibited lens AR by 50% (IC(50)) and 90% (IC(90)) at approximately 2 and 31.6 ug/mL, respectively, comparable to the effect of quercetin. The results indicate that ERC could be a promising candidate for the improvement of eye injury and visual dysfunction of dry eye and diabetic patients. PMID- 22232650 TI - Antifibrotic activity a fermentation filtrate of Ganoderma lucidum. AB - The effects of a fermentation filtrate of Ganoderma lucidum (FGL) on carbon tetrachloride (CCl(4))-induced hepatic fibrosis were investigated in rats. Male Sprague-Dawley rats were orally administered with FGL (20 or 100 mg/kg) for 33 days, and orally administered with CCl(4) (1.0 mL/kg; 2 mL/kg of 50% in corn oil) at 3-day intervals 1 h after FGL treatment. Body and liver weights, blood and histopathological findings in accordance with hydroxyproline concentrations were analyzed. Chronic exposure to CCl(4) reduced the body weight gain, but increased liver weights and fibrosis, resulting in 3.35-fold increase in hydroxyproline level. Although FGL did not significantly reduce the CCl(4)-induced body and liver weight changes, it attenuated the increases in the hepatic fibrosis and hydroxyproline contents. Taken together, it is suggested that FGL might prevent hepatic fibrosis, and that FGL or its ingredient could be a potential candidate for the prevention of chronic hepatic disorders. PMID- 22232652 TI - Structure of ice crystallized from supercooled water. AB - The freezing of water to ice is fundamentally important to fields as diverse as cloud formation to cryopreservation. At ambient conditions, ice is considered to exist in two crystalline forms: stable hexagonal ice and metastable cubic ice. Using X-ray diffraction data and Monte Carlo simulations, we show that ice that crystallizes homogeneously from supercooled water is neither of these phases. The resulting ice is disordered in one dimension and therefore possesses neither cubic nor hexagonal symmetry and is instead composed of randomly stacked layers of cubic and hexagonal sequences. We refer to this ice as stacking-disordered ice I. Stacking disorder and stacking faults have been reported earlier for metastable ice I, but only for ice crystallizing in mesopores and in samples recrystallized from high-pressure ice phases rather than in water droplets. Review of the literature reveals that almost all ice that has been identified as cubic ice in previous diffraction studies and generated in a variety of ways was most likely stacking-disordered ice I with varying degrees of stacking disorder. These findings highlight the need to reevaluate the physical and thermodynamic properties of this metastable ice as a function of the nature and extent of stacking disorder using well-characterized samples. PMID- 22232651 TI - Structural basis for membrane targeting by the MVB12-associated beta-prism domain of the human ESCRT-I MVB12 subunit. AB - MVB12-associated beta-prism (MABP) domains are predicted to occur in a diverse set of membrane-associated bacterial and eukaryotic proteins, but their existence, structure, and biochemical properties have not been characterized experimentally. Here, we find that the MABP domains of the MVB12A and B subunits of ESCRT-I are functional modules that bind in vitro to liposomes containing acidic lipids depending on negative charge density. The MABP domain is capable of autonomously localizing to subcellular puncta and to the plasma membrane. The 1.3 A atomic resolution crystal structure of the MVB12B MABP domain reveals a beta prism fold, a hydrophobic membrane-anchoring loop, and an electropositive phosphoinositide-binding patch. The basic patch is open, which explains how it senses negative charge density but lacks stereoselectivity. These observations show how ESCRT-I could act as a coincidence detector for acidic phospholipids and protein ligands, enabling it to function both in protein transport at endosomes and in cytokinesis and viral budding at the plasma membrane. PMID- 22232653 TI - Quasi-liquid layers on ice crystal surfaces are made up of two different phases. AB - Ice plays crucially important roles in various phenomena because of its abundance on Earth. However, revealing the dynamic behavior of quasi-liquid layers (QLLs), which governs the surface properties of ice crystals at temperatures near the melting point, remains an experimental challenge. Here we show that two types of QLL phases appear that exhibit different morphologies and dynamics. We directly visualized the two types of QLLs on ice crystal surfaces by advanced optical microscopy, which can visualize the individual 0.37-nm-thick elementary steps on ice crystal surfaces. We found that they had different stabilities and different interactions with ice crystal surfaces. The two immiscible QLL phases appeared heterogeneously, moved around, and coalesced dynamically on ice crystal surfaces. This picture of surface melting is quite different from the conventional picture in which one QLL phase appears uniformly on ice crystal surfaces. PMID- 22232654 TI - Translational inhibition by deadenylation-independent mechanisms is central to microRNA-mediated silencing in zebrafish. AB - MicroRNA (miRNA) is a class of small noncoding RNA approximately 22 nt in length. Animal miRNA silences complementary mRNAs via translational inhibition, deadenylation, and mRNA degradation. However, the underlying molecular mechanisms remain unclear. A key question is whether these three outputs are independently induced by miRNA through distinct mechanisms or sequentially induced within a single molecular pathway. Here, we successfully dissected these intricate outputs of miRNA-mediated repression using zebrafish embryos as a model system. Our results indicate that translational inhibition and deadenylation are independent outputs mediated by distinct domains of TNRC6A, which is an effector protein in the miRNA pathway. Translational inhibition by TNRC6A is divided into two mechanisms: PAM2 motif-mediated interference of poly(A)-binding protein (PABP), and inhibition of 5' cap- and poly(A) tail-independent step(s) by a previously undescribed P-GL motif. Consistent with these observations, we show that, in zebrafish embryos, miRNA inhibits translation of the target mRNA in a deadenylation- and PABP-independent manner at early time points. These results indicate that miRNA exerts multiple posttranscriptional outputs via physically and functionally independent mechanisms and that direct translational inhibition is central to miRNA-mediated repression. PMID- 22232655 TI - Osmotic spreading of Bacillus subtilis biofilms driven by an extracellular matrix. AB - Bacterial biofilms are organized communities of cells living in association with surfaces. The hallmark of biofilm formation is the secretion of a polymeric matrix rich in sugars and proteins in the extracellular space. In Bacillus subtilis, secretion of the exopolysaccharide (EPS) component of the extracellular matrix is genetically coupled to the inhibition of flagella-mediated motility. The onset of this switch results in slow expansion of the biofilm on a substrate. Different strains have radically different capabilities in surface colonization: Flagella-null strains spread at the same rate as wild type, while both are dramatically faster than EPS mutants. Multiple functions have been attributed to the EPS, but none of these provides a physical mechanism for generating spreading. We propose that the secretion of EPS drives surface motility by generating osmotic pressure gradients in the extracellular space. A simple mathematical model based on the physics of polymer solutions shows quantitative agreement with experimental measurements of biofilm growth, thickening, and spreading. We discuss the implications of this osmotically driven type of surface motility for nutrient uptake that may elucidate the reduced fitness of the matrix deficient mutant strains. PMID- 22232656 TI - Reconciling long-term cultural diversity and short-term collective social behavior. AB - An outstanding open problem is whether collective social phenomena occurring over short timescales can systematically reduce cultural heterogeneity in the long run, and whether offline and online human interactions contribute differently to the process. Theoretical models suggest that short-term collective behavior and long-term cultural diversity are mutually excluding, since they require very different levels of social influence. The latter jointly depends on two factors: the topology of the underlying social network and the overlap between individuals in multidimensional cultural space. However, while the empirical properties of social networks are intensively studied, little is known about the large-scale organization of real societies in cultural space, so that random input specifications are necessarily used in models. Here we use a large dataset to perform a high-dimensional analysis of the scientific beliefs of thousands of Europeans. We find that interopinion correlations determine a nontrivial ultrametric hierarchy of individuals in cultural space. When empirical data are used as inputs in models, ultrametricity has strong and counterintuitive effects. On short timescales, it facilitates a symmetry-breaking phase transition triggering coordinated social behavior. On long timescales, it suppresses cultural convergence by restricting it within disjoint groups. Moreover, ultrametricity implies that these results are surprisingly robust to modifications of the dynamical rules considered. Thus the empirical distribution of individuals in cultural space appears to systematically optimize the coexistence of short-term collective behavior and long-term cultural diversity, which can be realized simultaneously for the same moderate level of mutual influence in a diverse range of online and offline settings. PMID- 22232657 TI - Distinct conformations of the protein complex p97-Ufd1-Npl4 revealed by electron cryomicroscopy. AB - p97 is a key regulator of numerous cellular pathways and associates with ubiquitin-binding adaptors to remodel ubiquitin-modified substrate proteins. How adaptor binding to p97 is coordinated and how adaptors contribute to substrate remodeling is unclear. Here we present the 3D electron cryomicroscopy reconstructions of the major Ufd1-Npl4 adaptor in complex with p97. Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide. Our results suggest a model for substrate remodeling by p97 and also explains how p97-Ufd1-Npl4 could form other complexes in a hierarchical model of p97-cofactor assembly. PMID- 22232658 TI - Interplay between mismatch repair and chromatin assembly. AB - Single strand nicks and gaps in DNA have been reported to increase the efficiency of nucleosome loading mediated by chromatin assembly factor 1 (CAF-1). However, on mismatch-containing substrates, these strand discontinuities are utilized by the mismatch repair (MMR) system as loading sites for exonuclease 1, at which degradation of the error-containing strand commences. Because packaging of DNA into chromatin might inhibit MMR, we were interested to learn whether chromatin assembly is differentially regulated on heteroduplex and homoduplex substrates. We now show that the presence of a mismatch in a nicked plasmid substrate delays nucleosome loading in human cell extracts. Our data also suggest that, once the mismatch is removed, repair of the single-stranded gap is accompanied by efficient nucleosome loading. We postulated that the balance between MMR and chromatin assembly might be governed by proliferating cell nuclear antigen (PCNA), the processivity factor of replicative DNA polymerases, which is loaded at DNA termini and which interacts with the MSH6 subunit of the mismatch recognition factor MutSalpha, as well as with CAF-1. We now show that this regulation might be more complex; MutSalpha and CAF-1 interact not only with PCNA, but also with each other. In vivo this interaction increases during S-phase and may be controlled by the phosphorylation status of the p150 subunit of CAF-1. PMID- 22232659 TI - Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin. AB - Secondary active transporters use electrochemical gradients provided by primary ion pumps to translocate metabolites or drugs "uphill" across membranes. Here we report the ion-coupling mechanism of cystinosin, an unusual eukaryotic, proton driven transporter distantly related to the proton pump bacteriorhodopsin. In humans, cystinosin exports the proteolysis-derived dimeric amino acid cystine from lysosomes and is impaired in cystinosis. Using voltage-dependence analysis of steady-state and transient currents elicited by cystine and neutralization scanning mutagenesis of conserved protonatable residues, we show that cystine binding is coupled to protonation of a clinically relevant aspartate buried in the membrane. Deuterium isotope substitution experiments are consistent with an access of this aspartate from the lysosomal lumen through a deep proton channel. This aspartate lies in one of the two PQ-loop motifs shared by cystinosin with a set of eukaryotic membrane proteins of unknown function and is conserved in about half of them, thus suggesting that other PQ-loop proteins may translocate protons. PMID- 22232660 TI - Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene. AB - Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration. PMID- 22232661 TI - Unveiling the biosynthetic puzzle of destruxins in Metarhizium species. AB - Insect pathogenic fungi produce a plethora of insecticidally and pharmaceutically active compounds, including 39 cyclohexadepsipeptide destruxins (dtxs). Even though dtxs were first discovered more than 50 y ago, the genes responsible for their biosynthesis were unknown until this study. Based on our comparative genomic information and targeted gene disruptions, we report the gene cluster for dtx biosynthesis in the insect pathogen Metarhizium robertsii. The nonribosomal peptide synthetase DtxS1 has six adenylation domains, two of which are capable of selecting different amino acids to synthesize dtx B and its analogs. The cytochrome P450 enzyme DtxS2 converts dtx B into other dtxs by a chain of reactions, each producing a new derivative. The aldo-keto reductase DtxS3 and aspartic acid decarboxylase DtxS4 are responsible for the conversion and provision of the first and last substrates for the dtx assembly line, respectively. Insect bioassays showed that dtxs could suppress both cellular and humoral immune responses thereby assisting fungal propagation in insects. The differing abilities of Metarhizium species to produce toxins is dependent on the presence of the dtxS1 gene. The toxigenic species are capable of killing multiple orders of insects, whereas the nontoxigenic Metarhizium spp. have narrow host ranges. Thus, the acquisition or retention of the dtx biosynthesis gene cluster in Metarhizium lineages has been coordinated with the evolution of fungal host specificity. The data from this study will facilitate the development of dtxs as bioinsecticides or pharmaceuticals. PMID- 22232662 TI - Heterogeneity of hunting ability and nutritional status among domestic dogs in lowland Nicaragua. AB - In past and modern human societies, dogs have played an important role as hunting companions. Given considerable ethnographic evidence that dogs vary in their hunting abilities, this paper addresses the effects of key demographic variables, namely age and sex, on the amount of harvested game that dogs contribute in an indigenous Nicaraguan community. Controlling for variation in the time spent potentially hunting, male dogs and older dogs are significantly associated with greater harvests. These results may account for documented preferences for males in both archaeological and ethnographic contexts. Among societies in which dogs are used both as hunting companions and sources of food, the age-related delay in peak hunting ability also suggests a tradeoff that might explain the consumption of dogs shortly after they have reached adult size. Informant rankings of two cohorts of dogs indicate that residents of the community exhibit high agreement about the relative abilities of the dogs, and the rankings indicate that dogs from the same household exhibit comparable skill. There is little evidence that talented, highly-ranked dogs are provided a more nutritious diet, as measured by nitrogen-based and carbon-based isotopic analysis of hair samples. Overall, although dogs can be quite advantageous as hunting companions, this research suggests that the heterogeneity of hunting ability combines with the high mortality of dogs to impose risks on households that depend on dogs as a source of harvested meat. PMID- 22232663 TI - Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. AB - Leptin-deficient (Lep(ob/ob)) mice are obese, diabetic, and infertile. Ablation of neurons that make agouti-related protein (AgRP) in moderately obese adult Lep(ob/ob) mice caused severe anorexia. The mice stopped eating for 2 wk and then gradually recovered. Their body weight fell to within a normal range for WT mice, at which point food intake and glucose tolerance were restored to that of WT mice. Remarkably, both male and female Lep(ob/ob) mice became fertile. Ablation of neurons that express melanin-concentrating hormone (MCH) in adult Lep(ob/ob) mice had no effect on food intake, body weight, or fertility, but resulted in improved glucose tolerance. We conclude that AgRP-expressing neurons play a critical role in mediating the metabolic syndrome and infertility of Lep(ob/ob) mice, whereas MCH-expressing neurons have only a minor role. PMID- 22232664 TI - Indirect evidence that maternal microchimerism in cord blood mediates a graft versus-leukemia effect in cord blood transplantation. AB - During pregnancy women can develop B- and T-cell immunity against the inherited paternal antigens (IPAs) of the fetus, such as HLA, peptides of minor histocompatibilty antigens, and possibly onco-fetal antigens. The biological and pathological role of these pregnancy-induced immunological events is only understood in part. However, anti-IPA immunity in the mother persists for many decades after delivery and may reduce relapse in offspring with leukemia after HLA-haploidentical transplantation of maternal hematopoietic stem cells (HSC). We hypothesized that maternal anti-IPA immune elements cross the placenta and might confer a potent graft-versus-leukemia effect when cord blood (CB) is used in unrelated HSC transplantation. In a retrospective study of single-unit CB recipients with all grafts provided by the New York Blood Center, we show that patients with acute myeloid or lymphoblastic leukemia (n = 845) who shared one or more HLA-A, -B, or -DRB1 antigens with their CB donor's IPAs had a significant decrease in leukemic relapse posttransplantation [hazard ratio (HR) = 0.38, P < 0.001] compared with those that did not. Remarkably, relapse reduction in patients receiving CB with one HLA mismatch (HR = 0.15, P < 0.001) was not associated with an increased risk of severe acute graft-versus-host disease (HR = 1.43, P = 0.730). Our findings may explain the unexpected low relapse rate after CB transplantation, open new avenues in the study of leukemic relapse after HSC transplantation (possibly of malignancies in general), and have practical implications for CB unit selection. PMID- 22232665 TI - Structuring economic incentives to reduce emissions from deforestation within Indonesia. AB - We estimate and map the impacts that alternative national and subnational economic incentive structures for reducing emissions from deforestation (REDD+) in Indonesia would have had on greenhouse gas emissions and national and local revenue if they had been in place from 2000 to 2005. The impact of carbon payments on deforestation is calibrated econometrically from the pattern of observed deforestation and spatial variation in the benefits and costs of converting land to agriculture over that time period. We estimate that at an international carbon price of $10/tCO(2)e, a "mandatory incentive structure," such as a cap-and-trade or symmetric tax-and-subsidy program, would have reduced emissions by 163-247 MtCO(2)e/y (20-31% below the without-REDD+ reference scenario), while generating a programmatic budget surplus. In contrast, a "basic voluntary incentive structure" modeled after a standard payment-for-environmental services program would have reduced emissions nationally by only 45-76 MtCO(2)e/y (6-9%), while generating a programmatic budget shortfall. By making four policy improvements--paying for net emission reductions at the scale of an entire district rather than site-by-site; paying for reductions relative to reference levels that match business-as-usual levels; sharing a portion of district-level revenues with the national government; and sharing a portion of the national government's responsibility for costs with districts--an "improved voluntary incentive structure" would have been nearly as effective as a mandatory incentive structure, reducing emissions by 136-207 MtCO(2)e/y (17-26%) and generating a programmatic budget surplus. PMID- 22232666 TI - Virulence determinants in the obligate intracellular pathogen Chlamydia trachomatis revealed by forward genetic approaches. AB - Chlamydia trachomatis, a pathogen responsible for diseases of significant clinical and public health importance, remains poorly characterized because of its intractability to routine molecular genetic manipulation. We have developed a combinatorial approach to rapidly generate a comprehensive library of genetically defined mutants. Chemical mutagenesis, coupled with whole-genome sequencing (WGS) and a system for DNA exchange within infected cells, was used to generate Chlamydia mutants with distinct phenotypes, map the underlying genetic lesions, and generate isogenic strains. As a result, we identified mutants with altered glycogen metabolism, including an attenuated strain defective for type II secretion. The coupling of chemically induced gene variation and WGS to establish genotype-phenotype associations should be broadly applicable to the large list of medically and environmentally important microorganisms currently intractable to genetic analysis. PMID- 22232667 TI - T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease. AB - Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody- or B cell deficient mice failed to contain MHV CNS infection and developed progressive demyelinating disease, germline IgM produced in activation-induced cytidine deaminase-deficient mice (aicda(-/-)) provided long-term protection against the chronic multiple sclerosis-like disease. Furthermore, we found that appropriate B cell activation within the CNS-draining lymph node and subsequent CXCR3-mediated migration of antiviral IgM-secreting cells to the infected CNS was dependent on CD40-mediated interaction of B cells with T helper cells. These data indicate that the CD40-mediated collaboration of T and B cells is critical to secure neuroprotective IgM responses during viral CNS infection. PMID- 22232668 TI - Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis. AB - Neural stem cells (NSCs) reside in specialized niches in the adult mammalian brain, including the subventricular zone and the dentate gyrus, which act to control NSC behavior. Among other cell types within these niches, NSCs are found in close proximity to blood vessels. We carried out an analysis of the interaction between endothelial cells and NSCs, and show that betacellulin (BTC), a member of the EGF family and one of several signaling molecules made by the former, induces NSC proliferation and prevents spontaneous differentiation in culture. When infused into the lateral ventricle, BTC induces expansion of NSCs and neuroblasts, and promotes neurogenesis in the olfactory bulb and dentate gyrus, whereas specific blocking antibodies reduce the number of stem/progenitor cells. BTC-null mice are less able to regenerate neuroblast numbers compared with WT littermates following depletion of proliferating cells using cytosine-beta-d arabinofuranoside. BTC acts via both the EGF receptor, located on NSCs, and ErbB4, located on neuroblasts, with the latter explaining why its effects are distinct from those of EGF itself. Our results suggest that BTC could be a good candidate to aid regenerative therapies. PMID- 22232669 TI - Microbial diversity determines the invasion of soil by a bacterial pathogen. AB - Natural ecosystems show variable resistance to invasion by alien species, and this resistance can relate to the species diversity in the system. In soil, microorganisms are key components that determine life support functions, but the functional redundancy in the microbiota of most soils has long been thought to overwhelm microbial diversity-function relationships. We here show an inverse relationship between soil microbial diversity and survival of the invading species Escherichia coli O157:H7, assessed by using the marked derivative strain T. The invader's fate in soil was determined in the presence of (i) differentially constructed culturable bacterial communities, and (ii) microbial communities established using a dilution-to-extinction approach. Both approaches revealed a negative correlation between the diversity of the soil microbiota and survival of the invader. The relationship could be explained by a decrease in the competitive ability of the invader in species-rich vs. species-poor bacterial communities, reflected in the amount of resources used and the rate of their consumption. Soil microbial diversity is a key factor that controls the extent to which bacterial invaders can establish. PMID- 22232670 TI - Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice. AB - The aryl hydrocarbon receptor (AhR) knockout mice raised in the laboratory of Fujii-Kuriyama have been under investigation for several years because of the presence in their urinary bladder of large, yellowish stones. The stones are composed of uric acid and become apparent in the bladders as tiny stones when mice are 10 wk of age. By the time the mice are 6 mo of age, there are usually two or three stones with diameters of 3-4 mm. The urate concentration in the serum was normal but in the urine the concentration was 40-50 mg/dL, which is 10 times higher than that in the WT littermates. There were no apparent histological pathologies in the kidney or joints and the levels of enzymes involved in elimination of purines were normal. The source of the uric acid was therefore judged to be from degradation of nucleic acids due to a high turnover of cells in the bladder itself. The bladder was fibrotic and the luminal side of the bladder epithelium was filled with eosinophilic granules. There was loss of E-cadherin between some epithelial cells, with an enlarged submucosal area filled with immune cells and sometimes invading epithelial cells. We hypothesize that in the absence of AhR there is loss of detoxifying enzymes, which leads to accumulation of unconjugated cytotoxins and carcinogens in the bladder. The presence of bladder toxins may have led to the increased apoptosis and inflammation as well as invasion of epithelial cells in the bladders of older mice. PMID- 22232671 TI - Telomere length in early life predicts lifespan. AB - The attrition of telomeres, the ends of eukaryote chromosomes, is thought to play an important role in cell deterioration with advancing age. The observed variation in telomere length among individuals of the same age is therefore thought to be related to variation in potential longevity. Studies of this relationship are hampered by the time scale over which individuals need to be followed, particularly in long-lived species where lifespan variation is greatest. So far, data are based either on simple comparisons of telomere length among different age classes or on individuals whose telomere length is measured at most twice and whose subsequent survival is monitored for only a short proportion of the typical lifespan. Both approaches are subject to bias. Key studies, in which telomere length is tracked from early in life, and actual lifespan recorded, have been lacking. We measured telomere length in zebra finches (n = 99) from the nestling stage and at various points thereafter, and recorded their natural lifespan (which varied from less than 1 to almost 9 y). We found telomere length at 25 d to be a very strong predictor of realized lifespan (P < 0.001); those individuals living longest had relatively long telomeres at all points at which they were measured. Reproduction increased adult telomere loss, but this effect appeared transient and did not influence survival. Our results provide the strongest evidence available of the relationship between telomere length and lifespan and emphasize the importance of understanding factors that determine early life telomere length. PMID- 22232673 TI - Divergence of duplicate genes in exon-intron structure. AB - Gene duplication plays key roles in organismal evolution. Duplicate genes, if they survive, tend to diverge in regulatory and coding regions. Divergences in coding regions, especially those that can change the function of the gene, can be caused by amino acid-altering substitutions and/or alterations in exon-intron structure. Much has been learned about the mode, tempo, and consequences of nucleotide substitutions, yet relatively little is known about structural divergences. In this study, by analyzing 612 pairs of sibling paralogs from seven representative gene families and 300 pairs of one-to-one orthologs from different species, we investigated the occurrence and relative importance of structural divergences during the evolution of duplicate and nonduplicate genes. We found that structural divergences have been very prevalent in duplicate genes and, in many cases, have led to the generation of functionally distinct paralogs. Comparisons of the genomic sequences of these genes further indicated that the differences in exon-intron structure were actually accomplished by three main types of mechanisms (exon/intron gain/loss, exonization/pseudoexonization, and insertion/deletion), each of which contributed differently to structural divergence. Like nucleotide substitutions, insertion/deletion and exonization/pseudoexonization occurred more or less randomly, with the number of observable mutational events per gene pair being largely proportional to evolutionary time. Notably, however, compared with paralogs with similar evolutionary times, orthologs have accumulated significantly fewer structural changes, whereas the amounts of amino acid replacements accumulated did not show clear differences. This finding suggests that structural divergences have played a more important role during the evolution of duplicate than nonduplicate genes. PMID- 22232672 TI - Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. AB - More than 120 human papillomaviruses (HPVs) have now been identified and have been associated with a variety of clinical lesions. To understand the molecular differences among these viruses that result in lesions with distinct pathologies, we have begun a MS-based proteomic analysis of HPV-host cellular protein interactions and have created the plasmid and cell line libraries required for these studies. To validate our system, we have characterized the host cellular proteins that bind to the E7 proteins expressed from 17 different HPV types. These studies reveal a number of interactions, some of which are conserved across HPV types and others that are unique to a single HPV species or HPV genus. Binding of E7 to UBR4/p600 is conserved across all virus types, whereas the cellular protein ENC1 binds specifically to the E7s from HPV18 and HPV45, both members of genus alpha, species 7. We identify a specific interaction of HPV16 E7 with ZER1, a substrate specificity factor for a cullin 2 (CUL2)-RING ubiquitin ligase, and show that ZER1 is required for the binding of HPV16 E7 to CUL2. We further show that ZER1 is required for the destabilization of the retinoblastoma tumor suppressor RB1 in HPV16 E7-expressing cells and propose that a CUL2-ZER1 complex functions to target RB1 for degradation in HPV16 E7-expressing cells. These studies refine the current understanding of HPV E7 functions and establish a platform for the rapid identification of virus-host interactions. PMID- 22232674 TI - Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. AB - Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant enzyme superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood. PMID- 22232675 TI - BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus. AB - Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH. PMID- 22232676 TI - Digital RNA sequencing minimizes sequence-dependent bias and amplification noise with optimized single-molecule barcodes. AB - RNA sequencing (RNA-Seq) is a powerful tool for transcriptome profiling, but is hampered by sequence-dependent bias and inaccuracy at low copy numbers intrinsic to exponential PCR amplification. We developed a simple strategy for mitigating these complications, allowing truly digital RNA-Seq. Following reverse transcription, a large set of barcode sequences is added in excess, and nearly every cDNA molecule is uniquely labeled by random attachment of barcode sequences to both ends. After PCR, we applied paired-end deep sequencing to read the two barcodes and cDNA sequences. Rather than counting the number of reads, RNA abundance is measured based on the number of unique barcode sequences observed for a given cDNA sequence. We optimized the barcodes to be unambiguously identifiable, even in the presence of multiple sequencing errors. This method allows counting with single-copy resolution despite sequence-dependent bias and PCR-amplification noise, and is analogous to digital PCR but amendable to quantifying a whole transcriptome. We demonstrated transcriptome profiling of Escherichia coli with more accurate and reproducible quantification than conventional RNA-Seq. PMID- 22232677 TI - Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1. AB - Somatic hypermutation (SHM) of Ig variable region (IgV) genes requires both IgV transcription and the enzyme activation-induced cytidine deaminase (AID). Identification of a cofactor responsible for the fact that IgV genes are much more sensitive to AID-induced mutagenesis than other genes is a key question in immunology. Here, we describe an essential role for a splice isoform of the prototypical serine/arginine-rich (SR) protein SRSF1, termed SRSF1-3, in AID induced SHM in a DT40 chicken B-cell line. Unexpectedly, we found that SHM does not occur in a DT40 line lacking SRSF1-3 (DT40-ASF), although it is readily detectable in parental DT40 cells. Strikingly, overexpression of AID in DT40-ASF cells led to a large increase in nonspecific (off-target) mutations. In contrast, introduction of SRSF1-3, but not SRSF1, into these cells specifically restored SHM without increasing off-target mutations. Furthermore, we found that SRSF1-3 binds preferentially to the IgV gene and inhibits processing of the Ig transcript, providing a mechanism by which SRSF1-3 makes the IgV gene available for AID-dependent SHM. SRSF1 not only acts as an essential splicing factor but also regulates diverse aspects of mRNA metabolism and maintains genome stability. Our findings, thus, define an unexpected and important role for SRSF1, particularly for its splice variant, in enabling AID to function specifically on its natural substrate during SHM. PMID- 22232678 TI - Digoxin inhibits development of hypoxic pulmonary hypertension in mice. AB - Chronic hypoxia is an inciting factor for the development of pulmonary arterial hypertension. The mechanisms involved in the development of hypoxic pulmonary hypertension (HPH) include hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cell (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Recently, digoxin was shown to inhibit HIF-1 transcriptional activity. In this study, we tested the hypothesis that digoxin could prevent and reverse the development of HPH. Mice were injected daily with saline or digoxin and exposed to room air or ambient hypoxia for 3 wk. Treatment with digoxin attenuated the development of right ventricle (RV) hypertrophy and prevented the pulmonary vascular remodeling and increases in PASMC [Ca(2+)](i), pH, and RV pressure that occur in mice exposed to chronic hypoxia. When started after pulmonary hypertension was established, digoxin attenuated the hypoxia-induced increases in RV pressure and PASMC pH and [Ca(2+)](i). These preclinical data support a role for HIF-1 inhibitors in the treatment of HPH. PMID- 22232679 TI - Chlamydophila pneumoniae phospholipase D (CpPLD) drives Th17 inflammation in human atherosclerosis. AB - Phospholipases are produced from bacterial pathogens causing very different diseases. One of the most intriguing aspects of phospholipases is their potential to interfere with cellular signaling cascades and to modulate the host-immune response. Here, we investigated the role of the innate and acquired immune responses elicited by Chlamydophila pneumoniae phospholipase D (CpPLD) in the pathogenesis of atherosclerosis. We evaluated the cytokine and chemokine production induced by CpPLD in healthy donors' monocytes and in vivo activated T cells specific for CpPLD that infiltrate atherosclerotic lesions of patients with C. pneumoniae antibodies. We also examined the helper function of CpPLD-specific T cells for monocyte matrix metalloproteinase (MMP)-9 and tissue factor (TF) production as well as the CpPLD-induced chemokine expression by human venular endothelial cells (HUVECs). We report here that CpPLD is a TLR4 agonist able to induce the expression of IL-23, IL-6, IL-1beta, TGF-beta, and CCL-20 in monocytes, as well as CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1, and VCAM-1 in HUVECs. Plaque-derived T cells produce IL-17 in response to CpPLD. Moreover, CpPLD specific CD4(+) T lymphocytes display helper function for monocyte MMP-9 and TF production. CpPLD promotes Th17 cell migration through the induction of chemokine secretion and adhesion molecule expression on endothelial cells. These findings indicate that CpPLD is able to drive the expression of IL-23, IL-6, IL-1beta, TGF beta, and CCL-20 by monocytes and to elicit a Th17 immune response that plays a key role in the genesis of atherosclerosis. PMID- 22232680 TI - Phytochrome regulates translation of mRNA in the cytosol. AB - An array of photoreceptors including cryptochromes, phototropin, and phytochromes regulates various light responses in plants. Among these photoreceptors, phytochromes perceive red and far-red light by switching between two interconvertible spectral forms (Pr and Pfr). The Pfr form promotes light responses partly by destabilizing negatively acting, phytochrome-interacting basic helix-loop-helix transcription factors (PIFs), thus modulating transcription in the nucleus. The Pfr form is also present in the cytosol. However, the role of phytochromes in the cytosol is not well understood. Here we show that the Pfr form interacts with the cytosolic protein PENTA1 (PNT1) and inhibits the translation of protochlorophyllide reductase (PORA) mRNA. PNT1 possesses five C3H-type zinc finger domains and displays similarity to various RNA binding proteins including Tristetraprolin, which regulates stabilities of mRNAs such as TNF-alpha mRNA in humans. Consistent with its function as an RNA binding protein, PNT1 directly binds to mRNA of a key chlorophyll biosynthetic gene, protochlorophyllide reductase in vivo and inhibits the translation of PORA mRNA in the presence of phytochromes. The present results demonstrate that phytochromes transmit light signals to regulate not only transcription in the nucleus through PIFs, but also translation in the cytosol through PNT1. PMID- 22232681 TI - Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. AB - Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H(2)S formed by cystathionine beta-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H(2)S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia. PMID- 22232682 TI - CD14 cooperates with complement receptor 3 to mediate MyD88-independent phagocytosis of Borrelia burgdorferi. AB - Phagocytosis of Borrelia burgdorferi, the causative agent of Lyme disease, is a poorly understood process, despite its importance during the host immune response to infection. B. burgdorferi has been shown to bind to different receptors on the surface of phagocytic cells, including the beta(2) integrin, complement receptor 3 (CR3). However, whether these receptors mediate the phagocytosis of the spirochete remains unknown. We now demonstrate that CR3 mediates the phagocytosis of the spirochete by murine macrophages and human monocytes. Interaction of B. burgdorferi with the integrin is not sufficient, however, to internalize the spirochete; phagocytosis requires the interaction of CR3 with the GPI-anchored protein, CD14, independently of TLR/MyD88-induced or inside-out signals. Interestingly, the absence of CR3 leads to marked increases in the production of TNF in vitro and in vivo, despite reduced spirochetal uptake. Furthermore, the absence of CR3 during infection with B. burgdorferi results in the inefficient control of bacterial burdens in the heart and increased Lyme carditis. Overall, our data identify CR3 as a MyD88-independent phagocytic receptor for B. burgdorferi that also participates in the modulation of the proinflammatory output of macrophages. These data also establish a unique mechanism of CR3 mediated phagocytosis that requires the direct cooperation of GPI-anchored proteins. PMID- 22232683 TI - Metabolic click-labeling with a fucose analog reveals pectin delivery, architecture, and dynamics in Arabidopsis cell walls. AB - Polysaccharide-rich cell walls are a defining feature of plants that influence cell division and growth, but many details of cell-wall organization and dynamics are unknown because of a lack of suitable chemical probes. Metabolic labeling using sugar analogs compatible with click chemistry has the potential to provide new insights into cell-wall structure and dynamics. Using this approach, we found that an alkynylated fucose analog (FucAl) is metabolically incorporated into the cell walls of Arabidopsis thaliana roots and that a significant fraction of the incorporated FucAl is present in pectic rhamnogalacturonan-I (RG-I). Time-course experiments revealed that FucAl-containing RG-I first localizes in cell walls as uniformly distributed punctae that likely mark the sites of vesicle-mediated delivery of new polysaccharides to growing cell walls. In addition, we found that the pattern of incorporated FucAl differs markedly along the developmental gradient of the root. Using pulse-chase experiments, we also discovered that the pectin network is reoriented in elongating root epidermal cells. These results reveal previously undescribed details of polysaccharide delivery, organization, and dynamics in cell walls. PMID- 22232684 TI - High-yield maize with large net energy yield and small global warming intensity. AB - Addressing concerns about future food supply and climate change requires management practices that maximize productivity per unit of arable land while reducing negative environmental impact. On-farm data were evaluated to assess energy balance and greenhouse gas (GHG) emissions of irrigated maize in Nebraska that received large nitrogen (N) fertilizer (183 kg of N . ha(-1)) and irrigation water inputs (272 mm or 2,720 m(3) ha(-1)). Although energy inputs (30 GJ . ha( 1)) were larger than those reported for US maize systems in previous studies, irrigated maize in central Nebraska achieved higher grain and net energy yields (13.2 Mg . ha(-1) and 159 GJ . ha(-1), respectively) and lower GHG-emission intensity (231 kg of CO(2)e . Mg(-1) of grain). Greater input-use efficiencies, especially for N fertilizer, were responsible for better performance of these irrigated systems, compared with much lower-yielding, mostly rainfed maize systems in previous studies. Large variation in energy inputs and GHG emissions across irrigated fields in the present study resulted from differences in applied irrigation water amount and imbalances between applied N inputs and crop N demand, indicating potential to further improve environmental performance through better management of these inputs. Observed variation in N-use efficiency, at any level of applied N inputs, suggests that an N-balance approach may be more appropriate for estimating soil N(2)O emissions than the Intergovernmental Panel on Climate Change approach based on a fixed proportion of applied N. Negative correlation between GHG-emission intensity and net energy yield supports the proposition that achieving high yields, large positive energy balance, and low GHG emissions in intensive cropping systems are not conflicting goals. PMID- 22232685 TI - An rhs gene of Pseudomonas aeruginosa encodes a virulence protein that activates the inflammasome. AB - The rhs genes are a family of enigmatic composite genes, widespread among Gram negative bacteria. In this study, we characterized rhsT, a Pseudomonas aeruginosa rhs gene that encodes a toxic protein. Expression of rhsT was induced upon contact with phagocytic cells. The RhsT protein was exposed on the bacterial surface and translocated into phagocytic cells; these cells subsequently underwent inflammasome-mediated death. Moreover, RhsT enhanced host secretion of the potent proinflammatory cytokines IL-1beta and IL-18 in an inflammasome dependent manner. In a mouse model of acute pneumonia, infection with a P. aeruginosa strain lacking rhsT was associated with less IL-18 production, fewer recruited leukocytes, reduced pulmonary bacterial load, and enhanced animal survival. Thus, rhsT encodes a virulence determinant that activates the inflammasome. PMID- 22232686 TI - How Staphylococcus aureus biofilms develop their characteristic structure. AB - Biofilms cause significant problems in the environment and during the treatment of infections. However, the molecular mechanisms underlying biofilm formation are poorly understood. There is a particular lack of knowledge about biofilm maturation processes, such as biofilm structuring and detachment, which are deemed crucial for the maintenance of biofilm viability and the dissemination of cells from a biofilm. Here, we identify the phenol-soluble modulin (PSM) surfactant peptides as key biofilm structuring factors in the premier biofilm forming pathogen Staphylococcus aureus. We provide evidence that all known PSM classes participate in structuring and detachment processes. Specifically, absence of PSMs in isogenic S. aureus psm deletion mutants led to strongly impaired formation of biofilm channels, abolishment of the characteristic waves of biofilm detachment and regrowth, and loss of control of biofilm expansion. In contrast, induced expression of psm loci in preformed biofilms promoted those processes. Furthermore, PSMs facilitated dissemination from an infected catheter in a mouse model of biofilm-associated infection. Moreover, formation of the biofilm structure was linked to strongly variable, quorum sensing-controlled PSM expression in biofilm microenvironments, whereas overall PSM production remained constant to ascertain biofilm homeostasis. Our study describes a mechanism of biofilm structuring in molecular detail, and the general principle (i.e., quorum sensing controlled expression of surfactants) seems to be conserved in several bacteria, despite the divergence of the respective biofilm-structuring surfactants. These findings provide a deeper understanding of biofilm development processes, which represents an important basis for strategies to interfere with biofilm formation in the environment and human disease. PMID- 22232687 TI - Underground leaves of Philcoxia trap and digest nematodes. AB - The recently described genus Philcoxia comprises three species restricted to well lit and low-nutrient soils in the Brazilian Cerrado. The morphological and habitat similarities of Philcoxia to those of some carnivorous plants, along with recent observations of nematodes over its subterranean leaves, prompted the suggestion that the genus is carnivorous. Here we report compelling evidence of carnivory in Philcoxia of the Plantaginaceae, a family in which no carnivorous members are otherwise known. We also document both a unique capturing strategy for carnivorous plants and a case of a plant that traps and digests nematodes with underground adhesive leaves. Our findings illustrate how much can still be discovered about the origin, distribution, and frequency of the carnivorous syndrome in angiosperms and, more generally, about the diversity of nutrient acquisition mechanisms that have evolved in plants growing in severely nutrient impoverished environments such as the Brazilian Cerrado, one of the world's 34 biodiversity hotspots. PMID- 22232688 TI - A morphologically specialized soldier caste improves colony defense in a neotropical eusocial bee. AB - Division of labor among workers is common in insect societies and is thought to be important in their ecological success. In most species, division of labor is based on age (temporal castes), but workers in some ants and termites show morphological specialization for particular tasks (physical castes). Large-headed soldier ants and termites are well-known examples of this specialization. However, until now there has been no equivalent example of physical worker subcastes in social bees or wasps. Here we provide evidence for a physical soldier subcaste in a bee. In the neotropical stingless bee Tetragonisca angustula, nest defense is performed by two groups of guards, one hovering near the nest entrance and the other standing on the wax entrance tube. We show that both types of guards are 30% heavier than foragers and of different shape; foragers have relatively larger heads, whereas guards have larger legs. Low variation within each subcaste results in negligible size overlap between guards and foragers, further indicating that they are distinct physical castes. In addition, workers that remove garbage from the nest are of intermediate size, suggesting that they might represent another unrecognized caste. Guards or soldiers are reared in low but sufficient numbers (1-2% of emerging workers), considering that <1% usually perform this task. When challenged by the obligate robber bee Lestrimelitta limao, an important natural enemy, larger workers were able to fight for longer before being defeated by the much larger robber. This discovery opens up opportunities for the comparative study of physical castes in social insects, including the question of why soldiers appear to be so much rarer in bees than in ants or termites. PMID- 22232689 TI - Homeostatic plasticity mechanisms are required for juvenile, but not adult, ocular dominance plasticity. AB - Ocular dominance (OD) plasticity in the visual cortex is a classic model system for understanding developmental plasticity, but the visual cortex also shows plasticity in adulthood. Whether the plasticity mechanisms are similar or different at the two ages is not clear. Several plasticity mechanisms operate during development, including homeostatic plasticity, which acts to maintain the total excitatory drive to a neuron. In agreement with this idea, we found that an often-studied substrain of C57BL/6 mice, C57BL/6JOlaHsd (6JOla), lacks both the homeostatic component of OD plasticity as assessed by intrinsic signal imaging and synaptic scaling of mEPSC amplitudes after a short period of dark exposure during the critical period, whereas another substrain, C57BL/6J (6J), exhibits both plasticity processes. However, in adult mice, OD plasticity was identical in the 6JOla and 6J substrains, suggesting that adult plasticity occurs by a different mechanism. Consistent with this interpretation, adult OD plasticity was normal in TNFalpha knockout mice, which are known to lack juvenile synaptic scaling and the homeostatic component of OD plasticity, but was absent in adult alpha-calcium/calmodulin-dependent protein kinase II;T286A (alphaCaMKII(T286A)) mice, which have a point mutation that prevents autophosphorylation of alphaCaMKII. We conclude that increased responsiveness to open-eye stimulation after monocular deprivation during the critical period is a homeostatic process that depends mechanistically on synaptic scaling during the critical period, whereas in adult mice it is mediated by a different mechanism that requires alphaCaMKII autophosphorylation. Thus, our study reveals a transition between homeostatic and long-term potentiation-like plasticity mechanisms with increasing age. PMID- 22232690 TI - Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis. AB - Obligate intracellular pathogens such as Leishmania specifically target host phagocytes for survival and replication. Phosphoinositide 3-kinase gamma (PI3Kgamma), a member of the class I PI3Ks that is highly expressed by leukocytes, controls cell migration by initiating actin polymerization and cytoskeletal reorganization, which are processes also critical for phagocytosis. In this study, we demonstrate that class IB PI3K, PI3Kgamma, plays a critical role in pathogenesis of chronic cutaneous leishmaniasis caused by L. mexicana. Using the isoform-selective PI3Kgamma inhibitor, AS-605240 and PI3Kgamma gene deficient mice, we show that selective blockade or deficiency of PI3Kgamma significantly enhances resistance against L. mexicana that is associated with a significant suppression of parasite entry into phagocytes and reduction in recruitment of host phagocytes as well as regulatory T cells to the site of infection. Furthermore, we demonstrate that AS-605240 is as effective as the standard antileishmanial drug sodium stibogluconate in treatment of cutaneous leishmaniasis caused by L. mexicana. These findings reveal a unique role for PI3Kgamma in Leishmania invasion and establishment of chronic infection, and demonstrate that therapeutic targeting of host pathways involved in establishment of infection may be a viable strategy for treating infections caused by obligate intracellular pathogens such as Leishmania. PMID- 22232691 TI - beta3 integrin interacts directly with GluA2 AMPA receptor subunit and regulates AMPA receptor expression in hippocampal neurons. AB - The integrins are transmembrane receptors for ECM proteins, and they regulate various cellular functions in the central nervous system. In hippocampal neurons, the beta3 integrin subtype is required for homeostatic synaptic scaling of AMPA receptors (AMPARs) induced by chronic activity deprivation. The surface level of beta3 integrin in postsynaptic neurons directly correlates with synaptic strength and the abundance of synaptic GluA2 AMPAR subunit. Although these observations suggest a functional link between beta3 integrin and AMPAR, little is known about the mechanistic basis for the connection. Here we investigate the nature of beta3 integrin and AMPAR interaction underlying the beta3 integrin-dependent control of synaptic AMPAR expression and thus synaptic strength. We show that beta3 integrin and GluA2 subunit form a complex in mouse brain that involves the direct binding between their cytoplasmic domains. In contrast, beta3 integrin associates with GluA1 AMPAR subunit only weakly, and, in a heterologous expression system, the interaction requires the coexpression of GluA2. Surprisingly, in hippocampal pyramidal neurons, expressing beta3 integrin mutants with either increased or decreased affinity for extracellular ligands has no differential effects in elevating excitatory synaptic currents and surface GluA2 levels compared with WT beta3 integrin. Our findings identify an integrin family member, beta3, as a direct interactor of an AMPAR subunit and provide molecular insights into how this cell-adhesion protein regulates the composition of cell-surface AMPARs. PMID- 22232692 TI - Decoupling of deforestation and soy production in the southern Amazon during the late 2000s. AB - From 2006 to 2010, deforestation in the Amazon frontier state of Mato Grosso decreased to 30% of its historical average (1996-2005) whereas agricultural production reached an all-time high. This study combines satellite data with government deforestation and production statistics to assess land-use transitions and potential market and policy drivers associated with these trends. In the forested region of the state, increased soy production from 2001 to 2005 was entirely due to cropland expansion into previously cleared pasture areas (74%) or forests (26%). From 2006 to 2010, 78% of production increases were due to expansion (22% to yield increases), with 91% on previously cleared land. Cropland expansion fell from 10 to 2% of deforestation between the two periods, with pasture expansion accounting for most remaining deforestation. Declining deforestation coincided with a collapse of commodity markets and implementation of policy measures to reduce deforestation. Soybean profitability has since increased to pre-2006 levels whereas deforestation continued to decline, suggesting that antideforestation measures may have influenced the agricultural sector. We found little evidence of direct leakage of soy expansion into cerrado in Mato Grosso during the late 2000s, although indirect land-use changes and leakage to more distant regions are possible. This study provides evidence that reduced deforestation and increased agricultural production can occur simultaneously in tropical forest frontiers, provided that land is available and policies promote the efficient use of already-cleared lands (intensification) while restricting deforestation. It remains uncertain whether government- and industry-led policies can contain deforestation if future market conditions favor another boom in agricultural expansion. PMID- 22232694 TI - The take-it-or-leave-it option allows small penalties to overcome social dilemmas. AB - Self-interest frequently causes individuals engaged in joint enterprises to choose actions that are counterproductive. Free-riders can invade a society of cooperators, causing a tragedy of the commons. Such social dilemmas can be overcome by positive or negative incentives. Even though an incentive-providing institution may protect a cooperative society from invasion by free-riders, it cannot always convert a society of free-riders to cooperation. In the latter case, both norms, cooperation and defection, are stable: To avoid a collapse to full defection, cooperators must be sufficiently numerous initially. A society of free-riders is then caught in a social trap, and the institution is unable to provide an escape, except at a high, possibly prohibitive cost. Here, we analyze the interplay of (a) incentives provided by institutions and (b) the effects of voluntary participation. We show that this combination fundamentally improves the efficiency of incentives. In particular, optional participation allows institutions punishing free-riders to overcome the social dilemma at a much lower cost, and to promote a globally stable regime of cooperation. This removes the social trap and implies that whenever a society of cooperators cannot be invaded by free-riders, it will necessarily become established in the long run, through social learning, irrespective of the initial number of cooperators. We also demonstrate that punishing provides a "lighter touch" than rewarding, guaranteeing full cooperation at considerably lower cost. PMID- 22232693 TI - Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae. AB - The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ~100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants. PMID- 22232695 TI - Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. AB - To measure molecular changes underlying pathogen adaptation, we generated a searchable dataset of more than 12,000 mass spectrometry events, corresponding to lipids and small molecules that constitute a lipidome for Mycobacterium tuberculosis. Iron is essential for M. tuberculosis survival, and the organism imports this metal using mycobactin and carboxymycobactin siderophores. Detection of an unexpected siderophore variant and deletions of genes for iron scavenging has led to a revised mycobactin biosynthesis model. An organism-wide search of the M. tuberculosis database for hypothetical compounds predicted by this model led to the discovery of two families of previously unknown lipids, designated monodeoxymycobactins and monodeoxycarboxymycobactins. These molecules suggest a revised biosynthetic model that alters the substrates and order of action of enzymes through the mycobactin biosynthetic pathway. We tested this model genetically by solving M. tuberculosis lipidomes after deletion of the iron dependent regulator (ideR), mycobactin synthase B (mbtB), or mycobactin synthase G (mbtG). These studies show that deoxymycobactins are actively regulated during iron starvation, and also define essential roles of MbtG in converting deoxymycobactins to mycobactin and in promoting M. tuberculosis growth. Thus, lipidomics is an efficient discovery tool that informs genetic relationships, leading to a revised general model for the biosynthesis of these virulence conferring siderophores. PMID- 22232697 TI - Diabetes and risk of renal cell carcinoma. AB - BACKGROUND AND OBJECTIVES: There is evidence that the incidence of solid tumors is markedly increased in patients with diabetes mellitus. In the current study, we investigate the association between diabetes and renal cancer. PATIENTS AND METHODS: A single-center retrospective analysis of 473 patients who underwent nephrectomy for renal cell carcinoma (RCC) was performed. Diabetic RCC patients were screened for age, gender, ethnicity, HgA1C, glucose levels and renal function. RESULTS: Of the 473 cases with RCC, we identified 120 patients (25.4%) with a history of diabetes. The incidence of diabetes in RCC patients was higher in female than male subjects and in Hispanic compared to White and Other ethnic backgrounds. At diagnosis, the majority of diabetic RCC patients were 50-59 years of age. In diabetic RCC cases, clear cell type histology (92.0%), nuclear grade 2 (56.1%) and tumor size range from 1-5 cm (65.7%) were the most common in each category. CONCLUSION: Our findings indicate that diabetic RCC patients have a predominance of localized, small clear cell RCC. In addition, females with a history of RCC have a higher frequency of diabetes compared to males. This is the first report of clinical and histopathological features of RCC associated with diabetes. PMID- 22232696 TI - Properties of lewis lung carcinoma cells surviving curcumin toxicity. AB - The anti-inflammatory agent curcumin can selectively eliminate malignant rather than normal cells. The present study examined the effects of curcumin on the Lewis lung carcinoma (LLC) cell line and characterized a subpopulation surviving curcumin treatments. Cell density was measured after curcumin was applied at concentrations between 10 and 60 MUM for 30 hours. Because of the high cell loss at 60 MUM, this dose was chosen to select for surviving cells that were then used to establish a new cell line. The resulting line had approximately 20% slower growth than the original LLC cell line and based on ELISA contained less of two markers, NF-kappaB and ALDH1A, used to identify more aggressive cancer cells. We also injected cells from the original and surviving lines subcutaneously into syngeneic C57BL/6 mice and monitored tumor development over three weeks and found that the curcumin surviving-line remained tumorigenic. Because curcumin has been reported to kill cancer cells more effectively when administered with light, we examined this as a possible way of enhancing the efficacy of curcumin against LLC cells. When LLC cells were exposed to curcumin and light from a fluorescent lamp source, cell loss caused by 20 MUM curcumin was enhanced by about 50%, supporting a therapeutic use of curcumin in combination with white light. This study is the first to characterize a curcumin-surviving subpopulation among lung cancer cells. It shows that curcumin at a high concentration either selects for an intrinsically less aggressive cell subpopulation or generates these cells. The findings further support a role for curcumin as an adjunct to traditional chemical or radiation therapy of lung and other cancers. PMID- 22232698 TI - Effect of pulse direct current signals on electrotactic movement of nematodes Caenorhabditis elegans and Caenorhabditis briggsae. AB - The nematodes (worms) Caenorhabditiselegans and Caenorhabditisbriggsae are well known model organisms to study the basis of animal development and behaviour. Their sinusoidal pattern of movement is highly stereotypic and serves as a tool to monitor defects in neurons and muscles that control movement. Until recently, a simple yet robust method to initiate movement response on-demand did not exist. We have found that the electrical stimulation in a microfluidic channel, using constant DC electric field, induces movement (termed electrotaxis) that is instantaneous, precise, sensitive, and fully penetrant. We have further characterized this behaviour and, in this paper, demonstrate that electrotaxis can also be induced using a pulse DC electric signal. Worms responded to pulse DC signals with as low as 30% duty cycle by moving towards the negative electrode at the same speed as constant DC fields (average speed of C. elegans = 296 +/- 43 MUm/s and C. briggsae = 356 +/- 20 MUm/s, for both constant and pulse DC electric fields with various frequencies). C. briggsae was found to be more sensitive to electric signals compared to C. elegans. We also investigated the turning response of worms to a change in the direction of constant and pulse DC signals. The response for constant DC signal was found to be instantaneous and similar for most worms. However, in the case of pulse DC signal, alterations in duty cycle affected the turning response time as well as the number of responding worms. Our findings show that pulse DC method allows quantitative measurement of response behaviour of worms and suggest that it could be used as a tool to study the neuronal basis of such a behaviour that is not observed under constant DC conditions. PMID- 22232699 TI - Keith Burridge: cultivating knowledge on Rho. Interview by Caitlin Sedwick. PMID- 22232701 TI - Dynein-dependent processive chromosome motions promote homologous pairing in C. elegans meiosis. AB - Meiotic chromosome segregation requires homologue pairing, synapsis, and crossover recombination, which occur during meiotic prophase. Telomere-led chromosome motion has been observed or inferred to occur during this stage in diverse species, but its mechanism and function remain enigmatic. In Caenorhabditis elegans, special chromosome regions known as pairing centers (PCs), rather than telomeres, associate with the nuclear envelope (NE) and the microtubule cytoskeleton. In this paper, we investigate chromosome dynamics in living animals through high-resolution four-dimensional fluorescence imaging and quantitative motion analysis. We find that chromosome movement is constrained before meiosis. Upon prophase onset, constraints are relaxed, and PCs initiate saltatory, processive, dynein-dependent motions along the NE. These dramatic motions are dispensable for homologous pairing and continue until synapsis is completed. These observations are consistent with the idea that motions facilitate pairing by enhancing the search rate but that their primary function is to trigger synapsis. This quantitative analysis of chromosome dynamics in a living animal extends our understanding of the mechanisms governing faithful genome inheritance. PMID- 22232700 TI - Axon degeneration: molecular mechanisms of a self-destruction pathway. AB - Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra axonal calcium levels and calcium-dependent cytoskeletal breakdown. PMID- 22232702 TI - The septin cytoskeleton facilitates membrane retraction during motility and blebbing. AB - Increasing evidence supports a critical role for the septin cytoskeleton at the plasma membrane during physiological processes including motility, formation of dendritic spines or cilia, and phagocytosis. We sought to determine how septins regulate the plasma membrane, focusing on this cytoskeletal element's role during effective amoeboid motility. Surprisingly, septins play a reactive rather than proactive role, as demonstrated during the response to increasing hydrostatic pressure and subsequent regulatory volume decrease. In these settings, septins were required for rapid cortical contraction, and SEPT6-GFP was recruited into filaments and circular patches during global cortical contraction and also specifically during actin filament depletion. Recruitment of septins was also evident during excessive blebbing initiated by blocking membrane trafficking with a dynamin inhibitor, providing further evidence that septins are recruited to facilitate retraction of membranes during dynamic shape change. This function of septins in assembling on an unstable cortex and retracting aberrantly protruding membranes explains the excessive blebbing and protrusion observed in septin deficient T cells. PMID- 22232703 TI - alpha-Actinin-4/FSGS1 is required for Arp2/3-dependent actin assembly at the adherens junction. AB - We have developed an in vitro assay to study actin assembly at cadherin-enriched cell junctions. Using this assay, we demonstrate that cadherin-enriched junctions can polymerize new actin filaments but cannot capture preexisting filaments, suggesting a mechanism involving de novo synthesis. In agreement with this hypothesis, inhibition of Arp2/3-dependent nucleation abolished actin assembly at cell-cell junctions. Reconstitution biochemistry using the in vitro actin assembly assay identified alpha-actinin-4/focal segmental glomerulosclerosis 1 (FSGS1) as an essential factor. alpha-Actinin-4 specifically localized to sites of actin incorporation on purified membranes and at apical junctions in Madin Darby canine kidney cells. Knockdown of alpha-actinin-4 decreased total junctional actin and inhibited actin assembly at the apical junction. Furthermore, a point mutation of alpha-actinin-4 (K255E) associated with FSGS failed to support actin assembly and acted as a dominant negative to disrupt actin dynamics at junctional complexes. These findings demonstrate that alpha actinin-4 plays an important role in coupling actin nucleation to assembly at cadherin-based cell-cell adhesive contacts. PMID- 22232704 TI - Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion. AB - The lymphocyte homing receptor integrin alpha(4)beta(7) is unusual for its ability to mediate both rolling and firm adhesion. alpha(4)beta(1) and alpha(4)beta(7) are targeted by therapeutics approved for multiple sclerosis and Crohn's disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind alpha(4)beta(7). A long binding groove at the alpha(4)-beta(7) interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in alpha(4) ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion-dependent adhesion site in alpha(4)beta(7) is essential for binding to MAdCAM-1 in Mg(2+) yet swings away when RO0505376 binds. A novel intermediate conformation of the alpha(4)beta(7) headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled. PMID- 22232705 TI - A novel function for Cyclin A2: control of cell invasion via RhoA signaling. AB - Cyclin A2 plays a key role in cell cycle regulation. It is essential in embryonic cells and in the hematopoietic lineage yet dispensable in fibroblasts. In this paper, we demonstrate that Cyclin A2-depleted cells display a cortical distribution of actin filaments and increased migration. These defects are rescued by restoration of wild-type Cyclin A2, which directly interacts with RhoA, or by a Cyclin A2 mutant unable to associate with Cdk. In vitro, Cyclin A2 potentiates the exchange activity of a RhoA-specific guanine nucleotide exchange factor. Consistent with this, Cyclin A2 depletion enhances migration of fibroblasts and invasiveness of transformed cells via down-regulation of RhoA activity. Moreover, Cyclin A2 expression is lower in metastases relative to primary colon adenocarcinoma in matched human tumors. All together, these data show that Cyclin A2 negatively controls cell motility by promoting RhoA activation, thus demonstrating a novel Cyclin A2 function in cytoskeletal rearrangements and cell migration. PMID- 22232706 TI - A Microfluidic Study of Megakaryocytes Membrane Transport Properties to Water and Dimethyl Sulfoxide at Suprazero and Subzero Temperatures. AB - Megakaryocytes (MKs) are the precursor cells of platelets. Cryopreservation of MKs is critical for facilitating research investigations about the biology of this important cell and may help for scaling-up ex-vivo production of platelets from MKs for clinical transfusion. Determining membrane transport properties of MKs to water and cryoprotectant agents (CPAs) is essential for developing optimal conditions for cryopreserving MKs. To obtain these unknown parameters, membrane transport properties of the human UT-7/TPO megakaryocytic cell line were investigated using a microfluidic perfusion system. UT-7/TPO cells were immobilized in a microfluidic system on poly-D-lysine-coated glass substrate and perfused with various hyper-osmotic salt and CPA solutions at suprazero and subzero temperatures. The kinetics of cell volume changes under various extracellular conditions were monitored by a video camera and the information was processed and analyzed using the Kedem-Katchalsky model to determine the membrane transport properties. The osmotically inactive cell volume (V(b)=0.15), the permeability coefficient to water (Lp) at 37 degrees C, 22 degrees C, 12 degrees C, 0 degrees C, -5 degrees C, -10 degrees C, and -20 degrees C, and dimethyl sulfoxide (DMSO; Ps) at 22, 12, 0, -10, -20, as well as associated activation energies of water and DMSO at different temperature regions were obtained. We found that MKs have relatively higher membrane permeability to water (Lp=2.62 MUm/min/atm at 22 degrees C) and DMSO (Ps=1.8*10(-3) cm/min at 22 degrees C) than most other common mammalian cell types, such as lymphocytes (Lp=0.46 MUm/min/atm at 25 degrees C). This information could suggest a higher optimal cooling rate for MKs cryopreservation. The discontinuity effect was also found on activation energy at 0 degrees C-12 degrees C in the Arrhenius plots of membrane permeability by evaluating the slope of linear regression at each temperature region. This phenomenon may imply the occurrence of cell membrane lipid phase transition. PMID- 22232707 TI - Student feedback about The Skeptic Doctor, a module on pharmaceutical promotion. AB - Pharmaceutical promotion is an integral part of modern medical practice. Surveys show that medical students have a positive attitude towards promotion. Pharmaceutical promotion is not adequately taught in medical schools. A module based on the manual produced by Health Action International was conducted for second year medical students at KIST Medical College, Lalitpur, Nepal. Student feedback on various aspects of the module was obtained using a semi-structured questionnaire. Eighty-six of the 100 students (86%) provided feedback about the module. Forty-five (52.3%) were female and 39 (45.3%) were male. Participant feedback about the module was positive. Small group work and role plays were appreciated, and the ratings of the module and the manual were satisfactory. Respondents felt pharmaceutical promotion will play an important role in their future practice and that the module prepared them to respond appropriately to promotion and select and use medicines properly. The module further developed on issues covered during pharmacology practical and majority felt the module was of relevance to Nepal. Students appreciated the module though there were suggestions for improvement. The module should be considered during the years of clinical training (third and fourth years) and internship and in other medical schools. PMID- 22232708 TI - Feedback on and knowledge, attitude, and skills at the end of pharmacology practical sessions. AB - Concern has been raised about inadequate pharmacology teaching in medical schools and the high incidence of prescribing errors by doctors in training. Modifications in pharmacology teaching have been carried out in many countries. The present study was carried out using a semi-structured questionnaire to obtain students' perceptions of their knowledge, attitudes, and skills with regard to different subject areas related to rational prescribing at the end of two-year activity-based pharmacology practical learning sessions in a private medical school in Nepal. The effectiveness of the sessions and strengths and suggestions to further improve the sessions were also obtained. The median total knowledge, attitude, skills and overall scores were calculated and compared among different subgroups of respondents. The median effectiveness score was also calculated. Eighty of the 100 students participated; 37 were male and 43 female. The median knowledge, attitude, and skills scores were 24, 39, and 23, respectively (maximum scores being 27, 45, and 36). The median total score was 86 (maximum score being 108). The effectiveness score for most subject areas was 3 (maximum 4). The strengths were the activity-based nature of the session, use of videos and role plays, and repeated practice. Students wanted more sessions and practice in certain areas. They also wanted more resources and an internet connection in the practical room. The skills scores were relatively low. The immediate impact of the sessions was positive. Studies may be needed to assess the long term impact. Similar programs should be considered in other medical schools in Nepal and other developing countries. PMID- 22232709 TI - Clinical approaches for understanding the expression levels of pattern recognition receptors in otitis media with effusion. AB - OBJECTIVES: Bacterial infections in the normally sterile environment of the middle ear cavity usually trigger host immune response, whereby the innate immune system plays a dominant role as the host's first line of defense. We evaluated the expression levels of Toll-like receptors (TLRs) -2, -4, -5, -9, and nucleotide-binding oligomerization domain-containing proteins (NODs) -1 and -2, all of which are related to bacterial infection in pediatric patients with otitis media with effusion (OME). METHODS: The study sample consisted of 46 pediatric patients with OME, all of whom had ventilation tubes inserted. The expression levels of TLR-2, -4, -5, -9, NOD-1 and -2 mRNA in middle ear effusion were assessed by polymerase chain reaction (PCR). Difference of pattern recognition receptors (PRRs) expression level by presence of bacteria, ventilation tube insertion rate, and effusion fluid character was assessed. RESULTS: All effusion fluid samples collected from patients with OME showed expression of TLR-2, -4, 5, -9, NOD-1, and -2 mRNA by PCR. However, we found no differences among expression levels of PRRs in relation to characteristics of exudates, presence of bacteria, or frequencies of ventilation tube insertion (P>0.05). CONCLUSION: Our findings suggest that exudates of OME patients show PRR expressions that are related to the innate immune response regardless of the characteristics of effusion fluid, presence of bacteria in exudates, or frequency of ventilation tube insertion. PMID- 22232710 TI - What really decides the facial function of vestibular schwannoma surgery? AB - OBJECTIVES: To find the main cause of facial nerve dysfunction in vestibular schwannoma (VS) surgery and review the prognosis of facial function in relation to tumor size, preoperative facial function and surgical approach. METHODS: We reviewed the surgical outcome of 134 patients with VS treated in our department between 1994 and 2008. All patients included in the study had postoperative facial paralysis after surgical management of their VS. There were 14 women and 7 men. The mean age was 48.5 years, with a mean follow-up period of 57 months. RESULTS: Twenty-one patients (sustained facial palsy, 4; newly developed facial palsy, 17) had facial nerve paralysis after surgery: ten patients in large VS and eleven patients in small VS. In large VS group, 4 patients had facial nerve function of HB grade II, 3 patients had HB grade III, and 3 patients had HB grade IV. In small VS group, 9 patients had HB grade II and 2 patients had HB grade IV. Middle cranial fossa approach rather than translabyrinthine approach for the preservation of hearing, led to facial nerve deterioration and the patients who had facial nerve paralysis perioperatively, had resulted in permanent facial paralysis. CONCLUSION: The tumor size in VS is certainly one of the most important prognostic factors. However, VS tumor size alone should not be considered a unique prognostic indicator. The surgical approach used, which may be related to tumor size, based on the surgeon's experience, can be a deciding factor, and the status of the facial nerve injured by the tumor can influence postoperative facial nerve function. PMID- 22232711 TI - Skin prick test reactivity in patients with chronic eczematous external otitis. AB - OBJECTIVES: To investigate the incidence of skin prick test (SPT) positivity in patients with eczematous external otitis. METHODS: Forty-six patients with eczematous external otitis and forty-four healthy volunteers were included in the study. All the patients were skin-tested by prick test. Reactions were assessed by the degree of redness and swelling and the size of the wheal produced. RESULTS: According to SPT positivity and total immunoglobulin E values, the difference between the study and the control groups was statistically significant (P<0.05). The most common skin reactions were against to mites and grasses in this study. CONCLUSION: Eczematous external otitis is perhaps the most difficult to treat of all forms of external otitis because the provocative agents usually remain undiagnosed. Patients suffering from eczematous external otitis symptoms should be investigated for allergens and be informed for prevention of the causative agents. SPT might be performed in cases of prolonged or treatment resistant external otitis. PMID- 22232712 TI - The Effect of Doxycycline on PMA-Induced MUC5B Expression via MMP-9 and p38 in NCI-H292 Cells. AB - OBJECTIVES: Doxycycline is commonly used in medicine for its bacteriostatic antimicrobial properties. Recent studies have reported that doxycycline also has anti-inflammatory effects. Matrix metalloproteinase (MMP)-9 has been found to be involved in the physiological and pathological process of inflammatory airway disease. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, is known to stimulate the expression of MMP and mucin genes in the airway and intestinal epithelial cells. Therefore, the effects and signal pathways of doxycycline on PMA-induced MUC5B expression dependent MMP-9 in human airway epithelial cells were investigated. METHODS: In human NCI-H292 airway epithelial cells, MUC5B and MMP-9 mRNA expression, MUC5B protein expression, and MMP-9 protein activity after the treatment with PMA, MMP-9 or doxycycline were determined by reverse transcriptase-polymerase chain reaction, enzyme immunoassay, gelatin zymography, and Western blot analysis. RESULTS: PMA increased MMP-9 and MUC5B expression. MMP-9 increased MUC5B expression. Doxycycline inhibited PMA-induced MUC5B expression, and PMA-induced MMP-9 mRNA expression and protein activity. Doxycycline inhibited phosphorylation of p38 induced by PMA and MMP-9. CONCLUSION: The results of this study suggest that doxycycline inhibited PMA-induced MUC5B mRNA expression and protein production through the MMP-9 and p38 pathways in human NCI-H292 airway epithelial cells. PMID- 22232713 TI - Relationship between the Korean Version of the Sniffin' Stick Test and the T&T Olfactometer in the Korean Population. AB - OBJECTIVES: The Korean version of the Sniffin' stick (KVSS) test is widely used in Korea to evaluate olfactory function. However, its validity and reliability have not been studied well. In this study, the authors administered the KVSS and the T%T olfactometer test to evaluate olfactory function and to establish relationships between these two test measures. METHODS: Two hundred and eleven patients participated in this prospective randomized study. One hundred and nine patients with no olfactory symptoms and 102 patients with decreased olfaction participated. All participants were underwent KVSS II and T&T olfactometer testing. RESULTS: The mean recognition threshold of the T&T olfactometer was 1.8+/-0.9 for patients with normal olfaction and 4.0+/-2.6 for patients with decreased olfaction. The mean Threshold-Discrimination-Identification score of the KVSS II was 30.0+/-3.8 for patients with normal olfaction and 15.9+/-7.1 for patients with decreased olfaction. Correlation coefficient between the two tests was significantly high (r(s)=-0.725, P<0.01). CONCLUSION: The KVSS and T&T olfactometry test are both reliable tests of olfactory function and their results are well correlated with each other. PMID- 22232714 TI - Clinical analysis of acinic cell carcinoma in parotid gland. AB - OBJECTIVES: Acinic cell carcinoma (AciCC) is a rarely encountered malignancy in parotid gland. Because AciCC is rare and was recently recognized as the entity of malignancy, AciCC has been difficult to study. We aimed to analyze the diagnosis and treatment experience for this malignancy in our hospital. METHODS: We retrospectively reviewed medical records of the 20 patients with AciCC of parotid gland diagnosed from 1990 to 2009. The preoperative computed tomography scan, preoperative fine needle aspiration cytology (FNAC) and intraoperative frozen section results were compared with the final diagnosis. The survival and recurrence were analyzed with the cancer stages and treatment modalities. RESULTS: There were 10 males and 10 females, with a mean age of 44.4 years, ranging 8-77 years. The AJCC tumor stage distributions of the patients were 70%, 15%, and 15% for stages I, II, and IV, respectively. The sensitivity of FNAC and intraoperative frozen section was 26.7% and 50.0% respectively. The 10-year survival rate was 90.9% with a mean follow-up of 111 months, ranging 17-251 months. The 10-year disease free survival rate was 74.2% and the mean duration of recurrence from initial surgery was 92.3 months. CONCLUSION: AciCC of the parotid gland is a rare malignancy that has features of less aggressive behavior, and good prognosis. Intraoperative frozen section examination may be helpful in the diagnosis of AciCC of the parotid gland because of the low sensitivity of preoperative computed tomography scan and FNAC. Surgery with adjuvant postoperative radiotherapy is satisfactory for disease control. PMID- 22232715 TI - Association of the oncostatin m receptor gene polymorphisms with papillary thyroid cancer in the korean population. AB - OBJECTIVES: To investigate the association between papillary thyroid cancer (PTC) and single nucleotide polymorphisms (SNPs) of oncostatin M receptor (OSMR) in the Korean population. METHODS: Retrospective case-control study was done. Eighty five patients with PTC and 287 controls were studied. One missense SNP (rs2278329, Asp553Asn) and one promoter SNP (rs2292016, -100 G/T) of the OSMR gene were genotyped by direct sequencing. Genetic data were analyzed using the SNPStats, Helixtree, and SNPAnalyzer Pro. PTC patients were dichotomized and compared with respect to the clinicopathologic characteristics. RESULTS: There was no association between genotypes and allele frequencies of OSMR SNPs (rs2278329 and rs2292016) and PTC susceptibility. SNP rs2278329 was significantly associated with tumor size (dominant model; P=0.028; odds ratio [OR], 2.71; 95% confidence interval [CI], 1.12 to 6.57). The A allele was higher in sizes large than 1 cm (32.5% vs. 16.7%; P=0.018; OR, 2.41; 95% CI, 1.17 to 4.98). Regarding the number of tumors, we found no significant association with genotype, however, the A allele was higher in patients with multifocaltiy (33.3% vs. 19.1%; P=0.040; OR, 2.12; 95% CI, 1.03 to 4.34). CONCLUSION: The results suggest that OSMR polymorphism rs2278329 is associated with clinicopathologic characteristics of the tumor growth and multifocality development. PMID- 22232716 TI - Development of laser ruler in rigid laryngoscope. AB - OBJECTIVES: The objective of this study was to develop a new device that provides a simple, noninvasive method of measuring accurate lesion size while using an endoscope. METHODS: We developed a rigid laryngoscope with a built-in laser-ruler using a one-light emitting diode and an acrylic plate. The invention incorporates a built-in laser diode that projects an auto-parallel beam into the optical path of the rigid laryngoscope to form two spots in the field of view. RESULTS: While the interspot distance remains consistent despite changes in focal plane, magnification, or viewing angle of the laryngoscope, projection to an uneven surface introduces certain variations in the shape, and size of the spots, and the distance between the two spots. CONCLUSION: The device enables a laryngologist to easily measure the distance between landmarks, as well as the change in real size, and the progressive change of vocal fold lesions in an outpatient setting. PMID- 22232717 TI - Synovial sarcoma of the thyroid gland. AB - Primary synovial sarcoma of the thyroid is an extremely rare condition which has only been reported twice in the literature. We herein report a case of highly aggressive and rapidly lethal primary synovial sarcoma of the thyroid. A 72-year old woman presented with extensive local invasion, rapid progression, and early distant metastasis secondary to primary thyroid synovial sarcoma. The tumor exhibited an atypical histologic and immunohistochemical staining pattern. Detection of SYT/SSX fusion transcript confirmed the diagnosis of synovial sarcoma. Due to the aggressive nature of primary synovial sarcoma of the thyroid gland, early diagnosis and comprehensive treatment including wide resection and postoperative chemoradiation is required. PMID- 22232718 TI - Venous hemangioma of parapharyngeal space with calcification. AB - A hemangioma of the parapharyngeal space (PPS) is an extremely rare tumor and is responsible for 0.5-1% of all tumors occurring in the PPS. We report a case of PPS venous hemangioma in a 49-year-old woman presenting with diffuse swelling in the submandibular region. A preoperative computed tomography (CT) scan showed a cystic mass with multiple calcifications in the PPS. The calcific nodules were round and about 2 mm in diameter. The hemangioma was completely resected via a transcervical approach. During surgery, we found several calcific nodules, which represented phleoboliths or areas of thrombosis with dystrophic calcification. Despite its rarity, a venous hemangioma of the PPS should be considered in a differential diagnosis when a cystic mass with calcification is found by CT scan. To our knowledge, this is the first reported case of a PPS venous hemangioma; we describe its pathognomonic findings on imaging. PMID- 22232719 TI - Porphyromonas endodontalis in chronic periodontitis: a clinical and microbiological cross-sectional study. AB - BACKGROUND: Although previous studies have shown the presence of Porphyromonas endodontalis in chronic periodontitis associated with periapical lesions, the occurrence of this pathogen in diseased periodontal sites without periapical lesions has been poorly investigated. OBJECTIVE: The aims of this study were to quantify P. endodontalis in patients with chronic periodontitis without periapical lesions, to evaluate the potential correlation of P. endodontalis with Porphyromonas gingivalis and Tannerella forsythia, and to evaluate the ability of periodontal treatment to reduce these pathogens. DESIGN: Patients with generalized chronic periodontitis were selected by recording clinical attachment level (CAL), probing depth (PD), and bleeding on probing (BOP). Subgingival samples from 30 diseased nonadjacent sites (CAL>=5 mm, PD between 5 and 7 mm and positive BOP) and 30 healthy nonadjacent sites (PD<=3 mm and negative BOP) were collected and subjected to microbial analysis by quantitative polymerase chain reaction (qPCR) The variables of age, PD, CAL and BOP of all individuals were analyzed using the paired t-test (GrapPad Prism5((r))). Data of bacteria quantification were subjected to a normality test (D'Agostino-Pearson Test). For bacterial correlation analysis, the Spearman correlation was used. RESULTS: Our results showed that diseased sites had significantly higher levels of P. endodontalis compared to healthy sites, similar to the results obtained for P. gingivalis and T. forsythia. The numbers of all bacterial species were reduced significantly after mechanical periodontal treatment. P. endodontalis was significantly correlated with the presence of T. forsythia and P. gingivalis in the diseased group. CONCLUSION: Our results suggest that there is a high prevalence of P. endodontalis, P. gingivalis and T. forsythia in periodontitis sites and that mechanical periodontal treatment is effective at reducing the pathogens studied. PMID- 22232720 TI - Impact of supragingival therapy on subgingival microbial profile in smokers versus non-smokers with severe chronic periodontitis. AB - BACKGROUND: The aim of this study was to assess subgingival microbiological changes in smokers versus non-smokers presenting severe chronic periodontitis after supragingival periodontal therapy (ST). METHODS: Non-smokers (n=10) and smokers (n=10) presenting at least nine teeth with probing pocket depth (PPD) (>=5 mm), bleeding on probing (BoP), and no history of periodontal treatment in the last 6 months were selected. Clinical parameters assessed were plaque index (PI), BoP, PPD, relative gingival margin position (rGMP) and relative clinical attachment level (rCAL). Subgingival biofilm was collected before and 21 days after ST. DNA was extracted and the 16S rRNA gene was amplified with the universal primer pair, 27F and 1492R. Amplified genes were cloned, sequenced, and identified by comparison with known 16S rRNA sequences. Statistical analysis was performed by Student's t and Chi-Square tests (alpha=5%). RESULTS: Clinically, ST promoted a significant reduction in PI and PPD, and gain of rCAL for both groups, with no significant intergroup difference. Microbiologically, at baseline, data analysis demonstrated that smokers harbored a higher proportion of Porphyromonas endodontalis, Bacteroidetes sp., Fusobacterium sp. and Tannerella forsythia and a lower number of cultivated phylotypes (p<0.05). Furthermore, non-smokers featured significant reductions in key phylotypes associated with periodontitis, whereas smokers presented more modest changes. CONCLUSION: Within the limits of the present study, ST promoted comparable clinical improvements in smokers and non smokers with severe chronic periodontitis. However, in smokers, ST only slightly affected the subgingival biofilm biodiversity, as compared with non-smokers. PMID- 22232721 TI - Apoptosis Induced by Manganese on Neuronal SK-N-MC Cell Line: Endoplasmic Reticulum (ER) Stress and Mitochondria Dysfunction. AB - OBJECTIVES: Manganese chloride (MnCl(2)) is one of heavy metals for causing neurogenerative dysfunction like Manganism. The purpose of this study was to determine the acute toxicity of MnCl(2) using different times and various concentrations including whether manganese toxicity may involve in two intrinsic pathways, endoplasmic reticulum (ER) stress and mitochondria dysfunction and lead to neuronal apoptosis mediated by organelle disorders in neuroblastoma cell line SK-N-MC. METHODS: In the acute toxicity test, five concentrations (200, 400, 600, 800, 1,000 uM) of MnCl(2) with 3, 6, 12, 24, 48 hours exposure were selected to analyze cell viability. In addition, to better understand their toxicity, acute toxicity was examined with 1,000 uM MnCl(2) for 24 hours exposure via reactive oxygen species (ROS), mitochondria membrane potential, western blotting and mitochondrial complex activities. RESULTS: Our results showed that both increments of dose and time prompt the increments in the number of dead cells. Cells treated by 1,000 uM MnCl(2) activated 265% (+/-8.1) caspase-3 compared to control cell. MnCl(2) induced intracellular ROS produced 168% (+/-2.3%) compared to that of the control cells and MnCl(2) induced neurotoxicity significantly dissipated 48.9% of mitochondria membrane potential compared to the control cells. CONCLUSIONS: This study indicated that MnCl(2) induced apoptosis via ER stress and mitochondria dysfunction. In addition, MnCl(2) affected only complex I except complex II, III or IV activities. PMID- 22232722 TI - Diagnostic performance of cone-beam computed tomography on detection of mechanically-created artificial secondary caries. AB - PURPOSE: The aim of this study was to compare the diagnostic accuracy of cone beam computed tomography (CBCT) images and bitewing images in detection of secondary caries. MATERIALS AND METHODS: One hundred and twenty proximal slots of Class II cavities were randomly prepared on human premolar and molar teeth, and restored with amalgam (n=60) and composite resin (n=60). Then, artificial secondary caries lesions were randomly created using round steel No. 4 bur. The teeth were radiographed with a conventional bitewing technique and two CBCT systems; Pax-500ECT and Promax 3D. All images were evaluated by five observers. The area under the receiver operating characteristic (ROC) curve (A(z)) was used to evaluate the diagnostic accuracy. Significant difference was tested using the Friedman test (p value<0.05). RESULTS: The mean A(z) values for bitewing, Pax 500ECT, and Promax 3D imaging systems were 0.882, 0.995, and 0.978, respectively. Significant differences were found between the two CBCT systems and film (p=0.007). For CBCT systems, the axial plane showed the greatest A(z) value. CONCLUSION: Based on the design of this study, CBCT images were better than bitewing radiographs in detection of secondary caries. PMID- 22232723 TI - Description of mandibular bone quality based on measurements of cortical thickness using Mental Index of male and female patients between 40-60 years old. AB - PURPOSE: The purpose of this study was to obtain the description of the mandibular bone quality of male and female patients between 40-60 years old and their differences based on mandibular cortical bone thickness measured using Mental Index (MI). MATERIALS AND METHODS: Forty digital panoramic radiographs, which consisted of twenty male and twenty female patients, 40-60 years old, were observed. Mandibular cortical bone thickness was measured using MI on both sides of the mandible. The average MI score of two groups were then assessed using t sample independent test. RESULTS: There were significant differences of mandibular bone quality based on mandibular cortical bone thickness measurement using MI between male and female patients (p<0.05). CONCLUSION: Mandibular bone quality based on cortical bone thickness measurement using MI of male and female patients indicated a significant difference. PMID- 22232724 TI - Panoramic radiological study to identify locally displaced maxillary canines in Bangladeshi population. AB - PURPOSE: This study was performed to determine the prevalence of maxillary canine impaction on a basis of a single panoramic radiograph in Bangladeshi population. MATERIALS AND METHODS: A random sample of seven hundred panoramic radiographs was collected from the patient record of a dental clinic. All the selected panoramic radiographs were taken from January 2009 to August 2010 by a single panoramic radiograph machine with the same exposure time (19 seconds) for all radiographs. One hundred and twenty panoramic radiographs were excluded to minimize the selection bias. In a dim lit room, an observer assessed the radiographs on a standard radiographic light box. The position of the impacted maxillary canine was recorded in line with the longitudinal axis of a tooth using the edge of a metal ruler. Data were subsequently put on SPSS 11.5 software and chi-square (chi(2)) tests were applied to find out the association. RESULTS: Among 580 panoramic radiographs it was found that impacted maxillary canines were present in only 7 (1.2%) radiographs. A statistical significant difference was found between the age of the patients and the vertical position of the impacted canines (p=0.000) and between the age of the patients and the horizontal position of the impacted canines (p=0.003). CONCLUSION: The prevalence was found to be low compared with the present study from the limitation of panoramic image. Further study needs to include three-dimensional imaging modality. PMID- 22232725 TI - Extraoral periapical radiography: an alternative approach to intraoral periapical radiography. AB - It is difficult to take intraoral radiographs in some patients who are intolerable to place the film in their mouth. For these patients, Newman and Friedman recommended a new technique of extraoral film placement. Here we report various cases that diagnostic imaging was performed in patients using the extraoral periapical technique. This technique was used to obtain the radiographs for the patients with severe gag reflex, pediatric dental patients, and patients with restricted mouth opening. This technique can be recommended as an alternative to conventional intraoral periapical technique in cases where intraoral film placement is difficult to achieve. PMID- 22232726 TI - Ellis-van Creveld syndrome in an Indian child: a case report. AB - Ellis-van Creveld syndrome is a rare congenital genetic disorder having autosomal recessive inheritance. It is a syndrome affecting the Amish population of Pennsylvania in USA with prevalence rate of 1/5,000 live at birth. In non-Amish population, the birth prevalence is 7/1,000,000. The syndrome is characterized by bilateral postaxial polydactyly of the hands, chondrodysplasia of long bones resulting in acromesomelic dwarfism, ectodermal dysplasia affecting nails as well as teeth and congenital heart malformation. There were very rare reports of this syndrome in dentistry. The present case focuses on the striking and constant oral findings of these patients, which are the main diagnostic features of this syndrome. Since the oral manifestations affect the esthetic, speech, and jaw growth of the child, the dentists have an important role to play in proper management of such case. PMID- 22232728 TI - Pyknodysostosis: report of a rare case with review of literature. AB - Pyknodysostosis is a rare autosomal recessive disorder characterized by the post natal onset of short limbs, short stature, and generalized hyperostosis along with acro-osteolysis with sclerosis of the terminal phalanges, a feature that is considered essentially pathognomonic. Other features include persistence of fontanelles, delayed closure of sutures, wormian bones, absence of frontal sinuses, and obtuse mandibular gonial angle with relative mandibular prognathism. We report a case of 17-year-old girl who presented with a chief complaint of retention of deciduous teeth. General physical examination demonstrated short stature, frontal and parietal bossing, depressed nasal bridge, beaked nose, hypoplastic midface, wrinkled skin over the finger tips, and nail abnormalities. Radiographs showed multiple impacted permanent and supernumerary teeth, hypoplastic paranasal sinuses with acro-osteolysis of terminal phalanges, and open fontanelles, and sutures along with wormian bones in the lambdoidal region. PMID- 22232727 TI - Imaging findings in a case of Gorlin-Goltz syndrome: a survey using advanced modalities. AB - Gorlin-Goltz syndrome is an infrequent multi-systemic disease which is characterized by multiple keratocysts in the jaws, calcification of falx cerebri, and basal cell carcinomas. We report a case of Gorlin-Goltz syndrome in a 23-year old man with emphasis on image findings of keratocyctic odontogenic tumors (KCOTs) on panoramic radiograph, computed tomography, magnetic resonance (MR) imaging, and Ultrasonography (US). In this case, pericoronal lesions were mostly orthokeratinized odontogenic cyst (OOC) concerning the MR and US study, which tended to recur less. The aim of this report was to clarify the characteristic imaging features of the syndrome-related keratocysts that can be used to differentiate KCOT from OOC. Also, our findings suggested that the recurrence rate of KCOTs might be predicted based on their association to teeth. PMID- 22232729 TI - Three-dimensional imaging of progressive facial hemiatrophy (Parry-Romberg syndrome) with unusual conjunctival findings. AB - Progressive hemifacial atrophy, also known as Parry-Romberg syndrome, is an uncommon degenerative condition which is poorly defined. It is characterized by a slow and progressive atrophy affecting one side of the face. The onset usually occurs during the first two decades of life. Characteristically, the atrophy progresses slowly for several years, and then it becomes stable. Ophthalmic involvement is common, with progressive enophthalmos which is a frequent finding. Cutaneous pigmentation is common in such conditions, however its extension to the conjunctiva is rarely reported. We report a case of Parry Romberg syndrome with characteristic clinical and radiographic presentation accompanied with rare ocular findings. The clinical features, radiological findings, and differential diagnoses to be considered, and the available treatment options are discussed in this report. PMID- 22232730 TI - Application of radiographic images in diagnosis and treatment of deep neck infections with necrotizing fasciitis: a case report. AB - The advent and wide use of antibiotics have decreased the incidence of deep neck infection. When a deep neck infection does occur, however, it can be the cause of significant morbidity and death, resulting in airway obstruction, mediastinitis, pericarditis, epidural abscesses, and major vessel erosion. In our clinic, a patient with diffuse chronic osteomyelitis of mandible and fascial space abscess and necrotic fasciitis due to odontogenic infection at the time of first visit came. We successfully treated the patient by early diagnosis using contrast enhanced CT and follow up dressing through the appropriate use of radiographic images. PMID- 22232731 TI - Phase I trial of sorafenib in combination with 5-fluorouracil/leucovorin in advanced solid tumors. AB - This dose escalation, uncontrolled phase I study evaluated the tolerability, pharmacokinetics (PK), and antitumor activity of oral sorafenib 100, 200, or 400 mg twice daily (bid, continuous regimen) in combination with 5 fluorouracil/leucovorin (5-FU/LCV, intravenous infusion or bolus) in patients with advanced, solid tumors. A total of 47 patients (median age 57 years; colon cancer, 55%; pancreatic cancer, 21%; prior systemic therapy, 96%) received treatment; 24 were included in the PK analyses, and 38 were evaluable for tumor response. Treatment-emergent adverse events were observed in 98% of patients (>=grade 3, 55%); the most frequently reported were fatigue (51%), stomatitis/pharyngitis (47%), and hand-foot skin reaction (45%). Concomitant 5 FU/LCV resulted in no clinically relevant changes in the area under the plasma concentration-time curve in the dosing interval (AUC(0-12)) and maximum plasma concentration (C(max)) of sorafenib (100-400 mg bid) at steady state. Although the start of infusion until the last quantifiable plasma concentration (AUC(0 tn)) and C(max) of 5-FU were increased by concomitant sorafenib 100 to 200 mg, no consistent effect was observed with 400 mg sorafenib. Two (5%) patients with colon cancer achieved partial response; 16 (42%) patients (the majority with colon and pancreatic cancer) had stable disease. Sorafenib plus 5-FU/LCV was generally well tolerated with encouraging antitumor activity and no clinically relevant drug-drug interactions in patients with advanced solid tumors. PMID- 22232732 TI - The pattern of platelet response to clopidogrel in Iranian patients after percutaneous coronary intervention. AB - Despite certain clinical benefit in using clopidogrel in patients undergoing percutaneous coronary intervention (PCI), some patients do not attain adequate antiplatelet effects. In this study, the authors investigated the response to clopidogrel in Iranian patients after PCI. Patients who were candidates for elective PCI were enrolled in this study. All patients had received aspirin 80 to 325 mg daily for >=1 week before PCI. Blood samples were taken from patients at baseline, 2 hours after taking a 600-mg loading dose of clopidogrel, and 24 hours and 30 days after stenting. Platelet aggregation was measured by light transmittance aggregometry with adenosine diphosphate (5 and 20 MUM) and arachidonic acid (500 and 5000 MUg/mL). One hundred twelve patients were included (79 men, 33 women). Maximal and minimal clopidogrel nonresponsiveness occurred at 2 hours (26%) and 48 hours (13%) after taking 600 mg clopidogrel, respectively. Pretreatment platelet reactivity had no effects on posttreatment platelet reactivity. Moreover, clopidogrel responsiveness did not correlate with pretreatment reactivity. Patients' demographic and procedural characteristics had no significant effect on clopidogrel responsiveness. The frequency of clopidogrel nonresponsiveness in this study was similar to other studies. However, clopidogrel required more than 2 hours for induction of its maximal antiplatelet effect in this study. PMID- 22232733 TI - Pharmacokinetics of daily self-application of imiquimod 3.75% cream in adult patients with external anogenital warts. AB - Imiquimod 3.75% cream is a new formulation intended for daily self-application. The objective of this study was to characterize serum imiquimod pharmacokinetics under maximal use conditions. Adults with >=8 warts or total wart area >=100 mm2 applied up to 1 packet of imiquimod 3.75% cream (250 mg cream, 9.375 mg imiquimod) once daily for 3 weeks. Blood was obtained prior to doses 1, 7, 14, and 21 and at selected time points after doses 1 and 21. Eighteen patients (13 men and 5 women) with a median wart count of 16 and total wart area of 60 mm2 were enrolled. Day 21 mean (SD) serum C(max) was 0.49 (0.37) ng/mL, AUC0-24 6.80 (3.59) ng.h/mL, and t(1/2) 24.1 (12.4) hours. Steady state was achieved by day 7 with ~2-fold increase in C(max) and AUC after multiple dosing. Overall, C(max) was higher and t(max) shorter in women, with comparable AUC0-24. Imiquimod metabolites were sporadically quantifiable. No patients discontinued for adverse events; 1 interrupted dosing for an application site ulcer. Treatment-related adverse events occurred in 16.7% of the patients. In conclusion, serum imiquimod concentrations were low after daily self-application to external anogenital warts of up to 1 packet of imiquimod 3.75% cream for 21 days. PMID- 22232734 TI - Impact of circulating vitamin D binding protein levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk: a nested case-control study. AB - High concentrations of circulating 25-hydroxyvitamin D [25(OH)D] have been associated with elevated pancreatic cancer risk. As this is contrary to an expected inverse association between vitamin D status and cancer, we examined whether vitamin D binding protein (DBP), the primary carrier of vitamin D compounds in circulation, plays a role in this relationship. Prediagnostic serum DBP and 25(OH)D were studied in relation to risk of pancreatic cancer in a nested case-control study of 234 cases and 234 controls in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study of Finnish men. ORs and 95% CIs were estimated using logistic regression, and statistical tests were two-sided. We found that DBP and 25(OH)D were correlated (r = 0.27, P < 0.0001), and DBP was inversely associated with pancreatic cancer risk (OR = 0.66, 95% CI = 0.39-1.12, for the highest vs. lowest quartile; P(trend) = 0.02). Importantly, this association seemed to have a threshold between quartiles 2 to 4 and quartile 1, and was primarily evident among men with concurrent high 25(OH)D concentrations (OR = 0.33, 95% CI = 0.16-0.70 for highest vs. lowest quartile; P(trend) = 0.002), with no association in men with lower serum 25(OH)D (OR = 1.28, 95% CI = 0.62-2.61 for highest vs. lowest quartile, P(trend) 0.63, P(interaction) = 0.01). Men with higher 25(OH)D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR = 5.01, 95% CI 2.33-10.78, for highest vs. lowest quartile; P(trend) < 0.0001), while risk was weakly inversely associated with serum 25(OH)D when DBP concentrations were higher (P(interaction) = 0.001). Taken together, our findings indicate that higher DBP concentrations may sequester more 25(OH)D and reduce free 25(OH)D bioavailability. Simultaneous examination of DBP and 25(OH)D may be important in determining the association of vitamin D with cancer risk. PMID- 22232735 TI - Adoptive cell therapy for lymphoma with CD4 T cells depleted of CD137-expressing regulatory T cells. AB - Adoptive immunotherapy with antitumor T cells is a promising novel approach for the treatment of cancer. However, T-cell therapy may be limited by the cotransfer of regulatory T cells (T(reg)). Here, we explored this hypothesis by using 2 cell surface markers, CD44 and CD137, to isolate antitumor CD4 T cells while excluding T(regs). In a murine model of B-cell lymphoma, only CD137(neg)CD44(hi) CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137(pos)CD44hi CD4 T cells consisted primarily of activated T(regs). Notably, this CD137(pos) T(reg) population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, in vitro these CD137(pos) cells suppressed the proliferation of effector cells in a contact dependent manner, and in vivo adding the CD137(pos)CD44(hi) CD4 cells to CD137(neg)CD44(hi) CD4 cells suppressed the antitumor immune response. Thus, CD137 expression on CD4 T cells defined a population of activated T(regs) that greatly limited antitumor immune responses. Consistent with observations in the murine model, human lymphoma biopsies also contained a population of CD137(pos) CD4 T cells that were predominantly CD25(pos)FoxP3(pos) T(regs). In conclusion, our findings identify 2 surface markers that can be used to facilitate the enrichment of antitumor CD4 T cells while depleting an inhibitory T(reg) population. PMID- 22232736 TI - Hedgehog and Notch signaling regulate self-renewal of undifferentiated pleomorphic sarcomas. AB - Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial. PMID- 22232737 TI - Novel genetic markers of breast cancer survival identified by a genome-wide association study. AB - Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor-node-metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 associations were evaluated in an independent replication stage of 4,160 Shanghai patients with breast cancer. A consistent and highly significant association with total mortality was documented for SNPs rs3784099 and rs9934948. SNP rs3784099, located in the RAD51L1 gene, was associated with total morality in both the discovery stage (P = 1.44 * 10(-8)) and replication stage (P = 0.06; P-combined = 1.17 * 10(-7)). Adjusted HRs for total mortality were 1.41 [95% confidence interval (CI), 1.18-1.68] for the AG genotype and 2.64 (95% CI, 1.74-4.03) for the AA genotype, when compared with the GG genotype. The variant C allele of rs9934948, located on chromosome 16, was associated with a similarly elevated risk of total mortality (P-combined = 5.75 * 10(-6)). We also observed this association among 1,145 patients with breast cancer of European ancestry from the Nurses' Health Study (NHS; P = 0.006); the association was highly significant in a combined analysis of NHS and Chinese data (P = 1.39 * 10( 7)). Similar associations were observed for these two SNPs with breast cancer specific mortality. This study provides strong evidence suggesting that the RAD51L1 gene and a chromosome 16 locus influence breast cancer prognosis. PMID- 22232738 TI - ETS1 transcriptional activity is increased in advanced prostate cancer and promotes the castrate-resistant phenotype. AB - Advanced disease accounts for the majority of prostate cancer-related deaths and androgen deprivation therapy (ADT) is the standard of care for these patients. Many patients undergoing ADT become resistant to its effects and progress to castrate-resistant prostate cancer (CRPC). Current therapies for CRPC patients are inadequate, with progression-free survival rates as low as 2 months. The molecular events that promote CRPC are poorly understood. ETS (v-ets erythroblastosis virus E26 oncogene) transcription factors are regulators of carcinogenesis. Protein levels of the archetypical ETS factor, ETS1, are increased in clinical and latent prostate cancer relative to benign prostatic hyperplasia and normal prostate to promote multiple cancer-associated processes, such as energy metabolism, matrix degradation, survival, angiogenesis, migration and invasion. Our studies have found that ETS1 expression is highest in high grade prostate cancer (Gleason 7 and above). Increased ETS1 expression and transcriptional activity promotes an aggressive and castrate-resistant phenotype in immortalized prostate cancer cells. Elevated AKT (v-akt murine thymoma viral oncogene homolog) activity was demonstrated to increase ETS1 protein levels specifically in castrate-resistant cells and exogenous ETS1 expression was sufficient to rescue invasive potential decreased by inhibition of AKT activity. Significantly, targeted androgen receptor activity altered ETS1 expression, which in turn altered the castrate-resistant phenotype. These data suggest a role for oncogenic ETS1 transcriptional activity in promoting aggressive prostate cancer and the castrate-resistant phenotype. PMID- 22232742 TI - Green feces. PMID- 22232739 TI - Sphingosine-1-phosphate induces contraction of valvular interstitial cells from porcine aortic valves. AB - AIMS: Sphingosine-1-phosphate (S1P) has emerged as a potent bioactive lipid with multiple functions in cardiovascular pathophysiology. Potential roles of S1P in heart valve diseases and expression of relevant receptors (S1P1, S1P2, or S1P3) in valve tissue and in valvular interstitial cells (VICs), the major cell population with essential functions in maintenance of valvular structure, are currently unknown. METHODS AND RESULTS: Exposure to S1P (62-2000 nM) of cultured VICs from porcine aortic valves on cell culture polystyrene resulted in contraction and nodule formation. The S1P-dependent contraction was completely inhibited by blockers of S1P2, RhoA, and RhoA-associated protein kinase (ROCK). Activated RhoA was clearly increased after S1P treatment, whereas activated Rac1 was only slightly reduced. In addition, exposure to S1P induced a transient increase in cytosolic Ca(2+). Application of channel blockers and other effectors of Ca(2+) homeostasis showed that the S1P effect is largely caused by Ca(2+) release from internal stores. However, resistance to blocking S1P2, different kinetics, as well as concentration dependence exclude a major role of Ca(2+) influx in S1P-induced nodule formation. In order to verify the effects in situ, contractions of valve tissue slices were measured. The S1P-induced isometric contraction of valve leaflets was of similar force amplitude as observed with adrenaline. The effect was fully reversed by blocking S1P2. CONCLUSION: The results suggest that S1P induces contraction of VICs from porcine aortic valves by signalling via S1P2, RhoA, and ROCK. In this way, S1P may contribute to regulation of tissue tension in aortic valves. PMID- 22232743 TI - Sertoli cell differentiation in rhesus monkey (Macaca mulatta) is an early event in puberty and precedes attainment of the adult complement of undifferentiated spermatogonia. AB - In primates, the time course of Sertoli cell proliferation and differentiation during puberty and its relationship with the expansion of undifferentiated type A spermatogonia that occurs at this critical stage of development are poorly defined. Mid and late juvenile and early and late pubertal male rhesus monkeys were studied. Testes were immersion fixed, embedded in paraffin, and sectioned at 5 MUm. Sertoli cell number per testis, S-phase labeling (BrdU), and growth fraction (Ki67 labeling) were determined and correlated with corresponding parameters for undifferentiated type A spermatogonia (A dark and A pale). Dual fluorescence labeling was used in addition to histochemistry to monitor spermatogonial differentiation during the peripubertal period using GFRalpha-1 and cKIT as markers. While the adult complement of Sertoli cells/testis was attained in early pubertal monkeys after only a few weeks of exposure to the elevated gonadotropin secretion characteristic of this developmental stage, the number of undifferentiated type A spermatogonia several months later in mid pubertal monkeys was only 50% of that in adult testes. Both A dark and A pale spermatogonia exhibited high S-phase BrdU labeling at all stages of juvenile and pubertal development. Spermatogonial differentiation, as reflected histochemically and by relative changes in GFRalpha-1 and cKIT expression, was not observed until after the initiation of puberty. In the rhesus monkey and maybe in other higher primates including human, the pubertal proliferation of undifferentiated spermatogonia is insidious and proceeds in the wake of a surge in Sertoli cell proliferation following termination of the juvenile stage of development. PMID- 22232744 TI - Oestradiol transmission from males to females in the context of the Bruce and Vandenbergh effects in mice (Mus musculus). AB - Male mice actively direct their urine at nearby females, and this urine reliably contains unconjugated oestradiol (E(2)) and other steroids. Giving inseminated females minute doses of exogenous E(2), either systemically or intranasally, can cause failure of blastocyst implantation. Giving juvenile females minute doses of exogenous E(2) promotes measures of reproductive maturity such as uterine mass. Here we show that tritium-labelled E(2) ((3)H-E(2)) can be traced from injection into novel male mice to tissues of cohabiting inseminated and juvenile females. We show the presence of (3)H-E(2) in male excretions, transmission to the circulation of females and arrival in the female reproductive tract. In males, (3)H-E(2) given systemically was readily found in reproductive tissues and was especially abundant in bladder urine. In females, (3)H-E(2) was found to enter the system via both nasal and percutaneous routes, and was measurable in the uterus and other tissues. As supraoptimal E(2) levels can both interfere with blastocyst implantation in inseminated females and promote uterine growth in juvenile females, we suggest that absorption of male-excreted E(2) can account for major aspects of the Bruce and Vandenbergh effects. PMID- 22232746 TI - Design, conduct, analysis, and interpretation of clinical studies in patients with impaired kidney function. AB - Chronic kidney disease has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by metabolism or nonrenal transport. Guidance documents from regulatory agencies on the pharmacokinetics of drugs in patients with impaired kidney function provide a framework for facilitating study design, conduct, data analysis, and the generation of dosing recommendations. Design considerations include establishment of appropriate enrollment criteria, selection of appropriate matched control group(s), and staging of impaired kidney function by estimated glomerular filtration rate or creatinine clearance. When studies in hemodialysis patients are conducted, optimizing the timing of characterization of the pharmacokinetics profile based on the schedule of hemodialysis sessions will allow for a robust assessment in these patients. In addition to traditional noncompartmental approaches, the use of pharmacometric approaches can integrate data from multiple clinical studies and provide a quantitative rationale for dose selection in patients with impaired kidney function. This article addresses the challenges and opportunities associated with the design, conduct, analysis, and interpretation of clinical studies to allow for their future facilitation and for the establishment of safe and efficacious dosing in patients with impaired kidney function. PMID- 22232745 TI - Ovarian VEGF(165)b expression regulates follicular development, corpus luteum function and fertility. AB - Angiogenesis and vascular regression are critical for the female ovulatory cycle. They enable progression and regression of follicular development, and corpora lutea formation and regression. Angiogenesis in the ovary occurs under the control of the vascular endothelial growth factor-A (VEGFA) family of proteins, which are generated as both pro-(VEGF(165)) and anti(VEGF(165)b)-angiogenic isoforms by alternative splicing. To determine the role of the VEGF(165)b isoforms in the ovulatory cycle, we measured VEGF(165)b expression in marmoset ovaries by immunohistochemistry and ELISA, and used transgenic mice over expressing VEGF(165)b in the ovary. VEGF(165)b was expressed in the marmoset ovaries in granulosa cells and theca, and the balance of VEGF(165)b:VEGF(165) was regulated during luteogenesis. Mice over-expressing VEGF(165)b in the ovary were less fertile than wild-type littermates, had reduced secondary and tertiary follicles after mating, increased atretic follicles, fewer corpora lutea and generated fewer embryos in the oviduct after mating, and these were more likely not to retain the corona radiata. These results indicate that the balance of VEGFA isoforms controls follicle progression and luteogenesis, and that control of isoform expression may regulate fertility in mammals, including in primates. PMID- 22232747 TI - Current understanding of drug disposition in kidney disease. AB - Patients with chronic kidney disease (CKD) represent 13% of the American population. CKD has been shown to significantly alter drug disposition of nonrenally eliminated drugs. Indeed, modifications in the expression and function of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Uremic toxins, inflammatory cytokines, and parathyroid hormone have been implicated as causes. These changes can have an important clinical impact on drug disposition and lead to unintended toxicity if they are administered without dose adjustment in patients with impaired kidney function. This review summarizes recent preclinical and clinical studies and presents the current understanding of the effect of CKD on drug absorption, distribution, metabolism, and excretion. PMID- 22232748 TI - A pharmacometric approach to quantify the impact of chronic kidney disease and hemodialysis on systemic drug exposure: application to saxagliptin. AB - The draft United States Food and Drug Administration guidance recommends a dedicated pharmacokinetic (PK) study for most drugs intended for use in patients with chronic kidney disease (CKD), including stage V patients requiring hemodialysis (HD) treatment. However, clinical studies conducted in CKD patients are challenged by difficulties in recruiting stage IV and V patients not yet on dialysis, and in balancing patient characteristics among each studied CKD group. Furthermore, study design for dialysis patients often involves a single dose administered before an HD session. The design may not necessarily represent usual patient care in current clinical practice, in which multiple doses are more likely to be administered at varying times between HD sessions. Using exposure modeling of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, as an example, this work illustrates how these challenges can be alleviated by modeling the impact of HD on drug exposure in clinical studies and simulating the expected exposure level in patient care. The modeled PK profiles in dialysis patients were used to understand PK profiles in patients with various CKD stages. The applied pharmacometric approach increased the efficiency of knowledge generation from existing data. PMID- 22232749 TI - Understanding renal replacement therapy and dosing of drugs in pediatric patients with kidney disease. AB - Multifaceted factors need to be considered when prescribing renal replacement therapy (RRT) and dosing of drugs in pediatric patients with kidney disease. RRTs in pediatrics such as intermittent hemodialysis, continuous venovenous hemofiltration, continuous venovenous hemodialysis, and continuous venovenous hemodiafiltration affect solute and drug clearance. Drug properties such as molecular weight, molecular charge, volume of distribution, and protein binding affect drug clearance. RRT prescription parameters such as blood flow rate, ultrafiltration rate, membrane size, and pore size can also influence drug clearance. Furthermore, the pediatric patient presents additional concerns because of developmental factors in children that affect both pharmacokinetics of drugs. PMID- 22232750 TI - Impact of glomerular kidney diseases on the clearance of drugs. AB - Numerous physiologic variations, including urinary protein excretion, low serum albumin concentrations, and reductions in kidney function (clearance), exist in patients with glomerulonephritis. These factors could alter the disposition of numerous drugs. The purpose of the current article was to review the influence of glomerulonephritis on the pharmacokinetics of drugs used clinically or experimentally in the treatment of these conditions. Several articles or presentations were located that reported on the pharmacokinetics of immunosuppressant, cytotoxic, and therapeutic antibody drugs in populations with glomerulonephritis. Most publications reported an increase in systemic clearance in glomerulonephritis as compared with populations in whom the drugs were typically used and in patients with nonglomerular forms of chronic kidney disease. It appears that the increase in systemic clearance is predominantly through nonrenal clearance pathways, although enhancement of renal clearance has also been appreciated for some drugs. Available preliminary data suggest specific alterations in the activity of individual pathways of drug metabolism and transport. Recommendations are provided for the design of future studies of drugs in the glomerulonephritis population and for inclusion of patients with urinary protein excretion in studies that assess drug pharmacokinetics. PMID- 22232751 TI - Use of an in vitro model of renal replacement therapy systems to estimate extracorporeal drug removal. AB - The use of in vitro modeling to predict in vivo drug and solute clearance during renal replacement therapy has evolved to reflect the different dialytic therapies available in clinical practice. This area of renal replacement therapy research is representative of translational research that demonstrates a correlation from bench to bedside where results generated in the laboratory can assist with clinical decisions in the absence of in vivo studies. This review describes in vitro renal replacement therapy models and compares the findings of several in vitro and in vivo studies. PMID- 22232752 TI - Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function. AB - A physiologically based, multiscale model of calcium homeostasis and bone remodeling was used to describe the impact of progressive loss of kidney function over a typical 10-year course of chronic kidney disease (CKD), including the evolution of secondary hyperparathyroidism (HPT) caused by diminished renal phosphate clearance and increased plasma phosphate. An important sequela of HPT is marked elevations in bone resorption and loss of bone mineral density (BMD). Clinically, this CKD-related disease state is described as mineral bone disorder, or CKD-MBD. A multiscale physiologic model previously had been shown to describe CKD-MBD-related clinical changes in phosphate, parathyroid hormone (PTH), and calcitriol. The authors have extended the model to link bone remodeling markers with BMD elimination (0.000145 h(-1)) and formation rates. The composite model predicted lumbar spine BMD losses, relative to baseline, at months 28 (glomerular filtration rate = 58 mL/min), 50 (39 mL/min), and 120 (16 mL/min) of approximately -0.98%, -3.0%, and -6.5%, respectively, compared to the observed BMD values in corresponding renal function groups, scaled to a 100-mL/min baseline, of -0.5%, -4.0%, and -8.1%, respectively. In addition, simulated interventions with a hypothetical calcimimetic agent and calcitriol are provided to show the utility of this model as a platform for evaluating therapeutics. PMID- 22232753 TI - Optimizing drug development and use in patients with kidney disease: opportunities, innovations, and challenges. PMID- 22232754 TI - Characterizing the impact of renal impairment on the clinical pharmacology of biologics. AB - Similar to small-molecule drugs, there is also concern for protein-based therapeutics about their clinical use in patients with renal impairment including renal insufficiency and end-stage renal disease, which may modulate the efficacy and/or safety profile of these compounds. Theoretical considerations and clinical evidence suggest that the kidneys play a relevant role in the catabolism and thus elimination of only those protein therapeutics that have a size below the cutoff for glomerular filtration of approximately 60 kDa. Thus, the effect of renal impairment on protein therapeutics seems to be predictable and only relevant for compounds below this molecular weight cutoff. This is supported by clinical evidence that shows a lack of effect of renal impairment on large proteins such as monoclonal antibodies, whereas smaller proteins below the cutoff such as interleukin-10, growth hormone, erythropoietin, and anakinra experience a gradual decrease of their clearance and increase of their systemic exposure with increasing severity of renal impairment. Thus, dedicated renal impairment studies are warranted in the clinical development program of protein therapeutics that undergo glomerular filtration to establish the scientific rationale for their safe and efficacious use in patients with renal insufficiency. PMID- 22232755 TI - The old and new methods of assessing kidney function. AB - Chronic kidney disease is a worldwide problem. Accurate assessment of kidney function is important for defining stages of kidney disease and assisting with drug dosing. Glomerular filtration rate (GFR) is a good index of the health of the kidney. Although measured GFR using an exogenous substance is the most accurate, it is difficult to obtain due to cost and resources. Equations calculating creatinine clearance and estimated GFR as a measure of kidney function have been developed using serum creatinine as a marker of kidney function. The Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations have been shown to have statistically significant differences in estimating GFR in various populations. Drug-dosing adjustments based on the various equations may differ. However, without clinical outcome data, it is yet to be determined whether these differences are clinically significant. PMID- 22232756 TI - Novel dialysis modalities: do we need new metrics to optimize treatment? AB - Delivered dose of hemodialysis has long been an important predictor of mortality. The limitations of conventional hemodialysis treatments have led to a renewed interest in more frequent and longer hemodialysis treatments. As alternative hemodialysis schedules have become more prevalent, a need for modified metrics to measure adequacy has emerged. In addition, there is an interest in finding measures of hemodialysis adequacy that are more reliable in certain subgroups of patients, such as women, ethnic minority groups, or people with small body size. Finally, extended hemodialysis schedules suggest a need for metrics that can measure the clearance of solutes other than urea, such as middle-size molecules, and solutes for which clearance depends on intercompartmental transport across membranes. New metrics to quantify clearance in extended and alternate hemodialysis schedules are needed. As new metrics are developed, it is anticipated that they will also contribute to more accurate assessments of associations between clinical outcomes and delivered dose of dialysis in more intensive, nontraditional hemodialysis schedules. This review provides a historical prospective of dialysis dose and adequacy and describes the need for new metrics from both solute type and dialysis dose prospective as alternative hemodialysis schedules have emerged and become more prevalent. PMID- 22232757 TI - Regulatory perspectives on designing pharmacokinetic studies and optimizing labeling recommendations for patients with chronic kidney disease. AB - To optimize drug dosing, it is critical to understand how various intrinsic and extrinsic factors affect systemic exposure of the drug and the response. Chronic kidney disease (or renal impairment) can affect pharmacokinetic characteristics of a therapeutic drug and its metabolites and therefore is one of the most important intrinsic factors that can affect a patient's response to drugs. During drug development, it is critical to understand how renal impairment can affect a drug's pharmacokinetics so that appropriate dosing recommendations can be included in the label. The US Food and Drug Administration (FDA) has published various guidance documents and opinion papers to address scientific and regulatory issues in the study design, data analysis, and labeling recommendations related to dosing in patients with impaired renal function. The 2010 FDA draft guidance on renal impairment provides several updated recommendations that include criteria or principles for evaluating the pharmacokinetics of drugs that are either principally renally cleared or nonrenally cleared in subjects with renal impairment and for categorizing renal function by equations estimating glomerular filtration rate using the Modification of Diet in Renal Disease equations or creatinine clearance using the Cockcroft-Gault equation. The objective of this article is to discuss the FDA's current recommendations and provide examples that illustrate the importance of and challenges in studying effect of renal impairment during drug development. PMID- 22232758 TI - Early research on renal function and drug action. AB - Since the 1960s, systematic studies of drug action in renal failure have found many differences between patients with renal failure and those without. Impaired excretion of drugs was known much earlier and was related to glomerular filtration rate. Kunin first tabulated the pharmacokinetics of antimicrobials and dosage recommendations for azotemic patients in 1967. Other effects of renal failure on drug action include increases in some pathways of drug metabolism with decreases in others and no change in the rest. Some changes in specific drug distribution, drug-protein binding, and drug sensitivity have been demonstrated. This knowledge makes the response of an azotemic patient to a specific dose of a specific drug more predictable than before. This predictability makes drug therapy both safer and more effective for azotemic patients. PMID- 22232759 TI - Evaluation of exposure change of nonrenally eliminated drugs in patients with chronic kidney disease using physiologically based pharmacokinetic modeling and simulation. AB - Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI. PMID- 22232760 TI - Atmospheric carbon dioxide: a driver of photosynthetic eukaryote evolution for over a billion years? AB - Exciting evidence from diverse fields, including physiology, evolutionary biology, palaeontology, geosciences and molecular genetics, is providing an increasingly secure basis for robustly formulating and evaluating hypotheses concerning the role of atmospheric carbon dioxide (CO(2)) in the evolution of photosynthetic eukaryotes. Such studies span over a billion years of evolutionary change, from the origins of eukaryotic algae through to the evolution of our present-day terrestrial floras, and have relevance for plant and ecosystem responses to future global CO(2) increases. The papers in this issue reflect the breadth and depth of approaches being adopted to address this issue. They reveal new discoveries pointing to deep evidence for the role of CO(2) in shaping evolutionary changes in plants and ecosystems, and establish an exciting cross disciplinary research agenda for uncovering new insights into feedbacks between biology and the Earth system. PMID- 22232761 TI - Adaptive signals in algal Rubisco reveal a history of ancient atmospheric carbon dioxide. AB - Rubisco, the most abundant enzyme on the Earth and responsible for all photosynthetic carbon fixation, is often thought of as a highly conserved and sluggish enzyme. Yet, different algal Rubiscos demonstrate a range of kinetic properties hinting at a history of evolution and adaptation. Here, we show that algal Rubisco has indeed evolved adaptively during ancient and distinct geological periods. Using DNA sequences of extant marine algae of the red and Chromista lineage, we define positive selection within the large subunit of Rubisco, encoded by rbcL, to occur basal to the radiation of modern marine groups. This signal of positive selection appears to be responding to changing intracellular concentrations of carbon dioxide (CO(2)) triggered by physiological adaptations to declining atmospheric CO(2). Within the ecologically important Haptophyta (including coccolithophores) and Bacillariophyta (diatoms), positive selection occurred consistently during periods of falling Phanerozoic CO(2) and suggests emergence of carbon-concentrating mechanisms. During the Proterozoic, a strong signal of positive selection after secondary endosymbiosis occurs at the origin of the Chromista lineage (approx. 1.1 Ga), with further positive selection events until 0.41 Ga, implying a significant and continuous decrease in atmospheric CO(2) encompassing the Cryogenian Snowball Earth events. We surmise that positive selection in Rubisco has been caused by declines in atmospheric CO(2) and hence acts as a proxy for ancient atmospheric CO(2). PMID- 22232762 TI - Algal evolution in relation to atmospheric CO2: carboxylases, carbon concentrating mechanisms and carbon oxidation cycles. AB - Oxygenic photosynthesis evolved at least 2.4 Ga; all oxygenic organisms use the ribulose bisphosphate carboxylase-oxygenase (Rubisco)-photosynthetic carbon reduction cycle (PCRC) rather than one of the five other known pathways of autotrophic CO(2) assimilation. The high CO(2) and (initially) O(2)-free conditions permitted the use of a Rubisco with a high maximum specific reaction rate. As CO(2) decreased and O(2) increased, Rubisco oxygenase activity increased and 2-phosphoglycolate was produced, with the evolution of pathways recycling this inhibitory product to sugar phosphates. Changed atmospheric composition also selected for Rubiscos with higher CO(2) affinity and CO(2)/O(2) selectivity correlated with decreased CO(2)-saturated catalytic capacity and/or for CO(2) concentrating mechanisms (CCMs). These changes increase the energy, nitrogen, phosphorus, iron, zinc and manganese cost of producing and operating Rubisco PCRC, while biosphere oxygenation decreased the availability of nitrogen, phosphorus and iron. The majority of algae today have CCMs; the timing of their origins is unclear. If CCMs evolved in a low-CO(2) episode followed by one or more lengthy high-CO(2) episodes, CCM retention could involve a combination of environmental factors known to favour CCM retention in extant organisms that also occur in a warmer high-CO(2) ocean. More investigations, including studies of genetic adaptation, are needed. PMID- 22232763 TI - Morphological evolution in land plants: new designs with old genes. AB - The colonization and radiation of multicellular plants on land that started over 470 Ma was one of the defining events in the history of this planet. For the first time, large amounts of primary productivity occurred on the continental surface, paving the way for the evolution of complex terrestrial ecosystems and altering global biogeochemical cycles; increased weathering of continental silicates and organic carbon burial resulted in a 90 per cent reduction in atmospheric carbon dioxide levels. The evolution of plants on land was itself characterized by a series of radical transformations of their body plans that included the formation of three-dimensional tissues, de novo evolution of a multicellular diploid sporophyte generation, evolution of multicellular meristems, and the development of specialized tissues and organ systems such as vasculature, roots, leaves, seeds and flowers. In this review, we discuss the evolution of the genes and developmental mechanisms that drove the explosion of plant morphologies on land. Recent studies indicate that many of the gene families which control development in extant plants were already present in the earliest land plants. This suggests that the evolution of novel morphologies was to a large degree driven by the reassembly and reuse of pre-existing genetic mechanisms. PMID- 22232764 TI - A timeline for terrestrialization: consequences for the carbon cycle in the Palaeozoic. AB - The geochemical carbon cycle is strongly influenced by life on land, principally through the effects of carbon sequestration and the weathering of calcium and magnesium silicates in surface rocks and soils. Knowing the time of origin of land plants and animals and also of key organ systems (e.g. plant vasculature, roots, wood) is crucial to understand the development of the carbon cycle and its effects on other Earth systems. Here, we compare evidence from fossils with calibrated molecular phylogenetic trees (timetrees) of living plants and arthropods. We show that different perspectives conflict in terms of the relative timing of events, the organisms involved and the pattern of diversification of various groups. Focusing on the fossil record, we highlight a number of key biases that underpin some of these conflicts, the most pervasive and far-reaching being the extent and nature of major facies changes in the rock record. These effects probably mask an earlier origin of life on land than is evident from certain classes of fossil data. If correct, this would have major implications in understanding the carbon cycle during the Early Palaeozoic. PMID- 22232765 TI - Physiological framework for adaptation of stomata to CO2 from glacial to future concentrations. AB - In response to short-term fluctuations in atmospheric CO(2) concentration, c(a), plants adjust leaf diffusive conductance to CO(2), g(c), via feedback regulation of stomatal aperture as part of a mechanism for optimizing CO(2) uptake with respect to water loss. The operational range of this elaborate control mechanism is determined by the maximum diffusive conductance to CO(2), g(c(max)), which is set by the size (S) and density (number per unit area, D) of stomata on the leaf surface. Here, we show that, in response to long-term exposure to elevated or subambient c(a), plants alter g(c(max)) in the direction of the short-term feedback response of g(c) to c(a) via adjustment of S and D. This adaptive feedback response to c(a), consistent with long-term optimization of leaf gas exchange, was observed in four species spanning a diverse taxonomic range (the lycophyte Selaginella uncinata, the fern Osmunda regalis and the angiosperms Commelina communis and Vicia faba). Furthermore, using direct observation as well as flow cytometry, we observed correlated increases in S, guard cell nucleus size and average apparent 1C DNA amount in epidermal cell nuclei with increasing c(a), suggesting that stomatal and leaf adaptation to c(a) is linked to genome scaling. PMID- 22232766 TI - Genetic manipulation of stomatal density influences stomatal size, plant growth and tolerance to restricted water supply across a growth carbon dioxide gradient. AB - To investigate the impact of manipulating stomatal density, a collection of Arabidopsis epidermal patterning factor (EPF) mutants with an approximately 16 fold range of stomatal densities (approx. 20-325% of that of control plants) were grown at three atmospheric carbon dioxide (CO(2)) concentrations (200, 450 and 1000 ppm), and 30 per cent or 70 per cent soil water content. A strong negative correlation between stomatal size (S) and stomatal density (D) was observed, suggesting that factors that control D also affect S. Under some but not all conditions, mutant plants exhibited abnormal stomatal density responses to CO(2) concentration, suggesting that the EPF signalling pathway may play a role in the environmental adjustment of D. In response to reduced water availability, maximal stomatal conductance was adjusted through reductions in S, rather than D. Plant size negatively correlated with D. For example, at 450 ppm CO(2) EPF2 overexpressing plants, with reduced D, had larger leaves and increased dry weight in comparison with controls. The growth of these plants was also less adversely affected by reduced water availability than plants with higher D, indicating that plants with low D may be well suited to growth under predicted future atmospheric CO(2) environments and/or water-scarce environments. PMID- 22232767 TI - Megacycles of atmospheric carbon dioxide concentration correlate with fossil plant genome size. AB - Tectonic processes drive megacycles of atmospheric carbon dioxide (CO(2)) concentration, c(a), that force large fluctuations in global climate. With a period of several hundred million years, these megacycles have been linked to the evolution of vascular plants, but adaptation at the subcellular scale has been difficult to determine because fossils typically do not preserve this information. Here we show, after accounting for evolutionary relatedness using phylogenetic comparative methods, that plant nuclear genome size (measured as the haploid DNA amount) and the size of stomatal guard cells are correlated across a broad taxonomic range of extant species. This phylogenetic regression was used to estimate the mean genome size of fossil plants from the size of fossil stomata. For the last 400 Myr, spanning almost the full evolutionary history of vascular plants, we found a significant correlation between fossil plant genome size and c(a), modelled independently using geochemical data. The correlation is consistent with selection for stomatal size and genome size by c(a) as plants adapted towards optimal leaf gas exchange under a changing CO(2) regime. Our findings point to the possibility that major episodes of change in c(a) throughout Earth history might have selected for changes in genome size, influencing plant diversification. PMID- 22232768 TI - Evaluating the effects of terrestrial ecosystems, climate and carbon dioxide on weathering over geological time: a global-scale process-based approach. AB - Global weathering of calcium and magnesium silicate rocks provides the long-term sink for atmospheric carbon dioxide (CO(2)) on a timescale of millions of years by causing precipitation of calcium carbonates on the seafloor. Catchment-scale field studies consistently indicate that vegetation increases silicate rock weathering, but incorporating the effects of trees and fungal symbionts into geochemical carbon cycle models has relied upon simple empirical scaling functions. Here, we describe the development and application of a process-based approach to deriving quantitative estimates of weathering by plant roots, associated symbiotic mycorrhizal fungi and climate. Our approach accounts for the influence of terrestrial primary productivity via nutrient uptake on soil chemistry and mineral weathering, driven by simulations using a dynamic global vegetation model coupled to an ocean-atmosphere general circulation model of the Earth's climate. The strategy is successfully validated against observations of weathering in watersheds around the world, indicating that it may have some utility when extrapolated into the past. When applied to a suite of six global simulations from 215 to 50 Ma, we find significantly larger effects over the past 220 Myr relative to the present day. Vegetation and mycorrhizal fungi enhanced climate-driven weathering by a factor of up to 2. Overall, we demonstrate a more realistic process-based treatment of plant fungal-geosphere interactions at the global scale, which constitutes a first step towards developing 'next-generation' geochemical models. PMID- 22232769 TI - Evolution of C4 plants: a new hypothesis for an interaction of CO2 and water relations mediated by plant hydraulics. AB - C(4) photosynthesis has evolved more than 60 times as a carbon-concentrating mechanism to augment the ancestral C(3) photosynthetic pathway. The rate and the efficiency of photosynthesis are greater in the C(4) than C(3) type under atmospheric CO(2) depletion, high light and temperature, suggesting these factors as important selective agents. This hypothesis is consistent with comparative analyses of grasses, which indicate repeated evolutionary transitions from shaded forest to open habitats. However, such environmental transitions also impact strongly on plant-water relations. We hypothesize that excessive demand for water transport associated with low CO(2), high light and temperature would have selected for C(4) photosynthesis not only to increase the efficiency and rate of photosynthesis, but also as a water-conserving mechanism. Our proposal is supported by evidence from the literature and physiological models. The C(4) pathway allows high rates of photosynthesis at low stomatal conductance, even given low atmospheric CO(2). The resultant decrease in transpiration protects the hydraulic system, allowing stomata to remain open and photosynthesis to be sustained for longer under drying atmospheric and soil conditions. The evolution of C(4) photosynthesis therefore simultaneously improved plant carbon and water relations, conferring strong benefits as atmospheric CO(2) declined and ecological demand for water rose. PMID- 22232770 TI - Carbon dioxide and the uneasy interactions of trees and savannah grasses. AB - Savannahs are a mixture of trees and grasses often occurring as alternate states to closed forests. Savannah fires are frequent where grass productivity is high in the wet season. Fires help maintain grassy vegetation where the climate is suitable for woodlands or forests. Saplings in savannahs are particularly vulnerable to topkill of above-ground biomass. Larger trees are more fire resistant and suffer little damage when burnt. Recruitment to large mature tree size classes depends on sapling growth rates to fire-resistant sizes and the time between fires. Carbon dioxide (CO(2)) can influence the growth rate of juvenile plants, thereby affecting tree recruitment and the conversion of open savannahs to woodlands. Trees have increased in many savannahs throughout the world, whereas some humid savannahs are being invaded by forests. CO(2) has been implicated in this woody increase but attribution to global drivers has been controversial where changes in grazing and fire have also occurred. We report on diverse tests of the magnitude of CO(2) effects on both ancient and modern ecosystems with a particular focus on African savannahs. Large increases in trees of mesic savannahs in the region cannot easily be explained by land use change but are consistent with experimental and simulation studies of CO(2) effects. Changes in arid savannahs seem less obviously linked to CO(2) effects and may be driven more by overgrazing. Large-scale shifts in the tree-grass balance in the past and the future need to be better understood. They not only have major impacts on the ecology of grassy ecosystems but also on Earth-atmosphere linkages and the global carbon cycle in ways that are still being discovered. PMID- 22232772 TI - Implementation of a card with instructions for patients treated for thyroid carcinoma with 131I. AB - Patients discharged after their treatment with (131)I can become invisible sources of radiation for some members of the public. Even people who know that those patients have been treated with (131)I can easily forget the radiological risks that they represent. For this reason, it is essential to ensure that patients follow some instructions for a number of days until their remaining activity is low enough to irradiate members of the public under the recommended effective dose limits. Results in this study show that the number of days on which patients have to follow the mentioned instructions shows certain heterogeneity. Therefore, an individualised card with instructions given to patients after being discharged will tell them when they can restart their normal life, guaranteeing that members of the public do not receive an effective dose over the recommended limits. PMID- 22232773 TI - Mammography dosimetry using an in-house developed polymethyl methacrylate phantom. AB - Phantom-based measurements in mammography are well-established for quality assurance (QA) and quality control (QC) procedures involving equipment performance and comparisons of X-ray machines. Polymethyl methacrylate (PMMA) is among the best suitable materials for simulation of the breast. For carrying out QA/QC exercises in India, a mammographic PMMA phantom with engraved slots for keeping thermoluminescence dosemeters (TLD) has been developed. The radiation transmission property of the developed phantom was compared with the commercially available phantoms for verifying its suitability for mammography dosimetry. The breast entrance exposure (BEE), mean glandular dose (MGD), percentage depth dose (PDD), percentage surface dose distribution (PSDD), calibration testing of automatic exposure control (AEC) and density control function of a mammography machine were measured using this phantom. MGD was derived from the measured BEE following two different methodologies and the results were compared. The PDD and PSDD measurements were carried out using LiF: Mg, Cu, P chips. The in-house phantom was found comparable with the commercially available phantoms. The difference in the MGD values derived using two different methods were found in the range of 17.5-32.6 %. Measured depth ranges in the phantom lie between 0.32 and 0.40 cm for 75 % depth dose, 0.73 and 0.92 cm for 50 % depth dose, and 1.54 and 1.78 cm for 25 % depth dose. Higher PSDD value was observed towards chest wall edge side of the phantom, which is due to the orientation of cathode-anode axis along the chest wall to the nipple direction. Results obtained for AEC configuration testing shows that the observed mean optical density (O.D) of the phantom image was 1.59 and O.D difference for every successive increase in thickness of the phantom was within+/-0.15 O.D. Under density control function testing, at -2 and -1 density settings, the variation in film image O.D was within+/-0.15 O.D of the normal density setting '0' and at +2 and +1 density setting, it was observed to be within+/-0.30 O.D. This study indicates that the locally made PMMA TLD slot phantom can be used to measure various mammography QC parameters which are essentially required for better outcomes in mammography. PMID- 22232771 TI - Evolutionary context for understanding and manipulating plant responses to past, present and future atmospheric [CO2]. AB - Variation in atmospheric [CO(2)] is a prominent feature of the environmental history over which vascular plants have evolved. Periods of falling and low [CO(2)] in the palaeo-record appear to have created selective pressure for important adaptations in modern plants. Today, rising [CO(2)] is a key component of anthropogenic global environmental change that will impact plants and the ecosystem goods and services they deliver. Currently, there is limited evidence that natural plant populations have evolved in response to contemporary increases in [CO(2)] in ways that increase plant productivity or fitness, and no evidence for incidental breeding of crop varieties to achieve greater yield enhancement from rising [CO(2)]. Evolutionary responses to elevated [CO(2)] have been studied by applying selection in controlled environments, quantitative genetics and trait based approaches. Findings to date suggest that adaptive changes in plant traits in response to future [CO(2)] will not be consistently observed across species or environments and will not be large in magnitude compared with physiological and ecological responses to future [CO(2)]. This lack of evidence for strong evolutionary effects of elevated [CO(2)] is surprising, given the large effects of elevated [CO(2)] on plant phenotypes. New studies under more stressful, complex environmental conditions associated with climate change may revise this view. Efforts are underway to engineer plants to: (i) overcome the limitations to photosynthesis from today's [CO(2)] and (ii) benefit maximally from future, greater [CO(2)]. Targets range in scale from manipulating the function of a single enzyme (e.g. Rubisco) to adding metabolic pathways from bacteria as well as engineering the structural and functional components necessary for C(4) photosynthesis into C(3) leaves. Successfully improving plant performance will depend on combining the knowledge of the evolutionary context, cellular basis and physiological integration of plant responses to varying [CO(2)]. PMID- 22232775 TI - Radioactivity risk associated with the handling of compact fluorescent lamps. AB - The objective of this work is focused in measuring the level of naturally occurring radionuclides in compact fluorescent lamps commonly used in Egypt. The activity concentration of radionuclides in the (238)U and (232)Th decay chains and from (40)K were determined through gamma-ray spectrometry measurements using high-purity germanium in a low-background configuration. It was found that the activity concentrations ranged from 45 to 198 Bq kg(-1) for (238)U, from 30 to 191 Bqkg(-1) for (232)Th and from 419 to 935 Bq kg(-1) for (40)K. PMID- 22232774 TI - Multidetector CT fluoroscopy and cone-beam CT-guided percutaneous transthoracic biopsy: comparison based on patient doses. AB - In this study, two different techniques used for image-guided percutaneous transthoracic needle biopsy have been compared in terms of patient dose: computed tomography (CT) fluoroscopy (performed on a Toshiba Aquilion 64), supplied with several multidetector CT (MDCT), and cone-beam CT (CBCT) (performed on a Philips Allura Xper FD20), supplied with a few C-arm flat-panel angiographic devices. Dose data (10 patients for each technique) have been collected, and organ doses and effective dose have been evaluated using software packages enabling to simulate real acquisition geometry and X-ray exposure. As a result, higher doses were found for MDCT compared with CBCT: the effective dose is 50% higher for MDCT; ratios between mean organ doses range between 1.2 and 1.7, except for breast (0.9) and oesophagus (3.7). Even though the observed differences are not always statistically significant, the general distribution of organ doses confirms that the MDCT-guiding technique delivers higher dose than the CBCT guided one. PMID- 22232776 TI - Evaluating phantom image quality parameters to optimise patient radiation dose in dental digital radiology. AB - Our objective was to obtain images of a predictable level of quality using an intraoral X-ray system with digital imaging, avoiding patient overexposure. A polymethylmethacrylate (PMMA) physical test phantom was imaged at different exposure times and at various PMMA thicknesses using a dental imaging coupled charge device. Two identical regions of interest (ROIs) were chosen in every image file, and quality was numerically evaluated by measuring high-contrast spatial resolutions, low-contrast thresholds and signal-to-noise ratios. In addition, three practitioners proposed personal quality scores by image inspection. Numerical contents in the ROIs, related to the image quality, were plotted against exposure time. From here, a simple expression linking the exposure time with the thickness to obtain images of comparable quality was deduced. As a result, the optimum exposure time for imaging with a predictable level of quality can be inferred. The potential effect could imply savings above 1000 man Sv, roughly 20 % of the collective dose due to dental imaging, over a population of 1540 millions. PMID- 22232778 TI - The applicability of radiophotoluminescence dosemeter (RPLD) for measuring medical radiation (MR) doses. AB - The applicability of radiophotoluminescence dosimetry was determined by assessing various radiophotoluminescence dosemeter (RPLD) properties for measuring medical radiation doses from radiation sources of a continuous spectrum. The RPLD was found to be accurate for measuring doses in diagnostics (50-125 keV) and radiation therapy (6, 10 and 18 MV photons, 6 and 15 MeV electrons). The RPLD shows excellent dose linearity (R(2) > 0.99), reproducibility and batch uniformity, and minimal fading and accurate accumulated dose measurement. The dosemeter material is independent of photon energy in the diagnostic range; however, the dosemeter requires additional calibration in the mammography energy range and also for accurate dose measurement with photon or electron energies in radiation therapy. RPLD measurements with a tin filter show considerable angular dependence at angles exceeding 50 degrees between the photon beam and the normal to the long axis of the dosemeter. The RPLD measurement accuracy at high doses can be improved with optimised pre-heating schemes. PMID- 22232779 TI - Measurement of radon diffusion length in thin membranes. AB - Building regulations in Israel require the insulating of buildings against radon (222)Rn penetration from soil. In radon-prone areas membranes stretched between the soil and the building foundation are used, together with sealing other possible penetration routes. Designing the radon mitigation procedure requires checking that all sealing materials are practically, radon tight, having a thickness of at least three times the radon diffusion length. In this work, a very simple technique to evaluate the radon diffusion length in thin membranes, using a radon source of known activity and an activated charcoal canister as radon detector is presented. The theoretical formalism and measurement results for polyethylene membranes of different densities obtained in a recent comparison exercise are presented. PMID- 22232780 TI - The use of a figure-of-merit (FOM) for optimisation in digital mammography: a literature review. AB - The use of image quality parameters in digital mammography such as contrast-to noise ratio (CNR), signal-to-noise ratio (SNR) and detective quantum efficiency (DQE) has been widespread, with the intention of detector evaluation and/or quantitative evaluation of the system performance. These parameters are useful in ensuring adequate system performance when tests are done against international standards or guidelines. Parameters like CNR are relative quantities that lie within a range that is manufacturer and system dependent. The use of a figure-of merit (FOM) is a relatively new concept as a tool in digital mammography permitting quantitative assessment in terms of image quality and patient dose. This review summarises the available evidence for the use and applicability of an FOM in digital mammography. PMID- 22232781 TI - Importance of personal dose equivalent evaluation in Fukushima in overcoming social panic. AB - The relationship between the reported ambient dose equivalent (H*(10)) and the individual dose rate recorded by medical staff in Fukushima City after the accident at the Fukushima Daiichi nuclear power plant was evaluated, following a 9.0-magnitude earthquake that struck the east coast of Japan. Personal dose equivalent (H(p)(10)) ranged from 0.08 to 1.63 uSv h(-1) and H*(10) ranged from 0.86 to 12.34 uSv h(-1). H(p)(10) from March to July 2011 were significantly lower than H*(10). The relationships between these dose equivalents were moderately correlated. The regression equation was calculated as follows: H(p)(10)=0.0696*H*(10)+0.0538. The preliminary data of this study show that, in Fukushima, the individual dose is much lower than that determined H*(10). It is important to evaluate H(p)(10) in order to lessen the anxiety of the general population in Fukushima. PMID- 22232783 TI - Cliques must go. PMID- 22232782 TI - Guidelines, peritonitis, and guidelines about peritonitis. PMID- 22232784 TI - [Recommendations of the French Society of Endocrinology for the management of thyroid nodules]. PMID- 22232785 TI - Intrauterine growth restriction, neural microRNA expression and hypertension in the mouse. PMID- 22232786 TI - Placental variability in methylation reflects maternal and fetal pathogenesis. PMID- 22232787 TI - Intrauterine growth restriction disturbs mediators of placental protein turnover. PMID- 22232788 TI - A direct link between MYCN and BMI-1 in neuroblastoma. PMID- 22232789 TI - Could BMI-1 siRNA be a promising tool for cancer therapy? PMID- 22232790 TI - Reactivation of HIV-1 latent reservoir by an inhibitor of H3K9me2 methyl transferase G9a. PMID- 22232791 TI - [Metachromatic Leukodystrophy (MLD): MRI findings]. PMID- 22232792 TI - Methylation of CD44 as a candidate biomarker in lymphomas. PMID- 22232793 TI - Family health: expansion, consolidation and challenges. PMID- 22232794 TI - DNA hypomethylation in a spectrum of plasma cell disorders. PMID- 22232795 TI - [Family health strategy and analysis of the social reality: input for policies for promotion of health and permanent education]. AB - The results of a qualitative study, carried out between 2007 and 2009 in three cities of Greater Florianopolis into the reality of the family health teams are presented. The scope was to investigate if the analysis of social and health reality was conducted and to what extent it contributed to the inclusion of local actions aiming at health promotion (HP) and permanent education (PE). The results showed that HP and PE, respectively, were being confused with disease prevention and ongoing education and were seldom present in the work of the professionals. Also, they revealed an educational and preventive "spirit," with a didactic approach based on unidirectional transmission of content. Social and health reality were not analyzed in depth and in most cases did not create effective actions to promote health, nor were there processes of permanent education. The practices of recording data by the Health Community Agents were merely compliance with a bureaucratic necessity, although healthcare and prevention require actions of an educational nature. The conclusion reached is that permanent education does not exist in these teams and its introduction can contribute to broaden understanding of health promotion practices. PMID- 22232796 TI - [Multimodal imaging in Pheochromocytoma]. PMID- 22232797 TI - Legalise assisted suicide, UK Commission urges. PMID- 22232798 TI - Haiti prepares for cholera vaccination but concerns remain. PMID- 22232799 TI - Prescription drug addiction: the treatment challenge. PMID- 22232800 TI - The rise, fall, and revival of recovery in drug policy. PMID- 22232801 TI - Poster abstracts for the BASO ~ The Association for Cancer Surgery Scientific Conference 7th and 8th November 2011. PMID- 22232802 TI - The great divide in cancer care continues to fail Aborigines. PMID- 22232803 TI - Bitumens and bitumen emissions, and some heterocyclic polycyclic aromatic hydrocarbons. PMID- 22232804 TI - Till death do us part. PMID- 22232805 TI - Nine letters. PMID- 22232806 TI - Long-term health benefits of appetite suppressants remain unproven. AB - Because of the increasing prevalence of obesity, prevention and treatment of overweight has become a major public health concern. In addition to diet and exercise, drugs are needed for patients who failed to lose weight with behavioral treatment. The current article aimed to summarize recent concerns on the safety and efficacy of appetite suppressants. Several appetite suppressants have been banned for safety reasons. In 2010, sibutramine was withdrawn from the market because a long-term study showed it increased the risks of cardiovascular events. So far no study with a sufficiently large sample size has demonstrated that appetite suppressants can reduce morbidity and mortality associated with overweight. The withdrawal of sibutramine highlights that guidelines for the evaluation of weight control drugs must be more stringent, and studies on their long-term health benefits are needed prior to their marketing. PMID- 22232807 TI - Erratic control of breathing during exercise in patients with systemic lupus erythematosus: a pilot-study. AB - PURPOSE: The aim of this study was to provide a comprehensive evaluation of the pattern and timing of breathing during incremental exercise in a sample of women living with systemic lupus erythematosus (SLE). METHODS: In this cross-sectional study, 20 women with SLE without pulmonary involvement were compared with 20 gender-, body mass index- (BMI), and age-matched healthy individuals. By using a cardiopulmonary incremental exercise test, the following parameters were assessed: tidal volume (VT); breathing frequency (BF); total respiratory time (TOT); inspiratory time (TI); expiratory time (TE); inspiratory time to total time (TI/TOT); mean inspiratory flow (VT/TI); ventilatory equivalent for carbon dioxide (VE/VCO2) and end-tidal carbon dioxide pressure (PETCO2). RESULTS: BF and BF/VT were significantly higher in patients with SLE versus controls, whereas VT, TE, TI and TOT were significantly lower in the former group ( p<0.05). Additionally, patients with SLE presented higher VE/VCO2 and lower PETCO2 than controls ( p<0.05), suggesting a ventilatory inefficiency. CONCLUSION: We reported compelling evidence of abnormal pattern and timing of breathing during incremental exercise in SLE. Considering that an erratic control of breathing may play an important role in exercise intolerance and fatigue, respiratory exercises emerge as a potential treatment for these symptoms in patients with SLE. PMID- 22232808 TI - Endometriosis as an epigenetic disease. PMID- 22232809 TI - Epigenetic events in endometrial tumorigenesis. PMID- 22232810 TI - Biological significance of DNA methylation patterns in human progenitor cells. PMID- 22232811 TI - Induced pluripotent stem cells derived from liver disease patients can differentiate into functional hepatocytes. PMID- 22232812 TI - Natalizumab: infections, hypersensitivity, etc. PMID- 22232813 TI - Neuroleptics: monitor newborns exposed in utero. PMID- 22232814 TI - Refuse gifts, starting at university. PMID- 22232816 TI - Global botanical networks, political economy, and environmental discourses in cinchona transplantation to British India. PMID- 22232815 TI - Comparison of percutaneous screw fixation and calcium sulfate cement grafting versus open treatment of displaced intra-articular calcaneal fractures. AB - BACKGROUND: The conventional treatment for displaced intraarticular fractures of the calcaneus (DIACF), with open reduction and internal plate fixation (ORIF), carries the risk of wound infection and delayed recovery. Alternatively percutaneous fixation techniques offer the possibility of equivalent outcomes in with a reduction in soft tissue complications. The goal of the present study was to evaluate the outcome of percutaneous reduction (PR), screw fixation, and calcium sulphate cement (CSC) grafting in the treatment of DIACF. METHODS: Ninety patients were randomly assigned to PR and CSC grafting or ORIF between January 2006 and August 2008. The blood loss, Bohler's angle, calcaneal width, length, height and articular congruity of the posterior facet, wound complication, range of joint motion were compared, function scores such as American Orthopaedic Foot and Ankle Society score (AOFAS) and Maryland foot score (MFS) were measured. RESULTS: The quality of reduction was not significantly different between the two groups. There were significant differences favoring PR in blood loss (p < 0.01), range of joint motion (p < 0.01), AOFAS (p < 0.01) and MFS (p < 0.01) between the two groups. Postop infection was 12% ORIF and 3% PC (p = 0.23). Earlier weightbearing in the PR group did not result in a greater frequency of redisplacement than in the OR group. CONCLUSION: Our results indicate that compared with ORIF, the percutaneous reduction, fixation and CSC grafting for treatment of DIACF might allow accelerated weightbearing activity, reduce joint stiffness and improve the patients' satisfaction. PMID- 22232817 TI - Gene mapping in marsupials and monotremes. II. Assignments to the X chromosome of dasyurid marsupials. AB - Somatic cell hybrids have been obtained between HPRT Chinese hamster cells and cells from several dasyurid marsupial species. These hybrids show the extensive loss of marsupial chromosomes characteristic of the majority of marsupial eutherian somatic cell hybrids. Although all of the hybrids expressed the selected marsupial marker, HPRT, the only other markers observed were PGK, GLA, and G6PD, consistent with the conservation of X-linked genes extending to this major group of marsupials. Counterselection confirmed the synteny of PGK and GLA with HPRT, whereas G6PD showed decreased concordance. PMID- 22232818 TI - The Basel Declaration: a critical appraisal. PMID- 22232819 TI - [History, illness, and medicine in West Africa, 19th-20th centuries]. PMID- 22232821 TI - [Charity-based education in France: expansion and the crisis of adaptation from the mid-17th to the end of the 18th century]. PMID- 22232822 TI - [The old repressive Guinean systems and the introduction of the colonial prison]. PMID- 22232823 TI - [Students, tuberculosis, and the sanatorium from the Liberation through the 1950's]. PMID- 22232825 TI - [Mastering nature: a colonial wager. Botany and agronomy in Guiana and the Antilles in the 17th and 18th centuries]. PMID- 22232824 TI - [The state and physical and sports activities from the 1780's to the 1930's]. PMID- 22232826 TI - Acne treatments come out a wash. PMID- 22232827 TI - Fish-oil pills vs. claims. PMID- 22232828 TI - Top 10 heatlh tips for 2012. PMID- 22232829 TI - Most men don't need routine PSA tests. PMID- 22232830 TI - Arsenic in your juice: how much is too much? Federal limits don't exist. PMID- 22232831 TI - [Abstracts of the 16th French-speaking Pneumology Congress. January 27-29, 2012. Lyon, France]. PMID- 22232832 TI - [Senegal: the health of inmates in colonial prisons]. PMID- 22232833 TI - [Senegal: the imprisonment of women from the colonial period to the present]. PMID- 22232834 TI - [Senegal: a penitentiary system in crisis: actors and issues of the current debates]. PMID- 22232835 TI - [Lineage strategies and the occupation of space: the case of Adangbe migrants in the Akposso lands of Togo]. PMID- 22232837 TI - [An index of de-Christianization? The evolution of meat consumption during Lent in Paris under the Old Regime]. PMID- 22232838 TI - [A model of urban scenography: the example of the Burgundian Netherlands in the 15th century]. PMID- 22232839 TI - [Families with Austrian origins in Romanian society in the 19th and 20th centuries]. PMID- 22232840 TI - [Health problems of the Piedmontese expeditionary corps during the Crimean War]. PMID- 22232841 TI - [Maria Montessori: a woman of science]. PMID- 22232842 TI - ["Various and magnificent aggregations of buildings": hypotheses and projects for Piazza del Duomo in Milan in the first half of the 19th century]. PMID- 22232843 TI - [Total systemic management for poisoning]. PMID- 22232845 TI - [Cultivate human resources capable of bearing psychiatric care for children at general hospitals--wishes for the revitalization plan of the community health care]. PMID- 22232846 TI - [Mental care and relief support for victims of the earthquake occurred in eastern part of Japan]. PMID- 22232844 TI - [Survey of the current conditions in acute poisoning due to antispasmodic agents- special reference to eperisone hydrochloride and afloqualone]. PMID- 22232847 TI - Pharmacokinetics and bioequivalence study of two digoxin formulations after single-dose administration in healthy Chinese male volunteers. AB - The pharmacokinetics and relative bioavailability/bioequivalence of two formulations of digoxin (CAS 20830-75-5) were assessed in this paper. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single-blind, 2-way crossover study design with a wash-out phase of 14 days. Blood samples for pharmacokinetic profiling were taken up to 72 h post dose and digoxin plasma concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LCMS/MS) method. Based on the plasma concentration-time data of each individual during two periods, pharmacokinetic parameters, Cmax, AUC0-tau, AUC0-infinity and t1/2, were calculated by applying noncompartmental analysis. Pharmacokinetic data for test and reference formulations were analyzed statistically to evaluate bioequivalence of the two formulations. After oral administration, the values of Cmax Tmax, t1/2, AUC0-tau, AUC0-infinity for test and reference formulations were 2.61 +/- 0.98 and 2.68 +/- 1.09 ng/ mL, 1.0 +/- 0.4 and 1.0 +/- 0.4 h, 27.94 +/- 3.14 and 27.56 +/- 3.86 h, 28.57 +/- 4.99 and 28.77 +/- 6.53 ng x h/mL, 33.44 +/- 4.85 and 33.63 +/- 7.57 ng x h/mL, respectively. Both primary target parameters, AUC0-infinity and AUC0-tau, were tested parametrically by analysis of variance (ANOVA). Relative bioavailabilities were 102.5 +/- 19.2% for AUC0-infinity, 102.0 +/- 19.3% for AUC0-tau. Bioequivalence between test and reference formulations was demonstrated for both parameters, AUC0-infinity and AUC0-tau. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%, which means that the test formulation is bioequivalent to the reference formulation of digoxin. PMID- 22232848 TI - Effect of Lactobacillus sporogenes on oral isoflavones bioavailability: single dose pharmacokinetic study in menopausal women. AB - PURPOSE OF THE STUDY: To verify the single dose bioavailability of two oral formulations of soy isoflavones, with and without lactobacilli, in menopausal women in antibiotic therapy. METHODS: Twelve menopause women (mean age 54.3 years, BMI 25.0 kg/m2) participated in a controlled cross-over study. Reference and test treatments were: R = tablets containing soy isoflavones 60 mg (genistin 30 mg + daidzin 30 mg) + calcium and vitamin D3; E = R + 500 million vital spores of Lactobacillus sporogenes (E is Estromineral, a food supplement containing soy isoflavones 60 mg, calcium 141 mg and vitamin D3 5 microg). The design included 2 periods of 5 days of amoxicillin + clavulanate treatment with a 2-week wash-out. After each period alternatively a single dose of each formulation was given in randomised sequence. Genistein and daidzein were determined in plasma by HPLC, sampled 10 times within 24 h after dosing. RESULTS: Genistein pharmacokinetics parameters were higher after E than after R administration: peak plasma concentration (Cmax) +24.3%, area under the concentration curve (AUC0-24) +24.4% and mean residence time +11.0%. Daidzein Cmax and AUC showed a larger variability on R, evidenced by higher scatter from the mean on the formulation without lactobacilli. CONCLUSION: A trend is shown for a greater absorption of genistein from a formulation containing lactobacilli. PMID- 22232849 TI - Bioequivalence studies of film-coated tablet and chewable tablet generic formulations of montelukast in healthy volunteers. AB - Two studies were conducted in order to assess the bioequivalence of montelukast (CAS 151767-02-1) 10 mg film-coated tablet (FCT) and 5 mg chewable tablet (CT) test formulations in comparison with the original brands. Under fasting conditions, healthy male and female volunteers received one 10 mg FCT or 5 mg CT orally as a single dose of a test or reference formulation. Both studies were designed as open-label, randomized, two-period, two-sequence, crossover studies with a 7-day washout interval. Plasma samples were collected up to 24 h after drug administration and montelukast levels were determined by a validated LC/ MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental analysis and were statistically compared by analysis of variance for test and reference formulation. Bioequivalence between products was determined by calculating 90% confidence interval of the ratio test/reference of least-square means of logarithmically transformed Cmax and AUC0-t parameters. AUC0-infinity was also analysed to obtain additional information. The calculated 90% confidence intervals for the ratios of Cmax and AUC0-t parameters were 89.33-110.52 and 92.06-109.46, respectively, in the FCT study, and 91.58-101.86 and 92.15-98.83, respectively, in the CT study, which are all within the bioequivalence acceptance range of 80-125%. Based on the results, it can be concluded that the evaluated test FCT and CT formulations are bioequivalent to their respective reference formulation in terms of rate and extent of absorption. PMID- 22232850 TI - Pharmacokinetic and bioequivalence study of etoricoxib tablet in healthy Bangladeshi volunteers. AB - The aim of this study was to compare the pharmacokinetic properties of two etoricoxib (CAS 202409-33-4) 60 mg formulations, namely Etocox-60 (test product) and reference product, and to evaluate whether these two formulations meet the FDA criteria to assume bioequivalence. Twenty-four healthy volunteers were enrolled into this randomized, single-dose, 2-way crossover, open-label pharmacokinetic study. Subjects were randomly assigned to receive the test formulation followed by the reference formulation or vice versa as a single dose of 60 mg tablets after 12 h overnight fasting, with a washout period of two weeks. Following oral administration, blood samples were collected at 0 (baseline), 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0, and 120.0 h. Serum concentration of etoricoxib was assessed using a high performance liquid chromatographic-UV spectrometry procedure. The pharmacokinetic parameters were determined by the non-compartmental method. After administering a single dose of 60 mg of each etoricoxib formulation, the obtained mean (SD) values for the test and reference products were 1.26 (0.33) and 1.29 (0.35) microg/ml for Cmax; 3.25 (2.64) and 2.63 (1.40) h for t(max); 29.63 (8.31) and 30.40 (5.85) h x microg/ml for AUC0-120; and 31.84 (10.97) and 33.00 (8.10) h x microg/ml for AUC0-infinity, respectively. The mean t1/2 was found 27.99 (7.87) h and 29.84 (7.93) h for test and reference product respectively. From paired t test, no significant differences were observed (p > 0.05) for any pharmacokinetic parameters. After analysis of variance, no period, sequence or formulation effects were observed for any pharmacokinetic property. The 90% confidence intervals of the test/reference mean ratios of the 1n-transformed AUC0-120, AUC0 infinity and Cmax mean values were 95.90% (85.37%-107.74 %), 94.69% (84.43% 106.20%) and 97.87% (85.54 %-111.98 %), respectively, which fell within the predetermined FDA bioequivalence range of 80%-125%. This single-dose study found that the test and reference formulations of etoricoxib met the regulatory criteria for bioequivalence in terms of both rate and extent of absorption. PMID- 22232851 TI - Effects of the multidrug resistance modulator HZ08 on the apoptosis pathway in human chronic leukaemia cell line K562/A02. AB - oancer falls to respond to chemotherapy by acquiring multidrug resistance in over 90% of patients. A previous study revealed that multidrug resistance modulator HZ08 had great multidrug resistance reversal effect in vitro and in vivo. It could enhance adriamycin (doxorubicin) induced intrinsic apoptosis pathway and rectify cell cycle and some apoptosis related proteins in human breast resistant cancer MCF-7/ADM cells. This study detected Rh123 accumulation to assess the effect of HZ08 on P-glycoprotein function in human chronic leukaemia cell line K562/A02. Moreover, mitochondria membrane potential, cytochrome c release and caspase-3 activity were analyzed for HZ08 treatment with or without vincristine. Since pretreatment with HZ08 could also reverse the multidrug resistance to vincristine in K562/A02 cells, the individual influence of HZ08 was further detected on apoptotic regulator like Bcl-2, Bax, p53, cell cycle checkpoints and proliferation regulatory factors like survivin, hTERT, c-Myc, c-Fos, c-Jun. Finally, it revealed that HZ08 increased vincristine induced activation in intrinsic apoptosis pathway by inhibition of P-gp mediated efflux. In addition, the outstanding reversal effect of HZ08 should also attribute to its individual effect on apoptosis and proliferation related regulatory factors. It renders HZ08 possibility of application in pretreatment to reverse multidrug resistance while avoiding unexpected drug interactions and accumulative toxicity. PMID- 22232852 TI - [Should influenza vaccine be compulsory for medical staff?]. PMID- 22232853 TI - [Headaches, five expert opinions: the pitfalls involved in the diagnosis of giant cell arteritis]. AB - Giant cell arteritis (GCA) (or Horton's disease) is a systemic disease affecting the vessels of medium and large sizes. The incidence increases with age (the disease develops rarely before age 50) and the etiology remains unknown. Clinical manifestations may vary (including asthenia, temporal headache, visual disturbances, etc.) and GCA can potentially lead to dramatic consequences (permanent loss of vision). Although some anomalies in the investigations may help in the diagnosis of GCA, research and confirmation of the diagnosis of GCA may be difficult, especially when the symptoms presented by patients are spread out in time and appear to be nonspecific at first. PMID- 22232854 TI - [Vitamin D: update and recommendations]. AB - The number of studies related to vitamin D has increased exponentially in recent years and it becomes difficult to integrate these data into daily practice. This article focuses on the practice by offering an overview on screening, needs, treatment and consequences of deficiency. While in some areas, a consensus seems to emerge, other issues still require a lot of research in order to have an impact on practice. Independently of the threshold values we use, there is an increased prevalence, which makes vitamin D deficiency the most common and also the most underdiagnosed deficiency. Vitamin D is like a marker of good health and a marker of the evolution of our society. How can be used this marker by the practitioner? PMID- 22232855 TI - [Smoking, obesity and diabetes: a clinically important interaction]. AB - Smoking, obesity and diabetes are among the leading cause of premature death worldwide. Smokers have globally a lower body weight compared with non smokers but they tend to accumulate more fat in the abdomen. Most smokers gain weight when they quit smoking, however this does not seem to diminish the health benefits associated with smoking cessation. Smoking increases the risk of developing type 2 diabetes. Among people with diabetes, smoking significantly increases the risks of complications and mortality. Interventions with pharmacologic help should be offered to all smokers, with or without diabetes, in order to increase smoking cessation rates and limit weight gain. PMID- 22232856 TI - [Acute low back pain in general practice medicine]. AB - The practioner's first concern is knowing how to single out from the immense majority of situations susceptible to a favourable spontaneous evolution those patients with a bad prognostic necessitating reference to a specialist. We present in this paper the clinical steps designed to meet this challenge and a reminder of certain principles of patient diagnosis and care. PMID- 22232857 TI - [Hiking and useful advices to patients (part 1)]. AB - The attraction of walking as a pastime has grown enormously in Switzerland over the past few years. Synonym of health and well-being, this activity carries some risks which more and more patients are questioning; answering these questions is not always obvious, so we wanted to tackle the subject. Risks linked to certain animals will be covered. One of these risks is insect stings, particularly wasps and bees. This is a major problem which affects the whole population and more seriously those who are allergic, accounting for around 5% of the population. Another problem: snake bites. In Switzerland, there are about 20-25 bites each year. Poisoning from these can be divided into two categories: local or systemic. The effects are multiple and diverse, ranging from renal failure to discrasia to hypovolemic shock. Pre-hospitalisation measures are of paramount importance in the treatment. PMID- 22232858 TI - [Hiking and useful advices to patients: part II]. AB - The attraction of walking as a pastime has grown enormously in Switzerland over the past few years. Synonym of health and wellbeing, this activity carries some risks which more and more patients are questioning; answering these questions is not always obvious, so we wanted to tackle the subject. This second section concerns risks linked to food which can be found in the forest. Echinococcosis is an underestimated parasite which affects a large proportion of foxes in Switzerland. This infectious disease can also affect man following contamination which usually occurs through eating berries. Prevention is the most effective way to avoid poisoning by mushrooms. In case of poisoning, the physician must try and determine the toxidrome. The key element is the length of time before symptoms develop. Treatment is always symptomatic, using activated charcoal. PMID- 22232859 TI - [Interprofessional education for all... An awareness experience for undergraduate students in Vaud]. PMID- 22232860 TI - [Myocardial infarction and adult stem cells]. PMID- 22232861 TI - [On Telethon and imprecations]. PMID- 22232863 TI - [Perfect health]. PMID- 22232862 TI - [At the time when wines could be medoc]. PMID- 22232864 TI - Ballistic injuries in the emergency department. AB - According to 2007 data, gunshot wounds from homicides, suicides, and accidents caused 31,000 deaths in the United States, with even higher numbers of serious, nonfatal injuries. In recent years, new evidence on effective treatment of patients with gunshot wounds has come from military settings and is being adapted for civilian emergency departments (EDs). Effective, evidence-based management of ballistic injuries in the ED is vital. This issue reviews the physics of ballistics as it relates to the tracts and patterns of tissue injury caused by different types of firearms and missiles, and it takes a regional approach to reviewing the current evidence for managing gunshot wounds to the head, neck, thorax, abdomen, genitourinary (GU) system, extremities, and soft tissues. Current guidelines as well as new research and evidence regarding fluid resuscitation, airway management, evaluation strategies, drug therapies, and documentation are discussed. PMID- 22232865 TI - [Between quality, prostate, and surgery]. PMID- 22232866 TI - [Quality assessment in urology]. AB - Quality control (QuaCo) in urology is mandatory to standardize or even increase the level of care. While QuaCo is undertaken at every step in the clinical pathway, it should focus on the patient's comorbidities and on the urologist and its complication rate. Resulting from political and economical pressures, comparing QuaCo and outcomes between urologists and institutions is nowadays often performed. However, careful interpretation of these comparisons is mandatory to avoid potential discriminations. Indeed, the reader has to make sure that patients groups and surgical techniques are comparable, definitions of complications are similar, classification of complications is standardized, and finally that the methodology in collecting data is irreproachable. PMID- 22232867 TI - [Active surveillance in prostate cancer]. AB - Active surveillance in prostate cancer The spread of PSA in the screening of prostate cancer has almost doubled the incidence of this disease in the last twenty years. An improved understanding of the natural history of this cancer allows for risk stratification of the disease and to better predict insignificant prostate cancer. Active surveillance has recently been proposed as a new option to delay or avoid a radical treatment for patients with low-risk disease. The principle, results and future perspectives of this treatment modality are discussed in this review. PMID- 22232868 TI - [Should we prescribe phosphodiesterase inhibitors for the treatment of symptomatic benign prostatic hyperplasia]. AB - This October, the FDA has approved the use of phosphodiesterase inhibitors for the treatment of micurition symptoms due to benign prostatic hyperplasia, so as for erectile dysfunction. This decision is essentially based on the results of 2 studies that we discuss in this article. Although methodologically well designed, these works show that phosphodiesterase inhibitors decrease only weakly, but statistically sigificatively the micturition score of patients suffering from prostatism. Besides that, only one of these papers show a limited effect on a single objective micturitionnal parameter. According to the present knowledge, it appears judicious to prescribe tadalafil to treat benign prostatic hyperplasia symptoms of patients suffering simultaneously of a significant erectile dysfunction. PMID- 22232869 TI - [Testosterone and prostate]. AB - Age related testosterone deficiency syndrome may occur with other diseases of the elderly men, as prostate diseases. The relationship between testosterone and prostate has been widely studied the last 10 years, with the increased use of testosterone replacement therapy. The traditional belief that testosterone administration causes prostate cancer growth has been challenged by recent studies. To date, nothing has been found to support the evidence that restoring testosterone levels within physiological range increases the incidence of prostate cancer in hypogonadic patients. In these patients, testosterone replacement therapy does not seem to worsen lower urinary tract symptoms. PMID- 22232870 TI - [Testicular torsion: a tricky diagnosis]. AB - In common urological practice, testicular torsion is one of the most serious emergencies. Consequences can be devastating for the patient, both physically and psychologically. The primary care physician should be able to quickly identify the pathology and refer immediately the patient to a center with surgical facilities. Rapid diagnosis provides the best chances to save the patient's testicle, which may suffer irreversible damage as soon as 6 hours after the onset of the symptoms. History and clinical examination remain the cornerstones of the diagnosis, and are often sufficient to select patients who need surgical exploration. If time allows it, Doppler Ultrasound can often help distinguish torsion from other scrotal conditions, but cannot be considered as a 100% diagnostic tool. PMID- 22232871 TI - [Robotic partial nephrectomy: development and advantages]. AB - Surgery is the first line of treatment of renal cell carcinoma. For small tumours confined to the kidney (< or = 4 cm), partial tumour resection has logically become the standard treatment. When technically feasible, partial nephrectomy may be applied to treat tumors less than 7 cm, according to 2010 recommendations of the European Association of Urology. In addition, nephron-sparing surgery has proven to positively impact on quality of life. Robotic-assisted laparoscopy partial kidney resection has recently emerged. Its indications are as yet undergoing validation, while open surgery still remains the gold standard. For the patients, the consequences of this minimally invasive evolution are evident: The comfort and postoperative recovery are respectively greater and faster compared to conventional open surgery. PMID- 22232872 TI - [The inside story of thermal cures]. PMID- 22232873 TI - [AIDS: is it really the beginning of the end?]. PMID- 22232874 TI - [But, how can one be a psychiatry expert in France?]. PMID- 22232875 TI - [On veal stock and positivism]. PMID- 22232876 TI - [The childhood of a long-lived person]. PMID- 22232877 TI - [Carotenoids. Biological activities]. AB - The review provides data on the biological activities of the most prevalent carotenoids. Special attention is paid to theirs anticancer and antiatherogenic properties, immunomodulating action, cardioprotective, radioprotective and photoprotective effects. PMID- 22232878 TI - [Influence high-fat ration on plasma and erythrocyte lipids fatty acids of rats]. AB - Study character of the redistribution of fatty acids between the lipid fraction of plasma and erythrocytes in rats with prolonged high-fat diet (30, 90, 180 days). Shown that at long high-fat rations in the lipids of erythrocytes decreasing pool polyunsaturated fatty acids (oleic, dihomo-gamma-linoleic, eicosapentaenoic, arachidonic), increases of saturated fatty acids (myristic, stearic) levels. In lipids fractions of plasma revealed the opposite direction of changes in the level of the fatty acids: the accumulation of essential polyunsaturated fatty acids, reduction of saturated fatty acids. Supposedly, that high-fat diet promotes de novo compensatory synthesis of polyunsaturated fatty acids, but disturbed apoB-100 receptor-mediated active transport of fatty acids with low-density lipoproteins (LDL), synthesized in the liver fatty acids is not captured by the cells peripheral organs. Marker of the apoB-100 receptor breach of transfer low-density lipoprotein, transporting polyunsaturated fatty acids was to increase LDL cholesterol in serum. PMID- 22232879 TI - [Sanitary and epidemiological examination of foods under carrying sanitary and epidemiological surveillance on the customer border and at in the territory of the Customers Union]. AB - The article concerns peculiarities of sanitary and epidemiological and hygienic examination of foods under carrying of sanitary-epidemiologic surveillance on the customer border and of the custom territory of the Customers Union of the Russian Federation, Kazakhstan and Byelorussia. PMID- 22232880 TI - [Rated power of conscripts in the north]. AB - The nutrition on alimentary and power value in the term active duty soldier on the North on norm No 1 (troop ration) approaches to calculated sizes (with the exception of fat deficiency) that allows to support the physical working capacity and the body mass index on high enough level. However insufficient content of vitamins (polyhypovitaminosis) in organisms of most of studied persons was revealed. The dynamics of change of nutrition status in the soldiers on the North during year shows essential dependence on the weather rigidity parameters and the seasonal factor. PMID- 22232881 TI - [Zero valent seleniume nanoparticles bioavailability estimation in rats]. AB - Bioavailability of zero valent selenium (Se) nanoparticles with average size 60 nm was measured in rats receiving selenium deficient diet. There was demonstrated that intragastric administration of Se nanoparticles resulted in dose-dependent increase of serum Se level, normalization of tissue thiol pools, immune status and hepatocytes apoptosis. Possibilities are discussed of Se nanoparticles use in nutrition as a source of this trace element. PMID- 22232882 TI - [Influence of freezing and storage on food value of berries of the red currant]. AB - The red currant is perspective culture for use in industry functional pectin foodstuff. Freezing use as an effective way of conservation, allows to keep as much as possible vitamin properties of raw materials within all year and to expand assortment of fruit production. PMID- 22232883 TI - [Effectiveness of use in preventive nutrition the food ptoducts with contents of pectin and vitamins]. AB - Daily inclusion in the diet of Pskov GRES workers the drinks or kissels containing 2 g pectin per daily serving (cup) during 6 months was accompanied by a statistically significant decline of their supply with vitamins C, B2, A and beta-carotene. This is reflected both in reducing the average vitamin concentration in blood serum and in the increase of the quota of people with deficiency of several vitamins. Additional inclusion of 13 vitamins in these drinks and kissels, in a dose about 80% of the RDA, has prevented the deterioration of vitamin status. PMID- 22232884 TI - [The effect of various levels of chitosan in rat diet on vitamins assimilation under their combined deficiency]. AB - he effect of chitosan inclusion in the semi-synthetic diet of rats at a dose of 0,24 and 0,9% of dry weight on vitamin assimilation under combined moderate and deep deficiency has been studied. Four-week introduction of chitosan did not have a significant effect on levels of vitamins C, B1, B2 and A in the liver of animals, on vitamin B2 blood plasma concentration and thiamine and riboflavin urinary excretion regardless of the degree of vitamin deficiency intensity. The significantly decrease of vitamin E blood plasma concentration has been observed at high dose of chitosan in the diet under moderate vitamin deficiency, whereas under deep deficit such reduction has been detected even at a low dose. Thus, long-term chitosan inclusion in the diet under existing polyhypovitaminosis can lead to the deterioration of the sufficiency with fat-soluble vitamins. PMID- 22232885 TI - [Influence of hypocaloric diet with addition of a vitamin-mineral complex on status of patients with obesity 1st and 2nd degrees]. AB - Addition of a vitamin-mineral complex (VMC) to a standard hypocaloric diet leads to a positive dynamics of antropometric characteristics in patients with obesity 1st and 2nd degrees which is comparable to effectiveness of standard dietotherapy (dietary treatment) traditionally used in complex treatment of obesity. Addition of 1,8 mg of vitamin B2 as part of VMC to a hypocaloric diet is shown to be inadequate in eradication of marginal provision of riboflavin when using diets reduced in calories. PMID- 22232886 TI - [Major risk factors of glucose metabolism abnormalities]. AB - Using the data of population base study of adult residents of 2 districts of Moscow Region (2638 persons), prevalence is studied and influence on occurrence of glucose metabolism abnormalities of major risk factors is estimated. Influence of risk factors was estimated with Cox regression analyses. High prevalence undiagnosed glucose metabolism abnormalities among persons (24,9%) is taped; it is established that relative risk of diabetes mellitus type 2 significantly raised at persons is more than 50 years of age independently of BMI, at the same time first-degree obesity increased relative risk of diabetes mellitus type 2 in 4,3 times and third-degree obesity--in 9,0 times independently of age. PMID- 22232887 TI - [Breast hormones--regulators of energy homeostasis: growth of infants]. AB - Studied the possible relationship between the growth rate of children who are breastfed, and the level of protein, fat, insulin-like growth factor- 1 (IGF-1), ghrelin, leptin, adiponectin in breast milk. Examined 71 pair--a mother and a healthy child, who is breastfed. All infants were divided into 3 groups: low, normal and high weight gain. Daily breast milk intake, the level of fat, protein and hormones proteins regulators of energy homeostasis (adiponectin, grelin, IGF 1 and leptin) in breast milk were measured at 1, 2 and 3 months of lactation. It was found that daily breast milk consumption was higher in the group of infants with high weight gain and the content of protein and fat in it did not differ in three groups. Total daily consumption of protein and fat with breast milk was higher in groups of infants with high weight gain. There was significantly higher IGF-1 level and the tendency to higher grelin level in breast milk of mothers of infants with higher weight gain. The possible link of breast milk hormones with growth velocity of breast-fed infants is discussed. PMID- 22232888 TI - [Development of methods for determining acrylamide in food products by gas-liquid chromatography]. AB - The method of determination of acrylamide in various food (milk powder, potato chips, instant coffee) by gas-liquid chromatography after pre-bromination was developed. Studies have shown the possibility of using bromination of acrylamide to give it the necessary properties for better extraction, purification and detection. Also revealed the possibility of qualitative and quantitative determine a acrylamide in food by gas-liquid chromatography with detection by electron capture detector. PMID- 22232889 TI - [Quantitative determination of soya protein in canned meat indirect immune-enzyme a method]. AB - Description of sample preparation of bully, immune-enzyme analysis procedure and mathematical treatment of obtained results are presented. Metrological characteristics of the method are determined. PMID- 22232890 TI - [Inhibitors of proteolytic enzymes under abiotic stresses in plants (review)]. AB - Data on the role of proteolytic enzyme inhibitors in plant adaptation to various unfavorable environmental abiotic factors--water deficiency, salinization of soil, extreme temperatures, etc.--and also probable functions of proteinases inhibitors in natural plant senescense are considered. PMID- 22232891 TI - [Aerobic degradation of ethylenediaminetetraacetate (review)]. AB - Literature data on the influence of complexing compound ethylenediaminetetraacetate (EDTA) on environmental and ecological risks related with its application were analyzed and summarized. Methods of abiotic and biotic degradation of EDTA were systemized. Special attention was paid to microbiological degradation of EDTA was paid. Data on EDTA transport and metabolism pathways in aerobic bacteria are represented. The practical aspects of application of aerobic bacteria-destructors of EDTA in ecobiotechnology were discussed. PMID- 22232892 TI - [High-efficient renaturation of immobilized recombinant C-terminal fragment of human alpha-fetoprotein]. AB - C-terminal fragment of a human oncofetal alpha-fetoprotein (AFP) may be used in targeted cytostatics delivery to malignant cells of many tumors. AFP fragment (from 404 to 595 amino acids residues of a full-sized protein) was cloned and produced in Escherichia coli cells, BL21 strain (DE3) in the form of inclusion bodies. To obtain a functionally active protein, is it necessary to renature the protein. The renaturation procedure of the AFP third domain (rAFP3D) is considerably complicated by the fact that the protein is hydrophobic and contains a large number of S-S bonds. A renaturation technique of rAFP3D immobilized on silicic metal chelate resin has been developed. The yield of renatured C-terminal fragment was no less than 60% with purity on the order of 98%. The developed technique has been applied for the first time for hydrophobic protein with a large number of S-S bonds. The approach can be applied for efficient renaturation of other hydrophobic proteins with a large number of disulfide bonds for scientific and practical purposes. PMID- 22232893 TI - [Effect of triterpenoid glycosides on alpha- and beta-amylase activity and total protein content in wheat seedlings]. AB - Influence of the aleanolic acid glycosides from Silphium perfoliatum L. (silphioside B, C, E and G) and their progenins on the amylase activity and total protein content in wheat seedlings was studied. Treatment of the Triticum aestivum L. seeds with 1-10 microM water solutions of mono- and diglycosides (mono- and bisdesmosines) elevated the alpha-amylase and total amylase activities in seedlings. Silphioside E containing three glucose moieties in its molecule did not change alpha-amylase activity, but it did if bis-triglycoside acetylated carbohydrate (as in silphioside C). Effects of 5-10 microM solutions of the active glycosides was comparable with that of exogenous gibberellin A3 and 6 benzylaminopurine. PMID- 22232894 TI - Changes in gene transcription and protein expression involved in the response of Agrobacterium sp. ATCC 31749 to nitrogen availability during curdlan production. AB - The changes in transcription of genes involved in nitrogen metabolism and curdlan biosynthesis, and total protein expression were firstly analyzed to define the responses of Agrobacterium sp. ATCC 31749 to nitrogen source availability during curdlan fermentation. The transcription of all nitrogen metabolism and regulation genes increased significantly under nitrogen limitation. The genes of carbon (exoC) and nitrogen (ntrB, ntrC, and nifR) metabolism showed distinctive transcriptional responses to nitrogen limitation. Their relative expression level was increased by 14, 9, 7 and 7-fold, respectively. Two-dimentional electrophoresis (2-DE) revealed that the expression of 14 proteins were elevated and 6 proteins were down-regulated significantly under nitrogen starvation. Furthermore, 4 proteins (GroEL, ABC transporter, Atu1730 and enoyl-acyl carrier protein reductase) in which the expression level changed significantly were identified. The results showed that Agrobacterium sp. regulates its carbon flux and nitrogen assimilation effectively for better survival. PMID- 22232895 TI - [Synthesis of 3-hydroxybutyrate-CO-4-hydroxybutyrate copolymers by hydrogen oxidizing bacteria]. AB - Synthesis of 3- and 4-hydroxybutyrate copolymer (3HB-CO-4HB), the most promising member of the biodegradable polyhydroxyalcanoate (PHA) family, has been studied. Cultivation conditions of naturally occurring strains of hydrogen-oxidizing bacteria Ralstonia eutropha B5786 and Cupriavidus eutrophus B10646 have been optimized to ensure efficient synthesis of the 3HB-CO-4HB copolymer. A set of highly pure samples of the 3HB-CO-4HB copolymer with 4HB content varying from 8.7 to 24.3 mol % has been obtained. Incorporation of 4-HB into the copolymer was shown to cause a more pronounced decrease in polymer crystallinity than the incorporation of 3-hydroxyvalerate or 3-hydroxyhexanoate; samples with a degree of crystallinity below 30% have been obtained. The weight average molecular mass of the 3HB-CO-4HB copolymers was shown to be independent on the monomer ratio and to vary broadly (from 540 to 1110 kDa). PMID- 22232896 TI - [Obtaining of water soluble microbial melanin and study of its some properties]. AB - The effective sorption method for melanin isolation and purification from fermentation solutions of Bacillus thuringiensis serovar galleriae K1 has been elaborated, the principle process flowsheet is presented. The identification of obtained pigment with the samples of natural and synthetic melanin was done by IR spectroscopy, and the intensity ratio of optical absorption at 650 and 500 nm allows to refer the isolated melanin to eumelanin class. By thermal treatment it was determined, that melanin's amorphous sediment is steady at up to 120 degrees C temperatures, at that the concentration of paramagnetic centers is changed from 0.053 x 10(18) spin/g (48 degrees C) to 0.25 x 10(18) spin/g (120 degrees C). The rising of the temperature of treatment up to 210 degrees C brings to substantial increase of the concentration of unpaired electrons, and at 280 degrees C its sharp growth is observed. At 350 degrees C growth stops, then sharp decrease is observed. The obtained results were confirmed by methods of IR spectroscopy and derivatographic analysis. PMID- 22232897 TI - [Methanogenic destruction of (amino)aromatic compounds by anaerobic microbial communities]. AB - Destruction of a number of aromatic substrates by anaerobic microbial communities was studied. Active methanogenic microbial communities decomposing aminoaromatic acids and azo dyes into CH4 and CO2 were isolated. Products of primary conversion were found to be 2-hydroxybenzyl and benzyl alcohols gradually transforming into benzoate. It was shown that isolated microbial communities are capable of converting the initial substrates--benzyl alcohol, benzoate, salicylic acid, and golden yellow azo dye--into biogas without a lag-phase but with different velocities. Aromatic and linear intermediates of biodestruction of aromatic amines by obtained enrichment cultures were determined for the first time. Selective effect of aromatic substrates on a microbial community that was expressed in decrease in diversity and gradual change of dominant morphotypes was revealed. PMID- 22232898 TI - [Selective extraction of metals from zinc concentrate by association of chemolithotrophic bacteria]. AB - Ability for selective extraction of copper and zinc from zinc concentrate using association of chemolithotrophic bacteria was investigated. In the presence of bacterial association, the rate of desalinization of zinc, copper, and iron was increased 3-fold, 4-5-fold, and 2-fold, respectively. Zinc, copper, and iron were levigated with the most significant rate. It was revealed that addition of Fe3+ 2 g/l resulted in reduction of iron desalinization and in 3-fold increase of desalinization rate of copper at constant dissolution rate of mineral zinc. It is suggested that the intensification of copper desalinization is connected with the activity of sulfur-oxidizing bacteria able to activate the mineral surface via elimination of passivation layer of elemental sulfur. It was concluded that sulfur-oxidizing bacteria play a significant role in copper desalinization from zinc concentrate. A unique strain of mesophile sulfur-oxidizing bacteria was isolated from desalinization pulp of zinc concentrate; in the perspective, it may serve as efficient candidate for performing of selective extraction of copper from zinc concentrate. PMID- 22232899 TI - [Leaching of copper ore of the Udokanskoe deposit at low temperatures by an association of acidophilic chemolithotrophic microorganisms]. AB - Pure cultures of indigenous microorganisms Acidithiobacillus ferrooxidans strain TFUd, Leptospirillum ferrooxidans strain LUd, and Sulfobacillus thermotolerans strain SUd have been isolated from the oxidation zone of sulfide copper ore of the Udokanskoe deposit. Regimes of bacterial-chemical leaching of ore have been studied over a temperature range from -10 to +20 degrees C. Effects of pH, temperature, and the presence of microorganisms on the extraction of copper have been shown. Bacterial leaching has been detected only at positive values of temperature, and has been much more active at +20 than at +4 degrees C. The process of leaching was more active when the ore contained more hydrophilic and oxidized minerals. The possibility of copper ore leaching of the Udokanskoe deposit using sulfuric acid with pH 0.4 at negative values of temperature and applying acidophilic chemolithotrophic microorganisms at positive values of temperature and low pH values was shown. PMID- 22232900 TI - Increase of ethanol productivity by cell-recycle fermentation of flocculating yeast. AB - Using the recombinant flocculating Angel yeast F6, long-term repeated batch fermentation for ethanol production was performed and a high volumetric productivity resulted from half cells not washed and the optimum opportunity of residual glucose 20 g l(-1) of last medium. The obtained highest productivity was 2.07 g l-(1) h(-1), which was improved by 75.4% compared with that of 1.18 g l( 1) h(-1) in the first batch fermentation. The ethanol concentration reached 8.4% corresponding to the yield of 0.46 g g(-1). These results will contribute greatly to the industrial production of fuel ethanol using the commercial method with the flocculating yeast. PMID- 22232901 TI - Purification and characterisation of lignin peroxidase from Pycnoporus sanguineus MTCC-137. AB - Extracellular secretion of lignin peroxidase from Pycnoporus sanguineus MTCC-137 in the liquid culture growth medium amended with lignin containing natural sources has been shown. The maximum secretion of lignin peroxidase has been found in the presence of saw dust. The enzyme has been purified to homogeneity from the culture filtrate of the fungus using ultrafiltration and anion exchange chromatography on DEAE-cellulose. The purified lignin peroxidase gave a single protein band in sodium dodecylsulphate polyacrylamide gel electrophoresis corresponding to the molecular mass 40 kDa. The K(m)(, kcat) and k(cat)/K(m) values of the enzyme using veratryl alcohol and H2O2 as the substrate were 61 microM, 2.13 s(-1), 3.5 x 10(4) M(-1) s(-1) and 71 microM, 2.13 s(-1), 3.0 x 10(4) M(-1) s(-1) respectively at the optimum pH of 2.5. The temperature optimum of the enzyme was 25 degrees C. PMID- 22232902 TI - GC-MS and spectrophotometric analysis of biodegradation of new disazo dye by Trametes versicolor. AB - In this study; sub-tropical white rot fungi, Trametes versicolor was investigated for its ability to degrade 4-(3'-methyl-4'-(4"-nitrophenyl)azo- 1'H-pyrazol-5' ylazo)-3-methyl- H-pyrazol-5-on in the mediums containing glucose and different concentrations of degrade dye in batch systems. This dye was synthetized at Pamukkale Universtiy of Organic Chemistry research laboratory. Samples were collected on 10 days, and was detected by Shimadzu UV-1600A spectrophotometry. Decolorization study showed that this disazo dye was removed by more than 70% in 10 days. Laccase enzyme activity was detected in samples and then last sample was analyzed by GC-MS. Metabolites weren't showed in GC-MS result. It was concluded that T. versicolor could achieve the biodegradation of this new disazo dye. PMID- 22232903 TI - [Effect of polycyclic aromatic hydrocarbons on laccase production by white rot fungus Pleurotus ostreatus D1]. AB - The effect of polycyclic aromatic hydrocarbons (PAHs) on the dynamics of laccase production by the fungus Pleurotus ostreatus D1 under conditions of submerged cultivation on Kirk's medium has been studied. It has been shown that phenanthrene, fluoranthene, pyrene, and chrysene actively induce this enzyme, whereas fluorene and anthrecene had a smaller effect. Addition of Mn2+ ions to cultivation medium elevates the laccase activity twofold and more in the presence of all the studied PAHs. Electrophoresis under nondenaturing conditions demonstrates induction of additional laccase species by xenobiotics. Ligninolytic peroxidase activities are undetectable under the conditions used. PMID- 22232904 TI - [Salicylic and jasmonic acids in regulation of the proantioxidant state in wheat leaves infected by Septoria nodorum Berk]. AB - Influence of mediators of the signal systems of salicylic (SA) and jasmonic (JA) acids and their mixture on reactive oxygen species' (ROS) (superoxide radical O2* and H2O2) generation and activity of oxidoreductases (oxalate oxidase, peroxidase and catalase) in leaves of wheat Triticum aestivum L. infected by Septoria leaf blotch pathogen Septoria nodorum Berk. has been studied. Presowing treatment of seeds by SA and JA decreased the development rate of fungus on wheat leaves. SA provided earlier inductive effect on production of O2*- and H2O2 compared with JA. The protective effect of the salicylic and jasmonic acids against Septoria leaf blotch pathogen was caused by activation of oxalate oxidase, induction of anion and cation peroxidases, and decrease of catalase activity. Ability of compounds to stimulate ROS in the plant tissues can be used as criteria for evaluation of immune-modulating activity of new substances for protection of the plants. PMID- 22232905 TI - Application of standard addition for the determination of carboxypeptidase activity in Actinomucor elegans bran koji. AB - Leucine carboxypeptidase (EC 3.4.16) activity in Actinomucor elegans bran koji was investigated via absorbance at 507 nm after stained by Cd-nihydrin solution, with calibration curve A, which was made by a set of known concentration standard leucine, calibration B, which was made by three sets of known concentration standard leucine solutions with the addition of three concentrations inactive crude enzyme extract, and calibration C, which was made by three sets of known concentration standard leucine solutions with the addition of three concentrations crude enzyme extract. The results indicated that application of pure amino acid standard curve was not a suitable way to determine carboxypeptidase in complicate mixture, and it probably led to overestimated carboxypeptidase activity. It was found that addition of crude exact into pure amino acid standard curve had a significant difference from pure amino acid standard curve method (p < 0.05). There was no significant enzyme activity difference (p > 0.05) between addition of active crude exact and addition of inactive crude kind, when the proper dilute multiple was used. It was concluded that the addition of crude enzyme extract to the calibration was needed to eliminate the interference of free amino acids and related compounds presented in crude enzyme extract. PMID- 22232906 TI - [Analysis of the binding capacity of the benzodiazepine site of gabaa receptor in mice C57BL/6 and BALB/C pretreated with anxiolytics]. AB - The level of specific 3H-flunitrazepam binding in synaptosomal membranes of C57BL/6 and BALB/c mice brain underwent to the stress of different types has been studied. Mild stress (Elevated Plus Maze) was shown to induce the decrease of benzodiazepine binding in BALB/c mice only, while the strong one (Exposure to a predator) was revealed to cause this decrease in both strains. Behavioral effects of different non-benzodiazepine drugs possessing anxiolytic properties (Afobazol, Ladasten and Noopept) was accompanied with the normalization of the level of benzodiazepine reception, reduced by the stress of both modalities. PMID- 22232907 TI - [Effect of afobazole on the psychophysiological state of healthy volunteers]. AB - The influence of the selective anxiolytic drug afobazole in a single dose of 10 mg on the psychophysiological functions of healthy volunteers was studied in laboratory experiments. It is established that afobazole optimizes some psychophysiological characteristics of stress-labile individuals and has no negative influenceon the parameters of attention, psychomotor reaction a nd speed of decision making. PMID- 22232908 TI - [Pharmacological neuroprotection against brain damage in ischemiai/reperfusion experiment]. AB - Experiment carried out on laboratory animals (rats) were aimed at comparative evaluation of the effect of several neuroprotective drugs under the conditions of model brain ischemia-reperfusion. The experimental methods included staining of brain tissue sections by hematoxiline-eosine, Nissl staining, and expression of NOS1, NOS3, TRAIL by imunnohistological means. The intensity of damage in various parts of brain and the nature of apoptosis without neuroprotection and with popular neuroprotectors (cytoflavin, actovegin, mexidol) and a test drug at the stage ofpreclinical trial (AKF-90-7) were evaluated. Characteristic cytotoxic (coagulative pycnomorphic and colliquative necrosis of neurons) and vascular (hemostasia, erythropedesis) changes were revealed. The neuroprotective effectof drugs decreases in the following order: AKF-90-7 > cytoflavin > actovegin > mexidol. PMID- 22232909 TI - [Influence of 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate on cerebral blood perfusion in rats under experimental pathology conditions]. AB - Experiments on rats showed that 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate increases cerebral blood flow in the system of carotid arteries both in intact animals and under conditions of global transient ischemia. In combination with tropoxin, 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate enhances the blood flow in the inner carotid artery of intact rats and the local blood flow under conditions of global transient ischemia. A combination of 2-ethyl-6-methyl-3 hydroxypyridine hemisuccinate and tropoxin increases baseline cerebral blood flow and decreases the constrictor reaction of cerebral blood vessels to 5HT(2B/2C) receptor agonist meta-chlorophenylpiperazine. PMID- 22232910 TI - [Cerebrovascular and antiserotoninergic activity of the combination of tropoxin and mexidol]. AB - The results of experiments on narcotized rats showed that tropoxin substantially reduces the constrictor reactions of cerebral blood vessels to meta chlorophenylpiperazine, while not increasing the blood flow in the carotid system of either intact rats or animals with model ischemic damage of brain. In contrast, mexidol increases the cerebral blood flow in rats under conditions of global transient ischemia of brain. A combination of tropoxin and mexidol retains both the anti-serotoninergic activity of tropoxin and the vasodilating effect of mexidol. PMID- 22232911 TI - [Cerebrovascular effects of GABA conjugate with arachidonic acid under conditions of separate and combined vascular pathology of brain and heart]. AB - Experiments on rats showed that, under conditions of global transient ischemia, a conjugate of GABA with arachidonic acid enhances the local cerebral blood flow due to a decrease in the vascular tone. In intact rats, the examined neurolipin did not show unidirectional changes in the cerebral perfusion. Under conditions of experimental myocardial infarction and combined vascular pathology of brain and heart, the GABA conjugate with arachidonic acid increased the blood flow in the parietal region of brain cortex in most experiments, while decreasing the level of blood pressure. PMID- 22232912 TI - [Influence of GABA derivatives on some indices of lipid peroxidation in immunocompetent organs under experimental immunopathology conditions]. AB - The effects of GABA derivatives phenotropil (25 mg/kg), phenibut (25 mg/kg), and baclofen (2 mg/kg) on the process of lipid peroxidation (LPO), as manifested by the initial level of malonic dialdehyde, velocity of spontaneous and ascorbate dependent LPO, and the catalase activity in the homogenates of thymus and spleen, have been studied on rats of the Wistar line with cyclophosphamide (CPHA) immunodepression and lipopolysacharide (LPS) immune stress. It is established that, under the action of CPHA and LPS, activation of the LPO processes takes place in the immune organs. Under these conditions, changes of the catalase activity exhibited some specific features: in the animals under LPS action, the catalase activity increased in the spleen, while being decreased in the thymus; under the influence of CPHA, the activity of this enzyme decreased in both organs. An analysis of the antioxidant activity of GABA derivatives under the conditions of CPHA-induced immunodepression showed that all substances upon intraperitoneal introduction for 5 days favored the elimination of disturbances by suppressing the LPO processes and increasing the antioxidant protection activity. On the background of LPS-induced immune stress, all the tested substances showed a correcting action with respect to indicated biochemical processes in the thymus, while only phenibut activated the antioxidant system in the spleen. PMID- 22232913 TI - [Hepatoprotective effect of thiophane in rats with experimental carbon tetrachloride-induced hepatitis]. AB - A hepatoprotective effect of thiophan was studied on the model of carbon tetrachloride-induced hepatitis in rats. Therapeutic administration of thiophan repairs the antitoxic function of liver, normalizes cytolysis marker activity, and improves the synthetic function of liver and the carbohydrate and lipid metabolism. The hepatoprotective activity of thiophan is similar to effect of silimarin. PMID- 22232914 TI - [Improvement of treatment of inflammatory diseases in oral cavity]. AB - In order to determine the anti-pathogenic clinical efficacy of cycloferon liniment in the combined treatment of herpetic stomatitis and periodontitis, medical examination and treatment of these disorders have been carried out in a group of 80 patients. It is established that the use of cycloferon liniment in the combined treatment of herpetic stomatitis and periodontitis decreases the infectious load in parodontal recess, reduces the manifestations of local inflammation, normalizes the immunity indices, and decreases the level of endogenous intoxication, which ensures the acceleration of recuperation processes and lowers the frequency of recurrences. PMID- 22232915 TI - [Model of platelet activation as experimental test system for screening kappa opioid receptor ligands]. AB - A new model is proposed for in vitro testing the efficiency of new chemical substances with kappa-opioid receptor agonist ligand properties. PMID- 22232916 TI - [Molecular genetic investigation of sugar beet (Beta vulgaris L.)]. AB - Molecular genetic studies of sugar beet (Beta vulgaris L.) are reviewed as a basis for the development of genomics of this species. The methods used to study structural and functional genomics are considered. The results and their application to increase the efficiency of sugar beet breeding are discussed. PMID- 22232917 TI - [Genetic, molecular, and humoral endocycle-regulating mechanisms]. AB - The review presents data on the molecular genetic mechanisms controlling endoreduplication. The issues concerning the activity of the main cycle cell regulators, such as cyclins, cyclin-dependent kinases, and their inhibitors, under conditions of a modified cell cycle of polytene cells are considered. Specific features of regulation at the replication origin points and the role of hormones and phytohormones in the ontogenetic control of endoreduplication are analyzed. PMID- 22232918 TI - [Molecular genetic analysis of the X-chromosomal nuclear envelope attachment region in nurse cells of the malaria mosquitoes Anopheles messeae Fall]. AB - DNA of the X-chromosomal nuclear envelope attachment region was isolated from malaria mosquito Anopheles messeae Fall. nurse cells by chromosome microdissection. A DNA library of the region was constructed using a plasmid vector. DNA sequencing revealed gene fragments, tandem repeats, and a great variety of transposable elements (TEs). The X-chromosomal nuclear envelope attachment region was concluded to correspond in molecular organization and cytogenetics to diffuse intercalary heterochromatin. PMID- 22232919 TI - [Molecular phylogeny and the time of divergence of minges (Chironomidae, Nematocera, Diptera) inferred from a partial nucleotide sequence of the cytochrome oxidase I gene (COI)]. AB - This is the first study to infer the phylogenetic structure of minges of the subfamily Chironominae from the amino acid sequence of cytochrome oxidase I (COI). The subdivision of Chironominae into two tribes, Chironomini and Tanytarsini, has been confirmed. The segregation of the genera Pseudochironomus and Riethia into a separate tribe has not been confirmed. Stenochironomus gibbus forms a branch considerably deviating from the subfamily Chironominae. The genus Micropsectra is formed by a large polyphyletic cluster that also includes the genera Virgotanytharsus, Reotanytharsus, Kenopsectra, and Parapsectra. Tanytarsus is the basal genus of the tribe Tanytarsini. The times of divergence of the main taxa of Chironominae have been estimated. The calculated time of divergence of the genus Chironomus disproves the assumption that it is phylogenetically old. PMID- 22232920 TI - [Structural analysis of genes participating in melibiose fermentation and isocitrate lyase production in Yersinia pestis strains of main and non main subspecies]. AB - Comparative analysis of nucleotide sequences of genes participating in melibiose fermentation and isocitrate lyase production was conducted in 90 natural Yersinia pestis strains of main and non main subspecies. It was ascertained that the lack of the ability to utilize disaccharide melibiose in strains of the main subspecies is caused by integration of the insertion sequence IS285 at 73 bp from the beginning of the structural gene melB that encodes the transport protein galactoside permease. In contrast, strains of non main subspecies (caucasica, altaica, and ulegeica) contain the intact gene melB and are capable of fermenting melibiose. Differences in the manifestation of the other differential trait, production of isocitrate lyase, are connected with the presence of mutation (insertion of two nucleotides +CC) in the regulatory gene iclR encoding repressor protein of the acetate operon, which is the reason for constitutive synthesis of this enzyme. Strains of non main subspecies do not contain mutations in gene iclR, and this correlates in these strains with their capacity for inducible synthesis of isocitrate lyase. PMID- 22232921 TI - [Phylogenetic analysis of Altai osmans of the genus Oreoleuciscus (Pisces, Cyprinidae, Leuciscinae), based on the analysis of the cytochrome oxidase 1 gene (Co-1) sequence]. AB - Molecular genetic analysis of Altai osmans of the genus Oreoleuciscus from two different parts of the range was carried out. In this study, based on the mitochondrial Co-1 gene sequence, a total of 25 fish specimens belonging to four genera were examined: (1) O. humilis, 2 specimens; O. potanini, 13 specimens; (2) Pseudaspius leptocephalus, 1 specimen; (3) Tribolodon brandtii, T. hakonensis, and T. sachalinensis from the GenBank database, 8 speciens; and (4) Leuciscus waleckii, 1 specimen (used as an outgroup). The p-distances were very low both within and between the species: (1) 0.20 +/- 0.03%; (2) 0.40 +/- 0.12%; and (1-2) 0.80 +/- 0.04%. To visualize the relationships among all of the species examined, the neighbor joining (NJ), maximum parsimony (MP), Bayesian (BA), and maximum likelihood (ML) trees were constructed. The results obtained using these methods were very similar. It was demonstrated that species assignment of the individuals (barcoding) with the help Co-1 gene was effective, despite of very low divergence of the two osman taxa, which was comparable with typical intraspecific values in other animal groups. Taxonomic status of O. potanini and O. humilis requires further investigation with paying attention to low genetic distances between these species along with the lack of material from sympatric parts of the ranges. PMID- 22232922 TI - [Analysis of microsatellite variation in the rainbow trout (Parasalmo (Oncorhynchus) mykiss) from Kamchatka]. AB - Genetic variation of Kamchatka rainbow trout Parasalmo (O.) mykiss was examined using 10 microsatellite DNA loci, and phylogeographic comparison with other representatives of the species across the distribution range was performed. It was demonstrated that Kamchatka populations differed from other geographic groups of rainbow trout in a number of microsatellite loci. These populations also displayed distinct clustering and were characterized by lower genetic diversity. Analysis of a set of 26 different microsatellite loci (personal and literature data) demonstrated that most of the populations within the Kamchatka region were separated from one another, characterized by marked geographic differentiation, and affiliation to certain river basins. In Kamchatka rainbow trout, with high degree of probability, three geographic clusters (northwestern, southwestern, and eastern) were identified. In general, analysis of microsatellite DNA supported the data on low genetic diversity of the Kamchatka group Parasalmo (O.) mykiss, based on the variation estimates for a number of genes of nuclear and mitochondrial DNA, and allozyme loci. PMID- 22232923 TI - [The role of metabolic activation of promutagens in the genome destabilization under pheromonal stress in the house mouse (Mus musculus)]. AB - The hypothesis on a relationship between the high frequency of mitotic disturbances in bone marrow cells and the change in the activity of the S9 liver fraction containing promutagen-activating enzymes under olfactory stress in the house mouse Mus musculus has been tested. For this purpose, the effect of the pheromone 2,5-dimethylpyrazine on the frequency of mitotic disturbances in mouse bone marrow cells has been measured by the anaphase-telophase assay. The Ames test using Salmonella typhimurium has been employed to compare the capacities of the S9 liver fractions from stressed and intact mice for activating the promutagen 2-aminofluorene. It has been demonstrated that the increased frequency of mitotic disturbances in bone marrow cells induced by the pheromonal stressor in male house mice is accompanied by an increased promutagen-activating capacity of the S9 liver fraction. The model system used in the study allowed the genetic consequences of the exposure to the olfactory stressor to be estimated and the possible mechanisms of genome destabilization to be assumed. PMID- 22232924 TI - O-chromosome lethal frequencies in Serbian and Montenegrin Drosophila subobscura populations. AB - Lethal chromosomal frequencies were obtained from three Drosophila subobscura samples from the Mt. Avala (Serbia) population in September 2003 (0.218), June 2004 (0.204) and September 2004 (0.250). These values and those from other Balkan populations studied previously (Petnica, Kamariste, Zanjic and Djerdap) were used to analyze the possible effect of population, year, month and altitude above sea level on lethal chromosomal frequencies. According to ANOVAS no effect were observed. Furthermore, the lethal frequencies of the Balkan populations did not vary according to latitude. This is probably due to the relative proximity and high gene flow between these populations. From a joint study of all the Palearctic D. subobscura populations so far analyzed, it can be deduced that the Balkan populations are located in the central area of the species distribution. Finally, it seems that lethal chromosomal frequencies are a consequence of the genetic structure of the populations. PMID- 22232925 TI - [Increased genomic instability in somatic cells of the progeny of female mice exposed to acute X-radiation in the preconceptional period]. AB - The level of genome instability (GI) was studied in the progeny of female mice exposed in the preconceptional period to radiation doses of 0.5, 1, and 2 Gy in comparison to that in the progeny of the same parent pairs born before irradiation of the females. To assess the level of genome instability, we analyzed polymorphism of DNA fragments from postmitotic (blood and brain) and proliferating (spleen and tail tip) tissues amplified by AP-PCR (PCR amplification with an arbitrary primer). It was found that polymorphism of the spectrum of AP-PCR products, which is a multilocus genetic marker (MGM), in the genome of somatic cells in the progeny of female mice exposed to 2 Gy was higher than in the progeny of male mice exposed to the same doses. In the progenies of female mice born before and after irradiation, tissue-specific variations in the level of DNA polymorphism were detected. The maximum value of this polymorphism (with respect to the frequency of "nonparental bands") was determined for peripheral blood DNA in comparison with the other tissues. Estimations of the MGM polymorphism with the AP-PCR method demonstrate an increased level of genome instability in somatic cells of offsprings from female mice exposed to a single acute dose of X-rays (0.5, 1, and 2 Gy) in the pre-conceptional period. Radiation induced transgenerational genome instability with an increase in the dose of preconceptional irradiation of female mice was more pronounced in DNA of the postmitotic tissues (blood and brain DNA) than in DNA of the proliferating tissues (spleen and tail tip epithelium). PMID- 22232926 TI - [Polymorphism of the mitochondrial DNA control region in the population of raccoon dog (Nyctereutes procyonoides Gray, 1834) introduced into the Upper Volga basin]. AB - Analysis of sequences (n = 30) of a hypervariable segment (599 bp) of the mtDNA control region in raccoon dog Nyctereutes procyonoides Gray, 1834, introduced into the Upper Volga basin, revealed a high level of molecular genetic variation. Two statistically significantly different haplogroups were identified. These haplogroups, however, were not associated with spatial geographic structure of the population. Phylogenetic patterns of the introduced population were associated with probable heterogeneity of autochthonous donor populations with respect to relatively large group of founders and a dramatic increase in the species number after the introduction. PMID- 22232927 TI - [Polymorphic markers Ala455Val of the THBD gene and Arg353Gln of the F7 gene and association with unfavorable outcomes of coronary atherosclerosis in patients with a history of acute ischemic heart disease]. AB - The polymorphic markers Ala455Val of the THBD gene and Arg353Gln of the F7 gene were tested for association with the frequency of unfavorable outcomes in patients with a history of acute ischemic heart disease. The study involved 1145 patients hospitalized in cardiology clinics of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol, and Rostov-on-Don because of acute ischemic heart disease. The patients were followed up for up to 62.5 months. None of the markers displayed a significant association with the time to an endpoint. The patients were then grouped by sex. In females, the frequency of unfavorable outcomes (fatal or nonfatal myocardial infarction and fatal or nonfatal stroke) was higher in carriers of allele Val of the Ala344Val polymorphic marker of the THBD gene and carriers of genotype Arg/Arg of the Arg353Gln polymorphic marker of the F7 gene, but the difference was not statistically significant. Such an increase in frequency was not observed in males. To study the combined effect of the polymorphic markers of the THBD and F7 genes, the course of ischemic heart disease was compared for two female subgroups. One included carriers of allele Val of the Ala344Val polymorphic marker of the THBD gene and genotype Arg/Arg of the Arg353Gln polymorphic marker of the F7 gene; the other subgroup included carriers ofgenotype Ala/Ala of the Ala455Val polymorphic marker of the THBD gene and allele Gln of the Arg353Gln polymorphic marker of the F7 gene. The frequency of unfavorable outcomes in the first subgroup was higher than in the second one. The time to an endpoin was 40.5 months (95% confidence interval (CI) 33.5-47.6) in the first subgroup and 51.6 months (95% CI 45.0-58.1) in the second subgroup (chi2 = 4.15, P = 0.042). The results made it possible to assume that the F7 and THBD genes play an important role in genetic predisposition to unfavorable outcomes in patients with a history of acute ischemic heart disease. PMID- 22232928 TI - [Analysis association of acute ischemic stroke and DNA markers in Russian and Moldavian populations]. AB - Polymorphisms c.202G > A of prothrombin F2 gene, c.1691G > A of coagulation factor V F5 gene, c.675delinsG of plasminogen activator1 gene, and (-5)T > C Kozak gene of thrombocytic receptor were studied in the Russian and Moldavian ethnic groups. We have found no association between these polymorphisms and the risk of ischemic stroke development in both ethnic groups. No association was revealed between the risk of stroke development and various combinations of the single nucleotide polymorphisms examined in the sample of ischemic stroke patients from Russia. PMID- 22232929 TI - [Polymorphic markers of the CYP1B1 (4326C > G), CYP2F1 (c.14_15insC), CYP2J2 ( 76G > T), and CYP2S1 (13106C > T and 13255A > G) genes and genetic predisposition to chronic respiratory diseases induced by smoking and occupational factors]. AB - The contribution of the polymorphic markers of cytochrome P450 genes to respiratory diseases caused by smoking and occupational factors has been assessed. For this purpose, PCR-RFLP analysis of the CYP1B1 (rs1056836, 4326C > G), CYP2F1 (rs11399890, c.14_15insC), CYP2J2 (rs890293, -76G > T), and CYP2S1 (rs34971233, 13106C > T and rs338583, 13255A > G) gene polymorphisms has been performed. The analysis has shown that the polymorphic variants of the CYP1B1 (rs1056836, 4326C > G) and CYP2F1 (rs11399890, c. 14_15insC) genes may contribute to the development of occupational chronic bronchitis. The proportion of CYP1B1* 1*3 heterozygotes in the group of patients with occupational chronic bronchitis is considerably greater than in the group of healthy workers (69.16% versus 53.29%; chi2 = 5.94, P = 0.02, P(cor) = 0.04, OR = 1.97, the 95% CI is 1.13 3.42). Patients with occupational chronic bronchitis and healthy workers significantly differed from each other in the frequency distribution of the genotypes ofthe CYP2F1 (rs11399890, c.14_15insC) polymorphic marker (chi2 = 6.18, d.f = 2, P = 0.05). The frequency of the wild type/ins heterozygous genotype for the CYP2F1 gene is higher in healthy workers (36.08%) than in patients (22.22%) (chi2 = 5.48, P = 0.02, P(cor) = 0.04, OR = 0.51, the 95% CI is 0.28-0.90). No association has been found between the CYP2J2 (rs890293, -76G > T) or CYP2S1 (rs34971233, 13106C > T, P466L and rs338583, 13255A > G) gene polymorphisms and respiratory diseases. PMID- 22232930 TI - [Association of T3111C polymorphism in 3'-untranslated region of the CLOCK gene with the risk of essential arterial hypertension and coronary artery disease in the Russian population Karelia]. AB - Allele and genotype distributions of the T3111C polymorphism in 3'-untranslated region of the CLOCKgene were examined in the groups of Russian patients with essential arterial hypertension (EAH) and coronary artery disease (CAD), and in control group of Russia residents of the Republic of Karelia. The genotype frequency distributions of the polymorphism examined in the EAH and CAD patients were statistically significantly different from that in the individuals without clinical signs of these diseases. The CC genotype frequency in EAH and CAD males was higher, and in the corresponding females it was lower than in males and females from the control group. Male CC carriers were characterized by a possible increased risk of EAH: OR (95% CI) = 1.42 (0.56; 3.58). Moreover, the presence of the CC genotype in males could increase the risk of CAD: OR (95% CI) = 1.58 (0.63; 3.93). PMID- 22232931 TI - An improved polymerase chain reaction method for genetic testing of spinocerebellar ataxia type 3. AB - The development of a reliable PCR assay for genetic testing of spinocerebellar ataxia type 3. Touchdown PCR conditions were tested and different primer sets were evaluated with genomic DNA from blood sample of patients suffering from spinocerebellar ataxia type 3 (SCA3). An improved PCR assay was developed with a new set of primers and using the optimized touchdown PCR protocol. This new assay had been successfully employed in the screening of one identificated SCA3 family. Results from the present study document a simple and reliable PCR assay for genetic testing of SCA3. Strategies used in the present study may find applications in the optimization of PCR assay for triplet expansion with GC rich in the sequence context. PMID- 22232932 TI - [The role of alternative lengthening of telomeres mechanisms in carcinogenesis and prospects for using an anti-telomerase drugs in malignant tumors treatment]. AB - The review analyzes telomere lengthening mechanisms in cancer cells of two different tumor types--carcinomas and sarcomas. Basic attention is given to sarcomas which cells lengthen their telomeres through alternative mechanisms for lengthening telomeres (ALT). The features of ALT mechanisms functioning in these cells have been examined in detail. Moreover, the actually existing anti telomerase drugs and their efficiency in carcinomas treatment were analyzed. The experimental data showing that, contrary to theoretical expectations, activation of ALT was not observed on a background of such anti-telomerase, are presented. This portends a good prognosis in the treatment of the patients with carcinoma. Finally, on the basis of the data analyzed the candidates for a role of targets are proposed for development of anti-ALT antineoplastic therapy. Expected efficiency and toxicity of such drugs are considered in detail. PMID- 22232933 TI - [Compensatory function of transthyretin in Alzheimer's disease]. AB - Alzheimer's disease (AD) is the most common form of age-related primary neurodegenerative diseases characterized by progressive memory loss, aphasia, and intellectual and mental breakdown. Pathogenesis of AD is based on the early synaptic dysfunction following neurodegeneration and neuronal death. According to modern concepts, the development of neuropathological processes is due to progressively deposited intermediates of amyloid fibrils that represent oligomers consisting of short peptide named amyloid beta protein (Abeta). In this context, it is reasonable to propose that one of the compensatory mechanisms of AD might be inhibition of Abeta oligomerization by sequestration or clearance of Abeta. Experiments with transgenic animals and epidemiological studies demonstrate that major protein of cerebrospinal fluid, transthyretin, is a natural neuroprotector that inhibits Abeta amyloid formation and restore cognitive functions. The study of Abeta-transthyretin complexes allowed to create peptides that are mimetics of transthyretin. These mimetics inhibit amyloid formation in vitro and, therefore, could be used in therapeutic treatment of AD. PMID- 22232934 TI - [The mammalian gonocytes fate: oogenesis or spermatogenesis]. AB - Germ line cells become gonocytes after the completion of migration and colonization of gonadal anlages. After the contact with the somatic cells of genital ridges the reprogramming of gonocytes takes place. Upon entry the embryonic gonads germ cells undergo the most complete demethylation during germ line development, their chromatin tends to have an open conformation for a short period. This event promotes the susceptibility to meiosis-inducing factors signaling. The choice of the further path of gonocytes development just after the gonadal sex differentiation, mitotic arrest and meiotic entry are discussed. Analisis of the action mechanisms of meiosis-inducing and meiosis-preventing factors, especially retinoic acid and enzymes of its degradation and synthesis, was performed. PMID- 22232935 TI - [Nuclear texture in mitotic cells]. AB - Changes of nuclear texture in mitotic cells of Drosophila melanogaster imaginal discs were studied. The distribution of voxels DAPI fluorescence intensities was used as the quantitative measure of the nuclear texture. The integral characteristics such as the portion of voxels with a given fluorescent signal level and autocorrelation of pixel intensities were used. We showed the nuclear texture has specific changes at different mitotic stages and this can be used for more precise staging of mitosis. Colchicines treatment pathologies, connected to abnormal mitoses, by nuclear-texture approach. PMID- 22232937 TI - [Immunomodulating effect of cyclophosphamide on cytotoxic activity of rats and mice splenocytes]. AB - This study examines the immunomodulating effect of cytostatic drug- cyclophosphamide (Cy)--on natural cytotoxic activity of rats and mice splenocytes. The cytotoxicity of the effector cells against the confluent monolayer cell lines of rat hepatoma Zajdela and HTC and mice hepatoma MH-22a was estimated by means the morphometric analysis. It was shown, that 48 h after single intraperitoneal injection of Cy produced a immunomodulating effect on the activity of splenocytes--suppressor action on cells of Zajdela hepatoma and immunopotentiating action on the target cells of HTC and MH-22a hepatomas. The possible mechanisms of immunopotentiating effect of Cy are discussed. PMID- 22232936 TI - [Investigation vesicle cycle in nerve formations in somatic muscle of the earthworm Lumbricus terrestris]. AB - Luminous spots with a diameter of 1-2 microm, which are clusters of "synaptic buds", were revealed in the muscular wall of the earthworm using endocytotic fluorescent dyes FM1-43, FM2-10 and FM4-64. Application of the membrane probe Dil that is capable of being subjected to anterograde axonal transport to abdominal ganglia of the nervous chain, and subsequent (in a day) staining of nerve formations by endocytotic dye FM4-64 showed complete imposition of the emission data of the dyes that fluoresce in different parts of the spectrum. Using fluorescent marker DiBAC4(3) showed an increased emission of neural elements with increasing concentration of K+ in the extracellular environment. Application of FM2-10 showed that the higher concentration of K+ in solution, and hence the depolarization of the nerve cells, the faster the upload of the dye, and vice versa, the process slowed down in the absence of K+ in the medium. The seizure and removal of FM2-10 were blocked in calcium-free solutions in the presence of Ca2+ buffers, BABTA or BABTA-AM, but only after a preliminary 40 min incubation. The processes of exo- and endocytosis occurred in the clusters of synaptic "buds" and were preserved in conditions of "rest". This vesicle cycle depends on membrane potential and concentration of K+ and Ca2+, and, it is very likely that the calcium sensor operates on the principle "all or nothing". PMID- 22232938 TI - [The effect of red pigment of Saccharomyces cerevisiae on insulin fibril formation in vitro]. AB - The effect of the yeast red pigment, the result of polymerization of AIR, and of its low molecular weight derivative (presumably devoid of phosphoribosyl moiety) on the formation of amyloid fibrils in vitro was studied. Both the red pigment and its derivative, the result of acid hydrolysis of the original pigment, were shown to diminish the intensity of amyloid bound Thioflavine T fluorescence. Correlation between the decrease of the intensity of Thioflavine T fluorescence and the concentration of both forms of the red pigment was demonstrated. Both forms were also able to compete with Thioflavine T for amyloid fibrils. Electron microscopy permitted to visualize a drop of fibril size in the case of red pigments presence during their formation. PMID- 22232940 TI - [The interaction of DNA with sperm-specific histones of the H1 family]. AB - We have studied the interactions of DNA with sperm-specific histones of the H1 family of sea urchin Strongylocentrotus intermedius, sea starfish Aphelasterias japonica and bivalve mollusk Chlamis islandicus using circular dichroism and DNA melting analysis. It was shown that echinoderm's sperm H1 protein has additional alpha-helical domains in its C-terminus and it demonstrates stronger DNA compaction. The differential melting curves of DNA-protein complexes have two peaks. The low temperature peak characterized the melting temperature of free DNA within the complex. The higher temperature peak characterizes the melting temperature of DNA bond to protein. DNA is found to be in the most stable state in the complexes with mollusk sperm H1 protein. PMID- 22232939 TI - [Numbers of cells and cell proliferation in intima of different human arteries]. AB - Increased cell proliferation in early atherosclerotic lesions is recognized as an essential event of atherogenesis but the levels of cell proliferation in different stages of atherosclerotic plague formation in different types of human large arteries are still insufficiently studied. In the present work, we studied intima thickness and proliferation of newly "infiltrates" hematogenous and resident cells in atherosclerotic lesions of the carotid and coronary arteries and compared these parameters with those in the aorta, reported by us in earlier publication. Analysis of intima thickness and proliferation in grossly unaffected intima and in different types pf atherosclerotic lesions (initial lesions, fatty streaks, lipofibrous, plaques, and fibrous plaque) revealed that although there were similar tendencies in the change of the infiltration levels of hematogenous cells and proliferation in different types of arteries, there were significant quantitative differences between different types of arteries. Hematogenous cells in lipofibrous plaques of the coronary and carotid arteries were found to account for a third and almost for a half of the total cell population, respectively, while atherosclerotic lesions in the aorta, as it has been shown by us earlier, to contain no more than 15% ofhematogenous cells. This suggests that the contribution of hematogenous cells to the development of atherosclerosis in the carotid and the coronary artery appears to be more significant than that in the aorta. Despite the differences in numbers of accumulating hematogenous cells in the intima, a similar "bell-shaped" dependence of cell numbers on the lesion type, involved in the following sequence: unaffected intima-initial lesions-fatty streaks-lipofibrous plaques-fibrous plaques, was detected in the coronary and carotid arteries. The visualization of proliferating cells (PCNA-positive) in atherosclerotic and unaffected zones of the coronary and carotid arteries revealed similar patterns. The maximum numbers of PCNA-positive resident cells were identified in lipofibrous plaques. The changes in the total cell numbers were accompanied by the changes in the numbers of both proliferating resident cells and proliferating hematogenous cells. PMID- 22232941 TI - [Plasticity of malignant tumor cells]. PMID- 22232942 TI - [Eye in rheumatic diseases]. AB - Ocular inflammatory diseases are frequently a part of clinical features of numerous systemic rheumatic disorders. Furthermore, appearance of ophthalmic disease can precede the other manifestation of rheumatic disorders and can be the first sign of systemic disease. At the alredy known rheumatic disease, ocular inflammation may demonstrate the grade of systemic disorder. Therefore multidisciplinary approaches, timely and correct diagnosis, as well as appropriate therapy these ocular inflammatory conditions enable visual function protection, health improvement and life saving. PMID- 22232943 TI - [Epidemiology of spondylarthritides]. AB - Epidemiologic studies on spondyloarttritides (SpA) encompass mode descriptions on disease appearance within the population, levels of disease frequency: incidence and prevalence, comorbidity, mortality, geographical distribution and clinical features, as well as risk factors for disease appearance. Ethnical, genetic, environmental performers are linked with appearance and expression of the disease. Clear distinction among SpA subgroups, especially in their early phases might not always be possible due to clinical picture overlapping, thus within the initial phase of the disease, the diagnosis of certain SpA diseases might be underestimated. SpA prevalence with various different populations varies between 0.21% up to 1.9% worldwide, and it varies between 1% up to 2% within Europe. With Eskimo population on Alaska and population of Siberia, prevalence rates appear to be from 2% up to 3.4%. SpA are rare with African and Japanese populations. Differences between ethnical groups might be explained by different criteria for selection of a target population, but with differences in HLA-B27 frequency as well. HLA-B27 subtypes distribution plays significant impact on AS prevalence with different race/ethnical groups. Challenges that aggravate the exact evaluation of the SpA diseases with the population, include comprise heterogeneity of population, lack of application feasibility of valid criteria (like testing on HLA-B27 antigen, pelvis radiography and MR), but also transition issue of certain SpA symptoms (eg. peripheral arthritis, enthesitis). Spondyloarthtritis (SpA) present a serious health, social and economical problem everywhere in the world. Uniform data for all populations are significant for making a proper picture on this disease group arduousness, and for epidemiological studies such data, because of their mutual overlapping, should be united within one single group. PMID- 22232944 TI - [Etiology and pathogenesis of spondyloarthritides]. AB - Seronegative spondyloarthritides are inflammatory rheumatic diseases which are classified together because of numerous common and similar clinical, epidemiologic and genetic characteristics. Pathogenesis of seronegative spondyloarthritides is usually described as development of clinical characteristics of the disease in genetically susceptible person in the presence of favorable environmental factors. Development of seronegative spondyloarthritides, notably ankylosing spondylitis, is strongly connected with presence of the HLA-B27 gene. There are clear evidence that HLA-B27 positive individuals have significantly higher risk for disease development. The role of infection in occurence of seronegative spondyloarthritides is not completely understood--its role is better clarified in the case of reactive arthritis than in ankylosing spondylitis. The relation between HLA-B27 gene and infection is not clarified. Molecular mimicry theory is based on similarities between HLA-B27 molecule and microbial particle. PMID- 22232945 TI - [The classification of spondyloarthritides]. AB - Spondyloarthritides (SpA) are a heterogeneous group of HLA-B27 associated musculoskeletal diseases that affect the axial and peripheral skeleton and most of them have some extraskeletal manifestations. The last classification criteria for SpA that has developed ASAS (Assessment of SpondyloArthritis International Society) working group have been published recently. The new criteria include the typical clinical and laboratory characteristics of all entities from the spectrum of SpA, which enables early diagnosis and planning of treatment strategies. PMID- 22232946 TI - [The classification of juvenile spondyloarthritides]. AB - The classification of juvenile spondyloarthritides is presented. PMID- 22232947 TI - [The early diagnosis of spondyloarthritis]. AB - The most frequent early symptoms of spondyloarthritides are inflammatory back pain and asymetric peripheral arthritis. Currently the mean delay between the onset of first symptoms and diagnosing ankylosing spondylitis which is the frequent type of spondyloarthritis is over 5 years. The availability of effective therapies makes an early diagnosis mandatory. The clinical symptoms of inflammatory back pain, active inflamation on MR, and positivity for HLA-B27 are the most important parameters for an early diagnosis of spondyloarthritis, especially in combination. Moreover, the combination of clinical and laboratory parameters is necessary for the early diagnosis. PMID- 22232948 TI - [Spondyloarthritides--clinical features]. AB - The spondyloarthritides are group of interrelated and overlapping arthritic conditions which primarily include ankylosing spondylitis, reactive arthritis/Reiter's disease and arthritis associated with psoriasis and inflammatory bowel disease. They are characterised by the absence of rheumatoid factor and by association with HLA-B27 antigen. The main clinical features are inflammatory back pain, spondylitis, sacroileitis, asymmetric arthritis of lower limbs, enthesitis, dactylitis, besides fatigue, uveitis, skin and mucous membrane lesions, cardiac and pulmonary involvement. Although there are similarities among the spondyloarthritides, each of them have specific characteristic that help us to distinguish them. PMID- 22232949 TI - [Extra-articular manifestations of seronegative spondyloarthritides]. AB - The term seronegative spondyloarthritides (SpA) is used to refer to a family of inflammatory rheumatic diseases characterised by inflammation of axial joints, asymmetric oligoarthritis and enthesitis, sometimes involving nonarticular structures, such as skin, heart, aortic valve, eye and kidney. The SpA consist of the following entities: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, spondyloarthritis associated with IBD and undifferentiated spondyloarthritis. The prevalence of SpA in the population is 0,5-2%. PMID- 22232950 TI - [Imaging in diagnostics of spondyloarthritis]. AB - This article describes radiological possibilities in musculoskeletal imaging of patients with suspected spondyloarthritis, with point on new imaging methods. We show which method is the best to use in a certain scenario, and when to do US and when use CT, MR or tomosyntesis. We have to be mindful about the radiation doses and X-ray usage, taking into account the age of the patient and what benefits a certain method would bring. PMID- 22232951 TI - [The role of magnetic resonance imaging in seronegative spondyloarthritides]. AB - Seronegative spondyloarthritides (SpA) is a group of inflammatory rheumatic diseases characterized by inflammation of the sacroiliac joints and/or the spine, enthesitis and peripheral arthritis. MRI is the imaging method of choice for visualization of the sacroiliac joint and spine according to the new ASAS classification criteria for axial SpA. It can visualize both active inflammation and structural damage and is not associated with radiation exposure. MRI findings characteristic for active disease include bone marrow edema and contrast enhancement of the bone marrow and the joint space, while chronic changes include bone erosions, sclerosis, periarticular fatty tissue accumulation, bone spurs and ankylosis. MRI has higher sensitivity comparing to other radiological modalities. MRI.is the most important diagnostic imaging method in early SpA. It is sensitive and reliable for objective monitoring of the disease process and it is essential in the management of patients with SpA. PMID- 22232952 TI - [The pharmacotherapy of spondyloarthritis]. AB - The objectives of treatment of spondyloarthritis are to improve functional status, diminish pain, prevent structural deterioration and reach drug free remission of disease. Nonsteroidal antiinflammatory drugs are the cornerstone of pharmacological intervention for ankylosing spondylitis, rapidly reducing pain and stiffness, and possibly modifying natural course of disease when given continuously. Conventional disease-modifying antirheumatic drugs which have been shown to be effective in the treatment of rheumatoid arthritis, have no proven such efficacy in spondyloarthritis. TNF-alpha blockade is highly effective in targeting the different disease features (axial disease, peripheral arthritis, enthesitis, and extra-articular features such as psoriasis or uveitis). There is no current evidence for the efficacy of other biological therapies in ankylosing spondylitis and psoriatic arthritis and every effort must be made to use TNF alpha antagonists optimally. PMID- 22232953 TI - [Nonpharmacological treatment of patients with spondyloarthritides]. AB - Despite the advances in the pharmacological therapy non-pharmacologic methods and especially therapeutic exercise are a cornerstone in management of spondyloarthritides. In this review studies of various physical therapy programs in ankylosing spondylitis and other spondyloarthritides are addressed with emphasis on their benefits and potential indications as well as on limitations in clinical practice and in studying these treatments. Formal physical therapy under the supervision of a physical therapist has been shown to diminish pain and stiffness and to improve posture, mobility, function and quality of life. Apart form land exercises water therapy (including balneotherapy) may be beneficial and in most severe cases, inpatient rehabilitation may be indicated, too. Physicians should implement such non-pharmacological therapy as a part of a comprehensive management strategy. Even though data are not sufficient to determine which specific physical therapy programme should be recommended this review demonstrates that physical therapy is an effective form of intervention and remains an essential part of the management with the importance of emphasis on continued and regular exercise therapy. PMID- 22232954 TI - [Ultrasonographic semiology--correlation between anatomy and sonography of musculoskeletal tissue]. AB - Diagnostic ultrasound (US) as noninvasive, non-ionisating and cost-effective imaging diagnostic technique has emerged as a useful imaging modality in rheumatology for the assessment of joint and soft tissue pathology. It can detect both early inflammatory soft tissue lesions (synovitis, tenosynovitis) and early erosive bone lesions in arthritis. Thus Power Doppler ultrasonography can differentiate active from inactive joint processes allowing monitoring of the new anti-inflammatory drugs used to treat inflammatory rheumatological diseases. In the process of learning the diagnostic technique memorizing and recognition of specific sonografic presentation of the different tissue structures, pathological processes, artifacts and pitfalls known as basic sonografic semiology is essential for appropriate interpretation of ultrasound image. In this paper ultrasound appearance of normal and basic pathological findings of different structures and tissues of musculoskeletal system is described and illustrated. PMID- 22232955 TI - [The value of sonography and power Doppler in the detection of early arthritis]. AB - Magnetic resonance imaging (MRI) of small joints of the hands and feetis still "the gold standard" in detecting early inflammatory changes in the patients with rheumatoid arthritis (RA). Radiographic assessment has only limited value in early diagnostic of RA. The limited accessibility of MRI makes both ultrasound (US) and Power Doppler (PD) of small joints of hands and feet equally useful tools as they give the same results as MRI in evaluating some of the pathologies such as: bone erosions, intraarticular effusions and changes of tendons. Power Doppler can detect subclinically synovitis of the small joints in the early phase of RA. Nowdays, in the field of rheumatology we talk about US and PD as "a rheumatologist's prolonged finger" or as " a rheumatological stetoscope", exactly because of their accessibility and possibility of getting quick and useful information about the patient himself. Since US and PD are inexpensive and non invasive procedures, they can greatly improve diagnostics in RA and especially the assessment of the early phase of the inflammatory diseases, which can serve as a reliable indicator of the overal progression of the disease. Some new data show possibility of monitoring patients with RA and their response on disease modifying antirheumatic drugs (DMARDs) or biologicals by US and PD. PMID- 22232956 TI - [Low back pain--from definition to diagnosis]. AB - Low back pain is defined as pain and discomfort, localised below the costal margin and above the inferior gluteal folds, with or without leg pain. It is one of the most commonest cause of seeking physician office visits, secound cause of sick leave, and because of high direct and indirect costs it has great medical, social and economic impact for individual, family and society. Non-specific low back pain is defined as low back pain not attributed to recognisable, known specific pathology and specific low back pain which has known pathomorfological cause. For most patients with low back pain a thorough history taking and clinical examination are suffitient. Extended diagnostic analysis are needed in the case of nerve root pain/radicular pain and serious spinal pathology, respectively after identification of red flags. Moreover, great attention has to be achieved at psychosocial factors or so called yellow flags which increase the risk of developing chronic low back pain and long term disability (including work loss associated with low back pain). PMID- 22232957 TI - [Low back pain vs. leg dominant pain]. AB - There are two patterns of back pain: 1) back-dominant pain and 2) leg pain dominant, greater than back pain. The causes of back pain are very different and numerous, but mostly are due to vertebral, mechanical etiology, and rarely because of non vertebral, visceral etiology. Leg pain greater than back pain is mostly disease of spinal nerve root, generally presented by radicular pain in a dermatomal distribution. Mechanical compression of spinal roots, caused by disc herniation or by spinal stenosis, results in radicular symptoms. Rarely, in about 1% of patients, there are some other reasons except vertebral mechanical cause, like infection, tumor or fracture. There are several causes of pseudoradicular pain like periferal neuropathy, myifascial syndromes, vascular diseases, osteoarthritis. Spondylarthropathies should be taken in cosideration as well. A complete history and physical examination is important to determine further diagnostic evaluation and to provide eficient therapy. PMID- 22232958 TI - [An overview of conservative treatment for low back pain]. AB - Low back pain is the most frequent musculoskeletal complaint worldwide and leading cause of chronic disability. In this review we discuss knowledge about the role of management of non-invasive, conservative therapy for the nonspecific low back pain. Initial therapy includes modification of activity, pharmacological analgesic therapy and education of patients. In patients with sub acute or chronic low back pain, multimodal and interdisciplinary treatment approach is necessary with personalized and individual healthcare combined with different modality of therapy. PMID- 22232959 TI - [The role of rehabilitation in the treatment of low back pain]. AB - The frequency of symptoms that manifest in low back pain (LBP), whatever if its immediate cause, makes pain back an important medical, and also an socio economical theme. Rehabilitation is an important factor in the medical and curing process of such patients. Evaluation of the effect of medical rehabilitation is being monitored with a number of specific questionnaires, in which one of the most used is the Oswestry LBP Questionnaire, Roland-Morris Questionnaire and non specific WHOQOL. All the already mentioned mechanisms for LBP have its disadvantages but they also fit in well in the bio-psycho-social model of treatment, for which the LBP is a good example. LBP is not only a problem for itself, but also the cause of stress, disability and reduced functional ability of each patient. PMID- 22232960 TI - [What a rheumatologist must know about spine surgery?]. AB - Spine surgery is a matter of interest of several specialities. The development of new instrumentations brought a number of new operative techniques. Minimally invasive surgery, endoscopy, offers superior results, but first disapontiments appear as well. What to operate, when and how? A schematic presentation of pathology, operative procedures and indications are presented. PMID- 22232961 TI - [Musculoskeletal manifestations in lysosomal storage diseases]. AB - Lysosomal Storage Diseases (LSD) is a group of metabolic disorders caused by the deficiency of lysosomal enzymes needed for metabolism of lypids, glycoproteins, mucopolysaccharides. Deficit causes their progressive accumulation within the cells of various tissues throughout the body, ultimately compromising cell function. The major sites of disease differ depending on the specific enzyme deficiency; therefore, clinical presentation present a chronic multisystemic and progressive course and approaches to therapy are different for the various disease types. Because of multisystemic involvement in patients with LSD, treatment is multidisciplinary and encompasses both the curative and palliative elements. Replacing the deficient enzyme by enzyme replacement therapy (ERT), produced by recombinant DNA technology, may provide clinically important benefits, improve symptoms and delay disease-induced complications. Patients with lysosomal storage diseases demonstrate musculoskeletal manifestations (myopathy, joint contractures, vertebral deformities) early in life. Regular evaluation and recognition of musculoskeletal manifestations as an early symptom of LSD is important, because the posibility of early management of LSD before ireversible changes, can be provided. PMID- 22232962 TI - [Family based association study of MMP-9 gene-1562C>T polymorphism in schizophrenia]. AB - AIM: MMP-9 is a candidate gene related to the neurodevelopment hypothesis of schizophrenia. The aim of this research was TDT analysis of polymorphism -1562C>T MMP-9 gene in schizophrenia. METHODS: Research was carried out on 147 trios (patient and his/hers both healthy parents). Genetic material was isolated from leukocytes using the salting out method. Polymorphism was studied with PCR-RFLP, statistic analysis was made using transmission disquilibrium test by Haploview 4.2. RESULTS: There was no significant association between analyzed polymorphism of MMP-9 (-1562 C>T) and schizophrenia. CONCLUSIONS: Insignificant association doesn't exclude the possible contribution of MMP-9 to pathogenesis of schizophrenia. Further research is needed to be carried out on bigger groups and other populations. PMID- 22232963 TI - [Research on associations between selected polymorphisms of genes DRD2, 5HTT, GRIK3, ADH4 and alcohol dependence syndrome]. AB - Alcohol abuse is a complex multifactorial disease. It is believed that alcohol dependence is mostly caused by genetic (40-50%) and environmental (50-60%) factors. AIM: The aim of this study was to assess the relation between the alcohol dependence syndrome (ADS) and the polymorphism of the selected genes (GRIK3, 5HTT, ANKK1, ADH4). METHODS: The study was conducted in the Department and Clinic of Psychiatry, the Pomeranian Medical University in Szczecin in the years 2006-2008. It involved 100 patients hospitalised with Alcohol Dependence Syndrome (ADS). DNA polymorphisms were detected using the polymerase chain reaction (PCR). Statistical calculations were done with SPSS version 9.0. The chi square test was applied to calculate the differences in the frequency of allelic forms. RESULTS: Comparison between the patients with ADS and the patients from the control group demonstrated statistically significant association of ADH4 (rs1800759) with the alcohol dependence syndrome. Both the A/A genotype and the A allele were more common in patients with ADS. Also, analysis of the association of the ANKK1 gene revealed statistically significant differences (p = 0.004) between the ADS group and the control group. No statistically significant differences considering other associations were found. CONCLUSION: Our results suggest that the analysed polymorphisms ofANKK1 and ADH4 can play an important part in the pathogenesis of alcohol abuse. The greater study group would increase the statistical power of the study and help to isolate homogeneous sub-groups of patients. PMID- 22232964 TI - [The influence of parents personality and DRD4 and 5HTT genes polymorphisms on predisposition to alcohol dependence in their sons]. AB - AIM: The aim of this work was to investigate differences in parents' personality and dopaminergic and serotoninergic gene polymorphisms which may affect certain predispositions to alcohol dependence as described in the typology developed by R. Cloninger and O.M. Lesch. Also the possibility of recognising their genotypes DRD4 (Gene ID: 1815A ) and 5HTT (Gene ID: 6532) could be helpful in predicting predisposition to addiction. METHODS: A total number of 213 individuals (71 Polish trios), Caucasian families were investigated. Fathers' mean age was: 61.7 +/- 10.8 and mothers were 59 +/- 10 years old. None of the parents fulfilled the criteria of alcohol dependence. The alcohol dependent probands were male, with confirmed biological descent, mean age: 35.2 +/- 9.7 years. In all the participants TCI was performed. Characterisation of alcohol dependence and the course of withdrawal were obtained by SSAGA. Specially designed questionnaires based on Cloninger and Lesch typologies were used. The essential data on both parents was collected and AUDIT was performed. DRD4 and 5HTT gene polymorphisms were determined by PCR and TDT test was calculated. RESULTS: TDT analysis showed no differences in the transmission of alleles of 5HTT and DRD4 genes in the investigated families. The analysis of TCI personality profiles confirmed no statistically significant relations between Cloninger 1 and 2 subtypes of alcoholics. A statistically significant difference was recorded between the scores for groups I and II classified according to Lesch's typology in dimensions NS, NS2 and NS4. Fathers of probands characterised as type I according to Cloninger had statistically lower scores in dimension C and C5 in comparison to type II fathers. Fathers of type II alcoholics according to Lesch's typology had higher NS2. Mothers of type I alcoholics according to Cloninger had statistically lower scores in dimension HA2 in comparison with type II mothers. CONCLUSIONS: On the basis of the above presented findings it can be stated that there might be specific interactions between personality traits in alcohol dependent probands and their parents. Nevertheless, further studies are needed to establish whether this relationship may have a predictive value, which may implicate therapeutic implications, as proposed by the clinical algorithm of O. M. Lesch. PMID- 22232965 TI - [ANKK1 gene in psychiatry]. AB - According to last findings, one of the most commonly studied polymorphisms in psychiatry-Taq1A is located in the ANNK1 (Ankyrin Repeat and Kinase Domain containing 1) gene, not in the dopamine receptor 2 (DRD2) gene. This polymorphism has been extensively studied in relation to alcohol, nicotine and drugs addiction, eating disorders, ADHD, schizophrenia and pharmacogenetics. The ANKK1 gene contains single serine/threonine kinase domain and 11 ankyrin repeats. ANKK1 belongs to RIP (Receptor-Interacting Protein) serine/threonine kinase family. These kinases are important in cell proliferation, differentiation and activate transcription factors. DRD2 gene is probably regulated by ANKK1 through NF-kappaB (Nuclear Factor-kappaB). ANKK1 is activated by apomorphine-dopaminergic agonist, which indicates another link with the dopaminergic system. It seems accurate to search for associations of polymorphisms in ANKK1 gene with dopaminergic system disorders. PMID- 22232966 TI - [Fragile X syndrome--child's and parent's problem]. AB - Fragile X syndrome is the most common familial form of mental retardation. The incidence is estimated to be 1 in 4000 male births. The disease is caused by amplification oftrinucleotide repeats CGG in the first exon of FMR1 gene, located on the distal part of the long arm of the X chromosome. The main symptom of the disease is mental retardation, usually of moderate or profound degree. Characteristic clinical features of the disease observed in the affected person after puberty involve: an elongated face, large protruding ears and macroorchidism. Diagnosis is usually made late, when the child is 3-4 years old. Making diagnosis early is very difficult because of a lack of specific symptoms. We can observe developmental delay in children, with very late development of speech and behavioural problems with autistic features. Early diagnosis is very important, because its identification of high genetic family risk. The risk of recurrence for next children is as high as 50% and is stable for each pregnancy. PMID- 22232967 TI - [Visual-spatial functions and organisation of grapho-motor actions in ADHD children]. AB - AIM: The aim of the study was to test whether children with a diagnosis of ADHD at the age of 7-16 years have deficits in visual-spatial, visual memory, planning, and organisation of the visual-motor functions. METHODS: The study included 186 unrelated patients aged 7-16 years diagnosed with ADHD. The control group consisted of 156 healthy individuals aged 7-16 years. The methods applied were the Rey-Osterrieth Complex Figure Test (ROCF) and Matching (MFFT). RESULTS: The number of errors in the MFFT was significantly different between healthy combined subtype. There were no differences between inattentive and healthy children. In the Rey-Osterieth Complex Figure test, statistically significant differences were found between the control group and a group of combined ADHD in the number of points obtained when drawing back and reproduction from memory. In the latter index were also differences between ADHD inattentive children and the combined subtype. Children with ADHD obtained statistically significant different results than healthy children in the drawing category (which were treated as an indicator of the executive functions of planning) but only in reproduction from memory. Quality of the copy does not differentiate the groups. CONCLUSIONS: ROCF and MFFT are useful measures of visual-spatial function and visual memory of children with ADHD. They have less relevance in the assessment of executive functions. Visual-spatial disorders were found only in children with ADHD combined subtype. PMID- 22232968 TI - [Declared management methods used by the Polish psychiatrists among a group of people with a high risk syndrome of psychosis development: results of the National Polish Questionnaire]. AB - AIM: The aim of the study was to assess the declared management methods used byPolish psychiatrists among a group of people at high risk of psychosis development. METHOD: Management methods used among two kinds of UHR persons, i.e., (A) attenuated or brief, limited psychotic symptoms group and (B) state and trait risk factors group, were assessed during nationwide psychiatric conferences held in 2009, which gathered Polish psychiatrists practicing throughout the whole country. RESULTS: (A) For those experiencing attenuated or brief, limited psychotic symptoms (APS or BLIPS), the vast majority of respondents (88%) declared using pharmacological intervention. Moreover, all doctors choosing pharmacotherapy declared using antipsychotic drugs (AP). Second generation antipsychotics (SGA) (84%), i.e., risperidone (48%) and olanzapine (32%) were medications to be selected as the first choice. Most doctors declared that they use medium doses ofAP (46%) for minimum 6-12 months (31%). (B) Among the group of people with state and trait risk factors, the vast majority of respondents (81%) also declared using AP: mostly SGA (75%) and typical AP (20%). Medications used as the first choice in this group were also mostly risperidone and olanzapine (44% and 28% respectively). 65% of the doctors declared using low doses of antipsychotics for the minimum of 6-12 months (39%). CONCLUSIONS: A high percentage of Polish psychiatrists state that they use pharmacological intervention in persons at high risk of developing psychosis. Preferred medications are mainly SGA (risperidone and olanzapine), prescribed in medium and low doses for a minimum of 6-12 months. PMID- 22232969 TI - [Home care services as a social network compensation of the mentally ill]. AB - AIM: Research undertaken in order to assess possibilities of social network compensation amongst population supported with home care services adjusted to mentally ill needs. Analysis included scope of support functions, number of networks and its quality. METHOD: The study group consisted of 105 mentally ill persons participating in home care services program. Research tools used were as follows: sociodemographic questionnaire (prepared for the research purposes). Bizon's Map and Social Network Questionnare, Bizon's Social Support Inventory. RESULTS: Results show therapists participating in the home care services program as the basic category that composes networks indicated by respondents. Therapists significantly compensate sparse social support networks of the respondents. It can be assumed as a positive influence due to social functioning, feeling of secure and coping abilities of persons supported by home services. DISCUSSION: Benefits noted in compensation home care participants lead to another research question. Further research should considerate an issue of major participation of professionals as a specific block to involve those who constitute natural support resources, e.g., family members or neighbours into the networks. PMID- 22232970 TI - [Transcranial Doppler sonography study in schizophrenia--review]. AB - In this review, the authors describe the Transcranial Doppler sonography technique (TCD). They also make an analysis of the up-to-date publications on the use of TCD in the studies on schizophrenia. The current studies show a promising potential of TCD. Its benefits are connected with high time-output, low-cost and only slightly invasive character. The difficulty of using TCD lies in the experience of the technician and the quality of the equipment. What should be kept in mind, is the fact that the data received in the TCD study is only an indirect indication of CNS activity. The research described here shows two potential directions of applying TCD to schizophrenia studies. One of them concerns the intensity of psychotic symptoms as well as the medications given on the changes in transcranial blood-flow. The second connects the search for cognitive function disorders and the activity of certain brain regions with the transcranial blood-flow changes resulting from them. In such a protocol of research, where TCD technique is simultaneously applied along with an evaluation through neuropsychological tests, one could speak of a functional transcranial study--fTCD. The studies mentioned here, have only a pilot character owing to a low number of subjects studied. However, a picture of subtle differences in cerebral blood flow of schizophrenic patients does appear. The use of TCD requires further, deeper studies with the participation of a larger group of patients, along with a neuropsychological tool application. PMID- 22232971 TI - [The specificity of the prosecution of communist crime and ability to participate in court proceedings]. AB - OBJECTIVE: To assess the complexity of the mental state in terms of court trial participation of a person accused of communist crimes 50 years ago. METHOD: A description of the need for multiple tests at an interval of 16 months in connection with verifying the ability to participate in the trial. RESULTS: In the first opinion, team of experts put the diagnosis: characteristics of an organic brain syndrome in the form of mild dementia. In the second opinion, done after 16 months, experts recognised the developing process of a moderate dementia. CONCLUSIONS: In a 80-year-old person for whom the opinion was issued, in over 16 months there has been a significant increase in the process of dementia, which eventually prevented participation in the trial. PMID- 22232973 TI - [Intensity of negative symptoms, working memory and executive functions disturbances in schizophrenic patients in partial remission period]. AB - AIM: The aim of the study was to assess the correlation between the level of working memory and executive functions impairment in schizophrenic subjects in their partial remission period and the intensity of psychopathological symptoms measured by PANSS scale. METHOD: 45 patients with schizophrenia were included in the study (28 male and 17 female), aged 18-46 (mean 27 +/- 7) years during partial remission of psychopathological symptoms (PANSS < 70). The control group consisted in 35 age, gender and education matched healthy persons (13 male i 22 female), aged 21-49 (mean 30 +/- 8) years. To assess the intensity of psychopathological symptoms the PANSS scale was used, neuropsychological assessment included the Wisconsin Card Sorting Test (WCST), N-back test and Stroop test from the Vienna Tests Battery. RESULTS AND CONCLUSIONS: In schizophrenic patients in partial remission period, the significant dysfunctions of working memory and executive functions show association with negative (not positive) schizophrenic symptoms. PMID- 22232972 TI - [Psychotic disorders related with chronic use of mephedrone. Case report]. AB - AIM: The aim of the study was to present the case of a patient with psychotic disorders, o most probably connected with persistent mephedrone use. METHOD: The analysis of the clinical case and medical documentation. RESULTS: The presented patient had used mephedrone regularly (few times a week) for four months. Because of delusions of reference, delusions of persecution, agitation and anxiety, she required psychiatric hospitalisation. During the first hospitalisation she denied using legal highs, she was diagnosed as having schizophrenia and treated with olanzapine. After discharge, she didn't stop to use legal highs and psychotic symptoms occurred once again. The patient needed another hospitalisation. Despite the fact that antipsychotic treatment wasn't administered, the symptoms resolved. Nevertheless, somnolence, apathy and social isolation were observed. CONCLUSIONS: Recently legal highs are very popular, especially among adolescents and young adults. That is the reason why physicians have become more anxious because there is little information about their contents. In most of them, synthetic or botanical substances are included. In clinical practice not only somatic but also psychiatric complications connected with legal high use are observed. It is difficult to verify why this patient developed psychotic symptoms after recurrent intoxication. It is possible that she has an individual predisposition to develop psychosis. In this case, we have no information about previous features of ultra high risk state in this patient. PMID- 22232974 TI - [Differences in severity and comorbidity of panic and depressive symptoms in difficult and aspirin-induced asthma]. AB - AIM: The author examined psychiatrically a group of 106 patients with difficult asthma and 100 patients with aspirin-induced asthma. METHOD: 106 consecutive adults with confirmed, physician-diagnosed difficult asthma and 100 patients with aspirin-induced asthma underwent a psychiatric interview and assessment using M.I.N.I 5.0, Beck Depression Inventory (BDI) and Panic And Agoraphobia Scale (PAS). Psychiatric assessment was performed by an experienced liaison psychiatrist according to ICD-10 and DSM-IV diagnosis. In the difficult asthma group there were 78 women (74%) and 28 men (26%). The average age was 51.3 (SD = 14.5) for women and 47.5 (SD = 12.7) for men. In aspirin induced asthma group there were 66 women (66%) and 34 men (34%). The average age was 52.7 (SD = 12.3) for women and 48.8 (SD = 13.0) for men. RESULTS: In difficult asthma both panic and depressive symptoms were statistically much more severe than in aspirin induced asthma. Comorbidity between panic and depressive symptoms was almost equal in women and men with difficult asthma, but in aspirin-induced asthma, comorbidity was more common among women than men. Panic-depression comorbidity is regarded as a predictor of especially severe course and outcome of psychiatric disorder. CONCLUSIONS: It is possible that especially severe panic and depressive symptoms both with panic-depression comorbidity in women and men with difficult asthma have an impact on aethiology of this near-fatal and treatment resistant subtype of asthma. PMID- 22232975 TI - [General differences in the intensity of catastrophic interpretation of body sensations and it's specific links with severity of symptoms of panic disorder and depression in women and men with difficult and aspirin-induced asthma]. AB - AIM: The author examined psychiatrically a group of 106 patients with difficult asthma and 100 patients with aspirin-induced asthma. The special interest of the study were differences in the intensity of catastrophic interpretation of body sensations and it's specific links with severity of symptoms of panic disorder and depression in women and men from both groups. METHOD: 106 consecutive adults with confirmed, physician-diagnosed difficult asthma and 100 patients with aspirin-induced asthma underwent a psychiatric interview and assessment using M.I.N.I 5.0, Beck Depression Inventory (BDI), Panic And Agoraphobia Scale (PAS) and Body Sensations Interpretation Questionnaire (BSIQ). Psychiatric assessment was performed by an experienced liaison psychiatrist according to ICD-10 and DSM IV diagnosis. In the difficult asthma group there were 78 women (74%) and 28 men (26%). The average age was 51.3 (SD = 14.5) for women and 47.5 (SD = 12.7) for men. In aspirin induced asthma group, there were 66 women (66%) and 34 men (34%). The average age was 52.7 (SD = 12.3) for women and 48.8 (SD = 13.0) for men. RESULTS: General intensity of catastrophic interpretation ofbody sensations was much higher in the difficult asthma group. In both groups of asthmatic patients women were the majority, with more frequent severe panic and depressive symptoms than men. Nevertheless there was a very similar and strong tendency to increased intensity of catastrophic interpretation due to severity of both panic and depressive symptoms in subgroups of women and men with difficult and aspirin induced asthma. CONCLUSIONS: It is possible that differences in the intensity of catastrophic interpretation of body sensations used by women and men with difficult asthma affect the development, course and severity of their panic and depressive symptoms. This may play a special role in development of difficult asthma phenomenon. PMID- 22232976 TI - [Results of the Benton Visual Retention Test and the Bender Visual--Motor Gestalt Test among patients suffer from depressive disorders and organic depressive disorders]. AB - AIM: The comorbidity of depression and dementia has been extensively studied. Four main hypotheses have been suggested to explain the relationship between depression and dementia: 1. depression may be a psychological reaction to perceived cognitive decline, 2. depression may be an early symptom of dementia, 3. depression may be an etiologic risk factor for the onset of dementia, and 4. dementia and depression share common risk factors. The objective of this study was to examine the differences between depressive disorders and organic depressive disorders by using two neuropsychological tests. METHOD: A sample of 61 persons aged 23-62 years participated in the study. Patients who took part in the investigation were divided into two groups: depressive disorders (DD, n = 30), organic depressive disorders (ODD, n = 31). Cognitive functions were evaluated by the Benton Visual Retention Test (BVRT) and Bender Visual-Motor Gestalt Test (BVMGT). RESULTS: Relevant statistical differences among examined group were observed: in BVRT correct answers (p = 0.006), errors (p < 0.001); in BVMGT: (p < 0.001). DD patients achieved higher results in psychological test than ODD patients. DD group (average) in BVRT: correct answers (-1.33), errors (2.31); BVMGT (average): (50.37). ODD group (average) in BVRT: correct answers ( 2.71), errors (5.81); BVMGT (average): (72.01). CONCLUSIONS: Patients with organic depressive disorders achieved significantly lower results than patients with depressive disorders in BVRT and BVMGT. PMID- 22232977 TI - [Screening post-stroke depression using the Hospital Anxiety and Depression Scale]. AB - INTRODUCTION: Hospital Anxiety and Depression Scale (HADS) for its simplicity is potentially useful for screening depressive and anxiety disorders in post-stroke patients. To our best knowledge HADS hasn't been assessed in the Polish population of post-stroke survivors. AIM: Assessment of clinical value of HADS in screening depressive and anxiety disorders in post-stroke patients. METHOD: Patients included in this study were admitted do the Department of Neurology of the Medical University of Gdansk between 3rd April and 5th December, after first incident of ischaemic stroke. 116 subjects were included, depression was diagnosed in 29 and anxiety disorder in 16 of patients (13 with comorbid depressive episode). The test was done by 75 patients, 193 visits were assessed, from the following time after stroke: 6 weeks, 12 weeks, 6 months and 12 month. RESULT: Using the cut-off value > or = 7 points, the results were as following: depression subscale--sensitivity: 90.0%, specifity 92.2%, anxiety subscale: sensitivity: 86.5%, specifity 94.9%, which was the most optimal cut-off point. Cronbach a: for the depression subscale was 0.892, for the anxiety subscale was 0.815; each position of the scale correlated with the general result of both scales' result in a degree which increased the Cronbach a value. CONCLUSION: Hospital Anxiety and Depression Scale is useful for screening depression and anxiety in post-stroke patients. It is recommended to lower the cut-off value to 7 points. PMID- 22232978 TI - [Symptom checklist S-III]. AB - AIM: Symptom checklists enable clinicians and researchers to quickly estimate the probability of neurotic disorder presence. To pursue this goal, they should include a possibly limited number of items, describing symptoms most prevalent in the disordered population. Fluctuations in that prevalence force researchers to prepare new variants of checklists every few years, therefore the next (current) version of the checklist "S" for screening has been prepared. METHOD: The Symptom checklist S-III includes items regarding occurrence and intensity of 82 symptoms, chosen according to their highest prevalence in 1872 patients diagnosed before admission to psychotherapy in the years 2004-2008, because of neurotic disorders. There is the "truthfulness scale" included in the checklist, which enables an estimation of reliability of answers. Norms are calculated in the groups of 301 non-patients and 508 patients before admission to psychotherapy in 2009-2010. RESULTS: The cutoff point between Global Symptom Levels (OWK) in the nonclinical population and patients before admission to psychotherapy is estimated, and the value of 146 points for both men and women is suggested. CONCLUSIONS: Symptom checklist S-III has satisfactory psychometric properties and can be applied in a quick diagnosis of neurotic disorders occurrence. PMID- 22232979 TI - [Polish version of the Revised Hallucination Scale (RHS) by Morrison et al. Its factor analysis and the prevalence of hallucinatory-like experiences among healthy participants]. AB - AIM: The study aimed at presenting the Polish version of Morrison's et al. (2002) Revised Hallucinations Scale (RHS). Factor structure of the RHS was of interests. Moreover, we were interested in the incidence of hallucinatory-like experiences among healthy subjects. METHOD: Polish version of RHS was elaborated following the back-translation procedure. Then, it was administered to 213 healthy persons. Factor structure analysis of RHS was conducted. Finally, based on the RHS scores, frequency of selected visual and auditory hallucinatory like experiences were calculated. RESULTS: Factor analysis of RHS revealed four factors structure: 1) imagery vividness; 2) auditory and visual perceptual anomalies; 3) experience of dissociation; 4) auditory hallucinatory like experiences. Four factors explained 51.54% of total variance in the RHS. The scale has good reliability (Cronbach's alpha varied from 0.7 to 0.88). Frequency of selected auditory hallucinatory like experiences varies from several to a dozen percent. Similar results were revealed for visual hallucinatory like experiences. These experiences that are similar to hallucinations observed among psychotic patients were observed seldom. CONCLUSIONS: The factor structure of Polish versions of the RHS is comparable to the original one. However, we have found a new subscale that may represent the experience of dissociation. The Polish version of the RHS is characterised by good psychometric properties and may be used as an assessing scale for psychotic like experiences in a population. Our results suggest that hallucinatory like experiences are present among healthy subjects and those phenomenon may represent a psychosis phenotype. PMID- 22232980 TI - [Psychometric properties of the Polish version of the Metacognitions Questionnaire-30]. AB - AIM: The aim of the present study was to examine basic psychometric properties as well as to confirm the five-factor structure of the Polish version ofthe Metacognitions Questionnaire-30 (MCQ-30), a short instrument to measure various aspects of maladaptive metacognitions. METHOD: The sample consisted of 315 individuals (239 females and 76 males). Fourty-five of the participants were examined twice within the test-retest procedure. Among questionnaires used in the study were MCQ-30, the State-Trait Anxiety Inventory (STAI) and four subscales chosen from the Neurotic Personality Questionnaire (KON-2006). RESULTS: Cronbach alphas, coefficients ofreliability, reached acceptable values (0.70-0.87). Correlation coefficient (Pearson's r) between two separate administrations ofMCQ 30 was high (0.72). Correlation coefficients between results of the MCQ-30 and results of the STAI and the part of KON-2006 were statistically significant and positive (018-064). Confirmatory factor analysis confirmed the five-factor structure of the questionnaire (the model was modified, and the method of maximum likelihood along with bootstrap procedure was used; goodness-of-fit indices were e.g. Chi2 [391] = 764.50 with p < 0.001, Chi2/df = 1.95, GFI = 0.858, RMSEA = 0.055). CONCLUSIONS: The results from this study show generally good psychometric properties of the Polish version of the metacognitions questionnaire. Polish version of the MCQ-30 seems to be a measure comparable with the original version. PMID- 22232981 TI - [Geriatric Depression Scale (GDS). Validity and reliability of different versions of the scale--review]. AB - Diagnosing depression in the elderly poses a serious problem because of the ageing process and various diseases that influence and mask symptoms of depressed mood. For instance, depression is often confused with dementia. It is therefore crucial to use a diagnostic tool that takes these problems into account. The presented paper is a review of the recently published studies concerning the Geriatric Depression Scale (GDS). The properties of the original 30-items version of the GDS are described, along with the information on shorter versions of the scale (i.e. the scales consisting of 20, 15, 12, 10, 5, and 4 items). The psychometric properties i.e. validity, reliability, sensitivity, and specificity of the original version ofGDS are presented. Also presented is the information on scoring for both 30- and 15-item version of the scale. The results of the studies concerning shorter versions of the GDS were discussed in the context of their usability in various settings. Different ways of administering the GDS are mentioned. In the last part of the article, general problems concerning diagnostic usability of the Geriatric Depression Scale are discussed. PMID- 22232982 TI - [The role of the right hemisphere in the aetiology of the depressive disorders]. AB - Many differences between the hemispheres have been observed, from the gross anatomical level to differences in dendritic structure or neurotransmitter distribution. Analytic reasoning and language functions such as grammar and vocabulary are often lateralized to the left hemisphere of the brain. The right cerebral hemisphere plays a special role in tasks involving the direction of spatial attention, recognition of faces, perception, possibly generation of affect and affective prosody. Depression is associated with many different cognitive impairments e.g. in the domains of working memory and executive functions as well as interpersonal and social cognition problems. Little is known about the relationship between cognitive and affective deficits in depression. Researchers have hypothesised that the laterality of brain damage may facilitate the expression of emotional or affective disturbances. The aim of the study is to describe the role of the right hemisphere in the aetiology of depressive disorders. PMID- 22232983 TI - [Neurobiology of suicidal behaviour]. AB - The authors of this paper present a review of actual data on the neurobiological background of suicidal behaviour. The results of epidemiological studies suggest that suicidal behaviours have certain genetic background which do not depend on the presence of concomitant mental disorders. The estimated heritability rate of suicide is about 21-50%, while the heritability rate of suicidal ideation and behaviour is about 30-55%. The genes of serotonergic and noradrenergic systems, as well as the HPA axis genes, have been scrutinised in context of suicidal behaviour. Epigenetic factors are also believed to be involved in the pathogenesis of suicide. Serotonergic, noradrenergic, glutamatergic and GABAergic systems, as well as the HPA axis, are the main neural networks involved in the pathophysiology of suicide. Disorders of opioid and endocannabinoid systems can also be found in suicide victims. Pathogenesis of suicidal behaviour also contains abnormalities of cell signalising and pathology ofglial cells. Neurobiological background of akathisia and impulsivity (clinical issues closely related to the pathogenesis of suicidal behaviour) have also been presented. Most of the available trials on neurobiological background of suicidal behaviour have significant methodological weaknesses, making the results difficult to interpret. Usually they contain small samples and only single biological variables (without adjustment on environmental factors) are being analysed. PMID- 22232984 TI - [Diabetes mellitus and psychiatric diseases]. AB - Metabolic disorders, especially diabetes mellitus, occur more often in patients diagnosed with psychiatric diseases than in the general population. The suggested reasons include common environmental factors, like a lifestyle leading to obesity and insulin resistance, social and economic status. Moreover, these disorders partially share a common genetic background. The influence of antipsychotic therapy itself also plays an important role. An increased risk of metabolic disorders, like glucose dysregulation, dyslipidemia or weight gain, exists during antipsychotic treatment. These drugs influence the hypothalamic regions controlling food intake, impair the insulin release by beta cells or induce insulin resistance. Therefore the choice of antipsychotic drug should be dependent on the actual patient's metabolic status and his comorbidities. Patients treated with antipsychotics should be screened for several metabolic disorders. Periodic checks for abnormalities of body weight, waist circumference, blood glucose or lipid profile are recommended in these patients. Any abnormality noticed during such a check is the indication for antipsychotic treatment modification and adequate metabolic disorder treatment. PMID- 22232985 TI - [Dissociative fugue in a maternity ward patient--a case report]. AB - AIM: To pay attention to the role of stress connected with delivery, obstetric history, as to the pathologies in the infant as predictors of dissociative disturbances in the patient of the maternity ward. METHOD: The case analysis. CASE DESCRIPTION: The thirty-year-old woman with secondary education, married and employed had left the maternity ward with her baby unnoticed on the fourth day after giving birth. The patient didn't remember this fact after finding her and the infant by the police. The patient had no genetic predisposition in her history and had suffered head injury in her childhood. Her mother lost two of her siblings (miscarriage and early death of infant). The patient miscarried her first pregnancy, and then she had waited several years for the baby. The second pregnancy was at risk, the labor was premature and the infant was born with palatoschisis. In the maternity ward, the patient had difficulties with feeding the baby. She experienced fear about the baby's life, as well as the feeling of being neglected by the staff. In the psychiatry ward, the patient did not reveal any symptoms of mental illness. A memory gap covered the period of her flight. She had shown interest in her child and was motivated to nurse him by herself. The tendency to use immature defence mechanisms (denial and suppression), as well as mild cognitive dysfunctions were observed in psychological testing. Dissociative fugue was diagnosed. CONCLUSIONS: The interaction of past and present traumatic experiences with cognitive dysfunctions and immature defence mechanisms could influence the patient's ability to cope with fear about the child negatively. It led consequently to dissociative loss of memory with disintegration of perception, identity, and conscious control over the behaviour in the fugue. The case shows a need for early diagnosing and providing psychological support to patients of the maternity ward, especially those laden with multiple stress factors. PMID- 22232986 TI - [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. AB - The pharmacological properties and possible clinical use of trazodon in the treatment of depression are presented. Trazodon is the only antidepressant from the SARI (Serotonin Antagonists and Reuptake Inhibitors) group available in Poland. It has a wide pharmacodynamic profile (being an antagonist of 5-HT2A and 5-HT2C serotoninergic receptors, alpha1 and alpha2 adrenergic receptors as well as H1 histaminergic receptors, and in higher doses it blocks the SERT serotonine transporter) which explains its wide therapeutic spectrum ranging from symptomatic treatment, through the potentialization of other drugs activity, all the way to monotherapy of depressive syndromes. An especially complex action on the serotoninergic system results in the lack of unwanted side-effects during treatment with trazodon (e.g. sexual dysfunction, significant body weight gain), which may be present during the treatment with other drugs (selective serotonin reuptake inhibitors). It is metabolised by the CYP450 isoenzyme: mainly the 2D6 and 3A4. This requires its dose to be adjusted when administered simultaneously with other drugs influencing the activity of those isoenzymes. Trazodon CR is an orally administered controlled release form, which simplifies its dosage and reduces the risk of adverse effects. Usually doses of 75 to 600mg daily are used; in the elderly those doses should be lower. Trazodon turned out to be effective in the treatment of various depressive syndromes, amongst them depression with insomnia, with anxiety and unrest, as well as depression in the elderly. In the recommended dose spectrum, trazodon is well tolerated. Unwanted adverse effects of the drug appear rarely and they are: somnolence, dizziness, gastrointestinal dysfunctions, and dry mouth. PMID- 22232987 TI - [Provisionality phenomenon in the histo- organo- and systemogenesis]. AB - This review summarizes the results of the study of the provisionality phenomenon in the development of the organs of the urinary system (mesonephros, metanephros) in viviparous (human, rat) and oviparous (bird) amniotes, human organs of mixed origin (pituitary, ovary, stomodeum) reparative regeneration of supporting tissues (in humans and Syrian hamster), morphogenesis of primary hepatic cancer developing against the background of superinvasive opisthorchiasis. It is shown that during the development of tissues and organs, the stages of provisional and definitive histo- and organogenesis could be determined; saltatory mechanism is typical for embryonic organogenesis (formation of cartilaginous skeletal primordia, meso- and metanephrons) and foci of oncogenesis. Transformation zones of the type of tissue organization in the epithelium are located in the areas of contacts of the derivatives of different embryonic primordia. Mechanism of transformation of the epithelial layer of stomodeum and Rathke's pouch is provided by local activation of apoptosis and by the formation of the epithelial cells of a qualitatively new generation. PMID- 22232988 TI - [The assessment of the regularity of the nephron anlage tubule formation on the basis of provisionality principle]. AB - The study of the definitive kidneys of 94 human embryos and fetuses at 4.5 to 12 weeks of gestation, has demonstrated that the formation of the proximal nephron tubules resulted from the cellular proliferation in the area of transition of the capsule of the renal corpuscle into the tubular part of the nephron that occurs only after the completion of the segregation of the renal corpuscle and the distal tubule within the nephron anlage. The formation of the renal tubules in the nephron anlage seems to be determined phylogenetically, while the initial differentiation of the distal tubule is a provisional feature. PMID- 22232989 TI - [The sequence of nephron tubule differentiation in the definitive human kidney during the fetal period]. AB - The regularities of the formation of the undifferentiated renal tubules in the definitive kidney were studied in 174 human embryos and fetuses at 4.5 to 40 gestational weeks. On the basis of the study of morphological and morphometrical parameters of these tubules, it was shown that the increase of the average tubular crossectional area was associated with the consecutive formation of the nephrons of the definitive kidney and the differentiation of the segments of their tubular portions. The increase of the proportion of the epithelium in the structure of undifferentiated tubule is determined by the segregation of the proximal and distal tubules within the forming nephrons. The sequence of the initial stages of the renal tubule differentiation is dictated by the ergontic correlations; it developes from the proximal tubule to the distal one and is different from the succession of their formation in the process of the early nephronogenesis. PMID- 22232990 TI - [Morphogenesis of the structural changes of the internal organs in superinvasive opisthorchiasis]. AB - The study of the model of superinvasive opisthorchiasis (SO) in Syrian hamsters and autopsy material obtained from patients with SO, it was shown that during the early period of pulmonary disease, the lungs underwent changes developing on the basis of delayed-type hypersensitivity reactions. In the chronic phase of SO, exudative and predominant productive reactions were revealed leading to the interstitial lung disease, fibrosing alveolitis. In the heart in SO, eosinophilic cell myocarditis was found with subsequent diffuse cardiosclerosis. In the testes, sclerotic processes with atrophy of glandulocytes (Leydig cells) and sustentocytes (Sertoli cells) were detected. The structural changes in the lungs, heart and testes were induced by parasite metabolites, that are deposited in tissues in the form of granules and conglomerates. PMID- 22232991 TI - [Ecological-anthropological aspects of individual morphotype variability of children in Tyumen north]. AB - The complex study of the physical development of boys and girls aged 11-18 years of native and newly come population of Khanty-Mansiysk-Ugra Autonomous Region was performed. It was found that the native population had higher mass of fat component in all the age groups as compared to that of the newly come population. The data obtained reflect the regional peculiarities of the growth processes of the children of native and newly come population. These data help to reveal the mechanisms providing adaptive character of development at the pubertal stage the ontogenesis. PMID- 22232992 TI - Intra-abdominal recurrent abscess following sleeve gastrectomy. PMID- 22232993 TI - Left sided thoracic compression through an accidental fall. PMID- 22232995 TI - [Norman Rupert Barrett]. PMID- 22232996 TI - [Accuracy of multislice computed tomography in the diagnosis of hepatocellular carcinoma in patients with cirrhosis evaluated for liver transplantation]. AB - BACKGROUND: The presence of hepatocellular carcinoma (HCC) within Milan criteria provides additional points in the MELD (Model for end stage liver disease) system and benefits in the order of organ allocation. The imaging methods play a key role in this process and represent an essential tool in the diagnosis and staging of HCC. OBJECTIVES: 1) To assess the accuracy of dynamic multidetector computed tomography (MDCT) in the diagnosis of HCC in patients with cirrhosis who are listed for liver transplantation. 2) To evaluate the diagnostic performance of TCMD in relation to tumor size. MATERIAL AND METHODS: We retrospectively reviewed the reports of MDCT performed in our institution to 62 patients who were then transplanted The histological analysis of explants was considered as the reference method in the diagnosis of HCC. MDCT studies were performed with dynamic protocol in arterial, portal and late phases. RESULTS: Dynamic MDCT showed a sensitivity of 87.5% and correctly characterized 28 of 35 patients with pathology proved hepatocellular carcinoma. MDCT was negative in 25 of 30 patients without hepatocellular carcinoma in the explanted liver, with a specificity of 83.3%. Nodule by nodule evaluation revealed a sensitivity of 80.3% and a specificity of 72.2%. CONCLUSION: In our center MDCT presented high accuracy in the correct diagnosis of HCC, showing its reliability when requesting additional points for organ allocation. PMID- 22232997 TI - [Diffusion-weighted MR imaging in patients with rectal cancer: our initial experience]. AB - BACKGROUND: Pre-surgical characterization of post-neoadjuvant residual tumor response in patients with rectal cancer by means of an imaging technique could be useful in order to determine the therapeutic strategy or observation. OBJECTIVE: To evaluate the role of the diffusion magnetic resonance imaging (DWMR) in the determination of residual primary tumor (RPT) or post-neoadjuvant complete pathologic response (CPR) in patients with rectal cancer (RC). MATERIAL AND METHODS: Eighteen patients (13 males and 5 females) operated between June 2009 and September 2010 were included. The inclusion criteria were medial and low rectal tumors, with T3-T4- positive lymph nodes, defined by physical examination (rectal tact) and studies by imaging techniques (DWMR and multidetector computed tomography (MDCT). All patients received neoadjuvant treatment before surgery. Patients were later reevaluated with DWMR using visual and quantitative scales in order to measure the apparent diffusion coefficient (ADC). The results were compared to pathological anatomy (PA) as gold standard. DWMR was performed on a Siemens Avanto 1.5 T RESULTS: In the PA 15 of 18 patients presented RPT, whereas 3 patients showed a CPR. When the DWMR was used with the visual scale, RPT was detected in 14 of 15 patients, whereas all patients with RPT were detected using the quantitative scale. In those cases with complete CPR by PA, the DWMR and visual scale detected 2 of 3 patients whereas the quantitative scale in ADC detected all three cases. CONCLUSION: DWMR proved to be a useful method in the determination of post-neoadjuvant RPT and CPR in patients with rectal cancer, especially when the quantitative assessment of the ADC was performed, resulting in an improvement of the results obtained by means of the qualitative visual analysis. PMID- 22232998 TI - [Symptomatic correlation variables in patients with pathological gastroesophageal reflux disease]. AB - INTRODUCTION. There are three indexes that correlate symptoms and reflux episodes in pHmetry tests. The utility of these indexes have been evaluated in prospective trials but their advantages and disadvantages remain controversial. OBJECTIVE: To assess the clinical utility of the pHmetric symptomatic correlation indexes in patients with pathological acid reflux. MATERIAL AND METHODS: A sequential pilot study of pHmetry tests was performed between September 2008 and June 2010. Twenty patients with gastroesophageal reflux and a DeMeester score above 14.5 were included. For the analysis, a distinction was made between strong acid reflux episodes (pH < 4) and weak acid reflux episodes (pH < 7 and > 4). The following indexes were calculated for both groups mentioned before: symptom index (SI), symptom sensitivity index (SSI) and symptom association probability (SAP). RESULTS: The mean age was 54 and 55% of patients were male. There were 116 symptomatic episodes (mean 5.8 per patient), 1,634 strong acid reflux episodes and 555 weak acid reflux episodes. Twelve (60%) had positive SI for strong acid reflux. Twelve had positive SSI for strong acid reflux and 91.66% of them had positive SI. Only 4 patients had a positive SAP. Only 2 patients had a positive SI for weak acid reflux and none of them had either a positive SI for strong acid reflux or a positive SAP for weak acid reflux. Finally, 30% of patients had a positive SSI for weak acid reflux. CONCLUSION: Positive correlation was significantly higher in strong acid rather than in weak acid reflux. SAP was the index with the lowest percentage of positivity. On the other hand, there was a high concordance between SI and SSI. Thus, the PAS index does not seem to have enough clinical utility in this cohort of patients. PMID- 22232999 TI - [Propofol versus midazolam and pethidine in the colonoscopy realization]. AB - INTRODUCTION: Medications to relief pain are more common in the everyday use during the colonoscopy practice, although schemes of medications vary. OBJECTIVE: To evaluate the efficacy and the safety of propofol versus midazolam and petidhine in colonoscopy. METHOD: A randomized and simple-blind controlled clinical trial was carried out. We included 512 patients who underwent a colonoscopy during the period from February 2008 to January 2009. using propofol in one group and midazolam plus petidhine in another. RESULTS: Cecal intubation was achieved in 247 patients (96.5%) with propofol and in 256 patients (100%) with midazolam plus petidhine. There were no significant differences between both methods regarding to the explored colon distance. Fifty-five patients (21.5%) had complications in the group receiving midazolam plus petidhine and 3 (1.2%) in the group receiving propofol. Complications were mild in both groups. Propofol reduced the relative risk of complications in 94.6% and absolute risk in 20.3%. Patients referred the same satisfaction degree with both methods. CONCLUSIONS: The use of propofol and midazolam plus petidhine is equally efficacious in the performance of the colonoscopy, while propofol is safer than midazolam plus propofol as a method of deep sedation. PMID- 22233000 TI - [Liver involvement in hereditary hemorrhagic telangiectasia]. AB - Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease with an autosomal dominant inheritance pattern, characterized by widespread telangiectases that can involve the skin, mucous membranes, lung, brain, gastrointestinal tract and/or liver. It has an estimated prevalence of 1 to 2 cases per 10,000. The prevalence of hepatic involvement in HHT had been estimated in 8% to 31% in retrospective studies but in more recent large prospective series the prevalence is higher, ranging between 41% and 78%. Nevertheless, symptoms occur only in 8% of the patients with HHT and liver involvement. Liver involvement by HHT is characterized by widespread diffuse liver vascular malformations that give rise to three types of shunting: arteriovenous (hepatic artery to hepatic vein), arterioportal (hepatic artery to portal vein), and portovenous (portal vein to hepatic vein). The three most common initial clinical presentations are high-output heart failure, portal hypertension and biliary disease. We describe the case of a patient with diagnosis of HHT and hepatic involvement and we review of the literature. A 58-year-old woman with HHT came to consultation with heart failure symptoms and echographic and endoscopic findings of portal hypertension. The multislice computed tomography of the abdomen revealed the presence of multiple telangiectases in the hepatic parenchyma and a shunt from the hepatic artery to the portal vein. We conclude that the symptomatic involvement of the liver in HHT is an extremely infrequent entity. It must be suspected when clinical manifestations and compatible imagenologic findings exist in patients with antecedents of HHT. PMID- 22233001 TI - Different clinical aspects of Wirsungocele: case series of three patients and review of literature. AB - The association of Santorinicele with pancreas divisum has been described. This anatomic condition creates ideal conditions for acute pancreatitis episodes and chronic abdominal pain. Saccular dilation of main pancreatic duct has also been described as incidental finding and causing episodes of acute pancreatitis. However, there is no description of associated chronic abdominal pain. Three detailed cases of Wirsungocele demonstrated by endoscopic retrograde cholangiopancretography are presented. Two of them had episodes of acute pancreatitis and one had chronic abdominal pain. All patients were treated by endoscopic biliopancreatic sphincterotomy. After a follow-up for more than two years, none presents clinical recurrence. Endoscopic biliopancreatic sphincterotomy for symptomatic patients with this anatomic condition seems safe and effective. PMID- 22233002 TI - [Submucosal gastric tumour: heterotopic pancreas. A case report and review of the literature]. AB - Heterotopic pancreas is the presence of pancreatic tissue outside the anatomical location of the pancreas. It is a rare condition and can occur anywhere in the gastrointestinal tract with the stomach and small bowel as the most common sites. It is usually asymptomatic but may become clinically evident when complicates by pathologic changes such as inflammation, bleeding, obstruction and malignant transformation. We report the case of a 49-year-old man who presented with recurrent epigastric pain. The upper gastrointestinal endoscopy revealed a submucosal tumour in the antrum. The histopathology study after surgery showed a heterotopic pancreatic tissue. Ectopic pancreas should be considered in the differential diagnosis of a submucosal gastric tumour. PMID- 22233003 TI - [Leiomyomatosis peritonealis disseminata]. AB - Leiomyomatosis peritonealis disseminata (LPD) is a rare, benign proliferative process characterized by multiple smooth muscle nodules throughout the peritoneum. Predominantly affects women in their reproductive years. The cause of LPD is unknown although it may be associated with high estrogen state. The clinical appearance mimics a peritoneal carcinomatosis and the radiologic findings are unspecific. So, the definitive diagnosis is histological. Treatment must be individualized depending on age, hormonal status and symptomatology. To date, less than 140 cases have been reported. We report a case of LPD in a 50 year-old woman presented as an intestinal obstruction. PMID- 22233004 TI - [Liver trasplantation for the treatment of non-resectable metastases of neuroendocrine tumors: first report in Argentina]. AB - Neuroendocrine tumors are uncommon cancers characterized by a slow grow rate. Unresectable liver metastases are the main cause of death in patients with these tumors. This is the first Argentine report of a liver transplantation as an indication for the treatment of unresectable liver metastases from a pancreatic neuroendocrine tumor. We present a 48-year-old woman with diagnosis of a pancreatic neuroendocrine tumor with multiple bilobar unresectable liver metastases. A splenopancreatectomy was performed after a complete staging revealed absence of extrahepatic disease. Six months later, a follow-up performed with thoracoabdominal CT scan and octreo-scan was consistent with no tumor recurrence or extrahepatic disease. As the huge hepatomegaly caused a notorius deterioration in the patient's quality of life, we decided to include her in the waiting list for liver transplantation. Priority points were requested to the MELD (model for end stage liver disease) Exceptions Experts Committee with a positive response. Twelve months after the primary surgery, with a MELD score of 23 points, a deceased donor liver transplantation was performed without evidence at that moment of residual disease. Eighteen months after liver transplantation, the patient required the surgical repair of a stenosis in the biliary anastomosis. At the surgery peritoneal tumor recurrence was diagnosed. Now, 24 months after liver transplantation the patient has an excellent quality of life and a well functioning graft. We report this case of a liver transplantation as an indication for the treatment of liver metastases from a neuroendocrine tumor and we review the literature on this controversial issue. PMID- 22233006 TI - Here comes trouble. PMID- 22233005 TI - [Genetics and epigenetics of colorectal cancer]. AB - Genetic and epigenetic influences as well as dietary factors play an important role in the initiation and progression of cancer. More specifically, colorectal cancer (CRC) is influenced by dietary habits and it has been established that genetic and epigenetic changes are involved in the carcinogenesis. Within the CRC are hereditary syndromes (hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis), which present germ line mutations on specific genes like hMLH1 and also changes on promoter's methylation, and sporadic cases, where the environment and individual's habits, both major components of epigenetics, partly define the initiation and development of cancer. Therefore the epigenetic is established as another way of carcinogenesis. Identify the factors that would predict the beginning of CRC is critical, as it is a rather silent disease which is observed clinically at an advanced stage. PMID- 22233007 TI - Five strategies to tackle ICD-10. PMID- 22233008 TI - Good things to say about ICD-10. PMID- 22233009 TI - Regulatory relief tops CIO wish list. PMID- 22233010 TI - Keeping the EHR machine running. PMID- 22233011 TI - An appetite for risk. Interview by Elizabeth Gardner. PMID- 22233012 TI - Data reporting mandates, hardware selection, HIMSS Stage 7. PMID- 22233013 TI - Making the right hardware choices. AB - A rapid expansion of computing hardware options is paving the way to better patient engagement and increased productivity. For that to happen, CIOs must balance their choices against workflow issues, infrastructure requirements, and budgetary constraints. PMID- 22233014 TI - Enterprising organizations. AB - Here's an inside--and detailed--look at how three hospital systems achieved HIMSS Analytics Stage 7, an objective measure of progress toward EMR implementation. PMID- 22233015 TI - How to fast-track your meaningful use effort. AB - While there is no shortcut to meaningful use, getting the fundamentals right is essential to smoothing the way to qualifying for incentives. PMID- 22233016 TI - Nebraska creates HIE for behavioral providers. PMID- 22233018 TI - ACOs: challenges and opportunities. Interviewed by Mark Hagland. PMID- 22233017 TI - HIEs reduce ED costs. PMID- 22233019 TI - Path to professional growth. Interviewed by Mark Haglund. PMID- 22233020 TI - Information 'liberacion'. Interviewed by Mark Hagland. PMID- 22233021 TI - An evidence-based approach to activating your EMR. PMID- 22233022 TI - Hiring top-shelf talent. PMID- 22233023 TI - ["Personalized medicine" between genome and person]. PMID- 22233024 TI - [Therapy of gastroesophageal reflux disease (GERD)]. AB - Gastroesophageal reflux disease (GERD) comprises all symptoms and clinical consequences in the context of reflux of stomach contents into the esophagus. The symptoms reported by patients include heartburn, regurgitation and sour taste in the mouth. In some cases atypical reflux associated symptoms such as asthma, laryngitis or recurrent pneumonias are reported. Pathophysiologically an incompetence of the lower esophageal sphincter and a disturbed clearance of the esophagus are the underlying mechanisms. Current treatment recommendations include a change of lifestyle and a drug treatment with proton pump inhibitors (PPI) being widely used. In patients with persistent symptoms other diagnoses like functional dyspepsia should be considered especially when additional symptoms like epigastric pain, postprandial fullness and nausea are present. This review summarizes the current understanding of the pathophysiology, the diagnosis and the treatment of GERD and gives an outlook on therapies currently developed for the treatment of reflux disease. A promising new drug, presently classified as being a reflux inhibitor, is lesogaberan. Lesogaberan is presently studied in phase II clinical trials. PMID- 22233025 TI - [Pityriasis versicolor]. AB - The common superficial infection caused by Malassezia yeasts raises even today several questions concerning important pathogenetic and therapeutical aspects like an effective prevention therapy. PMID- 22233026 TI - [Cancer treatment in the elderly]. PMID- 22233027 TI - [Adjunctive treatment measures in sepsis and septic shock]. PMID- 22233028 TI - [Study on the correlation between the quality of Cornus officinalis and the contents of the inorganic elements in the planting soil]. AB - OBJECTIVE: To analyze the correlation between the quality of Cornus officinalis and the contents of the inorganic elements in the planting soil. METHODS: The contents of 11 kinds of inorganic elements including Zn, Mn, K, Fe, Mg, Ca, Cu, Cd, As, Pb and Hg in Cornus officinalis and the planting soil were determined; The contents of loganin, ursolic acid, polysaccharides, tannins, organic acid, water-soluble extractives and ethanol-soluble extractives in Cornus officinalis were determined; The correlation between the quality of Cornus officinalis and the contents of the inorganic elements in the planting soil was analyzed. RESULTS: There was no significant difference in the content of chemical components of Cornus officinalis produced in the three main areas. The contents of loganin and water-soluble extract complied with pharmacopoeial provisions. Especially, inorganic elements of Fe, Mn and K had significant effects on the quality of Cornus officinalis. CONCLUSION: The results provide the foundation for the selection of cultivating area and the reference for standard cultivation of Cornus officinalis. PMID- 22233029 TI - [Study on PLB induction and proliferation of Dendrobium officinale]. AB - OBJECTIVE: To study on the optimal medium ingredients for PLB induction and proliferation of Dendrobium officinale. METHODS: Seed embryos of Dendrobium officinale were cultivated in MS medium as the basic medium, along with different plant hormones like 6-BA, NAA,2,4-D and KT or their combinations added with organic additives like PE, BE, AE and CM. RESULTS: BA and NAA combination was not conductive to germination and the germination ratio was even lower than that of MS medium; 10% PE and CM was beneficial to PLB induction; 2,4-D was not conductive to growth and proliferation; A certain concentration of BA, KT and NAA was beneficial to PLB proliferation; KT at 1.0 mg/L recorded the highest 40 d PLB proliferation times at 9.0; PE, CM and AE could promote the PLB proliferation at different levels, among which 10% CM was the most effective. CONCLUSION: The optimized medium ingredients suitable for PLB induction are MS +10% CM +1.0g/L AC; The optimized medium ingredients suitable for PLB proliferation are MS + 1.0 mg/L KT + 0.2 mg/L NAA + 10% CM. PMID- 22233030 TI - [Study on the change of the content of cantharidin in Mylabris befere and after biortransfermation]. AB - OBJECTIVE: To compare the change of the content of cantharidin in Mylabris before and after biotransformation. METHODS: The content of cantharidin was determined by gas chromatography (GC). The conditions of GC were as follows: HP-5 column, vanillin as internal standard, the column temperature maintained at 175 degrees for 5 min, rised to 240 degrees C at the speed of 4 degrees C/min and the remained for 5 min. RESULTS: The GC method was good reproducibility. The content of cantharidin in Myabris before and after botransformation was 0.7% and 1.29% respectively. After biotranformation, the content of cantharidin was increased. CONCLUSION: Mylabris fermentated with Trametes cinnabarina has great significance for increasing the content of cantharidn and provides experimentd basis for efficient use of Mylabris. PMID- 22233031 TI - [Prokaryotic expression of LMoV CP gene and preparation of its antiserum]. AB - OBJECTIVE: To prepare antiserum against the CP of Lilg mottle virus (LMoV). METHODS: Specific primer was designed according to Genbank to amplify CP gene of LMoV of Fritillaria thumbergii and its sequence was analyzed. Then the CP gene was inserted into pSBET and expressed in Escherichia coli BL21 (DE3) plys E strain. The objective protein was purified by 12% SDS-PAGE firstly and subsequently 5% - 20% gradient SDS-PAGE. The antiserum against the CP was raised in mouse and their specificity was determined by Western blot. The ability to combine with nature LMoV particles was confirmed by ELISA analysis. RESULTS: LMoV CP gene shared 95% - 99% nucleotide identities and 98% - 100% amino acid identities with the CP genes reported on Genbank. The antiserum was special to LMoV CP and IgG against LMoV could combine LMoV particles. CONCLUSION: The antiserum prepared in this study is suitable for LMoV detection. PMID- 22233032 TI - [Influences of different initial processing methods on Rheum palmatum]. AB - OBJECTIVE: To choose the optimum initial processing methods of Rheum palmatum. METHODS: Fresh crude Rheum palmatum was sliced and dealt with the different drying methods such as sun drying, shady drying, microwave heating and various temperatures drying. The content of the Anthraquinones derivatives, slicing colors and dried rates were used as evaluation indexes. The sliced Rheum palmatum was compared with the traditional processing. RESULTS: Sliced fresh crude Rheum palmatum had the low content of the Anthraquinones derivatives and dry rates, slicing colours had obviously changes. For various drying methods, smoking drying was superior to sun drying, shady drying, microwave heating and various temperatures drying methods. CONCLUSION: Fresh crude Rheum palmatum is not suitable for slicing processing. The best drying method is smoking drying. PMID- 22233033 TI - [Study on the chemical constituents of Psoralea corylifolia]. AB - OBJECTIVE: To study the chemical constituents of Psoralea corylifolia. METHODS: Column chromatography was used in the isolation procedure. The structures of isolated compounds were elucidated by spectral data. RESULTS: Seven compounds were isolated and their structures were identified as isopsoralen (1), psoralen (2), bavachalcone (3), 4", 5"-dehydroisopsoralidin (4), methyl 4-hydroxybenzoate (5), psoralidin (6), corylin (7). CONCLUSION: Compounds 4 and 5 are obtained from Psoralea for the first time. PMID- 22233034 TI - [Study on the chemical constituents in roots of Gentiana dahurica]. AB - OBJECTIVE: To systematically study the chemical constituents in the roots of Gentiana dahurica. METHODS: Various column chromatographic techniques were used for isolation and purification. The structures were elucidated on the basis of spectral data (UV, IR, MS, NMR) and identified by comparing with the authentic substance. RESULTS: Seven compounds were isolated and identified as: roburic acid (1), oleanolic acid (2), beta-sitosterol (3), daucosterol (4), gentiopicroside(5), swertiamarine (6), sweroside (7). CONCLUSION: Compounds 1, 2 and 4 are isolated from this plant for the first time. PMID- 22233035 TI - [Study on the chemical constituents of roots and stems of Nardostachys chinensis]. AB - OBJECTIVE: To study the chemical constituents of roots and stems of Nardostachys chinensis. METHODS: The chemical constituents were isolated and purified by column chromatography including silica gel, Diaion HP-20, Sephadex LH-20, ODS, and HPLC. Their structures were elucidated on the basis of spectral data analyses. RESULTS: Six compounds were isolated and identified as 8 hydroxypinoresinol-4-O-beta-D-glucopyranoside (1), 8-hydroxypinoresinol-4'-O-beta D-glucopyranoside (2), 8-hydroxypinoresinol-4-O-(beta-D-glucopyranosyl) 4'-O-beta D-glucopyranoside (3), cycloolivil 6-O-beta-D-glucopyranoside(4), ferulic acid (5), chlorogenic acid methyl ester (6). CONCLUSION: All the compounds are isolated from this genus for the first time. PMID- 22233036 TI - [Isolation, purification and composition analysis of water-soluble polysaccharide from Halenia elliptica]. AB - OBJECTIVE: To provide scientific cue for the use of Halenia elliptica. METHODS: The crude polysaccharide was extracted from Halenia elliptica with hot water and precipitated by ethanol. The crude polysaccharide has been eliminated protein and fractionated by acidic ethanol. Four fractions HM1, HM2, HM3 and HM4 were got respectively. RESULTS: By using DEAE-Sephadex A-25 gel filtration, HM1 was got. GC analysis indicated that HM1, HM2, HM3, HM4 and HM41 were composed of Rha, Ara, Xyl, Man, Gal and Glc. But their molar ratios were different. CONCLUSION: Polysaccharide HM41 is isolated from Halenia elliptica for the first time. PMID- 22233037 TI - [Study on the chemical constituents of Leptopus chineseis]. AB - OBJECTIVE: To study the chemical constituents of the ethyl ether extract of the Leptopus chineseis. METHODS: The chemical constituents were isolated by means of chromatography and identified by spectra data and physicochemical characters. RESULTS: Three compounds were isolated and identified as friedelane-2alpha, 3beta diols (1), betulinic acid (2) and 3beta-O-trans-coumaroylbetulinic acid (3). CONCLUSION: The compounds are isolated from Leptopus chineseis for the first time. PMID- 22233038 TI - [GC-MS analysis and analgesic activity of essential oil from fresh rhizoma of Cyperus rotundus]. AB - OBJECTIVE: To observe the analgesic effect and analysis the chemical components of essential oil (EOC) from fresh rhizome of Cyperus rotundus. METHODS: Hydrodistillation method was used to extract EOC; Acetic acid induced mice stretching model was applied to evaluate the analgesic effect of EOC. Gas chromatography coupled with mass spectrometry (GC-MS) were applied for the analysis of EOC. RESULTS: The yield of EOC was 0.4%. The stretching times of mice induced by acetic acid were significantly reduced by EOC at dosage of 0.1 g/kg. 54 ingredients, 85.1% of which were EOC were identified by GC-MS analysis; The major compounds were cyperene (41.03%), beta-caryophyllene oxide (5.32%), alpha selinene (4.37%), alpha-copaene (4.36%), naphthalene, 6-isoproenyl-4,8a-dimethyl 1, 2, 3, 5, 6, 7, 8, 8a-octahydro-(3.80%) and alpha-cyperone (3.11%). CONCLUSION: The essential oil from fresh rhizome of Cyperus rotundus shows structure diversity and good analgesic effect. PMID- 22233039 TI - [Study on the activated fraction with proliferation and apoptosis effect on T lymphocyte of Celastrus aculeatus]. AB - OBJECTIVE: To screen the activated fraction from Celastrus aculeatus and study its effect on T lymphocyte apoptosis. METHODS: Different polarity fractions were isolated from Celastrus aculeatus extract. Flow Cytometry method was used to detect apoptosis ratio of the active fractions. RESULTS: Different fractions extract from Celastrus aculeatus and GSF-A could significantly inhibit T lymphocyte proliferation and induce T lymphocyte apoptosis. CONCLUSION: The activated fractions isolated from Celastrus aculeatus have anti-inflammatory effect. Its mechanism may be related to the apoptosis effect on T lymphocyte. PMID- 22233040 TI - [Protective effects of Lycium barbarum extract against MPP(+) -induced neurotoxicity in Caenorhabditis elegans and PC12 cells]. AB - OBJECTIVE: To investigate the neuroprotective effects of Lycium barbarum extract against MPP(+) -induced neurotoxicity in Caenorhabditis elegans and PC12 cells and its mechanism. METHODS: Pretreated MPP(+) -induced nearotoxicity in C. elegans and PC12 cells with Lycium barbarum at different dosages. The viability and DA neurodegeneration was assessed in C. elegans selectively expressing green fluorescent protein (GFP) in DA neurons. PC12 cell damage was measured using MTT and nuclear morphology. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential and total GSH were assessed. RESULTS: Lycium barbarum extract protected against MPP(+) -induced loss of viability and DA neurodegeneration in C. elegans in a dose-dependent manner. Similar neuroprotection was replicated in MPP + PC12 cell model. Lycium barbarum extract attenuated MPP(+) -induced intracellular ROS accumulation, loss of mitochondrial membrane potential and restored total GSH levels in PCl2 cells. CONCLUSIONS: Lycium barbarum extract protects against MPP(+) -induced neurotoxicity in C. elegans and PC12 cells and its machanism may be related to its antioxidative property and restoration of total GSH level. PMID- 22233041 TI - [Intestinal absorption of enteric coating potassium sodium dehydroandroan drographolide succinate pellets in rat and in vivo pharmacokinetics study]. AB - OBJECTIVE: To develop a method for determination the content of Potassium Sodium Dehydroandroan drographolide Succinate (PSDS) in rat intestinal contents and plasma and investigate the intestinal absorption of PSDS pellets in rat and in vivo pharmacokinetics of PSDS pellets. METHODS: The content of PSDS in rat intestinal contents and plasma was determined by HPLC. In vivo pharmacokinetic properties and intestinal absorption of PSDS pellets in rat were investigated. RESULTS: Two hours after administration, pellets were not found in the small intestine and large intestine, four hours after administration, the largest number of pellets were found in the small intestine and the concentration of PSDS was the highest in the intestinal contents (3593.13 microg). The characteristics of plasma concentration-time curve was consistent with a single compartment model. The main drug pharmacokinetic parameters were calculated. t1/2, T(max), C(max) and AUC were 2.69 h, 5 h, 3.02 microg/mL and 6.42 microg x h/mL, respectively. CONCLUSION: PSDS has a good absorption in the rat small intestine and it is feasible to prepare PSDS enteric-coated pellets for oral administration. PMID- 22233042 TI - [Kidney-tonifying and abortion preventing effects of Shou Tai Wan by different extration methods on rats]. AB - OBJECTIVE: To explore the Kidney-tonifying and abortion preventing effect of Shou Tai Wan (STW) by different extration methods on the SD Rats' abortion model. METHODS: Applied hydroxycarbamide and mifepristone (RU-486) to establish the abortion model of corpus luteum inhibition due to Kidney deficiency (disease syndorme combination model) on SD, rats. Treated the model rats with STW formula. Observed the uterus condition and recorded the embryo number and the miscarriage rate of each rat. 4 kinds of extractions including water extract of STW (A liquid), alcohol extract of STW (B liquid), after the ethanol water extract residue of STW (C liquid) and B + C liquid. Visual observed the uterine lesions embryos and calculated obortion rate. Used chemluninescence methed to cheek the serum estradiol (E2) and progesterone (P) level. Used quantitative RT-PCR (qRT PCR) to analyze the different of the PR mRNR between the model group and the treated group. RESULTS: Compared with the model group, the abortion rate of B + C liquid was greatly deduced and the embryo number of B + C liquid group, the E2 and P levels were obviously increased in the treated groups. CONCLUSION: STW (B + C) has the best effect of tonifying the kidney and preventing abortion. PMID- 22233043 TI - [The effect of total phenolics from abnormal savda munziq on cervical cancer cell lines]. AB - OBJECTIVE: To explore the feasibility of total phenolics from Abnormal Savda Munziq on treating human cervical carcinoma. METHODS: MTT assay was used to determine the growth inhibition ratio and IC50 on Hela cells and SiHa cells after treated with different concentrations of total phenolics. Morphologic changes of cells were observed by inverted microscope. RESULTS: Total phenolics inhibited the proliferation of Hela cells in the concentration range of 25 - 125 microg/mL; Total phenolics inhibited the proliferation of SiHa cells in the concentration range of 75 - 175 microg/mL; The inhibitory actions of total phenolics on the Hela and SiHa appeard dose-effect relationship and time-effect relationship obviously (P < 0.01); The IC50 of Hela was (125.26 +/- 16.15) microg/mL after 48h total phenolics treatment; The IC50 of SiHa was (134.51 +/- 2.55) microg/mL after 48h total phenolics treatment. And there was no statistical sense in the disparation of them (P > 0.05); Both of the cells showed apoptosis character evidently after total phenolics treatment, Along with the increasing of the concentration and the action time, morphologic changes of cells were more obviously. CONCLUSION: Total phenolics could inhibit the growth of Hela cells and SiHa cells and the inhibitory actions of total phenolics on the two cells is almostly the same. Therefore, total phenolics from abnormal savda munziq is deserved to be further studied for treating human cervical carcinoma. PMID- 22233044 TI - [Process optimization for extraction of immune active polysaccharides from Fomes fomentarius by introduction of ultrasonication]. AB - OBJECTIVE: To study the optimal extraction process of immune active polysaccharides from Fomes fomentarius by introduction of ultrasonication. METHODS: An orthogonal experimental design of L9 (3(4)) was used to investigate the effects of ultrasonication time, extraction temperature and extraction time on the extraction ratio, sugar content and immune stimulating activity (mouse splenocyte metabolic activity measured with MTT colorimetry) of the polysaccharides and the optimal extraction process was evaluated. RESULTS: Ultrasonication treatment had the most remarkable effect on the immune stimulating activity of the polysaccharides. The optimal extraction process for extraction of immune active polysaccharides was as follows: ultrasonication for 30min, extraction temperature at 80 degrees C and water extraction time for 2h. CONCLUSION: Ultrasonication can be used as a useful technique for extraction of immune active polysaccharides from Fomes fomentarius. PMID- 22233045 TI - [Study on the dynamic model with supercritical CO2 fluid extracting the lipophilic components in Panax notoginseng]. AB - OBJECTIVE: To establish a dynamics model for extracting the lipophilic components in Panax notoginseng with supercritical carbon dioxide (CO2). METHODS: Based on the theory of counter-flow mass transfer and the molecular mass transfer between the material and the supercritical CO2 fluid under differential mass-conservation equation, a dynamics model was established and computed to compare forecasting result with the experiment process. RESULTS: A dynamics model has been established for supercritical CO2 to extract the lipophilic components in Panax notoginseng, the computed result of this model was consistent with the experiment process basically. CONCLUSION: The supercritical fluid extract dynamics model established in this research can expound the mechanism in the extract process of which lipophilic components of Panax notoginseng dissolve the mass transfer and is tallied with the actual extract process. This provides certain instruction for the supercritical CO2 fluid extract' s industrialization enlargement. PMID- 22233046 TI - [Study on enriching total flavonoids from folium chrysanthemi with polyamide and macroporous resin]. AB - OBJECTIVE: To study the technology of enriching total flavonoids from Folium Chrysanthemi with polyamide and macroporous resin. METHODS: By using the content of flavonoids as index, firstly absorbed with polyamide and removed impurity with purified water. Then added polyamide to macroporous resin column, eluted with ethanol and determined the flavonoids content. RESULTS: Total flavonoids could be effectively purified by the polyamide and macroporous resin. Best technological conditions were as follows: resin of type X-5 was better, and elution agent was 70% ethanol, the ratio of extract amount (mL) and polyamide quantity (g) was 1. 5: 1, ratio of resin (g) - extract (mL) was 4: 3, ratio of diameter and height was 1: 20, the volume of collected eluent was 2BV. The purity of total flavonoids reached to 87.48%. CONCLUSION: The technology is stable and can be viewed as a way to study and develop the resources of Folium Chrysanthemi. PMID- 22233047 TI - [Study on Chinese herbs' volatile oil micro-emulsions by means of pseudo-ternary phase diagram]. AB - OBJECTIVE: To optimize the formulation of Chinese herbs' volatile oil micro emulsion. METHODS: Sreened the formulation of blank micro-emulsion and the formulation of micro-emulsion contained volatile oil by means of pseudo-ternary phase diagram. RESULTS: System of isopropyl myristate, polyoxyethylene hydrogenated castor oil, absolute ethyl alcohol and water could formed the largest area of micro-emulsion. The optimal formulation of micro-emulsion contained volatile oil was: volatile oil consisted of 2.852%, isopropyl myristate 6.65%, polyoxyethylene hydrogenated castor oil 30.42%, absolute ethyl alcohol 7.605% and water 52.47%. CONCLUSIONS: Using pseudo-ternary phase diagram to optimize the formulation of Chinese herbs' micro-emulsion is scientific and feasible. The volatile oil's solubility is also increased by made of oil-in-water type micro-emulsion and insured the stability. PMID- 22233048 TI - [Biosynthesis of epsilon-poly-L-lysine--a review]. AB - Epsilon-poly-L-lysine (epsilon-PL) is a natural biomaterial that is biodegradable, edible and non-toxic toward humans and the environment. Based on the research history of epsilon-PL, we reviewed the biosynthesis, degradation and the metabolic pathway of epsilon-PL. We also addressed the status of epsilon-PL research in China. PMID- 22233049 TI - [Analysis of bacterial immune system--a review]. AB - In the battle to phages, bacteria have evolved many immune mechanisms involved in the prevention of phage DNA entry, the degradation of entered DNA, and the limitation of the phage spreading at the cost of host cell death. An immune system in bacteria is formed by the collaboration of multiple immune mechanisms. In this paper, we reviewed the latest research progress of bacterial immune system and focused on the analysis of the operation mode of bacterial immune system and the evolution relationship between this system and phages. PMID- 22233050 TI - [Distribution and detection of pathogens in shellfish--a review]. AB - Shellfish is one of important vehicles for dissemination of food-borne pathogens. The incidence of food-borne diseases increases every year. Therefore, monitoring and control on the food safety of shellfish is a significant public health concern worldwide. In recent years, our group has studied the pathogens in molecular detection, bioaccumulation and control in shellfish. Based on the our previous studies, the purpose of this article was to provide a review on the pathogens in shellfish in four aspects: the detection methods, distribution, depuration and epidemiology. The molecular methods were widely used in detection of pathogens in shellfish. In addition, the pathogens were bio-accumulated in the gills and digestive glands, including stomach and digestive diverticula, which are good candidate sites for detection of pathogens. PMID- 22233051 TI - [Genetic diversity and phylogeny of bradyrhizobia associated with Desmodium spp]. AB - OBJECTIVE: Genetic diversity and phylogeny of bradyrhizobial strains associated with Desmodium spp. in subtropic and temperate regions of China were analyzed. METHODS: We studied 29 desmodia isolates from different regions with BOX-PCR fingerprinting and multilocus sequence analysis (nifH, nodC and recA gene) to describe the genotypic characteristics and phylogenetic relationships. RESULTS: We achieved 25 genotypes with BOX-PCR genomic fingerprinting analysis, indicating that the tested strains had a great diversity at genomic level. The representative bradyrhizobial strains were located in three phylogenic branches with multilocus sequence analysis (niffH, nodC and recA gene), that was closely related to Bradyrhizobium elkanii, Bradyrhizobium japonicum and Bradyrhizobium yuanmingense, respectively. CONCLUSION: The desmodia bradyrhizobia had abundantly diversity. Diverse symbiotic genes including nifH and nodC genes were also found in these strains that indicated that the symbiotic genes were mainly maintained by vertical transfer in these bradyrhizobial populations and coevolved with housekeeping genes. PMID- 22233052 TI - [Identification and characterization of a purple sulfur bacterium from mangrove with rhodopin as predominant carotenoid]. AB - OBJECTIVE: To exploit resources of purple sulfur bacteria in China and further investigate its response mechanism to ecological environment of mangrove. METHODS: Repeated agar shake dilution method, microscope techniques, UV-Vis absorption spectra, thin layer chromatography, HPLC and MS were used. RESULTS: We isolated a purple sulfur bacterium, designated as strain YL28, from a intertidal sediment sample collected from inshore mangrove near Luoyang Bridge of Quanzhou city, Fujian Province of China. Cells were ovoid to rod shaped, 0.5 microm - 1 microm x 2 microm - 3 microm. Color of cell suspensions was reddish-brown. It possessed vesicular intracytoplasmic membrane structures, contained rhodopin and phytylated bacteriochlorophyll a as well as the other two novel bacteriochlorophyll a intermediates. The optimum growth was at 2% - 3.5% NaCl, pH 5.7 - 6.7 and 20 degrees C - 35 degrees C. Photoautotrophically growth anaerobically in the light with sulphide, sulphur, thiosulfate, sulfite as electron donor. Globules of S(0) distributed inside the cells. Photoheterotrophic growth with various organic substrates, especially citrate, glucose, sucrose, fructose and propanol in the presence of sulfide. Nitrogen sources: ammonium salts, N2, urea, glutamate, nitrate and nitrite. Vitamins were not required. Qualitative assessment of IC50 values of chloromycetin, cefazolin, benzene, hydroxy biphenyl, enrofloxacin, acetamiprid, mercuric chloride and cadmium chloride were 70, 100, 20, 20, 3, 170, 5 mg/L and 25 mg/L, respectively. CONCLUSION: Based on phenotype characteristics and 16S rRNA gene sequence similarity of 99% to M. gracile, strain YL28 was identified as novel isolate of M. gracile despite its different physiological characteristics with respect to the species of M. gracile. The organism is possessed of slightly acid tolerance, higher amount of carotenoid of rhodopin and tolerance towards certain antibiotics, pesticide as well as heavy metals. PMID- 22233053 TI - [Identification and primary application of TSNA degrading bacterial strain AS97 isolated from aging tobacco leaves]. AB - OBJECTIVE: The purpose of this work was to screen strains having tobacco-specific nitrosamines (TSNA) deteriorating activity, isolated from the inner and superficial of tobacco plants. Then strain AS97 was isolated and identified for further application. METHODS: Strain AS97, with the highest conversion ability against both nitrate and nitrite, was screened by enrichment and selective medium. The strain was identified by morphological, physio-biochemical characteristics and 16S rRNA gene sequence analysis. The concentration of 4 (methylnitrosamino)-1-(3-pyridy)-1-butanone (NNK), N-nitrosonicotine (NNN), N nitrosoanatabine (NAT) and N-nitrosoanabasine (NAB) were determined by LC-MS/MS. The fermentation broth of strain AS97 was spraied on the leaves of tobacco to define inoculum concentration and fermentation condition. RESULTS: AS97 was identified as Pseudomonas fluorescens (Genbank accession number: JF 449445). Under the optimal growth conditions with inoculum concentration of 5%, at 30 degrees C for 10 d, AS97 had high biological activity against NNK and NNN with a degradation rate of 59.08% and 38.79%, respectively. The correlation analysis displayed a pronounced correlation (p > 0.01) among the concentration of nitrate, nitrite and TSNA. Furthermore, the results also exhibited that nitrate and nitrite were antecedent substance of TSNA. CONCLUSION: These results indicated that Pseudomonas fluorescens AS97 could be a promising microorganism in the practice of non-harmful cigarette production. PMID- 22233054 TI - [Identification of extracellular polysaccharide-associated genes in Xanthomonas oryzae pv. oryzicola]. AB - OBJECTIVE: Previously, seventeen extracellular polysaccharide-associated mutants of Xanthomonas oryzae pv. oryzicola (Xoc) were acquired from our randomly Tn5 inserted mutant library. To know the Tn5-inserted genes of these mutants and their contribution to EPS production and virulence in rice, METHODS: in this study, we first identified and characterized the Tn5-targeted genes in these mutants and then inoculated them in susceptible rice for virulence assessment. RESULTS: Tn5 transposon was inserted in genes of the gum, xan and wxoc clusters in the majority of EPS-reduced mutants. Of the EPS-reduced mutants, three were due to the Tn5 insertion in Xoryp_4217, Xoryp 2488 and Xoryp_0918 genes, respectively. In six EPS-increased mutants, three were in mutagenesis in fimO, pilY and xopQ genes, respectively, resulting in higher EPS production than the wild-type strain RS105. Other three were because of the mutation in Xoryp2392, Xoryp_4221 and Xoryp_3511 genes. Interestingly, XocORF-3511 only exists in X. oryzae but not in other Xanthomomas species. Virulence assays in rice showed that the less EPS production by the mutant, the weaker the virulence in rice. However, those mutants in higher EPS production did not increase virulence significantly in rice compared to that by the wild-type strain. CONCLUSION: Our findings will help further understand the metabolic pathways for EPS synthesis in Xoc and the specific roles of EPS-associated genes in Xoc-rice interactions. PMID- 22233055 TI - [Comparing the primer specificity for betaproteobacterial ammonia-oxidizing bacteria in recirculation aquaculture systems]. AB - OBJECTIVE: To analyze the difference of specificity of four primers for betaproteobacterial ammonia-oxidizing bacteria (beta-AOB) 16S rDNA gene from the biofilm of closed recirculation aquaculture systems. METHODS: We used 16S rDNA clone libraries to describe the beta-AOB diversity. RESULTS: CTO189f/CTO654r produced the highest frequency of beta-AOB-like sequences (67.3%). The amplification performance of primer was noticeably influenced by the biofilm samples. Hereinto, the biofilm of closed recirculation aquaculture systems of Tilapia nilotica resulted in the higher amplification performance of primers. CONCLUSION: CTO189f/CTO654r exhibited the highest specific for beta-AOB 16S rDNA gene from the biofilm of closed recirculation aquaculture systems. PMID- 22233056 TI - [Phylogenetic diversity of cultivable bacteria during the brewing process of the luzhou-flavor liquor in Yibin, Sichuan province, China]. AB - OBJECTIVE: In order to better understand the diversity of cultivable bacteria during the brewing process of the Luzhou-flavor liquor in Yibin, and to collect potential microbial resources. METHOD: The cultivable bacteria were isolated by using modified nutrient agar medium and Gogan-I medium, and then analyzed the 16S rRNA gene sequences of the 603 non-redundant isolates separated from the air of fermentation workshop, Pit mud, Zaopei, Chinese Qu and air of Qu workshop sampled from 6 luzhou-flavor liquor production enterprise in Yibin. RESULTS: Phylogenetic analysis based on 16S rRNA gene sequences showed that 599 of them belonged to 101 species of 34 genera, and 4 isolates with < 97% sequence similarities to their closely related members were presumed to be potential novel species. Bacillus is the most dominant genus with 315 strains; Streptomyces, Staphylococcus and Lysinibacillus were dominant genera, with 121, 45 and 35 strains, respectively. The number of isolates belong to the other 31 genera were less than 10 strains, furthermore, only one strain was detected in 16 genera. CONCLUSION: Bacteria during the brewing process of the Luzhou-flavor liquor in Yibin present plentiful diversity and relative stability. PMID- 22233057 TI - [Effect of adenine on metabolic fluxes in Escherichia coli DH5alpha and its acetate-tolerant mutant DA19]. AB - OBJECTIVE: In order to further understand the difference in metabolic regulation between Escherichia coli DH5alpha and its acetate-tolerant mutant DA19, we analyzed the effect of supplementing adenine in defined media on metabolic fluxes in the two strains. METHODS: E. coli DH5alpha and DA19 were continuously cultured in nitrogen-limited defined media without or with supplemented adenine. Based on mass balance and metabolic reaction stoichiometry, the metabolic fluxes in DH5alpha and DA19 at different culture condition were calculated, and the results were compared with the activities of key enzymes. RESULTS: The supplementation of adenine decreased specific glucose consumption rate and specific acetate production rate, and improved growth yield coefficient on glucose of DH5alpha. Nevertheless, specific pyruvate production rate did not significantly change. Furthermore acetate split ratio decreased whereas pyruvate and TCA split ratios increased. Obvious changes were observed in the activities of phosphofructokinase, 6-phosphoglucose dehydrogenase and acetokinase. Compared with DH5alpha, the supplementation of adenine increased rate specific pyruvate production rate of DA19 nearly 57%, and other parameters did not change. In addition, it showed decreased TCA split ratio and greatly increased pyruvate split ratio, whereas no changes in the key enzyme activities were observed. The differences of enzyme activities in the two strains were reasonably consistent with those in metabolic fluxes. CONCLUSION: Because there were differences in the de novo biosynthesis capacity of purine nucleotides between DH5alpha and DA19, supplementation of adenine had completely different effect on metabolic fluxes in two strains. PMID- 22233058 TI - [Analysis of xylanases derived from the metagenomic BAC clone library of yak rumen]. AB - OBJECTIVE: The diversity of rumen microbial xylanases and their degradation characteristics were studied and the resources of new xylanases genes and enzymes were provided. METHODS: According to the result of the high-throughput sequencing of the rumen microbial metagenome bacterial artificial chromosome (BAC) clones library, the diversity of xylanase genes was analyzed and screened. Then one xylanase and its downstream xylosidase gene screened was cloned and expressed in Escherichia coli. The enzyme characterization of the recombinant xylanase and xylosidase and their synergistic effect were studied. RESULTS: All 14 xylanases screened from the library belong to GH10 family proteins. These xylanases shared the amino acid sequence similarity between 20.5% and 91.3%. Intriguingly, 7 xylanase genes in different contigs were found to be followed by xylosidase gene. The specific enzyme activity of the xylanase (Xyn32) was 1.98 U/mg and no ferulic acid esterase activity was detected. The specific enzyme activity of the coupled xylosidase (Xy133) was 0.07 IU/mg, and xylosidase (Xy133) also displayed the activity of arabinofuranosidase. In addition, the in vitro experiment confirmed the synergistic effect between the coupled xylanase and xylosidase. PMID- 22233059 TI - [Heterologous expression and characterization of Yarrowia lipolytica lipase 4 and lipase 5 in Pichia pastoris]. AB - OBJECTIVE: To clone cDNA sequences of lipase 4 (LIP4) and lipase 5 (LIPS), analyze gene structures and express them in Pichia pastoris so as to investigate their enzymatic characteristics. METHODS: We first cloned cDNA sequences of LIP4 and LIP5 by reverse transcription PCR and analyzed their gene structures by SignalP 3.0. Then, intracellular expression vectors pPIC3. 5K-Lip4, pPIC3. 5K Lip5 and inducible secretion vectors pPIC9K-Lip4, pPIC9K-Lip5 were constructed. All vectors were transformed into Pichia pastoris GS115 by electroporation, resulting in a series of engineered strains. After fermentation and NTA-Ni resin purification, the enzymatic properties of LIP4 and LIP5 were examined. RESULTS: The cloned cDNA sequences revealed that there was no intron in both of Lip4 and Lip5. The two lipases both contained catalytic triads and conserved GHSLG motifs. Their optimal substrate, pH, temperature were respectively pNP-caprylate (C8), 7.0 and 40 degrees C. The activities of LIP4 and LIPS were 10.16 U/mg and 5.1 U/mg, respectively. It was found that LIP4 was more sensitive to the variations of pH and temperature than LIP5. LIP4 and LIP5 could both be stimulated by Ca2+, besides LIPS could also be activated by Mg2+. They were both strongly inhibited by Hg2+, Phenylmethanesulfonyl fluoride (PMSF) and Dithiothreitol (DTT). CONCLUSION: The cloning of Lip4 and Lip5, expression in P. pastoris and characterization of their properties would offer a solid basis for their large scale production and future application. In addition, the results also enriched the data for a systematic research on the lipase gene family of Y. lipolytica. PMID- 22233060 TI - [Screening and identification of two heterotrophic nitrifying bacteria and characterization of their capacity for nitrogen removal]. AB - OBJECTIVE: Two heterotrophic nitrifying bacteria, P2 and P9 isolated from piggery wastewater, were studied for their capacity of nitrification and nitrogen removal. METHODS: Physiological characteristics and phylogenetic analysis based on 16S rDNA sequences of strains P2 and P9 were analyzed. The ammonia removal characteristics of strains P2 and P9 were investigated. Furthermore, nitrogen removal ability of strains P2 and P9 individually or mixed were evaluated in the treatment of actual piggery wastewater. RESULTS: Strains P2 and P9 were identified as Paracoccus sp. and Shinella sp., respectively. Heterotrophic nitrification could occur by the strains when they utilized organics. After cultivation of 24 h, the ammonia removal rates by the strains were up to 80% approximately; meanwhile, there was almost no nitrite and nitrate accumulation. However, aerobic denitrification could not occur by the strains when NO3- or NO2- was provided as the sole nitrogen source, respectively. For heterotrophic nitrification, with strains P2 and P9, the optimal carbon source was sodium succinate, and the optimal C/N ratio was 9. Besides, the pH values rose from 6.8 to 8.9 in the whole ammonia removal process. The growth and nitrogen removal ability of the two strains depended much on the quantity of small molecule carbon source, and the nitrogen removal capability of strains P2 or P9 in wastewater with small molecule carbon source was improved evidently. The effect was strengthened especially when the two strains were mixed together. CONCLUSION: Nitrogen removal ability of strains P2 and P9 was relatively strong, and they may exhibit broad application prospects in wastewater treatment. PMID- 22233061 TI - [Methanogen diversity in the piglet colon and its correlation with environmental factors]. AB - OBJECTIVE: We investigated the correlation between the methanogen diversity in the piglet colon and the environmental factor (weaning stress, diet type and age). METHODS: The colonic contents of piglets at 7, 14, 21, 28 and 35 days old were collected for the determination of volatile fatty acids and total DNA extraction. DNA was subject to PCR-DGGE (Denaturing gradient gel electrophoresis) analysis and interesting bands were excised and sequenced. Redundancy analysis (RDA) was performed for the correlation between methanogen diversity and environmental factors. RESULTS: As the piglets grew, acetate, propionate and the total volatile fatty acid production increased significantly (P < 0.05), but butyrate concentration remained stable (P > 0.05). The similarity indices of DGGE profiles was higher during the period of the 7 day to 24 day after birth, with grouped in one cluster, and the samples from the 35 days were dropped into another cluster. DGGE analysis showed three dominant bands appeared in samples of 35 d old, with their 16S rRNA gene sequences closely related to Methanobacteria and a novel group of uncultivated Achaean. Redundancy analysis (RDA) showed that age has the largest relevance to the community structure of bacteria in colonic samples, followed by the diet type. CONCLUSION: The results indicated that the methanogen community in the piglet colon was stable during the first 24 days after birth, and became more diverse at 35 days of age. The methanogens community was mainly affected by age and the diet type. PMID- 22233062 TI - [Proteomics analysis of feather pulp from chickens infected with very virulent strain of Marek's disease virus]. AB - OBJECTIVE: Feather follicle epithelium (FFE) and feather of chicken are sites that produce and release enveloped infectious Marek's disease virus (MDV). In order to investigate host responses, the feather pulp from chickens infected with MDV was analyzed by proteomics. METHODS: Forty-eight one-day old specific pathogen free (SPF) chickens were randomly divided into two groups. One group of birds (n = 24) were inoculated intraperitoneally with 1000 plaque-forming unit (PFU) of the RB1B strain of MDV, the rest (n = 24) kept as uninfected control. Feather pulp were extracted from feather tips collected from chickens of infected and control group at 21 days post infected (dpi), and dissolved in two dimensional electrophoresis (2-DE) sample buffer. The soluble proteins were separated by 2-DE, 6 images (2 groups x 3 images) of 2-DE were used to analyze the differentially expressed proteins with PDQuest 8. 0. 1. Some of spots changed significantly were further analyzed by mass spectrometry. RESULTS: 41 spots, which expression level changed above two fold, were detected. Among of them, 25 of these spots were up-regulated, 7 spots down-regulated, 9 spots newly induced expression in group infected with MDV. 21 spots, corresponding to 20 proteins, were successfully identified by mass spectrometry. These differential expressed proteins are apolipoprotein A I, 14-3-3 sigma (two spots are the same protein), stathmin, and so on. CONCLUSION: Bioinformatics analysis indicates these differential proteins are mainly associated with host response, metabolism, cytoskeleton, and cell proliferation. PMID- 22233063 TI - [Immunosuppression effect of co-infection with MDRV and H9 AIV on thymus in muscovy ducks]. AB - OBJECTIVE: To study the immunosuppression effect on the thymus of muscovy ducks after infected with muscovy duck reovirus (MDRV) and H9 influenza virus (AIV). METHODS: After 8-day-old birds were infected with MDRV or H9 AIV, or both, the morbidity and mortality were totaled, the morphology and ultra-structure of the thymus were observed, proliferation ability of thymus cell were detected and the virus distrubition were detected by RT-PCR. RESULTS: After H9 AIV infection, The morbidity was low (10%) and without death. No obvious pathological change was observed on the thymus, whereas the proliferation ability of thymus cell was obviously suppressed. After MDRV infection, The birds grew slow, the morbidity was 80% and mortality was 50%. Thymus was atrophy appearing local necrosis and proliferation ability of thymus cell was obviously suppressed. After co-infection with MDRV and H9 AIV, the birds grew even slower growth. The morbidity was 90% and mortality was 70%. The thymus was atrophy appearing the lymphopenia and local necrosis and proliferation ability of thymus cell was also more obviously suppressed than MDRV infection. Virus duration time and detection ratio in co infection group were more than in AIV and MDRV group. CONCLUSION: H9 AIV could lead to minor immunosuppression and MDRV could cause serious immuno-suppression. H9 AIV could aggravate the immunosuppression of thymus after co-infected with MDRV, so MDRV and H9 AIV infection had synergic effect on immunosuppression of the thymus. PMID- 22233064 TI - [Drug resistance and related genes of chickenborne Salmonella to quinolone and fluoroquinolones]. AB - OBJECTIVE: Antimicrobial susceptibility to quinolone and fluoroquinolones and the related genes of chickenborne Salmonella in Shaanxi, Henan, Sichuan and Beijing provinces were studied to better understand the development of antimicrobial resistance and routes of transmission to ensure food safety. METHODS: Antimicrobial susceptibility was tested according to agar dilution method. GyrA and parC gene mutations of quinolone resistance determination region (QRDR) of fluoroquinolone resistant Salmonella and the resistant genes of qnrA, qnrB, qnrS and aac (6')-Ib-cr were determined using PCR and DNA sequencing analysis. RESULT: Among the 390 Salmonellae isolates, 63.59% were resistant to nalidixic acid, followed by ciprofloxacin (21.28%), levofloxacin (16.67%), and gatifloxacin (14.62%). Among 248 nalidixic acid resistant Salmonella, antimicrobial resistant genes carried by plasmid were detected as aac(6')-Ib-cr (20.16%), qnrA (10.89%), qnrB (10.08%) and qnrS (1.61%), respectively. In total 199 point mutations were detected in gyrA and parC of 83 fluoroquinolone-resistant Salmonella isolates. The most common mutations in gyrA gene was Ser83Phe and Asp87Gly double mutation, followed by Ser83Phe and Asp87Asn double mutation, Ser83Tyr, Ser83Phe, Asp87Gly. Sixty-five point mutations detected in parC was Ser80Arg. CONCLUSION: Antimicrobial resistance of Salmonella recovered from chicken in the four provinces was common. Genetic elements including mutations of unwindase, topoisomerase, and plasmid with antimicrobial, played important roles in the antimicrobial resistance of Salmonella. PMID- 22233065 TI - [Molecular typing and immunoblotting of 17 Mycoplasma ovipneumoniae isolates from China]. AB - OBJECTIVE: To study the heterogeneity and immunogenic variability among Mycoplasma ovipneumoniae (M. ovipneumoniae) isolates from different regions of China. METHODS: The heterogeneity of 17 strains of M. ovipneumoniae isolated from 8 regions of China was studied by the amplified fragment length polymorphism (AFLP) and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The software NTsys-2. 10e was used to analyze the profiles obtained from the AFLP and SDS-PAGE. The proteins reacted with the antiserum against M. ovipneumoniae type strain Y98 were then detected by Western-blot. RESULTS: Seventeen strains of M. ovipneumoniae were divided into 8 AFLP groups based on the source regions when the coefficient was 0.78. They were also divided into 8 SDS-PAGE groups based on the source regions when the coefficient was 0.85. A total of 6 immunogenic proteins were detected within 8 strains of M. ovipneumoniae, and their molecular weights were 105 kDa, 83 kDa, 65 kDa, 42 kDa, 40 kDa or 26 kDa, respectively. Interestingly, the 83 kDa and 40 kDa proteins were conserved in all the 8 isolates. CONCLUSION: M. ovipneumoniae isolates from some regions of China were genetically different, but the 83 kDa and 40 kDa antigenic proteins were conserved among the tested isolates. This study can provide some insights for the diagnosis and vaccine development of the disease caused by M. ovipneumoniae. PMID- 22233066 TI - [Preparation of monolithic materials and their applications in proteomic analysis]. AB - Proteomics is one of the core contents of life science in the post-genomic era, among which it is very important to develop the analytical techniques with high resolution, high sensitivity, high accuracy and high throughput. With the advantages of facile preparation, fast mass transfer, low backpressure and easy modification, monolithic materials have been widely used in proteomic analysis. This review summarizes the preparation methods of different kinds of monolithic materials (including organic polymer monoliths, silica-based monoliths, organic inorganic hybrid silica monoliths) and their applications in proteomic study such as the digestion of proteins, the separation of proteins or peptides, high throughput analysis integrating online digestion, separation and identification. PMID- 22233067 TI - [Principle, technique and applications of on-line focusing in capillary electrophoresis]. AB - Capillary electrophoresis (CE) has wide applications in many fields because of its extraordinary advantages, such as high efficiency of separation, high speed, and high throughput. However, the detection sensitivity is relatively low due to short detection window and short optical length. To improve the detection sensitivity, a number of on-line sample focusing and stacking modes have been developed, such as field-amplified sample stacking, pH gradient preconcentration, micellar electrokinetic capillary chromatography (MEKC), isotachophoresis (ITP). These on-line focusing techniques have been of intensive interest because of the ease of operation and simultaneous focusing during capillary electrophoresis separation. Here, we review the principle, advanced techniques and latest applications of on-line capillary electrophoresis focusing. PMID- 22233068 TI - [Preparation of C18-silica hybrid monolithic capillary column by "one-pot" process and its application]. AB - A "one-pot" process for the preparation of organic-silica hybrid capillary monolithic column by concurrently using tetramethoxysilane (TMOS), vinyltrimethoxysilane (VTMS) and the organic monomer, N-(2-(methacryloyloxy) ethyl) dimethyl-octadecylammonium bromide (MDOAB), is described. The polycondensation of alkoxysilanes and the copolymerization of MDOAB and VTMS were subsequently carried out within the confines of a capillary under the proper reaction conditions. The performance of the C18-silica hybrid monolithic column was investigated by capillary electrochromatography and capillary liquid chromatography. In addition, the C18-silica hybrid capillary monolithic column was also applied in the analysis of tryptic digests of bovine serum albumin by capillary liquid chromatography/tandem mass spectrometry (CLC-MS/MS) for demonstrating its potential in proteome analysis. This in situ process of incorporating functional groups into silica monolith provides a new way for the preparation of the organic-silica hybrid monolithic column. PMID- 22233069 TI - [Construction of a two-dimensional liquid chromatography separation system for high abundance proteins depletion in human plasma]. AB - High abundance proteins existing in human plasma severely impede the detection of low abundance proteins. This is one of the most difficult problems encountered in plasma proteomics research. We developed a two-dimensional liquid chromatography system with strong anion exchange chromatography-reversed-phase liquid chromatography (SAX-RPLC) for the extensive separation of plasma proteins and selective depletion of high abundance proteins. TSKgel SuperQ-5PW was selected as the first dimensional separation column for crude human plasma fractionation and Jupiter C4 column was selected as the second dimensional separation column. Separation gradients of the two-dimensional liquid chromatography system were optimized to ensure an extensive separation of plasma proteins. Ten peaks with high signal intensities ( >20 mAU) at 215 nm during the second dimensional separation were collected and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). As a result, 32 proteins, all of which were reported to be high abundance proteins in plasma, including human serum albumin (HSA), immunoglobulin G (IgG) and so on were successfully identified. This system provides an effective method for future depletion of more high abundance proteins and in-depth research in human plasma proteomics. PMID- 22233070 TI - [Study of phospholipid profile of ovarian tumor by high performance liquid chromatography-mass spectrometry]. AB - Ovarian tumor has been paid more and more attention since its influence on women's health and life quality is increasing. Ovarian cancer is one of the three gynecologic cancers, and its mortality is the highest one of them. Phospholipid metabolic profiling method based on high performance liquid chromatography electrospray mass spectrometry (HPLC/ESI-MS) has been applied in the study of ovarian tumors including benign (B) and malignant (M) ovarian tumors. The data of phospholipid profile collected by HPLC/ESI-MS were transformed and the peak list was obtained with the commercial software automatically. The total differences of phospholipids among M, B and normal (N) groups were found with the orthogonal signal correction and partial least-squares (OSC-PLS). Further, the differential phospholipids were selected according to the S-plot, the variable importance value (VIP > 1) and p (p < 0.05). These phospholipids were plasmalogen phospatidylethanol, phosphatidylcholine, plasmalogen phosphatidylcholine, sphingomyelin and lysophosphatidylcholine. This research provides some new and useful information of what has happened in phospholipids of the women with ovarian tumors. PMID- 22233071 TI - [Phosphorylated membrane proteome analysis of human neuroblastoma SH-SY5Y cell line]. AB - A strategy with the combination of multiprotease digestion and the selective enrichment of phosphopeptides by silica hybrid monolith based immobilized Ti4+ affinity chromatography (Ti4+ -IMAC) was proposed, and applied in the global profiling of phosphorylated membrane proteome of neuroblastoma SH-SY5Y cells. The fraction of membrane proteins was extracted by ultra speed centrifuge, followed by washing with 1 mol/L sodium chloride and 0.1 mol/L sodium carbonate. For digestion, chymotrypsin and pepsin with broader specificity were used as complementary enzymes to trypsin. The phosphopeptides were then selectively enriched by monolithic Ti4+ -IMAC column, and analyzed by nanoflow high performance liquid chromatography and mass spectrometry. A total of 43 phosphoproteins were identified, among which 14 proteins were located on the membrane. All these results demonstrated that the proposed strategy might be promising to promote the in-depth study of neuroblastoma and discover the candidate biomarkers. PMID- 22233072 TI - [Development of a droplet-interfaced high performance liquid chromatography capillary electrophoresis two dimensional separation platform]. AB - Proteomics demands high resolution multidimensional separation techniques due to its extremely high complexity. Droplet microfluidics provides a series of unique advantages in manipulating micro and nanolitre samples, such as micro-volume operation, limited diffusion and none cross-contaminating, therefore has the potential to be an ideal interface strategy for multidimensional separation. Using the microchips of different structures, functions such as "droplet generation" and "oil depletion" can be realized. Based on these functions, samples can be transferred from continuous flow to segmented flow and then back to continuous flow. In this way, different separation modes can be combined. In this study, droplet technology was utilized as a novel interface strategy in combining high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Using tryptic peptides mixture as a sample, this two dimensional HPLC-CE system provided high resolution separation with a peak capacity over 3000. This proof-of-principle study has demonstrated the usefulness of droplet interface technology in multidimensional separation. PMID- 22233073 TI - On-line preconcentration of sodium dodecyl sulfate-protein complexes using electrokinetic supercharging method with a prefilled water plug in capillary sieving electrophoresis. AB - An electrokinetic supercharging (EKS) method with a prefilled water plug at the head column of capillary was developed for on-line preconcentration of sodium dodecyl sulfate (SDS)-protein complexes in capillary sieving electrophoresis (CSE). Conventional EKS is a combination of electrokinetic injection with transient isotachophoresis (tr-ITP). The capillary is first filled with background electrolyte, then an appropriate amount of a leading electrolyte is filled and electro-injection is carried out for certain duration. After that, terminating electrolyte is filled, and tr-ITP is subsequently initiated, followed by capillary electrophoresis (CE) separation. In this work, the performance of EKS was evaluated by integrating multiple sub-methods step by step, and a water plug containing polymer was introduced before electrokinetic injection in order to further improve the concentration effect. The positive effects of the sub methods were verified, including molecular sieving effect of polymer, field enhanced sample injection (FESI) with and without a water plug, and transient isotachophoretic electrophoresis-based FESI. It was observed that analyte discrimination usually encountered in conventional electrokinetic injection was eliminated due to the similar charge to mass ratios of SDS-protein complexes. Based on these results, a hybrid on-line preconcentration method, EKS with injecting a water plug containing polymer before sample electrokinetic injection, was proposed and used to indiscriminately preconcentrate SDS-protein complexes, which provided a sensitivity enhancement factor of more than 1000. It was very suitable for the analysis of low-abundance proteins, providing the information of their molecular mass. PMID- 22233074 TI - Chemical enrichment of tyrosine phosphopeptides. AB - Tyrosine phosphorylation of proteins plays a vital role in signal transduction pathway. Currently, antibody-based method dominates the tyrosine phosphopeptide enrichment and there is a lack of other general approaches for selective isolation of tyrosine phosphopeptides. However, antibody-based methods are of high cost and biased to certain motifs. Here we developed a chemistry-based method for tyrosine phosphopeptide enrichment. This method utilized the beta elimination, which only occurs on phospho-serine/threonine residues, to achieve the reverse selection effect. After the dephosphorylation of serine/threonine phosphopeptides a sensitive phosphopeptide isolation method was applied to enrich tyrosine phosphopeptides. In this proof-of-concept study, it showed that the beta elimination for several standard serine phosphopeptides was completed over 99% while the recovery of tyrosine phosphopeptide remained at around 70% within 20 min. In the further test with 6-protein digests monitored by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis, only tyrosine phosphopeptides were detected. Due to the low-cost and unbiased properties, the method has potential applications in tyrosine signaling pathway analysis as an alternative to antibody-based approach. PMID- 22233075 TI - [Preparation of procion brilliant blue-doped silica nanorods and their recognition properties for proteins]. AB - Protein enrichment and separation is one of the pivotal preliminary steps of proteomics studies, which is important to medical diagnosis and treatment. In this study, procion brilliant blue-doped silica nanorod was prepared via self assembly sol-gel technology without any additional template. Procion brilliant blue was covalently linked to 3-aminopropyltriethyloxy silane in ethanol. Tetraethylorthosilane (TEOS) was then added into the mixture, subsequently hydrolyzed and co-condensed for 3 h under stirring. The resulted nanorods were isolated by centrifugation, re-dispersed in deionized water, and centrifuged again. This wash process was repeated three times. Finally, the nanorods were dried under vacuum. Procion brilliant blue acted simultaneously as a self assembly template during the preparation process, and subsequently as recognition probe for proteins. Scanning electron microscopy (SEM) image showed that the nanotubes were 2-16 microm in length and 200-500 nm in diameter. The obtained nanorods were further characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSA), separately. All these results indicated that procion brilliant blue were successfully doped into silica nanorods. The recognition property of nanorods for bovine serum albumin (BSA) was investigated under static condition. The resulted nanorods showed high binding capacity (57.6 mg/g) for BSA and fast adsorption equilibrium (within 60 min). The nanorods were also evaluated with four typical proteins, hemoglobin, trypsin, lysozyme and pepsin, with different relative molecular masses and isoelectric points. The results indicated that the prepared nanorods exhibited the highest binding capacity for trypsin (87.5 mg/g) and the least binding for hemoglobin (Hb, 3.0 mg/g). This easy preparation protocol and excellent recognition property make the prepared materials a bright future in proteomics research. PMID- 22233076 TI - [Preparation of strong cation-exchange monolithic column and its application in polypeptide separation by capillary electrochromatography]. AB - A strong cation-exchange monolithic column was prepared by polymerization inside the fused-silica capillary. The solution consisted of acrylic acid and 2 acrylamido-2-methyl-1-propanesulfonic acid as functional monomers, N,N' methylenebisacrylamide as a cross-linking agent, dimethyl suiphoxide and dodecanol, 1 , 4-butanediol as organic porogenic solvents and azobisisobutyronitrile as a suitable initiator. The effects of the applied voltage, concentrations of organic modifier and salt solution, pH value on the electroosmotic flow were investigated. The experimental results showed that there existed a good linear relationship between the applied voltage and electroosmotic flow with a correlation coefficient of 0.9981; When the concentration of organic modifier (acetonitrile, ACN) was less than 70%, the swelling degree of stationary phase played a main role and the electroosmotic flow was decreased abnormally with the increase of ACN concentration; The electroosmotic flow was decreased with the increase of the concentration of phosphate. When the pH value was in the range of 3-9, it did not exert a significant change in electroosmotic flow. These results were consistent with the theoretical role. At the same time, five peptides were separated successfully under the optimal experimental conditions on the monolithic column for capillary electrochromatography. The column has obvious advantages in polypeptide separation and will be favorable for the protein investigation. PMID- 22233077 TI - [Evaluation of the retention properties of two cyclodextrin stationary phases with different spacers]. AB - A set of 14 model compounds were selected to evaluate the retention properties of two silica-based cyclodextrin (CD) bonded stationary phases with different spacers (Click Alkyl-CD and Click OEG-CD) under reversed-phase liquid chromatographic (RPLC) mode. The gradient calculation method and CSASS software developed in our group were applied to obtain the retention parameters of the 14 solutes on the two CD bonded stationary phases under 3 gradient conditions. The effect of acetonitrile content in the mobile phase on the retention of both CD stationary phases was studied. It was found that the retention of non-polar and medium polar compounds on the both stationary phases was based on RPLC mode, while the retention of some compounds (such as indazole) on Click OEG-CD was influenced by several kinds of interactions and was not based on RPLC mode. The hydrophobic property of the two CD stationary phases in RPLC mode was studied. High correlation value (R = 0.7) between the retention parameter of Click Alkyl CD and n-octanol-water partition coefficients of the solutes indicated the high hydrophobicity of Click Alkyl-CD. Nevertheless, the low correlation value (R < 0.3) between the retention parameter of Click OEG-CD and n-octanol-water partition coefficients indicated the presence of influence of other interactions in addition to hydrophobic interaction on the retention in RPLC mode. PMID- 22233078 TI - [Synthesis of hollow titania microspheres by using microfluidic droplet template]. AB - Droplet-based microfluidics is of great interest due to its particular characteristics compared with the conventional methods, such as reduced reagent consumption, rapid mixing, high-throughput, shape controlled, etc. A novel method using microfluidic droplet as soft template for the synthesis of hollow titania microspheres was developed. A typical polydimethylsiloxane (PDMS) microfluidic device containing "flow-focusing" geometry was used to generate water/oil (W/O) droplet. The mechanism for the hollow structure formation was based on the interfacial hydrolysis reaction between the continuous phase containing titanium butoxide precursor and the dispersed containing water. The continuous phase mixed with butanol was added in the downstream of the channel after the hydrolysis reaction. This step was used for drawing the water out of the microgels for further hydrolysis. The microgels obtained through a glass pipe integrated were washed, dried under vacuum and calcined after aging for a certain time. The fluorescence and scanning electron microscope (SEM) image of the microspheres indicated the hollow structure and the thickness of the shell. In addition, these microspheres with thin shell (about 2 microm) were apt to rupture and collapse. Droplet-based microfluidic offered a gentle and size-controllable manner to moderate this problem. Moreover, it has potential applications in photocatalysis combined with some modification realized on the chip simultaneously. PMID- 22233079 TI - [Development and evaluation of a novel three-dimensional adjustable confocal laser-induced fluorescence detector]. AB - Laser-induced fluorescence detector (LIFD) is one of the most sensitive detectors in analytical chemical files. Confocal optical configuration is widely used in LIFDs. Two effective approaches used to achieve the best signal to noise ratio (S/N) are increasing the confocal precision and minimizing the background noise. A novel three-dimensional adjustable confocal LIFD was developed, using a new three-dimensional adjustable supporter of reflector and modularized optical system. A detection limit (S/N = 3) of 1 x 10(-12) mol/L and a linear dynamic range of 3 orders of magnitude were obtained using fluorescein isothiocyanate (FITC) standard as the test sample. The noise level and drift levels were 8.0 x 10(-3) mV and 1.4 x 10(-3) mV/h, respectively, which were almost 10 times lower than before. And the stability of the LIFD was evaluated by five replicate injections of 5 x 10(-9) mol/L FITC, and the relative standard deviations (RSDs) of peak height and peak area were 0.38% and 0.41%, respectively. Further more, three biogenic amines, which were derivatized by FITC, were separated by high performance liquid chromatography (HPLC) and then detected by the novel LIFD. And the detection limits (S/N = 3) ranged 0.01 to 0.02 nmol/L, which were better than other methods. Therefore, the LIFD is highly sensitive, as well as shows a real low noise level and good reproducibility. PMID- 22233080 TI - [A novel gas chromatography detector based on ion mobility spectrometry technology and its application]. AB - Ion mobility spectrometry (IMS) is an attractive detector of gas chromatography (GC) due to its high sensitivity, short response time, and comparatively low cost. The hyphenated GC-IMS instrument can simultaneously provide high separation ability of GC and high sensitivity of IMS. In this paper, one setup of a GC-IMS instrument is introduced. The parameters of IMS as the GC detector were evaluated and studied with respect to the resolution and sensitivity including temperature, total voltage and drift gas flow rate. Under the optimal conditions, GC-IMS was used to detect iodomethane, 1,2-dichloroethane, tetrachloromethane and dibromomethane and the detection limits were 2, 0.02, 1 and 0.1 ng, respectively. And the linear ranges of two orders of magnitude were achieved. As the detector of gas chromatography, IMS can provide more information for compound identification because of its second dimensional separation and can realize selective detection of different compounds. PMID- 22233081 TI - [Simultaneous determination of 20 underivatized amino acids by high performance liquid chromatography-evaporative light-scattering detection]. AB - An analytical method for the determination of underivatized amino acids was established with high performance liquid chromatography (HPLC) coupled with evaporative light-scattering detection (ELSD). A domestic evaporative light scattering detector was used to determine underivatized amino acids. A BISCHOFF C18 AQ PLUS column and a solvent gradient elution with 0.2% heptafluorobutyric acid containing 0.1% trifluoroacetic acid as mobile phase A and methanol as mobile phase B were used. The temperature of the drift tube in ELSD was 40 degrees C and the flow rate of dry air was 2.5 L/min. The logarithm of the peak area and logarithm of the mass of each separated amino acid was in good linearity. The linear ranges of the 20 amino acids were from 30-300 mg/L. The limits of detection (S/N > 3) for the underivatized amino acids were from 24 ng to 100 ng. The average recoveries of the 20 amino acids were between 90.6% and 106.0%. This method and system are simple, rapid and accurate for the determination of underivatized amino acids. It can be used for the determination of underivatized amino acids in pharmaceutical, food and chemical industry fields. PMID- 22233082 TI - [A novel vapor dynamic headspace enrichment equipment for nontarget screening of volatile organic compounds in drinking water]. AB - A novel vapor dynamic headspace enrichment device was set up for nontarget screening of volatile organic compounds (VOCs) in drinking water. The main operating parameters of this device, such as length of distillation tube, volume of collected condensate, and choice of absorbent, were optimized. In this device, vapor was utilized as a purge gas and water was utilized as a absorbent. With the help of the device, one liter of water sample could be concentrated to 5 mL and the sensitivity of traditional purge and trap-gas chromatography-mass spectrometry (P&T-GC-MS) could be improved 1-2 orders of magnitude. Source and disinfected water samples from a water treatment plant were analyzed with this method. Compared with the traditional P&T-GC-MS analysis without pre-enrichment, the numbers of identified VOCs were improved from 0 to 16 for source water and 5 to 35 for disinfected water samples. It is also shown that there are many halide compounds in VOCs in disinfected water which do not exist in source water. PMID- 22233083 TI - [Preparation of L-phenylalanine chiral ligand-exchange chromatographic stationary phase by atom transfer radical polymerization and resolution of racemates]. AB - A novel stationary phase was synthesized for chiral ligand-exchange chromatography via atom transfer radical polymerization (ATRP). Glycidyl methacrylate (GMA) was grafted onto the surface of the silica by ATRP using bromoisobutyryl bromide as an initiator, and the organic metal compound formed in the CuCl/2,2'-bipyridine(Bpy) system as a catalyst at room temperature. The chiral stationary phase was then synthesized by grafting L-phenylalanine on the surface of the silica. The stationary phase was characterized by means of elementary analysis and evaluated in detail to determine its separability. The amount of L-phenylalanine on the surface of silica was calculated to be 4.32 mg/m2. The results showed that the good enantioseparations of some DL-amino acids were obtained using ligand-exchange chromatography on the synthesized chiral stationary phase (50 degrees C) with 0.05 mol/L KH2PO4 and 0.1 mmol/L Cu(Ac)2 solution (pH 4.5) as the mobile phase at a flow rate of 1.0 mL/min and a wavelength of 223 nm. The influences of the mobile phase pH, concentration of Cu (II), and temperature of column on the resolution of DL-amino acids by ligand exchange chromatography were investigated. The results showed that these conditions could affect the resolution of racemates. Compared with the column prepared by radical method using L-phenylalanine directly bonded onto the surface of the silica, the synthesized stationary phase showed a better separation ability, and the DL-aspartic acids and DL-asparagines could be separated at baseline. PMID- 22233084 TI - [Determination of gibberellins in Arabidopsis thaliana by matrix solid-phase dispersion extraction and high performance liquid chromatography-tandem mass spectrometry]. AB - A method for the analysis of gibberellin A1 (GA1), gibberellin A3 (GA3) and gibberellin A4 (GA4) in Arabidopsis thaliana by matrix solid-phase dispersion extraction (MSPD) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed. The solid sample of Arabidopsis thaliana was gently blended with C18 to obtain a homogeneous mixture. This mixture was transferred to an SPE cartridge filled with 0.5 g C18 to form a MSPD column. GA1, GA3 and GA4 were eluted with cold 80% methanol aqueous solution. The target compounds were separated on a C18 column with a gradient elution of 0.05% formic acid aqueous solution and acetonitrile as the mobile phase. The identification and quantification were carried out by using electrospray ionization in negative ion mode (ESI-) with multiple reaction monitoring (MRM). The linear ranges for GA1, GA3 and GA4 were all from 10 to 300 ng/g with correlation coefficients greater than 0.98. The limits of detection were in the range of 1.1-4.1 ng/g. The average recoveries and relative standard deviations were 54.7%-102.6% and 3.2% 12.8% respectively in the spiked range of 10-50 ng/g. The method is simple, sensitive, efficient and accurate. It is suitable for the confirmation and quantitative determination of GA1, GA3 and GA4 in Arabidopsis thaliana. PMID- 22233085 TI - [Accurate determination of chloramphenicol in pork by isotope dilution liquid chromatography-electrospray ionization tandem mass spectrometry]. AB - An accurate method was described for the determination of chloramphenicol (CAP) in pork. The analyte was quantified by isotope dilution liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) operating in negative ion multiple reaction monitoring (MRM) mode. The sample was treated by liquid-liquid extraction with ethyl acetate followed by a clean-up step on an HLB solid-phase extraction cartridge. Chloramphenicol-D5 (CAP-D5) was added as an isotope internal standard. Under the optimized conditions, the calibration curve showed a good linearity in ranging from 0.01 to 0.5 ng/g CAP. The correlation coefficient r2 was 0.9998. The limit of detection and the limit of quantification were 0.004 and 0.02 ng/g, respectively. The average recoveries of CAP at 0.02 ng/g and 1.0 ng/g spiked levels ranged from 95.2%-109.1%, 99.7%-102.5%, respectively. The relative standard deviations (RSDs) of intra-day and inter-day were less than 2%. Meanwhile, matrix effect factors k of CAP and CAP-D5 were determined under different mobile phases and the sample solvent composition, the k was in the range of 0.950-1.015. The method can be used as a confirmed method for the determination of CAP in pork. PMID- 22233086 TI - [Preparation of flavonol glycoside reference standard series from Epimedium brevicornum Maxim using pilot-scale preparative high performance liquid chromatography]. AB - Icariin and epimedins A, B, C are a series of active flavonol glycoside in Epimedium brevicornum Maxim. A pilot-scale preparative high performance liquid chromatographic (HPLC) method was developed to purify the four flavonol glycosides as reference standards from the crude extract of Epimedium brevicornum Maxim. After the crude extract containing approximately 20% flavonols was enriched using macropore resin, the obtained target fractions were subjected to pilot-scale preparative HPLC purification. With the aid of a self-packed pilot scale preparative column (220 mm x 77 mm, 10 microm), the 4 target compounds were separated well within 35 min in a single chromatographic run by the elution with acetonitrile-water (26:74 or 30:70, v/v). By repetitive injection of the enriched target fraction onto the preparative column, 33 g icariin as well as 4.6 g epimedin C, 3.7 g epimedin B, and 0.6 g epimedin A were obtained from 300 g crude extract. The purities of all products were greater than 98%. This pilot-scale preparative HPLC technique and the two step separation technology for 4 target compounds are quite useful for the production of the reference standard series with good purity like icariin, epimedins A, B, C standards due to its high performance, rapid separation and more amounts of products obtained. PMID- 22233087 TI - [Isolation and analysis of a new phytoecdysteroid from Cyanotis arachnoidea C. B. Clarke]. AB - Cyanotis arachnoidea is a plant with plenty of phytoecdysteroid. To study the active compound in it, a new phytoecdysteroid with 5alpha-cholesta skeleton, was isolated from the whole plant of Cyanotis arachnoidea C. B. Clarke by using various chromatographic methods (alumina column chromatography, silica gel column chromatography, octadecyl silane (ODS) column chromatography, thin layer chromatography (TLC) and high performance liquid chromatography (HPLC)). Its structure was analyzed on the basis of 1D and 2D nuclear magnetic resonances (NMR), electrospray ionization mass spectrometry (ESI-MS) methods. It is a compound with structure of 3beta,14alpha, 14alpha,20R,22R,25-hexahydroxy-5alpha cholest-7-en-6-one, which is a rare phytoecdysteroid with 5alpha-H. PMID- 22233088 TI - [Characteristics of electroosmotic flow in open-tubular capillary electrochromatography with magnetic nanoparticle coating as mixed-mode stationary phase]. AB - A novel open-tubular capillary electrochromatography (OT-CEC) column with magnetic nanoparticle coating as mixed-mode stationary phase was prepared. The mixed-mode stationary phases were obtained by mixing C18 and amino modified magnetic nanoparticles with different ratios. The mixed modified magnetic nanoparticles as stationary phase were introduced into the capillary by using external magnetic force. The magnetic nanoparticle coating can be easily regenerated by removing the external magnetic field, and applied to other separation modes. The characteristics of electroosmotic flow (EOF) were theoretically investigated through the effect of physicochemical properties of different stationary phases on EOF. The experiment was conducted under different ratios of mixed-mode stationary phases and coating lengths, and it was verified that the theoretical conclusions accorded with the experimental results. It was shown that the EOF can be easily adjusted by changing the ratio of stationary phases or the number of permanent magnets. PMID- 22233089 TI - Molecular dynamics simulations for human CAR inverse agonists. AB - Constitutive androstane receptor (CAR), along with pregnane x receptor (PXR), is an important metabolic sensor in the hepatocytes. Like all other nuclear receptors (NRs), CAR works in concert with coregulator proteins, coactivators, and corepressors which bind to the NRs. The main basis for the receptor to distinguish between coactivators and corepressors is the position of the C terminal helix 12 (H12), which is determined by the bound NR ligand. CAR, having constitutive activity, can be repressed or further activated by its ligands. Crystal structure of human CAR bound to an agonist and a coactivator peptide is available, but no structural information on an inverse agonist-bound human CAR and a corepressor exists. In our previous molecular dynamics (MD) studies, no corepressor peptide was included. Therefore, probably due to the strong interactions which keep the relatively short H12 of CAR in the active position, the structural changes elicited by inverse agonists were very subtle, and H12 of CAR seemed to more or less retain its active conformation. Here, we have run a series of MD simulations to study the movement of H12 in the presence of both activating and repressing ligands as well as a corepressor peptide. The presence of the corepressor on the coregulator surface of CAR induced a clear shift of H12 of the inverse agonists-bound CAR. In general, H12 moved toward H10 and not away from the ligand binding domain, as seen in some other NRs. However, H12 of CAR is short enough that this movement seems to be adequate to accommodate the binding of the corepressor. PMID- 22233090 TI - Intelligence: new findings and theoretical developments. AB - We review new findings and new theoretical developments in the field of intelligence. New findings include the following: (a) Heritability of IQ varies significantly by social class. (b) Almost no genetic polymorphisms have been discovered that are consistently associated with variation in IQ in the normal range. (c) Much has been learned about the biological underpinnings of intelligence. (d) "Crystallized" and "fluid" IQ are quite different aspects of intelligence at both the behavioral and biological levels. (e) The importance of the environment for IQ is established by the 12-point to 18-point increase in IQ when children are adopted from working-class to middle-class homes. (f) Even when improvements in IQ produced by the most effective early childhood interventions fail to persist, there can be very marked effects on academic achievement and life outcomes. (g) In most developed countries studied, gains on IQ tests have continued, and they are beginning in the developing world. (h) Sex differences in aspects of intelligence are due partly to identifiable biological factors and partly to socialization factors. (i) The IQ gap between Blacks and Whites has been reduced by 0.33 SD in recent years. We report theorizing concerning (a) the relationship between working memory and intelligence, (b) the apparent contradiction between strong heritability effects on IQ and strong secular effects on IQ, (c) whether a general intelligence factor could arise from initially largely independent cognitive skills, (d) the relation between self regulation and cognitive skills, and (e) the effects of stress on intelligence. PMID- 22233092 TI - Role of subsurface diffusion and Ostwald ripening in catalyst formation for single-walled carbon nanotube forest growth. AB - Here we show that essentially any Fe compounds spanning Fe salts, nanoparticles, and buckyferrocene could serve as catalysts for single-walled carbon nanotube (SWNT) forest growth when supported on AlO(x) and annealed in hydrogen. This observation was explained by subsurface diffusion of Fe atoms into the AlO(x) support induced by hydrogen annealing where most of the deposited Fe left the surface and the remaining Fe atoms reconfigured into small nanoparticles suitable for SWNT growth. Interestingly, the average diameters of the SWNTs grown from all iron compounds studied were nearly identical (2.8-3.1 nm). We interpret that the offsetting effects of Ostwald ripening and subsurface diffusion resulted in the ability to grow SWNT forests with similar average diameters regardless of the initial Fe catalyst. PMID- 22233091 TI - SIRT1: new avenues of discovery for disorders of oxidative stress. AB - INTRODUCTION: The sirtuin SIRT1 is expressed throughout the body, has broad biological effects and can significantly affect both cellular survival and longevity during acute and long-term injuries, which involve both oxidative stress and cell metabolism. AREAS COVERED: SIRT1 has an intricate role in the pathology, progression, and treatment of several disease entities, including neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, tumorigenesis, cardiovascular disease with myocardial injury and atherosclerosis, metabolic disease, and aging-related disease. New areas of study in these disciplines, with discussion of the cellular biology, are highlighted. EXPERT OPINION: Novel signaling pathways for SIRT1, which can be targeted to enhance cellular protection and potentially extend lifespan, continue to emerge. Investigations that can further determine the intracellular signaling, trafficking and post-translational modifications that occur with SIRT1 in a variety of cell systems and environments will allow us to further translate this knowledge into effective therapeutic strategies that will be applicable to multiple systems of the body. PMID- 22233093 TI - SNP mining in C. clementina BAC end sequences; transferability in the Citrus genus (Rutaceae), phylogenetic inferences and perspectives for genetic mapping. AB - BACKGROUND: With the increasing availability of EST databases and whole genome sequences, SNPs have become the most abundant and powerful polymorphic markers. However, SNP chip data generally suffers from ascertainment biases caused by the SNP discovery and selection process in which a small number of individuals are used as discovery panels. The ongoing International Citrus Genome Consortium sequencing project of the highly heterozygous Clementine and sweet orange genomes will soon result in the release of several hundred thousand SNPs. The primary goals of this study were: (i) to estimate the transferability within the genus Citrus of SNPs discovered from Clementine BACend sequencing (BES), (ii) to estimate bias associated with the very narrow discovery panel, and (iii) to evaluate the usefulness of the Clementine-derived SNP markers for diversity analysis and comparative mapping studies between the different cultivated Citrus species. RESULTS: Fifty-four accessions covering the main Citrus species and 52 interspecific hybrids between pummelo and Clementine were genotyped on a GoldenGate array platform using 1,457 SNPs mined from Clementine BES and 37 SNPs identified between and within C. maxima, C. medica, C. reticulata and C. micrantha. Consistent results were obtained from 622 SNP loci. Of these markers, 116 displayed incomplete transferability primarily in C. medica, C. maxima and wild Citrus species. The two primary biases associated with the SNP mining in Clementine were an overestimation of the C. reticulata diversity and an underestimation of the interspecific differentiation. However, the genetic stratification of the gene pool was high, with very frequent significant linkage disequilibrium. Furthermore, the shared intraspecific polymorphism and accession heterozygosity were generally enough to perform interspecific comparative genetic mapping. CONCLUSIONS: A set of 622 SNP markers providing consistent results was selected. Of the markers mined from Clementine, 80.5% were successfully transferred to the whole Citrus gene pool. Despite the ascertainment biases in relation to the Clementine origin, the SNP data confirm the important stratification of the gene pools around C. maxima, C. medica and C. reticulata as well as previous hypothesis on the origin of secondary species. The implemented SNP marker set will be very useful for comparative genetic mapping in Citrus and genetic association in C. reticulata. PMID- 22233094 TI - Activation of p38 MAPK and expression of TGF-beta1 in rat colon enterocytes after whole body gamma-irradiation. AB - PURPOSE: To examine the p38 mitogen-activated protein kinase (p38) phosphorylation and transforming growth factor beta 1 (TGF-beta1) expression in rat colon enterocytes after irradiation and their contribution to pathology of intestinal radiation disease. MATERIALS AND METHODS: Male Wistar rats were irradiated with whole body gamma-radiation of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 Gy ((60)Co, 1.44 Gy.min(-1)). Samples were taken 4 and 24 h after irradiation, immunohistochemically stained, then p38 phosphorylation and TGF-beta1 expression were measured in apical and cryptal enterocytes using computer image analysis. In selected groups, morphometric parameters, mitosis and apoptosis were evaluated. RESULTS: P38 phosphorylation integrated optical density (IOD)-based levels increased 2.4-fold (p <= 0.01) and 3.6 to 22.8-fold (p <= 0.001) in apical enterocytes 4 h after 0.5 Gy and 24 h after 3-10 Gy, respectively. TGF-beta1 IOD based expression increased 3.3- to 6.9-fold (p <= 0.001) and 1.6- to 4.9-fold (p <= 0.001) in apical cells 4 h after 0.5-2, 4, 5 Gy and 24 h after 6-10 Gy, respectively. No changes were observed in crypts. CONCLUSIONS: We found a chronological and dose-dependent order of p38 activation and TGF-beta1 expression in apical enterocytes. Transient up-regulation of p38 and TGF-beta1 signalling observed 4 h after low-dose irradiation may participate in molecular mechanisms creating cellular over-expression in apical compartment, while persistent patterns measured 24 h after high-dose irradiation might provide protection of remaining cells in order to maintain tissue integrity. PMID- 22233095 TI - A frequency-based gene selection method to identify robust biomarkers for radiation dose prediction. AB - PURPOSE: A fast, radiation-specific and highly accurate prediction of the radiation dose of accidentally exposed individuals is essential for medical decision-making. The aim of the present study is to identify small gene signatures allowing the discrimination between low and medium dose exposure of low linear energy transfer (LET)-radiation. MATERIAL AND METHODS: We developed a framework for dose prediction using a frequency-based gene selection approach, based on a p-value and fold-change criterion applied to microarray expression data. A repeated cross-validated classification guarantees unbiased performance results. Human blood from six healthy donors was irradiated ex vivo with 0.5, 1, 2 and 4 Gy (Cs-137 gamma-rays). Expression levels of isolated blood lymphocytes were measured at 6, 24 and 48 h after irradiation. RESULTS: We identified radiation-responsive genes, most of them functionally linked to apoptosis, DNA damage or cell-cycle regulation. We extracted small subsets of genes, with which 95.7% of all samples can be correctly predicted, regardless of the time post irradiation. Seven of these genes were used for validation by Quantitative Real Time Polymerase Chain Reaction (qRT-PCR). CONCLUSION: The genes identified are potential robust biomarkers, which are particularly suitable for dose level discrimination at a window of time that would be appropriate for life-saving medical triage. PMID- 22233096 TI - Elevated albuminuria associated with increased risk of recurrent venous thromboembolism: results of a population-based cohort study. AB - This study examined the risk of recurrent venous thromboembolism (VTE) in patients with elevated albuminuria. In 1997-1998, inhabitants of Groningen, the Netherlands, aged 28-75 years (n=85,421), were invited to participate in the PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study, an observational, population-based cohort study. Albuminuria was measured and VTE occurrence was monitored in responding subjects (n=40,856). Patients with first VTE between study entry and January 2009, identified through databases of the national registry of hospital discharge diagnoses, death certificates, regional anticoagulation clinic and medical records, were used for analysis. Of 351 subjects with first VTE, 37 subjects developed a recurrence during a median follow-up period of 3.3 (interquartile range, 1.1-6.4) years. The annual incidence of recurrence in subjects with elevated albuminuria (>= 20 mg/l) was 5.00% [95% confidence interval (CI); 2.16-9.85], compared to 2.38% (95%CI; 1.59 3.41) in subjects with normal albuminuria (<20 mg/l). Hazard ratio for recurrence was 1.95 (95%CI; 0.89-4.30) after adjustment for age and sex. This hazard ratio was 3.35 (95%CI; 1.18-9.47) in patients with first unprovoked, and 1.12 (95%CI; 0.25-5.01) in those with a first provoked event. This study showed that subjects with elevated albuminuria who experience an unprovoked VTE are at an increased risk of recurrence, independent of age and sex. PMID- 22233097 TI - De-epithelialization of vitiliginous area for transplantation of cultured autologous melanocyte: a case report of two patients with different methods. PMID- 22233098 TI - Chestnut species and jasmonic acid treatment influence development and community interactions of galls produced by the Asian chestnut gall wasp, Dryocosmus kuriphilus. AB - Jasmonic acid (JA) is a plant-signaling hormone involved in defenses against insects and pathogens as well as the regulation of nutrient partitioning. Gall wasps (Hymenoptera: Cynipidae) induce the formation of galls on their host plants, which house immature wasps and provide them with nutrition and protection. The goal of this study was to investigate the effects of JA application on gall development and defenses. Dryocosmus kuriphilus Yasumatsu (Hymenoptera: Cynipidae) galls on American chestnut, Castanea dentata (Marsh.) Borkhausen (Fagales: Fagaceae), and Chinese chestnut, C. mollissima Blume, were treated with JA or a JA- inhibitor, diethyldithiocarbamic acid (DIECA), to determine the effects of these treatments on gall characteristics and defenses. Chinese chestnut galls treated with JA had greater volume and dry weight, thicker sclerenchyma layers, and fewer external fungal lesions compared with controls. Galls from both chestnut species treated with JA contained a lower proportion of empty chambers, and elevated tannin levels compared with controls. The effects of DIECA on galls were generally opposite from those of JA. American chestnut galls treated with DIECA had lower dry weight and fewer feeding punctures caused by the lesser chestnut weevil compared with controls. Galls from both chestnut species that were treated with DIECA were smaller and had more external fungal lesions compared with controls. Compared to American chestnut galls, Chinese chestnut galls had increased parasitism rates and fewer gall wasps. This study is the first to investigate the effects of JA on an insect gall, and indicates that JA treatments benefit gall wasps by increasing gall size and defenses. PMID- 22233099 TI - Automatic dirt trail analysis in dermoscopy images. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the US. Dermatoscopes are devices used by physicians to facilitate the early detection of these cancers based on the identification of skin lesion structures often specific to BCCs. One new lesion structure, referred to as dirt trails, has the appearance of dark gray, brown or black dots and clods of varying sizes distributed in elongated clusters with indistinct borders, often appearing as curvilinear trails. METHODS: In this research, we explore a dirt trail detection and analysis algorithm for extracting, measuring, and characterizing dirt trails based on size, distribution, and color in dermoscopic skin lesion images. These dirt trails are then used to automatically discriminate BCC from benign skin lesions. RESULTS: For an experimental data set of 35 BCC images with dirt trails and 79 benign lesion images, a neural network-based classifier achieved a 0.902 are under a receiver operating characteristic curve using a leave-one-out approach. CONCLUSION: Results obtained from this study show that automatic detection of dirt trails in dermoscopic images of BCC is feasible. This is important because of the large number of these skin cancers seen every year and the challenge of discovering these earlier with instrumentation. PMID- 22233101 TI - Measurement of macrophage marker in hyperhaemolytic transfusion reaction: a case report. AB - BACKGROUND: Hyperhaemolytic transfusion reaction (HHTR) has been well described in patients with sickle cell disease (SCD). It is characterised by a decrease in haemoglobin concentration to levels below those before transfusion and a fall in the absolute reticulocyte count. As red blood cells (RBC) alloantibodies are typically not detected in post-transfusion samples in acute forms of HHTR, we have previously proposed that both the transfused and autologous RBCs cells (HbSS/reticulocytes) are destroyed by activated macrophages. CASE REPORTS: We report a patient with SCD who presented with vaso-occlusive sickle cell crisis and developed a severe HHTR attributable to anti-Fy3. In addition to the usual supportive measures, the patient was treated with intravenous immunoglobulin (IVIG) and steroids. Serum ferritin levels were measured as an aspecific marker of macrophage activation. RESULTS: Steroids and IVIG were effective in managing HHTR. Ferritin levels were high at the time of haemolysis, (>10000 ug L(-1)) whereas recovery and cessation of haemolysis correlated with a decrease in ferritin levels. CONCLUSION: Serum ferritin values >10,000 ug L(-1) are considered pathognomic for conditions characterised by abnormal macrophage activation. In our case, serum ferritin levels correlate well with the disease activity and clinical response. This further supports our previous proposal that the activated macrophages play an important role in HHTR. Serum ferritin is a nonspecific marker of inflammation. A rapid specific bio-marker to measure the activity of macrophages in SCD in HHTR is desirable, and this area warrants further investigation. PMID- 22233102 TI - Using the theory of planned behaviour to understand binge drinking: the importance of beliefs for developing interventions. AB - OBJECTIVES: To elicit students' salient beliefs in relation to binge drinking, and to examine the extent to which individual salient beliefs predict theory of planned behaviour (TPB) constructs in relation to binge drink, and actual drinking behaviour assessed later that evening. DESIGN: Longitudinal, over a single evening. METHODS: 192 students were recruited as they entered a campus bar at the beginning of the evening. They completed questionnaires with open-ended questions eliciting beliefs concerning binge drinking, and ratings scales assessing standard TPB constructs in relation to binge drinking. At the end of the evening, 181 completed a second questionnaire and recorded the number of alcoholic drinks they had consumed. RESULTS: Beliefs were reliably coded (all kappas >=0.79). Students with higher intentions to binge drink were more likely to believe that their friends approved of binge drinking, and that (lack of) money would make it difficult. Students who reported drinking more alcohol at the end of the evening were more likely to believe that getting drunk is an advantage/what they would like about binge drinking tonight, that their sports teams would approve, and that celebrating, drinking patterns, and environment would make it easy to binge drink. CONCLUSIONS: The present study has identified the individually salient beliefs relating to drinking behaviour that the TPB states should be addressed by interventions to alter behaviour, and which that should be assessed as mediators in intervention research. As a whole, these findings highlight the importance of perceived peer norms in binge drinking in this population, and support the idea of interventions to challenge the perception of social pressure to binge drink. PMID- 22233103 TI - A theory-based intervention to reduce alcohol drinking in excess of guideline limits among undergraduate students. AB - OBJECTIVES: Undergraduate students frequently exceed guideline limits for alcohol intake in a single session and are highly susceptible to associated health, social, and economic problems. Psychological theory suggests that interventions aimed at reducing alcohol consumption should target both motivational and volitional phases of action to be effective. This study reports an integrated theory-based intervention aimed at reducing undergraduates' alcohol consumption in excess of guideline limits. DESIGN: The study adopted a 2 (motivation: mental simulation vs. no mental simulation) * 2 (volitional: implementation intention vs. no implementation intention) randomized controlled design presented in an online format. METHODS: Undergraduate students (N= 238; females, n= 133, M age = 20.11, SD= 2.09; males, n= 105, M age = 20.38, SD= 1.35) completed baseline psychological measures and self-reported alcohol consumption as units consumed and heavy episodic drinking occasions followed by the intervention manipulation (if any). One month later participants completed follow-up measures of the psychological variables and alcohol consumption. RESULTS: Significant reductions in alcohol consumption were observed at follow-up. Participants receiving a mental simulation intervention reported significantly fewer units of alcohol consumed and heavy episodic drinking occasions. Among participants with high baseline alcohol consumption, participants in the combined mental simulation and implementation intention intervention group consumed significantly fewer units than other groups. CONCLUSION: Results support the use of these theory-based strategies to reduce alcohol drinking in excess of guideline limits among undergraduates. There was preliminary support for the interaction between the two strategies among heavier drinkers. Targeting both motivational and implemental phases of action poses a high probability for success in changing alcohol-related behaviour in this population. PMID- 22233104 TI - The importance of coping appraisal in behavioural responses to pandemic flu. AB - OBJECTIVES: Behavioural responses to influenza pandemics can significantly influence the impact on public health. Protection motivation theory (PMT) provides a framework for understanding how people respond to health threats such as pandemics. The main aim of this study was to model the relative contribution of the components of PMT (threat and coping appraisal) to intentions to perform two behaviours recommended by the UK government in a pandemic: stay at home when ill and keep going to work when well. DESIGN: A 2*2 factorial design was used to test the effect of scenarios describing pandemic severity (low vs. high threat) and advice messages (standard government advice vs. theory-based advice) on measures of threat and coping appraisal, and intentions to carry out the two recommended behaviours. METHODS: A web-based survey designed to assess threat appraisal, coping appraisal, and behavioural intentions was completed by 883 adults (December 2009-January 2010) drawn from University College London staff and the local community. Structural equation modelling was used to test the PMT framework. RESULTS: Perceived pandemic severity influenced threat and coping appraisals and intentions. Structural equation modelling revealed that coping appraisal (i.e., perceptions of the costs, benefits, and feasibility of the recommended behaviours) was the principal predictor of variability in intentions for both behaviours and for both pandemic scenarios. CONCLUSIONS: Coping appraisals appear to be an important, and hitherto underresearched, predictor of how people may behave in pandemics, and our findings provide encouraging preliminary evidence that it may be possible to change these perceptions. PMID- 22233105 TI - An examination of hardiness throughout the sport injury process. AB - OBJECTIVES: This primary objective of the study was to examine the direct and moderating effects of hardiness on the prediction of sport injury, and the direct and indirect effects of hardiness on athletes' responses to injury. DESIGN: This study employed a longitudinal methodological design. Specifically, the injury status of 694 asymptomatic participants was monitored for 2 years. From the original sample, 104 athletes subsequently became injured and then completed a number of questionnaires throughout their recovery. METHODS: Logistic regression, Pearson product-moment correlation and Preacher and Hayes's (2008) bootstrapping procedure were used to analyse the data. RESULTS: Findings revealed a direct and moderating effect of hardiness on the prediction of injury. Hardiness was also found to positively correlate with desirable, and negatively correlate with undesirable post-injury psychological responses and coping strategies throughout recovery. Finally, problem-focused coping was found to mediate certain effects of hardiness on injured athletes' psychological responses. CONCLUSIONS: These findings have important implications for practitioners who have a vested interest in the health and well-being of those who participate in sport and exercise in terms of minimizing rates of injury occurrence and/or facilitating recovery from injury. PMID- 22233106 TI - The effects of vigour on measures of obesity across time. AB - OBJECTIVES: Past studies expected measures of obesity to be positively associated with positive affects. However, this hypothesis was not tested in reference to a specific positive affect. We tested the hypothesized unidirectional effects of measures of obesity on vigour, representing a positive affect, and of vigour on measures of obesity. DESIGN: We used a longitudinal design, separately for men and women. Participants were 1,876 and 931 healthy men and women, respectively, examined at Time 1 (T1) and Time 2 (T2), about 2 years apart. METHODS: Measures of obesity included body mass index, waist circumference, and waist-to-hip ratio. Vigour was assessed by the Shirom-Melamed Vigour Measure. We used structural equation modelling to test our hypotheses. RESULTS: We found that for both genders, T1 measures of obesity did not predict either T1 or T2 vigour. Among both genders, we found support for the effects of T1 vigour on T1 but not on T2 measures of obesity. CONCLUSIONS: To the extent that the 'Jolly fat hypothesis' refers to the effects of measures of obesity on positive affects, we failed to support it for vigour as a positive affect. Vigour has contemporaneous but not longitudinal effects on body weight. PMID- 22233107 TI - How do young adults perceive the risk of chlamydia infection? A qualitative study. AB - OBJECTIVES: This study aimed to improve understanding of how young UK genito urinary medicine (GUM) patients perceive the risk of chlamydia, and identify implications for health education. DESIGN: A qualitative methodology was chosen. METHODS: Semi-structured interviews with 27 respondents aged 16-22 years old were conducted. Data were subjected to thematic analysis. RESULTS: Respondents made assessments of the perceived seriousness of, and their personal susceptibility to, chlamydia infection. Judgements about seriousness were related to beliefs about the controllability of symptoms and the long-term health consequences of infection. Susceptibility estimates were related to beliefs about the extent to which personal exposure put them in contact with chlamydia, and about the prevalence of infection amongst their peer group. This is consistent with the content of illness risk representations proposed by Cameron (2003). Respondents demonstrated some beliefs, which appeared to influence perceptions of seriousness and susceptibility in unhelpful ways. CONCLUSIONS: Young people may be underestimating their risk of chlamydia infection due to the presence of unhelpful beliefs. Dialogue between health professionals and patients within GUM clinics, or through consultations as part of the National Chlamydia Screening Programme (NCSP), could provide vehicles to deliver health education to target these. Suggested health education includes highlighting false reassurance provided by treatment beliefs and exposing the fallibility of using overt characteristics to judge the likelihood that a potential sexual partner poses a risk of infection. PMID- 22233108 TI - Treatment decision making in breast cancer: a longitudinal exploration of women's experiences. AB - OBJECTIVES: To explore the lived experience of breast cancer in relation to the treatment decision-making process over time. DESIGN: Adopting a hermeneutic phenomenological approach, semi-structured interviews were undertaken at three points in time during the year following diagnosis. METHODS: After ethical approval had been obtained, 20 women who were recently diagnosed with breast cancer were recruited from a Symptomatic Breast Cancer Unit in the North East of England. RESULTS: Four themes emerged: role in the treatment decision-making process; acceptance of medical opinions; getting rid of it; and cancer schemas. The majority of women reported a passive role in the surgical treatment decision making process and all women did so in relation to subsequent treatment decisions. However, women adopted this role consciously and consequently were not disengaged from the process but maintained a sense of ownership and control over their health. The women did not describe experiencing decisional regret at any point in the year following diagnosis and rarely revisited the decisions made, only doing so in a positive manner. Trust in the abilities and experience of healthcare professionals and maximizing chances of survival were cited as reasons for not having had greater involvement. Despite being given information about treatment options, many women made the decision not to attend to this information perceiving this to be anxiety provoking. CONCLUSIONS: The findings from this study suggest a need for eliciting more specific psycho-social interactions in the treatment decision-making process in order to identify ways in which women can be supported throughout their experience. PMID- 22233110 TI - Thrombus in right ventricular outflow tract: unique cause of refractory cyanotic spell. AB - Iron deficiency state in patients with cyanotic congenital heart disease can mimic as well as aggravate hyperviscosity symptoms. Correction of iron deficiency in these cases is expected to improve symptoms. We report an unexpected occurrence of refractory cyanotic spell in a child with tetralogy of Fallot due to thrombus in right ventricular outflow tract following intravenous iron sucrose therapy. PMID- 22233111 TI - Intensive care unit management of patients with newly diagnosed acute myeloid leukemia with no organ failure. AB - Patients with acute myeloid leukemia (AML) may present with early complications from sepsis or leukemic infiltration. Benefits from early in-intensive care unit (ICU) hematological management was evaluated in 42 adults with newly diagnosed AML with hematological risk of early death (age 46 years, French-American-British [FAB] M4/5 58%, leukocytes 103 * 10(9)/L) first admitted to the ICU without immediate life support (early-ICU). Controls were 42 patients primarily admitted to hematology wards, matched for age, leukocytes and FAB subtype. Twenty (47.6%) control patients were subsequently admitted to the ICU (late-ICU). Late-ICU patients presented with increased respiratory and cardiac rates, decreased oxygen saturation (SpO(2)) and blood pressure, at hospital admission. Late-ICU admission resulted in increased use of mechanical ventilation (60% vs. 33%) and vasopressors (60% vs. 16%), longer ICU stay (9 [6-25] vs. 5 [2-9] days) and decreased ICU survival (65% vs. 79%). Direct admission to the ICU of patients with high-risk AML with physiological disturbances but no organ dysfunction is associated with improved outcomes. PMID- 22233112 TI - BCR-ABL activity measured by 50% inhibitory concentration for imatinib, p CrkL/CrkL ratio or p-CrkL ratio in CD34+ cells of patients with chronic myeloid leukemia does not predict treatment response. PMID- 22233113 TI - Clarithromycin potentiates tyrosine kinase inhibitor treatment in patients with resistant chronic myeloid leukemia. PMID- 22233114 TI - Prospects of transcript profiling for mRNAs and MicroRNAs using formalin-fixed and paraffin-embedded dissected autoptic multiple sclerosis lesions. AB - The elaboration of novel pathogenic aspects of multiple sclerosis (MS) requires the analysis of well-defined stages of lesion development. However, specimens of certain stages and lesion types are either present in small brain biopsies, insufficient in size for further molecular studies or available as formalin-fixed and paraffin-embedded (FFPE) material only. Therefore, application of current molecular biology techniques to FFPE tissue is warranted. We compared FFPE and frozen tissue by using quantitative polymerase chain reaction and report: (1) FFPE material is highly heterogeneous regarding the utility for transcript profiling of mRNAs; well-preserved FFPE samples had about a 100-fold reduced sensitivity compared with frozen tissue, but gave similar results for genes of sufficient abundance; (2) FFPE samples not suitable for mRNA analysis are still highly valuable for miRNA quantification; (3) the length of tissue fixation greatly affects utility for mRNA but not for miRNA analysis; (4) FFPE samples can be processed via a hot water bath for dissection of defined lesion areas; and (5) in situ hybridization for proteolipid protein (PLP) helps to identify samples not suitable for mRNA amplification. In summary, we present a detailed protocol how to use autoptic FFPE tissue for transcript profiling in dissected tissue areas. PMID- 22233115 TI - Physical exercise ameliorates deficits induced by traumatic brain injury. AB - The extent and depth of traumatic brain injury (TBI) remains a major determining factor together with the type of structural insult and its location, whether mild, moderate or severe, as well as the distribution and magnitude of inflammation and loss of cerebrovascular integrity, and the eventual efficacy of intervention. The influence of exercise intervention in TBI is multiple, ranging from anti-apoptotic effects to the augmentation of neuroplasticity. Physical exercise diminishes cerebral inflammation by elevating factors and agents involved in immunomodulatory function, and buttresses glial cell, cerebrovascular, and blood-brain barrier intactness. It provides unique non pharmacologic intervention that incorporate different physical activity regimes, whether dynamic or static, endurance or resistance. Physical training regimes ought necessarily to be adapted to the specific demands of diagnosis, type and degree of injury and prognosis for individuals who have suffered TBI. PMID- 22233116 TI - Individuals' expectations and challenges following total hip replacement: a qualitative study. AB - PURPOSE: Hip replacements are one of the most common operations for individuals with hip osteoarthritis. There have been numerous quantitative studies investigating the recovery from joint replacement surgery and these show how effective and satisfied patients are. However, little qualitative work has been conducted to explore patients' actual experiences. Therefore, this study aimed to detail the experiences of individuals undergoing a total hip replacement (THR) to determine whether their expectations were met. METHOD: The qualitative study was nested within a longitudinal study (n = 215) that was investigating biomedical and psychosocial outcomes from THR. We interviewed a purposive sample of individuals (n = 25) 6 months after THR to explore their experiences of having a THR. FINDINGS: Participants were aged 48-82 years. They felt disabled following the THR and some had unrealistic expectations of recovery. Most of them received minimal information and health professional support. Participants had to overcome a number of challenges such as diminished confidence, frustration over slow progress and reduced physical functioning. CONCLUSION: Individuals undergoing THR need to have the opportunity to discuss their expectations of THR, so there is no "false optimism". Support requirements, following THR, need to be reviewed as they were often underestimated by patients and health professionals. PMID- 22233117 TI - The safe distal tumour-free margin after sphincter preserving resection for rectal cancer: an ongoing debate. PMID- 22233118 TI - MicroRNA: future perspectives in colorectal cancer. PMID- 22233119 TI - Comment on Infantino et al. PMID- 22233122 TI - Pharmacokinetics of firocoxib and its interaction with enrofloxacin in horses. PMID- 22233123 TI - Functionalized DNA nanostructures. PMID- 22233124 TI - Advances in targeting the Hedgehog signaling pathway in cancer therapy. AB - The Hedgehog (Hh) pathway is one of the central developmental signaling mechanisms, which have recently been shown to contribute to malignant progression of a variety of human cancers. Additionally, the role of Hh and other embryonic signaling pathways in the regulation and maintenance of the tumorigenic cancer stem / -initiating subpopulation underlines the importance of this pathway in human malignancies. The review 'Targeting the Hedgehog signaling pathway for cancer therapy' by Li and coworkers has comprehensively described the potential of pharmacological targeting of Hh signaling. Here we provide an update on the current knowledge on i) the role of this pathway in human tumorigenesis and the rationale for therapeutic targeting, ii) the pharmacological approaches currently being investigated in preclinical and clinical studies, and iii) the outlook for future developments and efforts for establishing Hh antagonists as a valid approach in cancer treatment. Stratification of the tumor type according to Hh specific expression patterns and clinicopathological characteristics, as well as investigation of possible tumor cell resistance against Hh antagonists, is the central area for further development. PMID- 22233125 TI - Dynamics of solvent-mediated electron localization in electronically excited hexacyanoferrate(III). AB - We have used polarization-resolved UV pump-mid-IR probe spectroscopy to investigate the dynamics of electron hole localization for excited-state ligand to-metal charge-transfer (LMCT) excitation in Fe(CN)(6)(3-). The initially generated LMCT excited state has a single CN-stretch absorption band with no anisotropy. This provides strong evidence that this initial excited state preserves the octahedral symmetry of the electronic ground state by delocalizing the ligand hole in the LMCT excited state on all six cyanide ligands. This delocalized LMCT excited state decays to a second excited state with two CN stretch absorption bands. We attribute both peaks to a single excited state because the formation time for both peaks matches the decay time for the delocalized LMCT excited state. The presence of two CN-stretch absorption bands demonstrates that this secondary excited state has lower symmetry. This observation, in conjunction with the solvent-dependent time constant for the formation of the secondary excited state, leads us to conclude that the secondary excited state corresponds to a LMCT state with a localized ligand hole. PMID- 22233126 TI - Paradoxical physiological transitions from aging to late life in Drosophila. AB - In a variety of organisms, adulthood is divided into aging and late life, where aging is a period of exponentially increasing mortality rates and late life is a period of roughly plateaued mortality rates. In this study we used ~57,600 Drosophila melanogaster from six replicate populations to examine the physiological transitions from aging to late life in four functional characters that decline during aging: desiccation resistance, starvation resistance, time spent in motion, and negative geotaxis. Time spent in motion and desiccation resistance declined less quickly in late life compared to their patterns of decline during aging. Negative geotaxis declined at a faster rate in late life compared to its rate of decline during aging. These results yield two key findings: (1) Late-life physiology is distinct from the physiology of aging, in that there is not simply a continuation of the physiological trends which characterize aging; and (2) late life physiology is complex, in that physiological characters vary with respect to their stabilization, deceleration, or acceleration in the transition from aging to late life. These findings imply that a correct understanding of adulthood requires identifying and appropriately characterizing physiology during properly delimited late-life periods as well as aging periods. PMID- 22233127 TI - Gene fragmentation in bacterial draft genomes: extent, consequences and mitigation. AB - Ongoing technological advances in genome sequencing are allowing bacterial genomes to be sequenced at ever-lower cost. However, nearly all of these new techniques concomitantly decrease genome quality, primarily due to the inability of their relatively short read lengths to bridge certain genomic regions, e.g., those containing repeats. Fragmentation of predicted open reading frames (ORFs) is one possible consequence of this decreased quality. In this study we quantify ORF fragmentation in draft microbial genomes and its effect on annotation efficacy, and we propose a solution to ameliorate this problem. RESULTS: A survey of draft-quality genomes in GenBank revealed that fragmented ORFs comprised > 80% of the predicted ORFs in some genomes, and that increased fragmentation correlated with decreased genome assembly quality. In a more thorough analysis of 25 Streptomyces genomes, fragmentation was especially enriched in some protein classes with repeating, multi-modular structures such as polyketide synthases, non-ribosomal peptide synthetases and serine/threonine kinases. Overall, increased genome fragmentation correlated with increased false-negative Pfam and COG annotation rates and increased false-positive KEGG annotation rates. The false-positive KEGG annotation rate could be ameliorated by linking fragmented ORFs using their orthologs in related genomes. Whereas this strategy successfully linked up to 46% of the total ORF fragments in some genomes, its sensitivity appeared to depend heavily on the depth of sampling of a particular taxon's variable genome. CONCLUSIONS: Draft microbial genomes contain many ORF fragments. Where these correspond to the same gene they have particular potential to confound comparative gene content analyses. Given our findings, and the rapid increase in the number of microbial draft quality genomes, we suggest that accounting for gene fragmentation and its associated biases is important when designing comparative genomic projects. PMID- 22233128 TI - Adult acute lymphoblastic leukaemia in Denmark. A national population-based retrospective study on acute lymphoblastic leukaemia in Denmark 1998-2008. AB - Since July 2008, children and adults 1-45 years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To explore whether this strategy will improve survival compared with historical controls, we performed a retrospective national population-based study of adult ALL between 1998 and 2008. Patients were identified through the Danish Patobank and the Danish Cancer Registry; data was collected from patient files, and included 277 patients (median age, 47 years, range 15-91 years). The 5-year projected event-free survival (pEFS(5y)) and overall survival (pOS(5y)) for the whole cohort was 27.5% [95% confidence interval (CI) 22.4-33.6] and 34.1% (95% CI 28.7-40.4), respectively. No patient above 65 years survived beyond 5 years from diagnosis. For patients receiving curatively intended treatment, the pEFS(5y) and pOS(5y) were 36.6% and 44.1%, respectively, with a significantly higher pOS(5y) for patients 15-35 years compared with patients 36-65 years (50.7% vs. 38.9%, P = 0.006). Cox multiple regression analysis identified age (Hazard Ratio = 1.7, P < 0.006) as a statistically significant predictor of EFS. The cure rates, not least for the elderly, are unacceptably low, and call for new strategies in the treatment of adult ALL in all age groups. PMID- 22233129 TI - Coronary vasoreactivity in subjects with thyroid autoimmunity and subclinical hypothyroidism before and after supplementation with thyroxine. AB - BACKGROUND: The association of subclinical hypothyroidism (SCH) with increased risk for cardiovascular disease is still controversial. This study aimed to examine coronary vascular reactivity by positron emission tomography (PET) in asymptomatic patients with SCH before and after levothyroxine (LT4) supplementation. METHODS: Ten patients (7 women and 3 men; mean age 43+/-15 years) with untreated autoimmune SCH, defined by elevated levels of thyroid stimulating hormone (mean TSH: 16.9+/-11.3 MUU/mL), normal levels of free thyroxine (0.9+/-0.1 MUg/mL), free triiodothyronine (3.2+/-0.4 pg/mL), and positive thyroid peroxidase antibodies were studied. Eight euthyroid subjects with similar low-risk cardiovascular risk profile served as controls. Myocardial blood flow (MBF) and coronary flow reserve (CFR) were quantitatively assessed with rest/stress N-13 ammonia PET at baseline and after 6 months of LT4 replacement therapy (given only to patients). RESULTS: At baseline, stress MBF and CFR corrected (c) for rate pressure product (RPP) and myocardial vascular resistance (MVR) during stress were significantly reduced in SCH compared with controls (stress MBF: 2.87+/-0.93 vs. 4.79+/-1.16 mL/g/min, p=0.003; CFR: 2.6+/ 0.73 vs. 4.66+/-1.38, p=0.004; MVR: 40.14+/-18.76 vs. 20.47+/-6.24 mmHg/mL/min, p=0.02). Supplementation therapy with LT4 normalized TSH in all subjects and was associated with an increase in CFR (2.6+/-0.73 vs. 3.81+/-1.19, p=0.003) and with a tendency toward a decrease in MVR. Differences in CFR between SCH and controls were also seen after correction of resting MBF for RPP. CONCLUSIONS: In asymptomatic subjects with SCH due to thyroid autoimmunity, coronary microvascular function is impaired and improves after supplementation with LT4. This may partially explain the increased cardiovascular risk attributed to SCH. PMID- 22233130 TI - Long-term follow-up of at least five years after recombinant human thyrotropin compared to levothyroxine withdrawal for thyroid remnant ablation with radioactive iodine. PMID- 22233132 TI - Cold-induced urticarial vasculitis. PMID- 22233131 TI - Disparities in the initial presentation of differentiated thyroid cancer in a large public hospital and adjoining university teaching hospital. AB - BACKGROUND: Healthcare disparities associated with insurance and socioeconomic status have been well characterized for several malignancies, such as lung cancer. To assess whether there are healthcare disparities in thyroid cancer, this study evaluated the stage on initial presentation of patients with differentiated thyroid cancer (DTC) in a public versus university teaching hospital. METHODS: A retrospective chart review was performed to identify patients with a new diagnosis of DTC from January 1, 2007, to January 1, 2010, in a large public and adjoining university teaching hospital at a single academic medical center. Medical records were reviewed for demographics, pathology, and American Joint Committee on Cancer tumor-node-metastasis stage at initial presentation. RESULTS: There were 49 cases of well-DTC (96% papillary and 4% Hurthle) in the public hospital and 370 cases (95% papillary, 2% Hurthle, and 3% follicular) in the university teaching hospital. Median age (years) at presentation was 50 in the public versus 48 in the university teaching hospital (p=0.39). Ninety-six percent of public hospital patients were from ethnic minorities compared with 16% of university teaching hospital patients (p<0.0001). Only 1 (2%) public hospital patient had private insurance compared with 85% of university teaching hospital patients. Tumor status (p=0.002) and stage (p=0.03) were more advanced and extrathyroidal extension (p=0.02) was more prevalent among public hospital patients compared with university teaching hospital patients. In a multivariable analysis, public hospital, male gender, increasing age, advanced tumor status, and the presence of lymphovascular invasion were the best predictors of more advanced disease stage. Public hospital patients were 3.4 times more likely to present with advanced DTC than university teaching hospital patients of the same age, gender, tumor status, and lymphovascular invasion status (95% confidence interval 1.29-8.95). CONCLUSIONS: In a public hospital, where the patient population is defined primarily by insurance status, patients were more likely to present with advanced-stage DTC than patients presenting to an adjacent university teaching hospital. These results suggest a disparity in the stage on initial presentation of DTC, possibly resulting in a delayed diagnosis of cancer. PMID- 22233133 TI - Field-cage methodology for evaluating climatic suitability for introduced wood borer parasitoids: preliminary results from the emerald ash borer system. AB - Field-cage methods were developed to evaluate the abilities of Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae) and Spathius agrili Yang (Hymenoptera: Braconidae), biocontrol agents of Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), to parasitize, develop and overwinter following three late-season releases at both a northern (Michigan) and a southern (Maryland) location within the current North American range of A. planipennis. In August, September and October of 2009, five young green ash trees were selected at each location. Tetrastichus planipennisi and S. agrili were each randomly assigned to one of two cages attached to each tree, surrounding separate sections of trunk in which late-instar A. planipennis had been inserted. The following April, the caged trunk sections were dissected to determine the fate of each A. planipennis larva and the developmental stages of all recovered parasitoid progeny. At both locations, T. planipennisi and S. agrili were able to parasitize hosts and successfully overwinter (i.e., reach adulthood the following spring). For T. planipennisi, successful parasitism (i.e., parasitoid progeny reached adulthood) occurred for all caged releases in Maryland, but only for the August and September releases in Michigan. At both locations, percent parasitism by T. planipennisi was higher in August and September than in October. For S. agrili, successful parasitism occurred for all caged releases in Maryland, but only for the August release in Michigan. In Maryland, percent parasitism by S. agrili in August and September was higher than in October. The caging method described here should be useful in determining the climatic suitability of other regions before proceeding with large-scale releases of either species and may have utility in other wood-borer parasitoid systems as well. PMID- 22233134 TI - Gender-dependent differences in degree of facial wrinkles. AB - BACKGROUND/PURPOSE: This study aimed to reveal gender-dependent differences in the degree of facial wrinkles. METHODS: Subjects comprised 173 Japanese men and women, divided into four groups according to age. Photographs were taken from nine facial regions and used to classify the intensity of wrinkles into five grades. In addition, replicas were taken from five facial sites and used to measure surface roughness. Data were compared between men and women within each age group. RESULTS: In all age groups, men showed increased forehead wrinkles compared with women. In contrast, no gender-dependent differences were found in upper eyelid wrinkles. Other facial wrinkles were greater in men than in women in all except the oldest group (age, 65-75 years), in which wrinkles in women were greater than or equal to those in men. CONCLUSION: Our results showed that gender dependent differences exist in the degree of facial wrinkles. In general, men tend to have more severe wrinkles than women. This tendency disappeared or was reversed in some regions of the face and in individuals more than 60 years old. PMID- 22233135 TI - Relationship between behaviour problems and perceived parenting practices in Korean youth. AB - BACKGROUND: Parenting practices have been accepted as powerful risk factors for behaviour problems, even though previous studies have suffered from significant methodological problems, such as small, non-representative samples, cross sectional study designs, poor control for confounders, and minimal consideration of paternal parenting. This study examined whether three, specific maternal and paternal parenting practices are associated with internalizing and externalizing behavioural problems in youth. METHODS: A prospective, longitudinal, cohort study was conducted among 1641 seventh- and eighth-grade students from representative sample of middle school students. The measurements were the Korean Youth Self Report and the Childrearing Behavior Questionnaire (measuring three dimensions of parenting practice: warmth-acceptance, rejection-restriction and permissiveness non-intervention). Descriptive and logistic regression analyses were performed. RESULTS: Maternal rejection-restriction increased risks for internalizing problems (OR = 1.112), whereas paternal control-rejection increased risks for externalizing behavioural problem (OR = 1.125). CONCLUSIONS: Specific parenting practices showed differential associations with youth behaviour problems. These results suggest that further studies are necessary to understand the importance of unique and shared parenting practices as well as their interactions with other factors in the aetiology of youth behaviour problems. In the meantime, these findings point to therapeutic opportunities for both parents and their children. PMID- 22233136 TI - Bioinspired structured surfaces. AB - Nature has evolved objects with desired functionality using commonly found materials. Nature capitalizes on hierarchical structures to achieve functionality. The understanding of the functions provided by objects and processes found in nature can guide us to produce nanomaterials, nanodevices, and processes with desirable functionality. Various natural objects which provide functionality of commercial interest have been characterized to understand how a natural object provides functionality. We have modeled and fabricated structures in the lab using nature's route and developed optimum structures. Once it is understood how nature does it, optimum structures have been fabricated using smart materials and fabrication techniques. This feature article provides an overview of four topics: Lotus effect, rose petal effect, gecko feet, and shark skin. PMID- 22233137 TI - Potential risks of metformin in transplant patients. PMID- 22233138 TI - Cancer-associated ischemic stroke is associated with elevated D-dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer. AB - AIM: Although several studies have reported various causes of ischemic stroke in patients with cancer, only a few have evaluated the clinical relevance of ischemic stroke pathogenesis to cancer. The aim of the present study was to elucidate the clinical characteristics of cancer-associated ischemic stroke. METHODS: We evaluated 154 ischemic stroke patients without cancer and 57 ischemic stroke patients with cancer who had either received continuous treatment for cancer within 5 years before to the onset of ischemic stroke, or who had been diagnosed with cancer within 1 year after the onset of ischemic stroke. Cancer patients were grouped into "cancer-associated ischemic stroke," the "conventional ischemic stroke," or "other." RESULTS: A total of 15 patients (26%) were classified into the cancer-associated ischemic stroke in cancer patients. In univariate analysis of the cancer-associated ischemic stroke and the others, there were significant differences in the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d dimer, fibrin degradation product and hemoglobin. With multivariate regression analysis of those factors, the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of D-dimer and fibrin degradation product remained as statistically independent factors, which were associated with cancer-associated ischemic stroke (n = 111, chi(2) =67.21, P < 0.0001). CONCLUSION: In acute ischemic stroke, the cancer-associated ischemic stroke is associated with elevated D-dimer and fibrin degradation products, even after controlling hypertension, hyperlipidemia and advanced cancer (clinical stage IV). PMID- 22233139 TI - Metamaterials with tailored nonlinear optical response. AB - We demonstrate that the second-order nonlinear optical response of noncentrosymmetric metal nanoparticles (metamolecules) can be efficiently controlled by their mutual ordering in an array. Two samples with minor change in ordering have nonlinear responses differing by a factor of up to 50. The results arise from polarization-dependent plasmonic resonances modified by long-range coupling associated with metamolecular ordering. The approach opens new ways for tailoring the nonlinear responses of metamaterials and their tensorial properties. PMID- 22233140 TI - Rasmussen's aneurysm in childhood: a case report. AB - In medical literature, few cases of Rasmussen's aneurysm have been reported until now, and to the best of our knowledge, there has been no description of a case of Rasmussen's aneurysm in childhood. The child described in the case report had a restrictive cardiomyopathy, complicated by pulmonary hypertension, in association with miliary tuberculosis. PMID- 22233141 TI - Development of novel flurbiprofen-loaded solid self-microemulsifying drug delivery system using gelatin as solid carrier. AB - To develop a novel flurbiprofen-loaded solid self-microemulsifying drug delivery system (solid SMEDDS) with improved oral bioavailability using gelatin as a solid carrier, the solid SMEDDS formulation was prepared by spray-drying the solutions containing liquid SMEDDS and gelatin. The liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Transcutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z average diameter of about 100 nm. The flurbiprofen-loaded solid SMEDDS formulation gave a larger emulsion droplet size compared to liquid SMEDDS. Unlike conventional solid SMEDDS, it produced a kind of microcapsule in which liquid SMEDDS was not absorbed onto the surfaces of carrier but formed together with carrier in it. However, the drug was in an amorphous state in it like conventional solid SMEDDS. It greatly improved the oral bioavailability of flurbiprofen in rats. Thus, gelatin could be used as a carrier in the development of solid SMEDDS with improved oral bioavailability of poorly water-soluble drug. PMID- 22233142 TI - Are CT angiography source images accurate for evaluating infarct volume? AB - Noncontrast computed tomography (NCCT) has been considered the standard test for determining eligibility for thrombolysis from the beginning of the thrombolytic era. CT angiography (CTA) reveals the cranio-cervical vessel and the occlusion site. Furthermore, the source image (SI) of the CTA (CTA-SI) reflects cerebral blood volume and can detect the infarct core as hypoattenuated areas with higher sensitivity than ischemic changes on NCCT. However, it was recently reported that the CTA-SI using fast acquisition protocol significantly overestimated the infarct core mostly on the basis of the poor collaterals. On the other hand, CTA SI using standardized protocol was reported to be good predictor for final infarct extension. Imaging used in the setting of acute stroke should accurately address the presence and size of an irreversible ischemic core. Further studies are required to confirm whether another measure or adjustment in CTA-SI values can be more reliable for evaluating the infarct core. PMID- 22233143 TI - Cytokine expression in response to root canal infection in gnotobiotic mice. AB - AIM: To examine cytokine expression profiles during periapical lesion development in response to synergetic human pathogens in a gnotobiotic mouse model. METHODOLOGY: Human strains of Fusobacterium nucleatum and Peptostreptococcus prevotii were inoculated into the root canals of germ-free mice in either mono- or bi-association. Animals were killed 7 and 14 days after infection, and periapical tissues were collected. mRNA expression of the cytokines IFN-gamma, TNF-alpha, Receptor activator of nuclear factor kappa-B ligand (RANKL), IL-10, IL 4 and transforming growth factor beta (TGF-beta) was assessed using real-time PCR. Levene's test was used to assess the equality of variance of the data, whereas a t-test for independent samples was used to evaluate the significance of the differences between groups (P < 0.05). RESULTS: The mRNA expression of IFN gamma and TNF-alpha was up-regulated by F. nucleatum during the acute (day 7) and chronic phase (day 14) of periapical lesion development. However, in bi-infection the expression of IFN-gamma and TNF-alpha were effectively absent at both time points. RANKL mRNA expression was down-regulated during dual infection at the chronic phase. As IL-4 expression was similar at both time-points, IL-4 does not appear to be involved in the periapical response to these bacterial strains. IL 10 was up-regulated during the chronic phase by mono-infection with either F. nucleatum or P. prevotii. Dual infection increased TGF-beta mRNA expression on day 7, which paralleled the decrease in IFN-gamma and TNF-alpha mRNA levels at the same time-point. F. nucleatum increased TGF-beta mRNA expression during the chronic phase. CONCLUSION: Cytokine profiles depend on the nature of the bacterial challenge. Both TGF-beta and IL-10 appeared to be regulating the proinflammatory cytokine responses at both time-points of the periapical immune response. PMID- 22233144 TI - TBI 13 years on: factors associated with post-traumatic growth. AB - PURPOSE: To investigate factors associated with post-traumatic growth (PTG) 13 years after severe traumatic brain injury (TBI) and to see if PTG had remained consistent between 11 and 13 years after injury. METHOD: TBI survivors (n=21), were interviewed and completed face-to face administration of questionnaires measuring PTG and factors potentially associated with PTG. The design was a longitudinal follow-up study. RESULTS: Factors significantly associated with PTG included: having a sense of personal meaning (purpose and coherence), high life satisfaction now, social support, high-activity levels, a high number of life events, having paid work, new stable relationships after injury, milder disability, and having religious faith. Having a high level of "purpose" was the best predictor of PTG. There was no change in PTG between 11 and 13 years after injury suggesting PTG is a relatively stable phenomenon once established after the early years. CONCLUSION: Clinicians should be aware of PTG and how it is associated with factors such as "meaning" and "purpose" as well as demographic factors such as, social support, activity such as work, new and stable relationships, milder disability and a shift towards spiritual values. Clinicians can focus advice, resource and effort on supporting these developments. [ IMPLICATIONS FOR REHABILITATION: * People with TBI do perceive benefits or post traumatic growth (PTG), after time, which once established remains stable.* Factors such as having a sense of "meaning" and "purpose", are predictors of PTG.* Social support, activity such as work, new and stable relationships, a shift toward spiritual values, and milder disability are also associated with PTG.* Clinicians can focus effort into supporting these developments.] PMID- 22233145 TI - Conservative management of pelvi-ureteric junction obstruction (PUJO): is it appropriate and if so what duration of follow-up is needed? AB - OBJECTIVE: * To establish whether it is safe to manage minimally symptomatic and asymptomatic pelvi-ureteric junction obstruction (PUJO) conservatively. PATIENTS AND METHODS: * In all, 50 patients with PUJO diagnosed with dynamic renography, and monitored with at least two renograms. RESULTS: * In all, 19 patients were totally asymptomatic, while 31 patients had minimal symptoms at time of diagnosis. * The mean follow-up was 53 months. * During the course of follow-up 10 of the 50 patients deteriorated. * All patients who had asymptomatic renographic deterioration, deteriorated within 2 years of diagnosis. * Eight of the 10 patients that deteriorated needed pyeloplasty and two nephrectomy. CONCLUSIONS: * Conservative management of patients with minimally symptomatic and asymptomatic PUJO is safe. * Discharging patients could be considered at 2 years from diagnosis, if they remain renographically stable and asymptomatic or minimally symptomatic. PMID- 22233146 TI - Supporting international medical graduates in rural Australia: a mixed methods evaluation. AB - INTRODUCTION: In Australia, international medical graduates (IMGs) make a substantial contribution to rural medical workforces. They often face significant communication, language, professional and cultural barriers, in addition to the other challenges of rural clinical practice. The Gippsland Inspiring Professional Standards among International Experts (GIPSIE) program was designed to provide educational support to IMGs across a large geographical region using innovative educational methods to ultimately build capacity in the provision of rural medical education. GIPSIE offered 5 sessions over 3 months. Simulation-based training was a prominent theme and addressed clinical knowledge, attitudes and skills and included a range of activities (eg procedural skills training with benchtop models, management of the acutely ill patient with SimMan, patient assessment skills with simulated patients). Diverse clinical communication skills were explored (eg teamwork, handover, telephone, critical information). Audiovisual review of performance was enabled through the use of iPod nano devices. GIPSIE was underpinned by a website offering diverse learning resources. Content experts were invited to lead sessions that integrated knowledge and skills reflecting local practice. METHODS: IMGs were recruited from hospitals (n = 15) and general practices (n = 2) across the region. It was aimed to evaluate the impact of GIPSIE on the clinical practice of IMG participants. Evaluation measures included pre- and post-program 15 item multisource feedback (MSF), post program questionnaires and, in order to address retention, telephone interviews exploring participants' responses 3 months after the program finished. RESULTS: Fifteen participants completed GIPSIE and rated the program highly, especially the simulation-based activities with feedback and later audiovisual review on iPods and the GIPSIE website. Suggestions were made to improve several aspects of the program. Participants reported increased knowledge, skills and professionalism after the program. Although overall MSF scores showed no statistically significant changes, there were positive directional changes for the items 'technical skills appropriate to current practice', 'willingness and effectiveness when teaching/training colleagues' and 'communication with carers and family'. These developments were also supported in free-text comments. Learning was reported to be sustained 3 months after the program. CONCLUSIONS: GIPSIE was highly valued by participants who reported improvements in clinical knowledge and skills. A range of professional issues were raised and addressed. GIPSIE seemed to provide a platform for further development. Although new to many participants, simulation was embraced as an educational method. The relationship between regional clinicians and the medical school was pivotal to success. A feature of the study was tracking improvements in clinical practice as a consequence of participating in the GIPSIE program. Future work needs to focus on further promoting the transfer of learning to the workplace. However the sustainability of these programs requires significant commitment. PMID- 22233147 TI - Benefit of social support for resilience-building is contingent on social context: examining cardiovascular adaptation to recurrent stress in women. AB - Previous work on social support and stress tolerance using laboratory-based cardiovascular stress response paradigms has suggested that perceived social support may be effective in building resilience in recipients. However, such paradigms are often socially de-contextualized insofar as they fail to take account of the social aspects of stress itself. Using 90 healthy college women, the present study sought to examine the association between self-reported perceived social support and cardiovascular stress tolerance. Participants underwent two consecutive exposures to a mental arithmetic task. On second exposure to the stressor, participants completed the task under either social threat or control conditions. Social threat was manipulated using socially salient instructions, to create a high social context. Adaptation to stress was established in terms of comparisons between cardiovascular responses to successive exposures. Results showed that cardiovascular responses tended to habituate across time, with perceived social support associated with the degree of habituation, but only under certain contextual conditions; high perceived support was associated with effective habituation under control conditions only. This response pattern is consistent with the view that high perceived social support buffers against stress in healthful ways, but only in asocial contexts. PMID- 22233148 TI - Development of N-substituted hydroxylamines as efficient nitroxyl (HNO) donors. AB - Due to its inherent reactivity, nitroxyl (HNO), must be generated in situ through the use of donor compounds, but very few physiologically useful HNO donors exist. Novel N-substituted hydroxylamines with carbon-based leaving groups have been synthesized, and their structures confirmed by X-ray crystallography. These compounds generate HNO under nonenzymatic, physiological conditions, with the rate and amount of HNO released being dependent mainly on the nature of the leaving group. A barbituric acid and a pyrazolone derivative have been developed as efficient HNO donors with half-lives at pH 7.4, 37 degrees C of 0.7 and 9.5 min, respectively. PMID- 22233150 TI - A proposal for the treatment guideline in segmental vitiligo. PMID- 22233151 TI - Telomere dysfunction and its role in haematological cancer. AB - Observations in human tumours, as well as mouse models, have indicated that telomere dysfunction may be a key event driving genomic instability and disease progression in many solid tumour types. In this scenario, telomere shortening ultimately results in telomere dysfunction, fusion and genomic instability, creating the large-scale rearrangements that are characteristic of these tumours. It is now becoming apparent that this paradigm may also apply to haematological malignancies; indeed these conditions have provided some of the most convincing evidence of telomere dysfunction in any malignancy. Telomere length has been shown in several malignancies to provide clinically useful prognostic information, implicating telomere dysfunction in disease progression. In these malignancies extreme telomere shortening, telomere dysfunction and fusion have all been documented and correlate with the emergence of increased genomic complexity. Telomeres may therefore represent both a clinically useful prognostic tool and a potential target for therapeutic intervention. PMID- 22233149 TI - Comprehensive transcriptome analysis reveals novel genes involved in cardiac glycoside biosynthesis and mlncRNAs associated with secondary metabolism and stress response in Digitalis purpurea. AB - BACKGROUND: Digitalis purpurea is an important ornamental and medicinal plant. There is considerable interest in exploring its transcriptome. RESULTS: Through high-throughput 454 sequencing and subsequent assembly, we obtained 23532 genes, of which 15626 encode conserved proteins. We determined 140 unigenes to be candidates involved in cardiac glycoside biosynthesis. It could be grouped into 30 families, of which 29 were identified for the first time in D. purpurea. We identified 2660 mRNA-like npcRNA (mlncRNA) candidates, an emerging class of regulators, using a computational mlncRNA identification pipeline and 13 microRNA producing unigenes based on sequence conservation and hairpin structure-forming capability. Twenty five protein-coding unigenes were predicted to be targets of these microRNAs. Among the mlncRNA candidates, only 320 could be grouped into 140 families with at least two members in a family. The majority of D. purpurea mlncRNAs were species-specific and many of them showed tissue-specific expression and responded to cold and dehydration stresses. We identified 417 protein-coding genes with regions significantly homologous or complementary to 375 mlncRNAs. It includes five genes involved in secondary metabolism. A positive correlation was found in gene expression between protein-coding genes and the homologous mlncRNAs in response to cold and dehydration stresses, while the correlation was negative when protein-coding genes and mlncRNAs were complementary to each other. CONCLUSIONS: Through comprehensive transcriptome analysis, we not only identified 29 novel gene families potentially involved in the biosynthesis of cardiac glycosides but also characterized a large number of mlncRNAs. Our results suggest the importance of mlncRNAs in secondary metabolism and stress response in D. purpurea. PMID- 22233153 TI - Aqueous neem extract versus neem powder on Culex quinquefasciatus: implications for control in anthropogenic habitats. AB - Control programs using conventional insecticides to target anthropogenic mosquito habitats are very expensive because these habitats are widespread, particularly in cities of most African countries. Additionally, there are serious environmental concerns regarding large-scale application of most conventional insecticides. Clearly there is a need for alternative methods that are more effective, less expensive, and environmentally friendly. One such method would be the application of preparations made from parts of the neem tree, Azadirachta indica A. Jussieu (Sapindales: Meliaceae). In this study, aqueous crude extracts and crude powder were prepared from different parts of neem, and the efficacies of the preparations on juvenile stages of Culex quinquefasciatus Say (Diptera: Culicidae) were evaluated in the laboratory. When larvae were exposed to a concentration of 0.1 g/mL extract for 24 hours, percent mean mortality (+/- SE) was 72.7 plusmn; 1.8 for the bark, 68.7 +/- 1.6 for fruits and 60 +/- 1.6 for leaves. These means were not significantly different (chi(2) = 4.12; df = 2; p = 0.127). At a concentration of 0.01 g/mL, > 95% of the larvae died within 24 hours of exposure to powdered neem leaf, but it took 120 hours to reach the same level of larval mortality in aqueous leaf extract. The crude extract slowly inhibited the growth and development of mosquitoes while the crude powder acted more as a barrier; the mosquitoes probably died from suffocation. However, both types of preparations can be made and used by local people to control mosquito breeding in anthropogenic habitats, especially in urbanized areas. PMID- 22233154 TI - Computerised image analysis of vitiligo lesion: evaluation using manually defined lesion areas. AB - BACKGROUND: Vitiligo is a cutaneous pigmentary disorder characterized by depigmented macules and patches that result from loss of epidermal melanocytes. Physician evaluates the efficacy of treatment by comparing the extent of vitiligo lesions before and after treatment based on the overall visual impression of the treatment response. This method is called the physician's global assessment (PGA) which is subjective. In this article, we present an innovative digital image processing method to determine vitiligo lesion area in an objective manner. METHOD: The digital method uses Independent Component Analysis (ICA) to generate melanin-based images representing skin areas due to melanin followed by Region Growing process to segment vitiligo lesion from normal skin. RESULTS: Based on 41 digital images of vitiligo lesions taken from 18 patients, the proposed method achieved sensitivities of 0.9105 +/- 0.0161, specificities of 0.9973 +/- 0.0009 and accuracies of 0.9901 +/- 0.0028 at 95% confidence level. CONCLUSION: With the proposed method, physicians are able to assess vitiligo treatment efficacies objectively. PMID- 22233155 TI - Lack of effect of central nervous system-active doses of nabilone on capsaicin induced pain and hyperalgesia. AB - The aim of the present study was to investigate the effects of nabilone on capsaicin-induced pain and hyperalgesia, as well as on biomarkers of cannabinoid central nervous system (CNS) effects. A randomized, double-blind, placebo controlled, crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone (1, 2 or 3 mg). Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale (0-100 mm). Capsaicin cream was applied to the calf to induce hyperalgesia. Primary hyperalgesia was assessed by measuring heat pain thresholds, whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful. Pain and hyperalgesia were measured at baseline and 2-3.5 h after dosing. The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling 'stimulated', 'anxious', 'sedated' and 'down'. Plasma samples for pharmacokinetic analysis were obtained up to 24 h after drug administration. Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia, whereas dose-dependent CNS effects were observed from 1.5 to 6 h after dosing, being maximal at 4-6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1-2 h after dosing. Adverse events (AE) were common on nabilone treatment. Four subjects withdrew due to pronounced CNS AE (anxiety, agitation, altered perception, impaired consciousness). Although nabilone had marked CNS effects, no analgesic or antihyperalgesic effects were observed. PMID- 22233156 TI - Control of initiation, rate, and routing of spontaneous capillary-driven flow of liquid droplets through microfluidic channels on SlipChip. AB - This Article describes the use of capillary pressure to initiate and control the rate of spontaneous liquid-liquid flow through microfluidic channels. In contrast to flow driven by external pressure, flow driven by capillary pressure is dominated by interfacial phenomena and is exquisitely sensitive to the chemical composition and geometry of the fluids and channels. A stepwise change in capillary force was initiated on a hydrophobic SlipChip by slipping a shallow channel containing an aqueous droplet into contact with a slightly deeper channel filled with immiscible oil. This action induced spontaneous flow of the droplet into the deeper channel. A model predicting the rate of spontaneous flow was developed on the basis of the balance of net capillary force with viscous flow resistance, using as inputs the liquid-liquid surface tension, the advancing and receding contact angles at the three-phase aqueous-oil-surface contact line, and the geometry of the devices. The impact of contact angle hysteresis, the presence or absence of a lubricating oil layer, and adsorption of surface-active compounds at liquid-liquid or liquid-solid interfaces were quantified. Two regimes of flow spanning a 10(4)-fold range of flow rates were obtained and modeled quantitatively, with faster (mm/s) flow obtained when oil could escape through connected channels as it was displaced by flowing aqueous solution, and slower (micrometer/s) flow obtained when oil escape was mostly restricted to a micrometer-scale gap between the plates of the SlipChip ("dead-end flow"). Rupture of the lubricating oil layer (reminiscent of a Cassie-Wenzel transition) was proposed as a cause of discrepancy between the model and the experiment. Both dilute salt solutions and complex biological solutions such as human blood plasma could be flowed using this approach. We anticipate that flow driven by capillary pressure will be useful for the design and operation of flow in microfluidic applications that do not require external power, valves, or pumps, including on SlipChip and other droplet- or plug-based microfluidic devices. In addition, this approach may be used as a sensitive method of evaluating interfacial tension, contact angles, and wetting phenomena on chip. PMID- 22233157 TI - Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. AB - Dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway. Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence. No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease. This is the first reported case of recurrent dense deposit disease being managed with eculizumab. Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident. A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease. Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function. There was a marked clinical and biochemical response following the administration of eculizumab. This case provides the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease. More information is necessary to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging. The results of clinical trials of eculizumab in this condition are eagerly awaited. PMID- 22233158 TI - Screening tools for frailty in primary health care: a systematic review. AB - Frailty is the loss of resources in several domains leading to the inability to respond to physical or psychological stress. The evaluation of frailty is generally carried out using the Comprehensive Geriatric Assessment. For this evolving and potentially reversible syndrome, screening and early intervention are a priority in primary health care, and general practitioners require a simple screening tool. The aim of the present work was to review the literature for validated screening instruments for frailty in primary health care setting. A search was carried out on PubMed and Cochrane Central in June 2011. A total of 10 instruments screening for frailty in primary health care were listed, analysed and compared. It is difficult to show which tool today is the best for screening for frailty in the elderly in primary care settings. Two instruments are potentially suitable - the Tilburg Frailty Indicator and the SHARE Frailty Index. In addition, these instruments require validation in larger studies in primary health care settings and with more quality criteria. PMID- 22233159 TI - Longitudinal study of emotional intelligence, leadership, and caring in undergraduate nursing students. AB - This study describes the development of emotional intelligence (EI), leadership, and caring in undergraduate nursing students throughout their educational program. A correlational, repeated measures study design was used. Fifty-two nursing students completed four self-report questionnaires on three occasions (T1, T2, T3): BarOn Emotional Quotient Inventory: Short (EQ-i:S), Self-Assessment Leadership Instrument (SALI), Caring Ability Inventory (CAI), and Caring Dimensions Inventory (CDI). Mean scores for Total EI did not change significantly over time (T1, 100.1 +/- 13.8; T2, 103.1 +/- 13.8; T3, 101.6 +/- 14.7). However, EI adaptability was higher at T2 (101.6 +/- 13.1) and T3 (101.8 +/- 14.1) than at T1 (97.0 +/- 12.5; p = 0.03), as was CAI Courage (64.2 +/- 9.5, 66.7 +/- 9.5, 66.9 +/- 8.7; p = 0.04) and the CDI (96.8 +/- 18.1, 103.0 +/- 7.3, 102.0 +/- 10.9; p = 0.02). Changes in EI were positively correlated (r > 0.50, p < 0.001) with changes in SALI, CAI Knowing, and CAI Courage. During the undergraduate program, significant increases occurred in caring and EI adaptability but not in overall EI or leadership. PMID- 22233160 TI - A digital toolkit to implement and manage a multisite study. AB - Calls for multisite studies are increasing in nursing education. However, the challenge of implementing consistent protocols and maintaining rigorous standards across sites can be daunting. One purpose of a recent multisite, collaborative, simulation study was to evaluate a digital toolkit's effectiveness for managing a multisite study. We describe the digital toolkit composed of Web-based technologies used to manage a study involving five sites including one United Kingdom site. The digital toolkit included a wiki, a project Web site to coordinate the protocols and study materials, software to organize study materials, and a secure location for sharing data. Most of these are familiar tools; however, combined as a toolkit, they became a useful management system. Web-based communication strategies and coordinated technical support served as key adjuncts to foster collaboration. This article also offers practical implications and recommendations for using a digital toolkit in other multisite studies. PMID- 22233161 TI - Risk assessment profile and strategies for success instrument: determining prelicensure nursing students' risk for academic success. AB - The ultimate outcomes for succeeding in a collegiate prelicensure nursing program are earning a Bachelor of Science in Nursing degree and passing the NCLEX-RN(r). The Risk Assessment Profile, Strategies for Success (RAPSS) is a criterion-based instrument that incorporates demographic and academic risk indicators. A convenience sample (N = 255) obtained retrospectively from student files was used to determine whether the RAPSS could be used to predict whether completers of a baccalaureate, prelicensure program will pass or fail the NCLEX-RN. Results indicate that the scale does discriminate between candidates who fail and pass, even with as few as three of the 13 items. PMID- 22233162 TI - An unusual cardiomyopathy after physical stress in a child. AB - Takotsubo cardiomyopathy, or broken heart syndrome, is characterized by transient left ventricular dysfunction associated to chest pain, elevation of cardiac enzymes, and electrocardiographic changes, mimicking an acute coronary syndrome, especially in older women after a physical or emotional stress. It is extremely infrequent in children as well as after infective stress. We described a celiac 4 year-old girl, following a gluten-free diet, who developed features of cardiac failure few days after episodes of acute diarrhea with fever. The patient was treated with oral anticongestive therapy and intravenous immunoglobulins, and she had a dramatic and rapid improvement; echocardiographic features normalized in 48 hours. PMID- 22233163 TI - Shape-dependent oriented trapping and scaffolding of plasmonic nanoparticles by topological defects for self-assembly of colloidal dimers in liquid crystals. AB - We demonstrate scaffolding of plasmonic nanoparticles by topological defects induced by colloidal microspheres to match their surface boundary conditions with a uniform far-field alignment in a liquid crystal host. Displacing energetically costly liquid crystal regions of reduced order, anisotropic nanoparticles with concave or convex shapes not only stably localize in defects but also self-orient with respect to the microsphere surface. Using laser tweezers, we manipulate the ensuing nanoparticle-microsphere colloidal dimers, probing the strength of elastic binding and demonstrating self-assembly of hierarchical colloidal superstructures such as chains and arrays. PMID- 22233164 TI - Identification of nutritional risk by nursing staff in secure psychiatric settings: reliability and validity of St Andrew's Nutrition Screening Instrument. AB - Nutrition screening is the first-line approach to addressing the nutritional needs of service users and has been recommended as best practice by several authoritative and regulatory bodies. A simple and comprehensive screening tool, the St Andrew's Nutrition Screening Instrument (SANSI), was developed for use in an inpatient secure psychiatric setting. The aim of this study was to test the screening tool for reliability and validity. This study identified SANSI as reliable and valid for use in secure psychiatric settings for adolescents and adults. This should give confidence to regulatory and commissioning organizations, that the nutritional risk for patients in an organization which serves a diverse mental health population is being correctly identified, raising staff awareness and allowing appropriate action to be planned. PMID- 22233165 TI - Long-term neuropsychological and psychosocial outcomes of decompressive hemicraniectomy following malignant middle cerebral artery infarctions. AB - PURPOSE: This study examines long-term neuropsychological and psychosocial outcomes of survivors of malignant middle cerebral artery infarction treated via decompressive hemicraniectomy. METHOD: A case series design facilitated a detailed analysis of the outcomes among five participants. Neuropsychological domains assessed included premorbid and current IQ, sustained, selective and divided attention, visual and auditory memory, executive functioning and visuo spatial ability. Psychosocial domains assessed included self-rated depression, anxiety and quality of life. Participants and their main carer were asked about their retrospective view of surgery. RESULTS: All participants showed neuropsychological impairments in multiple cognitive domains, with preserved ability in others. Effects of laterality of brain function were evident in some domains. Clinically significant depression was evident in two participants. Overall quality of life was within average limits in three of four assessed participants. Four participants retrospectively considered surgery as having been a favourable course of action. CONCLUSION: While neuropsychological impairments are highly likely post-surgery, preserved abilities and social support may serve a protective function against depression and an unacceptably poor quality of life. Results do not support the suggestion that decompressive hemicraniectomy following malignant middle cerebral artery infarction necessarily leads to unacceptable neuropsychological or psychosocial outcomes. [ IMPLICATIONS FOR REHABILITATION: * Malignant middle cerebral artery infarction is a life threatening condition.* The neurosurgical procedure, "decompressive hemicraniectomy" has been shown to be life-saving among patients with this condition.* There is little known about the long-term neuropsychological and psychosocial outcomes following decompressive hemicraniectomy for malignant middle cerebral artery infarction.* This study concludes that neuropsychological impairments are highly probable post-surgery. However, preserved abilities and social support may serve a protective function against depression and an unacceptably poor quality of life.] PMID- 22233166 TI - Nocturia is associated with an increased risk of coronary heart disease and death. AB - What's known on the subject? and What does the study add? Nocturia has been associated with multiple chronic conditions, however, previous studies have been conducted only at a single time. We found that nocturia preceded the development CHD in young men. Moderate nocturia may be an early marker of CHD in young men. OBJECTIVE: To determine whether nocturia is associated with the development of diabetes mellitus, hypertension, coronary heart disease (CHD) and occurrence of death. MATERIALS AND METHODS: We studied data obtained from a retrospective cohort of randomly selected men, aged 40-79 years in 1990, from Olmsted County, MN, USA. Moderate nocturia was defined as waking to urinate >=2 times per night. Men were followed every 2 years through repeated questionnaires and community medical records to assess development of diabetes mellitus and hypertension, and occurrence of death. CHD was ascertained through ongoing surveillance of heart disease in Olmsted County. Cox proportional hazard models were used to estimate associations between baseline nocturia and each of the outcomes. RESULTS: A total of 2447 men were followed for a median of 17.1 years (25th and 75th percentiles: 15.0, 17.4 years). Moderate nocturia was not significantly associated with the later development of diabetes mellitus or hypertension in this study. Younger men (<60 years of age) with moderate nocturia were more likely to develop CHD later in life than younger men without nocturia (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.13, 2.49). This association was no longer significant when adjusted for age, body mass index (BMI) and urological medications (HR: 1.36; 95% CI: 0.87, 2.12). Older men (>=60 years of age) with moderate nocturia were more likely to die than older men without moderate nocturia, even after adjusting for age, BMI, urological medications and CHD (HR: 1.48; 95% CI: 1.15, 1.91). CONCLUSION: Nocturia may be a marker for increased risk of CHD in younger men, and death in older men. PMID- 22233167 TI - Using whole-body vibration training in patients affected with common neurological diseases: a systematic literature review. AB - OBJECTIVES: This systematic review critically evaluates the effects of whole body vibration (WBV) exercises on gait, balance, proprioception, strength, and health related quality of life in patients with common neurological diseases. It specifically focuses on assessing the quality of reported studies and comparing quantitative results. DESIGN: This is a systematic literature review. RESULTS: A specific search strategy of 11 databases identified 13 published articles (5 studies of patients with Parkinson disease, 2 with cerebral palsy, 3 with multiple sclerosis, and 3 with stroke) that fulfilled the selection criteria. The quality of the articles was evaluated using a Physiotherapy Evidence Database scale and Dutch Institute for Healthcare Improvement guidelines. CONCLUSIONS: There is moderate evidence that one session of WBV has positive effects on strength, whereas there is a weak level of evidence that WBV could improve proprioception and health-related quality of life measures in neurological patients. With respect to long-term effects of WBV, there is minor evidence from the studies with the best methodological quality that WBV improves strength, proprioception, gait, and balance. Further research on the intervention is strongly needed. PMID- 22233168 TI - Water gradient in the membrane-water interface: a time-resolved study of the series of n-(9-anthroyloxy) stearic acids incorporated in AOT/water/iso-octane reverse micelles. AB - The water radial distribution in AOT/iso-octane/water reverse micelles (RM), used to mimic the membrane-water interface, was examined by excited-state lifetime and transient spectral measurements of the series of n-(9-anthroyloxy) stearic acids (n-AS), with n = 2, 3, 6, 7, 9, 10, and 12. A water gradient in the RM extended from the polar head group region up to the middle of the surfactant carbon chains. A fast intramolecular excited-state relaxation, involving the rotation of the carboxylic group of the ester bond with respect to the anthracene ring, gave rise to a nanosecond time-dependent fluorescence Stokes shifts (TDFSS). In water filled RMs, we only observed a water-induced TDFSS occurring over subnano- and nanosecond time scales with decreasing amplitudes and rates as a function of depth, according to the decreasing water gradient and the slowing down of the anthroyloxy moiety rotational motion. This water-induced TDFSS is most likely the result of both H-bond formation and general dipolar relaxation, as indirectly showed by measurements with DMF (a nonprotic polar solvent) instead of water in RMs. PMID- 22233169 TI - Preparation and properties of a monomeric high-spin Mn(V)-oxo complex. AB - Oxomanganese(V) species have been implicated in a variety of biological and synthetic processes, including their role as a key reactive center within the oxygen-evolving complex in photosynthesis. Nearly all mononuclear Mn(V)-oxo complexes have tetragonal symmetry, producing low-spin species. A new high-spin Mn(V)-oxo complex that was prepared from a well-characterized oxomanganese(III) complex having trigonal symmetry is now reported. Oxidation experiments with [FeCp(2)](+) were monitored with optical and electron paramagnetic resonance (EPR) spectroscopies and support a high-spin oxomanganese(V) complex formulation. The parallel-mode EPR spectrum has a distinctive S = 1 signal at g = 4.01 with a six-line hyperfine pattern having A(z) = 113 MHz. The presence of an oxo ligand was supported by resonance Raman spectroscopy, which revealed O-isotope-sensitive peaks at 737 and 754 cm(-1) assigned as a Fermi doublet centered at 746 cm( 1)(Delta(18)O = 31 cm(-1)). Mn Kbeta X-ray emission spectra showed Kbeta' and Kbeta(1,3) bands at 6475.92 and 6490.50 eV, respectively, which are characteristic of a high-spin Mn(V) center. PMID- 22233171 TI - The microneedle roller is an effective device for enhancing transdermal drug delivery. PMID- 22233173 TI - The effect of kurtosis on the power of two test statistics in covariance structure analysis. AB - We study the effect of excess kurtosis on the non-centrality parameters of the rescaled and the residual-based test statistics for covariance structure models. The analysis is based on population matrices and parameters, which eliminates the sampling variability inherent in simulation studies. We show that the non centrality parameters, and consequently the asymptotic power, decrease as kurtosis in the data increases. Examples are provided to compare this decrease for the two test statistics, and to illustrate how substantial it is. PMID- 22233170 TI - A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection. AB - BACKGROUND: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. RESULTS: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. CONCLUSIONS: SCH 546738 is a novel, potent and non competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection. PMID- 22233174 TI - Evaluation of latent construct correlations in the presence of missing data: a note on a latent variable modelling approach. AB - A latent variable modelling approach is discussed, which can be used to evaluate indices of linear relationship between latent constructs in incomplete data sets. The method is based on an application of maximum-likelihood estimation and inclusion of covariates predictive of missing values. The approach can be employed for point and interval estimation of latent correlations in the presence of missing data, and capitalizes on enhanced plausibility of the assumption of data missing at random through introduction of informative covariates. The method is illustrated on empirical data. PMID- 22233175 TI - Logistic response models with item interactions. AB - Items that are clustered according to shared content may violate the principle of conditional independence commonly used in item response theory. This paper investigates the capabilities of a logistic item response model in relation to locally dependent item responses. The model includes main effect and interaction parameters that are computed as linear functions of the latent trait. The paper explains the interpretation of the parameters, the maximum likelihood estimation algorithm, the information matrix and some results concerning parameter identifiability. The problem of over-fitting the data is addressed in a simulation study, and two real data examples are described to illustrate the approach, one from the context of a sample survey and the other from ability testing using testlets. PMID- 22233177 TI - Bladder contractility and urethral resistance relation: what does a pressure flow study tell us? AB - Hydrodynamic analysis of a pressure flow study is the only reliable method to determine the presence or absence of a bladder outlet obstruction, especially benign prostatic obstruction. To interpret the results of pressure flow study in benign prostatic obstruction, understanding the outlines of the basic theory about evaluation of the relationship between bladder contractility and urethral resistance relation is of paramount importance. In contrast, hydrodynamic analysis of pressure flow study in conditions other than benign prostatic obstruction is complicated by the limits of theories about the hydrodynamics of the lower urinary tract. In this review, the proposed hydrodynamic theories about the relationship between bladder contractility and urethral resistance relation are outlined. Then, problems encountered in the application of hydrodynamic analysis of pressure flow study to diseases other than benign prostatic obstruction are discussed. PMID- 22233178 TI - Effect of polychlorinated biphenyls 118 and 153 on Th1/Th2 cells differentiation. AB - The objective of this study was evaluate the effect of coplanar polychlorinated biphenyls (PCB) 118-congener (PCB like-dioxin) and noncoplanar PCB 153-congener (PCB no like-dioxin) on differentiation of humans T-CD4+ lymphocytes into Th1 or Th2 subpopulations. Peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers (aged 25-30 years); T-CD4+ lymphocytes were separated from PBMC. Then, the differentiation of T-CD4+ cells into Th1 or Th2 subpopulation was performed and the intracellular cytokines analyses were assessed. No effect on IFNgamma (produced by Th1 cells) production was observed when the cells were treated with both PCBs congeners. However, the PCB 118-congener induced an increase of IL-4-producing T-CD4 cells (produced by Th2 cells), PCB153 not exerted any effect on IL-4 production. The clinical significance of our data is uncertain, therefore, more studies are necessary in order to elucidate the effects generated in exposed human individual. PMID- 22233179 TI - Oral simvastatin reduces the hypertensive response to air-jet stress. AB - Brain angiotensin (Ang) II and vasopressin play important roles in the neurogenic regulation of the circulatory system, such as in cardiovascular responses to stress. Recently, it has become evident that the positive effects of statins are not limited to their lipid-lowering actions; for example, it has been found that statins interact with angiotensin peptides. In the present study we tested the hypothesis that simvastatin affects haemodynamic responses to air-jet stress and intracerebroventricular infusions of vasopressin and AngII. We maintained 12-week old male Sprague-Dawley rats either on tap water (control) or on water containing simvastatin (20, 40 or 60 mg/L) for 4 weeks. Subsequently, we measured arterial blood pressure and heart rate (HR) at baseline and after air-jet stress or intracerebroventricular infusions over 30 s of 10 ng AngII, 20 ng vasopressin or their antagonists (10 MUg losartan and 400 ng d(CH(2) )(5) [Tyr(Me)(2) ,Ala-NH(2) (9) ] vasopressin, respectively). There were no significant differences between the control and simvastatin groups in terms of baseline mean arterial blood pressure (MAP) and HR. In rats given 60 mg/L simvastatin, the hypertensive response to air-jet stress was significantly smaller than in controls, as was the increase in MAP in response to AngII. In contrast, there was no significant difference between the groups in terms of the hypertensive response to vasopressin. These findings show that simvastatin affects the hypertensive response to air-jet stress and provide evidence that statins may affect the brain's regulation of the circulatory system. PMID- 22233180 TI - Combination injuries 3. The risk of pulp necrosis in permanent teeth with extrusion or lateral luxation and concomitant crown fractures without pulp exposure. AB - AIM: To analyze the influence of a crown fracture without pulp exposure on the risk of pulp necrosis (PN) in teeth with extrusion or lateral luxation. MATERIAL AND METHODS: The study included 82 permanent incisors with extrusion from 78 patients (57 male, 21 female) and 179 permanent incisors with lateral luxation from 149 patients (87 male, 62 female). A total of 25 teeth with extrusion and 33 teeth with lateral luxation had suffered a concomitant crown fracture (infraction, enamel fracture or enamel-dentin-fracture). All the teeth were examined and treated according to a standardized protocol. STATISTICS: The risk of PN was analyzed separately for teeth with immature and mature root development by the Kaplan-Meier method, the log-rank test and Cox regression (lateral luxation only). The level of significance was set at 5%. Risk factors included in the analysis were gender, age, crown fracture, and response to electric pulp test at the initial examination. RESULTS: A concomitant crown fracture significantly increased the risk of PN in teeth with lateral luxation. For teeth with immature root development (hazard ratio: 10 [95% confidence interval (CI): 1.1-100] P = 0.04), the overall risk increased from 4.7% (95% CI: 0-10.8) to 40% (95% CI: 2.8 77.2). For teeth with mature root development [hazard ratio: 2.4 (95% CI: 1.4 4.2) P < 0.001], the overall risk increased from 65.1% (95% CI: 55.2-75.1) to 93% (95% CI: 85.5-100). In teeth with extrusion and mature root development, the overall risk of PN increased from 56.5% (95% CI: 37.7-75.4) to 76.5% (95% CI: 58.9-94) in case of a concomitant crown fracture, but the difference was not statistically significant (P > 0.05). CONCLUSION: A concomitant crown fracture without pulp exposure significantly increased the risk of PN in teeth with lateral luxation. This risk factor may be used to identify teeth at increased risk of PN following lateral luxation injury. PMID- 22233181 TI - The role of race and poverty on steps to kidney transplantation in the Southeastern United States. AB - Racial disparities in access to renal transplantation exist, but the effects of race and socioeconomic status (SES) on early steps of renal transplantation have not been well explored. Adult patients referred for renal transplant evaluation at a single transplant center in the Southeastern United States from 2005 to 2007, followed through May 2010, were examined. Demographic and clinical data were obtained from patient's medical records and then linked with United States Renal Data System and American Community Survey Census data. Cox models examined the effect of race on referral, evaluation, waitlisting and organ receipt. Of 2291 patients, 64.9% were black, the mean age was 49.4 years and 33.6% lived in poor neighborhoods. Racial disparities were observed in access to referral, transplant evaluation, waitlisting and organ receipt. SES explained almost one third of the lower rate of transplant among black versus white patients, but even after adjustment for demographic, clinical and SES factors, blacks had a 59% lower rate of transplant than whites (hazard ratio = 0.41; 95% confidence interval: 0.28-0.58). Results suggest that improving access to healthcare may reduce some, but not all, of the racial disparities in access to kidney transplantation. PMID- 22233182 TI - Differences in outcomes between cholecalciferol and ergocalciferol supplementation in veterans with inflammatory bowel disease. AB - AIM: Vitamin D deficiency is a global health issue associated with increased health-care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitamin D deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. METHODS: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitamin D level were included. Initial and follow-up vitamin D values were recorded. The type of vitamin D supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitamin D were divided into separate inpatient and outpatient categories. RESULTS: Veterans (n = 108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitamin D level were studied. There were differences in follow-up vitamin D levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitamin D3 were less likely to use laboratory, pharmacy, radiology and fee-based services, and had lower laboratory and pharmacy costs. CONCLUSIONS: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health-care costs and expenses in patients with inflammatory bowel disease. PMID- 22233183 TI - The ideal spectral profile of topical sunscreens. AB - Sunscreens were originally designed to prevent sunburn and incorporated active ingredients that absorbed principally in the UVB region. However, over the past 20 years or so new ingredients have been developed that extend absorption across a much wider range of the solar ultraviolet spectrum in the belief that sunscreens should provide balanced spectral absorption. This article develops the rationale for spectral uniformity by showing that this requirement is aligned to more natural forms of photoprotection. It is shown that a modern sunscreen can provide a spectrally balanced absorption profile in line with shade and many types of clothing fabric. Finally, a new metric is introduced that measures how well the spectral absorption profile of topical sunscreens performs against this ideal. PMID- 22233184 TI - Evidence for epistatic gene interactions between growth factor genes in stroke outcome. AB - BACKGROUND AND PURPOSE: Growth factors are thought to modulate neurological function in stroke recovery through effects in angiogenesis, neurogenesis, and neuroprotection. METHODS: We tested the association of variants in the brain derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) genes, and epistatic interactions between them, with functional outcome in a sample of 546 stroke patients. RESULTS: While none of the tested genes was independently associated with stroke outcome, two significant gene-gene interaction models were identified. One model combined one BDNF and three FGF2 markers, with a global odds ratio (OR) (95% confidence interval [CI]) of 4.15 [2.86-6.04]. The second model included one FGF2 and two VEGFA markers with a global OR [95% CI] = 2.54 [1.76-3.67]. CONCLUSIONS: The results provide evidence for gene interactions in stroke outcome, highlighting the complexity of the recovery mechanisms after a stroke event. PMID- 22233186 TI - Can "inoperable" congenital heart defects become operable in patients with pulmonary arterial hypertension? Dream or reality? AB - The decision whether to repair congenital heart defects in patients with raised pulmonary vascular resistance to alleviate pulmonary hypertension is a complex one. The degree of pulmonary vascular disease is of paramount importance. Operating on patients with pulmonary vascular resistance above a certain threshold runs the risk of postoperative persistent pulmonary hypertension and a worse long-term prognosis. This review focuses on patients deemed "borderline inoperable" or "inoperable" due to pulmonary vascular disease and asks whether they can be "converted to an operable status" with pulmonary arterial hypertension-specific drugs that potentially modify the pulmonary vascular lesions and resistance. PMID- 22233185 TI - Neurocognitive correlates of nocturnal oxygen desaturation in a memory clinic population. AB - Previous studies suggested that sleep apnea is associated with neurocognitive impairments but did not examine populations most likely to have clinically relevant impairments. Cross-sectional, retrospective analyses were performed on 108 patients (65 with mild cognitive impairment, 43 with dementia) seen in an academic medical center. Results indicated that severity of oxygen desaturation was associated with cognitive impairments in attention and executive function domains, even after controlling for age, sex, education, and depressive symptoms. Strength of associations was influenced by cardiovascular disease. Screening for nocturnal oxygen desaturation may be a useful procedure to assess for a potentially reversible cause of cognitive impairment. PMID- 22233187 TI - Current status of molecular markers for prognostication and outcome in invasive bladder cancer. AB - What's known on the subject? and What does the study add? Currently, prognostication of patients with invasive BC is hampered owing to the inadequacy of standard clinicopathological risk factors to predict accurately individual treatment outcomes. This review provides a comprehensive albeit brief overview on current studies elucidating the potential role of different molecular markers to close this gap of evidence. It focuses on biostatistical considerations in the interpretation of study results which are essential to provide meaningful clinical conclusions for an individual patient. OBJECTIVE: * To improve prognostication and the management of patients with invasive bladder cancer (BC). METHODS: * Standard clinicopathological risk factors are not reliably enough to accurately predict outcomes in patients after radical treatment and guide clinicians for recommending selectively the use of adjuvant therapies. * With detailed insights into the molecular pathology of BC, biomarkers have come to the fore of researchers as a potential tool to close this gap of evidence. * However, their definitive role in the diagnostic and therapeutic management of patients with invasive BC has not clearly been addressed so far. RESULTS: * Invasive BC are an extremely heterogenenous group of malignancies which are characterized by multiple genetic alterations involved in the carcinogenesis and development of metastatic spread. Thus, it is questionable whether any single marker will provide superior prognostication compared with a combination of markers. * Current studies evaluating the predictive value of a multitude of markers have used high-throughput technologies and investigated the gain in predictive accuracy within new nomograms which encompass well-established clinicopathological and novel putative molecular parameters. p53 overexpression was found to be associated with increased risk of recurrence in urothelial and non-urothelial cancer. In pT1 disease, the combination of p53, p21 and p16 as well as epigenetic alterations of myopodin expression has been shown to provide improved prognostication, and this might help to advocate more selectively the use of early radical treatment. * After the bladder-sparing approach, p53 and p21 overexpression indicate decreased probability of long-term bladder preservation. Additionally, altered retinoblastoma expression is associated with improved survival after adjuvant chemotherapy. * To provide meaningful conclusions for individual prognosis and the need of adjuvant treatment, biostatistical pitfalls in the analysis and interpretation of results have to be taken into account. CONCLUSIONS: * Different molecular markers have the potential to improve prognostication of patients with invasive BC and provide improved evidence for targeted therapy in the neoadjuvant, adjuvant and metastatic setting. * However, in order to advocate their routine clinical use on a sound scientific basis prospective data are still necessary. PMID- 22233188 TI - Inclusion as a focus of employment-related research in intellectual disability from 2000 to 2010: a scoping review. AB - PURPOSE: This paper presents the results of a scoping review of the research literature on community-based employment for individuals with intellectual disabilities from 2000 to 2010. The review examined the variables studied in each paper, and considered the degree to which elements of social inclusion were addressed. METHOD: The search strategy identified a total of 245 articles, the total pool of which was reduced to 42 following abstract and text review. Two researchers reviewed the final set of articles and extracted information relevant to the study goals. Independent and dependent measures used in the studies were categorized relative to a conceptual model of social inclusion. The frequency with which each aspect of inclusion was addressed in the studies was totalled, and the resulting pattern analyzed qualitatively. RESULTS: The analysis revealed that the majority of papers identified the work role achieved (i.e. employment and pay rates, job titles) as the primary construct of interest, while fewer than 5 articles focused on central aspects of inclusion, such as sense of belonging, reciprocity, and need fulfillment. CONCLUSIONS: This study profiles the evidence base relative to inclusive employment for people with intellectual disabilities. The lack of evidence on the degree to which social inclusion is being achieved through community-based employment highlights a critical area requiring attention. PMID- 22233189 TI - The combination very low-dose naltrexone-clonidine in the management of opioid withdrawal. AB - BACKGROUND: The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy. OBJECTIVES: We investigated the effects of a VLNTX-clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial. METHODS: Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1-.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program. RESULTS: VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal. PMID- 22233190 TI - Rhodium(II)-catalyzed asymmetric sulfur(VI) reduction of diazo sulfonylamidines. AB - Diazo sulfonylamidines readily undergo enantioselective oxygen transfer from sulfur to carbon atom in the presence of chiral rhodium(II) carboxylates resulting in chiral sulfinylamidines. This unusual asymmetric atom transfer "reduction" occurs rapidly under mild conditions, and sulfinylamidines are obtained in excellent yield. PMID- 22233191 TI - Molecular dynamics of a polyaniline/beta-cyclodextrin complex investigated by 13C solid-state NMR. AB - The molecular dynamics of a polyaniline/beta-cyclodextrin inclusion complex (PANI/beta-CD IC) and its relation with optical properties were investigated using high-resolution solid-state (13)C nuclear magnetic resonance (NMR) and optical absorption spectroscopies. UV-vis measurements revealed a pi-pi* absorption peak of a PANI film that had a 10 nm blue-shift by inclusion of beta CD, indicating that pi-conjugation of PANI was shortened in the IC. Temperature dependent analysis of (13)C NMR spectra and spin-lattice relaxation times (T(1C)) revealed that the inclusion induced acceleration of the twisting motion of the PANI chain. Moreover, two twisting motions attributed to different torsional angle modes were observed following Arrhenius plots of T(1C) measurements, and the twisting frequency and angle increased above -25 degrees C. These results suggest that the beta-CD inclusion weakens the intermolecular pi-pi interaction and enhances the accompanying twisting motion, consequently leading to a blue shift of UV-vis absorption. PMID- 22233192 TI - Accumulation patterns of some seed oil components from wild sources of Turkey. AB - Accumulation profiles of fatty acids and alpha-tocopherol were analysed at three ripening stages in the seed oils of Primula and Echium species. Total seed oils were increased considerably with maturation, while alpha-tocopherol contents decreased in both species. Increased levels of ALA and oleic acid, and decrease in linoleic and palmitic acids at late ripening stages of Primula sibthorpii, and slightly fluctuations of all examined fatty acids in Echium italicum were observed. Considerable amounts of alpha-tocopherol (27.4 mg/100 g), linoleic acid (42.76%) and ALA (25.46%) and GLA (4.11%) were detected in Ribes alpinum. Typical accumulation patterns of the examined parameters may be useful for species characterisation and biochemical monitoring of seed development in natural conditions. PMID- 22233193 TI - Triacylglycerol synthesis by PDAT1 in the absence of DGAT1 activity is dependent on re-acylation of LPC by LPCAT2. AB - BACKGROUND: The Arabidopsis thaliana dgat1 mutant, AS11, has an oil content which is decreased by 30%, and a strongly increased ratio of 18:3/20:1, compared to wild type. Despite lacking a functional DGAT1, AS11 still manages to make 70% of WT seed oil levels. Recently, it was demonstrated that in the absence of DGAT1, PDAT1 was essential for normal seed development, and is a dominant determinant in Arabidopsis TAG biosynthesis. METHODS: Biochemical, metabolic and gene expression studies combined with genetic crossing of selected Arabidopsis mutants have been carried out to demonstrate the contribution of Arabidopsis PDAT1 and LPCAT2 in the absence of DGAT1 activity. RESULTS: Through microarray and RT-PCR gene expression analyses of AS11 vs. WT mid-developing siliques, we observed consistent trends between the two methods. FAD2 and FAD3 were up-regulated and FAE1 down-regulated, consistent with the AS11 acyl phenotype. PDAT1 expression was up-regulated by ca 65% while PDAT2 expression was up-regulated only 15%, reinforcing the dominant role of PDAT1 in AS11 TAG biosynthesis. The expression of LPCAT2 was up-regulated by 50-75%, while LPCAT1 expression was not significantly affected. In vitro LPCAT activity was enhanced by 75-125% in microsomal protein preparations from mid-developing AS11 seed vs WT. Co-incident homozygous knockout lines of dgat1/lpcat2 exhibited severe penalties on TAG biosynthesis, delayed plant development and seed set, even with a functional PDAT1; the double mutant dgat1/lpcat1 showed only marginally lower oil content than AS11. CONCLUSIONS: Collectively, the data strongly support that in AS11 it is LPCAT2 up-regulation which is primarily responsible for assisting in PDAT1 catalyzed TAG biosynthesis, maintaining a supply of PC as co-substrate to transfer sn-2 moieties to the sn-3 position of the enlarged AS11 DAG pool. PMID- 22233195 TI - Painful erosions induced by patch testing in a patient with Hailey-Hailey disease. PMID- 22233196 TI - Obesity and vascular dysfunction: the fat-e of rich and poor. PMID- 22233197 TI - Protective effect of apocynin in an established alcoholic steatohepatitis rat model. AB - Apocynin is a widely used antioxidant in both basic and clinical research. The current study aimed to investigate the protective effect of apocynin in an established alcoholic steatohepatitis rat model. Healthy SD rats were gastrically fed with ethanol (4.0 g/kg) for 8 weeks to induce alcoholic steatohepatitis. After 8 weeks, rats were fed with ethanol for another 2 weeks with or without a daily intraperitoneal injection of 25 mg/kg apocynin. After sacrificing, serum and liver samples were subjected to hepatic injury measurements. After 8-week ethanol induction, rats exhibited typical alcoholic steatohepatitis features including reduced body weight, hepatic histological changes, elevated serum alanine transaminase (ALT) level, increased levels of oxidative stress and inflammatory markers, NADPH oxidases, and renin-angiotensin system (RAS) marker. Co-treatment of apocynin alleviated the hepatic injury and biochemical parameters induced by alcoholic steatohepatitis. In conclusion, addition of apocynin significantly attenuates hepatic oxidative stress and inflammation induced by alcoholic steatohepatitis. This effect is partly through the inhibition of the RAS system. PMID- 22233198 TI - Comparative evaluation of Ca(OH)2 plus points and Ca(OH)2 paste in apexification. AB - AIM: The aim of this study was to compare calcium hydroxide plus points (CHPPs) with the conventional calcium hydroxide paste (CHP) clinically and radiographically as materials used in apexification treatment. MATERIAL AND METHODS: Sixteen children, each with at least one necrotic permanent central incisor requiring apexification treatment, were selected for this study. Twenty two selected teeth were divided into two test groups (10 CHP and 12 CHPP). The children were recalled for clinical evaluations every 3 weeks, and their radiographical evaluations were carried out every 3 months. Mann-Whitney U and Fisher's exact tests were used to evaluate the differences between the groups. RESULTS: The follow-up evaluations revealed that the success rate was 100% for CHP and 92% for CHPP. No statistically significant difference between the groups was observed (P > 0.05). CONCLUSIONS: CHPP-treated central incisors requiring apexification demonstrated good success. CHPP can be used for cases in which traditional Ca(OH)(2) apexification is indicated as it has a similar outcome with CHP. PMID- 22233199 TI - Fabrication of graphene with CuO islands by chemical vapor deposition. AB - Graphene prepared on Cu foil by chemical vapor deposition was studied as a function of post growth cooling conditions. CuO islands embedded in the graphene film were discovered and studied by scanning electron microscopy, atomic force microscopy, and X-ray photoemission spectroscopy. It is shown that nanostructured holes can be formed within a graphene film by reduction using hydrogen cooling immediately after film growth. We also observe the formation of symmetrical oxide islands in these holes. This study provides an easy way to fabricate a graphene + CuO composite, and the method may be extended to other graphene based structures. PMID- 22233202 TI - Factors affecting independence in eating among elderly with Alzheimer's disease. AB - AIM: In elderly patients with dementia, disturbed eating behavior is understood to be a core symptom or a behavioral and psychological symptom of dementia (BPSD). The purpose of the present study was to investigate the factors affecting self-feeding in elderly patients with Alzheimer's disease (AD). METHODS: A total of 150 AD patients who were hospitalized in dementia wards, or were residents of institutions or group homes were enrolled. The patients underwent an eating behavior examination, cognitive assessment, neurological examination and vital function tests. The eating behavior examination consisted of observation of the patients at mealtime. Items assessing eating behavior included the number of feeding cycles, stopping of eating or agitation and dysfunction. RESULTS: Logistic regression analysis carried out to identify factors with a significant effect on decreased independence in eating were difficulty in beginning a meal (OR = 14.498, CI = 2.067-101.690), presence of dysphagia signs (OR = 5.214, CI = 1.031-26.377) and the severity of dementia (OR = 4.538, CI = 1.154-17.843). CONCLUSION: The present study is the first to generate objective data showing that difficulty in beginning a meal is a factor that hinders independence in eating in AD, in addition to the presence of dysphagia signs and the severity of dementia. Assisting AD patients in maintaining eating independence might be effectively achieved by eliminating environmental factors that interfere with beginning a meal, and by providing assistance that will promote beginning a meal. The present results show the necessity of developing effective methods for assisting elderly patients with AD. PMID- 22233203 TI - Hypericin-mediated photodynamic antimicrobial effect on clinically isolated pathogens. AB - The aim of this study was to determine the photodynamic antimicrobial effect of hypericin on clinically isolated Staphylococcus aureus and Escherichia coli cells. Bacterial cells (10(8) cells per mL) were incubated with hypericin (0-40 MUM) for 30 min and followed by light irradiation of 600-800 nm at 5-30 J cm(-2). Cell survival was determined by colony counting, cellular hypericin uptake examined by flow cytometer, and cell membrane damage examined by scanning electron microscopy and leakage assay. The effectiveness of hypericin-mediated photodynamic killing was strongly affected by cellular structure and photosensitizer uptake. The combination of hypericin and light irradiation could induce significant killing of Gram positive methicillin-sensitive and -resistant S. aureus cells (>6 log reduction), but was not effective on Gram negative E. coli cells (<0.2 log reduction). The difference was caused by different cell wall/membrane structures that directly affected cellular uptake of hypericin. PMID- 22233204 TI - Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. * Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. * This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. WHAT THIS STUDY ADDS: * The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. * Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. * There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. AIMS: To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS: In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,infinity)). RESULTS: In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 um), CYP3A4 mRNA induction (observed at tofacitinib concentrations >= 25 um) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,infinity) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS: These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole. PMID- 22233205 TI - Ginsenoside-Rd improves outcome of acute ischaemic stroke - a randomized, double blind, placebo-controlled, multicenter trial. AB - BACKGROUND AND PURPOSE: Ginsenoside-Rd is a receptor-operated calcium channel antagonist and has shown promise as a neuroprotectant in our phase II study. As an extended work, we sought to confirm its efficacy and safety of Ginsenoside-Rd in patients with acute ischaemic stroke. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 390 patients with acute ischaemic stroke in a 3:1 ratio to receive a 14-day intravenous infusion of Ginsenoside-Rd or placebo within 72 h after the onset of stroke. Our primary end point was the distribution of disability scores on the modified Rankin scale (mRs) at 90 days. RESULTS: The efficacy analysis was based on 386 patients (Ginsenoside-Rd group: 290; placebo group: 96). Ginsenoside-Rd significantly improved the overall distribution of scores on the mRs, as compared with the placebo (P = 0.02; odds ratios [OR], 1.74; 95% confidence interval [CI], 1.08 2.78). There were significant differences between the two groups when we categorized the scores into 0-1 vs. 2-5 (P = 0.01; OR, 2.32; 95% CI, 1.23-4.38; 66.8% vs. 53.1%). It also improved the National Institutes of Health Stroke Scale (NIHSS) at 15 days [P < 0.01; least squares mean (LSM), -0.77; 95% CI, -1.31 to 0.24]. Mortality and rates of adverse events were similar in the two groups. CONCLUSIONS: Ginsenoside-Rd improved the primary outcome of acute ischaemic stroke and had an acceptable adverse-event profile. PMID- 22233207 TI - A new route to indazolone via amidation reaction of o-carboxyazobenzene. AB - One new route for the synthesis of amino-substituted indazol-3,5-dione via the amidation reaction of o-carboxyazobenzenes is reported. Optimization which includes effects of the solvents, molar ratio of starting materials, and dehydrating agents on this reaction has been studied. A possible reaction mechanism has been proposed on the basis of the product's structure, and the steric hindrance could be the main reason for low yield. PMID- 22233208 TI - Outcomes of the management of post-chemotherapy retroperitoneal lymph node dissection-associated anejaculation. AB - What's known on the subject? and What does the study add? Modern surgical techniques have allowed preservation of fertility in most patients after post chemotherapy retroperitoneal lymph node dissection (PC-RPLND), but some patients still have infertility after surgery. We reviewed our experience treating infertility in 26 men after PC-RPLND. Using a structured clinical pathway we obtained sperm in 81% of men for use in assisted reproduction. OBJECTIVE: To evaluate the effectiveness of a clinical pathway on sperm retrieval outcomes in patients presenting with infertility after post-chemotherapy (PC) retroperitoneal lymph node dissection (RPLND). PATIENTS AND METHODS: We carried out a retrospective review of patients with advanced testicular cancer, presenting with infertility after PC-RPLND in a large reproductive urology practice. We implemented a clinical pathway where pseudoephedrine was first administered. If this medication failed, electroejaculation (EEJ) and/or testicular sperm extraction (TESE) was carried out. The primary outcome was retrieval of sperm for use in assisted reproduction. RESULTS: Four men had retrograde ejaculation, of whom two converted to antegrade ejaculation with medical therapy. In all, 22 patients had failure of emission (FOE) and, of these, no patient converted to antegrade ejaculation with medication. In patients with FOE, sperm was found in 15/20 of those experiencing a successful EEJ. Seven patients underwent TESE for azoospermia on EEJ or no ejaculate on EEJ, three of whom had sperm found on TESE. Sperm was found for assisted reproduction in 81% (21/26) patients. CONCLUSIONS: There appears to be no role for the use of pseudoephedrine therapy in patients with FOE after PC-RPLND. The use of a structured clinical pathway may optimize patient care. PMID- 22233210 TI - Effect of the TiO2 reduction state on the catalytic CO oxidation on deposited size-selected Pt clusters. AB - The catalytic activity of deposited Pt(7) clusters has been studied as a function of the reduction state of the TiO(2)(110)-(1 * 1) support for the CO oxidation reaction. While a slightly reduced support gives rise to a high catalytic activity of the adparticles, a strongly reduced one quenches the CO oxidation. This quenching is due to thermally activated diffusion of Ti(3+) interstitials from the bulk to the surface where they deplete the oxygen adsorbed onto the clusters by the formation of TiO(x) (x ? 2) structures. This reaction is more rapid than the CO oxidation. The present results are of general relevance to heterogeneous catalysis on TiO(2)-supported metal clusters and for reactions involving oxygen as intermediate. PMID- 22233209 TI - Integrative taxonomy at work: DNA barcoding of taeniids harboured by wild and domestic cats. AB - In modern taxonomy, DNA barcoding is particularly useful where biometric parameters are difficult to determine or useless owing to the poor quality of samples. These situations are frequent in parasitology. Here, we present an integrated study, based on both DNA barcoding and morphological analysis, on cestodes belonging to the genus Taenia, for which biodiversity is still largely underestimated. In particular, we characterized cestodes from Italian wildcats (Felis silvestris silvestris), free-ranging domestic cats (Felis silvestris catus) and hybrids populations. Adult taeniids were collected by post-mortem examinations of the hosts and morphologically identified as Taenia taeniaeformis. We produced cox1 barcode sequences for all the analysed specimens, and we compared them with reference sequences of individuals belonging to the genus Taenia retrieved from GenBank. In order to evaluate the performance of a DNA barcoding approach to discriminate these parasites, the strength of correlation between species identification based on classical morphology and the molecular divergence of cox1 sequences was measured. Our study provides clear evidence that DNA barcoding is highly efficient to reveal the presence of cryptic lineages within already-described taeniid species. Indeed, we detected three well-defined molecular lineages within the whole panel of specimens morphologically identified as T. taeniaeformis. Two of these molecular groups were already identified by other authors and should be ranked at species level. The third molecular group encompasses only samples collected in Italy during this study, and it represents a third candidate species, still morphologically undescribed. PMID- 22233211 TI - Targeted delivery of a novel palmitylated D-peptide for antiglioblastoma molecular therapy. AB - Effective glioblastoma treatment with low toxicity is one of the most difficult challenges in cancer therapy. The interaction between tumor suppressor protein p53 and its negative regulator murine double minute 2 (MDM2) provides a promising target for specific therapy because an important subtype of glioblastoma harbors wild-type p53 and overexpressed MDM2. Several D-peptides have been previously reported to effectively antagonize MDM2 for binding to p53 with high affinity and unsurpassed specificity. However, poor cell penetration and lack of efficient delivery method hampered the therapeutic applicability of the most potent D peptide, D-PMIbeta. In this study, a novel lipophilic derivate of D-PMIbeta (pDP) was developed. Liposome was chosen as a carrier for pDP, and cyclic pentapeptide c(RGDyK) was used as a targeting moiety for the treatment of glioblastoma. D PMIbeta was N-terminally modified with palmitic acid and the resultant c(RGDyK) decorated liposomes (RGD-liposomal pDP) showed almost 100% encapsulation efficiency and 10% loading efficiency. The abilities of palmitylated D-peptide to antagonize MDM2 and reactivate p53 specifically were confirmed by the western blot assay. The IC50 ratio of RGD-liposomal pDP in treating human umbilical vascular endothelial normal cells vs. U87 tumor cells was 10 times higher than that of RGD-liposomal doxorubicin. After intravenous administration, the median survival time of intracranial U87 glioblastoma-bearing nude mice treated with RGD liposomal pDP (29 days) was significant longer than that of mice treated with blank RGD-liposome (23 days) (p<0.001). These results indicated that palmitylated D-peptide inhibitor of p53-MDM2 combined with RGD modified liposomes provided a potential molecular therapy for glioblastoma. PMID- 22233212 TI - Behavioral and hormonal consequences of transporting giant pandas from China to the United States. AB - Zoological institutions strive to ensure the welfare of nonhuman animals in captivity. Part of this effort involves reducing the level of distress experienced by an animal to the greatest extent possible. However, some necessary zoo management practices such as transportation induce stress responses. An extensive literature exists concerning the animal welfare implications of road transportation for farm and laboratory animals. There has, however, been little focus on the effects of air transportation on wild animals in captivity. Because many endangered species are transported by air for breeding purposes, it is especially important to study the effects of stress on these species. This study investigated the behavioral and hormonal consequences of transporting 4 giant pandas (2 male-female pairs) by air from China to the United States. An autoregressive test revealed that urinary cortisol measures were highest for 2 subjects, Lun Lun and Tian Tian, during the flight than during the remainder of the 30-day period posttransport (p < .01). No long-term behavioral changes or problems emerged as a result of the transport. The study found that more research is needed to develop a complete understanding of transportation stress and welfare in captive wildlife. PMID- 22233213 TI - Characteristics of relinquishing and adoptive owners of horses associated with U.S. nonprofit equine rescue organizations. AB - Nonprofit equine rescue organizations in the United States provide care for relinquished horses and may offer adoption programs. With an estimated 100,000 "unwanted" horses per year and few municipal shelters providing wholesale euthanasia, there is a need to minimize the number of unwanted horses and maximize their successful transition to new caregivers. This study's objectives were to characterize the relinquishing and adoptive owners interacting with nonprofit rescue organizations. Nonprofit organizations (n = 144) in 37 states provided information by survey on 280 horses relinquished between 2006 and 2009, from which 73 were adopted. Results show the majority of relinquishing owners were women, whereas adoptive owners were primarily families or couples. Most relinquishing owners had previous equine experience and had owned the horse for 1 to 5 years; about half owned 1 other horse. Three quarters of the adoptive owners possessed additional horses housed on their property. The primary use for rehomed horses was for riding or driving. These findings will serve to help develop effective education programs for responsible horse ownership and optimize acceptance criteria and successful adoption strategies of horses by nonprofit organizations. PMID- 22233214 TI - Catching the spirit: a study of Bureau of Land Management wild horse adopters in New England. AB - Between 1971 and 2009, the U.S. Bureau of Land Management (BLM) adopted out nearly 225,000 horses and burros in the wild (wild horses and burro) who were removed from public lands (BLM, 2009). The inability of the BLM to adopt out wild horses as quickly as they are removed and recurring reports that many wild horse adoptions fail suggests that a better understanding of the adoption program is warranted. This study surveyed and interviewed 38 New Englanders who collectively adopted 68 wild horses directly from the BLM during the last 15 years. Adopters who participated in the study generally described their experiences as positive. They desired a range of horses in terms of age, gender, and color; they were flexible when deciding the activities that best suited their horses. Adopters' past knowledge of, and experience with, horses appeared not to play a major role in the success of the adoption. However, willingness to seek assistance and the availability of support were crucial for many of them. Based on the findings, the study made recommendations for better marketing of the program and improvement of the quality of adoptions. PMID- 22233215 TI - Impact of a subsidized spay neuter clinic on impoundments and euthanasia in a community shelter and on service and complaint calls to animal control. AB - Reducing the number of homeless, nonhuman animals entering and being euthanatized in community shelters is the principal motivation for most spay/neuter (S/N) programs in the United States. This study evaluated the impact of a subsidized S/N clinic opened in 2005 in Transylvania County, North Carolina, on the numbers of impoundments (and euthanasia) of dogs and cats and on the number of animal related service and complaint calls at the community's only animal shelter. Before opening the local S/N clinic, a significant linear decline in the shelter's dog-intake rate per 1,000 human population was evident. This decline did not accelerate after the S/N clinic opened in 2005. The rate of decline in euthanasia did level off after the clinic opened, but the proportion of impounded dogs euthanatized did not change significantly. The median number of cats impounded and euthanatized yearly in the Transylvania County Animal Services shelter decreased significantly after the S/N clinic opened; the proportion of cats euthanatized did not change. The median annual number of service calls and complaints decreased or leveled off. Unfortunately, data regarding many factors essential for conclusively interpreting these results were not available. PMID- 22233216 TI - Using conjoint analysis to weight broiler welfare variables based on slaughterhouse data. AB - The Council of the European Union adopted the welfare directive for broiler chickens in 2007 (Commission of the European Communities, 2007). The directive defines minimum demands and objectives for broiler production ranging from stocking density to welfare. This study found that the level of nonhuman animal welfare can be determined, for example, with welfare indexes that have different weight values for welfare variables. A total of 20 poultry experts from slaughterhouses, the feed industry, administration, and research received simulated data on 24 flocks. This included data for 5 welfare variables based on postmortem meat inspection information on commercial flocks and based on literature: mortality during rearing, foot-pad score, and the incidence of ascites, dermatitis, and cachexia in routine meat inspection. The experts ranked these flocks from the worst to the best according to animal welfare. Conjoint analysis weighted the relative importance of the welfare variables for broiler welfare. The study based relative importance for broiler welfare on 20 expert opinions: 24.6% for mortality, 35.9% for foot-pad score, 19.7% for the incidence of ascites, 15.7% for the incidence of dermatitis, and 4.1% for the incidence of cachexia. In the future, an index for broiler welfare evaluation could be developed based on the results of this study. PMID- 22233217 TI - Impact of the economic recession on companion animal relinquishment, adoption, and euthanasia: a Chicago animal shelter's experience. AB - This study investigated how the current economic recession (since December 2007) has affected dog and cat relinquishment, adoption, and euthanasia at the Anti Cruelty Society animal shelter in Chicago, Illinois. The study compared temporal patterns of the investigated statistics before (2000-2007) the start of the current recession with the patterns after the start of the recession (2008-2010). The results showed that once the guardianship (ownership) of a nonhuman animal had been established, the recession did not greatly affect the owner's decision on relinquishment-except for the relinquishment of senior dogs, which may be associated with increased costs of care. However, an unfavorable economic environment may have reduced adoption of animals. The consequences of a decline in adoptions might be reflected in an increase in the proportion or number of sheltered animals euthanized. This study demonstrated how monitoring changes in temporal patterns in these shelter statistics can help guide animal shelters to better prepare for the current recession. PMID- 22233218 TI - Simple cannulation procedure for serial blood sampling through cutaneous ulnar vein in chickens. AB - The objective of the study was to collect repeated, low-stress blood samples from the ulnar vein of chickens required for pharmacokinetic studies or hormonal assays. The study used 5 apparently healthy, unsexed, commercial broiler chickens about 6 weeks old and weighing 1.7-1.9 kg for serial sampling of blood. The study prepared the birds prior to cannulation and penetrated the catheter through the skin and into the lumen of the ulnar vein. The study successfully carried out serial blood samplings in 4 of 5 cannulated birds. Heparin (10%) solution maintained patency and prevented blood clot formation inside the cannula. However, the study found repeated clotting occurring in 1 bird. Cannula failed to maintain patency; the study could not carry out blood sampling properly, which was attributed to air embolism that might have occurred during catheter manipulation or repeated filling of cannula with heparin solution. The study observed no hematoma or inflammation at the site of cannulation. Owing to the advantages and to facilitate compliance with nonhuman animal welfare, this technique seems simple and efficient, allowing adoption for serial blood collection in chickens. PMID- 22233219 TI - An integrated approach to the assessment of pollutant delivery chronologies to impacted areas: Hg in the Augusta Bay (Italy). AB - Assessing pollution levels and trends in heavily impacted environments is important but hardly achievable due to the difficulty of recovering suitable undisturbed sediment records. An integrated approach is here presented to solve this kind of problem. It was adopted in the Augusta Bay (Italy) for the study of Hg historical inputs and present trends. Archive information on dredging and mud disposal, together with bathymetry and high-resolution seismic profiles, were used to identify suitable sampling sites. Undisturbed sediment cores were collected in the port and bay. Sediments were analyzed for depth distributions of radiotracers ((210)Pb and (137)Cs), Hg, and main sediment parameters (magnetic susceptibility, grain size, dry bulk density, mineralogy, and organic carbon and nitrogen contents). Hexachlorobenzene (HCB) was also analyzed as an additional time tracer, since its production history in the area was well-known. Results show that peak Hg contamination (up to 575 mg.kg(-1)) was reached in the 1970s. Technological improvements and waste treatment in the following years determined a consistent decrease, but high concentrations still affect surficial sediments (0.25-92 mg.kg(-1)). Hg-HCB correlation suggests that this situation is likely the effect of resuspension and redistribution of deep sediments by dredging and naval traffic. PMID- 22233220 TI - A prolyl oligopeptidase inhibitor, KYP-2047, reduces alpha-synuclein protein levels and aggregates in cellular and animal models of Parkinson's disease. AB - BACKGROUND AND PURPOSE: The aggregation of alpha-synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of alpha-synuclein in vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP-2047, on alpha-synuclein aggregation in cell lines overexpressing wild-type or A30P/A53T mutant human alpha-syn and in the brains of two A30P alpha-synuclein transgenic mouse strains. EXPERIMENTAL APPROACH: Cells were exposed to oxidative stress and then incubated with the PREP inhibitor during or after the stress. Wild-type or transgenic mice were treated for 5 days with KYP-2047 (2 * 3 mg.kg(-1) a day). Besides immunohistochemistry and thioflavin S staining, soluble and insoluble alpha-synuclein protein levels were measured by Western blot. alpha-synuclein mRNA levels were quantified by PCR. The colocalization of PREP and alpha-synuclein,and the effect of KYP-2047 on cell viability were also investigated. KEY RESULTS: In cell lines, oxidative stress induced a robust aggregation of alpha-synuclein,and low concentrations of KYP-2047 significantly reduced the number of cells with alpha-synuclein inclusions while abolishing the colocalization of alpha-synuclein and PREP. KYP 2047 significantly reduced the amount of aggregated alpha-synuclein,and it had beneficial effects on cell viability. In the transgenic mice, a 5-day treatment with the PREP inhibitor reduced the amount of alpha-synuclein immunoreactivity and soluble alpha-synuclein protein in the brain. CONCLUSIONS AND IMPLICATIONS: The results suggest that the PREP may play a role in brain accumulation and aggregation of alpha-synuclein, while KYP-2047 seems to effectively prevent these processes. PMID- 22233222 TI - Colloid milium successfully treated with MAL-PDT. PMID- 22233221 TI - Comparing multiple competing interventions in the absence of randomized trials using clinical risk-benefit analysis. AB - BACKGROUND: To demonstrate the use of risk-benefit analysis for comparing multiple competing interventions in the absence of randomized trials, we applied this approach to the evaluation of five anticoagulants to prevent thrombosis in patients undergoing orthopedic surgery. METHODS: Using a cost-effectiveness approach from a clinical perspective (i.e. risk benefit analysis) we compared thromboprophylaxis with warfarin, low molecular weight heparin, unfractionated heparin, fondaparinux or ximelagatran in patients undergoing major orthopedic surgery, with sub-analyses according to surgery type. Proportions and variances of events defining risk (major bleeding) and benefit (thrombosis averted) were obtained through a meta-analysis and used to define beta distributions. Monte Carlo simulations were conducted and used to calculate incremental risks, benefits, and risk-benefit ratios. Finally, net clinical benefit was calculated for all replications across a range of risk-benefit acceptability thresholds, with a reference range obtained by estimating the case fatality rate - ratio of thrombosis to bleeding. RESULTS: The analysis showed that compared to placebo ximelagatran was superior to other options but final results were influenced by type of surgery, since ximelagatran was superior in total knee replacement but not in total hip replacement. CONCLUSIONS: Using simulation and economic techniques we demonstrate a method that allows comparing multiple competing interventions in the absence of randomized trials with multiple arms by determining the option with the best risk-benefit profile. It can be helpful in clinical decision making since it incorporates risk, benefit, and personal risk acceptance. PMID- 22233223 TI - 3D structure of lamellar domains in a surfactant solution below the Krafft temperature. AB - We have studied the 3D structure of lamellar domains in aqueous solutions of nonionic surfactant C(16)E(6) and C(16)E(7) below the Krafft temperature by means of confocal microscopy. A new morphology of lamellar domains has been found in the C(16)E(6) system, which is the network of lamellar domains. In the C(16)E(7) system, we have confirmed that the spherical vesicles have a hollow including excess water. Furthermore, we have investigated the initial formation process of lamellar domains in those two systems. It has been found that initial lamellar domains of both systems are tiny and plate-like and that the domains are gradually curved in the C(16)E(7) system, while in the C(16)E(6) system, they spread to fuse together and form networks. PMID- 22233224 TI - Management of maxillary alveolar bone fracture and severely intruded maxillary central incisor: report of a case. AB - An 11-year-old male who injured his maxilla and right maxillary central incisor and lip during a fall was presented to our hospital. His lower lip and upper gingiva were lacerated with swelling and epistaxis, and he had a maxillary alveolar bone fracture and severe intrusion of the right maxillary central incisor, which had penetrated the floor of the nasal cavity with avulsion. Under local anesthesia, we repositioned the incisor and bone segment and fixed them with a titanium micromesh plate and self-tapping screws and splints. The incisor was also treated by root canal 3 days after the operation and was restored with a crown. We performed root canal filling 1 month later. Five months later, the plate and screws were removed. In prognosis of our case, no symptoms of inflammatory root resorption or ankylosis have observed for more than 1 year and 6 months of follow up based on both clinical and radiographic findings. PMID- 22233225 TI - Histone deacetylases and their role in asthma. AB - OBJECTIVE: The aim of this article is to provide an overview of the classical histone deacetylase (HDAC) enzymes and HDAC inhibitors. The discussion is focused on the potential anti-asthmatic effects of this group of compounds. METHODS: Medline was used with the search terms, "asthma and HDAC," "asthma and Trichostatin A," "asthma and valproic acid," "allergic airways disease and HDAC," "allergic airways disease and Trichostatin A," and "allergic airways disease and valproic acid." Manuscripts from the past decade were accessed. Historical literature dating from the 1960s was accessed for the use of anti-epileptics in the treatment of asthma. RESULTS: Preliminary clinical trials with anti-epileptic drugs including the well-known HDAC inhibitor, valproic acid, have shown long lasting anti-asthmatic effects providing the basis for the evaluation of this class of compounds in asthma. Studies using the prototypical HDAC inhibitor, Trichostatin A, in well-established murine models of allergic airways disease have also indicated beneficial effects. CONCLUSION: Although the precise mechanisms are still controversial, inhibition of airway hyperresponsiveness and agonist-induced contraction as well as anti-inflammatory effects have been described for HDAC inhibitors in asthma. PMID- 22233226 TI - Identification of diacetyl substitutes at a microwave popcorn production plant. PMID- 22233227 TI - Association between polypharmacy and dementia in older people: a population-based case-control study in Taiwan. AB - AIM: The aim of the present study was to investigate whether polypharmacy correlates with the risk of dementia in older people. METHODS: From representative claims data established from the National Health Insurance with a population coverage rate of 99% in Taiwan, we identified 7135 newly diagnosed patients with dementia in 2000-2008 and 2,8540 randomly selected controls without dementia, both aged >= 65 years. The daily use of prescribed drugs in the past 2 years was compared between cases and controls, controlling for demographic characters and comorbidities. RESULTS: The incidence of dementia increased with the number of medications used and age. Cases were older than controls, predominant with women and more likely to use five or more drugs daily (44.0% vs 32.0%, P < 0.0001). Multivariate logistic regression analysis showed that, compared with participants using zero to one drug, the odds ratios (OR) of dementia were 1.28 (95% confidence interval [CI] 1.18-1.38) for those using two to four drugs, 1.34 (95% CI 1.23-1.46) for those using five to nine drugs and 1.56 (95% CI 1.38-1.76) for those using 10 or more drugs. Cerebrovascular disease (OR 3.19), diabetes mellitus (OR 1.23), chronic kidney disease (OR 1.21) and hypertension (OR 1.08) were significant comorbidities predicting the risk of dementia. There was significant interaction between cerebrovascular disease and the number of medications used in the dementia risk. CONCLUSIONS: The risk of dementia increases steadily with the number of medications used and age in older people in Taiwan. Cerebrovascular disease, diabetes mellitus, chronic kidney disease and hypertension might also correlate with the risk of dementia. PMID- 22233228 TI - Propulsion and trapping of microparticles by active cilia arrays. AB - We model the transport of a microscopic particle via a regular array of beating elastic cilia, whose tips experience an adhesive interaction with the particle's surface. At optimal adhesion strength, the average particle velocity is maximized. Using simulations spanning a range of cilia stiffness and cilia particle adhesion strength, we explore the parameter space over which the particle can be "released", "propelled", or "trapped" by the cilia. We use a lower-order model to predict parameters for which the cilia are able to "propel" the particle. This is the first study that shows how both stiffness and adhesion strength are crucial for manipulation of particles by active cilia arrays. These results can facilitate the design of synthetic cilia that integrate adhesive and hydrodynamic interactions to selectively repel or trap particulates. Surfaces that are effective at repelling particulates are valuable for antifouling applications, while surfaces that can trap and, thus, remove particulates from the solution are useful for efficient filtration systems. PMID- 22233229 TI - Ten-year experience of home parenteral nutrition in a single centre. AB - AIM: Recent data are scarce on the provision of home parenteral nutrition (HPN) in children from the UK but would help to commission intestinal failure services. Our aim was to describe 10 years of HPN experience in our centre, which serves a population of 650,000 children. METHODS: Outcome and complication data were collected retrospectively from hospital records of children receiving HPN from April 2001. Data from other centres were used to compare complications and outcomes in the provision of HPN. RESULTS: Nineteen children (12 females) received 10,213 days (28 years) of HPN. In this group, incidence of blood culture positive sepsis was four episodes/1000 days PN. Two children had early intestinal failure-associated liver disease. Of the 19, seven still receive HPN at our centre, six survived PN, three were transferred to other services while still on HPN and three died. CONCLUSION: Outcome and complication data for HPN from a single UK regional paediatric centre are similar to larger centres. These data provide recent evidence of the disease burden of HPN, which are important for the commissioning of intestinal failure services. PMID- 22233230 TI - Rhodotorula species fungaemia causes low mortality in haematopoietic stem-cell transplantation. A case report and review. PMID- 22233232 TI - Update on in vitro allergy diagnostics. AB - Component-resolved diagnostics (CRD) have become of growing importance in clinical investigation of IgE-mediated allergies. This review updates the current use of CRD in respiratory allergies (e. g. to pollen, animal dander, mites, latex), as well as in allergies to hymenoptera venom or in food allergies to plants (e. g. Bet v 1 homologues, lipid transfer proteins, storage proteins) or to animal-derived food allergens (e. g. milk, meat, fish). CRD may help to elucidate the clinical relevance of an allergic sensitization. In some cases, CRD may also be useful in predicting either severity of clinical reactions or the therapeutic effect of specific immunotherapy. PMID- 22233233 TI - How subjective are subjective language complaints. AB - BACKGROUND AND PURPOSE: Subjective language complaints (SLC) are common during ageing but have not been investigated in detail. We aim to determine their association with demographic and clinical variables and objective cognitive performance. METHODS: A sample of 479 individuals aged 50 years or above (average 66 +/- 9.1 years), followed in primary care, with no history of brain disorder were asked two questions concerning SLC, fulfilled a depression scale and undertook a battery of cognitive tests. Response to questions regarding proper name retrieval (PNR) and word finding difficulties (WFD) was studied and their contribution to each measure of the battery calculated by repeated linear regression analysis, adjusting for age, sex, education, living alone and depressive symptoms. RESULTS: Word finding difficulties (47.6%) were more frequently reported than problematic PNR (10.9%). Both were more common in women, in subjects with depressive symptoms and in those living alone, but were unrelated with age or education. Both symptoms contributed significantly to the variance in tests of semantic fluency and episodic memory. PNR was also associated with immediate phonological memory. CONCLUSIONS: Subjective language complaints are especially common amongst individuals living alone and/or with depressive symptoms. They are associated with a worse cognitive performance in some memory and language-executive tests. Further studies are needed to understand their predictive value for cognitive decline. PMID- 22233234 TI - Focal therapy for renal mass lesions: where do we stand in 2012? PMID- 22233235 TI - Mild and rapid method for the generation of ortho-(naphtho)quinone methide intermediates. AB - A new mild method has been devised for generating o-(naphtho)quinone methides via fluoride-induced desilylation of silyl derivatives of o-hydroxybenzyl(or 1 naphthylmethyl) nitrate. The reactive o-(naphtho)quinone methide intermediates were trapped by C, O, N, and S nucleophiles and underwent "inverse electron demand" hetero-Diels-Alder reaction with dienophiles to give stable adducts. The method has useful potential application in natural product synthesis and drug research. PMID- 22233236 TI - Dynamics of confined reactive water in smectite clay-zeolite composites. AB - The dynamics of water confined to mesoporous regions in minerals such as swelling clays and zeolites is fundamental to a wide range of resource management issues impacting many processes on a global scale, including radioactive waste containment, desalination, and enhanced oil recovery. Large-scale atomic models of freely diffusing multilayer smectite particles at low hydration confined in a silicalite cage are used to investigate water dynamics in the composite environment with the ReaxFF reactive force field over a temperature range of 300 647 K. The reactive capability of the force field enabled a range of relevant surface chemistry to emerge, including acid/base equilibria in the interlayer calcium hydrates and silanol formation on the edges of the clay and inner surface of the zeolite housing. After annealing, the resulting clay models exhibit both mono- and bilayer hydration structures. Clay surface hydration redistributed markedly and yielded to silicalite water loading. We find that the absolute rates and temperature dependence of water dynamics compare well to neutron scattering data and pulse field gradient measures from relevant samples of Ca montmorillonite and silicalite, respectively. Within an atomistic, reactive context, our results distinguish water dynamics in the interlayer Ca(OH)(2).nH(2)O environment from water flowing over the clay surface, and from water diffusing within silicalite. We find that the diffusion of water when complexed to Ca hydrates is considerably slower than freely diffusing water over the clay surface, and the reduced mobility is well described by a difference in the Arrhenius pre-exponential factor rather than a change in activation energy. PMID- 22233239 TI - Ferric Iron and Cobalt (III) compounds to safely decrease hydrogen sulfide in the body? AB - To sort out the putative roles of endogenous hydrogen sulfide (H2S) in clinical conditions wherein systemic inflammation or hypoxia is present, it becomes crucial to develop approaches capable of affecting H2S concentration that can be safely applied in humans. We have investigated a paradigm, which could achieve such a goal, using vitamin B12 (vit.B12), at the dose recommended in cyanide poisoning, and very low levels of methemoglobin (MetHb). Hydroxocobalamin in the plasma, supernatant of kidney, and heart tissue homogenates of rats that had received vit.B12 (140 mg.kg(-1) intravenous) was found in the MUM range. Exogenous H2S (100 MUM) added to the plasma or supernatants of these rats decreased at a significantly higher rate than in control rats. In the latter however a spontaneous oxidation of exogenous H2S occurred. In vitro, hydroxocobalamin solution (100 MUM) decreased, within <2 min, an equimolar concentration of H2S by 80%. Three to five percent MetHb prevented H2S induced hyperventilation in vivo and decreased exogenous H2S in vitro by 25-40 MUM within 30 s. Our observations lead to the hypothesis that innocuous levels of MetHb and vit.B12 could be a used as an effective and safe way to test the role of endogenous H2S in vivo. PMID- 22233240 TI - Editorial: JCCAP: past, present, and future. PMID- 22233238 TI - cAMP and Epac in the regulation of tissue fibrosis. AB - Fibrosis, the result of excess deposition of extracellular matrix (ECM), in particular collagen, leads to scarring and loss of function in tissues that include the heart, lung, kidney and liver. The second messenger cAMP can inhibit the formation and extent of ECM during this late phase of inflammation, but the mechanisms for these actions of cAMP and of agents that elevate tissue cAMP levels are not well understood. In this article, we review the fibrotic process and focus on two recently recognized aspects of actions of cAMP and its effector Epac (Exchange protein activated by cAMP): (a) blunting of epithelial-mesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-beta, angiotensin II), which may promote tissue fibrosis by decreasing Epac-mediated antifibrotic actions. Pharmacological approaches that raise cAMP or blunt the decrease in Epac expression by profibrotic agents may thus be strategies to block or perhaps reverse tissue fibrosis. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2. PMID- 22233241 TI - Impact of posttraumatic stress disorder and injury severity on recovery in children with traumatic brain injury. AB - The adverse impact on recovery of posttraumatic stress disorder (PTSD) in mild traumatic brain injury (TBI) has been demonstrated in returned veterans. The study assessed this effect in children's health outcomes following TBI and extended previous work by including a full range of TBI severity, and improved assessment of PTSD within a longitudinal design. There were 205 children and adolescents (6 to 15 years of age) who experienced a TBI that were assessed at 2, 3, 6, 12, and 18 months following the TBI. Severity of TBI was classified as mild, moderate, or severe. After controlling for the impact of the severity of TBI, premorbid behavioral and emotional problems and executive function, children with TBI and PTSD did not experience as much psychosocial recovery as those without PTSD. Furthermore the level of psychosocial function was no better than that experienced by children with a severe TBI. In contrast, severe TBI was predictive of a poorer physical recovery in the first 6 months, after which recovery was equivalent across all severity levels. PMID- 22233242 TI - Stability of posttraumatic stress reaction factors and their relation to general mental health problems in children: a longitudinal study. AB - The aim of this study was to evaluate the structure of posttraumatic stress reaction factors and their relation to general mental health problems in Norwegian children exposed to the tsunami on December 26, 2004. A total of 133 children and adolescents (ages 6-17) were interviewed 10 months posttsunami using the UCLA PTSD Reaction Index, and 104 were interviewed again 2.5 years after the tsunami. Confirmatory factor analyses supported the theory of a four-factor model of intrusion, active avoidance, numbing, and arousal as a better division of symptoms than the three-factor model used in the present diagnostic criteria. The factors of intrusion and active avoidance were highly correlated 2.5 years posttsunami. This association may be due to nonspecificity in these trauma related factors as posttraumatic stress reaction levels diminish over time. General mental health problems were highly related to arousal at both assessments, supporting the theory that some symptoms of posttraumatic stress reactions overlap with other, concurrent mental problems. PMID- 22233243 TI - Randomized trial comparison of emotion regulation and relational psychotherapies for PTSD with girls involved in delinquency. AB - Posttraumatic stress disorder (PTSD) is prevalent in youth involved in delinquency, but it is often not effectively treated. A randomized clinical trial was conducted comparing the outcomes of an emotion regulation therapy (Trauma Affect Regulation: Guide for Education and Therapy, or TARGET) with a relational supportive therapy (Enhanced Treatment as Usual, or ETAU) with 59 delinquent girls (age 13-17 years) who met criteria for full or partial PTSD. Mixed model regression analyses demonstrated generally large effects for pre-post change in PTSD symptoms for both therapies but not in emotion regulation. Both therapies had small to medium effect size changes in anxiety, anger, depression, and posttraumatic cognitions. Treatment * Time interactions showed small to medium effects favoring TARGET for change in PTSD (intrusive reexperiencing and avoidance) and anxiety symptoms, posttraumatic cognitions, and emotion regulation, and favoring ETAU for change in hope and anger. Results provide preliminary support for TARGET as a potentially efficacious therapy for PTSD with delinquent girls. Relational therapies such as ETAU also may be beneficial for delinquent girls with PTSD, particularly to enhance optimism and self-efficacy and reduce anger. PMID- 22233244 TI - Maternal jail time, conviction, and arrest as predictors of children's 15-year antisocial outcomes in the context of a nurse home visiting program. AB - Data from the Nurse-Family Partnership intervention program were analyzed to compare the "selection" versus "unique" effects of maternal jail time on adolescent antisocial and health risk outcomes. Data from 320 women and their firstborn children were available from the prenatal, birth, and 15-year assessments. Consistent with a selection perspective, prenatal and demographic risks directly and indirectly related to many adolescent antisocial outcomes. Maternal conviction and arrest were also associated with adolescent contact with the criminal justice system and health risk behaviors. Maternal jail time predicted whether or not children had ever been stopped by police, sent to youth corrections, or run away from home. However, these associations were not significant after controlling for prenatal risk factors and maternal conviction and arrest. The results highlight the importance of maternal criminality and other risk factors in children's environments, including prenatal variables. PMID- 22233246 TI - A sequential analysis of parent-child interactions in anxious and nonanxious families. AB - Although theoretical work has suggested that reciprocal behavior patterns between parent and child may be important in the development of childhood anxiety, most empirical work has failed to consider the bidirectional nature of interactions. The current study sought to address this limitation by utilizing a sequential approach to exploring parent-child interactions. Participants included 161 children (ages 3-12 years) and their parents. Parent and child dyads were classified into four categories: anxious parent-anxious child (n = 45), anxious parent-nonanxious child (n = 45), nonanxious parent-anxious child (n = 21), and nonanxious parent-nonanxious child (n = 50). Parent and child behaviors were coded from two 10-min interactions. Results indicated that anxious parents of children with anxiety disorders were more likely to respond with negative behaviors, which their child then mirrored. Nonanxious parents of nonanxious children responded with more warmth, which was then mirrored by their child. These results provide evidence for differential patterns of behaviors between anxious and nonanxious parents and children following critical moments in their interactions. PMID- 22233245 TI - Coaction of stress and serotonin transporter genotype in predicting aggression at the transition to adulthood. AB - Despite consistent evidence that serotonin functioning affects stress reactivity and vulnerability to aggression, research on serotonin gene-stress interactions (G * E) in the development of aggression remains limited. The present study investigated variation in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress-aggression association at the transition to adulthood. Multiple informants and multiple measures were used to assess aggression in a cohort of 381 Australian youth (61% female, 93% Caucasian) interviewed at ages 15 and 20. At age 20, semistructured interviews assessed acute and chronic stressors occurring in the past 12 months. Structural equation modeling analyses revealed a significant main effect of chronic stress, but not 5 HTTLPR or acute stress, on increases in aggression at age 20. Consistent with G * E hypotheses, 5-HTTLPR short allele carriers demonstrated greater increments in aggression following chronic stress relative to long allele homozygotes. The strength of chronic stress G * E did not vary according to sex. Variation at 5 HTTLPR appears to contribute to individual differences in aggressive reactions to chronic stress at the transition to adulthood. PMID- 22233247 TI - Diagnostic efficiency of the child and parent versions of the Multidimensional Anxiety Scale for Children. AB - The objective of this study is to evaluate the psychometrics and clinical efficiency of the Multidimensional Anxiety Scale for Children (MASC), which measures physical symptoms, harm avoidance, social anxiety, and separation/panic. Using a sample of 190 treatment-seeking Norwegian youth (aged 7-13 years, M (age) = 10.3 years, 62.1% male), the internal stability and ability to predict to disorder were examined for child, mother, and father reports on the MASC. Moderate to strong internal reliability was exhibited across all MASC subscales. Parent-child agreement was low, but mother-father agreement was high. MASC scores successfully distinguished between children with and without anxiety disorders and identified youth with separation anxiety disorder and social phobia, but less accurately generalized anxiety disorders. The MASC has favorable psychometric properties and is a useful screening instrument for identifying youth with anxiety disorders. PMID- 22233248 TI - Does social anxiety predict rumination and co-rumination among adolescents? AB - Social anxiety in adolescence is manifested by anxiety about and avoidance of social interactions. The present study examined whether social anxiety predicts higher levels of both rumination and co-rumination over time. Rumination and co rumination were studied as possible outcomes because the cognitive content of these processes often involves interpersonal concerns. A three-wave longitudinal study of 575 adolescents (aged 13-16 years old) was conducted over 6 months. Adolescent girls reported higher levels of social anxiety, rumination, and co rumination than boys. Structural equation modelling analysis showed that social anxiety directly predicted higher levels of rumination and indirectly predicted higher levels of co-rumination over time. A gender difference was noted in that these relationships were more robust for girls than for boys. PMID- 22233249 TI - Biased perception and interpretation of bodily anxiety symptoms in childhood social anxiety. AB - Cognitive models of social phobia (SP) and empirical evidence in adults suggest that affected individuals overestimate arousal symptoms such as heart rate (HR) during social stress and worry about their visibility in public. To date, little is known about these aspects in childhood social anxiety, an important precursor of the disorder. We assessed perception of--and worry about--HR visibility, actual HR, and subjective anxiety during public speaking in high socially anxious (HSA; n = 20) and low socially anxious (LSA; n = 20) Caucasian children, aged 10 to 12 years. Symptom visibility was manipulated by making a nonveridical HR feedback tone audible only to the participant (private condition, HR sounds via headphone) or to participant and observers (public condition, HR sounds via speakers). Further, we assessed interoceptive accuracy in a heartbeat counting task. As expected, HSA children perceived their HR as higher than LSA children in both private and public conditions despite similar actual HR and comparable interoceptive accuracy. Public feedback led to more worry about HR visibility only in HSA but not in LSA children. Biased perception and interpretation of bodily anxiety symptoms during social stress manifests early in social anxiety and might therefore play a crucial role in the aggravation of social anxiety and the development of SP. We discuss implications for current theory, clinical practice, and prevention. PMID- 22233250 TI - No need to worry: the promising future of child anxiety research. AB - Looking ahead, we review two themes concerning the treatment of youth anxiety: treatment personalization and its dissemination and implementation (DI). Anxious youth can be effectively treated, but not all youth respond, suggesting the need to further adapt, or personalize, interventions for nonresponders. Treatment personalization may benefit from increased knowledge of social phobia, modular and transdiagnostic treatments, and active mechanisms of change. Further, despite the availability of efficacious treatments, they remain underutilized in the community. DI needs to overcome concerns regarding treatment manuals, social and organizational factors, therapist training, and reaching underserved populations. Finally, computer-based programs can facilitate dissemination through both treating anxious youth and training therapists. PMID- 22233251 TI - In vitro sensitization of T cells with DC-associated/delivered HIV constructs can induce a polyfunctional CTL response, memory T-cell response, and virus suppression. AB - The absence of a suitable animal model for HIV infection is one of the major obstacles to the development of a preventive HIV vaccine. Vaccines showing good response in animal studies may fail in human efficacy trials. We have demonstrated DC-mediated in vitro sensitization of autologous T cells against three HIV constructs. The in vitro sensitized T cells were able to demonstrate a polyfunctional T-cell response, as well as central and effector memory T cells, and virus lysis in a virus inhibition assay, three potentially protective responses. However, none of the constructs could induce all three responses. Also there were variations from volunteer to volunteer. These may be due to genetic and other factors. This study provides evidence of an in vitro system that can be used to assess the immune response against a candidate vaccine, and may also provide the opportunity to modify vaccine constructs to achieve the goal of developing an ideal vaccine. PMID- 22233252 TI - Immunogenicity of a bovine herpes virus I peptide expressed in tandem copies in attenuated Salmonella. AB - A live system to release heterologous antigens using an attenuated Salmonella strain was developed. We transformed Salmonella typhimurium LVR03 (S. LVR03) with a recombinant pTECH2 vector encoding 0, 1, 2, and 4 tandem copies of an imunogenic peptide of bovine herpes virus-1 (BoHV-1) glycoprotein D (gD). The system used yielded peptides fused to the non-toxic C fragment of the tetanus toxin (TetC), which has been shown to have adjuvant properties. Inoculation of BALB/c mice with the transformed Salmonella strains gave rise to a mild self limited infection, with primary replication of bacteria occurring in Peyer's patches, even when the bacteria was administered intranasally. Humoral and cellular immune responses directed against the BoHV-1 antigens were evaluated after oral or intranasal administration of the recombinant bacteria. The results showed that the S. LVR03-dimer vaccine induced specific humoral (IgG in serum and IgG(1) and IgA in saliva), and cellular immune responses (lymphoproliferation and lymphokine secretion), against not only the selected peptide and whole gD, but also against BoHV-1, when administered intranasally. This is the first time Salmonella has been used as an expression vector to induce immunity against BoHV 1. This work demonstrates the feasibility of using this antigen-release system and encourages future experimentation with a bovine experimental model. PMID- 22233254 TI - Preliminary microRNA analysis in lung tissue to identify potential therapeutic targets against H5N1 infection. AB - Within the past decade, human infections with the highly pathogenic avian influenza H5N1 have resulted in approximately 60% mortality and increased the need for vaccines and therapeutics. Understanding the molecular events associated with pathology can aid this effort; therefore, this study was conducted to assess microRNA (miRNA) expression in mouse lungs infected with H5N1 A/Vietnam/1203/04. Intranasal administration of 1500 median tissue culture infectious dose of H5N1 promoted differences in the number and expression pattern of miRNA from lung tissue collected at 2, 4, 6, 24, and 96 h post-exposure that mapped to common biological functions. Informatics analysis identified miRNA-specific predicted genes known to be therapeutic drug targets in which Furin was common to all time periods. This study provides insight into the differential miRNA expression with respect to the host-pathogen relationship and identification of potential therapeutic drug targets. PMID- 22233253 TI - Effects on innate immunity of a therapeutic dendritic cell-based vaccine for HIV 1 infection. AB - Changes in natural killer (NK) cells according to their phenotype and expression of certain regulatory receptors were analyzed in a double-blind, controlled study of antiretroviral therapy (ART)-untreated HIV-seropositive patients, who had been vaccinated with monocyte-derived dendritic cells pulsed with inactivated HIV-1 autologous virus. This work extends other recently published studies of the same group of HIV-1(+) vaccinated patients, which demonstrated that the viral load significantly decreases and correlates inversely with an increase in HIV-specific T-cell responses in vaccinated patients, but not in controls who received placebo. Our results indicate that this vaccine raises the level of the NK CD56(neg) cell subpopulation, while levels of the NK CD56(dim) and NK CD56(bright) cells expressing the inhibitory receptor CD85j/ILT-2 fell in vaccinated patients. Taken together, these results suggest that this vaccine might enhance innate immunity by amplifying the inflammatory and cytolytic capacity. PMID- 22233256 TI - Water versus acetonitrile coordination to uranyl. Effect of chloride ligands. AB - Optimizations at the BLYP and B3LYP levels are reported for the mixed uranyl chloro/water/acetonitrile complexes [UO(2)Cl(n)(H(2)O)(x)(MeCN)(5-n-x)](2-n) (n = 1-3) and [UO(2)Cl(n)(H(2)O)(x)(MeCN)(4-n-x)](2-n) (n = 2-4), in both the gas phase and a polarizable continuum modeling acetonitrile. Car-Parrinello molecular dynamics (CPMD) simulations have been performed for [UO(2)Cl(2)(H(2)O)(MeCN)(2)] in the gas phase and in a periodic box of liquid acetonitrile. According to population analyses and dipole moments evaluated from maximally localized Wannier function centers, uranium is less Lewis acidic in the neutral UO(2)Cl(2) than in the UO(2)(2+) moiety. In the gas phase the latter binds acetonitrile ligands more strongly than water, whereas in acetonitrile solution, the trend is reversed due to cooperative polarization effects. In the polarizable continuum the chloro complexes have a slight energetic preference for water over acetonitrile ligands, but several mixed complexes are so close in free energy DeltaG that they should exist in equilibrium, in accord with previous interpretations of EXAFS data in solution. The binding strengths of the fifth neutral ligands decrease with increasing chloride content, to the extent that the trichlorides should be formulated as four-coordinate [UO(2)Cl(3)L](-) (L = H(2)O, MeCN). Limitations to their accuracy notwithstanding, density functional calculations can offer insights into the speciation of a complex uranyl system in solution, a key feature in the context of nuclear waste partitioning by complexant molecules. PMID- 22233255 TI - Inhibition of viral replication downregulates CD4(+)CD25(high) regulatory T cells and programmed death-ligand 1 in chronic hepatitis B. AB - Chronic hepatitis B is characterized by an impaired immune response to hepatitis B virus (HBV). Telbivudine treatment has significantly improved the clinical outcome of chronic HBV infection. However, the underlying mechanism behind the antiviral response of patients treated with nucleoside analogs remains unclear. To gather more evidence about the mechanism responsible for the weak immune response, in this study we analyzed the effects on HBV viral load of treatment with the nucleoside analogue telbivudine and the percentage of Tregs, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, and related cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum of 28 patients with chronic hepatitis B were collected at baseline, and 3 mo and 6 mo after therapy was begun. In parallel with the decline in viral load and serum ALT normalization, we found a decline in circulating CD4(+)CD25(high) Tregs, PD-L1 on CD4(+) T cells, and IL-9 production. The expression of PD-1 on CD4(+) T cells and the production of IFN-gamma did not increase during therapy. Our findings suggest that the antiviral effect of the nucleoside analogs may be attributable not only to their direct effect on virus suppression, but also to their immunoregulatory capabilities. PMID- 22233257 TI - A retrospective analysis comparing the safety and efficacy of chemotherapy in elderly and non-elderly non-small-cell lung cancer patients. AB - AIM: The number of elderly patients with non-small-cell lung cancer (NSCLC) is increasing in Japan. We retrospectively analyzed and compared the safety and efficacy of chemotherapy in elderly and non-elderly NSCLC patients who received chemotherapy at Shimane University Hospital. METHODS: We carried out a retrospective analysis of survival in a series of 112 NSCLC patients treated from 2004 through 2009. We compared the data from the elderly group (>= 70 years-of age, 56 patients) with the non-elderly group (< 70 years-of-age, 56 patients) who had similar characteristics, such as sex and Eastern Cooperative Oncology Group performance status. We analyzed the patient characteristics, therapeutic regimen, dose intensity, toxicity and survival time in both groups. RESULTS: The patient characteristics were comparable between the two groups; however, there was a significant difference between the choice of first-line therapeutic regimen. A platinum-doublet regimen was more frequently used in the non-elderly population (39.3% vs 64.3% for the elderly patients vs the non-elderly patients, respectively; P < 0.01), whereas single agents and epidermal growth factor receptor-tyrosine kinase inhibitors were more frequent in the elderly population (26.8% vs 10.7%, 19.6% vs 7.1%; P < 0.05, respectively). The relative dose intensity was approximately 80% or higher for all regimens, and toxicity was acceptable. The median survival time was 24.4 months and 18.6 months in the elderly and non-elderly groups, respectively. CONCLUSION: This retrospective study suggests that elderly patients can safely receive effective chemotherapy similar to non-elderly patients under careful observation and management. PMID- 22233259 TI - Rotational diffusion of neutral and charged solutes in 1-butyl-3 methylimidazolium-based ionic liquids: influence of the nature of the anion on solute rotation. AB - Temperature-dependent fluorescence anisotropies of two organic solutes, 2,5 dimethyl-1,4-dioxo-3,6-diphenylpyrrolo[3,4-c]pyrrole (DMDPP) and rhodamine 110 (R110), have been measured in 1-butyl-3-methylimidazolium ([bmim(+)])-based ionic liquids containing the anions hexafluorophosphate ([PF(6)(-)]), bis(trifluoromethylsulfonyl)imide ([Tf(2)N(-)]), tetrafluoroborate ([BF(4)(-)]), trifluoromethanesulfonate ([TfO(-)]), and nitrate ([NO(3)(-)]). This data has been used in conjunction with the recently published results (Dutt, G. B. J. Phys. Chem. B2010, 114, 8971) for the same solutes in [bmim(+)] tris(pentafluoroethyl)trifluorophosphate ([FAP(-)]) to understand the influence of various anions on solute rotation. The boundary condition parameter C(obs), which has been obtained from the analysis of the data using Stokes-Einstein-Debye hydrodynamic theory, for the neutral solute DMDPP is more or less the same in all the ionic liquids. Moreover, C(obs) values are close to the predictions of slip boundary condition, which indicates that solvent viscosity alone governs the rotation of DMDPP. In contrast, for R110, which experiences specific interactions with the anions of the ionic liquids, the C(obs) values are close to stick hydrodynamics. It has also been noticed that the C(obs) values vary with the nature of the anion and this variation correlates with the hydrogen bond basicities of the anions of the ionic liquids. PMID- 22233258 TI - If herpes does not heal...change strategy! PMID- 22233260 TI - A proof of principle for using adaptive testing in Routine Outcome Monitoring: the efficiency of the Mood and Anxiety Symptoms Questionnaire -Anhedonic Depression CAT. AB - BACKGROUND: In Routine Outcome Monitoring (ROM) there is a high demand for short assessments. Computerized Adaptive Testing (CAT) is a promising method for efficient assessment. In this article, the efficiency of a CAT version of the Mood and Anxiety Symptom Questionnaire, - Anhedonic Depression scale (MASQ-AD) for use in ROM was scrutinized in a simulation study. METHODS: The responses of a large sample of patients (N = 3,597) obtained through ROM were used. The psychometric evaluation showed that the items met the requirements for CAT. In the simulations, CATs with several measurement precision requirements were run on the item responses as if they had been collected adaptively. RESULTS: CATs employing only a small number of items gave results which, both in terms of depression measurement and criterion validity, were only marginally different from the results of a full MASQ-AD assessment. CONCLUSIONS: It was concluded that CAT improved the efficiency of the MASQ-AD questionnaire very much. The strengths and limitations of the application of CAT in ROM are discussed. PMID- 22233262 TI - Do nurses and social workers have different values? An exploratory study of the care for older people. AB - This study explored the different values of staff from two care homes for older people in which the managers had different qualifications (social worker vs. nursing). Their views were examined to explore whether the values of the staff might reflect any value difference originating in the professional backgrounds of the managers. There was little evidence of awareness in either home of the ethical principles underlying day-to-day decisions. However, a distinction based on care qualification did appear with "care-qualified" staff (defined in terms of qualification requirements for this care work) demonstrating a more reflective response and fewer ageist assumptions than their non-care-qualified colleagues. The study found no difference in values between the nursing and social worker-led homes. All respondents, regardless of the profession of their manager, were keenly aware that they have a "duty of care" and overwhelmingly they defined that as their duty to keep the resident safe, as opposed to allowing her to exercise autonomy. The study results suggest that value base constitutes a commonality between professions involved in the care of older people rather than a barrier to collaboration, as is sometimes posited. PMID- 22233261 TI - Peripheral natural killer cells exhibit qualitative and quantitative changes in patients with psoriasis and atopic dermatitis. AB - BACKGROUND: Psoriasis and atopic dermatitis are the most recurrent skin inflammatory disorders. Despite their distinct aetiology and clinical aspects, these diseases share several immunological features. Besides the largely documented role of T cells, emerging literature supports a potential involvement of innate immune effectors, the natural killer (NK) cells, in both pathologies. In the peripheral blood, NK cells consist of CD3-CD56dim and CD3-CD56bright cell subsets, harbouring a distinct cell surface phenotype, but both endowed with the main NK-cell effector functions: cytotoxicity and cytokine production. OBJECTIVES: To determine whether the frequency, the cell surface phenotype and the functional properties of peripheral NK cells were affected in patients with psoriasis or atopic dermatitis. METHODS: Peripheral blood mononuclear cells were isolated from 11 patients with psoriasis, nine patients with atopic dermatitis and 16 healthy individuals. By using flow cytometry, we analysed the following parameters of peripheral NK cells: the frequency, the cell surface expression of several NK-cell receptors (NKR) and the activation of the effector functions upon various in vitro stimuli. RESULTS: Peripheral NK cells were significantly reduced in both skin diseases. The cell surface expression of various NKR was differently modified in peripheral NK cells of the two cohorts of patients. Finally, NK-cell natural cytotoxicity was affected only in atopic dermatitis, while interferon gamma production was defective in both groups of patients. CONCLUSION: Psoriasis and atopic dermatitis are associated with quantitative and qualitative changes of peripheral NK cells, mostly shared by both diseases, supporting a common process implicating these innate effectors in skin inflammation. PMID- 22233263 TI - Modeling and analysis of electrorheological suspensions in shear flow. AB - A model capable of describing the flow behavior of electrorheological (ER) suspensions under different electric field strengths and over the full range of shear rates is proposed. Structural reformation in the low shear rate region is investigated where parts of a material are in an undeformed state, while aligned structures reform under the shear force. The model's predictions were compared with the experimental data of some ER fluids as well as the CCJ (Cho-Choi-Jhon) model. This simple model's predictions of suspension flow behavior with subsequent aligned structure reformation agreed well with the experimental data, both quantitatively and qualitatively. The proposed model plausibly predicted the static yield stress, whereas the CCJ model and the Bingham model predicted only the dynamic yield stress. The master curve describing the apparent viscosity was obtained by appropriate scaling both axes, which showed that a combination of dimensional analysis and flow curve analysis using the proposed model yielded a quantitatively and qualitatively precise description of ER fluid rheological behavior based on relatively few experimental measurements. PMID- 22233264 TI - Tear osmolarity in unilateral pseudoexfoliation syndrome. AB - PURPOSE: The aim was to evaluate tear osmolarity of patients with clinically unilateral pseudoexfoliation (PEX) syndrome and to compare the values with otherwise normal subjects. METHODS: Sixty-two eyes of 31 patients with unilateral PEX syndrome and 31 eyes of 31 normal subjects were studied. The TearLab osmolarity system (OcuSense, Inc, San Diego, CA, USA) was used to measure tear osmolarity. Eyes were grouped as normal eyes of patients having unilateral PEX syndrome (group A), eyes of patients having unilateral PEX syndrome with deposits of PEX material (group B) and eyes of normal subjects (group C). Differences in tear osmolarity were compared among groups A, B and C. Independent t-tests and paired t-tests were used for statistical analysis. RESULTS: The mean tear osmolarity was 298.7 +/- 7.8 mOsm/l (range 285 to 306) in the control group (group C), 306.3 +/- 6.6 mOsm/l (range 290 to 314) in the eyes of patients having PEX syndrome with deposits of pseudoexfoliative material (group B) and 301.4 +/- 7.1 mOsm/l (range 284 to 305) in the fellow eye of these patients (group A). There was a significant difference between tear osmolarity of groups C and B (independent t-test, p = 0.011). Also, there was a significant difference between the osmolarity of each eye of patients with unilateral PEX syndrome (groups A and B) (paired t-test, p = 0.001). The difference between tear osmolarity of groups A and C was not statistically significant (independent t-test, p = 0.146). CONCLUSION: In conclusion, tear osmolarity is higher in both eyes of patients when compared with normal subjects, using the independent t-test (although highest in clinically positive eyes of these patients). Both eyes of patients having PEX syndrome could be more prone to the development of dry eye syndrome. PMID- 22233265 TI - Comparative study of cone beam computed tomography and intraoral periapical radiographs in diagnosis of lingual-simulated external root resorptions. AB - BACKGROUND: Owing to a lack of symptoms and difficult visualization in routine intraoral radiographs, diagnosis of external root resorptions can be challenging. AIM: The goal of this study was to compare two image acquisition methods, intraoral radiographs and cone beam computed tomography (CBCT), in the diagnosis of external resorption. MATERIAL AND METHODS: Thirty-four maxillary and mandibular bicuspids were divided into three groups. Perforations measuring 0.3 and 0.6 mm in diameter and 0.15 and 0.3 mm in depth, respectively, were made on the lingual root surfaces in thirty teeth, and four were used as controls. Next, teeth were mounted on an apparatus and radiographed at mesial, distal, and orthoradial angulations. CBCT images were also taken. The analysis of the intraoral radiographic and tomographic images was carried out by two experts using standardized scores. Data were then compared statistically. RESULTS: A strong agreement between the examiners was observed in both diagnosis methods, the intraoral radiographic (r = 0.93) and the tomographic analysis (r = 1.0). Tomography had higher statistically significant detection values than intraoral radiography (P < 0.05). In intraoral radiographs, the detection was significantly greater (P < 0.05) in the mandibular bicuspids, compared with their maxillary counterparts. The ability to detect 0.6-mm perforations by intraoral radiography was significantly higher than that of 0.3-mm perforations (P < 0.05). CONCLUSION: Cone beam computed tomography showed better diagnostic ability compared with intraoral radiography, regardless of the tooth or the dimensions of the resorption evaluated. PMID- 22233266 TI - Collection and storage of red blood cells with anticoagulant and additive solution with a physiologic pH. AB - BACKGROUND: A donation of whole blood is most commonly collected in acidic citrate-phosphate-dextrose (CPD) variants with pH 5.2 to 6.2 as anticoagulants. Previously, we have shown that the initial pH after red blood cell (RBC) preparation can have an effect on RBCs during storage. First, we investigated the effect of the pH of the anticoagulant on RBCs. Second, we investigated the possibility of decreasing the pH of our new additive solution (AS) phosphate adenine-glucose-guanosine-gluconate-mannitol (PAGGGM) from pH 8.2 to 7.4 in combination with an anticoagulant with a physiologic pH. STUDY DESIGN AND METHODS: Whole blood was collected in CPD (pH 5.6) or trisodiumcitrate (TNC; pH 7.4), and leukoreduced units were prepared using saline-adenine-glucose-mannitol as AS. Second, whole blood was collected in TNC (pH 7.4), and leukoreduced units were prepared using PAGGGM (pH 7.4) or PAGGGM (pH 8.2) as AS. During cold storage, several in vitro characteristics were analyzed. RESULTS: In agreement with our previous findings, the initial pH of whole blood has an effect during storage of RBCs. In the second part we show that there are no differences between PAGGGM (pH 7.4) and PAGGGM (pH 8.2) units when an anticoagulant with a physiologic pH was used. CONCLUSION: These results indicate that the pH of the anticoagulant used during whole blood collection has an effect during storage of RBCs. When an anticoagulant with a physiologic pH is used during whole blood collection, the pH of PAGGGM can be decreased to physiologic levels, while maintaining adenosine triphosphate and 2,3-diphosphoglycerate levels. PMID- 22233267 TI - Species and susceptibility distribution of 1062 clinical yeast isolates to azoles, echinocandins, flucytosine and amphotericin B from a multi-centre study. AB - Descriptive values were determined for eight antifungal agents within the course of a multi-centre study encompassing 1062 German and Austrian clinical yeast isolates. Candida albicans (54%) was the predominant species isolated followed by Candida glabrata (22%), Candida parapsilosis (6%), Candida tropicalis (5.7%), Candida krusei (4.3%), as well as eleven further candidal and four non-Candida yeast species. While 519 (48.9%) isolates were tested susceptible to all antifungals tested, no isolate was found to exhibit complete cross resistance. For C. albicans, the proportions of susceptible isolates were 93.2% (amphotericin B), 95.6% (flucytosine), 84.3% (fluconazole), 83.8% (posaconazole), 91.8% (voriconazole), 96.5% (anidulafungin), 96.2% (caspofungin) and 97.6% (micafungin). Patterns of complete parallel resistances were observed within azoles (8.8%) and echinocandins (1.7%). While a decreased susceptibility was found infrequently for echinocandins and flucytosine, it was more common for azoles with highest proportions for isolates of C. glabrata (fluconazole, 40.6%; posaconazole, 37.2%), Candida guilliermondii (fluconazole and posaconazole, each 25.0%), C. krusei (posaconazole, 28.3%; voriconazole, 60%), C. parapsilosis (fluconazole, 70.3%) and C. tropicalis (fluconazole, 62.3%). The descriptive values obtained in this study represent a valid basis for the comparison of recent and future epidemiological surveys to analyse the susceptibility of yeast isolates towards major antifungal substances. PMID- 22233268 TI - PCA: prostate cancer, patient-centred approach or both? AB - What's known on the subject? and What does the study add? Several studies have explored patient-specific expectations of prostate cancer management, while others have investigated physicians' perceptions. However, the opinions of both groups have seldom been compared in one study. Therefore, the present study compares the results of two surveys, one among physicians and one among patients, on patient-physician communication and patients' expectations of prostate cancer management. The present review aims to highlight the differences and similarities in opinion on prostate cancer management between physicians and patients. It reflects the most important results of two surveys on patient-specific expectations in prostate cancer management, done among European prostate cancer specialists and patients with prostate cancer. These results are compared with published data. In addition, the authors' opinion on the survey results and on optimal prostate cancer management is included. To evaluate differences and similarities in opinions on and expectations of prostate cancer management between physicians and patients. Two surveys on patient-specific opinions and expectations in prostate cancer management were done in 2011 among European prostate cancer specialists and patients with prostate cancer. Survey results were complemented with existing published data and with the authors' opinion. Most specialists spent 15-29 min on delivering the diagnosis, and about the same amount of time on explaining treatment options. This time was considered insufficient by 35% and 48% of patients, respectively. There was a large discrepancy between physicians' and patients' opinions about the type of provided prognostic and therapeutic information, indicating that patients may not have completely understood this information. Shared decision-making was preferred by both patients and specialists. Treatment efficacy was the most important factor determining treatment choice for both groups, while the physician's opinion or experience also had a great impact on patients' treatment choice. Patient-support groups have an important role in providing relevant information and in exchanging experiences between patients. The supportive role of partners/relatives was more appreciated when discussing treatment options than during diagnosis. Although patients' expectations are generally matched by their caring physician(s), physicians can still improve quality of care by taking adequate time for their patients, by using terminology that is easily understood by patients and by encouraging shared decision-making. A multidisciplinary team may be an important part of the treatment paradigm, with the individual patient's needs and preferences as the centre of care. PMID- 22233270 TI - Rh(I)-catalyzed asymmetric 1,2-addition to alpha-diketones with chiral sulfur alkene hybrid ligands. AB - This paper describes a Rh(I)-catalyzed highly efficient and enantioselective 1,2 addition of arylboronic acids to alpha-diketones with the use of a simple sulfur alkene hybrid ligand. With as low as a 0.1 mol % catalyst loading, a variety of optically active alpha-hydroxyketones can be furnished in high yields with excellent ee's. PMID- 22233269 TI - Fatigue, sleep, and nocturnal complaints in patients with amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Although sleep disturbances are a candidate factor that may interfere with fatigue in patients with ALS, the role of sleep-related abnormalities in determining fatigue in ALS is unknown. OBJECTIVE: To evaluate the frequency and determinants of fatigue in a group of 91 consecutive patients with ALS, with special attention to the relationship between fatigue and sleep problems. METHODS: Measures included the Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating Scale-Revised (ALSFRS-R), and Beck Depression Inventory (BDI). RESULTS: The mean FSS score was 4.35 +/- 1.1, and 48 patients with ALS (52.75%) reported clinical significant fatigue. FSS score correlated with ALSFRS-R score, forced vital capacity, ESS, BDI, and global PSQI score. Patients with fatigue were significantly more disabled and more frequently reported difficulties staying asleep and nocturnal complaints, such as nocturia and disturbing muscle cramps. After multivariate analysis, patients' disability and nocturnal complaints were significantly associated with fatigue. CONCLUSION: In this study, we demonstrated that fatigue, a troublesome and disabling symptom in ALS, is associated with physical impairment and night-time complaints (such as nocturia and muscle cramps), suggesting that treating sleep problems might be useful in alleviating fatigue in these patients. PMID- 22233271 TI - Self-propelled nanotools. AB - We describe nanoscale tools in the form of autonomous and remotely guided catalytically self-propelled InGaAs/GaAs/(Cr)Pt tubes. These rolled-up tubes with diameters in the range of 280-600 nm move in hydrogen peroxide solutions with speeds as high as 180 MUm s(-1). The effective transfer of chemical energy to translational motion has allowed these tubes to perform useful tasks such as transport of cargo. Furthermore, we observed that, while cylindrically rolled-up tubes move in a straight line, asymmetrically rolled-up tubes move in a corkscrew like trajectory, allowing these tubes to drill and embed themselves into biomaterials. Our observations suggest that shape and asymmetry can be utilized to direct the motion of catalytic nanotubes and enable mechanized functions at the nanoscale. PMID- 22233272 TI - Bleeding risk and safety profile related to the use of eptifibatide: a current review. AB - INTRODUCTION: Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks the final common pathway of platelet aggregation. Its major adverse effect is bleeding. Balancing its safety and efficacy is paramount for its appropriate usage. AREAS COVERED: The development of eptifibatide and its mechanism of action are explored. Clinical trials evaluating its efficacy and safety in a variety of clinical settings, as well as newer dosing regimens, are discussed. Readers will be able to understand the bleeding risks of eptifibatide in specific patient populations. EXPERT OPINION: The risk of bleeding with eptifibatide needs to be weighed against the potential benefits. Understanding which patients are at higher risk of bleeding will help the clinician make appropriate decisions. PMID- 22233273 TI - Near infrared photochemistry of pyruvic acid in aqueous solution. AB - Recent experimental and theoretical results have suggested that organic acids such as pyruvic acid, can be photolyzed in the ground electronic state by the excitation of the OH stretch vibrational overtone. These overtones absorb in the near-infrared and visible regions of the spectrum where the solar photons are plentiful and could provide a reaction pathway for the organic acids and alcohols that are abundant in the earth's atmosphere. In this paper the overtone initiated photochemistry of aqueous pyruvic acid is investigated by monitoring the evolution of carbon dioxide. In these experiments CO(2) is being produced by excitation in the near-infrared, between 850 nm and ~1150 nm (11,765-8696 cm( 1)), where the second OH vibrational overtone (Deltanu = 3) of pyruvic acid is expected to absorb. These findings show not only that the overtone initiated photochemical decarboxylation reaction occurs but also that in the aqueous phase it occurs at a lower energy than was predicted for the overtone initiated reaction of pyruvic acid in the gas phase (13,380 cm(-1)). A quantum yield of (3.5 +/- 1.0) * 10(-4) is estimated, suggesting that although this process does occur, it does so with a very low efficiency. PMID- 22233274 TI - A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo. AB - BACKGROUND AND PURPOSE: We have tested the hypothesis that calcitonin gene related peptide (CGRP) is a mediator of capsaicin-induced angiogenesis in vivo. EXPERIMENTAL APPROACH: In a series of experiments, the knee joints of rats were injected with CGRP, capsaicin or vehicle control. Groups of animals (n=6) were treated with the CGRP receptor antagonist BIBN4096BS and/or the NK1 receptor antagonist SR140333. Endothelium, proliferating endothelial cell nuclei and macrophages were identified 24 h later in the synovium by immunohistochemistry and quantified by image analysis. mRNA for the receptors for CGRP and adrenomedullin were sought in normal and inflamed rat and human synovia using RT PCR. KEY RESULTS: Intra-articular CGRP injection increased the endothelial cell proliferation index, whereas macrophage infiltration and knee joint diameters were similar to saline-injected controls. CGRP-induced endothelial cell proliferation was dose-dependently inhibited by BIBN4096BS. mRNA for adrenomedullin and the CGRP receptor subunits were detected in normal and inflamed human and rat synovia. In capsaicin-induced synovitis, the increased endothelial cell proliferation index was partially blocked by administration of NK1 or CGRP antagonists individually and was reduced to the level of saline controls by coadministration of both receptor antagonists. CONCLUSIONS AND IMPLICATIONS: These data support the hypothesis that CGRP stimulates angiogenesis in vivo directly by activating CGRP receptors. Capsaicin-induced endothelial cell proliferation was completely blocked by coadministration of CGRP and NK1 receptor antagonists, indicating that both CGRP and substance P may contribute to angiogenesis in this model of synovitis. PMID- 22233275 TI - Enhanced intracellular accumulation of a non-nucleoside anti-cancer agent via increased uptake of its valine ester prodrug through amino acid transporters. AB - The phenomenon known as multiple-drug resistance, whereby anti-cancer agents are expelled from cancer cells, makes it necessary to develop methods that will reliably increase the accumulation of anti-cancer agents within cancer cells. To accomplish this goal, a new model compound, Val-SN-38, was synthesized by introducing valine to SN-38, an active ingredient of irinotecan. Val-SN-38 improved intracellular accumulation approximately 5-fold in MCF7 cells, compared with SN-38, and rather than changes in membrane permeability, the amino acid transporter ATB(0,+) played a role, whereas the dipeptide transporter PEPT1 did not. Other sodium-dependent amino acid transporters, namely ATA1, ATA2, and ASCT2, were unexpectedly involved in the uptake of Val-SN-38 as well. The efflux of Val-SN-38 by major efflux transporters was variably changed, but not significantly. In summary, the enhanced accumulation of Val-SN-38 in cancer cells was due to augmented uptake via various amino acid transporters. The results of the present study make a compelling argument in favour of a prodrug concept that can improve intracellular accumulation and take advantage of amino acid transporters without significantly inducing multiple-drug resistance. PMID- 22233277 TI - A novel 26 bp deletion [HBB: c.20_45del26bp] in exon 1 of the beta-globin gene causing beta-thalassemia major. AB - Molecular characterization of beta-thalassemia (beta-thal) is essential in prevention and in understanding the biology of the disease. Deletion mutations are relatively uncommon in beta-thal. In this report, we describe a novel 26 bp deletion from codon 6 to codon 14 in the beta-globin in a consanguineous family from Tamil Nadu, India. This novel mutation causes a shift in the normal reading frame of the beta-globin coding sequence, and consequently, a premature chain termination of translation due to the creation of a stop codon at the position of codon 21. The identification of this novel deletional mutation adds to the repertoire of beta-thal mutations in India. PMID- 22233276 TI - Chlamydia trachomatis hijacks intra-Golgi COG complex-dependent vesicle trafficking pathway. AB - Chlamydia spp. are obligate intracellular bacteria that replicate inside the host cell in a bacterial modified unique compartment called the inclusion. As other intracellular pathogens, chlamydiae exploit host membrane trafficking pathways to prevent lysosomal fusion and to acquire energy and nutrients essential for their survival and replication. The Conserved Oligomeric Golgi (COG) complex is a ubiquitously expressed membrane-associated protein complex that functions in a retrograde intra-Golgi trafficking through associations with coiled-coil tethers, SNAREs, Rabs and COPI proteins. Several COG complex-interacting proteins, including Rab1, Rab6, Rab14 and Syntaxin 6 are implicated in chlamydial development. In this study, we analysed the recruitment of the COG complex and GS15-positive COG complex-dependent vesicles to Chlamydia trachomatis inclusion and their participation in chlamydial growth. Immunofluorescent analysis revealed that both GFP-tagged and endogenous COG complex subunits associated with inclusions in a serovar-independent manner by 8 h post infection and were maintained throughout the entire developmental cycle. Golgi v-SNARE GS15 was associated with inclusions 24 h post infection, but was absent on the mid-cycle (8 h) inclusions, indicating that this Golgi SNARE is directed to inclusions after COG complex recruitment. Silencing of COG8 and GS15 by siRNA significantly decreased infectious yield of chlamydiae. Further, membranous structures likely derived from lysed bacteria were observed inside inclusions by electron microscopy in cells depleted of COG8 or GS15. Our results showed that C. trachomatis hijacks the COG complex to redirect the population of Golgi-derived retrograde vesicles to inclusions. These vesicles likely deliver nutrients that are required for bacterial development and replication. PMID- 22233278 TI - Versatile chemical transformations of benzoxazole based ligands on complexation with 3d-metal ions. AB - Two benzoxazoles derivative ligands were synthesized from the condensation of 3,5 di-tert-butyl-o-benzoquinone (DTBBQ) with ethanolamine or 1,3-diamino-2 hydroxypropane in methanol. Condensation of DTBBQ with ethanolamine gives the expected 5,7-di-tert-butyl-2-methylenhydroxylbenzoxazole (HL1) while with 1,3 diamino-2-hydroxypropane it gives (2-hydroxyethyl-2-{2,4-bis(1,1-dimethylethyl)-1 phenol-6 amino}-2{5,7-di-tert-butyl-benzoxazole}) (H(2)L2) with only one benzoxazole ring instead of the symmetric bis-benzoxazole derivative. The structure of HL1 and H(2)L2 were confirmed by NMR-spectroscopy and X-ray diffraction on a single crystal for HL1. The reaction of HL1 with CuCl(2) gives a mononuclear [Cu(II)(HL1)(2)Cl(2)] (1) complex for which the crystal structure shows that HL1 is preserved. In contrast, upon reaction with nickel(II), cobalt(II), and manganese(II) H(2)L2 is further oxidized and transformed in new ligands HL3 in mononuclear complexes [M(II)(L3)(2)] (M = Ni(II) (2); M = Co(II) (3)) and H(2)L4 in tetranuclear complex [Mn(II)(4)(HL4)(4)Cl(4)] (4) as found from the crystal structures of complexes 2-4. Electrochemical studies for complexes 2 and 3 evidence complicated redox properties. [Mn(II)(4)(HL4)(4)Cl(4)] (4) has a cubane-like structure with a "4 + 2" fashion The magnetic susceptibility of 4 is well fitted considering one Mn---Mn interaction J(a)(Mn(II)-Mn(II)) = -0.50(1) cm(-1) with g = 2.00(7). PMID- 22233280 TI - Recrystallization of water in non-water-soluble (meth)acrylate polymers is not rare and is not devitrification. AB - Change in the state of water sorbed into four kinds of non-water-soluble poly(meth)acrylates with low water content by temperature (T) perturbation was examined on the basis of T variable mid-infrared (MIR) spectroscopy. Many studies using differential scanning calorimetry suggested that there was no change in the state. T dependence of their MIR spectra, however, clearly demonstrated various changes in the state. Furthermore, recrystallization, which was crystallization during heating, was observed in all four polymers. The recrystallization observed in this study was not devitrification, which is the change in the state from glassy water to crystalline water, but vapor deposition during heating (vapor re deposition). There were only two reports about recrystallization of water in a non-water-soluble polymer before this report; therefore, it might be considered to be a rare phenomenon. However, as demonstrated in this study, it is not a rare phenomenon. Recrystallization (vapor re-deposition) of water in the polymer matrices is related to a balance between flexibility and strength of the electrostatic interaction sites of polymer matrices but might not be related to the biocompatibility of polymers. PMID- 22233279 TI - Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: an observational study. AB - BACKGROUND: The evaluation of patients with abdominal discomfort is challenging and patient selection for endoscopy based on symptoms is not reliable. We evaluated the diagnostic value of fecal calprotectin in patients with abdominal discomfort. METHODS: In an observational study, 575 consecutive patients with abdominal discomfort referred for endoscopy to the Department of Gastroenterology & Hepatology at the University Hospital Basel in Switzerland, were enrolled in the study. Calprotectin was measured in stool samples collected within 24 hours before the investigation using an enzyme-linked immunosorbent assay. The presence of a clinically significant finding in the gastrointestinal tract was the primary endpoint of the study. Final diagnoses were adjudicated blinded to calprotectin values. RESULTS: Median calprotectin levels were higher in patients with significant findings (N = 212, median 97 MUg/g, IQR 43-185) than in patients without (N = 326, 10 MUg/g, IQR 10-23, P < 0.001). The area under the receiver operating characteristics curve (AUC) to identify a significant finding was 0.877 (95% CI, 0.85-0.90). Using 50 MUg/g as cut off yielded a sensitivity of 73% and a specificity of 93% with good positive and negative likelihood ratios (10.8 and 0.29, respectively). Fecal calprotectin was useful as a diagnostic parameter both for findings in the upper intestinal tract (AUC 0.730, 0.66-0.79) and for the colon (AUC 0.912, 0.88-0.94) with higher diagnostic precision for the latter (P < 0.001). In patients > 50 years, the diagnostic precision remained unchanged (AUC 0.889 vs. 0.832, P = 0.165). CONCLUSION: In patients with abdominal discomfort, fecal calprotectin is a useful non-invasive marker to identify clinically significant findings of the gastrointestinal tract, irrespective of age. PMID- 22233281 TI - Doxorubicin-conjugated PEGylated dendrimers show similar tumoricidal activity but lower systemic toxicity when compared to PEGylated liposome and solution formulations in mouse and rat tumor models. AB - PEGylated polylysine dendrimers show promise as novel drug delivery systems with the potential to direct site specific deposition patterns and to reduce toxicity at nontarget sites. Here the activity and toxicity profiles of a generation 5 polylysine dendrimer with 50% surface conjugation of PEG1100 and 50% surface conjugation of doxorubicin (via an acid labile 4-hydrazinosulfonyl benzoic acid linker) have been compared in a Walker 256 rat tumor model and a human MDA-MB231 xenograft in mice. A direct comparison was also made to a PEGylated liposomal formulation of doxorubicin and a doxorubicin solution. In both rat and mouse breast cancer models, the dendrimer formulation gave equivalent antitumor efficacy when compared to the liposomal or solution doxorubicin formulations and administration of all three doxorubicin formulations resulted in a significant reduction (>75%) in tumor growth in both models at doses ranging from 2 to 10 mg/kg doxorubicin equivalents. The dendrimer formulation, however, was better tolerated by both rats and mice, and approximately 2-fold higher doses were required to induce similar levels of toxicity (as assessed by organ weight, peripheral white cell counts, body weight and survival curves) when compared to administration of the doxorubicin solution or PEGylated liposomal doxorubicin. In rats the appearance of palmar plantar erythematosis (PPE), or hand foot syndrome, was also less evident after administration of dendrimer doxorubicin when compared to the liposome. Finally, even after administration to mice at 2-fold higher doses, dendrimer-doxorubicin resulted in a reduced incidence of cardiotoxicity when compared with a simple solution formulation of doxorubicin. The data suggest that dendrimer-based doxorubicin formulations may provide advantage over solution and liposomal formulations of doxorubicin via a reduction in systemic toxicity. PMID- 22233282 TI - Cytotoxicity and effects on metabolism of contact lens care solutions on human corneal epithelium cells. AB - PURPOSE: The aim was to determine the cytotoxic effects of three multipurpose solutions (MPS) on human corneal epithelial cells (HCEC) and to assess the metabolic rates of recovering cells at different levels of cell membrane damage. METHOD: The effects of one to 15 minutes exposure to multipurpose solutions containing polyquaternium-1 (MPS-A), polyaminopropyl biguanide (MPS-B) and polyhexanide (MPS-C) on HCEC were determined. Recovery rates at different levels of cell membrane damage were assessed after re-culture for two hours at 37 degrees C. Cell viability and membrane integrity were assessed using Annexin V FITC/7-AAD staining and flow cytometry. Effects of concentrations of 10 to 40 per cent multipurpose solutions on the metabolic rate of recovering HCEC were assessed using a Vybrant MTT cell proliferation assay kit. RESULTS: The highest percentage of late necrotic cells resulted after exposure to MPS-A compared with other solutions and the control (p < 0.001). The percentages of early necrotic cells after 10 and 15 minutes of soaking in MPS-B were significantly higher than the control and other multipurpose solutions (p < 0.001). Although MPS-C exposure also resulted in statistically significant higher percentages of early necrotic cells than the control (p < 0.005), these differences were small. No recovery was noted when HCEC treated with multipurpose solutions were re-cultured, with numbers of dead cells in MPS-B-treated cultures increasing fourfold. The MTT assay showed significant dose-response decreases of 500 nm absorbance for all MPS treated cells. In 40 per cent MPS-A-treated HCEC, lack of activity indicated the cells were non-viable. CONCLUSIONS: Multipurpose solutions induced varying levels of irreversible tissue sensitivity reactions, with MPS-A showing the greatest effects. The solutions damaged cell integrity and reduced metabolic rates suggesting delayed healing ability. The formulations of multipurpose solutions need to balance antimicrobial effectiveness with low cytotoxicity, which might not be currently possible to achieve. In light of our results, we suggest that contact lens wearers should be advised to rinse the soaked lenses with saline before lens insertion. PMID- 22233283 TI - Efficacy and safety of topical antifungals in the treatment of dermatomycosis: a systematic review. AB - The analysis of comparative efficacy and safety of topical antifungals in the literature is restricted to the treatment of tinea pedis and onychomycosis. Therefore our objective was to evaluate and compare the efficacy and safety of topical antifungals used in the treatment of dermatomycosis, we performed a comprehensive search for randomized controlled trials (RCTs) in the following databases: Medline, Cochrane Central Register of Controlled Trials, EMBASE, Lilacs and International Pharmaceutical Abstracts, we identified studies that compared the use of topical antifungals with other antifungals or with placebo published up to July 2010 in English, Spanish or Portuguese. The quality of reporting was assessed according to the Jadad scale; only studies with a score of 3 or more were included. The outcomes evaluated were mycological cure at the end of treatment, sustained cure, occurrence of adverse events and tolerability, including withdrawals due to adverse events. A total of 104 RCTs satisfied the inclusion criteria, containing a total of 135 comparisons, with 55 out of 120 possible comparisons among the 16 drugs evaluated. Pooled data on efficacy showed that all the antifungals were better than placebo. There were no significant differences among antifungal classes. No differences were found in safety or tolerability in any direct comparison. Sensitivity analysis indicated the robustness of the findings. Our results indicate the clear superiority of topical antifungals over placebo but that there is no consistent difference among classes. Mixed treatment comparisons are necessary to rank antifungals, as direct comparisons among many of them are lacking. PMID- 22233284 TI - Generalized eruptive histiocytomas and juvenile eruptive xanthogranulomas in a 10 year-old boy: a potpourri of exotic terms indicating the need for unification. PMID- 22233285 TI - Collaborative care best practice models: a new educational paradigm for developing interprofessional educational (IPE) experiences. PMID- 22233286 TI - Diet and its role in interstitial cystitis/bladder pain syndrome (IC/BPS) and comorbid conditions. AB - What's known on the subject? and What does the study add? Nearly 90% of patients with interstitial cystitis/bladder pain syndrome (IC/BPS) report sensitivities to a wide variety of dietary comestibles. Current questionnaire-based literature suggests that citrus fruits, tomatoes, vitamin C, artificial sweeteners, coffee, tea, carbonated and alcoholic beverages, and spicy foods tend to exacerbate symptoms, while calcium glycerophosphate and sodium bicarbonate tend to improve symptoms. At present we recommend employing a controlled method to determine dietary sensitivities, such as an elimination diet, in order to identify sensitivities while at the same time maintain optimal nutritional intake. We review current literature with regard to diet's effect upon IC/BPS and common comorbidities (irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, neuropathic pain, vulvodynia, and headache) with a focus upon questionnaire-based investigations. We discuss the pathologic mechanisms that may link diet and IC/BPS related-pain, concentrating upon specific comestibles such as acidic foods, foods high in potassium, caffeine, and alcohol. Up to 90% of patients with interstitial cystitis/bladder pain syndrome (IC/BPS) report sensitivities to a wide variety of comestibles. Pathological mechanisms suggested to be responsible for the relationship between dietary intake and symptom exacerbation include peripheral and/or central neural upregulation, bladder epithelial dysfunction, and organ 'cross-talk', amongst others. Current questionnaire based data suggests that citrus fruits, tomatoes, vitamin C, artificial sweeteners, coffee, tea, carbonated and alcoholic beverages, and spicy foods tend to exacerbate symptoms, while calcium glycerophosphate and sodium bicarbonate tend to improve symptoms. Specific comestible sensitivities varied between patients and may have been influenced by comorbid conditions. This suggests that a controlled method to determine dietary sensitivities, such as an elimination diet, may play an important role in patient management. PMID- 22233287 TI - Abnormal CX3CR1+ lamina propria myeloid cells from intestinal transplant recipients with NOD2 mutations. AB - Although progress has been made in intestinal transplantation, chronic inflammation remains a challenge. We have reported that the risk of immunological graft loss is almost 100-fold greater in recipients who carry any of the prevalent NOD2 polymorphisms associated with Crohn's disease, and have shown that the normal levels of a key antimicrobial peptide produced by the Paneth cells of the allograft, fall as the graft becomes repopulated by hematopoietic cells of the NOD2 mutant recipient. These studies are extended in this report. Within several months following engraftment into a NOD2 mutant recipient the allograft loses its capacity to prevent adherence of lumenal microbes. Despite the significantly increased expression of CX3CL1, a stress protein produced by the injured enterocyte, NOD2 mutant CX3CR1(+) myeloid cells within the lamina propria fail to exhibit the characteristic morphological phenotype, and fail to express key genes required expressed by NOD2 wild-type cells, including Wnt 5a. We propose that the CX3CR1(+) myeloid cell within the lamina propria supports normal Paneth cell function through expression of Wnt 5a, and that this function is impaired in the setting of intestinal transplantation into a NOD2 mutant recipient. The therapeutic value of Wnt 5a administration in this setting is proposed. PMID- 22233288 TI - Alternative splicing of the auxin biosynthesis gene YUCCA4 determines its subcellular compartmentation. AB - Auxin is a major growth hormone in plants, and recent studies have elucidated many of the molecular mechanisms underlying its action, including transport, perception and signal transduction. However, major gaps remain in our knowledge of auxin biosynthetic control, partly due to the complexity and probable redundancy of multiple pathways that involve the YUCCA family of flavin-dependent mono-oxygenases. This study reveals the differential localization of YUCCA4 alternative splice variants to the endoplasmic reticulum and the cytosol, which depends on tissue-specific splicing. One isoform is restricted to flowers, and is anchored to the cytosolic face of the endoplasmic reticulum membrane via a hydrophobic C-terminal transmembrane domain. The other isoform is present in all tissues and is distributed throughout the cytosol. These findings are consistent with previous observations of yucca4 phenotypes in flowers, and suggest a role for intracellular compartmentation in auxin biosynthesis. PMID- 22233289 TI - Health-related quality of life and depressive symptoms in significant others of people with multiple sclerosis: a community study. AB - BACKGROUND AND PURPOSE: Uncertain prognosis and modest treatment efficacy make multiple sclerosis (MS) a particularly difficult disease to adjust to for both patients and their significant others (SOs). Few studies have assessed health related quality of life (HRQOL) and depressive symptoms in SOs of people with MS in the community. We assessed, and identified predictors of, HRQOL and depression in SOs of adults with MS. METHODS: POSMOS (postal survey of self-assessed health in MS adults and SOs) is a longitudinal survey on a random sample of 251 people with MS in the Milan area. In 2010, SOs and contemporaneous controls completed the SF-36 and Chicago Multiscale Depression Inventory (CMDI). RESULTS: Overall, 142 SOs (mean age 53.1 years; 50% women, 65% partners) and 120 controls (similar to SOs for sex and education, but older) participated. By multivariable modeling of the SO plus control population, SF-36 vitality was lower in SOs (proportional odds ratio 0.45; 95% confidence interval 0.28-0.70), women (0.41; 0.27-0.64), and older subjects (0.98; 0.97-0.99). SF-36 mental health was also lower in SOs (0.62; 0.40-0.96) and women (0.43; 0.28-0.67). Regarding MS characteristics associated with HRQOL and depression in SOs, severe disability [Expanded Disability Status Scale (EDSS > 6.5)] had no effect, whilst depressive symptoms (pathologic CMDI) negatively influenced most SF-36 and all CMDI scores in SOs. CONCLUSIONS: SOs had significantly lower vitality and psychological well-being than controls, identifying a burden in being the companion of a person with MS. This burden was unrelated to physical compromise but associated with depressive symptoms in MS. PMID- 22233291 TI - RAS signalling in the colorectum in health and disease. AB - RAS proteins act as molecular switches between several homeostatic inputs and signal transduction pathways that regulate important cellular processes including cell growth, differentiation and survival. Activating mutations change the function of normal proto-oncogenic RAS proteins to oncogenic RAS proteins that trigger a wide range of downstream effectors altering expression of transcription factors that together stimulate cell proliferation and modulate apoptosis and differentiation. RAS genes are amongst the most frequently mutated genes in human cancers, in particular KRAS is mutated in 40-50% of colorectal cancers. Mutation of this gene has a significant impact on treatment management and patients' survival, particularly in relation to anti-EGFR therapy, which is only effective in KRAS wild-type cases. Here, we discuss the regulation of KRAS signalling in the colorectum, some of the post-transcriptional and post-translational modifications that control its activity, the mutations and other DNA alterations that are found in this tumour type and the implications that they have for disease progression and current drug treatments. PMID- 22233290 TI - Diabetes augments and inhaled nitric oxide prevents the adverse hemodynamic effects of transfusing syngeneic stored blood in mice. AB - BACKGROUND: Stored red blood cells (RBCs) undergo progressive deleterious functional, biochemical, and structural changes. The mechanisms responsible for the adverse effects of transfusing stored RBCs remain incompletely elucidated. STUDY DESIGN AND METHODS: Awake wild-type (WT) mice, WT mice fed a high-fat diet (HFD-fed WT) for 4 to 6 weeks, and diabetic (db/db) mice were transfused with syngeneic leukoreduced RBCs or supernatant with or without oxidation (10% of total blood volume) after storage for not more than 24 hours (FRBCs) or 2 weeks (SRBCs). Inhaled nitric oxide (NO) at 80 parts per million was administered to a group of mice transfused with SRBCs. Blood and tissue samples were collected 2 hours after transfusion to measure iron and cytokine levels. RESULTS: SRBCs had altered RBC morphology and a reduced P(50) . Transfusion of SRBCs into WT or HFD fed WT mice did not produce systemic hemodynamic changes. In contrast, transfusion of SRBCs or supernatant from SRBCs into db/db mice induced systemic hypertension that was prevented by concurrent inhalation of NO. Infusion of washed SRBCs or oxidized SRBC supernatant into db/db mice did not induce hypertension. Two hours after SRBC transfusion, plasma hemoglobin (Hb), interleukin-6, and serum iron levels were increased. CONCLUSION: Transfusion of syngeneic SRBCs or the supernatant from SRBCs produces systemic hypertension and vasoconstriction in db/db mice. It is likely that RBC storage, by causing in vitro hemolysis and posttransfusion hemoglobinemia, produces sustained NO scavenging and vasoconstriction in mice with endothelial dysfunction. Vasoconstriction is prevented by oxidizing the supernatant of SRBCs or breathing NO during SRBC transfusion. PMID- 22233292 TI - Evaluation of the peptide nucleic acid fluorescence in situ hybridisation technology for yeast identification directly from positive blood cultures: an Italian experience. AB - Fungaemia is an increasing nosocomial pathology. The 'gold standard' for detection of fungaemia is blood culture, but it is time-consuming and its sensitivity for early detection is low. On the other hand, yeasts present different antifungal sensitivity patterns to be quickly detected to allow an effective treatment. The aim of this study was to evaluate the diagnostic performances of PNA-FISH to directly identify yeasts from blood cultures and to compare results with those obtained by culture. A total of 176 blood cultures positive for yeasts at direct Gram stain and 24 negative blood cultures as control collected from 15 Italian hospitals, included in a network coordinated by the Medical Mycology Committee, Italian Society of Clinical Microbiology (AMCLI), were examined both by culture and PNA-FISH technology. Sensitivity of the PNA FISH technique evaluated for five Candida species was 99.3% and specificity, 100%. Distinguishing which yeast is implicated in fungaemia and whether the infection is caused by multiple species are important for the selection of antifungal therapy. The PNA-FISH technique is a very useful approach because the test discriminates between groups of Candida species with different susceptibility pattern, particularly against azoles and echinocandins, with only a 90-minute turn-around time after the Gram-stain reading. PMID- 22233294 TI - Pharmaceutical industry perspective on risk evaluation and mitigation strategies: manufacturer take heed. AB - INTRODUCTION: Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its risk. REMS apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs). The objective of this review is to describe the impact of REMS requirements on the pharmaceutical industry. AREAS COVERED: Articles were identified in MEDLINE searches through October 11, 2011, using the MeSH terms and keywords pharmaceutical industry, risk management, United States Food and Drug Administration, REMS, ETASU, and Medication Guide in various combinations. EXPERT OPINION: The new powers ascribed to the FDA are notable, as they add enforceability to safety strategies that were not part of FDA's prior risk management tools, risk minimization action plans (RiskMAPs). Failure to comply with REMS can lead to financial penalties up to $10 million, and a drug could be deemed misbranded if the REMS is not followed. The new approach to risk management via FDAAA has elevated the rigor with which manufacturers must fulfill postmarketing safety commitments. PMID- 22233293 TI - Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. AB - BACKGROUND AND PURPOSE: Besides targeting the well-known oncogenic c-Met, crizotinib is the first oral tyrosine kinase inhibitor inhibiting anaplastic lymphoma kinase (ALK) in clinical trials for the treatment of non-small cell lung cancer. Here, we assessed the possible reversal of multidrug resistance (MDR) by crizotinib in vitro and in vivo. EXPERIMENTAL APPROACH: 1-(4,5-Dimethylthiazol-2 yl)-3,5- diphenylformazan was used in vitro and xenografts in nude mice were used in vivo to investigate reversal of MDR by crizotinib. To understand the mechanisms for MDR reversal, the alterations of intracellular doxorubicin or rhodamine 123 accumulation, doxorubicin efflux, ABCB1 expression level, ATPase activity of ABCB1 and crizotinib-induced c-Met, Akt and ERK1/2 phosphorylation were examined. KEY RESULTS: Crizotinib significantly enhanced the cytotoxicity of chemotherapeutic agents which are also ABCB1 substrates, in MDR cells with no effect found on sensitive cells in vitro and in vivo. Additionally, crizotinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in a concentration-dependent manner. However, expression of ABCB1 was not affected, and reversal of MDR by crizotinib was not related to the phosphorylation of c Met, Akt or ERK1/2. Importantly, crizotinib significantly enhanced the effect of paclitaxel against KBv200 cell xenografts in nude mice. CONCLUSIONS AND IMPLICATIONS: Crizotinib reversed ABCB1-mediated MDR by inhibiting ABCB1 transport function without affecting ABCB1 expression or blocking the Akt or ERK1/2 pathways. These findings are useful for planning combination chemotherapy of crizotinib with conventional chemotherapeutic drugs. PMID- 22233295 TI - Petasis three-component coupling reactions of hydrazides for the synthesis of oxadiazolones and oxazolidinones. AB - An application of readily available hydrazides in the Petasis 3-component coupling reaction is presented. An investigation of the substrate scope was performed to establish a general, synthetically useful protocol for the formation of hydrazido alcohols, which were selectively converted to oxazolidinone and oxadiazolone ring systems through triphosgene-mediated cyclization reactions. PMID- 22233296 TI - High-resolution absorption cross sections of formaldehyde in the 30,285-32,890 cm(-1) (304-330 nm) spectral region. AB - Absolute room temperature (294 +/- 2 K) absorption cross sections for the A(1)A(2)-X(1)A(1) electronic transition of formaldehyde have been measured over the spectral range 30,285-32,890 cm(-1) (304-330 nm) using ultraviolet (UV) laser absorption spectroscopy. Accurate high-resolution absorption cross sections are essential for atmospheric monitoring and understanding the photochemistry of this important atmospheric compound. Absorption cross sections were obtained at an instrumental resolution better than 0.09 cm(-1), which is slightly broader than the Doppler width of a rotational line of formaldehyde at 300 K (~0.07 cm(-1)) and so we were able to resolve all but the most closely spaced lines. Comparisons with previous data as well as with computer simulations have been made. Pressure broadening was studied for the collision partners He, O(2), N(2), and H(2)O and the resulting broadening parameters have been measured and increase with the strength of intermolecular interaction between formaldehyde and the collision partner. The pressure broadening coefficient for H(2)O is an order of magnitude larger than the coefficients for O(2) and N(2) and will contribute significantly to spectral line broadening in the lower atmosphere. Spectral data are made available as Supporting Information. PMID- 22233297 TI - Nanoporous waveguide sensor with optimized nanoarchitectures for highly sensitive label-free biosensing. AB - Label-free optical biosensors have attracted much attention, and nanoporous metal oxide membranes with uniform pore structure and diameter are promising candidates for platforms of label-free optical biosensors. However, development of such sensors with high sensitivity still remains challenging. In this paper, we report on the remarkably enhanced sensitivity of a label-free nanoporous optical waveguide (NPWG) sensor composed of a porous anodic alumina (PAA) waveguiding film and an aluminum cladding film. The enhanced sensitivity was achieved by engineering nanostructures and tuning optical properties of the PAA film. Careful tuning of the porosity, pore density, thickness, and refractive index of the PAA film could significantly improve the sensitivity of the NPWG sensor toward adsorption of bovine serum albumin (BSA) onto the PAA surface, and the optimized sensor responded to the adsorption of BSA with an extraordinarily large red shift (>300 nm) of a waveguide mode due to the large adsorption capacity of the PAA film and the inherently high sensitivity of the waveguide mode. The Fresnel calculations suggested that the potential sensitivity of the NPWG sensor was much higher than that of the conventional surface plasmon resonance (SPR) sensors. PMID- 22233299 TI - Variations in older persons' descriptions of the burden of loneliness. AB - Research indicates that approximately one-third of older people over the age of 65 years report loneliness, with even higher rates among those aged over 85. Loneliness is associated with a variety of health issues, such as depression, anxiety, physical impairment and social isolation. The purpose of this paper is to describe the characteristics of the burden of loneliness, and investigate the variability in how it is described by older. In-depth interviews were conducted with 12 older people in autumn 2006 and spring 2007 in Norway. Participants aged from 70 to 97 years were recruited from a variety of backgrounds, and varied in health status and social status. The findings reported in this paper are based on hermeneutic analyses of the interviews. Our findings indicate that some of the participants experienced loneliness that they felt able to manage. They experienced a fluctuating loneliness that was linked to feeling valuable and having power and energy. However, another group described experiences of agonising loneliness. They felt a present and extensive loneliness, together with feeling less valuable and lacking in power and initiative. They seemed trapped in their loneliness, and unable to overcome their situation themselves. Our findings indicate that the burden of loneliness is experienced differently. For some older persons, the experience of loneliness is so severe that they urgently need help to manage their situation. PMID- 22233298 TI - Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. AB - Mesenchymal stem cells (MSC) derived from bone marrow can potentially reduce the acute inflammatory response in spinal cord injury (SCI) and thus promote functional recovery. However, the precise mechanisms through which transplanted MSC attenuate inflammation after SCI are still unclear. The present study was designed to investigate the effects of MSC transplantation with a special focus on their effect on macrophage activation after SCI. Rats were subjected to T9-T10 SCI by contusion, then treated 3 days later with transplantation of 1.0*10(6) PKH26-labeled MSC into the contusion epicenter. The transplanted MSC migrated within the injured spinal cord without differentiating into glial or neuronal elements. MSC transplantation was associated with marked changes in the SCI environment, with significant increases in IL-4 and IL-13 levels, and reductions in TNF-alpha and IL-6 levels. This was associated simultaneously with increased numbers of alternatively activated macrophages (M2 phenotype: arginase-1- or CD206-positive), and decreased numbers of classically activated macrophages (M1 phenotype: iNOS- or CD16/32-positive). These changes were associated with functional locomotion recovery in the MSC-transplanted group, which correlated with preserved axons, less scar tissue formation, and increased myelin sparing. Our results suggested that acute transplantation of MSC after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, and that this may reduce the effects of the inhibitory scar tissue in the subacute/chronic phase after injury to provide a permissive environment for axonal extension and functional recovery. PMID- 22233300 TI - ROP11 GTPase is a negative regulator of multiple ABA responses in Arabidopsis. AB - The phytohormone abscisic acid (ABA) plays crucial roles in plant development and plant responses to environmental stresses. Although ABA receptors and a minimal set of core molecular components have recently been discovered, understanding of the ABA signaling pathway is still far from complete. In this work, we characterized the function of ROP11, a member of the plant-specific ROP small GTPases family, in the ABA signaling process. ROP11 is preferentially expressed in guard cells in all plant organs with stomata. Expression of a constitutively active ROP11 (CA-ROP11) suppresses ABA-mediated responses, whereas reduced expression of ROP11 or expression of its dominant-negative form (DN-ROP11) causes the opposite phenotypes. The affected ABA-mediated responses by ROP11 include seed germination, seedling growth, stomatal closure, induction of ABA-responsive genes, as well as plant response to drought stress. Furthermore, we showed that ROP11 and its closest-related family member, ROP10, act in parallel in mediating these responses. ABA treatment does not affect ROP11 transcription and protein abundance; however, it causes the accumulation of CA-ROP11 in the nucleus. These results demonstrated that ROP11 is a negative regulator of multiple ABA responses in Arabidopsis. PMID- 22233301 TI - Validity and reliability of "Asthma Quality of Life Questionnaire" in a sample of Turkish adult asthmatic patients. AB - We aimed to investigate the validity and reliability and of "Asthma Quality of Life Questionnaire (AQLQ)" in Turkish adult asthmatic patients. New or previously diagnosed [according to Global Initiative for Asthma (GINA) 2008] symptomatic 118 consecutive stable asthmatic patients between 18 and 55 years old were included. Asthma severity was determined and Turkish adaptation of the AQLQ was administered. Lara asthma symptom scales (LASS), pulmonary function tests, Turkish adaptation of Medical Outcomes Survey Short Form-36 (SF-36) were evaluated. All assessments were done twice at recruitment and after 10 weeks. During this period patients were allowed to make modifications on their medication when necessary. Among the recruited 118 patients 95 were female and 14 were lost in the follow-up. Sixty-two percentages of the patients had mild and 38% moderate asthma. The internal consistency of AQLQ was high (Cronbach's alpha 0.81-0.87) and item-total score correlations were ranging from 0.75-0.89. The cross-sectional and longitudinal correlations between AQLQ total and domain scores and SF36 domain scores were in a range of little or fair degree (r= 0.241 0.626, p< 0.005). Total AQLQ scores were observed significantly different according to disease severity and LASS both in the first (p< 0.001, both) and 10 weeks follow-up visits (p= 0.006, p< 0.001 respectively). A statistical significant change was observed in AQLQ symptom score as in total LASS changed (p< 0.001, both) in the follow-up. Our results demonstrated that Turkish version of AQLQ is feasible, reliable, valid and sensitive to changes in adult asthmatics. PMID- 22233302 TI - A cross-sectional observational study to investigate daily symptom variability, effects of symptom on morning activities and therapeutic expectations of patients and physicians in COPD-SUNRISE study. AB - Chronic obstructive pulmonary disease (COPD) is a lung disease characterized with limitation of airflow that is not completely reversible, progressive deterioration of airways and systemic inflammation. This study has been planned to determine daily symptom variability of patients, expectations of patient and physicians from treatment and patient profiles. A total of 514 patients with COPD from 25 centers were included in this national, multicenter, cross-sectional observational study. Data regarding demographic features, concomitant diseases, history and treatment of COPD and expectations of patients and physicians were all obtained in a single visit. Mean [standard deviation (SD)] age of the patients was 64.1 (9.5) years; age range was 41-92 years, 50% of the patients were younger than 65 years and 91% were males. Educational level of the patients was at least primary school in 80.2%; and 54.3% (30.4%) of the patients had at least one concomitant disease, particularly a cardiovascular disease. Mean (SD) duration of having COPD was 5.4 (4.6) years. The majority of patients were at moderate (43.2%) and severe (35.0%) COPD stages and one or more exacerbations per year was determined in 71%. Inhaled beta-2 agonists (84.2%), inhaled steroids (76.3%) and inhaled long-acting anti-cholinergics (70.0%) were the most commonly used medications. Dyspnea (99.0%), sputum production (92.8%) and wheezing (90.5%) were the most common symptoms, and symptom variability for dyspnea (41.1%), sputum production (61.0%) and cough (53.5%) were seen the most in the morning hours (p< 0.001). Most commonly affected morning activity was climbing up/down the stairs (point of effect: 6.7), followed by wearing socks/shoes (point of effect: 4.3) and showering/bathing (point of effect: 4.2) by COPD. Major treatment expectations of patients were greater symptomatic relief (82.3%) and greater mobility (70.0%), faster symptomatic relief (61.1%) and improvement in morning activities (59.3%); while major treatment expectations of physicians included increased quality of life (100.0%) and decreased morbidity (96.0%). Quitting smoking was the most commonly recommended (88.3%) and implemented (67.9%) non-drug protective approach aimed at decreasing the frequency of exacerbations. Consequently, our results demonstrate that COPD is not a disease of only the elderly, is an important healthcare issue that often disrupt daily living of the patients due to inadequate disease awareness leading to overlooking of the symptoms by patient and physicians, and that a patient-centered approach based on the living standards, life expectancies and preferences of patients was crucial in patient management. PMID- 22233303 TI - Does airway colonization cause systemic inflammation in bronchiectasis? AB - Recent evidence suggests the presence of accompanying systemic inflammation in chronic inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma; however little is known regarding the presence of systemic inflammation in bronchiectasis. Although bronchiectasis was initially considered a stationary process, chronic bacterial colonization causes airway inflammation and progressive airway damage. The aim of this study was to determine the level of systemic inflammation in bronchiectasis patients and identify its relationship with colonization. White blood cell (WBC) count, erythrocyte sedimentation rate, serum C-reactive protein (CRP), plasma fibrinogen, interleukin-8, tumor necrosis factor-alpha and leptin levels were determined in clinically stable bronchiectasis patients (n= 50), and age- and sex-matched controls. Bronchiectasis patients were also analyzed according to colonization in sputum samples. There was no significant difference between bronchiectasis and control groups with respect to inflammatory markers but median (interquartile range-IQR) WBC count, CRP and fibrinogen levels were significantly higher in colonized patients (n= 14) when compared to non-colonized patients [8.2 (6.4-9.5) vs. 6.4 (5.8-7.7) x 103/mm3, 0.91 (0.45-1.29) vs. 0.42 (0.30-0.77) mg/dL, 433.5 (390.3 490.3) vs. 392.0 (327.0-416.0) mg/dL, respectively; p< 0.05]. There was no evidence supporting the presence of systemic inflammation in the overall bronchiectasis group when compared to controls. However, elevated WBC count, CRP and fibrinogen levels in patients with colonization suggest the presence of a systemic inflammatory response in clinically stable bronchiectasis patients with colonization. PMID- 22233304 TI - [The comparison of patients with hospitalized health-care-associated pneumonia to community-acquired pneumonia]. AB - Health-care-associated pneumonia (HCAP) is defined as pneumonia that develops in patients with a history of recent hospitalization, hemodialysis as an outpatient, residence in a nursing home, outpatient intravenous therapy and home wound care. We aimed to compare the initial demographic characteristics, causative agents and prognosis between hospitalized HCAP and community-acquired pneumonia (CAP) patients. HCAP and CAP patients hospitalized between 01 September 2008-01 September 2009 were evaluated retrospectively. Out of 187 patients (131 males, mean age 66.3 +/- 14.3 years) who were hospitalized during one-year period, 98 were diagnosed as HCAP and 89 as CAP. Among HCAP patients, 64 (65.3%) had a history of hospitalization in the last 90 days, 26 (26.5%) received outpatient intravenous therapy, 17 (17.3%) had home wound care, 6 (6.1%) were on hemodialysis program in the last 30 days and 4 (4.1%) lived in a nursing home. The causative pathogen was detected in 39 (39.8%) HCAP and 8 (9.0%) CAP patients. The most frequently isolated microorganisms were Pseudomonas aeruginosa and Acinetobacter baumannii in HCAP, and Streptococcus pneumoniae and Haemophilus influenzae in CAP patients. Inappropriate empiric antibiotic treatment was documented in 8 (25.8%) of 39 HCAP patients, in whom a causative agent was isolated whereas the antibiotic treatment was appropriate in all CAP patients. The duration of hospitalization (14.4 +/- 11.4 vs. 10.7 +/- 7.9 days, p= 0.011) and mortality rate (34.7% vs. 9.0%, p< 0.001) were higher in HCAP compared with CAP patients. As HCAP is different than CAP in terms of patients' characteristics, causative microorganisms and prognosis, it should be considered in all patients hospitalized as CAP. Potentially drug-resistant microorganisms should be taken into consideration in the empirical antibiotic treatment of these patients. PMID- 22233305 TI - [Level of smoking of 3rd and 4th grade students studying health and related factors: follow-up study]. AB - The levels of smoking of 1st and 2nd year students at Faculty of Medicine and Manisa School of Health at Celal Bayar University were investigated in 2006-2007. This study is carried out in order to see if there is a change in the same students' level of smoking while they are in 3rd and 4th year. In addition, the study aimed to examine the factors affecting the level of use and attitudes towards the law effectuated in July 19, 2009. This is a follow-up study with 80.42% return rate. A 26-item structured questionnaire was administered. The participants filled out the questionnaires under supervision of the researchers in their classrooms. The University Institutional Review Board approved the study. The total of participants (263) of the follow-up study included 189 female and 74 male. The rate of experimenting with smoking was 49% with the mean age of 15.7 (SD= 4.01 years). The mean age of experimenting with smoking was the earliest on male students studying at faculty of medicine. The level of smoking was found to be the most on females, studying at faculty of medicine and staying at the dormitory, with smoking parents (p< 0.05). The most important reason to begin smoking was curiosity (55.2%) while bad breath and yellowing of teeth were the reasons to quit (91.7%). 83.3% of the students thought that the law will be effective on quit smoking. The level of both experimenting and use of smoking has been increased over time. It is suggested that medical students' awareness about the danger of smoking should be raised at earlier grades. In addition, lectures should be offered to students at School of Health and they should be encouraged to unite in order to fight with smoking. PMID- 22233306 TI - [Nicotine addiction and environmental tobacco smoke exposure]. AB - In present study it was aimed to determine the general characteristics of cases who cause environmental tobacco smoke (ETS) exposure. One hundred and forty five cases (53/92, F/M) who admitted to smoking cessation clinic were asked about general demographic characteristics, the history of ETS exposure in childhood and whether they cause of ETS exposure or not. Also Fagernstrom test for nicotine dependence (FTND) and hospital anxiety depression test (HADT) were performed. The mean age of the cases was 42.2 years. It was determined that 71% of cases exposed ETS in childhood and 69% of cases cause ETS exposure. There was no effect of the number of cigarette smoked per day and the amount of packet/years on to cause ETS exposure. The cases who cause ETS exposure to be forced more than others in places that it is forbidden smoking (p= 0.045), FTND score was higher (mean= 5.9) than others (mean= 4.8) (p= 0.009). The FTND score was >= 5 in 72% of cases who cause ETS exposure and in 53.3% of others (p= 0.045). 117 of cases were performed HADT, symptoms related with anxiety and depression were detected in 45 and 54 of cases respectively. The mean anxiety score was higher in cases who cause ETS exposure (p= 0.025). The symptoms related with anxiety and depression were determined similar in cases who cause ETS exposure or not. It was identified that there was no effect of gender, education, business status, another smoker at home, history of ETS exposure in childhood, socioeconomic status and to have knowledge about passive smoking on to cause ETS exposure. Prevention of nicotine addiction to be developed by starting smoking precludes the onset of the diseases related to smoking, and also enables inhibition of ETS exposure especially at home. PMID- 22233307 TI - Pulmonary artery sarcoma mimicking pulmonary thromboembolism. AB - A 30 years old male patient was referred to our hospital with a diagnosis of pulmonary thromboembolism due to thorax-computerized tomography (CT) angiography, revealing a thrombus totally occluding left main pulmonary artery. The lesion was evaluated as tumoural mass. Positron emission tomography (PET)-CT revealed pathologic uptake at pulmonary artery mass. Due to localization of tumour, left pneumonectomy was performed. The pathological diagnosis revealed to be pulmonary artery sarcoma. The patient was presented because pulmonary artery sarcomas are very rare tumors and can mimick pulmonary thromboembolism. The true prevalence is underestimated as many pulmonary artery sarcomas are misdiagnosed as pulmonary thromboembolism. PET-CT may help to make a differential diagnosis. PMID- 22233308 TI - [Hemophagocytic syndrome due to lung infection: a case report]. AB - A 31-year-old man with pneumonia and ampiema was treated with antibiotics and drainage. Hemophagocytic syndrome, characterized with pancytopenia was arised during this treatment. Nosocomial infection due to pancytopenia was treated with antibiotics. Hemophagocytic syndrome was recovered spontaneously after the treatment of this nosocomial infection. Such a severe hemophagocytic syndrome due to infection is a rare condition. PMID- 22233309 TI - Community-acquired Burkholderia cepacia pneumonia: a report of two immunocompetent patients. AB - Burkholderia cepacia is a gram-negative bacilli leading to pneumonia with poor prognosis and usually seen in patients with immunosuppression or with structural lung diseases. This report is about two patients with no underlying disease diagnosed as B. cepacia pneumonia mimicking malignancy and tuberculosis. Bronchoscopy was applied on both patients since no response to treatment with wide spectrum antibiotics and negative sputum smears for acid-fast bacili. B. cepacia was isolated from bronchial lavage culture. Antibiogram revealed sensitivity to quinolones in both cases. Radiological and clinical complete remission was seen in patients by quinolones. The current cases showed that community-acquired Burkholderia pneumonia is possible in healthy patients. Bronchial washing is important in diagnosis. PMID- 22233310 TI - Phrenic nerve injury due to thoracentesis for TPN effusion in a preterm newborn: consecutive two unusual complications. AB - Central venous catheters ara commonly used in neonatal intensive care units as routes of parenteral nutrition. Pleural effusions caused by extravasation of parenteral alimentation fluid are a rare complication of central venous catheters in the newborn. Diaphragmatic paralysis due to phrenic nerve injury is a rare respiratory condition which may be life-threatening in infants. PMID- 22233311 TI - [Does exposure to biomass and occupational dust can be causative for asthma among women?]. AB - In the developing countries, most of the house energy necessity is supplied from the biomass. Because of this reason, chronicle airway diseases and the respiratory symptoms that have been triggered by the house inside air pollution is very common. As an example from the real life of this entity, an asthmatic woman who has an history of using biomass in her house for heating, cleaning and cooking in all her life (because of the economical difficulties) and also an history of occupational organic dust exposure as a seasonal worker during the last 20 years was reported. After the medical investigation, the case was diagnosed as severe persistent asthma. The case was externated after ordering the appropriate inhaler treatment and she was taken to the follow up programme. PMID- 22233312 TI - Lung adenocarcinoma with endobronchial growth. AB - We report a rare case of lung adenocarcinoma with endobronchial growth in a 65 year-old woman. Chest computed tomography revealed an ill-defined mass in the lower lobe of the left lung and multiple sized nodular shadows in the both lungs. An endobronchial polypoid tumor in the left B8 bronchus was found by bronchoscopic examination. A biopsy specimen obtained from the tumor diagnosed lung adenocarcinoma. Although very rare, we should therefore keep in mind that patients who have a pulmonary tumor adjacent to the bronchus with an endobronchial polypoid lesion may have lung adenocarcinoma. PMID- 22233313 TI - Spontaneous pneumothorax in pregnancy: a case report. AB - Spontaneous pneumothorax is an extremely rare condition during pregnancy. Rupture of a subpleural apical bulla or blebs are the most common cause of spontaneous pneumothorax in young pregnant women. It is believed to be due to increase respiratory activity associated peripartum period. We present 27-year-old primigravid female with spontaneous pneumothorax. She was treated successfully with chest tube placement. PMID- 22233314 TI - Actinomyces israelii: a rare cause of thoracic empyema. AB - Actinomyces israelii usually causes chronic suppurative and granulomatous infections. Isolated pleural effusion due to Actinomycosis is rare. This report describes an unusual case of thoracic empyema caused by A. israelii with sudden onset and rapid deterioration that failed to respond to chest tube drainage and antibiotherapy. Empyema drainage and visceral parietal pleurectomy by a left postolateral thoracotomy proved to be of vital importance and a permanent solution. PMID- 22233315 TI - [Cardiovascular biomarkers in clinical practice of sleep apnea]. AB - Obstructive sleep apnea syndrome (OSAS) leads to cardiovascular complications such as coronary artery disease, left/right ventricular hypertrophy and dysfunction, heart failure, systemic and pulmonary hypertension, arrhythmias and stroke; and these all cardiovascular complications increase morbidity and mortality of OSAS. However, Cheyne-Stokes respiration, central and obstructive apneas may occur in the patient with heart failure. Increased sympathetic activity by hypoxemia and endothelial dysfunction play a role in cardiovascular complications. Some cardiovascular biomarkers have a role in early diagnosis, treatment and prognosis. In the present review, some cardiovascular biomarkers such as serum C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), interleukins, adiponectin, heart-type fatty acid binding protein (hFABP) and brain (B-type) natriuretic peptide (BNP), and their clinical importance were reviewed. PMID- 22233316 TI - [Long acting beta-2 agonists in the treatment of asthma and their safety]. AB - Inhaled corticosteroids are the preferred primary long-term treatment for asthma. The first option in patients who are uncontrolled with inhaled steroids is adding long-acting beta-2 agonists. The addition of a long-acting beta-agonist to an inhaled corticosteroid has been accepted as effective therapy for almost two decades Despite the widespread use and their clinical benefit, controversy regarding their safety arose after their introduction. Concerns about the safety of long-acting beta-2 agonist therapy, has led to the appearance of multiple publications and recommendations. The evidence supports the use of long-acting beta-2 agonists plus inhaled corticosteroids in a single inhaler device to increase adherence and reduce the potential use of long-acting beta-2 agonists monotherapy. This review examines and commands on the available clinical data and safety concerns of long-acting beta-2 agonists use in patients with asthma. PMID- 22233317 TI - [The importance of bronchoscopic anatomy for anesthesiologists]. AB - One-lung ventilation (OLV) is a sine qua non of thoracic surgery and requires knowledge and talent. Close familiarity with equipments used for OLV as well as bronchoscopy and respiratory tract anatomy is important for successful OLV. We aim to outline the bronchoscopic anatomy of the tracheobronchial tree and OLV equipment for anesthetists and thoracic surgeons in this review. The recorded preoperative and intraoperative bronchoscopic applications of the patients hospitalized in our Thoracic Surgery clinic for diagnosis and treatment have been evaluated from an anesthetist's perspective. Anatomic landmarks were identified in the bronchoscopic evaluation. Optimal and misplacement images of double-lumen tubes (DLT) and bronchial blockers (BB) used for OLV in our clinic were obtained via fiber optic bronchoscopy. While left lung isolation can be made more safely due to the anatomy of the left main bronchus, placement of both DLTs and BBs to the right main bronchus requires greater care. Success in OLV procedures would increase with anesthetists being well informed about the fiber optic bronchoscopic anatomy of the tracheobronchial tree and in close cooperation with the surgical team. PMID- 22233318 TI - [The relationship between stage and tumor type and serum leptin level and leptin expression on tumor tissue in lung cancer]. PMID- 22233319 TI - Evaluation of tuberculosis in chronic renal failure. PMID- 22233320 TI - Structural basis of selective inhibition of human tankyrases. AB - Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general. PMID- 22233321 TI - Molecular view on PRR cross-talk in antifungal immunity. AB - The identification of a major class of innate immune receptors, termed pattern recognition receptors (PRRs), has boosted research on innate pathogen recognition. The immune response to a specific pathogen is not restricted to the recognition by one type of PRR or activation of a single cell type, but instead comprises complex collaborations between different receptors, cells and signal mediators. Here we will discuss the cross-talk between PRRs involved in fungal recognition, focusing on the molecular interactions occurring at the plasma membrane. PMID- 22233323 TI - Neutral gold complexes with tridentate SNS thiosemicarbazide ligands. AB - Na[AuCl(4)].2H(2)O reacts with tridentate thiosemicarbazide ligands, H(2)L1, derived from N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chloride and thiosemicarbazides under formation of air-stable, green [AuCl(L1)] complexes. The organic ligands coordinate in a planar SNS coordination mode. Small amounts of gold(I) complexes of the composition [AuCl(L3)] are formed as side-products, where L3 is an S-bonded 5-diethylamino-3-phenyl-1-thiocarbamoyl-1,2,4-triazole. The formation of the triazole L3 can be explained by the oxidation of H(2)L1 to an intermediate thiatriazine L2 by Au(3+), followed by a desulfurization reaction with ring contraction. The chloro ligands in the [AuCl(L1)] complexes can readily be replaced by other monoanionic ligands such as SCN(-) or CN(-) giving [Au(SCN)(L1)] or [Au(CN)(L1)] complexes. The complexes described in this paper represent the first examples of fully characterized neutral Gold(III) thiosemicarbazone complexes. All the [AuCl(L1)] compounds present a remarkable cell growth inhibition against human MCF-7 breast cancer cells. However, systematic variation of the alkyl groups in the N(4)-position of the thiosemicarbazone building blocks as well as the replacement of the chloride by thiocyanate ligands do not considerably influence the biological activity. On the other hand, the reduction of Au(III) to Au(I) leads to a considerable decrease of the cytotoxicity. PMID- 22233322 TI - Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: clinical characteristics and treatment. AB - BACKGROUND: In many Asian countries, Klebsiella pneumoniae (KP) is the second pathogen responsible for community-acquired pneumonia. Yet, very little is known about KP etiology in ALRI in Cambodia, a country that has one of the weakest medical infrastructures in the region. We present here the first clinico radiological description of KP community-acquired ALRI in hospitalized Cambodian patients. METHODS: Through ALRI surveillance in two provincial hospitals, KP was isolated from sputum and blood cultures, and identified by API20E gallery from patients >= 5 years-old with fever and respiratory symptoms onset <=14 days. Antibiotics susceptibility testing was provided systematically to clinicians when bacteria were isolated. We collected patients' clinical, radiological and microbiological data and their outcome 3 months after discharge. We also compared KP-related with other bacteria-related ALRI to determine risk factors for KP infection. RESULTS: From April 2007 to December 2009, 2315 ALRI patients >= 5 years-old were enrolled including 587 whose bacterial etiology could be assigned. Of these, 47 (8.0%) had KP infection; their median age was 55 years and 68.1% were females. Reported prior medication was high (42.5%). Patients' chest radiographs showed pneumonia (61.3% including 39% that were necrotizing), preexisting parenchyma lesions (29.5%) and pleural effusions alone (4.5%) and normal parenchyma (4.5%). Five patients had severe conditions on admission and one patient died during hospitalization. Of the 39 patients that were hospital discharged, 14 died including 12 within 1 month after discharge. Only 13 patients (28%) received an appropriate antibiotherapy. Extended-spectrum beta-lactamases (ESBL) - producing strains were found in 8 (17.0%) patients. Female gender (Odds ratio (OR) 2.1; p = 0.04) and diabetes mellitus (OR 3.1; p = 0.03) were independent risk factors for KP-related ALRI. CONCLUSIONS: KP ALRI in Cambodia has high fatality rate, are more frequently found in women, and should be considered in diabetic patients. The extremely high frequency of ESBL-producing strains in the study is alarming in the context of uncontrolled antibiotic consumption and in absence of microbiology capacity in most public-sector hospitals. PMID- 22233325 TI - Factors associated with base-in prism treatment outcomes for convergence insufficiency in symptomatic presbyopes. AB - PURPOSE: The aim was to determine whether baseline measurements of binocular vision are associated with symptoms of convergence insufficiency (CI) both before and after CI treatment with base-in prism in symptomatic presbyopes. We further determined the factors that predicted CI treatment outcomes. METHODS: A total of 29 symptomatic CI subjects aged 45 to 68 years were examined and the following binocular vision measurements were obtained at the baseline: near heterophoria by cover test, associated phoria at near (AP), near point of convergence (NPC) and positive fusional vergence at near (PFV). Each subject wore each of two pairs of progressive addition spectacles for a three-week period, one with prism and one with the same prescription but no prism. The wear order was randomised across subjects. Subjects completed the CI symptom survey (CISS) before and at the end of the three weeks, thus baseline, placebo and treatment CISS scores were tabulated. The reduction in symptoms (CISS score improvement) was calculated as the difference between the placebo and treatment CISS scores. RESULTS: Neither baseline CISS score nor treatment CISS score had statistically significant correlations with any of the binocular vision measurements. CISS score improvement was statistically significantly associated with near heterophoria, AP and NPC break but not with PFV. CISS score improvement was significantly predicted by both near heterophoria and NPC break but not by AP and PFV. With other variables held constant, the CISS score improved by 1.57 for each additional prism dioptre of exophoria at near and by 0.81 for each additional centimetre that the NPC break was receded. CONCLUSION: There was no significant association between the CISS score with any of the baseline binocular vision measurements before or after prism treatment. Our findings suggest that a greater near heterophoria and/or more receded NPC before treatment are associated with more reduction in CI symptoms by prism treatment. PMID- 22233326 TI - The profile of executive function of very preterm children at 4 to 12 years. PMID- 22233324 TI - Detection and phylogenetic analysis of Wolbachia in the Asiatic rice leafroller, Cnaphalocrocis medinalis, in Chinese populations. AB - Wolbachia are a group of intracellular inherited endosymbiontic bacteria infecting a wide range of insects. In this study the infection status of Wolbachia (Rickettsiales: Rickettsiaceae) was measured in the Asiatic rice leafroller, Cnaphalocrocis medinalis (Guenee) (Lepidoptera: Pyralidae), from twenty locations in China by sequencing wsp, ftsZ and 16S rDNA genes. The results showed high infection rates of Wolbachia in C. medinalis populations. Wolbachia was detected in all geographically separate populations; the average infection rate was ~ 62.5%, and the highest rates were 90% in Wenzhou and Yangzhou populations. The Wolbachia detected in different C. medinalis populations were 100% identical to each other when wsp, ftsZ, and 16S rDNA sequences were compared, with all sequences belonging to the Wolbachia B supergroup. Based on wsp, ftsZ and 16S rDNA sequences of Wolbachia, three phylogenetic trees of similar pattern emerged. This analysis indicated the possibility of inter-species and intra-species horizontal transmission of Wolbachia in different arthropods in related geographical regions. The migration route of C. medinalis in mainland China was also discussed since large differentiation had been found between the wsp sequences of Chinese and Thai populations. PMID- 22233327 TI - Surgical simulators in urological training--views of UK Training Programme Directors. AB - What's known on the subject? and What does the study add? The role of surgical simulators is currently being debated in urological and other surgical specialties. Simulators are not presently implemented in the UK urology training curriculum. The availability of simulators and the opinions of Training Programme Directors' (TPD) on their role have not been described. In the present questionnaire-based survey, the trainees of most, but not all, UK TPDs had access to laparoscopic simulators, and that all responding TPDs thought that simulators improved laparoscopic training. We hope that the present study will be a positive step towards making an agreement to formally introduce simulators into the UK urology training curriculum. To discuss the current situation on the use of simulators in surgical training. To determine the views of UK Urology Training Programme Directors (TPDs) on the availability and use of simulators in Urology at present, and to discuss the role that simulators may have in future training. An online-questionnaire survey was distributed to all UK Urology TPDs. In all, 16 of 21 TPDs responded. All 16 thought that laparoscopic simulators improved the quality of laparoscopic training. The trainees of 13 TPDs had access to a laparoscopic simulator (either in their own hospital or another hospital in the deanery). Most TPDs thought that trainees should use simulators in their free time, in quiet time during work hours, or in teaching sessions (rather than incorporated into the weekly timetable). We feel that the current apprentice style method of training in urological surgery is out-dated. We think that all TPDs and trainees should have access to a simulator, and that a formal competency based simulation training programme should be incorporated into the urology training curriculum, with trainees reaching a minimum proficiency on a simulator before undertaking surgical procedures. PMID- 22233328 TI - N822K c-kit mutation in CD30-positive cutaneous pleomorphic mastocytosis after germ cell tumour of the ovary. PMID- 22233330 TI - Bile duct stenting in liver transplantation. PMID- 22233329 TI - The pathology and clinical features of early recurrent membranous glomerulonephritis. AB - We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria. PMID- 22233331 TI - Genetic bases and phenotypes of autosomal recessive Parkinson disease in a Turkish population. AB - BACKGROUND AND PURPOSE: To evaluate the phenotype and the frequencies of mutations in PRKN, DJ1 and PINK1 genes in patients with Parkinson disease (PD) in Turkey. METHODS: Eighty-six patients from 77 PD families participated in the study. Seventy-four families were originating from Turkey, two families from Greece and one family from Bulgaria. All patients underwent detailed neurological examination. PRKN, PINK1 and DJ1 genes were sequenced, and dosage analysis was performed by multiplex ligation-dependent probe amplification. RESULTS: Sixteen patients with PD were found to carry homozygous (n = 14) or compound heterozygous (n = 2) PRKN mutations. We identified exon rearrangements, three point mutations and one new point mutation in exon 2 (p.K27del). In two families, two new PINK1 point mutations (L31X and P416L) were identified. No pathogenic mutations were found in DJ1 gene. Clinical phenotypes of PRKN patients were comparable to previously described features, but only in four of 13 families, the pedigree structure was clearly consistent with an autosomal recessive (AR) mode of inheritance in comparison with nine families where also different pattern of transmission could have been possible. CONCLUSIONS: Our data suggest that the PRKN gene mutation is the most frequent form of ARPD in Turkey. The proportion of mutations with regard to the age of onset in our population is in the range of those previously described, but our pedigrees are characterized by high rate of consanguinity, which might explain the high proportion of families with homozygous mutations and of patients in more than one generation. Pathogenic DJ1 mutations do not seem to play a major role in Turkey. PMID- 22233332 TI - Thrombin receptor levels in platelet concentrates during storage and their impact on platelet functionality. AB - BACKGROUND: Quality control of platelet (PLT) concentrates is challenging, due to PLT lesions, which are difficult to detect with routine methods. The search for reliable PLT lesion biomarkers is focused on the role of PLTs in primary hemostasis. PLT transfusions also have a significant impact on secondary hemostasis. In this phase, responsiveness of PLTs to small amounts of thrombin is crucial. PAR1 and PAR4 are protease-activated receptors and are responsible for thrombin reactivity of human PLTs. This study should elucidate if levels of those two receptors are changing in PLT concentrates during storage and if those changes have an impact on PLT aggregation and support of thrombin generation. STUDY DESIGN AND METHODS: PLT concentrates from buffy coat preparations were stored in SSP+ solution for 9 days at 22+/-2 degrees C on a horizontal flatbed agitator, and samples were taken daily for analysis. PAR1 and PAR4 levels were evaluated using Western blot analysis. PLT aggregation was measured using Born aggregometry and specific PAR1 or PAR4 agonists. Thrombin generation was measured using calibrated automated thrombography. RESULTS: Levels of both receptors (PAR1 and PAR4) started to decrease after 5 days of storage. PAR1-mediated PLT aggregation remained constant, whereas PAR4-mediated PLT aggregation decreased with storage time. Rate of thrombin generation was accelerated after 5 days of storage. CONCLUSION: Decreasing levels of PARs in PLT concentrates after 5 days of storage influenced PAR4-mediated, but not PAR1-mediated, aggregation. Thrombin generation with senescent PLTs was increased, which may be attributed to other mechanisms promoting increased phosphatidylserine exposure. PMID- 22233333 TI - Progress in cancer therapy. PMID- 22233334 TI - Stable integration of an engineered megabase repeat array into the maize genome. AB - Plant genome engineering as a practical matter will require stable introduction of long and complex segments of DNA sequence into plant genomes. Here we show that it is possible to synthetically engineer and introduce centromere-sized satellite repeat arrays into maize. We designed a synthetic repeat monomer of 156 bp that contains five DNA-binding motifs (LacO, TetO, Gal4, LexA, and CENPB), and extended it into tandem arrays using an overlapping PCR method similar to that commonly used in gene synthesis. The PCR products were then directly transformed into maize using biolistic transformation. We identified three resulting insertion sites (arrayed binding sites), the longest of which is at least 1100 kb. The LacI DNA-binding module is sufficient to efficiently tether YFP to the arrayed binding sites. We conclude that synthetic repeats can be delivered into plant cells by omitting passage through Escherichia coli, that they generally insert into one locus, and that great lengths may be achieved. It is anticipated that these experimental approaches will be useful for future applications in artificial chromosome design. PMID- 22233335 TI - Is this the right time to join Turkey to the European interprofessional education community? PMID- 22233337 TI - Potential for pet animals to harbour methicillin-resistant Staphylococcus aureus when residing with human MRSA patients. AB - Colonization by methicillin-resistant Staphylococcus aureus (MRSA) may be persistent in people and is horizontally transmissible. The scientific literature suggests that domestic pets may also participate in cross-transmission of MRSA within households. The objectives of this study were to evaluate the prevalence of and risk factors for MRSA carriage by pets residing in households with an MRSA infected person. From 66 households in which an MRSA-infected patient resided, we screened 47 dogs and 52 cats using a swab protocol. Isolates from pets and humans were genotyped using two techniques and compared for concordance. Human participants completed a 22-question survey of demographic and epidemiologic data relevant to staphylococcal transmission. Eleven of 99 pets (11.5%) representing 9 (13.6%) of households were MRSA-positive, but in only six of these households were the human and animal-source strains genetically concordant. Human infection by strain USA 100 was significantly associated with pet carriage [OR = 11.4 (95% CI 1.7, 76.9); P = 0.013]. Yet, for each day of delay in sampling the pet after the person's MRSA diagnosis, the odds of isolating any type of MRSA from the pet decreased by 13.9% [(95% CI 2.6, 23.8); P = 0.017)]. It may be concluded that pets can harbour pandemic strains of MRSA while residing in a household with an infected person. However, the source of MRSA to the pet cannot always be attributed to the human patient. Moreover, the rapid attrition of the odds of obtaining a positive culture from pets over time suggests that MRSA carriage may be fleeting. PMID- 22233336 TI - Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5 HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice. AB - BACKGROUND AND PURPOSE: Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT](ext)). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA](ext)). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH: This study examined the effects of escitalopram, on both [5-HT](ext) and [NA](ext) in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT(-/-)) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA](ext), either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT](ext) elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT](ext) and/or [NA](ext) affected the antidepressant-like activity of escitalopram. KEY RESULTS: In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT](ext) and [NA](ext). As expected, escitalopram failed to increase cortical [5-HT](ext) in SERT(-/-) mice, whereas its neurochemical effects on [NA](ext) persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS: These experiments suggest that escitalopram enhances, although moderately, cortical [NA](ext) in vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET). PMID- 22233339 TI - Micro-Raman observation on the HPO4(2-) association structures in an individual dipotassium hydrogen phosphate (K2HPO4) droplet. AB - A single K(2)HPO(4) droplet with size of ~50 MUm on a Teflon substrate was forced to enter into the supersaturated state by decreasing the relative humidity (RH), allowing accurate control over the concentration of the solute within a droplet of a nanogram. The K(2)HPO(4) solutions from dilute (0.1-1.0 mol.L(-1) bulk) to concentrated state (a droplet from RH 98.2% to 25.1%) were studied through micro Raman spectroscopy in the spectral region of about 200-4000 cm(-1). The area ratio between the water stretching band to the sum of the nu(1)-PO(3), nu(2)-POH, and nu(4)-PO(3) bands of the HPO(4)(2-) at various RHs was used to describe the dehydration behavior of a microsized single K(2)HPO(4) droplet in dehumidifying process. The peak position of the v(1)-PO(3) band for the 1 mol.L(-1) bulk solution appeared at 991 cm(-1) and moved to 986 cm(-1) at 98.2% RH, to 978 cm( 1) at 70.2% RH, and then to 964 cm(-1) at 30.0% RH for a droplet, accompanying an increase of the full width at half-height (fwhh) of this peak from 16.3 to 17.2, 22.2, and then to 24.2 cm(-1), indicating transition of the HPO(4)(2-) anions from monomers to dimers/trimers/oligomers and then to polyanions with chain structures in the K(2)HPO(4) solutions. After 25.1% RH, the solid was proved to be K(2)HPO(4).3H(2)O according to the Raman spectral features. Furthermore, the O H stretching envelope of a K(2)HPO(4) droplet showed that the intensity ratios of the strong hydrogen bonding component (3255 cm(-1)) to the weak one (3417 cm(-1)) and the cage-like water (2925 cm(-1)) to the weak one (3417 cm(-1)) were sensitive to the HPO(4)(2-) association structures, which can be used to understand the effects of dimers/trimers/oligomers and chain structures of the HPO(4)(2-) associations on the hydrogen bonding of water molecules. PMID- 22233338 TI - Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report. AB - BACKGROUND: Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene. Since the initial manuscript, one further HOXD13 mutation has been reported only in a single family manifesting isolated BDE. CASE PRESENTATION: In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene. So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein. CONCLUSION: The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations. PMID- 22233340 TI - Protein kinase D2 has a restricted but critical role in T-cell antigen receptor signalling in mature T-cells. AB - PKD (protein kinase D) 2 is a serine/threonine kinase activated by diacylglycerol in response to engagement of antigen receptors in lymphocytes. To explore PKD2 regulation and function in TCR (T-cell antigen receptor) signal transduction we expressed TCR complexes with fixed affinity for self antigens in the T-cells of PKD2-null mice or mice deficient in PKD2 catalytic activity. We also developed a single cell assay to quantify PKD2 activation as T-cells respond to developmental stimuli or engagement of alpha/beta TCR complexes in vivo. Strikingly, PKD2 loss caused increases in thymic output, lymphadenopathy and splenomegaly in TCR transgenic mice. The precise magnitude and timing of PKD2 activation during T cell development is thus critical to regulate thymic homoeostasis. PKD2-null T cells that exit the thymus have a normal transcriptome, but show a limited and abnormal transcriptional response to antigen. Transcriptional profiling reveals the full consequences of PKD2 loss and maps in detail the selective, but critical, function for PKD2 in signalling by alpha/beta mature TCR complexes in peripheral T-cells. PMID- 22233342 TI - "Biological variability of C-reactive protein and specific canine pancreatic lipase immunoreactivity in apparently healthy dogs". PMID- 22233341 TI - Controlling self-assembly of engineered peptides on graphite by rational mutation. AB - Self-assembly of proteins on surfaces is utilized in many fields to integrate intricate biological structures and diverse functions with engineered materials. Controlling proteins at bio-solid interfaces relies on establishing key correlations between their primary sequences and resulting spatial organizations on substrates. Protein self-assembly, however, remains an engineering challenge. As a novel approach, we demonstrate here that short dodecapeptides selected by phage display are capable of self-assembly on graphite and form long-range ordered biomolecular nanostructures. Using atomic force microscopy and contact angle studies, we identify three amino acid domains along the primary sequence that steer peptide ordering and lead to nanostructures with uniformly displayed residues. The peptides are further engineered via simple mutations to control fundamental interfacial processes, including initial binding, surface aggregation and growth kinetics, and intermolecular interactions. Tailoring short peptides via their primary sequence offers versatile control over molecular self-assembly, resulting in well-defined surface properties essential in building engineered, chemically rich, bio-solid interfaces. PMID- 22233344 TI - Association of postprandial serum triglyceride concentration and serum canine pancreatic lipase immunoreactivity in overweight and obese dogs. AB - BACKGROUND: Hypertriglyceridemia has been proposed to contribute to the risk of developing pancreatitis in dogs. OBJECTIVES: To determine associations between postprandial serum triglyceride concentrations and canine pancreatic lipase immunoreactivity (cPLI) concentrations or pancreatic disease. ANIMALS: Thirty five client-owned overweight (n = 25) or obese (n = 10) dogs weighing >10 kg. METHODS: Healthy dogs were prospectively recruited for a cross-sectional study. Serum triglyceride concentrations were measured before and hourly for 12 hours after a meal. Fasting cPLI and canine trypsin-like immunoreactivity (cTLI) concentrations were assayed. Cut-off values for hypertriglyceridemia were set a priori for fasting (>= 88, >= 177, >= 354, >= 885 mg/dL) and peak postprandial (>= 133, >= 442, >= 885 mg/dL) triglyceride concentrations. The association between hypertriglyceridemia and high cPLI concentrations was assessed by exact logistic regression. Follow-up was performed 4 years later to determine the incidence of pancreatic disease. RESULTS: Eight dogs had peak postprandial triglycerides >442 mg/dL and 3 dogs had fasting serum cPLI concentrations >= 400 MUg/L. Odds of high cPLI concentrations were 16.7 times higher in dogs with peak postprandial triglyceride concentrations >= 442 mg/dL relative to other dogs (P < .001). Fasting triglyceride concentration was not significantly associated with cPLI concentrations. None of the dogs with high triglyceride concentrations and one of the dogs with low fasting and peak postprandial triglyceride concentrations developed clinically important pancreatic disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Overweight and obese dogs with peak serum postprandial triglyceride concentrations >= 442 mg/dL after a standard meal are more likely to have serum cPLI concentrations >= 400 MUg/L, but did not develop clinically important pancreatic disease. PMID- 22233345 TI - Clinicopathologic features of intracranial central neurocytomas in 2 dogs. AB - BACKGROUND: In humans, central neurocytomas are rare and typically benign intracranial tumors found within the lateral ventricles, although extraventricular variants have been reported. Intracranial central neurocytomas have not been previously recognized in domestic animals. OBJECTIVES: To describe the clinicopathologic features of canine intracranial central neurocytomas. ANIMALS: Two dogs with spontaneous intracranial and intraventricular neoplasms. RESULTS: Both dogs experienced seizures, rapid neurological deterioration, and death from tumor-associated complications within 5 days of the onset of clinical signs, and had neoplastic masses within the lateral ventricles. A brain MRI was performed in 1 dog, which revealed a T1-isointense, heterogeneously T2 and FLAIR hyperintense, and markedly and heterogeneously contrast-enhancing mass lesions within both lateral ventricles. Histologically, the neoplasms resembled oligodendrogliomas. The diagnosis of central neurocytoma was supported by documenting expression of multiple neuronal markers, including neuron-specific enolase, synaptophysin, neural-cell adhesion molecule, and neuronal nuclear antigen within the tumors, and ultrastructural evidence of neuronal differentiation of neoplastic cells. CONCLUSIONS AND CLINICAL IMPORTANCE: Central neurocytoma should be a differential diagnosis for dogs with intraventricular brain masses. Morphologic differentiation of central neurocytoma from other intraventricular neoplasms, such as ependymoma or oligdendroglioma, can be difficult, and definitive diagnosis often requires immunohistochemical or ultrastructural confirmation of the neural origin of the neoplasm. PMID- 22233346 TI - Evaluation of readmission ink as a marker for dispersal studies with the oriental fruit fly, Bactrocera dorsalis. AB - In this text we present a new marking dye, readmission ink, Blak-Ray, for the purpose of insect movement studies. The dye was tested in a controlled experiment with Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) in anticipation of a long distance movement study planned for the following year with the same species. 700 individuals of both sexes were marked with the dye and placed in holding containers. Both the percentage of mortality and the ease of dye detection were monitored throughout a five-week period. Results showed minimal fly mortality and exceptional ease of dye detection. PMID- 22233347 TI - Statins improve outcome in murine models of intracranial hemorrhage and traumatic brain injury: a translational approach. AB - Traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) are leading causes of neurological mortality and disability in the U.S. However, therapeutic options are limited and clinical management remains largely supportive. HMG-CoA reductase inhibitors (statins) have pleiotropic mechanisms of action in the setting of acute brain injury, and have been demonstrated to improve outcomes in preclinical models of ICH and TBI. To facilitate translation to clinical practice, we now characterize the optimal statin and dosing paradigm in murine models of ICH and TBI. In a preclinical model of TBI, mice received vehicle, simvastatin, and rosuvastatin at doses of 1 mg/kg and 5 mg/kg for 5 days after the impact. Immunohistochemistry, differential gene expression, and functional outcomes (rotarod and Morris water maze testing) were assessed to gauge treatment response. Following TBI, administration of rosuvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes. Rosuvastatin treatment was associated with histological evidence of reduced neuronal degeneration at 24 h post-TBI, reduced microgliosis at day 7 post-TBI, and preserved neuronal density in the CA3 region at 35 days post-injury. Administration of rosuvastatin following TBI was also associated with downregulation of inflammatory gene expression in the brain. Following ICH, treatment with simvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes, an effect that was independent of hemorrhage volume. Clinically relevant models of acute brain injury may be used to define variables such as optimal statin and dosing paradigms to facilitate the rational design of pilot clinical trials. PMID- 22233348 TI - Anti-inflammatory mechanism of 15,16-epoxy-3alpha-hydroxylabda-8,13(16),14-trien 7-one via inhibition of LPS-induced multicellular signaling pathways. AB - Phytochemical investigation of Leonurus japonicus has led to the isolation of a labdane diterpene derivative, 15,16-epoxy-3alpha-hydroxylabda-8,13(16),14-trien-7 one (1), which was tested for its in vitro anti-inflammatory effects. The results demonstrated that 1 exhibits an inhibitory effect on LPS-stimulated RAW 264.7 macrophages. The anti-inflammatory action shown by 1 suppressed LPS-induced NF kappaB activation, resulting in the down-regulation of iNOS and COX-2 protein expression, attributable to the inhibitory action of LPS-induced NO and PGE(2) production. Compound 1 inhibited LPS-induced phosphorylation and the degradation of inhibitory kappa B (IkappaBalpha) and decreased the nuclear translocation of p50 and p65. In addition, 1 exhibited an inhibitory effect on LPS-induced NF kappaB-DNA and AP-1-DNA binding activity, using an electrophoretic mobility shift assay with NF-kappaB- and AP-1-specific (32)P-labeled probes. The LPS-induced mitogen-activated protein kinases (p-JNK, p-p38, and p-ERK) and p-Akt were inhibited after 30 and 10 min of LPS stimulation, respectively. In addition, TNF alpha production was suppressed by 1. PMID- 22233349 TI - Isoquinoline-based lanthanide complexes: bright NIR optical probes and efficient MRI agents. AB - In the objective of developing ligands that simultaneously satisfy the requirements for MRI contrast agents and near-infrared emitting optical probes that are suitable for imaging, three isoquinoline-based polyaminocarboxylate ligands, L1, L2 and L3, have been synthesized and the corresponding Gd(3+), Nd(3+) and Yb(3+) complexes investigated. The specific challenge of the present work was to create NIR emitting agents which (i) have excitation wavelengths compatible with biological applications and (ii) are able to emit a sufficient number of photons to ensure sensitive NIR detection for microscopic imaging. Here we report the first observation of a NIR signal arising from a Ln(3+) complex in aqueous solution in a microscopy setup. The lanthanide complexes have high thermodynamic stability (log K(LnL) =17.7-18.7) and good selectivity for lanthanide ions versus the endogenous cations Zn(2+), Cu(2+), and Ca(2+) thus preventing transmetalation. A variable temperature and pressure (17)O NMR study combined with nuclear magnetic relaxation dispersion measurements yielded the microscopic parameters characterizing water exchange and rotation. Bishydration of the lanthanide cation in the complexes, an important advantage to obtain high relaxivity for the Gd(3+) chelates, has been demonstrated by (17)O chemical shifts for the Gd(3+) complexes and by luminescence lifetime measurements for the Yb(3+) analogues. The water exchange on the three Gd(3+) complexes is considerably faster (k(ex)(298) = (13.9-15.4) * 10(6) s(-1)) than on commercial Gd(3+)-based contrast agents and proceeds via a dissociative mechanism, as evidenced by the large positive activation volumes for GdL1 and GdL2 (+10.3 +/- 0.9 and +10.6 +/- 0.9 cm(3) mol(-1), respectively). The relaxivity of GdL1 is doubled at 40 MHz and 298 K in fetal bovine serum (r(1) = 16.1 vs 8.5 mM(-1) s( 1) in HEPES buffer), due to hydrophobic interactions between the chelate and serum proteins. The isoquinoline core allows for the optimization of the optical properties of the luminescent lanthanide complexes in comparison to the pyridinic analogues and provides significant shifts of the excitation energies toward lower values which therefore become more adapted for biological applications. L2 and L3 bear two methoxy substituents on the aromatic core in ortho and para positions, respectively, that further modulate their electronic structure. The Nd(3+) and Yb(3+) complexes of the ligand L3, which incorporates the p-dimethoxyisoquinoline moiety, can be excited up to 420 nm. This wavelength is shifted over 100 nm toward lower energy in comparison to the pyridine-based analogue. The luminescence quantum yields of the Nd(3+) (0.013-0.016%) and Yb(3+) chelates (0.028-0.040%) are in the range of the best nonhydrated complexes, despite the presence of two inner sphere water molecules. More importantly, the 980 nm NIR emission band of YbL3 was detected with a good sensitivity in a proof of concept microscopy experiment at a concentration of 10 MUM in fetal bovine serum. Our results demonstrate that even bishydrated NIR lanthanide complexes can emit a sufficient number of photons to ensure sensitive detection in practical applications. In particular, these ligands containing an aromatic core with coordinating pyridine nitrogen can be easily modified to tune the optical properties of the NIR luminescent lanthanide complexes while retaining good complex stability and MRI characteristics for the Gd(3+) analogues. They constitute a highly versatile platform for the development of bimodal MR and optical imaging probes based on a simple mixture of Gd(3+) and Yb(3+)/Nd(3+) complexes using an identical chelator. Given the presence of two inner sphere water molecules, important for MRI applications of the corresponding Gd(3+) analogues, this result is particularly exciting and opens wide perspectives not only for NIR imaging based on Ln(3+) ions but also for the design of combined NIR optical and MRI probes. PMID- 22233350 TI - Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901. AB - OBJECTIVE: To review long-term safety data from the rollover study ETV-901, focusing on adverse events (AEs) with a potential nucleos(t)ide association. METHODS: The open-label study ETV-901 (AI463901) assessed the safety of entecavir in chronic hepatitis B patients who received entecavir, lamivudine or adefovir monotherapy in previous entecavir Phase II/III studies. Long-term cumulative safety results are based on reported AEs, regardless of causal relationship. RESULTS: Median exposure to entecavir in study ETV-901 was 184 weeks. Commonly reported AEs (>= 10%) were upper respiratory tract infection, headache and nasopharyngitis. Most AEs were mild to moderate; 203 (19%) patients reported grade 3 - 4 AEs, with 45 (4%) considered related to entecavir. There were 14 (1%) discontinuations due to AEs. On-treatment alanine aminotransferase (ALT) flares were reported in 32 (3%) patients and were associated with a reduction in hepatitis B virus DNA of more than 2 log(10) copies/ml in 25/32 patients. AEs potentially associated with nucleos(t)ide analogs were infrequent, the most common being myalgia (n = 54; 5%) and neuropathy-related AEs (hypoparesthesia and hyperparesthesia, polyneuropathy; n = 42; 4%). CONCLUSIONS: Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. AEs potentially associated with nucleos(t)ide use occurred at low rates. PMID- 22233351 TI - Synthesis of C-glycoside analogues of alpha-galactosylceramide via linear allylic C-H oxidation and allyl cyanate to isocyanate rearrangement. AB - C-Glycoside analogues of alpha-galactosylceramide were synthesized in which several significant modifications known to promote Th-1 cytokine production were included. The key transformations include C-H oxidation, Sharpless asymmetric epoxidation, olefin cross metathesis, and an allyl cyanate to isocyanate rearrangement. PMID- 22233352 TI - Infant responsiveness, alertness, haemoglobin and growth in rural Sidama, Ethiopia. AB - Several recent studies have supported relations between infant behaviour (alertness and responsiveness) and nutrition in addition to investigating infant behaviour within the context of changes in iron status over time. Existing research is typically limited to the investigation of the effects of a single vitamin or mineral, and no studies have been found that examined the influence that early alertness and responsiveness have on growth in early infancy, despite the fact that relations between behaviour and nutritional status may be bidirectional. The current study used a sample of Ethiopian infants and investigated anthropometrics, haemoglobin, the frequency of alertness and the frequency of responsiveness at 6 and 9 months of age. Six-month weight-for-age predicted 9-month frequency of alertness, while 6-month haemoglobin predicted 9 month frequency of responsiveness. Compared with responsive infants, non responsive infants at 6 months remained more non-responsive at 9 months, although weight-for-age for both groups converged at 9 months. Results support relations between nutrition and behaviour (alertness and responsiveness) and provide evidence of a potentially useful tool (the Laboratory Temperament Assessment Battery) that was adapted to evaluate these relations in Ethiopia. PMID- 22233353 TI - A bacterial cysteine protease effector protein interferes with photosynthesis to suppress plant innate immune responses. AB - The bacterial pathogen Pseudomonas syringae pv tomato DC3000 suppresses plant innate immunity with effector proteins injected by a type III secretion system (T3SS). The cysteine protease effector HopN1, which reduces the ability of DC3000 to elicit programmed cell death in non-host tobacco, was found to also suppress the production of defence-associated reactive oxygen species (ROS) and callose when delivered by Pseudomonas fluorescens heterologously expressing a P. syringae T3SS. Purified His(6) -tagged HopN1 was used to identify tomato PsbQ, a member of the oxygen evolving complex of photosystem II (PSII), as an interacting protein. HopN1 localized to chloroplasts and both degraded PsbQ and inhibited PSII activity in chloroplast preparations, whereas a HopN1(D299A) non-catalytic mutant lost these abilities. Gene silencing of NtPsbQ in tobacco compromised ROS production and programmed cell death by DC3000. Our data reveal PsbQ as a contributor to plant immunity responses and a target for pathogen suppression. PMID- 22233354 TI - Differences in acetabular morphology related to side and sex in a Chinese population. AB - The purpose of the present study was to determine the side and sex differences in acetabular dimension and orientation in normal Chinese adults, which are not known well but are important in hip joint replacement surgery. The acetabular parameters, including anteversion angle (AV.A), abduction angle (AB.A), center edge angle (CE.A), acetabular width (Ac.W) and acetabular depth (Ac.D), were measured on CT images in 100 healthy Chinese adults. The acetabular index of depth to width (Ac.D/Ac.W) was calculated by depth/width * 100. Percentage side difference (PSD) was calculated for each parameter. The absolute numbers of PSD (aPSD) were compared between the groups of right positive (right PSD > left PSD) and left positive (left PSD > right PSD) groups. There was no significant side difference in any of the parameters. Compared to men, a significant increase in AB.A (P = 0.001) and significant decreases in Ac.W (P < 0.001), Ac.D (P < 0.001) and Ac.D/Ac.W (P < 0.05) occurred in women. The differences in Ac.W and Ac.D became insignificant when adjusted for body height. aPSD did not show a significant difference between right and left positive groups in both sexes. In conclusion, the side differences in acetabular parameters in a normal individual are likely to be associated with measurement error. In addition, the larger acetabular dimension in men is attributed to greater body height independent of sex. PMID- 22233355 TI - Natural history of lower urinary tract symptoms in Japanese men from a 15-year longitudinal community-based study. AB - Study Type - Symptom prevalence (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? There have been few longitudinal community-based studies on LUTS suggestive of BPH. It is important to determine the natural history of LUTS suggestive of BPH among men in various countries because it is known that there are differences according to race. Although we previously reported a cross-sectional community-based survey on LUTS suggestive of BPH in Japanese men, no longitudinal data were available. The present study provides 15-year longitudinal data on LUTS suggestive of BPH and related variables in Japanese men. OBJECTIVE: To report the natural history of benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in Japanese men. PATIENTS AND METHODS: From 1992 to 1993, we conducted a cross-sectional community based study on LUTS suggestive of BPH in Japanese men aged 40-79 years. * After 15 fifteen years, a follow-up study was conducted to determine their longitudinal changes of LUTS. * Of the 319 participants taking part in the initial study, 135 participated again in the follow-up study. * We investigated International Prostate Symptom Score (IPSS), quality of life index and bother score using a questionnaire, and measured prostate volume (PV), prostate-specific antigen (PSA) level and peak urinary flow rate (Q(max) ) using a method that we have employed previously. RESULTS: The change in the total IPSS during 15 years was significant (P= 0.001) and its mean (sd) annual change was 0.11 (0.40). * Although there was little change in the bother score, a significant correlation was observed between changes in the IPSS and bother score (r= 0.528, P < 0.001). * For the individual IPSS and bother scores, only changes in urgency, weak stream and nocturia were significant. * The changes in PV, PSA level and Q(max) were significant. * The change in the total IPSS did not correlate with the changes in these variables. CONCLUSION: In a 15-year-longitudinal community-based study for Japanese men, we have shown that the IPSS and quality of life index deteriorated, PV and PSA level increased, and Q(max) decreased. PMID- 22233356 TI - Granulomatous foreign-body reaction with facial dermal fillers after omalizumab treatment for severe persistent allergic asthma: a case report. PMID- 22233357 TI - Development of donor-specific isohemagglutinins following pediatric ABO incompatible heart transplantation. AB - Graft acceptance following pediatric ABO-incompatible heart transplantation has been associated with a deficiency of donor-specific isohemagglutinins (DSI) due to B-cell elimination. Recent observations suggest that some of these patients do produce DSI. The purpose of this study was to examine the pattern of, risk factors for development and clinical impact of DSI. All children who underwent an ABO-incompatible heart transplant (1996-2009) were included. Serial postheart transplantation DSI titers and clinical outcomes were reviewed. DSI were produced in 27% of the patients (n = 11/41). Anti-A production was significantly greater in "at risk" patients than Anti-B (39% vs. 8%; p = 0.04). Risk factors associated with the development of DSI included: older age at transplantation (HR: 1.15/month, p = 0.04), pretransplant Anti-B level >= 1:8 (HR: 9.61, p = 0.004) and HLA sensitization (HR: 2.80, p = 0.11). The presence of DSI did increase the risk of cellular rejection but not antibody-mediated rejection, allograft vasculopathy, graft loss or death. Although these antibodies do not result in any significant clinical consequences, their presence suggests that B-cell tolerance is not the sole mechanism of graft acceptance. PMID- 22233358 TI - The impact of apheresis platelet manipulation on corrected count increment. AB - BACKGROUND: Concentrating and washing apheresis platelets (APs) substantially reduce the number of allergic transfusion reactions likely due to removal of plasma. However, these processes may damage platelets (PLTs). This study evaluated whether concentrating or washing APs decrease the corrected count increment (CCI). STUDY DESIGN AND METHODS: This retrospective study evaluated individuals who initially received unmanipulated APs and subsequently received concentrated and/or washed APs at a large university hospital between 1998 and 2009. Concentrated units were prepared by reducing the plasma volume of APs by a goal of more than 67%. Washed units were prepared by washing the APs with 1 L of normal saline. The CCI (PLTs [*10(6)] * m(2)/L) for all transfusions was calculated. Hypothesis testing was performed with t tests for continuous variables and chi-square tests for dichotomous variables. RESULTS: We evaluated 121 individuals: 46 patients who received unmanipulated, concentrated, and then washed APs; 59 patients who received unmanipulated and then concentrated APs; and 16 patients who received unmanipulated and then washed APs. Patient demographics were similar among the three groups. The mean CCI for unmanipulated AP transfusions at 0 to 2 hours posttransfusion was significantly higher than concentrated and washed PLT transfusions (p<0.001). When accounting for PLT loss due to manipulation, concentrating APs did not impact the CCI. However, the CCI remained significantly lower for washed products at all time points after transfusion (40.7% mean reduction at 20-24 hr, p<0.001). CONCLUSIONS: Washing APs significantly reduces PLT count recovery and survival, as demonstrated by a significantly reduced CCI. PMID- 22233359 TI - CAG repeat length in androgen receptor gene is not associated with amyotrophic lateral sclerosis. AB - BACKGROUND: Epidemiological and clinical studies show higher prevalence of amyotrophic lateral sclerosis (ALS) in males than in females and more severe lesions in androgen receptor (AR)-expressing tissues. The AR gene contains a polymorphic CAG trinucleotide repeat, whose expansion over a certain threshold is toxic to motor neurons, causing spinal and bulbar muscular atrophy (SBMA). PURPOSE AND METHODS: We tested the hypothesis that the AR CAG repeat linked to SBMA is a risk factor for ALS. We analyzed AR CAG expansions in 336 patients with ALS and 100 controls. RESULTS: We found a negative association of AR CAG expansions with ALS susceptibility, clinical presentation, and survival. CONCLUSIONS: Our findings do not support a role of the AR CAG repeat length in ALS. PMID- 22233361 TI - Understanding the "impact" of the impact factor. PMID- 22233362 TI - Producing and translating health system evidence for improved global health. PMID- 22233363 TI - Collaboration: what is it like? - phenomenological interpretation of the experience of collaborating within rehabilitation teams. AB - Although a core component of many current health-care directions, interprofessional collaboration continues to challenge educators and health professionals. This paper aims to inform the development of collaborative practice by illuminating the experiences of collaborating within rehabilitation teams. The researchers focused on experiences that transcended team members' professional role categorizations in order to bring individuals and their lived experiences to the forefront. An inclusive view of "teams" and "collaboration" was adopted and the complexity and multifaceted nature of collaborating were explored through a hermeneutic phenomenological approach. Semi-structured interviews were used to gather data about experiences of collaborating in nine rehabilitation teams. Sixty-six team members across nine teams were interviewed. Eight interdependent dimensions, core to the experience of collaborating, emerged from the analysis of the data. Five dimensions expressed interpersonal dimensions of endeavor: engaging positively with other peoples' diversity; entering into the form and feel of the team; establishing ways of communicating and working together; envisioning together frameworks for patients' rehabilitation and effecting changes in people and situations. Three reviewing dimensions, reflexivity, reciprocity and responsiveness, operated across the endeavor dimensions. By identifying meaning structures of the experience of collaborating, this study highlights the importance of seeing beyond team members' professional affiliations and being aware of their contextualized interpersonal and activity related collaborating capabilities. PMID- 22233364 TI - From the nurses' station to the health team hub: how can design promote interprofessional collaboration? AB - Interprofessional practice implies that health professionals are able to contribute patient care in a collaborative environment. In this paper, it is argued that in a hospital the nurses' station is a form of symbolic power. The term could be reframed as a "health team hub," which fosters a place for communication and interprofessional working. Studies have found that design of the Nurses' Station can impact on the walking distance of hospital staff, privacy for patients and staff, jeopardize patient confidentiality and access to resources. However, no studies have explored the implications of nurses' station design on interprofessional practice. A multi-site collective case study of three rural hospitals in South Australia explored the collaborative working culture of each hospital. Of the cultural concepts being studied, the physical design of nurses' stations and the general physical environment were found to have a major influence on an effective collaborative practice. Communication barriers were related to poor design, lack of space, frequent interruptions and a lack of privacy; the name "nurses' station" denotes the space as the primary domain of nurses rather than a workspace for the healthcare team. Immersive work spaces could encourage all members of the healthcare team to communicate more readily with one another to promote interprofessional collaboration. PMID- 22233365 TI - The impact of an interprofessional standardized patient exercise on attitudes toward working in interprofessional teams. AB - Effective interprofessional education engages participants in authentic tasks, settings and roles. Using these guiding principles, an interprofessional standardized patient exercise (ISPE) was developed and implemented for 101 dental, medical, nurse practitioner, pharmacy and physical therapy students. This study describes the ISPE and evaluates its impact on students' attitudes toward working in interprofessional teams. The attitudes toward health care teams (ATHCT) survey was administered pre- and post-ISPE and to a sample of non participating students. Faculty and students were surveyed post-ISPE about outcomes and satisfaction. Focus groups were conducted with students from each profession. Students' attitudes toward team-based care improved significantly on the team value and team efficiency subscales of the ATHCT. There were significant differences in attitudes toward team-based care by profession. Faculty and student satisfaction with the ISPE was high. These findings contribute to the growing body of literature on efforts to generate positive attitudes toward interprofessional collaboration early in training, which may influence students' ability to be effective members of healthcare teams. PMID- 22233366 TI - Clients as mediators of interprofessional collaboration in mental health services in Iran. AB - Interprofessional collaboration (IPC) has long been identified as a way of providing optimal mental health services (MHS). It is important, therefore, to identify and facilitate factors driving IPC. This paper presents health professionals' experiences and perceptions regarding the clients' role as a driving factor for IPC in MHS in an Iranian context. Health professionals included nurses, physicians (general physicians and medical specialists), psychologists and consultants. Qualitative methods were employed in the form of in-depth individual interviews and focus groups to collect data from 24 professionals and 4 clients. Data analysis generated four key themes: "Clients as axis of IPC", "Seamless services as a common incentive for IPC", "Clients as a common interprofessional linkage" and "Clients as a driving force to achieve IPC". From the professionals' perspective, it was found that clients had a mediating role in their collaborative relationships and practices. These findings are discussed in relation to the interprofessional literature. This paper goes on to argue that professionals need to be aware of and be trained about how to manage, as well as benefit from, the clients' fundamental role in IPC. PMID- 22233367 TI - Interprofessional learning and virtual communities: an opportunity for the future. AB - As various agencies increasingly advocate interprofessional care (IPC), it is paramount that the educational implications of this approach are considered. Interprofessional learning (IPL) is necessary for IPC and this paper argues that an emerging educational model, narrative-based virtual communities (VCs), meets this goal. We therefore argue for the fusion of narrative pedagogy with the VC approach to further the IPL agenda. Using stories to teach is not new. Technological innovations now make the possibility of using narrative, a way to enable students to experience greater reality in complex situations. Recently, two multimedia VCs have been developed. Here, we review the use of "The Neighborhood" and "Stilwell", as IPL tools. Early evaluation of these communities has been very positive and they offer a unique and innovative approach to IPL in ways that immerse learners from many professions into the context of the lives of individuals requiring health and social care, and the people who provide that service. Thus, it is possible to more fully realize and teach about collaboration and partnerships among professionals and patients. PMID- 22233368 TI - Interprofessional clinical education for occupational therapy and psychology students: a social skills training program for children with autism spectrum disorders. AB - An interprofessional clinical learning experience was developed for pre-licensure occupational therapy (OT) and psychology graduate students. Students worked in interprofessional teams to plan and implement a social skills training program for children with autism spectrum disorders (ASD). The objectives were to provide a hands-on, student-led clinical experience; facilitate interprofessional collaborative learning through leadership partnerships and teach children with ASD to engage in appropriate social skill behaviors. Concurrently, faculty performed qualitative research to explore how the students worked together to provide intervention to the children. Data were collected via interview, direct observation of student planning sessions and student interprofessional interactions, and collection of posts from an online social network site used for session planning. There were six student participants and two faculty participants. Four themes emerged: learning who I am as a professional, learning to appreciate our professional differences, learning to communicate with each other and figuring it out, for the benefit of the kids. This interprofessional clinical learning experience and research helps ensure that students are adequately prepared to represent their profession as part of a diverse interprofessional health care team. PMID- 22233369 TI - Cultural adaptation and validating a Japanese version of the readiness for interprofessional learning scale (RIPLS). AB - Readiness for interprofessional education (IPE) can be an important factor to evaluate because of the influences of attitudes toward the outcomes of interprofessional learning activities. However, a dearth of Japanese evaluation tools hinders its evaluation. The readiness for interprofessional learning scale (RIPLS) was selected, because it has been validated in different countries and its items reflected our local situation best. This research aimed to develop and validate a Japanese version of the original 19-item RIPLS. We developed a Japanese RIPLS employing forward/backward translation. Reliability of the Japanese version was studied using classical test theory and structural equation modeling to construct a model to inform curriculum development. We obtained a 0.74 Cronbach's alpha, which indicates adequacy. Subscales of "interprofessional education opportunities" (alpha = 0.90) and "uniqueness of profession" (alpha = 0.60) have relatively little weight compared to "teamwork and collaboration" (alpha = 0.92). A one-way structure suggests that readiness for interprofessional learning starts with "teamwork & collaboration" followed by changes in "learning opportunities" and subsequently "uniqueness of profession" (root mean square error of approximation = 0.06, comparative fit index = 0.93). This Japanese RIPLS can be used in undergraduate health sciences students with appropriate caution. Further development of the subscales and a client-centered subscale would be beneficial to fully achieve its potential. The need for further research into its reliability and validity is identified. Recommendations are provided for cross cultural adaptation and for establishing validity across different contexts. PMID- 22233370 TI - The role of the emergency care practitioner in the provision of health advice and health promotion to patients within the UK National Health Service. PMID- 22233371 TI - Comparison of faculty and student attitudes toward teamwork and collaboration in interprofessional education. PMID- 22233372 TI - Problem-based learning tutors within medical curricula: an interprofessional analysis. PMID- 22233373 TI - Professional status and interprofessional collaboration: a view of massage therapy. PMID- 22233374 TI - The University of Virginia interprofessional education initiative: an approach to integrating competencies into medical and nursing education. PMID- 22233377 TI - One-year follow-up of patients with melamine-induced urolithiasis in Southwest China. AB - In 2008, more than 290,000 children suffered from urinary tract stones with a history of consuming melamine-contaminated powdered formula in China. Little was known about the long-term follow-up of outcomes of these patients in southwest China, so we conducted one-year follow-up investigation for further study. Thirty six of 51 inpatients with melamine-induced urolithiasis were enrolled in this study. After 12 months follow-up, none of the children had vomiting, oliguria, gross hematuria, or fever. Twenty-seven patients were stone free, stones decreased in size in six patients and increased in three. Serum total protein, albumin, and pre-albumin increased significantly from baseline to 12 months, and renal function remained normal. Melamine-induced urolithiasis could not lead renal dysfunction at 12 months follow-up. The results of our study indicated that more attention should be paid to the prevention of protein malnutrition in children with a history of consuming melamine-contaminated food products. PMID- 22233378 TI - Luminescence of ion-pair states of halogens in liquid perfluorocarbons. AB - The I(2)(D'-A') luminescence in liquid C(7)F(16), C(8)F(18), C(9)F(20), and C(12)F(26) has been observed following irradiation with visible (within the I(2) X -> B band region) and UV (lambda < 300 nm) lasers. The band is shifted by ~2000 cm(-1) to the red relative to the gas phase and is significantly broader (fwhm ~ 3000 cm(-1) vs 500 cm(-1) in the gas phase). Two-color excitation of other halogens in C(n)F(2n+2) solvents revealed similarly shifted and strongly broadened D'-A' bands of Br(2), IBr, and BrCl. The stability of the ion-pair states of halogens in room temperature liquids opens new experimental opportunities for condensed phase studies and may be of applied interest considering the increasing industrial applications of perfluorocarbons. PMID- 22233380 TI - proTRAC--a software for probabilistic piRNA cluster detection, visualization and analysis. AB - BACKGROUND: Throughout the metazoan lineage, typically gonadal expressed Piwi proteins and their guiding piRNAs (~26-32nt in length) form a protective mechanism of RNA interference directed against the propagation of transposable elements (TEs). Most piRNAs are generated from genomic piRNA clusters. Annotation of experimentally obtained piRNAs from small RNA/cDNA-libraries and detection of genomic piRNA clusters are crucial for a thorough understanding of the still enigmatic piRNA pathway, especially in an evolutionary context. Currently, detection of piRNA clusters relies on bioinformatics rather than detection and sequencing of primary piRNA cluster transcripts and the stringency of the methods applied in different studies differs considerably. Additionally, not all important piRNA cluster characteristics were taken into account during bioinformatic processing. Depending on the applied method this can lead to: i) an accidentally underrepresentation of TE related piRNAs, ii) overlook duplicated clusters harboring few or no single-copy loci and iii) false positive annotation of clusters that are in fact just accumulations of multi-copy loci corresponding to frequently mapped reads, but are not transcribed to piRNA precursors. RESULTS: We developed a software which detects and analyses piRNA clusters (proTRAC, probabilistic TRacking and Analysis of Clusters) based on quantifiable deviations from a hypothetical uniform distribution regarding the decisive piRNA cluster characteristics. We used piRNA sequences from human, macaque, mouse and rat to identify piRNA clusters in the respective species with proTRAC and compared the obtained results with piRNA cluster annotation from piRNABank and the results generated by different hitherto applied methods.proTRAC identified clusters not annotated at piRNABank and rejected annotated clusters based on the absence of important features like strand asymmetry. We further show, that proTRAC detects clusters that are passed over if a minimum number of single-copy piRNA loci are required and that proTRAC assigns more sequence reads per cluster since it does not preclude frequently mapped reads from the analysis. CONCLUSIONS: With proTRAC we provide a reliable tool for detection, visualization and analysis of piRNA clusters. Detected clusters are well supported by comprehensible probabilistic parameters and retain a maximum amount of information, thus overcoming the present conflict of sensitivity and specificity in piRNA cluster detection. PMID- 22233379 TI - The functions of TRPA1 and TRPV1: moving away from sensory nerves. AB - The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation. PMID- 22233381 TI - Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. AB - Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation. PMID- 22233382 TI - "A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies". AB - BACKGROUND: The study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis. METHODS: Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E) staining and immunohistochemistry (IHC). RESULTS: Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor alpha (ERalpha)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50 100 cells. Transplantation of 50 tumorspheres (1-5 * 103 cells) in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear beta catenin and fibronectin but were negative for ERalpha and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and beta catenin to the membrane of tumor cells was observed. ERalpha was re-expressed in lung metastatic cells in two of five samples. CONCLUSIONS: Tumorspheres isolated under defined culture conditions from patient core biopsies were tumorigenic when transplanted into the mammary fat pad of NUDE mice, and metastasized to multiple mouse organs. Micrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. The development of macrometastases with organ-specific phenotypic distinctions provides a superior model for the investigation of organ specific effects on metastatic cancer cell survival and growth. PMID- 22233383 TI - The effects of heparan sulphate mimetic RGTA-OTR4120 on irradiated murine salivary glands. AB - BACKGROUND: This study focuses on the potential of ReGeneraTing Agent OTR4120 (RGTA-OTR4120) to treat radiation-induced damage of salivary glands. RGTAs are biopolymers designed to mimic the effects of heparan sulphate, thereby stimulation tissue repair and regeneration. METHODS: C3H mice were irradiated with a single dose of 15 Gy in the head and neck region. RGTA-OTR4120 was injected 24 h after radiotherapy, followed by weekly injections. At 2, 6 and 10 weeks after radiotherapy, salivary flow rates were measured and animals were sacrificed to obtain parotid and submandibular glands for histology. Periodic acid Schiff stain was performed to visualize mucins that are produced by acinar cells. Amylase and total protein content were measured in saliva samples. RESULTS: Salivary flow rates were increased at 2 weeks, but not at 6 and 10 weeks after radiotherapy with RGTA-OTR4120 administration, compared to irradiated controls. Two and 10 weeks after radiotherapy, the mucin production activity of acinar cells was increased under influence of RGTA administration. RGTA-OTR4120 did not influence amylase or total protein secretion. CONCLUSION: RGTA-OTR4120 administration has a positive effect on salivary flow rates in irradiated mice on the short term. The effect was absent 10 weeks after radiotherapy, while at that time point, mucin producing activity of acinar cells was elevated by RGTA-OTR4120 administration. Given these results and the advantages of RGTA use in irradiated patients, further investigation on the potential of this drug to treat radiation induced salivary gland damage, alone or in combination with other drugs, such as amifostine, is suggested. PMID- 22233384 TI - Cortisol metabolism after weight loss: associations with 11 beta-HSD type 1 and markers of obesity in women. AB - OBJECTIVE: Increased glucocorticoid metabolite excretion and enhanced expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue are closely correlated with obesity and its detrimental consequences. Weight loss ameliorates the latter. The aim of this study was to explore whether increased glucocorticoid exposure in obesity is improved with substantial weight loss and thus is a consequence rather than a cause of obesity. DESIGN AND PATIENTS: A prospective cohort study in 31 women. MEASUREMENTS: 11beta-HSD type 1 expression and activity, urinary glucocorticoid metabolite excretion, body composition including regional adipose tissue depots and insulin resistance by HOMA-IR before and 2 years after gastric bypass surgery. RESULTS: After weight loss, excretion of cortisol and cortisone metabolites decreased. Both cortisol and cortisone metabolite excretion correlated with central obesity, where the intraabdominal fat depot showed the strongest association. Cortisol metabolites correlated with 11beta-HSD type 1 activity in abdominal subcutaneous adipose tissue. The ratio of cortisol to cortisone metabolites [(5alpha-tetrahydrocortisol (5alphaTHF) + tetrahydrocortisol (THF) + alpha-cortol)/(tetrahydrocortisone (THE) + alpha cortolone)] and the ratio of 5alpha-THF/THF both decreased after stable weight loss, reflecting a downregulation of the net activities of 11beta-HSD type 1 and 5alpha-reductase. CONCLUSION: Long-term weight loss in women is not only followed by reduced glucocorticoid production, but also favourably decreases the global and tissue-specific activity of the cortisol-activating enzyme 11 beta-HSD type 1, possibly contributing to the health benefits of bariatric surgery. PMID- 22233385 TI - Biology and life history of Balcha indica, an ectoparasitoid attacking the emerald ash borer, Agrilus planipennis, in North America. AB - Balcha indica Mani and Kaul (Hymenoptera: Eupelmidae) is a solitary ectoparasitoid attacking larvae, prepupae, and pupae of the emerald ash borer, Agrilus planipennis Fairmaire (Hymenoptera: Eupelmidae). Its fecundity, oviposition rate, longevity, and development time were determined in the laboratory under standard rearing conditions (25 +/- 2 degrees C, 65 +/- 10% relative humidity, and 14:10 L:D). Adults lived a mean of 59 days with a maximum of 117 days. Lifetime adult fecundity averaged 36 eggs with a maximum 94 eggs per female. The egg stage lasted for a maximum of four days with ~ 50% eggs hatched within two days. The development time of the first instars lasted for a maximum of nine days; 50% of the first instars completed their development (i.e., molted to the next instar) within five days. Instars of the intermediate and final stage larvae (after molting of the first instars occurred) could not be distinguished until they reached the pupal stage, and 50% of those larvae pupated ~ 62 days after adult oviposition. Under the standard rearing conditions, 50% of B. indica took ~ 83 days to complete the life cycle (from egg to adult emergence) ranging from 47 to 129 days. These results suggest that B. indica may not have more than two generations in the mid-Atlantic and Midwest regions of United States, where normal growing seasons--with average temperature above 25 degrees C--are normally less than six months (May-October). Because of the long life span and oviposition period of adults, however, B. indica is likely to have overlapping generations. PMID- 22233386 TI - Using the economics of certification to improve the safety and quality of male circumcision in developing countries: three models of implementation. AB - Although male circumcision (MC) has been a widespread practice in some regions, while relatively new in others, it has recently ascended in popularity as a HIV reduction intervention, particularly in areas with high rates of HIV but low rates of MC. However, the uptake and potential effectiveness of MC may be hampered by uneven levels of provider training and procedure skill within developing country settings. Indeed, this procedure that is otherwise considered simple and safe has witnessed complication rates as high as 25-35% in some areas, leaving some men with irreversible injuries. To improve the transparency of procedure quality for prospective patients, I borrow from a classic economics approach and advocate a new application in the form of provider certification. Building on some experience in the healthcare systems and economic rationale of high-income counties, I explore the potential for certifying providers of MC in low-income countries and compare and contrast three models of implementation: government agency, private certifiers and private MC device manufacturers. The hope is that increased transparency of provider quality through any or all three types of certifying programmes can better assist local men as they navigate this otherwise complex and unclear medical care market. As more resources are being devoted to MC scale up, I argue that certification should be considered for incorporation as a means of complementing both current and future efforts in order to enhance the effectiveness of MC campaigns. The two models based on privatized certification, as opposed to having the local government underwrite the intervention, may prove most useful when public or philanthropic funding is volatile or incomplete for a given location. The timing for MC campaign adoption and desired speed of scale up may vary across countries in ways that international assistance efforts cannot always immediately and flexibly adapt to. As such, the role of the diverse MC provider marketplace and accompanying quality revelation mechanisms may take on different levels of importance and expediency across settings as individual countries move forward with their respective HIV prevention campaigns. The subsequent challenge is to creatively design solutions that are sustainable and applicable within diverse host-country environments and expectations. This is where I believe some economic insights are currently lacking in the MC dialogue. Although I believe the three certification models exhibit much potential for enhancing medical care delivery in developing countries, they are not without their challenges, and implementation would not necessarily be a simple process. Local levels of medical knowledge, public and private resource constraints and the integrity of local business transactions and government practices would likely influence the nature and success of a certification intervention. However, with sufficient model adaptability and partnerships across public and private sectors, I argue that many of these implementation issues could be proactively addressed. Creative and careful certification structures should ultimately improve the MC circumstances across a variety of developing countries. PMID- 22233387 TI - Oxyanion-encapsulated caged supramolecular frameworks of a tris(urea) receptor: evidence of hydroxide- and fluoride-ion-induced fixation of atmospheric CO2 as a trapped CO3(2-) anion. AB - A tris(2-aminoethyl)amine-based tris(urea) receptor, L, with electron-withdrawing m-nitrophenyl terminals has been established as a potential system that can efficiently capture and fix atmospheric CO(2) as air-stable crystals of a CO(3)(2 )-encapsulated molecular capsule (complex 1), triggered by the presence of n tetrabutylammonium hydroxide/fluoride in a dimethyl sulfoxide solution of L. Additionally, L in the presence of excess HSO(4)(-) has been found to encapsulate a divalent sulfate anion (SO(4)(2-)) within a dimeric capsular assembly of the receptor (complex 2) via hydrogen-bonding-activated proton transfer between the free and bound HSO(4)(-) anions. Crystallographic results show proof of oxyanion encapsulation within the centrosymmetric cage of L via multiple N-H...O hydrogen bonds to the six urea functions of two inversion-symmetric molecules. The solution-state binding and encapsulation of oxyanions by N-H...O hydrogen bonding has also been confirmed by quantitative (1)H NMR titration experiments, 2D NOESY NMR experiments, and Fourier transform IR analyses of the isolated crystals of the complexes that show huge spectral changes relative to the free receptor. PMID- 22233388 TI - Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury. AB - Voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF) after traumatic brain injury (TBI) when it occurs during a delayed time window. In contrast, acute post-TBI exercise does not increase BDNF. It is well known that increases in glucocorticoids suppress levels of BDNF. Moreover, recent work from our laboratory showed that there is a heightened stress response after fluid percussion injury (FPI). In order to determine if a heightened stress response is also observed with acute exercise, at post-injury days 0-4 and 7-11, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) release were measured in rats running voluntarily or exposed to two daily 20-min periods of forced running wheel exercise. Forced, but not voluntary exercise, continuously elevated CORT. ACTH levels were initially elevated with forced exercise, but decreased by post-injury day 7 in the control, but not the FPI animals. As previously reported, voluntary exercise did not increase BDNF in the FPI group as it did in the control animals. Forced exercise did not increase levels of BDNF in any group. It did, however, decrease hippocampal glucocorticoid receptors in the control group. The results suggest that exercise regimens with strong stress responses may not be beneficial during the early post-injury period. PMID- 22233389 TI - Pazopanib for the treatment of breast cancer. AB - INTRODUCTION: Several clinical trials have shown clinical benefit of angiogenesis inhibitors in the treatment of solid tumors. Pazopanib is a multitargeted tyrosine kinase inhibitor that is currently approved for the treatment of patients with advanced renal cell carcinoma (RCC). AREAS COVERED: In this article, the clinical development of pazopanib as it relates to breast cancer is reviewed including its evaluation in clinical trials and side effect profile. Preclinical data show the anti-tumor activity of pazopanib in animal models. Several trials of pazopanib monotherapy and combination therapy in breast cancer have been completed or are underway. EXPERT OPINION: The development of biomarkers predictive of response and toxicity to angiogenesis inhibitors remains a challenging endeavor and is necessary to help guide treatment decision. PMID- 22233390 TI - Origin and variation of tunicate secondary metabolites. AB - Ascidians (tunicates) are rich sources of structurally elegant, pharmaceutically potent secondary metabolites and, more recently, potential biofuels. It has been demonstrated that some of these compounds are made by symbiotic bacteria and not by the animals themselves, and for a few other compounds evidence exists supporting a symbiotic origin. In didemnid ascidians, compounds are highly variable even in apparently identical animals. Recently, we have explained this variation at the genomic and metagenomic levels and have applied the basic scientific findings to drug discovery and development. This review discusses what is currently known about the origin and variation of symbiotically derived metabolites in ascidians, focusing on the family Didemnidae, where most research has occurred. Applications of our basic studies are also described. PMID- 22233391 TI - Magnetostimulation in the treatment of crural vein ulceration. AB - Chronic venous insufficiency, as well as crural vein ulceration, developing at its background, poses a serious clinical problem. Treatment is costly and lengthy. Intense development of physical medicine allows to reduce the time of treatment, as well as to improve the life quality in numerous soft tissue ailments, including wounds that are hard to heal. This article presents the beneficial results of treatment of a 67-year-old woman patient with a diagnosis of crural vein ulceration in the right limb. The applied physiotherapeutic method, in the form of magnetostimulation, contributed to complete healing of the lesion, subsidence of symptoms, as well as improved life quality of the treated patient. PMID- 22233392 TI - Innate host responses to enteric bacterial pathogens: a balancing act between resistance and tolerance. AB - Infection by enteric bacterial pathogens activates pathogen recognition receptors, leading to innate responses that promote host defence. While responses that promote host 'resistance' to infection, through the release of antimicrobial mediators, or the recruitment of inflammatory cells aimed at clearing the infection are best known, recent studies have begun to identify additional innate driven responses that instead promote intestinal tissue repair and host survival. Described as infection 'tolerance' responses, we and others have primarily studied these responses in the Citrobacter rodentium infection model. In this review we discuss the impact of innate resistance mechanisms on host defence, and describe how 'tolerance' responses act primarily on the intestinal epithelium, triggering epithelial cell proliferation, repair or promoting barrier function. Resistance and tolerance responses appear to work together, with tolerance repairing the tissue injury caused by resistance driven inflammation. Tolerance responses fit a pattern where innate immunity and inflammation are tightly regulated in the gastrointestinal tract. Moreover, tolerance may have developed due to the successful subversion and avoidance of host resistance by enteric bacterial pathogens. Further studies are needed to clarify the contribution of different pathogen recognition receptors to tolerance and resistance responses against bacterial pathogens, in the gut or in other host tissues. PMID- 22233393 TI - This is our time! PMID- 22233395 TI - Animal-assisted therapy at an outpatient pain management clinic. AB - OBJECTIVE: The objective of this study was to evaluate the effects of brief therapy dog visits to an outpatient pain management facility compared with time spent in a waiting room. DESIGN: The design of this study is open-label. Setting. This study was conducted in a university tertiary care adult chronic pain outpatient clinic. SUBJECTS: The subjects of this study include outpatients, adults accompanying outpatients to their appointments, and clinic staff. Intervention. Participants were able to spend clinic waiting time with a certified therapy dog instead of waiting in the outpatient waiting area. When the therapy dog was not available, individuals remained in the waiting area. OUTCOME MEASURES: Self-reported pain, fatigue, and emotional distress were recorded using 11-point numeric rating scales before and after the therapy dog visit or waiting room time. RESULTS: Two hundred ninety-five therapy dog visits (235 with patients, 34 family/friends, and 26 staff) and 96 waiting room surveys (83 from patients, 6 family/friends, and 7 staff) were completed over a 2-month study period. Significant improvements were reported for pain, mood, and other measures of distress among patients after the therapy dog visit but not the waiting room control, with clinically meaningful pain relief (decrease >=2 points) in 23% after the therapy dog visit and 4% in the waiting room control. Significant improvements were likewise seen after therapy dog visits for family/friends and staff. CONCLUSIONS: Therapy dog visits in an outpatient setting can provide significant reduction in pain and emotional distress for chronic pain patients. Therapy dog visits can also significantly improve emotional distress and feelings of well-being in family and friends accompanying patients to appointments and clinic staff. PMID- 22233396 TI - A randomized, one-year clinical trial comparing the efficacy of topiramate, flunarizine, and a combination of flunarizine and topiramate in migraine prophylaxis. AB - OBJECTIVES: The objective of this study was to observe the efficacy, safety, and side effects of a combination of flunarizine plus topiramate compared with either flunarizine and or toparamate alone for migraine prophylaxis. METHODS: Out of 150 patients with migraine recruited into the study and randomly assigned to one of three conditions, 126 completed the trial in their group: flunarizine (39), topiramate (44), and flunarizine plus topiramate (43). Patient information was assessed at enrollment and at follow-up visits at the end of months 1-3, 6, 9, and 12. The primary measure of efficacy reduction in mean monthly migraine frequency of at least 50% as compared with baseline. Secondary efficacy parameters included reduction in mean monthly migraine days and severity of headache. Side effects were compared in the three groups by recording adverse reactions and weight changes. RESULTS: The proportion whose monthly headache frequency decreased more than 50% was 66.7% (26/39) in the flunarizine group, 72.7% (32/44) in the topiramate group and 76.7% (33/43) in the combination group, respectively (P=0.593). The mean monthly days and severity of headache in the three groups also declined and was more significant in the flunarizine plus topiramate group than in the flunarizine group and the topiramate group (P<0.05). In the flunarizine group, the average weight change was 0.6kg. Topiramate was associated with a mean weight loss was of -0.9kg in the topiramate group and 0.2kg in the flunarizine plus topiramate group. CONCLUSION: Flunarizine, topiramate, and the combination of flunarizine with topiramate are all effective and have good tolerability in migraine prophylaxis. Adding topiramate to flunarizine may reduce the latter's impact on body weight. PMID- 22233394 TI - Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-alpha receptor II following a trial of hypnosis: results of a randomized controlled pilot study. AB - OBJECTIVE: Current evidence supports the efficacy of hypnosis for reducing the pain associated with experimental stimulation and various acute and chronic conditions; however, the mechanisms explaining how hypnosis exerts its effects remain less clear. The hypothalamic-pituitary-adrenal (HPA) axis and pro inflammatory cytokines represent potential targets for investigation given their purported roles in the perpetuation of painful conditions; yet, no clinical trials have thus far examined the influence of hypnosis on these mechanisms. DESIGN: Healthy participants, highly susceptible to the effects of hypnosis, were randomized to either a hypnosis intervention or a no-intervention control. Using a cold pressor task, assessments of pain intensity and pain unpleasantness were collected prior to the intervention (Pre) and following the intervention (Post) along with pain-provoked changes in salivary cortisol and the soluble tumor necrosis factor-alpha receptor II (sTNFalphaRII). RESULTS: Compared with the no intervention control, data analyses revealed that hypnosis significantly reduced pain intensity and pain unpleasantness. Hypnosis was not significantly associated with suppression of cortisol or sTNFalphaRII reactivity to acute pain from Pre to Post; however, the effect sizes for these associations were medium-sized. CONCLUSIONS: Overall, the findings from this randomized controlled pilot study support the importance of a future large-scale study on the effects of hypnosis for modulating pain-related changes of the HPA axis and pro-inflammatory cytokines. PMID- 22233397 TI - A randomized placebo-controlled study of noninvasive cortical electrostimulation in the treatment of fibromyalgia patients. AB - OBJECTIVE: The aim of this multicenter study was to evaluate the efficacy, safety, and tolerability of noninvasive cortical electrostimulation in the management of fibromyalgia (FM). DESIGN: A prospective, randomized, double-blind, placebo-controlled design was used. Setting. Subjects received therapy at two different outpatient clinical locations. PATIENTS: There were 77 subjects meeting the American College of Rheumatology 1990 classification criteria for FM. Intervention. Thirty-nine (39) active treatment (AT) FM patients and 38 placebo controls received 22 applications of either noninvasive cortical electrostimulation or a sham therapy over an 11-week period. OUTCOME MEASURES: The primary outcome measures were the number of tender points (TePs) and pressure pain threshold (PPT). Secondary outcome measures were responses to the Fibromyalgia Impact Questionnaire (FIQ), Symptom Checklist-90 (SCL-90), Beck Depression Inventory-II, and a novel sleep questionnaire, all evaluated at baseline and at the end of treatment. RESULTS: Intervention provided significant improvements in TeP measures: compared with placebo, the AT patients improved in the number of positive TePs (-7.4 vs -0.2, P<0.001) and the PPT (19.6 vs -3.2, P<0.001). Most secondary outcomes also improved more in the AT group: total FIQ score (-15.5 vs -5.6, P=0.03), FIQ pain (-2.0 vs -0.6, P=0.03), FIQ fatigue (-2.0 vs -0.4, P=0.02), and FIQ refreshing sleep (-2.1 vs -0.7, P=0.02); and while FIQ function improved (-1.0 vs -0.2), the between-group change had a 14% likelihood of occurring due to chance (P=0.14). There were no significant side effects observed. CONCLUSIONS: Noninvasive cortical electrostimulation in FM patients provided modest improvements in pain, TeP measures, fatigue, and sleep; and the treatment was well tolerated. This form of therapy could potentially provide worthwhile adjunctive symptom relief for FM patients. PMID- 22233399 TI - A role for neuroserpin in neuron morphological development. PMID- 22233400 TI - Serum and tissue CTACK/CCL27 chemokine levels in early mycosis fungoides may be correlated with disease-free survival following treatment with interferon alfa and psoralen plus ultraviolet A therapy. AB - BACKGROUND: Neoplastic T-cell recruitment into the skin is a critical step in the pathogenesis of mycosis fungoides (MF), and the cutaneous T-cell attracting chemokine, CTACK/CCL27, might be involved. OBJECTIVES: To investigate the clinical and prognostic significance of CTACK/CCL27 levels in patients with early stage MF. METHODS: Serum samples and skin biopsy specimens were collected from 15 patients at the time of diagnosis and after the end of treatment with psoralen plus ultraviolet A/interferon alfa-2b combination therapy. Serum samples were also collected from 20 healthy donors as controls. CTACK/CCL27 serum levels were analysed by enzyme-linked immunosorbent assays. CTACK/CCL27 tissue expression was determined by immunohistochemistry on skin biopsy specimens taken at diagnosis and after therapy. Event-free survival was taken as the primary clinical outcome. RESULTS: In patients with MF at diagnosis, CTACK/CCL27 serum levels were not significantly different from healthy controls, whereas CTACK/CCL27 expression in the skin was increased in 87% of cases compared with normal controls. After therapy, all patients obtained a clinical complete remission, serum levels did not change significantly and tissue expression remained abnormal in 80% of patients, even if complete histological remission was recorded. Serum levels were not significantly different in cases with different intensity of cutaneous immunostaining. Eight patients experienced a relapse: the combination of high CTACK/CCL27 levels both in sera and skin increased the probability of experiencing an event at 51 months from 36% to 83%. CONCLUSIONS: Our data seem to indicate that CTACK/CCL27 levels in skin and sera after therapy might be correlated with risk of recurrence. PMID- 22233401 TI - Donor-specific isohemagglutinins: measuring the unknown. PMID- 22233402 TI - Accurate prediction of hypoxic-ischaemic encephalopathy at delivery: a cohort study. AB - OBJECTIVE: Hypoxic-ischaemic encephalopathy (HIE) is a major acute neurologic manifestation of perinatal asphyxia associated with significant mortality and morbidity. The study aimed to develop a simple, accurate method of predicting HIE at delivery. METHODS: Between January 2003 and December 2009, all HIE cases were identified from the 38,404 deliveries at a single tertiary centre. Receiver operating curve (ROC) analysis and multivariate logistic regression assessed the ability of clinical and biochemical assessments to predict HIE. RESULTS: Sixty neonates met the HIE criteria: 39 were moderate-severe HIE. Univariate analyses identified clinical neonatal markers (Apgar scores and neonatal resuscitation level) to be better HIE predictors than biochemical markers (umbilical artery pH, base excess and lactate values). Multivariable models using two to four predictors had areas under ROC curves up to 0.98, sensitivities up to 93% and specificities up to 99%. For moderate-severe HIE, the most effective predictor was neonatal resuscitation level and arterial lactate (ROC 0.98, sensitivity 85%, specificity 99%). CONCLUSION: The combination of umbilical arterial lactate and neonatal resuscitation level provides a rapid and accurate method of predicting moderate-severe HIE that can identify neonates at birth that may benefit from tertiary care and neuroprotective therapies. PMID- 22233403 TI - Risk factors for wound complications in morbidly obese women undergoing primary cesarean delivery. AB - OBJECTIVE: To determine factors influencing separation and infectious type wound complications (WCs) in morbidly obese women undergoing primary cesarean delivery (CD). METHODS: Retrospective cohort study evaluating infectious and separation WC in morbidly obese (body mass index [BMI] > 35 kg/m(2)) women undergoing primary CD between January 1994 and December 2008. Chi-square, Fisher's exact and Student's t tests used to assess associated factors; backward logistic regression to determine unadjusted and adjusted odds ratios. RESULTS: Of 623 women, low transverse skin incisions were performed in 588 (94.4%), vertical in 35 (7%). Overall WC rate was 13.5%, which varied by incision type (vertical 45.7% vs. 11.6% transverse; p < 0.01), but not BMI class. Incision type and unscheduled CD were associated with infection risk, while incision type, BMI, race and drain use were associated with wound separation. CONCLUSION: In morbidly obese women both infectious and separation type WC are more common in vertical than low transverse incisions; therefore transverse should be preferred. PMID- 22233404 TI - The impact of caring for adults with intellectual disability on the quality of life of parents. AB - BACKGROUND: Because of an increase in life expectancy and de institutionalisation, many adults with intellectual disability (ID) live with and are cared for by their parents throughout their adult lives. Because of caring demands, the quality of life (QOL) of parents may be affected. The study explored the impact of caring for an adult with ID on the QOL of parents. METHODS: Participants were 12 parents who were the full-time carers of an adult with ID. Participants were interviewed about the effect of caring on their QOL. Interviews were analysed thematically. RESULTS: Caring had a positive impact on QOL by enabling participants to develop relationships and receive support, participate in leisure activities, achieve a sense of personal satisfaction and enable a more positive appraisal of their lives. Caring had a negative impact on participants' QOL by restricting their relationships, leisure activities and employment opportunities. Caring was also associated with financial insecurity, frustrations at the service system and fear of what the future held for their offspring. CONCLUSIONS: Caring for an adult with ID had both positive and negative effects on parents' QOL. Improving services and service delivery, including the provision of residential services and respite, would address many of the issues that were reported to have a negative impact on parents' QOL. PMID- 22233405 TI - Anti-AnWj causing acute hemolytic transfusion reactions in a patient with aplastic anemia. AB - BACKGROUND: AnWj is a high-prevalence red blood cell (RBC) antigen in the ISBT 901 series. Only nine reports of anti-AnWj have been published since it was first documented in 1972; two of these cases involved transfusion reactions. We present a case of a patient with aplastic anemia who developed anti-AnWj with clinically significant hemolysis after transfusion of AnWj-positive RBCs. STUDY DESIGN AND METHODS: A 56-year-old woman with aplastic anemia developed a pan-reactive antibody with clinically significant hemolysis after transfusion of RBCs. Investigations included antibody identification by serologic methods at the national immunohematology reference laboratory and the in vitro monocyte monolayer assay (MMA) to predict clinical significance. RESULTS: The antibody was identified as having specificity for the AnWj antigen. The posttransfusion MMA indicated that the antibody had complement-fixing capability highly likely to cause clinically significant acute hemolytic transfusion reactions. The patient required long-term transfusion support with AnWj-negative RBCs and Lu(a-b-) RBCs of the In(Lu) type which have reduced AnWj expression. Cross-Canada and international collaboration was required to obtain rare units for transfusion. CONCLUSION: A case of acute hemolytic transfusion reaction caused by anti-AnWj is reported in a patient with aplastic anemia requiring allogeneic stem cell transplantation. This is the second documented case of anti-AnWj to cause a hemolytic transfusion reaction. The case demonstrates the complexity of managing patients with rare antibodies and the importance of international collaboration in the management of these difficult cases. PMID- 22233406 TI - Treatment with pegylated interferon (PegIFN) combined with ribavirin (Rbv) is the only option for preventing HCV-related end stage liver disease. PMID- 22233407 TI - Clinical drivers in naive patient eligibility for treatment of chronic hepatitis C. AB - Hepatitis C virus (HCV) infection represents a major health problem, being a leading cause of cirrhosis and liver transplantation worldwide. Viral eradication achieved by Peginterferon and Ribavirin therapy is the only therapeutic option that can prevent fibrosis progression in chronic hepatitis and liver-related complications in cirrhotic patients. Unfortunately, the occurrence of potentially serious side effects argues against universal treatment of HCV-infected patients. Indeed most scientific societies suggest that eligibility for therapy be based on baseline factors, the so called clinical drivers for treatment eligibility. Current international guidelines recommend focusing on the severity of liver disease, likelihood of treatment response in terms of chances of sustained virological response (SVR) to antiviral therapy and risk of serious adverse events when making treatment decisions. However, evidence exists that treatment may benefit also patients with mild fibrosis and that baseline predictions of a SVR are inaccurate because of the key role of HCV kinetics while on-therapy. An extended treatment programme is further supported by the fact that an increase in the number of patients treated would ultimately result in a long-term reduction of liver-related deaths. PMID- 22233408 TI - Optimal treatment duration for patients with HCV genotype 1 infection. AB - The rapidity of viral disappearance on antiviral treatment of chronic hepatitis C with peginterferon/ribavirin correlates with the cure rate. The earlier the virus becomes undetectable, the higher are the response rates. This observation is the basis of response-guided therapy. Viral clearance within the first 4 weeks of treatment is called a rapid virologic response (RVR). The rate of RVR varies among various populations, with the highest one observed in Asian patients and the lowest in African-Americans. In patients infected with genotypes 1 and 4 who experience a RVR treatment with peginterferon/ribavirin can be shortened to just 24 weeks without losing efficacy (sustained virologic rate in RVR are >80%). In contrast, patients with a slow decline in viral load (> 2 log drop after 12 weeks with still detectable virus) may benefit from treatment extension to 72 weeks. Prolonged treatment reduces relapse rates but has no significant effect on cure rates. The data in patients with genotypes 2 and 3 are less clear, mostly because these genotypes are much easier to cure and a benefit is hard to detect. Nevertheless in patients with RVR and low baseline viral load treatment can be safely shortened to 16 weeks. The recently described polymorphism in the region of the IL28B gene may help to select patients for abbreviated or extended treatment schedules. PMID- 22233409 TI - Severe anaemia related to oseltamivir during treatment of chronic hepatitis C: a new drug interaction? AB - Treatment for hepatitis C virus is often complicated by anaemia from ribavirin related haemolysis and bone marrow suppression because of peginterferon alfa. An extensive literature search revealed no reports of drug interactions between ribavirin and oseltamivir. We report the case of a patient with chronic hepatitis C infection who developed severe anaemia during antiviral treatment with peginterferon alfa/ribavirin when oseltamivir was added to treat influenza. The adverse events related to ribavirin and drug-drug interactions during therapy for hepatitis C are discussed. PMID- 22233410 TI - How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C? AB - Chronic hepatitis C represents a major cause of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications. Formation and accumulation of fibrosis in the liver is the common pathway that leads to evolutive liver disease. Precise staging of liver fibrosis is essential for patient management in clinical practice because the presence of bridging fibrosis represents a strong indication for antiviral therapy, while cirrhosis requires a specific follow-up. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis, but it has limitations: it is invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the noninvasive assessment of liver fibrosis in hepatitis C. However, international guidelines do not recommend the widespread use of noninvasive methods for liver fibrosis in clinical practice. This is because of, in some cases, unsatisfactory accuracy and incomplete validation of others. Some studies suggest that the effectiveness of noninvasive methods for assessing liver fibrosis may increase when they are combined, and a number of sequential and synchronous algorithms have been proposed for this purpose, with the aim of reducing rather than substituting liver biopsies. This may represent a rational and reliable approach for implementing noninvasive assessment of liver fibrosis in clinical practice. It could allow more comprehensive first-line screening of liver fibrosis in hepatitis C than would be feasible with liver biopsy alone. PMID- 22233411 TI - Comparison of peginterferon pharmacokinetic and pharmacodynamic profiles. AB - The pharmacokinetics and in dosing regimens of the currently available pegylated interferon (peginterferon) alfa molecules differ greatly, depending on the size and nature of their polyethylene glycol (PEG) moiety. Peginterferon alfa-2a has a branched 40 kDa PEG chain covalently attached to lysine residues and circulates as an intact molecule. On the other hand, peginterferon alfa-2b has a linear 12 kDa PEG chain covalently attached to interferon-a-2b via an unstable urethane bond that is hydrolysed after injection, releasing native interferon alfa-2b. The difference in pegylation between the two peginterferons has a significant impact on their pharmacokinetic properties. Data from comparative and non-comparative studies indicate that peginterferon alfa-2b has a shorter half-life in serum than peginterferon alfa-2a, and a significant proportion of patients receiving peginterferon alfa-2b may have trough concentrations below the limit of detection during the latter part of the 7-day dosing schedule. However, the pharmacodynamic parameters of the two drugs appear to be similar. PMID- 22233412 TI - Comparative trials of peginterferon alpha2a and peginterferon alpha2b for chronic hepatitis C. AB - Standard of care for patients with chronic hepatitis C is pegylated interferon (pegIFN) combined with ribavirin (Rbv). It results in persistent viral eradication and prevents the progression of liver disease and the associated complications in about 50% of treated patients. Currently, two PegIFNs are available that differ significantly in terms of pharmacokinetic and pharmacodynamic profiles as a consequence of different pegylation chemistries. While the registration trials of the two therapeutic regimens demonstrated the superiority of each PegIFN vs the native IFN alpha2b, the superiority of one regimen over the other in terms of treatment efficacy remains unknown. Retrospective cohort studies and randomized prospective head-to-head trials have attempted to resolve the considerable controversy over this issue and support evidence-based treatment decisions. PMID- 22233413 TI - Steatosis and insulin resistance in response to treatment of chronic hepatitis C. AB - This review will focus on the impact of steatosis and insulin resistance on the response to antiviral therapy for chronic hepatitis C. Hepatitis C virus (HCV) infection is known to have direct and/or indirect effects on lipid and glucose metabolism, leading to, among other disturbances, steatosis and insulin resistance, respectively. Some of these disturbances have a marked HCV genotype distribution. For example, on average, patients with HCV genotype 3 have the highest prevalence and severity of viral fatty liver. On the other hand, the current global spread of the metabolic syndrome represents a formidable cofactor of morbidity in HCV-related chronic liver disease. Thus, the pathogenesis of steatosis and insulin resistance in patients with chronic hepatitis C may often be dual, i.e. viral and metabolic. This distinction is relevant because the effect (if any) of steatosis or insulin resistance on the response to antiviral agents seems to depend on their pathogenesis. Accumulating data suggest that viral fatty liver may not impact on response to therapy, while metabolic steatosis does. Similarly, viral insulin resistance may not reduce the rate of response to therapy to the same extent that metabolic insulin resistance does. Some implications for patient management are discussed. PMID- 22233414 TI - New developments in HCV therapy. AB - About half of the patients with chronic hepatitis C are still not cured by treatment with the current standard of care, peginterferon alpha/ribavirin. Direct antiviral drugs may overcome the limitations of standard antiviral therapy. The most promising new agents are inhibitors of the NS3/4A protease, the NS5B polymerase and the NS5A protein. Several compounds against these targets have entered clinical evaluation. Early clinical trials have emphasized the high potential for selecting resistant Hepatitis C virus variants. Furthermore, development of several new direct antivirals was stopped because of concerns over tolerability and safety. Then, in 2010, two phase III trials with the NS3/4A protease inhibitors boceprevir (SPRINT-2) and telaprevir (ADVANCE) showed that the combination of these compounds with standard care increases sustained virologic response rates in treatment-naive genotype 1 patients from 38-44% to 66 75%. Future goals of therapy with direct antiviral agents are to improve tolerability, shorten the duration of therapy and overcome the issue of resistance. Several studies have been initiated that combine different novel therapies, with and without interferon alpha/ribavirin. PMID- 22233415 TI - Thymosin alpha-1 with peginterferon alfa-2a/ribavirin for chronic hepatitis C not responsive to IFN/ribavirin: an adjuvant role? AB - This study was conducted to determine whether the adding thymosin alpha-1 to standard of care for re-treatment of nonresponding hepatitis C infections can improve sustained viral response (SVR) rates. Patients (n = 552) with hepatitis C infections not responding to the combination of Peginterferon alfa-2a or 2b with ribavirin (RBV)were randomized to receive peginterferon alfa-2a 180 mg/week with RBV 800-1200 mg/daily plus either thymosin alpha-1 1.6 mg SC twice weekly (n = 275) or placebo (n = 277) for 48 weeks. Eighty-eight per cent of patients had HCV genotype 1, 6.6% type 4, 2.2% type 2 and 3.6% type 3. SVR rates in the intention to treat population were similar between thymosin alpha-1 and placebo (12.7%vs 10.5%; P = 0.407). Among patients who completed all 48 weeks of therapy, the SVR rate was significantly higher in the thymosin alpha-1 group at 41.0% (34/83) compared with 26.3% (26/99) in the placebo group (P = 0.048). No significant difference was observed between treatment groups in the incidence of adverse events. The addition of thymosin alpha-1 to the standard of care did not increase the on-treatment HCV viral response. Thymosin alpha-1 seems to play no role in the primary therapy of the disease. This study raises the hypothesis that thymosin alpha-1 may have a secondary therapeutic role as an adjuvant in the prevention of relapses in patients achieving a virologic response during therapy. PMID- 22233417 TI - Stereoelectronic interactions and the one-bond C-F coupling constant in sevoflurane. AB - The conformational preference of the widely utilized anesthetic fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether (sevoflurane) has been investigated computationally and by NMR spectroscopy. Three conformational minima were located at the B3LYP/aug-cc-pVDZ level, but one is significantly more stable (by ca. 4 kcal/mol) than the other two. This is the case both for gas phase calculations and for solution NMR data. Although the main conformer is stabilized by electron delocalization (n(O) -> sigma*(C-F)), this type of hyperconjugation was not found to be the main driver for the conformer stabilization in the gas phase and, consequently, for the apparent anomeric effect in sevoflurane. Instead, more classical steric and electrostatic interactions appear to be responsible for the conformational energies. Also the (1)J(CF) coupling constants do not appear to be dominated by hyperconjugation; again, dipolar interactions are invoked instead. PMID- 22233416 TI - Inhibition of T-type Ca2+ channels by endostatin attenuates human glioblastoma cell proliferation and migration. AB - BACKGROUND AND PURPOSE: Endostatin (ES) is a c-terminal proteolytic fragment of collagen XVIII with promising antitumour properties in several tumour models, including human glioblastoma. We hypothesized that this peptide could interact with plasma membrane ion channels and modulate their functions. EXPERIMENTAL APPROACH: Using cell proliferation and migration assays, patch clamp and Western blot analysis, we studied the effects of ES on the proliferation and migration of human glioblastoma U87 cells, mediated by T-type Ca2+ channels. KEY RESULTS: Extracellular application of ES reversibly inhibited T-type Ca2+ channel currents (T-currents) in U87 cells, whereas L-type Ca2+ currents were not affected. This inhibitory effect was associated with a hyperpolarizing shift in the voltage dependence of inactivation but was independent of G-protein and protein tyrosine kinase-mediated pathways. All three alpha1 subunits of T-type Ca2+ channels (Ca(V) 3), alpha(1G) (Ca(V) 3.1), alpha(1H) (Ca(V) 3.2) and alpha(1I) (Ca(V) 3.3), were endogenously expressed in U87 cells. Using transfected HEK293 or CHO cells, we showed that only Ca(V) 3.1 and Ca(V) 3.2, but not Ca(V) 3.3 or Ca(V) 1.2 (L-type), channel currents were significantly inhibited. More interestingly, ES inhibited the proliferation and migration of U87 cells in a dose-dependent manner. Pretreatment of the cells with the specific T-type Ca2+ channel blocker mibefradil occluded these inhibitory effects of ES. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that the antitumour effects of ES on glioblastoma cells is through direct inhibition of T-type Ca2+ channels and gives new insights into the future development of a new class of antiglioblastoma agents that target the proliferation and migration of these cells. PMID- 22233420 TI - Comparative demography of the spider mite, Oligonychus afrasiaticus, on four date palm varieties in southwestern Tunisia. AB - The date palm mite, Oligonychus afrasiaticus (McGregor) (Acari: Tetranychidae), is a serious pest of palm date fruits. Life cycle, fecundity, and longevity of this mite were studied on fruits of four date palms, Phoenix dactylifera L. (Arecales: Arecaceae)(varieties: Deglet Noor, Alig, Kentichi, and Besser), under laboratory conditions at 27 = 1 degrees C, 60 +/- 10% RH. Total development time of immature female was shorter on Deglet Noor fruits than on the other cultivars. O. afrasiaticus on Deglet Noor had the highest total fecundity per female, while low fecundity values occurred on Besser. The comparison of intrinsic rates of natural increase (r(m)), net reproductive rates (R(o)), and the survival rates of immature stage of O. afrasiaticus on the host plants suggests that O. afrasiaticus performs better on Deglet Noor fruits. The mite feeding on Alig showed the lowest intrinsic rate of natural population increase (r(m) = 0.103 day (-1)). The estimation of difference in susceptibility of cultivars to O. afrasiaticus is crucial for developing efficient pest control programs. Indeed, less susceptible cultivars can either be left unsprayed or sprayed at low threshold. PMID- 22233419 TI - MetRxn: a knowledgebase of metabolites and reactions spanning metabolic models and databases. AB - BACKGROUND: Increasingly, metabolite and reaction information is organized in the form of genome-scale metabolic reconstructions that describe the reaction stoichiometry, directionality, and gene to protein to reaction associations. A key bottleneck in the pace of reconstruction of new, high-quality metabolic models is the inability to directly make use of metabolite/reaction information from biological databases or other models due to incompatibilities in content representation (i.e., metabolites with multiple names across databases and models), stoichiometric errors such as elemental or charge imbalances, and incomplete atomistic detail (e.g., use of generic R-group or non-explicit specification of stereo-specificity). DESCRIPTION: MetRxn is a knowledgebase that includes standardized metabolite and reaction descriptions by integrating information from BRENDA, KEGG, MetaCyc, Reactome.org and 44 metabolic models into a single unified data set. All metabolite entries have matched synonyms, resolved protonation states, and are linked to unique structures. All reaction entries are elementally and charge balanced. This is accomplished through the use of a workflow of lexicographic, phonetic, and structural comparison algorithms. MetRxn allows for the download of standardized versions of existing genome-scale metabolic models and the use of metabolic information for the rapid reconstruction of new ones. CONCLUSIONS: The standardization in description allows for the direct comparison of the metabolite and reaction content between metabolic models and databases and the exhaustive prospecting of pathways for biotechnological production. This ever-growing dataset currently consists of over 76,000 metabolites participating in more than 72,000 reactions (including unresolved entries). MetRxn is hosted on a web-based platform that uses relational database models (MySQL). PMID- 22233422 TI - Safe zone for bone harvesting from the interforaminal region of the mandible. AB - AIMS: The mandibular incisive nerve can be subjected to iatrogenic injury during bone graft harvesting. Using cone beam computed tomography (CBCT), this study aims to determine a safe zone for bone graft harvesting that avoids injuring this nerve. METHODS: Sixty CBCT examinations of patients were included in this study. The examinations were taken using the i-CAT CBCT imaging system, applying a standardized exposure protocol. Image reconstruction from the raw data was performed using the SimPlant dental implant software. The distances of mandibular incisive canal (MIC) to the inferior border and the labial and lingual cortices of the mandible were measured at 3, 5, 7 and 9 mm mesial to the mental foramen. RESULTS: The MIC was visible in all (100%) CBCT images. The median distance and interquartile range from the lower border of the mandible was 9.86 (2.51) mm, curving downwards toward the inferior mandibular border at the symphysis menti. It was located closer to the buccal border of the mandible (3.15 [1.28] mm) than lingual cortex (4.78 [2.0] mm). The MIC curves toward the lingual side at the symphysis menti. There was gender difference in a number of these measurements. Current recommendation for chin bone graft harvesting can be applied to Asian subjects. CONCLUSIONS: While acknowledging that there is human variability, this study provides an accurate anatomic location of the MIC, which in turn helps to determine a safe zone for chin bone graft harvesting. This information can become a useful guide in centers where CBCT is not available. PMID- 22233421 TI - AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. AB - Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). Incubation of freshly isolated rat hepatocytes with the pharmacological AMPK activators AICA riboside (5-aminoimidazole-4-carboxamide-1 beta-D-ribofuranoside) or A769662 led to persistent GYS inactivation and Ser7 phosphorylation, whereas inactivation by glucagon treatment was transient. In hepatocytes from mice harbouring a liver-specific deletion of the AMPK catalytic alpha1/alpha2 subunits, GYS2 inactivation by AICA riboside and A769662 was blunted, whereas inactivation by glucagon was unaffected. The results suggest that GYS inactivation by AMPK activators in hepatocytes is due to GYS2 Ser7 phosphorylation. PMID- 22233418 TI - Management of cryptorchidism: a survey of clinical practice in Italy. AB - BACKGROUND: An evidence-based Consensus on the treatment of undescended testis (UT) was recently published, recommending to perform orchidopexy between 6 and 12 months of age, or upon diagnosis and to avoid the use of hormones. In Italy, current practices on UT management are little known. Our aim was to describe the current management of UT in a cohort of Italian children in comparison with the Consensus guidelines. As management of retractile testis (RT) differs, RT cases were described separately. METHODS: Ours is a retrospective, multicenter descriptive study. An online questionnaire was filled in by 140 Italian Family Paediatricians (FP) from Associazione Culturale Pediatri (ACP), a national professional association of FP. The questionnaire requested information on all children with cryptorchidism born between 1/01/2004 and 1/01/2006. Data on 169 children were obtained. Analyses were descriptive. RESULTS: Overall 24% of children were diagnosed with RT, 76% with UT. Among the latter, cryptorchidism resolved spontaneously in 10% of cases at a mean age of 21.6 months. Overall 70% of UT cases underwent orchidopexy at a mean age of 22.8 months (SD 10.8, range 1.2-56.4), 13% of whom before 1 year. The intervention was performed by a paediatric surgeon in 90% of cases, with a success rate of 91%. Orchidopexy was the first line treatment in 82% of cases, while preceded by hormonal treatment in the remaining 18%. Hormonal treatment was used as first line therapy in 23% of UT cases with a reported success rate of 25%. Overall, 13 children did not undergo any intervention (mean age at last follow up 39.6 months). We analyzed the data from the 5 Italian Regions with the largest number of children enrolled and found a statistically significant regional difference in the use of hormonal therapy, and in the use of and age at orchidopexy. CONCLUSIONS: Our study showed an important delay in orchidopexy. A quarter of children with cryptorchidism was treated with hormonal therapy. In line with the Consensus guidelines, surgery was carried out by a paediatric surgeon in the majority of cases, with a high success rate. PMID- 22233423 TI - Adult-type hypolactasia and calcium intake in polycystic ovary syndrome. AB - OBJECTIVE: Adult-type hypolactasia (ATH) is related to lower calcium and milk intake, which might be associated with obesity and metabolic disturbances. Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances including central obesity. We aimed to examine the association of ATH and calcium intake with anthropometric, metabolic and endocrine parameters in a cohort of PCOS and control women. DESIGN: Metabolic, endocrine and anthropometric measurements and oral glucose tolerance tests were performed in 504 PCOS and 366 control women. Genotyping of ATH, defined by the -13910 variant of the MCM6 gene, was performed. Calcium intake was assessed by questionnaires. RESULTS: Adult-type hypolactasia was more prevalent in PCOS women (29.8%) than in controls (23.5%) (P = 0.040). PCOS women with ATH had higher waist-to-hip ratio (WHR) (0.80 [0.75-0.88] vs 0.78 [0.73-0.85], P = 0.046), glucose 2 h (5.28 [4.57 6.33] mmol/l vs 5.67 [4.68-6.78] mmol/l, P = 0.037), HbA1c (5.2 [5.0-5.4]%vs 5.1 [5.0-5.3]%, P = 0.009), parathyroid hormone (3.72(2.91-4.86] pmol/l vs 3.61 [2.94 4.63] pmol/l, P = 0.030) and Ferriman-Gallwey-Scores (FG Scores) (7 [3-12] vs 4 [1-9], P = 0.002) and lower 25(OH)D levels (54.4 [35.2-80.6] nmol/l vs 68.4 [49.7 89.4] nmol/l, P < 0.001) than PCOS women without ATH. The association of 25(OH)D and FG-Scores with ATH remained significant in age-, BMI- and WHR-adjusted analyses. PCOS women within the highest quartile of calcium intake had significantly lower testosterone (P = 0.023) and androstenedione (P = 0.032) and significantly higher high-density lipoprotein (HDL) levels (P = 0.035) than PCOS women with lower calcium intake. CONCLUSION: Our results indicate an association of ATH with PCOS susceptibility. Moreover, ATH might influence WHR, HbA1c and FG Scores as well as 25(OH)D levels. Higher calcium intake was associated with lower androgens and higher HDL levels. PMID- 22233424 TI - Heterodinuclear metal arrangement in a flat macrocycle with two chemically equivalent metal chelating sites. AB - A phenanthroline-based macrocycle 1 has been newly developed which has two chemically equivalent metal chelating sites within the spatially restricted cavity for dinuclear metal arrangement. The macrocycle 1 reacts with Zn(CF(3)CO(2))(2) or ZnCl(2) to form homodinuclear Zn(II)-complexes. A single crystal X-ray structural analysis of the resulting Zn(2)1(CF(3)CO(2))(4) determined the complex structure in which two Zn(II) ions are bound by two phenanthroline sites and two CF(3)CO(2)(-) ions bind to each Zn(II) ion in a tetrahedral geometry. Similarly, a homodinuclear Cu(I)-macrocycle was formed from 1 and Cu(CH(3)CN)(4)BF(4). Notably, from 1 and an equimolar mixture of Cu(CH(3)CN)(4)BF(4) and Zn(CF(3)CO(2))(2), a heterodinuclear Cu(I)-Zn(II) macrocycle was exclusively formed in high yield (>90%) because of the relatively low stability of the dinuclear Cu(I)-macrocycle. A heterodinuclear Ag(I)-Zn(II) macrocycle was similarly formed with fairly high selectivity from a mixture of Ag(I) and Zn(II) ions. Such selective heterodinuclear metal arrangement was not observed with other combinations of M-Zn(II) (M = Li(I), Mg(II), Pd(II), Hg(II), La(III), and Tb(III)). PMID- 22233425 TI - JBIR-94 and JBIR-125, antioxidative phenolic compounds from Streptomyces sp. R56 07. AB - Two phenolic compounds, JBIR-94 (1) and JBIR-125 (2), were isolated from the fermentation broth of strain R56-07, which was identified by phylogenetic methods as a novel species of Streptomyces. The structures of 1 and 2 were assigned on the basis of 1D and 2D NMR spectroscopy and MS analyses. Compounds 1 and 2 exhibited 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity with an IC(50) value of 11.4 and 35.1 MUM, respectively. These compounds are the first examples of hydroxycinnamic acid amides containing putrescine or spermidine produced by actinomycetes. PMID- 22233426 TI - Misoprostol for the prevention and treatment of postpartum hemorrhage. AB - INTRODUCTION: Uterotonic drugs are recommended for the prevention and treatment of postpartum hemorrhage (PPH), and oxytocin is considered the gold standard for both indications due to its established efficacy and safety. Unfortunately, access to oxytocin is still limited in many low-resource settings due to the need for cool storage, sterile equipment and administration by skilled personnel. Misoprostol , an E1 prostaglandin analog, has therefore been explored as an alternative for such settings due to its proven ability to induce uterine contractions, low cost, stability at room temperature and ease of administration. AREAS COVERED: This review covers evidence from 51 randomized controlled trials for both prevention and treatment of PPH. It discusses efficacy and side effects in the context of the various doses that have been studied using oral, sublingual or rectal routes of administration for both indications. EXPERT OPINION: There is now a solid body of evidence to justify the use of misoprostol for postpartum hemorrhage indications in many settings. The evidence supports use of 600 MUg orally for the prevention of PPH and 800 MUg sublingually for the treatment of PPH. There is no evidence to support the adjunct use of misoprostol following administration of conventional uterotonics for prevention or treatment purposes. PMID- 22233427 TI - Collagen fibril alignment and deformation during tensile strain of leather: a small-angle X-ray scattering study. AB - The distribution and effect of applied strain on the collagen fibrils that make up leather may have an important bearing on the ultimate strength and other physical properties of the material. While sections of ovine and bovine leather were being subjected to tensile strain up to rupture, synchrotron-based small angle X-ray scattering (SAXS) spectra were recorded edge-on to the leather at points from the corium to the grain. Measurements of both fibril orientation and collagen d spacing showed that, initially, the fibers reorient under strain, becoming more aligned. As the strain increases (5-10% strain), further fibril reorientation diminishes until, at 37% strain, the d spacing increases by up to 0.56%, indicating that significant tensile forces are being transmitted to individual fibrils. These changes, however, are not uniform through the cross section of leather and differ between leathers of different strengths. The stresses are taken up more evenly through the leather cross-section in stronger leathers in comparison to weaker leathers, where stresses tended to be concentrated during strain. These observations contribute to our understanding of the internal strains and structural changes that take place in leather under stress. PMID- 22233429 TI - Spotlight on dasatinib in chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. AB - Dasatinib (Sprycel(r)) is an orally administered small molecule inhibitor of multiple tyrosine kinases, including BCR-ABL and SRC family kinases, which is indicated for the treatment of adults with newly diagnosed chronic-phase chronic myeloid leukemia (CML), CML (chronic-, accelerated- or blast-phase) with resistance or intolerance to prior therapy, including imatinib, or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. Dasatinib is ~325-fold more active than imatinib in inhibiting wild-type BCR-ABL kinase in vitro and is active against a wide variety of imatinib-resistant BCR-ABL mutants, except for T315I. This article reviews the efficacy and tolerability of dasatinib in the treatment of patients with newly diagnosed chronic-phase CML or imatinib-resistant or -intolerant CML or Ph+ ALL, as well as summarizing its pharmacologic properties. In clinical trials, oral dasatinib was effective in achieving major or complete cytogenetic responses in both newly diagnosed and imatinib-resistant or -intolerant chronic-phase CML. Dasatinib was likewise effective in achieving major or overall hematologic responses in imatinib-resistant or -intolerant, accelerated- or blast-phase CML, or Ph+ ALL. Responses were rapidly achieved within 1-3 months and were durable over 1-5 years of follow-up. The majority of adverse events with dasatinib were of mild or moderate severity. Fluid retention (including pleural effusion) was the most common adverse event. Hematologic abnormalities were common and cytopenias were the most common grade 3/4 adverse events. Dasatinib 100 mg administered once daily was as effective as dasatinib 70 mg administered twice daily, and was better tolerated, being associated with lower incidences of pleural effusion and grade 3/4 thrombocytopenia, in particular. Dasatinib was more effective than high-dose imatinib in the treatment of patients with imatinib resistant chronic-phase CML and was more effective than standard dosages of imatinib, as well as being associated with less frequent fluid retention, in patients with newly diagnosed chronic-phase CML. Dasatinib was generally equally effective in patients with or without BCR-ABL mutations at baseline. Therefore, oral dasatinib is a highly effective, once-daily therapy for the first-line treatment of newly diagnosed patients with chronic-phase CML, as well as for the treatment of patients with imatinib-resistant or -intolerant chronic- and advanced-phase CML or Ph+ ALL. PMID- 22233428 TI - Patterns of plant subcellular responses to successful oomycete infections reveal differences in host cell reprogramming and endocytic trafficking. AB - Adapted filamentous pathogens such as the oomycetes Hyaloperonospora arabidopsidis (Hpa) and Phytophthora infestans (Pi) project specialized hyphae, the haustoria, inside living host cells for the suppression of host defence and acquisition of nutrients. Accommodation of haustoria requires reorganization of the host cell and the biogenesis of a novel host cell membrane, the extrahaustorial membrane (EHM), which envelops the haustorium separating the host cell from the pathogen. Here, we applied live-cell imaging of fluorescent-tagged proteins labelling a variety of membrane compartments and investigated the subcellular changes associated with accommodating oomycete haustoria in Arabidopsis and N. benthamiana. Plasma membrane-resident proteins differentially localized to the EHM. Likewise, secretory vesicles and endosomal compartments surrounded Hpa and Pi haustoria revealing differences between these two oomycetes, and suggesting a role for vesicle trafficking pathways for the pathogen-controlled biogenesis of the EHM. The latter is supported by enhanced susceptibility of mutants in endosome-mediated trafficking regulators. These observations point at host subcellular defences and specialization of the EHM in a pathogen-specific manner. Defence-associated haustorial encasements, a double layered membrane that grows around mature haustoria, were frequently observed in Hpa interactions. Intriguingly, all tested plant proteins accumulated at Hpa haustorial encasements suggesting the general recruitment of default vesicle trafficking pathways to defend pathogen access. Altogether, our results show common requirements of subcellular changes associated with oomycete biotrophy, and highlight differences between two oomycete pathogens in reprogramming host cell vesicle trafficking for haustoria accommodation. This provides a framework for further dissection of the pathogen-triggered reprogramming of host subcellular changes. PMID- 22233430 TI - Turnover of new graduate nurses in their first job using survival analysis. AB - PURPOSE: To examine factors related to turnover of new graduate nurses in their first job. DESIGN: Data were obtained from a 3-year panel survey (2006-2008) of the Graduates Occupational Mobility Survey that followed-up college graduates in South Korea. The sample consisted of 351 new graduates whose first job was as a full-time registered nurse in a hospital. METHODS: Survival analysis was conducted to estimate survival curves and related factors, including individual and family, nursing education, hospital, and job dissatisfaction (overall and 10 specific job aspects). FINDINGS: The estimated probabilities of staying in their first job for 1, 2, and 3 years were 0.823, 0.666, and 0.537, respectively. Nurses reporting overall job dissatisfaction had significantly lower survival probabilities than those who reported themselves to be either neutral or satisfied. Nurses were more likely to leave if they were married or worked in small (vs. large), nonmetropolitan, and nonunionized hospitals. Dissatisfaction with interpersonal relationships, work content, and physical work environment was associated with a significant increase in the hazards of leaving the first job. CONCLUSIONS: Hospital characteristics as well as job satisfaction were significantly associated with new graduates' turnover. CLINICAL RELEVANCE: The high turnover of new graduates could be reduced by improving their job satisfaction, especially with interpersonal relationships, work content, and the physical work environment. PMID- 22233431 TI - Efficacy of Annona squamosa on wound healing in streptozotocin-induced diabetic rats. AB - Annona squamosa L. (Annonaceae), commonly known as custard apple, mainly used for its edible fruit, is also recognised with numerous medicinal properties. As there is no report on the efficacy of this plant for wound healing, we examined the efficacy of ethanolic extract of A. squamosa leaves on wound repair in streptozotocin-nicotinamide-induced diabetic rats. Open excision wounds were made on the back of rats. The drug at a dosage of 100 mg/kg body wt was reconstituted in 200 ul of phosphate buffered saline and applied topically once daily for the treated wounds. The control wounds were left untreated. Wound tissues formed on days 4, 8, 12 and 16 (post-wound) were used to estimate DNA, total protein, total collagen, hexosamine and uronic acid. Levels of lipid peroxides were also evaluated along with tensile strength and period of epithelialisation. A. squamosa L. increased cellular proliferation and collagen synthesis at the wound site as evidenced by increase in DNA, protein and total collagen. The treated wounds were observed to heal much faster as proved by enhanced rates of epithelialisation and wound contraction, which was also confirmed by histopathological examinations. The results strongly substantiate the beneficial effects of the topical application of A. squamosa L. in the acceleration of normal and diabetic wound healing. PMID- 22233433 TI - Femtosecond LASIK flaps: excellent, but superior? PMID- 22233434 TI - Measurement of intraocular pressure during corneal flap preparation. PMID- 22233435 TI - A simple, reproducible, and cost effective axis marking system for toric lens implantation. PMID- 22233432 TI - Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury. AB - Disrupted regulation of extracellular glutamate in the central nervous system contributes to and can exacerbate the acute pathophysiology of traumatic brain injury (TBI). Previously, we reported increased extracellular glutamate in the striatum of anesthetized rats 2 days after diffuse brain injury. To determine the mechanism(s) responsible for increased extracellular glutamate, we used enzyme based microelectrode arrays (MEAs) coupled with specific pharmacological agents targeted at in vivo neuronal and glial regulation of extracellular glutamate. After TBI, extracellular glutamate was significantly increased in the striatum by (~90%) averaging 4.1+/-0.6 MUM compared with sham 2.2+/-0.4 MUM. Calcium dependent neuronal glutamate release, investigated by local application of an N type calcium channel blocker, was no longer a significant source of extracellular glutamate after TBI, compared with sham. In brain-injured animals, inhibition of glutamate uptake with local application of an excitatory amino acid transporter inhibitor produced significantly greater increase in glutamate spillover (~ 65%) from the synapses compared with sham. Furthermore, glutamate clearance measured by locally applying glutamate into the extracellular space revealed significant reductions in glutamate clearance parameters in brain-injured animals compared with sham. Taken together, these data indicate that disruptions in calcium mediated glutamate release and glial regulation of extracellular glutamate contribute to increased extracellular glutamate in the striatum 2 days after diffuse brain injury. Overall, these data suggest that therapeutic strategies used to regulate glutamate release and uptake may improve excitatory circuit function and, possibly, outcomes following TBI. PMID- 22233436 TI - IntraLase femtosecond laser vs mechanical microkeratomes in LASIK for myopia: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the safety, efficacy, and predictability of IntraLase (Abbott Medical Optics) femtosecond laser-assisted compared to microkeratome assisted myopic LASIK. METHODS: A comprehensive literature search of Cochrane Library, PubMed, and EMBASE was conducted to identify relevant trials comparing LASIK with IntraLase femtosecond laser to LASIK with microkeratomes for the correction of myopia. Meta-analyses were performed on the primary outcomes (loss of >=2 lines of corrected distance visual acuity [CDVA], uncorrected distance visual acuity [UDVA] 20/20 or better, manifest refraction spherical equivalent [MRSE] within +/-0.50 diopters [D], final refractive SE, and astigmatism), and secondary outcomes (flap thickness predictability, changes in higher order aberrations [HOAs], and complications). RESULTS: Fifteen articles describing a total of 3679 eyes were identified. No significant differences were identified between the two groups in regards to a loss of >=2 lines of CDVA (P=.44), patients achieving UDVA 20/20 or better (P=.24), final UDVA (P=.12), final mean refractive SE (P=.74), final astigmatism (P=.27), or changes in HOAs. The IntraLase group had more patients who were within +/-0.50 D of target refraction (P=.05) compared to the microkeratome group, and flap thickness was more predictable in the IntraLase group (P<.0001). The microkeratome group had more epithelial defects (P=.04), whereas the IntraLase group had more cases of diffuse lamellar keratitis (P=.01). CONCLUSIONS: According to the available data, LASIK with the IntraLase femtosecond laser offers no significant benefits over LASIK with microkeratomes in regards to safety and efficacy, but has potential advantages in predictability. PMID- 22233437 TI - Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients. AB - Over a 23-year period, our center performed 82 renal retransplants in prior simultaneous pancreas-kidney recipients with functioning pancreatic allografts. All patients were insulin-independent at retransplantation. We aimed to quantify the risk of returning to insulin therapy and to identify factors that predispose patients to pancreatic allograft failure after renal retransplantation. Among these 82 patients, pancreatic allograft survival after renal retransplantation was 78%, 49% and 40% at 1, 5 and 10 years. When analyzing risk factors, we unexpectedly found no clear relationship between the cause of primary renal allograft failure, hemoglobin A1c (HbA1c) or fasting C-peptide level at retransplant and subsequent pancreatic allograft failure. An elevated HbA1c in the month after renal retransplant correlated with subsequent pancreatic graft loss and patients experiencing pancreatic graft loss were more likely to subsequently lose their renal retransplant. Although it is difficult to prospectively identify those patients who will return to insulin therapy after repeat renal transplantation, the relatively high frequency of this event mandates that this risk be conveyed to patients. Nonetheless, the survival benefit associated with renal retransplantation justifies pursuing retransplantation in this population. PMID- 22233438 TI - Different potency of bacterial antigens TLR2 and TLR4 ligands in stimulating mature mast cells to cysteinyl leukotriene synthesis. AB - The aim of study was to compare the potency of different bacterial antigens to induce rat mature mast cell to cysteinyl leukotriene (cysLT) generation. We examined Toll-like receptor (TLR)2 agonists, i.e. lipoteichoic acid (LTA) Staphylococcus faecalis, Streptococcus pyogenes, Bacillus subtilis and Staphylococcus aureus, lipoarabinomannan (LAM) Mycobacterium smegmatis, peptydoglican (PGN) Staphylococcus aureus, as well as TLR4 agonists, i.e. lipopolysaccharide (LPS) Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enteritidis, Pophyromonas gingivalis and Escherichia coli. We also estimated the effect of tumor necrosis factor (TNF)-, interleukin (IL)-6-, CCL5-, and IL-10-priming on mast cell cysLT synthesis following bacterial antigen activation. We found that all bacterial antigens activated mast cells to cysLT generation; however, the extent of cysLT release in response to stimulation varied. Out of the examined antigens LPS P. gingivalis exhibited the highest potency, as it induced cysLT generation acting at a very low concentration (10( 4) ng/mL). Other LPSs affected mast cells at higher (up to 10(5) -fold) concentrations. LTAs were the most effective at concentrations of 5 * 10(2) ng/mL, while LAM and PGN stimulated mast cells to maximal cysLT generation at concentrations as high as 10(5) ng/mL. Anti-TLR2 and anti-TLR4 antibodies, as well as nuclear factor kappaB (NF-kappaB) inhibitor significantly diminished cysLT generation in response to bacterial antigen stimulation. Priming with TNF, IL-6 and CCL5 did not affect bacterial antigen-induced cysLT generation, while IL 10-pretreatment caused significant decrease in cysLT synthesis by mast cells. These observations might have a great pathophysiological importance; inasmuch cysLTs strongly influence the development and intensity of inflammation during bacterial infection. PMID- 22233439 TI - Peristomal skin ulcer with intestinal metaplasia. PMID- 22233440 TI - Unmanipulated HLA-mismatched/haploidentical peripheral blood stem cell transplantation for high-risk hematologic malignancies. AB - BACKGROUND: Haploidentical hematopoietic stem cell transplantation (HSCT) has been increasingly applied in high-risk hematologic patients due to the absence of HLA-matched donors. The aim of this study was to investigate the efficacy and safety of unmanipulated haploidentical allogeneic peripheral blood stem cells transplantation (PBSCT) for hematologic malignancies. STUDY DESIGN AND METHODS: Patients who underwent unmanipulated HLA-mismatched/haploidentical PBSCT from July 2007 to March 2010 with high-risk hematologic malignancies were enrolled for retrospective analysis. RESULTS: Twenty-one patients with high-risk hematologic malignancies underwent unmanipulated HLA-mismatched/haploidentical PBSCT with myeloablative conditioning. The numbers of CD34+ cells infused at transplantation were 4.81 (range, 2.61-11.47)*10(6)/kg. Patients achieved myeloid and platelet engraftment at a median of 16.5 and 20 days, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) on Day 100 was 52.7+/-10.7%, and the 2-year cumulative incidence of chronic GVHD was 39.5+/-10.6%. The cumulative incidences of cytomegalovirus antigenemia and hemorrhagic cystitis within 100 days after PBSCT were 59.5+/-16.7 and 34.8+/-13.3%, respectively. One hundred-day transplantation-related mortality (TRM) rate and the 2-year cumulative TRM rate were 14.3 and 20.5+/-7.8%, respectively. The 2-year cumulative overall survival was 62.1+/-11.4% and the probability of disease-free survival at 2 years was 55.6+/-10.7% with a 16-month median follow-up. CONCLUSION: Unmanipulated PBSCT is a promising protocol in HLA mismatched/haploidentical transplant settings. PMID- 22233441 TI - Increased nitric oxide and vascular endothelial growth factor levels in the aqueous humor of patients with coats' disease. AB - PURPOSE: To determine the aqueous humor levels of nitric oxide (NO) and vascular endothelial growth factor (VEGF) in the eyes of patients with Coats' disease and study the correlation between these levels. METHODS: Samples of aqueous humor were obtained from 7 patients with Coats' disease and 15 age-matched patients with congenital cataracts as controls. Nitrite and nitrate (NOx), the stable end products of NO, were detected by the Griess reaction, and VEGF levels were assessed by enzyme-linked immunosorbent assay. RESULTS: The aqueous humor NOx and VEGF levels were elevated in the eyes of patients with Coats' disease compared with those of controls (P=0.001 and P<0.001, respectively). The median NOx level was 55.2 MUM (range, 23.0-75.3 MUM) in the Coats' disease group and 18.8 MUM (range, 8.7-36.2 MUM) in the control group. The median VEGF level was 731.7 pg/mL (range, 288.3-1364.3 pg/mL) in the Coats' disease group and 33.3 pg/mL (range, 9.0-96.8 pg/mL) in the control group. No correlation was observed between the aqueous humor concentrations of NOx and VEGF. CONCLUSIONS: NOx and VEGF are increased but not related in the aqueous humor samples of patients with Coats' disease. NO and VEGF may play roles in the pathogenesis of Coats' disease. Further studies are needed to clearly elucidate the relationship among VEGF, NO, and other cytokines in Coats' disease. PMID- 22233442 TI - Enhanced alveolar bone loss in a model of non-invasive periodontitis in rice rats. AB - OBJECTIVE: The rice rat (Oryzomys palustris) develops periodontitis-like lesions when fed a diet rich in sucrose and casein (H-SC). We aimed to establish whether this model can accurately mimic the development of human periodontitis. MATERIALS AND METHODS: For this purpose, 28-day-old rice rats (15/group) were assigned to standard (STD) or H-SC diets and sacrificed after 6, 12, and 18 weeks. Jaws were processed for morphometric, histometric, histologic, histomorphometric, and micro CT analyses. RESULTS: We found a progressive increase in horizontal alveolar bone loss (ABL) with age in maxillae of rats fed the STD diet as determined by morphometry. The H-SC diet exacerbated horizontal ABL at the palatal surface at 12 and 18 weeks. Furthermore, increased vertical ABL was detected in mandibles and maxillae of rats fed the H-SC diet for 12 and/or 18 weeks by histometry and micro-CT. Remarkably, the H-SC diet significantly increased bone remodeling at the interproximal alveolar bone of mandibles from rats fed for 6 weeks, but not in those fed for longer periods. CONCLUSIONS: These findings indicate that the H SC diet induced a transient increase in alveolar bone remodeling, which is followed by ABL characteristic of moderate periodontitis. PMID- 22233444 TI - Polar assembly and scaffolding proteins of the virulence-associated ESX-1 secretory apparatus in mycobacteria. AB - The ESX-1 secretion system is required for pathogenicity of Mycobacterium tuberculosis (Mtb). Despite considerable research, little is known about the structural components of ESX-1, or how these proteins are assembled into the active secretion apparatus. Here, we exploit the functionally related ESX-1 apparatus of Mycobacterium smegmatis (Ms) to show that fluorescently tagged proteins required for ESX-1 activity consistently localize to the cell pole, identified by time-lapse fluoro-microscopy as the non-septal (old) pole. Deletions in Msesx1 prevented polar localization of tagged proteins, indicating the need for specific protein-protein interactions in polar trafficking. Remarkably, expression of the Mtbesx1 locus in Msesx1 mutants restored polar localization of tagged proteins, indicating establishment of the MtbESX-1 apparatus in M. smegmatis. This observation illustrates the cross-species conservation of protein interactions governing assembly of ESX-1, as well as polar localization. Importantly, we describe novel non-esx1-encoded proteins, which affect ESX-1 activity, which colocalize with ESX-1, and which are required for ESX-1 recruitment and assembly. This analysis provides new insights into the molecular assembly of this important determinant of Mtb virulence. PMID- 22233445 TI - Enzymatic activities of isolated cytochrome bc1-like complexes containing fused cytochrome b subunits with asymmetrically inactivated segments of electron transfer chains. AB - Homodimeric structure of cytochrome bc1, a common component of biological energy conversion systems, builds in four catalytic quinone oxidation/reduction sites and four chains of cofactors (branches) that, connected by a centrally located bridge, form a symmetric H-shaped electron transfer system. The mechanism of operation of this complex system is under constant debate. Here, we report on isolation and enzymatic examination of cytochrome bc1-like complexes containing fused cytochrome b subunits in which asymmetrically introduced mutations inactivated individual branches in various combinations. The structural asymmetry of those forms was confirmed spectroscopically. All the asymmetric forms corresponding to cytochrome bc1 with partial or full inactivation of one monomer retain high enzymatic activity but at the same time show a decrease in the maximum turnover rate by a factor close to 2. This strongly supports the model assuming independent operation of monomers. The cross-inactivated form corresponding to cytochrome bc1 with disabled complementary parts of each monomer retains the enzymatic activity at the level that, for the first time on isolated from membranes and purified to homogeneity preparations, demonstrates that intermonomer electron transfer through the bridge effectively sustains the enzymatic turnover. The results fully support the concept that electrons freely distribute between the four catalytic sites of a dimer and that any path connecting the catalytic sites on the opposite sides of the membrane is enzymatically competent. The possibility to examine enzymatic properties of isolated forms of asymmetric complexes constructed using the cytochrome b fusion system extends the array of tools available for investigating the engineering of dimeric cytochrome bc1 from the mechanistic and physiological perspectives. PMID- 22233443 TI - Protein docking prediction using predicted protein-protein interface. AB - BACKGROUND: Many important cellular processes are carried out by protein complexes. To provide physical pictures of interacting proteins, many computational protein-protein prediction methods have been developed in the past. However, it is still difficult to identify the correct docking complex structure within top ranks among alternative conformations. RESULTS: We present a novel protein docking algorithm that utilizes imperfect protein-protein binding interface prediction for guiding protein docking. Since the accuracy of protein binding site prediction varies depending on cases, the challenge is to develop a method which does not deteriorate but improves docking results by using a binding site prediction which may not be 100% accurate. The algorithm, named PI-LZerD (using Predicted Interface with Local 3D Zernike descriptor-based Docking algorithm), is based on a pair wise protein docking prediction algorithm, LZerD, which we have developed earlier. PI-LZerD starts from performing docking prediction using the provided protein-protein binding interface prediction as constraints, which is followed by the second round of docking with updated docking interface information to further improve docking conformation. Benchmark results on bound and unbound cases show that PI-LZerD consistently improves the docking prediction accuracy as compared with docking without using binding site prediction or using the binding site prediction as post-filtering. CONCLUSION: We have developed PI-LZerD, a pairwise docking algorithm, which uses imperfect protein-protein binding interface prediction to improve docking accuracy. PI LZerD consistently showed better prediction accuracy over alternative methods in the series of benchmark experiments including docking using actual docking interface site predictions as well as unbound docking cases. PMID- 22233446 TI - SRH and HrQOL: does social position impact differently on their link with health status? AB - BACKGROUND: Self-rated Health (SRH) and health-related quality of life (HRQoL) are used to evaluate health disparities. Like all subjective measures of health, they are dependent on health expectations that are associated with socioeconomic characteristics. It is thus needed to analyse the influence played by socioeconomic position (SEP) on the relationship between these two indicators and health conditions if we aim to use them to study health disparities. Our objective is to assess the influence of SEP on the relationship between physical health status and subjective health status, measured by SRH and HRQoL using the SF-36 scale. METHODS: We used data from the French National Health Survey. SEP was assessed by years of education and household annual income. Physical health status was measured by functional limitations and chronic low back pain. RESULTS: Regardless of their health status, people with lower SEP were more likely than their more socially advantaged counterparts to report poor SRH and poorer HRQoL, using any of the indicators of SEP. The negative impact of chronic low back pain on SRH was relatively greater in people with a high SEP than in those with a low SEP. In contrast, chronic low back pain and functional limitations had less impact on physical and mental component scores of quality of life for socially advantaged men and women. CONCLUSIONS: Both SRH and HRQoL were lower among those reporting functional limitations or chronic low back pain. However, the change varied according SEP and the measure. In relative term, the negative impact of a given health condition seems to be greater on SRH and lower on HRQoL for people with higher SEP in comparison with people with low SEP. Using SRH could thus decrease socioeconomic differences. In contrast using HRQoL could increase these differences, suggesting being cautious when using these indicators for analyzing health disparities. PMID- 22233447 TI - Expansion of antimonato polyoxovanadates with transition metal complexes: (Co(N3C5H15)2)2[{Co(N3C5H15)2}V15Sb6O42(H2O)].5H2O and (Ni(N3C5H15)2)2[{Ni(N3C5H15)2}V15Sb6O42(H2O)].8H2O. AB - Two new polyoxovanadates (Co(N(3)C(5)H(15))(2))(2)[{Co(N(3)C(5)H(15))(2)}V(15)Sb(6)O(42)(H(2)O)].5H(2)O (1) and (Ni(N(3)C(5)H(15))(2))(2)[{Ni(N(3)C(5)H(15))(2)}V(15)Sb(6)O(42)(H(2)O)].8H(2)O (2) (N(3)C(5)H(15) = N-(2-aminoethyl)-1,3-propanediamine) were synthesized under solvothermal conditions and structurally characterized. In both structures the [V(15)Sb(6)O(42)(H(2)O)](6-) shell displays the main structural motif, which is strongly related to the {V(18)O(42)} archetype cluster. Both compounds crystallize in the triclinic space group P1 with a = 14.3438(4), b = 16.6471(6), c = 18.9186(6) A, alpha = 87.291(3) degrees , beta = 83.340(3) degrees , gamma = 78.890(3) degrees , and V = 4401.4(2) A(3) (1) and a = 14.5697(13), b = 15.8523(16), c = 20.2411(18) A, alpha = 86.702(11) degrees , beta = 84.957(11) degrees , gamma = 76.941(11) degrees , and V = 4533.0(7) A(3) (2). In the structure of 1 the [V(15)Sb(6)O(42)(H(2)O)](6-) cluster anion is bound to a [Co(N(3)C(5)H(15))(2)](2+) complex via a terminal oxygen atom. In the Co(2+) centered complex, one of the amine ligands coordinates in tridentate mode and the second one in bidentate mode to form a strongly distorted CoN(5)O octahedron. Similarly, in compound 2 an analogous NiN(5)O complex is joined to the [V(15)Sb(6)O(42)(H(2)O)](6-) anion via the same attachment mode. A remarkable difference between the two compounds is the orientation of the noncoordinated propylamine group leading to intermolecular Sb...O contacts in 1 and to Sb...N interactions in 2. In the solid-state lattices of 1 and 2, two additional [M(N(3)C(5)H(15))(2)](2+) complexes act as countercations and are located between the [{M(N(3)C(5)H(15))(2)}V(15)Sb(6)O(42)(H(2)O)](4-) anions. Between the anions and cations strong N-H...O hydrogen bonds are observed. In both compounds the clusters are stacked along the b axis in an ABAB fashion with cations and water molecules occupying the space between the clusters. Magnetic characterization demonstrates that the Ni(2+) and Co(2+) cations do not significantly couple with the S = 1/2 vanadyl groups. The susceptibility data can be successfully reproduced assuming a distorted ligand field for the Co(2+) ions (1) and an O(h) symmetric Ni(2+) ligand field (2). PMID- 22233448 TI - Influence of hypodermic needle dimensions on subcutaneous injection delivery--a pig study of injection deposition evaluated by CT scanning, histology, and backflow. AB - BACKGROUND: Thinner and shorter needles for subcutaneous administration are continuously developed. Previous studies have shown that a thinner needle causes fewer occurrences of painful needle insertions and that a shorter needle decreases the occurrence of painful intramuscular injections. However, little is known about local drug delivery in relation to needle length and thickness. This study aimed to compare deposition depth and backflow from three hypodermic needles of 3 mm 34G (0.19 mm), 5 mm 32G (0.23 mm), and 8 mm 30G (0.30 mm) in length and thickness. METHODS: Ex vivo experiments were carried out on pigs, in neck tissue comparable to human skin at typical injection sites. Six pigs were included and a total of 72 randomized injections were given, i.e. 24 subcutaneous injections given with each needle type. Accordingly, 400 MUL was injected including 70% NovoRapid((r)) (Novo Nordisk A/S, BagsvMUrd, Denmark) and 30% Xenetix((r)) (Guerbet, Villepinte, France) contrast including 1 mg/mL Alcian blue. Surgical biopsies of injection sites were sampled and computer topographic (CT)-scanned in 3D to assess deposition and local distribution. Biopsies were prepared and stained to evaluate deposition in comparison to the CT-scanning findings. The backflow of each injection was collected with filter paper. The blue stains of filter paper were digitized and volume estimated by software calculation vs. control staining. RESULTS: CT-scanning (n = 57) and histology (n = 10) showed that, regardless of injection depth, the bulk of the injection was in the subcutaneous tissue and did not propagate from subcutis into dermis. With the 8 mm 30G needle all injections apart from one intramuscular injection were located in the subcutaneous layer. The volume depositions peaked in 4-5 mm depth for the 3 mm 34G needle, in 5-6 mm depth for the 5 mm 32G needle, and in 9-10 mm depth for the 8 mm 30G needle. In general, injection depositions evaluated by histology and CT-scans compared well for the individual biopsies. The amount of backflow (n = 69) from the 3 mm 34G needle was smaller (P < 0.05) as compared to the 5 mm 32G and the 8 mm 30G needles. Analysis showed a correlation between backflow and the needle's outer dimension with the needle diameter being the pivotal parameter. Furthermore, CT-scanning and histology confirmed that local propagation of the injection and final distribution followed a route of less mechanical resistance as determined by connective tissue barriers preset in the site of injection. CONCLUSION: Needles as short as 3 mm efficiently delivered injections into the subcutaneous target. The amount of backflow was smaller with thinner needles. Local distribution was variable and determined by mechanical barriers preset in the tissue. CT-scans and histology were concordant. PMID- 22233450 TI - Quantity and proliferation rate of mesenchymal stem cells in human cord blood during gestation. AB - UCB (umbilical cord blood) as a resource of MSCs (mesenchymal stem cells) is widely accepted, but the quantity and characteristics of UCB-MSCs from different gestational ages have not been well studied. We have quantified the number of MSCs in UCB at different gestational ages using a multi-colour flowcytometer and compared the cell proliferation rates of these UCB-MSCs. Defining MSCs as CD44+/CD105+/CD34-/CD45 population, their numbers declined in the UCB at the gestational age. Proliferation rates were significantly higher in UCB before term than at full term. Non-full term UCB samples may be a better source of MSCs. PMID- 22233451 TI - Natural products and traditional medicine: turning on a paradigm. AB - Paradigm shifts in the strategies and the sciences that would enhance the quality, safety, and efficacy of traditional medicines and dietary supplements in global health care are discussed. Some of the challenges facing traditional medicine in health care are described, and the importance of defining clear goals and directions for the information systems, botany, chemistry, and biology related to plants and health care, including for drug discovery and quality control, is indicated. PMID- 22233449 TI - Glial modulators: a novel pharmacological approach to altering the behavioral effects of abused substances. AB - INTRODUCTION: Commonly abused drugs including opioids, stimulants and alcohol activate glia cells, an effect that has been identified across species. Glia, specifically astrocytes and microglia, have been shown to contribute directly to behaviors predictive of the abuse liability of these drugs. Although still in its infancy, research investigating the effects of pharmacological modulation of glial activity on these behaviors has provided encouraging findings suggesting glial cell modulators as potential pharmacotherapies for substance-use disorders. AREAS COVERED: This review first explores the evidence establishing glial mediated modulations of behaviors associated with opioid, stimulant and alcohol exposure, with emphasis placed on the neuroanatomical substrates for these effects. Next, neurobiological and behavioral studies evaluating the ability of glial cell modulators to prevent and reverse the effects of these abused substances will be considered. Finally, the potential clinical efficacy of glial cell modulators as a novel pharmacological approach to treat substance-use disorders in relation to currently available, conventional pharmacotherapies will be discussed. EXPERT OPINION: Though the relationship between drug-induced glial activity and behaviors indicative of drug abuse and dependence is not yet fully elucidated, the evidence for the association continues to grow. The use of glial modulators as pharmacological tools to investigate this relationship has also yielded findings supporting their potential clinical efficacy for treating substance-use disorders. PMID- 22233452 TI - Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity. AB - OBJECTIVE: Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. DESIGN: Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. RESULTS: For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4.2 +/- 2.39 vs 1.6 +/- 0.19, P < 0.001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18.3 +/- 8.10 vs 37.3 +/- 6.48 bursts/min, P < 0.0001, respectively in patients and controls). A reduction in plasma leptin (1.6 +/- 1.04 vs 6.5 +/- 2.01 MUg/l, P < 0.0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0.0001). CONCLUSIONS: Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia. PMID- 22233453 TI - Variation in number and formation of repeat sequences in the rDNA ITS2 region of five sibling species in the Anopheles barbirostris complex in Thailand. AB - Repeat sequences of approximately 100 base pairs in length were found in the rDNA ITS2 region of Anopheles barbirostris van der Wulp (Diptera: Culicidae) species A1, A2, A3, A4, and An. campestris-like in the An. barbirostris complex. Variation in the number of repeats was observed among the five sibling species. Specifically, 10 repeats were observed in A1, eight in A2, A4, and campestris like, and three in A3. Based on similarities in the sequences of the repeats, related repeats were classified into nine groups. Although A2, A4, and the campestris-like species had the same number of repeats, the ITS2 region of the three species contained different groups of repeats. Excluding the repeat sequences facilitated good alignment of the ITS2 region in the five sibling species. Phylogenetic analyses of the 95 isolines were compared with results obtained from mitochondrial genes (COI and COII). The results revealed marked differences among the five sibling species, particularly regarding the ITS2 region of A3, which was more distinct from the other four species than COI and COIL Repeat sequences in the ITS2 region of other Anopheles species retrieved from GenBank also were analyzed. New repeat sequences were found in An. beklemishevi Stegnii and Kabanova, An. crucians Wiedemann and An. funestus Giles, suggesting that the occurrence of repeat sequences in the ITS2 region are not rare in anopheline mosquitoes. PMID- 22233454 TI - Newly visualized fibrillar collagen scaffolds dictate Entamoeba histolytica invasion route in the human colon. AB - The extracellular matrix (ECM) and its role in the outcome of infectious diseases have been poorly investigated. In this study, we determined the impact of the collagen fibres architecture on the invasive process of the enteric parasite Entamoeba histolytica. The behaviour of E. histolytica wild-type and silenced for the cysteine protease A5 (CP-A5) were compared on a three-dimensional collagen matrix and within human colon fragments for fibrillar collagen cleavage and migration. The interstitial collagen fibres within the connective tissue of the human colon, visualized by multiphoton and second harmonic generation signals imaging, presented a dense scaffold at the subepithelial level and a loose meshwork within the chorion. To penetrate the tissue, E. histolytica migrated on the dense scaffold that remained intact, reached the crypt of Lieberkhun, migrated along and then disorganized the loose scaffold to escape into the mucosa. Interestingly, in vitro, CP-A5 was not required for collagenase activity and migration through the matrix but was necessary within the tissue environment for collagen meshwork remodelling and subsequent invasion. The data point out that further step of invasion relay with ECM destruction that requires human components induced or activated in the presence of CP-A5. PMID- 22233455 TI - Possibility of a new anti-alzheimer's disease pharmaceutical composition combining memantine and vitamin D. AB - Alzheimer's disease (AD) is the leading cause of dementia. In addition to a decrease in brain cholinergic activity, AD is also marked by glutamatergic excitotoxicity that results in neuronal death, characterized clinically by a loss of learning and memory abilities. The currently available drugs for symptomatic treatment of AD (i.e. memantine and acetylcholinesterase inhibitors) only temporarily slow down the natural history of the disease process. Among them, memantine is the only one that acts as a non-competitive low-affinity modulator of N-methyl-D-aspartate (NMDA) receptors. Memantine's modulation of NMDA receptors has been reported to prevent the neuronal necrosis induced by glutamatergic calcium neurotoxicity, but not the neuronal apoptosis resulting from oxidative stress. This observation calls for new drug regimen strategies based on memantine combined with molecules having antioxidant effects, in order to create a multi-target therapy to increase neuronal protection and prevent AD progression. We wish to highlight that vitamin D is a secosteroid hormone that is suggested to have neuroprotective effects that include regulation of neuronal calcium homeostasis, as well as antioxidant, neurotrophic and anti-inflammatory properties. The combination of memantine plus vitamin D may provide, in one treatment, enhanced protection against several degenerative processes linked to AD. Based on the present rationale, a clinical trial testing this hypothesis is currently in recruitment (AD-IDEA trial; ClinicalTrials.gov identifier: NCT01409694). This new pharmaceutical composition may provide an effective solution to the problem of neuronal death and cognitive decline in AD. PMID- 22233457 TI - Cinnamon extract promotes type I collagen biosynthesis via activation of IGF-I signaling in human dermal fibroblasts. AB - The breakdown of collagenous networks with aging results in hypoactive changes in the skin. Accordingly, reviving stagnant collagen synthesis can help protect dermal homeostasis against aging. We searched for type I collagen biosynthesis inducing substances in various foods using human dermal fibroblasts and found that cinnamon extract facilitates collagen biosynthesis. Cinnamon extract potently up-regulated both mRNA and protein expression levels of type I collagen without cytotoxicity. We identified cinnamaldehyde as a major active component promoting the expression of collagen by HPLC and NMR analysis. Since insulin-like growth factor-I (IGF-I) is the most potent stimulator of collagen biosynthesis in fibroblasts, we examined the effect of cinnamaldehyde on IGF-I signaling. Treatment with cinnamaldehyde significantly increased the phosphorylation levels of the IGF-I receptor and its downstream signaling molecules such as insulin receptor substrate-1 and Erk1/2 in an IGF-I-independent manner. These results suggested that cinnamon extract is useful in antiaging treatment of skin. PMID- 22233458 TI - In silico characterization of atypical kinase PFD0975w from Plasmodium kinome: a suitable target for drug discovery. AB - RIO-2 kinase is known to regulate ribosome biogenesis and other cell cycle events. The 3D model of ATP bound and an unbound form of PFD0975w was generated using AfRIO-2 crystal structure 1TQI, 1ZAO as template employing Modeller9v7 program. Structural characterization identified N-terminal winged helix domain (1 84), C-terminal kinase domain (148-275), and presence of other critical residues known for ATP binding and kinase activity. Using Q-site and pocket finder, a number of well-defined substrate (peptide) binding regions were identified in the catalytic core of the protein. The peptide binding regions were further validated by molecular modeling a non-specific polyalanine peptide and a sequence-specific peptide2 into these sites to generate a stable PFD0975w/peptide complexes. Peptide fits well into identified pocket on PFD0975w and makes extensive interaction with the protein residues. These newly identified peptide binding sites potentially give opportunity to design a specific inhibitor against PFD0975w. There are subtle but significant differences between Plasmodium falciparum and human RIO-2 to exploit PFD0975w for drug development. In conclusion, our finding will let us to design effective chemotherapy against malaria parasite exploiting PFD0975w as a drug target. PMID- 22233456 TI - Three-year experience with alendronate treatment in postmenopausal osteoporotic Japanese women with or without renal dysfunction: a retrospective study. AB - BACKGROUND AND OBJECTIVE: Chronic kidney disease is associated with an increased risk of fragility fractures. A retrospective study was conducted to compare outcomes after 3 years of alendronate treatment in postmenopausal osteoporotic Japanese women with or without renal dysfunction (RD). METHODS: One hundred and thirty-five postmenopausal osteoporotic Japanese women (mean age at baseline: 68 years) who had been treated with alendronate in our outpatient clinic for more than 3 years were analysed. The lumbar spine bone mineral density (BMD) of patients was measured using dual energy x-ray absorptiometry, and urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) and serum levels of alkaline phosphatase (ALP) were monitored during the 3-year treatment period. The incidence of osteoporotic fractures was also assessed. RESULTS: Twenty-six women had RD with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. The urinary NTX and serum ALP levels significantly decreased and the lumbar spine BMD significantly increased, compared with the baseline values, in a manner that was similar among women with or without RD. However, the incidence of non-vertebral fractures, but not that of vertebral fractures, was significantly higher among women with RD than among women without RD. CONCLUSIONS: Alendronate treatment appeared to have a similar effect on surrogate markers in postmenopausal osteoporotic Japanese women with or without RD. However, further studies are needed to confirm that RD may increase the risk of non-vertebral fractures in patients treated with alendronate. PMID- 22233459 TI - Clinical practice guidelines for feeding behaviors and weight-for-age at 12 months: a secondary analysis of the Infant Feeding Practices Study II. AB - BACKGROUND: The World Health Organization has identified childhood obesity as a major threat to global health. Accumulating evidence indicates that excess weight early in life is predictive of later childhood and adolescent obesity. Clinical practice guidelines for infant feeding behaviors have been developed by national and international health organizations. The relationship between these guidelines and infant weight status has not been established. AIM: To examine the relationship between weight-for-age at 1 year and adherence to four clinical practice guidelines for feeding behaviors: no bottle-to-bed, minimal juice consumption, breastfeeding throughout the first year of life, and introduction to solid food no earlier than age 4-6 months. METHODS: Data were obtained from the Infant Feeding Practices Study II, a longitudinal, national survey administered by the U.S. Food and Drug Administration and Centers for Disease Control and Prevention that followed mother-infant dyads from pregnancy through 1 year postpartum. The sample was comprised of 691 infants for whom 12-month survey data were available. RESULTS: Significant associations with weight-for-age were found for juice consumption (p= 0.003), breastfeeding during the second half of infancy (p < 0.001), and introduction to solid foods prior to age 4 months (p < 0.001). A regression model that controlled for infant and maternal characteristics demonstrated that these feeding behaviors remained significant predictors of weight-for-age at 12 months. CONCLUSIONS AND IMPLICATIONS: Modifiable infant feeding behaviors contributed to weight-for-age at 1 year. Replication studies with economically and culturally diverse samples are needed. Further, testing longitudinal interventions that address infant feeding practices is likely to yield the evidence needed for shaping future clinical practice guidelines that reduce the risk for childhood obesity and related pediatric comorbidities. PMID- 22233460 TI - The effects of optimism and pessimism on updating emotional information in working memory. AB - In the present study we elucidate the emotional and executive control interactions that might underlie optimism and pessimism. Participants completed a self-report measure of optimism/pessimism and performed an emotion faces categorisation task and an emotion n-back task in which they indicated whether each of a series of faces had the same or a different emotional expression (happy, sad, neutral) as the face presented two trials before. Trials were structured to measure latency to update emotional content in working memory (WM). More pessimistic individuals formed connections among positive stimuli, and broke connections among positive and sad stimuli, in WM more slowly than did less pessimistic individuals; levels of optimism/pessimism did not affect the rate with which individuals formed and broke connections among neutral representations in WM. It appears, therefore, that levels of pessimism are related to specific affective cognitive mechanisms in WM that may be involved in emotion regulation. PMID- 22233461 TI - From Denis Burkitt to Dar es Salaam. What happened next in East Africa?- Tanzania's story. AB - East Africa was at the forefront of early achievements and discoveries in paediatric oncology thanks to Denis Burkitt's seminal work. Although these successes have been built upon and continued elsewhere, they were sadly not sustained in sub-Saharan Africa for a variety of reasons. In recent years however this situation is slowly changing in countries across the continent. Tanzania is one such African country. Until very recently, survival rates of 5-10% for all children's cancers were expected. However, change has been brought about thanks to the combined efforts and commitments of the Tanzanian Ministry of Health, non governmental organizations--such as The International Network for Cancer Treatment and Research, and Children in Crossfire-- and the participation of the private sector. Services are rapidly developing and outcomes are continuing to improve with 1-year survival rates of approximately 60% achieved. Efforts to maintain this early progress are concentrated around providing high quality local subspecialty medical training and continued local ownership of the programme. PMID- 22233462 TI - Mate choice for a male carotenoid-based ornament is linked to female dietary carotenoid intake and accumulation. AB - BACKGROUND: The coevolution of male traits and female mate preferences has led to the elaboration and diversification of sexually selected traits; however the mechanisms that mediate trait-preference coevolution are largely unknown. Carotenoid acquisition and accumulation are key determinants of the expression of male sexually selected carotenoid-based coloration and a primary mechanism maintaining the honest information content of these signals. Carotenoids also influence female health and reproduction in ways that may alter the costs and benefits of mate choice behaviours and thus provide a potential biochemical link between the expression of male traits and female preferences. To test this hypothesis, we manipulated the dietary carotenoid levels of captive female house finches (Carpodacus mexicanus) and assessed their mate choice behavior in response to color-manipulated male finches. RESULTS: Females preferred to associate with red males, but carotenoid supplementation did not influence the direction or strength of this preference. Females receiving a low-carotenoid diet were less responsive to males in general, and discrimination among the colorful males was positively linked to female plasma carotenoid levels at the beginning of the study when the diet of all birds was carotenoid-limited. CONCLUSIONS: Although female preference for red males was not influenced by carotenoid intake, changes in mating responsiveness and discrimination linked to female carotenoid status may alter how this preference is translated into choice. The reddest males, with the most carotenoid rich plumage, tend to pair early in the breeding season. If carotenoid-related variations in female choice behaviour shift the timing of pairing, then they have the potential to promote assortative mating by carotenoid status and drive the evolution of carotenoid-based male plumage coloration. PMID- 22233463 TI - Influence of VicRK and CovR on the interactions of Streptococcus mutans with phagocytes. AB - OBJECTIVE: Streptococcus mutans are members of the oral microbiota that are implicated in dental caries and infective endocarditis. To adapt to environmental stresses encountered during host colonization, these bacteria employ two component regulatory systems, which modulate global changes in gene expression. These include the systems VicRK and CovR. In this study, we investigate the influence of VicRK and CovR in S. mutans interactions with mononuclear and polymorphonuclear (PMN) phagocytes. METHODS: Patterns of S. mutans uptake by murine macrophages were determined in strains, which differ in the production of proteins regulated by VicRK and CovR. Bacterial uptake by murine macrophages and by PMN in human blood was analyzed in vicK and covR knockout mutants obtained in strains UA159 and LT11. RESULTS: Inactivation of covR did not affect uptake by macrophages, while vicK inactivation transiently reduced uptake only in LT11 (P < 0.05). In the two strains, inactivation of vicK and covR impaired uptake by PMN for a period of 1 h or more (P < 0.01-0.05). Mutant complementation with vicK or covR restored the PMN uptake phenotypes. CONCLUSION: This study indicates that VicRK and CovR regulate functions that influence bacterial susceptibility to phagocytosis, suggesting a novel role for these systems in the virulence of S. mutans. PMID- 22233465 TI - Analyzing the genetic characteristics and function of the swine leukocyte antigen 2 gene in a Chinese inbreed of pigs. AB - To study the genetic characteristics and function of swine leukocyte antigen (SLA) class I from the Hebao pig, a rare inbreed in China, a pair of primers was designed to amplify the SLA-2 gene (SLA-2-HB) and then the genetic characteristics of the gene were analyzed. The 3D homology modeling was used to analyze the structure and function of SLA-2-HB proteins. After cloning, sequencing and computer analysis, four SLA-2-HB alleles were found, all of 1119 bp. Sites 3-1097 were an open reading frame encoding 364 amino acids with two sets of intra-chain disulfide bonds comprising four cysteines situated in sites 125, 188, 227 and 283. By alignment of SLA-2-HB sequences with other SLA-2 alleles in the IPD database, 11 key variable amino acid sites were found in the extracellular domain of the SLA-2-HB alleles at sites 23(F), 24(I), 43(A), 44(K), 50(Q), 73(N), 95(I), 114(R), 155(G), 156(E) and 216(S), which could be used to differentiate other SLA-2 alleles. The 3D homology modeling demonstrated that the eight of 11 key variable amino acid sites were all in antigenic binding groove of SLA-2-HB proteins. The amino acid identities between SLA-2-HB and other SLA-2, SLA-1 and SLA-3 alleles were 86.2-97.0%, 85.0-93.9% and 83.3-88.6%, respectively. The phylogenetic tree of SLA-2-HB showed that it was relatively independent of the other SLA-2 genes. Furthermore, the SLA-2-HB alleles were similar to HLA-B15 and HLA-A2 functional domains and preserved some functional sites of HLA-A2. It was concluded that SLA-2-HB are novel alleles of SLA-2 and that the Hebao pig might have evolved independently in China. PMID- 22233464 TI - An obligatory role for lung infiltrating B cells in the immunopathogenesis of obliterative airway disease induced by antibodies to MHC class I molecules. AB - Using a murine model, we demonstrated that endobronchial administration of antibodies (Abs) to major histocompatibility complex (MHC) class I results in cellular infiltration, epithelial metaplasia, fibrosis and obstruction of the small airways (obliterative airway disease [OAD]) mediated predominantly by Th17 responses to self-antigens. This resembles bronchiolitis obliterans syndrome developed following human lung transplantation. Since B cells play a crucial role in induction of autoimmune responses, we defined the role of B cells and its antigen presenting properties in induction of OAD in this study. Anti-MHC class I was administered endobronchially in B(-/-) and wild-type mice. In contrast to wild type, B(-/-) animals did not demonstrate cellular infiltration, epithelial metaplasia and obstruction of airways following anti-MHC. Frequency of K-alpha1 tubulin and CollagenV-specific IL-17 cells was significantly decreased in B(-/-) mice. As expected, Abs against self-antigens and germinal center formation were not developed in B(-/-) mice. Thus, we conclude that B cells and its antigen presenting capacity play an important role in induction of immune responses to self-antigens and immunopathogenesis of OAD following the administration of anti MHC. Therefore, strategies to block B-cell and its antigen presenting functions should be considered for preventing the development of chronic rejection. PMID- 22233466 TI - Who is attending? End-of-life decision making in the intensive care unit. AB - PURPOSE: Traditional expectations of the single attending physician who manages a patient's care do not apply in today's intensive care units (ICUs). Although many physicians and other professionals have adapted to the complexity of multiple attendings, ICU patients and families often expect the traditional, single physician model, particularly at the time of end-of-life decision making (EOLDM). Our purpose was to examine the role of ICU attending physicians in different types of ICUs and the consequences of that role for clinicians, patients, and families in the context of EOLDM. METHODS: Prospective ethnographic study in a university hospital, tertiary care center. We conducted 7 months of observations including 157 interviews in each of four adult critical care units. RESULTS: The term "attending physician" was understood by most patients and families to signify an individual accountable person. In practice, "the attending physician" was an ICU role, filled by multiple physicians on a rotating basis or by multiple physicians simultaneously. Clinicians noted that management of EOLDM varied in relation to these multiple and shifting attending responsibilities. The attending physician role in this practice context and in the EOLDM process created confusion for families and for some clinicians about who was making patient care decisions and with whom they should confer. CONCLUSIONS: Any intervention to improve the process of EOLDM in ICUs needs to reflect system changes that address clinician and patient/family confusion about EOLDM roles of the various attending physicians encountered in the ICU. PMID- 22233467 TI - The POLST program: a retrospective review of the demographics of use and outcomes in one community where advance directives are prevalent. AB - OBJECTIVES: Determine the use and utility of the Physician Orders for Life Sustaining Treatment (POLST) program in a community where powers of attorney for health care (POAHCs) are prevalent. METHODS: A retrospective review of medical record and death certificate data of 400 adults who died between September 1, 2007, and March 31, 2008, in the La Crosse County, Wisconsin community. Demographic and cause-of-death data were collected from death certificates. Information about POAHC, POLST forms, and medical treatments provided in the last 30 days of life were abstracted from decedents' medical records. RESULTS: Sixty seven percent of decedents had a POLST form, whereas 22% had POAHC alone. In comparison with decedents with POAHC alone, decedents with a POLST form were significantly older (83 versus 77 years, p<0.001), more likely to die in a nursing home than in a hospital (p<0.001), and more likely to die from a terminal or chronic illnesses (97%). Decedents with POLST orders for higher levels of medical treatment received more treatment, and in only two cases was there evidence that treatment was discrepant with POLST orders. In 31% of all POLST forms, the person appointed in the POAHC consented to the POLST orders. CONCLUSIONS: POLST can be a highly effective program to ensure that patient preferences are known and honored in all settings. POAHCs are valuable because they identify appropriate surrogates when patients are incapacitated. PMID- 22233468 TI - Visual perceptual strengths and weaknesses in adults with intellectual disabilities compared with a birth year-matched norm. AB - BACKGROUND: The ventral and dorsal streams are considered to be the brain substrates of vision for perception and action, respectively. Using the Developmental Test of Visual Perception (DTVP), the current study examined whether visual perceptual strengths and weaknesses in adults with intellectual disabilities (ID) were attributable to the dichotomy of the visual streams. METHOD: In study 1, DTVP performance was compared among mild, moderate and severe adult ID groups; study 2 contrasted adult ID groups with and without Down syndrome (DS). To prevent possible contamination by the Flynn effect, participants were matched by birth year with the norm of the DTVP original edition. RESULTS: Independent of the extent of ID among the three groups in study 1 and the aetiological group difference in study 2, relative strength was found for two DTVP tasks: eye-hand coordination and distinguishing target figures from interference background. Relative weakness was obtained in identifying a figural category. Participants with DS demonstrated exceptional weakness in discerning a target from either mirror-imaged or rotated alternatives, in addition to figural category detection. CONCLUSIONS: Visual perceptual strengths and weaknesses in persons with ID were difficult to explain on the basis of two visual streams. An interpretation originating in a different research context (e.g. frontal-lobe dysfunction) appears to be required for explaining visual perceptual weaknesses in persons with ID. For persons with DS, strong frontal-lobe dysfunction with atypical lateralisation might be the pathological determinant of visual perceptual weaknesses. PMID- 22233470 TI - Does the distribution of health care benefits in Kenya meet the principles of universal coverage? AB - BACKGROUND: The 58th World Health Assembly called for all health systems to move towards universal coverage where everyone has access to key promotive, preventive, curative and rehabilitative health interventions at an affordable cost. Universal coverage involves ensuring that health care benefits are distributed on the basis of need for care and not on ability to pay. The distribution of health care benefits is therefore an important policy question, which health systems should address. The aim of this study is to assess the distribution of health care benefits in the Kenyan health system, compare changes over two time periods and demonstrate the extent to which the distribution meets the principles of universal coverage. METHODS: Two nationally representative cross-sectional households surveys conducted in 2003 and 2007 were the main sources of data. A comprehensive analysis of the entire health system is conducted including the public sector, private-not-for-profit and private-for profit sectors. Standard benefit incidence analysis techniques were applied and adopted to allow application to private sector services. RESULTS: The three sectors recorded similar levels of pro-rich distribution in 2003, but in 2007, the private-not-for-profit sector was pro-poor, public sector benefits showed an equal distribution, while the private-for-profit sector remained pro-rich. Larger pro-rich disparities were recorded for inpatient compared to outpatient benefits at the hospital level, but primary health care services were pro-poor. Benefits were distributed on the basis of ability to pay and not on need for care. CONCLUSIONS: The principles of universal coverage require that all should benefit from health care according to need. The Kenyan health sector is clearly inequitable and benefits are not distributed on the basis of need. Deliberate efforts should be directed to restructuring the Kenyan health system to address access barriers and ensure that all Kenyans benefit from health care when they need it. PMID- 22233471 TI - Systemic contact dermatitis following oral exposure to tramadol in a patient with allergic contact dermatitis caused by buprenorphine. PMID- 22233472 TI - Fixed drug eruption caused by etoricoxib with tolerance to celecoxib and parecoxib. PMID- 22233473 TI - Investigating contact allergy to CS spray. PMID- 22233474 TI - A case of SDRIFE induced by Nuvaring((r)). PMID- 22233475 TI - A case of allergic contact dermatitis caused by fructo oligosaccharide. PMID- 22233476 TI - Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations. AB - Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant disorder where affected individuals carry a 50% risk of developing cancer before 30 years of age. It is most commonly associated with mutations in the tumour suppressor gene, TP53. Adrenocortical carcinoma (ACC) is a very rare paediatric cancer, and up to 80% of affected children are found to carry germline TP53 mutations. Hence, we propose using childhood ACC incidence as selection criteria for referral for TP53 mutation testing, independent of familial cancer history. Under the auspices of the Malaysian Society of Paediatric Haematology-Oncology, four eligible children diagnosed with ACC over a 30-month study period were referred for mutation testing. Three had a germline TP53 mutation. Subsequent TP53 testing in relatives showed two inherited mutations and one de novo mutation. These findings strongly support paediatric ACC as a useful sentinel cancer for initiating a germline TP53/LFS detection programme, particularly in countries where the lack of structured oncogenetic practice precludes the identification of families with LFS features. PMID- 22233477 TI - Skin wrinkling morphology changes suddenly in the early 30s. AB - BACKGROUND/PURPOSE: Does the morphology of wrinkles alter gradually with aging or suddenly at a certain age? On the basis of the theoretic wrinkle simulation of ideal skin, we have suggested that the wrinkle morphology suddenly changes from stratum corneum wrinkling to epidermis wrinkling; the former induces shallow fine furrows, and the latter induces deep prominent wrinkles. To examine the existence of drastic change in wrinkling morphology, we developed a new measurement system for facial skin wrinkling test. METHODS: The mechanical compression test of facial skin was carried out for 102 Japanese women aged 25-56 years. The test was performed on the right temple area skin, and the area of wrinkles induced by the compression was measured using a digital video camera. The rate of increase in wrinkle area during compression was defined as the skin wrinkling rate, and it was calculated for all subjects automatically by image processing. RESULTS: The test results showed that the skin wrinkling rate underwent a step increase at the age 33, which means that the wrinkling morphologies of young and old skins are completely different, and so it changes suddenly in the early 30s. CONCLUSION: A new skin measurement system was developed to validate our theory of wrinkle formation mechanism with aging. The results demonstrated the wrinkling morphology changes suddenly at early 30s. PMID- 22233479 TI - Routine internal- and external-quality control data in clinical laboratories for estimating measurement and diagnostic uncertainty using GUM principles. AB - Healthcare laboratories are increasingly joining into larger laboratory organizations encompassing several physical laboratories. This caters for important new opportunities for re-defining the concept of a 'laboratory' to encompass all laboratories and measurement methods measuring the same measurand for a population of patients. In order to make measurement results, comparable bias should be minimized or eliminated and measurement uncertainty properly evaluated for all methods used for a particular patient population. The measurement as well as diagnostic uncertainty can be evaluated from internal and external quality control results using GUM principles. In this paper the uncertainty evaluations are described in detail using only two main components, within-laboratory reproducibility and uncertainty of the bias component according to a Nordtest guideline. The evaluation is exemplified for the determination of creatinine in serum for a conglomerate of laboratories both expressed in absolute units (MUmol/L) and relative (%). An expanded measurement uncertainty of 12 MUmol/L associated with concentrations of creatinine below 120 MUmol/L and of 10% associated with concentrations above 120 MUmol/L was estimated. The diagnostic uncertainty encompasses both measurement uncertainty and biological variation, and can be estimated for a single value and for a difference. This diagnostic uncertainty for the difference for two samples from the same patient was determined to be 14 MUmol/L associated with concentrations of creatinine below 100 MUmol/L and 14 % associated with concentrations above 100 MUmol/L. PMID- 22233478 TI - Lateral cervical lymph node metastases in papillary thyroid cancer: a systematic review of imaging-guided and prophylactic removal of the lateral compartment. AB - BACKGROUND: Papillary thyroid cancer (PTC) is a common endocrine cancer and frequently presents with lymph node (LN) metastases. The frequency of LN metastases in the lateral compartment and their surgical removal are poorly defined. There are no prospective randomised controlled trials addressing an eventual outcome difference relating to the extent of the initial surgical approach. The aim of this study was to define the extent of lateral LN involvement and the role of imaging in identification of these metastatic LN. DESIGN AND METHODS: A systematic review of studies of patients with PTC undergoing either prophylactic or therapeutic lymphadenectomy of the lateral cervical compartment. Studies involving imaging modalities in the detection of lateral cervical LNs in PTC were also analysed. RESULTS: Systematic review on the frequency of lateral LN metastases and their detection using various imaging tools identified 19 studies containing data on 5587 patients undergoing prophylactic or imaging-guided removal of the lateral compartment. Imaging-guided surgery retrieved cancerous lateral LNs in 446/3178 or 14% of eligible patients, whilst prophylactic lateral neck dissection yielded histopathological proof of cancer in 1177/204 or 57.5% of patients. The frequency of lateral compartment metastases increased with T stage. The sensitivity of ultrasound and CT was poor as low as 27% when accurately calculated. CONCLUSION: Metastatic cervical LNs were found in more than half of patients when prophylactic lateral LN dissection was performed. Use of conventional imaging for the selection of the surgical approach to the lateral cervical compartment may commonly identify stage N1a instead of N1b and thus lead to false stage assignment as stage III rather than stage IV, concealing the severe prognostic implications of this stage progression in individual patients. PMID- 22233480 TI - Haemostatic therapy in coronary artery bypass graft patients with decreased platelet function: comparison of fibrinogen concentrate with allogeneic blood products. AB - BACKGROUND: Patients undergoing coronary artery bypass grafting (CABG) are at risk of postoperative bleeding because of decreased platelet function and cardiopulmonary bypass (CPB)-induced haemostatic impairment. Fibrinogen concentration decreases by 34-42% of the preoperative level by the end of CPB. An inverse relationship between perioperative plasma fibrinogen levels and postoperative bleeding has been reported in CABG patients. Administration of fibrinogen concentrate after weaning from CPB in patients with diffuse microvascular bleeding may help promote haemostasis. We compared patient outcomes following fibrinogen concentrate administration or transfusion of allogeneics in CABG patients with decreased platelet function. METHODS: Thirty-eight patients with decreased preoperative platelet function in Multiplate aggregometry were included. Patients with bleeding after CPB received either fibrinogen concentrate (guided by the measurement of fibrin clot quality using the FIBTEM thromboelastometric test) or allogeneics. RESULTS: Twenty-nine of 38 patients received haemostatic therapy (bleeding + fibrinogen group, n = 10; bleeding + allogeneics group, n = 19). Total transfusion (median (interquartile range)) was significantly lower in the bleeding + fibrinogen group (0 (0, 3.8) units), compared with the bleeding + allogeneics group (6 (5, 8) units, p = 0.0073). Bolus administration of fibrinogen concentrate increased FIBTEM maximum clot firmness from 10.5 (9.3, 11) mm after CPB to 20.5 (20, 21.8) mm at the end of surgery. Postoperative outcomes were similar in both groups. No treatment-related complications were observed after fibrinogen concentrate. CONCLUSIONS: In CABG patients with bleeding after CPB, FIBTEM-guided administration of fibrinogen concentrate resulted in overall decreased transfusion, compared with haemostatic therapy with allogeneics. Fibrinogen concentrate administration increased the fibrin clot quality and helped achieve haemostasis. PMID- 22233481 TI - Cellular immune reactions of the sunn pest, Eurygaster integriceps, to the entomopathogenic fungus, Beauveria bassiana and its secondary metabolites. AB - In this study, five morphological types of circulating hemocytes were recognized in the hemolymph of the adult sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae), namely prohemocytes, plasmatocytes, granulocytes, adipohemocytes, and oenocytoids. The effects of the secondary metabolites of the entomopathogenic fungus Beauveria bassiana on cellular immune defenses of Eurygaster integriceps were investigated. The results showed that the fungal secondary metabolites inhibited phagocytic activity of E. integriceps hemocytes and hampered nodule formation. A reduction of phenoloxidase activity was also observed. The data suggest that B. bassiana produce secondary metabolites that disable several immune mechanisms allowing the fungus to overcome and then kill its host. This characteristic makes B. bassiana a promising model for biological control of insect pests such as E. integriceps. PMID- 22233482 TI - QSAR models for isoindolinone-based p53-MDM2 interaction inhibitors using linear and non-linear statistical methods. AB - The design and optimization of p53-MDM2 interaction inhibitors has attracted a great deal of interest in the development of new anticancer agents. Systematical 2D-QSAR studies on 98 isoindolinone-based p53-MDM2 interaction inhibitors were carried out using linear and the non-linear mathematical methods. At first, a forward stepwise-multiple linear regression model (FS-MLR) was proposed with reasonable statistical parameters (R(2)(train) =0.881, Q(2)(loo) =0.847, R(2)(test) =0.854). Then, enhanced replacement method-multiple linear regression (ERM-MLR) and support vector machine regression (SVMR) were applied to set up more accurate models (ERM-MLR: R(2)(train) =0.914, Q(2)(loo) =0.894 and R(2)(test) =0.903; SVMR: R(2)(train) =0.924, Q(2)(loo) =0.920 and R(test) (2) of 0.874). Furthermore, the reliability and application value of the ERM and SVMR model was also validated in virtual screening through receiver operating characteristic studies. PMID- 22233483 TI - Differential expression patterns of conserved miRNAs and isomiRs during Atlantic halibut development. AB - BACKGROUND: MicroRNAs (miRNAs) play a major role in animal ontogenesis. Size variants of miRNAs, isomiRs, are observed along with the main miRNA types, but their origin and possible biological role are uncovered yet. Developmental profiles of miRNAs have been reported in few fish species only and, to our knowledge, differential expressions of isomiRs have not yet been shown during fish development. Atlantic halibut, Hippoglossus hippoglossus L., undergoes dramatic metamorphosis during early development from symmetrical pelagic larval stage to unsymmetrical flatfish. No data exist on role of miRNAs in halibut metamorphosis. RESULTS: miRNA profiling using SOLiD deep sequencing technology revealed a total of 199 conserved, one novel antisense, and one miRNA* mature form. Digital expression profiles of selected miRNAs were validated using reverse transcription quantitative PCR. We found developmental transition-specific miRNA expression. Expression of some miRNA* exceeded the guide strand miRNA. We revealed that nucleotide truncations and/or additions at the 3' end of mature miRNAs resulted in size variants showing differential expression patterns during the development in a number of miRNA families. We confirmed the presence of isomiRs by cloning and Sanger sequencing. Also, we found inverse relationship between expression levels of sense/antisense miRNAs during halibut development. CONCLUSION: Developmental transitions during early development of Atlantic halibut are associated with expression of certain miRNA types. IsomiRs are abundant and often show differential expression during the development. PMID- 22233485 TI - New pharmacological avenues for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease: targeting glutamate and adenosine receptors. AB - INTRODUCTION: Parkinson's disease (PD) therapy is still centered on the use of L 3,4-dihydroxyphenylalanine (L-DOPA), which is hampered by numerous side effects, including abnormal involuntary movements known as L-DOPA-induced dyskinesias (LIDs). LIDs are the result of pre- and postsynaptic changes at the corticostriatal level, induced by chronic and pulsatile stimulation of striatal dopaminergic receptors. These changes impact on synaptic plasticity and involve also selected, nondopaminergic receptors expressed by striatal projection neurons. AREAS COVERED: Among nondopaminergic receptors, glutamate receptors - NMDA and mGluR5 subtypes in particular - and adenosine A(2A) receptors are those most likely involved in LIDs. The aim of the present review is to summarize results of studies undertaken with specific antagonists of these receptors, first conducted in animal models of LIDs, which in selected cases have been translated into clinical trials. EXPERT OPINION: Selected antagonists of glutamate and adenosine receptors have been proposed as anti-dyskinetic agents. Promising results have been obtained in preclinical investigations and in initial clinical trials, but long-term safety, tolerability and efficacy studies in patients are still required. The current development of novel antagonists, including tools able to act on receptor mosaics, may provide innovative tools for LIDs management in the next future. PMID- 22233484 TI - Pharmacotherapy for breakthrough cancer pain. AB - Breakthrough pain (BTP) is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The principal pharmacological treatment of BTP is represented by the administration of opioids as needed. Oral opioids have traditionally been the only available drugs for BTP. However, the onset and duration of action of oral opioids such as morphine or oxycodone may not be suitable for treating many episodes of BTP that are of short onset and duration. Transmucosal administration of lipophilic substances has gained a growing popularity in recent years due to the rapid effect, clinically observable 10-15 minutes after drug administration, and the non-invasive form. Different technologies have been developed to provide fast pain relief with potent opioid drugs such fentanyl, delivered by non-invasive routes (rapid onset opioids, ROOs). All the studies performed with ROOs have recommended that these drugs should be administered to opioid-tolerant patients receiving doses of oral morphine equivalents of at least 60 mg. These preparations, including oral transmucosal fentanyl citrate, fentanyl buccal tablet, sublingual fentanyl, intranasal fentanyl spray, fentanyl-pectin nasal spray and fentanyl buccal soluble film have shown better efficacy than placebo or oral opioids. Long-term studies have confirmed their efficacy and safety. PMID- 22233486 TI - Regulatory failure contributing to deaths of live kidney donors. AB - Hemorrhagic deaths of living kidney donors from failure of vascular clips used on the renal artery, first documented in 2006, have continued due to postoperative Hem-o-lok clip failure with sudden, massive bleeding. While the FDA issued a Class II recall of the Hem-o-lok clip for laparoscopic donor nephrectomies in 2006, two live kidney donors in the United States and one in India have since died. Compliance in timely reporting of deaths by the manufacturer and donor hospitals has not been enforced. Oversight agencies did not inform practitioners that donors died due to clip failures. A February 2011 survey disclosed that Hem o-lok or other clips are still used by some surgeons as a sole means of arterial control in laparoscopic donor nephrectomy; thus, a practice with documented fatal outcomes persists. We conclude that systems failures by oversight-regulatory agencies in communication to active clinicians led, at least in part, to preventable deaths. Information which was disseminated was neither complete nor timely. A corrective plan, funded by oversight agencies and the Hem-o-lok manufacturer, is proposed. All surgeons operating on a living organ donor must select vascular control techniques that entail tissue transfixion and assure a safe operative recovery. The Hem-o-lok and other surgical clips must not be used to control the donor renal artery. PMID- 22233487 TI - Myths and evidence on the link between recurrent aphthous stomatitis and systemic diseases. PMID- 22233489 TI - The effects of 11-ketotestosterone on occupation of downstream location and seawater in the New Zealand shortfinned eel, Anguilla australis. AB - The androgen 11-ketotestosterone (11KT) is associated with the physiological and morphological changes that occur during the transformation of sedentary ('yellow') freshwater eels (Anguilla spp.) into their migratory form ('silver') prior to their spawning migration in the ocean. In this study, we investigate the possible role of 11KT in modulating behaviors consistent with downstream migration; i.e., downstream and salinity preference in the New Zealand shortfinned eel (A. australis). Unlike silvering, 11KT did not induce preference for downstream locations, scored as presence at the downstream ends of 35 m raceways. Likewise, there was no evidence for increased salinity preference in 11KT-treated yellow eels, scored as preference for sea water over fresh water in a choice experiment. However, the 11KT treatment induced higher frequency of movements between fresh water and sea water, which may indicate restlessness. PMID- 22233490 TI - Developmental changes in the localization of protein kinase CK2 in non-diapause and diapause eggs of the silkworm, Bombyx mori. AB - To analyze the role of protein kinase CK2 (CK2) during early embryogenesis in non diapause and diapause of the silkworm, the distribution and localization of Bombyx mori CK2 (BmCK2) were investigated by an immunohistochemical technique using antibodies against the alpha- and beta-subunits of BmCK2. Both were localized in blastoderm cells of non-diapause and diapause eggs until 24 h after oviposition. More than 24 h after oviposition, however, the distribution of BmCK2 was different in non-diapause and diapause eggs. In non-diapause eggs, BmCK2 was mainly localized in yolk cells. In contrast, in diapause eggs, the localization was mainly observed in germ-band cells. Furthermore, we confirmed that the RNA helicase-like protein that was localized together with BmCK2 in non-diapause eggs was phosphorylated by BmCK2 in vitro. These data suggest that the role of BmCK2 is different in non-diapause and diapause eggs. PMID- 22233488 TI - Pseudomonas aeruginosa biofilm-associated homoserine lactone C12 rapidly activates apoptosis in airway epithelia. AB - Pseudomonas aeruginosa (PA) forms biofilms in lungs of cystic fibrosis (CF) patients, a process regulated by quorum-sensing molecules including N-(3 oxododecanoyl)-l-homoserine lactone (C12). C12 (10-100 uM) rapidly triggered events commonly associated with the intrinsic apoptotic pathway in JME (CF DeltaF508CFTR, nasal surface) epithelial cells: depolarization of mitochondrial (mito) membrane potential (Deltapsi(mito)) and release of cytochrome C (cytoC) from mitos into cytosol and activation of caspases 3/7, 8 and 9. C12 also had novel effects on the endoplasmic reticulum (release of both Ca(2+) and ER targeted GFP and oxidized contents into the cytosol). Effects began within 5 min and were complete in 1-2 h. C12 caused similar activation of caspases and release of cytoC from mitos in Calu-3 (wtCFTR, bronchial gland) cells, showing that C12 triggered responses occurred similarly in different airway epithelial types. C12 had nearly identical effects on three key aspects of the apoptosis response (caspase 3/7, depolarization of Deltapsi(mito) and reduction of redox potential in the ER) in JME and CFTR-corrected JME cells (adenoviral expression), showing that CFTR was likely not an important regulator of C12-triggered apoptosis in airway epithelia. Exposure of airway cultures to biofilms from PAO1wt caused depolarization of Deltapsi(mito) and increases in Ca(cyto) like 10-50 uM C12. In contrast, biofilms from PAO1DeltalasI (C12 deficient) had no effect, suggesting that C12 from P. aeruginosa biofilms may contribute to accumulation of apoptotic cells that cannot be cleared from CF lungs. A model to explain the effects of C12 is proposed. PMID- 22233491 TI - Establishment of enhancer detection lines expressing GFP in the gut of the ascidian Ciona intestinalis. AB - The gut is a tubular, endodermal organ for digesting food and absorbing nutrients. In this study, we characterized eight enhancer detection lines that express green fluorescent protein (GFP) in the whole or part of the digestive tube of the ascidian Ciona intestinalis. Three enhancer detection lines for the pyloric gland, a structure associated with the digestive tube, were also analyzed. These lines are valuable markers for analyzing the mechanisms of development of the gut. Based on the GFP expression of the enhancer detection lines together with morphological characteristics, the digestive tube of Ciona can be subdivided into at least 10 compartments in which different genetic cascades operate. Causal insertion sites of the enhancer detection lines were identified, and the expression pattern of the genes near the insertion sites were characterized by means of whole-mount in situ hybridization. We have characterized four and two genes that were specifically or strongly expressed in the digestive tube and pyloric gland, respectively. The present data provide the basic information and useful resources for studying gut formation in Ciona. PMID- 22233492 TI - Population subdivision of the brackish-water crab Deiratonotus cristatus on the Japanese coast. AB - We investigated the genetic structure of populations of the brackish-water crab Deiratonotus cristatus (de Man, 1895) (family Camptandriidae) on the Japanese coast, together with morphological and the ecological variations. Genetic characteristics of the local populations based on mitochondrial DNA COI sequence data have revealed genetic differentiation between many populations, with the haplotype networks forming three geographical clades: a clade occurring on the Pacific coast, one occurring predominantly in northern Hokkaido, Kyushu and the Seto Inland Sea, and a third occurring in the Ryukyu Islands. Male pleopod morphology, carapace length relative to carapace width, and carapace width of adult crabs varied inconsistently among the geographic groups corresponding to the three clades. Life history traits were similar throughout, although differences in the breeding season were apparent between populations on the Pacific coast, and in the Seto Inland Sea and the Ryukyu Islands. PMID- 22233493 TI - Differences in heat sensitivity between Japanese honeybees and hornets under high carbon dioxide and humidity conditions inside bee balls. AB - Upon capture in a bee ball (i.e., a dense cluster of Japanese honeybees forms in response to a predatory attack), an Asian giant hornet causes a rapid increase in temperature, carbon dioxide (CO2), and humidity. Within five min after capture, the temperature reaches 46 degrees C, and the CO2 concentration reaches 4%. Relative humidity gradually rises to 90% or above in 3 to 4 min. The hornet dies within 10 min of its capture in the bee ball. To investigate the effect of temperature, CO2, and humidity on hornet mortality, we determined the lethal temperature of hornets exposed for 10 min to different humidity and CO2/O2 (oxygen) levels. In expiratory air (3.7% CO2), the lethal temperature was >= 2 degrees lower than that in normal air. The four hornet species used in this experiment died at 44-46 degrees C under these conditions. Hornet death at low temperatures results from an increase in CO2 level in bee balls. Japanese honeybees generate heat by intense respiration, as an overwintering strategy, which produces a high CO2 and humidity environment and maintains a tighter bee ball. European honeybees are usually killed in the habitat of hornets. In contrast, Japanese honeybees kill hornets without sacrificing themselves by using heat and respiration by-products and forming tight bee balls. PMID- 22233494 TI - Combined effects of levonorgestrel and quinestrol on reproductive hormone levels and receptor expression in females of the Mongolian gerbil (Meriones unguiculatus). AB - The effects of treatment with a combination of levonorgestrel and quinestrol (EP 1; ratio of 2:1) on reproductive hormone levels and the expression of their receptors in female Mongolian gerbils were examined. We show that serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) decreased, whereas serum estradiol (E2) and progesterone (P4) increased after EP-1 treatment. EP1 down regulated mRNA expression of the follicle-stimulating hormone receptor (FSHR) and the estrogen receptor (ER) betain the ovary. EP-1 up-regulated the mRNA expression of the luteinizing hormone receptor (LHR) and the progesterone receptor (PR) in the ovary as well as ERalpha and PR in the uterus of Mongolian gerbils. The effects were time-dependent and dose-dependent. EP-1 had no obvious effects on ERalpha mRNA expression in the ovary. The current study demonstrates that the effect of EP-1 on the expression of ER subtypes is tissue-specific in Mongolian gerbils. EP-1 disrupted the reproductive endocrinology of the Mongolian gerbil. These findings suggest that the effects of EP-1 on reproductive hormone levels and their receptor expression in Mongolian gerbils may be the result of synergistic actions of levonorgestrel and quinestrol, with quinestrol playing the major role. PMID- 22233495 TI - Food deprivation increases the expression of the prepro-orexin gene in the hypothalamus of the barfin flounder, Verasper moseri. AB - Orexins (orexin-A and -B) are involved in the regulation of food intake in mammals. In the barfin flounder, Verasper moseri, we previously reported that orexin-A-like-immunoreactive (ir) cell bodies are localized in the hypothalamus, which is a possible orexigenic center in fish. However, the physiological roles of orexin in the barfin flounder remain unclear. Here, we cloned prepro-orexin cDNA and examined the effects of feeding status on orexin gene expression in the barfin flounder to obtain a better insight into the roles of orexins in feeding regulation. A molecular cloning study showed that barfin flounder prepro-orexin cDNA encodes a 145 amino acid (aa) polypeptide containing orexin-A (43 aa) and orexin-B (28 aa). Prepro-orexin gene transcripts were detected in the hypothalamus, pituitary, and several peripheral organs such as the eyeball, gills, head kidney, body kidney, spleen, testis, and the skin on the eye-side of the flounder's body. Furthermore, the mean prepro-orexin mRNA expression level in the hypothalamus was significantly higher in fasted than in fed fish. These results show that fasting regulates orexin mRNA in the hypothalamus and suggest that orexin is involved in feeding regulation in barfin flounder. PMID- 22233496 TI - Inheritance patterns of lateral dimorphism examined through breeding experiments in Tanganyikan cichlid (Julidochromis transcriptus) and Japanese Medaka (Oryzias latipes). AB - The asymmetry of mouth morphology, in which the mouth opens either leftward or rightward, is a unique example of antisymmetry that is widely found in fishes, such as Tanganyikan scale-eating cichlids, herbivorous cichlids, and the Japanese freshwater goby. This dimorphism is thought to be heritable in a Mendelian manner similar to that of the dominance of the lefty allele over righty, with homozygotes of lefty alleles being absent. This study aims to reveal whether this trait is inherited in the same Mendelian manner in fishes other than those examined to date, and whether the absence of the dominant homozygote is due to a lethal effect. We conducted F(1) and F(2) breeding experiments using the Tanganyikan cichlid Julidochromis transcriptus and Japanese medaka Oryzias latipes. For both J. transcriptus and O. latipes, the F(1) generations produced by incrossing lefty parents showed a lefty:righty ratio of 2:1, whereas incrosses of righties produced only righty offspring. Test crosses between lefty and righty produced a 1:1 ratio of lefty and righty offspring. These results are consistent with the inheritance model in which righty is homozygous for a recessive righty allele and lefty is heterozygous for dominant lefty and recessive righty alleles, in agreement with previous observations. The F(2) test cross also confirmed this pattern. Furthermore, no lethal effects on hatchability of O. latipes were detected, refuting the suggestion that the dominant homozygote is embryonic lethal. We conclude that mouth laterality is inherited in the same Mendelian manner in these two species, similar to that other fish species studied previously. However, the reason for absence of the dominant homozygote remains unclear. PMID- 22233497 TI - Phylogenetic relationships among Hoplobatrachus rugulosus in Thailand as inferred from mitochondrial DNA sequences of the cytochrome-b gene (Amphibia, Anura, Dicroglossidae). AB - A fragment (564 bp) of the mitochondrial cytochrome-b (Cyt-b) gene was studied for 73 individual rice field frogs (Hoplobatrachus rugulosus) from 18 geographical locations (populations) within Thailand. Sequence analysis revealed the presence of 12 haplotypes, with five haplotypes being represented in two or more populations, and the other seven being population-distinct haplotypes. Phylogenetic analysis by maximum parsimony, maximum likelihood, and neighbor joining analyses all placed the 12 haplotypes into two distinct and well separated clades with high bootstrap support, reflecting the high sequence divergences between the clades (25.3-32.3%). The mountain ranges and the Isthmus of Kra are likely to have played important roles in hindering gene flow among H. rugulosus populations in Thailand. From the sequence divergence values, the two clades of H. rugulosus can be classified into two distinct species, and therefore, the strains of H. rugulosus bred in farm stocks should be restricted to a population of one clade so as to avoid cross breeding between the two clades. PMID- 22233498 TI - Evidence for the morphological constraint hypothesis and optimal offspring size theory in the Mexican mud turtle (Kinosternon integrum). AB - Optimal offspring size theory states that natural selection should balance reproductive output by optimizing between offspring size and offspring number. If a species has evolved an optimal offspring size, the fitness of larger females should be increased by simply producing more offspring of an optimum size. In contrast, when offspring size is not optimized, the morphological constraint hypothesis may apply, and in this case, maternal fitness is increased by producing the greatest number of the largest offspring that mothers are physically capable of producing. We used a log-log allometric regression approach on clutch size, egg size, and body size data to test the application of optimal offspring size theory and the morphological constraint hypothesis in the Mexican mud turtle (Kinosternon integrum) in southern Mexico. Our results indicate that this turtle seems to follow the morphological constraint hypothesis when all data are analyzed together, but when data are divided between small (< 140 mm plastron length) and large females (> 140 mm plastron length), optimal offspring (egg) size theory was supported only in large females, while the morphological constraint hypothesis was supported in small females. Our results thus indicate that K. integrum females may increase their fitness in two different, size dependent ways as they grow from size at sexual maturity to maximum body size. PMID- 22233499 TI - Burkitt lymphoma and the discovery of Epstein-Barr virus. AB - The chance germinal encounter with the first lecture outside Africa on Burkitt lymphoma is described together with the hypothesis of a viral cause. Repeated virological investigations on lymphoma biopsies proved negative, leading to the idea that a latent virus might be activated if lymphoma cells could be cultured, although no human lymphoid cell had at that time ever been maintained in vitro. A chance event reminding of the need for suspension culture with mouse lymphomas led to success. The cultured cells carried a morphologically unequivocal, strangely inert, herpesvirus shown later to be immunologically, biologically and biochemically unique. How this new agent acquired its name, Epstein-Barr virus, is explained. PMID- 22233500 TI - In vitro culture and induced differentiation of sheep skeletal muscle satellite cells. AB - Skeletal muscle satellite cells are adult muscle-derived stem cells receiving increasing attention. Sheep satellite cells have a greater similarity to human satellite cells with regard to metabolism, life span, proliferation and differentiation, than satellite cells of the rat and mouse. We have used 2-step enzymatic digestion and differential adhesion methods to isolate and purify sheep skeletal muscle satellite cells, identified the cells and induced differentiation to examine their pluripotency. The most efficient method for the isolation of sheep skeletal muscle satellite cells was the type I collagenase and trypsin 2 step digestion method, with the best conditions for in vitro culture being in medium containing 20% FBS+10% horse serum. Immunofluorescence staining showed that satellite cells expressed Desmin, alpha-Sarcomeric Actinin, MyoD1, Myf5 and PAX7. After myogenic induction, multinucleated myotubes formed, as indicated by the expression of MyoG and fast muscle myosin. After osteogenic induction, cells expressed Osteocalcin, with Alizarin Red and ALP (alkaline phosphatase) staining results both being positive. After adipogenic induction, cells expressed PPARgamma2 (peroxisome-proliferator-activated receptor gamma2) and clear lipid droplets were present around the cells, with Oil Red-O staining giving a positive result. In summary, a successful system has been established for the isolation, purification and identification of sheep skeletal muscle satellite cells. PMID- 22233501 TI - Recognizing and responding to uncertainty: a grounded theory of nurses' uncertainty. AB - BACKGROUND: There has been little research to date exploring nurses' uncertainty in their practice. Understanding nurses' uncertainty is important because it has potential implications for how care is delivered. PURPOSE: The purpose of this study is to develop a substantive theory to explain how staff nurses experience and respond to uncertainty in their practice. METHODS: Between 2006 and 2008, a grounded theory study was conducted that included in-depth semi-structured interviews. Fourteen staff nurses working in adult medical-surgical intensive care units at two teaching hospitals in Ontario, Canada, participated in the study. FINDINGS: The theory recognizing and responding to uncertainty characterizes the processes through which nurses' uncertainty manifested and how it was managed. Recognizing uncertainty involved the processes of assessing, reflecting, questioning, and/or being unable to predict aspects of the patient situation. Nurses' responses to uncertainty highlighted the cognitive-affective strategies used to manage uncertainty. DISCUSSION: Study findings highlight the importance of acknowledging uncertainty and having collegial support to manage uncertainty. The theory adds to our understanding the processes involved in recognizing uncertainty, strategies and outcomes of managing uncertainty, and influencing factors. IMPLICATIONS: Tailored nursing education programs should be developed to assist nurses in developing skills in articulating and managing their uncertainty. Further research is needed to extend, test and refine the theory of recognizing and responding to uncertainty to develop strategies for managing uncertainty. CONCLUSIONS: This theory advances the nursing perspective of uncertainty in clinical practice. The theory is relevant to nurses who are faced with uncertainty and complex clinical decisions, to managers who support nurses in their clinical decision-making, and to researchers who investigate ways to improve decision-making and care delivery. PMID- 22233502 TI - New insights into the mechanisms of the vasorelaxant effects of apocynin in rat thoracic aorta. AB - Apocynin is a naturally occurring acetophenone widely used as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Recent data suggested that apocynin might exert NADPH oxidase-independent pharmacological properties. Among them, vasorelaxant properties have been described, but the mechanisms still give rise to debates. The present study investigated the mechanisms involved in the vasorelaxant effect of apocynin on the in vitro model of rat isolated thoracic aortic rings. Apocynin (30 MUM to 10 mM) induced a dose dependent relaxation in both endothelium-intact and endothelium-denuded aortic rings with respective EC50 values of 0.78 +/- 0.08 and 1.91 +/- 0.21 mM. Endothelium removal or inhibition of nitric oxide (NO) synthase with N(omega) nitro-L-arginine-methyl ester (L-NAME) significantly decreased but did not abolish the effect of apocynin. By contrast, apocynin-induced relaxation was unchanged after incubation with indomethacin or charybdotoxin plus apamin. In endothelium-denuded aortas, the vasorelaxant effect of apocynin was significantly reduced by glibenclamide but not by 4-aminopyridine nor by iberiotoxin. Apocynin significantly decreased Ca(2+)-induced contraction and inhibited intracellular Ca(2+) mobilization after contraction with phenylephrine. Finally, the acute intravenous injection of apocynin led to an immediate and transient hypotensive effect in spontaneously hypertensive rats (SHR). In conclusion, our data demonstrated that apocynin induces both endothelium-independent relaxant effects involving inhibition of Ca(2+) mobilization and activation of KATP channels in vascular smooth muscle cells and endothelium-dependent effects mediated by NO. These results should provide a basis for caution when interpreting results on the vascular effects of apocynin. PMID- 22233503 TI - Rare manifestations of Neu-Laxova syndrome. AB - Neu-Laxova syndrome is a rare lethal congenital disorder involving multiple systems. Intrauterine growth retardation, ichthyosis, microcephaly, abnormal facial findings and limb contractures are its key features. We present a stillborn female baby of 1.5 kg with characteristic features including growth retardation, microcephaly, severe ectropion, micrognathia, flattened nose, eclabion, large ears, puffy hands and feet. In addition to these features, lissencephaly, severely hypoplastic cerebrum and corpus callossum, Dandy-Walker malformation, Transposition of Great Vessels and hepatomegaly were noted at autopsy. The patient was born at 38 weeks of gestation to consanguineous (second degree) Indian parents. The mother was 26 year old second gravida with lack of prenatal followup. Therefore, the condition was diagnosed postnatally. Because of the autosomal recessive inheritence of Neu-Laxova syndrome, in countries with high rates of consanguineous marriage, serial prenatal ultrasound examinations with genetic counseling should be performed on pregnant women at high risk to offer termination of affected pregnancies. PMID- 22233504 TI - The expression of HoxB5 and its role in neonatal rats with chronic lung disease. AB - The purpose of this investigation is to research the expression and effect of HoxB5 during pulmonary injury and to investigate the repairing ability of alveolar epithelial cells in such processes. Eighty neonatal rats were randomly divided into two groups: a group of high concentration of oxygen and the control group. The high oxygen group would inhale 85 to 90% oxygen and the control group would inhale air. The lung tissues on the 1(st), 3(rd), 7(th), 14(th), and 21(st) days would be obtained, in which immunohistochemical assay and Reverse Transcription Polymerase Chain Reaction (RT-PCR) would be performed to test the expressions of proteins and mRNAs of surfactant protein C (SPC) and AQP5. For expression of HoxB5 protein and its mRNA, immunohistochemical assay, western blot, in-situ hybridization, and RT-PCR would be run. The expression of SPC in the group of high concentration of oxygen was significantly reduced on day 3. Its expressions on day 14 and day 21 were significantly higher than those of the control group (p < 0.05). The expression of AQP5 in the group of high concentration of oxygen progressively decreased and such difference with the control group was significant (p < 0.05). The four experimental methods all showed the expression of HoxB5 in the group with high concentration of oxygen gradually decreased since day 7 (p < 0.05). High concentration of oxygen is damaging to alveolar epithelial cells. Although the number of type II alveolar epithelial cells (AECII) increases, its ability to differentiate and transform is significantly reduced and the reduced expression level of HoxB5 is possibly the reason for AECII to lose differentiation function to AECI. PMID- 22233505 TI - Evaluation of analysis of polycyclic aromatic hydrocarbons by the QuEChERS method and gas chromatography-mass spectrometry and their formation in poultry meat as affected by marinating and frying. AB - The objectives of this research were to develop a method for the determination of 16 polycyclic aromatic hydrocarbons (PAHs) in poultry meat by combining the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method with gas chromatography-mass spectrometry (GC-MS) and study their formation during marinating and frying. The recoveries of 16 PAHs ranged from 94.5 to 104% in blank samples and from 71.2 to 104% in poultry meat samples. The quantitation limits of 16 PAHs were from 0.02 to 1 ng/mL, with the intraday variability being from 2.4 to 6.6% [percent relative standard deviation (RSD%)] and interday variability being from 3.3 to 7.1% (RSD%). Most PAHs followed a time-dependent increase over a 24 h marinating period, with naphthalene being generated in the largest amount. Among the various poultry meat, chicken gizzard produced the highest level of total PAHs after 24 h of marinating. A similar tendency was observed for most PAHs during frying of poultry meat, but a high amount of total PAHs was shown in duck drumstick after 15 min of frying. PMID- 22233506 TI - Secondary students with moderate/severe intellectual disability: considerations of curriculum and post-school outcomes from the National Longitudinal Transition Study-2. AB - BACKGROUND: A conversation currently exists regarding secondary curriculum (e.g. academics, functional) for students with moderate/severe intellectual disability (ID) without a large research base connecting curriculum to outcomes. METHOD: This study represented a secondary analysis of the National Longitudinal Transition Study-2 (NLTS2) data to understand in-school curriculum and educational programming for secondary students with moderate/severe ID as well as the relationship between curriculum and students' post-school outcomes. Statistical procedures such as frequency distributions, a significance test and logistic regression were utilised to analyse secondary data from the NLTS2. RESULTS: The results suggest the majority of students with moderate/severe ID received a functional curriculum as well as instruction in core content areas; however, their instruction primarily occurred in pull-out educational settings. The students also reported low rates for the post-school outcomes examined (i.e. independent living, employment and post-secondary attendance). Finally, curriculum (functional vs. academics) was not related to any post-school outcome examined (e.g. independent living, employment). CONCLUSIONS: The data suggest additional research is needed to understand what factors impact post-school outcomes for students with moderate/severe ID. Yet - and regardless of the lack of impact - additional work is needed to help students achieve better post-school outcomes, including further examination of curriculum and instructional environments. PMID- 22233508 TI - Bi(III)-catalyzed intermolecular reactions of (Z)-pent-2-en-4-yl acetates with ethynylarenes for the construction of multisubstituted fluorene skeletons through a cascade electrophilic addition/cycloisomerization sequence. AB - A Bi(III)-catalyzed method for the synthesis of highly conjugated aromatic multisubstituted fluorene with (Z)-pent-2-en-4-yl acetates and ethynylarenes via domino reaction is described. In this process, the reaction appears to be very general and suitable for a variety of multisubstituted fluorene. PMID- 22233509 TI - Female factor IX deficiency due to maternally inherited X-inactivation. AB - X-chromosome inactivation is normally a random event that is regulated by the X chromosome itself. Rarely, females are affected by X-linked disorders from extremely skewed X-chromosome inactivation. Here, we report a family with hemophilia B with female expression through inherited X skewing that appears to be independent of either X chromosome. This finding suggests the possibility of a dominant autosomal contribution to inherited skewed X inactivation. PMID- 22233511 TI - Nutrition and health of aquaculture fish. AB - Under intensive culture conditions, fish are subject to increased stress owing to environmental (water quality and hypoxia) and health conditions (parasites and infectious diseases). All these factors have negative impacts on fish well-being and overall performance, with consequent economic losses. Though good management practices contribute to reduce stressor effects, stress susceptibility is always high under crowded conditions. Adequate nutrition is essential to avoid deficiency signs, maintain adequate animal performance and sustain normal health. Further, it is becoming evident that diets overfortified with specific nutrients [amino acids, essential fatty acids (FAs), vitamins or minerals] at levels above requirement may improve health condition and disease resistance. Diet supplements are also being evaluated for their antioxidant potential, as fish are potentially at risk of peroxidative attack because of the large quantities of highly unsaturated FAs in both fish tissues and diets. Functional constituents other than essential nutrients (such as probiotics, prebiotics and immunostimulants) are also currently being considered in fish nutrition aiming to improve fish growth and/or feed efficiency, health status, stress tolerance and resistance to diseases. Such products are becoming more and more important for reducing antibiotic utilization in aquafarms, as these have environmental impacts, may accumulate in animal tissues and increase bacterial resistance. This study reviews knowledge of the effect of diet nutrients on health, welfare and improvement of disease resistance in fish. PMID- 22233510 TI - A randomized controlled trial testing the effectiveness of a universal school based depression prevention program 'Op Volle Kracht' in the Netherlands. AB - BACKGROUND: The incidence of depressive symptoms increases during adolescence, from 10.0% to 24.5% at age 11 to 15, respectively. Experiencing elevated levels of depressive symptoms increases the risk of a depressive disorder in adulthood. A universal school-based depression prevention program Op Volle Kracht (OVK) was developed, based on the Penn Resiliency Program, aimed at preventing the increase of depressive symptoms during adolescence and enhancing positive development. In this study the effectiveness of OVK will be tested and possible mediators of program effects will be focus of study as well. METHOD: The effectiveness of OVK will be tested in a randomized controlled trial with two conditions, intervention (OVK) and control condition (care as usual). Schools are randomly assigned to research conditions. OVK will be incorporated in the school curriculum, maximizing program attendance. OVK consists of 16 lessons of 50 min, given by trained psychologists to groups of 11-15 students. OVK contains Cognitive Behavioral Therapy, social skills training, problem solving and decision making. Outcomes are measured at 6, 12, 18 and 24 months follow up, to monitor long term program effects. Primary outcome is level of depressive symptoms, secondary outcomes are: anxiety, hopelessness, cognitive bias, substance use, truancy, life satisfaction, coping, self-efficacy, optimism, happiness, friendship, school performance and school attitude. The questionnaires for students will be administered in the school setting. Parents will complete a questionnaire at baseline only. DISCUSSION: In this paper the study into the effectiveness of the depression prevention program OVK was described. It is expected that OVK will prevent the increase in depressive symptoms during adolescence and enhance positive development in the intervention condition, compared to the control condition. If OVK will be effective, it can be implemented in the school context by which numerous adolescents can be reached. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2879. PMID- 22233512 TI - Tetradecylthioacetic acid modulates cardiac transcription in Atlantic salmon, Salmo salar L., suffering heart and skeletal muscle inflammation. AB - Heart and skeletal muscle inflammation (HSMI) is a disease causing considerable mortality in farmed Atlantic salmon. We have previously reported that pre-feeding of tetradecylthioacetic acid (TTA) reduces the mortality during a natural outbreak of HSMI. In the present paper we show that in the cardiac ventricle, during HSMI infection, pre-feeding TTA increases the expression of the immune genes: TNFalpha, VCAM-1, IgM and CD8alpha. We also show that TTA increases the cardiosomatic index potentially by elevating cardiomyogenesis through activation of the cardiac transcription factors MEF2C and Nkx2.5. Using the recently published genomic sequence of a HSMI associated piscine reovirus (PRV), we could show that the PRV levels have no confounding effects on the mRNA expression of the investigated genes. The results suggest that TTA induced cardiac growth, together with an elevated cardiac recruitment of immune cells, which might lead to increased robustness during HSMI infection. PMID- 22233513 TI - Parasites and hepatic lesions among pink salmon, Oncorhynchus gorbuscha (Walbaum), during early seawater residence. AB - Juvenile pink salmon, Oncorhynchus gorbuscha (Walbaum), in the Broughton Archipelago region of western Canada were surveyed over 2 years for sea lice (Lepeophtheirus salmonis and Caligus clemensi), gross and microscopic lesions and evidence of infections with viruses and bacteria. The 1071 fish examined had an approximate ocean residence time no longer than 3 months. A high prevalence of degenerative liver lesions, renal myxosporean parasites and a low prevalence of skin lesions and sea lice were observed. No indications of viral or bacterial diseases were detected in either year. The monthly prevalence of sea lice in 2007 (18-51%) was higher than in 2008 (1-26%), and the infestation density exceeded the lethal threshold in only two fish. Degenerative hepatic lesions and renal myxosporean parasites occurred in approximately 40% of the pink salmon examined in June of both years, and the peak monthly prevalence of hepatocellular hydropic degeneration was greater in 2007 (32%, in May) than in 2008 (12%, in June). Logistic regression analysis found skin lesions and hepatocellular hydropic degeneration significantly associated with sea lice. Most parasites and lesions occurred during both years, but the prevalence was often higher in 2007. Fish weight was 35% less in June 2007 than in June 2008, but condition factor was not different. Further research is required to monitor inter-annual variations and aetiology of the liver lesions and to assess their potential role on pink salmon survival. PMID- 22233514 TI - An aerolysin-like enterotoxin from Vibrio splendidus may be involved in intestinal tract damage and mortalities in turbot, Scophthalmus maximus (L.), and cod, Gadus morhua L., larvae. AB - Vibrio splendidus is a pathogen that can cause major losses during the early stages of larval turbot rearing when live feed (rotifers or Artemia) is used. As haemolytic bacteria have often been associated with larval rearing losses, we studied the role of the V. splendidus haemolysin in infection of larvae. From a bank of over 10,000 transposon mutants of V. splendidus, two different types of haemolysin-negative mutants were obtained. Both had lost virulence for larval fish, and immunohistochemistry showed that the transposon mutant studied colonized the turbot larval intestinal tract at a similar level to the wild-type organism but did not cause damage or signs of enteritis found with the wild-type organism. One transposon insertion site was located within a gene with high homology to aerolysin, the cytolytic toxin produced by several Aeromonas spp. The haemolysin, which we have termed vibrioaerolysin, had properties similar to aerolysin and osmotic protection studies showed that it formed pores in the membranes of erythrocytes of similar diameter to those of aerolysin. The Tn10 insertion site of the second transposon mutant was in an adjacent ToxR-like gene, suggesting that this might control expression of the vibrioaerolysin. The gastroenteritis caused by Aeromonas spp. in humans is considered to be due to production of aerolysin causing cyclic AMP-dependent chloride secretion in cells of the gastrointestinal tract. Damage to the intestinal tract of marine fish larvae could occur in a similar way, and it is possible that several Vibrio spp. found in the developing bacterial flora of the larval fish gut can secrete aerolysin-like toxins leading to death of larvae in the early rearing stages. Routine bacteriological screening on blood agar plates of live feed is recommended with measures to reduce the concentrations of haemolytic bacteria in rearing systems. PMID- 22233516 TI - Carotid intima-media thickness is increased in Turner syndrome: multifactorial pathogenesis depending on age, blood pressure, cholesterol and oestrogen treatment. AB - OBJECTIVE: Carotid intima-media thickness (IMT) may potentially supplement cardiovascular risk assessment in Turner syndrome (TS), where cardiovascular risk is high and appropriate risk stratification difficult. Knowledge of IMT in TS is scarce, and this study aimed to enhance insight into the cardiovascular risk marker. DESIGN, PATIENTS AND MEASUREMENTS: IMT was cross-sectionally assessed by ultrasonography of the common carotid artery (cIMT) and carotid bulb (bIMT) in TS (n = 69, age 40 +/- 10 years) and age-matched, healthy female controls (n = 67). Additional prospective IMT assessment was performed in TS over 2.4 +/- 0.3 years. Metabolic biomarkers and 24-h ambulatory blood pressure were also assessed. RESULTS: cIMT and bIMT (body surface area indexed) were increased in TS (P < 0.05) with 17-18% having IMTs that exceeded the 95th percentile of the controls (P < 0.05). Blood pressure, heart rate, glycosylated haemoglobin A1c and high density lipoprotein cholesterol were increased in TS, where 43% received antihypertensive treatment. cIMT decreased during follow-up, coinciding with intensified cardiovascular risk prophylaxis, whereas bIMT was unchanged. In multiple regression analyses (R = 0.52-0.69, P < 0.05), baseline IMT in TS increased with age, blood pressure and cholesterol as well as in the presence of diabetes whilst IMT was inversely associated with duration of oestrogen replacement. In an analogue analysis, the prospective changes in cIMT (R = 0.37, P < 0.05) were beneficially influenced by antihypertensive treatment and oestrogen therapy and adversely by the presence of diabetes. CONCLUSION: Carotid IMT was abnormal in TS and negatively influenced by age, metabolic biomarkers, blood pressure and short duration of oestrogen treatment. Attention to common cardiovascular and endocrine risk markers over more than 2 years appeared to influence IMT beneficially. PMID- 22233515 TI - Comparison of two encapsulated curcumin particular systems contained in different formulations with regard to in vitro skin penetration. AB - BACKGROUND: Curcumin is known for its anti-inflammatory, antioxidative, and anticarcinogenic properties. However, the strong lipophilic compound is not easily applicable, neither in water, nor directly in o/w formulations. So far, loading of nano or micro scaled carriers has enabled only an uptake up to 30% of curcumin. METHOD: In the present article, curcumin was successfully encapsulated into two different safe and inexpensive polymers, ethyl cellulose and methyl cellulose blended ethyl cellulose with a loading capacity of ~ 46-48%. In addition, the in vitro skin penetration of the two curcumin encapsulated particular systems, which were applied each in three different formulations, an o/w, w/o lotion, and water suspension, was investigated on porcine ear skin using Laser scanning microscopy. RESULTS: It was found that in comparison to water suspensions, o/w and w/o lotions enhanced, especially the follicular penetration of the encapsulated curcumin particles into porcine skin, whereas the w/o enhanced the penetration better than the o/w lotion. Furthermore, the application of ethyl cellulose blended with methyl cellulose improved the penetration of curcumin in all formulations. CONCLUSION: High loaded encapsulated curcumin systems, prepared from a simple and highly efficient encapsulation system can be used to transport curcumin effectively into the skin. PMID- 22233517 TI - Molecular dynamics in drug design: new generations of compstatin analogs. AB - We report the computational and rational design of new generations of potential peptide-based inhibitors of the complement protein C3 from the compstatin family. The binding efficacy of the peptides is tested by extensive molecular dynamics based structural and physicochemical analysis, using 32 atomic detail trajectories in explicit water for 22 peptides bound to human, rat or mouse target protein C3, with a total of 257 ns. The criteria for the new design are: (i) optimization for C3 affinity and for the balance between hydrophobicity and polarity to improve solubility compared to known compstatin analogs; and (ii) development of dual specificity, human-rat/mouse C3 inhibitors, which could be used in animal disease models. Three of the new analogs are analyzed in more detail as they possess strong and novel binding characteristics and are promising candidates for further optimization. This work paves the way for the development of an improved therapeutic for age-related macular degeneration, and other complement system-mediated diseases, compared to known compstatin variants. PMID- 22233518 TI - Interaction of a bacterial flagellar chaperone FlgN with FlhA is required for efficient export of its cognate substrates. AB - FlgN chaperone acts as a bodyguard to protect its cognate substrates, FlgK and FlgL, from proteolysis in the cytoplasm. Docking of the FlgN-FlgK complex with the FliI ATPase of the flagellar type III export apparatus is key to the protein export process. However, a DeltafliH-fliI flhB(P28T) mutant forms some flagella even in the absence of FliH and FliI, raising the question of how FlgN promotes the export of its cognate substrates. Here, we report that the interaction of FlgN with an integral membrane export protein, FlhA, is directly involved in efficient protein export. A DeltafliH-fliI flhB(P28T) DeltaflgN mutant caused extragenic suppressor mutations in the C-terminal domain of FlhA (FlhA(C) ). Pull down assays using GST affinity chromatography showed an interaction between FlgN and FlhA(C) . The FlgN-FlgK complex bound to FlhA(C) and FliJ to form the FlgN FlgK-FliJ-FlhA(C) complex. The FlgN-FlhA(C) interaction was enhanced by FlgK but not by FliJ. FlgN120 missing the last 20 residues still bound to FlgK and FliJ but not to FlhA(C) . A highly conserved Tyr-122 residue was required for the interaction with FlhA(C) . These results suggest that FlgN efficiently transfers FlgK/L subunits to FlhA(C) to promote their export. PMID- 22233520 TI - Three new species of shoot fly, Atherigona spp., from northern Thailand. AB - Three new species of shoot fly, Atherigona Rondani (subgenus Acritochaeta Grimshaw) (Diptera: Muscidae), are described from northern Thailand, based on morphological characteristics of males. Unique features of A. komi sp. n. include a distinct spiral groove on the dorsal aspect of the fore femur and two dark apical wing spots, whereas A. chiangmaiensis sp. n. is recognized by the presence of one large patch on the apical wing spot, appearing as a large and smaller wave shaped patch, and no distinct pattern on tergites. A. thailandica sp. n. displays a remarkable dark boomerang-shaped patch along the wing margin and fore femur, with two rows of long hairs on the dorsal surface. Male terminalia are also different in the new species, showing distinctive characteristics. This paper also presents five newly recorded species in Thailand; Atherigona maculigera Stein, Atherigona ovatipennis vietnamensis Shinonaga et Thinh, Atherigona pallidipalpis Malloch, Atherigona seticauda Malloch, and Atherigona setitarsus Shinonaga et Thinh. A key is provided for the adult males of Atherigona recorded in Thailand, all belonging to the subgenus Acritochaeta, except for A. soccata Rondani. PMID- 22233519 TI - A searchable cross-platform gene expression database reveals connections between drug treatments and disease. AB - BACKGROUND: Transcriptional data covering multiple platforms and species is collected and processed into a searchable platform independent expression database (SPIED). SPIED consists of over 100,000 expression fold profiles defined independently of control/treatment assignment and mapped to non-redundant gene lists. The database is thus searchable with query profiles defined over genes alone. The motivation behind SPIED is that transcriptional profiles can be quantitatively compared and ranked and thus serve as effective surrogates for comparing the underlying biological states across multiple experiments. RESULTS: Drug perturbation, cancer and neurodegenerative disease derived transcriptional profiles are shown to be effective descriptors of the underlying biology as they return related drugs and pathologies from SPIED. In the case of Alzheimer's disease there is high transcriptional overlap with other neurodegenerative conditions and rodent models of neurodegeneration and nerve injury. Combining the query signature with correlating profiles allows for the definition of a tight neurodegeneration signature that successfully highlights many neuroprotective drugs in the Broad connectivity map. CONCLUSIONS: Quantitative querying of expression data from across the totality of deposited experiments is an effective way of discovering connections between different biological systems and in particular that between drug action and biological disease state. Examples in cancer and neurodegenerative conditions validate the utility of SPIED. PMID- 22233521 TI - Association between alcohol consumption and metabolic syndrome among Korean adults: nondrinker versus lifetime abstainer as a reference group. AB - BACKGROUND: Discrepant results regarding the association between alcohol consumption and metabolic syndrome may be partly attributable to the different selection of the reference group. METHODS: Data from a representative sample of 6,432 Korean adults in 2008 were analyzed. RESULTS: Using lifetime abstainers as the reference group, the prevalence of metabolic syndrome among men was increased in ex-drinkers [3.15 (1.69-5.89)], responsible drinking [0.1-39.9 g/day; 1.77 (1.0-3.13)], and hazardous drinking [>=40 g/day; 2.06 (1.05-4.07)]. CONCLUSIONS: Alcohol consumption in men, but not in women, is associated with a higher prevalence of metabolic syndrome. PMID- 22233523 TI - Pricing human papillomavirus vaccines: lessons from Italy. PMID- 22233522 TI - Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial. AB - A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression. PMID- 22233524 TI - Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphorylation of phospho-Tyr705 largely through TC45. AB - Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor. It is activated by cytokines, including interleukin-6 (IL-6) through phosphorylation at Tyr705 (pY705), which is required for its dimerization and nuclear translocation. However, the role of Ser727 phosphorylation, occurring during activation, remains poorly understood. Using a combination of HepG2-stat3-knockdown cells reconstituted with various STAT3 mutants and protein kinase inhibitors, we showed that phospho-S727 has an intrinsic mechanism for shortening the duration of STAT3 activity, in turn shortening the duration of socs3 mRNA expression. Both STAT3WT and STAT3Ser727Asp (S727D) but not STAT3Ser727Ala (S727A) showed rapid dephosphorylation of pY705 after the inhibition of tyrosine kinases. We found that the nuclear TC45 phosphatase is most likely responsible for the phospho-S727-dependent pY705 dephosphorylation because TC45 knockdown caused prolonged pY705 with sustained socs3 mRNA expression in STAT3WT but not in STAT3S727A, and overexpressed TC45 caused rapid dephosphorylation of pY705 in STAT3WT but not in STAT3S727A. We further showed that phospho-S727 did not affect the interaction of TC45 with STAT3, and that a reported methylation at K140 of STAT3 occurring after phospho S727 was not involved in the pY705 regulation. These findings indicate that phospho-Ser727 determines the duration of STAT3 activity largely through TC45. PMID- 22233525 TI - Using the Promoting Action on Research Implementation in Health Services framework to guide research use in the practice setting. PMID- 22233526 TI - Viral infections and human cancers: the legacy of Denis Burkitt. AB - Denis Parsons Burkitt was born in 1911, and in the late 1950s, described the disease that has come to be known as Burkitt lymphoma based on cases he observed in Uganda. Subsequently, Burkitt lymphoma was recognized as the first human tumour associated with an infectious agent when Epstein-Barr virus was isolated from samples supplied by Burkitt. It is now recognized that over one-quarter of cancers worldwide are tied to infections. Notably, liver cancer is linked to hepatitis B virus and hepatitis C virus infections, and cervical cancer to infections involving the human papilloma viruses. In addition, immunocompromise arising from infection with the human immunodeficiency virus allows tumours (e.g., Kaposi sarcoma) caused by other viruses to arise. More than 50 years after the seminal paper by Burkitt based on his work in Africa, it is appreciated that the contribution of viral infections to cancers remains considerably higher in sub-Saharan Africa than in the rest of the world. PMID- 22233527 TI - GLP-1 based therapies: differential effects on fasting and postprandial glucose. AB - Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4 resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1 mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes. PMID- 22233528 TI - The core content of emergency medical services medicine. AB - On September 23, 2010, the American Board of Medical Specialties (ABMS) approved emergency medical services (EMS) as a subspecialty of emergency medicine. As a result, the American Board of Emergency Medicine (ABEM) is planning to award the first certificates in EMS medicine in the fall of 2013. The purpose of subspecialty certification in EMS, as defined by ABEM, is to standardize physician training and qualifications for EMS practice, to improve patient safety and enhance the quality of emergency medical care provided to patients in the prehospital environment, and to facilitate integration of prehospital patient treatment into the continuum of patient care. In February 2011, ABEM established the EMS Examination Task Force to develop the Core Content of EMS Medicine (Core Content) that would be used to define the subspecialty and from which questions would be written for the examinations, to develop a blueprint for the examinations, and to develop a bank of test questions for use on the examinations. The Core Content defines the training parameters, resources, and knowledge of the treatment of prehospital patients necessary to practice EMS medicine. Additionally, it is intended to inform fellowship directors and candidates for certification of the full range of content that might appear on the examinations. This article describes the development of the Core Content and presents the Core Content in its entirety. PMID- 22233529 TI - Pharmacokinetic profile and pharmacodynamic effects of romifidine hydrochloride in the horse. AB - Romifidine HCl (romifidine) is an alpha(2)-agonist commonly used in horses. This study was undertaken to investigate the pharmacokinetics (PK) of romifidine following intravenous (i.v.) administration and describe the relationship between PK parameters and simultaneously recorded pharmacodynamic (PD) parameters. Romifidine (80 MUg/kg) was administered by i.v. infusion over 2 min to six adult Thoroughbred horses, and plasma samples were collected and analyzed using liquid chromatography-mass spectrometry. Limit of quantification was <0.1 ng/mL. PD parameters and arterial blood gases were measured for 300 min following romifidine administration. Statistical PD data analysis included mixed-effect modeling. After i.v. administration of romifidine, the plasma concentration-vs. time curve was best described by a two-compartmental model. Terminal elimination half-life (t(1/2beta) ) was 138.2 (104.6-171.0) min and volumes for central (V(c)) and peripheral (V(2)) compartments were 1.89 (0.93-2.39) and 2.57 (1.71 4.19) L/kg, respectively. Maximum plasma concentration (C(max)) was 51.9 +/- 13.1 ng/mL measured at 4 min following commencement of drug administration. Systemic clearance (Cl) was 32.4 (25.5-38.4) mL . min/kg. Romifidine caused a significant reduction in heart rate and cardiac index and an increase in mean arterial pressure (P < 0.05). Sedation score and head height values were significantly different from the baseline values for 120 min (P < 0.05). The decline in cardiovascular and sedative effects correlated with the decline in plasma romifidine concentration (P < 0.05). In conclusion, a highly sensitive analytical technique for the detection of romifidine in equine plasma allowed detailed description of its PK profile. The drug produces long-lasting sedation in horses that corresponds with the long terminal elimination half-life of the drug. PMID- 22233530 TI - Demographic, knowledge, attitudinal, and accessibility factors associated with uptake of cervical cancer screening among women in a rural district of Tanzania: three public policy implications. AB - BACKGROUND: Cervical cancer is an important public health problem worldwide, which comprises approximately 12% of all cancers in women. In Tanzania, the estimated incidence rate is 30 to 40 per 100,000 women, indicating a high disease burden. Cervical cancer screening is acknowledged as currently the most effective approach for cervical cancer control, and it is associated with reduced incidence and mortality from the disease. The aim of the study was to identify the most important factors related to the uptake of cervical cancer screening among women in a rural district of Tanzania. METHODS: A cross sectional study was conducted with a sample of 354 women aged 18 to 69 years residing in Moshi Rural District. A multistage sampling technique was used to randomly select eligible women. A one hour interview was conducted with each woman in her home. The 17 questions were modified from similar questions used in previous research. RESULTS: Less than one quarter (22.6%) of the participants had obtained cervical cancer screening. The following characteristics, when examined separately in relation to the uptake of cervical cancer screening service, were significant: husband approval of cervical cancer screening, women's level of education, women's knowledge of cervical cancer and its prevention, women's concerns about embarrassment and pain of screening, women's preference for the sex of health provider, and women's awareness of and distance to cervical cancer screening services. When examined simultaneously in a logistic regression, we found that only knowledge of cervical cancer and its prevention (OR = 8.90, 95%CI = 2.14-16.03) and distance to the facility which provides cervical cancer screening (OR = 3.98, 95%CI = 0.18-5.10) were significantly associated with screening uptake. CONCLUSIONS: Based on the study findings, three recommendations are made. First, information about cervical cancer must be presented to women. Second, public education of the disease must include specific information on how to prevent it as well as screening services available. Third, it is important to provide cervical cancer screening services within 5 km of where women reside. PMID- 22233531 TI - Identification of novel HIV-1 integrase inhibitors using shape-based screening, QSAR, and docking approach. AB - The objective of this study is to identify novel HIV-1 integrase (IN) inhibitors. Here, shape-based screening and QSAR have been successfully implemented to identify the novel inhibitors for HIV-1 IN, and in silico validation is performed by docking studies. The 2D QSAR model of benzodithiazine derivatives was built using genetic function approximation (GFA) method with good internal (cross validated r(2) = 0.852) and external prediction (). Best docking pose of highly active molecule of the benzodithiazine derivatives was used as a template for shape-based screening of ZINC database. Toxicity prediction was also performed using Deductive Estimation of Risk from Existing Knowledge (DEREK) program to filter non-toxic molecules. Inhibitory activities of screened non-toxic molecules were predicted using derived QSAR models. Active, non-toxic screened molecules were also docked into the active site of HIV-1 IN using AutoDock and dock program. Some molecules docked similarly as highly active molecule of the benzodithiazine derivatives. These molecules also followed the same docking interactions in both the programs. Finally, four benzodithiazine derivatives were identified as novel HIV-1 integrase inhibitors based on QSAR predictions and docking interactions. ADME properties of these molecules were also computed using Discovery Studio. PMID- 22233532 TI - Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. AB - Activation of TLRs (Toll-like receptors) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of CVDs (cardio-vascular diseases). Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study, we hypothesize that inhibition of TLR4 decreases BP (blood pressure) and improves vascular contractility in resistance arteries from SHR (spontaneously hypertensive rats). TLR4 protein expression in mesenteric resistance arteries was higher in 15-week-old SHR than in age-matched Wistar controls or in 5-week-old SHR. To decrease the activation of TLR4, 15-week-old SHR and Wistar rats were treated with anti-TLR4 (anti-TLR4 antibody) or non-specific IgG control antibody for 15 days (1 MUg per day, intraperitoneal). Treatment with anti-TLR4 decreased MAP (mean arterial pressure) as well as TLR4 protein expression in mesenteric resistance arteries and IL-6 (interleukin 6) serum levels from SHR when compared with SHR treated with IgG. No changes in these parameters were found in treated Wistar control rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to NA (noradrenaline) compared with IgG-treated SHR. Inhibition of COX (cyclo-oxygenase)-1 and COX-2, enzymes related to inflammatory pathways, decreased NA responses only in mesenteric resistance arteries of SHR treated with IgG. COX-2 expression and TXA2 (thromboxane A2) release were decreased in SHR treated with anti-TLR4 compared with IgG-treated SHR. Our results suggest that TLR4 activation contributes to increased BP, low-grade inflammation and plays a role in the augmented vascular contractility displayed by SHR. PMID- 22233533 TI - Validation of a set of reference genes to study response to herbicide stress in grasses. AB - BACKGROUND: Non-target-site based resistance to herbicides is a major threat to the chemical control of agronomically noxious weeds. This adaptive trait is endowed by differences in the expression of a number of genes in plants that are resistant or sensitive to herbicides. Quantification of the expression of such genes requires normalising qPCR data using reference genes with stable expression in the system studied as internal standards. The aim of this study was to validate reference genes in Alopecurus myosuroides, a grass (Poaceae) weed of economic and agronomic importance with no genomic resources. RESULTS: The stability of 11 candidate reference genes was assessed in plants resistant or sensitive to herbicides subjected or not to herbicide stress using the complementary statistical methods implemented by NormFinder, BestKeeper and geNorm. Ubiquitin, beta-tubulin and glyceraldehyde-3-phosphate dehydrogenase were identified as the best reference genes. The reference gene set accuracy was confirmed by analysing the expression of the gene encoding acetyl-coenzyme A carboxylase, a major herbicide target enzyme, and of an herbicide-induced gene encoding a glutathione-S-transferase. CONCLUSIONS: This is the first study describing a set of reference genes (ubiquitin, beta-tubulin and glyceraldehyde-3 phosphate dehydrogenase) with a stable expression under herbicide stress in grasses. These genes are also candidate reference genes of choice for studies seeking to identify stress-responsive genes in grasses. PMID- 22233534 TI - A novel expression system for production of soluble prion proteins in E. coli. AB - Expression of eukaryotic proteins in Escherichia coli is challenging, especially when they contain disulfide bonds. Since the discovery of the prion protein (PrP) and its role in transmissible spongiform encephalopathies, the need to obtain large quantities of the recombinant protein for research purposes has been essential. Currently, production of recombinant PrP is achieved by refolding protocols. Here, we show that the co-expression of two different PrP with the human Quiescin Sulfhydryl OXidase (QSOX), a human chaperone with thiol/disulfide oxidase activity, in the cytoplasm of E. coli produces soluble recombinant PrP. The structural integrity of the soluble PrP has been confirmed by nuclear magnetic resonance spectroscopy, demonstrating that properly folded PrP can be easily expressed in bacteria. Furthermore, the soluble recombinant PrP produced with this method can be used for functional and structural studies. PMID- 22233535 TI - The role of IL-33 and its receptor ST2 in human nasal epithelium with allergic rhinitis. AB - BACKGROUND: Interleukin (IL)-33 is a novel member of the IL-1 cytokine family and a ligand for the orphan IL-1 family receptor ST2. The IL-33 induces T helper 2 type inflammatory responses and is considered to play a crucial rule in allergic inflammations, such as asthma and atopic dermatitis. However, the role of IL-33 and its receptor ST2 in allergic rhinitis remains unknown. OBJECTIVE: We investigated expression of IL-33 and ST2 in the nasal epithelium of patients with allergic rhinitis and the mechanisms of the production of cytokines/chemokines induced by treatment with IL-33 using normal human nasal epithelial cells (HNECs) in vitro. METHODS: Expression of IL-33 and ST2 in normal and allergic rhinitis nasal mucosa was evaluated by reverse transcription- and real-time polymerase chain reactions and immunohistochemical methods. The IL-33 in serum, and IL-8 and GM-CSF were measured by ELISA. For in vitro experiments, HNECs in primary culture were used. RESULTS: The IL-33 levels in the sera of patients with allergic rhinitis were significantly higher than that in normal controls. Expression of IL 33 and ST2 was significantly elevated in the epithelium from patients with allergic rhinitis. The IL-33 mRNA in HNECs in vitro was significantly induced by treatment with IFN-gamma and the toll-like receptor 9 ligand ODN2006. The IL-33 induced production of IL-8 and GM-CSF from HNECs in vitro was significantly suppressed by corticosteroid treatment and distinct signal transduction inhibitors of ERK, p38 MAPK, JNK, NF-kappaB and epidermal growth factor receptor. CONCLUSIONS AND CLINICAL RELEVANCE: The IL-33 and its receptor ST2 play important roles in allergic rhinitis. The IL-33-mediated inflammatory responses via ST2 are regulated by distinct signalling pathways in HNECs and the IL-33/ST2 pathway may provide new therapeutic targets for allergic rhinitis. PMID- 22233536 TI - Fatigue during Repeated Sprints: precision needed. PMID- 22233537 TI - Should we be recommending repeated sprints to improve repeated-sprint performance? PMID- 22233538 TI - Population prevalence, attributable risk, and attributable risk percentage for high methylmalonic acid concentrations in the post-folic acid fortification period in the US. AB - BACKGROUND: Serum methylmalonic acid (MMA) is regarded as a sensitive marker of vitamin B-12 status. Elevated circulating MMA is linked to neurological abnormalities. Contribution of age, supplement use, kidney dysfunction, and vitamin B-12 deficiency to high serum MMA in post-folic acid fortification period is unknown. METHODS: We investigated prevalence, population attributable risk (PAR), and PAR% for high MMA concentrations in the US. Data from 3 cross sectional National Health and Nutrition Examination Surveys conducted in post folic acid fortification period were used (n = 18569). RESULTS: Likelihood of having high serum MMA for white relative to black was 2.5 (P < 0.0001), >= 60 y old persons relative to < 60 y old persons was 4.0 (P < 0.0001), non-supplement users relative to supplement users was 1.8 (P < 0.0001), persons with serum creatinine >= 130 MUmol/L relative to those with < 130 MUmol/L was 12.6 (P < 0.0001), and persons with serum vitamin B-12 < 148 pmol/L relative to those with >= 148 pmol/L was 13.5 (P < 0.0001). PAR% for high MMA for old age, vitamin B-12 deficiency, kidney dysfunction, and non-supplement use were 40.5, 16.2, 13.3, and 11.8, respectively. By improving serum vitamin B-12 (>= 148 pmol/L), prevalence of high MMA would be reduced by 16-18% regardless of kidney dysfunction. CONCLUSIONS: Old age is the strongest determinant of PAR for high MMA. About 5 cases of high serum MMA/1000 people would be reduced if vitamin B-12 deficiency (< 148 pmol/L) is eliminated. Large portion of high MMA cases are not attributable to serum vitamin B-12. Thus, caution should be used in attributing high serum MMA to vitamin B-12 deficiency. PMID- 22233539 TI - Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: synthesis, structure-activity relationship analysis, and biological activity. AB - Four series of forty-five nitrogen-containing polyhydroxylated aromatics based on caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase (IN) inhibitors. Most of these compounds inhibited IN catalytic activities in low micromolar range. Among these new analogues, compounds 9e and 9f were the most potent IN inhibitors with IC(50) value of 0.7 MUM against strand transfer reaction. Their key structure-activity relationships were also discussed. PMID- 22233540 TI - Kinetic characterization of a slow-binding inhibitor of Bla2: thiomaltol. AB - The increasing prevalence of drug resistant bacteria is a pandemic problem. Metallo-beta-lactamases (MBLs) are one of the main causes of drug resistance due to hydrolysis of beta-lactam antibiotics. Thus, the development of effective inhibitors of MBLs remains urgent. The compound thiomaltol was used as a lead compound to investigate its ability to inhibit metallo-beta-lactamase from Bacillus anthracis (Bla2), which causes anthrax. Kinetic evaluation with nitrocefin as a substrate indicates that thiomaltol inhibits Bla2 in a time dependent manner with an IC(50) value of 290 uM after 20 min preincubation. Progress curve analysis and reversibility tests suggest that thiomaltol is a reversible, slow-binding inhibitor with a K(i) of 85 +/- 30 uM. Furthermore, studies on the modality of inhibition and in silico analysis indicate thiomaltol to be a competitive inhibitor. The results demonstrate that thiomaltol is a promising lead compound for slow binding inhibitor design of Bla2. PMID- 22233541 TI - Thioesters for the in vitro evaluation of agents to image brain cholinesterases. AB - Cholinesterases are associated with pathology characteristic of conditions such as Alzheimer's disease and are therefore, considered targets for neuroimaging. Ester derivatives of N-methylpiperidinol are promising potential imaging agents; however, methodology is lacking for evaluating these compounds in vitro. Here, we report the synthesis and evaluation of a series of N-methylpiperidinyl thioesters, possessing comparable properties to their corresponding esters, which can be directly evaluated for cholinesterase kinetics and histochemical distribution in human brain tissue. N-methylpiperidinyl esters and thioesters were synthesized and they demonstrated comparable cholinesterase kinetics. Furthermore, thioesters were capable, using histochemical method, to visualize cholinesterase activity in human brain tissue. N-methylpiperidinyl thioesters can be rapidly evaluated for cholinesterase kinetics and visualization of enzyme distribution in brain tissue which may facilitate development of cholinesterase imaging agents for application to conditions such as Alzheimer's disease. PMID- 22233542 TI - Investigation of heavy metal effects on immobilized paraoxanase by glutaraldehyde. AB - Serum paraoxonase 1 (PON1) was purified from bovine serum using hydrophobic interaction chromotography on Sepharose 4B-coupled l-tyrosine 1-naphthylamine gel, and monitored by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Paraoxonase enzyme was immobilized using different ratios of glutaraldehyde and the maximum activity was observed with 7% glutaraldehyde. The effects of inhibition by Mn(+2), Co(+2) and Cu(+2) heavy metals on the immobilized and free enzyme activities were studied. At the optimum pH and temperature, the K(m) and V(max) kinetic values for bovine serum paraoxonase and immobilized paraoxonase towards paraoxon substrate were determined as 0.296 * 10(-3) M & 37.04 EU vs. 0.727-10(-3) M & 36.36 EU, respectively. PMID- 22233543 TI - New protein farnesyltransferase inhibitors in the 3-arylthiophene 2-carboxylic acid series: diversification of the aryl moiety by solid-phase synthesis. AB - A new synthetic pathway was devised to reach tetrasubstituted 3-arylthiophene 2 carboxylic acids in a three-step solid-phase synthesis. This very efficient methodology provided more than 20 new compounds that were evaluated for their ability to inhibit protein farnesyltransferase from different species as well as Trypanosoma brucei and Plasmodium falciparum proliferation. PMID- 22233544 TI - The impact of health technology assessment reports on decision making in Austria. AB - OBJECTIVES: Health technology assessment (HTA) was established in Austria in the 1990s and, since then, it has gained considerable importance. In this study, we aim to analyze whether the HTA reports that have been produced at the Institute for Technology Assessment (ITA) and at the Ludwig Boltzmann Institute for HTA (LBI-HTA) have had an impact on decision making within the Austrian health care system. METHODS: We selected all reports that were intended for supporting (i) reimbursement/investment or (ii) disinvestment decisions. Eleven full HTA reports and fifty-eight rapid assessments fulfilled the inclusion criteria. We used interview data and administrative data on volumes, tariffs and expenditure of products/services to analyze whether and how reports were in reality used in decision making and what the consequences for health care expenditure and resource distribution have been. RESULTS: Five full HTA reports and fifty-six rapid technology assessments were used for reimbursement decisions. Four full HTA reports and two rapid assessments were used for disinvestment decisions and resulted in reduced volumes and expenditure. Two full HTA reports showed no impact on decision making. Impact was most evident for hospital technologies. CONCLUSIONS: HTA has played some role in reducing volumes of over-supplied hospital technologies, resulting in reduced expenditure for several hospital providers. Additionally, it has been increasingly included in prospective planning and reimbursement decisions of late, indicating re-distribution of resources toward evidence-based technologies. However, further factors may have influenced the decisions, and the impact could be considerably increased by systematically incorporating HTA into the decision-making process in Austria. PMID- 22233546 TI - Genetic and functional characterization of a yet-unclassified rhizobial Dtr (DNA transfer-and-replication) region from a ubiquitous plasmid conjugal system present in Sinorhizobium meliloti, in Sinorhizobium medicae, and in other nonrhizobial Gram-negative bacteria. AB - Rhizobia are Gram-negative bacteria that live in soils and associate with leguminous plants to establish nitrogen-fixing symbioses. The ability of these bacteria to undergo horizontal gene transfer (HGT) is thought to be one of the main features to explain both the origin of their symbiotic life-style and the plasticity and dynamics of their genomes. In our laboratory we have previously characterized at the species level the non-pSym plasmid mobilome in Sinorhizobium meliloti, the symbiont of Medicago spp., and have found a high incidence of conjugal activity in many plasmids (Pistorio et al., 2008). In this work we characterized the Dtr (DNA-transfer-and-replication) region of one of those plasmids, pSmeLPU88b. This mobilization region was found to represent a previously unclassified Dtr type in rhizobia (hereafter type-IV), highly ubiquitous in S. meliloti and found in other genera of Gram-negative bacteria as well; including Agrobacterium, Ochrobactrum, and Chelativorans. The oriT of the type-IV Dtr described here could be located by function within a DNA fragment of 278 bp, between the divergent genes parA and mobC. The phylogenetic analysis of the cognate relaxase MobZ indicated that this protein groups close to the previously defined MOB(P3) and MOB(P4) type of enzymes, but is located in a separate and novel cluster that we have designated MOB(P0). Noteworthy, MOB(P0) and MOB(P4) relaxases were frequently associated with plasmids present in rhizospheric soil bacteria. A comparison of the nod-gene locations with the phylogenetic topology of the rhizobial relaxases revealed that the symbiotic genes are found on diverse plasmids bearing any of the four Dtr types, thus indicating that pSym plasmids are not specifically associated with any particular mobilization system. Finally, we demonstrated that the type-IV Dtr promoted the mobilization of plasmids from S. meliloti to Sinorhizobium medicae as well as from these rhizobia to other bacteria by means of their own helper functions. The results present an as-yet-unclassified and seemingly ubiquitous conjugal system that provides a mechanistic support for the HGT between sympatric rhizobia of Medicago roots, and between other soil and rhizospheric bacteria. PMID- 22233545 TI - RFX2 is essential in the ciliated organ of asymmetry and an RFX2 transgene identifies a population of ciliated cells sufficient for fluid flow. AB - Motile cilia create asymmetric fluid flow in the evolutionarily conserved ciliated organ of asymmetry (COA) and play a fundamental role in establishing the left-right (LR) axis in vertebrate embryos. The transcriptional control of the large group of genes that encode proteins that contribute to ciliary structure and function remains poorly understood. In this study we find that the winged helix transcription factor Rfx2 is expressed in motile cilia in mouse and zebrafish embryos. Morpholino knockdown of Rfx2 function in the whole embryo or specifically in cells of the zebrafish COA (Kupffer's Vesicle, KV) leads to reduced KV cilia length and perturbations in LR asymmetry. LR patterning defects include randomization of the early asymmetric Nodal signaling pathway genes southpaw, lefty1 and lefty2 and subsequent reversals in the organ primordia of the heart and gut. Rfx2 is also required for ciliogenesis in zebrafish pronephric duct. We further show that by restoring Left-Right dynein (LRD) expression and motility specifically in a subset of ciliated cells of the mouse COA (posterior notochord, PNC), we can restore fluid flow, asymmetric expression of Pitx2 and partially rescue situs defects. PMID- 22233547 TI - Nanocrystals: comparison of the size reduction effectiveness of a novel combinative method with conventional top-down approaches. AB - Nanosizing is a non-specific approach to improve the oral bioavailability of poorly soluble drugs. The decreased particle size of these compounds results in an increase in surface area. The outcome is an increased rate of dissolution, which can lead to a better oral absorption. Standard approaches are bottom-up and top-down techniques. Combinative technologies are relatively new approaches, and they can be described as a combination of a bottom-up process followed by a top down step. The work presented in this paper can be described as a combination of a non-aqueous freeze drying step (bottom-up), followed by wet ball milling or high pressure homogenization (top-down) to produce fine drug nanocrystals. The crystal habit of the model drug glibenclamide was modified by freeze drying from dimethyl sulfoxide (DMSO)/tert-butanol (TBA) solvent mixtures using different ratios. The resulting drug powders were characterized by scanning electron microscopy (SEM) as well as by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). It was shown that the combinative approach can significantly improve the particle size reduction effectiveness of both top-down methods over conventional approaches. Drug lyophilization using DMSO:TBA in 25:75 and 10:90 v/v ratios resulted in a highly porous and breakable material. The milling time to achieve nanosuspensions was reduced from 24h with the jet-milled glibenclamide to only 1h with the modified starting material. The number of homogenization cycles was decreased from 20 with unmodified API to only 5 with the modified drug. The smallest particle size, achieved on modified samples, was 160nm by wet ball milling after 24h and 355nm by high pressure homogenization after 20 homogenization cycles at 1500bar. PMID- 22233548 TI - Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels. AB - The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40 degrees C/75% RH). PMID- 22233549 TI - Death within 48 h--adverse events after general surgical procedures. AB - BACKGROUND: Comorbidity and emergency intervention are established risk factors for post-operative mortality. This study sought to identify adverse events associated with death within 48 h of general surgical procedures. METHODS: All general surgical patients who died within 48 h of operative intervention from 2002-2006 in Scotland underwent retrospective peer review using established Scottish Audit of Surgical Mortality (SASM) methodologies (www.SASM.org). RESULTS: During the 5 years, 1299 patients died within 48 h of surgery, 1134 (87.3%) admitted as an emergency, with a mean age of 71 years; 898 patients (69.1%) were ASA grade 3, 4 or 5; 727 (56.0%) patients had cardiovascular, 398 (30.6%) respiratory and 191 (14.7%) renal comorbidity. Over time exploratory laparotomy (443, 34.1%) was carried out less often (p = 0.004) prior to death due to cardiovascular disease (435, 33.5%), mesenteric ischaemia (264, 20.3%) or multi-organ failure (255, 19.6%). The decision to operate by consultant surgeons rose significantly (p < 0.001). Adverse events were identified in 721 of the 1299 cases; concerns about inappropriate operations (p = 0.018) and poor pre-operative assessment (p = 0.012) decreased significantly. CONCLUSIONS: Patients dying within 48 h of surgery are usually elderly, emergency admissions with significant comorbidities who die of cardiovascular events. Timely, appropriate surgery and high quality peri-operative care delivered by consultant staff may prevent early post-operative mortality. PMID- 22233550 TI - Surgery for perforated small bowel malignancy: a single institution's experience over 4 years. AB - INTRODUCTION: Surgery for perforated small bowel malignancy is associated with dismal morbidity and mortality rates. The aim of the paper was to highlight our institution's surgical experience in the management of patients with malignant small bowel perforation. METHODS: A retrospective review of all patients who underwent operative intervention for malignant small bowel perforation from 2004 to 2007 was performed. The diagnosis was confirmed upon histological evaluation. RESULTS: Emergency surgery was performed in seven patients with perforated small bowel malignancy during the study period. All were above 55 years old, with the majority (6/7) having an ASA score of 3 and above. Pneumoperitoneum on chest radiograph was seen in only one patient while computed tomographic scans demonstrating the pathology were performed in the rest. All patients underwent exploratory laparotomy with resection of the diseased segments within 24 h of admission. Jejunum and the ileum were the sites of perforation in six and one patients, respectively. Three patients had synchronous small bowel tumours. Two patients had stoma created due to extensive peritoneal soilage and haemodynamic instability. Lymphoma was the aetiology in four patients. The other pathologies included leiomyosarcoma (n = 1) and metastatic lung tumours (n = 2). The 30-day peri-operative mortality rate was 42.9% (n = 3). One was discharged to a hospice while another two received chemotherapy upon discharge. These three patients passed away within a year from the surgery. The last patient defaulted follow up. CONCLUSION: In our small series, patients who were admitted for perforated small bowel malignancy have a high peri-operative mortality rates. For those who survived the initially operation, the long term outlook is still dismal. PMID- 22233551 TI - A survey of UK surgical trainees and trainers; latest reforms well understood but perceived detrimental to surgical training. AB - INTRODUCTION: In the United Kingdom, surgical training reforms as part of modernising medical careers (MMC) became fully operational in 2007. This study aims to establish the level of insight and views about MMC based surgical training amongst surgical trainers and trainees working in the National Health Service. METHODS: An electronic survey consisting of eight questions was disseminated to surgical trainers and trainees via a web-based link placed on Association of Surgeons in Training website. RESULTS: A total of 138 responses were received. Of those, 77% (n = 107) were from trainees. 92% (n = 127) of respondents understood that the purpose of MMC surgical reforms was to provide structured training. 98% (n = 135) agreed traditional SHO training was poorly structured. Two-thirds (67%, n = 92) believed that MMC will reduce the total time period to complete surgical training. 82% (n = 113) recognised work place assessments as an assessment tool for MMC competencies. 82% (n = 113) were aware that an educational supervisor is assigned to monitor individual training. 70% (n = 96) understood that training is a shared responsibility between trainee, educational supervisor and supervising consultants. However, 69% (n = 95) of respondents believed the standard of surgical training via MMC will deteriorate, 18% (n = 25) anticipated no difference, 8% (n = 11) passed no comments and a mere 5% (n = 7) perceived it as an improvement. CONCLUSIONS: This study confirms a generally good level of insight amongst trainers and trainees into the aims and structure of MMC based surgical training. However, the majority believe that ultimately the standard of surgical training is set to fall. PMID- 22233552 TI - Unplanned overnight admissions in day-case arthroscopic shoulder surgery. AB - The majority of arthroscopic shoulder procedures can be safely performed as day case surgery. However, despite better pain control and preoperative assessment; some patients end with unplanned overnight admission. The aim of this study was to investigate the reasons behind unplanned admissions of patients undergoing day case arthroscopic shoulder surgery. A retrospective review of 242 consecutive cases of arthroscopic shoulder surgery performed by the senior author over a period of two years (2007-2008) was carried out. Twenty cases were planned admissions and were therefore excluded. 222 cases were included, of which 40 (18%) were unplanned overnight admissions. Documented causes for overnight stay included abnormal post-operative observations, pain and wound ooze. The age of patients who stayed overnight was significantly higher (p = 0.006). The difference in ASA grade between both groups was less marked but still statistically significant (p = 0.031). More complex procedures, such as rotator cuff repair, were more likely to result in unplanned overnight admission (p < 0.001). The experience of the anaesthetist and administration of interscalene nerve block were not significantly different between the two groups. However, patients anesthetised by less experienced anaesthetists were less likely to receive an interscalene nerve block (p = 0.016). In conclusion; higher patient age, higher ASA grade and more complex arthroscopic procedures are significant risk factors for unplanned overnight admissions in day-case arthroscopic shoulder surgery. PMID- 22233553 TI - Increased bone mineral density in the non-resurfaced patella after total knee arthroplasty: a clinical and densitometric study. AB - We report the results of a longitudinal study of 40 patients with osteoarthritis who had primary prosthetic replacement without patellar resurfacing, and were followed at 6 months postoperatively with a densitometric study and clinically at a minimum follow-up of 2 years. Densitometric analysis showed a mean preoperative density at the affected knee of 0.69 g/cm(2) (CI: 0.62-0.76), compared to 0.86 g/cm(2) (CI: 0.79-0.93) for the opposite knee (p = 0.002). In our study population, the return to load and motion to the retained patella led to a significant increase in patellar bone density as measured by densitometry studies. This observation correlated with significant improvement in knee functional score. PMID- 22233554 TI - Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. AB - The use of bisphosphonate drugs has been popularised in the late 20th century for the management of many conditions associated with abnormalities of bone turnover, particularly metastatic and haematogenous malignancy and osteopenia. The increase in indications for the use of bisphosphonates was supported by what was thought to be a very good safety profile. However in 2003 cases of osteonecrosis related to the use of bisphosphonates were first described. The pathogenesis, and with this the explanation of why it only appears to affect the maxillofacial skeleton, and the best way of managing this problem remains unknown. In this review we examine the process of identification of this pathology and the development of guidelines from medical societies and professional bodies on the management of patients before commencing bisphosphonate therapy, requiring dental treatment whilst on therapy, or with a diagnosis of bisphosphonate associated osteonecrosis of the jaws. PMID- 22233555 TI - Emerging therapies for thyroid carcinoma. AB - Thyroid carcinoma is the most commonly diagnosed endocrine malignancy. Its incidence is currently rising worldwide. The discovery of genetic mutations associated with the development of thyroid cancer, such as BRAF and RET, has lead to the development of new drugs which target the pathways which they influence. Despite recent advances, the prognosis of anaplastic thyroid carcinoma is still unfavourable. In this review we look at emerging novel therapies for the treatment of well-differentiated and medullary thyroid carcinoma, and advances and future directions in the management of anaplastic thyroid carcinoma. PMID- 22233556 TI - Laparoscopic feeding jejunostomy: description of a modified technique with results. PMID- 22233558 TI - Effect of adjunctive low level laser therapy (LLLT) on nonsurgical treatment of chronic periodontitis. AB - OBJECTIVE: The aim of this split-mouth, double blinded, short-term, controlled clinical trial was to study the effect of low-level laser therapy (LLLT) as an adjunct to scaling and root planing (SRP) for treatment of chronic periodontitis. BACKGROUND DATA: LLLT is reported to improve the outcome of traditional SRP, but the evidence is still weak. MATERIALS AND METHODS: Sixteen patients with a probing pocket depth (PPD) of 4-6 mm involving at least three teeth in each quadrant were recruited for the study. Afterwards, SRP quadrants were randomly assigned for 10 sessions of LLLT. RESULTS: Results showed that when compared to sites treated with SRP alone, those treated with SRP+LLLT (10 sessions, 830 nm, 100 mW, 3 J per point, 3 J/cm(2)) exhibited greater reductions in PPD at 5 weeks and 3 months but not at 6 months. Further, SRP+LLLT-treated sites had a statistically significant increase in mean radiographic bone density when comparing 6- and 12-month data and overall from baseline to 12 months. There was a trend to reduce interleukin (IL)-1beta but the difference between control and laser sites was not statistically significant. CONCLUSIONS: SRP combined with LLLT improved radiographic bone density and short-term PPD reduction in patients with chronic periodontitis, but did not significantly affect either the gingival crevicular fluid of IL-1beta or the gingival or plaque index. PMID- 22233559 TI - Low level laser therapy (LLLT) and World Association for Laser Therapy (WALT) dosage recommendations. PMID- 22233557 TI - The importance of being supercoiled: how DNA mechanics regulate dynamic processes. AB - Through dynamic changes in structure resulting from DNA-protein interactions and constraints given by the structural features of the double helix, chromatin accommodates and regulates different DNA-dependent processes. All DNA transactions (such as transcription, DNA replication and chromosomal segregation) are necessarily linked to strong changes in the topological state of the double helix known as torsional stress or supercoiling. As virtually all DNA transactions are in turn affected by the torsional state of DNA, these changes have the potential to serve as regulatory signals detected by protein partners. This two-way relationship indicates that DNA dynamics may contribute to the regulation of many events occurring during cell life. In this review we will focus on the role of DNA supercoiling in the cellular processes, with particular emphasis on transcription. Besides giving an overview on the multiplicity of factors involved in the generation and dissipation of DNA torsional stress, we will discuss recent studies which give new insight into the way cells use DNA dynamics to perform functions otherwise not achievable. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22233561 TI - Biomedically important pathogenic fungi detection with volatile biomarkers. AB - Volatile chemical profiles collected from the headspace of Aspergillus fumigatus (a pathogenic fungus that causes invasive pulmonary aspergillosis, allergic bronchopulmonary aspergillosis and chronic fungal sinusitis) grown on media with the connective tissue protein elastin, found in lung tissue, contained a large abundance of the sesquiterpene farnesene (3,7,11-trimethyl-1,3,6,10 dodecatetraene) and, depending on extraction time and sorbent material, other farnesene isomers and sesquiterpenes such as bisabolene (methyl-4-(6-methylhepta 1,5-dien-2-yl)cyclohex-1-ene). When human lung cells were cultured externally and infected with A. fumigatus, farnesene was also detected in each model lung system. Volatiles measured from cultured nasal lavage collected from a patient diagnosed with chronic fungal sinusitis, a condition frequently caused by A. fumigatus, revealed the presence of another pathogenic fungus, less frequently responsible for sinusitis, Epicoccum nigrum. The volatile profile of E. nigrum differed markedly from that of A. fumigatus with no sesquiterpenes detected. PMID- 22233562 TI - Prevalence of diabetes among Han, Manchu and Korean ethnicities in the Mudanjiang area of China: a cross-sectional survey. AB - BACKGROUND: Rapid socioeconomic development resulting in changing lifestyles and life expectancy appears to be accompanied by an increasing prevalence of type 2 diabetes. Genetic predisposition related to ethnicity is a major determinant of diabetes risk. This study investigates the prevalences of diabetes and prediabetes in different ethnic populations residing in the Mudanjiang area located in the northeast of China. METHODS: A cross-sectional survey was carried out among Han, Manchu and Korean Chinese aged 20 years or older. Diabetes and prediabetes were diagnosed using standard oral glucose tolerance tests. RESULTS: The prevalence of diabetes in Manchu (8.39%) and Korean Chinese (9.42%) was significantly lower than that in Han (12.10%). The prevalence of prediabetes was 18.96%, 19.36% and 20.47% in Han, Manchu and Korean populations, respectively. Korean Chinese had a lower prevalence of isolated impaired fasting glucose and higher prevalence of isolated impaired glucose tolerance than the other two ethnic groups. Most patients with diabetes, especially ethnic minority patients, were undiagnosed. A multiple logistic regression analysis showed that age, family history of diabetes, control of diet, self-monitoring of weight, central obesity, increased heart rate, hypertension, elevated plasma triglyceride level, elevated plasma low-density lipoprotein cholesterol, and Han ethnicity were significantly associated with an increased risk of diabetes. Further, Manchu Chinese were found to have the lowest risk of diabetes. CONCLUSIONS: Our study indicates that diabetes is a major public health problem in the Mudanjiang area of China. Ethnicity plays a role in the different prevalences of diabetes and prediabetes among the three ethnic groups. Diabetes is less prevalent among Manchu Chinese compared with Han and Korean Chinese. PMID- 22233563 TI - Atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model. AB - BACKGROUND: One of the major complications of Plasmodium falciparum infection is cerebral malaria (CM), which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. Statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. Atorvastatin (AVA) has shown in vitro anti-malarial activity and has improved the activity of mefloquine (MQ) and quinine. METHODS: The efficiency of 40 mg/kg intraperitoneal AVA, alone or in association with MQ, was assessed in an experimental Plasmodium berghei ANKA rodent parasite model of CM and performed according to different therapeutic schemes. The effects on experimental CM were assessed through the evaluation of brain histopathological changes and neuronal apoptosis by TUNEL staining. RESULTS: AVA alone in the therapeutic scheme show no effect on survival, but the prophylactic scheme employing AVA associated with MQ, rather than MQ alone, led to a significant delay in mouse death and had an effect on the onset of CM symptoms and on the level of parasitaemia. Histopathological findings show a correlation between brain lesions and CM onset. A neuronal anti-apoptotic effect of AVA in the AVA + MQ combination was not shown. CONCLUSIONS: The combination of AVA and MQ therapy led to a significant delay in mouse mortality. There were differences in the incidence, time to cerebral malaria and the level of parasitaemia when the drug combination was administered to mice. When used in combination with MQ, AVA had a relevant effect on the in vivo growth inhibition and clinical outcome of P. berghei ANKA-infected mice. PMID- 22233564 TI - Investigating the spectrum of biological activity of substituted quinoline-2 carboxamides and their isosteres. AB - In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2 carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethyl)quinoline-2 carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonyl)quinoline and 1-(2 naphthoyl)pyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC(50) value of the most active compound N-benzyl-2-naphthamide was 7.5 MUmol/L. For all compounds, the structure-activity relationships are discussed. PMID- 22233565 TI - Synthesis of new liquid crystalline diglycidyl ethers. AB - The phenolic Schiff bases I-VI were synthesized by condensation reactions between various diamines, namely o-dianisidine, o-tolidine and ethylenediamine with vanillin or p-hydroxybenzaldehyde and subsequent reactions between these phenolic Schiff bases and epichlorohydrin to produce new diglycidyl ethers Ia-VIa. The structures of these compounds were confirmed by CHN, FT-IR, (1)H-NMR, and (13)C NMR spectroscopy. Their thermotropic liquid crystalline behavior was studied using differential scanning calorimetry (DSC) and polarizing optical microscopy (POM). All the diglycidyl ethers prepared exhibit nematic mesophases, except for Va and VIa, which did not show any transition mesophases, but simply flow to liquids. PMID- 22233566 TI - In search of work/life balance: trainee perspectives on part-time obstetrics and gynaecology specialist training. AB - BACKGROUND: Part-time training (PTT) is accessed by approximately 10% of Australian obstetrics and gynaecology trainees, a small but increasing minority which reflects the growing demand for improved work/life balance amongst the Australian medical workforce. This survey reports the attitudes and experiences of both full-time and part-time trainees to PTT. METHODS: An email-based anonymous survey was sent to all Australian obstetrics and gynaecology trainees in April 2009, collecting demographic and training status data, data on personal experiences of PTT and/or trainees, and attitudes towards PTT. RESULTS: 105 responses were received (20% response rate). These indicated strong support (90%) from both full-time (FT) and part-time (PT) trainees for the availability of PTT. PT trainees were significantly more likely than FT trainees to be female with children. Improved morale was seen as a particular advantage of PTT; decreased continuity of care as a disadvantage. CONCLUSIONS: Although limited by poor response rate, both PT and FT Australian obstetric trainees were supportive of part-time training. Both groups recognised important advantages and disadvantages of this mode of training. Currently, part-time training is accessed primarily by female trainees with family responsibilities, with many more trainees considering part-time training than the number that access it. PMID- 22233560 TI - Synaptic neurotransmitter-gated receptors. AB - Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families. PMID- 22233570 TI - Performance indicators for participation in organized mammography screening. AB - BACKGROUND: A population's acceptance of a screening programme is reflected by its participation. Participation can be measured by cross-section, in an individual screening round, or by cumulative examination rate, which covers participation in numerous rounds at a pre-specified frequency. To establish an informed overview of programme performance, the relationship between these measures was analysed. METHODS: The Central Population Register (CPR) of Denmark was used to define the total population. The data sources were mammography screening programmes in Copenhagen (1991-2008) and Funen (1993-2008) and participation and coverage rates were calculated according to European guidelines. Long-term adherence was defined as the cumulative examination rate. RESULTS: The participation rates were 71% in Copenhagen and 91% in Funen. The cumulative examination rates across all invitation rounds were between 21 and 24% lower than the average participation rates. CONCLUSIONS: If the cumulative examination rate across all, or the majority of, invitation rounds is substantially lower than the average participation rate it may suggest that standard cross-sectional performance indicators overestimate the level of protection provided to the women targeted by the programme. Consequently, it may prove valuable to include cumulative examination rate as a performance indicator of mammography screening. PMID- 22233571 TI - Bt rice evaluation and deployment strategies. AB - Bacillus thuringiensis (Bt), a gram positive soil bacteria was first identified and named by Japanese microbiologist Shigetane Ishiwata in 1901. During sporulation Bt produces proteinaceous parasporal crystal proteins called delta endotoxins, or Cry proteins, which are insecticidal. Numerous Cry proteins have been isolated and characterized from different Bt strains with activity against insects, mites and nematodes. Sprayable formulations containing these Cry proteins as active ingredients have contributed significantly in the field of insect pest management. Since the first cloning of cry genes from Bt,1 scientists have successively demonstrated that plants could be genetically engineered to express these cry genes for the control of dreadful insect pests. Eventually, the first transgenic crop expressing Btcry1Ac gene in cotton was approved in 1996 for commercial cultivation in the USA to manage bollworms. PMID- 22233577 TI - Neurotrophic factor changes in the rat thick skin following chronic constriction injury of the sciatic nerve. AB - BACKGROUND: Cutaneous peripheral neuropathies have been associated with changes of the sensory fiber innervation in the dermis and epidermis. These changes are mediated in part by the increase in local expression of trophic factors. Increase in target tissue nerve growth factor has been implicated in the promotion of peptidergic afferent and sympathetic efferent sprouting following nerve injury. The primary source of nerve growth factor is cells found in the target tissue, namely the skin. Recent evidence regarding the release and extracellular maturation of nerve growth factor indicate that it is produced in its precursor form and matured in the extracellular space. It is our hypothesis that the precursor form of nerve growth factor should be detectable in those cell types producing it. To date, limitations in available immunohistochemical tools have restricted efforts in obtaining an accurate distribution of nerve growth factor in the skin of naive animals and those with neuropathic pain lesions. It is the objective of this study to delineate the distribution of the precursor form of nerve growth factor to those cell types expressing it, as well as to describe its distribution with respect to those nerve fibers responsive to it. RESULTS: We observed a decrease in peptidergic fiber innervation at 1 week after the application of a chronic constriction injury (CCI) to the sciatic nerve, followed by a recovery, correlating with TrkA protein levels. ProNGF expression in CCI animals was significantly higher than in sham-operated controls from 1-4 weeks post-CCI. ProNGF immunoreactivity was increased in mast cells at 1 week post-CCI and, at later time points, in keratinocytes. P75 expression within the dermis and epidermis was significantly higher in CCI-operated animals than in controls and these changes were localized to neuronal and non-neuronal cell populations using specific markers for each. CONCLUSIONS: We describe proNGF expression by non neuronal cells over time after nerve injury as well as the association of NGF responsive fibers to proNGF-expressing target tissues. ProNGF expression increases following nerve injury in those cell types previously suggested to express it. PMID- 22233578 TI - A general RNA motif for cellular transfection. AB - We have developed a selection scheme to generate nucleic acid sequences that recognize and directly internalize into mammalian cells without the aid of conventional delivery methods. To demonstrate the generality of the technology, two independent selections with different starting pools were performed against distinct target cells. Each selection yielded a single highly functional sequence, both of which folded into a common core structure. This internalization signal can be adapted for use as a general purpose reagent for transfection into a wide variety of cell types including primary cells. PMID- 22233579 TI - Long-term persistence of CD4(+) but rapid disappearance of CD8(+) T cells expressing an MHC class I-restricted TCR of nanomolar affinity. AB - Most T cells have T cell receptors (TCR) of micromolar affinity for peptide-major histocompatibility complex (MHC) ligands, but genetic engineering can generate TCRs of nanomolar affinity. The affinity of the TCR used, m33, for its cognate non-self peptide-MHC-I complex (SIYRYYGL-K(b)) is 1,000-fold higher than of the wild-type TCR 2C. The affinity of m33 for the self-peptide dEV-8 on K(b) is only twofold higher. Mouse CD8(+) T cells transduced with an m33-encoding retrovirus showed binding of SIY-K(b) and potent function in vitro, but in vivo these T cells disappeared within hours after transfer into syngeneic hosts without causing graft-versus-host disease (GVHD). Accordingly, in cases where such CD8 dependent self-reactivity might occur in human adoptive T cell therapies, our results show that a peripheral T-cell deletion mechanism could operate to avoid reactions with the host. In contrast to CD8(+) T cells, we show that CD4(+) T cells expressing m33 survived for months in vivo. Furthermore, the m33-transduced CD4(+) T cells were able to mediate antigen-specific rejection of 6-day-old tumors. Together, we show that CD8(+) T cell expressing a MHC class I-restricted high-affinity TCR were rapidly deleted whereas CD4(+) T cells expressing the same TCR survived and provided function while being directed against a class I restricted antigen. PMID- 22233580 TI - Directing integrin-linked endocytosis of recombinant AAV enhances productive FAK dependent transduction. AB - Recombinant adeno-associated virus (rAAV) is a widely used gene therapy vector. Although a wide range of rAAV serotypes can effectively enter most cell types, their transduction efficiencies (i.e., transgene expression) can vary widely depending on the target cell type. Integrins play important roles as coreceptors for rAAV infection, however, it remains unclear how integrin-dependent and independent mechanisms of rAAV endocytosis influence the efficiency of intracellular virus processing and ultimately transgene expression. In this study, we examined the contribution of integrin-mediated endocytosis to transduction of fibroblasts by rAAV2. Mn(++)-induced integrin activation significantly enhanced (~17-fold) the efficiency of rAAV2 transduction, without altering viral binding or endocytosis. rAAV2 subcellular localization studies demonstrated that Mn(++) promotes increased clustering of rAAV2 on integrins and recruitment of intracellular vinculin (an integrin effector) to sites of rAAV2 binding at the cell surface. Focal adhesion kinase (FAK), a downstream effector of integrin signals, was essential for rAAV2/integrin complex internalization and transduction. These findings support a model whereby integrin activation at the cell surface can redirect rAAV2 toward a FAK-dependent entry pathway that is more productive for cellular transduction. This pathway appears to be conserved for other rAAV serotypes that contain a capsid integrin-binding domain (AAV1 and AAV6). PMID- 22233581 TI - Cell-penetrating peptides as versatile vehicles for oligonucleotide delivery. AB - Short regulatory oligonucleotides (ONs) have a great therapeutic potential for the modulation of gene expression due to their high specificity and low toxicity. The major obstacles for in vivo clinical applications of ONs are the poor permeability of plasma membrane to nucleic acids and the sensitivity of ONs to enzymatic degradation. Hence, various delivery vehicles have been developed to ensure the transduction of ONs into cells. Among these, the cell-penetrating peptides (CPPs) have gained quickly broadening popularity as promising nonviral transmembrane delivery vectors. For coupling of nucleic acids to CPPs, two distinct strategies may be applied-covalent and noncovalent. The majority of earlier studies have used covalent coupling of CPPs to ONs. However, the number of studies demonstrating very high therapeutic potential of noncovalent complexes of ONs with novel CPP-based delivery vehicles is explosively increasing. In this review, the recent developments in the application of CPP-mediated oligonucleotide delivery by noncovalent strategy will be discussed. PMID- 22233582 TI - Myxoma virus sensitizes cancer cells to gemcitabine and is an effective oncolytic virotherapeutic in models of disseminated pancreatic cancer. AB - Myxoma virus (MYXV) is a novel oncolytic virus that has been shown to replicate in pancreatic cancer cells, but its efficacy in animal models of pancreatic cancer has not been determined. The efficacy of MYXV as monotherapy or in combination with gemcitabine was evaluated in intraperitoneal dissemination (IPD) models of pancreatic cancer. The effects of an intact immune system on the efficacy of MYXV therapy was tested by comparing immunodeficient versus immunocompetent murine models and combination therapy with gemcitabine was also evaluated. In cell culture, MYXV replication was robust in a broad range of pancreatic cancer cells and also showed increased oncolysis in combination with gemcitabine. In animal models, MYXV treatment conferred survival benefits over control or gemcitabine-treated cohorts regardless of the cell line or animal model used. MYXV monotherapy was most effective in an immunocompetent IPD model, and resulted in 60% long-term survivors. In Pan02 engrafted immunocompetent IPD models, sequential treatment in which MYXV was administered first, followed by gemcitabine, was the most effective and resulted in 100% long-term survivors. MYXV is an effective oncolytic virus for pancreatic cancer and can be combined with gemcitabine to enhance survival, particularly in the presence of an intact host immune system. PMID- 22233583 TI - Immune-mediated loss of transgene expression from virally transduced brain cells is irreversible, mediated by IFNgamma, perforin, and TNFalpha, and due to the elimination of transduced cells. AB - The adaptive immune response to viral vectors reduces vector-mediated transgene expression from the brain. It is unknown, however, whether this loss is caused by functional downregulation of transgene expression or death of transduced cells. Herein, we demonstrate that during the elimination of transgene expression, the brain becomes infiltrated with CD4(+) and CD8(+) T cells and that these T cells are necessary for transgene elimination. Further, the loss of transgene expressing brain cells fails to occur in the absence of IFNgamma, perforin, and TNFalpha receptor. Two methods to induce severe immune suppression in immunized animals also fail to restitute transgene expression, demonstrating the irreversibility of this process. The need for cytotoxic molecules and the irreversibility of the reduction in transgene expression suggested to us that elimination of transduced cells is responsible for the loss of transgene expression. A new experimental paradigm that discriminates between downregulation of transgene expression and the elimination of transduced cells demonstrates that transduced cells are lost from the brain upon the induction of a specific antiviral immune response. We conclude that the anti-adenoviral immune response reduces transgene expression in the brain through loss of transduced cells. PMID- 22233584 TI - Direct healthcare costs of selected diseases primarily or partially transmitted by water. AB - Despite US sanitation advancements, millions of waterborne disease cases occur annually, although the precise burden of disease is not well quantified. Estimating the direct healthcare cost of specific infections would be useful in prioritizing waterborne disease prevention activities. Hospitalization and outpatient visit costs per case and total US hospitalization costs for ten waterborne diseases were calculated using large healthcare claims and hospital discharge databases. The five primarily waterborne diseases in this analysis (giardiasis, cryptosporidiosis, Legionnaires' disease, otitis externa, and non tuberculous mycobacterial infection) were responsible for over 40 000 hospitalizations at a cost of $970 million per year, including at least $430 million in hospitalization costs for Medicaid and Medicare patients. An additional 50 000 hospitalizations for campylobacteriosis, salmonellosis, shigellosis, haemolytic uraemic syndrome, and toxoplasmosis cost $860 million annually ($390 million in payments for Medicaid and Medicare patients), a portion of which can be assumed to be due to waterborne transmission. PMID- 22233586 TI - Community-based interventions for obesity prevention: lessons learned by Australian policy-makers. AB - BACKGROUND: Interest in community-based interventions (CBIs) for health promotion is increasing, with a lot of recent activity in the field. This paper aims, from a state government perspective, to examine the experience of funding and managing six obesity prevention CBIs, to identify lessons learned and to consider the implications for future investment. Specifically, we focus on the planning, government support, evaluation, research and workforce development required. METHODS: The lessons presented in this paper come from analysis of key project documents, the experience of the authors in managing the projects and from feedback obtained from key program stakeholders. RESULTS: CBIs require careful management, including sufficient planning time and clear governance structures. Selection of interventions should be based on evidence and tailored to local needs to ensure adequate penetration in the community. Workforce and community capacity must be assessed and addressed when selecting communities. Supporting the health promotion workforce to become adequately skilled and experienced in evaluation and research is also necessary before implementation.Comprehensive evaluation of future projects is challenging on both technical and affordability grounds. Greater emphasis may be needed on process evaluation complemented by organisation-level measures of impact and monitoring of nutrition and physical activity behaviours. CONCLUSIONS: CBIs offer potential as one of a mix of approaches to obesity prevention. If successful approaches are to be expanded, care must be taken to incorporate lessons from existing and past projects. To do this, government must show strong leadership and work in partnership with the research community and local practitioners. PMID- 22233587 TI - Antiviral drugs for influenza. PMID- 22233585 TI - Understanding the population genetics of Plasmodium vivax is essential for malaria control and elimination. AB - Traditionally, infection with Plasmodium vivax was thought to be benign and self limiting, however, recent evidence has demonstrated that infection with P. vivax can also result in severe illness and death. Research into P. vivax has been relatively neglected and much remains unknown regarding the biology, pathogenesis and epidemiology of this parasite. One of the fundamental factors governing transmission and immunity is parasite diversity. An understanding of parasite population genetic structure is necessary to understand the epidemiology, diversity, distribution and dynamics of natural P. vivax populations. In addition, studying the population structure of genes under immune selection also enables investigation of the dynamic interplay between transmission and immunity, which is crucial for vaccine development. A lack of knowledge regarding the transmission and spread of P. vivax has been particularly highlighted in areas where malaria control and elimination programmes have made progress in reducing the burden of Plasmodium falciparum, yet P. vivax remains as a substantial obstacle. With malaria elimination back on the global agenda, mapping of global and local P. vivax population structure is essential prior to establishing goals for elimination and the roll-out of interventions. A detailed knowledge of the spatial distribution, transmission and clinical burden of P. vivax is required to act as a benchmark against which control targets can be set and measured. This paper presents an overview of what is known and what is yet to be fully understood regarding P. vivax population genetics, as well as the importance and application of P. vivax population genetics studies. PMID- 22233588 TI - Vandetanib (Caprelsa) for medullary thyroid cancer. PMID- 22233589 TI - In brief: Ezetimibe/simvastatin (Vytorin) in chronic kidney disease. PMID- 22233591 TI - Detection of gastro-oesophageal reflux disease (GORD) in patients with obstructive lung disease using exhaled breath profiling. AB - Gastro-oesophageal reflux disease (GORD) has been implicated in the worsening of several respiratory disorders. Current methods of diagnosis lack accuracy, are invasive and can be costly. Recently, novel methods of analysing lung pathophysiology have been developed including the use of an electronic nose and analysis of components of exhaled breath condensate (EBC). We hypothesised that these methods would distinguish patients with GORD from those without GORD in the common obstructive lung diseases and healthy controls. In a cross-sectional study, exhaled breath was analysed using the Cyranose 320 electronic nose, using principal components and canonical discriminant analyses. EBC pH and pepsin were quantified using a pH meter and an enzyme-linked immunosorbent assay, respectively. A standardized reflux disease questionnaire (RDQ) was used to assess reflux symptoms. The Cyranose 320 distinguished exhaled breath profiles of obstructive lung disease patients without GORD from obstructive lung disease patients with GORD (p = 0.023, accuracy 67.6%), asthmatic patients with reflux from asthmatics without GORD (85%, p = < 0.015, interclass M distance > 2.8), but did not produce as robust a profile for patients with COPD and COPD with GORD (p = 0.047, accuracy 64%). Patients with obstructive lung disease and GORD had significantly higher levels of EBC pepsin (9.81 +/- interquartile range (IQR) 4.38 ng ml(-1)) than those without GORD (4.6 +/- IQR 6.95 ng ml(-1)), as well as healthy controls (3.44 +/- IQR 7.87 ng ml(-1); p = < 0.013). EBC pH was not significantly related to the presence of GORD in any group. The RDQ results correlated significantly with the presence of EBC pepsin. This pilot study has shown that exhaled breath profiling can be used for detecting GORD in obstructive lung diseases. While the electronic nose was useful in asthma, EBC pepsin was more helpful in COPD. In this study, several different confounders could potentially have affected results and larger prospective interventional studies are needed. PMID- 22233590 TI - Heavy burden of non-communicable diseases at early age and gender disparities in an adult population of Burkina Faso: World Health Survey. AB - BACKGROUND: WHO estimates suggest that age-specific death rates from non communicable diseases are higher in sub-Saharan Africa than in high-income countries. The objectives of this study were to examine, in Burkina Faso, the prevalence of non-communicable disease symptoms by age, gender, socioeconomic group and setting (rural/urban), and to assess gender and socioeconomic inequalities in the prevalence of these symptoms. METHODS: We obtained data from the Burkina Faso World Health Survey, which was conducted in an adult population (18 years and over) with a high response rate (4822/4880 selected individuals). The survey used a multi-stage stratified random cluster sampling strategy to identify participants. The survey collected information on socio-demographic and economic characteristics, as well as data on symptoms of a variety of health conditions. Our study focused on joint disease, back pain, angina pectoris, and asthma. We estimated prevalence correcting for the sampling design. We used multiple Poisson regression to estimate associations between non-communicable disease symptoms, gender, socioeconomic status and setting. RESULTS: The overall crude prevalence and 95% confidence intervals (CI) were: 16.2% [13.5; 19.2] for joint disease, 24% [21.5; 26.6] for back pain, 17.9% [15.8; 20.2] for angina pectoris, and 11.6% [9.5; 14.2] for asthma. Consistent relationships between age and the prevalence of non-communicable disease symptoms were observed in both men and women from rural and urban settings. There was markedly high prevalence in all conditions studied, starting with young adults. Women presented higher prevalence rates of symptoms than men for all conditions: prevalence ratios and 95% CIs were 1.20 [1.01; 1.43] for joint disease, 1.42 [1.21; 1.66] for back pain, 1.68 [1.39; 2.04] for angina pectoris, and 1.28 [0.99; 1.65] for asthma. Housewives and unemployed women had the highest prevalence rates of non communicable disease symptoms. CONCLUSIONS: Our work suggests that social inequality extends into the distribution of non-communicable diseases among social groups and supports the thesis of a differential vulnerability in Burkinabe women. It raises the possibility of an abnormally high rate of premature morbidity that could manifest as a form of premature aging in the adult population. Increased prevention, screening and treatment are needed in Burkina Faso to address high prevalence and gender inequalities in non-communicable diseases. PMID- 22233592 TI - A change in title. PMID- 22233593 TI - Vaccine adverse events. AB - Millions of adults are vaccinated annually against the seasonal influenza virus. An undetermined number of individuals will develop adverse events to the influenza vaccination. Those who suffer substantiated vaccine injuries, disabilities, and aggravated conditions may file a timely, no-fault and no-cost petition for financial compensation under the National Vaccine Act in the Vaccine Court. The elements of a successful vaccine injury claim are described in the context of a claim showing the seasonal influenza vaccination was the cause of Guillain-Barre syndrome. PMID- 22233594 TI - Reducing the frequency and severity of migraine headaches in the workplace: implementing evidence-based interventions. AB - The impact of migraine headaches on worker productivity and quality of life is significant. A medical center employee health department implemented an evidence based, multicomponent intervention to manage migraine headaches for a population of more than 3,500 employees. The intervention consisted of education to identify and avoid headache triggers, coaching on dietary and lifestyle changes, and prescriptions for medications to prevent and treat headaches. This article presents preliminary data on the feasibility and effectiveness of the intervention. The frequency and severity of headaches were measured at baseline and 3, 6, 9, and 12 months after baseline using the Migraine Disability Assessment questionnaire. At 12 months, 28 participants who completed testing reported that the frequency of headaches had decreased by 76.1%, severity by 31.3%, and perception of disability by 66.5%. This pilot study used a convenience sample and no control group. However, results are promising and recommendations are made for future studies. PMID- 22233595 TI - A pilot study of occupational injury and illness experienced by classical musicians. AB - Limited attention is paid to the hazards experienced by orchestra musicians in the occupational health and safety literature. Within that literature, the primary focus has been on noise exposure. A focus on this area is warranted because high sound pressure levels are a product of this work environment. However, in addition to being at risk for noise-induced hearing loss, workers are also at risk for musculoskeletal injury and illness related to stressful body postures held for prolonged work periods. The socio-political forces of employment may place workers at risk for mental health disorders (e.g., depression). The researchers distributed an anonymous survey to classical orchestra musicians in the southwestern United States. The survey inventoried several areas related to occupational health risks. Results suggest low health care-seeking behaviors relative to self-reported signs and symptoms of morbidity. Musicians also reported limited formal training and education regarding occupational health risks. Risk information was provided late in their professional development. This is a particular concern because of the young age at which music training is initiated. PMID- 22233596 TI - Relationship between handling heavy items during pregnancy and spontaneous abortion: a cross-sectional survey of working women in South Korea. AB - The researchers conducted a cross-sectional survey to determine the relationship between handling heavy items during pregnancy and spontaneous abortion among working women in South Korea. One thousand working women were selected from a database of those eligible for maternity benefits under the National Employment Insurance Plan. Study results showed that handling heavy items during pregnancy was associated with an increased risk of spontaneous abortion after adjusting for general characteristics of the participants and their work environment. A collective effort is needed on the parts of employers, employees, occupational health nurses, and the government to protect working women from lifting heavy items while pregnant. PMID- 22233597 TI - A comprehensive review of the Healthy People 2020 Occupational Safety And Health Objectives: Part 1. Tools for the occupational health nurse in goal attainment. AB - This is the first part of a two-part series introducing Healthy People 2020 and the foundational categories that are linked to overarching goals and corresponding measures for progress within the Healthy People 2020 initiative. The two articles together will review the 10 objectives for occupational safety and health within the American workplace, provide a resource guide for occupational health nurses, and discuss MAP-IT, the suggested implementation format to reach the Healthy People 2020 goals. The articles are intended to inform occupational health nurses about the current agenda for safety and health of the U.S. work force as articulated in Healthy People 2020 and provide a foundation for better understanding the requirements of a safe work environment in 2020 and beyond. PMID- 22233599 TI - Using social media and networking in health care. AB - Occupational health nurses must understand the benefits, risks, and consequences of participating in social media and networking. PMID- 22233602 TI - Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. AB - BACKGROUND: Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossification is considered a key pathophysiological process in the formation of osteophytes. OBJECTIVE: To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification. METHODS: Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, a specific small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed. RESULTS: Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathological signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression. CONCLUSIONS: The data indicate that blockade of hedgehog signalling by targeting Smo specifically inhibits osteophyte formation in arthritis without affecting inflammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifically influence the periosteal bone response in arthritis associated with bone apposition. PMID- 22233601 TI - Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. METHODS: A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. RESULTS: Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non European SLE may be due in part to this phenomenon. CONCLUSION: These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis. PMID- 22233603 TI - Quantitative effect of HLA-DRB1 alleles to ACPA levels in Japanese rheumatoid arthritis: no strong genetic impact of shared epitope to ACPA levels after stratification of HLA-DRB1*09:01. PMID- 22233605 TI - Modelling tuberculosis trends in the USA. AB - We present a mathematical transmission model of tuberculosis in the USA. The model is calibrated to recent trends of declining incidence in the US-born and foreign-born populations and is used in assessing relative impacts of treatment of latently infected individuals on elimination time, where elimination is defined as annual incidence <1 case/million. Provided current control efforts are maintained, elimination in the US-born population can be achieved before the end of this century. However, elimination in the foreign-born population is unlikely in this timeframe even with higher rates of targeted testing and treatment of residents of and immigrants to the USA with latent tuberculosis infection. Cutting transmission of disease as an interim step would shorten the time to elimination in the US-born population but foreign-born rates would remain above the elimination target. PMID- 22233604 TI - Imiquimod enhances excitability of dorsal root ganglion neurons by inhibiting background (K(2P)) and voltage-gated (K(v)1.1 and K(v)1.2) potassium channels. AB - BACKGROUND: Imiquimod (IQ) is known as an agonist of Toll-like receptor 7 (TLR7) and is widely used to treat various infectious skin diseases. However, it causes severe itching sensation as its side effect. The precise mechanism of how IQ causes itching sensation is unknown. A recent report suggested a molecular target of IQ as TLR7 expressed in dorsal root ganglion (DRG) neurons. However, we recently proposed a TLR7-independent mechanism, in which the activation of TLR7 is not required for the action of IQ in DRG neurons. To resolve this controversy regarding the involvement of TLR7 and to address the exact molecular identity of itching sensation by IQ, we investigated the possible molecular target of IQ in DRG neurons. FINDINGS: When IQ was applied to DRG neurons, we observed an increase in action potential (AP) duration and membrane resistance both in wild type and TLR7-deficient mice. Based on these results, we tested whether the treatment of IQ has an effect on the activity of K(+) channels, K(v)1.1 and K(v)1.2 (voltage-gated K(+) channels) and TREK1 and TRAAK (K(2P) channels). IQ effectively reduced the currents mediated by both K(+) channels in a dose dependent manner, acting as an antagonist at TREK1 and TRAAK and as a partial antagonist at K(v)1.1 and K(v)1.2. CONCLUSIONS: Our results demonstrate that IQ blocks the voltage-gated K(+) channels to increase AP duration and K(2P) channels to increase membrane resistance, which are critical for the membrane excitability of DRG neurons. Therefore, we propose that IQ enhances the excitability of DRG neurons by blocking multiple potassium channels and causing pruritus. PMID- 22233606 TI - Open-Source web-based Geographical Information System for health exposure assessment. AB - This paper presents the design and development of an open source web-based Geographical Information System allowing users to visualise, customise and interact with spatial data within their web browser. The developed application shows that by using solely Open Source software it was possible to develop a customisable web based GIS application that provides functions necessary to convey health and environmental data to experts and non-experts alike without the requirement of proprietary software. PMID- 22233607 TI - Hepatic reference gene selection in adult and juvenile female Atlantic salmon at normal and elevated temperatures. AB - BACKGROUND: The use of quantitative real-time polymerase chain reaction (qPCR) has become widespread due to its specificity, sensitivity and apparent ease of use. However, experimental error can be introduced at many stages during sample processing and analysis, and for this reason qPCR data are often normalised to an internal reference gene. The present study used three freely available algorithms (GeNorm, NormFinder and BestKeeper) to assess the stability of hepatically expressed candidate reference genes (Hprt1, Tbp, Ef1alpha and beta-tubulin) in two experiments. In the first, female Atlantic salmon (Salmo salar) broodstock of different ages were reared at either 14 or 22 degrees C for an entire reproductive season, therefore a reference gene that does not respond to thermal challenge or reproductive condition was sought. In the second, estrogen treated juvenile salmon were maintained at the same temperatures for 14 days and a reference gene that does not respond to temperature or estrogen was required. Additionally, we performed independent statistic analysis to validate the outputs obtained from the program based analysis. RESULTS: Based on the independent statistical analysis performed the stability of the genes tested was Tbp > Ef1alpha > Hprt1 > beta-tubulin for the temperature/reproductive development experiment and Ef1alpha > Hprt1 > Tbp for the estrogen administration experiment (beta-tubulin was not analysed). Results from the algorithms tested were quite ambiguous for both experiments; however all programs consistently identified the least stable candidate gene. BestKeeper provided rankings that were consistent with the independent analysis for both experiments. When an inappropriate candidate reference gene was used to normalise the expression of a hepatically expressed target gene, the ability to detect treatment-dependent changes in target gene expression was lost for multiple groups in both experiments. CONCLUSIONS: We have highlighted the need to independently validate the results of reference gene selection programs. In addition, we have provided a reference point for those wishing to study the effects of thermal challenge and/or hormonal treatment on gene stability in Atlantic salmon and other teleost species. PMID- 22233608 TI - An empirical approach to selecting community-based alcohol interventions: combining research evidence, rural community views and professional opinion. AB - BACKGROUND: Given limited research evidence for community-based alcohol interventions, this study examines the intervention preferences of rural communities and alcohol professionals, and factors that influence their choices. METHOD: Community preferences were identified by a survey of randomly selected individuals across 20 regional Australian communities. The preferences of alcohol professionals were identified by a survey of randomly selected members of the Australasian Professional Society on Alcohol and Other Drugs. To identify preferred interventions and the extent of support for them, a budget allocation exercise was embedded in both surveys, asking respondents to allocate a given budget to different interventions. Tobit regression models were estimated to identify the characteristics that explain differences in intervention preferences. RESULTS: Community respondents selected school programs most often (88.0%) and allocated it the largest proportion of funds, followed by promotion of safer drinking (71.3%), community programs (61.4%) and police enforcement of alcohol laws (60.4%). Professionals selected GP training most often (61.0%) and allocated it the largest proportion of funds, followed by school programs (36.6%), community programs (33.8%) and promotion of safer drinking (31.7%). Community views were susceptible to response bias. There were no significant predictors of professionals' preferences. CONCLUSIONS: In the absence of sufficient research evidence for effective community-based alcohol interventions, rural communities and professionals both strongly support school programs, promotion of safer drinking and community programs. Rural communities also supported police enforcement of alcohol laws and professionals supported GP training. The impact of a combination of these strategies needs to be rigorously evaluated. PMID- 22233610 TI - The lymphovenous microsurgical shunts for treatment of lymphedema of lower limbs: indications in 2011. AB - The microsurgical lympho-venous shunts have become one of the generally accepted modalities in treatment of limb lymphedema. This review highlight the indications for this procedure after over 40 years. This study was based on the personal experience of one surgeon and on the review of the literature. Patients with postinflammatory, postsurgical, idiopathic and hyperplastic lymphedema of lower limbs were included in the study. Basing on the review of results of the last 40 years the contemporary indications are: 1) lymphedema with local segmental obstruction but still partly patent distal lymphatics seen on functional lymphoscintigraphy (standard walking or pneumatic compression) and without an active inflammatory process in the skin, subcutaneous tissue and lymph vessels (DLA-dermatolymphangioadenitis); 2) classified according the etiology of lymphedema, this operation can bring about satisfactory results in cases of hyperplastic, postsurgical and postinflammatory types of lymphedema, whereas primary idiopathic lymphedema of non-genetic type should be treated with conservative means, although in a small number of cases an improvement was observed after lympho-venous shunting as long as 10 years. Microsurgical lymph node or lymphatic vessel to vein shunts have their established position among the therapy modalities for lymphedema of lower limbs in a strictly defined group of patients using lymphoscintigraphic imaging. PMID- 22233609 TI - Thymosin beta 4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition. AB - OBJECTIVE: Thymosin beta 4 (Tbeta(4)) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation during embryogenesis. Recently, a role for Tbeta(4) has been proposed in experimental and human carcinogenesis. This study was aimed at evaluating the correlation between Tbeta(4) immunoractivity and colorectal cancer, with particular attemption to tumor cells undergoing epithelial-mesenchymal transition. METHODS AND RESULTS: 86 intestinal biopsies were retrospectively analyzed including 76 colorectal adenocarcinomas with evident features of epithelial-mesenchymal transition, and 10 samples of normal colorectal mucosa. Paraffin sections were immunostained for Tbeta(4) and for E-cadherin. Total RNA was isolated from frozen specimens obtained, at surgery, from the normal colon mucosa, the deeper regions and the superficial tumor regions in four cases of colon cancer. Tbeta(4) immunoreactivity was detected in the vast majority (59/76) of colon carcinomas, showing a patchy distribution, with well differentiated areas significantly more reactive than the less differentiated tumor zones. We also noted a zonal pattern in the majority of tumors, characterized by a progressive increase in immunostaining for Tbeta(4) from the superficial toward the deepest tumor regions. The strongest expression for Tbeta(4) was frequently detected in invading tumor cells with features of epithelial-mesenchymal transition. The increase in reactivity for Tbeta(4) matched with a progressive decrease in E cadherin expression in invading cancer cells. At mRNA level, the differences in Tbeta(4) expression between the surrounding colon mucosa and the tumors samples were not significant. CONCLUSIONS: Our data show that Tbeta(4) is expressed in the majority of colon cancers, with preferential immunoreactivity in deep tumor regions. The preferential expression of the peptide and the increase in intensity of the immunostaining at the invasion front suggests a possible link between the peptide and the process of epithelial mesenchymal transition, suggesting a role for Tbeta(4) in colorectal cancer invasion and metastasis. PMID- 22233611 TI - General surgery, translational lymphology and lymphatic surgery. AB - A wide clinical experience in General Surgery has brought about a remarkable knowledge about lymphatic disorders both primary and secondary ones. Diagnostic and histopathological studies of lymphatic diseases allowed to better understand etiological aspects and pathophysiological mechanisms responsible of complex clinical features correlated to lymphatic dysfunctions. Translational lymphologic basic and clinical researches permitted to improve therapeutical approaches both from the medical and surgical point of view. Thus, strategies of treatment were proposed to prevent lymphatic injuries, to avoid lymphatic complications and to treat lymphatic diseases early in order to be able even to cure these pathologies. PMID- 22233612 TI - A new minimally invasive hybrid technique for femoro - above knee popliteal bypass. AB - Femoro above knee popliteal bypass using synthetic graft is a well recognized revascularization procedure in patients with severe lower limb ischemia with either critical limb ischemia (CLI), limiting claudication (IC) or with acute limb ischemia (ALI).Occasionally the patient's general condition would mandate a short and minimally invasive procedure. When endovascular revascularization is not possible or fails then the peripheral VORTEC technique is used. A telescopic sutureless anastomosis is created between an ePTFE graft to the above knee popliteal artery with a bridging piece of VIABHAN. The technique was described in detail and has been published in the August 2011 issue of the EJVES. Between April 2010 and October 2011 seventeen procedures were accomplished successfully in 16 patients. The median follow up was 13 months (range 3-17). Two patients died during follow up from unrelated caused, both from acute cardiac events and both with patent bypasses, one and 5 months after the index operation. There were 2 occasions of limb loss but only one graft loss related amputation. There were 4 thrombectomies for graft occlusions. All four did not have a distal anastomotic stenosis that could predict graft failure on pre occlusion follow up duplex scans. Primary patency for the whole cohort was 65%, the primary assisted patency was 70% and the secondary patency was 85%. In conclusion we believe that this technique could be advantageous in morbid patients and we therefore recommend using it in high risk patients if no endovascular option or saphenous vein are available. PMID- 22233613 TI - Dose finding for an optimal compression pressure to reduce chronic edema of the extremities. AB - AIM: The optimal pressure to reduce chronic extremity swelling is still a matter of debate. The aim of this paper was to measure volume reduction of a swollen extremity depending on the amount of pressure exerted by compression stockings and inelastic bandages. METHODS: Thirty-six patients with unilateral breast cancer related arm lymphedema were investigated in a lymph clinic in the Netherlands, 42 legs with chronic edema of the lower extremities were examined in a phlebological centre in Italy. The arm-patients were randomized to receive inelastic arm bandages with a pressure between 20-30 mmHg or 44-68 mmHg. The leg patients were either treated with compression stockings (23-32 mmHg) or with inelastic bandages (pressure 53-88 mmHg). Water-displacement volumetry and measurement of leg circumference was performed before and after compression. RESULTS: In the arm-patients low pressure after 2 hours achieved a higher degree of volume reduction (-2.3%, 95% CI 1.0-3.6) than high pressure (-1.5%, 95% CI 0.2 2.8) (n.s.). In patients with leg edema compression stockings in the range between 20 and 40 mmHg showed a positive correlation between exerted pressure and volume reduction, bandages applied with an initial resting pressure of more than 60 mm Hg resulted in a decreasing volume reduction. CONCLUSION: There is obviously an upper limit beyond which further increase of compression pressure seems counterproductive. For inelastic bandages this upper limit is around 30 Hg on the upper and around 50-60 mmHg on the lower extremity. PMID- 22233614 TI - Repair of abdominal aortic aneurysms in the presence of the horseshoe kidney. AB - AIM: Horseshoe kidney is the most common congenital kidney anomaly, occurring in 0.15-0.25% of all newborns. A medial fusion of the kidneys, mostly anteriorly to the aorta, is the main characteristic of this anomaly. The co-existence of abdominal aortic aneurysm (AAA) and horseshoe kidney is rare, occurring only in 0.12% of patients. The aim of this paper is to define the optimal management of patients with AAA associated with the horseshoe kidney. METHODS: This paper presents the analysis of patients operated at the Clinic for Vascular and Endovascular Surgery of the Clinical Center of Serbia in Belgrade due to AAA associated with the horseshoe kidney as well as the analysis of the previously published literature data regarding this topic. RESULTS: Between 1985 and 2011, data were collected retrospectively on 25 patients with the horseshoe kidney who underwent aortic surgery. Out of them, 6 patients had aortoiliac occlusive disease and 19 patients had aortic aneurysm. More detailed analysis of the aneurysmatic group was performed. Among them there were 16 male and three female patients, with the average age of 63.8 (50-76) years. Two patients had type IV of thoracoabdomial aortic aneurysm (TAA) according to Crawford-Saffi classification, while 17 had infrarenal abdominal aortic aneurysms. There were 15 elective and four urgent procedures due to aneurismal rupture. The presence of the horseshoe kidney was detected in 16 patients before surgery (84.2%) by means of Duplex ultrasonography, angiography, computed tomography and intravenous urography. Multiple renal arteries were presented in 12 (63.2%) cases. A transperitoneal approach was used in 16 cases with abdominal aortic aneurysm, while left retroperitoneal approach with partial extrapleural removal of the 11th rib was performed in two cases of thoracoabdominal aneurysm and in one patient with AAA. In 18 cases, kidney tissue transection was successfully avoided with vascular graft placement beneath the horseshoe kidney. In one case only, the division of the renal isthmus was performed. In all 12 cases with detected anomalous renal arteries, their reattachment into vascular graft has been performed. Two patients (10.5%) died during perioperative period. One of them had ruptured type IV TAA. Seventeen patients who survived were followed from one to twenty years (mean 6.6 years). During the follow up period we lost track of 4 patients. In this period there were no signs of graft occlusion, or renal failure. CONCLUSION: Repair of an abdominal aortic aneurysm in the presence of the horseshoe kidney is a truly particular surgical challenge. It is associated with three main problems: choice of the surgical approach; the procedure regarding kidney isthmus preservation as well as recognition and reattachment of all significant anomalous renal arteries. PMID- 22233615 TI - Identifying patient- and treatment-related factors related to amputation risk in cases of heparin-induced thrombocytopenia treated with argatroban. AB - AIM: The efficacy of argatroban as an anticoagulant in patients with heparin induced thrombocytopenia type II (HIT) was shown in two large trials (ARG 911 and ARG 915) using a composite endpoint of death, amputation and new thrombosis, but no benefit was seen in amputation rate. Factors that influenced patients proceeding to amputation are unclear. METHODS: We retrospectively undertook exploratory data analyses comparing patient- and treatment-related factors in patients with (N.=48) and without (N.=520) all-cause amputation. RESULTS: Of the amputation cases, 46% had received warfarin, and 97.9% had severe ischemia/gangrene diagnosed pre-argatroban. Thromboembolic complications prior to argatroban were more common in amputation cases (91.7% vs. 71.9%, P=0.003), with a higher proportion of arterial than venous events (68.2% vs. 52.3%, P=0.031; mean 1.7/patient vs. 1.4/patient, P=0.031), largely occurring in the limbs (94.1%). More females than males suffered amputation (P=0.003), and cardiovascular risk was more frequent in amputation cases than non-amputation (hypertension, P=0.008; peripheral vascular disease (PVD), P<0.001; diabetes, P<0.001). There were no differences in baseline platelet count, platelet recovery (24 h post-argatroban), or weighted mean aPTT between groups; amputation was associated with longer treatment duration (5 vs. 7 days, P=0.001). CONCLUSION: Almost all amputation cases had severe ischemia prior to argatroban; female gender and cardiovascular risk factors, in particular PVD with peripheral vascular surgery, appear to identify a subgroup of patients at high risk of amputation. The pharmacodynamics of argatroban appeared to be unchanged in the amputation cases suggesting that argatroban action was undiminished in the amputation cases despite the negative outcome of treatment. PMID- 22233616 TI - The importance of ophthalmic artery hemodynamics in patients with atheromatous carotid artery disease. AB - AIM: The aim of this paper was to provide an insight on the role of the ophthalmic artery blood flow changes due to significant carotid stenosis and the effects of carotid revascularization on the eye and cerebral circulation. METHODS: An electronic search (Medline) of the English literature was attempted. Measurements of Peak Systolic Velocity (PSV), end-diastolic velocity (EDV), mean velocity (Vmean), Resistance Index (RI) and flow direction, obtained in OA and its branches using transcranial Doppler, in to patients with significant stenosis >70% subjected to surgical or endovascular treatment, or in those with occlusion (unilateral or bilateral), symptomatic or not, in both eyes, prior to or/and after endarterectomy or stenting. RESULTS: As the degree of internal carotid artery (ICA) stenosis increases, the PSV in ophthalmic artery (OA) decreases. In severe stenoses the flow is not detectable or a reversed flow may be present. Following carotid endarterctomy or stenting, in almost all patients antegrade flow was detected, while in the patients with preoperative antegrade flow, an increase of the velocities was detected postoperatively. CONCLUSION: The reduced blood flow in the OA has consequences in the eye circulation. OA contributes to the collateral pathways in the perfusion of the brain but the importance of this collateral pathway has not been completely clarified. PMID- 22233617 TI - Prevention of ischemic events in patients with peripheral arterial disease design, baseline characteristics and 2-year results an observational study. AB - AIM: Peripheral arterial disease (PAD) is associated with frequent cardiovascular ischemic events. We followed the survival of PAD patients and tested whether PAD remains an adverse prognostic indicator in spite of treatment according to the current European guidelines on cardiovascular disease prevention. METHODS: Eight hundred eleven patients with PAD and 778 control subjects, aged 65 (SD 9) years at inclusion, with a male/female ratio of 3/2 were treated according to the European guidelines on cardiovascular disease prevention and evaluated yearly for occurrence of death, non-fatal acute coronary syndrome, stroke or critical limb ischemia (major events) and revascularization procedures (minor events). At baseline, classical risk factors were significantly more prevalent in the PAD group and protective cardiovascular medication was prescribed to patients with PAD more frequently than to control subjects. RESULTS: In the PAD group, the 2 year Kaplan-Meier survival estimate was 96.7% (CI 95.4-97.9) vs. 98.2% (CI 97.2 99.1) in the control group, P=0.059. The groups differed in the 2-year major event-free survival: 93.5% (CI 92.7-95.3) in PAD vs. 97.1% (CI 95.9-98.4) in controls, P<0.017, as well as in event-free survival: 79.9% (CI 77.1-82.9) in PAD vs.96.4% (CI 95.0-97.9) in controls, P<0.001. CONCLUSION: Patients with PAD had a borderline higher risk of all-cause death and a significantly higher risk of major and minor non-fatal cardiovascular events compared to control subjects. However, treatment according to the European guidelines on cardiovascular disease prevention resulted in encouragingly low absolute mortality and morbidity. (ClinicalTrials.gov number NCT00761969.). PMID- 22233618 TI - Electromuscular stimulation with VEINOPLUS(r) for the treatment of chronic venous edema. AB - AIM: Electromuscular stimulation (EMS) with VEINOPLUS(r) has recently emerged as a new technique to activate the calf muscle pump, improving the symptoms of venous disease. The aim of the study was to evaluate efficacy of EMS and its impact on evening edema, venous pain, venous outflow and patients quality of life. METHODS: Thirty patients (32 legs) aged 19-50 (mean 45.2+/-1.3) classified CEAP C3 with chronic evening venous edema took part in the study (22 limbs: C3, S, Ep, Asp, Pr and 10 limbs: C3, S, Es, Aspd, Pr). All patients were treated with CE-registered VEINOPLUS(r) neuromuscular stimulator for 30 days. 3 sessions per day (each session lasted for 20 minutes) for the first 10 days, the next 10 days 2 sessions per day and one session per day for the last 10 days. The main evaluated criteria for venous edema was the circumference of the supramaleoal shin segment, measured twice with a tape measure; in the evening the day before and then 5 days after the treatment. All measurements were taken during the interval between 6 and 8 o'clock P.M. All the patients were asked to evaluate venous pain using the Visual Analog Scale, and to fill in a CIVIQ questionnaire (validated for Russian patients) for the Quality Of Life (QOL) measurement. Also venous refilling time (RT) was measured by digital PPG. That was also made twice before the treatment and in 35 days after the treatment. No other treatments were used. RESULTS: The EMS treatment was well tolerated by patients. There were no drop outs and patients had no need to change their lifestyles. After the treatment, total or partial reduction of evening edema was shown in 93.8% of limbs, the circumference of the lower leg diminished by 20.3mm (P<0.001), the number of painful legs reduced from 28 to 12 and the severity score of venous pain was cut from 8.3 +/-1.1 to 3.8 points +/-0.9 (P<0.001), QOL improved significantly as the score dropped from 34.5 +/-7.8 to 17.2 points +/-4.6 (P<0.001) and RT increased from 17.3 +/-0.9 to 21.5 seconds +/-1.1 (P<0.001). Three months after VEINOPLUS(r) treatment, total remission of symptoms was observed in 50% of legs, despite there being no other treatments. CONCLUSION: VEINOPLUS(r) stimulation is an effective and well-tolerated therapeutic method for the treatment of chronic venous disease. The introduced scheme of EMS application was shown to be useful for treatment of chronic edema, for reducing pain and improving quality of life. It can be used as an additional mean in treatment and to prevent symptoms of CVI. This study also reveals that stimulation of calf muscles with VEINOPLUS(r) can improve venous outflow and symptoms of CVI. This finding should be investigated and confirmed in further studies. PMID- 22233619 TI - Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound -recommendations for a protocol. AB - Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome characterized by stenoses or obstructions of the internal jugular and/or azygos veins with disturbed flow and formation of collateral venous channels. Studies using ultrasound in patients with multiple sclerosis (MS) have demonstrated a high prevalence of CCSVI (mean 70%; range 0-100%; N.=1496), whereas, in normal controls and patients without MS the prevalence was much lower (mean 10%; range 0 36%; N.=635). Ultrasound uses a combination of physiological measurements as well as anatomical imaging and has been used for the detection of CCSVI by different centers with variable results. A high prevalence ranging from 62% to 100% of obstructive lesions has been found by some teams in patients with MS compared with a lower prevalence of 0-25% in controls. However, absence of such lesions or a lower prevalence (16-52%) has been reported by others. This variability could be the result of differences in technique, training, experience or criteria used. The current lack of a methodology shared among experts is a confounding element in epidemiologic studies, and does not permit further Bayesan or other kind of analysis. In order to ensure a high reproducibility of Duplex scanning with comparable accuracy between centers, a detailed protocol with standard methodology and criteria is proposed. This is also necessary for training. It has been shown that inter-rater variability increases post-training (from k=0.47 to k=0.80), while within-rater reproducibility in trained operators was k=0.75. Finally, the consensus document proposes a reporting standard of Duplex measurements, and future research to answer areas of uncertainty. PMID- 22233620 TI - Trace elements and toxic heavy metals play a role in Buerger's disease and atherosclerotic peripheral arterial occlusive disease. PMID- 22233622 TI - Complications following gastrointestinal bleeding and their impact on outcome and death. AB - BACKGROUND: Bleeding from the upper gastrointestinal tract is one of the most common life-threatening morbidities encountered by gastroenterologists. A mathematical model has been developed to gain insights into how, after an initial event of upper gastrointestinal bleeding, complications can accumulate in individual patients and expose them to an increased risk of death. METHODS: The occurrence of complications and possible death after gastrointestinal bleeding are simulated using a Markov chain model. RESULTS: The accumulation of complications in an individual patient is influenced by the length of time a patient remains vulnerable to the probability of developing new complications. The model illustrates how the initial bleeding episode sets the stage for the occurrence of subsequent complications and how each subsequent complication increases in an exponential manner the risk for additional complications. Because of such a pattern, complications tend to cluster in a group of patients who run into an ever-increasing risk of multiple complications. Although the majority of patients go through their initial bleeding episode without ever experiencing any secondary complication, in a subset of patients the initial complication sets in motion a vicious cycle with frequently more than one consecutive complication after the initial gastrointestinal bleed. CONCLUSION: The key to the successful management of a patient with gastrointestinal bleeding is to stop such a vicious cycle as early as possible, as each progression within the cycle renders the probability of additional complications more likely and its reversal more difficult. PMID- 22233623 TI - Exhaled breath condensate (EBC) biomarkers in pulmonary fibrosis. AB - The diffuse parenchymal lung diseases (DPLDs) are a group of clinicopathological entities which have recently undergone reclassification. The commonest type of idiopathic DPLD is interstitial pulmonary fibrosis (PF), which is histologically characterized by usual interstitial pneumonia (UIP), with inflammatory changes in the alveoli and subsequent collagen deposition. A similar type of inflammatory change can also be seen with connective tissue disorders. Many mediators are involved, but it is difficult to study these in a non-invasive manner in patients. The aim of the study detailed in this paper was to investigate inflammatory and oxidative stress biomarkers in PF and correlate these with lung function. 20 PF patients and 20 controls participated in the study. Exhaled breath condensate (EBC) was collected over 10 min using a refrigerated condenser, after fractional exhaled nitric oxide (FeNO) and carbon monoxide (eCO) measurement. EBC total nitrogen oxides (NOx), hydrogen peroxide (H(2)O(2)), 8 isoprostane (8-iso), 3-nitrotyrosine (3-NT), pH and total protein were measured. EBC biomarkers were significantly raised in PF compared with controls: EBC 3-NT (2.5 (0.7-8.9) versus 0.3 (0.1-1.1) ng ml(-1), p = 0.02); pH (7.6 +/- 0.3 versus 7.4 +/- 0.2, p = 0.004); 8-isoprostane (0.2 (0.1-0.4) versus 0.08 (0.04-0.2) ng ml(-1), p = 0.04) and total protein (24.7 +/- 21.1 versus 10.7 +/- 7.0 ug ml(-1), p = 0.008). FeNO and eCO were also increased (8.6 (7.1-10.4) versus 6.6 (5.6-7.8) ppb, p = 0.04, and 4.5 +/- 1.7 versus 2.7 +/- 0.7 ppm, p = 0.001, respectively), but no significant differences were found for NOx or H(2)O(2). In conclusion, inflammatory and oxidative stress biomarkers are raised in patients with PF compared with controls. EBC may be useful for detecting and monitoring lung inflammation in PF. PMID- 22233625 TI - Mechanism of supercooled droplet freezing on surfaces. AB - Understanding ice formation from supercooled water on surfaces is a problem of fundamental importance and general utility. Superhydrophobic surfaces promise to have remarkable 'icephobicity' and low ice adhesion. Here we show that their icephobicity can be rendered ineffective by simple changes in environmental conditions. Through experiments, nucleation theory and heat transfer physics, we establish that humidity and/or the flow of a surrounding gas can fundamentally switch the ice crystallization mechanism, drastically affecting surface icephobicity. Evaporative cooling of the supercooled liquid can engender ice crystallization by homogeneous nucleation at the droplet-free surface as opposed to the expected heterogeneous nucleation at the substrate. The related interplay between droplet roll-off and rapid crystallization is also studied. Overall, we bring a novel perspective to icing and icephobicity, unveiling the strong influence of environmental conditions in addition to the accepted effects of the surface conditions and hydrophobicity. PMID- 22233624 TI - Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds. AB - Multivalent effects dictate the binding affinity of multiple ligands on one molecular entity to receptors. Integrins are receptors that mediate cell attachment through multivalent binding to peptide sequences within the extracellular matrix, and overexpression promotes the metastasis of some cancers. Multivalent display of integrin antagonists enhances their efficacy, but current scaffolds have limited ranges and precision for the display of ligands. Here we present an approach to studying multivalent effects across wide ranges of ligand number, density, and three-dimensional arrangement. Using L-lysine gamma substituted peptide nucleic acids, the multivalent effects of an integrin antagonist were examined over a range of 1-45 ligands. The optimal construct improves the inhibitory activity of the antagonist by two orders of magnitude against the binding of melanoma cells to the extracellular matrix in both in vitro and in vivo models. PMID- 22233626 TI - Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. AB - Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-beta/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-beta pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general. PMID- 22233627 TI - Structural rearrangements underlying ligand-gating in Kir channels. AB - Inward rectifier potassium (Kir) channels are physiologically regulated by a wide range of ligands that all act on a common gate, although structural details of gating are unclear. Here we show, using small molecule fluorescent probes attached to introduced cysteines, the molecular motions associated with gating of KirBac1.1 channels. The accessibility of the probes indicates a major barrier to fluorophore entry to the inner cavity. Changes in fluorescence resonance energy transfer between fluorophores, attached to KirBac1.1 tetramers, show that phosphatidylinositol-4,5-bisphosphate-induced closure involves tilting and rotational motions of secondary structural elements of the cytoplasmic domain that couple ligand binding to a narrowing of the cytoplasmic vestibule. The observed ligand-dependent conformational changes in KirBac1.1 provide a general model for ligand-induced Kir channel gating at the molecular level. PMID- 22233628 TI - Biomedical photoacoustics beyond thermal expansion using triggered nanodroplet vaporization for contrast-enhanced imaging. AB - Since being discovered by Alexander Bell, photoacoustics may again be seeing major resurgence in biomedical imaging. Photoacoustics is a non-ionizing, functional imaging modality capable of high contrast images of optical absorption at depths significantly greater than traditional optical imaging techniques. Optical contrast agents have been used to extend photoacoustics to molecular imaging. Here we introduce an exogenous contrast agent that utilizes vaporization for photoacoustic signal generation, providing significantly higher signal amplitude than that from the traditionally used mechanism, thermal expansion. Our agent consists of liquid perfluorocarbon nanodroplets with encapsulated plasmonic nanoparticles, entitled photoacoustic nanodroplets. Upon pulsed laser irradiation, liquid perfluorocarbon undergoes a liquid-to-gas phase transition generating giant photoacoustic transients from these dwarf nanoparticles. Once triggered, the gaseous phase provides ultrasound contrast enhancement. We demonstrate in phantom and animal studies that photoacoustic nanodroplets act as dual-contrast agents for both photoacoustic and ultrasound imaging through optically triggered vaporization. PMID- 22233629 TI - Momentum-dependent multiple gaps in magnesium diboride probed by electron tunnelling spectroscopy. AB - The energy gap is the most fundamental property of a superconductor. MgB(2), a superconductor discovered in 2001, exhibits two different superconducting gaps caused by the different electron-phonon interactions in two weakly interacting bands. Theoretical calculations predict that the gap values should also vary across the Fermi surface sheets of MgB(2). However, until now, no such variation has been observed. It has been suggested that two gap values were sufficient to describe real MgB(2) samples. Here we present an electron tunnelling spectroscopy study on MgB(2)/native oxide/Pb tunnel junctions that clearly shows a distribution of gap values, confirming the importance of the anisotropic electron phonon interaction. The gap values, and their spreads found from the tunnel junction measurements, provide valuable experimental tests for various theoretical approaches to the multi-band superconductivity in MgB(2). PMID- 22233630 TI - Hydrothermal vent fields and chemosynthetic biota on the world's deepest seafloor spreading centre. AB - The Mid-Cayman spreading centre is an ultraslow-spreading ridge in the Caribbean Sea. Its extreme depth and geographic isolation from other mid-ocean ridges offer insights into the effects of pressure on hydrothermal venting, and the biogeography of vent fauna. Here we report the discovery of two hydrothermal vent fields on the Mid-Cayman spreading centre. The Von Damm Vent Field is located on the upper slopes of an oceanic core complex at a depth of 2,300 m. High temperature venting in this off-axis setting suggests that the global incidence of vent fields may be underestimated. At a depth of 4,960 m on the Mid-Cayman spreading centre axis, the Beebe Vent Field emits copper-enriched fluids and a buoyant plume that rises 1,100 m, consistent with >400 degrees C venting from the world's deepest known hydrothermal system. At both sites, a new morphospecies of alvinocaridid shrimp dominates faunal assemblages, which exhibit similarities to those of Mid-Atlantic vents. PMID- 22233631 TI - Rapid and adaptive evolution of MHC genes under parasite selection in experimental vertebrate populations. AB - The genes of the major histocompatibility complex are the most polymorphic genes in vertebrates, with more than 1,000 alleles described in human populations. How this polymorphism is maintained, however, remains an evolutionary puzzle. Major histocompatibility complex genes have a crucial function in the adaptive immune system by presenting parasite-derived antigens to T lymphocytes. Because of this function, varying parasite-mediated selection has been proposed as a major evolutionary force for maintaining major histocompatibility complex polymorphism. A necessary prerequisite of such a balancing selection process is rapid major histocompatibility complex allele frequency shifts resulting from emerging selection by a specific parasite. Here we show in six experimental populations of sticklebacks, each exposed to one of two different parasites, that only those major histocompatibility complex alleles providing resistance to the respective specific parasite increased in frequency in the next host generation. This result demonstrates experimentally that varying parasite selection causes rapid adaptive evolutionary changes, thus facilitating the maintenance of major histocompatibility complex polymorphism. PMID- 22233632 TI - Two rotating cilia in the node cavity are sufficient to break left-right symmetry in the mouse embryo. AB - Determination of left-right asymmetry in mouse embryos is achieved by a leftward fluid flow (nodal flow) in the node cavity that is generated by clockwise rotational movement of 200-300 cilia in the node. The precise action of nodal flow and how much flow input is required for the robust read-out of left-right determination remains unknown. Here we show that a local leftward flow generated by as few as two rotating cilia is sufficient to break left-right symmetry. Quantitative analysis of fluid flow and ciliary rotation in the node of mouse embryos shows that left-right asymmetry is already established within a few hours after the onset of rotation by a subset of nodal cilia. Examination of various ciliary mutant mice shows that two rotating cilia are sufficient to initiate left right asymmetric gene expression. Our results suggest the existence of a highly sensitive system in the node that is able to sense an extremely weak unidirectional flow, and may favour a model in which the flow is sensed as a mechanical force. PMID- 22233633 TI - Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. AB - Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies. PMID- 22233634 TI - Control of magnetohydrodynamic stability by phase space engineering of energetic ions in tokamak plasmas. AB - Virtually collisionless magnetic mirror-trapped energetic ion populations often partially stabilize internally driven magnetohydrodynamic disturbances in the magnetosphere and in toroidal laboratory plasma devices such as the tokamak. This results in less frequent but dangerously enlarged plasma reorganization. Unique to the toroidal magnetic configuration are confined 'circulating' energetic particles that are not mirror trapped. Here we show that a newly discovered effect from hybrid kinetic-magnetohydrodynamic theory has been exploited in sophisticated phase space engineering techniques for controlling stability in the tokamak. These theoretical predictions have been confirmed, and the technique successfully applied in the Joint European Torus. Manipulation of auxiliary ion heating systems can create an asymmetry in the distribution of energetic circulating ions in the velocity orientated along magnetic field lines. We show the first experiments in which large sawtooth collapses have been controlled by this technique, and neoclassical tearing modes avoided, in high-performance reactor-relevant plasmas. PMID- 22233635 TI - Conclusive quantum steering with superconducting transition-edge sensors. AB - Quantum steering allows two parties to verify shared entanglement even if one measurement device is untrusted. A conclusive demonstration of steering through the violation of a steering inequality is of considerable fundamental interest and opens up applications in quantum communication. To date, all experimental tests with single-photon states have relied on post selection, allowing untrusted devices to cheat by hiding unfavourable events in losses. Here we close this 'detection loophole' by combining a highly efficient source of entangled photon pairs with superconducting transition-edge sensors. We achieve an unprecedented ~62% conditional detection efficiency of entangled photons and violate a steering inequality with the minimal number of measurement settings by 48 s.d.s. Our results provide a clear path to practical applications of steering and to a photonic loophole-free Bell test. PMID- 22233636 TI - Elastic modulus determination of normal and glaucomatous human trabecular meshwork. PMID- 22233637 TI - Author response: On alternative methods for measuring visual field decay: Tobit linear regression. PMID- 22233638 TI - Mechanically strong, flexible polyimide aerogels cross-linked with aromatic triamine. AB - Polyimide gels are produced by cross-linking anhydride capped polyamic acid oligomers with aromatic triamine in solution and chemically imidizing. The gels are then supercritically dried to form nanoporous polyimide aerogels with densities as low as 0.14 g/cm(3) and surface areas as high as 512 m(2)/g. To understand the effect of the polyimide backbone on properties, aerogels from several combinations of diamine and dianhydride, and formulated oligomer chain length are examined. Formulations made from 2,2'-dimethylbenzidine as the diamine shrink the least but have among the highest compressive modulus. Formulations made using 4,4'-oxydianiline or 2,2'dimethylbenzidine can be fabricated into continuous thin films using a roll to roll casting process. The films are flexible enough to be rolled or folded back on themselves and recover completely without cracking or flaking, and have tensile strengths of 4-9 MPa. Finally, the highest onset of decomposition (above 600 degrees C) of the polyimide aerogels was obtained using p-phenylene diamine as the backbone diamine with either dianhydride studied. All of the aerogels are suitable candidates for high temperature insulation with glass transition temperatures ranging from 270-340 degrees C and onsets of decomposition from 460-610 degrees C. PMID- 22233643 TI - BMI among Timorese aged >= 40 years. AB - OBJECTIVE: To determine the distribution and sociodemographic associations of BMI (kg/m2) among adults aged >=40 years living in Timor-Leste. DESIGN: BMI was calculated for participants of a population-based cross-sectional survey. SETTING: Urban and rural Timor-Leste. SUBJECTS: Adults aged >=40 years living in Timor-Leste. RESULTS: Of those enumerated, 2014 participated (89.5 %). Male gender, rural domicile, older age, illiteracy and source of household income were associated with BMI < 18.5 kg/m2 on multivariate analysis. Female gender, urban domicile and literacy were associated with BMI >=25.0 and >=30.0 kg/m2. Adjusting for gender, age and domicile, and extrapolating to those aged >=40 years across Timor-Leste, 9.9 %, 36.0 %, 6.6 % and 0.8 % had BMI <16.0, <18.5, >=25.0 and >=30.0 kg/m2, respectively. CONCLUSIONS: At this time, being 'underweight' or 'severely thin' is more prevalent in the Timorese adult population than being 'overweight' or 'obese'. PMID- 22233646 TI - Hypothesis testing in high-throughput screening for drug discovery. AB - Following the success of small-molecule high-throughput screening (HTS) in drug discovery, other large-scale screening techniques are currently revolutionizing the biological sciences. Powerful new statistical tools have been developed to analyze the vast amounts of data in DNA chip studies, but have not yet found their way into compound screening. In HTS, characterization of single-point hit lists is often done only in retrospect after the results of confirmation experiments are available. However, for prioritization, for optimal use of resources, for quality control, and for comparison of screens it would be extremely valuable to predict the rates of false positives and false negatives directly from the primary screening results. Making full use of the available information about compounds and controls contained in HTS results and replicated pilot runs, the Z score and from it the p value can be estimated for each measurement. Based on this consideration, we have applied the concept of p-value distribution analysis (PVDA), which was originally developed for gene expression studies, to HTS data. PVDA allowed prediction of all relevant error rates as well as the rate of true inactives, and excellent agreement with confirmation experiments was found. PMID- 22233645 TI - A new approach to drug discovery: high-throughput screening of microbial natural extracts against Aspergillus fumigatus using resazurin. AB - Natural products are an inexhaustible source for drug discovery. However, the validation and selection of primary screening assays are vital to guarantee a selection of extracts or molecules with relevant pharmacological action and worthy of following up. The assay must be rapid, simple, easy to implement, and produce quick results and preferably at a low cost. In this work, we developed and validated a colorimetric microtiter assay using the resazurin viability dye. The parameters of the resazurin method for high-throughput screening (HTS) using natural extracts against Aspergillus fumigatus were optimized and set up. The extracts plus RPMI-1640 modified medium containing the spores and 0.002% resazurin were added per well. The fluorescence was read after 24 to 30 h of incubation. The resazurin proved to be as suitable as Alamar Blue for determining the minimal inhibitory concentration of different antifungals against A. fumigatus and effective to analyze fungicidal and fungistatic compounds. An HTS of 12 000 microbial extracts was carried out against two A. fumigatus strains, and 2.7% of the extracts displayed antifungal activity. Our group has been the first to use this methodology for screening a collection of natural extracts to identify compounds with antifungal activity against the medically important human pathogen A. fumigatus. PMID- 22233644 TI - Studies on the antihypertensive and antidyslipidemic activities of Viola odorata leaves extract. AB - BACKGROUND: This study was undertaken to provide pharmacological basis for the medicinal use of Viola odorata Linn. in hypertension and dyslipidemia using the in vivo and in vitro assays. RESULTS: Viola odorata leaves extract (Vo.Cr), which tested positive for alkaloids, saponins, tannins, phenolics, coumarins and flavonoids, caused a dose-dependent (0.1-1.0 mg/kg) decrease in mean arterial blood pressure in anaesthetized rats. In isolated guinea-pig atria, Vo.Cr equally inhibited force and rate of spontaneous atrial contractions. On the baseline of rat thoracic aortae (endothelium-intact and denuded), the plant extract caused phentolamine-sensitive vasoconstriction. When tested on phenylephrine (PE, 1 MUM) and K(+) (80 mM)-induced vasoconstriction, Vo.Cr caused a concentration-dependent relaxation and also caused a rightward shift of Ca(++) concentration-response curves as well as suppression of PE (1 MUM) control peaks in Ca(++)-free medium, similar to that caused by verapamil. In the presence of L-NAME, the relaxation curve of Vo.Cr was partially inhibited showing involvement of Nitric oxide (NO) mediated pathway. In Tyloxapol-induced dyslipidemia, Vo.Cr caused reduction in total cholesterol and triglyceride levels. In high-fat diet-induced dyslipidemia model, the plant extract caused a significant decrease in total cholesterol, LDL C, atherogenic index and prevented the increase in average body weights, while it increased HDL-C. CONCLUSIONS: These data indicate that the vasodilator effect of the plant extract is mediated through multiple pathways like inhibition of Ca(++) influx via membranous Ca(++) channels, its release from intracellular stores and NO-mediated pathways, which possibly explain the fall in BP. The plant also showed reduction in body weight and antidyslipidemic effect which may be due to the inhibition of synthesis and absorption of lipids and antioxidant activities. Thus, this study provides a pharmacologic rationale to the medicinal use of Viola odorata in hypertension and dyslipidemia. PMID- 22233647 TI - Identification of novel compounds that increase SMN protein levels using an improved SMN2 reporter cell assay. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disorder that is characterized by progressive loss of motor neuron function. It is caused by the homozygous loss of the SMN1 (survival of motor neuron 1) gene and a decrease in full-length SMN protein. SMN2 is a nearly identical homolog of SMN1 that, due to alternative splicing, expresses predominantly truncated SMN protein. SMN2 represents an enticing therapeutic target. Increasing expression of full-length SMN from the SMN2 gene might represent a treatment for SMA. We describe a newly designed cell-based reporter assay that faithfully and reproducibly measures full length SMN expression from the SMN2 gene. This reporter can detect increases of SMN protein by an array of compounds previously shown to regulate SMN2 expression and by the overexpression of proteins that modulate SMN2 splicing. It also can be used to evaluate changes at both the transcriptional and splicing level. This assay can be a valuable tool for the identification of novel compounds that increase SMN2 protein levels and the optimization of compounds already known to modulate SMN2 expression. We present here preliminary data from a high-throughput screen using this assay to identify novel compounds that increase expression of SMN2. PMID- 22233648 TI - A mechanism-based whole-cell screening assay to identify inhibitors of protein export in Escherichia coli by the Sec pathway. AB - More than 20% of bacterial proteins are noncytoplasmic, and most of these pass through the SecYEG channel en route to the periplasm, cell membrane, or surrounding environment. The Sec pathway, encompassing SecYEG and several associated proteins (SecA, SecB, YidC, SecDFYajC), is of interest as a potential drug target because it is distinct from targets of current drugs, is essential for bacterial growth, and exhibits dissimilarities in eukaryotes and bacteria that increase the likelihood of selectively inhibiting the microbial pathway. As a step toward validating the pathway as a drug target, we have adapted a mechanism-based whole-cell assay in a manner suitable for high-throughput screening (HTS). The assay uses an engineered strain of Escherichia coli that accumulates beta-galactosidase (beta-gal) in its cytoplasm if translocation through SecYEG is blocked. The assay should facilitate rapid identification of compounds that specifically block the Sec pathway because widely, toxic compounds and nonspecific protein synthesis inhibitors prevent beta-gal production and thus do not register as hits. Testing of current antibiotics confirmed that they do not generally act through the Sec pathway. A mini-screen of 800 compounds indicated the assay's readiness for larger screening projects. PMID- 22233649 TI - Phaedra, a protocol-driven system for analysis and validation of high-content imaging and flow cytometry. AB - High-content screening has brought new dimensions to cellular assays by generating rich data sets that characterize cell populations in great detail and detect subtle phenotypes. To derive relevant, reliable conclusions from these complex data, it is crucial to have informatics tools supporting quality control, data reduction, and data mining. These tools must reconcile the complexity of advanced analysis methods with the user-friendliness demanded by the user community. After review of existing applications, we realized the possibility of adding innovative new analysis options. Phaedra was developed to support workflows for drug screening and target discovery, interact with several laboratory information management systems, and process data generated by a range of techniques including high-content imaging, multicolor flow cytometry, and traditional high-throughput screening assays. The application is modular and flexible, with an interface that can be tuned to specific user roles. It offers user-friendly data visualization and reduction tools for HCS but also integrates Matlab for custom image analysis and the Konstanz Information Miner (KNIME) framework for data mining. Phaedra features efficient JPEG2000 compression and full drill-down functionality from dose-response curves down to individual cells, with exclusion and annotation options, cell classification, statistical quality controls, and reporting. PMID- 22233650 TI - Hepatitis B surface gene 145 mutant as a minor population in hepatitis B virus carriers. AB - BACKGROUND: Hepatitis B virus (HBV) can have mutations that include the a determinant, which causes breakthrough infection. In particular, a single mutation at amino acid 145 of the surface protein (G145) is frequently reported in the failure of prophylactic treatment. The aim of this study was to evaluate the frequency of the a determinant mutants, especially the G145 variant, in Japan, where universal vaccination has not been adopted. METHODS: The present study was a retrospective study. The study cohorts were defined as follows: group 1, children with failure to prevent mother-to-child transmission despite immunoprophylaxis (n = 18, male/female = 8/10, age 1-14 years; median 6 years); group 2, HBV carriers who had not received vaccination or hepatitis B immunoglobulin (n = 107, male/female = 107, age 1-52 years; median 16 years). To detect the G145R and G145A mutants in patients, we designed 3 probes for real time PCR. We also performed direct sequencing and cloning of PCR products. RESULTS: By mutant-specific real-time PCR, one subject (5.6%) was positive for the G145R mutant in group 1, while the G145 mutant was undetectable in group 2. The a determinant mutants were detected in one (5.6%) of the group 1 subjects and 10 (9.3%) of the group 2 subjects using direct sequencing, but direct sequencing did not reveal the G145 mutant as a predominant strain in the two groups. However, the subject who was positive according to the mutant-specific real-time PCR in group 1 had overlapped peaks at nt 587 in the electropherogram. In group 2, 11 patients had overlapped peaks at nt 587 in the electropherogram. Cloning of PCR products allowed detection of the G145R mutant as a minor strain in 7 (group 1: 1 subject, group 2: 6 subjects) of 12 subjects who had overlapped peaks at nt 587 in the electropherogram. CONCLUSIONS: The frequency of the a determinant mutants was not high in Japan. However, the G145R mutant was often present as a minor population in children and adults. HBV carriers might have the a determinant mutants as a minor form. PMID- 22233651 TI - A genome-wide association study of gestational diabetes mellitus in Korean women. AB - Knowledge regarding the genetic risk loci for gestational diabetes mellitus (GDM) is still limited. In this study, we performed a two-stage genome-wide association analysis in Korean women. In the stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic control women were compared using 2.19 million genotyped or imputed markers. We selected 11 loci for further genotyping in stage 2 samples of 931 case and 783 control subjects. The joint effect of stage 1 plus stage 2 studies was analyzed by meta-analysis. We also investigated the effect of known type 2 diabetes variants in GDM. Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P=6.65*10(-16)). A variant near MTNR1B, rs10830962, was also significantly associated with the risk of GDM (1.454; P=2.49*10(-13)). We found that there is an excess of association between known type 2 diabetes variants and GDM above what is expected under the null hypothesis. In conclusion, we have confirmed that genetic variants in CDKAL1 and near MTNR1B are strongly associated with GDM in Korean women. There seems to be a shared genetic basis between GDM and type 2 diabetes. PMID- 22233652 TI - Descriptive review and evaluation of the functioning of the International Health Regulations (IHR) Annex 2. AB - BACKGROUND: The International Health Regulations (IHRs) (2005) was developed with the aim of governing international responses to public health risks and emergencies. The document requires all 194 World Health Organization (WHO) Member States to detect, assess, notify and report any potential public health emergency of international concern (PHEIC) under specific timelines. Annex 2 of the IHR outlines decision-making criteria for State-appointed National Focal Points (NFP) to report potential PHEICs to the WHO, and is a critical component to the effective functioning of the IHRs. METHODS: The aim of the study was to review and evaluate the functioning of Annex 2 across WHO-reporting States Parties. Specific objectives were to ascertain NFP awareness and knowledge of Annex 2, practical use of the tool, activities taken to implement it, its perceived usefulness and user-friendliness. Qualitative telephone interviews, followed by a quantitative online survey, were administered to NFPs between October, 2009 and February, 2010. RESULTS: A total of 29 and 133 NFPs participated in the qualitative and quantitative studies, respectively. Qualitative interviews found most NFPs had a strong working knowledge of Annex 2; perceived the tool to be relevant and useful for guiding decisions; and had institutionalized management, legislation and communication systems to support it. NFPs also perceived Annex 2 as human and disease-centric, and emphasized its reduced applicability to potential PHEICs involving bioterrorist attacks, infectious diseases among animals, radio-nuclear and chemical spills, and water- or food-borne contamination. Among quantitative survey respondents, 88% reported having excellent/good knowledge of Annex 2; 77% reported always/usually using Annex 2 for assessing potential PHEICs; 76% indicated their country had some legal, regulatory or administrative provisions for using Annex 2; 95% indicated Annex 2 was always/usually useful for facilitating decisions regarding notifiability of potential PHEICs. CONCLUSION: This evaluation, including a large sample of WHO reporting States Parties, found that the IHR's Annex 2 is perceived as useful for guiding decisions about notifiability of potential PHEICs. There is scope for the WHO to expand training and guidance on application of the IHR's Annex 2 to specific contexts. Continued monitoring and evaluation of the functioning of the IHR is imperative to promoting global health security. PMID- 22233653 TI - Treatment of obstructive uropathy in one of three young brothers suffering from Gorlin-Cohen syndrome: a case report. AB - BACKGROUND: Frontometaphyseal dysplasia, or Gorlin-Cohen syndrome, is an X-linked disorder primarily characterized by skeletal dysplasia, such as hyperostosis of the skull and abnormalities of tubular bone modeling. Some patients develop extraskeletal manifestations, such as urinary tract anomalies. CASE PRESENTATION: A 26-year-old male patient was diagnosed with frontometaphyseal dysplasia and suffered from chronic urine retention. Although the patient was primarily diagnosed with a neurogenic bladder, our work-up revealed posterior urethral valves, bladder neck stenosis, and multiple bladder stones. The patient was treated by transurethral resection of the urethral valves and bladder neck with simultaneous open cystolithotomy to remove the bladder calculi. After removal of the catheter, the patient voided normally and had no post-void residual urine. At the 1-year follow-up, he was still voiding normally; his urodynamic investigation was also normal. CONCLUSIONS: In the recent literature, there is scarce information on the diagnosis, treatment, and follow-up of patients with malformations of the urinary tract as a result of Gorlin-Cohen syndrome. The case presented here could guide urological approaches to patients suffering from this rare condition. PMID- 22233654 TI - Efficacy and safety of once-daily ritonavir-boosted darunavir and abacavir/lamivudine for treatment-naive patients: a pilot study. AB - The efficacy and safety of once-daily darunavir/ritonavir and fixed-dose abacavir/lamivudine was examined in 22 treatment-naive patients with HIV-1 infection. Three patients discontinued antiretroviral therapy due to mild adverse events. Among 18 patients who continued therapy, 66.7% had viral load less than 50 copies/ml at week 48. Only two patients experienced virologic failure with the emergence of resistant virus. This pilot study demonstrated the viral efficacy and safety of darunavir/ritonavir and abacavir/lamivudine. PMID- 22233656 TI - Short- and long-term outcomes of self-expanding metal stent placement as a bridge to surgery for acute left-sided colorectal cancer obstruction. AB - AIM: The aim of this study was to evaluate the short- and long-term outcomes of self-expanding metal stent (SEMS) insertion as a bridge to surgery (BTS) in patients presenting with acute left-sided colorectal cancer obstruction (LCCO). METHODS: All patients with acute LCCO who underwent endoscopic SEMS placement as a BTS between January 2005 and December 2010 were reviewed and included in the study. RESULTS: Thirty-six patients (19M and 17F; mean age 68.5) were included. The most frequent location was the sigmoid colon (47.2%). Technical success was achieved in 91.6% and clinical success in 88.9%. Technical failure was related to the location of the stricture at the rectosigmoid junction (P=0.03). There were four SEMS-related complications: one fecal obstruction, one haemorrhage treated with APC and two silent perforations which were noted during surgical resection. The mean time between SEMS insertion and surgical treatment was 19 days (range 6 80 days) and the most frequent intervention was a left hemicolectomy (46.9%). No intraoperative mortality and morbidity, or postoperative mortality were observed. The postoperative morbidity rate was 18.8% (two wound infections, one deep venous thrombosis, one case of pneumonia and one anastomotic dehiscence). Finally, after discharge from hospital, a total of 29 patients (90%) were stoma free. At the end of the follow-up period, 24 patients are still alive and the mean survival rate was 37.3+/-18 months (range 9-72). CONCLUSION: In our experience, SEMS placement as a BTS is a safe and effective strategy for the treatment of patients with acute LCCO. PMID- 22233657 TI - Comparison of clinical and pathological tumor, node and metastasis staging of lung cancer: 15-year experience with 530 patients. AB - AIM: The prognosis of patients with lung cancer depends on early diagnosis and accurate staging. The present staging system for lung cancer is tumor (T), node (N), and metastasis (M) staging (TNM). We compared the accuracy of preoperative (clinical) and postoperative (pathological) TNM staging of lung cancer in this study and emphasized the preoperative mediastinoscopy is useful in selected patients. METHODS: We performed a retrospective comparison of the clinical and pathological TNM staging of 530 patients with lung cancer treated surgically. The preoperative clinical TNM staging of all patients was based on physical examination, radiological investigations and bronchoscopy. Mediastinoscopy was used routinely for all patients with an indication since 2000. RESULTS: We found the agreement between clinical and pathological TNM staging to be only 46.4%. The comparison between clinical and pathological TNM staging was 6.2-5.3% at stage Ia, 37.9%-36% at stage Ib, 0.7-0.9% at stage IIa, 23-25% at stage IIb, 27.1-16.2% at stage IIIa, and 3.2-14% at stage IIIb respectively. The frequency rates of the different clinical and pathologic stages were 6.2% and 5.3%, for stage Ia, 37.9% and 36% for stage Ib, 0.7% and 0.9% for stage IIa, 23% and 25% for stage IIb, 27.1% and 16.2% for stage IIIa, 3.2% and 14% for stage IIIb respectively. CONCLUSION: We compared the clinical and pathological staging in patients with non small cell lung cancer submitted to surgical treatment to identify the causes of any discordance. The clinical TNM and staging based on computerized tomography was found to be inaccurate. PMID- 22233658 TI - Barrett's esophagus after laparoscopic Nissen-Rossetti fundoplication: functional evaluation. AB - AIM: The aim of this study was to demonstrate the efficacy of laparoscopic antireflux surgery in controlling Barrett's esophagus progression, through functional study. METHODS: Between January 2008 and December 2009, 21 patients with a preoperative diagnosis of Barrett's esophagus underwent Nissen-Rossetti fundoplication. RESULTS: All patients underwent preoperatively a 24-hour pH-metry (100%). Twenty patients (95.2%) had postoperative pH monitoring at six months, 16 patients at 12 months (76.2%), eight at 24 months (57.14%). Median De Meester and Johnson score was preoperatively 18.55 (range 8.6-179.7), at six months 7.65 (range 6.4-13), at 12 months 7.5 (range 6.4-14.2), at 24 months 11.95 (range 6.4 20.6). CLE was still present in 18 patients (18/21, 85.7%), but no patient developed dysplasia or esophageal adenocarcinoma. Two patients with gastric- and one patient with intestinal metaplasia showed complete regression at 12 and 24 months after fundoplication (3/21, 14.3%). Symptom control alone does not manage acid reflux in patients with Barrett's esophagus after surgery, and postoperative 24-hour pH-metry confirms acid reflux abolition. A persistent reflux is more likely to develop cancer than in monitored patients. CONCLUSION: Only the presence of intact and effective anti-reflux wrap guarantees protection of the esophagus against CLE progression or its regression. Functional study after surgery identifies patients with Barrett's progression risk. PMID- 22233655 TI - Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AB - OBJECTIVE: To describe incidence of immune reconstitution inflammatory syndrome (IRIS) and its association with mortality in a large multisite US HIV-infected cohort applying an objective, comprehensive definition. DESIGN: We studied 2,610 patients seen during 1996-2007 who initiated or resumed highly active combination antiretroviral therapy (cART) and, during the next 6 months, demonstrated a decline in plasma HIV-RNA viral load of at least 0.5 log(10) copies/ml or an increase of at least 50% in CD4 cell count per microliter. We defined IRIS as the diagnosis of a type B or C condition [as per the Centers for Disease Control and Prevention (CDC) 1993 AIDS case definition] or any new mucocutaneous disorder during this same 6-month period. METHODS: We assessed the incidence of IRIS and evaluated risk factors for IRIS using conditional logistic regression and for all cause mortality using proportional hazards models. RESULTS: We identified 370 cases of IRIS (in 276 patients). Median and nadir CD4 cell counts at cART initiation were 90 and 43 cells/MUl, respectively; median viral load was 2.7 log(10) copies/ml. The most common IRIS-defining diagnoses were candidiasis (all forms), cytomegalovirus infection, disseminated Mycobacterium avium intracellulare, Pneumocystis pneumonia, varicella zoster, Kaposi's sarcoma and non-Hodgkin lymphoma. Only one case of Mycobacterium tuberculosis was observed. IRIS was independently associated with CD4 cell count less than 50 cells/MUl vs. at least 200 cells/MUl [odds ratio (OR) 5.0] and a viral load of at least 5.0 log(10) copies vs. less than 4.0 log(10) copies (OR 2.3). IRIS with a type B defining or type C-defining diagnosis approximately doubled the risk for all cause mortality. CONCLUSION: In this large US-based HIV-infected cohort, IRIS occurred in 10.6% of patients who responded to effective ART and contributed to increased mortality. PMID- 22233659 TI - [Robotic rectal resection in rectal cancer: short term results in a monocentric prospective study]. AB - AIM: The aim of this study was to evaluate technical feasibility, oncological safety and short-term clinical results of robotic rectal resection for cancer. METHODS: From January 2008 to July 2010, 46 patients (27 males and 19 females, median age 69 years, median BMI 24.6 kg/m2) with histologically-proven adenocarcinoma of medium and distal rectum were enrolled in a prospective database. Preoperative assessment was performed with colonoscopy with biopsies, thoraco-abdominal CT scan, pelvic MRI and endorectal-ultrasound (ERUS). In the case of locally advanced non metastatic disease (T3/4 or N1/2), patients received preoperative radiotherapy (45 Grays in 5 weeks) and chemotherapy (oral Capecitabine). The robotic system was a four-arms Da Vinci(r) (Intuitive Surgical, Sunnyvale, CA, USA); arms position is not modified during the entire surgical procedure. RESULTS: Twenty-five patients received a preoperative radio chemotherapy. Surgical procedure was an abdomino-perineal amputation in nine patients and an anterior resection in the remaining 37, with temporary ileostomy in 16 cases and a laparoscopic mobilization of splenic flexure in 25. Median operative time was 251 minutes, median time of first bowel movements 1.7 days and median hospital stay 6.7 days. Major complications requiring reoperation verified in 2 patients, while overall complication rate is 15.2%. Median number of harvested lymph nodes per patient was 18; median distance of the tumour from distal resection margin was 2 cm; distance of the tumour from circumferential margin was superior to 1 mm in all of the patients. At a median follow up of 11 months, all patients are alive and disease-free. CONCLUSION: Robotic rectal resection is a feasible technique which can provide good oncological and short term clinical results. PMID- 22233660 TI - Prediction model of pelvic lymph node metastasis in early stage cervical cancer and its clinical value. AB - AIM: This study was designed to investigate the risk factors of pelvic lymph node metastasis in early stage cervical cancer in order to establish a prediction model for this metastasis and to explore the feasibility of conservative surgery. METHODS: The records of 207 stage IB-IIA cervical cancer patients were retrospectivly analyzed. The risk factors of pelvic lymph node metastasis were analyzed using univariate and multivariate methods. The prediction model for pelvic lymph node metastasis was established by logistic regression. RESULTS: Without preoperative adjuvant therapy, the metastatic rate of pelvic lymph node in stage IB-IIA cervical cancer was 25.1%. The serum SCCAg, the tumor diameter, the depth of cervical stroma invasion, and the cervical canal involvement were revealed as the risk factors of pelvic lymph node metastasis by univariate analysis (P<0.05). Multivariate analysis showed that the serum SCCAg and the depth of cervical stroma invasion were the independent risk factors of pelvic lymph node metastasis (P<0.05, OR = 6.917, 2.227). The patients were divided into three groups according to different independent risk factors: the low-risk group, the medium-risk group, and the high-risk group, which showed metastatic rates of pelvic lymph node of 5.7%, 16.9%, and 48.7%, respectively (P<0.001). A prediction model for pelvic lymph node metastasis was established as follows: Logti(P) = 2.534 + serum SCCAg*1.934 + depth of cervical stroma invasion*0.801. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of this prediction model were 53.8%, 83.9 %, 52.8%, 84.4%, and 76.3%, respectively. CONCLUSION: The serum SCCAg and the depth of cervical stroma invasion were the independent risk factors of pelvic lymph node metastasis in early stage cervical cancer. The proposed prediction model may help to improve the conservative surgery for early stage cervical cancer. PMID- 22233661 TI - [Laparoscopic treatment of abdominal wall hernias: prosthesis material comparison]. AB - Hernia is due to abdominal wall weakening. This allows the contents of the abdomen to protrude from normal boundaries. Hernias are repaired by implanting a sterile surgical mesh to strengthen the weakened abdominal wall. Aim of this study is to compare the results obtained by bard Composix(r) L/P mesh or Dualmesh Plus Gore(r) implanting. The mesh has various beneficial characteristics. It is a reinforcing material for the abdominal wall, even when in the direct contact with the intestinal tract does not cause adhsion problems. The use of biocompatible materials is necessary in laparoscopic hernia repair. e-PTFE prosthesis and Dual Mesh(r) were the first to be used for laparoscopic treatment of the abdominal wall defects. These prosthesis are the result of many improvements, actually they are 1-mm thick and the two surfaces have different characteristics. Compound meshes are composed by e-PTFE and polypropylene with different percentage of the two materials and methods of interactions. The incidence of early complications were poor in relation to both types of implants, only seroma cases e-PTFE treated showed a prevalence of complication, in agreement with literature. About relapses in our experience we found that e-PTFE cases were predominantly. Dual Mesh(r) has better adaptability than Bard Composix(r), which allows easier placement of the prosthesis as well as a better adaptation to the wall surface. The Bard Composix(r), thanks to rigidity due to the polypropylene component has better handling than the Dual Mesh(r), as it promotes a rapid and easy deployment of the prosthesis inside the abdominal cavity, favoring its positioning. The use of both prosthesis depends also on the experience specific to each operator, moreover, a rigorous surgical technique remains fundamental for the application of the mesh used. PMID- 22233662 TI - Contrast media-induced nephropathy in patients undergoing angiography prior to or during vascular surgery: a systematic review. AB - Nephropathy induced after administration of contrast medium is an acute and severe complication that is of particular concern in vascular surgery. While patients undergoing coronary procedures have been extensively studied, there is a paucity of data on pre- and intraoperative prevention of contrast-induced nephropathy in vascular surgery patients. There is lack of a robust analysis exploring the additive effect of pre- or intraoperative administration of drugs such as N-acetylcysteine, dopamine and sodium bicarbonate in addition to adequate hydration in patients undergoing angiography prior to or after completion of vascular surgery. A systematic review of contrast-induced nephropathy after angiography in patients undergoing vascular surgery was carried out. Eligible trials were sought by multiple methods, and the pooled odds ratios for contrast induced nephropathy were computed under a random effects model. Twenty-one publications were identified for screening and 6 studies were included for systematic review. All 6 studies investigated preoperative angiography-related contrast-induced nephropathy; one study also investigated completion angiography. The overall frequency of contrast-induced nephropathy in patients undergoing vascular surgery was 9.2% (79/862). Risk factors for contrast-induced nephropathy identified were age >70 years, high contrast volume, pre-existing renal disease and antihypertensive medication. Two studies found that administration of N acetylcysteine prior to angiography does not provide added benefit in preventing contrast-induced nephropathy. Advanced age and pre-existing renal and vascular risk factors such as arterial hypertension expose vascular surgery patients to increased risk of contrast-induced nephropathy. Those undergoing completion angiography appear to be at even higher risk, particularly if severely azotemic. Further randomized clinical trials analyzing strategies for preventing contrast induced nephropathy are needed. PMID- 22233663 TI - What is new in liver surgery? Focus on thermoablation and the relevance of the inflammatory response. AB - Partial liver resection is a well established treatment for patients with liver tumors. It is associated with significant morbidity and some mortality, even in high volume centers. Less invasive modalities are currently available and deserve a place in the armamentarium of liver surgeons. This review discusses the role of thermoablation as a treatment modality for liver tumors. The minimal invasive possibility of percutaneous ablation is a great advantage. The limitation of ablation is the high incidence of ablation site recurrences. The inflammatory response is associated with the initiation of cancer at sites of chronic inflammation. There is also accumulating evidence that progression of tumors is also enhanced by an ongoing inflammatory response. The common denominator probably is angiogenesis. The paper supplies data about the interrelationship between inflammation, angiogenesis and tumor growth. Ablation of liver tumors is associated with a low inflammatory response, especially if it is performed percutaneous and thus deserves to be considered in patients with liver tumors. PMID- 22233664 TI - Current management of upper gastrointestinal bleeding. AB - Despite the introduction of proton pump inhibitors and modern flexible endoscopy techniques, upper gastrointestinal bleeding is still a common and serious condition. Once considered the domain of surgery, it is now uncommon to treat endoscopically controllable bleeding surgically. Therefore, most surgically treated cases are complicated and associated with a high mortality rate. This article presents the current management of upper gastrointestinal bleeding. Besides the description of current endoscopic treatment, medical prophylaxis and treatment, as well as radiological intervention, the article describes the indication and the surgical procedure. PMID- 22233665 TI - Current laparoscopic management of inflammatory bowel disease. AB - Since the introduction of laparoscopic surgery in the management of colorectal disease in the early '90s, minimally invasive techniques have gained popularity. While good quality studies have been published in the literature on laparoscopy for colorectal cancer, evidence supporting the use of minimally invasive surgery for inflammatory bowel disease is lacking. This patient population represents a challenge to the colorectal surgeon even in conventional open surgery and this has limited the widespread application of minimally invasive techniques especially in Crohn's disease. Laparoscopic ileocecal resection for Crohn's disease is the most performed minimally invasive procedure in the field of inflammatory bowel disease, with promising short-term outcomes but with still some concerns related to prolonged operative times and overall costs. For ulcerative colitis the magnitude of restorative procedures has also restricted the use of minimally invasive approaches to highly specialized tertiary referral centers. The benefits of performing restorative procedures laparoscopically for ulcerative colitis are less obvious based on the limited reports available in the literature with adequate follow-up for assessing long-term outcomes, and controversies still remains about the need for a staged approach in the era of biologic therapy. Nevertheless, surgeons are actively working in an effort to obviate to the current technical limitations of laparoscopy, and to further minimize surgical trauma. In this manuscript we will present the current evidence supporting the use of laparoscopy and minimally invasive techniques in inflammatory bowel disease and present the future direction of development and research. PMID- 22233666 TI - Robotic pancreatic resection: how far can we go? AB - Minimally invasive pancreatic resection remains one of the most challenging abdominal procedures. A wide diffusion of the laparoscopic approach for pancreatic resection is still waited. However, interest is growing since the introduction of robotics in this field and many reports have been published so far. Distal pancreatectomy with or without spleen-preservation, pancreaticoduodenectomy, total and middle pancreatectomy and even extended resections or reconstructions have been reported with good outcomes. This review reports and evaluates the robotic approach for such advanced pancreatic resections. While complex pancreatic resections are feasible and safe by a robotic approach, it is still very early to draw definitive conclusions. Further randomized and controlled studies are required to support a routine use of the robotic technology for pancreatic resection. PMID- 22233667 TI - A modeling-based evaluation of isothermal rebreathing for breath gas analyses of highly soluble volatile organic compounds. AB - Isothermal rebreathing has been proposed as an experimental technique for estimating the alveolar levels of hydrophilic volatile organic compounds (VOCs) in exhaled breath. Using the prototypic test compounds acetone and methanol, we demonstrate that the end-tidal breath profiles of such substances during isothermal rebreathing show a characteristic increase that contradicts the conventional pulmonary inert gas elimination theory due to Farhi. On the other hand, these profiles can reliably be captured by virtue of a previously developed mathematical model for the general exhalation kinetics of highly soluble, blood borne VOCs, which explicitly takes into account airway gas exchange as a major determinant of the observable breath output. This model allows for a mechanistic analysis of various rebreathing protocols suggested in the literature. In particular, it predicts that the end-exhaled levels of acetone and methanol measured during free tidal breathing will underestimate the underlying alveolar concentration by a factor of up to 1.5. Moreover, it clarifies the discrepancies between in vitro and in vivo blood-breath ratios of hydrophilic VOCs and yields further quantitative insights into the physiological components of isothermal rebreathing and highly soluble gas exchange in general. PMID- 22233677 TI - Remember your driver. PMID- 22233676 TI - Dynamin, a membrane-remodelling GTPase. AB - Dynamin, the founding member of a family of dynamin-like proteins (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live-cell imaging, cell-free studies, X-ray crystallography and genetic studies in mice, has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged, highlighting specific contributions of this GTPase to the physiology of different tissues. PMID- 22233678 TI - Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. AB - Gastrointestinal disturbances are commonly reported in children with autism and may be associated with compositional changes in intestinal bacteria. In a previous report, we surveyed intestinal microbiota in ileal and cecal biopsy samples from children with autism and gastrointestinal dysfunction (AUT-GI) and children with only gastrointestinal dysfunction (Control-GI). Our results demonstrated the presence of members of the family Alcaligenaceae in some AUT-GI children, while no Control-GI children had Alcaligenaceae sequences. Here we demonstrate that increased levels of Alcaligenaceae in intestinal biopsy samples from AUT-GI children result from the presence of high levels of members of the genus Sutterella. We also report the first Sutterella-specific PCR assays for detecting, quantitating, and genotyping Sutterella species in biological and environmental samples. Sutterella 16S rRNA gene sequences were found in 12 of 23 AUT-GI children but in none of 9 Control-GI children. Phylogenetic analysis revealed a predominance of either Sutterella wadsworthensis or Sutterella stercoricanis in 11 of the individual Sutterella-positive AUT-GI patients; in one AUT-GI patient, Sutterella sequences were obtained that could not be given a species-level classification based on the 16S rRNA gene sequences of known Sutterella isolates. Western immunoblots revealed plasma IgG or IgM antibody reactivity to Sutterella wadsworthensis antigens in 11 AUT-GI patients, 8 of whom were also PCR positive, indicating the presence of an immune response to Sutterella in some children. IMPORTANCE: Autism spectrum disorders affect ~1% of the population. Many children with autism have gastrointestinal (GI) disturbances that can complicate clinical management and contribute to behavioral problems. Understanding the molecular and microbial underpinnings of these GI issues is of paramount importance for elucidating pathogenesis, rendering diagnosis, and administering informed treatment. Here we describe an association between high levels of intestinal, mucoepithelial-associated Sutterella species and GI disturbances in children with autism. These findings elevate this little recognized bacterium to the forefront by demonstrating that Sutterella is a major component of the microbiota in over half of children with autism and gastrointestinal dysfunction (AUT-GI) and is absent in children with only gastrointestinal dysfunction (Control-GI) evaluated in this study. Furthermore, these findings bring into question the role Sutterella plays in the human microbiota in health and disease. With the Sutterella-specific molecular assays described here, some of these questions can begin to be addressed. PMID- 22233679 TI - The novel sigma factor-like regulator RpoQ controls luminescence, chitinase activity, and motility in Vibrio fischeri. AB - Vibrio fischeri, the bacterial symbiont of the Hawaiian bobtail squid, Euprymna scolopes, uses quorum sensing to control genes involved in bioluminescence, host colonization, and other biological processes. Previous work has shown that AinS/R directed quorum sensing also regulates the expression of rpoQ (VF_A1015), a gene annotated as an RpoS-like sigma factor. In this study, we demonstrate using phylogenetics that RpoQ is related to, but distinct from, the stationary-phase sigma factor RpoS. Overexpression of rpoQ results in elevated chitinase activity but decreased motility and luminescence, three activities associated with symbiosis. The reduction in bacterial luminescence associated with the overexpression of rpoQ occurs both in culture and within the light-emitting organ of the squid host. This suppression of bioluminescence is due to the repression of the luxICDABEG promoter. Our results highlight RpoQ as a novel regulatory component, embedded in the quorum-signaling network that controls several biological processes in V. fischeri. IMPORTANCE: Quorum signaling is a widely occurring phenomenon that functions in diverse bacterial taxa. It is most often found associated with species that interact with animal or plant hosts, either as mutualists or pathogens, and controls the expression of genes critical to tissue colonization. We present the discovery of rpoQ, which encodes a new regulatory component in the quorum-signaling pathway of Vibrio fischeri. RpoQ is a novel protein in the RpoS family of stationary-phase sigma factors. Unlike many other regulatory proteins involved in the quorum-signaling pathways of the Vibrionaceae, the distribution of RpoQ appears to be restricted to only two closely related species. The role of this regulator is to enhance some quorum signaling outputs (motility) while suppressing others (luminescence). We propose that RpoQ may be a recently evolved or acquired component in V. fischeri that provides this organism with an additional level of regulation to modulate its existing quorum-signaling pathway. PMID- 22233681 TI - PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis. AB - New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications. PMID- 22233680 TI - Expression of HOXA11 in the mid-luteal endometrium from women with endometriosis associated infertility. AB - BACKGROUND: A decrease in HOXA11 expression in eutopic mid-secretory endometrium has been found in women with endometriosis-associated infertility. METHODS: Using Real-time quantitative PCR (RQ-PCR) and western blotting analysis we studied the HOXA11 transcript and protein levels in mid-luteal eutopic endometrium from eighteen infertile women with minimal endometriosis, sixteen healthy fertile women and sixteen infertile women with fallopian tubal occlusion from the Polish population. We also evaluated transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in these groups of women. RESULTS: There were significantly lower levels of HOXA11 transcripts (p = 0.003, p = 0.041) and protein (p = 0.004, p = 0.001) in women with endometriosis as compared to fertile women and infertile women with tubal occlusion. Moreover, we found significantly higher methylation levels of the CpG region in the first exon of HOXA11 in infertile women with endometriosis compared with fertile women (p < 0.001) and infertile women with tubal occlusion (p < 0.001). We also observed significantly increased levels of DNMT3A transcript in women with endometriosis than fertile women (p = 0.044) and infertile women with tubal occlusion (p = 0.047). However, we did not observe significant differences in DNMT1 and DNMT3B transcript levels between these investigated groups of women. CONCLUSIONS: We confirmed that reduced HOXA11 expression may contribute to endometriosis-associated infertility. Moreover, we found that DNA hypermethylation can be one of the possible molecular mechanisms causing a decrease in HOXA11 expression in the eutopic mid-secretory endometrium in infertile women with endometriosis. PMID- 22233682 TI - Corneal stromal cells use both high- and low-contractility migration mechanisms in 3-D collagen matrices. AB - Corneal keratocyte migration can impact both corneal clarity and refractive outcome following injury or refractive surgery. In this study, we investigated how culture conditions, ECM properties, and Rho kinase activity regulate the mechanics of keratocyte migration, using a nested collagen matrix model. Time lapse imaging demonstrated that both serum and PDGF stimulate keratocyte migration into the outer matrix. Although the velocity of cell migration was similar, cells in serum were bipolar and induced significant matrix deformation during migration, whereas PDGF induced extension of branching dendritic processes with smaller, more localized force generation. These differences in cell-induced matrix reorganization were verified with a global matrix contraction assay and confocal reflection imaging, using both bovine and rat tail collagen. When constructs were detached from the substrate to lower the effective stiffness, migration was significantly reduced in serum; but was unchanged in PDGF. These differences in migration mechanics were mediated, in part, by Rho kinase. Overall, corneal keratocytes can effectively migrate through collagen matrices using varying degrees of cellular force generation. Low-contractility migration may facilitate keratocyte repopulation of the stroma following surgery or injury, without altering the structural and mechanical properties that are critical to maintaining corneal transparency. PMID- 22233683 TI - Contrasting protective effects of cannabinoids against oxidative stress and amyloid-beta evoked neurotoxicity in vitro. AB - Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer's protein, beta-amyloid (Abeta) in neuronal cell lines. PC12 or SH-SY5Y cells were selectively exposed to either hydrogen peroxide, tert-butyl hydroperoxide or Abeta, alone or in the presence of the CB1 specific agonist arachidonyl-2' chloroethylamide (ACEA), CB2 specific agonist JWH-015, anandamide or cannabidiol. Cannabidiol improved cell viability in response to tert-butyl hydroperoxide in PC12 and SH-SY5Y cells, while hydrogen peroxide-mediated toxicity was unaffected by cannabidiol pretreatment. Abeta exposure evoked a loss of cell viability in PC12 cells. Of the cannabinoids tested, only anandamide was able to inhibit Abeta evoked neurotoxicity. ACEA had no effect on Abeta-evoked neurotoxicity, suggesting a CB1 receptor-independent effect of anandamide. JWH-015 pretreatment was also without protective influence on PC12 cells from either pro-oxidant or Abeta exposure. None of the cannabinoids directly inhibited or disrupted preformed Abeta fibrils and aggregates. In conclusion, the endocannabinoid anandamide protects neuronal cells from Abeta exposure via a pathway unrelated to CB1 or CB2 receptor activation. The protective effect of cannabidiol against oxidative stress does not confer protection against Abeta exposure, suggesting divergent pathways for neuroprotection of these two cannabinoids. PMID- 22233684 TI - Aromatase up-regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER-alpha and GPER signalling. AB - For some years now, reduced testosterone levels have been related to obesity, insulin resistance, type 2 diabetes, heart disease, benign prostatic hypertrophy and even prostate cancer--often considered guilty more by association, than actual cause--with little attention paid to the important role of increased intracellular oestrogen, in the pathogenesis of these chronic diseases. In the final stage of the steroidogenic cascade, testosterone is metabolised to oestradiol by P450 aromatase, in the cytoplasm of adipocytes, breast cells, endothelial cells and prostate cells, to increase intracellular oestradiol concentration at the expense of testosterone. It follows therefore, that any compound that up-regulates aromatase, or any molecule that mimics oestrogen, will not only increase the activation of the mainly proliferative, classic ER-alpha, oestrogen receptors to induce adipogenesis and growth disorders in oestrogen sensitive tissues, but also activate the recently identified transmembrane G protein-coupled oestrogen receptors (GPER), and deleteriously alter important intracellular signalling sequences, that promote mitogenic growth and endothelial damage. This paper simplifies how stress, xeno-oestrogens, poor dietary choices and reactive toxins up-regulate aromatase to increase intracellular oestradiol production; how oestradiol in combination with leptin and insulin cause insulin resistance and leptin resistance through aberrant serine phosphorylation; how the increased oestradiol, insulin and leptin stimulate rapid, non-genomic G protein coupled phosphorylation cascades, to increase fat deposition and create the vasoconstrictive, dyslipidemic features of metabolic syndrome; how aberrant GPER signalling induces benign prostatic hypertrophy; and how increased intracellular oestradiol stimulates mitogenic change and tumour-cell activators, to cause prostate cancer. In essence, the up-regulation of aromatase produces increased intracellular oestradiol, increases ER-alpha activation and increases GPER activation, in combination with insulin, to cause aberrant downstream transduction signaling, and thus induce metabolic syndrome and mitogenic prostate growth. To understand this fact, that raised intracellular oestradiol levels in men, induce and promote obesity, gynecomastia, metabolic syndrome, type two diabetes, benign prostatic hypertrophy and prostate cancer, rather than low testosterone, represents a shift in medical thinking, a new awareness, that will reduce the rising incidence of obesity, metabolic syndrome and prostate disease, and significantly improve the health of men worldwide. PMID- 22233685 TI - Adult Gaucher disease in southern Tunisia: report of three cases. AB - BACKGROUND: Gaucher disease (GD) is the most frequent lysosomal storage disorder; type 1 is by far the most common form. It is characterized by variability in age of onset, clinical signs and progression. It is usually diagnosed in the first or second decade of life with the appearance of bone pains, splenomegaly and thrombocytopenia, but the disease may be diagnosed at any age between 1 and 73 years. In the present study, we report 3 cases with late onset of GD in whom the disease was a surprise finding including one patient with Parkinson disease. This late onset is described as an adult form of Gaucher disease. FINDINGS: Molecular investigation showed mutational homogeneity in Tunisian adult patients suffering from GD. Indeed, all patients carry the p.N370S mutation: two patients at a homozygous state and one patient at compound heterozygous state. CONCLUSION: The p.N370S mutation presents a large variability in the onset of the disease and its clinical manifestation supporting the view that GD should be considered as a continuum phenotype rather than a predefined classification. PMID- 22233686 TI - Cloning and expression of an endo-1,4-beta-xylanase from the coffee berry borer, Hypothenemus hampei. AB - BACKGROUND: The coffee berry borer, Hypothenemus hampei, reproduces and feeds exclusively on the mature endosperm of the coffee seed, which has a cell wall composed mainly of a heterogeneous mixture of hemicellulose polysaccharides, including arabinoxylans. Xylanases are digestive enzymes responsible for the degradation of xylan based polymers, hydrolyzing them into smaller molecules that are easier to assimilate by insects. We report the cloning, expression and enzymatic characterization of a xylanase gene that was identified in the digestive tract of the coffee berry borer. METHODS: The complete DNA sequence encoding a H. hampei xylanase (HhXyl) was obtained using a genome walking technique in a cDNA library derived from the borer digestive tract. The XIP-I gene was amplified from wheat (Triticum aestivum variety Soisson). A Pichia pastoris expression system was used to express the recombinant form of these enzymes. The xylanase activity and XIP-I inhibitory activity was quantified by the 3,5-dinitrosalicylic (DNS). The biological effects of XIP-I on borer individuals were evaluated by providing an artificial diet enriched with the recombinant XIP-I protein to the insects. RESULTS: The borer xylanase sequence contains a 951 bp open reading frame that is predicted to encode a 317-amino acid protein, with an estimated molecular weight of 34.92 kDa and a pI of 4.84. Bioinformatic analysis revealed that HhXyl exhibits high sequence homology with endo-beta-D-xylanases of Streptomyces bingchenggensis from glycosyl hydrolase 10 (GH10). The recombinant xylanase showed maximal activity at pH 5.5 and 37 degrees C. XIP-I expressed as a recombinant protein inhibited HhXyl activity in vitro and caused individual H. hampei mortality in bioassays when included as a supplement in artificial diets. CONCLUSION: A xylanase from the digestive tract of the coffee berry borer was identified and functionally characterized. A xylanase inhibitor protein, XIP-I, from wheat was shown to be a potent inhibitor of this xylanase, suggesting that its deployment has potential as a strategy to control coffee berry borer colonization of coffee plants. PMID- 22233687 TI - Diagnostic capacity for viral haemorrhagic septicaemia virus (VHSV) infection in rainbow trout (Oncorhynchus mykiss) is greatly increased by combining viral isolation with specific antibody detection. AB - Detection of disease specific antibodies in farmed rainbow trout (Oncorhynchus mykiss) has been proposed as an alternative or supplement to the currently approved procedures for diagnosis and surveillance in this species. In samples from natural outbreaks of the disease viral haemorrhagic septicaemia (VHS) at two freshwater farms in southern Denmark serologic testing was used to broaden the diagnostic window from outbreak to diagnosis in the laboratory as compared to traditional procedures of isolation and identification of the virus. The serologic assay clearly increased the chance of detecting present or previous infections where the pathogen could not be isolated by standard methods (indicating older infections where the virus had been cleared). Our data allowed us to monitor the levels of neutralising antibodies in relation to the presence of the virus in fish experiencing two different types of outbreaks at two different farms. By sequence analysis of the viral glycoprotein from selected isolates we found no evidence for escape mutants having developed in the fish showing high titres of neutralising antibodies. PMID- 22233688 TI - Re: "cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: multi-institutional phase II trial." - Proposal of a clinical trial of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced ovarian cancer, the CHORINE study. PMID- 22233689 TI - Risk assessment and clinical impact of liquid-based cytology, oncogenic human papillomavirus (HPV) DNA and mRNA testing in primary cervical cancer screening (the FASE study). AB - OBJECTIVE: New commercial HPV RNA assays require further validation studies in population-based cervical cancer screening settings. To assess the performance of (FDA-approved) APTIMA(r) HPV Assay (AHPV), Hybrid Capture 2 (HC2), in-house PCR genotyping, and ThinPrep LBC in population-based screening, stratified by three histological gold standards. STUDY DESIGN: A multi-center trial in 5006 women undergoing routine screening in France was designed to compare the absolute and relative risks of diagnosing CIN3+ and CIN2+ lesions by different diagnostic tests. RESULTS: Reproducibility between the primary and second pathology reading was excellent for CIN3+ and CIN2+ endpoints (Cohen's kappa 0.948 and 0.854). Absolute risks (PPV) of different tests (AHPV, HC2, PCR genotyping, LBC) in diagnosing CIN2+ (15-20%) and CIN3+ (4-6%) were similar for the first, second, and consensus pathology readings. The relative risks of diagnosing these lesions by the four tests were also similar when the first, second or third pathology readings were employed. AHPV had the highest absolute risk of both histological endpoints, and detects 5% to 15% more CIN3+ and CIN2+ lesions, respectively, than LBC. Compared with HC2 assay, the relative risk of AHPV is 24% to 29% higher, with a significant difference in CIN2+ detection. With LBC as reference, AHPV had the best sensitivity/specificity balance measured by AUC (area under ROC curve) comparison test (significant for CIN2+), and the colposcopy referral rate (9.2%) comparable to that of LBC (8.7%). CONCLUSIONS: These data corroborate the suitability of AHPV for the primary cervical cancer screening. PMID- 22233690 TI - Outcome of investigations for postmenopausal vaginal bleeding in women under the age of 50 years. AB - OBJECTIVE: The objective of this study is to determine the incidence of endometrial cancer in young postmenopausal women presenting with vaginal bleeding. METHODS: Cross-sectional study of postmenopausal women presenting with vaginal bleeding in a gynaecological oncology centre in the United Kingdom. All women underwent transvaginal ultrasound scanning (TVS) as the initial investigation tool to evaluate the endometrium. Endometrial biopsy was performed only in cases where endometrial thickness measured equal to or greater than 5mm. The patients were divided into two groups based on their age: less than 50 years (Group A) and 50 years or older (Group B). RESULTS: Over a 57-month period, 4454 women were investigated for postmenopausal vaginal bleeding. Of these, 259 (5.8%) women were diagnosed with endometrial carcinoma. 260 (5.8%) women were younger than 50 years. Endometrial biopsy was not performed in 130 women in Group A that had an endometrial thickness measurement of less than 5mm on ultrasonography. With a median follow-up period of 3 (1-5) years, we found no cases of endometrial cancer in women under the age of 50 that did not undergo endometrial biopsy at the time of initial evaluation. Overall, no cases of endometrial cancer were diagnosed in postmenopausal women under the age of 50 years. CONCLUSIONS: We found no cases of endometrial cancer amongst 260 women presenting with postmenopausal vaginal bleeding under the age of 50 years. These women could be investigated on a less urgent basis depending on the available resources. PMID- 22233692 TI - An evaluation of EU legislation concerning risk assessment and preventive measures in occupational safety and health. AB - The European Council Directive 89/391/EC of 12 June 1989 is concerned with the introduction of measures to encourage improvements in the occupational safety and health. For example, it deals with risk assessment and preventive measures. The Finnish legislation enacts the risk assessment and prevention measures in a similar way as the EU Directive 89/391/EC. The aim of this study was to examine: 1) the implementation of risk assessment process as a part of OSH management, and 2) the effectiveness of the OSH legislation concerned with risk assessment. The quantitative method involved an online questionnaire. The respondents were employers (N = 1478), workers (N = 1416) and occupational care (OHC) professionals' units (N = 469). Three quarters of the employer respondents and two thirds of the workers and OHC service providers felt that the EU legislative provisions have promoted the engagement of the management. According to the study, improvement is needed in ensuring the cooperation between employers and workers. The combined variables of Risk Assessment Process revealed positive impacts both on Cooperation and Management Measures and on the Concrete Preventive Measures among the employers and the workers. The combined variables of Use of Documents of Risk Assessments highlighted positive impacts on both the Exploiting of Results of Risk Assessments in Planning and Management and on the Exploiting of Results of Risk Assessment in Cooperation and Technology. PMID- 22233691 TI - A region-based palliative care intervention trial using the mixed-method approach: Japan OPTIM study. AB - BACKGROUND: Disseminating palliative care is a critical task throughout the world. Several outcome studies explored the effects of regional palliative care programs on a variety of end-points, and some qualitative studies investigated the process of developing community palliative care networks. These studies provide important insights into the potential benefits of regional palliative care programs, but the clinical implications are still limited, because: 1) many interventions included fundamental changes in the structure of the health care system, and, thus, the results would not be applicable for many regions where structural changes are difficult or unfeasible; 2) patient-oriented outcomes were not measured or explored only in a small number of populations, and interpretation of the results from a patient's view is difficult; and 3) no studies adopted a mixed-method approach using both quantitative and qualitative methodologies to interpret the complex phenomenon from multidimensional perspectives. METHODS/DESIGNS: This is a mixed-method regional intervention trial, consisting of a pre-post outcome study and qualitative process studies. The primary aim of the pre-post outcome study is to evaluate the change in the number of home deaths, use of specialized palliative care services, patient reported quality of palliative care, and family-reported quality of palliative care after regional palliative care intervention. The secondary aim is to explore the changes in a variety of outcomes, including patients' quality of life, pain intensity, family care burden, and physicians' and nurses' knowledge, difficulties, and self-perceived practice. Outcome measurements used in this study include the Care Evaluation Scale, Good Death Inventory, Brief pain Inventory, Caregiving Consequence Inventory, Sense of Security Scale, Palliative Care Knowledge test, Palliative Care Difficulties Scale, and Palliative Care Self reported Practice Scale. Study populations are a nearly representative sample of advanced cancer patients, bereaved family members, physicians, and nurses in the region.Qualitative process studies consist of 3 studies with each aim: 1) to describe the process in developing regional palliative care in each local context, 2) to understand how and why the regional palliative care program led to changes in the region and to propose a model for shaping regional palliative care, and 3) to systemically collect the barriers of palliative care at a regional level and potential resolutions. The study methodology is a case descriptive study, a grounded theory approach based on interviews, and a content analysis based on systemically collected data, respectively. DISCUSSION: This study is, to our knowledge, one of the most comprehensive evaluations of a region based palliative care intervention program. This study has 3 unique aspects: 1) it measures a wide range of outcomes, including quality of care and quality of life measures specifically designed for palliative care populations, whether patients died where they actually preferred, the changes in physicians and nurses at a regional level; 2) adopts qualitative studies along with quantitative evaluations; and 3) the intervention is without a fundamental change in health care systems. A comprehensive understanding of the findings in this study will contribute to a deeper insight into how to develop community palliative care. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR), Japan, UMIN000001274. PMID- 22233693 TI - Has there been a change in the natural history of Crohn's disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009. AB - OBJECTIVES: Medical therapy for Crohn's disease (CD) has changed significantly over the past 20 years with increasing use of immunosuppressives. In contrast, surgery rates are still high and there is little evidence that disease outcomes for CD have changed over the past decades. The objective of this study was to analyze the evolution of the surgical rates and medical therapy in the population based Veszprem province database. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 31.5 years, s.d. 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. The study population was divided into three groups by the year of diagnosis (cohort A: 1977 1989, cohort B: 1990-1998 and cohort C: 1999-2008). RESULTS: Overall, azathioprine (AZA), systemic steroid, and biological (only available after 1998) exposure was 45.8, 68.6, and 9.5%, respectively. The 1- and 5-year probability of AZA use were 3.2 and 6.2% in cohort A, 11.4 and 29.9% in cohort B, and 34.8 and 46.2% in cohort C. In a multivariate Cox-regression analysis, decade of diagnosis (P < 0.001, hazard ratio (HR)(cohorts B-C): 2.88-6.53), age at onset (P = 0.008, HR: 1.76), disease behavior at diagnosis (P < 0.001, HR(complicated): 1.76-2.07), and need for systemic steroids (P < 0.001, HR: 2.71) were significantly associated with the time to initiation of AZA therapy. Early AZA use was significantly associated with the time to intestinal surgery in CD patients; in a multivariate Cox analysis (HR: 0.43, 95% confidence interval (CI): 0.28-0.65) and after matching on propensity scores for AZA use (HR: 0.42, 95% CI: 0.26-0.67). CONCLUSIONS: This population-based inception cohort has shown that the recent reduction in surgical rates was independently associated with increased and earlier AZA use. PMID- 22233694 TI - Altered levels of fecal chromogranins and secretogranins in IBS: relevance for pathophysiology and symptoms? AB - OBJECTIVES: Chromogranins (Cg) and secretogranins (Sg) are proteins ubiquitous in secretory cells of the enteric, endocrine, and immune systems, and may reflect activity of these systems. We therefore performed a hypothesis generating study to evaluate the association between fecal levels of CgA, CgB, SgII, and SgIII, with the clinical and pathophysiological phenotype of irritable bowel syndrome (IBS) patients. METHODS: Analyses of CgA, CgB, SgII, SgIII, and calprotectin in fecal samples of 82 IBS patients and 29 healthy controls were performed. All IBS subjects completed validated questionnaires to assess gastrointestinal and psychological symptom severity, and underwent rectal barostat test and colonic transit time measurement. RESULTS: IBS patients demonstrated higher levels of fecal CgA (P=0.009), SgII (P<0.001), and SgIII (P<0.001), but lower levels of CgB (P<0.001) compared with controls. SgII had good discriminative validity to positively identify IBS patients, with an area under the receiver operating characteristics (ROC) curve (AUROC) of 0.86 (95% confidence interval (CI): 0.78 0.94). SgIII and CgB both had fairly good discriminative validity to positively identify IBS patients, with an AUROC of 0.79 (95% CI: 0.71-0.87) and 0.78 (95% CI: 0.69-0.87), respectively. There were negative correlations between the colonic transit time and fecal levels of CgA (r=-0.53, P<0.001), SgII (r=-0.55, P<0.001), and SgIII (r=-0.28, P=0.03). Perceived abdominal pain was moderately associated with levels of CgA (r=0.32, P=0.004), SgII (r=0.31, P=0.006), and SgIII (r=0.24, P=0.04). Calprotectin levels were not associated with the levels of granins or with the clinical or pathophysiological phenotype of IBS patients. CONCLUSIONS: Fecal levels of Cg and Sg may be related to the underlying pathophysiology of IBS and of potential importance for symptoms of the patients. Granins also show promise to serve as future biomarkers of IBS. Further studies are needed to explore the potential role of granins in IBS patients. PMID- 22233695 TI - Detection of lesions during capsule endoscopy: physician performance is disappointing. AB - OBJECTIVES: Limited data guide capsule endoscopists on how to view the many images collected in each capsule. The objective of this study was to compare the detection rates of clinically significant findings in different capsule endoscopy reading modes and speeds. METHODS: Seventeen capsule endoscopists with experience from 23 to > 1,000 total capsule procedures read 24 clips, 18 of which were abnormal. Clips were read in two different reading modes utilizing two speeds, including SingleView at 15 at frames per second (f.p.s.), SingleView 25 f.p.s., QuadView 20 f.p.s., and QuadView 30 f.p.s. The main outcome measurements were pathology detection rates correlated with reading mode, lesion type, reader experience, and timing order. RESULTS: SingleView 15, QuadView 20, and QuadView 30 had no significant difference in overall detection rate (45, 47, and 43%, respectively). SingleView 25 had a 26% detection rate, which was significantly lower than SingleView 15 (P = 0.04) and QuadView 20 (P = 0.002). The detection rates of angioectasias, ulcers/erosions, masses/polyps, and blood were 69, 38, 46, and 17%, respectively. Reader experience and timing of interpretation did not significantly impact detection rate. LIMITATIONS: Pathology was present on a few frames. Limited modes and speeds were assessed. Lesion types were not confirmed with surgical or deep enteroscopic methods. A relatively small number of readers provided interpretations. CONCLUSIONS: Overall, the detection rates in this study are lower than previously reported and not influenced by increasing experience. Detection rates are significantly higher when reading in SingleView 15 and QuadView 20 compared with reading in SingleView 25. Increasing viewing speed from QuadView 20 to QuadView 30 appears to have no significant effect on detection. Quality control measures to compare and improve lesion detection rates need further study. PMID- 22233696 TI - A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma. AB - OBJECTIVES: Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic diagnosis is often difficult. Our aim was to clarify which endoscopic findings are specific to SSAs. METHODS: The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing. RESULTS: Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns. CONCLUSIONS: Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance. PMID- 22233698 TI - Obtained effect size as a function of sample size in approved antidepressants: a real-world illustration in support of better trial design. AB - The high failure rate of antidepressant trials has spurred exploration of the factors that affect trial sensitivity. In the current analysis, Food and Drug Administration antidepressant drug registration trial data compiled by Turner et al. is extended to include the most recently approved antidepressants. The expanded dataset is examined to further establish the likely population effect size (ES) for monoaminergic antidepressants and to demonstrate the relationship between observed ES and sample size in trials on compounds with proven efficacy. Results indicate that the overall underlying ES for antidepressants is approximately 0.30, and that the variability in observed ES across trials is related to the sample size of the trial. The current data provide a unique real world illustration of an often underappreciated statistical truism: that small N trials are more likely to mislead than to inform, and that by aligning sample size to the population ES, risks of both erroneously high and low effects are minimized. The results in the current study make this abstract concept concrete and will help drug developers arrive at informed gate decisions with greater confidence and fewer risks, improving the odds of success for future antidepressant trials. PMID- 22233697 TI - Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. AB - This randomized, parallel-group, open study investigated the efficacy and safety of risperidone oral solution (RIS-OS) in combination with clonazepam and intramuscular haloperidol for the treatment of acute agitation in patients with schizophrenia, and the study explored the possibility of decreasing the efficacy of an acute 6-week treatment by switching intramuscular haloperidol injection to RIS-OS. Two hundred and five agitation-exhibiting schizophrenic inpatients at six hospitals were originally included in the study. The 47-day trial consisted of 5 days (session I) of receiving either oral treatment (RIS-OS plus clonazepam) or intramuscular treatment (intramuscular haloperidol) and a 42-day (session II) period of either withdrawing from clonazepam or shifting from intramuscular haloperidol to a RIS-OS period. The primary efficacy outcome was measured as the change in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) in session I and the change in the PANSS in session II. Safety was assessed by the frequency of the adverse events. Mean PANSS-EC improvement was significant after 5 days of treatment in both groups (P>0.05) and was similar between the two treatment groups (P<0.01). Most patients' PANSS-EC scores improved or remained stable during the drawback/shift treatment period. Efficacy was not significantly different between the two treatment groups after the 6-week treatment (P>0.05). However, combination treatment exhibited greater efficacy, and adverse events, especially extrapyramidal symptoms, were lower with the oral treatment than with the intramuscular treatment in session I. These results show that RIS-OS in combination with clonazepam is an effective treatment, comparable with intramuscular haloperidol, and is well-tolerated for acute agitation in patients with schizophrenia. PMID- 22233699 TI - The First Congress of the International Academy of Digital Pathology: digital pathology comes of age. PMID- 22233700 TI - The challenges of implementing a "patient-oriented" telepathology network; the Eastern Quebec telepathology project experience. AB - BACKGROUND: The aim of the Eastern Quebec telepathology project is to provide uniform diagnostic telepathology services across a huge geographic region with a low population density. This project is intended to provide surgeons and pathologists with frozen section and second opinion services anywhere and at any time across the entire region in order to avoid unnecessary patient transfer. METHODS: The project has been implemented in 21 sites, each equipped with a whole slide scanner, a macroscopy station, two videoconferencing devices and a viewer/case management and collaboration solution. Of the 21 sites, 6 are devoid of a pathology laboratory. Of the remaining 15 sites, two have no pathologists, 6 have one and 7 have two or more. RESULTS: The project has been successful and most appreciated by pathologists and surgeons. We report a number of challenges related to change management that we had to take into account in the course of implementation of this network. The challenges underscore the need for regular visits and active support to participating centers by the project team. CONCLUSION: The Eastern Quebec telepathology network is successful and improves medical care in this region. In the course of implementation, we encountered a number of challenges which required innovative solutions. PMID- 22233701 TI - Static digital telepathology: a model for diagnostic and educational support to pathologists in the developing world. AB - BACKGROUND: The practice of pathology in the developing world presents challenges in terms of limited resources, shortages of trained personnel, and lack of continuing education programs. Telepathology holds promise as a means of diagnostic and educational support. METHODS: We donated multiheaded teaching microscopes equipped with digital cameras to four hospitals in Eastern Africa and trained local pathologists on their use. Static images of challenging cases were posted on a web-based telepathology platform. A U.S.-based pathologist reviewed images in consultation with subspecialist colleagues. RESULTS: Over a period of 40 months, 109 cases were submitted for second opinion consultation, including 29 dermatopathology cases (26.6%), 14 hematopathology cases (12.8%), and 13 cases each (11.9%) in cytopathology and bone and soft tissue pathology. Static images enabled a complete or partial diagnosis in 100/109 cases (91.7%). Factors precluding a definitive diagnosis included absence of confirmatory immunophenotyping, technical issues, or lack of clinical history. Case responses included a diagnosis and discussion, including differential diagnosis, references, and treatment recommendations. CONCLUSION: Static digital telepathology is a simple, cost-effective, reliable and efficient means to provide diagnostic and educational support to pathologists in the developing world. Additional training may help overcome technical factors precluding a definitive diagnosis in certain cases. PMID- 22233702 TI - Digital pathology - implementation challenges in low-resource countries. AB - BACKGROUND: Medical education in pathology and histology in low-resource countries face many obstacles because of equipment cost and telecommunication deficiencies. Digital Pathology may provide solutions. We report student experience to virtual slides on a local network and a remote image server. METHODS: Using an iPad tablet device, fifty 3rd and 4th year medical students viewed digital pathology slides from a Web server at the National Library of Medicine and a mirror server on the local network. RESULTS: The quality of images from both servers was found to be satisfactory, but the local server was deemed faster and preferred by the participants in this study (p < 0.005). CONCLUSIONS: Virtual slides on a local network server may provide solutions to equipment and technical obstacles and could enhance student learning in developing countries. PMID- 22233703 TI - Differential response of lens crystallins and corneal crystallins in degenerative corneas. AB - Corneal degenerations, occurring either spontaneously or as a complication to other diseases, cause vision problems by endangering corneal transparency. Our past cornea research projects involving mice revealed that some recruited mice presented corneal problems similar to human corneal degeneration. The present study examines the histology of diseased mice corneas, including ultrastructure. Genome-wide microarray and proteomic methods were utilized to screen for molecular changes in the diseased corneas. It was found that abnormalities affected mainly anterior layers of the corneas. The most often observed histological abnormalities included neoplasm or detachment of the epithelial layer, erosion or breakage of Bowman membranes, blood vessel formation, and bleeding in the stroma. Microarray assay showed that among the 46 up-regulated probes in diseased corneas, 13 were for lens crystallins. However, all corneal crystallins genes remained unchanged. alphaA-crystallin was among the proteins that showed the greatest increase in diseased corneas, as detected by gel electrophoresis. We propose that lens crystallins, rather than corneal crystallins, are involved in the pathological process of corneal degeneration. Further study along these lines would provide insight into the mechanism of corneal transparency. PMID- 22233710 TI - Responsive PET nano/microfibers via surface-initiated polymerization. AB - Poly(ethylene terephthalate) (PET) is one of the most important thermoplastics in ubiquitous use today because of its mechanical properties, clarity, solvent resistance, and recyclability. In this work, we functionalize the surface of electrospun PET microfibers by growing poly(N-isopropylacrylamide) (PNIPAAm) brushes through a chemical sequence that avoids PET degradation to generate thermoresponsive microfibers that remain mechanically robust. Amidation of deposited 3-aminopropyltriethoxysilane, followed by hydrolysis, yields silanol groups that permit surface attachment of initiator molecules, which can be used to grow PNIPAAm via "grafting from" atom-transfer radical polymerization. Spectroscopic analyses performed after each step confirm the expected reaction and the ultimate growth of PNIPAAm brushes. Water contact-angle measurements conducted at temperatures below and above the lower critical solution temperature of PNIPAAm, coupled with adsorption of Au nanoparticles from aqueous suspension, demonstrate that the brushes retain their reversible thermoresponsive nature, thereby making PNIPAAm-functionalized PET microfibers suitable for filtration media, tissue scaffolds, delivery vehicles, and sensors requiring robust microfibers. PMID- 22233711 TI - Preferential nucleosome occupancy at high values of DNA helical rise. AB - Nucleosomes are the basic structural units of eukaryotic chromatin and play a key role in the regulation of gene expression. Nucleosome formation depends on several factors, including properties of the sequence itself, but also physical constraints and epigenetic factors such as chromatin-remodelling enzymes. In this view, a sequence-dependent approach is able to capture a general tendency of a region to bind a histone octamer. A reference data set of positioned nucleosomes of Saccharomyces cerevisiae was used to study the role of DNA helical rise in histone-DNA interaction. Genomic sequences were transformed into arrays of helical rise values by a tetranucleotide code and then turned into profiles of mean helical rise values. These profiles resemble maps of nucleosome occupancy, suggesting that intrinsic histone-DNA interactions are linked to helical rise. The obtained results show that preferential nucleosome occupancy occurs where the mean helical rise reaches its largest values. Mean helical rise profiles obtained by using maps of positioned nucleosomes of the Drosophila melanogaster and Plasmodium falciparum genomes, as well as Homo sapiens chromosome 20 confirm that nucleosomes are mainly located where the mean helical rise reaches its largest values. PMID- 22233713 TI - Use of twin dorsal middle phalangeal finger flaps for thumb or index finger reconstruction. AB - Amputation or degloving injuries of the thumb or index finger are highly disabling. We describe the use of twin dorsal middle finger flaps harvested from the dorsal aspects of the middle and ring fingers, and based on one palmar proper digital artery, its venae comitantes, and the dorsal branches of the palmar digital nerves of the middle and ring fingers, respectively. These flaps offer advantages when large soft tissue defects of the thumb or index finger are present. In this study, twin dorsal middle finger flaps were used in nine patients (six thumbs, three index fingers). All flaps completely survived. At the mean follow-up of 20 months, the appearance of the reconstructed thumbs or index fingers was acceptable, the length was maintained, and the mean static 2-point discrimination values were 10 mm in the palmar flap and 13 mm in the dorsal flap of the reconstructed digit. All patients were satisfied with the appearance and mobility of the donor fingers. All but one donor finger showed normal finger pulp sensibility, with a static 2-point discrimination between 3 and 6 mm. PMID- 22233712 TI - Health-related knowledge and preferences in low socio-economic kindergarteners. AB - OBJECTIVE: The aim of the present study was to determine physical activity (PA) and nutrition knowledge and preferences in low socio-economic status kindergarten children. METHODS: Following height and weight measurement, 795 low socio economic status kindergarten children (age 3.8-6.8 y.o) completed a photo-pair knowledge and preferences food and exercise questionnaire. RESULTS: No difference was found between nutrition and PA knowledge scores (52.3 +/- 0.9 versus 52.6 +/- 0.8%, respectively). There was no difference between the nutrition knowledge and preference score (52.3 +/- 0.9 versus 50.9 +/- 0.9%, respectively). PA preference was significantly higher than knowledge (56.9 +/- 1.5 versus 52.6 +/- 0.8%, respectively; p < 0.0001). Significant correlations were found between nutrition knowledge and preferences (r = 0.55, p < 0.0001), physical activity knowledge and preferences (r = 0.46, p < 0.0001), and nutrition and PA preferences (r = 0.46, p < 0.001). Nutrition preference scores were significantly lower in overweight compared to normal weight kindergartners 48.1 +/- 1.7 versus 52.0 +/- 1.0%; p < 0.05). PA knowledge and preference scores were significantly higher among male compared to the female kindergartners (p < 0.001 for both). CONCLUSION: Our data demonstrate diversities in physical activity and nutrition knowledge and preferences among low socio-economic status kindergarten children. These findings may be important for the development of health promotion programs in low socioeconomic kindergarten children. PMID- 22233714 TI - Risk factors for methicillin-resistant staphylococcal vascular graft infection in an 11-year cohort study. PMID- 22233715 TI - [Review articles in Ugeskrift for Laeger and Danish Medical Bulletin]. PMID- 22233716 TI - [Diphosphonate treatment of osteoporosis and risk of atypical femoral fractures]. PMID- 22233717 TI - [Atypical femur fracture in a patient not treated with bisphosphonate]. AB - The present case describes an atypical femur fracture in a patient, who had not previously been treated with bisphosphonate. The patient fulfilled the specific characteristics for an atypical fracture that have recently been suggested by an international expert group. For 15 years after her menopause the patient had been treated with oestrogen. Prospective studies to determine the frequency and pathogenesis of these fractures in patients treated with bisphosphonate and in bisphosphonate naive patients are suggested. PMID- 22233718 TI - [Treatment with bisphosphonates as a possible cause of bilateral spontaneous atypical femoral fracture]. AB - In recent years, case reports have suggested an association between long-term bisphosphonate treatment and spontaneous atypical femoral fractures. We present a case with a 67 year-old female who was treated with bisphosphonate for eight years and within one year sustained bilateral spontaneous atypical femoral fractures preceded by uncharacteristic hip/thigh pain. X-ray of proximal femur is indicated in patients with long-term bisphosphonate use and non-traumatic hip/thigh pain. PMID- 22233719 TI - [The effect of zinc therapy on common cold--a survey of a Cochrane review]. AB - The Cochrane review "Zinc and the common cold" included 15 randomized controlled double-blind trials. It was concluded, that zinc would shorten the duration of the episode of common cold and also could be used as a prevention so that the risk of developing an episode of common cold would be decreased. It is too early to give general recommendations for the use of zinc as we do not have sufficient knowledge about the optimal dose, formulation and duration of treatment. Further research should focus on the effect of zinc in patients who are at increased risk of developing complications after common cold. PMID- 22233720 TI - [Use of complementary and alternative medicine at Danish rehabilitation institutions and drug centres]. AB - The study has investigated the use of complementary and alternative medicine (CAM) at Danish rehabilitation institutions and drug centres. Questionnaires were sent to 147 centre leaders at 52 rehabilitation institutions and 95 drug centres. CAM is offered at 37.5% of the rehabilitation institutions and at 61.1% of the drug centres. Twenty-one different CAM modalities were used. Acupuncture and NADA acupuncture had the highest prevalence. Motives for offering CAM were most often experienced effects within the institution and inspiration from other institutions. PMID- 22233721 TI - [Postural kyphosis and morbus Scheuermann]. AB - Scheuermann's kyphosis is the most frequent structural kyphosis in adolescents. There are gaps in the knowledge of epidemiology, aetiology and treatment. There are strong genetic and mechanical factors in the aetiology. Treatment options depend on the cobb's angle measured and the skeletal maturity. Training and brace treatment yield good results for milder curves, while surgical correction is the most effective for severe curves > 70 degrees . Indications for surgery are subject of debate as complications are not uncommon. PMID- 22233722 TI - [Tranexamic acid reduces blood loss after major elective orthopaedic operations]. AB - Anaemia in surgical patients has been proven to increase morbidity and mortality. Due to the risk of adverse effects and the cost of blood transfusions it is important to reduce the need for transfusions by pre- and intra-operative interventions. Tranexamic acid has long been used in orthopaedic surgery as an antifibrinolytic agent. Several studies within the orthopaedic fields have underlined the effect of the drug in reducing blood loss and need for transfusions. However, more studies are needed to examine the optimal dosage and administration along with the risks associated with the drug. PMID- 22233723 TI - [Epistaxis]. AB - Epistaxis is a common clinical condition that can be challenging. Anterior epistaxis is managed by compression, cauterization or diathermy. Merocel and Rapid Rhino nasal packs are often successfully used. Refractory posterior epistaxis should be handled by otorhinolaryngologists. If conservative strategies such as combined anterior and posterior nasal packing fail the patient should be referred to surgical intervention. The evidence for early endoscopic ligation and/or diathermy of the sphenopalatine or etmoidal anterior arteries is significant, and the patients experience less co-morbidity. PMID- 22233724 TI - [Peritoneal tuberculosis in a patient with suspected disseminated ovarian cancer]. AB - We present a case study of a 43 year-old female immigrant from Turkey with abdominal pain, ascites and elevated cancer antigen 125. The symptoms were similar to those of ovarian cancer, and imaging (computed tomography (CT), positron emission tomography/computed tomography and magnetic resonance imaging) supported this suspicion. Peritoneal biopsy from laparoscopy showed granulomas with central necrosis. Microscopy, culture and polymerase chain reaction from biopsy samples were negative for Mycobacterium tuberculosis. Follow-up with a CT scan after six months of full tuberculosis treatment showed normal conditions. Peritoneal tuberculosis is a diagnostic challenge, but should be considered in case of immigrants from high-risk areas. PMID- 22233725 TI - Neuroimmunology: Interferon-gamma tunes the rhythm. PMID- 22233727 TI - Probucol and atorvastatin in combination protect rat brains in MCAO model: upregulating Peroxiredoxin2, Foxo3a and Nrf2 expression. AB - Inflammation and oxidative stress play an important role in cerebral ischemic pathogenesis. It has been well established that atorvastatin and probucol could elicit a variety of biological effects through its anti-inflammatory and anti oxidant properties respectively. This study was to examine whether probucol and atorvastatin in combination had the enhanced protective effect against cerebral ischemia. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). Experiment 1 was used to evaluate the time course expression of Peroxiredoxin2 (Prx2) and Foxo3a after cerebral ischemia. Experiment 2 was used to detect neuroprotective effect of atorvastatin and probucol in cerebral ischemia. At 24h or 72h, neurologic deficit, brain water content and infarct size were measured. Immunohistochemistry, RT-PCR, Western blot and confocal microscope were used to analyze the expressions of Prx2, Foxo3a and nuclear factor erythroid 2-related factor 2 (Nrf2). Compared with the normal control group, the expressions of Prx2 and Foxo3a were down-regulated in ischemic brain. Compared with the use of probucol or atorvastatin alone, the combined treatment dramatically reduced the brain water content and the infarct volume (P<0.05). Meanwhile, the decrease of Prx2, Foxo3a and Nrf2 was significantly alleviated in combined treatment group. Probucol combined with atorvastatin can get the augmented neuroprotection from the damage caused by MCAO, this effect may be through up-regulation of Prx2, Foxo3a and Nrf2. PMID- 22233728 TI - Double jeopardy--drug and sex risks among Russian women who inject drugs: initial feasibility and efficacy results of a small randomized controlled trial. AB - BACKGROUND: With HIV prevalence estimated at 20% among female injecting drug users (IDUs) in St. Petersburg, Russia, there is a critical need to address the HIV risks of this at-risk population. This study characterized HIV risks associated with injecting drug use and sex behaviors and assessed the initial feasibility and efficacy of an adapted Woman-Focused intervention, the Women's CoOp, relative to a Nutrition control to reduce HIV risk behaviors among female IDUs in an inpatient detoxification drug treatment setting. METHOD: Women (N = 100) were randomized into one of two one-hour long intervention conditions--the Woman-Focused intervention (n = 51) or a time and attention-matched Nutrition control condition (n = 49). RESULTS: The results showed that 57% of the participants had been told that they were HIV-positive. At 3-month follow-up, both groups showed reduced levels of injecting frequency. However, participants in the Woman-Focused intervention reported, on average, a lower frequency of partner impairment at last sex act and a lower average number of unprotected vaginal sex acts with their main sex partner than the Nutrition condition. CONCLUSION: The findings suggest that improvements in sexual risk reduction are possible for these at-risk women and that more comprehensive treatment is needed to address HIV and drug risks in this vulnerable population. PMID- 22233729 TI - Outcome of one hundred and forty-nine consecutive breast biopsies in Ibadan, Nigeria. AB - OBJECTIVE: To study the outcomes of one hundred and forty nine consecutive breast biopsies in both male and female patients in one arm of the general surgery division of the department of surgery, university college hospital Ibadan. METHODOLOGY: A retrospective study of the case files and histopathology reports of 149 patients who had biopsies of the breast from May 1996 to September 2004. RESULTS: The study showed that below the age of 30 years, there was no malignancy detected in 85 breast biopsies, however as the age increased it was seen that less than one out of four biopsies were malignant when the patients were aged between 31 and 40 years, rising to one out of four biopsies for the 41-50 and 51 60 age-groups. The 61-70 yielded roughly one out of three whilst two out of three breast biopsies were malignant in the 71-80 age-groups. CONCLUSIONS: Majority of breast lumps are benign and women have a probability of one chance in 10 that their biopsies may be malignant. However under 30 years this is unlikely. Above the age of 40 years the chance of malignancy rises to a one in four which will strongly support screening methods for women above 40 years. For record purposes, fibroadenoma is still the most common breast lesion in women under 30 years and invasive ductal carcinoma is the most common histopathological type of breast cancer in Ibadan, Nigeria. PMID- 22233726 TI - Spectral fingerprints of large-scale neuronal interactions. AB - Cognition results from interactions among functionally specialized but widely distributed brain regions; however, neuroscience has so far largely focused on characterizing the function of individual brain regions and neurons therein. Here we discuss recent studies that have instead investigated the interactions between brain regions during cognitive processes by assessing correlations between neuronal oscillations in different regions of the primate cerebral cortex. These studies have opened a new window onto the large-scale circuit mechanisms underlying sensorimotor decision-making and top-down attention. We propose that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes. PMID- 22233730 TI - The use of a Psoroptes ovis serodiagnostic test for the analysis of a natural outbreak of sheep scab. AB - BACKGROUND: Sheep scab is a highly contagious disease of sheep caused by the ectoparasitic mite Psoroptes ovis. The disease is endemic in the UK and has significant economic impact through its effects on performance and welfare. Diagnosis of sheep scab is achieved through observation of clinical signs e.g. itching, pruritis and wool loss and ultimately through the detection of mites in skin scrapings. Early stages of infestation are often difficult to diagnose and sub-clinical animals can be a major factor in disease spread. The development of a diagnostic assay would enable farmers and veterinarians to detect disease at an early stage, reducing the risk of developing clinical disease and limiting spread. METHODS: Serum samples were obtained from an outbreak of sheep scab within an experimental flock (n = 480 (3 samples each from 160 sheep)) allowing the assessment, by ELISA of sheep scab specific antibody prior to infestation, mid-outbreak (combined with clinical assessment) and post-treatment. RESULTS: Analysis of pre-infestation samples demonstrated low levels of potential false positives (3.8%). Of the 27 animals with clinical or behavioural signs of disease 25 tested positive at the mid-outbreak sampling period, however, the remaining 2 sheep tested positive at the subsequent sampling period. Clinical assessment revealed the absence of clinical or behavioural signs of disease in 132 sheep, whilst analysis of mid-outbreak samples showed that 105 of these clinically negative animals were serologically positive, representing potential sub-clinical infestations. CONCLUSIONS: This study demonstrates that this ELISA test can effectively diagnose sheep scab in a natural outbreak of disease, and more importantly, highlights its ability to detect sub-clinically infested animals. This ELISA, employing a single recombinant antigen, represents a major step forward in the diagnosis of sheep scab and may prove to be critical in any future control program. PMID- 22233731 TI - An investigation of modifying effects of metallothionein single-nucleotide polymorphisms on the association between mercury exposure and biomarker levels. AB - BACKGROUND: Recent studies have suggested that several genes that mediate mercury metabolism are polymorphic in humans. OBJECTIVE: We hypothesized that single nucleotide polymorphisms (SNPs) in metallothionein (MT) genes may underlie interindividual differences in mercury biomarker levels. We studied the potential modifying effects of MT SNPs on mercury exposure-biomarker relationships. METHODS: We measured total mercury in urine and hair samples of 515 dental professionals. We also surveyed occupational and personal exposures to dental amalgam and dietary fish consumption, from which daily methylmercury (MeHg) intake was estimated. Log-transformed urine and hair levels were modeled in multivariable linear regression separately against respective exposure surrogates, and the effect modification of 13 MT SNPs on exposure was investigated. RESULTS: The mean mercury levels in urine (1.06 MUg/L) and hair (0.51 MUg/g) were not significantly different from the U.S. general population (0.95 MUg/L and 0.47 MUg/g, respectively). The mean estimated daily MeHg intake was 0.084 MUg/kg/day (range, 0-0.98 MUg/kg/day), with 25% of study population intakes exceeding the current U.S. Environmental Protection Agency reference dose of 0.1 MUg/kg/day. Multivariate regression analysis showed that subjects with the MT1M (rs2270837) [corrected] AA genotype (n = 10) or the MT2A (rs10636) CC genotype (n = 42) had lower urinary mercury levels than did those with the MT1M or MT2A GG genotype (n = 329 and 251, respectively) after controlling for exposure and potential confounders. After controlling for MeHg intake, subjects with MT1A (rs8052394) GA and GG genotypes (n = 24) or the MT1M (rs9936741) TT genotype (n = 459) had lower hair mercury levels than did subjects with MT1A AA (n = 113) or MT1M TC and CC genotypes (n = 15), respectively. CONCLUSION: Our findings suggest that some MT genetic polymorphisms may influence mercury biomarker concentrations at levels of exposure relevant to the general population. PMID- 22233733 TI - Impact of in-scanner head motion on multiple measures of functional connectivity: relevance for studies of neurodevelopment in youth. AB - It has recently been reported (Van Dijk et al., 2011) that in-scanner head motion can have a substantial impact on MRI measurements of resting-state functional connectivity. This finding may be of particular relevance for studies of neurodevelopment in youth, confounding analyses to the extent that motion and subject age are related. Furthermore, while Van Dijk et al. demonstrated the effect of motion on seed-based connectivity analyses, it is not known how motion impacts other common measures of connectivity. Here we expand on the findings of Van Dijk et al. by examining the effect of motion on multiple types of resting state connectivity analyses in a large sample of children and adolescents (n=456). Following replication of the effect of motion on seed-based analyses, we examine the influence of motion on graphical measures of network modularity, dual regression of independent component analysis, as well as the amplitude and fractional amplitude of low frequency fluctuation. In the entire sample, subject age was highly related to motion. Using a subsample where age and motion were unrelated, we demonstrate that motion has marked effects on connectivity in every analysis examined. While subject age was associated with increased within-network connectivity even when motion was accounted for, controlling for motion substantially attenuated the strength of this relationship. The results demonstrate the pervasive influence of motion on multiple types functional connectivity analysis, and underline the importance of accounting for motion in studies of neurodevelopment. PMID- 22233734 TI - Antimalarial evaluation and docking studies of hybrid phenylthiazolyl-1,3,5 triazine derivatives: a novel and potential antifolate lead for Pf-DHFR-TS inhibition. AB - Present communication deals with the docking study of hybrid phenyl thiazolyl 1,3,5-triazine analogues (1a-36d) on three selected different binding site viz., alpha, beta and gamma of wild type Pf-DFHR-TS. In admiration of excellent H-bond scoring, with regard to cycloguanil and to a large extent similar scoring with WR99210, compound 4a, 12b, 21c, 23c, 28d, 29d, 34d, and 35d were selected for in vitro antimalarial activity against 3D7 strain of Plasmodium falciparum. Findings from the study disclose that a significant correlation was exist between in vitro results and in silico prediction (r(2)=0.543). Furthermore, investigation of structure-activity relationships elucidate crucial structural requirement for site specific binding of ligands. PMID- 22233732 TI - Positron emission tomography assessment of 8-OH-DPAT-mediated changes in an index of cerebral glucose metabolism in female marmosets. AB - As part of a larger experiment investigating serotonergic regulation of female marmoset sexual behavior, this study was designed to (1) advance methods for PET imaging of common marmoset monkey brain, (2) measure normalized FDG uptake as an index of local cerebral metabolic rates for glucose, and (3) study changes induced in this index of cerebral glucose metabolism by chronic treatment of female marmosets with a serotonin 1A receptor (5-HT(1A)) agonist. We hypothesized that chronic treatment with the 5-HT(1A) agonist 8-OH-DPAT would alter the glucose metabolism index in dorsal raphe (DR), medial prefrontal cortex (mPFC), medial preoptic area of hypothalamus (mPOA), ventromedial nucleus of hypothalamus (VMH), and field CA1 of hippocampus. Eight adult ovariectomized female common marmosets (Callithrix jacchus) were studied with and without estradiol replacement. In a crossover design, each subject was treated daily with 8-OH-DPAT (0.1mg/kg SC daily) or saline. After 42-49 days of treatment, the glucose metabolism radiotracer FDG was administered to each female immediately prior to 30 min of interaction with her male pairmate, after which the subject was anesthetized and imaged by PET. Whole brain normalized PET images were analyzed with anatomically defined regions of interest (ROI). Whole brain voxelwise mapping was also used to explore treatment effects and correlations between alterations in the glucose metabolism index and pairmate interactions. The rank order of normalized FDG uptake was VMH/mPOA>DR>mPFC/CA1 in both conditions. 8-OH DPAT did not induce alterations in the glucose metabolism index in ROIs. Voxelwise mapping showed a significant reduction in normalized FDG uptake in response to 8-OH-DPAT in a cluster in medial occipital cortex as well as a significant correlation between increased rejection of mount attempts and reduced normalized FDG uptake in an overlapping cluster. In conclusion, PET imaging has been used to measure FDG uptake relative to whole brain in marmoset monkeys. Voxelwise mapping shows that 8-OH-DPAT reduces this index of glucose metabolism in medial occipital cortex, consistent with alterations in female sexual behavior. PMID- 22233736 TI - Solution-based synthesis and low-temperature transport properties of CsBi4Te6. AB - The thermoelectric material CsBi(4)Te(6) was synthesized in nanometer thin flake like form by a low temperature solvothermal approach. The crystals were then densified by spark plasma sintering (SPS), resulting in a polycrystalline specimen with layered and partially orientated grains. The orientation of the CsBi(4)Te(6) flakes reflects the anisotropic crystal structure of the material aided by the unidirectional pressure during SPS. Hall, resistivity, Seebeck coefficient, and thermal conductivity was measured on the polycrystalline specimen in evaluating the potential of this approach for thermoelectric applications. PMID- 22233735 TI - Fibroid explants reveal a higher sensitivity against MDM2-inhibitor nutlin-3 than matching myometrium. AB - BACKGROUND: Spontaneous cessation of growth is a frequent finding in uterine fibroids. Increasing evidence suggests an important role of cellular senescence in this growth control. Deciphering the underlying mechanisms of growth control that can be expected not only to shed light on the biology of the tumors but also to identify novel therapeutic targets. METHODS: We have analyzed uterine leiomyomas and matching normal tissue for the expression of p14Arf and used explants to see if reducing the MDM2 activity using the small-molecule inhibitor nutlin-3 can induce p53 and activate genes involved in senescence and/or apoptosis. For these studies quantitative real-time RT-PCR, Western blots, and immunohistochemistry were used. Statistical analyses were performed using the student's t test. RESULTS: An in depth analysis of 52 fibroids along with matching myometrium from 31 patients revealed in almost all cases a higher expression of p14Arf in the tumors than in the matching normal tissue. In tissue explants, treatment with the MDM2 inhibitor nutlin-3 induced apoptosis as well as senescence as revealed by a dose-dependent increase of the expression of BAX as well as of p21, respectively. Simultaneously, the expression of the proliferation marker Ki-67 drastically decreased. Western-blot analysis identified an increase of the p53 level as the most likely reason for the increased activity of its downstream markers BAX and p21. Because as a rule fibroids express much higher levels of p14Arf, a major negative regulator of MDM2, than matching myometrium it was then analyzed if fibroids are more sensitive against nutlin-3 treatment than matching myometrium. We were able to show that in most fibroids analyzed a higher sensibility than that of matching myometrium was noted with a corresponding increase of the p53 immunopositivity of the fibroid samples compared to those from myometrium. CONCLUSIONS: The results show that uterine fibroids represent a cell population of advanced cellular age compared to matching myometrium. Moreover, the data point to members of the p53-network as to potential novel therapeutic targets for the treatment of uterine fibroids. PMID- 22233737 TI - An unusual presentation of primary cutaneous nocardiosis at a rare site: succesful treatment with a modified Welsh regimen. AB - INTRODUCTION: Primary cutaneous nocardiosis can present in various forms. Clinically, it can present as acute infection (abscess or cellulitis), mycetoma, or sporotrichoid infection. Mycetoma over the back is rare. CASE REPORT: We herein describe a case of primary cutaneous nocardiosis presenting as a mycetoma, caused by Nocardia brasiliensis. The patient had extensive lesions over the back, which can be attributed to the fact that the patient, being an agriculturist, has been exposed to recurrent trauma while carrying firewood and soiled sacks. He responded well to a modified Welsh regimen. Initially, within 2 cycles, the patient showed dramatic improvement clinically, wherein the sinuses, granulation tissue, and induration were no longer apparent. However, the patient showed a small discharging sinus at the end of 3rd pulse, so a total of 6 cycles were given. An additional 2 months of maintenance phase treatment with cotrimoxazole and rifampicin were given. On follow-up, the patient showed no recurrence at 6 months. CONCLUSION: We report a case of primary cutaneous nocardiosis presenting as a mycetoma on the back. Enlisting the help of a microbiologist allowed us to isolate the causative organism. Early recognition and prompt treatment prevents unwarranted surgical debridement and complications. PMID- 22233738 TI - Prurigo pigmentosa: report of two cases in the United States and review of the literature. AB - Prurigo pigmentosa is a rare inflammatory skin disease of unknown etiology presenting as a pruritic truncal eruption of reticulated and symmetric macules and papules with the predilection for young Japanese females. Although cases of PP are increasingly reported in the non-Japanese literature, dermatologists may be unfamiliar with this entity. Here we report a Caucasian American female and a Chinese American female with PP and a discussion of the literature. The treatments of choice for prurigo pigmentosa are tetracyclines such as doxycycline and minocycline, as well as dapsone. The prognosis is excellent. PMID- 22233739 TI - A study of HIV seropositivity with various clinical manifestation of herpes zoster among patients from Karnataka, India. AB - AIMS: To study the various clinical presentations of herpes zoster and to find out the proportion of HIV positivity in these patients. METHODS: A time bound study was conducted from November 2004 to October 2005. All clinically diagnosed cases of herpes zoster were tested for HIV infection with ELISA and confirmed by Tridot and Coomb AID. RESULTS: Total numbers of 90 zoster cases were recorded. Mean duration of pre herpetic neuralgia was 2.134 (standard deviation=1.424, F=8.951, P<0.001). The thoracic dermatome (46.66%) was most commonly involved, followed by the cranial nerves (18.88%), lumbar (14.44%), cervical (13.33%) and sacral (6.66%) nerves. A substantial proportion, 34 (37.77%) out of 90 cases, were found to be HIV positive. Of these, 64.7 percent of the HIV seropositive herpes zoster patients belonged to the age group of 21-40 years. Out of 39 who had a risk of exposure to STDs and whose ages were less than 50 years, 31 (79.48%) tested positive for HIV infection. CONCLUSION: The occurrence of zoster in the young age group in patients who report a history of risk factors for HIV, may need testing. Herpes zoster serves as a clinical indicator of HIV seropositivity and one of the earliest manifestations. PMID- 22233740 TI - Midline eccrine nevus. AB - Eccrine nevus is a rare benign solitary lesion with increased size and number of eccrine coils, ductal wall thickening, and luminal dilation, in the absence of collagen or fibroblast overgrowth. We present a 3-month-old male with a mid-line nuchal scalp lesion shaped like Mickey Mouse's head since birth that yielded a biopsy proven diagnosis of an eccrine nevus. PMID- 22233742 TI - Composite cutaneous atypical vascular lesion and Langerhans cell histiocytosis after radiation for breast carcinoma: can radiation induce Langerhans cell histiocytosis? AB - Atypical vascular lesions (AVLs) refer to small vascular proliferations in radiated skin that may progress to angiosarcoma and typically develop after breast-conserving therapy for breast carcinoma. We present a case of composite AVL and Langerhans cell histiocytosis (LCH) in a 57-year-old woman who received surgery and radiation therapy for ductal carcinoma of the breast. The patient developed AVLs 4 years after radiation. Biopsies of multiple erythematous nodules at the same site one year later revealed intermixed AVL and LCH, some of which coexisted within the same lesion. To our knowledge, LCH has not been recorded at the site of radiation in the English language literature. Our case not only highlights the importance of close cutaneous surveillance and a low threshold for biopsy in patients with breast-conserving surgery and radiation therapy, but also raises the possibility of radiation as the inducement of cutaneous LCH. PMID- 22233741 TI - Topical tacrolimus induced extensive varicella zoster infection. AB - Tacrolimus ointment 0.1 percent is a well-established topical therapy for treating atopic dermatitis. Efficacy and safety have been described in several trials. Here, we present a patient with rapid onset of extensive varicella zoster infection in tacrolimus-treated skin: a side effect that has only occasionally been reported. Early recognition is important because rapid treatment for herpes zoster may lead to less frequent post-herpetic neuralgia and serious complications. PMID- 22233743 TI - Chondroid syringoma: report of two cases in young patients. AB - Chondroid syringoma (CS) is a relatively rare cutaneous tumor arising from sweat glands. It usually presents in the head and neck area as an asymptomatic nodule. Although usually it presents in middle aged or older patients, we here present two much younger patients with CS, located over the nose and cheek areas, respectively. PMID- 22233744 TI - Pachydermodactyly, a new case from Iran. AB - Pachydermodactyly (PDD) is a rare form of benign digital fibromatosis involving the proximal portion of lateral sides of fingers. It is characterized by asymptomatic and symmetrical soft tissue swellings of the radial and ulnar aspects of proximal PIP joints of second to fifth fingers. Herein we report a 15 year-old boy with this condition. PMID- 22233745 TI - Unknown: Multiple painful nodules - what is the diagnosis? Chronic tophaceous gout. AB - Gout is a common rheumatologic condition of recurrent polyarticular involvement. Tophi may be the first sign of the disease. We report a 55-year-old hypertensive, chronic alcoholic and diabetic male with a three-year history of multiple painful skin-colored nodules on the forearms, elbows, feet, posterior thighs, and popliteal fossa associated with discharging sinuses. Serum uric acid was 8.1 mg/dL (normal: 2-7.4 mg/dL). Fine needle aspiration cytology showed monosodium urate crystals, which are pathognomonic for gout, confirmed histopathalogically. PMID- 22233746 TI - Giant cutaneous horn on the lower lip. AB - Cutaneous horn is a conical hyperkeratotic projection of the skin composed of compact keratin. A wide range of pathologic conditions may be found at its base, including a significant proportion of malignant tumors. A notable, giant cutaneous horn uncovering a keratoacanthoma/well-differentiated squamous cell carcinoma is presented, highlighting the importance of histopathological examination to rule out malignancy because clinical features cannot assure a correct diagnosis. PMID- 22233747 TI - Letter: Imported paracoccidioidomycosis in Japan. AB - A 39-year-old man from Argentina, who had come to Japan 13 years previously, had been suffering from oral pain for several months. He was biopsied twice and treated with oral predonisolone without improvement. A number of white granular lesions with erosions were observed on the hard palate and buccal mucosa. Histopathological examination revealed a well-demarcated abscess with an accumulation of neutrophils, surrounded by epithelioid cell granulomas. Round eosinophilic bodies, considered to be fungal elements, positive for PAS and Grocott staining, were observed. Chest CT revealed cavities in the lung. A white yeast-like colony was cultured from bronchial lavage fluid and Paracoccidioides brasiliensis was identified. The patient was treated with liposomal amphotericin B followed by oral itraconazole 400 mg/day, with a favorable clinical course. Paracoccidioidomycosis, an imported mycosis, is rare in Japan and sometimes causes difficulty in diagnosis, resulting in inappropriate treatment. PMID- 22233748 TI - Letter: Methotrexate for localized morphea with severe pain: a case report. AB - Morphea, also known as localized scleroderma, is characterized by idiopathic fibrosis of the skin and adjacent structures. Patients with morphea classically present with skin lesions without any associated symptoms and the lesions usually regress spontaneously over time. We describe a patient with morphea who presented with debilitating pain in her skin plaque. She failed topical therapy and required systemic methotrexate to control her disease. We titrated the methotrexate dose with the goal of pain relief. Although unusual, pain associated with morphea can be debilitating. Physicians should assess for pain in patients with morphea and prescribe treatments accordingly. We propose using pain, when present, in addition to physical examination as a guide for titrating morphea therapy. PMID- 22233749 TI - Letter: Two cases of metastases to the scalp bone mimicking epidermoid cyst. AB - Metastatic skin tumors present with a variety of clinical manifestations. We herein present two cases of metastases to the scalp, invading the skull, which showed epidermoid cyst-like appearances. PMID- 22233750 TI - Letter: Tetracycline-induced hepatotoxicity. AB - BACKGROUND: Tetracycline is a commonly used drug for rosacea and subantimicrobial doses may resolve the disease in many cases. Although this class of antibiotics has been linked to adverse effects, tetracycline is considered a safe drug. It can be associated with hepatotoxicity, but its role in these rare cases is unclear. PURPOSE: To report the case of a patient with rare tetracycline-induced hepatotoxicity. CASE PRESENTATION: A 49-year-old female with a history of multiple prednisone and methotrexate trials for relapsing polychondritis took oral tetracycline for rosacea. She developed facial and extremity swelling, weakness, and fatigue that corresponded with liver function test (LFT) abnormalities including hypoalbuminemia, low total protein, and elevated alkaline phosphatase. Tetracycline was discontinued and rapid resolution of symptoms and LFT abnormalities occurred after cessation of the drug. CONCLUSIONS: The dose dependency of rare tetracycline hepatotoxicity and the desire to reduce antibiotic resistance may prompt safe, yet effective, subantimicrobial doses for rosacea. PMID- 22233751 TI - Letter: an adult case of hand-foot-mouth disease showing severe mucous involvement. AB - Hand-foot-mouth disease is a common childhood viral infection. Generally, small vesicles and erosions occur on the hands, feet and oral mucosa. We report an unusual case of this disease that occurred in an immunocompent adult and resulted in severe erosion on the lips and mucous membranes. PMID- 22233752 TI - [Shiitake dermatitis in a Spanish patient]. AB - Shiitake dermatitis is a toxicodermia that occurs after ingestion of raw or half cooked shiitake. We present a Spanish patient who was referred to the emergency room after developing a pruritic, dermatographic, eruption that affected the trunk and neck region. The eruption occurred a few days after eating shiitake mushrooms. PMID- 22233754 TI - Targeting ASIC3 for pain, anxiety, and insulin resistance. AB - The acid-sensing ion channel 3 (ASIC3) is a pH sensor that responds to mild extracellular acidification and is predominantly expressed in nociceptors. There is much interest in targeting ASIC3 to relieve pain associated with tissue acidosis, and selective drugs targeting ASIC3 have been used to relieve acid evoked pain in animal models and human studies. There is accumulating evidence that ASIC3 is widely expressed in many neuronal and non-neuronal cells, such as neurons in the brain and adipose cells, albeit to a lesser extent than in nociceptors. Asic3-knockout mice have reduced anxiety levels and enhanced insulin sensitivity, suggesting that antagonizing ASIC3 has additional benefits. This view is tempered by recent studies suggesting that Asic3-knockout mice may experience cardiovascular disturbances. Due to the development of ASIC3 antagonists as analgesics, we review here the additional benefits, safety, risks, and strategy associated with antagonizing ASIC3 function. PMID- 22233753 TI - Integrins as receptor targets for neurological disorders. AB - This review focuses on the neurobiology of integrins, pathophysiological roles of integrins in neuroplasticity and nervous system disorders, and therapeutic implications of integrins as potential drug targets and possible delivery pathways. Neuroplasticity is a central phenomenon in many neurological conditions such as seizures, trauma, and traumatic brain injury. During the course of many brain diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such as extracellular matrix (ECM) are recognized as an essential process in forming and reorganizing neural connections. Integrins are heterodimeric transmembrane receptors that mediate cell-ECM and cell-cell adhesion events. Although the mechanisms of neuroplasticity remain unclear, it has been suggested that integrins undergo plasticity including clustering through interactions with ECM proteins, modulating ion channels, intracellular Ca(2+) and protein kinase signaling, and reorganization of cytoskeletal filaments. As cell surface receptors, integrins are central to the pathophysiology of many brain diseases, such as epilepsy, and are potential targets for the development of new drugs for neurological disorders. PMID- 22233755 TI - The N domain of Argonaute drives duplex unwinding during RISC assembly. AB - Small RNAs, such as microRNAs and small interfering RNAs, act through Argonaute (Ago) proteins as a part of RNA-induced silencing complexes (RISCs). To make RISCs, Ago proteins bind and subsequently unwind small RNA duplexes, finally leaving one strand stably incorporated. Here we identified the N domain of human AGO2 as the initiator of duplex unwinding during RISC assembly. We discovered that a functional N domain is strictly required for small RNA duplex unwinding but not for precedent duplex loading or subsequent target cleavage. We postulate that RISC assembly is tripartite, comprising (i) RISC loading, whereby Ago undergoes conformational opening and loads a small RNA duplex, forming pre-RISC; (ii) wedging, whereby the end of the duplex is pried open through active wedging by the N domain, in preparation for unwinding; and (iii) unwinding, whereby the passenger strand is removed through slicer-dependent or slicer-independent unwinding, forming mature RISC. PMID- 22233756 TI - Failure patterns and survival in patients with nasopharyngeal carcinoma treated with intensity modulated radiation in Northwest China: a pilot study. AB - PURPOSE: To evaluate the clinical outcomes and patterns of failure in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiotherapy (IMRT) in Northwest China. METHODS AND MATERIALS: From January 2006 to December 2009, 138 NPC patients were treated at Xijing Hospital. Of them, 25 cases with stage I-II received IMRT only, 113 cases with stage III-IVb received IMRT plus accomplished platinum-based chemotherapy. The IMRT prescribed dose was PTV 68-74 Gy to gross disease in nasopharynx and 66-72 Gy to positive lymph nodes in 30-33 fractions, and high risk and low risk region PTV was 60-63 Gy and 50.4~56 Gy in 30~33 and 28 fractions respectively. Plasma Epstein Barr virus (EBV) DNA load was measured before treatment. The clinical toxicities, outcomes and patterns of failure were observed. RESULTS: The median follow up time was 23 months (range 2 to 53 months). EBV infection positive was only 15.9%. Overall disease failure developed in 36 patients, 99% belonged to stage III/IV disease. Among these, there were 26 distant metastases, 6 local recurrence, and 4 regional recurrence. The 3-year local control rate(LCR), distant metastasis-free survival (MFS), disease-free survival (DFS) and the overall survival (OS) was 93.9%, 79.5%, 70% and 83.1% respectively. Multivariate analyses revealed that age and anemia pre radiotherapy were independent predictors for OS. CONCLUSION: IMRT with or without chemotherapy can improve the long term survival of NPC patients in Northwest China. Distant metastasis becomes the main cause of treatment failure. Age and anemia before radiotherapy were the main prognosis factors of NPC patients. PMID- 22233757 TI - Validation of interventional fiber optic spectroscopy with MR spectroscopy, MAS NMR spectroscopy, high-performance thin-layer chromatography, and histopathology for accurate hepatic fat quantification. AB - OBJECTIVES: To validate near-infrared (NIR)-based optical spectroscopy measurements of hepatic fat content using a minimally invasive needle-like probe with integrated optical fibers, enabling real-time feedback during percutaneous interventions. The results were compared with magnetic resonance spectroscopy (MRS) as validation and with histopathology, being the clinical gold standard. Additionally, ex vivo magic angle spinning nuclear magnetic resonance spectroscopy and high-performance thin-layer chromatography were performed for comparison. MATERIALS AND METHODS: Ten mice were used for the study, of which half received a regular chow diet and the other half received a high-fat diet to induce obesity and hepatosteatosis. The mice were imaged with a clinical 3-Tesla MR to select a region of interest within the right and left lobes of the liver, where MRS measurements were acquired in vivo. Subsequently, optical spectra were measured ex vivo at the surface of the liver at 6 different positions immediately after resection. Additionally, hepatic fat was determined by magic angle spinning nuclear magnetic resonance spectroscopy and high-performance thin-layer chromatography. Histopathologic analyses were performed and used as the reference standard. Pearson correlation and linear regression analyses were performed to assess the correlation of the various techniques with NIR. A 1-way analysis of variance including post hoc Tukey multiple comparison tests was used to study the difference in fat estimation between the various techniques. RESULTS: For both the mice groups, the estimated fat fractions by the various techniques were significantly similar (P = 0.072 and 0.627 for chow diet and high-fat diet group, respectively). The Pearson correlation value between NIR and the other techniques for fat determination showed the same strong linear correlation (P above 0.990; P < 0.001), whereas for histopathologic analyses, which is a rather qualitative measure, the Pearson correlation value was slightly lower (P = 0.925, P < 0.001) . Linear regression coefficient computed to compare NIR with the other techniques resulted in values close to unity with MRS having the narrowest confidence interval (r = 0.935, 95% confidence interval: 0.860-1.009), demonstrating highly correlating results between NIR and MRS. CONCLUSIONS: NIR spectroscopy measurements from a needle-like probe with integrated optical fibers for sensing at the tip of the needle can quickly and accurately determine hepatic fat content during an interventional procedure and might therefore be a promising novel diagnosing tool in the clinic. PMID- 22233758 TI - Effect of tumor size and tumor-to-liver contrast of hypovascular liver tumors on the diagnostic performance of hepatic CT imaging. AB - OBJECTIVE: To assess the effect of tumor size and tumor-to-liver contrast of simulated hypovascular liver tumors on the diagnostic accuracy of hepatic computed tomography (CT). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. A total of 153 simulated hypovascular liver tumors were embedded in 70 hepatic CT data sets that were acquired during the portal venous phase. The simulated tumors had 3 different diameters (6, 10, and 14 mm) and 3 different tumor-to-liver contrast values (20, 35, and 50 HU). There were also 30 hepatic CT data sets without liver tumors. Three radiologists independently performed tumor detection on the randomized 100 hepatic CT data sets. RESULTS: The lowest sensitivity was obtained for the 6-mm tumors with a tumor-to-liver contrast of 20 HU (4.1%), and the highest sensitivity was obtained for the 10- and 14-mm tumors with a tumor-to liver contrast of 50 HU (100%). Increasing the contrast from 20 to 35 to 50 HU in the 6-mm tumors yielded a significant increase in sensitivity (4.1%, 48.8%, and 92.4%, respectively; P < 0.0001). The sensitivity for the 10- and 14-mm tumors also increased significantly as the tumor-to-liver contrast value increased from 20 to 35 HU (P < 0.01). However, no significant increase in sensitivity was seen for the 10- and 14-mm tumors as the tumor-to-liver contrast values increased from 35 to 50 HU (P = 0.733 and P = 1.0, respectively). CONCLUSIONS: Increasing the tumor-to-liver contrast from 20 to 35 HU results in a significant increase in the detection of hypovascular liver tumors ranging from 6 to 14 mm in diameter. Optimization of the tumor-to-liver contrast is necessary for improved detection of hypovascular liver tumors. PMID- 22233759 TI - Development of an antibody-lectin enzyme immunoassay for fucosylated alpha fetoprotein. AB - BACKGROUND: Fucosylation is one of the most important types of glycosylations related to cancer. Our previous studies of the enzymatic basis and structural studies of alpha-fetoprotein (AFP) samples from liver cancer patients indicated that core-fucosylation by alpha1,6-fucosyltransferase (FUT8) resulted in the production of fucosylated AFP, and in fact fucosylated AFP allowed differential diagnosis in some types of liver cancer from liver cirrhosis. This served as a predictive biomarker for the development of liver cancer 3 to 18 months before it could be detected using imaging techniques. Fucosylated AFP is currently measured by means of a liquid-phase binding assay (LBA) or by an electrokinetic analyte transport assay (EATA). However, these methods require special instrumentation that is currently available only in major medical laboratories. To overcome this problem, we attempted to develop an enzyme immunoassay (EIA) based on the sandwich technique with specific antibody and lectin. RESULTS: Dilute solutions of highly fucosylated AFP in human sera were assayed using a microtiter plate coated with a periodate-oxidized anti-AFP antibody, a fucose-specific biotinylated Aleuria aurantia lectin (AAL), a peroxidase-conjugated streptoavidin, and a chemiluminescent detection system. The technique was able to measure highly fucosylated AFP diluted to 5 to 80ng/ml in human sera using the developed antibody-lectin EIA in combination with the enrichment of AFP. CONCLUSION: A simple method using an antibody-lectin EIA for quantifying fucosylated AFP that does not require special instrumentation was developed. GENERAL SIGNIFICANCE: The method can be generally applied to the quantitative measurement of various fucosylated glycoproteins using specific antibodies. This article is part of a Special Issue entitled Glycoproteomics. PMID- 22233760 TI - c-KIT receptor expression is strictly associated with the biological behaviour of thyroid nodules. AB - BACKGROUND: A large amount of information has been collected on the molecular tumorigenesis of thyroid cancer. A low expression of c-KIT gene has been reported during the transformation of normal thyroid epithelium to papillary carcinoma suggesting a possible role of the gene in the differentiation of thyroid tissue rather than in the proliferation. The initial presentation of thyroid carcinoma is through a nodule and the best way nowadays to evaluate it is by fine-needle aspiration (FNA). However many thyroid FNAs are not definitively benign or malignant, yielding an indeterminate or suspicious diagnosis which ranges from 10 to 25% of FNAs. BRAF mutational analysis is commonly used to assess the malignancy of thyroid nodules but unfortunately it still leaves indeterminate diagnoses. The development of molecular initial diagnostic tests for evaluating a thyroid nodule is needed in order to define optimal surgical approach for patients with uncertain diagnosis pre- and intra-operatively. METHODS: In this study we extracted RNA from 82 FNA smears, 46 malignant and 36 benign at the histology, in order to evaluate by quantitative Real Time PCR the expression levels of c-KIT gene. RESULTS: We have found a highly preferential decrease rather than increase in transcript of c-KIT in malignant thyroid lesions compared to the benign ones. To explore the diagnostic utility of c-KIT expression in thyroid nodules, its expression values were divided in four arbitrarily defined classes, with class I characterized by the complete silencing of the gene. Class I and IV represented the two most informative groups, with 100% of the samples found malignant or benign respectively. The molecular analysis was proven by ROC (receiver operating characteristic) analysis to be highly specific and sensitive improving the cytological diagnostic accuracy of 15%. CONCLUSION: We propose the use of BRAF test (after uncertain cytological diagnosis) to assess the malignancy of thyroid nodules at first, then the use of the c-KIT expression to ultimately assess the diagnosis of the nodules that otherwise would remain suspicious. The c KIT expression-based classification is highly accurate and may provide a tool to overcome the difficulties in today's preoperative diagnosis of thyroid suspicious malignancies. PMID- 22233761 TI - Alzheimer and vascular neuropathological changes associated with different cognitive States in a non-demented sample. AB - The state between aging with no cognitive impairment and dementia has become a major focus for intervention. The neuropathological and neurobiological correlates of this intermediate state are therefore of considerable interest, particularly from population representative samples. Here we investigate the neuropathological profile associated with different cognitive ability levels measured using strata defined by Mini Mental State Examination (MMSE) scores. One hundred and fifty one individuals were stratified into three cognitive groups including: non-, mildly, and moderately impaired at death. Alzheimer's disease, atrophy, and vascular pathologies were investigated. Mild impairment was associated with an increased risk of vascular pathologies including small vessel disease and lacunes. In contrast, the moderately impaired group showed a more extensive pattern of pathology, including tangles and neuritic plaques (entorhinal/hippocampus), atrophy (cortical and hippocampal), and vascular disease (small vessel disease, lacunes, and infarcts). In a population-based sample of older people, MMSE score defined strata are associated with multiple pathologies. The profile of AD and vascular changes becomes more complex with increased cognitive impairment and these changes are likely to constitute a major substrate for age associated cognitive impairment. The results highlight the need for rigorous investigation of both neurodegenerative and vascular risks factors in old age. PMID- 22233762 TI - Antibodies against the tom40 subunit of the translocase of the outer mitochondrial membrane complex and cognitive impairment in Alzheimer's disease. AB - Recent studies suggest that microvascular abnormalities are involved in pathology and progression of Alzheimer's disease. The purpose of this study was to examine the presence of antibodies against cerebral microvascular endothelial cells specific for Alzheimer's disease, and to evaluate the association of these antibodies with cognitive impairment. The study included patients with Alzheimer's disease (age >=60 years; 24 patients), control subjects without neurological diseases (age >=60 years; 19 subjects), patients with multiple sclerosis (all ages; 17 patients), and healthy control subjects (age <40 years; 18 subjects). Serum was analyzed with 2-dimensional electrophoresis and Western blot, with cultured human brain microvascular endothelial cells as the antigen source. The anti-Tom40 antibody was identified significantly more frequently in patients with Alzheimer's disease than control subjects or patients with multiple sclerosis. In patients with Alzheimer's disease, the mean scores for the Mini Mental State Examination were significantly lower for patients who were positive for anti-Tom40 antibody than those who were negative for anti-Tom40 antibody. In summary, the anti-Tom40 antibody is significantly associated with cognitive impairment in patients with Alzheimer's disease. PMID- 22233763 TI - Magnetic resonance imaging based clinical research in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia in elderly people in western countries. However important goals are unmet in the issue of early diagnosis and the development of new drugs for treatment. Magnetic resonance imaging (MRI) and volumetry of the medial temporal lobe structures are useful tools for diagnosis. Positron emission tomography is one of the most sensitive tests for making an early diagnosis of AD but the cost and limited availability are important caveats for its utilization. The importance of magnetic resonance techniques has increased gradually to the extent that most clinical works based on AD use these techniques as the main aid to diagnosis. However, the accuracy of structural MRI as biomarker of early AD generally reaches an accuracy of 80%, so additional biomarkers should be used to improve predictions. Other structural MRI (diffusion weighted, diffusion-tensor MRI) and functional MRI have also added interesting contribution to the understanding of the pathophysiology of AD. Magnetic resonance spectroscopy has proven useful to monitor progression and response to treatment in AD, as well as a biomarker of early AD in mild cognitive impairment. PMID- 22233764 TI - High prevalence of mild cognitive impairment and Alzheimer's disease in arabic villages in northern Israel: impact of gender and education. AB - The prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been well been studied in Arab populations. In a door-to-door study of all residents aged >= 65 years in Wadi-Ara, an Arab community in northern Israel, we estimated the prevalence of AD, MCI, and the risk of conversion to AD. Subjects were classified as cognitively normal, MCI, AD, or other based on neurological and cognitive examination (in Arabic). MCI subjects were re-examined (interval >= 1 year) to determine conversion to AD and contributions of age, gender, and education to the probability of conversion. Of the 944 participants (96.6% of those approached; 49.4% men), 92 (9.8%) had AD. An unusually high prevalence of MCI (n = 303, 32.1%) was observed. Since the majority of women (77.2%) had no schooling, we estimated the effect of gender on the risk of AD and MCI among subjects without schooling and of school years among men. Among subjects with no schooling (n = 452), age (p = 0.02) and female gender (p < 0.0001) were significant predictors of AD, whereas risk of MCI increased only with age (p = 0.0001). Among men (n = 318), age increased the risk (p < 0.0001), school years reduced the risk of AD (p = 0.039) and similarly for MCI [age (p = 0.0001); school years (p = 0.0007)]. Age (p = 0.013), but not gender or school years, was a significant predictor of conversion from MCI to AD (annual rate 5.7%). The prevalence of MCI and AD are unusually high in Wadi Ara, while the rate of conversion from MCI to AD is low. Yet unidentified genetic factors might underlie this observation. PMID- 22233765 TI - L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AbetaPP/PS1-Alzheimer's transgenic mice. AB - L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia and amyloid-beta (Abeta)-induced animal models by inhibiting oxidative injury, neuronal apoptosis and glial activation, regulating amyloid-beta protein precursor (AbetaPP) processing and reducing Abeta generation. The aim of the present study was to examine the effect of L-NBP on learning and memory in AbetaPP and presenilin 1 (PS1) double-transgenic AD mouse model (AbetaPP/PS1) and the mechanisms of L-NBP in reducing Abeta accumulation and tau phosphorylation. Twelve-month old AbetaPP/PS1 mice were given 15 mg/kg L NBP by oral gavage for 3 months. L-NBP treatment significantly improved the spatial learning and memory deficits compared to the vehicle-treated AbetaPP/PS1 mice, whereas L-NBP treatment had no effect on cerebral Abeta plaque deposition and Abeta levels in brain homogenates. However, we found an L-NBP-induced reduction of tau hyperphosphorylation at Ser199, Thr205, Ser396, and Ser404 sites in AbetaPP/PS1 mice. Additionally, the expressions of cyclin-dependent kinase and glycogen synthase kinase 3beta, the most important kinases involved in tau phosphorylation, were markedly decreased by L-NBP treatment. The effects of L-NBP on decreasing tau phosphorylation and kinases activations were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human AbetaPP695 (SK-N-SH AbetaPPwt). L-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of Alzheimer's disease. PMID- 22233766 TI - Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease. AB - Alzheimer's disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-epsilon4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and lower levels of Abeta1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Abeta1-42, APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia. PMID- 22233767 TI - Decrease of the immunophilin FKBP52 accumulation in human brains of Alzheimer's disease and FTDP-17. AB - Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or "tauopathies", include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed. PMID- 22233769 TI - Developmental and reproductive toxicity testing of vaccines. AB - The majority of new preventative and therapeutic vaccines are now assessed for developmental toxicity according to guidelines issued by the FDA in 2006. Despite the absence of confirmed effects in humans, vaccines are frequently suspected of having adverse side-effects on the development of children. Such suspicions are perhaps unavoidable considering the extremely widespread use of vaccines. The preclinical developmental toxicology studies are designed to assess possible influences of each component of the vaccine formulation-and the induced antibodies-on the development of the conceptus, neonate and suckling organism. Immune modulation by a vaccine or an adjuvant could, for instance, affect the outcome of pregnancy by interfering with the natural shift in immune balance of the mother during gestation. Maternal immunoglobulins are transferred from the mother to the offspring in order to confer passive immunity during early life. This maternal antibody transport is prenatal in humans and monkeys, but tends to be delayed until after birth in other species. Therefore, a suitable model species needs to be chosen for preclinical studies in order to ensure exposure of the foetus to the induced maternal antibodies following vaccination. Rabbits are the best laboratory model for prenatal immunoglobulin transfer, but rodents are more practical for the necessary postnatal investigations. Non-human primates are the only appropriate models for the testing of vaccines that are not immunogenic in lower species. It is advisable to test new adjuvants separately according to the ICH S5(R2) guidelines. Preclinical paediatric investigations are not currently required for vaccines, even though most vaccines are given to children. Other areas of regulatory concern include developmental immunotoxicity and effects on the preimplantation embryo. Because of the limitations of the available animal models for developmental toxicity testing, pharmacovigilance is essential. PMID- 22233768 TI - Differential distribution of subjective and objective cognitive impairment in the population: a nation-wide twin-study. AB - We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged >=65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence rates of SCI and CIND were 39% (95% CI 38 39%) and 25% (95% CI 24-25%). In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed the association of low education with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND. PMID- 22233770 TI - Missing from the table: role of the environmental public health community in governmental advisory commissions related to Marcellus Shale drilling. AB - BACKGROUND: The Marcellus Shale is a vast natural gas field underlying parts of Pennsylvania, New York, West Virginia, Virginia, and Maryland. Rapid development of this field has been enabled by advances in hydrofracking techniques that include injection of chemical and physical agents deep underground. Response to public concern about potential adverse environmental and health impacts has led to the formation of state and national advisory committees. OBJECTIVES: We review the extent to which advisory committees formed in 2011 by President Obama and governors of the states of Maryland and Pennsylvania contain individuals with expertise pertinent to human environmental public health. We also analyze the extent to which human health issues are of concern to the public by reviewing presentations at the public meeting of the Secretary of Energy Advisory Board (SEAB) Natural Gas Subcommittee formed by the U.S. President's directive. RESULTS: At a public hearing held by the SEAB Natural Gas Subcommittee 62.7% of those not in favor of drilling mentioned health issues. Although public health is specified to be a concern in the executive orders forming these three advisory committees, we could identify no individuals with health expertise among the 52 members of the Pennsylvania Governor's Marcellus Shale Advisory Commission, the Maryland Marcellus Shale Safe Drilling Initiative Advisory Commission, or the SEAB Natural Gas Subcommittee. CONCLUSIONS: Despite recognition of the environmental public health concerns related to drilling in the Marcellus Shale, neither state nor national advisory committees selected to respond to these concerns contained recognizable environmental public health expertise. PMID- 22233771 TI - Changes in the geographical distribution and abundance of the tick Ixodes ricinus during the past 30 years in Sweden. AB - BACKGROUND: Ixodes ricinus is the main vector in Europe of human-pathogenic Lyme borreliosis (LB) spirochaetes, the tick-borne encephalitis virus (TBEV) and other pathogens of humans and domesticated mammals. The results of a previous 1994 questionnaire, directed at people living in Central and North Sweden (Svealand and Norrland) and aiming to gather information about tick exposure for humans and domestic animals, suggested that Ixodes ricinus ticks had become more widespread in Central Sweden and the southern part of North Sweden from the early 1980s to the early 1990s. To investigate whether the expansion of the tick's northern geographical range and the increasing abundance of ticks in Sweden were still occurring, in 2009 we performed a follow-up survey 16 years after the initial study. METHODS: A questionnaire similar to the one used in the 1994 study was published in Swedish magazines aimed at dog owners, home owners, and hunters. The questionnaire was published together with a popular science article about the tick's biology and role as a pathogen vector in Sweden. The magazines were selected to get information from people familiar with ticks and who spend time in areas where ticks might be present. RESULTS: Analyses of data from both surveys revealed that during the near 30-year period from the early 1980s to 2008, I. ricinus has expanded its distribution range northwards. In the early 1990s ticks were found in new areas along the northern coastline of the Baltic Sea, while in the 2009 study, ticks were reported for the first time from many locations in North Sweden. This included locations as far north as 66 degrees N and places in the interior part of North Sweden. During this 16-year period the tick's range in Sweden was estimated to have increased by 9.9%. Most of the range expansion occurred in North Sweden (north of 60 degrees N) where the tick's coverage area doubled from 12.5% in the early 1990s to 26.8% in 2008. Moreover, according to the respondents, the abundance of ticks had increased markedly in LB- and TBE endemic areas in South (Gotaland) and Central Sweden. CONCLUSIONS: The results suggest that I. ricinus has expanded its range in North Sweden and has become distinctly more abundant in Central and South Sweden during the last three decades. However, in the northern mountain region I. ricinus is still absent. The increased abundance of the tick can be explained by two main factors: First, the high availability of large numbers of important tick maintenance hosts, i.e., cervids, particularly roe deer (Capreolus capreolus) during the last three decades. Second, a warmer climate with milder winters and a prolonged growing season that permits greater survival and proliferation over a larger geographical area of both the tick itself and deer. High reproductive potential of roe deer, high tick infestation rate and the tendency of roe deer to disperse great distances may explain the range expansion of I. ricinus and particularly the appearance of new TBEV foci far away from old TBEV-endemic localities. The geographical presence of LB in Sweden corresponds to the distribution of I. ricinus. Thus, LB is now an emerging disease risk in many parts of North Sweden. Unless countermeasures are undertaken to keep the deer populations, particularly C. capreolus and Dama dama, at the relatively low levels that prevailed before the late 1970s--especially in and around urban areas where human population density is high--by e.g. reduced hunting of red fox (Vulpes vulpes) and lynx (Lynx lynx), the incidences of human LB and TBE are expected to continue to be high or even to increase in Sweden in coming decades. PMID- 22233772 TI - Central and peripheral glucocorticoid receptors are involved in the plasma cortisol response to an acute stressor in rainbow trout. AB - Cortisol, the primary circulating corticosteroid in teleosts, is elevated during stress following activation of the hypothalamus-pituitary-interrenal (HPI) axis. Cortisol exerts genomic effects on target tissues in part by activating glucocorticoid receptors (GR). Despite a well-established negative feedback loop involved in plasma cortisol regulation, the role of GR in the functioning of the HPI axis during stress in fish is still unclear. We used mifepristone (a GR antagonist) to suppress GR signaling in rainbow trout (Oncorhynchus mykiss) and assessed the resultant changes to HPI axis activity. We show for the first time that mifepristone caused a functional knockdown of GR by depleting protein expression 40-75%. The lower GR protein expression corresponded with a compensatory up-regulation of GR mRNA levels across tissues. Mifepristone treatment completely abolished the stressor-induced elevation in plasma cortisol and glucose levels seen in the control fish. A reduction in corticotropin releasing factor (CRF) mRNA abundance in the hypothalamic preoptic area was also observed, suggesting that GR signaling is involved in maintaining basal CRF levels. We further characterized the effect of mifepristone treatment on the steroidogenic capacity of interrenal tissue in vitro. A marked reduction in cortisol production following adrenocorticotropic hormone stimulation of head kidney pieces was observed from mifepristone treated fish. This coincided with the suppression of steroidogenic acute regulatory protein, but not P450 side chain cleavage mRNA abundances. Overall, our results underscore a critical role for central and peripheral GR signaling in the regulation of plasma cortisol levels during stress in fish. PMID- 22233773 TI - Characterization of major elements of insulin signaling cascade in chicken adipose tissue: apparent insulin refractoriness. AB - The role of insulin in chicken adipose tissue appears weak or questionable. In a first study, proximal and distal components of the insulin signaling cascade were characterized in abdominal adipose tissue of fasted or fed chickens for the first time. Similar measurements were performed on epididymal adipose tissue from fasted or fed rats for comparison. Tyrosine phosphorylation of IR beta subunit, IRS-1 and Shc and phosphorylation of downstream components (Akt and MAPK ERK1/2) were significantly reduced as expected by fasting in rat, but not in chicken. Phosphorylation of MAPK P38 was increased by fasting in chicken but not in rat. Phosphorylation of AMPK was not affected in the conditions investigated in either species. Whatever the nutritional state, the protein levels of IR and IRS-1 were lower in chicken than in rat, whereas those of Shc, Akt, AMPK, MAPK ERK2 and MAPK P38 were similar in both species. In fed state, PI3K activity was higher in chicken than in rat. Insulin sensitivity of insulin cascade was further investigated in chicken adipose tissue following in vivo insulin neutralization for 1 or 5h in fed chickens. Insulin privation did not alter early insulin signaling steps (IRbeta, IRS-1 and Shc) or downstream elements (Akt, P70S6K, S6 ribosomal protein, AMPK, MAPK ERK2 and MAPK P38). Finally, phosphorylation of the transcription factor Creb was increased by 2-fold by 5h fasting or 5h insulin privation, most likely in response to an increase in plasma glucagon levels. Thus, insulin signaling is markedly different in chicken abdominal adipose tissue from that operating in mammals making chicken an interesting model of insulin resistance or refractoriness. PMID- 22233774 TI - Body weight and leukocyte infiltration after an acute exercise-related muscle injury in ovariectomized mice treated with estrogen and progesterone. AB - In both rats and mice, an acute skeletal muscle injury leads to leukocyte infiltration in which the leukocytes remove dead fibers and cellular debris, induce a secondary injury, and/or promote myofiber regeneration. Short-term exogenous estrogen treatment attenuates this leukocyte infiltration and prevents body weight gain in rat exercise-induced skeletal muscle injury models. But these estrogen effects may not occur in mice because body weight gain does not consistently occur in ovariectomized mice treated with estrogen. Additionally, progesterone may also attenuate this leukocyte infiltration without affecting body weight. The aim of the current study was to compare body weight and leukocyte infiltration in exercise-injured skeletal muscle of ovariectomized mice treated with exogenous estrogen and progesterone for the short period of 17 days with that of ovariectomized-placebo-treated mice and gonadal-intact male and female mice. There was no significant difference in body weight between the ovariectomized-estrogen-treated and the ovariectomized-placebo-treated mice. The amount of intramuscular leukocyte infiltration of ovariectomized mice treated with estrogen or progesterone was not significantly different from that of ovariectomized-placebo-treated mice. However, in the injured muscle, the mean area of the leukocyte antigen, 7/4, of the ovariectomized-estrogen-treated group was 2-3-fold greater than that of the ovariectomized-placebo-treated, ovariectomized-estrogen-progesterone-treated, and intact male groups (p<.05), suggesting that the 7/4-positive leukocytes of the ovariectomized-estrogen treated group were larger or had more antigen. In conclusion, ovariectomized mice demonstrate a different body weight and leukocyte response to short-term estrogen treatment than that of ovariectomized rats, and short-term estrogen treatment modulates leukocyte phenotype. These data broaden our understanding of estrogen's effects on body weight and leukocyte infiltration, and may aid in increasing our understanding of how males and females differ in response to acute muscle injury. PMID- 22233775 TI - 5-HTTLPR short allele, resilience, and successful aging in older adults. AB - OBJECTIVE: Resilience is proposed as a significant component of successful aging. Young adult carriers of the Serotonin Transporter Polymorphism (5-HTTLPR) short(s) allele appear to have reduced resilience to stress. We examined whether the presence of the short allele was associated with poorer emotional resilience in older adults. METHODS: In a cross-sectional study of 99 healthy, community dwelling, older adults, we determined 5-HTTLPR genotype status and administered the Connor-Davidson Resilience Scale and self-reported measures of successful aging, cognition, and health. RESULTS: There was no significant association between the 5-HTTLPR s allele and resilience. S allele carriers had worse cognition and self-report ratings of successful aging. CONCLUSION: These findings suggest that the impact of the 5-HTTLPR s allele on stress-related outcomes may attenuate with older age. However, s allele status appears to be a biomarker of poorer self-rated successful aging, and cognitive performance in older adults. PMID- 22233777 TI - Hierarchical top-porous/bottom-tubular TiO2 nanostructures decorated with Pd nanoparticles for efficient Photoelectrocatalytic decomposition of synergistic pollutants. AB - In this paper, top-porous and bottom-tubular TiO(2) nanotubes (TiO(2) NTs) loaded with palladium nanoparticles (Pd/TiO(2) NTs) were fabricated as an electrode for an enhanced photoelectrocatalytic (PEC) activity toward organic dye decomposition. TiO(2) NTs with a unique hierarchical top-porous and bottom tubular structure were prepared by a facile two-step anodization method and Pd nanoparticles were decorated onto the TiO(2) NTs via a photoreduction process. The PEC activity of Pd/TiO(2) NTs was investigated by decomposition of methylene blue (MB) and Rhodamine B (RhB). Because of formation Schottky junctions between TiO(2) and Pd, which significantly promoted the electron transfer and reduced the recombination of photogenerated electrons and holes, the Pd/TiO(2) NT electrode showed significantly higher PEC activities than TiO(2) NTs. Interestingly, an obvious synergy between two dyes was observed and corresponding mechanism based on facilitated transfer of electrons and holes as a result of a suitable energy level alignment was suggested. The findings of this work provide a fundamental insight not only into the fabrication but also utility of Schottky junctions for enhanced environmental remediation processes. PMID- 22233776 TI - Nurses' preparedness to care for women exposed to Intimate Partner Violence: a quantitative study in primary health care. AB - BACKGROUND: Intimate partner violence (IPV) has a deep impact on women's health. Nurses working in primary health care need to be prepared to identify victims and offer appropriate interventions, since IPV is often seen in primary health care. The aim of the study was to assess nurses' preparedness to identify and provide nursing care to women exposed to IPV who attend primary health care. METHOD: Data was collected using a questionnaire to nurses at the primary health care centres. The response rate was 69.3%. Logistic regression analysis was used to test relationships among variables. RESULTS: Shortcomings were found regarding preparedness among nurses. They lacked organisational support e.g. guidelines, collaboration with others and knowledge regarding the extensiveness of IPV. Only half of them always asked women about violence and mostly when a woman was physically injured. They felt difficulties to know how to ask and if they identified violence they mostly offered the women a doctor's appointment. Feeling prepared was connected to obtaining knowledge by themselves and also to identifying women exposed to IPV. CONCLUSION: The majority of the nurses were found to be quiet unprepared to provide nursing care to women exposed to IPV. Consequences might be treatment of symptoms but unidentified abuse and more and unnecessary suffering for these women. Improvements are needed on both at the level of the organisation and individual. PMID- 22233778 TI - AveLI: a robust lateralization index in functional magnetic resonance imaging using unbiased threshold-free computation. AB - The laterality index (LI) is often applied in functional magnetic resonance imaging (fMRI) studies to determine functional hemispheric lateralization. A difficulty in using conventional LI methods lies in ensuring a legitimate computing procedure with a clear rationale. Another problem with LI is dealing with outliers and noise. We propose a method called AveLI that follows a simple and unbiased computational principle using all voxel t-values within regions of interest (ROIs). This method first computes subordinate LIs (sub-LIs) using each of the task-related positive voxel t-values in the ROIs as the threshold as follows: sub-LI=(Lt-Rt)/(Lt+Rt), where Lt and Rt are the sums of the t-values at and above the threshold in the left and right ROIs, respectively. The AveLI is the average of those sub-LIs and indicates how consistently lateralized the performance of the subject is across the full range of voxel t-value thresholds. Its intrinsic weighting of higher t-value voxels in a data-driven manner helps to reduce noise effects. The resistance against outliers is demonstrated using a simulation. We applied the AveLI as well as other "non-thresholding" and "thresholding" LI methods to two language tasks using participants with right- and left-hand preferences. The AveLI showed a moderate index value among 10 examined indices. The rank orders of the participants did not vary between indices. AveLI provides an index that is not only comprehensible but also highly resistant to outliers and to noise, and it has a high reproducibility between tasks and the ability to categorize functional lateralization. PMID- 22233779 TI - The processing bias for threatening cues revealed by event-related potential and event-related oscillation analyses. AB - The processing bias of threat is crucial for survival. However, the neurophysiological underpinnings of this bias are not fully understood. To contribute to a better understanding of the processing bias for threat, both event-related potential (ERP) and event-related oscillation (ERO) analyses were applied to the electroencephalography (EEG) data recorded from subjects while performing a go/no-go variant of the dot-probe task. In the task, subjects responded to the infrequent target stimuli and didn't respond to the standard stimuli. Both target and standard stimuli were preceded by a bilateral picture pair [one emotional (threatening or pleasant) and one neutral] as an emotional cue. The behavioral data and the P1 elicited by standard stimuli didn't show any significant main effect or interaction. The mean amplitude of N1 was greater negative for threatening cues than pleasant cues with the most significant effect in the fronto-central region, indicating a processing bias for threat related to early attention processing. In addition, the theta synchronization was stronger for threatening cues than pleasant cues with significant effect in posterior regions, suggesting that the posterior theta synchronization reflects the evaluation of emotional significance of stimuli. Taken together, the ERP and ERO analyses provide some independent insights into the processing bias for threatening cues and illustrate this bias more comprehensively. PMID- 22233780 TI - Glutamatergic input-output properties of thalamic astrocytes. AB - Astrocytes in the somatosensory ventrobasal (VB) thalamus of rats respond to glutamatergic synaptic input with metabotropic glutamate receptor (mGluR) mediated intracellular calcium ([Ca2+](i)) elevations. Astrocytes in the VB thalamus also release the gliotransmitter (GT) glutamate in a Ca2+-dependent manner. The tripartite synapse hypothesis posits that astrocytic [Ca2+](i) elevations resulting from synaptic input releases gliotransmitters that then feedback to modify the synapse. Understanding the dynamics of this process and the conditions under which it occurs are therefore important steps in elucidating the potential roles and impact of GT release in particular brain activities. In this study, we investigated the relationship between VB thalamus afferent synaptic input and astrocytic glutamate release by recording N-methyl-D-aspartate (NMDA) receptor-mediated slow inward currents (SICs) elicited in neighboring neurons. We found that Lemniscal or cortical afferent stimulation, which can elicit astrocytic [Ca2+](i) elevations, do not typically result in the generation of SICs in thalamocortical (TC) neurons. Rather, we find that the spontaneous emergence of SICs is largely resistant to acute afferent input. The frequency of SICs, however, is correlated to long-lasting afferent activity. In contrast to short-term stimulus-evoked GT release effects reported in other brain areas, astrocytes in the VB thalamus do not express a straightforward input-output relationship for SIC generation but exhibit integrative characteristics. PMID- 22233781 TI - Lithium attenuates bupivacaine-induced neurotoxicity in vitro through phosphatidylinositol-3-kinase/threonine-serine protein kinase B- and extracellular signal-regulated kinase-dependent mechanisms. AB - Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. Lithium is a mood stabilizer for the treatment of bipolar disorder and may exert neuroprotective effects. In this study, we evaluated the effects of lithium on bupivacaine (a frequently used LAs)-induced injury in mouse neuroblastoma neuro 2a (N2a) cells. N2a cells were treated with bupivacaine in the presence or absence of lithium. After treatment, the cell injury was evaluated by examination of viability, morphology changes, and nuclear condensation. The levels of mitochondrial transmembrane potential (DeltaPsim) and activation of phosphatidylinositol-3-kinase (PI3K)/ threonine-serine protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also examined. In a separate experiment, we investigated the effect of Akt and ERK inhibition on cell injury after bupivacaine and lithium treatment. Pretreatment of N2a cells with lithium significantly attenuated bupivacaine-induced cell injury. Lithium pretreatment completely reversed the suppression of PI3K/Akt and ERK signalings and significantly prevented the decline of DeltaPsim in N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERK diminished the protective effect of lithium against bupivacaine-induced neuronal death. Our data suggest that lithium pretreatment provides a protective effect on bupivacaine-induced neuronal cell injury. This action of lithium is mediated through, at least in part, the activating of PI3K/Akt- and ERK-dependent mechanisms. Because lithium is a clinically proved safety drug for neurons, it is worthwhile to identify whether coadministration of LAs with lithium will decrease the risks of LAs-induced postoperative neurological complications in clinic practice. PMID- 22233782 TI - Neuronal populations mediating the effects of endocannabinoids on stress and emotionality. AB - An adequate emotional response to stress is essential for survival and requires the fine-tuned regulation of several distinct neuronal circuits. Therefore, a precise control of these circuits is necessary to prevent behavioral imbalances. During the last decade, numerous investigations have evidenced that the endocannabinoid (eCB) system is able to crucially control stress coping. Its central component, the cannabinoid type 1 receptor (CB1 receptor), is located at the presynapse, where it is able to attenuate neurotransmitter release after its activation by postsynaptically produced and released eCBs. To date, the eCB system has been found to control the neurotransmitter release from several neuron populations (e.g. GABA, glutamate, catecholamines and monoamines), suggesting a general mechanism for tuning neuronal activity, and thereby regulating emotion and stress responses. In this review, we aim at summarizing the anatomical and functional relation of the eCB system to an adequate response to stressful situations. Of special interest will be neuronal connections to the hypothalamic pituitary-adrenal axis, but also circuits between cortical structures, such as prefrontal cortex, amygdala and hippocampus, and subcortical regions, such as raphe nuclei and locus coeruleus. We further like to step toward allocating eCB system functions to distinct cellular subpopulations in the brain. It has emerged that the eCB system is spatially well defined, and its detailed knowledge is a prerequisite for understanding the eCB system in the context of controlling behavior. Thus, advanced approaches combining different genetic and pharmacological tools to dissect specific eCB system functions are of particular interest. PMID- 22233783 TI - Risk factor analysis for early femoral failure in metal-on-metal hip resurfacing arthroplasty: the effect of bone density and body mass index. AB - BACKGROUND: The importance of appropriately selecting patients based on factors such as bone mineral density, body mass index, age, gender, and femoral component size has been demonstrated in many studies as an aid in decreasing the rate of revisions and improving the outcomes for patients after hip resurfacing arthroplasty (HRA); however, there are few published studies quantitatively specifying the potential risk factors that affect early femoral component failures. Therefore, the purpose of this study was to investigate the specific causes of early femoral component failures in hip resurfacing separately and more carefully in order to develop strategies to prevent these failures, rather than excluding groups of patients from this surgical procedure. METHODS: This retrospective study included 373 metal-on-metal HRAs performed by a single surgeon using the vascular sparing posterior minimally invasive surgical approach. The average length of follow-up was 30 +/- 6 months. In order to understand the causes of early femoral failure rate, a multivariable logistic regression model was generated in order to analyze the effects of bone mineral density (T-score), gender, diagnosis, body mass index, femoral implant fixation type, age, and femoral component size. RESULTS: The average post-operative Harris hip score was 92 +/- 11 points and the average post-operative UCLA score was 7 +/ 2 points. There were three revisions due to femoral neck fracture and two for femoral component loosening. These occurred in two female and three male patients. In the multi-variable regression model, only T-score and body mass index showed significant effects on the failure rate of femoral components. Patients with a lower T-score and a higher body mass index had a significantly increased risk of early femoral component failure. CONCLUSION: We recommend that dual energy x-ray absorptiometry scan T-score tests should be routinely performed on all hip resurfacing patients pre-operatively. If a patient has a low T-score (<= -1.5), consideration should be given to additional precautions or treatments to alleviate his or her risk, especially when the patient has a higher body mass index (>= 29 kg/m2). PMID- 22233784 TI - Comparison of a field-based test to estimate functional threshold power and power output at lactate threshold. AB - It has been proposed that field-based tests (FT) used to estimate functional threshold power (FTP) result in power output (PO) equivalent to PO at lactate threshold (LT). However, anecdotal evidence from regional cycling teams tested for LT in our laboratory suggested that PO at LT underestimated FTP. It was hypothesized that estimated FTP is not equivalent to PO at LT. The LT and estimated FTP were measured in 7 trained male competitive cyclists (VO2max = 65.3 +/- 1.6 ml O2.kg(-1).min(-1)). The FTP was estimated from an 8-minute FT and compared with PO at LT using 2 methods; LT(Delta1), a 1 mmol.L(-1) or greater rise in blood lactate in response to an increase in workload and LT(4.0), blood lactate of 4.0 mmol.L(-1). The estimated FTP was equivalent to PO at LT(4.0) and greater than PO at LT(Delta1). VO2max explained 93% of the variance in individual PO during the 8-minute FT. When the 8-minute FT PO was expressed relative to maximal PO from the VO2max test (individual exercise performance), VO2max explained 64% of the variance in individual exercise performance. The PO at LT was not related to 8-minute FT PO. In conclusion, FTP estimated from an 8-minute FT is equivalent to PO at LT if LT(4.0) is used but is not equivalent for all methods of LT determination including LT(Delta1). PMID- 22233785 TI - Interrelationships between strength, anthropometrics, and strongman performance in novice strongman athletes. AB - The sport of strongman is relatively new; hence, specific research investigating this sport is currently very limited. The purpose of this study was to determine the relationships between anthropometric dimensions and maximal isoinertial strength to strongman performance in novice strongman athletes. Twenty-three semiprofessional rugby union players with considerable resistance training and some strongman training experience (age 22.0 +/- 2.4 years, weight 102.6 +/- 10.8 kg, height 184.6 +/- 6.5 cm) were assessed for anthropometry (height, body composition, and girth measurements), maximal isoinertial performance (bench press, squat, deadlift, and power clean), and strongman performance (tire flip, log clean, and press, truck pull, and farmer's walk). The magnitudes of the relationships were determined using Pearson correlation coefficients, and interpreted qualitatively according to Hopkins (90% confidence limits ~+/-0.37). The highest relationship observed was between system force (body mass + squat 1 repetition maximum) and overall strongman performance (r = 0.87). Clear moderate to very large relationships existed between performance in all strongman events and the squat (r = 0.61-0.85), indicating the importance of maximal squat strength for strongman competitors. Flexed arm girth and calf girth were the strongest anthropometric correlates of overall strongman performance (r = 0.79 and 0.70, respectively). The results of this study suggest that body structure and common gymnasium-based exercise strength are meaningfully related to strongman performance in novice strongman athletes. Future research should investigate these relationships using more experienced strongman athletes and determine the relationships between changes in anthropometry, isoinertial strength, and strongman performance to determine the role of anthropometry and isoinertial strength in the sport of strongman. PMID- 22233786 TI - Reliability of the one-repetition-maximum power clean test in adolescent athletes. AB - Although the power clean test is routinely used to assess strength and power performance in adult athletes, the reliability of this measure in younger populations has not been examined. Therefore, the purpose of this study was to determine the reliability of the 1-repetition maximum (1RM) power clean in adolescent athletes. Thirty-six male athletes (age 15.9 +/- 1.1 years, body mass 79.1 +/- 20.3 kg, height 175.1 +/-7.4 cm) who had >1 year of training experience in weightlifting exercises performed a 1RM power clean on 2 nonconsecutive days in the afternoon following standardized procedures. All test procedures were supervised by a senior level weightlifting coach and consisted of a systematic progression in test load until the maximum resistance that could be lifted for 1 repetition using proper exercise technique was determined. Data were analyzed using an intraclass correlation coefficient (ICC[2,k]), Pearson correlation coefficient (r), repeated measures analysis of variance, Bland-Altman plot, and typical error analyses. Analysis of the data revealed that the test measures were highly reliable demonstrating a test-retest ICC of 0.98 (95% confidence interval = 0.96-0.99). Testing also demonstrated a strong relationship between 1RM measures in trials 1 and 2 (r = 0.98, p < 0.0001) with no significant difference in power clean performance between trials (70.6 +/- 19.8 vs. 69.8 +/- 19.8 kg). Bland-Altman plots confirmed no systematic shift in 1RM between trials 1 and 2. The typical error to be expected between 1RM power clean trials is 2.9 kg, and a change of at least 8.0 kg is indicated to determine a real change in lifting performance between tests in young lifters. No injuries occurred during the study period, and the testing protocol was well tolerated by all the subjects. These findings indicate that 1RM power clean testing has a high degree of reproducibility in trained male adolescent athletes when standardized testing procedures are followed and qualified instruction is present. PMID- 22233787 TI - Concurrent validity of an OMNI rating of perceived exertion scale for bench stepping exercise. AB - To develop and validate a modified OMNI rating of perceived exertion (RPE) scale for use during bench stepping exercise (OMNI-BS). Thirty women (age: 19.8 +/- 1.8 years) undertook 2 experimental trials, separated by 7 days. Concurrent validity was established by examining the relation between physiological criterion variables, oxygen consumption (VO2), and heart rate (HR), with the concurrent variable, RPE from OMNI-BS, during 2 trials in which the intensity increased linearly (test 1) and intermittently (test 2). The first test consisted of 3 minute stages. Subjects stepped up and down on the bench at 120 b.min(-1). The test was terminated owing to subject fatigue. Exercise intensity increased as bench height increased every 3 minutes. The second test consisted of three 3 minute exercise bouts that reproduced exercise stage 1 (low intensity), stage 3 (moderate intensity), and stage 5 (high intensity) performed in the first test. The order of these 3 exercise bouts was counterbalanced. Intraclass correlation analysis from experimental trials indicated a strong positive association between RPE and VO2 (r = 0.96 and r = 0.95) and HR (r = 0.95 and r = 0.95). Concurrent validity for the OMNI-BS RPE scale was established for women performing bench stepping exercise. PMID- 22233788 TI - Low load exercises targeting the gluteal muscle group acutely enhance explosive power output in elite athletes. AB - The purpose of this study was to investigate the acute effect of 3 warm-up protocols on peak power production during countermovement jump (CMJ) testing. The intention was to devise and compare practical protocols that could be applied as a warm-up immediately before competition matches or weight training sessions. A group of 22 elite Australian Rules Football players performed 3 different warm-up protocols over 3 testing sessions in a randomized order. The protocols included a series of low load exercises targeting the gluteal muscle group (GM-P), a whole body vibration (WBV) protocol (WBV-P) wherein the subjects stood on a platform vibrating at 30 Hz for 45 seconds, and a no-warm-up condition (CON). The CMJ testing was performed within 5 minutes of each warm-up protocol on an unloaded Smith machine using a linear encoder to measure peak power output. Peak power production was significantly greater after the GM-P than after both the CON (p < 0.05) and WBV-P (p < 0.01). No significant differences in peak power production were detected between the WBV-P and CON. These results have demonstrated that a low load exercise protocol targeting the gluteal muscle group is effective at acutely enhancing peak power output in elite athletes. The mechanisms for the observed improvements are unclear and warrant further investigation. Coaches may consider incorporating low load exercises targeting the gluteal muscle group into the warm-up of athletes competing in sports requiring explosive power output of the lower limbs. PMID- 22233789 TI - Dry-land strength training vs. electrical stimulation in sprint swimming performance. AB - This study was undertaken to compare the effects of dry-land strength training vs. an electrical stimulation program on swimmers. Twenty-four national-level swimmers were randomly assigned to 3 groups: the dry-land strength training program (S), the electrical stimulation training program (ES), and the control (C) group. The training program lasted 4 weeks. The subjects were evaluated before the training, at the end of the training program, and 4 weeks later. The outcome values ascertained were peak torque during arm extension at different velocities (from -60 to 180 degrees .s(-1)) using an isokinetic dynamometer and performance, stroke rate, and stroke length during a 50-m front crawl. A significant increase in swimming velocity and peak torque was observed for both S and ES at the end of the training and 4 weeks later. Stroke length increased in the S group but not in the ES group. However, no significant differences in swimming velocity between S and ES groups were observed. No significant changes occurred in the C group. Programs combining swimming training with dry-land strength or electrical stimulation programs led to a similar gain in sprint performance and were more efficient than swimming alone. PMID- 22233790 TI - An examination of athletes' self-efficacy and strength training effort during an entire off-season. AB - Over the past 30-plus years in which self-efficacy (or confidence at a task) has been researched, findings have shown that in almost every domain of human functioning, self-efficacy positively relates to effort, persistence, and other adaptive behaviors. However, in the past decade, new research postulating that too much self-efficacy can lead to complacency and a subsequent downturn in behavior or performance has also experienced resurgence in the literature. Therefore, the purpose of this study was to test these opposing viewpoints regarding self-efficacy and effort for Division I athletes in a strength and conditioning domain over off-season training, a procedure yet to be undertaken. Subjects (N = 99), from 4 different sports (M(ag)e = 20.0 years, SD = 1.2 years), completed self-efficacy and effort measures at 4 distinct time points during off season training. In addition, strength and conditioning coaches also rated each subject's effort--at each time point--so that a more valid measure of this construct could be attained. Results were analyzed using a multilevel approach and revealed that self-efficacy was positively, and significantly, related to the current effort that athletes exerted in strength training sessions. Consequently, practitioners are advised to structure strength and conditioning training sessions and the overall environment in ways that will positively impact the 4 proven sources of self-efficacy. PMID- 22233791 TI - Movement demands in Australian rules football as indicators of muscle damage. AB - The purpose of this study was to determine if there is an association between variables that describe movements in an Australian Rules football (ARF) game with muscle damage. Fourteen elite junior ARF players were monitored with a global positioning system (GPS) during a match, and muscle damage was estimated by determining creatine kinase (CK) 24 hours postmatch. The players were median split based on CK levels, into a high and low CK group, and the groups were compared with independent t-tests. The primary finding was that the group that experienced greater muscle damage (high CK group) generally covered significantly (p < 0.05) greater distances. This was the case for running speeds between 4 and 7 m.s(-1) and, with the exception of high acceleration, all intensities of acceleration and deceleration. The high, as compared with the low, CK group also produced a significantly greater (42%) "player load." All of these significant differences were accompanied by large effect sizes. Group-specific Pearson (r) correlations between CK level and GPS variables suggest that a certain volume of movement is required before the elicitation of a positive relationship beyond trivial or small. Correlations between CK and running speeds >4 m.s(-1) and moderate-high acceleration and deceleration were negative in the low CK (lesser volumes) group. With the exception of low-intensity acceleration/deceleration, the same relationships were positive and generally of a moderate-to-large magnitude in the high CK (greater volumes) group. It may be that a certain volume of movement is required for that movement to be strongly associated with CK levels. It was concluded that selected GPS variables obtained from ARF games can be used as indicators of muscle damage, and this information may be used to individualize recovery strategies after games. PMID- 22233792 TI - Influence of field size on the physiological and skill demands of small-sided games in junior and senior rugby league players. AB - The purpose of this study was to investigate the effect of changes in field size on the physiological and skill demands of small-sided games in elite junior and senior rugby league players. Sixteen elite senior rugby league players ([mean +/- SE] age, 23.6 +/- 0.5 years) and 16 elite junior rugby league players ([mean +/- SE] age, 17.3 +/- 0.3 years) participated in this study. On day 1, 2 teams played an 8-minute small-sided game on a small field (10-m width * 40-m length), whereas the remaining 2 teams played the small-sided game on a larger sized field (40-m width * 70-m length). On day 2, the groups were crossed over. Movement was recorded by a global positioning system unit sampling at 5 Hz. Games were filmed to count the number of possessions and the number and quality of disposals. The games played on a larger field resulted in a greater (p < 0.05) total distance covered, and distances covered in moderate, high, and very-high velocity movement intensities. Senior players covered more distance at moderate, high, and very high intensities, and less distance at low and very-low intensities during small sided games than junior players. Although increasing field size had no significant influence (p > 0.05) over the duration of recovery periods for junior players, larger field size significantly reduced (p < 0.05) the amount of short-, moderate-, and long-duration recovery periods in senior players. No significant between-group differences (p > 0.05) were detected for games played on a small or large field for the number or quality of skill involvements. These results suggest that increases in field size serve to increase the physiological demands of small-sided games but have minimal influence over the volume or quality of skill executions in elite rugby league players. PMID- 22233793 TI - Lower-body work capacity and one-repetition maximum squat prediction in college football players. AB - The purpose of this study was to assess lower-body muscular strength and work capacity after off-season resistance training and the efficacy of predicting maximal squat strength (1 repetition maximum [1RM]) from repetitions to fatigue. National Collegiate Athletic Association Division-II football players (n = 58) were divided into low-strength (LS, 1RM < 365 lb, n = 32) and high-strength (HS, 1RM >= 365 lb, n = 26) groups before training based on median 1RM squat performance. Maximal repetitions to failure (RTFs) were performed with a relative load of 70% of 1RM before training and 60, 70, 80, and 90% of 1RM after 12 weeks of a linear periodization resistance training program. As a team, 1RM squat (32 +/- 27 lb), 70% RTF (4.5 +/- 4.5 reps), and work capacity at 70% 1RM load (1,482 +/- 1,181 lb reps) increased significantly after training. Likewise, training resulted in significant increases in 1RM, RTF at 70% 1RM, and work capacity (load * reps) in both LS (8 +/- 33 lb, 3.9 +/- 4.7 reps, 1,736 +/- 1,521 lb reps, respectively) and HS (27 +/- 21 lb, 4.9 +/- 4.4 reps, 2,387 +/- 1,767 lb reps, respectively), with no significant difference between groups. There was no relationship between the change in work capacity and the change in muscular strength for either the LS (r = 0.02) or HS (r = 0.06) group. Predicted 1RMs were best when RTFs were performed using 80% 1RM (5-17 RTFs), with an error of +/-5% in 95% of the subjects. In conclusion, the changes in muscular strength associated with an off-season training program appear to have a positive influence on squat work capacity at 70% of 1RM and allow favorable prediction of 1RM using submaximal loads. PMID- 22233794 TI - The reliability and validity of short-distance sprint performance assessed on a nonmotorized treadmill. AB - This study examined the interday and intraday reliabilities and validities of various sprint performance variables on a nonmotorized treadmill (NMT) over distances of 10, 20, and 30 m. After habituation, 12 male team-sport players performed 3 sprints on the NMT on 2 separate days and an assessment of overground running performance, separated by 24 hours. Measurements included sprint times, mean and peak sprint speeds, and step length and frequency. Data analysis revealed no significant mean differences (p > 0.05) between NMT variables recorded on the same day or between days. Ratio limits of agreement indicated that the best levels of agreement were in 20-m (1.02 *// 1.09) and 30-m (1.02 *// 1.07) sprint times, peak (1.00 *// 1.06) and mean (0.99 *// 1.07) running speed, and step length (0.99 *// 1.09) and frequency (1.01 *// 1.06). The poorest agreement was observed for time to peak running speed (1.10 *// 1.47). These reliability statements were reinforced by coefficients of variation being <5% for all the variables except time to peak running speed (11%). Significant differences (p < 0.05) were observed between NMT and overground sprint times across all distances, with times being lower (faster) by approximately 25-30% overground. The correlations between NMT and overground variables were generally modest (0.44-0.67), and optimal for time to cover 30 m on day 2. Our data support NMT ergometry as a reliable tool for most of the sprint performance variables measured and reveal that the fastest 30-m overground sprinters were likely to be identifiable via NMT ergometry. PMID- 22233795 TI - Bilateral and gender differences during single-legged vertical jump performance in healthy teenagers. AB - The determination of physiologic lower limb functional imbalance among healthy teenagers is important to follow the rehabilitation progress and return to normal activity of injured subjects. We investigated the differences in vertical jump capacity between both legs in a group of healthy boys and girls, considering the performances in the dominant vs. non-dominant, and in the most vs. least efficient leg. Strength and power performances were compared in 117 boys and 106 girls aged 10-16 years during a single-leg vertical countermovement jump (SLVCJ) test. When leg dominance was defined subjectively by the participant, no difference was noted between the 2 legs. Statistically significant differences were recorded between the most and less efficient leg in strength and power performances for both genders. Girls had significantly greater peak strength than did age-matched boys, but boys showed significant increases in maximal power outputs compared with that shown by age-matched girls. When the results were analyzed according to the percentage of participants falling within certain bands of limb asymmetry, approximately 20-30% showed a difference of >15% between the 2 limbs without any relation to gender. Subjective expression of leg dominance cannot be used as a predictor of SLVCJ performance. Differences of <15% in SLVCJ performance between both legs should be considered as the physiological norm in this age group. A greater appreciation of the potential diagnostic value of the SLVCJ test may be obtained if the results are interpreted in terms of the percentage of subjects falling within certain bands of limb asymmetry. Gender based differences in the SLVCJ test vary and depend upon whether the results are interpreted in terms of strength or power output. PMID- 22233796 TI - Effects of exercise intensity on rating of perceived exertion during a multiple set resistance exercise session. AB - The aim of this study was to analyze the effects of intensity on rating of perceived exertion (RPE) during a multiple-set resistance exercise session. Fourteen men (22.9 +/- 3.8 years) with previous experience in resistance training (22.9 +/- 3.8 years) performed 2 experimental sessions in random order: resistance exercise at 50% of 1 repetition maximum (1RM) (E50%) and resistance exercise at 70% of 1RM (E70%). In both sessions, 5 exercises (bench press, bent over row, frontal raises, arm curl, and overhead triceps extension) were performed in 3 sets of 12, 9, and 6 repetitions, respectively. Active muscle RPEs were measured after each repetition using the OMNI-Resistance Exercise Scale (OMNI-RES). In the 3 sets of 5 exercises, the RPE was higher at E70% than that at E50%. The differences in RPE between intensities were observed in both the first and the sixth repetitions for each exercise. In the E70% session, the RPE increased between sets in all exercises, whereas it did not change in the E50% session. In conclusion, the RPE was higher at 70% of 1RM than that at 50% of 1RM. Moreover, in a multiple-set prescription, the RPE did not change between sets with 50% of 1RM, whereas the RPE increased between sets with 70% of 1RM. These findings suggest that RPE can be effectively used to prescribe and monitor resistance exercise intensity during an entire multiple-set exercise session in young men with previous experience in resistance training. PMID- 22233797 TI - The difference is in the start: impact of timing and start procedure on sprint running performance. AB - The difference is in the start: impact of timing and start procedure on sprint running performance. The purpose of this study was to compare different sprint start positions and to generate correction factors between popular timing triggering methods on 40-m/40-yd sprint time. Fourteen female athletes (17 +/- 1 years), personal best 100 m: 13.26 (+/-0.68) seconds and 11 male athletes (20 +/- 5 years), personal best 100 m: 11.58 (+/-0.74) seconds participated. They performed 2 series of 3 40-m sprints in randomized order: (a) start from the block, measured by means of Brower audio sensor (BAS) and Dartfish video timing (DVT), (b) 3-point start, measured by using hand release pod (HR) and DVT, and (c) standing start, triggered by both photocell across starting line (SFC), and foot release (FR) plus DVT. Video analysis was performed by 2 independent observers and averaged. Simultaneous measurements at national athletics competitions demonstrated that DVT and BAS were equivalent to Omega Timing within the limits of precision of video timing (+/-0.01 seconds). Hand and floor timer triggering showed small but significant biases compared with movement captured from video (0.02-0.04 seconds), presumably because of sensitivity of pressure thresholds. Coefficient of variation for test-retest timing using different starting positions ranged from 0.7 to 1.0%. Compared with block starts reacting to gunfire, HR, SFC, and FR starts yielded 0.17 +/- 0.09, 0.27 +/- 0.12, and 0.69 +/- 0.11 second faster times, respectively, over 40 m (all p < 0.001) because of inclusion or exclusion of reaction time, plus momentum, and body position differences at trigger moment. Correction factors for the conversion of 40 m/40 yd and 40 yd/40 m were 0.92 and 1.08, respectively. The correction factors obtained from this study may facilitate more meaningful comparisons of published sprint performances. PMID- 22233798 TI - Total circumferential separation of a valved aortic conduit from the left ventricular outflow tract. PMID- 22233799 TI - Pneumonectomy: calculable or non-tolerable risk factor in trimodal therapy for Stage III non-small-cell lung cancer? AB - OBJECTIVES: Lung cancer is the leading cause of death in cancer statistics throughout developed countries. While single surgical approach provides best results in early stages, multimodality approaches have been employed in advanced disease and demonstrated superior results in selected patients. With either full dose chemotherapy and/or radiotherapy, patients usually have a poor general condition when entering surgical therapy and therefore neoadjuvant therapy can lead to a higher morbidity and mortality. Especially in the case of pneumonectomy as the completing procedure, mortality rate can exceed over 40%. Therefore, chest physicians often shy away from recommending pneumonectomy as final step in trimodal protocols. We analysed our experience with pneumonectomy after neoadjuvant chemoradiotherapy in advanced non-small-cell lung cancer (NSCLC) with a focus on feasibility, outcome and survival. METHODS: Retrospective, single centre study of 146 patients with trimodal neoadjuvant therapy for NSCLC Stage III over 17 years time span. Follow-up was taken from our own outpatient files and with survival check of central registry office in Baden-Wurttemberg, Germany. RESULTS: A total of 118 men and 28 women received 62 lobectomies, 6 bi lobectomies and 78 pneumonectomies after two different neoadjuvant protocols for Stage III NSCLC. Overall morbidity rate was 53 and 56% after pneumonectomy. Overall hospital mortality rate was 4.8 and 6.4% after pneumonectomy. Overall median survival rate was 31 months with a 5-year survival rate of 38% (Kaplan Meier). Pneumonectomy, right-sited pneumonectomy and initial T- and N-stages were no risk factors for survival (log-rank test). Significant factors for survival were ypT-stage, ypN-stage, yUICC-stage in univariate testing (log-rank test) and ypUICC-stage in multivariate testing (Cox's regression). CONCLUSIONS: Pneumonectomy in neoadjuvant trimodal approach for Stage III NSCLC can be done safe with acceptable mortality rate. Patients should not withhold from operation because of necessitating pneumonectomy. Not the procedure but the selection, response rate and R0-resection are crucial for survival after trimodal therapy in experienced centres. PMID- 22233800 TI - Treatment of lone atrial fibrillation: a look at the past, a view of the present and a glance at the future. AB - Despite its proven efficacy, the Cox-Maze III procedure did not gain widespread acceptance for the treatment of lone atrial fibrillation (LAF) because of its complexity and technical difficulty. Surgical ablation for LAF can now be successfully performed utilizing minimally invasive techniques. This article provides an overview of the current state of the art in the surgical treatment of LAF. A brief review of pathophysiology, pharmacological treatment as well as catheter ablation is also provided. The most widely employed minimally invasive approach to LAF has been the video-assisted bilateral mini-thoracotomy or thoracoscopic pulmonary vein island creation and left atrial appendage removal or exclusion, usually with ganglionic plexi evaluation and destruction. Recently, a hybrid approach has been introduced, which combines a mono or bilateral epicardial approach with a percutaneous endocardial ablation in a single-step procedure to limit the shortcomings of both techniques. Suboptimal results of both catheter ablation and surgery suggest that success in the treatment of LAF will probably rely on a close collaboration between the surgeon and the electrophysiologist. Further studies are warranted to determine whether the hybrid approach is effective, especially in patients with long-standing persistent and persistent LAF. PMID- 22233801 TI - Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1. AB - BACKGROUND: Bcl-2 is believed to contribute to melanoma chemoresistance. However, expression of Bcl-2 proteins may be different among melanomas. Thus correlations among expression of Bcl-2-related proteins and in vivo melanoma progression, and resistance to combination therapies, was investigated. METHODS: Human A375 melanoma was injected s.c. into immunodeficient nude mice. Protein expression was studied in tumor samples obtained by laser microdisection. Transfection of siRNA or ectopic overexpression were applied to manipulate proteins which are up- or down-regulated, preferentially, during melanoma progression. Anti-bcl-2 antisense oligonucleotides and chemoradiotherapy (glutathione-depleting agents, paclitaxel protein-binding particles, daunorubicin, X rays) were administered in combination. RESULTS: In vivo A375 cells down-regulated pro-apoptotic bax expression; and up-regulated anti-apoptotic bcl-2, bcl-xl, and mcl-1, however only Bcl-2 appeared critical for long-term tumor cell survival and progression in vivo. Reduction of Bcl-2, combined with partial therapies, decreased melanoma growth. But only Bcl-2 targeting plus the full combination of chemoradiotherapy eradicated A375 melanoma, and led to long-term survival (> 120 days) without recurrence in 80% of mice. Tumor regression was not due to immune stimulation. Hematology and clinical chemistry data were within accepted clinical toxicities. CONCLUSION: Strategies to target Bcl-2, may increase the effectiveness of antitumor therapies against melanomas overexpressing Bcl-2 and likely other Bcl-2 related antiapoptotic proteins. PMID- 22233802 TI - Changes in white matter integrity follow excitatory rTMS treatment of post-stroke aphasia. AB - PURPOSE: In this study, we examine whether an excitatory repetitive transcranial magnetic stimulation (rTMS) protocol called intermittent theta burst stimulation (iTBS) applied to the affected left hemisphere leads to changes in white matter fractional anisotropy (FA). METHODS: Diffusion tensor imaging (DTI) data were collected in 8 aphasic stroke patients before and after 10 daily iTBS treatments. Alignment of structural and DTI data and derivation of diffusion index maps were performed using Analysis of Functional NeuroImages software followed by Tract Based Spatial Statistics using FMRIB Software Library. Paired t-tests were performed to compare pre- to post-rTMS changes in FA. RESULTS: There were significant (p < 0.001) left-hemispheric FA increases near the inferior and superior frontal gyri and anterior corpus callosum. FA also increased in the right midbrain and bilaterally near temporal, parietal and posterior cingulate regions. FA decreased bilaterally near the fusiform gyrus and in left cerebellum. CONCLUSIONS: Overall, left-hemispheric regions that showed increased FA corresponded to areas previously shown to have increases in fMRI language activation after iTBS. The increased white matter integrity near the stimulation sites may reflect improvements in cortical function mediated by excitatory rTMS through its ability to facilitate synaptic connections. PMID- 22233803 TI - Liquid crystal self-assembly of random-sequence DNA oligomers. AB - In biological systems and nanoscale assemblies, the self-association of DNA is typically studied and applied in the context of the evolved or directed design of base sequences that give complementary pairing, duplex formation, and specific structural motifs. Here we consider the collective behavior of DNA solutions in the distinctly different regime where DNA base sequences are chosen at random or with varying degrees of randomness. We show that in solutions of completely random sequences, corresponding to a remarkably large number of different molecules, e.g., approximately 10(12) for random 20-mers, complementary still emerges and, for a narrow range of oligomer lengths, produces a subtle hierarchical sequence of structured self-assembly and organization into liquid crystal (LC) phases. This ordering follows from the kinetic arrest of oligomer association into long-lived partially paired double helices, followed by reversible association of these pairs into linear aggregates that in turn condense into LC domains. PMID- 22233805 TI - Elucidating the mechanism of selective ion adsorption to the liquid water surface. AB - Adsorption of aqueous thiocyanate ions from bulk solution to the liquid/vapor interface was measured as a function of temperature by resonant UV second harmonic generation spectroscopy. The resulting adsorption enthalpy and entropy changes of this prototypical chaotrope were both determined to be negative. This surprising result is supported by molecular simulations, which clarify the microscopic origins of observed thermodynamic changes. Calculations reveal energetic influences of adsorbed ions on their surroundings to be remarkably local. Negative adsorption enthalpies thus reflect a simple repartitioning of solvent density among surface, bulk, and coordination regions. A different, and much less spatially local, mechanism underlies the concomitant loss of entropy. Simulations indicate that ions at the interface can significantly bias surface height fluctuations even several molecular diameters away, imposing restrictions consistent with the scale of measured and computed adsorption entropies. Based on these results, we expect an ion's position in the Hofmeister lyotropic series to be determined by a combination of driving forces associated with the pinning of capillary waves and with a competition between ion hydration energy and the neat liquid's surface tension. PMID- 22233804 TI - Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1. AB - We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10/BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression. PMID- 22233806 TI - Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation. AB - A blastocyst will implant only when the uterus becomes receptive. Following attachment, luminal epithelial cells undergo degeneration at the site of the blastocyst. Although many genes critical for uterine receptivity are primarily regulated by ovarian hormones, Kruppel-like factor 5 (KLF5), a zinc finger containing transcription factor, is persistently expressed in epithelial cells independently of ovarian hormones. Loss of uterine Klf5 causes female infertility due to defective implantation. Cox2 is normally expressed in the luminal epithelium and stroma at the site of blastocyst attachment, but luminal epithelial COX2 expression is absent with loss of Klf5. This is associated with the retention of the epithelium around the implantation chamber with arrested embryonic growth. These results suggest that Klf5 is indispensable for normal implantation. PMID- 22233807 TI - Chemical data quantify Deepwater Horizon hydrocarbon flow rate and environmental distribution. AB - Detailed airborne, surface, and subsurface chemical measurements, primarily obtained in May and June 2010, are used to quantify initial hydrocarbon compositions along different transport pathways (i.e., in deep subsurface plumes, in the initial surface slick, and in the atmosphere) during the Deepwater Horizon oil spill. Atmospheric measurements are consistent with a limited area of surfacing oil, with implications for leaked hydrocarbon mass transport and oil drop size distributions. The chemical data further suggest relatively little variation in leaking hydrocarbon composition over time. Although readily soluble hydrocarbons made up ~25% of the leaking mixture by mass, subsurface chemical data show these compounds made up ~69% of the deep plume mass; only ~31% of the deep plume mass was initially transported in the form of trapped oil droplets. Mass flows along individual transport pathways are also derived from atmospheric and subsurface chemical data. Subsurface hydrocarbon composition, dissolved oxygen, and dispersant data are used to assess release of hydrocarbons from the leaking well. We use the chemical measurements to estimate that (7.8 +/- 1.9) * 10(6) kg of hydrocarbons leaked on June 10, 2010, directly accounting for roughly three-quarters of the total leaked mass on that day. The average environmental release rate of (10.1 +/- 2.0) * 10(6) kg/d derived using atmospheric and subsurface chemical data agrees within uncertainties with the official average leak rate of (10.2 +/- 1.0) * 10(6) kg/d derived using physical and optical methods. PMID- 22233808 TI - Dynamic autoinoculation and the microbial ecology of a deep water hydrocarbon irruption. AB - The irruption of gas and oil into the Gulf of Mexico during the Deepwater Horizon event fed a deep sea bacterial bloom that consumed hydrocarbons in the affected waters, formed a regional oxygen anomaly, and altered the microbiology of the region. In this work, we develop a coupled physical-metabolic model to assess the impact of mixing processes on these deep ocean bacterial communities and their capacity for hydrocarbon and oxygen use. We find that observed biodegradation patterns are well-described by exponential growth of bacteria from seed populations present at low abundance and that current oscillation and mixing processes played a critical role in distributing hydrocarbons and associated bacterial blooms within the northeast Gulf of Mexico. Mixing processes also accelerated hydrocarbon degradation through an autoinoculation effect, where water masses, in which the hydrocarbon irruption had caused blooms, later returned to the spill site with hydrocarbon-degrading bacteria persisting at elevated abundance. Interestingly, although the initial irruption of hydrocarbons fed successive blooms of different bacterial types, subsequent irruptions promoted consistency in the structure of the bacterial community. These results highlight an impact of mixing and circulation processes on biodegradation activity of bacteria during the Deepwater Horizon event and suggest an important role for mixing processes in the microbial ecology of deep ocean environments. PMID- 22233809 TI - Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. AB - Defining the molecular genetic alterations underlying pancreatic cancer may provide unique therapeutic insight for this deadly disease. Toward this goal, we report here an integrative DNA microarray and sequencing-based analysis of pancreatic cancer genomes. Notable among the alterations newly identified, genomic deletions, mutations, and rearrangements recurrently targeted genes encoding components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARCA4). Whereas alterations of each individual SWI/SNF subunit occurred at modest-frequency, as mutational "hills" in the genomic landscape, together they affected at least one third of all pancreatic cancers, defining SWI/SNF as a major mutational "mountain." Consistent with a tumor-suppressive role, re-expression of SMARCA4 in SMARCA4-deficient pancreatic cancer cell lines reduced cell growth and promoted senescence, whereas its overexpression in a SWI/SNF-intact line had no such effect. In addition, expression profiling analyses revealed that SWI/SNF likely antagonizes Polycomb repressive complex 2, implicating this as one possible mechanism of tumor suppression. Our findings reveal SWI/SNF to be a central tumor suppressive complex in pancreatic cancer. PMID- 22233810 TI - Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. AB - Tuberculosis (TB) is a major public health problem. One-third of the world's population is estimated to be infected with Mycobacterium tuberculosis (MTB), the etiological agent causing TB, and active disease kills nearly 2 million individuals worldwide every year. Several lines of evidence indicate that interindividual variation in susceptibility to TB has a heritable component, yet we still know little about the underlying genetic architecture. To address this, we performed a genome-wide mapping study of loci that are associated with functional variation in immune response to MTB. Specifically, we characterized transcript and protein expression levels and mapped expression quantitative trait loci (eQTL) in primary dendritic cells (DCs) from 65 individuals, before and after infection with MTB. We found 198 response eQTL, namely loci that were associated with variation in gene expression levels in either untreated or MTB infected DCs, but not both. These response eQTL are associated with natural regulatory variation that likely affects (directly or indirectly) host interaction with MTB. Indeed, when we integrated our data with results from a genome-wide association study (GWAS) for pulmonary TB, we found that the response eQTL were more likely to be genetically associated with the disease. We thus identified a number of candidate loci, including the MAPK phosphatase DUSP14 in particular, that are promising susceptibility genes to pulmonary TB. PMID- 22233811 TI - Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state. AB - The metabolic state of a cell is a key determinant in the decision to live and proliferate or to die. Consequently, balanced energy metabolism and the regulation of apoptosis are critical for the development and maintenance of differentiated organisms. Hypoxia occurs physiologically during development or exercise and pathologically in vascular disease, tumorigenesis, and inflammation, interfering with homeostatic metabolism. Here, we show that the hypoxia-inducible factor (HIF)-1-regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. We provide evidence for a direct molecular interactor of HKII and show that, together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation. HKII both protects cells from death during hypoxia and functions as a sensor of glucose availability during normoxia, inducing apoptosis in response to glucose depletion. Thus, HKII-mediated apoptosis may represent an evolutionarily conserved altruistic mechanism to eliminate cells during metabolic stress to the advantage of a multicellular organism. PMID- 22233812 TI - Coexistence of fibrotic and chondrogenic process in the capsule of idiopathic frozen shoulders. AB - OBJECTIVE: To analyze changes in the capsule from idiopathic frozen shoulders and clarify their etiology. MATERIALS AND METHODS: Samples (the rotator interval capsule, middle glenohumeral ligament (MGHL), and inferior glenohumeral ligament (IGHL)) were collected from 12 idiopathic frozen shoulders with severe stiffness and 18 shoulders with rotator cuff tears as a control. The number of cells was counted and the tissue elasticity of the samples was calculated by scanning acoustic microscopy (SAM). The amount of glycosaminoglycan content was assessed by alcian blue staining. Gene and protein expressions related to fibrosis, inflammation, and chondrogenesis were analyzed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Furthermore, the total genes of the two groups were compared by DNA microarray analysis. RESULTS: The number of cells was significantly higher and the capsular tissue was significantly stiffer in idiopathic frozen shoulders compared with shoulders with rotator cuff tears. Staining intensity of alcian blue was significantly stronger in idiopathic frozen shoulders. Gene expressions related to fibrosis, inflammation, and chondrogenesis were significantly higher in idiopathic frozen shoulders compared with shoulders with rotator cuff tears assessed by both qPCR and DNA microarray analysis. CONCLUSION: In addition to fibrosis and inflammation, which used to be considered the main pathology of frozen shoulders, chondrogenesis is likely to have a critical role in pathogenesis of idiopathic frozen shoulders. PMID- 22233813 TI - Reply to "Human genetic studies on osteoarthritis from clinicians' viewpoints". PMID- 22233814 TI - Echinocandins: are they all the same? AB - The discovery of echinocandins, and their development and approval, was hailed as a significant addition to our antifungal armamentarium, previously predominated by polyenes and azoles. To date, three echinocandins (anidulafungin, caspofungin, and micafungin) have been approved by the U.S. Food and Drug Administration for the treatment of fungal infections. Since all three echinocandins target the fungal cell wall and share a similar structural chemical backbone, they are perceived to be identical. However, a scientific literature review shows distinct differences among the echinocandins in terms of in vitro activity, fungicidal activity, post-antifungal effect, paradoxical effect, and activity on biofilms. More investigation is warranted to determine if the observed differences among the echinocandins can translate to clinical advantages. PMID- 22233815 TI - Thalidomide: an old drug with new action. AB - Thalidomide is a drug that, since its development, has made history in the world of medicine--having been withdrawn and now has returned with a boom as an anticancer and immunomodulatory drug. However, its mode of action in various diseases (i.e. different types of hematologic malignancies, solid tumors) as well as in various infections (i.e. pneumonia, tuberculosis, HIV infection etc.) and related inflammatory conditions is not well understood. As the immune system plays an important role in the pathogenesis of both infection-related as well as noninfectious (i.e. cancer) inflammatory diseases, much research has been done in the past few years to discover and design better immunomodulatory agents. Such immunomodulatory agents should be able to target the immune system in such a way that host suffers minimum damage and normal function of the immune system remains intact. In the present review an attempt is made to highlight the immunomodulatory action of thalidomide in various pathologic conditions. PMID- 22233816 TI - In vitro activity studies of doripenem and two other carbapenems tested against Pseudomonas aeruginosa and other non-fermentative bacilli. AB - Over the past decade, an increasing prevalence of infections caused by non fermenting Gram-negative bacteria has been reported in many countries. Among these bacteria, Pseudomonas aeruginosa and Acinetobacter baumannii have been associated with high mortality and treatment failures. Treatment options for multidrug-resistant P. aeruginosa and A. baumannii infections are limited to carbapenems in most cases. The mechanisms of carbapenem resistance have been identified in P. aeruginosa and other Gram-negative non-fermenters, including enzyme production, overexpression of efflux pumps, porin deficiencies, and target site alterations. This article reviews the in vitro activity of doripenem and compares it with that of imipenem and meropenem against a large collection of non fermenting Gram-negative bacilli, obtained in worldwide surveillance studies between 2000 and 2010. A detailed examination of the available data demonstrate that doripenem has more potent in vitro antibacterial activity against P. aeruginosa and Acinetobacter species compared to other carbapenems. Furthermore, doripenem has a limited ability to select for carbapenem-resistant mutants in vitro. PMID- 22233817 TI - Impact of ceftriaxone de-restriction on the occurrence of ESBL-positive bacterial strains and antibiotic consumption. AB - As a cost-saving measure, the Drug and Therapeutics Committee (DTC) removed ceftriaxone from the list of restricted antibiotics in May, 2008, which permitted its use as a first-line antibiotic. To evaluate the impact of this change, the occurrence of extended-spectrum beta-lactamase (ESBL)-positive bacterial strains and antibiotic consumption were monitored for 2 years before and after the intervention. In the post-intervention period, ceftriaxone utilization increased, while total antibiotic utilization did not change significantly. The utilization of all restricted antibiotics decreased (p <0.05) in the post-intervention period. Utilization of carbapenems increased (p <0.05), while utilization of quinolones increased nonsignificantly. The density of resistant ESBLs increased (p = 0.001) from 0.99 to 1.34 per 1000 bed-days from the pre- to the postintervention period. Ceftriaxone use was significantly correlated with ESBL occurrence (p <0.005). It can be concluded that ceftriaxone de-restriction increased the occurrence of ESBLs and the utilization of carbapemens. PMID- 22233818 TI - Is tigecyclin a good choice in the treatment of multidrug-resistant Acinetobacter baumannii pneumonia? AB - The aim of this study was to evaluate the efficacy of tigecycline in multidrug resistant (MDR) Acinetobacter baumannii pneumonia. We retrospectively evaluated the outcome of adult patients with culture proven MDR A. baumannii pneumonia treated with tigecycline between January 2009 and March 2011. The study comprised a total of 72 MDR A. baumannii pneumonia cases (44 men, mean age 65.9+/-15.0). Tigecycline was used for a mean duration of 10.7+/-4.8 days. Microbiological eradication was observed in 47 cases (65.3%). Overall mortality was 55.5% and was lower in cases with microbiological eradication vs others (15/47 32% vs 25/25 100%, p<0.0001). Mortality and microbiological eradication rates were not different with monotherapy vs combination therapy (p>0.05). Patients who died had lower albumin levels, higher APACHE-II scores and CRP levels. The microbiological eradication rate of tigecycline in MDR A. baumannii was considerable. However, eradication of A. baumannii did not result in favorable clinical outcomes in those patients with low albumin, higher APACHE-II scores and CRP levels. PMID- 22233819 TI - A switch therapy protocol with intravenous azithromycin and ciprofloxacin combination for severe, relapsing chronic bacterial prostatitis: a prospective non-comparative pilot study. AB - Chronic bacterial prostatitis (CBP) is characterized by intense clinical symptoms, frequent relapse episodes and poor quality of life. Aggressive antibacterial therapy is warranted to eradicate the causative pathogens and to achieve a permanent cure. We administered a "switch-therapy" protocol to 30 patients showing severe CBP symptoms and two or more relapse episodes in the previous 12 months. Patients received intravenous azithromycin (500 mg/day) and ciprofloxacin (800 mg/day) for 3 days, followed by oral ciprofloxacin (1 g/day) for 25 days.Twenty-seven (90%) patients showed pathogen eradication at test-of cure (TOC) visit. Five cases of infection relapse were detected at follow-up. At the TOC visit, 25 patients (83%) showed mild/absent symptoms, measured with the NIH-chronic prostatitis symptom index.These results indicate the efficacy of a "switch-therapy" protocol, based on combined azithromycin and ciprofloxacin. Comparative studies on larger CBP patient populations are warranted to confirm these encouraging results. PMID- 22233820 TI - Relationship between thymidylate synthase and p53 and response to FEC versus taxane adjuvant chemotherapy for breast carcinoma. AB - Many drugs can be used for adjuvant therapy of breast cancer, including anthracyclines, cyclophosphamide, 5-fluorouracil (5-fU) and, recently, taxanes (TXT) have shown promising results. 5-FU blocks thymidylate synthase (TS) which cross-links p53 mRNA, inhibiting its synthesis. TS overexpression is one of the main mechanisms involved in 5-FU drug resistance. Enough p53 mutations can confer resistance to chemotherapy using anthracyclines and 5-FU, while are associated with improved responses to TXT. The aim of this study was to examine the TS and p53 levels in tumor samples and to compare the efficacy of FEC (5-FU, epirubicin, cyclophosphamide) and TXT chemotherapy in a group of patients with differing TS and p53 status. We examined 84 breast tumor samples using immunohistochemistry. TS and p53 levels were inversely related, and TS and p53 positivity was significantly associated with the failure of FEC treatment and with a good response to TXT therapy (p <0.001). This confirms the predictive role of these two markers, which should be considered when choosing the appropriate adjuvant therapy for breast cancer. PMID- 22233821 TI - FOLFIRI chemotherapy in patients with advanced non resectable esophageal or junctional adenocarcinoma: a pilot study. AB - In this prospective pilot study, we assessed the efficacy and safety of the FOLFIRI regimen (irinotecan 180 mg/m2, leucovorin 200 mg/m2 d1 followed by bolus 400 mg/m2 5-fluorouracil (5-FU) and by a 46-h 2400 mg/m2 5-FU infusion, every 2 weeks) in patients with advanced esophageal or junctional adenocarcinoma. Twenty nine patients were included. A complete response was obtained in 2 patients, a partial response in 7 patients (objective response rate 31.0%). Stable disease was obtained in 13 patients (disease control rate 75.9%). The median progression free and overall survivals were 5.9 and 8.6 months, respectively. One patient died from chemotherapy-related diarrhea after one cycle but this patient presented concomitant disease progression with cerebral metastases. We observed one additional grade 4 diarrhea, one grade 3 vomiting, and two grade 3 neutropenias. To conclude, FOLFIRI regimen appears quite active, with an acceptable safety profile in patients with advanced esophageal or junctional adenocarcinoma. PMID- 22233822 TI - Chronic anemia due to mitomycin C is drug dose-dependent, normocytic, progressive, related to erythropoietin levels and quantitatively predictable: implications for radiochemotherapy. AB - Mitomycin C (MC) is used as therapy against solid tumors, also combined with other chemotherapeutic agents or radiotherapy. It may cause acute, subacute, or chronic anemia capable of modifying the results of chemo- and radiotherapy. Erythropoietin may be lowered by cancer itself or because of chemoradiotherapy. There are few studies investigating the relationship between erythropoietin and chronic anemia.We prospectively analyzed the chronic anemia and erythropoietin in 38 patients with solid cancer. Patients were 40 to 82 years of age. MC was randomly given every 3 weeks as a single drug at 10 or 20 mg/m2. When myelotoxicity occurred the next therapy cycle was delayed until recovery. RBC indices, hemolysis, erythropoietin, liver and kidney function were studied. MC cycles were 136 (3.6 +/- 1.4 per pt), 32 being delayed because of myelotoxicity.Hematocrit, hemoglobin and RBC were inversely related to the cumulative dose (r = 0.70 to 0.86; p 0.03 to 0.01) of MC. Other tests remained stable. Anemia occurred almost twofold earlier in the 20 mg/m2 group (p=0.049). basal erythropoietin, already lower than in age and sex watched 81 non cancerous subjects (p<0.001), decreased during MC therapy (p<0.01). For each given MC mg/m2 a 0.0372 Hb mg/dl reduction occurred. Chronic anemia due to MC is accompanied by erythropoietin reduction. These results can help in designing chemoradiotherapy. PMID- 22233823 TI - Effect of topotecan as second-line chemotherapy for small cell lung cancer patients with interstitial lung disease. AB - Small cell lung cancer with interstitial lung disease (ILD-SCLC) is difficult to treat because of the risk of fatal pneumonitis. Our study aims to evaluate the validity of topotecan (TOP) as chemotherapy for patients with relapsed ILD-SCLC. Overall survival was compared between TOP and other drugs as second-line treatments for ILD-SCLC patients. Forty-seven patients began chemotherapy and second-line treatment was administered in 48.5% of relapsed cases. The response rate of TOP for second-line therapy was 16.7%. Hematologic toxicities were grade 4 anemia, grade 3 neutropenia and grade 3 thrombocytopenia. Mild pulmonary toxicity was observed in 1 case. Patients receiving TOP as second-line treatment showed no significant difference in survival when compared to patients who underwent other regimens (median survival time 179 vs. 76 days; p =0.76). TOP is a well tolerated drug and is a viable candidate for second-line treatment of ILD SCLC patients. PMID- 22233824 TI - In vitro selection and transferability of antibiotic resistance in the probiotic strain Lactobacillus reuteri DSM 17938. PMID- 22233825 TI - Emergence of 16s rRNA methylase-producing nosocomial Acinetobacter baumannii isolates in a university hospital in Bulgaria. PMID- 22233826 TI - Klebsiella pneumoniae septic wrist arthritis successfully treated with ertapenem and levofloxacin. PMID- 22233827 TI - Erysipelas-cellulitis of the leg: impact of the application of a guideline in an infectious diseases unit. PMID- 22233828 TI - A case of fluconazole, voriconazole-resistant Cryptococcus neoformans isolated from and immunocompetent patient. PMID- 22233829 TI - Impact of Taenia solium neurocysticercosis upon endocrine status and its relation with immuno-inflammatory parameters. AB - Neurocysticercosis (NC) is a parasitic disease caused by the infiltration of the larval stage of Taenia solium in the central nervous system. Clinical presentations are heterogeneous and particularly depend, on the age and gender of the host. We designed a clinical study to evaluate the hormonal changes associated with neurocysticercosis and the relationships between disease heterogeneity, endocrine and immunological status. A total of 50 patients and 22 healthy subjects were included. A precise clinical and radiological description of disease for each patient was recorded. A broad hormonal profile was assessed for each participant and, in a sub-group of patients, immunological features were also evaluated. Compared with controls, all patients had lower dehydroepiandrosterone (DHEA) concentration; male patients also had lower concentrations of 17beta-estradiol and higher concentrations of luteinising hormone (LH). In the clinically severe patients, lower concentrations of progesterone and androstenedione were found in women. Higher concentrations of follicle stimulating hormone (FSH) and lower concentrations of testosterone were found in men when compared with the less clinically severe patients. Significant correlations were found between estradiol and IL-10 in male patients, and between dehydroepiandrosterone (DHEA) and IL-1beta, and androstenedione and IL-17 in female patients. To our knowledge the present study constitutes the first demonstration that the presence of T. solium larvae in the central nervous system can modify the host environment by the induction of endocrine and immunological changes. These results provide a stimulating background to analyse the repercussions of these changes on the course of the disease and on patient reproductive health. PMID- 22233830 TI - A highly sensitive DNA bead-based suspension array for the detection and species identification of bovine piroplasms. AB - Piroplasms are among the most harmful tick-borne pathogens for livestock and sensitive and specific diagnostic methods for rapid detection and identification of the different species are needed for effective control. Reverse Line Blot has been the molecular technique of choice but it is laborious, time-consuming and highly susceptible to subjective variation in the interpretation of the hybridisation signal. Here, an oligonucleotide multiplex suspension microarray (Luminex(r) microsphere system) was developed for bovine piroplasms. Probes previously used in Reverse Line Blot for Babesia divergens, Babesia bovis, Babesia occultans, Babesia bigemina and Theileria buffeli, and a catch-all Theileria and Babesia control probe, were included in the Luminex assay together with newly designed probes for Theileria annulata and Babesia major. An internal amplification control that was detected with a Luminex probe was included to monitor for inhibition. Serially diluted linearised recombinant plasmids of the different species were used to assess the analytical sensitivity and specificity, and the detection limit of the Luminex assay was determined using serial dilutions of infected blood from an animal with a known level of T. annulata parasitaemia. The assay was then validated on 214 bovine blood samples analysed in parallel by Reverse Line Blot and Luminex. The Luminex assay proved to be highly specific and more sensitive than Reverse Line Blot, detecting 0.05 parasites/MUl of blood. Technically, the Luminex procedure was rapid, provided high throughput screening, transformed the subjective interpretation of Reverse Line Blot results into numerical objective values, and allowed more flexibility in array preparation than Reverse Line Blot. The method described herein can substantially improve the detection of piroplasm carriers and thus better protect livestock trade and facilitate preventive control programs. PMID- 22233831 TI - Inhibition of dendritic cell migration by transforming growth factor-beta1 increases tumor-draining lymph node metastasis. AB - BACKGROUND: Transforming growth factor (TGF)-beta is known to be produced by progressor tumors and to immobilize dendritic cells (DCs) within those tumors. Moreover, although TGF-beta1 has been shown to promote tumor progression, there is still no direct, in vivo evidence as to whether TGF-beta1 is able to directly induce distant metastasis. METHODS: To address that issue and investigate the mechanism by which TGF-beta1 suppresses DC activity, we subdermally inoculated mouse ears with squamous cell carcinoma cells stably expressing TGF-beta1 or empty vector (mock). RESULTS: The numbers of DCs within lymph nodes draining the resultant TGF-beta1-expressing tumors was significantly lower than within nodes draining tumors not expressing TGF-beta1. We then injected fluorescently labeled bone marrow-derived dendritic cells into the tumors, and subsequent analysis confirmed that the tumors were the source of the DCs within the tumor-draining lymph nodes, and that there were significantly fewer immature DCs within the nodes draining TGF-beta1-expressing tumors than within nodes draining tumors not expressing TGF-beta1. In addition, 14 days after tumor cell inoculation, lymph node metastasis occurred more frequently in mice inoculated with TGF-beta1 transfectants than in those inoculated with the mock transfectants. CONCLUSIONS: These findings provide new evidence that tumor-derived TGF-beta1 inhibits migration of DCs from tumors to their draining lymph nodes, and this immunosuppressive effect of TGF-beta1 increases the likelihood of metastasis in the affected nodes. PMID- 22233832 TI - Microvascular breast reconstruction and lymph node transfer for postmastectomy lymphedema patients. AB - OBJECTIVE: Postoperative lymphedema after breast cancer surgery is a challenging problem. Recently, a novel microvascular lymph node transfer technique provided a fresh hope for patients with lymphedema. We aimed to combine this new method with the standard breast reconstruction. METHODS: During 2008-2010, we performed free lower abdominal flap breast reconstruction in 87 patients. For all patients with lymphedema symptoms (n = 9), we used a modified lower abdominal reconstruction flap containing lymph nodes and lymphatic vessels surrounding the superficial circumflex vessel pedicle. Operation time, donor site morbidity, and postoperative recovery between the 2 groups (lymphedema breast reconstruction and breast reconstruction) were compared. The effect on the postoperative lymphatic vessel function was examined. RESULTS: The average operation time was 426 minutes in the lymphedema breast reconstruction group and 391 minutes in the breast reconstruction group. The postoperative abdominal seroma formation was increased in patients with lymphedema. Postoperative lymphoscintigraphy demonstrated at least some improvement in lymphatic vessel function in 5 of 6 patients with lymphedema. The upper limb perimeter decreased in 7 of 9 patients. Physiotherapy and compression was no longer needed in 3 of 9 patients. Importantly, we found that human lymph nodes express high levels of endogenous lymphatic vessel growth factors. Transfer of the lymph nodes and the resulting endogenous growth factor expression may thereby induce the regrowth of lymphatic network in the axilla. No edema problems were detected in the lymph node donor area. CONCLUSION: Simultaneous breast and lymphatic reconstruction is an ideal option for patients who suffer from lymphedema after mastectomy and axillary dissection. PMID- 22233834 TI - Synthesis of high-density nickel cobalt aluminum hydroxide by continuous coprecipitation method. AB - Spherical nickel cobalt aluminum hydroxide (Ni(0.80)Co(0.15)Al(0.05)-hydroxide, NCA) was prepared by a continuous coprecipitation method. A new design of the Al solution and the feeding method was applied, which enabled to prevent rapid precipitation of Al(OH)(3) and to obtain spherical NCA with large enough particle size and high density. The active material (LiNi(0.80)Co(0.15)Al(0.05)O(2) or LNCA) prepared from it showed higher tap-density than that made from NCA prepared by general processes, and homogeneity of Al-distribution was also improved. It is expected that the electrode density of lithium ion batteries adopting LNCA could be improved with the new process proposed in this study. PMID- 22233833 TI - Does GP training in depression care affect patient outcome? - A systematic review and meta-analysis. AB - BACKGROUND: Primary care practices provide a gate-keeping function in many health care systems. Since depressive disorders are highly prevalent in primary care settings, reliable detection and diagnoses are a first step to enhance depression care for patients. Provider training is a self-evident approach to enhance detection, diagnoses and treatment options and might even lead to improved patient outcomes. METHODS: A systematic literature search was conducted reviewing research studies providing training of general practitioners, published from 1999 until May 2011, available on the electronic databases Medline, Web of Science, PsycINFO and the Cochrane Library as well as national guidelines and health technology assessments (HTA). RESULTS: 108 articles were fully assessed and 11 articles met the inclusion criteria and were included. Training of providers alone (even in a specific interventional method) did not result in improved patient outcomes. The additional implementation of guidelines and the use of more complex interventions in primary care yield a significant reduction in depressive symptomatology. The number of studies examining sole provider training is limited, and studies include different patient samples (new on-set cases vs. chronically depressed patients), which reduce comparability. CONCLUSIONS: This is the first overview of randomized controlled trials introducing GP training for depression care. Provider training by itself does not seem to improve depression care; however, if combined with additional guidelines implementation, results are promising for new-onset depression patient samples. Additional organizational structure changes in form of collaborative care models are more likely to show effects on depression care. PMID- 22233835 TI - Prevalence of serum anti-rubella virus antibodies among pregnant women in southern Italy. AB - OBJECTIVE: To determine the prevalence of anti-rubella virus antibodies and the level of knowledge about congenital rubella syndrome (CRS) among pregnant women living in southern Italy. METHODS: A seroepidemiologic study was conducted between July 1, 2006, and December 31, 2007. Five-hundred women resident in Messina were enrolled in the study; the participants were in the 4th to 39th week of pregnancy. Anti-rubella virus antibodies were assayed using a microparticle enzyme immunoassay. Demographic details, vaccination history, and participants' knowledge of the potential risks of rubella infection during pregnancy were assessed via questionnaire. RESULTS: On the basis of the questionnaire results, 70.4% of women were classed as immune to rubella virus infection; however, the prevalence of IgG anti-rubella virus antibodies measured in the participants' serum was 85.8%. Although 55.2% of women had undergone pre-pregnancy rubella screening, only 81 participants reported that they had been vaccinated before becoming pregnant. The participants' general knowledge about CRS was poor, as was their understanding of the importance of undergoing screening. CONCLUSION: The number of women at risk of rubella infection fell short of the national target set for elimination of CRS. Increased involvement and collaboration by all healthcare workers are, therefore, required to disseminate the information necessary to prevent CRS. PMID- 22233836 TI - Immunohistochemical study on the ontogenetic development of the regional distribution of peptide YY, pancreatic polypeptide, and glucagon-like peptide 1 endocrine cells in bovine gastrointestinal tract. AB - The regional distribution and relative frequency of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and glucagon-like peptide 1 (GLP-1)-immunoreactive (IR) cells were determined immunohistochemically in the gastrointestinal tract at seven ontogenetic stages in pre- and postnatal cattle. Different frequencies of PYY-, PP-, and GLP-1-IR cells were found in the intestines at all stages; they were not found in the esophagus and stomach. The frequencies varied depending on the intestinal segment and the developmental stage. The frequencies of PYY- and PP-IR cells were lower in the small intestine and increased from ileum to rectum, whereas GLP-1-IR cells were more numerous in duodenum and jejunum, decreased in ileum and cecum, and increased again in colon and rectum. The frequencies also varied according to pre- and postnatal stages. All three cell types were most numerous in fetus, and decreased in calf and adult groups, indicating that the frequencies of these three types of endocrine cells decrease with postnatal development. The results suggest that these changes vary depending on feeding habits and adaptation of growth, secretion, and motility of intestine at different ontogenetic stages of cattle. PMID- 22233838 TI - [Accidents and emergencies, year zero. Over 100 words, over 100 causes]. PMID- 22233837 TI - Atrial fibrillation after pulmonary lobectomy for lung cancer affects long-term survival in a prospective single-center study. AB - BACKGROUND: Atrial fibrillation (AF) after thoracic surgery is a continuing source of morbidity and mortality. The effect of postoperative AF on long-term survival however has not been studied. Our aim was to evaluate the impact of AF on early outcome and on survival > 5 years after pulmonary lobectomy for lung cancer. METHODS: From 1996 to June 2009, 454 consecutive patients undergoing lobectomy for lung cancer were enrolled and followed-up until death or study end (October 2010). Patients with postoperative AF were identified; AF was investigated with reference to its predictors and to short- and long-term survival (> 5 years). RESULTS: Hospital mortality accounted for 7 patients (1.5%), while postoperative AF occurred in 45 (9.9%). Independent AF predictors were: preoperative paroxysmal AF (odds ratio [OR] 5.91; 95%CI 2.07 to 16.88), postoperative blood transfusion (OR 3.61; 95%CI 1.67 to 7.82) and postoperative fibro-bronchoscopy (OR 3.39; 95%CI 1.48 to 7.79). Patients with AF experienced higher hospital mortality (6.7% vs. 1.0%, p = 0.024), longer hospitalization (15.3 +/- 10.1 vs. 12.2 +/- 5.2 days, p = 0.001) and higher intensive care unit admission rate (13.3% vs. 3.9%, p = 0.015). The median follow-up was 36 months (maximum: 179 months). Among the 445 discharged subjects with complete follow-up, postoperative AF was not an independent predictor of mortality; however, among the 151 5-year survivors, postoperative AF independently predicted poorer long term survival (HR 3.75; 95%CI 1.44 to 9.08). CONCLUSION: AF after pulmonary lobectomy for lung cancer, in addition to causing higher hospital morbidity and mortality, predicts poorer long-term outcome in 5-year survivors. PMID- 22233839 TI - [The short version of Critical Care Family Needs Inventory (CCFNI): adaptation and validation for a spanish sample]. AB - Relatives play an important role in the disease process of patients admitted to Intensive Care Units (ICU). It is therefore important to know the needs of people close to the patient in order to try to improve their adaption to a situation as difficult as an ICU admission. The aim of this study was the adaptation and validation of the short version of the Critical Care Family Needs Inventory (CCFNI) for a Spanish sample. The inventory was applied to 55 relatives of patients admitted to the ICU of the Hospital General de Castellon. After the removal of three items for different reasons, we performed an Exploratory Factor Analysis with the 11 remaining items to determine the factor structure of the questionnaire. We also made a descriptive analysis of the items, and internal consistency and construct validity were calculated through Cronbach's alpha and Pearson correlation coefficient respectively. The results of the principal components factor analysis using varimax rotation indicated a four-factor solution. These four factors corresponded to: medical attention to the patient, personal attention to the relatives, communication between the family and the doctor, and perceived improvements in the Unit. The short version of CCFNI showed good internal consistency for both the total scale and factors. The results suggest that the CCFNI is a suitable measure for assessing the different needs presented by the relatives of patients admitted to an Intensive Care Unit, showing adequate psychometric properties. PMID- 22233840 TI - [Metabolic syndrome and its components in patients with sleep apnea syndrome]. AB - BACKGROUND: Sleep Apnea Syndrome (SAHS) represents a significant risk factor for the development of cardiovascular disease and evidence suggests a relation with Metabolic Syndrome (MS). The aim of this study was to determine the prevalence of individual components of MS and of MS as an entity, in patients with clinical suspicion of SAHS, and their relation to central obesity. METHODS: We examined the records of 486 consecutive patients, 359 (73.9%) men, with a mean age of 57.3 +/- 13.5 years and a mean body mass index (BMI) of 32.1 +/- 6.5 kg/m(2)), with clinical suspicion of SAHS. SAHS was diagnosed from the nocturnal register. An Apnea-Hipopnea Index (AHI) > 5 was considered SAHS. MS was evaluated according to the diagnostic criteria of the International Diabetes Federation. RESULTS: Three hundred and twenty-five (66.9%) of the entire group were moderate-severe SAHS. The mean of AHI was 30.2 +/- 23.8. We had sufficient data available on 456 patients (93.8%) for MS diagnosis and its prevalence was 64.7% (295 patients). Multivariate analysis showed that age and abdominal perimeter were predictors of SAHS and MS (p<0.05). CONCLUSIONS: Patients with SAHS have a high prevalence of MS and their prevalence is greater in patients with major levels of SAHS. The rate of central obesity, measured by abdominal perimeter, predicts SAHS and MS. PMID- 22233841 TI - [Nursing registers on sleep and patient perception in a psychiatric unit. A comparative study]. AB - BACKGROUND: Insomnia is a frequent problem in people who suffer from mental illnesses. The nursing staff control and register whether or not patients sleep. The aim of this article is to analyze the concordance between the perceptions of the patients of a psychiatric unit on the quality of sleep, and the notes in this respect contained in the nursing records. METHODS: A comparative study between the answers given by the patients of our unit to 126 questions on insomnia on specific nights, and what was reflected in their nursing records. A reduced version of the Athens Insomnia Scale (AIS-5) was used. RESULTS: The average value obtained according to the patients' answers was higher (worse sleep) than that given by the nurses, both globally and by item. The nursing records showed much lower values than those given by the patient; Pearson's correlation analysis gave a coefficient of 0.26. Analysis of the degree of agreement provided an index of 0.13 that does not differ significantly from nil agreement. CONCLUSIONS: There is a difference between the nursing observations and the subjective sensations of the patients about how they sleep. They indicate that they sleep worse than the nursing records reflect. External observation and self-perception are not antagonistic aspects, but two complementary aspects of patients' sleep. PMID- 22233842 TI - [Evaluation of results of a program of Responsible Alcoholic Beverage Dispensing]. AB - Selective prevention programs in the Responsible Dispensing of Beverages (DRA - Dispensacion Responsable de Bebidas Alcoholicas) have provided varying evidence of their effectiveness in other countries. In Spain, however, data is only available for the implementation of DRA in Barcelona. This article has two aims: to assess the effectiveness of an intervention in DRA with waiters in Pamplona, and to evaluate individual and group results in order to identify areas for improvement. The sample consisted of 40 hostelry professionals who participated in one of the 4 courses of DRA. Questionnaires were used to measure pre-/post knowledge, attitudes, perceived self-efficacy and expectations about the training. We present descriptive analyses of all the variables and individual and overall results of the evolution of each participant. The DRA program provides overall data of significant improvements in knowledge, attitudes and expectations. The results show the need to consider the analysis of the evolution of individual subjects in each item. PMID- 22233843 TI - [Identification of problems and proposals for improving outpatient emergency care in Navarre: a Delphi study]. AB - BACKGROUND: Two years ago there were alterations to outpatient A and E departments in Navarre; in particular, a rural A and E service (Servicio de Urgencias Rural- SUR) was set up, which coexists geographically with the normal A and E service. The aim of this study is to determine the opinion of experts on problems and recommendations for improvements that affect outpatient A and E services. METHODOLOGY: A Delphi study was carried out with the participation of 37 experts (doctors and nurses). Three successive rounds of questionnaires were completed using email. The final questionnaire identified degree of agreement with the group's ideas, and the 15 most relevant problems and recommendations were identified; those ideas that were selected achieved at least 50% agreement and their priority was above 25%. We grouped the ideas using a hierarchic cluster analysis. RESULTS: Four cluster problems were identified; the most outstanding amongst them being "the population uses A and E for banal pathologies, just like any other consultation" with a score of 297 points. Outstanding amongst the recommendations, with 3 identified clusters, were the "need to design a strategic plan for A and E care with resources appropriate to the needs" (310 priority points) and "sending clear messages to the population on the correct use of A and E" (192 priority points). CONCLUSION: The Delphi method identifies problems and improvement areas through consensus. PMID- 22233844 TI - [Initiating breastfeeding: experiences of first-time mothers]. AB - BACKGROUND: Breastfeeding is important for promoting the healthy development of the newborn. Despite its benefits, the abandonment of breastfeeding is massive in the first three months of life. The aim of this research was to explore how first time mothers perceived and experienced breastfeeding in order to identify issues affecting its establishment. METHODS: A qualitative study with a descriptive phenomenological approach was used. Twelve first-time mothers were interviewed in depth on two occasions: once a few days after childbirth, and another time one month from giving birth. The data were recorded and transcribed verbatim. Giorgi's method was used for the analysis. RESULTS: The essential meaning of the experience undergone by the mothers who took part in this study can be described by the following five themes: an idealization of breastfeeding; uncertainty over the difficulties; a desire for privacy during breastfeeding; shared responsibility with the child for breastfeeding to succeed; and, finally, disruption to the women's lives and changes in their role. CONCLUSIONS: This study allowed access to the experiences of first-time mothers during the establishment of breastfeeding. This information will facilitate the design of tailored interventions taking into account the mothers' reports. Health professionals should: consider women's expectations and how they face their new role, provide practical and emotional support, be consistent and avoid giving conflicting advice, and acknowledge the importance of the fathers' support. PMID- 22233845 TI - [Evaluation of the Sentinel Surveillance Program in Occupational Health in Navarra (1998-2007)]. AB - BACKGROUND: To evaluate the Sentinel Surveillance Program in Occupational Health in Navarre for the 1998-2007 period, identify factors that facilitate its implementation and describe the socioeconomic characteristics of the notified cases. METHOD: An analysis was made of all occupational sentinel events reported by primary care between 1998 and 2005. All of these were followed through to 2007. RESULTS: In the whole period 2,055 cases were notified; 1,223 with personal identifications and 832 without (59.5% and 40.5%). These included 1,192 elbow tendinitis, 354 carpal tunnel and 417 dermatitis cases. This represents an incidence rate of 332.8 per 100,000 workers in 2005. Only 21% took sick leave and 10.5% had come to primary care after being refused attention by occupational medical insurers. The positive predictive value was 70% (confirmed as occupational). 41% of those work-related diseases were officially notified, 51% received official notification first and the remaining 49% received notification after being seen by a doctor in the public health system. CONCLUSIONS: The Sentinel Surveillance Program in Occupational Health in Navarra is a good experience in obtaining an information system that connects the public health system and the occupational compensation system in Spain, but it requires close monitoring and coordination. PMID- 22233846 TI - [Preliminary study of the characteristics of attempted suicide in the province of Granada]. AB - BACKGROUND: Suicides account for a number of deaths that is higher than other traumatic deaths in Spain. Non-fatal suicidal behaviour occurs in a greater proportion than such behaviour with a deadly outcome. There are many causes for this behaviour and it is important to become familiar with them if it is to be prevented. The aim of this article is to describe the characteristics of non mortal suicidal behaviour in the province of Granada. METHOD: A retrospective descriptive study of the characteristics of non-mortal suicidal behaviour in Granada during the years 2008 and 2009, according to the database of the Provincial 061 Service in Granada. The sample includes the demands made to this service in which the literal reason for the alert included the terms: suicide, self-harm or the threat of suicide. The statistical analysis was done with the SPSS 15.0 program. We analyzed the variable non-mortal suicidal behaviour with respect to the independent variables: sex, age, month, day of the week, time slot, health district, resolution of the demand (assigned priority) and further attempts. RESULTS: In total we analyzed 535 demands typified as intentional self injury by unspecified means. Statistically significant differences were found when comparing the data for the two years with respect to the month chosen, and in the relationship between age range and time slot of the suicide attempts. CONCLUSIONS: Despite its limitations, the characterization of suicidal behaviour in our province offers essential information, and could be useful in designing and developing a program of psychosocial intervention for the prevention of suicidal behaviour adjusted to the specific profiles of our population. PMID- 22233847 TI - [A review of questionnaires exploring driver's exposure and risk factors in road crashes]. AB - Given the diversity of questionnaires currently being used in the study of the analytic epidemiology of traffic injuries, we made a review of studies on this question published between 1989 and 2011 in order to identify their advantages and disadvantages. We were able to observe that most of the questionnaires were focused on the human factor regarding the risk of road crashes, but very few of them included intensity of exposure and its association with other risk factors in road crashes. Many questionnaires have a high number of items and complex rating scales. Furthermore, in Spain there are few validated questionnaires which contain complete information about exposure and road crashes. In Spain we should work on the design and validation of questionnaires containing questions aimed at obtaining complete and easy information about the epidemiology of traffic injuries. In this way we would be able to increase our awareness of traffic injuries and how to prevent them. PMID- 22233848 TI - [Cystinuria: diagnosis and therapeutic approach]. AB - Cystinuria is an aminoaciduria due to the impairment of transport of cystine and dibasic amino acids (arginine, ornithine, and lysine) in the apical membrane of the intestinal epithelium and proximal renal tubule. The result is an absence of cystine reabsorption in the renal tubule producing an excess of cystine in urine and stone formation. Unlike the other stones, cystine stones are very difficult to eliminate with lithotripsy. Noninvasive therapy should therefore be used to prevent relapse in stone formation. This therapy is based on the use of high fluid intake, urine alkalinization, and chelating agents. In order to preserve renal function, a combination of these three therapeutic measures is necessary to produce a low recurrence and morbidity of the disease. PMID- 22233849 TI - [Dependence and the caring family: reflections for a family approach]. AB - Ageing and dependence, which are closely interrelated, are currently challenging the "family potential for care" and posing the dilemma of whether the family can provide an answer to these new situations where assistance is called for. Elderly dependants have long-term care needs, which are sometimes of great complexity. In order to correctly carry out this care it is necessary to have the necessary training, and this must be done under the supervision and with the support of suitable professionals. Otherwise, the consequences for the person receiving the care will be an additional factor of tension placed on the family model of care. The so-called "caregiver burden" has an impact on the family caregivers and on the family, social and economic environment, as well as on their own health. An integrated approach to care, focused on the family, could enhance the autonomy of these caring families and to some extent alleviate their limitations and suffering. PMID- 22233850 TI - [Asthenia in advanced cancer and the use of psychostimulants]. AB - Asthenia is the most frequent symptom in patients with advanced cancer and is probably what most affects the quality of life of oncology patients since it interferes in their physical and social activity. Treatment in the majority of cases is symptomatic. There is growing interest in the use of psychostimulants for treating asthenia. Methylphenidate and modafinil are two psychostimulants that have already been tested in controlled studies on asthenia of the patient with advanced cancer; they have proved to be efficient, particularly in patients in very advanced stages who are very tired. PMID- 22233851 TI - [Video-assisted resection of a mediastinal hydatid cyst]. PMID- 22233852 TI - Open fracture of a cervical transverse process as a result of a bull-horn wound. PMID- 22233853 TI - [Osteonecrosis of the jaw associated with oral treatment with ibandronate]. PMID- 22233854 TI - [Primitive neuroectodermal tumour of the kidney. A case report]. PMID- 22233855 TI - [Prostatic nephrogenic adenoma. A case report]. PMID- 22233856 TI - [Do people go to the doctor less in times of economic crisis?]. PMID- 22233857 TI - Post traumatic retroperitoneal fibrosis as a cause of low-back pain. AB - We present the case of a male patient with post traumatic retroperitoneal fibrosis whose main clinical expression was low-back pain. Diagnosis was established using CAT-scan and MRI, which revealed a large mass of soft tissue that almost entirely enveloped the abdominal aorta. Treatment with 40 mg of prednisone every 24 hours was established. This dose was reduced gradually, and progressive remission of clinical signs and symptoms was achieved, with a significant improvement of subsequent imaging-test results. Treatment was continued for one year. Two and a half years later the patient remains symptom free, with no recurrence of his condition. PMID- 22233858 TI - [Dural metastasis as the first manifestation of prostate cancer]. AB - Metastases of prostate cancer to intracranial meninges are rare and often confused with meningiomas or chronic subdural hematomas. These usually occur in patients with a known cancer diagnosis in advanced stages of the disease, and only in some rare cases do its manifestations precede the detection of the primary tumour. The clinical presentation is unspecific. However, due to the affinity of this tumour for the base of the skull, it must be included in the differential diagnosis of men over 70 years of age with cranial nerve palsy. The treatment of these lesions has not been standardized. Within the therapeutic options we find surgical resection, chemotherapy, radiotherapy or a combination of these measures, and yet survival is poor. We present the case of a 77 year old male patient whose initial symptoms of prostate cancer were caused by a metastatic lesion to the dura, confirmed by histopathology. We also review the epidemiological, clinical and imaging highlights of this condition. PMID- 22233859 TI - [Subdural empyema secondary to sinusitis. A pediatric case report]. AB - We present the case of 9 year old male referred to the A and E service with right ocular proptosis and progressive migraine in the context of a sinusitis diagnosed two days earlier by compatible clinical and radiological tests, and receiving treatment with amoxicillin-clavulanic acid. Physcial exploration revealed right ocular proptosis with a slight limitation for conjugate gaze. Facing the suspicion of a possible neurological complication of the sinusitis, cranial computer aided tomography (CAT) was carried out, with right frontal subdural empyema observed. He was admitted for intravenous antibiotic treatment with cefotaxime, vancomicin and metronidazole. He was evaluated by child Neurosurgery, Maxillofacial Surgery and Otorhinolaryngology (ORL) services; the decision was taken to only drain the primary focus, while an expectant neurosurgical attitude was maintained. The patient evolved favourably with a progressive disappearance of the symptoms. Periodical magnetic resonances were carried out, which showed a clear improvement up until the complete resolution of the empyema. Following four weeks of antibiotherapy iv., and after clinical and radiological normalization, the patient was discharged. PMID- 22233860 TI - [Urinary retention in immunocompetent patient: acute transverse myelitis]. AB - A heterogeneous group of diseases is included under the term acute transverse myelitis (ATM); these have the common factor of producing an inflammatory focal injury of the spinal cord in an acute form. Understanding of ATM is being constantly improved with the arrival of new diagnostic techniques and theories about its immune origin. Responsibility for making an early diagnosis lies primarily in the field of primary care and must always be based on the completion of a detailed clinical report together with a thorough neurological examination. Once detected, correct handling of the clinical situation will require an urgent referral to a hospital for evaluation and treatment at an early stage by multidisciplinary teams. Early intervention in many of these diseases is vital, because it improves the prognosis of these patients and significantly reduces injuries. PMID- 22233861 TI - [Maturity-onset diabetes of the young type 5: a case report]. AB - MODY-5 diabetes is an infrequent type of monogenic diabetes, caused by mutation in the gene of the nuclear hepatic transcription factor 1-beta (HNF-1beta). This mutation can be of a momentary type or it might correspond to big deletions, and, in its turn, it can appear due to spontaneous de novo mutation or it can be transmitted by hereditary with an autosomal dominant character. It is associated with a high risk of microvascular complications that appear early in affected people, as well as with characteristic renal alterations of the cyst type, and anomalies of the genital tract, which are present even before birth. That is why it is justified to carry out detection tests for HNF-1beta mutations in non-obese diabetics, above all when there are associated renal or genital alterations, without consideration of family antecedents. PMID- 22233862 TI - The antifungal constituents from the seeds of Itoa orientalis. AB - Three new phenolic constituents, itolide A (1), itolide B (2), itoside P (3), and 1D-3-deoxy-3-hydroxymethyl-myo-inositol (4), which is described herein for the first time as a natural product, were isolated along with four other known compounds (5 to 8) from the methanol extract of the seeds of Itoa orientalis Hemsl by the activity-guided fractionation. Their structures were determined by spectroscopic means. Compounds 1 to 8 exhibited antifungal activities against Sclerotium rolfsii with IC50 values ranging from 60.12 to 240.00 MUM and against Rhizoctonia solani with IC50 values ranging from 45.34 to 233.14 MUM, respectively, and compounds 1, 2, 5 exhibited cytotoxic activity against Tn5B1-4 insect cell line with EC50 values of 203.68, 93.41 and 40.37 MUM, respectively. PMID- 22233863 TI - Sesquiterpenes and acetogenins from the marine red alga Laurencia okamurai. AB - Three new halogenated sesquiterpenes, 10-bromo-7alpha,8alpha-expoxychamigr-1-en-3 ol (1), 10-bromo-beta-chamigren-8-ol (2), and 10-bromo-3-chlorocupar-5-en-2-ol (3), one new C12-acetogenin, desepilaurallene (7), one new naturally occurring sesquiterpene, 7-hydroxylaurene acetate (4), two known sesquiterpenes, allolaurinterol acetate (5) and laurene (6), and one known C15-acetogenin, epilaurallene (8), were isolated from the marine red alga Laurencia okamurai collected from the coast of Rongcheng, China. The structures of these compounds were unambiguously established by 1D, 2D NMR and mass spectroscopic techniques. The bioassay results showed that 4, 5 exhibited potent antibacterial activity, and 1, 4, 5 were toxic to brine shrimp. PMID- 22233864 TI - Pyrenocines J-M: four new pyrenocines from the endophytic fungus, Phomopsis sp. AB - Four new pyrenocines, named pyrenocines J-M (1-4), were isolated from an endophytic fungus, Phomopsis sp, by a bioassay-guided method. The structures of the new compound have been assigned from 1H and 13C NMR spectra, DEPT, and by 2D COSY, HMQC, and HMBC experiments. Preliminary studied showed that compounds 1, 2 and 4 showed good antifungal, antibacterial, and algicidal properties, while compound 3 had good antibacterial and algicidal properties. PMID- 22233865 TI - Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells. AB - BACKGROUND: Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet beta cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D. METHODS: We developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n=15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21). RESULTS: Stem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual beta cell function (n=6) and patients with no residual pancreatic islet beta cell function (n=6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n=3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance. CONCLUSIONS: Stem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet beta cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01350219. PMID- 22233877 TI - Handover patterns: an observational study of critical care physicians. AB - BACKGROUND: Handover (or 'handoff') is the exchange of information between health professionals that accompanies the transfer of patient care. This process can result in adverse events. Handover 'best practices', with emphasis on standardization, have been widely promoted. However, these recommendations are based mostly on expert opinion and research on medical trainees. By examining handover communication of experienced physicians, we aim to inform future research, education and quality improvement. Thus, our objective is to describe handover communication patterns used by attending critical care physicians in an academic centre and to compare them with currently popular, standardized schemes for handover communication. METHODS: Prospective, observational study using video recording in an academic intensive care unit in Ontario, Canada. Forty individual patient handovers were randomly selected out of 10 end-of-week handover sessions of attending physicians. Two coders independently reviewed handover transcripts documenting elements of three communication schemes: SBAR (Situation, Background, Assessment, Recommendations); SOAP (Subjective, Objective, Assessment, Plan); and a standard medical admission note. Frequency and extent of questions asked by incoming physicians were measured as well. Analysis consisted of descriptive statistics. RESULTS: Mean (+/- standard deviation) duration of patient-specific handovers was 2 min 58 sec (+/- 57 sec). The majority of handovers' content consisted of recent and current patient status. The remainder included physicians' interpretations and advice. Questions posed by the incoming physicians accounted for 5.8% (+/- 3.9%) of the handovers' content. Elements of all three standardized communication schemes appeared repeatedly throughout the handover dialogs with no consistent pattern. For example, blocks of SOAP's Assessment appeared 5.2 (+/- 3.0) times in patient handovers; they followed Objective blocks in only 45.9% of the opportunities and preceded Plan in just 21.8%. Certain communication elements were occasionally absent. For example, SBAR's Recommendation and admission note information about the patient's Past Medical History were absent from 22 (55.0%) and 20 (50.0%), respectively, of patient handovers. CONCLUSIONS: Clinical handover practice of faculty-level critical care physicians did not conform to any of the three predefined structuring schemes. Further research is needed to examine whether alternative approaches to handover communication can be identified and to identify features of high-quality handover communication. PMID- 22233878 TI - A strategy for phage display selection of functional domain-exchanged immunoglobulin scaffolds with high affinity for glycan targets. AB - Monoclonal antibodies are essential reagents for deciphering gene or protein function and have been a fruitful source of therapeutic and diagnostic agents. However, the use of anticarbohydrate antibodies to target glycans for these purposes has been less successful. Glycans contain less hydrophobic functionality than do proteins or nucleic acids, thus individual glycan-antibody interactions are relatively weak. Information encoded by glycans often involves subtle variations of branched oligosaccharides that cannot be detected with conventional antibodies. Here we describe a new phage display selection strategy for identification of high-affinity and specific glycan antibodies. We designed and characterized a phage clone that functionally displays the unique architectural scaffold of 2G12, an antibody that targets oligomannoses on the HIV-1 glycoprotein gp120. The two heavy chain variable domains of 2G12 exchange positions to create an extended recognition surface containing four oligomannose binding sites per IgG molecule. We designed and characterized a phage clone in which this domain exchange architecture was recapitulated as an antigen binding fragment dimer [(Fab)(2)]on the phage surface by protein engineering. The functional display of the 2G12 (Fab)(2) fragment was validated by Western blot and phage enzyme-linked immunosorbent assay. Furthermore, we demonstrate that this 2G12 (Fab)(2) display system is amenable to selection of functional clones using a mock selection. These results provide proof-of-concept that the privileged 2G12 domain-exchanged scaffold can be used for design of novel antibody libraries that are biased toward glycan recognition. PMID- 22233879 TI - Foot health education for people with rheumatoid arthritis: the practitioner's perspective. AB - BACKGROUND: Patient education is considered to be a key role for podiatrists in the management of patients with rheumatoid arthritis (RA). Patient education has undoubtedly led to improved clinical outcomes, however no attempts have been made to optimise its content or delivery to maximise benefits within the context of the foot affected by rheumatoid arthritis. The aim of this study was to identify the nature and content of podiatrists' foot health education for people with RA. Any potential barriers to its provision were also explored. METHODS: A focus group was conducted. The audio dialogue was recorded digitally, transcribed verbatim and analysed using a structured, thematic approach. The full transcription was verified by the focus group as an accurate account of what was said. The thematic analysis framework was verified by members of the research team to ensure validity of the data. RESULTS: Twelve members (all female) of the north west Podiatry Clinical Effectiveness Group for Rheumatology participated. Six overarching themes emerged: (i) the essence of patient education; (ii) the content; (iii) patient-centred approach to content and timing; (iv) barriers to provision; (v) the therapeutic relationship; and (vi) tools of the trade. CONCLUSION: The study identified aspects of patient education that this group of podiatrists consider most important in relation to its: content, timing, delivery and barriers to its provision. General disease and foot health information in relation to RA together with a potential prognosis for foot health, the role of the podiatrist in management of foot health, and appropriate self-management strategies were considered to be key aspects of content, delivered according to the needs of the individual. Barriers to foot health education provision, including financial constraints and difficulties in establishing effective therapeutic relationships, were viewed as factors that strongly influenced foot health education provision. These data will contribute to the development of a patient-centred, negotiated approach to the provision of foot health education for people with RA. PMID- 22233880 TI - Unique aspects of a shape memory polymer as the substrate for surface wrinkling. AB - Typical bilayer wrinkle systems employ soft elastomers as the substrates. In contrast, shape memory polymers have recently emerged as attractive alternatives. Besides the shape fixing capability, shape memory polymers distinguish from elastomers in that they are rigid at room temperature, but experience significant modulus drop upon heating. We hereby report unique aspects of shape memory polymers as the wrinkle substrate utilizing a metallic thin film as the top layer. The feasibility to create both reversible and irreversible wrinkles (and diffraction colors) on a single substrate is demonstrated. Experimental conditions are identified to create crack free wrinkles and the impact of various experimental parameters on the wrinkle wavelength and amplitude is investigated. The results suggest that the wrinkle mechanics deviate notably from the existing theories established with elastomers as the wrinkle substrates. Thus, a new theory will need to be developed in the future, taking into account of unique thermomechanical properties of the shape memory substrate and possible plastic deformation of the thin film. PMID- 22233881 TI - Clinical and radiological evidence of the recurrence of reversible pegvisomant related lipohypertrophy at the new site of injection in two women with acromegaly: a case series. AB - INTRODUCTION: Pegvisomant-related lipohypertrophy may revert when changing the site of injection, but the lipohypertrophy may recur at the new site of injection. The strength of evidence, however, is weak and comes from information obtained from physical examination only. CASE PRESENTATION: We studied two Caucasian women with acromegaly, aged 51 and 71 years, with pegvisomant-related lipohypertrophy. Our two patients were evaluated at baseline, when the site of pegvisomant injection was the periumbilical abdominal region, and then four months after switching the injection site from the abdomen to both thighs. Both physical examination and radiological studies (magnetic resonance imaging and dual energy X-ray absorptiometry) demonstrated that the abdominal lipohypertrophy progressively reverted in both patients after switching the site of injection to the thighs. However, lipohypertrophy reappeared at the new site of injection. The radiological outcome confirmed the reversibility of pegvisomant-related lipohypertrophy and strengthened the body of evidence on this issue. CONCLUSION: In clinical practice, physical examination of the injection site or sites leads to an early detection of lipohypertrophy during pegvisomant treatment. Radiological procedures may be of help to confirm subcutaneous fat changes and for a precise monitoring of fat redistribution. Patients should get appropriate information about lipohypertrophy before starting pegvisomant treatment since the rotation of the site of injection may prevent lipohypertrophy. PMID- 22233882 TI - Nucleotide polymorphism in the 5.8S nrDNA gene and internal transcribed spacers in Phakopsora pachyrhizi viewed from structural models. AB - The assessment of nucleotide polymorphisms in environmental samples of obligate pathogens requires DNA amplification through the polymerase chain reaction (PCR) and bacterial cloning of PCR products prior to sequencing. The drawback of this strategy is that it can give rise to false polymorphisms owing to DNA polymerase misincorporation during PCR or bacterial cloning. We investigated patterns of nucleotide polymorphism in the internal transcribed spacer (ITS) region for Phakopsora pachyrhizi, an obligate biotrophic fungus that causes the Asian soybean rust. Field-collected samples of P. pachyrhizi were obtained from all major soybean production areas worldwide, including Brazil and the United States. Bacterially-cloned, PCR products were obtained using a high fidelity DNA polymerase. A total of 370 ITS sequences that were subjected to an array of complementary sequence analyses, which included analyses of secondary structure stability, the pattern of nucleotide polymorphisms, GC content, and the presence of conserved motifs. The sequences exhibited features of functional rRNAs. Overall, polymorphisms took place within less conserved motives, such as loops and bulges; alternatively, they gave rise to non-canonical G-U pairs within conserved regions of double stranded helices. We discuss the usefulness of structural analyses to filter out putative 'suspicious' bacterially cloned ITS sequences, thus keeping artificially-induced sequence variation to a minimum. PMID- 22233883 TI - Ten-year stability and variability, drinking patterns, and impairment in community youth with diagnostic orphan status of alcohol dependence. AB - OBJECTIVE: Some adolescents and young adults who do not fulfill criteria for DSM IV alcohol abuse (AA) report symptoms of DSM-IV alcohol dependence (AD) below the diagnostic threshold (diagnostic orphans, DOs; 1 or 2 symptoms). Contemporarily, little is known on the long-term stability, risk of progression to AD, impairment, and drinking patterns possibly associated with this status in the first decades of life. AIM: (1) To identify prevalence rates of the DO status from adolescence to early adulthood. To investigate (2) stability and variability of the DO status over time and (3) associations between DO status, drinking patterns and impairment in comparison to subjects with AA, with AD, or without any symptoms. METHOD: N=2039 community subjects (aged 14-24 years at baseline) were assessed at baseline and at about four and ten years after baseline. DSM-IV AUD diagnoses were obtained with the DIA-X/M-CIDI. RESULTS: About 11-12% of the sample was classified as DOs at all waves. Over a period of ten years, 18% of DOs were stable in their diagnosis and additional 10% progressed to AD. DOs were comparable to subjects with AA in drinking patterns, impairment and stability of diagnostic status. DOs progressed to AD significantly more often than AA. AD was associated with highest levels in all outcomes of interest. CONCLUSIONS: The DO status in adolescence and early adulthood is associated with considerable stability, risk of progression and problematic alcohol intake. In consequence, it can be meaningful for the timely identification of early stages of clinically relevant alcohol problems. For subjects with DO status early specific interventions are required. PMID- 22233884 TI - Chitinase-like proteins are candidate biomarkers for sepsis-induced acute kidney injury. AB - Sepsis-induced acute kidney injury (AKI) is a frequent complication of critically ill patients and leads to high mortality rates. The specificity of currently available urinary biomarkers for AKI in the context of sepsis is questioned. This study aimed to discover urinary biomarkers for septic AKI by contemporary shotgun proteomics in a mouse model for sepsis and to validate these in individual urine samples of mice and human septic patients with and without AKI. At 48 h after uterine ligation and inoculation of Escherichia coli, aged mice (48 weeks) became septic. A subgroup developed AKI, defined by serum creatinine, blood urea nitrogen, and renal histology. Separate pools of urine from septic mice with and without AKI mice were collected during 12 h before and between 36-48 h after infection, and their proteome compositions were quantitatively compared. Candidate biomarkers were validated by Western blot analysis of urine, plasma, and renal tissue homogenates from individual mice, and a limited number of urine samples from human septic patients with and without AKI. Urinary neutrophil gelatinase-associated lipocalin, thioredoxin, gelsolin, chitinase 3-like protein 1 and -3 (CHI3L3) and acidic mammalian chitinase were the most distinctive candidate biomarkers selected for septic AKI. Both neutrophil gelatinase associated lipocalin and thioredoxin were detected in urine of septic mice and increased with severity of AKI. Acidic mammalian chitinase was only present in urine of septic mice with AKI. Both urinary chitinase 3-like protein 1 and -3 were only detected in septic mice with severe AKI. The human homologue chitinase 3-like protein 1 was found to be more excreted in urine from septic patients with AKI than without. In summary, urinary chitinase 3-like protein 1 and -3 and acidic mammalian chitinase discriminated sepsis from sepsis-induced AKI in mice. Further studies of human chitinase proteins are likely to lead to additional insights in septic AKI. PMID- 22233885 TI - Proton production, regulation and pathophysiological roles in the mammalian brain. AB - The recent demonstration of proton signaling in C. elegans muscle contraction suggests a novel mechanism for proton-based intercellular communication and has stimulated enthusiasm for exploring proton signaling in higher organisms. Emerging evidence indicates that protons are produced and regulated in localized space and time. Furthermore, identification of proton regulators and sensors in the brain leads to the speculation that proton production and regulation may be of major importance for both physiological and pathological functions ranging from nociception to learning and memory. Extracellular protons may play a role in signal transmission by not only acting on adjacent cells but also affecting the cell from which they were released. In this review, we summarize the upstream and downstream pathways of proton production and regulation in the mammalian brain, with special emphasis on the proton extruders and sensors that are critical in the homeostatic regulation of pH, and discuss their potential roles in proton signaling under normal and pathophysiological conditions. PMID- 22233886 TI - Caspase-3 activation as a bifurcation point between plasticity and cell death. AB - Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer's disease. However, emerging evidence suggests that in addition to their classical role in cell death, caspases play a key role in modulating synaptic function. It is remarkable that active caspases-3, which can trigger widespread damage and degeneration, aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death. Here, we evaluate this dichotomy, and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling, able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling. We propose that temporal, spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons. This concept has implications for differential roles of caspase-3 activation across the lifespan. Specifically, we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain. PMID- 22233887 TI - No phylogeny without ontogeny: a comparative and developmental search for the sources of sleep-like neural and behavioral rhythms. AB - A comprehensive review is presented of reported aspects and putative mechanisms of sleep-like motility rhythms throughout the animal kingdom. It is proposed that 'rapid eye movement (REM) sleep' be regarded as a special case of a distinct but much broader category of behavior, 'rapid body movement (RBM) sleep', defined by intrinsically-generated and apparently non-purposive movements. Such a classification completes a 2 * 2 matrix defined by the axes sleep versus waking and active versus quiet. Although 'paradoxical' arousal of forebrain electrical activity is restricted to warm-blooded vertebrates, we urge that juvenile or even infantile stages of development be investigated in cold-blooded animals, in view of the many reports of REM-like spontaneous motility (RBMs) in a wide range of species during sleep. The neurophysiological bases for motorically active sleep at the brainstem level and for slow-wave sleep in the forebrain appear to be remarkably similar, and to be subserved in both cases by a primitive diffuse mode of neuronal organization. Thus, the spontaneous synchronous burst discharges which are characteristics of the sleeping brain can be readily simulated even by highly unstructured neural network models. Neuromotor discharges during active sleep appear to reflect a hierarchy of simple relaxation oscillation mechanisms, spanning a wide range of spike-dependent relaxation times, whereas the periodic alternation of active and quiet sleep states more likely results from the entrainment of intrinsic cellular rhythms and/or from activity-dependent homeostatic changes in network excitability. PMID- 22233889 TI - Involvement of microglia and interleukin-18 in the induction of long-term potentiation of spinal nociceptive responses induced by tetanic sciatic stimulation. AB - OBJECTIVE: The present study aimed to investigate the potential roles of spinal microglia and downstream molecules in the induction of spinal long-term potentiation (LTP) and mechanical allodynia by tetanic stimulation of the sciatic nerve (TSS). METHODS: Spinal LTP was induced in adult male Sprague-Dawley rats by tetanic stimulation of the sciatic nerve (0.5 ms, 100 Hz, 40 V, 10 trains of 2-s duration at 10-s intervals). Mechanical allodynia was determined using von Frey hairs. Immunohistochemical staining and Western blot were used to detect changes in glial expression of interleukin-18 (IL-18) and IL-18 receptor (IL-18R). RESULTS: TSS induced LTP of C-fiber-evoked field potentials in the spinal cord. Intrathecal administration of the microglial inhibitor minocycline (200 MUg/20 MUL) 1 h before TSS completely blocked the induction of spinal LTP. Furthermore, after intrathecal injection of minocycline (200 MUg/20 MUL) by lumbar puncture 1 h before TSS, administration of minocycline for 7 consecutive days (once per day) partly inhibited bilateral allodynia. Immunohistochemistry showed that minocycline inhibited the sequential activation of microglia and astrocytes, and IL-18 was predominantly colocalized with the microglial marker Iba-1 in the spinal superficial dorsal horn. Western blot revealed that repeated intrathecal injection of minocycline significantly inhibited the increased expression of IL 18 and IL-18Rs in microglia induced by TSS. CONCLUSION: The IL-18 signaling pathway in microglia is involved in TSS-induced spinal LTP and mechanical allodynia. PMID- 22233888 TI - Progression of motor symptoms in Parkinson's disease. AB - Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have different rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed. PMID- 22233890 TI - Aquaporin-4 deficiency attenuates acute lesions but aggravates delayed lesions and microgliosis after cryoinjury to mouse brain. AB - OBJECTIVE: To determine whether aquaporin-4 (AQP4) regulates acute lesions, delayed lesions, and the associated microglial activation after cryoinjury to the brain. METHODS: Brain cryoinjury was applied to AQP4 knockout (KO) and wild-type mice. At 24 h and on days 7 and 14 after cryoinjury, lesion volume, neuronal loss, and densities of microglia and astrocytes were determined, and their changes were compared between AQP4 KO and wild-type mice. RESULTS: Lesion volume and neuronal loss in AQP4 KO mice were milder at 24 h following cryoinjury, but worsened on days 7 and 14, compared to those in wild-type mice. Besides, microglial density increased more, and astrocyte proliferation and glial scar formation were attenuated on days 7 and 14 in AQP4 KO mice. CONCLUSION: AQP4 deficiency ameliorates acute lesions, but worsens delayed lesions, perhaps due to the microgliosis in the late phase. PMID- 22233891 TI - Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen glucose deprivation in vitro. AB - OBJECTIVE: Postsynaptic density protein 95 (PSD-95) plays important roles in the regulation of glutamate signaling, such as that of N-methyl-D-aspartate receptors (NMDARs). In this study, the functional roles of PSD-95 in tyrosine phosphorylation of NMDAR subunit 2A (NR2A) and in apoptosis-like cell death induced by oxygen-glucose deprivation (OGD) in cultured rat cortical neurons were investigated. METHODS: We used immunoprecipitation and immunoblotting to detect PSD-95 protein level, tyrosine phosphorylation level of NR2A, and the interaction between PSD-95 and NR2A or Src. Apoptosis-like cells were observed by 4,6 diamidino-2-phenylindole staining. RESULTS: Tyrosine phosphorylation of NR2A and apoptosis-like cell death were increased after recovery following 60-min OGD. The increases were attenuated by pretreatment with antisense oligonucleotides against PSD-95 before OGD, but not by missense oligonucleotides or vehicle. PSD-95 antisense oligonucleotides also inhibited the increased interaction between PSD 95 and NR2A or Src, while NR2A expression did not change under this condition. CONCLUSION: PSD-95 may be involved in regulating NR2A tyrosine phosphorylation by Src kinase. Inhibition of PSD-95 expression can be neuroprotective against apoptosis-like cell death after recovery from OGD. PMID- 22233892 TI - Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: implications for affective pain. AB - OBJECTIVE: The rostral anterior cingulate cortex (rACC) is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors (NMDARs) are highly expressed in the rACC and mediate pain-related affect by activating a signaling pathway that involves cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and/or extracellular regulated kinase (ERK)/cAMP response element-binding protein (CREB). The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB both in vitro and in vivo in rat rACC. METHODS: Immunohistochemistry and Western blot analysis were used to separately assess the expression of phospho-ERK (pERK) and phospho-CREB (pCREB) in vitro and in vivo. Double immunostaining was also used to determine the colocalization of pERK and pCREB. RESULTS: Both bath application of NMDA in brain slices in vitro and intraplantar injection of formalin into the rat hindpaw in vivo induced significant up regulation of pERK and pCREB in the rACC, which was inhibited by the NMDAR antagonist DL-2-amino-5-phospho-novaleric acid. Selective blockade of the NMDAR GluN2B subunit and the glycine-binding site, or degradation of endogenous D serine, a co-agonist for the glycine site, significantly decreased the up regulation of pERK and pCREB expression in the rACC. Further, the activated ERK predominantly colocalized with CREB. CONCLUSION: Either the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats, and these might be fundamental molecular mechanisms underlying pain affect. PMID- 22233894 TI - Molecular differentiation of Chenopodium album complex and some related species using ISSR profiles and ITS sequences. AB - The present study was undertaken to understand the genetic differentiation and relationships in various components of C. album complex, C. giganteum and some related species using inter simple sequence repeats (ISSR) profiles and internal transcribed spacer (ITS) sequences. The relationships based on UPGMA dendrograms have shown the heterogenous nature of C. album complex. The 2x taxa while showing close relation among themselves are sharply segregated from 4x and 6x taxa belonging to C. album and C. giganteum. Among the three cytotypes from North Indian plains the 4x shows greater similarity to 6x than to 2x which is corroborated by the karyotypic studies. Furthermore, the 6x C. album and C. giganteum accessions of American and European origin are clearly segregated from those of Indian origin which may show their separate origin. Other related species show relationships according to their taxonomic position. The present study based on ISSR profiles and ITS sequences has therefore been very useful in explaining the relationships between various components of C. album complex and related species. However, more work needs to be done using different CpDNA loci to define correct species boundary of the taxa under C. album complex from Himalayas and North Indian Plains. PMID- 22233893 TI - Differences in mtDNA whole sequence between Tibetan and Han populations suggesting adaptive selection to high altitude. AB - We performed a mitochondrial whole-genome comparison study in 40 Tibetan and 50 Han Chinese. All subjects could be classified into 13 haplogroups pertained to the Macrohaplogroup M and N that pitched different quadrants by principal component analysis. We observed a difference in the M9 haplogroup and identified 18 significant variants by comparing whole sequences between Tibetan and Han populations. Variants in ND2, COX2, tRNA alanine and 12S rRNA were predicted to confer increased protein stability in Tibetans. We compared the base substitutions of nonsynonymous (NS) versus synonymous (S) of 13 protein-encoding genes and found the NS/S values of the ATP6, ATP8, and Cyt b genes were larger (>1) in Tibetans than that in Han population. Our findings provide clues for the existence of adaptive selection for the ATP6, ATP8, Cyt b, ND2, COX2, tRNA alanine and 12S rRNA genes in Tibetans which likely contributed to adaptation to their specific geographic environment, such as high altitude. PMID- 22233895 TI - Ammonia oxidizing bacterial community composition and process performance in wastewater treatment plants under low temperature conditions. AB - Nitrification can be difficult to maintain at wastewater treatment plants (WWTPs) during cold periods resulting in disrupted nitrogen removal. The aim of this study was to relate nitrification process performance to abundance and composition of the ammonia oxidizer communities in two closely located municipal WWTPs in Sweden during an eight month period covering seasonal changes and low temperature conditions. Both facilities showed lower NH(4)(+)-N removal efficiency and nitrification rates as temperature decreased. However, one of the plants had a more stable nitrification rate and higher ammonia removal efficiency throughout the entire period. The differences in performance was related to a shift in the composition of the bacterial ammonia oxidizing community from a Nitrosomonas oligotropha-dominated community to a mixed community including also Nitrosomonas ureae-like ammonia oxidizers. This was likely a response to differences in NH(4)(+)-N and organic loading. PMID- 22233896 TI - An asymptotic observer-based monitoring scheme for a class of plug flow reactors. AB - In this paper a monitoring tool is designed for a class of plug flow reactors whose mathematical model is described by a set of first-order partial differential equations with different coefficients in the convective terms. The infinite dimensional structure of such a tool is derived according to the methodology established in the design of the well-known asymptotic observer. As a consequence, it preserves the robustness of the aforementioned observer against the lack of information of the nonlinear terms involved in the model. The original structure of the estimator is then represented as a couple of integral equations by means of the method of characteristics and its behaviour is analyzed through simulation experiments. These simulations show that the mean square observation error is 0.58 when the proposed observer is implemented in a solid waste anaerobic digestion process to estimate the evolution of biomass concentration. PMID- 22233897 TI - Optimization of municipal sludge and grease co-digestion using disintegration technologies. AB - Many drivers tend to foster the development of renewable energy production in wastewater treatment plants as many expectations rely upon energy recovery from sewage sludge, for example through biogas use. This paper is focused on the assessment of grease waste (GW) as an adequate substrate for co-digestion with municipal sludge, as it has a methane potential of 479-710 LCH(4)/kg VS, as well as the evaluation of disintegration technologies as a method to optimize the co digestion process. With this objective three different pre-treatments have been selected for evaluation: thermal hydrolysis, ultrasound and enzymatic treatment. Results have shown that co-digestion processes without pre-treatment had a maximum increment of 128% of the volumetric methane productivity when GW addition was 23% inlet (at 20 days of HRT and with an OLR of 3.0 kg COD/m(3)d), compared with conventional digestion of sewage sludge alone. Concerning the application of the selected disintegration technologies, all pre-treatments showed improvements in terms of methane yield (51.8, 89.5 and 57.6% more for thermal hydrolysis, ultrasound and enzymatic treatment, respectively, compared with non-pretreated wastes), thermal hydrolysis of GW and secondary sludge being the best configuration as it improved the solubilization of the organic matter and the hydrodynamic characteristics of digestates. PMID- 22233898 TI - Heterogeneous photo-catalysis system for the degradation of azo dye Reactive Black 5 (RB5). AB - This study investigated a heterogeneous photo-catalysis system by introducing a novel brick supported iron oxide (denoted as B1) for the heterogeneous photoassisted degradation of Reactive Black 5 (RB5) at pH value from 3 to 7 in a three-phase (gas-liquid-solid) fluidized bed reactor (3P-FBR). Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray powder diffraction (XRD) and N(2) adsorption/desorption were used to characterize the B1 catalyst. The in situ formation of hydrogen peroxide and the depletion of oxalic acid by photochemical cycle of Fe(III)-oxalate complex under UVA light (lambda = 365 nm) were studied. The effects of the solution pH and the concentration of oxalic acid on the degradation of RB5 are elucidated. About 90% decolourization was measured and 80% of the total organic carbon (TOC) was eliminated at pH 5.0 after 120 min for 20 mg/L RB5 in presence of 10 g/L B1 catalyst, 30 mg/L oxalic acid under 15 W UVA light. A mechanism for the photocatalytic degradation of RB5 over B1 catalyst is proposed. PMID- 22233899 TI - Comparison of methods for the enumeration of Clostridium perfringens spores in water. AB - Four methods for enumerating Clostridium perfringens spores in water were evaluated: (1) the IMM (Iron Milk Medium) method (MPN); (2) the LS (Lactose Sulfite Broth) method (MPN); (3) the m-CP (membrane filtration Clostridium perfringens Agar) method (membrane filtration); and (4) the TSC (Tryptose Sulfite Cycloserine Agar) method (membrane filtration). The performance of these methods was compared with that of the DRCM (Differential Reinforced Clostridium Medium) method (MPN) as adopted by CETESB (Brazil's Environmental Sanitation Technology Company) for the analysis of C. perfringens spores in water. Statistical analysis was performed according to ISO 17994:2004 (Water Quality - Criteria for Establishing Equivalence between Microbiological Methods). The LS, m-CP, and TSC methods were considered not equivalent to the DRCM method, as they gave significantly lower results. The IMM showed inconclusive results and, according to ISO 17994:2004, analysis of a greater number of samples is needed to draw definitive conclusions comparing IMM and DRCM. PMID- 22233900 TI - Impact of influent data frequency and model structure on the quality of WWTP model calibration and uncertainty. AB - Application of activated sludge models (ASMs) to full-scale wastewater treatment plants (WWTPs) is still hampered by the problem of model calibration of these over-parameterised models. This either requires expert knowledge or global methods that explore a large parameter space. However, a better balance in structure between the submodels (ASM, hydraulic, aeration, etc.) and improved quality of influent data result in much smaller calibration efforts. In this contribution, a methodology is proposed that links data frequency and model structure to calibration quality and output uncertainty. It is composed of defining the model structure, the input data, an automated calibration, confidence interval computation and uncertainty propagation to the model output. Apart from the last step, the methodology is applied to an existing WWTP using three models differing only in the aeration submodel. A sensitivity analysis was performed on all models, allowing the ranking of the most important parameters to select in the subsequent calibration step. The aeration submodel proved very important to get good NH(4) predictions. Finally, the impact of data frequency was explored. Lowering the frequency resulted in larger deviations of parameter estimates from their default values and larger confidence intervals. Autocorrelation due to high frequency calibration data has an opposite effect on the confidence intervals. The proposed methodology opens doors to facilitate and improve calibration efforts and to design measurement campaigns. PMID- 22233901 TI - Microaerophilic conditions support elevated mixed culture polyhydroxyalkanoate (PHA) yields, but result in decreased PHA production rates. AB - For commercial polyhydroxyalkanoate (PHA) production the objective is to maximise the fraction of feedstock that ends up as polymer, and minimise biomass growth. In this paper, oxygen limitation was applied to achieve this. Intracellular PHA content in mixed cultures in batch systems operated with low and high DO was compared. It is shown that in microaerophilic conditions a higher fraction of substrate is accumulated as PHA in comparison to high DO conditions, evidenced by elevated intracellular PHA content: in the order of 50% higher in the early stages of accumulation. However, the accumulation capacity is not affected by DO. The PHA content in biomass in both the low and high DO systems reached approximately 35%. The time taken for the PHA content in the low DO system to reach capacity was three times longer than in the high DO system. PMID- 22233902 TI - UV disinfection of stabilization pond effluent: a feasible alternative for areas with land restriction. AB - The purpose of this research was to determine the feasibility of a UV photoreactor for the disinfection of effluent from a polishing pond following a UASB reactor treating domestic wastewater. For this, a 20 mm diameter photoreactor (20.7 litre volume) equipped with four 30 W submerged low-pressure mercury arc lamps was used. Three tests with contact times and doses ranging from 45 to 90 s and from 16.9 to 31.3 mW s cm(-2) were carried out. Inactivation of total coliforms and Escherichia coli varied from 2.6 to 3.4 log-units, even with the presence of suspended solids in the range of 87 to 102 mg L(-1). These results have shown that UV radiation disinfection of pond effluents can be a feasible alternative in areas with land restriction. PMID- 22233904 TI - Effect of pH control strategies and substrate concentration on the hydrogen yield from fermentative hydrogen production in large laboratory-scale. AB - A series of batch experiments investigating two different pH control strategies, initial pH adjustment and continuous pH control, have been carried out in large laboratory-scale reactors with working volumes of 30 L. In both cases, pH was varied between 5 and 7.5. Sucrose concentrations were also varied starting from 0 up to 30 g/L. Higher hydrogen production yields can be achieved by batch experiments through continuous pH control than by simple initial pH adjustment. In the case of continuous pH control, maximization of hydrogen yield was acquired for slightly acidic pH of 6.5. Continuous pH control in the neutral pH range of 7.0 and in pH lower than 6.5, induced a reduction in the hydrogen production yield. Sucrose can be completely degraded only for a pH higher than 6. Lower pH values seem to inhibit the hydrogen-producing bacteria. Under the conditions of continuous pH adjustment at pH 6.5 and a sucrose concentration of 25 g/L the maximum hydrogen yield of 1.79 mol H(2)/mol hexose was obtained. These conditions could be applied for the batch start-up of large fermentors. PMID- 22233903 TI - Microbial community characterization of an UASB treating increased organic loading rates of vitamin C biosynthesis wastewater. AB - The microbial community of a mesophilic lab-scale upflow anaerobic sludge blanket (UASB) reactor treating vitamin C biosynthesis wastewater at gradually elevated organic loading rates (OLRs) was characterized using 16S rDNA-based polymerase chain reaction-DGGE (denatured gradient gel electrophoresis) analysis. The DGGE fingerprints suggested that the elevated OLRs did not cause any significant changes in the microbial community. The predominant bacterial bands were affiliated with the Firmicutes (Clostridiales, four bands), Proteobacteria (Deltaproteobacteria, six bands), Bacteroidetes, and Synergistetes, respectively. All the archaeal bands were very similar to already known methanogenic species: Methanobacterium formicicum (two bands), Methanomethylovorans hollandica (one band) and Methanosaeta concilli (two bands), which belonged to the divisions Methanobacteria and Methanomicrobia, respectively. PMID- 22233905 TI - Estimating evolution of delta(13)CH(4) during methanization of municipal solid waste based on chemical reactions, isotope accumulation in products and microbial ecology. AB - Natural isotopic composition in substrate may be used to reveal the metabolic pathways of substrate transformation by microbial community. In this paper, a change in delta(13)CH(4) during methanization of reconstituted municipal solid waste was described using a mathematical model based on stoichiometric chemical reactions, equation for the (13)C isotope accumulation in products at the low natural C(13)/C(12) ratio and microbial ecology. A set of experimental data used in the model was taken from Qu et al. (2009a). According to the model, during mesophilic municipal solid waste methanization initially hydrogenotrophic and further aceticlastic methanogenesis dominated. At the final stage hydrogenotrophic methanogenesis followed by acetate oxidation dominated again. In spite of rather high measured values of delta(13)C for CO(2) above -210/00, a sharp decrease in delta(13)CH(4) from -200/00 to -600/00 at the final stage was explained by a larger fractionation against (13)C during methanogenesis from H(2)/H(2)CO(3) due to a kinetic isotope effect when hydrogenotrophic methanogens preferentially take down light (12)C. The model also confirmed that in thermophilic conditions a comparatively stable value of delta(13)CH(4) about 600/00 measured earlier (Qu et al. 2009b) was due to a dominance of hydrogenotrophic methanogenesis during all methanization process of cardboard waste. PMID- 22233906 TI - Icelandic experience with water safety plans. AB - The aim of this study was to investigate accumulated experience with water safety plans in one of the first countries to adopt systematic preventive management for drinking-water safety. Water utilities in Iceland have had a legal obligation since 1995 to implement a systematic preventive approach to secure safety of drinking water and protect public health. The water utilities responded by implementing either an adapted HACCP (Hazard Analysis Critical Control Points) model for larger water utilities or a simpler five step model for smaller water utilities. The research was carried out at 16 water utilities that serve about two-thirds of the population of Iceland. Both qualitative and quantitative methods were used with the aim of analysing if and what benefits water safety plans bring for water utilities and what is needed for successful implementation and operation of such systems. The results of the study show that numerous benefits and even the process of going through the implementing process were considered to be of advantage and change the attitude of the staff and the utility culture. Some obstacles and shortcomings came to light, such as lack of documentation and lack of regular internal and external audit. There was little communication with the public, although some mentioned that good public relations are important to succeed with water safety plans. Many important elements of success were revealed of which intensive training of staff and participation of staff in the whole process are deemed the most important. It is also important to have simple and well-structured guidelines, and good cooperation with the health authorities. PMID- 22233907 TI - Effects of oxygen concentration on the nitrifying activity of an aerobic hybrid granular sludge reactor. AB - The aim of the work was to quantify the influence of the simultaneous presence of flocs and granules in the nitrifying activity in a sequencing batch airlift reactor (SBAR). The nitrification rate and oxygen limitation of flocs, granules and hybrid sludge was investigated using respirometric assays at different dissolved oxygen concentrations. The spatial distribution of Ammonium Oxidizing Bacteria (AOB) and Nitrite Oxidizing Bacteria (NOB) was investigated using fluorescence in situ hybridization (FISH). Results showed that the nitrification rate was much less sensitive to oxygen limitation in systems containing a fraction of flocs than in pure granular sludge. Ammonium Oxidizing Bacteria (AOB) were found to be distributed in similar quantities in flocs and granules whereas the Nitrite Oxidizing Bacteria (NOB) were located preferentially in granules. This study showed that the presence of flocs with granules could increase the robustness of the process to transitory reductions of aeration. PMID- 22233908 TI - Arsenate removal using a combination treatment of precipitation and nanofiltration. AB - A combination treatment of Ca-precipitation and nanofiltration membrane was studied to remove arsenate from water. The selected nanofiltration membrane was an amphoteric charged membrane, proved by the results of ATR-FTIR spectra and zeta potential. The arsenate and calcium removal efficiencies had the lowest values at the isoelectric point of the nanofiltration membrane, attributed to the loosest steric hindrance and the weakest electrostatic repulsion. Above the isoelectric point, arsenate precipitated with calcium ion to form the low solubility compound calcium arsenate, while steric hindrance was the main mechanism of arsenate removal. In contrast, below the isoelectric point, the nanofiltration membrane with positive charges rejected calcium ion by electrostatic repulsion. The high electrostatic shielding of calcium ion prevented arsenate from coming close to the NF membrane. Either high feed arsenate concentration or high calcium oxide dose improved the removal amount of arsenate during the nanofiltration membrane separation process. In addition, the arsenate removal efficiency approached the highest value at 200 MUg/L of feed arsenate concentration. The optimal transmembrane pressure was in a range of 0.5 0.7 MPa to restrict the formation of fouling cake on the nanofiltration membrane surface. PMID- 22233909 TI - Feasibility tests for treating shampoo and hair colorant wastewaters using anaerobic processes. AB - Wastes from the personal care product (PCP) industry are often high in biodegradable carbon, which makes them amenable to aerobic biological treatment, although process costs are usually high due to aeration inefficiencies, high electricity demand and production of large amounts of sludge. As such, anaerobic treatment technologies are being considered to lower net energy costs by reducing air use and increasing methane production. To assess the amenability of PCP wastes to anaerobic treatment, methane yields and rates were quantified in different anaerobic reactors treating typical PCP wastes, including wastes from shampoo and hair colorant products. Overall, shampoo wastes were more amenable to methanogenesis with almost double the methane yields compared with colour wastes. To assess relevant microbial guilds, qPCR was performed on reactor biomass samples. Methanosaetaceae abundances were always significantly higher than Methanosarcinaceae and Methanomicrobiales abundances (P < 0.05), and did not differ significantly between waste types. Although colour wastes were less amenable to anaerobic treatment than shampoo wastes, differences cannot be explained by relative microbial abundances and probably result from the presence of inhibiting compounds in hair colorants (e.g., oxidants) at higher levels. Results showed that anaerobic technologies have great potential for treating PCP wastes, but additional work is needed to establish the basis of elevated methane yields and inhibition, especially when colorant wastes are present. PMID- 22233910 TI - Strength characteristics of aerobic granular sludge. AB - Aerobic granular sludge has a number of advantages over conventional activated sludge flocs, such as cohesive and strong matrix, fast settling characteristic, high biomass retention and ability to withstand high organic loadings, all aspects leading towards a compact reactor system. Still there are very few studies on the strength of aerobic granules. A procedure that has been used previously for anaerobic granular sludge strength analysis was adapted and used in this study. A new coefficient was introduced, called a stability coefficient (S), to quantify the strength of the aerobic granules. Indicators were also developed based on the strength analysis results, in order to categorize aerobic granules into three levels of strength, i.e. very strong (very stable), strong (stable) and not strong (not stable). The results indicated that aerobic granules grown on acetate were stronger (high density: >150 g T SSL(-1) and low S value: 5%) than granules developed on sewage as influent. A lower value of S indicates a higher stability of the granules. PMID- 22233911 TI - Efficiency of RO/NF membranes at the removal of veterinary antibiotics. AB - The production of pharmaceuticals has increased rapidly during the last several decades as they have been used for the health of both humans and animals. Routes of environmental exposure include the release of treated wastewater, the land disposal of livestock manures and municipal biosolids (i.e. sewage sludge), as well as the use of medicated aquaculture feed. This study deals with application of reverse osmosis (RO) and nanofiltration (NF) membranes for removing of antibiotic residues (sulfamethoxazole, trimethoprim, ciprofloxacin, dexamethasone and febantel) and their mixture. According to the results obtained in this work the use of RO (LFC-1 and XLE) and the tight NF (NF90) membranes are recommended to achieve a high level of retention (>95%) of all selected veterinary antibiotics (VAs). Nanofiltration NF270, NF and HL membranes showed a lower rejection of individual components, but much higher in a mixture solution, due to the synergistic effect. PMID- 22233912 TI - Regeneration of barium carbonate from barium sulphide in a pilot-scale bubbling column reactor and utilization for acid mine drainage. AB - Batch regeneration of barium carbonate (BaCO(3)) from barium sulphide (BaS) slurries by passing CO(2) gas into a pilot-scale bubbling column reactor under ambient conditions was used to assess the technical feasibility of BaCO(3) recovery in the Alkali Barium Calcium (ABC) desalination process and its use for sulphate removal from high sulphate Acid Mine Drainage (AMD). The effect of key process parameters, such as BaS slurry concentration and CO(2) flow rate on the carbonation, as well as the extent of sulphate removal from AMD using the recovered BaCO(3) were investigated. It was observed that the carbonation reaction rate for BaCO(3) regeneration in a bubbling column reactor significantly increased with increase in carbon dioxide (CO(2)) flow rate whereas the BaS slurry content within the range 5-10% slurry content did not significantly affect the carbonation rate. The CO(2) flow rate also had an impact on the BaCO(3) morphology. The BaCO(3) recovered from the pilot-scale bubbling column reactor demonstrated effective sulphate removal ability during AMD treatment compared with commercial BaCO(3). PMID- 22233913 TI - Synergistic effect of biological activated carbon and enhanced coagulation in secondary wastewater effluent treatment. AB - The use of secondary wastewater effluent (SWWE) is an essential strategy for making better use of limited water resources. However, a wide range of organic compounds eventually renders them unsuitable for recycling. In water treatment processes, biologically activated carbon (BAC) is adopted after physicochemical treatment. However, the effectiveness of such combination for SWWE remains poorly understood. This study investigates the effectiveness of various combinations: BAC/enhanced coagulation (EC) or EC/BAC, especially in terms of dissolved organic carbon (DOC) removal. The results showed that distinct advantage could be obtained by adopting BAC/EC combination rather than EC/BAC, as microbes in BAC not only remove non-coagulable compounds but also synergize the removal efficiency by releasing some coagulable humic substances. PMID- 22233914 TI - Impediments and constraints in the uptake of water sensitive urban design measures in greenfield and infill developments. AB - Water sensitive urban developments are designed with integrated urban water management concepts and water sensitive urban design measures. The initiatives that may be included are the substitution of imported drinking water with alternative sources using a fit-for-purpose approach and structural and non structural measures for the source control of stormwater. A water sensitive approach to urban development can help in achieving sustainability objectives by minimising disturbance to ecological and hydrological processes, and also relieve stress on conventional water systems. Water sensitive urban developments remain novel in comparison with conventional approaches, so the understanding and knowledge of the systems in regards to their planning; design; implementation; operation and maintenance; health impacts and environmental impacts is still developing and thus the mainstream uptake of these approaches faces many challenges. A study has been conducted to understand these challenges through a detailed literature review, investigating a large number of local greenfield and infill developments, and conducting extensive consultation with water professionals. This research has identified the social, economic, political, institutional and technological challenges faced in implementing water sensitive urban design in greenfield and infill developments. The research found in particular that there is the need for long-term monitoring studies of water sensitive urban developments. This monitoring is important to validate the performance of novel approaches implemented and improve associated guidelines, standards, and regulatory and governance frameworks, which can lead to mainstream acceptance of water sensitive urban development approaches. The dissemination of this research will help generate awareness among water professionals, water utilities, developers, planners and regulators of the research challenges to be addressed in order to achieve more mainstream acceptance of water sensitive approaches to urban development. This study is based on existing water sensitive urban developments in Australia, however, the methodology adopted in investigating impediments to the uptake of these developments can be applied globally. It is hoped that insights from this study will benefit water professionals in other countries where there is also a move towards water sensitive urban development. PMID- 22233915 TI - Effect of alternating and direct current in an electrocoagulation process on the removal of cadmium from water. AB - The main objective of this study was to investigate the effects of AC and DC on the removal of cadmium from water using iron as anode and cathode. The various operating parameters on the removal efficiency of cadmium were investigated. The results showed that the optimum removal efficiency of 98.1 and 97.3% with the energy consumption of 0.734 and 1.413 kWh/kL was achieved at a current density of 0.2 A/dm(2), at pH of 7.0 using AC and DC respectively. The adsorption process follows second order kinetics and the temperature studies showed that adsorption was endothermic and spontaneous in nature. PMID- 22233916 TI - Improving bioretention/biofiltration performance with restorative maintenance. AB - One of the most popular Stormwater Control Measures is bioretention, or biofiltration. Anecdotal evidence suggests that well-designed bioretention cells are often not adequately installed and that maintenance is lacking, leading to less-than-adequate water storage volume and/or surface infiltration rates post construction. In March 2009, two sets of bioretention cells were repaired by excavating the top 75 mm of fill media, increasing the bioretention surface storage volume by nearly 90% and the infiltration rate by up to a factor of 10. Overflow volume decreased from 35 and 37% in the pre-repair state for two different sets of cells, respectively, to 11 and 12%. Nearly all effluent pollutant loads exiting the post-repair cells were lower than their pre-repair conditions. The bioretention systems employed two different media depths (0.6 and 0.9 m). The deeper media cells discharged less outflow volume than the shallower cells, with 10-11% more runoff volume leaving as exfiltration from the 0.9-m than from the 0.6-m media depth cells. This study showed that maintenance is both critical and beneficial to restore otherwise poorly performing bioretention. Moreover, while deeper media cells did outperform the shallower systems, the improvement in this case was somewhat modest vis-a-vis additional construction costs. PMID- 22233917 TI - Linking sanitation and wastewater treatment: from evaluation on the basis of effluent pollutant concentrations to evaluation on the basis of pollutant removal efficiencies. AB - The evaluation of centralised wastewater treatment plants (WWTPs) in planning and management is sometimes based solely on effluent pollutant concentrations or pollutant loads. For sanitation purposes, the effluent pollutant concentrations/loads of WWTPs are important; of course, but from the point of view of wastewater treatment, the pollutant removal performance should also be evaluated. Focussing on low- and middle-income countries, especially those in tropical regions, published kinetics studies on biological WWTPs (such as oxidation ditches and aerated lagoons) are summarised in this paper. In most studies, effluent pollutant concentrations/loads are described as first-order linear functions of influent pollutant concentrations/loads. Therefore, pollutant removal efficiencies can be expressed as first-order linear functions of the reciprocal of influent pollutant concentrations/loads with negative coefficients. This implies that pollutant removal efficiencies increase with influent pollutant concentration/load increases. Based on pollutant removal efficiency functions, biological or ecological WWTPs when operating with small influent pollutant concentrations/loads should change their management to increase influent pollutant concentrations/loads in order to increase pollutant removal efficiencies. It may, however, be possible for technological development in wastewater treatment to overcome this problem. PMID- 22233918 TI - Specific energy consumption of membrane bioreactor (MBR) for sewage treatment. AB - This paper provides an overview of current electric energy consumption of full scale municipal MBR installations based on literature review and case studies. Energy requirements of several MBRs were linked to operational parameters and reactor performance. Total and specific energy consumption data were analysed on a long-term basis with special attention given to treated flow, design capacity, membrane area and effluent quality. The specific energy consumption of an MBR system is dependent on many factors, such as system design and layout, volume of treated flow, membrane utilization and operational strategy. Operation at optimal flow conditions results in a low specific energy consumption and energy efficient process. Energy consumption of membrane related modules was in the range of 0.5 0.7 kWh/m(3) and specific energy consumption for membrane aeration in flat sheet (FS) was 33-37% higher than in a hollow fibre (HF) system. Aeration is a major energy consumer, often exceeding 50% share of total energy consumption. In consequence, coarse bubble aeration applied for continuous membrane cleaning remains the main target for energy saving actions. Also, a certain potential for energy optimization without immediate danger of affecting the quality of the produced effluent was observed. PMID- 22233919 TI - Assessment of sediment quality and pore water ecotoxicity in Kebir Rhumel basin (NE-Algeria): a combined approach. AB - The objectives of this study are to use different approaches to assess the current pollution status in the wadis of the Kebir Rhumel basin. First, sediment trace metal contents were measured by flame atomic absorption spectroscopy. Then, sediment quality was assessed on the basis of contamination assessment indexes such as: Geoaccumulation Index (Igeo), Contamination factor (C(f)), Contamination degree (C(d)), Sediment Pollution Index (SPI) and SEQ guidelines (Consensus Sediment Quality Guidelines). In addition, several toxicity tests (Daphnia magna mobility inhibition acute test-48 h, Aliivibrio fischeri luminescence inhibition acute test - 15/30 mn and Pseudokirchneriella subcapitata growth inhibition chronic test - 72 h) were conducted to assess sediment pore water ecotoxicity. Trace metal concentrations followed the order: Mn > Zn > Pb > Cr > Cu > Ni > Co > Cd. Indexes used indicate varying degrees of sediment quality. Igeo, C(f), C(d) and SPI reveal a polymetallic contamination dominated by two or more elements in which Cd, Cu and Pb are of greatest concern. SEQ guidelines showed that biological effects on fauna would likely be observed occasionally and/or frequently for Cd, Cr, Cu, Pb and Zn contents. Test organisms exposed to sediment pore water showed that the algal P. subcapitata test was more sensitive than the D. magna and A. fischeri tests. Hence, algal growth inhibition proved to be the most sensitive response to contaminants present in sediment extracts but a significant relationship with trace metal contents was not demonstrated. PMID- 22233921 TI - NeuroTouch: a physics-based virtual simulator for cranial microneurosurgery training. AB - BACKGROUND: A virtual reality neurosurgery simulator with haptic feedback may help in the training and assessment of technical skills requiring the use of tactile and visual cues. OBJECTIVE: To develop a simulator for craniotomy-based procedures with haptic and graphics feedback for implementation by universities and hospitals in the neurosurgery training curriculum. METHODS: NeuroTouch was developed by a team of more than 50 experts from the National Research Council Canada in collaboration with surgeons from more than 20 teaching hospitals across Canada. Its main components are a stereovision system, bimanual haptic tool manipulators, and a high-end computer. The simulation software engine runs 3 processes for computing graphics, haptics, and mechanics. Training tasks were built from magnetic resonance imaging scans of patients with brain tumors. RESULTS: Two training tasks were implemented for practicing skills with 3 different surgical tools. In the tumor-debulking task, the objective is complete tumor removal without removing normal tissue, using the regular surgical aspirator (suction) and the ultrasonic aspirator. The objective of the tumor cauterization task is to remove a vascularized tumor with an aspirator while controlling blood loss using bipolar electrocautery. CONCLUSION: NeuroTouch prototypes have been set up in 7 teaching hospitals across Canada, to be used for beta testing and validation and evaluated for integration in a neurosurgery training curriculum. PMID- 22233922 TI - Use of a Y-tube conduit after facial nerve injury reduces collateral axonal branching at the lesion site but neither reduces polyinnervation of motor endplates nor improves functional recovery. AB - BACKGROUND: Despite increased understanding of peripheral nerve regeneration, functional recovery after surgical repair remains disappointing. A major contributing factor is the extensive collateral branching at the lesion site, which leads to inaccurate axonal navigation and aberrant reinnervation of targets. OBJECTIVE: To determine whether the Y tube reconstruction improved axonal regrowth and whether this was associated with improved function. METHODS: We used a Y-tube conduit with the aim of improving navigation of regenerating axons after facial nerve transection in rats. RESULTS: Retrograde labeling from the zygomatic and buccal branches showed a halving in the number of double labeled facial motor neurons (15% vs 8%; P < .05) after Y tube reconstruction compared with facial-facial anastomosis coaptation. However, in both surgical groups, the proportion of polyinnervated motor endplates was similar (~ 30%; P > .05), and video-based motion analysis of whisking revealed similarly poor function. CONCLUSION: Although Y-tube reconstruction decreases axonal branching at the lesion site and improves axonal navigation compared with facial-facial anastomosis coaptation, it fails to promote monoinnervation of motor endplates and confers no functional benefit. PMID- 22233923 TI - Microcalcifications in breast cancer: novel insights into the molecular mechanism and functional consequence of mammary mineralisation. AB - BACKGROUND: Mammographic microcalcifications represent one of the most reliable features of nonpalpable breast cancer yet remain largely unexplored and poorly understood. METHODS: We report a novel model to investigate the in vitro mineralisation potential of a panel of mammary cell lines. Primary mammary tumours were produced by implanting tumourigenic cells into the mammary fat pads of female BALB/c mice. RESULTS: Hydroxyapatite (HA) was deposited only by the tumourigenic cell lines, indicating mineralisation potential may be associated with cell phenotype in this in vitro model. We propose a mechanism for mammary mineralisation, which suggests that the balance between enhancers and inhibitors of physiological mineralisation are disrupted. Inhibition of alkaline phosphatase and phosphate transport prevented mineralisation, demonstrating that mineralisation is an active cell-mediated process. Hydroxyapatite was found to enhance in vitro tumour cell migration, while calcium oxalate had no effect, highlighting potential consequences of calcium deposition. In addition, HA was also deposited in primary mammary tumours produced by implanting the tumourigenic cells into the mammary fat pads of female BALB/c mice. CONCLUSION: This work indicates that formation of mammary HA is a cell-specific regulated process, which creates an osteomimetic niche potentially enhancing breast tumour progression. Our findings point to the cells mineralisation potential and the microenvironment regulating it, as a significant feature of breast tumour development. PMID- 22233924 TI - Estimating the asbestos-related lung cancer burden from mesothelioma mortality. AB - BACKGROUND: Quantifying the asbestos-related lung cancer burden is difficult in the presence of this disease's multiple causes. We explore two methods to estimate this burden using mesothelioma deaths as a proxy for asbestos exposure. METHODS: From the follow-up of 55 asbestos cohorts, we estimated ratios of (i) absolute number of asbestos-related lung cancers to mesothelioma deaths; (ii) excess lung cancer relative risk (%) to mesothelioma mortality per 1000 non asbestos-related deaths. RESULTS: Ratios varied by asbestos type; there were a mean 0.7 (95% confidence interval 0.5, 1.0) asbestos-related lung cancers per mesothelioma death in crocidolite cohorts (n=6 estimates), 6.1 (3.6, 10.5) in chrysotile (n=16), 4.0 (2.8, 5.9) in amosite (n=4) and 1.9 (1.4, 2.6) in mixed asbestos fibre cohorts (n=31). In a population with 2 mesothelioma deaths per 1000 deaths at ages 40-84 years (e.g., US men), the estimated lung cancer population attributable fraction due to mixed asbestos was estimated to be 4.0%. CONCLUSION: All types of asbestos fibres kill at least twice as many people through lung cancer than through mesothelioma, except for crocidolite. For chrysotile, widely consumed today, asbestos-related lung cancers cannot be robustly estimated from few mesothelioma deaths and the latter cannot be used to infer no excess risk of lung or other cancers. PMID- 22233925 TI - The cyclin-dependent kinase inhibitor p57(Kip2) is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the CDK inhibitor seliciclib in ovarian cancer. AB - BACKGROUND: Carboplatin remains a first-line agent in the management of epithelial ovarian cancer (EOC). Unfortunately, platinum-resistant disease ultimately occurs in most patients. Using a novel EOC cell line with acquired resistance to carboplatin: PEO1CarbR, genome-wide micro-array profiling identified the cyclin-dependent kinase inhibitor p57(Kip2) as specifically downregulated in carboplatin resistance. Presently, we describe confirmation of these preliminary data with a variety of approaches. METHODS: Cytotoxicity testing (MTT) and cell cycle blockade assessed drug responsiveness. Methylation specific PCR and pyrosequencing identified sites of promoter methylation in p57(Kip2). siRNA to p57(Kip2) was used to look at the changes in apoptosis of carboplatin treated EOC cells. EOC tissues (20 cases) were assessed for mRNA levels of p57(Kip2). RESULTS: Carboplatin resistance was reversed using 5-aza cytidine in vitro. Promoter methylation sites and preferential sensitivity to seliciclib were seen in PEO1CarbR cells. Silencing p57(Kip)2 decreased the apoptotic response to the effects of platinum but produced sensitisation to seliciclib. EOC biopsies indicated an association of high levels of p57(Kip2)mRNA with complete responses to chemotherapy and improved outcome. CONCLUSION: We conclude that p57(Kip2) is a candidate biomarker of platinum sensitivity/resistance in EOC and such cases may show preferential response to the cyclin-dependent kinase inhibitor seliciclib. PMID- 22233926 TI - Brain metastases free survival differs between breast cancer subtypes. AB - BACKGROUND: Brain metastases (BM) are frequently diagnosed in patients with HER-2 positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010. METHODS: Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34-16.66) compared with 18 months (95% CI: 14.46-21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71-44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER 2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014). CONCLUSION: Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes. PMID- 22233927 TI - Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C. AB - Activation of protein kinase C (PKC) via adenosine receptors is known to be involved in the cardioprotection of ischemic preconditioning (IPC). Specifically, activation of PKCepsilon is critical for cardioprotection. There is ample evidence that PKCepsilon resides in cardiac mitochondria. However, the signals that promote translocation of PKCepsilon are largely unknown. The present study was designed to determine whether and how adenosine receptor activation induces translocation of PKCepsilon to mitochondria. Freshly isolated adult rat cardiac myocytes and rat heart-derived H9c2 were used in the study. Immunofluorescence imaging of isolated mitochondria showed that PKCepsilon but not PKCdelta was localized in mitochondria and this mitochondrial localization of PKCepsilon was significantly increased by adenosine treatment. The adenosine-induced increase in PKCepsilon-positive mitochondria was largely prevented not only by PKC inhibitor chelerythrine, but also by the HSP90 inhibitor geldanamycin and by siRNA targeting HSP90. Immunoblot analysis from percoll-purified mitochondria further demonstrated that adenosine mediated a significant increase in mitochondrial PKCepsilon? but not PKCdelta. This effect was blocked by inhibiting PKC activity with chelerythrine and bisindolylmaleimide. Furthermore, co-immunoprecipitation data showed that PKCepsilon but not PKCdelta was associated with TOM70 and HSP90, and this association was enhanced by adenosine treatment. Moreover, adenosine induced association of PKCepsilon with TOM70 was reduced by suppressing HSP90 expression with siRNA. In conclusion, we demonstrate that adenosine induces HSP90 dependent translocation of PKCepsilon to mitochondria, possibly through mitochondrial import machinery TOM70. These results point out a novel mechanism in regulating PKC in mitochondria and suggest an important implication in ischemic preconditioning or postconditioning. PMID- 22233928 TI - Use of dietary supplements among people living with HIV/AIDS is associated with vulnerability to medical misinformation on the internet. AB - BACKGROUND: Use of dietary supplements is common among people living with HIV/AIDS. Because dietary supplements are used in the context of other health behaviors, they may have direct and indirect health benefits. However, supplements may also be associated with vulnerability to medical misinformation and unfounded health claims. We examined use of dietary supplements among people living with HIV/AIDS (PLWH) and the association between use of dietary supplements and believing medical misinformation. METHODS: A convenience sample of 268 men and 76 women living with HIV was recruited from AIDS services and clinics in Atlanta, GA. Participants completed measures of demographic and health characteristics, dietary supplement use, beliefs about dietary supplements, internet use, and an internet evaluation task designed to assess vulnerability to medical misinformation. RESULTS: One out of four PLWH currently used at least one dietary supplement product excluding vitamins. Dietary supplement use was associated with higher education and greater use of the internet for health related information. Dietary supplement users also endorsed greater believability and trust in unfounded claims for HIV cures. CONCLUSIONS: Dietary supplement use is common among PLWH and is associated with a broad array of health information seeking behaviors. Interventions are needed to reduce the vulnerability of PLWH, particularly dietary supplement users, to medical misinformation propagated on the internet. PMID- 22233929 TI - Effect of host-guest interactions on the cloud points of neutral thermosensitive homopolymers: poly(N-n-propylmethacrylamide) and polymers with similar structures. AB - We investigated effect of cyclodextrins (CDs) on the cloud point of several thermosensitive polymers that are not ionizable. alpha-CD increased the cloud point of the poly(N-n-propylmethacrylamide) (PnPMAm) aqueous solution; by contrast, beta-CD or gamma-CD did not affect the cloud point of the PnPMAm solution. The cloud point of the PnPMAm solution increased gradually with an increase in the concentration of alpha-CD. Furthermore, we compared the effect of the CDs on the cloud points of four polymers with similar structures. As for poly(N-isopropylacrylamide) (PiPAAm), neither alpha-CD nor beta-CD affected its cloud point. On the basis of the effect of the differently sized CDs on the cloud point of five polymers and the corresponding NOESY NMR data, we inferred that steric hindrance by the main chain of PiPAAm might be responsible for the bulky CD being unable to form a complex with the short isopropyl group. PMID- 22233930 TI - Predictors of dropout in the German disease management program for type 2 diabetes. AB - BACKGROUND: To improve and assess the effectiveness of disease management programs (DMPs), it is critical to understand how many people drop out of disease management programs and why. METHODS: We used routine data provided by a statutory health insurance fund from the regions North Rhine, North Wurttemberg and Hesse. As part of the German DMP for type 2 diabetes, the insurance fund received regular documentation of all members participating in the program. We followed 10,989 patients who enrolled in the DMP between July 2004 and December 2005 until the end of 2007 to study how many patients dropped out of the program. Dropout was defined based on the discontinuation of program documentation on a particular patient, excluding situations in which the patient died or left the insurance fund. Predictors of dropout, assessed at the time of program enrolment, were explored using logistic regression analysis. RESULTS: 5.5% of the patients dropped out of the disease management program within the observation period. Predictors of dropout at the time of enrolment were: region; retirement status; the number of secondary diseases; presence of a disabling secondary disease; doctor's recommendations to stop smoking or to seek nutritional counselling; and the completion and outcome of the routine foot and eye exams. Different trends of dropout were observed among retired and employed patients: retired patients of old age, who possibly drop out of the program due to other health care priorities and employed people of younger age who have not yet developed many secondary diseases, but were recommended to change their lifestyle. CONCLUSIONS: Overall, dropout rates for the German disease management programs for type 2 diabetes were low compared to other studies. Factors assessed at the time of program enrolment were predictive of later dropout and should be further studied to provide information for future program improvements. PMID- 22233931 TI - CD40/APC-specific antibodies with three T-cell epitopes loaded in the constant domains induce CD4+ T-cell responses. AB - CD4+ T lymphocytes play a central role in the orchestration and maintenance of the adaptive immune response. Targeting of antigen to antigen presenting cells (APCs) increases peptide loading of major histocompatibility complex (MHC) class II molecules and CD4+ T-cell activation. APCs have been targeted by APC-specific recombinant antibodies (rAbs) with single T-cell epitopes integrated in the constant region of the heavy chain (C(H)). However, the strategy may be improved if several T-cell epitopes could be delivered simultaneously by one rAb. We here demonstrate that a single rAb can be loaded with multiple identical or different T-cell epitopes, integrated as loops between beta-strands in C(H) domains. One epitope was inserted in C(H)1, while two were placed in C(H)2 of IgG. T-cell proliferation assays showed that all three peptides were excised from loops and presented on MHC class II to T-cells. Induction of T-cell activation by each epitope in the multi-peptide rAb was as good, or even better, than that elicited by corresponding single-peptide rAbs. Furthermore, following DNA vaccination of mice with plasmids that encode CD40-specific rAbs loaded with either one or three peptides, T-cell responses were induced. Thus, integration of multiple epitopes in C(H) region loops of APC-specific rAbs is feasible and may be utilized in design of multi-vaccines. PMID- 22233932 TI - Chronic cold acclimation increases thermogenic capacity, non-shivering thermogenesis and muscle citrate synthase activity in both wild-type and brown adipose tissue deficient mice. AB - The purpose of this study was to determine whether chronic cold exposure would increase the aerobic capacity of skeletal muscle in UCP-dta mice, a transgenic line lacking brown adipose tissue (BAT). Wild type and UCP-dta mice were acclimated to either warm (23 degrees C), or cold (4 degrees C) conditions. Cold increased muscle oxidative capacity nearly equivalently in wild-type and UCP dta mice, but did not affect the respiratory function of isolated mitochondria. Summit metabolism ( V O2summit) and norepinephrine-induced thermogenesis ( V O2NST) were significantly lower in UCP-dta mice relative to wild-type mice regardless of temperature treatment, but both were significantly higher in cold relative to warm acclimated mice. BAT mass was significantly higher in the cold relative to warm acclimated wild-type mice, but not in cold acclimated UCP-dta mice. BAT citrate synthase activity was lower in transgenic animals regardless of acclimation temperature and BAT citrate synthase activity per depot was significantly higher only in the cold acclimated wild-type mice. Muscle citrate synthase activity was increased in both genotypes. As defects in muscle oxidative function have been observed with obesity and type 2 diabetes, these results suggest that chronic cold exposure is a useful intervention to drive skeletal muscle oxidative capacity in mouse models of obesity. PMID- 22233933 TI - Within- and across-colony effects of hyperpolyandry on immune function and body condition in honey bees (Apis mellifera). AB - Honey bees (Apis mellifera) have become a model system for studies on the influence of genetic diversity on disease. Honey bee queens mate with a remarkably high number of males-up to 29 in the current study-from which they produce a colony of genetically diverse daughter workers. Recent evidence suggests a significant benefit of intracolony genetic diversity on disease resistance. Here, we explored the relationship between the level of genetic diversity and multiple physiological mechanisms of cellular and humoral immune defense (encapsulation response and phenoloxidase activity). We also investigated an effect of genetic diversity on a measure of body condition (fat body mass). While we predicted that mean colony phenoloxidase activity, encapsulation response, and fat body mass would show a positive relationship with increased intracolonial genetic diversity, we found no significant relationship between genetic diversity and these immune measures, and found no consistent effect on body condition. These results suggest that high genetic diversity as a result of extreme polyandry may have little bearing on the physiological mechanisms of immune function at naturally occurring mating levels in honey bees. PMID- 22233934 TI - Consequences of constitutive and induced variation in the host's food plant quality for parasitoid larval development. AB - Constitutive and induced changes in plant quality impact higher trophic levels, such as the development of parasitoids, in different ways. An efficient way to study how plant quality affects parasitoids is to examine how the parasitoid larva is integrated within the host during the growth process. In two experiments, we investigated the effects of varying nutritional quality of Brassica oleracea on parasitoid larval development inside the host, the diamondback moth (Plutella xylostella). First, we compared larval growth of the specialist Diadegma semiclausum and the generalist Diadegma fenestrale, when the host was feeding on Brussels sprout plants that were either undamaged or were previously induced by caterpillar damage. Larvae of the generalist D. fenestrale showed lower growth rates than larvae of the specialist D. semiclausum, and this difference was more pronounced on herbivore-induced plants, suggesting differences in host-use efficiency between parasitoid species. The growth of D. semiclausum larvae was also analyzed in relation to herbivore induction on Brussels sprouts and on a wild B. oleracea strain. Parasitoid growth was more depressed on induced than on undamaged control plants, and more on wild cabbage than on Brussels sprouts, which was largely explained by differences in host mass. The effects of induction of wild Brassica on parasitoid development were pronounced early on, but as P. xylostella feeding began inducing the previously undamaged control plants, the effect of induction disappeared, revealing a temporal component of plant-parasitoid interactions. This study demonstrates how insights into the physiological aspects of host-parasitoid interactions can improve our understanding of the effects of plant-related traits on parasitoid wasps. PMID- 22233935 TI - About the need to use specific population references in estimating paediatric hypertension: Sardinian blood pressure standards (age 11-14 years). AB - BACKGROUND: Previous Italian paediatric blood pressure (BP) tables overestimated the prevalence of hypertension in adolescents of specific geographic areas, such as Sardinia, an island in the Mediterranean Sea. This is probably due to a not very homogeneous distribution of the subjects studied, most from Middle and Northern Italy, and the long period from the survey. METHODS: BPs were repeatedly measured over a period of 3 years in 839 children (52.6% males. Age range: from 11 to 14 years during this period), using a standard mercury sphygmomanometer. For each gender, the specific percentile curves of systolic and diastolic BP were constructed. RESULTS: (corrected by the 50th percentile of height): males (11-14 YEARS): mean systolic BP (50th centile): from 111 to 115 mmHg. Hypertensive systolic BP (> 95th percentile): from 127 to 135 mmHg. Mean diastolic BP (50th centile): from 65 to 69 mmHg. Hypertensive diastolic BP (> 95th percentile): from 78 to 82 mmHg. Females (11-14 YEARS): mean systolic BP (50th centile): from 110 to 112 mmHg. Hypertensive systolic BP (> 95th percentile): from 127 to 130 mmHg. Mean diastolic BP (50th centile): from 65 to 67. Hypertensive diastolic BP (> 95th percentile): from 78 to 80 mmHg. CONCLUSIONS: Sardinian BP tables emphasizes the need to integrate the previous standards with more up-to-date and representative reports on Italian children, as periodically performed in the USA, in order to increase the number of subjects to be checked, and to obtain a national coverage better and more completely representative of every geographic area of our country. PMID- 22233936 TI - Total hip replacement infected with Mycobacterium tuberculosis complicated by Addison disease and psoas muscle abscess: a case report. AB - INTRODUCTION: Prosthetic joint infection due to Mycobacterium tuberculosis is occasionally encountered in clinical practice. To the best of our knowledge, this is the first report of a prosthetic joint infection due to Mycobacterium tuberculosis complicated by psoas abscesses and secondary Addison disease. CASE PRESENTATION: A 67-year-old immunocompetent Caucasian woman underwent total left hip arthroplasty because of osteoarthritis. After 18 months, she underwent arthroplasty revision for a possible prosthetic infection. Periprosthetic tissue specimens for bacteria were negative, and empirical antibiotic therapy was unsuccessful. She was then admitted to our department because of complications arising 22 months after arthroplasty. A physical examination revealed a sinus tract overlying her left hip and skin and mucosal pigmentation. Her levels of C reactive protein, basal cortisol, adrenocorticotropic hormone, and sodium were out of normal range. Results of the tuberculin skin test and QuantiFERON-TB Gold test were positive. Computed tomography revealed a periprosthetic abscess and the inclusion of the left psoas muscle. Results of microbiological tests were negative, but polymerase chain reaction of a specimen taken from the hip fistula was positive for Mycobacterium tuberculosis. Our patient's condition was diagnosed as prosthetic joint infection and muscle psoas abscess due to Mycobacterium tuberculosis and secondary Addison disease. She underwent standard treatment with rifampicin, ethambutol, isoniazid, and pyrazinamide associated with hydrocortisone and fludrocortisone. At 15 months from the beginning of therapy, she was in good clinical condition and free of symptoms. CONCLUSIONS: Prosthetic joint infection with Mycobacterium tuberculosis is uncommon. A differential diagnosis of tuberculosis should be considered when dealing with prosthetic joint infection, especially when repeated smears and histology examination from infected joints are negative. Clinical outcomes of prosthetic joint infection by Mycobacterium tuberculosis are unpredictable, especially given the limited literature in this field and the uncertainty of whether medical treatment alone can eradicate the infection without prosthesis removal. Furthermore, this case report raises interesting issues such as the necessity of a follow-up evaluation after treatment based on clinical conditions, the utility of a more standardized length of treatment for periprosthetic tuberculous infection, and the importance of a high diffusion capacity of anti-mycobacterial agents in order to eradicate the infection. PMID- 22233937 TI - Are general practitioners prepared to end life on request in a country where euthanasia is legalised? AB - BACKGROUND: In 2002, Belgium set a legal framework for euthanasia, whereby granting and performing euthanasia is entrusted entirely to physicians, and-as advised by Belgian Medical Deontology--in the context of a trusted patient- physician relationship. Euthanasia is, however, rarely practiced, so the average physician will not attain routine in this matter. AIM: To explore how general practitioners in Flanders (Belgium) deal with euthanasia. This was performed via qualitative analysis of semistructured interviews with 52 general practitioners (GPs). RESULTS: Although GPs can understand a patient's request for euthanasia, their own willingness to perform it is limited, based on their assumption that legal euthanasia equates to an injection that ends life abruptly. Their willingness to perform euthanasia is affected by the demanding nature of a patient's request, by their views on what circumstances render euthanasia legitimate and by their own ability to inject a lethal dose. Several GPs prefer increasing opioid dosages and palliative sedation to a lethal injection, which they consider to fall outside the scope of euthanasia legislation. CONCLUSIONS: Four attitudes can be identified: (1) willing to perform euthanasia; (2) only willing to perform as a last resort; (3) feeling incapable of performing; (4) refusing on principle. The situation where GPs have to consider the request and if they grant it-to perform the act may result in arbitrary access to euthanasia for the patient. The possibility of installing transparent referral and support strategies for the GPs should be further examined. Further discussion is needed in the medical profession about the exact content of the euthanasia law. PMID- 22233938 TI - Effect of subchronic zinc toxicity on rat salivary glands and serum composition. AB - BACKGROUND: Zinc plays an important role in a wide variety of metabolic processes in animal systems. The role of zinc in preservative treatment, fungicidal action and medicine, and addition of supplementary zinc have increased the probability of zinc toxicity, specially the chronic type. It is known that the composition and quantity of saliva influence the oral health. Regarding people's exposure to zinc in routine life and the importance of saliva, our purpose was to investigate the effects of oral zinc intoxication on secretory function in rat salivary glands and also on serum composition. METHODS: In this study, there were five groups of female rats. Four groups received zinc acetate dehydrate through their drinking water. After 3 months of experiment, the chemical characteristics and flow rate of saliva and weight of salivary glands were determined. The effects of zinc on hematological and chemical factors of plasma were assessed too. RESULTS: Flow rate of submandibular glands was significantly lower in experimental groups and there were significant changes in Na(+), Ca(2+) and K(+) concentration both in saliva and in plasma. The serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, glucose levels in the plasma and urine creatinine levels were also altered in experimental groups in comparison with the control group. CONCLUSION: Our results show that zinc toxicity will affect the quantity and quality of saliva probably through changes in the various neurologic pathways to the salivary glands or effects on acinar cells of the salivary glands. Furthermore, our results showed that zinc toxicity will affect the liver and renal function. PMID- 22233939 TI - The hormesis effect of BDE-47 in HepG2 cells and the potential molecular mechanism. AB - Polybrominated diphenyl ethers (PBDEs) had been used extensively in electrical and electronic products as brominated flame retardants. PBDEs are widely distributed in environment media and wildlife since they are lipophilic and persistent, resulting in bioaccumulation and bioamplification through food chains. Accumulation of PBDEs in the environment and human tissues will consequently cause potential negative effects on the ecological environment and human health. To date, some in vitro and in vivo studies have reported that PBDEs possess neurotoxicity, hepatotoxicity, immunotoxicity, reproduction toxicity, endocrine disrupting activity and carcinogenicity. BDE-47 is one of the most predominant PBDE congeners detected in human tissues. The objective of this study is to investigate whether low concentration of BDE-47 could cause hormesis effect in the human hepatoma HepG(2) cells, and to explore the possible molecular mechanism. The results showed that low concentration of BDE-47 (10(-10), 10(-9) and 10(-8) M) could promote cell proliferation and cause no obvious change in DNA damage or cell apoptosis, while the high concentration significantly inhibit cell proliferation. Meanwhile, the reactive oxygen species (ROS) in low concentration BDE-47 (10(-10), 10(-9) and 10(-8) M) treated groups significantly elevated compared with the control group. After low concentration BDE-47 treatment, the expression of proliferating cell nuclear antigen (PCNA), Cyclin D1, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylated protein kinase B (p-Akt) in the HepG(2) cells was markedly up-regulated. However, in DNA-PKcs inhibited cells, the promotion effect on cell proliferation was significantly suppressed. Cell cycle analysis showed a significant decrease in G1 phase after exposure to low concentration of BDE-47. Moreover, pre-exposure to low concentration BDE-47 seemed alleviate the negative effects of high concentration (50 MUM) exposure to cause DNA damage and apoptosis. These results suggested that BDE-47 has a hormesis effect in HepG(2) cells and DNA-PKcs/Akt pathway may be involved in regulation of cell proliferation and apoptosis. PMID- 22233940 TI - Reconstruction method after pancreaticoduodenectomy. Idea to prevent serious complications. AB - Pancreatic fistula after pancreaticoduodenectomy represents a critical trigger of potentially life-threatening complications and is also associated with markedly prolonged hospitalization. Many arguments have been proposed for the method to anastomosis the pancreatic stump with the gastrointestinal tract, such as invagination vs. duct-to-mucosa, Billroth I (Imanaga) vs. Billroth II (Whipple and/or Child) or pancreaticogastrostomy vs. pancreaticojejunostomy. Although the best method for dealing with the pancreatic stump after pancreaticoduodenectomy remains in question, recent reports described the invagination method to decrease the rate of pancreatic fistula significantly compared to the duct-to-mucosa anastomosis. In Billroth I reconstruction, more frequent anastomotic failure has been reported, and disadvantages of pancreaticogastrostomy have been identified, including an increased incidence of delayed gastric emptying and of pancreatic duct obstruction due to overgrowth by the gastric mucosa. We review recent several safety trials and methods of treating the pancreatic stump after pancreaticoduodenectomy, and demonstrate an operative procedure with its advantage of the novel reconstruction method due to our experiences. PMID- 22233941 TI - EUS-guided biliary drainage: a review article. AB - CONTEXT: To demonstrate a comprehensive review of published articles regarding EUS-guided biliary drainage. METHODS: Review of studies regarding EUS-guided biliary drainage including case reports, case series and previous reviews. RESULTS: EUS-guided hepaticogastrostomy, choledochoduodenostomy and choledochoantrostomy are advanced procedures on biliary and pancreatic endoscopy and together make up the echo-guided biliary drainage. Hepaticogastrostomy is indicated in cases of hilar obstruction, while the procedure of choice is choledochoduodenostomy in distal lesions. Both procedures must be done only after unsuccessful ERCP. The indication of these procedures must be made under a multidisciplinary view while sharing information with the patient or legal guardian. CONCLUSION: Hepaticogastrostomy and choledochoduodenostomy are feasible when performed by endoscopists with expertise in biliopancreatic endoscopy and advanced echo-endoscopy and should be performed currently under rigorous protocol in educational institutions. PMID- 22233942 TI - Management of duodenal perforation post-endoscopic retrograde cholangiopancreatography. When and whom to operate and what factors determine the outcome? A review article. AB - CONTEXT: Endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a diagnostic tool to primarily therapeutic procedure. With this, the complexity of the procedure and risk of complication including duodenal perforation have increased. In this article, the recent literature is reviewed to identify the optimal management and factors influencing the clinical outcome. METHOD: Recent literature in English language from the year 2000 onwards, containing major studies of 9 or more cases on duodenal perforation post ERCP were analyzed. RESULTS: Literature review revealed a total of 251 cases of duodenal perforation reported in 10 major reports presenting 9 or more cases each. The mean age of these patients was 58.5 years with nearly two third (62.9%) being female patients. The predominant location of the perforation was: duodenal wall (34.5%), perivaterian (31.3%), common bile duct (23.0%), and unknown in 7.9%.Early diagnosis within 24 hours was made in 78.5%, with 55.8% of these being diagnosed during or immediately after ERCP. CT scan was the most useful investigations in detecting perforations missed during ERCP (44.6%). Conservative management was employed in 62.2%, which was successful in 92.9% of these cases. Ten of these who failed conservative management required salvage surgery (6.4%) and one died of pneumothorax (0.6%). The predominant surgical intervention was closure of perforation (49.0%) with or without other procedures, retroperitoneal drainage (39.0%), duodenal exclusion (24.0%) and common bile duct exploration and T tube insertion (13.0%). The overall mortality was 8.0% which appears to be better than previously reported (16-18%). Among the 20 patients who died, six (30.0%) had salvage surgery, five (25.0%) had delay in diagnosis/intervention beyond 3 days and 3 (15.0%) required multiple operations. CONCLUSION: While the patients with duodenal perforation invariably require surgical intervention, most of the patients with perivaterian injuries can be successfully managed conservatively. The most important factors for recent better outcome were early detection and prompt treatment. Delay in diagnosis and intervention, salvage surgery after failed conservative management, multiple operations, and older age group contributed significantly to the poor outcome. PMID- 22233943 TI - Use of endoscopic ultrasound in diagnosing plasmacytoma of the pancreas. AB - CONTEXT: An extramedullary plasmacytoma is a discrete collection of monoclonal plasmocytes arising in tissues other than the bone. Gastrointestinal involvement has been reported in approximately 10% of cases and usually involves the liver; however, there have been a number of cases involving the pancreas. DISCUSSION: Although helical CT can be used to diagnose pancreatic plasmacytomas based on a typical radiological appearance, there are a number of pitfalls with CT including similar radiologic appearances of other pancreatic tumors, malignant seeding induced by CT biopsy, and creation of multiple secondary plasmacytomas precipitated by CT biopsy. Tissue diagnosis is critical to management in pancreatic lesions as the decision to pursue surgery (pancreatic adenocarcinoma) versus chemotherapy (lymphoma) or radiation (extramedullary plasmacytoma) is dependent on a correct tissue diagnosis. Tissue diagnosis can change morbidity and mortality with respect to specific treatment of pancreatic lesions in the milieu of pancreatic tumor variance. In the confirmed tissue diagnosis of pancreatic plasmacytoma, radiation and chemotherapy can be preferentially chosen over high risk surgery. EUS-FNA has a lower risk of malignant seeding, complications, and a high sensitivity in the diagnosis of pancreatic plasmacytomas, especially with an increased number of passes and bedside cytopathologists. CONCLUSION: It is important for physicians to have a high index of suspicion for diagnosing pancreatic plasmacytomas in the appropriate clinical setting (i.e., a previously diagnosed multiple myeloma, extramedullary plasmacytoma or any other plasma cell neoplasm). EUS-FNA is now an indispensable imaging modality to achieve the diagnosis of pancreatic extramedullary plasmacytomas with an inherently lower rate of complications, and should be the first choice for tissue evaluation. PMID- 22233944 TI - A dog model of pancreaticojejunostomy without duct-to-mucosa anastomosis. AB - CONTEXT: Various anastomosis techniques have been introduced for the safe pancreaticoenterostomy. Objective In the present study, we developed an experimental animal model for simple pancreaticojejunostomy and evaluated the feasibility, safety, and efficacy of this technique. ANIMALS: Ten dogs were studied. INTERVENTION: The dogs underwent the simple approximation ("docking") method for pancreaticojejunostomy and were re-explored on the 30th post-operative day. MAIN OUTCOME MEASURE: After excision of the remnant pancreas with the jejunal segment of the pancreaticojejunostomy, the degrees of fibrosis in the remnant pancreas were analyzed according to the patency of the pancreaticojejunostomy. RESULTS: There were no mortalities and clinically significant complications. The patency of pancreaticojejunostomy remained in six cases and was obliterated in four cases. It was noted that obliterated pancreaticojejunostomy accompanied cases with more dilated pancreatic ducts (3.1 +/- 0.4 mm vs. 5.5 +/- 0.6 mm, P = 0.008). The grade of pancreatic fibrosis was significantly correlated with the obliterated pancreaticojejunostomy (P = 0.038) and the size change of the remnant pancreatic duct (P = 0.040). CONCLUSIONS: The suggested simple pancreaticojejunostomy method is easy and shows no evidence of significant pancreatic fistula. However, the potential risk of dysfunction in the remnant pancreas limits its possible clinical applications. The meticulous duct to-mucosa pancreaticojejunostomy is highly preferred to manage the remnant pancreas following pancreaticoduodenectomy. PMID- 22233945 TI - Evaluation of ultrasound based acoustic radiation force impulse (ARFI) and eSie touch sonoelastography for diagnosis of inflammatory pancreatic diseases. AB - CONTEXT: Pathology changes the consistency of the tissues. OBJECTIVE: To prospectively assess the accuracy of per-abdominal US elastography in the form of acoustic radiation force impulse--virtual touch tissue quantification (ARFI-VTQ) and eSie touch elasticity imaging in characterizing and differentiating inflammatory pancreatic diseases. PATIENTS: One-hundred and 66 patients from among the patients that visited the Asian Institute of Gastroenterology, Hyderabad, India, during the period April 2009 to December 2010, for master health check-up, blood donation and those with pancreatic pathology. SETTING: Based on the clinical symptomatic criteria and diagnostic imaging findings, the patients were divided into normal, chronic and acute, or acute resolving, pancreatitis group. MAIN OUTCOME MEASURES: The ultrasound based ARFI-VTQ and eSie touch elasticity imaging techniques were applied. DESIGN: Prospective single center study. RESULTS: The mean ARFI-VTQ values were 1.28 m/s, 1.25 m/s and 3.28 m/s for the normal, chronic and acute pancreas, respectively. The eSie touch gray scale and color elastograms were light gray and purple-greenish, respectively for both normal and chronic pancreas, while for acute pancreas the elastograms were dark black on the gray scale and orange to red on color scale. CONCLUSION: Both the ARFI-VTQ and eSie touch elasticity imaging techniques may be successfully adopted in order to diagnose acute pancreatitis, to assess extent of inflammation (whether focal or diffuse), to assess peripancreatic edema, to identify presence of necrotic areas and early pseudocyst formation, to early diagnose acute recurrent attacks and to monitor patient's response to treatment. PMID- 22233946 TI - Newcastle disease virus LaSota strain kills human pancreatic cancer cells in vitro with high selectivity. AB - CONTEXT: Pancreatic cancer is highly resistant to treatment. Previously, we showed that Newcastle disease virus (NDV) strain 73-T was highly cytotoxic to a range of tumor types in vitro and in vivo but the effects of NDV on pancreatic tumors are unknown. We determined the cytotoxicity of the lentogenic LaSota strain of NDV (NDV-LS) toward 7 different human pancreatic tumor cell lines and 4 normal human cell lines (keratinocytes, fibroblasts, pancreatic ductal cells, and vascular endothelial cells). METHODS: Cytotoxicity assays used serially diluted NDV incubated for 96 hours post-infection. Cells were fixed, stained, and minimum cytotoxic plaque forming unit (PFU) doses were determined (n = 10-24/cell line). RESULTS: Normal cells were killed only by high doses of NDV-LS. The cytotoxic doses for pancreatic ductal cells, fibroblasts, and vascular endothelial cells were 729, 626, and 1,217 plaque forming units, respectively. In contrast, most pancreatic cancer cells were killed by much lower doses. The doses for PL45, Panc 10.05, PANC-1, BxPC3, SU.86.86, Capan-1 and CFPAC-1 were 0.15, 0.41, 0.43, 0.55, 1.30, 17.1 and 153 plaque forming units, respectively. CONCLUSIONS: Most pancreatic tumor cells were more than 700 times more sensitive to NDV-LS killing than normal cells. Such avirulent, lentogenic NDV strains may have therapeutic potential in the treatment of pancreatic cancers. PMID- 22233947 TI - Replacement gastrostomy tube causing acute pancreatitis: case series with review of literature. AB - CONTEXT: Percutaneous endoscopic gastrostomy (PEG) feedings are generally considered safe with few serious complications. Acute pancreatitis is a rare complication associated with replacement percutaneous endoscopic gastrostomy tubes. CASE REPORT: We report two cases of acute pancreatitis induced by migrated replacement percutaneous endoscopic gastrostomy tubes. CONCLUSIONS: Migration of a balloon into the duodenum can result in external manipulation of the ampulla of Vater thereby disturbing the flow of pancreatic secretions leading to acute pancreatitis. Recognition of this complication is important and should be included as potential etiology of acute pancreatitis in patients receiving percutaneous endoscopic gastrostomy feedings. Periodic examination and documentation of the distance of the balloon from the skin should be performed to document the position of the tubes or any inadvertent migration of the tubes. The use of Foley catheters as permanent replacement tubes should be considered medically inappropriate. PMID- 22233948 TI - Carcinoma of the tail of the pancreas presenting as acute abdomen. AB - CONTEXT: Large bowel obstruction with perforation is an anomalous presentation of pancreatic tail carcinoma. Pancreatic cancer is often difficult to diagnose clinically and is especially furtive when it is located in the tail of the pancreas. CASE REPORT: We describe a patient who presented with large bowel obstruction due to splenic flexure mass which proved to be due to pancreatic mucinous adenocarcinoma. CONCLUSIONS: Pancreatic adenocarcinoma can rarely have the same presentation as colon cancer, and should therefore be considered in the differential diagnosis of large bowel obstruction. PMID- 22233949 TI - Intraductal papillary-mucinous neoplasm of the pancreas penetrating to the stomach and the common bile duct. AB - CONTEXT: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas occasionally penetrates to others organs. We present a case of IPMN penetrating to the stomach and the common bile duct. CASE REPORT: A 75-year-old man was admitted to the hospital because of epigastric pain. Computed tomography (CT) showed a papillary tumor protruding into the markedly dilated main pancreatic duct and splenic vein obstruction. The tumor was diagnosed as IPMN arising in the main duct, but he rejected surgery and he was followed without treatment. One year later, gastroduodenoscopy revealed gastropancreatic fistula and we were able to pass an endoscope through the fistula and directly examine the lumen of the main pancreatic duct and the papillary tumor adjacent to the fistula. Absence of malignant cells on histopathology suggested mechanical penetration rather than invasive penetration. CT showed splenic vein reperfusion due to decreased inner pressure of the main pancreatic duct. Two and a half years later, CT revealed biliopancreatic fistula formation. Endoscope biliary drainage was performed but failed. Despite jaundice, he is still ambulatory and seen in the clinic three years after the first admission. CONCLUSIONS: We have experienced a case of IPMN penetrating to the stomach and the common bile duct that has taken a slow course. It represents the importance of distinguishing mechanical penetration from invasive penetration as well as mechanical splenic vein obstruction from splenic vein invasion. PMID- 22233951 TI - Lipemic serum in a toddler with new-onset diabetes mellitus presenting with diabetic ketoacidosis. AB - CONTEXT: Significant hyperlipidemia causing lipemic serum in patients with poorly controlled diabetes is under-reported in children. The recognition of the severe hyperlipidemia is important for proper management and to prevent associated morbidities. Severe hyperlipidemia in patients with diabetic ketoacidosis should be considered. CASE REPORT: In this case we report a 2-year-old girl with new onset type 1 diabetes mellitus, who presented with severe diabetic ketoacidosis and hyperlipidemia. Hyperlipidemia was resolved with hydration and insulin therapy. CONCLUSION: It is important to diagnose hyperlipidemia by checking serum lipid profile for all pediatric patients presenting with hyperglycemic crisis to prevent morbidities. PMID- 22233950 TI - Mature cystic teratoma of the pancreas. Case report and review of the literature of a rare pancreatic cystic lesion. AB - CONTEXT: Pancreatic cystic lesions are increasingly recognized and comprise different pathological entities. The management of these lesions is challenging, because of inadequate preoperative histological diagnosis. Among this family of lesions, mature cystic teratomas are an extremely rare finding. CASE REPORT: We present the case of a 61-year-old man with a mature cystic teratoma of the pancreas' uncinate process, incidentally discovered at diagnostic imaging. CONCLUSIONS: This case highlights the difficulty to obtain a preoperative diagnosis of this pathological entity and the need of increased awareness about mature cystic teratoma when examining a pancreatic cystic lesion. PMID- 22233952 TI - A case of traumatic pancreaticoduodenal injury: a simple and an organ-preserving approach as damage control surgery. AB - CONTEXT: Traumatic pancreaticoduodenal injury still remains challenging with high morbidity and mortality. Optimal management by performing simple and fast damage control surgery ensures better outcomes. CASE REPORT: A 36-year-old man was admitted with a combined pancreaticoduodenal injury after being assaulted. More than 80% of duodenal circumference (first portion) was disrupted and the neck of the pancreas was transected. Primary repair of the duodenum and pancreaticogastrostomy were performed. The stump of the proximal pancreatic duct was also sutured. The patient developed an intra-abdominal abscess with pancreatic fistula that eventually recovered by conservative treatment. CONCLUSION: Pancreaticogastrostomy can be a treatment option for pancreatic transection. Rapid and simple damage control surgery with functional preservation of the organ will be beneficial for trauma patients. PMID- 22233953 TI - Acute pancreatitis-induced thrombotic thrombocytopenic purpura. AB - CONTEXT: Acute pancreatitis due to thrombotic thrombocytopenic purpura is a well recognized condition. Here, we are reporting a rare converse phenomenon, in which thrombocytopenic purpura occurred secondary to acute pancreatitis. CASE REPORT: A 19-year-old male referred to our intensive care unit with diagnosis of acute pancreatitis with multi-organ dysfunction. He had history of severe abdominal pain and recurrent vomiting about one month ago, requiring hospital admission. There, on diagnostic work-up at admission, abdominal ultrasonography was suggestive of pancreatitis. His serum amylase and lipase were 1,900 and 1,582 U/L, respectively. Other laboratory parameters were within normal limits. He was managed conservatively with intravenous fluids, antibiotics and analgesics; and discharged after about 2 weeks One week after discharge he was readmitted in same hospital with abdominal pain, multiple episodes of bilious vomiting and abdominal distention. Later on he was referred to our intensive care unit; having classical pentad of thrombocytopenic purpura, i.e., thrombocytopenia, micro-angiopathic hemolytic anemia, renal failure, encephalopathy, and fever. His condition improved with plasma exchange therapy and transferred out from our ICU to ward after 10 days of stay. CONCLUSION: Thrombocytopenic purpura may be precipitate by acute pancreatitis due to multiple mechanisms. A high clinical suspicion is required to make an early diagnosis and allow early initiation of plasma exchange therapy, resulting in a good prognosis. PMID- 22233954 TI - Pitfalls in diagnostic imaging of cystic pancreatic masses: a case of true cystic lesion mimicking a mucinous cystadenoma. AB - CONTEXT: Imaging characterization is a frequent topic in diagnostic evaluation of patients with pancreatic cystic lesions. CASE REPORT: We present a patient with a true pancreatic cyst with internal septation in an adult female. The presence of the internal septum should be considered in the differential diagnosis, in fact in our case CT and MR imaging findings were incorrectly suggestive of mucinous cystadenoma. CONCLUSION: True pancreatic cyst may show septate architecture and thus for imaging characterization this feature should be considered in the differential diagnosis of cystic pancreatic masses. PMID- 22233955 TI - Acinar cell carcinoma of the pancreas: a possible role of S-1 as chemotherapy for acinar cell carcinoma. A case report. AB - CONTEXT: Acinar cell carcinoma of the pancreas is a rare malignancy, accounting for 1-2% of pancreatic exocrine malignancies. This rarity makes it difficult to standardize a protocol of treatment for acinar cell carcinoma. CASE REPORT: A 71 year-old male without any particular past history was referred to our institute with abdominal distention and mild liver dysfunction. Computed tomography (CT) revealed a cystic lesion with a diameter of 3.5 cm, which originated from the neck of pancreas and had solid nodules inside. Several nodules were demonstrated surrounding the cystic tumor. Laparotomy and histological study demonstrated peritoneal dissemination of acinar cell carcinoma. The patient was treated with S 1 monotherapy (80 mg/m2 for four weeks with a two-week interval as one cycle). After one cycle of S-1 monotherapy, CT demonstrated remarkable shrinkage of the main tumor and disappearance of the nodules on the peritoneum. The patient underwent a radical distal pancreatectomy. The patient was then treated with 16 cycles of S-1 monotherapy after the radical pancreatectomy and remains without any recurrence of the disease two years later. CONCLUSION: Initially inoperable acinar cell carcinoma was treated by monotherapy using S-1, resulting in curative operation and two years disease free survival post operation. S-1 might be more effective on acinar cell carcinoma, rather than gemcitabine. PMID- 22233956 TI - Interventional radiology in acute pancreatitis: friend or foe? AB - CONTEXT: Peripancreatic fluid collections are known complications of pancreatitis. The majority of fluid collections can be drained percutaneously under radiological guidance. Although radiological percutaneous drainage is regarded as safe, here it resulted in catastrophic haemorrhage from the colon due to an iatrogenic injury. CASE REPORT: We present a case of a 70-year-old man who presented with acute alcohol-related severe necrotizing pancreatitis and an associated massive peripancreatic fluid collection. The drainage of this collection was attempted under computed tomography (CT) scan guidance. During the procedure the splenic artery and the splenic flexure of the colon were inadvertently damaged leading to life threatening per rectal bleeding requiring emergency angiographic embolisation of the splenic artery. CONCLUSION: Radiological drainage of peripancreatic fluid collections is generally regarded as having lower rates of complications compared to surgical necrosectomy. However, in this case it leads to a life threatening per rectal bleed requiring emergency splenic artery embolisation. PMID- 22233957 TI - Castleman's disease mimetizing pancreatic tumor. AB - CONTEXT: Angiofollicular lymph node hyperplasia or Castleman's disease is a rare clinical condition. Knowledge about etiology and physiopathology; and treatment management as well are yet to be defined. Unicentric presentation of this disease affecting single lymph nodes in the mediastinum seems to be the most common presentation. Castleman's disease localized in the pancreas topographic area that mimics a pancreatic neoplasm is an even more uncommon event, with available published data of less than 15 cases until now. CASE REPORT: We present a 64-year old male patient with a six-month past history of asthenia, adynamia, and lack of general clinical conditions. Imaging studies showed a nodular hypoechoic mass in the pancreatic head. Enucleation of the lesion was performed. Histopathological study revealed unicentric form of Castleman's Disease. CONCLUSIONS: Castleman's disease mimetizing pancreatic tumor is uncommon and it also curses with a difficult preoperative diagnosis. Surgery seems to be the best therapeutic alternative for this disease. PMID- 22233958 TI - Endoluminal ultrasound of neoduodenum following pancreas-preserving total duodenectomy for familial adenomatous polyposis. AB - CONTEXT: Familial adenomatous polyposis affects around 2-10 per 100,000 population. Untreated, it inevitably leads to colon cancer. Prophylactic panproctocolectomy has led to improved survival. The resulting extension to follow-up has revealed that 70-100% of patients with familial adenomatous polyposis go on to develop duodenal polyposis and the lifetime risk of duodenal carcinoma in this group is up to 10%. Treatment for those not locally resectable requires pancreaticoduodenectomy. In recent years, pancreas-preserving total duodenectomy has emerged as a safe alternative to pancreaticoduodenectomy. Endoscopy has previously been safely performed in patients following pancreas preserving total duodenectomy. CASE REPORT: We report successful endoscopic ultrasound (EUS) assessment and trans-neoduodenal EUS-guided fine needle aspiration biopsy (EUS-FNA) of the pancreas and adjacent tissue in a 45-year-old man with familial adenomatous polyposis who has previously undergone pancreas preserving total duodenectomy. EUS confirmed the mass was most likely to represent a metastasis in a local lymph node. EUS-FNA confirmed invasive malignancy. A Kausch-Whipple pancreaticoduodenectomy was performed successfully and post-operative recovery has been excellent. CONCLUSION: The authors consider this to be the first report of successful EUS and EUS-FNA performed through the neoduodenum fashioned during pancreas-preserving total duodenectomy. PMID- 22233959 TI - Laser lithotripsy to treat basket impaction during mechanical lithotripsy of a pancreatic duct stone. AB - CONTEXT: Though uncommon, pancreatic duct stones can cause significant discomfort and morbidity. Endoscopic removal of pancreatic stones may decrease intraductal pressure by augmenting ductal drainage. Endoscopy is shown to be most effective when used early in the course of the disease. Endoscopic methods such as mechanical lithotripsy are often successful in removing the majority of pancreatic stones. However, its complication rate is quite high, with basket malfunction being the one most frequently encountered. CASE REPORT: We report a case of a patient with idiopathic chronic calcific pancreatitis presenting with symptomatic pancreatic duct stones. During one attempt of basket mechanical lithotripsy, the basket wires fractured. The basket and stone thus became entrapped in the patient's pancreatic duct. Holmium laser lithotripsy was applied via the mother-baby system of the endoscope. The stone was crushed, and the basket and stone fragments were able to be removed. CONCLUSIONS: To our knowledge, this is the first time laser lithotripsy has been employed to relieve basket impaction during attempted mechanical lithotripsy of a pancreatic duct stone. This method may be considered as a rescue technique by endoscopists encountering basket impaction in the future. PMID- 22233960 TI - Wernicke encephalopathy presenting in a patient with severe acute pancreatitis. AB - CONTEXT: Acute pancreatitis can lead to prolonged fasting and malnutrition. Many metabolic changes, including thiamine deficiency, may lead to the well know pancreatic encephalopathy. In this condition however the thiamine deficiency is rarely suspected. CASE REPORT: We report the case of a 17-year-old woman with severe acute pancreatitis who developed mental status changes and ophthalmoplegia. A magnetic resonance image showed hyperintensive signals in periventricular areas, medial thalamus, and mammillary bodies, findings consistent with the diagnosis of Wernicke encephalopathy. Thiamine treatment reversed neurological complications. CONCLUSION: Wernicke encephalopathy secondary to thiamine deficiency should be considered as a possible cause of acute mental status changes in patients with acute pancreatitis and malnutrition. Prophylactic doses of thiamine could be considered in susceptible patients. PMID- 22233961 TI - Imaging findings in agenesis of the dorsal pancreas. Report of three cases. AB - CONTEXT: Agenesis of the dorsal pancreas is rare. The dorsal pancreatic agenesis is described in two forms, the partial and the complete form. PATIENTS: with this anomaly may be asymptomatic or may present with diabetes mellitus, epigastric pain, acute or chronic pancreatitis. CASE REPORT: We report the computed tomography (CT), magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) findings in three cases with dorsal pancreatic agenesis, one with partial and the other two with complete form. Speckled calcification at pancreatic head was observed in one patient. Lateral contour lobulation of pancreatic head which is seen in one third of normal population is believed to be due to variation in fusion between ventral and dorsal pancreas. In contrast, we observed lateral contour lobulation of pancreatic head in a case of complete agenesis of the dorsal pancreas where structures derived from dorsal pancreas are undeveloped. The ventral and dorsal pancreatic duct lengths were measured on MRCP images and we observed that in partial agenesis, the duct of Wirsung was shorter in length, compared to the duct of Santorini. The duct of Wirsung was relatively longer in cases of complete agenesis of the dorsal pancreas. CONCLUSION: The CT, MRI and MRCP findings in dorsal pancreatic agenesis and the relationship between the length of ventral duct with the type of dorsal pancreatic agenesis will provide a new insight into this particular anomaly. PMID- 22233962 TI - Hemosuccus pancreaticus associated with splenic artery aneurysms and hepatic artery thrombosis late after liver transplantation. PMID- 22233963 TI - Pancreas divisum and acute or chronic pancreatitis. PMID- 22233964 TI - Taking heroic steps to protect the lives of infants and their mothers. PMID- 22233965 TI - Inkjet-printed gold electrodes on paper: characterization and functionalization. AB - Gold nanoparticles were synthesized and inkjet-printed on a paper substrate and IR-sintered to produce conductive electrodes. The electrodes were further functionalised by using self-assembled octadecanethiol monolayers (SAMs). The effect of sintering, print quality, and SAM formation were examined by topographical, chemical and electrical methods. With optimised printing parameters, a volume resistivity of ~1.6 * 10(-7) Omega m was attained by a single print layer. PMID- 22233966 TI - What we know and mostly do not know about bronchiolitis obliterans syndrome. PMID- 22233967 TI - Effects of chest physiotherapy and aerobic exercise training on physical fitness in young children with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a multisystem disease where the main problems are existing in the respiratory system. Aerobic exercise programs are effective in increasing physical fitness and muscle endurance in addition to chest physiotherapy. OBJECTIVE: The aim of this study was to evaluate the effects of chest physiotherapy and aerobic exercise training on physical fitness in young children with cystic fibrosis. METHODS: Sixteen patients with cystic fibrosis, between the ages 5-13 years, were included in this study. All children were assessed at the beginning and at the end of 6 week of the training. Modified Bruce protocol was used for assessing the cardiovascular endurance. The sit-up test was used to evaluate the dynamic endurance of abdominal muscles, standing long jump was used to test power, sit and reach, trunk lateral flexion, trunk hyperextension, trunk rotation and forward bending tests were used to assess flexibility, 20 m shuttle run test and 10-step stair climbing tests were used to assess power and agility. All patients received chest physiotherapy and aerobic training, three days a week for six weeks. Active cycle of breathing technique and aerobic exercise training program on a treadmill were applied. RESULTS: By evaluating the results of the training, positive progressions in all parameters except 20 m shuttle run and 10 stairs climbing tests were observed (p < 0.05). Active cycle of breathing techniques were used together with exercise training in clinically stable cystic fibrosis patients increases thoracic mobility (p < 0.05) and the physical fitness parameters such as muscle endurance, strength and speed (p < 0.05). Comparison of the results in sit and reach and forward bending tests were not significant (p > 0.05). CONCLUSION: It is thought that in addition to medical approaches to the systems affected, the active cycle of breathing techniques along with aerobic training helps to enhance the aerobic performance, thoracic mobility and improves physical fitness in children with cystic fibrosis. PMID- 22233968 TI - Treating childhood pneumonia in hard-to-reach areas: a model-based comparison of mobile clinics and community-based care. AB - BACKGROUND: Where hard-to-access populations (such as those living in insecure areas) lack access to basic health services, relief agencies, donors, and ministries of health face a dilemma in selecting the most effective intervention strategy. This paper uses a decision mathematical model to estimate the relative effectiveness of two alternative strategies, mobile clinics and fixed community based health services, for antibiotic treatment of childhood pneumonia, the world's leading cause of child mortality. METHODS: A "Markov cycle tree" cohort model was developed in Excel with Visual Basic to compare the number of deaths from pneumonia in children aged 1 to 59 months expected under three scenarios: 1) No curative services available, 2) Curative services provided by a highly-skilled but intermittent mobile clinic, and 3) Curative services provided by a low skilled community health post. Parameter values were informed by literature and expert interviews. Probabilistic sensitivity analyses were conducted for several plausible scenarios. RESULTS: We estimated median pneumonia-specific under-5 mortality rates of 0.51 (95% credible interval: 0.49 to 0.541) deaths per 10,000 child-days without treatment, 0.45 (95% CI: 0.43 to 0.48) with weekly mobile clinics, and 0.31 (95% CI: 0.29 to 0.32) with CHWs in fixed health posts. Sensitivity analyses found the fixed strategy superior, except when mobile clinics visited communities daily, where rates of care-seeking were substantially higher at mobile clinics than fixed posts, or where several variables simultaneously differed substantially from our baseline assumptions. CONCLUSIONS: Current evidence does not support the hypothesis that mobile clinics are more effective than CHWs. A CHW strategy therefore warrants consideration in high mortality, hard-to-access areas. Uncertainty remains, and parameter values may vary across contexts, but the model allows preliminary findings to be updated as new or context-specific evidence becomes available. Decision analytic modelling can guide needed field-based research efforts in hard-to-access areas and offer evidence-based insights for decision-makers. PMID- 22233969 TI - Prolonged analgesia from Bupisome and Bupigel formulations: from design and fabrication to improved stability. AB - There is a compelling need for an ultralong-acting local anesthetic. Previously, we demonstrated in mice and humans that encapsulation of bupivacaine into large multivesicular liposomes (Bupisome) prolongs drug residence time and analgesic duration at the injection site while reducing peak plasma concentration. However, we observed considerable leakage of bupivacaine from the liposomes during storage at 4 degrees C. This deficiency was overcome by modifying the lipid composition of Bupisome and by entrapping them in a Ca-alginate cross-linked hydrogel (Bupigel), forming stable, soft, injectable (3-5 mm) beads. Bupisome are not released from Bupigel, but their encapsulated bupivacaine is released into the bulk solution. Adding 0.5% to 2.0% free bupivacaine to the Bupigel prevented net loss of bupivacaine from the Bupisome after storage at 4 degrees C for 2 years, and at 37 degrees C enough bupivacaine was released to prolong analgesia. For injection subcutaneously into mice, the beads are drawn into a syringe, leaving the small amount of free bupivacaine behind. Both Bupisome and Bupigel formulations significantly prolonged analgesia in mice compared to standard bupivacaine, with Bupigel performing better than Bupisome. PMID- 22233970 TI - The effect of tocopherol on the structure and permeability of phosphatidylcholine liposomes. AB - There are numerous phospholipid formulations that incorporate alpha-tocopherol as a stabilizing agent but there are few studies of the effect of alpha-tocopherol on phospholipid structure and bilayer permeability. This study uses synchrotron X ray powder diffraction methods to investigate how alpha-tocopherol changes the structure of distearoylphosphatidylcholines bilayers. Increasing proportions of alpha-tocopherol up to 20 mol% induces ripple structures in the bilayers. Two types of ripple structure are produced which are seen in electron micrographs of freeze-fracture replicas with periodicities of 16 and 12 nm, respectively. The stoichiometry of phospholipid: alpha-tocopherol in the ripple structures at 37 degrees C is 8:1. The presence of alpha-tocopherol tends to reduce the angle of tilt of the hydrocarbon chains of the phospholipid in the gel phase from about 34 degrees to the bilayer normal at 20 degrees C into a more vertical orientation. Increasing proportions of alpha-tocopherol progressively decrease the temperature of the gel to liquid-crystal phase transition of the phospholipid. The presence of up to 20 mol% alpha-tocopherol in 1-palmitoyl-2-oleoyl-phosphocholine inhibits leakage of phenol red dye from liposomes. The effect of 7 mol% alpha-tocopherol on leakage was compared with phospholipid liposomes containing 50 mol% cholesterol. The cholesterol-containing liposomes inhibited leakage to a greater extent than the vesicles incorporating alpha-tocopherol but the effect of alpha tocopherol at equivalent molar proportions was comparable to cholesterol. PMID- 22233971 TI - Predictability of drug release from cochlear implants. AB - A simplified mathematical theory is presented allowing for in silico simulation of the effects of key parameters of miniaturized implants (size and composition) on the resulting drug release kinetics. Such devices offer a great potential, especially for local drug treatments, e.g. of the inner ear. However, the preparation and characterization of these systems is highly challenging, due to the small system dimensions. The presented mathematical theory is based on Fick's second law of diffusion. Importantly, theoretical predictions do not require the knowledge of many system-specific parameters: Only the "apparent" diffusion coefficient of the drug within the implant matrix is needed. This parameter can be easily determined via drug release measurements from thin, macroscopic films. The validity of the theoretical model predictions was evaluated by comparison with experimental results obtained with a cochlear implant. The latter consisted of miniaturized electrodes, which were embedded in a silicone matrix loaded with various amounts of dexamethasone. Importantly, independent experimental results confirmed the theoretical predictions. Thus, the presented simplified theory can help to significantly speed up the optimization of this type of controlled drug delivery systems, especially if long release periods are targeted (e.g., several months or years). Straightforward experiments with thin, macroscopic films and computer simulations can allow for rapid identification of optimal system design. PMID- 22233972 TI - A low dimensional dynamical model of the initial pulmonary innate response to infection. AB - In order to gain a deeper understanding of the onset and progression of pulmonary infections we present and analyze a low dimensional, phenomenological model of infection and the innate immune response in the lungs. Because pulmonary innate immunity has features unique to itself, general mathematical models of the immune system may not be appropriate. The differential equations model that we propose is based on current knowledge of the biology of pulmonary innate immunity and accurately reproduces known features of the initial phase of the dynamics of pulmonary innate system as exhibited in recent experiments. Further, we propose to use the model as a starting point for interrogation with clinical data from a new noninvasive technique for sampling alveolar lining fluid. PMID- 22233973 TI - A mutation in the interferon regulatory element of HBV may influence the response of interferon treatment in chronic hepatitis B patients. AB - BACKGROUND: A functional interferon regulatory element (IRE) has been found in the EnhI/X promoter region of hepatitis B virus (HBV) genome. The purpose of this study is to compare the gene order of responder and non-responder to interferon therapy in patients with chronic hepatitis B (CHB), so as to evaluate the relationship between IRE mutation and the response to interferon treatment for CHB patients. RESULTS: Synthetic therapeutic effect is divided into complete response (CR), partial response (PR) and non-response (NR). Among the 62 cases included in this study, 40 cases (64.5%) were in the response group (CR and PR) and 22 (35.5%) cases were in the NR group. Wild type sequence of HBV IRE TTTCACTTTC were found in 35 cases (56.5%), and five different IRE gene sequences. included TTTtACTTTC, TTTCAtTTTC, TTTtAtTTTC, TTTtACTTTt and cTTtACcTTC, were found in 22 cases (35.5%), 1 case (1.6%), 1 case (1.6%), 2 cases (3.2%) and 1 case (1.6%) respectively. There were 41.9%cases (26/62) with forth base C->T mutation, consisted of 32.5% (13/40) cases in response group and 59.1% (13/22) cases in NR group. Among the 35 cases with IRE sequences, there were 67.5% (27/40) cases in response group and 36.4% (8/22) in NR group, and the difference in IRE sequences between two groups was statistic significantly (P = 0.027). The result suggested that there is likely relationship between the forth base mutation (C->T) of IRE region and the response of HBV to Interferon therapy, and this mutation may partially decrease the inhibition effect of interferon on HBV. CONCLUSION: The forth base C->T mutation in IRE element of HBV may partially influence the response of Interferon treatment in CHB patients. PMID- 22233974 TI - The link between small heat shock proteins and the immune system. AB - There is now compelling evidence that members of the family of small heat shock proteins (HSP) can be secreted by a variety of different types of cells. Secretion of small HSP may at times represent altruistic delivery of supporting and stabilizing factors from one cell to another. A probably more general effect of extracellular small HSP, however, is exerted by their ability to activate macrophages and macrophage-like cells. When doing so, small HSP induce an immune regulatory state of activation, stimulating macrophages to suppress inflammation. For this reason, small HSP deserve consideration as broadly applicable therapeutic agents for inflammatory disorders. In one particular case, however, adaptive immune responses to the small HSP itself may subvert the protective quality of the innate immune response it triggers. This situation only applies to alpha B-crystallin, and is unique for humans as well. In this special case, local concentrations of alpha B-crystallin determine the balance between protective innate responses and destructive adaptive responses, the latter of which are held responsible for the development of multiple sclerosis lesions. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22233975 TI - Adiponectin oligomerization state and adiponectin receptors airway expression in chronic obstructive pulmonary disease. AB - Adiponectin (Acrp30) shows several beneficial properties and circulates as different oligomers. The role of Acrp30 in lung is not fully clear, but a link with chronic obstructive pulmonary disease (COPD) has been highlighted. In this study, we analyzed the anthropometrical and biochemical features and evaluated total Acrp30 levels of a COPD cohort without metabolic complications compared to healthy controls. In addition, being the oligomerization state critical for its biological activities, we characterized the pattern of Acrp30 circulating oligomers focusing on the high molecular weight (HMW) oligomers to verify whether it correlates to COPD. Finally, we investigated AdipoR1 and AdipoR2 expression in lung from COPD. Interestingly, we found for the first time that the oligomerization state of Acrp30 is altered in COPD; particularly, we observed that the higher levels of Acrp30 are associated with a significant and specific increase of HMW. In addition, we demonstrated the presence of AdipoRs with a lower expression of AdipoR2 compared to AdipoR1. In conclusion, we demonstrated that in COPD, the higher levels of Acrp30 are associated with the significantly increase of HMW representing the most biologically active forms. The important role of Acrp30 in pathophysiological conditions of lung is supported also by the modulation of AdipoRs with the down regulation of AdipoR2. The low expression of AdipoR2 could suggest a specific role of this receptor, mainly implicated in Acrp30 effects on inflammation and oxidative stress. Thus, total Acrp30, HMW and its receptors could be considered critical targets to improve diagnostic and therapeutic strategies for lung diseases. PMID- 22233976 TI - Management of hyperlipidemia in pediatrics. AB - PURPOSE OF REVIEW: The purpose of this review is to provide up-to-date information on diagnosis and management of hyperlipidemia in children and adolescents. RECENT FINDINGS: Recent research reemphasizes the importance of dyslipidemia as a risk factor for cardiovascular disease and supports a universal approach to screening for genetic dyslipidemias. SUMMARY: The approach to management of hyperlipidemia should take two forms. First, a population-based approach to improve lifestyle and lipid levels in all children. Second, a high risk strategy to identify children with genetic and environmental dyslipidemias through screening and appropriately treat those children and adolescents with dyslipidemia. PMID- 22233977 TI - Ischemic mitral regurgitation: the challenge goes on. PMID- 22233978 TI - Recent advances in the management of chronic heart failure. AB - PURPOSE OF REVIEW: This review will provide an overview of the recent advances in the management of chronic heart failure, with special focus on major publications in the past 2 years, 2010-2011. RECENT FINDINGS: In the past 1-2 years, there have been a number of publications that promise to make a major difference in patient management and outcome in heart failure. These include two clinical trials in patients with less symptomatic heart failure, namely the use of cardiac resynchronization therapy (CRT) and eplerinone, an aldosterone receptor antagonist, and another study using ivabradine, which belongs to a new class of If channel blocking drugs used for heart rate reduction in patients with moderate heart failure. The evolving role of telemedicine in remote management of patients with heart failure is reviewed. SUMMARY: New data demonstrate the benefit of CRT and aldosterone antagonists in milder heart failure, the benefit of ivabradine in moderate heart failure with heart rate of 70 or more, and the potential role of telemedicine. PMID- 22233979 TI - Cardiac resynchronization therapy: expanding clinical indications and refining patient selection. AB - PURPOSE OF REVIEW: Cardiac resynchronization therapy (CRT) can reduce morbidity and mortality in patients with heart failure. However, a proportion of patients do not respond to CRT. This review addresses important clinical questions regarding patient selection for CRT. RECENT FINDINGS: Three recent large randomized trials show that CRT reduces morbidity and mortality in patients with New York Heart Association (NYHA) functional class II heart failure. Observational studies and a recent meta-analysis suggest that patients with NYHA III heart failure and atrial fibrillation may benefit from CRT. However, atrioventricular node ablation should be considered in this population to ensure greater than 92% biventricular pacing. Data from clinical trials do not support the use of CRT in patients with baseline right bundle branch block (RBBB). SUMMARY: Careful selection of CRT candidates is vital to improve patient outcomes and reduce exposure to unnecessary complications. This review summarizes recent data on the selection of CRT candidates, with emphasis on patients with NYHA I and II heart failure, atrial fibrillation and RBBB. PMID- 22233980 TI - How to create memorizable and strong passwords. PMID- 22233981 TI - Reducing post-caesarean surgical wound infection rate: an improvement project in a Norwegian maternity clinic. AB - BACKGROUND: During 2006 and 2007 the rate of caesarean section surgical wound infection was 17,4 % in Baerum Hospital. OBJECTIVE: The objective was to reduce the incidence to below the Norwegian national level of 8 %. DESIGN: The intervention (a quality improvement project) was implemented in September 2008. A bundle of measures were introduced. Staff from all aspects of patient flow was recruited. Cochrane literature was used as gold standard. Data registration was based upon CDC criteria. RESULTS: were based on data collected through the Norwegian national surveillance system for infections in health care, NOIS. Study setting This Maternity clinic has about 2500 births annually and a caesarean section rate pushing 15 %. PATIENT GROUP: The study was conducted on caesarean section patients registered in NOIS (2008-2010). From September 2009 data were harvested continuously. ASSESSMENT: Data were monitored as cumulative incidence rate and by statistical process control as g chart (number of surgeries between infections including a delayed moving average). Infection control staff reported results to Head of Maternity Clinic monthly. RESULTS: The overall rate of caesarean section surgical wound infections was significantly reduced to 3,1 % (2008-2010 about 1 % in 2010). This result was demonstrated elegantly as a marked shift in process in g-chart. We found the g-chart was efficient, sensitive and simple to handle. PMID- 22233982 TI - Determining the variables associated to clean intermittent self-catheterization adherence rate: one-year follow-up study. AB - PURPOSE: To determine adherence rate and variables associate with patients' adherence to Clean Intermittent Self Catheterization (CISC). MATERIALS AND METHODS: Patients referred to CISC training program between July 2006 and May 2008, were prospectively evaluated with urodynamic, 3 days bladder diary (BD) and WHOQoL-brief questionnaire. After training to perform CISC, patients were evaluated at 2 weeks, monthly for 6 months and at 12 months with clinical visits and BD. Patients were considered adherent if they were performing at least 80% of the initial recommendation. RESULTS: Sixty patients (50.4 +/- 19.9 years old) were trained to perform CISC (21 female and 39 male). Out of them, 30 (50%) had neurogenic and 30 (50%) had a non-neurogenic voiding dysfunction. The adherence rate at 6 and 12 months was 61.7%, 58%, respectively. Patients < 40 years old had adherence rate of 86%. Women and neurogenic patients had higher adherence rate than their counterparts (p = 0.024 and p = 0.016, respectively). In the WHOQoL brief, patients that adhere to the program had a significant higher score on psychological and social relationships domains. There was not difference in pre and post training WHOQoL-brief scores. Educational background, marriage status, detrusor leak point pressure, Bladder Capacity, number of leakage episodes did not play a role on the adherence rate. CONCLUSION: Patients in CISC program present a reasonable adherence after one year. Women, neurogenic voiding dysfunction and patients under 40 years old were significantly more adherents. The psychological and social relationship status seems to positively interfere on adherence. CISC did not affect patient's QoL evaluated by WHOQoL-brief. PMID- 22233983 TI - Phasic or terminal detrusor overactivity in women: age, urodynamic findings and sphincter behavior relationships. AB - OBJECTIVES: To search for relationships between phasic (P) and terminal (T) DO with age, urodynamic findings and sphincter behavior during involuntary detrusor contraction in woman. MATERIALS AND METHODS: Urodynamic studies (triple lumen catheter 7F, seated position) of 164 successive women referred for LUTS with diagnosis of DO were reviewed. Patients were stratified in 4 sub-groups: pre- (18 44 y), peri- (45-54 y), post-menopause (55-74 y) and oldest old (= 75 y). The urethral sensor was positioned at the level of the maximum urethral closure pressure for sphincter behavior analysis. A variation of at least 5 cmH(2)O in pressure (detrusor or urethra) was chosen to assert DO or sphincter response. Sphincter response was classified as relaxation (re) before or during DO, or steady (st). RESULTS: Occurrence of P and TDO was similar: 77 P and 87 T. The PDO group was significantly younger (p = 0.0003). TDO was more frequent in patients with a history of neurological disease. The percentage of PDO remained almost constant in age groups, while that of TDO increased with age from 6.7% to 23.2% (p = 0.0013). Uninhibited contraction occurred at a smaller bladder volume in the P group: 149 +/- 95 vs. 221 +/- 113 mL (p < 0.0001). Steady sphincter predominated in the TDO subgroup: 45.9% vs. 32.1% and increased significantly in each DO sub-group of >= 75 y. CONCLUSION: Steady sphincter during both P and TDO, and occurrence of TDO appear as specific of aging. The last result could be related to structural changes in the detrusor muscle with aging. PMID- 22233999 TI - Biophysiologic considerations in cryoablation: a practical mechanistic molecular review. AB - Cryotherapy techniques date back as far as the mid-1800s, when James Arnott demonstrated the effectiveness of salt/ice mixtures in palliation of breast, uterine, and skin cancers. Subsequent advances saw the use of liquid air and solid carbon dioxide in the treatment of various conditions, particularly benign dermatologic lesions (1). Cooper and Lee introduced the first automated cryosurgical apparatus cooled by circulating liquid nitrogen in 1961 and initially used it for treating neuromuscular disorders (2). Liquid nitrogen probes were soon being used in the treatment of benign prostatic hypertrophy and prostate cancer, though complications were quite common, resulting in the procedures falling out of favor until the 1990s, when intraoperative ultrasound techniques were developed, allowing more accurate monitoring of the freezing process (1). The advent of "third-generation" argon and helium gas probes in 2000 and preoperative computer thermal mapping techniques have allowed even more precise placement, temperature control, and further reduction in post-procedural morbidity (3). Cryosurgical techniques are currently used to treat a wide variety of conditions, but significant urologic indications include treatment of low and intermediate risk prostate cancer and renal cell carcinoma < 4 cm in diameter. PMID- 22234000 TI - Efficacy and safety of parecoxib in the treatment of acute renal colic: a randomized clinical trial. AB - PURPOSE: Although non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and opioids are effective treatments for acute renal colic, they are associated with adverse events (AEs). As cyclooxygenase-2 selective NSAIDs may provide a safer alternative, we compared the efficacy and safety of parecoxib versus an nsNSAID in subjects with acute renal colic. MATERIALS AND METHODS: Phase IV., multicenter, double-blind, noninferiority, active-controlled study: 338 subjects with acute renal colic were randomized to parecoxib 40 mg i.v. plus placebo (n = 174) or ketoprofen 100 mg IV plus placebo (n = 164). 338 subjects with acute renal colic were randomized to parecoxib 40 mg IV (n = 174) or ketoprofen 100 mg IV(n = 164) plus placebo. Subjects were evaluated 15, 30, 45, 60, 90 and 120 minutes after treatment start and 24 hours after discharge. Primary endpoint was the mean pain intensity difference (PID) at 30 minutes by visual analog scale (VAS) (per-protocol population). An ANCOVA model was used with treatment group, country, and baseline score as covariates. Non-inferiority of parecoxib to ketoprofen was declared if the lower bound of the 95% confidence interval (CI) for the difference between the two groups excluded the pre-established margin of 10 mm for the primary endpoint. RESULTS: Baseline demographics were similar. The mean (SD) mPID30 min was 33.84 (24.61) and 35.16 (26.01) for parecoxib and ketoprofen, respectively. For treatment difference (parecoxib-ketoprofen) the lower bound of the 95% CI was 6.53. The mean change from baseline in VAS 30 minutes after study medication was ~43 mm; AEs were comparable between treatments. CONCLUSIONS: Parecoxib is as effective as ketoprofen in the treatment of pain due to acute renal colic, is well tolerated, and has a comparable safety profile. PMID- 22234001 TI - Patients with a negative cystoscopy and negative Nmp22(r) Bladderchek(r) test are at low risk of missed transitional cell carcinoma of the bladder: a prospective evaluation. AB - OBJECTIVES: Urine based tumor markers have uncertain utility in diagnosis or surveillance of patients with bladder cancer while cytology is commonly used. We evaluated whether cytology provides additional diagnostic information in patients with a negative NMP22(r) BladderChek(r) test (BladderChek) and negative cystoscopy. MATERIALS AND METHODS: We performed subset analyses of 2 large prospective multi-center databases evaluating BladderChek for UCB detection and surveillance. These cohorts were analyzed for presence of cancer and result of urine cytology in setting of a negative cystoscopy and negative BladderChek. Subsequently, we prospectively performed cystoscopy, cytology and BladderChek on 434 patients at our institution being evaluated for UCB. RESULTS: In the detection database (n = 1331), 1065 patients had a negative cystoscopy and BladderChek. There were 3 cancers (stages Ta, Tis and T1) and cytology was atypical in one and reactive in two. In the surveillance cohort (n = 668) patients, 437 patients had negative cystoscopy and BladderChek. Cancer was found in 2 patients (stages Tis and Ta). The patient with Tis has dysplastic cytology and Ta tumor had reactive cytology. In our cohort of 434 patients, 288 pts had negative cystoscopy and BladderChek. One cancer was missed, a Ta ureteral urothelial carcinoma with a reactive cytology. CONCLUSIONS: In patients with negative cystoscopy and BladderChek, very few cancers are missed and cytology was not effective in detection. Use of a point-of-care test in conjunction with cystoscopy in lieu of cytology could decrease cost, provide immediate results, improve negative predictive value and reduce the uncertainty that results from inconclusive cytologic results. PMID- 22234003 TI - Intraoperative maximal urethral closing pressure measurement: a new technique of tape tension adjustment in transobturator sling surgery? AB - PURPOSE: Tape tension adjustment is an essential procedure in mid-urethral sling surgery. The goal of this study was to determine if intraoperative maximal urethral closing pressure (MUCP) elevation could be used as a reference value for adequate tape tension adjustment and predict transobturator (TOT) sling surgery outcome. MATERIALS AND METHODS: A prospective study was performed using MUCP measurements just before tape insertion and just after tension adjustment during surgery. Clinical data including preoperative urodynamic results were collected. The cure rate was determined by questionnaire. Patients were divided into two groups. The MUCP elevation group included patients with a MUCP elevation of more than 10 cmH(2)O before tape insertion; the others were regarded as the non elevation group. The cure rate and pre- and postoperative clinical variables were compared between the two groups. RESULTS: A total of 48 patients had TOT surgery. The MUCP elevation group (n = 19) and the non-elevation group (n = 29) were similar with regard to patient characteristics and the preoperative parameters including age, mixed incontinence prevalence, Q-tip angle, peak flow rate, MUCP and the valsalva leak point pressure (VLPP). The mean follow-up period was nine months. The cure rate was significantly higher in the group with MUCP elevation than in the non-elevation group (84% vs. 52%, p = 0.02). There was no significant difference in the mean postoperative peak flow rate between the two groups and there was no retention episode. CONCLUSIONS: MUCP elevation of more than 10 cmH(2)O just after tape insertion was a prognostic factor. PMID- 22234002 TI - The effect of cardiopulmonary bypass in coronary artery bypass surgeries (on-pump versus off-pump) on erectile function and endothelium-derived nitric oxide levels. AB - PURPOSE: To investigate the effects of on-pump and off-pump coronary artery bypass grafting (CABG) on the erectile function and endothelium-derived nitric oxide (eNO) levels. MATERIALS AND METHODS: Twenty-eight consecutive patients were randomized into two groups depending on use of cardiopulmonary bypass in CABG surgery. The erectile function was evaluated by using the IIEF-5 questionnaire. The plasma eNO levels were determined at baseline and after reactive hyperemia before and after surgery. Blood was collected in one minute after cuff deflation from the radial artery on the same side. RESULTS: After CABG surgery the mean IIEF-5 score increased insignificantly over baseline from 14.8 to 15.8 (p = 0.29) and 12.4 to 14.3 (p = 0.11) after on-pump and off-pump CABG surgeries, respectively. The baseline plasma NO levels before surgery were 18.16 +/- 7.63 nmol/L in on-pump and 21.76 +/- 11.08 nmol/L in off-pump CABG. After reactive hyperemia the plasma NO levels were 22.14 +/- 10.52 nmol/L in on-pump and 21.49 +/- 9.13 nmol/L in off-pump CABG before the surgery. The difference in the plasma NO levels before surgery was not significant (p = 0.51). Two hours after surgery, the difference of the plasma NO levels at baseline (24.44 +/- 12.31 on -pump and 20.58 +/- 6.74 nmol/L off-pump CABG) and after reactive hyperemia (35.55 +/- 23.54 nmol/L on-pump and 23.00 +/- 15.40 nmol/L off-pump CABG) were not significantly different from each other (p = 0.11). CONCLUSIONS: Patients who had on-pump or off-pump CABG surgeries had higher IIEF-5 scores. Nevertheless, the improvement was insignificant in both groups. Meanwhile, on-pump or off-pump CABG surgeries did not have significant effect on plasma eNO levels. PMID- 22234004 TI - HASTE MRU in the evaluation of acute flank pain. PMID- 22234005 TI - Assessment of the short-term functional outcome after urethroplasty: a prospective analysis. AB - OBJECTIVES: To assess the short-term functional outcomes on urinary symptoms, erectile function, urinary continence and patient's satisfaction after urethroplasty. MATERIALS AND METHODS: A prospective analysis was done in 21 patients who underwent urethroplasty. An assessment of the urinary flow, urinary symptoms (International Prostate Symptoms Score ), erectile function (International Index of Erectile Function-5 ) and urinary continence International Consultation Committee on Incontinence Questionnaire male Short Form ) was done before urethroplasty and 6 weeks and 6 months after urethroplasty. Patients were also asked to score their satisfaction with the urethroplasty after 6 weeks and 6 months. RESULTS: Mean patient's age was 48 years range: 26-80 years). Mean stricture length was 4.2 cm (range: 1-12 cm). Three patients suffered a stricture recurrence. Mean maximum urinary flow increased from 5.83 mL/s to 24.92 mL/s (p < 0.001). Mean IPSS preoperative, 6 weeks and 6 months postoperative was respectively 15.86, 4.60 and 6.41(p < 0.001). The mean IIEF-5 score preoperative, 6 weeks and 6 months postoperative was respectively 15, 12.13 and 11.62 (not significant). The mean ICI-Q-SF score preoperative, 6 weeks and 6 months postoperative was respectively 10.47, 8.33 (p = 0.04) and 9.47 (p = 0.31). Patient's satisfaction 6 weeks and 6 months postoperative was respectively 17.14/20 and 17.12/20. CONCLUSIONS: Urethroplasty leads to a significant improvement in urinary flow and IPSS and urinary continence is tending to improve. Although not significant, erectile function was slightly diminished after urethroplasty. Functional outcome should be assessed when urethroplasty is performed. PMID- 22234006 TI - Controversies in using urine samples for Prostate Cancer detection: PSA and PCA3 expression analysis. AB - PURPOSE: Prostate cancer (PCa) is one of the most commonly diagnosed malignancies in the world. Although PSA utilization as a serum marker has improved prostate cancer detection it still presents some limitations, mainly regarding its specificity. The expression of this marker, along with the detection of PCA3 mRNA in urine samples, has been suggested as a new approach for PCa detection. The goal of this work was to evaluate the efficacy of the urinary detection of PCA3 mRNA and PSA mRNA without performing the somewhat embarrassing prostate massage. It was also intended to optimize and implement a methodological protocol for this kind of sampling. MATERIALS AND METHODS: Urine samples from 57 patients with suspected prostate disease were collected, without undergoing prostate massage. Increased serum PSA levels were confirmed by medical records review. RNA was extracted by different methods and a preamplification step was included in order to improve gene detection by Real-Time PCR. RESULTS: An increase in RNA concentration with the use of TriPure Isolation Reagent. Despite this optimization, only 15.8% of the cases showed expression of PSA mRNA and only 3.8% of prostate cancer patients presented detectable levels of PCA3 mRNA. The use of a preamplification step revealed no improvement in the results obtained. CONCLUSION: This work confirms that prostate massage is important before urine collection for gene expression analysis. Since PSA and PCA3 are prostate specific, it is necessary to promote the passage of cells from prostate to urinary tract, in order to detect these genetic markers in urine samples. PMID- 22234007 TI - Findings concerning testis, vas deference, and epididymis in adult cases with nonpalpable testes. AB - In this study, we aimed to state the relationship between testis, epididymis and vas deference, in adult cases with nonpalpable testis. Between January 1996 and December 2009, we evaluated 154 adult cases with nonpalpable testes. Mean age was 23 years (20-27 years). Explorations were performed by open inguinal incision, laparoscopy, and by inguinal incision and laparoscopy together on 22, 131 and 1 patient, respectively. Of all the unilateral cases, 32 were accepted as vanishing testis. In five of these cases, vas deference was ending inside the abdomen, and in the others, it was ending inside the scrotum. In the remaining 99 unilateral and 22 bilateral cases, 143 testes were found in total. Testes were found in the inguinal canal as atrophic in one case, at the right renal pedicle level with dysmorphic testis in one case, and anterior to the internal ring between the bladder and the common iliac vessels at a smaller than normal size in 119 cases. One (0.69%) case did not have epididymis. While epididymis was attached to the testis only at the head and tail locations in 88 (61.53%) cases, it was totally attached to the testis in 54 (37.76%) cases. There is an obviously high incidence rate of testis and vas deference anomalies, where epididymis is the most frequent one. In cases with abdominal testes, this rate is highest for high localised abdominal testes. PMID- 22234008 TI - PCNL--A comparative study in nonoperated and in previously operated (open nephrolithotomy/pyelolithotomy) patients--a single-surgeon experience. AB - PURPOSE: Re-procedure in patients with history of open stone surgery is usually challenging due to the alteration in the retroperitoneal anatomy. The aim of this study was to determine the possible impact of open renal surgery on the efficacy and morbidity of subsequent percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: From March 2009 until September 2010, 120 patients underwent PCNL. Of these, 20 patients were excluded (tubeless or bilateral simultaneous PCNL). Of the remaining 100, 55 primary patients were categorized as Group 1 and the remaining (previous open nephrolithotomy) as Group 2. Standard preoperative evaluation was carried out prior to intervention, Statistical analysis was performed using SPSS v. 11 with the chi-square test, independent samples t-test, and Mann-Whitney U test. A p-value < 0.05 was taken as statistically significant. RESULTS: Both groups were similar in demographic profile and stone burden. Attempts to access the PCS was less in Group 1 compared to Group 2 (1.2 + 1 2 vs. 3 + 1.3 respectively) and this was statistically significant (p < 0.04). However, the mean operative time between the two groups was not statistically significant (p = 0.44). Blood transfusion rate was comparable in the two groups (p = 0.24). One patient in Group 2 developed hemothorax following a supra-11th puncture. Remaining complications were comparable in both groups. CONCLUSION: Patients with past history of renal stone surgery may need more attempts to access the pelvicaliceal system and have difficulty in tract dilation secondary to retroperitoneal scarring. But overall morbidity and efficacy is same in both groups. PMID- 22234009 TI - Does the duration of infertility affect semen parameters and pregnancy rate after varicocelectomy? A retrospective study. AB - OBJECTIVES: The most common indication for treatment of varicocele is still male subfertility. The aim of this study was to explore the effect of infertility duration on semen parameters and spontaneous pregnancy rate after varicocelectomy. MATERIALS AND METHODS: The medical records of 183 infertile patients with clinical varicocele were retrospectively reviewed. The patients were divided into three groups according to the duration of infertility (group I, 1-3 years, group II, 3-6 years and group III, > 6 years). Total sperm motility counts (TMCs) before and after varicocelectomy and spontaneous pregnancy rate among these groups were statistically compared. RESULTS: The greatest changes, regarding preoperative and postoperative TMCs and spontaneous pregnancy rate were noticed between group I and III. Preoperative TMCs in group I and III was 15.2 +/ 1.2, 7.8 +/- 1.4, respectively (p < 0.05). Postoperative TMCs in group I and III was 33.7 +/- 2.5, 25.2 +/- 1.9, respectively (p < 0.05). An overall spontaneous pregnancy rate of 34.4% was achieved after inguinal varicocelectomy. The greatest spontaneous pregnancy rate was achieved in Group I (37.3%), and the lowest pregnancy rate in Group III (26.3%) (P < 0.05). CONCLUSIONS: Surgical varicocelectomy improves the total sperm motility counts especially in patients who have a TMCS more than 5 million and improves the spontaneous pregnancy rates. The improvement in the spontaneous pregnancy rates after varicocelectomy correlates negatively with the duration of infertility. Therefore, duration of infertility should be considered in treating a patient with a varicocele as a cause of infertility. PMID- 22234010 TI - Elderly men's quality of life and lower urinary tract symptoms: an intricate relationship. AB - PURPOSE: To evaluate the impact of lower urinary tract symptoms (LUTS) on the quality of life (QoL) in a group of elderly men. MATERIALS AND METHODS: Observational clinical study contained 200 men recruited between March-September 2008 in the community and Urology and Geriatrics ambulatories. The data collected included health and sociodemographic conditions; the International Prostate Symptom Score (IPSS); an anxiety/depression inventory; the World Health Organization Quality of Life -Bref and -Old questionnaires (WHOQoL). Participants were classified according to IPSS: Group I (moderate/severe symptoms) and Group II (absence/mild symptoms) and 100 men were included in each group. RESULTS: The groups were statistically similar in sociodemographic, morbidity, and anxiety/depression scores. Both QoL scales showed significant lower median scores in group I in all parameters, except the global subjective self-evaluation of QoL. The domains social and environmental relations presented the most significative differences (p < 0.0005) in both questionnaires, and final mean WHOQoL-OLD score was lower in group I (p < 0.0005). CONCLUSIONS: For elderly men, moderate to severe LUTS do significantly impact almost all parameters of QoL proposed by the WHO, especially social and environmental relations. PMID- 22234013 TI - Scientific publications from India--on the right trajectory? PMID- 22234014 TI - Are tranexamic acid and epsilon-aminocaproic acid adequate substitutes for aprotinin? PMID- 22234015 TI - Risk factors associated with postoperative seizures in patients undergoing cardiac surgery who received tranexamic acid: a case-control study. AB - Antifibrinolytic agents are used during cardiac surgery to minimize bleeding and reduce exposure to blood products. Several reports suggest that tranexamic acid (TA) can induce seizure activity in the postoperative period. To examine factors associated with postoperative seizures in patients undergoing cardiac surgery who received TA. University-affiliated hospital. Case-control study. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) between January 2008 and December 2009 were identified. During this time, all patients undergoing heart surgery with CPB received TA. Cases were defined as patients who developed seizures that required initiation of anticonvulsive therapy within 48 h of surgery. Exclusion criteria included subjects with preexisting epilepsy and patients in whom the convulsive episode was secondary to a new ischemic lesion on brain imaging. Controls who did not develop seizures were randomly selected from the initial cohort. From an initial cohort of 903 patients, we identified 32 patients with postoperative seizures. Four patients were excluded. Twenty-eight cases and 112 controls were analyzed. Cases were more likely to have a history of renal impairment and higher preoperative creatinine values compared with controls (1.39 +/- 1.1 vs. 0.98 +/- 0.02 mg/dL, P = 0.02). Significant differences in the intensive care unit, postoperative and total lengths of stay were observed. An association between high preoperative creatinine value and postoperative seizure was identified. TA may be associated with the development of postoperative seizures in patients with renal dysfunction. Doses of TA should be reduced or even avoided in this population. PMID- 22234016 TI - Urinary neutrophil gelatinase-associated lipocalin as an early predictor of prolonged intensive care unit stay after cardiac surgery. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is a protein of lipocalin family highly expressed in various pathologic states and is an early biomarker of acute kidney injury in cardiac surgery. We performed an observational study to evaluate the role of NGAL in predicting postoperative intensive care stay in high risk patients undergoing cardiac surgery. We enrolled 27 consecutive patients who underwent high-risk cardiac surgery with cardiopulmonary bypass. Urinary NGAL (uNGAL) was measured before surgery, at intensive care unit (ICU) arrival and 24 h later. Univariate and multivariate predictors of ICU stay were performed. uNGAL was 18.0 (8.7-28.1) ng/mL at baseline, 10.7 (4.35-36.0) ng/mL at ICU arrival and 29.6 (9.65-29.5) 24 h later. The predictors of prolonged ICU stay at the multivariate analysis were body mass index (BMI), uNGAL 24 h after surgery, and aortic cross-clamp time. The predictors of high uNGAL levels 24 h after at a multivariate analysis were preoperative uNGAL and logistic European System for Cardiac Operative Risk Evaluation. At a multivariate analysis the only independent predictors of prolonged ICU stay were BMI, uNGAL 24 h after surgery and aortic cross-clamp time. PMID- 22234017 TI - The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. AB - The clinical study was designed to evaluate and compare single preoperative dose of pregabalin to a placebo regarding hemodynamic responses to laryngoscopy and endotracheal intubation, to assess perioperative fentanyl requirement and any side-effects. It was a randomized, double-blind, placebo-controlled, parallel assignment, efficacy study. The study was done at a tertiary university hospital. This study was a comparison between two groups of 30 adult patients scheduled for elective off pump coronary artery bypass surgery. In the control group, the patients were given placebo capsules, and in the pregabalin group, the patients were given pregabalin 150 mg capsule orally 1 h before surgery. The patients were compared for hemodynamic changes before the start of the surgery, after induction, 1, 3, and 5 min after intubation. Additionally, fentanyl requirement during surgery and the first postoperative day was also compared. The present study shows that a single oral dose of 150 mg pregabalin given 1 h before surgery attenuated the pressor response to tracheal intubation in adults, but the drug did not show any effect on perioperative opioid consumption and was devoid of side-effects in the given dose. PMID- 22234018 TI - Utility of Sonoclot analysis and tranexamic acid in tetralogy of Fallot patients undergoing intracardiac repair. AB - Sonoclot analysis is a point of care test to monitor the coagulation process, presenting a comprehensive evaluation of the clot formation and retraction as well as platelet function. This randomized double-blinded study was designed to investigate the utility of Sonoclot analysis in monitoring the coagulation profile as also the antifibrinolytic effects of tranexamic acid administered in patients with tetralogy of Fallot undergoing intracardiac repair. Eighty of a total 94 patients were randomly divided into two groups of 40 each. In the study group, TA was administered thrice at a dosage of 10 mg/kg, i.e. before CPB, on CPB and after CPB, whereas in the control group, placebo was administered at the same time intervals. Sonoclot analysis and D-dimer measurement were performed at baseline and following heparin neutralisation. An additional variable, DR15 (diminishing rate of clot strength at 15 min postmaximal clot strength), was calculated from the Sonoclot graph and was compared with d-dimer levels as a measure of fibrinolysis. The three Sonoclot variables, i.e. activated clotting time, clot rate and platelet function, were deranged at baseline in all the patients. Post-CPB, the change in these variables was not significant. ACT, clot rate and platelet function showed no significant (P > 0.05) difference in both the groups at both the time intervals. DR15 and d-dimer values were comparable at baseline in both the groups. However, a significant (P < 0.05) difference was seen in these variables in the control group as compared with the TA group following heparin neutralisation. To conclude, Sonoclot analysis is a useful, point of care method for the monitoring of coagulation and fibrinolysis in patients with tetralogy of Fallot undergoing intracardiac repair. PMID- 22234019 TI - The effect of low-dose intravenous ketamine on continuous intercostal analgesia following thoracotomy. AB - Ketamine, a noncompetitive N-methyl-d-aspartate antagonist, provides analgesia and prevents chronic pain following thoracotomy. The study was aimed to assess the effect of intravenous low-dose ketamine on continuous intercostal nerve block analgesia following thoracotomy. The study was a prospective, randomized, double blinded, and placebo-controlled clinical study, performed in a single university hospital. Sixty patients, undergoing elective lobectomy through an open posterolateral thoracotomy, were included. For postoperative pain, all patients received a continuous intercostal nerve block with bupivacaine plus intravenous paracetamol and ketoprofen. In addition, patients were randomized to have intravenous ketamine (0.1 mg/kg as a preincisional bolus followed by a continuous infusion of 0.05 mg/kg/h) in group 1 or intravenous placebo in group 2. Patients reporting a visual analog scale pain score at rest >=40 mm received intravenous morphine sulfate as rescue analgesia. The following parameters were assessed every 6 hours for 3 postoperative days: Visual analog scale pain scores at rest and during coughing, requirement of rescue analgesia with morphine, Ramsay sedation scores and psychomimetic adverse effects. Both the groups were statistically comparable regarding visual analog scale pain scores at rest (P=0.75) and during coughing (P=0.70), number of morphine deliveries (P=0.17), cumulative dose of rescue morphine (P=0.2), sedation scores (P=0.4), and psychomimetic adverse effects (P=0.09). Intravenous low-dose ketamine, when combined with continuous intercostal nerve block, did not decrease acute pain scores and supplemental morphine consumption following thoracotomy. PMID- 22234020 TI - The effects of dexmedetomidine on attenuation of stress response to endotracheal intubation in patients undergoing elective off-pump coronary artery bypass grafting. AB - This study was designed to study the efficacy of intravenous dexmedetomidine for attenuation of cardiovascular responses to laryngoscopy and endotracheal intubation in patients with coronary artery disease. Sixty adult patients scheduled for elective off-pump coronary artery bypass surgery were randomly allocated to receive dexmedetomidine (0.5 mcg/kg) or normal saline 15 min before intubation. Patients were compared for hemodynamic changes (heart rate, arterial blood pressure and pulmonary artery pressure) at baseline, 5 min after drug infusion, before intubation and 1, 3 and 5 min after intubation. The dexmedetomidine group had a better control of hemodynamics during laryngoscopy and endotracheal intubation. Dexmedetomidine at a dose of 0.5 mcg/kg as 10-min infusion was administered prior to induction of general anaesthesia attenuates the sympathetic response to laryngoscopy and intubation in patients undergoing myocardial revascularization. The authors suggest its administration even in patients receiving beta blockers. PMID- 22234021 TI - Anaesthetic management of peripartum cardiomyopathy using "epidural volume extension" technique: a case series. AB - Peripartum cardiomyopathy is a rare cause of dilated cardiomyopathy in parturients, occurring in approximately one in 1000 deliveries, manifesting during the last few months or the first 5 months of the postpartum period. It can result in severe ventricular dysfunction during late puerperium. The major concern while managing these patients is to optimize fluid administration and avoid myocardial depression, while maintaining stable intraoperative hemodynamics. We present a case series of five parturients that were posted for elective cesarean section and managed successfully by the epidural volume extension technique. PMID- 22234022 TI - Earthing defect: a cause for unstable hemodynamics. AB - Interference of monitored electrocardiogram (ECG) is a common event in intensive care units and operation theaters. Artifacts in the ECG tracing can resemble serious arrhythmia, thus leading to unnecessary usage of antiarrhythmics or electrical defibrillation. In addition, ECG artifacts may lead to serious hemodynamic consequences secondary to intra-aortic balloon pump (IABP) trigger failure. We report a rare event of IABP failure due to ECG artifact, which appeared on placement of the transthoracic echocardiography probe over the chest. Subsequent evaluation revealed potential current leakage from echocardiography machine secondary to earthing defect in the machine. PMID- 22234023 TI - Perioperative challenges in a patient of severe G6PD deficiency undergoing open heart surgery. AB - We describe a successful perioperative management of a case of 38-year-old male, presented with chronic jaundice with severe mitral stenosis and moderate tricuspid regurgitation; upon evaluation, he was found to have severe glucose-6 phosphate dehydrogenase (G6PD) deficiency. Usually, patients deficient in G6PD exhibit increased hemolysis and therefore increased need for blood transfusion after cardiac surgery as well as impaired oxygenation in the postoperative period leading to prolonged ventilation. On reperfusion after a period of ischemia, the antioxidant system recruits all of its components in an attempt to neutralize the overwhelming oxidative stress of free radicals, as the free radical scavenging system is deficient in these patients, the chances of free-radical-induced injury is more. Our patient underwent mitral valve replacement and tricuspid annuloplasty under cardiopulmonary bypass with necessary precautions to reduce the formation of free radicals. Treatment was targeted toward the prevention of free radical injury in the G6PD-deficient patient. He had an uneventful intraoperative and postoperative course. PMID- 22234024 TI - Anaesthetic management of transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is an emergent technique for high risk patients with aortic stenosis. TAVI poses significant challenges about its management because of the procedure itself and the population who undergo the implantation. Two devices are currently available and marketed in Europe and several other technologies are being developed. The retrograde transfemoral approach is the most popular procedure; nevertheless, it may not be feasible in patients with significant aortic or ileo-femoral arterial disease. Alternatives include a transaxillary approach, transapical approach, open surgical access to the retroperitoneal iliac artery and the ascending aorta. A complementary approach using both devices and alternative routes tailored to the anatomy and the comorbidities of the single patient is a main component for the successful implementation of a TAVI program. Anaesthetic strategies vary in different centers. Local anaesthesia or general anaesthesia are both valid alternatives and can be applied according to the patient's characteristics and procedural instances. General anaesthesia offers many advantages, mainly regarding the possibility of an early diagnosis and treatment of possible complications through the use of transesophageal echocardiography. However, after the initial experiences, many groups began to employ, routinely, sedation plus local anaesthesia for TAVI, and their procedural and periprocedural success demonstrates that it is feasible. TAVI is burdened with potential important complications: vascular injuries, arrhythmias, renal impairment, neurological complications, cardiac tamponade, prosthesis malpositioning and embolization and left main coronary artery occlusion. The aim of this work is to review the anaesthetic management of TAVI based on the available literature. PMID- 22234025 TI - ST segment depression following pulmonary artery banding. PMID- 22234026 TI - Incidental transarterial placement of a dialysis catheter into the femoral vein. PMID- 22234027 TI - Extracorporeal membrane oxygenation--an anaesthesiologist's perspective--Part II: clinical and technical consideration. AB - Although the concept of extracorporeal membrane oxygenation (ECMO) has remained unchanged, component technology has evolved considerably over the past three decades. Presently the clinical conditions requiring ECMO support have been updated with input from the outcome data of patient registries. Modern circuit configuration has become less cumbersome, safer, and more efficient. Technological advances now allow prolonged support with fewer complications compared to the past eras and facilitate transition to a single bedside caregiver model, similar to hemofiltration or ventricular-assist devices. The clinical considerations and indicators for placing the patient on ECMO, the various circuit configurations, clinical and technical issues, and management aspects are considered in this article. PMID- 22234028 TI - Coronary artery bypass grafting and dengue fever. PMID- 22234029 TI - Off-pump cardiac surgery (OPCAB) in a patient with recent leech therapy. PMID- 22234030 TI - Artifactual electrocardiographic ST segment depression: less likely due to electrocautery. PMID- 22234031 TI - TRALI: a volley of caution. PMID- 22234032 TI - Lumbar epidural analgesia in pain management of Nuss procedures: paediatric case. PMID- 22234033 TI - Irreversible loss of vision in a paediatric patient due to occipital infarction after cardiopulmonary bypass. PMID- 22234034 TI - Decompression of superior vena cava during bidirectional Glenn shunt: a simple but risky technique. PMID- 22234035 TI - Prophylactic percutaneous minitracheostomy after omentoplasty for sternal wound infection. PMID- 22234036 TI - Left hepatic lobe herniation through an incisional anterior abdominal wall hernia and right adrenal myelolipoma: a case report and review of the literature. AB - INTRODUCTION: Herniation of the liver through an anterior abdominal wall hernia defect is rare. To the best of our knowledge, only three cases have been described in the literature. CASE PRESENTATION: A 70-year-old Mexican woman presented with a one-week history of right upper quadrant abdominal pain, nausea, vomiting, and jaundice to our Department of General Surgery. Her medical history included an open cholecystectomy from 20 years earlier and excessive weight. She presented with jaundice, abdominal distension with a midline surgical scar, right upper quadrant tenderness, and a large midline abdominal wall defect with dullness upon percussion and protrusion of a large, tender, and firm mass. The results of laboratory tests were suggestive of cholestasis. Ultrasound revealed choledocholithiasis. A computed tomography scan showed a protrusion of the left hepatic lobe through the anterior abdominal wall defect and a well-defined, soft tissue density lesion in the right adrenal topography. An endoscopic common bile duct stone extraction was unsuccessful. During surgery, the right adrenal tumor was resected first. The hernia was approached through a median supraumbilical incision; the totality of the left lobe was protruding through the abdominal wall defect, and once the lobe was reduced to its normal position, a common bile duct surgical exploration with multiple stone extraction was performed. Finally, the abdominal wall was reconstructed. Histopathology revealed an adrenal myelolipoma. Six months after the operation, our patient remains in good health. CONCLUSIONS: The case of liver herniation through an incisional anterior abdominal wall hernia in this report represents, to the best of our knowledge, the fourth such case reported in the literature. The rarity of this medical entity makes it almost impossible to specifically describe predisposing risk factors for liver herniation. Obesity, the right adrenal myelolipoma mass effect, and the previous abdominal surgery are likely to have contributed to incisional hernia formation. PMID- 22234037 TI - How to score points at an interview. PMID- 22234038 TI - Investigation on formulation and preparation of adenovirus encoding human endostatin lyophilized powders. AB - A recombinant adenovirus encoding human endostatin gene, E10A, has finished phase II trials for head and neck cancer. However, the rigid storage temperature (-80 degrees C) and the toxicity of glycerol in the E10A liquid preparation limited its clinical application. In this study, lyophilization was applied to develop a stable E10A lyophilized powder without glycerol that is able to maintain biological activity at 4 degrees C and suitable for intravenous administration. The E10A lyophilized formulations composed of nontoxic and already clinically used excipients were characterized in terms of the pH change during freezing, the eutectic melting temperature (T(eu)) and the collapse temperature (T(c)). Freeze thawing tests were carried out to examine the protective effect of various excipients during freezing. Mannitol and its combinations with sucrose or inulin showed effective protection of E10A. The E10A lyophilized powders were analyzed by particle size measurement, residual humidity quantification, infectivity assay and gene expression level. An optimized formulation (formulation I1) yielded a good recovery of 76% of the starting infectivity after lyophilization and 89% of the original infectivity after storage at 4 degrees C for 180 days. Also the gene expression capability of E10A in formulation I1 was maintained after lyophilization. In addition, it was found that the matrix of amorphous excipients, mannitol combinations with sucrose or inulin, was indispensible in protecting E10A against the stress of freezing and dehydration. Hereby, the E10A lyophilized powder with eliminated glycerol toxicity and improved stability could enhance the applicability of E10A for cancer gene therapy through intravenous administration. PMID- 22234039 TI - Uric acid is an independent risk factor for carotid atherosclerosis in a Japanese elderly population without metabolic syndrome. AB - BACKGROUND: Carotid intima-media thickness (IMT) is an useful surrogate marker of cardiovascular disease. Associations between uric acid (UA), metabolic syndrome (MetS) and carotid IMT have been reported, but findings regarding the relationship have been inconsistent. METHODS: A total of 1,579 Japanese elderly subjects aged >=65 years {663 men aged, 78 +/- 8 (mean +/- standard deviation) years and 916 women aged 79 +/- 8 years} were divided into 4 groups according to UA quartiles. We first investigated the association between UA concentrations and confounding factors including MetS; then, we assessed whether there is an independent association of UA with carotid IMT and atherosclerosis in participants subdivided according to gender and MetS status. RESULTS: Carotid IMT was significantly increased according to the quartiles of UA in both genders without MetS and women with MetS. Multivariate logistic regression analysis showed that odds ratio (OR) {95% confidence interval (CI)} in men for carotid atherosclerosis was significantly increased in the third (OR, 1.75; 95% CI, 1.02 3.02), and fourth quartiles (OR, 2.01; 95% CI, 1.12-3.60) of UA compared with that in the first quartile of UA, and the OR in women was significantly increased in the fourth quartile (OR, 2.10; 95% CI, 1.30-3.39). Similarly, the ORs were significantly associated with increasing quartiles of UA in both genders without MetS, but not necessarily increased in those with MetS. CONCLUSIONS: UA was found to be an independent risk factor for incidence of carotid atherosclerosis in both genders without MetS. PMID- 22234040 TI - Rational design of an auxin antagonist of the SCF(TIR1) auxin receptor complex. AB - The plant hormone auxin is a master regulator of plant growth and development. By regulating rates of cell division and elongation and triggering specific patterning events, indole 3-acetic acid (IAA) regulates almost every aspect of plant development. The perception of auxin involves the formation of a ternary complex consisting of an F-box protein of the TIR1/AFB family of auxin receptors, the auxin molecule, and a member the Aux/IAA family of co-repressor proteins. In this study, we identified a potent auxin antagonist, alpha-(phenylethyl-2-oxo) IAA, as a lead compound for TIR1/AFB receptors by in silico virtual screening. This molecule was used as the basis for the development of a more potent TIR1 antagonist, auxinole (alpha-[2,4-dimethylphenylethyl-2-oxo]-IAA), using a structure-based drug design approach. Auxinole binds TIR1 to block the formation of the TIR1-IAA-Aux/IAA complex and so inhibits auxin-responsive gene expression. Molecular docking analysis indicates that the phenyl ring in auxinole would strongly interact with Phe82 of TIR1, a residue that is crucial for Aux/IAA recognition. Consistent with this predicted mode of action, auxinole competitively inhibits various auxin responses in planta. Additionally, auxinole blocks auxin responses of the moss Physcomitrella patens, suggesting activity over a broad range of species. Our works not only substantiates the utility of chemical tools for plant biology but also demonstrates a new class of small molecule inhibitor of protein-protein interactions common to mechanisms of perception of other plant hormones, such as jasmonate, gibberellin, and abscisic acid. PMID- 22234041 TI - Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT. AB - BACKGROUND/OBJECTIVES: Our objective was to investigate effects of an oral nutritional supplement containing n-3 polyunsaturated fatty acids (FAs) on quality of life, performance status, handgrip strength and physical activity in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment. SUBJECTS/METHODS: In a double-blind experiment, 40 patients with stage III NSCLC were randomised to receive 2 cans/day of a protein- and energy-dense oral nutritional supplement containing n-3 polyunsaturated FAs (2.02 g eicosapentaenoic acid+0.92 g docosahexaenoic acid/day) or an isocaloric control supplement, during multimodality treatment. Quality of life, Karnofsky Performance Status, handgrip strength and physical activity (by wearing an accelerometer) were assessed. Effects of intervention were analysed by generalised estimating equations. P-values <0.05 were regarded as statistically significant. RESULTS: The intervention group reported significantly higher on the quality of life parameters, physical and cognitive function (B=11.6 and B=20.7, P<0.01), global health status (B=12.2, P=0.04) and social function (B=22.1, P=0.04) than the control group after 5 weeks. The intervention group showed a higher Karnofsky Performance Status (B=5.3, P=0.04) than the control group after 3 weeks. Handgrip strength did not significantly differ between groups over time. The intervention group tended to have a higher physical activity than the control group after 3 and 5 weeks (B=6.6, P=0.04 and B=2.5, P=0.05). CONCLUSION: n-3 Polyunsaturated FAs may beneficially affect quality of life, performance status and physical activity in patients with NSCLC undergoing multimodality treatment. PMID- 22234042 TI - Adherence to the European food safety authority's dietary recommendations and colorectal cancer risk. AB - BACKGROUND/OBJECTIVE: The European Food Safety Authority (EFSA) recently published dietary guidelines for the intakes of carbohydrates, fiber, fats and water. We evaluated their role on the risk of a specific disease, known to be related to diet. SUBJECTS/METHODS: We used data from an Italian case-control study including 1953 colorectal cancer (CRC) cases and 4154 controls. We developed a so-called EFSA index summing up 1 point for adherence to each EFSA guideline. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) of CRC and its subsites were derived from unconditional multiple logistic regression models, for both the index and its components. RESULTS: When each EFSA index component was analyzed separately, we found significant increased risks of CRC for non adherence to the guidelines on linoleic (OR=1.20, 95% CI, 1.07-1.36) and alpha-linolenic fatty acids (OR=1.19, 95% CI, 1.06-1.34). When all the guidelines were included in the same model, no significant association emerged. Compared with minimal adherence, the ORs of CRC for subsequent EFSA index scores were 1.03 (95% CI, 0.72-1.47), 1.05 (95% CI, 0.75-1.48), 1.04 (95% CI, 0.81-1.60), 0.99 (95% CI, 0.69-1.43), and 1.04 (95% CI, 0.67-1.61). No significant association emerged for colon and rectal cancer separately, and for males and females. CONCLUSIONS: Overall adherence to the EFSA dietary guidelines is not associated to colorectal, colon and rectal cancer risk in our population. Adherence to guidelines on linoleic and alpha-linolenic fatty acids may have a modest beneficial role on CRC risk. PMID- 22234043 TI - The effect of dairy consumption on blood pressure in mid-childhood: CAPS cohort study. AB - BACKGROUND/OBJECTIVES: It has been postulated that a higher dairy consumption may affect blood pressure regulation. The aim of this study was to examine the association between dairy consumption and blood pressure in mid-childhood. SUBJECTS/METHODS: Subjects (n = 335) were participants of a birth cohort at high risk of asthma with information on diet at 18 months and blood pressure at 8 years. Multivariate analyses were used to assess the association of dairy consumption (serves) and micronutrient intakes (mg). In a subgroup of children (n = 201), dietary intake was also measured at approximately 9 years. RESULTS: Children in the highest quintile of dairy consumption at 18 months had lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 8 years (2.5 mm Hg, P=0.046 and 1.9 mm Hg, P = 0.047, respectively) than those in the lowest quintiles. SBP was lowest among children in the highest quintiles of calcium, magnesium and potassium intakes. Significant negative linear trends were observed between SBP and intakes of dairy serves, calcium, magnesium and potassium. Furthermore, SBP and DBP were lowest in the group of children that consumed at least two dairy serves at both 18 months and the follow-up dietary data collection at 9 years, compared with all other children (SBP 98.7 vs 101.0 mm Hg, P = 0.07; and DBP 56.5 vs 59.3 mm Hg, P = 0.006, respectively). CONCLUSION: These results are consistent with a protective effect of dairy consumption in childhood on blood pressure at age 8 years. PMID- 22234044 TI - Associations between dietary patterns at 6 and 15 months of age and sociodemographic factors. AB - BACKGROUND/OBJECTIVES: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) have previously shown that dietary patterns are observable by 3 years. However, it is not clear when dietary patterns emerge. We aimed to describe dietary patterns in early life and their associations with maternal and infant sociodemographic characteristics. SUBJECTS/METHODS: Principal component analysis was applied to diet questionnaires of ALSPAC participants at 6 months (n = 7052) and 15 months (n = 5610) to extract dietary patterns. The sociodemographic factors associated with dietary patterns were investigated using regression analyses. RESULTS: Four dietary patterns were extracted at both 6 and 15 months. A traditional-style pattern characterized by home-prepared meats, vegetables and desserts, a second pattern characterized by ready-prepared baby foods and a third pattern characterized by discretionary foods such as biscuits, sweets and crisps were identified at both ages. At 6 months, the fourth pattern was characterized predominantly by breastfeeding and at 15 months, by contemporary-style foods including herbs, legumes, nuts, raw fruit and vegetables. Higher maternal age and education, number of siblings and lower body mass index (BMI) was associated with higher scores on the breastfeeding or meat, vegetables and desserts patterns, whereas higher discretionary food pattern scores were associated with younger maternal age, lower education, higher BMI and more siblings. Associations between sociodemographic factors and the ready prepared baby food pattern scores were inconsistent across ages. CONCLUSIONS: Dietary patterns emerge from infancy and are associated with sociodemographic characteristics. PMID- 22234045 TI - Comparison of dietary intakes according to breakfast choice in Australian boys. AB - BACKGROUND: There is little information on how breakfast choices are associated with dietary intakes in Australian boys. OBJECTIVE: (i) To determine the proportion of breakfast skippers, ready-to-eat cereal (RTEC) consumers and non RTEC consumers at breakfast; (ii) to compare breakfast, and daily nutrient intakes and nutrient density, between the three groups; and (iii) to compare daily nutrient intakes against nutrient recommendations. SUBJECTS/METHODS: Cross sectional analysis of 12 to 16-year-old boys (n = 781) from the 2007 Australian National Children's Nutrition and Physical Activity Survey. RESULTS: Forty-two percent of boys consumed RTEC at breakfast; 38% did not consume RTECs; and 20% skipped breakfast. Breakfast skippers had a higher body mass index and waist circumference compared with RTEC consumers (P <= 0.05). At breakfast, RTEC consumers had a higher intake of total sugars and a lower intake of fat and sodium versus non-RTEC consumers. Total daily nutrient density for calcium, iron, thiamin, riboflavin, zinc, dietary folate equivalents, magnesium and iodine was higher for RTEC consumers versus non-RTEC consumers and breakfast skippers (all P <= 0.05). Fifty-nine percent of 14 to 16-year-old RTEC consumers reached the fibre adequate intake versus 34% and 24% of non-RTEC consumers and breakfast skippers, respectively (all P <= 0.01). More RTEC consumers met the calcium estimated average requirements versus non-RTEC consumers and breakfast skippers (P <= 0.01). CONCLUSIONS: Breakfast choice, specifically RTECs and the foods consumed with them, provide valuable nutrients that may assist boys in meeting nutrient requirements. Consumption of RTECs may be one way in which intakes of key nutrients, relevant for growth and development, could be increased in older boys. PMID- 22234046 TI - Breakfast skipping in prepubertal obese children: hormonal, metabolic and cognitive consequences. AB - BACKGROUND AND AIMS: Skipping breakfast influences cognitive performance. The aim of our study was to investigate the relationship between the variation of hormonal and metabolic postprandial parameters induced by breakfast consumption or fasting and cognitive performance in obese children. METHODS: Cross-sectional study for repeated measures. Memory and attention assessment tests, hormones and nutrient oxidation were measured before and after consuming breakfast vs fasting in 10 prepubertal obese children. RESULTS: Fasting induced a significant (P<0.05) increase of the Overall Index of the Continuous Performance Test II (a global index of inattention) and the Test of Memory and Learning Word Selective Reminding (a test of verbal memory), whereas no changes were found after breakfast. Fasting was associated with a reduction of insulin and an increase in glucagon, with no changes in glucose. The increase in inattention was associated with a reduction of carbohydrate oxidation (rho=-0.66, P<0.05). We found no difference in the area under the curve of peptide YY and glucagon-like peptide-1 after breakfast or fasting, whereas Ghrelin was significantly lower. No association between postprandial hormone variation and cognitive performance was found. CONCLUSIONS: Attention and visual memory performance in the morning were reduced when the children skipped breakfast. No association was found with hormones or metabolic changes, but we did find an association with a reduction of carbohydrate oxidation. Nevertheless, these preliminary findings need confirmation in larger sample size. PMID- 22234047 TI - AAHA canine life stage guidelines. AB - Guidelines are offered to guide the veterinary practitioner in designing a comprehensive, individualized wellness plan for each stage of a dog's life. Life stages are defined by both age and breed characteristics for practical purposes. Each patient visit should use an individualized approach to patient handling, preventive care, and early disease detection. Environment, behavior, nutrition, parasite control, vaccinations, dental care, zoonotic disease control, safety, and reproductive health should be addressed. PMID- 22234048 TI - EGF-like peptide of Dictyostelium discoideum is not a chemoattractant but it does restore folate-mediated chemotaxis in the presence of signal transduction inhibitors. AB - A synthetic EGF-like (EGFL) peptide (DdEGFL1), equivalent to the first EGFL domain in the extracellular matrix protein CyrA, has previously been shown to enhance random cell motility and cAMP-mediated chemotaxis in Dictyostelium discoideum. However the role of DdEGFL1 as a potential chemoattractant had not been addressed. In this study, a micropipette assay and an under-agarose migration assay showed that DdEGFL1 is not a chemoattractant for Dictyostelium cells. A radial bioassay was used to show that DdEGFL1 does not significantly enhance folate-mediated chemotaxis in contrast to its chemokinetic effect during chemotaxis toward cAMP. However, DdEGFL1 was able to rescue chemotaxis toward folate when the pathway was inhibited by pharmacological agents that inhibit known components of the signaling cascade (e.g. phosphatidylinositol 3-kinase, phospholipase A2, tyrosine kinases, and calmodulin). These data suggest that DdEGFL1 may activate a novel motility pathway that when coupled with folic acid receptor activation, can maintain the normal migratory response to folic acid in vegetative cells. Together, this data provides new insight into the function of EGFL repeats during Dictyostelium chemotaxis and the existence of a novel motility pathway regulated by EGFL peptides and/or repeats in this model organism. PMID- 22234049 TI - Enhanced activity of punicalagin delivered via polymeric implants against benzo[a]pyrene-induced DNA adducts. AB - We investigated the effect of punicalagin (PC) on benzo[a]pyrene (BP)-induced DNA adducts in vitro and in vivo. Incubation of BP (1 MUM) with rat liver microsomes, appropriate co-factors and DNA in the presence of vehicle or punicalagin (1-40 MUM) showed dose-dependent inhibition of the resultant DNA adducts, with essentially complete (97%) inhibition at 40 MUM. However, PC failed to inhibit anti-BPDE-induced DNA adducts when tested in an in vitro non-microsomal system, suggesting that the inhibition of the microsomal BP-DNA adducts occurred due to inhibition of P450 1A1 by PC. To determine its efficacy in vivo, female S/D rats were administered punicalagin via the diet (1500 ppm; approximately 19 mg/day/animal) or subcutaneous polymeric implants (two 2-cm, 200mg with 20% drug load; 40 mg PC/implant) and then treated with continuous low-dose of BP by a subcutaneous polymeric implant (2 cm, 200mg with 10% load; 20mg BP/implant) and euthanized after 10 days. Analysis of the lung DNA by (32)P-postlabeling showed significant (60%; p=0.029) inhibition of DNA adducts by PC administered via the implants; the dietary route showed modest (34%) but statistically insignificant inhibition. Furthermore, total PC administered by implants was approximately 38 fold lower compared with the dietary route. Analysis of the lung microsomes showed significant inhibition of cytochrome P450 1A1 activity and induction of glutathione. Release of PC from the implants was found to be biphasic starting with a burst release, followed by a gradual decline. Ultra performance liquid chromatography analysis showed no detectable PC in the plasma but its hydrolyzed product, ellagic acid was readily detected. The plasma concentration of ellagic acid was over two orders of magnitude higher (589 +/- 78 ng/mL) in the implant group compared with diet (4.36 +/- 0.83 ng/mL). Together, our data show that delivery of PC by implants can reduce its effective dose substantially, and that the inhibition of DNA adducts in vivo occurred presumably due to the conversion of PC to ellagic acid. PMID- 22234050 TI - Breast reconstruction following prophylactic mastectomy for smaller breasts: the superiorly based pectoralis fascial flap with the Becker 35 expandable implant. AB - INTRODUCTION: Immediate reconstruction using tissue expander/implants following prophylactic mastectomy for smaller breasts is a reliable means of providing similar size, shape and symmetrical reconstructions. The superiorly based pectoralis fascial flap allows an immediate reconstruction of the inferior pole and may eliminate the need for tissue expansion. METHODS: The superiorly based pectoralis fascial flap and implant was performed on 5 patients (10 breasts). The Becker 35 expandable implant was used in all cases and average size was 349 (range 290-400cc). Average age was 33 (range 21-43). The average BMI was 23 (range 20-26). One patient underwent further tissue expansion of the Becker 35 postoperatively. One patient developed a seroma in the abdominal fascial flap donor site that settled without the need for drainage. There were no other complications. CONCLUSION: The superiorly based pectoralis fascial flap provides a one-stop reconstruction of the lower pole and can eliminate the need for tissue expansion in patients with small breasts. PMID- 22234051 TI - Selenium and its' role in the maintenance of genomic stability. AB - Selenium (Se) is an essential micronutrient for humans, acting as a component of the unusual amino acids, selenocysteine (Se-Cys) and selenomethionine (Se-Met). Where Se levels are low, the cell cannot synthesise selenoproteins, although some selenoproteins and some tissues are prioritised over others. Characterised functions of known selenoproteins, include selenium transport (selenoprotein P), antioxidant/redox properties (glutathione peroxidases (GPxs), thioredoxin reductases and selenoprotein P) and anti-inflammatory properties (selenoprotein S and GPx4). Various forms of Se are consumed as part of a normal diet, or as a dietary supplement. Supplementation of tissue culture media, animal or human diets with moderate levels of certain Se compounds may protect against the formation of DNA adducts, DNA or chromosome breakage, and chromosome gain or loss. Protective effects have also been shown on mitochondrial DNA, and on telomere length and function. Some of the effects of Se compounds on gene expression may relate to modulation of DNA methylation or inhibition of histone deacetylation. Despite a large number of positive effects of selenium and selenoproteins in various model systems, there have now been some human clinical trials that have shown adverse effects of Se supplementation, according to various endpoints. Too much Se is as harmful as too little, with animal models showing a "U"-shaped efficacy curve. Current recommended daily allowances differ among countries, but are generally based on the amount of Se necessary to saturate GPx enzymes. However, increasing evidence suggests that other enzymes may be more important than GPx for Se action, that optimal levels may depend upon the form of Se being ingested, and vary according to genotype. New paradigms, possibly involving nutrigenomic tools, will be necessary to optimise the forms and levels of Se desirable for maximum protection of genomic stability in all humans. PMID- 22234052 TI - Development of persistent HCV genotype 3a infection cell culture model in huh-7 cell. AB - BACKGROUND: Hepatitis C virus (HCV) is one of the major health concerns globally, with genotype 3a as the most prevalent in Pakistan. Lack of efficient HCV genotype 3a small animal models as well as genomic replicons has hampered the complete understanding of its life cycle, pathogenesis and therapeutic options. In this study we aimed to develop a persistent HCV genotype 3a infectious cell culture model. METHODS: We inoculated Huh-7 cells with HCV genotype 3a serum. Cells and media supernatant were collected at different time periods up to 40th day post infection. Culture media supernatant was also collected to find out its ability to infect naive Huh-7 cells. RESULTS: HCV replication was confirmed at both RNA and protein level through Real Time RCR and western blot using HCV core as marker. In order to validate the persistence of our model for HCV genotype 3a replication we inhibited the HCV replication through core specific siRNAs. The HCV RNA was detected intracellularly from the day one post infection up till 40th day, while HCV core protein was detected from the second day up to 40th day consistently. In culture media supernatant HCV RNA was also actively detected conferring its ability to infect the naive Huh-7 cells. Furthermore, core specific siRNA showed significant inhibition at 24th hour post transfection both at RNA and protein level with progressive increase in the expression of core gene after 3rd day. It clearly depicts that the Huh-7 successfully retained the HCV replication after degradation of siRNA. CONCLUSION: Finally, we report that our persistent infection cell culture model consistently replicate HCV genotype 3a for more than 1 month. PMID- 22234053 TI - Novel treatments for vasospasm after subarachnoid hemorrhage. AB - PURPOSE OF REVIEW: Cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage remains a considerable challenge in neurocritical care medicine. This review aims to cover the recent novel aspects and results in CVS treatment. RECENT FINDINGS: On the basis of the recent literature, treatment focusing on CVS alone is outdated. A considerable amount of evidence suggests CVS not to be the sole cause of delayed cerebral ischemia (DCI) and poor outcome. Early brain injury, cortical spreading depolarization, inflammation and microthrombosis have recently been discussed as additional factors. The results of a well designed phase III trial, using an endothelin-1 antagonist, indicated a decrease in the occurrence of CVS but did not change the clinical outcome significantly. Induced hypertension is currently recommended for treating suspected DCI, whereas hemodilution and hypervolemia are not. Endovascular intervention is only recommended in case of refractory symptomatic CVS. A couple of newer treatment strategies are under evaluation. Phase III trials are underway for magnesium sulfate and statins. Clinical trials aiming specifically at recently discussed factors other than CVS have not been reported. SUMMARY: Reviewing the recent literature, there have been some updates on recommendations and newer treatment modalities are under evaluation. However, a novel treatment with convincing evidence has not been reported so far. PMID- 22234054 TI - Role of EUS/EUS-guided FNA in the management of proximal biliary strictures. AB - BACKGROUND/AIMS: Optimal management of proximal biliary strictures depends on staging and adequate tissue diagnosis of suspected malignant lesions. Sensitivity of ERCP brush cytology is poor. EUS/EUS-FNA of these lesions is challenging with limited data on its diagnostic accuracy. We report our experience of EUS/ EUS guided FNA of proximal biliary strictures in a tertiary referral centre. METHODOLOGY: All patients who underwent EUS guided FNA of hilar lesions between October 2003 to July 2007 were identified. The final diagnosis was determined by surgical pathology, results of EUS-FNA or follow-up. RESULTS: 32 patients underwent 36 procedures for hilar lesions during the study period. EUS detected a mass in 9/14 patients who did not have a mass seen on imaging. The mean followup period was 39.43 months. The cytological specimen was adequate in 26 patients. The final diagnosis was adenocarcinoma (24) and benign (8). The overall accuracy, sensitivity, specificity, positive predictive value and negative predictive value of EUS-FNA were 68%, 52 %, 100%, 100% and 54%, respectively. If only adequate aspirates were included in the analysis, the values were 74%, 60%, 100%, 100% and 55% respectively. CONCLUSIONS: EUS guided FNA is a useful modality in the diagnosis and management of hilar lesions. PMID- 22234056 TI - Adoption of new selection criteria on living donor liver transplantation for hepatocellular carcinoma and their impact on the outcome. AB - BACKGROUND/AIMS: In cadaveric liver transplantation, the Milan criteria have been accepted as the selection criteria for HCC in considering organ allocation. However, the situation in LDLT is different. METHODOLOGY: This is a retrospective study on 518 recipients who underwent LDLT. The exclusion criteria included HCC with extrahepatic spread and HCC extending to the major hepatic vessels detected during the preoperative evaluation. RESULTS: HCC was the indication in 96 patients (18.5%); 52/96 patients (54.2%) fulfilled Milan criteria and 44/96 patients (45.8%) did not. The 5-year survival rate among patients fulfilling Milan criteria was 40/52 (77.0%) while for those who did not 30/44 (68.0%). Although these results show better survival rates among patients with HCC within the Milan criteria, they are insignificant (p=0.01) and they clearly demonstrate that patients with HCC outside the Milan criteria have nearly the same survival rate as patients with HCC within Milan criteria. CONCLUSIONS: Transplantation is the best treatment option for patients with HCC if a careful search reveals no extra-hepatic disease. The application of the Milan criteria for all patients with HCC would have denied many patients who can survive after transplantation. In LDLT programs, where the patient has a special living donor, the Milan criteria are not necessarily relevant. PMID- 22234055 TI - Phase I trial of neoadjuvant chemoradiation with gemcitabine and surgical resection for cholangiocarcinoma patients (NACRAC study). AB - BACKGROUND/AIMS: The feasibility of neoadjuvant chemoradiation therapy for cholangiocarcinoma, followed by conventional resection, has not been determined yet. Here, a phase I study of neoadjuvant chemoradiation therapy, named NACRAC, was performed to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of gemcitabine when combined with external beam radiation therapy for resectable cholangiocarcinoma. METHODOLOGY: From August 2007 to June 2008, 12 patients provided informed consent. Preoperative radiation was administered in 1.8Gy daily fractions up to a total dose of 45Gy. Gemcitabine was administered at day 1 and 8 every three weeks. The initial dose of gemcitabine was started from 400mg/m2. RESULTS: One patient was not able to start treatment because of bleeding caused by a duodenal ulcer and cholangitis. At 800mg/m2 of gemcitabine, one patient out of three failed to complete the treatment because of Grade 3 hematological toxicity. In another three cases of 800mg/m2, the second case could not complete the treatment because of cholangitis. Then, 600mg/m2 was determined to be the MTD, and the RD dose decided as 600mg/m2. CONCLUSIONS: The RD of gemcitabine in NACRAC study was determined to be 600mg/m2. NACRAC study should proceed to a phase II trial to evaluate the effectiveness. PMID- 22234057 TI - Dressing change reduces the central venous catheter-related bloodstream infection. AB - BACKGROUND/AIMS: To compare the time interval from insertion until development of central venous catheter related bloodstream infection (CVC-RBSI) between patients who received non-routine dressing change group (Group 1) and patients who received routine dressing change group (Group 2). METHODOLOGY: Between March 2006 and July 2008, patients who underwent CVC were randomly divided into Groups 1 and 2. Comparative study between the two groups was performed by reference to the incidences of CVC-RBSI from the prospectively obtained database. RESULTS: One hundred-eighty nine patients underwent 530 CVC insertions. Group 1 had 254 CVCs and Group 2 had 276 CVCs. There were no significant inter-group differences in patient background factors, except for gender. In addition, Group 1 had a shorter duration of catheter insertion than Group 2. Nevertheless, Group 1 had not only a significantly shorter period from insertion until the development of CVC-RBSI but also a higher frequency of fever than Group 2. CONCLUSIONS: The results of our comparison between non-routine dressing change group and routine dressing change group indicate that routine dressing change can reduce the incidence of CVC-RBSI in patients undergoing CVC insertions. PMID- 22234058 TI - Is there any link between oxidative stress and lung involvement due to inflammatory bowel disease: an experimental study. AB - BACKGROUND/AIMS: Lung involvement due to inflammatory bowel disease (IBD) is frequent, however the pathogenic mechanism is still debatable. Although the evidence of inflammation in colonic and lung tissue has been documented, the possible effect of oxidative stress in lung tissue has not been evaluated to date. We sought to assess the effects of oxidant/antioxidants on lung tissue in a model of experimental colitis. METHODOLOGY: Colitis was induced with intra colonic administration of 4% acetic acid. Control group received isotonic saline. Serum and lung tissue markers of oxidative stress were explored. RESULTS: Serum total oxidant status was significantly higher in the colitis group than the controls while total antioxidant status was similar. The determinants of oxidants including lipid peroxidation assay and myeloperoxidase activity were significantly higher in the lung tissue of the colitis group whereas the indicators of antioxidant capacity determined as superoxide dismutase, catalase, glutathione and glutathione peroxidase were decreased (p<0.05). CONCLUSIONS: This study showed that oxidative stress is not restricted to the bowel and the lung is a main target of oxidant overload. Pulmonary injury caused by increased oxidant stress may be the underlying reason of pulmonary involvement due to IBD. PMID- 22234059 TI - Laparoscopic splenectomy for inflammatory pseudotumor of the spleen. AB - We report two cases of inflammatory pseudotumor of the spleen treated by laparoscopic splenectomy. The first patient was a 61-year-old woman with a 3cm splenic tumor detected incidentally by ultrasonography. Computed tomography showed a well-demarcated splenic mass. She underwent hand-assisted laparoscopic splenectomy. The second patient was a 51-year-old man in whom a splenic tumor was found on follow-up computed tomography after resection of occipital malignant neurinoma. Ultrasound and magnetic resonance imaging confirmed a splenic tumor, which showed no uptake on 18F-fluorodeoxyglucose positron emission tomography. Laparoscopic splenectomy was performed. The histopathological diagnosis was inflammatory pseudotumor in both cases. Their postoperative course was uneventful, with a postoperative hospital stay of 11 and 8 days, respectively. Splenectomy is usually performed in patients with splenic tumors because imaging techniques cannot exclude malignancy. Laparoscopic splenectomy may be a useful option for patients with splenic tumors. PMID- 22234060 TI - A case of ruptured segmental arterial mediolysis of the hepatic artery: report of a case. AB - This article reports a patient with intra-abdominal hemorrhage secondary to a rare vascular disease, segmental arterial mediolysis (SAM). The patient was a 68 year-old male who presented with chilling and severe abdominal pain. Abdominal computed tomography results suggested the presence of an intra-abdominal hemorrhage. Although visceral angiography illustrated multiple aneurysms in the branches of the hepatic artery, active bleeding was not evident. Conservative therapy including transfusion was performed, and re-angiography revealed the disappearance of multiple hepatic arterial aneurysms 8 months later. This is the first case of intra-abdominal hemorrhage related to SAM of the hepatic artery in which natural history of SAM was seen. PMID- 22234061 TI - Laparoscopic hyperthermic intraperitoneal chemotherapy for the management of advanced peritoneal carcinomatosis. AB - The role of laparoscopic HIPEC has been reported by several centers around the world as a promising and appealing therapeutical alternative in the management of patients suffering of advanced intra-abdominal malignancies and peritoneal carcinomatosis. Laparoscopic HIPEC is implemented as a neoadjuvant and adjuvant therapeutical modality before and after open cytoreductive surgery. The diagnostic and therapeutical impact of laparoscopic HIPEC is well appreciated and generally is associated with many advantages when compared to classical open HIPEC and simultaneous open cytoreductive surgery. PMID- 22234062 TI - Clinical relevance of uPA, uPAR, PAI 1 and PAI 2 tissue expression and plasma PAI 1 level in colorectal carcinoma patients. AB - BACKGROUND/AIMS: Urokinase (uPA) is a serine protease, which together with uPAR, tPA, PAI 1 and PAI 2 forms the plasminogen activator system, a component of metastatic cascade contributing to the invasive growth and angiogenesis of malignant tumours. METHODOLOGY: Both preceding therapy and after 6-8 weeks of the treatment, plasma PAI 1 levels (photometric microplate method on the ELISA) and uPA, uPAR, PAI 1 and PAI 2 tissue expression (immunohistochemical reaction) were analysed from 80 colorectal carcinoma patients. RESULTS: Analysis showed higher pre-treatment plasma levels of PAI 1 in patients with advanced tumours, which decreased after surgery or the start of therapy (p=0.004); Patients with higher plasma level PAI 1 before (0.013) and after therapy (0.004) had significantly shorter survival. There was a higher expression of uPA (p<0.001), uPAR (p<0.001), PAI 1 (p=0.042) and PAI 2 (p<0.001) in advanced colorectal carcinoma. A relationship between PAI 2 (p=0.010) and uPAR (p=0.019) expression and survival was demonstrated. There is a correlation between pre-treatment plasma PAI 1 levels and PAI 2 (p=0.028) and uPAR (p=0.043) expression. CONCLUSIONS: Immunohistochemical analysis of PAS in tumour tissue and plasma PAI 1 levels was found to be a useful prognostic factor in colorectal carcinoma patients. Plasma PAI 1 could be advantageous in evaluating the effectiveness of a mode of treatment. PMID- 22234063 TI - P53 codon 72 polymorphism and colorectal cancer: a meta-analysis of epidemiological studies. AB - BACKGROUND/AIMS: Studies investigating the association between p53 codon 72 polymorphism and colorectal cancer risk report conflicting results. In order to clarify this, we carried out a meta-analysis using published data to obtain more precise estimates of risk. METHODOLOGY: Electronic searches of PubMed and EMBASE were conducted to select studies for this meta- analysis. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of colorectal cancer associated with p53 codon 72 genotype. RESULTS: We identified seven epidemiological studies, which included 1964 colorectal cancer cases and 2943 controls. The combined results based on all studies showed that there was no significant difference in genotype distribution [Arg/Arg (OR=0.86, 95% CI=0.68, 1.08); Pro/Pro (OR=1.27, 95% CI=0.96, 1.68); Pro/Arg (OR=1.04, 95% CI=0.92, 1.17)] between colorectal cancer and non-cancer patients. When stratifying for race, we found that patients with colorectal cancer had a significantly higher frequency of Pro/ Pro (OR=1.79, 95% CI=1.37, 2.35) and lower frequency of Arg/Arg (OR=0.66, 95% CI=0.44, 0.98) than controls among Asians. No statistical association was found between this genotype and alcohol, tobacco, stage, histological differentiation, lymph node metastasis of colorectal cancer. CONCLUSIONS: Our meta-analysis suggests that the p53 codon 72 polymorphism may be associated with colorectal cancer among Asians. PMID- 22234064 TI - Scheduled prospective tri-weekly modified FOLFOX6 maintenance chemotherapy in the treatment of metastatic colorectal cancer. AB - BACKGROUND/AIMS: Oxaliplatin, which is effective for colorectal cancer (CRC) in combination with 5-fluorouracil (5-FU) and leucovorin (LV), is widely used for metastatic CRC. With the increasing use of oxaliplatin, however, serious adverse events have been experienced, including hematologic and neurologic toxicities. The aim of this study was to evaluate whether tri-weekly modified FOLFOX6 (mFOLFOX6) maintenance chemotherapy is associated with a low incidence of severe hematologic and neurologic toxicities in the treatment of patients with metastatic CRC. METHODOLOGY: We developed a new treatment regimen with mFOLFOX6 biweekly for 8-10 consecutive cycles (induction phase) followed by a 3-week rest period, after which treatment was resumed with cycles of tri-weekly mFOLFOX6 at standard doses (maintenance phase). Validity and complications were investigated retrospectively. RESULTS: Twenty-nine patients were enrolled in this study. The median progression-free survival (PFS) and overall survival (OS) times were 9.4 months and 23 months, respectively. All patients had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 2 patients (6.9%). CONCLUSIONS: mFOLFOX6 maintenance chemotherapy was associated with a very low incidence of grade 3 hematologic and neurologic toxicities. The toxicities associated with PFS and OS were comparable to those reported in the treatment of patients with metastatic CRC. A tri-weekly mFOLFOX maintenance strategy of alternative treatment with a less-toxic regimen may reduce toxicity and maintain efficacy. PMID- 22234065 TI - Double stents: airway stenting after esophageal-stent implantation for esophageal cancer. AB - BACKGROUND/AIMS: Esophageal stenting with self-expandable metallic stents can effectively relieve malignant esophageal strictures in patients in whom chemoradiotherapy has failed. However, airway stenosis can sometimes occur after esophageal stenting. This study aims to evaluate the efficacy of double stents (combined esophageal and airway stents) in patients with recurrent and unresectable esophageal carcinoma in whom definitive chemoradiotherapy has failed. METHODOLOGY: We retrospectively studied 35 patients who underwent esophageal stenting for recurrent esophageal carcinoma after failure of chemoradiotherapy. These patients were divided into 2 groups; the E group, consisting of patients who underwent esophageal stenting alone and the D group, consisting of patients who required airway stenting after esophageal stenting due to airway compression. Bronchoscopy was performed before esophageal stenting in all patients. RESULTS: In all 5 patients developed airway stenosis after esophageal stenting. With regard to the bronchoscopic findings before esophageal stenting, the incidence of category-2b findings was significantly higher in the D group than in the E group. Mean survival was 60 days (range 24-102 days). CONCLUSIONS: Accurate bronchoscopic examination with special attention to compression of the airway should be performed before esophageal stenting in patients in whom the bronchoscopic findings are classified as category 2b or higher. PMID- 22234066 TI - How much length of the distal esophagus is removed by transhiatal approach for squamous cell carcinoma and Barrett's adenocarcinoma in Japanese patients? AB - BACKGROUND/AIMS: The removed length of the esophagus by transhiatal distal esophagectomy (THDE) for patients with squamous cell carcinoma (SCC) and Barrett's adenocarcinoma (BAC) in the distal/abdominal esophagus was investigated. METHODOLOGY: Twenty six patients with carcinoma mainly located in the distal/ abdominal esophagus were treated by THDE: SCC (Group-S, n=17) and BAC (Group-A, n=9). The length of the mobilized esophagus (D1) and that of the removed esophagus (D2) were measured. After surgery, we measured the distance between the stapled line of the esophagogastrostomy and the diaphragmatic hiatus (D3). The ratio of D3 to the distance between the bronchial bifurcation and the hiatus (D3-ratio) was calculated. RESULTS: The mean D1, D2 and D3 were 91.2mm, 65.2mm and 63.2mm, respectively. There were no differences among D1, D2 and D3 between Group-S and Group-A. The mean D3-ratio was 51.9%, and there was no difference between Group-S and Group-A. No postoperative mortality was observed, although postoperative complications were observed in 2 patients (7.7%). After THDE, no local recurrence was observed, node recurrence in 4 (15.4%) and distant metastasis in 7 (26.9%). Five-year survival rate after THDE was 70.1%. Seven patients (26.9%) complained of heartburn and only one of Group-S frequently felt heartburn. In endoscopic findings, most of the patients with heartburn were classified as Grade M. CONCLUSIONS: Approximately 65mm of the distal esophagus and approximately 50% of the distance between the bronchial bifurcation and the hiatus was safely removed by THDE for SCC and BAC of the distal/abdominal esophagus, in spite of limited cases. PMID- 22234067 TI - Endoscopic metal stents for the palliation of malignant upper gastroduodenal obstruction. AB - BACKGROUND/AIMS: Gastric outlet obstruction (GOO) is frequently caused by tumor. Recently, endoscopic implantation of self-expanding metallic stents (SEMS) has been introduced as an improved palliative treatment for GOO. This study aims to study the effect of SEMS placement on nutrient intake in patients with GOO and correlate different SEMS positions with postoperative clinical outcomes. METHODOLOGY: Fifty six non-operable patients with GOO were enrolled. Obstruction of the duodenum (n=23) or gastric outlet (n=33) were commonly found. Either Wallstent Enteral Stents, WallFlex Enteral Duodenal or partially covered Ultraflex esophageal stents were placed under endoscopic and fluoroscopic guidance. The Gastric Outlet Obstruction Score (GOOSS) was used as the main outcome measurement. RESULTS: The procedure was technically feasible in 100% of patients and gave satisfactory clinical results in 98.2% (55/56). The patients had a median survival time of 97.5 days (range 9-380). Median stent patency was 72 days with a range of 8 to 267 days. The average GOOSS, measuring oral intake, was significantly improved, regardless of obstruction site (p<0.05). We also found that the site of SEMS placement did not affect the clinical outcome. CONCLUSIONS: Palliation with SEMS is a safe and effective method for restoring gastric intake in patients with malignant GOO. PMID- 22234068 TI - Diagnostic power of inflammatory markers in predicting severity of appendicitis. AB - BACKGROUND/AIMS: Severity of inflammation may be a risk factor for negative outcome in non-operative therapy of appendicitis. However, optimal screening test for predicting the pathological severity of appendicitis has not been established. METHODOLOGY: 632 consecutive patients who underwent appendectomy at a single institute were retrospectively reviewed. Clinical parameters are compared among the three pathological grades: simple (G1), gangrenous (G2), and perforated appendicitis (G3). The diagnostic power of inflammatory markers (WBC count and CRP concentration) in discriminating the advanced appendicitis from the milder one was evaluated. RESULTS: CRP concentration was well correlated with the severity of appendicitis (p>0.0001), while WBC count showed only slight increase in advanced pathology (G1 vs. G2-G3). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was remarkably higher in CRP (AUC 0.809) compared with that in WBC count (AUC 0.617), suggesting that CRP is a more sensitive test in discriminating the pathological severity of appendicitis. Multivariate analysis confirmed that CRP concentration >6.2mg/dL (OR: 5.12; 95% CI: 2.17-12.7) and diameter >12mm (OR: 4.33; 95% CI: 1.98-9.90) were strong predictive factors for advanced appendicitis. CONCLUSIONS: CRP concentration may be a potent objective predictor of pathological severity in appendicitis. Combination with the other diagnostic modalities may improve the diagnostic accuracy in predicting the severity of appendicitis. PMID- 22234069 TI - Analysis of the RUNX3 gene methylation in serum DNA from esophagus squamous cell carcinoma, gastric and colorectal adenocarcinoma patients. AB - BACKGROUND/AIMS: Human runt-related transcription factor 3 (RUNX3) gene was a new candidate tumor suppressor gene involved in the TGF-beta signaling pathway. We evaluated the diagnostic role of RUNX3 gene methylation in serum DNA of esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) and colorectal cancer (CRC) patients. METHODOLOGY: Methylation-specific polymerase chain reaction (MSP) was used to determine the promoter methylation status of RUNX3 gene in serum DNA. The combination of RUNX3 hypermethylation and conventional tumor markers was further analyzed. RESULTS: Hypermethylation of RUNX3 was detected in 51.4% (36/70) of ESCC, 45.2% (28/62) of GC and 41.5% (27/65) of CRC patients, which was significantly higher than that of benign gastrointestinal diseases and healthy donors (p<0.001). Interestingly, aberrant RUNX3 methylation in serum DNA was associated with advanced stage (p=0.027) and lymph metastasis (p=0.032) in ESCC, but not in GC and CRC. Furthermore, the combinational analysis of CEA, CA19-9 and RUNX3 methylation showed a higher sensitivity and no reduced diagnostic specificity than CEA and CA19-9 combination in the three cancers. CONCLUSIONS: The serum RUNX3 promoter hypermethylation may be a promising biomarker for the early diagnosis of ESCC, GC and CRC, which was further confirmed by combining with CEA and CA19-9. PMID- 22234070 TI - Gastric emptying in Billroth-I and Roux-en-Y reconstruction after distal gastrectomy using C-acetate breath test. AB - BACKGROUND/AIMS: Billroth-I and Roux-en-Y procedures have been applied generally as reconstruction techniques after distal gastrectomy. There have been few reports regarding the physiological differences of these two procedures. We compared gastric emptying after Roux-en-Y procedure with the Billroth-I procedure using the 13C-acetate breath test. METHODOLOGY: Eleven patients who underwent distal gastrectomy, using reconstruction procedures of Billroth- I (B-I group: n=7) and Roux-en-Y (R-Y group: n=6), and 4 healthy volunteers (Control group) were studied. After ingestion of 200mL of liquid diet labelled with 100mg 13C acetate, breath samples were collected every 5-15 minutes for 3 hours. The analysis of 13C-acetate enrichment was measured using infrared spectrometer. RESULTS: Mean breath-Tmax of B-I group (14.2min) and R-Y group (13.0min) were significantly shorter compared with that of the control group (42.5min). Mean breath-T1/2 of B-I group (76.8min) and R-Y group (80.2min) were significantly shorter compared with that of the control group (133.3min). Mean breath-Cmax of B I group (60.1min) and R-Y group (59.3min) were significantly higher than that of the control group (27.6min). CONCLUSIONS: 13C-acetate breath test was useful to evaluate gastric emptying. There were no differences in gastric emptying for both Billroth-I and Roux-en-Y reconstruction. PMID- 22234071 TI - Effective treatment for duodenal variceal bleeding using endoscopic ligation. AB - Duodenal variceal rupture is rare, and there is little agreement on the best therapeutic option. A 72-year old man treated for liver cirrhosis with HCV visited the emergency room complaining of dizziness and tarry stool. Fiberscope images showed varices (F2CbRC+) with white plaques at the horizontal region of the duodenum. The patient was treated using endoscopic variceal ligation (EVL), and no more bleeding has been detected. PMID- 22234072 TI - Early implantation of Denver shunt. AB - BACKGROUND/AIMS: The Denver peritoneovenous shunt is useful in the resolution of refractory ascites, because it alleviates symptoms and allows effective palliation. However, this shunt did not prolong the life expectancy of patients with decompensated liver cirrhosis. Therefore, when deciding whether or not to implant a Denver shunt, it is important to determine the condition of the patient with refractory ascites. Here, we determined the appropriate time for Denver shunt implantation. METHODOLOGY: We retrospectively studied 21 patients who underwent Denver shunt implantation for hepatic failure-related ascites. The patients were divided into PC and WPC groups depending on whether or not paracentesis was performed before implantation of the Denver shunt, respectively. RESULTS: The mean interval from hospital admission to Denver shunt implantation was significantly shorter in the WPC group (9.0+/-2.2 days) than in the PC group (25.9+/-5.9 days) (p<0.0001). The mean survival time was significantly longer in the WPC group (8.4+/-2.5 months) (p<0.0071) than in the PC group (5.6+/-1.7 months). CONCLUSIONS: Early implantation of a Denver shunt should be considered for the treatment of ascites that is resistant to conservative medical therapy. PMID- 22234073 TI - Changes in staging for hepatocellular carcinoma after radiofrequency ablation prior to liver transplantation as found in the explanted liver. AB - BACKGROUND/AIMS: To analyze the efficacy of radiofrequency ablation (RFA) prior to liver transplantation (LT) in liver explants. METHODOLOGY: We reviewed pathological findings in the explanted livers of 13 patients with histologically proven HCC and liver cirrhosis who underwent RFA as bridging treatment prior to LT. Eight patients had solitary nodules with a median diameter of 4cm, whereas five patients had two tumors each with a median total diameter of 3.3cm prior to RFA. One session of RFA was performed by all patients. RESULTS: Tumor regression was proved in 3/13 patients whereas steady disease was observed in 5/13 patients (38%). Tumor regression was observed only in one of the five patients having two tumors prior to RFA. Pathology proved a multifocal tumor in four patients, including one patient with a radiological presumed solitary tumor. Tumor progression was observed in 5/13 patients (38%). CONCLUSIONS: Although the majority of our patients (8/13, 62%) had a solitary tumor at the beginning of treatment, tumor progression was observed in a large proportion (38%) among them. The underestimation of tumor lesions in radiology and partial necrosis of the tumor achieved in most patients limit the role of RFA as bridging treatment prior to LT. PMID- 22234074 TI - Protective effects of physiological doses of estrogen during hepatocarcinogenesis induced by diethylnitrosamine and N-nitrosomorpholine. AB - BACKGROUND/AIMS: Concern that much controversy exists with respect to the role of estrogen in hepatocarcinogenesis prompted us to examine the effect of estrogen, at physiological concentrations, on our established HCC rat model induced by diethylnitrosamine and N-nitrosomorpholine. METHODOLOGY: Female Sprague-Dawley rats were randomly divided into four groups (Group 1: Control, Group 2: Sham operated, Group 3: Ovariectomy, Group 4: ovariectomy+estrogen) with treatment of a single i.p. injection of diethylnitrosamine (100mg/ kg body weight) followed by N-nitrosomorpholine (100ppm) in drinking water for 20 weeks for the established rat HCC model. Physiological estrogen was administered by 17alpha Ethynylestradiol at a dose of 30MUg/ kg body weight while rats in the sham operated group were treated with saline after initiation of liver carcinogenesis. RESULTS: Treatment of ovariectomized animals with 17alpha-Ethynylestradiol (30MUg/kg body weight/ day) resulted in a significant decrease in the initiation, development and metastasis of HCC and an increase in the survival time of animals dead before the termination of experiment as compared with rats treated with ovariectomy only (p<0.05); whereas this difference disappeared when compared with the other three groups. CONCLUSIONS: These findings show for the first time that estrogen, at physiological concentrations may reveal a protective role in hepatocarcinogenesis. PMID- 22234075 TI - Comparison of the hemodynamics between patients with alcoholic or HCV-related cirrhosis. AB - BACKGROUND/AIMS: Hyperdynamic circulation, which is characterized by increased cardiac output (CO), normal or low arterial blood pressure (BP), and decreased systemic vascular resistance (SVR), occurs in patients with liver cirrhosis (LC). However, differences of hemodynamics between patients with alcoholic LC (ALC) and viral LC are not well understood. The aim of the present study was to compare hemodynamics between patients with alcoholic LC and patients with HCV-related LC (CLC). METHODOLOGY: Eighteen healthy Japanese volunteers (HV), 10 patients with chronic hepatitis (CH), 46 patients with CLC, and 22 ALC patients with ALC were included in the study. The CLC group was divided into two subgroups (34 non ascites and 12 ascites patients), as was the ALC group (11 non-ascites and 11 ascites patients). The CO, portal blood flow (PBF), and hepatic congestion index (HCI) were measured by ultrasound. RESULTS: The CO of the CLC and the ALC groups was higher than that of the HV group, while the SVR of the CLC and ALC groups was lower than that of the HV group. These changes were more marked in the ALC group. The HCI of the ascitic ALC subgroup was higher than that of the HV group. PBF did not differ among the CLC, ALC and HV groups. CONCLUSIONS: Progression of liver diseases such as ALC or CLC leads to a hyperdynamic circulation. The decrease of SVR was more marked in ALC patients than that CLC patients and an increase of the HCI was only found in ALC patients with ascites. PMID- 22234076 TI - Terlipressin facilitates gastric and autonomic system dysfunctions in liver cirrhosis. AB - BACKGROUND/AIMS: The aim of this study was to evaluate gastric myoelectric activity and autonomic activity in patients with esophageal varices treated by an analogue of vasopressin. METHODOLOGY: Included in this study are 20 patients divided into two groups: Group A: 10 patients treated with terlipressin (the bleeding from oesophageal varices) and Group B: 10 healthy persons matched with age and gender. The studies were performed before and after intravenous administration of vasopressin (VP) analogue. In both groups the fasting plasma levels of vasopressin, adrenaline and noradrenaline were measured by immunochemistry. RESULTS: In group A disturbances of gastric myoelectric activity with high timing of dysrhythmic pattern were observed before VP. VP administration further increased the timing of gastric dysrhythmia from 35 +/- 16 to 41 +/- 13%, and decreased PDF from 1.4 +/- 0.6cpm to 1.19 +/- 0.6cpm, PDP from 1891 +/- 851MUV2 to 718 +/- 678MUV2. VP induced an increase in SDANN, lnLF, nLF (p<0.05) as well as a decrease in SDNN, pNN50, lnHF (p<0.05). Although there was no retching or vomiting, 80% of patients presented with nausea and exhibited a significant increase in plasma levels of VP, adrenaline and noradrenaline after administration of VP analogue. CONCLUSIONS: VPinduced gastroparesis is characterized by suppressed slow wave amplitude and with increase of their frequency. The existing parasympathetic impairment and increased sympathetic drive of the autonomic system is responsible for vasopressin-induced gastric dysrrhythmia and its clinical consequences. PMID- 22234077 TI - Hospital costs and length of hospital stay for hepatectomy in patients with hepatocellular carcinoma:results of a prospective case series. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) has become an important health concern. However, data on its economic burden are limited. This study was undertaken to estimate the hospital costs and length of hospital stay (LOHS) for hepatectomy in patients with HCC, and identify the contributing factors to them. METHODOLOGY: A prospective case series observation was performed from January 2009 to December 2009 at two general hospitals in China. The information, such as demographic and clinical data, of HCC patients undergoing hepatectomy was recorded. Hospital costs and LOHS were analyzed to estimate the distribution of healthcare utilization. The multiple linear regression analysis was utilized to determine the impact of different demographic and clinical factors on costs and LOHS. RESULTS: A total of 220 patients were enrolled. The median hospital costs were $3453.7. The median LOHS was 13 days. The major fraction of the total costs was medication costs, accounting for 40.2%. LOHS was the key determinant of hospital costs. Blood transfusion, postoperative complication and Child-Pugh score were also independent but less contributory determinants. Additionally, predictors for prolonged LOHS included postoperative complication and surgical procedure. CONCLUSIONS: Hospital costs and LOHS for hepatectomy have their particular contributing factors. The results may be useful in resource allocation and cost-effectiveness analysis of intervention for HCC treatment. PMID- 22234078 TI - Usefulness of preoperative partial splenic embolization in hepatocellular carcinoma and hypersplenic thrombocytopenia. AB - BACKGROUND/AIMS: Patients with both hepatocellular carcinoma and hypersplenic thrombocytopenia are occasionally seen and this condition can severely complicate liver resection. This study evaluated the usefulness of preoperative partial splenic embolization (PSE) as an alternative to splenectomy (SP). METHODOLOGY: Twenty-eight patients with hypersplenic thrombocytopenia underwent hepatectomy for hepatocellular carcinoma. Five patients underwent preoperative PSE and 23 patients underwent concomitant splenectomy. The blood cell counts, laboratory chemistry data, and operative morbidity, prognosis were all examined. RESULTS: There were no severe PSE-related complications such as splenic abscess seen after PSE. The platelet counts in the PSE group significantly increased in comparison to those in the SP group before the operation. The frequency of blood transfusion and postoperative complications in the PSE group was significantly less than that in the SP group. The duration of surgery, blood loss, and performance of PSE were significant factors to predict postoperative complications. The overall survival after liver resection was not significantly different between patients in the PSE and SP group. CONCLUSIONS: Preoperative PSE could be safely performed without severe adverse effects prior to liver resection and it was thus considered to be useful for increasing the number of platelets and reducing postoperative complications. PMID- 22234079 TI - Posterior approach pancreaticoduodenectomy: best option for hepatic artery anatomical variants. AB - Pancreaticoduodenectomy is the best treatment for the patients with malignant tumors of the pancreatic head. However, the procedure is also recommended in some benign pancreatic tumors. The posterior approach allows early dissection of the superior mesenteric artery, portal vein and retroportal pancreatic lamina, before any pancreatic or digestive transection. We present a 42 year old woman diagnosed with a pancreatic tumor. The clinical and biological data suggested the diagnosis of insulinoma. The computed tomography showed a nodule located in the pancreatic head with a typical vascular pattern for endocrine tumor. The exam also revealed a rare vascular variant, a common hepatic artery which arises from the superior mesenteric artery. A pancreaticoduodenectomy has been performed. We used the posterior approach which allowed the correct dissection and exposure of the abnormal common hepatic artery. The postoperative course was uneventful. Posterior approach during the pancreaticoduodenectomies avoids arterial injuries that might compromise the liver arterial supply. It is especially indicated when preoperative imaging studies diagnose anatomic variants of the hepatic arteries. PMID- 22234080 TI - Reversal of liver cirrhosis in autoimmune hepatitis. AB - Liver cirrhosis is generally considered irreversible but there are reports in which there is documented reversal of fibrosis/cirrhosis in various clinical conditions like Wilson's disease, hemochromatosis, primary biliary cirrhosis and autoimmune hepatitis. The subgroup of patients with autoimmune hepatitis that will have reversal of cirrhosis is not known. We present two cases with documented liver cirrhosis that had reversal of cirrhosis after treatment with immunosuppressive agents. We postulate that patients presenting with acute hepatitis and no other fibrogenic factors have higher chances of reversal of liver cirrhosis as compared to those presenting as chronic liver injury. PMID- 22234081 TI - Radical surgery for advanced pure squamous cell carcinoma of the gallbladder: report of a case. AB - Squamous cell carcinoma (SCC) of the gallbladder is frequently detected at an advanced stage because of its tendency to infiltrate adjacent organs. In addition, more rapid growth of this type of carcinoma compared to that of adenocarcinoma, the most frequent subtype of gallbladder carcinoma, has been reported. Although it is not rare to find squamous cell carcinoma components in cases other than the usual adenocarcinoma of the gallbladder, these cases must be distinguished from those of pure squamous cell carcinoma, as diagnosed in the present case. Pure squamous cell carcinoma is characterized by a well-localized growth, no visceral metastasis, and a rarity or lack of lymph node metastasis, even when the tumor has grown to a large size locally. Prognosis of SCC of the gallbladder has generally been considered poor. Nevertheless, long-term survival after curative resection in patients with SCC of the gallbladder has been sporadically reported. We performed extended right hemihepatectomy with portal vein resection after portal vein embolization for a 55-year-old woman with advanced SCC of the gallbladder. The patient has not developed any signs of recurrence 40 months after the surgery. Although such radical surgery remains challenging, it may lead to a favorable outcome in selected patients with advanced SCC of the gallbladder. PMID- 22234082 TI - Delayed gastric emptying accelerates pancreatic anastomotic stricture formation after pancreaticogastrostomy for soft pancreas. AB - BACKGROUND/AIMS: Pancreatic duct dilatation induced anastomotic stenosis of the pancreatic duct is frequently observed in patients who have undergone pancreaticoduodenectomy (PD) with pancreaticogastrostomy (PG). Patency of the pancreaticoenteric anastomosis is one of the most important factors affecting the function of the remnant pancreas and quality of life. Anastomotic stenosis after PG is observed in some patients after approximately 1 to 2 postoperative weeks and is attributed to acute inflammation and fibrosis around the anastomosis. We therefore evaluated the early postoperative changes in remnant pancreatic duct diameter after PG in patients with soft pancreas in terms of delayed gastric emptying (DGE). METHODOLOGY: We retrospectively studied 42 patients with soft pancreas who underwent PD with PG. They were divided into 2 groups depending on the grade of DGE; without or slightly DGE group (WS group) and moderate or severe DGE group (MS group). RESULTS: The mean diameter of the pancreatic duct of the remnant pancreas was significantly smaller in the WS group than in the MS group. CONCLUSIONS: DGE accelerates pancreatic anastomotic stricture development after PG in patients having soft pancreas with a pancreatic duct with a small diameter. Hence, to maintain the pancreatic duct patency, preventing DGE is important. PMID- 22234083 TI - Modified duval procedure for small-duct chronic pancreatitis without head dominance. AB - BACKGROUND/AIMS: In the case of small-duct chronic pancreatitis, surgery for pain relief is broadly divided into resection and drainage procedures. These procedures should be selected according to the location of dominant lesion, diameter of the pancreatic duct and extent of the disease. The appropriate procedure for the treatment of small-duct chronic pancreatitis, especially small duct chronic pancreatitis without head dominance, remains controversial. We developed the modified Duval procedure for the treatment of small-duct chronic pancreatitis without head dominance and determined the efficacy of this procedure. METHODOLOGY: We retrospectively studied 14 patients who underwent surgical drainage with or without pancreatic resection for chronic pancreatitis with small pancreatic duct (<7mm) without head dominance. These patients were divided into 2 groups; the modified Puestow procedure group and the modified Duval procedure group. RESULTS: No complications occurred in the modified Duval group. In the modified Puestow procedure group, complete and partial pain relief were observed in 62.5%, and 37.5% of patients respectively. In contrast, complete pain relief was observed in all the patients in the modified Duval procedure group. CONCLUSIONS: Our modified Duval procedure is useful and should be considered the appropriate surgical technique for the treatment of small-duct chronic pancreatitis without head dominance. PMID- 22234084 TI - A long-term controlled trial of endoscopic pancreatic stenting for treatment of main pancreatic duct stricture in chronic pancreatitis. AB - BACKGROUND/AIMS: Endoscopic pancreatic stenting (EPS) has been used to treat main pancreatic duct (MPD) stricture in chronic pancreatitis (CP), with favourable reported results. However, most studies were retrospective and uncontrolled. We conducted a longterm prospective controlled study of EPS for treatment of MPD stricture in CP. METHODOLOGY: Consecutive patients with CP were treated to remove pancreatic stones by extracorporeal shock-wave lithotripsy or endoscopic basket extraction. After treatment, 41 patients were enrolled in the study upon meeting the criteria of complete removal of stones, pain relief after the treatment, and dominant stricture of the MPD. Twenty patients chose EPS, while 22 control patients did not. We compared recurrence of pain and pancreatic function between groups for over 3 years of follow-up. RESULTS: The mean follow-up period was 62.5 +/- 20.9 months. Pain recurred in 15% of EPS patients (3/20) and in 50.0% of control patients (11/22), a significant difference (p<0.05). Progression of exocrine insufficiency in the EPS group was significantly slower than in the control group (p<0.05), while endocrine function showed no difference between groups. CONCLUSIONS: EPS reduced pain recurrence and slowed down the progression of exocrine insufficiency in CP patients with MPD stricture. PMID- 22234085 TI - The directionality of lymphatic spreading as a prognostic factor in gastric cancer: uni- or multidirectional lymphatic metastases. AB - BACKGROUND/AIMS: The most critical problem of the numerical lymph node staging system is difficulty in evaluating preoperative staging. We investigated the directionality of metastatic lymph nodes as an alternative prognostic indicator of gastric cancer. METHODOLOGY: One hundred and seventy two patients who had undergone curative gastrectomy were examined. We divided the stations of lymph nodes into three zones according to the anatomical site. Then patients were classified into two groups according to the number of positive zones, unidirectional or multidirectional lymphatic spreading. RESULTS: Seventy-five patients showed unidirectional lymphatic spreading, whereas 97 patients showed multidirectional. Logistic regression analysis showed that directionality correlated with the number of metastatic nodes. Directionality was found to be a significant prognostic factor on univariate analysis, but not on multivariate analysis. CONCLUSIONS: The directionality could be a surrogate marker of total number of metastatic lymph nodes as a prognostic factor in patients with gastric cancer. PMID- 22234086 TI - Predictors of long-term survival in large gastric carcinoma patients. AB - BACKGROUND/AIMS: To improve the treatment results for large gastric carcinoma, it is important to know the characteristics of long-term survivors. The aim of this study was to analyze the clinicopathological features of large gastric carcinoma patients and clarify the prognostic factors associated with long-term survival. METHODOLOGY: Between December 1996 and December 2002, a total of 334 patients entered the study. They underwent surgery for gastric carcinomas measuring 10cm or more in diameter. We examined 12 clinicopathological factors associated with the patient, tumor and surgery. Multivariate analysis was performed using Cox's proportional hazards model. RESULTS: The 5-year survival rate was influenced by the extent of lymph node dissection, histological type, depth on invasion, lymph node metastasis, peritoneal dissemination, liver metastasis and disease stage. Of these, two independent prognostic factors were depth on invasion and lymph node metastasis. CONCLUSIONS: Depth on invasion and lymph node metastasis emerged as two independent prognostic factors for the prediction of long-term survival in large gastric carcinoma patients. We can make a suitable treatment strategy for patients with gastric cancer through consideration of the prognostic factors. PMID- 22234087 TI - Synchronous appearance of gastric gastrointestinal stromal tumors and colorectal adenocarcinoma:a case report. AB - Gastrointestinal stromal tumors (GIST) represent the most usual mesenchymal tumors of the gastrointestinal tract. In this paper we present a case of a 59 year old patient with an adenocarcinoma of the transversal colon near the lienal flexure without breaking of the intestinal membrane synchronous with an intramural tumor in the antral region of the stomach which was not registered before the operation. Final immunohistochemical findings of the operation specimens: 1. Adenocarcinoma of the large intestine (histological grade I, nuclear grade I, Dukes A, invasion to submucosa) and 2. GIST with low malignant potential. Synchronous appearance of GISTs and colorectal adenocarcinoma, although very rare, has been increasingly observed in the last five years. Because of the small number of cases, a causal connection between these different types of tumors cannot be proven. Through this case report we hope to contribute to the adequate preoperative preparation, operation technique and postoperative monitoring of such patients. Surgical treatment is a dominant way of treating these synchronous tumors, so the surgeon has high responsibility for adequate selection of operative procedure on these patients. PMID- 22234088 TI - Bismuth iodoform paraffin paste hypersensitivity reactions in mastoid cavities following isolation of mucosal lining: a series of 587 patients. AB - AIM: (1) To assess hypersensitivity to bismuth iodoform paraffin paste impregnated ribbon gauze following its use in packing canal wall down mastoidectomy cavities; (2) to determine if isolation of the skin and mucosa from the pack, using thin Silastic sheeting and Cortisporin ointment, reduces hypersensitivity reactions, compared with a previous series; and (3) to review the literature and to determine if bismuth iodoform paraffin paste hypersensitivity precludes the consumption of seafood (due to its high iodine content). MATERIALS AND METHODS: All patients undergoing canal wall down mastoidectomy with intra-operative bismuth iodoform paraffin paste packing between 1985 and 2009 were identified and reviewed. RESULTS: Of 587 patients identified, the overall bismuth iodoform paraffin paste reaction rate was 1 per cent. All reactions were in patients undergoing revision mastoidectomy procedures, giving a reaction rate for revision procedures of 2.4 per cent. CONCLUSION: Reactions are an uncommon event following post-operative mastoid cavity packing using bismuth iodoform paraffin paste. Reaction rates may be lowered by preparing the cavity with Silastic sheeting and Cortisporin ointment prior to packing, thus isolating the skin and mucosal surfaces. Development of such a reaction does not preclude the consumption of seafood. PMID- 22234089 TI - Core biopsies of the breast: diagnostic pitfalls. AB - The incidence of breast cancer is increasing worldwide. In this review article, the authors compare and contrast the incidence of breast cancer, and the inherent differences in the United States (US) and India in screening techniques used for diagnosing breast cancer. In spite of these differences, core biopsies of the breast are common for diagnosis of breast cancer in both countries. The authors describe "Best Practices" in the reporting and processing of core biopsies and in the analysis of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor Receptor 2 (Her2/neu). The pitfalls in the diagnosis of fibroepithelial lesions of the breast on core biopsy are discussed, as also the significance of pseudoangiomatous stromal hyperplasia of the breast (PASH) is discussed in core biopsy. In this review, the management and diagnosis of flat epithelial atypia and radiation atypia are elaborated and the use of immunohistochemistry (IHC) in papillary lesions, phyllodes tumor, and complex sclerosing lesions (radial scars) is illustrated. Rarer lesions such as mucinous and histiocytoid carcinoma are also discussed. PMID- 22234090 TI - The prognostic impact of O6-methylguanine DNA methyltransferase and epidermal growth factor receptor expressions on primary gliosarcoma: a clinicopathologic and immunohistochemical study of seven cases at a single institution. AB - CONTEXT: Gliosarcoma is an uncommon variant of glioblastoma characterized by a biphasic tissue pattern of glial and mesenchymal differentiation. O6 methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O6-guanine in DNA. Lack of MGMT protein expression immunohistochemically is related to drug responses in patients of malignant glioma treated with alkylating agents. Epidermal growth factor receptor (EGFR) is the most frequently amplified gene in glioblastoma and associated with tumor invasiveness, angiogenesis, poor survival, and resistance to radiation therapy. AIMS: To elucidate the relationship between the statuses of the MGMT as well as EGFR proteins and the prognosis. The study was undertaken on samples received at the Department of Pathology from 2003 to 2009. MATERIALS AND METHODS: Clinicopathologic and immunohistochemical study of seven cases was performed. RESULTS: This series included three men and four women with a mean age of 49.3 years at first surgery. The median progression-free survival (PFS) was 22.2 months and 8.6 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively; the median overall survival (OS) was 27.5 months and 14.2 months for primary tumors with 0 to 1+ and 2+ to 3+ MGMT staining, respectively. The median PFS was 17.2 months and 11.2 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively; the median OS was 20.4 months and 17.7 months for primary tumors with 0 to 1+ and 2+ to 3+ EGFR staining, respectively. CONCLUSIONS: The series showed that MGMT and EGFR protein expressions were both unfavorable prognostic factors for patients with gliosarcoma. PMID- 22234091 TI - Frequency of Ki-67 (MIB-1) and P53 expressions among patients with prostate cancer. AB - CONTEXT: Prostate cancer is the most common malignant tumor in men. Tumor grade is one of the most important prognostic factors of prostate cancer. P53 and Ki-67 expressions have also been considered to be prognostic factors. AIMS: This study was performed to investigate the frequency of these proteins expression and compare the obtained results with Gleason's grading. SETTINGS AND DESIGN: In this cross-sectional study, 49 paraffin blocks of prostate cancers were assessed. Tumor grade was determined according to the Gleason's criteria. MATERIALS AND METHODS: Ki-67 and P53 expressions were determined by immunohistochemical staining. STATISTICAL ANALYSIS: The obtained results were analyzed and evaluated using Spearman's statistical test (SPSS version 15). RESULTS: Three out of 49 (6.1%) cases were well differentiated, 21 (43%) moderately differentiated and 25 (51%) were poorly differentiated. P53 was negative in all well-differentiated cases. Ki-67 was negative in 14 cases (28%) including all well-differentiated tumors. Among moderately and poorly differentiated tumors Ki-67 was negative in eight (38%) and three (12%) of cases, respectively. A statistically significant relation was observed between the increased Ki-67 labeling index (LI) and increased Gleason's grade. Conversely, no statistically significant relation was found between P53 expression and increased Gleason's grade. CONCLUSIONS: According to the findings of this study, it seems that Ki-67 can be used as a prognostic factor for prostate cancer. On the other hand, the probable relation between P-53 and prostate cancer prognosis requires further studies. PMID- 22234092 TI - Prevalence of pituitary incidentaloma in the Iranian cadavers. AB - AIM: Although one-fourth of the pituitary tumors are inactive and silent, increased total volume of the pituitary gland exerts pressure on sella turcica and corrodes the clinoid processes, resulting in several problems. Therefore, determination of the prevalence of the concealed pituitary tumors is of major concern among clinical practitioners. This study was performed to determine the prevalence of these tumors in cadavers referred to the Iranian Legal Medicine Organization (Kahrizak, Tehran). MATERIALS AND METHODS: This cross-sectional descriptive study was performed between June 2007 and February 2008. A total of 485 cadavers were selected by simple random sampling method. Pituitary glands were removed and then horizontally cut and four slides were prepared from each of them, stained by hematoxylin and eosin, and evaluated by a light microscope. For statistical analysis, SPSS software (version 16), Mann-Whitney U test, Kolmogorov Smirnov nonparametric test (K-S test), and Chi-square test were used. RESULTS: Of the 485 investigated cadavers, 365 (75.3%) were males with an average age of 42 +/- 20.5 years and 120 (24.7%) were females with an average age of 44 +/- 22 years. A total of 61 (12.6%) had concealed pituitary masses. No statistically significant difference was found between the mean age, sex, and body mass index (BMI) of the cadavers with and without concealed tumors (P=0.380 P=0.450, and P=0.884, respectively). CONCLUSIONS: In the present study, the prevalence of the concealed pituitary adenomas was 12.6%. There was no correlation between age, sex, and BMI and the prevalence of the concealed masses. PMID- 22234093 TI - A study on expression pattern of cyclooxygenase-2 in carcinoma of cervix. AB - OBJECTIVE: The purpose of the present study was to determine the differential expression pattern of cyclooxygenase-2 (COX-2) in patients of carcinoma of uterine cervix and its correlation with tumor differentiation and lymphovascular invasion. MATERIALS AND METHODS: Seventy (70) cases of cervical carcinoma were included (20 in-situ, 42 invasive squamous cell, and 8 cases of adenocarcinoma). Formalin-fixed paraffin-embedded tissue sections were stained by Hematoxylin and Eosin. Immunohistochemistry for COX-2 were performed on these blocks. RESULTS: A higher expression of COX-2 was seen in invasive squamous cell carcinoma than in in-situ carcinoma (P = 0.002). Five out of eight cases of adenocarcinoma showed strong positivity for COX-2 antibody. Among the histopathological correlates, tumor differentiation did not show a positive correlation (P = 0.717), while lymphovascular invasion was associated with positive staining in majority of the cases (P = 0.001). CONCLUSION: Expression of COX-2 is more in cases of invasive than in in-situ carcinoma. Adenocarcinomas showed a strong expression of COX-2. A positive association of COX-2 expression and the presence of lymphovascular emboli were found in the present study. COX-2 inhibitors need to be studied as a therapeutic adjunct for the treatment of carcinoma cervix. PMID- 22234094 TI - Nonrejection pathology of renal allograft biopsies: 10 years experience from a tertiary care center in north India. AB - BACKGROUND: Renal dysfunction in allograft transplant is common and its assessment is done using Revised Banff '97 working classification, which is the accepted formulation for the evaluation of histological appearance of renal allograft biopsies. The nonrejection category under the Banff working classification of renal allograft pathology forms a large group resulting in allograft dysfunction. AIM: To evaluate the spectrum of histopathological changes seen in renal allograft dysfunction. MATERIALS AND METHODS: A total of 119 renal biopsies were studied over 10 years presenting with renal allograft dysfunction from a tertiary center in North India. RESULTS: Majority of the biopsies were in the nonrejection category (47.1%), which included few cases of acute tubular necrosis (25.2%), cyclosporine nephrotoxicity (16%), infections (10.9%), and thrombotic microangiopathy (3.4%). The second largest category in our study was acute/active cellular rejection group (31.9%), which displayed moderate to severe tubulitis, mononuclear cell infiltrate in the interstitium, and vasculitis. Antibody-mediated rejection cases were seen in 28.6% of the renal biopsies followed by chronic allograft nephropathy cases (12.6%) showing features of tubular atrophy and interstitial fibrosis. Borderline changes with features of mild tubulitis contributed to 7.6% of the biopsies. The smallest group comprised of only 4.2%, which were within normal histological limits. CONCLUSION: Timely accurate diagnosis of renal allograft dysfunction is essential for prompt, effective management of renal transplant patients. Thus, nonrejection pathology forms a significant cause of renal dysfunction in patients with renal allograft transplantation. PMID- 22234095 TI - Uterine smooth muscle tumors of uncertain malignant potential and atypical leiomyoma: a morphological study of these grey zones with clinical correlation. AB - OBJECTIVES: To study the histological features in uterine STUMP, and atypical leiomyomas (AL), and to correlate with clinical outcome. MATERIALS AND METHODS: From January 2004 to August 2010, a total of 21 cases were retrieved from records, labeled as STUMP(7), AL (5), AL with low risk of recurrence (2), smooth muscle tumor of low malignant potential (STLMP) (2), and symplastic leiomyoma (5). The slides were reviewed for coagulative tumor cell necrosis (CTCN), hyaline necrosis/ infarction type necrosis, presence and degree of cytological atypia, mitotic activity, epithelioid morphology and myxoid features. The other characteristics (such as size, circumscription, individual tumor cell necrosis), were noted, wherever available. RESULTS: The mean age was 45 years (median 46; range 24-67 yrs). CTCN was seen in 2 cases on examination of additional material; wherein a revised diagnosis of leiomyosarcoma had been given. Infarction type necrosis and individual cell necrosis was seen in 2 and 3 cases, respectively. Mitoses were less than 5/10 hpf in all the cases. One of the tumours labeled as STUMP also had concurrent endometrial adenocarcinoma. Follow up: Follow-up was available in 11 cases (52.3%). One patient had died. (cause not known). In 10 patients, the follow-up ranged from 4 to 56 months (mean 20.9 months; median 15 months) nine patients were alive and well. One patient (labeled STLMP) had metastatic liver disease 3 yrs after the primary surgery, at the last follow-up. CONCLUSIONS: 1) There is an overlap in using the terminologies as STUMP, AL, AL with low risk of recurrence, AL with low malignant potential. A designation of STUMP does convey a category of borderline malignancy to the gynecological surgeons. Most behave in a benign fashion and follow-up without adjuvant therapy is currently recommended. Critical evaluation of coagulative tumor necrosis is essential. Follow-up remains a challenge in our setting. PMID- 22234096 TI - Gastrointestinal lymphomas: pattern of distribution and histological subtypes: 10 years experience in a tertiary centre in South India. AB - BACKGROUND AND AIM: Gastrointestinal tract (GIT) is one of the major sites of extra-nodal lymphomas constituting 10-15% of all non-Hodgkin's lymphoma cases and about 30-40% of extra-nodal lymphomas. Considerable variation exists in the literature with respect to incidence of the various histological subtypes and sites of involvement. This study was undertaken to ascertain the anatomic distribution, histological subtypes and sites of all GIT lymphomas presenting to a tertiary referral hospital in southern India. MATERIALS AND METHODS: The histological material of 361 patients over a period of 10 years (2001-2010), with histopathological diagnosis of lymphoma involving the GIT (both primary and secondary), was analyzed retrospectively. All lymphomas were reclassified according to the World Health Organization 2008 classification. RESULTS: These 361 cases include 336 primary and 25 cases of lymphomas, where the involvement was secondary. Primary lymphomas consisted of 267 males (79.64%) and 68 females (20.24%) with a male:female ratio of 3.93:1. The mean age was 45 years (range 3 88). Diffuse large B-cell lymphoma (DLBCL) was the commonest subtype (222 cases; 66.71%), followed by low-grade marginal zone lymphoma of the mucosa associated lymphoid tissue (MALT) type (34 cases; 10.12%) and Burkitt's lymphoma (35 cases; 10.48%). The commonest site was stomach (180 cases; 53.57%), followed by small intestine (79 cases; 23.51%) and large intestine (68 cases; 20.23%), respectively. There were some uncommon types of GIT lymphomas documented during the study. CONCLUSION: In this largest retrospective single centre study from India, we establish that the pattern of distribution of primary GIT lymphomas (PGLs) in India is similar to the western literature in that the stomach is the commonest site of PGL and DLBCL is the commonest histological subtype. Immunoproliferative small intestinal disease cases were seen in this study, which is uncommon in the west. PMID- 22234097 TI - The association of Epstein-Barr virus infection with multiple myeloma. AB - BACKGROUND: Multiple myeloma is a conventional term for clonal proliferation of plasma cells. It is suggested that viruses may have a significant role in the pathogenesis of multiple myeloma. AIMS: The aim of this study was to evaluate whether there is an association between multiple myeloma and Epstein-Barr Virus (EBV) by the polymerase chain reaction (PCR) method. MATERIALS AND METHODS: This case-control study was performed on 60 paraffin-embedded bone marrow biopsies (30 multiple myeloma and 30 normal bone marrow specimens) in the molecular pathology section of our hospital. The patients and control groups were matched according to gender and age. Several sections were cut from each paraffin blocks, and then the deoxyribonucleic acid (DNA) was extracted by the non-heating extraction method. In the next step, PCR was carried out for detection of EBV genome and finally its products were analyzed by electrophoresis. RESULTS: DNA of EBV was detected in 10 patients of the case group (5 males and 5 females) and 3 subjects (2 males and 1 female) of the control group. The Pearson chi-square test showed significant difference between case and control group (P=0.03) for detection of the EBV genome. In myeloma patients, the mean white blood cell count was 9.05 + 4.02 and 5.20 + 2.02 Chi 10(9) /L in EBV positive and negative groups, respectively and a significant difference count was seen for the WBC count. RECOMMENDATIONS: Our results show an association between multiple myeloma and EBV infection. PMID- 22234098 TI - Sporadic colorectal polyps and mismatch repair proteins. AB - BACKGROUND: Colorectal cancers often arise from benign polyps. Adenomatous polyps and serrated polyps progress step by step to adenocarcinoma and change into malignant cancers. Genetic and epigenetic changes have correlation with specific stages of polyp-adenocarcinoma progression and colorectal cancer histopathological changes. AIMS: In this study we used immunohistochemistry (IHC) staining in sporadic colorectal polyps to assay functional status of MLH1, MSH2, MSH6, and PMS2 proteins, to track genetic/epigenetic roles of this issue in our patients. MATERIALS AND METHODS: In this cross-sectional study we assessed all patients who were admitted with sporadic colorectal polyps and underwent polypectomy in endoscopy department during 2004-2008. RESULT: IHC results were abnormal in 6.8% cases for MLH1, in 4.5% cases for MSH2, in 3% for MSH6, and in 4.8% for PMS2. In all cases with abnormal PMS2, MLH1 was also reported as abnormal. Same results were reported for abnormal MSH2, which is accompanied with abnormal MSH6 in all cases (P values < 0.001). There is no significant difference between IHC staining results, gender, dysplasia grade, adenomatous type, and invasion. On the other hand, there was significant difference between IHC staining results, polyp location, and mean age of patients. The same significant difference was between adenomatous polyps and serrated adenoma polyps by MLH1 and PMS2 (P values < 0.05). CONCLUSION: According to our findings, maybe MMR dysfunction is the cause of sporadic colorectal polyps in younger age and its increasing risk of dysplasia progression and malignancy progression is only in serrated adenoma. Sporadic polyps in left colon had a higher risk to progress to malignancies, and abnormal IHC staining for MLH1 and PMS2 in serrated polyps is much more than in other adenomatous polyps. PMID- 22234099 TI - Immature teratoma of the ovary: a clinicopathological study of 28 cases. AB - AIM: Immature teratoma (IT) of the ovary represents 1% of all ovarian cancers and 20% of malignant ovarian germ cell tumors. This retrospective study of 28 such cases aims to look at its morphological spectrum and to study the correlation of the grade and stage of the tumor with prognosis. MATERIALS AND METHODS: A retrospective study of 28 cases of IT of the ovary was done. Neuroepithelium was graded as grade I, II and III according to the standard criteria. The presence of immature mesenchyme was also looked for and similarly graded. RESULTS: The median age for the cases was 19 years and abdominal pain was the commonest symptom. Neuroepithelium was seen in 26 cases (6 were grade I, 13 were grade II, and 7 were grade III); and two showed immature mesenchymal tissue (IM) only. IM was seen in all 28 cases, but no correlation with the grade of the IT of the ovary is found. The follow up is available in 23 cases ranging from 6 months to 78 months (median 33 months). Of these, 13 were stage I, 3 were stage II and 7 were stage III ITs. Out of 23 patients, 17 patients were alive without evidence of disease recurrence during the last follow up. Adverse events in the form of death and local recurrence occurred in 6 patients. One patient died of the disease at 7 months duration from the disease onset (stage III, grade II IT). CONCLUSION: Morphological spectrum of IT of ovary is varied. Immature mesenchyme was seen in all the cases of IT of ovary and its presence should prompt a careful search for immature neuroepithelium. Stage I IT of ovary has better prognosis. Combination of surgery and chemotherapy can give longer survival even in recurrent disease. PMID- 22234100 TI - Increased liver mast cells in patients with chronic hepatitis C. AB - BACKGROUND AND AIM: The aim of the study was to investigate the mast cell (MC) concentration in the liver tissue of patients diagnosed with chronic hepatitis C and to determine whether there was a correlation with clinical and pathological characteristics of patients. MATERIALS AND METHODS: The study was conducted on liver biopsy samples from 60 patients with chronic hepatitis C. Clinical and laboratory data were obtained from follow-up records. Stained liver biopsies were examined. Immunohistochemical staining was performed by using an anti-c-kit antibody. Patients were divided into four groups (minimal, mild, moderate, and severe) based on the intensity of inflammation and their hepatic activity index scores and into two groups (no-mild, moderate-severe) according to fibrosis grade. RESULTS: Among patients enrolled, 60.0% (n=36) were men with a mean age of 48.3 +/- 12.7 (range 18-64) years. The mean number of mast cells per portal area in the liver was 0.87 +/- 0.86 (0-4.0). No correlation was found between alanine aminotransferase (ALT) and hepatitis C virus (HCV). Ribonucleic acid ( RNA ) levels and the degree of inflammation of cases with number of mast cells and liver steatosis (P>0.05). As the degree of fibrosis increased in the liver so did the number of mast cells in portal areas (P=0.001). On the other hand, no correlation was found between the degree of fibrosis and the number of MCs in the sinusoids and steatosis (P<0.05). The increase in the number of MCs in the portal areas correlated with an increase in liver steatosis (t: 0.02, P=0.04). CONCLUSION: In light of these findings, it appears possible that MC accumulation in chronic HCV patients may be used as an indicator of fibrosis and possibly be considered in the follow-up of these patients. PMID- 22234101 TI - Comparison of stromal CD10 expression in benign, borderline, and malignant phyllodes tumors among Egyptian female patients. AB - BACKGROUND: Phyllodes tumors are group of biphasic fibroepithelial tumors of the breast of varying malignant potential, ranging from benign tumors to fully malignant sarcomas. According to the Egyptian National Cancer Institute, female malignant cases showed appreciable increase in the recent time period for breast cancer with the malignant phyllodes tumors representing 0.41% of cases in the year 2003-2004. AIMS: This is an immunohistochemical study to compare CD10 expression in benign, borderline, and malignant phyllodes tumors, in order to highlight its diagnostic and prognostic values. MATERIALS AND METHODS: This study conducted 34 Egyptian female cases of phyllodes tumors of different grades to be studied histologically and immunohistochemically using antibodies against CD10. STATISTICAL ANALYSIS: The Chi-square test was used to determine differences in CD10 expression between benign, borderline, and malignant tumors. One-way ANOVA test was used to determine whether the difference was significant. Significance was established at P<0.05. RESULTS: In the 24 cases of benign phyllodes tumors, only four cases (16.7%) showed positive CD10 reactivity. Three cases (60%) out of five borderline phyllodes tumors showed positive CD10 reactivity, while four (80%) out of five cases of malignant phyllodes tumors showed positive CD10 staining. CONCLUSION: From these highly significant results, we believe that there is a strong correlation between CD10 expression and tumor grade, which could be an important observation that may have both diagnostic and prognostic implications as well as promising potential target for development of novel therapies. PMID- 22234102 TI - Sodium iodide symporter, estrogen receptor, and progesterone receptor expression in carcinoma breast--an immunohistochemical analysis. AB - BACKGROUND: Sodium iodide symporter (NIS), a transporter of iodine is essential for thyroid hormone biosynthesis. It also plays a role in the radioiodine treatment of thyroid cancers. NIS mediated radioiodine transport to breast cancers is under active investigation due to its potential therapeutic utility. Cellular localization and quantification using immunohistochemistry may provide clues for its utility in management of carcinoma breast. MATERIALS AND METHODS: Human NIS (hNIS) expression was therefore assessed by utilizing a rabbit polyclonal antibody raised against a cloned hNIS in different grades of infiltrating duct carcinoma of breast and its metastatic deposits namely in lymph nodes, bone marrow, and endometrium. Further, hNIS expression was compared with prognostic markers namely estrogen receptor (ER) and progesterone receptor (PR). RESULTS: hNIS was positive in 90.6% cases (29/32) and Scarff-Bloom-Richardson grading was done in 25 cases and 23 cases were NIS positive. Among nongraded cases, 2/2 cases of carcinoma in-situ were positive and 4/5 were positive in cases having post therapy residual tumor status. The strong positivity for hNIS was seen irrespective of ER or PR status and of grade of breast carcinoma and correlated well with western blot analysis. In all the three metastatic sites, NIS was positive in the tumor. CONCLUSION: These findings indicate the utility of immunohistochemistry for NIS as a new potential prognostic marker and may provide guidance for possible radio iodine therapy in breast cancer patients. PMID- 22234103 TI - Coagulation inhibitors and activated protein C resistance in recurrent pregnancy losses in Indian women. AB - BACKGROUND: Thrombophilias, both acquired and inherited, have been investigated in the etiopathogenesis of unexplained recurrent pregnancy loss. AIM: To study coagulation inhibitors and activated protein C resistance (APCR) in recurrent pregnancy losses (RPL) occurring in second and third trimesters. MATERIALS AND METHODS: A total of 30 pregnant women (group A) with two or more recurrent unexplained fetal loses were evaluated for APCR, protein C deficiency, protein S deficiency, antithrombin deficiency, and antiphospholipid antibodies (APLA). Thirty age-matched controls were taken (group B) comprising of pregnant women with at least one live issue. STATISTICAL ANALYSIS: Comparisons between two group frequencies and group means were made using Chi square test and Student's t test, respectively. RESULTS: Protein C and protein S levels were reduced in group A compared with group B and the difference was statistically significant (P=0.005 and P=0.032, respectively). The mean value of antithrombin was slightly reduced in group A compared with group B. APCR was observed in 16.6% cases and 3.3% controls. However, the difference was not statistically significant. APLA was observed in 20% cases and none of the controls. Of these, lupus anticoagulant was positive in 16.6% cases and anticardiolipin antibodies in 10% cases. Combined defects were seen in seven patients. CONCLUSION: There is a significant risk of RPL in pregnant women with thrombophilias. Therefore, screening for thrombophilias may be justified in pregnant women with unexplained recurrent fetal wastage, especially in second and third trimester. PMID- 22234104 TI - Serodiagnosis of celiac disease in children referred for evaluation of anemia: a pediatric hematology unit's experience. AB - BACKGROUND: Children presenting with typical clinical features of celiac disease (CD) are diagnosed relatively easily, however, diagnosis remains challenging and is often delayed when they present with 'difficult to treat anemia' without overt gastrointestinal manifestations. Index study was undertaken to report profile of patients referred to pediatric hematology unit with 'difficult anemia' who subsequently were diagnosed with CD. MATERIALS AND METHODS: The records of 83 patients (1988-2008) with CD were scrutinized retrospectively who had presented with predominant hematological manifestations. RESULTS: CD was confirmed histologically in 31 (37%), while 52 (63%) were diagnosed by serology alone. The mean age at diagnosis was 8.0 +/- 2.8 years. The mean duration of symptom diagnosis interval was 40.9 +/- 30.6 months. Eighty-one (98%) children had anemia (Hb < 11 g/dl) and 55 (66%) had received iron supplements without discernible benefit. Thirty-nine (47%) patients received a blood transfusion. Thirty-six (43%) patients did not have diarrhea. Majority of the patients had either a microcytic-hypochromic (48%) or dimorphic (43%) anemia. Twenty-four (33%) had thrombocytosis, while 5 (7%) had thrombocytopenia. Mean duration of follow-up for patients on roll in the clinic for more than six months was 17.7 +/- 20.9 months. CONCLUSION: Pediatricians and hematologists need to be aware of the extra intestinal manifestations of CD. Prolonged duration of symptoms and a diagnosis at a relatively older age is striking in children presenting with predominantly hematological manifestations. Investigations for CD are recommended in children presenting with iron deficiency anemia refractory to hematinics or who have coexisting growth retardation. Necessity for biopsy in overtly symptomatic cases is discussed. PMID- 22234105 TI - Antioxidant status in beta thalassemia major: a single-center study. AB - BACKGROUND: Homozygous beta thalassemia may lead to a marked reduction or absence of normal beta chain production and accumulation of unpaired alpha-globin chains. A crucial component in the oxidant susceptibility of the thalassemic RBC is the release of heme and iron from the excessive, unpaired alpha-globin chains. This release can initiate self-amplifying redox reactions, which deplete the cellular reduction potential (e.g., GSH), oxidize additional hemoglobin and accelerate RBC destruction. Furthermore, beta-thalassemia patients are under continuous blood transfusion, which, although life-saving, leads to an iron overload with a resultant increase in non-transferrin-bound iron that may cause greater tissue toxicity than iron in other forms. Iron-induced oxidative stress is known to be one of the most important factors determining cell injury in thalassemic patients. Therefore, we designed this study to obtain a comprehensive picture of the iron overload, antioxidant status and cell damage in beta thalassemia major patients undergoing regular blood transfusion. MATERIALS AND METHODS: A total of 48 diagnosed patients of beta thalassemia major and 30 age- and sex-matched healthy subjects were included in the study. Estimation of hemoglobin, hematocrit, glutathione peroxidase (GPX), superoxide dismutase (SOD),vitamin E, serum ferritin, total and direct bilirubin, AST and ALT was carried out. RESULTS: The levels of vitamin E, antioxidant enzymes GPX and SOD were significantly lowered in beta thalassemic patients as compared with the control group (P<0.001). Serum total and direct bilirubin, AST and ALT were significantly elevated in thalassemic subjects as compared with the control group, indicating liver cell damage. CONCLUSION: Thus, our findings indicate that thalassemics are in a state of enhanced oxidative stress and that the administration of selective antioxidants would represent a promising approach toward counteracting oxidative damage and its deleterious effects on the disease status. PMID- 22234106 TI - Evaluation of non cyanide methods for hemoglobin estimation. AB - BACKGROUND: The hemoglobincyanide method (HiCN) method for measuring hemoglobin is used extensively worldwide; its advantages are the ready availability of a stable and internationally accepted reference standard calibrator. However, its use may create a problem, as the waste disposal of large volumes of reagent containing cyanide constitutes a potential toxic hazard. AIMS AND OBJECTIVE: As an alternative to drabkin's method of Hb estimation, we attempted to estimate hemoglobin by other non-cyanide methods: alkaline hematin detergent (AHD-575) using Triton X-100 as lyser and alkaline- borax method using quarternary ammonium detergents as lyser. MATERIALS AND METHODS: The hemoglobin (Hb) results on 200 samples of varying Hb concentrations obtained by these two cyanide free methods were compared with a cyanmethemoglobin method on a colorimeter which is light emitting diode (LED) based. Hemoglobin was also estimated in one hundred blood donors and 25 blood samples of infants and compared by these methods. Statistical analysis used was Pearson's correlation coefficient. RESULTS: The response of the non cyanide method is linear for serially diluted blood samples over the Hb concentration range from 3 gm/dl -20 gm/dl. The non cyanide methods has a precision of + 0.25 g/dl (coefficient of variation= (2.34%) and is suitable for use with fixed wavelength or with colorimeters at wavelength- 530 nm and 580 nm. Correlation of these two methods was excellent (r=0.98). The evaluation has shown it to be as reliable and reproducible as HiCN for measuring hemoglobin at all concentrations. The reagents used in non cyanide methods are non-biohazardous and did not affect the reliability of data determination and also the cost was less than HiCN method. CONCLUSIONS: Thus, non cyanide methods of Hb estimation offer possibility of safe and quality Hb estimation and should prove useful for routine laboratory use. Non cyanide methods is easily incorporated in hemoglobinometers by using very minute quantities of reagents and test sample; hence, these methods can be used to provide point of care testing in blood banks for hemoglobin (Hb) estimation in blood donors. PMID- 22234107 TI - Moraxella catarrhalis as a respiratory pathogen. AB - BACKGROUND: Moraxella catarrhalis is gaining significance as a pathogen over few decades because of increased rate of isolation in respiratory specimens and due to emergence of multidrug resistant strains. Therefore, appropriate antimicrobial agents are required for eradication and prevention of spread of the organism. MATERIAL AND METHODS: The study was conducted over 1-year period inpatients of lower respiratory tract infections (L.R.T.I.) in P.G.I.M.S. Rohtak (Haryana) . Assessment of clinical significance of M.catarrhalis was ascertained on the basis of preformed criteria. RESULTS: A total of 63 clinically significant M. catarrhalis were isolated from a tertiary care hospital. The isolates showed maximum resistance to cotrimoxazole (82.5%), penicillin (77.7%), and ampicillin (71.4%) while susceptibility was maximum to cefotaxime (87.3%) followed by tetracycline (85.7%) ciprofloxacin (84.1%), erythromycin (80.9%) amikacin (79.3%), gentamycin (77.7%), and cefazolin (76.2%). Multidrug resistance to >3 antimicrobials was seen in 22 (34.9%) of cases. CONCLUSIONS: Predominant or pure growth of M.catarrhalis in throat swabs from cases of L.R.T.I. should be reported and treated by microbiologist and clinician respectively. Antibiotic therapy should be decided based on sensitivity report for rapid response and recovery of patients. PMID- 22234108 TI - Epidemiologic lessons: chickenpox outbreak investigation in a rural community around Chandigarh, North India. AB - PURPOSE: Primary infection with Varicella Zoster virus (VZV) leads to Varicella or chickenpox. The epidemiology of Varicella has changed dramatically since the introduction of the Varicella vaccine in 1995. The routine childhood immunization in a few countries in the western world like Germany and the United States has reduced the incidence of the disease, associated complications, hospital admissions and deaths related to its complications. However, chickenpox outbreaks are common in naive unvaccinated communities in India. MATERIALS AND METHODS: We report an outbreak of chickenpox that occurred in a village situated on the outskirts of Chandigarh city in North India in the winter of 2007. The outbreak was confirmed by the detection of VZV IgM by enzyme-linked immunosorbent assay (ELISA) on serum samples from the patients. In patients showing active lesions, Giemsa and indirect immunofluorescence was carried out on scrapings from vesicular lesions. RESULTS: A total of 162 cases occurred in the present outbreak. The serum samples were collected from 20 patients, and all of them showed positive serology for VZV IgM antibodies while 19 showed a positive VZV IgG result by ELISA. The scrapings were collected from two patients showing active lesions, and both were positive by the Tzanck smear examination, and VZV antigen could be demonstrated by immunofluorescence. CONCLUSIONS: There is an urgent need to identify naive communities and unvaccinated individuals at risk. Also, there is a need for regular training programmes of health workers posted in peripheral centers so that highly contagious communicable diseases can be picked up in time and such outbreaks can be prevented. PMID- 22234109 TI - Lymphocyte activation test for diagnosis of seronegative brucellosis in humans. AB - BACKGROUND: Seronegative brucellosis is occasionally encountered in clinical practice especially in localized disease where diagnosis is reached mainly through positive blood culture. Cellular immune responses are pivotal for protection against intracellular bacteria such as Brucella. This study was performed to evaluate the expression of activation markers on peripheral blood mononuclear cells in response to in vitro stimulation by whole-cell suspension of Brucella melitensis for the diagnosis of brucellosis. MATERIALS AND METHODS: Fifteen seronegative patients with positive blood cultures for Brucella and twenty-five unexposed healthy blood donors serving as controls were recruited for the study. Peripheral blood mononuclear (PBMC) cells were obtained by the method of Ficoll Hypaque density gradient and stimulated in vitro with Brucella antigen. Expression of activation markers was assessed by flow cytometry after staining of PBMC with mononuclear cells with relevant monoclonal antibodies. RESULTS: Incubation with mitogen induced expression of all the four markers was demonstrated in all blood samples. In contrast, samples from all patients of Brucellosis showed significant positive responses with the expression of activation markers (CD38, CD69, CD25, and CD71) on both CD4+ and CD8+ cells as compared with the control group (P < 0.001). CONCLUSION: It is inferred that there was a remarkable upregulation of activation markers on CD4+ and CD8+ in seronegative patients with Brucellosis. It is recommended that the method can be utilized as a novel diagnostic test for detection of brucellosis where serology is negative. PMID- 22234110 TI - Detection of IgM and IgG antibodies to Chlamydophila pneumoniae in pediatric community-acquired lower respiratory tract infections. AB - CONTEXT: Chlamydophila pneumoniae (C. pneumoniae) is an emerging infectious agent with a spectrum of clinical manifestations including lower and upper respiratory tract infections. AIMS: To investigate the role of C. pneumoniae in community acquired lower respiratory tract infections (LRTIs) in children using serological tests. SETTINGS AND DESIGN: Two hundred children, age 2 months to 12 years, hospitalized for community-acquired LRTIs were investigated for C. pneumoniae etiology. MATERIALS AND METHODS: We investigated 200 children hospitalized for community-acquired LRTIs, using ELISA for detecting anti-C. pneumoniae IgM and IgG antibodies. The demographic, clinical and radiological findings for C. pneumoniae antibody positive and C. pneumoniae antibody negative cases were compared. STATISTICAL ANALYSIS USED: Data analysis was performed by Chi-square test and Fisher's exact tests using Epi Info (2002). RESULTS: Clinical and radiological findings in both the groups were comparable. Serological evidence of C. pneumoniae infection was observed in 12 (6%) patients; specific IgM antibodies were detected in 11 (91.67%; specific IgG antibodies in 1 (8.33%) patients, while 4-fold rise in C. pneumoniae IgG antibody titers were noted in none of the patients. CONCLUSIONS: C. pneumoniae has a role in community-acquired LRTIs, even in children aged < 5 years. Serological detection using ELISA would enable pediatricians in better management of C. pneumoniae infections. PMID- 22234111 TI - Laboratory diagnosis of Toxoplasma gondii infection with direct and indirect diagnostic techniques. AB - BACKGROUND: Toxoplasma gondii infection, common parasitic zoonoses, is an important cause of spontaneous abortion, mental retardation, encephalitis, ocular disease and death worldwide. Today the major diagnostic techniques for the toxoplasmosis are serological assays, but its have many limitations. AIM: The goal in this study is to improve the diagnostic accuracy of T. gondii infection, using direct (Real Time PCR) and indirect (IgM, IgA, IgG and IgG avidity) diagnostic techniques. MATERIALS AND METHODS: In the period between 2007 and 2008, 96 non consecutive different clinical samples (38 blood, 40 amniotic fluids, 8 cerebrospinal fluids, 10 vitreous humors) and 96 sera have been studied simultaneously through molecular biology and serological techniques. RESULTS: Direct and indirect diagnostic techniques used in this study for laboratory diagnosis of T. gondii infection were always concordant. CONCLUSIONS: The high correlation between direct and indirect diagnostic techniques exhibit that serologic techniques are accurate diagnostic assays as screening test in laboratory diagnosis of toxoplasmosis. PMID- 22234112 TI - Microfibrillar cardiomyopathy: a rare case. AB - Microfibrillar cardiomyopathy is a very rare cause of restrictive cardiomyopathy (RCM). The index case was a male patient who presented with shortness of breath and pedal edema. Further clinical investigations favored a clinical diagnosis of RCM. An endomyocardial biopsy revealed subendocardial and interstitial hyaline eosinophilic material resembling amyloid that did not stain with Congo red. An electron microscopic examination showed that this material was composed of twisted linear and bundles of tangled microfibrils. The etiology of the microfibrillar deposition is currently unknown. The pathologists should entertain the diagnosis of microfibrillar cardiomyopathy in suspected cases of amyloidosis that are negative for Congo red. PMID- 22234113 TI - Cherubism--a case report with long term follow up. AB - Cherubism is a rare non-neoplastic disease of the bone characterized by bilateral painless enlargement of the jaws giving a cherubic appearance to the patient. It is an autosomal dominant disorder but may occur sporadically. In this paper, we have tried to explain about the clinical, radiological and histopathologic features of cherubism by presenting a case study. A case study of a 7 year old male patient, who first presented with mandibular bilateral swellings to our department in 1998, has been presented. In-depth clinical, radiological and histopathologic examination was done. An extensive long-term follow-up till 11 years was maintained. When presented for the first time, radiological investigation showed characteristic multilocular lytic lesions of the mandible bilaterally. Histopathological examination of the biopsy specimen showed proliferating fibrous connective tissue interspersed by multinucleated giant cells. It was diagnosed as a case nonfamilial cherubism. Follow-up after 5 years showed involvement of the maxilla as well, which was then corrected by surgical methods. Upon follow up 11 years after the first presentation, it was seen that the lesion was regressing by itself and there was improvement in facial contour. The natural course of Cherubism through its progression, stabilization and involution of the disease after puberty, has been highlighted in this case. More, in-depth studies to understand the nature and the pathogenesis of this condition better are required. PMID- 22234114 TI - Anaplastic transformation of metastatic papillary thyroid carcinoma at shoulder mimicking soft tissue sarcoma. AB - A 52-year-old woman presented with fracture upper end of the left humerus after trivial trauma and aspiration cytology from the lytic lesion in the upper humerus seen on X-ray revealed a metastatic papillary carcinoma from the thyroid. Total thyroidectomy confirmed the papillary carcinoma thyroid. Post-operatively, she was given radioactive iodine (I-131) ablation therapy for 8 years and was asymptomatic during this period; however, for the last 1 year, she has been complaining of swelling in the shoulder, which did not respond to palliative radiotherapy and rapidly increased in size. Disarticulation of the shoulder joint was performed, which showed anaplastic carcinoma on histopathological examination. Anaplastic transformation of papillary carcinoma at the metastatic sites is well documented in the literature and is rare. However, the same has not been reported at the shoulder and from India before. Although soft tissue sarcomas are most common at this site, however, the possibility of anaplastic transformation should be kept in the differential diagnosis of rapidly enlarging painful mass in a known case of metastatic thyroid carcinoma to prevent misdiagnosis. PMID- 22234115 TI - The synchronous primary carcinomas of the rectum and prostate. AB - The diagnosis of synchronous prostatic and rectal carcinomas is uncommon. To make a correct diagnosis, biopsies of both sites are mandatory. Pathological slides should be compared and immunohistochemical staining should be taken into consideration. In this paper, an unexpected case of synchronous rectal and prostatic carcinomas arising in an 84-year-old male with hematemesis and pelvic pain is reported. These two tumoral components have a distinctive histological appearance. Immunohistochemical evaluation confirmed the diagnosis of these synchronous tumors. This case emphasizes that rectal and prostatic carcinomas can arise simultaneously. In this situation, providing clinicopathological correlation and deciding the necessity of intraoperative consultation in proper time are extremely important. PMID- 22234116 TI - Congenital extraskeletal Ewing's sarcoma of chest wall--a rare case report. AB - Congenital extraskeletal Ewing's sarcoma or peripheral primitive neuroectodermal tumor is an extremely uncommon and invariably fatal tumor. We report a case of extraskeletal congenital Ewing's sarcoma in a female fetus delivered at 34 weeks of gestation who died immediately after birth. In English literature, majority of cases of Ewing's sarcoma in neonates reported were skeletal. To the best of our knowledge, very few cases of extra-skeletal Ewing's sarcoma in neonates are reported in the literature. PMID- 22234117 TI - Cytohistological features of rhinoscleroma. AB - Rhinoscleroma, also known as Mikulicz disease, is a chronic progressive disease caused by Klebsiella rhinoscleromatis. The disease is uncommon in Delhi. There are no cytological references of this disease. We describe the cytological features which should alert the pathologist to rule out this entity, which needs to be treated early. Immunohistochemistry on histopathological material is a useful adjunct to the diagnosis. PMID- 22234118 TI - Composite epithelial kidney tumor comprising of adeno and neuroendocrine carcinomatous components: an unusual variant of renal cell carcinoma. AB - Renal cell carcinomas accounts for an approximately 2% of human malignancies with at least ten different histological subtypes recognized by the World Health Organization (WHO) 2004 classification. Composite carcinomas with dual divergent epithelial differentiation in kidneys are extremely uncommon. We report an unusual case of a 37-year-old female who presented with symptoms related to renal tumor for the last three years. Computed tomography scan revealed a large heterogeneously contrast enhancing left kidney mass comprising of two distinct histological components of low grade adenocarcinomatous and carcinoid-like low grade neuroendocrine carcinomas with presence of hilar lymph nodal metastases of both the components. The component of adenocarcinoma was immunoreactive to E cadherin, cytokeratins 7 and 19 with negativity for cluster of differentiation 10, cytokeratin 20, CD117, and vimentin; while the neuroendocrine component was immunoreactive for vimentin, chromogranin and synaptophysin with negativity for CD10, CD117, and cytokeratins 7, 19 and 20. MIB-1 labeling index in the both the components was 2-3%. The present case is the first of its kind to be reported in the kidney and emphasizes the diversity potential of kidney tumors. PMID- 22234119 TI - Diffuse infiltration of Aspergillus hyphae in the thyroid gland with multinodular goiter. AB - A 35-year-old woman presented with a thyroid mass, weakness and shortness of breath of 3 years duration. On physical examination, she had a diffusely enlarged thyroid gland with multiple nodules. There were no signs to suggest immune suppression. The patient farmed and raised livestock. Biochemical tests and hemogram were normal. She underwent surgery, and a histological examination of the surgical specimen revealed nodular hyperplasia. Microscopically, silver methenamine (PASM) stain-positive hyphae that divided into branches at 45 degrees and conidia were detected beside the thyroid capsule, with conidia in the cystic nodule. Moreover, ischemic changes of the thyroid tissue were observed closer to the capsule. We report a case of Aspergillosis of the thyroid of a patient who underwent surgery for a multinodular goiter. PMID- 22234120 TI - Vulvar hibernoma. AB - A 35 year old woman presented with 18 months history of a painless, soft, well circumscribed, vulvar subcutaneous lump which measured approximately 7 cm. The lesion was completely excised and microscopically was consistent with a hibernoma. According to the available literature in English, this is the first reported case of hibernoma of the vulva. PMID- 22234121 TI - Cytomorphology and immunohistochemistry of extrarenal rhabdoid tumor: a case report with review of literature. AB - Extrarenal rhabdoid tumor (ERRT) is a rare, aggressive tumor with extremely poor prognosis. We report a case of ERRT with intraspinal extension in a 1.5-year-old child diagnosed by fine needle aspiration cytology (FNAC) and immunohistochemistry. The child presented with a right lumbar region lump of two months duration. Ultrasound guided FNAC was performed and cell block was prepared. Smears were highly cellular and showed a dispersed population of large round cells having abundant pale eosinophilic cytoplasm, centrally to eccentrically placed nucleus with large prominent nucleoli. Immunohistochemistry was carried out on cell block which was positive for epithelial membrane antigen EMA and Vimentin. It was negative for leucocyte common antigen [LCA], wilms tumor 1, WT1, desmin and neuron specific enolase NSE, thus ruling out other tumors like lymphoma, Wilms tumor, rhabdomyosarcoma, and neuroblastoma. A final diagnosis of ERRT was given. ERRT is an extremely rare tumor of retroperitoneal area; it should be included in the differential diagnosis of malignant round cell tumor in children. Cell block in this case is mandatory for putting up the panel of immunohistochemistry which can clinch the diagnosis of rhabdoid tumor and treatment can be started as early as possible. PMID- 22234122 TI - Multiple focal nodular hyperplasia, an incidental finding on autopsy. AB - Focal nodular hyperplasia (FNH) is a benign condition of the liver often discovered incidentally on radiological investigation. Although FNH is a well described lesion in the literature considerable diagnostic problems regarding this entity still remains. We report a case of multiple FNH in a 23-year-old male patient detected as an incidental finding in autopsy. On gross examination FNH was not suspected because of the multiple lesions and the lack of central scar which is characteristically described in FNH. The diagnosis was established on histopathology after examination of multiple sections of the lesions. PMID- 22234123 TI - Malignant transformation in a hybrid schwannoma/perineurioma: addition to the spectrum of a malignant peripheral nerve sheath tumor. AB - Benign nerve sheath tumors include schwannomas, neurofibromas and perineuriomas. The malignant counterpart of a nerve sheath tumor is designated as a malignant peripheral nerve sheath tumor (MPNST). Lately, benign nerve sheath tumors comprising more than one component have been described, including hybrid schwannomas/perineuriomas. However, malignant transformation in a hybrid schwannoma/perineurioma has not been documented so far. Herein, we present a rare case of a young adult male who presented with a soft tissue mass in his right thigh that was excised elsewhere and submitted to us for histopathological review. One of the tissue sections displayed histopathological features of a hybrid schwannoma/perineurioma, including alternate arrangement of benign schwann and perineurial cells, reinforced with S100-P and epithelial membrane antigen positivity, respectively, along with low MIB1 and negative p53 immunostaining. The other two tissue sections showed a spindly sarcomatous tumor that was immunohistochemically positive for S100-P, CD34, p53 and exhibited high MIB1 (30 40%). Diagnosis of a MPNST arising in a hybrid schwannoma/perineurioma was made. This unusual case forms yet another addition to the spectrum of a MPNST. PMID- 22234124 TI - Splenic angiomatoid nodular transformation in child with inflammatory pseudotumor like areas. AB - Reports of sclerosing angiomatoid transformation (SANT) in the pediatric age group are rare. We present a case of SANT in an 11-year-old child with a history of trauma presenting with rapidly growing splenic lesion since 2 months. A partial splenectomy revealed a well-demarcated nodular lesion 5 * 4 * 4 cm with central area of fibrosis. Most part of the lesion showed ill-defined nodules or diffuse areas of plump epithelioid appearing endothelial units that marked with CD31, but the internodular stroma was inflammatory pseudotumor (IPT)-like with a mitotic count of 1-2/10 hpf. The angiomatoid nodules were diffusely positive for CD31, CD163, and CD68; however, they were negative for CD34, CD30, smooth muscle actin, and CD8. Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) was negative. The MIB1 labeling was fairly high in the IPT area but low in the angiomatoid areas. After the diagnosis of SANT, the patient has had an uneventful follow-up for more than 3 years since surgery. The morphologic findings in the case being discussed reaffirm the finding that SANT may have an IPT component and it can be seen even in pediatric age group. PMID- 22234125 TI - Gastric myeloid sarcoma--a report of two cases addressing diagnostic issues. AB - Presented herein are two cases of gastric myeloid sarcoma to highlight the diagnostic conundrum and pointers toward accurate diagnosis in such instances. The first case was a 35-year-old man with an ulceronodular mass in the body of stomach. Multiple biopsies were reported as inconclusive chiefly due to the fact that the lamina propria infiltrate was innocuous and failed to mark with CD20 or CD3. Subsequently the patient had extensive disseminated disease which was recognized as myeloid sarcoma but patient succumbed to the disease soon. The second case was a 25-year-old boy who presented with symptoms of gastric outlet obstruction since 6 months. An endoscopy revealed diffuse gastric wall thickening which on biopsy was recognized as myeloid sarcoma but patient developed intestinal obstruction and required ileal resection for symptomatic relief, postoperative patient never recovered and succumbed to the disease. Both patients had marrow involvement by acute myeloid leukemia (AML-M2) with a normal leukocyte count in peripheral blood. Thus gastric myeloid sarcomas are prone to a delayed diagnosis chiefly due to rarity. Pathologist should think of myeloid sarcoma in a hematolymphoid appearing tumor in stomach that is CD20, CD3 negative, has avid Ki67 and shows an infiltrate chiefly centered in lamina propria. PMID- 22234126 TI - Cystalline inclusions in plasma cells. PMID- 22234127 TI - Juvenile hyaline fibromatosis: a rare lesion. PMID- 22234128 TI - Bugs on film: the presence of bacterial rods (Citrobacter koseri) on a routine blood film in a septic immunocompromised patient with a femoral vein line. PMID- 22234129 TI - Paratesticular multicystic mesothelioma. PMID- 22234130 TI - Myxoinflammatory fibroblastic sarcoma--report of two uncommon tumors occurring at classical and unusual sites. PMID- 22234132 TI - Blastoschizomyces capitatus pneumonia: a rare case. PMID- 22234131 TI - Prevalence of dengue and chickungunya fever and their co-infection. PMID- 22234133 TI - Fournier's gangrene with testicular infarction caused by mucormycosis. PMID- 22234134 TI - A rare case of a rectal polyp with gastric heterotopia. PMID- 22234135 TI - Dual Salmonella typhi infection. PMID- 22234136 TI - G6PD deficiency in females screened at tertiary care hospital. PMID- 22234137 TI - Hydrops fetalis due to maternal anti Jk b. PMID- 22234138 TI - Cytomegalovirus esophagitis in nonimmunocompromised patient--presenting as an acute necrotic (black) esophagitis. PMID- 22234139 TI - Differential diagnosis of oncocytic pleomorphic adenoma. PMID- 22234140 TI - Systemic mastocytosis with an associated non mast cell lineage clonal hematological disease in a child. PMID- 22234141 TI - Inflammatory myofibroblastic tumor of renal pelvis: a rare entity. PMID- 22234142 TI - CDX2 positivity in metastatic endometrial carcinoma to the lung: a diagnostic pitfall. PMID- 22234143 TI - Aberrant CDX2 expression and metastatic endometrial adenocarcinoma to the lung. PMID- 22234144 TI - Dengue rapid strip test: a Sri Lankan experience. PMID- 22234145 TI - Zosteriform cutaneous metastasis: a primary manifestation of carcinoma breast, rare case report. PMID- 22234146 TI - Diffuse nesidioblastosis of the pancreas in a neonate with seizures. PMID- 22234147 TI - Coexisting intramedullary schwannoma with intramedullary cysticercus: report of an unusual collision. PMID- 22234148 TI - Development of low blood glucose readings in nine non-diabetic patients treated with tumor necrosis factor-alpha inhibitors: a case series. AB - INTRODUCTION: Treatment with various biological agents in disease states such as rheumatoid arthritis has been associated with multiple side effects. Whereas many of these are frequently reported in the literature, hypoglycemia, a possible side effect of tumor necrosis factor-alpha inhibitors, may be underpublicized. CASE PRESENTATION: We report nine cases of non-diabetic Caucasian women who were between 29 and 68 years of age and who developed low glucose readings after treatment with tumor necrosis factor-alpha inhibitors. We provide a more detailed discussion of existing evidence of the role of tumor necrosis factor-alpha in the pathogenesis of inflammation and its impact on glycemic equilibrium. CONCLUSIONS: Physicians using tumor necrosis factor-alpha inhibitors in the treatment of various rheumatic and other autoimmune diseases should be aware of the potential for the development of glycemic disturbance in these patients. A further role of tumor necrosis factor-alpha inhibitors in the glycemic equilibrium warrants larger controlled trials in patients with and those without a history of diabetes. PMID- 22234149 TI - Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. AB - BACKGROUND: This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments. METHODS: This was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis. RESULTS: Of 5239 treated patients (mean +/- SD HbA1c 65 +/- 10 mmol/mol [8.0 +/- 0.9%], age 58 +/- 10 years, BMI 29 +/- 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]). CONCLUSIONS: These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM. PMID- 22234150 TI - Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies). PMID- 22234151 TI - A large duplication involving the IHH locus mimics acrocallosal syndrome. AB - Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a ~600-kb deletion 5' of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a ~900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35. PMID- 22234152 TI - Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women. AB - The P2X7 receptor gene (P2RX7) is highly polymorphic with five previously described loss-of-function (LOF) single-nucleotide polymorphisms (SNP; c.151+1G>T, c.946G>A, c.1096C>G, c.1513A>C and c.1729T>A) and one gain-of function SNP (c.489C>T). The purpose of this study was to determine whether the functional P2RX7 SNPs are associated with lumbar spine (LS) bone mineral density (BMD), a key determinant of vertebral fracture risk, in post-menopausal women. We genotyped 506 post-menopausal women from the Aberdeen Prospective Osteoporosis Screening Study (APOSS) for the above SNPs. Lumbar spine BMD was measured at baseline and at 6-7 year follow-up. P2RX7 genotyping was performed by homogeneous mass extension. We found association of c.946A (p.Arg307Gln) with lower LS-BMD at baseline (P=0.004, beta=-0.12) and follow-up (P=0.002, beta=-0.13). Further analysis showed that a combined group of subjects who had LOF SNPs (n=48) had nearly ninefold greater annualised percent change in LS-BMD than subjects who were wild type at the six SNP positions (n=84; rate of loss=-0.94%/year and 0.11%/year, respectively, P=0.0005, unpaired t-test). This is the first report that describes association of the c.946A (p.Arg307Gln) LOF SNP with low LS-BMD, and that other LOF SNPs, which result in reduced or no function of the P2X7 receptor, may contribute to accelerated bone loss. Certain polymorphic variants of P2RX7 may identify women at greater risk of developing osteoporosis. PMID- 22234153 TI - Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta. AB - Mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), genes involved in nucleotide excision repair and transcription, can cause several disorders including trichothiodystrophy (TTD) and xeroderma pigmentosum (XP). In this study, we tested the hypothesis that mutations in the XPD gene affect placental development in a phenotype-specific manner. To test our hypothesis and decipher potential biologic mechanisms, we compared all XPD-associated TTD (n=43) and XP (n=37) cases reported in the literature with respect to frequencies of gestational complications. Our genetic epidemiologic investigations of TTD and XP revealed that the exact genetic abnormality was relevant to the mechanism leading to gestational complications such as preeclampsia. Through structural mapping, we localized the preeclampsia-associated mutations to a C-terminal motif and the helicase surfaces of XPD, most likely affecting XPD's binding to cdk-activating kinase (CAK) and p44 subunits of transcription factor (TF) IIH. Our results suggested a link between TTD- but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta. Our findings highlight the importance of the fetal genotype in development of gestational complications, such as preeclampsia. Therefore, future studies of genetic associations of preeclampsia and other placental vascular complications may benefit from focusing on genetic variants within the fetal DNA. PMID- 22234154 TI - Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. AB - The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4 12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care. PMID- 22234155 TI - Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother. AB - The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5 30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28-30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40-29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children. PMID- 22234156 TI - Association of TCF4 and CLU polymorphisms with Fuchs' endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process. AB - Fuchs' endothelial dystrophy (FED) is a disease affecting the corneal endothelium. Recent studies reported significant association of polymorphisms in the TCF4 (transcription factor 4) gene, and a borderline association of PTPRG (protein tyrosine phosphatase, receptor type, G) variants with late-onset FED in Caucasians from the United States. Association of TCF4 has also been reported in the Chinese population. We aimed to determine association of the reported polymorphisms in TCF4 and PTPRG, and association of polymorphisms in the candidate genes ZEB1 (zinc-finger E-box binding homoebox 1), COL8A2 (collagen, type VIII, alpha 2), TGFBI (transforming growth factor, beta-induced) and CLU (clusterin) in Australian cases. We also compared the expression of TGFBI and CLU proteins between FED and normal whole corneas. In all, 30 single-nucleotide polymorphisms (SNPs) from the candidate genes were genotyped in 103 cases and 275 controls. Each SNP and haplotype was assessed for association with the disease. SNP analysis identified an association of TCF4 (rs613872 (P=5.25 * 10(-15), OR=4.05), rs9954153 (P=3.37 * 10(-7), OR=2.58), rs2286812 (P=4.23 * 10(-6), OR=2.55) and rs17595731 (P=3.57 * 10(-5), OR=3.79)), CLU (rs17466684; P=0.003, OR=1.85) and one haplotype of TGFBI SNPs (P=0.011, OR=2.29) with FED in Caucasian Australians. No evidence for genetic association of PTPRG, ZEB1 and COL8A2 was found. Immunohistochemistry showed differential expression of CLU and TGFBI proteins in FED-affected compared with normal corneas. In conclusion, variation in TCF4, CLU and TGFBI, but not PTPRG, ZEB1 and COL8A2 genes are associated with FED in Caucasian Australian cases. Differential expression of CLU and TGFBI proteins in FED-affected corneas provides novel insights into the disease mechanism. PMID- 22234157 TI - Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies. AB - In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development. PMID- 22234158 TI - Low prevalence of lactase persistence in Neolithic South-West Europe. AB - The ability of humans to digest the milk component lactose after weaning requires persistent production of the lactose-converting enzyme lactase. Genetic variation in the promoter of the lactase gene (LCT) is known to be associated with lactase production and is therefore a genetic determinant for either lactase deficiency or lactase persistence during adulthood. Large differences in this genetic trait exist between populations in Africa and the Middle-East on the one hand, and European populations on the other; this is thought to be due to evolutionary pressures exerted by consumption of dairy products in Neolithic populations in Europe. In this study, we have investigated lactase persistence of 26 out of 46 individuals from Late Neolithic through analysis of ancient South-West European DNA samples, obtained from two burials in the Basque Country originating from 5000 to 4500 YBP. This investigation revealed that these populations had an average frequency of lactase persistence of 27%, much lower than in the modern Basque population, which is compatible with the concept that Neolithic and post Neolithic evolutionary pressures by cattle domestication and consumption of dairy products led to high lactase persistence in Southern European populations. Given the heterogeneity in the frequency of the lactase persistence allele in ancient Europe, we suggest that in Southern Europe the selective advantage of lactose assimilation in adulthood most likely took place from standing population variation, after cattle domestication, at a post-Neolithic time when fresh milk consumption was already fully adopted as a consequence of a cultural influence. PMID- 22234159 TI - ironXS: high-school screening for hereditary haemochromatosis is acceptable and feasible. AB - As the results of the Human Genome Project are realised, screening for genetic mutations that predispose to preventable disease is becoming increasingly possible. How and where such screening should best be offered are critical, unanswered questions. This study aimed to assess the acceptability and feasibility of genetic screening for preventable disease, using the model of hereditary haemochromatosis, in high-school students. Screening was offered for the HFE C282Y substitution to 17,638 students. Questionnaires were administered at the time of screening (Q1) and approximately 1 month after results were communicated (Q2). Outcomes assessed were uptake of screening, change in scores of validated anxiety, affect and health perception scales from Q1 to Q2, knowledge and iron indices in C282Y homozygous individuals. A total of 5757 (32.6%) students had screening and 28 C282Y-homozygous individuals (1 in 206) were identified, and none of the 27 individuals who had iron indices measures had significant iron overload. There was no significant change in measures of anxiety, affect or health perception in C282Y homozygous or non-homozygous individuals. Over 86% of students answered each of five knowledge questions correctly at Q1. Genetic population-based screening for a preventable disease can be offered in schools in a way that results in minimal morbidity for those identified at high risk of disease. The results of this study are not only relevant for haemochromatosis, but for other genetic markers of preventable disease such as those for cardiovascular disease and cancer. PMID- 22234160 TI - Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects. AB - We studied the genomic instability and methylation status of the mismatch-repair (MMR) genes hMLH1 and hMSH2, and the imprinted genes H19/IGF2, in fetuses with neural tube defects (NTDs) to explore the pathogenesis of the disease. Microsatellite instability (MSI) was observed in 23 of 50 NTD patients. Five NTD patients showed high-degree MSI (MSI-H) and 18 showed low-degree MSI (MSI-L). The frequencies of mutated microsatellite loci were 3/50 (6%) for BatT-25, 10/50 (20%) for Bat-26, 3/50 (6%) for Bat34C4, 6/50 (12%) for D2S123, 4/50 (8%) for D2S119, and 3/50 (6%) for D3S1611. The promoter regions of the hMLH1 and hMSH2 genes were unmethylated in NTD patients, as determined by methylation-specific PCR. The hMLH1 and hMSH2 promoter methylation patterns, the methylation levels of H19 DMR1, and IGF2 DMR0 were detected by bisulfite sequencing PCR, sub-cloning, and sequencing. The hMSH2 promoter sequence was unmethylated, and the hMLH1 promoter showed a specific methylation pattern at two CpG sites. The methylation levels of H19 DMR1 in the NTD and control groups are 73.3% +/- 15.9 and 58.3% +/- 11.2, respectively. The methylation level of the NTD group was higher than that of the control group (Student's t-test, P<0.05). There is no significant difference in IGF2 DMR0 methylation level between the two groups. All of the results presented here suggest that genomic instability, the MMR system, and hyper-methylation of the H19 DMR1 may be correlated with the occurrence of NTDs. PMID- 22234161 TI - Semi-automatic attenuation of cochlear implant artifacts for the evaluation of late auditory evoked potentials. AB - Electrical artifacts caused by the cochlear implant (CI) contaminate electroencephalographic (EEG) recordings from implanted individuals and corrupt auditory evoked potentials (AEPs). Independent component analysis (ICA) is efficient in attenuating the electrical CI artifact and AEPs can be successfully reconstructed. However the manual selection of CI artifact related independent components (ICs) obtained with ICA is unsatisfactory, since it contains expert choices and is time consuming. We developed a new procedure to evaluate temporal and topographical properties of ICs and semi-automatically select those components representing electrical CI artifact. The CI Artifact Correction (CIAC) algorithm was tested on EEG data from two different studies. The first consists of published datasets from 18 CI users listening to environmental sounds. Compared to the manual IC selection performed by an expert the sensitivity of CIAC was 91.7% and the specificity 92.3%. After CIAC-based attenuation of CI artifacts, a high correlation between age and N1-P2 peak-to-peak amplitude was observed in the AEPs, replicating previously reported findings and further confirming the algorithm's validity. In the second study AEPs in response to pure tone and white noise stimuli from 12 CI users that had also participated in the other study were evaluated. CI artifacts were attenuated based on the IC selection performed semi-automatically by CIAC and manually by one expert. Again, a correlation between N1 amplitude and age was found. Moreover, a high test retest reliability for AEP N1 amplitudes and latencies suggested that CIAC-based attenuation reliably preserves plausible individual response characteristics. We conclude that CIAC enables the objective and efficient attenuation of the CI artifact in EEG recordings, as it provided a reasonable reconstruction of individual AEPs. The systematic pattern of individual differences in N1 amplitudes and latencies observed with different stimuli at different sessions, strongly suggests that CIAC can overcome the electrical artifact problem. Thus CIAC facilitates the use of cortical AEPs as an objective measurement of auditory rehabilitation. PMID- 22234162 TI - Signaling the induction of sporulation involves the interaction of two secondary metabolites in Aspergillus nidulans. AB - When growing Aspergillus nidulans hyphae encounter the atmosphere, they initiate a morphogenetic program leading to the production of spores. Mutants that are defective in the fluG gene fail to undergo sporulation because they lack an endogenous diffusible factor that purportedly accumulates on aerial hyphae, thus signaling the initiation of development. In this study, the defect could be reversed by adding culture extracts from a wild-type strain onto a mutant colony. Moreover, a bioassay-guided purification of the active culture extract resulted in the identification of the active agent as dehydroaustinol. However, this meroterpenoid was active only when administered in conjunction with the orsellinic acid derivative diorcinol. These two compounds formed an adduct that was detected by HRMS in an LC-MS experiment. The diorcinol-dehydroaustinol adduct prevented crystal formation of the signal on the surface of aerial hyphae and on an artificially prepared aqueous film and also increased the signal lipophilicity. PMID- 22234163 TI - The impact of premorbid diabetic status on the relationship between the three domains of glycemic control and mortality in critically ill patients. AB - PURPOSE OF REVIEW: Hyperglycemia, hypoglycemia and increased glycemic variability are independently associated with increased risk of mortality in critically ill patients. The purpose of this review is to evaluate the evidence from interventional trials of intensive insulin therapy, as well as observational cohort studies, relating premorbid diabetic status and these three domains of glycemic control to mortality. RECENT FINDINGS: Hyperglycemia has a stronger association with mortality in critically ill patients without diabetes than in those with diabetes. Hypoglycemia is independently associated with increased risk of mortality in both populations. Limited data suggest that increased glycemic variability may have a stronger association with mortality in patients without diabetes than in those with diabetes. SUMMARY: Premorbid diabetic status impacts the relationship of the three domains of glycemic control to risk of mortality in critically ill patients. The data presented in this review are hypothesis generating; future trials of IIT in the critically ill should stratify management and outcomes by premorbid diabetic status. PMID- 22234164 TI - Alternatives to prokinetics to move the pylorus and colon. AB - PURPOSE OF REVIEW: Gastrointestinal motility disorders (GMDs) are common in the ICU. When encountering these problems, one typically thinks of prokinetics. This review summarizes current evidence of treatments. RECENT FINDINGS: Prokinetics are not the first-line therapy for GMDs. In fact, the clinical implications of using prokinetic agents are rather controversial. Current evidence on alternative treatment modalities such as fluid and electrolyte management, laxatives, opioid antagonists, purgative enemas, acupuncture, physical therapies and probiotics is growing. SUMMARY: Current state of the art to treat GMDs is primarily focused at the elimination of underlying trigger factors. Fluid and electrolyte management as well as laxatives and peripherally acting MU-opioid receptor antagonists are the recommended first-line therapies that can be complemented with prokinetics. Acupuncture as well as physical modalities, such as massage or warming of the abdomen, is promising with few side-effects and should be considered as well. PMID- 22234165 TI - G-protein-coupled receptors as fat sensors. AB - PURPOSE OF REVIEW: It has been demonstrated that fatty acids (FAs) are physiological ligands of G-protein-coupled receptors (GPRs). Activation of the GPRs (40, 41, 43, 84, 119 and 120) by FAs or synthetic agonists modulates several responses. In this review, we discuss the current knowledge on the actions of FA activated GPRs and their relevance in normal and pathological conditions. RECENT FINDINGS: Studies have shown that FA-activated GPRs modulate hormone secretion (incretin, insulin and glucagon), activation of leukocytes and several aspects of metabolism. SUMMARY: Understanding GPR actions and their involvement in the development of insulin-resistance, beta-cell failure, dyslipidemia and inflammation associated with obesity, type 2 diabetes, metabolic syndrome and cardiovascular diseases is important for the comprehension of the mechanisms underlying these pathological conditions and for the establishment of new and effective interventions. PMID- 22234166 TI - Role of polyunsaturated fatty acids and lipid peroxidation on colorectal cancer risk and treatments. AB - PURPOSE OF REVIEW: The review aims at elucidating the role of lipid peroxidation of polyunsaturated fatty acids (PUFAs) in colorectal cancer (CRC) risk and treatment. RECENT FINDINGS: CRC is one of the most overriding threats to public health. Despite a broad range of treatments, up to 50% of patients will inevitably develop incurable metastatic disease. Peroxidation of PUFAs contributes to augmentation of oxidative stress and causes in consequence inflammation, which is one of the possible carcinogenic factors of CRC. End products of PUFAs might be used as biomarkers for CRC detection and surveillance for treatment. They also have cytotoxic effect in CRC cells. Experimental results suggest that omega-3 PUFAs could increase the efficacy of radiotherapy and chemotherapy of CRC. SUMMARY: Lipid peroxidation, one factor of oxidative stress, might play a paramount role not only in carcinogenesis but also in potential therapeutic strategy on CRC. End products of lipid peroxidation, such as malondialdehyde, 4-hydroxy-2-nonenal, and isoprostanes, could be used as biomarkers for cancer detection, surveillance of treatment outcome and prognostic index for CRC patients. Furthermore, malondialdehyde and 4-hydroxy-2-nonenal have cytotoxic effect not only in normal cells but also in CRC cancer cells, which implies the potential role of PUFAs in CRC treatment. PMID- 22234167 TI - The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation. AB - Cord blood (CB) is increasingly used as a source of stem cells for hematopoietic stem cell transplantation, and natural killer (NK) cells may be the effectors of the antileukemic response observed after CB transplantation. Here, we analyzed the phenotype and functions of CB NK cell subsets. We determined that the percentage of NK cells was higher in CB compared with peripheral blood (PB). Furthermore, there was a higher percentage of the CD56(bright) subset in CB. CB NK cells reached a late stage of differentiation, but exhibited higher expression of NKG2A and expressed fewer killer-cell immunoglobulin-like receptors, suggesting an incomplete maturation. CB NK cells highly expressed CXCR4, but did not express L-selectin, highlighting unique homing properties of CB NK cells. CB NK cells proliferated in response to interleukin-2 and degranulated in response to stimulation with tumor cells, but failed to lyse K562 cells in (51)Cr-release assay. CB NK cells exhibited a lower interferon-gamma production in comparison with PB NK cells. Culture with IL-2 increased CB NK cell functions. Our study sheds light on CB NK cell properties and highlights the potential of CB as a source of NK cells for immunotherapy. PMID- 22234168 TI - Performance monitoring following conflict: internal adjustments in cognitive control? AB - The purpose of this study was to investigate the effects of strategic conflict related adjustments in cognitive control processes on indices of performance monitoring. Previous research has examined the ability of parametric task-related manipulations to bias attention to errors; however, the present study sought to elucidate the effects of internal adjustments in control mediated by the anterior cingulate cortex on error-related conflict processing. High-density event-related potentials (ERPs) were obtained from 124 healthy individuals (68 female, 66 male) during a modified Eriksen flanker task. Behavioral measures (i.e., error rates, response times [RTs]) and N2 amplitudes showed significant conflict adaptation (i.e., previous-trial congruencies influenced current-trial measures). For error trials, the error-related negativity (ERN) was more negative for errors on high conflict (i.e., incongruent) trials following high-conflict trials relative to errors on high-conflict trials following low-conflict (i.e., congruent) trials. These findings indicate that error-related conflict-monitoring processes adjust according to the post-conflict recruitment of strategic cognitive control and suggest an ongoing interplay between conflict and internal adjustments in control resources. Interpretations from the perspective of the conflict monitoring theory of cognitive control, the reinforcement learning theory, and the response-outcome theory of the ERN are discussed. PMID- 22234169 TI - Evaluation of human enterovirus 71 and coxsackievirus A16 specific immunoglobulin M antibodies for diagnosis of hand-foot-and-mouth disease. AB - BACKGROUND: Hand-foot-and-mouth disease (HFMD) is caused mainly by the human enterovirus type 71 (HEV71) and the Coxsackievirus A group type 16 (CVA16). Large outbreaks of disease have occurred frequently in the Asia-Pacific region. Reliable methods are needed for diagnosis of HFMD in children. IgM-capture ELISA, with its notable advantages of convenience and low cost, provides a potentially frontline assay. We aimed to evaluate the newly developed IgM-capture ELISAs for HEV71 and CVA16 in the diagnosis of HFMD, and to measure the kinetics of IgM over the course of HEV71 or CVA16 infections. RESULTS: We mapped, for the first time, the kinetics of IgM in HEV71 and CVA16 infection. HEV71- and CVA16-IgM were both detectable in some patients on day 1 of illness, and in 100% of patients by day 5 (HEV71) and day 8 (CVA16) respectively; both IgMs persisted for several weeks. The IgM detection rates were 90.2% (138 of 153 sera) and 68.0% (66 of 97 sera) for HEV71 and CVA16 infections, respectively, during the first 7 days of diseases. During the first 90 days after onset these values were 93.6% (233 of 249 sera) and 72.8% (91 of 125 sera) for HEV71 and CVA16 infections, respectively. Some cross-reactivity was observed between HEV71- and CVA16-IgM ELISAs. HEV71-IgM was positive in 38 of 122 (31.1%) CVA16 infections, 14 of 49 (28.6%) other enteroviral infections and 2 of 105 (1.9%) for other respiratory virus infected sera. Similarly, CVA16-IgM was apparently positive in 58 of 211 (27.5%) HEV71 infections, 16 of 48 (33.3%) other enterovirus infections and 3 of 105 (2.9%) other respiratory virus infected sera. Nevertheless, the ELISA yielded the higher OD450 value of main antibody than that of cross-reaction antibody, successfully identifying the enteroviral infection in 96.6% (HEV71) and 91.7% (CVA16) cases. When blood and rectal swabs were collected on the same day, the data showed that the agreement between IgM-capture ELISA and real-time RT-PCR in HEV71 was high (Kappa value = 0.729) while CVA16 somewhat lower (Kappa value = 0.300). CONCLUSIONS: HEV71- and CVA16-IgM ELISAs can be deployed successfully as a convenient and cost-effective diagnostic tool for HFMD in clinical laboratories. PMID- 22234171 TI - Growth defects and impaired cognitive-behavioral abilities in mice with knockout for Eif4h, a gene located in the mouse homolog of the Williams-Beuren syndrome critical region. AB - Protein synthesis is a tightly regulated, energy-consuming process. The control of mRNA translation into protein is fundamentally important for the fine-tuning of gene expression; additionally, precise translational control plays a critical role in many cellular processes, including development, cellular growth, proliferation, differentiation, synaptic plasticity, memory, and learning. Eukaryotic translation initiation factor 4h (Eif4h) encodes a protein involved in the process of protein synthesis, at the level of initiation phase. Its human homolog, WBSCR1, maps on 7q11.23, inside the 1.6 Mb region that is commonly deleted in patients affected by the Williams-Beuren syndrome, which is a complex neurodevelopmental disorder characterized by cardiovascular defects, cerebral dysplasias and a peculiar cognitive-behavioral profile. In this study, we generated knockout mice deficient in Eif4h. These mice displayed growth retardation with a significant reduction of body weight that began from the first week of postnatal development. Neuroanatomical profiling results generated by magnetic resonance imaging analysis revealed a smaller brain volume in null mice compared with controls as well as altered brain morphology, where anterior and posterior brain regions were differentially affected. The inactivation of Eif4h also led to a reduction in both the number and complexity of neurons. Behavioral studies revealed severe impairments of fear-related associative learning and memory formation. These alterations suggest that Eif4h might contribute to certain deficits associated with Williams-Beuren syndrome. PMID- 22234170 TI - Cloning and heterologous expression of Plasmodium ovale dihydrofolate reductase thymidylate synthase gene. AB - Plasmodial bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a validated antimalarial drug target. In this study, expression of the putative dhfr-ts of Plasmodium ovale rescued the DHFR chemical knockout and a TS null bacterial strain, demonstrating its DHFR and TS catalytic functions. PoDHFR-TS was expressed in Escherichia coli BL21 (DE3) and affinity purified by Methotrexate Sepharose column. Biochemical and enzyme kinetics characterizations indicated that PoDHFR-TS is similar to other plasmodial enzymes, albeit with lower catalytic activity but better tolerance of acidic pH. Importantly, the PoDHFR from Thai isolate EU266602 remains sensitive to the antimalarials pyrimethamine and cycloguanil, in contrast to P. falciparum and P. vivax isolates where resistance to these drugs is widespread. PMID- 22234172 TI - Chronic alcohol exposure stimulates adipose tissue lipolysis in mice: role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis. AB - Alcohol consumption induces liver steatosis; therefore, this study investigated the possible role of adipose tissue dysfunction in the pathogenesis of alcoholic steatosis. Mice were pair-fed an alcohol or control liquid diet for 8 weeks to evaluate the alcohol effects on lipid metabolism at the adipose tissue-liver axis. Chronic alcohol exposure reduced adipose tissue mass and adipocyte size. Fatty acid release from adipose tissue explants was significantly increased in alcohol-fed mice in association with the activation of adipose triglyceride lipase and hormone-sensitive lipase. Alcohol exposure induced insulin intolerance and inactivated adipose protein phosphatase 1 in association with the up regulation of phosphatase and tensin homolog (PTEN) and suppressor of cytokine signaling 3 (SOCS3). Alcohol exposure up-regulated fatty acid transport proteins and caused lipid accumulation in the liver. To define the mechanistic link between adipose triglyceride loss and hepatic triglyceride gain, mice were first administered heavy water for 5 weeks to label adipose triglycerides with deuterium, and then pair-fed alcohol or control diet for 2 weeks. Deposition of deuterium-labeled adipose triglycerides in the liver was analyzed using Fourier transform ion cyclotron mass spectrometry. Alcohol exposure increased more than a dozen deuterium-labeled triglyceride molecules in the liver by up to 6.3-fold. These data demonstrate for the first time that adipose triglycerides due to alcohol-induced hyperlipolysis are reverse transported and deposited in the liver. PMID- 22234173 TI - Cathepsin cleavage of sirtuin 1 in endothelial progenitor cells mediates stress induced premature senescence. AB - Stress-induced premature senescence (SIPS) of endothelial cells (ECs) has emerged as a contributor to global EC dysfunction. One of the cellular abnormalities mechanistically linked to SIPS is lysosomal dysfunction. In this study, we examined the impact of a range of cardiovascular risk factors on the expression of sirtuin 1 (SIRT1), SIPS, and apoptosis, and we documented the role of SIRT1 in reduced EC and endothelial progenitor cell (EPC) viability. These findings were confirmed in mice with selective endothelial SIRT1 knockout. The effects of stressors could be partially mimicked by inducing lysosomal membrane permeabilization or inhibiting autophagy, and were reversed by a cathepsin inhibitor. We provide evidence that SIRT1 is an important substrate of cysteine cathepsins B, S, and L. An antioxidant/peroxynitrite scavenger, ebselen, prevented stress-induced SIRT1 depletion and subversion of autophagy by mitigating lysosomal dysfunction. In conclusion, our data advance the concept of "stem cell aging" by establishing the critical role of lysosomal dysfunction in the development of SIPS through the cathepsin-induced proteolytic cleavage of SIRT1, a mechanism linking cell stress to apoptosis and SIPS. Ebselen potently protects lysosomal membrane integrity, preventing cathepsin-induced cleavage of SIRT 1 in EPCs and blunting SIPS and apoptotic cell death induced by relevant cardiovascular stressors. The proposed mechanism of SIRT1 depletion in stress has all of the attributes of being a paradigm of SIPS of EPCs. PMID- 22234175 TI - Accuracy of magnetic resonance imaging in diagnosing thyroid cartilage and thyroid gland invasion by squamous cell carcinoma in laryngectomy patients. AB - OBJECTIVES: We examined the accuracy of magnetic resonance imaging in assessing thyroid cartilage and thyroid gland invasion in patients undergoing total laryngectomy for squamous cell carcinoma, by comparing histopathology results with imaging findings. STUDY DESIGN: A retrospective study reviewed histology and magnetic resonance scan results for all total laryngectomies performed between 1998-2008 at University Hospital Aintree, Liverpool. METHODS: Pre-operative magnetic resonance images were reviewed independently by two consultant head and neck radiologists masked to the histology; their opinions were then compared with histology findings. RESULTS: Eighty-one magnetic resonance scans were reviewed. There were 22 laryngectomy patients with histologically verified thyroid cartilage invasion and one patient with thyroid gland invasion. There were 31 patients with apparent radiological thyroid cartilage invasion pre-operatively (with 17 false positives), giving sensitivity, specificity, and positive and negative predictive values of 64, 71, 45 and 84 per cent, respectively. On assessing thyroid gland invasion, there were nine false positive scans and no false negative scans, giving sensitivity, specificity, and positive and negative predictive values of 100, 89, 10 and 100 per cent, respectively. CONCLUSION: Magnetic resonance scanning over-predicts thyroid cartilage and gland invasion in patients undergoing total laryngectomy. Magnetic resonance scans have limited effectiveness in predicting thyroid cartilage invasion by squamous cell carcinoma in laryngectomy patients. PMID- 22234174 TI - Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. AB - Small, noncoding microRNAs (miRNAs) have been shown to be abnormally expressed in every tumor type examined. We used comparisons of global miRNA expression profiles of head and neck squamous cell carcinoma (HNSCC) samples and adjacent normal tissue to rank those miRNAs that were most significantly altered in our patient population. Rank Consistency Score analysis revealed miR-375 to have the most significantly lowered miRNA levels in tumors relative to matched adjacent nonmalignant tissue from the same patient among 736 miRNAs that were evaluated. This result has been previously observed by other groups; however, we extend this finding with the unique observation that low miR-375 expression levels correlate significantly with cancer survival and distant metastasis. In a study of 123 primary HNSCC patients using multivariable Cox proportional hazard ratios (HR) and 95% confidence intervals (CI), both death from disease (HR: 12.8, 95% CI: 3 to 49) and incidence of distant metastasis (HR: 8.7, 95% CI: 2 to 31) correlated with lower expression levels of miR-375 regardless of the site or stage of the tumor. In addition, we found that oral cavity tumor cell lines (eg, UMSCC1 and UMSCC47) overexpressing miR-375 were significantly less invasive in vitro than their matched empty vector controls. We conclude that miR-375 represents a potential prognostic marker of poor outcome and metastasis in HNSCC and that it may function by suppressing the tumor's invasive properties. PMID- 22234176 TI - Responsiveness of a patient in a persistent vegetative state after a coma to weekly injections of autologous activated immune cells: a case report. AB - INTRODUCTION: An 82-year-old Caucasian woman had remained in a persistent vegetative state after a coma of seven months duration, which occurred after a stroke with hemiplegia, nine years previously. The persistent vegetative state could be reversed in part by weekly injections with activated immune cells. After therapy, our patient responded to commands in addition to regaining spontaneous movements of both arms and the ability to swallow. This is the first report on the treatment with activated immune cells of a patient in a persistent vegetative state after a coma. CASE PRESENTATION: An 82-year-old Caucasian woman presented with a persistent vegetative state subsequent to a coma. She retained respiratory and autonomic functions. As contact was not possible, physiotherapy was passive. Her skin was yellowish, and our patient did not move by herself. Vomiting repeatedly resulted from tube feeding. After a once-weekly treatment with activated immune cells sampled from our patient's blood and activated in vitro, several of her functions gradually returned. Our patient opened her eyes in the requested direction and turned her head toward people entering the room. She 'supported' nursing efforts, as the nurse noted a loss of spastic motions. The strength in both her arms returned, and she spontaneously moved her arm on the side experiencing hemiplegia. After three months, our patient could stick out her tongue upon demand. Finally, the swallow reflexes of our patient started to return. However, tube feeding was continued, and our patient died after aspiration of vomit following a feeding. CONCLUSION: The success of treatment with autologous activated immune cells in this patient may have resulted from the production of neuroactive substances, such as neurotrophin-3 and brain-derived neurotrophic factor, by activated immune cells. The deterioration of our patient could be reversed, as demonstrated by the restoration of motor strength in her hemiplegic side. In addition, our patient was able to induce motor responses upon request. It seems reasonable to conclude that activated immune cells may improve the chronic vegetative state in some patients. PMID- 22234177 TI - Effects of type 5-phosphodiesterase inhibition on energy metabolism and mitochondrial biogenesis in human adipose tissue ex vivo. AB - OBJECTIVE: An excess of adipose tissue (AT) in obese individuals is linked to increased cardiovascular risk and mitochondria have been shown to be defective in the muscle and AT of patients with metabolic disorders such as obesity and Type 2 diabetes. Nitric oxide (NO) generated by endothelial NO synthase (eNOS) plays a role in mitochondrial biogenesis through cyclic-GMP (cGMP). AT harbors the whole molecular signaling pathway of NO, together with type 5-phosphodiesterase (PDE- 5), the main cGMP catabolising enzyme. AIM: Our aim was to evaluate the effect of the modulation of NO pathway, through PDE-5 inhibition, on energy metabolism and mitochondria biogenesis in human omental AT. METHODS AND MEASUREMENTS: Cultured human omental AT was stimulated with PDE-5 inhibitor, vardenafil, at different concentration for 24 and 72 h. Analysis of the expression of both key-regulator genes of adipocyte metabolism and mitochondria-biogenesis markers was performed. RESULTS: We found an increased gene expression of peroxisome proliferator activated receptor-gamma (PPAR-gamma), adiponectin, and proliferator- activated receptor gamma coactivator-1 alpha (PGC-1alpha) after a 24-h stimulation with vardenafil at the lowest concentration employed compared to controls (p<0.05). After 72 h of stimulation, a significant increase of mitochondrial DNA was found compared to control samples (p<0.05). CONCLUSION: Our data suggest that PDE-5 inhibition could have an impact on mitochondrial content of human AT suggesting a positive effect on energy metabolism and adding new elements in the comprehension of AT pathophysiology. PMID- 22234179 TI - Endocrinology and art. Judgement (Giudizio Universale) Pietro De' Cerroni called Pietro Cavallini. PMID- 22234178 TI - Which is the eligible patient to be treated with pioglitazone? The expert view. AB - Pioglitazone has an important role in the treatment of patients with Type 2 diabetes. The drug can help patients to achieve sustained glycemic control and may delay the requirement for insulin. Pioglitazone may provide benefits beyond its effects on glycemia, with data suggesting it may confer anti-atherosclerotic and cardioprotective properties. Attention should be given to possible side effects relating to class effects of TZD, and selection of appropriate patients to be prescribed pioglitazone will enable optimum benefits to be derived from pioglitazone treatment. PMID- 22234181 TI - Hypertrophic-congestive and fibro-sclerotic ultrasound variants of male accessory gland infection have different sperm output. AB - INTRODUCTION: Male accessory gland infection (MAGI) exerts a negative influence on male fertility which depends upon its extension. Indeed, we have shown that patients with MAGI involving prostate, seminal vesicles and epididymis have worse sperm parameters compared with patients with prostatitis alone or prostate vesiculitis. Similarly, MAGI extending bilaterally is associated with a worse sperm output. The aims of this study were to evaluate the prevalence of two different additional ultrasound (US) findings (hypertrophic- congestive and a fibro-sclerotic US form) and to evaluate their semen quality. MATERIALS AND METHODS: One hundred infertile patients with MAGI, diagnosed according to the World Health Organization (WHO) 1993 criteria, were evaluated by scrotal and transrectal ultrasound scans. The control group consisted of 100 healthy, age matched men. RESULTS: The ultrasound examination confirms two separate US variants of MAGI: a hypertrophic-congestive (prevalence of 56%) and a fibro sclerotic form (prevalence of 29%). Patients with hypertrophic-congestive MAGI showed higher sperm concentration, motility and normal forms, but also higher sperm leukocytes concentration and seminal reactive oxygen species compared to patients with fibro-sclerotic MAGI. However, all these parameters were significantly worse than those observed in the control group. DISCUSSION: Infertile patients with hypertrophic-congestive MAGI have a better sperm quality compared with patients with fibrosclerotic MAGI; however, they showed higher oxidative stress in semen. PMID- 22234180 TI - Arterial erectile dysfunction: reliability of new markers of endothelial dysfunction. AB - OBJECTIVE: Blood endothelial progenitor cells (EPC) and microparticles (EMP) have been proposed as markers of endothelial dysfunction. Aim of this study was to evaluate a new immunophenotype of EPC and EMP in patients with arterial erectile dysfunction (AED) compared to psychogenic erectile dysfunction (PED). MATERIALS AND METHODS: One hundred patients (63.2+/-2.6 yr) with AED were enrolled in this study. Their EPC and EMP concentrations were compared to those of 40 patients with PED (64.2+/-2.7 yr). EPC (CD45(neg)/CD34(pos)/ CD144(pos)) and EMP (CD45(neg)/CD144(pos)/AnnexinV(pos)) blood concentrations were evaluated by flow cytometry. RESULTS: Patients with AED had significantly higher blood pressure, triglycerides, homeostasis model assessment index of insulin resistance, and cavernous artery acceleration time and intima-media thickness than PED; whereas international index of erectile function 5 score, HDL-cholesterol, and cavernous artery peak systolic velocity was lower than PED. Both EPC and EMP were significantly higher in patients with AED compared to patients with PED. CONCLUSIONS: Patients with AED showed worse metabolic parameters, cavernous artery parameters, and higher EPC and EMP compared to patients with PED. This suggests that AED is an expression of endothelial dysfunction and that EPC and EMP may be considered predictors of endothelial dysfunction in patients with AED. PMID- 22234182 TI - A microRNA that limits metastatic colonisation and endothelial recruitment. PMID- 22234183 TI - CaMKII binding to GluN2B is critical during memory consolidation. AB - Memory is essential for our normal daily lives and our sense of self. Ca(2+) influx through the NMDA-type glutamate receptor (NMDAR) and the ensuing activation of the Ca(2+) and calmodulin-dependent protein kinase (CaMKII) are required for memory formation and its physiological correlate, long-term potentiation (LTP). The Ca(2+) influx induces CaMKII binding to the NMDAR to strategically recruit CaMKII to synapses that are undergoing potentiation. We generated mice with two point mutations that impair CaMKII binding to the NMDAR GluN2B subunit. Ca(2+)-triggered postsynaptic accumulation is largely abrogated for CaMKII and destabilized for TARPs, which anchor AMPA-type glutamate receptors (AMPAR). LTP is reduced by 50% and phosphorylation of the AMPAR GluA1 subunit by CaMKII, which enhances AMPAR conductance, impaired. The mutant mice learn the Morris water maze (MWM) as well as WT but show deficiency in recall during the period of early memory consolidation. Accordingly, the activity-driven interaction of CaMKII with the NMDAR is important for recall of MWM memory as early as 24 h, but not 1-2 h, after training potentially due to impaired consolidation. PMID- 22234184 TI - A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta catenin signalling. AB - The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/beta-catenin signalling through their interaction with beta-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/beta catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of beta-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to beta-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/beta-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of beta-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of beta-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of beta-catenin. PMID- 22234185 TI - dNTP pools determine fork progression and origin usage under replication stress. AB - Intracellular deoxyribonucleoside triphosphate (dNTP) pools must be tightly regulated to preserve genome integrity. Indeed, alterations in dNTP pools are associated with increased mutagenesis, genomic instability and tumourigenesis. However, the mechanisms by which altered or imbalanced dNTP pools affect DNA synthesis remain poorly understood. Here, we show that changes in intracellular dNTP levels affect replication dynamics in budding yeast in different ways. Upregulation of the activity of ribonucleotide reductase (RNR) increases elongation, indicating that dNTP pools are limiting for normal DNA replication. In contrast, inhibition of RNR activity with hydroxyurea (HU) induces a sharp transition to a slow-replication mode within minutes after S-phase entry. Upregulation of RNR activity delays this transition and modulates both fork speed and origin usage under replication stress. Interestingly, we also observed that chromosomal instability (CIN) mutants have increased dNTP pools and show enhanced DNA synthesis in the presence of HU. Since upregulation of RNR promotes fork progression in the presence of DNA lesions, we propose that CIN mutants adapt to chronic replication stress by upregulating dNTP pools. PMID- 22234186 TI - RP58 controls neuron and astrocyte differentiation by downregulating the expression of Id1-4 genes in the developing cortex. AB - Appropriate number of neurons and glial cells is generated from neural stem cells (NSCs) by the regulation of cell cycle exit and subsequent differentiation. Although the regulatory mechanism remains obscure, Id (inhibitor of differentiation) proteins are known to contribute critically to NSC proliferation by controlling cell cycle. Here, we report that a transcriptional factor, RP58, negatively regulates all four Id genes (Id1-Id4) in developing cerebral cortex. Consistently, Rp58 knockout (KO) mice demonstrated enhanced astrogenesis accompanied with an excess of NSCs. These phenotypes were mimicked by the overexpression of all Id genes in wild-type cortical progenitors. Furthermore, Rp58 KO phenotypes were rescued by the knockdown of all Id genes in mutant cortical progenitors but not by the knockdown of each single Id gene. Finally, we determined p57 as an effector gene of RP58-Id-mediated cell fate control. These findings establish RP58 as a novel key regulator that controls the self-renewal and differentiation of NSCs and restriction of astrogenesis by repressing all Id genes during corticogenesis. PMID- 22234188 TI - Duchenne or Becker muscular dystrophy: a clinical, genetic and immunohistochemical study in China. AB - BACKGROUND AND OBJECTIVE: Duchenne and Becker muscular dystrophies are X-linked diseases caused by mutations in the dystrophin gene, which affect approximately 1 in 3,500 and 1 in 18,000 boys, respectively. The aim of this work was to develop a method to assist the diagnosis and classification of the disease. MATERIALS AND METHODS: A large data set of dystrophin mutations was detected in 167 Chinese patients by multiplex ligation-dependent probe amplification and sequencing. Muscle biopsy, immunohistochemistry and STR analysis were also carried out in the patients and carriers. RESULTS: One hundred and three deletions, 23 duplications and two-point mutations. The deletion of one or more exons was detected in 103 (61.7%) patients. The region spanning exons 44-55 was the most frequent deletion. The duplication was identified in 23 (13.8%) patients, which was more common than previously reported. Most duplications were found in exons 2-18. Six out of the 45 muscle biopsies analyzed showed the presence of other muscle diseases. CONCLUSIONS: This study may be important to enable comparisons of mutation type and the most appropriate analytical approach for samples from different geographical areas and ethnicities. PMID- 22234189 TI - Identification of deletions and duplications in the Duchenne muscular dystrophy gene and female carrier status in western India using combined methods of multiplex polymerase chain reaction and multiplex ligation-dependent probe amplification. AB - BACKGROUND: The technique of multiplex ligation-dependent probe amplification (MLPA) assay is an advanced technique to identify deletions and duplications of all the 79 exons of DMD gene in patients with Duchenne/Becker muscular dystrophy (DMD/BMD) and female carriers. AIM: To use MLPA assay to detect deletions which remained unidentified on multiplex polymerase chain reaction (mPCR) analysis, scanning 32 exons of the "hot spot" region. Besides knowing the deletions and/or duplications, MLPA was also used to determine the carrier status of the females at risk. MATERIALS AND METHODS: Twenty male patients showing no deletions on mPCR and 10 suspected carrier females were studied by MLPA assay using P-034 and P 035, probe sets (MRC Holland) covering all the 79 exons followed by capillary electrophoresis on sequencing system. RESULTS: On MLPA analysis, nine patients showed deletions of exons other than 32 exons screened by mPCR represented by absence of peak. Value of peak areas were double or more in four patients indicating duplications of exons. Carrier status was confirmed in 50% of females at risk. CONCLUSION: Combining the two techniques, mPCR followed by MLPA assay, has enabled more accurate detection and extent of deletions and duplications which otherwise would have remained unidentified, thereby increasing the mutation pick up rate. These findings have also allowed prediction of expected phenotype. Determining carrier status has a considerable significance in estimating the risk in future pregnancies and prenatal testing options to limit the birth of affected individuals. PMID- 22234187 TI - Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype. AB - The integrity of the genome depends on diverse pathways that regulate DNA metabolism. Defects in these pathways result in genome instability, a hallmark of cancer. Deletion of ELG1 in budding yeast, when combined with hypomorphic alleles of PCNA results in spontaneous DNA damage during S phase that elicits upregulation of ribonucleotide reductase (RNR) activity. Increased RNR activity leads to a dramatic expansion of deoxyribonucleotide (dNTP) pools in G1 that allows cells to synthesize significant fractions of the genome in the presence of hydroxyurea in the subsequent S phase. Consistent with the recognized correlation between dNTP levels and spontaneous mutation, compromising ELG1 and PCNA results in a significant increase in mutation rates. Deletion of distinct genome stability genes RAD54, RAD55, and TSA1 also results in increased dNTP levels and mutagenesis, suggesting that this is a general phenomenon. Together, our data point to a vicious circle in which mutations in gatekeeper genes give rise to genomic instability during S phase, inducing expansion of the dNTP pool, which in turn results in high levels of spontaneous mutagenesis. PMID- 22234190 TI - Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a preliminary study. AB - OBJECTIVE: Despite dramatic advances in all medical era, cerebral vasospasm is still the major complication in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to assess the influence of intraarterial (IA) nimodipine in the treatment of symptomatic vasospasm and in preventing neurological disabilities. MATERIALS AND METHODS: We retrospectively reviewed 10 patients of SAH who received IA nimodipine in 15 procedures. The decision to perform angiography and endovascular treatment was based on the neurological examination, brain computed tomography (CT) and CT-angiography. The procedure reports, anesthesia records, neurological examination before and after the procedure, brain imaging and short- and long-term outcome were studied. RESULTS: The average dose of nimodipine was 2 mg. The median change in mean arterial pressure at 10 min was -10 mmHg. No significant change of heart rate was observed at 10 min. There was radiological improvement in 80% of the procedures. Neurological improvement was noted after eight out of 12 procedures when nimodipine was used as the sole treatment and after 10 out of 15, overall. Six patients clinically improved after the treatment and had good outcome. In one patient, an embolus caused fatal anterior and middle cerebral arteries infarction. There was no other neurological deficit or radiological abnormality due to the nimodipine treatment itself. CONCLUSION: Low-dose IA nimodipine is a valid adjunct for the endovascular treatment of cerebral vasospasm. Beneficial effects are achieved in some patients, prompting a prospective control study. PMID- 22234191 TI - Detection of progesterone receptor and the correlation with Ki-67 labeling index in meningiomas. AB - CONTEXT: Although most of the meningiomas are benign, some of them are associated with a less favorable clinical outcome. The major prognostic question regarding meningiomas is the prediction of recurrence which is largely dependent on the histopathological type, grading, proliferation indices and progesterone receptor status. AIMS: Our study was done to assess the expression of Ki-67 and progesterone receptor (PR) in different histological types, grades, recurrent and non-recurrent meningiomas. MATERIALS AND METHODS: A total of 60 cases were collected over a period of 2.5 years. Hematoxylin and eosin staining was done for histological typing and grading of the tumors. Immunohistochemical staining was done for Ki-67 and PR using standard immunoperoxidase technique and Ki-67 Labeling Index (LI) and PR score was calculated. RESULTS: Mean Ki-67 LI was significantly higher in males versus females, in Grade II versus Grade I, in recurrent versus non-recurrent and in PR-negative versus PR-positive meningiomas. Moreover, considering Grade I and Grade II-meningiomas separately, mean Ki-67 LI was significantly higher in recurrent cases. PR positivity was significantly higher in females versus males, in Grade I versus Grade II and in non-recurrent versus recurrent meningiomas. Correlation between Ki-67 LI and PR expression was also evaluated and a strong inverse correlation was found between Ki-67 LI and PR expression. A strong negative correlation was also established between the values of Ki-67 LI and recurrence-free survival. CONCLUSION: Our results establish that the immunodetection of Ki-67 LI and PR expression in meningiomas provides a practical tool for assessing the biological behavior of meningiomas. PMID- 22234192 TI - Factors affecting the outcome of patients undergoing corrective surgery for craniosynostosis: a retrospective analysis of 95 cases. AB - BACKGROUND: Surgical procedures for correction of craniosynostosis are often performed in pediatric patients who have a small blood volume; it represents major surgery. Literature is scarce on factors affecting blood loss, intensive care unit (ICU) and hospital stay in these patients. OBJECTIVES: To identify the factors which directly affect the outcome of craniosynostosis surgery. MATERIALS AND METHODS: A detailed review of records pertaining to preanesthetic evaluation, associated anomalies, intraoperative course, and postoperative follow-up was done for patients who underwent craniosynostosis surgery between June 2000 and June 2010. The correlation between different variables was evaluated using Spearman's rank correlation. RESULTS: During the study period 95 patients (mean age 29 months, range: 3 months-13 years) underwent corrective surgery for craniosynostosis. Hospital stay was found to be significantly associated with type of surgery and postoperative complications (P<0.001) Factors such as number of associated medical conditions, number of postoperative complications, type of induction of anesthesia, duration of surgery, type of recovery affected the ICU stay in these patients (P = 0.01). CONCLUSION: The outcome of patients undergoing craniosynostosis in terms of ICU and hospital stay is affected by the number of medical and postoperative conditions, type of anesthesia induction, duration of surgery and type of recovery. PMID- 22234193 TI - Preliminary evaluation of the role of surgical microscope-integrated intraoperative FLOW 800 colored indocyanine fluorescence angiography in arteriovenous malformation surgery. AB - OBJECTIVE: To discuss the role of FLOW 800 innovative software for analytical color visualization and objective evaluation of fluorescence videos obtained by microscope-integrated intraoperative indocyanine green (ICG) fluorescence angiography in arteriovenous malformations (AVM) surgery. MATERIALS AND METHODS: Microscope-integrated intraoperative FLOW 800 was used and evaluated in three consecutive AVM surgeries over a period of two months. The role of FLOW 800 to distinguish feeding arteries from arterialized veins and other arteries was evaluated. Its advantages and limitations over conventional intraoperative ICG angiography were evaluated. RESULTS: This software was found to be useful in identifying arterial feeders, arterialized veins and other arteries in all the three patients and it gives additional information on the status of AVM before and after clipping suspected feeders which is sometimes difficult to interpret on conventional ICG angiography. CONCLUSION: Flow 800 is a reliable and useful addition to microscope-integrated color ICG video angiography. Although its role is limited in deep-seated AVMs, if properly dissected and exposed it can give useful information which can be easily interpretable and reproducible. PMID- 22234194 TI - Characteristics and endovascular treatment of intracranial vertebral artery aneurysms. AB - OBJECTIVE: The clinical and angiographic characteristics of vertebral artery (VA) aneurysm were evaluated to demonstrate the safety and efficacy of endovascular techniques of VA aneurysms. MATERIALS AND METHODS: Case records of 38 consecutive patients with 40 VA aneurysms admitted during a 2-year period were reviewed. The data analyzed included age, sex, size of aneurysm, ruptured or unruptured, endovascular techniques, angiographic results after embolization, duration of follow-up, angiographic follow-up results and Glasgow Outcome Score at follow-up. RESULTS: Of the 38 patients, 33 patients had 35 dissecting aneurysms and five patients had five saccular aneurysms. Seventeen (42.5%) aneurysms were ruptured. Of the 34 patients treated with endovascular techniques, immediate post procedural angiograms showed complete and subtotal occlusion (>90%) of 27 (67.5%) aneurysms and incomplete and no occlusion of 13 (32.5%) aneurysms, including four conservatively treated aneurysms. A clinical improvement or stable outcome was achieved in all the patients (100%) during a mean 12.1-month follow-up. There was no complication related to endovascular treatment and no rebleeding during the follow-up period. Angiographic follow-up (mean of 7.2 months, range 1-18 months) was available in all the patients. Complete and subtotal occlusion was observed in 31 (81.6%) patients, including one spontaneous thrombosis of a conservatively treated VA dissecting aneurysm. Recanalization in two patients (5.9%) at 6 and 9 months did not require retreatment. CONCLUSION: This series demonstrates the safety and efficacy of multimodality of endovascular techniques for VA aneurysms. PMID- 22234195 TI - Detection of brain lesions at the skull base using diffusion-weighted imaging with readout-segmented echo-planar imaging and generalized autocalibrating partially parallel acquisitions. AB - OBJECTIVE: To analyze the value of readout-segmented echo-planar imaging (rs-EPI) with parallel imaging and a two-dimensional (2D) navigator-based reacquisition technique in the detection of brain lesions at the skull base. MATERIALS AND METHODS: A total of 54 patients (male 37, female 17) with suspected skull-base intracranial lesions underwent magnetic resonance imaging (MRI), including pre-T1 weighted imaging, T2-weighted imaging, Fluid Attenuated Inversion Recovery (FLAIR), standard single shot echo-planar imaging diffusion weighted imaging (ss EPI DWI) and rs-EPI DWI, post-contrast T1-weighted. The total number of lesions and the number of lesions at different sites on all MRI sequences were used as reference measures. Then differences in detecting lesions and image quality between standard ss-EPI DWI and rs-EPI DWI were analyzed. RESULTS: There was a significant difference in the total number of lesions detected by rs-EPI DWI and standard ss-EPI DWI (P = 0.01). But this difference was mainly due to an improved ability of rs-EPI DWI to detect lesions located in the anterior cranial fossa, compared to ss-EPI DWI (P=0.02); the ability of ss-EPI and rs-EPI DWI to detect lesions in the middle cranial fossa and posterior cranial fossa was not significantly different (P = 0.471, P = 0.486, respectively). For image quality, rs-EPI images were significantly better than standard ss-EPI DWI images (P<0.001). CONCLUSION: The rs-EPI DWI technique is a useful tool for the detection and evaluation of lesions located at the skull base. PMID- 22234196 TI - The role of repeat endoscopic third ventriculostomy after failure of the initial procedure. PMID- 22234197 TI - Therapy of obstructive hydrocephalus due to intraventricular hemorrhage: is there a need for neuroendoscopy? PMID- 22234198 TI - Endoscopic third ventriculostomy for hydrocephalus: a review of indications, outcomes, and complications. AB - Endoscopic third ventriculostomy (ETV) has been in vogue for the past two decades, as a tool in the armamentarium of the neurosurgeon, for the management of hydrocephalus. Its utility has been proven consistently in congenital / acquired aqueductal stenosis, although the outcomes in communicating hydrocephalus as well as hydrocephalus secondary to other etiologies have not been as impressive. It is a relatively safe procedure with the appropriate selection of patients with a low rate of permanent morbidity. This review aims to define the current indications, management outcomes, and complications of ETV. PMID- 22234199 TI - Endoscopic third ventriculostomy in tubercular meningitis with hydrocephalus. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) is increasingly being used as an alternative treatment in tubercular meningitis (TBM) hydrocephalus. This study is aimed to evaluate the role of ETV in TBM hydrocephalus. MATERIALS AND METHODS: This is a prospective study of 59 patients with TBM and obstructive hydrocephalus. The diagnosis was confirmed by a computed tomography scan and/or magnetic resonance imaging scan preoperatively. The procedure was performed using the standard technique or water jet dissection. RESULTS: Three (5.1%) patients had blocked stoma, 31 (53%) had associated malnutrition, and 13 (22%) had complex hydrocephalus. Clinical improvement was seen in 34 (58%) after ETV and in 47 (80%) patients after ETV with lumber peritoneal shunt. Thirteen patients with patent stoma and complex hydrocephalus did not improve after ETV alone; an additional lumber peritoneal shunt was required. Clinical outcome was significantly better in good grade. Early recovery was observed in 81%. Results of ETV were better in patients without cisternal exudates, good nutritional status, thin and identifiable floor of third ventricle compared to cases with cisternal exudates, malnourished, thick and unidentifiable floor respectively, although the difference was statistically insignificant. There was no operative death. Three patients with normal ICP did not show any improvement. The radiological recovery after 3 weeks of surgery was 52%; follow-up ranged between 7 and 54 months. Six patients developed CSF leak. CONCLUSION: Endoscopic third ventriculostomy was safe and effective in TBM hydrocephalus. Complex hydrocephalus and associated cerebral infarcts were the major causes of failure to improve. Good results were observed in better grades. PMID- 22234200 TI - Application of neuroendoscopy in the treatment of obstructive hydrocephalus secondary to hypertensive intraventricular hemorrhage. AB - OBJECTIVE: Neuroendoscopy has become an integral part of neurosurgery, in particular in the ventricular system. Obstructive hydrocephalus secondary to intraventricular hemorrhage (IVH) is a good indication for neuroendoscopic surgery. We evaluated its efficacy and limitations in these patients. MATERIALS AND METHODS: During a 5-year period, 13 patients with obstructive hydrocephalus secondary to hypertensive IVH were studied. Patients with IVH with no evidence of obstructive hydrocephalus or with a large parenchymal hematoma or IVH of vascular origin were excluded. Rigid endoscope was used to evacuate hematoma in lateral ventricles and third ventricle in all patients. Glasgow Coma Scale (GCS), Graeb score and ventriculo-cranial ratio were evaluated before and after endoscopic intervention and Glasgow Outcome Scale (GOS) was appraised at 1 month and 12 months, postoperatively. RESULTS: Of the 13 patients, eight (61.5%) patients had thalamus hemorrhage. A successful endoscopic removal of intraventricular hematoma was achieved in all patients. Complications observed included, fornix contusion (1) and meningitis (1) and there was no procedure-related mortality. The mean Graeb score reduced from 8.69 +/- 1.89 to 6.00 +/- 2.68 (P=0.001) and ventriculo cranial ratio decreased from 0.41 +/-0.05 to 0.39 +/- 0.05 (P=0.085) following the procedure. The mean GOS scores at 1 month and 12 months both were 2.7, but a bipolar distribution was observed at 12 months. The Graeb score changed significantly with positive correlation to GCS score change (=0.565 and P<0.05). CONCLUSIONS: Endoscopic management of severe IVH with obstructive hydrocephalus allows effective reduction of the amount of ventricular blood and improves level of consciousness. Future refinement in instrumentation and discreet case selection may make this method more applicable and effective. PMID- 22234201 TI - Ostomy closure and the role of repeat endoscopic third ventriculostomy (re-ETV) in failed ETV procedures. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) has replaced shunt surgery for several indications. Failure of ETV secondary to restenosis can result in recurrence of symptoms of raised intracranial pressure. OBJECTIVE: To analyze the rates of restenosis due to ostomy closure and factors resulting in failures and to assess the role of re-ETV in such cases. MATERIALS AND METHODS: Re-ETV was performed after counselling and obtaining informed consent. The technique of re ETV was essentially the same as in primary ETV. Video analysis of primary ETV was performed before selecting a patient for re-ETV. Factors analyzed included age, gender, etiology of hydrocephalus, cerebrospinal fluid (CSF) findings, presence of shunt tube and adequacy of ETV and bleeding at the time of ETV. RESULTS: Thirty-two patients underwent re-ETV. The mean interval between the first ETV and re-ETV was 1.4 years (3 days to 2.9 years). Overall failure of ETV due to restenosis was 8.78%. The technical success rate of performing re-ETV was 93.2%. The overall clinical recovery following surgery was observed in 89% of the patients, three from early and 25 from delayed ETV failures. The radiological recovery was seen in 20 (63%) patients. The good flow of CSF via the re-ETV site was documented with cine mode magnetic resonance imaging (MRI) in seven patients. Unlike primary ETV, the success of re-ETV in children aged less than 2 years was 90% (P < 0.005). There were 56.25% failure of ETV in patients with previous infection or foreign body within the ventricle (P < 0.001). While the chances of restenosis were high in the procedure with some infections, the outcome was equally better. Gender of the patients and CSF findings had no influence on ostomy closure. CONCLUSIONS: re-ETV can be considered in carefully selected patients of failed ETV. It is more useful in delayed ETV failures and can be offered before a patient is advised VP shunt. PMID- 22234202 TI - A retrospective analysis of perioperative complications during intracranial neuroendoscopic procedures: our institutional experience. AB - BACKGROUND: Neuroendoscopic procedures are now being performed more frequently, and with advancement in technology, complications related to the procedure and equipments have also minimized or changed. We report our experience with 223 patients who underwent intracranial neuroendoscopic procedures. MATERIALS AND METHODS: The rates of various perioperative complications, both surgical and anesthesia related, during intracranial neuroendoscopic surgeries were studied. Data collected included demographics, patient's medical history and any associated comorbid conditions, diagnosis, procedure performed, anesthetic management, intraoperative and postoperative complications and outcomes. RESULTS: Of the 223 patients studied, 119 were pediatric (age <14 years) and 104 were adults. Hypothermia (25.1%) and cardiovascular complications (such as tachycardia 18.8%, bradycardia 11.3%, hypertension 16.1%, and hypotension 16.6%) were the commonly observed complications during intraoperative period both in pediatric and adult patients. At the end of the procedure, delayed arousal was observed in 17 patients and 19 patients required postoperative ventilatory support. Postoperative frequent complications included: fever (34.1%), tachycardia (32.7%), nausea and vomiting (18.8%). Potentially fatal complications such as intraoperative hemorrhage, air embolism, etc. were rare. Most of the complications were transient and self-limiting. CONCLUSION: Although endoscopic procedures are considered minimally invasive, at times may lead to life threatening complications and one should be aware of them. PMID- 22234203 TI - Congenital myopathies: clinical and immunohistochemical study. AB - Congenital myopathies (CMs), a group of relatively non-progressive disorders presents with weakness and hypotonia of varying severity, morphologically recognized by specific structural abnormalities within the myofiber. This report presents the clinical and Histopathological features of 40 patients with CMs. Centronuclear myopathy was the commonest (40%) followed by congenital fiber type disproportion (37.5%). Other less common CMs included: myotubular myopathy (5%), nemaline myopathy (5%), central core disease (5%), multicore disease (2.5%) and congenital myopathy with tubular aggregate (5%). Immunolabeling to desmin corresponded to morphological changes within the myofibers while vimentin was negative in all the patients. There is no combined role of these proteins in the disease process. PMID- 22234204 TI - Glycogen storage disease type V (Mc Ardle's disease): a report on three cases. AB - McArdle's disease (myophosphorylase deficiency), an uncommon autosomal recessive metabolic disorder, is characterized clinically by exercise intolerance beginning in childhood, myalgia, cramps, exercise-induced rhabdomyolysis, "second wind" phenomenon, elevated Creatine Kinase (CK) levels at rest, and previous episodes of raised CK levels following exercise. Several mutations in the PYGM gene and geographic variations have been described. We report three biopsy confirmed cases of McArdle's disease. PMID- 22234205 TI - Dual pathology of corticobasal degeneration and Parkinson's disease in a patient with clinical features of progressive supranuclear palsy. AB - Corticobasal degeneration and Parkinson's disease are pathologically distinct disorders with unique histological and biochemical features of a tauopathy and a synucleinopathy respectively. We report the first case of co-occurrence of these pathologies in the same patient. Convergence of such distinctly separate neuropathology in the same brain highlights the need for extensive brain banking and further research in supporting the hypothesis that tauopathies and a synucleinopathies might share common pathogenic mechanisms. PMID- 22234206 TI - Unique case of postpartum cerebral angiopathy requiring surgical intervention: case report and review of literature. AB - Postpartum cerebral angiopathy (PPCA) is a rare form of reversible cerebral vasoconstriction syndrome. A 39-year-old female presented with a 5*6 cm left frontal intracerebral hemorrhage (ICH) and following an emergent neurosurgical evacuation of ICH, she developed a contralateral ICH and intraventricular hemorrhage. Her postoperative course was highlighted by the finding of diffuse bilateral segmental vasospasm on angiography and trans-cranial Doppler, left anterior cerebral artery region infarct and intractable elevated intracranial pressure (ICP). Medical management including osmotic therapy, nimodipine, corticosteroids, and phenytoin was unable to control ICP. Intractable elevated ICP led to evacuation of the right-sided ICH. After 3.5 years, the patient appears to be cognitively intact but continues to have right lower extremity weakness and is wheelchair-bound. Our case suggests that PPCA can rarely manifest as a life-threatening emergency for which neurosurgical intervention may be life saving. PMID- 22234207 TI - Covered coronary stent grafts as a treatment option for carotid-cavernous fistulas: our initial experience. AB - Treatment of Type 1 carotid-cavernous fistula (CCF) is complex and endovascular stent grafting is proving to be an excellent technique not only in successful treatment of fistula but also preserving patency of parent artery. We describe our initial experience in the use of covered coronary stent grafts in the treatment of three patients with Type 1 post-traumatic CCF. All patients were successfully treated with placement of stent grafts. Immediate closure of fistula was achieved in all the three patients. One patient developed partial in-stent thrombosis. In this patient antiplatelet therapy had to be stopped as he developed a small intracerebral hematoma post procedure. Subsequently, he was restarted on antiplatelets and recovered completely. Except for this no other complication was observed. Covered stent grafts may be the procedure of choice for treatment of post-traumatic Type 1 CCF especially in young patients with favorable anatomy. PMID- 22234208 TI - Dural arteriovenous fistula with spinal perimedullary venous drainage. AB - The purpose of this study was to investigate the characteristics of six patients with dural arteriovenous fistula (DAVF) with drainage directly into the perimedullary venous system. In five patients with subarachnoid hemorrhage (SAH), cerebral angiography revealed a DAVF with spinal venous drainage located at the petrosal sinus in one, at the tentorium in one, and at the craniocervical junction in four. In the patient with myelopathy, angiographic exploration began with a spinal angiogram. Bilateral vertebral angiography initially failed to demonstrate the fistula, and a tentorial DAVF was established with carotid artery angiography. Patients had no myelopathy when the venous drainage was limited to the cervical cord; myelopathy was present when the venous drainage descended toward the conus medullaris. Diagnosis of a DAVF presenting with myelopathy is more challenging than of those presenting with SAH. PMID- 22234209 TI - Chronic encapsulated intracerebral hematoma associated with cavernous angioma: Expression of vascular endothelial growth factor and its receptor. PMID- 22234210 TI - Segmental myoclonus and marked ataxia in a patient of pulmonary tuberculosis. PMID- 22234211 TI - Diagnosing paroxysmal autonomic instability with dystonia following intracerebral hemorrhage. PMID- 22234212 TI - Acute embolic occlusion of the accessory middle cerebral artery mimicking an internal carotid artery terminus aneurysm. PMID- 22234213 TI - Infectious psychosis: cryptococcal meningitis presenting as a neuropsychiatry disorder. PMID- 22234214 TI - Deep brain stimulation surgery complicated by Parkinson hyperpyrexia syndrome. PMID- 22234215 TI - Anti-Ma2-positive paraneoplastic brainstem encephalitis associated with prostatic adenocarcinoma. PMID- 22234216 TI - Magnetic resonance perfusion and spectroscopy in a giant tuberculoma. PMID- 22234217 TI - Idiopathic hypertrophic pachymeningitis successfully treated with intravenous cyclophosphamide. PMID- 22234218 TI - Role of endovascular embolisation in treatment of pediatric dural arteriovenous fistula: a case report with a review of the literature. PMID- 22234219 TI - Glioblastoma multiforme with epithelial differentiation. PMID- 22234220 TI - Traumatic giant pseudoaneurysm of the middle meningeal artery causing intracerebral hematoma. PMID- 22234221 TI - Cysticercosis of filum terminale. PMID- 22234222 TI - Intraparenchymal schwannoma of brainstem in a pediatric patient. PMID- 22234223 TI - Distant extraventricular recurrence in central neurocytoma. PMID- 22234224 TI - Cholesterol granuloma of the petrous apex: a benign lesion with aggressive behavior. PMID- 22234225 TI - Extraskeletal intracranial mesenchymal chondrosarcoma: report of a rare case. PMID- 22234226 TI - Acute cauda equina syndrome due to primary Ewing's sarcoma of the spine. PMID- 22234227 TI - Hemorrhagic subependymal giant cell astrocytoma in a patient with tuberous sclerosis: case report and review of the literature. PMID- 22234228 TI - A large vertex extradural hematoma due to traumatic bilateral coronal suture diastasis. PMID- 22234229 TI - Sporadic pituitary stalk hemangioblastoma. PMID- 22234230 TI - Traumatic calvarial stone: a rare case report and review of the literature. PMID- 22234231 TI - Traumatic bilateral frontal extradural hematomas with coronal suture diastases. PMID- 22234232 TI - Direct visualization of thrombus load in MCA in acute stroke on susceptibility weighted imaging. PMID- 22234233 TI - Microsurgical management of prolactinomas - clinical and hormonal outcomes. PMID- 22234234 TI - Encephalopathy as an initial symptom of rhabdomyolysis: a commentary. PMID- 22234235 TI - Spontaneous cerebrospinal fluid leak associated with idiopathic intracranial hypertension. PMID- 22234236 TI - The efficacy of transforaminal epidural steroid injections in lumbosacral radiculopathy: a commentary. PMID- 22234237 TI - Truncated N-terminal huntingtin fragment with expanded-polyglutamine (htt552 100Q) suppresses brain-derived neurotrophic factor transcription in astrocytes. AB - Although huntingtin (htt) can be cleaved at many sites by caspases, calpains, and aspartyl proteases, amino acid (aa) 552 was defined as a preferred site for cleavage in human Huntington disease (HD) brains in vivo. To date, the normal function of wild-type N-terminal htt fragment 1-552 aa (htt552) and its pathological roles of mutant htt552 are still unknown. Although mutant htt (mhtt) is also expressed in astrocytes, whether and how mhtt contributes to the neurodegeneration through astrocytes in HD remains largely unknown. In this study, a glia HD model, using an adenoviral vector to express wild-type htt552 (htt552-18Q) and its mutation (htt552-100Q) in rat primary cortical astrocytes, was generated to investigate the influence of htt552 on the transcription of brain-derived neurotrophic factor (BDNF). Results from enzyme linked immunosorbent assay showed that the level of BDNF in astrocyte-conditioned medium was decreased in the astrocytes expressing htt552-100Q. Quantitative real-time polymerase chain reaction demonstrated that htt552-100Q reduced the transcripts of the BDNF III and IV, hence, repressed the transcription of BDNF. Furthermore, immunofluorescence showed that aggregates formed by htt552-100Q entrapped transcription factors cAMP-response element-binding protein and stimulatory protein 1, which might account for the reduction of BDNF transcription. These findings suggest that mhtt552 reduces BDNF transcription in astrocytes, which might contribute to the neuronal dysfunction in HD. PMID- 22234238 TI - Casein phosphopeptides drastically increase the secretion of extracellular proteins in Aspergillus awamori. Proteomics studies reveal changes in the secretory pathway. AB - BACKGROUND: The secretion of heterologous animal proteins in filamentous fungi is usually limited by bottlenecks in the vesicle-mediated secretory pathway. RESULTS: Using the secretion of bovine chymosin in Aspergillus awamori as a model, we found a drastic increase (40 to 80-fold) in cells grown with casein or casein phosphopeptides (CPPs). CPPs are rich in phosphoserine, but phosphoserine itself did not increase the secretion of chymosin. The stimulatory effect is reduced about 50% using partially dephosphorylated casein and is not exerted by casamino acids. The phosphopeptides effect was not exerted at transcriptional level, but instead, it was clearly observed on the secretion of chymosin by immunodetection analysis. Proteomics studies revealed very interesting metabolic changes in response to phosphopeptides supplementation. The oxidative metabolism was reduced, since enzymes involved in fermentative processes were overrepresented. An oxygen-binding hemoglobin-like protein was overrepresented in the proteome following phosphopeptides addition. Most interestingly, the intracellular pre-protein enzymes, including pre-prochymosin, were depleted (most of them are underrepresented in the intracellular proteome after the addition of CPPs), whereas the extracellular mature form of several of these secretable proteins and cell-wall biosynthetic enzymes was greatly overrepresented in the secretome of phosphopeptides-supplemented cells. Another important 'moonlighting' protein (glyceraldehyde-3-phosphate dehydrogenase), which has been described to have vesicle fusogenic and cytoskeleton formation modulating activities, was clearly overrepresented in phosphopeptides-supplemented cells. CONCLUSIONS: In summary, CPPs cause the reprogramming of cellular metabolism, which leads to massive secretion of extracellular proteins. PMID- 22234239 TI - The lesser known story of X chromosome reactivation: a closer look into the reprogramming of the inactive X chromosome. AB - X-chromosome inactivation (XCI) is an important mechanism employed by mammalian XX female cells to level X-linked gene expression with that of male XY cells. XCI occurs early in development as the pluripotent cells of the inner cell mass (ICM) in blastocysts successively differentiate into cells of all three germ layers. X chromosome reactivation (XCR), the reversal of XCI, is critical for germ cell formation as a mechanism to diversify the X-chromosome gene pool. Here we review the characterization of XCR, and further explore its natural occurrence during development and the in vitro models of cellular reprogramming. We also review the key regulators involved in XCI for their role in suppressing the active histone marks and the genes in the active chromosome for their inhibition of X inactivation signals. PMID- 22234240 TI - Subcutaneous immunoglobulins in ocular myositis. PMID- 22234242 TI - A systematic review of the safety information contained within the Summaries of Product Characteristics of medications licensed in the United Kingdom for Attention Deficit Hyperactivity Disorder. how does the safety prescribing advice compare with national guidance? AB - BACKGROUND: The safety of paediatric medications is paramount and contraindications provide clear pragmatic advice. Further advice may be accessed through Summaries of Product Characteristics (SPCs) and relevant national guidelines. The SPC can be considered the ultimate independent guideline and is regularly updated. In 2008, the authors undertook a systematic review of the SPC contraindications of medications licensed in the United Kingdom (UK) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). At that time, there were fewer contraindications reported in the SPC for atomoxetine than methylphenidate and the specific contraindications varied considerably amongst methylphenidate formulations. In 2009, the European Medicines Agency (EMA) mandated harmonisation of methylphenidate SPCs. Between September and November 2011, there were three changes to the atomoxetine SPC that resulted in revised prescribing information. In addition, Clinical Guidance has also been produced by the National Institute for Health and Clinical Excellence (NICE) (2008), the Scottish Intercollegiate Guidelines Network (SIGN) (2009) and the British National Formulary for Children (BNFC). METHODS: An updated systematic review of the Contraindications sections of the SPCs of all medications currently licensed for treatment of ADHD in the UK was undertaken and independent statements regarding contraindications and relevant warnings and precautions were then compared with UK national guidance with the aim of assessing any disparity and potential areas of confusion for prescribers. RESULTS: As of November 2011, there were seven medications available in the UK for the treatment of ADHD. There are 15 contraindications for most formulations of methylphenidate, 14 for dexamfetamine and 5 for atomoxetine. Significant differences exist between the SPCs and national guidance part due to the ongoing reactive process of amending the former as new information becomes known. In addition, recommendations are made outside UK SPC licensed indications and a significant contraindication for methylphenidate (suicidal behaviours) is missing from both the NICE and SIGN guidelines. Particular disparity exists relating to monitoring for suicidal and psychiatric side effects. The BNFC has not yet been updated in line with the European Union (EU) Directive on methylphenidate; it does not include any contraindications for atomoxetine but describes contraindications for methylphenidate that are no longer in the SPC. CONCLUSION: Clinicians seeking prescribing advice from critical independent sources of data, such as SPCs and national guidelines, may be confused by the disparity that exists. There are major differences between guidelines and SPCs and neither should be referred to in isolation. The SPC represents the most relevant source of safety data to aid prescribing of medications for ADHD as they present the most current safety data in line with increased exposure. National guidelines may need more regular updates. PMID- 22234241 TI - Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. AB - Aging drives large systemic reductions in oxidative mitochondrial function, shifting the entire body metabolically towards aerobic glycolysis, a.k.a, the Warburg effect. Aging is also one of the most significant risk factors for the development of human cancers, including breast tumors. How are these two findings connected? One simplistic idea is that cancer cells rebel against the aging process by increasing their capacity for oxidative mitochondrial metabolism (OXPHOS). Then, local and systemic aerobic glycolysis in the aging host would provide energy-rich mitochondrial fuels (such as L-lactate and ketones) to directly "fuel" tumor cell growth and metastasis. This would establish a type of parasite-host relationship or "two-compartment tumor metabolism", with glycolytic/oxidative metabolic-coupling. The cancer cells ("the seeds") would flourish in this nutrient-rich microenvironment ("the soil"), which has been fertilized by host aging. In this scenario, cancer cells are only trying to save themselves from the consequences of aging, by engineering a metabolic mutiny, through the amplification of mitochondrial metabolism. We discuss the recent findings of Drs. Ron DePinho (MD Anderson) and Craig Thomspson (Sloan-Kettering) that are also consistent with this new hypothesis, linking cancer progression with metabolic aging. Using data mining and bioinformatics approaches, we also provide key evidence of a role for PGC1a/NRF1 signaling in the pathogenesis of (1) two-compartment tumor metabolism, and (2) mitochondrial biogenesis in human breast cancer cells. PMID- 22234244 TI - Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema. AB - PURPOSE: The purpose of this study was to report the 24-month findings of a randomized clinical trial comparing intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment for diabetic macular edema. METHODS: The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB; the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT; and the MPC group, patients who underwent focal or modified grid laser. Of 150 eyes (50 in each group) in the primary trial, 123, 119, and 113 eyes completed follow-ups at 12, 18, and 24 months, respectively. A total of 39 (78%), 36 (72%), and 38 (76%) eyes in the IVB, IVB/IVT, and MPC groups remained in the study within 24 months, respectively. Retreatment was performed at 3-month intervals whenever indicated. Data from a 24-month follow-up are presented. Changes in best-corrected visual acuity and central macular thickness up to 24 months were the main outcome measures in this study. RESULTS: Retreatment was required in 37 (94.9%), 27 (75.0%), and 31 (81.6%) eyes, respectively, in the IVB, IVB/IVT, and MPC groups up to 24 months. The significant superiority of visual acuity improvement in the IVB group, which had been noted at Month 6, did not sustain thereafter up to 24 months, and the difference among the groups was not significant at all visits. However, the mean visual acuity improvement was greater in the IVB group than the other groups and in the IVB/IVT group compared with the MPC group. The reduction of central macular thickness was more in the IVB group in relation to the other two treatment groups; however, the difference among the groups was not statistically significant at any of the follow-up visits. CONCLUSION: In terms of vision improvement, the significant superiority of the IVB over the combined IVB/IVT and MPC treatment that had been observed at Month 6 did not sustain up to 24 months. This means that although IVB treatment may be a better choice than two other options in short term, the magnitude of this beneficial effect diminishes over time. PMID- 22234243 TI - Examining the genetic and neural components of cognitive flexibility using mice. AB - This commentary summarizes the research presented during the symposium "Examining the genetic and neural components of cognitive flexibility using mice" at the annual meeting of the International Behavioral Neuroscience Society 2011. Research presented includes examining: 1) Corticostriatal networks underlying reversal learning using GluN2B knockout mice, cFos expression, and in vivo electrophysiological recording; 2) Cerebellar contribution to reversal learning using mutants with Purkinje cell loss and in vivo electrochemical recording; 3) Parvalbumin contribution to reversal learning and set-shifting using PLAUR mutants and in vitro recording to examine fast-spiking interneurones; and 4) Alpha 7 nAChR contribution to reversal learning, set-shifting, motivation, and the 'eureka moment' of rule acquisition. It is proposed that these studies revealed more about the neurobiology underlying these behaviors than could be discovered using pharmacological techniques alone. Together, the research presented stressed the importance of exploring the genetic contribution to neuropsychiatric disease and the important role that the mouse, coupled with robust behavioral measures, can play in understanding neurobiology underlying cognitive flexibility. PMID- 22234245 TI - Genetic basis of stage-specific melanism: a putative role for a cysteine sulfinic acid decarboxylase in insect pigmentation. AB - Melanism, the overall darkening of the body, is a widespread form of animal adaptation to particular environments, and includes bookcase examples of evolution by natural selection, such as industrial melanism in the peppered moth. The major components of the melanin biosynthesis pathway have been characterized in model insects, but little is known about the genetic basis of life-stage specific melanism such as cases described in some lepidopteran species. Here, we investigate two melanic mutations of Bicyclus anynana butterflies, called Chocolate and melanine, that exclusively affect pigmentation of the larval and adult stages, respectively. Our analysis of Mendelian segregation patterns reveals that the larval and adult melanic phenotypes are due to alleles at different, independently segregating loci. Our linkage mapping analysis excludes the pigmentation candidate gene black as the melanine locus, and implicates a gene encoding a putative pyridoxal phosphate-dependant cysteine sulfinic acid decarboxylase as the Chocolate locus. We show variation in coding sequence and in expression levels for this candidate larval melanism locus. This is the first study that suggests a biological function for this gene in insects. Our findings open up exciting opportunities to study the role of this locus in the evolution of adaptive variation in pigmentation, and the uncoupling of regulation of pigment biosynthesis across developmental stages with different ecologies and pressures on body coloration. PMID- 22234246 TI - Genetic uniqueness of the Waorani tribe from the Ecuadorian Amazon. AB - South America and especially the Amazon basin is known to be home to some of the most isolated human groups in the world. Here, we report on a study of mitochondrial DNA (mtDNA) in the Waorani from Ecuador, probably the most warlike human population known to date. Seeking to look in more depth at the characterization of the genetic diversity of this Native American tribe, molecular markers from the X and Y chromosomes were also analyzed. Only three different mtDNA haplotypes were detected among the Waorani sample. One of them, assigned to Native American haplogroup A2, accounted for more than 94% of the total diversity of the maternal gene pool. Our results for sex chromosome molecular markers failed to find close genetic kinship between individuals, further emphasizing the low genetic diversity of the mtDNA. Bearing in mind the results obtained for both the analysis of the mtDNA control region and complete mitochondrial genomes, we suggest the existence of a 'Waorani-specific' mtDNA lineage. According to current knowledge on the phylogeny of haplogroup A2, we propose that this lineage could be designated as subhaplogroup A2s. Its wide predominance among the Waorani people might have been conditioned by severe genetic drift episodes resulting from founding events, long-term isolation and a traditionally small population size most likely associated with the striking ethnography of this Amazonian community. In all, the Waorani constitute a fine example of how genetic imprint may mirror ethnopsychology and sociocultural features in human populations. PMID- 22234247 TI - Two distinct genomic regions, harbouring the period and fruitless genes, affect male courtship song in Drosophila montana. AB - Acoustic signals often have a significant role in pair formation and in species recognition. Determining the genetic basis of signal divergence will help to understand signal evolution by sexual selection and its role in the speciation process. An earlier study investigated quantitative trait locus for male courtship song carrier frequency (FRE) in Drosophila montana using microsatellite markers. We refined this study by adding to the linkage map markers for 10 candidate genes known to affect song production in Drosophila melanogaster. We also extended the analyses to additional song characters (pulse train length (PTL), pulse number (PN), interpulse interval, pulse length (PL) and cycle number (CN)). Our results indicate that loci in two different regions of the genome control distinct features of the courtship song. Pulse train traits (PTL and PN) mapped to the X chromosome, showing significant linkage with the period gene. In contrast, characters related to song pulse properties (PL, CN and carrier FRE) mapped to the region of chromosome 2 near the candidate gene fruitless, identifying these genes as suitable loci for further investigations. In previous studies, the pulse train traits have been found to vary substantially between Drosophila species, and so are potential species recognition signals, while the pulse traits may be more important in intra-specific mate choice. PMID- 22234248 TI - AFLPs do not support deep phylogenetic relationships among darters (Teleostei: Percidae: Etheostomatinae). PMID- 22234249 TI - A brief note on the resemblance between relatives in the presence of population stratification. AB - Population stratification occurs when a study population is comprised of several sub-populations, and can result in increased false positive findings in genomewide-association studies. Recently published work shows that sub-population specific positive assortative mating at the genotypic level results in population stratification. We show that if the allele frequency of a single nucleotide polymorphism responsible for a trait varies between sub-populations and there is no dominance variance, then the heritability of the trait increases, primarily due to an increase in the additive genetic variance of the trait. PMID- 22234250 TI - The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1. AB - Inactivation of the von Hippel-Lindau (VHL) tumor suppressor is associated with renal carcinoma, hemangioblastoma and pheochromocytoma. The VHL protein is a component of a ubiquitin ligase complex that ubiquitinates and degrades hypoxia inducible factor-alpha (HIF-alpha). Degradation of HIF-alpha by VHL is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in tumor suppression and other biological processes. Using GST-VHL pull-down experiment and mass spectrometry, we detected an interaction between VHL and heterochromatin protein 1 (HP1). We identified a conserved HP1-binding motif (PXVXL) in the beta domain of VHL, which is disrupted in a renal carcinoma-associated P81S mutant. We show that the VHL P81S mutant displays reduced binding to HP1, yet retains the ability to interact with elongin B, elongin C, and cullin 2 and is fully capable of degrading HIF-alpha. We also demonstrate that HP1 increases the chromatin association of VHL. These results suggest a role for the VHL-HP1 interaction in VHL chromatin targeting. PMID- 22234251 TI - Reflection of light by metal nanoparticles at electrodes. AB - We present model calculations for the reflection spectrum of an ordered two dimensional array of metallic nanoparticles located near an electrochemical interface. We consider three cases, nanoparticles at: (i) a metal electrode, (ii) a transparent semiconductor electrode, and (iii) an electrified liquid/liquid interface. In the case of a metal electrode, the presence of nanoparticles introduces dips in reflection, whose position and depth are affected by the distance and size of the nanoparticles. For both a transparent semiconductor electrode and a liquid/liquid interface, the presence of nanoparticles enhances reflectivity. The spectra are sensitive to the particle spacing and size. The response from all three systems exhibits a strong dependence on the polarisation of light. The dependence on the angle of incidence reveals shallow dips typical of surface plasmon resonance spectra. These findings suggest diagnostic tools for the detection and characterisation of nanoparticle monolayers on functionalised electrodes, and enable electrovariable optical devices based on the controlled assembly of nanoparticles at interfaces. PMID- 22234252 TI - Allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia in adults. AB - PURPOSE OF REVIEW: Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, for which treatment guidelines are still evolving. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic modality for ALL, and this review describes the recent studies and current practice patterns concerning the who, when, and how of allo-HCT in the management of ALL. RECENT FINDINGS: Allogeneic stem cell transplantation is the treatment of choice for patients with ALL after first relapse and is also recommended for high-risk patients in first complete remission (CR1). Minimal residual disease evaluation and monitoring is developing as an important prognostic factor and could guide physicians in determining which patients, especially those with standard risk, might require transplant. Tyrosine kinase inhibitor (TKI) therapy allows a much higher proportion of Philadelphia-chromosome-positive ALL patients to attain remission and proceed to transplant with improved results; posttransplant TKI maintenance therapy may also provide survival benefit. Reduced-intensity conditioning regimens are a reasonable alternative for patients who would otherwise be ineligible for transplant because of age or comorbidity. SUMMARY: For patients with high-risk features, there is general agreement that allo-HCT in CR1 is a potentially curative option; however, there is no consensus on early transplant for standard-risk patients. PMID- 22234254 TI - Merkel cell carcinoma: recent insights and new treatment options. AB - PURPOSE OF REVIEW: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin demonstrating a high propensity of recurrence and metastasis. Its 5-year disease-specific survival rate is only about 60%. Although MCC is still regarded as a very rare tumor entity, its incidence is rapidly increasing. In this regard, the American Cancer Society estimated almost 1500 new cases in the United States in 2008. RECENT FINDINGS: The newly identified Merkel cell polyomavirus (MCV) has been found associated to most MCC cases. Nevertheless, the distinct molecular pathogenesis of MCC and its link to MCV is not yet fully understood. Moreover, the impact of MCV positivity on the course of disease and prognosis of MCC patients is controversially discussed. SUMMARY: This review summarizes recent findings on MCC pathogenesis with a special emphasis on the impact of MCV, presents an overview of clinical aspects, and discusses treatment options. PMID- 22234253 TI - Hematopoietic stem cell transplantation for chronic lymphocytic leukemia. AB - PURPOSE OF REVIEW: Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many aggressive hematologic malignancies, the role of HSCT in chronic lymphocytic leukemia (CLL) has remained controversial. Now in the era of improved conventional treatment and better prognostication of long-term outcome, a review of autologous and allogeneic HSCT in CLL treatment is warranted. RECENT FINDINGS: Despite an improved disease-free survival in some patients, multiple, prospective, randomized autologous HSCT CLL trials fail to demonstrate an overall survival benefit as compared to conventional therapy. Allogeneic bone marrow transplantation, although limited by donor availability, can successfully eradicate CLL with adverse prognostic features. In the older CLL patients, nonmyeloablative allogeneic transplants are better tolerated than myeloablative transplants. Nonmyeloablative allogeneic transplants are less effective in heavily diseased burdened patients. SUMMARY: Outside of a clinical protocol, autologous HSCT for CLL cannot be justified. Nonmyeloablative allogeneic transplantation should be considered in high-risk populations early in the disease process, when disease burden is most easily controlled. Alternative donor selection using haploidentical donors and posttransplantation cyclophosphamide has the potential to vastly increase the availability of curative therapy in CLL while retaining a low treatment-related toxicity. PMID- 22234255 TI - Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity? AB - PURPOSE OF REVIEW: Ulceration of a primary cutaneous melanoma has for many years been recognized as a very important prognostic factor associated with increased risk for recurrence and mortality. Patients with an ulcerated melanoma do much worse than patients with a nonulcerated melanoma with the same breslow thickness. Ulceration may indicate a separate biologic entity. RECENT FINDINGS: Gene profiling studies of fresh frozen melanoma samples indicated that ulcerated melanomas have a very different profile. Analysis of the results of the two largest adjuvant interferon (IFN) trials ever conducted in 2644 patients [European Organization for Research and Treatment of Cancer (EORTC) 18952 and 18991], which used ulceration of the primary as a stratification factor, indicated that ulceration was not only a very strong prognostic factor, but more importantly a significant predictive factor for outcome of adjuvant IFN treatment. Only in patients with an ulcerated primary, was a similar and significant impact on disease-free survival, distant metastasis-free survival and overall survival observed. As a more general finding, in trials independent of ulceration used as a stratification factor, this IFN sensitivity of ulcerated melanomas has been reported in a meta-analysis in more than 3000 patients. It was also identified as a predictive factor of outcome in the Sunbelt adjuvant IFN trial in the USA. SUMMARY: These important findings regarding ulceration need biologic studies to identify the differences between ulcerated and nonulcerated melanoma at the molecular level. Moreover, the importance of ulceration will be assessed prospectively in the EORTC 18081 trial in patients with primary ulcerated melanomas more than 1 mm. PMID- 22234256 TI - Ocular melanoma: what's new? AB - PURPOSE OF REVIEW: The purpose of this review was to summarize available data on uveal melanoma biology and treatment in order to provide the medical community with a basic reference that would help to make further progress in this rare disease, which remains difficult to treat. RECENT FINDINGS: The most relevant recent findings driving current clinical developments are in the elucidation of uveal melanoma genetics and genomics. The key driving mutations - that differ completely from cutaneous melanoma - have been identified. Based on the novel insights into key signaling pathways, the first clinical trials with targeted treatments have been implemented. However, systemic and regional chemotherapy approaches as well as other regional treatment modalities for liver metastases are also a major part of the current treatment armamentarium and are prospectively being evaluated. SUMMARY: In summary, the recent biological findings and the creation of a series of clinical trials underscore how the international community is able to perform relevant advances in an extremely rare disease. PMID- 22234257 TI - Anti-mycobacterial diynes from the Canadian medicinal plant Aralia nudicaulis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aralia nudicaulis, or wild sarsaparilla, is used as a traditional medicinal plant for the treatment of various illnesses by many of the Canadian First Nations. Iroquois and Algonquin First Nations of Eastern Canada use a tea prepared from dried Aralia nudicaulis rhizome as a cough medicine and for the treatment of tuberculosis. Previous investigations of aqueous extracts of Aralia nudicaulis rhizomes have shown it to possess antimycobacterial activity. AIM OF THE STUDY: To isolate and identify antimycobacterial constituents from Aralia nudicaulis rhizomes. MATERIALS AND METHODS: Methanolic extracts of Aralia nudicaulis rhizomes were subjected to bioassay guided fractionation using the microplate resazurin assay (MRA) to assess inhibitory activity against Mycobacterium tuberculosis strain H37Ra. The antimycobacterial constituents were identified by NMR, MS and polarimetry. RESULTS: Two C17 polyacetylenes with significant antimycobacterial activity were isolated from the Aralia nudicaulis rhizome extract. The polyacetylenes were identified as (3R)-falcarinol and (3R, 9R, 10S)-panaxydol. Falcarinol and panaxydol displayed MICs of 25.6MUM and 36.0MUM and IC(50)s of 15.3MUM and 23.5MUM against Mycobacterium tuberculosis H37Ra. CONCLUSIONS: Falcarinol and panaxydol were identified as the principal constituents responsible for the antimycobacterial activity of Aralia nudicaulis rhizomes validating an ethnopharmacological use of this plant by the Canadian First Nations. PMID- 22234261 TI - Phospholipid flippases: building asymmetric membranes and transport vesicles. AB - Phospholipid flippases in the type IV P-type ATPase family (P4-ATPases) are essential components of the Golgi, plasma membrane and endosomal system that play critical roles in membrane biogenesis. These pumps flip phospholipid across the bilayer to create an asymmetric membrane structure with substrate phospholipids, such as phosphatidylserine and phosphatidylethanolamine, enriched within the cytosolic leaflet. The P4-ATPases also help form transport vesicles that bud from Golgi and endosomal membranes, thereby impacting the sorting and localization of many different proteins in the secretory and endocytic pathways. At the organismal level, P4-ATPase deficiencies are linked to liver disease, obesity, diabetes, hearing loss, neurological deficits, immune deficiency and reduced fertility. Here, we review the biochemical, cellular and physiological functions of P4-ATPases, with an emphasis on their roles in vesicle-mediated protein transport. This article is part of a Special Issue entitled Lipids and Vesicular Transport. PMID- 22234263 TI - Expression of infectious pancreatic necrosis virus (IPNV) VP2-VP3 fusion protein in Lactobacillus casei and immunogenicity in rainbow trouts. AB - Infectious pancreatic necrosis virus (IPNV) infects wild and cultured salmonids, causing high mortality in juvenile trouts and salmons. IPNV VP2-VP3 fusion gene was constructed by splicing overlap extension (SOE) PCR and inserted into Lactobacillus/Escherichia coli shuttle vectors (pPG1and pPG2) followed by transformation of Lactobacillus casei competent cell to yield two recombinant strains: Lc:PG1-VP2-VP3 (surface-displayed) and Lc:PG2-VP2-VP3 (secretory). Subsequently, juvenile rainbow trouts were inoculated with the recombinant strains via orogastric route. Our results demonstrated that Lactobacillus-derived VP2-VP3 fusion protein could induce production of serum IgM specific for IPNV with neutralizing activity in rainbow trouts. Statistical analyses of IgM levels showed that immunogenicity of Lc:PG1-VP2-VP3 was more powerful than that of Lc:PG2-VP2-VP3 (P<0.001) in rainbow trouts. This result has been confirmed by viral loads reduction analyzed by real-time RT-PCR in orogastrically immunized rainbow trouts after virus challenging. Comparing to trouts received Lactobacillus (control), rainbow trouts orogastrically dosed with Lc:PG1-VP2-VP3 resulted in ~10-fold reduction in viral loads on day 10 post-virus challenging, and ~4-fold did by Lc:PG2-VP2-VP3. Taken together, Lc:PG1-VP2-VP3 functions as novel mucosal vaccine against IPNV infection in rainbow trouts, which most likely come true. PMID- 22234264 TI - Toward interactive, Internet-based decision aid for vaccination decisions: better information alone is not enough. AB - Vaccination decisions, as in choosing whether or not to immunize one's small child against specific diseases, are both psychologically and computationally complex. The psychological complexities have been extensively studied, often in the context of shaping convincing or persuasive messages that will encourage parents to vaccinate their children. The computational complexity of the decision has been less noted. However, even if the parent has access to neutral, accurate, credible information on vaccination risks and benefits, he or she can easily be overwhelmed by the task of combining this information into a well-reasoned decision. We argue here that the Internet, in addition to its potential as an information source, could provide useful assistance to parents in integrating factual information with their own values and preferences - that is, in providing real decision aid as well as information aid. We sketch one approach for accomplishing this by means of a hierarchy of interactive decision aids ranging from simple advice to full-scale decision analysis. PMID- 22234262 TI - Inclusion of a CRF01_AE HIV envelope protein boost with a DNA/MVA prime-boost vaccine: Impact on humoral and cellular immunogenicity and viral load reduction after SHIV-E challenge. AB - The current study assessed the immunogenicity and protective efficacy of various prime-boost vaccine regimens in rhesus macaques using combinations of recombinant DNA (rDNA), recombinant MVA (rMVA), and subunit gp140 protein. The rDNA and rMVA vectors were constructed to express Env from HIV-1 subtype CRF01_AE and Gag-Pol from CRF01_AE or SIVmac 239. One of the rMVAs, MVA/CMDR, has been recently tested in humans. Immunizations were administered at months 0 and 1 (prime) and months 3 and 6 (boost). After priming, HIV env-specific serum IgG was detected in monkeys receiving gp140 alone or rMVA but not in those receiving rDNA. Titers were enhanced in these groups after boosting either with gp140 alone or with rMVA plus gp140. The groups that received the rDNA prime developed env-specific IgG after boosting with rMVA with or without gp140. HIV Env-specific serum IgG binding antibodies were elicited more frequently and of higher titer, and breadth of neutralizing antibodies was increased with the inclusion of the subunit Env boost. T cell responses were measured by tetramer binding to Gag p11c in Mamu A*01 macaques, and by IFN-gamma ELISPOT assay to SIV-Gag. T cell responses were induced after vaccination with the highest responses seen in macaques immunized with rDNA and rMVA. Macaques were challenged intravenously with a novel SHIV-E virus (SIVmac239 Gag-Pol with an HIV-1 subtype E-Env CAR402). Post challenge with SHIV-E, antibody titers were boosted in all groups and peaked at 4 weeks. Robust T cell responses were seen in all groups post challenge and in macaques immunized with rDNA and rMVA a clear boosting of responses was seen. A greater than two-log drop in RNA copies/ml at peak viremia and earlier set point was achieved in macaques primed with rDNA, and boosted with rMVA/SHIV-AE plus gp140. Post challenge viremia in macaques immunized with other regimens was not significantly different to that of controls. These results demonstrate that a gp140 subunit and inclusion of SIV Gag-Pol may be critical for control of SHIV post challenge. PMID- 22234265 TI - Aggregate travel vs. single trip assessment: arguments for cumulative risk analysis. AB - Vaccine recommendations for travellers are based on individual risk assessments of multiple factors, most importantly the destination and duration of the impending trip. Many people undertake frequent trips, but existing WHO, CDC and national advisory board recommendations do not explicitly consider cumulative travel-associated risks. Given the period of protection provided by many vaccines, in particular rabies, hepatitis A, hepatitis B and yellow fever vaccines, an aggregate multi-trip risk assessment which views vaccines as an investment for future travel health may be more appropriate than separately evaluating the risks for each trip. PMID- 22234267 TI - Recombinant outer membrane secretin PilQ(406-770) as a vaccine candidate for serogroup B Neisseria meningitidis. AB - Secretin PilQ is an antigenically conserved outer membrane protein which is present on most meningococci. This protein naturally expressed at high levels and is essential for meningococcal pilus expression at the cell surface. A 1095 bp fragment of C-terminal of secretin pilQ from serogroup B Neisseria meningitidis was cloned into prokaryotic expression vector pET-28a. Recombinant protein was overexpressed with IPTG and affinity-purified by Ni-NTA agarose. BALB/c mice were immunized subcutaneously with purified rPilQ(406-770) mixed with Freund's adjuvant. Serum antibody responses to serogroups A and B N. meningitidis whole cells or purified rPilQ(406-770) and functional activity of antibodies were determined by ELISA and SBA, respectively. The output of rPilQ(406-770) was approximately 50% of the total bacterial proteins. Serum IgG responses were significantly increased in immunized group with PilQ(406-770) mixed with Freund's adjuvant in comparison with control groups. Antisera produced against rPilQ(406 770) demonstrated strong surface reactivity to serogroups A and B N. meningitidis tested by whole-cell ELISA. Surface reactivity to serogroup B N. meningitidis was higher than serogroup A. The sera from PilQ(406-770) immunized animals were strongly bactericidal against serogroups A and B. These results suggest that rPilQ(406-770) is a potential vaccine candidate for serogroup B N. meningitidis. PMID- 22234266 TI - Evaluation of Lassa virus vaccine immunogenicity in a CBA/J-ML29 mouse model. AB - Lassa fever (LF) is one of the most prevalent viral hemorrhagic fevers in West Africa responsible for thousands of deaths annually. The BSL-4 containment requirement and lack of small animal model to evaluate Lassa virus (LASV) specific cell-mediated immunity (CMI) complicate development of effective LF vaccines. Here we have described a CBA/J-ML29 model allowing evaluation of LASV specific CMI responses in mice. This model is based on Mopeia virus reassortant clone ML29, an attractive immunogenic surrogate for LASV. A single intraperitoneal (i.p.) immunization of CBA/J mice with ML29 protected animals against a lethal homologous intracerebral (i.c.) challenge with 588 LD(50). The ML29-immunized mice displayed negligible levels of LASV-specific antibody titers, but LASV-specific CMI responses were detectable early and peaked on day 8-10 after immunization. A T cell cytotoxicity assay in vivo showed a correlation between LASV-specific cytotoxicity and the timing of protection induced by the ML29 immunization. Notably, CBA/J mice that received CD8+ T cell-depleted splenocytes from ML29-immunized donors all succumbed to a lethal i.c. challenge, demonstrating that CD8+ T cells are critical in protection. The CBA/J-ML29 model can be useful immunological tool for the preliminary evaluation of immunogenicity and efficacy of vaccine candidates against LASV outside of BSL-4 containment facilities. PMID- 22234268 TI - Role of TLRs in Brucella mediated murine DC activation in vitro and clearance of pulmonary infection in vivo. AB - Brucellosis is worldwide zoonoses affecting 500,000 people annually with no approved human vaccines available. Live attenuated Brucella abortus vaccine strain RB51 protects cattle through CD4 and CD8 T-cell mediated responses. However, limited information is known regarding how Brucella stimulate innate immunity. Although the most critical toll like receptors (TLRs) involved in the recognition of Brucella are TLR2, TLR4 and TLR9, it is important to identify the essential TLRs that induce DC activation/function in response to Brucella, to be able to upregulate both vaccine strain RB51-mediated protection, and clearance of pathogenic strain 2308. Furthermore, in spite of the importance of aerosol transmission of Brucella, no published studies have addressed the role of TLRs in the clearance of strain 2308 or strain RB51 from intranasally infected mice. Therefore, we used a (a) bone marrow derived dendritic cell model in TLRKO and control mice to assess the differential role of pathogenic and vaccine strains to induce DC activation and function in vitro, and (b) respiratory model in TLRKO and control mice to assess the critical roles for TLRs in clearance of strains in vivo. In support of the essential TLRs in clearance and protection, we performed challenge experiments to identify if these critical TLRs (as agonists) could enhance vaccine induced protection against pathogenic strain 2308 in a respiratory model. We determined: vaccine strain RB51 induced significant (p<=0.05) DC activation vs. strain 2308 which was not dependent on a specific TLR; strain RB51 induced TNF-alpha production was TLR2 and TLR9 dependent, and IL 12 production was TLR2 and TLR4 dependent; TLR4 and TLR2 were critical for clearance of vaccine and pathogenic Brucella strains respectively; and TLR2 (p<0.05), TLR4 (p<0.05) and TLR9 (p=0.075) agonists enhanced vaccine strain RB51 mediated protection against respiratory challenge with strain 2308 in the lung. PMID- 22234270 TI - Impact of exposure to combat during deployment to Iraq and Afghanistan on mental health by gender. AB - BACKGROUND: Interest in the mental health of women deployed to modern military campaigns is increasing, although research examining gender differences is limited. Little is known about experiences women have had on these deployments, or whether men and women respond differently to combat exposure. METHOD: The current study used data from a representative sample of UK Armed Forces personnel to examine gender differences among those deployed to Iraq and Afghanistan (n=432 women, n=4554 men) in three measures of experience: 'risk to self', 'trauma to others' and 'appraisal of deployment'. We examined the impact of such experiences on post-deployment symptoms of post-traumatic stress disorder (PTSD), symptoms of common mental disorder (CMD) and hazardous alcohol use. RESULTS: After adjustment, men reported more exposure to 'risk to self' and 'trauma to others' events and more negative appraisals of their deployment. Among both genders, all measures of combat experience were associated with symptoms of PTSD and CMD (except 'risk to self' events on symptoms of CMD among women) but not with alcohol misuse. Women reported higher scores on the PTSD Checklist--Civilian Version (PCL-C) among those exposed to lower levels of each experience type but this did not hold in the higher levels. Women reported greater symptoms of CMD and men reported greater hazardous alcohol use across both levels of each experience type. Examining men and women separately suggested similar responses to exposure to adverse combat experiences. CONCLUSIONS: The current findings suggest that, although gender differences in mental health exist, the impact of deployment on mental health is similar among men and women. PMID- 22234269 TI - Bacteriophages and their implications on future biotechnology: a review. AB - Recently it has been recognized that bacteriophages, the natural predators of bacteria can be used efficiently in modern biotechnology. They have been proposed as alternatives to antibiotics for many antibiotic resistant bacterial strains. Phages can be used as biocontrol agents in agriculture and petroleum industry. Moreover phages are used as vehicles for vaccines both DNA and protein, for the detection of pathogenic bacterial strain, as display system for many proteins and antibodies. Bacteriophages are diverse group of viruses which are easily manipulated and therefore they have potential uses in biotechnology, research, and therapeutics. The aim of this review article is to enable the wide range of researchers, scientists, and biotechnologist who are putting phages into practice, to accelerate the progress and development in the field of biotechnology. PMID- 22234271 TI - Use of chlorophyll a fluorescence to detect the effect of microcystins on photosynthesis and photosystem II energy fluxes of green algae. AB - The phenomenon of cyanobacteria bloom occurs widely in lakes, reservoirs, ponds and slow flowing rivers. Those blooms can have important repercussions, at once on recreational and commercial activities but also on the health of animals and human beings. Indeed, many species are known to produce toxins which are released in water mainly at cellular death. The cyanotoxin most frequently encountered is the microcystin (MC), a hepatotoxin which counts more than 70 variants. The use of fast tests for the detection of this toxin is thus a necessity for the protection of the ecosystems and the human health. A promising method for their detection is a bioassay based on the chlorophyll a fluorescence of algae. Many studies have shown that algae are sensible to diverse pollutants, but were almost never used for cyanotoxins. Therefore, our goals were to evaluate the effect of microcystin on the fluorescence of different species of algae and how it can affect the flow of energy through photosystem II. To reach these objectives, we exposed four green algae (Scenedesmus obliquus CPCC5, Chlamydomonas reinhardtii CC125, Pseudokirchneriella subcapitata CPCC37 and Chlorella vulgaris CPCC111) to microcystin standards (variants MC-LF, LR, RR, YR) and to microcystin extracted from Microcystis aeruginosa (CPCC299), which is known to produce mainly MC-LR. Chlorophyll a fluorescence was measured by PEA (Plant Efficiency Analyzer) and LuminoTox. The results of our experiment showed that microcystins affect the photosynthetic efficiency and the flow of energy through photosystem II from 0.01 MUg/mL, within only 15 min. From exposure to standard of microcystin, we showed that MC-LF was the most potent variant, followed by MC-YR, LR and RR. Moreover, green algae used in this study demonstrated different sensitivity to MCs, S. obliquus being the more sensitive. We finally demonstrated that LuminoTox was more sensitive to MCs than parameters measured with PEA, although the latter brings indication on the mode of action of MCs at the photosynthetic apparatus level. This is the first report showing a photosynthetic response within 15 min of exposure. Our results suggest that bioassay based on chlorophyll fluorescence can be used as a rapid and sensitive tool to detect microcystin. PMID- 22234272 TI - Novel germline MSH2 mutation in lynch syndrome patient surviving multiple cancers. AB - Lynch syndrome (LS) individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers.We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear.In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up. PMID- 22234273 TI - Diesel exhaust particles and airway inflammation. AB - PURPOSE OF REVIEW: Epidemiologic investigation has associated traffic-related air pollution with adverse human health outcomes. The capacity of diesel exhaust particles (DEPs), a major emission source air pollution particle, to initiate an airway inflammation has subsequently been investigated. We review the recent controlled human exposures to diesel exhaust and DEPs, and summarize the investigations into the associations between this emission source air pollution particle and airway inflammation. RECENT FINDINGS: Using bronchoalveolar lavage, bronchial biopsies, and sputum collection, studies have demonstrated inflammation in the airways of healthy individuals after exposure to diesel exhaust and DEPs. This inflammation has included neutrophils, eosinophils, mast cells, and lymphocytes. Elevated expression and concentrations of inflammatory mediators have similarly been observed in the respiratory tract after diesel exhaust and DEP exposure. An increased sensitivity of asthmatic individuals to the proinflammatory effects of DEPs has not been confirmed. SUMMARY: Inflammation after diesel exhaust and DEP exposure is evident at higher concentrations only; there appears to be a threshold dose for DEPs approximating 300 MUg/m. The lack of a biological response to DEPs at lower concentrations may reflect a contribution of gaseous constituents or interactions between DEPs and gaseous air pollutants to the human inflammatory response and function loss. PMID- 22234274 TI - Occupational diesel exhaust exposure as a risk factor for chronic obstructive pulmonary disease. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a major source of morbidity and mortality worldwide. Although cigarette smoking is the major cause of COPD, occupational exposures have emerged as an important risk factor, especially in nonsmokers. In this review, we assess the state of the literature on the association of COPD with a specific occupational exposure, diesel exhaust. RECENT FINDINGS: A large body of literature links general occupational exposures to dust and fumes with an increased risk of COPD, particularly in nonsmokers. Few studies, however, have explicitly examined the role of occupational diesel exhaust exposures to COPD risk. Suggestive recent findings link occupational diesel exposures to an increased risk of COPD. SUMMARY: The available literature directly examining the effects of occupational diesel exhaust on risk of COPD is quite small, but does suggest that increasing exposures are associated with increasing risk. Additional research, with more advanced exposure metrics, is needed to fully elucidate this association. PMID- 22234275 TI - Hypogonadism in chronic obstructive pulmonary disease: incidence and effects. AB - PURPOSE OF REVIEW: This review summarizes the literature on hypogonadism in men with chronic obstructive pulmonary disease (COPD). RECENT FINDINGS: COPD is a systemic disease with effects beyond the lungs. Many prior studies have shown that middle-aged and elderly COPD patients may develop hypogonadism. Prevalence of hypogonadism in men with COPD can range from 22 to 69% and has been associated with several other systemic manifestations including osteoporosis, depression, and muscle weakness. Recent studies have revealed conflicting results with regards to these previous perceptions. The discrepancies in the findings can be mainly attributed to small sample size, differences in patient selection, and inconsistent findings. Testosterone replacement therapy may result in modest improvements in fat-free mass and limb muscle strength but its therapeutic efficacy in COPD patients still remains controversial. SUMMARY: The relationship between hypogonadism and COPD still remains poorly understood. The current literature is at best circumstantial. PMID- 22234276 TI - Happy hookah hour. PMID- 22234277 TI - Physical activity and weight gain prevention in older men. AB - BACKGROUND: Physical activity and adiposity are important predictors of mortality, even in older individuals. However, it is unclear how much physical activity is needed to prevent weight gain in older persons. PURPOSE: To examine the associations of different amounts of physical activity with weight gain prevention in older men. METHODS: A total of 5973 healthy men (mean age, 65.0 years) from the Harvard Alumni Health Study were followed from 1988 to 1998. At baseline (1988), in 1993 and 1998, men reported their recreational physical activity and body weight. Physical activity was categorized as: <7.5 metabolic equivalent (MET)-h per week (7.5 MET-h per week corresponds to the minimum required by the 2008 US federal guidelines), 7.5 to <21 MET-h per week (21 MET-h per week corresponds to the 2002 Institute of Medicine (IOM) guideline) and ?21 MET-h per week. Meaningful weight gain was defined as an increase of >=3% of body weight. RESULTS: Overall, weight tended to be stable over any 5-year period; mean change, -0.08 (s.d.=4.44) kg. However, ~21% of men experienced meaningful weight gain over any 5-year period. In multivariate analyses, compared with men expending >= 21 MET-h per week, those expending 7.5 to <21 MET-h per week had an odds ratio (OR) of 1.35 (95% confidence interval: 1.03, 1.77) for meaningful weight gain, and men expending <7.5 MET-h per week, an OR of 1.16 (1.01, 1.33; P trend=0.09). CONCLUSIONS: Among older men, those with lesser levels of physical activity were more likely to gain weight than men satisfying the 2002 IOM guidelines of >=21 MET-h per week (~60 min day(-1) of moderate-intensity physical activity). PMID- 22234278 TI - Location of breakfast consumption predicts body mass index change in young Hong Kong children. AB - OBJECTIVE: An association between weight gain and breakfast skipping has been reported, but breakfast location was rarely considered. We investigated the prospective associations between breakfast location, breakfast skipping and body mass index (BMI) change in a large cohort of Chinese children. DESIGN: Our baseline cohort consisted of 113,457 primary 4 (US grade 4) participants of the Hong Kong Department of Health Student Health Service in 1998-2000. Of these, 68,606 (60.5%) had complete records and were successfully followed-up 2 years later. Data on breakfast consumption and location were collected at both time points along with other lifestyle characteristics. BMI was derived from objectively measured height and weight. Associations between breakfast habits and BMI change were assessed by multivariable linear regression, adjusting for demographic, socioeconomic and lifestyle characteristics. RESULTS: At baseline, 85.3, 9.4 and 5.2% of children had breakfast at home, away from home and skipped breakfast, respectively. Prospectively, having breakfast away from home (vs at home) predicted a greater BMI increase over two years (beta = 0.15; 95% CI: 0.11 0.18). Breakfast skipping had a comparable, slightly smaller effect (0.13; 0.09 0.18). CONCLUSION: Both breakfast skipping and eating breakfast away from home predict greater increases in BMI during childhood, the effect being slightly stronger in the latter. Having breakfast, particularly at home, could have important implications for weight management and reducing obesity in children. Further research is required to gain insight into potential underlying mechanisms. PMID- 22234279 TI - Childhood psychological function and obesity risk across the lifecourse: findings from the 1970 British Cohort Study. AB - BACKGROUND: Psychological comorbidities of obesity are well recognised. However, the role of childhood psychological problems in the aetiology of later obesity has been little studied. DESIGN: Secondary analyses of a national birth cohort (1970 British Cohort Study). ANALYSIS: Logistic regression models to predict obesity risk at 26, 30 and 34 years related to hypothesised predictors: maternal and teacher reported child psychological function at 5 and 10 years (general behavioural, conduct, emotional or attentional/hyperactivity problems) and maternal psychological function. RESULTS: General behavioural problems at age 5 years increased the risk of obesity at 30 and 34 years. Persistence of these problems through childhood further increased the obesity risk. Inattention/hyperactivity at 10 years similarly increased risk of obesity at 30 years (adjusted odds ratios (AOR) 1.3). Chronic conduct problems at 5 and 10 years also increased the obesity risk at 30 years (AOR 1.6 (1.1, 2.4) P<0.05). Childhood emotional disorders and maternal psychological function were not associated with adult obesity. CONCLUSION: Children with early and persistent behavioural problems, particularly conduct problems, hyperactivity and inattention in early and mid-childhood are at an increased risk of obesity in adult life. The promotion of child and adolescent mental health and well-being may form an important part of future obesity prevention strategies. The promotion of healthy eating and activity should form part of secondary prevention and management strategies for children with disruptive behaviour disorders. PMID- 22234280 TI - Distinct associations between energy balance and the sleep characteristics slow wave sleep and rapid eye movement sleep. AB - CONTEXT: Epidemiologically, an inverse relationship between body mass index (BMI) and sleep duration is observed. Intra-individual variance in the amount of slow wave sleep (SWS) or rapid eye movement (REM) sleep has been related to variance of metabolic and endocrine parameters, which are risk factors for the disturbance of energy balance (EB). OBJECTIVE: To investigate inter-individual relationships between EB (EB= energy intake-energy expenditure?, MJ/24 h), SWS or REM sleep, and relevant parameters in normal-weight men during two 48 h stays in the controlled environment of a respiration chamber. SUBJECTS AND METHODS: A total of 16 men (age 23+/-3.7 years, BMI 23.9+/-1.9 kg m(-2)) stayed in the respiration chamber twice for 48 h to assure EB. Electroencephalography was used to monitor sleep (2330-0730 hrs). Hunger and fullness were scored by visual analog scales; mood was determined by State Trait Anxiety Index-state and food reward by liking and wanting. Baseline blood and salivary samples were collected before breakfast. Subjects were fed in EB, except for the last dinner, when energy intake was ad libitum. RESULTS: The subjects slept on average 441.8+/-49 min per night, and showed high within-subject reliability for the amount of SWS and REM sleep. Linear regression analyses showed that EB was inversely related to the amount of SWS (r=-0.43, P<0.03), and positively related to the amount of REM sleep (r=0.40, P<0.05). Relevant parameters such as hunger, reward, stress and orexigenic hormone concentrations were related to overeating, as well as to the amount of SWS and REM sleep, however, after inclusion of these parameters in a multiple regression, the amount of SWS and REM sleep did not add to the explained variance of EB, which suggests that due to their individual associations, these EB parameters are mediator variables. CONCLUSION: A positive EB due to overeating, was explained by a smaller amount of SWS and higher amount of REM sleep, mediated by hunger, fullness, State Trait Anxiety Index-state scores, glucose/insulin ratio, and ghrelin and cortisol concentrations. PMID- 22234281 TI - Vitamin D status and glucose homeostasis in obese children and adolescents living in the tropics. AB - BACKGROUND: Pediatric obesity continues to rise and has become a major health problem worldwide. Vitamin D deficiency has been increasing among obese non-Asian children and is associated with abnormal glucose homeostasis in obese adults. However, data on the vitamin D status and its association with glucose homeostasis in obese children residing in tropical Asian countries are unavailable. OBJECTIVE: To assess vitamin D status and glucose homeostasis in obese Thai children. PATIENTS AND METHODS: A total of 150 obese, and 29 healthy non-obese children and adolescents were enrolled. Weight, height, body mass index (BMI) and waist circumference were obtained. All obese children underwent an oral glucose tolerance test with glucose and insulin measurements. Plasma 25 hydroxyvitamin D (25-OHD) and calciotropic blood chemistries were measured in all participants. Insulin sensitivity indices were calculated from the measured glucose and insulin levels. RESULTS: Approximately 25% of the obese children and adolescents had impaired glucose tolerance, impaired fasting plasma glucose (FPG) and diabetes. Seventeen out of 150 (11.3%) obese children and 3 out of 29 (10.3%) non-obese children had vitamin D deficiency, which was defined as a 25-OHD level of <50 nmol l(-1). Glucose tolerance and insulin sensitivity indices were comparable between obese children with sufficient vitamin D and those with vitamin D deficiency. There were no relationships among serum 25-OHD; weight, height, and BMI standard deviation scores; insulin sensitivity indices; FPG and insulin; and 2-h plasma glucose and insulin levels. CONCLUSION: Vitamin D deficiency is not as prevalent in obese Thai children as in obese non-Asian children from high-latitude countries. Adiposity per se is unlikely to be a determinant of vitamin D status in these obese individuals. There was no association between vitamin D deficiency and abnormal glucose homeostasis. PMID- 22234283 TI - Higher-order split operator schemes for solving the Schrodinger equation in the time-dependent wave packet method: applications to triatomic reactive scattering calculations. AB - The efficiency of the numerical propagators for solving the time-dependent Schrodinger equation in the wave packet approach to reactive scattering is of vital importance. In this Perspective, we first briefly review the propagators used in quantum reactive scattering calculations and their applications to triatomic reactions. Then we present a detailed comparison of about thirty higher order split operator propagators for solving the Schrodinger equation with their applications to the wave packet evolution within a one-dimensional Morse potential, and the total reaction probability calculations for the H + HD, H + NH, H + O(2), and F + HD reactions. These four triatomic reactions have quite different dynamic characteristics and thus provide a comprehensive picture of the relative advantages of these higher-order propagation methods for describing reactive scattering dynamics. Our calculations reveal that the most often used second-order split operator method is typically more efficient for a direct reaction, particularly for those involving flat potential energy surfaces. However, the optimal higher-order split operator methods are more suitable for a reaction with resonances and intermediate complexes or a reaction experiencing potential energy surface with fluctuations of considerable amplitude. Three 4th order and one 6th-order split operator methods, which are most efficient for solving reactive scattering in various conditions among the tested ones, are recommended for general applications. In addition, a brief discussion on the relative performance between the Chebyshev real wave packet method and the split operator method is given. The results in this Perspective are expected to stimulate more applications of (high-order) split operators to the quantum reactive scattering calculation and other related problems. PMID- 22234282 TI - Children's binge eating and development of metabolic syndrome. AB - BACKGROUND: Binge eating predisposes children to excessive weight gain. However, it is unknown if pediatric binge eating predicts other obesity-associated adverse health outcomes. OBJECTIVE: The objective of this study was to investigate the relationship between binge eating and metabolic syndrome (MetS) in children. METHOD: Children aged 5-12 years at high risk for adult obesity, either because they were overweight/obese when first examined or because their parents were overweight/obese, were recruited from Washington, DC and its suburbs. Children completed a questionnaire assessment of binge eating at baseline and underwent measurements of MetS components at baseline and at a follow-up visit approximately 5 years later. Magnetic resonance imaging was used to measure the visceral adipose tissue (VAT) in a subset. RESULTS: In all, 180 children were studied between July 1996 and August 2010. Baseline self-reported binge eating presence was associated with a 5.33 greater odds of having MetS at follow-up (95% confidence interval (CI): 1.47, 19.27, P=0.01). The association between binge eating and body mass index (BMI) only partially explained changes in MetS components: baseline binge eating predicted higher follow-up triglycerides, even after accounting for baseline triglycerides, baseline BMI, BMI change, sex, race, baseline age and time in study (P = 0.05). Also, adjusting for baseline VAT and demographics, baseline binge eating predicted greater follow-up L(2-3) VAT (P = 0.01). DISCUSSION: Children's reports of binge eating predicted development of MetS, worsening triglycerides and increased VAT. The excessive weight gain associated with children's binge eating partly explained its adverse metabolic health outcomes. Reported binge eating may represent an early behavioral marker upon which to focus interventions for obesity and MetS. PMID- 22234284 TI - Cannabinoids and monoamine neurotransmission with focus on monoamine oxidase. AB - Progress in understanding the mechanisms of action of cannabinoids was made after discovery of cannabinoid receptors and finding their endogenous ligands. New findings are obtained using both endogenous cannabinoids and plant or synthetic cannabinoids. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some neurodegenerative and mental disorders. Brain monoamines are involved in many of the same processes affected by neuropsychiatric disorders and by different psychotropic drugs, including cannabinoids. Basic information is summarized in the paper about mechanisms of action of cannabinoids on monoaminergic systems, with a view to inhibition of monoamine oxidase. PMID- 22234285 TI - Conformational change opening the CFTR chloride channel pore coupled to ATP dependent gating. AB - Opening and closing of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are controlled by ATP binding and hydrolysis by its nucleotide binding domains (NBDs). This is presumed to control opening of a single "gate" within the permeation pathway, however, the location of such a gate has not been described. We used patch clamp recording to monitor access of cytosolic cysteine reactive reagents to cysteines introduced into different transmembrane (TM) regions in a cysteine-less form of CFTR. The rate of modification of Q98C (TM1) and I344C (TM6) by both [2-sulfonatoethyl] methanethiosulfonate (MTSES) and permeant Au(CN)(2)(-) ions was reduced when ATP concentration was reduced from 1mM to 10MUM, and modification by MTSES was accelerated when 2mM pyrophosphate was applied to prevent channel closure. Modification of K95C (TM1) and V345C (TM6) was not affected by these manoeuvres. We also manipulated gating by introducing the mutations K464A (in NBD1) and E1371Q (in NBD2). The rate of modification of Q98C and I344C by both MTSES and Au(CN)(2)(-) was decreased by K464A and increased by E1371Q, whereas modification of K95C and V345C was not affected. These results suggest that access from the cytoplasm to K95 and V345 is similar in open and closed channels. In contrast, modifying ATP-dependent channel gating alters access to Q98 and I344, located further into the pore. We propose that ATP-dependent gating of CFTR is associated with the opening and closing of a gate within the permeation pathway at the level of these pore-lining amino acids. PMID- 22234287 TI - Effects of high-speed power training on functional capacity and muscle performance in older women. AB - The purpose of the study was to examine the effects of 12 weeks high-speed power training on isometric contraction (handgrip strength), maximal strength (1RM), muscle power (walking velocity, counter movement jump and ball throwing) and functional tasks of the arm and leg muscles (sit-to-stand and get-up and go). Fifty-six older women were divided into an experimental group and a control group [EG, n=28, 62.5 (5.4) years; CG: n=28, 62.5 (4.3) years]. The EG was submitted to a high-speed power training that consisted of 40% of one repetition maximum (1 0.05). TPC of SM (grown in stress NaCl) containing high amounts of C-PC groups, showed strong antioxidant activity compared with ascorbic acid (standard antioxidant). Although, it activity against different free radicals were found to be variable and dose-dependent. Moreover, the TPC showed lower antimicrobial activity (MIC values in the range of 250-300 MUg mL(-1)) than that of chloramphinicol (30 MUg mL(-1), reference antimicrobial). Therefore, Spirulina maxima could be cultivated in a salinated open pond, and considered as highly healthy foods and source of natural pigments. PMID- 22234292 TI - On the analyses of fluorescence depolarisation data in the presence of electronic energy migration. Part II: Applying and evaluating two-photon excited fluorescence. AB - Electronic energy migration within a bifluorophoric molecule has been studied by time-resolved two-photon excited (TPE) fluorescence depolarisation experiments. Data were analysed by using a recently developed quantitative approach [O. Opanasyuk and L. B.-A. Johansson, On the Analyses of Fluorescence Depolarisation Data in the Presence of Electronic Energy Migration. Part I: Theory and General Description, Phys. Chem. Chem. Phys., submitted]. The energy migration occurs between the 9-anthrylmethyl groups of the bifluorophoric molecule, bis-(9 anthrylmethylphosphonate) bisteroid. These groups undergo local reorientations, while overall tumbling of the bisteroid is strongly hampered in the used viscous solvent, 1,2-propanediol. To solely obtain information about local reorientations of the 9-anthrylmethyl group, also the mono-(9-anthrylmethylphosphonate) bisteroid was studied, which enabled modelling of the ordering potential shape. The analysis of data is partly performed in the Fourier domain and the best-fit parameters are determined by using an approach based on a Genetic Algorithm. The energy migration process was described by an extended Forster theory (EFT). A reasonable value of the distance between the 9-anthrylmethyl groups, as well as for the mutual orientation of the ordering potentials, is found. Furthermore, values of the two-photon tensor components were obtained. PMID- 22234293 TI - Autologous Descemet membrane endothelial keratoplasty. PMID- 22234290 TI - CM156, a sigma receptor ligand, reverses cocaine-induced place conditioning and transcriptional responses in the brain. AB - Repeated exposure to cocaine induces neuroadaptations which contribute to the rewarding properties of cocaine. Using cocaine-induced conditioned place preference (CPP) as an animal model of reward, earlier studies have shown that sigma (sigma) receptor ligands can attenuate the acquisition, expression and reactivation of CPP. However, the underlying molecular mechanisms that are associated with these changes are not yet understood. In the present study, CM156, a novel antagonist with high selectivity and affinity for sigma receptors was used to attenuate the expression of cocaine-induced CPP in mice. Immediately following the behavioral evaluations, mouse brain tissues were collected and alterations in gene expression in half brain samples were profiled by cDNA microarray analysis. Microarray data was analyzed by three distinct normalization methods and four genes were consistently found to be upregulated by cocaine when compared to saline controls. Each of these gene changes were found by more than one normalization method to be reversed by at least one dose of CM156. Quantitative real time PCR confirmed that a single administration of CM156 was able to reverse the cocaine-induced increases in three of these four genes: metastasis associated lung adenocarcinoma transcript 1 (malat1), tyrosine 3 monooxygenase/tryptophan 5-monooxygenase activation protein (ywhaz), and transthyretin (ttr). These genes are involved in processes related to neuroplasticity and RNA editing. The data presented herein provides evidence that pharmacological intervention with a putative sigma receptor antagonist reverses alterations in gene expression that are associated with cocaine-induced reward. PMID- 22234294 TI - Microbial production of levansucrase for synthesis of fructooligosaccharides and levan. AB - A newly isolated thermophilic bacterial strain from Tunisian thermal source was identified as Bacillus sp. and was selected for its ability to produce extracellular levansucrase. Following the optimization of carbon source, nitrogen source, temperature and initial pH of the growth medium in submerged liquid cultures. In fact, sucrose was found to be a good inducer of levansucrase enzymes. The optimal temperature and pH of the levansucrase were 50 degrees C and 6.5, respectively and its activity increased four folds in the presence of 50mM Fe(2+). This enzyme exhibited a remarkable stability and retained 100% of its original activity at 50 degrees C for more than 1h at pH 6.5. The half-life of the enzyme was 1h at 90 degrees C. Crude enzyme of Bacillus sp. rich in levansucrase was established for the synthesis of fructooligosaccharides and levan. Bacillus sp. could therefore be considered as a satisfactory and promising producer of thermostable levansucrases. Contrary to other levansucrases, the one presented in the current study was able to produce high levels of levan with high molecular weight at 50 degrees C and having an important effect as a hypoglycemic agent which was demonstrated in our previous publications (Dahech et al., 2011 [25]) and as a hypo-cholesterolemic agent which will be investigated in further research. PMID- 22234295 TI - Synthesis of lauryl grafted sodium alginate and optimization of the reaction conditions. AB - Lauryl grafted sodium alginate (SA-C(12)) was prepared by the reaction between sodium alginate and dodecanol with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) as a coupling agent. The structure of SA-C(12) was confirmed by FT-IR, (1)H NMR, and thermoanalysis. Meantime, the degree of substitution (DS) of SA-C(12) was determined by GC. The reaction conditions were studied systematically, which included reaction time and temperature, the molar ratio of hexuronic acid in alginate to dodecanol (N(hexuronic)/N(dodecanol)) and N(hexuronic)/N(EDC), the mass of toluenesulfonic acid. By investigating the relationship between these conditions and DS, the optimal conditions with the maximum DS were obtained. PMID- 22234296 TI - Preparation and characterization of chitosan-carbon nanotube scaffolds for bone tissue engineering. AB - In recent years, significant development has been given to chitosan for orthopedic application. In this study, we have prepared scaffolds with the use of low and high molecular weight chitosan with 0.0025%, 0.005% and 0.01% weight of f multiwalled carbon nanotube (f-MWCNT) by freezing and lyophilization method and physiochemically characterized as bone graft substitutes. Fourier Transform Infrared Spectroscopy, X-Ray Diffraction Analysis, Thermal Gravimetric Analysis, Scanning Electron Microscopy and Optical Microscopy results indicated that the f MWCNT was uniformly dispersed in chitosan matrix and there was a chemical interaction between chitosan and f-MWCNT. The water uptake ability and porosity of scaffolds increased with an increase the amount of f-MWCNT. The cell proliferation, protein content, alkaline phosphatase and mineralization of the composite scaffolds were higher than chitosan scaffold due to the addition of f MWCNT. Herewith, we are suggesting that chitosan/f-MWCNT scaffolds are promising biomaterials for bone tissue engineering. PMID- 22234297 TI - Lanostane-type triterpenes from the sporoderm-broken spores of Ganoderma lucidum. AB - PMID- 22234298 TI - Jogyamycin, a new antiprotozoal aminocyclopentitol antibiotic, produced by Streptomyces sp. a-WM-JG-16.2. PMID- 22234299 TI - Cytochalasans with different amino-acid origin from the plant endophytic fungus Trichoderma gamsii. PMID- 22234300 TI - Virgaricin produced by Virgaria sp. FKI-4860. PMID- 22234301 TI - Constrained alpha/gamma-peptides: a new stable extended structure in solution without any hydrogen bond and characterized by a four-fold symmetry. AB - Small alpha/gamma-peptides alternating alpha-aminoisobutyric acid and cyclic gamma-amino acid residues are described. NMR studies together with restrained simulated annealing revealed that an extended backbone conformation largely dominates in solution for as short as 4-residues long oligomers. This new fold type is devoid of any hydrogen bond and characterized by a four-fold symmetry. PMID- 22234302 TI - Temperature profoundly affects ataxin-3 fibrillogenesis. AB - Ataxin-3 (AT3) triggers spinocerebellar ataxia type 3 when it carries a polyglutamine stretch expanded beyond a critical threshold. By Fourier transform infrared spectroscopy and atomic force microscopy we previously showed that a normal (AT3Q24) and an expanded (AT3Q55) variant were capable of evolving into oligomers and protofibrils at 37 degrees C, whereas only the expanded form generated irreversibly aggregated fibrils that also were associated with a network of side-chain glutamine hydrogen bonding [Natalello et al. (2011) PLoS One. 6:e18789]. We report here that AT3Q24, when gradually heated up to 85 degrees C, undergoes aggregation similar to that observed at 37 degrees C; in contrast, AT3Q55 only generates large, amorphous aggregates. We propose a possible interpretation of the mechanism by which temperature affects the outcome of fibrillogenesis. PMID- 22234303 TI - Regulation of gene expression and the transcription factor cycle hypothesis. AB - Post-genomic data show unexpected extent of the transcribed genome and the size of individual primary transcripts. Hence, most cis-regulatory modules (CRMs) binding transcription factors (TFs) at promotor, enhancer and other sites are actually transcribed within full domain transcripts (FDTs). The ensemble of these CRMs placed way upstream of exon clusters, downstream and in intronic or intergenic positions represent a program of gene expression which has been formally analysed within the Gene and Genon concept [1,2]. This concept has emphasised the necessity to separate product information from regulative information to allow information-theoretic analysis of gene expression. Classically, TFs have been assumed to act at DNA level exclusively but evidence has accumulated indicating eventual post-transcriptional functions. The transcription factor cycle (TFC) hypothesis suggests the transfer of DNA-bound factors to nascent RNA. Exerting downstream functions in RNA processing and transport, these factors would be liberated by RNA processing and cycle back to the DNA maintaining active transcription. Sequestered on RNA in absence of processing they would constitute a negative feedback loop. The TFC concept may explain epigenetic regulation in mitosis and meiosis. In mitosis control factors may survive as single proteins but also attached to FDTs as organised complexes. This process might perpetuate in cell division conditioning of chromatin for transcription. As observed on lampbrush chromosomes formed in avian and amphibian oogenesis, in meiosis the genome is fully transcribed and oocytes conserve high Mr RNA of high sequence complexity. When new interphase chromosomes form in daughter cells and early embryogenesis, TFs and other factors attached to RNA might be reinserted onto the DNA. PMID- 22234304 TI - Mesenchymal stem cell isolation and characterization from human spinal ligaments. AB - Mesenchymal stem cells (MSCs) have a fibroblast-like morphology, multilineage potential, long-term viability and capacity for self-renewal. While several articles describe isolating MSCs from various human tissues, there are no reports of isolating MSCs from human spinal ligaments, and their localization in situ. If MSCs are found in human spinal ligaments, they could be used to investigate hypertrophy or ossification of spinal ligaments. To isolate and characterize MSCs from human spinal ligaments, spinal ligaments were harvested aseptically from eight patients during surgery for lumbar spinal canal stenosis and ossification of the posterior longitudinal ligament. After collagenase digestion, nucleated cells were seeded at an appropriate density to avoid colony-to-colony contact. Cells were cultured in osteogenic, adipogenic or chondrogenic media to evaluate their multilineage differentiation potential. Immunophenotypic analysis of cell surface markers was performed by flow cytometry. Spinal ligaments were processed for immunostaining using MSC-related antibodies. Cells from human spinal ligaments could be extensively expanded with limited senescence. They were able to differentiate into osteogenic, adipogenic or chondrogenic cells. Flow cytometry revealed that their phenotypic characteristics met the minimum criteria of MSCs. Immunohistochemistry revealed the localization of CD90-positive cells in the collagenous matrix of the ligament, and in adjacent small blood vessels. We isolated and expanded MSCs from human spinal ligaments and demonstrated localization of MSCs in spinal ligaments. These cells may play an indispensable role in elucidating the pathogenesis of numerous spinal diseases. PMID- 22234305 TI - Apoptosis inducer NGFI-B is degraded by the proteasome and stabilized by treatment with EGF. AB - NGFI-B is a nuclear receptor and immediate early gene that is upregulated in many different tumour cell lines. As it is involved in cell death and survival, it has been suggested as a target for anti-cancer drugs. The protein level of NGFI-B is important for its functions and may be regulated through induction or stabilization. NGFI-B protein stability was studied using the protein synthesis inhibitor cycloheximide in CV1 cells transiently transfected with NGFI-B. Inhibiting the proteasome with MG132 stabilized NGFI-B, indicating that the proteasome is responsible for break-down of NGFI-B, as it is for many nuclear receptors. In order to determine regions responsible for the break-down of NGFI-B two N-terminal regions with high PEST-scores were deleted. Deletion of amino acids 122-195 containing a PEST-sequence which includes an ERK2 phosphorylation target, gave a more stable protein. In addition, treatment of the cells with the ERK2 activator EGF increased the stability of wild type NGFI-B. We then tested whether a mutation at threonine 142 influenced the stability of NGFI-B. We found that the phosphorylation-mimicking mutant NGFI-B T142E had an increased stability, while the non-phosphorylable mutant (T142A) showed similar stability to the wild type. Thus, EGF-stimulation of cells may be a mechanism for priming the cells for effects of NGFI-B by increasing its stability. PMID- 22234306 TI - Vibrio vulnificus AphB is involved in interleukin-8 production via an NF-kappaB dependent pathway in human intestinal epithelial cells. AB - We previously reported that the aphB gene mutant of Vibrio vulnificus had significantly impaired motility and adherence to host cells. In this study, we investigated the role of V. vulnificus AphB on the production of interleukin-8 (IL-8), a proinflammatory cytokine, as well as its underlying mechanism in human intestinal epithelial INT-407 cells. The aphB gene mutation significantly reduced the ability of V. vulnificus to stimulate IL-8 production and IL-8 gene promoter activation in INT-407 cells. The V. vulnificusaphB mutant also induced lower levels of NF-kappaB DNA binding activity and NF-kappaB minimal promoter activation than did the wild-type of V. vulnificus. Importantly, the observed reductions in IL-8 production, IL-8 gene promoter activation and NF-kappaB DNA binding activity were significantly restored by complementing the aphB gene into the V. vulnificusaphB mutant. These results indicate that V. vulnificus AphB is involved in the IL-8 production via an NF-kappaB dependent pathway in human intestinal epithelial cells. PMID- 22234307 TI - Human hepatitis B viral e antigen and its precursor P20 inhibit T lymphocyte proliferation. AB - The hepatitis B virus (HBV) Precore protein is processed through the secretory pathway directly as HBeAg or with the generation of an intermediate (P20). Precore gene has been shown to be implicated in viral persistence, but the functions of HBeAg and its precursors have not been fully elucidated. We show that the secreted proteins HBeAg and P20 interact with T cell surface and alter Kit-225 and primary T cells proliferation, a process which may facilitate the establishment of HBV persistence. Our data indicate that the N-terminal end of Precore is important for these inhibitory effects and exclude that they are dependent on the association of HBeAg and P20 with two characterized cell surface ligands, the Interleukin-1 Receptor Accessory Protein and gC1qR (present study). PMID- 22234308 TI - POTE protein, a cancer-testis antigen, is highly expressed in spermatids in human testis and is associated with apoptotic cells. AB - The POTE gene family encodes very closely related proteins that are highly expressed in testis and in many cancers. Recent studies indicate that the POTE proteins have a pro-apoptotic function. To examine if POTE is associated with cells that are undergoing apoptosis in testis, we determined the cellular location of POTE and of Cleaved Caspase-3 in testicular tissues from 26 azoospermic men. We found intense expression of POTE in round spermatids that are undergoing apoptosis, which are positive for Cleaved Caspase-3. This study suggests POTE may have a role in apoptosis in the human testis. PMID- 22234309 TI - Macrophage expression of LRP1, a receptor for apoptotic cells and unopsonized erythrocytes, can be regulated by glucocorticoids. AB - Macrophage phagocytosis of apoptotic cells, or unopsonized viable CD47(-/-) red blood cells, can be mediated by the interaction between calreticulin (CRT) on the target cell and LDL receptor-related protein-1 (LRP1/CD91/alpha2-macroglobulin receptor) on the macrophage. Glucocorticoids (GC) are powerful in treatment of a range of inflammatory conditions, and were shown to enhance macrophage uptake of apoptotic cells. Here we investigated if the ability of GC to promote macrophage uptake of apoptotic cells could in part be mediated by an upregulation of macrophage LRP1 expression. Using both resident peritoneal and bone marrow derived macrophages, we found that the GC dexamethasone could dose- and time dependently increase macrophage LRP1 expression. The GC receptor-inhibitor RU486 could dose-dependently prevent LRP1 upregulation. Dexamethasone-treated macrophages did also show enhanced phagocytosis of apoptotic thymocytes as well as unopsonized viable CD47(-/-) red blood cells, which was sensitive to inhibition by the LRP1-agonist RAP. In conclusion, these data suggest that GC stimulated macrophage uptake of apoptotic cells may involve an upregulation of macrophage LRP1 expression and enhanced LRP1-mediated phagocytosis. PMID- 22234310 TI - Protein misfolding, mitochondrial dysfunction and muscle loss are not directly dependent on soluble and aggregation state of mSOD1 protein in skeletal muscle of ALS. AB - Mutant superoxide dismutase 1 (mSOD1) is often found as aggregates at the outer membrane of mitochondria in motor neurons of various mouse models and familial amyotrophic lateral sclerosis (f-ALS) patients. It has been postulated that disruption of mitochondrial function by physical association of misfolded mSOD1 aggregates may actually be the trigger for initiation of degeneration of motor neurons in ALS. However, it was not clear if the same mechanism is involved in muscle degeneration and mitochondrial dysfunction in skeletal muscles of ALS. Recent study from our laboratory show that two skeletal muscle proteins, namely creatine kinase (CK) and glyceraldehydes-3-phosphate dehydrogenase (GAPDH) undergo major conformational and functional changes in the f-ALS mouse model of ALS (G93A). In this paper, we report two intriguing observations which are as follows:(i) G93A protein does not form aggregates in skeletal muscle at any stages of disease process probably due to high chymotrypsin-like activity of proteasome and thus G93A protein aggregates have no direct effects on progressive loss of muscle mass and global changes in protein conformation in ALS, and (ii) the soluble G93A protein does not have direct effects on mitochondrial dysfunction as determined by quantifying the release of reactive oxygen species (ROS) in skeletal muscle mitochondria; instead, the proteins affected by G93A possibly affect mitochondrial ROS release. These data strongly suggest for the first time that unlike in motor neurons, the soluble and aggregation states of the G93A protein do not have direct effects on protein misfolding and mitochondrial dysfunction in skeletal muscle during ALS. PMID- 22234311 TI - Optical and electrical applications of ZnS(x)Se(1-x) nanowires-network with uniform and controllable stoichiometry. AB - Single crystalline ternary ZnS(x)Se(1-x) nanowires with uniform chemical stoichiometry and accurately controllable compositions (0<=x<= 1) were synthesized through a simple and yet effective one-step approach with a specially designed modification. Energy-gap-tuning via compositional change was achieved for a direct band gap from 2.6 to 3.6 eV. Raman spectroscopy studies revealed typical two-mode behavior indicative of high miscibility in the alloyed compound. Moreover, the enhanced electrical-conductivity and gating effect behavior after the formation of ternary alloy enable their application in nano/micro-field effect transistor devices. In addition, the slow recombination rate in the photo response process indicates their potential for photoelectric applications. PMID- 22234313 TI - Prothrombin complex concentrate-related thrombotic risk following anticoagulation reversal. PMID- 22234312 TI - A review of the two major regulatory pathways for non-proprietary low-molecular weight heparins. AB - With the expiry or pending expiry of originator low-molecular-weight heparin (LMWH) patents, pharmaceutical companies have invested in developing non proprietary versions of LMWHs. LMWHs are manufactured by depolymerising highly purified unfractionated heparin. In contrast to traditional synthetic drugs with well-defined chemical structures, LMWHs contain complex oligosaccharide mixtures and the different manufacturing processes for LMWHs add to the heterogeneity in their physicochemical properties such that the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) consider existing originator LMWHs to be distinct medicinal entities that are not clinically interchangeable. The FDA views LMWHs as drugs and has approved two non-proprietary (generic) LMWHs, using the Abbreviated New Drug Application pathway. In contrast, the World Health Organization and the EMA view LMWHs as biological medicines. Therefore, the EMA and also the Scientific and Standardization Subcommittee on Anticoagulation of the International Society on Thrombosis and Haemostasis and the South Asian Society of Atherosclerosis and Thrombosis have all published specific guidelines for assessing non-proprietary (biosimilar) LMWHs. This manuscript reviews why there are two distinct pathways for approving non-proprietary LMWHs. Available literature on non-proprietary LMWHs approved in some jurisdictions is also reviewed in order to assess whether they satisfy the requirements for LMWHs in the three guidance documents. The review also highlights some of the significant difficulties the two pathways pose for manufacturers and an urgent need to develop a consensus governing the manufacture and regulation of non-proprietary LMWHs to make them more widely available. PMID- 22234314 TI - Rescue splenectomy in a case of humoral rejection in ABO-incompatible simultaneous liver-kidney transplantation. PMID- 22234315 TI - Calcium channel blockers or angiotensin-converting enzyme inhibitors for de novo hypertension after liver transplant: and the winner is ...? PMID- 22234316 TI - Primary hepatic leiomyoma in a transplant patient: characterization with magnetic resonance imaging. PMID- 22234317 TI - Detection and quantification of major toxigenic Microcystis genotypes in Moo-Tan reservoir and associated water treatment plant. AB - Two molecular methods, denaturing gradient gel electrophoresis (DGGE) and quantitative real-time polymerase chain reaction (qPCR) with the Universal ProbeLibrary (UPL) probe, were developed and used for the characterization and quantification of several microcystin producers in Moo-Tan Reservoir (MTR), Taiwan and its associated water treatment plant (Shih-Men Water Treatment Plant, SMWTP). Internal transcribed spacer (ITS) sequence, a highly diversified region between the 16S rRNA and 23S rRNA genes, was used to further identify the isolated strains from MTR and also used in DGGE for the detection of the specific DNA fragments and biomarkers for 11 strains observed in MTR. These ITS-DGGE biomarkers were successfully applied to monitor the community changes of potential toxigenic Microcystis sp. over a period of five years. Two highly specific primers were combined with UPL probes to measure microcystins synthesis gene (mcyB) and phycocyanin intergenic spacer region (cpcB) concentrations in water samples. The copy concentrations of UPL-mcyB and UPL-cpcB correlated well with MC-RR concentrations/water temperature and Microcystis sp. cell numbers in the water samples, respectively. For SMWTP, toxin concentrations were low, but the DGGE bands clearly demonstrated the presence of potential microcystin producers in both water treatment plants and finished water samples. It was demonstrated that toxigenic Microcystis sp. may penetrate through the treatment processes and pose a potential risk to human health in the drinking water systems. PMID- 22234318 TI - Comparing the content of instruments assessing environmental factors using the International Classification of Functioning, Disability and Health. AB - PURPOSE: To describe and compare the content of instruments that assess environmental factors using the International Classification of Functioning, Disability and Health (ICF). METHODS: A systematic search of PubMed, CINAHL and PEDro databases was conducted using a pre-determined search strategy. The identified instruments were screened independently by two investigators, and meaningful concepts were linked to the most precise ICF category according to published linking rules. RESULTS: Six instruments were included, containing 526 meaningful concepts. Instruments had between 20% and 98% of items linked to categories in Chapter 1. The highest percentage of items from one instrument linked to categories in Chapters 2-5 varied between 9% and 50%. The presence or absence of environmental factors in a specific context is assessed in 3 instruments, while the other 3 assess the intensity of the impact of environmental factors. DISCUSSION: Instruments differ in their content, type of assessment, and have several items linked to the same ICF category. Most instruments primarily assess products and technology (Chapter 1), highlighting the need to deepen the discussion on the theory that supports the measurement of environmental factors. This discussion should be thorough and lead to the development of methodologies and new tools that capture the underlying concepts of the ICF. : PMID- 22234319 TI - Perceived occupational gaps one year after stroke: an explorative study. AB - OBJECTIVE: To explore and describe factors associated with occupational gaps and to identify factors at 3 months that predict occupational gaps one year post stroke. A gap, a restriction in participation, is considered to be present when there is a discrepancy between what the individual wants to do and what they actually do in everyday life. DESIGN: Prospective longitudinal study. SUBJECTS: Two hundred persons with stroke. METHODS: Data from the Occupational Gaps Questionnaire, one year post-stroke, was used as the dependent variable in 3- and 12-month regression analyses. Domains of the Stroke Impact Scale, global life satisfaction, demographic and medical factors were used as independent variables. RESULTS: At 3 months, activities of daily living abilities, social participation and not being born in Sweden predicted occupational gaps at 12 months. Stroke severity and not being born in Sweden and 3 factors at 12 months: social participation, self-rated recovery, and global life satisfaction were associated with occupational gaps. CONCLUSION: Activities of daily living ability at 3 months predicted occupational gaps after stroke. Thus, it is possible to identify early on, and provide interventions for, those that risk participation restrictions. Not being born in the country might be an indicator of a risk for participation restrictions. PMID- 22234320 TI - Walkway lengths for measuring walking speed in stroke rehabilitation. AB - OBJECTIVES: To investigate the effect of walkway length (5, 8 or 10 m) on measurements of comfortable and maximum walking speed. DESIGN: A cross-sectional study. SETTING: University-based rehabilitation centre. SUBJECTS: Patients (n = 25) with chronic stroke. METHODS: Timed walking with different walkway lengths (5, 8 and 10 m) walkways were recorded using a stop-watch. RESULTS: No significant effect of walkway length was found on either the comfortable or maximum walking speed in subjects with chronic stroke. For all walkway lengths, comfortable speed was significantly different from maximum speed (p<0.001). CONCLUSION: There is no significant effect of walkway length (5, 8 and 10 m) on either comfortable or maximum walking speed. Different walkway lengths can yield consistent results in measuring gait speed clinically. A 5-m walkway with standardized 2-m acceleration and deceleration distances is recommended as it occupies the least space and imposes less stress on subjects. PMID- 22234321 TI - Comparison of functional exercise capacity, pulmonary function and respiratory muscle strength in patients with multiple sclerosis with different disability levels and healthy controls. AB - OBJECTIVE: To compare functional exercise capacity, pulmonary function and respiratory muscle strength in fully ambulatory patients with multiple sclerosis with different disability levels and healthy controls, and to elucidate the determinant factors of functional exercise capacity. METHODS: Forty-three fully ambulatory patients with multiple sclerosis and 30 healthy controls were included in the study. Patients were grouped according to Expanded Disability Status Scale (EDSS); Group I (EDSS 0-2), Group II (EDSS 2.5-4.5). Functional exercise capacity was evaluated using a six-minute walk test, and measurement of pulmonary function, and maximal inspiratory and expiratory pressures (MIP, MEP). The Pulmonary Index was used as a clinical predictor of respiratory dysfunction. RESULTS: Respiratory muscle strength was lower in multiple sclerosis groups compared with controls, but the difference in MIP and %MIP did not reach statistical significance in Group I. The six-minute walk test distance was significantly shorter and peak expiratory flow was lower in multiple sclerosis groups (p < 0.05). Of the variance in the six-minute walk test distance, 75% was explained by EDSS (R2 = 0.55, p < 0.001), difference in heart rate (R2 = 0.06, p = 0.007), age (R2 = 0.05, p = 0.009) and gender (R2 = 0.09, p = 0.003). CONCLUSION: Respiratory muscles are weakened, functional exercise capacity is reduced and pulmonary function is affected even in the early phase of multiple sclerosis. Ambulatory patients with multiple sclerosis who have a higher level of disability have lower pulmonary function, respiratory muscle strength and functional capacity than less disabled ones and controls. Neurological disability level, age, gender and heart rate difference on exertion are the determinants of functional exercise capacity. PMID- 22234322 TI - Cognitive behavioural therapy in multiple sclerosis: a randomized controlled pilot study of acceptance and commitment therapy. AB - OBJECTIVE: The aim of this study was to design a trial that could evaluate the effect of acceptance and commitment therapy as a group-intervention for multiple sclerosis patients with psychological distress. DESIGN: Randomized controlled trial with assessment at pretreatment, end of treatment, and at 3-month follow up. SUBJECTS: Multiple sclerosis outpatients with elevated symptoms of anxiety and/or depression (n = 21). METHODS: Patients were randomly assigned to acceptance and commitment therapy or relaxation training. Both treatments consisted of 5 sessions over 15 weeks containing didactic sessions, group discussions, and exercises. Outcome was assessed by self-rated symptoms of anxiety, depression, and a measure of acceptance. RESULTS: At 3-month follow-up, the relaxation training group had a significant decline in anxiety symptoms whereas the acceptance and commitment therapy group showed a maintained improvement in rated acceptance at follow-up. CONCLUSION: The results reflect the different emphases of the therapies. Acceptance and commitment therapy is aimed at living an active, valued life and increasing acceptance, while relaxation training focuses directly on coping strategies to handle emotional symptoms. The results are preliminary, but supportive of further study of brief group interventions for reducing psychological distress in patients with multiple sclerosis. PMID- 22234323 TI - Commentary on "Past and present issues in Rasch analysis: the FIM revisited". PMID- 22234325 TI - Influence of gastric digestive reaction on subsequent in vitro intestinal digestion of sodium caseinate-stabilized emulsions. AB - In this study, in vitro intestinal lipid digestion and the physicochemical and microstructural changes of sodium caseinate-stabilized emulsions were examined after the emulsions had been digested in a model simulated gastric fluid containing pepsin for different times. The average size, size distribution, microstructure, proteolysis of interfacial proteins and lipolysis of the emulsion droplets were monitored as a function of digestion time. The emulsion droplets underwent extensive droplet flocculation, with some coalescence together with proteolysis of interfacial proteins, in simulated gastric fluid, resulting in changes in the droplet size and the microstructure of the emulsions. In general, digestion in simulated gastric fluid containing pepsin accelerated coalescence of the emulsion droplets during subsequent digestion in simulated intestinal fluid containing pancreatic lipase. However, the changes in the size, the microstructure and the proteolysis of the interfacial proteins of the emulsions under gastric conditions did not influence the rate and the extent of lipid digestion in the subsequent intestinal environment. PMID- 22234327 TI - Exploring similarities in reactivity of superatom species: a combined theoretical and experimental investigation. AB - The replacement of group 10-based materials by superatoms has gained great attention due to studies presenting similarities in electronic character and reactive nature between pairs. The current study extends the concept to systems of larger and varied composition as the pairs PdO(+) and ZrO(2)(+) as well as NiO(+) and TiO(2)(+) are interacted with C(2)H(4) and CO through DFT calculations and guided-ion-beam mass spectrometry. It is determined that the pairs readily oxidize C(2)H(4) while oxygen transfer is limited towards CO. Interestingly, within the reaction profiles for oxidation of C(2)H(4) by PdO(+) and NiO(+), a spin crossover is observed which greatly increases the exothermicity of the process. This investigation presents a major step in identifying replacements for expensive group 10 metals in catalytic materials. PMID- 22234326 TI - Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. AB - Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1, STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites. PMID- 22234328 TI - One-dimensional confinement of a nanosized metal organic framework in carbon nanofibers for improved gas adsorption. AB - The loading of a Zn-terephthalate based MOF in the inner cavity as well as on the outer walls of a hollow carbon nanofiber (CNF) creates MOF@CNF hybrids. This hybrid ''MOF@CNF'' displayed improved thermal stability as well as gas adsorption compared to the individual counterparts. PMID- 22234329 TI - Effects of a novel amiodarone-like compound SAR114646A on the pig atrium and susceptibility to ventricular fibrillation in dogs and pigs. AB - Amiodarone is one of the most effective antiarrhythmic drugs. However, poor solubility of this compound has limited its intravenous application. SAR11464A is a water-soluble amiodarone-like drug that lacks iodine and inhibits multiple cardiac ion channels in vitro. This study evaluated the antiarrhythmic efficacy of this drug in vivo. In porcine studies, atrial effective refractory period (AERP) was measured in pentobarbital-anesthetized thoracotomized pigs and atrial fibrillation (AF) was induced by a premature beat. Ventricular fibrillation (VF) was induced via either burst pacing or programmed electrical stimulation (a series of progressively shorter beats, S1-S5). In canine studies, VF was induced by a 2-min occlusion of the left circumflex coronary artery during the last minute of exercise in dogs with healed myocardial infarctions (n = 8). One week later, this test was repeated after pretreatment with SAR114646A (3.0 mg/kg, i.v., slow bolus). SAR114646A produced a significant dose-dependent prolongation of AERP, inhibited AF induced by a premature stimulus, and electrically induced VF in anesthetized pigs. At 1.0 and 3.0 mg/kg, i.v., it was superior to amiodarone, dofetilide, and flecainide. In dogs, SAR114646A did not alter any ECG parameter including QTc (control, 236.9 +/- 8.5 ms vs. SAR, 237.2 +/- 3.5 ms) but significantly reduced the incidence of VF, protecting six of eight animals (Fisher's exact test, P = 0.01). SAR114646A was effective against both atrial and ventricular arrhythmias without altering ventricular repolarization. These data suggest that the amiodarone-like drug SAR114646A may be an effective antiarrhythmic intervention that does not adversely prolong ventricular repolarization. PMID- 22234330 TI - Substrate inhibition and allosteric regulation by heparan sulfate of Trypanosoma brucei cathepsin L. AB - The cysteine protease brucipain is an important drug target in the protozoan Trypanosoma brucei, the causative agent of both Human African trypanosomiasis and Animal African trypanosomiasis. Brucipain is closely related to mammalian cathepsin L and currently used as a framework for the development of inhibitors that display anti-parasitic activity. We show that recombinant brucipain lacking the C-terminal extension undergoes inhibition by the substrate benzyloxycarbonyl FR-7-amino-4-methylcoumarin at concentrations above the K(m), but not by benzyloxycarbonyl-VLR-7-amino-4-methylcoumarin. The allosteric modulation exerted by the substrate is controlled by temperature, being apparent at 25 degrees C but concealed at 37 degrees C. The behavior of the enzyme in vitro can be explained by discrete conformational changes caused by the shifts in temperature that render it less susceptible to substrate inhibition. Enzyme inhibition by the di peptydyl substrate impaired the degradation of human fibrinogen at 25 degrees C, but not at 37 degrees C. We also found that heparan sulfate acts as a natural allosteric modulator of the enzyme through interactions that prevent substrate inhibition. We propose that brucipain shifts between an active and an inactive form as a result of temperature-dependent allosteric regulation. PMID- 22234331 TI - Stereoisomers ginsenosides-20(S)-Rg3 and -20(R)-Rg3 differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma. AB - Ginsenosides are considered the major constituents that are responsible for most of the pharmacological actions of ginseng. However, some ginsenosides exist as stereoisomeric pairs, detailed and molecular exposition based on the structural differences of ginsenoside stereoisomers has not been emphasized in most studies. Here we explore the functional differences of ginsenoside Rg3 stereoisomers on angiogenesis. In this study, we demonstrated the distinctive differential angiogenic activities of 20(S)-Rg3 and 20(R)-Rg3 stereoisomers. 20(S)-Rg3 at micromolar concentration promotes human endothelial cells proliferation, migration and tube formation in vitro, as well as ex vivo endothelial sprouting. The effects induced by 20(S)-Rg3 are significantly more potent than 20(R)-Rg3. These effects are partially mediated through the activation of AKT/ERK-eNOS signaling pathways. Moreover, knockdown of peroxisome proliferator-activated receptor-gamma (PPARgamma) by specific small interference RNA abolished the 20(S) Rg3-induced angiogenesis, indicating that PPARgamma is responsible for mediating the angiogenic activity of Rg3. Using reporter gene assay, the PPARgamma agonist activity of 20(S)-Rg3 has been found 10-fold higher than that of 20(R)-Rg3. Computer modeling also revealed the differential binding is due to the chiral center of 20(S)-Rg3 can form a critical hydrogen bond with Tyr473 of PPARgamma ligand binding domain. The present study elucidated the differential angiogenic effects of Rg3 stereoisomers by acting as agonist of PPARgamma. The results shed light on the structural difference between two ginsenoside stereoisomers that can lead to significant differential physiological outcomes which should be carefully considered in the future development of ginsenoside-based therapeutics. PMID- 22234332 TI - Modelling very large magnetoresistance of graphene nanoribbon devices. AB - We model a very large, tunable magnetoresistance (MR) in a graphene nanoribbon field-effect transistor, without artificial engineering of ferromagnetic contacts. A high MR of nearly 100% (about 50%) is obtained at low temperature (room temperature). We show that the MR ratio can be further tuned by using conventional electric field, in agreement with a recent experiment. The simulation results indicate that the large MR of GNRs stems from reduction of the bandgap of GNRs in the presence of applied magnetic field related to the 0(th) Landau level in graphene. Interestingly, in a more realistic device with edge roughness, the MR ratio is not degraded but rather enhanced, caused by the magnetic field induced spatial separation of the transport states. The large, tunable MR of GNRs resistant to edge roughness is attractive to device applications. PMID- 22234333 TI - Psychiatry and informatics - joining forces to improve mental health. PMID- 22234334 TI - Cerebral microinfarcts: a systematic review of neuropathological studies. AB - Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 MUm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment. PMID- 22234335 TI - The two pathophysiologies of focal brain ischemia: implications for translational stroke research. AB - Brain injury after focal ischemia evolves along two basically different pathophysiologies, depending on the severity of the primary flow reduction and the dynamics of postischemic recirculation. In permanent and gradually reversed focal ischemia as after thromboembolic occlusion, primary core injury is irreversible but the expansion of the core into the penumbra can be alleviated by hemodynamic and molecular interventions. Such alleviation can only be achieved within 3 hours after the onset of ischemia because untreated core injury expands to near maximum size during this interval. In promptly reversed transient ischemia as after mechanical vascular occlusion, primary core injury may recover but a secondary delayed injury evolves after a free interval of as long as 6 to 12 hours. This injury can be alleviated throughout the free interval but the longer window is without clinical relevance because transient mechanical vascular occlusion is not a model of naturally occurring stroke. As this difference is widely ignored in stroke research, most clinical trials have been designed with a far too long therapeutic window, which explains their failure. Transient mechanical vascular occlusion models should, therefore, be eliminated from the repertoire of preclinical stroke research. PMID- 22234336 TI - Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. AB - Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH(4)) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH(4) supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH(4) by GTP-CH induced by insulin promoted NOS uncoupling. PMID- 22234337 TI - In vivo mesolimbic D2/3 receptor binding predicts posttherapeutic clinical responses in restless legs syndrome: a positron emission tomography study. AB - Although D2/3 agonists have been used as a first-line medication for idiopathic restless legs syndrome (iRLS), findings on D2/3 receptors have been inconsistent. Here, we aimed to clarify the contribution of D2/3 receptor function to the clinical symptoms of iRLS by comparing the binding potential (BP(ND)) of [(11)C]raclopride with clinical improvements after D2/3 stimulation by pramipexole. Eight drug-naive, iRLS patients and eight age-matched healthy subjects were scanned with positron emission tomography (PET). After PET scans, all patients received pramipexole (0.125 mg) orally for 2 weeks. Patients were evaluated every day with several standardized clinical tests. The BP(ND) values were compared using regions of interest and voxel-based methods. Results showed that the mean magnitude of [(11)C]raclopride BP(ND) in the mesolimbic dopamine region (nucleus accumbens (NA) and caudate) was significantly lower in the iRLS group. No significant differences between groups were observed in the putamen. The NA [(11)C]raclopride BP(ND) levels correlated negatively with clinical severity scores and positively with the degree of posttreatment improvement in iRLS. The present results suggest that alterations in mesolimbic D2/3 receptor function reflect the pathophysiology of iRLS, and the baseline availability of D2/3 receptors may predict the clinical outcome after D2/3 agonist treatment. PMID- 22234338 TI - Functional significance of central D1 receptors in cognition: beyond working memory. AB - The role of dopamine D1 receptors in prefrontal cortex function, including working memory, is well acknowledged. However, relatively little is known about their role in other cognitive or emotional functions. We measured both D1 and D2 receptors in the brain using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in cognitive and emotional functions beyond working memory. We found an inverted U-shaped relation between prefrontal D1 receptor availability and Wisconsin Card Sorting Test performance, indicating that too little or too much D1 receptor stimulation impairs working memory or set shifting. In addition, variability of D1 receptor availability in the amygdala and striatum was related to individual differences in emotional responses and decision-making processes, respectively. These observations suggest that the variability of available D1 receptors might be associated with individual differences in brain functions that require phasic dopamine release. An interdisciplinary approach combining molecular imaging of dopamine neurotransmission with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders such as schizophrenia, addiction and Parkinson's disease, as well as novel therapeutics for cognitive impairments observed in them. PMID- 22234340 TI - C-GRAAL: common-neighbors-based global GRAph ALignment of biological networks. AB - Networks are an invaluable framework for modeling biological systems. Analyzing protein-protein interaction (PPI) networks can provide insight into underlying cellular processes. It is expected that comparison and alignment of biological networks will have a similar impact on our understanding of evolution, biological function, and disease as did sequence comparison and alignment. Here, we introduce a novel pairwise global alignment algorithm called Common-neighbors based GRAph ALigner (C-GRAAL) that uses heuristics for maximizing the number of aligned edges between two networks and is based solely on network topology. As such, it can be applied to any type of network, such as social, transportation, or electrical networks. We apply C-GRAAL to align PPI networks of eukaryotic and prokaryotic species, as well as inter-species PPI networks, and we demonstrate that the resulting alignments expose large connected and functionally topologically aligned regions. We use the resulting alignments to transfer biological knowledge across species, successfully validating many of the predictions. Moreover, we show that C-GRAAL can be used to align human-pathogen inter-species PPI networks and that it can identify patterns of pathogen interactions with host proteins solely from network topology. PMID- 22234339 TI - The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice. AB - The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor alpha (TNFalpha) production. Fisetin also inhibited LPS-induced TNFalpha production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor kappaB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. PMID- 22234341 TI - The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation without impairing re-endothelialisation. AB - Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation. PMID- 22234342 TI - Hedgehog signaling in myofibroblasts directly promotes prostate tumor cell growth. AB - Despite strong evidence for the involvement of the stroma in Hedgehog signaling, little is known about the identity of the stromal cells and the signaling mechanisms that mediate the growth promoting effect of Hh signaling. We developed an in vitro co-culture model using microchannel technology to examine the effect of paracrine Hh signaling on proliferation of prostate cancer cells. We show here that activation of Hh signaling in myofibroblasts is sufficient to accelerate tumor cell growth. This effect was independent of any direct effect of Hh ligand on tumor cells or other cellular components of the tumor stroma. Further, the trophic effect of Hh pathway activation in myofibroblasts does not require collaboration of other elements of the stroma or direct physical interaction with the cancer cells. By isolating the tropic effect of Hh pathway activation in prostate stroma, we have taken the first step toward identifying cell-specific mechanisms that mediate the effect of paracrine Hh signaling on tumor growth. PMID- 22234343 TI - Bullying as a mediator of relationships between adiposity status and weapon carrying. AB - OBJECTIVES: Although evidence links increased adiposity status with bullying involvement, it is unknown whether this leads to behaviors such as weapon carrying. The purpose of this study was to: (1) analyze relationships between adiposity status and risks for weapon carrying among Canadian school children, and (2) whether this relationship was mediated by reports of bullying. METHODS: We conducted a cross-sectional analysis of the health experiences of 7,877 Canadian children. Relationships between adiposity status and weapon carrying were evaluated. Evidence of mediation by bullying involvement was assessed. RESULTS: Overweight (OR: 1.45, 95% CI 1.04-2.02) and obese (OR: 2.19, 95% CI 1.43 3.35) males reported higher odds of weapon carrying relative to normal weight males. There was partial mediation of this relationship by physical and relational bullying, both as a perpetrator or a victim. No evidence of a relationship was identified for female students. CONCLUSIONS: Overweight and obese male students appear to be more likely to carry weapons for defensive and offensive purposes, a behavior mediated partially by bullying involvement. However, other factors may play a role as mediators in these etiological relationships. PMID- 22234344 TI - Intersectoral action for health: more research is needed! PMID- 22234346 TI - The once-daily formulation of tacrolimus: a step forward in kidney transplantation? AB - Nonadherence is a critical issue in transplantation. Recently, Astellas designed a once-daily-extended release formulation of tacrolimus (Tac). Despite initial reports showing bioequivalence of Tac once-daily (Advagraf) with the original formulation requiring twice-daily intake (Tac twice-daily, Prograf), several groups have now shown a sustained decrease in Tac exposure upon conversion from Prograf to Advagraf. Here, we discuss the possible reasons for this observation and how it could affect the expected benefits of Advagraf, and we comment on the fact that a similar lack of bioequivalence might prevail with generic immunosuppressive drugs. PMID- 22234345 TI - Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein levels in human breast cancer cells. AB - Aberrant expression of mitotic checkpoint genes compromises mitotic checkpoint, leads to chromosome instability and tumorigenesis. However, the cell signals that control mitotic checkpoint gene expression have not been reported so far. In the present study we show that, in human breast cancer cells, chemical inhibition of Bone morphogenetic proteins (BMPs), but not Transforming Growth Factor-beta (TGF beta), abrogates the mitotic arrest induced by nocodazole. Protein expression analysis reveals that inhibition of BMP signaling dramatically down regulates protein levels of mitotic checkpoint components BUB3, Hec1, TTK and MAD2, but inhibition of TGF-beta has relatively minor effect on the expression of these proteins. Activation of BMP signaling specifically up regulates BUB3, and activation of Activin A signaling globally down regulates these proteins level. Furthermore, overexpressing MAD2, TTK, BUB3 or Hec1 significantly rescues the mitotic arrest defect caused by BMP inhibition. Our results demonstrated for the first time that TGF-beta family cytokines are cellular signals regulating mitotic checkpoint and perturbations in intrinsic BMP signaling could lead to suppression of mitotic checkpoint signaling by downregulating key checkpoint proteins. The results suggest a possible mechanism by which dysregulation of TGF-beta signaling causes mitotic checkpoint defects and drives tumorigenesis. The finding also provides a potential and more specific strategy for cancer prevention by targeting BMP and mitotic checkpoint connection. PMID- 22234347 TI - Profiling posttransplant circulating antibodies in kidney transplantation using donor endothelial cells. AB - BACKGROUND: Pathogenesis of antibody (Ab) responses to transplant are yet not well defined. This study aimed to detect and to analyze posttransplant circulating allo-Abs reacting toward graft endothelial cells (ECs) using primary EC cultures prospectively isolated from the transplant donor at the time of transplantation. METHODS: This study shows a retrospective analysis performed using a dedicated EC crossmatch (ECXM) assay that we developed for the experimental assessment of donor-specific EC-reactive Abs. Donor-specific ECXM was performed by flow cytometry on posttransplant sera (n=256) from an historical cohort of 22 kidney allograft recipients. RESULTS: In this study, we show that 27.3% (6/22) of recipients have a positive ECXM that strictly correlates (100%, 6/6) with the presence of anti-human leukocyte antigen (HLA) Abs posttransplantation. ECXM identifies both donor-specific Abs (DSA; 50%) and non DSA (50%) reactive to EC. DSA and non-DSA are mostly IgG1 and exhibit peak titers ranging from 1/8 to 1/1024. ECXM indicates that DSA correspond to anti-HLA class II Abs; this immunization is late (M3-M60) but persistent (still detected at M60). In contrast, non-DSA are non-HLA-type Abs reacting with third-party EC and reflecting an early but transient immunization (ended at M3-M12). Our findings demonstrate selective regulatory pathways initiated by anti-HLA class II and non DSA in graft EC reflected by CCR4 and interleukin 1beta up-regulation, respectively. CONCLUSIONS: We provide evidence that circulating Abs in HLA sensitized transplant recipients include both DSA and non-HLA/non-DSA able to bind to graft EC and induce specific gene transcription. PMID- 22234348 TI - Kidney transplantation search filters for PubMed, Ovid Medline, and Embase. AB - BACKGROUND: Clinicians commonly search bibliographic databases such as Medline to find sound evidence to guide patient care. Unfortunately, this can be a frustrating experience because database searches often miss relevant articles. We addressed this problem for transplant professionals by developing kidney transplantation search filters for use in Medline through PubMed and Ovid Technologies, and Embase. METHODS: We began by reading the full-text versions of 22,992 articles from 39 journals published across 5 years. These articles were labeled relevant to kidney transplantation or not forming our "gold standard." We then developed close to five million kidney transplantation filters using different terms and their combinations. Afterward, these filters were applied to development and validation subsets of the articles to determine their accuracy and reliability in identifying articles with kidney transplantation content. The final kidney transplantation filters used multiple terms in combination. RESULTS: The best performing filters achieved 97.5% sensitivity (95% confidence interval, 96.4%-98.5%), and 98.0% specificity (95% confidence interval, 97.8%-98.3%). Similar high performance was achieved for filters developed for Ovid Medline and Embase. Proof-of-concept searches confirmed more relevant articles are retrieved using these filters. CONCLUSIONS: These kidney transplantation filters can now be used in Medline and Embase databases to improve clinician searching. PMID- 22234349 TI - Plasmablastic posttransplant lymphoma: cytogenetic aberrations and lack of Epstein-Barr virus association linked with poor outcome in the prospective German Posttransplant Lymphoproliferative Disorder Registry. AB - BACKGROUND: Plasmablastic posttransplant lymphoma is a rare subtype of monomorphic B-cell posttransplant lymphoproliferative disorder (PTLD). There is little published clinical data to guide treatment. METHODS: The German prospective PTLD registry D2006-2012 records baseline features, treatment, and outcome of rare PTLD subtypes in adults after solid organ transplantation. Treatment is at the discretion of the local physician. Clinical data on the patients in the registry is collected before, during, and at least 4 weeks, 6 months, 12 and 24 months after treatment. RESULTS: Eight cases of plasmablastic posttransplant lymphoma were reported to the registry until 2011. The majority occurred as late PTLD in male heart transplant recipients. Extranodal manifestations were common in stage I and in stage IV disease. Histological Epstein-Barr virus (EBV) association was confirmed in five of eight cases. MYC/IGH rearrangement was present in two of six patients examined. Although five of eight patients died from early disease progression, we observed that long-term survival can be achieved in localized (2/3) and in disseminated disease (1/5) by immunosuppression reduction (IR) followed by immediate systemic chemotherapy. However, all patients with cytogenetic aberrations and patients with non-EBV associated PTLD were refractory to IR and to chemotherapy. Chemotherapy parallel to IR was associated with a high rate of infectious complications. CONCLUSIONS: In this series, IR and local therapy were not sufficient to treat plasmablastic posttransplant lymphoma even in localized disease whereas IR and systemic chemotherapy (CHOP-21) could achieve lasting complete remissions. Cytogenetic aberrations and lack of EBV association were linked with poor outcome. PMID- 22234350 TI - Genetic polymorphisms of the transcription factor NFATc4 and development of new onset diabetes after transplantation in Hispanic kidney transplant recipients. AB - Transcription factors of the nuclear factor of activated T cells (NFAT) family regulate both immune activation and insulin production. Calcineurin inhibitors (CNIs) target NFAT activation. Hence, CNIs not only prevent organ transplant rejection but also contribute to the development of new-onset diabetes after transplantation (NODAT). Given individual variation in the susceptibility to NODAT, we hypothesized that polymorphisms in the cytoplasmic NFAT (NFATc)4 gene, which is expressed in pancreatic islets, may be associated with NODAT. Haplotype tagging single-nucleotide polymorphisms (SNPs) of the NFATc4 gene were genotyped in Hispanic renal transplant patients. Cumulative incidences of NODAT were compared between recipients of different NFATc4 genotypes and haplotypes. The Cox proportional hazard model was used to examine risks for NODAT. Nongenetic and genetic characteristics were included in the multivariate risk model. The SNP (rs10141896) T allele was associated with a lower cumulative incidence of NODAT (P=0.02). This is a tagging SNP for one of the five dominant NFATc4 haplotypes, T T-T-T-G, and CNI-treated recipients with this haplotype had a reduced adjusted risk for NODAT (hazard ratio: 0.45; 95% confidence interval: 0.19-1.01). Conversely, patients homozygous for the C-C-C-G-G haplotype were at an increased risk (hazard ratio: 2.13; 95% confidence interval: 1.01-4.46) for NODAT in subanalysis. Of the nongenetic factors, use of tacrolimus, sirolimus, and older age were associated with increased risk for NODAT. Polymorphisms in the NFATc4 gene may confer certain protection or predisposition for NODAT. PMID- 22234351 TI - Persistent subretinal fluid after surgery for rhegmatogenous retinal detachment: hypothesis and review. AB - BACKGROUND: Persistent subretinal fluid after rhegmatogenous retinal detachment (RRD) surgery is responsible for delayed recovery, and may affect the final visual outcome. Cause, consequences, and treatment remain elusive. DESIGN: Literature review and case series. METHODS: We reviewed the pathophysiological principles and therapeutic options from the literature, and we report the results from a subretinal fluid cytology study. Nine eyes from nine patients with macula involving RRD underwent surgical repair. The cellular content of subretinal fluid (SRF) was studied by electron microscopy and anti-rhodopsin immunostaining. All eyes were assessed postoperatively with optical coherence tomography for the detection of persistent submacular fluid (PSF) (Ethics Committee Ghent University Hospital, registration number B6702006169). RESULTS: Certain patient characteristics as well as surgical methods were implicated. PSF appears to occur more frequently in patients with longstanding detachments treated with buckling surgery. Several therapeutic options have been suggested but safety and efficacy remain unclear. We found PSF in three eyes on postoperative OCT scans, which corresponded to the three cell-rich subretinal samples. CONCLUSIONS: PSF after successful RRD repair seems to be related to fluid composition. We hypothesize, in the absence of an effective treatment, that a modified surgical drainage, including a washout of the subretinal space, could evacuate the subretinal fluid more completely, and may prevent this complication. PMID- 22234353 TI - Photo-controlled metal-ion (Zn2+ and Cd2+) release in aqueous Tween-20 micelle solution. AB - Photo-controlled metal-ion (Zn(2+) and Cd(2+)) release in aqueous micelle solution (tris-HCl, pH = 7.4) has been described using 2-((2 mercaptophenylimino)methyl) phenol as ligand. It is found that both the ligand-Zn complex (1) and the ligand-Cd complex (2) are stable in micelle solution, and Zn(2+) (Cd(2+)) can be released from the complex with 365 nm light trigger. Accompanying the metal-ion release, the ligand is photo-converted to 2 (benzothiazol-2-yl) phenol (3) as product, and the turn-on fluorescence is detected. The fluorescence intensity increases with the photo-triggered release until Zn(2+) (Cd(2+)) is completely released, which is beneficial for monitoring the process of photo-controlled metal ion release. Control experiments demonstrate that no binding occurs between 3 and Zn(2+) (Cd(2+)) in micelle solution and there is no binding between cations and micelle, either. PMID- 22234352 TI - Correlation between elevation of serum antinuclear antibody titer and decreased therapeutic efficacy in the treatment of Behcet's disease with infliximab. AB - BACKGROUND: Infliximab, an anti-TNF-alpha monoclonal antibody, administered to Behcet's disease (BD) patients in Japan with refractory intraocular inflammation, has shown excellent clinical results. However, some patients demonstrate a decreased response to infliximab during the course of the treatment. In the present study, we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody (ANA) titers in patients with BD who were undergoing infliximab therapy. METHODS: Seventeen patients (14 males and three females) with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled. Their blood test results and clinical histories were obtained from medical records. RESULTS: One patient (5.9%) was ANA-positive prior to the initiation of infliximab, and 11 patients (64.7%) developed positive ANA during the therapy. The appearance of ANA was observed 6 months after the initiation of the infliximab therapy, and its titers gradually increased. None of the patients showed lupus symptoms. Five patients (29.4%) have suffered from ocular inflammatory attacks since the sixth month from the initiation of infliximab treatment and all of them were ANA-positive. In contrast, four patients (23.5%) who were ANA-negative experienced no ocular attacks during the follow-up period. CONCLUSIONS: Here we report the positive conversion and subsequent elevation of serum ANA titers in some patients with BD after the initiation of infliximab therapy. Since all recurrences of uveitis were shown only in the ANA-positive patients, serum ANA titer may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti-TNF-alpha antibody therapies. PMID- 22234354 TI - Synthesis of 3,3-disubstituted alpha-tetralones by rhodium-catalysed reaction of 1-(2-haloaryl)cyclobutanols. AB - The rhodium-catalysed reaction of 1-(2-haloaryl)cyclobutanols afforded 3,3 disubstituted alpha-tetralones. The reaction was applied to the asymmetric synthesis of alpha-tetralones bearing a chiral quaternary carbon centre at the 3 position, which was otherwise difficult to execute. PMID- 22234355 TI - Evaluation of laboratory markers of progression of HIV disease to death. AB - INTRODUCTION: One of the important current problems in HIV/AIDS infection is the establishment of epidemiological and laboratorial prognostic parameters during patient follow-up. This study aimed at analyzing the evolution of laboratory tests: CD4 lymphocyte count, viral load, hemoglobin (Hb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the epidemiological variables sex and age as prognostic factors for survival in progression to death among AIDS patients. METHODS: A retrospective study was conducted using analysis of medical records, and prospective 24-month follow-up of patients with HIV/ AIDS attended at the President Vargas Hospital Outpatient Clinic, a reference center in HIV/AIDS attendance in the State of Maranhao, Brazil. The study analyzed patients aged 10 to 60 years old, who manifested AIDS and who were not using antiretroviral therapy or had used it for less than 5 years. The Chi-square test was used for statistical analysis. RESULTS: The sample included 100 patients--57 were current outpatients, and 43 had died. The variables viral load (p=0.726), ALT (p=0.314), sex (p=0.687), and age (p=0.742) were analyzed, and no evidence of association between them and worst prognosis was observed. CONCLUSIONS: A significant relation was verified between low Hb levels (p=0.000) and CD4 (p=0.000) and shorter survival. PMID- 22234356 TI - Clinical and laboratory findings in patients with dengue associated with hepatopathy. AB - INTRODUCTION: Hepatic disorders caused by dengue infection may progress to severe manifestations, including mortality and morbidity. Cytokines are involved in it, such as the migration inhibitory factor of macrophages (MIF), tumor necrosis factor (TNF), natural killer cells (NK), B lymphocytes, and macrophages. METHODS: This study was carried out from January to April 2007 at a public hospital from the Federal University of Mato Grosso do Sul, Campo Grande, Brazil. Sixty-eight patients were studied concerning hepatic alterations, with 56 reported having classic dengue, 6 with hemorrhagic dengue grade I, and 6 with hemorrhagic dengue grade II. RESULTS: Among the 56 with classic dengue, 83.3% had aspartate aminotransferase (AST) alterations, and 69.6% had altered alanine aminotransferase (ALT). For those with hemorrhagic dengue grade I, 100% had AST alterations, and 83.3% had altered ALT. All the patients with hemorrhagic dengue grade II had AST and ALT alterations. AST variations reached 22.0 and 907.0, with an average value of 164.6. For ALT, we found variations between 25.0 and 867.0, with an average value of 166.07. There had been statistical significance between dengue clinical shapes and hepatic function markers. CONCLUSIONS: We conclude that the infection was predominant in adults, females, and in those with low income and education. The liver enzymes were of larger amount in hemorrhagic dengue, but there was weak statistical evidence of the clinical manifestations and transaminases. Major signs and clinical symptoms were fever, headache, myalgia, arthralgia, weakness, severe pain behind the eyes, and rashes. PMID- 22234357 TI - Fungemia in a university hospital: an epidemiological approach. AB - INTRODUCTION: Fungemia corresponds to the isolation of fungi in the bloodstream and occurs mostly in immunosuppressed patients. The early diagnosis and treatment of these infections are relevant given the serious threat to the affected patients and possible spread to other organs, often becoming fatal. The growing number of fungemia associated with poor prognosis resulted in this research aiming to diagnose and assess the epidemiological aspects of hematogenous infections by fungi. METHODS: The study included 58 blood samples collected within a 1-year period, from patients at the Hospital das Clinicas, Federal University of Pernambuco, by venipuncture in vacuum tubes. Blood samples were processed for direct examination and culture and identification, conducted by observing the macroscopic and microscopic characteristics, as well as physiological characteristics when necessary. RESULTS: Eight (13.8%) episodes of fungemia were identified, accounting for the total sample, and these pathogens were Candida, Histoplasma, Trichosporon, Cryptococcus, and a dematiaceous fungus. C. albicans was the prevalent species, accounting for 37.5% of the cases. Most affected patients were adult males. There was no predominance for any activity, and the risk of acquired immunodeficiency syndrome was the underlying pathology most often cited. CONCLUSIONS: The isolation of fungi considered as emergent species, such as C. membranifaciens and dematiaceous species, highlights the importance of epidemiological monitoring of cases of fungemia in immunocompromised patients, as the therapy of choice depends on the knowledge of the etiological agent. PMID- 22234358 TI - Comparative analysis of secreted proteins from normal and preeclamptic trophoblastic cells using proteomic approaches. AB - Preeclampsia (PE) is a pathology of pregnancy which represents the main cause of maternal and perinatal morbidity and mortality. Defective placentation is the first event of this pathology. The purpose of this study was to identify the proteins secreted by cytotrophoblastic cells (CTB) using proteomic approach that are associated with PE. Comparison of secreted proteins by mass spectrometry allowed us to identify 21 proteins which were significantly differentially secreted by control and PE CTB. One protein has been detected exclusively in supernatant of control CTB and was identified as factor XIII chain A. To determine if this observation is due to a difference of protein secretion or gene expression, its mRNA was quantified in all CTB. We found that it was significantly decreased in PE CTB compared to control. Collectively, these data suggest that decrease of factor XIII chain A might be associated with development of PE. PMID- 22234359 TI - Proteome changes in the myocardium of experimental chronic diabetes and hypertension: role of PPARalpha in the associated hypertrophy. AB - Diabetes with or without the presence of hypertension damages the heart. However, there is currently a lack of information about these associated pathologies and the alteration of linked proteins. For these reasons, we were interested in the potential synergistic interaction of diabetes and hypertension in the heart, focusing on the proteome characterization of the pathological phenotypes and the associated hypertrophic response. We treated normotensive and spontaneously hypertensive (SHR) rats with either streptozotocin or vehicle. After 22weeks, type-I diabetic (DM1), SHR, SHR/DM1 and control left-ventricles were studied using proteomic approaches. Proteomics revealed that long-term DM1, SHR and SHR/DM1 rats exhibited 24, 53 and 53 altered proteins in the myocardia, respectively. DM1 myocardium showed over-expression of apoptotic and cytoskeleton proteins, and down-regulation of anti-apoptotic and mitochondrial metabolic enzymes. In both SHR and SHR/DM1 these changes were exacerbated and free fatty acid (FFA) beta-oxidation enzymes were additionally decreased. Furthermore, SHR/DM1 hearts exhibited a misbalance of specific pro-hypertrophic, anti apoptotic and mitochondrial ATP-carrier factors, which could cause additional damage. Differential proteins were validated and then clustered into different biological pathways using bioinformatics. These studies suggested the implication of FFA-nuclear receptors and hypertrophic factors in these pathologies. Although key beta-oxidation enzymes were not stimulated in DM1 and hypertensive hearts, peroxisome proliferator-activated receptors-alpha (PPARalpha) were potentially activated for other responses. In this regard, PPARalpha stimulation reduced hypertrophy and pro-hypertrophic factors such as annexin-V in high-glucose and angiotensin-II induced cardiomyocytes. Thus, activation of PPARalpha could reflect a compensatory response to the metabolic-shifted, apoptotic and hypertrophic status of the hypertensive-diabetic cardiomyopathy. PMID- 22234361 TI - Ni/graphene/Ni nanostructures for spintronic applications. AB - Here, we demonstrate chemical synthesis of graphene based nano-spin valve like structures using nickel layers as ferromagnetic contacts grown on both sides of graphene sheets. Magnetic measurements indicate that the spins on two opposite nickel layers are coupled through antiferromagnetic interaction up to room temperature. However, they switch into parallel configuration when a magnetic field of about 2000 Oe is applied resulting in a change in magnetoresistance of ~19%. PMID- 22234360 TI - Proteomics in chromatin biology and epigenetics: Elucidation of post translational modifications of histone proteins by mass spectrometry. AB - Histone proteins contribute to the maintenance and regulation of the dynamic chromatin structure, to gene activation, DNA repair and many other processes in the cell nucleus. Site-specific reversible and irreversible post-translational modifications of histone proteins mediate biological functions, including recruitment of transcription factors to specific DNA regions, assembly of epigenetic reader/writer/eraser complexes onto DNA, and modulation of DNA-protein interactions. Histones thereby regulate chromatin structure and function, propagate inheritance and provide memory functions in the cell. Dysfunctional chromatin structures and misregulation may lead to pathogenic states, including diabetes and cancer, and the mapping and quantification of multivalent post translational modifications has therefore attracted significant interest. Mass spectrometry has quickly been accepted as a versatile tool to achieve insights into chromatin biology and epigenetics. High sensitivity and high mass accuracy and the ability to sequence post-translationally modified peptides and perform large-scale analyses make this technique very well suited for histone protein characterization. In this review we discuss a range of analytical methods and various mass spectrometry-based approaches for histone analysis, from sample preparation to data interpretation. Mass spectrometry-based proteomics is already an integrated and indispensable tool in modern chromatin biology, providing insights into the mechanisms and dynamics of nuclear and epigenetic processes. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. PMID- 22234362 TI - All that glitters is not gold. PMID- 22234364 TI - Extraversion and fronto-posterior EEG spectral power gradient: an independent component analysis. AB - Several studies show that the fronto-posterior EEG spectral power gradient is a stable individual characteristic related to personality. Whether this characteristic is specifically related to agentic extraversion and theta band of frequencies or is associated with a broader set of personality traits and frequency bands is a matter of debate, as well as the specific cortical regions contributing to this effect. To clarify these questions, we used group independent component analysis (ICA) and source localization techniques. Agentic extraversion was associated with higher theta activity in the default mode network's (DMN) posterior hub and lower theta activity in the orbitofrontal cortex (OFC). Regression analyses showed that theta activity predicted agentic extraversion better than other frequency bands and agentic extraversion predicted posterior versus frontal activity better than other personality dimensions. These results are taken to indicate higher tonic activity in OFC and lower activity in DMN in extraverts as compared to introverts. PMID- 22234363 TI - The thrombin inhibitors hirudin and Refludan((r)) activate the soluble guanylyl cyclase and the cGMP pathway in washed human platelets. AB - A number of direct thrombin inhibitors are successfully used clinically and experimentally as novel antithrombotics and specific anticoagulants. They are also used as anticoagulants in certain blood collection tubes for the analysis of platelet function. A series of platelet function tests have emerged to measure adequate responses to antiplatelet therapy. For comparative and practical reasons, it would be of advantage to use the same anticoagulant in blood collection tubes for different methods, e.g. thrombin inhibitors. However, there are little data on the effects of thrombin inhibitors on platelet signalling pathways that could influence results. We examined the applicability of thrombin inhibitor containing blood for platelet reactivity index (PRI) measurements of the VASP assay and investigated the effects of two thrombin inhibitors (hirudin and lepirudin) on cAMP- and cGMP-mediated signalling pathways in washed human platelets. We show that induction of VASP phosphorylation by PGE1 is markedly reduced in lepirudin containing blood samples. In consequence, PRI levels were highly variable compared to routinely used citrated blood. Surprisingly, in vitro incubation of platelets with thrombin inhibitors increases platelet cGMP levels and induces NOS independent sGC/PKG-mediated VASP phosphorylation. We conclude that thrombin inhibitors activate sGC/PKG-dependent pathways resulting in an increase of VASP phosphorylation which contributes to deviations in PRI measurements. These effects of thrombin inhibitors on sGC- and cGMP-mediated pathways including increased VASP phosphorylation may indicate the presence of an important additional platelet-based mechanism for the reduction of thrombus formation and thromboembolism by thrombin inhibitors. PMID- 22234365 TI - Awareness affects motor planning for goal-oriented actions. AB - We studied pre-movement cortical activity related to praxic actions performed at self-paced rate and having ecological meanings and functions. Motor-related cortical potentials were recorded using 64-channels EEG in two experiments. Experiment 1 included 15 subjects performing in separate blocks two object oriented actions: grasping a tea-cup and impossible grasping of a tea-cup (same goal but the grasp was mechanically hindered). Experiment 2 included a subset of 7 subjects from Exp. 1 and the action was reaching a tea-cup; this control condition had a different goal but was kinematically similar to impossible grasping. Different activity patterns in terms of onset, amplitude, duration and, at least in part, sources were recorded in the preparation phase (BP component) according to the specific action and to the possibility of accomplishing it. The main result is that parietal areas were involved in grasping preparation (called "posterior" BP) and not in reaching and impossible grasping preparation. The anterior frontal-central activity (called "anterior" BP) during preparation for grasping started earlier than the other two conditions. The cortical activity during preparation for reaching was similar to that for impossible grasping, except for a frontal activity only detected in the latter condition. It is concluded that the action preparation, even in its early phase, is affected by action meaning and by the awareness of being able to perform the requested action. PMID- 22234366 TI - Signal transduction pathways regulating hematopoietic stem cell biology: introduction to a series of Spotlight Reviews. PMID- 22234367 TI - Four novel mutations in the beta-galactosidase gene identified in infantile type of GM1 gangliosidosis. AB - OBJECTIVES: The aim of this study is to find out mutations of Turkish GM1 gangliosidosis patients and to make genotype-phenotype correlations. DESIGN AND METHODS: beta-galactosidase activities were measured by using fluorometric substrate. Mutation screening of 16 exons of beta-galactosidase gene and mutation detection were done by PCR-SSCP and DNA sequencing, respectively. RESULTS: Four new mutations, c.188_189insT in exon 2, c.569_570insA in exon 6, p.K142Q in exon 4, p.G190D in exon 6, and one known mutation p.P549L in exon 15, were identified in the beta-galactosidase gene in 5 Turkish patients. Mutations in exons 4 and 6 are in the active site and mutation in exon is in the galactose-binding domain of the beta-galactosidase gene. CONCLUSION: This is the first mutational analysis performed in Turkish GM1 gangliosidosis patients and shows the molecular heterogeneity of the disease in Turkish population. All identified mutations result in severe enzyme deficiency and infantile phenotype. PMID- 22234368 TI - Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor. AB - Several studies have suggested that both testosterone and dehydroepiandrosterone (DHEA) have weight-reducing and antidiabetic effects, especially in rodent studies; however, the precise mechanism of their action remains unclear. Here, we investigated the effect of DHEA on cell growth in adipose tissue. The appearance of senescence-associated beta-galactosidase in stromal vascular fraction (SVF) isolated from Otsuka Long-Evans Tokushima fatty rats, an animal model of inherent obese type 2 diabetes, was prevented by DHEA administration. Next, the effects of DHEA and testosterone were compared in vivo and in vitro to evaluate whether these hormones influence cell growth in adipose tissue. Both DHEA and testosterone reduced body weight and epididymal fat weight equivalently when administered for 4 wk. To assess the effect of DHEA and testosterone on cell growth in adipose tissue, 5-bromo-2'-deoxyuridine (BrdU) uptake by SVF was measured. Quantification analysis of BrdU uptake by examining DNA isolated from each SVF revealed that treatment with DHEA and testosterone reduced cell replication. These results indicated that DHEA- and testosterone-induced decreased adiposity was associated with reduced SVF growth. Incubation with DHEA and testosterone equally decreased BrdU uptake by 3T3-L1 preadipocytes. Pretreatment with the androgen receptor (AR) inhibitor flutamide, but not the estrogen receptor inhibitor fulvestrant, abolished these effects. Knockdown of AR with siRNA also inhibited DHEA-induced decreases in BrdU uptake. These results suggest that DHEA-induced growth suppression of preadipocytes is mediated via AR. Therefore, both DHEA and testosterone similarly decrease adipocyte growth possibly via a common mechanism. PMID- 22234369 TI - Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy. AB - Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance, and fatty liver. BSCL2 is caused by loss-of-function mutations in the BSCL2/seipin gene, which encodes seipin. The essential role for seipin in adipogenesis has recently been established both in vitro and in vivo. However, seipin is highly upregulated at later stages of adipocyte development, and its role in mature adipocytes remains to be elucidated. We therefore generated transgenic mice overexpressing a short isoform of human BSCL2 gene (encoding 398 amino acids) using the adipocyte-specific aP2 promoter. The transgenic mice produced ~150% more seipin than littermate controls in white adipose tissue. Surprisingly, the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets. This may be due in part to elevated lipolysis rates in the transgenic mice. Moreover, there was a nearly 50% increase in the triacylglycerol content of transgenic liver. These results suggest that seipin promotes the differentiation of preadipocytes but may inhibit lipid storage in mature adipocytes. PMID- 22234370 TI - Potential interaction of brain natriuretic peptide with hyperadiponectinemia in preeclampsia. AB - Adiponectin was reported recently to have roles in the pathophysiology of preeclampsia. Moreover, elevation of adiponectin and brain natriuretic peptide (BNP) has been observed in preeclampsia. We examined the possible links between adiponectin and BNP in the pathophysiology of preeclampsia. We performed a cross sectional study in 56 preeclampsia patients and 56 controls matched for gestational age and body mass index. The BNP, leptin, and adiponectin levels were measured by ELISA, and their mRNA expressions were evaluated in omental adipose tissue by real-time PCR. The effects of BNP on adiponectin and leptin mRNA expression and secretion were investigated in primary cultures of adipocytes from obese and normal-weight women. The BNP, adiponectin, and leptin levels were significantly higher in preeclampsia patients compared with controls. The adiponectin level was increased significantly in normal-weight preeclampsia patients compared with overweight preeclampsia patients. Adiponectin mRNA expression was increased significantly in adipose tissues of preeclampsia patients compared with controls and was also increased significantly in normal weight preeclampsia patients compared with overweight preeclampsia patients, whereas leptin was not. BNP and adiponectin showed significant positive correlations in both normal-weight and overweight preeclampsia patients. BNP had a significantly weaker effect on adiponectin in overweight compared with normal weight preeclampsia patients. Moreover, BNP had a weaker effect on adiponectin production in adipocytes from overweight women compared with adipocytes from normal-weight women using primary culture of human adipocytes. These data suggested that BNP may play a role in hyperadiponectinemia of preeclampsia patients. The weaker effect of BNP on adiponectin production may participate in the pathophysiology of overweight preeclampsia patients. PMID- 22234371 TI - SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion. AB - Glucagon-like peptide-1 (GLP-1)-based incretin therapy is becoming central to the treatment of type 2 diabetes. Activation of incretin hormone receptors results in rapid elevation of cAMP followed by enhanced insulin secretion. However, the incretin effect may be significantly impaired in diabetes. The objective of this study is to investigate downregulation of GLP-1 signaling by small ubiquitin related modifier protein (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Overexpression of SUMO-1 in mouse insulinoma 6 (MIN6) cells and primary mouse beta-cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1 receptor (GLP-1R) agonist. GLP1-R was covalently modified by SUMO. Overexpression of SUMO 1 attenuated cell surface trafficking of GLP-1R, which resulted in significantly reduced insulin secretion when stimulated by exendin-4. Partial knock down of SUMO-conjugating enzyme Ubc-9 resulted in enhanced exendin-4-stimulated insulin secretion in mouse islets exposed to high glucose. Thus, SUMO modification of the GLP-1R could be a contributing factor to reduced incretin responsiveness. Elucidating mechanisms of GLP-1R regulation by sumoylation will help improve our understanding of incretin biology and of GLP-1-based treatment of type 2 diabetes. PMID- 22234372 TI - Myositis ossificans of the rotator cuff muscle. PMID- 22234373 TI - Galeazzi's modified technique for recurrent patella dislocation in skeletally immature patients. AB - BACKGROUND: A large number of surgical techniques have been proposed for the treatment of recurrent patellar dislocation in adolescents, one of the most famous being Galeazzi's semitendinosus tenodesis as modified by Baker. The aim of this study was to verify the mid-term results of this technique, the effectiveness of restoring the patellofemoral congruency, by both static and dynamic computed tomography (CT), and to determine whether the preoperative type of patellofemoral relationship affects the results. METHODS: The study included 14 patients (16 knees), with a mean age of 11.6 years, Tanner stage <=3, with at least two to three episodes of patellar dislocation. The patients underwent surgery using Baker's modification of Galeazzi's technique. All 14 patients were evaluated preoperatively and at least 4 years afterward by static and dynamic CT. Clinical evaluation at follow-up was performed using the criteria described by Crosby and Insall. RESULTS: Clinical results at follow-up were excellent in 62.5% and good in 37.5%. As preoperative evaluation showed a high patella in 7 out of 16 knees, two groups were considered: A, high patella; B, not high patella. The data obtained with static CT show that the patella reached a satisfactory congruence in all knees. The data obtained with dynamic CT showed different results between group A and B. A preoperative high patella remains high with quadriceps contraction and again shows the change of tilt and subluxation. In group B, the data obtained with dynamic CT are comparable with those obtained with static CT. CONCLUSIONS: This technique produces good mid-term clinical results. However, the dynamic CT showed that in those patients with high patellas, semitendinosus tenodesis alone is not enough to stabilize the patella. PMID- 22234374 TI - Preliminary study of the biomechanical behavior and physical characteristics of tantalum (Ta)-coated prostheses. AB - BACKGROUND: Use of Ta biomaterials in medicine started in the middle of the last century. The good biocompatibility and chemical stability, and the unique physical characteristics of Ta metal have resulted in many possible developments of Ta biomaterials. METHODS: In this study, histopathological observation, histomorphometric analysis, scanning electron microscope (SEM) observation, energy-dispersive X-ray spectroscopy (EDX) analysis, biomechanical testing, and examination of the coating's mechanical strength have been used to evaluate the value of clinical application of Ta-coated prostheses prepared by a plasma spraying process. RESULTS: Histopathological observation has demonstrated that the periprosthetic new bone tissues tightly and stably adhere to the Ta coating after the implantation, with no signs of loosening. Early after implantation, there is no significant difference in periprosthetic bone volume and ultimate shear strength between Ta-coated and Ti-coated prostheses (P > 0.05). EDX analysis suggests that the ultimate shear stress does not damage Ta coating. Mechanical strength testing shows that the adhesive strength and Vicker's surface hardness (HV) of the Ta coating are significantly higher than those of the Ti coating (P < 0.01). CONCLUSIONS: Ta coating has good stability and bone biocompatibility; the extraordinary physical characteristics of Ta coating have great significance in maintaining prosthetic stability and surface porosity after implantation. PMID- 22234375 TI - Tailored SERS substrates obtained with cathodic arc plasma ion implantation of gold nanoparticles into a polymer matrix. AB - This manuscript reports on the fabrication of plasmonic substrates using cathodic arc plasma ion implantation, in addition to their performance as SERS substrates. The technique allows for the incorporation of a wide layer of metallic nanoparticles into a polymer matrix, such as PMMA. The ability to pattern different structures using the PMMA matrix is one of the main advantages of the fabrication method. This opens up new possibilities for obtaining tailored substrates with enhanced performance for SERS and other surface-enhanced spectroscopies, as well as for exploring the basic physics of patterned metal nanostructures. The architecture of the SERS-active substrate was varied using three adsorption strategies for incorporating a laser dye (rhodamine): alongside the nanoparticles into the polymer matrix, during the polymer cure and within nanoholes lithographed on the polymer. As a proof-of-concept, we obtained the SERS spectra of rhodamine for the three types of substrates. The hypothesis of incorporation of rhodamine molecules into the polymer matrix during the cathodic arc plasma ion implantation was supported by FDTD (Finite-Difference Time-Domain) simulations. In the case of arrays of nanoholes, rhodamine molecules could be adsorbed directly on the gold surface, then yielding a well-resolved SERS spectrum for a small amount of analyte owing to the short-range interactions and the large longitudinal field component inside the nanoholes. The results shown here demonstrate that the approach based on ion implantation can be adapted to produce reproducible tailored substrates for SERS and other surface-enhanced spectroscopies. PMID- 22234376 TI - A flux monitoring method for easy and accurate flow rate measurement in pressure driven flows. AB - We propose a low-cost and versatile method to measure flow rate in microfluidic channels under pressure-driven flows, thereby providing a simple characterization of the hydrodynamic permeability of the system. The technique is inspired by the current monitoring method usually employed to characterize electro-osmotic flows, and makes use of the measurement of the time-dependent electric resistance inside the channel associated with a moving salt front. We have successfully tested the method in a micrometer-size channel, as well as in a complex microfluidic channel with a varying cross-section, demonstrating its ability in detecting internal shape variations. PMID- 22234377 TI - A histone deacetylase inhibitory prodrug - butyroyloxymethyl diethyl phosphate - protects the heart and cardiomyocytes against ischemia injury. AB - Butyroyloxymethyl diethylphosphate (AN-7) is a prodrug of butyric acid effective in reducing cardiotoxicity caused by chemotherapy. In this study, we tested whether AN-7 protects the heart and cardiomyocytes against ischemia injury. A single oral dose of AN-7 was given to mice or rats. Animals were sacrificed 1.5 or 24 h later and the hearts were subjected to ischemia and reperfusion ex-vivo (Langendorff). The mechanical performance was recorded throughout and the infarct size was measured at the end of reperfusion. Neonatal rat cardiomyocytes were subjected to 24-48 h hypoxia (1% O(2)) in the absence or presence of AN-7 and mitochondria damage and cell death were assessed. Proteins were analyzed by Western immunoblotting. In the two rodents, a single dose of AN-7 given in vivo preconditioned the hearts for improved functional recovery from ischemia and reperfusion performed ex-vivo. Both 1.5 h and 24 h treatments improved the pressure-related parameters whereas the coronary flow was ameliorated in the 24 h treatment only. Infarct size was smaller in the AN-7 treated hearts. In cardiomyocytes, AN-7 diminished the hypoxia induced dissipation of mitochondria membrane potential and cell death. Compared with untreated controls, AN-7-treated hearts recovering from global ischemia and cardiomyocytes undergoing hypoxia, displayed significantly higher levels of the cytoprotective heme oxygenase-1. Our findings indicate that AN-7 imparts cardioprotection against ischemia both in vivo and in vitro and emerges as a potential treatment modality for cardiac injury. PMID- 22234379 TI - A randomized, placebo-controlled laboratory study of the effects of D-cycloserine on craving in cocaine-dependent individuals. AB - RATIONALE: D-Cycloserine (DCS), a partial glutamate N-methyl-D-aspartate (NMDA) receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggest that it may facilitate extinction of drug cue reactivity. OBJECTIVE: This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects. METHODS: Thirty-two subjects were randomly assigned to receive (1) DCS only, (2) DCS before sessions 1 and 3, placebo (PBO) before session 2, or (3) PBO only 15-min before each of 3 1-h cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during, and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session. RESULTS: Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received three doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue induced craving at follow-up. The group that received two doses of DCS did not differ from the PBO group. There were no group differences in postextinction cocaine use. CONCLUSIONS: The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes. PMID- 22234380 TI - The effects of exercise on cigarette cravings and brain activation in response to smoking-related images. AB - RATIONALE: Smokers show heightened activation toward smoking-related stimuli and experience increased cravings which can precipitate smoking cessation relapse. Exercise can be effective for modulating cigarette cravings and attenuating reactivity to smoking cues, but the mechanism by which these effects occur remains uncertain. OBJECTIVE: The objective of the study was to assess the effect of exercise on regional brain activation in response to smoking-related images during temporary nicotine abstinence. METHODS: In a randomised crossover design, overnight abstinent smokers (n = 20) underwent an exercise (10-min moderate intensity stationary cycling) and passive control (seating for the same duration) treatment, following 15 h of nicotine abstinence. After each treatment, participants underwent functional magnetic resonance imaging (fMRI) brain scanning while viewing a random series of blocked smoking or neutral images. Self reported cravings were assessed at baseline, mid-, and post-treatments. RESULTS: There was a significant interaction effect (treatment * time) for desire to smoke, F (2,32) = 12.5, p < 0.001, with significantly lower scores following the exercise at all time points compared with the control treatment. After both exercise and rest, significant areas of activation were found in areas of the limbic lobe and in areas associated with visual attention in response to smoking related stimuli. Smokers showed increased activation to smoking images in areas associated with primary and secondary visual processing following rest, but not following a session of exercise. CONCLUSION: The study shows differing activation towards smoking images following exercise compared to a control treatment and may point to a neuro-cognitive process following exercise that mediates effects on cigarette cravings. PMID- 22234378 TI - Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters. AB - RATIONALE: Atypical antipsychotic drugs (AAPDs) such as olanzapine have a serious side effect profile including weight gain and metabolic dysfunction, and a number of studies have suggested a role for gender in the susceptibility to these effects. In recent times, the gut microbiota has been recognised as a major contributor to the regulation of body weight and metabolism. Thus, we investigated the effects of olanzapine on body weight, behaviour, gut microbiota and inflammatory and metabolic markers in both male and female rats. METHODS: Male and female rats received olanzapine (2 or 4 mg/kg/day) or vehicle for 3 weeks. Body weight, food and water intake were monitored daily. The faecal microbial content was assessed by 454 pyrosequencing. Plasma cytokines (tumour necrosis alpha, interleukin 8 (IL-8), interleuin-6 and interleukin 1-beta (IL 1beta)) as well as expression of genes including sterol-regulatory element binding protein-1c and CD68 were analysed. RESULTS: Olanzapine induced significant body weight gain in the female rats only. Only female rats treated with olanzapine (2 mg/kg) had elevated plasma levels of IL-8 and IL-1beta, while both males and females had olanzapine-induced increases in adiposity and evidence of macrophage infiltration into adipose tissue. Furthermore, an altered microbiota profile was observed following olanzapine treatment in both genders. CONCLUSIONS: This study furthers the theory that gender may impact on the nature of, and susceptibility to, certain side effects of antipsychotics. In addition, we demonstrate, what is to our knowledge the first time, an altered microbiota associated with chronic olanzapine treatment. PMID- 22234381 TI - Influence of risperidone on balance control in young healthy individuals. AB - RATIONALE: It has previously been shown that impairment of postural stability is a side effect of typical antipsychotic drugs, which are largely administered to control psychosis and behavioral symptoms in elderly patients. Surprisingly, no study has yet addressed this problem with second-generation antipsychotics. OBJECTIVE: The objective of this study was to determine the extent to which risperidone at low doses altered balance control in healthy participants. METHODS: Twelve healthy young adults received, following a randomized double blind crossover design, a single oral dose of placebo, 1 and 3 mg of risperidone on separate days at least 14 days apart. Evaluation of extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale-abbreviated scoring form (ESRS-A) and measures of postural sway using a force platform were assessed over 9 h following drug ingestion. RESULTS: There is a significant increase in the postural stability item of the ESRS-A parkinsonism subscale at 3 and 6 h following 3 mg of risperidone only when compared to placebo. With regard to balance control, body sway measures were increased at 1 mg of risperidone but more pronounced at 3 mg. The peak effects were observed at 3 h after administration of the drug and had not completely returned to baseline after 9 h. CONCLUSIONS: Risperidone administered at low doses did not elicit clinically detectable EPS but had significant effects on balance control. A dose-response effect on impairment of balance was observed that followed the expected time course of the drug pharmacokinetics. These results are likely to apply to older or demented individuals who have pre-existing balance control deficit. PMID- 22234383 TI - Manchester Clinical Placement Index (MCPI). Conditions for medical students' learning in hospital and community placements. AB - The drive to quality-manage medical education has created a need for valid measurement instruments. Validity evidence includes the theoretical and contextual origin of items, choice of response processes, internal structure, and interrelationship of a measure's variables. This research set out to explore the validity and potential utility of an 11-item measurement instrument, whose theoretical and empirical origins were in an Experience Based Learning model of how medical students learn in communities of practice (COPs), and whose contextual origins were in a community-oriented, horizontally integrated, undergraduate medical programme. The objectives were to examine the psychometric properties of the scale in both hospital and community COPs and provide validity evidence to support using it to measure the quality of placements. The instrument was administered twice to students learning in both hospital and community placements and analysed using exploratory factor analysis and a generalizability analysis. 754 of a possible 902 questionnaires were returned (84% response rate), representing 168 placements. Eight items loaded onto two factors, which accounted for 78% of variance in the hospital data and 82% of variance in the community data. One factor was the placement learning environment, whose five constituent items were how learners were received at the start of the placement, people's supportiveness, and the quality of organisation, leadership, and facilities. The other factor represented the quality of training-instruction in skills, observing students performing skills, and providing students with feedback. Alpha coefficients ranged between 0.89 and 0.93 and there were no redundant or ambiguous items. Generalisability analysis showed that between 7 and 11 raters would be needed to achieve acceptable reliability. There is validity evidence to support using the simple 8-item, mixed methods Manchester Clinical Placement Index to measure key conditions for undergraduate medical students' experience based learning: the quality of the learning environment and the training provided within it. Its conceptual orientation is towards Communities of Practice, which is a dominant contemporary theory in undergraduate medical education. PMID- 22234382 TI - NMDA receptor-mediated Ca(2+) influx triggers nucleocytoplasmic translocation of diacylglycerol kinase zeta under oxygen-glucose deprivation conditions, an in vitro model of ischemia, in rat hippocampal slices. AB - Diacylglycerol kinase (DGK) plays a key role in pathophysiological cellular responses by regulating the levels of a lipid messenger diacylglycerol. Of DGK isozymes, DGKzeta localizes to the nucleus in various cells such as neurons. We previously reported that DGKzeta translocates from the nucleus to the cytoplasm in hippocampal CA1 pyramidal neurons after 20 min of transient forebrain ischemia. In this study, we examined the underlying mechanism of DGKzeta translocation using hippocampal slices exposed to oxygen-glucose deprivation (OGD) to simulate an ischemic model of the brain. DGKzeta-immunoreactivity gradually changed from the nucleus to the cytoplasm in CA1 pyramidal neurons after 20 min of OGD and was never detected in the nucleus after reoxygenation. Intriguingly, DGKzeta was detected in the nucleus at 10 min OGD whereas the following 60 min reoxygenation induced complete cytoplasmic translocation of DGKzeta. Morphometric analysis revealed that DGKzeta cytoplasmic translocation correlated with nuclear shrinkage indicative of an early process of neuronal degeneration. The translocation under OGD conditions was blocked by NMDA receptor (NMDAR) inhibitor, and was induced by activation of NMDAR. Chelation of the extracellular Ca(2+) blocked the translocation under OGD conditions. These results show that DGKzeta cytoplasmic translocation is triggered by activation of NMDAR with subsequent extracellular Ca(2+) influx. Furthermore, inhibition of PKC activity under OGD conditions led to nuclear retention of DGKzeta in about one third of the neurons, suggesting that PKC activity partially regulates DGKzeta cytoplasmic translocation. These findings provide clues to guide further investigation of glutamate excitotoxicity mechanisms in hippocampal neurons. PMID- 22234384 TI - Correlates of hazardous drinking among Veterans with and without hepatitis C. AB - Hazardous drinking is a major barrier to antiviral treatment eligibility among hepatitis C (HCV) patients. We evaluated differences in substance-related coping, drinking-related consequences, and importance and confidence in ability to change alcohol use among hazardous drinkers with and without HCV (N = 554; 93.5% male). We examined group differences between HCV+ patients (n = 43) and their negative HCV counterparts (n = 511). Results indicate a higher percentage of HCV+ patients report using substances to cope with possible symptoms of PTSD (P < .05) and depression (P < .01), and endorse more lifetime drinking-related negative consequences than HCV patients (P < .01). Furthermore, HCV+ patients place greater importance on changing alcohol use (P < .01) but report less confidence in their ability to change (P < .01). Use of brief assessment and feedback with skills-based interventions to decrease alcohol use may be well-received by HCV+ patients. PMID- 22234385 TI - Contemporary use of glycoprotein IIb/IIIa inhibitors. AB - Platelet glycoprotein IIb/IIIa inhibitors (GPI) are antithrombotic agents preventing the binding of fibrinogen to GP IIb/IIIa receptors. Thus, GPI interfere with interplatelet bridging mediated by fibrinogen. Currently, three generic GPI with different antithrombotic properties are available for intravenous administration: abciximab, eptifibatide, and tirofiban. The development of oral GPI was abandoned, whereas intravenous GPI were introduced in various clinical settings during the 1990s, yielding substantial benefit in the treatment of acute coronary syndromes, particularly during percutaneous coronary interventions. Results of the many randomised trials evidenced the efficacy of this drug class, though these trials were conducted prior to the emergence of modern oral antiplatelet therapy with efficient P2Y(12) inhibitors. Subsequent trials failed to consolidate the strongly favourable impression of GPI, and indications for their use have been more restricted in recent years. Nonetheless, GPI may still be beneficial during coronary interventions among high-risk patients including acute ST-elevation and non-ST-elevation myocardial infarctions, particularly in the absence of adequate pretreatment with oral antiplatelet drugs or when direct thrombin inhibitors are not utilised. Intracoronary GPI administration has been suggested as adjunctive therapy during primary percutaneous coronary intervention, and the results of larger ongoing trials are expected to elucidate its clinical potential. The present review outlines the key milestones of GPI development and provides an up-to-date overview of the clinical applicability of these drugs in the era of refined coronary stenting, potent antithrombotic drugs, and novel thrombin inhibiting agents. PMID- 22234386 TI - Comment on "Serum AMH concentration as a marker evaluating gonadal function in boys operated on for unilateral cryptorchidism between 1st and 4th year of life". PMID- 22234387 TI - Accuracy of asthma and COPD diagnosis in Australian general practice: a mixed methods study. AB - BACKGROUND: Spirometry is the 'gold standard' for diagnosing asthma and chronic obstructive pulmonary disease (COPD) but is rarely used in general practice. AIMS: To compare doctor diagnoses with patient reports/spirometry and to determine doctors' perceptions of spirometry. METHODS: Patients prescribed inhaled medication were recruited from 31 practices. Doctor diagnoses were extracted from practice records. Patients completed a questionnaire and spirometry before and after bronchodilator. In-depth interviews were conducted with a sample of doctors. RESULTS: Doctor diagnoses were available for 278 patients: asthma 192 (69%), COPD 38 (14%), asthma/COPD 40 (14%), and eight patients (3%) with other conditions. The diagnosis of asthma was correctly reported by 93% of patients, but only by 61% of those with COPD alone. Among those with both diagnoses, 83% reported asthma and 48% reported COPD. Of those with a diagnosis of COPD, 65% had fixed airflow limitation. Conversely, only 14% of those had been diagnosed with COPD alone. There was no significant difference in reversibility in forced expiratory volume in 1 second between diagnoses. While recognising the value of spirometry in differentiating between asthma and COPD, most general practices only used spirometry in diagnostically difficult cases. CONCLUSIONS: Doctor-diagnosed asthma is accurately reported by patients. However, COPD remains substantially under-diagnosed. Spirometry needs to be more widely used to improve the accuracy of respiratory diagnoses in general practice. PMID- 22234388 TI - ALMA, a new tool for the management of asthma patients in clinical practice: development, validation and initial clinical findings. AB - BACKGROUND: Several instruments have been developed for measuring asthma control, but there is still a need to provide a structure for primary care asthma reviews. AIMS: The Active Life with Asthma (ALMA) tool was developed with the aim of structuring patient visits and assessing asthma treatment in primary care. The ability of ALMA to map out the care of asthma patients was evaluated and validated. METHODS: ALMA was developed with patient and clinical expert input. Questions were generated in focus groups and the resulting tool was subsequently validated by factor analysis in 1779 patients (1116 females) of mean age 51 years (range 18-89) in primary care. RESULTS: The ALMA tool includes 19 questions, 14 of which belong to a subset assessing asthma control. In this subset, factor analysis revealed three domains (factors): physical, psychological, and environmental triggers. Correlation with the Asthma Control Questionnaire was 0.72 and the Cronbach's alpha was 0.88. The test-retest reliability was 0.93. Of the 1779 patients tested with ALMA in primary care, 62% reported chest tightness, 30% nightly awakenings and 45% asthma breakthrough despite medication. CONCLUSIONS: The ALMA tool is useful as a follow-up instrument in clinical practice to structure patient visits and assess asthma treatment in primary care. The breadth of the questions and the pragmatic use in clinical practice also make it useful as an outcome measure. PMID- 22234389 TI - Newer equations better predict lung age in smokers: a retrospective analysis using a cohort of randomly selected participants. AB - AIMS: To produce new lung age equations using four previously published predictive equations for forced expiratory volume in 1 second and to compare them with lung age equations published in 1985 and 2010. METHODS: Initial comparisons used phantom subjects of different ages and levels of lung function. Comparison of lung age equations by regression analysis used an independent dataset of 3,206 randomly selected community-dwelling adults aged >18 years in the North West Adelaide Health Study. RESULTS: The more recent equations estimated lung age as greater than chronological age as lung function decreased, whereas the oldest equations estimated lung age as less than chronological age until lung function was severely limited. Significant differences (p<0.001) were detected by regression analysis, with four newer lung age equations being significantly different from the 1985 equation and one being no different. CONCLUSIONS: Lung age estimates using six predictive equations spanning 50 years show differences attributable to cohort and period effects. This reinforces the need for regular updating of predictive equations for lung function. These results further confirm the need to use modern lung age equations which will provide a stronger message in smoking cessation counselling. PMID- 22234391 TI - Nanoscale probing of transient carrier dynamics modulated in a GaAs-PIN junction by laser-combined scanning tunneling microscopy. AB - The modulation of carrier dynamics in a GaAs-PIN junction after photoexcitation by an ultrashort-pulse laser was probed by shaken-pulse-pair-excited scanning tunneling microscopy (SPPX-STM), which enables nanoscale mapping of time-resolved STM images. The effect of the built-in potential on the carrier dynamics, diffusion and drift, which cannot be probed by the optical pump-probe technique, was successfully visualized in real space. PMID- 22234390 TI - Electrochemical and structural coupling of the naphthoquinone amino acid. AB - As a prelude to engineering artificial energy conversion proteins emulating biology, we examine the inclusion of a synthetic naphthoquinone amino acid in a characterized host-guest protein and determine the effects of its quinone and hydroquinone forms on the helix-coil distribution. PMID- 22234392 TI - Thiacalix[4]arene-cinnamaldehyde derivative: ICT-induced preferential nanomolar detection of Ag+ among different transition metal ions. AB - A new thiacalix[4]arene-cinnamaldehyde derivative 3, which undergoes red shift in the fluorescence spectrum in the presence of Ag(+) ions, has been synthesized. This emission shift is attributed to the intramolecular charge transfer process in the presence of Ag(+) ions with a detection limit in the nanomolar range. PMID- 22234394 TI - Faraday rotation and its dispersion in the visible region for saturated organic liquids. AB - Faraday rotation and its dispersion have been measured and calculated in the 400 800 nm wavelength range for a set of saturated organic liquids. The resulting Verdet constants are fitted and trends are analyzed. Comparisons are made to both the polarizability and diamagnetic susceptibility. The data are applied to a connectivity index model, allowing prediction of Verdet constants of aliphatic organic liquids from 400 to 800 nm. The observed correlations and connectivity model improve the understanding of Faraday rotation in diamagnetic materials, allowing for future optimization. PMID- 22234393 TI - A prospective study of childhood and adolescent antecedents of homelessness among a community population of African Americans. AB - Much is known about contemporaneous correlates of homelessness from studies of homeless individuals. However, few studies have prospectively examined early antecedents and prevalence of homelessness in community populations. We use data from a 35-year study of a community population of African Americans to examine relationships between homelessness and prior structural, family, school, and behavioral influences. Nearly 22% of males and 16% of females reported homelessness between ages 15 and 42, providing a rare estimate within an African American urban community population. In bivariate analyses, lower school bonds, depressed mood, violent behavior, and running away in adolescence are predictive for both males and females. Teen parenting and angry mood are unique influences for females, while for males, poor first grade classroom conduct and adolescent substance use are unique risks. In multivariate analyses, poor classroom conduct and weaker school bonds predict homelessness among males, while teen parenting does so for females. Running away before age 15 is strongly predictive of later homelessness for both males and females. These results reveal the relative influence of multiple, interrelated early risks on homelessness and confirm our hypothesis that factors linked to other poor outcomes also relate to homelessness, underscoring another benefit to early prevention efforts. PMID- 22234395 TI - Mortality predictors of snake bite envenomation in southern India--a ten-year retrospective audit of 533 patients. AB - Snake bite incidence is highest in Asia and sub-Saharan Africa. This retrospective audit of 533 adult patients, who had presented to the Emergency Department, collates clinical features, effect of pharmacologic interventions and the risk factors that influence morbidity and mortality. Dual toxicity, neurological and haematological, was observed in 30.4% of patients. Laboratory evidence of haematotoxicity was demonstrated in 314 (58.9%) and 40% demonstrated clinical evidence of bleeding. However, 7.3% of these patients did not have laboratory evidence of bleeding disorder (p < 0.001). Conversely, 60% did not have clinical evidence of bleeding, but demonstrated laboratory evidence of abnormal parameters. Acute kidney injury (AKI) was evident in 28% of patients and 15.3% required haemodialysis. About 25% with no haematotoxicity showed evidence of AKI. The majority received 6-12 vials of poly-valent anti-snake venom. Hypersensitivity reaction rate was 8% and predominantly anaphylactoid in nature. The length of hospital stay ranged from 2 to 28 days and 20% required mechanical ventilation. Overall mortality rate was 7.5% with significant association to AKI, haematotoxicity and assisted ventilation. The mortality rate was 18% in patients with pre-hospital delay more than 24 h, as against 5% when admitted within the above specified period (p = <0.001). The strength of this study is the accrued information of over a period of 10 years of snake-bite management through the Emergency Department of a university hospital setting. The limitations are the retrospective study design and the rejection percentage of 15.5% due to insufficient information from the total chart pool. PMID- 22234396 TI - Functional mapping of the A2 domain from human factor VIII. AB - Coagulation factor VIII (FVIII) is a multidomain glycoprotein in which the FVIII A2 domain is a key structural element. We aimed at identifying residues within FVIII A2 domain that are crucial for the maintenance of the cofactor function. A high number (n=206) of mutants were generated by substituting original residues with alanine. The mutants were expressed in COS-1 cells and their antigen levels and procoagulant activities were measured. The residues were classified in three categories: those with a non-detrimental alteration of their activities (activity >50 % of control FVIII; n=98), those with a moderate alteration (15 % 100 ug/mL) against all the tested microorganisms. PMID- 22234411 TI - History and epidemiology of Swine influenza in Europe. AB - In Europe, swine influenza is considered one of the most important primary pathogens of swine respiratory disease and infection is primarily with H1N1, H1N2 and H3N2 influenza A viruses. The antigenetic characteristics of these viruses distinguish them from others circulating at a global level in pigs. These viruses have remained endemic in European pig populations but significant differences in the circulation of these strains occur at a regional level across Europe. The dynamic of co-circulation of viruses, impact of prior immunity, husbandry practices and other local factors all contribute to the complex epidemiology. Surveillance programmes in European pigs did not reveal the presence of pandemic H1N1 virus prior to its detection in humans in 2009 but there is evidence that the virus can be maintained in European pigs even when there are relatively good levels of herd immunity to other H1 viruses. Evidence for the pig as a 'mixing vessel' of influenza viruses of non-swine-origin has been demonstrated in Europe on several occasions. Furthermore significant and highly variable genetic diversity occurs at the whole genome level for all virus subtypes and this has contributed to changing patterns of virus epidemiology over time. PMID- 22234412 TI - Are temporomandibular disorder symptoms and diagnoses associated with pubertal development in adolescents? An epidemiological study. AB - BACKGROUND: In addition to low back pain, temporomandibular disorders (TMDs) are the most prevalent pain- and disability-related musculoskeletal conditions. However, the influence of pubertal development on TMD diagnoses remains unknown. OBJECTIVE: To assess whether the prevalence of TMD diagnoses, in addition to self reported symptoms (pain, restricted mandibular mobility, clicking), change according to pubertal stage. METHODS: A random sample of 1,011 children and adolescents was chosen from the general population of 24,129 children and adolescents aged 10-17 years living in the urban area of Halle, Germany. Study participants were examined for TMD symptoms and diagnoses according to the Research Diagnostic Criteria for TMDs (RDC/TMD). Status of pubertal development was assessed using the Pubertal Development Scale (PDS). The chi(2) tests and multivariate logistic regression models were used, and odds ratios (ORs) and 95% confidence intervals calculated. RESULTS: The observed increase in TMD symptoms during adolescence was mainly due to the higher frequency of self-reports of these symptoms by girls than boys (ORs for girls vs. boys: 1.42-1.53; p <= 0.05), whereas clinical TMD diagnoses (any RDC/TMD diagnosis, or RDC/TMD group IIa diagnosis) in adolescence increased mainly due to pubertal development itself (ORs for subjects beyond vs. before puberty: 1.58-2.00; p < 0.05; no significant sex-related effect was found). CONCLUSION: Pubertal development increases the probability of self-reported TMD symptoms among girls, while the probability thereof decreases among boys. Independent of sex, pubertal growth increases the prevalence of RDC/TMD-related diagnoses-mainly disk displacement-in both sexes. PMID- 22234414 TI - Morphological and structural characteristics of orthodontic mini-implants. AB - AIM: The purpose of this study was to investigate the geometric characteristics, composition, microstructure, and pullout strength of commercially available orthodontic mini-implants. MATERIAL AND METHODS: The mini-implants used were AbsoAnchor(r), Dual-TopTM JA, Spider Screws(r) K1, and Vector-TASTM. The geometric features were measured by optical microscopy. Surface texture and elemental composition were examined by scanning electron microscopy and energy dispersive X-ray microanalysis. Surface 3D roughness was estimated by optical profilometry, and pullout strength measured in artificial bone blocks with two bone densities. RESULTS: The AbsoAnchor(r) showed the highest intra-osseous surface area, followed by the Dual-TopTM, Spider Screw(r), and Vector-TASTM. The mini-implants were composed of a Ti6Al4V alloy. The Vector-TASTM had the highest oxygen and phosphorus content with the most homogeneous surface texture. No significant differences were detected in amplitude surface roughness parameters (Sa, Sz) between the implants. However, differences existed in hybrid (Sdr, Sds) and functional (Sci) parameters. AbsoAnchor(r) achieved the highest pullout strength, followed by the Dual-TopTM, Spider Screw(r), and Vector-TASTM, with highest values in the high density group. The intra-osseous surface area of mini implants showed a positive correlation with pullout strength, especially in the high density group. CONCLUSION: All the mini-implants tested were made of Ti6Al4V alloy. Significant differences were found in the surface area of the threaded parts. The significant differences documented in 3D surface roughness parameters (hybrid and functional) and pullout strength may anticipate variations in their clinical performance. PMID- 22234413 TI - Orthodontic screws to extrude impacted maxillary canines. AB - OBJECTIVE: The impaction of maxillary canines is a frequently encountered clinical problem in orthodontic practice. Patients' refusal to participate in long-term treatment or ankylosis of the impacted tooth result in various treatment difficulties. The aim of this study was to evaluate the possible role of mini-screws in the management of unerupted upper canines. PATIENTS AND METHODS: In a series of 63 consecutive patients (27 males and 36 females, age range 14-49 years, mean 22.7 years) with a total of 69 impacted maxillary canines, each impacted tooth was surgically exposed and an attachment bonded. An intraosseous screw with an endosseous body and intraoral neck section was inserted into the premolar-molar interradicular space. Following soft tissue healing, orthodontic traction was initiated. After correction of the canine angulation, the mini-screw was removed and conventional orthodontic therapy completed. RESULTS: Of the 69 canines, 61 (88.41%) were extruded successfully. In the 7 cases that failed, skeletal anchorage spared both patients and clinicians the disappointment of customary long-term, unsuccessful orthodontic therapy. In one patient, the mini-screw was removed because of inflammation and pain before initiating orthodontic traction. CONCLUSION: Our results demonstrate that mini screw anchorage should be taken into consideration when extrusion of an impacted canine is planned. PMID- 22234416 TI - Nutrient removal and energy production in a urine treatment process using magnesium ammonium phosphate precipitation and a microbial fuel cell technique. AB - Urine pretreatment has attracted increasing interest as it is able to relieve the nitrogen and phosphorus overloading problems in municipal wastewater treatment plants. In this study, an integrated process, which combines magnesium ammonium phosphate (MAP) precipitation with a microbial fuel cell (MFC), is proposed for the recovery of a slow-release fertilizer and electricity from urine. In such a two-step process, both nitrogen and phosphorus are recovered through the MAP process, and organic matters in the urine are converted into electricity in the MFCs. With this integrated process, when the phosphorus recovery is maximized without a dose of PO(4)(3-)-P in the MAP precipitation process, removal efficiencies for PO(4)(3)-P and NH(4)(+)-N of 94.6% and 28.6%, respectively, were achieved with a chemical oxygen demand (COD) of 64.9% accompanied by a power output of 2.6 W m(-3). Whereas removal efficiencies for PO(4)(3)-P and NH(4)(+)-N of 42.6% and 40%, respectively, and a COD of 62.4% and power density of 0.9 W m( 3) were obtained if simultaneous recovery of phosphorus and nitrogen was required through dosing with 620 mg L(-1) of PO(4)(3-)-P in the MAP process. This work provides a new sustainable approach for the efficient and cost-effective treatment of urine with the recovery of energy and resources. PMID- 22234417 TI - Predicting efficacy of photodynamic therapy by real-time FDG-PET in a mouse tumour model. AB - Dynamic positron emission tomography (PET) combined with the constant infusion of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) as a tracer permits real-time monitoring of systemic transient metabolic changes resulting from photodynamic therapy (PDT) in tumour bearing animals. The effect of PDT on tumour FDG uptake rates was evaluated using four different sulfonated phthalocyanine analogs as photosensitizers (PS) in combination with either continuous or fractionated illumination protocols. Mice bearing two EMT-6 tumours were infused with FDG to start PDT 30 min later. Dynamic images were acquired to produce FDG uptake over time for the treated and reference tumours. Practically all PDT protocols induced a reduction in the FDG uptake rates in the treated tumour during PDT, except for the zinc tetrasulfophthalocyanine, when using fractionated light, reflecting the low photodynamic efficacy of this PS. In general, the response to PDT was characterized by a rebound in the FDG uptake rate after illumination. A strong drop in FDG tumour uptake rates during PDT, followed by a strong rebound, together with short delay-to-response times, corresponded to optimal long-term tumour response outcomes. This dynamic FDG-PET protocol provides real-time observations to predict long-term PDT efficacy, while using fewer animals than conventional methods, thus making possible the rapid optimization of treatment parameters. PMID- 22234418 TI - Impact of directed movement on invasive spread in periodic patchy environments. AB - To address the effect of taxis of invasive animals on their spreading speed in heterogeneous environments, we deal with an advection-diffusion-reaction equation (ADR) in a periodic patchy environment. Two-types of advection that spatially vary depending on environmental heterogeneity are taken into consideration: a stepwise taxis function and a saw-like taxis function. We first analyze the ADR with the stepwise taxis advection, and derive an invasion criterion. When the invasion criterion holds, an initially localized population evolves to a traveling periodic wave (TPW). The asymptotic speed of the TPW is found to be equal to the minimal speed of the TPW analytically derived. Thus, we examine how the minimal speed is influenced by the taxis. The major results are: (1) As the magnitude of the taxis toward favorable patches increases, invasion becomes more feasible. However, the spreading speed increases at first, and then decreases to show a one-humped curve against the magnitude of the taxis; (2) As the scale of fragmentation in the patchy environment is increased, the spreading speed increases when the magnitude of the taxis is small, while it decreases when the magnitude of the taxis becomes sufficiently large. These characteristic features qualitatively apply to the ADR model with the saw-like taxis function. PMID- 22234419 TI - Searching for ancestral areas and artifactual centers of origin in biogeography: with comment on east-west patterns across Southern Australia. PMID- 22234420 TI - Modular recognition of nucleic acids by PUF, TALE and PPR proteins. AB - Sequence specific binding of DNA and RNA is of fundamental importance in the regulation of cellular gene expression. Because of their modular structure repeat domain proteins are particularly well suited for these processes and have been widely adopted throughout evolution. Detailed biochemical and structural data has revealed the key residues responsible for recognition of RNA by Pumilio and FBF homology (PUF) repeat proteins and shown that the base specificity can be predicted and re-engineered. Recent work on the DNA-binding properties of transcription activator-like effector (TALE) proteins has shown that their specificity also relies on only a few key residues with a predictable code that can be used to design new DNA-binding proteins. Although less well understood, pentatricopeptide repeat (PPR) proteins contain motifs that appear to contribute to RNA recognition and comparisons to TALE and PUF proteins may help elucidate the code by which they recognize their RNA targets. Understanding how repeat proteins bind nucleic acids enables their biological roles to be uncovered and the design of engineered proteins with predictable RNA and DNA targets for use in biotechnology. PMID- 22234421 TI - Effect of lymphocytes culture variations on the mitotic index and on the dicentric yield following gamma radiation exposure. AB - Fundamentals of biological dosimetry are described in the International Atomic Energy Agency manual, but all over the world each laboratory is using its own protocol. To test the influence of protocol variations, some blood samples were exposed to 0.5 Gy of gamma radiation and mitotic index and dicentric rates were measured under different experimental conditions. The effect of seven parameters [bromodeoxyuridin (BrdU), phytohaemagglutinin and colcemid concentrations, blood and medium volumes, culture duration and incubation temperature] was tested using a Placket and Burman experimental design. The analysis reveals that the mitotic index was influenced by the concentration of BrdU, medium and blood volumes, the culture duration and the temperature. However, none of the factors has a significant impact on the yield of dicentrics. The dicentric assay is robust against reagent variations within the range tested. These results could be used by relevant laboratories as elements of their procedures robustness in any event requiring such demonstration. PMID- 22234422 TI - Radiation exposure of the operator during cardiac catheter ablation procedures. AB - Radiation exposure of the operator during cardiac catheter ablation procedures was assessed for an experienced cardiologist adopting various measures of radiation protection and utilised electroanatomic navigation. Chip thermoluminescent dosemeters were placed at the eyes, chest, wrists and legs of the operator. The ranges of fluoroscopy time and air kerma area product values associated with cardiac ablation procedures were wide (6.3-48.3 min and 1.7-80.3 Gy cm(2), respectively). The measured median radiation doses per procedure for each monitored position were 23.6 and 21.3 MUSv to the left and right wrists, respectively, 25.3 and 30.4 MUSv to the left and right legs, respectively. The doses to the eyes were below the minimum detectable dose of 9 MUSv. The estimated median effective dose was 22.5 MUSv. Considering the actual workload of the operator, the calculated annual doses to the hands, legs and eyes, as well as the annual effective dose, were all below the corresponding limits. The findings of this study indicate that cardiac ablation procedures performed at a modern laboratory do not impose a high radiation hazard to the operator when radiation protection measures are routinely adopted. PMID- 22234423 TI - Radiofrequency fields associated with the Itron smart meter. AB - This study examined radiofrequency (RF) emissions from smart electric power meters deployed in two service territories in California for the purpose of evaluating potential human exposure. These meters included transmitters operating in a local area mesh network (RF LAN, ~250 mW); a cell relay, which uses a wireless wide area network (WWAN, ~1 W); and a transmitter serving a home area network (HAN, ~70 mW). In all instances, RF fields were found to comply by a wide margin with the RF exposure limits established by the US Federal Communications Commission. The study included specialised measurement techniques and reported the spatial distribution of the fields near the meters and their duty cycles (typically <1 %) whose value is crucial to assessing time-averaged exposure levels. This study is the first to characterise smart meters as deployed. However, the results are restricted to a single manufacturer's emitters. PMID- 22234424 TI - Fertility preservation practices among Ontario oncologists. AB - This study explores the attitudes, knowledge, and referring behaviors in fertility preservation among Ontario physicians providing adult cancer care. Ontario physicians with specialties in medical oncology, radiation oncology, gynaecologic oncology, and urology were invited to complete a 48-item questionnaire. A total of 152 questionnaires were available for analysis with a response rate of 23.7%. Seventy-four percent of the physicians indicated that they rarely or never modified cancer treatment due to concern about future fertility. Differences were found in fertility preservation knowledge among respondents in different medical specialties (p < 0.01) and clinical settings (p < 0.05). The frequency of initiating a referral was strongly associated with knowing where to refer patients (p < 0.001). The odds of knowing where to refer cancer patients was higher for physicians who work in a teaching hospital (p < 0.01) and a cancer centre (p < 0.01) compared with those who primarily work in a community setting. About 45% did not know where to refer female patients, and 69.7% rarely ever made a fertility preservation consultation referral for their female patients. The majority of respondents had positive attitudes despite their lack of current knowledge in cryopreservation services and fertility preservation options through assisted reproductive technologies. Our findings provide further insights of the relevance of considering physicians' medical backgrounds and practice settings when designing training modules to raise their awareness in fertility preservation issues. PMID- 22234425 TI - Performance of five D-dimer assays for the exclusion of symptomatic distal leg vein thrombosis. AB - The diagnostic value of D-dimer (DD) in the exclusion of proximal deep-vein thrombosis (DVT) is well-established but is less well-known in the exclusion of distal (infrapopliteal) DVT. Therefore, we evaluated the diagnostic abilities of five DD assays (Vidas-DD, Liatest-DD, HemosIL-DD, HemosIL-DDHS, Innovance-DD) for excluding symptomatic proximal and distal leg DVT. A total of 243 outpatients whose symptoms were suggestive of DVT received complete compression ultrasonography (cCUS) of the symptomatic leg(s). The clinical probability of DVT (PTP) was assessed by Wells score. Thirty-eight proximal and 31 distal DVTs (17 tibial/fibular DVTs, 14 muscle DVTs) were diagnosed by cCUS. Although all assays showed high sensitivity for proximal DVT (range 97-100%), the sensitivity was poor for distal DVT (range 78-93%). None of the assays were individually able to rule out all DVTs as a stand-alone test (negative predictive value [NPV] 91-96%). However, a negative DD test result combined with a low PTP exhibited a NPV of 100% for all DVTs (including proximal, tibial/fibular, and muscle DVTs) with the HemosIL-DDHS and Innovance-DD. All proximal and tibial/fibular DVTs, but not all muscle DVTs, could be ruled out with this strategy using the Liatest-DD and Vidas DD. The HemosIL-DD could not exclude distal leg DVT, even in combination with a low PTP. The combination of a negative DD with a low PTP showed a specificity of 32-35% for all DVTs. In conclusion, our study shows that when used in conjunction with a low PTP some DD assays are useful tools for the exclusion of distal leg DVT. PMID- 22234426 TI - Efficient iron(III)-catalyzed three-component coupling reaction of alkynes, CH2Cl2 and amines to propargylamines. AB - An iron(III)-catalyzed three-component coupling reaction of alkynes, CH(2)Cl(2) and amines was developed for facile synthesis of propargylamines. Preliminary mechanism investigation using in situ FT-IR reveals that the crucial Fe-acetylide intermediate could be formed through C-H bond activation of alkynes thanks to cooperative effect of FeCl(3) and 1,1,3,3-tetramethylguanidine. PMID- 22234427 TI - Persistent sodium current and Na+/H+ exchange contributes to the augmentation of the reverse Na+/Ca2+ exchange during hypoxia or acute ischemia in ventricular myocytes. AB - The increases in persistent sodium currents (I (Na.P)) and Na(+)/H(+) exchange (NHE) causes intracellular Ca(2+) overload. The objective of this study was to determine the contribution of I (Na.P) and NHE on the hypoxia- or acute ischemia induced increase in the reverse Na(+)/Ca(2+) exchange current (HIR- or AIR-I (NCX)). I (Na.P) and I (NCX) in rabbit ventricular myocytes were recorded during hypoxia or acute ischemia, combination of acidosis (pH values were 6.0 intracellularly and 6.8 extracellularly) and hypoxia, using whole-cell patch clamp techniques. The results indicate that (1) under hypoxic condition, the augmentation of both HIR-I (NCX) and I (Na.P) was inhibited by TTX (2 to 8 MUM) in a concentration-dependent manner. The inhibitions of I (Na,P) and HIR-I (NCX) reached maximum in the presence of either 4 MUM TTX or 10 MUM KR-32568 (a NHE inhibitor), respectively. The maximal inhibitions of HIR-I (NCX) by 4 MUM TTX and 10 MUM KR-32568 were 72.54% and 16.89%, respectively. (2) Administration of 2 MUM TTX and 10 MUM KR-32568 in either order in the same cells decreased HIR-I (NCX) by 64.83% and 16.94%, respectively. (3) I (Na.P) and the reverse I (NCX) were augmented during acute ischemia. TTX (4 MUM) and KR-32568 (10 MUM) reduced AIR-I (NCX) by 73.39% and 24.13%, respectively. (4) Under normoxic condition, veratridine (20 MUM) significantly increased I (Na.P) and the reverse I (NCX), which was reversed by 4 MUM TTX. In conclusion, during hypoxia or acute ischemia, both increased I (Na.P) and NHE contribute to the HIR- or AIR-I (NCX) with the former playing a major role comparing with the latter. PMID- 22234428 TI - Composition of extrafloral nectar influences interactions between the myrmecophyte Humboldtia brunonis and its ant associates. AB - Ant-plant interactions often are mediated by extrafloral nectar (EFN) composition that may influence plant visitation by ants. Over a 300 km range in the Indian Western Ghats, we investigated the correlation between the EFN composition of the myrmecophytic ant-plant Humboldtia brunonis (Fabaceae) and the number and species of ants visiting EFN. EFN composition varied among H. brunonis populations and between plant organs (floral bud vs. young leaf EFN). In general, EFN was rich in sugars with small quantities of amino acids, especially essential amino acids, and had moderate invertase activity. In experiments at the study sites with sugar and amino acid solutions and with leaf or floral bud EFN mimics, dominant EFN feeding ants differentiated between solutions as well as between mimics. The castration parasite Crematogaster dohrni (northern study site) was the least selective and did not exhibit any clear feeding preferences, while the largely trophobiont-tending non-protective Myrmicaria brunnea (middle study site) preferred higher sucrose concentrations and certain essential/non-essential amino acid mixtures. The mutualistic Technomyrmex albipes (southern study site) preferred sucrose over glucose or fructose solutions and consumed the leaf EFN mimic to a greater extent than the floral bud EFN mimic. This young leaf EFN mimic had low sugar concentrations, the lowest viscosity and sugar:amino acid ratio, was rich in essential amino acids, and appeared ideally suited to the digestive physiology of T. albipes. This preference for young leaf EFN may explain the greater protection afforded to young leaves than to floral buds by T. albipes, and may also help to resolve ant-pollinator conflicts. The differential response of dominant ants to sugar, amino acids, or solution viscosity suggests that plants can fine-tune their interactions with local ants via EFN composition. Thus, EFN can mediate local partner-choice mechanisms in ant-plant interactions. PMID- 22234429 TI - Hydrocarbon signatures of egg maternity, caste membership and reproductive status in the common wasp. AB - In most ants, bees, and wasps, the workers are capable of challenging the reproductive monopoly of the queen by laying unfertilized, male eggs. An important mechanism that can resolve this conflict is policing, whereby the queen or workers prevent successful worker reproduction by selectively eating worker laid eggs or by attacking egg-laying workers. Egg policing by workers has been shown to occur in several social wasp species, but the information used by worker wasps to discriminate between queen-laid and worker-laid eggs has never been investigated. Our aim, therefore, was to investigate if hydrocarbons might be used in egg policing by workers in the common wasp, Vespula vulgaris, where worker policing previously has been shown to be effective. Our results show that 51 different hydrocarbons are present on the surface of newly-laid eggs, and that there are pronounced quantitative differences in the hydrocarbon profiles of queen-laid and worker-laid eggs, with longer-chained alkenes and methylated alkanes (C(28)-C(31)) in particular being more abundant on the surface of queen laid eggs. We further show that the hydrocarbon profiles on the surface of queen laid and worker-laid eggs resemble those found on the mother queen's and workers' cuticles. Interestingly, longer-chained methylated alkanes also were more abundant on the cuticle of both mother queens and reproductive workers, suggesting that these compounds are linked to fertility, as has also been found to be the case in several ant species. PMID- 22234431 TI - With long hours of work, might depression then lurk? A nationwide prospective follow-up study among Danish senior medical consultants. AB - OBJECTIVE: The aim of this study was to examine depression as a potential negative health effect of long work hours, anticipating an exposure-response relationship. METHOD: A nationwide prospective cohort study of 2790 Danish senior medical consultants was conducted (61.7% response rate). With the consent of Danish Data Protection Agency, data from a questionnaire survey was linked with data from a Medical Products Agency Register. Long work hours were defined based on a self-reported average of weekly work hours >40, while redemption of anti depressive (AD) drug prescriptions defined depression. Proportional hazards Cox regression analyses were conducted adjusting for gender, age, marital status, medical specialty, decision authority at work, work social support, quantitative work demands, and AD drugs prescribed before baseline. RESULTS: Long weekly work hours did not increase the risk of redeeming AD drug prescriptions at all times during follow-up compared to the reference of 37-40 work hours [41-44 hours: hazard ratio (HR) 0.95, 95% confidence interval (95% CI) 0.5-1.8; 45-49 hours: HR 0.88, 95% CI 0.4-1.8; 50-54 hours: HR 0.83, 95% CI 0.3-2.1; 55-59 hours: HR 0.67, 95% CI 0.2-2.9; >= 60 hours: HR 0.48, 95% CI 0.1-3.7]. The same result emerged when work hours was applied in a continuous form (from 25-36 hours to 37-40 hours to 41-44 hours and so on) (HR 0.93, 95% CI 0.76-1.13) and when robust analyses were conducted (data not shown). CONCLUSIONS: This study does not support the anticipation that long work hours increase the risk of depression. If anything, long work hours vaguely appear to decrease the risk of redeeming AD drug prescriptions. PMID- 22234432 TI - Enhanced piezoresponse of electrospun PVDF mats with a touch of nickel chloride hexahydrate salt. AB - PVDF nanofibers are prepared using electrospinning. The effect of addition of a hydrated salt, nickel chloride hexahydrate (NiCl(2).6H(2)O), on the phase formation is examined. Addition of the hydrated salt (NC) is found to enhance the polar beta phase by about 30%. The peak to peak piezo-voltage generated for PVDF NC is almost 0.762 V, a factor of 3 higher than that for PVDF. The fiber mats exhibit a significantly enhanced dynamic strain sensor response. The voltage generated per unit micro-strain developed during the free vibration test for PVDF was 0.119 mV whereas it was 0.548 mV for PVDF NC, exhibiting a non-linearly enhanced performance vis a vis the increase in the beta phase component. PMID- 22234433 TI - Multiple Synchronous Tumors in a Patient: A Rare Entity. PMID- 22234434 TI - People post-stroke perceive movement fluency in virtual reality. AB - We investigated the visual perception of biological movement by people post stroke, using minimal kinematic displays. A group of twenty patients and a group of twelve age-matched healthy controls were asked to judge movement fluency. The movements to judge were either displayed as an end-point dot or as a stick-figure of the arm and trunk. It was found that the perception of movement fluency was preserved post-stroke, however, with an increase in the variability of judgment. Moreover, the end-point dot representation ameliorated what was perceived and judged, presumably by directing attention to the important kinematic cues: smoothness and directness of the trajectory. We conclude that, despite perception of actions is influenced by the ability of the observer to execute the observed movement, hemiparesis has a mild effect on the perception of biological movement. Yet, a valuable virtual learning environment for upper-limb rehabilitation should be implemented to provide the observer with neither too much, nor too little information to maximize learning. PMID- 22234435 TI - Reduced interhemispheric inhibition in mild cognitive impairment. AB - In mild cognitive impairment (MCI), the corpus callosum is known to be affected structurally. We evaluated callosal function by interhemispheric inhibition (IHI) using transcranial magnetic stimulation (TMS) in MCI patients. We investigated 12 amnestic MCI patients and 16 healthy age-matched control subjects. The IHI was studied with a paired-pulse TMS technique. The conditioning TMS was given over the right primary motor cortex (M1) and the test TMS over the left M1. Motor evoked potentials were recorded from the relaxed first dorsal interosseous muscle. We also studied other motor cortical circuit functions; short-latency afferent inhibition (SAI), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Both the amount of IHI and SAI were significantly reduced in MCI patients as compared with control subjects, whereas SICI or ICF did not differ between them. The degree of IHI significantly correlated with neither the mini-mental state examination score nor the degree of SAI. Our results suggest that transcallosal connection between bilateral M1 is primarily involved in MCI, regardless of SAI dysfunction. PMID- 22234436 TI - Efficacy of HIV/STI behavioral interventions for heterosexual African American men in the United States: a meta-analysis. AB - This meta-analysis estimates the overall efficacy of HIV prevention interventions to reduce HIV sexual risk behaviors and sexually transmitted infections (STIs) among heterosexual African American men. A comprehensive search of the literature published during 1988-2008 yielded 44 relevant studies. Interventions significantly reduced HIV sexual risk behaviors and STIs. The stratified analysis for HIV sexual risk behaviors indicated that interventions were efficacious for studies specifically targeting African American men and men with incarceration history. In addition, interventions that had provision/referral of medical services, male facilitators, shorter follow-up periods, or emphasized the importance of protecting family and significant others were associated with reductions in HIV sexual risk behaviors. Meta-regression analyses indicated that the most robust intervention component is the provision/referral of medical services. Findings indicate that HIV interventions for heterosexual African American men might be more efficacious if they incorporated a range of health care services rather than HIV/STI-related services alone. PMID- 22234437 TI - [Health-care provision - health-care planning - health-care politics - health care research]. PMID- 22234438 TI - [The most cited work in the 36th year of "Psychiatrischen Praxis." Congratulations!]. PMID- 22234439 TI - [Closed psychiatric homes]. PMID- 22234440 TI - [German language psychiatry journals in Germany - a quantitative analysis]. AB - OBJECTIVE: Although English is medicine's lingua franca, practising physicians in Germany express the need for articles in German. This study aimed at surveying the number and characteristics of German-language psychiatric journals in Germany. METHODS: Journals were identified by the standard handbook "Fachmedien Gesundheit" as well as by an online and library search, and divided into specialty journals and general psychiatry journals. Volume 2009 of all general psychiatry journals was analyzed regarding form and content. RESULTS: In 2009 74 journals addressed psychiatrists, albeit many not exclusively. Ten were general psychiatry journals publishing 391 review articles and 97 original papers. They differed with regard to focus (science, education, health politics) and formal characteristics, such as circulation (500-30 000), share of academia-affiliated authors (39-93 %), female first-authors (13-44 %), COI statements (0-98 % of articles), and international visibility. CONCLUSIONS: While much of German psychiatric science appears in English, there are still a substantial number of original articles published in German, and there is a diverse psychiatric journal scene in Germany. PMID- 22234441 TI - [Mental health in the working world from the perspective of occupational physicians]. AB - OBJECTIVE: As a contact person for mental health problems, occupational physicians have a wide range of tasks including the assessment and adaption of company-related psychosocial conditions and the implementation of treatment and rehabilitation measures. It is of interest how they perceive the relevance and occurrence of mental disorders on one hand, and the prevention and treatment of employees' mental disorders within the company on the other. METHOD: Data collection with paper-and-pencil and Internet survey. Statistical analysis was performed with PASW. RESULTS: The majority said that sickness absence and occupational invalidity due to mental disorders have increased in the past years. 65.4 % of the company physicians said that their company has not implemented any prevention programmes. About one third said that mental disorders are handled differently in comparison to physical disorders (insecurity, concealment and social exclusion of the persons affected). Information and education of the company's management are of great importance. CONCLUSION: There is need for action when it comes to the qualification and further education of occupational physicians and the implementation of prevention programmes. PMID- 22234442 TI - [Ketamine-induced vesicopathy]. AB - We report about a 25-year-old patient with transnasal ketamine abuse over years presenting with severe irritative urinary dysfunction (imperative urinary urgency, pollakisuria, dysuria) and severe alguria. Cystoscopia showed ketamine induced vesicopathy with errosive cystitis; other etiologies could be excluded. Despite serious effort the patient was not motivated for abstinence from ketamine. After two ineffecient therapies with botulinum toxin A (200 and 400 I. E.) injected into the bladder, a prostate preserving cystectomia and ileum neobladder were mandatory. PMID- 22234443 TI - Highly efficient sorghum transformation. AB - A highly efficient microprojectile transformation system for sorghum (Sorghum bicolor L.) has been developed by using immature embryos (IEs) of inbred line Tx430. Co-bombardment was performed with the neomycin phosphotransferase II (nptII) gene and the green fluorescent protein (gfp) gene, both under the control of the maize ubiquitin1 (ubi1) promoter. After optimization of both tissue culture media and parameters of microprojectile transformation, 25 independent transgenic events were obtained from 121 bombarded IEs. The average transformation frequency (the total number of independent transgenic events divided by the total number of bombarded IEs) was 20.7% in three independent experiments. Transgenic events were confirmed by both PCR screening and Southern hybridization of genomic DNA from primary transgenics (T0). More than 90% of transformants were fertile and displayed normal morphology in a containment glasshouse. Co-transformation rate of the nptII and gfp genes was 72% in these experiments. The segregation of nptII and gfp in T1 progenies was observed utilizing fluorescence microscopy and geneticin selection of seedlings indicating both were inherited in the T1 generation. The transformation procedure, from initiating IEs to planting putative transgenic plantlets in the glasshouse, was completed within 11-16 weeks, and was approximately threefold more efficient than the previously reported best sorghum transformation system. PMID- 22234444 TI - The natural DNA bending angle in the lac repressor headpiece-O1 operator complex is determined by protein-DNA contacts and water release. AB - We performed molecular dynamics simulations of the lac repressor headpiece-O1 operator complex for natural, over and underbent DNA to assess the factors that determine the natural DNA bending angle. At the natural angle, the specific and nonspecific contacts between the protein and DNA are optimized. Protein-DNA contacts show different angle dependences in the right and left sites, with the left site generally getting weaker and the right site getting stronger as the bending angle increases. Two entropic factors were identified as well: at the natural bending angle, water release and the quasiharmonic protein configurational entropy are maximized. The gain in protein configurational entropy might stem from an entropy-entropy compensation mechanism, in which a reduction in protein fluctuations is offset by a loss in correlations between the right and left sites. PMID- 22234445 TI - Thoracic endometriosis unmasked by ovarian hyperstimulation for in vitro fertilization. AB - Thoracic endometriosis syndrome is a well-described, rare manifestation of endometriosis. We present a case of a 35-year old woman undergoing controlled ovarian stimulation prior to in vitro fertilization (IVF) who developed bilateral hemorrhagic pleural effusions. She was initially diagnosed with ovarian hyperstimulation syndrome, a complication of infertility therapy; however, she was later found to have occult thoracic endometriosis. We describe ovarian hyperstimulation syndrome and review the manifestations of thoracic endometriosis syndrome. Although endometriosis is a hormone-dependent disease, the rate of IVF complications related to endometriosis is low. PMID- 22234446 TI - Language-induced modulation during the prediction of others' actions. AB - Processing of action words has been shown to influence the perception of the actions the words refer to. Specifically, the accuracy with which people predict the future course of actions observed in another individual seems to be affected by verbal primes. Two processes may be involved in action prediction; dynamic simulation (updating) and static matching. The present study examined this issue by testing the impact of action verb processing on action prediction performance using a masked priming paradigm. Evidence of dynamic updating was revealed after prime verbs expressing dynamic actions (e.g., 'to catch') but not those expressing static actions (e.g., 'to lean'). In contrast to previous work, the primes were masked and did not require any response at all. Hence, our results indicate that implicit action-related linguistic processing may trigger action simulation that in turn might affect action prediction (see also Liepelt, Dolk, & Prinz, Psychological Research, 2012, in this issue). PMID- 22234447 TI - Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Increased complement activation has been implicated in the pathogenesis of APS in animal models. It was our objective to evaluate complement activation in patients with aPL or primary antiphospholipid syndrome (PAPS). We measured complement activation products, fragments Bb and C3a desArg by ELISA in 186 aPL/PAPS patients and 30 healthy controls. All patients with aPL had significantly increased levels of complement activation products. Fragment Bb levels (mean, 95% CI); (thrombotic APS 0.54 units/ml, 0.31-0.83, obstetric APS 0.60 units/ml,0.39-1.02, isolated aPL 0.48 units/ml, 0.29-0.85, overall 0.39 units/ml, 0.33-0.47) and C3a-desArg levels (mean, 95% CI): (thrombotic APS 261 ng/ml, 219-311, obstetric APS 308 ng/ml, 243-391, isolated aPL 258 ng/ml, 193-337, overall 225 ng/ml, 202-251) were significantly higher compared to controls (fragment Bb 0.06 units/ml, 0.03-0.11, C3a-desArg 69 ng/ml, 50-92). There were correlations between Fragment Bb and C3a-desArg levels in all patients with aPL. Receiver operator characteristic (ROC) analysis showed increased fragment Bb and C3a-desArg levels had strong associations with the presence of persistent lupus anticoagulant (area under ROC: Bb 0.89, and C3a desArg 0.90), dual and triple aPL positivity (Bb 0.71-0.82, C3a-desArg 0.71-0.80) but not with high titre anti-cardiolipin antibodies (Bb 0.62, C3a-desArg 0.65), or anti beta2-glycoprotein 1 antibodies (Bb 0.66, C3a-desArg 0.67). Complement activation is present in all patient groups within this large cohort of patients aPL. This suggests it may have a major role in the pathogenesis of APS and merits further study. PMID- 22234448 TI - Bonding situation and N-O-bond strengths in amine-N-oxides--a combined experimental and theoretical study. AB - The bonding situation and energetics of the N-O bond in a series of amine-N oxides, Ph(x)(CH(3))(3-x)N-O, where x = 0-3, were analyzed experimentally and theoretically. There is a notable nearly linear decrease of the N-O bond dissociation energies (BDEs) for this series with an increasing number of phenyl groups x. This was investigated experimentally by X-ray high angle multipole refinement techniques in combination with subsequent topological analysis of the electron density for the representative (CH(3))(2)PhN-O, 2, and complementary theoretical calculations at the DFT and multireference CASSCF and MR-perturbation theory (MCQDPT2) levels. Both the theoretical and experimental results unambiguously revealed a polar covalent sigma-bond for the N-O bond with an essentially identical bonding situation for all amine-N-oxides studied. This apparent disparity between the bonding situation and the trend of BDEs is attributed to the large differences of the relaxation energies of the corresponding amines Ph(x)(CH(3))(3-x)N, (x = 0-3), respectively, the required preparation energies (DeltaE(prep)) for the reverse N-O bond forming process. The detailed theoretical analysis of the amines allowed us to trace the trend of larger values of DeltaE(prep) for a higher number of phenyl groups x to an increase of n(N) -> pi*(C-C) delocalization interactions. PMID- 22234449 TI - Urogenital sinus cyst in a 21-year-old man. AB - We report a case of a rare congenital malformation, a urogenital sinus cyst in a young patient with non-specific symptoms for several months. A 21-year-old male presented with vague and intermittent abdominal pain. Ultrasound scan showed a retrovesical hypoechoic collection (approximately 6 cm) and left renal agenesis, compatible with a possible congenital malformation. These findings were confirmed by MRI. A laparoscopic excision of the cyst was performed with no complications. Pathology report confirmed a urogenital sinus cyst. The postoperative recovery was uneventful and the patient was discharged within 48 h. Urogenital sinus cysts are rare entities with few cases described in the literature. Imaging techniques such as ultrasound, CT or MRI may help with diagnosis. Therapeutic modalities range from observation to needle aspiration or surgical removal. In our case, we chose a laparoscopic approach to minimize morbidity and achieve an early recovery. PMID- 22234451 TI - Highly selective, naked-eye and fluorescent "off-on" probe for detection of histidine/histidine-rich proteins and its application in living cell imaging. AB - A highly selective colorimetric and fluorescence enhanced probe S1 (M2@Cu) for histidine and histidine-rich proteins has been developed. In neutral aqueous ethanol solution, probe S1 can selectively detect histidine out of twenty DNA encoded amino acids by showing a color change from brownish red to light green, and with a fluorescence enhancement up to 99-fold at 537 nm, simultaneously. PMID- 22234452 TI - [Langerhans cell histiocytosis as a cause of central diabetes insipidus: MR findings typical of cerebral imaging]. PMID- 22234453 TI - [Contrast agent changes of pineal cysts in late post-contrast acquired images: case report and case series]. PMID- 22234454 TI - [Unruptured brain aneurysms: when to screen and when to treat?]. AB - The detection rate of intracranial aneurysms has increased with the improved availability of non-invasive imaging methods. Moreover, persons who have relatives with intracranial aneurysms increasingly demand imaging to rule out aneurysms. To deal with these problems, radiologists require basic knowledge regarding the detection and treatment of unruptured intracranial aneurysms. The prevalence of aneurysms in the normal population is 2 - 3 %. It increases to 4 - 10 % in persons with one relative with an aneurysm and to about 20 % in persons with two relatives with an aneurysm. The average natural rupture risk is estimated to be 5 % within 5 years of detection. In the individual case it depends on several variables that are discussed here. According to the literature, the risk of endovascular aneurysm treatment is about 5 %. On the basis of these data, the benefit of MRA screening needs to be discussed individually with the patient. PMID- 22234456 TI - Cutting edge of neurocritical care. PMID- 22234455 TI - The utility of EEG, SSEP, and other neurophysiologic tools to guide neurocritical care. AB - Neuromonitoring is an emerging field that aims to characterize real-time neurophysiology to tailor therapy for acute injuries of the central nervous system. While cardiac telemetry has been used for decades among patients requiring critical care of all kinds, neurophysiology and neurotelemetry has only recently emerged as a routine screening tool in comatose patients. The increasing utilization of electroencephalography in comatose patients is primarily due to the recognition of the common occurrence of nonconvulsive seizures among comatose patients, the development of quantitative measures to detect regional ischemia, and the appreciation of electroencephalography phenotypes that indicate prognosis after cardiac arrest. Other neuromonitoring tools, such as somatosensory evoked potentials have a complementary role, surveying the integrity of the neuroaxis as an indicator of prognosis or illness progression in both acute brain and spinal injuries. PMID- 22234457 TI - Different impact of intermediate and unfavourable cytogenetics at the time of diagnosis on outcome of de novo AML after allo-SCT: a long-term retrospective analysis from a single institution. AB - Karyotype of myeloblasts at the time of AML diagnosis has been shown to be prognostic significant for pre-remission outcome and outcome after allo-SCT, but the latter requires further studies. We conducted a retrospective analysis of the impact of intermediate and unfavourable cytogenetics at the time of primary diagnosis on outcome after allo-SCT in de novo AML. The study included 169 patients who underwent allo-SCT at Karolinska University Hospital between 1980 and 2010. Intermediate and unfavourable cytogenetics were found in 129 (76%) and 40 patients (24%), respectively. Myeloablative and reduced-intensity conditioning were given to 120 (71%) and 49 (29%) patients, respectively. Allo-SCT was performed in CR1 in 122 patients (72%). TRM was 16% in both cytogenetics groups. Relapse occurred in 29% patients with intermediate and in 45% patients with unfavourable cytogenetics (P=0.01). The probabilities of 5-year OS for patients with intermediate and unfavourable cytogenetics were 60 and 43%, respectively (P=0.02). Multivariate analysis revealed intermediate cytogenetics, chronic GVHD, and recipient CMV-negative serostatus as variables associated with favourable OS. Our study showed that outcome after allo-SCT in de novo AML differs depending on cytogenetic risk-group; however its position in post-remission therapy of eligible AML patients is not threatened. PMID- 22234458 TI - Universal correlation between solvent polarity, fluorescence lifetime and macroscopic viscosity of alcohol solutions. AB - In this report, we show interesting correlation between solvent polarity of alcohol solutions and fluorescence lifetime (tau(av)), estimated from time resolved fluorescence spectroscopy (TRFS), and macroscopic viscosity (eta). Non functionalized carbon nanoparticles (NCNP) were successfully used as flurophores in these measurements. The solvent polarity, described through polarizability (Deltaf) of dielectric continuum theory, could universally describe both tau(av)/tau(max) and eta/eta(max) through the relation, [Formula: see text] with X = tau(av)/tau(max) or eta/eta(max), (subscript OH represents corresponding values for alcohols) for alcohol solutions of methanol, ethanol and 1-propanol at room temperature. We show that fluorescence lifetime and solvent viscosity are universal functions of solvent polarity for alcohol solutions. PMID- 22234459 TI - A label-free oligonucleotide based thioflavin-T fluorescent switch for Ag+ detection with low background emission. AB - A novel fluorescent Ag(+) sensor was developed based on the label-free silver (I) specific oligonucleotide (SSO) and Thioflavine T (ThT) monomer-excimer switch. C rich SSO which contain C-C mismatched base pairs can selectively bind to Ag(+) ions and the formed duplexes which constructed by C-Ag(+)-C structure are thermally stabilized without largely altering the double helical structure. ThT give very weak fluorescent in bulk solution and/or in the presence of SSO. However ThT shows high fluorescence in the presence of SSO and Ag(+) at the same time mainly because ThT excimer, which has the high quantum yield, formed and stabilized in the minor or major groove. Based on the discovery, we developed the novel Ag(+) sensor. Under the optimum condition, the selectivity of this system for Ag(+) over other metal ions in aqueous solution is remarkably high, and Ag(+) can be quantified over the dynamic range of 30-450 nM, with a limit of detection of ~16 nM and a linear correlation coefficient of 0.995. PMID- 22234460 TI - The joint association of sleep duration and insomnia symptoms with disability retirement--a longitudinal, register-linked study. AB - OBJECTIVE: The aim of this study was to examine the joint association of sleep duration and insomnia symptoms with subsequent disability retirement. METHODS: Baseline survey data were collected in 2000-2002 from 40-60-year-old employees of the City of Helsinki, all working at baseline. Baseline data were linked with disability retirement data until the end of 2010, obtained from the Finnish Centre for Pensions registers (N=6042). Sleep duration and self-reported insomnia symptoms (non-restorative sleep and difficulties in initiating and maintaining sleep) were derived from the baseline surveys. All-cause disability retirement (N=561) and the most prevalent diagnostic groups - musculoskeletal diseases (43%) and mental disorders (26%) - were examined. Cox regression analysis was used to yield hazard ratios (HR) with 95% confidence intervals (95% CI). RESULTS: A joint association of sleep duration and insomnia symptoms with disability retirement was found, implying a higher risk for those with frequent insomnia symptoms. HR for all-cause disability retirement ranged among those with frequent symptoms from 2.02 (95% CI 1.53-2.68, sleeping 7 hours) to 3.92 (95% CI 2.57-5.97, sleeping <= 5 hours). Adjusting for sociodemographic, work, and health-related factors attenuated the associations, which nevertheless remained. The associations were similar for the two diagnostic groups, although stronger for those with mental disorders. CONCLUSION: Frequent insomnia symptoms dominate the joint association of sleep duration and insomnia symptoms with subsequent disability retirement. Examining exclusively sleep duration would provide an incomplete understanding of the consequences of poor sleep. PMID- 22234461 TI - Occurrence of polybrominated diphenyl ethers, polychlorinated biphenyls, and phthalates in freshwater fish from the Orge river (Ile-de France). AB - Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and phthalates were investigated from July 2009 to April 2010 in three fish species from the Orge river, which flows in a densely populated area of Ile-de-France. In two Cyprinidae (roach and chub) and one Percidae (perch), muscle contents in increasing order ranged as follows: 12-18 ng g(-1) dw for PBDEs (Sigmatri-hepta), 120-170 ng g(-1) dw for PCBs (Sigma7), and 2,250-5,125 ng g(-1) dw for phthalates (Sigma7). No variation was observed between contaminant contents and lipid levels. No biomagnification was found according to the trophic level for PBDEs and PCBs, whereas for phthalates the highest contents were found in perch. Seasonal variations were observed with the lowest PBDE and PCB contents occurring in July after spawning in roach and perch (p < 0.001). PBDE content followed a decreasing trend-gonad > liver > muscle-whatever the period. For PCBs, gonad and liver contents remained greater than that of muscle (p < 0.05). Our results indicate a preferential accumulation of halogenated compounds in gonad and liver outside the reproduction period. Bioaccumulation factors for PCBs in muscle were significantly correlated to their chlorination degree in perch (p < 0.01) and roach (p < 0.01). In roach, that correlation slope was by decreasing importance order as follows: gonad > liver > muscle. The biota-sediment accumulation factors varied from 0.1 to 29.2, from 1.6 to 4.8, and from 1 to 123.5 for PBDEs, PCBs, and phthalates, respectively. These results contribute to document the use of freshwater fish as bioindicators of river quality. PMID- 22234462 TI - Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. AB - This study evaluated early renal functional, structural, and biochemical changes in high-calorie/high-fat diet fed mice, a model of prediabetes and alimentary obesity. Male C57BL6/J mice were fed normal (11 kcal% fat) or high-fat (58 kcal% fat) diets for 16 wk. Renal changes were evaluated by histochemistry and immunohistochemistry, Western blot analysis, ELISA, enzymatic assays, and chemiluminometry. High-fat diet consumption led to increased body and kidney weights, impaired glucose tolerance, hyperinsulinemia, polyuria, a 2.7-fold increase in 24-h urinary albumin excretion, 20% increase in renal glomerular volume, 18% increase in renal collagen deposition, and 8% drop of glomerular podocytes. It also resulted in a 5.3-fold increase in urinary 8-isoprostane excretion and a 38% increase in renal cortex 4-hydroxynonenal adduct accumulation. 4-hydroxynonenal adduct level and immunoreactivity or Sirtuin 1 expression in renal medulla were not affected. Studies of potential mechanisms of the high-fat diet induced renal cortex oxidative injury revealed that whereas nicotinamide adenine dinucleotide phosphate reduced form oxidase activity only tended to increase, 12/15-lipoxygenase was significantly up-regulated, with approximately 12% increase in the enzyme protein expression and approximately 2 fold accumulation of 12(S)-hydroxyeicosatetraenoic acid, a marker of 12/15 lipoxygenase activity. Accumulation of periodic acid-Schiff -positive material, concentrations of TGF-beta, sorbitol pathway intermediates, and expression of nephrin, CAAT/enhancer-binding protein homologous protein, phosphoeukaryotic initiation factor-alpha, and total eukaryotic initiation factor-alpha in the renal cortex were indistinguishable between experimental groups. Vascular endothelial growth factor concentrations were reduced in high-fat diet fed mice. In conclusion, systemic and renal cortex oxidative stress associated with 12/15 lipoxygenase overexpression and activation is an early phenomenon caused by high calorie/high-fat diet consumption and a likely contributor to kidney disease associated with prediabetes and alimentary obesity. PMID- 22234463 TI - GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. AB - Liraglutide and exenatide are glucagon-like peptide receptor (GLP-1R) agonists used in the treatment of type 2 diabetes. Both molecules have been associated with the development of thyroid C-cell tumors after lifetime exposure in rodents. Previously, it has been reported that these tumors are preceded by increased plasma calcitonin and C-cell hyperplasia. We can now document that the murine C cell effects are mediated via GLP-1R. Thus, 13 wk of continuous exposure to GLP 1R agonists was associated with marked increases in plasma calcitonin and in the incidence of C-cell hyperplasia in wild-type mice. In contrast, similar effects were not seen in GLP-1R knockout mice. Human C-cell cancer is often caused by activating mutations in the rearranged-during-transfection (RET) protooncogene. We developed an immunohistochemical method to assess RET activation in tissues. Liraglutide dosing to mice was not found to activate RET. Further evaluation of the signaling pathways demonstrated that liraglutide increased ribosomal S6, but not MAPK kinase, phosphorylation. These observations are consistent with effects of GLP-1R agonists on rodent C cells being mediated via mammalian target of rapamycin activation in a RET- and MAPK-independent manner. PMID- 22234466 TI - Conversion of TSH heterodimer to a single polypeptide chain increases bioactivity and longevity. AB - TSH is a dimeric glycoprotein hormone composed of a common alpha-subunit noncovalently linked to a hormone-specific beta-subunit. Previously, the TSH heterodimer was successfully converted to an active single-chain hormone by genetically fusing alpha and beta genes with [TSHbeta- carboxyl-terminal peptide (CTP)-alpha] or without (TSHbeta-alpha) the CTP of human chorionic gonadotropin beta-subunit as a linker. In the present study, TSH variants were expressed in Chinese hamster ovarian cells. The results indicated that TSHbeta-alpha single chain has the highest binding affinity to TSH receptor and the highest in vitro bioactivity. With regard to the in vivo bioactivity, all TSH variants increased the levels of T(4) in circulation after 2 and 4 h of treatment. However, the level of T(4) after treatment with TSH-wild type was significantly decreased after 6 and 8 h, compared with the levels after treatment with the other TSH variants. TSHbeta-alpha and TSHbeta-CTP-alpha single chains exhibited almost the same bioactivity after 8 h of treatment. Evaluating the half-life of TSH variants, TSHbeta-CTP-alpha single chain revealed the longest half-life in circulation, whereas TSH-wild type exhibited the shortest serum half-life. These findings indicate that TSH single-chain variants with or without CTP as a linker may display conformational structures that increase binding affinity and serum half-life, thereby, suggesting novel attitudes for engineering and constructing superagonists of TSH, which may be used for treating different conditions of defected thyroid gland activity. Other prominent potential clinical use of these variants is in a diagnostic test for metastasis and recurrence of thyroid cancer. PMID- 22234464 TI - Lipocalin 2 deficiency alters estradiol production and estrogen receptor signaling in female mice. AB - We have previously characterized lipocalin 2 (Lcn2) as a new adipokine having a critical role in energy and lipid metabolism in male mice. Previous studies by others have suggested that Lcn2 is a putative target gene of estrogens. In this study, we reported the effect of Lcn2 deficiency on estradiol biosynthesis and estrogen receptor signaling in female Lcn2-deficient (Lcn2-/-) mice. We found that Lcn2 expression in white adipose tissue is gender, depot, and age dependent. In female mice, Lcn2 is predominantly expressed in inguinal adipose tissue but at relatively very low levels in perigonadal depot and ovary. After 22 wk of high fat diet (HFD) feeding or at old age, Lcn2-/- female mice had significantly reduced levels of serum 17beta-estradiol and down-regulated expression of estrogen receptor alpha in multiple metabolic tissues. Consistently, the expression of estrogen-regulated genes involved in cholesterol homeostasis, such as liver X receptor beta and low-density lipoprotein receptor was also down regulated in the adipose tissue of Lcn2-/- mice. These changes were in line with the development of atherogenic dyslipidemia in response to HFD feeding; female Lcn2-/- mice had significantly elevated levels of total cholesterol and low density lipoprotein cholesterol, whereas reduced high-density lipoprotein cholesterol levels compared with wild-type female mice. Interestingly, when compared with wild-type controls, HFD-fed female Lcn2-/- mice had significantly reduced expression levels of aromatase, a key enzyme regulating estradiol biosynthesis, in adipose tissue. Moreover, Lcn2 deficiency markedly blunted age related increase in adipose aromatase expression but had no significant impact on age-related reduction in ovarian aromatase expression. Our findings suggest that Lcn2 has a tissue-specific role in adipose estradiol biosynthesis, which may link Lcn2 to obesity- and age-related estradiol production and metabolic complications in females. PMID- 22234467 TI - Differential regulation of glucose transporters mediated by CRH receptor type 1 and type 2 in human placental trophoblasts. AB - Glucose transport across the placenta is mediated by glucose transporters (GLUT), which is critical for normal development and survival of the fetus. Regulatory mechanisms of GLUT in placenta have not been elucidated. Placental CRH has been implicated to play a key role in the control of fetal growth and development. We hypothesized that CRH, produced locally in placenta, could act to modulate GLUT in placenta. To investigate this, we obtained human placentas from uncomplicated term pregnancies and isolated and cultured trophoblast cells. GLUT1 and GLUT3 expressions in placenta were determined, and effects of CRH on GLUT1 and GLUT3 were examined. GLUT1 and GLUT3 were identified in placental villous syncytiotrophoblasts and the endothelium of vessels. Treatment of cultured placental trophoblasts with CRH resulted in an increase in GLUT1 expression while a decrease in GLUT3 expression in a dose-dependent manner. Cells treated with either CRH antibody or nonselective CRH receptor (CRH-R) antagonist astressin showed a decrease in GLUT1 and an increase in GLUT3 expression. CRH-R1 antagonist antalarmin decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 antagonist astressin2b increased the expression of both GLUT1 and GLUT3. Knockdown of CRH-R1 decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 knockdown caused an increase in both GLUT1 and GLUT3 expression. Our data suggest that, in placenta, CRH produced locally regulates GLUT1 and GLUT3 expression, CRHR1 and CRHR2-mediated differential regulation of GLUT1 and GLUT3 expression. Placental CRH may regulate the growth of fetus and placenta by modulating the expression of GLUT in placenta during pregnancy. PMID- 22234465 TI - Angiotensin II reduces food intake by altering orexigenic neuropeptide expression in the mouse hypothalamus. AB - Angiotensin II (Ang II), which is elevated in many chronic disease states such as end-stage renal disease and congestive heart failure, induces cachexia and skeletal muscle wasting by increasing muscle protein breakdown and reducing food intake. Neurohormonal mechanisms that mediate Ang II-induced appetite suppression are unknown. Consequently, we examined the effect of Ang II on expression of genes regulating appetite. Systemic Ang II (1 MUg/kg . min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Ang II markedly reduced phosphorylation of AMP-activated protein kinase (AMPK), an enzyme that is known to regulate Npy expression. Intracerebroventricular Ang II infusion (50 ng/kg . min) caused a reduction of food intake, and Ang II dose dependently reduced Npy and orexin expression in the hypothalamus cultured ex vivo. The reduction of Npy and orexin in hypothalamic cultures was completely prevented by candesartan or the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated. PMID- 22234468 TI - Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. AB - The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg . d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy. PMID- 22234469 TI - Activation of latent human GDF9 by a single residue change (Gly 391 Arg) in the mature domain. AB - Growth differentiation factor 9 (GDF9) controls granulosa cell growth and differentiation during early ovarian folliculogenesis and regulates cumulus cell function and ovulation rate in the later stages of this process. Similar to other TGF-beta superfamily ligands, GDF9 is secreted from the oocyte in a noncovalent complex with its prodomain. In this study, we show that prodomain interactions differentially regulate the activity of GDF9 across species, such that murine (m) GDF9 is secreted in an active form, whereas human (h) GDF9 is latent. To understand this distinction, we used site-directed mutagenesis to introduce nonconserved mGDF9 residues into the pro- and mature domains of hGDF9. Activity based screens of the resultant mutants indicated that a single mature domain residue (Gly(391)) confers latency to hGDF9. Gly(391) forms part of the type I receptor binding site on hGDF9, and this residue is present in all species except mouse, rat, hamster, galago, and possum, in which it is substituted with an arginine. In an adrenocortical cell luciferase assay, hGDF9 (Gly(391)Arg) had similar activity to mGDF9 (EC(50) 55 ng/ml vs. 28 ng/ml, respectively), whereas wild-type hGDF9 was inactive. hGDF9 (Gly(391)Arg) was also a potent stimulator of murine granulosa cell proliferation (EC(50) 52 ng/ml). An arginine at position 391 increases the affinity of GDF9 for its signaling receptors, enabling it to be secreted in an active form. This important species difference in the activation status of GDF9 may contribute to the variation observed in follicular development, ovulation rate, and fecundity between mammals. PMID- 22234471 TI - Glucocorticoid receptor signaling is essential for mesoderm formation and muscle development in zebrafish. AB - Glucocorticoid receptor (GR) signaling is thought to play a key role in embryogenesis, but its specific developmental effects remain unclear. Cortisol is the primary ligand for GR activation in teleosts, and in zebrafish (Danio rerio), the prehatch embryo content of this steroid is of maternal origin. Using early zebrafish developmental stages, we tested the hypothesis that GR signaling is critical for embryo growth and hatching. In zebrafish, maternal GR mRNA is degraded quickly, followed by zygotic synthesis of the receptor. GR protein is widely expressed throughout early development, and we were able to knockdown this protein using morpholino oligonucleotides. This led to a more than 70% reduction in mRNA abundance of matrix metalloproteinase-13 (mmp13), a glucocorticoid responsive gene. The GR morphants displayed delayed somitogenesis, defects in somite and tail morphogenesis, reduced embryo size, and rarely survived after hatch. This correlated with altered expression of myogenic markers, including myogenin, myostatin, and muscle-specific myosin heavy chain and troponin genes. A key finding was a 70-90% reduction in the mRNA abundance of bone morphogenetic proteins (BMP), including bmp2a, bmp2b, and bmp4 in GR morphants. Bioinformatics analysis confirmed multiple putative glucocorticoid response elements upstream of these BMP genes. GR morphants displayed reduced expression of BMP-modulated genes, including eve1 and pax3. Zebrafish GR mRNA injection rescued the GR morphant phenotype and reversed the disrupted expression of BMP and myogenic genes. Our results for the first time indicate that GR signaling is essential for zebrafish muscle development, and we hypothesize a role for BMP morphogens in this process. PMID- 22234470 TI - Mineralocorticoid receptor overexpression facilitates differentiation and promotes survival of embryonic stem cell-derived neurons. AB - Mineralocorticoid receptor (MR), highly expressed in the hippocampus, binds corticosteroid hormones and coordinately participates, with the glucocorticoid receptor, to the control of stress responses, memorization, and behavior. To investigate the impact of MR in neuronal survival, we generated murine embryonic stem (ES) cells that overexpress human MR (hMR) (P1-hMR) and are induced to differentiate into mature neurons. We showed that recombinant MR expression increased throughout differentiation and is 2-fold higher in P1-hMR ES-derived neurons compared with wild-type controls, whereas glucocorticoid receptor expression was unaffected. Although proliferation and early neuronal differentiation were comparable in P1-hMR and wild-type ES cells, MR overexpression was associated with higher late neuronal marker expression (microtubule-associated protein 2 and beta-tubulin III). This was accompanied by a shift towards neuron survival with an increased ratio of anti- vs. proapoptotic molecules and 50% decreased caspase 3 activity. Knocking down MR overexpression by small interfering RNA drastically reversed neuroprotective effects with reduced Bcl(2)/Bax ratio and decreased microtubule-associated protein 2 expression. P1-hMR neurons were protected against oxidative stress-induced apoptosis through reduced caspase 3 activation and drastically increased Bcl(2)/Bax ratio and beta-tubulin III expression. We demonstrated the involvement of MR in neuronal differentiation and survival and identify MR as an important neuroprotective mediator opening potential pharmacological strategies. PMID- 22234472 TI - Norepinephrine, active norepinephrine transporter, and norepinephrine-metabolism are involved in the generation of reactive oxygen species in human ovarian granulosa cells. AB - The neurotransmitter norepinephrine (NE) is derived from the sympathetic nervous system and may be involved in the regulation of ovarian functions. Ovarian innervation increases in patients with polycystic ovarian syndrome (PCOS), prompting us to readdress a role of NE in the human ovary. In vitro fertilization derived granulosa cells (GC), follicular fluids (FF), and ovarian sections were studied. NE was found in FF and freshly isolated GC, yet significantly lower levels of NE were detected in samples from PCOS patients. Furthermore, the metabolite normetanephrine was detected in FF. Together this suggests cellular uptake and metabolism of NE in GC. In accordance, the NE transporter and NE metabolizing enzymes [catechol-o-methyltransferase (COMT) and monoamine oxidase A] were found in GC, COMT in GC and thecal cells of large human antral follicles in vivo and in cultured GC. Cellular uptake and metabolism of NE also occurred in cultured GC, events that could be blocked pharmacologically. NE, in the range present in FF, is unlikely to affect GC via activation of typical alpha- or beta receptors. In line with this assumption, it did not alter phosphorylation of MAPK. However, NE robustly induced the generation of reactive oxygen species (ROS). This action occurred even when receptors were blocked but was prevented by blockers of NE transporter, COMT, and monoamine oxidase A. Thus, NE contributes to the microenvironment of preovulatory human follicles and is lower in PCOS. By inducing the production of ROS in GC, NE is linked to ROS-regulated events, which are emerging as crucial factors in ovarian physiology, including ovulation. PMID- 22234473 TI - Patterned polymer brushes. AB - This critical review summarizes recent developments in the fabrication of patterned polymer brushes. As top-down lithography reaches the length scale of a single macromolecule, the combination with the bottom-up synthesis of polymer brushes by surface-initiated polymerization becomes one main avenue to design new materials for nanotechnology. Recent developments in surface-initiated polymerizations are highlighted along with diverse strategies to create patterned polymer brushes on all length scales based on irradiation (photo- and interference lithography, electron-beam lithography), mechanical contact (scanning probe lithography, soft lithography, nanoimprinting lithography) and on surface forces (capillary force lithography, colloidal lithography, Langmuir Blodgett lithography) (116 references). PMID- 22234474 TI - Novel nanobiotechnological concepts in electrochemical biosensors for the analysis of toxins. AB - This article gives an overview of the biosensors for the analysis of mycotoxins, marine toxins and cyanobacterial toxins, describing in depth the electrochemical biosensors that incorporate nanobiotechnological concepts. Firstly, it presents tailor-designed biomolecules, such as recombinant enzymes, recombinant antibody fragments and aptamers as novel biorecognition elements in biosensors. It also reviews the use of metallic nanoparticles (NPs) and carbon nanotubes (CNTs) aiming at improving the electrochemical transduction strategies. Finally, the exploitation of magnetic particles (MPs) as immobilisation carriers in flow systems and the development of arrays are also described. The incorporation of these nanobiotechnological concepts provides with electrochemical biosensors with superior analytical performance in terms of specificity, sensitivity, stability and analysis time. PMID- 22234475 TI - The evolution of mammalian body temperature: the Cenozoic supraendothermic pulses. AB - In this study, I investigated the source(s) of variation in the body temperatures of mammals. I also attempted to reconstruct ancestral normothermic rest-phase body temperature states using a maximum parsimony approach. Body temperature at the familial level is not correlated with body mass. For small mammals, except the Macroscelidae, previously identified correlates, such as climate adaptation and zoogeography explained some, but not all, T(b) apomorphies. At the species level in large cursorial mammals, there was a significant correlation between body temperature and the ratio between metatarsal length and femur length, the proxy for stride length and cursoriality. With the exception of two primate families, all supraendothermic (T(b) > 37.9 degrees C) mammals are cursorial, including Artiodactyla, Lagomorpha, some large Rodentia, and Carnivora. The ruminant supraendothermic cursorial pulse is putatively associated with global cooling and vegetation changes following the Paleocene-Eocene Thermal Maximum. Reconstructed ancestral body temperatures were highly unrealistic deep within the mammalian phylogeny because of the lack of fossil T(b) data that effectively creates ghost lineages. However, it is anticipated that the method of estimating body temperature from the abundance of 13C-18O bonds in the carbonate component of tooth bioapatite in both extant and extinct animals may be a very promising tool for estimating the T(b) of extinct mammals. Fossil T(b) data are essential for discerning derived T(b) reversals from ancestral states, and verifying the dates of supraendothermic pulses. PMID- 22234476 TI - The effects of dissolved oxygen levels on the metabolic interaction between digestion and locomotion in Cyprinid fishes with different locomotive and digestive performances. AB - To test whether the effects of water oxygen concentration ([O(2)]) on the metabolic interaction between locomotion and digestion differ between fish species with different locomotive and digestive behaviours in normoxia, we investigated the swimming performance of fasted and fed fish at water [O(2)] of 1, 2 and 8 (normoxia) mg L(-1) (2.5, 5 and 20 kPa) at 25 degrees C in three juvenile Cyprinidae fish species: goldfish (Carassius auratus), common carp (Cyprinus carpio) and qingbo (Spinibarbus sinensis). Digestion, taxon and water [O(2)] all had significant effects on the pre-exercise oxygen consumption rate [Formula: see text] and the swimming performance (P < 0.05). Among the three fishes, qingbo showed the highest swimming performance and the lowest feeding [Formula: see text] at the saturated water [O(2)], and its active oxygen consumption rate [Formula: see text] and critical swimming speed (U (crit)) decreased the most with decreases in water [O(2)]. Qingbo exhibited a locomotion priority metabolic mode at all three water [O(2)]. Digestion was sacrificed to locomotion in a postprandial swimming situation, but fed qingbo could not maintain their U (crit) at water [O(2)] of 2 and 1 mg L(-1). Goldfish showed the lowest swimming performance and the highest feeding [Formula: see text] at the saturated water [O(2)]. They exhibited a digestion-priority metabolic mode at high water [O(2)]. However, with a decrease in water [O(2)], the feeding [Formula: see text] decreased more acutely than the respiratory capacity; thus, digestion and locomotion performed independently in a postprandial swimming situation (i.e., an additive metabolic mode) at a water [O(2)] of 1 mg L(-1). The common carp showed moderate and balanced swimming performance and feeding [Formula: see text] at the saturated water [O(2)], and exhibited an additive metabolic mode at all 3 water [O(2)], because digestion, swimming and respiratory capacities decreased in parallel with the decrease in water [O(2)]. PMID- 22234477 TI - Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I Registry. AB - Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler-Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since laronidase became available in 2003 (gap during 2006-2009: Hurler--0.2 year, Hurler-Scheie--0.5 year, Scheie--1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler-Scheie and Scheie patients (gap during 2006-2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with laronidase (42 out of 45 patients by 2009). CONCLUSIONS: Despite the availability of laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler-Scheie and Scheie phenotypes, which can lead to a sub-optimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients. PMID- 22234478 TI - Lessons learned from 5 years of newborn screening for congenital adrenal hyperplasia in the Czech Republic: 17-hydroxyprogesterone, genotypes, and screening performance. AB - The aims were to summarize the experience and to determine the performance metrics of newborn screening (NBS) for congenital adrenal hyperplasia (CAH) in the Czech Republic. 17-Hydroxyprogesterone (17OHP) was measured in NBS samples prospectively in 545,026 newborns and retrospectively in 31 CAH patients born outside the study period. A total of 2,811 screened newborns had abnormal 17OHP; CAH was confirmed in 46 probands. One patient with a severe-moderate genotype of CAH had 17OHP below the cut-off and was diagnosed clinically. This corresponds to a screening sensitivity of 98% and a false positive rate (FPR) of 0.51%. The median of 17OHP in the most severe genotypes was 484 nmol/L (n = 21); in severe/moderate, 321 nmol/L (n = 30); in moderate, 61 nmol/L (n = 20); and in mild genotypes, 31 nmol/L (n = 7). NBS is efficient to detect severe CAH but may fail to detect milder variants. However, the FPR is too high but could be improved by application of a second tier test. PMID- 22234479 TI - Severe episodic viral wheeze in preschool children: High risk of asthma at age 5 10 years. AB - In population studies, most children with episodic viral wheeze (EVW) become symptom free by 6 years. We studied the outcome of children with severe EVW, treated and followed up in hospital. We followed up 78 children <4 years, managed by paediatricians for severe EVW, to the age of 5-10 years. We recorded respiratory symptoms, spirometry and exhaled nitric oxide (FeNO). At follow-up, 42 children (54%) had current wheeze or dyspnoea, and 52 (67%) had current asthma. There was no significant difference between children with and without current asthma in FEV1 (p = 0.420), but FeNO was higher in children with current asthma (median (interquartile range) 14.5 (11.25-21.50) ppb) than in those without (12.0 (10.0-13.8) ppb, p = 0.020). Positive family history of asthma was the only factor associated with current asthma (odds ratio 8.77, 95% CI 2.88 26.69, p < 0.001). This remained significant after adjustment for duration of follow-up, gender and parental smoking. Conclusion. Severe EVW at preschool age has a high risk of asthma at age 5-10 years, and this is reinforced by a positive family history of asthma and to elevated FeNO levels. PMID- 22234480 TI - Multifocal infantile hepatic hemangiomas--imaging strategy and response to treatment after propranolol and steroids including review of the literature. AB - Infantile hepatic hemangioma is the most common benign liver tumor during infancy. Prompt diagnosis and timely institution of therapy are of utmost importance. Magnetic resonance imaging (MRI) plays a key role in the correct diagnosis and monitoring of treatment. We report on a 15-week-old girl with multifocal infantile hemangiomas of the liver and high output congestive heart failure. Diagnosis was confirmed by MRI. Subsequent treatment with propranolol and steroids showed dramatic regression of the lesions within 24 weeks. We present the characteristic MRI findings and discuss treatment options together with a comprehensive review of the relevant literature. Conclusion Propranolol appears highly efficacious in the management of infantile hepatic hemangioma; dedicated MRI is essential in confirming the diagnosis and monitoring of treatment. PMID- 22234481 TI - Successful vitrification of mouse ovaries using less-concentrated cryoprotectants with Supercool X-1000 supplementation. AB - The purpose of our study was to investigate the feasibility of using less concentrated cryoprotectants supplemented with ice blocker Supercool X-1000 to vitrify ovarian tissues. Mouse ovaries were cryopreserved in different concentrations of vitrification solution alone or with Supercool X-1000, and fresh non-frozen ovaries were used as control. The proportions of morphological normality of follicles, normal GCs in follicular fluids and developing to blastocysts were higher in 12.5% ethylene glycol (EG) + 12.5% dimethylsulfoxide (DMSO) with Supercool X-1000 than those of treated in 10% EG + 10% DMSO or 15% EG + 15% DMSO alone or with Supercool X-1000. In conclusion, the inclusion of Supercool X-1000 in less-concentrated vitrification solution was effective to improve the efficiency and efficacy of cryopreservation of ovarian tissues. PMID- 22234482 TI - Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): objectives and design. AB - Although low- and middle-income countries still bear the burden of major infectious diseases, chronic noncommunicable diseases are becoming increasingly common due to rapid demographic, epidemiologic, and nutritional transitions. However, information is generally scant in these countries regarding chronic disease incidence, social determinants, and risk factors. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) aims to contribute relevant information with respect to the development and progression of clinical and subclinical chronic diseases, particularly cardiovascular diseases and diabetes. In this report, the authors delineate the study's objectives, principal methodological features, and timeline. At baseline, ELSA-Brasil enrolled 15,105 civil servants from 5 universities and 1 research institute. The baseline examination (2008-2010) included detailed interviews, clinical and anthropometric examinations, an oral glucose tolerance test, overnight urine collection, a 12 lead resting electrocardiogram, measurement of carotid intima-media thickness, echocardiography, measurement of pulse wave velocity, hepatic ultrasonography, retinal fundus photography, and an analysis of heart rate variability. Long-term biologic sample storage will allow investigation of biomarkers that may predict cardiovascular diseases and diabetes. Annual telephone surveillance, initiated in 2009, will continue for the duration of the study. A follow-up examination is scheduled for 2012-2013. PMID- 22234484 TI - Triggers for attacks in familial Mediterranean fever: application of the case crossover design. AB - The etiology of recurrent attacks of serositis in familial Mediterranean fever (FMF) is not completely understood. Uncontrolled clinical case series have reported that factors associated with emotional, physiological, or physical stress precede and might trigger the attacks. This case-crossover study, conducted between July 2007 and May 2008, aimed to estimate the role of precipitating factors in attacks in a sample of Armenian FMF patients in Yerevan, Armenia, where 104 patients contributed 55 case and 189 control time periods. The authors used conditional logistic regression to compare frequency of exposure to stressful events, strenuous physical activity, menstrual periods, and high-fat food consumption prior to FMF attacks and on attack-free random days. Multiple stressful life events predicted FMF attacks 2 days following the event. After adjustment for treatment, an additional stressful event was associated with an estimated 70% increase in the odds of having an FMF attack on the second day (95% confidence interval: 1.04, 2.79). High levels of perceived stress were also associated with FMF attacks. Physical exertion and high-fat diet did not increase the likelihood of FMF attacks. The possibility of prevention of attacks in FMF needs to be tested through stress-reduction interventions. PMID- 22234483 TI - Hair relaxer use and risk of uterine leiomyomata in African-American women. AB - Hair relaxers are used by millions of black women, possibly exposing them to various chemicals through scalp lesions and burns. In the Black Women's Health Study, the authors assessed hair relaxer use in relation to uterine leiomyomata incidence. In 1997, participants reported on hair relaxer use (age at first use, frequency, duration, number of burns, and type of formulation). From 1997 to 2009, 23,580 premenopausal women were followed for incident uterine leiomyomata. Multivariable Cox regression was used to estimate incidence rate ratios and 95% confidence intervals. During 199,991 person-years, 7,146 cases of uterine leiomyomata were reported as confirmed by ultrasound (n = 4,630) or surgery (n = 2,516). The incidence rate ratio comparing ever with never use of relaxers was 1.17 (95% confidence interval (CI): 1.06, 1.30). Positive trends were observed for frequency of use (P(trend) < 0.001), duration of use (P(trend) = 0.015), and number of burns (P(trend) < 0.001). Among long-term users (>=10 years), the incidence rate ratios for frequency of use categories 3-4, 5-6, and >=7 versus 1 2 times/year were 1.04 (95% CI: 0.92, 1.19), 1.12 (95% CI: 0.99, 1.27), and 1.15 (95% CI: 1.01, 1.31), respectively (P(trend) = 0.002). Risk was unrelated to age at first use or type of formulation. These findings raise the hypothesis that hair relaxer use increases uterine leiomyomata risk. PMID- 22234485 TI - Sphingosine kinase inhibition exerts both pro- and anti-atherogenic effects in low-density lipoprotein receptor-deficient (LDL-R(-/-)) mice. AB - Sphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R(-/-)mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-gamma production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c(+) cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4(+) splenocyte proliferation, IFN-gamma and IL-2 production, and CD69 expression. Concomitantly, however, ABC294640 treatment redistributed CD4(+) and CD8(+) cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640 treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R(-/-) mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma. PMID- 22234487 TI - Mobile technologies in the study, assessment, and treatment of schizophrenia. PMID- 22234486 TI - Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects. AB - OBJECTIVE: Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls. METHODS: African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and adult controls (n = 300) completed diagnostic interviews and computerized neurocognitive tests. PCH were estimated from 9 neurocognitive domains. Three PCH, PCH1-PCH3, were modeled to determine if status (SZ, relative, and control), other psychiatric covariates, and education were significant predictors of mean values. A small-scale linkage analysis was also conducted in a subset of the sample. RESULTS: PCH1, PCH2, and PCH3 account for 72% of the genetic variance. PCH1 represents 8 of 9 neurocognitive domains, is most highly correlated with spatial processing and emotion recognition, and has unadjusted heritability of 68%. The means for PCH1 differ significantly among SZ, their relatives, and controls. PCH2, orthogonal to PCH1, is most closely correlated with working memory and has an unadjusted heritability of 45%. Mean PCH2 is different only between SZ families and controls. PCH3 apparently represents a heritable component of neurocognition similar across the 3 diagnostic groups. No significant linkage evidence to PCH1-PCH3 or individual neurocognitive measures was discovered. CONCLUSIONS: PCH1 is highly heritable and genetically correlated with SZ. It should prove useful in future genetic analyses. Mean PCH2 differentiates SZ families and controls but not SZ and unaffected family members. PMID- 22234488 TI - One-stage repair for stanford type B aortic dissection concomitant with cardiac diseases: open stented elephant trunk technique combined with cardiac operation. AB - BACKGROUND: We evaluated an open stented elephant trunk (sET) technique combined with cardiac operations for a one-stage treatment of patients with complicated Stanford type B aortic dissection (AoD) and cardiac diseases. METHODS: Between April 2007 and March 2010, 16 patients with Stanford B AoD and cardiac diseases (mean age 49.75 +/- 13.42 years) underwent sET combined with cardiac operations. Under deep hypothermic cardiac arrest (DHCA), a stented graft was directly delivered via the incision of aortic arch and the proximal graft was sutured on the normal distal aortic arch wall in a continuous circumferential full-thickness fashion. The combined cardiac operations (Bentall procedure, etc.) were performed before sET implantation while cooling. RESULTS: Average time of cardiopulmonary bypass, aortic cross clamping durance, and DHCA was 131.62 +/- 23.85, 64.69 +/- 9.72, and 21.94 +/- 3.60 minutes, respectively. There were no early deaths and no neurological complications. During a follow-up of 18.69 +/- 9.94 months, computed tomographic angiography was performed in all patients. Neither endoleak nor stent shifting was observed. Retrograde type A AoD was not found during follow-up. Thrombus was formed in the false lumen from the proximal descending aorta to the diaphragmatic section. CONCLUSIONS: The open sET technique combined cardiac procedures can reliably treat Stanford type B AoD concomitant with surgical cardiac disease in a single stage. PMID- 22234489 TI - Renal graft outcome in combined heart-kidney transplantation compared to kidney transplantation alone: a single-center, matched-control study. AB - BACKGROUND: Renal allograft outcome in heart-kidney transplantation (HKTx) might be affected by hemodynamic instability and high levels of calcineurin inhibitor dependent immunosuppression. METHODS: From November 1999 to March 2008, 13 patients who received HKTx were compared with a matched control group of 13 kidney transplantation (KTx) recipients with similar cardiovascular risk factors. Graft function, rejection periods, and patient survival were analyzed. RESULTS: Renal allograft rejection was noted in three patients (23%) after HKTx and in four patients (31%) after KTx. Serum creatinine levels were comparable at 1 week, 1 month, 1, 2, and 3 years after transplantation. Patient survival rates at 1, 2, and 3 years were 100% for HKTx recipients and 100, 92, and 92% for isolated KTx patients. Graft survival was 92% at 1, 2, and 3 years after HKTx and 100% at 1 year and 92% at 2 and 3 years after isolated KTx. CONCLUSIONS: Our results with excellent long-term graft function and survival after combined HKTx indicate that this procedure is a valuable option for a growing number of patients suffering from coexistent cardiac and renal failure. PMID- 22234490 TI - Anti-TNF therapy for polymyalgia rheumatica: report of 99 cases and review of the literature. AB - The objective of this study was to analyze the clinical, laboratorial, and therapeutical response of polymyalgia rheumatica (PMR) to anti-tumor necrosis factor (anti-TNF) treatment. We systematically searched English articles on the subjects of PMR who were treated with TNF blockers in Pubmed from 1994 to 2010. In addition, we reported on two patients with PMR who were treated by the Rheumatology Division of the Hospital das Clinicas da Faculdade de Medicina da Universidade in Sao Paulo, Brazil. Ninety-nine cases of patients with PMR treated with anti-TNF were reviewed. The age of these patients ranged from 63 to 84 years, and 70.7% of them were female. Disease duration varied from 10.5 weeks to 95 months, and time of follow-up varied from 2 weeks to 21 months. Infliximab was the anti-TNF of choice in three studies, while etanercept was in five. Time to response varied from 2 to 8 weeks. After anti-TNF treatment, prednisone reduction was observed in all studies. Clinical improvement was found in 7/7 studies, and laboratory improvement of at least 50% of inflammatory markers was observed in 6/7 studies. This study demonstrated a good clinical and laboratory response to anti-TNF therapy in patients with PMR, with or without glucocorticoid. PMID- 22234491 TI - Inflammatory arthritis: case review and primary care perspectives. AB - Inflammatory arthritis (IA) has significant physical, psychosocial and economic consequences. Delays in diagnosis and initiation of treatment significantly impact on prognosis. The infrequent, variable, non-specific and, sometimes, indolent presentation make recognition of IA by primary care physicians (PCPs) challenging. To undertake an in-depth case review assessing the diagnostic trajectory of patients diagnosed with IA to inform development of practical recommendations to facilitate timely recognition and referral of suspected IA to specialist services, a case review was undertaken in one UK general practice using a proforma to collect information on patient demographics, diagnostic activities (presentation to PCP, specialist referral and final diagnosis) and documentation of disease-specific features for all patients diagnosed with IA between January 2000 and February 2011. Cases were excluded if consultation notes, a definitive diagnosis or evidence of specialist assessment were absent. Twenty-four cases were included in the final analysis. Duration from first primary care presentation to specialist rheumatological referral ranged from 4 to 2,165 days. Undertaking radiographs significantly lengthened delays from presentation to referral. Patients with IA attended between 2 and 41 primary care appointments before being referred. None of the cases identified had a comprehensive record of symptoms documented in the medical record. Once patients present to primary care, specialist referral is not always in accordance with the urgency necessitated in current guidelines. Improving PCPs' knowledge and awareness of IA, development of screening tools and improvement in record keeping are proposed to facilitate early recognition and referral of IA and subsequently reduce the disease burden of IA. PMID- 22234492 TI - Association of amyotrophic lateral sclerosis and Behcet's disease: is there a relationship? A multi-national case series. AB - Neurological involvement may be seen in 5-30% of the patients with Behcet's disease (BD). Occasionally, parenchymal neurological involvement in BD can present as a spinal cord syndrome. However, motor neuron disease-like presentation is extremely uncommon. Here we are reporting five patients (all male; median age, 38) fulfilling both International Study Group criteria for BD and El Escorial criteria for amyotrophic lateral sclerosis (ALS). These patients were identified by a questionnaire sent to the members of the Neuro-Behcet Study Group of the International Study Group for BD. Three out of five patients had only motor presentations. In two patients, sensory and urinary manifestations were present as well. Spinal cord MRIs were normal in all, and brain MRIs were normal in four patients; one patient had nonspecific white matter changes. Two patients passed away 1-3 years after diagnosis of ALS, and two patients were lost to follow-up 3 and 11 years after admission; one patient is still alive 3 years after onset. The patients that are presented here might represent a rare form of neurological involvement in BD as well as sole coincidence. Larger prospective series are needed to further answer this issue. PMID- 22234493 TI - A modified juvenile arthritis damage index to improve articular damage assessment in juvenile idiopathic arthritis--enthesitis-related arthritis (JIA-ERA). AB - Juvenile arthritis damage index (JADI) consists of two parts which measure articular (JADI-A) and extra-articular (JADI-E) damage in patients with juvenile idiopathic arthritis (JIA). It does not include assessment of cardiac dysfunction and joint areas commonly affected in enthesitis-related arthritis (ERA) category of JIA. We have tried to study if modification of JADI will improve its performance in JIA-ERA. We studied 101 consecutive patients of JIA-ERA. JADI-A was modified (JADI-AM) to include damage assessment of tarsal joints and lumbar spine. JADI-E was modified (JADI-EM) to include assessment of symptomatic cardiac dysfunction. The performances of the modified and standard JADI were compared. Ninety-seven patients were male. The median age was 18 years (9-36). At a median disease duration of 6 years (1-24), joint damage was observed in 47 as assessed by JADI-A. JADI-AM could identify 11 more patients (N = 58) with articular damage. JADI-AM had good correlation with number of joints with limitation of movement (Spearman's [rS] = 0.9) and low to moderate correlation (rS < 0.7) with measures of disease activity and functional status. JADI-AM discriminated well among patients with different disability levels. Extra-articular damage was observed in 35, and modification of JADI-E with inclusion of cardiac dysfunction did not identify any additional patient. Thus, we propose a modification of the JADI-A (JADI-AM). In JIA-ERA, modification of JADI-A improves its ability to identify articular damage. Modification of the JADI-E may not be needed as symptomatic cardiac involvement is rare. PMID- 22234494 TI - The role of regulatory T cells in familial Mediterranean fever (FMF). AB - The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 +/- 0.4 (0-3). The mean age was 31.6 +/- 6.2. The mean age at onset was 9.3 +/- 9.3. The mean colchicine dose was 2.6 mg +/- 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 +/- 2.36 vs. 7.005 +/- 0.3 vs. 5.3 +/- 1.06 vs. 4.44 +/- 1.8; p < 0.05 (Fig.1). The percentage of T-regs in peripheral blood was not statistically different between the four groups. Theexpression of Foxp3 by T-regs increases 7 days after attacks of FMF. Anti-inflammatory cytokines interleukin-10 and TGF-beta are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks. PMID- 22234495 TI - Effects of Selenoprotein W gene expression by selenium involves regulation of mRNA stability in chicken embryos neurons. AB - Selenium (Se) and Selenoprotein W (SelW) plays a pivotal role in the brain development, function, and degeneration and that SelW expression in the brain may be affected by Se. However, the mechanism which Se regulates the SelW gene expression in neurons remains to be unclear. To investigate the effects of the SelW gene expression and mRNA stability induced by Se, primary cultured chicken embryos neurons derived from 8-day-old chick embryo cerebral hemispheres were treated with 10(-9)-10(-5) mol/l Se as selenite for 3, 6, 12, 24 or 48 h, respectively. The morphology and viability of Neurons was detected. The SelW mRNA expression level and mRNA half-life was examined in Se-treated neurons. The relative low concentrations of Se enhanced the neurite outgrowth, increased the SelW mRNA levels and elevated the mRNA half-life of chick embryo neurons. In contrast, the high concentrations of Se presented neurotoxic to neurons, decreased the SelW mRNA levels and reduced the mRNA half-life of neuronal cells. These results suggest that the alteration of post-transcriptional stabilization of SelW mRNA is an important mechanism of Se-induced the elevation or reduction of the SelW expression level in chick embryo neurons. PMID- 22234496 TI - Effect of tellurite-mediated oxidative stress on the Escherichia coli glycolytic pathway. AB - To unveil the metabolic impact of tellurite in the bacterial cell, the effect of this toxicant on the expression and activity of key enzymes of the Escherichia coli glycolytic pathway was analyzed. E. coli exposure to tellurite results in: (i) increased glucose consumption, which was paralleled by an increased expression of the glucose transporter-encoding gene ptsG, (ii) augmented phosphoglucoisomerase activity and pgi transcription, (iii) decreased activity of the enzymatic regulators phosphofructokinase and pyruvate kinase. In spite of these observations, increased intracellular pyruvate, phosphoenol pyruvate and phosphorylated sugars was observed. E. coli lacking key glycolytic enzymes was considerably more sensitive to tellurite than the parental, isogenic, wild type strain. Taken together, these results suggest that increasing the availability of key metabolites (pyruvate, phosphoenol pyruvate, NADPH), required to respond to tellurite mediated-stress, E. coli shifts the carbon flux towards the pentose phosphate pathway thus facilitating the functioning of the Entner-Doudoroff pathway and/or the glycolytic productive phase. PMID- 22234497 TI - Zinc enhances adiponectin oligomerization to octadecamers but decreases the rate of disulfide bond formation. AB - Adiponectin, a hormone secreted from adipocytes, has been shown to protect against development of insulin resistance, ischemia-reperfusion injury, and inflammation. Adiponectin assembles into multiple oligomeric isoforms: trimers, hexamers and several higher molecular weight (HMW) species. Of these, the HMW species are selectively decreased during the onset of type 2 diabetes. Despite the critical role of HMW adiponectin in insulin responsiveness, its assembly process is poorly understood. In this report, we investigated the role of divalent cations in adiponectin assembly. Purified adiponectin 18mers, the largest HMW species, did not collapse to smaller oligomers after treatment with high concentrations of EDTA. However, treatment with EDTA or another chelator DTPA inhibited the oligomerization of 18mers from trimers in vitro. Zn(2+) specifically increased the formation of 18mers when compared with Cu(2+), Mg(2+), and Ca(2+). Distribution of adiponectin oligomers secreted from zinc chelator TPEN-treated rat adipocytes skewed toward increased proportions of hexamers and trimers. While we observed presence of zinc in adiponectin purified from calf serum, the role of zinc in disulfide bonding between oligomers was examined because the process is critical for 18mer assembly. Surprisingly, Zn(2+) inhibited disulfide bond formation early in the oligomerization process. We hypothesize that initial decreases in disulfide formation rates could allow adiponectin subunits to associate before becoming locked in fully oxidized conformations incapable of further oligomerization. These data demonstrate that zinc stimulates oligomerization of HMW adiponectin and possibly other disulfide dependent protein assembly processes. PMID- 22234498 TI - Superstructure based on beta-CD self-assembly induced by a small guest molecule. AB - The size, shape and surface chemistry of nanoparticles play an important role in cellular interaction. Thus, the main objective of the present study was the determination of the beta-cyclodextrin (beta-CD) self-assembly thermodynamic parameters and its structure, aiming to use these assemblies as a possible controlled drug release system. Light scattering measurements led us to obtain the beta-CD's critical aggregation concentration (cac) values, and consequently the thermodynamic parameters of the beta-CD spontaneous self-assembly in aqueous solution: Delta(agg)G(o) = -16.31 kJ mol(-1), Delta(agg)H(o) = -26.48 kJ mol(-1) and TDelta(agg)S(o) = -10.53 kJ mol(-1) at 298.15 K. Size distribution of the self-assembled nanoparticles below and above cac was 1.5 nm and 60-120 nm, respectively. The number of beta-CD molecules per cluster and the second virial coefficient were identified through Debye's plot and molecular dynamic simulations proposed the three-fold assembly for this system below cac. Ampicillin (AMP) was used as a drug model in order to investigate the key role of the guest molecule in the self-assembly process and the beta-CD:AMP supramolecular system was studied in solution, aiming to determine the structure of the supramolecular aggregate. Results obtained in solution indicated that the beta-CD's cac was not affected by adding AMP. Moreover, different complex stoichiometries were identified by nuclear magnetic resonance and isothermal titration calorimetry experiments. PMID- 22234499 TI - An efficient protocol for the solid-phase synthesis of glycopeptides under microwave irradiation. AB - A standardized and smooth protocol for solid-phase glycopeptides synthesis under microwave irradiation was developed. Double activation system was proved to allow for highly efficient coupling of Tn-Ser/Thr and bulky core 2-Ser/Thr derivatives. Versatility and robustness of the present strategy was demonstrated by constructing a Mucine-1 (MUC1) fragment and glycosylated fragments of tau protein. The success of this approach relies on the combination of microwave energy, a resin consisting totally of polyethylene glycol, a low excess of sugar amino acid and the "double activation" method. PMID- 22234501 TI - Well-differentiated liposarcoma/atypical lipomatous tumor of the oral cavity: report of three cases and review of the literature. AB - Atypical Lipomatous Tumor/Well Differentiated Liposarcoma (ALT/WDLS) is a soft tissue sarcoma of intermediate malignant behavior, most frequently affecting the retroperitoneum and lower extremities. Oral liposarcomas are very rare neoplasms, the most common histological subtype being ALT/WDLS. In this study, three additional cases of ALT/WDLS located on the tongue (2 cases) and the lower lip (1 case), respectively, are described. Analysis of the salient clinicopathologic features of 63 oral ALT/WDLS cases previously reported in the English language literature, as well as of the 3 cases presented in this study, indicates that the indolent biologic behavior of this tumor justifies its designation as a locally spreading malignant neoplasm, affording a rather conservative surgical approach. PMID- 22234502 TI - Characterization of antioxidant and anti-inflammatory activities of bioactive fractions recovered from a glucose-lysine Maillard reaction model system. AB - A glucose-lysine (Glu-Lys) Maillard reaction mixture heated at 121 degrees C for 60 min was processed by ultrafiltration, ethyl acetate extraction, and semi preparative HPLC to recover a bioactive fraction, termed F3. F3, characterized by spectral analysis to contain three distinct components, inhibited NO and IL-8 by 70 and 61%, respectively, at a concentration of 50 MUg/ml in inflamed Caco-2 cells induced by IFN-gamma and phorbol 12-myristate 13-acetate (PMA). F3 significantly (P < 0.05) down-regulated several genes involved in nuclear factor kappa B (NF-kappaB) signaling pathway. These genes included the cytokine receptors, TNFRSF10A and TNFRSF10B; receptor-associated proteins, IRAK2 and TICAM1; the inhibitor kappaB kinase, IKBKE; the NF-kappaB inhibitor, NFKBIA; and the NF-kappaB subunits, REL, RELA, and RELB. F3 also down-regulated the NF-kappaB responsive genes IL-8, NOS2, and ICAM1, attenuated the gene expression of peroxidases such as DUOX1 and DUOX2, and relieved the down-regulated GCFHR that are involved in the biosynthesis of NO and TROAP, a gene suppressed by NO. The anti-inflammatory activity of F3 was mediated through multiple processes that included regulation of gene expressions involved in NF-kappaB signaling, the inhibition of IL-8 and iNOS translation, a decrease in NO synthesis and attenuating oxidative stress in inflamed Caco-2 cells. Our results show that MRP components have the potential to suppress inflammation in IFN-gamma and PMA induced Caco-2 cells. PMID- 22234503 TI - Inducible nitric oxide synthase haplotype associated with migraine and aura. AB - Migraine is a complex neurological disorder with a clear neurogenic inflammatory component apparently including enhanced nitric oxide (NO) formation. Excessive NO amounts possibly contributing to migraine are derived from increased expression and activity of inducible NO synthase (iNOS). We tested the hypothesis that two functional, clinically relevant iNOS genetic polymorphisms (C(-1026)A-rs2779249 and G2087A-rs2297518) are associated with migraine with or without aura. We studied 142 healthy women without migraine (control group) and 200 women with migraine divided into two groups: 148 with migraine without aura (MWA) and 52 with aura (MA). Genotypes were determined by real-time polymerase chain reaction using the Taqman((r)) allele discrimination assays. The PHASE 2.1 software was used to estimate the haplotypes. The A allele for the G2087A polymorphism was more commonly found in the MA group than in the MWA group (28 vs. 18%; P < 0.05). No other significant differences in the alleles or genotypes distributions were found (P > 0.05). The haplotype combining both A alleles for the two polymorphisms was more commonly found in the MA group than in the control group or in the MWA group (19 vs. 10 or 8%; P = 0.0245 or 0.0027, respectively). Our findings indicate that the G2087A and the C(-1026)A polymorphism in the iNOS gene affect the susceptibility to migraine with aura when their effects are combined within haplotypes, whereas the G2087A affects the susceptibility to aura in migraine patients. These finding may have therapeutic implications when examining the effects of selective iNOS inhibitors. PMID- 22234504 TI - [Not Available]. PMID- 22234505 TI - [Not Available]. PMID- 22234506 TI - [The ICRU Report 83: prescribing, recording and reporting photon-beam intensity modulated radiation therapy (IMRT)]. PMID- 22234509 TI - Perceived relative importance of pain-related functions among patients with low back pain. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between the functional status of patients with low back pain and the perceived importance of pain-related everyday functions assessed in the Oswestry Disability Index. DESIGN: The sample was based on 219 successive adult patients with low back pain referred to a tertiary clinic. PATIENTS: A total of 168 patients (76.6%) participated in the study, mean age 48.2 years (standard deviation 11.6). METHODS: In a questionnaire the patients were asked to complete the Oswestry Disability Index and the same domains using visual analogue scales. Subjects were also asked to assess the relative importance of these domains by using a visual analogue scale. RESULTS: Sleeping, walking and personal care were the 3 most important functions for both men and women. Patients with low back pain gave more importance to most of the functional abilities that are needed in everyday life and self-management than to the intensity of pain. However, when the patients reported their current experience in functions, greatest difficulty was experienced in lifting. CONCLUSION: Development of outcome measure instruments for patients with low back pain could benefit from taking into account patients' perceptions. In addition, functional measures should be weighted according to the relative importance of each function to the patients. PMID- 22234508 TI - Automated MALDI matrix coating system for multiple tissue samples for imaging mass spectrometry. AB - Uniform matrix deposition on tissue samples for matrix-assisted laser desorption/ionization (MALDI) is key for reproducible analyte ion signals. Current methods often result in nonhomogenous matrix deposition, and take time and effort to produce acceptable ion signals. Here we describe a fully-automated method for matrix deposition using an enclosed spray chamber and spray nozzle for matrix solution delivery. A commercial air-atomizing spray nozzle was modified and combined with solenoid controlled valves and a Programmable Logic Controller (PLC) to control and deliver the matrix solution. A spray chamber was employed to contain the nozzle, sample, and atomized matrix solution stream, and to prevent any interference from outside conditions as well as allow complete control of the sample environment. A gravity cup was filled with MALDI matrix solutions, including DHB in chloroform/methanol (50:50) at concentrations up to 60 mg/mL. Various samples (including rat brain tissue sections) were prepared using two deposition methods (spray chamber, inkjet). A linear ion trap equipped with an intermediate-pressure MALDI source was used for analyses. Optical microscopic examination showed a uniform coating of matrix crystals across the sample. Overall, the mass spectral images gathered from tissues coated using the spray chamber system were of better quality and more reproducible than from tissue specimens prepared by the inkjet deposition method. PMID- 22234510 TI - Fungal growth and biomass development is boosted by plants in snow-covered soil. AB - Soil microbial communities follow distinct seasonal cycles which result in drastic changes in processes involving soil nutrient availability. The biomass of fungi has been reported to be highest during winter, but is fungal growth really occurring in frozen soil? And what is the effect of plant cover on biomass formation and on the composition of fungal communities? To answer these questions, we monitored microbial biomass N, ergosterol, and the amount of fungal hyphae during summer and winter in vegetated and unvegetated soils of an alpine primary successional habitat. The winter fungal communities were identified by rDNA ITS clone libraries. Winter soil temperatures ranged between -0.6 degrees C and -0.1 degrees C in snow-covered soil. We found distinct seasonal patterns for all biomass parameters, with highest biomass concentrations during winter in snow covered soil. The presence of plant cover had a significant positive effect on the amount of biomass in the soil, but the type of plant cover (plant species) was not a significant factor. A mean hyphal ingrowth of 5.6 m g(-1) soil was detected in snow-covered soil during winter, thus clearly proving fungal growth during winter in snow-covered soil. Winter fungal communities had a typical species composition: saprobial fungi were dominating, among them many basidiomycete yeasts. Plant cover had no influence on the composition of winter fungal communities. PMID- 22234511 TI - Gut-associated bacteria throughout the life cycle of the bark beetle Dendroctonus rhizophagus Thomas and Bright (Curculionidae: Scolytinae) and their cellulolytic activities. AB - Dendroctonus rhizophagus Thomas and Bright (Curculionidae: Scolytinae) is an endemic economically important insect of the Sierra Madre Occidental in Mexico. This bark beetle has an atypical behavior within the genus because just one beetle couple colonizes and kills seedlings and young trees of 11 pine species. In this work, the bacteria associated with the Dendroctonus rhizophagus gut were analyzed by culture-dependent and culture-independent methods. Analysis of 16S rRNA sequences amplified directly from isolates of gut bacteria suggests that the bacterial community associated with Dendroctonus rhizophagus, like that of other Dendroctonus spp. and Ips pini, is limited in number. Nine bacterial genera of gamma-Proteobacteria and Actinobacteria classes were detected in the gut of Dendroctonus rhizophagus. Stenotrophomonas and Rahnella genera were the most frequently found bacteria from Dendroctonus rhizophagus gut throughout their life cycle. Stenotrophomonas maltophilia, Ponticoccus gilvus, and Kocuria marina showed cellulolytic activity in vitro. Stenotrophomonas maltophilia, Rahnella aquatilis, Raoultella terrigena, Ponticoccus gilvus, and Kocuria marina associated with larvae or adults of Dendroctonus rhizophagus could be implicated in nitrogen fixation and cellulose breakdown, important roles associated to insect development and fitness, especially under the particularly difficult life conditions of this beetle. PMID- 22234512 TI - Matrix metalloprotein-9 activation under cell-to-cell interaction between endothelial cells and monocytes: possible role of hypoxia and tumor necrosis factor-alpha. AB - Matrix metalloproteinase (MMP)-9 plays an important role in cardiovascular events. However, the mechanisms underlying in vivo activation of MMP-9 are largely unknown. We investigated the secretion and activation of MMP-9 under a cell-to-cell interaction, and the effects of hypoxia and cytokine. Human umbilical vein endothelial cell (HUVEC) and THP-1 (human monocyte cell line) were cultured individually, or cocultured under normoxic and hypoxic conditions. In a coculture of HUVEC and THP-1, proMMP-9 secretion was increased twofold compared with individual culture of HUVEC and THP-1, whereas MMP-2 secretion was unchanged. The increase in proMMP-9 secretion was suppressed by antiadhesion molecule antibodies and mitogen-activated protein kinase inhibitors, PD98059 (MAPK/ERK kinase1 inhibitor) and SP600125 (Jun N-terminal kinase inhibitor). ProMMP-9 secretion was increased by tumor necrosis factor (TNF)-alpha at 50 ng/ml (P < 0.05) but was not activated under normoxic (20%) conditions. ProMMP-9 in coculture was activated under hypoxic (<1%) conditions, and was potentiated by TNF-alpha (both P < 0.05). To further investigate the mechanism of hypoxia induced MMP-9 activation, heat shock protein (Hsp)90, which was suggested to be related to MMP-9 activation, was measured by Western blot analysis. The ratio of Hsp90 to glyceraldehyde-3-phosphate dehydrogenase was increased in hypoxic (<1%) coculture conditions with TNF-alpha (P < 0.05). Treatment with geldanamycin and 17-DMAG (Hsp90 inhibitor) suppressed the active form of MMP-9. Cell-to-cell interaction between endothelial cells and monocytes promotes proMMP-9 synthesis and secretion. Hypoxia and inflammation are suggested to play an important role in activating proMMP-9, presumably via Hsp90. PMID- 22234513 TI - N-terminal pro-brain natriuretic peptide could be a marker of subclinical atherosclerosis in patients with type 2 diabetes. AB - N-terminal pro-brain natriuretic peptide (NT-proBNP), which is a useful biomarker of chronic heart failure, has been shown to be a strong predictor of cardiovascular mortality. The aim of this study was to evaluate the relationships between NT-proBNP and markers of subclinical atherosclerosis in patients with type 2 diabetes. Relationships of NT-proBNP to pulse wave velocity (PWV) or ankle brachial index (ABI) as well as to various parameters, including body mass index, blood pressure, serum lipid concentration, serum uric acid concentration, and glycemic control (hemoglobin A1c), age, hemoglobin, serum creatinine concentration, severity of diabetic nephropathy or retinopathy, current treatment of diabetes, cardiothoracic ratio on chest radiograph, presence of left ventricular hypertrophy and/or ST-T changes evaluated by electrocardiograph, smoking status and presence of cardiovascular disease were investigated in 323 consecutive patients with type 2 diabetes. Log (NT-proBNP) correlated positively with PWV (r = 0.283, p < 0.0001) and correlated negatively with ABI (r = -0.144, p = 0.0094). Multiple regression analysis demonstrated that age (beta = 0.200, p = 0.0033), systolic blood pressure (beta = 0.246, p < 0.0001), total cholesterol (beta = -0.135, p = 0.0326), uric acid (beta = 0.133, p = 0.0462), creatinine (beta = -0.184, p = 0.0122), smoking status (beta = -0.129, p = 0.0499) and log (NT-proBNP) (beta = 0.177, p = 0.0149) were independently correlated with PWV and that systolic blood pressure (beta = -0.145, p = 0.0310), log triglyceride (beta = -0.151, p = 0.0397) and log (NT-proBNP) (beta = -0.207, p = 0.0094) were independently correlated with ABI. In conclusion, NT-proBNP could be a marker of subclinical atherosclerosis in patients with type 2 diabetes. PMID- 22234514 TI - Generation of SV40-transformed rabbit tracheal-epithelial-cell-derived blastocyst by somatic cell nuclear transfer. AB - The prospect of developing large animal models for the study of inherited diseases, such as cystic fibrosis (CF), through somatic cell nuclear transfer (SCNT) has opened up new opportunities for enhancing our understanding of disease pathology and for identifying new therapies. Thus, the development of species specific in vitro cell systems that will provide broader insight into organ- and cell-type-specific functions relevant to the pathology of the disease is crucial. Studies have been undertaken to establish transformed rabbit airway epithelial cell lines that display differentiated features characteristic of the primary airway epithelium. This study describes the successful establishment and characterization of two SV40-transformed rabbit tracheal epithelial cell lines. These cell lines, 5RTEo- and 9RTEo-, express the CF transmembrane conductance regulator (CFTR) gene, retain epithelial-specific differentiated morphology and show CFTR-based cAMP-dependent Cl(-) ion transport across the apical membrane of a confluent monolayer. Immunocytochemical analysis indicates the presence of airway cytokeratins and tight-junction proteins in the 9RTEo- cell line after multiple generations. However, the tight junctions appear to diminish in their efficacy in both cell lines after at least 100 generations. Initial SCNT studies with the 9RTEo- cells have revealed that SV40-transformed rabbit airway epithelial donor cells can be used to generate blastocysts. These cell systems provide valuable models for studying the developmental and metabolic modulation of CFTR gene expression and rabbit airway epithelial cell biology. PMID- 22234515 TI - Silica-based nanoprobes for biomedical imaging and theranostic applications. AB - Nanoparticle-based contrast agents are attracting a great deal of attention for various biomedical imaging and theranostic applications. Compared to conventional contrast agents, nanoparticles possess several potential advantages to improve in vivo detection and to enhance targeting efficiency. Silica-based nanoprobes can be engineered to achieve longer blood circulation times, specific clearance pathways, and multivalent binding. In this tutorial review, we summarize the latest progress on designing silica-based nanoprobes for imaging and theranostic applications. The synthesis of both solid silica and mesoporous silica nanoparticles is described, along with different approaches used for surface functionalization. Special emphasis is placed on the application of silica-based nanoprobes in optical, magnetic resonance, and multimodal imaging. The latest breakthroughs in the applications of silica nanoparticles as theranostic agents are also highlighted. PMID- 22234516 TI - An egg-enriched diet attenuates plasma lipids and mediates cholesterol metabolism of high-cholesterol fed rats. AB - We investigated the influence of an egg-enriched diet on plasma, hepatic and fecal lipid levels and on gene expression levels of transporters, receptors and enzymes involved in cholesterol metabolism. Sprague-Dawley rats fed an egg enriched diet had lower plasma triglycerides, total cholesterol, low density lipoprotein (LDL)-cholesterol, hepatic triglyceride, and cholesterol concentrations, and greater plasma high-density lipoprotein cholesterol concentration, fecal neutral sterol and bile acid concentrations than those fed a plain cholesterol diet. Chicken egg yolk had no effect on sterol 12alpha hydroxylase and sterol 27alpha-hydroxylase; but upregulated mRNA levels of hepatic LDL-receptor, cholesterol 7alpha-hydroxylase (CYP7A1) and lecithin cholesterol acyltransferase, and downregulated hepatic hydroxymethylglutaryl (HMG)-CoA reductase and acyl-CoA:cholesterol acyltransferase (ACAT) after 90 days. Modification of the lipoprotein profile by an egg-enriched diet was mediated by reducing de novo cholesterol synthesis and enhancing the excretion of fecal cholesterol, via upregulation of CYP7A1 and the LDL receptor, and downregulation of HMG-CoA reductase and ACAT. PMID- 22234518 TI - Molecular insights on basal-like breast cancer. AB - Molecular classification of breast cancer (BC) identified diverse subgroups that encompass distinct biological behavior and clinical implications, in particular in relation to prognosis, spread, and incidence of recurrence. Basal-like breast cancers (BLBC) compose up to 15% of BC and are characterized by lack of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification with expression of basal cytokeratins 5/6, 14, 17, epidermal growth factor receptor (EGFR), and/or c-KIT. There is an overlap in definition between triple-negative BC and BLBC due to the triple-negative profile of BLBC. Also, most BRCA1 associated BCs are BLBC, triple negative, and express basal cytokeratins (5/6, 14, 17) and EGFR. There is a link between sporadic BLBC (occurring in women without germline BRCA1 mutations) with dysfunction of the BRCA1 pathway. Despite the molecular and clinical similarities, these subtypes respond differently to neoadjuvant therapy. BLBCs are associated with an aggressive phenotype, high histological grade, poor clinical behavior, and high rates of recurrences and/or metastasis. Their molecular features render these tumors especially refractory to anti-hormonal-based therapies and the overall prognosis of this subset remains poor. In this article, the molecular profile, genomic, and epigenetic characteristics as well as BRCA1 pathway dysfunction, clinicopathological behavior, and therapeutic options in BLBC are presented, with emphasis on the discordant findings in current literature. PMID- 22234519 TI - Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04). AB - Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women. PMID- 22234520 TI - A short half-life of the administered factor XIII (FXIII) concentrates after the first replacement therapy in a newborn with severe congenital FXIII deficiency. PMID- 22234522 TI - Knockdown of eukaryotic translation initiation factors 3B (EIF3B) inhibits proliferation and promotes apoptosis in glioblastoma cells. AB - Eukaryotic initiation factors 3 (EIF3) complex is essential for initiation of protein synthesis for both cells and virus. It consists of 13 subunits (EIF3A to M), among which EIF3B serves as a major scaffolding subunit. However, its functions in human glioblastoma have not been explored yet. Here, we showed that EIF3B was expressed in human glioblastoma (Grade I-IV) and human glioblastoma cell lines (U251, U87, A172 and U373). Loss of function analysis was performed on U87 cells using lentivirus-mediated siRNA against EIF3B. EIF3B-shRNA expressing lentivirus could effectively infect U87 glioma cells and downregulate EIF3B expression. Knockdown of EIF3B expression significantly inhibited proliferation of U87 cells. Further study showed that the proliferation inhibitory effect was associated with accumulation in G0/G1-phase cell number and an increased rate of apoptosis. In conclusion, EIF3B promotes the proliferation of U87 cells and may play an important role in human glioblastoma development. PMID- 22234523 TI - Legionellosis presenting as singultus and external ophthalmoplegia. AB - We report a 71-year-old man with legionellosis, who presented with abducens nerve palsy, singultus, confusion, memory impairment, ataxia, and hyporeflexia. Legionella pneumonia was diagnosed on the basis of detection of Legionella pneumophila antigen in the urine. The cerebrospinal fluid was negative for the antigen and antibody, but an oligoclonal band was detected, and the IgG index was elevated. It was speculated that an undetermined immune-mediated mechanism had contributed to the development of the neurological manifestations. PMID- 22234524 TI - Simulated Brown syndrome in the contralateral eye in superior oblique palsy. PMID- 22234525 TI - LIBP-Pred: web server for lipid binding proteins using structural network parameters; PDB mining of human cancer biomarkers and drug targets in parasites and bacteria. AB - Lipid-Binding Proteins (LIBPs) or Fatty Acid-Binding Proteins (FABPs) play an important role in many diseases such as different types of cancer, kidney injury, atherosclerosis, diabetes, intestinal ischemia and parasitic infections. Thus, the computational methods that can predict LIBPs based on 3D structure parameters became a goal of major importance for drug-target discovery, vaccine design and biomarker selection. In addition, the Protein Data Bank (PDB) contains 3000+ protein 3D structures with unknown function. This list, as well as new experimental outcomes in proteomics research, is a very interesting source to discover relevant proteins, including LIBPs. However, to the best of our knowledge, there are no general models to predict new LIBPs based on 3D structures. We developed new Quantitative Structure-Activity Relationship (QSAR) models based on 3D electrostatic parameters of 1801 different proteins, including 801 LIBPs. We calculated these electrostatic parameters with the MARCH-INSIDE software and they correspond to the entire protein or to specific protein regions named core, inner, middle, and surface. We used these parameters as inputs to develop a simple Linear Discriminant Analysis (LDA) classifier to discriminate 3D structure of LIBPs from other proteins. We implemented this predictor in the web server named LIBP-Pred, freely available at , along with other important web servers of the Bio-AIMS portal. The users can carry out an automatic retrieval of protein structures from PDB or upload their custom protein structural models from their disk created with LOMETS server. We demonstrated the PDB mining option performing a predictive study of 2000+ proteins with unknown function. Interesting results regarding the discovery of new Cancer Biomarkers in humans or drug targets in parasites have been discussed here in this sense. PMID- 22234526 TI - Lawesson's reagent-initiated domino reaction of aminopropenoyl cyclopropanes: synthesis of thieno[3,2-c]pyridinones. AB - A convenient and efficient synthesis of substituted 2,3-dihydrothieno[3,2 c]pyridin-4(5H)-ones has been developed and relies upon a domino reaction of dimethylaminopropenoyl cyclopropanes initiated by Lawesson's reagent. A mechanism involving regioselective thionation, ring-enlargement, and an intramolecular aza cyclization sequence is proposed. This protocol was utilized as a one-pot route to thieno[3,2-c]pyridin-4(5H)-ones with DDQ as an oxidant. PMID- 22234527 TI - Prevalence of monoclonal gammopathy of undetermined significance in Thailand. AB - Individuals with monoclonal gammopathy of undetermined significance (MGUS) develop multiple myeloma and related malignancies at the rate of 1% per year. Given differences in ethnicity, data on prevalence and risk factors of MGUS in Thai population will be helpful in understanding the pathogenesis of plasma cell disorders and designing an early cancer detection strategy. Subjects of 50 years or older were included. Demographic data and suspected risk factors were collected. Monoclonal proteins were detected using serum protein electrophoresis. Serum was obtained from 3,260 participants; 1,104 males (33.9%) and 2,156 females (66.1%). The median age was 57 years (range 50-93 years). Monoclonal proteins were detectable in 2.3% (95% confidence interval [CI] 1.8-2.8). M spikes were found in gamma- and beta-globulin regions in 50 (1.5%) and 25 (0.8%) subjects, respectively. The prevalence of MGUS in subjects 50-59, 60-69, and 70 years or older was 2.0% (41/1,975), 2.6% (22/851), and 2.8% (12/434), respectively. By multivariate analysis, MGUS was associated with living outside Bangkok (odds ratio 2.25, 95% CI 1.11-4.58). The overall prevalence of MGUS in the Thai population was 2.3%, which was lower than that in Western countries, but comparable to that in Japan. PMID- 22234529 TI - Evaluation of the commercial rapid trehalose test (GLABRATA RTT) for the point of isolation identification of Candida glabrata isolates in primary cultures. AB - Candidaemias account for 10-20% of nosocomial bloodstream infections depending on the study. Whilst Candida albicans remains the most frequently isolated species, Candida glabrata may be responsible for as many as 10-25% of all candidaemias. Moreover, C. glabrata is generally less susceptible to the azole antifungals than the majority of other pathogenic yeast species. Thus, a rapid test for the specific identification of isolates of C. glabrata would be useful for patient management if it could be performed at point of isolation, on primary cultures grown on standard mycological media directly from patient specimens. Under certain conditions, C. glabrata rapidly hydrolyses trehalose into glucose. The GLABRATA RTT kit allows detection of the preformed enzyme responsible for this action. This study has assessed GLABRATA RTT as an identification tool specifically at point of isolation. Sixty test isolates were evaluated: 39 clinical isolates of C. glabrata identified at the UK Mycology Reference Laboratory, examples of the recently described genetic relatives of C. glabrata, Candida nivariensis (n = 6) and Candida bracarensis (n = 1), and a selection of other common pathogenic yeast species (n = 14). The test provided results within 30 min. Although 77% (30/39) of confirmed C. glabrata isolates were correctly identified by GLABRATA RTT (positive trehalase test), 23% (9/39) of isolates gave negative or equivocal results. All other yeast species gave negative results. The performance of GLABRATA RTT in this study is compared to previous evaluations of the test which employed isolates pre-cultured on specialised media and to other existing conventional identification methodologies. PMID- 22234528 TI - Mutations in epigenetic regulators in myelodysplastic syndromes. AB - Until recently, the genetic aberrations that are causally linked to the pathogenesis of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms were largely unknown. Using novel technologies like high-resolution SNP-array analysis and next generation sequencing, various genes have now been identified that are recurrently mutated. Strikingly, several of the newly identified genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, and TET2) are involved in the epigenetic regulation of gene expression. Aberrant epigenetic modifications have been described in many types of cancer, including myeloid malignancies. It has been proposed that repression of genes that are crucial for the cessation of the cell cycle and induction of differentiation might contribute to the malignant transformation of normal hematopoietic cells. Several therapies that aim to re express silenced genes are currently being tested in MDS, like histone deacetylase inhibitors and hypomethylating agents. It will be interesting to assess whether patients carrying mutations in epigenetic regulators respond differently to these novel forms of epigenetic therapies. PMID- 22234530 TI - Modification of the secondary structure of angiotensin II by substitution of hydrogen with Cs cations: an experimental and theoretical study. AB - MALDI mass spectrometry in combination with post-source decay (PSD) analysis is a fast and easy to apply method for peptide sequencing. In this study, the PSD technique was used to investigate the influence of the adaption of one, two, and three caesium cations to angiotensin II in the gas phase. The PSD spectra of caesium-aggregated angiotensin II show far less fragmentation in comparison to the protonated one. In the case of singly (doubly) Cs(+) substituted angiotensin II, the PSD mass spectrum shows only fragments with one (two) Cs cation(s). These results are interpreted in terms of additional interactions of the caesium cation(s) with the peptide. In order to investigate this suggestion, the molecular structures were calculated with semi-empirical molecular dynamic (MD) simulations and further optimized at the quantum chemical level (BP86, SVP) of theory. On the one hand, secondary structures of Cs(+) substituted angiotensin II are more compact than the structure of protonated angiotensin II, indicating electrostatic interactions of the Cs cations and the heterocyclic structures. Moreover, oxyphilic interactions of the cations with the oxygen atoms of the peptide backbone also contribute as further van-der-Waals interactions of the Cs(+) substituted angiotensin II. These interactions are able to explain its higher stability due to reduced dissociation in comparison to the protonated angiotensin II. On the other hand, most MD simulations of doubly and triply Cs(+) substituted angiotensin II show a formation of a [2 Cs] cluster, surrounded by the peptide molecule. The formation of this cluster would explain the lack of singly Cs(+) substituted fragments in the PSD mass spectrum of doubly Cs(+) substituted angiotensin II. PMID- 22234531 TI - Screening of enzymatic activities for the depolymerisation of the marine bacterial exopolysaccharide HE800. AB - The exopolysaccharide (EPS) HE800 is a marine-derived polysaccharide (from 8 * 10(5) to 1.5 * 10(6) g mol(-1)) produced by Vibrio diabolicus and displaying original structural features close to those of glycosaminoglycans. In order to confer new biological activities to the EPS HE800 or to improve them, structural modifications need to be performed. In particular, depolymerisation is required to generate low-molecular-weight derivatives. To circumvent the use of chemical methods that lack specificity and reproducibility, enzymes able to perform such reaction are sought. This study reports the screening for enzymes capable of depolymerising the EPS HE800. A large diversity of enzyme sources has been studied: commercially available glycoside hydrolases with broad substrate specificity, lyases, and proteases as well as growing microorganisms. Interestingly, we found that the genus Enterococcus and, more particularly, the strain Enterococcus faecalis were able to depolymerise the EPS HE800. Partial characterization of the enzymatic activity gives evidence for a random and incomplete depolymerisation pattern that yields low-molecular-weight products of 40,000 g mol(-1). Genomic analysis and activity assays allowed the identification of a relevant open reading frame (ORF) which encodes an endo-N-acetyl galactosaminidase. This study establishes the foundation for the development of an enzymatic depolymerisation process. PMID- 22234532 TI - Modelling growth of, and removal of Zn and Hg by a wild microalgal consortium. AB - Microorganisms isolated from sites contaminated with heavy metals usually possess a higher removal capacity than strains from regular cultures. Heavy metal containing soil samples from an industrial dumpsite in Northern Portugal were accordingly collected; following enrichment under metal stress, a consortium of wild microalgae was obtained. Their ability to grow in the presence of, and their capacity to recover heavy metals was comprehensively studied; the datasets thus generated were fitted to by a combined model of biomass growth and metal uptake, derived from first principles. After exposure to 15 and 25 mg/L Zn(2+) for 6 days, the microalgal consortium reached similar, or higher cell density than the control; however, under 50 and 65 mg/L Zn(2+), 71% to 84% inhibition was observed. Growth in the presence of Hg(2+) was significantly inhibited, even at a concentration as low as 25 MUg/L, and 90% inhibition was observed above 100 MUg/L. The maximum amount of Zn(2+) removed was 21.3 mg/L, upon exposure to 25 mg/L for 6 day, whereas the maximum removal of Hg(2+) was 335 MUg/L, upon 6 day in the presence of 350 MUg/L. The aforementioned mechanistic model was built upon Monod assumptions (including heavy metal inhibition), coupled with Leudeking Piret relationships between the rates of biomass growth and metal removal. The overall fits were good under all experimental conditions tested, thus conveying a useful tool for rational optimisation of microalga-mediated bioremediation. PMID- 22234533 TI - Tryptophan catabolism via kynurenine production in Streptomyces coelicolor: identification of three genes coding for the enzymes of tryptophan to anthranilate pathway. AB - Most enzymes involved in tryptophan catabolism via kynurenine formation are highly conserved in Prokaryotes and Eukaryotes. In humans, alterations of this pathway have been related to different pathologies mainly involving the central nervous system. In Bacteria, tryptophan and some of its derivates are important antibiotic precursors. Tryptophan degradation via kynurenine formation involves two different pathways: the eukaryotic kynurenine pathway, also recently found in some bacteria, and the tryptophan-to-anthranilate pathway, which is widespread in microorganisms. The latter produces anthranilate using three enzymes also involved in the kynurenine pathway: tryptophan 2,3-dioxygenase (TDO), kynureninase (KYN), and kynurenine formamidase (KFA). In Streptomyces coelicolor, where it had not been demonstrated which genes code for these enzymes, tryptophan seems to be important for the calcium- dependent antibiotic (CDA) production. In this study, we describe three adjacent genes of S. coelicolor (SCO3644, SCO3645, and SCO3646), demonstrating their involvement in the tryptophan-to-anthranilate pathway: SCO3644 codes for a KFA, SCO3645 for a KYN and SCO3646 for a TDO. Therefore, these genes can be considered as homologous respectively to kynB, kynU, and kynA of other microorganisms and belong to a constitutive catabolic pathway in S. coelicolor, which expression increases during the stationary phase of a culture grown in the presence of tryptophan. Moreover, the S. coelicolor DeltakynU strain, in which SCO3645 gene is deleted, produces higher amounts of CDA compared to the wild-type strain. Overall, these results describe a pathway, which is used by S. coelicolor to catabolize tryptophan and that could be inactivated to increase antibiotic production. PMID- 22234534 TI - Improvement of glutathione production by metabolic engineering the sulfate assimilation pathway of Saccharomyces cerevisiae. AB - Glutathione (GSH) is a valuable tri-peptide that is widely used in the pharmaceutical, food, and cosmetic industries. Glutathione is produced industrially by fermentation using Saccharomyces cerevisiae. In this study, we demonstrated that engineering in sulfate assimilation metabolism can significantly improve GSH production. The intracellular GSH content of MET14 and MET16 over-expressing strains increased up to 1.2 and 1.4-fold higher than that of the parental strain, respectively, whereas those of APA1 and MET3 over expressing strains decreased. Especially, in the MET16 over-expressing strain, the volumetric GSH concentration was up to 1.7-fold higher than that of the parental strain as a result of the synergetic effect of the increases in the cell concentration and the intracellular GSH content. Additionally, combinatorial mutant strains that had been engineered to contain both the sulfur and the GSH synthetic metabolism synergistically increased the GSH production. External addition of cysteine to S. cerevisiae is well known as a way to increase the intracellular GSH content; however, it results a decrease in cell growth. This study showed that the engineering of sulfur metabolism in S. cerevisiae proves more valuable than addition of cysteine as a way to boost GSH production due to the increases in both the intracellular GSH content and the cell growth. PMID- 22234535 TI - Biosorption behavior and mechanism of heavy metals by the fruiting body of jelly fungus (Auricularia polytricha) from aqueous solutions. AB - The aim of this study was to investigate the biosorption characteristics of Cd(2+), Cu(2+), and Pb(2+) by the fruiting body of jelly fungus Auricularia polytricha. Batch experiments were conducted to characterize the kinetics, equilibrium, and mechanisms of the biosorption process. Optimum values of pH 5, biomass dosage 4 g L(-1), and contact time 60 min provided maximum biosorption capacities of A. polytricha for Cd(2+), Cu(2+), and Pb(2+) of 63.3, 73.7, and 221 mg g(-1), respectively. The maximum desorption was achieved using 0.05 mol L(-1) HNO(3) as an elute. The fruiting body was reusable at least for six cycles of operations. The pseudo-second-order model was the best to describe the biosorption processes among the three kinetic models tested. Freundlich and Dubinin-Radushkevich models fitted the equilibrium data well, indicating a heterogeneous biosorbent surface and the favorable chemisorption nature of the biosorption process. A Fourier transform infrared spectroscopy analysis indicated that carboxyl, amine/hydroxyl, amino, phosphoryl, and C-N-C were the main functional groups to affect the biosorption process. Synergistic ion exchange and surface complexation were the dominant mechanisms in the biosorption process. The present work revealed the potential of jelly fungus (fruiting body of A. polytricha) to remove toxic heavy metals from contaminated water. PMID- 22234536 TI - Fermentative production of isobutene. AB - Isobutene (2-methylpropene) is one of those chemicals for which bio-based production might replace the petrochemical production in the future. Currently, more than 10 million metric tons of isobutene are produced on a yearly basis. Even though bio-based production might also be achieved through chemocatalytic or thermochemical methods, this review focuses on fermentative routes from sugars. Although biological isobutene formation is known since the 1970s, extensive metabolic engineering is required to achieve economically viable yields and productivities. Two recent metabolic engineering developments may enable anaerobic production close to the theoretical stoichiometry of 1isobutene + 2CO(2) + 2H(2)O per mol of glucose. One relies on the conversion of 3 hydroxyisovalerate to isobutene as a side activity of mevalonate diphosphate decarboxylase and the other on isobutanol dehydration as a side activity of engineered oleate hydratase. The latter resembles the fermentative production of isobutanol followed by isobutanol recovery and chemocatalytic dehydration. The advantage of a completely biological route is that not isobutanol, but instead gaseous isobutene is recovered from the fermenter together with CO(2). The low aqueous solubility of isobutene might also minimize product toxicity to the microorganisms. Although developments are at their infancy, the potential of a large scale fermentative isobutene production process is assessed. The production costs estimate is 0.9 Euro kg(-1), which is reasonably competitive. About 70% of the production costs will be due to the costs of lignocellulose hydrolysate, which seems to be a preferred feedstock. PMID- 22234537 TI - Characterization and application of fusidane antibiotic biosynethsis enzyme 3 ketosteroid-?1-dehydrogenase in steroid transformation. AB - Microbial ?(1)-dehydrogenation is one of the most important transformations in the synthesis of steroid hormones. In this study, a 3-ketosteroid-?(1) dehydrogenase (kstD(F)) involved in fusidane antibiotic biosynthesis from Aspergillus fumigatus CICC 40167 was characterized for use in steroid transformation. KstD(F) encodes a polypeptide consisting of 637 amino acid residues. It shows 51% amino acid identity with a kstD from Thermomicrobium roseum DSM 5159. Expression of kstD(F) in Escherichia coli and Pichia pastoris showed that all kstD(F) activity is located in the cytoplasm. This indicates that it is a soluble intracytoplasmic enzyme, unlike most kstDs from bacteria, which are membrane-bound. The expression of kstD(F) was performed in P. pastoris, both intracellularly and extracelluarly. The intracellularly expressed protein displayed good activity in steroid transformation, while the extracellularly expressed protein showed nothing. Interestingly, the engineered P. pastoris KM71 (KM71(I)) and GS115 (GS115(I)) showed different transformation activities for 4 androstene-3,17-dione (AD) when kstD(F) was expressed intracellularly. Under the same conditions, KM71(I) was found capable of transforming 1.0 g/l AD to 1,4 androstadiene-3,17-dione (ADD), while GS115(I) could transform 1.5 g/l AD to both ADD and boldenone (BD). The production of BD is attributed to a 17beta hydroxysteroid dehydrogenase in P. pastoris GS115(I), which catalyzes the reversible reaction between C17-one and C17-alcohol of steroids. The conversion of AD by GS115(I) and KM71(I) may provide alternative means of preparing ADD or BD. In brief, we show here that kstD(F) is a promising enzyme in steroid ?(1) dehydrogenation that is propitious to construct genetically engineered steroid transforming recombinants by heterologous overexpression. PMID- 22234538 TI - Resection plus whole-brain irradiation versus resection plus whole-brain irradiation plus boost for the treatment of single brain metastasis. AB - BACKGROUND: The optimal treatment for patients with a single brain metastasis is controversial. This study investigated the value of a radiation boost given in addition to neurosurgerical resection and whole-brain irradiation (WBI). PATIENTS AND METHODS: In this retrospective study, outcome data of 105 patients with a single brain metastasis receiving metastatic surgery plus WBI (S + WBI) were compared to 90 patients receiving the same treatment plus a boost to the metastatic site (S + WBI + B). The outcomes that were compared included local control of the resected metastasis (LC) and overall survival (OS). In addition to the treatment regimen, eight potential prognostic factors were evaluated including age, gender, performance status, extent of metastatic resection, primary tumor type, extracerebral metastases, recursive partitioning analysis (RPA) class, and interval from first diagnosis of cancer to metastatic surgery. RESULTS: The LC rates at 1 year, 2 years, and 3 years were 38%, 20%, and 9%, respectively, after S + WBI, and 67%, 51%, and 33%, respectively, after S + WBI + B (p = 0.002). The OS rates at 1 year, 2 years, and 3 years were 52%, 25%, and 19%, respectively, after S + WBI, and 60%, 40%, and 26%, respectively, after S + WBI + B (p = 0.11). On multivariate analyses, improved LC was significantly associated with OP + WBI + B (p = 0.006) and total resection of the metastasis (p = 0.014). Improved OS was significantly associated with age <= 60 years (p = 0.028), Karnofsky Performance Score > 70 (p = 0.015), breast cancer (p = 0.041), RPA class 1 (p = 0.012), and almost with the absence of extracerebral metastases (p = 0.05). CONCLUSION: A boost in addition to WBI significantly improved LC but not OS following resection of a single brain metastasis. PMID- 22234539 TI - Radiosensitizing effect of epothilone B on human epithelial cancer cells. AB - BACKGROUND: A combined modality treatment employing radiation and chemotherapy plays a central role in the management of solid tumors. In our study, we examined the cytotoxic and radiosensitive effect of the microtubule stabilizer epothilone B on two human epithelial tumor cell lines in vitro and its influence on the microtubule assembly. METHODS: Cancer cells were treated with epothilone B in proliferation assays and in combination with radiation in colony-forming assays. For the analysis of ionizing radiation-induced DNA damage and the influence of the drug on its repair a gammaH2AX foci assay was used. To determine the effect of epothilone B on the microtubule assembly in cells and on purified tubulin, immunofluorescence staining and tubulin polymerization assay, respectively, were conducted. RESULTS: Epothilone B induced a concentration- and application dependent antiproliferative effect on the cells, with IC(50) values in the low nanomolar range. Colony forming assays showed a synergistic radiosensitive effect on both cell lines which was dependent on incubation time and applied concentration of epothilone B. The gammaH2AX assays demonstrated that ionizing radiation combined with the drug resulted in a concentration-dependent increase in the number of double-strand breaks and suggested a reduction in DNA repair capacity. Epothilone B produced enhanced microtubule bundling and abnormal spindle formation as revealed by immunofluorescence microscopy and caused microtubule formation from purified tubulin. CONCLUSION: The results of this study showed that epothilone B displays cytotoxic antitumor activity at low nanomolar concentrations and also enhances the radiation response in the tumor cells tested; this may be induced by a reduced DNA repair capacity triggered by epothilone B. It was also demonstrated that epothilone B in fact targets microtubules in a more effective manner than paclitaxel. PMID- 22234541 TI - Ultrahigh sensitivity assays for human cardiac troponin I using TiO2 nanotube arrays. AB - Rapid, highly sensitive troponin assays for the analysis of serum at the point-of care are particularly desirable for the effective treatment of myocardial infarction (MYI). TiO(2) nanotube arrays constitute a low cost, high surface area, semiconducting architecture with great promise for biosensing applications due to their compatibility with multiple detection techniques. Using TiO(2) nanotube arrays functionalized with highly robust and ordered carboxyalkylphosphonic acid self-assembled monolayers, we have developed a simple and highly sensitive fluorescence immunoassay which can detect concentrations of human cardiac troponin I as low as 0.1 pg ml(-1) without the use of enzymatic amplification. Varying the morphological parameters of the nanotube arrays allows tuning the detection range over 6 orders of magnitude of the troponin concentration from 0.1 pg ml(-1)-100 ng ml(-1). PMID- 22234540 TI - Numerical deconvolution to enhance sharpness and contrast of portal images for radiotherapy patient positioning verification. AB - PURPOSE: The quality of megavoltage clinical portal images is impaired by physical and geometrical effects. This image blurring can be corrected by a fast numerical two-dimensional (2D) deconvolution algorithm implemented in the electronic portal image device. We present some clinical examples of deconvolved portal images and evaluate the clinical advantages achieved by the improved sharpness and contrast. MATERIALS AND METHODS: The principle of numerical 2D image deconvolution and the enhancement of sharpness and contrast thereby achieved are shortly explained. The key concept is the convolution kernel K(x,y), the mathematical equivalent of the smearing or blurring of a picture, and the computer-based elimination of this influence. RESULTS: Enhancements of sharpness and contrast were observed in all clinical portal images investigated. The images of fine bone structures were restored. The identification of organ boundaries and anatomical landmarks was improved, thereby permitting a more accurate comparison with the x-ray simulator radiographs. The visibility of prostate gold markers is also shown to be enhanced by deconvolution. CONCLUSION: The blurring effects of clinical portal images were eliminated by a numerical deconvolution algorithm that leads to better image sharpness and contrast. The fast algorithm permits the image blurring correction to be performed in real time, so that patient positioning verification with increased accuracy can be achieved in clinical practice. PMID- 22234542 TI - Increasing knowledge of best practices for occupational therapists treating post stroke unilateral spatial neglect: results of a knowledge-translation intervention study. AB - OBJECTIVE: The aim of this study was to investigate: (i) the feasibility of delivering a multi-modal knowledge translation intervention specific to the management of acute post-stroke unilateral spatial neglect; and (ii) the impact of the knowledge translation intervention on occupational therapists' knowledge of evidence-based unilateral spatial neglect problem identification, assessment and treatment, and self-efficacy related to evidence-based practice implementation. DESIGN: A 3-period (pre-post) repeated measures design. SUBJECTS: Acute care occupational therapists treating patients with post-stroke unilateral spatial neglect were recruited from two major Canadian cities. METHODS: Participants completed two pre-intervention assessments, took part in a day-long interactive multi-modal knowledge translation intervention and a subsequent 8 week follow-up, and completed a post-intervention assessment. Knowledge of evidence-based problem identification, assessment and treatment of unilateral spatial neglect, and self-efficacy to perform evidence-based practice activities were measured using standard scales. RESULTS: The intervention was tested on 20 occupational therapists. Results indicate a significant improvement in knowledge of best practice unilateral spatial neglect management (p < 0.000) and evidence based practice self-efficacy in carrying out evidence-based practice activities (p < 0.045) post-intervention. CONCLUSION: Use of a multi-modal knowledge translation intervention is feasible and can significantly improve occupational therapists' knowledge of unilateral spatial neglect best practices and self efficacy. The findings should help advance best practices specific to the management of post-stroke unilateral spatial neglect as well as informing knowledge translation studies in other areas of practice. PMID- 22234544 TI - Surgical complications of pediatric auditory brain stem implantation in patients with narrow internal auditory canal following retrosigmoid approach. PMID- 22234543 TI - Increased cortical expression of FK506 binding protein-51 in HIV-associated neurocognitive disorders. AB - FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p < 0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p = 0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p = 0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND. PMID- 22234545 TI - Health-related problems and quality of life in patients with syndromic and complex craniosynostosis. AB - PURPOSE: We conducted this study to gauge the health-related problems, quality of life and the performance of the Health Utility Index Mark 3 (HUI-3) in patients with syndromic and complex craniosynostosis. Patients with syndromic and complex craniosynostosis have various physical and mental problems. More insight on these problems, per syndrome, could provide guidance to improve patient treatment and follow-up. METHODS: A cross-sectional, comparative study on 131 patients and their parents was performed. Health-related quality of life was measured with the HUI-3 and the Visual Analogue Scale (VAS). All data were compared to a normative Dutch population. Vision, hearing and intelligence were objectively measured. RESULTS: The HUI-3 and the VAS were significant lower compared to the normative Dutch population. All syndromes have a high prevalence of vision and speech problems. Cognitive problems were mainly reported in patients with Apert, Crouzon and Muenke syndrome. Ambulation and dexterity problems were seen in Apert, Crouzon, Saethre-Chotzen and complex craniosynostosis. Only patients with Apert syndrome scored significantly worse on pain. The HUI-3 had a medium to strong correlation with the objectively measured outcomes. CONCLUSIONS: The overall quality of life is lower in patients with syndromic and complex craniosynostosis. To improve quality of life, more attention is needed for problems with vision and speech. PMID- 22234546 TI - Expanding the organic toolbox: a guide to integrating biocatalysis in synthesis. AB - This critical review presents an introduction to biocatalysis for synthetic chemists. Advances in biocatalysis of the past 5 years illustrate the breadth of applications for these powerful and selective catalysts in conducting key reaction steps. Asymmetric synthesis of value-added targets and other reaction types are covered, with an emphasis on pharmaceutical intermediates and bulk chemicals. Resources of interest for the non-initiated are provided, including specialized websites and service providers to facilitate identification of suitable biocatalysts, as well as references to recent volumes and reviews for more detailed biocatalytic procedures. Challenges related to the application of biocatalysts are discussed, including how 'green' a biocatalytic reaction may be, and trends in biocatalyst improvement through enzyme engineering are presented (152 references). PMID- 22234548 TI - To reach out more widely and interact. PMID- 22234549 TI - Subcutaneous rupture of the triceps tendon with avulsion fracture of the olecranon spur. PMID- 22234547 TI - Genomic organization and comparative chromosome mapping of the U1 snRNA gene in cichlid fish, with an emphasis in Oreochromis niloticus. AB - To better understand genomic and chromosomal organization and evolutionary patterns of the U1 snRNA gene in cichlid fish, the gene was cytogenetically mapped and comparatively analyzed in 19 species belonging to several clades of the group. Moreover, the distribution and organization of U1 snRNA gene was analyzed in the Oreochromis niloticus genome. The results indicated high conservation of one chromosomal cluster of U1 snRNA in the African, Asian, and South American species, with few variations in the chromosomal position of the clusters in the South American species. The genomic analysis of U1 revealed a distinct scenario from that observed under the cytogenetic mapping. An enrichment of the U1 gene on linkage group (LG) 14 was observed that did not correspond to the same chromosome that harbors the U1 cluster identified by cytogenetic mapping. Moreover, it was revealed that the presence of several distinct transposable elements in the U1 gene flanking regions could be involved in the spreading of this sequence, but the generation of new, large snRNA clusters (detectable by fluorescent in situ hybridization, FISH) is apparently hampered. These results contribute to the understanding of multigene families' evolution and reinforce the utility of integrative analysis and the use of cytogenetic and bioinformatic methods to address the genomic and chromosomal evolutionary patterns of repeated DNAs among vertebrates. Moreover, the U1 gene represents a useful new chromosomal marker for cytogenetic studies. PMID- 22234552 TI - Socio-economic status influences blood pressure control despite equal access to care. AB - OBJECTIVE: Denmark has a health care system with free and equal access to care irrespective of age and socio-economic status (SES). We conducted a cross sectional study to investigate a possible association between SES and blood pressure (BP) control of hypertensive patients treated in general practice. METHODS: We enrolled 184 general practices and 5260 hypertensive patients. The general practitioners reported information about BP and diagnosis of diabetes. Information about education, income, antihypertensive drug treatment and other co morbidity was retrieved from relevant registers from Statistics Denmark. The outcome measure was BP control defined as BP <140/90 mmHg in general and <130/80 mmHg in diabetics. RESULTS: Patients <65 years and with an educational level of 10-12 years had increased odds ratio (OR) of BP control compared to patients with an educational level <10 years. Patients >=65 years had increased OR of BP control if they were married/cohabiting as compared to being single, whereas education and income had no impact in this age group. Diabetics had significantly reduced odds of BP control irrespective of age, educational or income level. CONCLUSIONS: Despite equal access to care for all patients, SES had significant impact on BP control in this survey. Diabetes and cardiovascular disease also had a substantial influence irrespective of age, educational and income level. PMID- 22234554 TI - A new standard for radical prostatectomy in Ireland? PMID- 22234555 TI - Extensive up-regulation of gene expression in cancer: the normalised use of microarray data. AB - Based on the assumption that only a few genes are differentially expressed in a disease and have balanced upward and downward expression level changes, researchers usually normalise microarray data by forcing all of the arrays to have the same probe intensity distributions to remove technical variations in the data. However, accumulated evidence suggests that gene expressions could be widely altered in cancer, so we need to evaluate the sensitivities of biological discoveries to violation of the normalisation assumption. Here, we show that the medians of the original probe intensities increase in most of the ten cancer types analyzed in this paper, indicating that genes may be widely up-regulated in many cancer types. Thus, at least for cancer study, normalising all arrays to have the same distribution of probe intensities regardless of the state (diseased vs. normal) tends to falsely produce many down-regulated differentially expressed (DE) genes while missing many truly up-regulated DE genes. We also show that the DE genes solely detected in the non-normalised data for cancers are highly reproducible across different datasets for the same cancers, indicating that effective biological signals naturally exist in the non-normalised data. Because the powers of current statistical analyses using the non-normalised data tend to be low, we suggest selecting DE genes in both normalised and non-normalised data and then filter out the false DE genes extracted from the normalised data that show opposite deregulation directions in the non-normalised data. PMID- 22234556 TI - Matrix isolation ESR spectroscopy and quantum chemical calculations on 5 methylhexa-1,2,4-triene-1,3-diyl, a highly delocalized triplet "hybrid" carbene. AB - The ESR spectrum of 5-methylhexa-1,2,4-triene-1,3-diyl (1) was recorded in an argon matrix at 15 K. The derived zero-field splitting (ZFS) parameters (D = 0.5054 +/- 0.0006 cm(-1) and E = 0.0045 +/- 0.0002 cm(-1)) fall between those determined previously for propargylene (2) and vinylcarbene (3). DFT and ab initio (CAS and MRCI) quantum-chemical calculations of the ZFS parameters of 1, 2, and 3 were performed. These calculations indicate that multireference methods are needed to successfully predict ZFS parameters of delocalized carbenes/biradicals such as 1-3. The calculated singly occupied MOs and spin density distributions show that the spin is more delocalized in 1 than in 2 and 3, indicating that 1 is a "hybrid" of the constituent ethynyl- and vinylcarbenes, 2 and 3, respectively. The dominant contribution to the D-value in 1 and 2 is found to result from spin-spin interactions on the C atoms of the propylidene moiety, which is strongly affected by spin polarization. Accurate values for the D-parameter are also predicted for other types of delocalized triplet carbenes such as HC(5)H and HCCN. PMID- 22234557 TI - A test for the "physiological phagemia" hypothesis-natural intestinal coliphages do not penetrate to the blood in horses. PMID- 22234558 TI - Quantitative trait loci for seed yield and yield-related traits, and their responses to reduced phosphorus supply in Brassica napus. AB - BACKGROUND AND AIMS: One of the key targets of breeding programmes in rapeseed (Brassica napus) is to develop high-yield varieties. However, the lack of available phosphorus (P) in soils seriously limits rapeseed production. The aim of this study was to dissect the genetic control of seed yield and yield-related traits in B. napus grown with contrasting P supplies. METHODS: Two-year field trials were conducted at one site with normal and low P treatments using a population of 124 recombinant inbred lines derived from a cross between 'B104-2' and 'Eyou Changjia'. Seed yield, seed weight, seed number, pod number, plant height, branch number and P efficiency coefficient (PEC) were investigated. Quantitative trait locus (QTL) analysis was performed by composite interval mapping. KEY RESULTS: The phenotypic values of most of the tested traits were reduced under the low P conditions. In total, 74 putative QTLs were identified, contributing 7.3-25.4 % of the phenotypic variation. Of these QTLs, 16 (21.6 %) were detected in two seasons and in the mean value of two seasons, and eight QTLs for two traits were conserved across P levels. Low-P-specific QTLs were clustered on chromosomes A1, A6 and A8. By comparative mapping between Arabidopsis and B. napus, 161 orthologues of 146 genes involved in Arabidopsis P homeostasis and/or yield-related trait control were associated with 45 QTLs corresponding to 23 chromosomal regions. Four gene-based markers developed from genes involved in Arabidopsis P homeostasis were mapped to QTL intervals. CONCLUSIONS: Different genetic determinants were involved in controlling seed yield and yield-related traits in B. napus under normal and low P conditions. The QTLs detected under reduced P supply may provide useful information for improving the seed yield of B. napus in soils with low P availability in marker-assisted selection. PMID- 22234559 TI - The effect of environmental heterogeneity on RPW8-mediated resistance to powdery mildews in Arabidopsis thaliana. AB - BACKGROUND AND AIMS: The biotic and abiotic environment of interacting hosts and parasites may vary considerably over small spatial and temporal scales. It is essential to understand how different environments affect host disease resistance because this determines frequency of disease and, importantly, heterogeneous environments can retard direct selection and potentially maintain genetic variation for resistance in natural populations. METHODS: The effect of different temperatures and soil nutrient conditions on the outcome of infection by a pathogen was quantified in Arabidopsis thaliana. Expression levels of a gene conferring resistance to powdery mildews, RPW8, were compared with levels of disease to test a possible mechanism behind variation in resistance. KEY RESULTS: Most host genotypes changed from susceptible to resistant across environments with the ranking of genotypes differing between treatments. Transcription levels of RPW8 increased after infection and varied between environments, but there was no tight association between transcription and resistance levels. CONCLUSIONS: There is a strong potential for a heterogeneous environment to change the resistance capacity of A. thaliana genotypes and hence the direction and magnitude of selection in the presence of the pathogen. Possible causative links between resistance gene expression and disease resistance are discussed in light of the present results on RPW8. PMID- 22234560 TI - Physiological, biochemical and transcriptional analysis of onion bulbs during storage. AB - BACKGROUND AND AIMS: During the transition from endo-dormancy to eco-dormancy and subsequent growth, the onion bulb undergoes the transition from sink organ to source, to sustain cell division in the meristematic tissue. The mechanisms controlling these processes are not fully understood. Here, a detailed analysis of whole onion bulb physiological, biochemical and transcriptional changes in response to sprouting is reported, enabling a better knowledge of the mechanisms regulating post-harvest onion sprout development. METHODS: Biochemical and physiological analyses were conducted on different cultivars ('Wellington', 'Sherpa' and 'Red Baron') grown at different sites over 3 years, cured at different temperatures (20, 24 and 28 degrees C) and stored under different regimes (1, 3, 6 and 6 -> 1 degrees C). In addition, the first onion oligonucleotide microarray was developed to determine differential gene expression in onion during curing and storage, so that transcriptional changes could support biochemical and physiological analyses. KEY RESULTS: There were greater transcriptional differences between samples at harvest and before sprouting than between the samples taken before and after sprouting, with some significant changes occurring during the relatively short curing period. These changes are likely to represent the transition from endo-dormancy to sprout suppression, and suggest that endo-dormancy is a relatively short period ending just after curing. Principal component analysis of biochemical and physiological data identified the ratio of monosaccharides (fructose and glucose) to disaccharide (sucrose), along with the concentration of zeatin riboside, as important factors in discriminating between sprouting and pre-sprouting bulbs. CONCLUSIONS: These detailed analyses provide novel insights into key regulatory triggers for sprout dormancy release in onion bulbs and provide the potential for the development of biochemical or transcriptional markers for sprout initiation. Evidence presented herein also suggests there is no detrimental effect on bulb storage life and quality caused by curing at 20 degrees C, producing a considerable saving in energy and costs. PMID- 22234561 TI - Correlation between apparent diffusion coefficient and viscoelasticity of articular cartilage in a porcine model. AB - OBJECTIVE: Quantitative MR imaging techniques of degenerative cartilage have been reported as useful indicators of degenerative changes in cartilage extracellular matrix, which consists of proteoglycans, collagen, non-collagenous proteins, and water. Apparent diffusion coefficient (ADC) mapping of cartilage has been shown to correlate mainly with the water content of the cartilage. As the water content of the cartilage in turn correlates with its viscoelasticity, which directly affects the mechanical strength of articular cartilage, ADC can serve as a potentially useful indicator of the mechanical strength of cartilage. The aim of this study was to investigate the correlation between ADC and viscoelasticity as measured by indentation testing. MATERIALS AND METHODS: Fresh porcine knee joints (n = 20, age 6 months) were obtained from a local abattoir. ADC of porcine knee cartilage was measured using a 3-Tesla MRI. Indentation testing was performed on an electromechanical precision-controlled system, and viscosity coefficient and relaxation time were measured as additional indicators of the viscoelasticity of cartilage. The relationship between ADC and viscosity coefficient as well as that between ADC and relaxation time were assessed. RESULTS: ADC was correlated with relaxation time and viscosity coefficient (R(2) = 0.75 and 0.69, respectively, p < 0.01). The mean relaxation time values in the weight-bearing and non-weight bearing regions were 0.61 +/- 0.17 ms and 0.14 +/- 0.08 ms, respectively. CONCLUSIONS: This study found a moderate correlation between ADC and viscoelasticity in the superficial articular cartilage. Both molecular diffusion and viscoelasticity were higher in weight bearing than non-weight-bearing articular cartilage areas. PMID- 22234563 TI - Abnormal inflammation leads to maternal coagulopathies associated with placental haemostatic alterations in a rat model of foetal loss. AB - Spontaneous pregnancy loss is often associated with aberrant maternal inflammation and systemic coagulopathies. However, the role of inflammation in the development of obstetric coagulopathies is poorly understood. Further, questions remain as to whether systemic coagulopathies are linked to placental haemostatic alterations, and whether these local alterations contribute to a negative foetal outcome. Using a model of spontaneous foetal loss in which pregnant rats are given a single injection of bacterial lipopolysaccharide (LPS), we characterised the systemic maternal coagulation status following LPS administration using thromboelastography (TEG), a global haemostatic assay that measures the kinetics of clot formation. Systemic maternal coagulopathy was evident in 82% of LPS-treated rats. Specifically, we observed stage-I, -II, and III disseminated intravascular coagulation (DIC) and hypercoagulability. Modulation of inflammation through inhibition of tumour necrosis factor alpha with etanercept resulted in a 62% reduction in the proportion of rats exhibiting coagulopathy. Moreover, inflammation-induced systemic coagulopathies were associated with placental haemostatic alterations, which included increased intravascular, decidual, and labyrinth fibrin deposition in cases of DIC-I and hypercoagulability, and an almost complete absence of fibrin deposition in cases of DIC-III. Furthermore, systemic and placental haemostatic alterations were associated with impaired utero-placental haemodynamics, and inhibition of these haemostatic alterations by etanercept was associated with maintenance of utero placental haemodynamics. These findings indicate that modulation of maternal inflammation may be useful in the prevention of coagulopathies associated with complications of pregnancy. PMID- 22234564 TI - [Assessment of the strategies to improve therapeutic compliance in routine clinical practice in noncompliant patients with Alzheimer-type dementia]. AB - INTRODUCTION AND AIM: The potential benefits of the therapy for patients with chronic diseases such as Alzheimer's disease depends largely on adherence to the treatment. The main objective of this study was to assess which of the strategies used by physicians in clinical practice were effective in improving adherence in noncompliant patients with Alzheimer-type dementia (ATD). PATIENTS AND METHODS: An epidemiological, multicenter, observational, prospective, study in non compliant patients with diagnosis of ATD with a baseline assessment and two follow-up visits at three and at six months. The primary outcome was treatment adherence in the last month. Patients who had missed more than 20% of the prescribed doses or who had failed to have the doses in the time, dose or dosage form prescribed by the physician in more than 20% of the cases were considered as non-compliant. RESULTS: The first cause of non-adherence was forgetfulness, followed by the caregiver burden. Overall, the use of one or more strategies to improve adherence was effective. The percentage of non-adherent patients was reduced to 26% at three months and up to 14% at six months. CONCLUSION: The modification of treatment for Alzheimer's disease psychoeducation are effective interventions to reduce treatment failure in patients with ATD. PMID- 22234565 TI - [Analyses of the patient knowledge about the medical report and its usefulness in neurology]. AB - INTRODUCTION: The medical report is a legal, written document issued by the physician, exposing the clinical history and the diagnostic and therapeutic protocols applied to the patient. AIM: To evaluate the patient knowledge about the medical report and its usefulness. PATIENTS AND METHODS: We included consecutive first-visit patients attended in four general neurology offices. The descriptive analysis included: demographic data (age, sex, level of studies), degree of knowledge on the referring doctor (name, specialty, reason for referral), medical history (medical antecedents, treatment, dosage, reasons for its intake, reasons for not providing it) and the medical report (applications, reasons for not providing it and awarded usefulness). These data were compared between different sanitary areas and cultural levels. RESULTS: We included 378 patients (average age: 49.1 +/- 20.6 years-old; 62.2% women; 40.2% with primary studies; 23.3% with secondary studies). 41.5% did not know the name of the referring doctor, 5.5% his specialty and 2.6% the reason for referral. 3.7% did not know their medical antecedents, 20.4% did not provide the treatment (49.3% did not know it was necessary), 4.8% did not know why they took it and 27.6% the dosage. 14.3% did not provide the medical report and 18.0% applied it (61.7% for bureaucratic reasons and 28.0% for information). Only 18.0% knew that the medical report included the medical information of the patient. CONCLUSION: The patient does not know the usefulness and importance of the medical report, despite being a legal document exposing the medical information of the patient disease. PMID- 22234566 TI - [Primary and secondary cardiovascular prevention results in patients with stroke: relapse risk and associated survival (Ebrictus study)]. AB - INTRODUCTION: The prevalence and cardiovascular risk factors control (CVRF) are determining to suffer a stroke and its relapse which arise the mortality and disability. AIM: To estimate the incidence of the first episode of ictus and describe the results in primary and secondary cardiovascular prevention. PATIENTS AND METHODS: Observational and prospective study of a fix cohort of 130,649 people, 15-90-year-old assigned to participants centers between 01/04/2006 and 31/03/2008. Community based register. Analyses were performed with the use of time-to-event methods, included Cox's multivariate on survival, risk of it's relapse; the CVRF diagnosed and it's relative risk (RR); cardiovascular risk. RESULTS: 553 patients were enrolled (48,8% female), average age 73.3 +/- 11.6 years with the first episode of stroke. After the episode, the hypertension (74.9% vs 88.7%), atrial fibrillation (9.9% vs 16%) and dislipemia (37.8% vs 49.8%) increased significantly as well its control. The 47% (95% CI = 42.8-51.2) of the cases had high risk of relapsing. In the 15.7% of the patients happened relapse of cardiovascular event, 48.3% of which were stroke. The main predictors variables were history of recurrent cardiovascular event (RR = 6.7; 95% CI = 2.2 21.7) and the aging (RR = 1,08; 95% CI = 1.01-1.2). CONCLUSION: The cardiovascular secondary prevention seems to be more effective both in CVRF's detection and its control and is extremely important to get better results of survival. PMID- 22234567 TI - [Endovascular treatment of carotid stenosis: an experience in the Hospital Universitario Central de Asturias]. AB - INTRODUCTION: Carotid stenosis accounts for about 25% of all ischaemic cerebrovascular events. Carotid angioplasty and stenting (CAS) is a minimally invasive procedure used as an alternative to carotid endarterectomy, especially in high surgical risk patients. AIM: To analyse the effectiveness and safety of the endovascular treatment of carotid stenosis in the Hospital Universitario Central de Asturias. PATIENTS AND METHODS: The study consisted in a retrospective analysis of the carotid stenoses treated by means of CAS between February 2005 and April 2010, and the following information was recorded: demographic data, clinical diagnosis, indication of treatment, time between the onset of symptoms and beginning of treatment, angiographic findings, complications and long-term follow-up (including the rate of restenosis). RESULTS: Altogether 121 patients were treated (77.8% males and 22.2% females), with a mean age of 70.8 +/- 10.7 years. The main vascular risk factors were arterial hypertension (65.3%), smoking (61.2%) and dyslipidaemia (42.1%). In 86% of cases the stenoses were symptomatic and in the remaining 14% they were asymptomatic. In 60.3% of cases they were stenoses > 70%, in 30.6% they were preocclusive stenoses and in 9.1% they were recanalisations of unstable carotid occlusions. The mean treatment time was 17.0 +/- 8.3 days after the ischaemic event. The residual stenosis was less than 30% in all cases. The morbidity and mortality rate at 30 days was 4.1% and the rate of restenosis throughout a mean follow-up of 31.2 +/- 10.8 months was 2.4%. CONCLUSIONS: In our hospital CAS is considered an effective and safe technique, with a rate of complications that is within the parameters that justify its indication. PMID- 22234568 TI - [Multiple mononeuritis and eosinophilic fasciitis in a patient with idiopathic hypereosinophilic syndrome]. AB - INTRODUCTION: Hypereosinophilic syndrome is produced by what is usually a multiple infiltration of eosinophils into tissues, and may be secondary or idiopathic, depending on whether it is related to a specific aetiology or not. It is not uncommon for it to include nerve disease, but it is unusual for it to do so in the form of multineuritis. Exceptionally, pathogenesis into multiple mononeuritis appears to be related with neurotoxicity due to products derived from eosinophils rather than with infiltrating or inflammatory phenomena. This study describes the case of a female patient with hypereosinophilic syndrome with no verifiable cause, multineuritis and eosinophilic fasciitis. CASE REPORT: A 30 year-old female with no relevant history who visited because of some painless inguinal nodules that had appeared several weeks before. At almost the same time, she presented painful sensitive symptoms in her legs with a significant functional incapacity. An important degree of hypereosinophilia, eosinophilic fasciitis and non-neoplastic eosinophilic infiltration of the bone marrow was found, together with multiple mononeuritis. Treatment with oral corticoids improved the dermatological and haematological clinical features, and associating it with gabapentin improved the neuropathic symptoms. CONCLUSIONS: The patient, in accordance with current criteria, presented idiopathic hypereosinophilic syndrome with an undetermined subtype. To our knowledge, the association with eosinophilic fasciitis and multineuritis has not been reported to date. There is no proven infiltrating mechanism in multiple mononeuritis, which corroborates the poor control of the neuropathic clinical symptoms with oral corticoid therapy. Association with gabapentin, which stabilises the axonal membrane, also backs up the neurotoxic pathogenetic hypothesis. PMID- 22234569 TI - [Non-convulsive status epilepticus in the 21st century: clinical characteristics, diagnosis, treatment and prognosis]. AB - Non-convulsive status epilepticus is a significant issue for a neurologist because, despite its low prevalence, it mimics other pathologies, with therapeutics and prognostic outcomes. Diagnosis is based on clinical features, mainly mental status or impaired consciousness and electroencephalographic changes, so electroencephalogram is the first exploration we must perform with clinical suspicion. There are three clinical forms: generalized or absence status, with diffuse epileptiform discharges; focal, with epileptic discharges located in a specific brain area and may not affect consciousness; and subtle, with diffuse or local epileptic activity after a tonic-clonic seizure or convulsive status and limited or no motor activity. Treatment are benzodiazepines and antiepileptic drugs; anesthetic drugs are only recommended for patients with subtle status and in some with partial complex status. Prognosis is mainly determined by etiology and associated brain damage. PMID- 22234570 TI - [Guidelines on the appropriate use of animal models for developing therapies in multiple sclerosis]. AB - INTRODUCTION: The advance in the achievement of effective therapies for multiple sclerosis (MS), the definition of appropriate therapeutic windows and to establish better diagnostic and prognostic biomarkers have become a challenging task for both researchers and clinicians. Some pitfalls in clinical trials might be related to lack of adequacy of the preclinical studies in MS experimental animal models. AIM: To standardize the methodological protocols of experimental models by developing a set of guidelines for preclinical studies by groups of experts from REEM (Spanish Network for MS). DEVELOPMENT: A guide with recommendations for the application of MS models including a detailed assessment of appropriate experimental models taking into account the objective of the study that has been presented. Standards and quality criteria necessary in a preclinical study have been included. CONCLUSIONS: Standardized animal models of MS are essential to increase the success of the preclinical findings in order to transfer them to the clinical practice. PMID- 22234571 TI - [Successful treatment with benzathine penicillin of two patients suspected of suffering from PANDAS]. PMID- 22234572 TI - [Clinical and functional features of patients with cerebrovascular disease]. PMID- 22234573 TI - Audit of antibiotic duration of therapy, appropriateness and outcome in patients with nosocomial pneumonia following the removal of an automatic stop-date policy. AB - Automatic stop-orders (ASOs) have been utilized to discourage inappropriately prolonged antibiotic therapy. An ASO policy, which required reordering of antibiotics after 7 days of therapy, had been in place at our institution prior to 2002, but was revoked after instances of compromised patient care due to inadvertent and inappropriate interruption of antimicrobial treatment. The objective of this study was to evaluate the impact of revoking the ASO policy on the duration of antibiotic therapy, infection-related outcome (cure vs failure), relapsing infection, occurrence of resistant bacteria and superinfection in patients with nosocomial pneumonia. A retrospective chart review of adult patients (>= 18 years old) admitted to Sunnybrook Health Sciences Centre with nosocomial pneumonia requiring antibiotic therapy was conducted. Duration of antibiotic therapy, infection-related outcome (cure vs failure), rate of relapsing infection, resistant organisms and superinfection were determined for each cohort. Forty-six eligible adults with nosocomial pneumonia per cohort were included [corrected]. Duration of antibiotic therapy was not significantly different in the pre- (11.4 +/- 3.8 days) compared with the post-ASO revocation cohort (10.8 +/- 4.1 days; p=0.43). There were also no significant differences between the cohorts with regard to infection-related outcome (cure vs failure), relapsing infection, or the occurrence of resistant bacteria or superinfection (p>0.5). Revocation of the ASO policy for antibiotics at our institution was not associated with a longer duration of antibiotic therapy, or increased incidence of infection-related mortality, relapsing infection, resistant bacteria or superinfection for patients with nosocomial pneumonia. PMID- 22234574 TI - Design of N-cinnamyl sulfinamides as new sulfur-containing olefin ligands for asymmetric catalysis: achieving structural simplicity with a categorical linear framework. AB - The design and development of an extraordinarily interesting new class of chiral sulfur-olefin hybrid ligands with remarkable structural simplicity were described. These unique sulfinamide-olefin ligands have been proved to be highly effective ligands in rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids to alpha,beta-unsaturated carbonyl compounds (up to 99% yield and 98% ee). PMID- 22234575 TI - "Getting confirmation": gender in expectations and experiences of healthcare for neck or back patients. AB - OBJECTIVE: The aim of this study was to explore, from a gender perspective, patients' expectations prior to seeking healthcare for neck or back pain, and their subsequent experiences of the care and rehabilitation they received. METHODS: Thematized interviews with 12 patients, 7 women and 5 men, using open ended questions, were analysed according to grounded theory. Each patient was interviewed before their first appointment with a physiotherapist or general practitioner and 3 months later. RESULTS: Analysis resulted in 5 categories: "To be taken seriously", "Getting an explanation", "To be invited to participate", "To be assessed and treated individually", and "To be taken care of in a trustworthy environment", which were linked by a core category "Getting confirmation". Two ideal types were identified: the "Confident" type, characterized by self-confidence and pride, and the "Ambiguous" type, characterized by disparagement and shame. The categories were partly perceived in different ways from the two ideal types. The ideal types were not defined by sex; however, more men were found to be of the "Confident" type and more women of the "Ambiguous" type. CONCLUSION: Gender appears to affect expectations and experiences, in addition to how patients view and express their problems. Healthcare professionals should take this into account in consultations. PMID- 22234576 TI - [Low-dose droperidol in children: rescue therapy for persistent postoperative nausea and vomiting]. AB - BACKGROUND: Droperidol had been used as an effective antiemetic since the 1970s but was withdrawn from the market in 2001 because of a black box warning about QT prolongation and possible cardiac arrhythmia after high doses. In the meantime the black box warning has seriously been questioned and parenteral droperidol has again been licensed in 2008. Because droperidol acts on dopaminergic receptors different to 5-HT(3) antagonists and dexamethasone, it could possibly serve as a rescue drug after failed postoperative nausea and vomiting (PONV) prophylaxis. Persistent PONV after the recommended prophylaxis is a significant problem in pediatric anesthesia but a satisfactory strategy has not yet been defined. Therefore a retrospective audit was performed in order to evaluate whether low dose droperidol (10 ug/kgBW) would be an effective rescue drug for failed antiemetic prophylaxis. PATIENTS AND METHODS: The electronic anesthesia patient data base of the University Children's Hospital Zurich was searched from 2004 2009 for patients who received low-dose droperidol in the postanesthesia care unit as rescue therapy for persistent PONV after antiemetic prophylaxis. Based on the recorded electronic data the effectiveness of low-dose droperidol as PONV rescue therapy and possible side effects were analyzed. RESULTS: A total of 338 patients who received droperidol were found from a total of 34,032 patients and the charts were analyzed. Of these patients 134 were excluded because they had received droperidol for indications other than PONV, 43 patients were excluded because they had not received antiemetic prophylaxis before droperidol and in 17 patients the data were incomplete, leaving 144 patients with an average age of 12.3 years (interquartile range IQR 9.5-15.2 years) for analysis. The upper range of ages resulted from patients with chronic diseases who were still being treated in the Children's Hospital. Low-dose droperidol was given because of persistent nausea to 59 patients (41%) and to 85 patients (59%) for persistent vomiting. Initial antiemetic prophylaxis and/or therapy had consisted of dexamethasone plus tropisetrone in 80 patients and tropisetrone or dexamethasone alone in 64 patients. In 128 patients (89%) rescue therapy with a median dose of 10.9 ug/kgBW droperidol was effective but vomiting persisted in 16 patients (11%). Sedation was the only side effect recorded and this was observed in 39 patients (27%). CONCLUSIONS: Low-dose droperidol (10 ug/kgBW) was found to be effective as rescue medication in pediatric patients experiencing PONV despite various prophylactic antiemetic regimens. No neurological or cardiopulmonary side effects were recorded after this low dosage. PMID- 22234578 TI - Amidines, isothioureas, and guanidines as nucleophilic catalysts. AB - Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong organic bases however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in organic synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalysing aldol reactions, Morita-Baylis-Hillman reactions, conjugate additions, carbonylations, methylations, silylations, and brominations. PMID- 22234580 TI - White phosphorus as a ligand for the coinage metals. AB - Reaction of equimolar quantities of MX (M = Au, Cu, X = Cl; M = Ag, X = OTf) and GaCl(3) in CH(2)Cl(2) with P(4) leads to phosphorus ligating a cationic coinage metal centre. For Cu and Ag, ion-contacted coordination polymers are formed; for Au, an ion-separated complex is observed that features the [Au(eta(2) P(4))(2)](+) cation, which is the first homoleptic Au-P(4) complex to be characterised in the condensed phase. PMID- 22234579 TI - Ganglioside GM1/galectin-dependent growth regulation in human neuroblastoma cells: special properties of bivalent galectin-4 and significance of linker length for ligand selection. AB - Orchestrated upregulation of cell surface presentation of ganglioside GM1 and homodimeric galectin-1 is the molecular basis for growth regulation of human neuroblastoma (SK-N-MC) cells. Further study led to the discovery of competitive inhibition by galectin-3, prompting us to test tandem-repeat-type galectin-4 (two different lectin domains connected by a 42-amino-acid linker). This lectin bound to cells at comparably high affinity without involvement of the ganglioside, as disclosed by assays in the presence of cholera toxin B-subunit or galectin-1 and blocking glucosylceramide synthesis. Notably, when tested separately, binding of both lectin domains showed partial sensitivity to the bacterial agglutinin. Despite its ability for cross-linking surface association of galectin-4 did not affect proliferation, in contrast to homodimeric galectins. The truncation of linker length from 42 to 16 amino acids altered binding properties to let partial sensitivity to the bacterial lectin emerge. Cross-competition between parental and engineered proteins did not exceed 40%. No effect on cell growth was detected. This study reveals complete functional divergence between galectins differing in the spatial mode of lectin-site presentation and dependence of reactivity to distinct counter-receptor(s) on linker length. Due to the documented presence of galectin-4 in the nervous system and its affinity for sulfatide these in vitro results indicate the potential for a distinct functionality profile of this lectin in vivo, giving further research direction. PMID- 22234581 TI - Integrated assessment of biomarker responses in caged shrimps (Litopenaeus vannamei) exposed to complex contaminants from the Maluan Bay of China. AB - The marine shrimp Litopenaeus vannamei were used as an active biomonitoring organism to assess the bioavailability and impact of metal contaminants in seven study sites along the Maluan Bay of China. Metal concentrations in the hepatopancreas of shrimps were determined in conjunction with four biomarkers responses after a 7 day in situ cage exposures. The results showed that contaminant tissue burdens at the deployment sites were greater than those of the reference site, and antioxidant enzyme activities were strongly inhibited compared to those of reference organisms. Variations in these biomarker responses were correlated significantly (p < 0.05 or p < 0.01) with the specific metal pollutants at the study sites, but no significant correlations existed between catalase activity responses and the metal contaminants. This suggests the presence of undetermined contaminants or other exposure routes that may be responsible for the decreased catalase activity. Multivariate analysis revealed a causal relationship between contaminants at each deployment site and the biochemical "response" of the caged shrimps at these sites and demonstrated the presence of two contaminant "hot" spots. This investigation suggested that the incorporation of chemical data on trace metal concentrations with the analysis of antioxidant enzymatic activities in caged shrimps can be a useful tool for the identification of causal toxic contaminants in complex mixtures. PMID- 22234582 TI - Well differentiated thyroid carcinoma: current treatment. AB - OPINION STATEMENT: Well differentiated thyroid carcinoma (WDTC) is a relatively common malignancy accounting for an estimated 37,000 thousand cases in the United States in 2009 [1]. WDTC also has a generally high 5 year survival rate that correlates with age. Papillary thyroid carcinoma (PTC) greater than 1 cm is best managed by total thyroidectomy. Thyroid lobectomy and isthmusectomy may be adequate for unifocal PTC less than 1 cm in patients without negative prognostic factors. Central compartment and possible lateral neck dissections should be performed when nodal metastases are present in the respective nodal basins. Post operatively, radioactive iodine ablation with (131)I followed by thyroid stimulating hormone (TSH) suppression is indicated in certain patients to improve locoregional control and reduce recurrence. PMID- 22234583 TI - Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells. AB - Phytochemicals constitute a heterogeneous group of substances with an evident role in human health. Their properties on cancer initiation, promotion and progression are well documented. Particular attention is now devoted to better understand the molecular basis of their anticancer action. In the present work, we studied the effect of resveratrol on the ovarian cancer cell line OVCAR-3 by a proteomic approach. Our findings demonstrate that resveratrol down-regulates the protein cyclin D1 and, in a concentration dependent manner, the phosphorylation levels of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK-3beta). The dephosphorylation of these kinases could be responsible for the decreased cyclin D1 levels observed after treatment. We also showed that resveratrol reduces phosphorylation levels of the extracellular signal-regulated kinase (ERK) 1/2. Chemical inhibitors of phosphatidylinositol 3-kinase (PI3K) and ERK both increased the in vitro therapeutic efficacy of resveratrol. Moreover, resveratrol had an inhibitory effect on the AKT phosphorylation in cultured cells derived from the ascites of ovarian cancer patients and in a panel of human cancer cell lines. Thus, resveratrol shows antitumor activity in human ovarian cancer cell lines targeting signalling pathway involved in cell proliferation and drug resistance. PMID- 22234584 TI - Ezrin expression in rectal cancer predicts time to development of local recurrence. AB - PURPOSE: Improved outcome after rectal cancer surgery requires identification of novel risk factors of tumour recurrence in order to personalise therapy, that is, enhanced selection of high-risk patients to additional radiochemotherapy or intensified follow-up. In several tumour types, including colorectal cancer, high expression of the membrane-cytoskeleton linker ezrin has been suggested to impair prognosis but has not yet reached clinical application. We evaluated the expression of ezrin in rectal cancer with a focus on the identification of a marker for local tumour recurrence. METHODS: Immunohistochemical expression of ezrin was analysed in 104 primary rectal cancers from patients who developed local recurrences despite being treated with R0 major abdominal surgery. Time to local recurrence and distant metastasis as well as 5-year overall and cancer specific survival were used as end points. RESULTS: Ezrin expression was weak in 17% of the tumours, moderate in 62%, and intense in 21%. The time to local recurrence was significantly shorter (p = 0.0004) for patients with tumours showing high ezrin expression. No correlation between ezrin expression and time to distant metastasis was identified. Survival data were similar between groups irrespective of ezrin expression in the primary tumours. CONCLUSIONS: Our findings suggest that increased expression of ezrin may represent a marker of aggressive biological behaviour in rectal cancer. Although further validation is needed, ezrin may represent a relevant marker for personalised treatment of rectal cancer with respect to risk of local recurrence after R0 surgery. PMID- 22234585 TI - Advanced stereoscopic projection technology significantly improves novice performance of minimally invasive surgical skills. AB - BACKGROUND: Three-dimensional (3D) surgical imaging systems provide stereoscopic depth cues that are lost in conventional two-dimensional (2D) display systems. Recent improvements in stereoscopic projection technology using passive polarising displays may improve performance of minimally invasive surgical skills. This study aims to identify the effect of passive polarising stereoscopic displays on novice surgeon performance of minimally invasive surgical skills. METHODS: 20 novice surgeons performed 10 repetitions of 4 surgical skills tasks using a new passive polarising stereoscopic display under 3D and 2D conditions. The previously validated tasks used were rope pass, paper cut, needle capping and knot tying. Outcome measures included total error rate and time for task completion. RESULTS: Novice surgeons demonstrated a significant reduction in error rates for sequential repetitions of each task using the passive polarising stereoscopic display compared with the 2D display. Mean errors for the 3D versus the 2D mode were 2.0 versus 4.3 for rope pass (P <= 0.001), 0.8 versus 1.6 for paper cut (P = 0.001), 1.3 versus 4.2 for needle capping (P <= 0.001) and 2.8 versus 8.0 for knot tying (P <= 0.001). Novice surgeons demonstrated a significant improvement in mean time for completion for all four tasks when using the 3D system. Mean time (in seconds) for 3D versus 2D were 106.5 versus 134.4 for rope pass (P <= 0.001), 116.1 versus 176.3 for paper cut (P <= 0.001), 76.3 versus 141.6 for needle capping (P <= 0.001) and 153.4 versus 252.6 for knot tying (P <= 0.001). CONCLUSION: Passive polarising stereoscopic displays significantly improve novice surgeon performance during acquisition of minimally invasive surgical skills. PMID- 22234586 TI - The revised ACGME laparoscopic operative requirements: how have they impacted resident education? AB - BACKGROUND: Laparoscopic surgery has been an essential component of surgical education for the last two decades. The Accreditation Council for Graduate Medical Education (ACGME) changed the requirements for laparoscopic cases beginning with graduates in 2008, and the Fundamentals of Laparoscopic Surgery program was introduced over a decade ago as a method of measuring competency with laparoscopic techniques. The purpose of this study was to determine what changes have been made to meet these requirements and how these changes have impacted general surgery residents in their preparation to perform both basic and complex laparoscopic procedures upon completion of residency. METHODS: A 23-question survey was distributed electronically to all fourth- and fifth-year residents of United States general surgery residency programs. Respondents were queried about demographics, perception of surgical education, and their level of preparedness to perform laparoscopic cases upon graduation. RESULTS: The survey was completed by a total of 321 residents (174 fourth-year and 147 fifth-year). Nineteen percent of respondents indicated that they anticipated problems meeting the new ACGME guidelines and 18.7% of all respondents indicated that changes had been made to their program to meet those new requirements. The majority of residents felt they had adequate laparoscopic training upon graduation, but there was a disparity between program types. Despite this finding, more than one-third of respondents believed that it would be necessary to seek additional laparoscopic training post-residency graduation. CONCLUSION: Residency training programs have had to keep pace with evolving technology while preparing future surgeons to perform with confidence upon completion of residency training. The majority of residents feel their training has been adequate, but there are also a great number who believe they will need to continue their education in laparoscopic surgery to keep pace with this ever-evolving field. PMID- 22234587 TI - Predictive factors of excess body weight loss 1 year after laparoscopic bariatric surgery. AB - BACKGROUND: Bariatric surgery (BS) is widely accepted for the treatment of patients with morbid obesity (MO). We aimed to determine presurgical predictors of and surgical technique-related differences in excess weight loss (EWL) 1 year after BS. METHODS: This retrospective study included 407 subjects (F/M 3:1, median age = 44 years) who underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n = 307) or sleeve gastrectomy (SG, n = 100) at our University Hospital and were evaluated 1 year after surgery. RESULTS: Baseline median (min-max) body mass index (BMI) was 47 kg/m(2) (range = 36-71). BMI was higher in the SG than in the RYGB group (53 vs. 46 kg/m(2), p < 0.0001). Simple correlation analysis showed negative associations between EWL and age, BMI, waist circumference (WC), fasting glucose, HbA1c, triglycerides (TG), blood pressure, and total cholesterol (all p < 0.01). EWL (mean +/- SD) did not differ by gender (p = 0.2), was lower in diabetic than in nondiabetic subjects (71 +/- 17% vs. 79 +/- 17%, p < 0.0001), and higher in the RYGB vs. SG group (76 +/- 18% vs. 68 +/- 15%, p < 0.0001). However, SG vs. RYGB differences in EWL disappeared (p = 0.4) after taking into account baseline BMI. Multiple regression and logistic analysis showed that younger individuals with lower BMI but higher WC, and lower HbA1c and TG, had higher EWL and a higher rate of successful (EWL >= 60%) weight loss. CONCLUSIONS: Our data indicate that some of the characteristics that would have subjects referred early for BS were associated with higher weight loss. Therefore, the timing of laparoscopic BS might be an important factor for MO individuals in which medical weight loss intervention has failed. PMID- 22234588 TI - Minimally invasive esophagectomy: current status and future direction. PMID- 22234589 TI - Management of pyloric stricture in children: endoscopic balloon dilatation and surgery. AB - BACKGROUND: Surgical correction is the most preferred treatment modality in pyloric stricture (PS). Recently a few studies reported the experience of balloon dilation in children with PS. This study was designed to present our experiences of the management of the patients with PS with balloon dilation and corrective surgery. METHODS: The records of 14 patients who were treated with the diagnosis of PS between August 2003 and August 2011 were reviewed retrospectively. RESULTS: There were nine boys and five girls (mean age, 3.4 +/- 1.7 years). The history of caustic ingestion was detected in eight patients; six of them were admitted on the day of ingestion. Two patients were admitted with nonbilious vomiting more than 2 weeks after ingestion. Four patients did not have a remarkable medical history, including caustic ingestion. They admitted with the complaint of nonbilious vomiting. PS was detected during endoscopy in two patients who had a diagnosis of peptic ulcer disease. PS was shown by barium meal study in all patients. Endoscopy was performed in all patients. Endoscopic balloon dilation was tried in 12 patients. Overall eight patients required surgical procedures for PS. The complaints were resolved by endoscopic balloon dilation of pylorus in the remaining six patients. CONCLUSIONS: Although endoscopic balloon dilatation for benign PS in adults is a generally accepted method of treatment, there is less experience with endoscopic balloon dilatation for PS in children. PS due to benign disorders can be effectively and successfully treated through endoscopic balloon dilatation in suitable patients. In patients with successful pyloric balloon dilatation, surgery can be avoided. PMID- 22234590 TI - Video: Single-incision video-assisted thoracoscopic right pneumonectomy. AB - BACKGROUND: The most common approach for Video-assisted thoracoscopic (VATS) lobectomy is undertaken with three or four incisions, including a utility incision of about 3-5 cm. However, major pulmonary resections are amenable by using only a single utility incision. This video shows the technical procedure of a right pneumonectomy by single-incision approach with no rib spreading. METHODS: A 52-year-old woman was proposed for single-incision VATS resection of a 5-cm right lower lobe adenocarcinoma. A 4-cm incision was made in the fifth intercostal space. We placed a 30-degree, high-definition, 10-mm thoracoscope in the posterior anterior part of the incision. Digital palpation confirmed that the tumor involved the fissure and the posterior portion of the upper lobe, which indicated the need for right pneumonectomy. We inserted the instruments through the anterior part of the utility incision to start the detachment of the right upper lobe by using a harmonic scalpel. The first step was dissecting the inferior pulmonary vein. The hilar structures were exposed by using harmonic scalpel and a long dissector (Fig. 1A). The upper and middle-lobe pulmonary veins were dissected and transected, allowing visualization of truncus anterior, which was then stapled. The inferior pulmonary vein and the intermediate truncus artery were divided, allowing optimal exposure to the main bronchus, which was stapled. The lung was removed in a protective bag by adding 1 cm to the incision, and a systematic lymph node dissection was performed. A single chest tube was placed in the posterior part of the utility incision. RESULTS: Total surgery time was 210 min. The chest tube was removed on postoperative day 2 (Fig. 1B), and the patient was discharged home on day 4 with no complications. CONCLUSIONS: Single-port VATS pneumonectomy for selected cases is a feasible procedure, especially when performed from a center with previous experience in double-port VATS approach. DISCUSSION: Recent advances in surgical and video-assisted techniques have allowed minimally invasive pneumonectomy to be undertaken safely. VATS pneumonectomy is not a new procedure and in fact was initially reported 15 years ago and was felt to result in less postoperative pain and a faster return to normal activities [1]. Despite this, there have been only a few case reports or series published of VATS pneumonectomies [2, 3]. PMID- 22234591 TI - Laparoendoscopic single-site minor hepatectomy for liver tumors. AB - BACKGROUND: Laparoscopic liver surgery is gaining increasing acceptance worldwide, but its frontiers are constantly challenged. Laparoendoscopic single site surgery (LESS) has been performed for various organs, but the feasibility of LESS hepatectomies has yet to be explored fully. METHODS: From May 2010 to March 2011, seven patients underwent LESS minor hepatectomies. Patient demographic, operative, and clinical data were reviewed. RESULTS: Five left lateral sectionectomies, one segment 3, and one segment 5 resection were performed. The median operative time was 142 min (range, 104-171 min), and the median blood loss was 200 ml (range, 100-450 ml). The median hospital stay was 3 days (range, 1-11 days). For all the patients, the indications for surgery were suspected malignant tumors, and the surgical resection margins were clear for every patient. CONCLUSIONS: Laparoendoscopic single-site minor hepatectomy is a novel modification to traditional laparoscopic surgery. The method is safe and feasible without any compromise to oncologic safety for selected patients with hepatocellular carcinoma (HCC) and colorectal liver metastases that are peripheral and smaller than 5 cm in size. PMID- 22234592 TI - Laparoscopic restoration of intestinal continuity (the LapRICon procedure): a safe and feasible technique for restoration of transanal defecation. AB - BACKGROUND: The restoration of intestinal continuity after open abdominal surgery can be technically challenging. The authors describe their experience with the laparoscopic approach to attempted reversal for patients with an exteriorized intestine. METHODS: A consecutive series of patients under the care of a single surgeon (D.B.) underwent laparoscopic restoration of intestinal continuity (LapRICon). All the patients first underwent exclusion of intraabdominal sepsis with computed tomography (CT) scanning and then preoperative localization of proximal and distal bowel ends via water-soluble contrast studies. Stomal sites were used for initial access, establishment of capnoperitoneum, and formation of anastomoses extracorporeally. All adhesiolysis and mobilization of bowel ends were performed intracorporeally. Pre-, intra-, and postoperative data were collected for all the patients. Return of intestinal function, overall hospital length of stay, and postoperative complications were collected. Nonparametric statistics were used to analyze the data. RESULTS: A total of 13 patients (6 women) were followed up for 9 months (interquartile range [IQR], 5-16 months). The median age of the patients was 39 years (IQR, 28-64 years). Nine patients were categorized as American Society of Anesthesiology (ASA) class 1. One patient was ASA 2, and the remaining patients were ASA 3. The median colorectal physiologic and operative severity scores for the enumeration of mortality and morbidity (CR-POSSUM) were 0.68 (IQR, 0.68-1.72). The intraoperative blood loss was minimal (median 30 ml; IQR, 20-125 ml). The median operative duration was 240 min (IQR, 180-240 min), and a median of 4 ports (IQR, 3-5 ports) were used. Enterocolonic anastomoses were fashioned in six patients, enterorectal anastomoses in two patients, and enteroentero anastomoses in three patients. A single patient had multiple anastomoses. The median time to return of intestinal function was 5 days (IQR, 3-13 days), and the overall hospital stay was 8 days (IQR, 5-24 days). Four complications (25%) (2 recurrent fistulas, 1 anastomotic leak, and 1 open conversion) occurred in this series of patients. CONCLUSIONS: The LapRICon procedure is a feasible technique with acceptable morbidity. Several principles and techniques are described to aid the surgeon who wishes to embark on use of such a technique. PMID- 22234593 TI - Assessment of joystick and wrist control in hand-held articulated laparoscopic prototypes. AB - BACKGROUND: Various steerable instruments with flexible distal tip have been developed for laparoscopic surgery. The problem of steering such instruments, however, remains a challenge, because no study investigated which control method is the most suitable. This study was designed to examine whether thumb (joystick) or wrist control method is designated for prototypes of steerable instruments by means of motion analysis. METHODS: Five experts and 12 novices participated. Each participant performed a needle-driving task in three directions (right -> left, up -> down, and down -> up) with two prototypes (wrist and thumb) and a conventional instrument. Novices performed the tasks in three sessions, whereas experts performed one session only. The order of performing the tasks was determined by Latin squares design. Assessment of performance was done by means of five motion analysis parameters, a newly developed matrix for assigning penalty points, and a questionnaire. RESULTS: The thumb-controlled prototype outperformed the wrist-controlled prototype. Comparison of the results obtained in each task showed that regarding penalty points, the up -> down task was the most difficult to perform. CONCLUSIONS: The thumb control is more suitable for steerable instruments than the wrist control. To avoid uncontrolled movements and difficulties with applying forces to the tissue while keeping the tip of the instrument at the constant angle, adding a "locking" feature is necessary. It is advisable not to perform the needle driving task in the up -> down direction. PMID- 22234595 TI - The world is getting smaller. PMID- 22234594 TI - Hysteroscopic placement of tubal sterilization implants: virtual reality simulator training. AB - STUDY OBJECTIVE: To assess face and construct validity of a new virtual reality (VR) training simulator for hysteroscopic placement of tubal sterilization implants. DESIGN: Nonrandomized, controlled trial comparing responses and performance of novices and experts on the simulator. DESIGN CLASSIFICATION: Canadian task force II-1. SETTING: Forty-six gynecologists were personally invited or recruited at the 33rd Conference of the French National College of Gynecologists and Obstetricians (CNGOF) from December 9 to 12, 2009, grouped as 20 experts and 26 novices. They all performed the defined sequence of virtual procedures on the simulator (case 1 for familiarization, case 4 for study assessment) and finally completed the study questionnaire. MEASUREMENTS AND MAIN RESULTS: Responses to realism, educational potential, and general opinion were excellent, proving face validity. Significant differences between novices and experts were assessed for 7 of the 15 metrics analyzed, proving construct validity. CONCLUSIONS: We established face and construct validity for EssureSim, an educational VR simulator for hysteroscopic tubal sterilization implant placement. The next steps are to investigate convergent and predictive validity to affirm the real capacity of transferring the skills learned on the training simulator to the patient in the operating room. PMID- 22234597 TI - A novel synergistic galactomannan-based unit dosage form for sustained release of acarbose. AB - In the current study, the potential of a novel combination of a galactomannan with acarbose (100 mg) was evaluated for attaining a desired hypoglycaemic effect over a prolonged period of time. Three major antidiabetic galactomannans viz., fenugreek gum, Boswellia gum, and locust bean gum were selected in order to achieve a synergistic effect in the treatment along with retardation in drug release. In vitro studies indicated that batches containing various proportions of fenugreek gum (AF40-60) were able to control drug release for a longer duration of approximately 10-12 h. In contrast, the matrices prepared using Boswellia and locust bean gum were able to sustain the release for relatively shorter durations. Drug release mainly followed first-order release kinetics owing to the highly soluble nature of the drug. In vivo study depicted a significant reduction (p < 0.001) in the postprandial blood glucose and triglyceride levels in the diabetic rats on treatment with formulation AF40. Thus, the developed system provides a better control of the postprandial glycaemic levels and it also obviates the need of conventional multiple dosing of acarbose. Furthermore, it also reduces the occurrence of side effects like diarrhea and loss of appetite. PMID- 22234598 TI - Nanostructured lipid carriers improve skin permeation and chemical stability of idebenone. AB - Idebenone (IDB) is a synthetic antioxidant and analog of coenzyme Q10. The percutaneous permeation of IDB was investigated in guinea pig skin after application of different formulations. The enhancing effects of various formulations [nanostructured lipid carriers (NLCs), nanoemulsion (NE), or oil solution] on the permeation of IDB were evaluated using ex vivo guinea pig skins. Furthermore, stability of different formulations and in which chemical stability of IDB was determined during storage. Permeation experiments revealed that formulations varied in their ability to enhance the skin permeation of IDB. For NLC formulation, the cumulative amount of IDB in the epidermis, dermis, and acceptor medium of diffusion cells was approximately threefold more than NE or oil solution at the end of 24-h experiment. No significant difference between NE and oil solution was observed in the enhancement of penetration efficacy of IDB. Different formulations resulted in stability with different properties. NLC formulation revealed preferentially more stable than NE. The residual percentage of IDB loaded in NLCs, NE, and oil solution was 90.1%, 65.4%, and 51.3%, respectively, when stored at 40 degrees C under 75% RH and 3,000 lx light conditions for 180 days. The results obtained here demonstrated that the abilities of NLCs to improve the chemical stability of IDB and enhance the skin permeation are much better than NE and oil solution. These suggest that NLCs containing IDB have significant potential use for skin care as an alternative topical formulation. PMID- 22234599 TI - Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study. AB - Heparin-induced thrombocytopenia (HIT) remains a challenge, with diagnosis confirmed only by functional assays. The gold standard 14C-serotonin release assay (SRA) is highly sensitive but technically challenging and unsuitable for routine use. We conducted a large study to validate whole blood impedance aggregometry (WBIA) as a suitable diagnostic tool for HIT. WBIA and SRA were used to test 181 samples positive for H-PF4 antibodies by PaGIA or ELISA. Using the same high responder donor, 77 samples were positive by WBIA (aggregation with low dose but not high-dose heparin). Using the strict definition for SRA positivity, 72 samples were true HIT. In nine samples, serotonin release with high-dose heparin dropped by > 50% but was still >20%; these were retested after a one-half dilution and 8/9 became positive. Ten other samples were discrepant between the two assays: one strongly positive (89% release) and six weakly positive samples by SRA (average release 56%) were WBIA negative. When these samples were retested using a random donor, only two remained SRA positive. Three samples were strongly WBIA positive but SRA negative; two were retested by SRA with 0.5IU/ml heparin and one became positive. Under controlled conditions, using the same selected high-responder donor, WBIA and SRA performed similarly with slightly increased sensitivity of the WBIA when using the strict definition of SRA positivity. WBIA is easy to perform with rapid turn-around time and warrants a multi-laboratory trial to complete its validation as a confirmatory assay for platelet-activating HIT antibodies. PMID- 22234600 TI - FP-CIT SPECT evaluation: time to go beyond visual assessment! PMID- 22234601 TI - Virtual genomes in flux: an interplay of neutrality and adaptability explains genome expansion and streamlining. AB - The picture that emerges from phylogenetic gene content reconstructions is that genomes evolve in a dynamic pattern of rapid expansion and gradual streamlining. Ancestral organisms have been estimated to possess remarkably rich gene complements, although gene loss is a driving force in subsequent lineage adaptation and diversification. Here, we study genome dynamics in a model of virtual cells evolving to maintain homeostasis. We observe a pattern of an initial rapid expansion of the genome and a prolonged phase of mutational load reduction. Generally, load reduction is achieved by the deletion of redundant genes, generating a streamlining pattern. Load reduction can also occur as a result of the generation of highly neutral genomic regions. These regions can expand and contract in a neutral fashion. Our study suggests that genome expansion and streamlining are generic patterns of evolving systems. We propose that the complex genotype to phenotype mapping in virtual cells as well as in their biological counterparts drives genome size dynamics, due to an emerging interplay between adaptation, neutrality, and evolvability. PMID- 22234602 TI - Plasma-activated carbon nanotube-based high sensitivity immunosensors for monitoring Legionella pneumophila by direct detection of maltose binding protein peptidoglycan-associated lipoprotein (MBP-PAL). AB - Transferred multi-walled carbon nanotube (MWCNT)-modified platinum thin-film immunosensing electrode material was engineered on a glass substrate and fabricated a fully-integrated electrochemical three-electrode system for monitoring Legionella pneumophila. The transferred MWCNT film was treated with oxygen plasma to improve its electrochemical response and electrical conductivity. We voltammetrically characterized and optimized the electrochemical performance of the fabricated electrode for direct detection of Legionella pneumophila-specific peptidoglycan-associated lipoprotein (PAL) and maltose binding protein (MBP) peptidoglycan-associated lipoprotein (MBP-PAL) fusion. The latter, as an intermediate product to yield the former, has important roles in the growth and purification of PAL, which commercial enzyme-linked immunosorbent assay (ELISA) kits require as a target substrate. Consequently, direct electrochemical detection of MBP-PAL compared to PAL by square-wave voltammetry showed a greater than 50% increase in sensitivity with a lower detection limit of 5 pg mL(-1). We also investigated the affinity properties by determining kinetic parameters of the PAL and the MBP-PAL in relation to polyclonal antibodies immobilized on transferred MWCNT substrates using Michaelis-Menten assumptions and a Hanes-Woolf plot. This new method presented herein could save the time and effort for the separation and purification of PAL form MBP-PAL fusions that are required for performing ELISA-based immunoassay. PMID- 22234603 TI - Maximal cardiac output during arm exercise in the sitting position after cervical spinal cord injury. AB - OBJECTIVE: To determine and compare haemodynamic responses at maximal arm-crank (ACE) and wheelchair exercise (WCE) in individuals with cervical spinal cord injury and pair-matched able-bodied individuals. METHODS: Nine male, motor complete cervical spinal cord injured and 9 able-bodied individuals performed graded, maximal ACE and WCE. Cardiac output, heart rate, and stroke volume were determined at rest and at maximal exercise in cervical spinal cord injured individuals. In able-bodied individuals, measurements were performed at rest and at the maximal workload of the matched cervical spinal cord injured individuals. RESULTS: In cervical spinal cord injured, maximal cardiac output (ACE 7.4 (standard deviation (SD) 1.6); WCE 7.3 (SD 2.1) l/min) and heart rate (ACE 101 (SD 22); WCE 103 (SD 27) bpm) increased significantly compared with rest (4.6 (SD 1.0) l/min; 65 (SD 12) bpm), while stroke volume (ACE 77 (SD 22); WCE 73 (SD 21) ml) did not differ from rest (73 (SD 20) ml). In able-bodied individuals, cardiac output (rest 4.8 (SD 1.4); ACE 10.7 (SD 1.8); WCE 10.3 (SD 2.2) l/min), heart rate (rest 68 (SD 10); ACE 103 (SD 27); WCE 109 (SD 27) bpm), and stroke volume (rest 70 (SD 10); ACE 105 (SD 20); WCE 96 (SD 17) ml) increased significantly compared with rest. Cardiac output and stroke volume were significantly lower in cervical spinal cord injured compared with able-bodied individuals at the same workloads. CONCLUSION: Haemodynamic responses to maximal exercise were similar for both exercise modes in individuals with cervical spinal cord injury. The lower cardiac output in individuals with cervical spinal cord injury compared with able-bodied individuals at equivalent workloads reflects the inability of the circulatory system to increase stroke volume. PMID- 22234604 TI - First-principles study of the triwing graphene nanoribbons: junction-dependent electronic structures and electric field modulations. AB - Using first-principles calculations, we investigate the structural, electronic and magnetic properties of triwing zigzag graphene nanoribbons (TW-ZGNRs), as well as the electric field effects on their electronic structures. The TW-ZGNRs have comparable energetic stabilities to the normal ZGNRs and exhibit fascinating junction-dependent electronic properties. With the sp(2) hybridized junctions, the TW-ZGNRs undergo a Peierls distortion and behave as ferromagnetic metals. While the TW-ZGNRs with sp(3) hybridized junctions become semiconductors, which have a ferrimagnetic ground state. An external electric field can further modulate the band structures of semiconducting TW-ZGNRs. The parallel electric field directly moves the flat bands around the Fermi level, while the perpendicular field controls the edge states at the ribbon wings. By these electric field modulations, the band gaps are effectively tuned and half metallicity can be induced into TW-ZGNRs. Our studies demonstrate that the junctions play an important role in the electronic structures of TW-ZGNRs, which have well-tunable electronic and magnetic properties for potential applications in nanoelectronics and spintronics. PMID- 22234605 TI - Detection of favorable alleles for plant height and crown rust tolerance in three connected populations of perennial ryegrass (Lolium perenne L.). AB - Plant height, which is an estimator of vegetative yield, and crown rust tolerance are major criteria for perennial ryegrass breeding. Genetic improvement has been achieved through phenotypic selection but it should be speeded up using marker assisted selection, especially in this heterozygous species suffering from inbreeding depression. Using connected multiparental populations should increase the diversity studied and could substantially increase the power of quantitative trait loci (QTL) detection. The objective of this study was to detect the best alleles for plant height and rust tolerance among three connected populations derived from elite material by comparing an analysis per parent and a multipopulation connected analysis. For the studied traits, 17 QTL were detected with the analysis per parent while the additive and dominance models of the multipopulation connected analysis made it possible to detect 33 and 21 QTL, respectively. Favorable alleles have been detected in all parents. Only a few dominance effects were detected and they generally had lower values than the additive effects. The additive model of the multipopulation connected analysis was the most powerful as it made it possible to detect most of the QTL identified in the other analyses and 11 additional QTL. Using this model, plant growth QTL and rust tolerance QTL explained up to 19 and 38.6% of phenotypic variance, respectively. This example involving three connected populations is promising for an application on polycross progenies, traditionally used in breeding programs. Indeed, polycross progenies actually are a set of several connected populations. PMID- 22234606 TI - Alien genes introgression and development of alien monosomic addition lines from a threatened species, Allium roylei Stearn, to Allium cepa L. AB - To produce alien monosomic addition lines (AMALs) of Allium cepa (genomes CC, 2n = 2x = 16) carrying extrachromosomes from Allium roylei (RR, 2n = 2x = 16), reciprocal backcrossing of allotriploids (2n = 24, CCR) with diploids (2n = 16, CC) and selfing of a single allotriploid were carried out. The chromosome numbers in the BC(2)F(1) and BC(1)F(2) progenies ranged from 16 to 32. Forty-eight plants were recorded to possess 2n = 17 among a total of 169 plants in observation. Through the analyses of isozymes, expressed sequence tag (EST) markers, and karyotypes, all eight possible types of A. cepa-A. roylei monosomic addition lines (CC+1R-CC+8R) could be identified. Seven types of representative AMALs (without CC+2R) were used for the GISH analysis of somatic chromosomes. Except for CC+6R, all AMALs showed an entire (unrecombined) extrachromosome from A. roylei in the integral diploid background of A. cepa. A single recombination between A. cepa and A. roylei was observed on the extrachromosome in the remaining type. All alloplasmic AMALs possessing A. roylei cytoplasm showed high or complete pollen sterility. Only the autoplasmic CC+4R with A. cepa cytoplasm possessed relatively high pollen fertility. The bulbs of CC+4R displayed the distinct ovoid shape that discriminates them from spherical or oval ones in other AMALs. Downy mildew screening in the field showed higher resistance in A. roylei, a hypo-allotriploid (CCR-nR, 2n = 23), and an allotriploid (CCR, 2n = 24). Meanwhile, no complete resistance was found in some AMALs examined. This was the first trial toward the establishment of a complete set of A. cepa-A. roylei monosomic additions. PMID- 22234607 TI - Tetraglyme-mediated synthesis of Pd nanoparticles for dehydrogenation of ammonia borane. AB - Palladium nanoparticles (PdNPs) were conveniently prepared in tetraglyme (TG) solution using a variety of palladium precursors. At 140 degrees C, TG promoted Pd(3)(OAc)(6) to produce irregular shaped PdNPs with an average size of 4 nm. When these PdNPs were re-dispersed in TG and used for the dehydrogenation of ammonia borane (AB) at 85 degrees C, remarkably enhanced catalytic performance was achieved to release 2.3 equiv. of H(2) in 1 h. PMID- 22234608 TI - Probing the functional limits of the norepinephrine transporter with self reporting, fluorescent stilbazolium dimers. AB - A series of stilbazolium dimers were synthesized and investigated as sterically demanding ligands targeting the norepinephrine transporter (NET). The environmentally sensitive fluorescence of the dyes enables their use as self reporting ligands; binding to and displacement from NET can be monitored by fluorescence microscopy. PMID- 22234609 TI - Focus issue: Wnt and beta-catenin signaling in development and disease. AB - The Wnt pathways represent key signaling networks involved in development, both in tissue specification and in cellular migration. Wnt signaling also plays key roles in tissue homeostasis in adult animals, and aberrant Wnt signaling is associated with several forms of cancer. This issue includes descriptions of a proapoptotic function for Wnt signaling in melanoma, an interplay between Wnt and bone morphogenetic proteins in tooth organogenesis, and a noncanonical role for Wnt in neuronal guidance. PMID- 22234610 TI - A dual array-based approach to assess the abundance and posttranslational modification state of signaling proteins. AB - A system-wide analysis of cell signaling requires detecting and quantifying many different proteins and their posttranslational modification states in the same cellular sample. Here, we present Protocols for two miniaturized, array-based methods, one of which provides detailed information on a central signaling protein and the other of which provides a broad characterization of the surrounding signaling network. We describe a bead-based array and its use in characterizing the different forms and functions of beta-catenin, as well as lysate microarrays (reverse-phase protein arrays) and their use in detecting and quantifying proteins involved in the canonical and noncanonical Wnt signaling pathways. As an application of this dual approach, we characterized the state of beta-catenin signaling in cell lysates and linked these molecule-specific data with pathway-wide changes in signaling. The Protocols described here provide detailed instructions for cell culture methods, bead arrays, and lysate microarrays and outline how to use these complementary approaches to obtain insight into a complex network at a systems level. PMID- 22234611 TI - Wnt-induced calcium signaling mediates axon growth and guidance in the developing corpus callosum. AB - Wnt5a gradients guide callosal axons by repulsion through Ryk receptors in vivo. We recently found that Wnt5a repels cortical axons and promotes axon outgrowth through calcium signaling in vitro. Here, using cortical slices, we show that Wnt5a signals through Ryk to guide and promote outgrowth of callosal axons after they cross the midline. Calcium transient frequencies in callosal growth cones positively correlate with axon outgrowth rates in vitro. In cortical slices, calcium release through inositol 1,4,5-trisphosphate (IP(3)) receptors and calcium entry through transient receptor potential channels modulate axon growth and guidance. Knocking down Ryk inhibits calcium signaling in cortical axons, reduces rates of axon outgrowth subsequent to midline crossing, and causes axon guidance defects. Calcium- and calmodulin-dependent protein kinase II (CaMKII) is required downstream of Wnt-induced calcium signaling for postcrossing callosal axon growth and guidance. Taken together, these results suggest that growth and guidance of postcrossing callosal axons by Wnt-Ryk-calcium signaling involves axon repulsion through CaMKII. PMID- 22234613 TI - A Wnt-bmp feedback circuit controls intertissue signaling dynamics in tooth organogenesis. AB - Many vertebrate organs form through the sequential and reciprocal exchange of signaling molecules between juxtaposed epithelial and mesenchymal tissues. We undertook a systems biology approach that combined the generation and analysis of large-scale spatiotemporal gene expression data with mouse genetic experiments to gain insight into the mechanisms that control epithelial-mesenchymal signaling interactions in the developing mouse molar tooth. We showed that the shift in instructive signaling potential from dental epithelium to dental mesenchyme was accompanied by temporally coordinated genome-wide changes in gene expression in both compartments. To identify the mechanism responsible, we developed a probabilistic technique that integrates regulatory evidence from gene expression data and from the literature to reconstruct a gene regulatory network for the epithelial and mesenchymal compartments in early tooth development. By integrating these epithelial and mesenchymal gene regulatory networks through the action of diffusible extracellular signaling molecules, we identified a key epithelial-mesenchymal intertissue Wnt-Bmp (bone morphogenetic protein) feedback circuit. We then validated this circuit in vivo with compound genetic mutations in mice that disrupted this circuit. Moreover, mathematical modeling demonstrated that the structure of the circuit accounted for the observed reciprocal signaling dynamics. Thus, we have identified a critical signaling circuit that controls the coordinated genome-wide expression changes and reciprocal signaling molecule dynamics that occur in interacting epithelial and mesenchymal compartments during organogenesis. PMID- 22234612 TI - Wnt/beta-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. AB - Because the Wnt/beta-catenin signaling pathway is linked to melanoma pathogenesis and to patient survival, we conducted a kinome small interfering RNA (siRNA) screen in melanoma cells to expand our understanding of the kinases that regulate this pathway. We found that BRAF signaling, which is constitutively activated in many melanomas by the BRAF(V600E) mutation, inhibits Wnt/beta-catenin signaling in human melanoma cells. Because inhibitors of BRAF(V600E) show promise in ongoing clinical trials, we investigated whether altering Wnt/beta-catenin signaling might enhance the efficacy of the BRAF(V600E) inhibitor PLX4720. We found that endogenous beta-catenin was required for PLX4720-induced apoptosis of melanoma cells and that activation of Wnt/beta-catenin signaling synergized with PLX4720 to decrease tumor growth in vivo and to increase apoptosis in vitro. This synergistic enhancement of apoptosis correlated with reduced abundance of an endogenous negative regulator of beta-catenin, AXIN1. In support of the hypothesis that AXIN1 is a mediator rather than a marker of apoptosis, siRNA directed against AXIN1 rendered resistant melanoma cell lines susceptible to apoptosis in response to treatment with a BRAF(V600E) inhibitor. Thus, Wnt/beta catenin signaling and AXIN1 may regulate the efficacy of inhibitors of BRAF(V600E), suggesting that manipulation of the Wnt/beta-catenin pathway could be combined with BRAF inhibitors to treat melanoma. PMID- 22234615 TI - Serial overshadowing of taste aversion learning by stimuli preceding the target taste. AB - Three experiments tested whether events taking place before a rat has access to a target taste, sucrose, can proactively interfere with the acquisition of a sucrose aversion when sucrose is followed by a lithium chloride injection. Using a serial overshadowing procedure with various delays before lithium injection, proactive interference by a taste (Experiments 1 and 3) and by a novel context (Experiment 2) was found following two conditioning sessions, but not after a single conditioning session. Conversely, overshadowing by a taste given after the target was detectable after a single conditioning trial (Experiment 3) and, thus, indicated that retroactive interference involves a process different from that producing proactive interference. A simulation confirmed that the results are consistent with a modified Rescorla and Wagner (1972) interpretation of Revusky's (1971) concurrent interference theory of delay learning. PMID- 22234614 TI - Narrowing down the conditions for extinction of Pavlovian feature-positive discriminations in humans. AB - The aim of this study was to delineate the minimal conditions for extinction of Pavlovian modulation in humans. Previous experiments at our lab showed that, after X-- A+/A- acquisition training, X- trials did not extinguish differential X - A+/A- responding, while X-- A- trials did. Additionally, X-- A- extinction training seemed only to extinguish differential X-- A+/A- responding, while leaving differential responding on a concurrently trained Y [Symbol: see text] B+/B- discrimination intact. It thus seemed that the X-- A+/A- discrimination can only be extinguished by X-- A- extinction trials. (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986), on the other hand, found that the minimal conditions for extinction were broader in pigeons: Namely, he found that an acquired X-- A+/A- discrimination could be extinguished by presenting the original feature X in combination with a different target (B) that was minimally trained as an exciter. We thus wanted to examine whether this was also the case in humans. We found that nonreinforced X-- B- presentations did not abolish discriminative X-- A/A responding when target B was a nonreinforced stimulus. Nonreinforced X-- B- trials did extinguish the X-- A+/A- discrimination when target B had previously been trained as a target for modulation (X-- B+/B- or Y [Symbol: see text] B+/B- training) or as a reinforced exciter (B+). Our results thusf parallel and extend those in nonhuman animals (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986). PMID- 22234616 TI - Copper levels in buccal cells of vineyard workers engaged in various activities. AB - OBJECTIVES: Copper-based compounds have been used as agricultural fungicides for many years. Their use in Australia is escalating with increase in the scale of planting and associated pest problems. The objective of this study was to identify viticulture activities associated with high exposure to foliage sprays. It would be determined if occupational exposure of vineyard workers to copper based sprays was associated with raised body copper levels through analysis of saliva and buccal cells. METHODS: The activities of six vineyard workers from four vineyards in the Yarra Valley Victoria, Australia, were monitored over a period of 2 years. During this period, workers carried out seasonal activities, including fungicide spraying, canopy management, and tractor operation. Saliva and buccal cells from workers were collected and analysed for copper levels that were then correlated with the different types of vineyard activity. RESULTS: The buccal cells of vineyard workers exposed to copper through seasonal activities including fungicide spraying, canopy management, and tractor operation contained copper levels of 0.87, 1.24, and 0.95 ng Cu per 10(6) cells, respectively. This was up to 10-fold higher than the copper levels in buccal cells from the control subjects (0.1 ng Cu per 10(6)). Copper levels in buccal cells from workers participating in other viticulture activities such as shoot thinning, bunch counting, and disbudding were not significantly different from those of control subjects. The levels of copper in saliva samples of both workers undertaking any vineyard activity and control subjects were below the level of detection. CONCLUSIONS: Seasonal activities undertaken in vineyards that involved direct contact with copper, in particular canopy management, fungicidal spraying, and tractor operation were associated with high copper levels in buccal cells of workers. This indicates that copper derived from copper-based fungicidal compounds is accumulated within body cells. The lack of detectable copper levels in saliva suggests that the route of transport of copper into buccal cells is not through saliva. The results indicate potential adverse health risks associated with use of copper fungicide. Recommendations are made in relation to the precautions that should be taken in relation to use of copper sprays and to validate buccal cells as an indicator of body copper status. PMID- 22234617 TI - Force dependent internalization of magnetic nanoparticles results in highly loaded endothelial cells for use as potential therapy delivery vectors. AB - PURPOSE: To investigate the kinetics, mechanism and extent of MNP loading into endothelial cells and the effect of this loading on cell function. METHODS: MNP uptake was examined under field on/off conditions, utilizing varying magnetite concentration MNPs. MNP-loaded cell viability and functional integrity was assessed using metabolic respiration, cell proliferation and migration assays. RESULTS: MNP uptake in endothelial cells significantly increased under the influence of a magnetic field versus non-magnetic conditions. Larger magnetite density of the MNPs led to a higher MNP internalization by cells under application of a magnetic field without compromising cellular respiration activity. Two-dimensional migration assays at no field showed that higher magnetite loading resulted in greater cell migration rates. In a three dimensional migration assay under magnetic field, the migration rate of MNP loaded cells was more than twice that of unloaded cells and was comparable to migration stimulated by a serum gradient. CONCLUSIONS: Our results suggest that endothelial cell uptake of MNPs is a force dependent process. The in vitro assays determined that cell health is not adversely affected by high MNP loadings, allowing these highly magnetically responsive cells to be potentially beneficial therapy (gene, drug or cell) delivery systems. PMID- 22234619 TI - Chromium complexes supported by phenanthrene-imine derivative ligands: synthesis, characterization and catalysis on isoprene cis-1,4 polymerization. AB - Reactions of CrCl(2)(THF)(2) with N-aryl-9,10-iminophenanthraquinone in CH(2)Cl(2) give the monoimine chromium complexes (Ar)IPQCrCl(2)(THF)(2) (1, Ar = 2,6-Me(2)C(6)H(3); 2, Ar = 2,6-Et(2)C(6)H(3); 3, Ar = 2,6-(i)Pr(2)C(6)H(3)). Molecular structures of 1 and 3 were revealed to be monomeric with the chromium atoms in distorted octahedral geometries. Similar reactions of CrCl(2)(THF)(2) with N,N-bis(arylimino)phenanthrene ligands afford the diimine complexes (Ar1,Ar2)BIPCrCl(MU-Cl)(3)Cr(THF)(Ar1,Ar2)BIP (4, Ar(1) = Ar(2) = 2,6 Me(2)C(6)H(3); 5, Ar(1) = Ar(2) = 2,6-Et(2)C(6)H(3); 6, Ar(1) = Ar(2) = 2,6 (i)Pr(2)C(6)H(3); 7, Ar(1) = 2,6-Me(2)C(6)H(3), Ar(2) = 2,6-(i)Pr(2)C(6)H(3)). The X-ray diffraction analysis shows that 4, 5, and 7 are chlorine-bridged dimers with each chromium atom in a distorted octahedral geometry. Upon activation with MAO, all these complexes exhibit good catalytic activities for isoprene polymerization affording polyisoprene with predominantly a cis-1,4 unit. PMID- 22234618 TI - Rectal absorption of vigabatrin, a substrate of the proton coupled amino acid transporter (PAT1, Slc36a1), in rats. AB - PURPOSE: To investigate the rectal absorption of vigabatrin in rats, based on the hypothesis that PAT1 (Slc36a1) is involved. METHODS: Male Sprague-Dawley rats were dosed rectally with five different gels, varying in buffer capacity, the amount of vigabatrin, and co-administration of proline or tryptophan. Western blotting was used to detect rPAT1 in rat rectal epithelium. X. Laevis oocytes were injected with SLC36A1 cRNA for the expression of hPAT1, prior to two electrode voltage clamp measurements. RESULTS: rPAT1 protein was present in rat rectal epithelium. Approximately 7%-9% of a 1 mg/kg vigabatrin dose was absorbed after rectal administration, regardless of the formulation used. Increasing the dose of vigabatrin 10-fold decreased the absolute bioavailability to 4.2%. Co administration of proline or tryptophan changed the pharmacokinetic profile, indicating a role of PAT1 in the rectal absorption of vigabatrin. Transport of vigabatrin via hPAT1 expressed in X. Laevis oocytes had a K(m) of 5.2 +/- 0.6 mM and was almost completely inhibited by tryptophan. CONCLUSIONS: Although vigabatrin is a PAT1 substrate and the rPAT1 protein is expressed in the rectum epithelium, vigabatrin has low rectal absorption in rats. PMID- 22234620 TI - Frequency of heparin/platelet factor 4-dependent platelet antibodies in patients undergoing angioplasty and stenting for cardiovascular disease and their role for on-clopidogrel platelet reactivity. AB - BACKGROUND: The frequency of heparin-induced platelet antibodies (H/PF4 antibodies) following heparin exposure during percutaneous intervention with stent implantation is unknown. These antibodies may activate platelets and therefore contribute to high on-clopidogrel residual platelet reactivity (HRPR). METHODS: We screened 288 patients after angioplasty and stenting for H/PF4 antibodies by an IgG/A/M ELISA. The 44 (15.3%) positive samples were further evaluated for IgG only antibodies, by the particle gel immunoassay (PaGIA), the heparin induced platelet activation assay (HIPA) and MEA. Further, we determined on-treatment platelet reactivity by multiple electrode aggregometry (MEA) in these patients. In vivo platelet activation was assessed by P-selectin expression. RESULTS: The prevalence of H/PF4 antibodies in the total patients' cohort was 15.3% (95% CI 11.3-20%) by the IgG/A/M ELISA, 9.4% (95% CI 6.3-13.4%) by the IgG ELISA, 11.5% (95% CI 8-15.7%) by PaGIA, 14.2% (95% CI 10.4-18.8%) by MEA, and 2.4% (95% CI 1-4.9%) by HIPA. On-treatment platelet reactivity was similar between patients without and with H/PF4 antibodies [39 AU (6-110 AU) vs. 41 AU (7-91 AU); P = 0.85]. HRPR was seen in 105 patients (37.5%), and occurred to a similar extent in patients without and with H/PF4 antibodies in all test systems (all P > 0.2). Further, there was no difference of the ELISA optical densities using the IgG/A/M or the IgG only ELISA between patients without or with HRPR (all P > 0.3). There was no significant difference of P-selectin expression between patients without or with H/PF4 antibodies (P = 0.97). Noteworthy, none of the patients who developed H/PF4 antibodies had heparin induced thrombocytopenia or a thromboembolic event. CONCLUSION: H/PF4 antibodies are not rare in patients undergoing angioplasty and stenting. However, these antibodies are not associated with the occurrence of HRPR. PMID- 22234621 TI - Treatment of older patients with chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is typically a disease of older individuals. Yet most of the literature on various chemotherapeutic regimens includes patients who are 10 to 15 years younger than the median age at diagnosis of this disease. The older patient population is grossly underrepresented in clinical trials. Currently available therapies are often too toxic for this older patient population, so their efficacy is reduced. This review discusses some of the results of treatment in older patients with CLL. A discussion of factors that often affect outcome, such as comorbidities, renal function, bone marrow reserve, and infection, are also reviewed, along with quality of life. PMID- 22234623 TI - Detection of expressed gene in isolated single cells in microchambers by a novel hot cell-direct RT-PCR method. AB - In order to be able to detect the expression of a gene in individual cells, the ability to isolate and lyse a single cell and to perform reverse transcription polymerase chain reaction (RT-PCR) in one device is important. As is common, when performing cell lysis and RT-PCR in the same reaction chamber, it is necessary to add the reagent for RT-PCR after cell lysis. In this study, we propose an original formula for cell lysis and RT-PCR in the same reaction chamber without the addition of reagent by only a heat process, which we termed hot cell-direct RT-PCR. Hot cell-direct RT-PCR was enabled by using Tth DNA polymerase, which is a thermostable polymerase and has high reverse transcription activity in the presence of manganese ions. Direct detection of RT-PCR products was performed by detecting fluorescence with the use of a double-dye fluorescent probe. We attempted to detect the mRNA of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene in isolated Jurkat cells on a microfluidic device, which we had already developed for single cell isolation. After cell isolation and successive hot cell-direct RT-PCR on the device, fluorescent signals from RT-PCR products for a single cell were detected and differentiated from the chamber containing no cells. A highly positive linear relationship (r = 0.9933) was observed between the number of chambers containing cell(s) and those containing RT-PCR products from 10 to 400 cells MUL(-1). Thus it was possible to use the novel hot cell direct RT-PCR method to detect the expressed gene in isolated cells. PMID- 22234625 TI - Managing children under 36 months of age with febrile urinary tract infection: a new approach. AB - BACKGROUND: Recent guidelines on urinary tract infection (UTI) agree on reducing the number of invasive procedures. None of these has been validated by a long term study. We describe our 11-years experience in the application of a diagnostic protocol that uses a reduced number of invasive procedures. METHODS: We reviewed retrospectively the records of 406 children aged between 1 and 36 months at their first UTI. All patients underwent renal ultrasound (RUS). Children with abnormal RUS and those with UTI recurrences underwent voiding cystourethrography (VCUG) and dimercaptosuccinic acid (DMSA) renal scans. RESULTS: RUS after the first UTI was pathological in 7.4% children; 4.4 % had a second UTI. We performed 48 VCUG: 14 patients (29%) had vesicoureteral reflux (VUR), 12 of which showed an abnormal RUS while 2 had recurrent UTI. After DMSA renal scan renal damage appeared in only 6 of them (12.5%); all these children showed grade IV VUR. CONCLUSIONS: The application of our guidelines leads to a decrease in invasive examinations without missing any useful diagnoses or compromising the child's health. PMID- 22234624 TI - ABVD as the treatment option in advanced Hodgkin's lymphoma patients older than 45 years. AB - Advanced age is considered an unfavourable prognostic factor for Hodgkin's lymphoma (HL). The optimal treatment for these patients is not yet defined, especially for the advanced stages. We analysed the outcome and prognostic relevance of patient and disease characteristics in 46 advanced stage HL patients who were older than 45 years, treated with ABVD. Elderly patients (>60 year) had a significantly higher rate of comorbidities (p < 0.05). The complete remission rate was significantly lower in elderly patients and in patients with an IPS >= 3 (p < 0.05, p < 0.05, respectively). Elderly patients had significantly shorter event-free survival (p < 0.01) and overall survival (p < 0.01) compared to patients of 45-60 year. Extranodal disease, an IPS >= 3, bulky disease, an ESR > 50 and the presence of a large mediastinal tumour mass didn't have an influence on survival (p > 0.05). The multivariate Cox regression analysis identified the age of >60 year as an independent prognostic factor. The prospective clinical trials seem to be needed for defining the optimal therapeutic approach in elderly patients. PMID- 22234626 TI - Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy with no hysterectomy in patients with a (clinical and radiological) complete response after chemoradiation therapy for stage IB2 or II cervical cancer. AB - BACKGROUND: Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery. METHODS: A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6-8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003-2006) and are reported on here. RESULTS: Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively. CONCLUSIONS: Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power). PMID- 22234627 TI - Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab containing therapy. AB - BACKGROUND: Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. METHODS: The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER 2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark(r) assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. RESULTS: A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). CONCLUSIONS: These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group. PMID- 22234629 TI - Maintenance therapy for first-line metastatic colorectal cancer: activity and sustainability. PMID- 22234628 TI - Vitamin D and breast cancer. AB - In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results. Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention. PMID- 22234630 TI - Cancer-associated isocitrate dehydrogenase mutations. PMID- 22234631 TI - Curative strategies for liver metastases from colorectal cancer: a review. AB - Colorectal cancer is a very common malignancy and frequently manifests with liver metastases, often without other systemic disease. Margin-negative (R0) resection of limited metastatic disease, in conjunction with systemic antineoplastic agents, is the primary treatment strategy, leading to long survival times for appropriately selected patients. There is debate over whether the primary tumor and secondaries should be removed at the same time or in a staged manner. Chemotherapy is effective in converting some unresectable liver metastases into resectable disease, with a correspondingly better survival outcome. However, the ideal chemotherapy with or without biological agents and when it should be administered in the course of treatment are uncertain. The role of neoadjuvant chemotherapy in initially resectable liver metastases is controversial. Local delivery of chemotherapy, with and without surgery, can lead to longer disease free survival times, but it is not routinely used with curative intent. This review focuses on methods to maximize the disease-free survival interval using chemotherapy, surgery, and local methods. PMID- 22234632 TI - Shared decision making in oncology practice: what do oncologists need to know? AB - BACKGROUND: There is growing interest by patients, policy makers, and clinicians in shared decision making (SDM) as a means to involve patients in health decisions and translate evidence into clinical practice. However, few clinicians feel optimally trained to implement SDM in practice, and many patients report that they are less involved than they desire to be in their cancer care decisions. SDM might help address the wide practice variation reported for many preference-sensitive decisions by incorporating patient preferences into decision discussions. METHODS: This paper provides a perspective on how to incorporate SDM into routine oncology practice to facilitate patient-centered communication and promote effective treatment decisions. Oncology practice is uniquely positioned to lead the adoption of SDM because of the vast number of preference-sensitive decisions in which SDM can enhance the clinical encounter. RESULTS: Clinicians can facilitate cancer decision making by: (a) determining the situations in which SDM is critical; (b) acknowledging the decision to a patient; (c) describing the available options, including the risks, benefits, and uncertainty associated with options; (d) eliciting patients' preferences; and (e) agreeing on a plan for the next steps in the decision-making process. CONCLUSION: Given recent policy movements toward incorporating SDM and translating evidence into routine clinical practice, oncologists are likely to continue expanding their use of SDM and will have to confront the challenges of incorporating SDM into their clinical workflow. More research is needed to explore ways to overcome these challenges such that both quality evidence and patient preferences are appropriately translated and incorporated into oncology care decisions. PMID- 22234634 TI - Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current treatment strategies. AB - Recent advancements in the molecular characterization of renal cell carcinoma altered the classification system and now kidney cancer is divided into several distinct histologic subtypes. Although once a separate histologic category, sarcomatoid renal cell carcinoma is no longer considered a separate tumor type because it can occur with all histologic subtypes. Limited research on tumors with sarcomatoid change has led to minimal progress in the understanding and treatment of these tumors. Because the sarcomatoid variant of renal cell carcinoma can account for approximately one in six cases of advanced kidney cancer, we hope to familiarize clinicians with these tumors by describing the historic background, histologic features, molecular characterization, diagnosis, prognosis, treatment strategies, and active clinical trials of this aggressive type of tumor. PMID- 22234633 TI - First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. AB - PURPOSE: The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety. RESULTS: The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0-53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand-foot syndrome, and neuropathy. CONCLUSION: Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients. PMID- 22234635 TI - Structure and haemostatic effects of generic versions of enoxaparin available for clinical use in Brazil: similarity to the original drug. AB - Patent protection for enoxaparin has expired. Generic preparations are developed and approved for clinical use in different countries. However, there is still skepticism about the possibility of making an exact copy of the original drug due to the complex processes involved in generating low-molecular-weight heparins. We have undertaken a careful analysis of generic versions of enoxaparin available for clinical use in Brazil. Thirty-three batches of active ingredient and 70 of the final pharmaceutical product were obtained from six different suppliers. They were analysed for their chemical composition, molecular size distribution, in vitro anticoagulant activity and pharmacological effects on animal models of experimental thrombosis and bleeding. Clearly, the generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. Only three out of 33 batches of active ingredient from one supplier showed differences in molecular size distribution, resulting from a low percentage of tetrasaccharide or the presence of a minor component eluted as monosaccharide. Three out of 70 batches of the final pharmaceutical products contained lower amounts of the active ingredient than that declared by the suppliers. Our results suggest that the generic versions of enoxaparin are a viable therapeutic option, but their use requires strict regulations to ensure accurate standards. PMID- 22234636 TI - A copper-based catalytic system for carboxylation of terminal alkynes: synthesis of alkyl 2-alkynoates. AB - An efficient coupling of terminal alkynes and CO(2) in the presence of alkyl halides can be achieved under ambient conditions using a copper/phosphine catalyst system, providing facile access to a variety of functionalised alkyl 2 alkynoates. PMID- 22234637 TI - Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial. AB - BACKGROUND: Control of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors. METHODS: Patients received either vorinostat 300 mg bid for 3 consecutive days followed by 4 rest days per cycle (n = 10) or vorinostat 400 mg qd for 21 consecutive days per cycle (n = 6). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response. RESULTS: The median treatment duration of 300 mg bid was 52.0 days and of 400 mg qd was 51.5 days. The most common drug related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400 mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300 mg bid experienced DLT. Five patients taking 300 mg bid and 2 patients taking 400 mg qd maintained stable disease for >8 weeks, with the maximum duration of 245 days. Mean drug exposure (+/-SD) was generally higher with 400 mg qd (area under the curve [AUC(0-infinity)] of 7.75 +/- 2.79 MUM h on Day 1 post-dose) compared with 300 mg bid (AUC(0-infinity) of 3.94 +/- 1.56 MUM h on Day 1 post-dose). CONCLUSIONS: Vorinostat 300 mg bid for 3 consecutive days followed by 4 days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8 weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer. PMID- 22234638 TI - Early mesothelioma revisited. PMID- 22234639 TI - Photophysics of indole-2-carboxylic acid in an aqueous environment studied by fluorescence spectroscopy in combination with ab initio calculations. AB - The photo-physics and -chemistry of indoles are known to be highly complex and strongly dependent on their precise molecular structure and environment. Combination of spectroscopic analysis with quantum chemical calculations should be a powerful tool to unravel precise excited state deactivation mechanisms. At the same time, combined studies are seldom and likely far from trivial. In this work we explore the feasibility of combining spectroscopic and quantum-chemical data into one consistent model. The molecule of choice is indole-2-carboxylic acid (ICA) in aqueous media. Excited state dynamics are determined by time resolved fluorescence experiments, while excited state reaction pathways of ICA H(2)O clusters are explored by ab initio calculations. PMID- 22234640 TI - Neoplastic brachial plexopathy detected by ultrasonography in a patient with chronic cervicobrachialgia. AB - OBJECTIVE: We report here a case of neoplastic brachial plexopathy detected by musculoskeletal ultrasonography in a patient with chronic cervicobrachialgia. METHODS/RESULTS: A 71-year-old man presented at Gulhane Military Medical Academy, Turkish Armed Forces Rehabilitation Center, Ankara, Turkey with a one-year history of cervicobrachial pain radiating to the left arm and numbness in the medial aspect of the left arm and hand. He could not tolerate magnetic resonance imaging because his pain was exacerbated by cervical extension. Radiographs of his chest and cervical spine were normal. Ultrasound examination of the left brachial plexus revealed segmental fusiform swelling, suggestive for a compressing lesion. Magnetic resonance imaging of the brachial plexus performed under general anaesthesia revealed a left apical lung tumour (Pancoast) infiltrating the brachial plexus. CONCLUSION: Clinicians should consider neoplastic brachial plexopathy, which is an uncommon diagnosis, when evaluating patients with unrelenting and severe cervicobrachialgia. Musculoskeletal ultrasonography can be beneficial for examining brachial plexus lesions. PMID- 22234641 TI - An efficient palladium-benzimidazolyl phosphine complex for the Suzuki-Miyaura coupling of aryl mesylates: facile ligand synthesis and metal complex characterization. AB - A new class of easily accessible hemilabile benzimidazolyl phosphine ligands has been developed. The ligand skeleton is prepared from commercially available and inexpensive o-phenylenediamine and 2-bromobenzoic acid. With catalyst loading down to 0.5 mol% palladium, excellent catalytic activity towards the Suzuki Miyaura coupling of aryl mesylates is still observed. This represents the lowest catalyst loading achieved so far for this reaction in general. X-Ray crystallography shows that new ligand L2 is coordinated with Pd in a kappa(2)-P,N fashion. PMID- 22234642 TI - Three brief assessments of math achievement. AB - Because of wide disparities in college students' math knowledge-that is, their math achievement-studies of cognitive processing in math tasks also need to assess their individual level of math achievement. For many research settings, however, using existing math achievement tests is either too costly or too time consuming. To solve this dilemma, we present three brief tests of math achievement here, two drawn from the Wide Range Achievement Test and one composed of noncopyrighted items. All three correlated substantially with the full achievement test and with math anxiety, our original focus, and all show acceptable to excellent reliability. When lengthy testing is not feasible, one of these brief tests can be substituted. PMID- 22234643 TI - Assessing the health of an urban stream: a case study of Suzhou Creek in Shanghai, China. AB - Restoration of urban streams and rivers has increased rapidly in developing countries in recent years. Estimating river health provides a new perspective on evaluating the ecological conditions of streams and rivers. The Suzhou Creek restoration project in Shanghai, China is a milestone for environmental protection. Based on the environmental and ecological data, including 17 indicators in five categories, collected from March 11 to April 20, 2007, the river health index (RHI) for Suzhou Creek was constructed and analysed to quantify the ecosystem of this urban river after a restoration project. The RHI scores of 34 sites ranged from 19.24 to 33.36, i.e. from poor to good. There were no significant RHI differences among stream orders, while differences in land use resulted in significant differences in channel flow status (B12), channel alteration (B21), channel sinuosity (B22), bank stability (B23), bank profile type (B25) and riparian vegetative zone width (B31). River restoration led to improved hydrological condition and channel physical form, while ammonia nitrogen (B44) and indicator scores of the presence of macro-invertebrate families (B51) were the lowest of any indicator. This case study supports the use of river health assessment as a supplement to water quality analysis in China. PMID- 22234644 TI - Status of the Southern Carpathian forests in the long-term ecological research network. AB - Air pollution, bulk precipitation, throughfall, soil condition, foliar nutrients, as well as forest health and growth were studied in 2006-2009 in a long-term ecological research (LTER) network in the Bucegi Mountains, Romania. Ozone (O(3)) was high indicating a potential for phytotoxicity. Ammonia (NH(3)) concentrations rose to levels that could contribute to deposition of nutritional nitrogen (N) and could affect biodiversity changes. Higher that 50% contribution of acidic rain (pH < 5.5) contributed to increased acidity of forest soils. Foliar N concentrations for Norway spruce (Picea abies), Silver fir (Abies alba), Scots pine (Pinus sylvestris), and European beech (Fagus sylvatica) were normal, phosphorus (P) was high, while those of potassium (K), magnesium (Mg), and especially of manganese (Mn) were significantly below the typical European or Carpathian region levels. The observed nutritional imbalance could have negative effects on forest trees. Health of forests was moderately affected, with damaged trees (crown defoliation >25%) higher than 30%. The observed crown damage was accompanied by the annual volume losses for the entire research forest area up to 25.4%. High diversity and evenness specific to the stand type's structures and local climate conditions were observed within the herbaceous layer, indicating that biodiversity of the vascular plant communities was not compromised. PMID- 22234645 TI - Synthesis, crystal structures and magnetic properties of bis(MU-dialkoxo)-bridged linear trinuclear copper(II) complexes with aminoalcohol ligands: a theoretical/experimental magneto-structural study. AB - The bis(MU-dialkoxo)-bridged trinuclear copper(II) complexes [Cu(3)(ap)(4)(ClO(4))(2)EtOH] (1), [Cu(3)(ap)(4)(NO(3))(2)] (2), [Cu(3)(ap)(4)Br(2)] (3) and [Cu(3)(ae)(4)(NO(3))(2)] (4) (ae = 2-aminoethanolato and ap = 3-aminopropanolato) have been synthesised via self-assembly from chelating aminoalcohol ligands with the corresponding copper(II) salts. The complexes are characterised by single-crystal X-ray diffraction analyses and variable temperature magnetic measurements. The crystal structures of complexes 1 4 consist of slightly bent linear or linear trinuclear [Cu(3)(aa)(4)](2+) (aa = aminoalcoholato) units to which the perchlorate, nitrate or bromide anions are weakly coordinated. The adjacent trinuclear units of 1-4 are connected together by hydrogen bonds and bridging nitrate or bromide anions resulting in the formation of 2D layers. Magnetic studies of 1, 2 and 4 show that J values vary from -379 to +36.0 cm(-1) as the Cu-O-Cu angle (theta) and the out-of-plane shift of the carbon atom of the bridging alkoxo group (tau) vary from 103.7 to 94.4 degrees and from 0.9 to 35.5 degrees , respectively. Magnetic exchange coupling constants calculated by DFT methods are of the same nature and magnitude as the experimental ones. For complexes 1, 2 and 4, which have complementarity effects between the theta and tau angles (small theta values are associated with large tau values and vice versa), an almost linear relationship between the calculated J values with theta angles could be established, thus supporting that the theta and tau angles are the two key structural factors that determine the magnetic exchange coupling for such a type of compounds. Complex 3 does not obey this linear correlation because of the existence of counter-complementarity effects between these angles (small theta values are associated with small tau values and vice versa). It is of interest that the theoretical calculations for the magnetic exchange interaction between next-nearest neighbours indicate that the usual approximation in experimental studies of neglecting the magnetic coupling between the next-nearest neighbours in linear trinuclear complexes could lead to considerable errors, especially when J(1) and J(2) are of the same order of magnitude as J(3). PMID- 22234647 TI - Transcriptional analysis reveals a high impact of conjugated linoleic acid on stearoyl-Coenzyme A desaturase 1 mRNA expression in mice gastrocnemius muscle. AB - We examined the potential implication of skeletal muscle in the fat-lowering effect observed in mice treated with moderate doses of CLA. In experiment 1, mice fed with a standard-fat diet were orally treated with sunflower oil (control) and 3 or 10 mg CLA mixture/day for 37 days. In experiment 2, mice were fed with a high-fat diet for 65 days. For the first 30 days, they received the same doses as in experiment 1 and, from that time onwards, animals received double doses. Gene expression of key proteins involved in fatty acid transport, oxidation, regulation of lipid and carbohydrate utilization, composition of muscle fiber, and thermogenesis were determined and, in most of them, no major impact of CLA was seen. Therefore, enhancement of fatty acid oxidation in muscle did not seem to contribute to the antiobesity effect of CLA as seen in other studies with higher CLA doses. However, a strong induction of classically associated lipogenic genes such as Fasn (up to twofold) and, particularly, Scd1 (up to ninefold) was found. This activation could contribute to a protective role in muscle cells, since expression of ER stress markers was decreased and inversely correlated with the induction of Scd1. PMID- 22234650 TI - Pseudomyxoma peritonei: some different sonographic findings. AB - OBJECTIVES: The purpose of our study was to assess the sonographic features of pseudomyxoma peritonei (PMP). MATERIALS AND METHODS: All records of peritoneal biopsies under the guidance of ultrasound in our institutional database from April 2007 to June 2011 were retrospectively reviewed. 19 cases of PMP and 279 cases of other peritoneal lesions were included in the study. The sonograms of peritoneum, ascites, and parenchymal organs involved by PMP were evaluated, respectively, and compared with sonograms of other peritoneal lesions. RESULTS: Anechoic areas were found in 89.5% cases of PMP at high frequency of insonation and the sensitivity in indicating PMP was 100%. In the pelvic cavity, echogenic foci in ascites of PMP in 52.6% cases were mobile. The specificity of "starburst" appearance and sensitivity of scalloping of the liver margin were relatively high (82.3 and 88.1%), but the sensitivity and specificity (57.9 and 42.1%) of these two signs were relatively low. CONCLUSION: Anechoic area in the thickened peritoneum was a specific sign in indicating the diagnosis of PMP and high frequency transducer could reveal these tiny anechoic areas more explicitly. In the pelvic cavity, echogenic foci in ascites of PMP could be observed to be mobile and scalloping of the liver margin and "starburst" appearance also played a significant role in indicating PMP. PMID- 22234648 TI - Relationship of exercise volume to improvements of quality of life with supervised exercise training in patients with type 2 diabetes in a randomised controlled trial: the Italian Diabetes and Exercise Study (IDES). AB - AIMS/HYPOTHESIS: A positive impact of exercise intervention programmes on quality of life (QoL) may be important for long-term patient compliance to exercise recommendations. We have previously shown that QoL improves significantly with supervised exercise, whereas it worsens with counselling alone, in patients with type 2 diabetes from the Italian Diabetes and Exercise Study (IDES). Here, we report data on the relationship between changes in QoL and volume of physical activity/exercise in these individuals. METHODS: This multicentre parallel randomised controlled, open-label, trial enrolled sedentary patients with type 2 diabetes (n = 606 of 691 eligible) in 22 outpatient diabetes clinics. Patients were randomised by centre, age and diabetes treatment using a permuted-block design to twice-a-week supervised aerobic and resistance training plus exercise counselling (exercise group) versus counselling alone (control group) for 12 months. Health-related QoL was assessed by the 36-Item Short Form (SF-36) Health Survey. RESULTS: In the exercise group (n = 268 of 303 randomised), there was a trend for increasing QoL with increasing exercise volume, with significant improvement of the physical component summary (PCS) measure only above 17.5 metabolic equivalents h-1 week-1 and a clear volume-relationship for the mental component summary (MCS) measure. A relationship with volume of physical activity also was observed in the control group (n = 260 of 303 randomised), despite overall deterioration of all scores. Independent correlates of improvements in both PCS and MCS were exercise volume, study arm and, inversely, baseline score. CONCLUSIONS/INTERPRETATION: This large trial shows a relationship between changes in physical and mental health-related QoL measures and volume of physical activity/exercise, with supervised exercise training also providing volume independent benefits. PMID- 22234649 TI - Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat. AB - AIMS/HYPOTHESIS: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. METHODS: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1). RESULTS: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. CONCLUSIONS/INTERPRETATION: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure. PMID- 22234655 TI - Tunable ferromagnetism in assembled two dimensional triangular graphene nanoflakes. AB - Triangular graphene nanoflakes (TGFs), due to their novel magnetic configurations, can serve as building blocks to design new magnetic materials. Based on spin polarized density functional theory, we show that the two dimensional (2D) structures composed of zigzag-edged TGFs linked by 1,3,5 benzenetriyl units (TGF(N)-C(6)H(3)) are ferromagnetic. Their magnetic moments can be tuned by changing the size and edge termination of TGFs, namely magnetic moments increase linearly with the size of TGFs, and double hydrogenation of the edge carbon atoms can significantly enhance stability of the ferromagnetic states. The dynamic stability of the assembled 2D structures is further confirmed by frequency calculations. The characteristic breathing mode is identified where the frequency changes with the inverse square root of the TGFs width, which can be used to identify the size of TGF(N)-C(6)H(3) in Raman experiments. This study provides new pathways to assemble 2D ferromagnetic carbon materials. PMID- 22234653 TI - Off-label and unlicensed drug use in neonatal intensive care units in Turkey: the old-inn study. AB - BACKGROUND: Recently several developed countries have improved the safety and efficacy of drugs used in infants and pediatric patients. Most drugs administered to adults have licensed approvals outlining indications, doses, and the recommended route of administration. However, many drugs that are given to children are unlicensed or used off-label. OBJECTIVES: To assess the extent and nature of unregistered and off-label drug use in neonatal intensive care units (NICUs) in Turkey, and to explore awareness and views of the general public on the unlicensed use of medicine in preterm and term infants in developing countries. STUDY DESIGN: A prospective observational study of a dynamic cohort of 464 neonates from 17 NICUs in Turkey. All medications administered to neonates who were hospitalized and admitted to the NICU over a 24-h period were recorded. The prescriptions were analyzed to determine whether the medicines were used in a licensed or unlicensed manner. RESULTS: In total, 1,315 prescriptions comprising 93 different medicines were written. We found that 62.3% of the drugs prescribed to the neonates over the 24-h period were unlicensed or off-labeled. CONCLUSIONS: The present study indicates that unlicensed and off-label medicines are frequently used in preterm and term infants in Turkish NICUs. This finding is consistent and reported in other countries. We believe that the needs of the neonatal population must be a priority and access to safe and appropriate medicines requires urgent attention. PMID- 22234656 TI - Kinetics and mechanism of light-driven oxygen evolution at thin film alpha-Fe2O3 electrodes. AB - Rate constants for recombination and hole transfer during oxygen evolution at illuminated alpha-Fe(2)O(3) electrodes were measured by intensity-modulated photocurrent spectroscopy and found to be remarkably low. Treatment of the electrode with a Co(II) solution suppressed surface recombination but did not catalyse hole transfer. Intermediates in the reaction were detected spectroscopically. PMID- 22234657 TI - The incidence of venous thromboembolism in patients with overt hyperthyroidism: a retrospective multicentre cohort study. AB - Hyperthyroidism is associated with several changes in the haemostatic system resulting in a hypercoagulable state. It is uncertain at this stage whether this leads to an increased risk of venous thromboembolism (VTE). The aim of this retrospective cohort study was to determine the risk of VTE in all patients with overt hyperthyroidism and to compare this to the risk of VTE in the general population. In three hospitals in the Netherlands, patients with biochemically confirmed hyperthyroidism caused by Graves' disease, multinodular goiter or toxic adenoma were included. All available electronic and handwritten records were examined. Primary outcome was the occurrence of VTE within six months before and until six months after the diagnosis of hyperthyroidism. We included a total of 587 patients. Five patients experienced a VTE during the study period, resulting in an incidence rate of 8.7 (95% CI 2.8 - 20.2) per 1,000 person-years. Three of these five patients had a first VTE (incidence rate for first VTE was 5.3 [95% CI 1.1 - 15.6] per 1,000 person-years). Incidence rates of VTE in the general population are between 0.6 and 1.6 per 1,000 person-years for first VTE and 0.7 and 1.8 per 1,000 person-years for all VTE. In conclusion, the incidence rate of VTE in patients with hyperthyroidism appears to be high. Future prospective studies are needed to further explore this possible association and to address its clinical implications. PMID- 22234659 TI - General and reliable quantitative measurement of fluorescence resonance energy transfer using three fluorescence channels. AB - In this paper, we describe a comprehensive general system adapted for quantitative fluorescence resonance energy transfer (FRET) measurement using signals from three channels of a fluorescence instrument. The general FRET measurement system involves two established methods, as well as two novel approaches. Unlike the previous measurements, which can be taken correctly only when the quantity of the acceptor is greater than or equal to that of the donor, one of our novel methods can overcome this obstacle and take quantitative FRET measurements when the donor is in excess of the acceptor. Hence the general FRET measurement system allowed one to determine the exact distance when the donor and acceptor were present in different quantities, and integrated the methods for quantitative FRET measurements. The uniformity of measured values and utility of each method were validated using molecular standards based on DNA oligonucleotide rulers. We also discussed and validated the use of a novel method for estimating the relative quantities of the donor and acceptor fluorophores when they were not known before an appropriate method of this system can be selected. PMID- 22234660 TI - Using military friendships to optimize postdeployment reintegration for male Operation Iraqi Freedom/Operation Enduring Freedom veterans. AB - Social relationships are important to health out comes. The postdeployment family reintegration literature focuses on the role of the civilian family in facilitating the transition from Active Duty military deployment to civilian society. The focus on the civilian family relationship may miss other important personal connections in veterans' lives. One such connection is the relationship many veterans have with former military unit members who served with them when deployed. Drawing on interviews with male Operation Iraqi Freedom/Operation Enduring Freedom veterans conducted from 2008 to 2009, we argue that the members of a military unit, especially during armed conflict, should be considered a resource to help the "family" reintegration process rather than impede it. This research has implications for current reintegration policy and how best to assist veterans transitioning into civilian society. PMID- 22234658 TI - Photochemical release of methotrexate from folate receptor-targeting PAMAM dendrimer nanoconjugate. AB - Nanoparticle (NP)-based targeted drug delivery involves cell-specific targeting followed by a subsequent therapeutic action from the therapeutic carried by the NP system. NPs conjugated with methotrexate (MTX), a potent inhibitor of dihydrofolate reductase (DHFR) localized in cytosol, have been under investigation as a delivery system to target cancer cells to enhance the therapeutic index of methotrexate, which is otherwise non-selectively cytotoxic. Despite improved therapeutic activity from MTX-conjugated NPs in vitro and in vivo, the therapeutic action of these conjugates following cellular entry is poorly understood; in particular it is unclear whether the therapeutic activity requires release of the MTX. This study investigates whether MTX must be released from a nanoparticle in order to achieve the therapeutic activity. We report herein light-controlled release of methotrexate from a dendrimer-based conjugate and provide evidence suggesting that MTX still attached to the nanoconjugate system is fully able to inhibit the activity of its enzyme target and the growth of cancer cells. PMID- 22234662 TI - Activity-promoting gaming systems in exercise and rehabilitation. AB - Commercial activity-promoting gaming systems provide a potentially attractive means to facilitate exercise and rehabilitation. The Nintendo Wii, Sony EyeToy, Dance Dance Revolution, and Xbox Kinect are examples of gaming systems that use the movement of the player to control gameplay. Activity-promoting gaming systems can be used as a tool to increase activity levels in otherwise sedentary gamers and also be an effective tool to aid rehabilitation in clinical settings. Therefore, the aim of this current work is to review the growing area of activity promoting gaming in the context of exercise, injury, and rehabilitation. PMID- 22234661 TI - Mental health diagnosis and occupational functioning in National Guard/Reserve veterans returning from Iraq. AB - Occupational functioning represents both an important outcome for military service members returning from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom and a predictor for long-term mental health functioning. We investigated the role of mental health diagnoses, determined by structured clinical interviews, on occupational functioning in a group of 262 National Guard/Reserve service members within 1 year of returning from a 16-month OIF combat deployment. We assessed occupational functioning at the time of diagnostic interviews and 1 year later. We hypothesized that service members with diagnoses of posttraumatic stress disorder (PTSD), depression, and/or alcohol abuse or dependence would exhibit lower rates of employment at both time points and lower rates of reported work and/or school role functioning. Service members with a diagnosis of PTSD (5%, n = 13), subthreshold PTSD (6%, n = 15), a major depressive disorder (11%, n = 29), or alcohol abuse or dependence (11%, n = 28) did not differ on employment status from service members without a diagnosis at either time point. However, those with a diagnosis of PTSD, depression, and/or alcohol abuse or dependence reported lower levels of work role functioning. In addition, service members with a diagnosis of PTSD reported greater rates of deterioration in work role functioning over time. PMID- 22234663 TI - Reliability of daily step activity monitoring in adults with incomplete spinal cord injury. AB - We determined the number of days of step activity monitoring required to establish stable measures of walking activity in adults with incomplete spinal cord injury (iSCI). Eleven individuals with iSCI (mean age 49 +/- 14 years) wore a StepWatch Activity Monitor during waking hours for 7 consecutive days. We used generalizability theory to identify sources of variance in daily step counts and determine the minimum number of days necessary to obtain a reliability coefficient (G-coefficient) greater than or equal to 0.80. Average daily step activity (DSA) was 1,281 +/- 1,594 steps. Participants and days accounted for 70.9% and 1.3% of total variance in DSA, respectively, while unidentifiable error accounted for 27.8% of the total variance in DSA. A minimum of 2 days was required to achieve a G-coefficient greater than or equal to 0.80. An acceptably stable measure of walking activity in adults with iSCI can be obtained by averaging step count values from any 2-day period in a week. Results from this investigation should be useful in evaluating the effect of activity-based programs designed to enhance locomotor function in persons with iSCI. PMID- 22234665 TI - Translating measurement findings into rehabilitation practice: an example using Fugl-Meyer Assessment-Upper Extremity with patients following stroke. AB - Standardized assessments are critical for advancing clinical rehabilitation, yet assessment scores often provide little information for rehabilitation treatment planning. A keyform recovery map is an innovative way for a therapist to record patient responses to standardized assessment items. The form enables a therapist to view the specific items that a patient can or cannot perform. This information can assist a therapist in tailoring treatments to a patient's individual ability level. We demonstrate how a keyform recovery map can be used to inform clinical treatment planning for individuals with stroke-related upper-limb motor impairment. A keyform map of poststroke upper-limb recovery defined by items of the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) was generated by a previously published Rasch analysis. Three individuals with stroke enrolled in a separate research study were randomly selected from each of the three impairment strata of the FMA-UE. Their performance on each item was displayed on the FMA-UE keyform. The forms directly connected qualitative descriptions of patients' motor ability to assessment measures, thereby suggesting appropriate shorter and longer term rehabilitation goals. This study demonstrates how measurement theory can be used to translate a standardized assessment into a useful, evidence-based tool for making clinical practice decisions. PMID- 22234664 TI - Arthroplasty in veterans: analysis of cartilage, bone, serum, and synovial fluid reveals differences and similarities in osteoarthritis with and without comorbid diabetes. AB - Osteoarthritis patients with diabetes who receive total knee arthroplasty are more vulnerable to complications, including aseptic loosening and need for revision surgery. To elucidate mechanisms related to arthroplasty failure in diabetes, we examined serum and synovial fluid markers as well as collagen crosslinks in bone and cartilage of 20 patients (10 with diabetes, 10 controls without) undergoing this procedure. Hemoglobin A1c, body mass index, bone alkaline phosphatase, leptin, osteocalcin, and pyridinium were analyzed along with tissue content of the crosslinks hydroxylysylpyridinoline, lysylpyridinoline, and pentosidine. Pentosidine levels in tissue specimens from diabetic subjects were higher than in control subjects. Osteocalcin levels negatively correlated with hydroxylysylpyridinoline levels in cartilage. Osteocalcin levels also negatively correlated with pentosidine levels in cartilage, but only in subjects with diabetes. This study suggests potential metabolic mechanisms for arthroplasty failure in patients with diabetes. PMID- 22234666 TI - Disease-modifying agents in progressive multiple sclerosis: management of 100 patients at Louis Stokes Cleveland VAMC, Spinal Cord Injury Division. AB - Multiple sclerosis (MS) is a chronic disease in which disability progresses over time. Progressive forms of MS have a poor prognosis, are associated with greater levels of disability and, unfortunately, are unresponsive to current treatments. Here, we have reviewed the management of 100 patients with MS. The majority of these patients had progressive disease, Expanded Disability Status Scale scores >6, and extensive medical complications. A significant number of patients in this cohort were also treated with MS disease-modifying agents that lack efficacy in patients with progressive disease. Although these drugs are relatively safe, their use here is significantly costly to the healthcare system, with limited benefit to patients. We suggest that these drugs be discontinued in these patients and resources be directed toward symptomatic treatment, rehabilitation needs, and management of medical complications until drugs with proven efficacy become available. PMID- 22234667 TI - Effects of elevated vacuum on in-socket residual limb fluid volume: case study results using bioimpedance analysis. AB - Bioimpedance analysis was used to measure the residual limb fluid volume of seven transtibial amputee subjects using elevated vacuum sockets and nonelevated vacuum sockets. Fluid volume changes were assessed during sessions with the subjects sitting, standing, and walking. In general, fluid volume losses during 3 or 5 min walks and losses over the course of the 30 min test session were less for elevated vacuum than for suction. Numerous variables, including the time of day that data were collected, soft tissue consistency, socket-to-limb size and shape differences, and subject health, may have affected the results and had an equivalent or greater effect on limb fluid volume compared with elevated vacuum. Researchers should well consider these variables in the study design of future investigations on the effects of elevated vacuum on residual limb volume. PMID- 22234668 TI - Determining asymmetry of roll-over shapes in prosthetic walking. AB - How does the inherent asymmetry of the locomotor system in people with lower-limb amputation affect the ankle-foot roll-over shape of prosthetic walking? In a single-case design, we evaluated the walking patterns of six people with lower limb amputation (3 transtibial and 3 transfemoral) and three matched nondisabled controls. We analyzed the walking patterns in terms of roll-over characteristics and spatial and temporal factors. We determined the level of asymmetry by roll over shape comparison (root-mean-square distance) as well as differences in radius of curvature. In addition, we calculated ratios to determine spatial and temporal asymmetries and described different aspects of asymmetry of roll-over shapes. All participants showed some level of asymmetry in roll-over shape, even the nondisabled controls. Furthermore, we found good intralimb reproducibility for the group as a whole. With respect to spatial and temporal factors, the participants with transtibial amputation had a quite symmetrical gait pattern, while the gait in the participants with transfemoral amputation was more asymmetrical. The individual ankle-foot roll-over shapes provide additional insight into the marked individual adjustments occurring during the stance phase of the nondisabled limb. The two methods we present are suitable for determining asymmetry of roll-over shapes; both methods should be used complementarily. PMID- 22234669 TI - Effect of home-based exercise program on lymphedema and quality of life in female postmastectomy patients: pre-post intervention study. AB - Lymphedema is a debilitating complication following mastectomy, affecting the arm functions and quality of life (QOL) of breast cancer patients. Studies have shown the beneficial effects of upper-limb exercises on lymphedema in clinical settings. However, there is a dearth of evidence regarding the effect of home based exercises on lymphedema; therefore, we examined the effect of a home-based exercise program on lymphedema and QOL in postmastectomy patients. Thirty-two female postmastectomy lymphedema patients participated in an individualized home based exercise program for 8 weeks. Arm circumference, arm volume, and QOL (36 Item Short Form Health Survey) were measured before and after the program. Data were analyzed with the use of paired t-tests for circumferential and volumetric measures and Wilcoxon signed ranks tests for QOL. Significance level was set at p < 0.01 with Bonferroni correction (alpha/n = 0.05/5 = 0.01). Analysis showed a statistically significant improvement in the affected upper-limb circumference and volume (~122 mL reduction, p < 0.001) and in the QOL scores (p < 0.001) at the end of the home-based exercise program. The individualized home-based exercise program led to improvement in affected upper-limb volume and circumference and QOL of postmastectomy lymphedema patients. PMID- 22234670 TI - Repeated concussion among U.S. military personnel during Operation Iraqi Freedom. AB - Concussions are a predominant injury of the conflicts in Iraq and Afghanistan. The aims of this study were to describe repeated concussive events among U.S. military personnel injured in Operation Iraqi Freedom and examine subsequent healthcare utilization. We reviewed clinical records from the Expeditionary Medical Encounter Database to identify service members with repeat concussions. We abstracted demographic and injury-specific variables, calculated time between events, and identified healthcare utilization from electronic medical databases. Overall, 113 personnel experienced more than one concussion between 2004 and 2008. A majority of these incidents were blast related. The median time between events was 40 days, with 20% experiencing a second event within 2 weeks of the first and 87% within 3 months. Time between events was not associated with severity of the second event. Greater severity of the second concussive event was associated with higher postinjury utilization of mental health and neurology services. This study is one of the first to describe repeated concussions in a combat setting. We found that repeated concussions occur within a short interval among deployed personnel, although the effects of the first event are unclear. Further research is needed to define the effect of repeated concussions on the health of combat veterans. PMID- 22234671 TI - Paralympics and veterans. PMID- 22234672 TI - On enhancing productivity of bioethanol with multiple species. AB - The present work is initiated to investigate whether a defined culture comprising a mixture of three yeast species, Kluyveromyces marxianus, Saccharomyces cerevisiae, and Pichia stipitis can ferment a mixture of sugars to produce bioethanol at rates higher than those achieved by pure cultures of the same. For this purpose, we develop models of single species based on the hybrid cybernetic model framework, and simulate fermentations in the mixed culture by combining individual models. An underlying assumption is that the behavior of each species is determined only by the common environment independently of the presence and metabolism of other species. Model performance is thoroughly assessed using the experimental data available in the literature. The dynamic behavior of mixed cultures in mixed culture experiments are accurately predicted by the model reflecting faithfully the simultaneous/sequential uptake patterns of mixed substrates. This model is then used to investigate performance of various possible reactor configurations. With the foregoing species of organisms, mixed culture itself does not lead to a significant increase of bioethanol productivity. Rather, the model shows that substantial improvement is acquired by sequential use of different, properly chosen organisms during fermentation. Thus, the successive use of K. marxianus and P. stipitis is shown to increase bioethanol productivity up to about 58% in comparison to fermentation by single species alone. PMID- 22234673 TI - Cross-regional validity of the assessment of motor and process skills for use in middle Europe. AB - OBJECTIVE: To evaluate cross-regional validity of the Assessment of Motor and Process Skills (AMPS) with a specific focus on valid use with Middle Europeans. DESIGN: Descriptive cross-regional validation study. PARTICIPANTS: A total of 1346 participants from Middle Europe and 144,143 participants from North America, UK/Ireland, the Nordic Countries, other Europe, Australia/New Zealand and Asia, between the ages of 3 and 103 years, in good health and with a variety of diagnoses, were selected from the AMPS database. METHODS: Many-facet Rasch analysis was used to analyse participant raw data, and effect sizes were used to evaluate for differential item functioning. Evaluation for differential test functioning was also implemented. RESULTS: None of the 20 activity of daily living process items, and only one of the activity of daily living motor items demonstrated differential item functioning. The activity of daily living motor item Aligns exceeded the significant effect size criterion of +/- 0.55 logit, but the significant differential item functioning did not lead to differential test functioning (i.e. all measures fell within the 95% confidence bands). CONCLUSION: This study provides further evidence of validity of the AMPS when used to evaluate quality of daily living performance across world regions. The AMPS measures can be used as objective indices of activity of daily living ability in rehabilitation settings and in international collaborative research related to activity of daily living task performance. PMID- 22234675 TI - Synthesis and solvent dependent reactivity of chelating bis-N-heterocyclic carbene complexes of Fe(II) hydrides. AB - The synthesis and isolation of low coordinate methylenebis-(N-DIPP-imidazole-2 ylidene)iron((II))hydrides, (((DIPP)C)(2)CH(2))FeH(2-y)I(y) ((DIPP = 2,6-di isopropylphenyl, y = 1 or 0), was complicated by competitive reactions with solvent, rapid reductive elimination of H(2) and/or dissociation of the bis-N heterocyclic carbene ligand. Addition of KH to (((DIPP)C)(2)CH(2))FeI(2) in THF/haloalkane mixtures enabled a short lived mono-hydride to be trapped by reaction with CH(2)Cl(2) or cyclo-heptylbromide to form (((DIPP)C)(2)CH(2))FeI(X) (X = Cl or Br, respectively). Toluene coordination stabilises iron-mono hydride complexes as (((DIPP)C)(2)CH(2))Fe(II)H{eta(6)-(toluene)} species, which can be isolated in low yield from combination of borohydride salts and (((DIPP)C)(2)CH(2))FeI(2) in toluene, including an imidazole C4 deprotonated carbene-borane, methylene(N-DIPP-imidazole-2-ylidene)(N-DIPP-4-triethyl-borane imidazole-2-ylidene)](hydrido)(eta(6)-toluene)iron. In the absence of toluene, or at short reaction times compounds with empirical formula (((DIPP)C)(2)CH(2))Fe(H)(HB(R)(3)).LiI (R = Et or sec-Bu) that function as a masked Fe((II))-dihydride are isolated. Whilst (((DIPP)C)(2)CH(2))Fe(H)(HB(R)(3)).LiI was stable for days in Et(2)O, more polar solvents (MeCN, THF) led to formation of the carbene borane adducts (((DIPP)C)(2)CH(2))(BR(3))(2). The addition of CO or cyclo-heptylbromide to (((DIPP)C)(2)CH(2))Fe(H)(HB(R)(3)).LiI formed (((DIPP)C)(2)CH(2))Fe(CO)(3) and (((DIPP)C)(2)CH(2))FeBr(2), respectively with BR(3) evolved from both reactions as a by-product. PMID- 22234674 TI - Left ventricular endocardial pacing and multisite pacing to improve CRT response. AB - Cardiac resynchronization therapy (CRT) is an established treatment for patients with moderate-to-severe heart failure and a wide QRS complex. However, the amount of reverse remodeling and clinical improvement is highly variable and poorly predictable. The left ventricular pacing site is of critical importance for the CRT response but is often imposed by the coronary sinus anatomical constraints and may result in suboptimal resynchronization. Alternative pacing sites, such as endocardial LV pacing or multisite pacing, have been proposed to improve CRT response rates and may be considered in nonresponders to standard resynchronization. However, adequately powered randomized studies are required to determine whether these pacing strategies result in improved outcome. PMID- 22234676 TI - Protective effect of aqueous extract of Spinacia oleracea leaves in experimental paradigms of inflammatory bowel disease. AB - The present study was aimed to assess the protective effect of aqueous extract of Spinacia oleracea leaves (AESO 250, 500, and 1,000 mg/kg, p.o.) in inflammatory bowel disease using acetic acid- and ethanol-induced colitis in mice and indomethacin-induced enterocolitis in rats. The preliminary phytochemical analysis and further high performance thin layer chromatographic (HPTLC) analysis and phytochemical tests of HPTLC bands confirmed the presence of flavonoids and tannins in AESO. In acute oral toxicity study, administration of AESO (5,000 mg/kg, p.o.) did not show any sign of toxicity and mortality. The treatment with AESO significantly increased body weight, decreased diarrhea with bloody stools, increased blood hemoglobin and plasma total protein, and decreased serum and ileum or colon malondialdehyde content and attenuated the extent of lesions and ameliorated the histological injury of mucosa in all paradigms. The most prominent effects were evident for AESO 1,000 mg/kg. The results of the present study revealed that AESO was effective in attenuating almost all the symptoms of IBD in experimental paradigms. The effect might be due to the antioxidant activity of the flavonoids present in the AESO. PMID- 22234677 TI - Immunotoxicity of tannery effluent to the freshwater fish Cyprinous carpio. AB - This study was undertaken to determine the effect of chronic exposure to sub lethal concentrations of tannery effluent (TE) on the humoral antibody response and the cell-mediated immune response of the fish Cyprinous carpio. The LC(50) value of the TE for C. carpio was determined by bioassay to be 3.8%. Sub-lethal concentrations of TE (0.6% and 0.3%) significantly suppressed the humoral and cell-mediated immune responses. Exposure of C. carpio to the TE had a significant effect on mean acceptance time (MAT) for transplanted scales. MAT was found to be 5-8 days for autografts and 4-7 days for allografts. The somatic indices of the kidney and spleen were reduced compared with controls. PMID- 22234679 TI - Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database. AB - Few randomized trials have compared therapies in mantle cell lymphoma (MCL), and the role of aggressive induction is unclear. The National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma (NHL) Database, a prospective cohort study collecting clinical, treatment, and outcome data at 7 NCCN centers, provides a unique opportunity to compare the effectiveness of initial therapies in MCL. Patients younger than 65 diagnosed between 2000 and 2008 were included if they received RHCVAD (rituximab fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone), RCHOP+HDT/ASCR (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone + high-dose therapy/autologous stem cell rescue), RHCVAD+HDT/ASCR, or RCHOP. Clinical parameters were similar for patients treated with RHCVAD (n = 83, 50%), RCHOP+HDT/ASCR (n = 34, 20%), RCHOP (n = 29, 17%), or RHCVAD+HDT/ASCR (n = 21, 13%). Overall, 70 (42%) of the 167 patients progressed and 25 (15%) expired with a median follow-up of 33 months. There was no difference in progression-free survival (PFS) between aggressive regimens (P > .57), which all demonstrated superior PFS compared with RCHOP (P < .004). There was no difference in overall survival (OS) between the RHCVAD and RCHOP+HDT/ASCR (P = .98). RCHOP was inferior to RHCVAD and RCHOP+HDT/ASCR, which had similar PFS and OS. Despite aggressive regimens, the median PFS was 3 to 4 years. Future trials should focus on novel agents rather than comparing current approaches. PMID- 22234678 TI - The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. AB - Studies by the International Working Group showed that the prognosis of myelofibrosis patients is predicted by the Dynamic International Prognostic Scoring System (DIPSS) risk categorization, which includes patient age, constitutional symptoms, hemoglobin, leukocyte count, and circulating blasts. We evaluated the prognostic usefulness of the DIPSS in 170 patients with myelofibrosis, 12 to 78 years of age (median, 51.5 years of age), who received hematopoietic cell transplantation (HCT) between 1990 and 2009 from related (n = 86) or unrelated donors (n = 84). By DIPSS, 21 patients had low-risk disease, 48 had intermediate-1, 50 had intermediate-2, and 51 had high-risk disease. Five year incidence of relapse, relapse-free survival, overall survival, and nonrelapse mortality for all patients were 10%, 57%, 57%, and 34%, respectively. Among patients with DIPSS high-risk disease, the hazard ratio for post-HCT mortality was 4.11 (95% CI, 1.44-11.78; P = .008), and for nonrelapse mortality was 3.41 (95% CI, 1.15-10.09; P = .03) compared with low-risk patients. After a median follow-up of 5.9 years, the median survivals have not been reached for DIPSS risk groups low and intermediate-1, and were 7 and 2.5 years for intermediate-2 and high-risk patients, respectively. Thus, HCT was curative for a large proportion of patients with myelofibrosis, and post-HCT success was dependent on pre-HCT DIPSS classification. PMID- 22234680 TI - HIV-1 envelope-dependent restriction of CXCR4-using viruses in child but not adult untransformed CD4+ T-lymphocyte lines. AB - Phytohemagglutin-stimulated child and adult leukocytes equally supported CCR5 dependent (R5) and CXCR4-dependent (X4) HIV-1 replication. In contrast, when phytohemagglutin-stimulated leukocytes from either healthy or congenitally immunodeficient children were cultured on feeder cells, they well supported R5, but not X4 HIV-1 replication, whereas both viruses equally spread in adult cells maintained in similar conditions. Both child and adult cells showed similar levels of proliferation and surface expression of CD4, CCR5, CXCR4, CD25, CD69, and HLA-DR. Lack of X4 HIV-1 replication in child versus adult cells was not caused by a differential expression of several known HIV-1 restriction factors. Similar levels of HIV DNA synthesis occurred in child cells infected with R5 and X4 viruses up to 48 hours after infection when R5 HIV-1 showed a significantly superior capacity to spread in culture than X4 virus. Cultured child cells well supported single round vescicular stomatitis virus-G pseudotyped virus replication, whereas superinfection of R5-infected cells with X4 HIV-1 (or vice versa) rescued the replication of this latter virus. Thus, child cells exposed to feeder cell culture represent a novel model system in which the superior capacity of R5 versus X4 viruses to spread can be investigated in primary, untransformed CD4(+) cells. PMID- 22234681 TI - Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. AB - Role of interim-PET (I-PET) in diffuse large B-cell Lymphoma (DLBCL) is controversial. To determine predictive value of I-PET on progression-free survival (PFS), we enrolled 88 first-line DLBCL patients treated with 6-8 R-CHOP courses regardless of I-PET. PET/CT were performed at diagnosis, after 2 to 4 courses and at the end of therapy with central reviewing according to visual dichotomous criteria. Results are as follows: I-PET, 72% negative, 28% positive; final-PET (F-PET), 88% negative, 12% positive; clinical complete response 90%. Concordance between clinical response and F-PET negativity was 97% because of 2 false positive. With a median follow-up of 26.2 months, 2-year overall survival and PFS were 91% and 77%, respectively. Two-year PFS for I-PET and F-PET negative versus positive were as follows: I-PET 85% versus 72% (P = .0475); F-PET 83% versus 64% (P < .001). Because of a small number of events, 2 independent bivariate Cox models were tested for PFS. In model 1, F-PET contradicted I-PET (hazard ratio [HR] = 5.03, P = .015 vs 1.27, P = 691); in model 2, F-PET (HR = 4.54) and International propnostic Index score (HR = 5.36, P = .001) remained independent prognostic factors. In conclusion, positive I-PET is not predictive of a worse outcome in DLBCL; larger prospective studies and harmonization of I PET reading criteria are needed. PMID- 22234682 TI - Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study. AB - Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL. PMID- 22234683 TI - Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. AB - Essential thrombocythemia (ET) is characterized by enhanced platelet generation and thrombotic complications. Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A(2) (TXA(2)) in the majority of ET patients. In the present study, we investigated the determinants of aspirin-insensitive platelet TXA(2) biosynthesis and whether it could be further suppressed by changing the aspirin dose, formulation, or dosing interval. In 41 aspirin-treated ET patients, the immature platelet count predicted serum TXB(2) independently of platelet count, age, JAK-2 V617F mutation, or cytoreduction (beta = 3.53, P = .001). Twenty-one aspirin-treated patients with serum TXB(2) >= 4 ng/mL at 24 hours after dosing were randomized to the following 7-day regimens in a crossover design: enteric coated aspirin 100 mg twice daily, enteric-coated aspirin 200 mg once daily, or plain aspirin 100 mg once daily. A twice-daily regimen caused a further 88% median (IQR, 78%-92%, P < .001) TXB(2) reduction and normalized the functional platelet response to aspirin, as assessed by urinary 11-dehydro-TXB(2) excretion and the VerifyNow Aspirin assay. Doubling the aspirin dose reduced serum TXB(2) only partially by 39% median (IQR, 29%-54%, P < .05). We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1, and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose. PMID- 22234684 TI - Solulin increases clot stability in whole blood from humans and dogs with hemophilia. AB - Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)-deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)-dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor-initiated fibrin formation and tissue-plasminogen activator-induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/MUM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses. PMID- 22234685 TI - MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia. AB - MicroRNAs (miRNAs) play a key role in chronic lymphocytic leukemia as well as in normal B cells. Notably, miRNA gene encoding miR-650 and its homologs overlap with several variable (V) subgenes coding for lambda immunoglobulin (IgLlambda). Recent studies describe the role of miR-650 in solid tumors, but its role in chronic lymphocytic leukemia (CLL) has not yet been studied. Our experiments demonstrate that miR-650 expression is regulated by coupled expression with its host gene for IgLlambda. This coupling provides a unique yet unobserved mechanism for microRNA gene regulation. We determine that higher expression of miR-650 is associated with a favorable CLL prognosis and influences the proliferation capacity of B cells. We also establish that in B cells, miR-650 targets proteins important in cell proliferation and survival: cyclin dependent kinase 1 (CDK1), inhibitor of growth 4 (ING4), and early B-cell factor 3 (EBF3). This study underscores the importance of miR-650 in CLL biology and normal B-cell physiology. PMID- 22234686 TI - T-cell immunity to Kaposi sarcoma-associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells. AB - T-cell immunity is important for controlling Kaposi sarcoma-associated herpesvirus (KSHV) diseases such as the endothelial cell malignancy Kaposi sarcoma, or the B-cell malignancy, primary effusion lymphoma (PEL). However, little is known about KSHV-specific T-cell immunity in healthy donors and immune control of disease. Using PBMCs from healthy KSHV-infected donors, we found weak ex vivo responses to the KSHV latent antigens LANA, vFLIP, vCyclin, and Kaposin, with LANA most frequently recognized. CD4(+) T-cell clones specific to LANA, a protein expressed in all KSHV-infected cells and malignancies, were established to determine whether they could recognize LANA-expressing cells. B-cell targets expressing or fed LANA protein were consistently recognized by the clones; however, most PEL cell lines were not. PELs express the KSHV protein vIRF3 that inhibits promoter function of the HLA class II transactivator, decreasing expression of genes controlled by this transactivator. Re-expressing the class II transactivator in the PELs increased expression of downstream targets such as HLA class II and restored recognition but not killing by the LANA-specific clones. We suggest that PELs are poorly controlled in vivo because of inefficient recognition and killing by T cells. PMID- 22234687 TI - Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. AB - Routine incorporation of FISH into multiple myeloma (MM) diagnostic testing has led to a better appreciation of the heterogeneity of genetic abnormalities associated with this disease. We studied a group of 484 patients with newly diagnosed symptomatic MM to better understand the prevalence of the various abnormalities and the prognostic significance of the overlapping abnormalities. A translocation involving the IgH locus and 1 of the 5 recurrent partner chromosomes was seen in 161 (33%) patients, and 275 (57%) had trisomy of at least 1 odd-numbered chromosome. High-risk FISH, defined as the presence of t(4;14), t(14;16), t(14;20), or loss of P53, was seen in 115 (24%) patients; the median overall survival for this group was 3.9 years, compared with "not reached" for standard-risk patients (P < .001). Among the patients with high-risk FISH, 49 patients who also had at least 1 trisomy had a median overall survival that was not reached, compared with 3 years for high-risk patients without a concurrent trisomy (P = .01). Based on the current findings, we conclude that the presence of trisomies in patients with t(4;14), t(14;16), t(14;20), or p53 deletion abnormalities in MM ameliorates the usual adverse impact associated with these prognostic markers. PMID- 22234688 TI - Emerging role of serpinE2/protease nexin-1 in hemostasis and vascular biology. AB - Serine protease inhibitors, termed serpins, are key regulators in many biologic events. Protease nexin-1 (PN-1) is a serpin that is barely detectable in plasma but found in many organs and produced by most cell types, including monocytes, platelets, and vascular cells. It has a large inhibition spectrum because it is the most efficient tissue inhibitor of thrombin but also a powerful inhibitor of plasminogen activators and plasmin. It has a high affinity for glycosaminoglycans, such as heparan sulfates, which potentiate its activity toward thrombin and target it to the pericellular space. PN-1 has been previously largely described as a crucial regulator of the proteolytic activity in nerves and of central and peripheral nervous system function. In contrast, little was known about its involvement in hemostasis and vascular biology. This article reviews recent data underlining its emerging role as a key factor in the responses of vessels to injury. Indeed, studies of PN-1-deficient mice have established important antithrombotic and antifibrinolytic properties of this serpin that have heretofore gone unrecognized. The roles of PN-1 in the areas of hemostasis and thrombosis summarized here provide insights that may allow the development of drugs and treatment strategies to prevent or limit thrombotic disorders. PMID- 22234690 TI - Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). AB - Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD. PMID- 22234689 TI - Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. AB - STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2(V617F) failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2(V617F), and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs. PMID- 22234691 TI - Macrophage LRP1 contributes to the clearance of von Willebrand factor. AB - The relationship between low-density lipoprotein receptor-related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophage-specific deficiency of LRP1 (macLRP1( )) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1(-) mice compared with control mice (1.6 +/- 0.4 vs 1.0 +/- 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1(-) mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1(-) mice did not result in further rise of VWF levels (0.1 +/- 0.2 U/mL), in contrast to macLRP1(+) mice (rise in VWF, 0.8 +/- 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWF-coated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm(2), implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving beta2-integrins that binds both VWF and LRP1 also is implicated because inhibition of beta2-integrins led to increased VWF levels in control (rise, 0.19 +/- 0.16 U/mL) but not in macLRP1(-) mice (0.08 +/- 0.15 U/mL). PMID- 22234692 TI - Dendritic cell-mediated activation-induced cytidine deaminase (AID)-dependent induction of genomic instability in human myeloma. AB - Tumor microenvironment (TME) is commonly implicated in regulating the growth of tumors, but whether it can directly alter the genetics of tumors is not known. Genomic instability and dendritic cell (DC) infiltration are common features of several cancers, including multiple myeloma (MM). Mechanisms underlying genomic instability in MM are largely unknown. Here, we show that interaction between myeloma and DCs, but not monocytes, leads to rapid induction of the genomic mutator activation-induced cytidine deaminase (AID) and AID-dependent DNA double strand breaks (DSBs) in myeloma cell lines as well as primary MM cells. Both myeloid as well as plasmacytoid DCs have the capacity to induce AID in tumor cells. The induction of AID and DSBs in tumor cells by DCs requires DC-tumor contact and is inhibited by blockade of receptor activator of NF-kappaB/receptor activator of NF-kappaB ligand (RANKL) interactions. AID-mediated genomic damage led to altered tumorigenicity and indolent behavior of tumor cells in vivo. These data show a novel pathway for the capacity of DCs in the TME to regulate genomic integrity. DC-mediated induction of AID and resultant genomic damage may therefore serve as a double-edged sword and be targeted by approaches such as RANKL inhibition already in the clinic. PMID- 22234693 TI - Romiplostim administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of MYH9-RD. AB - Macrothrombocytopenia in MYH9-related disease (MYH9-RD) results from defects in nonmuscular myosin-IIA function. Thrombopoietin receptor agonists (eltrombopag; romiplostim) seem to improve hemostasis, but little is known about their biologic effects in MYH9-RD. We administered romiplostim to Myh9(-/-) mice (100 MUg/kg, every 3 days, during 1 month). MKs increased to similar numbers in Myh9(-/-) and wild-type (WT) mice (with an increase in immature MKs), but Myh9(-/-) platelet count response was much less (2.5-fold vs 8-fold increase). A strong increase in MK nuclei emboli in the lung, in WT and Myh9(-/-) mice, indicates increased transmigration of MKs from the BM. Prolonged (but not acute) treatment with romiplostim decreased expression of GPIb-IX-V complex and GPVI, but not of GPIIbIIIa, and bleeding time increased in WT mice. Microcirculation was not altered by the increased number of large platelets in any of the assessed organs, but in Myh9(-/-) mice a much stronger increase in BM reticulin fibers was present after 4 weeks of romiplostim treatment vs WT mice. These data further encourage short-term use of thrombopoietic agents in patients with MYH9-RDs; however, myelofibrosis has to be considered as a potential severe adverse effect during longer treatment. Reduction of GPIbIX/GPVI expression by romiplostim requires further studies. PMID- 22234694 TI - The C-type lectin receptor CLEC9A mediates antigen uptake and (cross )presentation by human blood BDCA3+ myeloid dendritic cells. AB - CLEC9A is a recently discovered C-type lectin receptor involved in sensing necrotic cells. In humans, this receptor is selectively expressed by BDCA3(+) myeloid dendritic cells (mDCs), which have been proposed to be the main human cross-presenting mDCs and may represent the human homologue of murine CD8(+) DCs. In mice, it was demonstrated that antigens delivered with antibodies to CLEC9A are presented by CD8(+) DCs to both CD4(+) and CD8(+) T cells and induce antitumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3(+) mDCs, which represent < 0.05% of peripheral blood leukocytes. We demonstrate that CLEC9A is only expressed on immature BDCA3(+) mDCs and that cell surface expression is lost after TLR mediated maturation. CLEC9A triggering via antibody binding rapidly induces receptor internalization but does not affect TLR-induced cytokine production or expression of costimulatory molecules. More importantly, antigens delivered via CLEC9A antibodies to BDCA3(+) mDCs are presented by both MHC class I (cross presentation) and MHC class II to antigen-specific T cells. We conclude that CLEC9A is a promising target for in vivo antigen delivery in humans to increase the efficiency of vaccines against infectious or malignant diseases. PMID- 22234695 TI - Recombinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen. AB - Leukemia cells from patients with chronic lymphocytic leukemia (CLL) express a highly restricted immunoglobulin heavy variable chain (IGHV) repertoire, suggesting that a limited set of antigens reacts with leukemic cells. Here, we evaluated the reactivity of a panel of different CLL recombinant antibodies (rAbs) encoded by the most commonly expressed IGHV genes with a panel of selected viral and bacterial pathogens. Six different CLL rAbs encoded by IGHV1-69 or IGHV3-21, but not a CLL rAb encoded by IGHV4-39 genes, reacted with a single protein of human cytomegalovirus (CMV). The CMV protein was identified as the large structural phosphoprotein pUL32. In contrast, none of the CLL rAbs bound to any other structure of CMV, adenovirus serotype 2, Salmonella enterica serovar Typhimurium, or of cells used for propagation of these microorganisms. Monoclonal antibodies or humanized rAbs of irrelevant specificity to pUL32 did not react with any of the proteins present in the different lysates. Still, rAbs encoded by a germ line IGHV1-69 51p1 allele from CMV-seropositive and -negative adults also reacted with pUL32. The observed reactivity of multiple different CLL rAbs and natural antibodies from CMV-seronegative adults with pUL32 is consistent with the properties of a superantigen. PMID- 22234696 TI - Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets. AB - Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein for the G-alpha-q and G-alpha-i subunits of heterotrimeric G-proteins that turns off signaling by G-protein coupled receptors. RGS18 is highly expressed in platelets. In the present study, we show that the 14-3-3gamma protein binds to phosphorylated serines 49 and 218 of RGS18. Platelet activation by thrombin, thromboxane A2, or ADP stimulates the association of 14-3-3 and RGS18, probably by increasing the phosphorylation of serine 49. In contrast, treatment of platelets with prostacyclin and nitric oxide, which trigger inhibitory cyclic nucleotide signaling involving cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI), induces the phosphorylation of serine 216 of RGS18 and the detachment of 14-3-3. Serine 216 phosphorylation is able to block 14-3-3 binding to RGS18 even in the presence of thrombin, thromboxane A2, or ADP. 14-3-3-deficient RGS18 is more active compared with 14-3 3-bound RGS18, leading to a more pronounced inhibition of thrombin-induced release of calcium ions from intracellular stores. Therefore, PKA- and PKGI mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signaling. These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq. PMID- 22234697 TI - Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling. AB - Prostaglandin E(2) (PGE(2)) is a lipid mediator that acts by ligating 4 distinct G protein-coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE(2) in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE(2) receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2 deficient (EP2(-/-)) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2(-/-) mice exhibited a higher percentage of F4/80(high)/CD11b(high) cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE(2) analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2(-/-) mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE(2)/EP2/protein kinase A signaling in the suppression of macrophage maturation. PMID- 22234698 TI - High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. AB - To identify cooperating lesions in core-binding factor acute myeloid leukemia, we performed single-nucleotide polymorphism-array analysis on 300 diagnostic and 41 relapse adult and pediatric leukemia samples. We identified a mean of 1.28 copy number alterations per case at diagnosis in both patient populations. Recurrent minimally deleted regions (MDRs) were identified at 7q36.1 (7.7%), 9q21.32 (5%), 11p13 (2.3%), and 17q11.2 (2%). Approximately one-half of the 7q deletions were detectable only by single-nucleotide polymorphism-array analysis because of their limited size. Sequence analysis of MLL3, contained within the 7q36.1 MDR, in 46 diagnostic samples revealed one truncating mutation in a leukemia lacking a 7q deletion. Recurrent focal gains were identified at 8q24.21 (4.7%) and 11q25 (1.7%), both containing a single noncoding RNA. Recurrent regions of copy-neutral loss-of-heterozygosity were identified at 1p (1%), 4q (0.7%), and 19p (0.7%), with known mutated cancer genes present in the minimally altered region of 1p (NRAS) and 4q (TET2). Analysis of relapse samples identified recurrent MDRs at 3q13.31 (12.2%), 5q (4.9%), and 17p (4.9%), with the 3q13.31 region containing only LSAMP, a putative tumor suppressor. Determining the role of these lesions in leukemogenesis and drug resistance should provide important insights into core binding factor acute myeloid leukemia. PMID- 22234700 TI - Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice. AB - Personalized immunotherapy of lymphoma based on tumor idiotype (Id) has shown anti-idiotype humoral immune responses in 40%-50% and cellular immune responses in 50%-75% of follicular lymphoma patients, indicating that this therapy can be clinically successful. We have developed a novel vaccine against lymphoma consisting of an anti-CD40 Ab (ADX40) chemically conjugated to the tumor idiotype A20 and tested it in a murine lymphoma model. BALB/c mice were immunized with 2 doses of immunogen alone or in conjunction with additional adjuvants before tumor challenge. ADX40-Id vaccination resulted in significantly retarded tumor growth and reduced mouse morbidity. Moreover, similar mouse survival was obtained with 2 injections of ADX40-Id as with 8 injections using the standard therapy of keyhole limpet hemocyanin Id + GM-CSF. Co-administration of ADX40-Id with 3-O-deacyl-4' monophosphoryl lipid A further significantly enhanced vaccine efficacy, resulting in an increased overall survival. Anti-Id-specific Abs were detected at elevated levels after ADX40-Id immunization; however, in vivo depletion of CD4 and/or CD8 T cells before challenge showed that CD8 effector T cells were the major mediators of tumor protection. The results of the present study show that the ADX40-Id conjugate vaccine is a potential candidate as a stand-alone vaccine or in combination with currently licensed adjuvants for lymphoma immunotherapy. PMID- 22234699 TI - p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes. AB - Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNFalpha, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNFalpha in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist-stimulated FANCC- and Fanconi anemia, complementation group A (FANCA)-deficient macrophages containing an NF-kappaB/AP-1-responsive reporter gene (SEAP). Of the 75 small molecules screened, the p38 MAPK inhibitor BIRB 796 and dasatinib potently suppressed TLR8-dependent expression of the reporter gene. Fanconi anemia (FA) macrophages were hypersensitive to the TLR7/8 activator R848, overproducing SEAP and TNFalpha in response to all doses of the agonist. Low doses (50nM) of both agents inhibited p38 MAPK-dependent activation of MAPKAPK2 (MK2) and suppressed MK2-dependent TNFalpha production without substantially influencing TNFalpha gene transcription. Overproduction of TNFalpha by primary FA cells was likewise suppressed by these agents and involved inhibition of MK2 activation. Because MK2 is also known to influence production and/or sensitivity to 2 other suppressive factors (MIP-1alpha and IFNgamma) to which FA hematopoietic progenitor cells are uniquely vulnerable, targeting of p38 MAPK in FA hematopoietic cells is a rational objective for preclinical evaluation. PMID- 22234701 TI - The IGHV1-69/IGHJ3 recombinations of unmutated CLL are distinct from those of normal B cells. AB - IGHV1-69/51p1 is expressed by ~ 30% of unmutated chronic lymphocytic leukemia (U CLL) and combines with selected IGHD and IGHJ genes generating stereotypes if HCDR3 amino acid homology is > 60%. We had previously revealed stereotypic IGHV1 69/IGHJ6 rearrangements in normal naive B cells, thereby identifying potential counterparts of U-CLL. A different stereotypic IGHV1-69/IGHD3-16(RF2)/IGHJ3 rearrangement carrying the CAR(GGx)YD motif in the N1-region, recurrent in 6% IGHV1-69+ve CLL, is exceptionally sequence restricted, strongly suggestive of shared antigen recognition. We have now analyzed IGHV1-69/IGHJ3 rearrangements in circulating B cells of healthy individuals using several PCR-based approaches with IGHV1-69/IGHJ3 CLL sequences for reference. Stereotypes were found, but all were distinct from CLL. Remarkably, even a highly sensitive semi-nested PCR, specific for the CLL-expressed IGHV1-69/IGHD3-16(RF2)/IGHJ3 stereotype, failed to identify the CAR(GGx)YD sequence, although similar motifs were found. These highly specific B cells are not apparent in the accessible normal repertoire and may expand in response to rarely expressed antigens important in the pathogenesis of CLL. PMID- 22234702 TI - Epigenetic modifications in cardiovascular disease. AB - Epigenetics represents a phenomenon of altered heritable phenotypic expression of genetic information occurring without changes in DNA sequence. Epigenetic modifications control embryonic development, differentiation and stem cell (re)programming. These modifications can be affected by exogenous stimuli (e.g., diabetic milieu, smoking) and oftentimes culminate in disease initiation. DNA methylation has been studied extensively and represents a well-understood epigenetic mechanism. During this process cytosine residues preceding a guanosine in the DNA sequence are methylated. CpG-islands are short-interspersed DNA sequences with clusters of CG sequences. The abnormal methylation of CpG islands in the promoter region of genes leads to a silencing of genetic information and finally to alteration of biological function. Emerging data suggest that these epigenetic modifications also impact on the development of cardiovascular disease. Histone modifications lead to the modulation of the expression of genetic information through modification of DNA accessibility. In addition, RNA based mechanisms (e.g., microRNAs and long non-coding RNAs) influence the development of disease. We here outline the recent work pertaining to epigenetic changes in a cardiovascular disease setting. PMID- 22234703 TI - Survivin in solid tumors: rationale for development of inhibitors. AB - Survivin is a 16.5 kDa protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Absent in most adult tissues, survivin is selectively upregulated in many human tumors, where its overexpression correlates with poor outcome and treatment resistance. Consequently, survivin is a promising target for cancer therapy. Preclinical data demonstrate that survivin inhibition reduces cell proliferation, increases apoptosis, and sensitises cells to cytotoxic agents and radiotherapy. The pharmacological survivin inhibitors LY2181308 and YM155 have demonstrated acceptable toxicity and evidence of therapeutic efficacy as single agents in early-phase clinical trials. Current efforts seek to define the optimum use of survivin inhibitors in combination with cytotoxic therapies, where it is hoped that preclinical evidence of treatment synergy will translate into improved therapeutic efficacy. Results from these ongoing studies are keenly awaited. PMID- 22234704 TI - Cementation and interface analysis of early failure cases after hip-resurfacing arthroplasty. AB - PURPOSE: The use of inappropriate cementation techniques has been suggested as an adverse factor for the long-term survival of hip-resurfacing arthroplasty. Inadequate initial fixation, thermal osteonecrosis and interface biological reactions are possible causes of failure. We analysed morphological changes associated with the cementation technique in a large collection of retrieved femoral components. METHODS: One hundred and fifty femoral components (mean time to failure of 8.3 months+/-11.0) obtained at revision surgery were analysed morphometrically and histopathologically. Cement mantle and penetration were quantified in six different regions of interest. Histopathological analysis of the bone-cement interface was performed on undecalcified processed bone tissue. RESULTS: The vast majority of the cases differed substantially from laboratory based cement-penetration depth recommendations. Fifty-nine cases had a fibrous membrane at the cement-bone interface. This membrane was significantly thicker in cases with osteonecrosis compared to cases viable bone. CONCLUSIONS: Our results demonstrate that most failures were cemented inappropriately. We suggest that poor cementation was an important adverse factor; however, the cause of the failures was obviously multifactorial. The thickness of the fibrous membrane at the cement-bone interface differed significantly between cases with osteonecrosis and specimens with viable bone tissue. PMID- 22234705 TI - Kyphotic deformity in spinal tuberculosis and its management. AB - Spinal tuberculosis is the most common cause of severe kyphosis in many parts of the world. Three percent of patients treated conservatively end up with a deformity greater than 60 degrees which can cause serious cosmetic, psychological, cardio-respiratory and neurological problems. Severe kyphotic deformities are usually the result of childhood spinal deformities and 'Spine at risk' radiological signs are helpful to identify children at risk of deformity. In children, a severe type of collapse, termed as 'Buckling Collapse' is also noted where the kyphosis is more than 120 degrees. Risk factors for buckling collapse include an age of less than seven years at the time of infection, thoracolumbar involvement, loss of more than two vertebral bodies and the presence of radiographic 'Spine-at-risk' signs. In correction of established deformity, posterior only surgery with a variety of osteotomies is now preferred. In patients with deformity of more than 90 degrees, an opening-closing wedge osteotomy must be done to prevent neurological deficit. PMID- 22234706 TI - Causes of a painful total knee arthroplasty. Are patients still receiving total knee arthroplasty for extrinsic pathologies? AB - PURPOSE: Whilst patients undergoing total knee replacements generally have good relief of their symptoms, up to 20% complain of persisting pain. Revision rates have therefore been rising, particularly so for unexplained pain. We reviewed the causes of painful total knee replacements including extrinsic causes. METHODS: Forty-five consecutive patients referred to our department with painful total knee replacement were reviewed with our standard protocol, including history and examination, inflammatory markers and radiological studies including radiographs of the hip and knee and computed tomography scan of the knee joint. RESULTS: Of the 45 patients, 15 patients had degenerative hip and lumbar spine disease which resolved after injections of the relevant joints. Nine patients had unexplained pain. CONCLUSIONS: Patients may still be undergoing knee arthroplasty for degenerative lumbar spine and hip osteoarthritis. We suggest heightened awareness at pre- and post-operative assessment and thorough history and examination with the use of diagnostic injections to identify the cause of pain if there is doubt. PMID- 22234708 TI - A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies. AB - Acquired haemophilia A (AHA) is caused by the development of factor (F)VIII autoantibodies, demonstrating type 1 or type 2 inhibitory behaviour, and results in more serious haemorrhagic symptoms than in congenital severe HA. The reason(s) for this remains unknown, however. The global coagulation assays, thrombin generation tests and clot waveform analysis, demonstrated that coagulation parameters in patients with AHA-type 2 inhibitor were more significantly depressed than those in patients with moderate HA with similar FVIII activities. Thrombin and intrinsic FXa generation tests were significantly depressed in AHA type 1 and AHA-type 2 compared to severe HA, and more defective in AHA-type 1 than in AHA-type 2. To investigate these inhibitory mechanism(s), anti-FVIII autoantibodies were purified from AHA plasmas. AHA-type 1 autoantibodies, containing an anti-C2 ESH4-epitope, blocked FVIII(a)-phospholipid binding, whilst AHA-type 2, containing an anti-C2 ESH8-epitope, inhibited thrombin-catalysed FVIII activation. The coagulation function in a reconstituted AHA-model containing exogenous ESH4 or ESH8 was more abnormal than in severe HA. The addition of anti-FIX antibody to FVIII-deficient plasma resulted in lower coagulation function than its absence. These results support the concept that global coagulation might be more suppressed in AHA than in severe HA due to the inhibition of FIXa-dependent FX activation by steric hindrance in the presence of FVIII-anti-C2 autoantibodies. Additionally, AHA-type 1 inhibitors prevented FVIIIa-phospholipid binding, essential for the tenase complex, whilst AHA-type 2 antibodies decreased FXa generation by inhibiting thrombin-catalysed FVIII activation. These two distinct mechanisms might, in part, contribute to and exacerbate the serious haemorrhagic symptoms in AHA. PMID- 22234709 TI - Effect of prosthetic ankle units on roll-over shape characteristics during walking in persons with bilateral transtibial amputations. AB - Some important walking functions are adversely affected or eliminated in prosthesis users because of reduced or absent ankle motion. This retrospective data analysis determined the effect of prosthetic ankle units on the characteristics of the ankle-foot roll-over shape in persons with bilateral transtibial amputations. Seventeen subjects were fitted with Endolite Multiflex Ankles to provide ankle plantar-/dorsiflexion during the stance phase of gait. Quantitative gait analyses were performed as subjects walked with (1) Seattle Lightfoot II feet (baseline condition) and (2) the prosthetic ankle units added. Roll-over shape radii and effective foot length ratio were calculated and compared for the two prosthetic configurations. When subjects walked with the ankle units, ankle motion increased (p < 0.001), peak ankle plantarflexion moment during stance decreased slightly, and ankle-foot roll-over shape radii were significantly decreased (p < 0.001) compared with the baseline condition. The effective foot length ratio of the roll-over shape was found to increase with walking speed (p < 0.001), but it was not significantly affected by the prosthetic ankle units (p = 0.07). Prosthetists and manufacturers are encouraged to consider the effect of combining prosthetic components on the overall characteristics of the prosthesis and the functions they impart to the user. PMID- 22234710 TI - Effects of type and mode of propulsion on hand-cycling biomechanics in nondisabled subjects. AB - This study investigated the range of motion (ROM) (in degrees) of the upper limb and trunk, forces (Newtons), two-dimensional fraction effective force (FEF(2D)) (in percent), and torque (Newton meters) during hand cycling. Seven nondisabled participants performed a 1 min exercise test at 70 rpm on a hand cycle (HC) fixed to an ergometer in synchronous (SC) mode versus asynchronous (AC) mode and in arm power (AP) versus arm-trunk-power (ATP) type of propulsion. Higher (p < 0.001) flexion/extension of the trunk was found during ATP versus AP type and higher (p < 0.001) lateral flexion and rotation of the trunk in AC versus SC mode. The trunk ROM should explain the different force generation patterns observed in this investigation between AC and SC modes and AP and ATP types. However, kinetic results do not allow the most effective type or mode of propulsion (FEF(2D): from 72.9% to 89.3%) to be established. We conclude that trunk movement is an important parameter to consider in ergonomically optimizing hand cycling. Nevertheless, future studies in experienced HC users, especially with limited trunk function, should be performed. PMID- 22234711 TI - IntellWheels: modular development platform for intelligent wheelchairs. AB - Intelligent wheelchairs (IWs) can become an important solution to the challenge of assisting individuals who have disabilities and are thus unable to perform their daily activities using classic powered wheelchairs. This article describes the concept and design of IntellWheels, a modular platform to facilitate the development of IWs through a multiagent system paradigm. In fact, modularity is achieved not only in the software perspective, but also through a generic hardware framework that was designed to fit, in a straightforward manner, almost any commercial powered wheelchair. Experimental results demonstrate the successful integration of all modules in the platform, providing safe motion to the IW. Furthermore, the results achieved with a prototype running in autonomous mode in simulated and mixed-reality environments also demonstrate the potential of our approach. Although some future research is still necessary to fully accomplish our objectives, preliminary tests have shown that IntellWheels will effectively reduce users' limitations, offering them a much more independent life. PMID- 22234713 TI - Self-management in neurological disorders: systematic review of the literature and potential interventions in multiple sclerosis care. AB - Our objective was to review the current body of evidence supporting the efficacy of self-management programs in individuals with multiple sclerosis (MS) and other chronic neurological conditions. We reviewed published literature using standardized search terms; examined self-management interventions in a variety of chronic neurological disorders, including MS; and classified studies using the evidence classification established by the American Academy of Neurology. We reviewed 527 abstracts, of which 39 met our inclusion criteria for evaluation. Of the 39 studies, 3 provided class I evidence assessing the efficacy of self management interventions: a randomized controlled trial of a telephone counseling program for health promotion in MS, a home-based exercise program for reducing falls in people with Parkinson disease, and the comparison of a fitness center program versus a home-based exercise program for people with traumatic brain injury. The remaining studies provided additional support for self-management interventions with a lesser degree of methodologic rigor (class II, class III, or class IV evidence). We concluded that self-management strategies are applicable to chronic neurological diseases, but a need exists for more rigorous studies in this area. We provide recommendations for future intervention study methodologies with a specific emphasis on MS care. PMID- 22234712 TI - Analyzing wheelchair mobility patterns of community-dwelling older adults. AB - This study determined and compared wheelchair mobility patterns for older adults during an organized sporting event and within their community. In July 2008, 39 veterans participating in the 28th National Veterans Wheelchair Games (Omaha, Nebraska) completed the study. Of these, 26 were manual wheelchair and 13 were power wheelchair users. We collected wheelchair-related mobility data using wheelchair data-logging devices. Participants were significantly more active using manual wheelchairs during the games than when using their wheelchairs in their homes in terms of distance traveled (4,466.2 vs 1,367.4 m, p < 0.001) and average speed of propulsion (0.76 vs 0.64 m/s, p < 0.001). The trend was the same for power wheelchair users, with respect to distance (7,306.2 vs 3,450.5 m, p = 0.004) and average speed (0.9 vs 0.7 m/s, p = 0.002). This study demonstrates an objective method of evaluating wheelchair use in community-dwelling older adults. PMID- 22234714 TI - Effect of depression on actual and perceived effects of reading rehabilitation for people with central vision loss. AB - To investigate the relationship between depression and quantitative measures of visual function, we recruited 18 subjects with central scotomas from macular degeneration who were enrolled in a reading rehabilitation program. Psychological batteries and reading assessments were administered prior to rehabilitation; reading assessments and a measure of adaptation to vision loss were administered following rehabilitation. We investigated relationships between reported levels of depressive symptoms and reading and adaptation outcome measures by using Pearson product moment correlation analysis. Results revealed a significant relationship between depression levels and reading acuity difference scores (r(16) = 0.54, p = 0.02) and changes in adaptation to vision loss levels (r(16) = 0.62, p = 0.01), suggesting that those who reported greater depressive symptoms did not respond as well functionally to reading rehabilitation but reported greater improvement in levels of adaptation to vision loss following rehabilitation. Future research should focus on defining standard methods to assess and remediate depression as part of the rehabilitation process. PMID- 22234715 TI - Effect of position feedback during task-oriented upper-limb training after stroke: five-case pilot study. AB - Feedback is an important element in motor learning during rehabilitation therapy following stroke. The objective of this pilot study was to better understand the effect of position feedback during task-oriented reach training of the upper limb in people with chronic stroke. Five subjects participated in the training for 30 minutes three times a week for 6 weeks. During training, subjects performed reaching movements over a predefined path. When deviation from this path occurred, shoulder and elbow joints received position feedback using restraining forces. We recorded the amount of position feedback used by each subject. During pre- and posttraining assessments, we collected data from clinical scales, isometric strength, and workspace of the arm. All subjects showed improvement on one or several kinematic variables during a circular motion task after training. One subject showed improvement on all clinical scales. Subjects required position feedback between 7.4% and 14.7% of training time. Although augmented feedback use was limited, kinematic outcome measures and movement performance during training increased in all subjects, which was comparable with other studies. Emphasis on movement errors at the moment they occur may possibly stimulate motor learning when movement tasks with sufficiently high levels of difficulty are applied. PMID- 22234716 TI - Complementary and alternative medicine use among veterans with chronic noncancer pain. AB - We describe prior use and willingness to try complementary and alternative medicine (CAM) among 401 veterans experiencing chronic noncancer pain and explore differences between CAM users and nonusers. Participants in a randomized controlled trial of a collaborative intervention for chronic pain from five Department of Veterans Affairs (VA) primary care clinics self-reported prior use and willingness to try chiropractic care, massage therapy, herbal medicines, and acupuncture. Prior CAM users were compared with nonusers on demographic characteristics, pain-related clinical characteristics, disease burden, and treatment satisfaction. A majority of veterans ( n = 327, 82%) reported prior use of at least one CAM modality, and nearly all (n = 399, 99%) were willing to try CAM treatment for pain. Chiropractic care was the least preferred option, whereas massage therapy was the most preferred (75% and 96%, respectively). CAM users were less likely to have service-connection disabilities (54% vs 68%; chi square = 4.64, p = 0.03) and reported having spent a larger percentage of their lives in pain (26% vs 20%; Z = 1.40, p = 0.04) than nonusers. We detected few differences between veterans who had tried CAM and those who had not, suggesting that CAM may have broad appeal among veterans with chronic pain. Implications for VA policy and practice and for clinicians treating veterans with chronic pain are discussed. PMID- 22234717 TI - Increasing physical activity in multiple sclerosis: replicating Internet intervention effects using objective and self-report outcomes. AB - Our previous research indicated that an Internet intervention was effective in increasing self-reported physical activity in persons with multiple sclerosis (MS). The present study examined the efficacy of the same Internet intervention in persons with MS by using both objective and self-report measures of physical activity. Participants (N = 21) wore an accelerometer around the waist for 7 days and then completed the International Physical Activity Questionnaire (IPAQ) and Godin Leisure-Time Exercise Questionnaire (GLTEQ) before and after receiving the 12-week Internet intervention. The Internet intervention resulted in moderate increases in accelerometer activity counts (d = 0.68) and steps counts (d = 0.60), and this was paralleled by small increases in IPAQ (d = 0.43) and GLTEQ (d = 0.34) scores. The number of weeks that persons logged on was correlated with change in accelerometer activity counts (r = 0.42) and step counts (r = 0.37) but not change in IPAQ (r = 0.10) or GLTEQ (r = 0.08) scores. The novel contribution of this study was the observation that an Internet intervention was efficacious for increasing physical activity in persons with MS by using both objective and self-report measures. PMID- 22234718 TI - Reliability and validity of trunk accelerometry-derived performance measurements in a standardized heel-rise test in elderly subjects. AB - This cross-sectional study evaluated the intrasession reliability and concurrent validity of trunk accelerometry (with force plate measurements) for vertical ground reaction force and external mechanical power recorded during a standardized heel-rise (HR) test in 54 elderly subjects (mean +/- standard deviation age 81.2 +/- 6.4 yr).Peak force as well as peak and average power revealed intraclass correlation coefficients of >0.75 and low standard errors of measurement for both the force plate- and the accelerometer-based curves. Correlation coefficients for these variables ranged from 0.95 to 0.98. The accelerometry-derived variables indicated significantly lower absolute values.Trunk accelerometry can be used as a reliable and valid tool for the quantification of the HR test in the elderly population. However, due to several limitations in the protocol, the use of this tool can currently only be recommended in a test-retest manner. Therefore, more research is needed to fully validate this tool for clinical use. PMID- 22234719 TI - Regulatory regions of SERPINC1 gene: identification of the first mutation associated with antithrombin deficiency. AB - Antithrombin is the main endogenous anticoagulant. Impaired function or deficiency of this molecule significantly increases the risk of thrombosis. We studied the genetic variability of SERPINC1 , the gene encoding antithrombin, to identify mutations affecting regulatory regions with functional effect on its levels. We sequenced 15,375 bp of this gene, including the potential promoter region, in three groups of subjects: five healthy subjects with antithrombin levels in the lowest (75%) and highest (115%) ranges of our population, 14 patients with venous thrombosis and a moderate antithrombin deficiency as the single thrombophilic defect, and two families with type I antithrombin deficiency who had neither mutations affecting exons or flanking regions, nor gross gene deletions. Our study confirmed the low genetic variability of SERPINC1 , particularly in the coding region, and its minor influence in the heterogeneity of antithrombin levels. Interestingly, in one family, we identified a g.2143 C>G transversion, located 170 bp upstream from the translation initiation codon. This mutation affected one of the four regions located in the minimal promoter that have potential regulatory activity according to previous DNase footprinting protection assays. Genotype-phenotype analysis in the affected family and reporter analysis in different hepatic cell lines demonstrated that this mutation significantly impaired, although it did not abolish, the downstream transcription. Therefore, this is the first mutation affecting a regulatory region of the SERPINC1 gene associated with antithrombin deficiency. Our results strongly sustain the inclusion of the promoter region of SERPINC1 in the molecular analysis of patients with antithrombin deficiency. PMID- 22234720 TI - Multilevel oblique corpectomy for cervical spondylotic myelopathy preserves segmental motion. AB - PURPOSE: To document the neurological outcome, spinal alignment and segmental range of movement after oblique cervical corpectomy (OCC) for cervical compressive myelopathy. METHODS: This retrospective study included 109 patients- 93 with cervical spondylotic myelopathy and 16 with ossified posterior longitudinal ligament in whom spinal curvature and range of segmental movements were assessed on neutral and dynamic cervical radiographs. Neurological function was measured by Nurick's grade and modified Japanese Orthopedic Association (JOA) scores. Eighty-eight patients (81%) underwent either a single- or two-level corpectomy; the remaining (19%) undergoing three- or four-level corpectomies. The average duration of follow-up was 30.52 months. RESULTS: The Nurick's grade and the JOA scores showed statistically significant improvements after surgery (p < 0.001). The mean postoperative segmental angle in the neutral position straightened by 4.7 +/- 6.5 degrees . The residual segmental range of movement for a single-level corpectomy was 16.7 degrees (59.7% of the preoperative value), for two-level corpectomy it was 20.0 degrees (67.2%) and for three-level corpectomies it was 22.9 degrees (74.3%). 63% of patients with lordotic spines continued to have lordosis postoperatively while only one became kyphotic without clinical worsening. Four patients with preoperative kyphotic spines showed no change in spine curvature. None developed spinal instability. CONCLUSIONS: The OCC preserves segmental motion in the short-term, however, the tendency towards straightening of the spine, albeit without clinical worsening, warrants serial follow-up imaging to determine whether this motion preservation is long lasting. PMID- 22234721 TI - Drug overdose resulting in quadriplegia. AB - PURPOSE: To describe a case of cervical flexion myelopathy resulting from a drug overdose. METHODS: A 56-year-old male presented to the emergency department unable to move his extremities following drug overdose. Neurological examination revealed him to be at C6 ASIA A spinal cord injury. The CT of his cervical spine revealed no fracture; however, an MRI revealed cord edema extending from C3 to C6 as well as posterior paraspinal signal abnormalities suggestive of ligamentous injury. RESULTS: The patient underwent a posterior cervical laminectomy and fusion from C3 to C7. Neurologically he regained 3/5 bilateral tricep function and 2/5 grip; otherwise, he remained at ASIA A spinal cord injury at 6 months. CONCLUSION: Our patient suffered a spinal cord injury likely due to existing cervical stenosis, and in addition to an overdose of sedating medications, he likely sat in flexed neck position for prolonged period of time with the inability to modify his position. This likely resulted in cervical spine vascular and/or neurological compromise producing an irreversible spinal cord injury. Spinal cord injury is a rare finding in patients presenting with drug overdose. The lack of physical exam findings suggestive of trauma may delay prompt diagnosis and treatment, and thus clinicians must have a high index of suspicion when evaluating patients in this setting. PMID- 22234722 TI - Continuing conservative care versus crossover to radiofrequency kyphoplasty: a comparative effectiveness study on the treatment of vertebral body fractures. AB - BACKGROUND: There is controversy about how to treat vertebral fractures. Conservative care is the default approach. Radiofrequency kyphoplasty uses ultrahigh viscosity cement to restore spinal posture and stabilize the fracture. The aims of this study were to compare radiofrequency kyphoplasty to conservative care and assess the usual algorithm of starting all patients on conservative care for 6 weeks before offering surgery. METHODS: Elderly patients with painful osteoporotic vertebral compression fractures were all treated with 6 weeks of conservative care (analgesics, bracing, and physiotherapy). They were then offered the choice of continuing conservative care or crossing over to radiofrequency kyphoplasty, at 6 and 12 weeks. Clinical success was defined as: (1) VAS pain improvement >=2, (2) final VAS pain <=5, (3) no functional worsening on ODI. RESULTS: After the initial 6 weeks of conservative care, only 1 of 65 patients met the criteria for clinical success, and median VAS improvement was 0. After 12 weeks of conservative care, only 5 of 38 patients met the criteria for clinical success, and median VAS improvement was 1. At the 6-week follow-up after radiofrequency kyphoplasty, 31 of 33 surgery patients met the criteria for clinical success, and median VAS improvement was 5. CONCLUSION: For the vast majority of patients with a VAS >=5, conservative care did not provide meaningful clinical improvement. In contrast, nearly all patients who underwent radiofrequency kyphoplasty had rapid substantial improvement. Surgery was clearly much more effective than conservative care and should be offered to patients much sooner. PMID- 22234724 TI - Intramolecular folding in three tandem guanine repeats of human telomeric DNA. AB - Intramolecular folding in three tandem guanine repeats of human telomeric DNA has been investigated using optical-tweezers, MD simulation and circular dichroism. A mechanically and thermodynamically stable species in this sequence shows a structure consistent with a triplex conformation. A similar species has also been observed to coexist with a G-quadruplex in a DNA sequence with four tandem guanine repeats. PMID- 22234723 TI - 360-degree osteosynthesis via a posterolateral transpedicular approach in high risk patients. AB - PURPOSE: Patients requiring anterior-posterior thoracic spine stabilization and suffering from concomitant cardiopulmonary disease are at increased risk to develop procedure-related complications. In order to reduce cardiopulmonary complications, the efficacy of a posterolateral transpedicular approach for 360 degree fusion was investigated. METHODS: Fourteen consecutive patients presenting with spinal cord compression from osteoporotic, metastatic and tuberculotic fractures were treated. Spinal cord decompression was achieved by laminectomy, facetectomy and corpectomy with subsequent posterior instrumented fusion using a screw-rod system. RESULTS: The procedure was successfully performed in 14 high risk patients. Preoperatively, all patients presented with thoracic and lower back pain and nine patients with a paraparesis (Frankel grade C). The implants were introduced monoportally or biportally. In all cases, neurological symptoms moderately improved. CONCLUSION: The posterolateral transpedicular approach might be a safe, less-invasive and efficient alternative to anterior-posterior fusion. However, biomechanic efficacy and long-term outcome as compared to the transthoracic technique remains to be studied in a larger patient cohort. PMID- 22234725 TI - Kinetic modeling of free fatty acid production in Escherichia coli based on continuous cultivation of a plasmid free strain. AB - The microbial production of free fatty acids (FFAs) and reduced derivatives is an attractive process for the renewable production of diesel fuels. Toward this goal, a plasmid-free strain of Escherichia coli was engineered to produce FFAs by integrating three copies of a thioesterase gene from Umbellularia californica (BTE) under the control of an inducible promoter onto the chromosome. In batch culture, the resulting strain produced identical titers to a previously reported strain that expressed the thioesterase from a plasmid. The growth rate, glucose consumption rate, and FFA production rate of this strain were studied in continuous cultivation under carbon limitation. The highest yield of FFA on glucose was observed at a dilution rate of 0.05 h(-1) with the highest specific productivity observed at a dilution rate of 0.2 h(-1). The observed yields under the lowest dilution rate were 15% higher than that observed in batch cultures. An increase in both productivity and yield (~ 40%) was observed when the composition of the nutrients was altered to shift the culture toward non-carbon limitation. A deterministic model of the production strain has been proposed and indicates that maintenance requirements for this strain are significantly higher than wild-type E. coli. PMID- 22234726 TI - Lung cancer risk in subjects exposed to organic dust: an unexpected and surprising story. PMID- 22234727 TI - Evidence for a national problem: continued rise in tuberculosis case numbers in urban areas outside London. AB - WHO standards for tuberculosis (TB) control require monitoring and evaluation of TB control programmes. In London, TB rates have stabilised at 44 per 100,000 since 2005. In 38 urban areas outside London with TB rates above the national average, these continued to rise after 2004, to 28 per 100,000 in 2008 (15% increase). London has the highest proportion of TB cases in certain risk groups, but these are increasing rapidly outside London. Many TB control efforts focus on the capital, but with rates rising elsewhere in the country, this strategy is likely to fail in the long term. PMID- 22234728 TI - Interactions between migraine and tension-type headache and alcohol drinking, alcohol flushing, and hangover in Japanese. AB - The aim of the study was to investigate associations between headache types and alcohol drinking, alcohol flushing, and hangover. Alcohol consumption is inhibited by the presence of inactive aldehyde dehydrogenase-2 (ALDH2) whose carriers are susceptible to alcohol flushing and hangovers. We conducted a cross sectional study of the 2,577 subjects (men/women: 1,018/1,559) who reported having ever experienced headaches unrelated to common colds and alcohol hangovers among 5,408 (2,778/2,630) Tokyo health checkup examinees. We used a questionnaire inquiring about current and past facial flushing after drinking a glass of beer which identifies the presence of inactive ALDH2 with a sensitivity and specificity of approximately 90%. Based on ICHD-II criteria migraine was diagnosed in 419 (75/344) subjects, and tension-type headache (TTH) in 613 (249/364). We classified the headaches of the remaining 1,545 (694/851) of headaches sufferers into the category "other headaches (OH)". The migraineurs drank alcohol less frequently than the subjects with TTH among current/past alcohol flushers and than the subjects with OH regardless of flushing category. No such difference in drinking frequency was observed between TTH and OH. Current/past flushers drank alcohol less frequently than never flushers, and the likelihood that male migraineurs would avoid alcohol drinking than men with TTH or OH was stronger among current/past flushers than among never flushers. Flushers and women were more susceptible to hangover than never flushers and men, respectively, regardless of headache type. Among never flushers, women with migraine were more susceptible to hangover than women with OH. The difference in alcohol sensitivity may partly explain less alcohol consumption by migraineurs. PMID- 22234729 TI - Dual wavelength tumor targeting for detection of hypopharyngeal cancer using near infrared optical imaging in an animal model. AB - Optical imaging is a promising technique to visualize cancer tissue during surgery. In this study, we explored the use of combinations of near-infrared (NIR) fluorescence agents that emit fluorescence signal at different wavelengths and each target specific tumor characteristics. Two combinations of agents (ProSense680 combined with 2DG CW800 and MMPSense680 combined with EGF CW800) were used to detect hypopharyngeal cancer in an animal model. ProSense680 and MMPSense680 detect increased activity of cathepsins and matrix metalloproteinases, respectively. These enzymes are mainly found in the invasive tumor border due to degradation of the extracellular matrix. 2DG CW800 detects tumor cells with high glucose metabolism and EGF CW800 is internalized by the epidermal growth factor receptor of tumor cells. Whole-body imaging revealed clear demarcation of tumor tissue using all four agents. The tumor-to-background ratio (standard deviation, p-value) was 3.69 (0.72, p < 0.001) for ProSense680; 4.26 (1.33, p < 0.001) for MMPSense680; 5.81 (3.59, p = 0.02) for 2DG CW800 and 4.84 (1.56, p < 0.001) for EGF CW800. Fluorescence signal corresponded with histopathology and immunohistochemistry, demonstrating signal of ProSense680 and MMPSense680 in the invasive tumor border, and signal of 2DG CW800 and EGF CW800 in the tumor tissue. In conclusion, we demonstrated the feasibility of dual wavelength tumor detection using different targeting strategies simultaneously in an animal model. Combined targeting at different wavelengths allowed simultaneous imaging of different tumor characteristics. NIR fluorescence optical imaging has the potential to be translated into the clinic in order to improve the complete removal of tumors by real-time image-guided surgery. PMID- 22234731 TI - Intrathecal baclofen pump: a foreign-body reaction case report and its solution. AB - CASE REPORT: A 43-year-old woman with cerebral palsy and disabling spasticity underwent a series of 4 implantations of intrathecal baclofen pumps, performed by two teams. A history of 3 aseptic local skin reactions over the site of insertion started 4 months after the first insertion, once with partial pump exposure. There were no clinical or biological signs of infection. Skin patch tests were negative. Relocation of the system was followed by a relapse, while removal of the pump was followed each time by complete resolution of the symptoms. Histological findings showed slight mononuclear dermal infiltration without epidermal lesions, which excluded contact dermatitis. Pump intolerance with a foreign-body reaction was diagnosed. A pump wrapped with polyethylene terephthalate was reimplanted. No recurrence of symptoms occurred after a 3-year follow-up period, with improvement in impairment, activity and satisfaction due to intrathecal baclofen therapy. CONCLUSION: A foreign-body reaction after intrathecal baclofen pump implantation is a rare complication, which has not been reported previously, and which is associated with negative skin patch tests. In cases with no signs of infection, skin intolerance must be suspected and dermatological assessments should be carried out. Replacement with a pump wrapped in an inert coating is an effective and available solution. PMID- 22234732 TI - On the modeling of aggregates of an optically active regioregular polythiophene. AB - The conformational properties of the optically active regioregular poly[(R)-3-(4 (4-ethyl-2-oxazolin-2-yl) phenyl) thiophene] (PEOPT) were explored by molecular dynamics on a single chain using several solvents of increasing polarity. Furthermore, their aggregate formation was studied over a wide range of temperatures using a replica exchange molecular dynamics simulation providing simulation data representative of the equilibrium behaviour of their aggregates. Results show a clear tendency of PEOPT to keep a syn-gauche conformation between continuous backbone thiophene rings favouring a bent chain structure in solvent. After studying their aggregation behaviour in acetonitrile, a strong tendency to pack stabilizing structures that reinforce the chirality of the polymer, in concordance with experimental data, was found. Two different aggregated structures were observed depending on oligomer length, a self-assembled helical aggregate based on stacked octamers and a bent double helix aggregate in large oligomers. PMID- 22234733 TI - Seasonal source influence on river mass flows of benzotriazoles. AB - The anticorrosive agents 1H-benzotriazole (1H-BT), 4-methyl-1H-benzotriazole (4 Me-BT) and 5-methyl-1H-benzotriazole (5 Me-BT), which are usually added to dishwasher detergents, automotive antifreeze formulations and aircraft de icing/anti-icing fluids (ADAFs), were measured in river water. Samples were collected from 15 sampling sites in the mainstream and selected tributaries of a medium-sized catchment area during summer and winter periods. The aim of this study was to assess a seasonal source influence on mass flows of benzotriazoles (BTs). The study area was representatively selected for an area with a possible influence of airport surface runoff. River discharge measurements were also performed. Moreover, BT concentrations were measured in an anti-icing and a de icing fluid used at German airports as well as in several dishwasher detergents. The highest concentrations of all three compounds in river water were measured during the winter seasons. The maximum BT mass flows were calculated for all three substances in January when the mean monthly air temperature was the lowest; mass flows were the lowest in July when the mean monthly air temperature was the highest. A significant seasonal influence on BT mass flows in river water was observed for monitoring stations with a possible influence of airport surface runoff and for sampling locations where such an influence could be excluded. This indicates an input of BTs from other temperature-dependent applications, e.g. the use of antifreeze formulations in automotive windscreen wiper or cooling systems. 1H-BT was detected in two dishwasher tablets; 4 Me-BT and 5 Me-BT were not detected. BTs were measured in the anti-icing fluid with concentrations of 715 ng g(-1) (1H-BT), 1425 ng g(-1) (4 Me-BT) and 536 ng g(-1) (5 Me-BT); none of the BTs were detected in the de-icing fluid. Distribution patterns of BTs in ADAF and dishwasher detergents differed from those in river water. PMID- 22234734 TI - The role of serology in active ocular toxoplasmosis. AB - Our purpose was to examine toxoplasmic serology in relation to episodes of suspected acute toxoplasmic retinochoroiditis and evaluate its use in the appraisal of patients. The mean values of enzymatic immunoassay (EIA) titers for toxoplasmic antibodies were retrospectively compared in patients with active and inactive toxoplasmosis and in a third group of uveitis cases not caused by toxoplasmosis. The proportion of cases under and above a predefined serology value above cut-off was compared in all groups. Between 1995 and 2010, 97 out of 1,276 new uveitis cases seen at the Centre for Ophthalmic Specialized Care (COS), Lausanne, Switzerland were diagnosed as toxoplasmic retinochoroiditis, of which 51 had documented serology available. The mean EIA values for immunoglobulin (Ig) G were 147.75 +/- 259.4 IU/ml for patients with active disease, 18.93 +/- 23.09 (p < 0.05) for patients with inactive toxoplasmosis and 18.35 +/- 20.82 for controls (p < 0.017). The proportion of cases under the designated limit value were 2/51 (4%) in the active retinitinochoroiditis group, 14/27 (52%) (p < 0.05) in the control group, and 7/7 (100%) in the inactive toxoplasmic group (p < 0.001). Three out of 51 cases showed high IgM values in addition to IgG elevation and were primary infections. Toxoplasmosis serology, contrary to popular belief, is useful to confirm active toxoplasmic retinochoroiditis; it is easy to perform, cheap and supports clinical diagnosis in up to 96% of cases, not only by showing positivity but by also showing a significant elevation of titers. In atypical cases serology is not only useful but essential. PMID- 22234735 TI - Expression of three sHSP genes involved in heat pretreatment-induced chilling tolerance in banana fruit. AB - BACKGROUND: Banana fruit is highly susceptible to chilling injury. In previous research it was shown that heat pretreatment of banana fruit at 38 degrees C for 3 days before storage at a chilling temperature of 8 degrees C for 12 days prevented increases in visible chilling injury index, electrolyte leakage and malondialdehyde content and also decreases in lightness and chroma, indicating that heat pretreatment could effectively alleviate chilling injury of banana fruit. However, little is known about the role of small heat shock proteins (sHSPs) in postharvest chilling tolerance of banana fruit. In the present study, three cytosolic sHSP expression profiles in peel and pulp tissues of banana fruit during heat pretreatment and subsequent chilled storage (8 degrees C) were investigated in relation to heat pretreatment-induced chilling tolerance. RESULTS: Three full-length cDNAs of cytosolic sHSP genes, including two class I sHSP (CI sHSP) and one class II sHSP (CII sHSP) cDNAs, named Ma-CI sHSP1, Ma-CI sHSP2 and Ma-CII sHSP3 respectively, were isolated and characterised from harvested banana fruit. Accumulation of Ma-CI sHSP1 mRNA transcripts in peel and pulp tissues and Ma-CII sHSP3 mRNA transcripts in peel tissue increased during heat pretreatment. Expression of all three Ma-sHSP genes in peel and pulp tissues was induced during subsequent chilled storage. Furthermore, Ma-CI sHSP1 and Ma CII sHSP3 mRNA transcripts in pulp tissue and Ma-CI sHSP2 mRNA transcripts in peel and pulp tissues were obviously enhanced by heat pretreatment at days 6 and 9 of subsequent chilled storage. CONCLUSION: These results suggested that heat pretreatment enhanced the expression of Ma-sHSPs, which might be involved in heat pretreatment-induced chilling tolerance of banana fruit. PMID- 22234737 TI - Preferences for cancer treatments: an overview of methods and applications in oncology. AB - This review provides cancer clinicians and researchers with an overview of methods for assessing preferences, with examples and recommendations for their application in oncology. Decisions about cancer treatments involve trade-offs between their relative benefits and harms. An individual's preference for a cancer treatment reflects their evaluation of the relative benefits and harms in comparison with a given alternative or alternatives. Methods of preference assessment include the ranking or rating scale, standard gamble (SG), time trade off (TTO), visual analogue scale, discrete choice experiment (DCE), and multi attribute utility instrument (MAUI). The choice of method depends on the purpose of preference assessment; the ranking or rating scale, SG, TTO, and DCEs are best suited to clinical decisions, whereas MAUIs are best suited to health policy decisions. Knowledge of patients' preferences for cancer treatments can better inform clinical decisions about patient management by enabling the tailoring of decisions to individual patients' values, attitudes, and priorities and health policy decisions through economic evaluations of cancer treatments and their suitability for coverage by health payers. PMID- 22234736 TI - Effects of different tidal volumes in pulmonary and extrapulmonary lung injury with or without intraabdominal hypertension. AB - PURPOSE: We hypothesized that: (1) intraabdominal hypertension increases pulmonary inflammatory and fibrogenic responses in acute lung injury (ALI); (2) in the presence of intraabdominal hypertension, higher tidal volume reduces lung damage in extrapulmonary ALI, but not in pulmonary ALI. METHODS: Wistar rats were randomly allocated to receive Escherichia coli lipopolysaccharide intratracheally (pulmonary ALI) or intraperitoneally (extrapulmonary ALI). After 24 h, animals were randomized into subgroups without or with intraabdominal hypertension (15 mmHg) and ventilated with positive end expiratory pressure = 5 cmH(2)O and tidal volume of 6 or 10 ml/kg during 1 h. Lung and chest wall mechanics, arterial blood gases, lung and distal organ histology, and interleukin (IL)-1beta, IL-6, caspase 3 and type III procollagen (PCIII) mRNA expressions in lung tissue were analyzed. RESULTS: With intraabdominal hypertension, (1) chest-wall static elastance increased, and PCIII, IL-1beta, IL-6, and caspase-3 expressions were more pronounced than in animals with normal intraabdominal pressure in both ALI groups; (2) in extrapulmonary ALI, higher tidal volume was associated with decreased atelectasis, and lower IL-6 and caspase-3 expressions; (3) in pulmonary ALI, higher tidal volume led to higher IL-6 expression; and (4) in pulmonary ALI, liver, kidney, and villi cell apoptosis was increased, but not affected by tidal volume. CONCLUSIONS: Intraabdominal hypertension increased inflammation and fibrogenesis in the lung independent of ALI etiology. In extrapulmonary ALI associated with intraabdominal hypertension, higher tidal volume improved lung morphometry with lower inflammation in lung tissue. Conversely, in pulmonary ALI associated with intraabdominal hypertension, higher tidal volume increased IL-6 expression. PMID- 22234738 TI - Dietary fiber and breast cancer risk: a systematic review and meta-analysis of prospective studies. AB - BACKGROUND: Evidence from case-control studies suggest that dietary fiber may be inversely related to breast cancer risk, but it is unclear if this is supported by prospective data. We conducted a systematic review and meta-analysis of the evidence from prospective studies. METHODS: PubMed was searched for prospective studies of fiber intake and breast cancer risk until 31st August 2011. Random effects models were used to estimate summary relative risks (RRs). RESULTS: Sixteen prospective studies were included. The summary RR for the highest versus the lowest intake was 0.93 [95% confidence interval (CI) 0.89-0.98, I(2) = 0%] for dietary fiber, 0.95 (95% CI 0.86-1.06, I(2) = 4%) for fruit fiber, 0.99 (95% CI 0.92-1.07, I(2) = 1%) for vegetable fiber, 0.96 (95% CI 0.90-1.02, I(2) = 5%) for cereal fiber, 0.91 (95% CI 0.84-0.99, I(2) = 7%) for soluble fiber and 0.95 (95% CI 0.89-1.02, I(2) = 0%) for insoluble fiber. The summary RR per 10 g/day of dietary fiber was 0.95 (95% CI 0.91-0.98, I(2) = 0%, P(heterogeneity) = 0.82). In stratified analyses, the inverse association was only observed among studies with a large range (>=13 g/day) or high level of intake (>=25 g/day). CONCLUSION: In this meta-analysis of prospective studies, there was an inverse association between dietary fiber intake and breast cancer risk. PMID- 22234740 TI - The posterolateral approach for plating tibial plateau fractures: problems in secondary hardware removal. PMID- 22234739 TI - Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008-02). AB - BACKGROUND: Preclinical studies suggest that insulin-like growth factor-1 receptor (IGF-1R) blockage could be a promising therapeutic target in squamous cell carcinoma of the head and neck (SCCHN). Therefore, we investigated the efficacy and toxicity of figitumumab, an anti-IGF-1R monoclonal antibody, in palliative SCCHN. PATIENTS AND METHODS: Patients with palliative SCCHN progressing after platinum-based therapy were treated with figitumumab i.v. 20 mg/kg, every 3 weeks. The primary end point was the disease control rate at 6-8 weeks after treatment initiation. Tumor biopsies and plasma samples were collected before and after figitumumab administration to monitor the molecular response. RESULTS: Seventeen patients were included. Only two patients achieved stable disease at 6-8 weeks. Median overall survival and progression-free survival were 63 and 52 days, respectively. The main grade 3-4 adverse event was hyperglycemia (41%). Translational research showed that figitumumab downregulated IGF-1R at the surface of tumor cells with activation of the epidermal growth factor receptor (EGFR) pathway, as shown by the upregulation of p-EGFR in tumor cells (P=0.016), and an increase in the plasma level of tumor growth factor-alpha (P=0.006). CONCLUSION: Figitumumab monotherapy has no clinically significant activity in unselected palliative SCCHN. PMID- 22234741 TI - Sclerostin: therapeutic horizons based upon its actions. AB - Inactivating mutations of the SOST gene cause a reduction in sclerostin levels and are associated with high bone mass. The clinical phenotypes, sclerosteosis and van Buchem's disease, were described in 1950s. Much later, it was learned that both diseases are due to loss-of-function mutations in the SOST gene. As a regulator of an important osteoanabolic pathway, Wnt, inactivation of SOST leads to a stimulation of the pathway it regulates. The high bone mass in patients with either sclerosteosis or van Buchem's disease is associated with unusual skeletal strength; they do not fracture. Knowledge of this molecule and its actions led rather quickly to the development of anti-sclerostin antibodies that lead to marked increases in bone mass in both animals and human subjects. Blocking sclerostin action with anti-sclerostin antibodies is a promising new therapeutic approach to osteoanabolic therapy of osteoporosis. PMID- 22234742 TI - Nationwide survey on adult type chronic intestinal pseudo-obstruction in surgical institutions in Japan. AB - BACKGROUND: No appropriate management of chronic intestinal pseudo-obstruction (CIP) has been established. PATIENTS AND METHODS: The clinicopathological parameters of 103 cases collected by a nationwide questionnaire study were reviewed. RESULTS: The CIP cases were primary in 86 (83%) cases and secondary in 15 (15%) cases. The age of onset of the primary type was significantly younger than that of the secondary type (p = 0.011). The diseased segments of the bowel were the large bowel in 60 (58%), the small bowel in 17 (17%), and both in 23 (22%) cases, respectively. Abdominal distension and pain were common symptoms regardless of the types of the diseased bowel; however, constipation was frequently seen in the large bowel type (p = 0.0258). Vomiting and diarrhea were seen with marginally higher frequency in the small bowel type (p = 0.0569, 0.0642). Surgical treatment was most effective in the large bowel type, less effective in the small bowel type, and least effective in the large and small bowel type. The prognosis of the primary CIP was significantly better than that of the secondary CIP (p = 0.033). CONCLUSIONS: The segments of the diseased bowels should be considered in determining the indications for surgical treatments in CIP patients. PMID- 22234743 TI - Differences in sensitivity to tumor-specific CTLs between primary and metastatic esophageal cancer cell lines derived from the same patient. AB - PURPOSE: MHC antigens and adhesion molecules, such as the intracellular adhesion molecule (ICAM-I), play an important role in cellular immune response. We examined the expression patterns of these molecules in both primary and metastatic esophageal carcinoma cells from the same patient and evaluated the cellular immune responses against these cells. MATERIALS AND METHODS: In the esophageal cancer patient (H122), tumor cell lines were established from primary and subcutaneous metastatic lesions. We compared the expression of cell surface molecules on the metastatic tumor cell line (H122SC) with that on the primary tumor cell line (H122ESO) using flow cytometry. Moreover, we analyzed the differences in cellular immune responses against these cell lines, which expressed similar levels of the Tara antigen, using the Tara antigen-specific CTL clone. RESULTS: H122SC ICAM-1 expression was significantly lower in H122ESO, and the Tara antigen-specific CTL clone produced lower levels of TNF in response to H122SC than H122ESO. ICAM-1 transfection into the H122SC rendered these cells as sensitive to the CTL clone as the H122ESO. CONCLUSION: The metastatic tumor cells displayed lower regulated ICAM-1 expression levels and were less sensitive to specific CTLs. ICAM-1 downregulation may be one mechanism by which tumor cells escape immunologic surveillance. PMID- 22234744 TI - A modified sublay-keyhole technique for in situ parastomal hernia repair. AB - OBJECTIVE: The surgical treatment of a parastomal hernia is always challenging due to the high incidence of recurrence following primary repair, or stoma relocation and severe morbidities in prosthetic repair with polypropylene materials. We therefore developed a modified sublay-keyhole technique employing a polypropylene material to minimize the associated high risk of the procedure. We herein describe our initial clinical experience with this modified procedure. METHODS: A retrospective review was performed to obtain the clinical data for 11 patients with parastomal hernias who underwent the modified in situ Sublay keyhole repair from November 2008 to August 2010. RESULTS: The mean hernia size was 58.7 cm(2) (range 30-96 cm(2)), with an average polypropylene mesh size of 376.3 cm(2) (range 270-464 cm(2)). The mean length of the operation was 147.9 min (range 120-195.0 min), and the mean postoperative hospital stay was 11 days (range 9-14 days). All patients had an uneventful incisional recovery, with no infections. Two seromas and one hematoma were found and treated with conservative management, such as with aspiration, physical therapy and compression. All patients had been followed up, with a mean length of follow-up of 23.5 months (range 11-39 months). One parastomal hernia recurrence was seen 11 months postoperatively. Breakdown of the sutures and an over-sized aperture cut in the mesh were detected as the causes of the recurrence during the secondary repair procedure. Only re-sutures in both the mesh aperture and myofascial dehiscence were executed for this patient, and no re-recurrence was observed during an additional follow-up of 15 months. No recurrence of the parastomal hernia or presentation of an incisional hernia was detected during the follow-up. CONCLUSIONS: The modified Sublay-keyhole repair appears to be an effective procedure for parastomal hernias, with a low incidence of recurrence and risk of morbidities. Collection of more cases and further follow-up examinations will be needed to confirm our findings. PMID- 22234746 TI - Upregulation of CD40 ligand and enhanced monocyte-platelet aggregate formation are associated with worse clinical outcome after ischaemic stroke. AB - The white blood cell count and mean platelet volume determined shortly after the symptom onset are known as independent predictors for clinical outcome after stroke. In the present study we sought to evaluate the prognostic value of platelet-derived inflammatory biomarkers measured prospectively after an ischaemic event. Using five-colour flow cytometry, the platelet surface expression of CD40L, CD62P and subpopulations of leukocyte-platelet aggregates were assessed in 93 stroke patients on the first (V(0)), 10th (V(1)) and 90th (V(2)) day after stroke, and once in 65 disease controls. The clinical outcome was evaluated using the Scandinavian Stroke Scale (SSS) and modified Rankin Scale (mRS) at the same time points as blood sampling and 24 months after the event. Patients with either CD40L surface expression or the percentage of monocyte platelet aggregates (M-plt) in the third tertile (T3) at V0 had a significantly lower score on the SSS at V(1). Patients with the percentage M-plt at V(0) higher than the median value of M-plt in controls were at increased risk of SSS < 40 at V(1) (odds ratio: 2.6; 95% confidence interval [CI]: 1.4 - 8.7; p=0.006). Patients with the percentage of M-plt in T3 at V(0) showed progressive decline in survival (hazard ratio [HR]: 1.6; 95% CI: 1.1-1.9; p=0.02) and a significantly higher number of recurrent vascular events (HR: 2.64; 95% CI: 1.3-3.2; p=0.02) when compared to the first tertile. In conclusion, increased levels of M-plt could be a predictive marker for both early outcome and long-term prognosis while increased CD40L was correlated with worse clinical outcome. PMID- 22234748 TI - US Food and Drug Administration approval of generic versions of complex biologics: implications for the practicing physician using low molecular weight heparins. AB - Low-molecular-weight heparins (LMWHs) have shown equivalent or superior efficacy and safety to unfractionated heparin as antithrombotic therapy for patients with acute coronary syndromes. Each approved LMWH is a pleotropic biological agent with a unique chemical, biochemical, biophysical and biological profile and displays different pharmacodynamic and pharmacokinetic profiles. As a result, LMWHs are neither equipotent in preclinical assays nor equivalent in terms of their clinical efficacy and safety. Previously, the US Food and Drug Administration (FDA) cautioned against using various LMWHs interchangeably, however recently, the FDA approved generic versions of LMWH that have not been tested in large clinical trials. This paper highlights the bio-chemical and pharmacological differences between the LMWH preparations that may result in different clinical outcomes, and also reviews the implications and challenges physicians face when generic versions of the original/innovator agents are approved for clinical use. PMID- 22234747 TI - Simultaneous measurement of adenosine triphosphate release and aggregation potentiates human platelet aggregation responses for some subjects, including persons with Quebec platelet disorder. AB - Platelet aggregometry and dense granule adenosine triphosphate (ATP) release assays are helpful to diagnose platelet disorders. Some laboratories simultaneously measure aggregation and ATP release using Chronolume(r) a commercial reagent containing D-luciferin, firefly luciferase and magnesium. Chronolume(r) can potentiate sub-maximal aggregation responses, normalising canine platelet disorder findings. We investigated if Chronolume(r) potentiates human platelet aggregation responses after observing discrepancies suspicious of potentiation. Among patients simultaneously tested by light transmission aggregometry (LTA) on two instruments, 18/43 (42%), including 14/24 (58%) with platelet disorders, showed full secondary aggregation with one or more agonists only in tests with Chronolume(r). As subjects with Quebec platelet disorder (QPD) did not show the expected absent secondary aggregation responses to epinephrine in tests with Chronolume(r), the reason for the discrepancy was investigated using samples from 10 QPD subjects. Like sub-threshold ADP (0.75 MUM), Chronolume(r) significantly increased QPD LTA responses to epinephrine (p<0.0001) and it increased both initial and secondary aggregation responses, leading to dense granule release. This potentiation was not restricted to QPD and it was mimicked adding 1-2 mM magnesium, but not D-luciferin or firefly luciferase, to LTA assays. Chronolume(r) potentiated the ADP aggregation responses of QPD subjects with a reduced response. Furthermore, it increased whole blood aggregation responses of healthy control samples to multiple agonists, tested at concentrations used for the diagnosis of platelet disorders (p values <0.05). Laboratories should be aware that measuring ATP release with Chronolume(r) can potentiate LTA and whole blood aggregation responses, which alters findings for some human platelet disorders, including QPD. PMID- 22234749 TI - Severe skin rash in case of readministration of telaprevir in a patient who previously experienced a non severe rash. PMID- 22234751 TI - Prevention of post-ERCP pancreatitis. PMID- 22234750 TI - Evaluation of the hybrid capture 2 assay for detecting anal high-grade dysplasia. AB - Hybrid Capture 2 (HC2) Human Papillomavirus (HPV) DNA Test(r) is FDA approved and is a proven aid in detecting HPV infections of the cervix and as an aid in diagnosing, with cytology, cervical disease. A prospective feasibility study was conducted to determine if HC2 testing has utility when screening for high-grade anal dysplasia (AIN2+). We enrolled 298 patients (45% HIV+) who had AIN2+ screening with cytology, histology and HC2 testing for two specimens: a swab into liquid-based cytology medium and either a swab or a brush collection in specimen transport medium (STM). High-resolution anoscopy was performed on all patients with biopsy of AIN2+ suspicious lesions. Cytology was benign (42%), atypical squamous cells of undetermined significance (30%), low-grade squamous intraepithelial lesion (18%), high-grade squamous intraepithelial lesion (1%), ASCUS possibly high-grade dysplasia (1.7%) and nondiagnostic (7%) and 36% had AIN2+ histology. Sensitivity and specificity for predicting AIN2+ histology for any abnormal cytology were 77 and 52%, whereas HC2 sensitivity and specificity were 91 and 40% (p = 0.005 for sensitivity), respectively. There was no significant difference in HC2 sensitivity or specificity between brush and swab or STM and residual cells from cytology. AIN2+ was found in 20% of patients with benign cytology. Only nine AIN2+ specimens were HC2-. This prospective study indicates that HC2 may be useful when screening for anal dysplasia; however, a larger study is recommended. PMID- 22234752 TI - Non-erosive reflux disease compared with erosive esophagitis with regards to acid reflux and symptom patterns. AB - BACKGROUND/AIMS: Non-erosive reflux disease and erosive esophagitis are the most common phenotypic presentations of gastroesophageal reflux disease. Recent reports suggest that patients with non-erosive reflux disease treated with antireflux medications show lower symptom improvement rates than patients with erosive esophagitis treated with the same medications. The aim was to assess the acid reflux and symptom patterns of patients with non-erosive reflux disease in comparison with those with erosive esophagitis and to identify different non erosive reflux disease subgroups. MATERIAL AND METHODS: One hundred and twenty consecutive patients (67 male, age: 37.6+/-12.9 years) seen for classic heartburn symptoms were evaluated for the study. The patients underwent upper endoscopy and 24-hour ambulatory pH monitoring. RESULTS: Erosive esophagitis was identified in 51 patients and nonerosive reflux disease in 69 patients. According to pH metric findings (DeMeester Score >14.72 or Fraction Time >4%), 31.9% of the non-erosive reflux disease group and 47.1% of the erosive gastroesophageal reflux disease group had abnormal acid reflux (p=0.134). Erosive esophagitis patients showed a similar pattern of acid reflux to non-erosive reflux disease patients in the different positions (supine and upright). Non-erosive reflux disease-negative (normal pH test) patients demonstrated a significantly lower degree of esophageal acid exposure when compared with those with erosive esophagitis. About 10.6% of the non-erosive reflux disease-negative patients and 45.5% of the non-erosive reflux disease-positive (abnormal pH test) patients had a positive symptom index (>=50%) during the distal pH metry (p=0.003). CONCLUSIONS: Acid reflux characteristics and symptom patterns suggest that the non-erosive reflux disease group represents a heterogeneous group of patients. PMID- 22234753 TI - Comparison of 19- and 22-gauge needles in EUS-guided fine needle aspiration in patients with mediastinal masses and lymph nodes. AB - BACKGROUND/AIMS: Endoscopic ultrasound-guided fine needle aspiration is an established tissue-acquisition technique for mediastinal lesions. However, there are limitations to endoscopic ultrasound-guided fine needle aspiration of mediastinal masses in certain neoplasms and granulomatous diseases. Most studies have used 22-gauge aspiration and/or 19-gauge Tru-cut needles, and only limited data exist on larger-caliber aspiration needles. We aimed to compare prospectively the diagnostic yield of endoscopic ultrasound-guided fine needle aspiration using 19- and 22-gauge aspiration needles in patients with mediastinal lesions of unknown origin. MATERIAL AND METHODS: Using a consecutive entry design, 57 patients with mediastinal mass or lymph node, in whom previous investigations, including bronchoscopy and computed tomography-guided biopsy, had not provided a final diagnosis, underwent endoscopic ultrasound-guided fine needle aspiration biopsy using 19-gauge or 22-gauge aspiration needle. Determination of the adequacy and cytopathologic interpretation of fine needle aspiration materials were done by two pathologists blinded to the clinical condition of the patient. Fine needle aspiration specimens were placed in four categories as: (1) nondiagnostic, (2) benign, (3) granulomatous disease, and (4) malignant. RESULTS: Among 57 patients [35 (61.4%) with mediastinal lymph nodes and 22 (38.5%) with pulmonary masses], adequate tissue was obtained in 52 (91.2%) of the cases (with a mean of 3.3 needle passes). Correct cytopathologic diagnoses were made based on the endoscopic ultrasound-guided fine needle aspiration specimens obtained by 19- and 22-gauge needles in 96% and 92% of the samples, respectively (p>0.05). CONCLUSIONS: As concerns endoscopic ultrasound-guided fine needle aspiration of mediastinal masses and lymph nodes, the diagnostic sensitivity of aspirated material obtained using 19- and 22-gauge fine needle aspiration needles was found to be comparable in our study. PMID- 22234754 TI - Efficacy evaluation of imatinib in the treatment of patients with gastrointestinal stromal tumors. AB - BACKGROUND/AIMS: Published data on the dose of imatinib to treat gastrointestinal stromal tumors seemed inconclusive. To derive a more precise estimation of dose of imatinib to treat gastrointestinal stromal tumors, a meta-analysis was performed. MATERIAL AND METHODS: Studies have been identified by searching PubMed and Embase. Inclusion criteria were patients with incurable or advanced gastrointestinal stromal tumors, received chemotherapy of imatinib of 400 mg once a day (low-dose group) or 300 mg/400 mg twice a day (high-dose group) for controlled trial, and efficacy evaluation were cumulative response based on SWOG criteria, including complete response and partial response. The safety evaluation of imatinib included toxic effect and dose reduction. The odds ratio for cumulative response, toxic effect and dose reduction in patients with low-dose of imatinib over those with high-dose of imatinib with 95% confidence interval was calculated for each study as an estimation of the better effect of imatinib. RESULTS: A total of 3 studies including 1,787 patients were involved in this meta analysis. The overall odds ratio for cumulative response, toxic effect and dose reduction were 0.91 (95% confidence interval, 0.75-1.09; p=0.31, Pheterogeneity=0.80), 0.55 (95% confidence interval, 0.42-0.72; p<0.0001, Pheterogeneity=0.01), respectively. CONCLUSION: The meta-analysis indicated that cumulative response for patients with low-dose imatinib showed no significant difference compared with that with high-dose imatinib. However, high-dose imatinib brought patients more toxic effect and more dosage adjustment for down regulation was made for these patients with severe toxic effect. With long follow up of the patients, result of neither progression-free survival nor overall survival reached statistical significance between low-dose arm and high-dose arm. PMID- 22234755 TI - Treating TNBS-induced colitis in rats with probiotics. AB - BACKGROUND/AIMS: We aimed to investigate the therapeutic effects of Peifeikang, a probiotics compound, on colitis in rats induced by trinitrobenzene sulfonic acid and to elucidate its potential mechanism. MATERIAL AND METHODS: We evaluated the therapeutic effects of Peifeikang by analysis of the disease activity index, colonic mucosa damage index, and histopathological score of the inflamed colons, by measurement of colonic myeloperoxidase activity through spectrophotometric assay, by determination of colonic positivities of tumor necrosis factor-alpha and interleukin-10 via immunochemical staining, and by detection of serum levels of tumor necrosis factor-alpha and interleukin-10 with enzyme-linked immunosorbent assay. RESULTS: Intrarectal administration of trinitrobenzene sulfonic acid caused colonic inflammation similar to human ulcerative colitis with significantly increased disease activity index, colonic mucosa damage index, histopathological score, and colonic myeloperoxidase activities (p<0.05). After treatment with Peifeikang or olsalazine alone, or both, disease activity index, colonic mucosa damage index, histopathological score, and colonic myeloperoxidase activities decreased significantly (p<0.05). The relief of trinitrobenzene sulfonic acid-induced colitis was accompanied by significantly decreased production of tumor necrosis factor-alpha in both serum and intra-colon (p<0.05) and by significantly increased production of interleukin-10 in both serum and intra-colon (p<0.05). CONCLUSIONS: Peifeikang can effectively ameliorate trinitrobenzene sulfonic acid-induced colitis in rats, the underlying mechanism of which may be attributed to the modulatory effects of Peifeikang on the production of tumor necrosis factor-alpha and interleukin-10. PMID- 22234756 TI - Ornidazole-induced autoimmune hepatitis. AB - BACKGROUND/AIMS: Certain drugs including oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, interferon, infliximab, pemoline, minocycline, atorvastatin, and rosuvastatin can induce hepatocellular injury that mimics autoimmune hepatitis. Whether drugs and herbs unmask or induce autoimmune hepatitis or simply cause a drug-induced hepatitis with accompanying autoimmune features is unclear. We describe the clinicopathologic details of eight cases with ornidazole-induced hepatitis with autoimmune features. MATERIAL AND METHODS: Patients who presented with acute hepatitis between February 2001 and March 2009 were reevaluated for the etiology of liver disease. Patients with acute viral hepatitis, metabolic liver disease, vascular liver disease such as Budd-Chiari syndrome, biliary obstruction, or alcohol consumption were excluded. The autoimmune hepatitis scores, which were calculated at the time of diagnosis according to the criteria of the International Autoimmune Hepatitis Group, were recorded. In addition, the simplified criteria of the same group were applied retrospectively to each patient. Patients with ornidazole-induced toxic hepatitis with autoimmune hepatitis were included to constitute the study group of this report. All patients underwent initial liver biopsy, and one patient underwent liver biopsy three years later. All biopsies were scored according to the hepatitis scoring system by Ishak et al. (10). RESULTS: Overall, eight patients (all female) were diagnosed as drug-induced autoimmune hepatitis. With the exception of one patient, all were treated with prednisolone 30 mg/day + azathioprine 50 mg/day. The prednisolone dose was tapered according to the decrease in the level of transaminases. A two-year treatment program was planned for all patients. CONCLUSIONS: Ornidazole may cause drug-induced autoimmune hepatitis. Withdrawal of the drug may not provide the recovery despite a rather long wait. Thus, immunosuppressive therapy may be suggested in these cases. PMID- 22234757 TI - Pediatric Gaucher experience in South Marmara region of Turkey. AB - BACKGROUND/AIMS: The aim was to represent the clinical characteristics of six children with Gaucher disease and to describe the results of three years' enzyme replacement therapy. MATERIAL AND METHODS: The data of six Gaucher patients treated with imiglucerase for more than three years were collected. Age, gender, anthropometric measurements, physical examination findings, ophthalmological evaluations, blood counts, liver function tests, liver and spleen sizes, and bone mineral density of the patients were recorded. Clinical presentations, progressions and therapeutic achievements were evaluated. RESULTS: At the time of diagnosis, all patients were clinically type 1 Gaucher disease. Bone lesions, thrombocytopenia and hepatosplenomegaly were found in all patients at diagnosis. After three years of therapy, normalization of blood cell counts, liver and spleen sizes, bone mineral density, and growth was achieved in all patients. Two patients developed neurological symptoms on enzyme replacement therapy, and the diagnosis in these patients was changed to Gaucher type 3. We observed progression of vertebral bone lesions in three patients despite treatment. CONCLUSIONS: The results of enzyme replacement therapy are satisfying, but the possibility of deterioration in clinical findings despite therapy should be kept in mind. PMID- 22234758 TI - Gallbladder perforation: clinical presentation, predisposing factors, and surgical outcomes of 46 patients. AB - BACKGROUND/AIMS: We aimed to investigate the clinical features and the relation between patient characteristics and the different types of gallbladder perforation and to determine the predisposing factors. MATERIAL AND METHODS: The medical records of 478 patients who received urgent surgical treatment with the diagnosis of acute cholecystitis and underwent urgent surgery in our clinics between January 1997 and November 2008 were reviewed retrospectively. The demographic data of patients, time elapsed from the onset of the symptoms to the time of surgery, comorbidity status, American Society of Anesthesiologists classification, laboratory data, imaging results, surgical procedures, postoperative complications, and postoperative length of stay of the patients were analyzed. RESULTS: There were 46 (9.6%) patients with the diagnosis of gallbladder perforation. Morbidity and mortality occurred in 15 (32.6%) and 7 (15.2%) patients, respectively. Advanced age, male gender, fever >38 degrees C, high white blood cell count, and presence of cardiovascular comorbidity were found to be significant risk factors for gallbladder perforation. CONCLUSIONS: While early diagnosis and early surgical intervention are the keys to managing gallbladder perforation, we suggest that patients having the above-mentioned clinical features should be carefully investigated. PMID- 22234759 TI - Incidental gallbladder cancer diagnosed during or after laparoscopic cholecystectomy in members of the Turkish population with gallstone disease. AB - BACKGROUND/AIMS: Gallbladder cancer is a rare neoplasm. We report our experience with gallbladder cancer that was incidentally diagnosed during or after laparoscopic cholecystectomy performed for gallstone disease. MATERIAL AND METHODS: This study included all laparoscopic cholecystectomies due to gallstone disease undertaken from May 1999 to June 2010. Exclusion criteria were suspicion of malignancy and/or existence of gallbladder polyps detected with ultrasonography preoperatively. Patients with incidentally diagnosed gallbladder cancer were recorded, and the clinical and demographic characteristics of these patients were reviewed. RESULTS: Of 5,382 patients in whom laparoscopic cholecystectomy was attempted, 5,164 were included in this study. Incidental gallbladder cancer was found in five patients, with a mean age of 66.2 years. The histological tumor stages were adenocarcinoma in situ in one patient, pT1b in one patient, pT2 in one patient, and pT3 in two patients. Two patients who underwent laparoscopic cholecystectomy alone underwent no additional surgery because of the low stage of the tumors. The three remaining patients, whose laparoscopic cholecystectomies were converted to open surgeries, underwent cholecystectomy, excision of the liver bed and lymph node dissection. The overall median survival time was 32 months. CONCLUSION: The incidence of incidental gallbladder cancer has been reported to vary, up to 2.85%. In this single-center study, the rate of incidental gallbladder cancer was found to be 0.09%. Female gender and advanced age are demographic risk factors for gallbladder carcinoma. Although gallbladder cancer is well known for its poor prognosis, tumors that are incidentally diagnosed are often found at an early stage and have a better prognosis. PMID- 22234760 TI - Does presence of common bile duct stones in patients with acute biliary pancreatitis affect the severity of illness or laboratory findings? AB - BACKGROUND/AIMS: To determine the effect of stone within the common bile duct, on the severity of acute biliary pancreatitis. MATERIAL AND METHODS: This is a prospective and cross sectional study which was conducted at a tertiary care hospital including 103 patients. Serum biochemical values and white blood cell counts at the first 12th and 72nd hours of presentation were evaluated. The patients were grouped according to the presence or absence of common bile duct stones which were diagnosed by endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography. Besides, the patients were classified as mild and severe acute pancreatitis according to the data provided by computed tomography (Balthazar scoring) and clinical assessment and blood samples. RESULTS: Among the 103 patients with acute biliary patients, radial endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography revealed stones and/or sludge within the common bile duct or ampulla in 41 (39.8%) patients. There was not any persistent common bile duct stone in 62 (60.2%) patients. Severe pancreatitis developed in 9 (22%) of 41 patients who were determined to have stones by endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography, and in 13 (21%) of 62 patients who were not. There was no difference in the incidence of progressing to severe acute biliary patients between patients with and without common bile duct stones (p=0.45). CONCLUSION: Presence of common bile duct stones do not correlate with the severity of acute biliary pancreatitis. PMID- 22234761 TI - Postoperative complications after abdominal surgery in patients with chronic obstructive pulmonary disease. AB - BACKGROUND/AIMS: Chronic obstructive pulmonary disease is a well-known independent risk factor for the development of postoperative pulmonary and cardiac complications after thoracic or nonthoracic surgery. We aimed to determine the risk factors and complications of abdominal surgery in chronic obstructive pulmonary disease patients. MATERIAL AND METHODS: Thirty-two patients diagnosed with chronic obstructive pulmonary disease out of 89 patients who underwent abdominal surgery at Zonguldak Karaelmas University Medical School Hospital enrolled in the study. RESULTS: Pulmonary and cardiac complication ratios were found high in chronic obstructive pulmonary disease patients. Postoperative pulmonary and cardiac complications were documented in 21.8% and 28.1% of chronic obstructive pulmonary disease patients respectively. There were no differences in terms of complications, according to the severity of the disease in chronic obstructive pulmonary disease patients. While smoking and age did not effect the postoperative complications in chronic obstructive pulmonary disease patients, bronchodilator use increased postoperative cardiac risks. We found that laparoscopic surgery reduced the risk for postoperative pulmonary complications compared with open surgical procedures. No differences were found in terms of complication regarding to the type of incision and the duration of surgery. CONCLUSION: The patients with chronic obstructive pulmonary disease had high ratio of the pulmonary and cardiac complications. The complication rate was higher for surgical sites closer to the diaphragm such as the upper abdomen. Laparoscopy will reduce the risk for postoperative pulmonary complications compared with open surgical procedures. Based on our preliminary data and considering the lack of controlled trials, bronchodilators should be used with great caution particularly in the individuals with chronic obstructive pulmonary disease and cardiac comorbidity. PMID- 22234762 TI - Esophageal perforation due to inadvertent swallowing of a dental prosthesis. AB - Intentional or inadvertent swallowing of foreign bodies can lead to severe complications in the gastrointestinal tract, primarily in the esophagus, and requires an urgent approach. In children, coins are the most commonly seen foreign bodies in the esophagus. However, in adults, the solid components of meals, like bones, and in the elderly population dental prostheses are the most frequently observed ingested foreign bodies. Even though a swallowed dental prosthesis is usually seen as a geriatric problem, esophageal obstruction and/or perforation can occur in any denture user in any age group. Thus, the aim of this report was to present one of these interesting cases of esophageal perforation due to a partial denture ingestion and its treatment in a 32-year-old male. PMID- 22234763 TI - Intraabdominal gossypiboma mimicking gastrointestinal stromal tumor: a case report. AB - Gossypiboma is used to describe a retained surgical swab in the body after an operation. Intraabdominal surgical sponge is an uncommon surgical error. Gossypiboma may cause serious morbidity and may lead to mortality. Gossypibomas should be included in the differential diagnosis of soft-tissue masses detected in patients with a history of a prior operation. In this case we present a 67 year-old female who had a laparotomy for acute cholecistecytitis 5 years previously and was discovered to have a retained surgical swab. PMID- 22234764 TI - Infliximab- and azathioprine-related severe neutropenia and thrombocytopenia in a case with Crohn's disease. AB - A 25-year-old female patient with Crohn's disease had been using azathioprine and metronidazole for an extended period because of recurrent perianal and rectovaginal fistulae. Infliximab was added to the treatment regimen following postoperative recurrence of a rectovaginal fistula. Upon the development of severe neutropenia and thrombocytopenia after the third dose of infliximab, azathioprine and infliximab were stopped. Neutropenia work-up did not reveal any other cause. Neutropenia was ameliorated with use of granulocyte colony stimulating factor. Treatment was restarted with infliximab alone upon leakage from the rectovaginal fistula with no hematologic toxicity. This case was considered as a serious adverse effect of infliximab and azathioprine combination therapy. PMID- 22234765 TI - Stump appendicitis and chorioamnionitis due to incomplete appendectomy: a case report. AB - Acute appendicitis represents the most common non-obstetric indication for surgical intervention in pregnant women, with a reported incidence of 1 in 1440 pregnancies. Stump appendicitis is a rare clinical situation when there is incomplete appendectomy. A rare case occurred of stump appendicitis and chorioamnionitis complicating after incomplete appendectomy. In this way the literature review suggests that only a few cases have been reported so far. We report a case of stump appendicitis and chorioamnionitis occurring three weeks after an appendectomy performed in another medical center. This will involve the discussion of clinical presentation, diagnosis, surgical management and literature review. PMID- 22234766 TI - Hypoglycemia, a rare presentation of a solid pseudopapillary neoplasm of the pancreas: a case report. AB - A solid pseudopapillary neoplasm of the pancreas is an uncommon and 'enigmatic' pancreatic neoplasm of low malignant potential generally occurring in young women. The pathologic features of this tumor are characteristic, and adequate surgical intervention is associated with an excellent prognosis. We report the first case of combined solid pseudopapillary neoplasm and islet cell hyperplasia of the pancreas in the pediatric age group. A 16-year-old Saudi female presented to the Emergency Room with a history of frequent attacks of hypoglycemia. Radiologically, a mass in the tail of the pancreas was identified. The pre operative diagnosis of insulinoma was suggested, and en bloc distal pancreatectomy with splenectomy was performed. A solid pseudopapillary neoplasm and islet cell hyperplasia of the tail of the pancreas was diagnosed by routine histology and by immunohistochemistry. The patient was treated successfully and is now in good health with regular follow-up for the last 13 months. In the pediatric age group, these tumors are very rare and can present as repeated episodes of hypoglycemia. This association sheds light on the histogenesis of solid pseudopapillary neoplasm of the pancreas and also allows appropriate and prompt management to be undertaken by the clinicians. PMID- 22234767 TI - Extremely high values of CA 19-9 in liver hydatidosis and frank biliary rupture. AB - Elevation of carbohydrate antigen 19-9 has been observed in jaundiced patients with benign biliary tract diseases. No clear answer has explained that relationship. Patients with liver hydatidosis and frank intrabiliary rupture could present obstructive jaundice due to the presence of liver cyst material in the bile duct. We present two cases of huge elevation of carbohydrate antigen 19 9 in jaundiced patients with liver hydatidosis and biliocystic communication, and we assess the different theories presented in the medical literature today. PMID- 22234768 TI - Castleman's disease mimicking right adrenal neoplasm: a case report. AB - Castleman's disease usually manifests as a solitary mediastinal tumor and only rarely as an isolated retroperitoneal mass. This disorder is often undiagnosed or misdiagnosed. Thus, only very few patients have been reported and little information is available in the literature. The definitive diagnosis is based on postoperative pathological findings. We report a case of a 57-year-old female with a Castleman's tumor located superomedial to the upper pole of the right kidney that mimicked an adrenal neoplasm. The mass was surgically resected, and the histopathological diagnosis of the resected tissue was hyaline-vascular type of Castleman's disease. Although retroperitoneal Castleman's disease is rare, it should be considered in the differential diagnosis of retroperitoneal masses. PMID- 22234769 TI - A case of tuberculosis diagnosed with EUS-guided aspiration biopsy. PMID- 22234770 TI - Hydatid cyst-like intra-abdominal esophageal duplication cyst in an endemic region. PMID- 22234771 TI - Gastrointestinal stromal tumor presenting as dyspareunia. PMID- 22234772 TI - Novel strategy in retrieving a long foreign material using single balloon enteroscope with caps. PMID- 22234774 TI - An unexpected cause of occult bleeding. PMID- 22234773 TI - Mesenteric inflammatory veno-occlusive disease: an unusual cause of colonic ischemia. PMID- 22234775 TI - Primary giant hydatid cyst of the diaphragm. PMID- 22234776 TI - A case of isolated pancreatic tuberculosis mimicking pancreatic carcinoma. PMID- 22234777 TI - The inhibition of hyaluronan degradation reduced pro-inflammatory cytokines in mouse synovial fibroblasts subjected to collagen-induced arthritis. AB - Hyaluronan (HA) degradation produces small oligosaccharides that are able to increase pro-inflammatory cytokines in rheumatoid arthritis synovial fibroblasts (RASF) by activating both CD44 and the toll-like receptor 4 (TLR-4). CD44 and TLR 4 stimulation in turn activate the NF-kB that induces the production of pro inflammatory cytokines. Degradation of HA occurs via two mechanisms: one exerted by reactive oxygen species (ROS) and one controlled by different enzymes in particular hyaluronidases (HYALs). We aimed to investigate the effects of inhibiting HA degradation (which prevents the formation of small HA fragments) on synovial fibroblasts obtained from normal DBA/J1 mice (NSF) and on synovial fibroblasts (RASF) obtained from mice subjected to collagen induced arthritis (CIA), both fibroblast types stimulated with tumor necrosis factor alpha (TNF alpha). TNF-alpha stimulation produced high mRNA expression and the related protein production of CD44 and TLR-4 in both NSF and RASF, and activation of NF kB was also found in all fibroblasts. TNF-alpha also up-regulated the inflammatory cytokines, interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and other pro-inflammatory mediators, such as matrix metalloprotease-13 (MMP-13), inducible nitric oxide synthase (iNOS), as well as HA levels and small HA fragment production. Treatment of RASF with antioxidants and specific HYAL1, HYAL2, and HYAL3 small interference RNA (siRNAs) significantly reduced TLR-4 and CD44 increase in the mRNA expression and the related protein synthesis, as well as the release of inflammatory mediators up-regulated by TNF-alpha. These data suggest that the inhibition of HA degradation during arthritis may contribute to reducing TLR-4 and CD44 activation and the inflammatory mediators response. PMID- 22234778 TI - Transgene copy number distribution profiles in recombinant CHO cell lines revealed by single cell analyses. AB - Clonally derived recombinant cell lines are highly desired to achieve consistent production of recombinant biotherapeutics. Despite repeated rounds of cloning by limiting dilution or single cell cloning, the resulting cell lines have often been observed to diverge, becoming a heterogeneous population and losing productivity over long-term sub-culturing. To understand the underlying molecular mechanisms, we developed quantitative polymerase chain reaction (qPCR) assays for the analysis of transgene copy number distribution in single recombinant cells isolated from Chinese hamster ovary (CHO) cell lines. Single cells were obtained by fluorescence activated cell sorting (FACS) technology and lysed directly in 96 well plates. qPCR assays were then applied to analyze the quantity and distribution of transgenes in those single cells. Results revealed multiple types of transgene copy number distribution profiles from those clonally derived CHO cell lines. The cell lines that maintained productivity over time displayed relatively constant and homogeneous transgene copy number distributions; while most of those cell lines exhibiting a loss of productivity over time showed varying degrees of transgene copy number heterogeneity and distribution drift with passaging. Some cell lines showed the existence of a significant portion of cells lacking the transgenes (referred to as negative cells in this study) and the percentage of those negative cells increased with subsequent generations. Criteria based on transgene copy number distribution profiles were developed to assess cell line suitability for clinical applications, which include (i) percentage of negative cells; (ii) standard deviation of qPCR threshold cycle (C(t) ) value, a measure of population heterogeneity; (iii) mean C(t) changes during aging, a measure of population drift. By implementing these criteria, undesirable cell lines were eliminated for further clinical and commercial applications. PMID- 22234779 TI - Mechanical behaviour of in-situ chondrocytes subjected to different loading rates: a finite element study. AB - Experimental findings indicate that in-situ chondrocytes die readily following impact loading, but remain essentially unaffected at low (non-impact) strain rates. This study was aimed at identifying possible causes for cell death in impact loading by quantifying chondrocyte mechanics when cartilage was subjected to a 5% nominal tissue strain at different strain rates. Multi-scale modelling techniques were used to simulate cartilage tissue and the corresponding chondrocytes residing in the tissue. Chondrocytes were modelled by accounting for the cell membrane, pericellular matrix and pericellular capsule. The results suggest that cell deformations, cell fluid pressures and fluid flow velocity through cells are highest at the highest (impact) strain rate, but they do not reach damaging levels. Tangential strain rates of the cell membrane were highest at the highest strain rate and were observed primarily in superficial tissue cells. Since cell death following impact loading occurs primarily in superficial zone cells, we speculate that cell death in impact loading is caused by the high tangential strain rates in the membrane of superficial zone cells causing membrane rupture and loss of cell content and integrity. PMID- 22234780 TI - The influence of mechanical stretching on mitosis, growth, and adipose conversion in adipocyte cultures. AB - The mechanotransduction of adipocytes is not well characterized in the literature. In this study, we employ stochastic modeling fitted to experiments for characterizing the influence of mechanical stretching delivered to adipocyte monolayers on the probabilities of commitment to the adipocyte lineage, mitosis, and growth after mitosis in 3T3-L1 adipocytes. We found that the probability of a cell to become committed to the adipocyte lineage in a single division when cultured on an elastic substrate was 0.025, which was indistinguishable between cultures that were radially stretched (to 12% strain) and control cultures. The probability of undergoing mitosis however was different between the groups, being 0.4 in the stretched cultures and 0.6 in the controls. The probability of growing after mitosis was affected by the stretching as well and was 0.9 and 0.8 in the stretched and control groups, respectively. We conclude that static stretching of the substrate of adipocyte cultures influences the mitotic potential of the cells as well as the growth potential post-mitosis. The present work provides better understanding of the mechanotransduction of adipocytes and in particular quantify how stretching influences the likelihood of cell proliferation and differentiation and, consequently, adipogenesis in the adipocyte cultures. PMID- 22234781 TI - A prospective cohort study challenging the effectiveness of population-based medical intervention for smoking cessation. AB - OBJECTIVE: To examine the population effectiveness of nicotine replacement therapies (NRTs), either with or without professional counselling, and provide evidence needed to better inform healthcare coverage decisions. METHODS: A prospective cohort study was conducted in three waves on a probability sample of 787 Massachusetts adult smokers who had recently quit smoking. The baseline response rate was 46%; follow-up was completed with 56% of the designated cohort at wave 2 and 68% at wave 3. The relationship between relapse to smoking at follow-up interviews and assistance used, including NRT with or without professional help, was examined. RESULTS: About one-fourth of recent quitters at each wave reported to have relapsed by the subsequent interview. Odds of relapse were unaffected by use of NRT for >6 weeks either with (p=0.117) or without (p=0.159) professional counselling and were highest among prior heavily dependent persons who reported NRT use for any length of time without professional counselling (OR 2.68). CONCLUSIONS: This study finds that persons who have quit smoking relapsed at equivalent rates, whether or not they used NRT to help them in their quit attempts. Cessation medication policy should be made in the larger context of public health, and increasing individual treatment coverage should not be at the expense of population evidence-based programmes and policies. PMID- 22234783 TI - Three-dimensional ordered arrays of 58*58*58 A3 hollow frameworks in ionic crystals of M2Zn2-substituted polyoxometalates. PMID- 22234782 TI - Pseudocontinuous arterial spin labeling with optimized tagging efficiency. AB - The adiabatic inversion of blood in pseudocontinuous arterial spin labeling (PCASL) is highly sensitive to off-resonance effects and gradient imperfections and this sensitivity can lead to tagging efficiency loss and unpredictable variations in cerebral blood flow estimates. This efficiency loss is caused by a phase tracking error between the RF pulses and the flowing spins. This article introduces a new method, referred to as Optimized PCASL (OptPCASL), that minimizes the phase tracking error by applying an additional compensation RF phase term and in-plane gradients to the PCASL pulse train. The optimal RF phase and gradient amplitudes are determined using a prescan procedure, which consists of a series of short scans interleaved with automated postprocessing routines integrated to the scanner console. The prescan procedure is shown to minimize the phase tracking error in a robust and time efficient manner. As an example of its application, the use of OptPCASL for the improved detection of functional activation in the visual cortex is demonstrated and temporal signal-to-noise ratio (SNR), image SNR, and baseline cerebral blood flow measures are compared to those acquired from conventional PCASL. PMID- 22234784 TI - Development of a homogeneous immunoassay based on the AlphaLISA method for the detection of chloramphenicol in milk, honey and eggs. AB - BACKGROUND: A homogenous light-induced chemiluminescence immunoassay was developed using AlphaLISA technology for the detection of chloramphenicol (CAP). This technology is based on two different kinds of bead, namely light-sensitive donor beads and beads containing chemiluminescers, also called acceptor beads. A competitive CAP AlphaLISA method was established using artificial antigen-coated acceptor beads, polyclonal antibodies, biotinylated goat anti-rabbit IgG and streptavidin-coated donor beads. RESULTS: The sensitivity of detection was 0.0086 ng mL-1 and the working range was from 0.0096 to 25 ng mL-1. The intra- and inter assay coefficients of variation were both below 10%. The average recovery rates at spiked levels of 0.05-10 ng mL-1 were 103.2, 108.4 and 91.6% for milk, honey and eggs respectively. The data obtained from the samples showed good correlation with ELISA results. CONCLUSION: The CAP AlphaLISA method is highly sensitive, specific and rapid and is suitable for screening large quantities of samples. PMID- 22234785 TI - Double-bundle bone-patellar tendon-bone and gracilis in ACL reconstruction. AB - An original technique for the reconstruction of the anterior cruciate ligament is explained. Two bundles are reconstructed using the central third of the patellar tendon and the gracilis tendon, passed through four tunnels but requiring only two interference screws for fixation. Level of evidence V. PMID- 22234786 TI - The study of laparoscopic electrosurgical instruments on thermal effect of uterine tissues. AB - PURPOSE: It is to compare the thermal damage on myometrium tissue caused by five electrosurgical instruments, including monopolar forceps, bipolar forceps, PK scalpel, Ligasure and BiClamp. METHODS: Normal myometrium in vitro was collected and electric coagulation was conducted with five electrosurgical instruments under corresponding powers. The zones of thermal injury (ZTI) in each coagulation sites were examined histologically, while the width and depth of thermal damage were measured. RESULTS: 1. There were significant differences among various groups' widths of ZTI of myometrium (P < 0.05). Ligasure produced the greatest width of ZTI, and it was statistically greater than that of PK scalpel and BiClamp (P < 0.05). While the widths of ZTI caused by monopolar and bipolar electrocoagulation lied between that of Ligasure and PK scalpel, but the differences were of no statistical significance (P > 0.05). 2. The depths of ZTI in different groups were of significant differences (P < 0.05). Both monopolar and bipolar forceps had greater depths of ZTI compared with BiClamp (P < 0.05) but not had statistical differences with Ligasure and PK scalpel (P > 0.05). CONCLUSIONS: As for myometrium, the thermal damage is rather small in the horizontal and vertical directions when using BiClamp and PK scalpel. Ligasure places larger range of thermal damage in horizontal direction with little depth in vertical direction, which is rather safe when acting on uterine surface. Electrocoagulation was conducted with monopolar (the power is 55 W) and bipolar forceps (the power is 40 W) continuously for 3 s, whose thermal damage range is fairly safe to corpus uteri wall and fundus uteri. PMID- 22234787 TI - Relationships among maternal nutrient intake and placental biomarkers during the 1st trimester in low-income women. AB - PURPOSE: Pre-eclampsia is a multi-system disorder caused by inadequate placentation in early pregnancy; however, little is known about the influence of nutrient intake on placental development during the crucial 1st trimester. The objective of this study was to examine the relationships between nutrient intake and the raw values and ratios of angiogenic [placental growth factor (PlGF)] and antiangiogenic [soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng)] placental biomarkers in the 1st trimester. METHODS: A cross-sectional study of low-income, pregnant women (n = 118). Average nutrient intake was calculated from three 24-h dietary recalls. Biomarker values were adjusted for gestational age and nutrients were adjusted for energy. RESULTS: The angiogenic to antiangiogenic ratio [PlGF/(sFlt-1 * sEng)] was positively related to intake of vitamin D (r = 0.24), vitamin B(2) (r = 0.25), B(12) (r = 0.20), dietary folate equivalents (r = 0.19), iron (r = 0.19), and zinc (r = 0.19) and negatively related to transfats (r = -0.24). Principal component analysis revealed that a vitamin/mineral factor [t (112) = 2.58, p = 0.011] and transfats factor [t (112) = -2.03, p = 0.045] were significant predictors of the PlGF/(sFlt 1 * sEng) ratio. The vitamin and mineral factor was a significant predictor of sFlt-1 [t (122) = 2.29, p = 0.024]. CONCLUSIONS: Expression of placental biomarkers in the early weeks of pregnancy may be influenced by intake of nutrients. Understanding the influence of maternal nutrient intake and placental development in the 1st trimester may provide the opportunity to avert the development or blunt the severity of preeclampsia. PMID- 22234788 TI - The effects of running exercise on oxidative capacity and PGC-1alpha mRNA levels in the soleus muscle of rats with metabolic syndrome. AB - Skeletal muscles in animals with metabolic syndrome exhibit reduced oxidative capacity. We investigated the effects of running exercise on fiber characteristics, oxidative capacity, and mRNA levels in the soleus muscles of rats with metabolic syndrome [SHR/NDmcr-cp (cp/cp); CP]. We divided 5-week-old CP rats into non-exercise (CP) and exercise (CP-Ex) groups. Wistar-Kyoto rats (WKY) were used as the control group. CP-Ex rats were permitted voluntary exercise on running wheels for 10 weeks. Triglyceride levels were higher and adiponectin levels lower in the CP and CP-Ex groups than in the WKY group. However, triglyceride levels were lower and adiponectin levels higher in the CP-Ex group than in the CP group. The soleus muscles in CP-Ex rats contained only high oxidative type I fibers, whereas those in WKY and CP rats contained type I, IIA, and IIC fibers. Muscle succinate dehydrogenase (SDH) activity was higher in the CP-Ex group than in the CP group; there was no difference in SDH activity between the WKY and CP-Ex groups. Muscle proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA levels were higher in the CP-Ex group than in the CP group; there was no difference in PGC-1alpha mRNA levels between the WKY and CP-Ex groups. In CP-Ex rats, longer running distance was associated with increased muscle SDH activity and PGC-1alpha mRNA levels. We concluded that running exercise restored decreased muscle oxidative capacity and PGC-1alpha mRNA levels and improved hypertriglyceridemia in rats with metabolic syndrome. PMID- 22234789 TI - Prenatal testosterone supplementation alters puberty onset, aggressive behavior, and partner preference in adult male rats. AB - The objective of this study was to investigate whether prenatal exposure to testosterone (T) could change the body weight (BW), anogenital distance (AGD), anogenital distance index (AGDI), puberty onset, social behavior, fertility, sexual behavior, sexual preference, and T level of male rats in adulthood. To test this hypothesis, pregnant rats received either 1 mg/animal of T propionate diluted in 0.1 ml peanut oil or 0.1 ml peanut oil, as control, on the 17th, 18th and 19th gestational days. No alterations in BW, AGD, AGDI, fertility, and sexual behavior were observed (p > 0.05). Delayed onset of puberty (p < 0.0001), increased aggressive behavior (p > 0.05), altered pattern of sexual preference (p < 0.05), and reduced T plasma level (p < 0.05) were observed for adult male rats exposed prenatally to T. In conclusion, the results showed that prenatal exposure to T was able to alter important aspects of sexual and social behavior although these animals were efficient at producing descendants. In this sense more studies should be carried to evaluated the real impact of this hormonal alteration on critical period of sexual differentiation on humans, because pregnant women exposed to hyperandrogenemia and then potentially exposing their unborn children to elevated androgen levels in the uterus can undergo alteration of normal levels of T during the sexual differentiation period, and, as a consequence, affect the reproductive and behavior patterns of their children in adulthood. PMID- 22234790 TI - A new ultrahigh-speed method for the preparation of nanofibers containing living cells: a bridge towards industrial bioengineering applications. AB - A novel method is reported of producing nanofibers/nanotubes (measuring from tens of nanometres to several hundreds of nanometres) containing living cells, mechanically and with ultrahigh speed and at low cost. High-pressure gas was used to extrude viscous precursors through a spray with micron-sized holes into air. The sprayed micro-sized droplets had high velocity and were continuously elongated into uniform nanofibers/nanotubes in a temperature field during their flight. We demonstrated that the throughput of this spinning method to fabricate nanofibers/nanotubes from an individual setup could be as high as 10 g s(-1). A possible mechanism for this extrusion method was proposed based on flow mechanics and the experimental results. Additionally, it was shown that the new method could be used to directly prepare nanofibers containing living cells. It was demonstrated that the living cells with high survival rate can be used in bioengineering. PMID- 22234791 TI - Analysis of human leucocyte antigen genes in Caucasian patients with idiopathic moyamoya angiopathy. AB - BACKGROUND: The etiology and genetic susceptibility of Moyamoya angiopathy (MMA) (Moyamoya disease, Moyamoya syndrome and unilateral type of MMA) still remain unclear. In Asian patient cohorts several HLA markers were described to be associated with MMA, but in Caucasians very little is known about genetic susceptibility of this angiopathy. METHOD: We analysed DNA of 33 Caucasian patients with MMA for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 markers, respectively. HLA frequencies of all 33 patients with MMA were compared with HLA-frequencies of Caucasian controls. Additionally, subgroup analysis of 22 patients with Moyamoya disease (MMD) and 11 patients with unilateral type of MMA was performed. FINDINGS: Significant association was observed for HLA-DRB1*03 and HLA-DRB1*13 in all 33 patients (P (c) < 0.001 and P (c) < 0.001, respectively). Moreover, HLA A*02 (P (c) = 0.009); HLA-B*08 (P (c) = 0.009), and HLA-DQB1*03 (P (c) = 0.003) frequencies were higher in all patients with MMA when compared with the controls. In addition, in 22 patients with MMD a higher frequency of HLA-DRB1*03 (P (c) < 0.001) was observed when compared with controls. CONCLUSIONS: The results of this study indicate a putative association of HLA markers with MMA in Caucasian patients. Further studies are needed to elucidate the role of human MHC in the pathogenesis of this angiopathy. PMID- 22234792 TI - About the article "Primary Ewing's sarcoma of cranial bones: analysis of ten patients" by Pravin Shashikant Salunke et al. Can we tell the exact origin of cranial Ewing's sarcoma? PMID- 22234794 TI - Acute perfusion changes after spontaneous SAH: a perfusion CT study. AB - BACKGROUND: Perfusion computed tomography (CT) is a rapid technique that allows the measurement of acute disturbances in local and global cerebral blood flow in patients suffering stroke and spontaneous subarachnoid haemorrhage (SAH). The purpose of this study was to establish the relationship between different measures of brain perfusion made on dynamic-contrast CT reconstructions performed as soon as SAH has been diagnosed and the severity of the bleeding determined by the clinical grade, the extent of the bleeding and the outcome of the patients. METHODS: After the diagnosis of SAH by conventional CT, a perfusion CT was performed before CT angiography. All imaging studies were performed on a six slice spiral CT scanner. All images were analysed using perfusion software developed by Philips, which produces perfusion CT quantitative data based on temporal changes in signal intensity during the first pass of a bolus of an iodinated contrast agent. Measurements of mean transient time (MTT), time to peak (TTP), cerebral blood volume (CBV) and cerebral blood flow (CBF) in volumes of interest corresponding to territories perfused by the major cerebral arteries were performed. Different data regarding severity of the bleeding-such as level of consciousness, amount of bleeding in conventional CT-were collected. All poor grade patients received a ventriculostomy catheter so that ICP recordings were obtained. Also, the occurrence of delayed cerebral ischaemia (DCI) was recorded. Outcome was assessed by the Glasgow Outcome Scale 6 months after the bleeding. For statistical analysis, non-parametric correlations between variables were performed. FINDINGS: Thirty-nine patients have been included in the study since January 2007. In SAH patients there are increasing perfusion abnormalities as the severity of the bleeding increases. The most affected perfusion parameters are TTP and MTT, as they significantly increase with the clinical severity of the bleeding and the total volume of bleeding (P < 0.01, Spearman's Rho). When average MTT time is increased over 5.9 s there is a 20-fold (95% CI = 2.1-182) risk of poor outcome. All patients presenting this MTT time suffered from DCI. This value has a positive predictive value of 100% for DCI and 90% for a poor outcome. CONCLUSIONS: SAH causes cerebral blood flow abnormalities even in the acute phase of the illness, consisting mainly of an increase in circulation times (TTP and MTT), which are correlated with the severity of the bleeding. PMID- 22234795 TI - Urinary calcium excretion and insulin resistance in patients with acromegaly. AB - BACKGROUND: Renal complications in acromegaly include glomerular hyperfiltration, insulin resistance, hypercalciuria and urolithiasis. The aim of this study was to investigate whether urinary calcium (U(Ca)) excretion is a direct consequence of growth hormone secretion or secondary to hyperfiltration and/or insulin resistance. METHODS: We performed a cross-sectional study of 58 patients diagnosed with acromegaly. Demographic data were obtained, serum analysis was performed, including insulin-like growth factor (IGF)-1, and 24-h urine collection, to measure urinary protein excretion, U(Ca) and phosphate excretion, as well as fractional excretion of sodium and potassium. We also calculated the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Patients were predominantly male (60.3%), and their mean age was 45.9 +/- 14 years. Hypercalciuria was present in 24% of patients. Patients with higher HOMA-IR had higher IGF-1 levels, a trend toward higher body mass index and higher U(Ca) excretion. In univariate analysis, U(Ca) excretion was associated with HOMA-IR (r = 0.472, P = 0.001), phosphaturia (r = 0.457, P = 0.001), IGF-1 (r = 0.398, P = 0.002) and creatinine clearance (r = 0.394, P = 0.001). HOMA-IR and phosphaturia were independently associated with U(Ca) excretion. No independent associations were found between phosphaturia and HOMA-IR or IGF-1. CONCLUSIONS: The present study revealed an association between hypercalciuria and insulin resistance in patients with acromegaly. Further studies are required to fully understand the pathogenesis of these abnormalities in patients with acromegaly. PMID- 22234796 TI - The application of the first year inventory for ASD screening in Israel. AB - This study was designed to examine the generalizability and validity of the First Year Inventory (FYI) in Israel. Parents completed the FYI about their 12-month olds (N = 471). Up to one month later, 17 at-risk and 38 non-risk infants participated in an assessment in which the Autism Observation Scale for Infants (AOSI) and the Mullen Scales of Early Learning (MSEL) were administered. Using the original FYI 95th percentile cutoff the risk rate in this Israeli sample was 11%. The current sample's 95th percentile cutoff was 4.8 points higher than the original US sample. Infants in the risk group obtained significantly higher AOSI scores and lower MSEL scores. Socio-demographic factors may influence risk results suggesting the need to adapt screening to serve all. PMID- 22234797 TI - Effect of antisense oligodeoxynucleotide targeted against NF-kappaB/P65 on cell proliferation and tumorigenesis of gastric cancer. AB - To study the inhibitory effect of nuclear transcription factor-kappa B(NF-kappaB) antisense oligodeoxynucleotide(ASODN) on the growth and tumorgenesis of human gastric cancer. We synthesized and transfected the ASODN of NF-kappaB/P65 to gastric cancer cell line. The effect of ASODN of NF-kappaB/P65 on the proliferation of gastric cancer cells was measured by MTT method. The subcutaneous xenograft model of human gastric cancer was established in nude mice, and the tumor growth curve was observed. The cell proliferation was significantly inhibited in P65 ASODN-transfected group in vitro (P<0.05). In vivo, tumor formation test showed that the tumor volume in nude mice in ASODN group was obviously smaller than in other groups (P<0.05); the apoptosis index (AI) was significantly higher (P<0.001). Simultaneously, MVD in ASODN group was markedly lower than in other groups (P<0.01). NF-kappaB could be used as a new biological therapeutic target of gastric cancer. PMID- 22234798 TI - Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation. AB - Gliomas are the most common type of primary brain tumor in the central nervous system of adults. Maternally Expressed Gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes a non-coding RNA (ncRNA) associated with tumorigenesis. However, little is known about whether and how MEG3 regulates glioma development. In the present study we assayed the expression of MEG3 in glioma tissue samples by real-time polymerase chain reaction assay, and defined the biological functions and target genes by CCK-8 assay, flow cytometry, and RNA immunoprecipitation. We first demonstrated that MEG3 expression was markedly decreased in glioma tissues compared with adjacent normal tissues. Moreover, ectopic expression of MEG3 inhibited cell proliferation and promoted cell apoptosis in U251 and U87 MG human glioma cell lines. We further verified that MEG3 was associated with p53 and that this association was required for p53 activation. These data suggest an important role of MEG3 in the molecular etiology of glioma and implicate the potential application of MEG3 in glioma therapy. PMID- 22234799 TI - [Does sodium restriction reduce cardiovascular risk?]. PMID- 22234800 TI - [Do sport programmes lower mortality and morbidity in patients with coronary heart disease?]. PMID- 22234801 TI - [What can be done about the yo-yo effect?]. PMID- 22234802 TI - Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma. AB - About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy (MYCN-) tumors; G2, stage 4 patients, <= 18 months of age, MYCN- tumors and favorable outcome and G3, Stage 4 patients, >= 19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 (p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 (p < 2.35 E-05). Noteworthy, G3/MYCN- NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/MYCN- NBs than in MYCN amplified G3 may also explain why patients >= 19 months have a poor outcome independently by MYCN status. PMID- 22234803 TI - Combining submerged electrospray and UV photopolymerization for production of synthetic hydrogel microspheres for cell encapsulation. AB - Microencapsulation within hydrogel microspheres holds much promise for drug and cell delivery applications. Synthetic hydrogels have many advantages over more commonly used natural materials such as alginate, however their use has been limited due to a lack of appropriate methods for manufacturing these microspheres under conditions compatible with sensitive proteins or cells. This study investigated the effect of flow rate and voltage on size and uniformity of the hydrogel microspheres produced via submerged electrospray combined with UV photopolymerization. In addition, the mechanical properties and cell survival within microspheres was studied. A poly(vinyl alcohol) (PVA) macromer solution was sprayed in sunflower oil under flow rates between 1-100 uL/min and voltages 0 10 kV. The modes of spraying observed were similar to those previously reported for electrospraying in air. Spheres produced were smaller for lower flow rates and higher voltages and mean size could be tailored from 50 to 1,500 um. The microspheres exhibited a smooth, spherical morphology, did not aggregate and the compressive modulus of the spheres (350 kPa) was equivalent to bulk PVA (312 kPa). Finally, L929 fibroblasts were encapsulated within PVA microspheres and showed viability >90% after 24 h. This process shows great promise for the production of synthetic hydrogel microspheres, and specifically supports encapsulation of cells. PMID- 22234805 TI - Influence of knee flexion and femoral cross-pin insertion angle on posterolateral structures of the knee and lateral fixation lengths during ACL reconstruction. AB - PURPOSE: Some studies have investigated knee flexion angle on the sagittal plane and insertion angle of the cross-pin on the coronal plane to evaluate proper femoral fixation. They evaluated the possibilities of injury to the posterolateral (PL) and neurovascular structures using several methods. The purposes of this study were to evaluate (1) the influence of knee flexion and femoral cross-pin insertion angles on knee PL structures and (2) the lateral fixation length of the cross-pin. METHODS: Ten fresh cadaveric knees with no previous surgeries around the knee were used. Transtibial femoral tunnels (1:30 or 10:30 o'clock position) were made at three different knee flexion angles (70 degrees , 90 degrees , and 110 degrees ). Two cross-pin guidewires (superior and inferior pins) were drilled at three different insertion angles [downward 30 degrees , 0 degrees (parallel to floor line), and upward 30 degrees ] for each knee flexion position. The distances from the insertion point of the two cross pins to the lateral collateral ligament (LCL) and popliteus tendon (PT), and the distance from the lateral wall of the femoral tunnel to the lateral cortex of the femoral condyle were measured. RESULTS: No significant differences were observed in the superior and inferior pin depths (p = 0.56 and 0.39). The distances from the superior pin to the LCL and from the inferior pin to the LCL were significantly shorter in all knee flexions with 0 degrees and an upward 30 degrees insertion angle than with 70 degrees and 90 degrees knee flexion with a downward 30 degrees insertion angle, respectively (superior pin: p = 0.02 and 0.03; inferior pin: p = 0.03 and 0.03). No significant difference was observed in the distance between the superior pin and inferior pins and the PT (p = 0.25). CONCLUSIONS: The cross-pin was inserted close to the LCL and PT, and a downward 30 degrees angle was the safest insertion angle. Lateral fixation length was sufficient for the cross-pin fixation in the 10:30- or 1:30-positioned femoral tunnel. PMID- 22234804 TI - Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution. AB - The aim of this study is to determine whether early viral dynamics and evolution predict outcome of primary acute hepatitis C virus (HCV) infection. HCV- and human immunodeficiency virus-negative injection drug users were enrolled prospectively and followed monthly to identify acute HCV infection using RNA detection. Subjects with more than 1 month between HCV-RNA-negative and -positive visits were excluded to ensure stringent acute infection. Differences in medians of log-transformed viral RNA levels and evolutionary rates in each gene of a 5' hemigenomic amplicon were assessed using Mann-Whitney's rank-sum test. Correlation coefficient was calculated using Spearman's rank order. Initial viremia level was 50-fold higher in subjects with spontaneous clearance (compared with persistence) of primary acute HCV infection (median, 7.1 versus 5.4 log(10) IU/mL; P = 0.002). Initial viremia level in subjects with interleukin (IL)28B-C allele at rs12979860 and clearance was higher than that in subjects with IL28B-T allele and persistence (P = 0.001). Evolutionary rates in the hypervariable region 1 (HVR1) region of the E2 gene were significantly higher in self-resolvers than those in persistence subjects during early infection, whereas other genes or regions had comparable rates. All major substitutions in HVR1 in persistence subjects were convergent changes, whereas over the same time interval clearance subjects displayed divergent evolution, indicating different immune responses between the two groups. CONCLUSION: Spontaneous clearance of acute HCV infection is predicted by high initial viremia as well as favorable IL28B genotype and is associated with rapid envelope-sequence evolution. This linkage of host genetics, viral dynamics, and evolution provides new directions for mechanistic studies. (HEPATOLOGY 2012;55:1684-1691). PMID- 22234806 TI - Main-group metal-alkyls: simple formulae but complex structural chemistry. PMID- 22234808 TI - TRAIL signaling and synergy mechanisms used in TRAIL-based combination therapies. AB - TRAIL and agonistic antibodies raised against TRAIL death receptors are highly promising new anticancer agents. In this brief review, we describe the recent advances in the molecular understanding of TRAIL signaling and the progress made in using TRAIL or agonistic antibodies clinically in mono- and combination therapies. Synergies have been reported in various scenarios of TRAIL-based multidrug treatments, and these can be used to potentiate the efficacy of therapies targeting TRAIL death receptors. We pay particular attention to structure the current knowledge on the diverse molecular mechanisms that are thought to give rise to these synergies and describe how different signaling features evoking synergies can be associated with distinct classes of drugs used in TRAIL-based combination treatments. PMID- 22234810 TI - A comparison of case-finding strategies in the UK for the management of hip fractures. AB - Treatment criteria published by the National Osteoporosis Guideline Group (NOGG) in the UK make more efficient use of bone mineral density (BMD) resources than the previous Royal College of Physicians (RCP) guideline. INTRODUCTION: We compared the effectiveness of the RCP case-finding strategy previously used in the UK and the updated guideline published by NOGG, which incorporates the FRAX(r) fracture probability tool. METHODS: Comparisons were made by simulating population samples of 1000 women at ages between 50 and 85 years, using age specific prevalence of risk factors and UK-derived fracture and mortality rates. Comparators comprised the number identified at high risk, the incidence of hip fracture and the femoral neck BMD in those identified, the number needed to scan to identify a hip fracture, the acquisition cost and the cost per hip fracture averted RESULTS: Compared with the RCP strategy, NOGG identified slightly reduced numbers of women at high risk (average 34.6% vs. 35.7% across all ages), but with lower numbers of scans required at each age. For example, NOGG required only 3.5 scans at the age of 50 years to identify one case of hip fracture, whereas RCP required 13.9. At 75 years, the corresponding numbers were 0.9 and 1.5. Thus, the acquisition costs for identifying a hip fracture case and the total costs (acquisition and treatment) per hip fracture averted were lower. CONCLUSION: Compared to the RCP strategy, the FRAX-based NOGG strategy uses BMD resources more efficiently with lower acquisition costs and lower costs per hip fracture averted. PMID- 22234809 TI - Oncogenic viruses and tumor glucose metabolism: like kids in a candy store. AB - Oncogenic viruses represent a significant public health burden in light of the multitude of malignancies that result from chronic or spontaneous viral infection and transformation. Although many of the molecular signaling pathways that underlie virus-mediated cellular transformation are known, the impact of these viruses on metabolic signaling and phenotype within proliferating tumor cells is less well understood. Whether the interaction of oncogenic viruses with metabolic signaling pathways involves enhanced glucose uptake and glycolysis (both hallmark features of transformed cells) or dysregulation of molecular pathways that regulate oxidative stress, viruses are adept at facilitating tumor expansion. Through their effects on cell proliferation pathways, such as the PI3K and MAPK pathways, the cell cycle regulatory proteins p53 and ATM, and the cell stress response proteins HIF-1alpha and AMPK, viruses exert control over critical metabolic signaling cascades. Additionally, oncogenic viruses modulate the tumor metabolomic profile through direct and indirect interactions with glucose transporters, such as GLUT1, and specific glycolytic enzymes, including pyruvate kinase, glucose 6-phosphate dehydrogenase, and hexokinase. Through these pathways, oncogenic viruses alter the phenotypic characteristics and energy-use methods of transformed cells; therefore, it may be possible to develop novel antiglycolytic therapies to target these dysregulated pathways in virus-derived malignancies. PMID- 22234811 TI - Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study. AB - We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (>=65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (>=65 years) best maintains better bone health later in life. INTRODUCTION: Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (>=65 years). METHODS: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. RESULTS: The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (>=65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. CONCLUSION: Our findings conclude that lifelong physical activity with continuation into old age (>=65 years) best maintains better bone health in the elderly. PMID- 22234813 TI - ["Fortschritte neurologie psychiatrie" in 2011]. PMID- 22234812 TI - Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients. AB - Hemodialyzed patients have decreased bone strength not completely characterized. We evaluated bone microarchitecture in hemodialysis patients and compared it to that of subjects without renal disease by high-resolution peripheral quantitative computed tomography (HR-pQCT). Hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women. INTRODUCTION: Although fracture risk is greatly increased in dialysis patients, the corresponding decreased in bone strength has not been completely characterized. METHODS: We evaluated volumetric bone mineral density (vBMD) and bone microstructure by HR-pQCT at the distal radius and tibia in 50 hemodialyzed (HD) patients (30 females, mean age 53.2 +/- 6 years and 20 males, mean age 59.1 +/- 11 years) and 50 sex- and age-matched controls. RESULTS: At the distal radius HD, women showed a 29% reduction in total and trabecular density and trabecular bone volume fraction (p < 0.0001) compared to controls. Trabecular number was reduced by 25% (p < 0.0001), while trabecular separation was increased by 51%. Cortical thickness (-40%, p < 0.0001) and cortical area (-42%, p < 0.0001) were the parameters most reduced, while compact density was the parameter least reduced (-15%, p < 0.0001). Similar findings were found at the tibia. In HD men, HR-pQCT at the distal radius and tibia showed a reduction in volumetric density and microstructure parameters to a lesser extent than in women. In the hemodialyzed group, cortical thickness at the radius was negatively correlated with age both in women and men. At the distal radius and tibia, we found significant negative correlations between Log iPTH and total alkaline phosphatase with cortical vBMD(r = -0.48, p < 0.01; r = -0.69, p < 0.001), thickness (-0.37, p < 0.05; r = -0.60, p < 0.001), and area ((r = -0.43, p = 0.02; r = -0.65, p < 0.001) but only in women. CONCLUSION: We conclude that hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women. PMID- 22234814 TI - [Neuroethics of pharmaceutical cognitive enhancement: the first ten years: current problems and practical guiding principles]. AB - An evaluating survey of the development of the neuroethics of pharmaceutical cognitive enhancement (PCE) during the last decade, focussing on the situation in Germany, has been undertaken. This article presents the most important conceptual problems, current substances and central ethical and legal issues. Very first guidelines and recommendations for policy-makers are formulated at the end of the text. PMID- 22234815 TI - [Contribution of the cerebellum to cognition]. AB - The role of the cerebellum in motor control and motor learning is well recognised. Patients with cerebellar disease consult a doctor because of their motor dysfunction (ataxia). For nearly three decades intense research has been addressing the question to what extent the cerebellum may support cognitive functions. Neuroanatomic findings support the notion that posterolateral parts of the cerebellum contribute to cognition. Although there is a huge number of neuropsychological studies in patients with cerebellar disease, interpretation of findings is frequently hampered by the accompanying motor disorders and extracerebellar lesions. This review summarises the anatomic findings and attempts to give a critical evaluation of findings in human lesion studies. There are good reasons to believe that cerebellar disorders, both cerebellar degeneration and focal cerebellar lesions, may lead to certain cognitive dysfunctions. Disorders in executive function, in particular working memory, and certain higher language tasks are best documented. However, disorders in adults with chronic diseases tend to be mild. Dysfunction appears to be more prominent in patients with acute disease. PMID- 22234816 TI - [Medical documentation in psychiatry]. PMID- 22234817 TI - Alveolar soft part sarcoma in childhood: is Sunitinib-Sutent(r) treatment an effective approach? PMID- 22234818 TI - Lens invasion in retinoblastoma. PMID- 22234819 TI - Genetic variation of coat protein gene among the isolates of Rice tungro spherical virus from tungro-endemic states of the India. AB - Rice tungro disease, one of the major constraints to rice production in South and Southeast Asia, is caused by a combination of two viruses: Rice tungro spherical virus (RTSV) and Rice tungro bacilliform virus (RTBV). The present study was undertaken to determine the genetic variation of RTSV population present in tungro endemic states of Indian subcontinent. Phylogenetic analysis based on coat protein sequences showed distinct divergence of Indian RTSV isolates into two groups; one consisted isolates from Hyderabad (Andhra Pradesh), Cuttack (Orissa), and Puducherry and another from West Bengal, Coimbatore (Tamil Nadu), and Kanyakumari (Tamil Nadu). The results obtained from phylogenetic study were further supported with the SNPs (single nucleotide polymorphism), INDELs (insertion and deletion) and evolutionary distance analysis. In addition, sequence difference count matrix revealed 2-68 nucleotides differences among all the Indian RTSV isolates taken in this study. However, at the protein level these differences were not significant as revealed by Ka/Ks ratio calculation. Sequence identity at nucleotide and amino acid level was 92-100% and 97-100%, respectively, among Indian isolates of RTSV. Understanding of the population structure of RTSV from tungro endemic regions of India would potentially provide insights into the molecular diversification of this virus. PMID- 22234820 TI - Head-up tilt and hyperventilation produce similar changes in cerebral oxygenation and blood volume: an observational comparison study using frequency-domain near infrared spectroscopy. AB - PURPOSE: During anesthesia, maneuvers which cause the least disturbance of cerebral oxygenation with the greatest decrease in intracranial pressure would be most beneficial to patients with intracranial hypertension. Both head-up tilt (HUT) and hyperventilation are used to decrease brain bulk, and both may be associated with decreases in cerebral oxygenation. In this observational study, our null hypothesis was that the impact of HUT and hyperventilation on cerebral tissue oxygen saturation (SctO2) and cerebral blood volume (CBV) are comparable. METHODS: Surgical patients without neurological disease were anesthetized with propofol-remifentanil. Before the start of surgery, frequency-domain near infrared spectroscopy was used to measure SctO2 and CBV at the supine position, at the 30 degrees head-up and head-down positions, as well as during hypoventilation and hyperventilation. RESULTS: Thirty-three patients were studied. Both HUT and hyperventilation induced small decreases in SctO2 [3.5 (2.6)%; P < 0.001 and 3.0 (1.8)%; P < 0.001, respectively] and in CBV [0.05 (0.07) mL x 100 g(-1); P < 0.001 and 0.06 (0.05) mL x 100 g(-1); P < 0.001, respectively]. There were no differences between HUT to 30 degrees and hyperventilation to an end-tidal carbon dioxide (ETCO2) of 25 mmHg (from 45 mmHg) in both SctO2 (P = 0.3) and CBV (P = 0.4). DISCUSSION: The small but statistically significant decreases in both SctO2 and CBV caused by HUT and hyperventilation are comparable. There was no correlation between the decreases in SctO2 and CBV and the decreases in blood pressure and cardiac output during head-up and head-down tilts. However, the decreases in both SctO2 and CBV correlate with the decreases in ETCO2 during ventilation adjustment. PMID- 22234821 TI - Economic assessment of screening for pre-eclampsia. AB - BACKGROUND: Pre-eclampsia is a major contributor to maternal and neonatal morbidity and mortality. Our objectives in this study are to economically assess, from the payer perspective, routine screening for pre-eclampsia using placental markers -placental protein 13 and placental growth factor - and uterine artery Doppler compared with standard care. METHODS: A decision model was developed, which progresses through three sequential endpoints, and compares screening with no screening: (1) Pre-eclampsia yes/no: calculation of the incremental cost of pre-eclampsia-case averted; (2) Hospital discharge: calculation of the mean accumulated costs until discharge after delivery; and (3) Offspring death: calculation of the incremental cost per quality of life-adjusted life-year gained by screening. Data used includes: (1) Obstetrical data of 14 500 births; (2) cost data from the Israeli Ministry of Health and the literature; and (3) screening performance and outcome from the literature. RESULTS: (1) The incremental cost of pre-eclampsia-case averted is $66,949 and $24,723 when the prevalence is 1.7 and 5% respectively. (2) With test cost of $112, the total cost until discharge with/without screening is equal. With pre-eclampsia prevalence of 3%, screening is cheaper. (3) The cost per quality of life-adjusted life-year with screening is $18,919 and < $10,000 with pre-eclampsia prevalence of 1.7 and 3%, respectively. CONCLUSIONS: Screening for pre-eclampsia is cost-effective under various scenarios. PMID- 22234822 TI - Three-dimensional epithelial and mesenchymal cell co-cultures form early tooth epithelium invagination-like structures: expression patterns of relevant molecules. AB - Epithelium invagination is the key feature of early tooth development. In this study, we built a three-dimensional (3D) model to represent epithelium invagination-like structure by tissue engineering. Human normal oral epithelial cells (OECs) and dental pulp stem cells (DPSCs) were co-cultivated for 2-7 weeks on matrigel or collagen gel to form epithelial and mesenchymal tissues. The histological change and gene expression were analyzed by HE staining, immunostaining, and quantitative real-time RT-PCR (qRT-PCR). After 4 weeks of cultivation, OECs-formed epithelium invaginated into DPSCs-derived mesenchyme on both matrigel and collagen gel. OEC-DPSC co-cultures on matrigel showed typical invagination of epithelial cells and condensation of the underlying mesenchymal cells. Epithelial invagination-related molecules, CD44 and E-cadherin, and mesenchymal condensation involved molecules, N-cadherin and Msx1 expressed at a high level in the tissue model, suggesting the epithelial invagination is functional. However, when OECs and DPSCs were co-cultivated on collagen gel; the invaginated epithelium was transformed to several epithelial colonies inside the mesenchyme after long culture period. When DPSCs were co-cultivated with immortalized human OECs NDUSD-1, all of the above-mentioned features were not presented. Immunohistological staining and qRT-PCR analysis showed that p75, BMP2, Shh, Wnt10b, E-cadherin, N-cadherin, Msx1, and Pax9 are involved in initiating epithelium invagination and epithelial-mesenchymal interaction in the 3D OEC-DPSC co-cultures. Our results suggest that co-cultivated OECs and DPSCs on matrigel under certain conditions can build an epithelium invagination-like model. This model might be explored as a potential research tool for epithelial mesenchymal interaction and tooth regeneration. PMID- 22234823 TI - Cord blood levels of toxic and essential trace elements and their determinants in the Terai region of Nepal: a birth cohort study. AB - The purpose of this study is to evaluate the cord blood level of toxic and trace elements and to identify their determinants in Terai, Nepal. One hundred pregnant women were recruited from one hospital in Chitwan, Nepal in 2008. The cord blood levels of toxic [lead (Pb), arsenic (As), and cadmium (Cd)], essential trace elements [zinc (Zn), selenium (Se), and copper (Cu)], demographic, socioeconomic, and behavioral variables were measured. The mean values of Pb, As, Cd, Zn, Se, and Cu in cord blood level were found as 31.7, 1.46, 0.39, 2,286, 175, and 667 MUg/L, respectively. In the multivariate regression model, cord blood As levels from less educated mothers were higher than those from educated mothers (coefficient = -0.01, 95% confidence interval [CI] = -0.02-0.00). The maternal age was positively associated with the cord blood Cd level (coefficient = 0.02, 95% CI = 0.01-0.03), while it was negatively associated with the cord blood As level (coefficient = -0.01, 95% CI = -0.03--0.01). Cord blood levels of Pb, Zn, Se, and Cu were not associated with maternal age, socioeconomic status, living environment, and smoking status. As and Cd levels were relatively lower than those reported in previous studies in Asia, while the levels of Pb and the trace elements were similar. Less educated mothers are more likely to become a higher in utero As source to their fetus, and fetuses of older mothers were more likely to have higher in utero Cd exposure in Terai, Nepal. PMID- 22234824 TI - Evaluation of dog bones in the indirect assessment of environmental contamination with trace elements. AB - The aim of this paper was to determine the level of five elements, two essential for life [zinc (Zn) and copper (Cu)] and three distinctly toxic [lead (Pb), cadmium (Cd), and mercury (Hg)], in four types of biological material in bones of the dog Canis lupus familiaris. The experiment was carried out on bones from the hip joints of dogs. The samples of cartilage, compact bone, spongy bone, and cartilage with adjacent compact bone came from 26 domestic dogs from northwestern Poland. Concentrations of Cu, Zn, Pb, and Cd were determined by ICP-AES (atomic absorption spectrophotometry) in inductively coupled argon plasma, using a Perkin Elmer Optima 2000 DV. Determination of Hg concentration was performed by atomic absorption spectroscopy. In the examined bone material from the dog, the greatest concentrations (median) were observed for Zn and the lowest for Hg (98 mg Zn/kg and 0.0015 mg Hg/kg dw, respectively). In cartilage and spongy bone, metal concentrations could be arranged in the following descending order: Zn > Pb > Cu > Cd > Hg. In compact bone, the order was slightly different: Zn > Pb > Cd > Cu > Hg (from median 70 mg/kg dw to 0.002 mg/kg dw). The comparisons of metal concentrations between the examined bone materials showed distinct differences only in relation to Hg: between concentrations in spongy bone, compact bone, and in cartilage, being greater in cartilage than in compact bone, and lower again in spongy bone. PMID- 22234825 TI - Mineral element levels in wild edible mushrooms from Yunnan, China. AB - Ten species of wild edible mushrooms (Boletus griseus, Boletus speciosus, Lactarius hygrophoroides, Leucopaxillus giganteus, Macrocybe gigantea, Melanoleuca arcuata, Morchella deliciosa, Mycena haematopus, Pulveroboletus ravenelii, and Tricholoma matsutake) collected from Yunnan province of China, were analyzed for ten mineral elements (calcium, chromium, cobalt, copper, iron, magnesium, manganese, potassium, sodium, and zinc) contents using ICP-AES. The minimum and maximum element contents of mushrooms were determined as milligrams per kilograms dry weight for Ca (38-470), Cr (0.45-6.3), Co (0.29-2.3), Cu (13 58), Fe (22-510), Mg (84-550), Mn (1.4-70), K (1,300-4,600), Na (190-670), and Zn (16-160). The mushrooms species with the highest levels of mineral elements were B. griseus for K and Na, P. ravenelii for Cu, M. deliciosa for Mn, L. giganteus for Cr and Fe, M. gigantea for Ca, Mg and Zn, T. matsutake for Co. These results demonstrate that the mineral element contents in mushrooms are considerably species dependent and affected by environmental factors. PMID- 22234826 TI - Suitability of isolated rat jejunum model for demonstration of complete absorption in humans for BCS-based biowaiver request. AB - The objective of this study was to evaluate the suitability and acceptance criteria of isolated rat jejunum model for Biopharmaceutics Classification System (BCS)-permeability classification. The evaluation followed recommended procedures including investigation of tissue integrity by applying damage triggers (nitrogen gassing, elevated temperature, azide addition), characterization of transporter functionality, and expression and development of correlation between rats' apparent permeability coefficient (P(app) ) versus humans' and versus oral fraction absorbed (f(a) ) in humans. Firstly, damage triggers caused a decrease in transepithelial resistance and potential difference and increase in lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran P(app) . However, only FITC-dextran P(app) 's increase was considered significant in all treatment groups, making FITC-dextran a better indicator of jejunum integrity than LY. Secondly, the expression level of selected intestinal transporters highly correlated between rat and human and functionality of P-glycoprotein was confirmed. P(app) of investigated drugs correlated with human f(a) (R(2) = 0.85, n = 20) and with human permeability coefficients (R(2) = 0.86, n = 13). Utility of described model for BCS classification was shown on levetiracetam, where significantly higher permeability of levetiracetam as compared with internal standard metoprolol was determined (t-test, p = 0.005). In conclusion, isolated rat jejunum model is a useful tool not only for mechanistic investigation, but also for permeability classification according to BCS and consequently for BCS based biowaiver procedures. PMID- 22234827 TI - Economic evaluation of the national immunization program of rotavirus vaccination for children in Korea. AB - The authors assessed the cost-effectiveness of rotavirus vaccination to develop an evidence-based national immunization program in Korea. A Markov model was constructed to compare the costs and clinical outcomes of vaccination versus no vaccination. The birth cohort of 493189 infants in 2007 was followed until the age of 5 years. Korea-specific data for epidemiological characteristics and economic burden of rotavirus diarrhea were used for the modeled estimation. Efficacy of RotaTeq(r) was based on a recent clinical trial. Rotavirus vaccination would prevent 181238 symptomatic cases (reduction rate = 63.2%) over 5 years after birth. From the societal perspective, at a vaccination cost of 100000 Korean won (KW; 1 US$ ~ 1200 KW) per dose, universal vaccination would cost 375 620 KW per case averted. The breakeven price of vaccine was 56061 KW. Rotavirus vaccination would reduce the burden of the disease substantially and be a cost-effective strategy to prevent rotavirus diarrhea in Korea. PMID- 22234828 TI - Effects of eating behaviors on being overweight in japanese university students: a cross-sectional survey at the Okayama University. AB - Being overweight is an important risk factor for lifestyle-related diseases. The objective of the present study was to examine whether eating until full, eating quickly, or both eating behaviors were associated with being overweight, defined as a body mass index (BMI) >= 25, in young adults. This cross-sectional survey comprised 1918 students (1139 male and 779 female students) at the Okayama University in Japan. In logistic regression analysis, eating until full was not associated with being overweight in either sex. The adjusted odds ratio of being overweight among those who reported eating quickly was 3.93 (2.45-6.31; P < .0001) for male and 1.59 (0.79-3.21; P = .193) for female students. Moreover, the adjusted odds ratio of being overweight was 2.72 (1.72-4.30; P < .001) in male students who frequently reported eating a fatty diet. The combination of eating quickly and frequently eating a fatty diet had a supra-additive effect on being overweight in the male students. PMID- 22234829 TI - Domperidone with ORT in the treatment of pediatric acute gastroenteritis in Japan: a multicenter, randomized controlled trial. AB - Domperidone is an antiemetic that is often prescribed for children with acute gastroenteritis in Japan. In this study, the authors assessed the efficacy of domperidone prescription in combination with oral rehydration treatment (ORT) in the treatment of vomiting during acute gastroenteritis in children during the early period. They performed a prospective multicenter randomized trial in Japan. Patients received either ORT or ORT and domperidone prescription. The primary outcome was the proportion of patients who had vomiting during the first 2 hours after randomization. A total of 56 children were eligible; 24 received ORT alone, and 32 received ORT and prescribed domperidone suppository. Results showed that 27.3% of children in the ORT group vomited as compared with 20.7% of children in the ORT and domperidone group (P = .41). In this study, it appears that domperidone in combination with ORT in the treatment of acute gastroenteritis does not reduce vomiting in the early period. PMID- 22234830 TI - Study on the factors related with intention of cancer screening among Korean residents: application of information-motivation-behavioral skills model. AB - This study investigated the relationship between intention of undergoing cancer screening and information, motivation, and behavioral skills using an information motivation-behavioral skills model. The authors performed a telephone survey of a random sample of 2030 residents aged 30 to 69 years from 6 counties of Gangwon province, South Korea from July 15 to July 25, 2009. Questions about information, motivation, and behavioral skills were examined using a confirmatory factor analysis and relationships among factors were analyzed using a structure equation model. The intention of undergoing cancer screening showed a positive relationship between intention to undergo cancer screening and information(r = .134, P < .001), social norms(r = .059, P = .009), and behavioral skills(r = .129, P < .001). Therefore, comprehensive intervention considering motivation and behavioral skills as well as information is necessary to improve cancer screening rates. PMID- 22234831 TI - Leveraging community-based financing for women's nonmaternal health care: experiences of rural Indian women. AB - Given the increasing need for mainstreaming household financing for women's nonmaternal health care and evidences on community-based financing's contribution to women's health care in general, this study explored their scope for nonmaternal health care in Orissa. A qualitative assessment conducted focus group discussions with rural women who met the eligibility criteria. Community-based financing provided financial access and risk protection for women's nonmaternal health care during the previous 1 year, though not adequately. Schemes covering outpatient care (or mild illnesses) provided relatively more financial access. The major determinants of their restricted financial access were limited sum assured, noncomprehensive coverage of services, exclusion of elderly women, and the lower priority households gave to nonmaternal health care. Community-based financing requires relevant structural changes along with demand-side behavioral modifications to ensure optimal attention to women's nonmaternal health care. PMID- 22234832 TI - The Bahasa Melayu version of the Global Physical Activity Questionnaire: reliability and validity study in Malaysia. AB - This study aimed to assess the reliability and concurrent validity of the Bahasa Melayu version of the Global Physical Activity Questionnaire (GPAQ-M) by comparing it with the short form of the International Physical Activity Questionnaire (IPAQ-S) and objectively measuring physical activity using a Yamax DigiWalker (Yamax, Tokyo, Japan) pedometer. A total of 100 adults aged between 20 and 58 years from Kelantan in Malaysia voluntarily participated in this study. The Wilcoxon signed-rank analysis showed no significant differences in 2-week test-retest scores for total metabolic equivalent?minutes?per week and 4 domains of the GPAQ-M. There was a low but significant relationship between time spent on total physical activity measured by the GPAQ-M and average steps per day recorded using the pedometer (r s = .265, P = .013). Significant correlations were also found between GPAQ-M and the IPAQ-S for varying levels of intensity during physical activities (r s = .309-.466, P < .01). PMID- 22234833 TI - Monoesterase activity of a purple acid phosphatase mimic with a cyclam platform. AB - The synthesis and characterization of a novel dinucleating ligand L (L=4,11 dimethyl-1,8-bis{2-[N-(di-2-pyridylmethyl)amino]ethyl}cyclam) and its MU-oxo bridged diferric complex [(H(2)L){Fe(III)(2)(O)}(Cl)(4)](2+) are reported. This diiron(III) complex is the first example of a truly functional purple acid phosphatase (PAP) mimic as it accelerates the hydrolysis of the activated phosphomonoester 2,4-dinitrophenyl phosphate (DNPP). The spectroscopic and kinetic data indicate that only substrates that are monodentately bound to one of the two ferric ions can be attacked by a suitable nucleophile. This is, most probably, a terminal iron(III)-bound hydroxide. DFT calculations support this assumption and also highlight the importance of secondary interactions, exerted by the protonated cyclam platform, for the positioning and activation of the iron(III)-bound substrate. Similar effects are postulated in the native enzyme but addressed in PAP mimics for the first time. PMID- 22234834 TI - Germination and ROS detoxification in bell pepper (Capsicum annuum L.) under NaCl stress and treatment with microalgae extracts. AB - We evaluated the salt tolerance of hybrids of pepper (Capsicum annuum L.) during germination. Treatments were applied at 0, 25, and 50 mM NaCl with preparations of supplemental extracts of the microalgae Dunaliella salina and Phaeodactylum tricornutum to determine the percentage germination rate as well as measured indicators of oxidative stress caused by the salt treatments during seed germination. We found that root growth was favorably influenced by the microalgae leading to increased germination rate. Tissues were analyzed in terms of superoxide radical production, lipid peroxidation, and activity of antioxidant enzymes viz. superoxide dismutase, catalase, and glutathione peroxidase. Our results suggest that application of microalgae extracts significantly reduced (p < 0.05) superoxide radical production, as well as lower lipid peroxidation in comparison to plants without extracts of microalgae. The antioxidant enzymes increased in the presence of microalgae showing a significant difference (p < 0.05). The results suggest differences in oxidative metabolism in response to the magnitude of salt stress and concentrations of microalgae help mitigate salt stress in plants during the germination process. PMID- 22234835 TI - MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are known to be involved in carcinogenesis and tumor progression in hepatocellular carcinoma (HCC). Recently, microRNA-7 (miR-7) has been proven to play a substantial role in glioblastoma and breast cancer, but its functions in the context of HCC remain unknown. Here, we demonstrate that miR-7 inhibits HCC cell growth and metastasis in vitro and in vivo. We first screened and identified a novel miR-7 target, phosphoinositide 3-kinase catalytic subunit delta (PIK3CD). Overexpression of miR-7 would specifically and markedly down regulate its expression. miR-7-overexpressing subclones showed significant cell growth inhibition by G(0) /G(1) -phase cell-cycle arrest and significant impairment of cell migration in vitro. To identify the mechanisms, we investigated the phosphoinositide 3-kinase (PI3K)/Akt pathway and found that Akt, mammalian target of rapamycin (mTOR), and p70S6K were down-regulated, whereas 4EBP1 was up-regulated in miR-7-overexpressing subclones. We also identified two novel, putative miR-7 target genes, mTOR and p70S6K, which further suggests that miR-7 may be a key regulator of the PI3K/Akt pathway. In xenograft animal experiments, we found that overexpressed miR-7 effectively repressed tumor growth (3.5-fold decrease in mean tumor volume; n = 5) and abolished extrahepatic migration from liver to lung in a nude mouse model of metastasis (n = 5). The number of visible nodules on the lung surface was reduced by 32-fold. A correlation between miR-7 and PIK3CD expression was also confirmed in clinical samples of HCC. CONCLUSION: These findings indicate that miR-7 functions as a tumor suppressor and plays a substantial role in inhibiting the tumorigenesis and reversing the metastasis of HCC through the PI3K/Akt/mTOR-signaling pathway in vitro and in vivo. By targeting PIK3CD, mTOR, and p70S6K, miR-7 efficiently regulates the PI3K/Akt pathway. Given these results, miR-7 may be a potential therapeutic or diagnostic/prognostic target for treating HCC. PMID- 22234836 TI - An interactive system for computer-aided diagnosis of breast masses. AB - Although mammography is the only clinically accepted imaging modality for screening the general population to detect breast cancer, interpreting mammograms is difficult with lower sensitivity and specificity. To provide radiologists "a visual aid" in interpreting mammograms, we developed and tested an interactive system for computer-aided detection and diagnosis (CAD) of mass-like cancers. Using this system, an observer can view CAD-cued mass regions depicted on one image and then query any suspicious regions (either cued or not cued by CAD). CAD scheme automatically segments the suspicious region or accepts manually defined region and computes a set of image features. Using content-based image retrieval (CBIR) algorithm, CAD searches for a set of reference images depicting "abnormalities" similar to the queried region. Based on image retrieval results and a decision algorithm, a classification score is assigned to the queried region. In this study, a reference database with 1,800 malignant mass regions and 1,800 benign and CAD-generated false-positive regions was used. A modified CBIR algorithm with a new function of stretching the attributes in the multi dimensional space and decision scheme was optimized using a genetic algorithm. Using a leave-one-out testing method to classify suspicious mass regions, we compared the classification performance using two CBIR algorithms with either equally weighted or optimally stretched attributes. Using the modified CBIR algorithm, the area under receiver operating characteristic curve was significantly increased from 0.865 +/- 0.006 to 0.897 +/- 0.005 (p < 0.001). This study demonstrated the feasibility of developing an interactive CAD system with a large reference database and achieving improved performance. PMID- 22234837 TI - The faithful copy neuron. AB - Theoretical and experimental evidence is presented for the presence in nervous tissue of neurons whose firing rate faithfully follow their input stimulus. Such neurons are shown to deliver their spikes with minimum dissipation per spike. This optimal performance is likely accomplished by use of local circuitry that adjusts conductances to match input currents so that the neuron operates near the threshold for firing. This results in an unusual mechanism for neuronal firing that uses background noise to achieve the desired firing rate. This framework takes place dynamically, and the present deliberations apply under time varying conditions. It is shown that an analytically explicit probability distribution function, which depends on one dimensionless parameter, can account for the interspike interval statistics under general time varying conditions. An innovative analysis based on the unsteady firing rate fits data to the appropriate probability distribution function. PMID- 22234838 TI - Langerhans/dendritic cell sarcoma arising from hairy cell leukemia: a rare phenomenon. PMID- 22234839 TI - Non-atopic IgE and eosinophil cationic protein after allogeneic hematopoietic stem cell transplantation in children. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) in childhood is associated with severe pulmonary complications, but the pathophysiologic mechanisms remain unclear. Our aim was to evaluate the association of total and specific IgE, eosinophil cationic protein (ECP) and eosinophilia in HSCT recipients with pulmonary complications. We prospectively measured total and specific serum IgE, eosinophils, and ECP before and 28, 100, and 180 days after HSCT. We included 30 children (age 2-17 years) undergoing HSCT. Nine patients had a history of previous atopy without being associated with pulmonary complications after HSCT until day +360. Specific IgE levels showed a decline after HSCT, associated with the absence of allergy symptoms, suggesting a reduction of atopy. Elevated total serum IgE levels occurred in seven patients on day +28 after HSCT. This elevation did not coincide with allergy symptoms. ECP showed no correlation with total allergy symptoms, eosinophilia, IgE levels, or pulmonary complications. There was a significant correlation (p = 0.0367) between ECP levels on day +28 and concurrent acute graft-versus-host disease (GvHD). Non atopic serum ECP and IgE levels are elevated on day +28 after HSCT in children, with ECP showing a potential relation to acute GvHD. PMID- 22234840 TI - History of the 'geste antagoniste' sign in cervical dystonia. AB - The geste antagoniste is a voluntary maneuver that temporarily reduces the severity of dystonic posture or movements. It is a classical feature of focal and particularly cervical dystonia. However, the precise historical aspects of geste antagoniste still remain obscure. The goals of this review were (1) to clarify the origin of the geste antagoniste sign; (2) to identify the factors that led to its diffusion in the international literature; (3) to follow the evolution of that term across the twentieth century. We used medical and neurological French, German and English literature of the late nineteenth and early twentieth centuries, and the PubMed database by entering the terms geste antagoniste, antagonistic gesture and sensory trick. The geste antagoniste sign is a legacy of the Paris Neurological School of the end of the nineteenth century. The term was introduced by Meige and Feindel in their 1902 book on tics, written in the vein of their master, Brissaud, who first described this sign in 1893. The almost immediate translations of this book by Giese into German and Kinnier Wilson into English contributed to the rapid spreading of the term geste antagoniste, which is still in use worldwide today. The term antagonistic gesture is the translation proposed by Kinnier Wilson, which also led to the use of the term geste antagonistique. The geste antagoniste sign has long been considered a solid argument for the psychogenic origins of dystonia until the 1980s when Marsden made strong arguments for its organic nature. PMID- 22234841 TI - Interleukin-1A -889C/T polymorphism and risk of Alzheimer's disease: a meta analysis based on 32 case-control studies. AB - The Interleukin-1A (IL-1A) -889C/T polymorphism has been reported to be associated with Alzheimer's disease (AD) susceptibility, but the results of these previous studies have been inconsistent. The aim of this study was to explore whether the IL-1A -889C/T polymorphism confers susceptibility to AD. All studies published up to July 2011 on the association between the IL-1A -889C/T polymorphism and AD risk were identified by searching electronic databases PubMed, Embase and Alzgene. The association between the IL-1A -889C/T polymorphism and AD risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). A total of 32 case-control studies including 7,046 AD cases and 7,534 controls were eventually identified. Overall, positive associations of the IL-1A -889C/T polymorphism with AD risk were found in allele comparison T versus C (OR = 1.019, 95% CI= 1.027-1.198), recessive model TT versus CT + CC (OR = 1.278, 95% CI = 1.073-1.522) and dominant model TT + CT versus CC (OR = 1.102, 95% CI = 1.013-1.200). In subgroup analysis stratified by ethnicity, significant associations were demonstrated in Caucasians but not in Asians. In subgroup analysis according to the age of onset, no significant association was detected. The present meta-analysis suggests that the IL-1A is a candidate gene for AD susceptibility. The IL-1A -889C/T889C/T polymorphism may be a risk factor for AD in Caucasians. Further investigations taking the APOE epsilon4 status and other confirmed genetic factors and potential gene-gene and gene-environmental interactions into consideration for this polymorphism should be conducted. PMID- 22234842 TI - Delirium in acute stroke: screening tools, incidence rates and predictors: a systematic review. AB - Delirium is a common complication in acute stroke yet there is uncertainty regarding how best to screen for and diagnose delirium after stroke. We sought to establish how delirium after stroke is identified, its incidence rates and factors predicting its development. We conducted a systematic review of studies investigating delirium in acute stroke. We searched The Cochrane Collaboration, MEDLINE, EMBASE, CINHAL, PsychINFO, Web of Science, British Nursing Index, PEDro and OT Seeker in October 2010. A total of 3,127 citations were screened, full text of 60 titles and abstracts were read, of which 20 studies published between 1984 and 2010 were included in this review. The methods most commonly used to identify delirium were generic assessment tools such as the Delirium Rating Scale (n = 5) or the Confusion Assessment Method (n = 2) or both (n = 2). The incidence of delirium in acute stroke ranged from 2.3-66%, with our meta-analysis random effects approach placing the rate at 26% (95% CI 19-33%). Of the 11 studies reporting risk factors for delirium, increased age, aphasia, neglect or dysphagia, visual disturbance and elevated cortisol levels were associated with the development of delirium in at least one study. The outcomes associated with the condition are increased morbidity and mortality. Delirium is found in around 26% of stroke patients. Difference in diagnostic and screening procedures could explain the wide variation in frequency of delirium. There are a number of factors that may predict the development of the condition. PMID- 22234844 TI - Development of a thermostable beta-glucuronidase-based reporter system for monitoring gene expression in hyperthermophiles. AB - Mesophilic glucuronidases are the most widely used reporters of gene expression in plants, but unsuitable as reporters in (hyper-)thermophiles due their insufficient thermal stability. Here we present the native 66.8 kDa thermostable beta-glucuronidase of Sulfolobus solfataricus. The enzyme activity is characterized in a wide temperature range ideal for, but not limited to, in vivo genetic study of hyperthermophiles. As a proof of concept, we demonstrate its use as a reporter of gene expression in Sulfolobus, by monitoring a promoter fusion created with the beta-glucuronidase coding gene gusB and a copper-responsive promoter. PMID- 22234845 TI - Reversible protonation of a thiolate ligand in an [Fe]-hydrogenase model complex. PMID- 22234846 TI - Inhibition of voltage-gated Na(+) current by nanosecond pulsed electric field (nsPEF) is not mediated by Na(+) influx or Ca(2+) signaling. AB - In earlier studies, we found that permeabilization of mammalian cells with nsPEF was accompanied by prolonged inhibition of voltage-gated (VG) currents through the plasma membrane. This study explored if the inhibition of VG Na(+) current (I(Na)) resulted from (i) reduction of the transmembrane Na(+) gradient due to its influx via nsPEF-opened pores, and/or (ii) downregulation of the VG channels by a Ca(2+)-dependent mechanism. We found that a single 300 ns electric pulse at 1.6-5.3 kV/cm triggered sustained Na(+) influx in exposed NG108 cells and in primary chromaffin cells, as detected by increased fluorescence of a Sodium Green Dye. In the whole-cell patch clamp configuration, this influx was efficiently buffered by the pipette solution so that the increase in the intracellular concentration of Na(+) ([Na](i)) did not exceed 2-3 mM. [Na](i) increased uniformly over the cell volume and showed no additional peaks immediately below the plasma membrane. Concurrently, nsPEF reduced VG I(Na) by 30-60% (at 4 and 5.3 kV/cm). In control experiments, even a greater increase of the pipette [Na(+)] (by 5 mM) did not attenuate VG I(Na), thereby indicating that the nsPEF-induced Na(+) influx was not the cause of VG I(Na) inhibition. Similarly, adding 20 mM of a fast Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) into the pipette solution did not prevent or attenuate the inhibition of the VG I(Na) by nsPEF. These findings point to possible Ca(2+)-independent downregulation of the VG Na(+) channels (e.g., caused by alteration of the lipid bilayer) or the direct effect of nsPEF on the channel. PMID- 22234848 TI - [Gottingen sentence in noise for different audiogram classes]. AB - BACKGROUND: In addition to the standardized Freiburg sentence test in silence validated speech tests in noise are available. They are mainly used to test the benefit of hearing systems in everyday-life situations. In diagnostics tests in noise can also give additional information of the patients' hearing impairment. The determined speech reception threshold (SRT) depends on the degree of hearing loss and the used speech and noise test material. Aim of this study was to analyze the results of the Gottingen sentence test in noise in relation to different audiogram classes. MATERIAL AND METHODS: The Gottingen sentence test in stationary noise (65 dB) was performed for 135 patients with different degrees of hearing losses. Based on the air-conducted threshold all ears were categorized to an audiogram class by an automated procedure. RESULTS: For the mild hearing losses the results of the Gottingen sentence test increased with increasing pure tone-average (PTA) and the values are smaller than 0 dB SNR with a small standard deviation (+/- 1-2 dB SNR). For the moderate hearing losses values of 5 dB SNR with a standard deviation of 6 dB SNR were achieved on average. Patients with a high hearing loss achieved values higher than 20 dB SNR. CONCLUSION: For the mild hearing losses the results were located in a small range. However, they can give important information about the patient's hearing impairment mainly appears in a noisy environment. With increasing hearing loss also the reduced hearing in silence affects the results achieved with the Gottingen sentence test in noise. Therefore the hearing in silence has to be taken into account at the interpretation of the results. PMID- 22234851 TI - Phytoremediation of 2,4-dichlorophenol using wild type and transgenic tobacco plants. AB - INTRODUCTION: Transgenic plant strategies based on peroxidase expression or overexpression would be useful for phenolic compound removal since these enzymes play an important role in phenolic polymerizing reactions. MATERIAL AND METHODS: Thus, double transgenic (DT) plants for basic peroxidases were obtained and characterized in order to compare the tolerance and efficiency for 2,4 dichlorophenol (2,4-DCP) removal with WT and simple transgenic plants expressing TPX1 or TPX2 gene. Several DT plants showed the expression of both transgenes and proteins, as well as increased peroxidase activity. RESULTS: DT lines showed higher tolerance to 2,4-DCP at early stage of development since their germination index was higher than that of WT seedlings exposed to 25 mg/L of the pollutant. High 2,4-DCP removal efficiencies were found for WT tobacco plants. TPX1 transgenic plants and DT (line d) reached slightly higher removal efficiencies for 10 mg/L of 2,4-DCP than WT plants, while DT plants (line A) showed the highest removal efficiencies (98%). These plants showed an increase of 21% and 14% in 2,4-DCP removal efficiency for solutions containing 10 and 25 mg/L 2,4 DCP, respectively, compared with WT plants. In addition, an almost complete toxicity reduction of postremoval solutions using WT and DT plants was obtained through AMPHITOX test, which indicates that the 2,4-DCP degradation products would be similar for both plants. CONCLUSION: These results are relevant in the field of phytoremediation application and, moreover, they highlight the safety of using DT tobacco plants because nontoxic products were formed after an efficient 2,4-DCP removal. PMID- 22234849 TI - Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats. AB - In the present study, the putative antihyperglycemic and antioxidant effects of a flavanone, naringenin, were evaluated in comparison with those of glyclazide, a standard drug for therapy of diabetes mellitus. Diabetes was induced experimentally in 12-h-fasted rats by intraperitoneal injections of first streptozotocin (50 mg/kg b.w.) and then of nicotinamide (110 mg/kg b.w.) after a 15-min interval. Untreated diabetic rats revealed the following in comparison with normal rats: significantly higher mean levels of blood glucose and glycosylated hemoglobin, significantly lower mean levels of serum insulin, significantly lower mean activities of pancreatic antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase), significantly lower mean levels of plasma non-enzymatic antioxidants (reduced glutathione, vitamin C , vitamin E), significantly elevated mean levels of pancreatic malondialdehyde (MDA) and significantly elevated mean activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Following oral administration of naringenin (50 mg/kg b.w./day) to diabetic rats for 21 days, the following observations were made in comparison with untreated diabetic rats: significantly lower mean levels of fasting blood glucose and glycosylated hemoglobin, significantly elevated serum insulin levels, significantly higher mean activities of pancreatic enzymatic antioxidants, significantly higher mean levels of plasma non-enzymatic antioxidants, lower mean pancreatic tissue levels of MDA and lower mean activities of ALT, AST, ALP and LDH in serum. The values obtained in the naringenin-treated animals approximated those observed in glyclazide-treated animals. Histopathological studies appeared to suggest a protective effect of naringenin on the pancreatic tissue in diabetic rats. These results suggest that naringenin exhibits antihyperglycemic and antioxidant effects in experimental diabetic rats. PMID- 22234852 TI - Fuzzy-logic modeling of Fenton's oxidation of anaerobically pretreated poultry manure wastewater. AB - PURPOSE: A multiple inputs and multiple outputs (MIMO) fuzzy-logic-based model was proposed to estimate color and chemical oxygen demand (COD) removal efficiencies in the post-treatment of anaerobically pretreated poultry manure wastewater effluent using Fenton's oxidation process. Three main input variables including initial pH, Fe+2, and H2O2 dosages were fuzzified in a new numerical modeling scheme by the use of an artificial intelligence-based approach. MATERIALS AND METHODS: Trapezoidal membership functions with eight levels were conducted for the fuzzy subsets, and a Mamdani-type fuzzy inference system was used to implement a total of 70 rules in the IF-THEN format. The product (prod) and the center of gravity (centroid) methods were applied as the inference operator and defuzzification methods, respectively. Fuzzy-logic predicted results were compared with the outputs of two first-order polynomial regression models derived in the scope of this study. Estimated results were also compared to the multiple regression approach by means of various descriptive statistical indicators, such as root mean-squared error, index of agreement, fractional variance, proportion of systematic error, etc. RESULTS AND DISCUSSION: Results of the statistical analysis clearly revealed that, compared to conventional regression models, the proposed MIMO fuzzy-logic model produced very smaller deviations and demonstrated a superior predictive performance on forecasting of color and COD removal efficiencies with satisfactory determination coefficients over 0.98. CONCLUSIONS: Due to high capability of the fuzzy-logic methodology in capturing the non-linear interactions, it was demonstrated that a complex dynamic system, such as Fenton's oxidation, could be easily modeled. PMID- 22234853 TI - Assessment of copper and zinc levels in fish from freshwater ecosystems of Moldova. AB - PURPOSE: The aim of this work was to assess the levels of copper and zinc in fish from the main freshwater ecosystems of Moldova, in relation with species, habitat, age, sex, season, and development stage. METHODS: Fish from Cyprinidae and Percidae families (Cyprinus carpio, Carassius auratus gibelio, Rutilus rutilus heckeli, Abramis brama, Aristichthys nobilis, Hypophtalmichthys molitrix, Sander lucioperca) were collected from Prut and Dniester rivers, Cuciurgan, Dubasari, and Costesti-Stanca reservoirs, and ponds of farms in the Dniester delta. The Cu and Zn content of fish tissues (skeletal muscles, liver, gonads, gills, skin, and scales) was determined by flame atomic absorption spectrophotometer AAS-3, of water by graphite furnace HGA 900 of AAnalist 400. RESULTS: The level of heavy metals accumulation in muscles of immature fish follows their dynamics in water. The highest concentration of zinc was registered in the gonads of mature fish, and of copper-in the liver. The lowest Cu and Zn contents were recorded in the muscles and are in the United Nations Food and Agriculture Organization safety-permissible levels for human consumption. Cu and Zn contents in muscles of fish depend on specimen age. Their level in fish gonads was sharply increasing during pre-spawning period. During the early developmental stages, the metal concentration in fish eggs and larvae varies within wide limits, but the accumulation pattern is similar in the investigated species. CONCLUSIONS: The fish represent one of the most indicative factors for the estimation of trace metals pollution in freshwater systems and this is important not only for monitoring purposes, but also for the fish culture ones. PMID- 22234854 TI - Human umbilical cord Wharton's jelly mesenchymal stem cells do not transform to tumor-associated fibroblasts in the presence of breast and ovarian cancer cells unlike bone marrow mesenchymal stem cells. AB - Human bone marrow mesenchymal stem cells (hBMMSCs) were shown to transform into tumor-associated fibroblasts (TAFs) when in the vicinity of breast cancer tumors and played an important role in tumor enhancement and metastasis. In early human development MSCs migrating from the yolk sac and aorta-gonad-mesonephros (AGM) via the umbilical cord to the placenta and back to the fetal bone marrow were shown to get trapped in the gelatinous Wharton's jelly of the umbilical cord. The common origin of the Wharton's jelly MSCs and the finally homed hBMMSCs prompted us to evaluate whether hWJSCs are also involved in TAF transformation. hWJSCs and hBMMSCs were grown in the presence of breast and ovarian cancer cell conditioned medium (MDA-TCM, TOV-TCM) for 30 days. No changes were observed in the hWJSCs but the hBMMSCs transformed from short to thin long fibroblasts, their proliferation rates increased and CD marker expression decreased. The transformed hBMMSCs showed positive staining for the tumor-associated markers FSP, VEGF, EGF, and Tn C. Real-time PCR and multiplex luminex bead analysis showed upregulation of TAF related genes (FSP, FAP, Tn-C, Tsp-1, EGF, bFGF, IL-6, alpha-SMA, VEGF, and TGF beta) for hBMMSCs with low expression for hWJSCs. The luciferase assay showed that hWJSCs previously exposed to MDA-TCM or TOV-TCM had no stimulatory growth effect on luciferase-tagged MDA or TOV cells unlike hBMMSCs. The results confirmed that hWJSCs do not transform to the TAF phenotype and may therefore not be associated with enhanced growth of solid tumors making them a safe MSC for cell based therapies. PMID- 22234855 TI - Quantitative in-line monitoring of solvent-mediated polymorphic transformation of sulfamerazine by near-infrared spectroscopy. AB - The in-line monitoring of pharmaceutical processes with high risk, such as crystallization, has been one of the most popular research topics in recent years. Sulfamerazine (SMZ), a well-known sulfonamide antibacterial agent was investigated to examine the mechanism of polymorphic conversion by solvent mediated polymorphic transformation (SMPT). The primary purpose of this study is to monitor the polymorphic transformation through in-line near-infrared (NIR) measurements and concurrently interpret the whole process quantitatively with off line characterizations. Samples taken at every hour during SMPT were analyzed by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). NIR spectra in the range of 7500-4900 cm(-1) were taken into account for multivariate analysis, which included partial least square (PLS) regression and principal component analysis (PCA). In brief, the form II content was estimated very accurately and reproducibly during the SMPT process not only by XRD but also by the DSC measurements. In addition, the form II content values were predicted very accurately by separate experiments at two designated time points. In a separate study, it was demonstrated that PCA could be employed to explain a complicated process such as SMPT mechanistically by several stages. PMID- 22234856 TI - "Point" centromeres of Saccharomyces harbor single centromere-specific nucleosomes. AB - The "point" centromere of budding yeast is genetically defined by an ~ 125-bp sequence. Recent fluorescence measurements of kinetochore clusters have suggested that this sequence specifies multiple centromere histone 3 (CenH3) nucleosomes. However, high-resolution mapping demonstrates that there is only one CenH3 nucleosome per centromere, providing biochemical confirmation of the point centromere model. PMID- 22234857 TI - A novel downstream regulatory element cooperates with the silencing machinery to repress EPA1 expression in Candida glabrata. AB - Candida glabrata, an opportunistic fungal pathogen, adheres to mammalian epithelial cells; adherence is mediated primarily by the Epa1 adhesin. EPA1 is a member of a large gene family of ~ 23 paralogues, which encode putative adhesins. In this study, we address how EPA1 transcription is regulated. Our data show that EPA1 expression is subject to two distinct negative regulatory mechanisms. EPA1 transcription is repressed by subtelomeric silencing: the Sir complex (Sir2 Sir4), Rap1, Rif1, yKu70, and yKu80 are required for full repression. Activation of EPA1 occurs immediately after dilution of stationary phase (SP) cells into fresh media; however, transcription is rapidly repressed again, limiting expression to lag phase, just as the cells exit stationary phase. This repression following lag phase requires a cis-acting regulatory negative element (NE) located in the EPA1 3'-intergenic region and is independent of telomere proximity. Bioinformatic analysis shows that there are 10 copies of the NE-like sequence in the C. glabrata genome associated with other EPA genes as well as non EPA genes. PMID- 22234858 TI - Gene genealogies within a fixed pedigree, and the robustness of Kingman's coalescent. AB - We address a conceptual flaw in the backward-time approach to population genetics called coalescent theory as it is applied to diploid biparental organisms. Specifically, the way random models of reproduction are used in coalescent theory is not justified. Instead, the population pedigree for diploid organisms--that is, the set of all family relationships among members of the population--although unknown, should be treated as a fixed parameter, not as a random quantity. Gene genealogical models should describe the outcome of the percolation of genetic lineages through the population pedigree according to Mendelian inheritance. Using simulated pedigrees, some of which are based on family data from 19th century Sweden, we show that in many cases the (conceptually wrong) standard coalescent model is difficult to reject statistically and in this sense may provide a surprisingly accurate description of gene genealogies on a fixed pedigree. We study the differences between the fixed-pedigree coalescent and the standard coalescent by analysis and simulations. Differences are apparent in recent past, within ~ 0.99). However, the RI decreased as the IES increased (from 0.30 +/- 0.11 to 0.26 +/- 0.11, 0.23 +/- 0.11, 0.22 +/- 0.12, and 0.20 +/- 0.12; IES 1-2 vs. 1-3 to 1-6, P < 0.01), as did the OI (from 0.39 +/- 0.14 to 0.34 +/- 0.12, 0.32 +/- 0.13, 0.29 +/- 0.13, and 0.28 +/- 0.13; IES 1-2 vs. 1-3 to 1-6, P < 0.01). CONCLUSIONS: A wider IES might detect dyssynchronous activations, leading to a reduced CFE-mean and RI and OI. Therefore, bipolar signals recorded with a narrower IES might be preferable to more precisely localizing CFAEs and DF sites. PMID- 22234866 TI - Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. AB - In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2)=0.55) with rs429358 of the APOE-epsilon4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected=0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N=563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity. PMID- 22234869 TI - Retrograde popliteal access as bail-out strategy for challenging occlusions of the superficial femoral artery: a multicenter registry. AB - BACKGROUND: The concomitant use of femoral and popliteal accesses has been recommended for challenging superficial femoral artery (SFA) occlusions, but no comprehensive comparison of this approach to a strategy of femoral access only is available. We thus aimed to appraise the risk-benefit balance of retrograde popliteal access as bail-out strategy for SFA occlusions. METHODS: Consecutive patients with symptomatic SFA occlusion and undergoing percutaneous revascularization were enrolled. We distinguished patients in whom retrograde popliteal access was required as bail-out strategy versus those not requiring such access. The primary end-point was procedural success. RESULTS: A total of 130 patients (152 limbs) were included, with 23 patients (25 limbs) requiring retrograde popliteal access. Occlusion length was 20.6 +/- 8.8 cm in those requiring popliteal access versus 18.5 +/- 8.5 cm in those without popliteal access, with TASC C/D lesions in 23 (92%) versus 106 (83%). Procedural success was achieved in 92 out of 107 patients (86.0%) treated with a standard approach and 22 out of 23 patients (95.7%) treated with retrograde popliteal access (total 114 out of 130 [87.7%]) and 112 out of 127 limbs (88.2%) and 24 out of 25 limbs (96.0%), respectively (total 136 out of 152 [89.5%]). No significant increase in early or long-term adverse events was associated with retrograde popliteal access. CONCLUSIONS: Whenever standard access sites do not enable successful recanalization of SFA occlusions, retrograde popliteal access can be safely and effectively envisioned as bail-out strategy. PMID- 22234871 TI - Analysis of ethyl glucuronide in hair samples by liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). AB - Many different biomarkers can be used to evaluate ethanol intake. Ethyl glucuronide (EtG) is a direct phase II and minor metabolite of ethanol formed through the UDP-glucuronosyl transferase-catalyzed conjugation of ethanol with glucuronic acid. Its investigation is of interest in both clinical and forensic contexts because of the wide window of detection. A sensitive LC-MS/MS procedure has been developed and fully validated according to the guidelines of forensic toxicology for the analysis of EtG in hair. Sample preparation and chromatographic separation were thoroughly optimized. The analysis was performed in the multiple reaction monitoring mode using the transitions m/z 221 -> 203 (for the quantification) and 221 -> 85 or 75 (for the qualification) for EtG, and m/z 226 -> 208 (for quantification) and 226 -> 75 or 85 (for qualification) for EtG-D5, used as the internal standard. Analyses were carried out using an Inertsil ODS-3 column (100 * 3 mm i.d., 3 um particle size) and a mobile phase composed of formic acid and acetonitrile. Various SPE cartridges and solvents were tested in order to obtain the highest recoveries and cleanest extracts. The assay linearity of EtG was confirmed over the range from 20 to 2500 pg mg(-1), with a coefficient of determination (R(2) ) above 0.99. The lower limit of quantitation (LLOQ) was 20 pg mg(-1) and the limit of detection was 10 pg mg(-1). Intra- and inter-day assays were less than 15% except at the LLOQ (20%). The analytical method was applied to 72 post-mortem hair samples. EtG concentration in the hair ranged from 0 to 653 pg mg(-1) hair. PMID- 22234868 TI - TGFbeta-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFbeta Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1 encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2+/-23 years, MLVWT 20.8+/-4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM. PMID- 22234873 TI - Nondestructive detection of glass vial inner surface morphology with differential interference contrast microscopy. AB - Glass particles generated by glass dissolution and delamination of the glass container for pharmaceutical products have become a major issue in the pharmaceutical industry. The observation of glass particles in certain injectable drugs, including several protein therapeutics, has recently resulted in a number of product recalls. Glass vial surface properties have been suggested to play a critical role in glass dissolution and delamination. Surface characterization of glass container, therefore, is important to evaluate the quality of the glass container. In this work, we demonstrate that differential interference contrast (DIC) microscopy is a powerful, effective, and convenient technique to examine the inner surface morphology of glass vials nondestructively. DIC microscopy does not require the cutting of the glass vial for scanning the inner surface and has sufficient spatial resolution to reveal glass pitting, phase separation, delamination scars, and other defects. Typical surface morphology of pharmaceutical glass vials with different alkalinity are compared and discussed. PMID- 22234874 TI - The practical understanding and treatment of asthma. AB - Asthma is a syndrome which is seen by physicians in nearly every specialty and affects millions of people throughout the world. Although the geoepidemiology with respect to prevalence and incidence of asthma does vary, even under the most mild of circumstance, asthma is among the leading causes of school absenteeism, work loss, and physician visits. In the past, it was considered primarily a disorder of childhood. Hence, the adage that children outgrow their asthma. We now realize that children really only outgrow their pediatrician and the genetic predisposition to asthma and bronchial hyperactivity persists throughout life. This issue is devoted to key papers that focus on important clinical problems in allergies and asthma. This issue is dedicated to helping the many sufferers of asthma with the hope that this topic will eventually become a medical anachronism. PMID- 22234875 TI - Physical activity in nursing homes--barriers and facilitators: a cross-sectional study. AB - PURPOSE: To explore different institutional barriers to and facilitators of physical activity (PA) in nursing homes. METHODS: Cross-sectional survey of 40 German nursing homes and 217 nursing-home residents (NHRs; M +/- SD age 80 +/- 10.2 yr, 55% women, MMSE >=20). Quantitative data were collected on the structural characteristics of nursing homes and the PA services available. RESULTS: Forms of exercise available were not adequately communicated to residents. Overall participation was below 50%. Awareness was significantly higher in residents with informed relatives (p = .003). A broad range of forms of exercise was generally available (M +/- SD 5 +/- 2.22, range 0-10), but they were rarely tailored to NHRs' needs and their effectiveness remains questionable. CONCLUSION: Multidimensional opportunities to promote PA in NHRs are identified. PMID- 22234876 TI - Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. AB - Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ~ 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4(+) CD25(+++) FOXP3(+) ) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3(+) /4(+) ); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 +/- 8.0; 3.5 +/- 2.1 years post-liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3(+) cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. CONCLUSIONS: TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal. PMID- 22234879 TI - Twisted amide analogues of Troger's base. PMID- 22234877 TI - Structural mechanism of the phosphorylation-dependent dimerization of the MDC1 forkhead-associated domain. AB - MDC1 is a key mediator of the DNA-damage response in mammals with several phosphorylation-dependent protein interaction domains. The function of its N terminal forkhead-associated (FHA) domain remains elusive. Here, we show with structural, biochemical and cellular data that the FHA domain mediates phosphorylation-dependent dimerization of MDC1 in response to DNA damage. Crystal structures of the FHA domain reveal a face-to-face dimer with pseudo-dyad symmetry. We found that the FHA domain recognizes phosphothreonine 4 (pT4) at the N-terminus of MDC1 and determined its crystal structure in complex with a pT4 peptide. Biochemical analysis further revealed that in the dimer, the FHA domain binds in trans to pT4 from the other subunit, which greatly stabilizes the otherwise unstable dimer. We show that T4 is phosphorylated primarily by ATM upon DNA damage. MDC1 mutants with the FHA domain deleted or impaired in its ability to dimerize formed fewer foci at DNA-damage sites, but the localization defect was largely rescued by an artificial dimerization module, suggesting that dimerization is the primary function of the MDC1 FHA domain. Our results suggest a novel mechanism for the regulation of MDC1 function through T4 phosphorylation and FHA-mediated dimerization. PMID- 22234880 TI - A Men's Health National Policy Agenda. PMID- 22234878 TI - The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator. AB - Mdc1 is a large modular phosphoprotein scaffold that maintains signaling and repair complexes at double-stranded DNA break sites. Mdc1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with the tail of gammaH2AX following DNA damage, but the role of the N-terminal forkhead associated (FHA) domain remains unclear. We show that a major binding target of the Mdc1 FHA domain is a previously unidentified DNA damage and ATM-dependent phosphorylation site near the N-terminus of Mdc1 itself. Binding to this motif stabilizes a weak self-association of the FHA domain to form a tight dimer. X-ray structures of free and complexed Mdc1 FHA domain reveal a 'head-to-tail' dimerization mechanism that is closely related to that seen in pre-activated forms of the Chk2 DNA damage kinase, and which both positively and negatively influences Mdc1 FHA domain-mediated interactions in human cells prior to and following DNA damage. PMID- 22234881 TI - Copy number variations of GSTT1 and GSTM1, colorectal cancer risk and possible effect modification of cigarette smoking and menopausal hormone therapy. AB - Copy number variations (CNVs) of the glutathione-S-transferase theta-1 (GSTT1) and glutathione-S-transferase MU-1 (GSTM1) gene loci can lead to complete lack of enzyme and have been associated with colorectal cancer (CRC) risk. As GSTs are involved in the detoxification of xenobiotics, CNVs may modify CRC risk associated with smoking exposure and menopausal hormone therapy (MHT) use. We investigated CRC risk associated with GSTT1 and GSTM1 CNVs and their interaction with smoking in 1,796 cases and 1,806 age-, sex- and residence-matched controls from a German population-based case-control study (DACHS). The interaction with MHT was assessed in the subset of 684 postmenopausal female cases and 681 controls. Trimodular genotypes (0/0, 1/0 and 1/1) were determined with relative quantification based on multiplex real-time polymerase chain reaction. The associations with CRC risk as well as possible effect modifications were evaluated using conditional logistic regression analysis. CNVs of GSTT1 and GSTM1 were not significantly associated with CRC risk. Compared to the 1/1 genotype, odds ratios (ORs) for the 0/1 genotype and the 0/0 genotype were 0.89 [95% confidence interval (CI): 0.77-1.04] and 0.97 (95% CI: 0.80-1.18) for GSTT1, and 0.99 (95% CI: 0.78-1.27) and 1.03 (95% CI: 0.81-1.31) for GSTM1. Compared to the non-null genotype, ORs for the null-genotype were 1.04 (95% CI: 0.87-1.23) for GSTT1 and 1.03 (95% CI: 0.91-1.18) for GSTM1. No significant interaction with smoking and MHT use was observed. Our study does not provide evidence for a strong association between CRC risk and CNVs of GSTT1 or GSTM1 or for an effect modification of smoking or MHT use. PMID- 22234882 TI - Cortical hyperexcitability in migraine and aversion to patterns. AB - BACKGROUND: Patients with migraine are averse to certain visual stimuli, such as flicker and striped patterns that evoke paroxysmal EEG activity in patients with photosensitive epilepsy. Migraineurs demonstrate a hyper-responsiveness to such stimuli, and there is debate as to whether the aversion and hyper-responsiveness are due to a hyperexcitability of the cortex similar to that in patients with photosensitive epilepsy. In these patients grating patterns with certain spatial characteristics can be epileptogenic, depending critically on their movement. If the contours of the grating drift continually, the grating is not epileptogenic, but if the contours are static or if their direction is repeatedly and rapidly reversed so as to vibrate, the grating then becomes highly epileptogenic. METHODS: We compared aversion to vibrating, drifting and static gratings in migraineurs and controls. The contrast of each grating was gradually increased, but only until the participant felt discomfort, so as to obtain a contrast threshold for aversion with minimal exposure. RESULTS: Migraineurs had lower thresholds than the control group, indicating greater aversion. For both groups the threshold was higher (aversion was lower) for static than for both types of moving gratings. The drifting gratings were more aversive than the vibrating gratings when both groups were combined. CONCLUSION: The findings suggest that the aversion shown by migraineurs is not attributable to a cortical hyperexcitability similar to that in photosensitive epilepsy. PMID- 22234883 TI - Early dosing and efficacy of triptans in acute migraine treatment: the TEMPO study. AB - AIM: To compare the effectiveness of early or late triptan intake in the treatment of acute migraine attacks. METHODS: The TEMPO study was a French prospective, multicentre, two-phase study conducted in neurological practice. Two hundred-and-ten migraine patients who were regular triptan users were enrolled. In the first phase, patients treated three attacks as they usually did. In the second phase, those who initially practiced late dosing ( >= 1 hour after headache onset) were instructed to change to early dosing ( < 1 hour). RESULTS: A total of 144 patients completed the first phase. Seventy-nine patients constituted the 'early dosers' group and 65 patients the 'late dosers' group. In this phase, early dosing produced higher rates (n = 38; 52.8%) of freedom from pain at 2 hours in at least two of three attacks compared with late dosing (n = 19; 30.2%; p < 0.01). In the second phase, switching from late to early dosing following the physician's instruction (n = 42 patients) also improved the rates of freedom from pain at 2 hours (from 38.1% (n = 16) to 53.7% (n = 22); p < 0.05). CONCLUSION: This suggests that advising patients on the importance of early triptan intake after headache onset may help improve the efficacy of acute migraine treatments. PMID- 22234884 TI - Comparative long-term efficacy and safety of drug-eluting stent versus coronary artery bypass grafting in ostial left main coronary artery disease: analysis of the MAIN-COMPARE registry. AB - BACKGROUND: To date, drug-eluting stent (DES) implantation has not been compared with coronary artery bypass grafting (CABG) for ostial left main coronary artery (LMCA) lesions. METHODS: Of the 263 patients in the MAIN-COMPARE registry with ostial LMCA stenosis, 123 were treated with percutaneous coronary intervention (PCI) with DES and 140 with CABG. We compared their 5-year overall survival, composite outcomes of death, Q-wave myocardial infarction (MI) or stroke, and target vessel revascularization (TVR) rates. RESULTS: Unadjusted analysis showed no significant differences between CABG and DES in overall survival rates (95% confidence interval (CI) for hazard ratio (HR): 0.44 to 1.77, P = 0.71), composite outcomes (death, Q-wave MI, or stroke)-free survival rates (95% CI for HR: 0.41-1.63, P = 0.56), and TVR-free survival rates (95% CI for HR: 0.79-5.03, P = 0.14). Multivariate adjusted Cox regression analysis also showed no significant between-group differences in TVR (95% CI for HR: 0.52-3.79, P = 0.49), death (95% CI for HR: 0.79-2.82, P = 0.22) and the composite of death, Q wave MI, or stroke (95% CI for HR: 0.65-2.57, P = 0.46). These results were sustained after propensity score adjustment and propensity score matching analysis. CONCLUSIONS: DES implantation for ostial LMCA lesions showed similar 5 year outcomes of death, major adverse events, and TVR compared with CABG. Although meticulous adjustments decreased baseline difference between the two treatments, the absence of statistical significance could be attributable to the size of the study sample and hidden bias. PMID- 22234885 TI - Chiral mercaptoacetamides display enantioselective inhibition of histone deacetylase 6 and exhibit neuroprotection in cortical neuron models of oxidative stress. AB - Mercaptoacetamide-based ligands have been designed as a new class of histone deacetylase (HDAC) inhibitors for possible use in the treatment of neurodegenerative diseases. The thiol group of these compounds provides a key binding element for interaction with the catalytic zinc ion, and thus differs from the more typically employed hydroxamic acid based zinc binding groups. Herein we disclose the chemistry and biology of some substituted mercaptoacetamides with the intention of increasing HDAC6 isoform selectivity while maintaining potency similar to their hydroxamic acid analogues. The introduction of a stereocenter alpha to the thiol group was found to have a considerable impact on HDAC inhibitor potency. These new compounds were also profiled for their therapeutic potential in an in vitro model of stress-induced neuronal injury and were found to act as nontoxic neuroprotective agents. PMID- 22234886 TI - Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer. AB - Nek2A (NIMA-related kinases 2A) has been known as an important centrosome regulatory factor. The aim of this study was to investigate the expression of Nek2A and the role it played in different stages of breast cancer. We detected the expression of Nek2A in both mRNA and protein levels in MCF10 cell lines including MCF-10A, MCF-10DCIS.com, MCF-10CA1a and in human breast samples which contained normal breast tissue (NBT), breast ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Our study revealed that the mRNA and protein expression of Nek2A were significantly up-regulated in MCF-10DCIS.com and MCF 10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). Our study also presented a correlation between Nek2A mRNA expression and some clinic pathological factors. We found that Nek2A mRNA expression was associated with molecular subtypes, ER, PR and Ki-67 immunoreactivity (P<0.05) in DCIS and associated with histological grade, lymph node metastasis, molecular subtypes, c-erbB-2, and Ki-67 expression (P<0.05) in IDC. In addition, we observed that ectopic expression of Nek2A in "normal" immortalized MCF-10A breast epithelial cell resulted in increased Nek2A which lead to abnormal centrosomes. Furthermore, knockdown of Nek2A in MCF-10DCIS.com could remarkably inhibit cell proliferation and induce cell cycle arrest in MCF-10DCIS.com cell line. These data suggested that Nek2A might bear a close relationship with development and progression of breast carcinoma, and highlighted its role as a novel potential biomarker for diagnosis and a possible therapeutic target for human breast cancer especially for DCIS. PMID- 22234887 TI - A fatigue-resistant photoswitchable fluorescent protein for optical nanoscopy. PMID- 22234888 TI - Selective domain stabilization as a strategy to reduce fusion protein aggregation. AB - A human serum albumin-human growth hormone (HSA-hGH) fusion protein was used as a model to understand the contributions of individual domains to the aggregation behavior of the overall fusion protein. Aggregation of HSA-hGH was studied at two different pH conditions, pH 5 and pH 7. Conformational stability of the HSA domain was modulated by addition of octanoic acid, a binding ligand. Conformational stability of the fusion protein and the HSA domain were determined from experimentally measured values for free energies of unfolding (DeltaG(unf) ) with midpoint of apparent unfolding temperatures (T(m) ) used as surrogate in some cases. Apparent T(m) s of both HSA and HSA-hGH were increased by octanoic acid binding. Osmotic second virial coefficients were measured to monitor protein protein interactions in solution. Reductions in rates of aggregation were observed under solution conditions that increased protein-protein repulsive interactions even when no changes in conformational stability were detected. The results indicate that colloidal instabilities are responsible for HSA-hGH aggregation and that conformational stability of the HSA domain does not play a dominant role in the aggregation of HSA-hGH. PMID- 22234890 TI - HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. AB - Pigmentation of skin, eye, and hair reflects some of the most evident common phenotypes in humans. Several candidate genes for human pigmentation are identified. The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species. However, the exact functional role of HERC2 rs12913832 in human pigmentation is unknown. Here we demonstrate that the HERC2 rs12913832 region functions as an enhancer regulating OCA2 transcription. In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. In contrast, in lightly pigmented melanocytes carrying the rs12913832 C-allele, chromatin-loop formation, transcription factor recruitment, and OCA2 expression are all reduced. Hence, we demonstrate that allelic variation of a common noncoding SNP located in a distal regulatory element not only disrupts the regulatory potential of this element but also affects its interaction with the relevant promoter. We provide the key mechanistic insight that allele-dependent differences in chromatin-loop formation (i.e., structural differences in the folding of gene loci) result in differences in allelic gene expression that affects common phenotypic traits. This concept is highly relevant for future studies aiming to unveil the functional basis of genetically determined phenotypes, including diseases. PMID- 22234889 TI - An ancient genomic regulatory block conserved across bilaterians and its dismantling in tetrapods by retrogene replacement. AB - Developmental genes are regulated by complex, distantly located cis-regulatory modules (CRMs), often forming genomic regulatory blocks (GRBs) that are conserved among vertebrates and among insects. We have investigated GRBs associated with Iroquois homeobox genes in 39 metazoans. Despite 600 million years of independent evolution, Iroquois genes are linked to ankyrin-repeat-containing Sowah genes in nearly all studied bilaterians. We show that Iroquois-specific CRMs populate the Sowah locus, suggesting that regulatory constraints underlie the maintenance of the Iroquois-Sowah syntenic block. Surprisingly, tetrapod Sowah orthologs are intronless and not associated with Iroquois; however, teleost and elephant shark data demonstrate that this is a derived feature, and that many Iroquois-CRMs were ancestrally located within Sowah introns. Retroposition, gene, and genome duplication have allowed selective elimination of Sowah exons from the Iroquois regulatory landscape while keeping associated CRMs, resulting in large associated gene deserts. These results highlight the importance of CRMs in imposing constraints to genome architecture, even across large phylogenetic distances, and of gene duplication-mediated genetic redundancy to disentangle these constraints, increasing genomic plasticity. PMID- 22234891 TI - Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia. AB - Type 2 diabetes mellitus (T2DM) impairs hepatic clearance of atherogenic postprandial triglyceride-rich lipoproteins (TRLs). We recently reported that livers from T2DM db/db mice markedly overexpress the heparan sulfate glucosamine 6-O-endosulfatase-2 (SULF2), an enzyme that removes 6-O sulfate groups from heparan sulfate proteoglycans (HSPGs) and suppresses uptake of TRLs by cultured hepatocytes. In the present study, we evaluated whether Sulf2 inhibition in T2DM mice in vivo could correct their postprandial dyslipidemia. Selective second generation antisense oligonucleotides (ASOs) targeting Sulf2 were identified. Db/db mice were treated for 5 weeks with Sulf2 ASO (20 or 50 mg/kg per week), nontarget (NT) ASO, or phosphate-buffered saline (PBS). Administration of Sulf2 ASO to db/db mice suppressed hepatic Sulf2 messenger RNA expression by 70%-80% (i.e., down to levels in nondiabetic db/m mice) and increased the ratio of tri- to disulfated disaccharides in hepatic HSPGs (P < 0.05). Hepatocytes isolated from db/db mice on NT ASO exhibited a significant impairment in very-low-density lipoprotein (VLDL) binding that was entirely corrected in db/db mice on Sulf2 ASO. Sulf2 ASO lowered the random, nonfasting plasma triglyceride (TG) levels by 50%, achieving nondiabetic values. Most important, Sulf2 ASO treatment flattened the plasma TG excursions in db/db mice after corn-oil gavage (iAUC, 1,500 +/- 470 mg/dL.h for NT ASO versus 160 +/- 40 mg/dL . h for Sulf2 ASO?P < 0.01). CONCLUSIONS: Despite extensive metabolic derangements in T2DM mice, inhibition of a single dys-regulated molecule, SULF2, normalizes the VLDL-binding capacity of their hepatocytes and abolishes postprandial hypertriglyceridemia. These findings provide a key proof of concept in vivo to support Sulf2 inhibition as an attractive strategy to improve metabolic dyslipidemia. PMID- 22234892 TI - Functional recovery after hip resurfacing and rehabilitation. AB - CONTEXT: Surface replacement of the hip is aimed especially at active patients, and it seems to achieve optimal functional results in a short time if associated with a tailored rehabilitation protocol. OBJECTIVE: To assess the functional outcome in a group of active patients after hip resurfacing. DESIGN: Clinical measurement and controlled laboratory study in a case series. SETTING: Gait analysis laboratory. PARTICIPANTS: 8 patients and a control group of 10 subjects. INTERVENTIONS: Patients treated with Birmingham hip-resurfacing system and a tailored rehabilitation protocol MAIN OUTCOME MEASURES: Clinical assessment (Harris Hip Score [HHS]) and instrumented gait analysis including muscular electromyographic assessment. Patients were assessed preoperatively and at 3 and 9 mo follow-up after surgery. RESULTS: HHS showed a significant increase from the baseline to 3- (P = .008) and 9-month (P = .014) follow-up; 5 patients returned to sport. Gait pattern in the presented case series of patients improved substantially 3 mo postoperatively, and minimal further changes were present 9 months postoperatively. Residual abnormalities of time-distance and hip kinematics parameters were consistent with a slow gait. A complete restoration of the muscle-activation pattern during gait was achieved. CONCLUSION: Hip resurfacing associated with a rehabilitation protocol based on the characteristics of the implant provides excellent clinical and functional outcome, especially for very active patients. PMID- 22234893 TI - Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base," are associated with anaplasia in human brain tumors. AB - 5-Methylcytosine (5 mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5 hmC) is generated from 5 mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5 mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5 hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5 hmC positive cells in the cortex and 32.4% 5 hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5 hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5 hmC/dG. levels were related to tumor differentiation, ranging from lowest values of 0.078% 5 hmC/dG in GBMs (WHO Grade IV) to 0.24% 5 hmC/dG in WHO Grade II diffuse astrocytomas. 5 hmC measurements were unrelated to 5 mC values. We find that the number of 5 hmC positive cells and the amount of 5 hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia. PMID- 22234895 TI - Improving the photoinduced charge separation parameters in corrole-perylene carboximide dyads by tuning the redox and spectroscopic properties of the components. AB - A couple of corrole-perylene carboximide dyads (C2-PIa and C2-PIx) have been synthesized and their photoreactivity has been evaluated. We aimed at obtaining better performances for photoinduced charge separation, both in terms of efficiency and in terms of lifetime, with respect to formerly studied systems. The energy level of the charge-separated state was tuned by selecting perylene and corrole components with diverse redox and spectroscopic properties. High spectroscopic energy levels of the perylene carboximide derivatives (PIs) allow a fast charge separation to be maintained in competition with an energy-transfer process from the PI to the corrole unit. Yields and lifetimes of charge separation in toluene are, respectively, 75% and 2.5 MUs for C2-PIa and 65% and 24 ns for C2-PIx. The results and the effect of solvent polarity are discussed in the framework of current energy- and electron-transfer theories. PMID- 22234896 TI - Effects of medium calcium, and agents affecting cytoskeletal function, on cellular volume and morphology in liver tissue in vitro. AB - The possible role of an exocytotic, vesicular mechanism in cellular volume regulation under iso-osmotic conditions has been studied in slices of rat liver. The effects of incubation conditions and agents affecting the actin cytoskeleton were examined for changes of water, ionic composition, and ultrastructure. Slices were pre-incubated at 1 degrees C in an iso-osmotic buffered medium to induce swelling. Upon restoration to 37 degrees C in the same medium, tissue lost water. The Na+-K+ adenosine triphosphatase (ATPase) inhibitor ouabain inhibited water extrusion of about 50%, an effect that was accompanied by the formation of characteristic vesicles in the cytoplasmic region between the Golgi apparatus and the bile canaliculi. Water extrusion in the presence of ouabain was partially inhibited by trifluoroperazine and completely inhibited when the medium was free of Ca2+. In the presence of ouabain, brefeldin A caused a small reduction of water extrusion, whereas phalloidin and cytochalasins A, D, or E caused a marked inhibition. In these conditions there was a marked increase in size and number of cytoplasmic vesicles and a more widespread distribution of them within the cells, lacking the more specific orientation to the Golgi and canalicular regions that was seen in the presence of ouabain alone. Water extrusion was inhibited by phalloidin and cytochalasins in the absence of ouabain. In conclusion, our results are consistent with the hypothesis that iso-osmotic expulsion of water from hepatocytes can proceed partly through an accumulation of water in cytoplasmic vesicles, followed by exocytosis. This mechanism does not depend on Na+-K+ ATPase activity. PMID- 22234897 TI - Diclofenac salts, part 7: are the pharmaceutical salts with aliphatic amines stable? AB - Eight cyclic aliphatic amines, pyrrolidine (Py), piperidine (Pp), morpholine (M), piperazine (Pz), and the N-hydroxyethyl (HE) analogues, were employed to prepare a salt with acidic diclofenac (D). These salts were examined by thermal [differential scanning calorimetry (DSC), thermogravimetric analysis, and hot stage microscopy (HSM)] and spectroscopic [Fourier transform infrared (FTIR), Raman, (1) H NMR, and ultraviolet] analysis. The results show the thermal instability of these salts: the thermal dissociation leaves the starting acidic D, evidenced by the FTIR and Raman spectra inside the molten mass of the salts with M and HEM. The nature of the salt with Pz (1:1 or 1:2) and HEPy (anhydrous or hydrate polymorph), but not for the salt with HEPz and Py, depends on the polarity of the solvent used for the preparation of the salt. Incomplete dehydration of the hydrate Py and Pz salts progressively modifies the thermogram profiles and originates false information. Melting of the salts with Pp, M, and HEM could be demonstrated by HSM, but not with DSC. The difficulty of providing a description of these salts in a simple way originates doubts on the utility of a wide application of aliphatic amines to prepare pharmaceutical salts with D, whose solubility in water does not significantly differ from that of the common sodium D. PMID- 22234898 TI - Fistula between right coronary artery vein graft and right atrium as an immediate complication of percutaneous coronary intervention. AB - Fistula between saphenous vein graft (SVG) and a cardiac chamber or structure is a rare complication after coronary artery bypass grafting (CABG). We report the first case of a fistula between SVG and the right atrium (RA) as an immediate complication after a percutaneous coronary intervention (PCI) in an 86-year-old female. She presented with inferior ST-elevation myocardial infarction (STEMI) and was treated with thrombolytic therapy in a peripheral hospital, which was unsuccessful. PCI to SVG to the right coronary (RCA) was complicated by a fistula to RA. Cardiac magnetic resonance (CMR) confirmed the site of the fistula and also presence of a significant arteriovenous (AV) shunt. Reversal of anticoagulation had no effect on fistula closure. Therefore, a covered stent was deployed for closure of the fistula to avoid long-term complications of the significant AV shunt. In summary, the diagnosis and appropriate management of this rare complication is challenging, but excellent result can be achieved by the use of appropriate percutaneous techniques. PMID- 22234899 TI - Na11Hg52: complexity in a polar metal. PMID- 22234900 TI - Towards the new evolutionary synthesis: gene regulatory networks as information integrators. PMID- 22234904 TI - The minimum sit-to-stand height test: reliability, responsiveness and relationship to leg muscle strength. AB - OBJECTIVE: To determine the reliability of the minimum sit-to-stand height test, its responsiveness and its relationship to leg muscle strength among rehabilitation unit inpatients and outpatients. DESIGN: Reliability study using two measurers and two test occasions. Secondary analysis of data from two clinical trials. SETTING: Inpatient and outpatient rehabilitation services in three public hospitals. SUBJECTS: Eighteen hospital patients and five others participated in the reliability study. Seventy-two rehabilitation unit inpatients and 80 outpatients participated in the clinical trials. METHODS: The minimum sit to-stand height test was assessed using a standard procedure. For the reliability study, a second tester repeated the minimum sit-to-stand height test on the same day. In the inpatient clinical trial the measures were repeated two weeks later. In the outpatient trial the measures were repeated five weeks later. Knee extensor muscle strength was assessed in the clinical trials using a hand-held dynamometer. RESULTS: The reliability for the minimum sit-to-stand height test was excellent (intraclass correlation coefficient (ICC) 0.91, 95% confidence interval (CI) 0.81-0.96). The standard error of measurement was 34 mm. Responsiveness was moderate in the inpatient trial (effect size: 0.53) but small in the outpatient trial (effect size: 0.16). A small proportion (8-17%) of variability in minimum sit-to-stand height test was explained by knee extensor muscle strength. CONCLUSIONS: The minimum sit-to-stand height test has excellent reliability and moderate responsiveness in an inpatient rehabilitation setting. Responsiveness in an outpatient rehabilitation setting requires further investigation. Performance is influenced by factors other than knee extensor muscle strength. PMID- 22234905 TI - Impact of a baseline polymorphism on the emergence of resistance to the hepatitis C virus nonstructural protein 5A replication complex inhibitor, BMS-790052. AB - The influence of naturally occurring polymorphisms on the potency of the HCV nonstructural protein 5A (NS5A) replication complex inhibitor, BMS-790052, was investigated by evaluating hybrid replicons in which the entire NS5A coding region of genotype (GT) la and 1b laboratory (lab) strains (H77c and Con1) were replaced with the corresponding regions of specimens collected from 10 GT-1a- and 6 GT-1b-infected subjects. For baseline (BL) specimens, with no previously observed resistance variants identified by population sequencing, the median 50% effective concentration (EC(50) ) values for BMS-790052 were similar for the clinically derived and lab strains. A Q30R variant was observed at viral breakthrough (VBT) in one of the GT-1a-infected subjects. Because the lowest plasma exposure of BMS-790052 observed in this subject was 117 nM and the median 50% effective concentration value for a GT-1a H77c replicon containing a Q30R substitution is ~7 nM, a rigorous investigation was initiated to determine the basis for resistance. Three approaches were used: (1) replacement of the entire H77c NS5A or (2) replacement of the N-terminal region of NS5A, with sequence from BL and day 14, and (3) substitution of specific amino acids. A BL polymorphism (E62D) did not contribute resistance to BMS-790052; however, the linked variant, Q30R-E62D, conferred high-level resistance in vitro and is likely responsible for VBT in vivo. CONCLUSION: Our data show that a BL polymorphism with minimal effect on the anti-HCV effect of BMS-790052 can affect the emergence of resistance and significantly affect clinical outcome. This work establishes a clear, systematic approach to monitor resistance to NS5A inhibitors in the clinic. PMID- 22234906 TI - Vitamin A supplementation in children and hearing loss. PMID- 22234908 TI - US advisory panellists on drug's safety had ties to manufacturers. PMID- 22234907 TI - Vitamin A supplementation in preschool children and risk of hearing loss as adolescents and young adults in rural Nepal: randomised trial cohort follow-up study. AB - OBJECTIVE: To determine whether vitamin A supplementation administered in the preschool years can lower the risk of hearing loss in adolescence and adulthood. DESIGN: Follow-up study of adolescents and young adults who, as preschool aged children in 1989, were enrolled into a cluster randomised, double blinded, placebo controlled trial of vitamin A supplementation. SETTING: South central, rural Nepal. PARTICIPANTS: 2378 adolescents and young adults aged 14 to 23, representing 51% of those who finished the original trial and 71% of those living in the study area in 2006. INTERVENTIONS: Every four months for 16 months preschool children were visited at home, given an oral 200,000 IU dose of vitamin A (half dose at age 1-11 months, quarter dose at <1 month) or placebo and the parents were queried about any childhood illnesses in the previous week, including purulent discharge from the ears. MAIN OUTCOME MEASURES: Prevalence of mild or worse hearing loss (>= 30 dB) in the most affected ear and tympanometric measures of middle ear function (peak height, ear canal volume, and gradient). RESULTS: During the original trial, the prevalence of middle ear infection during the preschool years did not differ between the supplement groups. By adolescence and early adulthood, a non-significant 17% reduction in hearing loss occurred among those who had periodically received vitamin A compared with placebo as preschool aged children (odds ratio 0.83, 95% confidence interval 0.62 to 1.12). Among participants with any ear discharge in early childhood, vitamin A supplementation was associated with a reduced risk of hearing loss, by 42% (0.58, 0.37 to 0.92) compared with controls, after adjusting the confidence interval for the design effect of the original trial. Abnormal tympanometric peak height of the middle ear system was less likely among participants supplemented with vitamin A in childhood. CONCLUSION: In undernourished settings, periodic, high dose vitamin A supplementation may reduce the risk of hearing loss associated with purulent ear infections in early childhood. PMID- 22234909 TI - Tribal violence worsens humanitarian crisis in South Sudan. PMID- 22234910 TI - Clinical negligence claims against plastic surgeons rise "significantly". PMID- 22234911 TI - Haiti's cholera outbreak provides important lessons for global health. PMID- 22234912 TI - Show us the data: why clinical outcomes matter. PMID- 22234913 TI - Higher senior staffing levels at weekends and reduced mortality. PMID- 22234914 TI - Effective exercises for targeting the gluteus medius. AB - CLINICAL SCENARIO: The gluteus medius (GM) is thought to play an important role in stabilizing the pelvis and controlling femoral adduction and internal rotation during functional activity. GM weakness, resulting in decreased stabilization and control, has been suggested to be related to lower extremity dysfunction and injury. Many clinicians focus on strengthening the GM to improve lower extremity kinematics for the prevention and rehabilitation of injury. An indirect way to measure GM strength is through electromyography. It is generally assumed that exercises producing higher levels of activation will result in greater strengthening effects.3 Understanding what exercises result in the greatest level of GM activation will assist clinicians in their injury prevention and rehabilitation efforts. FOCUSED CLINICAL QUESTION: In a healthy adult population, what lower extremity exercises produce the greatest mean GM activation, expressed as a percentage of maximum voluntary isometric contraction? PMID- 22234915 TI - Impact of a health safety warning and prior authorisation on the use of piroxicam: a time-series study. AB - BACKGROUND: The aim of this study was to assess the quantitative changes in systemic use of piroxicam after the issue of a health safety warning about its risks and the subsequent implementation of prior authorisation. METHODS: We determined the number of monthly daily defined doses/1000 inhabitants/day (DHDs) of piroxicam in the period 2005-2008 in a health area in Spain. The data were analysed graphically, and the impact of the safety warning and introduction of prior authorisation were estimated by using segmented regression analysis. RESULTS: The graph showed that the number of DHDs of piroxicam was stable both before and after the health safety warning but registered a very marked decrease after implementation of prior authorisation, after which DHDs of piroxicam remained stable at a 98% inferior level compared with previous to prior authorisation. Segmented regression analysis showed no statistically significant immediate jump in piroxicam utilisation after the safety warning nor a change in the slope afterwards, but it did show a significant immediate jump after prior authorisation. CONCLUSION: Population exposure to systemic piroxicam remained unaffected by a previous health safety warning but declined sharply after the introduction of prior authorisation. PMID- 22234916 TI - In-vivo Tumor detection using diffusion reflection measurements of targeted gold nanorods - a quantitative study. AB - The ability to quantitatively and non-invasively detect nanoparticles has important implications on their development as an in-vivo cancer diagnostic tool. The Diffusion Reflection (DR) method is a simple, non-invasive imaging technique which has been proven useful for the investigation of tissue's optical parameters. In this study, Monte Carlo (MC) simulations, tissue-like phantom experiments and in-vivo measurements of the reflected light intensity from tumor bearing mice are presented. Following intravenous injection of antibody conjugated poly (ethylene glycol)-coated (PEGylated) gold nanorods (GNR) to tumor bearing mice, accumulation of GNR in the tumor was clearly detected by the DR profile of the tumor. The ability of DR measurements to quantitate in-vivo the concentration of the GNR in the tumor was demonstrated and validated with Flame Atomic Absorption spectroscopy results. With GNR as absorbing contrast agents, DR has important potential applications in the image guided therapy of superficial tumors such as head and neck cancer, breast cancer and melanoma. PMID- 22234917 TI - Heme induced oxidative stress attenuates sirtuin1 and enhances adipogenesis in mesenchymal stem cells and mouse pre-adipocytes. AB - Patho-physiological conditions with high oxidative stress, such as conditions associated with increased denatured heme-proteins, are associated with enhanced adipogenic response. This effect predominantly manifests as adipocyte hypertrophy characterized by dysfunctional, pro-inflammatory adipocytes exhibiting reduced expression of anti-inflammatory hormone, adiponectin. To understand how increased levels of cellular heme, a pro-oxidant molecule, modulates adipogenesis; the following study was designed to evaluate effects of heme on adipogenesis in human mesenchymal stem cells (hMSCs) and mouse pre-adipocytes (3T3L1). Experiments were conducted in the absence and in the presence of a superoxide dismutase (SOD) mimetic (tempol, 100 uM). Heme (10 uM) increased (P<0.05) adipogenesis in hMSCs and mouse pre-adipocytes, where tempol alone (100 umol/L) attenuated adipogenesis in these cells (P<0.05). Tempol also reversed heme-induced increase in adipogenesis in both hMSCs and mouse pre-adipocytes (P<0.05). In addition, heme exposed 3T3L1 exhibited reduced (P<0.05) expression of transcriptional regulator sirtuin 1 (Sirt1), along with, increased (P<0.05) expression of adipogenic markers peroxisome proliferators-activated receptor-gamma (PPARgamma), C/EBPalpha, and aP2. These effects of heme were rescued (P<0.05) in cells concurrently treated with heme and tempol (P<0.05) and prevented in cells over expressing Sirt1. Taken together, our results indicate that heme-induced oxidative stress inhibits Sirt1, thus un-inhibiting adipogenic regulators such as PPARgamma and C/EBPalpha; which in turn induce increased adipogenesis along with adipocyte hypertrophy in pre-adipocytes. Anti-oxidant induced offsetting of these effects of heme supports the role of heme-dependent oxidative stress in mediating such events. PMID- 22234918 TI - Microparticle generation and leucocyte death in Shiga toxin-mediated HUS. AB - BACKGROUND: Shiga toxin-induced haemolytic uraemic syndrome (STEC-HUS) is an acute multisystem disorder characterized by renal failure, neurological dysfunction, haemolysis and intravascular thrombosis. Circulating microparticles originating from a number of cell types including thrombocytes and leucocytes are elevated in paediatric patients. In vitro data also suggest modification of leucocyte death by Shiga toxin. Here, we investigated microparticle generation and leucocyte cell death in vivo in adult STEC-HUS patients during acute disease and recovery. METHODS: Multi-colour flow cytometry and immunofluorescence were used to assess microparticle concentration and provenience thrombocyte microparticle seeding to leucocytes and leucocyte cell death in adult STEC-HUS patients treated at a tertiary care centre during the STEC-HUS outbreak in Germany in 2011. RESULTS: Plasma microparticle concentrations of both platelet and leucocyte origin were elevated during acute STEC-HUS. Platelet microparticles (MP) were detected on a high proportion of monocytes and granulocytes. Among therapeutic interventions, plasma exchange reduced platelet marker expression on leucocytes, inhibition of complement had only moderate impact on the number of circulating MP and did not alter platelet microparticle binding to leucocytes. Numbers of apoptotic and necrotic monocytes and granulocytes were significantly increased in patients with STEC-HUS compared to healthy controls. Complement inhibition significantly increased the number of circulating apoptotic cells. Monocyte apoptosis on admission was significantly higher in patients subsequently assigned to plasma exchange or admitted to the intensive care unit. CONCLUSIONS: In STEC-HUS, elevated numbers of circulating MP and dead leucocytes were detected. Monocyte and granulocyte deaths are novel markers of acute STEC-HUS that may actively contribute to tissue destruction by liberation of pro inflammatory enzymes and cytokines. PMID- 22234919 TI - Steroids with local enteric action in IgA nephropathy and the association between kidney and bowel disease. PMID- 22234920 TI - Effect of powder substrate on foaml drainage and collapse: implications to foam granulation. AB - Foam granulation is a relatively newer wet granulation process whereby foamed binder solutions are added to powders in a mixer. It is essential to understand the effect of powder substrate on foam drainage and half-life, which are relevant to nucleation and agglomeration during foam granulation. Hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) foams were characterized. Anhydrous lactose and stearic acid were selected as model soluble and insoluble substrates, respectively. The effect of these substrates on foam stability was measured by foam drainage and collapse time and microscopic observations. Both HPMC and HPC foams were similar in foam quality and foam density. Lactose destabilized both HPMC and HPC foams and foam drainage and collapse times were reduced two to four times in the presence of lactose. On the contrary, stearic acid did not significantly change foam drainage and collapse times. Microscopically, lactose exhibited rapid wetting within 15 s upon contacting the HPMC and HPC foam beds, whereas stearic acid remained unwetted even after 8 min and collapse of the foam beds. Substrate solubility can influence foam-substrate interaction. On the basis of this, we suggest potential mechanisms of nucleation and agglomeration of soluble and insoluble substrates during foam granulation. PMID- 22234921 TI - "CIN" no more: the use of contrast volume to e-GFR ratio to predict and prevent contrast-induced acute kidney injury. PMID- 22234922 TI - 8q24 risk alleles in West African and Caribbean men. AB - BACKGROUND: Multiple genetic studies have confirmed associations of 8q24 variants with susceptibility to prostate cancer (CaP). However, the magnitude of risk conferred in men living in West Africa is unknown. METHODS: Here we determine the prevalence of 8q24 risk alleles and test for association with CaP risk alleles in West African (WA) descent populations from rural Nigeria, Cameroon, and the Caribbean island of Jamaica. Ten 8q24 SNPs were genotyped in histologically confirmed CaP cases (n = 308) and clinically evaluated controls (n = 469). In addition, unrelated individuals from Sierra Leone (n = 380) were genotyped for comparison of allele frequency comparisons. RESULTS: SNPs rs6983561, rs7008482, and rs16901979 were significantly associated with CaP risk in WAs (P < 0.03). No associations with CaP were observed in our Caribbean samples. Risk alleles for rs6983267, rs7008482, and rs7000448 were highly prevalent (>84%) in West Africa. We also reveal that the A-risk allele for the 'African-specific' SNP bd11934905 was not observed in 1,886 chromosomes from three WA ethnic groups suggesting that this allele may not be common across West Africa, but is geographically restricted to specific ethnic group(s). CONCLUSIONS: We provide evidence of association of 8q24 SNPs with prostate cancer risk in men from Nigeria and Cameroon. Our study is the first to reveal genetic risk due to 8q24 variants (in particular, region 2) with CaP within two WA countries. Most importantly, in light of the disparate burden of CaP in African-Americans, our findings support the need for larger genetic studies in WA descent populations to validate and discern function of susceptibility loci in the 8q24 region. PMID- 22234923 TI - Catalytic asymmetric anti-selective nitroaldol reaction en route to zanamivir. PMID- 22234924 TI - Combined effects of different interleukin-28B gene variants on the outcome of dual combination therapy in chronic hepatitis C virus type 1 infection. AB - In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1-infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P = 0.018). CONCLUSION: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP. (HEPATOLOGY 2012;55:1700-1710). PMID- 22234925 TI - Deep friction massage to treat tendinopathy: a systematic review of a classic treatment in the face of a new paradigm of understanding. AB - STUDY DESIGN: Systematic literature review. OBJECTIVE: To assess the efficacy of deep friction massage (DFM) in the treatment of tendinopathy. CONTEXT: Anecdotal evidence supports the efficacy of DFM for the treatment of tendinopathy. An advanced understanding of the etiopathogenesis of tendinopathy and the resultant paradigm shift away from an active inflammatory model has taken place since the popularization of the DFM technique by Cyriax for the treatment of "tendinitis." However, increasing mechanical load to the tendinopathic tissue, as well as reducing molecular cross-linking during the healing process via transverse massage, offers a plausible explanation for observed responses in light of the contemporary understanding of tendinopathy. EVIDENCE ACQUISITION: The authors surveyed research articles in all languages by searching PubMed, Scopus, Pedro, CINAHL, PsycINFO, and the Cochrane Library using the terms deep friction massage, deep tissue massage, deep transverse massage, Cyriax, soft tissue mobilization, soft tissue mobilisation, cross friction massage, and transverse friction massage. They included 4 randomized comparison trials, 3 at the extensor carpi radialis brevis (ECRB) and 1 supraspinatus outlet tendinopathy; 2 nonrandomized comparison trials, both receiving DFM at the ECRB; and 3 prospective noncomparison trials-supraspinatus, ECRB, and Achilles tendons. Articles meeting inclusion criteria were assessed based on PEDro and Centre for Evidence-Based Medicine rating scales. RESULTS: Nine studies met the inclusion criteria. EVIDENCE SYNTHESIS: The heterogeneity of dependent measures did not allow for meta-analysis. CONCLUSION: The varied locations, study designs, etiopathogenesis, and outcome tools used to examine the efficacy of DFM make a unified conclusion tenuous. There is some evidence of benefit at the elbow in combination with a Mills manipulation, as well as for supraspinatus tendinopathy in the presence of outlet impingement and along with joint mobilization. The examination of DFM as a single modality of treatment in comparison with other methods and control has not been undertaken, so its isolated efficacy has not been established. Excellent anecdotal evidence remains along with a rationale for its use that fits the current understanding of tendinopathy. PMID- 22234926 TI - Euscaphic acid isolated from roots of Rosa rugosa inhibits LPS-induced inflammatory responses via TLR4-mediated NF-kappaB inactivation in RAW 264.7 macrophages. AB - As an attempt to search for bioactive natural products exerting anti-inflammatory activity, we have evaluated the anti-inflammatory effects of euscaphic acid (19alpha-hydroxyursane-type triterpenoids, EA) isolated from roots of Rosa rugosa and its underlying molecular mechanisms in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. EA concentration-dependently reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) induced by LPS in RAW 264.7 macgophages. Consistent with these data, expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and iNOS, COX-2, TNF-alpha, and IL-1beta mRNA were inhibited by EA in a concentration-dependent manner. In addition, EA attenuated LPS-induced DNA binding and transcriptional activity of nuclear factor kappa B (NF-kappaB), which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa Balpha (IkappaBalpha) and consequently by decreased nuclear translocation of p65 subunit of NF-kappaB. Pretreatment with EA significantly inhibited the LPS-induced phosphorylation of IkappaB kinase beta (IKKbeta), p38, and JNK, whereas the phosphorylation of ERK1/2 was unaffected. Furthermore, EA interfered with the LPS-induced clustering of TNF receptor associated factor 6 (TRAF6) with interleukin receptor associated kinase 1 (IRAK1) and transforming growth factor-beta-activated kinase 1 (TAK1). Taken together, these results suggest that EA inhibits LPS-induced inflammatory responses by interference with the clustering of TRAF6 with IRAK1 and TAK1, resulting in blocking the activation of IKK and MAPKs signal transduction to downregulate NF kappaB activations. PMID- 22234927 TI - 4-Bromo-2,5-dimethoxyphenethylamine (2C-B): presence in the recreational drug market in Spain, pattern of use and subjective effects. AB - 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) is a psychoactive analogue of mescaline that is becoming increasingly popular as a rave and club drug. We investigated its presence in the illicit drug market in Spain, its pattern of use and profile of subjective effects. Drug material was analysed for 2C-B and information on pattern of use and subjective effects was obtained from recreational users. Scores were statistically compared with previously collected data on psychostimulants (d-amphetamine), entactogens (MDMA) and psychedelics (ayahuasca and Salvia divinorum). The percentage of samples containing 2C-B doubled between 2006 and 2009, evolved from powder to tablet form and showed low falsification rates. Respondents reported taking 2C-B orally in doses of about 20 mg. Subjective effects involved perceptual modifications analogous to those observed after ayahuasca and salvia but absent after amphetamine and MDMA. Pleasure and sociability effects did not differ from those after MDMA and incapacitation was lower than for the psychedelics used as comparators. In conclusion, we found 2C-B is consistently present in the illicit drug market in Spain. While it elicits perceptual modifications that are analogous to other psychedelics, the lower impairment and higher pleasurable effects make it comparable with entactogens. PMID- 22234928 TI - Comparative effectiveness of switching antipsychotic drug treatment to aripiprazole or ziprasidone for improving metabolic profile and atherogenic dyslipidemia: a 12-month, prospective, open-label study. AB - We studied the effects of switching antipsychotic drug-treated patients with schizophrenia or bipolar disorder who evidenced adverse metabolic side effects as indicated by a triglyceride/high-density lipoprotein ratio (TG/HDL) >= 3.5 to aripiprazole (ARIP; 5-30 mg/day, n = 24) or ziprasidone (ZIP; 40-160 mg/day, n = 28). Anthropometric and metabolic measures, psychopathology, quality of life and motor adverse effects were assessed over a 52-week period with evaluations at baseline, 6, 12, 26 and 52 weeks. There were statistically significant improvements in body weight, body mass index (BMI), TG, HDL and TG/HDL which did not differ between treatments. However, numerous secondary measures including weight and BMI, and the proportion of patients who lost >= 7% or who no longer met criteria for obesity, favored ZIP over ARIP. Decreases in total cholesterol and increases in HDL-cholesterol also favored ZIP. On the other hand, decreases in TG/HDL ratio and reduction in HgbA1c favored ARIP. There were no significant time or group * time interaction effects for most psychopathology measures; however, Global Assessment of Functioning Scores favored ARIP at 6 and 12 months. We conclude that switching patients with evidence of metabolic side effects to either ARIP or ZIP may be beneficial for some, but not all metabolic measures, with minimal risk of worsening of psychopathology and possibly some benefit in that regard as well. PMID- 22234930 TI - Backup support of the mother-child technique: technical considerations for the size of the mother guiding catheter. AB - BACKGROUND: We previously proposed a technique called the "mother-child technique" to facilitate stent delivery for complex coronary lesions. This technique is applicable when the backup support of the guiding catheter is insufficient. In this study, we used an in vitro coronary artery tree model to determine the impact of the size of the mother guiding catheter on the backup support of the mother-child guiding system. METHODS: The backup support was measured for the 4-in-5, 4-in-6, 4-in-7, and 4-in-8 systems as well as for the 5 in-6, 5-in-7, and 5-in-8 systems. RESULTS: Advancement of the child catheter into the coronary artery tree model improved the backup support of the mother-child system. When a 4-Fr child catheter was advanced by 9 cm, the relative increase in the backup support was 174% in the 4-in-5 system; it was 203% in the 4-in-6, and 135% in the 4-in-7 system (P < 0.05 vs. the mother catheter alone). The relative increase with the 5-Fr child catheter was 289% in the 5-in-6 system, and 152% in the 5-in-7 system (P < 0.0001 vs. the mother catheter alone). However, the improvement in the backup support with 9-cm child catheter advancement did not reach statistical significance for either the 4-in-8 (115%) or the 5-in-8 (112%) system (P = NS). CONCLUSIONS: The relative increase in the backup support of the mother-child system was inversely related to the size of the mother guiding catheter. Thus, the mother-child technique may be most useful for PCIs in which a small guiding catheter is used, such as transradial coronary interventions. PMID- 22234931 TI - Completeness of dictated operative reports in breast cancer--the case for synoptic reporting. AB - BACKGROUND: Currently, the dictated operative report forms the cornerstone of documenting breast cancer surgery. Synoptic electronic reporting using a standardized template has been proposed for breast cancer operative notes to improve documentation. The goal of this study was to determine the current completeness of dictated operative reports for breast cancer surgery. METHODS: An iterative, consensus-based approach to determining elements of a proposed synoptic surgical operative report identified critical elements. We then evaluated the dictated operative reports of 100 consecutive breast cancer patients for completeness of these elements. RESULTS: Details regarding presentation and diagnosis were frequently incomplete (84%). Among patients undergoing mastectomy, the potential for breast conservation was partially described in only 60%. Only 41% had data regarding intra-operative margin assessment during breast conservation surgery. In axillary lymph node dissections, 92% of patients had complete data about preservation of nerves, yet only 14% of reports contained complete information regarding sentinel lymph node biopsy. Closure was partially described in 91%. CONCLUSIONS: The dictated operative report for breast cancer surgery does not adequately capture important data. A synoptic reporting system, which requires documentation of important elements, is a potentially beneficial tool in breast cancer surgery. PMID- 22234929 TI - Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings. AB - Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of alpha2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal. PMID- 22234932 TI - Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion. AB - We performed a review of public microarray data that revealed a significant down regulation of Rnd3 expression in hepatocellular carcinoma (HCC), as compared to nontumor liver. Rnd3/RhoE is an atypical RhoGTPase family member because it is always under its active GTP-bound conformation and not sensitive to classical regulators. Rnd3 down-regulation was validated by quantitative real-time polymerase chain reaction in 120 independent tumors. Moreover, Rnd3 down expression was confirmed using immunohistochemistry on tumor sections and western blotting on human tumor and cell-line extracts. Rnd3 expression was significantly lower in invasive tumors with satellite nodules. Overexpression and silencing of Rnd3 in Hep3B cells led to decreased and increased three-dimensional cell motility, respectively. The short interfering RNA-mediated down-regulation of Rnd3 expression induced a loss of E-cadherin at cell-cell junctions that was linked to epithelial-mesenchymal transition through the up-regulation of the zinc finger E-box binding homeobox protein, ZEB2, and the down-regulation of miR-200b and miR-200c. Rnd3 knockdown mediated tumor hepatocyte invasion in a matrix metalloproteinase-independent, and Rac1-dependent manner. CONCLUSION: Rnd3 down regulation provides an invasive advantage to tumor hepatocytes, suggesting that RND3 might represent a metastasis suppressor gene in HCC. PMID- 22234933 TI - Attention: Minimal hepatic encephalopathy and road accidents. PMID- 22234934 TI - Efficient synthesis of thiopyrans using a sulfur-enabled anionic cascade. PMID- 22234935 TI - Effects of arthroscopic partial meniscectomy on quadriceps strength: a systematic review. AB - CONTEXT: Arthroscopic partial meniscectomy (APM) after meniscal tear has been widely accepted and associated with quick return to activity. Unfortunately, meniscectomy is associated with risk for knee osteoarthritis, which may be attributed to postsurgical quadriceps weakness. This has important implications, as the quadriceps play a prominent role in knee stabilization and energy attenuation in the lower extremity. OBJECTIVE: To determine the magnitude of interlimb quadriceps strength deficits in people with unilateral APM by systematically reviewing the current literature. EVIDENCE ACQUISITION: The Web of Knowledge databases were searched on September 22, 2010, using terms meniscus OR meniscectomy AND quadriceps strength OR quadriceps weakness. Included articles were written in English, reporting means and SDs of isokinetic peak torque at 60 degrees and 180 degrees /s for both limbs. EVIDENCE SYNTHESIS: Four articles were included in the final analysis. Effect sizes and 95% confidence intervals (CI) were calculated between limbs for periods less than 1 mo, 1-3 mo, 3-6 mo, and more than 6 mo. CONCLUSION: Homogeneous effect sizes indicate quadriceps weakness in the involved limb. Effects were strong at less than 1 mo (d = -1.01 to -1.62), while weak to strong effects were found for 1-3 mo (d = -0.40 to 8.04) and 3-6 mo (d = -0.40 to -5.11). Weak effects were found at more than 6 mo (d = -0.30 to -0.37). Definitive effects with a CI not crossing zero were found in 65% of the data. Although APM patients return to function within weeks after surgery, prolonged quadriceps strength deficits may increase the risk of knee joint degeneration. Furthermore, evidence of bilateral dysfunction after unilateral injury may suggest that neuromuscular deficits post-APM are greater than the interlimb differences found in this review. Further research should be conducted to determine the nature of strength deficits and the best methods for restoring strength after APM. PMID- 22234936 TI - Seeing touch and pain in a stranger modulates the cortical responses elicited by somatosensory but not auditory stimulation. AB - Viewing other's pain inhibits the excitability of the motor cortex and also modulates the neural activity elicited by a concomitantly delivered nociceptive somatosensory stimulus. As the neural activity elicited by a transient nociceptive stimulus largely reflects non nociceptive-specific, multimodal neural processes, here we tested, for the first time, whether the observation of other's pain preferentially affects the brain responses elicited by nociceptive stimulation, or instead similarly modulates those elicited by stimuli belonging to a different sensory modality. Using 58-channel electroencephalography (EEG), we recorded the cortical responses elicited by laser and auditory stimulation during the observation of videoclips showing either noxious or non-noxious stimulation of a stranger's hand. We found that the observation of other's pain modulated the cortical activity consisting in an event-related desynchronization in the beta band (beta ERD), and elicited by nociceptive laser stimuli, but not by auditory stimuli. Using three different source analysis approaches, we provide converging evidence that such modulation affected neural activity in the contralateral primary sensorimotor cortex. The magnitude of this modulation correlated well with a subjective measure of similarity between the model's hand and the onlooker's representation of the hand. Altogether, these findings demonstrate that the observation of other's pain modulates, in a somatosensory specific fashion, the cortical responses elicited by nociceptive stimuli in the sensorimotor cortex contralateral to the stimulated hand. PMID- 22234937 TI - Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12. AB - While many cancers show a sex bias, the genetic basis and molecular mechanisms underlying sex bias are not always clear. Astrocytoma and glioblastoma show male predominance in humans. We have shown previously that glial tumors forming in the Nf1-/+; Trp53-/+cis (NPcis) mouse model also show a sex bias in some genetic contexts. Using cross-species comparisons we have identified candidate male specific modifiers of astrocytoma/glioblastoma. Linkage analysis of B6X(B6X129) NPcis mice identifies a modifier of astrocytoma resistance specific to males, named Arlm1, on distal mouse Chr 12. Arlm1 is syntenic to human Chr 7p15, 7p21, 7q36, and 14q32 regions that are altered in human glioblastoma. A subset of these genes shows male-specific correlations to glioblastoma patient survival time and represents strong candidates for the Arlm1 modifier gene. Identification of male specific modifier genes will lead to a better understanding of the molecular basis of male predominance in astrocytoma and glioblastoma. PMID- 22234938 TI - Regulation of spinal interneuron differentiation by the paracrine action of glycine. AB - Glycine and gamma-aminobutyric acid (GABA) are depolarizing during early development but the purpose is unclear. We tested the effect of altering glycine signaling in zebrafish embryos by overexpressing the potassium-chloride co transporter type 2 (KCC2) to reverse the chloride gradient or by blocking glycine receptors with strychnine or by selectively knocking down the embryonic glycine receptor (GlyR KD). Using a variety of markers we observed in all three cases a reduction of all types of spinal interneuron populations examined, indicating that glycine modulates their overall differentiation rather than choice of cell fate. Other cell populations (motor, sensory, and glial cells) were unaffected. As glycine appeared to act preceding neural and synaptic development, we examined the bandoneon (beo) mutant in which glycine receptors are functional but not clustered at synapses. Neural populations in beo embryos appeared normal, suggesting a paracrine action of circulating glycine in promoting interneuron differentiation. PMID- 22234939 TI - The PPARdelta ligand L-165041 inhibits VEGF-induced angiogenesis, but the antiangiogenic effect is not related to PPARdelta. AB - Peroxisome proliferator-activated receptor (PPAR)delta is known to be expressed ubiquitously and involved in lipid and glucose metabolism. Recent studies have demonstrated that PPARdelta is expressed in endothelial cells (ECs) and plays a potential role in endothelial survival and proliferation. Although PPARalpha and PPARgamma are well recognized to play anti-inflammatory, antiproliferative, and antiangiogenic roles in ECs, the general effect of PPARdelta on angiogenesis in ECs remains unclear. Thus, we investigated the effect of the PPARdelta ligand L 165041 on vascular EC proliferation and angiogenesis in vitro as well as in vivo. Our data show that L-165041 inhibited VEGF-induced cell proliferation and migration in human umbilical vein ECs (HUVECs). L-165041 also inhibited angiogenesis in the Matrigel plug assay and aortic ring assay. Flow cytometric analysis indicated that L-165041 reduced the number of ECs in the S phase and the expression levels of cell cycle regulatory proteins such as cyclin A, cyclin E, CDK2, and CDK4; phosphorylation of the retinoblastoma protein was suppressed by pretreatment with L-165041. We confirmed whether these antiangiogenic effects of L-165041 were PPARdelta-dependent using GW501516 and PPARdelta siRNA. GW501516 treatment did not inhibit VEGF-induced angiogenesis, and transfection of PPARdelta siRNA did not reverse this antiangiogenic effect of L-165041, suggesting that the antiangiogenic effect of L-165041 on ECs is PPARdelta independent. Together, these data indicate that the PPARdelta ligand L-165041 inhibits VEGF-stimulated angiogenesis by suppressing the cell cycle progression independently of PPARdelta. This study highlights the therapeutic potential of L 165041 in the treatment of many disorders related to pathological angiogenesis. PMID- 22234940 TI - Association of coronary lipid core plaque with intrastent thrombus formation: a near-infrared spectroscopy and optical coherence tomography study. AB - BACKGROUND: Optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS) allow assessment of the anatomy (OCT) and composition (NIRS) of coronary lesions. We sought to examine the association between pre-stenting lipid core plaque (LCP), as assessed by NIRS and post-stenting thrombus formation, as assessed by OCT. METHODS: We reviewed the angiograms of nine patients who underwent coronary stenting in association with NIRS and OCT imaging. A large LCP by NIRS was defined as at least three 2-mm yellow blocks on the NIRS block chemogram with >200 degrees angular extent. Intracoronary thrombus was defined as a mass of medium reflectivity protruding into the vessel lumen, discontinuous from the surface of the vessel wall. RESULTS: Mean age was 67 +/- 7 years, and all patients were men, presenting with stable angina (56%), unstable angina (11%), or acute myocardial infarction (33%). The mean vessel lipid core burden index (LCBI) was 120 +/- 45, and the mean highest 6-mm LCBI was 386 +/- 190. Three patients had a large LCP and two of them (66%) developed intrastent thrombus after stent implantation compared to none of six patients without large LCPs (0%, P = 0.02). The thrombus resolved after intracoronary glycoprotein IIb/IIIa administration and balloon postdilation. Postprocedural myocardial infarction occurred in 33% versus 17% of patients with and without large LCP, respectively (P = 0.57). CONCLUSION: Stenting of large LCPs may be associated with intrastent thrombus formation, suggesting that more intensive anticoagulant and/or antiplatelet therapy may be beneficial in such lesions. (c) 2012 Wiley Periodicals, Inc. PMID- 22234942 TI - Colorful calcium sensors. AB - (R)evolution of protein-based calcium sensors: Expanding the toolbox of genetically encoded calcium sensors with new colors and traits is important for understanding calcium signaling and its relation to other intracellular pathways. Campbell and co-workers have used a new directed-evolution strategy to develop a rich palette of new sensors, including the first red-shifted, genetically encoded calcium sensor. PMID- 22234941 TI - Comparison of hepatocellular carcinoma in American and Asian patients by tissue array analysis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although some epidemiologic and etiologic differences between Asian and Western HCC are known, detailed comparative studies with pathologic correlations have not been performed. METHODS: Paraffin sections of resected HCC specimens from Memorial Sloan-Kettering Cancer Center and Korea University Medical Center were used to construct tissue microarrays. Immunohistochemical staining of microarray sections was performed using antibodies against markers of proliferation and regulators of cell cycle. Patient data were correlated with staining results. RESULTS: When comparing both cohorts, significant differences were found in expression of p53 and MDM2. In the Asian group, more frequent positive staining for p53 (24%) was observed compared with the American group (9%; P = 0.037). For MDM2, 26% of American cases stained positive compared with 2% of Asian cases (P = 0.0003). No significant differences were found in expression of Ki67, p21, p27, cyclin D1, or bcl2. Female gender, vascular invasion, and lack of viral hepatitis infection correlated with positive MDM2 staining. CONCLUSION: These data likely correlate with differences in molecular pathogenesis of HCC based on racial and regional differences. These findings may have implications in choice of molecular targeted therapies based on patient ethnicity. PMID- 22234944 TI - A gender comparison of central and peripheral neuromuscular function after exercise. AB - CONTEXT: Central and peripheral muscle fatigue during exercise may exacerbate neuromuscular factors that increase risk for noncontact anterior cruciate ligament injury. OBJECTIVE: To compare lower extremity motor-evoked potentials (MEPs), muscle strength, and electromyography (EMG) activation after an exercise protocol. DESIGN: Pretest, posttest group comparison. SETTING: University laboratory. PARTICIPANTS: 34 healthy volunteers (17 female, age = 21.9 +/- 2.3 years, weight = 77.8 +/- 3.0 kg, height = 171.1 +/- 6.6 cm, and 17 male, age = 23.4 +/- 6.5 years, weight = 81.6 +/- 3.3 kg, height = 179.6 +/- 7.3 cm). INTERVENTION: A standardized 30-min exercise protocol that involved 5 repeated cycles of uphill walking, body-weight squatting, and step-ups. MAIN OUTCOME MEASURES: Quadriceps and hamstring MEP amplitude (mV) and transmission velocity normalized to subject height (m/s) were elicited via transcranial magnetic stimulation and measured via surface EMG. Quadriceps and hamstring peak EMG activation (% MVIC) and peak torque (Nm/kg) were measured during MVICs. Separate ANCOVAs were used to compare groups after exercise while controlling for baseline measurement. RESULTS: At baseline, males exhibited significantly greater knee extension torques (males = 2.47 +/- 0.68 Nm/kg, females = 1.95 +/- 0.53 Nm/kg; P = .036) and significantly higher hamstring MEP amplitudes (males = 223.5 +/- 134.0 mV, females = 89.3 +/- 77.6 mV; P = .007). Males exhibited greater quadriceps MEP amplitude after exercise than females (males = 127.2 +/- 112.7 mV, females = 32.3 +/- 34.9 mV; P = .016). CONCLUSIONS: Males experienced greater peripheral neuromuscular changes manifested as more pronounced reductions in quadriceps torque after exercise. Females experienced greater central neuromuscular changes manifested as more pronounced reduction in quadriceps MEP amplitude. Reduced central neural drive of the quadriceps coupled with knee extension torque preservation after exercise may increase risk of knee injury in females. PMID- 22234943 TI - Genome-wide DNA methylation profiles in hepatocellular carcinoma. AB - Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). We have previously demonstrated that hypermethylation in candidate genes can be detected in plasma DNA before HCC diagnosis. To identify, with a genome-wide approach, additional genes hypermethylated in HCC that could be used for more accurate analysis of plasma DNA for early diagnosis, we analyzed tumor and adjacent nontumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays (Illumina, Inc., San Diego, CA) that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor, compared to nontumor tissues. Array data were validated with pyrosequencing in a subset of five of these genes; correlation coefficients ranged from 0.92 to 0.97. Analysis of plasma DNA from 38 cases demonstrated that 37%-63% of cases had detectable hypermethylated DNA (>= 5% methylation) for these five genes individually. At least one of these genes was hypermethylated in 87% of the cases, suggesting that measurement of DNA methylation in plasma samples is feasible. CONCLUSION: The panel of methylated genes indentified in the current study will be further tested in a large cohort of prospectively collected samples to determine their utility as early biomarkers of HCC. PMID- 22234945 TI - Hibernation does not reduce cortical bone density, area or second moments of inertia in woodchucks (Marmota monax). AB - Long periods of inactivity in most mammals result in bone loss that may not be completely recoverable during an individual's lifetime regardless of future activity. Prolonged inactivity is normal during hibernation, but it remains uncertain whether hibernating mammals suffer decreased bone properties after hibernation that affects survival. We test the hypothesis that relative cortical area (C(A) ), apparent density, bone area fraction (B.Ar/T.Ar), and moments of inertia do not differ between museum samples of woodchucks (Marmota monax) collected before and after hibernation. We used peripheral quantitative computed tomography to examine bone geometry in the femur, tibia, humerus and mandible. We see little evidence for changes in bone measures with hibernation supporting our hypothesis. In fact, when including subadults to increase sample sizes and controlling age statistically, we observed a trend toward increased bone properties following hibernation. Diaphyses were significantly denser in the humerus, femur, and tibia after hibernation, and relative mandibular cortical area was significantly larger. Similarly, relative mechanical indices were significantly larger in the mandible after hibernation. Although tests of individual measures in many cases were not significantly different prehibernation versus posthibernation, the overall pattern of average increase posthibernation was significant for relative C(A) and densities as well as relative diaphyseal mechanical indices when examining outcomes collectively. The exception to this pattern was a reduction in metaphyseal trabecular bone following hibernation. Individually, only humeral B.Ar/T.Ar was significantly reduced, but the average reduction in trabecular measures post-hibernation was significant when examined collectively. Because the sample included subadults, we suggest that much of the increased bone relates to their continued growth during hibernation. Our results indicate that woodchucks are more similar to large hibernators that maintain skeletal integrity compared to smaller-bodied hibernators that may lose bone. This result suggests a potential size-related trend in bone response to hibernation across mammals. PMID- 22234947 TI - Intermediate catheter injections in closed segments during acute stroke intervention: a cautionary note. AB - OBJECTIVE AND IMPORTANCE: In the setting of stroke intervention, there is typically an occlusion that limits angiographic visualization of patent vasculature distal to the embolus. Certain mechanical thrombectomy paradigms include angiography of the vasculature distal to the point of occlusion in preparation for thrombectomy, typically using a microcatheter. Injections using an intermediate catheter allows for higher volume of injection at a faster rate, resulting in radically different pressure gradients. CLINICAL PRESENTATIONS: Two patients presenting with acute ischemic stroke were treated via mechanical thrombectomy using the Penumbra 054 system. The first was a tandem occlusion with a high grade narrowing and occlusion of the internal carotid artery (ICA) origin and an ICA terminus thrombus. The second was a long segment, high volume thrombus extending from the cavernous segment to the ICA terminus. INTERVENTION: Conventional access techniques were utilized to position the Penumbra 054 catheter in the ICA in both cases. Intraprocedurally, angiography through the 054 catheter within the closed segment resulted in contrast extravasation adjacent to the tentorium, originating from the communicating segment of the ICA, both of which cleared within 48 h. Due to the extravasation, the interventions were both terminated, and the infarcts went on to complete. CONCLUSION: During an acute stroke, flow within large vessels is abnormal, and rapid changes in volume may result in drastic changes in pressure which may lead to extravasation. The authors recommend never performing a contrast injection through a large lumen catheter when flow may be impeded proximally and distally. Closed segment injections of large volumes at a high rate are probably at high risk for vessel injury. PMID- 22234946 TI - Dye coupling and connexin expression by cortical radial glia in the early postnatal subventricular zone. AB - In this study, we have analyzed the specific contribution of the cortical radial glia (RG) for gap junctional communication (GJC) within the postnatal subventricular zone (SVZ). To specifically target RG as source of dye-coupling in situ, we have developed a new technique that involves direct cell loading through the processes that reach the pial surface, with a mix of gap junction permeant (Lucifer yellow, LY) and nonpermeant (rhodamine-conjugated dextran 3 KDa, RD) fluorochromes, the latter used as a marker for direct loaded cells. Tissue sections were analyzed for identification of directly loaded (LY+RD+) and coupled cells (LY+RD-) in the SVZ. Directly loaded cells were restricted to the region underlying the pial loading surface area. Coupled cells were distributed in a bistratified manner, along the outer dorsal surface of the SVZ and aligning the ventricle, leaving the SVZ core relatively free. Blocking GJC prior to pial loading greatly reduced dye coupling. Phenotypic analysis indicated that coupling by RG excludes neuroblasts and is mostly restricted to cells of glial lineage. Notwithstanding, no corresponding restriction to specific cell phenotype was found for two connexin isotypes, Cx43 and Cx45, in the postnatal SVZ. The extensive homocellular cell coupling by RG suggests an important role in the regulation of neurogenesis and functional compartmentalization of the postnatal SVZ. PMID- 22234948 TI - Low turnover osteoporosis in sheep induced by hypothalamic-pituitary disconnection. AB - The hypothalamus is of critical importance in regulating bone remodeling. This is underscored by the fact that intracerebroventricular-application of leptin in ewe leads to osteopenia. As a large animal model of osteoporosis, this approach has some limitations, such as high technical expenditure and running costs. Therefore we asked if a surgical ablation of the leptin signaling axis would have the same effects and would thereby be a more useful model. We analyzed the bone phenotype of ewe after surgical hypothalamo-pituitary disconnection (HPD + OVX) as compared to control ewe (OVX) after 3 and 12 months. Analyses included histomorphometric characterization, micro-CT and measurement of bone turnover parameters. Already 3 months after HPD we found osteopenic ewe with a significantly decreased bone formation (69%) and osteoclast activity (49%). After a period of 12 months the HPD group additionally developed an (preclinical) osteoporosis with significant reduction (33%) of femoral cortical thickness, as compared to controls (OVX). Taken together, HPD leads after 12 month to osteoporosis with a reduction in both trabecular and cortical bone caused by a low bone turnover situation, with reduced osteoblast and osteoclast activity, as compared to controls (OVX). The HPD-sheep is a suitable large animal model of osteoporosis. Furthermore our results indicate that an intact hypothalamo-pituitary axis is required for activation of bone turnover. PMID- 22234949 TI - Activin A and cardiovascular disease in type 2 diabetes mellitus. AB - BACKGROUND: Silent coronary artery disease is a frequent complication of type 2 diabetes (T2DM). Based on its multiple roles in inflammation, atherogenesis and glucose homeostasis, we hypothesised that activin A could be related to coronary atherosclerosis in T2DM. METHODS: Activin A and follistatin were measured in 102 patients with T2DM and 20 age- and sex-matched healthy controls. Coronary angiography was performed in a sub-population of patients and associations with activin A were examined using multiple linear regression. RESULTS: Serum activin A and the activin A/follistatin ratio were increased in patients with T2DM and coronary artery disease (CAD) compared with healthy volunteers and the elevated activin A was associated with the severity of coronary atherosclerotic burden as determined by the proportion of >=2 vessel disease (p = 0.035) after multivariable-adjusted trend analysis. No significant association between presence of CAD or extent score and activin A was observed. CONCLUSION: In patients with T2DM, increased activin A may reflect chronic underlying pathophysiological processes involved in development of cardiovascular disease. PMID- 22234950 TI - Sub-optimal achievement of guideline-derived lipid goals in management of diabetes patients with atherosclerotic cardiovascular disease, despite high use of evidence-based therapies. AB - Guidelines recommend aggressive goals for lipid and blood pressure reduction for high risk patients with diabetes mellitus and atherosclerotic coronary disease. However, it remains unclear how many patients achieve treatment goals versus the number of people merely placed on treatment. We conducted an observational study in an academic cardiology clinic. A total of 926 patients with atherosclerotic cardiovascular disease and concomitant diabetes mellitus met criteria. Mean age was 68.4 +/- 10.2, 65.6% were male, and 86.8% were Caucasian. By the last visit a high percentage of patients were receiving recommended medications. Mean LDL cholesterol achieved was 80.4 mg/dl with 40.9% reaching <= 70 mg/dl, and 61.7% reaching SBP <= 130 mmHg. Many patients with diabetes mellitus and atherosclerotic cardiovascular disease are prescribed recommended medications; however, few achieve guidelines-specified therapeutic goals for LDL-cholesterol and blood pressure. Studies evaluating performance improvement should include percentage of patients reaching treatment goals. Mechanisms underlying the treatment gap need to be identified and addressed. PMID- 22234951 TI - Waist circumference is a strong and independent determinant of the distribution of HDL subfractions in overweight patients with cardiovascular risk factors. AB - PURPOSE: Our aim was to determine the influence of waist circumference on the repartition of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) subfractions in patients with increased waist perimeter and one or more cardiovascular risk factor. METHODS: All 117 patients without lipid-lowering therapy underwent routine clinical, biological evaluation and isolation of the following lipid subfractions: HDL2b, HDL2a, HDL3a, HDL3b, HDL3c and LDL1, LDL2, LDL3, LDL4. RESULTS: Mean waist circumference was 102.9 cm for women and 109.4 cm for men, and 92 patients presented with metabolic syndrome. In the highest waist circumference tertile, when compared with the lowest one, an increased HDL3c (7.7% vs. 5.7% p=0.02) and a non-significant decrease of HDL2b percentages were observed with no difference in other subfractions. In multivariate analysis, only plasma triglycerides and waist circumference remained independent predictors of HDL3c percentage. CONCLUSION: In our population, waist circumference was a strong and independent determinant of a shift in the distribution of HDL toward denser particles. PMID- 22234952 TI - Outcomes of primary percutaneous coronary intervention for acute myocardial infarction with unprotected left main coronary artery occlusion. AB - BACKGROUND: We determined the in-hospital and the long-term outcomes of primary percutaneous coronary intervention (PCI) for acute left main coronary artery (LMCA) occlusion. METHODS: Between 1988 and 2009, 72 patients with acute myocardial infarction (AMI) underwent primary PCI for unprotected LMCA occlusion. The short- and the long-term outcomes of primary PCI in these patients were retrospectively evaluated. RESULTS: Upon arrival, cardiogenic shock was observed in 33 (46%) patients and cardiopulmonary arrest (CPA) in 12 (17%). Twenty-three (32%) required extracorporeal life support and 64 (89%) intra-aortic balloon pumping. Although successful reperfusion was achieved in 60 (83%) patients, in hospital death was observed in 32 (44%). Multivariate analysis revealed predictors of in-hospital death to be CPA on arrival (RR, 7.05; 95% CI: 1.28 39.0; P = 0.025). During 1.7 +/- 2.9 years of follow-up, 10 of the 40 hospital survivors died. All presenting CPA on arrival died within 2 years. Although the estimated survival of the all study patients was only 26.2% at 8 years by the Kaplan-Meier methods, those without shock/CPA on arrival showed nearly flat survival curve after 4 years. CONCLUSIONS: Despite performance of primary PCI, patients with AMI due to LMCA occlusion were associated with >50% in-hospital mortality. Hemodynamic deficit upon arrival was the major determinant of their poor hospital outcomes. The hospital survivors, however, were associated with favorable long-term outcomes. PMID- 22234953 TI - A fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition. AB - Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major primary liver cancers in adults. The phenotypic overlap between HCC and CC has been shown to comprise a continuous liver cancer spectrum. As a proof of this concept, a recent study demonstrated a genomic subtype of HCC that expressed CC-like gene expression traits, such as CC-like HCC, which revealed the common genomic trait of stem-cell-like properties and aggressive clinical outcomes. Scirrhous HCC (S HCC), a rare variant of HCC, is characterized by abundant fibrous stroma and has been known to express several liver stem/progenitor cell markers. This suggests that S-HCC may harbor common intermediate traits between HCC and CC, including stem-cell traits, which are similar to those of CC-like HCC. However, the molecular and pathological characteristics of S-HCC have not been fully evaluated. By performing gene-expression profiling and immunohistochemical evaluation, we compared the morphological and molecular features of S-HCC with those of CC and HCC. S-HCC expresses both CC-like and stem-cell-like genomic traits. In addition, we observed the expression of core epithelial-mesenchymal transition (EMT)-related genes, which may contribute to the aggressive behavior of S-HCC. Overexpression of transforming growth factor beta (TGF-beta) signaling was also found, implying its regulatory role in the pathobiology of S-HCC. CONCLUSION: We suggest that the fibrous stromal component in HCC may contribute to the acquisition of CC-like gene-expression traits in HCC. The expression of stem-cell-like traits and TGF-beta/EMT molecules may play a pivotal role in the aggressive phenotyping of S-HCC. (HEPATOLOGY 2012;55:1776-1786). PMID- 22234954 TI - Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. AB - BACKGROUND: Depression, like adverse events and psychological stress, can trigger relapse in inflammatory bowel disease (IBD); however, the effects of psychoactive drugs on disease course are unclear. METHODS: Using retrospective electronic case note review, after exclusion of five patients on low-dose tricyclic antidepressants we compared the course of IBD in 29 patients (14 ulcerative colitis and 15 Crohn's disease), during the years before (year 1) and after (year 2) they were started on an antidepressant for a concomitant mood disorder to that of controls matched for age, sex, disease type, medication at baseline, and relapse rate in year 1. RESULTS: Patients had fewer relapses and courses of steroids in the year after starting an antidepressant than in the year before (1 [0-4] (median [range]) vs. 0 [0-4], P = 0.002; 1 [0-3] vs. 0 [0-4], P < 0.001, respectively); the controls showed no changes between years 1 and 2 in relapses (1 [0-4] vs. 1 [0-3], respectively) or courses of steroids (1 [0-2] vs. 0 [0-3]). Although there were no differences in the use of other relapse-related medications, outpatient attendances, or hospital admissions, the number of endoscopies fell significantly in the antidepressant group in year 2 compared with year 1 (P < 0.01). No such changes were seen in the controls. CONCLUSIONS: Antidepressants, when used to treat concomitant mood disorders in IBD, seem to reduce relapse rates, use of steroids, and endoscopies in the year after their introduction. These results suggest the need for a prospective controlled trial to evaluate their effects on disease course in patients with IBD. PMID- 22234955 TI - Effect of mouth-rinse formulations on oral malodour processes in tongue-derived perfusion biofilm model. AB - An in vitro matrix biofilm perfusion model of tongue-derived microcosms for studying volatile sulfur compound (VSC) biogenesis has been previously described. The model was modified in order to monitor H(2)S in situ by use of a specialized electrode assembly based on microbial fuel cell technology. This system was designed to give real-time measurements expressed as electrode power output, which were proportional to H(2)S levels, measured by other means. In addition to the model modifications, the aim of this study was to demonstrate the biofilm responses following single or multiple exposure to biocidal, biostatic or VSC inhibiting active compounds used in products. Tongue-derived biofilms (n = 6 per experiment) were perfused with one-fifth strength BHI at 20 ml h(-1) pH 7.2 and pulsed with putative treatment agent, placebo and controls including Zn(2+) ions and chlorhexidine (CHX). Compared with their pre-treatment conditions, all biofilms responded to the treatments in terms of reductions in hydrogen sulfide generation (as detected by the biofilm-electrode response) and other microbial volatile organic compounds (VOCs) as detected using a selected ion flow tube mass spectrometry analyser. The microbiological analysis of the treated and control biofilms show that test products (formulations with active agents) all gave reduced cell populations compared to the control biofilm. An order of effects (magnitude and duration) suggests that both the test agent and CHX produced the strongest reductions, distinct from the responses obtained for the placebo and water controls, which were largely similar. It is concluded that the in vitro perfusion model may be used to replicate many of the activities and reactions believed to be occurring by the tongue biofilm microflora within a real mouth, including H(2)S and VOC biogenesis and their inhibition by exposure to active agents. PMID- 22234956 TI - Effect of individual proton pump inhibitors on cardiovascular events in patients treated with clopidogrel following coronary stenting: results from the Ibaraki Cardiac Assessment Study Registry. AB - OBJECTIVES: The aim of this study was to evaluate whether combination therapy of clopidogrel and proton pump inhibitors (PPIs) causes higher numbers of cardiovascular events than clopidogrel alone in Japanese patients. BACKGROUND: PPIs are often prescribed in combination with clopidogrel following coronary stenting. PPIs are reported to diminish the effect of clopidogrel because both are metabolized by CYP2C19. However, no reports address the effects of PPIs on cardiovascular events following coronary stenting in the Japanese population. METHODS: A total of 1,887 patients treated with clopidogrel following coronary stenting were enrolled in the Ibaraki Cardiac Assessment Study (ICAS) registry. All subjects were classified into two groups according to treatment without (n = 819) or with (n = 1,068) PPI. Propensity score analysis matched 1:1 according to treatment without PPI (n = 500) or with PPI (n = 500). Primary endpoint was the composite of all-cause death or myocardial infarction. RESULTS: No significant difference was observed in the primary endpoint between the group without PPI and the group with PPI (4.6% vs. 4.6%, P = 0.77). In contrast, a significant difference was found between the group without PPI and with PPI in regard to the incidence of gastrointestinal bleeding at the end of the follow-up period and the specific PPI prescribed (2.4% vs. 0.8%, adjusted HR = 0.30, 95% Confidence interval 0.08-0.87, P = 0.026) after propensity score matching. CONCLUSIONS: No significant association between PPI use and primary endpoint was observed in the Japanese population, whereas PPI use resulted in a significant reduction in the rate of gastrointestinal bleeding. PMID- 22234958 TI - Comparison of the oropharyngeal cavity in the Starksiini (Teleostei: Blenniiformes: Labrisomidae): taste buds and teeth, including a comparison with closely-related genera. AB - The present study describes the distribution of taste buds and teeth in the oropharyngeal cavity of 13 species of adult (18-60 mm SL) Starksiini fishes inhabiting subtidal waters of the Neotropical region. Four types of taste buds described previously in other fish groups were observed within the oropharyngeal cavity, of which type I, situated on prominent protruding papillae, is the most common. The number of taste buds in this cavity varies considerably, ranging from ca. 202 in Starksia lepicoelia to ca. 770 in S. sluiteri. In all the studied species, taste buds are more numerous on the posterior (160-396) than on the anterior (42-294) part of the oropharyngeal cavity. The presence of different numbers of taste buds in different Starksiini species of the same standard length suggests that numbers of taste buds are not directly correlated with size and may be species-specific. Teeth are found on the premaxilla, dentary, vomer, palatine (in some species) and the upper and lower pharyngeal jaws (third pharyngobranchials and fifth ceratobranchials, respectively); the form and number of teeth and taste buds on each of these sites differs among the various species of Starksiini and between them and closely related species of the labrisomid tribes Labrisomini, Mnierpini, and Paraclinini. The results thus suggest potential systematic value in certain features of the oropharyngeal cavity for blenniiform fishes. It is also shown that benthic-feeding omnivorous fishes have higher densities of taste buds than piscivorous fishes. A possible correlation among numbers of taste buds, their positions in the oropharyngeal cavity, and other parameters is discussed. PMID- 22234959 TI - Improved guideline compliance after a 3-year audit of multidisciplinary colorectal cancer care in the western part of the Netherlands. AB - BACKGROUND: From 2006 to 2008, an audit of the multidisciplinary diagnosis and treatment of colorectal cancer patients in the western part of the Netherlands was carried out. We evaluated whether compliance with guidelines had improved. METHODS: All patients with newly diagnosed and surgically treated colon (n = 1,667) and rectal cancer (n = 544) stage I-III were evaluated. Nine quality indicators were derived from the evidence-based guidelines. In order to compare hospital performances, hospital results were adjusted for casemix differences between hospitals. RESULTS: Colon cancer patients showed an increase in the examination of 10 or more lymph nodes (from 53% to 78%, P < 0.0001). For rectal cancer patients there was an increase in preoperative visualisation of the total colon (63-74%, P = 0.02), MRI (73-85%, P = 0.003), radiotherapy (from 82% to 93% for patients <75 years, P = 0.01) and examination of at least 10 lymph nodes (40 55%, P = 0.004). In 2006, standardised hospital performances differed widely for all quality indicators. Two years later, hospital performances for some quality indicators were more similar. CONCLUSIONS: After the feedback of benchmark information, compliance with guidelines for diagnosis and treatment of colorectal cancer patients improved, and differences between individual hospitals decreased. Although secular trends cannot be ruled out, it is highly likely that these results can be attributed to the audit. PMID- 22234960 TI - Improving fixation strength of pedicle screw by microarc oxidation treatment: an experimental study of osteoporotic spine in sheep. AB - Failure of fixation caused by loosening of pedicle screws in osteoporosis is a problem in spinal surgery. We compared the in vivo fixation strength between pedicle screws treated with microarc oxidation (MAO) and untreated screws in an osteoporotic model of ovariectomized sheep. The MAO treated and untreated screws were placed in lumbar vertebral bodies. After 3 months of implantation, biomechanical tests, micro-CT analysis, and histological observations were conducted to examine the performance of the two groups. At time 0, no significant difference was found between the two groups in biomechanical tests (p > 0.05); 3 months later, higher pull-out strength and load with less displacement were detected in the MAO-treated group (p < 0.05). Micro-CT analysis showed that the tissue mineral density, bone volume fraction, trabecular thickness, and trabecular number in the MAO-treated group were all higher than those in untreated group (p < 0.05), and trabecular spacing was smaller (p < 0.05). Histologically, the bone-implant interface in the MAO-treated group was better than that in untreated group (p < 0.05). In conclusion, pedicle screws with a bioactive surface treated by MAO can improve screw fixation strength in osteoporotic spines in sheep. PMID- 22234957 TI - Structure-function analysis of endogenous lectin mind-the-gap in synaptogenesis. AB - Mind-the-Gap (MTG) is required for neuronal induction of Drosophila neuromuscular junction (NMJ) postsynaptic domains, including glutamate receptor (GluR) localization. We have previously hypothesized that MTG is secreted from the presynaptic terminal to reside in the synaptic cleft, where it binds glycans to organize the heavily glycosylated, extracellular synaptomatrix required for transsynaptic signaling between neuron and muscle. In this study, we test this hypothesis with MTG structure-function analyses of predicted signal peptide (SP) and carbohydrate-binding domain (CBD), by introducing deletion and point-mutant transgenic constructs into mtg null mutants. We show that the SP is required for MTG secretion and localization to synapses in vivo. We further show that the CBD is required to restrict MTG diffusion in the extracellular synaptomatrix and for postembryonic viability. However, CBD mutation results in elevation of postsynaptic GluR localization during synaptogenesis, not the mtg null mutant phenotype of reduced GluRs as predicted by our hypothesis, suggesting that proper synaptic localization of MTG limits GluR recruitment. In further testing CBD requirements, we show that MTG binds N-acetylglucosamine (GlcNAc) in a Ca(2+) dependent manner, and thereby binds HRP-epitope glycans, but that these carbohydrate interactions do not require the CBD. We conclude that the MTG lectin has both positive and negative binding interactions with glycans in the extracellular synaptic domain, which both facilitate and limit GluR localization during NMJ embryonic synaptogenesis. PMID- 22234961 TI - Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. Activation of AhR mediates the expression of target genes (e.g., CYP1A1) by binding to dioxin response element (DRE) sequences in their promoter region. To understand the multiple mechanisms of AhR-mediated gene regulation, a microarray analysis on liver isolated from ligand-treated transgenic mice expressing a wild type (WT) Ahr or a DRE-binding mutant Ahr (A78D) on an ahr-null background was performed. Results revealed that AhR DRE binding is not required for the suppression of genes involved in cholesterol synthesis. Quantitative reverse transcription polymerase chain reaction performed on both mouse liver and primary human hepatocyte RNA demonstrated a coordinated repression of genes involved in cholesterol biosynthesis, namely, HMGCR, FDFT1, SQLE, and LSS after receptor activation. An additional transgenic mouse line was established expressing a liver-specific Ahr-A78D on a Cre(Alb)/Ahr(flox/flox) background. These mice displayed a similar repression of cholesterol biosynthetic genes, compared to Ahr(flox/flox) mice, further indicating that the observed modulation is AhR specific and occurs in a DRE-independent manner. Elevated hepatic transcriptional levels of the genes of interest were noted in congenic C57BL/6J-Ah(d) allele mice, when compared to the WT C57BL/6J mice, which carry the Ah(b) allele. Down regulation of AhR nuclear translocator levels using short interfering RNA in a human cell line revealed no effect on the expression of cholesterol biosynthetic genes. Finally, cholesterol secretion was shown to be significantly decreased in human cells after AhR activation. CONCLUSION: These data firmly establish an endogenous role for AhR as a regulator of the cholesterol biosynthesis pathway independent of its DRE-binding ability, and suggest that AhR may be a previously unrecognized therapeutic target. PMID- 22234962 TI - A halide-induced copper(I) disulfide/copper(II) thiolate interconversion. PMID- 22234963 TI - CRMP4 suppresses apical dendrite bifurcation of CA1 pyramidal neurons in the mouse hippocampus. AB - Collapsin response mediator proteins (CRMPs) are a family of cytosolic phosphoproteins that consist of 5 members (CRMP 1-5). CRMP2 and CRMP4 regulate neurite outgrowth by binding to tubulin heterodimers, resulting in the assembly of microtubules. CRMP2 also mediates the growth cone collapse response to the repulsive guidance molecule semaphorin-3A (Sema3A). However, the role of CRMP4 in Sema3A signaling and its function in the developing mouse brain remain unclear. We generated CRMP4-/- mice in order to study the in vivo function of CRMP4 and identified a phenotype of proximal bifurcation of apical dendrites in the CA1 pyramidal neurons of CRMP4-/- mice. We also observed increased dendritic branching in cultured CRMP4-/- hippocampal neurons as well as in cultured cortical neurons treated with CRMP4 shRNA. Sema3A induces extension and branching of the dendrites of hippocampal neurons; however, these inductions were compromised in the CRMP4-/- hippocampal neurons. These results suggest that CRMP4 suppresses apical dendrite bifurcation of CA1 pyramidal neurons in the mouse hippocampus and that this is partly dependent on Sema3A signaling. PMID- 22234964 TI - Work-related sickness absence as reported by UK general practitioners. AB - BACKGROUND: Issues surrounding sickness absence are of interest due to growing awareness of the costs to employers and the UK economy, a greater understanding of the interaction between health and work, and increasing evidence that work is beneficial to physical and mental well-being. The Health & Occupation Reporting network in General Practice (THOR-GP) is a national source of information on work related sickness absence. AIMS: To assess the factors influencing work-related sickness absence in the UK. METHODS: General practitioners (GPs) report cases of work-related ill-health via an online web form. Sickness absence information reported with each case was compared by demographic information, diagnosis/symptom and employment factors. RESULTS: Between 2006 and 2009, THOR-GP received 5683 case reports of work-related ill-health; 53% were musculoskeletal diagnoses and 31% were mental ill-health diagnoses. Over half (56%) of cases reported had associated sickness absence. Diagnosis had a highly significant influence on the occurrence of any associated sickness absence. Eighty-one per cent of mental ill-health cases were reported to result in sickness absence compared to 50% of musculoskeletal cases. Public sector employees incurred sickness absence more frequently than those from the private sector. Industries with the highest mental ill-health incidence rates had sickness absence episodes most frequently. Within employment groups, levels of sickness absence were inversely proportional to the level of self-employment. CONCLUSIONS: These data reported by GPs with vocational training in occupational medicine may help to inform policy decisions targeting work-related exposures and the management of sickness absence, thereby reducing the UK burden of work-related sickness absence. PMID- 22234965 TI - From the Schnauzenorgan to the back: morphological comparison of mormyromast electroreceptor organs at different skin regions of Gnathonemus petersii. AB - The nocturnally active weakly electric fish Gnathonemus petersii is known to employ active electrolocation for the detection of objects and for orientation in its environment. The fish emits pulse-type electric signals with an electric organ and perceives these signals with more than 3,000 epidermal electroreceptor organs, the mormyromasts, which are distributed over the animal's skin surface. In this study, we measured the metric dimensions of the mormyromasts from different body regions to find structural and functional specialization of the various body parts. We focused on the two foveal regions of G. petersii, which are located at the elongated and movable chin (the Schnauzenorgan; SO) and at the nasal region (NR), the skin region between the mouth and the nares. These two foveal regions were compared to the dorsal part (back) of the fish, which contains typical nonfoveal mormyromasts. While the gross anatomy of the mormyromasts from all skin regions is similar, the metric dimensions of the main substructures differed. The mormyromasts at the SO are the smallest and contain the smallest receptor cells. In addition, the number of receptor cells per organ is lowest at the SO. In contrast, at the back the biggest receptor organs with the highest amount of receptor cells per organ occur. The mormyromasts at the NR are in several respects intermediate between those from the back and the SO. However, mormyromasts at the NR are longer than those at all other skin regions, the canal leading from the receptor pore to the inner chambers were the longest and the overlaying epidermal layers are the thickest. These results show that mormyromasts and the epidermis they are embedded in at both foveal regions differ specifically from those found on the rest of the body. The morphological specializations lead to functional specialization of the two foveae. PMID- 22234967 TI - Humeral head resurfacing in central bone defects: in vitro stability of different implants with increasing defect size. AB - We examined the rotary motions of two distinct cementless surface replacement arthroplasties of the shoulder that were implanted on humeri with central spherical bone defects of 8%, 17%, and 37% of the head volume (n = 5 each). Rotary motions were measured under a cyclic torque application and translated into relative micromotions. Implant A with a perforated central crown had micromotions < 150 um in all bony defects and during all simulated shoulder activities. Implant B with a central tapered tri-fin pin had no micromotions > 150 um in defects of 0% and 8% during a strenuous activity like lifting 10 kg, but did exhibit micromotion > 150 um in 40% of the experiments in defects of 17% and 37%, which could impair bony ingrowth. Implant B displayed a significant increase in micromotions for defects of 8% and 17% (p < 0.05). Our results suggest that implant A could be used without risk in spherical head defects up to 37% of volume, even in strenuous shoulder activities immediately after its implantation. Implant B, however, is recommended in spherical defects starting from 8% and only during light shoulder activities until bony integration of the implant has occurred. PMID- 22234966 TI - Improved physical fitness among older female participants in a nationally disseminated, community-based exercise program. AB - BACKGROUND: Strength training (ST) is an important health behavior for aging women; it helps maintain strength and function and reduces risk for chronic diseases. This study assessed change in physical fitness following participation in a ST program implemented and evaluated by community leaders. METHOD: The StrongWomen Program is a nationally disseminated, research-based, community ST program active in 40 states. The Senior Fitness Test is used to assess upper and lower body strength, upper and lower body flexibility, aerobic fitness, and agility; data are collected prior to and following program participation. RESULTS: For these analyses, five states provided deidentified data for 367 female participants, mean age 63 (+/-11) years. Attendance in approximately 10 weeks of twice-weekly classes was 69.4%. Paired t tests were used to analyze pre post change. Significant improvements were observed (p < .01) in all Senior Fitness Test measures. Data are stratified by age-group and compared with published, age-based norms. CONCLUSIONS: This study demonstrates that it is feasible for community leaders to conduct pre-post physical fitness evaluations with participants and that participants experienced improvements across several important domains of physical fitness. PMID- 22234968 TI - Changes in the efficiency of fertiliser use in China. AB - Results of three nationwide fertiliser efficiency studies in recent history in China are reviewed. The results indicate that after a long history using organic recycling to maintain soil fertility in China, nitrogen (N) became the first yield-limiting nutrient in the first national fertiliser efficiency study in 1935 1940. With N fertilisation being used, phosphorus (P) and potassium (K) deficiencies were gradually revealed and developed in the following national fertiliser efficiency studies in 1958-1962 and 1981-1983. Research conducted through the International Plant Nutrition (IPNI) cooperative network in China in 2000-2006 indicates that agronomic efficiencies of N fertiliser (yield increase per kilogram from the application of 1 kg N) for rice, wheat and maize are 11.7 kg, 10.8 kg and 12.2 kg grain per kilogram of N, respectively, while crop recovery efficiency of N (percentage of N taken up by plant in total N applied) with rice, wheat and maize were 24.8%, 35.7% and 30.5%, respectively. Both agronomic efficiency and crop recovery efficiency of N are significantly lower than the average N use efficiency reported in international literature for other countries. Current agronomic efficiency of P and K are also discussed. Measures to improve fertiliser use in China are discussed. PMID- 22234969 TI - High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. AB - Hypoxia is often found in solid tumors and is associated with tumor progression and poor clinical outcomes. The exact mechanisms related to hypoxia-induced invasion and metastasis remain unclear. We elucidated the mechanism by which the nuclear-damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), released under hypoxic stress, can induce an inflammatory response to promote invasion and metastasis in hepatocellular carcinoma (HCC) cells. Caspase 1 activation was found to occur in hypoxic HCC cells in a process that was dependent on the extracellular release of HMGB1 and subsequent activation of both Toll-like receptor 4 (TLR4)- and receptor for advanced glycation endproducts (RAGE)-signaling pathways. Downstream from hypoxia-induced caspase-1 activation, cleavage and release of proinflammatory cytokines interleukin (IL)-1beta and -18 occurred. We further demonstrate that overexpression of HMGB1 or treatment with recombinant HMGB1 enhanced the invasiveness of HCC cells, whereas stable knockdown of HMGB1 remarkably reduced HCC invasion. Moreover, in a murine model of HCC pulmonary metastasis, stable knockdown of HMGB1 suppressed HCC invasion and metastasis. CONCLUSION: These results suggest that in hypoxic HCC cells, HMGB1 activates TLR4- and RAGE-signaling pathways to induce caspase-1 activation with the subsequent production of multiple inflammatory mediators, which, in turn, promote cancer invasion and metastasis. PMID- 22234970 TI - Structural basis of beta-amyloid-dependent synaptic dysfunctions. PMID- 22234971 TI - A method for deriving homogenous population of oligodendrocytes from mouse embryonic stem cells. AB - There is a pressing need for new therapeutics for the generation and transplantation of oligodendrocyte to the white matter to help replace and render injured cells that are lost in demyelinating disease. There are a few protocols describing a homogenous derivation of non-manipulated mouse embryonic stem cells to oligodendrocytes (ES-OL). Moreover, protocols that are successful in producing ES-OL do so with low efficiency. Therefore, we describe clear methodology for differentiation of mouse ES cells to oligodendrocyte to a high degree of homogenity and reproducibility in vitro. In addition, taking advantage of three defined media, we can generate a defined ES to oligodendrocyte lineage while selecting against neurons and astrocytes. More specifically, (1) Glial stem cell defining media (GSCDM), supplemented with appropriate combination of SHH and RA support pro-oligodendrocyte developing neural spheres from ES cells, (2) Oligodendrocyte differentiating media, induces lineage selection of oligodendrocytes progenitors from neural stem cells, and (3) Oligodendrocyte maturation media, supports oligodendrocytes progenitor maturation. Moreover, the ES cell derived oligodendrocytes display mature properites in the prescence of rat dorsal root gangila in vitro. Thus confirming thier potential for use to invesitgate developmental pathways and future potential use of cells in transplantation towards myelin repair. PMID- 22234972 TI - Small molecule inhibitors of histone acetyltransferases as epigenetic tools and drug candidates. AB - Alteration of the acetylation state of histone proteins contributes to transcriptional regulation and epigenetic inheritance. Dysregulation of these processes may lead to human diseases, especially cancer. One of the major chromatin modifications is histone acetylation and this review gives an overview of the role of histone acetyltransferases, their structural aspects, as well as of chemical modulators targeting their enzymatical activities. Inhibitors and activators of histone acetyltransferases are presented and their capability to influence histone and non-histone protein acetylation levels is discussed. Development of small molecules as epigenetic tools that alter histone acetyltransferase activity will be helpful to better understand the consequences of histone and generally protein acetylation and potentially offer novel therapeutic approaches for the treatment of cancer and other diseases. PMID- 22234973 TI - An efficient synthesis of aripiprazole, buspirone and NAN-190 by the reductive alkylation of amines procedure. AB - The reductive alkylation of amines procedure was applied for the synthesis of aripiprazole 1a, buspirone 1b, and NAN-190 1c. PMID- 22234974 TI - A meta-analysis of randomized, double-blind, placebo-controlled trials for the effects of garlic on serum lipid profiles. AB - BACKGROUND: Inconsistent results were obtained for the lipid-regulating effects of garlic in clinical trials. With increasing interest in complementary medicine for hyperlipoidemia, it is important to explore the real effects of garlic. This meta- analysis was performed to investigate the influence of garlic on serum lipid parameters. RESULTS: A total of 26 studies were included into meta analysis. Overall, garlic was superior to placebo in reducing serum total cholesterol (TC) and triglyceride (TG) levels. Compared with the placebo groups, serum TC and TG levels in the garlic group were reduced by 0.28 (95% CI, -0.45, 0.11) mmol L-1 (P = 0.001) and 0.13 (95% CI, -0.20, -0.06) mmol L-1 (P < 0.001), respectively. The effects of garlic were more striking in subjects with long-term intervention and higher baseline TC levels. Garlic powder and aged garlic extract were more effective in reducing serum TC levels, while garlic oil was more effective in lowering serum TG levels. In contrast, garlic did not influence other lipid parameters, including low-density lipoprotein cholesterol, high density lipoprotein cholesterol (HDL-C), apolipoprotein B, and TC/HDL-C ratio. CONCLUSION: Garlic could reduce serum TC and TG levels, and garlic therapy should benefit patients with risk of cardiovascular diseases. PMID- 22234975 TI - Financial satisfaction and its relationship to depressive symptoms in middle-aged and older adults: results from the FIN-D2D survey. AB - BACKGROUND: Studies using traditional measures of socio-economic position, such as education, income and occupation, have found inequalities in depressive symptoms, but less is known about the association between financial satisfaction and depressive symptoms. AIMS: To examine the association of depressive symptoms with financial satisfaction in Finnish adults in a population-based cross sectional FIN-D2D survey. METHODS: Four thousand, five hundred randomly selected individuals aged 45-74 years were invited to the study. Participation rate for health examinations was 64%. Complete information on depressive symptoms and financial satisfaction was available for 2,819 individuals. Financial satisfaction was asked using a questionnaire. Depressive symptoms were measured by Beck Depression Inventory (>= 10) and/or use of antidepressants. RESULTS: Altogether 11.6% of individuals who were satisfied with their financial situation had depressive symptoms. Corresponding figures for individuals who were somewhat satisfied or dissatisfied were 20.6% and 42.6%, respectively. Individuals who were less satisfied with their financial situation were more likely to suffer from depressive symptoms even after adjusting for gender, age, marital status, number of chronic diseases, smoking, binge drinking, physical activity, education and household income. CONCLUSIONS: Instead of more traditional measures of socio economic position, financial dissatisfaction seems to be associated with depressive symptoms in Finnish adults. PMID- 22234976 TI - Adrenocortical dysfunction in liver disease: a systematic review. AB - In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-MUg adreno-cortico-tropic hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies. PMID- 22234977 TI - All-boron planar B6 ring in the solid-state phase Ti7Rh4Ir2B8. PMID- 22234978 TI - Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis. PMID- 22234979 TI - The brain--gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. AB - OBJECTIVE: Psychological factors are known to be associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD). No prospective studies have evaluated whether it is the brain (eg, via anxiety) that drives gut symptoms, or whether gut dysfunction precipitates the central nervous system features such as anxiety. In a 12-year longitudinal, prospective, population-based study, we aimed to determine the directionality of the brain-gut mechanism in FGIDs. DESIGN: Participants (n=1775) were a random population sample from Australia who responded to a survey on FGIDs in 1997 and agreed to be contacted for future research; 1002 completed the 12 year follow-up survey (response rate =60%), with 217, 82 and 45 people meeting Rome II for new onset FGIDs, IBS and FD, respectively. Anxiety and depression were measured using the Delusions Symptom States Inventory at baseline and follow up. RESULTS: Among people free of a FGID at baseline, higher levels of anxiety (OR 1.11; 95% CI 1.03 to 1.19, p=0.006) but not depression at baseline was a significant independent predictor of developing new onset FGIDs 12 years later. Among people who did not have elevated levels of anxiety and depression at baseline, those with a FGID at baseline had significantly higher levels of anxiety and depression at follow-up (mean difference coefficient 0.76, p<0.001 and 0.30, p=0.01 for anxiety and depression, respectively). In IBS higher levels of anxiety and depression at baseline were predictive of IBS at follow-up, while only depression was predictive of FD at follow-up. CONCLUSIONS: The central nervous system and gut interact bidirectionally in FGIDs. PMID- 22234981 TI - MRI as the new reference standard in quantifying liver steatosis: the need for international guidelines. PMID- 22234980 TI - Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice. AB - BACKGROUND AND AIMS: Pigment epithelium-derived factor (PEDF), a non-inhibitory SERPIN with potent antiangiogenic activity, has been recently implicated in metabolism and adipogenesis, both of which are known to influence pancreatic cancer progression. Increased pancreatic fat in human pancreatic tumour correlates with greater tumour dissemination while PEDF deficiency in mice promotes pancreatic hyperplasia and visceral obesity. Oncogenic Ras, the most common mutation in pancreatic ductal adenocarcinoma (PDAC), has similarly been shown to promote adipogenesis and premalignant lesions. METHODS: In order to determine whether concurrent loss of PEDF is sufficient to promote adipogenesis and tumorigenesis in the pancreas, the authors ablated PEDF in an EL-Kras(G12D) mouse model of non-invasive cystic papillary neoplasms. RESULTS: EL Kras(G12D)/PEDF deficient mice developed invasive PDAC associated with enhanced matrix metalloproteinase (MMP)-2 and MMP-9 expression and increased peripancreatic fat with adipocyte hypertrophy and intrapancreatic adipocyte infiltration (pancreatic steatosis). In support of increased adipogenesis, the stroma of the pancreas of EL-Kras(G12D)/PEDF deficient mice demonstrated higher tissue levels of two lipid droplet associated proteins, tail-interacting protein 47 (TIP47, perilipin 3) and adipose differentiation-related protein (ADRP, Pperilipin 2), while adipose triglyceride lipase, a key factor in lipolysis, was decreased. In patients with PDAC, both tissue and serum levels of PEDF were decreased, stromal TIP47 expression was higher and the tissue VEGF to PEDF ratio was increased (p<0.05). CONCLUSIONS: These data highlight the importance of lipid metabolism in the tumour microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumour invasion in the pancreas. PMID- 22234982 TI - The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. PMID- 22234983 TI - Quantitative assessment of small bowel motility by nonrigid registration of dynamic MR images. AB - Evaluation of small bowel motility from two-dimensional dynamic MRI is of increasing interest for the assessment of segmental diseases such as Crohn's disease. We propose to use nonrigid image registration for automated motility analysis. Registration is particularly difficult when localized intensity changes occur (e.g., due to intraluminal flow or through-plane motion). Therefore, displacements were extracted using a joint registration and modeling of intensity changes. Results were analyzed in 10 patients with known or suspected Crohn's disease. Bowel wall displacements were assessed by tracking bowel cross-sectional markers over time. Automated tracking with the proposed technique was in good agreement with manual tracking (similar bias, improved standard deviations). The ability to quantify different grades of bowel motility was investigated by comparing direct motion measures (i.e., changes in bowel cross-sectional diameter or area) and various parametric maps, e.g., based on the Jacobian of the measured displacements with expert grading. Among these measures, the standard deviation over time of the Jacobian was the best at predicting grades from 1 (moving normally) to 4 (not moving at all) in 50 bowel regions with normal and pathologically reduced motility, yielding 93% correct classification with a 1 class tolerance (i.e., same score as the expert +/- 1). PMID- 22234984 TI - The adhesive disc in the mobilid ciliate Trichodina pediculus: evidence for centrin-related, calcium-sensitive filaments. AB - The adhesive disc is a highly complex apparatus that allows mobilid ciliates to attach to the tissues of a variety of aquatic invertebrates and vertebrates. The disc comprises concentric rings of rigid skeletal pieces interconnected by filamentous material. This study explored the biochemical properties of the filamentous disc material in the trichodinid Trichodina pediculus. Calcium sensitivity of this material was suggested in vitro by the appearance of transverse cross-striation along bundles of filaments following calcium shock, and complete solubilization of the filamentous material in the presence of EGTA. A 23-kDa immunoanalog of centrins was immunoprecipitated from the EGTA extract. The protein binds calcium as indicated by (45) Ca(2+) blot overlay and Ca(2+) induced shifts in electrophoretic mobility. Using Ca(2+) /EGTA buffers, we demonstrated a direct relationship between extraction of the filaments and solubilization of the protein. Immunofluorescence and immunoelectron microscopy confirmed that the protein localized to the filamentous disc material and revealed cross-reactivity with the spasmoneme, which is the prototype of ion sensitive, centrin-like contractile systems in ciliates. The possibility that the filamentous disc material may be a novel example of Ca(2+) -sensitive, centrin based systems found in ciliates is discussed. PMID- 22234985 TI - The cyclin-dependent kinase inhibitor roscovitine inhibits kinase activity, cell proliferation, multicellular development, and Cdk5 nuclear translocation in Dictyostelium discoideum. AB - Roscovitine, a cyclin-dependent kinase (Cdk) inhibitor, inhibited kinase activity and the axenic growth of Dictyostelium discoideum at micromolar concentrations. Growth was almost fully rescued in 50 uM and ~ 50% rescued in 100 uM roscovitine treated cultures by the over-expression of Cdk5-GFP. This supports the importance of Cdk5 function during cell proliferation in Dictyostelium and indicates that Cdk5 is a primary target of the drug. Roscovitine did not affect the expression of Cdk5 protein during axenic growth but did inhibit its nuclear translocation. This novel result suggests that the effects of roscovitine could be due in part to altering Cdk5 translocation in other systems as well. Kinase activity was inhibited by roscovitine in assays using AX3 whole cell lysates, but not in assays using lysates from Cdk5-GFP over-expressing cells. At higher concentrations, roscovitine impaired slug and fruiting body formation. Fruiting bodies that did form were small and produced relatively fewer spores many of which were round. However, roscovitine did not affect stalk cell differentiation. Together with previous findings, these data reveal that roscovitine inhibits Cdk5 during growth and as yet undefined Cdks during mid-late development. PMID- 22234986 TI - Production, purification and characterisation of polysaccharides from Pleurotus ostreatus with antitumour activity. AB - BACKGROUND: Mushroom polysaccharides play an important role in functional foods because they exhibit biological modulator properties such as antitumour, antiviral and antibacterial activities. The present study involved the production, purification and characterisation of intracellular and extracellular free and protein-bound polysaccharides from Pleurotus ostreatus and the investigation of their growth-inhibitory effect on human carcinoma cell lines. RESULTS: Several fermentation parameters were obtained: batch polysaccharide productivities of 0.013 +/- 8.12 * 10-5 and 0.037 +/- 0.0005 g L-1 day-1 for intracellular and extracellular polysaccharides respectively, a maximum biomass concentration of 9.35 +/- 0.18 g L-1 , P(max) = 0.935 +/- 0.018 g L-1 day-1, u(max) = 0.218 +/- 0.02 day-1, Y(EP/X) = 0.040 +/- 0.0015 g g-1 and Y(IP/X) = 0.014 +/- 0.0003 g g-1 . Some polysaccharides exhibited superoxide dismutase (SOD)-like activity of 50-200 units. Fourier transform infrared analysis of the polysaccharides revealed absorption bands characteristic of such biological macromolecules. Cytotoxicity assays showed that both intracellular and extracellular polysaccharides exhibited antitumour activity towards several tested human carcinoma cell lines in a dose-dependent manner. CONCLUSION: The polysaccharides of P. ostreatus exhibited high SOD-like activity, which strongly supports their biological effect on tumour cell lines. The extracellular polysaccharides presented the highest antitumour activity towards the RL95 carcinoma cell line and should be further investigated as an antitumour agent. PMID- 22234987 TI - Modifying chemical landscapes by coupling to vacuum fields. PMID- 22234988 TI - Inhibition of gecko GSK-3beta promotes elongation of neurites and oligodendrocyte processes but decreases the proliferation of blastemal cells. AB - GSK-3beta signaling is involved in regulation of both neuronal and glial cell functions, and interference of the signaling affects central nervous system (CNS) development and regeneration. Thus, GSK-3beta was proposed to be an important therapeutic target for promoting functional recovery of adult CNS injuries. To further clarify the regulatory function of the kinase on the CNS regeneration, we characterized gecko GSK-3beta and determined the effects of GSK-3beta inactivation on the neuronal and glial cell lines, as well as on the gecko tail (including spinal cord) regeneration. Gecko GSK-3beta shares 91.7-96.7% identity with those of other vertebrates, and presented higher expression abundance in brain and spinal cord. The kinase strongly colocalized with the oligodendrocytes while less colocalized with neurons in the spinal cord. Phosphorylated GSK-3beta (pGSK-3beta) levels decreased gradually during the normally regenerating spinal cord ranging from L13 to the 6th caudal vertebra. Lithium injection increased the pGSK-3beta levels of the corresponding spinal cord segments, and in vitro experiments on neurons and oligodendrocyte cell line revealed that the elevation of pGSK-3beta promoted elongation of neurites and oligodendrocyte processes. In the normally regenerate tails, pGSK-3beta kept stable in 2 weeks, whereas decreased at 4 weeks. Injection of lithium led to the elevation of pGSK-3beta levels time-dependently, however destructed the regeneration of the tail including spinal cord. Bromodeoxyuridine (BrdU) staining demonstrated that inactivation of GSK-3beta decreased the proliferation of blastemal cells. Our results suggested that species-specific regulation of GSK-3beta was indispensable for the complete regeneration of CNS. PMID- 22234989 TI - Influenza in solid organ transplant recipients. AB - OBJECTIVE: To review available data describing the epidemiology, outcomes, prevention, and treatment of influenza virus in the solid organ transplant population and to evaluate the strengths and limitations of the current literature, with a focus on literature reviewing annual influenza strains and the recent pandemic novel influenza A/H1N1 strain. DATA SOURCES: A systematic literature search (July 1980-June 2011) was performed via PubMed using the following key words: influenza, human; influenza; novel influenza A H1/N1; transplantation; solid organ transplantation; kidney transplant; renal transplant; lung transplant; heart transplant; and liver transplant. STUDY SELECTION AND DATA EXTRACTION: Papers were excluded if they were not written in English or were animal studies or in vitro studies. Data from fully published studies and recent reports from international conferences were included. DATA SYNTHESIS: The influenza virus presents a constant challenge to immunocompromised patients and their health care providers. The annual influenza strain introduces a highly infectious and pathogenic risk to solid organ transplant recipients. In 2009, the World Health Organization declared a pandemic as a result of a novel influenza A/H1N1 strain. The pandemic introduced an additional viral threat to solid organ transplant patients at increased risk for infectious complications. The mainstay for prevention of influenza infection in all at-risk populations is appropriate vaccination. Antiviral therapies against influenza for chemoprophylaxis and treatment of infection are available; however, dosing strategies in the solid organ transplant population are not well defined. CONCLUSIONS: The solid organ transplant population is at an increased risk of severe complications from influenza infection. Identifying risks, preventing illness, and appropriately treating active infection is essential in this patient population. PMID- 22234990 TI - Predictors of emergency department and outpatient visits for hypoglycemia in type 2 diabetes: an analysis of a large US administrative claims database. AB - BACKGROUND: Although hypoglycemia is a well-recognized complication of type 1 diabetes and insulin treatment in type 2 diabetes, less research exists on hypoglycemia in the large number of patients with type 2 diabetes who are treated with oral antidiabetic agents. OBJECTIVE: To identify predictors of hypoglycemia related emergency department (ED) and outpatient visits in patients with type 2 diabetes. METHODS: We used the 2004-2008 MarketScan database to conduct a nested case-control analysis. Cohort members were 18 years of age or older with type 2 diabetes and taking an oral antidiabetic agent at cohort entry. We required 12 months or more of continuous enrollment in a noncapitated plan and excluded persons with type 1 or gestational diabetes. Within the cohort, we selected 11,375 cases (first outpatient hypoglycemic event) and 68,247 controls using 6:1 incidence density sampling. A conditional logistic regression model estimated the adjusted odds ratios (AORs) and corresponding 95% confidence intervals of predictors. RESULTS: Cases were more likely than controls to have diabetic complications and other comorbidity, and to be using the most antidiabetic or other medications. The presence of individual micro- and macrovascular complications of diabetes increased the relative rate of hypoglycemia. With no antidiabetic drug therapy as the referent (within 30 days preceding the index date), insulin monotherapy (AOR 1.76; 95% CI 1.50 to 2.05) and insulin in combination with other oral antidiabetic agents (AOR 1.80; 95% CI 1.65 to 1.97) had the highest relative rates of hypoglycemia. Metformin monotherapy (AOR 0.65; 95% CI 0.61 to 0.70), thiazolidinedione monotherapy (AOR 0.71; 95% CI 0.63 to 0.79), and dipeptidyl peptidase-4 inhibitor monotherapy (AOR 0.63; 95% CI 0.45 to 0.89) had decreased relative rates of hypoglycemia. Monotherapy with sulfonylureas, other injectable agents, meglitinides or alpha-glucosidase inhibitors was not predictive. CONCLUSIONS: Medications should be prescribed carefully for patients at high risk of hypoglycemia, particularly those with diabetes complications or those taking insulin alone or in combination. Additional studies are needed to carefully examine the nature of the association between diabetes-related complications and hypoglycemic episodes. PMID- 22234991 TI - Efficacy and safety of deep brain stimulation as an adjunct to pharmacotherapy for the treatment of Parkinson disease. AB - OBJECTIVE: To review the literature describing the efficacy and safety of deep brain stimulation (DBS) as an adjunct to pharmacotherapy and to determine the best treatment option for patients with Parkinson disease (PD). DATA SOURCES: Literature was obtained through MEDLINE/PubMed (1948-September, week 2, 2011) and a bibliographic review of relevant articles. Key words included Parkinson disease, medication, pharmacotherapy, surgery, deep brain stimulation, and best medical therapy. STUDY SELECTION AND DATA EXTRACTION: Five English-language studies that compared the efficacy of DBS as an adjunct to pharmacologic treatment versus pharmacologic treatment alone in patients with PD met our inclusion criteria and were selected for this review. DATA SYNTHESIS: PD is a progressive neurodegenerative disease with limited treatment options, and levodopa is considered the pharmacologic gold standard. However, long-term levodopa use leads to decreased efficacy and increased incidence of adverse effects. Hence, DBS has been investigated as an adjunctive option for patients with PD both to overcome the adverse events of levodopa as well as to treat the disease. DBS, when used in conjunction with pharmacologic therapy, has resulted in improved motor function and quality of life in several trials compared with medication alone. Its benefit is limited by adverse events that are generally more frequent and severe than those with pharmacotherapy alone. Study limitations included small patient population and/or weak design. CONCLUSIONS: DBS may be an option as adjunct therapy in patients whose symptoms are no longer controlled with maximum pharmacologic therapy, but benefits of surgery must be weighed against the risks. PMID- 22234992 TI - Transcatheter closure of atrial septal defect in a geriatric population. AB - OBJECTIVES: To evaluate the efficacy and safety of transcatheter closure of atrial septal defects (ASD) in patients over 70 years of age. BACKGROUND: Transcatheter closure of ASD is an established procedure in children and young adults, but the benefits of this procedure in geriatric patients are still unclear. METHODS: Between 2005 and 2010, 430 patients with ASD underwent transcatheter closure in our hospital. Among those patients, 30 consecutive patients older than 70 years of age were prospectively evaluated. RESULTS: Mean age at procedure was 75.8 +/- 3.8 years (range: 70-85 years). Mean Qp/Qs was 2.4 +/- 0.7 and mean ASD diameter was 20.3 +/- 6.4 mm. Nine patients (30%) had a history of hospitalization due to heart failure. ASD closure was successfully performed in 28 patients (93%) without significant complications. During the follow-up period (mean period of 19.1 +/- 11.3 months), New York Heart Association (NYHA) functional class was significantly improved in 20 patients (74%). Significant improvements of plasma BNP level, resting heart rate, and systolic pulmonary artery pressure were also observed. Improvement of tricuspid regurgitation was observed in 11 of 17 patients with moderate or severe regurgitation during the follow-up period. Conversely, worsening of mitral regurgitation was observed in 10 of the 27 patients. CONCLUSION: Transcatheter closure of ASD in geriatric patients can be performed safely. This procedure contributes to significant improvement of symptoms and positive cardiac remodeling. Long-term follow-up is mandatory, especially for patients with mitral regurgitation. PMID- 22234994 TI - Gene prioritization for livestock diseases by data integration. AB - Identifying causal genes that underlie complex traits such as susceptibility to disease is a primary aim of genetic and biomedical studies. Genetic mapping of quantitative trait loci (QTL) and gene expression profiling based on high throughput technologies are common first approaches toward identifying associations between genes and traits; however, it is often difficult to assess whether the biological function of a putative candidate gene is consistent with a particular phenotype. Here, we have implemented a network-based disease gene prioritization approach for ranking genes associated with quantitative traits and diseases in livestock species. The approach uses ortholog mapping and integrates information on disease or trait phenotypes, gene-associated phenotypes, and protein-protein interactions. It was used for ranking all known genes present in the cattle genome for their potential roles in bovine mastitis. Gene-associated phenome profile and transcriptome profile in response to Escherichia coli infection in the mammary gland were integrated to make a global inference of bovine genes involved in mastitis. The top ranked genes were highly enriched for pathways and biological processes underlying inflammation and immune responses, which supports the validity of our approach for identifying genes that are relevant to animal health and disease. These gene-associated phenotypes were used for a local prioritization of candidate genes located in a QTL affecting the susceptibility to mastitis. Our study provides a general framework for prioritizing genes associated with various complex traits in different species. To our knowledge this is the first time that gene expression, ortholog mapping, protein interactions, and biomedical text data have been integrated systematically for ranking candidate genes in any livestock species. PMID- 22234993 TI - Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice. AB - Limb anomalies are important birth defects that are incompletely understood genetically and mechanistically. GLI3, a mediator of hedgehog signaling, is a genetic cause of limb malformations including pre- and postaxial polydactyly, Pallister-Hall syndrome and Greig cephalopolysyndactyly. A closely related Gli (glioma-associated oncogene homolog)-superfamily member, ZIC3, causes X-linked heterotaxy syndrome in humans but has not been investigated in limb development. During limb development, post-translational processing of Gli3 from activator to repressor antagonizes and posteriorly restricts Sonic hedgehog (Shh). We demonstrate that Zic3 and Gli3 expression overlap in developing limbs and that Zic3 converts Gli3 from repressor to activator in vitro. In Gli3 mutant mice, Zic3 loss of function abrogates ectopic Shh expression in anterior limb buds, limits overexpression in the zone of polarizing activity and normalizes aberrant Gli3 repressor/Gli3 activator ratios observed in Gli3+/- embryos. Zic3 null;Gli3+/- neonates show rescue of the polydactylous phenotype seen in Gli3+/- animals. These studies identify a previously unrecognized role for Zic3 in regulating limb digit number via its modifying effect on Gli3 and Shh expression levels. Together, these results indicate that two Gli superfamily members that cause disparate human congenital malformation syndromes interact genetically and demonstrate the importance of Zic3 in regulating Shh pathway in developing limbs. PMID- 22234995 TI - Identification of prognostic and diagnostic biomarkers of glucose intolerance in ApoE3Leiden mice. AB - The prevalence of diabetes mellitus Type 2 could be significantly reduced by early identification of subjects at risk, allowing for better prevention and earlier treatment. Glucose intolerance (GI) is a hallmark of the prediabetic stage. This study aims at identifying 1) prognostic biomarkers predicting the risk of developing GI later in life and 2) diagnostic biomarkers reflecting the degree of already manifest GI. To this end, disease development was followed over time in mice, and biomarkers were identified using lipidomics and transcriptomics. Young adult ApoE3Leiden mice were treated a high-fat diet for 12 wk to induce GI. Blood was collected before and during disease development. The individual extent of GI was determined with a glucose tolerance test and the area under the curve (AUC) was calculated for each animal. Subject-specific AUC values were correlated to the plasma lipidome (t = 0) and the white blood cell (WBC) transcriptome (t = 0, 6, and 12 wk) to identify prognostic and diagnostic biomarkers, respectively. The plasma ratio of specific free fatty acids prior to high-fat feeding (C16:1/C16:0, C18:1/C18:0 and C18:2/C22:6) was significantly correlated with the AUC and predictive for future GI. Subsequently, the expression level of specific WBC genes (Acss2, Arfgap1, Tfrc, Cox6b2, Barhl2, Abcb4, Cyp4b1, Sars2, Fgf16, and Tceal8) reflected the individual degree of GI during disease progression. Specific plasma free fatty acids as well as their ratio can be used to predict future GI. The expression levels of specific WBC genes can serve as easy accessible markers to diagnose and monitor already existing GI. PMID- 22234997 TI - Localized iron supply triggers lateral root elongation in Arabidopsis by altering the AUX1-mediated auxin distribution. AB - Root system architecture depends on nutrient availability, which shapes primary and lateral root development in a nutrient-specific manner. To better understand how nutrient signals are integrated into root developmental programs, we investigated the morphological response of Arabidopsis thaliana roots to iron (Fe). Relative to a homogeneous supply, localized Fe supply in horizontally separated agar plates doubled lateral root length without having a differential effect on lateral root number. In the Fe uptake-defective mutant iron-regulated transporter1 (irt1), lateral root development was severely repressed, but a requirement for IRT1 could be circumvented by Fe application to shoots, indicating that symplastic Fe triggered the local elongation of lateral roots. The Fe-stimulated emergence of lateral root primordia and root cell elongation depended on the rootward auxin stream and was accompanied by a higher activity of the auxin reporter DR5-beta-glucuronidase in lateral root apices. A crucial role of the auxin transporter AUXIN RESISTANT1 (AUX1) in Fe-triggered lateral root elongation was indicated by Fe-responsive AUX1 promoter activities in lateral root apices and by the failure of the aux1-T mutant to elongate lateral roots into Fe-enriched agar patches. We conclude that a local symplastic Fe gradient in lateral roots upregulates AUX1 to accumulate auxin in lateral root apices as a prerequisite for lateral root elongation. PMID- 22234996 TI - Dynamic phosphometabolomic profiling of human tissues and transgenic models by 18O-assisted 31P NMR and mass spectrometry. AB - Next-generation screening of disease-related metabolomic phenotypes requires monitoring of both metabolite levels and turnover rates. Stable isotope (18)O assisted (31)P nuclear magnetic resonance (NMR) and mass spectrometry uniquely allows simultaneous measurement of phosphometabolite levels and turnover rates in tissue and blood samples. The (18)O labeling procedure is based on the incorporation of one (18)O into P(i) from [(18)O]H(2)O with each act of ATP hydrolysis and the distribution of (18)O-labeled phosphoryls among phosphate carrying molecules. This enables simultaneous recording of ATP synthesis and utilization, phosphotransfer fluxes through adenylate kinase, creatine kinase, and glycolytic pathways, as well as mitochondrial substrate shuttle, urea and Krebs cycle activity, glycogen turnover, and intracellular energetic communication. Application of expanded (18)O-labeling procedures has revealed significant differences in the dynamics of G-6-P[(18)O] (glycolysis), G-3 P[(18)O] (substrate shuttle), and G-1-P[(18)O] (glycogenolysis) between human and rat atrial myocardium. In human atria, the turnover of G-3-P[(18)O], which defects are associated with the sudden death syndrome, was significantly higher indicating a greater importance of substrate shuttling to mitochondria. Phosphometabolomic profiling of transgenic hearts deficient in adenylate kinase (AK1-/-), which altered levels and mutations are associated to human diseases, revealed a stress-induced shift in metabolomic profile with increased CrP[(18)O] and decreased G-1-P[(18)O] metabolic dynamics. The metabolomic profile of creatine kinase M-CK/ScCKmit-/--deficient hearts is characterized by a higher G-6 [(18)O]P turnover rate, G-6-P levels, glycolytic capacity, gamma/beta-phosphoryl of GTP[(18)O] turnover, as well as beta-[(18)O]ATP and beta-[(18)O]ADP turnover, indicating altered glycolytic, guanine nucleotide, and adenylate kinase metabolic flux. Thus, (18)O-assisted gas chromatography-mass spectrometry and (31)P NMR provide a suitable platform for dynamic phosphometabolomic profiling of the cellular energetic system enabling prediction and diagnosis of metabolic diseases states. PMID- 22234998 TI - Chemical quenching of singlet oxygen by carotenoids in plants. AB - Carotenoids are considered to be the first line of defense of plants against singlet oxygen ((1)O(2)) toxicity because of their capacity to quench (1)O(2) as well as triplet chlorophylls through a physical mechanism involving transfer of excitation energy followed by thermal deactivation. Here, we show that leaf carotenoids are also able to quench (1)O(2) by a chemical mechanism involving their oxidation. In vitro oxidation of beta-carotene, lutein, and zeaxanthin by (1)O(2) generated various aldehydes and endoperoxides. A search for those molecules in Arabidopsis (Arabidopsis thaliana) leaves revealed the presence of (1)O(2)-specific endoperoxides in low-light-grown plants, indicating chronic oxidation of carotenoids by (1)O(2). beta-Carotene endoperoxide, but not xanthophyll endoperoxide, rapidly accumulated during high-light stress, and this accumulation was correlated with the extent of photosystem (PS) II photoinhibition and the expression of various (1)O(2) marker genes. The selective accumulation of beta-carotene endoperoxide points at the PSII reaction centers, rather than the PSII chlorophyll antennae, as a major site of (1)O(2) accumulation in plants under high-light stress. beta-Carotene endoperoxide was found to have a relatively fast turnover, decaying in the dark with a half time of about 6 h. This carotenoid metabolite provides an early index of (1)O(2) production in leaves, the occurrence of which precedes the accumulation of fatty acid oxidation products. PMID- 22235001 TI - A novel device for endovascular native aortic valve resection for transapical transcatheter aortic valve implantation. AB - We developed a novel resection device to use during transapical transcatheter aortic valve implantation (TAVI) using a circular blade. We assessed the device in 15 human cadavers by transapical approach. After the resection, the aortic annulus was measured using standard probes. A careful examination of the aortic wall, left ventricular outflow tract, coronary ostia and mitral valve was performed using an endpoint checklist, developed specifically for the new device. The resection was successfully completed in 14 out of 15 (93%) cases. All the resected leaflets and debris have been successfully evaluated in 15 out of 15 (100%) cases. One case of a bicuspid valve had a prominent calcification of the median raphe. The resection tool could only perform a partial resection. The mean duration of the resection was 45 +/- 30 s. The surrounding tissue examination did not reveal any injury to the anatomical structures. Endovascular resection of the native valve using transapical approach is feasible and effective. Further developments are necessary before the definitive clinical use during percutaneous aortic valve implantation. PMID- 22235003 TI - Current practice of antiplatelet and anticoagulation management in post-cardiac surgery patients: a national audit. AB - The Audit and Guidelines Committee of the European Association for Cardio Thoracic Surgery recently published a guideline on antiplatelet and anticoagulation management in cardiac surgery. We aimed to assess the awareness of the current guideline and adherence to it in the National Health Service through this National Audit. We designed a questionnaire consisting of nine questions covering various aspects of antiplatelet and anticoagulation management in post-cardiac surgery patients. A telephonic survey of the on-call cardiothoracic registrars in all the cardiothoracic centres across the UK was performed. All 37 National Health Service hospitals in the UK with 242 consultants providing adult cardiac surgical service were contacted. Twenty (54%) hospitals had a unit protocol for antiplatelet and anticoagulation management in post-cardiac surgery. Only 23 (62.2%) registrars were aware of current European Association for Cardio-Thoracic Surgery guidelines. Antiplatelet therapy is variable in the cardiac surgical units across the country. Low-dose aspirin is commonly used despite the recommendation of 150-300 mg. The loading dose of aspirin within 24 h as recommended by the guideline is followed only by 60.7% of surgeons. There was not much deviation from the guideline with respect to the anticoagulation therapy. PMID- 22235002 TI - Seronegative rheumatoid arthritis: a rare cause of effusive-constrictive pericarditis requiring pericardiectomy. AB - Effusive-constrictive pericarditis is a rare condition. In this report, we describe a case of effusive-constrictive pericarditis caused by seronegative rheumatoid arthritis which was successfully treated with surgical pericardiectomy. PMID- 22234999 TI - Cross talk among calcium, hydrogen peroxide, and nitric oxide and activation of gene expression involving calmodulins and calcium-dependent protein kinases in Ulva compressa exposed to copper excess. AB - To analyze the copper-induced cross talk among calcium, nitric oxide (NO), and hydrogen peroxide (H(2)O(2)) and the calcium-dependent activation of gene expression, the marine alga Ulva compressa was treated with the inhibitors of calcium channels, ned-19, ryanodine, and xestospongin C, of chloroplasts and mitochondrial electron transport chains, 3-(3,4-dichlorophenyl)-1,1-dimethylurea and antimycin A, of pyruvate dehydrogenase, moniliformin, of calmodulins, N-(6 aminohexyl)-5-chloro-1-naphtalene sulfonamide, and of calcium-dependent protein kinases, staurosporine, as well as with the scavengers of NO, 2-(4-carboxyphenyl) 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and of H(2)O(2), ascorbate, and exposed to a sublethal concentration of copper (10 MUm) for 24 h. The level of NO increased at 2 and 12 h. The first peak was inhibited by ned-19 and 3-(2,3 dichlorophenyl)-1,1-dimethylurea and the second peak by ned-19 and antimycin A, indicating that NO synthesis is dependent on calcium release and occurs in organelles. The level of H(2)O(2) increased at 2, 3, and 12 h and was inhibited by ned-19, ryanodine, xestospongin C, and moniliformin, indicating that H(2)O(2) accumulation is dependent on calcium release and Krebs cycle activity. In addition, pyruvate dehydrogenase, 2-oxoxglutarate dehydrogenase, and isocitrate dehydrogenase activities of the Krebs cycle increased at 2, 3, 12, and/or 14 h, and these increases were inhibited in vitro by EGTA, a calcium chelating agent. Calcium release at 2, 3, and 12 h was inhibited by 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide and ascorbate, indicating activation by NO and H(2)O(2). In addition, the level of antioxidant protein gene transcripts decreased with N-(6-aminohexyl)-5-chloro-1-naphtalene sulfonamide and staurosporine. Thus, there is a copper-induced cross talk among calcium, H(2)O(2), and NO and a calcium-dependent activation of gene expression involving calmodulins and calcium-dependent protein kinases. PMID- 22235004 TI - Heart team approach for transcatheter aortic valve implantation procedures complicated by coronary artery occlusion. AB - We report on three out of 270 consecutive patients (1.1%) suffering from coronary artery obstruction or occlusion at the end of transcatheter aortic valve implantation (TAVI). The partial or total obstruction of the coronary artery seen in the post-implantation aortography was accompanied by haemodynamic instability and electrocardiographic changes typical for myocardial ischaemia. Immediate percutaneous coronary intervention with stent implantation was successful in two cases, while in the third case it was not possible to cross the occluded right coronary artery. Emergency coronary artery bypass grafting was performed resulting in uneventful myocardial recovery. All patients were discharged home. These cases highlight the awareness of this rare, life-threatening complication of TAVI, which is in need of a dedicated heart team involved not only in decision making, but also in the procedure itself. PMID- 22235005 TI - Does posterior pericardiotomy reduce the incidence of atrial fibrillation after coronary artery bypass grafting surgery? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether posterior pericardiotomy (PP) reduces the incidence of atrial fibrillation (AF) after coronary artery bypass grafting surgery. Twelve papers were found using the reported search, of which seven represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. One non-randomized prospective cohort controlled study generated early evidence that PP reduced the rate of postoperative AF and pericardial effusion. The operative details of PP were clearly explained in this paper. The efficacy of this procedure was subsequently examined in five prospective randomized controlled trials performed with some limitations, listed in the table. Meta-analysis of the randomized control trials examined a group of 763 patients (PP = 389, control = 374). It revealed a highly significant reduction in total arrhythmias and AF in the PP group (odds ratio 0.31 and 0.33, respectively). There was a 10.8% AF rate in the PP group (41/379) and a 28.1% AF rate in the control group (108/384). Furthermore, the PP group had a significant reduction in the rate of early and late pericardial effusion (P < 0.001). Moreover, the reduction in the incidence of arrhythmias was significantly associated with the reduction in the incidence of pericardial effusion. Referring to these studies, two guidelines recommend PP to reduce postoperative AF with grade B strength of recommendation. We conclude that PP significantly reduces the incidence of postoperative AF. The number needed to treat to prevent one case of AF is six. PMID- 22235006 TI - NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association. AB - Congenital diseases are increasingly being recognised in adults because of clinical mimicry, variable clinical picture or rarity of the disease; pregnancy is a valuable diagnostic occasion. The present case is the first report of an association report between NEMO syndrome (an acronym of the mutated, non functioning gene, NF-kB essential modulator), a rare X-linked disease, characterised by developmental anomalies, immunodepression and skin lesions, and systemic lupus erythematosus (SLE). A 35-year-old patient affected by SLE sought clinical advice in the 8th week of gestation. The diagnosis of SLE dated back to the age of 24, when multisystemic manifestations (pleuropericarditis, weight loss, alopecia, skin involvement, joint pain, kidney involvement) were observed. She had been treated with steroids since 1999; immunosuppressive drugs had been added for short periods. Developmental anomalies were present, including oligodontia, retinal problems, anomalies of the corpus callosum and pes planovalgus. Family history included multiple miscarriages, dental malformations and oligodontia and skin blistering in the first months of life. On these bases, incontinentia pigmenti (IP; or NEMO syndrome) was diagnosed and confirmed by genetic testing. The NEMO gene is implicated in immune deficiencies as well as in autoimmune diseases. This report may suggest a role for NF-kB essential modulator in the pathogenesis of SLE, in the context of the complex immunologic deficiencies increasingly associated with autoimmune diseases. PMID- 22235007 TI - Drug industry is now biggest defrauder of US government. PMID- 22235008 TI - Time to act on nonsensical outpatient follow-up ratio targets. PMID- 22235009 TI - Doctor begins "Bevan's Run" to stop the health bill. PMID- 22235010 TI - Is a clinician's "gut feeling" enough to identify self harm? PMID- 22235011 TI - Difficulties in managing young people who self harm. PMID- 22235013 TI - Life goes on for patients with cancer, as they desire. PMID- 22235014 TI - Let's simply scrap authorship and move to contributorship. PMID- 22235015 TI - Why not switch to movie-style credits for research papers? PMID- 22235016 TI - Keep it small and personal in any reconfiguration of healthcare providers. PMID- 22235017 TI - Root causes of doctors' dissatisfaction must be tackled to stop brain drain. PMID- 22235018 TI - Patient related factors are also important in treating gout. PMID- 22235019 TI - Realities of medicine in South Africa lie behind its brain drain. PMID- 22235020 TI - The emperor's NICE new clothes. PMID- 22235021 TI - US publishes first global health strategy to improve health of Americans and rest of the world. PMID- 22235022 TI - Wakefield sues BMJ over MMR articles. PMID- 22235023 TI - Appeal court will rule on children's heart surgery at London's Royal Brompton Hospital. PMID- 22235024 TI - Doctors are told to "make every contact count" to reduce costs of poor lifestyles. PMID- 22235026 TI - Inflammation, DNA methylation and colitis-associated cancer. AB - Inflammation can result from a range of sources including microbial infections, exposure to allergens and toxic chemicals, autoimmune disease and obesity. A well balanced immune response can be anti-tumorigenic; however, a sustained or chronic inflammatory response is generally harmful as the immune response becomes distorted. A causal link between chronic inflammation and cancer is now well accepted and many chronically inflamed organs of the gastrointestinal tract show this association. For example, patients with inflammatory bowel disease (IBD), including both ulcerative colitis and Crohn's disease, have a 2- to 3-fold greater lifetime risk of developing colorectal cancer compared with the general population. The development of colitis-associated cancer (CAC) is thought to be multifaceted and is probably due to a combination of genetic factors, epigenetic factors and the duration, extent and severity of disease. Recently, epigenetic alterations, in particular alterations in DNA methylation, have been observed during inflammation and inflammation-associated carcinogenesis. The mediators of this, the significance of these changes in DNA methylation and the effect this has on gene expression and the malignant transformation of the epithelial cells during IBD and CAC are discussed in this review. The recent advances in technologies to study genome-wide DNA methylation and the therapeutic potential of understanding these molecular mechanisms are also highlighted. PMID- 22235025 TI - Susceptibility genetic variants associated with early-onset colorectal cancer. AB - Colorectal cancer (CRC) is the second most common cancer in Western countries. Hereditary forms only correspond to 5% of CRC burden. Recently, genome-wide association studies have identified common low-penetrant CRC genetic susceptibility loci. Early-onset CRC (CRC<50 years old) is especially suggestive of hereditary predisposition although 85-90% of heritability still remains unidentified. CRC<50 patients (n = 191) were compared with a late-onset CRC group (CRC>65 years old) (n = 1264). CRC susceptibility variants at 8q23.3 (rs16892766), 8q24.21 (rs6983267), 10p14 (rs10795668), 11q23.1 (rs3802842), 15q13.3 (rs4779584), 18q21 (rs4939827), 14q22.2 (rs4444235), 16q22.1 (rs9929218), 19q13.1 (rs10411210) and 20p12.3 (rs961253) were genotyped in all DNA samples. A genotype-phenotype correlation with clinical and pathological characteristics in both groups was performed. Risk allele carriers for rs3802842 [Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.05, P = 0.0096, dominant model) and rs4779584 (OR = 1.39, 95% CI 1.02-1.9, P = 0.0396, dominant model) were more frequent in the CRC<50 group, whereas homozygotes for rs10795668 risk allele were also more frequent in the early-onset CRC (P = 0.02, codominant model). Regarding early-onset cases, 14q22 (rs4444235), 11q23 (rs3802842) and 20p12 (rs961253) variants were more associated with family history of CRC or tumors of the Lynch syndrome spectrum excluding CRC. In our entire cohort, sum of risk alleles was significantly higher in patients with a CRC family history (OR = 1.40, 95% CI 1.06-1.85, P = 0.01). In conclusion, variants at 10p14 (rs10795668), 11q23.1 (rs3802842) and 15q13.3 (rs4779584) may have a predominant role in predisposition to early-onset CRC. Association of CRC susceptibility variants with some patient's familiar and personal features could be relevant for screening and surveillance strategies in this high-risk group and it should be explored in further studies. PMID- 22235027 TI - Evaluation of microRNA expression profiles and their associations with risk alleles in lymphoblastoid cell lines of familial ovarian cancer. AB - Interindividual variations of microRNA expression are likely to influence the expression of microRNA target genes and, therefore, contribute to phenotypic differences in humans, including cancer susceptibility. Whether microRNA expression variation has any role in ovarian cancer development is still unknown. Here, we evaluated microRNA expression profiles in lymphoblastoid cell lines from 74 women with familial ovarian cancer and 47 unrelated controls matched on gender and race. We found that the cases and unrelated controls can be clustered using 95 differentially expressed microRNAs with 91% accuracy. To assess the potential implications of microRNAs in ovarian cancer, we investigated the associations between microRNA expression and seven ovarian cancer risk variants discovered from genome-wide association studies (GWAS), namely, rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21 and rs2363956 on 19p13. We observed 130 significant associations at a permutation level of 0.01. Compared with other risk variants, rs3814113 and rs2072590 had the greatest number of significant associations (68 and 37, respectively). Interestingly, 14 microRNAs that were associated with ovarian cancer risk alleles belong to five microRNA clusters. The most notable cluster is the tumorigenic miR-17-92 cluster with five microRNAs, all of which are significantly associated with rs3814113. Using pathway analysis, several key biological pathways were significantly overrepresented, such as cellular response to stress (P = 2.87 * 10(-06)), etc. Further characterization of significant associations between microRNAs and risk alleles could facilitate the understanding of the functions of these GWAS discovered risk alleles in the genetic etiology of ovarian cancer. PMID- 22235029 TI - Practical divinity and medical ethics: lawful versus unlawful medicine in the writings of William Perkins (1558-1602). AB - This article examines for the first time the theologically based medical ethics of the late sixteenth-century English Calvinist minister William Perkins. Although Perkins did not write a single focused book on the subject of medical ethics, he addressed a variety of moral issues in medicine in his numerous treatises on how laypeople should conduct themselves in their vocations and in all aspects of their daily lives. Perkins wrote on familiar issues such as the qualities of a good physician, the conduct of sick persons, the role of the minister in healing, and obligations in time of pestilence. His most significant contribution was his distinction between "lawful" and "unlawful" medicine, the latter category including both medical astrology and magic. Perkins's works reached a far greater audience in England and especially New England than did the treatises of contemporary secular medical ethics authors and his writings were influential in guiding the moral thinking of many pious medical practitioners and laypersons. PMID- 22235028 TI - T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells. AB - AIMS: T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes. METHODS AND RESULTS: We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC. CONCLUSION: T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRes. PMID- 22235030 TI - Neural mechanisms of short-term plasticity in the human visual system. AB - Following circumscribed retinal damage, extensive reorganization of topographically organized visual cortical areas has been demonstrated in several species of mammals (including humans). Although reorganization is often studied over extended time scales, neural response properties change within seconds of retinal deafferentation. Understanding the mechanisms underlying these short-term effects is essential for developing a complete picture of representational plasticity. One approach to the study of short-term plasticity has been to use an artificial scotoma, a stimulus-induced analog of a retinal scotoma, as a model. Here, we use event-related potentials in an artificial scotoma paradigm to examine 2 aspects of short-term plasticity in the human visual system. First, we investigated the changes within visual representations temporarily deprived of patterned visual input by probing the inner boundaries of an artificial scotoma. We found an enhanced early sensory P1, consistent with a reduction in inhibition (disinhibition), a proposed mechanism of short-term visual plasticity. Second, we investigated mechanisms through which representations of surrounding space invade a visually deprived area by probing the outer boundaries of an artificial scotoma. In this case, a later visual component, the N1, was enhanced, suggesting that feedback may provide a source of unmasked, or invading, activity to visually deprived representations. PMID- 22235031 TI - The association between resting functional connectivity and creativity. AB - The analysis of functional connectivity at rest (rFC) enables us to know how brain regions within and between networks interact. In this study, we used resting-state functional magnetic resonance imaging and a creativity test of divergent thinking (DT) to investigate the relationship between creativity measured by DT and rFC. We took the medial prefrontal cortex (mPFC) to be the seed region and investigated correlations across subjects between the score of the DT test and the strength of rFC between the mPFC and other brain regions. Our results showed that the strength of rFC with the mPFC significantly and positively correlated with creativity as measured by the DT test in the posterior cingulate cortex (PCC). These results showed that higher creativity measured by DT is associated with rFC between the mPFC and the PCC, the key nodes of the default mode network (DMN). Increased rFC between these regions is completely opposite from that is generally expected from the association between higher creativity and reduced deactivation in DMN during an externally directed attention-demanding task shown in our previous study but is similar to the pattern seen in relatives of schizophrenia. These findings are comparable to the previously reported psychological associations between schizotypy and creativity. PMID- 22235032 TI - Acting alters visual processing: flexible recruitment of visual areas by one's own actions. AB - Using functional magnetic resonance imaging, we investigated the effect of motor preparation/execution on the activation of visual cortical areas by action observation. We presented videos of human actors performing several fine manipulative actions (e.g., grasping) with the hand or foot, together with appropriate control stimuli. Subjects either responded in a central fixation task with the hand (A) or foot (B) or viewed the stimuli passively (C). Experimental conditions were arranged according to a 2 * 2 * 3 factorial design with action, effector, and response as factors. Bilateral posterior parietal cortex was more strongly activated for action videos compared with controls during active runs (A or B) contrasted with passive runs (C). Two neighboring regions in the right fusiform gyrus (FG) were activated when the effector employed to respond in the task matched that displayed in the videos (A or B), independently of whether the stimulus was an action or a control. Neighboring regions in the right posterior middle temporal gyrus (MTG) were also activated when the effector observed and that used to respond matched (A or B), but only for action videos, not controls. Our results indicate flexible modulation of visual areas during concurrent action observation and action execution/preparation, which was effector specific in the FG and MTG. PMID- 22235033 TI - Transcriptional analysis of Gli3 mutants identifies Wnt target genes in the developing hippocampus. AB - Early development of the hippocampus, which is essential for spatial memory and learning, is controlled by secreted signaling molecules of the Wnt gene family and by Wnt/beta-catenin signaling. Despite its importance, little is known, however, about Wnt-regulated genes during hippocampal development. Here, we used the Gli3 mutant mouse extra-toes (Xt(J)), in which Wnt gene expression in the forebrain is severely affected, as a tool in a microarray analyses to identify potential Wnt target genes. This approach revealed 53 candidate genes with restricted or graded expression patterns in the dorsomedial telencephalon. We identified conserved Tcf/Lef-binding sites in telencephalon-specific enhancers of several of these genes, including Dmrt3, Gli3, Nfia, and Wnt8b. Binding of Lef1 to these sites was confirmed using electrophoretic mobility shift assays. Mutations in these Tcf/Lef-binding sites disrupted or reduced enhancer activity in vivo. Moreover, ectopic activation of Wnt/beta-catenin signaling in an ex vivo explant system led to increased telencephalic expression of these genes. Finally, conditional inactivation of Gli3 results in defective hippocampal growth. Collectively, these data strongly suggest that we have identified a set of direct Wnt target genes in the developing hippocampus and provide inside into the genetic hierarchy underlying Wnt-regulated hippocampal development. PMID- 22235034 TI - Distinguishing self and other in joint action. Evidence from a musical paradigm. AB - The capacity to distinguish between one's own and others' behavior is a cognitive prerequisite for successful joint action. We employed a musical joint action task to investigate how the brain achieves this distinction. Pianists performed the right-hand part of piano pieces, previously learned bimanually, while the complementary left-hand part either was not executed or was (believed to be) played by a co-performer. This experimental setting served to induce a co representation of the left-hand part reflecting either the self or the co performer. Single-pulse transcranial magnetic stimulation was applied to the right primary motor cortex and motor-evoked potentials (MEPs) were recorded from the resting left forearm. Results show that corticospinal excitability was modulated by whether the representation of the left hand was associated with the self or the other, with the MEP amplitude being low and high, respectively. This result remained unchanged in a separate session where participants could neither see nor hear the other but still infer his presence by means of contextual information. Furthermore, the amplitude of MEPs associated with co-performer presence increased with pianists' self-reported empathy. Thus, the sociality of the context modulates action attribution at the level of the motor control system. PMID- 22235036 TI - Low atrial fibrillatory rate is associated with poor outcome in patients with mild to moderate heart failure. AB - BACKGROUND: Atrial fibrillatory rate (AFR) is a measure of atrial remodeling caused by atrial fibrillation (AF), and its acceleration negatively affects outcome of interventions for persistent AF. However, the prognostic value of AFR in patients with congestive heart failure (CHF) has not been studied. We sought to evaluate whether AFR can predict outcome in patients with mild to moderate (New York Health Association II-III) CHF. METHODS AND RESULTS: High-resolution 20 minute long Holter ECGs obtained from 169 CHF patients with AF at enrollment were analyzed. AFR was estimated using spatiotemporal QRST cancellation and time frequency analysis. The patients were followed for a median of 44 months, with primary end point defined as total mortality and secondary end points as sudden death and heart failure death. Atrial signal quality was sufficient for AFR estimation in 142 patients (mean age 69+/-11 years, 101 male). Of those, 48 patients died during follow-up, including 18 because of CHF progression. Mean AFR was 390+/-60 fpm and decreased with age (r=-0.3, P<0.001). Patients with AFR <=371 fpm (lower tertile) had 44% 3-year mortality as compared with 26% with higher AFR. Lower AFR was an independent predictor of all cause mortality (HR=1.99, 95% CI=1.09-3.63, P=0.025) and CHF death (HR=3.74, 95% CI=1.38-10.14, P=0.010) after adjustment for significant clinical covariates in multivariable Cox analysis. CONCLUSIONS: In CHF patients with AF, reduced AFR assessed using noninvasive approach is associated with increased risk of death because of heart failure progression, and may be considered a predictor of outcome. PMID- 22235035 TI - The left occipitotemporal cortex does not show preferential activity for words. AB - Regions in left occipitotemporal (OT) cortex, including the putative visual word form area, are among the most commonly activated in imaging studies of single word reading. It remains unclear whether this part of the brain is more precisely characterized as specialized for words and/or letters or contains more general use visual regions having properties useful for processing word stimuli, among others. In Analysis 1, we found no evidence of greater activity in left OT regions for words or letter strings relative to other high-spatial frequency high contrast stimuli, including line drawings and Amharic strings (which constitute the Ethiopian writing system). In Analysis 2, we further investigated processing characteristics of OT cortex potentially useful in reading. Analysis 2 showed that a specific part of OT cortex 1) is responsive to visual feature complexity, measured by the number of strokes forming groups of letters or Amharic strings and 2) processes learned combinations of characters, such as those in words and pseudowords, as groups but does not do so in consonant and Amharic strings. Together, these results indicate that while regions of left OT cortex are not specialized for words, at least part of OT cortex has properties particularly useful for processing words and letters. PMID- 22235038 TI - Isolated left ventricular noncompaction in sub-Saharan Africa: a clinical and echocardiographic perspective. AB - BACKGROUND: Isolated left ventricular noncompaction (ILVNC) is a cardiomyopathy caused by intrauterine failure of the myocardium to compact. Common clinical complications are heart failure, arrhythmias, and cardioembolism. A paucity of data exists relating to clinical and echocardiographic features of ILVNC in Africans. METHODS AND RESULTS: This study is a single-center, prospective case control study, whereby subjects attending a dedicated cardiomyopathy clinic were screened for and diagnosed with ILVNC, provided they had no other associated structural heart disease and fulfilled all the accompanying echocardiographic criteria: (1) end-systolic ratio of noncompacted layer to compacted layer >2, (2) presence of >3 prominent apical trabeculations, and (3) deep intertrabecular recesses that fill with blood from the ventricular cavity visualized using color Doppler ultrasound. Fifty-four subjects were identified, age 45.4+/-13.1 years (mean+/-SD), 95% confidence interval 3.6 to 10.2, 55.6% male, and 63.0% New York Health Association Class II, and prevalence of LVNC in our clinic was 6.9%, 95% confidence interval 3.6 to 10.2. Heart failure because of systolic dysfunction was the most common clinical presentation (53 subjects, 98.1%). Left ventricular end-diastolic diameter was 61.4+/-7.2 mm (mean+/-SD) and ejection fraction 26.7+/ 11.9% (mean+/-SD). Common sites of noncompaction were the apical (100%), midinferior (74.1%), and midlateral (64.8%) walls. Right ventricular noncompaction occurred in 12 subjects (22.2%). Pulmonary hypertension was documented in 45 cases (83.3%). Right ventricular dilation was noted in 40 subjects (74.1%), while right ventricular function was depressed in 32 (59.3%). Tricuspid S' was 9.6+/-2.8 cm/s (mean+/-SD). No echocardiographic features suggestive of ILVNC were noted in a healthy control group of African descent. CONCLUSIONS: ILVNC in patients of African descent can be characterized by biventricular abnormality and pulmonary hypertension, in addition to isolated left-sided abnormality. PMID- 22235040 TI - The spectrum of ASIA: 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants'. PMID- 22235041 TI - Silicone and scleroderma revisited. AB - Silicone, a synthetic polymer considered to be a biologically inert substance, is used in a multitude of medical products, the most publicly recognized of which are breast implants. Silicone breast implants have been in use since the early 1960s for cosmetic and reconstructive purposes, and reports of autoimmune disease like syndromes began appearing in the medical literature soon thereafter. Over the previous year, silicone implants have been suggested as playing a role in a new syndrome that encompasses a wide array of immune-related manifestations, termed ASIA ('Autoimmune Syndrome Induced by Adjuvant'). Scleroderma, a relatively rare connective tissue disease with skin manifestations and systemic effects, has also been described in association with silicone implantation and rupture. However, epidemiological studies and meta-analyses have failed to corroborate the clinical impression of silicone-induced scleroderma. The following review describes the mechanisms by which silicone may mediate autoimmunity in general, as well as the evidence for causal associations with more specific autoimmune syndromes in general, and scleroderma in particular. PMID- 22235037 TI - A genetic risk score is associated with incident cardiovascular disease and coronary artery calcium: the Framingham Heart Study. AB - BACKGROUND: Limited data exist regarding the use of a genetic risk score (GRS) for predicting risk of incident cardiovascular disease (CVD) in US-based samples. METHODS AND RESULTS: By using findings from recent genome-wide association studies, we constructed GRSs composed of 13 genetic variants associated with myocardial infarction or other manifestations of coronary heart disease (CHD) and 102 genetic variants associated with CHD or its major risk factors. We also updated the 13 single-nucleotide polymorphism (SNP) GRSs with 16 SNPs recently discovered by genome-wide association studies. We estimated the association, discrimination, and risk reclassification of each GRS for incident cardiovascular events and prevalent coronary artery calcium (CAC). In analyses adjusted for age, sex, CVD risk factors, and parental history of CVD, the 13 SNP GRSs were significantly associated with incident hard CHD (hazard ratio, 1.07; 95% CI, 1.00 1.15; P=0.04), CVD (hazard ratio per allele, 1.05; 95% CI, 1.01-1.09; P=0.03), and high CAC (defined as >75(th) age- and sex-specific percentile; odds ratio per allele, 1.18; 95% CI, 1.11-1.26; P=3.4*10(-7)). The GRS did not improve discrimination for incident CHD or CVD but led to modest improvements in risk reclassification. However, significant improvements in discrimination and risk reclassification were observed for the prediction of high CAC. The addition of 16 newly discovered SNPs to the 13 SNP GRSs did not significantly modify these results. CONCLUSIONS: A GRS composed of 13 SNPs associated with coronary disease is an independent predictor of cardiovascular events and of high CAC, modestly improves risk reclassification for incident CHD, and significantly improves discrimination for high CAC. The addition of recently discovered SNPs did not significantly improve the performance of this GRS. PMID- 22235042 TI - Human adjuvant disease induced by foreign substances: a new model of ASIA (Shoenfeld's syndrome). AB - OBJECTIVE: To investigate the clinical, laboratory and histological manifestations of patients who received illegal injections of foreign substances for cosmetic purposes. PATIENTS AND METHODS: We studied patients who met the following inclusion criteria: 1) history of application of foreign substances for cosmetic purposes, 2) clinical data of autoimmune disease or non-specific autoimmune manifestation (i.e. arthralgias, myalgia, malaise, fever, and weight loss), 3) detection of autoantibodies in patients' sera, 4) histological evidence of chronic inflammation and/or granulomatous reaction to foreign body. RESULTS: Fifty female patients aged 44.4 +/- 10 years were studied. The mean time between application of foreign substances and onset of symptoms was 4.5 +/- 4.3 years. Patients were followed for 12 +/- 7.5 years. Forty-one patients were injected with mineral oil, nine patients received other substances: three iodine gadital, one guayacol, one guayacol plus silicone fluid, two collagen, two silicone fluid. The sites of application were: buttocks (36), legs and/or thighs (11), breasts (eight) hands and face (one), face (two) (seven patients received an injection to more than one site). Thirty patients presented with non-specific autoimmune manifestations, whereas 20 patients fulfilled the criteria for a defined autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, overlap syndrome, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune hepatitis, and ulcerative colitis. CONCLUSIONS: Cases of human adjuvant disease following illegal injections of oil substances for cosmetic purposes are reported. Patients presented with defined autoimmune diseases as well as with non-specific autoimmune manifestations. Illegal injection of these substances could lead to serious local and systemic complications, even to death. These cases represent another model of Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA). The use of these substances should be prohibited. PMID- 22235043 TI - Autoimmune syndrome induced by adjuvants (ASIA) in the Middle East: morphea following silicone implantation. AB - Morphea and other scleroderma-like skin conditions are occasionally linked with exposure to chemical compounds such as silicone. We treated a 56-year-old woman with generalized severe skin induration accompanied with systemic symptoms and peripheral eosinophilia, which appeared 2.5 years after breast silicone implantation and abdominal liposuction. Blood test results and histopathological examination of her skin suggested the diagnosis of morphea overlapping with eosinophilic fasciitis. Her skin disease was presumed to be an autoimmune reaction to silicone implantation. While the removal of the implants did not improve her illness, treatment with 1 mg/kg prednisone and PUVA bath was initiated, with some improvement. This patient illustrates an example of ASIA (Autoimmune Syndrome Induced by Adjuvants), as her disease appeared following exposure to an adjuvant stimulus, with 'typical', although not well-defined, autoimmune manifestations. PMID- 22235044 TI - Still's disease, lupus-like syndrome, and silicone breast implants. A case of 'ASIA' (Shoenfeld's syndrome). AB - In recent years, four conditions, siliconosis, Gulf War syndrome (GWS), macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena, were linked to a previous exposure to an adjuvant, suggesting a common denominator, and it has been proposed to incorporate comparable conditions under a common syndrome entitled Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA). We report a case of a female who at the age of 11 years was diagnosed with Still's disease. At the age of 22 she underwent silicone breast implants and presented with a transient lupus-like syndrome. Then, at 25 years old she had a severe activation of Still's disease in association with rupture of silicone breast implants. When the prostheses were removed, the clinical picture improved. This case fulfills the criteria for ASIA and complements seven previous reports of Still's disease in association with silicone breast implants. PMID- 22235045 TI - Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases. AB - OBJECTIVES: In this study we analyzed the clinical and demographic manifestations among patients diagnosed with immune/autoimmune-mediated diseases post-hepatitis B vaccination. We aimed to find common denominators for all patients, regardless of different diagnosed diseases, as well as the correlation to the criteria of Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants (ASIA). PATIENTS AND METHODS: We have retrospectively analyzed the medical records of 114 patients, from different centers in the USA, diagnosed with immune-mediated diseases following immunization with hepatitis-B vaccine (HBVv). All patients in this cohort sought legal consultation. Of these, 93/114 patients diagnosed with disease before applying for legal consultation were included in the study. All medical records were evaluated for demographics, medical history, number of vaccine doses, peri-immunization adverse events and clinical manifestations of diseases. In addition, available blood tests, imaging results, treatments and outcomes were recorded. Signs and symptoms of the different immune-mediated diseases were grouped according to the organ or system involved. ASIA criteria were applied to all patients. RESULTS: The mean age of 93 patients was 26.5 +/- 15 years; 69.2% were female and 21% were considered autoimmune susceptible. The mean latency period from the last dose of HBVv and onset of symptoms was 43.2 days. Of note, 47% of patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neuro-psychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal (50%) complaints. Elevated titers of autoantibodies were documented in 80% of sera tested. In this cohort 80/93 patients (86%), comprising 57/59 (96%) adults and 23/34 (68%) children, fulfilled the required criteria for ASIA. CONCLUSIONS: Common clinical characteristics were observed among 93 patients diagnosed with immune-mediated conditions post-HBVv, suggesting a common denominator in these diseases. In addition, risk factors such as history of autoimmune diseases and the appearance of adverse event(s) during immunization may serve to predict the risk of post-immunization diseases. The ASIA criteria were found to be very useful among adults with post-vaccination events. The application of the ASIA criteria to pediatric populations requires further study. PMID- 22235046 TI - Giant cell arteritis and polymyalgia rheumatica after influenza vaccination: report of 10 cases and review of the literature. AB - Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases common in people over the age of 50 years. Herein, we report 10 cases of previously healthy subjects who developed GCA/PMR within 3 months of influenza vaccination (Inf-V). A Medline search uncovered additional 11 isolated cases of GCA/PMR occurring after Inf-V. We discuss the role of individual susceptibility, the potential function of immune adjuvants as triggers of autoimmunity post-vaccination, and the correlation of our observation with the 'ASIA' syndrome, i.e. autoimmune/inflammatory syndrome induced by adjuvants and including post-vaccination phenomena. PMID- 22235047 TI - Systemic lupus erythematosus following HPV immunization or infection? AB - BACKGROUND AND PURPOSE: The link between autoimmunity and infectious agents has been strongly suggested by reports of lupus or lupus-like syndromes following immunization. This report describes three patients with either newly diagnosed systemic lupus erythematosus (SLE) or SLE flare, following vaccination for human papilloma virus (HPV). CASE 1: A 17-year-old female completed two doses of HPV vaccine uneventfully. Two months later, she developed arthralgias with pruritic rashes on both lower extremities, later accompanied by livedo reticularis, bipedal edema with proteinuria, anemia, leucopenia, hypocomplementemia and high titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA). Kidney biopsy showed International Society of Nephrology/Renal Pathology Society Class III lupus nephritis. She was started on high dose steroids followed by pulse cyclophosphamide therapy protocol for lupus nephritis, and subsequently went into remission. CASE 2: A 45-year-old housewife, previously managed for 11 years as having rheumatoid arthritis, had been in clinical remission for a year when she received two doses of HPV immunization. Four months later, she developed fever accompanied by arthritis, malar rash, oral ulcers, recurrent ascites with intestinal pseudo-obstruction, and behavioral changes. Cranial MRI showed vasculitic lesions on the frontal and parietal lobes. Laboratory tests showed anemia with leucopenia, hypocomplementemia, proteinuria, ANA positive at 1:320, and antibodies against dsDNA, Ro/SSA, La/SSB and histone. She improved following pulse methylprednisolone with subsequent oral prednisone combined with hydroxychloroquine. CASE 3: A 58-year-old housewife diagnosed with SLE had been in clinical remission for 8 years when she received two doses of HPV immunization. Three months later, she was admitted to emergency because of a 1 week history of fever, malar rash, easy fatigability, cervical lymph nodes, gross hematuria and pallor. Laboratory exams showed severe anemia, thrombocytopenia, active urine sediments, and hypocomplementemia. Despite pulse steroid therapy, blood transfusions, intravenous immunoglobulin and aggressive resuscitative measures, she expired a day after hospital admission. SUMMARY: These cases narrate instances of the onset or exacerbation of lupus following HPV immunization suggesting adjuvant-induced autoimmunity. On the other hand, there are reports of higher incidence of HPV infection in SLE, with the infection per se possibly contributing to disease activity. Thus, the benefit of HPV immunization may still outweigh the risk among these individuals. PMID- 22235048 TI - Immunization of patients with autoimmune inflammatory rheumatic diseases (the EULAR recommendations). AB - The European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) have been recently published. These evidence-based recommendations were based on existing literature in combination with expert opinion. Although patients with AIIRD are at increased risk of suffering from (complicated) infectious diseases--and vaccination seems a tool to reduce this risk--still many questions and controversies remain for the individual patient. In this overview, taking influenza as an example, the background of the recommendations, their clinical implications, and the direction of future research are discussed. The increase in knowledge on vaccine-preventable infections will allow us to further improve vaccination strategies. PMID- 22235050 TI - Autoimmune response following influenza vaccination in patients with autoimmune inflammatory rheumatic disease. AB - Vaccines have undoubtedly brought overwhelming benefits to mankind and are considered safe and effective. Nevertheless, they can occasionally stimulate autoantibody production or even a recently defined syndrome known as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). There is scarce data regarding autoimmune response after seasonal/influenza A (H1N1) vaccine in patients with autoimmune inflammatory rheumatic disease (AIRD). The objective of our study was therefore to determine autoimmune response in a large group of AIRD patients vaccinated against seasonal and/or H1N1 influenza. We conducted a prospective cohort study with a 6-month follow-up. Two-hundred and eighteen patients with AIRD (50 vaccinated against seasonal influenza, six against H1N1, 104 against both, 58 non-vaccinated controls) and 41 apparently healthy controls (nine vaccinated against seasonal influenza, three against H1N1, 18 against both, 11 non-vaccinated controls) were included. Blood samples were taken and screened for autoantibodies [antinuclear antibody (ANA), anti-extractable nuclear antigen (anti-ENA), anticardiolipin (aCL) IgG/IgM antibodies, anti-beta 2-glycoprotein I (anti-beta2GPI)] at inclusion in the study, before each vaccination, 1 month after the last vaccination and 6 months after inclusion. For non-vaccinated participants (patients and healthy controls) blood samples were taken at the time of inclusion in the study and 6 months later. We report that after the administration of seasonal/H1N1 vaccine there were mostly transient changes in autoantibody production in AIRD patients and in healthy participants. However, a small subset of patients, especially ANA-positive patients, had a tendency towards anti-ENA development. Although no convincing differences between the seasonal and H1N1 vaccines were observed, our results imply that there might be a slight tendency of the H1N1 vaccine towards aCL induction. Although seasonal and H1N1 vaccines are safe and effective, they also have the potential to induce autoantibodies in selected AIRD patients and healthy adults. Follow-up of such individuals is proposed and further research is needed. PMID- 22235049 TI - Influenza vaccination can induce new-onset anticardiolipins but not beta2 glycoprotein-I antibodies among patients with systemic lupus erythematosus. AB - BACKGROUND: Antiphospholipid syndrome is characterized by autoantibodies against cardiolipins (aCL), lupus anticoagulant, and independent beta2-glycoprotein (beta2GPI). Controversy exists as to whether vaccination triggers the development of antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE (101) and matched controls (101) were enrolled from 2005-2009 and received seasonal influenza vaccinations. Sera were tested by ELISA for aCL at baseline, 2, 6, and 12 weeks after vaccination. Vaccine responses were ranked according to an overall anti-influenza antibody response index. Individuals with positive aCL were further tested for beta2GPI antibodies. RESULTS: Patients with SLE and healthy controls can develop new-onset aCL post vaccination, although at rates which do not differ between patients and controls (12/101 cases and 7/101 controls, OR 1.81, p = 0.34). New-onset moderate aCL are slightly enriched in African American SLE patients (5/36 cases; p = 0.094). The optical density measurements for aCL reactivity in patients were significantly higher than baseline at 2 weeks (p < 0.05), 6 weeks (p < 0.05), and 12 weeks (p < 0.05) post vaccination. No new beta2GPI antibodies were detected among patients with new aCL reactivity. Vaccine response was not different between patients with and without new-onset aCL reactivity (p = 0.43). CONCLUSIONS: This study shows transient increases in aCL, but not anti-beta2GPI responses, after influenza vaccination. PMID- 22235051 TI - Macrophagic myofasciitis: characterization and pathophysiology. AB - Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated 'autoimmune/inflammatory syndrome induced by adjuvants' (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain. PMID- 22235052 TI - Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). AB - Gulf War syndrome (GWS) is a multi-symptom condition comprising a variety of signs and symptoms described in the literature, which not been fully resolved. The various symptoms of the condition include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. In addition, excessive chemical sensitivity and odour intolerance is reported. The aetiology of the condition is unclear, but many reviews and epidemiological analyses suggest association with pyridostigmine bromide (PB), certain vaccination regimes, a variety of possible chemical exposures, including smoke from oil-well fires or depleted uranium from shells, as well as physical and psychological stress. Recently, Shoenfeld et al. suggested that four conditions--siliconosis, macrophagic myofaciitis (MMF), GWS and post-vaccination phenomena--that share clinical and pathogenic resemblances, may be incorporated into common syndrome called 'Autoimmune (Autoinflammatory) Syndrome induced by Adjuvants' (ASIA). Symptoms and signs of the four conditions described by Shoenfeld et al. show that at least eight out of ten main symptoms are in correlation in all four conditions. Namely, myalgia, arthralgias, chronic fatigue, neurological cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin manifestations and appearance of autoantibodies. Regardless of the aetiology of GWS, be it exposure to environmental factors or chemical drugs, vaccinations or the adjuvants in them, GWS fits well with the definition of ASIA and is included as part of 'Shoenfeld's syndrome'. PMID- 22235053 TI - Vaccine model of antiphospholipid syndrome induced by tetanus vaccine. AB - Successful induction of antiphospholipid syndrome (APS) in two different non autoimmune prone mouse strains, BALB/c and C57BL/6, was achieved by tetanus toxoid (TTd) hyperimmunization using different adjuvants (glycerol or aluminium hydroxide), and different adjuvant pretreatments (glycerol or Complete Freund's Adjuvant (CFA)). APS had different manifestations of reproductive pathology in BALB/c and C57BL/6 mice: fetal resorption (as a consequence of extreme T-cell activation obtained in the course of pretreatment), and lowering of fecundity (as a consequence of polyclonal B-cell stimulation), respectively. In BALB/c mice fetal resorption coincided with glycerol and CFA pretreatments, while in C57BL/6 mice lowering of fecundity was most obvious in CFA-pretreated mice immunized with TTd in aluminium hydroxide. Both molecular mimicry and polyclonal B-cell activation occur in APS induction, with molecular mimicry effects being dominant in BALB/c mice, and polyclonal cell activation being dominant in C57BL/6 mice. Confirmation of molecular mimicry effects, which in the condition of T-cell stimulation generated fetal resorptions in the BALB/c strain, was achieved by passive infusion of monoclonal antibody (MoAb) T-26 specific for TTd and anti beta(2)-glycoprotein I obtained after TTd hyperimunization. High polyclonal B cell activation in C57BL/6 mice prevented fetal resorption but induced fecundity lowering, as was the case in passive administration of MoAb T-26 in this mouse strain. Passive infusion of anti-idiotypic MoAb Y7 into C57BL/6 mice induced fetal resorptions and confirmed the above suggestion on the protective role of polyclonal B-cell stimulation in fetal resorptions. PMID- 22235054 TI - Induction of the 'ASIA' syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA). AB - Adjuvants, commonly used in vaccines, may be responsible for inducing autoimmunity and autoimmune diseases, both in humans and mice. The so-called 'ASIA' (Autoimmune/inflammatory Syndrome Induced by Adjuvants) syndrome has been recently described, which is caused by the exposure to a component reproducing the effect of adjuvants. The aim of our study was to evaluate the effect of injection of complete Freund's adjuvant (CFA) in NZB/NZWF1 mice, a lupus-prone murine model. We injected 10 NZB/NZWF1 mice with CFA/PBS and 10 with PBS, three times, 3 weeks apart, and followed-up until natural death. CFA-injected mice developed both anti-double-stranded DNA and proteinuria earlier and at higher levels than the control group. Proteinuria-free survival rate and survival rate were significantly lower in CFA-treated mice than in the control mice (p = 0.002 and p = 0.001, respectively). Histological analyses showed a more severe glomerulonephritis in CFA-injected mice compared with the control mice. In addition, lymphoid hyperplasia in spleen and lungs, myocarditis, and vasculitis were observed in the former, but not in the latter group. In conclusion, the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling 'ASIA' syndrome in humans. PMID- 22235055 TI - Adjuvant immunization induces high levels of pathogenic antiphospholipid antibodies in genetically prone mice: another facet of the ASIA syndrome. AB - Adjuvants may induce autoimmune diseases in susceptible individuals, a phenomenon recently defined as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Patients with both antiphospholipid antibodies (aPL) and the genetic coagulopathy factor V Leiden (FVL) are frequently found. We therefore evaluated whether adjuvant can induce aPL in heterozygous FVL mice. aPL were measured in naive mice and at 1 and 5 months after immunization with either complete or incomplete Freund's adjuvant (CFA, IFA) in FVL and control C57/B6 background mice. We defined antibody levels 3 SD above the mean of C57/B6 mice immunized with adjuvant as positive (specificity of 99%). For beta(2)GPI-dependent aPL, 28.6% (6/21) of FVL mice 5 months after immunization with adjuvant (both IFA and CFA) were positive compared with 4.8% (1/22) of FVL mice 1 month after adjuvant and 0% of naive FVL and C57/B6 mice (0/16, p < 0.001). aPL levels correlated with behavioral hyperactivity in the staircase test. FVL mice immunized with adjuvant did not develop beta(2)GPI-independent aPL. We hypothesize that the FVL aPL association is not a coincidence, but that chronic coagulation defects combined with external inflammatory stimuli analogous to adjuvant may induce aPL and also antiphospholipid syndrome, thus supporting the notion of ASIA. PMID- 22235056 TI - Oily adjuvants and autoimmunity: now time for reconsideration? AB - Immunologists have relied heavily on oil-based adjuvants to generate antibodies or induce auto-allergic responses in experimental animals. These are rarely used today for human vaccination because of their persistent irritancies and propensity to cause ulcers at sites of injection. However oily materials with adjuvant properties abound in our modern environment, both personal and extraneous. Their inadvertent impact as cryptotoxins may contribute to the rising incidence of auto-allergic diseases in recent times. Experimentally, the potential adjuvanticity of various oils, fats and other lipids can be evaluated by their ability (or otherwise) to induce auto-allergic disease(s) in rats and mice with, or even without, the addition of a mycobacterial immunostimulant. Genetic factors have been recognized that determine an animal's susceptibility or resistance to these oil-induced immunopathies. So it may be profitable to further characterize these factors, first in animals and then perhaps in human populations, to help find ways to enhance natural resistance to those adjuvant active oils that may be widely distributed in the personal environment, notably mineral oil(s). (The six tables in this article summarize some relevant facts and a few conjectures.) A caveat: This review is restricted to the adjuvant properties of some oils in the personal environment. It does not cover the mechanisms of adjuvanticity. PMID- 22235057 TI - Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations. AB - Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as "small adults" with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., "ASIA"), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in "ASIA" and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuro-immune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed. PMID- 22235058 TI - Aluminum as an adjuvant in Crohn's disease induction. AB - Alum (AlK(SO(4))(2)) is an adjuvant commonly utilized in vaccines, and is a ubiquitous element used extensively in contemporary life. Food, air, water, waste, the earth's surface, and pharmaceuticals all represent pathways of aluminum (Al) exposure. Crohn's disease (CD) is a chronic relapsing intestinal inflammation in genetically susceptible individuals and is caused by yet unidentified environmental factors. Al is a potential factor for the induction of inflammation in CD, and its immune activities share many characteristics with the immune pathology of CD: many luminal bacterial or dietary compounds can be adsorbed to the metal surface and induce Th1 profile cytokines, shared cytokines/chemokines, co-stimulatory molecules, and intracellular pathways and stress-related molecular expression enhancement, affecting intestinal macrobiota, trans-mural granuloma formation, and colitis induction in an animal CD model. The inflammasome plays a central role in Al mode of action and in CD pathophysiology. It is suggested that Al adjuvant activity can fit between the aberrations of innate and adaptive immune responses occurring in CD. The CD mucosa is confronted with numerous inappropriate bacterial components adsorbed on the Al compound surface, constituting a pro-inflammatory supra-adjuvant. Al fits the diagnostic criteria of the newly described autoimmune/inflammatory syndrome induced by adjuvants. If a cause and effect relationship can be established, the consequences will greatly impact public health and CD prevention and management. PMID- 22235059 TI - Clinical relevance of action observation in upper-limb stroke rehabilitation: a possible role in recovery of functional dexterity. A randomized clinical trial. AB - OBJECTIVE: A randomized controlled observer-blind trial was designed to evaluate the effectiveness of action observation as an add-on treatment to the standard rehabilitation of upper-limb function, early after stroke. METHODS: Stroke survivors (N = 102) were consecutively recruited from 13 centers 30 days (+/-7) after a first-ever stroke and randomly assigned to the experimental (EG) or control group (CG). EG participants watched video footage of daily routine tasks (actions) carried out with the upper limb in order to prepare to imitate the presented action. At the end of each sequence, a therapist prompted the patient to perform the same movement for 2 minutes, providing help when needed. Static images without animals or human beings were shown to the CG. At the end of each sequence, the CG executed movements that simulated the shoulder and elbow joint mobilization activities performed by the EG. RESULTS: for the Fugl-Meyer test, Frenchay Arm test, Box and Block test (BBT), Modified Ashworth Scale, and Functional Independence Measure Motor items were recorded before treatment (T0), after 4 weeks of treatment (T1), and at the follow-up visit 4 to 5 months after the conclusion of treatment (T2). Results. An improvement over time was appreciated on all measures of impairment and functional ability with both treatment programs. A Time * Treatment interaction emerged from the generalized estimating equations analysis of BBT, showing significant T0-T1 and T0-T2 differences in favor of EG. CONCLUSION: This multicenter trial endorses the use of action observation in upper-extremity rehabilitation, along with a role for the mirror neuron system in poststroke recovery. PMID- 22235061 TI - Suspected serotonin syndrome in a patient being treated with methylene blue for ifosfamide encephalopathy. AB - Methylene blue has been used not only as a diagnostic agent, but also as an agent in the treatment of ifosfamide-induced encephalopathy (IIE) for several years. Recently, several cases of suspected serotonin syndrome have been reported in patients who received methylene blue in combination with serotonin active agents. Rodent models have revealed that methylene blue is a potent, reversible inhibitor of monoamine oxidase A. It is well known that serotonin active drugs, in combination with monoamine oxidase inhibitors can produce profound serotonin syndrome. To date, cases of serotonin syndrome, which resulted from concurrent methylene blue and serotonin active agents, have been published in the anesthesia literature. We report the first known case of serotonin syndrome in a patient receiving methylene blue for IIE. PMID- 22235060 TI - Epilepsy as a disorder of cortical network organization. AB - The brain is naturally considered as a network of interacting elements which, when functioning properly, produces an enormous range of dynamic, adaptable behavior. However, when elements of this network fail, pathological changes ensue, including epilepsy, one of the most common brain disorders. This review examines some aspects of cortical network organization that distinguish epileptic cortex from normal brain as well as the dynamics of network activity before and during seizures, focusing primarily on focal seizures. The review is organized around four phases of the seizure: the interictal period, onset, propagation, and termination. For each phase, the authors discuss the most common rhythmic characteristics of macroscopic brain voltage activity and outline the observed functional network features. Although the characteristics of functional networks that support the epileptic seizure remain an area of active research, the prevailing trends point to a complex set of network dynamics between, before, and during seizures. PMID- 22235062 TI - Bilateral Wilms' tumor: Mansoura multi-centers 15 years experience. AB - PURPOSE: Bilateral Wilms' tumor (WT) is a challenge. Aggressive surgical resection is needed to prevent recurrence. We revised the clinico-epidemiological criteria of bilateral WT patients in our locality and relation to outcome. SUBJECTS AND METHODS: 462 WT patients were registered in three medical centers at Mansoura, Egypt. Twenty five patients had bilateral WT whose medical records were revised for all clinico-epidemiologic data plus treatment details, toxicity, and outcome. RESULTS: The mean age was 34.5 months; 64% of cases were female. Abdominal mass was the commonest presentation (72%). Congenital anomalies were reported in two cases (one case showed hemihypertrophy and the other showed aniridia). About 60% had favorable pathology. Nineteen cases had synchronous bilateral WT (76%) and the remaining (six cases) had metachronous tumors. For the synchronous cases, the response rate to preoperative chemotherapy was 79% and nephron sparing surgery for the least involved kidney was possible in all. Survival rate was 74%. Metachronous tumor management included nephrectomy followed by chemotherapy for the initially diagnosed tumors. However, nephron sparing surgery of the contralateral tumors following preoperative chemotherapy was possible in two cases and the survival rate was 33%. No renal failure or any therapy-related complications were reported. CONCLUSIONS: Bilateral WT is predominantly synchronous with favorable histology, with female predilection and possibly congenital anomalies. Preoperative chemotherapy followed by nephron sparing surgery has a favorable outcome with preserved renal function especially in patients with synchronous WT. Response to preoperative chemotherapy had a statistically significant prognostic impact. PMID- 22235064 TI - Medicare services provided by cardiologists in the United States: 1999-2008. AB - BACKGROUND: Services provided by cardiologists represent a major portion of Medicare expenditures for specialist physicians. The absolute growth and distribution of these services over the past decade have not been well described. METHODS AND RESULTS: We analyzed fee-for-service Medicare Part B claims for each year from 1999-2008 and selected claims from physicians whose specialty code was cardiology. We then grouped approximately 1000 CPT-9 codes into 45 specific service groups that were then further aggregated into 3 broad service categories: evaluation and management, noninvasive procedures, and invasive procedures. Our main outcome measures were services and allowed charges per 1000 beneficiaries. Sample size ranged from 30.9 million beneficiaries in 1999 to 31.7 million in 2008. During this 10-year period, the number of claims from cardiologists increased 44% (from 2082-2997 per 1000 beneficiaries) while the allowed charges increased 28% after adjusting for inflation (in 2008 dollars, from $181,397 231,728 per 1000 beneficiaries). Evaluation and management services and invasive procedures contributed relatively little to this growth. Instead, most of the growth involved noninvasive procedures--with a 70% increase in claims. Although the most dramatic increases in noninvasive procedures involved emerging imaging technologies (cardiac CT, MRI, and PET scanning), the bulk of the growth occurred in two established technologies: resting echocardiograms and stress tests with nuclear imaging. CONCLUSIONS: Most of the growth in services provided by cardiologists over the past decade is the result of increased noninvasive imaging. PMID- 22235063 TI - A comparison of long-term mortality for off-pump and on-pump coronary artery bypass graft surgery. AB - BACKGROUND: The survival difference between off-pump and on-pump coronary artery bypass graft surgery for follow-up longer than 5 years is not well-understood. The objective of this study is to examine the difference in 7-year mortality after these 2 procedures. METHODS AND RESULTS: The state of New York's Cardiac Surgery Reporting System was used to identify the 2640 off-pump and 5940 on-pump patients discharged from July through December 2000. The National Death Index was used to ascertain patients' vital statuses through 2007. A logistic regression model was fit to predict the probability of receiving an off-pump procedure using baseline patient characteristics. Off-pump and on-pump patients were matched with a 1:1 ratio based on the probability of receiving an off-pump procedure. Kaplan Meier survival curves for the 2 procedures were compared using the propensity matched data, and the hazard ratio for death for off-pump in comparison with on pump procedures was obtained. In subgroup analyses, the significance of interactions between type of surgery and baseline risk factors was tested. In this study, 2631 pairs of off-pump and on-pump patients were propensity matched. The 7-year Kaplan-Meier survival rates were 71.2% and 73.4% (P=0.07) for off-pump and on-pump surgery, respectively. The hazard ratio for death (off-pump versus on pump) was 1.10 (95% confidence interval: 0.99 to 1.21, P=0.07). No statistical significance was detected for the interaction terms between the type of surgery and a number of different baseline risk factors. CONCLUSIONS: The difference in long-term mortality between on-pump and off-pump coronary artery bypass graft surgery is not statistically significant. PMID- 22235065 TI - Bivalirudin therapy is associated with improved clinical and economic outcomes in ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention: results from an observational database. AB - BACKGROUND: Randomized trials show improved outcomes among acute coronary syndrome patients treated with bivalirudin. The objective of this analysis was to compare clinical and economic outcomes in ST-elevation myocardial infarction (STEMI) patients encountered in routine clinical practice undergoing primary percutaneous coronary intervention (PPCI), treated with bivalirudin or heparin+GP IIb/IIIa receptor inhibitor (heparin+GPI). METHODS AND RESULTS: STEMI admissions from January 1, 2004 through March 31, 2008 among patients receiving PPCI and bivalirudin or heparin+GPI in the Premier hospital database were identified. The probability of receiving bivalirudin was estimated using individual and hospital variables; using propensity scores, each bivalirudin patient was matched to 3 heparin+GPI treated patients. The primary outcome was in-hospital death. Rates of bleeding, transfusion, length of stay, and in-hospital cost were secondary outcomes. There were 59,917 STEMI PPCIs receiving bivalirudin (n=6735) or heparin+GPI (n=53,182). Seventy-nine percent of bivalirudin patients matched, resulting in 21,316 STEMI PPCIs for analysis. Compared with heparin+GPI patients, bivalirudin patients had fewer deaths (3.2% versus 4.0%; P=0.011) and less inpatient bleeding (clinically apparent bleeding [6.9% versus 10.5%, P<0.0001], clinically apparent bleeding with transfusion [1.6% versus 3.0%, P<0.0001], and transfusion [5.9% versus 7.6%, P<0.0001]). Patients receiving bivalirudin had shorter average length of stay (mean 4.3 versus 4.5 days; P<0.0001), with lower in-hospital cost (mean $18,640 versus $19,967 [median $14,462 versus $16,003], P<0.0001). CONCLUSIONS: This large "real-world" retrospective analysis demonstrates that bivalirudin therapy compared with heparin+GPI is associated with a lower rate of inpatient death, inpatient bleeding, and decreased overall in-hospital cost in STEMI patients undergoing PPCI. PMID- 22235066 TI - Public reporting on risk-adjusted mortality after percutaneous coronary interventions in New York State: forecasting ability and impact on market share and physicians' decisions to discontinue practice. AB - BACKGROUND: Since the advent of public reporting on risk-adjusted mortality for coronary artery bypass graft surgery, public reporting on outcomes has expanded to include a variety of dissimilar conditions and procedures. We have little evidence to support such broad-based efforts. METHODS AND RESULTS: We examined the quality performance of 351 cardiologists at 48 hospitals in New York State, using publicly reported risk-adjusted mortality rates (RAMRs) for nonemergent percutaneous coronary interventions between 1998 and 2007. In the year after report release, we examined the following: (1) average RAMR for hospitals, (2) change in market share for hospitals and cardiologists, and (3) proportion of physicians leaving practice. We found that patients who picked a hospital that performed significantly better than expected in prior years had lower RAMRs (0.47, 0.61, and 0.72 for patients choosing hospitals whose prior reports were better than, as, and worse than expected; P=0.02). However, choosing a hospital in the top quartile (or decile) of performance in prior years did not decrease a patient's chance of dying (P=0.29, or P=0.27). Performance ranking was not associated with a change in market share for hospitals or for physicians, or with leaving practice (all P>0.05). CONCLUSIONS: Public reporting on nonemergent percutaneous coronary interventions in New York State identifies very high and low performers but provides insufficient information to differentiate between most hospitals. It appears to have had no effect on market share or physicians' decisions to leave practice. The utility of public reporting on RAMRs may differ for different conditions and procedures. PMID- 22235067 TI - Get With The Guidelines program participation, process of care, and outcome for Medicare patients hospitalized with heart failure. AB - BACKGROUND: Hospitals enrolled in the American Heart Association's Get With The Guidelines Program for heart failure (GWTG-HF) have improved their process of care. However, it is unclear if process of care and outcomes are better in the GWTG-HF hospitals compared with hospitals not enrolled. METHODS AND RESULTS: We compared hospitals enrolled in GWTG-HF from 2006 to 2007 with other hospitals using data on 4 process of heart failure care measures, 5 noncardiac process measures, risk-adjusted 30-day mortality, and 30-day all-cause readmission after a heart failure hospitalization, as reported by the Center for Medicare and Medicaid Services (CMS). Among the 4460 hospitals reporting data to CMS, 215 (5%) were enrolled in GWTG-HF. Of the 4 CMS heart failure performance measures, GWTG HF hospitals had significantly higher documentation of the left ventricular ejection fraction (93.4% versus 88.8%), use of angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist (88.3% versus 86.6%), and discharge instructions (74.9% versus 70.5%) (P<0.005 for all). Smoking cessation counseling rates were similar (94.1% versus 94.0%; P=0.51). There was no significant difference in compliance with noncardiac process of care. After heart failure discharge, all-cause readmission at 30 days was 24.5% and mortality at 30 days after admission was 11.1%. After adjustment for hospital characteristics, 30-day mortality rates were no different (P=0.45). However, 30-day readmission was lower for GWTG hospitals (-0.33%; 95% CI, -0.53% to -0.12%; P=0.002). CONCLUSIONS: Although there was evidence that hospitals enrolled in the GTWG-HF program demonstrated better processes of care than other hospitals, there were few clinically important differences in outcomes. Further identification of opportunities to improve outcomes, and inclusion of these metrics in GTWG-HF, may further support the value of GTWG-HF in improving care for patients with HF. PMID- 22235068 TI - Care and outcomes of Asian-American acute myocardial infarction patients: findings from the American Heart Association Get With The Guidelines-Coronary Artery Disease program. AB - BACKGROUND: Asian-Americans represent an important United States minority population, yet there are limited data regarding the clinical care and outcomes of Asian-Americans following acute myocardial infarction (AMI). Using data from the American Heart Association Get With The Guidelines-Coronary Artery Disease (GWTG-CAD) program, we compared use of and trends in evidence-based care AMI processes and outcome in Asian-American versus white patients. METHODS AND RESULTS: We analyzed 107,403 AMI patients (4412 Asian-Americans, 4.1%) from 382 United States centers participating in the Get With The Guidelines-Coronary Artery Disease program between 2003 and 2008. Use of 6 AMI performance measures, composite "defect-free" care (proportion receiving all eligible performance measures), door-to-balloon time, and in-hospital mortality were examined. Trends in care over this time period were explored. Compared with whites, Asian-American AMI patients were significantly older, more likely to be covered by Medicaid and recruited in the west region, and had a higher prevalence of diabetes, hypertension, heart failure, and smoking. In-hospital unadjusted mortality was higher among Asian-American patients. Overall, Asian-Americans were comparable with whites regarding the baseline quality of care, except that Asian-Americans were less likely to get smoking cessation counseling (65.6% versus 81.5%). Asian American AMI patients experienced improvement in the 6 individual measures (P<=0.048), defect-free care (P<0.001), and door-to-balloon time (P<0.001). The improvement rates were similar for both Asian-Americans and whites. Compared with whites, the adjusted in-hospital mortality rate was higher for Asian-Americans (adjusted relative risk: 1.16; 95% confidence interval: 1.00-1.35; P=0.04). CONCLUSIONS: Evidence-based care for AMI processes improved significantly over the period of 2003 to 2008 for Asian-American and white patients in the Get With The Guidelines-Coronary Artery Disease program. Differences in care between Asian Americans and whites, when present, were reduced over time. PMID- 22235069 TI - Long-term survival and unnatural deaths of patients with repaired tetralogy of Fallot in an Asian cohort. AB - BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in Taiwan. This study investigates the long-term survival and risks of TOF in an Asian cohort. METHODS AND RESULTS: This study enrolled 819 consecutive patients with TOF (61.1% male), who received total correction between 1970 and 2002, as participants. Patient medical records were reviewed, and the survival status of those out of contact was confirmed by death records retrieved from the National Health database. The mean (+/-SD) patient age at cardiac repair was 6.5+/-7.6 years, and a prior shunt operation was performed in 119 (14.5%) of the patients. At cardiac repair, a transannular patch for right ventricle outlet reconstruction was required in 444 (54.2%) of the patients. After 13,808 patient years of follow-up, the 30-year survival rate was 90.5%. The annual mortality rate increased from 0.123% in the initial 15 years after repair to 0.395% thereafter (P<0.05). The presence of major aortopulmonary collateral arteries, older operative age, and previous shunt operation are independent risks of late cardiac deaths. Secondary to cardiac mortality, unnatural deaths (accident and suicide) accounted for 27.6% of late deaths, significantly higher compared with that of the general population (odds ratio, 2.18; P=0.028). CONCLUSIONS: In this Asian TOF cohort, except for a late decrease after 15 years, long-term survival after cardiac repair was satisfactory. Although cardiac death was the most common cause of late death, accidents or suicide may also be associated with late mortality, suggesting a potential role for psychosocial support. PMID- 22235072 TI - The cover. Thomas Cromwell. PMID- 22235070 TI - Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. AB - BACKGROUND: Atrial fibrillation (AF) is a common and costly problem among older persons. The frequency of AF increases with age, but representative national data about incidence and prevalence are limited. We examined the annual incidence, prevalence, and mortality associated with AF among older persons. METHODS AND RESULTS: In a retrospective cohort study of Medicare beneficiaries 65 years and older diagnosed with AF between 1993 and 2007, we measured annual age- and sex adjusted incidence and prevalence of AF and mortality following an AF diagnosis. Among 433,123 patients with incident AF, the mean age was 80 years, 55% were women, and 92% were white. The incidence of AF remained steady during the 14-year study period, ranging from 27.3 to 28.3 per 1000 person-years. Incidence rates were consistently higher among men and white beneficiaries. The prevalence of AF increased across the study period (mean, 5% per year) and was robust to sensitivity analyses. Among beneficiaries with incident AF in 2007, 36% had heart failure, 84% had hypertension, 30% had cerebrovascular disease, and 8% had dementia. Mortality after AF diagnosis declined slightly over time but remained high. In 2007, the age- and sex-adjusted mortality rates were 11% at 30 days and 25% at 1 year. CONCLUSIONS: Among older Medicare beneficiaries, incident AF is common and has remained relatively stable for more than a decade. Incident AF is associated with significant comorbidity and mortality; death occurs in one quarter of beneficiaries within 1 year. PMID- 22235071 TI - Outcomes of elective total laryngectomy for laryngopharyngeal dysfunction in disease-free head and neck cancer survivors. AB - OBJECTIVE: Total laryngectomy (TL) can be offered for management of chronic aspiration, radionecrosis, and/or airway compromise after head and neck cancer (HNC) treatment. The objective of this study was to evaluate functional outcomes after TL in disease-free HNC survivors. DESIGN: Retrospective case series with chart review. SETTING: The University of Texas MD Anderson Cancer Center. PATIENTS: Twenty-three disease-free HNC survivors who underwent TL for laryngopharyngeal dysfunction. INTERVENTION: TL +/- pharyngectomy. MAIN OUTCOME MEASURES: Post-TL swallowing-related (diet, gastrostomy dependence, and pneumonia rates) and communication outcomes. RESULTS: All patients who underwent TL for dysfunction were previously treated with radiotherapy (12/23, 52%) or chemoradiotherapy (11/23, 48%). Preoperative complications included aspiration (22/23, 96%), pneumonia (16/23, 70%), tracheostomy (9/23, 39%), and stricture (7/23, 30%); 17 patients (74%) required enteral/parenteral nutrition, and 13 of 23 (57%) were nothing per oral (NPO). Rates of pneumonia, NPO status, and feeding tube dependence significantly decreased after TL (P < .001). At last follow-up after TL, all patients tolerated oral intake, but 4 (17%) required supplemental enteral nutrition. Continued smoking after radiotherapy and a preoperative history of recurrent pneumonia were significantly (P < .05) associated with final tube dependence and/or diet level. Sixteen patients (70%) underwent tracheoesophageal (TE) puncture, and 57% (13 of 23) communicated using TE voice after TL. CONCLUSION: Salvage TL may improve health status by significantly decreasing the rate of pneumonia and improve quality of life by restoring oral intake in patients with refractory laryngopharyngeal dysfunction after HNC treatment. TE voice restoration may enhance functional outcomes in select patients treated with elective TL for dysfunction. PMID- 22235073 TI - New reports examine psychiatric risks of varenicline for smoking cessation. PMID- 22235074 TI - NIH shifts focus from sequencing genes to fostering clinical applications. PMID- 22235075 TI - Expert panel advocates surveillance for men with low-risk prostate cancer. PMID- 22235076 TI - Sex-specific prevalence of adenomas and colorectal cancer. PMID- 22235077 TI - Sex-specific prevalence of adenomas and colorectal cancer. PMID- 22235078 TI - Supplementation in acute lung injury. PMID- 22235079 TI - Supplementation in acute lung injury. PMID- 22235080 TI - Supplementation in acute lung injury. PMID- 22235081 TI - Thromboaspiration before intra-aortic balloon counterpulsation. PMID- 22235082 TI - Addressing requests by patients for nonbeneficial interventions. PMID- 22235083 TI - The courts, futility, and the ends of medicine. PMID- 22235084 TI - A prescription for drug shortages. PMID- 22235085 TI - A piece of my mind. On grace. PMID- 22235086 TI - Serum potassium levels and mortality in acute myocardial infarction. AB - CONTEXT: Clinical practice guidelines recommend maintaining serum potassium levels between 4.0 and 5.0 mEq/L in patients with acute myocardial infarction (AMI). These guidelines are based on small studies that associated low potassium levels with ventricular arrhythmias in the pre-beta-blocker and prereperfusion era. Current studies examining the relationship between potassium levels and mortality in AMI patients are lacking. OBJECTIVE: To determine the relationship between serum potassium levels and in-hospital mortality in AMI patients in the era of beta-blocker and reperfusion therapy. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study using the Cerner Health Facts database, which included 38,689 patients with biomarker-confirmed AMI, admitted to 67 US hospitals between January 1, 2000, and December 31, 2008. All patients had in-hospital serum potassium measurements and were categorized by mean postadmission serum potassium level (<3.0, 3.0-<3.5, 3.5-<4.0, 4.0-<4.5, 4.5-<5.0, 5.0-<5.5, and >=5.5 mEq/L). Hierarchical logistic regression was used to determine the association between potassium levels and outcomes after adjusting for patient- and hospital-level factors. MAIN OUTCOME MEASURES: All-cause in-hospital mortality and the composite of ventricular fibrillation or cardiac arrest. RESULTS: There was a U-shaped relationship between mean postadmission serum potassium level and in-hospital mortality that persisted after multivariable adjustment. Compared with the reference group of 3.5 to less than 4.0 mEq/L (mortality rate, 4.8%; 95% CI, 4.4% 5.2%), mortality was comparable for mean postadmission potassium of 4.0 to less than 4.5 mEq/L (5.0%; 95% CI, 4.7%-5.3%), multivariable-adjusted odds ratio (OR), 1.19 (95% CI, 1.04-1.36). Mortality was twice as great for potassium of 4.5 to less than 5.0 mEq/L (10.0%; 95% CI, 9.1%-10.9%; multivariable-adjusted OR, 1.99; 95% CI, 1.68-2.36), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. In contrast, rates of ventricular fibrillation or cardiac arrest were higher only among patients with potassium levels of less than 3.0 mEq/L and at levels of 5.0 mEq/L or greater. CONCLUSION: Among inpatients with AMI, the lowest mortality was observed in those with postadmission serum potassium levels between 3.5 and <4.5 mEq/L compared with those who had higher or lower potassium levels. PMID- 22235087 TI - Association of incident dementia with hospitalizations. AB - CONTEXT: Dementia is associated with increased rates and often poorer outcomes of hospitalization, including worsening cognitive status. New evidence is needed to determine whether some admissions of persons with dementia might be potentially preventable. OBJECTIVE: To determine whether dementia onset is associated with higher rates of or different reasons for hospitalization, particularly for ambulatory care-sensitive conditions (ACSCs), for which proactive outpatient care might prevent the need for a hospital stay. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of hospitalizations among 3019 participants in Adult Changes in Thought (ACT), a longitudinal cohort study of adults aged 65 years or older enrolled in an integrated health care system. All participants had no dementia at baseline and those who had a dementia diagnosis during biennial screening contributed nondementia hospitalizations until diagnosis. Automated data were used to identify all hospitalizations of all participants from time of enrollment in ACT until death, disenrollment from the health plan, or end of follow-up, whichever came first. The study period spanned February 1, 1994, to December 31, 2007. MAIN OUTCOME MEASURES: Hospital admission rates for patients with and without dementia, for all causes, by type of admission, and for ACSCs. RESULTS: Four hundred ninety-four individuals eventually developed dementia and 427 (86%) of these persons were admitted at least once; 2525 remained free of dementia and 1478 (59%) of those were admitted at least once. The unadjusted all cause admission rate in the dementia group was 419 admissions per 1000 person years vs 200 admissions per 1000 person-years in the dementia-free group. After adjustment for age, sex, and other potential confounders, the ratio of admission rates for all-cause admissions was 1.41 (95% confidence interval [CI], 1.23-1.61; P < .001), while for ACSCs, the adjusted ratio of admission rates was 1.78 (95% CI, 1.38-2.31; P < .001). Adjusted admission rates classified by body system were significantly higher in the dementia group for most categories. Adjusted admission rates for all types of ACSCs, including bacterial pneumonia, congestive heart failure, dehydration, duodenal ulcer, and urinary tract infection, were significantly higher among those with dementia. CONCLUSION: Among our cohort aged 65 years or older, incident dementia was significantly associated with increased risk of hospitalization, including hospitalization for ACSCs. PMID- 22235088 TI - Association between marijuana exposure and pulmonary function over 20 years. AB - CONTEXT: Marijuana smoke contains many of the same constituents as tobacco smoke, but whether it has similar adverse effects on pulmonary function is unclear. OBJECTIVE: To analyze associations between marijuana (both current and lifetime exposure) and pulmonary function. DESIGN, SETTING, AND PARTICIPANTS: The Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal study collecting repeated measurements of pulmonary function and smoking over 20 years (March 26, 1985-August 19, 2006) in a cohort of 5115 men and women in 4 US cities. Mixed linear modeling was used to account for individual age-based trajectories of pulmonary function and other covariates including tobacco use, which was analyzed in parallel as a positive control. Lifetime exposure to marijuana joints was expressed in joint-years, with 1 joint-year of exposure equivalent to smoking 365 joints or filled pipe bowls. MAIN OUTCOME MEASURES: Forced expiratory volume in the first second of expiration (FEV(1)) and forced vital capacity (FVC). RESULTS: Marijuana exposure was nearly as common as tobacco exposure but was mostly light (median, 2-3 episodes per month). Tobacco exposure, both current and lifetime, was linearly associated with lower FEV(1) and FVC. In contrast, the association between marijuana exposure and pulmonary function was nonlinear (P < .001): at low levels of exposure, FEV(1) increased by 13 mL/joint year (95% CI, 6.4 to 20; P < .001) and FVC by 20 mL/joint-year (95% CI, 12 to 27; P < .001), but at higher levels of exposure, these associations leveled or even reversed. The slope for FEV(1) was -2.2 mL/joint-year (95% CI, -4.6 to 0.3; P = .08) at more than 10 joint-years and -3.2 mL per marijuana smoking episode/mo (95% CI, -5.8 to -0.6; P = .02) at more than 20 episodes/mo. With very heavy marijuana use, the net association with FEV(1) was not significantly different from baseline, and the net association with FVC remained significantly greater than baseline (eg, at 20 joint-years, 76 mL [95% CI, 34 to 117]; P < .001). CONCLUSION: Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function. PMID- 22235090 TI - Purple urine. PMID- 22235089 TI - Prognostic indices for older adults: a systematic review. AB - CONTEXT: To better target services to those who may benefit, many guidelines recommend incorporating life expectancy into clinical decisions. OBJECTIVE: To assess the quality and limitations of prognostic indices for mortality in older adults through systematic review. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane, and Google Scholar from their inception through November 2011. STUDY SELECTION: We included indices if they were validated and predicted absolute risk of mortality in patients whose average age was 60 years or older. We excluded indices that estimated intensive care unit, disease-specific, or in-hospital mortality. DATA EXTRACTION: For each prognostic index, we extracted data on clinical setting, potential for bias, generalizability, and accuracy. RESULTS: We reviewed 21,593 titles to identify 16 indices that predict risk of mortality from 6 months to 5 years for older adults in a variety of clinical settings: the community (6 indices), nursing home (2 indices), and hospital (8 indices). At least 1 measure of transportability (the index is accurate in more than 1 population) was tested for all but 3 indices. By our measures, no study was free from potential bias. Although 13 indices had C statistics of 0.70 or greater, none of the indices had C statistics of 0.90 or greater. Only 2 indices were independently validated by investigators who were not involved in the index's development. CONCLUSION: We identified several indices for predicting overall mortality in different patient groups; future studies need to independently test their accuracy in heterogeneous populations and their ability to improve clinical outcomes before their widespread use can be recommended. PMID- 22235091 TI - Potassium concentration and repletion in patients with acute myocardial infarction. PMID- 22235092 TI - Prevention of unnecessary hospitalization for patients with dementia: the role of ambulatory care. PMID- 22235093 TI - The central role of prognosis in clinical decision making. PMID- 22235094 TI - JAMA patient page. Respiratory syncytial virus bronchiolitis. PMID- 22235095 TI - Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography. AB - PURPOSE: (11)C-Choline-positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts. EXPERIMENTAL DESIGN: (11)C-Choline, (11)C-methyl-[1,2-(2)H(4)] choline ((11)C-D4-choline), and (18)F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft bearing mice. RESULTS: Oxidation of choline analogs to betaine was highest with (11)C-choline, with reduced oxidation observed with (11)C-D4-choline and substantially reduced with (18)F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (K(i) and k(3)) of (11)C-choline and (11)C-D4-choline, compared with (18)F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of (18)F-D4-choline in three tumors with similar radiotracer delivery (K(1)) and choline kinase alpha expression-HCT116, A375, and PC3-M-were the same, suggesting that (18)F-D4-choline has utility for cancer detection irrespective of histologic type. CONCLUSION: We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. (18)F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation. PMID- 22235096 TI - Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. AB - PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. RESULTS: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. CONCLUSIONS: The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2). PMID- 22235097 TI - Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer. AB - PURPOSE: To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights. METHODS: Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t test and gene set analysis were used to identify differentially expressed genes and pathways. RESULTS: The ER and HER2 status based on mRNA expression remained stable in all but two cases, and there were no changes in proliferation metrics (Ki67 and proliferating cell nuclear antigen expression). Molecular class changed in 8 cases (33.3%), usually to normal-like class, which was associated with low residual cancer cell cellularity. The expression of 200 to 600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of phosphoinositide 3-kinase, small G proteins, and calmodulin-dependent protein kinase II and energy metabolism were enriched, whereas immune cell-derived and the sonic hedgehog pathways were depleted in residual cancer. In non-basal-like breast cancers, notch signaling and energy metabolism (e.g., fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial-mesenchymal transition or cancer stem cell signatures. CONCLUSIONS: Our data indicate that energy metabolism related processes are upregulated and immune-related signals are depleted in residual cancers. Targeting these biologic processes may represent promising adjuvant treatment strategies for patients with residual cancer. PMID- 22235098 TI - Optical imaging with her2-targeted affibody molecules can monitor hsp90 treatment response in a breast cancer xenograft mouse model. AB - PURPOSE: To determine whether optical imaging can be used for in vivo therapy response monitoring as an alternative to radionuclide techniques. For this, we evaluated the known Her2 response to 17-dimethylaminoethylamino-17 demethoxygeldanamycin hydrochloride (17-DMAG) treatment, an Hsp90 inhibitor. EXPERIMENTAL DESIGN: After in vitro 17-DMAG treatment response evaluation of MCF7 parental cells and 2 HER2-transfected clones (clone A medium, B high Her2 expression), we established human breast cancer xenografts in nude mice (only parental and clone B) for in vivo evaluation. Mice received 120 mg/kg of 17-DMAG in 4 doses at 12-hour intervals intraperitonially (n = 14) or PBS as carrier control (n = 9). Optical images were obtained both pretreatment (day 0) and posttreatment (day 3, 6, and 9), always 5 hours postinjection of 500 pmol of anti Her2 Affibody-AlexaFluor680 via tail vein (with preinjection background subtraction). Days 3 and 9 in vivo optical imaging signal was further correlated with ex vivo Her2 levels by Western blot after sacrifice. RESULTS: Her2 expression decreased with 17-DMAG dose in vitro. In vivo optical imaging signal was reduced by 22.5% in clone B (P = 0.003) and by 9% in MCF7 parental tumors (P = 0.23) 3 days after 17-DMAG treatment; optical imaging signal recovered in both tumor types at days 6 to 9. In the carrier group, no signal reduction was observed. Pearson correlation of in vivo optical imaging signal with ex vivo Her2 levels ranged from 0.73 to 0.89. CONCLUSIONS: Optical imaging with an affibody can be used to noninvasively monitor changes in Her2 expression in vivo as a response to treatment with an Hsp90 inhibitor, with results similar to response measurements in positron emission tomography imaging studies. PMID- 22235099 TI - Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non small cell lung cancer. AB - PURPOSE: Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib. RESULTS: Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism. CONCLUSIONS: Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers. PMID- 22235100 TI - Characterization and clinical evaluation of CD10+ stroma cells in the breast cancer microenvironment. AB - PURPOSE: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance. EXPERIMENTAL DESIGN: We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets. RESULTS: This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients. CONCLUSIONS: Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease. PMID- 22235102 TI - Sizing up cell-free DNA. PMID- 22235101 TI - Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. AB - PURPOSE: Cervical tumor response on posttherapy 2[(18)F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) is predictive of survival outcome. The purpose of this study was to use gene expression profiling to identify pathways associated with tumor metabolic response. EXPERIMENTAL DESIGN: This was a prospective tissue collection study for gene expression profiling of 62 pretreatment biopsies from patients with advanced cervical cancer. Patients were treated with definitive radiation. Fifty-three patients received concurrent chemotherapy. All patients underwent a pretreatment and a 3-month posttherapy FDG PET/computed tomography (CT). Tumor RNA was harvested from fresh frozen tissue and hybridized to Affymetrix U133Plus2 GeneChips. Gene set enrichment analysis (GSEA) was used to identify signaling pathways associated with tumor metabolic response. Immunohistochemistry and in vitro FDG uptake assays were used to confirm our results. RESULTS: There were 40 biopsies from patients with a complete metabolic response (PET-negative group) and 22 biopsies from patients with incomplete metabolic response (PET-positive group). The 3-year cause specific survival estimates were 98% for the PET-negative group and 39% for the PET-positive group (P < 0.0001). GSEA identified alterations in expression of genes associated with the PI3K/Akt signaling pathway in patients with a positive follow-up PET. Immunohistochemistry using a tissue microarray of 174 pretreatment biopsies confirmed p-Akt as a biomarker for poor prognosis in cervical cancer. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 inhibited FDG uptake in vitro in cervical cancer cell lines. CONCLUSIONS: Activation of the PI3K/Akt pathway is associated with incomplete metabolic response in cervical cancer. Targeted inhibition of PI3K/Akt may improve response to chemoradiation. PMID- 22235103 TI - Fragile X mental retardation 1 (FMR1) intron 1 methylation in blood predicts verbal cognitive impairment in female carriers of expanded FMR1 alleles: evidence from a pilot study. AB - BACKGROUND: Cognitive status in females with mutations in the FMR1 (fragile X mental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X-related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS: Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55-200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ <70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS: A methylation analysis of intron 1 CpG sites 10-12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 * 10(-5)) after adjustment for multiple measures. CONCLUSIONS: The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment in FM females, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population. PMID- 22235104 TI - New knowledge stimulated by debate. PMID- 22235105 TI - Adding supplemental parenteral nutrition to hypocaloric enteral nutrition: lessons learned from the Casaer Van den Berghe study. PMID- 22235106 TI - Drivers of oxidative stress in acute pancreatitis: the role of nutrition therapy. AB - Severe acute pancreatitis is a disease process distinguished by increasing oxidative stress and potential destruction of the pancreatic gland. An initial injury to the acinar cell initiates a sentinel event, which leads to a vicious cycle of inflammation and cell death by either apoptosis or necrosis. Whether the acute inflammation resolves or goes on to a pattern of chronicity may be related to genetic predisposition, failure to remove injurious agents, and innate systems for antioxidant defense. The degree to which nutrition therapy can modulate oxidative stress, maintain intestinal function, and preserve the structure of the acinar cell is truly amazing. Understanding the mechanisms involved in this complex disease process and the manner in which these mechanisms are influenced by dietary agents affords new and exciting therapeutic options for the future. PMID- 22235107 TI - Evaluation of the effects of a preoperative 2-hour fast with maltodextrine and glutamine on insulin resistance, acute-phase response, nitrogen balance, and serum glutathione after laparoscopic cholecystectomy: a controlled randomized trial. AB - BACKGROUND: Prolonged preoperative fasting increases insulin resistance (IR). The authors investigated whether an abbreviated preoperative fast with glutamine (GLN) plus a carbohydrate (CHO)-based beverage would improve the organic response after surgery. METHODS: Forty-eight female patients (19-62 years) were randomized to either standard fasting (control group) or to fasting with 1 of 3 different beverages before video-cholecystectomy. Beverages were consumed 8 hours (400 mL; placebo group: water; GLN group: water with 50 g maltodextrine plus 40 g GLN; and CHO group: water with 50 g maltodextrine) and 2 hours (200 mL; placebo: water; GLN: water with 25 g maltodextrine plus 10 g GLN; and CHO: water with 25 g maltodextrine) before anesthesia. Blood samples were collected pre- and postoperatively. RESULTS: The mean (SEM) postoperative homeostasis model assessment-insulin resistance was greater (P < .05) in control patients (4.3 [1.3]) than in the other groups (placebo, 1.6 [0.3]; CHO, 2.3 [0.4]; and GLN, 1.5 [0.1]). Glutathione was significantly higher (P < .01) in the GLN group than in both CHO and control groups. Interleukin-6 increased in all groups except the GLN group. The C-reactive protein/albumin ratio was higher (P < .05) in controls than in CHO and GLN groups. The nitrogen balance was less negative in GLN (-2.5 [0.8] gN) than in both placebo (-9.0 [2] gN; P = .001) and control (-6.6 [0.4] gN; P = .04) groups. CONCLUSIONS: Preoperative intake of a GLN-enriched CHO beverage appears to improve IR and antioxidant defenses and decreases the inflammatory response after video-cholecystectomy. PMID- 22235109 TI - Design and simulation of a new powered gait orthosis for paraplegic patients. AB - BACKGROUND AND AIM: This article describes the development and testing of a new powered gait orthosis to potentially assist spinal cord injury patients to walk by producing synchronized hip and knee joint movements. TECHNIQUE: The first evaluation of the orthosis was performed without users, and was followed by evaluation of the orthosis performance using three healthy subjects to test the structure under weight-bearing conditions. The orthosis was primarily evaluated to ascertain its ability to generate appropriate hip and knee motion during walking. The walking experiments replicated the flexion and extension of both the hip and knee produced by the actuators which had previously been demonstrated during the initial computer simulations. DISCUSSION: The results suggest that this new orthosis could be used to assist paraplegic subjects who have adequate ranges of motion and also with weakness or reduced tone to ambulate, and may also be suitable for other subjects with impaired lower limb function (e.g. stroke, poliomyelitis, myelomeningocele and traumatic brain injury provided they do not have increased tone or movement disorders. PMID- 22235108 TI - Advances in the science and application of body composition measurement. PMID- 22235110 TI - Evaluation of a novel powered hip orthosis for walking by a spinal cord injury patient: a single case study. AB - BACKGROUND: The aim of this case study was to identify the effect of a powered hip orthosis on the kinematics and temporal-spatial parameters of walking by a patient with spinal cord injury (SCI). CASE DESCRIPTION AND METHODS: Two orthoses were evaluated while worn by an incomplete SCI subject with a T-8level of injury. Gait evaluation was performed when walking with an Isocentric Reciprocating Gait Orthosis (IRGO) and compared to that demonstrated by a newly powered version of the orthosis; based on the IRGO superstructure but incorporating powered hip joints using an electrically motorized actuator that produced active hip joint extension and flexion. FINDINGS AND OUTCOMES: The powered hip orthosis, when compared to the IRGO, increased the speed of walking, the step length and also the cadence demonstrated by this subject. Vertical and horizontal compensatory motions with new orthosis decreased. Hip angles when walking with this orthosis were comparative to those demonstrated by normal walking patterns. CONCLUSIONS: The hip actuator produced positive effects on the kinematics and temporal-spatial parameters of gait during level-ground walking trials, resulting in an alternative approach to walking by SCI patients. PMID- 22235111 TI - Transient P2X7 receptor activation triggers macrophage death independent of Toll like receptors 2 and 4, caspase-1, and pannexin-1 proteins. AB - The function of P2X(7) receptors (ATP-gated ion channels) in innate immune cells is unclear. In the setting of Toll-like receptor (TLR) stimulation, secondary activation of P2X(7) ion channels has been linked to pro-caspase-1 cleavage and cell death. Here we show that cell death is a surprisingly early triggered event. We show using live-cell imaging that transient (1-4 min) stimulation of mouse macrophages with high extracellular ATP ([ATP]e) triggers delayed (hours) cell death, indexed as DEVDase (caspase-3 and caspase-7) activity. Continuous or transient high [ATP]e did not induce cell death in P2X(7)-deficient (P2X(7)(-/-)) macrophages or neutrophils (in which P2X(7) could not be detected). Blocking sustained Ca(2+) influx, a signature of P2X(7) ligation, was highly protective, whereas no protection was conferred in macrophages lacking caspase-1 or TLR2 and TLR4. Furthermore, pannexin-1 (Panx1) deficiency had no effect on transient ATP induced delayed cell death or ATP-induced Yo-Pro-1 uptake (an index of large pore pathway formation). Thus, "transient" P2X(7) receptor activation and Ca(2+) overload act as a death trigger for native mouse macrophages independent of Panx1 and pro-inflammatory caspase-1 and TLR signaling. PMID- 22235112 TI - gamma-Aminobutyric acid type A (GABAA) receptor activation modulates tau phosphorylation. AB - Abnormal phosphorylation and aggregation of the microtubule-associated protein Tau are hallmarks of various neurodegenerative diseases, such as Alzheimer disease. Molecular mechanisms that regulate Tau phosphorylation are complex and currently incompletely understood. We have developed a novel live cell reporter system based on protein-fragment complementation assay to study dynamic changes in Tau phosphorylation status. In this assay, fusion proteins of Tau and Pin1 (peptidyl-prolyl cis-trans-isomerase 1) carrying complementary fragments of a luciferase protein serve as a sensor of altered protein-protein interaction between Tau and Pin1, a critical regulator of Tau dephosphorylation at several disease-associated proline-directed phosphorylation sites. Using this system, we identified several structurally distinct GABA(A) receptor modulators as novel regulators of Tau phosphorylation in a chemical library screen. GABA(A) receptor activation promoted specific phosphorylation of Tau at the AT8 epitope (Ser 199/Ser-202/Thr-205) in cultures of mature cortical neurons. Increased Tau phosphorylation by GABA(A) receptor activity was associated with reduced Tau binding to protein phosphatase 2A and was dependent on Cdk5 but not GSK3beta kinase activity. PMID- 22235113 TI - Endotoxin priming of neutrophils requires endocytosis and NADPH oxidase-dependent endosomal reactive oxygen species. AB - NADPH oxidase 2 (Nox2)-generated reactive oxygen species (ROS) are critical for neutrophil (polymorphonuclear leukocyte (PMN)) microbicidal function. Nox2 also plays a role in intracellular signaling, but the site of oxidase assembly is unknown. It has been proposed to occur on secondary granules. We previously demonstrated that intracellular NADPH oxidase-derived ROS production is required for endotoxin priming. We hypothesized that endotoxin drives Nox2 assembly on endosomes. Endotoxin induced ROS generation within an endosomal compartment as quantified by flow cytometry (dihydrorhodamine 123 and Oxyburst Green). Inhibition of endocytosis by the dynamin-II inhibitor Dynasore blocked endocytosis of dextran, intracellular generation of ROS, and priming of PMN by endotoxin. Confocal microscopy demonstrated a ROS-containing endosomal compartment that co-labeled with gp91(phox), p40(phox), p67(phox), and Rab5, but not with the secondary granule marker CD66b. To further characterize this compartment, PMNs were fractionated by nitrogen cavitation and differential centrifugation, followed by free flow electrophoresis. Specific subfractions made superoxide in the presence of NADPH by cell-free assay (cytochrome c). Subfraction content of membrane and cytosolic subunits of Nox2 correlated with ROS production. Following priming, there was a shift in the light membrane subfractions where ROS production was highest. CD66b was not mobilized from the secondary granule compartment. These data demonstrate a novel, nonphagosomal intracellular site for Nox2 assembly. This compartment is endocytic in origin and is required for PMN priming by endotoxin. PMID- 22235114 TI - Follicle-stimulating hormone regulates pro-apoptotic protein Bcl-2-interacting mediator of cell death-extra long (BimEL)-induced porcine granulosa cell apoptosis. AB - The pro-apoptotic protein Bim (B-cell lymphoma-2 (Bcl-2)-interacting modulator of cell death) has recently been identified and shown to promote cell death in response to several stimuli. In this report, we investigated the role of Bim in porcine follicular atresia. Initially, Bim cDNA was cloned and characterized from porcine ovarian tissue. Porcine Bim had three alternative splicing variants (Bim extra long, Bim-long, and Bim-short), all containing the consensus Bcl-2 homology 3 domain. We then found the Bim-extra long (Bim(EL)) protein, the most abundant isoform of Bim, was strongly expressed and co-localized with apoptotic (TUNEL positive) granulosa cells from porcine atretic follicles. Furthermore, overexpression of Bim(EL) triggered apoptosis in granulosa cells. In primary granulosa cell cultures under basal conditions, we observed that Bim(EL) expression was dampened by treatment with follicle-stimulating hormone (FSH). The role of the PI3K/Akt pathway in the regulation of repression was clarified by the use of the PI3K inhibitor, LY294002, and by transfection with Akt siRNA. Forkhead Box Protein O3a (FoxO3a), a well defined transcriptional activator of Bim, was phosphorylated at Ser-253 and inactivated after FSH stimulation. Also, FSH abolished FoxO3a nuclear accumulation in response to LY294002. Finally, chromatin immunoprecipitation assays demonstrated that FoxO3a directly bound and activated the bim promoter. Taken together, we conclude that Bim(EL) induces porcine granulosa cell apoptosis during follicular atresia, and its expression is regulated by FSH via the PI3K/Akt/FoxO3a pathway. PMID- 22235115 TI - Trimeric, coiled-coil extension on peptide fusion inhibitor of HIV-1 influences selection of resistance pathways. AB - Peptides corresponding to N- and C-terminal heptad repeat regions (HR1 and HR2, respectively) of viral fusion proteins can block infection of viruses in a dominant negative manner by interfering with refolding of the viral HR1 and HR2 to form a six-helix bundle (6HB) that drives fusion between viral and host cell membranes. The 6HB of the HIV gp41 (endogenous bundle) consists of an HR1 coiled coil trimer with grooves lined by antiparallel HR2 helices. HR1 peptides form coiled-coil oligomers that may bind to gp41 HR2 as trimers to form a heterologous 6HB (inhibitor bundle) or to gp41 HR1 as monomers or dimers to form a heterologous coiled coil. To gain insights into mechanisms of Env entry and inhibition by HR1 peptides, we compared resistance to a peptide corresponding to 36 residues in gp41 HR1 (N36) and the same peptide with a coiled-coil trimerization domain fused to its N terminus (IZN36) that stabilizes the trimer and increases inhibitor potency (Eckert, D. M., and Kim, P. S. (2001) Proc. Nat. Acad. Sci. U.S.A. 98, 11187-11192). Whereas N36 selected two genetic pathways with equal probability, each defined by an early mutation in either HR1 or HR2, IZN36 preferentially selected the HR1 pathway. Both pathways conferred cross resistance to both peptides. Each HR mutation enhanced the thermostability of the endogenous 6HB, potentially allowing the virus to simultaneously escape inhibitors targeting either gp41 HR1 or HR2. These findings inform inhibitor design and identify regions of plasticity in the highly conserved gp41 that modulate virus entry and escape from HR1 peptide inhibitors. PMID- 22235116 TI - Neurexin-1alpha contributes to insulin-containing secretory granule docking. AB - Neurexins are a family of transmembrane, synaptic adhesion molecules. In neurons, neurexins bind to both sub-plasma membrane and synaptic vesicle-associated constituents of the secretory machinery, play a key role in the organization and stabilization of the presynaptic active zone, and help mediate docking of synaptic vesicles. We have previously shown that neurexins, like many other protein constituents of the neurotransmitter exocytotic machinery, are expressed in pancreatic beta cells. We hypothesized that the role of neurexins in beta cells parallels their role in neurons, with beta-cell neurexins helping to mediate insulin granule docking and secretion. Here we demonstrate that beta cells express a more restricted pattern of neurexin transcripts than neurons, with a clear predominance of neurexin-1alpha expressed in isolated islets. Using INS-1E beta cells, we found that neurexin-1alpha interacts with membrane-bound components of the secretory granule-docking machinery and with the granule associated protein granuphilin. Decreased expression of neurexin-1alpha, like decreased expression of granuphilin, reduces granule docking at the beta-cell membrane and improves insulin secretion. Perifusion of neurexin-1alpha KO mouse islets revealed a significant increase in second-phase insulin secretion with a trend toward increased first-phase secretion. Upon glucose stimulation, neurexin 1alpha protein levels decrease. This glucose-induced down-regulation may enhance glucose-stimulated insulin secretion. We conclude that neurexin-1alpha is a component of the beta-cell secretory machinery and contributes to secretory granule docking, most likely through interactions with granuphilin. Neurexin 1alpha is the only transmembrane component of the docking machinery identified thus far. Our findings provide new insights into the mechanisms of insulin granule docking and exocytosis. PMID- 22235117 TI - Ssu72 phosphatase-dependent erasure of phospho-Ser7 marks on the RNA polymerase II C-terminal domain is essential for viability and transcription termination. AB - The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) serves an important role in coordinating stage-specific recruitment and release of cellular machines during transcription. Dynamic placement and removal of phosphorylation marks on different residues of a repeating heptapeptide (YSPTSPS) of the CTD underlies the engagement of relevant cellular machinery. Whereas sequential placement of phosphorylation marks is well explored, genome-wide engagement of phosphatases that remove these CTD marks is poorly understood. In particular, identifying the enzyme that erases phospho-Ser7 (Ser7-P) marks is especially important, because we find that substituting this residue with a glutamate, a phospho-mimic, is lethal. Our observations implicate Ssu72 as a Ser7 P phosphatase. We report that removal of all phospho-CTD marks during transcription termination is mechanistically coupled. An inability to remove these marks prevents Pol II from terminating efficiently and will likely impede subsequent assembly into the pre-initiation complex. PMID- 22235118 TI - Critical role of leucine-valine change in distinct low pH requirements for membrane fusion between two related retrovirus envelopes. AB - Many viruses use a pH-dependent pathway for fusion with host cell membrane, the mechanism of which is still poorly understood. Here we report that a subtle leucine (Leu)-valine (Val) change at position 501 in the envelope glycoproteins (Envs) of two related retroviruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), is responsible for their distinct low pH requirements for membrane fusion and infection. The Leu and Val residues are predicted to reside within the C-terminal heptad repeat (HR2) region of JSRV and ENTV Envs, particularly proximal to the hairpin turn of the putative six-helix bundle (6HB). Substitution of the JSRV Leu with a Val blocked the Env-mediated membrane fusion at pH 5.0, whereas replacement of the ENTV Val with a Leu rendered the ENTV Env capable of fusing at pH 5.0. A Leu-Val change has no apparent effect on the stability of native Env, but appears to stabilize an intermediate induced by receptor binding. These results are consistent with the existence of at least two metastable conformations of these viral glycoproteins, the native prefusion conformation and a receptor-induced metastable intermediate. Collectively, this work represents an interesting perhaps unique example whereby a simple Leu-Val change has critical impact on pH-dependent virus fusion and entry. PMID- 22235119 TI - alpha-Catenin uses a novel mechanism to activate vinculin. AB - Vinculin, an actin-binding protein, is emerging as an important regulator of adherens junctions. In focal-adhesions, vinculin is activated by simultaneous binding of talin to its head domain and actin filaments to its tail domain. Talin is not present in adherens junctions. Consequently, the identity of the ligand that activates vinculin in cell-cell junctions is not known. Here we show that in the presence of F-actin, alpha-catenin, a cytoplasmic component of the cadherin adhesion complex, activates vinculin. Direct binding of alpha-catenin to vinculin is critical for this event because a point mutant (alpha-catenin L344P) lacking high affinity binding does not activate vinculin. Furthermore, unlike all known vinculin activators, alpha-catenin binds to and activates vinculin independently of an A50I substitution in the vinculin head, a mutation that inhibits vinculin binding to talin and IpaA. Collectively, these data suggest that alpha-catenin employs a novel mechanism to activate vinculin and may explain how vinculin is differentially recruited and/or activated in cell-cell and cell-matrix adhesions. PMID- 22235120 TI - Structural insight into unique cardiac myosin-binding protein-C motif: a partially folded domain. AB - The structural role of the unique myosin-binding motif (m-domain) of cardiac myosin-binding protein-C remains unclear. Functionally, the m-domain is thought to directly interact with myosin, whereas phosphorylation of the m-domain has been shown to modulate interactions between myosin and actin. Here we utilized NMR to analyze the structure and dynamics of the m-domain in solution. Our studies reveal that the m-domain is composed of two subdomains, a largely disordered N-terminal portion containing three known phosphorylation sites and a more ordered and folded C-terminal portion. Chemical shift analyses, d(NN)(i, i + 1) NOEs, and (15)N{(1)H} heteronuclear NOE values show that the C-terminal subdomain (residues 315-351) is structured with three well defined helices spanning residues 317-322, 327-335, and 341-348. The tertiary structure was calculated with CS-Rosetta using complete (13)C(alpha), (13)C(beta), (13)C', (15)N, (1)H(alpha), and (1)H(N) chemical shifts. An ensemble of 20 acceptable structures was selected to represent the C-terminal subdomain that exhibits a novel three-helix bundle fold. The solvent-exposed face of the third helix was found to contain the basic actin-binding motif LK(R/K)XK. In contrast, (15)N{(1)H} heteronuclear NOE values for the N-terminal subdomain are consistent with a more conformationally flexible region. Secondary structure propensity scores indicate two transient helices spanning residues 265-268 and 293-295. The presence of both transient helices is supported by weak sequential d(NN)(i, i + 1) NOEs. Thus, the m-domain consists of an N-terminal subdomain that is flexible and largely disordered and a C-terminal subdomain having a three-helix bundle fold, potentially providing an actin-binding platform. PMID- 22235121 TI - Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis. AB - The de novo thymidylate biosynthetic pathway in mammalian cells translocates to the nucleus for DNA replication and repair and consists of the enzymes serine hydroxymethyltransferase 1 and 2alpha (SHMT1 and SHMT2alpha), thymidylate synthase, and dihydrofolate reductase. In this study, we demonstrate that this pathway forms a multienzyme complex that is associated with the nuclear lamina. SHMT1 or SHMT2alpha is required for co-localization of dihydrofolate reductase, SHMT, and thymidylate synthase to the nuclear lamina, indicating that SHMT serves as scaffold protein that is essential for complex formation. The metabolic complex is enriched at sites of DNA replication initiation and associated with proliferating cell nuclear antigen and other components of the DNA replication machinery. These data provide a mechanism for previous studies demonstrating that SHMT expression is rate-limiting for de novo thymidylate synthesis and indicate that de novo thymidylate biosynthesis occurs at replication forks. PMID- 22235122 TI - The trans-autostimulatory activity of Rad27 suppresses dna2 defects in Okazaki fragment processing. AB - Dna2 and Rad27 (yeast Fen1) are the two endonucleases critical for Okazaki fragment processing during lagging strand DNA synthesis that have been shown to interact genetically and physically. In this study, we addressed the functional consequences of these interactions by examining whether purified Rad27 of Saccharomyces cerevisiae affects the enzymatic activity of Dna2 and vice versa. For this purpose, we constructed Rad27DA (catalytically defective enzyme with an Asp to Ala substitution at amino acid 179) and found that it significantly stimulated the endonuclease activity of wild type Dna2, but failed to do so with Dna2Delta405N that lacks the N-terminal 405 amino acids. This was an unexpected finding because dna2Delta405N cells were still partially suppressed by overexpression of rad27DA in vivo. Further analyses revealed that Rad27 is a trans-autostimulatory enzyme, providing an explanation why overexpression of Rad27, regardless of its catalytic activity, suppressed dna2 mutants as long as an endogenous wild type Rad27 is available. We found that the C-terminal 16-amino acid fragment of Rad27, a highly polybasic region due to the presence of multiple positively charged lysine and arginine residues, was sufficient and necessary for the stimulation of both Rad27 and Dna2. Our findings provide further insight into how Dna2 and Rad27 jointly affect the processing of Okazaki fragments in eukaryotes. PMID- 22235123 TI - Identification of novel interaction between annexin A2 and keratin 17: evidence for reciprocal regulation. AB - Keratins are cytoplasmic intermediate filament proteins providing crucial structural support in epithelial cells. Keratin expression has diagnostic and even prognostic value in disease settings, and recent studies have uncovered modulatory roles for select keratin proteins in signaling pathways regulating cell growth and cell death. Elevated keratin expression in select cancers is correlated with higher expression of EGF receptor (EGFR), whose overexpression and/or mutation give rise to cancer. To explore the role of keratins in oncogenic signaling pathways, we examined the regulation of epithelial growth-associated keratin 17 (K17) in response to EGFR activation. K17 is specifically up-regulated in detergent-soluble fraction upon EGFR activation, and immunofluorescence analysis revealed alterations in K17-containing filaments. Interestingly, we identified AnxA2 as a novel interacting partner of K17, and this interaction is antagonized by EGFR activation. K17 and AnxA2 proteins show reciprocal regulation. Modulating expression of AnxA2 altered K17 stability, and AnxA2 overexpression delays EGFR-mediated change in K17 detergent solubility. Down regulation of K17 expression, in turn, results in decreased AnxA2 phosphorylation at Tyr-23. These findings uncover a novel interaction involving K17 and AnxA2 and identify AnxA2 as a potential regulator of keratin filaments. PMID- 22235124 TI - Mast cell restricted mouse and human tryptase.heparin complexes hinder thrombin induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen. AB - The mouse and human TPSB2 and TPSAB1 genes encode tetramer-forming tryptases stored in the secretory granules of mast cells (MCs) ionically bound to heparin containing serglycin proteoglycans. In mice these genes encode mouse MC protease 6 (mMCP-6) and mMCP-7. The corresponding human genes encode a family of serine proteases that collectively are called hTryptase-beta. We previously showed that the alpha chain of fibrinogen is a preferred substrate of mMCP-7. We now show that this plasma protein also is highly susceptible to degradation by hTryptase beta. and mMCP-6.heparin complexes and that Lys(575) is a preferred cleavage site in the protein alpha chain. Because cutaneous mouse MCs store substantial amounts of mMCP-6.heparin complexes in their secretory granules, the passive cutaneous anaphylaxis reaction was induced in the skin of mMCP-6(+)/mMCP-7(-) and mMCP-6( )/mMCP-7(-) C57BL/6 mice. In support of the in vitro data, fibrin deposits were markedly increased in the skin of the double-deficient mice 6 h after IgE sensitized animals were given the relevant antigen. Fibrinogen is a major constituent of the edema fluid that accumulates in tissues when MCs degranulate. Our discovery that mouse and human tetramer-forming tryptases destroy fibrinogen before this circulating protein can be converted to fibrin changes the paradigm of how MCs hinder fibrin deposition and blood coagulation internally. Because of the adverse consequences of fibrin deposits in tissues, our data explain why mice and humans lack a circulating protease inhibitor that rapidly inactivates MC tryptases and why mammals have two genes that encode tetramer-forming serine proteases that preferentially degrade fibrinogen. PMID- 22235125 TI - ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. AB - ETS-related gene (ERG) is a member of the ETS transcription factor family. Our previous studies have shown that ERG expression is highly enriched in endothelial cells (EC) both in vitro and in vivo. ERG expression is markedly repressed in response to inflammatory stimuli. It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. In this study we have identified a novel role for ERG in the regulation of EC barrier function. ERG knockdown results in marked increases in EC permeability. This is associated with a significant increase of stress fiber and gap formation in EC. Furthermore, we identify CLDN5 as a downstream target of ERG in EC. Thus, our results suggest that ERG plays a pivotal role in regulating EC barrier function and that this effect is mediated in part through its regulation of CLDN5 gene expression. PMID- 22235126 TI - Pattern recognition protein binds to lipopolysaccharide and beta-1,3-glucan and activates shrimp prophenoloxidase system. AB - The prophenoloxidase (proPO) system is activated upon recognition of pathogens by pattern recognition proteins (PRPs), including a lipopolysaccharide- and beta-1,3 glucan-binding protein (LGBP). However, shrimp LGBPs that are involved in the proPO system have yet to be clarified. Here, we focus on characterizing the role of a Penaeus monodon LGBP (PmLGBP) in the proPO system. We found that PmLGBP transcripts are expressed primarily in the hemocytes and are increased at 24 h after pathogenic bacterium Vibrio harveyi challenge. The binding studies carried out using ELISA indicated that recombinant (r)PmLGBP binds to beta-1,3-glucan and LPS with a dissociation constant of 6.86 * 10(-7) M and 3.55 * 10(-7) M, respectively. Furthermore, we found that rPmLGBP could enhance the phenoloxidase (PO) activity of hemocyte suspensions in the presence of LPS or beta-1,3-glucan. Using dsRNA interference-mediated gene silencing assay, we further demonstrated that knockdown of PmLGBP in shrimp in vivo significantly decreased the PmLGBP transcript level but had no effect on the expression of the other immune genes tested, including shrimp antimicrobial peptides (AMPs). However, suppression of proPO expression down-regulated PmLGBP, proPO-activating enzyme (PmPPAE2), and AMPs (penaeidin and crustin). Such PmLGBP down-regulated shrimp showed significantly decreased total PO activity. We conclude that PmLGBP functions as a pattern recognition protein for LPS and beta-1,3-glucan in the shrimp proPO activating system. PMID- 22235128 TI - Structure/function analysis of Pasteurella multocida heparosan synthases: toward defining enzyme specificity and engineering novel catalysts. AB - The Pasteurella multocida heparosan synthases, PmHS1 and PmHS2, are homologous (~65% identical) bifunctional glycosyltransferase proteins found in Type D Pasteurella. These unique enzymes are able to generate the glycosaminoglycan heparosan by polymerizing sugars to form repeating disaccharide units from the donor molecules UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP GlcNAc). Although these isozymes both generate heparosan, the catalytic phenotypes of these isozymes are quite different. Specifically, during in vitro synthesis, PmHS2 is better able to generate polysaccharide in the absence of exogenous acceptor (de novo synthesis) than PmHS1. Additionally, each of these enzymes is able to generate polysaccharide using unnatural sugar analogs in vitro, but they exhibit differences in the substitution patterns of the analogs they will employ. A series of chimeric enzymes has been generated consisting of various portions of both of the Pasteurella heparosan synthases in a single polypeptide chain. In vitro radiochemical sugar incorporation assays using these purified chimeric enzymes have shown that most of the constructs are enzymatically active, and some possess novel characteristics including the ability to produce nearly monodisperse polysaccharides with an expanded range of sugar analogs. Comparison of the kinetic properties and the sequences of the wild type enzymes with the chimeric enzymes has enabled us to identify regions that may be responsible for some aspects of both donor binding specificity and acceptor usage. In combination with previous work, these approaches have enabled us to better understand the structure/function relationship of this unique family of glycosyltransferases. PMID- 22235127 TI - A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated alphaIIbbeta3 integrin coactivation. AB - The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin beta subunits. Binding of the talin FERM (four point-one, ezrin, radixin, moesin) domain to the integrin beta tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin beta subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in alphaIIbbeta3 integrin activation, but not for kindlin binding to integrin beta tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well beta-integrin tails contribute to the ability of kindlins to activate integrins. PMID- 22235129 TI - Direct in vitro and in vivo evidence for interaction between Hsp47 protein and collagen triple helix. AB - Hsp47 (heat shock protein 47), a collagen-specific molecular chaperone, is essential for the maturation of various types of procollagens. Previous studies have suggested that Hsp47 may preferentially recognize the triple-helix form of procollagen rather than unfolded procollagen chains in the endoplasmic reticulum. However, the underlying mechanism has remained unclear because of limitations in the available methods for detecting in vitro and in vivo interactions between Hsp47 and collagen. In this study, we established novel methods for this purpose by adopting a time-resolved FRET technique in vitro and a bimolecular fluorescence complementation technique in vivo. Using these methods, we provide direct evidence that Hsp47 binds to collagen triple helices but not to the monomer form in vitro. We also demonstrate that Hsp47 binds a collagen model peptide in the trimer conformation in vivo. Hsp47 did not bind collagen peptides that had been modified to block their ability to form triple helices in vivo. These results conclusively indicate that Hsp47 recognizes the triple-helix form of procollagen in vitro and in vivo. PMID- 22235130 TI - Apolipoprotein A-II-mediated conformational changes of apolipoprotein A-I in discoidal high density lipoproteins. AB - It is well accepted that HDL has the ability to reduce risks for several chronic diseases. To gain insights into the functional properties of HDL, it is critical to understand the HDL structure in detail. To understand interactions between the two major apolipoproteins (apos), apoA-I and apoA-II in HDL, we generated highly defined benchmark discoidal HDL particles. These particles were reconstituted using a physiologically relevant phospholipid, 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) incorporating two molecules of apoA-I and one homodimer of apoA-II per particle. We utilized two independent mass spectrometry techniques to study these particles. The techniques are both sensitive to protein conformation and interactions and are namely: 1) hydrogen deuterium exchange combined with mass spectrometry and 2) partial acetylation of lysine residues combined with MS. Comparison of mixed particles with apoA-I only particles of similar diameter revealed that the changes in apoA-I conformation in the presence of apoA-II are confined to apoA-I helices 3-4 and 7-9. We discuss these findings with respect to the relative reactivity of these two particle types toward a major plasma enzyme, lecithin:cholesterol acyltransferase responsible for the HDL maturation process. PMID- 22235131 TI - An acidic amino acid transmembrane helix 10 residue conserved in the neurotransmitter:sodium:symporters is essential for the formation of the extracellular gate of the gamma-aminobutyric acid (GABA) transporter GAT-1. AB - GAT-1 mediates transport of GABA together with sodium and chloride in an electrogenic process enabling efficient GABAergic transmission. Biochemical and modeling studies based on the structure of the bacterial homologue LeuT are consistent with a mechanism whereby the binding pocket is alternately accessible to either side of the membrane and which predicts that the extracellular part of transmembrane domain 10 (TM10) exhibits aqueous accessibility in the outward facing conformation only. In this study we have engineered cysteine residues in the extracellular half of TM10 of GAT-1 and probed their state-dependent accessibility to sulfhydryl reagents. In three out of four of the accessible cysteine mutants, the inhibition of transport by a membrane impermeant sulfhydryl reagent was diminished under conditions expected to increase the proportion of inward-facing transporters, such as the presence of GABA together with the cotransported ions. A conserved TM10 aspartate residue, whose LeuT counterpart participates in a "thin" extracellular gate, was found to be essential for transport and only the D451E mutant exhibited residual transport activity. D451E exhibited robust sodium-dependent transient currents with a voltage-dependence indicative of an increased apparent affinity for sodium. Moreover the accessibility of an endogenous cysteine to a membrane impermeant sulfhydryl reagent was enhanced by the D451E mutation, suggesting that sodium binding promotes an outward-facing conformation of the transporter. Our results support the idea that TM10 of GAT-1 lines an accessibility pathway from the extracellular space into the binding pocket and plays a role in the opening and closing of the extracellular transporter gate. PMID- 22235133 TI - Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R. AB - IL-21 is a class I cytokine that exerts pleiotropic effects on both innate and adaptive immune responses. It signals through a heterodimeric receptor complex consisting of the IL-21 receptor (IL-21R) and the common gamma-chain. A hallmark of the class I cytokine receptors is the class I cytokine receptor signature motif (WSXWS). The exact role of this motif has not been determined yet; however, it has been implicated in diverse functions, including ligand binding, receptor internalization, proper folding, and export, as well as signal transduction. Furthermore, the WXXW motif is known to be a consensus sequence for C mannosylation. Here, we present the crystal structure of IL-21 bound to IL-21R and reveal that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan. We furthermore demonstrate that a sugar chain bridges the two fibronectin domains that constitute the extracellular domain of IL-21R and anchors at the WSXWS motif through an extensive hydrogen bonding network, including mannosylation. The glycan thus transforms the V-shaped receptor into an A-frame. This finding offers a novel structural explanation of the role of the class I cytokine signature motif. PMID- 22235132 TI - Amyloid-beta oligomers induce differential gene expression in adult human brain slices. AB - Cognitive decline in Alzheimer disease (AD) is increasingly attributed to the neuronal impact of soluble oligomers of the amyloid-beta peptide (AbetaOs). Current knowledge on the molecular and cellular mechanisms underlying the toxicity of AbetaOs stems largely from rodent-derived cell/tissue culture experiments or from transgenic models of AD, which do not necessarily recapitulate the complexity of the human disease. Here, we used DNA microarray and RT-PCR to investigate changes in transcription in adult human cortical slices exposed to sublethal doses of AbetaOs. The results revealed a set of 27 genes that showed consistent differential expression upon exposure of slices from three different donors to AbetaOs. Functional classification of differentially expressed genes revealed that AbetaOs impact pathways important for neuronal physiology and known to be dysregulated in AD, including vesicle trafficking, cell adhesion, actin cytoskeleton dynamics, and insulin signaling. Most genes (70%) were down-regulated by AbetaO treatment, suggesting a predominantly inhibitory effect on the corresponding pathways. Significantly, AbetaOs induced down-regulation of synaptophysin, a presynaptic vesicle membrane protein, suggesting a mechanism by which oligomers cause synapse failure. The results provide insight into early mechanisms of pathogenesis of AD and suggest that the neuronal pathways affected by AbetaOs may be targets for the development of novel diagnostic or therapeutic approaches. PMID- 22235135 TI - An unusual subtilisin-like serine protease is essential for biogenesis of quinohemoprotein amine dehydrogenase. AB - Quinohemoprotein amine dehydrogenase (QHNDH), an alphabetagamma heterotrimer present in the periplasm of several Gram-negative bacteria, catalyzes the oxidative deamination of various aliphatic amines such as n-butylamine for assimilation as carbon and energy sources. The gamma subunit of mature QHNDH contains a protein-derived quinone cofactor, cysteine tryptophylquinone, and three intrapeptidyl thioether cross-links between Cys and Asp or Glu residues. In its cytoplasmic nascent form, the gamma subunit has a 28-residue N-terminal leader peptide that is necessary for the production of active QHNDH but must be removed in the following maturation process. Here, we describe the role of a subtilisin-like serine protease encoded in the fifth ORF of the n-butylamine utilizing operon of Paracoccus denitrificans (termed ORF5) in QHNDH biogenesis. ORF5 disruption caused bacterial cell growth inhibition in n-butylamine containing medium and production of inactive QHNDH, in which the gamma subunit retained the leader peptide. Supply of plasmid-encoded ORF5 restored the cell growth and production of active QHNDH, containing the correctly processed gamma subunit. ORF5 expressed in Escherichia coli but not its catalytic triad mutant cleaved synthetic peptides surrogating for the gamma subunit leader peptide, although extremely slowly. The cleaved leader peptide remained unstably bound to ORF5, most likely as an acyl enzyme intermediate attached to the active-site Ser residue. These results demonstrate that ORF5 is essential for QHNDH biogenesis, serving as a processing protease to cleave the gamma subunit leader peptide nearly in a disposable manner. PMID- 22235134 TI - Cellular model of TAR DNA-binding protein 43 (TDP-43) aggregation based on its C terminal Gln/Asn-rich region. AB - TDP-43 is one of the major components of the neuronal and glial inclusions observed in several neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These characteristic aggregates are a "landmark" of the disease, but their role in the pathogenesis is still obscure. In previous works, we have shown that the C-terminal Gln/Asn-rich region (residues 321-366) of TDP-43 is involved in the interaction of this protein with other members of the heterogeneous nuclear ribonucleoprotein protein family. Furthermore, we have shown that the interaction through this region is important for TDP-43 splicing inhibition of cystic fibrosis transmembrane regulator exon 9, and there were indications that it was involved in the aggregation process. Our experiments show that in cell lines and primary rat neuronal cultures, the introduction of tandem repeats carrying the 331-369-residue Gln/Asn region from TDP-43 can trigger the formation of phosphorylated and ubiquitinated aggregates that recapitulate many but not all the characteristics observed in patients. These results establish a much needed cell-based TDP-43 aggregation model useful to investigate the mechanisms involved in the formation of inclusions and the gain- and loss-of-function consequences of TDP-43 aggregation within cells. In addition, it will be a powerful tool to test novel therapeutic strategies/effectors aimed at preventing/reducing this phenomenon. PMID- 22235137 TI - Principles and plans. PMID- 22235136 TI - T7 RNA polymerases backed up by covalently trapped proteins catalyze highly error prone transcription. AB - RNA polymerases (RNAPs) transcribe genes through the barrier of nucleoproteins and site-specific DNA-binding proteins on their own or with the aid of accessory factors. Proteins are often covalently trapped on DNA by DNA damaging agents, forming DNA-protein cross-links (DPCs). However, little is known about how immobilized proteins affect transcription. To elucidate the effect of DPCs on transcription, we constructed DNA templates containing site-specific DPCs and performed in vitro transcription reactions using phage T7 RNAP. We show here that DPCs constitute strong but not absolute blocks to in vitro transcription catalyzed by T7 RNAP. More importantly, sequence analysis of transcripts shows that RNAPs roadblocked not only by DPCs but also by the stalled leading RNAP become highly error prone and generate mutations in the upstream intact template regions. This contrasts with the transcriptional mutations induced by conventional DNA lesions, which are delivered to the active site or its proximal position in RNAPs and cause direct misincorporation. Our data also indicate that the trailing RNAP stimulates forward translocation of the stalled leading RNAP, promoting the translesion bypass of DPCs. The present results provide new insights into the transcriptional fidelity and mutual interactions of RNAPs that encounter persistent roadblocks. PMID- 22235139 TI - Brivaracetam disposition in renal impairment. AB - Brivaracetam is a novel high-affinity SV2A ligand currently in clinical development for epilepsy. The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/min, n = 6; 15-29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The C(max) of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01-1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m(2). Exposure to the acid, hydroxy, and hydroxyacid metabolites was markedly increased: C(max) by 2.4-, 2.0 , and 11.7-fold and AUC by 3.2-, 4.1-, and 21.5-fold. Renal clearance of these rapidly cleared metabolites was decreased 10-fold in patients with severe renal impairment. Nonclinical toxicology studies concluded to the absence of safety issues related to the increased levels of metabolites. These observations suggest that dose adjustment of brivaracetam should not be required at any stage of renal dysfunction. PMID- 22235140 TI - Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. AB - This retrospective analysis characterizes rituximab population pharmacokinetics in combination with fludarabine and cyclophosphamide and its effect on fludarabine and cyclophosphamide disposition in chronic lymphocytic leukemia (CLL) patients. Rituximab concentration data were well described by a 2 compartment model comprising a time-varying clearance component related to the target-mediated clearance pathway and a constant clearance component reflecting catabolic elimination pathway. Marked differences were observed compared to pharmacokinetic parameters for non-Hodgkin lymphoma (NHL) obtained previously: in CLL, time-varying clearance at time zero (CL(2)) was faster, volumes of distribution (V(1) and V(2)) were larger, and rate of change (K(des)) from the targetmediated clearance pathway to catabolic elimination was lower than NHL. Fludarabine and cyclophosphamide disposition showed no apparent change when co administered with rituximab. A positive correlation between pharmacokinetic parameters and clinical response was observed, supporting the use of the higher rituximab dose of 500 mg/m(2) in CLL patients (vs 375 mg/m(2) in NHL) to achieve an effective clinical response. PMID- 22235141 TI - Successful genotyping of microsatellites in the woolly mammoth. AB - Genetic analyses using ancient DNA from Pleistocene and early Holocene fossils have largely relied on mitochondrial DNA (mtDNA) sequences. Among woolly mammoths, Mammuthus primigenius, mtDNA analyses have identified 2 distinct clades (I and II) that diverged 1-2 Ma. Here, we establish that microsatellite markers can be effective on Pleistocene samples, successfully genotyping woolly mammoth specimens at 2 loci. Although significant differentiation at the 2 microsatellite loci was not detected between 16 clade I and 4 clade II woolly mammoths, our results demonstrate that the nuclear population structure of Pleistocene species can be examined using fast-evolving nuclear microsatellite markers. PMID- 22235142 TI - Targeted therapies for renal cell carcinoma: review of adverse event management strategies. AB - With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC. PMID- 22235143 TI - (153)Sm-EDTMP appears to accumulate only trivially within peritoneal ascites. AB - (153)Sm-lexidronam (EDTMP) is a therapeutic radiopharmaceutical used for palliation of pain resulting from osseous metastatic disease. METHODS: We recently treated with (153)Sm-EDTMP a patient who had extensive osseous metastases and malignant ascites requiring intermittent drainage from an indwelling catheter. Because we could find no useful data regarding quantification of accumulation of this agent within ascites, we opted to assay the fluid after treatment. RESULTS: The measured ratio of (153)Sm-EDTMP activity in peritoneal fluid (1.71 L) relative to injected dose was 0.01% (i.e., trivially above background level). CONCLUSION: To our knowledge, this represents the first published measurement of (153)Sm-EDTMP accumulation within peritoneal fluid. This information may be useful to the nuclear medicine community since malignant ascites is not uncommon in patients with widely metastatic carcinoma and such patients may be referred for (153)Sm-EDTMP therapy. PMID- 22235144 TI - Eye movements in a sequential scanning task: evidence for distributed processing. AB - Current models of eye movement control are derived from theories assuming serial processing of single items or from theories based on parallel processing of multiple items at a time. This issue has persisted because most investigated paradigms generated data compatible with both serial and parallel models. Here, we study eye movements in a sequential scanning task, where stimulus n indicates the position of the next stimulus n + 1. We investigate whether eye movements are controlled by sequential attention shifts when the task requires serial order of processing. Our measures of distributed processing in the form of parafoveal-on foveal effects, long-range modulations of target selection, and skipping saccades provide evidence against models strictly based on serial attention shifts. We conclude that our results lend support to parallel processing as a strategy for eye movement control. PMID- 22235145 TI - Serial exploration of faces: comparing vision and touch. AB - Even though we can recognize faces by touch surprisingly well, haptic face recognition performance is still worse than for visual exploration. One possibility for this performance difference might be due to different encoding strategies in the two modalities, namely, holistic encoding in vision versus serial encoding in haptics. Here, we tested this hypothesis by promoting serial encoding in vision, using a novel, gaze-restricted display that limited the effective field of view in vision to resemble that of haptic exploration. First, we compared haptic with gaze-restricted and unrestricted visual face recognition. Second, we used the face inversion paradigm to assess how encoding differences might affect processing strategies (featural vs. holistic). By promoting serial encoding in vision, we found equal face recognition performance in vision and haptics with a clear switch from holistic to featural processing, suggesting that performance differences in visual and haptic face recognition are due to modality specific encoding strategies. PMID- 22235147 TI - Selective glucocorticoid receptor agonists for the treatment of inflammatory bowel disease: studies in mice with acute trinitrobenzene sulfonic acid colitis. AB - Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4 (2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option. PMID- 22235148 TI - Prediction of human serotonin and norepinephrine transporter occupancy of duloxetine by pharmacokinetic/pharmacodynamic modeling in the rat. AB - Translation of central nervous system occupancy and clinical effect from animal models to humans has remained elusive for many pharmacological targets. The current studies evaluate the ability of a rodent pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to translate ex vivo occupancy determined in rats to that observed after positron emission tomography (PET) imaging in humans for the dual serotonin transporter (SERT) and norepinephrine transporter (NET) inhibitor duloxetine. Ex vivo transporter occupancy in rat spinal cord was evaluated after single oral doses of 0.3 to 60 mg/kg. A novel methodology, based on the initial rates of association of transporter selective radioligands to tissue homogenates, was developed and validated for the assessment of ex vivo transporter occupancy. Duloxetine exhibited selectivity for occupancy of SERT over NET in rat spinal cord with ED(50) values of 1 and 9 mg/kg, respectively. Corresponding EC(50) values for the inhibition of SERT and NET based on unbound duloxetine spinal cord concentrations were 0.5 and 8 nM. An effect compartment PK/PD modeling approach was used to analyze the relationship between the time course of duloxetine plasma concentration and SERT and NET occupancy. Duloxetine inhibited SERT and NET in rat spinal cord with a plasma EC(50) of 2.95 and 59.0 ng/ml, respectively. Similar plasma EC(50) values for the inhibition of SERT (2.29-3.7 ng/ml) have been reported from human PET studies. This study illustrates the value of translational PK/PD modeling approaches and suggests that the preclinical modeling approach used in the current study is capable of predicting plasma concentrations associated with 50% occupancy of SERT in the human central nervous system. PMID- 22235149 TI - The health and wellbeing of the Pacific indigenous peoples. PMID- 22235146 TI - Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis. AB - Bortezomib (BTZ), a registered proteasome inhibitor (PI) for multiple myeloma, has also been proposed as a potential antirheumatic agent. Its reported side effects, however, make it unappealing for long-term administration, and resistance may also develop. To overcome this, second-generation PIs became available. Here, we investigated whether a novel class of peptide epoxyketone based PIs, including carfilzomib, N-((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1 ((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2 yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (ONX0912), and (S)-3 (4-methoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2 ((S)-2-(2-morpholinoacetamido)propanamido)propanamide (ONX0914), might escape two established BTZ-resistance mechanisms: 1) mutations in the proteasome beta5 subunit (PSMB5) targeted by these PIs, and 2) drug efflux mediated by ATP-binding cassette transporters. THP1 myeloid sublines with acquired resistance to BTZ (54- to 235-fold) caused by mutations in the PSMB5 gene displayed marked cross resistance but less pronounced cross-resistance to carfilzomib (9- to 32-fold), ONX0912 (39- to 62-fold), and ONX0914 (27- to 97-fold). As for ATP-binding cassette transporter-mediated efflux, lymphoid CEM/VLB cells with P-glycoprotein (Pgp)/multidrug resistance 1 overexpression exhibited substantial resistance to carfilzomib (114-fold), ONX0912 (23-fold), and ONX0914 (162-fold), whereas less resistance to BTZ (4.5-fold) was observed. Consistently, beta5 subunit-associated chymotrypsin-like proteasome activity was significantly less inhibited in these CEM/VLB cells. Ex vivo analysis of peripheral blood mononuclear cells from therapy-naive patients with rheumatoid arthritis revealed that, although basal Pgp levels were low, P-glycoprotein expression compromised the inhibitory effect of carfilzomib and ONX0914. However, the use of P121 (reversin 121), a Pgp transport inhibitor, restored parental cell inhibitory levels in both CEM/VLB cells and peripheral blood mononuclear cells. These results indicate that the pharmacologic activity of these PIs may be hindered by drug resistance mechanisms involving PSMB5 mutations and PI extrusion via Pgp. PMID- 22235150 TI - Health care for Micronesians and constitutional rights. AB - Under the Compacts of Free Association (COFA), people from the Freely Associated States--the Republic of Palau (ROP), the Republic of the Marshall Islands (RMI), and the Federated States of Micronesia (FSM)--have been migrating to the United States in increasing numbers. In 1996, Congress passed broad welfare reform (Personal Responsibility and Work Opportunity Reconciliation Act) which limited certain federal benefits previously available to COFA migrants, including Medicaid benefits. Prior to July 2010, the State of Hawai'i had continued to include COFA migrants under its state-funded Medicaid program. In the face of budget constraints, the State removed these people from its Medicaid rolls. A challenge on the legal basis of the denial of equal protection of the laws, ie, the Fourteenth Amendment to the US Constitution, was successful in reinstating health care to the COFA migrants in December 2010. From the health worker's perspective, regardless of various social justice arguments that may have been marshaled in favor of delivering health care to the people, it was an appeal to the judicial system that succeeded. From the attorney's perspective, the legal victories are potentially limited to the four walls of the courtroom without community involvement and related social justice movements. Together, the authors propose that in order to better address the issue of health care access for Micronesian peoples, we must work together, as health and legal advocates, to define a more robust vision of both systems that includes reconciliation and community engagement. PMID- 22235152 TI - An innovative approach to developing a cultural competency curriculum; efforts at the John A. Burns School of Medicine, Department of Native Hawaiian Health. AB - INTRODUCTION: Initial efforts to teach cultural competency at the University of Hawai'i John A. Burns School of Medicine began in the late 1990s through the Native Hawaiian Center of Excellence. With the formation of the Department of Native Hawaiian Health in 2003, cultural competency training was added as a key area of focus for the department. A multidisciplinary team was formed to do the ground work. Physicians (Family Medicine and Internal Medicine) and an administrator (MBA now at Queens Medical Center) from the Department of Native Hawaiian Health were joined by a cultural anthropologist (Department of Family Medicine and Community Health), a social worker (UH Myron B. Thompson School of Social Work), and a retired DrPH/Registered Dietician from the State Department of Health to form the cultural competency curriculum team. All but one of the team members is Native Hawaiian. DISCUSSION: As cultural competency training is a relatively new, rapidly developing field, there is no consensus on how to teach it. The department decided early on to focus on a variety of methodologies using Native Hawaiian health as the curriculum's foundation. Many different paths were taken toward the development of the present curriculum which utilized different components within the medical school's curriculum. This paper describes the process and development of a cultural competency training curriculum at the University of Hawai'i medical school. Recent literature recommendations by experts in the field reinforce the current curricular content that resulted from this developmental process. PMID- 22235151 TI - Social determinants of health for Native Hawaiian children and adolescents. AB - INTRODUCTION: Traditional Hawaiian thought places children in a position of prominence in the family. Yet in Hawai'i, Native Hawaiian children and adolescents face significant inequity in health outcomes. From prenatal alcohol and tobacco use, late or no prenatal care, macrosomia as well as low birth rates, to exclusive breastfeeding rates at 6 months, and high rates of infant mortality, Native Hawaiians face inequities in pre and early childhood indicators. During childhood and adolescence, Native Hawaiians experience high rates of obesity, and physical, mental and sexual abuse. This review examines the determinants behind the health inequities encountered by Native Hawaiian children and adolescents, and contextualizes those inequities s in a human rights-based approach to health. METHODS: A literature review was conducted for relevant research on Native Hawaiian and other indigenous children and adolescents. Existing data sources were also reviewed for relevant Native Hawaiian data. RESULTS: There is a significant dearth of data on the determinants of health for Native Hawaiian children and adolescents. Some prenatal data is available from the Prenatal Risk Assessment Monitoring System, while selected youth data is available from the Youth Behavioral Risk Factor system. Available data show significant inequities for Native Hawaiian children and adolescents, compared to other groups in Hawai'i. Based on comparisons with other indigenous and marginalized peoples, the etiology of these disparities may be a lack of health equity, deriving from multigenerational trauma and discrimination as well as poverty and inequities of housing, education, environment, healthcare access, and social capital. CONCLUSIONS: The significant barriers facing Native Hawaiian children and adolescents achieving their full potential constitute a challenge to the fulfillment of the human right to health. Future research needs to more fully articulate the linkage between the health status of Native Hawaiian children and adolescents, the determinants of that status, and the requirements of the human right to health. Needed particularly are longitudinal studies which provide data that may link multigenerational trauma and discrimination to poverty and other factors, ultimately producing healthy inequity for Native Hawaiian children and adolescents. PMID- 22235153 TI - Recommendations for medical training: a Native Hawaiian patient perspective. AB - BACKGROUND: Culturally competent health care providers are needed to eliminate healthcare disparities. In the State of Hawai'i, Native Hawaiians suffer some of the worst health disparities. Prior to implementing a cultural competency curriculum to address these disparities, the John A. Burns School of Medicine's Department of Native Hawaiian Health Cultural Competency Curriculum Development team asked Native Hawaiian patients about their experiences and recommendations. METHODS: We conducted four focus groups of Native Hawaiians to obtain recommendations on physician training, to be incorporated into the curriculum. Participants came from both rural and urban areas. Classical qualitative analysis of data identified recurrent themes. RESULTS: Five primary themes, arising in all four groups, were: (1) customer service; (2) respect for the patient; (3) inter personal skills; (4) thoroughness of care; and (5) costs of medical care. Secondary themes, occurring in three of the four groups, were: (1) cultural competency training; (2) the training of medical office staff; (3) continuity of care; and (4) the role of the patient. Participants specifically requested that medical students receive cultural competency training about the host culture, its history, values, and traditional and alternative healing practices. DISCUSSION: The emphasis participants placed on the need for cultural competency training of physicians supports the need to address the role of culture in medical education. Although most of the issues raised are not unique to Hawai'i, participants' recommendations to teach students about the host culture and traditional healing practices identify important themes not usually found in medical school curricula. PMID- 22235154 TI - Imi Ho'ola program: producing primary care physicians for Hawai'i and the Pacific. AB - BACKGROUND: The impact on health care delivery due to the impending shortage of primary care physicians is of national concern. To meet the growing health care needs of Hawai'i and the Pacific, the Imi Ho'ala Post-Baccalaureate Program (IHP) provides educational opportunities for students from disadvantaged backgrounds to pursue careers in medicine. Students selected to participate in the IHP have demonstrated a commitment to serve in areas of need of Hawai'i and the Pacific. IHP alumni enter the John A. Burns School of Medicine (JABSOM) as first year medical students. Following graduation, these students enter a variety of residency training programs. PURPOSE: The purpose of this study was to determine whether IHP alumni who successfully graduate from JABSOM choose primary care as their specialty of choice. METHODS: A retrospective review of IHP alumni from 1973 - 2010 was conducted. All IHP alumni who graduated from JABSOM and are currently in practice were included in the study. RESULTS: Of the 213 IHP graduates, 71.6% (n=152) are primary care physicians currently in practice. CONCLUSIONS: The majority of IHP alumni are currently serving as primary care physicians. Selection criteria, educational curriculum, and experiential nature of the program may contribute to Imi Ho'ala's success in producing primary care physicians. PMID- 22235155 TI - Palliative care and traditional practices of death and dying in Wa'ab (Yap Proper) and in the Outer Islands of Yap. AB - BACKGROUND: Death remains one of the most important and significant activities in Yap, an event that involves the entire island. A death of a Yapese not only unites the family, it initiates a complex series of reaffirmed kinship ties, rituals and exchanges that refocus the entire community and create new social identities for the participants. How these ties, exchanges, and identities are changing due to new economic challenges and new social pressures were the focus of this preliminary study, which sought to document the resiliency or fragility of traditional structures, measured in the efforts around death and dying in Yap and to identify ways that the health care system can intervene to improve palliative care. METHODS: 226 persons (49 on Wa'ab--Yap Proper--and 177 on the Outer Islands) participated in 16 focus groups, of which eight were on Wa'ab and eight on four Outer Islands: Fais, Falalop, Fetherai, and Mogmog. We additionally conducted 6 semi-structured open-ended key informant interviews, added to capture more of Yap's enormous sociocultural diversity. RESULTS: The islands of Yap, particularly the Outer Islands, continue to support one of the world's best traditional palliative care involving the immediate family, more distant relatives and in many cases the entire community. However, participants showed considerable concern for ways that this system is weakening and offered numerous suggestions for improving and strengthening palliative care in Yap. DISCUSSION: Although caution must be exercised not to undermine the existing system, six recommendations on how the health system can intervene can be identified. These involve identifying a key resource person on each island; supplying small, practical "comfort care" kits; making more pain medication available; conducting regular home visits; improving patient-physician and physician-family communication; designing a suicide intervention strategy; and documenting existing variations of how the dying are cared for on the other Outer Islands of Yap. PMID- 22235156 TI - Local food policies can help promote local foods and improve health: a case study from the Federated States of Micronesia. AB - The Federated States of Micronesia (FSM) and other countries throughout the Pacific are facing an epidemic of non-communicable disease health problems. These are directly related to the increased consumption of unhealthy imported processed foods, the neglect of traditional food systems, and lifestyle changes, including decreased physical activity. The FSM faces the double burden of malnutrition with both non-communicable diseases and micronutrient deficiencies, including vitamin A deficiency and anemia. To help increase the use of traditional island foods and improve health, the Island Food Community of Pohnpei has initiated a program in the FSM to support and promote local food policies, along with its Go Local awareness campaign. Such local food policies are defined broadly and include individual and family commitments, community group local food policies and policies established by government, including presidential proclamations and increased taxation on soft drinks. The aim of this paper is to describe this work. An inter-agency, community- and research-based, participatory and media approach was used. Partners are both non-governmental and governmental. The use of continuing awareness work along with local food policy establishment and the acknowledgement of the individuals and groups involved are essential. The work is still in the preliminary stage but ad hoc examples show that this approach has had success in increased awareness on health issues and improving dietary intake on both an individual and group basis. This indicates that further use of local food policies could have an instrumental impact in FSM as well as other Pacific Island countries in promoting local foods and improving dietary intake and health, including the control of non-communicable diseases and other dietary related health problems. PMID- 22235157 TI - Needs and experiences of Samoan breast cancer survivors in Southern California. AB - OBJECTIVE: Breast cancer rates are increasing among Samoan and other Pacific Islander women, yet studies of their social support needs are nearly non existent. The purpose of this paper is to report on the cultural dimensions of social support among Samoan breast cancer survivors in Southern California. METHODS: Data for this paper came from a larger one-and-a-half year study of the social support needs of Samoan breast cancer survivors and their family and friends. In-depth, retrospective, qualitative interviews were conducted with a purposeful sample of 20 Samoan survivors who were recruited from an existing social support program as well as the general community. RESULTS: We documented important informational needs and behaviors, social support needs and experiences, and spirituality issues for the Samoan breast cancer survivors. CONCLUSIONS: Our findings underscore the need for culturally-specific social support services for Samoans, as well as the necessity of community-based participatory research to define and explore social support and other survivorship needs in this understudied population. Recommendations from the community report-back, stressed the importance of expanding community Samoan cancer social support groups through collaborations with Samoan leaders and churches. PMID- 22235158 TI - Cancer mortality following polychlorinated biphenyl (PCB) contamination of a Guam village. AB - Beginning more than 10 years after the release of polychlorinated biphenyl (PCB) contamination in the favored fishing grounds of Merizo village, an increase in the proportional cancer mortality rate was observed among residents of the village. This increased rate continued for approximately 20 years after which it returned to near island-wide Guam levels. Although the temporal association between PCB contamination of the environment of this village and an increase in cancer mortality is intriguing, it does not necessarily demonstrate a cause and effect relationship. OBJECTIVE: To investigate a possible temporal relationship between PCB contamination of the Cocos Lagoon and cancer deaths in the adjoining village of Merizo. METHODS: Data utilized in the study included deaths recorded by the Guam Cancer Registry (years 2000 to 2007) and data collected from original death certificates (years 1968-1999). To check whether there was a significant difference in the proportion of deaths due to cancer in Merizo compared with the rest of Guam, deaths were grouped in four 10-year periods, 1968-1977, 1978-1987, 1988-1997, and 1998-2007, and the Pearson Chi-Square test was calculated for each period separately RESULTS: While the number of new cancer cases recorded in the village of Merizo were insufficient in number to draw a statistically significant conclusion when single year incidence rates were compared to the rest of the island, a proportional mortality study showed a distinct increase for the village of Merizo compared to other villages for the period 1978-1997. CONCLUSION: While it is not possible to conclude with certainty that PCB contamination of the Cocos Lagoon was responsible for the observed increase in the proportion of cancer deaths in Merizo village beginning during the 10-year period 1978-1987, that increase and the subsequent decrease as PCB levels also decreased presents the possibility that these trends may be related. PMID- 22235159 TI - Higher percent body fat in young women with lower physical activity level and greater proportion Pacific Islander ancestry. AB - Samoan women exhibit high rates of obesity, which can possibly be attenuated through diet and physical activity. Obesity, and body fatness in particular, is associated with increased risk for chronic diseases. Ancestry, physical activity, and dietary patterns have been associated with body composition. Using a cross sectional design, the relative importance of proportion of Pacific Islander (PI) ancestry, level of physical activity, and macronutrients among healthy women in Honolulu, Hawai'i, ages 18 to 28 years was examined. All data were collected between January 2003 and December 2004. Percent body fat (%BF) was determined by whole body dual energy x-ray absorptiometry (DXA). Nutrient data were derived from a three-day food record. Means and standard deviations were computed for all variables of interest. Bivariate correlation analysis was used to determine correlates of %BF. Multiple regression analysis was used to determine relative contribution of variables significantly associated with %BF. Proportion of PI ancestry was significantly positively associated with %BF (P=0.0001). Physical activity level was significantly negatively associated with %BF (P=0.0006). Intervention to increase physical activity level of young Samoan women may be effective to decrease body fat and improve health. CRC-NIH grant: 0216. PMID- 22235160 TI - An assessment of the Pacific Regional Cancer Coalition: outcomes and implications of a regional coalition internal and external assessment. AB - SIGNIFICANCE: The Pacific Regional Cancer Coalition (PRCC) provides regional leadership in the U.S. Affiliated Pacific Islands (USAPI) to implement the Regional Comprehensive Control Plan: 2007-2012, and to evaluate its coalition and partnerships. The Pacific Center of Excellence in the Elimination of Disparities (CEED), aims to reduce cancer disparities and conducts evaluation activities relevant to cancer prevention and control in the USAPI. PURPOSE: The PRCC Self (internal) and Partner (external) Assessments were conducted to assess coalition functioning, regional and national partnerships, sustainability, and the role of regionalism for integrating all chronic disease prevention and control in the Pacific. METHODS: Self-administered questionnaires and key informant telephone interviews with PRCC members (N=20), and representatives from regional and national partner organizations were administered (N=26). Validated multi item measures using 5-point scales on coalition and partnership characteristics were used. Chronbach's alphas and averages for the measures were computed. RESULTS: Internal coalition measures: satisfaction (4.2, SD=0.48) communication (4.0, SD=0.56), respect (4.0, SD=0.60) were rated more highly than external partnership measures: resource sharing (3.5, SD=0.74), regionalism (3.9, SD=0.47), use of findings (3.9, SD=0.50). The PRCC specifically identified its level of "collaboration" with external partners including Pacific CEED. External partners identified its partnership with the PRCC in the "coalition" stage. PRINCIPAL CONCLUSIONS: PRCC members and external partners are satisfied with their partnerships. All groups should continue to focus on building collaboration with partners to reflect a truly regional approach to sustain the commitment, the coalitions and the programming to reduce cancer in the USAPI. PRCC and partners should also work together to integrate all chronic disease prevention and control efforts in the Pacific. PMID- 22235161 TI - UH Cancer Center Hotline: the training and education program of the University of Guam/University of Hawai'i Cancer Center Partnership. PMID- 22235162 TI - Keeping Track of Panel Members: An Experimental Test of a Between-Wave Contact Strategy. AB - The Panel Study of Income Dynamics (PSID) is a nationally representative longitudinal survey of approximately 9,000 families and their descendants that has been ongoing since 1968. Since 1969, families have been sent a mailing asking them to update or verify their contact information to keep track of their whereabouts between waves. Having updated contact information prior to data collection is associated with fewer call attempts and refusal conversion efforts, less tracking, and lower attrition. Given these apparent advantages, a study was designed in advance of the 2009 PSID field effort to improve the response rate of the contact update mailing. Families were randomly assigned to the following conditions: mailing design (traditional versus new), $10 as a prepaid versus postpaid incentive, timing and frequency of the mailing (July 2008 versus October 2008 versus both times) and whether or not they were sent a study newsletter. This paper reports on findings with regards to response rates to the mailing and the effect on production outcomes including tracking rates and number of calls during 2009 by these different conditions, examines whether the treatment effects differ by key characteristics of panel members including likelihood of moving and anticipated difficulty in completing an interview, and provides some recommendations for the use of contact update strategies in panel studies. PMID- 22235163 TI - Unique Ethical Concerns in Clinical Trials Comparing Psychosocial and Psychopharmalogical Interventions. AB - In recent years, there has been a particular emphasis placed on conducting randomized controlled trials (RCTs) that compare the relative efficacy of psychosocial and pharmacological interventions. This article addresses relevant ethical considerations in the conduct of these treatment trials, with a focus on RCTs with children. Ethical concerns, including therapeutic misconception, treatment preference, therapeutic equipoise, structure of treatments, and balancing risks versus benefits, are introduced through a clinical scenario and discussed as they relate to psychotherapy versus medication RCTs. In each case, suggestions are made for researchers seeking to minimize the impact of these ethical concerns on research participants. PMID- 22235164 TI - Implementation of a Contingency Management-Based Intervention in a Community Supervision Setting: Clinical Issues and Recommendations. AB - A cognitive-behaviorally based substance abuse treatment program was implemented within a Community Supervision setting. This program included a goals group that included a contingency management component and included the probation agent as a part of treatment. This paper describes the contingency management component of the treatment and discusses, in detail, issues that arose throughout the course of the study. Possible causes and solutions to the issues are discussed from a contingency management perspective that can result in improved reinforcements to achieve better probationer outcomes. PMID- 22235166 TI - Soft tissue response to the presence of polypropylene-G-poly(ethylene glycol) comb-type graft copolymers containing gold nanoparticles. AB - The aim of this study is to evaluate the soft tissue response of the pure and Au embedded PPg-PEG. PP-g-PEG2000, PP-g-PEG4000, Au-PP-g-PEG2000, and AuPP-g-PEG4000 were obtained via chlorination of polypropylene and polyethylene glycol in the presence of a base with a "grafting onto" technique. Solvent cast films of these four copolymers with PP as a control group were embedded into five different rats. After 30 days of implantation, microscopic evaluation of inflammation and SEM analysis were done. PP had the most intense inflammatory reaction among the other polymers. PP-PEG block copolymers with high molecular weight and gold nanoparticles-embedded ones revealed mild inflammatory reaction independently. SEM assessment revealed punched hole-like defects on the surface of all polymer samples except for PP. Graft copolymers with PEG, especially Au-attached ones, have favorable soft tissue response, and inflammatory reaction becomes milder as the number of PEG side chains increases. PMID- 22235168 TI - Giant leiomyoma of the gastroesophageal junction: technique and results of endoscopic full-thickness resection. AB - Four consecutive patients with a giant leiomyoma originating from the posterior aspect of the gastroesophageal junction were treated with full-thickness endoscopic retroflex dissection. A complete removal of the lesion was obtained in all cases. No complications were observed except for some degree of air filtration causing symptomatic pneumoperitoneum in one patient. Retroflex endoscopic full-thickness resection of giant leiomyoma at the gastroesophageal junction is feasible and safe. PMID- 22235165 TI - Mycoplasma genitalium: an emerging cause of pelvic inflammatory disease. AB - Mycoplasma genitalium is a sexually transmitted pathogen that is increasingly identified among women with pelvic inflammatory disease (PID). Although Chlamydia trachomatis and Neisseria gonorrhoeae frequently cause PID, up to 70% of cases have an unidentified etiology. This paper summarizes evidence linking M. genitalium to PID and its long-term reproductive sequelae. Several PCR studies have demonstrated that M. genitalium is associated with PID, independent of gonococcal and chlamydial infection. Most have been cross-sectional, although one prospective investigation suggested that M. genitalium was associated with over a thirteenfold risk of endometritis. Further, a nested case-control posttermination study demonstrated a sixfold increased risk of PID among M. genitalium positive patients. Whether or not M. genitalium upper genital tract infection results in long-term reproductive morbidity is unclear, although tubal factor infertility patients have been found to have elevated M. genitalium antibodies. Several lines of evidence suggest that M. genitalium is likely resistant to many frequently used PID treatment regimens. Correspondingly, M. genitalium has been associated with treatment failure following cefoxitin and doxycycline treatment for clinically suspected PID. Collectively, strong evidence suggests that M. genitalium is associated with PID. Further study of M. genitalium upper genital tract infection diagnosis, treatment and long-term sequelae is warranted. PMID- 22235169 TI - Strongyloides stercoralis hyperinfection in a post-renal transplant patient. AB - Strongyloides stercoralis is an intestinal nematode that is able to infect the host tissue and persist asymptomatic for many years through autoinfection. It causes life-threatening hyperinfection in immunocompromised hosts. This report describes a rare case of strongyloidiasis in a 40-year-old male following renal transplant, which was diagnosed by colonoscopic biopsy. The literature on the subject is also reviewed. PMID- 22235167 TI - The role of costimulatory receptors of the tumour necrosis factor receptor family in atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease that is mediated by both the innate and adaptive immune responses. T lymphocytes, that together with B cells are the cellular effectors of the adaptive immune system, are currently endowed with crucial roles in the development and progression of atherosclerosis. Costimulatory receptors are a class of molecules expressed by T lymphocytes that regulate the activation of T cells and the generation of effector T-cell responses. In this review we present the roles of costimulatory receptors of the tumour necrosis factor receptor (TNFR) superfamily in atherosclerosis and discuss the implications for future therapies that could be used to specifically modulate the immune response of pathogenic T cells in this disease. PMID- 22235170 TI - Oral metronidazole as antibiotic prophylaxis for patients with nonperforated appendicitis. AB - BACKGROUND: The rate of wound infection after appendectomy without antibiotic prophylaxis is 10%-30%. The role of prophylactic antibiotic therapy in nonperforated appendicitis is still controversial. Metronidazole is against anaerobic organisms and its bioavailability after oral and parenteral administration has been shown to be similar. The objective of the present study is to compare the infective complications rate after open appendectomy for nonperforated appendicitis receiving either oral or intravenous metronidazole as prophylaxis. METHODS AND MATERIALS: From June 2007 to July 2009 in a randomized controlled trial, 204 patients with nonperforated appendicitis underwent an open appendectomy; 122 male and 82 female with mean age of 25 years. Among these, 102 (case group) received oral metronidazole and in 102 (control group) metronidazole was administered intravenously before surgery. The rate of wound infection and duration of the postoperative hospital stay was studied in the two groups. RESULTS: The rate of wound infection was not significantly different in the two groups. (6% and 4% in study and control group, respectively, P = 0.861). Also the hospital stay was equal in two groups (2.3 days and 2.7 days in study and control group, respectively, P = 0.293). CONCLUSION: Single dose of oral metronidazole prior to operation can provide a sufficient prophylaxis for nonperforated appendicitis; so, it can be substitute the parental route of antibiotic administration. PMID- 22235171 TI - Assessment of quality in screening colonoscopy for colorectal cancer. AB - INTRODUCTION: The effectiveness of screening colonoscopy in decreasing the incidence of colorectal cancer (CRC) is largely dependent on the detection of polyps and the quality of the procedure. Several key quality measures have been proposed to improve the effectiveness of screening colonoscopies. AIM: To evaluate quality indicators of screening colonoscopy in a tertiary hospital. METHODS: All CRC screening colonoscopies performed between 2005 and 2009 in a single tertiary center were reviewed for internationally accepted quality measures. RESULTS: Of the 1545 individuals who underwent first-time screening colonoscopy 38% were male and 62% were female. The mean age of the patients was 60.4 years and the mean difference in ages was +/- 10.3 years. Cecal intubation rate was 91% (1336), however ileocecal valve photo documentation was performed in only 81% (1248) colonoscopies. The quality of bowel preparation was classified as: good 76% (1171), reasonable 11% (174), and poor 13% (200). Polyp detection rate (PDR) was 33% (503). The prevalence of polyps >=1 cm in size was 5% (82). PDR was significantly higher in men than in women (44% [260] vs 25% [243], P = 0.0001). Other factors significantly influencing PDR were quality of bowel preparation (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 0.9-1.6) and age over 50 (OR: 1.9, 95% CI: 1.3-2.9). Left colonic polyps were associated with a risk ratio of 2.3 (95% CI: 1.8-2.9) of lesions in the other colonic segments compared to no polyps in the left colon. None of the colonoscopists reported withdrawal time. CONCLUSION: Cecal intubation rate and quality of bowel preparation were suboptimal. The polyp detection rate compares favorably to accepted standards and its main determinants are male sex, age >50 years, quality of bowel preparation, and the presence of left colonic polyps. PMID- 22235172 TI - Diagnostic indicators for peptic ulcer perforation at a tertiary care hospital in Thailand. AB - INTRODUCTION: Limited data currently exists regarding the diagnostic indicators of peptic ulcer perforation for early detection among patients in Thailand. Delayed diagnosis and treatment for an ulcer can be life-threatening, resulting in shock or death. OBJECTIVE: To determine the diagnostic indicators of peptic ulcer perforation. MATERIAL AND METHODS: A cohort study was conducted in a tertiary care hospital in Thailand from 2005 to 2009. Peptic ulcer patients aged 15 years and over admitted to the surgical department were included. The diagnostic indicators used criteria of the patients' final diagnoses and operations, coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, which included patient profiles, gender, age, coexisting illnesses, personal habits, signs and symptoms, laboratory investigations, radiological finding, and treatment role. Exponential risk regression analyses to obtain relative risk (RR) estimates for diagnostic indicators were analyzed using Stata((r)) statistical software package, version 11 (StataCorp LP, College Station, TX). RESULTS: The study included 1290 patients. Of these, 57% reported perforated peptic ulcer. Multivariate analysis showed five diagnostic indicators: signs and symptoms including intense abdominal pain (RR = 1.53, 95% confidence interval [CI] 1.14-2.06), tenderness (RR = 1.94, 95% CI 1.17-3.21), and guarding (RR = 1.52, 95% CI 1.05-2.20); X-ray with free air (RR = 2.80, 95% CI 2.08-3.77); and referral from other hospitals (RR = 1.37, 95% CI 1.03-1.82). CONCLUSION: Five diagnostic indicators for peptic ulcer perforation monitoring were suggested from this study. Improving diagnostic indicators for medical care may improve the outcome of patients that have perforated peptic ulcer. PMID- 22235173 TI - Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans. AB - BACKGROUND: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans. METHODS: The study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5) was started on Rikkunshito (2.5 g three times daily, orally) from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5). All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin. RESULTS: In the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period. CONCLUSION: Rikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule. PMID- 22235174 TI - Update on celiac disease - etiology, differential diagnosis, drug targets, and management advances. AB - Celiac disease (CD) is an immune-mediated enteropathy triggered by exposure to wheat gluten and similar proteins found in rye and barley that affects genetically susceptible persons. This immune-mediated enteropathy is characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Once thought a disease that largely presented with malnourished children, the wide spectrum of disease activity is now better recognized and this has resulted in a shift in the presenting symptoms of most patients with CD. New advances in testing, both serologic and endoscopic, have dramatically increased the detection and diagnosis of CD. While the gluten-free diet is still the only treatment for CD, recent investigations have explored alternative approaches, including the use of altered nonimmunogenic wheat variants, enzymatic degradation of gluten, tissue transglutaminase inhibitors, induction of tolerance, and peptides to restore integrity to intestinal tight junctions. PMID- 22235175 TI - Some insights into analytical bias involved in the application of grab sampling for volatile organic compounds: a case study against used Tedlar bags. AB - In this study, we have examined the patterns of VOCs released from used Tedlar bags that were once used for the collection under strong source activities. In this way, we attempted to account for the possible bias associated with the repetitive use of Tedlar bags. To this end, we selected the bags that were never heated. All of these target bags were used in ambient temperature (typically at or below 30 degrees C). These bags were also dealt carefully to avoid any mechanical abrasion. This study will provide the essential information regarding the interaction between VOCs and Tedlar bag materials as a potential source of bias in bag sampling approaches. PMID- 22235176 TI - The inflammatory process in response to nanoparticles. PMID- 22235177 TI - Complications of circumcision. AB - In the United States, circumcision is a commonly performed procedure. It is a relatively safe procedure with a low overall complication rate. Most complications are minor and can be managed easily. Though uncommon, complications of circumcision do represent a significant percentage of cases seen by pediatric urologists. Often they require surgical correction that results in a significant cost to the health care system. Severe complications are quite rare, but death has been reported as a result in some cases. A thorough and complete preoperative evaluation, focusing on bleeding history and birth history, is imperative. Proper selection of patients based on age and anatomic considerations as well as proper sterile surgical technique are critical to prevent future circumcision-related adverse events. PMID- 22235178 TI - Measurement of mercury in flue gas based on an aluminum matrix sorbent. AB - The measurement of total mercury in flue gas based on an economical aluminum matrix sorbent was developed in this paper. A sorbent trap consisted of three tubes was employed to capture Hg from flue gas. Hg trapped on sorbent was transferred into solution by acid leaching and then detected by CVAAS. Hg adsorbed on sorbent was recovered completely by leaching process. The 87.7% recovery of Hg in flue gas by tube 1 and tube 2 was obtained on the equipment of coal combustion and sampling in lab. In order to evaluate the ability to recover and accurately quantify Hg(0) on the sorbent media, the analytical bias test on tube 3 spiked with Hg(0) was also performed and got the average recovery of 97.1%. Mercury measurements based on this method were conducted for three coal fired power plants in China. The mercury in coal is distributed into bottom ash, electrostatic precipitator (ESP) ash, wet flue gas desulfurization (WFGD) reactant, and flue gas, and the relative distribution varied depending on factors such as the coal type and the operation conditions of plants. The mercury mass balances of three plants were also calculated which were 91.6%, 77.1%, and 118%, respectively. The reliability of this method was verified by the Ontario Hydro (OH) method either in lab or in field. PMID- 22235179 TI - In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis. AB - We recently reported that after LPS stimulation, IL-37 translocates to the nucleus and reduces the expression of proinflammatory cytokines. The aim of this study was to investigate whether transiently expressed IL-37 in mice reduces inflammation in concanavalin A (ConA)-induced hepatitis and LPS-induced sepsis. Transgene IL-37 expression was detected in the liver lysate of mice injected with IL-37 plasmid-DNA after hydrodynamic tail vein injection. All mice developed severe acute hepatitis after ConA injection. No difference in the histological score and serum ALT was observed between the two groups that might be explained by patchy expression of IL-37 protein in the liver. However, 2 hrs after ConA injection, serum levels for IL-1alpha, IL-6, IL-5, and IL-9 were significantly reduced in IL-37-expressing mice as seen for the LPS model. In conclusion, in vivo expression of human IL-37 in mice reduces local and systemic inflammation in ConA-induced hepatitis and LPS challenge. PMID- 22235181 TI - Cytokines: pulling the body together as a whole. PMID- 22235180 TI - Midkine in inflammation. AB - The 13 kDa heparin-binding growth factor midkine (MK) was originally identified as a molecule involved in the orchestration of embryonic development. Recent studies provided evidence for a new role of MK in acute and chronic inflammatory processes. Accordingly, several inflammatory diseases including nephritis, arthritis, atherosclerosis, colitis, and autoimmune encephalitis have been shown to be alleviated in the absence of MK in animal models. Reduced leukocyte recruitment to the sites of inflammation was found to be one important mechanism attenuating chronic inflammation when MK was absent. Furthermore, MK was found to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells. Here, we review the current understanding of the role of MK in different inflammatory disorders and summarize the knowledge of MK biology. PMID- 22235183 TI - Advances in nephelometry through the Ecotech Aurora nephelometer. AB - The challenge for instrument manufacturers is to continuously improve and evolve their instrumentation to keep pace with scientific research. One field where this is evident is atmospheric aerosol research. The variety in aerosol size, shape, chemical composition, and their ability to change properties under varying atmospheric conditions creates many challenges in quantifying their impact on the global energy balance. As such a wide variety of instrumentation from a selection of manufacturers are used for analysing aerosols, all of which provide a little extra information for deciphering the puzzle. Recent advancements in commercial nephelometers by Australian manufacturer Ecotech have helped to piece some more of this puzzle together. This paper will detail these advances. PMID- 22235182 TI - Macrophages, meta-inflammation, and immuno-metabolism. AB - Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes. PMID- 22235185 TI - Emerging endoscopic and photodynamic techniques for bladder cancer detection and surveillance. AB - This review provides an overview of emerging techniques, namely, photodynamic diagnosis (PDD), narrow band imaging (NBI), Raman spectroscopy, optical coherence tomography, virtual cystoscopy, and endoscopic microscopy for its use in the diagnosis and surveillance of bladder cancer. The technology, clinical evidence and future applications of these approaches are discussed with particular emphasis on PDD and NBI. These approaches show promise to optimise cystoscopy and transurethral resection of bladder tumours. PMID- 22235184 TI - Spatial variability and application of ratios between BTEX in two Canadian cities. AB - Spatial monitoring campaigns of volatile organic compounds were carried out in two similarly sized urban industrial cities, Windsor and Sarnia, ON, Canada. For Windsor, data were obtained for all four seasons at approximately 50 sites in each season (winter, spring, summer, and fall) over a three-year period (2004, 2005, and 2006) for a total of 12 sampling sessions. Sampling in Sarnia took place at 37 monitoring sites in fall 2005. In both cities, passive sampling was done using 3M 3500 organic vapor samplers. This paper characterizes benzene, toluene, ethylbenzene, o, and (m + p)-xylene (BTEX) concentrations and relationships among BTEX species in the two cities during the fall sampling periods. BTEX concentration levels and rank order among the species were similar between the two cities. In Sarnia, the relationships between the BTEX species varied depending on location. Correlation analysis between land use and concentration ratios showed a strong influence from local industries. Use one of the ratios between the BTEX species to diagnose photochemical age may be biased due to point source emissions, for example, 53 tonnes of benzene and 86 tonnes of toluene in Sarnia. However, considering multiple ratios leads to better conclusions regarding photochemical aging. Ratios obtained in the sampling campaigns showed significant deviation from those obtained at central monitoring stations, with less difference in the (m + p)/E ratio but better overall agreement in Windsor than in Sarnia. PMID- 22235186 TI - Inconspicuous penis. AB - Inconspicous penis refers to a constellation of conditions that make the penis look diminutive and small. This could be secondary to short penile shaft often termed as micropenis. But more commonly, this inconspicuous appearance is secondary to other causes ranging from congenital conditions such as penoscrotal webbing or megaprepuce, developmental conditions like prepubic adiposity that overhang the penis, and iatrogenic causes like trapped penis after adhesions secondary to circumcision. In this paper, we propose to define these entities and provide their descriptions and then to describe their management including surgical correction. PMID- 22235187 TI - Bladder cancer. PMID- 22235188 TI - Tissue engineering of the penis. AB - Congenital disorders, cancer, trauma, or other conditions of the genitourinary tract can lead to significant organ damage or loss of function, necessitating eventual reconstruction or replacement of the damaged structures. However, current reconstructive techniques are limited by issues of tissue availability and compatibility. Physicians and scientists have begun to explore tissue engineering and regenerative medicine strategies for repair and reconstruction of the genitourinary tract. Tissue engineering allows the development of biological substitutes which could potentially restore normal function. Tissue engineering efforts designed to treat or replace most organs are currently being undertaken. Most of these efforts have occurred within the past decade. However, before these engineering techniques can be applied to humans, further studies are needed to ensure the safety and efficacy of these new materials. Recent progress suggests that engineered urologic tissues and cell therapy may soon have clinical applicability. PMID- 22235189 TI - Alternative splicing of RNA triplets is often regulated and accelerates proteome evolution. AB - Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3' splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that NAGNAG splicing is purely stochastic and nonfunctional. Here, we used deep RNA-Seq data from 16 human and eight mouse tissues to analyze the regulation and evolution of NAGNAG splicing. Using both biological and technical replicates to estimate false discovery rates, we estimate that at least 25% of alternatively spliced NAGNAGs undergo tissue-specific regulation in mammals, and alternative splicing of strongly tissue-specific NAGNAGs was 10 times as likely to be conserved between species as was splicing of non-tissue-specific events, implying selective maintenance. Preferential use of the distal NAG was associated with distinct sequence features, including a more distal location of the branch point and presence of a pyrimidine immediately before the first NAG, and alteration of these features in a splicing reporter shifted splicing away from the distal site. Strikingly, alignments of orthologous exons revealed a ~15-fold increase in the frequency of three base pair gaps at 3' splice sites relative to nearby exon positions in both mammals and in Drosophila. Alternative splicing of NAGNAGs in human was associated with dramatically increased frequency of exon length changes at orthologous exon boundaries in rodents, and a model involving point mutations that create, destroy, or alter NAGNAGs can explain both the increased frequency and biased codon composition of gained/lost sequence observed at the beginnings of exons. This study shows that NAGNAG alternative splicing generates widespread differences between the proteomes of mammalian tissues, and suggests that the evolutionary trajectories of mammalian proteins are strongly biased by the locations and phases of the introns that interrupt coding sequences. PMID- 22235190 TI - Role of pleiotropy in the evolution of a cryptic developmental variation in Caenorhabditis elegans. AB - Robust biological systems are expected to accumulate cryptic genetic variation that does not affect the system output in standard conditions yet may play an evolutionary role once phenotypically expressed under a strong perturbation. Genetic variation that is cryptic relative to a robust trait may accumulate neutrally as it does not change the phenotype, yet it could also evolve under selection if it affects traits related to fitness in addition to its cryptic effect. Cryptic variation affecting the vulval intercellular signaling network was previously uncovered among wild isolates of Caenorhabditis elegans. Using a quantitative genetic approach, we identify a non-synonymous polymorphism of the previously uncharacterized nath-10 gene that affects the vulval phenotype when the system is sensitized with different mutations, but not in wild-type strains. nath-10 is an essential protein acetyltransferase gene and the homolog of human NAT10. The nath-10 polymorphism also presents non-cryptic effects on life history traits. The nath-10 allele carried by the N2 reference strain leads to a subtle increase in the egg laying rate and in the total number of sperm, a trait affecting the trade-off between fertility and minimal generation time in hermaphrodite individuals. We show that this allele appeared during early laboratory culture of N2, which allowed us to test whether it may have evolved under selection in this novel environment. The derived allele indeed strongly outcompetes the ancestral allele in laboratory conditions. In conclusion, we identified the molecular nature of a cryptic genetic variation and characterized its evolutionary history. These results show that cryptic genetic variation does not necessarily accumulate neutrally at the whole-organism level, but may evolve through selection for pleiotropic effects that alter fitness. In addition, cultivation in the laboratory has led to adaptive evolution of the reference strain N2 to the laboratory environment, which may modify other phenotypes of interest. PMID- 22235192 TI - Antarctic marine biodiversity and deep-sea hydrothermal vents. AB - The diversity of many marine benthic groups is unlike that of most other taxa. Rather than declining from the tropics to the poles, much of the benthos shows high diversity in the Southern Ocean. Moreover, many species are unique to the Antarctic region. Recent work has shown that this is also true of the communities of Antarctic deep-sea hydrothermal vents. Vent ecosystems have been documented from many sites across the globe, associated with the thermally and chemically variable habitats found around these, typically high temperature, streams that are rich in reduced compounds and polymetallic sulphides. The animal communities of the East Scotia Ridge vent ecosystems are very different to those elsewhere, though the microbiota, which form the basis of vent food webs, show less differentiation. Much of the biological significance of deep-sea hydrothermal vents lies in their biodiversity, the diverse biochemistry of their bacteria, the remarkable symbioses among many of the marine animals and these bacteria, and the prospects that investigations of these systems hold for understanding the conditions that may have led to the first appearance of life. The discovery of diverse and unusual Antarctic hydrothermal vent ecosystems provides opportunities for new understanding in these fields. Moreover, the Antarctic vents south of 60 degrees S benefit from automatic conservation under the Convention on the Conservation of Antarctic Marine Living Resources and the Antarctic Treaty. Other deep-sea hydrothermal vents located in international waters are not protected and may be threatened by growing interests in deep-sea mining. PMID- 22235193 TI - Opening up the politics of knowledge and power in bioscience. AB - Public engagement is not in tension with science, but actually a way to be more rigorous - as well as more democratic - about social choice of biotechnology. PMID- 22235191 TI - Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. AB - A large proportion of age-related hearing loss is caused by loss or damage to outer hair cells in the organ of Corti. The organ of Corti is the mechanosensory transducing apparatus in the inner ear and is composed of inner hair cells, outer hair cells, and highly specialized supporting cells. The mechanisms that regulate differentiation of inner and outer hair cells are not known. Here we report that fibroblast growth factor 20 (FGF20) is required for differentiation of cells in the lateral cochlear compartment (outer hair and supporting cells) within the organ of Corti during a specific developmental time. In the absence of FGF20, mice are deaf and lateral compartment cells remain undifferentiated, postmitotic, and unresponsive to Notch-dependent lateral inhibition. These studies identify developmentally distinct medial (inner hair and supporting cells) and lateral compartments in the developing organ of Corti. The viability and hearing loss in Fgf20 knockout mice suggest that FGF20 may also be a deafness-associated gene in humans. PMID- 22235195 TI - DNA Interaction and DNA Cleavage Studies of a New Platinum(II) Complex Containing Aliphatic and Aromatic Dinitrogen Ligands. AB - A new Pt(II) complex, [Pt(DIP)(LL)](NO(3))(2) (in which DIP is 4,7-diphenyl-1,10 phenanthroline and LL is the aliphatic dinitrogen ligand, N,N-dimethyl trimethylenediamine), was synthesized and characterized using different physico chemical methods. The interaction of this complex with calf thymus DNA (CT-DNA) was investigated by absorption, emission, circular dichroism (CD), and viscosity measurements. The complex binds to CT-DNA in an intercalative mode. The calculated binding constant, K(b), was 6.6 * 10(4) M(-1). The enthalpy and entropy changes of the reaction between the complex and CT-DNA showed that the van der Waals interactions and hydrogen bonds are the main forces in the interaction with CT-DNA. In addition, CD study showed that phenanthroline ligand insert between the base pair stack of double helical structure of DNA. It is remarkable that this complex has the ability to cleave the supercoiled plasmid. PMID- 22235196 TI - Triple-tube-ostomy: a novel technique for the surgical treatment of iatrogenic duodenal perforation. AB - Although duodenal perforation is currently an infrequent complication of medical procedures, its incidence in the future predictably will increase as endoscopic treatment of duodenal neoplasms becomes more frequently used. In some cases, duodenal perforation is difficult to treat even surgically. We report here a novel technique called 'triple-tube-ostomy' for the treatment of iatrogenic duodenal perforation. Since November 2009, there have been three cases of iatrogenic perforation of the duodenum, due to various causes, which we have treated with our novel technique. The main principles of the technique are biliary diversion, decompression of the duodenum, and early enteral nutrition. All patients who underwent the triple-tube-ostomy procedure had good postoperative courses, with few complications. The novel surgical technique we describe in this report is safe, reliable, easy to learn and perform, and led to a good postoperative course in all cases where we performed it. PMID- 22235194 TI - The discovery of new deep-sea hydrothermal vent communities in the southern ocean and implications for biogeography. AB - Since the first discovery of deep-sea hydrothermal vents along the Galapagos Rift in 1977, numerous vent sites and endemic faunal assemblages have been found along mid-ocean ridges and back-arc basins at low to mid latitudes. These discoveries have suggested the existence of separate biogeographic provinces in the Atlantic and the North West Pacific, the existence of a province including the South West Pacific and Indian Ocean, and a separation of the North East Pacific, North East Pacific Rise, and South East Pacific Rise. The Southern Ocean is known to be a region of high deep-sea species diversity and centre of origin for the global deep-sea fauna. It has also been proposed as a gateway connecting hydrothermal vents in different oceans but is little explored because of extreme conditions. Since 2009 we have explored two segments of the East Scotia Ridge (ESR) in the Southern Ocean using a remotely operated vehicle. In each segment we located deep sea hydrothermal vents hosting high-temperature black smokers up to 382.8 degrees C and diffuse venting. The chemosynthetic ecosystems hosted by these vents are dominated by a new yeti crab (Kiwa n. sp.), stalked barnacles, limpets, peltospiroid gastropods, anemones, and a predatory sea star. Taxa abundant in vent ecosystems in other oceans, including polychaete worms (Siboglinidae), bathymodiolid mussels, and alvinocaridid shrimps, are absent from the ESR vents. These groups, except the Siboglinidae, possess planktotrophic larvae, rare in Antarctic marine invertebrates, suggesting that the environmental conditions of the Southern Ocean may act as a dispersal filter for vent taxa. Evidence from the distinctive fauna, the unique community structure, and multivariate analyses suggest that the Antarctic vent ecosystems represent a new vent biogeographic province. However, multivariate analyses of species present at the ESR and at other deep-sea hydrothermal vents globally indicate that vent biogeography is more complex than previously recognised. PMID- 22235197 TI - Nonlinear elasto-mammography for characterization of breast tissue properties. AB - Quantification of the mechanical behavior of normal and cancerous tissues has important implication in the diagnosis of breast tumor. The present work extends the authors' nonlinear elastography framework to incorporate the conventional X ray mammography, where the projection of displacement information is acquired instead of full three-dimensional (3D) vector. The elastic parameters of normal and cancerous breast tissues are identified by minimizing the difference between the measurement and the corresponding computational prediction. An adjoint method is derived to calculate the gradient of the objective function. Simulations are conducted on a 3D breast phantom consisting of the fatty tissue, glandular tissue, and cancerous tumor, whose mechanical responses are hyperelastic in nature. The material parameters are identified with consideration of measurement error. The results demonstrate that the projective displacements acquired in X ray mammography provide sufficient constitutive information of the tumor and prove the usability and robustness of the proposed method and algorithm. PMID- 22235198 TI - Role of mindin in diabetic nephropathy. AB - A number of studies have shown that proinflammatory cytokines have important roles in determining the development of microvascular diabetic complications, including nephropathy. Inflammatory biomarkers should be useful for diagnosis or monitoring of diabetic nephropathy. Mindin (spondin 2) is a member of the mindin /F-spondin family of secreted extracellular matrix (ECM) proteins. Recent studies showed that mindin is essential for initiation of innate immune response and represents a unique pattern-recognition molecule in the ECM. Previously, we demonstrated that the levels of urinary mindin in patients with type 2 diabetes were higher than those in healthy individuals. We propose that urinary mindin is a potent biomarker for the development of diabetic nephropathy. PMID- 22235200 TI - Antinociceptive and Anti-Inflammatory Activities of Leaf Methanol Extract of Cotyledon orbiculata L. (Crassulaceae). AB - Leaf methanol extract of C. orbiculata L. was investigated for antinociceptive and anti-inflammatory activities using acetic acid writhing and hot-plate tests and carrageenan-induced oedema test in mice and rats, respectively. C. orbiculata (100-400 mg/kg, i.p.) significantly inhibited acetic acid-induced writhing and significantly delayed the reaction time of mice to the hot-plate-induced thermal stimulation. Paracetamol (300 mg/kg, i.p.) significantly inhibited the acetic acid-induced writhing in mice. Morphine (10 mg/kg, i.p.) significantly delayed the reaction time of mice to the thermal stimulation produced with hot plate. Leaf methanol extract of C. orbiculata (50-400 mg/kg, i.p.) significantly attenuated the carrageenan-induced rat paw oedema. Indomethacin (10 mg/kg, p.o.) also significantly attenuated the carrageenan-induced rat paw oedema. The LD(50) value obtained for the plant species was greater than 4000 mg/kg (p.o.). The data obtained indicate that C. orbiculata has antinociceptive and anti-inflammatory activities, justifying the folklore use of the plant species by traditional medicine practitioners in the treatment of painful and inflammatory conditions. The relatively high LD(50) obtained shows that C. orbiculata may be safe in or nontoxic to mice. PMID- 22235199 TI - Capsule endoscopy in celiac disease. AB - Capsule endoscopy (CE) has been increasingly used for diagnosing disease of the small bowel. It is an attractive technique for assessing celiac disease (CD) because it is noninvasive and provides a close and magnified view of the mucosa of the entire small bowel. The aim of this paper is to update the current data on the use of CE for diagnosing villous atrophy and complications of CD. PMID- 22235201 TI - The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. AB - Despite the discovery of 5 alpha-reduction as an enzymatic step in steroid metabolism in 1951, and the discovery that dihydrotestosterone is more potent than testosterone in 1968, the significance of 5 alpha-reduced steroids in human diseases was not appreciated until the discovery of 5 alpha-reductase type 2 deficiency in 1974. Affected males are born with ambiguous external genitalia, despite normal internal genitalia. The prostate is hypoplastic, nonpalpable on rectal examination and approximately 1/10th the size of age-matched normal glands. Benign prostate hyperplasia or prostate cancer does not develop in these patients. At puberty, the external genitalia virilize partially, however, secondary sexual hair remains sparse and male pattern baldness and acne develop rarely. Several compounds have been developed to inhibit the 5 alpha-reductase isozymes and they play an important role in the prevention and treatment of many common diseases. This review describes the basic biochemical properties, functions, tissue distribution, chromosomal location, and clinical significance of the 5 alpha-reductase isozyme family. PMID- 22235202 TI - Androgens and adipose tissue in males: a complex and reciprocal interplay. AB - Clinical evidence shows that in males obesity is frequently associated with hypogonadism and vice versa; also, low testosterone levels have been considered a "hallmark" of metabolic syndrome in men. These observations indicate that there is a strict connection between anatomically and functionally distinct cell types such as white adipocytes and Leydig cells, that synthesize testosterone. Adipose tissue is able to control several functions of the testis through its products secreted in the bloodstream. On the other hand, circulating levels of testosterone and estradiol deeply affect adipocyte proliferation, differentiation, and fat mass distribution, hereby controlling critical metabolic functions, such as food intake, insulin sensitivity, vascular reactivity, and immunity. This paper highlights the existing clinical and experimental evidence linking androgens and adipose tissue and illustrates the consequences occurring when the balance between fat mass distribution and eugonadism is lost. PMID- 22235203 TI - Ovarian cancer: opportunity for targeted therapy. AB - Ovarian cancer is a common cause of cancer mortality in women with limited treatment effectiveness in advanced stages. The limitation to treatment is largely the result of high rates of cancer recurrence despite chemotherapy and eventual resistance to existing chemotherapeutic agents. The objective of this paper is to review current concepts of ovarian carcinogenesis. We will review existing hypotheses of tumor origin from ovarian epithelial cells, Fallopian tube, and endometrium. We will also review the molecular pathogenesis of ovarian cancer which results in two specific pathways of carcinogenesis: (1) type I low grade tumor and (2) type II high-grade tumor. Improved understanding of the molecular basis of ovarian carcinogenesis has opened new opportunities for targeted therapy. This paper will also review these potential therapeutic targets and will explore new agents that are currently being investigated. PMID- 22235204 TI - Towards a "Sample-In, Answer-Out" Point-of-Care Platform for Nucleic Acid Extraction and Amplification: Using an HPV E6/E7 mRNA Model System. AB - The paper presents the development of a "proof-of-principle" hands-free and self contained diagnostic platform for detection of human papillomavirus (HPV) E6/E7 mRNA in clinical specimens. The automated platform performs chip-based sample preconcentration, nucleic acid extraction, amplification, and real-time fluorescent detection with minimal user interfacing. It consists of two modular prototypes, one for sample preparation and one for amplification and detection; however, a common interface is available to facilitate later integration into one single module. Nucleic acid extracts (n = 28) from cervical cytology specimens extracted on the sample preparation chip were tested using the PreTect HPV Proofer and achieved an overall detection rate for HPV across all dilutions of 50%-85.7%. A subset of 6 clinical samples extracted on the sample preparation chip module was chosen for complete validation on the NASBA chip module. For 4 of the samples, a 100% amplification for HPV 16 or 33 was obtained at the 1 : 10 dilution for microfluidic channels that filled correctly. The modules of a "sample-in, answer-out" diagnostic platform have been demonstrated from clinical sample input through sample preparation, amplification and final detection. PMID- 22235205 TI - Integrin inhibitors as a therapeutic agent for ovarian cancer. AB - Ovarian cancer is a deadly disease, with a cure rate of only 30%. Despite aggressive treatments, relapse remains almost inevitable in patients with advanced-stage disease. In recent years, great progress has been made towards targeting integrins in cancer treatment, and clinical studies with various integrin inhibitors have demonstrated their effectiveness in blocking cancer progression. Given that the initial critical step of ovarian cancer metastasis is the attachment of cancer cells onto the peritoneum or omentum, in addition to the proven positive clinical results of anti-angiogenic therapy, targeting integrins is likely to be one of the most feasible approaches. This paper summarizes the current understanding of the integrin biology in ovarian cancer metastasis and the various therapeutic approaches attempted with integrin inhibitors. Although no integrin inhibitors have shown favorable results so far, integrin-targeted therapies continue to be a promising approach to be explored for further clinical investigation. PMID- 22235207 TI - Piperacillin-induced immune hemolysis presenting with tachycardia and cardiac arrest. AB - A 20-year-old nonverbal patient with profound developmental disabilities was treated with intravenous piperacillin-tazobactam for respiratory infection. After 8 days, he became afebrile with normal pulmonary status, but his pulse remained inexplicably rapid (114/minute). Investigations revealed severe normochromic normocytic hemolytic anemia (hemoglobin: 40 g/L, reticulocytes: 9.4%, nucleated erythrocytes: 5%). While being hospitalized, patient experienced sudden cardiac arrest from which he was successfully resuscitated. He had no blood loss or intrinsic heart disease to explain the acute anemia or cardiac arrest. He had uneventfully received piperacillin-tazobactam on 7 occasions during the preceding 5 years for >50 days. Patient was treated with intravenous crystalloids, methylprednisolone and transfusion of 3 units of packed erythrocytes. Piperacillin-tazobactam was discontinued. A direct antiglobulin test was positive for immunoglobulin G and complement. Antibody to piperacillin was detected in patient's serum by the "immune-complex" method confirming "piperacillin-induced immune hemolytic anemia (PIHA)". On discharge (day 15), patient's hemoglobin improved to 115 g/L (baseline: 131 g/L). Vigilant clinical and hematological monitoring for anemia is indicated in piperacillin-treated patients, particularly in those unable to verbalize their discomfort. Repeated piperacillin exposure may sensitize and predispose patients to PIHA. PMID- 22235208 TI - Yaws in the Western pacific region: a review of the literature. AB - Until the middle of the 20th century, yaws was highly endemic and considered a serious public health problem in the Western Pacific Region (WPR), leading to intensive control efforts in the 1950s-1960s. Since then, little attention has been paid to its reemergence. Its current burden is unknown. This paper presents the results of an extensive literature review, focusing on yaws in the South Pacific. Available records suggest that the region remains largely free of yaws except for Papua New Guinea, Solomon Islands, and Vanuatu. Many clinical cases reported recently were described as "attenuated"; advanced stages are rare. A single intramuscular injection of benzathine penicillin is still effective in curing yaws. In the Pacific, yaws may be amenable to elimination if adequate resources are provided and political commitment revived. A mapping of yaws prevalence in PNG, Solomon, and Vanuatu is needed before comprehensive country tailored strategies towards yaws elimination can be developed. PMID- 22235206 TI - Hosting infection: experimental models to assay Candida virulence. AB - Although normally commensals in humans, Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Candida krusei are capable of causing opportunistic infections in individuals with altered physiological and/or immunological responses. These fungal species are linked with a variety of infections, including oral, vaginal, gastrointestinal, and systemic infections, with C. albicans the major cause of infection. To assess the ability of different Candida species and strains to cause infection and disease requires the use of experimental infection models. This paper discusses the mucosal and systemic models of infection available to assay Candida virulence and gives examples of some of the knowledge that has been gained to date from these models. PMID- 22235209 TI - Neonatal stridor. AB - Neonatal stridor is an important condition, in many cases implying an impending disaster with a very compromised airway. It is a sign that has to be considered with the rest of the history and examination findings, and appropriate investigations should then be undertaken to confirm the source of the noise. Neonates with stridor should be managed in a multidisciplinary setting, by clinicians familiar with the intricate physiology of these children, and with access to the multitude of medical and surgical investigative and therapeutic options required to provide first-rate care. PMID- 22235211 TI - Noninvasive evaluation of liver fibrosis in patients with chronic hepatitis C. PMID- 22235212 TI - Treatment of chronic delta hepatitis. PMID- 22235210 TI - Mercury toxicity and treatment: a review of the literature. AB - Mercury is a toxic heavy metal which is widely dispersed in nature. Most human exposure results from fish consumption or dental amalgam. Mercury occurs in several chemical forms, with complex pharmacokinetics. Mercury is capable of inducing a wide range of clinical presentations. Diagnosis of mercury toxicity can be challenging but can be obtained with reasonable reliability. Effective therapies for clinical toxicity have been described. PMID- 22235213 TI - Post-transfusion occult hepatitis B (OBI): a global challenge for blood recipients and health authorities. AB - Hepatitis B is one of the most frequent post-transfusion infections. Occult hepatitis B infection (OBI) is a form of hepatitis B infection in which, despite the presence of HBV-DNA in the serum and hepatocytes of the carrier, HBsAg is absent. In addition to the risk of transmission through the transfusion of infected blood, reactivation of hepatitis B in OBI patients and recipients of their blood can lead to cirrhosis, hepatic cancer, and reactivation of viral replication in the carrier. Therefore, effective assays to assess and screen for OBI in blood donors are of paramount importance and require urgent attention. Recently, several investigations in various regions of Iran have reported OBI in blood donors. In response, there has been a drive to apply more specific, sensitive, and accurate methods for the detection of HBV, which should become an obligatory screening process for all blood transfusion services. In this review, we address the progression of occult hepatitis B and the common problems associated with occult hepatitis B worldwide. Finally, we reflect on the research and screening that is being performed in Iran to deal with this problem. PMID- 22235214 TI - Possible down regulation of the p16 gene promoter in individuals with hepatocellular carcinoma. AB - BACKGROUND: The p16 tumor suppressor gene is an important negative regulator of the cell cycle. Inactivation of p16, especially via promoter hypermethylation, has been found in numerous human cancers such as breast, lung, colorectal, and liver. OBJECTIVES: To determine the role of epigenetic methylation in p16 regulation in Iranian patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The methylation pattern in the p16 gene promoter was analyzed by bisulfite direct sequencing in 43 paraffin-embedded formalin-fixed tissues from patients with HCC. In addition, normal specimens from liver graft donors were used as the control group. RESULTS: The bisulfite direct sequencing showed heterozygous hypermethylation in 13.9% of individuals with HCC. Homozygous methylation within the GC-box IV was detected in another 58.1% of the patients. CONCLUSIONS: It is proposed that methylation, but not necessarily hypermethylation, may play a role in the down-regulation of the p16 gene promoter at least in some Iranian patients with HCC. PMID- 22235215 TI - Examination of the activity of camel milk casein against hepatitis C virus (genotype-4a) and its apoptotic potential in hepatoma and hela cell lines. AB - BACKGROUND: Hepatitis C is a global health concern that represents a major cause of liver disease and socioeconomic burden. Currently, there is no vaccine that protects against this infection or drug that treats it effectively. The current treatment for hepatitis C virus (HCV) infection does not produce a sustained virologic response. Therefore,discovery and identification of a new drug for HCV treatment is a high priority.Camel milk is a traditional medicine that could improve the control of HCV. OBJECTIVES: To assess the potential effect of casein purified from camel milk on HCV cellular infectivity in a tissue culture model. MATERIALS AND METHODS: Casein was purified from defatted camel milk to electrophoretic homogeneity. PBMCs and HepG2 and HeLa cell lines were used. Three kinds of experiments were conducted. HCV was directly interacted with casein and then mixed with different cell types, casein was incubated with the cells and then exposed to HCV, and the HCV pre-infected cells were treated with casein at different concentrations and time intervals. Non-infected cells were used to assess cytotoxicity and the apoptosis effect of casein. RESULTS: Direct interaction of casein (with or without alpha-lactalbumin) with neither the virus nor the cells prevented HCV cell entry. However, casein with alpha-lactalbumin induced a cytotoxic effect in HepG2 and HeLa cell lines but not in human naive leukocytes. At all concentrations tested, casein with alpha-lactalbumin could induce apoptosis in both infected and non-infected HepG2 cells. CONCLUSIONS: Camel milk casein (with or without alpha-lactalbumin) did not demonstrate any anti-HCV activity. However, the cellular apoptotic cascade was initiated in HepG2 and HeLa cells treated with casein (with alpha-lactalbumin) but not in naive leukocytes. PMID- 22235216 TI - Treatment of chronic delta hepatitis: a nine-year retrospective analysis. AB - BACKGROUND: Chronic delta hepatitis is the most severe form of viral hepatitis, for which interferon administration is the only available treatment. However, the efficacy of interferon treatment is affected by the dose and duration of treatment, and relapse rates are high. OBJECTIVES: In this study, we sought to evaluate the efficacy of treatment with pegylated interferon and observe the relapse rates of delta hepatitis after treatment. PATIENTS AND METHODS: Forty-six patients with chronic delta hepatitis were retrospectively studied between January 2002 and December 2010. Patients were evaluated for biochemical, virological, and histological responses. They were then followed-up for at least 1 year after discontinuation of the treatment. RESULTS: All the 46 patients in the study received PEG-IFN therapy. Of the 46 patients,25 were treated with PEG IFN for 1 year and 21 were treated for 2 years. Sixteen patients(34.7%) showed a biochemical response, 27 (58.6%) showed a virological response, and 39 (84.7%) showed a histological response. Sustained virological and biochemical responseswere achieved in 41% and 47.8% of the patients, respectively. Sixteen (84.2%) patients of the 19 with high levels of hepatitis delta virus RNA (HDV RNA) (HDV RNAlevel > 1 * 105) and 10 (71.4%) of the 14 patients with high titers of hepatitis B surface antigen(HbsAg) (HbsAg > 102 IU/mL) at the beginning of the treatment showed relapse after treatment. CONCLUSIONS: We found no significant differences between 1-year and 2-year treatments.However, the relapse rate was lower in the 2-year treatment group. Higher HDV RNA and HbsAg levels before treatment were associated with higher relapse rates. Younger age was a significant factor in predicting response. PMID- 22235217 TI - Hepatitis C and hepatitis B virus infection: epidemiology and risk factors in a large cohort of pregnant women in Lorestan, West of Iran. AB - BACKGROUND: There are little data on the prevalence of serological markers of hepatitis B and hepatitis C viruses in pregnant women in Iran. OBJECTIVES: This study was designed to determine the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among pregnant women in Lorestan, west of Iran. PATIENTS AND METHODS: Serum samples of 827 pregnant women who lived in rural (36.8%) and urban areas (63.2%) of Lorestan were collected during 2007-2008. Data were obtained through questionnaires. Samples were first screened for anti-HCV and anti-HBc by ELISA. Those who were positive for anti-HBc were tested for HBsAg. RESULTS: Anti-HBc was found in 28 of 827 pregnant women (overall prevalence, 3.4%; 14 of 523 in urban areas, 2.7%; 14 of 304 in rural areas, 4.6%). Of the 28 positive samples, 6(0.7%) were positive for HBs-Ag. Only 2 samples (0.2%) were anti-HCV-positive. CONCLUSIONS: These results underscore the need for prenatal screening for HBV infection in pregnant women and treatment of newborns from HBsAg-positive mothers.More studies are needed to identify risk factors of HCV infection and highlight the importance of HCV screening and treatment programs. PMID- 22235218 TI - Comparison of portal vein doppler indices and hepatic vein doppler waveform in patients with nonalcoholic fatty liver disease with healthy control. AB - BACKGROUND: The purpose of the present study is to investigate the association of nonalcoholic fatty liver disease (NAFLD) with the doppler waveform pattern of hepatic veins and portal vein doppler indices. OBJECTIVES: This assay may be useful in evaluating the natural course of NAFLD and monitor treatment efficacy on follow-up. PATIENTS AND METHODS: This case control study was performed in 31 patients with NAFLD and 31 normal healthy adults who served as the control group. The patients presented with elevated liver enzymes levels (ALT/AST) and hyperechogenic livers in the B-mode ultrasonography examination. Eleven patients had a liver biopsy. After an 8-hour fast,B-mode and duplex doppler ultrasonography were performed, and the waveform patterns of the right hepatic vein, portal vein diameter, grade of fatty liver, portal vein pulsatility index (VPI), and mean flow velocity (MFV) were measured. RESULTS: VPI and MFV values were 0.42 +/- 0.92 and 17.27 +/- 5.34 cm/second, respectively, in the control group and 0.25 +/- 0.50 and 12.82 +/- 4.32 cm/second in patients with NAFLD (P< 0.01). The frequency of abnormal hepatic vein doppler waveform patterns (biphasic or monophasic) was significantly higher in patients with NAFLD (55.2%) versus control subjects (3.2%) (P < 0.001). There was no correlation between the degree of fat infiltration and VPI (P = 0.714), MFV (P = 0.911), or hepatic vein waveform pattern (P = 0.197). We found no correlation between liver enzyme levels and MFV or VPI. However, the rate of abnormal hepatic vein was higher in patients with enzyme levels that exceeded twice the normal value (P = 0.05). CONCLUSIONS: Patients with NAFLD have a high rate of abnormal hepatic vein doppler waveform patterns, and decreased VPI and MFV are suggestive of reduced vascular compliance in the liver. Elevated liver enzymes levels do not influence VPI or MFV, but patients with abnormal enzymes have higher rates of abnormal hepatic vein doppler waveform patterns. PMID- 22235219 TI - Seroepidemiology and molecular characterization of hepatitis E Virus in Macaca mulatta from a village in Yunnan, China, where infection with this virus is endemic. AB - BACKGROUND: Hepatitis E virus (HEV) infection is a significant public health concern and has been identified as a zoonotic infection. OBJECTIVES: Since no reports have characterized the epidemiological and genotypic features of HEV infections in Macaca mulatta (rhesus macaques) from Yunnan, China, where swine HEV infections are endemic, we aimed to investigate these characteristics. MATERIALS AND METHODS: Seroepidemiological and molecular characterization of HEV in both Macaca mulatta and pigs from the Yunnan province of China were conducted using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-nested PCR (RT-nPCR). Four hundred and eighty-two stool samples (320 from Macaca mulatta and 162 from pigs) and 92 serum samples (all from Macaca mulatta) were collected for the detection of HEV RNA and anti-HEV antibodies (IgG/IgM). RESULTS: Thirty three rhesus macaques (35.87%) were positive for HEV IgG. Of these, 3 were also positive for HEV IgM. Four different strains of swine HEV RNA were detected in pigs; however, we failed to detect any in Macaca mulatta. CONCLUSIONS: Results indicate that Macaca mulatta may not be a natural reservoir of HEV. PMID- 22235220 TI - Epidemiological impact of mandatory vaccination against hepatitis B in Italian young adults. AB - BACKGROUND: Viral hepatitis caused by hepatitis B virus (HBV) is a leading cause of acute and chronic liver diseases worldwide. OBJECTIVES: In Italy, a mandatory vaccination policy was introduced in 1991 and was established for all newborns and 12-year-old individuals. In 2004, vaccination of 12-year old adolescents was discontinued, and that of infants was maintained. PATIENTS AND METHODS: We evaluated the seroprevalence of HBV markers in 806 individuals, who were vaccinated at birth or at 12 years of age, to assess the effectiveness of the national policy against HBV. RESULTS: The overall prevalence of anti-HBs antibodies was 90.32% (95% confidence interval [CI]: 88.28-92.36%); 2.23% (95% CI: 1.21-3.25%) of the subjects were positive for both antibodies to HBsAg (anti HBs) and antibodies to hepatitis B core antigen (anti-HBc), whereas 5.83% (95% CI 4.21-7.45) of the subjects were negative for all markers tested. Further, 1.61% (95% CI: 0.74-2.48%) of the subjects were positive for hepatitis B surface antigen (HBsAg). CONCLUSIONS: Our data provide additional evidence that HBV vaccination can confer long-term immunity when performed at birth and when performed for healthy adolescents; moreover, the results show the effectiveness of the application of a national vaccination strategy. PMID- 22235221 TI - Receiver operating characteristic curve and odds ratio should be used with caution. PMID- 22235222 TI - Noninvasive methods to evaluate liver fibrosis in chronic HCV infection. PMID- 22235223 TI - Gender-specific cytokine pathways, targets, and biomarkers for the switch from health to adenoma and colorectal cancer. AB - Studies focusing on gender have shown that differences exist in how the immune system responds to disease and therapy. Understanding how gender influences immunological mechanisms in health and disease and identifying gender-specific biomarkers could lead to specifically tailored treatment and ultimately improve therapeutic success rates. T helper1 (Th1) and Th2 cytokines (Th1/Th2) have pivotal roles in the homeostasis of Th1 and Th2 cell network functions in the immune response but sex steroids affect Th1/Th2 production in different ways and a natural sexual dimorphism in the immune response has been shown. In order to investigate these differences further, we developed Th-cytokine data-driven models of the immune response and evaluated healthy subject peripheral blood samples. Independent cohorts of colorectal cancer and adenoma patients were also studied for comparison purposes. Our results show that the interferon (IFN)gamma production pathway for immune response homeostasis is specific to men whilst the interleukin- (IL-) 6 production pathway for immune response homeostasis is specific to women. The IL-10 pathway for restoring immune system resting homeostasis was common to both but was controlled by the respective gender specific pathways. These gender pathways could well be used as targets and biomarkers in translational research into developing new clinical strategies. PMID- 22235224 TI - Monoclonal antibodies in gynecological cancer: a critical point of view. AB - During the last decades, several improvements in treating gynecological malignancies have been achieved. In particular, target therapies, mostly monoclonal antibodies, have emerged as an attractive option for the treatment of these malignancies. In fact, various molecular-targeted agents have been developed for a variety of malignancies with the objective to interfere with a precise tumor associated receptor, essential for cancer cell survival or proliferation, blocking its function, of the cancer cells. Alternatively, monoclonal antibodies have been developed to block immune suppression or enhance functions of immune effector cells. So far, several monoclonal antibodies have been tested for clinical efficacy for the treatment of gynecological cancers. Antibodies against Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) have been used in different neoplasms such as ovarian and cervical cancer. Catumazumab, a bivalent antibody against CD3 and EpCAM, is effective in the treatment of neoplastic ascites. Other antibodies are peculiar for specific cancer-associated antigen such as Oregovomab against CA125 or Farletuzumab against the folate receptor. Here we describe the preclinical and clinical experience gained up to now with monoclonal antibodies in tumors of the female genital tract and trace future therapeutic and research venues. PMID- 22235225 TI - Immunology and immunodiagnosis of cystic echinococcosis: an update. AB - Cystic echinococcosis (CE) is a cosmopolitan zoonosis caused by the larval cystic stage of the dog tapeworm Echinococcus granulosus. This complex multicellular pathogen produces various antigens which modulate the host immune response and promote parasite survival and development. The recent application of modern molecular and immunological approaches has revealed novel insights on the nature of the immune responses generated during the course of a hydatid infection, although many aspects of the Echinococcus-host interplay remain unexplored. This paper summarizes recent developments in our understanding of the immunology and diagnosis of echinococcosis, indicates areas where information is lacking, and suggests possible new strategies to improve serodiagnosis for practical application. PMID- 22235226 TI - Perinatal cat and dog exposure and the risk of asthma and allergy in the urban environment: a systematic review of longitudinal studies. AB - BACKGROUND: The literature is contradictory concerning pet exposure and the risk of development of asthma and other allergic diseases. Using longitudinal studies, we aimed to systematically review the impact of pet ownership in the critical perinatal period as a risk factor for allergies in childhood. METHODS: Medline database was searched for urban cohort studies with perinatal exposure to cats and/or dogs and subsequent asthma or allergic disease. RESULTS: Nine articles, comprising 6498 participants, met inclusion criteria. Six found a reduction in allergic disease associated with perinatal exposure to dogs or, cats or dogs. One study found no association. Two found increased risk only in high-risk groups. CONCLUSION: Longitudinal studies in urban populations suggest that perinatal pets, especially dogs, may reduce the development of allergic disease in those without a family history of allergy. Other unmeasured factors such as pet-keeping choices in allergic families may be confounding the association seen in these high-risk families, and further study is required. PMID- 22235227 TI - Developing and activated T cell survival depends on differential signaling pathways to regulate anti-apoptotic Bcl-x(L). AB - Survival of T cells in both the central and peripheral immune system determines its ultimate function in the regulation of immune responses. In the thymus, developing T cells undergo positive and negative selection to generate a T cell repertoire that responds to foreign, but not self, antigens. During T cell development, the T cell receptor alpha chain is rearranged. However, the first round of rearrangement may fail, which triggers another round of alpha chain rearrangement until either successful positive selection or cell death occurs. Thus, the lifespan of double positive (CD4(+)CD8(+); DP) thymocytes determines how many rounds of alpha chain rearrangement can be carried out and influences the likelihood of completing positive selection. The anti-apoptotic protein Bcl x(L) is the ultimate effector regulating the survival of CD4(+)CD8(+) thymocytes subject to the selection process, and the deletion of Bcl-x(L) leads to premature apoptosis of thymocytes prior to the completion of the developmental process. In addition to its critical function in the thymus, Bcl-x(L) also regulates the survival of peripheral T cells. Upon engagement with antigens, T cells are activated and differentiated into effectors. Activated T cells upregulate Bcl x(L) to enhance their own survival. Bcl-x(L)-mediated survival is required for the generation of effectors that carry out the actual immune responses. In the absence of Bcl-x(L), mature T cells undergo apoptosis prior to the completion of the differentiation process to become effector cells. Therefore, Bcl-x(L) ensures the survival of both developing and peripheral T cells, which is essential for a functional immune system. PMID- 22235229 TI - Effect of an Ethanol Extract of Scutellaria baicalensis on Relaxation in Corpus Cavernosum Smooth Muscle. AB - Aims of study. The aim of the present study was to investigate whether an ethanol extract of Scutellaria baicalensis (ESB) relaxes penile corpus cavernosum muscle in organ bath experiments. Materials and methods. Changes in tension of cavernous smooth muscle strips were determined by penile strip chamber model and in penile perfusion model. Isolated endothelium-intact rabbit corpus cavernosum was precontracted with phenylephrine (PE) and then treated with ESB. Results. ESB relaxed penile smooth muscle in a dose-dependent manner, and this was inhibited by pre-treatment with N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide (NO) synthase inhibitor, and 1H-[1, 2, 4]-oxadiazolo-[4,3-alpha]-quinoxalin-1-one (ODQ), a soluble guanylyl cyclase (sGC) inhibitor. ESB-induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA), a nonselective K(+) channel blocker, and charybdotoxin, a selective Ca(2+) dependent K(+) channel inhibitor. ESB increased the cGMP levels of rabbit corpus cavernosum in a concentration-dependent manner without changes in cAMP levels. In a perfusion model of penile tissue, ESB also relaxed penile corpus cavernosum smooth muscle in a dose-dependent manner. Conclusion. Taken together, these results suggest that ESB relaxed rabbit cavernous smooth muscle via the NO/cGMP system and Ca(2+)-sensitive K(+) channels in the corpus cavernosum. PMID- 22235228 TI - IgG placental transfer in healthy and pathological pregnancies. AB - Placental transfer of maternal IgG antibodies to the fetus is an important mechanism that provides protection to the infant while his/her humoral response is inefficient. IgG is the only antibody class that significantly crosses the human placenta. This crossing is mediated by FcRn expressed on syncytiotrophoblast cells. There is evidence that IgG transfer depends on the following: (i) maternal levels of total IgG and specific antibodies, (ii) gestational age, (iii) placental integrity, (iv) IgG subclass, and (v) nature of antigen, being more intense for thymus-dependent ones. These features represent the basis for maternal immunization strategies aimed at protecting newborns against neonatal and infantile infectious diseases. In some situations, such as mothers with primary immunodeficiencies, exogenous IgG acquired by intravenous immunoglobulin therapy crosses the placenta in similar patterns to endogenous immunoglobulins and may also protect the offspring from infections in early life. Inversely, harmful autoantibodies may cross the placenta and cause transitory autoimmune disease in the neonate. PMID- 22235230 TI - Zingiber officinale Improves Cognitive Function of the Middle-Aged Healthy Women. AB - The development of cognitive enhancers from plants possessing antioxidants has gained much attention due to the role of oxidative stress-induced cognitive impairment. Thus, this study aimed to determine the effect of ginger extract, or Zingiber officinale, on the cognitive function of middle-aged, healthy women. Sixty participants were randomly assigned to receive a placebo or standardized plant extract at doses of 400 and 800 mg once daily for 2 months. They were evaluated for working memory and cognitive function using computerized battery tests and the auditory oddball paradigm of event-related potentials at three different time periods: before receiving the intervention, one month, and two months. We found that the ginger-treated groups had significantly decreased P300 latencies, increased N100 and P300 amplitudes, and exhibited enhanced working memory. Therefore, ginger is a potential cognitive enhancer for middle-aged women. PMID- 22235231 TI - Systematic review on the efficacy and safety of herbal medicines for vascular dementia. AB - We present a systematic review of existing research that aims to assess the efficacy and safety of herbal medications (HM), as either monotherapy or adjunct to orthodox medications (OM), mainly comprised of cholinesterase inhibitors, for vascular dementia (VaD). We included 47 studies conducted in mainland China, each testing different HM. Of 43 HM monotherapy studies, 37 reported HM to be significantly better than OM or placebo; six reported similar efficacy between HM and OM. All four HM adjuvant studies reported significant efficacy. No major adverse events for HM were reported. Heterogeneity in diagnostic criteria, interventions and outcome measures hindered comprehensive data analysis. Studies suggested that HM can be a safe and effective treatment for VaD, either alone or in conjunction with OM. However, methodological flaws in the design of the studies limited the extent to which the results could be interpreted. Thirty most commonly used herbal constituents, including Rhizoma Chuanxiong (Chuanxiong in Chinese), Radix Polygoni Multiflori (Heshouwu in Chinese) and Radix Astragali (Huangqi in Chinese). were ranked. Further multi-center trials with large sample sizes, high methodological quality and standardized HM ingredients are necessary for clinical recommendations to be made. PMID- 22235233 TI - On the Feasibility of Verification of 3D Dosimetry Near Brachytherapy Sources Using PRESAGE/Optical-CT. AB - PURPOSE: The feasibility of using the PRESAGE/Optical-CT system for 3D dosimetry verification around a brachytherapy source is investigated. METHOD AND MATERIALS: Brachytherapy dose distributions were obtained by irradiation of cylindrical PRESAGE volumes 6cm in diameter by 8cm height with a GammaMed 12i Ir 192 HDR unit (Varian Medical Systems). A narrow channel on the central axis was created by setting a steel catheter in the Presage during manufacture, enabling measurements close to the source (~3mm). RESULTS: Comparison of dose line profiles shows good agreement between PRESAGE and verified calculated dose calculation, in both high and low dose regions. CONCLUSION: The PRESAGE/Optical CT shows good potential in verification of 3D dose distributions around brachytherapy sources. PMID- 22235232 TI - Comprehensive evidence-based assessment and prioritization of potential antidiabetic medicinal plants: a case study from canadian eastern james bay cree traditional medicine. AB - Canadian Aboriginals, like others globally, suffer from disproportionately high rates of diabetes. A comprehensive evidence-based approach was therefore developed to study potential antidiabetic medicinal plants stemming from Canadian Aboriginal Traditional Medicine to provide culturally adapted complementary and alternative treatment options. Key elements of pathophysiology of diabetes and of related contemporary drug therapy are presented to highlight relevant cellular and molecular targets for medicinal plants. Potential antidiabetic plants were identified using a novel ethnobotanical method based on a set of diabetes symptoms. The most promising species were screened for primary (glucose-lowering) and secondary (toxicity, drug interactions, complications) antidiabetic activity by using a comprehensive platform of in vitro cell-based and cell-free bioassays. The most active species were studied further for their mechanism of action and their active principles identified though bioassay-guided fractionation. Biological activity of key species was confirmed in animal models of diabetes. These in vitro and in vivo findings are the basis for evidence-based prioritization of antidiabetic plants. In parallel, plants were also prioritized by Cree Elders and healers according to their Traditional Medicine paradigm. This case study highlights the convergence of modern science and Traditional Medicine while providing a model that can be adapted to other Aboriginal realities worldwide. PMID- 22235234 TI - Core Depressive Symptoms In Depressed Cancer OutpatientsB. AB - OBJECTIVE: This study aimed to estimate the prevalence of core depressive symptoms among cancer outpatients diagnosed with depressive or adjustment disorders with depressed mood. We also aimed to detect potential differences between patient self-assessment and psychiatrist evaluation in classifying the severity of depression. METHODS: Fifty-two outpatients diagnosed with solid tumor malignancy and depressive or adjustment disorder with depressed mood were assessed using the Hamilton Depression Rating Scale (HAMD-17) (and its shortened version the HAMD-7) and the Zung Self-Rating Depression Scale (ZSDS) (and its shortened version BZSDS). RESULTS: Based on HAMD-7 results, the prevalence of moderate depression was low (7.7%); using the BZSDS moderate depression was absent. Mild depression was identified in 82.3% and 73% of our subjects using the HAMD-7 and the BZSDS, respectively. The strength of agreement between psychiatrist and patients' self-evaluation for mild depression was "slight", employing the original and the abbreviated versions of both scales. CONCLUSION: Our findings suggest that the prevalence of core depressive symptoms is very low in cancer patients diagnosed with depressive disorder. The lack of a strong agreement between psychiatrist and patient in classifying the severity of depression highlights the importance of factors such as well-being and functional status among depressed cancer patients in their self assessment of depression. PMID- 22235236 TI - Toll-like receptor 2 gene polymorphisms associated with aggressive periodontitis in Japanese. AB - BACKGROUND AND OBJECTIVE: Aggressive periodontitis is a rare and very severe periodontal disease of early onset, which is closely associated with Porphyromonas.gingivalis (P.g.) infection in the Japanese population. TLR2 encodes Toll-like receptor 2, which plays an important role in the protective response to P.g. infection. We investigated a possible association between TLR2 and aggressive periodontitis. MATERIAL AND METHODS: Of 2,460 Japanese patients with periodontitis, 38 patients with aggressive periodontitis were enrolled in this study. These 38 aggressive periodontitis patients and 190 Japanese healthy controls were examined for an insertion/deletion (Ins/Del) polymorphism in exon 1, a polymorphism in intron 1 (rs7696323), and a synonymous polymorphism in exon 3 (rs3804100) in TLR2. RESULTS: We found significant associations of resistance to aggressive periodontitis with the Ins allele (allele frequency in the patients versus controls, 0.540 vs. 0.676, OR=0.56, 95% confidence interval (CI); 0.34 0.92, p=0.022) and the T allele of rs3804100 (0.579 vs. 0.716, OR=0.55, 95% CI; 0.33-0.91, p=0.018), although the C allele of rs7696323 showed no significant association (0.733 vs. 0.829, OR=0.58). A permutation test of Ins/Del-rs7696323 rs3804100 haplotype revealed a significant association between Ins-C-T haplotype (0.252 vs. 0.479, p=0.0003) and resistance to aggressive periodontitis. CONCLUSIONS: The TLR2 polymorphisms were suggested to confer protection against aggressive periodontitis in a Japanese population. The association should be replicated in other cohorts to further identify the responsible TLR polymorphism(s) involved in the pathogenesis of aggressive periodontitis. PMID- 22235235 TI - Antisocial personality and bipolar disorder: interactions in impulsivity and course of illness. AB - Antisocial personality disorder (ASPD) and bipolar disorder are both characterized by impulsive behavior, increased incarceration or arrest, addictive disorders and suicidal behavior. These characteristics appear more severe in the combined disorders. Individuals with ASPD who also have bipolar disorder have higher rates of addictive disorders and suicidal behavior and are more impulsive, as measured by questionnaires or behavioral laboratory tests. Those with bipolar disorder who have ASPD have higher rates of addictive, criminal and suicidal behavior, earlier onset of bipolar disorder with a more recurrent and predominately manic course and increased laboratory-measured, but not questionnaire-rated, impulsivity. These characteristics may result in part from differential impulsivity mechanisms in the two disorders, with bipolar disorder driven more by excessive catecholamine sensitivity and ASPD by deficient serotonergic function. PMID- 22235237 TI - Differences in external and internal cortical strain with prosthesis in the femur. AB - The contact between a femoral stem prosthesis and the internal surface of the cortical bone with the stress in the interface is of crucial importance with respect to loosening. However, there are no reports of strain patterns at this site, and the main aim of the current study was to investigate differences of internal and external cortical strain in the proximal femur after insertion of a stem prosthesis. The external cortical strain of a human cadaveric femur was measured with strain gauges before and after implantation of a stem prosthesis. By use of optical fibres embedded longitudinally in the endosteal cortex, deformations at the implant-internal cortex interface could also be measured. The main external deformation during loading of the intact femur occurred as compression of the medial cortex; both at the proximal and distal levels. The direction of the principal strain on the medial and lateral aspects was close to the longitudinal axis of the bone. After resection of the femoral neck and insertion of a stem prosthesis, the changes in external strain values were greatest medially at the proximal level, where the magnitude of deformation in compression was reduced to about half the values measured on the intact specimen. Otherwise, there were rather small changes in external principal strain. However, by comparing vertical strain in the external and internal cortex of the proximal femur, there were great differences in values and patterns at all positions. The transcortical differences in strain varied from compression on one side to distraction on the other and vice versa in some of the positions with a correlation coefficient of 0.07. Our results show that differences exist between the external and internal cortical strain when loading a stem prosthesis. Hence, strain at the internal cortex does not correspond and can not be deducted from measured strain at the external cortex. PMID- 22235240 TI - Three-dimensional structure of the Trypanosome flagellum suggests that the paraflagellar rod functions as a biomechanical spring. AB - Flagellum motility is critical for normal human development and for transmission of pathogenic protozoa that cause tremendous human suffering worldwide. Biophysical principles underlying motility of eukaryotic flagella are conserved from protists to vertebrates. However, individual cells exhibit diverse waveforms that depend on cell-specific elaborations on basic flagellum architecture. Trypanosoma brucei is a uniflagellated protozoan parasite that causes African sleeping sickness. The T. brucei flagellum is comprised of a 9+2 axoneme and an extra-axonemal paraflagellar rod (PFR), but the three-dimensional (3D) arrangement of the underlying structural units is poorly defined. Here, we use dual-axis electron tomography to determine the 3D architecture of the T. brucei flagellum. We define the T. brucei axonemal repeating unit. We observe direct connections between the PFR and axonemal dyneins, suggesting a mechanism by which mechanochemical signals may be transmitted from the PFR to axonemal dyneins. We find that the PFR itself is comprised of overlapping laths organized into distinct zones that are connected through twisting elements at the zonal interfaces. The overall structure has an underlying 57 nm repeating unit. Biomechanical properties inferred from PFR structure lead us to propose that the PFR functions as a biomechanical spring that may store and transmit energy derived from axonemal beating. These findings provide insight into the structural foundations that underlie the distinctive flagellar waveform that is a hallmark of T. brucei cell motility. PMID- 22235241 TI - African ancestry is associated with asthma risk in African Americans. AB - BACKGROUND: Asthma is a common complex condition with clear racial and ethnic differences in both prevalence and severity. Asthma consultation rates, mortality, and severe symptoms are greatly increased in African descent populations of developed countries. African ancestry has been associated with asthma, total serum IgE and lower pulmonary function in African-admixed populations. To replicate previous findings, here we aimed to examine whether African ancestry was associated with asthma susceptibility in African Americans. In addition, we examined for the first time whether African ancestry was associated with asthma exacerbations. METHODOLOGY/PRINCIPAL FINDINGS: After filtering for self-reported ancestry and genotype data quality, samples from 1,117 self-reported African-American individuals from New York and Baltimore (394 cases, 481 controls), and Chicago (321 cases followed for asthma exacerbations) were analyzed. Genetic ancestry was estimated based on ancestry informative markers (AIMs) selected for being highly divergent among European and West African populations (95 AIMs for New York and Baltimore, and 66 independent AIMs for Chicago). Among case-control samples, the mean African ancestry was significantly higher in asthmatics than in non-asthmatics (82.0+/-14.0% vs. 77.8+/-18.1%, mean difference 4.2% [95% confidence interval (CI):2.0-6.4], p<0.0001). This association remained significant after adjusting for potential confounders (odds ratio: 4.55, 95% CI: 1.69-12.29, p = 0.003). African ancestry failed to show an association with asthma exacerbations (p = 0.965) using a model based on longitudinal data of the number of exacerbations followed over 1.5 years. CONCLUSIONS/SIGNIFICANCE: These data replicate previous findings indicating that African ancestry constitutes a risk factor for asthma and suggest that elevated asthma rates in African Americans can be partially attributed to African genetic ancestry. PMID- 22235242 TI - Turning text into research networks: information retrieval and computational ontologies in the creation of scientific databases. AB - BACKGROUND: Web-based, free-text documents on science and technology have been increasing growing on the web. However, most of these documents are not immediately processable by computers slowing down the acquisition of useful information. Computational ontologies might represent a possible solution by enabling semantically machine readable data sets. But, the process of ontology creation, instantiation and maintenance is still based on manual methodologies and thus time and cost intensive. METHOD: We focused on a large corpus containing information on researchers, research fields, and institutions. We based our strategy on traditional entity recognition, social computing and correlation. We devised a semi automatic approach for the recognition, correlation and extraction of named entities and relations from textual documents which are then used to create, instantiate, and maintain an ontology. RESULTS: We present a prototype demonstrating the applicability of the proposed strategy, along with a case study describing how direct and indirect relations can be extracted from academic and professional activities registered in a database of curriculum vitae in free-text format. We present evidence that this system can identify entities to assist in the process of knowledge extraction and representation to support ontology maintenance. We also demonstrate the extraction of relationships among ontology classes and their instances. CONCLUSION: We have demonstrated that our system can be used for the conversion of research information in free text format into database with a semantic structure. Future studies should test this system using the growing number of free-text information available at the institutional and national levels. PMID- 22235243 TI - Influence of IL28B polymorphisms on response to a lower-than-standard dose peg IFN-alpha 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients. AB - BACKGROUND: Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-alpha 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV coinfected patients. METHODS AND FINDINGS: Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 ug peginterferon-alpha 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-alpha 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-alpha 2a concentrations, ribavirin levels or rs129679860 genotype. CONCLUSIONS: Weekly 135 ug pegIFN-alpha 2a could be as effective as the standard 180 ug dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00553930. PMID- 22235244 TI - Biosecurity on cattle farms: a study in north-west England. AB - BACKGROUND: Few studies have considered in detail the range of biosecurity practices undertaken on cattle farms, particularly within the UK. In this study, 56 cattle farmers in a 100 km2 area of north-west England were questioned regarding their on-farm biosecurity practices, including those relating to animal movements, equipment sharing and companies and contractors visiting the farms. METHODOLOGY/PRINCIPAL FINDINGS: There was great variation between farms in terms of the type of, and extent to which, biosecurity was carried out. For example, the majority of farmers did not isolate stock bought onto the farm, but a small proportion always isolated stock. Many farmers administered treatments post movement, primarily vaccinations and anthelmintics, but very few farms reported carrying out any health checks after moving animals on. In addition, there appeared to be much variation in the amount of biosecurity carried out by the different companies and contractors visiting the farms. Deadstock collectors and contracted animal waste spreaders, although likely to have a high potential for contact with infectious agents, were reported to infrequently disinfect themselves and their vehicles. CONCLUSIONS/SIGNIFICANCE: These findings suggest that although certain biosecurity practices are undertaken, many are carried out infrequently or not at all. This may be due to many factors, including cost (in time and money), lack of proven efficacies of practices and lack of relevant education of veterinary surgeons, producers and other herd health specialists. Further research exploring the reasons for the lack of uptake is imperative if preventive medicine is to be utilised fully by the farming industry. PMID- 22235245 TI - Genome-wide gene expression analysis suggests an important role of suppressed immunity in pathogenesis of Kashin-Beck disease. AB - OBJECTIVE: To investigate the differences between the gene expression profiles in peripheral blood mononuclear cells (PBMC) from normal controls and patients with Kashin-Beck disease (KBD). METHODS: Twenty KBD patients and 12 normal subjects were selected from a KBD-endemic area and divided into four pairs of KBD vs. control (KBD, n = 5 per pair; control, n = 3 per pair). RNAs were respectively isolated from KBD PBMCs and normal PBMCs. Gene expression profiles were analyzed by oligonucleotide microarray. The gene expression profiles in PBMCs from KBD patients and normal controls were compared and the differentially expressed genes were identified. The obtained microarray data was further confirmed by using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Approximately 501 genes, corresponding to 2.4% of the total probe transcripts, showed a 2-fold change in differential expression. 19.4% (97 out of 501)of the differentially expressed genes were commonly detected in all the four pairs. Among the 97 differentially expressed genes, 83 genes were up-regulated and 14 genes were down-regulated, compared with those in the normal controls. Some differentially expressed genes were found to be related to functions such as immunity, metabolism, apoptosis, cystoskeleton and cell movement, and extracellular matrix. The validity of our microarray data were supported by the results of qRT-PCR assay. CONCLUSION: Differences in the PBMC gene expression profile between the KBD patients and the normal controls exhibited a similar pattern among all the four pairs of microarrays examined, indicating that the suppressed immunity may play an important role in the pathogenesis of KBD. PMID- 22235246 TI - Estimating the diets of animals using stable isotopes and a comprehensive Bayesian mixing model. AB - Using stable isotope mixing models (SIMMs) as a tool to investigate the foraging ecology of animals is gaining popularity among researchers. As a result, statistical methods are rapidly evolving and numerous models have been produced to estimate the diets of animals--each with their benefits and their limitations. Deciding which SIMM to use is contingent on factors such as the consumer of interest, its food sources, sample size, the familiarity a user has with a particular framework for statistical analysis, or the level of inference the researcher desires to make (e.g., population- or individual-level). In this paper, we provide a review of commonly used SIMM models and describe a comprehensive SIMM that includes all features commonly used in SIMM analysis and two new features. We used data collected in Yosemite National Park to demonstrate IsotopeR's ability to estimate dietary parameters. We then examined the importance of each feature in the model and compared our results to inferences from commonly used SIMMs. IsotopeR's user interface (in R) will provide researchers a user-friendly tool for SIMM analysis. The model is also applicable for use in paleontology, archaeology, and forensic studies as well as estimating pollution inputs. PMID- 22235247 TI - In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy. AB - AIMS: The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice. METHODS AND RESULTS: Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non SPF facility) using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV) and right ventricular (RV) systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy. CONCLUSIONS: MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases. PMID- 22235248 TI - Do herbivores eavesdrop on ant chemical communication to avoid predation? AB - Strong effects of predator chemical cues on prey are common in aquatic and marine ecosystems, but are thought to be rare in terrestrial systems and specifically for arthropods. For ants, herbivores are hypothesized to eavesdrop on ant chemical communication and thereby avoid predation or confrontation. Here I tested the effect of ant chemical cues on herbivore choice and herbivory. Using Margaridisa sp. flea beetles and leaves from the host tree (Conostegia xalapensis), I performed paired-leaf choice feeding experiments. Coating leaves with crushed ant liquids (Azteca instabilis), exposing leaves to ant patrolling prior to choice tests (A. instabilis and Camponotus textor) and comparing leaves from trees with and without A. instabilis nests resulted in more herbivores and herbivory on control (no ant-treatment) relative to ant-treatment leaves. In contrast to A. instabilis and C. textor, leaves previously patrolled by Solenopsis geminata had no difference in beetle number and damage compared to control leaves. Altering the time A. instabilis patrolled treatment leaves prior to choice tests (0-, 5-, 30-, 90-, 180-min.) revealed treatment effects were only statistically significant after 90- and 180-min. of prior leaf exposure. This study suggests, for two ecologically important and taxonomically diverse genera (Azteca and Camponotus), ant chemical cues have important effects on herbivores and that these effects may be widespread across the ant family. It suggests that the effect of chemical cues on herbivores may only appear after substantial previous ant activity has occurred on plant tissues. Furthermore, it supports the hypothesis that herbivores use ant chemical communication to avoid predation or confrontation with ants. PMID- 22235249 TI - Role of the lateral paragigantocellular nucleus in the network of paradoxical (REM) sleep: an electrophysiological and anatomical study in the rat. AB - The lateral paragigantocellular nucleus (LPGi) is located in the ventrolateral medulla and is known as a sympathoexcitatory area involved in the control of blood pressure. In recent experiments, we showed that the LPGi contains a large number of neurons activated during PS hypersomnia following a selective deprivation. Among these neurons, more than two-thirds are GABAergic and more than one fourth send efferent fibers to the wake-active locus coeruleus nucleus. To get more insight into the role of the LPGi in PS regulation, we combined an electrophysiological and anatomical approach in the rat, using extracellular recordings in the head-restrained model and injections of tracers followed by the immunohistochemical detection of Fos in control, PS-deprived and PS-recovery animals. With the head-restrained preparation, we showed that the LPGi contains neurons specifically active during PS (PS-On neurons), neurons inactive during PS (PS-Off neurons) and neurons indifferent to the sleep-waking cycle. After injection of CTb in the facial nucleus, the neurons of which are hyperpolarized during PS, the largest population of Fos/CTb neurons visualized in the medulla in the PS-recovery condition was observed in the LPGi. After injection of CTb in the LPGi itself and PS-recovery, the nucleus containing the highest number of Fos/CTb neurons, moreover bilaterally, was the sublaterodorsal nucleus (SLD). The SLD is known as the pontine executive PS area and triggers PS through glutamatergic neurons. We propose that, during PS, the LPGi is strongly excited by the SLD and hyperpolarizes the motoneurons of the facial nucleus in addition to local and locus coeruleus PS-Off neurons, and by this means contributes to PS genesis. PMID- 22235250 TI - Quantile-specific penetrance of genes affecting lipoproteins, adiposity and height. AB - Quantile-dependent penetrance is proposed to occur when the phenotypic expression of a SNP depends upon the population percentile of the phenotype. To illustrate the phenomenon, quantiles of height, body mass index (BMI), and plasma lipids and lipoproteins were compared to genetic risk scores (GRS) derived from single nucleotide polymorphisms (SNP)s having established genome-wide significance: 180 SNPs for height, 32 for BMI, 37 for low-density lipoprotein (LDL)-cholesterol, 47 for high-density lipoprotein (HDL)-cholesterol, 52 for total cholesterol, and 31 for triglycerides in 1930 subjects. Both phenotypes and GRSs were adjusted for sex, age, study, and smoking status. Quantile regression showed that the slope of the genotype-phenotype relationships increased with the percentile of BMI (P = 0.002), LDL-cholesterol (P = 3*10-8), HDL-cholesterol (P = 5*10-6), total cholesterol (P = 2.5*10-6), and triglyceride distribution (P = 7.5*10-6), but not height (P = 0.09). Compared to a GRS's phenotypic effect at the 10(th) population percentile, its effect at the 90(th) percentile was 4.2-fold greater for BMI, 4.9 fold greater for LDL-cholesterol, 1.9-fold greater for HDL-cholesterol, 3.1-fold greater for total cholesterol, and 3.3-fold greater for triglycerides. Moreover, the effect of the rs1558902 (FTO) risk allele was 6.7-fold greater at the 90(th) than the 10(th) percentile of the BMI distribution, and that of the rs3764261 (CETP) risk allele was 2.4-fold greater at the 90(th) than the 10(th) percentile of the HDL-cholesterol distribution. Conceptually, it maybe useful to distinguish environmental effects on the phenotype that in turn alters a gene's phenotypic expression (quantile-dependent penetrance) from environmental effects affecting the gene's phenotypic expression directly (gene-environment interaction). PMID- 22235251 TI - Identification of autotoxic compounds in fibrous roots of Rehmannia (Rehmannia glutinosa Libosch.). AB - Rehmannia is a medicinal plant in China. Autotoxicity has been reported to be one of the major problems hindering the consecutive monoculture of Rehmannia. However, potential autotoxins produced by the fibrous roots are less known. In this study, the autotoxicity of these fibrous roots was investigated. Four groups of autotoxic compounds from the aqueous extracts of the fibrous roots were isolated and characterized. The ethyl acetate extracts of these water-soluble compounds were further analyzed and separated into five fractions. Among them, the most autotoxic fraction (Fr 3) was subjected to GC/MS analysis, resulting in 32 identified compounds. Based on literature, nine compounds were selected for testing their autotoxic effects on radicle growth. Seven out of the nine compounds were phenolic, which significantly reduced radicle growth in a concentration-dependent manner. The other two were aliphatic compounds that showed a moderate inhibition effect at three concentrations. Concentration of these compounds in soil samples was determined by HPLC. Furthermore, the autotoxic compounds were also found in the top soil of the commercially cultivated Rehmannia fields. It appears that a close link exists between the autotoxic effects on the seedlings and the compounds extracted from fibrous roots of Rehmannia. PMID- 22235252 TI - Clinical subtypes of depression are associated with specific metabolic parameters and circadian endocrine profiles in women: the power study. AB - BACKGROUND: Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes. METHODS: Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin. RESULTS: Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup. CONCLUSIONS: Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences. TRIAL REGISTRATION: ClinicalTrials.gov NCT00006180. PMID- 22235254 TI - Mapping migratory bird prevalence using remote sensing data fusion. AB - BACKGROUND: Improved maps of species distributions are important for effective management of wildlife under increasing anthropogenic pressures. Recent advances in lidar and radar remote sensing have shown considerable potential for mapping forest structure and habitat characteristics across landscapes. However, their relative efficacies and integrated use in habitat mapping remain largely unexplored. We evaluated the use of lidar, radar and multispectral remote sensing data in predicting multi-year bird detections or prevalence for 8 migratory songbird species in the unfragmented temperate deciduous forests of New Hampshire, USA. METHODOLOGY AND PRINCIPAL FINDINGS: A set of 104 predictor variables describing vegetation vertical structure and variability from lidar, phenology from multispectral data and backscatter properties from radar data were derived. We tested the accuracies of these variables in predicting prevalence using Random Forests regression models. All data sets showed more than 30% predictive power with radar models having the lowest and multi-sensor synergy ("fusion") models having highest accuracies. Fusion explained between 54% and 75% variance in prevalence for all the birds considered. Stem density from discrete return lidar and phenology from multispectral data were among the best predictors. Further analysis revealed different relationships between the remote sensing metrics and bird prevalence. Spatial maps of prevalence were consistent with known habitat preferences for the bird species. CONCLUSION AND SIGNIFICANCE: Our results highlight the potential of integrating multiple remote sensing data sets using machine-learning methods to improve habitat mapping. Multi-dimensional habitat structure maps such as those generated from this study can significantly advance forest management and ecological research by facilitating fine-scale studies at both stand and landscape level. PMID- 22235253 TI - FcgammaRIIIa expression on monocytes in rheumatoid arthritis: role in immune complex stimulated TNF production and non-response to methotrexate therapy. AB - OBJECTIVE: The expression of FcgammaRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcgammaRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. METHODS: FcgammaRIIIa/CD16 expression on CD14(low) and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcgammaRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. RESULTS: Increased FcgammaRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcgammaRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcgammaRIIIa/CD16 at baseline in early DMARD-naive RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcgammaRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. CONCLUSION: Increased FcgammaRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy. PMID- 22235256 TI - Comparative evaluation of light-trap catches, electric motor mosquito catches and human biting catches of Anopheles in the Three Gorges Reservoir. AB - The mosquito sampling efficiency of light-trap catches and electric motor mosquito catches were compared with that of human biting catches in the Three Gorges Reservoir. There was consistency in the sampling efficiency between light trap catches and human biting catches for Anopheles sinensis (r = 0.82, P<0.01) and light-trap catches were 1.52 (1.35-1.71) times that of human biting catches regardless of mosquito density (r = 0.33, P>0.01), while the correlation between electric motor mosquito catches and human biting catches was found to be not statistically significant (r = 0.43, P>0.01) and its sampling efficiency was below that of human biting catches. It is concluded that light-traps can be used as an alternative to human biting catches of Anopheles sinensis in the study area and is a promising tool for sampling malaria vector populations. PMID- 22235255 TI - The stress-response factor SigH modulates the interaction between Mycobacterium tuberculosis and host phagocytes. AB - The Mycobacterium tuberculosis stress response factor SigH plays a crucial role in modulating the pathogen's response to heat, oxidative-stress, envelope damage and hypoxia. We hypothesized that the lack of this key stress response factor would alter the interaction between the pathogen and its host cells. We compared the interaction of Mtb, Mtb:Delta-sigH and a strain where the mutation had been genetically complemented (Mtb: Delta-sigH:CO) with primary rhesus macaque bone marrow derived macrophages (Rh-BMDMs). The expression of numerous inducible and homeostatic (CCL) beta-chemokines and several apoptotic markers was induced to higher levels in the cells infected with Mtb:Delta-sigH, relative to Mtb or the complemented strain. The differential expression of these genes manifested into functional differences in chemotaxis and apoptosis in cells infected with these two strains. The mutant strain also exhibited reduced late-stage survival in Rh BMDMs. We hypothesize that the product of one or more SigH-dependent genes may modulate the innate interaction of Mtb with host cells, effectively reducing the chemokine-mediated recruitment of immune effector cells, apoptosis of infected monocytes and enhancing the long-term survival and replication of the pathogen in this milieu The significantly higher induction of Prostaglandin Synthetase 2 (PTGS2 or COX2) in Rh-BMDMs infected with Mtb relative to Mtb: Delta-sigH may explain reduced apoptosis in Mtb-infected cells, as PTGS2 is known to inhibit p53 dependent apoptosis.The SigH-regulon modulates the innate interaction of Mtb with host phagocytes, perhaps as part of a strategy to limit its clearance and prolong its survival. The SigH regulon appears to be required to modulate innate immune responses directed against Mtb. PMID- 22235257 TI - The characteristics of blood glucose and WBC counts in peripheral blood of cases of hand foot and mouth disease in China: a systematic review. AB - BACKGROUND: Outbreaks of Hand Foot and Mouth Disease (HFMD) have occurred in many parts of the world especially in China. We aimed to summarize the characteristics of the levels of blood glucose and white blood cell (WBC) counts in cases of HFMD in Mainland China and Taiwan, using meta-analysis based on systematic review of published articles. METHODS: We systematically reviewed published studies, from the MEDLINE and WANFANG Data, about the levels of blood glucose and WBC counts in cases of HFMD until 15(th) June 2011, and quantitatively summarized the characteristics of them using meta-analysis. RESULTS: In total, 37 studies were included in this review. In Mainland China and Taiwan, generally, the average level of blood glucose, the prevalence of hyperglycemia, WBC counts and the prevalence of leukocytosis increased with the severity of the illness. There was no significant difference in the prevalence of leukocytosis between ANS (autonomic nervous system dysregulation)/PE (pulmonary edema) group and CNS (central nervous system) group, and in the average level of blood glucose between healthy controls and mild cases of HFMD. WBC counts in cases infected by EV71 were less than those in cases infected by CA16. CONCLUSIONS: our analyses indicated that blood glucose and WBC counts increased with the severity of HFMD disease, which would help doctors to manage patients efficiently. PMID- 22235258 TI - Low dose aerosol fitness at the innate phase of murine infection better predicts virulence amongst clinical strains of Mycobacterium tuberculosis. AB - BACKGROUND: Evaluation of a quick and easy model to determine the intrinsic ability of clinical strains to generate active TB has been set by assuming that this is linked to the fitness of Mycobacterium tuberculosis strain at the innate phase of the infection. Thus, the higher the bacillary load, the greater the possibility of inducting liquefaction, and thus active TB, once the adaptive response is set. METHODOLOGY/PRINCIPAL FINDINGS: The virulence of seven clinical Mycobacterium tuberculosis strains isolated in Spain was tested by determining the bacillary concentration in the spleen and lung of mice at weeks 0, 1 and 2 after intravenous (IV) inoculation of 104 CFU, and by determining the growth in vitro until the stationary phase had been reached. Cord distribution automated analysis showed two clear patterns related to the high and low fitness in the lung after IV infection. This pattern was not seen in the in vitro fitness tests, which clearly favored the reference strain (H37Rv). Subsequent determination using a more physiological low-dose aerosol (AER) inoculation with 102 CFU showed a third pattern in which the three best values coincided with the highest dissemination capacity according to epidemiological data. CONCLUSIONS/SIGNIFICANCE: The fitness obtained after low dose aerosol administration in the presence of the innate immune response is the most predictive factor for determining the virulence of clinical strains. This gives support to a mechanism of the induction of active TB derived from the dynamic hypothesis of latent tuberculosis infection. PMID- 22235259 TI - DNA double-strand breaks induced by cavitational mechanical effects of ultrasound in cancer cell lines. AB - Ultrasonic technologies pervade the medical field: as a long established imaging modality in clinical diagnostics; and, with the emergence of targeted high intensity focused ultrasound, as a means of thermally ablating tumours. In parallel, the potential of [non-thermal] intermediate intensity ultrasound as a minimally invasive therapy is also being rigorously assessed. Here, induction of apoptosis in cancer cells has been observed, although definitive identification of the underlying mechanism has thus far remained elusive. A likely candidate process has been suggested to involve sonochemical activity, where reactive oxygen species (ROS) mediate the generation of DNA single-strand breaks. Here however, we provide compelling new evidence that strongly supports a purely mechanical mechanism. Moreover, by a combination of specific assays (neutral comet tail and staining for gammaH2AX foci formation) we demonstrate for the first time that US exposure at even moderate intensities exhibits genotoxic potential, through its facility to generate DNA damage across multiple cancer lines. Notably, colocalization assays highlight that ionizing radiation and ultrasound have distinctly different signatures to their respective gammaH2AX foci formation patterns, likely reflecting the different stress distributions that initiated damage formation. Furthermore, parallel immuno-blotting suggests that DNA-PKcs have a preferential role in the repair of ultrasound-induced damage. PMID- 22235260 TI - Rapid accumulation of polymorphonuclear neutrophils in the Corpus luteum during prostaglandin F(2alpha)-induced luteolysis in the cow. AB - Prostaglandin F(2alpha) (PGF(2alpha)) induces luteolysis within a few days in cows, and immune cells increase in number in the regressing corpus luteum (CL), implying that luteolysis is an inflammatory-like immune response. We investigated the rapid change in polymorphonuclear neutrophil (PMN) numbers in response to PGF(2alpha) administration as the first cells recruited to inflammatory sites, together with mRNA of interleukin-8 (IL-8: neutrophil chemoattractant) and P selectin (leukocyte adhesion molecule) in the bovine CL. CLs were collected by ovariectomy at various times after PGF(2alpha) injection. The number of PMNs was increased at 5 min after PGF(2alpha) administration, whereas IL-8 and P-selectin mRNA increased at 30 min and 2 h, respectively. PGF(2alpha) directly stimulated P selectin protein expression at 5-30 min in luteal endothelial cells (LECs). Moreover, PGF(2alpha) enhanced PMN adhesion to LECs, and this enhancement by PGF(2alpha) was inhibited by anti-P-selectin antibody, suggesting that P-selectin expression by PGF(2alpha) is crucial in PMN migration. In conclusion, PGF(2alpha) rapidly induces the accumulation of PMNs into the bovine CL at 5 min and enhances PMN adhesion via P-selectin expression in LECs. It is suggested that luteolytic cascade by PGF(2alpha) may involve an acute inflammatory-like response due to rapidly infiltrated PMNs. PMID- 22235261 TI - Denervation causes fiber atrophy and myosin heavy chain co-expression in senescent skeletal muscle. AB - Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav1.5, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638+/-34 MNs*mm-1) and SEN (469+/-13 MNs*mm-1). Nav1.5 positive fibers (1548+/-70 MUm2) were 35% smaller than Nav1.5 negative fibers (2367+/-78 MUm2; P<0.05) in SEN muscle, whereas Nav1.5 negative fibers in SEN were only 7% smaller than fibers in YA (2553+/-33 MUm2; P<0.05) where no Nav1.5 labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav1.5 positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy. PMID- 22235263 TI - Bayesian variable selection in searching for additive and dominant effects in genome-wide data. AB - Although complex diseases and traits are thought to have multifactorial genetic basis, the common methods in genome-wide association analyses test each variant for association independent of the others. This computational simplification may lead to reduced power to identify variants with small effect sizes and requires correcting for multiple hypothesis tests with complex relationships. However, advances in computational methods and increase in computational resources are enabling the computation of models that adhere more closely to the theory of multifactorial inheritance. Here, a Bayesian variable selection and model averaging approach is formulated for searching for additive and dominant genetic effects. The approach considers simultaneously all available variants for inclusion as predictors in a linear genotype-phenotype mapping and averages over the uncertainty in the variable selection. This leads to naturally interpretable summary quantities on the significances of the variants and their contribution to the genetic basis of the studied trait. We first characterize the behavior of the approach in simulations. The results indicate a gain in the causal variant identification performance when additive and dominant variation are simulated, with a negligible loss of power in purely additive case. An application to the analysis of high- and low-density lipoprotein cholesterol levels in a dataset of 3895 Finns is then presented, demonstrating the feasibility of the approach at the current scale of single-nucleotide polymorphism data. We describe a Markov chain Monte Carlo algorithm for the computation and give suggestions on the specification of prior parameters using commonly available prior information. An open-source software implementing the method is available at http://www.lce.hut.fi/research/mm/bmagwa/ and https://github.com/to-mi/. PMID- 22235262 TI - Pre-existing isoniazid resistance, but not the genotype of Mycobacterium tuberculosis drives rifampicin resistance codon preference in vitro. AB - Both the probability of a mutation occurring and the ability of the mutant to persist will influence the distribution of mutants that arise in a population. We studied the interaction of these factors for the in vitro selection of rifampicin (RIF)-resistant mutants of Mycobacterium tuberculosis. We characterised two series of spontaneous RIF-resistant in vitro mutants from isoniazid (INH) sensitive and -resistant laboratory strains and clinical isolates, representing various M. tuberculosis genotypes. The first series were selected from multiple parallel 1 ml cultures and the second from single 10 ml cultures. RIF-resistant mutants were screened by Multiplex Ligation-dependent Probe Amplification (MLPA) or by sequencing the rpoB gene. For all strains the mutation rate for RIF resistance was determined with a fluctuation assay. The most striking observation was a shift towards rpoB-S531L (TCG->TTG) mutations in a panel of laboratory generated INH-resistant mutants selected from the 10-ml cultures (p<0.001). All tested strains showed similar mutation rates (1.33*10-8 to 2.49*10-7) except one of the laboratory-generated INH mutants with a mutation rate measured at 5.71*10 7, more than 10 times higher than that of the INH susceptible parental strain (5.46-7.44*10-8). No significant, systematic difference in the spectrum of rpoB mutations between strains of different genotypes was observed. The dramatic shift towards rpoB-S531L in our INH-resistant laboratory mutants suggests that the relative fitness of resistant mutants can dramatically impact the distribution of (subsequent) mutations that accumulate in a M. tuberculosis population, at least in vitro. We conclude that, against specific genetic backgrounds, certain resistance mutations are particularly likely to spread. Molecular screening for these (combinations of) mutations in clinical isolates could rapidly identify these particular pathogenic strains. We therefore recommend that isolates are screened for the distribution of resistance mutations, especially in regions that are highly endemic for (multi)drug resistant tuberculosis. PMID- 22235264 TI - Using the Tg(nrd:egfp)/albino zebrafish line to characterize in vivo expression of neurod. AB - In this study, we used a newly-created transgenic zebrafish, Tg(nrd:egfp)/albino, to further characterize the expression of neurod in the developing and adult retina and to determine neurod expression during adult photoreceptor regeneration. We also provide observations regarding the expression of neurod in a variety of other tissues. In this line, EGFP is found in cells of the developing and adult retina, pineal gland, cerebellum, olfactory bulbs, midbrain, hindbrain, neural tube, lateral line, inner ear, pancreas, gut, and fin. Using immunohistochemistry and in situ hybridization, we compare the expression of the nrd:egfp transgene to that of endogenous neurod and to known retinal cell types. Consistent with previous data based on in situ hybridizations, we show that during retinal development, the nrd:egfp transgene is not expressed in proliferating retinal neuroepithelium, and is expressed in a subset of retinal neurons. In contrast to previous studies, nrd:egfp is gradually re-expressed in all rod photoreceptors. During photoreceptor regeneration in adult zebrafish, in situ hybridization reveals that neurod is not expressed in Muller glial-derived neuronal progenitors, but is expressed in photoreceptor progenitors as they migrate to the outer nuclear layer and differentiate into new rod photoreceptors. During photoreceptor regeneration, expression of the nrd:egfp matches that of neurod. We conclude that Tg(nrd:egfp)/albino is a good representation of endogenous neurod expression, is a useful tool to visualize neurod expression in a variety of tissues and will aid investigating the fundamental processes that govern photoreceptor regeneration in adults. PMID- 22235265 TI - Dynamic patterns of circulating seasonal and pandemic A(H1N1)pdm09 influenza viruses from 2007-2010 in and around Delhi, India. AB - Influenza surveillance was carried out in a subset of patients with influenza like illness (ILI) presenting at an Employee Health Clinic (EHS) at All India Institute of Medical Sciences (AIIMS), New Delhi (urban) and pediatric out patients department of civil hospital at Ballabhgarh (peri-urban), under the Comprehensive Rural Health Services Project (CRHSP) of AIIMS, in Delhi region from January 2007 to December 2010. Of the 3264 samples tested, 541 (17%) were positive for influenza viruses, of which 221 (41%) were pandemic Influenza A(H1N1)pdm09, 168 (31%) were seasonal influenza A, and 152 (28%) were influenza B. While the Influenza viruses were detected year-round, their types/subtypes varied remarkably. While there was an equal distribution of seasonal A(H1N1) and influenza B in 2007, predominance of influenza B was observed in 2008. At the beginning of 2009, circulation of influenza A(H3N2) viruses was observed, followed later by emergence of Influenza A(H1N1)pdm09 with co-circulation of influenza B viruses. Influenza B was dominant subtype in early 2010, with second wave of Influenza A(H1N1)pdm09 in August-September, 2010. With the exception of pandemic H1N1 emergence in 2009, the peaks of influenza activity coincided primarily with monsoon season, followed by minor peak in winter at both urban and rural sites. Age group analysis of influenza positivity revealed that the percent positivity of Influenza A(H1N1)pdm09 influenza virus was highest in >5-18 years age groups (OR 2.5; CI = 1.2-5.0; p = 0.009) when compared to seasonal influenza. Phylogenetic analysis of Influenza A(H1N1)pdm09 from urban and rural sites did not reveal any major divergence from other Indian strains or viruses circulating worldwide. Continued surveillance globally will help define regional differences in influenza seasonality, as well as, to determine optimal periods to implement influenza vaccination programs among priority populations. PMID- 22235266 TI - Estimating diarrhea mortality among young children in low and middle income countries. AB - BACKGROUND: Diarrhea remains one of the leading causes of morbidity and mortality among children under 5 years of age, but in many low and middle-income countries where vital registration data are lacking, updated estimates with regard to the proportion of deaths attributable to diarrhea are needed. METHODS: We conducted a systematic literature review to identify studies reporting diarrhea proportionate mortality for children 1-59 mo of age published between 1980 and 2009. Using the published proportionate mortality estimates and country level covariates we constructed a logistic regression model to estimate country and regional level proportionate mortality and estimated uncertainty bounds using Monte-Carlo simulations. FINDINGS: We identified more than 90 verbal autopsy studies from around the world to contribute data to a single-cause model. We estimated diarrhea proportionate mortality for 84 countries in 6 regions and found diarrhea to account for between 10.0% of deaths in the Americas to 31.3% of deaths in the South-east Asian region. DISCUSSION: Diarrhea remains a leading cause of death for children 1-59 mo of age. Published literature can be used to create a single cause mortality disease model to estimate mortality for countries lacking vital registration data. PMID- 22235268 TI - Characterizing spatiotemporal dynamics of methane emissions from rice paddies in Northeast China from 1990 to 2010. AB - BACKGROUND: Rice paddies have been identified as major methane (CH(4)) source induced by human activities. As a major rice production region in Northern China, the rice paddies in the Three-Rivers Plain (TRP) have experienced large changes in spatial distribution over the recent 20 years (from 1990 to 2010). Consequently, accurate estimation and characterization of spatiotemporal patterns of CH4 emissions from rice paddies has become an pressing issue for assessing the environmental impacts of agroecosystems, and further making GHG mitigation strategies at regional or global levels. METHODOLOGY/PRINCIPAL FINDINGS: Integrating remote sensing mapping with a process-based biogeochemistry model, Denitrification and Decomposition (DNDC), was utilized to quantify the regional CH(4) emissions from the entire rice paddies in study region. Based on site validation and sensitivity tests, geographic information system (GIS) databases with the spatially differentiated input information were constructed to drive DNDC upscaling for its regional simulations. Results showed that (1) The large change in total methane emission that occurred in 2000 and 2010 compared to 1990 is distributed to the explosive growth in amounts of rice planted; (2) the spatial variations in CH4 fluxes in this study are mainly attributed to the most sensitive factor soil properties, i.e., soil clay fraction and soil organic carbon (SOC) content, and (3) the warming climate could enhance CH4 emission in the cool paddies. CONCLUSIONS/SIGNIFICANCE: The study concluded that the introduction of remote sensing analysis into the DNDC upscaling has a great capability in timely quantifying the methane emissions from cool paddies with fast land use and cover changes. And also, it confirmed that the northern wetland agroecosystems made great contributions to global greenhouse gas inventory. PMID- 22235267 TI - Comprehensive in vivo mapping of the human basal ganglia and thalamic connectome in individuals using 7T MRI. AB - Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects. PMID- 22235269 TI - Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases. AB - BACKGROUND: Dermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood. METHODOLOGY AND FINDINGS: We analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN)-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN)-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN g, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin. CONCLUSIONS AND SIGNIFICANCE: As in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue. PMID- 22235270 TI - Disease-free survival after hepatic resection in hepatocellular carcinoma patients: a prediction approach using artificial neural network. AB - BACKGROUND: A database for hepatocellular carcinoma (HCC) patients who had received hepatic resection was used to develop prediction models for 1-, 3- and 5 year disease-free survival based on a set of clinical parameters for this patient group. METHODS: The three prediction models included an artificial neural network (ANN) model, a logistic regression (LR) model, and a decision tree (DT) model. Data for 427, 354 and 297 HCC patients with histories of 1-, 3- and 5-year disease-free survival after hepatic resection, respectively, were extracted from the HCC patient database. From each of the three groups, 80% of the cases (342, 283 and 238 cases of 1-, 3- and 5-year disease-free survival, respectively) were selected to provide training data for the prediction models. The remaining 20% of cases in each group (85, 71 and 59 cases in the three respective groups) were assigned to validation groups for performance comparisons of the three models. Area under receiver operating characteristics curve (AUROC) was used as the performance index for evaluating the three models. CONCLUSIONS: The ANN model outperformed the LR and DT models in terms of prediction accuracy. This study demonstrated the feasibility of using ANNs in medical decision support systems for predicting disease-free survival based on clinical databases in HCC patients who have received hepatic resection. PMID- 22235271 TI - Determinants of sustained viral suppression in HIV-infected patients with self reported poor adherence to antiretroviral therapy. AB - BACKGROUND: Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels. METHODS: Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA <400 copies/ml throughout the study period. RESULTS: From January 2003 until May 2009, 37 individuals on EFV (28 suppressed and 9 not suppressed) and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56). CONCLUSIONS: The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population. PMID- 22235272 TI - Permanent neonatal diabetes caused by creation of an ectopic splice site within the INS gene. AB - BACKGROUND: The aim of this study was to characterize the genetic etiology in a patient who presented with permanent neonatal diabetes at 2 months of age. METHODOLOGY/PRINCIPAL FINDINGS: Regulatory elements and coding exons 2 and 3 of the INS gene were amplified and sequenced from genomic and complementary DNA samples. A novel heterozygous INS mutation within the terminal intron of the gene was identified in the proband and her affected father. This mutation introduces an ectopic splice site leading to the insertion of 29 nucleotides from the intronic sequence into the mature mRNA, which results in a longer and abnormal transcript. CONCLUSIONS/SIGNIFICANCE: This study highlights the importance of routinely sequencing the exon-intron boundaries and the need to carry out additional studies to confirm the pathogenicity of any identified intronic genetic variants. PMID- 22235274 TI - New ophthalmosaurid ichthyosaurs from the European Lower Cretaceous demonstrate extensive ichthyosaur survival across the Jurassic-Cretaceous boundary. AB - BACKGROUND: Ichthyosauria is a diverse clade of marine amniotes that spanned most of the Mesozoic. Until recently, most authors interpreted the fossil record as showing that three major extinction events affected this group during its history: one during the latest Triassic, one at the Jurassic-Cretaceous boundary (JCB), and one (resulting in total extinction) at the Cenomanian-Turonian boundary. The JCB was believed to eradicate most of the peculiar morphotypes found in the Late Jurassic, in favor of apparently less specialized forms in the Cretaceous. However, the record of ichthyosaurs from the Berriasian-Barremian interval is extremely limited, and the effects of the end-Jurassic extinction event on ichthyosaurs remains poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Based on new material from the Hauterivian of England and Germany and on abundant material from the Cambridge Greensand Formation, we name a new ophthalmosaurid, Acamptonectes densus gen. et sp. nov. This taxon shares numerous features with Ophthalmosaurus, a genus now restricted to the Callovian-Berriasian interval. Our phylogenetic analysis indicates that Ophthalmosauridae diverged early in its history into two markedly distinct clades, Ophthalmosaurinae and Platypterygiinae, both of which cross the JCB and persist to the late Albian at least. To evaluate the effect of the JCB extinction event on ichthyosaurs, we calculated cladogenesis, extinction, and survival rates for each stage of the Oxfordian-Barremian interval, under different scenarios. The extinction rate during the JCB never surpasses the background extinction rate for the Oxfordian Barremian interval and the JCB records one of the highest survival rates of the interval. CONCLUSIONS/SIGNIFICANCE: There is currently no evidence that ichthyosaurs were affected by the JCB extinction event, in contrast to many other marine groups. Ophthalmosaurid ichthyosaurs remained diverse from their rapid radiation in the Middle Jurassic to their total extinction at the beginning of the Late Cretaceous. PMID- 22235273 TI - Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model. AB - Insulin-like growth factor I (IGF-I) and its type I receptor (IGF-IR) play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs) for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2'-O-methyl modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD). Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- alpha and IFN-gamma. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2'-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines. PMID- 22235275 TI - Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. AB - A fundamental question in G protein coupled receptor biology is how a single ligand acting at a specific receptor is able to induce a range of signaling that results in a variety of physiological responses. We focused on Type 1 cannabinoid receptor (CB1R) as a model GPCR involved in a variety of processes spanning from analgesia and euphoria to neuronal development, survival and differentiation. We examined receptor dimerization as a possible mechanism underlying expanded signaling responses by a single ligand and focused on interactions between CB1R and delta opioid receptor (DOR). Using co-immunoprecipitation assays as well as analysis of changes in receptor subcellular localization upon co-expression, we show that CB1R and DOR form receptor heteromers. We find that heteromerization affects receptor signaling since the potency of the CB1R ligand to stimulate G protein activity is increased in the absence of DOR, suggesting that the decrease in CB1R activity in the presence of DOR could, at least in part, be due to heteromerization. We also find that the decrease in activity is associated with enhanced PLC-dependent recruitment of arrestin3 to the CB1R-DOR complex, suggesting that interaction with DOR enhances arrestin-mediated CB1R desensitization. Additionally, presence of DOR facilitates signaling via a new CB1R-mediated anti-apoptotic pathway leading to enhanced neuronal survival. Taken together, these results support a role for CB1R-DOR heteromerization in diversification of endocannabinoid signaling and highlight the importance of heteromer-directed signal trafficking in enhancing the repertoire of GPCR signaling. PMID- 22235276 TI - Seasonal variation in vitamin D3 levels is paralleled by changes in the peripheral blood human T cell compartment. AB - It is well-recognized that vitamin D3 has immune-modulatory properties and that the variation in ultraviolet (UV) exposure affects vitamin D3 status. Here, we investigated if and to what extent seasonality of vitamin D3 levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D3 and 1,25(OH)(2)D3 levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells. In addition, an increase in naive CD4+CD45RA+ T cells with a reciprocal drop in memory CD4+CD45RO+ T cells was observed. The increase in CD4+CD45RA+ T cell count was a result of heightened proliferative capacity rather than recent thymic emigration of T cells. The percentage of Treg dropped in summer, but not the absolute Treg numbers. Notably, in the Treg population, the levels of forkhead box protein 3 (Foxp3) expression were increased in summer. Skin, gut and lymphoid tissue homing potential was increased during summer as well, exemplified by increased CCR4, CCR6, CLA, CCR9 and CCR7 levels. Also, in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines. In conclusion, seasonal variation in vitamin D3 status in vivo throughout the year is associated with changes in the human peripheral T cell compartment and may as such explain some of the seasonal variation in immune status which has been observed previously. Given that the current observations are limited to healthy adult males, larger population-based studies would be useful to validate these findings. PMID- 22235277 TI - Plants can benefit from herbivory: stimulatory effects of sheep saliva on growth of Leymus chinensis. AB - BACKGROUND: Plants and herbivores can evolve beneficial interactions. Growth factors found in animal saliva are probably key factors underlying plant compensatory responses to herbivory. However, there is still a lack of knowledge about how animal saliva interacts with herbivory intensities and how saliva can mobilize photosynthate reserves in damaged plants. METHODOLOGY/PRINCIPAL FINDINGS: The study examined compensatory responses to herbivory and sheep saliva addition for the grass species Leymus chinensis in three experiments over three years. The first two experiments were conducted in a factorial design with clipping (four levels in 2006 and five in 2007) and two saliva treatment levels. The third experiment examined the mobilization and allocation of stored carbohydrates following clipping and saliva addition treatments. Animal saliva significantly increased tiller number, number of buds, and biomass, however, there was no effect on height. Furthermore, saliva effects were dependent on herbivory intensities, associated with meristem distribution within perennial grass. Animal saliva was found to accelerate hydrolyzation of fructans and accumulation of glucose and fructose. CONCLUSIONS/SIGNIFICANCE: The results demonstrated a link between saliva and the mobilization of carbohydrates following herbivory, which is an important advance in our understanding of the evolution of plant responses to herbivory. Herbivory intensity dependence of the effects of saliva stresses the significance of optimal grazing management. PMID- 22235278 TI - Multiple routes of pesticide exposure for honey bees living near agricultural fields. AB - Populations of honey bees and other pollinators have declined worldwide in recent years. A variety of stressors have been implicated as potential causes, including agricultural pesticides. Neonicotinoid insecticides, which are widely used and highly toxic to honey bees, have been found in previous analyses of honey bee pollen and comb material. However, the routes of exposure have remained largely undefined. We used LC/MS-MS to analyze samples of honey bees, pollen stored in the hive and several potential exposure routes associated with plantings of neonicotinoid treated maize. Our results demonstrate that bees are exposed to these compounds and several other agricultural pesticides in several ways throughout the foraging period. During spring, extremely high levels of clothianidin and thiamethoxam were found in planter exhaust material produced during the planting of treated maize seed. We also found neonicotinoids in the soil of each field we sampled, including unplanted fields. Plants visited by foraging bees (dandelions) growing near these fields were found to contain neonicotinoids as well. This indicates deposition of neonicotinoids on the flowers, uptake by the root system, or both. Dead bees collected near hive entrances during the spring sampling period were found to contain clothianidin as well, although whether exposure was oral (consuming pollen) or by contact (soil/planter dust) is unclear. We also detected the insecticide clothianidin in pollen collected by bees and stored in the hive. When maize plants in our field reached anthesis, maize pollen from treated seed was found to contain clothianidin and other pesticides; and honey bees in our study readily collected maize pollen. These findings clarify some of the mechanisms by which honey bees may be exposed to agricultural pesticides throughout the growing season. These results have implications for a wide range of large-scale annual cropping systems that utilize neonicotinoid seed treatments. PMID- 22235279 TI - Recombinant probiotic expressing Listeria adhesion protein attenuates Listeria monocytogenes virulence in vitro. AB - BACKGROUND: Listeria monocytogenes, an intracellular foodborne pathogen, infects immunocompromised hosts. The primary route of transmission is through contaminated food. In the gastrointestinal tract, it traverses the epithelial barrier through intracellular or paracellular routes. Strategies to prevent L. monocytogenes entry can potentially minimize infection in high-risk populations. Listeria adhesion protein (LAP) aids L. monocytogenes in crossing epithelial barriers via the paracellular route. The use of recombinant probiotic bacteria expressing LAP would aid targeted clearance of Listeria from the gut and protect high-risk populations from infection. METHODOLOGY/PRINCIPAL FINDINGS: The objective was to investigate the ability of probiotic bacteria or LAP-expressing recombinant probiotic Lactobacillus paracasei (Lbp(LAP)) to prevent L. monocytogenes adhesion, invasion, and transwell-based transepithelial translocation in a Caco-2 cell culture model. Several wild type probiotic bacteria showed strong adhesion to Caco-2 cells but none effectively prevented L. monocytogenes infection. Pre-exposure to Lbp(LAP) for 1, 4, 15, or 24 h significantly (P<0.05) reduced adhesion, invasion, and transepithelial translocation of L. monocytogenes in Caco-2 cells, whereas pre-exposure to parental Lb. paracasei had no significant effect. Similarly, Lbp(LAP) pre exposure reduced L. monocytogenes translocation by as much as 46% after 24 h. Lbp(LAP) also prevented L. monocytogenes-mediated cell damage and compromise of tight junction integrity. Furthermore, Lbp(LAP) cells reduced L. monocytogenes mediated cell cytotoxicity by 99.8% after 1 h and 79% after 24 h. CONCLUSIONS/SIGNIFICANCE: Wild type probiotic bacteria were unable to prevent L. monocytogenes infection in vitro. In contrast, Lbp(LAP) blocked adhesion, invasion, and translocation of L. monocytogenes by interacting with host cell receptor Hsp60, thereby protecting cells from infection. These data show promise for the use of recombinant probiotics in preventing L. monocytogenes infection in high-risk populations. PMID- 22235280 TI - Identification of naturally processed hepatitis C virus-derived major histocompatibility complex class I ligands. AB - Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS31406-1415 and NS5B2594 2602). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future. PMID- 22235281 TI - Genomic HIV RNA induces innate immune responses through RIG-I-dependent sensing of secondary-structured RNA. AB - BACKGROUND: Innate immune responses have recently been appreciated to play an important role in the pathogenesis of HIV infection. Whereas inadequate innate immune sensing of HIV during acute infection may contribute to failure to control and eradicate infection, persistent inflammatory responses later during infection contribute in driving chronic immune activation and development of immunodeficiency. However, knowledge on specific HIV PAMPs and cellular PRRs responsible for inducing innate immune responses remains sparse. METHODS/PRINCIPAL FINDINGS: Here we demonstrate a major role for RIG-I and the adaptor protein MAVS in induction of innate immune responses to HIV genomic RNA. We found that secondary structured HIV-derived RNAs induced a response similar to genomic RNA. In primary human peripheral blood mononuclear cells and primary human macrophages, HIV RNA induced expression of IFN-stimulated genes, whereas only low levels of type I IFN and tumor necrosis factor alpha were produced. Furthermore, secondary structured HIV-derived RNA activated pathways to NF kappaB, MAP kinases, and IRF3 and co-localized with peroxisomes, suggesting a role for this organelle in RIG-I-mediated innate immune sensing of HIV RNA. CONCLUSIONS/SIGNIFICANCE: These results establish RIG-I as an innate immune sensor of cytosolic HIV genomic RNA with secondary structure, thereby expanding current knowledge on HIV molecules capable of stimulating the innate immune system. PMID- 22235282 TI - Ureteral stent retrieval using the crochet hook technique in females. AB - INTRODUCTION: We developed a method for ureteral stent removal in female patients that requires no cystoscopy or fluoroscopic guidance using a crochet hook. In addition, we also investigated the success rate, complications and pain associated with this procedure. METHODS: A total of 40 female patients (56 stents) underwent the removal of ureteral stents. All procedures were carried out with the patients either under anesthesia, conscious sedation, or analgesic suppositories as deemed appropriate for each procedure including Shock Wave Lithotripsy (SWL), Ureteroscopy (URS), Percutaneous Nephrolithotomy (PCNL), and ureteral stent removal. At the time of these procedures, fluoroscopy and/or cystoscopy were prepared, but they were not used unless we failed to successfully remove the ureteral stent using the crochet hook. In addition, matched controls (comprising 50 stents) which were removed by standard ureteral stent removal using cystoscopy were used for comparison purposes. RESULTS: A total of 47 of the 56 stents (83.9%) were successfully removed. In addition, 47 of 52 (90.4%) were successfully removed except for two migrated stents and two heavily encrusted stents which could not be removed using cystoscopy. Ureteral stent removal using the crochet hook technique was unsuccessful in nine patients, including two encrustations and two migrations. Concerning pain, ureteral stent removal using the crochet hook technique showed a lower visual analogue pain scale (VAPS) score than for the standard technique using cystoscopy. CONCLUSIONS: Ureteral stent removal using a crochet hook is considered to be easy, safe, and cost effective. This technique is also easy to learn and is therefore considered to be suitable for use on an outpatient basis. PMID- 22235283 TI - Challenge of pigs with classical swine fever viruses after C-strain vaccination reveals remarkably rapid protection and insights into early immunity. AB - Pre-emptive culling is becoming increasingly questioned as a means of controlling animal diseases, including classical swine fever (CSF). This has prompted discussions on the use of emergency vaccination to control future CSF outbreaks in domestic pigs. Despite a long history of safe use in endemic areas, there is a paucity of data on aspects important to emergency strategies, such as how rapidly CSFV vaccines would protect against transmission, and if this protection is equivalent for all viral genotypes, including highly divergent genotype 3 strains. To evaluate these questions, pigs were vaccinated with the Riemser(r) C strain vaccine at 1, 3 and 5 days prior to challenge with genotype 2.1 and 3.3 challenge strains. The vaccine provided equivalent protection against clinical disease caused by for the two challenge strains and, as expected, protection was complete at 5 days post-vaccination. Substantial protection was achieved after 3 days, which was sufficient to prevent transmission of the 3.3 strain to animals in direct contact. Even by one day post-vaccination approximately half the animals were partially protected, and were able to control the infection, indicating that a reduction of the infectious potential is achieved very rapidly after vaccination. There was a close temporal correlation between T cell IFN gamma responses and protection. Interestingly, compared to responses of animals challenged 5 days after vaccination, challenge of animals 3 or 1 days post vaccination resulted in impaired vaccine-induced T cell responses. This, together with the failure to detect a T cell IFN-gamma response in unprotected and unvaccinated animals, indicates that virulent CSFV can inhibit the potent antiviral host defences primed by C-strain in the early period post vaccination. PMID- 22235284 TI - The molecular balance between receptor tyrosine kinases Tie1 and Tie2 is dynamically controlled by VEGF and TNFalpha and regulates angiopoietin signalling. AB - Angiopoietin-1 (Ang1) signals via the receptor tyrosine kinase Tie2 which exists in complex with the related protein Tie1 at the endothelial cell surface. Tie1 undergoes regulated ectodomain cleavage in response to phorbol esters, vascular endothelial growth factor (VEGF) and tumour necrosis factor-alpha (TNFalpha). Recently phorbol esters and VEGF were found also to stimulate ectodomain cleavage of Tie2. Here we investigate for the first time the effects of factors activating ectodomain cleavage on both Tie1 and Tie2 within the same population of cells, and their impact on angiopoietin signalling. We find that phorbol ester and VEGF activated Tie1 cleavage within minutes followed by restoration to control levels by 24 h. However, several hours of PMA and VEGF treatment were needed to elicit a detectable decrease in cellular Tie2, with complete loss seen at 24 h of PMA treatment. TNFalpha stimulated Tie1 cleavage, and induced a sustained decrease in cellular Tie1 over 24 h whilst increasing cellular Tie2. These differential effects of agonists on Tie1 and Tie2 result in dynamic modulation of the cellular Tie2?Tie1 ratio. To assess the impact of this on Ang1 signalling cells were stimulated with VEGF and TNFalpha for differing times and Ang1-induced Tie2 phosphorylation examined. Elevated Tie2?Tie1, in response to acute VEGF treatment or chronic TNFalpha, was associated with increased Ang1-activated Tie2 in cells. These data demonstrate cellular levels of Tie1 and Tie2 are differentially regulated by pathophysiologically relevant agonists resulting in dynamic control of the cellular Tie2?Tie1 balance and modulation of Ang1 signalling. These findings highlight the importance of regulation of signalling at the level of the receptor. Such control may be an important adaptation to allow modulation of cellular signalling responses in systems in which the activating ligand is normally present in excess or where the ligand provides a constitutive maintenance signal. PMID- 22235285 TI - Body composition, symptoms, and survival in advanced cancer patients referred to a phase I service. AB - BACKGROUND: Body weight and body composition are relevant to the outcomes of cancer and antineoplastic therapy. However, their role in Phase I clinical trial patients is unknown. METHODS: We reviewed symptom burden, body composition, and survival in 104 patients with advanced cancer referred to a Phase I oncology service. Symptom burden was analyzed using the MD Anderson Symptom Assessment Inventory(MDASI); body composition was evaluated utilizing computerized tomography(CT) images. A body mass index (BMI)>=25 kg/m2 was considered overweight. Sarcopenia, severe muscle depletion, was assessed using CT-based criteria. RESULTS: Most patients were overweight (n = 65, 63%); 53 patients were sarcopenic (51%), including 79% of patients with a BMI<25 kg/m2 and 34% of those with BMI>=25 kg/m2. Sarcopenic patients were older and less frequently African American. Symptom burden did not differ among patients classified according to BMI and presence of sarcopenia. Median (95% confidence interval) survival (days) varied according to body composition: 215 (71-358) (BMI<25 kg/m2; sarcopenic), 271 (99-443) (BMI<25 kg/m2; non-sarcopenic), 484 (286-681) (BMI>=25 kg/m2; sarcopenic); 501 d (309-693) (BMI>=25 kg/m2; non-sarcopenic). Higher muscle index and gastrointestinal cancer diagnosis predicted longer survival in multivariate analysis after controlling for age, gender, performance status, and fat index. CONCLUSIONS: Patients referred to a Phase I clinic had a high frequency of sarcopenia and a BMI>=25 kg/m2, independent of symptom burden. Body composition variables were predictive of clinically relevant survival differences, which is potentially important in developing Phase I studies. PMID- 22235286 TI - Intra- and inter-tumor heterogeneity of BRAF(V600E))mutations in primary and metastatic melanoma. AB - The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAF(V600E) as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAF(V600E) mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAF(V600E) allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAF(V600E)-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAF(V600E)and BRAF(wild-type) cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAF(V600E) mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAF(V600E) mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful. PMID- 22235287 TI - CART peptide is a potential endogenous antioxidant and preferentially localized in mitochondria. AB - The multifunctional neuropeptide Cocaine and Amphetamine Regulated Transcript (CART) is secreted from hypothalamus, pituitary, adrenal gland and pancreas. It also can be found in circulatory system. This feature suggests a general role for CART in different cells. In the present study, we demonstrate that CART protects mitochondrial DNA (mtDNA), cellular proteins and lipids against the oxidative action of hydrogen peroxide, a widely used oxidant. Using cis-parinaric acid as a sensitive reporting probe for peroxidation in membranes, and a lipid-soluble azo initiator of peroxyl radicals, 2,2'-azobis(2,4-dimethylvaleronitrile) we found that CART is an antioxidant. Furthermore, we found that CART localized to mitochondria in cultured cells and mouse brain neuronal cells. More importantly, pretreatment with CART by systemic injection protects against a mouse oxidative stress model, which mimics the main features of Parkinson's disease. Given the unique molecular structure and biological features of CART, we conclude that CART is an antioxidant peptide (or antioxidant hormone). We further propose that it may have strong therapeutic properties for human diseases in which oxidative stress is strongly involved such as Parkinson's disease. PMID- 22235288 TI - Acute respiratory distress syndrome induced by a swine 2009 H1N1 variant in mice. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) induced by pandemic 2009 H1N1 influenza virus has been widely reported and was considered the main cause of death in critically ill patients with 2009 H1N1 infection. However, no animal model has been developed for ARDS caused by infection with 2009 H1N1 virus. Here, we present a mouse model of ARDS induced by 2009 H1N1 virus. METHODOLOGY PRINCIPAL FINDINGS: Mice were inoculated with A/swine/Shandong/731/2009 (SD/09), which was a 2009 H1N1 influenza variant with a G222D mutation in the hemagglutinin. Clinical symptoms were recorded every day. Lung injury was assessed by lung water content and histopathological observation. Arterial blood gas, leukocyte count in the bronchial alveolar lavage fluid and blood, virus titers, and cytokine levels in the lung were measured at various times post inoculation. Mice infected with SD/09 virus showed typical ARDS symptoms characterized by 60% lethality on days 8-10 post-inoculation, highly edematous lungs, inflammatory cellular infiltration, alveolar and interstitial edema, lung hemorrhage, progressive and severe hypoxemia, and elevated levels of proinflammatory cytokines and chemokines. CONCLUSIONS/SIGNIFICANCE: These results suggested that we successfully established an ARDS mouse model induced by a virulent 2009 H1N1 variant without previous adaptation, which may be of benefit for evaluating the pathogenesis or therapy of human ARDS caused by 2009 H1N1 virus. PMID- 22235289 TI - Statistical properties and robustness of biological controller-target networks. AB - Cells are regulated by networks of controllers having many targets, and targets affected by many controllers, in a "many-to-many" control structure. Here we study several of these bipartite (two-layer) networks. We analyze both naturally occurring biological networks (composed of transcription factors controlling genes, microRNAs controlling mRNA transcripts, and protein kinases controlling protein substrates) and a drug-target network composed of kinase inhibitors and of their kinase targets. Certain statistical properties of these biological bipartite structures seem universal across systems and species, suggesting the existence of common control strategies in biology. The number of controllers is ~8% of targets and the density of links is 2.5%+/-1.2%. Links per node are predominantly exponentially distributed. We explain the conservation of the mean number of incoming links per target using a mathematical model of control networks, which also indicates that the "many-to-many" structure of biological control has properties of efficient robustness. The drug-target network has many statistical properties similar to the biological networks and we show that drug target networks with biomimetic features can be obtained. These findings suggest a completely new approach to pharmacological control of biological systems. Molecular tools, such as kinase inhibitors, are now available to test if therapeutic combinations may benefit from being designed with biomimetic properties, such as "many-to-many" targeting, very wide coverage of the target set, and redundancy of incoming links per target. PMID- 22235290 TI - A-site residues move independently from P-site residues in all-atom molecular dynamics simulations of the 70S bacterial ribosome. AB - The ribosome is a large macromolecular machine, and correlated motion between residues is necessary for coordinating function across multiple protein and RNA chains. We ran two all-atom, explicit solvent molecular dynamics simulations of the bacterial ribosome and calculated correlated motion between residue pairs by using mutual information. Because of the short timescales of our simulation (ns), we expect that dynamics are largely local fluctuations around the crystal structure. We hypothesize that residues that show coupled dynamics are functionally related, even on longer timescales. We validate our model by showing that crystallographic B-factors correlate well with the entropy calculated as part of our mutual information calculations. We reveal that A-site residues move relatively independently from P-site residues, effectively insulating A-site functions from P-site functions during translation. PMID- 22235292 TI - Retrieval of context-associated memory is dependent on the Ca(v)3.2 T-type calcium channel. AB - Among all voltage-gated calcium channels, the T-type Ca2+ channels encoded by the Ca(v)3.2 genes are highly expressed in the hippocampus, which is associated with contextual, temporal and spatial learning and memory. However, the specific involvement of the Ca(v)3.2 T-type Ca2+ channel in these hippocampus-dependent types of learning and memory remains unclear. To investigate the functional role of this channel in learning and memory, we subjected Ca(v)3.2 homozygous and heterozygous knockout mice and their wild-type littermates to hippocampus dependent behavioral tasks, including trace fear conditioning, the Morris water maze and passive avoidance. The Ca(v)3.2 -/- mice performed normally in the Morris water-maze and auditory trace fear conditioning tasks but were impaired in the context-cued trace fear conditioning, step-down and step-through passive avoidance tasks. Furthermore, long-term potentiation (LTP) could be induced for 180 minutes in hippocampal slices of WTs and Ca(v)3.2 +/- mice, whereas LTP persisted for only 120 minutes in Ca(v)3.2 -/- mice. To determine whether the hippocampal formation is responsible for the impaired behavioral phenotypes, we next performed experiments to knock down local function of the Ca(v)3.2 T-type Ca2+ channel in the hippocampus. Wild-type mice infused with mibefradil, a T-type channel blocker, exhibited similar behaviors as homozygous knockouts. Taken together, our results demonstrate that retrieval of context-associated memory is dependent on the Ca(v)3.2 T-type Ca2+ channel. PMID- 22235291 TI - Pharmacological inhibition of caspase and calpain proteases: a novel strategy to enhance the homing responses of cord blood HSPCs during expansion. AB - BACKGROUND: Expansion of hematopoietic stem/progenitor cells (HSPCs) is a well known strategy employed to facilitate the transplantation outcome. We have previously shown that the prevention of apoptosis by the inhibition of cysteine proteases, caspase and calpain played an important role in the expansion and engraftment of cord blood (CB) derived HSPCs. We hypothesize that these protease inhibitors might have maneuvered the adhesive and migratory properties of the cells rendering them to be retained in the bone marrow for sustained engraftment. The current study was aimed to investigate the mechanism of the homing responses of CB cells during expansion. METHODOLOGY/PRINCIPAL FINDINGS: CB derived CD34(+) cells were expanded using a combination of growth factors with and without Caspase inhibitor -zVADfmk or Calpain 1 inhibitor- zLLYfmk. The cells were analyzed for the expression of homing-related molecules. In vitro adhesive/migratory interactions and actin polymerization dynamics of HSPCs were assessed. In vivo homing assays were carried out in NOD/SCID mice to corroborate these observations. We observed that the presence of zVADfmk or zLLYfmk (inhibitors) caused the functional up regulation of CXCR4, integrins, and adhesion molecules, reflecting in a higher migration and adhesive interactions in vitro. The enhanced actin polymerization and the RhoGTPase protein expression complemented these observations. Furthermore, in vivo experiments showed a significantly enhanced homing to the bone marrow of NOD/SCID mice. CONCLUSION/SIGNIFICANCE: Our present study reveals another novel aspect of the regulation of caspase and calpain proteases in the biology of HSPCs. The priming of the homing responses of the inhibitor-cultured HSPCs compared to the cytokine graft suggests that the modulation of these proteases may help in overcoming the major homing defects prevalent in the expansion cultures thereby facilitating the manipulation of cells for transplant procedures. PMID- 22235293 TI - Enhanced fatty acid oxidation and FATP4 protein expression after endurance exercise training in human skeletal muscle. AB - FATP1 and FATP4 appear to be important for the cellular uptake and handling of long chain fatty acids (LCFA). These findings were obtained from loss- or gain of function models. However, reports on FATP1 and FATP4 in human skeletal muscle are limited. Aerobic training enhances lipid oxidation; however, it is not known whether this involves up-regulation of FATP1 and FATP4 protein. Therefore, the aim of this project was to investigate FATP1 and FATP4 protein expression in the vastus lateralis muscle from healthy human individuals and to what extent FATP1 and FATP4 protein expression were affected by an increased fuel demand induced by exercise training. Eight young healthy males were recruited to the study. All subjects were non smokers and did not participate in regular physical activity (<1 time per week for the past 6 months, VO(2peak) 3.4+/-0.1 l O2 min-1). Subjects underwent an 8 week supervised aerobic training program. Training induced an increase in VO(2peak) from 3.4+/-0.1 to 3.9+/-0.1 l min-1 and citrate synthase activity was increased from 53.7+/-2.5 to 80.8+/-3.7 umol g-1 min-1. The protein content of FATP4 was increased by 33%, whereas FATP1 protein content was reduced by 20%. Interestingly, at the end of the training intervention a significant association (r2 = 0.74) between the observed increase in skeletal muscle FATP4 protein expression and lipid oxidation during a 120 min endurance exercise test was observed. In conclusion, based on the present findings it is suggested that FATP1 and FATP4 proteins perform different functional roles in handling LCFA in skeletal muscle with FATP4 apparently more important as a lipid transport protein directing lipids for lipid oxidation. PMID- 22235294 TI - The complete mitochondrial genome and novel gene arrangement of the unique-headed bug Stenopirates sp. (Hemiptera: Enicocephalidae). AB - Many of true bugs are important insect pests to cultivated crops and some are important vectors of human diseases, but few cladistic analyses have addressed relationships among the seven infraorders of Heteroptera. The Enicocephalomorpha and Nepomorpha are consider the basal groups of Heteroptera, but the basal-most lineage remains unresolved. Here we report the mitochondrial genome of the unique headed bug Stenopirates sp., the first mitochondrial genome sequenced from Enicocephalomorpha. The Stenopirates sp. mitochondrial genome is a typical circular DNA molecule of 15, 384 bp in length, and contains 37 genes and a large non-coding fragment. The gene order differs substantially from other known insect mitochondrial genomes, with rearrangements of both tRNA genes and protein-coding genes. The overall AT content (82.5%) of Stenopirates sp. is the highest among all the known heteropteran mitochondrial genomes. The strand bias is consistent with other true bugs with negative GC-skew and positive AT-skew for the J-strand. The heteropteran mitochondrial atp8 exhibits the highest evolutionary rate, whereas cox1 appears to have the lowest rate. Furthermore, a negative correlation was observed between the variation of nucleotide substitutions and the GC content of each protein-coding gene. A microsatellite was identified in the putative control region. Finally, phylogenetic reconstruction suggests that Enicocephalomorpha is the sister group to all the remaining Heteroptera. PMID- 22235295 TI - HIV Pol inhibits HIV budding and mediates the severe budding defect of Gag-Pol. AB - The prevailing hypothesis of HIV budding posits that the viral Gag protein drives budding, and that the Gag p6 peptide plays an essential role by recruiting host cell budding factors to sites of HIV assembly. HIV also expresses a second Gag protein, p160 Gag-Pol, which lacks p6 and fails to bud from cells, consistent with the prevailing hypothesis of HIV budding. However, we show here that the severe budding defect of Gag-Pol is not caused by the absence of p6, but rather, by the presence of Pol. Specifically, we show that (i) the budding defect of Gag Pol is unaffected by loss of HIV protease activity and is therefore an intrinsic property of the Gag-Pol polyprotein, (ii) the N-terminal 433 amino acids of Gag and Gag-Pol are sufficient to drive virus budding even though they lack p6, (iii) the severe budding defect of Gag-Pol is caused by a dominant, cis-acting inhibitor of budding in the HIV Pol domain, and (iv) Gag-Pol inhibits Gag and virus budding in trans, even at normal levels of Gag and Gag-Pol expression. These and other data support an alternative hypothesis of HIV budding as a process that is mediated by the normal, non-viral pathway of exosome/microvesicle biogenesis. PMID- 22235298 TI - High prevalence of human parvovirus 4 infection in HBV and HCV infected individuals in shanghai. AB - Human parvovirus 4 (PARV4) has been detected in blood and diverse tissues samples from HIV/AIDS patients who are injecting drug users. Although B19 virus, the best characterized human parvovirus, has been shown to co-infect patients with hepatitis B or hepatitis C virus (HBV, HCV) infection, the association of PARV4 with HBV or HCV infections is still unknown.The aim of this study was to characterise the association of viruses belonging to PARV4 genotype 1 and 2 with chronic HBV and HCV infection in Shanghai.Serum samples of healthy controls, HCV infected subjects and HBV infected subjects were retrieved from Shanghai Center for Disease Control and Prevention (SCDC) Sample Bank. Parvovirus-specific nested PCR was performed and results confirmed by sequencing. Sequences were compared with reference sequences obtained from Genbank to derive phylogeny trees.The frequency of parvovirus molecular detection was 16-22%, 33% and 41% in healthy controls, HCV infected and HBV infected subjects respectively, with PARV4 being the only parvovirus detected. HCV infected and HBV infected subjects had a significantly higher PARV4 prevalence than the healthy population. No statistical difference was found in PARV4 prevalence between HBV or HCV infected subjects. PARV4 sequence divergence within study groups was similar in healthy subjects, HBV or HCV infected subjects.Our data clearly demonstrate that PARV4 infection is strongly associated with HCV and HBV infection in Shanghai but may not cause increased disease severity. PMID- 22235296 TI - Profiling of differentially expressed genes using suppression subtractive hybridization in an equine model of chronic asthma. AB - BACKGROUND: Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. OBJECTIVE: To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tissue of horses with heaves, a naturally occurring asthma-like condition. METHODS: Eleven adult horses (6 heaves-affected and 5 controls) were studied while horses with heaves were in clinical remission (Pasture), and during disease exacerbation induced by a 30-day natural antigen challenge during stabling (Challenge). Large peripheral lung biopsies were obtained by thoracoscopy at both time points. Using suppression subtractive hybridization (SSH), lung cDNAs of controls (Pasture and Challenge) and asymptomatic heaves-affected horses (Pasture) were subtracted from cDNAs of horses with heaves in clinical exacerbation (Challenge). The differential expression of selected genes of interest was confirmed using quantitative PCR assay. RESULTS: Horses with heaves, but not controls, developed airway obstruction when challenged. Nine hundred and fifty cDNA clones isolated from the subtracted library were screened by dot blot array and 224 of those showing the most marked expression differences were sequenced. The gene expression pattern was confirmed by quantitative PCR in 15 of 22 selected genes. Novel genes and genes with an already defined function in asthma were identified in the subtracted cDNA library. Genes of particular interest associated with asthmatic airway inflammation and remodeling included those related to PPP3CB/NFAT, RhoA, and LTB4/GPR44 signaling pathways. CONCLUSIONS: Pathways representing new possible targets for anti-inflammatory and anti-remodeling therapies for asthma were identified. The findings of genes previously associated with asthma validate this equine model for gene expression studies. PMID- 22235297 TI - siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis. AB - Keratosis linearis with ichthyosis congenita and keratoderma (KLICK) is an autosomal recessive skin disorder associated with a single-nucleotide deletion in the 5'untranslated region of the proteasome maturation protein (POMP) gene. The deletion causes a relative switch in transcription start sites for POMP, predicted to decrease levels of POMP protein in terminally differentiated keratinocytes. To investigate the pathophysiology behind KLICK we created an in vitro model of the disease using siRNA silencing of POMP in epidermal air-liquid cultures. Immunohistochemical analysis of the tissue constructs revealed aberrant staining of POMP, proteasome subunits and the skin differentiation marker filaggrin when compared to control tissue constructs. The staining patterns of POMP siRNA tissue constructs showed strong resemblance to those observed in skin biopsies from KLICK patients. Western blot analysis of lysates from the organotypic tissue constructs revealed an aberrant processing of profilaggrin to filaggrin in samples transfected with siRNA against POMP. Knock-down of POMP expression in regular cell cultures resulted in decreased amounts of proteasome subunits. Prolonged silencing of POMP in cultured cells induced C/EBP homologous protein (CHOP) expression consistent with an activation of the unfolded protein response and increased endoplasmic reticulum (ER) stress. The combined results indicate that KLICK is caused by reduced levels of POMP, leading to proteasome insufficiency in differentiating keratinocytes. Proteasome insufficiency disturbs terminal epidermal differentiation, presumably by increased ER stress, and leads to perturbed processing of profilaggrin. Our findings underline a critical role for the proteasome in human epidermal differentiation. PMID- 22235299 TI - High phosphorus diet-induced changes in NaPi-IIb phosphate transporter expression in the rat kidney: DNA microarray analysis. AB - The mechanism by which phosphorus levels are maintained in the body was investigated by analyzing changes in gene expression in the rat kidney following administration of a high phosphorus (HP) diet. Male Wistar rats were divided into two groups and fed a diet containing 0.3% (control) or 1.2% (HP) phosphorous for 24 days. Phosphorous retention was not significantly increased in HP rats, but fractional excretion of phosphorus was significantly increased in the HP group compared to controls, with an excessive amount of the ingested phosphorus being passed through the body. DNA microarray analysis of kidney tissue from both groups revealed changes in gene expression profile induced by a HP diet. Among the genes that were upregulated, Gene Ontology (GO) terms related to ossification, collagen fibril organization, and inflammation and immune response were significantly enriched. In particular, there was significant upregulation of type IIb sodium-dependent phosphate transporter (NaPi-IIb) in the HP rat kidney compared to control rats. This upregulation was confirmed by in situ hybridization. Distinct signals for NaPi-IIb in both the cortex and medulla of the kidney were apparent in the HP group, while the corresponding signals were much weaker in the control group. Immunohistochemical analysis showed that NaPi IIb localized to the basolateral side of kidney epithelial cells surrounding the urinary duct in HP rats but not in control animals. These data suggest that NaPi IIb is upregulated in the kidney in response to the active excretion of phosphate in HP diet-fed rats. PMID- 22235300 TI - Genomic arrangement of regulons in bacterial genomes. AB - Regulons, as groups of transcriptionally co-regulated operons, are the basic units of cellular response systems in bacterial cells. While the concept has been long and widely used in bacterial studies since it was first proposed in 1964, very little is known about how its component operons are arranged in a bacterial genome. We present a computational study to elucidate of the organizational principles of regulons in a bacterial genome, based on the experimentally validated regulons of E. coli and B. subtilis. Our results indicate that (1) genomic locations of transcriptional factors (TFs) are under stronger evolutionary constraints than those of the operons they regulate so changing a TF's genomic location will have larger impact to the bacterium than changing the genomic position of any of its target operons; (2) operons of regulons are generally not uniformly distributed in the genome but tend to form a few closely located clusters, which generally consist of genes working in the same metabolic pathways; and (3) the global arrangement of the component operons of all the regulons in a genome tends to minimize a simple scoring function, indicating that the global arrangement of regulons follows simple organizational principles. PMID- 22235301 TI - Connecting the dots between PubMed abstracts. AB - BACKGROUND: There are now a multitude of articles published in a diversity of journals providing information about genes, proteins, pathways, and diseases. Each article investigates subsets of a biological process, but to gain insight into the functioning of a system as a whole, we must integrate information from multiple publications. Particularly, unraveling relationships between extra cellular inputs and downstream molecular response mechanisms requires integrating conclusions from diverse publications. METHODOLOGY: We present an automated approach to biological knowledge discovery from PubMed abstracts, suitable for "connecting the dots" across the literature. We describe a storytelling algorithm that, given a start and end publication, typically with little or no overlap in content, identifies a chain of intermediate publications from one to the other, such that neighboring publications have significant content similarity. The quality of discovered stories is measured using local criteria such as the size of supporting neighborhoods for each link and the strength of individual links connecting publications, as well as global metrics of dispersion. To ensure that the story stays coherent as it meanders from one publication to another, we demonstrate the design of novel coherence and overlap filters for use as post processing steps. CONCLUSIONS: WE DEMONSTRATE THE APPLICATION OF OUR STORYTELLING ALGORITHM TO THREE CASE STUDIES: i) a many-one study exploring relationships between multiple cellular inputs and a molecule responsible for cell-fate decisions, ii) a many-many study exploring the relationships between multiple cytokines and multiple downstream transcription factors, and iii) a one-to-one study to showcase the ability to recover a cancer related association, viz. the Warburg effect, from past literature. The storytelling pipeline helps narrow down a scientist's focus from several hundreds of thousands of relevant documents to only around a hundred stories. We argue that our approach can serve as a valuable discovery aid for hypothesis generation and connection exploration in large unstructured biological knowledge bases. PMID- 22235302 TI - Henoch schonlein purpura--a 5-year review and proposed pathway. AB - Henoch Schonlein Purpura (HSP) is the commonest systemic vasculitis of childhood typically presenting with a palpable purpuric rash and frequently involving the renal system. We are the first group to clinically assess, critically analyse and subsequently revise a nurse led monitoring pathway for this condition.A cohort of 102 children presenting with HSP to a secondary/tertiary level UK paediatric hospital over a five year period, were monitored using a nurse led care pathway. Using this cohort, the incidence (6.21 cases per 100,000 children per year) and natural disease course of HSP nephritis (46% initial renal inflammation; 9% subsequent renal referral; 1% renal biopsy and immunosuppression) was determined. Older patients were at higher risk of requiring a renal referral (renal referral 12.3 (8.4-13.5) years vs. normal outcome 6.0 (3.7-8.5) years; p<0.01). A normal urinalysis on day 7 had a 97% (confidence interval 90 to 99%) negative predictive value in predicting a normal renal outcome.Using this data and existing literature base, The Alder Hey Henoch Schonlein Purpura Pathway was developed, a revised pathway for the screening of poor renal outcome in HSP. This is based on a six-month monitoring period for all patients presenting with HSP, which importantly prioritises patients according to the urine findings on day 7 and thus intensively monitors those at higher risk of developing nephritis. The pathway could be easily adapted for use in different settings and resources.The introduction of a standardised pathway for the monitoring of HSP will facilitate the implementation of disease registries to further our understanding of the condition and permit future clinical trials. PMID- 22235303 TI - A functional and structural investigation of the human fronto-basal volitional saccade network. AB - Almost all cortical areas are connected to the subcortical basal ganglia (BG) through parallel recurrent inhibitory and excitatory loops, exerting volitional control over automatic behavior. As this model is largely based on non-human primate research, we used high resolution functional MRI and diffusion tensor imaging (DTI) to investigate the functional and structural organization of the human (pre)frontal cortico-basal network controlling eye movements. Participants performed saccades in darkness, pro- and antisaccades and observed stimuli during fixation. We observed several bilateral functional subdivisions along the precentral sulcus around the human frontal eye fields (FEF): a medial and lateral zone activating for saccades in darkness, a more fronto-medial zone preferentially active for ipsilateral antisaccades, and a large anterior strip along the precentral sulcus activating for visual stimulus presentation during fixation. The supplementary eye fields (SEF) were identified along the medial wall containing all aforementioned functions. In the striatum, the BG area receiving almost all cortical input, all saccade related activation was observed in the putamen, previously considered a skeletomotor striatal subdivision. Activation elicited by the cue instructing pro or antisaccade trials was clearest in the medial FEF and right putamen. DTI fiber tracking revealed that the subdivisions of the human FEF complex are mainly connected to the putamen, in agreement with the fMRI findings. The present findings demonstrate that the human FEF has functional subdivisions somewhat comparable to non-human primates. However, the connections to and activation in the human striatum preferentially involve the putamen, not the caudate nucleus as is reported for monkeys. This could imply that fronto-striatal projections for the oculomotor system are fundamentally different between humans and monkeys. Alternatively, there could be a bias in published reports of monkey studies favoring the caudate nucleus over the putamen in the search for oculomotor functions. PMID- 22235304 TI - Knockdown of ZNF268, which is transcriptionally downregulated by GATA-1, promotes proliferation of K562 cells. AB - The human ZNF268 gene encodes a typical KRAB-C2H2 zinc finger protein that may participate in hematopoiesis and leukemogenesis. A recent microarray study revealed that ZNF268 expression continuously decreases during erythropoiesis. However, the molecular mechanisms underlying regulation of ZNF268 during hematopoiesis are not well understood. Here we found that GATA-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of ZNF268. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that GATA-1 directly bound to a GATA binding site in the ZNF268 promoter in vitro and in vivo. Knockdown of ZNF268 in K562 erythroleukemia cells with specific siRNA accelerated cellular proliferation, suppressed apoptosis, and reduced expression of erythroid-specific developmental markers. It also promoted growth of subcutaneous K562-derived tumors in nude mice. These results suggest that ZNF268 is a crucial downstream target and effector of GATA-1. They also suggest the downregulation of ZNF268 by GATA-1 is important in promoting the growth and suppressing the differentiation of K562 erythroleukemia cells. PMID- 22235305 TI - miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma. AB - Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by gamma-secretase inhibitors (GSIs), we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sezary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL. PMID- 22235306 TI - Managing the marine aquarium trade: revealing the data gaps using ornamental polychaetes. AB - The marine aquarium industry has great potential to generate jobs in low-income coastal communities creating incentives for the maintenance of a healthy coral reef, if effectively managed. In the absence of current monitoring or legislation to govern the trade, baseline information regarding the species, number and source location of animals traded is missing despite being critical for its successful management and sustainability. An industry assessment to establish the number and provenance of species of ornamental polychaetes (sabellids and serpulids) traded was undertaken across UK wholesalers and retailers. Six geographical regions exporting fan worms were identified. Singapore contributed the highest percentage of imports, but of only one worm "type" whereas Bali, the second largest source, supplied five different worm "types". Over 50% of UK retailers were supplied by one wholesaler while the remainder were stocked by a mixture of one other wholesaler and/or direct imports from the source country. We estimate that up to 18,500 ornamental polychaetes (16,980 sabellids and 1,018 serpulids) are sold annually in the UK revealing a drastic underestimation of currently accepted trade figures. Incorrect identification (based on exporting region or visual characteristics) of traded animals exacerbates the inaccuracy in market quantification, although identification of preserved sabellids using published keys proved just as inconclusive with high within-species variability and the potential for new or cryptic species. A re-description of the polychaete groups traded using a combination of molecular and morphological techniques is necessary for effective identification and market quantification. This study provides the first assessment of ornamental polychaetes but more importantly highlights the issues surrounding the collection of baseline information necessary to manage the aquarium trade. We recommend that future management should be community based and site-specific with financial and educational support from NGOs, local governments and industry members. PMID- 22235307 TI - Distinct roles for aryl hydrocarbon receptor nuclear translocator and ah receptor in estrogen-mediated signaling in human cancer cell lines. AB - The activated AHR/ARNT complex (AHRC) regulates the expression of target genes upon exposure to environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD). Importantly, evidence has shown that TCDD represses estrogen receptor (ER) target gene activation through the AHRC. Our data indicates that AHR and ARNT act independently from each other at non-dioxin response element sites. Therefore, we sought to determine the specific functions of AHR and ARNT in estrogen-dependent signaling in human MCF7 breast cancer and human ECC-1 endometrial carcinoma cells. Knockdown of AHR with siRNA abrogates dioxin inducible repression of estrogen-dependent gene transcription. Intriguingly, knockdown of ARNT does not effect TCDD-mediated repression of estrogen-regulated transcription, suggesting that AHR represses ER function independently of ARNT. This theory is supported by the ability of the selective AHR modulator 3',4' dimethoxy-alpha-naphthoflavone (DiMNF) to repress estrogen-inducible transcription. Furthermore, basal and estrogen-activated transcription of the genes encoding cathepsin-D and pS2 are down-regulated in MCF7 cells but up regulated in ECC-1 cells in response to loss of ARNT. These responses are mirrored at the protein level with cathepsin-D. Furthermore, knock-down of ARNT led to opposite but corresponding changes in estrogen-stimulated proliferation in both MCF7 and ECC-1 cells. We have obtained experimental evidence demonstrating a dioxin-dependent repressor function for AHR and a dioxin-independent co activator/co-repressor function for ARNT in estrogen signalling. These results provide us with further insight into the mechanisms of transcription factor crosstalk and putative therapeutic targets in estrogen-positive cancers. PMID- 22235308 TI - Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention. AB - Helicobacter pylori (HP) is a bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa. Persistent Hp infection often induces gastritis and is associated with the development of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Virulent HP isolates harbor the cag (cytotoxin-associated genes) pathogenicity island (cagPAI), a 40 kb stretch of DNA that encodes components of a type IV secretion system (T4SS). This T4SS forms a pilus for the injection of virulence factors into host target cells, such as the CagA oncoprotein. We analyzed the genetic variability in cagA and other selected genes of the HP cagPAI (cagC, cagE, cagL, cagT, cagV and cag Gamma) using DNA extracted from frozen gastric biopsies or from clinical isolates. Study subjects were 95 cagA+ patients that were histologically diagnosed with chronic gastritis or gastric cancer in Venezuela and Mexico, areas with high prevalence of Hp infection. Sequencing reactions were carried out by both Sanger and next-generation pyrosequencing (454 Roche) methods. We found a total of 381 variants with unambiguous calls observed in at least 10% of the originally tested samples and reference strains. We compared the frequencies of these genetic variants between gastric cancer and chronic gastritis cases. Twenty six SNPs (11 non-synonymous and 14 synonymous) showed statistically significant differences (P<0.05), and two SNPs, in position 1039 and 1041 of cagE, showed a highly significant association with cancer (p-value = 2.07*10-6), and the variant codon was located in the VirB3 homology domain of Agrobacterium. The results of this study may provide preliminary information to target antibiotic treatment to high-risk individuals, if effects of these variants are confirmed in further investigations. PMID- 22235310 TI - Cryptic polyketide synthase genes in non-pathogenic Clostridium SPP. AB - Modular type I polyketide synthases (PKS) produce a vast array of bacterial metabolites with highly diverse biological functions. Notably, all known polyketides were isolated from aerobic bacteria, and yet no example has been reported for strict anaerobes. In this study we explored the diversity and distribution of PKS genes in the genus Clostridium. In addition to comparative genomic analyses combined with predictions of modular type I polyketide synthase (PKS) gene clusters in sequenced genomes of Clostridium spp., a representative selection of other species inhabiting a variety of ecological niches was investigated by PCR screening for PKS genes. Our data reveal that all studied pathogenic Clostridium spp. are devoid of putative PKS genes. In stark contrast, cryptic PKS genes are widespread in genomes of non-pathogenic Clostridium species. According to phylogenetic analyses, the Clostridium PKS genes have unusual and diverse origins. However, reverse transcription quantitative PCR demonstrates that these genes are silent under standard cultivation conditions, explaining why the related metabolites have been overlooked until now. This study presents clostridia as a putative source for novel bioactive polyketides. PMID- 22235309 TI - The transmembrane domain of CEACAM1-4S is a determinant of anchorage independent growth and tumorigenicity. AB - CEACAM1 is a multifunctional Ig-like cell adhesion molecule expressed by epithelial cells in many organs. CEACAM1-4L and CEACAM1-4S, two isoforms produced by differential splicing, are predominant in rat liver. Previous work has shown that downregulation of both isoforms occurs in rat hepatocellular carcinomas. Here, we have isolated an anchorage dependent clone, designated 253T-NT that does not express detectable levels of CEACAM1. Stable transfection of 253-NT cells with a wild type CEACAM1-4S expression vector induced an anchorage independent growth in vitro and a tumorigenic phenotype in vivo. These phenotypes were used as quantifiable end points to examine the functionality of the CEACAM1-4S transmembrane domain. Examination of the CEACAM1 transmembrane domain showed N terminal GXXXG dimerization sequences and C-terminal tyrosine residues shown in related studies to stabilize transmembrane domain helix-helix interactions. To examine the effects of transmembrane domain mutations, 253-NT cells were transfected with transmembrane domain mutants carrying glycine to leucine or tyrosine to valine substitutions. Results showed that mutation of transmembrane tyrosine residues greatly enhanced growth in vitro and in vivo. Mutation of transmembrane dimerization motifs, in contrast, significantly reduced anchorage independent growth and tumorigenicity. 253-NT cells expressing CEACAM1-4S with both glycine to leucine and tyrosine to valine mutations displayed the growth enhanced phenotype of tyrosine mutants. The dramatic effect of transmembrane domain mutations constitutes strong evidence that the transmembrane domain is an important determinant of CEACAM1-4S functionality and most likely by other proteins with transmembrane domains containing dimerization sequences and/or C terminal tyrosine residues. PMID- 22235311 TI - Factors affecting soil fauna feeding activity in a fragmented lowland temperate deciduous woodland. AB - British temperate broadleaf woodlands have been widely fragmented since the advent of modern agriculture and development. As a result, a higher proportion of woodland area is now subject to edge effects which can alter the efficiency of ecosystem functions. These areas are particularly sensitive to drought. Decomposition of detritus and nutrient cycling are driven by soil microbe and fauna coactivity. The bait lamina assay was used to assess soil fauna trophic activity in the upper soil horizons at five sites in Wytham Woods, Oxfordshire: two edge, two intermediate and one core site. Faunal trophic activity was highest in the core of the woodland, and lowest at the edge, which was correlated with a decreasing soil moisture gradient. The efficiency of the assay was tested using four different bait flavours: standardised, ash (Fraxinus excelsior L.), oak (Quercus robur L.), and sycamore (Acer pseudoplatanus L.). The standardised bait proved the most efficient flavour in terms of feeding activity. This study suggests that decomposition and nutrient cycling may be compromised in many of the UK's small, fragmented woodlands in the event of drought or climate change. PMID- 22235312 TI - True versus false parasite interactions: a robust method to take risk factors into account and its application to feline viruses. AB - BACKGROUND: Multiple infections are common in natural host populations and interspecific parasite interactions are therefore likely within a host individual. As they may seriously impact the circulation of certain parasites and the emergence and management of infectious diseases, their study is essential. In the field, detecting parasite interactions is rendered difficult by the fact that a large number of co-infected individuals may also be observed when two parasites share common risk factors. To correct for these "false interactions", methods accounting for parasite risk factors must be used. METHODOLOGY/PRINCIPAL FINDINGS: In the present paper we propose such a method for presence-absence data (i.e., serology). Our method enables the calculation of the expected frequencies of single and double infected individuals under the independence hypothesis, before comparing them to the observed ones using the chi-square statistic. The method is termed "the corrected chi-square." Its robustness was compared to a pre existing method based on logistic regression and the corrected chi-square proved to be much more robust for small sample sizes. Since the logistic regression approach is easier to implement, we propose as a rule of thumb to use the latter when the ratio between the sample size and the number of parameters is above ten. Applied to serological data for four viruses infecting cats, the approach revealed pairwise interactions between the Feline Herpesvirus, Parvovirus and Calicivirus, whereas the infection by FIV, the feline equivalent of HIV, did not modify the risk of infection by any of these viruses. CONCLUSIONS/SIGNIFICANCE: This work therefore points out possible interactions that can be further investigated in experimental conditions and, by providing a user-friendly R program and a tutorial example, offers new opportunities for animal and human epidemiologists to detect interactions of interest in the field, a crucial step in the challenge of multiple infections. PMID- 22235313 TI - Functional divergence in the genus Oenococcus as predicted by genome sequencing of the newly-described species, Oenococcus kitaharae. AB - Oenococcus kitaharae is only the second member of the genus Oenococcus to be identified and is the closest relative of the industrially important wine bacterium Oenococcus oeni. To provide insight into this new species, the genome of the type strain of O. kitaharae, DSM 17330, was sequenced. Comparison of the sequenced genomes of both species show that the genome of O. kitaharae DSM 17330 contains many genes with predicted functions in cellular defence (bacteriocins, antimicrobials, restriction-modification systems and a CRISPR locus) which are lacking in O. oeni. The two genomes also appear to differentially encode several metabolic pathways associated with amino acid biosynthesis and carbohydrate utilization and which have direct phenotypic consequences. This would indicate that the two species have evolved different survival techniques to suit their particular environmental niches. O. oeni has adapted to survive in the harsh, but predictable, environment of wine that provides very few competitive species. However O. kitaharae appears to have adapted to a growth environment in which biological competition provides a significant selective pressure by accumulating biological defence molecules, such as bacteriocins and restriction-modification systems, throughout its genome. PMID- 22235314 TI - Vitamins A & D inhibit the growth of mycobacteria in radiometric culture. AB - BACKGROUND: The role of vitamins in the combat of disease is usually conceptualized as acting by modulating the immune response of an infected, eukaryotic host. We hypothesized that some vitamins may directly influence the growth of prokaryotes, particularly mycobacteria. METHODS: The effect of four fat soluble vitamins was studied in radiometric Bactec(r) culture. The vitamins were A (including a precursor and three metabolites,) D, E and K. We evaluated eight strains of three mycobacterial species (four of M. avium subspecies paratuberculosis (MAP), two of M. avium and two of M. tb. complex). PRINCIPAL FINDINGS: Vitamins A and D cause dose-dependent inhibition of all three mycobacterial species studied. Vitamin A is consistently more inhibitory than vitamin D. The vitamin A precursor, beta-carotene, is not inhibitory, whereas three vitamin A metabolites cause inhibition. Vitamin K has no effect. Vitamin E causes negligible inhibition in a single strain. SIGNIFICANCE: We show that vitamin A, its metabolites Retinyl acetate, Retinoic acid and 13-cis Retinoic acid and vitamin D directly inhibit mycobacterial growth in culture. These data are compatible with the hypothesis that complementing the immune response of multicellular organisms, vitamins A and D may have heretofore unproven, unrecognized, independent and probable synergistic, direct antimycobacterial inhibitory activity. PMID- 22235315 TI - Post-GWAS functional characterization of susceptibility variants for chronic lymphocytic leukemia. AB - Recent genome-wide association studies (GWAS) have identified several gene variants associated with sporadic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Many of these CLL/SLL susceptibility loci are located in non coding or intergenic regions, posing a significant challenge to determine their potential functional relevance. Here, we review the literature of all CLL/SLL GWAS and validation studies, and apply eQTL analysis to identify putatively functional SNPs that affect gene expression that may be causal in the pathogenesis of CLL/SLL. We tested 12 independent risk loci for their potential to alter gene expression through cis-acting mechanisms, using publicly available gene expression profiles with matching genotype information. Sixteen SNPs were identified that are linked to differential expression of SP140, a putative tumor suppressor gene previously associated with CLL/SLL. Three additional SNPs were associated with differential expression of DACT3 and GNG8, which are involved in the WNT/beta-catenin- and G protein-coupled receptor signaling pathways, respectively, that have been previously implicated in CLL/SLL pathogenesis. Using in silico functional prediction tools, we found that 14 of the 19 significant eQTL SNPs lie in multiple putative regulatory elements, several of which have prior implications in CLL/SLL or other hematological malignancies. Although experimental validation is needed, our study shows that the use of existing GWAS data in combination with eQTL analysis and in silico methods represents a useful starting point to screen for putatively causal SNPs that may be involved in the etiology of CLL/SLL. PMID- 22235316 TI - Moderate multiple parentage and low genetic variation reduces the potential for genetic incompatibility avoidance despite high risk of inbreeding. AB - BACKGROUND: Polyandry is widespread throughout the animal kingdom. In the absence of direct benefits of mating with different males, the underlying basis for polyandry is enigmatic because it can carry considerable costs such as elevated exposure to sexual diseases, physical injury or other direct fitness costs. Such costs may be balanced by indirect genetic benefits to the offspring of polyandrous females. We investigated polyandry and patterns of parentage in the spider Stegodyphus lineatus. This species experiences relatively high levels of inbreeding as a result of its spatial population structure, philopatry and limited male mating dispersal. Polyandry may provide an opportunity for post mating inbreeding avoidance that reduces the risk of genetic incompatibilities arising from incestuous matings. However, multiple mating carries direct fitness costs to females suggesting that genetic benefits must be substantial to counter direct costs. METHODOLOGY/PRINCIPAL FINDINGS: Genetic parentage analyses in two populations from Israel and a Greek island, showed mixed-brood parentage in approximately 50% of the broods. The number of fathers ranged from 1-2 indicating low levels of multiple parentage and there was no evidence for paternity bias in mixed-broods from both populations. Microsatellite loci variation suggested limited genetic variation within populations, especially in the Greek island population. Relatedness estimates among females in the maternal generation and potentially interacting individuals were substantial indicating full-sib and half sib relationships. CONCLUSIONS/SIGNIFICANCE: Three lines of evidence indicate limited potential to obtain substantial genetic benefits in the form of reduced inbreeding. The relatively low frequency of multiple parentage together with low genetic variation among potential mates and the elevated risk of mating among related individuals as corroborated by our genetic data suggest that there are limited actual outbreeding opportunities for polyandrous females. Polyandry in S. lineatus is thus unlikely to be maintained through adaptive female choice. PMID- 22235317 TI - A new threat to honey bees, the parasitic phorid fly Apocephalus borealis. AB - Honey bee colonies are subject to numerous pathogens and parasites. Interaction among multiple pathogens and parasites is the proposed cause for Colony Collapse Disorder (CCD), a syndrome characterized by worker bees abandoning their hive. Here we provide the first documentation that the phorid fly Apocephalus borealis, previously known to parasitize bumble bees, also infects and eventually kills honey bees and may pose an emerging threat to North American apiculture. Parasitized honey bees show hive abandonment behavior, leaving their hives at night and dying shortly thereafter. On average, seven days later up to 13 phorid larvae emerge from each dead bee and pupate away from the bee. Using DNA barcoding, we confirmed that phorids that emerged from honey bees and bumble bees were the same species. Microarray analyses of honey bees from infected hives revealed that these bees are often infected with deformed wing virus and Nosema ceranae. Larvae and adult phorids also tested positive for these pathogens, implicating the fly as a potential vector or reservoir of these honey bee pathogens. Phorid parasitism may affect hive viability since 77% of sites sampled in the San Francisco Bay Area were infected by the fly and microarray analyses detected phorids in commercial hives in South Dakota and California's Central Valley. Understanding details of phorid infection may shed light on similar hive abandonment behaviors seen in CCD. PMID- 22235319 TI - Carbon stocks and fluxes in tropical lowland dipterocarp rainforests in Sabah, Malaysian Borneo. AB - Deforestation in the tropics is an important source of carbon C release to the atmosphere. To provide a sound scientific base for efforts taken to reduce emissions from deforestation and degradation (REDD+) good estimates of C stocks and fluxes are important. We present components of the C balance for selectively logged lowland tropical dipterocarp rainforest in the Malua Forest Reserve of Sabah, Malaysian Borneo. Total organic C in this area was 167.9 Mg C ha-1+/-3.8 (SD), including: Total aboveground (TAGC: 55%; 91.9 Mg C ha-1+/-2.9 SEM) and belowground carbon in trees (TBGC: 10%; 16.5 Mg C ha-1+/-0.5 SEM), deadwood (8%; 13.2 Mg C ha-1+/-3.5 SEM) and soil organic matter (SOM: 24%; 39.6 Mg C ha-1+/-0.9 SEM), understory vegetation (3%; 5.1 Mg C ha-1+/-1.7 SEM), standing litter (<1%; 0.7 Mg C ha-1+/-0.1 SEM) and fine root biomass (<1%; 0.9 Mg C ha-1+/-0.1 SEM). Fluxes included litterfall, a proxy for leaf net primary productivity (4.9 Mg C ha-1 yr-1+/-0.1 SEM), and soil respiration, a measure for heterotrophic ecosystem respiration (28.6 Mg C ha-1 yr-1+/-1.2 SEM). The missing estimates necessary to close the C balance are wood net primary productivity and autotrophic respiration.Twenty-two years after logging TAGC stocks were 28% lower compared to unlogged forest (128 Mg C ha-1+/-13.4 SEM); a combined weighted average mean reduction due to selective logging of -57.8 Mg C ha-1 (with 95% CI -75.5 to 40.2). Based on the findings we conclude that selective logging decreased the dipterocarp stock by 55-66%. Silvicultural treatments may have the potential to accelerate the recovery of dipterocarp C stocks to pre-logging levels. PMID- 22235318 TI - Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat. AB - Previously we have demonstrated that a Rhodiola crenulata extract (RCE), containing a potent antioxidant salidroside, promotes neurogenesis in the hippocampus of depressive rats. The current study was designed to further investigate the protective effect of the RCE on neurogenesis in a rat model of Alzheimer's disease (AD) induced by an intracerebroventricular injection of streptozotocin (STZ), and to determine whether this neuroprotective effect is induced by the antioxidative activity of salidroside. Our results showed that pretreatment with the RCE significantly improved the impaired neurogenesis and simultaneously reduced the oxidative stress in the hippocampus of AD rats. In vitro studies revealed that (1) exposure of neural stem cells (NSCs) from the hippocampus to STZ strikingly increased intracellular reactive oxygen species (ROS) levels, induced cell death and perturbed cell proliferation and differentiation, (2) hydrogen peroxide induced similar cellular activities as STZ, (3) pre-incubation of STZ-treated NSCs with catalase, an antioxidant, suppressed all these cellular activities induced by STZ, and (4) likewise, pre incubation of STZ-treated NSCs with salidroside, also an antioxidant, suppressed all these activities as catalase: reduction of ROS levels and NSC death with simultaneous increases in proliferation and differentiation. Our findings indicated that the RCE improved the impaired hippocampal neurogenesis in the rat model of AD through protecting NSCs by its main ingredient salidroside which scavenged intracellular ROS. PMID- 22235320 TI - Effects of interleukin-10 polymorphisms, Helicobacter pylori infection, and smoking on the risk of noncardia gastric cancer. AB - OBJECTIVE: Both variations in the interleukin-10 (IL10) gene and environmental factors are thought to influence inflammation and gastric carcinogenesis. Therefore, we investigated the associations between IL10 polymorphisms, Helicobacter pylori (H. pylori) infection, and smoking in noncardia gastric carcinogenesis in Koreans. METHODS: We genotyped three promoter polymorphisms ( 1082A>G, -819T>C, and -592 A>C) of IL10 in a case-control study of 495 noncardia gastric cancer patients and 495 sex- and age-matched healthy controls. Multiple logistic regression models were used to detect the effects of IL10 polymorphisms, H. pylori infection, and smoking on the risk of gastric cancer, which was stratified by the histological type of gastric cancer. RESULTS: The IL10-819C and -592C alleles were found to have complete linkage disequilibrium, and all three IL10 polymorphisms were associated with an increased risk of intestinal-type noncardia gastric cancer. These associations were observed only in H. pylori positive subjects and current smokers. A statistically significant interaction between the IL10-592 genotype and H. pylori infection on the risk of intestinal type gastric cancer was observed (P for interaction = 0.047). In addition, H. pylori-positive smokers who were carriers of either the IL10-1082G (OR [95% CI] = 17.76 [6.17-51.06]) or the -592C (OR [95% CI] = 8.37 [2.79-25.16]) allele had an increased risk of intestinal-type gastric cancer compared to H. pylori negative nonsmokers homozygous for IL10-1082A and -592A, respectively. The interaction between the IL10-1082 polymorphism and the combined effects of H. pylori infection and smoking tended towards significance (P for interaction = 0.080). CONCLUSIONS: Inflammation-related genetic variants may interact with H. pylori infection and smoking to increase the risk of noncardia gastric cancer, particularly the intestinal-type. These findings may be helpful in identifying individuals at an increased risk for developing noncardia gastric cancer. PMID- 22235321 TI - Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL)-mediated inhibition of endometrial angiogenesis. AB - Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with beta2-glycoprotein I (beta2GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. beta2GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind beta2GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor kappaB (NF-kappaB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-kappaB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in APS. PMID- 22235322 TI - Cerebellar globular cells receive monoaminergic excitation and monosynaptic inhibition from Purkinje cells. AB - Inhibitory interneurons in the cerebellar granular layer are more heterogeneous than traditionally depicted. In contrast to Golgi cells, which are ubiquitously distributed in the granular layer, small fusiform Lugaro cells and globular cells are located underneath the Purkinje cell layer and small in number. Globular cells have not been characterized physiologically. Here, using cerebellar slices obtained from a strain of gene-manipulated mice expressing GFP specifically in GABAergic neurons, we morphologically identified globular cells, and compared their synaptic activity and monoaminergic influence of their electrical activity with those of small Golgi cells and small fusiform Lugaro cells. Globular cells were characterized by prominent IPSCs together with monosynaptic inputs from the axon collaterals of Purkinje cells, whereas small Golgi cells or small fusiform Lugaro cells displayed fewer and smaller spontaneous IPSCs. Globular cells were silent at rest and fired spike discharges in response to application of either serotonin (5-HT) or noradrenaline. The two monoamines also facilitated small Golgi cell firing, but only 5-HT elicited firing in small fusiform Lugaro cells. Furthermore, globular cells likely received excitatory monosynaptic inputs through mossy fibers. Because globular cells project their axons long in the transversal direction, the neuronal circuit that includes interplay between Purkinje cells and globular cells could regulate Purkinje cell activity in different microzones under the influence of monoamines and mossy fiber inputs, suggesting that globular cells likely play a unique modulatory role in cerebellar motor control. PMID- 22235323 TI - Cloning and characterization of maize miRNAs involved in responses to nitrogen deficiency. AB - Although recent studies indicated that miRNAs regulate plant adaptive responses to nutrient deprivation, the functional significance of miRNAs in adaptive responses to nitrogen (N) limitation remains to be explored. To elucidate the molecular biology underlying N sensing/signaling in maize, we constructed four small RNA libraries and one degradome from maize seedlings exposed to N deficiency. We discovered a total of 99 absolutely new loci belonging to 47 miRNA families by small RNA deep sequencing and degradome sequencing, as well as 9 new loci were the paralogs of previously reported miR169, miR171, and miR398, significantly expanding the reported 150 high confidence genes within 26 miRNA families in maize. Bioinformatic and subsequent small RNA northern blot analysis identified eight miRNA families (five conserved and three newly identified) differentially expressed under the N-deficient condition. Predicted and degradome validated targets of the newly identified miRNAs suggest their involvement in a broad range of cellular responses and metabolic processes. Because maize is not only an important crop but is also a genetic model for basic biological research, our research contributes to the understanding of the regulatory roles of miRNAs in plant adaption to N-deficiency stress. PMID- 22235324 TI - Long-term infection and vertical transmission of a gammaretrovirus in a foreign host species. AB - Increasing evidence has indicated natural transspecies transmission of gammaretroviruses; however, viral-host interactions after initial xeno-exposure remain poorly understood. Potential association of xenotropic murine leukemia virus-related virus (XMRV) in patients with prostate cancer and chronic fatigue syndrome has attracted broad interests in this topic. Although recent studies have indicated that XMRV is unlikely a human pathogen, further understanding of XMRV xenoinfection would allow in vivo modeling of the initial steps of gammaretroviral interspecies transmission, evolution and dissemination in a new host population. In this study, we monitored the long-term consequences of XMRV infection and its possible vertical transmission in a permissive foreign host, wild-derived Mus pahari mice. One year post-infection, XMRV-infected mice showed no notable pathological changes, while proviral DNA was detected in three out of eight mice. XMRV-infected mice remained seropositive throughout the study although the levels of gp70 Env- and p30 capsid-specific antibodies gradually decreased. When vertical XMRV transmission was assessed, no viremia, humoral immune responses nor endogenization were observed in nine offspring from infected mothers, yet one offspring was found PCR-positive for XMRV-specific sequences. Amplified viral sequences from the offspring showed several mutations, including one amino acid deletion in the receptor binding domain of Env SU. Our results therefore demonstrate long-term asymptomatic infection, low incidence of vertical transmission and limited evolution of XMRV upon transspecies infection of a permissive new host, Mus pahari. PMID- 22235325 TI - Reproducibility and concordance of differential DNA methylation and gene expression in cancer. AB - BACKGROUND: Hundreds of genes with differential DNA methylation of promoters have been identified for various cancers. However, the reproducibility of differential DNA methylation discoveries for cancer and the relationship between DNA methylation and aberrant gene expression have not been systematically analysed. METHODOLOGY/PRINCIPAL FINDINGS: Using array data for seven types of cancers, we first evaluated the effects of experimental batches on differential DNA methylation detection. Second, we compared the directions of DNA methylation changes detected from different datasets for the same cancer. Third, we evaluated the concordance between methylation and gene expression changes. Finally, we compared DNA methylation changes in different cancers. For a given cancer, the directions of methylation and expression changes detected from different datasets, excluding potential batch effects, were highly consistent. In different cancers, DNA hypermethylation was highly inversely correlated with the down regulation of gene expression, whereas hypomethylation was only weakly correlated with the up-regulation of genes. Finally, we found that genes commonly hypomethylated in different cancers primarily performed functions associated with chronic inflammation, such as 'keratinization', 'chemotaxis' and 'immune response'. CONCLUSIONS: Batch effects could greatly affect the discovery of DNA methylation biomarkers. For a particular cancer, both differential DNA methylation and gene expression can be reproducibly detected from different studies with no batch effects. While DNA hypermethylation is significantly linked to gene down-regulation, hypomethylation is only weakly correlated with gene up regulation and is likely to be linked to chronic inflammation. PMID- 22235326 TI - The making of a monster: postnatal ontogenetic changes in craniomandibular shape in the great sabercat Smilodon. AB - Derived sabercats had craniomandibular morphologies that in many respects were highly different from those of extant felids, and this has often been interpreted functionally as adaptations for predation at extreme gape angles with hypertrophied upper canines. It is unknown how much of this was a result of intraspecific postnatal ontogeny, since juveniles of sabercats are rare and no quantitative study has been made of craniomandibular ontogeny. Postnatal ontogenetic craniomandibular shape changes in two morphologically derived sabercats, Smilodon fatalis and S. populator, were analysed using geometric morphometrics and compared to three species of extant pantherines, the jaguar, tiger, and Sunda clouded leopard. Ontogenetic shape changes in Smilodon usually involved the same areas of the cranium and mandible as in extant pantherines, and large-scale modularization was similar, suggesting that such may have been the case for all felids, since it followed the same trends previously observed in other mammals. However, in other respects Smilodon differed from extant pantherines. Their crania underwent much greater and more localised ontogenetic shape changes than did the mandibles, whereas crania and mandibles of extant pantherines underwent smaller, fewer and less localised shape changes. Ontogenetic shape changes in the two species of Smilodon are largely similar, but differences are also present, notably those which may be tied to the presence of larger upper canines in S. populator. Several of the specialized cranial characters differentiating adult Smilodon from extant felids in a functional context, which are usually regarded as evolutionary adaptations for achieving high gape angles, are ontogenetic, and in several instances ontogeny appears to recapitulate phylogeny to some extent. No such ontogenetic evolutionary adaptive changes were found in the extant pantherines. Evolution in morphologically derived sabercats involved greater cranial ontogenetic changes than among extant felids, resulting in greatly modified adult craniomandibular morphologies. PMID- 22235327 TI - Non-photochemical quenching in cryptophyte alga Rhodomonas salina is located in chlorophyll a/c antennae. AB - Photosynthesis uses light as a source of energy but its excess can result in production of harmful oxygen radicals. To avoid any resulting damage, phototrophic organisms can employ a process known as non-photochemical quenching (NPQ), where excess light energy is safely dissipated as heat. The mechanism(s) of NPQ vary among different phototrophs. Here, we describe a new type of NPQ in the organism Rhodomonas salina, an alga belonging to the cryptophytes, part of the chromalveolate supergroup. Cryptophytes are exceptional among photosynthetic chromalveolates as they use both chlorophyll a/c proteins and phycobiliproteins for light harvesting. All our data demonstrates that NPQ in cryptophytes differs significantly from other chromalveolates - e.g. diatoms and it is also unique in comparison to NPQ in green algae and in higher plants: (1) there is no light induced xanthophyll cycle; (2) NPQ resembles the fast and flexible energetic quenching (qE) of higher plants, including its fast recovery; (3) a direct antennae protonation is involved in NPQ, similar to that found in higher plants. Further, fluorescence spectroscopy and biochemical characterization of isolated photosynthetic complexes suggest that NPQ in R. salina occurs in the chlorophyll a/c antennae but not in phycobiliproteins. All these results demonstrate that NPQ in cryptophytes represents a novel class of effective and flexible non photochemical quenching. PMID- 22235328 TI - Keratinocyte-targeted overexpression of the glucocorticoid receptor delays cutaneous wound healing. AB - Delayed wound healing is one of the most common secondary adverse effects associated to the therapeutic use of glucocorticoid (GC) analogs, which act through the ligand-dependent transcription factor GC-receptor (GR). GR function is exerted through DNA-binding-dependent and -independent mechanisms, classically referred to as transactivation (TA) and transrepression (TR). Currently both TA and TR are thought to contribute to the therapeutical effects mediated by GR; however their relative contribution to unwanted side effects such as delayed wound healing is unknown. We evaluated skin wound healing in transgenic mice with keratinocyte-restricted expression of either wild type GR or a mutant GR that is TA-defective but efficient in TR (K5-GR and K5-GR-TR mice, respectively). Our data show that at days (d) 4 and 8 following wounding, healing in K5-GR mice was delayed relative to WT, with reduced recruitment of granulocytes and macrophages and diminished TNF-alpha and IL-1beta expression. TGF-beta1 and Kgf expression was repressed in K5-GR skin whereas TGF-beta3 was up-regulated. The re epithelialization rate was reduced in K5-GR relative to WT, as was formation of granulation tissue. In contrast, K5-GR-TR mice showed delays in healing at d4 but re-established the skin breach at d8 concomitant with decreased repression of pro inflammatory cytokines and growth factors relative to K5-GR mice. Keratinocytes from both transgenic mice closed in vitro wounds slower relative to WT, consistent with the in vivo defects in cell migration. Overall, the delay in the early stages of wound healing in both transgenic models is similar to that elicited by systemic treatment with dexamethasone. Wound responses in the transgenic keratinocytes correlated with reduced ERK activity both in vivo and in vitro. We conclude that the TR function of GR is sufficient for negatively regulating early stages of wound closure, while TA by GR is required for delaying later stages of healing. PMID- 22235329 TI - Deep evolutionary conservation of an intramolecular protein kinase activation mechanism. AB - DYRK-family kinases employ an intramolecular mechanism to autophosphorylate a critical tyrosine residue in the activation loop. Once phosphorylated, DYRKs lose tyrosine kinase activity and function as serine/threonine kinases. DYRKs have been characterized in organisms from yeast to human; however, all entities belong to the Unikont supergroup, only one of five eukaryotic supergroups. To assess the evolutionary age and conservation of the DYRK intramolecular kinase-activation mechanism, we surveyed 21 genomes representing four of the five eukaryotic supergroups for the presence of DYRKs. We also analyzed the activation mechanism of the sole DYRK (class 2 DYRK) present in Trypanosoma brucei (TbDYRK2), a member of the excavate supergroup and separated from Drosophila by ~850 million years. Bioinformatics showed the DYRKs clustering into five known subfamilies, class 1, class 2, Yaks, HIPKs and Prp4s. Only class 2 DYRKs were present in all four supergroups. These diverse class 2 DYRKs also exhibited conservation of N terminal NAPA regions located outside of the kinase domain, and were shown to have an essential role in activation loop autophosphorylation of Drosophila DmDYRK2. Class 2 TbDYRK2 required the activation loop tyrosine conserved in other DYRKs, the NAPA regions were critical for this autophosphorylation event, and the NAPA-regions of Trypanosoma and human DYRK2 complemented autophosphorylation by the kinase domain of DmDYRK2 in trans. Finally, sequential deletion analysis was used to further define the minimal region required for trans-complementation. Our analysis provides strong evidence that class 2 DYRKs were present in the primordial or root eukaryote, and suggest this subgroup may be the oldest, founding member of the DYRK family. The conservation of activation loop autophosphorylation demonstrates that kinase self-activation mechanisms are also primitive. PMID- 22235330 TI - Classification of Camellia (Theaceae) species using leaf architecture variations and pattern recognition techniques. AB - Leaf characters have been successfully utilized to classify Camellia (Theaceae) species; however, leaf characters combined with supervised pattern recognition techniques have not been previously explored. We present results of using leaf morphological and venation characters of 93 species from five sections of genus Camellia to assess the effectiveness of several supervised pattern recognition techniques for classifications and compare their accuracy. Clustering approach, Learning Vector Quantization neural network (LVQ-ANN), Dynamic Architecture for Artificial Neural Networks (DAN2), and C-support vector machines (SVM) are used to discriminate 93 species from five sections of genus Camellia (11 in sect. Furfuracea, 16 in sect. Paracamellia, 12 in sect. Tuberculata, 34 in sect. Camellia, and 20 in sect. Theopsis). DAN2 and SVM show excellent classification results for genus Camellia with DAN2's accuracy of 97.92% and 91.11% for training and testing data sets respectively. The RBF-SVM results of 97.92% and 97.78% for training and testing offer the best classification accuracy. A hierarchical dendrogram based on leaf architecture data has confirmed the morphological classification of the five sections as previously proposed. The overall results suggest that leaf architecture-based data analysis using supervised pattern recognition techniques, especially DAN2 and SVM discrimination methods, is excellent for identification of Camellia species. PMID- 22235331 TI - Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. AB - Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1delta variants with impaired kinase activity on SV40 induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1delta mutants exhibited a reduced kinase activity compared to wtCK1delta in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1delta activity. When stably over-expressed in maximal transformed SV-52 cells, CK1delta mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1delta. To characterize the effects of CK1delta on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1delta under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1delta/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP mutCK1delta/WAP-T bi-transgenic animals. The reduced CK1delta activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1delta activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP mutCK1delta/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1delta impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. PMID- 22235332 TI - MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells. AB - MicroRNA-34a (miR-34a), a potent mediator of tumor suppressor p53, has been reported to function as a tumor suppressor and miR-34a was found to be downregulated in prostate cancer tissues. We studied the functional effects of miR-34a on c-Myc transcriptional complexes in PC-3 prostate cancer cells. Transfection of miR-34a into PC-3 cells strongly inhibited in vitro cell proliferation, cell invasion and promoted apoptosis. Transfection of miR-34a into PC-3 cells also significantly inhibited in vivo xenograft tumor growth in nude mice. miR-34a downregulated expression of c-Myc oncogene by targeting its 3' UTR as shown by luciferase reporter assays. miR-34a was found to repress RhoA, a regulator of cell migration and invasion, by suppressing c-Myc-Skp2-Miz1 transcriptional complex that activates RhoA. Overexpression of c-Myc reversed miR 34a suppression of RhoA expression, suggesting that miR-34a inhibits invasion by suppressing RhoA through c-Myc. miR-34a was also found to repress c-Myc-pTEFB transcription elongation complex, indicating one of the mechanisms by which miR 34a has profound effects on cellular function. This is the first report to document that miR-34a suppresses assembly and function of the c-Myc-Skp2-Miz1 complex that activates RhoA and the c-Myc-pTEFB complex that elongates transcription of various genes, suggesting a novel role of miR-34a in the regulation of transcription by c-Myc complex. PMID- 22235333 TI - Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families. AB - BACKGROUND: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). METHODOLOGY AND PRINCIPAL FINDINGS: We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. CONCLUSIONS: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change. PMID- 22235334 TI - BED estimates of HIV incidence: resolving the differences, making things simpler. AB - OBJECTIVE: Develop a simple method for optimal estimation of HIV incidence using the BED capture enzyme immunoassay. DESIGN: Use existing BED data to estimate mean recency duration, false recency rates and HIV incidence with reference to a fixed time period, T. METHODS: Compare BED and cohort estimates of incidence referring to identical time frames. Generalize this approach to suggest a method for estimating HIV incidence from any cross-sectional survey. RESULTS: Follow-up and BED analyses of the same, initially HIV negative, cases followed over the same set time period T, produce estimates of the same HIV incidence, permitting the estimation of the BED mean recency period for cases who have been HIV positive for less than T. Follow-up of HIV positive cases over T, similarly, provides estimates of the false-recent rate appropriate for T. Knowledge of these two parameters for a given population allows the estimation of HIV incidence during T by applying the BED method to samples from cross-sectional surveys. An algorithm is derived for providing these estimates, adjusted for the false-recent rate. The resulting estimator is identical to one derived independently using a more formal mathematical analysis. Adjustments improve the accuracy of HIV incidence estimates. Negative incidence estimates result from the use of inappropriate estimates of the false-recent rate and/or from sampling error, not from any error in the adjustment procedure. CONCLUSIONS: Referring all estimates of mean recency periods, false-recent rates and incidence estimates to a fixed period T simplifies estimation procedures and allows the development of a consistent method for producing adjusted estimates of HIV incidence of improved accuracy. Unadjusted BED estimates of incidence, based on life-time recency periods, would be both extremely difficult to produce and of doubtful value. PMID- 22235335 TI - Molecular networks in FGF signaling: flotillin-1 and cbl-associated protein compete for the binding to fibroblast growth factor receptor substrate 2. AB - Fibroblast growth factor receptor substrate 2 (FRS2alpha) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases. During signal transduction, FRS2 can be both tyrosine and threonine phosphorylated and forms signaling complexes with other adaptor proteins and tyrosine phosphatases. We have here identified flotillin-1 and the cbl-associated protein/ponsin (CAP) as novel interaction partners of FRS2. Flotillin-1 binds to the phosphotyrosine binding domain (PTB) of FRS2 and competes for the binding with the fibroblast growth factor receptor. Flotillin-1 knockdown results in increased Tyr phosphorylation of FRS2, in line with the inhibition of ERK activity in the absence of flotillin-1. CAP directly interacts with FRS2 by means of its sorbin homology (SoHo) domain, which has previously been shown to interact with flotillin-1. In addition, the third SH3 domain in CAP binds to FRS2. Due to the overlapping binding domains, CAP and flotillin-1 appear to compete for the binding to FRS2. Thus, our results reveal a novel signaling network containing FRS2, CAP and flotillin-1, whose successive interactions are most likely required to regulate receptor tyrosine kinase signaling, especially the mitogen activated protein kinase pathway. PMID- 22235336 TI - Global gene expression analysis of the interaction between cancer cells and osteoblasts to predict bone metastasis in breast cancer. AB - BACKGROUND: Bone metastasis is a main cause of morbidity in breast cancer. Since breast cancer is a heterogeneous disease, the interactions of cancer cells with the skeletal host cells might also be diverse. We hypothesized that gene expression signatures induced by heterotypic interaction of breast cancer cells and osteoblasts might be of clinical relevance. METHODOLOGY/PRINCIPAL FINDINGS: We established an ex vivo co-culture model using benign breast epithelial cells or a panel of 5 malignant breast epithelial cells in combination with primary human osteoblasts and determined associated gene expression changes with HEEBO microarrays. Pretreatment gene expression profiles of 295 early stage breast cancers published from the Netherlands Cancer Institute with a median follow up of 12.6 years allowed evaluating in vitro effects in the in vivo situation.The effects of the interaction between osteoblasts and breast cancer cell lines of different origin were very heterogeneous. Hs578T cells started to proliferate in co-culture with osteoblasts, SKBR-3 induced a TGF-beta response and MDA-MB231 cells showed two distinct sets of up-regulated genes: A set of interferon response genes associated with an up-regulation of STAT1 was in vivo remarkably coherent providing a basis for segregation of tumors into two groups. In a uni variate analysis, early stage tumors with high expression levels (n = 136) of this gene set had a significantly lower overall survival rate (p = 0.005) (63% at 10 years) than tumors with low expression levels (n = 159) (overall survival: 77% at 10 years). The second gene set was associated with IL-6 and did not significantly change the overall survival rate (p = 0.165), but was significantly associated with a shorter time to bone metastasis (p = 0.049; 74% vs. 83% at 10 years). CONCLUSION/SIGNIFICANCE: An IL-6 gene expression pattern induced by heterotypic interaction of breast cancer cells with osteoblasts in vitro is associated with a higher rate of bone metastasis in vivo. PMID- 22235337 TI - AP-1 transcription factors, mucin-type molecules and MMPs regulate the IL-11 mediated invasiveness of JEG-3 and HTR-8/SVneo trophoblastic cells. AB - This study examines the IL-11 mediated activation of downstream signaling and expression of effector molecules to resolve the controversies associated with the IL-11 mediated regulation of the invasiveness of two commonly used trophoblastic cell models viz. JEG-3 and HTR-8/SVneo cells. It has been reported that IL-11 increases the invasiveness of JEG-3 cells while, reduces the invasiveness of HTR 8/SVneo cells. Invasion assay performed simultaneously for both the cell lines confirmed the above findings. In addition, HTR-8/SVneo cells showed a higher basal invasiveness than JEG-3 cells. Western blot showed the IL-11 mediated activation of STAT3(tyr705) and STAT1(tyr701) in both the cell lines. However, IL 11 activated the ERK1/2 phosphorylation in JEG-3 cells but, inhibited it in HTR 8/SVneo cells. Within 10 min of IL-11 treatment, p-STAT3(tyr705) was localized inside the nucleus of both the cell lines but, there was enhanced co-localization of protein inhibitor of activated STAT1/3 (PIAS1/3) and p-STAT3(tyr705) in HTR 8/SVneo cells and not in JEG-3 cells. This could be reason for the poor responsiveness of STAT3 responsive genes like mucin 1 (MUC1) in HTR-8/SVneo cells and not in JEG-3 cells. Further, microarray analysis of the IL-11 treated cells revealed differential responsiveness of JEG-3 as compared to HTR-8/SVneo cells. Several family of genes like activator protein-1 (AP-1) transcription factors (Jun and Fos), mucin-type molecules, MMP23B etc showed enhanced expression in IL 11 treated JEG-3 cells while, there was no response or decrease in their expression in IL-11 treated HTR-8/SVneo cells. Expression of these molecules was confirmed by quantitative RT-PCR. In addition, HTR-8/SVneo cells also showed a significant decrease in the expression of MMP2, MMP3 and MMP9 upon IL-11 treatment. Hence, IL-11 mediated differential activation of signaling and expression of effector molecules is responsible for the differential invasive response of JEG-3 and HTR-8/SVneo cells. PMID- 22235338 TI - MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and in vivo by targeting tumor suppressor CHD5. AB - BACKGROUND: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: miR 211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116(miR-211)) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116(miR-211) cells was upregulated by 16-fold compared to vector control cells (HCT-116(vector)). Exogenous miR-211 directly binds to the 3'-untranslated region (3'-UTR) of CHD5 mRNA, resulting in a 50% decrease in CHD5 protein level in HCT-116(miR-211) cells. The levels of cell proliferation, tumor growth, and cell migration of HCT 116(miR-211) cells were significantly higher than HCT-116(vector) cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, scratch assay, and tumor xenografts, respectively. In addition, we found that enforced expression of miR-211 in HCT 116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax. CONCLUSION/SIGNIFICANCE: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression of miR 211 promotes tumor cell growth at least in part by downregulating the expression level of the CHD5 tumor suppressor. Our results provide a better understanding of the association of between miR-211-regulated CHD5 expression and CHD5 function in colorectal tumorigenesis. PMID- 22235339 TI - The S. pombe histone H2A dioxygenase Ofd2 regulates gene expression during hypoxia. AB - Post-translational modification of histone proteins are known to play an important role in regulating chromatin structure. In an effort to find additional histone modifications we set out to screen enzymes of the 2-oxoglutarate and Fe(II)-dependent (2-OG-Fe(II)) dioxygenase family for activity towards histones. Here we show that the Schizosaccharomyces pombe 2-OG-Fe(II) dioxygenase domain containing protein-2 (Ofd2) is a histone H2A dioxygenase enzyme. Using a combination of peptide screening and alanine scanning substitution analysis, we identify an HxxLR motif in H2A as a substrate for Ofd2 activity. Transcriptional profiling indicates that Ofd2 regulates the repression of oxidative phosphorylation genes during hypoxic stress. We show that Ofd2 is recruited to the 5' end of oxidative phosphorylation genes specifically during hypoxia and that it uses its dioxygenase activity to regulate their transcription. Together, these data uncover a novel histone H2A modifying activity involved in the regulation of gene expression during hypoxia. PMID- 22235340 TI - Loss of Col3a1, the gene for Ehlers-Danlos syndrome type IV, results in neocortical dyslamination. AB - It has recently been discovered that Collagen III, the encoded protein of the type IV Ehlers-Danlos Syndrome (EDS) gene, is one of the major constituents of the pial basement membrane (BM) and serves as the ligand for GPR56. Mutations in GPR56 cause a severe human brain malformation called bilateral frontoparietal polymicrogyria, in which neurons transmigrate through the BM causing severe mental retardation and frequent seizures. To further characterize the brain phenotype of Col3a1 knockout mice, we performed a detailed histological analysis. We observed a cobblestone-like cortical malformation, with BM breakdown and marginal zone heterotopias in Col3a1-/- mouse brains. Surprisingly, the pial BM appeared intact at early stages of development but starting as early as embryonic day (E) 11.5, prominent BM defects were observed and accompanied by neuronal overmigration. Although collagen III is expressed in meningeal fibroblasts (MFs), Col3a1-/- MFs present no obvious defects. Furthermore, the expression and posttranslational modification of alpha-dystroglycan was undisturbed in Col3a1-/- mice. Based on the previous finding that mutations in COL3A1 cause type IV EDS, our study indicates a possible common pathological pathway linking connective tissue diseases and brain malformations. PMID- 22235341 TI - Neutralization of LINGO-1 during in vitro differentiation of neural stem cells results in proliferation of immature neurons. AB - Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in betaIII tubulin positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for betaIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain. PMID- 22235342 TI - Glucose-induced O2 consumption activates hypoxia inducible factors 1 and 2 in rat insulin-secreting pancreatic beta-cells. AB - BACKGROUND: Glucose increases the expression of glycolytic enzymes and other hypoxia-response genes in pancreatic beta-cells. Here, we tested whether this effect results from the activation of Hypoxia-Inducible-factors (HIF) 1 and 2 in a hypoxia-dependent manner. METHODOLOGY/PRINCIPAL FINDINGS: Isolated rat islets and insulin-secreting INS-1E cells were stimulated with nutrients at various pO2 values or treated with the HIF activator CoCl2. HIF-target gene mRNA levels and HIF subunit protein levels were measured by real-time RT-PCR, Western Blot and immunohistochemistry. The formation of pimonidazole-protein adducts was used as an indicator of hypoxia. In INS-1E and islet beta-cells, glucose concentration dependently stimulated formation of pimonidazole-protein adducts, HIF1 and HIF2 nuclear expression and HIF-target gene mRNA levels to a lesser extent than CoCl2 or a four-fold reduction in pO2. Islets also showed signs of HIF activation in diabetic Lepr(db/db) but not non-diabetic Lepr(db/+) mice. In vitro, these glucose effects were reproduced by nutrient secretagogues that bypass glycolysis, and were inhibited by a three-fold increase in pO2 or by inhibitors of Ca2+ influx and insulin secretion. In INS-1E cells, small interfering RNA-mediated knockdown of Hif1alpha and Hif2alpha, alone or in combination, indicated that the stimulation of glycolytic enzyme mRNA levels depended on both HIF isoforms while the vasodilating peptide adrenomedullin was a HIF2-specific target gene. CONCLUSIONS/SIGNIFICANCE: Glucose-induced O2 consumption creates an intracellular hypoxia that activates HIF1 and HIF2 in rat beta-cells, and this glucose effect contributes, together with the activation of other transcription factors, to the glucose stimulation of expression of some glycolytic enzymes and other hypoxia response genes. PMID- 22235343 TI - Variation within the Huntington's disease gene influences normal brain structure. AB - Genetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain. PMID- 22235344 TI - Melanopsin-expressing amphioxus photoreceptors transduce light via a phospholipase C signaling cascade. AB - Melanopsin, the receptor molecule that underlies light sensitivity in mammalian 'circadian' receptors, is homologous to invertebrate rhodopsins and has been proposed to operate via a similar signaling pathway. Its downstream effectors, however, remain elusive. Melanopsin also expresses in two distinct light sensitive cell types in the neural tube of amphioxus. This organism is the most basal extant chordate and can help outline the evolutionary history of different photoreceptor lineages and their transduction mechanisms; moreover, isolated amphioxus photoreceptors offer unique advantages, because they are unambiguously identifiable and amenable to single-cell physiological assays. In the present study whole-cell patch clamp recording, pharmacological manipulations, and immunodetection were utilized to investigate light transduction in amphioxus photoreceptors. A G(q) was identified and selectively localized to the photosensitive microvillar membrane, while the pivotal role of phospholipase C was established pharmacologically. The photocurrent was profoundly depressed by IP3 receptor antagonists, highlighting the importance of IP3 receptors in light signaling. By contrast, surrogates of diacylglycerol (DAG), as well as poly unsaturated fatty acids failed to activate a membrane conductance or to alter the light response. The results strengthen the notion that calcium released from the ER via IP3-sensitive channels may fulfill a key role in conveying--directly or indirectly--the melanopsin-initiated light signal to the photoconductance; moreover, they challenge the dogma that microvillar photoreceptors and phoshoinositide-based light transduction are a prerogative of invertebrate eyes. PMID- 22235345 TI - Dynamic activation and repression of the plasmodium falciparum rif gene family and their relation to chromatin modification. AB - The regulation of variant gene expression in Plasmodium falciparum is still only partially understood. Regulation of var genes, the most studied gene family involved in antigenic variation, is orchestrated by a dynamic pattern of inherited chromatin states. Although recent evidence pointed to epigenetic regulation of transcribed and repressed rif loci, little is known about specific on/off associated histone modifications of individual rif genes. To investigate the chromatin marks for transcribed and repressed rif loci, we cultivated parasites and evaluated the transcriptional status of chosen rif targets by qRT PCR and performed ChIP assays using H3K9ac and H3K9me3 antibodies. We then monitored changes in the epigenetic patterns in parasites after several reinvasions and also evaluated the "poised" mark in trophozoites and schizonts of the same erythrocytic cycle by ChIP using H3K4me2 specific antibodies. Our results show that H3K9 is acetylated in transcribed rif loci and trimethylated or even unmodified in repressed rif loci. These transcriptional and epigenetic states are inherited after several reinvasions. The poised modification H3K4me2 showed a tendency to be more present in loci in trophozoites that upon progression to schizonts strongly transcribe the respective locus. However, this effect was not consistently observed for all monitored loci. While our data show important similarities to var transcription-associated chromatin modifications, the observed swiftly occurring modifications at rif loci and the absence of H3K9 modification point to a different dynamic of recruitment of chromatin modifying enzymes. PMID- 22235346 TI - Friend of GATA (FOG) interacts with the nucleosome remodeling and deacetylase complex (NuRD) to support primitive erythropoiesis in Xenopus laevis. AB - Friend of GATA (FOG) plays many diverse roles in adult and embryonic hematopoiesis, however the mechanisms by which it functions and the roles of potential interaction partners are not completely understood. Previous work has shown that overexpression of FOG in Xenopus laevis causes loss of blood suggesting that in contrast to its role in mammals, FOG might normally function to repress erythropoiesis in this species. Using loss-of-function analysis, we demonstrate that FOG is essential to support primitive red blood cell (RBC) development in Xenopus. Moreover, we show that it is specifically required to prevent excess apoptosis of circulating primitive RBCs and that in the absence of FOG, the pro-apoptotic gene Bim-1 is strongly upregulated. To identify domains of FOG that are essential for blood development and, conversely, to begin to understand the mechanism by which overexpressed FOG represses primitive erythropoiesis, we asked whether FOG mutants that are unable to interact with known co-factors retain their ability to rescue blood formation in FOG morphants and whether they repress erythropoiesis when overexpressed in wild type embryos. We find that interaction of FOG with the Nucleosome Remodeling and Deacetylase complex (NuRD), but not with C-terminal Binding Protein, is essential for normal primitive RBC development. In contrast, overexpression of all mutant and wild type constructs causes a comparable repression of primitive erythropoiesis. Together, our data suggest that a requirement for FOG and its interaction with NuRD during primitive erythropoiesis are conserved in Xenopus and that loss of blood upon FOG overexpression is due to a dominant-interfering effect. PMID- 22235347 TI - First description of natural and experimental conjugation between Mycobacteria mediated by a linear plasmid. AB - BACKGROUND: In a previous study, we detected the presence of a Mycobacterium avium species-specific insertion sequence, IS1245, in Mycobacterium kansasii. Both species were isolated from a mixed M. avium-M. kansasii bone marrow culture from an HIV-positive patient. The transfer mechanism of this insertion sequence to M. kansasii was investigated here. METHODOLOGY/PRINCIPAL FINDINGS: A linear plasmid (pMA100) was identified in all colonies isolated from the M. avium-M. kansasii mixed culture carrying the IS1245 element. The linearity of pMA100 was confirmed. Other analyses suggested that pMA100 contained a covalently bound protein in the terminal regions, a characteristic of invertron linear replicons. Partial sequencing of pMA100 showed that it bears one intact copy of IS1245 inserted in a region rich in transposase-related sequences. These types of sequences have been described in other linear mycobacterial plasmids. Mating experiments were performed to confirm that pMA100 could be transferred in vitro from M. avium to M. kansasii. pMA100 was transferred by in vitro conjugation not only to the M. kansasii strain from the mixed culture, but also to two other unrelated M. kansasii clinical isolates, as well as to Mycobacterium bovis BCG Moreau. CONCLUSIONS/SIGNIFICANCE: Horizontal gene transfer (HGT) is one of most important mechanisms leading to the evolution and diversity of bacteria. This work provides evidence for the first time on the natural occurrence of HGT between different species of mycobacteria. Gene transfer, mediated by a novel conjugative plasmid, was detected and experimentally reproduced. PMID- 22235348 TI - Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction. AB - BACKGROUND: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. METHODS: RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 ug/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-kappaB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1beta, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. RESULTS: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF kappaB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. CONCLUSION: CERA protects against sepsis induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response. PMID- 22235349 TI - Down-regulation of myogenin can reverse terminal muscle cell differentiation. AB - Certain higher vertebrates developed the ability to reverse muscle cell differentiation (dedifferentiation) as an additional mechanism to regenerate muscle. Mammals, on the other hand, show limited ability to reverse muscle cell differentiation. Myogenic Regulatory Factors (MRFs), MyoD, myogenin, Myf5 and Myf6 are basic-helix-loop-helix (bHLH) transcription factors essential towards the regulation of myogenesis.Our current interest is to investigate whether down regulation of MRFs in terminally differentiated mouse myotubes can induce reversal of muscle cell differentiation. Results from this work showed that reduction of myogenin levels in terminally differentiated mouse myotubes can reverse their differentiation state. Down-regulation of myogenin in terminally differentiated mouse myotubes induces cellular cleavage into mononucleated cells and cell cycle re-entry, as shown by re-initiation of DNA synthesis and increased cyclin D1 and cyclin E2 levels. Finally, we provide evidence that down-regulation of myogenin causes cell cycle re-entry (via down-regulation of MyoD) and cellularisation through separate pathways. These data reveal the important role of myogenin in maintaining terminal muscle cell differentiation and point to a novel mechanism by which muscle cells could be re-activated through its down regulation. PMID- 22235350 TI - gamma-Tubulin 2 nucleates microtubules and is downregulated in mouse early embryogenesis. AB - gamma-Tubulin is the key protein for microtubule nucleation. Duplication of the gamma-tubulin gene occurred several times during evolution, and in mammals gamma tubulin genes encode proteins which share ~97% sequence identity. Previous analysis of Tubg1 and Tubg2 knock-out mice has suggested that gamma-tubulins are not functionally equivalent. Tubg1 knock-out mice died at the blastocyst stage, whereas Tubg2 knock-out mice developed normally and were fertile. It was proposed that gamma-tubulin 1 represents ubiquitous gamma-tubulin, while gamma-tubulin 2 may have some specific functions and cannot substitute for gamma-tubulin 1 deficiency in blastocysts. The molecular basis of the suggested functional difference between gamma-tubulins remains unknown. Here we show that exogenous gamma-tubulin 2 is targeted to centrosomes and interacts with gamma-tubulin complex proteins 2 and 4. Depletion of gamma-tubulin 1 by RNAi in U2OS cells causes impaired microtubule nucleation and metaphase arrest. Wild-type phenotype in gamma-tubulin 1-depleted cells is restored by expression of exogenous mouse or human gamma-tubulin 2. Further, we show at both mRNA and protein levels using RT qPCR and 2D-PAGE, respectively, that in contrast to Tubg1, the Tubg2 expression is dramatically reduced in mouse blastocysts. This indicates that gamma-tubulin 2 cannot rescue gamma-tubulin 1 deficiency in knock-out blastocysts, owing to its very low amount. The combined data suggest that gamma-tubulin 2 is able to nucleate microtubules and substitute for gamma-tubulin 1. We propose that mammalian gamma-tubulins are functionally redundant with respect to the nucleation activity. PMID- 22235351 TI - ABO blood group and the risk of hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B. AB - BACKGROUND: Studies have observed an association between the ABO blood group and risk of certain malignancies. However, no studies of the association with hepatocellular carcinoma (HCC) risk are available. We conducted this hospital based case-control study to examine the association with HCC in patients with chronic hepatitis B (CHB). METHODS: From January 2004 to December 2008, a total of 6275 consecutive eligible patients with chronic hepatitis B virus (HBV) infection were recruited. 1105 of them were patients with HBV-related HCC and 5,170 patients were CHB without HCC. Multivariate logistic regression models were used to investigate the association between the ABO blood group and HCC risk. RESULTS: Compared with subjects with blood type O, the adjusted odds ratio (AOR) for the association of those with blood type A and HCC risk was 1.39 [95% confidence interval (CI), 1.05-1.83] after adjusting for age, sex, type 2 diabetes, cirrhosis, hepatitis B e antigen, and HBV DNA. The associations were only statistically significant [AOR (95%CI) = 1.56(1.14-2.13)] for men, for being hepatitis B e antigen positive [AOR (95%CI) = 4.92(2.83-8.57)], for those with cirrhosis [AOR (95%CI), 1.57(1.12-2.20)], and for those with HBV DNA<=10(5)copies/mL [AOR (95%CI), 1.58(1.04-2.42)]. Stratified analysis by sex indicated that compared with those with blood type O, those with blood type B also had a significantly high risk of HCC among men, whereas, those with blood type AB or B had a low risk of HCC among women. CONCLUSIONS: The ABO blood type was associated with the risk of HCC in Chinese patients with CHB. The association was gender-related. PMID- 22235352 TI - Genomic characterization of the Taylorella genus. AB - The Taylorella genus comprises two species: Taylorella equigenitalis, which causes contagious equine metritis, and Taylorella asinigenitalis, a closely related species mainly found in donkeys. We herein report on the first genome sequence of T. asinigenitalis, analyzing and comparing it with the recently sequenced T. equigenitalis genome. The T. asinigenitalis genome contains a single circular chromosome of 1,638,559 bp with a 38.3% GC content and 1,534 coding sequences (CDS). While 212 CDSs were T. asinigenitalis-specific, 1,322 had orthologs in T. equigenitalis. Two hundred and thirty-four T. equigenitalis CDSs had no orthologs in T. asinigenitalis. Analysis of the basic nutrition metabolism of both Taylorella species showed that malate, glutamate and alpha-ketoglutarate may be their main carbon and energy sources. For both species, we identified four different secretion systems and several proteins potentially involved in binding and colonization of host cells, suggesting a strong potential for interaction with their host. T. equigenitalis seems better-equipped than T. asinigenitalis in terms of virulence since we identified numerous proteins potentially involved in pathogenicity, including hemagluttinin-related proteins, a type IV secretion system, TonB-dependent lactoferrin and transferrin receptors, and YadA and Hep_Hag domains containing proteins. This is the first molecular characterization of Taylorella genus members, and the first molecular identification of factors potentially involved in T. asinigenitalis and T. equigenitalis pathogenicity and host colonization. This study facilitates a genetic understanding of growth phenotypes, animal host preference and pathogenic capacity, paving the way for future functional investigations into this largely unknown genus. PMID- 22235353 TI - Low efficacy of single-dose albendazole and mebendazole against hookworm and effect on concomitant helminth infection in Lao PDR. AB - BACKGROUND: Albendazole and mebendazole are increasingly deployed for preventive chemotherapy targeting soil-transmitted helminth (STH) infections. We assessed the efficacy of single oral doses of albendazole (400 mg) and mebendazole (500 mg) for the treatment of hookworm infection in school-aged children in Lao PDR. Since Opisthorchis viverrini is co-endemic in our study setting, the effect of the two drugs could also be determined against this liver fluke. METHODOLOGY: We conducted a randomized, open-label, two-arm trial. In total, 200 children infected with hookworm (determined by quadruplicate Kato-Katz thick smears derived from two stool samples) were randomly assigned to albendazole (n=100) and mebendazole (n=100). Cure rate (CR; percentage of children who became egg negative after treatment), and egg reduction rate (ERR; reduction in the geometric mean fecal egg count at treatment follow-up compared to baseline) at 21 23 days posttreatment were used as primary outcome measures. Adverse events were monitored 3 hours post treatment. PRINCIPAL FINDINGS: Single-dose albendazole and mebendazole resulted in CRs of 36.0% and 17.6% (odds ratio: 0.4; 95% confidence interval: 0.2-0.8; P=0.01), and ERRs of 86.7% and 76.3%, respectively. In children co-infected with O. viverrini, albendazole and mebendazole showed low CRs (33.3% and 24.2%, respectively) and moderate ERRs (82.1% and 78.2%, respectively). CONCLUSIONS/SIGNIFICANCE: Both albendazole and mebendazole showed disappointing CRs against hookworm, but albendazole cured infection and reduced intensity of infection with a higher efficacy than mebendazole. Single-dose administrations showed an effect against O. viverrini, and hence it will be interesting to monitor potential ancillary benefits of a preventive chemotherapy strategy that targets STHs in areas where opisthorchiasis is co-endemic. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ISRCTN29126001. PMID- 22235354 TI - Management and outcome of cardiac and endovascular cystic echinococcosis. AB - BACKGROUND: Cystic echinococcosis (CE) can affect the heart and the vena cava but few cases are reported. METHODS: A retrospective case series of 11 patients with cardiac and/or endovascular CE, followed-up over a period of 15 years (1995-2009) is reported. RESULTS: Main clinical manifestations included thoracic pain or dyspnea, although 2 patients were asymptomatic. Cysts were located mostly in the right atrium and inferior vena cava. Nine patients were previously diagnosed with disseminated CE. Echocardiography was the diagnostic method of choice, although serology, electrocardiogram, chest X-ray, computed tomography/magnetic resonance imaging and histology aided with diagnosis and follow-up. Nine patients underwent cardiac surgery and nine received long-term antiparasitic treatment for a median duration of 25 months (range 4-93 months). One patient died intra-operatively due to cyst rupture and endovascular dissemination. Two patients died 10 and 14 years after diagnosis, due to pulmonary embolism (PE) and cardiac failure, respectively. One patient was lost to follow-up. Patients who had cardiac involvement exclusively did not have complications after surgery and were considered cured. There was only one recurrence requiring a second operation. Patients with vena cava involvement developed PEs and presented multiple complications. CONCLUSIONS: Cardiovascular CE is associated with a high risk of potentially lethal complications. Clinical manifestations and complications vary according to cyst location. Isolated cardiac CE may be cured after surgery, while endovascular extracardiac involvement is associated with severe chronic complications. CE should be included in the differential diagnosis of cardiovascular disease in patients from endemic areas. PMID- 22235355 TI - Identification and characterization of a Mef2 transcriptional activator in schistosome parasites. AB - Myocyte enhancer factor 2 protein (Mef2) is an evolutionarily conserved activator of transcription that is critical to induce and control complex processes in myogenesis and neurogenesis in vertebrates and insects, and osteogenesis in vertebrates. In Drosophila, Mef2 null mutants are unable to produce differentiated muscle cells, and in vertebrates, Mef2 mutants are embryonic lethal. Schistosome worms are responsible for over 200 million cases of schistosomiasis globally, but little is known about early development of schistosome parasites after infecting a vertebrate host. Understanding basic schistosome development could be crucial to delineating potential drug targets. Here, we identify and characterize Mef2 from the schistosome worm Schistosoma mansoni (SmMef2). We initially identified SmMef2 as a homolog to the yeast Mef2 homolog, Resistance to Lethality of MKK1P386 overexpression (Rlm1), and we show that SmMef2 is homologous to conserved Mef2 family proteins. Using a genetics approach, we demonstrate that SmMef2 is a transactivator that can induce transcription of four separate heterologous reporter genes by yeast one-hybrid analysis. We also show that Mef2 is expressed during several stages of schistosome development by quantitative PCR and that it can bind to conserved Mef2 DNA consensus binding sequences. PMID- 22235356 TI - Analysis of epitopes on dengue virus envelope protein recognized by monoclonal antibodies and polyclonal human sera by a high throughput assay. AB - BACKGROUND: The envelope (E) protein of dengue virus (DENV) is the major target of neutralizing antibodies and vaccine development. While previous studies on domain III or domain I/II alone have reported several epitopes of monoclonal antibodies (mAbs) against DENV E protein, the possibility of interdomain epitopes and the relationship between epitopes and neutralizing potency remain largely unexplored. METHODOLOGY/PRINCIPAL FINDINGS: We developed a dot blot assay by using 67 alanine mutants of predicted surface-exposed E residues as a systematic approach to identify epitopes recognized by mAbs and polyclonal sera, and confirmed our findings using a capture-ELISA assay. Of the 12 mouse mAbs tested, three recognized a novel epitope involving residues (Q211, D215, P217) at the central interface of domain II, and three recognized residues at both domain III and the lateral ridge of domain II, suggesting a more frequent presence of interdomain epitopes than previously appreciated. Compared with mAbs generated by traditional protocols, the potent neutralizing mAbs generated by a new protocol recognized multiple residues in A strand or residues in C strand/CC' loop of DENV2 and DENV1, and multiple residues in BC loop and residues in DE loop, EF loop/F strand or G strand of DENV1. The predominant epitopes of anti-E antibodies in polyclonal sera were found to include both fusion loop and non-fusion residues in the same or adjacent monomer. CONCLUSIONS/SIGNIFICANCE: Our analyses have implications for epitope-specific diagnostics and epitope-based dengue vaccines. This high throughput method has tremendous application for mapping both intra and interdomain epitopes recognized by human mAbs and polyclonal sera, which would further our understanding of humoral immune responses to DENV at the epitope level. PMID- 22235358 TI - Negative regulation of Schistosoma japonicum egg-induced liver fibrosis by natural killer cells. AB - The role of natural killer (NK) cells in infection-induced liver fibrosis remains obscure. In this study, we elucidated the effect of NK cells on Schistosoma japonicum (S. japonicum) egg-induced liver fibrosis. Liver fibrosis was induced by infecting C57BL/6 mice with 18-20 cercariae of S. japonicum. Anti-ASGM1 antibody was used to deplete NK cells. Toll-like receptor 3 ligand, polyinosinic polycytidylic acid (poly I:C) was used to enhance the activation of NK cells. Results showed that NK cells were accumulated and activated after S. japonicum infection, as evidenced by the elevation of CD69 expression and IFN-gamma production. Depletion of NK cells markedly enhanced S. japonicum egg-induced liver fibrosis. Administration of poly I:C further activated NK cells to produce IFN-gamma and attenuated S. japonicum egg-induced liver fibrosis. The observed protective effect of poly I:C on liver fibrosis was diminished through depletion of NK cells. Disruption of IFN-gamma gene enhanced liver fibrosis and partially abolished the suppression of liver fibrosis by poly I:C. Moreover, expression of retinoic acid early inducible 1 (RAE 1), the NKG2D ligand, was detectable at high levels on activated hepatic stellate cells derived from S. japonicum-infected mice, which made them more susceptible to hepatic NK cell killing. In conclusion, our findings suggest that the activated NK cells in the liver after S. japonicum infection negatively regulate egg-induced liver fibrosis via producing IFN-gamma, and killing activated stellate cells. PMID- 22235357 TI - The genetic and molecular basis of O-antigenic diversity in Burkholderia pseudomallei lipopolysaccharide. AB - Lipopolysaccharide (LPS) is one of the most important virulence and antigenic components of Burkholderia pseudomallei, the causative agent of melioidosis. LPS diversity in B. pseudomallei has been described as typical, atypical or rough, based upon banding patterns on SDS-PAGE. Here, we studied the genetic and molecular basis of these phenotypic differences. Bioinformatics was used to determine the diversity of genes known or predicted to be involved in biosynthesis of the O-antigenic moiety of LPS in B. pseudomallei and its near relative species. Multiplex-PCR assays were developed to target diversity of the O-antigen biosynthesis gene patterns or LPS genotypes in B. pseudomallei populations. We found that the typical LPS genotype (LPS genotype A) was highly prevalent in strains from Thailand and other countries in Southeast Asia, whereas the atypical LPS genotype (LPS genotype B) was most often detected in Australian strains (~13.8%). In addition, we report a novel LPS ladder pattern, a derivative of the atypical LPS phenotype, associated with an uncommon O-antigen biosynthesis gene cluster that is found in only a small B. pseudomallei sub-population. This new LPS group was designated as genotype B2. We also report natural mutations in the O-antigen biosynthesis genes that potentially cause the rough LPS phenotype. We postulate that the diversity of LPS may correlate with differential immunopathogenicity and virulence among B. pseudomallei strains. PMID- 22235359 TI - Murine dendritic cells transcriptional modulation upon Paracoccidioides brasiliensis infection. AB - Limited information is available regarding the modulation of genes involved in the innate host response to Paracoccidioides brasiliensis, the etiologic agent of paracoccidioidomycosis. Therefore, we sought to characterize, for the first time, the transcriptional profile of murine bone marrow-derived dendritic cells (DCs) at an early stage following their initial interaction with P. brasiliensis. DCs connect innate and adaptive immunity by recognizing invading pathogens and determining the type of effector T-cell that mediates an immune response. Gene expression profiles were analyzed using microarray and validated using real-time RT-PCR and protein secretion studies. A total of 299 genes were differentially expressed, many of which are involved in immunity, signal transduction, transcription and apoptosis. Genes encoding the cytokines IL-12 and TNF-alpha, along with the chemokines CCL22, CCL27 and CXCL10, were up-regulated, suggesting that P. brasiliensis induces a potent proinflammatory response in DCs. In contrast, pattern recognition receptor (PRR)-encoding genes, particularly those related to Toll-like receptors, were down-regulated or unchanged. This result prompted us to evaluate the expression profiles of dectin-1 and mannose receptor, two other important fungal PRRs that were not included in the microarray target cDNA sequences. Unlike the mannose receptor, the dectin-1 receptor gene was significantly induced, suggesting that this beta-glucan receptor participates in the recognition of P. brasiliensis. We also used a receptor inhibition assay to evaluate the roles of these receptors in coordinating the expression of several immune-related genes in DCs upon fungal exposure. Altogether, our results provide an initial characterization of early host responses to P. brasiliensis and a basis for better understanding the infectious process of this important neglected pathogen. PMID- 22235360 TI - Validation of a new test for Schistosoma haematobium based on detection of Dra1 DNA fragments in urine: evaluation through latent class analysis. AB - BACKGROUND: Diagnosis of urogenital schistosomiasis in chronically infected adults is challenging but important, especially because long term infection of the bladder and urinary tract can have dire consequences. We evaluated three tests for viable infection: detection of parasite specific DNA Dra1 fragments, haematuria and presence of parasite eggs for sensitivity (Se) and specificity (Sp). METHODS: Over 400 urine specimens collected from adult volunteers in an endemic area in Western Nigeria were assessed for haematuria then filtered in the field, the filter papers dried and later examined for eggs and DNA. The results were stratified according to sex and age and subjected to Latent Class analysis. CONCLUSIONS: Presence of Dra1 in males (Se=100%; Sp=100%) exceeded haematuria (Se=87.6%: Sp=34.7%) and detection of eggs (Se=70.1%; Sp=100%). In females presence of Dra1 was Se=100%: Sp=100%, exceeding haematuria (Se=86.7%: Sp=77.0%) and eggs (Se=70.1%; Sp=100%). Dra1 became undetectable 2 weeks after praziquantel treatment. We conclude detection of Dra1 fragment is a definitive test for the presence of Schistosoma haematobium infection. PMID- 22235361 TI - Advances and challenges in islet transplantation: islet procurement rates and lessons learned from suboptimal islet transplantation. AB - The initial step in successful islet transplantation is procurement of healthy donor islets. Given the limited number of donor pancreata selected for islet isolation and that islets from multiple donors are typically required to obtain insulin independence, it is critical to improve pancreas procurement rates and yield of islets for transplantation. Islets are delicate microorgans that are susceptible to apoptosis, hypoxia, and ischemia during isolation, culture, and the peritransplant period. Once the islets are engrafted, both prompt revascularization and protection from beta-cell death and graft rejection are key to secure long-term survival and function. To facilitate the engraftment of more robust islets suitable for combating the challenging isolation period and proinflammatory transplantation milieu, numerous approaches have been employed to prevent beta-cell dysfunction and death including immune modulation, prevention of apoptosis and hypoxia, as well as stimulation of growth factors, angiogenesis, and reinnervation. In addition to briefly discussing islet isolation procedures, procurement rates, and islet transplantation, the relevant literature pertaining to successful suboptimal islet transplantation is reviewed to provide insight into potential approaches to balance the limited supply of available donor islets. PMID- 22235362 TI - Effect of intravitreal ranibizumab in the treatment of peripapillary choroidal neovascularisation. AB - Intravitreal ranibizumab therapy is widely used in treatment of subfoveal choroidal neovascularisation (CNV) in age-related macular degeneration. We wanted to study the effect of intravitreal ranibizumab therapy in peripapillary CNV. A prospective recording of treatment outcomes in twelve eyes (12 patients) with peripapillary CNV with intravitreal injections of ranibizumab was performed. The patients received a series of 3 injections 4-6 weeks apart, and then a new ophthalmic examination was made including OCT and further therapy was given if the peripapillary CNV was still active. Nine patients had idiopathic peripapillary CNV, and in 3 patients it was associated to age-related macular degeneration. Followup had to be at least 6 months. The mean follow-up time was 15.9 (range 9-27) months and the mean number of injections 6.2 (3-10). In 10 patients treatment had resulted in an inactivation of the peripapillary CNV, but 3 of them had reactivation, while 2 patients had no inactivation. Currently, 5 patients are continuous to receive treatment. VA improved in 10 patients. Intravitreal ranibizumab therapy appears to be effective in patients with peripapillary CNV, but in some cases there is repeated reactivation or continuous activity of the peripapillary CNV. PMID- 22235363 TI - TRC120038, a Novel Dual AT(1)/ET(A) Receptor Blocker for Control of Hypertension, Diabetic Nephropathy, and Cardiomyopathy in ob-ZSF1 Rats. AB - In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT(1)/ET(A) receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat. PMID- 22235364 TI - Activated charcoal-a potential material in glucoamylase recovery. AB - The potential of activated charcoal in the purification of fungal glucoamylase was investigated. Various concentrations of activated charcoal (1-4% w/v) were used to concentrate crude glucoamylase from Rhizopus oligosporus at different temperature values (30-50 degrees C). Effects of pH (3.0-6.0) and contact time (0 60 min) on enzyme purification were also monitored. Activated charcoal (3% w/v) gave a 16-fold purification in a single-step purification at 50 degrees C for 20 min and pH 5.5. The result of SDS-PAGE analysis of purified glucoamylase showed two major protein bands with corresponding molecular weight of 36 kDa and 50 kDa. The method is inexpensive, rapid, and simple which could facilitate downstream processing of industrial enzyme. PMID- 22235366 TI - Changes in erythrocyte sedimentation rate, white blood cell count, liver enzymes, and magnesium after gastric bypass surgery. AB - Background. Roux-en-Y gastric bypass (RYGBP) is an established method for treatment of obesity, a condition of chronic inflammation with liver steatosis, characterised by increased erythrocyte sedimentation rate (ESR), white blood cell count (WBC), liver enzymes, and decreased magnesium (Mg). We investigated alterations, if any, in ESR, WBC, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and Mg after RYGBP. Methods. 21 morbidly obese nondiabetic patients who underwent RYGBP surgery were evaluated preoperatively (baseline), then 1 year (1st followup) and 3.5 years (2nd followup) after RYGBP and compared to an untreated control group. Results. Body mass index, ESR, WBC, ALT, and GGT were all significantly reduced at 1 year in the RYGBP group (30%, 35%, 20%, 45%, and 57%, resp.) while Mg increased by 6%, compared to control group (P = 0.001 0.009). Conclusions. Obese patients treated by RYGBP show sustained reductions in ESR, WBC, ALT, and GGT possibly due to reduced liver steatosis and increased Mg. PMID- 22235367 TI - Community-Specific BMI Cutoff Points for South Indian Females. AB - Objective. To analyze multiparameters related to total body composition, with specific emphasis on obesity in South Indian females, in order to derive community-specific BMI cutoff points. Patients and Methods. A total number of 87 females (of age 37.33 +/- 13.12 years) from South Indian Chennai urban population participated in this clinical study. Body composition analysis and anthropometric measurements were acquired after conducting careful clinical examination. Results. BMI demonstrated high significance when normal group (21.02 +/- 1.47 kg/m(2)) was compared with obese group (29.31 +/- 3.95 kg/m(2)), P < 0.0001. BFM displayed high significance when normal group (14.92 +/- 4.28 kg) was compared with obese group (29.94 +/- 8.1 kg), P < 0.0001. Conclusion. Community-specific BMI cutoffs are necessary to assess obesity in different ethnic groups, and relying on WHO-based universal BMI cutoff points would be a wrong strategy. PMID- 22235365 TI - B-cell-activating factor and autoimmune myasthenia gravis. AB - BAFF is a potent B-cell survival factor, and it plays an essential role in B-cell homeostasis and B-cell function in the periphery. Both normal and autoreactive B cells are BAFF dependent; however, excess BAFF promotes the survival, growth, and maturation of autoreactive B cells. When overexpressed, BAFF protects B cells from apoptosis, thereby contributing to autoimmunity. Three independent studies have shown higher BAFF levels in the circulation of MG patients. BAFF may play an important role in the pathogenesis of MG. BAFF antagonists may well provide new treatment options for MG patients, particularly those patients with thymic lymphoid follicular hyperplasia. PMID- 22235368 TI - Adolescent weight status and self-reported school performance in South Korea. AB - Using a nationally representative sample of 142 783 middle school (13-15 years old) and high school (16-18 years old) students in South Korea, this study examined whether (1) overweight and obesity are more likely to be associated with lower self-reported school performance; (2) overweight and obese students are more likely to enrol in a vocational high school as opposed to a general high school; (3) the association between obesity and poorer self-reported school performance is mediated through body image stress and health status. We found that excess weight was negatively associated with self-reported school performance among middle and general high school students, and that obese students had a higher probability of being enrolled in a vocational over a general high school. We did not find strong evidence on the mediating role of body image stress and health status. PMID- 22235369 TI - The carnivore connection hypothesis: revisited. AB - The "Carnivore Connection" hypothesizes that, during human evolution, a scarcity of dietary carbohydrate in diets with low plant : animal subsistence ratios led to insulin resistance providing a survival and reproductive advantage with selection of genes for insulin resistance. The selection pressure was relaxed at the beginning of the Agricultural Revolution when large quantities of cereals first entered human diets. The "Carnivore Connection" explains the high prevalence of intrinsic insulin resistance and type 2 diabetes in populations that transition rapidly from traditional diets with a low-glycemic load, to high carbohydrate, high-glycemic index diets that characterize modern diets. Selection pressure has been relaxed longest in European populations, explaining a lower prevalence of insulin resistance and type 2 diabetes, despite recent exposure to famine and food scarcity. Increasing obesity and habitual consumption of high glycemic-load diets worsens insulin resistance and increases the risk of type 2 diabetes in all populations. PMID- 22235370 TI - The challenge of appropriate identification and treatment of starvation, sarcopenia, and cachexia: a survey of Australian dietitians. AB - Malnutrition is an umbrella term that includes starvation, sarcopenia, and cachexia; however, differentiating between these terms is infrequent in clinical practice. Given that the effectiveness of treatment depends on the aetiology of unintentional weight loss, it is important that clinicians are aware of the defining characteristics. The aim of this study was to determine whether Australian dietitians understand and use the terms starvation, sarcopenia, and cachexia and provide targeted treatment strategies accordingly. Members of the Dietitians Association of Australia were surveyed to gain information on practices and attitudes to diagnosis and treatment of adult malnutrition. In addition, three case studies were provided to examine understanding of starvation, sarcopenia, and cachexia. 221 dietitians accessed the survey. 81 respondents (43%) indicated the use of at least one alternate term (starvation, sarcopenia, and/or cachexia). Muscle wasting was the most commonly used diagnostic criterion. High-energy high-protein diet was the most common therapy prescribed. Correct diagnoses for case studies were recorded by 6% of respondents for starvation, 46% for sarcopenia, and 21% for cachexia. There is a need for increased awareness of the existence of starvation, sarcopenia, and cachexia amongst Australian dietitians and research into appropriate methods of identification and treatment for each condition. PMID- 22235371 TI - Extracellular Signal-Regulated Kinase (ERK) Activation and Mitogen-Activated Protein Kinase Phosphatase 1 Induction by Pulsatile Gonadotropin-Releasing Hormone in Pituitary Gonadotrophs. AB - The frequency of gonadotropin-releasing hormone (GnRH) pulse secreted from the hypothalamus differently regulates the expressions of gonadotropin subunit genes, luteinizing hormone beta (LHbeta) and follicle-stimulating hormone beta (FSHbeta), in the pituitary gonadotrophs. FSHbeta is preferentially stimulated at slower GnRH pulse frequencies, whereas LHbeta is preferentially stimulated at more rapid pulse frequencies. Several signaling pathways are activated, including mitogen-activated protein kinase (MAPK), protein kinase C, calcium influx, and calcium-calmodulin kinases, and these may be preferentially regulated under certain conditions. Previous studies demonstrated that MAPK pathways, especially the extracellular signal-regulated kinase (ERK), play an essential role for induction of gonadotropin subunit gene expression by GnRH, whereas, MAPK phosphatases (MKPs) inactivate MAPKs through dephosphorylation of threonine and/or tyrosine residues. MKPs are also induced by GnRH, and potential feedback regulation between MAPK signaling and MKPs within the GnRH signaling pathway is evident in gonadotrophs. In this paper, we reviewed and mainly focused on our observations of the pattern of ERK activation and the induction of MKP by different frequencies of GnRH stimulation. PMID- 22235373 TI - Imaging and resuscitation in trauma. PMID- 22235374 TI - Patients prefer boarding in inpatient hallways: correlation with the national emergency department overcrowding score. AB - Objective. The boarding of patients in Emergency Department (ED) hallways when no inpatient beds are available is a major cause of ED crowding. One solution is to board admitted patients in an inpatient rather than ED hallway. We surveyed patients to determine their preference and correlated their responses to real time National Emergency Department Overcrowding Score (NEDOCS). Methods. This was a survey of admitted patients in the ED of an urban university level I trauma center serving a community of 5 million about their personal preferences regarding boarding. Real-time NEDOCS was calculated at the time each survey was conducted. Results. 99 total surveys were completed during October 2010, 42 (42%) patients preferred to be boarded in an inpatient hallway, 33 (33%) preferred the ED hallway, and 24 (24%) had no preference. Mean (+/-SD) NEDOCS (range 0-200) was 136 +/- 46 for patients preferring inpatient boarding, 112 +/- 39 for ED boarding, and 119 +/- 43 without preference. Male patients preferred inpatient hallway boarding significantly more than females. Preference for inpatient boarding was associated with a significantly higher NEDOCS. Conclusions. In this survey study, patients prefer inpatient hallway boarding when the hospital is at or above capacity. Males prefer inpatient hallway boarding more than females. The preference for inpatient hallway boarding increases as the ED becomes more crowded. PMID- 22235372 TI - Matrix metalloproteinases contribute to neuronal dysfunction in animal models of drug dependence, Alzheimer's disease, and epilepsy. AB - Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy. PMID- 22235375 TI - Tumor Suppressor Function of CYLD in Nonmelanoma Skin Cancer. AB - Ubiquitin and ubiquitin-related proteins posttranslationally modify substrates, and thereby alter the functions of their targets. The ubiquitination process is involved in various physiological responses, and dysregulation of components of the ubiquitin system has been linked to many diseases including skin cancer. The ubiquitin pathways activated among skin cancers are highly diverse and may reflect the various characteristics of the cancer type. Basal cell carcinoma and squamous cell carcinoma, the most common types of human skin cancer, are instances where the involvement of the deubiquitination enzyme CYLD has been recently highlighted. In basal cell carcinoma, the tumor suppressor protein CYLD is repressed at the transcriptional levels through hedgehog signaling pathway. Downregulation of CYLD in basal cell carcinoma was also shown to interfere with TrkC expression and signaling, thereby promoting cancer progression. By contrast, the level of CYLD is unchanged in squamous cell carcinoma, instead, catalytic inactivation of CYLD in the skin has been linked to the development of squamous cell carcinoma. This paper will focus on the current knowledge that links CYLD to nonmelanoma skin cancers and will explore recent insights regarding CYLD regulation of NF-kappaB and hedgehog signaling during the development and progression of these types of human tumors. PMID- 22235377 TI - Fractalkine and other chemokines in primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is characterized by the autoimmune injury of small intrahepatic bile duct. On this basis, it has been suggested that the targeted biliary epithelial cells (BEC) play an active role in the perpetuation of autoimmunity by attracting immune cells via chemokine secretion. To address this issue, we challenged BEC using multiple toll-like receptor (TLR) ligands as well as autologous liver infiltrating mononuclear cells (LMNC) with subsequent measurement of BEC phenotype and chemokine production and LMNC chemotaxis by quantifying specific chemokines, specially CX3CL1 (fractalkine). We submit the hypothesis that BEC are in fact the innocent victims of the autoimmune injury and that the adaptive immune response is critical in PBC. PMID- 22235376 TI - Radioembolization in the treatment of neuroendocrine tumor metastases to the liver. AB - Surgical excision remains the preferred treatment for resectable hepatic metastases of neuroendocrine tumors. In cases of more disseminated hepatic disease, transarterial radioembolization with Yttrium-90- (90Y-) labeled microspheres has been demonstrated as a viable option for symptom and locoregional tumor control. On an outpatient basis, radioembolization can be utilized from early line to salvage phases, in various combinations with systemic therapies. Review of available data shows encouraging safety and efficacy profiles for the intraarterial application of 90Y for the treatment of mNETs of the liver. Symptom control and decrease in somatostatin analog use can be achieved, as well as prolonged survival. PMID- 22235378 TI - The natural history and clinical presentation of cervical spondylotic myelopathy. AB - Cervical spondylotic myelopathy (CSM) refers to impaired function of the spinal cord caused by degenerative changes of the cervical spine resulting in spinal cord compression. It is the most common disorder in the United States causing dysfunction of the spinal cord. A literature review of the natural history of mild cervical myelopathy is undertaken. Clinical presentation and current concepts of pathophysiology are also discussed. While many patients with mild signs of CSM will stabilize or improve over time with conservative treatment, the clinical course of a specific individual patient cannot be predicted. Asymptomatic patients with cervical stenosis and abnormalities on electrophysiologic studies may be at higher risk for developing myelopathy. PMID- 22235379 TI - Tumor Vascular Morphology Undergoes Dramatic Changes during Outgrowth of B16 Melanoma While Proangiogenic Gene Expression Remains Unchanged. AB - In established tumors, angiogenic endothelial cells (ECs) coexist next to "quiescent" EC in matured vessels. We hypothesized that angio-gene expression of B16.F10 melanoma would differ depending on the growth stage. Unraveling the spatiotemporal nature thereof is essential for drug regimen design aimed to affect multiple neovascularization stages. We determined the angiogenic phenotype represented by 52 angio-genes-and vascular morphology of small, intermediate, and large s.c. growing mouse B16.F10 tumors and demonstrated that expression of these genes did not differ between the different growth stages. Yet vascular morphology changed dramatically from small vessels without lumen in small to larger vessels with increased lumen size in intermediate/large tumors. Separate analysis of these vascular morphologies revealed a significant difference in alphaSMA expression in relation to vessel morphology, while no relation with VEGF, HIF 1alpha, nor Dll4 expression levels was observed. We conclude that the tumor vasculature remains actively engaged in angiogenesis during B16.F10 melanoma outgrowth and that the major change in tumor vascular morphology does not follow molecular concepts generated in other angiogenesis models. PMID- 22235380 TI - A novel antireflux technique for orthotopic ileal bladder substitutes-flat segment technique: preliminary results. AB - Objective. Although a large debate exists regarding the need for reflux prevention in ileal orthotopic neobladders, it is our policy to continue performing nonrefluxing ureteroileal anastomoses for our patients. An ideal uretero-ileal anastomosis must be simple, nonrefluxing, as well as non obstructive. Here, we present a new antireflux mechanism for orthotopic ileal neobladders. Methods. 12 radical cystectomy patients for muscle invasive bladder cancer were candidates for orthotopic urinary diversion and underwent a non refluxing uretero-ileal anastomosis using the flat-segment technique with a follow up of 6 to 18 months. Results. Preliminary results after the short-term followup showed that the success rate in reflux prevention was 92% and no cases of obstruction. The upper tracts were preserved or improved in all 12 patients. Operative time for neobladder creation ranged between 120-240 minutes, with a mean of 165 minutes (+/-36 minutes). No diversion-related complications. Conclusions. Based on our early data, we believe that the flat-segment uretero ileal anastomosis technique for reflux prevention in orthotopic ileal bladder substitutes is simple, easy to learn and carries no additional morbidity to a standard refluxing uretero-ileal anastomosis, but has the advantage of effective reflux prevention. A longer follow-up period study with more patient numbers is ongoing. PMID- 22235383 TI - Role of serum renin and aldosterone in animal adaptation to high-altitude conditions. AB - Adaptation to high-altitude conditions in rats with experimental renal failure is associated with shifts in the rennin-angiotensin-aldosterone system, which manifested in different serum levels of renin and aldosterone in response to water and salt loads depending on the stage of the compensation processes. PMID- 22235384 TI - Effects of electrical stimulation of the hunger center in the lateral hypothalamus and food reinforcement on impulse activity of the mylohyoid muscle in rabbits under conditions of hunger and satiety. AB - Effects of electrical stimulation of the hunger center in the lateral hypothalamus and food reinforcement on impulse activity of mylohyoid muscle were studied in chronic experiments under conditions of hunger and satiety. Threshold stimulation of the lateral hypothalamus in starving and satiated rabbits in the absence of food induced searching behavior associated with burst-like impulse activity with a bimodal distribution of interpulse intervals. Regular spike burst in the mylohyoid muscle during stimulation of the lateral hypothalamus in the absence of food serves as an example of the anticipatory type reaction. Increased food motivation during threshold stimulation of the lateral hypothalamus in starving and satiated rabbits with food offered led to successful food-procuring behavior, during which the frequency of spike bursts in the mylohyoid muscle became comparable with that under conditions of natural foraging behavior stimulated by the need in nutrients. Our results suggest that temporal structure of mylohyoid muscle impulse activity reflects convergent interactions of food motivation excitation with reinforcement excitation on neurons of the masticatory and deglutitive centers. PMID- 22235385 TI - Experimental modeling of preclinical and clinical stages of Parkinson's disease. AB - Degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system is the key stage in the pathogenesis of Parkinson's disease. The first symptoms of this disease are observed after degeneration of 70-80% neurons, which occurs over 20 30 years. The clinical stage of Parkinson's disease begins after this period. Late diagnostics of Parkinson's disease contributes to low efficiency of therapy for this disorder. Detailed study of the pathogenesis and development of preclinical diagnostic methods for Parkinson's disease are the urgent problems. This work was designed to develop a new experimental model of the preclinical and clinical stages of the disease. Experimental modeling was performed on C57Bl/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This agent is converted into the MPP(+)-neurotoxin in brain DAergic neurons. We showed that MPTP in a dose of 4 mg/kg has no effect on the nigrostriatal DAergic system. MPTP in a dose of 8-16 mg/kg produced the toxic effect only on DAergic axons, which simulates the preclinical stage of Parkinson's disease. MPTP in a dose of 20-40 mg/kg had the toxic effect on neuronal axons and bodies, which simulates the clinical stage of Parkinson's disease. The data suggest that progressive degeneration of DAergic neurons is accompanied by activation of compensatory mechanisms for functional deficiency of these cells. PMID- 22235382 TI - Systemic arthritis in children: a review of clinical presentation and treatment. AB - Systemic juvenile idiopathic arthritis (sJIA) constitutes a small part of juvenile idiopathic arthritis (JIA), yet has a disproportionally higher rate of mortality. Despite being grouped under JIA, it is considered to be a multifactorial autoinflammatory disease. The objective of this paper is to review the epidemiology, pathogenesis, genetics, clinical manifestations, complications, therapy, prognosis, and outcome of sJIA. The presentation and clinical manifestations of sJIA have not changed much in the past several decades, but the collective understanding of the pathogenesis and the development of new targeted therapies (particularly the biologic agents) have transformed and improved the disease outcome for children with sJIA. PMID- 22235386 TI - Lipid peroxidation during cardiac remodeling in 12-month-old rats with experimental infarction. AB - Blood serum was from 12-month-old Wistar rats with experimental myocardial infarction caused by occlusion of the upper third of the left coronary artery was analyzed. The content of conjugated dienes by the 45th day after primary experimental myocardial infarction returned to normal and did not differ from that in intact animals of the same age group. MDA concentration in rats of the treatment group was lower compared to normal. It was demonstrated that normalization of LPO was accompanied by significant exhaustion of the endogenous antioxidant system (SOD and catalase). Our results suggest that special therapy is required for correction of the endogenous antioxidant defense system. PMID- 22235381 TI - Recent advances in underlying pathologies provide insight into interleukin-8 expression-mediated inflammation and angiogenesis. AB - Interleukin-8 has long been recognized to have anti-inflammatory activity, which has been established in various models of infection, inflammation, and cancer. Several cell types express the receptor for the cytokine IL-8 and upon its recognition produce molecules that are active both locally and systemically. Many different types of cells, in particular monocytes, neutrophils, epithelial, fibroblast, endothelial, mesothelial, and tumor cells, secrete IL-8. Increased expression of IL-8 and/or its receptors has been characterized in many chronic inflammatory conditions, including psoriasis, ARDS, COPD, and RA as well as many cancers, and its upregulation often correlates with disease activity. IL-8 constitutes the CXC class of chemokines, a potent chemoattractant and activator of neutrophils and other immune cells. It is a proangiogenic cytokine that is overexpressed in many human cancers. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention. PMID- 22235387 TI - Excessive glycation of pericapillary pericytic matrix components is an essential mechanism of arterial hypertension development in hyperglycemia. AB - In patients with essential hypertension, inhibition of glucose utilization in tissues was detected similar to that in diabetics. High levels of glycated compounds were found in cerebral, cardiac, and renal tissues of patients dead from coronary heart disease complicated and not complicated from diabetes mellitus and essential hypertension compared to victims dead from traumas. Experimental studies on rabbits and rats showed that the content of glycoconjugates in tissues did not increase in short-term (exogenous or stress associated) hyperglycemia, while accumulation of glycoconjugates in pericapillary, pericytic, and cellular structures in long-term hyperglycemia caused deformation of tissue ultrastructure. These disorders can impede capillary transudation, initiate and stabilize arterial hypertension, and lead to multiple organ failure. PMID- 22235388 TI - Possibilities of regulating disorders in functional activity of the retina with antioxidants under conditions of high-intensity light exposure. AB - We studied the effects of natural (alpha-tocopherol and SOD) and synthetic (potassium phenosane and hydroxypyridine) antioxidants on the recovery of disordered parameters of the electroretinogram under conditions of high-intensity light exposure. Potassium phenosane and tocopherol acetate more effectively normalized parameters of electroretinogram in monotherapy. The use of a complex of antioxidants completely prevented the disorders in the electroretinogram parameters in retinopathy after exposure to intense light. PMID- 22235389 TI - Effect of glucocorticoid receptor blockade on analgesic effect of corticotropin releasing factor. AB - The role of glucocorticoid receptors in the analgesic effect of corticotropin releasing factor in rats was studied after glucocorticoid receptor blockade with antagonist RU 38486. Glucocorticoid hormones can potentiate the analgesic effect of corticotropin-releasing factor or modulate the mechanisms of this effect, which depends on the type of painful stimulus. PMID- 22235390 TI - Perinatal hypoxic-ischemic brain injury affects the glutamatergic signal transduction coupled with neuronal ADP-ribosyl cyclase activity. AB - Agonists of glutamate ionotropic (NMDA) and metabotropic receptors (mGluRI and mGluRIII) had the regulatory effect on ADP-ribosyl cyclase/CD38 activity in cerebellar granular cells of newborn rats. Perinatal hypoxic-ischemic brain injury was followed by dysregulation of this mechanism. PMID- 22235391 TI - On the activation of calcium-dependent proteolysis in brain neurons of spontaneously hypertensive rats (SHR strain). AB - Females of spontaneously hypertensive (SHR strain) and normotensive rats (WKY strain and Wistar) received drinking water with normal (80 mg/liter) or reduced concentration of Ca(2+)(8 mg/liter). Activity of calcium-dependent calpain protease in neurons did not differ in 18-day-old rat pups born and suckled by these animals. Our results are consistent with published data on normal metabolism of SHR rats up to the age of 30 days. PMID- 22235392 TI - Common regularities in changes of the neutrophil functional activity during in vivo growth of tumors of different immunogenic activity. AB - Studies on BALB/c mice with tumors of different immunogenic activity (nonimmunogenic J774, WEHI 164 and immunogenic NS0) have showed that the development of a tumor is associated with changes in the neutrophil morphology and functions: the counts and size of the cells migrating to the focus increase and their capacity to produce active oxygen species is changed. PMID- 22235393 TI - Role of stromal and Thy 1,2+ cells in the mechanisms of action of immobilized granulocyte colony-stimulating factor during cytostatic-induced myelosuppression. AB - The effects of immobilized granulocyte colony-stimulating factor (mediated by cells of the hemopoiesis-inducing microenvironment) on hemopoietic precursors of various classes were studied on the model of cytostatic-induced myelosuppression (administration of cyclophosphamide). The action of this preparation was compared with that of the standard preparation of granulocyte colony-stimulating factor. Thy 1,2(+)cells potentiated the effects of immobilized and standard granulocyte colony-stimulating factors on granulocyte-erythroid-macrophage-megakaryocyte precursors. Stromal cells were shown to potentiate the influence of these agents on granulocyte precursors. Induction of proliferation of precursor cells by the immobilized factor mediated by cells of the hemopoiesis-inducing microenvironment persisted for a longer period compared to that induced by the standard product. PMID- 22235394 TI - Study of anti-inflammatory effects of GB-115, a glycine-containing retropeptide cholecystokinin analog. AB - Anti-inflammatory effects of GB-115 compound (N-phenylhexanoyl-glycyl-L tryptophan amide) injected intraperitoneally in doses of 0.1, 1, and 10 mg/kg were demonstrated on the model of ConA- and carrageenan-induced inflammation. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg to C57Bl/6 female mice with experimental autoimmune encephalomyelitis significantly alleviated the pathological symptoms, improved spontaneous locomotor activity, promoted recovery of thymus weight, and reduced edema and neutrophil infiltration of the perivascular space of the brain tissue. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg suppressed generation of active oxygen forms by neutrophils in the chemiluminescence test. PMID- 22235395 TI - Time course of histone deacetylase 1 and acetylated H3 and H4 histones in the brain of rats treated with ladasten. AB - We studied the effects of single intragastric administration of ladasten in a dose of 50 mg/kg on the time course of histone deacetylase 1 (HDAC1) and levels of acetylated histones H3 (Lys9) and H4 (Lys8) in the striatum, hippocampus, and hypothalamus. Ladasten reduced HDAC1 level in rat striatum and hippocampus and modified H3acK9 and H4acK8 levels in various structures of rat brain. PMID- 22235396 TI - In vitro study of neuroprotective properties of GK-2, a new original nerve growth factor mimetic. AB - New nerve growth factor (NGF) mimetic GK-2, a substituted dimeric dipeptide, in a concentration of up to 10(-9)M produced a protective effect on the culture of immortalized mouse hippocampal neurons (line HT-22) after addition of H(2)O(2)and glutamate. GK-2 in a concentration of 10(-8)M protected rat PC-12 pheochromocytoma cells from the neurotoxin MPTP. The neuroprotective effect of this peptide on the model of oxidative stress was also observed in the primary culture of embryonic rat hippocampal neurons. PMID- 22235397 TI - Mechanism of cardioprotective effect of adenocine and non-glycoside cardiotonic drugs during experimental chronic cardiac insufficiency. AB - The therapeutic action of adenocine during cardiac insufficiency (heart failure) caused by ischemic (stenosis) or reperfusion (removal of ligature) injury to the myocardium prevents depletion of ATP, the major energy source for myocytes in the right and left ventricles, and a drop in NAD/NADH ratio. The development of energy shortage during heart failure cannot be eliminated by beta-acetyldigoxin, levosimendan, or milrinone: the content of ATP in the right and left ventricular myocardium remained below the normal level by 28 and 29%, 37 and 33%, 32 and 28%, respectively; the NAD/NADH ratio of the energy supply system in cardiomyocytes did not return to normal. Adenocine increased the content of NAD to the normal level in both the right and left ventricles, while it remained below the normal level after administration of beta-acetyldigoxin (by 24 and 19.5%, respectively), levosimendan (by 27 and 29%), and milrinone (by 26 and 24%). In contrast to beta acetyldigoxin, levosimendan, and milrinone, adenocine inhibited activity of poly(ADP-ribose) polymerase in both ventricles. It is concluded that adenocine directly inhibits the key enzyme triggering apoptosis; we also hypothesized that this drug activates the regulatory and signal mechanisms arresting apoptotic alterations in the myocardium during heart failure. PMID- 22235399 TI - Pathogenetic role of Yersinia pseudotuberculosis endotoxin in hemostasis and microcirculation disturbances. AB - We studied the role of Y. pseudotuberculosis endotoxin (LPS) in the pathogenesis of hemostasis and microcirculation disorders. It was found that changes in the hemostasis system after injection of LPS had biphasic character corresponding to the stages of DIC syndrome development. Pathomorphological findings in animals with endotoxemia induced by Y. pseudotuberculosis LPS attested to increased permeability and destruction of the vascular endothelium in the microcirculatory bed and focal degenerative and necrotic changes in cells of the target organs (kidney, liver, and lungs) progressing with increasing the duration of the pathological process, which was determined by microcirculation disturbances and development of multiple organ failure. PMID- 22235398 TI - Hemopoiesis-stimulating activity of immobilized oligonucleotides and hyaluronidase during cytostatic-induced myelosuppression. AB - The hemopoiesis-stimulating effect of combined treatment with immobilized oligonucleotides and hyaluronidase preparations was studied during cytostatic induced myelosuppression caused by cyclophosphamide administration. Immobilized hyaluronidase was shown to increase the efficiency of correction of changes in the erythroid and granulocytic hemopoietic stems with immobilized oligonucleotides. This potentiation of the effect of immobilized oligonucleotides by immobilized hyaluronidase was related to an increase in functional activity of committed hemopoietic precursors. PMID- 22235400 TI - Mouse splenocyte blast transformation in the presence of plasma gamma-globulin fraction proteins and their complexes with copper and zinc. AB - Plasma gamma-globulin fraction proteins, copper and zinc cations, and metal complexes formed by these cations and human serum gamma-globulin induce blast transformation of splenocytes from BALB/c mice at a level comparable to that induced by concanavalin A. Zinc bound to gamma-globulin reduces by 25% and copper in complex with this protein stimulates by 1.6 times its capacity to induce blast transformation. Combinations with concanavalin A reproduce the effects of gamma globulin-metal complex under conditions of mitogen induction. Incorporation of(3)H-thymidine in splenocytes incubated with combinations of gamma-globulin copper metalcomplex, copper cations, and control protein with concanavalin A was by 1.4, 1.3 (p<0.1), and 1.25 times higher (p<0.05), respectively, than after incubation with concanavalin A alone. PMID- 22235401 TI - Study of genetic stability of human bone marrow multipotent mesenchymal stromal cells. AB - Immunophenotype, proliferation rate, and genetic stability parameters of bone marrow multipotent mesenchymal stromal cells were studied. Despite the reduction of proliferative activity by passages 11-12, the cells retained the characteristic immunophenotype. The incidence of spontaneous aneuploidy for autosomes 6, 8, 11 and sex chromosomes was evaluated. Two cultures of mesenchymal stromal cells carrying aneuploid cell clones were detected: with chromosome 8 trisomy and X chromosome monosomy. The results indicate the possibility of genetic transformation and selection of mesenchymal stromal cells with abnormal karyotype during in vitro culturing. PMID- 22235402 TI - Effects of expression of transcriptional factor AP-1 FOSL1 gene on psoriatic process. AB - We performed quantitative analysis of FOSL1 gene expression in lesional psoriatic skin. The expression of this gene in lesional psoriatic skin was significantly increased compared to that in unaffected areas. Enhanced FOSL1 expression significantly correlated with high psoriasis area and severity index (PASI). High level of FOSL1 gene expression was proposed to be a marker of pathological process activity in psoriasis. PMID- 22235403 TI - Granulosa cell tumors of the ovary and inhibin B. AB - We present the results of immunoenzyme detection of inhibin B in blood serum of patients with adult-type granulosa cell tumors of the ovary. Blood concentration of inhibin B at the end of menstrual cycle in patients with tumor relapse was significantly higher than in patients during remission and in virtually healthy women. The increase in inhibin B concentration preceded clinical manifestation of the disease relapse by 2-13 months, which demonstrates high diagnostic sensitivity of this marker and suggests that it can be recommended for the use in diagnostics and monitoring of granulosa cell tumors of the ovaries. PMID- 22235404 TI - Changes in blood lymphocyte enzyme profile in patients with renal cancer after a course of interferon therapy. AB - Activities of NAD(P)-dependent dehydrogenases in blood lymphocytes of patients with renal cell cancer were studied. The enzyme profiles in patients were different before and after the course of immunotherapy. A relationship between changes in the enzyme status and in vitro cell sensitivity to IFN-alpha2a was detected. PMID- 22235406 TI - Modification of intracellular level of free radicals and apoptosis in cultured human endotheliocytes and carcinoma cells. AB - The intracellular levels of superoxide O(2)(-)and nitric oxide NO were directly measured under intravital conditions in cultured human endotheliocytes ECV 304 and carcinoma cells HeLa G-63. Comparative analysis of changes in the intracellular levels of superoxide and NO induced by ascorbic acid revealed a negative correlation between NO and O(2)(-)levels, whose strength depended on concentration of the acid. In pharmacological concentrations, ascorbic acid induced apoptotic death of carcinoma cells, but did not trigger apoptosis of endotheliocytes. The study demonstrated a possible way of cytotoxic action of ascorbic acid in pharmacological concentrations. PMID- 22235405 TI - Systemic taxotere chemotherapy for metastatic tumor pleurisy in cats with spontaneous breast cancer. AB - Systemic and intrapleural chemotherapy for metastatic tumor pleurisy was carried out in cats with breast carcinoma. The animals (n=18) were divided into 2 groups. Cats of the systemic chemotherapy group received 3-6 courses of taxotere (30 mg/m(2); n=7) or 3 courses of taxotere (20 mg/m(2)) in combination with doxorubicin (20 mg/m(2)at 21-day intervals (n=5) during the adjuvant period of therapy for metastatic tumor pleurisy. Objective effect was attained in 10 (84.6%) cats: partial remission in 3 (25%) and complete remission in 7 (58.3%, p>0.05) cats. Metastatic pleurisy progressed in 2 (16.7%) cats. The median time to progression reached 1.79 months, median lifespan 2.8 months. The animals of intrapleural chemotherapy group (n=6) received 1-4 courses of cyclophosphamide (250 mg/m(2)) at 1-week interval during the adjuvant period without therapy for malignant pleurisy. Malignant pleurisy progressed in all cats. The median time to progression was equal to median lifespan (0.6 months). The therapy for malignant pleurisy in cats with breast cancer is regarded as the second-line chemotherapy with taxotere preferable as a monotherapy or in combination with doxorubicin. PMID- 22235407 TI - Role of ribose deficit in rat testicular metabolism under conditions of overtraining. AB - Acute disorders of purine metabolism develop in rat testes under conditions of overtraining. These disorders are characterized by enhanced catabolism and reduced reutilization of purine mononucleotides and activation of lipid peroxidation of membrane structures against the background of reduced activities of the pentose cycle and antioxidant system. Administration of D-ribose to rats subjected to overtraining improves purine reutilization, stimulates the pentose cycle work, inhibits lipid peroxidation in membrane structures of the testes, and saves the testicular incretory function. PMID- 22235408 TI - Changes in systolic and diastolic functions of the left ventricle and endothelium function against the background of electric stimulation in athletes. AB - Against the background of 10 procedures of electric stimulation of the quadriceps muscle of the thigh performed in 72 athletes we observed a significant increase in volume parameters of the left-ventricular systolic function and increase in diastolic function in a group of athletes during the recovery period. Significant increase in endothelium-dependent values was noted in both groups during electric myostimulation; it directly correlated with all metric and integral echocardiography parameters in main group. PMID- 22235409 TI - Changes in the concentration of monocytic chemotaxic protein-1 in patients with unstable angina treated with arixtra. AB - The time course of inflammatory reaction markers in the blood of patients with unstable angina was studied during therapy including arixtra. Plasma concentration of monocytic chemotaxic protein-1 (MCP-1) decreased on days 2 and 3 in patients receiving arixtra and a trend to an increase in MCP-1 concentration was observed on day 7 after the drug was discontinued. After 1 month, MCP-1 level decreased in all patients. The concentration of highly sensitive C-reactive protein also decreased 1 month after the disease onset; no changes in the concentrations of IL-8 and IL-2 receptor alpha-subunit were detected during these periods. It seems that arixtra is characterized by an anti-inflammatory effect manifesting by reduction of plasma chemokine MCP-1 concentration. PMID- 22235410 TI - Morphofuctional aspects of antitumor activity of low-intensity microwave resonance radiation in experiment. AB - Effects of low-intensity microwave radiation with bioactive frequency were studied in rats with transplanted sarcoma 45. After exposure to microwave radiation in the regimen of activation therapy, the antitumor effect was observed in 50% animals (marked inhibition of tumor growth or its partial regression). Light and electron microscopy revealed destructive changes in the tumor tissue, accumulation of activation of immune system cells, and signs of the increase in tumor cell differentiation. PMID- 22235411 TI - Effect of zinc chloride on picrotoxin-induced hyperkinesis depends on its concentration in solution injected into rat neostriatum. AB - The hyperkinekic effect (increase in spontaneous activity and development of choreomyoclonic hyperkinesis of the extremities and body) of picrotoxin injected into the rostral neostriatum of rats in a dose of 2 MUg was reduced if the drug was injected together with ZnCl(2) in a concentration of 0.1 MUg/MUl. ZnCl(2) in a concentration of 1 MUg/MUl did not modulate the effects of picrotoxin, while in a concentration of 3 MUg/MUl it increased spontaneous motor activity in the open field test without affecting the symptoms of choreomyoclonic hyperkinesis. PMID- 22235412 TI - Different mechanisms of intensification of contractile activity in the proximal and distal portions of the duodenum in psychogenic stress in rabbits. AB - Psychogenic stress in rabbits induced by fixation of the animals to a frame was accompanied by an increase in contractile activity of the duodenum. Against the background of blockade of muscarinic and nicotinic cholinergic receptors and beta(1)/beta(2)-adrenoceptors this increase was observed in postpyloric portion, but not in the distal third of the duodenum. The increase in contractile activity was determined by the direct effect of the hormonal stress factor on smooth muscles in the first case and by the influence of circulating catecholamines on excitatory beta-adrenoceptors of cholinergic neurons of the enteral nervous system in the second. PMID- 22235413 TI - Activities of some caspase cascade enzymes and myocardial contractility in experimental left ventricular focal ischemia. AB - Focal left ventricular ischemia was modeled in male Chinchilla rabbits. Activities of caspase-3 and caspase-8 in the left and right ventricular myocardium and myocardial contractility were studied after 1, 3, and 5 days. Caspase-3 activity increased significantly in the left ventricular peri infarction zone and right ventricular myocardium, while caspase-8 activity did not differ from the control. Left ventricular contractility decreased significantly and the hemodynamic load of the right ventricle sharply increased. These results attest to induction of the internal (mitochondrial) pathway of apoptosis in myocardial cells most likely caused by left ventricular hypoxia and right ventricular overload. PMID- 22235414 TI - Structural and functional peculiarities of mast cells in undifferentiated connective tissue dysplasia. AB - We performed an immunomorphological study of mast cells from undamaged skin in women with phenotypical evidence of undifferentiated connective tissue dysplasia syndrome, patients of cosmetological clinics. It was found that the numerical density of mast cells containing chymase granules in this condition 1.7-fold surpassed the corresponding parameter in patients without signs of connective tissue dysplasia syndrome, which probably was a result of compensatory and adaptive reaction aimed at activation of the synthesis of the connective tissue extracellular matrix components. It was hypothesized that increased content of chymase-positive mast cells in the skin of patients with connective tissue dysplasia syndrome contributed to the formation of associated arterial hypertension. PMID- 22235415 TI - Reduced content of alpha-synuclein in peripheral blood leukocytes of patients with LRRK2-associated Parkinson's disease. AB - Measurement of alpha-synuclein level in the peripheral blood was proposed as a diagnostic test for Parkinson's disease. However, the results of these studies remain contradictory, probably because the examined samples included patients with different etiology of Parkinson's disease. To verify this assumption we studied the levels of alpha-synuclein in peripheral blood leukocytes of patients with Parkinson's disease associated with mutations in the gene of leucine-rich kinase 2 (LRRK2). The mean alpha-synuclein level was significantly lower in patients with LRRK2-associated Parkinson's disease (N=8) than in patients with sporadic form of the disease (N=33; p<0.02) and in controls (N=18; p<0.05). On the other hand, we found no differences in the level of alpha-synuclein level between patients with sporadic form of the disease and controls. We hypothesize that the level of alpha-synuclein in the peripheral blood largely depends on the etiology of the disease and cannot be used as a universal diagnostic test for Parkinson's disease. PMID- 22235416 TI - Relationship between apoptosis and expression of heat shock proteins in peripheral blood lymphocytes of patients with myocardial infarction. AB - We studied activity and dynamics of apoptosis of peripheral blood lymphocytes in patients with myocardial infarction and analyzed the relationship of these processes with expression of heat shock proteins with a molecular weight of 70 kDa playing an essential role in preventing cell death. Thus, we first demonstrated activation of apoptosis in peripheral blood cells of patients with myocardial infarction compared to the control (healthy individuals) and revealed the expected negative correlation between the expression of heat shock proteins with a molecular weight of 70 kDa by lymphocytes and intensity of their death. The observed dynamics of mononuclear cell apoptosis in the peripheral blood of patients with myocardial infarction can reflect activity of programmed cardiomyocyte death in the focus of ischemic injury. PMID- 22235417 TI - Urgent reaction of the complement system to hypoxic exposure in rats sensitive to hypoxia. AB - Different modes of hypoxic exposure led to phasic changes in activities of the complement system components in rats sensitive to hypoxia starting from the first minutes of the posthypoxic period and persisting for 24 h and longer. The direction of shifts in the complement system depended on the duration and intensity of oxygen deficiency. Single one-hour interval hypoxia led to a moderate elevation of activities of virtually all the studied components. A more intense hypoxic exposure (1-h hypobaric hypoxia at a height of 5000 m) induced a biphasic response: reduction of activities of the majority of complement system components during the first hour of posthypoxic period and subsequent elevation of these activities above the normal. Exposure to severe hypobaric hypoxia (7000 m) led to a longer and more pronounced primary reduction of complement components activities, while the phase of their activity increase was blurred. Animal capacity to the formation of urgent tolerance of hypoxia was retained and increased with increasing the severity of hypoxic exposure. The complement consumption during the posthypoxic period was presumably a programmed reaction preventing hyperactivation of complement system components and essential for tolerance formation. PMID- 22235418 TI - Status of free-radical oxidation and proliferation processes in patients with atopic dermatitis and lichen planus. AB - We studied the status of proliferation processes (by Ki-67 expression) and biogenesis of free radicals (by chemiluminescence method) in skin biopsy specimens from patients with atopic dermatitis and lichen planus. The index of Ki 67-positive nuclei significantly (p<0.05) increased to 28.40+/-2.00% in patients with dermatitis and to 32.6+/-1.9% in patients with lichen planus vs. 8.65+/ 1.31% in the reference sample. Decompensated accumulation of free-radical oxidation products and inhibition of detoxification systems in skin biopsy specimens indicate the development of local oxidative stress. After therapy consisting of two 10-day courses of thymodepressin injections (0.1%, 1.0 ml) over 30 days, normalization of epidermis proliferation was observed. Labeling index in atopic dermatitis and lichen planus significantly decreased (p<0.05) to 17.00+/ 1.87 and 10.9+/-1.1%, respectively. The role of free radicals in the development of hyperregeneratory processes during dermatoses is discussed. PMID- 22235419 TI - Effect of a blocker of nitric oxide production on albumin excretion by rat kidney. AB - Experiments on Wistar rats showed that single intraperitoneal injection nonselective NO-synthase inhibitor L-NAME in a dose of 50 mg/kg was followed by transient proteinuria and albuminuria. This effect was not reproduced by injection of ODQ, an inhibitor of intracellular effects of NO, and arginine, but D-NAME, an optical isomer of L-NAME not blocking NO-synthase, produced similar, though less pronounced effect. The degree of proteinuria and albuminuria increased in combined treatment with nitroarginine methyl esters and 1-deamino arginine vasotocin or arginine vasopressin. Proteinuria during treatment with arginine derivatives attests to not only their effect on the charge of the filtration membrane, but also the participation of NO-dependent processes in the regulation of ultrafiltration in renal glomeruli. PMID- 22235420 TI - Second messengers cAMP, Ca2+, and NO modulate functional properties of human lymphocytes under conditions of exposure to UV light. AB - We studied the effect of UV light (240-390 nm) in doses of 75.5-4530 J/m(2) on functional properties and level of intracellular messengers (cAMP, Ca(2+), NO) in lymphocytic cells of the peripheral blood. Correcting effects of UV light in a dose of 151 J/m(2) on cytotoxic activity of lymphocytes against Ehrlich ascetic carcinoma and calcium concentration in lymphocyte cytosol were observed. We found that UV light reduces the cAMP content and increases NO concentration (151-4530 J/m(2)) in photomodified cells. The involvement of adenylate cyclase and phosphoinositide signaling pathway into the mechanisms of modulation of functional properties of lymphocytes after exposure to UV light was demonstrated. PMID- 22235421 TI - Regulation of lipid peroxidation in the retina under the effect of bright light. AB - Changes in LPO intensity under the effect of exposure to bright light and the possibility of their correction with antioxidants were studied on rabbits with diabetic retinopathy. It was found that enhanced LPO caused by exposure to bright light in rabbits with diabetic retinopathy can be corrected with antioxidants. Phenosan potassium salt, alpha-tocopherol, and oxypyridine were more effective than SOD and taurine in preventing MDA accumulation. A complex of natural and synthetic antioxidants was most efficient in correcting LPO under conditions of exposure to bright light. PMID- 22235422 TI - Mechanisms of hemostimulating effects of granulocytic CSF and pantohematogen under conditions of cytostatic myelosuppression. AB - We compared hemostimulating activity of pantohematogen and granulocytic CSF under conditions of 5-fluorouracil-induced cytostatic myelosuppression. It was found that activation of hemopoiesis regeneration under the effect of the test preparations was accompanied by the development of hyperplasia of the granulocytic and monocytic hemopoietic bone marrow lineages and more rapid recovery of the count of pholymorphonuclear leukocytes and monocytes in the peripheral blood (more marked under the effect of pantohematogen) followed by neutrophilia and monocytosis. PMID- 22235423 TI - Preventive efficacy of oxidized dextran and pathomorphological processes in mouse lungs in avian influenza A/H5N1. AB - Oxidized dextran (60 kDa) exerted a pronounced preventive effect in laboratory mice infected with avian influenza subtype H5N1 A/Goose/Krasnoozerskoye/627/05 virus, which manifested in a significant increase in mouse lifetime (by 24.4%) and a decrease in mortality rate (3.3-fold). This was probably related to significant alleviation of pathological changes in the lungs and severity of hemodynamic and inflammatory complications and early fibrosis [corrected]. PMID- 22235424 TI - Selective cytokine-inducing effects of low dose Echinacea. AB - Echinacea purpurea is a widely used plant immunomodulator with a selective immunomodulatory effect depending on the dilution of the initial preparation. In low doses, it causes selective induction of pro- and anti-inflammatory cytokines. The results recommend this preparation in a wide range of concentrations for adequate correction of the immune system work aimed at restoring the Th1/Th2 balance in various diseases. PMID- 22235425 TI - Flavonoid composition of Juniperus oblonga Bieb. AB - Juniperus oblonga Bieb is widely spread in the Caucasus Mountains, particularly in its eastern and southern regions. Diuretic effect of juniper berries is determined by the presence of volatile oils and polyphenol complex, particularly flavonoids. Flavonoids were extracted from raw material with 70% ethanol and then with ethyl acetate. Column chromatography of ethyl acetate fraction on polyamide yielded 5 compounds, which were identified on the basis of physicochemical constants of parent compounds and products of acid hydrolysis and alkaline degradation of aglycones and on the basis of UV-spectroscopy as apigenin, isoquercitrin, apigenin-7-glucoside, quercetin-3-rutinoside, and scutellarin-7 glucoside. Quantitative composition of flavonoid in equivalent to rutin concentration in Juniperus oblonga Bieb was 0.910+/-0.007% (UV-spectrophotometry data). PMID- 22235426 TI - Reactions of granulocytic lineage of hemopoiesis and mechanisms of their development in combined treatment with adriablastin and taxotere. AB - We studied myelotoxic effects of adriablastin and taxotere combination on granulocytic lineage cells and processes of their recovery in patients with stage III-IV breast cancer. Intensive maturation of granulocytic CFU provided regeneration of the hemopoiesis even under conditions of reduced proliferative activity of these cells, which, in turn, led to accumulation of mature and immature neutrophilic granulocytes in the bone marrow and improved reserve capacities of the neutrophil pool in the bone marrow. PMID- 22235427 TI - Production of late IFN-alpha induced by plasma gamma-globulin fraction proteins and their metal complexes. AB - Plasma gamma-globulin fraction proteins, copper and zinc cations, and metal complexes they form with human serum gamma-globulin induce the production of IFN alpha by human blood cells throughout the periods of up to 72 h. Zinc cation modified protein by 1.6 times (p<0.05) more actively induces late IFN-alpha than the control gamma-globulin; gamma-globulin-copper metal complex is 2-fold (p<0.002) more effective than the control protein. The results indicate that functional relationships between the components inducing the production of late IFN-alpha differ from the effects realized during the early period of induction. PMID- 22235428 TI - Morphofunctional characteristics of the immune system in CBA and C57Bl/6g mice. AB - We studied peculiarities of morphofunctional organization of the immune system in C57Bl/6g and CBA mice differing by their susceptibility to various types of infectious agents. The revealed differences in the structure of lymphoid organs, T lymphocyte subpopulation ratio and their differentiation into Th1/Th2 cells after mitogen stimulation drove us to a conclusion on genetically determined regularities in the development of the immune response in these animal strains. PMID- 22235429 TI - Specifics of immunogenesis and metabolism in young hogs under biogeochemical conditions of Chuvash Center. AB - Combined treatment of young hogs with Trepel food supplement and Polystim immunomodulator with consideration for specific biogeochemical properties of Chuvash Center produced immunostimulating and metabolic effects and optimized the balance between free radical oxidation response and body antioxidant potential. PMID- 22235430 TI - Neurospecific proteins in the serum of patients with brain tumors. AB - Neurospecific proteins S-100 and GFAP were measured in the serum of 145 patients with neural tumors and 69 healthy individuals. In patients with glyoblastomas, the concentrations of S-100 and GFAP were significantly higher than in patients with anaplastic astrocytomas, benign meningiomas, and brain metastases and in healthy individuals. Serum S-100 concentrations in patients with anaplastic astrocytomas, benign meningiomas, and brain metastases were similar; significant difference from the control was found only for patients with cerebral metastases. A specific feature of GFAP was high incidence of its detection in patients with glioblastomas (83%) compared to other groups of patients with neural tumors and healthy volunteers who demonstrated practically zero level of this protein. These findings attest to the possibility of using S-100 as an additional biochemical criterion of brain involvement in tumor patients and GFAP as a glioblastoma marker. PMID- 22235431 TI - Neuroendocrine and proliferative potential of human intestinal cells during aging. AB - A population of neuroendocrine cells secreting chromogranin A was verified in the intestine of subjects aged over 60 years. The count of intestinal cells expressing chromogranin A and Ki-67 proliferation protein increases with aging. More intensive expression of chromogranin A and Ki-67 protein in senile age and in long-livers is presumably a compensatory mechanism aimed at the gastrointestinal function maintenance during its age-associated involution. PMID- 22235433 TI - Comparative analysis of expression of human telomerase catalytic subunit at the transcription level in cell cultures of different origin. AB - The expression of human telomerase catalytic subunit in HL-60 and HT-1080 malignant transformed cells and telomerized fibroblasts was studied by quantitative PCR. It was found that the number of transcripts of human telomerase catalytic subunit per cell in telomerized fibroblasts could be hundreds of times higher than in HL-60 and HT-1080 cells. Telomerized fibroblast cultures are suggested as experimental systems for selection of basal compounds for creation of anticancer drug prototypes, the molecular target of which is human telomerase catalytic subunit. The effects of human telomerase catalytic subunit expression on the fibroblast proteome are analyzed. PMID- 22235432 TI - Evaluation of effects of histochrome and mexidol on structural and functional characteristics of the brain in senescence-accelerated OXYS rats by magnetic resonance imaging. AB - The effects of histochrome and mexidol on the morphology and function of the brain and behavior were studied in senescence-accelerated OXYS and Wistar rats. MRI showed that signs of neurodegenerative changes were present in OXYS rats at the age of 3 months and were pronounced at the age of 12 months. Histochrome (1 mg/kg, 5 days) more effectively than mexidol (4 mg/kg, 7 days) reduced anxiety and increased exploratory activity of 1-year-old OXYS rats. Both drugs improved the morphology and function of the brain. Their effects consisting in correction of diffuse changes in the white matter and reduction of edema were comparable; in addition, histochrome reduced the intensity of demyelinization processes. PMID- 22235434 TI - Ultrastructure of acinar cell injuries in experimental acute pancreatitis created by common bile duct ligation. AB - Morphogenesis of acute pancreatitis induced by ligation of the common bile duct and the ultrastructure of autolytic transformations of acinar cells were studied. Autolytic changes in acinar cells started from the basal zones and then involved the apical zones. Violation of the zymogen granules integrity, interactions of their contents with the adjacent ultrastructures, destruction (melting) of ultrastructures, and formation of huge autophagosomes play an important role in the development of autolysis. Disordered secretion of zymogen granules (foci of their accumulation in the apical zone), hyperplasia and hypertrophy of centroacinar cells and ductal epitheliocytes aimed at restoration of the pancreatic secretion discharge pathways were seen in the retained acini. PMID- 22235435 TI - Intensity of in vitro incorporation of 3H-melatonin in the thyroid gland of rabbits with pineal gland hypofunction. AB - The structure and hormonal activity of the thyroid gland and its capacity to bind (3)H-melatonin were studied in young adult Chinchilla rabbits with pineal gland hypofunction induced by 2-month exposure to constant illumination. After 2 months of constant exposure to light, the experimental animals exhibited signs of the so called "latent hypothyroidism" and more intense binding of (3)H-melatonin by the thyroid gland. This fact indicated intactness of its receptor system underlying the possibility of restoring activity of the thyroid gland under conditions of melatonin replacement therapy in hypothyroidism induced by chronic melatonin insufficiency. PMID- 22235436 TI - Angiogenesis in rat uterine cicatrix after injection of autologous bone marrow mesenchymal stem cells. AB - Results of injection of autologous bone marrow mesenchymal stem cells with transfected GFP gene into the rat uterine horn cicatrix were studied by light microscopy. Large groups of blood vessels with blood cells inside were seen after injection of autologous bone marrow cells into the cicatrix on the right horn, formed 2 months after its ligation; no groups of vessels of this kind were found in the cicatrix in the contralateral horn. Examination of unstained sections in reflected UV light showed sufficiently bright fluorescence in the endothelium and outer vascular membrane in the uterine horn cicatrix only on the side of injection. Hence, autologous mesenchymal stem cells injected into the cicatrix formed the blood vessels due to differentiation into endotheliocytes and pericytes. The expression of GFP gene not only in the vascular endothelium, but also in vascular outer membranes indicated that autologous mesenchymal stem cells differentiated in the endothelial and pericytic directions. PMID- 22235438 TI - Emulsive polymerization as a method of enzyme modification preserving biological properties of nanostructures. AB - The proposed method of emulsive polymerization provides the possibility of modifying and obtaining insoluble forms of superoxide dismutase (SOD), glutathione reductase, and streptolysin-O preserving nanoobjects (conformationally active centers and antigenic determinants) in their native states. Apart from enzymatic and immunological properties, the samples acquired some new features: resistance to high temperature, resistance to 3 M KCNS solution and buffer solutions with high concentration of hydrogen ions, and resistance to preserving solutions. Magnetic properties provide the possibility of simplifying enzyme-linked immunosorbent and immunofluorescence assays. In addition, sensitivity of these assays was by an order of magnitude higher and the specificity fully preserved. Taking all the facts into account, we prepared agents for long-term and repeated use. Due to preserved enzymatic properties, insoluble forms of SOD and glutathione reductase can be considered as a tool for correction of peroxide-antioxidant balance and associated immunological abnormalities. PMID- 22235437 TI - New specific marker of cytochrome P450 1A2 activity. AB - Various methods were proposed for phenotyping of patients by activity of cytochrome P450 1A2, each has some advantages and disadvantages. However, no reference parameters were developed for measuring CYP1A2 activity that could be used as a unified standard for phenotyping of patients. We propose a mathematic model of caffeine metabolism allowing calculation of rate constants for the formation of its primary metabolites. First-order rate constant of paraxanthine formation was tested as a new specific marker of isoenzyme 1A2 in healthy volunteers. PMID- 22235439 TI - Faith community nurses: implementing Healthy People standards to promote the health of elderly clients. AB - The face of aging in our society has changed dramatically over the past generation. Many seniors struggle to access needed services, which include health promotion and disease prevention activities. A "Parish Nurse Questionnaire" was developed by the authors using the Healthy People 2010 Critical Health Indicators, the International Parish Nurse Resource Center functions of the parish (faith community) nurse, and the ANA Scope and Standards for Faith Community Nurses to ascertain if, and how frequently, faith community nurses practice interventions that address strategies mandated by theses organizations. Data collected on 102 participants supported that the faith community nurse model of community-based practice guides the development of strategies addressing those established standards. Those who provide health promotion and disease prevention activities in faith communities serve as viable partners with community initiatives, which may help to provide more seamless and efficient services to the elder in the community. PMID- 22235440 TI - GAPNA 30th conference: improving lives of older adults--practice & policy. PMID- 22235441 TI - Assisted living nurses gather for 7th Annual National Conference. PMID- 22235443 TI - [Check the iron-status in pregnant and breastfeeding women]. PMID- 22235442 TI - NICHE resets Knowledge Center for greater access to tools, resources and information for the care of older adult patients. PMID- 22235444 TI - Levels of liver fluke disease in Scottish livestock expected to remain high. PMID- 22235445 TI - Motility disorders and genetics: the future is bright. PMID- 22235446 TI - Non-acid reflux as a cause of symptoms. PMID- 22235447 TI - Role of diagnostic tests in GERD. PMID- 22235448 TI - Non-pharmacological therapies for GERD in infants and children. PMID- 22235449 TI - Uses and abuses of acid-suppression therapy in children. PMID- 22235450 TI - Emerging therapies for GERD. PMID- 22235451 TI - Endoscopic approaches to the treatment of GERD. PMID- 22235452 TI - Eosinophilic esophagitis. PMID- 22235453 TI - Gastrointestinal manifestation of cow's milk protein allergy or intolerance and gastrointestinal motility. PMID- 22235454 TI - New insights in pathophysiology and management of achalasia. PMID- 22235455 TI - Belching, aerophagia, and rumination. PMID- 22235456 TI - Pharyngo-esophageal motility in neurologically impaired children. PMID- 22235457 TI - Extra-esophageal symptoms: how do we treat them? PMID- 22235458 TI - Obesity and its relation to motility disorders. PMID- 22235459 TI - The gut: key to treating obesity in adolescents? PMID- 22235460 TI - Swallowing and GI physiology following laparoscopic adjustable gastric banding. PMID- 22235461 TI - Surgical treatment of the obese adolescent. PMID- 22235462 TI - Probiotics and functional gastrointestinal disorders. PMID- 22235463 TI - Gut microbiota and GI health and disease. PMID- 22235464 TI - Abstracts of the Annual Meeting of the British Paediatric Neurology Association. January 18-20, 2012. London, United Kingdom. PMID- 22235465 TI - Visceral hypersensitivity in IBS: from bench to bedside. PMID- 22235466 TI - Expanding precompetitive space. PMID- 22235467 TI - Functional GI disorders and infectious disease. PMID- 22235468 TI - What do we really need in the workup of abdominal pain? PMID- 22235469 TI - Pharmacological treatment of abdominal pain related functional gastrointestinal disorders. PMID- 22235470 TI - Childhood abuse is not only a case of bruises and broken bones: role of abuse in unexplained GI symptoms in children. PMID- 22235471 TI - Non-pharmacological treatment for abdominal pain. PMID- 22235472 TI - Role of placebo in irritable bowel syndrome. PMID- 22235473 TI - Advances in enteric neurobiology: how close are we to clinical use? PMID- 22235474 TI - Brain imaging in visceral pain. PMID- 22235475 TI - Rectal hyposensitivity and functional hindgut disorders: cause and effect or an epiphenomenon? PMID- 22235476 TI - Diagnostic testing in constipation: is it necessary? PMID- 22235477 TI - Treatment of slow transit constipation in children. PMID- 22235478 TI - Treatment of constipation: where do we go? PMID- 22235479 TI - Mast cells in intestinal inflammation, barrier function, and postoperative motility. PMID- 22235480 TI - Clinical picture of intestinal pseudo-obstruction syndrome. PMID- 22235481 TI - From ACE to replace: role of surgery and transplantation in motility disorders. PMID- 22235482 TI - [Regarding the effective dose in the diagnosis for patients -- specific dosimetry in nuclear medicine therapy]. PMID- 22235483 TI - Review of computational fluid dynamics applications in biotechnology processes. AB - Computational fluid dynamics (CFD) is well established as a tool of choice for solving problems that involve one or more of the following phenomena: flow of fluids, heat transfer,mass transfer, and chemical reaction. Unit operations that are commonly utilized in biotechnology processes are often complex and as such would greatly benefit from application of CFD. The thirst for deeper process and product understanding that has arisen out of initiatives such as quality by design provides further impetus toward usefulness of CFD for problems that may otherwise require extensive experimentation. Not surprisingly, there has been increasing interest in applying CFD toward a variety of applications in biotechnology processing in the last decade. In this article, we will review applications in the major unit operations involved with processing of biotechnology products. These include fermentation,centrifugation, chromatography, ultrafiltration, microfiltration, and freeze drying. We feel that the future applications of CFD in biotechnology processing will focus on establishing CFD as a tool of choice for providing process understanding that can be then used to guide more efficient and effective experimentation. This article puts special emphasis on the work done in the last 10 years. PMID- 22235484 TI - Large-scale compatible methods for the preservation of human embryonic stem cells: current perspectives. AB - Human embryonic stem cells (hESCs) and hESC-derived cells are of great interest, not only because of their therapeutic potential but also their prospective uses in in vitro drug and toxicity screening. The ability to preserve these cells is critical, allowing for the generation of quality-controlled stocks of cells, transport of cells between sites, and avoiding the need for expensive and time consuming continuous culture. Current methodologies, namely conventional slow freezing and vitrification, can successfully preserve hESCs and their differentiated progeny, retaining the key characteristics of the cells. However, there is a significant gap between the number of cells potentially needed to either treat patients or run a high-throughput drug screen and how many cells can be preserved using these techniques.Therefore, this review focuses on the scalability of slow freezing and vitrification, identifying key barriers to success and whether they can be overcome. Given the precedent with other mammalian cells in using slow freezing to successfully preserve large quantities of cells and its compatibility with current and emerging culture methods for hESCs, it is likely to become the method of choice for cryopreserving these cells at scale. However, issues other than scale still exist; therefore, alternatives to cryopreservation should also be explored. Here,the potential to lyophilize hESCs for long-term storage is considered as one such alternative. PMID- 22235485 TI - Enzyme activity evaluation of organic solvent-treated phenylalanine ammonia lyase. AB - The direct one-step synthesis of L-phenylalanine methyl ester in an organic aqueous biphasic system using phenylalanine ammonia lyase (E.C.4.3.1.5, PAL) containing Rhodotorula glutinis yeast whole cells was reported earlier. We report here further optimization of this biotransformation using isolated PAL, when the lyophilized enzyme is treated with different water miscible and water immiscible organic solvents. Use of isolated PAL enzyme is advantageous in overcoming diffusion barriers encountered when using PAL containing R.glutinis whole cells, and resulted in increased product yield due to better interaction of enzyme with the substrate. Among the water miscible solvents, ethanol treated and methanol treated enzymes supported maximum PAL forward and reverse activities; respectively. In the water immiscible solvents category, heptane-treated enzyme exhibited maximal activity for both PAL forward and reverse reactions. PAL activity obtained with enzyme specimens treated with methanol, ethanol, and heptane varied in the range of 91-99% of that observed in aqueous buffer medium for the forward reaction; and 89-95% for the reverse reaction. n-butanol,acetone, and benzene were found to have a inhibitory effect on PAL enzyme, in that, it resulted in only 31-33% activity of that obtained with aqueous solution. Raman spectroscopy was used to monitor amide I and II bands which are sensitive to changes in the secondary structure of proteins. No changes in structure could be detected from the analyses of AI and AII bands of PAL spectra. This data obtained for PAL, a tetramer, could be significant in predicting how solvent interactions affect the structure and function of multimeric proteins and enzymes in nonaqueous media. PMID- 22235486 TI - Simultaneous saccharification and fermentation and economic evaluation of ultrasonic and jet cooking pretreatment of corn slurry. AB - The potential of ultrasonics to replace hydrocooking in corn-to-ethanol plants was examined in this study. Batch and continuous experiments were conducted on corn slurry with sonication at a frequency of 20 kHz. Batch mode used a catenoidal horn operated at an amplitude of 144 MUm peak-to-peak (p-p) for 90 s. Continuous experiments used a donut horn operating at inner radius amplitude of 12 MUm p-p. Jet-cooked samples from the same ethanol plant were compared with ultrasonicated samples. The highest starch-to-ethanol conversion was obtained by the jet-cooked samples with a yield of 74% of the theoretical yield. Batch and continuous sonication achieved 71.2% and 68% conversion, respectively, however, statistical analysis showed no significant difference between the jet cooking and ultrasonication. On the basis of the similar performance, an economic analysis was conducted comparing jet cooking and ultrasonic pretreatment. The analysis showed that the capital cost for the ultrasonics system was ~10 times higher compared to the capital cost of a hydrocooker. However,due to the large energy requirements of hydrocookers, the analysis showed lower total overall costs for continuous ultrasonication than that for jet cooking, assuming the current energy prices. Because of the high utility cost calculated for jet cooking, it is concluded that ultrasonication poses as a more economical option than jet cooking. Overall, the study shows that ultrasonics is a technically and economically viable alternative to jet cooking in dry-grind corn ethanol plant. PMID- 22235487 TI - Protein recovery from surfactant precipitation. AB - The recovery of lysozyme from an aqueous solution containing precipitated lysozyme-AOT complexes formed by the direct addition of sodium bis-(2-ethylhexyl) sulfosuccinate (AOT) to a lysozyme solution was studied using both solvents, and a counterionic surfactant. Ethanol,methanol and solvent mixtures dissolved the surfactant precipitate and recovered lysozyme as a solid. Recovery efficiency and protein stability varied with the type of solvent used. An entirely different method of recovery was also evaluated using a counterionic surfactant: tri octylmethylammonium chloride (TOMAC) which bound to AOT releasing lysozyme into solution.Complete recovery (100%) of lysozyme was achieved at a molar ratio of 2:1(TOMAC:AOT), and the original protein activity was maintained in the final aqueous phase.The recovered lysozyme retained its secondary structure as observed in circular dichroism(CD) spectra. Specific activity studies show that counterionic surfactant extraction does not alter the biological activity of the enzyme. PMID- 22235488 TI - Ready to catch the next wave? The new accountability agenda in healthcare. AB - With several healthcare reform-related programs already beginning to demand an extremely broad range of data reporting from providers, and the meaningful use process under HITECH continuing to move forward, healthcare IT leaders are faced as never before with a menu of data reporting mandates that are set to redraw the landscape of healthcare. in this cover story package, we look first at the overall picture, and then offer case studies from the pioneering organizations that are already moving forward into the future of healthcare, one organized around the industry's new accountability agenda. PMID- 22235489 TI - Inner lives: creativity and survival in Irish rural life. PMID- 22235490 TI - "I listened with my eyes": writing speech and reading deafness in the fiction of Charles Dickens and Wilkie Collins. AB - While characters with disabilities appear frequently in Victorian fiction, deaf characters, specifically, are almost entirely absent. In fact, the only deaf characters who use sign language in Victorian fiction are Madonna Blyth in Wilkie Collins's Hide and Seek and Sophy Marigold in Charles Dickens's "Doctor Marigold." Grounding its analysis in these two texts, this article contends that it is, in particular, a deaf character's relationship to language that disqualifies him or her from conventional representation in Victorian fiction. Through reading Hide and Seek and "Doctor Marigold" in the context of Victorian deaf history, Collins and Dickens's realist aims, and Victorian generic conventions rooted in transcribing orality, this essay argues that the absence of deaf characters reveals the investment of mid-Victorian fiction in a particular and normativized relationship between bodies, spoken language, and textuality. PMID- 22235491 TI - Grassroots development and upwards accountabilities: tensions in the reconstruction of Aceh's fishing industry. AB - This article explores the tensions between aid funding and grassroots development goals in the context of post-disaster fisheries reconstruction in Aceh, Indonesia. We argue that both short- and long-term grassroots goals are distorted by upward accountability requirements which lead to unsatisfactory aid outcomes. Our analysis employs the concept of aid webs and draws on fifty-one formal interviews with stakeholders in Aceh in 2007/2008. The findings initially concentrate on the impacts of upward accountability on project cycles, with a particular focus on the problematic incorporation of private boat-building contractors and commercial values during the implementation phase. We then discuss the more subtle, long-term impacts of upward accountability on the professionalization of community institutions - in this case, the Panglima Laot Lhok. We conclude with a few observations about the hybrid institutions - combining elements of local and development cultures - that are produced within the current political economy of aid. PMID- 22235492 TI - Animal husbandry and agricultural improvement: the archaeological evidence from animal bones and teeth. PMID- 22235493 TI - Common meeting places and the brightening of rural life: local debates on village halls in Sussex after the First World War. PMID- 22235494 TI - Conservation, class and custom: lifespace and conflict in a nineteenth-century forest environment. PMID- 22235495 TI - English emigration, kinship and the recruitment process: migration from Melbourn in Cambridgeshire to Melbourne in Victoria in the mid-nineteenth century. PMID- 22235496 TI - Case of trichomycosis axillaris and erythrasma. PMID- 22235497 TI - Allopurinol--dose according to effect, not renal function. PMID- 22235498 TI - Food, orality, and nostalgia for childhood: gastronomic Slavophilism in mid nineteenth-century Russian fiction. PMID- 22235499 TI - From Great Wen to Toad Hall: aspects of the urban-rural divide in inter-war Britain. PMID- 22235500 TI - [History and "psychology": some reflections on the specificity of history in the 19th century]. PMID- 22235501 TI - Comparative analysis of bioremediation potential of adapted and non-adapted fungi on azo dye containing textile effluent. AB - About 4 different predominant adapted fungal strains (screened from effluent sample) Aspergillus sp., Penicillium sp., Fusarium sp. and Mucor sp. and 4 predominant non-adapted strains (screened from soil, water and fungal fruiting bodies) Aspergillus sp., Penicillium sp., Fusarium sp. and Rhizopus sp., with potential dye decolorization ability on Reactive black 5, Amido black-10B, Red 5B, Reactive red 120 and Anthraquinone violet R were isolated. These organisms were used to develop a consortium which was used in analyzing the bioremediation efficiency on textile effluents containing a mixture of azo dyes. There was about 67% of reduction in color along with 34% of COD reduction by non-adapted fungal consortium while effective bioremediation efficiency was observed in adapted fungal consortium (Color 75% and COD 50%). The regression co-efficient for Langmuir and Freundlich adsorption isotherms were found to be higher for adapted fungal consortium (R2 = 0.97 and R2 = 0.92) than the non-adapted consortium (R2 = 0.97 and R2 = 0.85) proving that both monolayer and multilayer adsorption of dyes were observed on treating the samples with the adapted fungal consortium. On analyzing the results observed through chi-square test, the calculated value (28.712) was higher than the tabulated value (9.49) at a 4 degree freedom hence the hypothesis was rejected. So, there was an association between adapted fungal consortium and non-adapted fungal consortium and hence the adapted fungal consortium could be considered potentially useful for the bioremediation of textile effluent. PMID- 22235502 TI - Chemopreventive potential of 18beta-glycyrrhetinic acid: an active constituent of liquorice, in 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. AB - Chemoprevention, a useful and attractive approach in experimental oncology, helps to investigate the cancer preventive potential of natural products and synthetic entities. Present study evaluated the chemopreventive potential of glycyrrhetinic acid in 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Oral tumor was developed in the buccal pouch of golden Syrian hamsters by painting with DMBA three times a week for 14 weeks. The tumor incidence and the status of phase I and phase II detoxification enzymes were assessed in hamsters treated with DMBA alone and DMBA+glycyrrhetinic acid treated hamsters. One hundred percent tumor formations, which were histopathologically confirmed as well-differentiated squamous cell carcinoma, were observed in hamsters treated with DMBA alone. Also, the status of detoxification enzymes were markedly altered in the liver and buccal mucosa of hamsters treated with DMBA alone. Oral administration ofglycyrrhetinic acid at a dose of 45 mg kg(-1) body weight to hamsters treated with DMBA completely prevented the tumor formation as well as restored the status of detoxification enzymes. Present study thus demonstrated the chemopreventive potential of glycyrrhetinic acid in DMBA induced oral carcinogenesis. PMID- 22235504 TI - Effect of hydroalcoholic extract of Lavandula officinalis on nicotine-induced convulsion in mice. AB - Epilepsy an important CNS (central nervous system) problem that about 1% of world's population suffer of it. The aim of study was to evaluate of anticonvulsant effect of hydroalcoholic extract of Lavandula officinalis. In this study, anticonvulsant activity of the hydroalcoholic extract of Lavandula officinalis (L. officinalis) was studied against chemoconvulsant-induced seizures in male mice. Lavandula officinalis (100, 200, 400, 600 and 800 mg kg(-1)), diazepam (0.15 mg kg(-1)) and normal saline (10 mL kg(-1)) were injected intraperitoneally, respectively in different groups of mice, 30 min before nicotine (5 mg kg(-) i.p.). The onset time intensity and duration of convulsions and the percentage of death were recorded. Also the time-response (0, 15, 30, 45, 60 min before nicotine injection) for most effective dose of plant extract (600 mg kg(-1)) was investigated. The results showed that hydroalcoholic extract of Lavandula officinalis had anticonvulsant effect. The most effective dose of plant extract was 600 mg kg(-1). In time-response study for the most effective dose of extract (600 mg kg(-1)), the onset, duration and intensity of convulsion significantly (p < 0.05) increased, decreased and decreased, respectively for all tested times. The best response observed in 30, 45 and 60 min. The results showed significant anticonvulsant effect for hydroalcoholic extract of Lavandula. PMID- 22235503 TI - Nephrotoxicity and oxidative stress of single large dose or two divided doses of gentamicin in rats. AB - Gentamicin (GS) is a potent antimicrobial exhibiting concentration dependent bacterial killing. A high dose ofgentamicin (10 mg kg(-1)) is required to reach sufficient concentrations in specific fluids as cerebrospinal fluid and to be effective on antibiotics resistant bacteria as well as treatment of acute and dangerous illness. Using a rat model, the renal toxicity and oxidative stress of administering gentamicin (10 mg kg(-1) daily for 7 days) either in a single dose or divided into 2 doses was investigated. The safety of dose regimens was assessed through oxidant-antioxidant parameters as well as renal function tests. Typical renal damage and high oxidative stress were evident in the control group receiving 100 mg kg(-1) gentamicin daily for 7 days. This was verified by high serum urea, uric acid, creatinine as well as increase in the levels of oxidative stress biomarkers as malondialdehyde, NO, total antioxidant capacity and decrease in reduced glutathione level. At any of the used regimen, 10 mg kg(-1) gentamicin did not provide high compromise for renal functions nor significantly increased the oxidative stress and tissue damage. Based on microscopic lesions scores and biochemical analysis, there were no significant differences between single or two divided dosages of gentamicin at dose rate of 10 mg kg(-1) day(-1). Further studies are required for applications in other animals of human subjects. PMID- 22235505 TI - Human papillomavirus infection in lung vs. oral squamous cell carcinomas: a polymerase chain reaction study. AB - The role of Human Papillomavirus (HPV) has been suspected in pathogenesis of various malignancies; however, the available data are not conclusive. This study aimed to determine and compare the frequency of HPV infection in oral and lung Squamous Cell Carcinoma (SCC) by a sensitive method. Sixty specimens of oral and lung SCC (30 cases each one) were reevaluated in Tabriz Imam Reza Centre in a 24 month period. Following genomic DNA extract, the Polymerase Chain Reaction (PCR) amplification was performed in presence of specific MY11 and MY09 primers for HPV infection. Three cervical specimens and a combination of PCR solution lacking DNA plus healthy persons' DNA samples were employed as positive and negative controls, respectively. The oral group was significantly older than the lung group (68.90 vs. 56.67 y, p < 0.001) with more males in the latter (83.3 vs. 60%; p = 0.04). Percentages of HPV infection in the oral and lung groups were comparable (20 vs. 10%, respectively; p = 0.47). Majority of patients with HPV infection were older than 60 years (88.9%) or male (88.9%). In the oral group, all these cases were well differentiated and the majority was of lower lip origin (83.3%). In the lung group, 66.7% of these specimens were moderately differentiated and the origin was bronchus in all cases. In conclusion, the rate of HPV infection in lung and oral SCC samples is rather lower than the previous reports in the literature. This rate is apparently higher in the oral than the lung SCC specimens. PMID- 22235506 TI - Clinical evaluation of detomidine-butorphanol-guaifenesin-ketamine as short term TIVA in Spiti ponies. AB - Veterinarians working under remote field conditions are routinely presented with variety of surgical interventions in equines like castrations, management of wound, traumatic and congenital hernias and musculoskeletal disorders thus necessitating the use of general anaesthesia for management of these conditions. The present study was carried out to evaluate and recommend the suitable short term anaesthetic technique for Spiti ponies under field conditions. Seven clinically healthy male Spiti ponies presented for castration were evaluated for short term Total Intravenous Anaesthesia (TIVA) using detomidine (0.02 mg kg( 1)), butorphanol (0.01 mg kg(-1)), 5% guaifenesin (20 mg kg(-1)) and ketamine (2.0 mg kg(-1)). The studies conducted were open label trials and all the animals received same treatment. After proper tetanus prophylaxis and preanesthetic fasting, detomidine was administered intravenously. Subsequently at head down position the animals received butorphanol intravenously. Thereafter, guaifenesin was administered intravenously. As soon as the signs of ataxia developed, the induction of surgical anaesthesia was achieved by intravenous administration of ketamine hydrochloride. The onset of sedation was observed in 2.43 +/- 0.53 min following detomidine administration and the animals were ataxic in 1.43 +/- 0.43 min after butorphanol and guaifenesin administration when ketamine was injected. The ponies were in surgical plane of anaesthesia within 2.28 +/- 0.42 min following ketamine administration. During recovery the limb/head movement and sternal recumbency were attained in 18.71 +/- 1.98 and 26.14 +/- 1.62 min, respectively whereas standing ataxia and normal gait were seen at 29.42 +/- 3.21 and 71.14 +/- 4.74 min, respectively. There was excellent to good muscle relaxation. The surgical anaesthesia remained for 22.57 +/- 1.48 min. The recovery was smooth. Moderate to good suppression of palpebral and corneal reflexes were observed immediately after induction and during anaesthesia. The analgesia was excellent. A highly significant (p < 0.01) to significant (p < 0.05) decrease in respiration rate was observed after induction, during anaesthesia and after recovery. The mean SpO2 value in equines of this group was 76.50 +/- 4.14 and 83.33 +/- 4.18% after induction and during anaesthesia, respectively. Some of the blood biochemical parameters like plasma alanine amino transferase (ALT), total proteins and glucose showed significant increase without clinical consequence. It was concluded that detomidine (0.02 mg kg(-1)), butorphanol (0.01 mg kg(-1)), guaifenesin 5% (20 mg kg(-1)) and ketamine (2.0 mg kg(-1)) combination can safely be used for short term total intravenous anaesthesia in equines under field conditions where the monitoring facilities are meager. PMID- 22235507 TI - To study various concentrations of magnesium and aluminium on amylin hormone conformation. AB - Type 2 diabetes mellitus can be defined as a conformational disease since a beta cell producing protein called amylin undergoes a change in the tertiary structure followed by self-aggregation and deposition. Amylin deposition causes destruction of pancreatic beta-cells. The aim of this study was to investigate whether different concentrations of magnesium and aluminium alter amylin conformation under near-physiological circumstances. Conformational variations were monitored by fluorescent method before and after incubation by shaker incubator in 37 degrees C by LS55 spectrofluorometer instrument. This in vitro study showed that magnesium had contradictory effects on amylin folding and these effects were magnesium concentration dependent. Magnesium with concentration of 1 to 1.5 mM had inhibitory effect but in 2.5 to 3.5 microM promoted amylin misfolding significantly (p < 0.05). The obtained data also demonstrated that aluminium with concentrations of 5, 10 and 20 microM had stimulatory effects on formation of beta-amyloid sheet significantly (p < 0.05). It may be concluded that islet amyloid misfolding and cytotoxicity to beta-cells might be magnesium dose dependent in diabetic patients. PMID- 22235508 TI - Therapeutic effects of biguanide vs. statin in polycystic ovary syndrome: a randomized clinical trial. AB - Various classes of medication are currently being used in Polycystic Ovary Syndrome (PCOS) patients including the biguanides and the statins. However, their efficacies are rarely compared. This study aimed to compare efficacy ofa biguanide and a statin in treating PCOS. In a randomized double-blind clinical trial, 400 women with PCOS were recruited within 15 months in Taleghani Hospital. They randomly received either a biguanide (metformin 500 mg three times daily) or a statin (simvastatin 20 mg daily) for three consecutive months. Changes of clinical and laboratory variables were compared. In the biguanide group the serum glucose status (abnormal fasting and non-fasting sugar and insulin levels and percentage of hyperinsulinemic cases) and menstrual abnormalities improved significantly after treatment (p < 0.05). In the statin group the lipid profile status (abnormal total cholesterol, high and low density lipoproteins), C Reactive Protein (CRP), serum dehydroepiandrosterone sulfate, hyperinsulinemia, severity of acne and menstrual abnormalities improved significantly after treatment (p < 0.05). Comparing the two groups, the improvements in fasting blood sugar and serum insulin levels were significantly better in the biguanide group (p = 0.04 for both parameters); whereas the improvements in serum total cholesterol (p < 0.001), low density lipoprotein (p < 0.001), CRP (p < 0.001) and acne status (p = 0.04) were significantly superior in the statin receivers. Based on these results, each medication is only effective on some aspects of the disease. Overall, the simvastatin was superior to metformin with regard to the number of beneficial effects. PMID- 22235509 TI - Lavender essence for post-cesarean pain. AB - Post cesarean (CS) pain is a challenging problem for the obstetricians, because it may interfere with mother and baby's well-being. Many approaches have been ever proposed to diminish this pain, each one with particular benefits and limitations. Aromatherapy is a complementary therapy especially for controlling pain. This study aimed at evaluating the effect of lavender essence on post CS pain. In a single-blind clinical trial, 200 term pregnant women with planned elective CS were recruited in a 12 month period of time. They were randomized in two 100-patient groups; received either lavender essence (the case group) or a similar clinically neutral aromatic material (the control group) thorough oxygen mask for 3 min 3 h after receiving similar intravenous analgesics. The Visual Analogue Scale (VAS) was employed to determine the level of post CS pain. The VAS was documented half hour after first intervention. Eight and 16 h later, the aromatherapy was repeated and half hour after each intervention, corresponding VAS was documented. The two groups were matched for demographics and obstetrical history. The baseline VAS was comparable between the two groups. The mean VAS decreased significantly by 16 h after the first intervention in both groups (p < 0.001). However, this amelioration of pain was significantly more prominent in the cases group comparing with that in the controls in all documented stages half hour, 8 and 16 h after the first intervention (p < 0.001 for all measurements). In conclusion, aromatherapy by using lavender essence is a successful and safe complementary therapy in reducing pain after CS. PMID- 22235510 TI - [The complete dental prosthesis gets a closer look]. PMID- 22235511 TI - [Articain can be a dangerous anesthetic. Yes]. PMID- 22235512 TI - [Articain can be a dangerous anesthetic. No]. PMID- 22235513 TI - [Lentigo maligna]. PMID- 22235514 TI - [Lentigo maligna]. PMID- 22235515 TI - [The use of digital technology for care-dependent patients]. AB - Several research reports have indicated that patients with dementia are likely to exhibit poor oral health. In the case of a 78-year-old women with Alzheimer's disease, tooth 22 had a crown fracture. The patient had always practiced good oral hygiene self care, but her self care was diminished drastically due to care dependency. It was decided to remove the root of tooth 22 and to fabricate an adhesive bridge. The digital technology was a welcome treatment aid. PMID- 22235516 TI - [An immediate removable complete denture for the transition from a natural to a prosthetic occlusal system]. AB - During the process of losing teeth, the fabrication of an immediate removable complete denture usually plays an important role. The path from a natural to a prosthetic occlusal system separates itself into a phased and a non-phased treatment. Various patient-related factors are of importance in the decision making process for a phased or a non-phased treatment, such as the patient's time available, the medical indication, the complexity of the natural occlusal system, and the motivation for treatment. A positive result can be more confidently predicted in the case of a phased treatment than a non-phased treatment. Placement of an immediate removable complete denture requires immediate aftercare. Particularly in the case of non-phased treatment, the fabrication of a new complete removable denture will be required within 1 year. PMID- 22235517 TI - [Improvement of a removable complete denture by relining or rebasing]. AB - When the fit of a removable complete denture is diminished as a result of progressive alveolar bone reduction, relining or rebasing might be indicated. In clinical practice, a degree of confusion exists concerning the concepts relining, and rebasing. Relining is resurfacing the tissue side of a denture with a new material to fill the space which exists between the original denture contour and the altered tissue contour. Rebasing is resurfacing the fitting surface of a denture by replacing the entire denture base with new material, also to fill the space which exists between the original denture contour and the altered tissue contour. In particular, attention is given to 3 specific forms ofrelining and rebasing which serve to restore the maxillomandibular relationship, to extend effectively the palatal denture surface of the maxillary denture and to reline or rebase an implant-supported overdenture. PMID- 22235518 TI - [Anatomy and procedure for making an impression for a removable complete denture]. AB - Making an impression of an edentulous jaw is an essential part of producing a removable complete denture, because the proper functioning of the denture is partially dependent on the volume and form of the alveolar ridge and the surrounding soft tissue, in particular the musculature. Before the impression of the maxillary and mandibular jaw is made, insight into the anatomy of the maxilla and the mandible as well as the soft oral tissues is also essential. With respect to this, a 5-phase approach for the impression-making procedure is introduced, which gives guidelines for the fabrication of the preliminary impression, the preliminary cast, the individual impression tray, the final impression and the final cast. In each phase, the concern is to achieve the best possible stability of the denture. Adequate stability can only be achieved by determining the denture borders accurately. PMID- 22235519 TI - [Neutral zone. An anatomic space which is often neglected while fabricating removable complete dentures]. AB - When designing complete dentures, consideration should not only be given to the occlusal concept but also to the occlusal system as a whole. An important part of that system is the position of the artificial teeth. This prosthetic part of the occlusal system is directly related to the tongue, the floor of the mouth, the cheeks and the lips. The artificial teeth of the mandibular dentures have to be positioned in the so-called 'neutral zone' of the edentulous mandible. The neutral zone is the stress-free area between the tongue on one side and, on the other side, the mimic muscles, which are responsible for the movement of the lips and cheeks. Moreover, the maxillary posterior artificial teeth and the supporting acrylic surfaces of the maxillary denture have an important function in providing support for the upper lip and cheeks in order to prevent a 'denture look' appearance. PMID- 22235520 TI - [Influence of a maxillary complete denture on taste perception Patients regularly report an alteration in taste perception after the insertion]. AB - Patients regularly report an alteration in taste perception after the insertion of a maxillary complete denture. It is generally accepted that changes in temperature and texture perception of the food induced by covering the hard palate are the principalfactors contributing to this alteration. Besides temperature and texture, other factors contributing to taste perception are smell, age and saliva composition. PMID- 22235521 TI - [An implant-supported overdenture in an edentulous upper jaw]. AB - An implant-supported overdenture is a good alternative treatment to a conventional denture for patients with complaints about the retention and stability of their removable complete denture. These complaints more often have to do with the mandibular than the maxillary denture. Implant-supported overdentures offer better results in the mandible than in the maxilla. In cases of insujficient bone volume in the maxilla for inserting implants, maxillary sinus floor elevation using an autogenous bone graft from the oral cavity or the iliac crest may be carried out. Treatment of the edentulous maxilla by inserting 6 implants followed by manufacturing a bar-clip mesostructure and an implant supported overdenture is the most successful, followed closely by the treatment option of inserting 4 implants and fabricating a similar mesostructure and overdenture. Aftercare by routine preventive examinations is required. PMID- 22235522 TI - Automation in surgery: the impact of navigated-control assistance on performance, workload, situation awareness, and acquisition of surgical skills. AB - OBJECTIVE: Human performance consequences of a new technology of image-guided navigation (IGN) support for surgeons are investigated. BACKGROUND: Navigated control (NC) represents an advancement of IGN technology. In contrast to currently available pointer-based systems, it represents a higher degree of automation that supports processes not only of information analysis and integration but also of intraoperative decision making. METHOD: In the first experiment, 14 surgical novices performed a simulated mastoidectomy with and without NC support. Effects of provision of the system were analyzed with respect to different measures of surgical performance and outcome, workload, and situation awareness. In the second experiment, 21 advanced medical students were trained to perform a mastoidectomy by practicing it either with or without NC support. It was investigated to what extent the provision of the system during practice would affect the acquisition of surgical skills. RESULTS: The results reveal that NC support can reduce both the risk of intraoperative injuries and complications as well as the physiological effort of surgeons. "Cost effects" compared to a conventional (i.e., not supported) surgery emerged with respect to the time needed for the surgery, increased subjective workload, reduced spare capacity, and a reduced level of situation awareness. However, no significant effects on processes of skill acquisition were found. CONCLUSION: NC systems can contribute to improved patient safety. Most of the cost effects seem to be related not to the basic principle of NC but to its current technological implementation. APPLICATION: The results have consequences for the design and clinical use of automated navigation support. PMID- 22235523 TI - Continuously informing vibrotactile displays in support of attention management and multitasking in anesthesiology. AB - OBJECTIVE: A novel vibrotactile display type was investigated to determine the potential benefits for supporting the attention and task management of anesthesiologists. BACKGROUND: Recent research has shown physiological monitoring and multitasking performance can benefit from displaying patient data via alarm like tactile notifications and via continuously informing auditory displays (e.g., sonifications). The current study investigated a novel combination of these two approaches: continuously informing tactile displays. METHOD: A tactile alarm and two continuously informing tactile display designs were evaluated in an anesthesia induction simulation with anesthesiologists as participants. Several performance measures were collected for two tasks: physiological monitoring and anesthesia induction. A multitask performance score equivalently weighted components from each task, normalized across experimental scenarios. Subjective rankings of the displays were also collected. RESULTS: Compared to the baseline (visual and auditory only) display configuration, each tactile display significantly improved performance in several objective measures, including multitask performance score. The continuously informing display that encoded the severity of patient health into the salience of its signals supported significantly better performance than the other two tactile displays. Contrasting the objective results, participants subjectively ranked the tactile alarm display highest. CONCLUSION: Continuously informing tactile displays with alarm-like properties (e.g., salience mapping) can better support anesthesiologists' physiological monitoring and multitasking performance under the high task demands of anesthesia induction. Adaptive display mechanisms may improve user acceptance. APPLICATION: This study can inform display design to support multitasking performance of anesthesiologists in the clinical setting and other supervisory control operators in work domains characterized by high demands for visual and auditory resources. PMID- 22235524 TI - Development and validation of a virtual reality simulator: human factors input to interventional radiology training. AB - OBJECTIVE: This study developed and validated a virtual reality (VR) simulator for use by interventional radiologists. BACKGROUND: Research in the area of skill acquisition reports practice as essential to become a task expert. Studies on simulation show skills learned in VR can be successfully transferred to a real world task. Recently, with improvements in technology, VR simulators have been developed to allow complex medical procedures to be practiced without risking the patient. METHOD: Three studies are reported. In Study I, 35 consultant interventional radiologists took part in a cognitive task analysis to empirically establish the key competencies of the Seldinger procedure. In Study 2, 62 participants performed one simulated procedure, and their performance was compared by expertise. In Study 3, the transferability of simulator training to a real-world procedure was assessed with 14 trainees. RESULTS: Study I produced 23 key competencies that were implemented as performance measures in the simulator. Study 2 showed the simulator had both face and construct validity, although some issues were identified. Study 3 showed the group that had undergone simulator training received significantly higher mean performance ratings on a subsequent patient procedure. CONCLUSION: The findings of this study support the centrality of validation in the successful design of simulators and show the utility of simulators as a training device. APPLICATION: The studies show the key elements of a validation program for a simulator. In addition to task analysis and face and construct validities, the authors highlight the importance of transfer of training in validation studies. PMID- 22235525 TI - Improving medication management through the redesign of the hospital code cart medication drawer. AB - OBJECTIVE: This study utilized usability testing and human factors engineering (HFE) principles to create efficient code cart medication drawer modifications to improve code blue medical emergency (code) medication management. BACKGROUND: Effective access to medications during a code is a key component in delivering optimal care and has been found to be a major problem among health care organizations; however, little research has been conducted to improve the efficiency of medication management during a code. METHOD: A total of 26 health care professionals (13 pharmacists and 13 nurses) were asked to locate items within a code cart medication drawer during two independent simulated code scenarios alternately using either a baseline medication drawer (control; Drawer 1) or a prototype medication drawer (prototype; Drawer 2), which was developed using HFE principles and usability testing. Overall medication retrieval time, wasteful actions, and survey responses were recorded. RESULTS: Drawer 2 had significantly faster trial completion times (p = .005) and fewer wasteful actions (p < .001) compared to Drawer 1. Participant survey results rated Drawer 2 (prototype) significantly higher (more favorable) for medication drawer visibility (p < .001), usability (p = .011), and organization (p < .001) compared to Drawer I (baseline). CONCLUSION: The HFE redesign concepts incorporated into Drawer 2 (consisting of visibility, grouping, and organization) produced successful, low-cost, and generalizable modifications that can improve patient care. APPLICATION: The findings demonstrate that HFE and usability applied to code cart design are effective, are customizable, and can affect patient safety by saving valuable time and reducing wasted motions (including errors) during code situations. PMID- 22235526 TI - Promoting colorectal cancer screening in public health outreach campaigns. AB - OBJECTIVE: Research on public outreach campaigns is presented. BACKGROUND: One study examines the effects of instruction design on adherence to cancer self screening instructions. A second study examines the effect of persuasive announcements on increasing screening campaign participation. METHOD: The first study examined adherence to screening (operationalized as returning results for evaluation) given standard instructions, or one of three other versions: persuasive, human factored, or a combination of the two.The second study investigated combining persuasion with a campaign announcement to increase participation (operationalized as picking up a test kit). RESULTS: The first study found that among first-time participants, the persuasive and human-factored instructions evoked higher result return rates than did the standard. The second study found that participation was significantly increased by adding persuasion to the campaign announcement. CONCLUSION: Enhancing motivation and reducing cognitive barriers increase adherence to test instructions and increase participation. APPLICATION: These are simple, cost-effective strategies that increase adherence to cancer screening in public outreach campaigns,which may reduce cancer-specific mortality. PMID- 22235527 TI - Using the landmark-route-survey framework to evaluate spatial knowledge obtained from synthetic vision systems. AB - OBJECTIVE: Using the landmark-route-survey framework, this research investigated the effect of synthetic vision systems (SVS) in either low or high visibility conditions on performance in wayfinding and spatial-knowledge-based tasks that probed spatial awareness. BACKGROUND: SVS are cockpit displays that depict computer-generated views of the terrain surrounding an aircraft and have been developed to support flight efficiency through improved spatial awareness. No studies have directly measured SVS impact on the three levels of spatial knowledge (landmark, route, and survey). METHOD: A total of 55 nonpilots learned a route in four different experimental conditions (high or low visibility, either with or without SVS). Subsequently, they underwent four recall tasks: way finding, scene recognition, scene classification, and sketch map. Six dependent measures were used to probe the three levels of spatial knowledge (selection errors, sorting errors, number of landmarks depicted, bidimensional regression) and their use in the wayfinding task (direction errors, designated landmark errors, and wayfinding verbalized hesitations). RESULTS: SVS produced higher performance in all four tasks. The low visibility condition lowered the wayfinding and scene-recognition performance. CONCLUSION: The overall results indicated that visibility mostly affected the first level of spatial knowledge (landmark) inducing a decreased wayfinding performance, whereas the use of SVS influenced the three levels of spatial knowledge (route and survey) inducing an increased wayfinding performance. APPLICATION: Potential applications of this work include spatial knowledge-based measures to evaluate SVS prototypes as well as to assess the relationship between spatial knowledge and spatial awareness. PMID- 22235528 TI - Using spatial context to support prospective memory in simulated air traffic control. AB - OBJECTIVE: The aim was to examine whether prospective memory error and response costs to ongoing tasks in an air traffic control simulation could be reduced by providing spatial context. BACKGROUND: Prospective memory refers to remembering to perform an intended action at an appropriate point in the future. Failures of prospective memory can occur in air traffic control. METHOD: For this study, three conditions of participants performed an air traffic control task that required them to accept and hand off aircraft and to prevent conflicts. The prospective memory task required participants to remember to press an alternative key rather than the routine key when accepting target aircraft. A red line separated the display into upper and lower regions. Participants in the context condition were told that the prospective memory instruction would apply only to aircraft approaching from one region (upper or lower). Those in the standard condition were not provided this information. In the control condition, participants did not have to perform the prospective memory task. RESULTS: In the context condition, participants made fewer prospective memory errors than did those in the standard condition and made faster acceptance decisions for aircraft approaching from irrelevant compared with relevant regions. Costs to hand-off decision time were also reduced in the context condition. Spatial context provided no benefit to conflict detection. CONCLUSION: Participants could partially localize their allocation of attentional resources to the prospective memory task to relevant display regions. APPLICATION: The findings are potentially applicable to air traffic control, whereby regularities in airspace structure and standard traffic flows allow controllers to anticipate the location of specific air traffic events. PMID- 22235530 TI - A contribution to situation awareness analysis: understanding how mismatched expectations affect road safety. AB - OBJECTIVE: The aim of the study was to clarify how knowledge elaborated by specific experience may lead to erroneous expectations during interactions between drivers and riders. BACKGROUND: Situation awareness is partly determined by prior knowledge. Unshared knowledge may cause difficulties in managing driving interactions, but there is still an important gap in the literature devoted to this field of research. METHOD: There were 226 participants, distinguished according to their vehicle use (for drivers, type of vehicle driven and whether they were exclusive or dual drivers; for motorcycle and scooter riders, the type of powered two-wheeler [PTW] used and its engine size) and their driving experience. Focusing on the most vulnerable users, we studied prior representations to interactions using a series of closed questions on drivers' performance relating to different stages of the interaction process from the perspective both of drivers' self-reflection and of riders' expectations. RESULTS: Although most drivers are self-confident, their abilities tend to be questioned by riders. Owners of medium or large motorbikes feel that drivers do not assess their approach speed accurately. Similarly, scooter riders doubt drivers' ability to assess the distance that separates them from PTWs. Riders who use medium or large motorbikes are more likely to question drivers' skills in relation to crossing situations. Scooter riders do so more often for overtaking situations. CONCLUSION: The development of shared prior knowledge is essential to prevent accidents and incidents between drivers and riders. APPLICATION: To help improve effectiveness, we recommend specific ways of embedding each type of road user profile in training, prevention, and research. PMID- 22235529 TI - Understanding the effect of workload on automation use for younger and older adults. AB - OBJECTIVE: This study examined how individuals, younger and older, interacted with an imperfect automated system. The impact of workload on performance and automation use was also investigated. BACKGROUND: Automation is used in situations characterized by varying levels of workload. As automated systems spread to domains such as transportation and the home, a diverse population of users will interact with automation. Research is needed to understand how different segments of the population use automation. METHOD: Workload was systematically manipulated to create three levels (low, moderate, high) in a dual task scenario in which participants interacted with a 70% reliable automated aid. Two experiments were conducted to assess automation use for younger and older adults. RESULTS: Both younger and older adults relied on the automation more than they complied with it. Among younger adults, high workload led to poorer performance and higher compliance, even when that compliance was detrimental. Older adults' performance was negatively affected by workload, but their compliance and reliance were unaffected. CONCLUSION: Younger and older adults were both able to use and double-check an imperfect automated system. Workload affected how younger adults complied with automation, particularly with regard to detecting automation false alarms. Older adults tended to comply and rely at fairly high rates overall, and this did not change with increased workload. APPLICATION: Training programs for imperfect automated systems should vary workload and provide feedback about error types, and strategies for identifying errors. The ability to identify automation errors varies across individuals, thereby necessitating training. PMID- 22235531 TI - Impact of two adjustable-autonomy models on the scalability of single human/multiple-robot teams for exploration missions. AB - OBJECTIVE: The aim of this study was to evaluate two models for adjusting autonomy in mobile robots to find out the best way for the operator to interact with the system with as many robots as possible. The first model is the most used in mobile robots; the second proposes a flexible autonomy management. BACKGROUND: There are different ways of adjusting the autonomy level in man-machine systems: adjustable autonomy, in which the operator has the initiative over the autonomy level; adaptive autonomy, in which the autonomy level is adjusted depending on the task and context; and mixed initiatives. One of the drawbacks of using adjustable autonomy is that it is claimed not to be flexible enough, resulting in a high operator workload. We propose and evaluate a flexible adjustable autonomy model for robot-team supervision. METHOD: Two experiments were designed to test the scalability and performance of the man-machine system with two alternative configurations for the autonomy management. The independent variable is the number of robots, and the measured variable is the man-machine system performance. The experiments are between subjects. We have used ANOVA and Bonferroni post hoc analysis for analyzing the results. RESULTS: On the basis of these analyses,we conclude that a flexible adjustable autonomy model results in better performance than the classic, rigid one, in which the operator directly chooses the autonomy level. CONCLUSION: Flexible autonomy adjustment permits one operator to control a team of robots with better results in terms of performance and robot use, as he or she can directly act at the error level, leaving the responsibility of readjusting and resuming the task to the system and hence reducing the operator's workload. APPLICATION: The results can be applied to exploration robotics, mainly, in which one operator controls a team of robots. In general, these principles can be extended to other single-man/multiple-machine systems. PMID- 22235532 TI - Human performance consequences of automated decision aids in states of sleep loss. AB - OBJECTIVE: The authors investigated how human performance consequences of automated decision aids are affected by the degree of automation and the operator's functional state. BACKGROUND: As research has shown, decision aids may not only improve performance but also lead to new sorts of risks.Whereas knowledge exists about the impact of system characteristics (e.g., reliability) on human performance, little is known about how these performance consequences are moderated by the functional state of operators. METHOD: Participants performed a simulated supervisory process control task with one of two decision aids providing support for fault identification and management. One session took place during the day, and another one took place during the night after a prolonged waking phase of more than 20 hr. RESULTS: Results showed that decision aids can support humans effectively in maintaining high levels of performance, even in states of sleep loss, with more highly automated aids being more effective than less automated ones. Furthermore, participants suffering from sleep loss were found to be more careful in interaction with the aids, that is, less prone to effects of complacency and automation bias. However, cost effects arose that included a decline in secondary-task performance and an increased risk of return-to-manual performance decrements. CONCLUSION: Automation support can help protect performance after a period of extended wakefulness. In addition, operators suffering from sleep loss seem to compensate for their impaired functional state by reallocating resources and showing a more attentive behavior toward possible automation failures. APPLICATION: Results of this research can inform the design of automation, especially decision aids. PMID- 22235533 TI - Effect of lead use on back and shoulder postural muscle activity in healthy young adults. AB - OBJECTIVE: The primary goal of this study was to test the hypothesis that wearing the 3.7 kg vest portion of a radiological shielding garment (a "lead") significantly increases lower back and shoulder muscle activity in quasistatic erect and forward-flexed postures. Secondarily, the authors examined the effects of gender and forward-flexed posture as well as their interactions with lead use. BACKGROUND: The use of a lead is mandatory for interventionalists during surgical procedures. Because the vest portion of a lead weighs considerably more than normal clothing, there is concern that its use increases the risk of developing back and shoulder pain. METHOD: In a repeated-measures study design, 19 young healthy male and female adults assumed standardized erect or forward-flexed postures, both with and without wearing the vest portion of a lead. Shoulder and lower back muscle activity was measured via surface electromyography, normalized by maximum voluntary contraction values. Data were analyzed using general linear models and repeated-measures ANOVA (significant for p < .05). RESULTS: Use of the lead did not result in a significant increase in muscle activity in the lower back or shoulders, despite perceived increases in effort and discomfort. Posture proved to be the most significant secondary factor affecting activity in the lower back, and participant gender proved insignificant. CONCLUSION: Short-term use of the lead does not appear to contribute to the incidence of back pain or injury in interventionalists. Avoiding flexed postures could more directly reduce the likelihood of pain or injury. APPLICATION: Potential applications include assessing and improving operating room ergonomics for physicians. PMID- 22235534 TI - Grip surface affects maximum pinch force. AB - OBJECTIVE: The aim of this study was to investigate whether people change their isometric pinch grip generation depending on the surface they gripped. Specifically, the effect of grip surface friction condition on (a) maximum force produced in the direction normal to the contact surface, (b) fluctuation of normal force, and (c) the digit force's angular deviation from the direction normal to the grip surface was quantified. BACKGROUND: Isometric pinch grip has been traditionally thought to be independent from the friction condition between the finger and gripped surface, which may be questionable. METHOD: For this study, 12 healthy participants performed maximum isometric pinch grip exertion on high-friction rubber and low-friction paper surfaces. Maximum normal force, normal force variance,and digit force's angular deviation from the normal direction were quantified. RESULTS: Pinch grip on the high-friction rubber surface was associated with 10% greater maximum normal force and 50% reduced normal force variance, compared with the low-friction paper surface (p < .05). Digit force's angular deviation was not significantly different between the two surface friction conditions. CONCLUSION: The data support that people do change their pinch grip generation (maximum normal force and normal force variance) depending on the surface they gripped, potentially by using sensory feedback. The results of this study demonstrate that even a simple isometric pinch grip (no lifting associated) is affected by grip surface friction. APPLICATION: Grip surface condition should be considered for clinical assessments, biomechanical investigation, and motor control studies to ensure consistency in measurements and validity of comparisons. PMID- 22235535 TI - Procedural instructions, principles, and examples: how to structure instructions for procedural tasks to enhance performance, learning, and transfer. AB - OBJECTIVE: The goal of this article is to investigate how instructions can be constructed to enhance performance and learning of procedural tasks. BACKGROUND: Important determinants of the effectiveness of instructions are type of instructions (procedural information, principles, and examples) and pedagogical goal (initial performance, learning, and transfer). METHOD: Procedural instructions describe how to complete tasks in a stepwise manner, principles describe rules governing the tasks, and examples demonstrate how instances of the task are carried out. The authors review the research literature associated with each type of instruction to identify factors determining effectiveness for different pedagogical goals. RESULTS: The results suggest a trade-off between usability and learnability. Specific instructions help initial performance, whereas more general instructions, requiring problem solving, help learning and transfer. Learning from instructions takes cognitive effort, and research suggests that learners typically opt for low effort. However, it is possible to meet both goals of good initial performance and learning with methods such as fading and by combining different types of instructions. CONCLUSION: How instructions are constructed influences their effectiveness for the goals of good initial performance, learning, and transfer, and it is therefore important for researchers and practitioners alike to define the pedagogical goal of instructions. APPLICATION: If the goal is good initial performance, then instructions should highly resemble the task at hand (e.g., in the form of detailed procedural instructions and examples), but if the goal is good learning and transfer, then instructions should be more abstract, inducing learners to expend the necessary cognitive effort for learning. PMID- 22235536 TI - 70 km/h speed limits on former 90 km/h roads: effects of sign repetition and distraction on speed. AB - OBJECTIVE: It was investigated how speed limit repetition and distraction affect drivers' speed management throughout a road section where the imposed speed limit is not in accordance (too low) with road design. BACKGROUND: It is not clear how driving speed evolves and to what degree speed limit repetition is necessary on roads where the imposed speed limit is not in accordance (too low) with road design. It is furthermore of interest how all these factors are influenced by driver distraction. METHOD: In a driving simulator, 47 volunteers completed one trip with and without distraction. Within each trip, three configurations were presented: speed limit sign repetition after every intersection, repetition only in the middle of a segment, or no repetition. RESULTS: Distraction lowered driving speed. Speed management varied depending on speed limit repetition. The speed limit was exceeded more often when speed limit signs were repeated less frequently. When drivers were not reminded of the limit, speed linearly increased throughout the segment. In all three configurations, speed increased toward the end of the segment, but this increase was largest when there had been no repetition at all of the speed limit. CONCLUSION: In low-demanding road designs that allow drivers to exceed the speed limit, limit repetition is necessary. Frequent repetition may be preferred, as speed management was most homogenous in that case. APPLICATION: The proposed analysis of speed management throughout a section increases our understanding of how speed evolves and thereby shows where repetition of the speed limit is necessary. PMID- 22235537 TI - Building fundamental performance improvement capabilities: the Kaiser Permanente experience. PMID- 22235538 TI - Kaiser Permanente's performance improvement system, Part 4: Creating a learning organization. AB - BACKGROUND: In 2006, recognizing variations in performance in quality, safety, service, and efficiency, Kaiser Permanente leaders initiated the development of a performance improvement (PI) system. Kaiser Permanente has implemented a strategy for creating the systemic capacity for continuous improvement that characterizes a learning organization. Six "building blocks" were identified to enable Kaiser Permanente to make the transition to becoming a learning organization: real-time sharing of meaningful performance data; formal training in problem-solving methodology; workforce engagement and informal knowledge sharing; leadership structures, beliefs, and behaviors; internal and external benchmarking; and technical knowledge sharing. Putting each building block into place required multiple complex strategies combining top-down and bottom-up approaches. SUCCESSES AND CHALLENGES: Although the strategies have largely been successful, challenges remain. The demand for real-time meaningful performance data can conflict with prioritized changes to health information systems. It is an ongoing challenge to teach PI, change management, innovation, and project management to all managers and staff without consuming too much training time. Challenges with workforce engagement include low initial use of tools intended to disseminate information through virtual social networking. Uptake of knowledge-sharing technologies is still primarily by innovators and early adopters. Leaders adopt new behaviors at varying speeds and have a range of abilities to foster an environment that is psychologically safe and stimulates inquiry. CONCLUSIONS: A learning organization has the capability to improve, and it develops structures and processes that facilitate the acquisition and sharing of knowledge. PMID- 22235539 TI - Michigan Health & Hospital Association Keystone Obstetrics: a statewide collaborative for perinatal patient safety in Michigan. AB - BACKGROUND: Preventable harm to mothers and infants during labor and birth is a significant patient safety and professional liability issue. A Michigan Health & Hospital Association Keystone Center for Patient Safety & Quality Obstetric Collaborative Project involved perinatal teams from 15 Michigan hospitals during an 11-month period in 2009. The purpose of the project was to promote safe care practices during labor and birth using the Comprehensive Unit-based Safety Program (CUSP). Consistent with the CUSP model, this project's components included assessing and promoting a culture of safety; interdisciplinary team building; case review; learning from defects through multiple methods of education; team and individual coaching and peer encouragement; administrative support for the establishment of a fundamental safety infrastructure; and ongoing evaluation of care processes and outcomes. METHODS: Study measures included 32 components of a perinatal patient infrastructure, 6 care processes during labor and birth, and 4 neonatal outcomes. RESULTS: Significant improvements were found in the safety culture (Safety Attitudes Questionnaire), the perinatal patient safety infrastructure components, and all care processes. CONCLUSIONS: Although the project was successful, getting buy-in from all members of the clinical team in each hospital for all of the measures was challenging at times. There was initial resistance to some of the measures and their various expected aspects of care. For example, some of the clinicians were initially reluctant to adopt the recommended standardized oxytocin protocol. Peer encouragement and unit-based feedback on progress in minimizing early elective births proved useful in many hospitals. A CUSP in obstetrics can be beneficial in improving the care of mothers and infants during labor and birth. PMID- 22235540 TI - Exportability of an intervention to increase HIV testing in the Veterans Health Administration. AB - BACKGROUND: Exportability, or the dissemination of successful health services interventions from one site to another, must be demonstrated before systemwide implementation. METHODS: The effectiveness of a previously successful multicomponent intervention to increase rates of HIV testing in Veterans Health Administration (VHA) health care facilities among those without records of previous testing was evaluated in two other VHA facilities. Whereas the principle responsibility for the provider-activation component of the intervention was previously borne by research staff, nonresearch staff now took on these responsibilities. RESULTS: The annual rate of HIV testing among persons with documented risk factors for acquiring HIV infection increased by 5.8% and 16% after the end of the first year of implementation for the sites to which the project was newly exported and where nonresearch staff were responsible for implementation. In contrast, for the original implementation sites, where research staff played a major role in implementation, testing rates increased by 9.3% and 12.4%. There was no change in the rate of testing at a control site. At one site, HIV testing rates increased before implementation of the provider activation aspect of the intervention program. CONCLUSIONS: An intervention to increase HIV testing rates, which combines informatics, organizational support, and provider activation, can be successfully exported and implemented by nonresearch staff and may not require an extensive provider activation program. The resultant increases in HIV testing are similar to those seen in facilities where research staff play an active role. This work provides support for further efforts to refine this program to promote non-risk-based testing for HIV infection, as per current VHA policy and to more broadly implement this program. PMID- 22235541 TI - Using a novel patient medication list for ambulatory pediatric patients within a hospital-based complex care program. AB - BACKGROUND: Medication errors are common in the pediatric outpatient setting, and children with multiple prescriptions are at increased risk. Little is known about medication reconciliation's application in the ambulatory setting. Caregivers' perceptions of a patient medication list (PML), created for children with complex health needs, were assessed. METHODS: Caregivers of children followed by a tertiary care hospital ambulatory complex care program from February through December 2009 were enrolled in the study. An electronic PML software was nested within a clinical database. At the clinic visit, the medications were updated in the database by a nurse practitioner, and a PML was created and printed for the caregivers. Caregivers were asked to complete a pre-questionnaire before using the PML and a post-questionnaire 12 weeks later. RESULTS: The pre-questionnaire demonstrated that 19 (68%) of 28 caregivers expected the PML to be very helpful. After a mean of 19.3 weeks, on the post-questionnaire, 14 (50%) of the 28 caregivers reported that the PML was very helpful, 10 (40%) of 25 caregivers used the PML at every follow-up clinic visit, and 18 (67%) of 27 caregivers were satisfied with the PML. Five (18%) of 28 caregivers strongly agreed that the PML increased their knowledge of the child's medications, and 3 (11%) of 28 caregivers strongly agreed that the PML helped them remember to give the child's medications at home. CONCLUSIONS: A subset of caregivers in a complex care program reported that a PML was helpful during interactions with their medical team. Yet in general, caregivers did not find the PML helpful in increasing their medication knowledge or reminding them to administer their child's medications. PMID- 22235542 TI - Identifying women at risk of delayed breast cancer diagnosis. AB - BACKGROUND: Delays in breast cancer diagnosis contribute to increased morbidity and mortality. Factors related to the occurrence of delayed diagnosis have not been well studied. METHODS: A retrospective cohort study of 5,464 women newly diagnosed with breast cancer from 1999 through 2006 was conducted at a comprehensive cancer center in Boston. A delayed diagnosis was defined as an interval greater than 90 days between the patient's first breast-related problem that prompted seeking of medical care and the breast cancer diagnosis based on biopsy. RESULTS: 938 (17%) patients had a delayed breast cancer diagnosis. Non white race or Hispanic ethnicity (adjusted odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.13-1.90), living more than 26 miles from Boston (OR 1.46, 95% CI = 1.25-1.71), and initial presentation with a lump found by the patient herself (OR = 2.89, 95% CI = 2.36-3.55) or another breast symptom (OR = 0.25, 95% CI = 1.79-2.82) compared to an abnormal mammogram were significantly associated with a delay in diagnosis. In contrast, the odds of a delay were lower for women who were older than 18-39 years of age and for women living with two or more household members (OR = 0.72, 95% CI = 0.59-0.87). The likelihood of experiencing a delayed breast cancer diagnosis increased markedly if a woman had multiple risk factors, with a nearly 12-fold increase among women with five or more risk factors (OR = 11.96, 95% CI = 6.32-22.61). CONCLUSIONS: Younger age, minority race, and self-identification of breast symptom affect the likelihood of delayed breast cancer diagnosis. Awareness of these issues could help focus efforts to develop algorithms that identify women at risk for a delay and build programs that facilitate their timely access to care. PMID- 22235543 TI - Running on empty. PMID- 22235544 TI - Have working-age people with disabilities shared in the gains of Massachusetts health reform? AB - The Massachusetts health reform, implemented in 2006 and 2007, reduced the uninsurance rate for working-age people with disabilities by nearly half Enrollment in Medicaid and subsidized insurance accounted for most of the gain in insurance coverage. The reduction in uninsurance was greatest among younger adults. The reform also reduced cost-related problems obtaining care; however, cost remains an obstacle, particularly among young adults with disabilities. The Massachusetts outcomes demonstrate that insurance subsidies, Medicaid expansions for low-income adults, individual insurance mandates, and enrollment initiatives can lead to substantial reductions in uninsurance and cost-related problems obtaining care among working-age people with disabilities. PMID- 22235545 TI - Medicaid enrollment at early stage of disease: the Breast and Cervical Cancer Prevention and Treatment Act in Georgia. AB - This study linked data from the Georgia Comprehensive Cancer Registry to Medicaid enrollment and claims to test whether the Breast and Cervical Cancer Prevention and Treatment Act (BCCPTA), which provided a new and quicker pathway to Medicaid eligibility for low-income breast cancer patients, led to more patients enrolling at an early stage of disease. Results based on difference-in-differences analysis indicated that Georgia's BCCPTA increased by 11 percentage points the probability of breast cancer patients enrolling in Medicaid at an early stage (p = .024). This effect could mean more treatment options and higher survival rates for these patients. PMID- 22235546 TI - Do minority patients use lower quality hospitals? AB - Employing three years of inpatient discharge data from 11 states and inpatient and patient safety quality indicators from the Agency for Healthcare Research and Quality (AHRQ), this paper explored whether minority (black, Hispanic, and Asian) patients used lower quality hospitals. We found that the association between the share of minority patients and hospital quality depended on how quality was measured and varied by race and ethnicity. Hospitals serving Hispanics performed well on most patient safety measures. Higher percentages of all three minority patient groups corresponded to lower quality for only one measure, postoperative sepsis. Our analysis indicates that it is incorrect to generalize that minorities use lower quality hospitals. Analysts and policymakers should be cautious when making generalizations about the overall service quality of hospitals that treat minority patients. PMID- 22235547 TI - What factors influence participation in an exercise-focused, employer-based wellness program? AB - Following the recent introduction of an incentive-based, exercise-focused wellness program at a large public university, this paper investigates the factors that influence employees' behavior with respect to participation and regular exercise. Results suggest that an employee's probability of signing up for the program is related to her exercise behavior prior to the program's inception, the time cost of exercise, taste for fitness center exercise, and attitudes about the benefits and barriers of exercise. Employees who are older, male, and were regular fitness center exercisers prior to the program's inception are more likely to be regular exercisers. PMID- 22235548 TI - Implications of the accuracy of MEPS prescription drug data for health services research. AB - This paper assesses the quality of the Medical Expenditure Panel Survey (MEPS) drug data and the impact that misreporting prescription drug data has on descriptive and behavioral analyses. It does this by matching MEPS participants with Medicare Part D coverage during the period 2006-2007 to their Part D claims data. In the validation sample, the number of drug fills and total expenditures are reasonably accurate compared with claims. Household respondents tended to underreport the number of different drugs taken, but tended to overreport the number of fills of each drug. Behavioral analyses of the determinants of medication use and expenditures were largely unaffected because underreporting cut across most sociodemographic groups. PMID- 22235549 TI - Strokes have declined but atrial fibrillation is still undertreated. PMID- 22235550 TI - Improving outcomes in lung cancer patients. AB - Lung cancer is the leading cause of cancer mortality in the UK resulting in more than 33,500 deaths in 2008, 4,000 more than for bowel and breast cancer combined. Five-year survival figures are poor but have recently improved from around 5% to 7.5% in men and 8.5% in women. The key recommendations in the updated NICE guideline seek to ensure that: all multidisciplinary teams apply efficient methods to diagnose and stage patients accurately; fitness assessment is an objective process; as many patients as possible are offered treatment with curative intent; those with small cell lung cancer are offered the most effective treatment; and patients are referred early for endobronchial treatment. There are potentially more important and difficult challenges for primary and integrated care. Almost three quarters of patients with lung cancer have advanced disease atpresentation, and many of these have had symptoms for many months. Early diagnosis, awareness of warning symptoms and prompt referral are therefore major priorities. If we are to improve outcomes in lung cancer, more patients need to be sent for chest X-ray and referred urgently. If the chest X-ray is normal but there is a high suspicion of lung cancer the patient should still be referred urgently. To ensure that all patients have the best chance of being offered curative treatment, patients should be re-assessed by the surgeon and/or radiation oncologist after any optimisation. Patients should be encouraged to stop smoking, as this reduces postoperative complications, but surgery should not be postponed. Surgery that minimises loss of lung tissue is recommended. The latest radiotherapy techniques, such as stereotactic body radiotherapy, that minimise dose to normal lung are encouraged. PMID- 22235551 TI - New tests will improve detection of latent TB. AB - In the UK cases of active TB have risen substantially over the past 20 years. This increase has occurred almost exclusively in individuals born outside the UK, who now constitute more than two-thirds of cases. Only around one in ten people who are infected will develop active disease. The remaining 90% are presumed to have latent TB infection (LTBI) where viable mycobacteria are thought to persist for decades, and may reactivate if the host's immune system is weakened. In a country such as the UK with a low incidence of TB, a high proportion of cases result from reactivation of latent TB, rather than transmission by infectious cases. In the past 10 years a novel type of diagnostic test for LTBI has been developed: the interferon-gamma release assays (IGRA). Their major advantage over the tuberculin skin test is that they are not affected by prior BCG vaccination and they have a specificity of well over 90%. These tests are unable to distinguish between active and latent TB infection: this distinction must be performed purely on clinical grounds. Patients with a positive test should be assessed by a clinician with expertise in TB to ensure an appropriate management plan for each patient. The role of IGRAs in diagnosis of active TB is limited since in a patient with suspected active TB a positive result may indicate LTBI in combination with an alternative diagnosis. At a population level screening and chemoprophylaxis contributes usefully to TB control. However, only those under 35 with LTBI should receive prophylaxis. After this age the increasing risks of hepatotoxicity begin to outweigh the diminishing benefits of prophylaxis. The exceptions are healthcare workers, where the benefits are not just to the individual but also extend to their patients, and immunocompromised patients. The IGRAs represent a major development in the diagnosis of LTBI. While currently most of their use is through established TB screening services, it is likely in future that they will also be used routinely in general practice to screen individuals at high risk of LTBI. PMID- 22235553 TI - Lumps and bumps: Part 2. PMID- 22235552 TI - Diagnosing autism spectrum disorders in primary care. AB - Autism is a disorder of social communication, originally described as a triad of impaired social interaction, communication, and imagination, associated with a rigid, repetitive pattern of behaviour. More recently the core deficit has been described as a lack of social instinct. The term autism spectrum disorder (ASD) includes autism, atypical autism and Asperger's syndrome. According to NICE, diagnostic assessment should start within three months of referral. The decision to refer should be made on the basis of signs or symptoms. Information from all sources (i.e. medical history, parental concerns, clinical judgement) should be used to diagnose ASD based on ICD-10 or DSM-IV criteria. Clinicians should not rely on any one autism-specific diagnostic tool alone to diagnose ASD. Diagnosis is based primarily on the recognition and interpretation of behavioural symptoms. CHAT or the modified version (M-CHAT) are simple checklists that can be used for the assessment of young children in primary care when ASD is suspected. They can identify clinical features indicative of increased risk but should not be used to rule out ASD. PMID- 22235554 TI - Tuberculin in pulmonary tuberculosis. 1911. PMID- 22235555 TI - Saving face in front of your patients. PMID- 22235556 TI - Antitrust, dentistry, and you: what you should know. PMID- 22235557 TI - The need for grassroots advocacy. PMID- 22235558 TI - General dentists advertising specialty services. PMID- 22235559 TI - My hygienist's drunk driving arrest. PMID- 22235560 TI - Noncompliance with peer review; withholding patient records. PMID- 22235561 TI - 'One size' malpractice insurance does NOT fit all. PMID- 22235562 TI - The risks of 'hiring blind'. PMID- 22235563 TI - Non-covered services: can't we all just get a law? PMID- 22235565 TI - How to manage the third molar--the emerging evidence base. PMID- 22235564 TI - Your practice success: why it's better with membership. PMID- 22235566 TI - Significance of cannabis use to dental practice. AB - The illicit use of the three main forms of cannabis--marijuana, hash, hash oil- pose certain obstacles and challenges to the dental professional. There are a number of systemic, as well as oral/head and neck manifestations, associated with cannabis use. Dentists need to be aware of these manifestations in order to take whatever precautions and/or modifications to the proposed treatment that might be necessary. PMID- 22235567 TI - Is your dental assistant practicing legally? PMID- 22235568 TI - Michigan's new business tax: good news for most dentists. PMID- 22235569 TI - [Quality: accessible and attainable]. PMID- 22235570 TI - [Choice menu]. PMID- 22235571 TI - [Henk Vaarkamp brought about synergism]. PMID- 22235572 TI - [Your practice; what is your diagnosis?]. PMID- 22235573 TI - [Trends from the GD monitoring]. PMID- 22235574 TI - [Risk factors for persistent presence of salmonella antibodies in bulk tank milk]. AB - Given bulk milk serology, salmonellosis is present on a restricted number of Dutch dairy farms. The affected farms are clustered in some regions of the country. This study was designed to find risk factors for having persistent positive bulk milk serology for salmonella within the regions with the highest prevalence. With that knowledge, a reduction of persistent infected farms may be achieved. To this end, we performed a rather small matched case-control study with two groups of 24 farms each. Case herds were characterized by having a positive bulk milk serology for salmonella for all three samplings during one year, whereas control farms were located near the positive farms and were negative in all these three samplings. Several risk factors were found not significant, while the significant risk factors concerned general on farm hygiene practices. Significant risk factors in the multivariate analyses were less hygienic calf facilities (OR = 6.1, p = 0.04), lower cleaning frequency of alleys (OR = 5.7, p = 0.08), and a higher frequency of claw trimmers visiting the farm (OR = 5.9, p = 0.07). We concluded that these risk factors are similar to those found outside the regions with a high number of farms with a positive bulk milk serology for salmonella. PMID- 22235575 TI - [Ear injuries in young pigs]. PMID- 22235576 TI - New developments in veterinary education in the republic of Azerbaijan. AB - After the collapse of the Soviet Union in 1991, the agrarian sector in the former member states fell into a steep decline, and veterinary training and education came to a standstill. Before the collapse, veterinary care was free, but thereafter few could afford to pay for the services of a veterinarian. Veterinary science became an unpopular study and attracted less motivated students. However, some veterinarians started Private Veterinary Units (PVU) and became successful. It will take time for veterinary training and education to catch up with modern developments. In the meantime, the establishment of a Private Veterinary Unit connected to the Veterinary Faculty could play an important role in accelerating the availability of competent veterinarians. PMID- 22235577 TI - [Paratuberculosis infection through inhaling contaminated dust particles]. PMID- 22235578 TI - ['Clinic director' develops question directed approach]. PMID- 22235579 TI - [Cat hoarders]. PMID- 22235580 TI - [Development project young veterinarians, also positive for the employer!]. PMID- 22235581 TI - [Proud occupational group solves the antibiotic problem themselves]. PMID- 22235582 TI - [Rabies in bats: be alert]. PMID- 22235583 TI - [The contribution of paraveterinary professionals within veterinary medicine]. PMID- 22235584 TI - [GGG guidelines for responsible veterinary handling when it comes to breeding of pets]. PMID- 22235585 TI - ['In the end it is about the health of the people']. PMID- 22235586 TI - [John Akkermans: researcher 'pur sang']. PMID- 22235587 TI - [Prevention of tick borne diseases]. PMID- 22235588 TI - [Air traffic is never idle]. PMID- 22235589 TI - Polymorphic repetitive loci of the amphibian pathogen Batrachochytrium dendrobatidis. AB - Batrachochytrium dendrobatidis (Bd), the cause of a fatal fungal skin disease of amphibians that has led to massive die-offs, global declines and extinctions, has spread internationally as a pandemic clone with low genetic diversity. A need exists to develop highly polymorphic markers to determine centers of origin and patterns of spread to assist in the development of management strategies. Comparison of paralogous sequences, obtained from the 2 sequenced Bd genomes, indicates useful levels of inter-strain polymorphism in repetitive fragments. We assessed 6 repetitive loci for variation within and among Australian isolates using standard fragment analysis and capillary electrophoresis-single strand conformation polymorphism (CE-SSCP) analysis. Confirmation of inter-isolate polymorphism was achieved for 2 marker systems, highlighting the potential of repetitive loci for the development of polymorphic markers in Bd. In addition, we found that repetitive loci in Bd include possible orthologs of virulence-related genes from pathogenic fungi. PMID- 22235590 TI - Molecular analysis of parapoxvirus from a spotted seal Phoca largha in Japan. AB - A spotted seal Phoca largha with nodular and scab lesions on the whole body was brought to an aquarium in Nagoya, Japan. We extracted DNA from the lesions and used the polymerase chain reaction (PCR) method for detecting orthopoxvirus and parapoxvirus DNA. Parapoxvirus but not orthopoxvirus DNA was detected. The partial nucleotide sequence of the envelope gene was determined from the PCR product, and the sequence was seen to be closely related to 2 parapoxvirus strains from spotted seals in Alaska, showing 100% identity at the amino acid level, with one nucleotide substitution. Virus-neutralizing (VN) antibody against canine distemper virus (CDV) was not detected in the serum, indicating that this individual was not infected with CDV or phocine distemper virus (PDV), which both have a high mortality rate for marine mammals. These results suggest that the lesions were caused by infection with pinniped parapoxvirus, and that the viruses spread and are maintained within the habitat range or populations of spotted seals from the Bering Sea to the Japan Sea. This is the first report of molecular analysis of parapoxvirus in marine mammals in Japan. PMID- 22235591 TI - Epidemiology and phylogenetic analysis of Taura syndrome virus in cultured Pacific white shrimp Litopenaeus vannamei B. in Taiwan. AB - Taura syndrome virus (TSV) has spread worldwide, causing significant economic losses since Taura syndrome was first described in Ecuador in 1992. To determine the prevalence and impact of TSV infection on the shrimp farming industry in Taiwan, Pacific white shrimp Litopenaeus vannamei B. were collected from 220 farms between 2004 and 2006 for viral detection by reverse transcription polymerase chain reaction. Data showed that the overall TSV prevalence rate was 20% (43/220 farms). Comparing shrimp growth stages, TSV prevalence rates were 4% for postlarvae, 24% for juveniles, 24% for subadults, 32% for adults, and 5% for brooders. Among TSV-positive farms, average infection incidence was 35% in postlarvae farms, 55% in juvenile farms, 39% in subadult farms, 31% in adult farms, and 20% in brooder farms. Notably, TSV was also detected in Exopalaemon orientis H. from 1 of 10 farms. Tail fans and appendages had red pigmentation, which is characteristic of TSV infection. Of shrimp with pathological lesions, 100% had lesions on tail fans, 88% on appendages, and 80% in gills. Sequence comparison using the TSV VP1 (structural protein) gene showed that 9 isolates from the farms had 92.3 to 99.5% nucleotide sequence identity with strains in the GenBank database from Taiwan (AF406789 and AY355310) and Venezuela (DQ212790). This is the first broad epidemiological study of TSV infection in L. vannamei in Taiwan. PMID- 22235592 TI - Generation and characterization of NV gene-knockout recombinant viral hemorrhagic septicemia virus (VHSV) genotype IVa. AB - A recombinant viral hemorrhagic septicemia virus (rVHSV-deltaNV-EGFP) containing the enhanced green fluorescent protein (EGFP) gene instead of the NV gene was produced using the reverse-genetics method. For use as a positive control, another recombinant virus (rVHSV-wild) was also generated, which had an identical nucleotide sequence to the wild-type VHSV genome except for a few artificially replaced nucleotides. The rVHSVs were rescued using a system controlled by T7 RNA polymerase supplied by a retroviral vector. Generation of rVHSV-deltaNV-EGFP and rVHSV-wild was confirmed by sequencing of RT-PCR products, and rescue of infectious rVHSVs was confirmed by observation of plaque formation. Replication efficiency of rVHSV-wild was distinctly lower than that of wild-type VHSV, suggesting that the artificially replaced nucleotides, especially when immediately preceding the G or NV gene start codons, might affect the replication of the virus. Replication of rVHSV-deltaNV-EGFP was slightly lower than that of rVHSV-wild when epithelioma papulosum cyprini cells were infected with multiplicity of infection (MOI) 1.0, but much lower when cells were infected with MOI 0.00001. These results suggest that the NV gene plays an important role in VHSV replication through interactions with host-cell responses, and the lower replication ability of rVHSV-wild compared to wild-type VHSV might be caused by replaced nucleotides just before the NV gene open reading frame (ORF) rather than the G gene ORF. In olive flounder Paralichthys olivaceus, rVHSV-wild produced slower-progressing mortalities than wild-type VHSV, whereas rVHSV-deltaNV-EGFP pathogenesis was highly attenuated. These results suggest that the NV protein of VHSV may play an important role not only in viral replication but also in viral pathogenesis. PMID- 22235593 TI - Flavobacterium psychrophilum associated with septicaemia and necrotic myositis in Atlantic salmon Salmo salar: a case report. AB - We describe the first case from Norway of increased mortality in Atlantic salmon Salmo salar (L.), with septicaemia and necrotic myositis, associated with infection by Flavobacterium psychrophilum. The outbreak occurred in smolt of 60 to 100 g in fresh water on a land-based farm in Western Norway during winter 2008 2009. The water temperature was < 5 degrees C and the accumulated mortality was 7.0%. Necropsy of dead and moribund fish revealed a swollen dark spleen, pale liver, serohaemorrhagic ascites and haemorrhage in the abdominal fat and muscle. F. psychrophilum was isolated from the kidney and spleen of diseased fish. Muscle biopsy revealed the presence of long filamentous rods in necrotic areas of skeletal muscle. Immunohistochemistry was positive for F. psychrophilum. Identification of cultured isolates as F. psychrophilum was confirmed using phenotypic testing and sequencing of the 16S rRNA gene. Analysis by allele specific polymerase chain reaction (allele-specific PCR) indicated that 2 different genotypes of the bacterium were present in the outbreak. PMID- 22235594 TI - Individual fish tank arrays in studies of Lepeophtheirus salmonis and lice loss variability. AB - In studies of the salmon louse Lepeophtheirus salmonis (Kroyer, 1837), experimental design is complicated by a highly variable and unpredictable lice loss among common experimental tanks and a substantial rate of host transfer within tanks. When fish hosting L. salmonis are maintained in individual tanks, unspecific effects such as host transfer, louse predation by cohabitant hosts and agonistic host interactions are excluded. This study suggests that it is possible to maintain Atlantic salmon Salmo salar infected with L. salmonis in an array of small, single fish tanks and, by doing so, provide an experimental system in which the loss of motile pre-adult and adult stages of L. salmonis is predictable. Here, lice can be collected shortly after detachment for detailed studies or to provide mortality curves of lice from individual fish. This represents an experimental approach improving precision in studies of L. salmonis, such as drug and vaccine efficacy assays, RNA interference (RNAi) studies and host-parasite interactions. The natural loss of pre-adult/adult L. salmonis from the system was higher for males than females. The loss of females appeared to be a process somewhat selective against large individuals. Inherent qualities of the host appeared to be of little significance in explaining the variability in loss of preadult/adult lice. PMID- 22235595 TI - Wild arctic char Salvelinus alpinus and trout Salmo trutta: hosts and reservoir of the salmonid pathogen Spironucleus salmonicida (Diplomonadida; Hexamitidae). AB - Spironucleus salmonicida is a diplomonad flagellate known to cause systemic infections in farmed salmonids. In northern Norway, outbreaks of spironucleosis in farmed Atlantic salmon Salmo salar have been a recurring problem. Common to all these outbreaks was the origin of smolts: all came from the same farm. In the present study, wild Arctic char Salvelinus alpinus and brown trout Salmo trutta were sampled from the lakes used as a water source for the smolt supplier. In addition, smolt and three-spined sticklebacks Gasterosteus aculeatus were sampled from the smolt farm. Bile and intestinal contents from the sampled fish were examined by light microscopy and PCR. Spironucleus salmonicida was identified in both wild Arctic char and brown trout from the lakes used as water sources by the smolt farm, suggesting that the farmed fish were exposed to this pathogen before transfer to the sea. Spironucleus barkhanus and Spironucleus salmonis were also identified in the sampled fish. The present study also demonstrated that infections with multiple Spironucleus species are present in wild salmonids. No indications of disease related to diplomonad infections were observed in the wild fish, suggesting that wild salmonids are reservoir hosts of Spironucleus salmonicida. PMID- 22235596 TI - Parasite fauna of introduced pumpkinseed fish Lepomis gibbosus: first British record of Onchocleidus dispar (Monogenea). AB - A survey of pumpkinseed Lepomis gibbosus from a stillwater fishery in southern England revealed infections by the ancyrocephalid monogenean Onchocleidus dispar at 100% prevalence. Host specificity of O. dispar to North American centrarchid fish suggests that it is a non-native parasite, introduced to Britain with L. gibbosus. Mean intensity of O. dispar was significantly higher in male (25.5 parasites) compared to female (15) and immature (7) hosts, but was not influenced by host standard length or sampling time. This sex-biased parasitism is likely to be related to both ecological and physiological factors, such as differential exposure to infective stages during nest building, or higher susceptibility to infection due to enhanced host stress levels. O. dispar significantly dominated the external surfaces and the outer gill arches. Analysis of the spatial distribution of the parasite between the 9 regions of gill surface determined that as density increased, higher numbers of parasites were found on the anterior and central gill regions compared to posterior (distal) regions. Apparent microhabitat selection is discussed in terms O. dispar life cycle, maximising oxygen availability, avoiding unstable areas and increasing intraspecific contact. The absence of O. dispar in the gills of roach, rudd and gudgeon sampled from the same fishery supports the assumption that this parasite is currently of little threat to native fish populations. PMID- 22235597 TI - Potent infection reservoir of crayfish plague now permanently established in Norway. AB - Noble crayfish Astacus astacus is threatened in Europe due to invasive crayfish carrying the crayfish plague agent Aphanomyces astaci. Norway is among the last countries in which the introduction of non-indigenous crayfish has been limited through strict legislation practices. However, North American signal crayfish Pacifastacus leniusculus were recently discovered in a water-course that has been repeatedly hit by the plague. We mapped the distribution and relative density (catch per unit effort) of signal crayfish within this lake, and performed agent specific real-time PCR to estimate the prevalence of A. astaci in the population. The resulting length frequencies and relative density estimates clearly demonstrate a well-established signal crayfish population, in which 86.4% of the analysed individuals were confirmed carriers. The success of detection was significantly higher (84.1%) in the crayfish tailfan (i.e. uropods) than in the soft abdominal cuticle (38.4%), which is commonly used in prevalence studies. We therefore propose tailfan (uropods and telson) as the preferred tissue for studying A. astaci prevalence in signal crayfish populations. The likelihood of detecting an A. astaci-positive signal crayfish increased significantly with increasing crayfish length. Further, large female crayfish expressed significantly higher PCR-forming units values than large males. In surveys primarily exploring the presence of A. astaci-positive individuals in a population, large females should be selected for molecular analyses. Our study demonstrates that a potent crayfish plague infection reservoir, evidently originating from the illegal human introduction of signal crayfish, has permanently been established in Norway. PMID- 22235598 TI - The public health impact of industrial disasters. AB - The recent Deepwater Horizon oil spill and Japanese earthquake/tsunami radiation disaster have increased public concerns regarding the public health impact of industrial disasters. Industrial disasters are known to impose a unique set of challenges for public health emergency response. There are critical gaps in scientific knowledge regarding assessment and control of public health disasters related to industrial releases of hazardous materials. There is also a fundamental lack of familiarity regarding industrial disasters among the public health and medical communities, in general. There are few sources in the current public health literature that review this disaster phenomenon in a comprehensive manner. This article offers a review of the public health impact and unique considerations related to industrial disasters. PMID- 22235599 TI - Factors associated with inpatient mortality in a field hospital following the Haiti earthquake, January-May 2010. AB - OBJECTIVE: To describe factors associated with inpatient mortality in a field hospital established following the 2010 Haiti earthquake. DESIGN: Data were abstracted from medical records of patients admitted to the University of Miami Global Institute/Project Medishare hospital. Decedents were compared to survivors in terms of age, sex, length of stay, admission ward, diagnosis, and where relevant, injury mechanism and surgical procedure. Three multivariate logistic regression models were constructed to determine predictors of death among all patients, injured patients, and noninjured patients. RESULTS: During the study period, 1,339 patients were admitted to the hospital with 100 inpatient deaths (7.5 percent). The highest proportion of deaths occurred among patients aged < or = 15 years. Among all patients, adult intensive care unit (ICU) admission (adjusted odds ratio [AOR] = 7.6 and 95% confidence interval [CI] = 3.4-16.8), neonatal ICU/pediatric ICU (NICU/PICU) admission (AOR = 7.8 and 95% CI = 2.7 22.9), and cardiac/respiratory diagnoses (AOR = 8.5 and 95% CI = 4.9-14.8) were significantly associated with death. Among injured patients, adult ICU admission (AOR = 7.4 and 95% CI = 1.7-33.3) and penetrating injury (AOR = 3.3 and 95% CI = 1.004-11.1) were significantly associated with death. Among noninjured patients, adult ICU admission (AOR = 6.6 and 95% CI = 2.7-16.4), NICU/PICU admission (AOR = 8.2 and 95% CI = 2.1-31.8), and cardiac/ respiratory diagnoses (AOR = 6.5 and 95% CI = 3.6-12.0) were significantly associated with death. CONCLUSIONS: Following earthquakes in resource-limited settings, survivors may require care in field hospitals for injuries or exacerbation of chronic medical conditions. Planning for sustained post-earthquake response should address these needs and include pediatric-specific preparation and long-term critical care requirements. PMID- 22235600 TI - Radiostethoscopes: an innovative solution for auscultation while wearing protective gear. AB - OBJECTIVE: To demonstrate a radiostethoscope that could be modified and successfully used while wearing protective gear to solve the problem of auscultation in a hazardous material or infectious disease setting. DESIGN: This study was a randomized, prospective, and blinded investigation. SETTING: The study was conducted at the University of Miami-Jackson Memorial Hospital Center for Patient Safety. PARTICIPANTS: Two blinded anesthesiologists using a radiostethoscope performed a total of 100 assessments (50 each) to evaluate endotracheal tube position on a human patient simulator (HPS). INTERVENTIONS: Each lung of the HPS was ventilated separately using a double lumen tube. Four ventilation patterns (ie, right lung ventilation only; left lung ventilation only; ventilation of both lungs; and an esophageal intubation or no breath sounds) were simulated. The ventilation pattern was determined randomly and participants were blinded. An Ambu-Bag was used for ventilation. An assistant moved the radiostethoscope to the right and left lung fields and then to the abdomen of the HPS while ventilating. Subjects had to identify the ventilation pattern after listening to all three locations. A third member of the research team collected responses. Each subject, who wore both types of respirator (positive and negative), performed a total of 25 trials. Participants later compared the two types of respirators and their ability to auscultate for breath sounds. RESULTS: Subjects were able to verify the correct ventilation pattern in all attempts (100 percent). CONCLUSIONS: Radiostethoscopes appear to provide a viable solution for the problem of patient auscultation while wearing protective gear. PMID- 22235601 TI - Comparative study of physiological and anatomical triage in major incidents using a new simulation model. AB - OBJECTIVES: To develop and evaluate a simulation model making it possible to evaluate the accuracy and efficiency of different triage methods; to compare the results of physiological and anatomical triage performed by medical staff with different levels of skills with the use of this model. DESIGN AND OUTCOME MEASURES: A simulation model was created based on patient cards giving sufficient physiological data as a base for physiological triage and anatomical data as description of findings at exposure, providing a base for anatomical triage. Three groups with different skills in disaster medicine, nurse students (n = 23), ambulance nurses (n = 20), and surgeons (n = 30), performed triage based on the patient cards. The outcome was given as potential avoidable mortality. The results of the triage for the two methods were compared to the result of the same triage performed by an expert group. RESULTS: Differences in triage: Within the groups, the difference between the two triage methods was only significant for the surgeons (p < 0.001), who had a better result using the anatomical triage. For the "physiological triage," there were no significant differences between the three groups. Regarding the results for the "anatomical triage," there were significant differences between both the nurse students and the surgeons (p < 0.001) and the ambulance nurses and the surgeons (p < 0.05). Results in distribution of patients and potential avoidable mortality: Within the groups, the difference between the two methods was significant for all the groups (nurse students, p < 0.01; ambulance nurses, p < 0.01; and surgeons, p < 0.001). They all had a better outcome with anatomical triage (nurse students, 6.1 percent; ambulance nurses, 6.1 percent; and surgeons 19.5 percent less mortality than physiological triage). The group that made the best outcome from physiological triage was the ambulance nurses who had a significantly better result than both nurse students (p < 0.01) and surgeons (p < 0.001). The mean mortality rate for ambulance nurses was 31.1 percent, nurse students, 37 percent, and surgeons was 38.1 percent. Regarding the anatomical triage, there was a significant difference (p < 0.001) between the groups of nurse students (30.9 percent mortality) and surgeons (18.9 percent mortality). The differences between the rest of the groups were also significant (p < 0.05). CONCLUSIONS: The model developed for this study made it possible to compare different methods of triage and also triage performed by staff of different levels of training and experience. Anatomical triage for all test groups in this study gave significantly better results than physiological triage regarding calculated outcome and this difference increased with increasing experience. PMID- 22235602 TI - Characterizing public health emergency perceptions and influential modifiers of willingness to respond among pediatric healthcare staff. AB - OBJECTIVES: The aim of this study was to characterize the public health emergency perceptions and willingness to respond (WTR) of hospital-based pediatric staff and to use these findings to propose a methodology for developing an institution specific training package to improve response willingness. METHODS: A prospective anonymous web-based survey was conducted at the Johns Hopkins Hospital, including the 180-bed Johns Hopkins Children's Center, between January and March 2009. In this survey, participants' attitudes/beliefs regarding emergency response to a pandemic influenza and a radiological dispersal device (RDD or "dirty bomb") event were assessed. RESULTS: Of the 1,620 eligible pediatric staff 246 replies (15.2 percent response rate) were received, compared with an overall staff response rate of 18.4 percent. Characteristics of respondent demographics and professions were similar to those of overall hospital staff. Self-reported WTR was greater for a pandemic influenza than for an RDD event if required (84.6 percent vs 75.1 percent), and if asked, but not required (74.4 percent vs 64.5 percent). The majority of pediatric staff were not confident in their safety at work (pandemic influenza: 51.8 percent and RDD: 76.6 percent), were far less likely to respond if personal protective equipment was unavailable (pandemic influenza: 33.5 percent and RDD: 21.6percent), and wanted furtherpre-event preparation and training (pandemic influenza: 89.6 percent and RDD: 82.6 percent). The following six distinct perceived attitudes / beliefs were identified as having institution-specific high impact on response willingness: colleague response, skill mastery, safety getting to work, safety at work, ability to perform duties, and individual response efficacy. CONCLUSIONS: Children represent a uniquely vulnerable population in public health emergencies, and pediatric hospital staff accordingly represent a vital subset of responders distinguished by specialized education, training, clinical skills, and disaster competencies. Even though the majority of pediatric hospital staff report WTR, nearly 15 percent for a pandemic influenza emergency and 25 percent for an RDD event would not respond if required. Other institutions can apply the methodology used here to identify particularly influential response willingness modifiers for pediatric care providers. These insights can inform customized preparedness training for pediatric healthcare workers, through identification of high-impact attitudes/beliefs, and training initiatives focused on addressing these modifiers. PMID- 22235603 TI - A survey on disaster management among postgraduate students in a private dental institution in India. AB - OBJECTIVE: To assess the knowledge, attitude, and behavior regarding disaster management among postgraduate (PG) students in a private dental institution in India. DESIGN: Questionnaire survey with cross-sectional design. SETTING: Sri Dharmasthala Manjunatheshwara (SDM) College of Dental Sciences and Hospital, Dharwad, Karnataka, India. PATIENTS AND PARTICIPANTS: All PG students in SDM college of Dental Sciences and Hospital, Dharwad, Karnataka, were included. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Knowledge, attitude, and behavior regarding disaster management. RESULTS: A total of 125 of 135 PG students participated (response rate of 92.59 percent) in the study. Mean knowledge, attitude, and behavior scores were 58.74, 85.78, and 31.60 percent, respectively. Significant correlations were observed between knowledge and year of study (chi2 value = 45.301, p = 0.000), and behavior and place of residence of respondents (chi2 value = 4.112, p = 0.043). CONCLUSIONS: Participants had low knowledge and behavior scores, but high attitude scores regarding disaster management. The year of study and the place of residence were associated with knowledge and behavior, respectively. This study highlights the need for curriculum changes in dental education and has policy implications for disaster management in India. PMID- 22235604 TI - Experience with the use of close-relative allograft for the management of extensive thermal injury in local national casualties during Operation Iraqi Freedom. AB - The care of host nation burn victims in Iraq and Afghanistan has been a significant challenge to US military healthcare providers. To provide burn care in an austere environment is more challenging by limitations in resources such as inadequate medical supplies, infection control issues, and a lack of blood or tissue banking capabilities. Large full thickness burns pose a significant obstacle due to limitations in the casualties' available donor skin, which can be used to achieve wound coverage. In US burn centers, allograft stored in skin banks provides temporary coverage during donor site healing in the management of large total body surface area burns. This report is a study of two severely burned Iraqi children with inadequate donor site surface area to achieve wound coverage that were managed with close-relative allograft harvested from their fathers to achieve temporary wound closure. A brief literature review and future recommendations are included. PMID- 22235605 TI - [Conflict of interest and tropical medicine]. PMID- 22235606 TI - [Thailand: resurgence of infectious diseases and epidemiologic transition]. AB - Despite progress in various facts (sanitation, education, access to health care...) that allowed a significant reduction in infectious and parasitic diseases, they persist in some poor geographical areas and populations most in need, especially in young children. An epidemiological transition (increased incidence of cancers, cardiovascular attacks...) clearly tends to replace the old public health problems, rather in urban areas and among the most advantaged social classes. Diseases (re)emerging are also serious concerns for the future: return of resistant malaria, outbreaks of severe clinic forms of dengue, explosion of VHI/TB resistant.... PMID- 22235607 TI - [Response to the cholera epidemic at Port au Prince (Haiti) in December 2010]. AB - Cholera, that had been present in rural areas north of Port-au-Prince, Haiti since October 2010, reached the urban area in November. Due to the novelty of the disease in this region, to the lack of health care, clean water, and waste disposal facilities, and to the extensive damage caused by the earthquake on January 12, 2010, that left a large victim population living in camps, a large scale health disaster was feared. However, after two months, the disease appeared to be relatively well-controlled and treated with a fatality rate of less than 1% in the urban area. Actions implemented by the Ministry of Health long with its efforts to coordinate the intervention of the many humanitarian partners played a role in this outcome. PMID- 22235608 TI - [The 4th international conference on snake bites and scorpion stings in Dakar, April 25-29, 2011]. PMID- 22235609 TI - [Temporary vascular shunt technique for resource scarce environments]. AB - The purpose of this report is to describe a simple and reproducible technique for temporary vascular shunting. This technique is appropriate only for exceptional situations involving scant resource availability. It is not intended to replace conventional vascular shunting techniques. PMID- 22235610 TI - [AIDS revealed following detection of histoplasmosis in a blood smear]. PMID- 22235611 TI - [Esophageal perforation following ingestion of a coin battery by a 5-year-old child in Djibouti]. PMID- 22235612 TI - [Georges Moustardier, physician of the Colonial Health Service and Overseas Pasteur Institutes and university professor]. AB - The purpose of this article is to provide a step-by-step description of Georges Moustardier's career. After completing studies at the Ecole Principale du Service de Sante de la Marine et des Colonies in Bordeaux, and at the Ecole d'Application du Service de Sante des Troupes Coloniales in Marseille, he was deployed to Indochina where he served as physician first at the Poulo Condor penitentiary from (1929 to 1930) and then in Cambodia from (1931 to 32). In 1933, he returned to Paris where he followed lectures on Microbiology at the Institut Pasteur, in Paris. He was then assigned to the Institut Pasteur in Madagascar from 1931 to 1932. From 1939 to 1944, he was Head of the General Hospital in Brazzaville, Congo and Director of the Medical School in French Equatorial Africa. He retired from the army in 1946. From 1949 to 1972, he held an academic position as Professor of Bacteriology at the Bordeaux School of Medicine. PMID- 22235613 TI - [Frizzy hair pathology]. AB - Frizzy hair syndrome is frequent. It is due to sideways growth and tight coiling of the hair fiber. It is often secondary to unsuitable grooming practices causing ingrown hair (pili incarnati) followed by infection and?or damage. The fragility of frizzy hair promotes alopecia due to chronic traction, use of hair relaxers, and perming. Treatment of complications is difficult so awareness of precautionary measures is important. PMID- 22235614 TI - [Epidemiological and pathological aspects of the gynecological and mammary cancers in Togo]. AB - OBJECTIVE: Gynecologic and mammary cancers occupy a prominent place in female tumor pathology. The purpose of this report is to describe aspects of these cancers in Togo. MATERIAL AND METHODS: This retrospective and descriptive study includes all gynecologic and mammary cancers diagnosed between 1987 and 2006 in the pathology laboratory of Tokoin University Hospital in Lome, Togo. RESULTS: During the study period, 882 gynecologic and mammary cancers were diagnosed. Breast cancer accounted for 440 cases (49.88%). The most common gynecologic cancer locations were the cervix in 212 cases (24.03%) and uterine corpus in 108 cases (12.25%). Mean patient age was 48.3 years overall, 48,6 years for breast cancer and 49 years for cervical cancer. In almost all cases, cancer was diagnosed at an invasive stage. CONCLUSION: Gynecologic and mammary cancers are common in Togo and most cases are diagnosed at a late stage. An epidemiological monitoring program is needed. PMID- 22235615 TI - [Pulmonary abscess: a 111-case series in Madagascar]. AB - The purpose of this report is to present a series of 111 cases of pulmonary abscess observed over a 4-year period in Madagascar. There were 75 men (67.6%) and 36 women (32.4%) with a mean age of 38 years. Alcohol and tobacco use was found in 32.2% of cases. Thirteen patients (11.7%) used chewing tobacco and all patients were exposed to passive smoking. Eighty-eight patients (79.2%) had a history of bronchopulmonary disorders. Onset was progressive in 63% of cases. The main symptoms were fever (81.9%), pulmonary condensation (74.7%) and pleurisy (9.9%). Coughing was productive in 91.8% cases including 54% of patients having muco-purulent expectorations. In 49 patients (44.1%), chest radiography showed an opacity with a hydroaeric level. The abscess was solitary in 40 cases, multiple in 9, and bilateral in 5. In-hospital antibiotherapy was performed on a presumptive basis: tritherapy in 92 patients (82.9%), bitherapy in 18 (16.2%) and monotherapy in one (0.9%). Other treatment modalities inculuded respiratory kinesitherapy in 57 cases (51.3%), surgical drainage in four (3.6%) and pneumonectomy in one (0.9%). Outcome was favorable in 93 cases (8,7%) but there were 18 deaths (16.2%). This study emphasizes the value of achieving early diagnosis, identifying supporting factors and starting appropriate treatment promptly. PMID- 22235616 TI - [Contribution of the musculocutaneous flap of pectoralis major in head and neck oncology: 26 observations in Senegal]. AB - INTRODUCTION: The pectoralis major musculocutaneous flap constitutes a significant advance in cervicofacial carcinology. At our institution, it has allowed most surgical problems to be resolved in a single-stage procedure. The objective of this study was to report our experience with this flap. PATIENTS AND METHODS: This retrospective study includes 26 cases observed over a 10-year period (January 1994-December 2003). The parameters studied were clinical and paraclinical. All patients included in this study received a pectoralis major musculocutaneous flap. Patients treated using another type of flap were not included. RESULTS: Mean patient age was 51 years (range, 20 to 74). The sex ratio was 12 (24 men and 2 women). At the time of admission, 73% of patients showed marked impairment of general condition. In 21 patients (81%), the effect of the pectoralis major musculocutaneous flap was observed immediately after surgery unlike pharyngostome (19%) in which the flap is used in a second stage procedure. With a mean follow-up of 7 years, failure has been observed in 4 cases (15%). CONCLUSION: The pectoralis major musculocutaneous flap is an excellent tool for cervicofacial reconstruction after carcinological exeresis. It reduces the duration of hospitalization. Acquiring proper flap harvesting technique is an important factor in improving outcome. PMID- 22235617 TI - [Simplified preparation of test-red blood cells for ABO blood grouping in a laboratory in Madagascar]. AB - INTRODUCTION: To ensure self-sufficiency and lower costs associated with reagent red blood cells, some medical laboratories produce their own test-red blood cells for plasma ABO blood grouping. However, given the vital importance of blood goup testing, it is essential to verify the reliability of these cells. The purpose of this study was to assess the quality of laboratory-made ABO test-red blood cells. MATERIAL AND METHODS: This study comparing house made and commercially available test-red blood cells was carried out at the Medical Biology Training and Research Laboratory in Madagascar. This laboratory is attended by people wishing to obtain their blood group card. RESULTS: In this population, no discrepancy was found between the red cell and plasma tests. Comparison of test-red blood cells with commercially available reagent red blood cells showed no difference in reactivity in the first four days of conservation. However a decrease in the reactivity of house made cells appeared on the 5th day. CONCLUSION: House made red blood cells are costless than commercially available reagent red blood cells mainly due to the simplified method of preparation. However, since laboratory-made cells progressivley lose antigenic reactivity quicly, production must be repeated regularly and good internal quality control is necessary to ensure reliability. PMID- 22235618 TI - [Prevalence and risk factors associated with infection by human immunodeficiency virus, hepatitis B virus, syphilis and bacillary pulmonary tuberculosis in prisons in Burkina Faso]. AB - This purpose of this study was to determine prevalences and risk factors associated with infection by human immunodeficiency virus, hepatitis B Virus, syphilis and bacillary pulmonary tuberculosis in prisons in Burkina Faso. From February 20 to March 20, 2009, 300 prisoners over 18 years of age held in Ouagadougou were selected to take part in this descriptive and analytical cross sectional study. Sociodemographic data, confinement information (number, motive and prison time), medical history, substance addiction (alcohol, tobacco, drug), and the other risk behaviors (sexual relations, type of partners, sharing of toiletries or razor) were compiled for each prisoner. Serological tests were performed to detect anti-HIV antibodies, Hbs antigen, and anti-treponema antibody. In prisoners presenting signs of tuberculosis, BAAR detection was performed by direct examination of sputum. Men represented 95% of the study population. Median age was of 30.1 +/- 8.9 years (range, 18 and 63). The prevalences of HIV infection, Hbs antigen and positive syphilitic serology were 5%, 27.3% and 5.7% respectively. Four prisoners (1.3%) had bacillary pulmonary tuberculosis. Two prisoners reported homosexual intercourse and 44 reported drug abuse. Sharing of toiletries and razor blades was reported by 18.7% and 20% of the prisoners respectively. Immediate measures are needed reduce the spread of these infections in prisons in Africa. PMID- 22235619 TI - [Peritoneal dialysis in a tropical area, a reality]. AB - INTRODUCTION: Chronic kidney disease is now regarded as amajor public health concern. This is especially true in developing countries where it accounts for significant morbidity, mortality and decreased life expectancy. The main problem for developing countries is the cost of dialysis. Indeed, the availability of peritoneal dialysis for renal replacement therapy is low in sub-Saharan Africa. Since March 2004 peritoneal dialysis has been available to some patients with end stage renal disease in Senegal. The purpose of this study was to assess epidemiologic, clinical, technical patterns and outcomes in patients who underwent peritoneal dialysis in the first three years of the program. MATERIALS AND METHODS: This three-year retropective study identified 26 patients who underwent peritoneal dialysis for end-stage renal disease for a period of at least 15 days. Patients not meeting these criteria were not included. All patients had a Baxter type transfer set. Lactate-bicarbonate solution was used for countinuous ambulatory peritoneal dialysis. In 3 cases, Icodextrin- and amino acid based-solutions were employed. In automated peritoneal dialysis, the Home Choice machine was used for all patients. Epidemiological, clinical/paraclinical data and outcomes were noted for each patient. RESULTS: Twenty-six patients were included in the study. Median age was 48 +/- 6 years with a M/F sex ratio of 1.17. Most patients (84%) were literate. Diabetic nephropathy and nephroangiosclerosis were the main causes of end-stage renal disease. The mean Charlson score was 3 (range, 2 to 5). Mean residual diuresis was 435 mL/day. The peritonitis rate was 1 per 20 patient months. Staphylococcus aureus and Pseudomonas aeruginosa were the most common germs. Six patients presented catheter infection: exit-site in 4 and tunnel in 2. Catheter obstruction occurred in three cases. At the end of the study, 6 patients were still in automated peritoneal dialysis and 8 in countinuous ambulatory peritoneal dialysis. Six 6 patients died and 6 were switched to hemodialysis. CONCLUSION: Peritoneal dialysis is available as a renal replacement therapy in Senegal. It has allowed end-stage renal disease patients greater autonomy in their working place. PMID- 22235620 TI - [Knowledge, attitudes and practices about prevention of mother to child transmission of HIV (PMTCT) among pregnant women in antenatal clinic at 2010 in Togo]. AB - PURPOSE: The purpose of this study carried out among pregnant women in antenatal clinics in Togo was to evaluate knowledge, attitudes and practices related to prevention of mother-to-child transmission of HIV (PMTCT). METHODS: A qualitative cross-sectional study was conducted in 22 antenatal clinics. Data were collected by interviewing all pregnant women examined from January 18th to February 4th, 2010. RESULTS: A consecutive series of 210 pregnant women was compiled. The women identified sexual relations (93.8%), objects soiled with blood (80.5%) and transmission from mother to child (27.1%) as routes of HIV transmission. A large majority (77.1%) agreed that unprotected sexual relations raised the risk of HIV transmission to the child and most (61%) expressed willingness to use condoms during pregnancy or breastfeeding, A high percentage (68.1%) believed that contamination during pregnancy increased the risk of HIV transmission to the child, and 61% knew that the risk of HIV transmission to the child was higher for mixed breastfeeding than for exclusive breastfeeding. The acceptance rate for HIV testing was 92.4%. The percentage of women who never used condoms (male or female) was 51% and the percentage considering that HIV-positive woman should not have children was 29.5%. CONCLUSION: The results of this study indicate that pregnant women in Togo have fairly good knowledge about HIV/AIDS. Attitudes towards PMTCT were generally positive but some behaviors such as condom use still require improvement. PMID- 22235621 TI - [Histoid leprosy in Morocco: retrospective study of 18 cases]. AB - INTRODUCTION: Histoid leprosy is a special and rare anatomoclinical form of multibacillary leprosy. Most of the few large series describing this entity In literature have been reported from India. The purpose of this study was to analyze the epidemiological, clinical and therapeutic characteristics of patients with histoid leprosy in Morocco. MATERIAL AND METHODS: This retrospective study was conducted at the National Centre of Leprology (CNL) in Casablanca from January 1991 to December 2006. Only histologially confirmed cases of histoid leprosy were included. Epidemiological, clinical, histological and therapeutic characteristics were compiled from records and analyzed using EPI-Info version 6. RESULTS: Confirmed histoid leprosy accounted for 18 of the new cases of leprosy recorded at CNL recorded during the 16-year study period. There were 13 men and 5 women with a mean age of 35.2 years. Family exposure was noted in 9 patients (50%) including two who had more than two relatives with leprosy. Nodules/subcutaneous nodules were the most common morphological pattern (88.8%). Neurological involvement was found in 10 patients. Seven patients had grade 1 deformities. Slit skin smears from histoid lesions revealed abundant bacilli with a high bacteriological index ranging from 3 + to 5 + according to the Ridley index. All patients received antibiotic treatment according to the Moroccan protocol. Outcome was favorable in all patients. Six patients (33.3%) developed erythema nodosum leprosum during the course of disease. With a average follow-up of 9 years, no recurrence has been observed. DISCUSSION: Because of its multibacillary character and despite its rarity, histoid leprosy poses a challenge to the leprosy eradication in Morocco. Like other forms of multibacillary leprosy, histoid leprosy requires early detection and prompt multidrug therapy. These requirments should be made a priority in the national program against leprosy. PMID- 22235622 TI - [Ultrasound and epidemiological features of ectopic pregnancy in a suburb of Abidjan (Cote d'Ivoire)]. AB - OBJECTIVE: The aim of our study was to describe current ultrasound and epidemiological features of ectopic pregnancy in Abidjan, Cote d'Ivoire. PATIENTS AND METHODS: This prospective study was carried out over a 24-month period (February 2006 to January 2008) at Nangle Medical Clinic, i.e., a private clinic located in Abidjan's Yopougon suburb. RESULTS: A total of 32 cases of ectopic pregnancy were discovered by suprapubic and/or endovaginal ultrasound scan. The estimated frequency of ectopic pregnancy was 1.7%. Mean patient age was 26.2 years. The main risk factors were prior history of abortion (32%) and adnexal infection (20%). Most patients (52.5%) were nulliparous. The most frequent indication for ultrasound scan was metrorrhagia. Diagnosis of ectopic pregnancy was made at the ruptured stage in 65.6% of cases and nonruptured stage in 34.4%. The presenting lesions was hematosalpinx in 40.6% of cases and embryonate ectopic gestational sac in 31.3%. Salpingectomy and salpingorrhaphy were successful in 65.6% and 34.4% of cases respectivlely. CONCLUSION: In Abidjan, ectopic pregnancy involves young nulliparous women with a prior history of abortion and adnexal infection. Ultrasound allowed early diagnosis and, consequently, tube preservation in 34.4% of cases. PMID- 22235623 TI - [Epidemiological, clinical and ultrasonographic aspects of right-sided infective endocarditis in Senegal: 6 cases]. AB - Right-sided infective endocarditis accounts for 5 to 10% of endocarditic involvement and usually affects the tricuspid valve. The purpose of this report is to describe epidemiological, clinical and echocardiographical aspects of 6 cases of right-sided infective endocarditis observed in the Cardiology Department of Aristide Le Dantec Hospital in Dakar, Senegal from December 2007 to February 2010. Diagnosis was based on Duke's modified criteria. There were 3 men and 3 women with a mean age of 28.2 years (range: 20 and 43). Five of the 6 patients presented tricuspid endocarditis including one case associated with pulmonary endocarditis. In another case, pulmonary endocarditis was associated with aortic endocarditis. Infective endocarditis was acute in three cases and primary in four. One case of infective endocarditis was observed in a tetralogy of Fallot. Fever was present in 4 cases with an mean temperature of 38.4 degrees C (range, 37.2 to 40 degrees C) and heart failure was present in 5 cases. In 2 patients, blood cultures were positive for Staphylococcus aureus. All patients had leucocytosis with a neutrophilic predominance. Doppler echocardiography depicted vegetations in all cases. Contributing factors included congenital heart disease in 1 case, insertion of a venous catheter in 2 and dental infection in 2. No patient was addicted to intravenous drugs or infected by HIV. Outcomes included one in-hospital death with signs of refractory heart failure. Right-sided endocarditis is often primary and is dominated by the tricuspid involvement. It affects both sexes. Contributing factors include venous catheterization during the postpartum period and dental infection. Prevention requires strict asepsis during venous catheter insertion, treatment of dental infections and improved management of congenital heart disease. PMID- 22235624 TI - [Study of treatment adherence by patients living with HIV in 2009 at the outpatient care and treatment center of Brazzaville, Congo]. AB - OBJECTIVES: The purpose of this study was to evaluate treatment adherence and its determinants in patients living with HIV followed up at the outpatient care and treatment center in Brazzaville, Congo. METHODS: This cross-sectional study included patients who attended the center from July to October 2009. Adherence was evaluated using a self-administered questionnaire, 5 distinct measurement tools, and global adherence index. Correlations between patient characteristics and adherence data were analyzed. RESULTS: A total of 214 patients were enrolled in the study. Mean patient age was 42 years. The female-to-male ratio was 2. There were 6 children. Most patients (92.5%) were receiving a first-line antiretroviral regimen; it consisted of a combination of zidovudine, lamivudine and nevirapine in 53.3% of cases. Adherence was estimated at 55.4-86.9% depending on the measurement tool. The global adherence index was significantly higher in patients who achieved their pre-defined life project (OR 4.33, p = 0.04) and in those who spoke lingala (OR 3.99, p = 0.01). After 6 months of antiretroviral therapy, mean weight gain was 4.8 kg; mean increase in CD4 was 104/mm3 (262 versus 158); and viral load was undetectable in 89.4% of patients. CONCLUSION: This study in Brazzaville (Congo) confirms that antiretroviral treatment adherence is satisfactory in sub-Saharan Africa. Adherence was mainly correlated with structural factors, e.g. language and life project, and with the patient friendliness of the regime. Most patients had favourable responses based on clinical, immunological, and virological criteria. PMID- 22235625 TI - [Descriptive study of cerebrovascular accidents in Douala, Cameroon]. AB - A cerebrovascular accident or stroke is a sudden-onset cerebral deficit of vascular origin lasting more than 24 hours. These events represent the second leading cause of death in the world and take a particularly heavy toll in third world countries. The purpose of this study was to describe cerebrovascular lesions (type, location, size) as well as patient age and gender in Cameroon. Brain CT-scan and MRI findings from 50 stroke patients admitted to two health centers in Douala were reviewed. Data showed that 74% of patients were over 50 years of age, the 51-60 year group being the most affected. Patients were male in 64% of cases. Ischemic stroke accounted for 60% of cases versus 40% for hemorrhagic stroke. The most affected sites were the sylvian territory site in ischemic stroke and the temporal lobe in hemorrhagic stroke, acconting for 43.3% and 35% of cases respectively. The median size of ischemic and hemorrhagic lesions were 2.81 cm3, and 26.98 cm3 respectively. Hemorrhagic stroke and lacunar infarcts were more common in this sample. Discrepancies between results at the two hospitals may be due to the use of different imaging techniques. Indeed, MRI is known to be more sensitive than CT-scan for acute detection of stroke lesions. PMID- 22235626 TI - [Pyonephrosis: 44 cases in Senegal]. AB - PURPOSE: To report epidemiological, clinical and paraclinical features of pyonephrosis and describe current management methods in Senegal. PATIENTS AND METHODS: This retrospective study includes a series of patients admitted for pyonephrosis to the Urology Department of the Aristide Le Dantec Hospital in Dakar between 1995 and 2009. The following information was collected for each patient: age, sex, clinical manifestations, diagnostic findings, treatment modalities and outcomes. RESULTS: A total of 44 patients with a mean age of 34 years were included. The most common clinical manifestations were acute flank pain, sepsis and renal mass. Diagnostic was usually based on medical imaging, i.e., renal utrasonography and computed tomography. Urolithiasis was the underlying etiology in 73.2% of cases. Nephrectomy was performed in 83% of cases with or without preliminary nephrostomy catheterization. CONCLUSION: Development of both diagnostic (medical imaging) and therapeutic methods for management of pyonephrosis has been consistent with the rarity of this condtion in Senegal. PMID- 22235627 TI - [Abdominal actinomycosis mimicking an abdominal tumor. Case report in Senegal]. AB - The purpose of this report is to describe a case of abdominal actinomycosis (Actinomyces israelii) with a pseudo-tumoral appearance in a 57-year-old Senegalese woman. PMID- 22235628 TI - [Parasitic infection causing appendicitis]. AB - Retrospective analysis of the medical records of patients who underwent acute appendectomy in the Gastrointestinal Surgery Department of the Desgenettes Military Hospital in Lyon, France from the 1st of November 2009 to the 21th of February 2011, turned up two cases of appendicular parasitosis for a prevalence of 3.3%. Both patients presented acute appendicular oxyuriasis caused by Enterobius vermicularis that was discovered inadvertently after appendectomy. This unexpected diagnosis raises questions about the exact role of parasites in the physiopathology of appendicitis. Though appendicitis is the most common surgical emergency in France, appendix vermicularis is rare. In comparison, developing countries and particularly endemic areas such as sub-Saharan Africa show considerably higher appendicular parasitosis prevalence rates and greater variety in the parasites involved. The purpose of this article is to describe the different parasites with potential to affect the appendix, to discuss the different pathophysiological mechanisms underlying acute appendicitis, and to recall the need for medical treatment after appendectomy. PMID- 22235629 TI - [Rare cause of heart failure in an elderly woman in Djibouti: left ventricular non compaction]. AB - The purpose of this report is to describe the first case of left ventricular non compaction diagnosed in Djibouti. The patient was a 74-year-old Djiboutian woman with symptomatic heart failure. Echocardiography is the key tool for assessment of left ventricular non compaction. This rare cardiomyopathy is probably underdiagnosed in Africa. PMID- 22235630 TI - [Acceptability of implementation of mutual health in a Senegalese rural area]. AB - Funding for healthcare poses a major problem in developing countries. The purpose of this study was to assess public perceptions toward the implementation of mutual healthcare coverage in rural Senegal. METHODS: A descriptive transversal study was conducted from 24/09/07 to 05/10/07 in a randomly selected sample of 208 heads of households living in the rural communities of Ngogom and Refane. Data were collected by means of individual interviews and focus group discussions. Topics included population health, community solidarity, health insurance and implementation of mutual healthcare insurance. RESULTS: The sample population was 94% male, 91% married, 36% uneducated and 11% unemployed. Household income was irregular in 36% and 84% had no savings. In case of medical emergency, 43% relied on family for assistance, 36% had no recourse and 21% would have to contract, a loan. Nearly half the sample population, i.e., 46%, were familiar with the principle of mutual healthcare insurance and 98% wanted to join. The main reasons for wanting to join were to reduce medical costs (57%), improve access to care (25%) and build community solidarity (11%). In focus groups, people expressed the need for micro health insurance. Findings also showed good community dynamics and a tradition of pooling resources to implement collective activities. CONCLUSION: The public perception of mutual healthcare insurance is favorable. However, due to economic difficulties, support from political and health authorities will be needed. PMID- 22235631 TI - [Scarification in children hospitalized in Congo]. AB - OBJECTIVE: The purpose of this report is to describe the epidemiologic, prognostic and clinic features of scarification in children in Congo. MATERIAL AND METHOD: A transversal study of scarification was conducted from January 1, 2006 to December 31, 2008 in children hospitalized in neonatology and pediatrics department of Loandjili General Hospital. RESULTS: During the study period, therapeutic scarifications were observed in 130 patients including 74 (56.9%) girls. Median age was 17 months (range, 1 month to 9 years). Multiple scarifications were observed in 31.5% of cases. The main site of scarification was the hypochondrias (82.4%) followed by the flanks (14.6%) and hemithorax (13.8%). Scarification was performed for curative purposes in 114 cases (88%; p 0.001) and prophylaxis in the remaining cases. The main indications for curative scarifications were big belly in 46 cases, ponderal stagnation in 23 and recurrent bronchitis in 22. The most frequently used scarification instrument was a razor blade in 102 cases (78.5%). Risk factors included being the oldest sibling child and low socioeconomic level. In all cases, the influence of the grandparents was clear. Complications were treated in 34 cases including local infection in 26 cases, distant infection (particularly severe sepsis) in 7 cases and pulmonary-pleurostaphylococci in one case. CONCLUSION: These findings show that scarification is still common in the Congo. Because of potential complications and therapeutic inefficiency of scarification, an effort should be made to eliminate this practice. PMID- 22235632 TI - [Lung cancer in Dakar, Senegal]. AB - A prospective, multicenter was conducted in all specialized centers in the city of Dakar. The objective was to describe the epidemiology to assess the management of lung cancer. 45 patients were included. The sex ratio M/F = 8. The average age of patients was 57.5 years. Smoking was found in 84.4% of cases. The average time for consultation after the onset of symptoms was 6 months. The average time to diagnosis was 2 months. Two out of three patients (66%) had seen beyond the stage III B. Improved diagnostic performance for early diagnosis of cancer is needed. Emphasis should be on prevention through tobacco control. PMID- 22235633 TI - [Factors justifying the choice of labor epidural analgesia by nulliparous women: experience at a maternity center in Antananarivo, Madagascar]. AB - Epidural analgesia is the most effective method for pain relief during labor. This 10-year exploratory descriptive study on factors underlying women's decisions to request or refuse labor epidural analgesia (LEA) was carried out at a level III maternity hospital in Antananarivo, Madagascar. All patients underwent a pre-anesthesia check-up (PAC) between 32 and 34 weeks of amenorrhea. During the PAC, a questionnaire was administered to determine socio-economic aspects, level of education, and knowledge about labor pain and LEA. In addition, LEA was proposed and patients were asked to explain their reasons for accepting or refusing the procedure. The purpose of this report was to describe the factors underlying acceptance or refusal of EA by nulliparous women. A total of 41 nulliparous women were included. Fourteen (34.14%) accepted LEA and 27 (63.86%) refused. Mean age was 27 years in the acceptance group and 25 years in the refusal group. No patient had good knowledge about LEA. Nulliparous women that accepted EA had a higher socio-economic level, expected stronger labor pain, were better informed about EA, and expressed greater confidence in medical care. In addition to economic aspects, the main reasons for refusing EA involved fear and family background. PMID- 22235634 TI - [Seroprevalence of HBV and HCV in blood donors at the Blood Transfusion Center of Mohammed V Military Teaching Hospital in Rabat Morocco]. AB - The purpose of this report is to present the findings of a retrospective study (2008-2009) to determine the seroprevalence of hepatitis B and C virus in blood donors at the Blood Transfusion Center of Military Teaching Hospital Mohammed V in Rabat, Morocco. Samples from 19,801 consecutive blood donors were analyzed by the immuno-enzymatic method (Enzyme Linked Immunosorbent Assay, third generation). The overall seroprevalence of HBV and HCV was 0.8% and 0.2% respectively. A total of 98 units were rejected because of elevated alanine transaminase. No case of co-infection was found. From 1991 to 2010, HBV and HCV seropositivity showed a significant declining trend. In spite of the low prevalence observed, this study confirms that the risk of transfusion transmitted infection exists and thus underlines the need to implement preventive strategies to improve blood transfusion safety. PMID- 22235635 TI - [Reasons for consultation in a dermatology/venereology department in 2009 in Cotonou, Benin]. AB - The purpose of this retrospective study was to determine the reasons for consultation in a Dermatology Venereology Department in Cotonou, Benin. A total of 1,070 new patients were included. The main reason for consultation was immunoallergic dermatosis. PMID- 22235636 TI - [Trachoma rapid assessment in the infantile population of Togo]. AB - AIM: The aim of this study was to determine the prevalence and types of trachoma in children of central Togo. MATERIALS AND METHODS: This descriptive cross sectional investigation was conducted in central Togo in November 2009. At every peripheral health unit (PHU) in 2 villages of the sanitary district, 15 schoolchildren between 6 and 9 years old and 35 children from the community between 1 and 5 years old were examined to detect signs of trachoma using a lamp wipes coupled with binocular magnifying loupes (2.5X). Data were analysed with Excel 2007. RESULTS: A total of 8200 children were examined at 82 PHU in 164 villages in the sanitary districts. In the 1-5 year age group including 5,740 children, follicular trachomatous inflammation (TF) was observed in 326 cases and intense trachomatous inflammation (TI) in 9 for a prevalence rate of 5.83%. In the 6-9 year age group including 2,460 schoolchildren, TF was observed in 144 and TI in 8 for a prevalence rate of 6.18%. The overall prevalence rate of active trachoma was 5.94 % (n = 487). CONCLUSION: This study confirms the persistence of active trachoma in children in central Togo. Trachoma may be public health problem in 2 districts: Blitta and Sotouboua. A population-based survey will be carried our to evaluate trachoma prevalence prior to implementation of the SAFE strategy in this region. PMID- 22235637 TI - [Serological study of leptospirosis in equids, camelids and bovids from Djibouti]. AB - Sera obtained from 31 domestic and feral animals in Djibouti were assayed for leptospiral antibodies using the microscopic agglutination test. Antibodies were detected in 26 samples (84%), corresponding to 116 positive reactions. The most common antigen serogroups were Icterohaemorrhagiae and Australis. The highest titre was recorded for serovar Munchen (1:1280) in sera from Somalian wild asses and goats. This study shows a broad dispersion and high prevalence of the different Leptospira serogroups tested. High biodiversity has been previously reported in tropical countries and is thought to be linked to the wide range of reservoir mammals. Additional study will be needed to identify the reservoirs of the different serogroups in this part of Africa. PMID- 22235638 TI - [Cervicofacial cellulitis in Ouagadougou, Burkina Faso: report of 26 cases]. AB - Cervicofacial cellulitis is still observed in Burkina Faso and can be severe. The aim of this study was to review diagnostic and therapeutic challenges associated with management of cericofacial cellulitis in our region where medical facilities are poor. A retrospective study of patients treated between January 1999 and December 2008 was performed. A total of 26 cases of cervicofacial cellulites were compiled. All patients underwent broad spectrum antibiotherapy associated imidazols. Surgical treatment was performed in 60% of the cases. Early diagnosis and treatment is essential for favorable outcome. PMID- 22235639 TI - [Symptoms of the compression of median nerve in patients after fractures of the distal radius treated operatively]. AB - As distal end of the radius is anatomically localised close to the carpal tunnel, fractures of this part of the bone is fairly commonly associated with symptoms typical for median nerve compression. The objective of the study was to assess frequency of the occurrence of these symptoms in patients after operative treatment of the fractures of the distal radius, and, additionally to evaluate the validity and specificity of the Levine questionnaire in the detection of symptoms of median nerve compression. PATIENTS AND METHODS: In 101 patients, at a mean of 9 weeks after surgery for fracture of the distal radius, the following variables were assessed: 1) pain intensity in visual analogue scale as well as 2) complaints and functional impairment of the hand typical for carpal tunnel syndrome with the Levine questionnaire. RESULTS: Pain intensity in the affected hand averaged 2.8 points in 0-10 scale, the Levine symptom score amounted a mean of 2.1 (range 1.0-3.7) and the Levine function score amounted a mean of 2.1 (range 1.0-5.0). Nine patients had score at least 3 in both symptom and function sub-scales of the Levine form, suggesting carpal tunnel syndrome. However, at the assessment at a mean of 15 months thereafter, none of these patients were treated for carpal tunnel syndrome, although, five of them still suffered from similar symptoms. The results of this study show transient character of compressions symptoms on the median nerve In patients after fractures of the distal radius, and, moreover, suggest poor validity and specificity of the Levine questionnaire as the diagnostic tool in suspicion of carpal tunnel syndrome associated with other diseases and injuries of the hand. PMID- 22235640 TI - [Association of anthropometric factors and predisposition to carpal tunnel syndrome]. AB - BACKGROUND: An observation of patients suffering from carpal tunnel syndrome shows distinct overweight, short stature and relatively thick hands in majority of them. Objective of this study was evaluation of the relationship of anthropometric and anatomical factors related to the hand with incidence of the syndrome. PATIENTS AND METHODS: The anthropometric measurements of body weight and height, as well as anatomical of wrist girth, hand length and volume were performed in 105 patients, 84 women (80%) and 21 men (20%), aged a mean of 59 years, with idiopathic carpal tunnel syndrome. The same examinations were made in a control group consisting of 105 healthy individuals, age and gender matched. RESULTS: Statistically significant differences (t-Student or U Mann-Whitney test, p < 0,05) were noted in all considered variables: patients with carpal tunnel syndrome were heavier (of a mean of 6%), shorter (of 1,5%) and had of a mean of 9% greater body mass index. They had also statistically significantly greater hand volume (of 13%), hand length (of 2%) and wrist girth (of 5%). Although all variables were statistically significantly greater in a study group, the clinically meaningful were considered only differences of hand volume, wrist girth, body weight and body mass index. CONCLUSION: Individuals with overweight and with thicker than average hands and wrists are more predisposed to carpal tunnel syndrome. PMID- 22235641 TI - [Porous tantalum modular cups in revision hip arthroplasty]. AB - INTRODUCTION: Modem indications for use of cemented or uncemented implants in revision hip arthroplasty are comparable. The use of bone cement provides predictable short term results, but the lack of osteointegration deteriorates its long term durability. Uncemented implants undergo osteointegration, but reduced contact with host bone may cause early loosening. Modular porous tantalum implants are highly osteointegrative, and the availability of bone stock augments increases the versatility of this system. MATERIAL AND METHODS: The study group consisted of 20 patients (21 hips) who underwent a revision hip arthroplasty using Trabecular Metal acetabular revision system. The follow-up period was between 7 and 31 months (average 20 months). All patients were evaluated with HHS and conventional radiography. RESULTS: The mean HHS increased form40.45 (range 18.74-56.65) preoperatively to 78.8 (56.5-96) at the last follow-up. No mechanical failures, nor septic complications were noted. PMID- 22235642 TI - [Synovial chondromatosis and tuberculosis of the hip coexistence]. AB - This article describes a rare case of primary synovial chondromatosis of the hip associated with active tuberculosis of the hip. Twenty four years old patient underwent total hip replacement at our institution. No reactivation of the infection was detected in the four-years follow-up. Clinical and radiological evaluation of our material showed that joint space widening may be the first sign in synovial chondromatosis of the hip. Importantly, if the tuberculosis infection is suspected we have to take the material for bacteriological investigation, regardless of others, obvious diagnosis. PMID- 22235643 TI - [Two-stage revision procedure for septic complicated endoprosthesis of the hip]. AB - Total hip arthroplasty is commonly used way for treatment of degenerative changes of a hip joint. Continuous progress of medicine enables use of more and more modern implants, that are supposed to provide to patients comfortable and painless motility. Nevertheless, with increasing number of implanted endoprostheses, rising numer of loosened impants is observed. Proper laboratory dignostics and postoperative proceedings as well as systematic follow up with standard X-ray scans allow for early recognition of loosened prostheses and implementation of surgical procedure. In the article two-stage method for treatment of septic loosened primary total hip arthroplasties applied in CMKP Orthopedic Clinic in Otwock, Poland as well as results of treatment of selected cases are presented. PMID- 22235644 TI - [Tibio-talo-calcaneal arthrodesis by retrograde intramedullary nail--a case report]. AB - We described a case of 64 year old overweight women, who was treated with revision tibio-talo-calcaneal artrodesis with the use of retrograde intramedullary nail. The procedure was performed after failed primary arthrodesis with the use of lateral approach and fibula osteotomy. Stabilization with intramedullary nail gave good clinical and functional result with a good bone healing. PMID- 22235645 TI - [Septic complications after multilocal fractures and multiple traumatic injury]. AB - INTRODUCTION: The increase of the number of the multiple traumatic injuries is related to social factors, such as: the development of industry, the change of life style and the conditions of work, the manner and the speed of relocation and the biological factors related with the elongation of life time. According to the World Health Organization data the injuries are one of the main health problems in the world. AIM: The clinical analysis of multitrauma patients treated due to the septic complications of the fractures. MATERIAL AND METHODS: The material consists of 34 multitrauma patients treated in The Osteomyelitis and Septic Complications Unit in Prof. A. Gruca Orthopedic and Trauma Hospital in Otwock, Poland between 2005 and 2010. The cause of trauma, the timing of arrival to our unit, the number of the days of treatment, the number and the specificity of bone and internal injuries, the bacteriology of bone infections and operative techniques and pharmacologic treatment were analyzed. RESULTS: The causes of the injuries were: road accident (79%), fall from the height (8.8%), others (12.2%). The first stay in our unit was 21 months after the injury on average (1-129 months), the number of stays in the unit was 2,8 on average (1-6), the length of stay was 25.7 days on average (4-108 days). In analyzed group of 34 patients, we found: 12 opened fractures of single bone, 11 opened fractures of more than one bone, 22 closed fractures of single bone, 12 closed fracture of more than one bone. Central nervous system (55.9%), abdominal organs (35.3%) and thorax (29.4%) were the most common internal organs ocuppied with the injury. Osteomyelitis was the most frequently diagnosed in femur (50%) and tibia (41.2%). The main reasons of bone infection were: Methycylin-Sensitive Staphylococcus Aureus (35,3%), Methycylin-Resistant Staphylococcus Aureus (17,3%), Pseudomonas aeruginosa (23,5%), Escherichia coli, Acinetobacter baumani, Enterococcus faecalis. The following treatment was undertaken: the debridement of septic bone, usually together with the removal of the hardware stabilization (73,5%), the removal of the damaged or improperly fixed stabilization (44%), the conversion of the internal fixation into the external fixation(62%). All the patients were taken intravenous antibiotics according to The Hospital Commission for Preventing of Infections, i.e. 2nd generation cephalosporin and gentamycin. Culture directed antibiotics were started after receiving the bacteriology results. The outcomes. The control of infection in 14 patients (41.3%), 18 patients (52.9%) still remain under the treatment, bad outcome (persistent infection, amputation of a extremity) we had in 2 patients. CONCLUSIONS: Multiple traumatic injury and its immunologic consequences predispose to systemic infections including bone infections. Posttraumatic osteomyelitis is the indication to chronic treatment. Surgical management of the wound and external fixation of the fractures of the long bones according to the control damage surgery is the most important in prevention of posttraumatic osteomyelitis. PMID- 22235646 TI - [Anxiety level and its determinants in rheumatoid arthritis patients]. AB - Rheumatoid arthritis (RA) is a chronic disease with many somatic, psychological and social consequences. Somatic consequences are connected mainly with increasing levels of negative emotions such as depression, anxiety and a tendency to react with anger to many daily life situations. Additionally, loss of hope has been reported as another effect of rheumatoid arthritis. The goal of the study was to describe anxiety levels and its determinants in RA patients. The study was carried out on 31 RA patients, 22 (71%) of whom were females and 9 (29%) of whom were males. The respondents were assessed with a set of questionnaires such as Spielberger's State-Trait Anxiety Inventory (STAI), Multidimensional Health Locus of Control Scale (MHLC), The Coping Inventory for Stressful Situations (CISS) and Eysenck's Personality Questionnaire - Revised (EPQ-R). We have found the relationship between anxiety as (1) a state and external locus of control - powerful others (tau-b = 0.23, p = 0.09), task - oriented style of coping (tau-b = -0.34, p = 0.01), emotion-oriented style of coping (tau-b = 0.33, p = 0.02) and neuroticism levels (tau-b = 0.29, p = 0.03) and (2) anxiety as a trait and external locus of control - powerful others (tau-b = 0.40, p = 0.01), task - oriented style of coping (tau-b = 0.36, p = 0.01), emotion-oriented style of coping (tau-b = 0.33, p = 0.02) and neuroticism levels (tau-b = 0.47, p = 0,01). PMID- 22235647 TI - [Place of bisphosphonates in the primary andsecondary prophylaxis of osteoporotic fractures: the role of parenteral therapy--proposal to modify the standards of treatment]. AB - Oral bisphosphonates are currently known as medicines of a first choice in the treatment of osteoporosis and in preventing age-related fractures. However, despite their advantages, these medicines are not free of limitations. The most significant one is a complicated way of tablet administration, requiring from patients to remain upright position and to take a tablet before a meal. This may make the administration of other, chronic medicines, such as thyroid hormones, more difficult. Complications of the therapy include dyspepsia and gastrointestinal disorders. Approximately 48% of individuals taking bisphosphonates once a week resign from therapy within one year from the beginning of the treatment. There is a group of individuals who cannot take bisphosphonates orally at all. The alternative here is an intravenous injection. Therefore, there is a need for modifications of the existing therapeutic standards for osteoporosis. It is also necessary to emphasise the significance of intravenous medicines in the treatment of this disease. PMID- 22235648 TI - [Suffering pain in segment lumbar spine and occurrence of weak links of biokinematics chain in kayakers and rowers]. AB - INTRODUCTION: Spine pain is a serious clinical problem of physically active people and sportplayers . The pain may have different nature, related to different segments of the spine. Its intensity and frequency may impair the functionality of man. Most back pain is connected with the lumbo-sacral and cervical part of a spine. MAIN AIM: The hypothesis was: 1) That there were not any weak links of biokinematics chain. 2) Pain feeling in young players in the lumbar spine (LBP). The aim of this study was to determine in which direction and location the most weak links would occur in biokinematics chain and whether it was correlated with gender. In addition, it was examined whether a correlation between the weak links' presence in the lumbar spine and the occurrence of LBP existed and if it was connected with gender of the player. MATERIALS AND METHODS: This study involved 40 players from Walcz School Sports Championships, including the twenty kayakers (8 women and 12 men), 13 canoeists and 7 rowers. The average age of players was 16.00 +/- 0.99, mean of training years was 4.92 +/- 2.20. Low threshold Performance Matrix tests were used for assessing the presence of weak links. Through analysis and identification of performed movement the weakest links in the biokinetics chain were found. Numeric scale was used for the evaluation of lumbar pain (LBP). The results were statistically analyzed. RESULTS: The main characteristics of statistical and graphical presentations were performed for the received values of weak links. The hypothesis of variances equality was verified, and all the hypotheses mentioned above were also verified using ANOVA analysis of variations and Tukey test for low threshold of weak links. CONCLUSION: 1) The presence of weak links of biokinematics chain was found in all players especially in the lumbar spine, the presence is not associated with gender. Most weak links in the lumbar part occurred in the direction of rotation. 2) There is a correlation of the weak links of the lumbar spine and LBP, but it is not connected with gender. 3) The relationship between pain suffering in the lumbar spine (LBP) and the number of weak links of biokinematics chain was defined. PMID- 22235649 TI - [The influence of copy number polymorphism on the human phenotype]. AB - The variability of human populations in a large part is determined by two complementary factors: environment and genetic information. Genetic variation is caused by different genetic variants (polymorphisms and mutations) present in the human genome. Until recently it was thought that most of these variants are small changes of one or several nucleotides (SNPs) which in their millions are present in the human genome. However, it was recently shown that there are also polymorphisms that extend over hundreds of thousands of DNA base pairs in the human genome. Such alternations called copy number variation (CNV) often include genes and other functional genetic elements. In this article we present the general characteristics of copy number polymorphism and we discuss some examples of CNVs that influence human phenotypes. PMID- 22235650 TI - [The role of piRNA and Piwi proteins in regulation of germline development]. AB - A new group of small noncoding RNAs of 24-30 nucleotides in length, piRNAs, are mainly expressed in germline cells. They form complexes with Piwi proteins, members of the Argonaute family and unlike other small RNAs they are created without RNase Dicer participation. They are present in male and female germinal cells of numerous animals, from flies to humans. The piRNA biogenesis mechanism is unknown, however, it is postulated that they are formed from long single stranded RNA precursors coded by repetitive sequences occurring in the genome. A large part of piRNA corresponds to retrotranspozon sequences, which may indicate their participation in silencing the mobile elements and maintaining genome integrity of germinal cells. However, disruption of the piRNA biosynthesis pathway and mutations genes encoding Piwi proteins cause the activation of transpozons and a number of defects in the course of gametogenesis, resulting in reproduction disturbance. In this review, the current state of knowledge on the structure, biogenesis and function of piRNA and their interactions with Piwi proteins is presented. PMID- 22235651 TI - [Disturbances of alternative splicing in cancer]. AB - Splicing of pre-mRNA is one of the post-transcriptional modifications in which introns are removed from primary transcript and exons are joined. pre-mRNA splicing reactions are catalyzed by dynamic complex called spliceosome. Exons can be joined on different manners in a process known as alternative splicing, that provide production of multiple mRNA and protein isoforms from relatively low number of genes. Alternative splicing is regulated by cis elements localized within exons or introns and trans-acting factors including spliceosome components and members of the SR and hnRNP protein family that exert antagonistic effects on splicing. Aberrant pre-mRNA splicing may be caused by mutations in cis elements and altered expression of splicing factors. This review describes disturbances in splicing of genes controlling proliferation and metastasis that can lead to tumoral transformation. Also, potential applications of abnormally spliced transcripts that may potentially serve as diagnostic biomarkers of cancer or targets in anticancer therapy are discussed. PMID- 22235652 TI - [The structure of cellular vaults, their role in the normal cell and in the multidrug resistance of cancer]. AB - The cellular vaults have been described for the first time in 1986 as ribonucleoprotein complexes composed of three proteins, MVP, TEP1 and vPARP and several vRNA strains. Biochemical and structural studies revealed their ubiquitous existence in the cytoplasm of many eukaryotic cells and their barrel like structure indicating their engagement in the intracellular transport. Furthermore, the high homology between MVP and LRP which was already known to be involved in multidrug resistance mechanism opened a discussion about the role of vaults in both normal and cancer cells. The histopathology research demonstrated an increased amount of MVP/LRP proteins in the cancer as well as showed translocation possibility between cytoplasm and nuclear envelope, which can be of crucial point in the prevention of nucleus against anticancer drugs. PMID- 22235653 TI - [Cytosolic protein quality control system--the role of molecular chaperones in the biology of neurodegenerative diseases]. AB - In this article we describe the role of molecular chaperones and cellular proteases in the cytosolic protein quality control system that controls and regulates in all living organisms folding status of proteins and their proper function. Thanks to cooperative action of molecular chaperones and proteases the acumulation of misfolded proteins in the cytosol is limited. In particular, the links between chaperones to protein degradation and the role of molecular chaperones in the biology of neurodegnerative diseases are discussed. PMID- 22235654 TI - [Molecular pathogenesis of hereditary motor and sensory neuropathy]. AB - Charcot-Marie-Tooth disease 2 is an inherited axonal motor and sensory neuropathy. It is very heterogenous, both clinically and genetically. Till present, 15 types of CMT2, 14 loci and 13 genes are known to be causative of CMT2. Studying mechanisms of molecular pathogenesis is very important for finding a therapy for patients but the diversity of proteins involved in pathogenesis makes this very difficult. Proteins involved in molecular pathogenesis are e.g. proteins of the mitochondrial outer membrane with opposite functions (mitofusin 2 and GDAP1) responsible for fusion and fission of the mitochondrial network. Mutations also occur in genes encoding tRNA-synthetases, neuronal cytoskeletal protein, cation channel protein and molecular chaperones. This review presents knowledge of CMT2 and possible pathogenetic mechanisms responsible for the disease. PMID- 22235655 TI - [The role of ectonucleotides metabolizing enzymes in purinergic signaling]. AB - Purinergic signaling plays an important role in the regulation of many physiological processes. The concentration of nucleotides in extracellular space is controlled by at least two families of nucleotidases: NPPases and NTPDases. These families are examples of convergent evolution of proteins. Above ezymes are not phylogenetically related, but they catalyze the same type of reaction. They hydrolyzed tri- and diphosphonucleosides to monophosphonucleosides and orthophosphate or pyrophosphate. This degradation terminates the nucleotide signaling process and also produces other signaling molecules like ADP, and with 5'-nucleotidase, adenosine. Most of known animal NPPases and NTPDases were found as membranous ectoenzymes or soluble proteins localized in tissue fluids. The aim of this work is to provide information about localization, structure, properties and function of NPPases and NTPDases in the regulation of extracellular concentration of nucleotides and purinergic signaling. PMID- 22235656 TI - [2-Oxoglutarate dehydrogenase complex and its multipoint control]. AB - Enzymes control the course of biochemical reactions. The enzymes involved in bioenergetic processes play most important role in cell metabolism. One of them is 2-oxoglutarate dehydrogenase complex (OGDHC), the key regulatory enzyme of Krebs cycle. Krebs cycle integrates basic metabolic pathways of carbohydrates, fatty acids and amino acids during catabolic as well as anabolic reactions. Due to the key position of OGDHC in mitochondrial metabolism, its activity is controlled by many factors. Allosteric regulation by positive effectors (ADP, Pi, Ca2+, Mn2+) of the complex is very important. These effectors strongly enhances affinity of the first component of OGDHC to 2-oxoglutarate. Moreover there are negative effectors (ATP, NADH, succinyl-CoA) which affect all three enzymes of the complex. Regulation of biosynthesis of individual components of the complex by activation or inactivation of genes expression is very important for proper OGDHC activity too. Activity of OGDHC also depends on posttranslational modifications of its components. All of this control processes maintain OGDHC activity on adequate level and prevent the complex against its excessive action. PMID- 22235657 TI - [Mechanisms of bile acid biosynthesis regulation--autoregulation by bile acids]. AB - Bile acids play significant role in body homeostasis regulation. They are products of cholesterol catabolism and ligands for some nuclear receptors regulating crucial metabolic pathways. The main enzyme regulating bile acids biosynthesis is CYP7A1 (7alpha-cholesterol hydroxylase). Its activity is controlled mainly at the transcription level and the key transcription factor is FXR. It is activated by other nuclear receptors like SHP, HNF-4alpha or LRH-1 and bile acids themselves, and represses CYP7A1 gene. The other transcription factors that inhibit CYP7A1 activity, are PXR, VDR, PPARalpha. The main activator is LXR (in rodents), increasing CYP7A1 transcriptional activity. CYP7A1 activity increases in presence of insulin and glucocorticoids. It is also regulated by diurnal rhythm. Some of those factors influence the activities of other bile acids biosynthesis enzymes--CYP7B1, CYP27A1, CYP8B1. Because of bile acids significant function in body metabolism this article presents the newest knowledge on mechanisms of key enzymes activities control. PMID- 22235658 TI - [The ABC transporters of Saccharomyces cerevisiae]. AB - The ABC transporters (ATP Binding Cassette) compose one of the bigest protein family with the great medical, industrial and economical impact. They are found in all organism from bacteria to man. ABC proteins are responsible for resistance of microorganism to antibiotics and fungicides and multidrug resistance of cancer cells. Mutations in ABC transporters genes cause seriuos deseases like cystic fibrosis, adrenoleucodystrophy or ataxia. Transport catalized by ABC proteins is charged with energy from the ATP hydrolysis. The ABC superfamily contains transporters, canals, receptors. Analysis of the Saccharomyces cerevisiae genome allowed to distinguish 30 potential ABC proteins which are classified into 6 subfamilies. The structural and functional similarity of the yeast and human ABC proteins allowes to use the S. cerevisiae as a model organism for ABC transporters characterisation. In this work the present state of knowleadge on yeast S. cerevisiae ABC proteins was summarised. PMID- 22235659 TI - Are ACOs the magic bullet? PMID- 22235660 TI - This is our rainy day! PMID- 22235661 TI - Let's not throw out the good with the bad. PMID- 22235662 TI - Physician leadership. Introduction. PMID- 22235663 TI - Physicians leading change: towards what end? PMID- 22235664 TI - In sickness and in health: physicians as captains of the ship. PMID- 22235665 TI - About leadership. PMID- 22235666 TI - The physician leadership imperative: new opportunities for physician leaders due to health care reform. AB - During times of change there can be danger, but also opportunity. Such is the case now for physician leaders. Physicians are needed in numerous leadership positions as the healthcare system is reformed, and new roles for physicians emerge on a regular basis. If physicians want to succeed, they will need to learn new skills and acquire more knowledge. They may even want to obtain an advanced degree in order to maximize their effectiveness. Carpe diem! PMID- 22235667 TI - The Physicians Foundation: inspiring physician leadership in organizations & at the bedside. PMID- 22235668 TI - Physicians versus hospitals as leaders of accountable care organizations. PMID- 22235669 TI - Transformations. PMID- 22235670 TI - [A review of WHO Laboratory Manual for the Examination and Processing of Human Semen (5th edition)]. AB - This paper presents a review of the contribution, revision and defects of the 5th edition of WHO Laboratory Manual for the Examination and Processing of Human Semen published in 2010. The pity is that the book lacks the data from China. The normal spermatozoon morphology as 4% seems incredible and hard to be applied in practice. The reference values provided by WHO are important records of past findings, but do not hold good for all time. The Manual cannot be looked upon as a "Bible" but a new starting point. It is an inescapable responsibility of Chinese andrologists to establish a set of criteria for human semen analysis specifically applicable to Chinese males. PMID- 22235671 TI - [Transrectal ultrasound-guided systematic 12-core biopsy of the prostate improves prostate cancer detection]. AB - OBJECTIVE: To evaluate transrectal ultrasound-guided systematic 12-core biopsy of the prostate for the detection and characterization of prostate cancer in different age and prostate specific antigen (PSA) groups. METHODS: Totally 210 patients were divided into four age groups (< or = 59 yr, 60-69 yr, 70-79 yr, and > or = 80 yr) and five PSA groups (0-4 microg/L, 4.1-10 microg/L, 10.1 -20 microg/L, 20.1-50 microg/L, and > 50 microg/L), and underwent transrectal ultrasound-guided systematic 12-core biopsy of the prostate at various sites for detecting prostate cancer. Clinical data and the results of various biopsy schemes were analyzed and compared. RESULTS: Ninety-one cases of prostate cancer were detected among the 210 patients, with a total detection rate of 43.3%, and the percentage was higher with the increase of age and PSA level. Larger and higher-grade tumors were associated with older age and higher PSA level, and higher detection rates were related to laterally directed and apical biopsies. The 12-core biopsy outperformed other biopsy schemes in detecting prostate cancer in patients under 60 years of age and with PSA < 20 microg/L. CONCLUSION: The 12 core biopsy scheme can make up for the inadequacy of sextant biopsy in detecting prostate cancer, and less influenced by the age and PSA level of the patients. Generally larger and higher-grade tumors are associated with older age and higher PSA level. PMID- 22235672 TI - [Ureaplasma urealyticum infection affects sperm plasma membrane integrity in infertile men]. AB - OBJECTIVE: To determine the impact of Ureaplasma urealyticum (Uu) infection on the integrity of sperm plasma membrane in infertile males. METHODS: Sixty-three semen samples were divided into a Uu infection group (n = 32) and a normal control group (n = 31). Conventional semen analyses were performed by computer assisted semen analysis (CASA) and Uu detected by the culture method. The semen samples were washed with PBS and dyed by SYBR-14/PI double fluorescent staining, followed by detection of the integrity of sperm plasma membrane by flow cytometry. The percentage of the sperm with intact plasma membrane was indicated as the percentage of sperm emitting green fluorescence (SYBR-14+/PI-%). RESULTS: The Uu infection group showed a significantly decreased integrity of sperm plasma membrane ([45.14 +/- 10.69]%) and reduced percentage of grade a + b sperm ([23.29 +/- 8.81]%) as compared with the normal control group ([72.68 +/- 9.91]% and [46.32 +/- 9.54]%) (P < 0.01). But there were no significant differences in the semen volume, pH value, and sperm concentration between the two groups (P > 0.05). CONCLUSION: Uu infection decreases the integrity of sperm plasma membrane, which might be an important factor of male infertility. PMID- 22235673 TI - [Multivariate analysis of dyspareunia in women]. AB - OBJECTIVE: Dyspareunia is a common sexual trouble in women during the sexual intercourse. This study is to investigate the risk factors for dyspareunia in urban Chinese women and to supply some evidence for its preventive measures. METHODS: We conducted a hospital-based survey by distributing 2 658 copies of a questionnaire among the women in Nanjing urban area who came for regular physical examination in Nanjing Maternity and Child Health Hospital and their female companions aged over 20 years. The sexual function of the subjects was evaluated according to female sexual function indexes, dyspareunia indicated by sexual pain score < 4.4, and the results analyzed by multiple logistic regression analysis. RESULTS: Totally, 1 856 (69.8%) of the subjects completed the questionnaire, and 1 457 that met the criteria were included for analysis, of whom 43.0% (626/1457) admitted to dyspareunia during the sexual intercourse. Multiple logistic regression analysis showed that age (> or = 50 years) , smoking, hysterectomy, vaginal lubrication disorder, lack of sexual communication with partners were independent risk factors for dyspareunia (P < 0.05). CONCLUSION: Dyspareunia is associated with multiple factors including age (> or = 50 years), smoking, hysterectomy, vaginal lubrication disorder, lack of sexual communication with partners. PMID- 22235674 TI - [Preparation and identification of recombinant human neutrophil elastase]. AB - OBJECTIVE: To prepare a purified recombinant human neutrophil elastase (HNE) using genetic engineering technology, and pave the way for the preparation of the antibody to HNE and establishment of semen HNE detection methods. METHODS: HNE mRNA was obtained from human peripheral blood granulocytes with specific HNE primers, and the cDNA of HNE was cloned into the plasmid pGEX-2T to derive a recombinant plasmid pGEX-2T/HNE. After PCR identification, double-enzyme digestion and gene sequencing, the recombinant plasmid was transferred into competent Escherichia coli DH5alpha and further induced to express the recombinant fusion protein GST/HNE by isopropyl beta-D-thiosulfate galactosidase (IPTG). The recombinant fusion protein was cleaved by thrombin and further purified with glutathione agarose beads to obtain purified recombinant HNE. RESULTS: The recombinant plasmid pGEX-2T/HNE was successfully prepared and transferred into E. coli DH5o; the expression of the recombinant fusion protein GST/ HNE was successfully induced by IPTG at 18 degrees C overnight; and the purified recombinant protein HNE was successfully obtained by thrombin cleavage and purification of glutathione agarose beads. CONCLUSION: The acquirement of purified recombinant HNE has prepared the ground for the preparation of the antibody to HNE and establishment of semen HNE detection methods. PMID- 22235675 TI - [Sperm chromatin integrity test for predicting the outcomes of IVF and ICSI]. AB - OBJECTIVE: To explore the predictive value of sperm chromatin integrity test (SCIT) in assisted reproductive technology (ART) by analyzing the relationship of sperm chromatin integrity (SCI) with the outcomes of IVF-ET and ICSI. METHODS: Sperm chromatin structure assay (SCSA) was performed to test SCI in 187 ART cycles, and the results were expressed as DNA fragmentation index (DFI). According to the level of DFI, the 187 cycles were allocated to a high DFI group (DFI > or = 30% ) and a low DFI group (DFI < 30%), each of which was again divided into an IVF and an ICSI subgroup. Comparisons were made between the IVF and ICSI subgroups of the high and low DFI groups in the fertilization rate, cleavage rate, embryo quality, and clinical pregnancy rate. RESULTS: The clinical pregnancy rate of ICSI was significantly higher than that of IVF in the high DFI group, while the clinical outcomes showed no significant differences between the high and low DFI groups in either the IVF or the ICSI subgroup. CONCLUSION: Sperm DNA damage affects the outcome of ART, and therefore SCIT can be used as a supplementary option to standard semen analysis in choosing the method for ART. PMID- 22235676 TI - [Appropriate prolongation of GnRH-a down-regulation improves the synchronism of follicular development]. AB - OBJECTIVE: To determine the relatively appropriate actuation time for ovarian super-stimulation of IVF-ET by comparing the influences of different down regulation days of chorionic gonadotrophin releasing hormone agonist (GnRH-a) upon the follicular diameter, endometrial thickness and the levels of follicle- stimulating hormone (FSH) , luteinizing hormone (LH) and estradiol (E2). METHODS: We adopted the long protocol of GnRH-a down-regulation in the midluteal phase for 42 patients undergoing IVF-ET. According to the time of GnRH-a down-regulation, we divided the patients into a 10 d, a 15 d and an 18 d group, measured their follicular diameters and endometrial thickness by B-mode ultrasonography, detected the levels of FSH, LH and E2 in the blood, and analyzed the influences of different days of GnRH-a down-regulation on the follicular diameter, endometrial thickness and sexual hormone levels. At 1, 7, 10 and 14 d of down regulation, we compared the levels of FSH and LH in the blood before the injection of GnRH-a with those 2 and 3 h after it. RESULTS: At 10, 15 and 18 d after down-regulation, the ovarian follicles with the diameter of 3-4 mm accounted for 16.8, 7.09 and 10.38% (P < 0.05, 10 d vs 15 d and 18 d), those with the diameter of 4.5-7.0 mm made up 80.24, 89.55 and 84.62% (P < 0.05, 15 d vs 10 d and 18 d), and those with the diameter of 7.5-10 mm constituted 2.96, 3.36 and 5%, respectively. Endometrial thickness was (7.73 +/- 2.48) mm in the 10 d group, significantly thicker than (5.41 +/- 0.79) mm and (5.24 +/- 0.85) mm in the 15 d and 18 d groups (P < 0.05). The FSH levels in the 10 d, 15 d and 18 d groups were (3.70 +/- 1.10), (3.51 +/- 0.72) and (3.47 +/- 0.61) mIU/ml, the LH levels were (1.23 +/- 1.00), (1.09 +/- 0.47) and (1.22 +/- 0.72) mIU/ml, and the E2 levels were 41.84 +/- 36.81, 32.84 +/- 14.32 and 9.50 +/- 8.23, respectively, with no significant differences among the three groups. At 1, 7, 10 and 14 d of down regulation, both FSH and LH levels in the blood were increased at 2 and 3 h after GnRH-a injection, most significantly at 1 d (1.87 +/- 1.49 vs 13.33 +/- 7.81 for FSH, 1.06 +/- 1.13 vs 47.40 +/- 29.97 for LH, (P < 0.05). CONCLUSION: In the long protocol of ovarian super-stimulation of IVF-ET, endometrial thickness and the levels of FSH, LH and E2 tended to be stable at 10 d of GnRH-a down-regulation. The percentage of the follicles with the diameter of 4.5-7.0 mm was higher at 15 d than at 10 d, but rose no more at 18 d except for an increased number of smaller follicles 3-4 mm in diameter. Therefore, appropriate prolongation of GnRH a down-regulation can improve the synchronism of follicular development. PMID- 22235677 TI - [Efficacy and safety of vardenafil in the treatment of erectile dysfunction: a report of 700 cases]. AB - OBJECTIVE: To evaluate the efficacy and safety of long-term on-demand use of vardenafil in the treatment of erectile dysfunction (ED). METHODS: We conducted a questionnaire investigation among 891 ED patients treated by on-demand use of oral vardenafil at 20 mg every 3 days from March 2007 to January 2010, covering the general information of the patients, their need for and attitudes towards the treatment, clinical efficacy and adverse events of the drug, and satisfaction of the patients and their partners after 12 weeks of treatment. RESULTS: Treatment and follow-up were completed in 700 patients, of whom 504 (72%) achieved sufficient hardness and duration of penile erection and overall sexual satisfaction, 84 (12%) admitted to improvement of erectile hardness and duration but not adequate satisfaction, and the other 112 (16%) experienced no significant changes. Significant differences were found in IIEF-5 scores, Rigiscan test results and partners TSS scores before and after the treatment (P < 0.05). Most frequent adverse events included flushing (15%), dizziness and headache (10%), dyspepsia (3%), and nasal congestion (1%). CONCLUSION: Long-term on-demand use of oral vardenafil, in addition to its safety and good tolerance, can effectively improve the erectile function of ED patients, their success rate of sexual intercourse, and overall quality of sexual life. PMID- 22235678 TI - [Causes, location and management of BPH surgery-related urethral stricture]. AB - OBJECTIVE: To analyze the possible causes of BPH surgery-related urethral stricture and summarize the experience in its clinical management. METHODS: The clinical data of 37 cases of BPH surgery-related urethral stricture were analyzed retrospectively. The patients averaged 68.5 years in age, of whom 12 had the history of open surgery, and 25 transurethral surgery. Anterior urethral stricture was found in 6 cases, and posterior urethra in stricture 31. Thirty five cases were treated by holmium laser urethrotomy (HLU) or a combination of HLU with transurethral resection of the scar in the stenotic segment, and the results were evaluated based on the maximum flow rate (Qmax). RESULTS: Two cases of full penile urethral stricture were treated by urinary diversion, and all the rest by urethral stricture surgery. Catheters were indwelt in 4 cases of urethral stenosis for 5-7 days post-operatively, and smooth urination was achieved after their removal, with a Qmax of > 15 ml/s. Another 31 cases of membranous urethral stricture received catheter indwelling of 2 -4 weeks and were followed up for 1 - 21 (mean 11. 5) months, of whom 23 experienced satisfactory voiding, with an average Qmax of 14.3 ml/s, and the other 8 poor voiding, with a Qmax of < 8 ml/s. CONCLUSION: HLU or a combination of HLU with transurethral resection of the scar in the stenotic segment is an effective method for the treatment of BPH surgery related urethral stricture. And conscientiously performed BPH surgery can reduce the incidence of urethral stricture. PMID- 22235679 TI - [Single-port laparoscopic ligation with suture silk for varicocele: a report of 20 cases]. AB - OBJECTIVE: To evaluate the clinical effect of single-port laparoscopic ligation (SPLL) with suture silk for the management of varicocele. METHODS: We analyzed the clinical effects of SPLL with suture silk in the treatment of 20 cases of varicocele, and compared them with those of conventional three-port laparoscopic ligation (TPLL) for another 24 varicocele patients. RESULTS: All the operations were successful. The operation time was 20-35 (mean 28) minutes and the hospital stay was 2 days for SPLL, as compared with 15-28 (mean 20) minutes and 3 days for TPLL. The cure rate was 75% for the former, and 67% for the latter, with no signification difference between the two groups (P > 0.05). CONCLUSION: SPLL with suture silk for the treatment of varicocele has more advantages over TPLL for minimal invasiveness, faster recovery, and less scarring and extraneous residual. PMID- 22235680 TI - [Correlation of bilateral testicular volume discrepancy with semen parameters in men with varicocele]. AB - OBJECTIVE: To investigate the influence of varicocele on the volume discrepancy of bilateral testes, and the relationship between testicular volume discrepancy and semen parameters. METHODS: This study included 181 varicocele patients and 102 normal fertile men without varicocele. We retrospectively analyzed their clinical data, including the grades and locations of varicocele, testis volume and semen parameters. RESULTS: Bilateral testicular volume discrepancy was found in 132 (72.9%) of the varicocele patients (including 117 cases of left testicular hypotrophy [88.6%]), and 35 (34.3%) of the non-varicocele fertile men. The rates of bilateral testicular volume discrepancy were 61.3%, 3.5%, 20.9% and 14.3% in the grade-III, grade-II, grade-I and non-varicocele groups, respectively (P < 0.05), with statistically significant differences among different age groups (P < 0.05). The percentage of morphologically normal sperm and sperm motility were reduced differently with different degrees of testicular volume discrepancy (P <0.05). CONCLUSION: Testicular volume discrepancy is more common in men with left varicocele, and its prevalence and degree are correlated with the grade of varicocele. Semen quality decreases with the increase of testicular volume discrepancy. PMID- 22235681 TI - [Inflammatory myofibroblastic tumor of the prostate: a case report and review of the literature]. AB - OBJECTIVE: To discuss the diagnosis and treatment of inflammatory myofibroblastic tumor (IMT) of the prostate. METHODS: We retrospectively analyzed the clinical data of a case of IMT of the prostate and reviewed relevant literature. The patient was a 62-year-old man, who was twice referred to the local hospital for recurrence of dysuria. He was diagnosed as with benign prostatic hyperplasia (BPH) and twice underwent transurethral resection of the prostate (TURP). But frequent recurrence of dysuria followed postoperatively, for which he came to our hospital and received another TURP and transurethral resection of the bladder tumor (TURBT). Pathological findings showed chronic inflammation of the bladder, papillary hyperplasia with mild dysplasia in regional urothelial and IMT of the prostate. Six months later, the patient came again to our hospital for recurrence of dysuria. Computed tomography revealed a large mass in the bladder. RESULTS: The patient underwent laparoscopic bladder radical resection and ileal conduit diversion, simultaneously with pelvic lymph node dissection. The pathological examination confirmed it to be an IMT of the prostate with the bladder but not regional lymph nodes involved. An 11-month follow-up showed neither local recurrence nor distant metastasis. CONCLUSION: IMT of the prostate is a rare borderline lesion, whose diagnosis is very difficult and mainly depends on pathological findings. IMT of the prostate is liable to recur and even invade the bladder. Radical resection is recommended for patients with large and recurrent tumors, and close follow-up is strongly warranted. PMID- 22235682 TI - [A meta-analysis of holmium laser enucleation of the prostate for benign prostatic hyperplasia]. AB - OBJECTIVE: To evaluate the effectiveness and safety of holmium laser enucleation of the prostate (HoLEP) and transurethral resection of the prostate (TURP)/open prostatectomy (OP) in the treatment of bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH). METHODS: We searched Medline, Cochrane Library, Embase, Wanfang and CBM for randomized controlled trials (RCT) comparing HoLEP with TURP/OP. Comparable data were extracted from eligible studies and pooled for meta-analysis using RevMan5.1. RESULTS: Nine RCTs were included in this study, 6 comparing HoLEP with TURP, and the other 3 comparing HoLEP with OP. Meta-analysis showed that, compared with TURP, HoLEP was associated with shorter hospital stay and catheterization time, less hemoglobin loss, longer operative time, and better improvement in international prostate symptom score (IPSS) , peak urinary flow rate (Qmax) and post void residual (PVR) , but the incidences of postoperative urethral stricture and urinary incontinence had no statistically significant difference between the two. Compared with OP, HoLEP showed shorter hospital stay and catheterization time, a lower rate of blood transfusion, longer operative time, and removal of fewer tissues, but the two procedures exhibited no significant differences in either the improvement of IPSS and Qmax or the incidence of urethral stricture. CONCLUSION: HoLEP is a minimally invasive technique, safe and highly effective for the treatment of BOO secondary to BPH, with its advantages of lower peri-operative morbidity and faster recovery over TURP and OP. However, more high-quality RCTs with larger sample sizes and longer follow-ups need to be carried out to obtain better evidence. PMID- 22235683 TI - [Impact of hypertension on female sexual function]. AB - Female sexual dysfunction (FSD) is an age-related progressive disease and may affect up to half of adult women, but it has failed to receive due attention for a long time. Hypertension is a common and frequently encountered disease, and female sexual dysfunction is closely related to hypertension and antihypertensive drugs. Hypertension-related atherosclerosis, endothelial disorder and antihypertensive drugs are important risk factors for female sexual function. This article reviews the mechanisms of hypertension-induced FSD and advances in their studies. PMID- 22235684 TI - [Single nucleotide polymorphisms of the genes related with spermatogenesis impairment]. AB - Male infertility is a complex disease affecting the reproduction of childbearing couples, for which genetic polymorphism of spermatogenesis genes is an important genetic pathogenic factor. Lots of genes closely related with spermatogenesis have been successfully identified through the gene knockout technology. Spermatogenesis impairment related genes include those associated with expression enzymes, receptors, cell apoptosis, transcription regulation, and so on. The genetic susceptibility of these genes, infection, and environment jointly contribute to non-obstructive azoospermia and oligozoospermia in males. The analysis of the single nucleotide polymorphism (SNP) of spermatogenesis impairment related genes helps explain the possible mechanism of pathogenesis at the molecular level, and provides theoretical evidence for the clinical diagnosis and treatment of male infertility. The article focuses on the correlation of the SNPs of spermatogenesis impairment related genes with azoospermia and oligozoospermia. PMID- 22235685 TI - [Failed fertilization after ICSI: causes and countermeasures]. AB - As a new technique for IVF, ICSI has a high rate of monospermy but cannot prevent all fertilization failures, of which the possible causes are poor oocytes or sperm, abnormal oocyte activation, and ICSI technical problems. Controlled ovarian hyperstimulation during IVF could increase the apoptosis of oocytes and subsequently induce fertilization failure. There are several methods for artificial activation in case of oocyte activation failure. Sperm-induced fertilization failure is mostly due to minute malformation of sperm, for which morphologically selective ICSI is generally employed. However, totally failed fertilization after ICSI remains a real challenge. PMID- 22235686 TI - [Qilin pills for oligoasthenospermia: a multi-centered clinical trial]. AB - OBJECTIVE: To observe the efficacy of Qilin Pills in the treatment of oligoasthenospermia. METHODS: We conducted a multi-centered open controlled clinical trial by including 220 oligoasthenospermia patients in a trial group and another 110 as controls. The patients in the trial group were treated with Qilin Pills at the dose of 6 g tid, and the controls given Wuziyanzong Pills at 6 g bid, both for a course of 12 weeks. Then we evaluated the clinical effects of Qilin Pills with sperm concentration, the numbers of grade a and grade a + b sperm, and sperm motility as the primary, and the pregnancy rate of the patients'spouses as the secondary therapeutic indexes. RESULTS: A total of 310 patients accomplished the clinical trial, 208 in the trial and 102 in the control group. Compared with the baseline, significant improvement was observed in the semen parameters after 4, 8 and 12 weeks of treatment in both the trial and control groups except sperm density and the number of grade a sperm in the control after 4 weeks (P < 0.01), and the improvement was even more significant in all the semen parameters at the same time points in the trial than in the control group (P < 0.01). CONCLUSION: Qilin Pills can evidently improve the seminal quality of oligoasthenospermia patients with no obvious adverse events. PMID- 22235687 TI - [Psychological factors involved in erectile dysfunction]. AB - Erectile dysfunction (ED) is a major sexual dysfunction involving both physiological and psychological factors. While the primary physiological cause of ED is associated with endocellular degeneration and disorders of neural reflex, its psychological causes are mainly hyposexuality, anxiety and depression. Increasing importance is being attached to the psychological aspects in the diagnosis and management of ED in recent years, and the evaluation questionnaires aimed at the psychosocial significance in ED patients' conditions and psychological interventions solo or combined with drugs have inspired many researches for an optimal solution of the disease. Improvement of the patient's erectile performance is no longer the only outcome we pursue. Instead, the satisfaction of both the patient and his partner has a rising weight in the final evaluation of a therapy. The wide application of PED5 inhibitors and their psychological effect on ED patients makes it necessary for us gain a deeper insight into the combination of psychological intervention and drug therapy in the management of ED. PMID- 22235688 TI - The realist adjusts the sails: a commitment to transform nursing education models. PMID- 22235689 TI - Extending our understanding of cultural competence in nursing education. PMID- 22235690 TI - Betsy. PMID- 22235691 TI - Methodological quality and scientific impact of quantitative nursing education research over 18 months. AB - The methodological quality of nursing education research has not been rigorously studied. The purpose of this study was to evaluate the methodological quality and scientific impact of nursing education research reports. The methodological quality of 133 quantitative nursing education research articles published between July 2006 and December 2007 was evaluated using the Medical Education Research Study Quality Instrument (MERSQI).The mean (+/- SD) MERSQI score was 9.8 +/- 2.2. It correlated (p < .05) with several scientific impact indicators: citation counts from Scopus (r = .223), Google Scholar (r = .224), and journal impact factor (r = .216); it was not associated with Web of Science citation count, funding, or h Index. The similarities between this study's MERSQI ratings for nursing literature and those reported for the medical literature, coupled with the association with citation counts, suggest that the MERSQI is an appropriate instrument to evaluate the quality of nursing education research. PMID- 22235692 TI - Helping students who struggle academically: finding the right level of involvement and living with our judgments. AB - This article addresses findings from a three-year study that examined how teachers help and hinder students who struggle academically. Thirty nurse educators from 18 schools of nursing shared stories of how they helped and hindered their academically at-risk students. Hermeneutical analysis revealed several themes. This article addresses the pattern of Presencing and two themes: Finding the Right Level of Involvement and Living with Our Judgments. PMID- 22235693 TI - An innovative, multidisciplinary strategy to improve retention of nursing students from disadvantaged backgrounds. AB - Nursing students from disadvantaged backgrounds must overcome many barriers in order to succeed. This article will focus on how a multidisciplinary team helped 76 percent of these high-risk students persist in their nursing programs by addressing some of these barriers. Three baccalaureate nursing schools in the Texas Medical Center embarked on a three-year retention program designed to enhance the success of students identified by federal criteria as being at risk. Multidisciplinary teams led various activities, including a study skills component, which included preparing for lectures, taking notes, critical thinking, and test-taking strategies. Also addressed were written and oral communication skills, medical terminology, critical thinking, career coaching, and socialization activities. Collaboration among faculty and students at the three schools was key to the success of the program. PMID- 22235694 TI - Exploring nursing students' level of preparedness for disaster response. AB - This descriptive study explores students' perceptions of personal and program preparedness for disasters. Participants in this online survey included 1,348 nursing students from every state plus Guam, Puerto Rico, and theVirgin Islands. The study explored three questions: a) the level of preparedness, including learning about different types of disasters, preparing disaster plans, creating disaster kits, and participating in community disaster response efforts; b) the impact of disasters on nursing students; and c) strategies to assist nursing students during disasters. Results indicated that nursing students throughout the country are generally not well prepared for disasters. Nurse educators need to develop strategies to prepare their students for disasters. The American Red Cross provides templates for organizations, including colleges and universities, to prepare their campuses for emergencies. Faculty need to collaborate with staff and students to develop and implement plans appropriate for their programs. PMID- 22235695 TI - NCLEX-RN pass rate peril: one school's journey through curriculum revision, standardized testing, and attitudinal change. AB - Processes used by a university to reverse the downward spiral of NCLEX-RN pass rates are described. Reasons for poor pass rates were found to be multifaceted and included gaps in curriculum content, student attitudes toward taking the licensure exam, delays in taking the exam following graduation, inadequate student preparation for taking standardized exams, and inappropriate and ineffective exit examinations. Various strategies for reversing the trend of the NCLEX failure rate included: addressing areas of weakness in the curriculum; revising courses; engaging students; changing standardized exit exams; employing a midcurricular and other standardized exams; and implementing remedial courses for poor performance on standardized exams. Change was effected and pass rates on the NCLEX-RN improved dramatically. Future possibilities and proactive measure are described. PMID- 22235696 TI - A conceptual model to support curriculum review, revision, and design in an associate degree nursing program. AB - In light of declining NCLEX-RN first-write pass rates and the National League for Nursing call to transform nursing education, faculty at an associate degree nursing program in the southeastern United States began the process of intensive critique of its curriculum and program outcomes. Based on in-depth analysis and assessment of program outcomes, a conceptual framework was created to guide curriculum revision, development, and implementation processes. The framework serves as a guide for ongoing and systematic curriculum review and revision based upon evaluation findings. The basis of the conceptual framework was the result of an extensive literature review and an incorporation of the faculty-created philosophy. PMID- 22235697 TI - The experiences of faculty teaching in an innovative clinical immersion nursing curriculum. AB - A lack of research exists regarding the impact of substantive curriculum reform on faculty teaching and attitudes. This report of an interpretive phenomenological study of one group of baccalaureate nursing faculty undergoing implementation of an innovative curriculum revealed that the curricular structure and program philosophy offered multiple new challenges. These included the integration of multiple concurrent learning activities, expansion of simulation, and a renewed focus on student assessment. The study design used Heideggerian hermeneutics, a reflexive approach to text analysis of interviews of seven full time faculty who had worked in the school's traditional curriculum prior to the implementation of the clinical immersion model. The research offers insights into faculty adaptation to curriculum change and its effect on teaching and instruction. The results of this study may assist other schools contemplating or in the process of similar overarching program reforms. PMID- 22235698 TI - Service-learning in nursing education: its impact on leadership and social justice. AB - Although studies suggest that service-learning is positive for students, findings reported are primarily qualitative. A convenience sample of 306 senior-level nursing students completed the Service-Learning Self-Evaluation Tool (SLSET) pre- and post-service-learning experience over a six-year span. The constructs measured were leadership skills and social justice. Paired t-tests were calculated. Statistically significant differences were noted between pre- and post-service-learning experience, with students rating themselves higher on leadership and social justice items after the experience. Cronbach's alpha for leadership and social justice were greater than 0.80. Service-learning as an educational methodology that combines community service with academic learning objectives is a viable strategy for facilitating leadership skills and increased awareness of social justice issues in nursing students. PMID- 22235700 TI - A tribute to Steve P. Jobs. PMID- 22235699 TI - The effect of type of learning environment on perceived learning among graduate nursing students. AB - A quasi-experimental study was conducted to examine the effect of type of learning environment (Internet only, compressed video remote-site, and compressed video host-site) on perceived learning among graduate nursing students. A convenience sample of 49 students enrolled in a graduate nursing research course was selected for the study. The findings showed no differences in perceived learning and final course grades among students enrolled in the three sections of the research course. While the effects of type of learning environment, feelings of connectedness, learner-learner, and learner-system interactions on perceived learning were not statistically significant, learner-instructor interactions had a significant effect on perceived learning. The study findings are encouraging in that students felt that they learned the course content and these perceptions were the same regardless of type of learning environment. The findings also suggest that the quality of instruction is more of an influence on learning than type of teaching modality. PMID- 22235701 TI - Nursing students and end-of-life care: a play. PMID- 22235702 TI - An experience of excellence in nursing education. PMID- 22235703 TI - Retaining the art of medicine. PMID- 22235704 TI - Teaching the art of medicine: a changing portrait in today's medical schools. PMID- 22235705 TI - Coronary artery bypass grafting (CABG) in patients with immune thrombocytopenia (ITP): a community hospital experience and review of the literature. AB - We reviewed the records of 51 patients with Immune Thrombocytopenia (ITP) who underwent Coronary Artery Bypass Grafting (CABG) at Charleston Area Medical Center between June 1992 and September 2005. There were 41 males and 10 females with a median age of 68 years (range 49-87). Four patients had a previous splenectomy, one of whom had it performed concomitantly with the CABG. Three patients were on chronic corticosteroids on admission. The median pump time was 114 minutes (range: 42-244 minutes). The median cross-clamp time was 62 minutes (range 22-192 minutes). The median total chest tube drainage postoperatively was 1,346 cc (range: 265-9875cc). The mean preoperative and 24 hour postoperative platelet count was 126,000 (range 58,000-323,000) and 99,000/mm3 (range: 27,000 194,000), respectively. Twenty-one (40%) patients received platelet transfusions. Platelets were given intraoperatively or postoperatively in all but two of those patients. The median number of units of platelets given was 10 (range: 6-52). Twenty-seven (53%) received packed red cells intraoperatively or postoperatively. The median number of red cells given was 2 (range: 1-34). Other hemostatic agents given intraoperatively/ postoperatively included aprotinin (8 patients), aminocaproic acid (10 patients), DDAVP (5 patients), and intravenous gammaglobulin (IgG) in 3 patients. Thirteen patients were given corticosteroids preoperatively with little improvement in platelet count. CABG may be successfully performed in ITP patients with moderate thrombocytopenia (> or = 50,000/mm3) using conventional therapies (e.g., transfusions, IV IgG, hematinics) without the need for preoperative splenectomy or prolongation of hospital stay. However, a prospective study on the ideal management of ITP patients undergoing CABG would be beneficial. PMID- 22235706 TI - Urinothorax: a rare cause of pleural effusion. AB - There are many benign causes of pleural effusions that can be followed expectantly. This case report will detail a rare cause of pleural effusion. The evaluation of this patient led to a diagnosis of urinothorax. This case will highlight the importance of a thorough history and physical, as well as diagnostic evaluation of effusions of unknown etiology. With the increasing number of urological procedures being performed, it will likely become a more frequent finding. PMID- 22235707 TI - The integration of clerkships: WVU's innovative approach to curriculum delivery at a regional campus. AB - PURPOSE: The purpose of this descriptive paper is to examine the development of West Virginia University School of Medicine's integrated medical school curriculum on a regional campus. BACKGROUND: In 2003, the West Virginia University School of Medicine created a regional campus, the WVU Eastern Division, for third- and fourth-year medical students. The campus is located in a semi-rural area served by 3 small hospitals with lower numbers of physicians than average for West Virginia. Our campus was one of the first models in the United States using an integrated curricular design. CONCLUSIONS: Assessment data suggest that students do as well on high-stakes examinations and have acquired preferred residency placements as well as students who learn in more traditional curricular models. Graduates have also remained to practice in West Virginia's Eastern panhandle, helping to meet the patient care demands of an expanding population. Our experience may help inform future efforts to develop new curricular models for student education. PMID- 22235708 TI - Dog bites of the face, head and neck in children. AB - Dog bites of the facial region are increasing in children according to the Center for Disease Control. To evaluate the epidemiology of such injuries in our medical provider region, we undertook a retrospective review of those children treated for facial, head and neck dog bite wounds at a level 1 trauma center. Most dog bites occurred in or near the home by an animal known to the child/family. Most injuries were soft tissue related, however more severe bites and injuries were observed in attacks from the pit-bull and Rottweiler breeds. Younger (under five years) children sustained more of the injuries requiring medical treatment. Injury Severity Scales were determined as well as victim and payer mix demographics, type and characteristics of injury, and complications from the attack. PMID- 22235710 TI - Keeping a healthy West Virginia: a mission impossible? PMID- 22235709 TI - Enhancing community partnerships during a public health emergency: the school located vaccination clinics model in Kanawha County, WV during the 2009 influenza A (H1N1) pandemic. AB - Broad based community support is vital in developing a comprehensive national strategy to protect the public's health prior to, during and after a disaster such as pandemic influenza. When disaster strikes, the successful response is often dependent upon the degree of collaboration, coordination, and shared decision making occurring among a wide-ranging group of public and private stakeholders in the community. Since these preparedness and response activities must occur at a local level, the degree to which a certain community can become resilient after an event is directly dependent upon the success of the response activities. In order to protect its citizens, the Kanawha-Charleston Health Department (KCHD) led a comprehensive community based response to the 2009 Influenza A (H1N1) pandemic. By organizing a high level strategic team consisting of major community stakeholders, KCHD was able to develop broad based community support for its mitigation and countermeasure delivery strategies. The timely enhancement of the existing community partnerships enabled us to successfully conduct several response activities with local community support including school located vaccination (SLV) clinics. We describe the process, results and challenges faced during our SLV clinics campaign which resulted in exceptionally high vaccination rates for school aged children compared to other jurisdictions across the nation. We also discuss how such partnerships can be sustained resulting in resilient communities and mention some strategies for those contemplating such partnerships in future public health emergency. PMID- 22235711 TI - President of Kanawha County Medical Society among first to attain electronic health record designation. PMID- 22235712 TI - Donation by EHRsolutions and Greenway Medical Technologies to WVSOM. PMID- 22235713 TI - What definition of disability is in your policy? PMID- 22235714 TI - Dear food diary. Recording what you eat can help with weight and blood glucose control. PMID- 22235715 TI - A fiery foe. The link between chronic inflammation and disease. PMID- 22235716 TI - Playing his part. Actor Stephen Wallem deals with diabetes on-screen- and off. Interviewed by Carolyn Butler. PMID- 22235717 TI - Team players. PMID- 22235718 TI - Pleasing a crowd. PMID- 22235719 TI - Hospital of today is a remarkable testimonial to the scientific advances of the 20th century. PMID- 22235720 TI - The role of hospitals within the framework of the renewed primary health care (PHC) strategy. AB - This article summarizes a presentation made at the IHF Leadership Summit held in Chicago, USA in June 2010, by Denis Porignon from the World Health Organization (WHO) and Reynaldo Holder from the Pan American Health Organization (PAHO/WHO). It focuses on the role of hospitals within the framework of the renewed PHC strategy. PMID- 22235721 TI - The role of the hospital in the changing landscape of UAE health care: a focus on Dubai. AB - In the UAF, health services have developed greatly in the past 40 years and there have been enormous improvements in population health. The hospital sector is growing strongly with private sector investment. However the current and future health needs of the population are complex and may not be properly served by the continued expansion of hospital capacity. In this paper, using the Emirate of Dubai as a case study, we examine the changes that have taken place in health services and attempt to predict their optimum configuration and capacity in the future taking into account population structure and growth and levels of morbidity and service use. PMID- 22235722 TI - Hospitals of the future. AB - Hospitals and health systems face unprecedented demand to change in both the near and longer-term future, ranging from demographic changes to increasing reliance on value-based payment, and to the uncertainty surrounding governmental reform. the American Hospital Association Board Committee on Performance Improvement embarked on an initiative to identify the top ten strategies all hospitals must adopt in order to be successful care systems of the future. As a result of the committee's survey research, four top strategies were identified: (1) Aligning hospitals, physicians, and other providers across the continuum of care; (2) Using evidenced-based practices to improve quality and patient safety; (3) Improving efficiency through productivity and financial management; and (4) Developing integrated information systems. This article summarizes ten strategies and the measures to assess the accomplishment of these strategies. PMID- 22235723 TI - The underlying theories of health care reform in the United States--strategy implications for hospitals. AB - The United State Health Reform (Affordable Care Act) presents health provides with the goals that should be achieved in the reformed health care environment and rationale for those goals. Developing strategies to implement the act's policies by any health care organization must take into account the underlying theories of the act: managed change though payment design and funds flow. Market place competition. To execute strategy effective internal organizational management is a must and can be facilitated through a strong alignment between mission and opperating factors. The mission must relate to the organization's markets. Markets are best addressed through a local perspective where the ACA goals can be applied within a specific community or culture. The systems approach brings as many participants in the system to define their mutual success as it relates to reform. PMID- 22235724 TI - Effects of payment mechanisms on hospital behaviours in Brazil: evidence from a multi-payer and multi-payment system. AB - A variety of provider payment mechanisms (PPMs) are used in Brazil to direct funds to hospitals. This article examines their effect on hospital efficiency, cost and quality. Public hospitals funded through the traditional line-item public budget are the best least efficient. Those funded through global budgets and other decentralized budget modalities perform on a par with private providers funded mainly by private prepaid health plans. Private hospitals that are dependent on government payments exhibit lower levels of quality. However, the overall effects of PPMs on performance are less than expected for some groups of hospitals. Factors compromising the impact of PPMs on performance are examined. PMID- 22235725 TI - Hospitals and delivery systems: the need for change. AB - Hospitals across Europe are facing huge pressures and need to change. They are not very well adapted to deal with these challenges and in many cases the policy frameworks are poorly adapted to help them change. Hospitals increasingly need to be seen as part of the wider system and need bold and imaginative solutions to deal with the problems they face. PMID- 22235726 TI - Better than a crystal ball? Using simulation to foresee emerging issues in the Australian Healthcare System. AB - A change in the national government of Australia in 2007 lead to a process of review and reform in healthcare which is now being implemented. The Australian Healthcare and Hospitals Association (AHHA) ran a simulation exercise to model the likely impact of the planned reforms. This paper describes the background to these changes, the process of consultation and implementation of the reforms, and the results of the reforms, and the results of the simulation exercise. The process identified the risks inherent in the reform and the need to address long term structural issues in the Australian health care system in order to ensure optimal patient-centred care. PMID- 22235727 TI - Reshuffling the pack in the Swiss hospital market. AB - Swiss hospitals face two major changes: one is the introduction of DRG as the currency for payment and the other one is the shortage of personnel due to demographic changes. They will do so by strengthening their accounting systems to be able to calculate costs per patient. First steps to attract new personnel are taken withiin the new professional educational system. A third change, the evolving landscape of social health insurance companies, is hard to predict. PMID- 22235728 TI - The evolving roles of hospitals in health systems: the Lagos-Nigeria example. AB - With the revision of the definitions of health systems and the expectations of the public there is a need to reassess the roles of hospitals. Hospitals remain the centre of health care services and they face lots of challenges in service delivery. Lagos State in Nigeria has analyzed her perculiar circumstances and formulated a Health Service Reform law. This law seeks to restructure the State's health system with an emphasis on improving the functioning of the hospitals. This article highlights the roles of hospitals in general with an insight into how the Health Service Reforms seek to improve Lagos hospitals and health system. PMID- 22235729 TI - The Lesotho Hospital PPP experience: catalyst for integrated service delivery. AB - For many years, Lesotho urgently needed to replace its main public hospital, Queen Elizabeth II. The project was initially conceived as a single replacement hospital, but eventually included the design and construction of a new 425 bed public hospital and adjacent primary care clinic, the renovation and expansion of three strategically located primary care clinics in the region and the management of all facilities, equipment and delivery of all clinical services in the health network by a private operator under contract for 18 years. The project's design was influenced by the recognition that a new facility alone would not address the underlying issues in service provision. The creation of this PPP health network and the contracting mechanism has increased accountability for service quality, shifted Government to a more strategic role and may also benefit other public facilities and providers in Lesotho. The county is considering the PPP approach for other health facilities. PMID- 22235730 TI - MRI = stress relief? PMID- 22235731 TI - Preparing for (and surviving) an ACR on site accreditation inspection. PMID- 22235732 TI - Reducing risk to reduce costs. PMID- 22235733 TI - Turn everyday tasks into employee engagement opportunities. PMID- 22235734 TI - New year, new codes. PMID- 22235735 TI - ICD-10: bone density studies. PMID- 22235736 TI - Roadmap for reform: outlook for imaging under accountable care. AB - The primary goals of the Patient Protection and Affordable Care Act are to expand insurance coverage through an individual mandate, and to reduce growing healthcare costs through new risk-based payment models and the formation of ACOs. With the high cost of exams and steady growth through the last decade, imaging appears to be a prime target for savings under accountable care. Given that some of the reform payment models are set to begin as early as next year, and private payers are increasingly instituting similar risk-based payment models in their plans, it is critical for imaging leaders to understand how these models will affect their growth strategy and prepare accordingly. A thorough analysis of the various payment models, considering all possible targets for cost savings, is required to accurately determine the timing and impact for imaging. PMID- 22235737 TI - Losing it with Gary. PMID- 22235738 TI - The changing face of staffing in the current healthcare environment. AB - Although the current economic crisis in the country provides a less than positive outlook for future employment opportunities, healthcare managers could very well find themselves with open positions that are difficult to fill. According to the Bureau of Labor and Statistics, the healthcare industry is one of the largest employers, with 14.3 million jobs. Ten of the 20 fastest growing occupations are healthcare related. For radiology professionals, employment opportunities are expected to increase 17% by 2018, an increase that exceeds the average of many other occupations. As we look at the current operating environment within our own organizations, we may question the likelihood of those numbers, especially as we face the unknown with healthcare reform and continued cuts by Medicare, as well as other insurance providers. However, there are several factors that influence current staffing and how to prepare departments for future needs. PMID- 22235739 TI - Outpatient staffing and productivity during changing times. PMID- 22235740 TI - Imaging professionals' beliefs on overutilization of CT and MRI exams. AB - The intent of an independent study was to see if radiologists, administrators, and technologists would agree that there is a problem with CT and MRI overutilization. Another goal was to see if they are doing anything about this issue, to determine if there are best practices in place, and to set the basis for future studies. A literature review uncovered United States utilization rates compared to the global community. It also revealed economic concerns and relevance to an increase in healthcare costs. The recognition of overutilization exists; however, many still have not put a program in place to help with mitigation. PMID- 22235741 TI - A culture of extraordinary care: Part 5. PMID- 22235742 TI - 60: the good, the bad, and the ugly. PMID- 22235746 TI - Activation of human mitochondrial lysyl-tRNA synthetase upon maturation of its premitochondrial precursor. AB - The cytoplasmic and mitochondrial species of human lysyl-tRNA synthetase are encoded by a single gene by means of alternative splicing of the KARS1 gene. The cytosolic enzyme possesses a eukaryote-specific N-terminal polypeptide extension that confers on the native enzyme potent tRNA binding properties required for the vectorial transfer of tRNA from the synthetase to elongation factor EF1A within the eukaryotic translation machinery. The mitochondrial enzyme matures from its precursor upon being targeted to that organelle. To understand how the cytosolic and mitochondrial enzymes are adapted to participate in two distinct translation machineries, of eukaryotic or bacterial origin, we characterized the mitochondrial LysRS species. Here we report that cleavage of the precursor of mitochondrial LysRS leads to a mature enzyme with reduced tRNA binding properties compared to those of the cytoplasmic counterpart. This adaptation mechanism may prevent inhibition of translation through sequestration of lysyl-tRNA on the synthetase in a compartment where the bacterial-like elongation factor EF-Tu could not assist in its dissociation from the synthetase. We also observed that the RxxxKRxxK tRNA-binding motif of mitochondrial LysRS is not functional in the precursor form of that enzyme and becomes operational after cleavage of the mitochondrial targeting sequence. The finding that maturation of the precursor is needed to reveal the potent tRNA binding properties of this enzyme has strong implications for the spatiotemporal regulation of its activities and is consistent with previous studies suggesting that the only LysRS species able to promote packaging of tRNA(Lys) into HIV-1 viral particles is the mature form of the mitochondrial enzyme. PMID- 22235747 TI - Domino alkene-isomerization-Claisen rearrangement strategy to substituted allylsilanes. AB - A one-pot isomerization-Claisen protocol has been developed for the synthesis of highly substituted allylsilanes. Monosilylated divinyl ethers can be isomerized using a cationic iridium(I) catalyst followed by a thermal Claisen rearrangement to provide the allylsilanes in excellent yields and diastereoselectivities. PMID- 22235748 TI - Improved folate extraction and tracing deconjugation efficiency by dual label isotope dilution assays in foods. AB - A dual label stable isotope dilution assay was developed to trace the deconjugation efficiency of polyglutamic folate vitamers converted to their monoglutamic analogues. For this purpose, [(13)C(5)]-pteroylheptaglutamate was synthesized and added during extraction of foods as a tracer isotopologue along with [(2)H(4)]-5-methyltetrahydrofolate, [(2)H(4)]-5-formyltetrahydrofolate, [(2)H(4)]-tetrahydrofolate, [(2)H(4)]-10-formylfolate, and [(2)H(4)]-folic acid. The [(2)H(4)]-labeled folates were used as internal standards for the monoglutamates. Deconjugation converted the addition tracer [(13)C(5)] pteroylheptaglutamate to the detection tracer [(13)C(5)]-folic acid, which was quantified along with unlabeled folic acid using [(2)H(4)]-folic acid as the internal standard. LC-MS/MS enabled the unequivocal differentiation of the three isotopologues. This tracing was used to optimize deconjugation efficiency, which was achieved by using 4-morpholineethanesulfonic acid buffer for extraction at pH 5.0 . The optimized assay revealed limits of detection for the folate vitamers ranging between 2.0 and 5.6 pmol per assay (equivalent to 2.2-6.6 MUg/100 g dry mass), recoveries ranging between 98 and 105% and relative standard deviations in inter-assay precision ranging between 2 and 6%. The assay was applied to quantitate folates in spinach, beans, cheeses, bread, wheat germs, and yeast . PMID- 22235749 TI - Detection and quantitation of bacterial acylhomoserine lactone quorum sensing molecules via liquid chromatography-isotope dilution tandem mass spectrometry. AB - A range of acylhomoserine lactones (AHLs) are used as intraspecies quorum sensing signals by Gram-negative bacteria, and the detection and quantitation of these molecules is of interest. This manuscript reports a liquid chromatographic isotope dilution tandem mass spectrometric method for the quantitation of these molecules. A divergent solid-phase synthesis of stable-isotope-labeled AHLs suitable for use as an internal standard is reported. This route relies on the biomimetic conversion of a dideuterated methionine equivalent, N-Fmoc-(4,4 (2)H(2))methionine, to the desired labeled AHL, and a representative series of eight of these molecules was produced in >95% purity and yields up to ~50%. The representative AHL internal standards were then used to develop an optimized liquid chromatography-tandem mass spectrometric (LC-MS/MS) separation and detection protocol for these molecules, which relies on a high-efficiency C18 core-shell column to minimize the time necessary for separation. The addition of internal standards at different steps during sampling was also found to affect the analysis for hydrophobic AHLs with addition prior to cell removal giving the most accurate results. Taken together, the use of the internal standards and separation method reported herein provides a rapid and quantitative method for the study of AHL production in bacteria. PMID- 22235750 TI - Liquid-crystalline membrane permeation ability for selected nitro hair dyes. AB - AIM: A comparison of permeation ability of selected semi-permanent hair dyes and an attempt to estimate the influence of fundamental physicochemical parameters on dyes' epidermal penetration rate. METHODS: Dyes' permeation ability through liposome membrane (as a model of stratum corneum) with side-by-side cells was assessed. RESULTS: It has been shown that the chosen dyes are capable of permeating the membrane. High penetration coefficients (Kp) were obtained for a simple nitrophenylenediamines and nitroaminophenols. Their N-, O-hydroxyalkyl substitution significantly limits penetration. H-bonding capability has a major impact on the investigated dyes' permeation ability. Substituents with H-bonding properties can significantly limit dyes' penetration, even in the case of lipophilic structures. Special attention should be placed into compounds with strong intramolecular H-bonding properties, which improve transmembrane transport. CONCLUSION: Substitution patterns have an influence on selected nitro dyes' permeation through a model stratum corneum. Permeation is limited by dyes diffusive properties (mostly by its H-bonding properties). Hydroxyalkylation results in hindered dyes permeation: purple, violet and blue nitrophenylenediamine or nitroaminophenol derivatives are less permeable than its not substituted analogues. PMID- 22235751 TI - The metastasis-associated gene MTA3 is an independent prognostic parameter in uterine non-endometrioid carcinomas. PMID- 22235753 TI - Negative participation of the left posterior fascicle in the reentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia. AB - Left posterior fascicle and idiopathic Left VT. The left posterior fascicle may be a bystander of the circuit of verapamil-sensitive idiopathic left ventricular tachycardia. During ventricular tachycardia (VT), 3 sequences of potentials were seen at the left posterior septum: diastolic Purkinje potentials propagating from base to apex and presystolic left posterior fascicular potentials and systolic left ventricular (LV) myocardial potentials propagating in the reverse direction. Selective capture of the left posterior fascicle by the sinus beat did not affect the VT cycle length. Entrainment pacing revealed that the retrograde limb of the circuit was not the left posterior fascicle, but the LV myocardium. PMID- 22235752 TI - The pathogenesis of COPD and IPF: distinct horns of the same devil? AB - New paradigms have been recently proposed in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), evidencing surprising similarities between these deadly diseases, despite their obvious clinical, radiological and pathologic differences. There is growing evidence supporting a "double hit" pathogenic model where in both COPD and IPF the cumulative action of an accelerated senescence of pulmonary parenchyma (determined by either telomere dysfunction and/or a variety of genetic predisposing factors), and the noxious activity of cigarette smoke-induced oxidative damage are able to severely compromise the regenerative potential of two pulmonary precursor cell compartments (alveolar epithelial precursors in IPF, mesenchymal precursor cells in COPD/emphysema). The consequent divergent derangement of signalling pathways involved in lung tissue renewal (mainly Wnt and Notch), can eventually lead to the distinct abnormal tissue remodelling and functional impairment that characterise the alveolar parenchyma in these diseases (irreversible fibrosis and bronchiolar honeycombing in IPF, emphysema and airway chronic inflammation in COPD). PMID- 22235755 TI - Menstrual exacerbation of schizophrenia symptoms. AB - OBJECTIVE: To better understand premenstrual exacerbations of schizophrenia in women and weigh treatment options. METHOD: A PubMed literature search was conducted, using the search terms 'schizophrenia', 'psychosis', 'menstrual exacerbation', 'hormones' and assessing relevance to premenstrual exacerbation of schizophrenia symptoms. RESULTS: Exacerbations are usually distinguishable from periodic or menstrual psychosis, a relatively rare condition. Controversy continues about whether low estrogen periods of the month lead to an increase in schizophrenia symptoms among women of reproductive age or whether some women suffer from both schizophrenia and premenstrual dysphoric disorder (PMDD). No treatment trials of specific interventions have been conducted so that physicians must decide on a case-by-case basis whether to raise antipsychotic doses premenstrually, try estrogens or estrogen/progesterone combinations or selective estrogen receptor modulators, or target PMDD symptoms. CONCLUSION: Clinicians need to be aware of premenstrual symptom aggravation in a large minority of women with schizophrenia. Treatment strategies will depend on the nature of the symptoms that are exacerbated. Optimal treatment needs to be adjusted to the individual woman. PMID- 22235754 TI - Rapid access to conformational analogues of (+)-peloruside A. AB - An efficient synthetic strategy for rapid access to analogues of peloruside A has been demonstrated. The synthetic route was highlighted by a simple esterification based fragment coupling and a late stage ring-closing metathesis reaction. This convergent route has provided access to rationally designed analogues inspired by the solution conformational preferences of peloruside A. PMID- 22235756 TI - Collaborating across agencies and professionals to provide interprofessional practice: a case analysis. PMID- 22235757 TI - Changes in women's condom use over the first year of college. AB - Most college students are sexually active, engage in serially monogamous relationships, and use condoms inconsistently. Little is known about how condom use changes during college, and even less about variables predicting changes in use. Latent growth modeling (LGM) was used to examine changes in condom use during the first year of college among 279 women (mean age = 18.0; 74% White), who provided monthly reports on condom use frequency. At study entry, participants also reported on theoretically suggested risk and protective factors. Predictors of changes in use were examined after controlling for use of alternative contraception and partner type. LGM showed that women decreased their condom use during the first year of college. Levels of condom use were initially lower among women with strong alcohol-sexual risk expectancies, women with more previous sexual partners, women who did not smoke marijuana, and African American women. Decreases in condom use were greater among women with lower grade point averages, women from lower socioeconomic status families, and women who engaged in binge drinking. Reductions in condom use may place women at greater risk of unplanned pregnancy and sexually transmitted infections. Identification of factors associated with decreases in condom use will enable targeted educational and intervention efforts. PMID- 22235758 TI - Anti-biofilm activity of Salvadora persica on cariogenic isolates of Streptococcus mutans: in vitro and molecular docking studies. AB - Salvadora persica sticks are used for chewing and oral-hygiene measures worldwide. The growth inhibition and anti-biofilm effects of various extracts on cariogenic Streptococcus mutans isolates were evaluated. Biofilm inhibition, gas chromatography-mass spectrometry (GC-MS) analyses for phytochemicals and their possible mode of interaction with biofilm response regulators were revealed using LigandFit docking protocols. All S. persica extracts showed considerable inhibitory activity and the cariogenic S. mutans showed varied susceptibility when compared with controls. The percentage reduction in biofilm inhibition obtained for methanol, ethanol, chloroform, acetone, and aqueous extracts were 87.92%, 85.75%, 72.44%, 61.66% and 58.68%, respectively. GC-MS analyses revealed >28 compounds, of which benzyl (6Z,9Z,12Z)-6,9,12-octadecatrienoate, 3-benzyloxy 1-nitro-butan-2-ol and 1,3-cyclohexane dicarbohydrazide interacted efficiently with the bacterial communication quorum-sensing (QS) regulators Streptococcus OmpP and Staphylococcus Lux proteins. The bioactive, dual-function, anti-biofilm agents in S. persica not only inhibit growth, but also control the colonization and accumulation of caries-causing S. mutans. PMID- 22235759 TI - The planetary biology subcommittee versus Richard M. Nixon. PMID- 22235760 TI - Accumulation of explosives in hair--Part 3: Binding site study. AB - This study extends previous work on the sorption of explosives to the hair matrix. Specifically, we have studied the interaction of 2,4,6-trinitrotoluene (TNT) and triacetone triperoxide (TATP) as a function of chemical pretreatment with acetonitrile, neutral and alkaline hydrogen peroxide, methanolic KOH and potassium permanganate, and the morphological changes that accompany these treatments. While differences in vapor pressure can account for quantitative differences between TNT and TATP sorption, both are markedly affected by the chemical rinses. Examination of the hair surface shows different degrees of smoothening following rinsing, suggesting that the attachment to hair is largely a surface phenomenon involving the 18-methyleicosanoic acid lipid layer. Density functional theory calculations were employed to explore possible nucleation sites of TATP microcrystals on the hair. We conclude that some of the sites on melanin granular surfaces may support nucleation of TATP microcrystals. Moreover, the calculations support the experimental finding that dark hair adsorbs explosives better than light hair. PMID- 22235761 TI - From interleukin-9 to T helper 9 cells. AB - Interleukin-9 (IL-9), cloned more than 20 years ago, was initially thought to be a Th2-specific cytokine. This assumption was initially confirmed by functional analyses showing that both IL-9 and Th2 cells play an important role in the pathogenesis of asthma, IgE class switch recombination, and resolution of parasitic infections. However, recently it was shown that IL-9-producing CD4(+) T cells represent the discrete T helper subset Th9 cells. Herein, we will review the cytokines and transcription factors known to promote the development of Th9 cells and their potential functional properties in relation to the biological activities of IL-9. In addition, we will discuss how Th9 cells are related to Th2, Th17, and T(reg) cells, as both an alternative source of IL-9 and in view of the fact that plasticity of CD4(+) T cell differentiation is currently a strong matter of debate in immunologic research. PMID- 22235762 TI - Electrical mallet provides essential advantages in maxillary bone condensing. A prospective clinical study. AB - PURPOSE: The aim of this study was to compare the use of hand mallet versus electrical mallet (magnetic mallet, Meta-Ergonomica, Turbigo, Milan, Italy) in osteotome-assisted surgery for condensing bone procedure in edentulous molar and premolar maxillary regions. MATERIALS AND METHODS: Patients edentulous in maxillary premolar and molar regions with type 3 or 4 bone were enrolled in this prospective clinical study. The patients were randomly divided in two groups: in the test group, the implant site was prepared with osteotomes pushed by magnetic mallet, while in the control group, the implant site was performed with osteotomes pressed by hand mallet. Intraoral digital radiographic measurements were reported at 6, 12, and 24 months. RESULTS: Thirty-six patients were enrolled in the study. Eighteen patients (21 women and 15 men) were included in the test group and 18 patients in the control group. The mean patient age was 56.1 years (range 41-71 years). Fifty dental implants were placed. In 10 cases, five in control and five in test group, sinus elevation was performed. After 24 months follow-up, a survival rate of 96.0% was reported. In the control group, two patients claimed benign paroxysmal positional vertigo following the use of osteotomes with hand hammer. Marginal bone levels remained stable over time for both groups, and not statistically significant differences were found. After 12 months, the bone height incremented in both groups and, at 24 months, was stable. Statistical analysis reported not statistically significant differences between test and control group. CONCLUSIONS: These results demonstrated a stable marginal bone levels over time and a significant increase in bone height between 6 and 12 months in osteotome technique (not sinus elevation). The use of magnetic mallet provided some essential clinical advantages during surgical procedure in comparison with hand mallet. PMID- 22235765 TI - Cardiac movement identified on prehospital echocardiography predicts outcome in cardiac arrest patients. AB - INTRODUCTION: The prognostic value of emergency echocardiography (EE) in the management of cardiac arrest patients has previously been studied in an in hospital setting. These studies mainly included patients who underwent cardiopulmonary resuscitation (CPR) by emergency medicine technicians at the scene and who arrived at the emergency department (ED) still in a state of cardiac arrest. In most European countries, cardiac arrest patients are normally treated by physician-staffed emergency medical services (EMS) teams on scene. Transportation to the ED while undergoing CPR is uncommon. OBJECTIVE: To evaluate the ability of EE to predict outcome in cardiac arrest patients when it is performed by ultrasound-inexperienced emergency physicians on scene. METHODS: We performed a prospective, observational study of nonconsecutive, nontrauma, adult cardiac arrest patients who were treated by physician-staffed urban EMS teams on scene. Participating emergency physicians (EPs) received a two-hour course in EE during CPR. After initial procedures were accomplished, EE was performed during a rhythm and pulse check. A single subxiphoid, four-chamber view was required for study enrollment. We defined sonographic evidence of cardiac kinetic activity as any detected motion of the myocardium, ranging from visible ventricular fibrillation to coordinated ventricular contractions. The CPR had to be continued for at least 15 minutes after the initial echocardiography. No clinical decisions were made based on the results of EE. RESULTS: Forty-two patients were enrolled in the study. The heart could be visualized successfully in all patients. Five (11.9%) patients survived to hospital admission. Of the 32 patients who had cardiac standstill on initial EE, only one (3.1%) survived to hospital admission, whereas four out of 10 (40%) patients with cardiac movement on initial EE survived to hospital admission (p = 0.008). Neither asystole on initial electrocardiogram nor peak capnography value, age, bystander CPR, or downtime was a significant predictor of survival. Only cardiac movement was associated with survival, and cardiac standstill at any time during CPR resulted in a positive predictive value of 97.1% for death at the scene. CONCLUSION: Our results support the idea of focused echocardiography as an additional criterion in the evaluation of outcome in CPR patients and demonstrate its feasibility in the prehospital setting. PMID- 22235766 TI - Evaluation of prognostic indicators in dogs with multiple, simultaneously occurring cutaneous mast cell tumours: 63 cases. AB - Sixty-three dogs with multiple contemporaneous cutaneous mast cell tumours (MCTs) were identified. The aim of this study was to determine the significance of breed, concurrent dermatological condition; number of cutaneous MCTs, size, location, histological grade and mitotic index; completeness of excision (complete, close or incomplete); local recurrence, metastasis and adjuvant therapy for the prognostic evaluation of dogs with a unique disease presentation of multiple, simultaneously occurring cutaneous MCTs. On the basis of multivariable survival analysis, dogs with one recorded grade 3 MCT had shorter progression-free survival (PFS) times (18.7 versus 2.2 months) and median survival times (MSTs) (24 versus 3 months). Dogs treated with adjuvant vinblastine/lomustine had a 16 times increased risk of dying. MSTs were found to be significantly longer in dogs with one recorded MCT on an extremity. For all dogs, the PFS (range 14-1835 days) and MSTs (range 28-1835 days) were not reached. PMID- 22235767 TI - Optimization of the lyophilization process for long-term stability of solid-lipid nanoparticles. AB - OBJECTIVES: To optimize a lyophilization protocol for solid-lipid nanoparticles (SLNs) loaded with dexamethasone palmitate (Dex-P) and to compare the long-term stability of lyophilized SLNs and aqueous SLN suspensions at two storage conditions. MATERIALS AND METHODS: The effect of various parameters of the lyophilization process on SLN redispersibility was evaluated. A three month stability study was conducted to compare changes in the particle size and drug loading of lyophilized SLNs with SLNs stored as aqueous suspensions at either 4 degrees C or 25 degrees C/60% relative humidity (RH). RESULTS AND DISCUSSION: Of nine possible lyoprotectants tested, sucrose was shown to be the most efficient at achieving SLN redispersibility. Higher freezing temperatures, slower freezing rates, and longer secondary drying times were also shown to be beneficial. Loading of the SLNs with Dex-P led to slightly larger particle size and polydispersity index increases, but both parameters remained within an acceptable range. Drug loading and particle shape were maintained following lyophilization, and no large aggregates were detected. During the stability study, significant growth and drug loss were observed for aqueous SLN suspensions stored at 25 degrees C/60% RH. In comparison, lyophilized SLNs stored at 4 degrees C exhibited a consistent particle size and showed <20% drug loss. Other storage conditions led to intermediate results. CONCLUSIONS: A lyophilization protocol was developed that allowed SLNs to be reconstituted with minimal changes in their physicochemical properties. During a three month period, lyophilized SLNs stored at 4 degrees C exhibited the greatest stability, showing no change in the particle size and a minimal reduction in drug retention. PMID- 22235768 TI - Sputter-deposition of silver nanoparticles into ionic liquid as a sacrificial reservoir in antimicrobial organosilicate nanocomposite coatings. AB - We present a new approach for fabricating robust, regenerable antimicrobial coatings containing an ionic liquid (IL) phase incorporating silver nanoparticles (AgNPs) as a reservoir for Ag(0)/Ag(+) species within sol-gel-derived nanocomposite films integrating organosilicate nanoparticles. The IL serves as an ultralow volatility (vacuum-compatible) liquid target, allowing for the direct deposition and dispersion of a high-density AgNP "ionosol" following conventional sputtering techniques. Two like-anion ILs were investigated in this work: methyltrioctylammonium bis(trifluoromethylsulfonyl)imide, [N(8881)][Tf(2)N], and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [emim][Tf(2)N]. Silver ionosols derived from these two ILs were incorporated into silica-based sol-gel films and the resultant antimicrobial activity evaluated against Pseudomonas aeruginosa bacteria. Imaging of the surface morphologies of the as prepared films established a link between an open macroporous film architecture and the observation of high activity. Nanocomposites based on [N(8881)][Tf(2)N] displayed excellent antimicrobial activity against P. aeruginosa over multiple cycles, reducing cell viability by 6 log units within 4 h of contact. Surprisingly, similar films prepared from [emim][Tf(2)N] presented negligible antimicrobial activity, an observation we attribute to the differing abilities of these IL cations to infiltrate the cell wall, regulating the influx of silver ions to the bacterium's interior. PMID- 22235771 TI - The role of beta-bulky substituents in aldol reactions of boron enolates of methylketones with aldehydes: experimental and theoretical studies by DFT analysis. AB - In this work, we show the influence of the volume of the beta-substituents on the levels of 1,5-stereoselectivities of aldol reactions of boron enolates generated from beta-alkoxy methylketones with aldehydes. Excellent levels of 1,5-syn stereoinduction were obtained when the beta-protecting group is a silicon ether. This remarkable selectivity is attributed to the volume of the beta-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of beta-alkyl-beta-alkoxy methylketones. PMID- 22235772 TI - In vitro assessment of the bioaccessibility of fatty acids and tocopherol from soybean oil body emulsions stabilized with iota-carrageenan. AB - The present investigation aimed to expand the knowledge of the in vitro bioaccessibility of fatty acids and tocopherol from natural soybean oil body emulsions stabilized with different concentrations of iota-carrageenan. Several physicochemical parameters including proteolysis of the interfacial layer, interfacial composition, and microstructure were evaluated with regard to their impact on the bioaccessibility of fatty acids and tocopherol. Results from simulated human digestion in vitro indicated that the bioaccessibility of total fatty acids and tocopherol decreased (62.7-8.3 and 59.7-19.4%, respectively) with the increasing concentration of iota-carrageenan. During the in vitro digestion procedure, iota-carrageenan affected physicochemical properties of the emulsions, thereby controlling the release of fatty acids and tocopherol. These results suggested that soybean oil body emulsions stabilized with iota-carrageenan could provide natural emulsions in foods that were digested at a relatively slow rate, the important physiological consequence of which might be increasing satiety. PMID- 22235773 TI - Asymmetric synthesis of dihydroindanes by convergent alkoxide-directed metallacycle-mediated bond formation. AB - A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2 + 2 + 2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne-alkyne coupling, followed by metal-centered [4 + 2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry. PMID- 22235775 TI - Complications after acute coronary syndrome are reduced by perceived control of cardiac illness. AB - AIMS: To investigate the relationship between anxiety, perceived control and rate of in-hospital complications after acute coronary syndrome. BACKGROUND: Anxiety may be associated with higher risk of complications following acute myocardial infarction; perceived control may moderate this relationship. DESIGN: Prospective observational study. METHODS: Patients enrolled in a trial investigating delay in seeking treatment for acute coronary syndrome had anxiety measured at enrolment and 3 months using the Brief Symptom Inventory anxiety subscale. The acute coronary syndrome hospital presentations investigated occurred between 2001-2006. Patients with anxiety scores greater than the population norm at both time points were categorized as persistently anxious. Perceived control was measured at enrolment using the control attitudes scale-revised. Data were collected from the medical record on in-hospital complications in patients presenting with acute coronary syndrome within 2 years of enrolment. Chi-square and t-tests were used for univariate analyses and multiple logistic regression to identify independent predictors of complications. RESULTS: Patients (n = 171) were 64% men with mean age 69 years. Ischaemic or arrhythmic complications occurred in 26 patients (15%) with no difference in complication rates between those persistently anxious and others. Important univariate predictors of in-hospital complications were lower perceived control, diagnosis of acute myocardial infarction, heart failure and higher pulse rate on admission. Low perceived control and diagnosis of acute myocardial infarction were independent predictors of in-hospital complications in the multiple logistic regression. CONCLUSION: Perceived control, but not persistent anxiety, prior to acute coronary syndrome was an important predictor of in-hospital complications after acute coronary syndrome. Interventions to increase cardiac patients' perceived control of their cardiac illness may reduce in-hospital complications after acute coronary syndrome. PMID- 22235774 TI - Desmosomal cadherins in zebrafish epiboly and gastrulation. AB - BACKGROUND: The desmosomal cadherins (DCs), desmocollin (Dsc) and desmoglein (Dsg), are the adhesion molecules of desmosomes, intercellular adhesive junctions of epithelia and cardiac muscle. Both the DCs and desmosomes have demonstrably essential roles in mammalian development. In order to initiate their study in a more tractable developmental system we have characterised zebrafish DCs and examined their roles in early zebrafish development. RESULTS: We find that zebrafish possess one Dsc, the orthologue of mammalian Dsc1, which we designate zfDsc. Unlike mammalian Dscs, zfDsc exists only as the "a" form since it lacks the alternatively-spliced mini-exon that shortens the cytoplasmic domain to produce the "b" form. Zebrafish possess two Dsgs, designated zfDsgalpha and zfDsgbeta, orthologues of mammalian Dsg2. They show 43.8% amino acid identity and the alpha form has a 43 amino acid glycine-rich sequence of unknown function in its extracellular domain. Both zfDsc and zfDsgalpha were present as maternal and zygotic transcripts whereas zfDsgbeta was first expressed from 8 hours post fertilisation (hpf). All three transcripts were present throughout subsequent stages of development. Morpholino knockdown of both zfDsc and zfDsgalpha expression produced similar defects in epiboly, axis elongation and somite formation, associated with abnormal desmosomes or reduced desmosome numbers. CONCLUSIONS: These results demonstrate an important role for DCs and desmosomes in the early morphogenesis of the zebrafish embryo, provide a basis for more detailed analysis of their role and raise interesting questions relating to the evolution and functional significance of DC isoforms. PMID- 22235776 TI - Aorto-right atrial fistula following transseptal catheterization and catheter ablation for atrial fibrillation. AB - Aorto-cameral fistula, either congenital or acquired, is an abnormal connection between the ascending aortic root and one of the cardiac chambers. We report a case of a 61-year-old male with history of atrial fibrillation and 2 radiofrequency ablation procedures, referred to us for surgical Cox Maze procedure. Preoperative cardiac computerized tomography revealed a fistulous connection between the aortic root and the right atrium. Later, the patient underwent successful surgical closure of the fistula during the Cox Maze procedure. In this paper, we also discuss the clinical presentation, natural history, anatomy of the interatrial septum, and management of aorto-cameral fistula. PMID- 22235777 TI - Construction of cyclopentanol derivatives via three-component coupling of silyl glyoxylates, acetylides, and nitroalkenes. AB - The three-component coupling of Mg acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective Kuwajima-Reich/vinylogous Michael cascade that provides tetrasubstituted silyloxyallene products. The regio and diastereoselectivity were studied using DFT calculations. These silyloxyallenes were converted to cyclopentenols and cyclopentitols via a unique Lewis acid assisted Henry cyclization. The alkene functionality present in the cyclopentanol products can be elaborated using diastereoselective ketohydroxylation reactions. PMID- 22235778 TI - The functional exercise capacity is correlated with global functioning in patients with schizophrenia. AB - OBJECTIVE: The 6-minute walk test (6MWT) is commonly used to measure the functional exercise capacity in chronic patients with cardiovascular diseases. The purpose of this study was to determine whether the 6MWT is associated with the global assessment of functioning (GAF) score in patients with schizophrenia. METHODS: A total of 68 male and 25 female in-patients with schizophrenia (34.6 +/ 9.7 years; body mass index = 24.9 +/- 4.4) performed a 6MWT and were assessed with the GAF scale and the Psychosis Evaluation tool for Common use by Caregivers (PECC). RESULTS: The mean distance walked on the 6MWT was 587.3 +/- 98.4 m, while the mean GAF score was 52.0 +/- 10.4. The Pearson's correlation coefficient between the 6MWT and the GAF score was 0.59 (P < 0.001), indicating a moderate association between both measures. The 6MWT was also significantly related to negative (r = -0.45, P < 0.001), depressive (r = -0.48, P < 0.001) and cognitive (r=, P) symptoms and with body mass index (r = -0.31, P < 0.005), smoking behaviour (r = -0.36, P < 0.001)) and dose of antipsychotic medication (r = 0.38, P < 0.001). CONCLUSION: Next to the GAF scale, clinicians in in-patient settings should consider incorporating the 6MWT into their test battery to measure the functional consequences of schizophrenia and its treatment. PMID- 22235779 TI - Chemical inducers of heat shock proteins derived from medicinal plants and cytoprotective genes response. AB - Environmental stress induces damage that activates an adaptive response in any organism. The cellular stress response is based on the induction of cytoprotective proteins, the so-called stress or heat shock proteins (HSPs). HSPs are known to function as molecular chaperones which are involved in the therapeutic approach of many diseases. Therefore in the current study we searched nontoxic chaperone inducers in chemical compounds isolated from medicinal plants. Screening of 80 compounds for their Hsp70-inducing activity in human lymphoma U937 cells was performed by western blotting. Five compounds showed significant Hsp70 up-regulation among them shikonin was most potent. Shikonin was able to induce Hsp70 at 0.1 uM after 3 h without activation of heat shock transcription factor 1 (HSF-1). It also induces significant reactive oxygen species generation. The expression level of genes responsive to shikonin was studied using global scale microarrays and computational gene expression analysis tools. Significant increase in the nuclear factor erythroid 2-related factor 2 (Nrf2, NFEL2L2) mediated oxidative stress response was observed that leads to the activation of HSP. The results of gene chip analysis were further confirmed by real-time qPCR assay. In short, the detailed mechanisms of Hsp70 induction by shikonin is not fully understood, Nrf2 and its target genes might be involved in the Hsp70 up regulation in U937 cells. PMID- 22235781 TI - Priming of the sweat glands explains reflex sweating in the heat. AB - The purpose of this study was to determine whether reflex sweating during isometric handgrip exercise (IHG) in the heat was due to a priming effect in the sweat glands or an increase in skin temperature. Ten male subjects completed four trials where they performed IHG for three minutes at 40% of their maximal voluntary contraction (MVC). The four trials included: (1) a control trial in thermoneutral conditions (23+/-1 degrees C), (2) after sitting in hyperthermic conditions (35+/-1 degrees C) for 30 min, (3) a local heating trial after having their non-exercising arm wrapped in a heat pad that maintained forearm skin temperature at ~35 degrees C for 30 min, 4) and after pilocarpine iontophoresis to a 5 cm(2) area of the forearm. The sweating rate (SR), as measured by resistance hygrometry, was not significantly different (P>0.05) from baseline during IHG in either the control or local heating trial, but was significantly increased (P<0.05) from baseline during the hyperthermic and pilocarpine trials. Baseline SR values of the hyperthermic and pilocarpine trials (~0.25mg/cm(2)/min) were significantly greater than the control and local heating trials (~0.05 mg/cm(2)/min). These results suggest that reflex sweating in the heat during IHG is primarily due to a priming effect in the sweat glands and not because of an increase in skin temperature. PMID- 22235780 TI - Effector CD8+ T cell IFN-gamma production and cytotoxicity are enhanced by mild hyperthermia. AB - PURPOSE: Clinical trials combining hyperthermia with radiation and/or chemotherapy for cancer treatment have resulted in improved overall survival and control of local recurrences. The contribution of thermally enhanced anti-immune function in these effects is of considerable interest, but not understood; studies on the fundamental effects of elevated temperature on immune effector cells are needed. The goal of this study is to investigate the potential of mild hyperthermia to impact tumour antigen-specific (Ag) effector CD8+ T cell functions. METHOD: Pmel-1 Ag-specific CD8+ T cells were exposed to mild hyperthermia and tested for changes in IFN-gamma production and cytotoxicity. Additionally, overall plasma membrane organisation and the phosphorylation of signalling proteins were also investigated following heat treatment. RESULTS: Exposing effector Pmel-1-specific CD8+ T cells to mild hyperthermia (39.5 degrees C) resulted in significantly enhanced Ag-specific IFN-gamma production and tumour target cell killing compared to that seen using lower temperatures (33 degrees and 37 degrees C). Further, inhibition of protein synthesis during hyperthermia did not reduce subsequent Ag-induced IFN-gamma production by CD8+ T cells. Correlated with these effects, we observed a distinct clustering of GM1(+) lipid microdomains at the plasma membrane and enhanced phosphorylation of LAT and PKCtheta which may be related to an observed enhancement of Ag-specific effector CD8+ T cell IFN-gamma gene transcription following mild hyperthermia. However, mitogen-mediated production of IFN-gamma, which bypasses T cell receptor activation with antigen, was not enhanced. CONCLUSIONS: Antigen-dependent effector T cell activity is enhanced following mild hyperthermia. These effects could potentially occur in patients being treated with thermal therapies. These data also provide support for the use of thermal therapy as an adjuvant for immunotherapies to improve CD8+ effector cell function. PMID- 22235782 TI - Hyperthermia worsens ischaemic brain injury through destruction of microvessels in an embolic model in rats. AB - PURPOSE: Basal lamina is a major part of the microvascular wall and plays a critical role in the integrity of microvasculature. The aim of this study is to determine whether hyperthermia worsens the destruction of microvascular integrity in the ischaemic injured brain. MATERIALS AND METHODS: Focal cerebral ischaemia was induced by embolising a pre-formed clot into the middle cerebral artery (MCA). Rats received either normothermic or hyperthermic treatment. Neurological score and infarct size were evaluated at 24 h after the MCA occlusion. Microvascular collagen type IV and laminin were measured with fluorescence microscopy. The activities of matrix metalloproteinases (MMP-2 and MMP-9) and plasminogen activators (tPA and uPA) were determined by zymography. RESULTS: Treatment with hyperthermia significantly increased infarct volume (p<0.01), cortex swelling (p<0.01), striatum swelling (p<0.05) and neurologic score (p<0.01) at 24 h after the MCA occlusion. Compared to the normothermic groups, hyperthermia significantly worsened the losses of microvascular basal lamina structure proteins, collagen type IV and laminin, at 6 h (p<0.001) and 24 h (p<0.01) after MCA occlusion. Hyperthermia increased the MMP-9 activity at 6 and 24 h after MCA occlusion compared with normothermia (p<0.05), whereas increased the MMP-2 activity at 6 h only (p<0.05). Hyperthermia also elevated uPA activity significantly at 6 and 24 h after MCA occlusion compared to normothermia (p<0.05). CONCLUSIONS: These results demonstrate that hyperthermia exacerbates the destruction of microvascular integrity possibly by increasing the activities of MMP-2, MMP-9 and uPA in the ischaemic cerebral tissues. PMID- 22235783 TI - Modified vaccinia virus Ankara delivers a robust surrogate marker for immune monitoring to sarcoma cells even if cells are being exposed to chemotherapy and heat treatment. AB - PURPOSE: Adding hyperthermia to chemotherapy improved the clinical outcome of patients with high risk soft tissue sarcoma. Further improvement might be possible if combined with vaccination strategies. As no sarcoma-associated antigens are known, the ectopic expression of a surrogate marker for which immune monitoring tools are available, is envisaged. We tested surrogate marker transfer into sarcoma cells in vitro using modified vaccinia virus Ankara (MVA), which has well established clinical safety. We examined its robustness against standard sarcoma treatment modalities, such as ifosfamide and hyperthermia. MATERIALS AND METHODS: We transduced sarcoma cell lines and primary tumour cells from sarcoma patients with MVA encoding the human tyrosinase gene (MVA-hTyr). Kinetics of tyrosinase expression and the potency to activate tyrosinase-specific cytotoxic T cells were assessed. In addition cells were exposed to chemotherapy and heat, imitating the clinical setting. RESULTS: Tyrosinase was ectopically expressed in sarcoma cells. Infected cells presented tyrosinase epitopes for T cell recognition even if exposed to ifosfamide/heat. CONCLUSIONS: As sarcoma patients receive surgery up front or after neoadjuvant systemic chemotherapy/hyperthermia, tumour material is generally available. Our data document that primary sarcoma cells can be infected with MVA-hTyr in vitro and antigen presentation is not affected by ifosfamide or heat treatment. Infected cells can serve as a source for vaccine preparation. MVA-hTyr infection of tumour cells lacking defined antigens is a feasible system to introduce a robust surrogate marker to provide an immune monitoring marker for assessing the induction of antigen-specific T cell activation. PMID- 22235784 TI - Microwave ablation of ex vivo human liver and colorectal liver metastases with a novel 14.5 GHz generator. AB - PURPOSE: This study assessed the relationship between time, power and ablation size using a novel high-frequency 14.5 GHz microwave applicator in ex vivo human hepatic parenchyma and colorectal liver metastases. Previous examination has demonstrated structurally normal but non-viable cells within the ablation zone. This study aimed to further investigate how ablation affects these cells, and to confirm non-viability. MATERIALS AND METHODS: Ablations were performed in ex vivo human hepatic parenchyma and tumour for a variety of time (10-180 s) and power (10-50 W) settings. Histological examination was performed to assess cellular anatomy, whilst enzyme histochemistry was used to confirm cellular non-viability. Transmission electron microscopy was used to investigate the subcellular structural effects of ablation within these fixed cells. Preliminary proteomic analysis was also performed to explore the mechanism of microwave cell death. RESULTS: Increasing time and power settings led to a predictable and reproducible increase in size of ablation. At 50 W and 180 s application, a maximum ablation diameter of 38.8 mm (+/-1.3) was produced. Ablations were produced rapidly, and at all time and power settings ablations remained spherical (longest:shortest diameter <1.2). Routine histological analysis using haematoxylin-eosin (H&E) confirmed well preserved cellular anatomy despite ablation. Transmission electron microscopy demonstrated marked subcellular damage. Enzyme histochemistry showed complete absence of viability in ablated tissue. CONCLUSIONS: Large spherical ablation zones can be rapidly and reproducibly achieved in ex vivo human hepatic parenchyma and colorectal liver metastases using a 14.5 GHz microwave generator. Despite well preserved cellular appearance, ablated tissue is non-viable. PMID- 22235785 TI - CT-based temperature monitoring during hepatic RF ablation: feasibility in an animal model. AB - PURPOSE: The aim of this paper was to establish non-invasive CT-based temperature monitoring during hepatic radiofrequency (RF) ablation in an ex vivo porcine model followed by transfer of the technique into a feasibility in vivo experiment. MATERIALS AND METHODS: Bipolar RF ablations were performed in 10 specimens of porcine liver. Parallel to the needle-shaped RF applicator three optical temperature probes were inserted into the liver specimens at fixed distances of 5, 10 and 15 mm from the RF probe. During energy application (20 W) unenhanced sequential MSCT scans were acquired using the following scan protocol: 140 kV tube voltage, 300 mAs/rotation tube current time product, collimation 24 * 1.2 mm, rotation time 0.5 s. Axial image data was reconstructed using a soft tissue convolution kernel. Temperature data was recorded during every CT scan. Using a circular 0.5 cm(2) region of interest local CT values were measured at the tips of the temperature probes and matched with the measured temperatures. Regression analysis was performed to analyse the relationship between local temperatures and CT values for each temperature probe position. Furthermore, the same experimental design was used in four anaesthetised female pigs in order to investigate the potential of this technique for an in vivo application. RESULTS: A negative correlation was found for the relationship between temperature and CT value. Regression coefficients were -0.44 (5 mm), -0.35 (10 mm) and -0.37 (15 mm) for ex vivo data. Analysis of in vivo experiments showed regression coefficients between -0.025 and -0.434. CONCLUSION: Multislice computed tomography is able to depict temperature changes in liver tissue during RFA. PMID- 22235786 TI - Relationship between roll-off occurrence and spatial distribution of dehydrated tissue during RF ablation with cooled electrodes. AB - PURPOSE: To study the relationship between roll-off (sudden increase in impedance) and spatial distribution of dehydrated tissue during RF ablation using a cooled electrode (temperatures around 100 degrees C). METHODS: We used a double approach: (1) theoretical modelling based on the finite element method, and (2) 20 ablations using an experimental study on ex vivo excised bovine liver in which we measured impedance progress and temperature at three points close to the electrode surface: 0.5 (T1), 1.5 (T2) and 2.5 (T3) mm from the tip. T2 was located exactly at the centre of the 30 mm long electrode. RESULTS: Temperatures at T1 and T3 quickly rose to 100 degrees C (at ~20 and 40 s, respectively), while at the rise at T2 was somewhat slower, stabilized around 50 s and reached a maximum value of 99 degrees C at about 60 s. Impedance reached a minimum of 65 Omega (plateau), began increasing at 50 s and continued rising throughout the procedure, reaching a value equal to the initial value at 70 s. Likewise, computed impedance dropped to ~73 Omega (plateau), began increasing at 50 s and reached an impedance value equal to the initial value at ~78 s, which approximately coincided with the time when the entire zone surrounding the electrode was within the 100 degrees C isotherm. CONCLUSION: There is a close relationship between the moment at which roll-off occurs and the time when the entire electrode is completely encircled by the dehydrated tissue. The mid electrode zone is the last in which tissue desiccation occurs. PMID- 22235788 TI - Investigation of power and frequency for 3D conformal MRI-controlled transurethral ultrasound therapy with a dual frequency multi-element transducer. AB - Transurethral ultrasound therapy uses real-time magnetic resonance (MR) temperature feedback to enable the 3D control of thermal therapy accurately in a region within the prostate. Previous canine studies showed the feasibility of this method in vivo. The aim of this study was to reduce the procedure time, while maintaining targeting accuracy, by investigating new combinations of treatment parameters. Simulations and validation experiments in gel phantoms were used, with a collection of nine 3D realistic target prostate boundaries obtained from previous preclinical studies, where multi-slice MR images were acquired with the transurethral device in place. Acoustic power and rotation rate were varied based on temperature feedback at the prostate boundary. Maximum acoustic power and rotation rate were optimised interdependently, as a function of prostate radius and transducer operating frequency. The concept of dual frequency transducers was studied, using the fundamental frequency or the third harmonic component depending on the prostate radius. Numerical modelling enabled assessment of the effects of several acoustic parameters on treatment outcomes. The range of treatable prostate radii extended with increasing power, and tended to narrow with decreasing frequency. Reducing the frequency from 8 MHz to 4 MHz or increasing the surface acoustic power from 10 to 20 W/cm(2) led to treatment times shorter by up to 50% under appropriate conditions. A dual frequency configuration of 4/12 MHz with 20 W/cm(2) ultrasound intensity exposure can treat entire prostates up to 40 cm(3) in volume within 30 min. The interdependence between power and frequency may, however, require integrating multi-parametric functions in the controller for future optimisations. PMID- 22235787 TI - Considerations for theoretical modelling of thermal ablation with catheter-based ultrasonic sources: implications for treatment planning, monitoring and control. AB - PURPOSE: To determine the impact of including dynamic changes in tissue physical properties during heating on feedback controlled thermal ablation with catheter based ultrasound. Additionally, we compared the impact of several indicators of thermal damage on predicted extents of ablation zones for planning and monitoring ablations with this modality. METHODS: A 3D model of ultrasound ablation with interstitial and transurethral applicators incorporating temperature-based feedback control was used to simulate thermal ablations in prostate and liver tissue. We investigated five coupled models of heat dependent changes in tissue acoustic attenuation/absorption and blood perfusion of varying degrees of complexity. Dimensions of the ablation zone were computed using temperature, thermal dose, and Arrhenius thermal damage indicators of coagulative necrosis. A comparison of the predictions by each of these models was illustrated on a patient-specific anatomy in the treatment planning setting. RESULTS: Models including dynamic changes in blood perfusion and acoustic attenuation as a function of thermal dose/damage predicted near-identical ablation zone volumes (maximum variation < 2.5%). Accounting for dynamic acoustic attenuation appeared to play a critical role in estimating ablation zone size, as models using constant values for acoustic attenuation predicted ablation zone volumes up to 50% larger or 47% smaller in liver and prostate tissue, respectively. Thermal dose (t(43) >= 240 min) and thermal damage (Omega >= 4.6) thresholds for coagulative necrosis are in good agreement for all heating durations, temperature thresholds in the range of 54 degrees C for short (<5 min) duration ablations and 50 degrees C for long (15 min) ablations may serve as surrogates for determination of the outer treatment boundary. CONCLUSIONS: Accounting for dynamic changes in acoustic attenuation/absorption appeared to play a critical role in predicted extents of ablation zones. For typical 5-15 min ablations with this modality, thermal dose and Arrhenius damage measures of ablation zone dimensions are in good agreement, while appropriately selected temperature thresholds provide a computationally cheaper surrogate. PMID- 22235789 TI - Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. AB - Recent findings provide evidence of inflammasome critical role in the predisposition to autoimmune disorders. The involvement of inflammasome in the pathogenesis of systemic lupus erythematosus (SLE) has been hypothesized even if no significant association within inflammasome genes mutations or polymorphisms and lupus has been reported yet. We analyzed 14 single nucleotide polymorphisms (SNPs) within 7 inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1, IL1B) in 144 patients affected by systemic lupus erythematosus and in 158 healthy controls from Southern Brazilian (state of Sao Paulo) with the aim of disclosing the possible role of inflammasome genes in the susceptibility of SLE. Our results demonstrated that NLRP1 rs2670660 SNP and the NLRP1 rs12150220-rs2670660 A-G haplotype were associated with SLE in our study population, and in particular with the development of nephritis, rash and arthritis. These findings are concordant with previously reported association of NLRP1 with vitiligo and type-1 diabetes underlining once more the involvement of NALP1 inflammasome in the pathogenesis of autoimmune disorders. PMID- 22235790 TI - Preventing ascidian fouling in aquaculture: screening selected allelochemicals for anti-metamorphic properties in ascidian larvae. AB - Fouling by ascidians causes major stock losses and disrupts production in marine aquaculture, especially bivalve aquaculture. Currently, no cost effective solution exists despite the testing of many prospective control techniques. This study examined a range of allelochemicals suspected to inhibit metamorphosis in marine larvae. Five allelochemicals were screened in a larval metamorphosis bioassay using Ciona savignyi Herdman to determine their potential as a remedy for ascidian fouling in bivalve aquaculture. Three of the compounds tested inhibited ascidian larval metamorphosis and increased mortality at low concentrations. These were radicicol (99% inhibition of metamorphosis [IC99], 0.8 MUg ml-1; 99% lethal concentration [LC99], 2.5 MUg ml-1; 99% lethal time [LT99], 7.0 days), polygodial (IC99, 0.003 MUg ml-1; LC99, 0.9 MUg ml-1; LT99, 6.4 days), and ubiquinone-10 (IC99, 3.2 MUg cm-2; LC99, 14.5 MUg cm-2; LT99, 5.6 days; expressed as MUg cm-2 due to insolubility in water and ethanol). While spermidine significantly affected metamorphosis and mortality of C. savignyi, the effect was insufficient to achieve inhibition in 99% of larvae over the 7-day timeframe of the assay. Muscimol did not affect metamorphosis or mortality at the concentrations tested. The present study demonstrates that radicicol, polygodial and ubiquinone-10 have potential for future development in antifoulant formulations targeted towards the inhibition of metamorphosis in ascidian larvae, while spermidine and muscimol appear unsuitable. PMID- 22235791 TI - Validation of powder X-ray diffraction following EN ISO/IEC 17025. AB - Powder X-ray diffraction (PXRD) is used widely in forensic science laboratories with the main focus of qualitative phase identification. Little is found in literature referring to the topic of validation of PXRD in the field of forensic sciences. According to EN ISO/IEC 17025, the method has to be tested for several parameters. Trueness, specificity, and selectivity of PXRD were tested using certified reference materials or a combination thereof. All three tested parameters showed the secure performance of the method. Sample preparation errors were simulated to evaluate the robustness of the method. These errors were either easily detected by the operator or nonsignificant for phase identification. In case of the detection limit, a statistical evaluation of the signal-to-noise ratio showed that a peak criterion of three sigma is inadequate and recommendations for a more realistic peak criterion are given. Finally, the results of an international proficiency test showed the secure performance of PXRD. PMID- 22235792 TI - Conventional multi-slice computed tomography (CT) and cone-beam CT (CBCT) for computer-aided implant placement. Part II: reliability of mucosa-supported stereolithographic guides. AB - PURPOSE: Deviations of implants that were placed by conventional computed tomography (CT)- or cone beam CT (CBCT)-derived mucosa-supported stereolithographic (SLA) surgical guides were analyzed in this study. MATERIALS AND METHODS: Eleven patients were randomly scanned by a multi-slice CT (CT group) or a CBCT scanner (CBCT group). A total of 108 implants were planned on the software and placed using SLA guides. A new CT or CBCT scan was obtained and merged with the planning data to identify the deviations between the planned and placed implants. Results were analyzed by Mann-Whitney U test and multiple regressions (p < .05). RESULTS: Mean angular and linear deviations in the CT group were 3.30 degrees (SD 0.36), and 0.75 (SD 0.32) and 0.80 mm (SD 0.35) at the implant shoulder and tip, respectively. In the CBCT group, mean angular and linear deviations were 3.47 degrees (SD 0.37), and 0.81 (SD 0.32) and 0.87 mm (SD 0.32) at the implant shoulder and tip, respectively. No statistically significant differences were detected between the CT and CBCT groups (p = .169 and p = .551, p = .113 for angular and linear deviations, respectively). CONCLUSIONS: Implant placement via CT- or CBCT-derived mucosa-supported SLA guides yielded similar deviation values. Results should be confirmed on alternative CBCT scanners. PMID- 22235793 TI - Davos declaration: allergy as a global problem. PMID- 22235794 TI - Glucocorticoids 'on air'. PMID- 22235796 TI - Serum neopterin, sialic acid and nitric oxide levels in dogs with malignant mammary tumours. AB - Mammary cancer is one of the leading causes of death in pet population. Early diagnosis and malignancy detection is important for prognosis. The levels of neopterin, sialic acid and nitric oxide in serum of dogs with malignant mammary tumours were evaluated to investigate the importance of these biochemical parameters for malign mammary tumour. Twelve healthy dogs and twenty dogs with malignant mammary tumours were used as research materials. Blood samples were collected from both groups for neopterin analysis by enzyme-linked immunosorbent assay, whereas nitric oxide and sialic acid were measured by modified nitrate reductase method and spectrophotometry, respectively. Tissue specimens were evaluated and defined as malignant tumours. Serum nitric oxide and sialic acid levels in dogs with mammary tumours were significantly higher than those in the healthy dogs. Serum neopterin levels were not found significantly different in dogs with mammary tumours compared to healthy dogs. Malignancy of canine mammary tumours are accompained by an elevation of nitric oxide and sialic acid levels. PMID- 22235797 TI - Centrifugation assay for measuring adhesion of serially passaged bovine chondrocytes to polystyrene surfaces. AB - A major obstacle in chondrocyte-based therapy for cartilage repair is the limited availability of cells that maintain their original phenotype. Propagation of chondrocytes as monolayer cultures on polystyrene surfaces is used extensively for amplifying cell numbers. However, chondrocytes undergo a phenotypic shift when propagated in this manner and display characteristics of more adherent fibroblastic cells. Little information is available about the effect of this phenotypic shift on cellular adhesion properties. We evaluated changes in adhesion property as bovine chondrocytes were serially propagated up to five passages in monolayer culture using a centrifugation cell adhesion assay, which was based on counting of cells before and after being exposed to centrifugal dislodgement forces of 120 and 350 g. Chondrocytes proliferated well in a monolayer culture with doubling times of 2-3 days, but they appeared more fibroblastic and exhibited elongated cell morphology with continued passage. The centrifugation cell adhesion assay showed that chondrocytes became more adhesive with passage as the percentage of adherent cells after centrifugation increased and was not statistically different from the adhesion of the fibroblast cell line, L929, starting at passage 3. This increased adhesiveness correlated with a shift to a fibroblastic morphology and increased collagen I mRNA expression starting at passage 2. Our findings indicate that the centrifugation cell adhesion assay may serve as a reproducible tool to track alterations in chondrocyte phenotype during their extended propagation in culture. PMID- 22235798 TI - Prehospital chemical restraint of a noncommunicative autistic minor by law enforcement. AB - When responders are dealing with an agitated patient in the field, safety for all involved may sometimes only be accomplished with physical or chemical restraints. While experiences using chemical restraint in the prehospital setting are found in the medical literature, the use of this by law enforcement as a first-response restraint has not previously been described. We report a case of successful law enforcement-administered sedation of a noncommunicative, autistic, and violent minor using intramuscular droperidol and diphenhydramine. Although this case has some unique characteristics that allowed chemical restraint to be given by the law enforcement agency, it calls attention to some specific prehospital issues that need to be addressed when dealing with autistic patients with extreme agitation. PMID- 22235799 TI - COX-2 and c-kit expression in canine gliomas. AB - Gliomas are among the most common primary neural tumours of dogs. Cyclooxygenase 2 (COX-2) and c-kit overexpression are associated with increased aggressiveness of gliomas and decreased survival in human beings. COX-2 is the inducible form of cyclooxygenase, which catalyzes prostaglandin formation and may increase tumour proliferation and angiogenesis. C-kit is a tyrosine kinase receptor involved in normal cell physiology; c-kit is upregulated in some canine tumours. In this retrospective study, 20 canine gliomas were identified: 11 (55%) oligodendrogliomas, including 1 anaplastic variant; 1 (5%) oligoastrocytoma; and 8 (40%) astrocytomas, of which 2 were glioblastoma multiforme. None of the gliomas expressed COX-2. None of the gliomas were immunoreactive for c-kit, although all three high-grade tumours had intramural vascular expression. Consequently, COX-2 inhibitors would likely be ineffective against canine gliomas. C-kit inhibitors may have an anti-angiogenic effect in high-grade gliomas, but would likely be ineffective in low- and medium-grade tumours. PMID- 22235800 TI - Continuous glucose monitoring in patients undergoing cardiac surgery. AB - OBJECTIVES: Hyperglycemia is a prominent feature among patients exposed to major stress such as in cardiac surgery. The implementation of a continuous glucose monitoring system (CGMS) for glucose monitoring during cardiac surgery was assessed. SUBJECTS AND METHODS: Fifty-nine consecutive patients who underwent cardiac surgery were monitored by CGMS. Patients' fluid glucose content, drug requirements, and hemodynamic and physiologic parameters were evaluated. RESULTS: Of the 59 patients, 32 completed the monitoring with CGMS. Patients were divided into three groups: diabetes patients, patients without diabetes history who developed significant hyperglycemia perioperatively, and patients who did not develop hyperglycemia. Hyperglycemia was most frequently observed postoperatively. Hyperglycemic patients required significantly more insulin (81+/ 40 vs. 34+/-37 units, P=0.005) and experienced an increased early complication rate, although this difference was not significant. CGMS erroneously detected late-phase operative and immediate postoperative hypoglycemia in approximately one-third of patients as reflected from venous blood sample measurements. CONCLUSIONS: CGMS enables close monitoring and optimal control of blood glucose among patients undergoing major cardiac surgery, although its reliability is limited during the cardiac surgery phase and in the early postoperative period, because of incorrect hypoglycemic readings. PMID- 22235801 TI - Ratiometric detection of Cr3+ and Hg2+ by a naphthalimide-rhodamine based fluorescent probe. AB - Newly synthesized rhodamine derivatives, L(1) and L(2), are found to bind specifically to Hg(2+) or Cr(3+) in presence of large excess of other competing ions with associated changes in their optical and fluorescence spectral behavior. These spectral changes are significant enough in the visible region of the spectrum and thus, allow the visual detection. For L(1), the detection limit is even lower than the permissible [Cr(3+)] or [Hg(2+)] in drinking water as per standard U.S. EPA norms; while the receptor, L2 could be used as a ratiometric sensor for detection of Cr(3+) and Hg(2+) based on the resonance energy transfer (RET) process involving the donor naphthalimide and the acceptor Cr(3+)/Hg(2+) bound xanthene fragment. Studies reveal that these two reagents could be used for recognition and sensing of Hg(2+)/Cr(3+). Further, confocal laser microscopic studies confirmed that the reagent L(2) could also be used as an imaging probe for detection of uptake of these ions in A431 cells. PMID- 22235803 TI - Isotropic high field NMR spectra of Li-ion battery materials with anisotropy >1 MHz. AB - The use of a magic-angle turning and phase-adjusted spinning sideband NMR experiment to resolve and quantify the individual local environments in the high field (7)Li and (31)P NMR spectra of paramagnetic lithium-ion battery materials is demonstrated. The use of short radio frequency pulses provides an excitation bandwidth that is sufficient to cover shift anisotropy of >1 MHz in breadth, allowing isotropic and anisotropic components to be resolved. PMID- 22235804 TI - A new methodology for quantitative LSPR biosensing and imaging. AB - A new quantitative analysis methodology for localized surface plasmon resonance (LSPR) biosensing which determines surface-receptor fractional occupancy, as well as an LSPR imaging technique for the spatiotemporal mapping of binding events, is presented. Electron beam nanolithography was used to fabricate 20 * 20 arrays of gold nanostructures atop glass coverslips. A single biotinylated array was used to measure the association kinetics of neutravidin to the surface by spectroscopically determining the fractional occupancy as a function of time. By regenerating the same array, a reliable comparison of the kinetics could be made between control samples and neutravidin concentrations ranging from 1 MUM to 50 nM. CCD-based imagery of the array, taken simultaneously with the spectroscopic measurements, reveals the binding of neutravidin to the surface as manifested by enhanced scattering over the majority of the resonance peak. The temporal resolution of the LSPR imaging technique was 200 ms and the spatial resolution was 8 MUm(2). PMID- 22235806 TI - Kicking off the 60th anniversary. PMID- 22235808 TI - Music in mind, a randomized controlled trial of music therapy for young people with behavioural and emotional problems: study protocol. AB - AIMS: This article is a report of a trial protocol to determine if improvizational music therapy leads to clinically significant improvement in communication and interaction skills for young people experiencing social, emotional or behavioural problems. BACKGROUND: Music therapy is often considered an effective intervention for young people experiencing social, emotional or behavioural difficulties. However, this assumption lacks empirical evidence. STUDY DESIGN: Music in mind is a multi-centred single-blind randomized controlled trial involving 200 young people (aged 8-16 years) and their parents. Eligible participants will have a working diagnosis within the ambit of international classification of disease 10 mental and behavioural disorders and will be recruited over 15 months from six centres within the Child and Adolescent Mental Health Services of a large health and social care trust in Northern Ireland. Participants will be randomly allocated in a 1:1 ratio to receive standard care alone or standard care plus 12 weekly music therapy sessions delivered by the Northern Ireland Music Therapy Trust. Baseline data will be collected from young people and their parents using standardized outcome measures for communicative and interaction skills (primary endpoint), self-esteem, social functioning, depression and family functioning. Follow-up data will be collected 1 and 13 weeks after the final music therapy session. A cost-effectiveness analysis will also be carried out. DISCUSSION: This study will be the largest trial to date examining the effect of music therapy on young people experiencing social, emotional or behavioural difficulties and will provide empirical evidence for the use of music therapy among this population. Trial registration. This study is registered in the ISRCTN Register, ISRCTN96352204. Ethical approval was gained in October 2010. PMID- 22235805 TI - HOXA13 and HOXD13 expression during development of the syndactylous digits in the marsupial Macropus eugenii. AB - BACKGROUND: Kangaroos and wallabies have specialised limbs that allow for their hopping mode of locomotion. The hindlimbs differentiate much later in development but become much larger than the forelimbs. The hindlimb autopod has only four digits, the fourth of which is greatly elongated, while digits two and three are syndactylous. We investigated the expression of two genes, HOXA13 and HOXD13, that are crucial for digit patterning in mice during formation of the limbs of the tammar wallaby. RESULTS: We describe the development of the tammar limbs at key stages before birth. There was marked heterochrony and the hindlimb developed more slowly than the forelimb. Both tammar HOXA13 and HOXD13 have two exons as in humans, mice and chickens. HOXA13 had an early and distal mRNA distribution in the tammar limb bud as in the mouse, but forelimb expression preceded that in the hindlimb. HOXD13 mRNA was expressed earlier in the forelimb than the hindlimb and was predominantly detected in the interdigital tissues of the forelimb. In contrast, the hindlimb had a more restricted expression pattern that appeared to be expressed at discrete points at both posterior and anterior margins of the limb bud, and was unlike expression seen in the mouse and the chicken. CONCLUSIONS: This is the first examination of HOXA and HOXD gene expression in a marsupial. The gene structure and predicted proteins were highly conserved with their eutherian orthologues. Interestingly, despite the morphological differences in hindlimb patterning, there were no modifications to the polyalanine tract of either HOXA13 or HOXD13 when compared to those of the mouse and bat but there was a marked difference between the tammar and the other mammals in the region of the first polyserine tract of HOXD13. There were also altered expression domains for both genes in the developing tammar limbs compared to the chicken and mouse. Together these findings suggest that the timing of HOX gene expression may contribute to the heterochrony of the forelimb and hindlimb and that alteration to HOX domains may influence phenotypic differences that lead to the development of marsupial syndactylous digits. PMID- 22235809 TI - Au(III)-catalyzed tandem amination-hydration of alkynes: synthesis of alpha-(N-2 pyridonyl)ketones. AB - A new Au(III)-catalyzed tandem amination-hydration reaction has been discovered, leading to the formation of alpha-(N-2-pyridonyl)ketones and heterocyclic analogues in good to excellent yields (14 examples, 48-90%). This reaction demonstrates the unusual use of a heterocyclic sp(2) nitrogen nucleophile in a gold-catalyzed 6-endo-dig cyclization. The tandem process allows rapid access to alpha-(N-2-pyridonyl)ketones, making them a convenient building block for the synthesis of more complex N-alkyl pyridone targets. PMID- 22235810 TI - Oncolytic measles virus encoding thyroidal sodium iodide symporter for squamous cell cancer of the head and neck radiovirotherapy. AB - Oncolytic measles virus (MV) encoding the human thyroidal sodium iodide symporter (MV-NIS) has proved to be safe after intraperitoneal or intravenous administration in patients with ovarian cancer or multiple myeloma, respectively, but it has not yet been administered through intratumoral injection in humans. Squamous cell carcinoma (SCC) of the head and neck (SCCHN) usually is locally invasive and spreads to the cervical lymph nodes, which are suitable for the intratumoral administration of oncolytic viruses. To test whether oncolytic MV is an effective treatment for SCCHN, we used oncolytic MV-NIS to infect SCCHN in vitro and in vivo. The data show that SCCHN cells were infected and killed by MV NIS in vitro. Permissiveness of the tumor cells to MV infection was not affected by irradiation after viral addition. Monitored noninvasively through radioiodine based single-photon emission computed tomography/computed tomography, intratumorally virus-delivered NIS has concentrated the radioiodine in the MV-NIS treated tumors in the FaDu mouse xenograft model of human SCCHN, and the antitumor effect could be boosted significantly (p<0.05) either with concomitant cyclophosphamide therapy or with appropriately timed administration of radioiodine (131)I. MV-NIS could be a promising new anticancer agent that may substantially enhance the outcomes of standard therapy after intratumoral administration in patients with locally advanced SCCHN. PMID- 22235812 TI - The autoimmune nature of post-infarct myocardial healing: oral tolerance to cardiac antigens as a novel strategy to improve cardiac healing. AB - Following a myocardial infarction, lymphocytes have been suggested to react with the damaged heart tissue, which can impair proper tissue healing. In the present work, we investigate whether ingestion of a myocardial homogenate and the consequent development of immunological tolerance can modify the course of post infarction myocardial repair. Infarction-like myocardial lesions were induced in Wistar rats by injecting high doses of isoproterenol. The healing process was evaluated morphologically and functionally for 60 days. Cardiac function was evaluated using isolated and perfused heart (Langendorff) preparations. At day 14 after isoproterenol treatment, lymphocytes from the mediastinal lymph nodes proliferated when exposed in vitro to myocardial homogenate. Moreover, TNF-alpha, IFN-gamma and CCL-5, but not FOXP3+ expression, was increased in draining lymph nodes in isoproterenol-injured animals, indicating that the observed lymphocyte population that proliferated in response to cardiac components presented a pro inflammatory and pro-fibrotic profile. In contrast, lymphocytes from draining lymph nodes of rats given a heart homogenate by gavage 7 days before isoproterenol did not proliferate. Furthermore, the group rendered tolerant expressed cardiac FOXP3+ earlier than did the control group, and showed a milder inflammatory infiltrate, lower MMP-9 expression, less collagen deposition, and improved cardiac performance when compared to animals that received only isoproterenol administration. The present findings suggest that the establishment of oral tolerance to heart components prior to myocardial infarction may drive the cardiac healing process to proceed with less inflammation and fibrosis, thus preserving contractile organ function. PMID- 22235813 TI - Diversity in biofilm formation and production of curli fimbriae and cellulose of Salmonella Typhimurium strains of different origin in high and low nutrient medium. AB - The biofilm forming behavior of 51 Salmonella Typhimurium strains was determined in Tryptone Soya Broth (TSB) and 20 times diluted TSB (1/20TSB) at 25 degrees C and 37 degrees C. The results indicated that biofilm forming behavior is influenced by environmental conditions and associated with the origin of the strains. Clinical, outbreak-associated and retail product isolates showed dense biofilm formation in both media at 25 degrees C, and in TSB also at 37 degrees C. However, industrial isolates only showed dense biofilm formation in 1/20TSB at 25 degrees C. By enumeration of biofilm cells, LIVE/DEAD staining and SEM analysis of biofilms it was found that the ratio of cells and extracellular matrix is affected by environmental conditions. Indeed, the genes involved in curli fimbriae and cellulose production are highly induced during biofilm formation at 25 degrees C in 1/20TSB. This indicates that these are important matrix components during biofilm formation in 1/20TSB at 25 degrees C and that other factors contribute to biofilm formation of clinical, outbreak-associated and retail product isolates at 37 degrees C and/or nutrient-rich conditions. PMID- 22235814 TI - Do trained dogs discriminate individual body odors of women better than those of men? AB - Scent identification lineups using dogs are a potentially valuable forensic tool, but have been dismissed by some critics because of cases where a false identification was shown to have occurred. It is not known, however, why dogs appear to make more false indications to the odors of some persons than of others. In this study, human genders were compared as to the degree their individual odors are distinguishable or "attractive" to dogs. Six dogs were trained to smell an individual's hand odor sample and then find the matching hand odor sample in a lineup of five odors. Using one-gender lineups and two-gender lineups with different gender ratios, it was found that dogs trained for the study identified individual women's hand odors more accurately than those of men. It is hypothesized that this is either because of differences in chemical compounds making discrimination of women's odors easier, or because of greater "odor attractiveness" of women's scents to dogs. PMID- 22235815 TI - The new International Classification of Diseases (ICD-10): the hypertension community needs a greater input. PMID- 22235816 TI - Nondrug interventions for the treatment of hypertension: varying effect. PMID- 22235817 TI - "Refractory" resistant hypertension: new terminology for an old problem. PMID- 22235818 TI - Refractory hypertension: definition, prevalence, and patient characteristics. AB - Among patients with resistant hypertension (RHTN), there are those whose blood pressure (BP) remains uncontrolled in spite of maximal medical therapy. This retrospective analysis aims to characterize these patients with refractory hypertension. Refractory hypertension was defined as BP that remained uncontrolled after >=3 visits to a hypertension clinic within a minimum 6-month follow-up period. Of the 304 patients referred for RHTN, 29 (9.5%) remained refractory to treatment. Patients with refractory hypertension and those with controlled RHTN had similar aldosterone levels and plasma renin activity (PRA). Patients with refractory hypertension had higher baseline BP (175+/-23/97+/-15 mm Hg vs 158+/-25/89+/-15 mm Hg; P=.001/.005) and heart rate, and higher rates of prior stroke and congestive heart failure. During follow-up, the BP of patients with refractory hypertension remained uncontrolled (168.4+/-14.8/93.8+/-17.7 mm Hg) in spite of use of an average of 6 antihypertensive medications, while those of patients with controlled RHTN decreased to 129.3+/-11.2/77.6+/-10.8 mm Hg. Spironolactone reduced the BP by 12.9+/-17.8/6.6+/-13.7 mm Hg in patients with refractory hypertension and by 24.1+/-16.7/9.2+/-12.0 mm Hg in patients with controlled RHTN. In patients with RHTN, approximately 10% remain refractory to treatment. Similar aldosterone and PRA levels and a diminished response to spironolactone suggest that aldosterone excess does not explain the treatment failure. PMID- 22235819 TI - Markers of inflammation, metabolic risk factors, and incident heart failure in American Indians: the Strong Heart Study. AB - Inflammation may play a role in increased risk of heart failure (HF) that is associated with obesity, metabolic syndrome (MS), and diabetes. This study investigated associations between inflammatory markers, MS, and incident HF in a population with a high prevalence of diabetes, obesity, and MS. The cohort consisted of 3098 American Indians without prevalent cardiovascular disease who had C-reactive protein (CRP) and fibrinogen measured at the Strong Heart Study phase II examination. Independent associations between inflammatory markers, MS, and HF were analyzed by Cox hazard models. During a mean follow-up of 11 years, 218 participants developed HF. After the adjustment for cardiovascular risk factors, fibrinogen, (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.15 1.59) but not CRP (HR, 1.25; 95% CI, 0.97-1.32) remained a significant HF predictor. In individuals without diabetes, concomitant presence of MS and elevated CRP or fibrinogen increased HF risk (for MS and CRP: HR, 2.02; 95% CI, 0.95-4.31; for CRP and fibrinogen: HR, 1.75; 95% CI, 0.83-3.72). In a population with a high prevalence of obesity, MS, and diabetes, elevated CRP and fibrinogen increased HF risk. These associations are attenuated by the adjustments for conventional risk factors suggesting that inflammation acts in concert with metabolic and clinical risk factors in increasing HF risk. PMID- 22235820 TI - Mortality and morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. AB - A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and >= 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension. PMID- 22235821 TI - A pilot study comparing furosemide and hydrochlorothiazide in patients with hypertension and stage 4 or 5 chronic kidney disease. AB - Furosemide is the diuretic of choice for the treatment of hypertension in chronic kidney disease but the adaptative changes in the distal nephron may decrease its efficacy. Hydrochlorothiazide is not believed to be efficient in this setting. In a randomized, double-blind, cross-over trial, 23 patients with hypertension and stage 4 or 5 chronic kidney disease received long-acting furosemide (60 mg) and hydrochlorothiazide (25 mg) for 3 months and then both diuretics for 3 months. Sodium and chloride fractional excretions were measured after 3 months of each diuretic and then after their association. A trend towards an increase in the fractional excretion of sodium and chloride was observed with furosemide and hydrochlorothiazide (P=not significant). The association of the two diuretics increased the fractional excretions of sodium and chloride from 3.4+/-1.8 to 4.9+/-2.8 and from 3.8+/-2.0 to 6.0+/-3.1, respectively (P<.05). Furosemide and hydrochlorothiazide decreased mean blood pressure by the same extent. The association of the two diuretics was more efficient on blood pressure. There were no differences between furosemide and hydrochlorothiazide with respect to natriuresis and blood pressure control in patients with hypertension and chronic kidney disease. PMID- 22235822 TI - Understanding minority patients' beliefs about hypertension to reduce gaps in communication between patients and clinicians. AB - The authors' objective was to gain a better understanding of minority patients' beliefs about hypertension and to use this understanding to develop a model to explain gaps in communication between patients and clinicians. Eighty-eight hypertensive black and Latino adults from 4 inner-city primary care clinics participated in focus groups to elucidate views on hypertension. Participants believed that hypertension was a serious illness in need of treatment. Participants' diverged from the medical model in their beliefs about the time course of hypertension (believed hypertension was intermittent); causes of hypertension (believed stress, racism, pollution, and poverty were the important causes); symptoms of hypertension (believed hypertension was primarily present when symptomatic); and treatments for hypertension (preferred alternative treatments that reduced stress over prescription medications). Participants distrusted clinicians who prioritized medications that did not directly address their understanding of the causes or symptoms of hypertension. Patients' models of understanding chronic asymptomatic illnesses such as hypertension challenge the legitimacy of lifelong, pill-centered treatment. Listening to patients' beliefs about hypertension may increase trust, improve communication, and encourage better self-management of hypertension. PMID- 22235823 TI - Using an established telehealth model to train urban primary care providers on hypertension management. AB - The objective of this study was to determine whether a videoconference-based telehealth network can increase hypertension management knowledge and self assessed competency among primary care providers (PCPs) working in urban Federally Qualified Health Centers (FQHCs). We created a telehealth network among 6 urban FQHCs and our institution to support a 12-session educational program designed to teach state-of-the-art hypertension management. Each 1-hour session included a brief lecture by a university-based hypertension specialist, case presentations by PCPs, and interactive discussions among the specialist and PCPs. Twelve PCPs (9 intervention and 3 controls) were surveyed at baseline and immediately following the curriculum. The mean number of correct answers on the 26-item hypertension knowledge questionnaire increased in the intervention group (13.11 [standard deviation (SD)]=3.06) to 17.44 [SD=1.59], P<.01) but not among controls (14.33 [SD=3.21] to 13.00 [SD=3.46], P=.06). Similarly, the mean score on a 7-item hypertension management self-assessed competency scale increased in the intervention group (4.68 [SD=0.94] to 5.41 [SD=0.89], P<.01) but not among controls (5.28 [SD=0.43] to 5.62 [SD=0.67], P=.64). This model holds promise for enhancing hypertension care provided by urban FQHC providers. PMID- 22235826 TI - Effect of metabolic components on the incidence of cerebrovascular/cardiovascular disease among male workers in Japan: 3-year follow-up study. PMID- 22235824 TI - The hypertension team: the role of the pharmacist, nurse, and teamwork in hypertension therapy. AB - Team-based care is one of the key components of the patient-centered medical home. Studies have consistently demonstrated that teams involving pharmacists or nurses in patient management can significantly improve blood pressure control. These findings have been demonstrated in several meta-analyses and systematic reviews. These reviews have generally found that team-based care can reduce systolic blood pressure by 4-10 mm Hg over usual care. However, these reviews have also concluded that many of the studies had various limitations and that additional research should be conducted. The present state of the art review paper will highlight newer studies, many of which were funded by the National Institutes of Health. Newer strategies involve telephone and/or web-based management which is an evolving area to improve blood pressure control in large populations. Social media and other technology is currently being investigated to assist pharmacists or nurses in communicating with patients to improve hypertension management. Few cost-effectiveness analyses have been performed but generally have found favorable costs for team-based care when considering the potential to reduce morbidity and mortality. The authors will suggest additional research that needs to be conducted to help evaluate strategies to best implement team-based care to improve blood pressure management. PMID- 22235827 TI - First-line treatment for hypertension. PMID- 22235828 TI - Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy. AB - In dermal photodamage the ratio of the collagen types III to I changes. This makes the investigation of the fibrillar collagen type characteristics interesting for skin research. In this study collagen types were characterized using 5-dimensional multiphoton laser scanning microscopy (5D-IVT) that can be applied in vivo. Second harmonic generation (SHG) signals and fluorescence lifetimes of the collagen autofluorescence were analysed. Collagen type I generates a higher SHG intensity and a longer fluorescence lifetime compared to collagen type III. Thus, the SHG intensity decrease found in photodamaged skin might be explained by the increase in collagen type III. Calculating the in vivo relevant increase of collagen type III gives a negligible difference in fluorescence lifetime not qualifying this method for the determination of collagen type changes in dermal photodamage in vivo in human skin. However, for pathologies that exhibit higher differences in collagen types 5D-IVT analysis might be a suitable method. PMID- 22235831 TI - Investigation of a screening programme and the possible identification of biomarkers for early disseminated histiocytic sarcoma in Bernese Mountain dogs. AB - The aim of the study was to construct a screening programme for disseminated histiocytic sarcoma (DHS) in Bernese Mountain dogs using diagnostic imaging and blood analysis and evaluate blood borne biomarkers as early disease detection biomarkers. Healthy Bernese Mountain dogs were screened on four occasions in an attempt to detect early disease. Eleven blood borne biomarkers were examined for their worth as early tumour biomarkers. During 2.5 years, five dogs with early DHS were identified; four of these by diagnostic imaging. No dogs developed symptomatic DHS without being detected within 6 months of the screening programme. Only serum ferritin showed potential as a blood borne marker of the disease. Median survival times for the dogs with early DHS were 226 days. Screening programmes every 6 months for Bernese Mountain dogs over 4 years of age including diagnostic imaging and ferritin measurements may identify early DHS. PMID- 22235829 TI - Decreased myosin phosphatase target subunit 1(MYPT1) phosphorylation via attenuated rho kinase and zipper-interacting kinase activities in edematous intestinal smooth muscle. AB - BACKGROUND: Intestinal edema development after trauma resuscitation inhibits intestinal motility which results in ileus, preventing enteral feeding and compromising patient outcome. We have shown previously that decreased intestinal motility is associated with decreased smooth muscle myosin light chain (MLC) phosphorylation. The purpose of the present study was to investigate the mechanism of edema-induced decreases in MLC in a rodent model of intestinal edema. METHODS: Intestinal edema was induced by a combination of resuscitation fluid administration and mesenteric venous hypertension. Sham operated animals served as controls. Contractile activity and alterations in the regulation of MLC including the regulation of MLC kinase (MLCK) and MLC phosphatase (MLCP) were measured. KEY RESULTS: Contraction amplitude and basal tone were significantly decreased in edematous intestinal smooth muscle compared with non-edematous tissue. Calcium sensitivity was also decreased in edematous tissue compared with non-edematous intestinal smooth muscle. Although inhibition of MLCK decreased contractile activity significantly less in edematous tissue compared with non edematous tissue, MLCK activity in tissue lysates was not significantly different. Phosphorylation of MYPT was significantly lower in edematous tissue compared with non-edematous tissue. In addition, activities of both rho kinase and zipper-interacting kinase were significantly lower in edematous tissue. CONCLUSIONS & INFERENCES: We conclude from these data that interstitial intestinal edema inhibits MLC phosphorylation predominantly by decreasing inhibitory phosphorylation of the MLC targeting subunit (MYPT1) of MLC phosphatase via decreased ROCK and ZIPK activities, resulting in more MLC phosphatase activity. PMID- 22235832 TI - Engineering an integrated cellular interface in three-dimensional hydrogel cultures permits monitoring of reciprocal astrocyte and neuronal responses. AB - This study reports a new type of three-dimensional (3D) tissue model for studying interactions between cell types in collagen hydrogels. The aim was to create a 3D cell culture model containing separate cell populations in close proximity without the presence of a mechanical barrier, and demonstrate its relevance to modeling the axon growth-inhibitory cellular interfaces that develop in the central nervous system (CNS) in response to damage. This provides a powerful new tool to determine which aspects of the astroglial scar response and subsequent neuronal regeneration inhibition are determined by the presence of the other cell types. Astrocytes (CNS glia) and dissociated dorsal root ganglia (DRG; containing neurons and peripheral nervous system [PNS] glia) were seeded within collagen solution at 4 degrees C in adjacent chambers of a stainless steel mould, using cells cultured from wild-type or green fluorescent protein expressing rats, to track specific populations. The divider between the chambers was removed using a protocol that allowed the gels to integrate without mixing of the cell populations. Following setting of the gels, they were maintained in culture for up to 15 days. Reciprocal astrocyte and neuronal responses were monitored using confocal microscopy and 3D image analysis. At DRG:astrocyte interfaces, by 5 days there was an increase in the number of astrocytes at the interface followed by hypertrophy and increased glial fibrillary acidic protein expression at 10 and 15 days, indicative of reactive gliosis. Neurons avoided crossing DRG:astrocyte interfaces, and neuronal growth was restricted to the DRG part of the gel. By contrast, neurons were able to grow freely across DRG:DRG interfaces, demonstrating the absence of a mechanical barrier. These results show that in a precisely controlled 3D environment, an interface between DRG and astrocyte cultures is sufficient to trigger reactive gliosis and inhibition of neuronal regeneration across the interface. Different aspects of the astrocyte response could be independently monitored, providing an insight into the formation of a glial scar. This technology has wide potential for researchers wishing to maintain and monitor interactions between adjacent cell populations in 3D culture. PMID- 22235833 TI - The metastatic potential of canine mammary tumours can be assessed by mRNA expression analysis of connective tissue modulators. AB - Metastases are the crucial factor for the prognosis of canine mammary tumours (CMTs). In women, the peptide hormone relaxin is linked with metastatic breast cancer. Therefore, the impact of relaxin and its receptors on matrix metalloproteinase (MMP) expression, metastatic disease and survival was analysed using qRT-PCR and immunohistochemistry of CMT samples from 59 bitches. The expression of relaxin and its receptor RXFP1 (relaxin family peptide receptor 1) was discovered on gene and protein levels. Intratumoural relaxin mRNA expression and relaxin plasma levels had no prognostic value. High mRNA levels RXFP1 were an independent marker of metastatic potential, with a more than 15-fold risk increase, and a predictor for shorter survival. Also, MMP-2 expression was associated with early death because of CMT. The mRNA expressions of relaxin, RXFP1 and MMP-2 were positively correlated indicating a common pathogenetic linkage. Thus, RXFP1 is proposed as a new early marker of metastatic potential in CMT and a possible therapeutic target. PMID- 22235834 TI - Role of immune reactions in drug-induced liver injury (DILI). AB - Although some drugs cause drug-induced liver injury (DILI) through direct damage to hepatocytes or intereference with bile secretion, others cause delayed, often idiosyncratic, DILI with clinical features, such as mild lymphocytic infiltrate, that are reminiscent of allergic reactions involving activation of the adaptive immune system. Even in cases of direct drug-induced hepatotoxicity, infiltration of inflammatory cells into the liver is often observed, suggesting a role for the innate immune system (e.g., neutrophils, macrophages, and so on). Therefore, a variety of hypotheses for the pathogenesis of DILI center around a pathogenic role of drug- (or drug-metabolite-) specific adaptive immune cells, as well as hepatic-injury-induced innate immune responses in the development, progression, and/or resolution of DILI. PMID- 22235835 TI - Site-specific analysis of gas-phase hydrogen/deuterium exchange of peptides and proteins by electron transfer dissociation. AB - To interpret the wealth of information contained in the hydrogen/deuterium exchange (HDX) behavior of peptides and proteins in the gas-phase, analytical tools are needed to resolve the HDX of individual exchanging sites. Here we show that ETD can be combined with fast gas-phase HDX in ND(3) gas and used to monitor the exchange of side-chain hydrogens of individual residues in both small peptide ions and larger protein ions a few milliseconds after electrospray. By employing consecutive traveling wave ion guides in a mass spectrometer, peptide and protein ions were labeled on-the-fly (0.1-10 ms) in ND(3) gas and subsequently fragmented by ETD. Fragment ions were separated using ion mobility and mass analysis enabled the determination of the gas-phase deuterium uptake of individual side-chain sites in a range of model peptides of different size and sequence as well as two proteins; cytochrome C and ubiquitin. Gas-phase HDX-ETD experiments on ubiquitin ions ionized from both denaturing and native solution conditions suggest that residue-specific HDX of side-chain hydrogens is sensitive to secondary and tertiary structural features occurring in both near-native and unfolded gas-phase conformers present shortly after electrospray. The described approach for online gas-phase HDX and ETD paves the way for making mass spectrometry techniques based on gas-phase HDX more applicable in bioanalytical research. PMID- 22235836 TI - Structurally tailored hexagonal ferroelectricity and multiferroism in epitaxial YbFeO3 thin-film heterostructures. AB - Multiferroics have received a great deal of attention because of their fascinating physics of order-parameter cross-couplings and their potential for enabling new device paradigms. Considering the rareness of multiferroic materials, we have been exploring the possibility of artificially imposing ferroelectricity by structurally tailoring antiferromagnets in thin-film forms. YbFeO(3) (YbFO hereafter), a family of centrosymmetric rare-earth orthoferrites, is known to be nonferroelectric (space group Pnma). Here we report that a YbFO thin-film heterostructure fabricated by adopting a hexagonal template surprisingly exhibits nonferroelastic ferroelectricity with the Curie temperature of 470 K. The observed ferroelectricity is further characterized by an extraordinary two-step polarization decay, accompanied by a pronounced magnetocapacitance effect near the lower decay temperature, ~225 K. According to first-principles calculations, the hexagonal P6(3)/mmc-P6(3)mc-P6(3)cm consecutive transitions are primarily responsible for the observed two-step polarization decay, and the ferroelectricity originates from the c-axis-oriented asymmetric Yb 5d(z(2))-O 2p(z) orbital hybridization. Temperature-dependent magnetization curves further reveal an interesting phenomenon of spontaneous magnetization reversal at 83 K, which is attributed to the competition between two distinct magnetocrystalline anisotropy terms, Fe 3d and Yb 4f moments. PMID- 22235838 TI - Synthesis of mixed tin-ruthenium and tin-germanium-ruthenium carbonyl clusters from [Ru3(CO)12] and diaminometalenes (M = Sn, Ge). AB - Diaminostannylenes react with [Ru(3)(CO)(12)] without cluster fragmentation to give carbonyl substitution products regardless of the steric demand of the diaminostannylene reagent. Thus, the Sn(3)Ru(3) clusters [Ru(3){MU Sn(NCH(2)(t)Bu)(2)C(6)H(4)}(3)(CO)(9)] (4) and [Ru(3){MU-Sn(HMDS)(2)}(3)(CO)(9)] (6) [HMDS = N(SiMe(3))(2)] have been prepared in good yields by treating [Ru(3)(CO)(12)] with an excess of the cyclic 1,3-bis(neo-pentyl)-2 stannabenzimidazol-2-ylidene and the acyclic and bulkier Sn(HMDS)(2), respectively, in toluene at 110 degrees C. The use of smaller amounts of Sn(HMDS)(2) (Sn/Ru(3) ratio = 2.5) in toluene at 80 degrees C afforded the Sn(2)Ru(3) derivative [Ru(3){MU-Sn(HMDS)(2)}(2)(MU-CO)(CO)(9)] (5). Compounds 5 and 6 represent the first structurally characterized diaminostannylene-ruthenium complexes. While a further treatment of 5 with Ge(HMDS)(2) led to a mixture of uncharacterized compounds, a similar treatment with the sterically alleviated diaminogermylene Ge(NCH(2)(t)Bu)(2)C(6)H(4) provided [Ru(3){MU-Sn(HMDS)(2)}(2){MU Ge(NCH(2)(t)Bu)(2)C(6)H(4)}(CO)(9)] (7), which is a unique example of Sn(2)GeRu(3) cluster. All these reactions, coupled to a previous observation that [Ru(3)(CO)(12)] reacts with excess of Ge(HMDS)(2) to give the mononuclear complex [Ru{Ge(HMDS)(2)}(2)(CO)(3)] but triruthenium products with less bulky diaminogermylenes, indicate that, for reactions of [Ru(3)(CO)(12)] with diaminometalenes, both the volume of the diaminometalene and the size of its donor atom (Ge or Sn) are of key importance in determining the nuclearity of the final products. PMID- 22235839 TI - Fabrication, characterization, and application of a composite adsorbent for simultaneous removal of arsenic and fluoride. AB - Coexisting arsenic (As) and fluoride (F) in groundwater poses severe health risks worldwide. Highly efficient simultaneous removal of As and F is therefore of great urgency and high priority. The purpose of this study was to fabricate a novel composite adsorbent and explore the mechanism for concurrent removal of As(V) and F at the molecular level. This bifunctional adsorbent with titanium and lanthanum oxides impregnated on granular activated carbon (TLAC) exhibits a pronounced As(V) and F adsorption capacity over commercially available iron- and aluminum-based adsorbents for synthetic and real contaminated groundwater samples. Synchrotron-based X-ray microfluorescence analysis demonstrates that La and Ti were homogeneously distributed on TLAC. Extended X-ray absorption fine structure spectroscopic results suggest that As(V) formed bidentate binuclear surface complex as evidenced by an averaged Ti-As bond distance of 3.34 A in the presence of F. Adsorption tests and Fourier transform infrared spectroscopy analysis indicate that F was selectively adsorbed on lanthanum oxides. The surface configurations constrained with the spectroscopic results were formulated in the charge distribution multisite complexation model to describe the competitive adsorption behaviors of As(V) and F. The results of this study indicate that TLAC could be used as an effective adsorbent for simultaneous removal of As(V) and F. PMID- 22235840 TI - Polymorphism discovery and allele frequency estimation using high-throughput DNA sequencing of target-enriched pooled DNA samples. AB - BACKGROUND: The central role of the somatotrophic axis in animal post-natal growth, development and fertility is well established. Therefore, the identification of genetic variants affecting quantitative traits within this axis is an attractive goal. However, large sample numbers are a pre-requisite for the identification of genetic variants underlying complex traits and although technologies are improving rapidly, high-throughput sequencing of large numbers of complete individual genomes remains prohibitively expensive. Therefore using a pooled DNA approach coupled with target enrichment and high-throughput sequencing, the aim of this study was to identify polymorphisms and estimate allele frequency differences across 83 candidate genes of the somatotrophic axis, in 150 Holstein-Friesian dairy bulls divided into two groups divergent for genetic merit for fertility. RESULTS: In total, 4,135 SNPs and 893 indels were identified during the resequencing of the 83 candidate genes. Nineteen percent (n = 952) of variants were located within 5' and 3' UTRs. Seventy-two percent (n = 3,612) were intronic and 9% (n = 464) were exonic, including 65 indels and 236 SNPs resulting in non-synonymous substitutions (NSS). Significant (P < 0.01) mean allele frequency differentials between the low and high fertility groups were observed for 720 SNPs (58 NSS). Allele frequencies for 43 of the SNPs were also determined by genotyping the 150 individual animals (Sequenom(r) MassARRAY). No significant differences (P > 0.1) were observed between the two methods for any of the 43 SNPs across both pools (i.e., 86 tests in total). CONCLUSIONS: The results of the current study support previous findings of the use of DNA sample pooling and high-throughput sequencing as a viable strategy for polymorphism discovery and allele frequency estimation. Using this approach we have characterised the genetic variation within genes of the somatotrophic axis and related pathways, central to mammalian post-natal growth and development and subsequent lactogenesis and fertility. We have identified a large number of variants segregating at significantly different frequencies between cattle groups divergent for calving interval plausibly harbouring causative variants contributing to heritable variation. To our knowledge, this is the first report describing sequencing of targeted genomic regions in any livestock species using groups with divergent phenotypes for an economically important trait. PMID- 22235841 TI - Onset of action of formoterol versus salmeterol via dry powder inhalers in moderate chronic obstructive pulmonary disease: a randomized, placebo-controlled, double-blind, crossover study. AB - BACKGROUND: Bronchodilator therapy is central to the symptomatic management of chronic obstructive pulmonary disease (COPD), and treatment with short-acting bronchodilators is recommended in patients with mild COPD. OBJECTIVE: This study aimed to evaluate the onset of effect of single-dose formoterol 9 MUg versus single-dose salmeterol 50 MUg in patients with moderate COPD. METHODS: In this multicentre, double-blind, double-dummy, placebo-controlled, three-way single dose crossover study, patients >=40 years of age with moderate COPD were randomized to single-dose formoterol 9 MUg via Turbuhaler(r) plus placebo via Diskus(r), single-dose salmeterol 50 MUg via Diskus(r) plus placebo via Turbuhaler(r) or placebo via Turbuhaler(r) and Diskus(r) (washout period 2-7 days). Terbutaline 0.5 mg/actuation via Turbuhaler(r) was used as reliever medication throughout. The primary endpoint was forced expiratory volume in 1 second (FEV1) at 5 minutes post-dose. Secondary endpoints included proportion of patients achieving >=12% increase in FEV1 at 5 minutes post-dose. RESULTS: 109 patients were randomized, and 108 completed the study. The increase in FEV1 5 minutes post-dose versus pre-dose was 7.2% for formoterol, 4.1% for salmeterol and 0.7% for placebo, and significantly greater for formoterol versus salmeterol (ratio of treatment effects: 1.030; 95% CI 1.008, 1.052; p = 0.009), for formoterol versus placebo (1.064, 95% CI 1.041, 1.087; p < 0.001) and for salmeterol versus placebo (1.033, 95% CI 1.011, 1.056; p = 0.003). The proportions of patients with >=12% increase in FEV1 5 minutes post-dose were 23.1%, 9.2% and 6.4% for formoterol, salmeterol and placebo, respectively; this was statistically significantly larger after formoterol than salmeterol (p = 0.008) or placebo (p < 0.001). All treatments were well tolerated. CONCLUSION: In COPD patients, formoterol 9 MUg has an onset of bronchodilatory effect that is more rapid than salmeterol 50 MUg based on FEV1 at 5 minutes post-dose. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01048333; AstraZeneca study code: D5127C00001. PMID- 22235842 TI - Legionella micdadei prosthetic valve endocarditis complicated by brain abscess: case report and review of the literature. AB - Legionella endocarditis is extremely uncommon, and embolic phenomena have never been reported. We report the first case of Legionella micdadei prosthetic valve endocarditis complicated by brain abscess. A 57-y-old immunocompromised woman with a history of mitral valve replacement developed confusion and left-sided weakness. Brain magnetic resonance imaging showed a 3-cm peripheral-enhancing mass. Transoesophageal echocardiography suggested a perivalvular abscess. Blood cultures and valve cultures were negative. She was diagnosed with 16S rRNA polymerase chain reaction and silver stain, and was discharged with levofloxacin after a redo mitral valve replacement. Twelve cases of Legionella endocarditis were reviewed. Only one case had a native valve, and her endocarditis occurred after pneumonia. All cases were cured. The duration of antibiotic therapy was variable. Legionella species should be considered in the differential diagnosis of culture-negative endocarditis in both immunocompetent and immunocompromised patients. Molecular techniques and silver impregnation stains are useful, especially when cultures using buffered charcoal-yeast extract agar are negative. PMID- 22235843 TI - The use of the African green monkey as a preclinical model for ocular pharmacokinetic studies. AB - PURPOSE: This investigation evaluated the ocular and systemic pharmacokinetics of besifloxacin in African green monkeys compared with cynomolgus monkeys following topical ocular dosing. METHODS: A suspension formulation containing 0.6% besifloxacin was administered to African green and cynomolgus monkeys. Animals were euthanized at predetermined time intervals, and ocular tissue and systemic blood samples were collected and analyzed by LC/MS/MS. RESULTS: In both African green and cynomolgus monkeys, high concentrations of besifloxacin were detected in anterior segment tissues, while levels in posterior segment tissues and plasma were low. Mean concentration versus time profiles of besifloxacin were generally similar between species, with rapid absorption into ocular tissues after a single dose. In anterior segment tissues, concentrations of besifloxacin were measurable throughout the 24-h sampling period in both species. Quantitatively, concentrations were consistently higher in the conjunctiva of African green monkeys compared with cynomolgus monkeys. Besifloxacin levels were also higher during the first 3 h following dosing in the tear fluid of African green monkeys, but lower in the iris/ciliary body during this timeframe. However after the 3-h time point, concentrations in the tear fluid and iris/ciliary body were similar between species. Exposure in cornea tended to be higher in African green monkeys, but the difference was less pronounced than for conjunctiva. Exposure in aqueous humor was comparable between species. In posterior segment tissues, exposure to besifloxacin tended to be higher in cynomolgus monkeys. Systemic exposure also tended to be higher in cynomolgus monkeys, but measurable levels were present in the plasma of both species throughout the 24-h sampling period. With the exception of iris/ciliary body and vitreous humor, mean ocular tissue weights were generally similar between species although a small, but statistically significant, difference was also observed in the choroid. CONCLUSIONS: African green monkeys may be a suitable model for preclinical ocular pharmacokinetic studies. Additional studies using a variety of compounds would be useful in determining whether the quantitative differences in ocular exposures and ocular tissue weights observed in the present investigation reflect slight variations in the procedures used in these separate experiments, or true physiological and anatomical differences between species. PMID- 22235844 TI - Study of antiproliferative effects of synthetic substances against lens epithelial cell line (SRA 01/04). AB - A cataract is a clouded area of the eye, which impairs vision. Cataracts can be caused by a natural hardening of the lens in the elderly, or may be the result of eye injury. However there is a treatment by extracapsular surgery, almost 50% of operations are followed by another posterior capsule opacification. This secondary cataract is due to abnormal cellular proliferation. Pharmacologic inhibition of this cellular proliferation would be a very promising treatment. The objective of our study is to test some antiproliferative drugs, less toxic than those currently used such as 5-FU or mytomycin C. We have investigated the in vitro effects of several molecules (V0 and its derivatives) on a proliferative human lens epithelial cell line (SRA 01/04). During a first step, we have measured the IC50 of each molecule. After this first screening, we have studied the kinetic of the cell growth with or without the molecules at different concentration. Then, flow cytometry was used to determine the phase of the cell cycle at which the proliferation stopped. This study has shown that 3 molecules V19, V1, and A190 have an interesting profile in vitro and were selected to analyze their mechanism of action. PMID- 22235845 TI - A multilingual audiometer simulator software for training purposes. AB - CONCLUSION: A set of algorithms, which allows a computer to determine the answers of simulated patients during pure tone and speech audiometry, is presented. Based on these algorithms, a computer program for training in audiometry was written and found to be useful for teaching purposes. OBJECTIVES: To develop a flexible audiometer simulator software as a teaching and training tool for pure tone and speech audiometry, both with and without masking. METHODS: First a set of algorithms, which allows a computer to determine the answers of a simulated, hearing-impaired patient, was developed. Then, the software was implemented. Extensive use was made of simple, editable text files to define all texts in the user interface and all patient definitions. RESULTS: The software 'audiometer simulator' is available for free download. It can be used to train pure tone audiometry (both with and without masking), speech audiometry, measurement of the uncomfortable level, and simple simulation tests. Due to the use of text files, the user can alter or add patient definitions and all texts and labels shown on the screen. So far, English, French, German, and Portuguese user interfaces are available and the user can choose between German or French speech audiometry. PMID- 22235847 TI - Rapid separation and characterization of cocaine and cocaine cutting agents by differential mobility spectrometry-mass spectrometry. AB - Forensic drug laboratories are inundated with cases requiring time-consuming GC- or LC-based chromatographic separations of submitted samples. High-throughput analytical methods would be of great practical utility within forensic drug analysis. Recently developed ion-mobility-based separation methods combined with mass spectrometry can often be used without chromatography, suppress chemical interferents of similar mass, and operate in seconds. We have evaluated differential mobility spectrometry-mass spectrometry (DMS-MS) for performance on adulterated cocaine mixtures. The DMS interface is only a few centimeters in length, operates in seconds, and can be adapted to any MS system using atmospheric pressure ionization. Drug cutting agents, typical targets such as cocaine, and drug metabolites are rapidly separated by the DMS ion prefilter. Tests demonstrated characterization of complex mixtures, such as isolation of levamisole, an adulterant with alarming side effects, from a 13-component mixture. DMS-MS holds great potential for the analysis of drug samples submitted for forensic analysis. PMID- 22235846 TI - Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity. AB - Ectopic deposition of lipids in liver and other extrahepatic tissues alters their function and occurs once adipose tissue fat storage capacity is exceeded. We investigated sexual dimorphism in the effects of dietary obesity on the liver insulin signaling pathway, as well as its connection to differences in hepatic fat accumulation. Ten-week-old Wistar rats of both sexes were fed a standard diet or a high-fat diet for 26 weeks. Insulin, adipokine levels, and glucose tolerance were measured. Lipid content, PPARalpha mRNA expression and protein levels of insulin receptor subunit beta (IRbeta), IR substrate 2 (IRS-2), Ser/Thr kinase A (Akt), and pyruvate dehydrogenase kinase isozyme 4 (PDK4) were measured in liver. In control rats, serum parameters and hepatic levels of IRbeta, IRS-2, and Akt proteins pointed to a profile of better insulin sensitivity in females. In response to dietary treatment, female rats exhibited a greater increase in body mass and adiposity and lower liver fat accumulation than males, but maintained better glucose tolerance. The reduced insulin signaling capacity in the liver of obese female rats seems to prevent lipid accumulation and probably lipotoxicity associated hepatic disorders. PMID- 22235848 TI - Proteins as sponges: a statistical journey along protein structure organization principles. AB - The analysis of a large database of protein structures by means of topological and shape indexes inspired by complex network and fractal analysis shed light on some organizational principles of proteins. Proteins appear much more similar to "fractal" sponges than to closely packed spheres, casting doubts on the tenability of the hydrophobic core concept. Principal component analysis highlighted three main order parameters shaping the protein universe: (1) "size", with the consequent generation of progressively less dense and more empty structures at an increasing number of residues, (2) "microscopic structuring", linked to the existence of a spectrum going from the prevalence of heterologous (different hydrophobicity) to the prevalence of homologous (similar hydrophobicity) contacts, and (3) "fractal shape", an organizing protein data set along a continuum going from approximately linear to very intermingled structures. Perhaps the time has come for seriously taking into consideration the real relevance of time-honored principles like the hydrophobic core and hydrophobic effect. PMID- 22235849 TI - Induction of cyclooxygenase (COX)-2 in human vaginal epithelial cells in response to TLR ligands and TNF-alpha. AB - PROBLEM: Mucosal inflammation caused by infections of the female lower genital tract is considered to be an important cofactor for HIV transmission. We hypothesize that COX-2, a key inflammation-related enzyme, is involved in these responses and is upregulated by microbial ligands and pro-inflammatory cytokines. METHOD OF STUDY: Human vaginal epithelial cells (VK-2/E6E7) and ectocervical biopsy tissues were stimulated with TLR ligands and the cytokine TNF-alpha, used as surrogates of vaginal infections, and assessed for COX-2 expression and activity by microarray, real-time RT-PCR, immunoblotting, immunohistochemistry, and ELISA. RESULTS: TLR agonists and TNF-alpha induce transcriptional and translational expression of COX-2 in vaginal cells. TLR ligands, MALP2, Pam3CSK4, LTA, and imiquimod induced high epithelial COX-2 expression, while zymosan and poly dI:dC induced very low enzyme expression. Induced mRNA and protein expression correlated with increased COX-2 activity, which led to increased levels of PGE(2) in the cell culture supernatant. These cell-based findings were confirmed in primary cervicovaginal tissue explants. CONCLUSION: Induction of COX 2 expression and activity and the consequent increased levels of prostaglandins are common inflammatory pathways in human cervicovaginal epithelial cells and tissues in response to diverse TLR ligands and pro-inflammatory cytokines. These findings are relevant to the understanding of genital mucosal inflammation, its potential treatment, and its possible relationship with increased tissue susceptibility to HIV-1 infection. PMID- 22235850 TI - Induction of settlement in mussel (Perna canaliculus) larvae by vessel noise. AB - Underwater sound plays an important role in the settlement behaviour of many coastal organisms. Large steel-hulled vessels are known to be a major source of underwater sound in the marine environment. The possibility that underwater sound from vessels may promote biofouling of hulls through triggering natural larval settlement cues was investigated for the mussel, Perna canaliculus. The mussel larvae showed significantly faster settlement when exposed to the underwater noise produced by a 125-m long steel-hulled passenger and freight ferry. Median time to attachment on the substrata (ie settlement) was reduced by 22% and the time taken for all experimental larvae to settle was reduced by 40% relative to a silent control. There was no difference in the survival of the mussel larvae among the various noise treatments. The decrease in settlement time of the mussel larvae appeared to correlate with the intensity of the vessel sound, suggesting that underwater sound emanating from vessels may be an important factor in exacerbating hull fouling by mussels. PMID- 22235851 TI - EZH2 mutations and their association with PICALM-MLLT10 positive acute leukaemia. PMID- 22235852 TI - The Northwick Park Heart Studies: contrasts between the two factor VII assays used. PMID- 22235853 TI - Comparison of the motor discharge to the voluntary sphincters of continence in the rat. AB - BACKGROUND: The rat external anal sphincter (EAS) and external urethral sphincter (EUS) are voluntary muscles of continence that can display similar synchronous electromyographic (EMG) activity patterns. However, the two sphincters are quite different in structure and function. The EUS is a fast twitch muscle and contains fibers expressing type 2B myosin. In contrast, the EAS exhibits slower kinetics and lacks type 2B fibers. This striking contrast in kinetics and fiber type profiles may be shaped by differences in the basal motor drive that each sphincter receives. METHODS: A double EMG approach was used to obtain spontaneously active single motor unit action potentials from the EUS and EAS simultaneously and compare their basal discharge frequencies in urethane anaesthetized rats. KEY RESULTS: The basal firing rates of motor units of the EUS and EAS were not significantly different (3.9 +/- 0.9 Hz vs. 3.1 +/- 1.6 Hz, respectively, n = 7 animals, P = 0.32, paired Student's t-test). However, auto correlogram analysis showed that EUS is driven by neurons with faster instantaneous firing frequencies: 30.5 +/- 2.4 Hz vs 14.3 +/- 0.9 Hz in the EAS (P = 0.03, paired Student's t-test). CONCLUSIONS & INFERENCES: The oscillator(s) driving the EUS operate(s) at a frequency twice that of the EAS. This may explain the presence of type 2B fibers in the EUS. In the inter micturition periods no cross correlation was found in motor discharge to the sphincters suggesting that the two muscles do not share a common central drive to sustain the continent tonus of the two outlet tracts. PMID- 22235855 TI - Expression of PDGFR-beta and Kit in canine anal sac apocrine gland adenocarcinoma using tissue immunohistochemistry. AB - Canine anal sac apocrine gland adenocarcinoma (ASAGAC) is an uncommon but highly invasive and metastatic malignancy. Toceranib phosphate (Palladia) is a receptor tyrosine kinase (RTK) inhibitor that targets several members of the split kinase RTK family. These membrane receptors are important for cell cycling, apoptosis and angiogenesis, all of which can contribute to carcinogenesis. The objective of this study was to evaluate archived, paraffin-embedded canine ASAGAC and normal canine anal sacs for immunohistochemical detection of Kit and platelet-derived growth factor receptor beta (PDGFR-beta). Two of 77 neoplasms (2.6%) expressed Kit. Fifteen of the neoplasms (19.5%) were positive for PDGFR-beta expression. None of the normal canine anal sac epithelium expressed Kit or PDGFR-beta. Because of these results, further investigation should be considered to determine the role of RTKs in the clinical course and treatment of canine ASAGAC. PMID- 22235856 TI - High occurrence of various Clostridium difficile PCR ribotypes in pigs arriving at the slaughterhouse. AB - BACKGROUND: Clostridium difficile is recognized as an important cause of nosocomial diarrhoea in humans, especially in association with the administration of antibiotics. Furthermore, C. difficile can not only cause neonatal enteritis in pigs but can also be found in pigs without any clinical disease symptoms. Clostridium difficile had been found on pork samples destined for human consumption. However, little is known about the risk of food-borne transmission. OBJECTIVE: To elaborate the risk of food-borne transmission of C. difficile via pigs. ANIMALS AND METHODS: The occurrence of C. difficile was assessed in pigs arriving at a slaughterhouse in the Netherlands. Rectal faecal samples from 50 pigs originating from 10 different farms were taken just after the pigs were stunned and bled. These samples were examined using a real-time PCR (BD GeneOhmTM Cdiff Assay) combined with culturing following enrichment. RESULTS: Using real time PCR, none of the faecal samples were found positive for C. difficile while after culturing following enrichment, 14 out of 50 samples (28%) contained C. difficile. The positive samples were derived from nine different farms and encompassed seven different PCR ribotypes (015 predominant). All isolated C. difficile strains were positive for the toxin A and B genes. CONCLUSION: These results indicate that C. difficile can be found in faecal samples obtained from pigs after they were stunned and bled in a slaughterhouse. CLINICAL IMPORTANCE: The potential risk of these findings on food-borne transmission via pigs and associated impact on human health cannot be excluded and needs further study. PMID- 22235857 TI - DCE-MRI: a review and applications in veterinary oncology. AB - Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is a functional imaging technique that assesses the physiology of tumour tissue by exploiting abnormal tumour microvasculature. Advances made through DCE-MRI include improvement in the diagnosis of cancer, optimization of treatment choices, assessment of treatment efficacy and non-invasive identification of prognostic information. DCE-MRI enables quantitative assessment of tissue vessel density, integrity, and permeability, and this information can be applied to study of angiogenesis, hypoxia and the evaluation of various biomarkers. Reproducibility of DCE-MRI results is important in determining the significance of observed changes in the parameters. As improvements are made towards the utility of DCE MRI and interpreting biologic associations, the technique will be applied more frequently in the study of cancer in animals. Given the importance of tumour perfusion with respect to tumour oxygenation and drug delivery, the use of DCE MRI is a convenient and powerful way to gain basic information about a tumour. PMID- 22235858 TI - Life satisfaction of couples 3 years after stroke. AB - PURPOSE: To compare the life satisfaction of stroke patients to that of their spouses, and to examine spouses' variables as determinants of the patients' life satisfaction. METHOD: Patients with a first-ever stroke who were admitted to an inpatient rehabilitation centre and their spouses were included (n=78 couples). Measurements took place 3 years after the stroke. Life satisfaction was measured using the Life Satisfaction Questionnaire (LiSat-9). RESULTS: More spouses (50%) than patients (28%) were dissatisfied with their life as a whole. Spouses were also more likely to be dissatisfied with all other domains of life satisfaction than patients. The associations between the life satisfaction of patients and of spouses were weak (Cramer's V 0.00-0.43). In the backward linear regression analysis both patients' participation in social activities and spouses' life satisfaction were significantly related to patients' life satisfaction. A total of 17.8% of the variance of patients' life satisfaction could be explained by the model. CONCLUSIONS: Both spouse and patient in a couple experience decreased life satisfaction in the chronic phase after stroke, spouses even more so than patients. The life satisfaction of stroke patients was significantly related to spouses' life satisfaction. Family-centred care should be an important part of the rehabilitation process. [ IMPLICATIONS FOR REHABILITATION: * Both spouse and patient in a couple experience decreased life satisfaction in the chronic phase after stroke.* The life satisfaction of stroke patients was significantly related to spouses' life satisfaction.* Family-centred care, in which the spouse is closely involved, should be an important part of the rehabilitation process.] PMID- 22235859 TI - Emerging themes and therapeutic prospects for anti-infective peptides. AB - Pathogens resistant to most conventional anti-infectives are a harbinger of the need to discover and develop novel anti-infective agents and strategies. Endogenous host defense peptides (HDPs) have retained evolution-tested efficacy against pathogens that have become refractory to traditional antibiotics. Evidence indicates that HDPs target membrane integrity, bioenergetics, and other essential features of microbes that may be less mutable than conventional antibiotic targets. For these reasons, HDPs have received increasing attention as templates for development of potential anti-infective therapeutics. Unfortunately, advances toward this goal have proven disappointing, in part owing to limited understanding of relevant structure-activity and selective toxicity relationships in vivo, a limited number of reports and overall understanding of HDP pharmacology, and the difficulty of cost-effective production of such peptides on a commodity scale. However, recent molecular insights and technology innovations have led to novel HDP-based and mimetic anti-infective peptide candidates designed to overcome these limitations. Although initial setbacks have presented challenges to therapeutic development, emerging themes continue to highlight the potential of HDP-based anti-infectives as a platform for next generation therapeutics that will help address the growing threat of multidrug resistant infections. PMID- 22235861 TI - Integrative continuum: accelerating therapeutic advances in rare autoimmune diseases. AB - Autoimmune diseases are chronic, life threatening, and of burgeoning public health concern. They rank among the 10 most common causes of death in women, and some have incidence rates surpassing those of heart disease and cancer. Emerging information regarding molecular and cellular mechanisms affords opportunities for the discovery of novel therapeutic strategies or the repurposing of FDA-approved pharmacologic agents. Yet, obstacles to drug development amplify as an inverse function of the incidence of rare autoimmune disease; challenges include heterogeneous clinical presentation, paucity of definitive biomarkers, and poorly validated measures of therapeutic response. An integrative continuum model to address these challenges is being applied to neuromyelitis optica (NMO)-a potentially devastating neurodegenerative process that has had limited therapeutic options. This model links target discovery with pharmacologic application to accelerate improved clinical efficacy. The application of such innovative strategies may help researchers overcome barriers to therapeutic advances in NMO and other rare autoimmune diseases. PMID- 22235860 TI - Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. AB - Systems approaches have long been used in pharmacology to understand drug action at the organ and organismal levels. The application of computational and experimental systems biology approaches to pharmacology allows us to expand the definition of systems pharmacology to include network analyses at multiple scales of biological organization and to explain both therapeutic and adverse effects of drugs. Systems pharmacology analyses rely on experimental "omics" technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug action. A major use of omics technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, pharmacokinetic and pharmacodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic efficacy. Network analyses based on publicly available databases such as the U.S. Food and Drug Administration's Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organismal levels. The current state of systems pharmacology allows us to formulate a set of questions that could drive future research in the field. The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy. PMID- 22235862 TI - Exploiting the cancer genome: strategies for the discovery and clinical development of targeted molecular therapeutics. AB - Our biological understanding of the molecular basis of cancer has benefited from advances in basic research, accelerated recently by cancer genome sequencing and other high-throughput, genome-wide profiling technologies. Given the diverse heterogeneity among tumors, the traditional cytotoxic chemotherapy and one-size fits-all approaches to cancer discovery and development are not appropriate for molecularly targeted agents. Selection of new drug targets is based on achieving cancer selectivity through exploiting specific dependencies and vulnerabilities predicted from tumor genetics. Discovery of highly target-selective agents is enhanced by integrating multiple modern technologies, particularly structure based design. Efficient clinical evaluation requires smart, hypothesis-testing studies using validated pharmacodynamic and predictive biomarkers. We discuss and exemplify biomarker-driven clinical development and the concept of the Pharmacologic Audit Trail. We detail the exciting approaches offered by drugging the cancer genome, focusing on blocking oncogene addiction, drugging the oncogenic lipid kinome, addressing nononcogene addiction, exploiting synthetic lethality, and overcoming apoptotic resistance, leading to personalized molecular medicine. PMID- 22235865 TI - Synthesis of alkaline earth diazenides M(AE)N2 (M(AE) = Ca, Sr, Ba) by controlled thermal decomposition of azides under high pressure. AB - The alkaline earth diazenides M(AE)N(2) with M(AE) = Ca, Sr and Ba were synthesized by a novel synthetic approach, namely, a controlled decomposition of the corresponding azides in a multianvil press at high-pressure/high-temperature conditions. The crystal structure of hitherto unknown calcium diazenide (space group I4/mmm (no. 139), a = 3.5747(6) A, c = 5.9844(9) A, Z = 2, wR(p) = 0.078) was solved and refined on the basis of powder X-ray diffraction data as well as that of SrN(2) and BaN(2). Accordingly, CaN(2) is isotypic with SrN(2) (space group I4/mmm (no. 139), a = 3.8054(2) A, c = 6.8961(4) A, Z = 2, wR(p) = 0.057) and the corresponding alkaline earth acetylenides (M(AE)C(2)) crystallizing in a tetragonally distorted NaCl structure type. In accordance with literature data, BaN(2) adopts a more distorted structure in space group C2/c (no. 15) with a = 7.1608(4) A, b = 4.3776(3) A, c = 7.2188(4) A, beta = 104.9679(33) degrees , Z = 4 and wR(p) = 0.049). The N-N bond lengths of 1.202(4) A in CaN(2) (SrN(2) 1.239(4) A, BaN(2) 1.23(2) A) correspond well with a double-bonded dinitrogen unit confirming a diazenide ion [N(2)](2-). Temperature-dependent in situ powder X-ray diffractometry of the three alkaline earth diazenides resulted in formation of the corresponding subnitrides M(AE(2))N (M(AE) = Ca, Sr, Ba) at higher temperatures. FTIR spectroscopy revealed a band at about 1380 cm(-1) assigned to the N-N stretching vibration of the diazenide unit. Electronic structure calculations support the metallic character of alkaline earth diazenides. PMID- 22235863 TI - Using commercially available personal glucose meters for portable quantification of DNA. AB - DNA detection is commonly used in molecular biology, pathogen analysis, genetic disorder diagnosis, and forensic tests. While traditional methods for DNA detection such as polymerase chain reaction (PCR) and DNA microarrays have been well developed, they require sophisticated equipment and operations, and thus it is still challenging to develop a portable and quantitative DNA detection method for the public use at home or in the field. Although many other techniques and devices have been reported to make the DNA detection simple and portable, very few of them are currently accessible to the public for quantitative DNA detection because of either the requirement of laboratory-based instrument or lack of quantitative detection. Herein we report application of personal glucose meters (PGMs), which are widely available, low cost, and simple to use, for quantitative detection of DNA, including a hepatitis B virus DNA fragment. The quantification is based on target-dependent binding of cDNA-invertase conjugate with the analyte DNA, thereby transforming the concentration of DNA in the sample into glucose through invertase-catalyzed hydrolysis of sucrose. Instead of amplifying DNA strands through PCR, which is vulnerable to contaminations commonly encountered for home and field usage, we demonstrate here signal amplifications based on enzymatic turnovers, making it possible to detect 40 pM DNA using PGM that can detect glucose only at the mM level. The method also shows excellent selectivity toward single nucleotide mismatches. PMID- 22235866 TI - Unconventional, highly selective CO2 adsorption in zeolite SSZ-13. AB - Low-pressure adsorption of carbon dioxide and nitrogen was studied in both acidic and copper-exchanged forms of SSZ-13, a zeolite containing an 8-ring window. Under ideal conditions for industrial separations of CO(2) from N(2), the ideal adsorbed solution theory selectivity is >70 in each compound. For low gas coverage, the isosteric heat of adsorption for CO(2) was found to be 33.1 and 34.0 kJ/mol for Cu- and H-SSZ-13, respectively. From in situ neutron powder diffraction measurements, we ascribe the CO(2) over N(2) selectivity to differences in binding sites for the two gases, where the primary CO(2) binding site is located in the center of the 8-membered-ring pore window. This CO(2) binding mode, which has important implications for use of zeolites in separations, has not been observed before and is rationalized and discussed relative to the high selectivity for CO(2) over N(2) in SSZ-13 and other zeolites containing 8-ring windows. PMID- 22235867 TI - Functional mesoporous silica nanoparticles for the selective sequestration of free fatty acids from microalgal oil. AB - A series of 2d-hexagonally packed mesoporous silica nanoparticle material with 10 nm pore diameter (MSN-10) covalently functionalized with organic surface modifiers have been synthesized via a post-synthesis grafting method. The material structure has been characterized by powder X-ray diffraction, electron microscopy, and nitrogen sorption analyses, and the free fatty acid (FFA) sequestration capacity and selectivity was investigated and quantified by thermogravimetric and GC/MS analysis. We discovered that aminopropyl functionalized 10 nm pore mesoporous silica nanoparticle material (AP-MSN-10) sequestered all available FFAs and left nearly all other molecules in solution from a simulated microalgal extract containing FFAs, sterols, terpenes, and triacylglycerides. We also demonstrated selective FFA sequestration from commercially available microalgal oil. PMID- 22235868 TI - Lipopolysaccharide priming enhances expression of effectors of immune defence while decreasing expression of pro-inflammatory cytokines in mammary epithelia cells from cows. AB - BACKGROUND: Udder infections with environmental pathogens like Escherichia coli are a serious problem for the dairy industry. Reduction of incidence and severity of mastitis is desirable and mild priming of the immune system either through vaccination or with low doses of immune stimulants such as lipopolysaccharide LPS was previously found to dampen detrimental effects of a subsequent infection. Monocytes/macrophages are known to develop tolerance towards the endotoxin LPS (endotoxin tolerance, ET) as adaptation strategy to prevent exuberant inflammation.We have recently observed that infusion of 1 MUg of LPS into the quarter of an udder effectively protected for several days against an experimentally elicited mastitis. We have modelled this process in primary cultures of mammary epithelial cells (MEC) from the cow. MEC are by far the most abundant cells in the healthy udder coming into contact with invading pathogens and little is known about their role in establishing ET. RESULTS: We primed primary MEC cultures for 12 h with LPS (100 ng/ml) and stimulated three cultures either 12 h or 42 h later with 107/ml particles of heat inactivated E. coli bacteria for six hours. Priming-related alterations in the global transcriptome of those cells were quantified with Affymetrix microarrays. LPS priming alone caused differential expression of 40 genes and mediated significantly different response to a subsequent E. coli challenge of 226 genes. Expression of 38 genes was enhanced while that of 188 was decreased. Higher expressed were anti microbial factors (beta-defensin LAP, SLPI), cell and tissue protecting factors (DAF, MUC1, TGM1, TGM3) as well as mediators of the sentinel function of MEC (CCL5, CXCL8). Dampened was the expression of potentially harmful pro inflammatory master cytokines (IL1B, IL6, TNF-alpha) and immune effectors (NOS2, matrix metalloproteases). Functional network analysis highlighted the reduced expression of IL1B and of IRF7 as key to this modulation. CONCLUSION: LPS-primed MEC are fitter to repel pathogens and better protected against misguided attacks of the immune response. Attenuated is the exuberant expression of factors potentially promoting immunopathological processes. MEC therefore recapitulate many aspects of ET known so far from professional immune cells. PMID- 22235869 TI - Therapeutic drug monitoring of aminoglycosides in acute myeloid leukaemia patients. AB - International guidelines limit the use of aminoglycosides in febrile neutropenia to severe situations. We retrospectively reviewed the use of aminoglycosides in adult acute myeloid leukaemia patients admitted in 2009. Our guidelines include precise indications (severe sepsis, shock, drug resistance), dosing regimens (once-daily 20 mg/kg/day amikacin, 5 mg/kg/day gentamicin), durations of treatment, drug monitoring timing, and target C(max) concentrations (40 mg/l amikacin, 20 mg/l gentamicin). Thirty-one patients received 46 aminoglycoside courses: 31 amikacin and 15 gentamicin. The mean prescribed dosage was 19 +/- 2.8 mg/kg/day for amikacin and 4.7 +/- 0.9 mg/kg/day for gentamicin. The mean duration of use was 2.9 days for both drugs. The mean C(max) for amikacin was 47 +/- 13 mg/l and for gentamicin was 13.6 +/- 7.5 mg/l. In compliant regimens, all amikacin patients and a third of gentamicin patients had adequate C(max). Among 23 isolated pathogens, 65.5% were susceptible to both drugs and 11.5% to amikacin only. This vindicates the 20 mg/kg/day amikacin dosage and suggests a need to increase the gentamicin dosage. PMID- 22235871 TI - Tonsil surgery efficiently relieves symptoms: analysis of 54 696 patients in the National Tonsil Surgery Register in Sweden. AB - CONCLUSION: Patients operated with tonsillar surgery report a high degree of symptom relief 6 months after surgery. OBJECTIVE: The purpose of this study was to analyze symptom relief 6 months after tonsil surgery in relation to age, indication, surgical procedure, primary bleeding and unplanned postoperative visits. The National Tonsil Surgery Register in Sweden offers data from 54,696 patients registered during 1997-2008. METHODS: This was a prospective assessment by questionnaire. Data were collected using three questionnaires, two completed by professionals and one 6 months postoperatively by the parents/patients. RESULTS: Among 54,696 patients, the most common surgical indications were obstruction (49.7%), followed by recurrent tonsillitis (35.2%). Symptom relief 6 months after surgery was high in all indication groups (>92%), and highest for patients operated on the indication peritonsillitis (>98%). The indications obstruction, recurrent tonsillitis or chronic tonsillitis reported a high degree (>96%) of symptom relief. Of the patients who underwent tonsillectomy with adenoidectomy, 97.5% were symptom-free compared to 96% of patients who had tonsillectomy alone and 96.1% who underwent tonsillotomy (p < 0.0001). In all, 13.9% of patients required an unplanned visit to the clinic postoperatively. Only 148 of 54,696 patients reported worsening of symptoms after surgery. PMID- 22235872 TI - Nontoxic Nep1-like proteins of the downy mildew pathogen Hyaloperonospora arabidopsidis: repression of necrosis-inducing activity by a surface-exposed region. AB - The genome of the downy mildew pathogen Hyaloperonospora arabidopsidis encodes necrosis and ethylene-inducing peptide 1 (Nep1)-like proteins (NLP). Although NLP are widely distributed in eukaryotic and prokaryotic plant pathogens, it was surprising to find these proteins in the obligate biotrophic oomycete H. arabidopsidis. Therefore, we analyzed the H. arabidopsidis NLP (HaNLP) family and identified 12 HaNLP genes and 15 pseudogenes. Most of the 27 genes form an H. arabidopsidis-specific cluster when compared with other oomycete NLP genes, suggesting this class of effectors has recently expanded in H. arabidopsidis. HaNLP transcripts were mainly detected during early infection stages. Agrobacterium tumefaciens-mediated transient expression and infiltration of recombinant NLP into tobacco and Arabidopsis leaves revealed that all HaNLP tested are noncytotoxic proteins. Even HaNLP3, which is most similar to necrosis inducing NLP proteins of other oomycetes and which contains all amino acids that are critical for necrosis-inducing activity, did not induce necrosis. Chimeras constructed between HaNLP3 and the necrosis-inducing PsojNIP protein demonstrated that most of the HaNLP3 protein is functionally equivalent to PsojNIP, except for an exposed domain that prevents necrosis induction. The early expression and species-specific expansion of the HaNLP genes is suggestive of an alternative function of noncytolytic NLP proteins during biotrophic infection of plants. PMID- 22235870 TI - Current and potential pharmacological treatment options for maintenance therapy in opioid-dependent individuals. AB - Opioid dependence, manifesting as addiction to heroin and pharmaceutical opioids is increasing. Internationally, there are an estimated 15.6 million illicit opioid users. The global economic burden of opioid dependence is profound both in terms of HIV and hepatitis C virus transmission, direct healthcare costs, and indirectly through criminal activity, absenteeism and lost productivity. Opioid agonist medications, such as methadone and buprenorphine, that stabilize neuronal systems and provide narcotic blockade are the most effective treatments. Prolonged provision of these medications, defined as maintenance treatment, typically produces improved outcomes when compared with short-duration tapers and withdrawal. The benefits of opioid agonist maintenance include decreased illicit drug use, improved retention in treatment, decreased HIV risk behaviours and decreased criminal behaviour. While regulations vary by country, these medications are becoming increasingly available internationally, especially in regions experiencing rapid transmission of HIV due to injection drug use. In this review, we describe the rationale for maintenance treatment of opioid dependence, discuss emerging uses of opioid antagonists such as naltrexone and sustained release formulations of naltrexone and buprenorphine, and provide a description of the experimental therapies. PMID- 22235873 TI - The re-emergence of the bed bug as a nuisance pest: implications of resistance to the pyrethroid insecticides. AB - A global resurgence of bed bugs (Hemiptera: Cimicidae) has led to renewed scientific interest in these insects. The current bed bug upsurge appears to have started almost synchronously in the late 1990 s in Europe, the U.S.A. and Australia. Several factors have led to this situation, with resistance to applied insecticides making a significant contribution. With a growing number of insecticides (DDT, carbamates, organophosphates etc.) being no longer available as a result of regulatory restrictions, the mainstay chemistry used for bed bug control over the past few decades has been the pyrethroid insecticides. With reports of increasing tolerance to pyrethroids leading to control failures on the rise, containing and eradicating bed bugs is proving to be a difficult task. Consequently, several recent studies have focused on determining the mode of action of pyrethroid resistance in bed bug populations sourced from different locations. Correct identification of the factor(s) responsible for the increasing resistance is critical to the development of effective management strategies, which need to be based, wherever possible, on firm scientific evidence. Here we review the literature on this topic, highlighting the mechanisms thought to be involved and the problems currently faced by pest control professionals in dealing with a developing pandemic. PMID- 22235874 TI - Histological and enzyme histochemical investigation of the hemal nodes of the hair goat. AB - We investigated the structure of the hemal node in six healthy hair goats using histological and enzyme histochemical methods. After processing, tissue sections were stained with Crossman's trichrome, Gordon-Sweet's silver and Pappenheim's panoptic stains. Alpha-naphthyl acetate esterase (ANAE) and acid phosphatase (ACP ase) were demonstrated in frozen sections. Hemal nodes were encapsulated by connective tissue and few smooth muscle cells. Several trabeculae originated from the capsule and extended into the hemal node. A subcapsular sinus was present beneath the capsule and was continuous with the deeper sinuses. Subcapsular and deep sinuses were filled with erythrocytes. The parenchyma consisted of lymphoid follicles, diffuse interfollicular lymphocytes and irregular wide lymphoid cords. Cortical and medullary regions were not distinct. ANAE (+) and ACP-ase (+) cells were located mainly in the germinal centers of the lymphoid follicles and also were scattered equally in the interfollicular region and lymphoid cords. Monocytes, macrophages and reticular cells displayed a diffuse positive reaction, whereas localized granular positivity was observed in lymphocytes. We demonstrated that the general structure of the hair goat hemal nodes is similar to that of other ruminant species. PMID- 22235875 TI - Forensic fluid dynamics and the Indian Spring (1991) cave collapse problem. AB - Nof and Paldor (Safety Sci 2010;48:607-14) suggested that resonance in the air pockets in the Indian Spring cavern might have contributed to the 1991 collapse. Here, we extend the resonance theory to one pocket in the cavern and a very broad basin that serves as the other branch of the U-tube. Our methodology is to apply familiar fluid dynamics principles to the situation that occurred in the cave. We did so on the basis of our interviews with four of the five surviving cave divers. We dissected their testimonies to arrive at a physically plausible scenario determined on the basis of a fluid dynamics application to the natural flow in the cave, the flow induced by the compressed air released by the divers and the mudslide. We found that there was a temporary flow blocking during the collapse, but no total flow reversal within the cave. PMID- 22235876 TI - Prospective study of seasonal patterns in hemostatic factors in older men and their relation to excess winter coronary heart disease deaths. AB - BACKGROUND: In England and Wales, approximately 20% extra deaths from coronary heart disease (CHD) occur between December and March, among older people. Circulating concentrations of tissue plasminogen activator (t-PA), von Willebrand factor (VWF) and fibrin D-dimer are associated with arterial disease, and tend to peak in winter. The potential contributions of these hemostatic activation measures to excess winter mortality are unknown. OBJECTIVES: To estimate contributions of hemostatic factors to excess winter mortality. METHODS: Seasonal patterns in t-PA, VWF and D-dimer were investigated in 4088 men aged 60-79 years from 24 British towns. Data on established coronary risk factors were collected by questionnaire, physical examination and blood sampling. The adjusted mean increase in hemostatic markers during winter months, after adjustment for a range of coronary risk factors, was combined with associations of each marker with CHD mortality obtained from 9 years' follow-up of participants, to predict degree of excess CHD winter mortality. Associations of hemostatic markers with CHD incidence from large meta-analyses were also used. RESULTS: All three markers showed peaks in winter; the adjusted mean increases during winter months were 0.21, 0.15 and 0.12 standard deviations for t-PA, VWF and log(D-dimer), respectively. Predicted excess hazard ratios for winter CHD mortality were 3.0%, 2.4% and 3.1%, respectively, in combination, representing an 8.6% excess. This increased to 14% when applying meta-analysis estimates. CONCLUSIONS: Seasonal patterns in three hemostatic markers predict at least 8.6% excess CHD mortality in winter in Great Britain, potentially accounting for over half the excess observed in recent years. PMID- 22235877 TI - Evaluation of minichromosome maintenance protein 7 as a prognostic marker in canine cutaneous mast cell tumours. AB - Minichromosome maintenance proteins (MCMs) are sensitive markers of cellular proliferation and have been shown to be significant predictors of survival in several human malignancies. MCM7 was evaluated as a prognostic marker in canine cutaneous mast cell tumours (MCTs). MCM7 immunohistochemistry was performed and an index of MCM7-positive cells calculated in dogs with known outcome. The Receiver Operating Characteristics method was used to individuate the best cut off value of MCM7 score as predictor of survival. Survival analysis and prognostic variables were analysed with statistical methods. Ninety-five dogs were included with 31 dying of MCTs. A value of 0.18 was used as cut-off value of MCM7 score as a binary variable. The median survival time for MCM7 score <=0.18 was not reached at 3668 days, whereas for MCM7 score >0.18 was 187 days (log-rank test; P < 0.0001). In the multivariable analysis, MCM7 was significantly associated with survival after controlling for age, surgical margins and histological grade (hazard ratio 9.2; P = 0.001). PMID- 22235878 TI - Reliability and accuracy of an automated tracking algorithm to measure controlled passive and active muscle fascicle length changes from ultrasound. AB - Manual tracking of muscle fascicle length changes from ultrasound images is a subjective and time-consuming process. The purpose of this study was to assess the repeatability and accuracy of an automated algorithm for tracking fascicle length changes in the medial gastrocnemius (MG) muscle during passive length changes and active contractions (isometric, concentric and eccentric) performed on a dynamometer. The freely available, automated tracking algorithm was based on the Lucas-Kanade optical flow algorithm with an affine optic flow extension, which accounts for image translation, dilation, rotation and shear between consecutive frames of an image sequence. Automated tracking was performed by three experienced assessors, and within- and between-examiner repeatability was computed using the coefficient of multiple determination (CMD). Fascicle tracking data were also compared with manual digitisation of the same image sequences, and the level of agreement between the two methods was calculated using the coefficient of multiple correlation (CMC). The CMDs across all test conditions ranged from 0.50 to 0.93 and were all above 0.98 when recomputed after the systematic error due to the estimate of the initial fascicle length on the first ultrasound frame was removed from the individual fascicle length waveforms. The automated and manual tracking approaches produced similar fascicle length waveforms, with an overall CMC of 0.88, which improved to 0.94 when the initial length offset was removed. Overall results indicate that the automated fascicle tracking algorithm was a repeatable, accurate and time-efficient method for estimating fascicle length changes of the MG muscle in controlled passive and active conditions. PMID- 22235879 TI - Modeling flexible pharmacophores with distance geometry, scoring, and bound stretching. AB - The study of pharmacophores, i.e., of common features between different ligands, is important for the quantitative identification of "compatible" enzymes and binding species. A pharmacophore-based technique is developed that combines multiple conformations with a distance geometry method to create flexible pharmacophore representations. It uses a set of low-energy conformations combined with a new process we call bound stretching to create sets of distance bounds, which contain all or most of the low-energy conformations. The bounds can be obtained using the exact distances between pairs of atoms from the different low energy conformations. To avoid missing conformations, we can take advantage of the triangle distance inequality between sets of three points to logically expand a set of upper and lower distance bounds (bound stretching). The flexible pharmacophore can be found using a 3-D maximal common subgraph method, which uses the overlap of distance bounds to determine the overlapping structure. A scoring routine is implemented to select the substructures with the largest overlap because there will typically be many overlaps with the maximum number of overlapping bounds. A case study is presented in which 3-D flexible pharmacophores are generated and used to eliminate potential binding species identified by a 2-D pharmacophore method. A second case study creates flexible pharmacophores from a set of thrombin ligands. These are used to compare the new method with existing pharmacophore identification software. PMID- 22235880 TI - Topographic and manometric characterization of the recto-anal inhibitory reflex. AB - BACKGROUND: Recto-anal inhibitory reflex (RAIR) is an integral part of normal defecation. The physiologic characteristics of RAIR along anal length and anterior-posterior axis are unknown. The aim of this study was to perform topographic and vector-graphic evaluation of RAIR along anal canal using high definition manometry (HDM), and examine the role of various muscle components. METHODS: Anorectal topography was assessed in 10 healthy volunteers using HDM probe with 256 sensors. Recto-anal inhibitory reflex data were analyzed every mm along the length of anal canal for topographic, baseline, residual, and plateau pressures during five mean volumes of balloon inflation (15 cc, 40 cc, 71 cc, 101 cc, 177 cc), and in 3D by dividing anal canal into 4 * 2.1 mm grids. KEY RESULTS: Relaxation pressure progressively increases along anal canal with increasing balloon volume up to 71 cc and thereafter plateaus. In 3D, RAIR is maximally seen at the middle and upper portions of anal canal (levels 1.2-3.2 cm) and posteriorly. Peak residual pressure was seen at proximal anal canal. CONCLUSIONS & INFERENCES: Recto-anal inhibitory reflex is characterized by differential anal relaxation along anterior-posterior axis, longitudinally along the length of anal canal, and it depends on the rectal distention volume. It is maximally seen at internal anal sphincter pressure zone. Multidimensional analyses indicate that external anal sphincter provides bulk of anal residual pressure. Our findings emphasize importance of sensor location and orientation; as anterior and more distal location may miss RAIR. PMID- 22235883 TI - Indicators of distress in families of children with cerebral palsy. AB - PURPOSE: To describe family distress as reported by parents of children with cerebral palsy (CP) and to identify factors associated with distress. METHOD: In this descriptive, historical cohort study, parents of school-age children (9.2 +/ 2.1 years) with CP completed the Parenting Stress Index, the Impact on Family Scale and family-related items on the Child Health Questionnaire. Predictor variables considered were sociodemographic factors, motor, cognitive and behavioral difficulties and functional limitations. These were assessed using the Gross Motor Function Measure, Leiter IQ, Strengths and Difficulties Questionnaire and Vineland Adaptive Behavior Scale. RESULTS: Parents of 95 children were recruited, of whom 45% were highly stressed and 11% defensive. Half indicated that their child's health impacted on their time, emotional status and family activities. Family distress measures were modestly associated with motor (r = 0.30-0.48) and cognitive abilities (r = 0.29-0.37) but more strongly correlated with particular behavioral difficulties (r = -0.42 to 0.55). Activity limitations across domains were highly associated with measures of distress. CONCLUSIONS: Parents of school-aged children with CP are likely to experience high stress, increased time constraints and financial and psychological burden. Findings illustrate the need to monitor family functioning intermittently as the child develops and direct appropriate resources to optimize child and family well being. PMID- 22235884 TI - Hepatoprotective activity of Cyperus alternifolius on carbon tetrachloride induced hepatotoxicity in rats. AB - OBJECTIVE: The present work explored the potential hepatoprotective activity of total ethanol and successive extracts of Cyperus alternifolius L (Cyperaceae) against carbon tetrachloride (CCl(4))-induced hepatotoxicity in rats and to isolate their bioactive constituents. METHODS: For isolation and identification of the compounds, column chromatography and spectroscopic analysis were used, a model of hepatotoxicity by CCl(4) in rats was used to evaluate the total ethanol extract and its successive fractions. RESULTS: Phytochemical screening of C. alternifolius revealed the presence of different phytochemical groups. The plant proved to be safe for human use because it did not induce any signs of toxicity or mortality in mice when administered orally at doses up to 5000 mg kg(-1). The total alcoholic extract in doses of 100 and 200 mg kg(-1) and the successive extracts (ether, chloroform and ethyl acetate) in a dose of 10 mg kg(-1) exhibited a significant (p <= 0.05) protective effect by lowering the elevated serum levels of aspartate aminotransferase: 230.4, 218.8, 224.6, 227.4 and 231.6 U L(-1), respectively, compared with 111.6 U L(-1) for silymarin (25 mg kg(-1)). Serum levels of alanine aminotransferase were also reduced: 77.4, 72.7, 79.7, 76.0 and 79.7 U L(-1) compared to 63.7 U L(-1) for silymarin. Alkaline phosphatase: 164.6, 158.0, 163.6, 154.7 and 166.4 U L(-1) compared to 138.2 U L( 1) for silymarin. Total bilirubin: 0.50, 0.46, 0.55, 0.52 and 0.57 mg dl(-1) compared to 0.42 mg dl(-1) for silymarin. Cholesterol: 213.1, 200.0, 192.7, 193.6 and 197.1 mg dl(-1) compared to 180.3 mg dl(-1) for silymarin. Triglycerides: 237.3, 222.4, 209.5, 206.8 and 210.2 mg dl(-1) compared to 196.8 mg dl(-1) for silymarin. Eight phenolic compounds were isolated from C. alternifolius for the first time and identified as esculetin 1, umbelliferon 2, imperatorin 3, psoralen 4, xanthotoxin 5, quercetin 6, quercetin-3-O-rutinoside 7 and gallic acid 8. CONCLUSIONS: The results concluded that C. alternifolius possesses significant protective effect against hepatotoxicity induced by CCl(4). PMID- 22235885 TI - Trypanocide, cytotoxic, and antifungal activities of Momordica charantia. AB - CONTEXT: Chagas disease, caused by Trypanosoma cruzi, is a public health problem. Currently, chemotherapy is the only available treatment for this disease, and the drugs used, nifurtimox and benzonidazol, present high toxicity levels. An alternative for replacing these drugs are natural extracts from Momordica charantia L. (Cucurbitaceae) used in traditional medicine because of their antimicrobial and biological activities. OBJECTIVE: In this study, we evaluated the extract of M. charantia for its antiepimastigote, antifungal, and cytotoxic activities. MATERIALS AND METHODS: An ethanol extract of leaves from M. charantia was prepared. To research in vitro antiepimastigote activity, T. cruzi CL-B5 clone was used. Epimastigotes were inoculated at a concentration of 1 * 10(5) cells/mL in 200 ul tryptose-liver infusion. For the cytotoxicity assay, J774 macrophages were used. The antifungal activity was evaluated by microdilution using strains of Candida albicans, Candida tropicalis, and Candida krusei. RESULTS: The effective concentration capable of killing 50% of parasites (IC(50)) was 46.06 ug/mL. The minimum inhibitory concentration (MIC) was <= 1024 ug/mL. Metronidazole showed a potentiation of its antifungal effect when combined with an extract of M. charantia. CONCLUSIONS: Our results indicate that M. charantia could be a source of plant-derived natural products with antiepimastigote and antifungal-modifying activity with moderate toxicity. PMID- 22235886 TI - Antioxidative and antitumor properties of in vitro-cultivated broccoli (Brassica oleracea var. italica). AB - CONTEXT: Broccoli [Brassica oleracea L. var. italica Plenck. (Brassicaceae)] contains substantial quantities of bioactive compounds, which are good free radical scavengers and thus might have strong antitumor properties. Enhancing production of plant secondary metabolites could be obtained with phytohormones that have significant effects on the metabolism of secondary metabolites. In that manner, in vitro culture presents good model for manipulation with plant tissues in order to affect secondary metabolite production and thus enhance bioactive properties of plants. OBJECTIVE: Estimation of the antioxidative and antitumor properties of broccoli cultivated in different in vitro conditions. MATERIALS AND METHODS: In vitro germinated and cultivated broccoli seedlings, as well as spontaneously developed calli, were subjected to Soxhlet extraction. Antioxidative activity of the herbal extracts was determined using 1,1-diphenyl-2 picrylhydrazyl (DPPH(*)) radical method. Antitumor properties of the extracts were determined using crown-gall tumor inhibition (potato disc) assay. RESULTS: Three, 10, 20, and 30 days old broccoli seedlings, cultivated in vitro on three different Murashige-Skoog media, two types of callus, and seedlings from sterile filter paper were used for extraction. In total, 15 aqueous extracts were tested for antioxidative and antitumor potential. Three day-old seedlings showed the highest antioxidative activity. Eleven out of 15 aqueous extracts demonstrated above 50% of crown-gall tumor inhibition in comparison with the control. Tumor inhibition was in association with types and concentrations of phytohormones presented in growing media. DISCUSSION AND CONCLUSIONS: It is demonstrated that phytohormones in plant-growing media could affect the bioactive properties of broccoli either through increasing or decreasing their antioxidative and antitumor potential. PMID- 22235887 TI - In vivo antiplasmodial activities of aqueous extract of Bridelia ferruginea stem bark against Plasmodium berghei berghei in mice. AB - CONTEXT: Bridelia ferruginea Benth (Euphorbiaceae) is an indigenous medicinal plant in Nigeria. It is usually a gnarled shrub which sometimes reaches the size of a tree in suitable condition. Decoctions of parts of this plant have been employed in ethno medicine in many parts of Africa for treatment of many ailments including malaria fever. OBJECTIVE: In vivo antiplasmodial activity of aqueous stem bark extract of BF was investigated against Plasmodium berghei-infected mice. MATERIALS AND METHODS: The aqueous stem bark extract of BF (100-400 mg/kg) was administered orally to P. berghei-infected mice in both early and established models of antiplasmodial studies. RESULTS: The extract exhibited significant (p < 0.05) antiplasmodial activity in early and established infection tests with a considerable mean survival time comparable to that of chloroquine, 10 mg/kg. The oral LD(50) obtained was greater than 5000 mg/kg in mice. DISCUSSION AND CONCLUSIONS: The findings show that aqueous stem bark extract of Bridelia ferruginea possesses considerable antiplasmodial activity which can be developed in malaria therapy. PMID- 22235888 TI - Anti-aging efficacy of topical formulations containing niosomes entrapped with rice bran bioactive compounds. AB - CONTEXT: Rice [Oryza sativa L. (Gramineae)] bran is a rich source of phytochemicals. Its oil also contains several bioactive components that exhibit antioxidative properties such as ferulic acid (F), gamma-oryzanol (O), and phytic acid (P) which can be a new source of cosmetic raw materials. OBJECTIVE: To evaluate the anti-aging effects of the gel and cream containing niosomes entrapped with the rice bran bioactive compounds. MATERIALS AND METHODS: The semi purified rice bran extracts containing F, O, and P which indicated the growth stimulation of human fibroblasts and the inhibition of MMP-2 by sulforhodamine B and gelatin zymography, respectively, were entrapped in niosomes by supercritical carbon dioxide fluid (scCO(2)) and incorporated in gel and cream formulations. The skin hydration, elasticity, thickness and roughness, and pigmentation in human volunteers after treated with these gel and creams were investigated by corneometer, cutometer, visiometer, and mexameter, respectively. RESULTS: Gel and cream containing the semi-purified rice bran extracts entrapped in niosomes gave no sign of erythema and edema detected within 72 h on the shaved rabbit skin by the closed patch test investigated by mexameter and visual observation, respectively. These formulations also demonstrated higher hydration enhancement and improvement of skin lightening, thickness, roughness, and elasticity on the skin of 30 human volunteers within the 28-day treatment not more than 9, 27, 7, 3, and 3 times, respectively. DISCUSSION AND CONCLUSIONS: The formulations containing niosomes entrapped with the rice bran bioactive compounds gave superior clinical anti-aging activity which can be applied as a novel skin product. PMID- 22235889 TI - Chemical compositions extracted from Wikstroemia indica and their multiple activities. AB - CONTEXT: The rhizome of Wikstroemia indica (L.) C. A. Mey (Thymelaeaceae) is widespread in China which has been widely used in China as folk medicine for the treatment of syphilis, arthritis, whooping cough, and cancer. Due to its multiactivities, its extract has an attractive potential as a promising natural agent in the pharmaceutical industries. OBJECTIVE: Aims of this study were to optimize the extraction process of the flavonoids from W. indica, and evaluate its multiple activities. MATERIALS AND METHODS: An orthogonal test design was employed to optimize the extraction procedure of flavonoids from W. indica. And multichromatography and spectroscopy were used to study the chemical compounds of W. indica, while several bioactivity assays were used to evaluate the antibacterial, anti-inflammatory, and antitumor activities of W. indica. RESULTS: Optimal extraction conditions were determined: ethanol concentration was 60%; extraction time was 60 min; liquid-solid ratio was 16:1 and the power of ultrasonic instrument was 160 W. Four compounds: daphnoretin, chrysophanol, myricitrime and rutin were purified from W. indica, and chrysophanol was identified from this plant for the first time. The extract of W. indica displayed significant antimicrobial and anti-inflammatory activities. Daphnoretin showed a significant inhibition effect on CNE cells and HeLa cells lines at the concentrations ranging from 15.6 to 125 MUg/mL, the tendency of antitumor effect was displayed in a concentration-dependent manner. DISCUSSION AND CONCLUSIONS: Extracts of W. indica could potentially be used as a promising natural agent in the pharmaceutical industries. PMID- 22235890 TI - Toxicity-structure activity evaluation of limonoids from Swietenia species on Artemia salina. AB - CONTEXT: Many plant extracts and compounds are being investigated for their cytotoxicity and hence their medicinal or therapeutic properties. Reports of toxicity studies with limonoid analogs have been sparse and have involved mainly crude extracts. In this study, individual natural limonoids have been isolated and their toxicity manipulated via semisynthesis. OBJECTIVE: The lethality of limonoid analogs from Swietenia macrophylla King and Swietenia aubrevilleana Stehle & Cusin (Meliaceae) against Artemia salina Leach was determined. MATERIALS AND METHODS: Four known natural limonoids were isolated from the dry ground seeds of S. macrophylla and S. aubrevilleana, modified using acylation and hydrolysis reactions and tested in A. salina lethality assays at 1-400 ppm. A 50% lethal concentration (LC(50)) was determined by probit analysis. RESULTS: Higher levels of toxicity were achieved in most of the prepared analogs compared with the parent natural limonoids. The compound showing the highest toxicity with LC(50) 3.9 ppm was 3-O-benzoyl-3-detigloylisoswietenine (20). Other analogs with high toxicity were 6-O-benzoylswietenolide (7), 6-O-benzoylswietenine (17), and 3,6 O,O-dipropionylswietenolide (9), which showed LC(50) values of 4.3, 7.5, and 28.5 ppm, respectively. DISCUSSION AND CONCLUSIONS: Toxicity can be improved via semisynthesis. The compounds exhibiting high toxicity (low LC(50)) may be good candidates for cytotoxicity studies. PMID- 22235891 TI - Myeloid metaplasia in canine mixed mammary tumors: occurrence and characterization. AB - BACKGROUND: Mixed tumors are among the most frequent mammary neoplasms in female dogs. Some of these tumors present bone marrow associated with the newly formed osseous tissue, characteristic of myeloid metaplasia. OBJECTIVE: To evaluate the occurrence of these lesions in a series of mixed tumors, and determine its histomorphological characteristics. ANIMALS AND METHODS: In total, 384 canine mammary mixed tumors from 289 animals have been reviewed. The lesions were classified according to the presence of osseous metaplasia associated with myeloid metaplasia or extramedullary hematopoiesis. Myeloid metaplasia characterization was determined from the morphological characteristics and organization of the cells and adjacent tissues. Cytoplasmic staining for CD31 and Factor VIII were used as a criterion to confirm the presence of blood vessels and megakaryocytes, respectively. RESULTS: The 384 cases included 206 benign and 178 carcinomas in mixed tumors. Osseous metaplasia was present in 16.1% and calcified areas exclusively in 3.1% lesions. Among all osseous metaplasia, 33.9% presented some type of extramedullary hematopoiesis, of which 71.4% were classified as myeloid metaplasia and 28.6% as extramedullary hematopoiesis. Myeloid metaplasia cases consisted of 67% benign mixed tumors and 33% carcinomas in mixed tumors. CD31 and Factor VIII expression occurred in all myeloid metaplasia, confirming the presence of blood capillaries and megakaryocytes. Myeloid metaplasia was observed in 24% of mixed tumors containing osseous metaplasia and in 4% of all mixed tumors analyzed. CONCLUSION: Despite the low frequency of this lesion, additional studies are needed to understand the implications of myeloid metaplasia in canine mammary mixed tumors. PMID- 22235892 TI - Do lions have manes? For children, generics are about kinds rather than quantities. AB - Generic statements (e.g., "Lions have manes") make claims about kinds (e.g., lions as a category) and, for adults, are distinct from quantificational statements (e.g., "Most lions have manes"), which make claims about how many individuals have a given property. This article examined whether young children also understand that generics do not depend purely on quantitative information. Five-year-olds (n = 36) evaluated pairs of questions expressing properties that were matched in prevalence but varied in whether adults accept them as generically true (e.g., "Do lions have manes?" [true] vs. "Are lions boys?" [false]). Results demonstrated that children evaluate generics based on more than just quantitative information. Data suggest that even young children recognize that generics make claims about kinds. PMID- 22235893 TI - Phase-transfer behavior of cross-linked poly(acrylic acid) particles prepared by dispersion polymerization from ionic liquid to water. AB - The phase-transfer behavior of poly(acrylic acid) (PAA) particles from the hydrophobic ionic liquid N,N-diethyl-N-methyl-N-(2-methoxyethyl)ammonium bis(trifluoromethanesulfonyl)amide phase to the water phase in the particle state, which we reported previously, was examined in more detail. PAA particles were prepared in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([Bmim][TFSA]) and the organic solvent chloroform and were extracted. The transfer of PAA particles to water in the particle state was also observed in [Bmim][TFSA] systems. In contrast, the transfer phenomenon was not observed in the chloroform system. It was clarified that water/oil interfacial tension gamma(wo) is an important parameter in the extraction of PAA in the particle state from the viewpoint of free energy. When the cationic surfactant tetradecyltrimethylammonium bromide, aqueous solution was used as the extraction medium, the PAA particles were extracted in the particle state from chloroform to water, in which gamma(wo) became as low as that of the ionic liquid. This suggests that the phase-transfer phenomenon of PAA particles in the particle state was induced by the ionic liquid's unique property of low interfacial tension with water despite its high hydrophobic character. PMID- 22235895 TI - Nanohole-based surface plasmon resonance instruments with improved spectral resolution quantify a broad range of antibody-ligand binding kinetics. AB - We demonstrate an affordable low-noise surface plasmon resonance (SPR) instrument based on extraordinary optical transmission (EOT) in metallic nanohole arrays and quantify a broad range of antibody-ligand binding kinetics with equilibrium dissociation constants ranging from 200 pM to 40 nM. This nanohole-based SPR instrument is straightforward to construct, align, and operate, since it is built around a standard microscope and a portable fiber-optic spectrometer. The measured refractive index resolution of this platform is 3.1 * 10(-6) without on chip cooling, which is among the lowest reported for SPR sensors based on EOT. This is accomplished via rapid full-spectrum acquisition in 10 ms followed by frame averaging of the EOT spectra, which is made possible by the production of template-stripped gold nanohole arrays with homogeneous optical properties over centimeter-sized areas. Sequential SPR measurements are performed using a 12 channel microfluidic flow cell after optimizing surface modification protocols and antibody injection conditions to minimize mass-transport artifacts. The immobilization of a model ligand, the protective antigen of anthrax on the gold surface, is monitored in real-time with a signal-to-noise ratio of ~860. Subsequently, real-time binding kinetic curves were measured quantitatively between the antigen and a panel of small, 25 kDa single-chain antibodies at concentrations down to 1 nM. These results indicate that nanohole-based SPR instruments have potential for quantitative antibody screening and as a general purpose platform for integrating SPR sensors with other bioanalytical tools. PMID- 22235896 TI - Toll-like receptor expression and function in the COV434 granulosa cell line. AB - PROBLEM: Bacterial infections perturb ovarian follicle function, despite the lack of immune cells such as macrophages within healthy ovarian follicles. This study examined whether the granulosa cells that line ovarian follicles could, like macrophages, use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns (PAMPs) and initiate inflammation. METHOD OF STUDY: The COV434 human granulosa and THP-1 macrophage cell lines were used to determine the expression of TLRs and measure the production of cytokines, chemokines and estradiol in response to the PAMPs lipopolysaccharide, peptidoglycan, lipoteichoic acid and flagellin from bacteria. RESULTS: The THP-1 and granulosa cells expressed mRNA for TLR1-10 and TLR4-10, respectively. The supernatants of THP-1 cells accumulated IL-1beta, IL-6, IL-8 and CCL5 in response to PAMPs. Treatment of granulosa cells with PAMPs increased expression of IL1B mRNA after 3 hr, but did not change the accumulation of IL-1beta, IL-6, IL-8, CCL5 or estradiol. Granulosa cells produced IL-8 constitutively, and this was reduced using chemical inhibitors for p38 and JNK mitogen-activated protein kinases. CONCLUSION: The COV434 human granulosa cell line expresses TLRs and constitutively secretes IL-8 but only mounts an inflammatory response to PAMPs at the transcriptional level. PMID- 22235897 TI - Charge delocalization of 1,4-benzenedicyclometalated ruthenium: a comparison between tris-bidentate and bis-tridentate complexes. AB - A dimetallic biscyclometalated ruthenium complex, [(bpy)(2)Ru(dpb)Ru(bpy)(2)](2+) (bpy = 2,2'-bipyridine; dpb = 1,4-di-2-pyridylbenzene), with a tris-bidentate coordination mode has been prepared. The electronic properties of this complex were studied by electrochemical and spectroscopic analysis and DFT/TDDFT calculations on both rac and meso isomers. Complex [(bpy)(2)Ru(dpb)Ru(bpy)(2)](2+) has a similar 1,4-benzenedicyclometalated ruthenium (Ru-phenyl-Ru) structural component with a previously reported bis tridentate complex, [(tpy)Ru(tpb)Ru(tpy)](2+) (tpy = 2,2';6',2"-terpyridine; tpb = 1,2,4,5-tetra-2-pyridylbenzene). The charge delocalizations of these complexes across the Ru-phenyl-Ru array were investigated and compared by studying the corresponding one-electron-oxidized species, generated by chemical oxidation or electrochemical electrolysis, with DFT/TDDFT calculations and spectroscopic and EPR analysis. These studies indicate that both [(bpy)(2)Ru(dpb)Ru(bpy)(2)](3+) and [(tpy)Ru(tpb)Ru(tpy)](3+) are fully delocalized systems. However, the coordination mode of the metal component plays an important role in influencing their electronic properties. PMID- 22235898 TI - Decoupling the electrical conductivity and Seebeck coefficient in the RE2SbO2 compounds through local structural perturbations. AB - Compromise between the electrical conductivity and Seebeck coefficient limits the efficiency of chemical doping in the thermoelectric research. An alternative strategy, involving the control of a local crystal structure, is demonstrated to improve the thermoelectric performance in the RE(2)SbO(2) system. The RE(2)SbO(2) phases, adopting a disordered anti-ThCr(2)Si(2)-type structure (I4/mmm), were prepared for RE = La, Nd, Sm, Gd, Ho, and Er. By traversing the rare earth series, the lattice parameters of the RE(2)SbO(2) phases are gradually reduced, thus increasing chemical pressure on the Sb environment. As the Sb displacements are perturbed, different charge carrier activation mechanisms dominate the transport properties of these compounds. As a result, the electrical conductivity and Seebeck coefficient are improved simultaneously, while the number of charge carriers in the series remains constant. PMID- 22235899 TI - Spectroscopic ellipsometry analysis of a thin film composite membrane consisting of polysulfone on a porous alpha-alumina support. AB - Exposure of a thin polymer film to a fluid can affect properties of the film such as the density and thickness. In particular in membrane technology, these changes can have important implications for membrane performance. Spectroscopic ellipsometry is a convenient technique for in situ studies of thin films, because of its noninvasive character and very high precision. The applicability of spectroscopic ellipsometry is usually limited to samples with well-defined interfacial regions, whereas in typical composite membranes, often substantial and irregular intrusion of the thin film into the pores of a support exists. In this work, we provide a detailed characterization of a polished porous alumina membrane support, using variable-angle spectroscopic ellipsometry in combination with atomic force microscopy and mercury porosimetry. Two Spectroscopic ellipsometry optical models are presented that can adequately describe the surface roughness of the support. These models consider the surface roughness as a distinct layer in which the porosity gradually increases toward the outer ambient interface. The first model considers the porosity profile to be linear; the second model assumes an exponential profile. It is shown that the models can be extended to account for a composite membrane geometry, by deposition of a thin polysulfone film onto the support. The developed method facilitates practicability for in situ spectroscopic ellipsometry studies of nonequilibrium systems, i.e., membranes under actual permeation conditions. PMID- 22235900 TI - Successful pregnancy outcome in a patient following heart, lung and renal transplant. PMID- 22235903 TI - Evaluation of catmint oil and hydrogenated catmint oil as repellents for the flour beetles, Tribolium castaneum and Tribolium confusum. AB - Catmint oil and hydrogenated catmint oil were evaluated as repellents for adult Tribolium casteneum (Herbst) (Coleoptera: Tenebrionidae), the red flour beetle, and T. confusum (DuVal), the confused flour beetle, using both a traditional method of visual assessment of distribution and a video recording method to determine movement patterns of individual insects. Visual assessments of distribution using groups of adults showed that the hydrogenated catmint oil was more effective than the pure catmint oil, but there was no significant difference between species. However, when repellency was measured using single insects and the visual recording system, both oils were significantly more repellent to T. castaneum than T. confusum at the concentrations evaluated in the study. Avoidance movement and change in direction when T. castaneum encountered the repellent were observed. Results indicate that repellents may be more accurately assessed using single insects rather than groups of individuals, and simple visual observations of distribution may be less sensitive in measuring repellent efficacy. Procedures for utilizing a video system are described as models for future evaluations of repellents for stored-product beetles. PMID- 22235902 TI - Endophytic fungal association via gibberellins and indole acetic acid can improve plant growth under abiotic stress: an example of Paecilomyces formosus LHL10. AB - BACKGROUND: Endophytic fungi are little known for exogenous secretion of phytohormones and mitigation of salinity stress, which is a major limiting factor for agriculture production worldwide. Current study was designed to isolate phytohormone producing endophytic fungus from the roots of cucumber plant and identify its role in plant growth and stress tolerance under saline conditions. RESULTS: We isolated nine endophytic fungi from the roots of cucumber plant and screened their culture filtrates (CF) on gibberellins (GAs) deficient mutant rice cultivar Waito-C and normal GAs biosynthesis rice cultivar Dongjin-byeo. The CF of a fungal isolate CSH-6H significantly increased the growth of Waito-C and Dongjin-byeo seedlings as compared to control. Analysis of the CF showed presence of GAs (GA1, GA3, GA4, GA8, GA9, GA12, GA20 and GA24) and indole acetic acid. The endophyte CSH-6H was identified as a strain of Paecilomyces formosus LHL10 on the basis of phylogenetic analysis of ITS sequence similarity. Under salinity stress, P. formosus inoculation significantly enhanced cucumber shoot length and allied growth characteristics as compared to non-inoculated control plants. The hypha of P. formosus was also observed in the cortical and pericycle regions of the host plant roots and was successfully re-isolated using PCR techniques. P. formosus association counteracted the adverse effects of salinity by accumulating proline and antioxidants and maintaining plant water potential. Thus the electrolytic leakage and membrane damage to the cucumber plants was reduced in the association of endophyte. Reduced content of stress responsive abscisic acid suggest lesser stress convened to endophyte-associated plants. On contrary, elevated endogenous GAs (GA3, GA4, GA12 and GA20) contents in endophyte-associated cucumber plants evidenced salinity stress modulation. CONCLUSION: The results reveal that mutualistic interactions of phytohormones secreting endophytic fungi can ameliorate host plant growth and alleviate adverse effects of salt stress. Such fungal strain could be used for further field trials to improve agricultural productivity under saline conditions. PMID- 22235904 TI - Flagella mediate endophytic competence rather than act as MAMPS in rice-Azoarcus sp. strain BH72 interactions. AB - Azoarcus sp. strain BH72 is an endophytic betaproteobacterium able to colonize rice roots without induction of visible disease symptoms. BH72 possesses one polar flagellum. The genome harbors three copies of putative fliC genes, generally encoding the major structural protein flagellin. It is not clear whether, in endophytic interactions, flagella mediate endophytic competence or act as MAMPs (microbe-associated molecular patterns) inducing plant defense responses. Therefore, possible functions of the three FliC proteins were investigated. Only fliC3 was found to be highly expressed in pure culture and in association with rice roots and to be required for bacterial motility, suggesting that it encodes the major flagellin. Endophytic colonization of rice roots was significantly reduced in the in-frame deletion mutant, while the establishment of microcolonies on the root surface was not affected. Moreover, an elicitation of defense responses related to FliC3 was not observed. In conclusion, our data support the hypothesis that FliC3 does not play a major role as a MAMP but is required for endophytic colonization in the Azoarcus-rice interaction, most likely for spreading inside the plant. PMID- 22235905 TI - Giant intradiploic calvarial abscess of posterior fossa behaving progressive mass lesion. AB - A unique case of a large intradiploic abscess involving posterior fossa osseous structures is reported. A 16-year-old boy presented with a hard mass in the calvarium of posterior fossa region, fever and confusion. Radiological examination revealed an intradiploic collection with compression to cerebellum, fourth ventricle and brain stem, resulting in syringomyelia in cervical and thoracic spinal cord. After drainage and resection of the abscess wall, closure of a round dural defect was performed. The medical history of the patient and the intraoperative observations support the contention that the abscess in the reported case was a result of chronic and subclinical process of an intraosseous infection. The features concerned with diagnosis, differential diagnosis and pathogenesis of this rare entity are discussed. PMID- 22235906 TI - Ruptured infectious aneurysms of the distal MCA treated with trapping and STA-MCA bypass surgery. AB - We describe two patients with ruptured infectious aneurysms of the distal MCA, which were successfully treated by trapping and superficial temporal artery (STA) middle cerebral artery (MCA) bypass surgery. Our patients had not experienced any ischemic attack postoperatively. Trapping and STA-MCA bypass surgery can be a useful option. PMID- 22235907 TI - Are we having fun yet? Fostering adherence to injury preventive exercise recommendations in young athletes. AB - Sport and recreational activities are the leading cause of injury in youth, yet there is increasing evidence that many sport-related injuries are preventable. For injury prevention strategies to be effective, individuals must understand, adopt and adhere to the recommended prevention strategy or programme. Despite the recognized importance of a behavioural approach, the inclusion of behavioural change strategies in sport injury prevention has been historically neglected. The purpose of this commentary is to outline the rationale for the inclusion and application of behavioural science in reducing the burden of injury by increasing adherence to proven prevention strategies. In an effort to provide an illustrative example of a behavioural change approach, the authors suggest a specific plan for the implementation of a neuromuscular training strategy to reduce the risk of lower limb injury in youth sport. Given the paucity of evidence in the sport injury prevention setting, and the lack of application of theoretical frameworks to predicting adoption and adherence to injury preventive exercise recommendations in youth sport, data from the related physical activity promotion domain is utilized to describe how sound, theory-based injury prevention exercise interventions in youth may be developed. While the question of how to facilitate behavioural change and optimize adherence to preventive exercise recommendations remains an ongoing challenge, the authors detail several strategies based on two prominent behavioural theories to aid the reader in conceptualizing, designing and implementing effective interventions. Despite the minimal application of behavioural theory within the field of sport injury prevention in youth, behavioural science has the potential to make a significant impact on the understanding and prevention of youth sport injury. Appropriate evaluation of adherence and maintenance components based on models of behavioural change should be a critical component of future injury prevention research and practice. PMID- 22235908 TI - Ultra-low-volume space sprays in mosquito control: a critical review. AB - The availability of tools to control mosquito (Diptera:Culicidae) vectors that transmit disease is often limited by a variety of economic, environmental and social issues. In emergency conditions (epidemics, hurricanes, floods etc.), the application of pesticides as space sprays (either by ground or air) is the common method of choice in order to rapidly limit adult local mosquito production in the affected area. Space spray application now employs ultra-low-volume technology for the control of adult mosquitoes. However, the use of space sprays often raises social and environmental concerns by the general public that is served. This review will define and illustrate modern ultra-low-volume technology for the purpose of application as a space spray, as well as describing the engineering controls that have been developed to minimize the environmental impact. The primary social concern is validity and efficacy of application. To address this point, the review will attempt to synthesize the global literature to address the effectiveness of space sprays to significantly impact mosquito vectors in relation to human disease. PMID- 22235909 TI - Localization and regulation of aquaporins in the murine larynx. AB - CONCLUSION: Expression of aquaporins (AQPs) in the vocal folds and the parasympathetic regulation of AQPs in the laryngeal glands may be important for controlling laryngeal secretion and vocal fold hydration. These findings are thought to be an initial step towards understanding potential mechanisms of water flow through the vocal fold surface. OBJECTIVES: Lubrication of the vocal folds is important for phonation and laryngeal defense. However, the system of water transport in the laryngeal epithelium has not yet been clarified. We investigated the expression of AQP water channnels (AQP1-9) in the murine larynx and examined the neural regulating mechanisms of these subtypes. METHODS: The distribution of AQPs (AQP1-9) in the murine larynx was examined by immunohistochemistry. Next, the neural mechanism regulating AQPs in the larynx was investigated using unilaterally vagotomized mice. RESULTS: AQP1, 4, and 5 were expressed in the laryngeal epithelium including the vocal folds. Vocal fold AQP expression was minimal at the vocal process. AQP2, 3, 5, 6, 7, and 8 were localized to the submucosal glands. Expression of AQPs in the vagotomized region was significantly decreased compared with the contralateral intact side. The expression in the laryngeal glands was also decreased in the aged mice. PMID- 22235910 TI - Three-dimensional conformal versus non-graphic radiation treatment planning for apocrine gland adenocarcinoma of the anal sac in 18 dogs (2002-2007). AB - Differences in dose homogeneity and irradiated volumes of target and surrounding normal tissues between 3D conformal radiation treatment planning and simulated non-graphic manual treatment planning were evaluated in 18 dogs with apocrine gland adenocarcinoma of the anal sac. Overall, 3D conformal treatment planning resulted in more homogenous dose distribution to target tissues with lower hot spots and dose ranges. Dose homogeneity and guarantee of not under-dosing target tissues with 3D conformal planning came at the cost, however, of delivering greater mean doses of radiation and of irradiating greater volumes of surrounding normal tissue structures. PMID- 22235911 TI - Binding of heparin-dependent antibodies to PF4 modified by enoxaparin oligosaccharides: evaluation by surface plasmon resonance and serotonin release assay. AB - BACKGROUND: The minimal structural requirements of low-molecular-weight heparins that determine the risk of developing heparin-induced thrombocytopenia (HIT) are not fully defined. OBJECTIVES: The ability of enoxaparin-derived oligosaccharides (OS) to induce platelet activation and exposure of platelet-factor 4 (PF4) epitopes recognized by antibodies developed in HIT was studied by surface plasmon resonance (SPR) and serotonin release assay. RESULTS: Decasaccharides with >= 11 sulfate groups induced platelet activation in the presence of plasma from patients with confirmed HIT. Serotonin release of > 80% without full inhibition at 100 MUg mL(-1) was achieved with decasaccharides containing 14 or 15 sulfate groups, 2 dodecasaccharides and 2 tetradecasaccharides. An SPR method was developed using purified PF4 immobilized on carboxymethylated dextran. Antibodies from all HIT samples bound to PF4/heparin in SPR assays with resonance units (RU) ratio of 109-173 with HIT plasma vs. 88-93 with control plasma. RU ratios > 100 were measured when PF4 was pre-incubated with OS with >= 10 saccharide units and one octasaccharide containing 10 sulfate groups. RU ratios > 140, similar to those measured when PF4 was pre-incubated with unfractionated heparin or enoxaparin, were obtained with purified dodeca- and tetradecasaccharides. RU values strongly correlated with the number of sulfate groups in the decasaccharides tested (r = 0.93, P = 0.02). CONCLUSIONS: LMWHs with fragments > 10 saccharides and a large number of sulfate groups are more likely to be associated with a higher risk of HIT. These structure-activity relationships were independent of the ability of the OS to bind antithrombin. PMID- 22235912 TI - Synthesis and antitumour activities of a novel class of dehydroabietylamine derivatives. AB - Structural modification is still a popular and important route in the forest chemical field for finding novel tricyclic diterpenes with more potential bioactivities and broad bioactive spectra. In this study, a series of dehydroabietylamine derivatives containing tricyclic diterpene structures were synthesised through oxidation in the 7th position of ring B and nitrification in the 12th position of ring C using dehydroabietylamine as the starting material. Structures of the synthesised compounds were confirmed by IR, (1)H-NMR, (13)C NMR, MS and HRMS. The cytotoxicities of these compounds against PC-3 (human prostate carcinoma cell line) and Hey-1B (human ovarian carcinoma cell line) cells by the MTT assay were investigated. The results showed that the presence of a nitro group at 12th position and a carbonyl group at 7th position resulted in an increase of cytotoxic activity. Our findings present more evidence, showing the relationship between the chemical structure and biological function. PMID- 22235913 TI - Increased rectal wall stiffness after prostate radiotherapy: relation with fecal urgency. AB - BACKGROUND: Late anorectal toxicity is a frequent adverse event of external beam radiotherapy (EBRT) for prostate cancer. The pathophysiology of anorectal toxicity remains unknown, but we speculate that rectal distensibility is impaired due to fibrosis. Our goal was to determine whether EBRT induces changes of rectal distensibility as measured by an electronic barostat and to explore whether anorectal complaints are related to specific changes of anorectal function. METHODS: Thirty-two men, irradiated for localized prostate carcinoma, underwent barostat measurements, anorectal manometry, and completed a questionnaire prior to and 1 year after radiotherapy. The primary outcome measure was rectal distensibility in response to stepwise isobaric distensions. In addition, we assessed sensory thresholds, anal pressures, and anorectal complaints. KEY RESULTS: External beam radiotherapy reduced maximal rectal capacity (227 +/- 14 mL vs 277 +/- 15 mL; P < 0.001), area under the pressure-volume curve (3212 +/- 352 mL mmHg vs 3969 +/- 413 mL mmHg; P < 0.005), and rectal compliance (15.7 +/- 1.2 mL mmHg(-1) vs 17.6 +/- 0.9 mL mmHg(-1) ; P = 0.12). Sensory pressure thresholds did not significantly change. Sixteen of the 32 patients (50%) had one or more anorectal complaints. Patients with urgency (n = 10) had a more reduced anal squeeze and maximum pressure (decrease 29 +/- 11 mmHg vs 1 +/- 7 mmHg; P < 0.05 and 31 +/- 12 mmHg vs 2 +/- 8 mmHg; P < 0.05 respectively) compared with patients without complaints, indicating a deteriorated external anal sphincter function. CONCLUSIONS & INFERENCES: Irradiation for prostate cancer leads to reduced rectal distensibility. In patients with urgency symptoms, anal sphincter function was also impaired. PMID- 22235914 TI - Safety evaluation of combination vinblastine and toceranib phosphate (Palladia(r)) in dogs: a phase I dose-finding study. AB - Combining drugs with known single-agent activity that lack overlapping dose limiting toxicities (DLT) and exert antitumour activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed in combination in dogs with mast cell tumours. The DLT for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg m(-2) every other week) concurrent with toceranib (3.25 mg kg(-1) PO, every other day). This represents greater than a 50% reduction in dose intensity for vinblastine (compared with single-agent use) and as such does not support this combination based on current drug combination paradigms. Although a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential. PMID- 22235915 TI - Met interacts with EGFR and Ron in canine osteosarcoma. AB - The receptor tyrosine kinase (RTK) Met is known to be over-expressed in canine osteosarcoma (OSA). In human cancers, the RTKs Met, epidermal growth factor receptor (EGFR) and Ron are frequently co-expressed and engage in heterodimerization, altering signal transduction and promoting resistance to targeted therapeutics. We found that EGFR and Ron are expressed in canine OSA cell lines and primary tissues, EGFR and Ron are frequently phosphorylated in OSA tumour samples, and Met is co-associated with EGFR and Ron in canine OSA cell lines. Transforming growth factor alpha (TGFalpha) and hepatocyte growth factor (HGF) stimulation induced amplification of ERK1/2 and STAT3 phosphorylation in OSA cells and Met was phosphorylated following TGFalpha stimulation providing evidence for receptor cross-talk. Lastly, treatment of OSA cells with combined gefitinib and crizotinib inhibited cell proliferation in an additive manner. Together, these data support the notion that Met, EGFR and Ron interact in OSA cells and as such, may represent viable targets for therapeutic intervention. PMID- 22235918 TI - The effects of a high-fat and high-energy diet on the hepatic expression of CYP3A in developing female rats. AB - We aimed to investigate the effects of high-fat and high-energy (HFHE) diets on the hepatic expression of cytochrome P-450 3A (CYP3A) in developing female rats. The pups of the dams fed with the standard diet were defined as the NN group and those fed the HFHE diet were defined as the NH group. The mRNA and protein expression, the protein localization and activity was determined. The mRNA expression of CYP3A1 on day 3 in the NH group were higher versus NN groups (p < 0.05) and the expression of the NH group on days 28 and 56 were lower versus the NN group (p < 0.01). CYP3A1 immunolabeling had a zonal-restricted expressions pattern on day 28 and after in the NN groups, while the obvious zonal expression pattern was observed in the NH group on day 84. The mean activity for the NH groups on days 3, 7, 14 and 28 was higher versus the NN groups (p < 0.05). On day 84, the activity was lower for the NH group versus the NN group (p < 0.05). Our findings provide a basis for further studies on appropriate medication regimen in obese children. PMID- 22235917 TI - Poly(galactaramidoamine) is an efficient cationic polymeric non-viral vector with low cytotoxicity for transfecting human embryonic kidney (HEK293) and murine macrophage (RAW264.7) cells. AB - Poly(galactaramidoamine) (PGAA) is a cationic co-polymer of dimethyl-meso galactarate and pentaethylenehexamine. PGAA electrostatically complexes with plasmid DNA (pDNA) to form nano-sized particles. In this study, we show that PGAA pDNA polyplexes generate high transfection efficiencies in human embryonic kidney (HEK293) and murine macrophage-like (RAW264.7) cell lines. PGAA-pDNA mediated transfection is a function of the amine:phosphate (N/P) ratio at which the polyplexes are prepared. The maximum expression of luciferase was obtained using polyplexes prepared at an N/P ratio of 40. Polyplexes prepared at increasing N/P ratios did not significantly increase in size but did result in decreasing luciferase expression. Cellular toxicity increased as the N/P ratios at which the polyplexes were prepared increased. PMID- 22235919 TI - Dexamethasone-mediated transcriptional regulation of rat carboxylesterase 2 gene. AB - Rat carboxylesterase 2 (rCES2), which was previously identified as a methylprednisolone 21-hemisuccinate hydrolase, is highly inducible by dexamethasone in the liver. In the present study, we investigated the molecular mechanisms by which this induction occurs. Injection of dexamethasone (1 mg/kg weight) into rats resulted in increases in the expression of rCES2 mRNA in a time dependent manner with a peak at 12 h after injection. In primary rat hepatocytes, the expression level of rCES2 mRNA was increased by treatment with 100 nM dexamethasone, and the increase was completely blocked in the presence of 10 uM mifepristone (RU-486), a potent inhibitor of glucocorticoid receptor (GR), or 10 ug/mL cycloheximide, a translation inhibitor. Luciferase assays revealed that 100 nM dexamethasone increased rCES2 promoter activities, although the effect of dexamethasone on the promoter activity was smaller than that on rCES2 mRNA expression. The increased activities were completely inhibited by treatment of the hepatocytes with 10 uM RU-486. Based on these results, it is concluded that dexamethasone enhances transcription of the rCES2 gene via GR in the rat liver and that the dexamethasone-mediated induction of rCES2 mRNA may be dependent on de novo protein synthesis. Our results provide clues to understanding what compounds induce rCES2. PMID- 22235920 TI - The pace of vocabulary growth helps predict later vocabulary skill. AB - Children vary widely in the rate at which they acquire words--some start slow and speed up, others start fast and continue at a steady pace. Do early developmental variations of this sort help predict vocabulary skill just prior to kindergarten entry? This longitudinal study starts by examining important predictors (socioeconomic status [SES], parent input, child gesture) of vocabulary growth between 14 and 46 months (n = 62) and then uses growth estimates to predict children's vocabulary at 54 months. Velocity and acceleration in vocabulary development at 30 months predicted later vocabulary, particularly for children from low-SES backgrounds. Understanding the pace of early vocabulary growth thus improves our ability to predict school readiness and may help identify children at risk for starting behind. PMID- 22235922 TI - Functionalized nanoporous thin films from metallo-supramolecular diblock copolymers. AB - A polystyrene-[Ni(2+)]-poly(ethylene oxide) metallo-supramolecular block copolymer (PS-[Ni(2+)]-PEO), where -[ is a terpyridine, is used to create nanoporous thin films with free terpyridine ligands homogenously distributed on the pore walls. The PS-[Ni(2+)]-PEO block copolymer is synthesized by a two step assembly process, and is then self-assembled into a thin film in order to obtain PEO cylinders oriented perpendicularly to the film surface. The supramolecular junction is opened by exposing the film to an excess of a competing ligand, and the free PEO block is then rinsed away by a selective solvent. The presence of the terpyridines on the pore walls is evidenced by fluorescence spectroscopy after formation of a fluorescent complex with an europium salt. PMID- 22235921 TI - The interpretability of family history reports of alcoholism in general community samples: findings in a midwestern U.S. twin birth cohort. AB - BACKGROUND: Although there is a long tradition in alcoholism research of using family history ratings, the interpretability of family history reports of alcoholism from general community samples has yet to be established. METHODS: Telephone interview data obtained from a large cohort of female like-sex twins (N = 3,787, median age 22) and their biological parents (N = 2,928, assessed at twins' median age 15) were analyzed to determine agreement between parent self report, parent ratings of coparent, and twin narrow (alcohol problems) and broad (problem or excessive drinking) ratings of each parent. RESULTS: In European ancestry (EA) families, high tetrachoric correlations were observed between twin and cotwin ratings of parental alcohol problems, between twin and parent ratings of coparent alcohol problems using symptom-based and single-item assessments, as well as moderately high correlations between twin and both mother and father self reports. In African American (AA) families, inter-rater agreement was substantially lower than for EA families, with no cases where father ratings of maternal alcohol problems agreed with either twin ratings or mother self-report, and both cotwin agreement and mother-twin agreement were reduced. Differences between EA and AA families were not explained by differences in years of cohabitation with father or mother's education; however, underreporting of problems by AA parents may have contributed. CONCLUSIONS: Results support the use of family history ratings of parental alcoholism in general community surveys for EA families, but suggest that family history assessment in AA families requires improved methods. PMID- 22235925 TI - Preparation and characterization of solid lipid nanoparticles-a review. AB - In the present scenario, most of the developed and new discovered drugs are posing real challenge to the formulation scientists due to their poor aqueous solubility which in turn is responsible for poor bioavailability. One of the approach to overcome above problem is the packaging of the drug in to particulate carrier system. Among various carriers, lipid emerged as very attractive candidate because of its unique property of enhancing the bioavailability of poorly water soluble drugs. Solid lipid, one of the physical forms of lipid, is used to formulate nanoparticles, popularly known as Solid lipid nanoparticles (SLNs), as an alternative carrier system to emulsions, liposomes and polymeric micro- and nano-particles. SLNs combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews numerous production techniques for SLNs along with their advantages and disadvantages. Special attention is paid to the characterization of the SLNs by using various analytical tools. It also emphasizes on physical state of lipid (supercooled melts, different lipid modifications). PMID- 22235926 TI - Structural analysis of 2-piperidin-4-yl-actamide derivatives for hERG blocking and MCH R1 antagonistic activities. AB - In the present investigation, a computational based structural analysis was performed on a series of 2-piperidin- 4-yl-acetamide derivatives to investigate the physicochemical features of the molecules responsible for the hERG blocking and melanin concentrating hormone receptor-1 (MCH R1) antagonistic activities. The QSAR models derived from MLR analysis were validated by various validation methods and they provided significant statistical results such as Q(2), F, t(test), R, predicated residual error values, etc. These significant models were constructed with different type of physicochemical descriptors which showed that the hydrophobic properties on the vdW surface of the molecules are favorable for both the activities (MCH R1 antagonistic and hERG blocking activities) and the presence of polar/electronegative groups in the molecules is detrimental for those activities. The presence of flexible aromatic rings in the molecules has favorable hERG blocking activity. The MCH R1 antagonistic activity also depends upon the vdW volume, shape and flexibility of the molecules. In addition, the presented results will guide for the optimized design of novel bioactive molecules with less/free of hERG blocking activities to avoid unwanted potential cardiotoxic side effects related with the use of these possible antiarrhythmic and anti-obesity agents in humans. PMID- 22235927 TI - Sitting at the edge: how biomolecules use hydrophobicity to tune their interactions and function. AB - Water near extended hydrophobic surfaces is like that at a liquid-vapor interface, where fluctuations in water density are substantially enhanced compared to those in bulk water. Here we use molecular simulations with specialized sampling techniques to show that water density fluctuations are similarly enhanced, even near hydrophobic surfaces of complex biomolecules, situating them at the edge of a dewetting transition. Consequently, water near these surfaces is sensitive to subtle changes in surface conformation, topology, and chemistry, any of which can tip the balance toward or away from the wet state and thus significantly alter biomolecular interactions and function. Our work also resolves the long-standing puzzle of why some biological surfaces dewet and other seemingly similar surfaces do not. PMID- 22235928 TI - The significance of insecure and disorganized attachment for children's internalizing symptoms: a meta-analytic study. AB - This meta-analytic review examines the association between attachment and internalizing symptomatology during childhood, and compares the strength of this association with that for externalizing symptomatology. Based on 42 independent samples (N = 4,614), the association between insecurity and internalizing symptoms was small, yet significant (d = 0.15, CI 0.06~0.25) and not moderated by assessment age of internalizing problems. Avoidance, but not resistance (d = 0.03, CI -0.11~0.17) or disorganization (d = 0.08, CI -0.06~0.22), was significantly associated with internalizing symptoms (d = 0.17, CI 0.03~0.31). Insecurity and disorganization were more strongly associated with externalizing than internalizing symptoms. Discussion focuses on the significance of attachment for the development of internalizing versus externalizing symptomatology. PMID- 22235929 TI - Isolation and structure elucidation of ovatoxin-a, the major toxin produced by Ostreopsis ovata. AB - Since 2005, the benthic dinoflagellate Ostreopsis cf. ovata has bloomed across the Mediterranean basin, provoking serious toxic outbreaks. LC/MS studies have identified a number of palytoxin-like compounds, termed ovatoxins, along with trace amounts of putative palytoxin as the causative agents of the O. cf. ovata related human sufferings. So far, any risk assessment for ovatoxins as well as establishment of their allowance levels in seafood has been prevented by the lack of pure toxins. The present paper reports on the isolation, NMR-based structural determination, and preliminary mouse lethality evaluation of ovatoxin-a, the major toxic compound contained in O. cf. ovata extracts. Availability of pure ovatoxin-a will open the double prospect of fully evaluating its toxicity and preparing reference standards to be employed in LC/MS quantitative analyses. Elucidation of ovatoxin-a's complex structure will ultimately herald the understanding of the molecular bases of ovatoxins bioactivity. PMID- 22235930 TI - Liposome technology for cardiovascular disease treatment and diagnosis. AB - INTRODUCTION: Over the past several decades, liposomes have been used in a variety of applications, from delivery vehicles to cell membrane models. In terms of pharmaceutical use, they can offer control over the release of active agents encapsulated into their lipid bilayer or aqueous core, while providing protection from degradation in the body. In addition, liposomes are versatile carriers, because targeting moieties can be conjugated on the surface to enhance delivery efficiency. It is for these reasons that liposomes have been applied as carriers for a multitude of drugs and genetic material, and as contrast agents, aimed to treat and diagnose cardiovascular diseases. AREAS COVERED: This review details advancements in liposome technology used in the field of cardiovascular medicine. In particular, the application of liposomes to cardiovascular disease treatment and diagnosis, with a focus on delivering drugs, genetic material and improving cardiovascular imaging, will be explored. Advances in targeting liposomes to the vasculature will also be detailed. EXPERT OPINION: Liposomes may provide the means to deliver drugs and other pharmaceutical agents for cardiovascular applications; however, there is still a vast amount of research and clinical trials that must be performed before a formulation is brought to market. Advancements in targeting abilities within the body, as well as the introduction of theranostic liposomes, capable of both delivering treating and imaging cardiac diseases, may be expected in the future of this burgeoning field. PMID- 22235932 TI - Anti-tumour and immunomodulating activities of diosgenin, a naturally occurring steroidal saponin. AB - Diosgenin is a naturally occurring steroidal saponin abundantly present in many medical plants. In this study, diosgenin could significantly inhibit the growth of sarcoma-180 tumour cells in vivo, and remarkably increase thymus and spleen weights of S-180-bearing mice and upgrade the secretion level of TNF-alpha in serum. Moreover, diosgenin could stimulate lymphocyte transformation and enhance phagocytic capability of macrophages in vitro, and remarkably promoted the secretion of NO and TNF-alpha in macrophages. These results suggested that diosgenin could improve both specific and non-specific cellular immune responses, and the anti-tumour effects of diosgenin were achieved by immunostimulating properties instead of direct cytotoxicity. PMID- 22235933 TI - Nuclear morphometry in cytological specimens of canine ceruminous adenomas and carcinomas. AB - Stained cytological specimens from eight canine ceruminous adenomas and eight canine ceruminous carcinomas were analysed by computer-assisted nuclear morphometry. Three carcinomas had metastases in regional lymph nodes at the time of the diagnosis. The morphometric parameters evaluated in this study were mean nuclear area (MNA, um(2) ), mean nuclear perimeter (MNP, um), mean nuclear diameter (D mean, um), minimum nuclear diameter (D min, um) and maximum nuclear diameter (D max, um). The study aimed to evaluate (1) the possibility of using nuclear cytomorphometry as an auxiliary diagnostic method to differentiate between canine ceruminous adenomas and adenocarcinomas, and (2) the prognostic value of nuclear morphometry in canine ceruminous carcinomas. The results indicated that (1) MNA, MNP, D mean, D min and D max could be used as effective auxiliary tools for differential diagnosis between canine ceruminous adenomas and adenocarcinomas, and (2) MNA, MNP, D mean and D max are reliable prognostic indicators for canine ceruminous adenocarcinomas. PMID- 22235934 TI - Significance of close relationships after the tsunami disaster in connection with existential health--a qualitative interpretive study. AB - BACKGROUND: In an existential health perspective, the potential for recovery and development through natural life circumstances provides a factor to be taken into account. Earlier research on disaster-stricken people indicates that people create their own ways of recovering and that natural caring encounters (with family or friends) imply important health factors. AIM: The aim of the study is to acquire an in-depth understanding of the significance of natural close relationships for survivors of the tsunami disaster in Southeast Asia in connection with the development of existential health and understanding of life in a long-term perspective. The sample consists of 19 persons afflicted by the 2004 tsunami in Southeast Asia, both Swedish tourists and relatives at home. Data were collected from interviews recurring five times during 2006. FINDINGS: What is evidently seen is how the ontological aspects are expressed in data in relation to the existential and relational aspects. In concrete terms, this is understood when survivors say that their lives are completely changed (an ontological turn in their understanding of life). A change also occurs in the way they relate to others (a concrete existential turn), for example, in their families. When the findings on communion as an utterance of interdependence were read comprehensively, it was seen that human encounters in the aftermath of a disaster are not only about relationships but inherently affect people's entire understanding of life both ontologically and existentially. Relationships with others and communion become a way of understanding or defining life. To conclude, in line with the aim of the study, the data suggest that relationships and communion with other people helped the survivors of the tsunami to discover a new understanding of life. It is also clear that natural encounters have had great importance for progress in existential health. PMID- 22235935 TI - Cyclodextrin-based nanosponges: effective nanocarrier for tamoxifen delivery. AB - The purpose of the present study was to develop Tamoxifen loaded beta cyclodextrin nanosponges for oral drug delivery. The three types of Tamoxifen loaded beta-cyclodextrin nanosponges were synthesized by varying the molar ratios of beta-cyclodextrin to carbonyldiimidazole as a crosslinker viz. 1:2, 1:4 and 1:8. The Tamoxifen nanosponge complex (TNC) with particle size of 400-600 nm was obtained by freeze drying method. Differential scanning calorimetry, Fourier transformed infra-red spectroscopy and X-ray powder diffraction studies confirmed the complexation of Tamoxifen with cyclodextrin nanosponge. AUC and Cmax of TNC formulation (1236.4 +/- 16.12 ug . mL(-1) h, 421.156 +/- 0.91 ug/mL) after gastric intubation were 1.44 fold and 1.38 fold higher than plain drug (856.079 +/- 15.18 ug . mL(-1) h, 298.532 +/- 1.15 ug/mL). Cytotoxic studies on MCF-7 cells showed that TNC formulation was more cytotoxic than plain Tamoxifen after 24 and 48 h of incubation. PMID- 22235936 TI - Classification of functional dyspepsia based on concomitant bowel symptoms. AB - BACKGROUND: Functional dyspepsia (FD) is a heterogeneous disease, and categorized into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). However, many FD patients have overlap of both PDS and EPS. The present study was designed to examine whether FD could be categorized based on the presence of concomitant gastrointestinal symptoms. METHODS: A web survey comprised of the Gastrointestinal Symptom Rating Scale (GSRS), Rome III criteria of FD, and demographic information was sent to public participants who have no history of severe illness. Factor and cluster analyses were conducted to identify sub-categories of FD based on GSRS. KEY RESULTS: A total of 8038 participants completed the survey. A total of 563 participants met the criteria for FD, whereas 6635 participants did not have dyspepsia symptoms. The remainder had either organic disease (377) or uninvestigated dyspepsia (463). The cluster analysis categorized participants as constipation predominant (cluster C), diarrhea predominant (cluster D), or having neither diarrhea nor constipation (cluster nCnD). Cluster C and D were significantly associated with the presence of FD [odds ratio (OR) 2.57, 95% confidence interval (CI) 2.06-3.21; OR 2.80; 95% CI 2.27-3.45, respectively]. In FD, especially in PDS cases, the scores of upper gastrointestinal symptoms were higher in cluster C or D than in cluster nCnD. CONCLUSIONS & INFERENCES: The severity of dyspepsia symptoms is associated with the presence of bowel symptoms especially in PDS. This novel categorization of FD based on concomitant constipation or diarrhea may improve classification of patients. PMID- 22235937 TI - Defying stereotypes: the elusive search for a universal model of LysR-type regulation. AB - LysR-type transcriptional regulators (LTTRs) compose the largest family of homologous regulators in bacteria. Considering their prevalence, it is not surprising that LTTRs control diverse metabolic functions. Arguably, the most unexpected aspect of LTTRs is the paucity of available structural information. Solubility issues are notoriously problematic, and structural studies have only recently begun to flourish. In this issue of Molecular Microbiology, Taylor et al. (2012) present the structure of AphB, a LysR-type regulator of virulence in Vibrio cholerae. This contribution adds significantly to the group of known full length atomic LTTR structures, which remains small. Importantly, this report also describes an active-form variant. Small conformational changes in the effector binding domain translate to global reorganization of the DNA-binding domain. Emerging from these results is a model of theme-and-variation among LTTRs rather than a unified regulatory scheme. Despite common structural folds, LTTRs exhibit differences in oligomerization, promoter recognition and communication with RNA polymerase. Such variation mirrors the diversity in sequence and function associated with members of this very large family. PMID- 22235938 TI - Electrophysiological correlates of associative learning in smokers: a higher order conditioning experiment. AB - BACKGROUND: Classical conditioning has been suggested to play an important role in the development, maintenance, and relapse of tobacco smoking. Several studies have shown that initially neutral stimuli that are directly paired with smoking are able to elicit conditioned responses. However, there have been few human studies that demonstrate the contribution of higher-order conditioning to smoking addiction, although it is assumed that higher-order conditioning predominates learning in the outside world. In the present study a higher-order conditioning task was designed in which brain responses of smokers and non-smokers were conditioned by pairing smoking-related and neutral stimuli (CS1smoke and CS1neutral) with two geometrical figures (CS2smoke and CS2neutral). ERPs were recorded to all CSs. RESULTS: Data showed that the geometrical figure that was paired with smoking stimuli elicited significantly larger P2 and P3 waves than the geometrical figure that was paired with neutral stimuli. During the first half of the experiment this effect was only present in smokers whereas non smokers displayed no significant differences between both stimuli, indicating that neutral cues paired with motivationally relevant smoking-related stimuli gain more motivational significance even though they were never paired directly with smoking. These conclusions are underscored by self-reported evidence of enhanced second-order conditioning in smokers. CONCLUSIONS: It can be concluded that smokers show associative learning for higher-order smoking-related stimuli. The present study directly shows the contribution of higher-order conditioning to smoking addiction and is the first to reveal its electrophysiological correlates. Although results are preliminary, they may help in understanding the etiology of smoking addiction and its persistence. PMID- 22235939 TI - Dynamics of ice nucleation on water repellent surfaces. AB - Prevention of ice accretion and adhesion on surfaces is relevant to many applications, leading to improved operation safety, increased energy efficiency, and cost reduction. Development of passive nonicing coatings is highly desirable, since current antiicing strategies are energy and cost intensive. Superhydrophobicity has been proposed as a lead passive nonicing strategy, yet the exact mechanism of delayed icing on these surfaces is not clearly understood. In this work, we present an in-depth analysis of ice formation dynamics upon water droplet impact on surfaces with different wettabilities. We experimentally demonstrate that ice nucleation under low-humidity conditions can be delayed through control of surface chemistry and texture. Combining infrared (IR) thermometry and high-speed photography, we observe that the reduction of water surface contact area on superhydrophobic surfaces plays a dual role in delaying nucleation: first by reducing heat transfer and second by reducing the probability of heterogeneous nucleation at the water-substrate interface. This work also includes an analysis (based on classical nucleation theory) to estimate various homogeneous and heterogeneous nucleation rates in icing situations. The key finding is that ice nucleation delay on superhydrophobic surfaces is more prominent at moderate degrees of supercooling, while closer to the homogeneous nucleation temperature, bulk and air-water interface nucleation effects become equally important. The study presented here offers a comprehensive perspective on the efficacy of textured surfaces for nonicing applications. PMID- 22235940 TI - Factor seven activating protease (FSAP): does it activate factor VII? AB - BACKGROUND: Factor seven activating protease (FSAP) was initially reported as an activator of single-chain urokinase-type plasminogen activator (scuPA) and factor VII (FVII). Subsequently, numerous additional substrates have been identified, and multiple other biological effects have been reported. Due to the apparent lack of specificity, the physiological role of FSAP has become increasingly unclear. Rigorous studies have been limited by the difficulty of obtaining intact FSAP from blood or recombinant sources. OBJECTIVES: Our aim was to produce intact recombinant human FSAP, and to assess its role as a trigger of coagulation and fibrinolysis. RESULTS: Expression of wild-type FSAP in various mammalian cells invariably resulted in the accumulation of degraded FSAP due to autoactivation and degradation. To overcome this problem, we constructed a variant in which Arg(313) at the natural activation site was replaced by Gln, creating a cleavage site for the bacterial protease thermolysin. HEK293 cells produced FSAP(R313Q) in its intact form. Thermolysin-activated FSAP displayed the same reactivity toward the substrate S-2288 as plasma-derived FSAP, and retained its ability to activate scuPA. Polyphosphate and heparin increased V(max) by 2-3-fold, without affecting K(m) (62 nm) of scuPA activation. Surprisingly, FVII activation by activated FSAP proved negligible, even in the presence of calcium ions, phospholipid vesicles and recombinant soluble tissue factor. On membranes of 100% cardiolipin FVII cleavage did occur, but this resulted in transient activation and rapid degradation. CONCLUSIONS: While FSAP indeed activates scuPA, FVII appears remarkably resistant to activation. Therefore, reappraisal of the putative role of FSAP in hemostasis seems appropriate. PMID- 22235941 TI - Safety evaluation of combination toceranib phosphate (Palladia(r)) and piroxicam in tumour-bearing dogs (excluding mast cell tumours): a phase I dose-finding study. AB - Toceranib phosphate and piroxicam have individually demonstrated antineoplastic activity. Additionally, non-steroidal anti-inflammatory therapy is often warranted in aged cancer-bearing dogs for management of osteoarthritis comorbidity. As concurrent use may be warranted for a given individual and the adverse event (AE) profile for each can be overlapping (gastrointestinal), a phase I trial was performed in tumour-bearing (non-mast cell) dogs to establish the safety of the combination using a standard 3+3 cohort design. Five dose escalating cohorts, up to and including approved label dosage for toceranib and standard dosage for piroxicam, were completed without observing a frequency of dose-limiting AEs necessitating cohort closure. Therefore, the combination of standard dosages of both drugs (toceranib, 3.25 mg kg(-1), every other day; piroxicam, 0.3 mg kg(-1) daily) is generally safe. Several antitumour responses were observed. As with single-agent toceranib, label-indicated treatment holidays and dose reductions (e.g. 2.5-2.75 mg kg(-1)) may occasionally be required owing to gastrointestinal events. PMID- 22235942 TI - Solid-stemmed wheat does not affect overwintering mortality of the wheat stem sawfly, Cephus cinctus. AB - The wheat stem sawfly, Cephus cinctus Norton (Hymenoptera: Cephidae), is a key pest of wheat in the northern Great Plains of North America. Host plant resistance in the form of solid-stemmed wheat cultivars is the main control strategy for C. cinctus. This study investigated the effect of novel and traditional solid wheat hosts on the overwintering mortality and cold-hardiness of C. cinctus. Field conditions from 2003-2005 showed that overwintering mortality in various wheat cultivars averaged 8% and was not related to the type of wheat cultivar. Similarly, supercooling points (-22 degrees C) were not influenced by wheat host type. C. cintus are cold-hardy; up to 80% survive 10 days at -20 degrees C and 10% survive 40 days. Its overwintering microhabitat near the crown area of the plant is well insulated for temperatures above -10 degrees C and remains ~ 20 degrees C above ambient minima. These data suggest that winter mortality is a minor factor in the population dynamics of wheat stem sawfly, and despite clear detrimental effects on larval weight and adult fitness, solid-stemmed cultivars do not reduce the ability of larvae to survive winters. PMID- 22235943 TI - Executive function deficits in persons with mild cognitive impairment: a study with a Tower of London task. AB - This study assessed executive functions in persons with mild cognitive impairment (MCI) using the Tower of London (TOL). A second objective was to study the impact of three types of problem selected according to the presence or absence of a "trigger." A trigger (T) is an incitation to the participant, at the first move, to move a ball to its final position according to the model. A positive trigger (T+) is helpful, while a negative trigger (T-) creates an obstruction. Some problems have no trigger (N). This study includes 81 participants with MCI. After follow-up, one year later, two subgroups were distinguished: (a) 51 (63%) participants did not convert or decline (stable MCI); (b) 30 (37%) participants showed significant decline or progressed to dementia (decliner MCI). Persons with MCI were compared to an older adult group matched with respect to sex, age, and education. For the successes, there was a significant group difference between the three types of problem. The post hoc analysis showed that T+ took significantly less time than N or T-. There were significantly more successes for T+ than N, and these two types of problem had more success than T-. For "total number of moves," there was no significant difference between the groups. In post hoc analysis, T- involved more moves than N or T+. In qualitative analysis, T- MCI decliners produced significantly more rule breakings than the stable MCI and controls. A dysfunction in self-monitoring is a characteristic feature of persons with MCI. PMID- 22235945 TI - Bulk heterojunction formation between indium tin oxide nanorods and CuInS2 nanoparticles for inorganic thin film solar cell applications. AB - In this study, we developed a novel inorganic thin film solar cell configuration in which bulk heterojunction was formed between indium tin oxide (ITO) nanorods and CuInS(2) (CIS). Specifically, ITO nanorods were first synthesized by the radio frequency magnetron sputtering deposition method followed by deposition of a dense TiO(2) layer and CdS buffer layer using atomic layer deposition and chemical bath deposition method, respectively. The spatial region between the nanorods was then filled with CIS nanoparticle ink, which was presynthesized using the colloidal synthetic method. We observed that complete gap filling was achieved to form bulk heterojunction between the inorganic phases. As a proof-of concept, solar cell devices were fabricated by depositing an Au electrode on top of the CIS layer, which exhibited the best photovoltaic response with a V(oc), J(sc), FF, and efficiency of 0.287 V, 9.63 mA/cm(2), 0.364, and 1.01%, respectively. PMID- 22235946 TI - Absence of singlet fission and carrier multiplication in a model conjugated polymer: tracking the triplet population through phosphorescence. AB - Singlet fission, or multiple exciton generation, has been purported to occur in a variety of material systems. Given the current interest in exploiting this process in photovoltaics, we search for the direct signature of singlet fission, phosphorescence from the triplet state, in a model polymeric organic semiconductor for which photoinduced absorption experiments have implied a tripling of the intersystem crossing yield at the onset of fission. Fluorescence and phosphorescence are clearly discriminated using a picosecond gated photoluminescence excitation technique, at variable temperature. At low excitation densities, in a quasi-steady-state experiment, we detect no change of the relative triplet yield to within 4% for photon energies of almost three times the triplet energy of 2.1 eV. Identical results are obtained under nonlinear two photon excitation. We conclude that assignments of singlet fission based on induced absorptions alone should be treated with caution and may substantially overestimate excited-state intersystem crossing yields, raising questions with regards to the applicability of the process in devices. PMID- 22235947 TI - Heritability of level of response and association with recent drinking history in nonalcohol-dependent drinkers. AB - BACKGROUND: Level of response (LR) to alcohol has been shown to be associated with the risk of developing alcohol dependence and can be measured using the self rating of the effects of alcohol (SRE) questionnaire. This study examined the heritability of the SRE-measured LR and the relationship between LR and recent alcohol drinking history (RDH) in a predominantly African American nonalcohol dependent population. METHODS: This was a sibling study of 101 social drinkers aged 21 to 35 years recruited from the Washington, DC metropolitan area. Participants were administered the SRE to assess LR and the timeline followback (TLFB) to assess RDH. The indices of SRE used were total SRE score (SRTT), early drinking SRE score (SRED), regular drinking SRE score (SRRD), and heavy drinking SRE score (SRHD). Pearson's product-moment correlation and linear regression were used to analyze SRE indices and RDH variables (quantity and drinks per drinking occasion). Heritability analysis was conducted using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software with SRE indices as traits of interest. RESULTS: There was a significant relationship between SRE and RDH measures. Drinks per drinking day, maximum drinks, and quantity of drinks were significantly associated with SRTT, SRHD, and SRRD (all p < 0.05). SRTT showed significant heritability (h(2) = 0.67, p = 0.025), however, the SRE subindices (SRED, SRRD, SRHD) were not significantly heritable. Analysis performed in the subset consisting of only African Americans (n = 86) showed similar trends. CONCLUSIONS: LR, as measured by the SRE, is associated with RDH. The high level of heritability of the SRE total score suggests that genetics accounts for a significant proportion of the variation in the LR to alcohol in social drinkers. PMID- 22235949 TI - Detection of low quantum yield fluorophores and improved imaging times using metallic nanoparticles. AB - The behavior of a fluorophore near a gold nanoparticle is rationalized by a theoretical description of the parameters that modify the fluorescence emission: nanoparticle-fluorophore distance, fluorescence quantum yield (phi(0)), and fluorophore absorption and emission spectra, to find optimum conditions for designing fluorophore-nanoparticle probes. The theoretical maximum gain in brightness of the nanoparticle-fluorophore system with respect to the isolated molecule increases almost inversely proportional to phi(0). The brightness enhancement in imaging experiments in vitro was assessed by using Au-SiO(2) core shell nanoparticles deposited on glass. A ~13-fold emission brightness enhancement for weakly fluorescent molecules was observed. A significant increase in fluorophore photostability, rendering longer imaging times, was obtained for fluorophores interacting with gold nanoparticles incorporated by endocytosis in cells. Our results illustrate a way to increase imaging times and to study molecules in the vicinity of a metallic nanoparticle after photobleaching of background fluorescence. PMID- 22235950 TI - B-type natriuretic peptide in children with atrial or ventricular septal defect: a cardiac catheterization study. AB - In this study, we investigated the relationship between plasma B-type natriuretic peptide (BNP) levels and hemodynamics from cardiac catheterization in pediatric patients with atrial or ventricular septal defect. A total of 59 patients were studied including 80% of patients had Qp/Qs > 1.5 and 25% of patients had pulmonary hypertension. The mean BNP value and BNP z-score were 10.9 +/- 11.2 pg/mL and -0.28 +/- 1.7 (-2.85 to 3.29), respectively. There was a statistically significant linear correlation between BNP value and the size of defects (r = 0.303, p = 0.002) and a trend toward to positive correlation between BNP value and Qp/Qs ratio (r = 0.183, p = 0.166) among all patients. To identify patients with a Qp/Qs ratio >1.5, the sensitivity and specificity were 28%, 100% in all patients at a plasma BNP cut-off point of 15 pg/mL. We concluded that a BNP > 15 pg/mL would help identify patients who need further intervention. PMID- 22235951 TI - MRI characteristics of cerebral microbleeds in four dogs. AB - Cerebral microbleeds in people are small foci of hemosiderin-containing macrophages in normal brain parenchyma. They are the remnant of previous hemorrhage and occur with greater frequency in older individuals. Our purpose was to describe the magnetic resonance (MR) appearance of cerebral microbleeds in four dogs. These lesions appeared as round, hypointense foci measuring <=4 mm on T2*-gradient-recalled echo images. They were less conspicuous or absent on T2 weighting, being iso- or hypointense, and uniformly invisible on T1-weighted images. No contrast enhancement was seen in any of the cerebral microbleeds. Necropsy-derived histopathologic analysis of one brain confirmed these lesions to be chronic cerebrocortical infarcts containing hemosiderin. The MR changes seen in dogs were analogous to what has been described in people and will be helpful in distinguishing cerebral microbleeds from other brain lesions. PMID- 22235952 TI - Cost of self-monitoring of blood glucose in the United States among patients on an insulin regimen for diabetes. AB - BACKGROUND: People with diabetes are at an increased risk of developing numerous complications, resulting in increased health care expenditures, economic burden, and higher mortality. For patients using an insulin pump or multiple insulin injections, self-monitoring of blood glucose (SMBG) is recognized as a core component of effective diabetes self-management. However, little is known about the real-world frequency and true costs associated with SMBG as a percentage of an insulin regimen in the United States. OBJECTIVE: To evaluate SMBG frequency, SMBG-related costs (including blood glucose test strips and testing supplies), and insulin therapy costs among insulin-dependent patients with diabetes and at least 1 pharmacy claim for blood glucose testing strips during a 12-month follow up period. METHODS: A retrospective database analysis was conducted using the IMS LifeLink Health Plan Claims database to capture the frequency and costs associated with SMBG in relation to a specific insulin regimen, and SMBG expenditure compared with other treatment costs. The study employed a retrospective cohort analysis of patients with 2 or more claims for insulin between January 1, 2007, and June 30, 2009, with the first such claim representing the index date. All patients were required to have 6 months of pre index continuous enrollment (pre-index period) and 12 months of post-index continuous enrollment (follow-up period). Patients were also required to have a diagnosis of diabetes in the pre-index period and to have no gaps of more than 90 days between consecutive insulin claims during the 360-day follow-up period. Patients without at least 1 pharmacy claim for blood glucose testing strips during the 12-month follow-up period and patients with pharmacy claims with extreme values (greater than 1,500 strips) were excluded. Depending on the insulin types used within the 30 days immediately following their index date, patients were subcategorized into 1 of 4 insulin regimen groups (basal, bolus, premixed, or basal-bolus). Patients' frequency of blood glucose testing was measured throughout their 12-month post-index follow-up period through analysis of clinical codes found on pharmacy claims. Quantity supplied fields on pharmacy claims were used to calculate total tests utilized over the follow-up period (e.g., 50 test strips dispensed=50 tests assumed). Insulin-related costs were also evaluated for the 12-month follow-up period. RESULTS: Among an initial sample of 373,946 patients with at least 2 claims for insulin between January 1, 2007, and June 30, 2009, 45,555 patients (12.2%) formed the final overall cohort who met the inclusion and exclusion criteria. SMBG-related pharmacy costs accounted for 27% of the insulin-and SMBG-related treatment costs for insulin users with an average $772 per patient in prescription testing strips and supplies versus $2,078 for insulin prescriptions and supplies. With an overall mean utilization for pharmacy-based SMBG testing of 764.3 strips per year, the average cost per testing strip was $0.98. Annual SMBG costs were 24.5% of total insulin and SMBG-related pharmacy costs for the basal insulin group compared with 35.8% for bolus, 21.0% for premixed, and 26.4% for basal-bolus. CONCLUSION: For insulin users with at least 1 pharmacy claim for glucose test strips, SMBG related costs accounted for about one-fourth of total insulin and SMBG-related pharmacy costs. PMID- 22235953 TI - Evaluation of a wireless handheld medication management device in the prevention of drug-drug interactions in a Medicaid population. AB - BACKGROUND: With the passage of the Health Information Technology for Economic and Clinical Health (HITECH) Act, widespread adoption of certain health information technologies, such as electronic health records (EHRs) and electronic prescribing (e-prescribing), is imminent. Drug-drug interaction (DDI) screening and medication history information are commonly incorporated into health information exchange systems to improve medical decision making, safety, and quality of care, but the value of these features is unclear. OBJECTIVE: To evaluate the effect of providing access to an early generation electronic medication management program with medication history accessible to prescribers via a wireless handheld personal digital assistant (PDA) device on the incidence of potential DDIs (i.e., DDIs that may or may not cause patient harm). METHODS: This study employed a retrospective pre-intervention/post-intervention study design with a comparison group to evaluate the effectiveness of a wireless handheld medication management program in preventing serious potential DDIs. Licensed prescribers in a state Medicaid program who wrote prescriptions during the period from August 2003 through June 2006 were included in this study. The intervention (PDA) group consisted of clinicians who requested and were granted access to the wireless handheld device containing prescription drug history between August 1, 2004, and June 30, 2005. Initially the device contained 100-day patient-specific medication history, but other functionalities were added during the study period including the ability to check for drug-drug interactions and e prescribing. The comparison group consisted of prescribers who sent a request to obtain, but did not receive, the wireless handheld device during the same time period. Baseline prescribing patterns of 25 previously identified clinically important potential DDIs were assessed over two 12-month periods, one period prior to (baseline) and one period after (follow-up) an index date (date of device deployment for PDA group; date of request for comparison group). A random effects negative binomial model was used to analyze the primary outcome, the number of potential DDIs per prescriber per 12-month time period. A secondary outcome of interest, the likelihood that a prescriber would prescribe at least 1 potentially interacting medication pair during the baseline and follow-up periods, was analyzed using a random-effects logistic model. RESULTS: A total of 1,615 prescribers constituted the PDA group, and 600 prescribers made up the comparison group. Prescribers in the 2 groups were significantly different in their specialty practice areas (P less than 0.001), number of pharmacy claims at baseline (P less than 0.001), and the likelihood of prescribing at least 1 potential DDI combination during the 1-year baseline period (P=0.003). However, the prescriber groups were similar in their average age (P=0.241) and geographic location (P=0.181). The most widely prescribed potential DDIs included those involving warfarin with nonsteroidal anti-inflammatory drugs (NSAIDs) and thyroid hormones. The median number of patient medication history updates requested per PDA group prescriber during follow-up was 24 (range 0 to 1,073). At baseline, 1,104 (68.4%) of the PDA group and 449 (74.8%) of the comparison group had no potential DDIs. During the next year, 1,131 (70.0%) and 462 (77.0%) of the PDA group and comparison group, respectively, had no DDIs. The incidence rate ratio was 1.01 (95% CI=0.87-1.17) for the PDA group relative to the comparison group for change in number of potential DDIs. In the logistic regression model, the odds of prescribing at least 1 potential DDI did not significantly differ by group (odds ratio=1.26, 95% CI=0.96-1.66). These results indicate that there was no significant difference between the intervention and comparison group with regard to the change in the rate of potential DDIs between the baseline and follow-up periods. CONCLUSION: A stand-alone medication management program in a wireless PDA device was not frequently used by most prescribers to update patient medication histories and was not associated with a reduction in the rate of prescribing potentially clinically important DDIs. PMID- 22235954 TI - Implementation of a peer review process to improve documentation consistency of care process indicators in the EMR in a primary care setting. AB - BACKGROUND: Kaiser Permanente Colorado is a group model nonprofit HMO that provides health care services to more than 500,000 members. The Primary Care Clinical Pharmacy Services (PCCPS) department consists of 33 clinical pharmacy specialists (CPS), who are located in 19 primary care clinics. OBJECTIVES: To develop and implement a peer review process to (a) improve the consistency of documentation of process indicators in the electronic medical record (EMR), (b) ensure compliance with existing standards, and (c) share best practices among PCCPS with varying geographical locations and practice styles. METHODS: A committee was formed to undertake the peer review process. An audit tool consisting of yes/no questions was created to assess chart documentation by PCCPS and to provide feedback for improvement. Four sections were included in the evaluation tool: (a) content, (b) collaborative drug therapy management, (c) nonformulary reviews, and (d) pharmacy system documentation. Peer reviews occurred quarterly, and all CPS participated. Copies of reviews were distributed to PCCPS clinicians and their supervisors. Questions and inconsistencies regarding the process were identified by the peer review committee to provide feedback to the group to optimize reviews. After completion of each quarter's reviews, error rates were calculated by dividing the total number of "no" answers by the total number of PCCPS notes reviewed that quarter. A 2-tailed Fisher's exact test was used to compare the error rate at the last quarter of each year (2007 to 2010) with baseline (2007 Q1). RESULTS: A total of 1,856 reviews were conducted between 2007 Q1 and 2010 Q2. Significant improvements in documentation were demonstrated over the first 12 months and sustained for the next 2.5 years. From 2007 Q1 to 2010 Q2, the rate of noncompliant elements decreased from 14.1% to 2.5% (P=0.001) in the content section and decreased from 31.3% to 8.3% (P less than 0.001) across all sections. CONCLUSIONS: Over 3 years of follow-up, the peer review process was successful in improving the consistency of documentation by PCCPS and compliance with existing standards. The process was well received by participants. The peer review document is easily adaptable and can be updated to address changes in drug therapy management protocols and nonformulary medication reviews as needed. This process also allows for sharing of best practices among high-functioning PCCPS practitioners who otherwise could remain isolated. PMID- 22235955 TI - Approaches to the management of agents used for the treatment of multiple sclerosis: consensus statements from a panel of U.S. managed care pharmacists and physicians. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, disabling, and costly disease with several treatment options available; however, there is variability in evidence-based clinical guidelines. Therefore, payers are at a disadvantage when making management decisions without the benefit of definitive guidance from treatment guidelines. OBJECTIVE: To outline approaches for the management of agents used to treat MS, as determined from a group of U.S. managed care pharmacists and physicians. METHODS: A modified Delphi process was used to develop consensus statements regarding MS management approaches. The panel was composed of experts in managed care and included 8 pharmacy directors and 6 medical directors presently or previously involved in formulary decision making from 12 health plans, 1 specialty pharmacy, and 1 consulting company. These decision makers, who have experience designing health care benefits that include MS treatments, provided anonymous feedback through 2 rounds of web-based surveys and participated in 1 live panel meeting held in December 2010. Consensus was defined as a mean response of at least 3.3 or 100% of responses either "agree" or "strongly agree" (i.e., no panelist answered "disagree" or "strongly disagree") on a 4-item Likert scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). RESULTS: After 3 phases, these managed care representatives reached consensus on 25 statements for management of patients with MS. Consistent with managed care principles, this group of managed care experts found that health plans should consider efficacy, effectiveness, and safety, as well as patient preference, when evaluating MS therapies for formulary placement. Cost and contracting should be considered if efficacy and safety are judged to be comparable between agents. CONCLUSION: The consensus statements developed by a panel of managed care representatives provide some insight into decision making in formulary and utilization management of MS therapies. PMID- 22235956 TI - Analysis of nonformulary use of PPIs and excess drug cost in a Veterans Affairs population. AB - BACKGROUND: In the Veterans Affairs (VA) health care system, a formulary-based approach without beneficiary cost-share incentives is used to limit the pharmacy cost of proton pump inhibitors (PPIs). However, the effectiveness of this approach in reducing the cost of PPIs is unknown. OBJECTIVES: To (a) compare cost differences between the formulary PPI (generic omeprazole) and nonformulary PPIs and (b) evaluate reasons for nonformulary PPI use in order to identify opportunities to increase formulary drug use and discourage unnecessary use of nonformulary PPIs. METHODS: A list of patients with receipt of PPIs from July 1, 2008, through June 30, 2009, was obtained from the Loma Linda VA Healthcare System pharmacy. Subjects with receipt of at least 120 units (capsules or tablets) of any PPI in the study period were considered long-term users. Demographic information was collected. Pharmacy consult records were reviewed to identify reasons for nonformulary use and dosing regimen of the formulary PPI prior to the switch. Cost analysis was done based on the VA contract prices for the drugs at the time of the study. RESULTS: Of 58,605 unique patients seen in this VA health care system in the 12-month period from July 1, 2008, through June 30, 2009, 13,713 (23.4%) received a PPI, and of these, 10,483 (76.4%) received at least 120 PPI units and were defined as long-term users. Of the long-term users, 9,462 (90.3%) were on the formulary PPI generic omeprazole, and 1,021 were nonformulary PPI users. Use of nonformulary PPIs (esomeprazole, pantoprazole, lansoprazole, rabeprazole) accounted for 10.5% of the PPI units and 9.7% of the users but 57.3% of total PPI cost. This pattern resulted in $570,263 in excess spending (i.e., $570,263 would have been saved in the study period if the nonformulary PPI users had used the formulary drug). The most common reason for nonformulary long-term PPI use was persistent symptoms (n=901, 88.2%). Adverse reaction was cited by 111 (10.9%) of nonformulary PPI users, 33.3% (n=37) of whom reported diarrhea. Of those who switched to a nonformulary PPI due to persistent symptoms, 363 (40.3%) were on once-daily dosing prior to the switch; 379 (42.1%) were on twice-daily dosing; and 159 (17.6%) were transfers from other places in which prior dosing information was not available in the hospital pharmacy records. CONCLUSIONS: One-year PPI use prevalence was 23% in this VA population, and long-term use prevalence was 18%. Nonformulary PPI use accounted for 10.5% of the PPI units and 9.7% of the users but 57.3% of total PPI drug cost. Opportunities to reduce nonformulary PPI use in order to reduce overall expenditures on PPIs include verification of optimal formulary PPI use, titration to twice-daily dosing, and confirmation of adverse reaction as being attributable to PPI use. PMID- 22235957 TI - Knowing how to stop: ceasing prescribing when the medicine is no longer required. PMID- 22235958 TI - Glycemic control was unchanged in Veterans Health Administration patients converted from glyburide to glipizide. PMID- 22235959 TI - Economic evaluation of denosumab compared with zoledronic acid in hormone refractory prostate cancer patients with bone metastases. PMID- 22235961 TI - The Braillon affair. PMID- 22235960 TI - High-resolution cone-beam computed tomography: a potential tool to improve atraumatic electrode design and position. AB - CONCLUSIONS: Flat-panel cone-beam computed tomography (CBCT) is able to assess the trajectory of the implanted cochlear implant (CI) array. This is essential to determine specific effects of electrode design and surgical innovations on outcomes in cochlear implantation. CBCT is a non-invasive approach yielding similar data to histopathological analyses, with encouraging potential for use in surgical, clinical and research settings. OBJECTIVES: To examine the fidelity of CBCT imaging and custom 3D visualization in characterizing CI insertion in comparison to gold standard, histopathological examination. METHODS: Eleven human temporal bones were implanted with the 'Straight Research Array' (SRA). Post insertion, they were imaged with a prototype mobile C-arm for intraoperative CBCT. Post-acquisition processing of low-dose CBCT images produced high resolution 3D volumes with sub-millimetre spatial resolution (isotropic 0.2 mm(3) voxels). The bones were resin impregnated and sectioned for light microscopic examination. Dimensional electrode characteristics visible in section images were compared with corresponding CBCT images by independent observers. RESULTS: Overall, CBCT demonstrated adequate resolution to detect: 1) scala implanted; 2) kinking; 3) number of intracochlear contacts; 4) appropriate ascension of the array; and overall confirms ideal insertion. CBCT did not demonstrate adequate resolution to detect reversal of electrode contacts or basilar membrane rupture. PMID- 22235962 TI - Developmental changes and individual differences in young children's moral judgments. AB - Developmental trajectories and individual differences in 70 American middle income 21/2- to 4-year olds' moral judgments were examined 3 times across 1 year using latent growth modeling. At Wave 1, children distinguished hypothetical moral from conventional transgressions on all criteria, but only older preschoolers did so when rating deserved punishment. Children's understanding of moral transgressions as wrong independent of authority grew over time. Greater surgency and effortful control were both associated with a better understanding of moral generalizability. Children higher in effortful control also grew more slowly in understanding that moral rules are not alterable and that moral transgressions are wrong independent of rules. Girls demonstrated sharper increases across time than boys in understanding the nonalterability of moral rules. PMID- 22235963 TI - A unified route to the welwitindolinone alkaloids: total syntheses of (-)-N methylwelwitindolinone C isothiocyanate, (-)-N-methylwelwitindolinone C isonitrile, and (-)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate. AB - As part of a comprehensive strategy to the welwitindolinone alkaloids possessing a bicyclo[4.3.1]decane core, we report herein concise asymmetric total syntheses of (-)-N-methylwelwitindolinone C isothiocyanate (2a), (-)-N methylwelwitindolinone C isonitrile (2b), and (-)-3-hydroxy-N methylwelwitindolinone C isothiocyanate (3a) from a common tetracyclic intermediate. The crucial vinyl chloride moiety was installed through electrophilic chlorination of a hydrazone, but only after adjustment of reactivity to circumvent a facile skeletal rearrangement. Selective desulfurization and oxidation of 2a provided access to 2b and 3a, respectively. Notably, this work provides corrected (1)H and (13)C NMR spectral data for 3a. PMID- 22235965 TI - A review of imaging methods for measuring drug release at nanometre scale: a case for drug delivery systems. AB - INTRODUCTION: Current drug delivery research is focused on improving the efficacy of drug delivery systems, with emphasis on precise targeting, accurate dose delivery, strategies for overcoming the tissue barrier and monitoring the effects of drugs on their targets. To realize these goals, it is essential to determine the spatio-temporal bio-distribution of particles in the whole animal. Enabling such a measurement at the nanometer scale helps in the design of efficient systems. AREAS COVERED: This article discusses the need for molecular imaging in drug delivery development and also reviews promising imaging methods. Moreover, the physics behind each method is explained and evaluated to derive advantages and limitations. The review enables the readers to select, use and modify the existing methods to implement imaging protocols for studying drug release from particular drug delivery. EXPERT OPINION: Currently, the difference in pharmacodynamics obtained via various imaging modalities cannot be verified and hinders clinical use. To establish imaging as a scientific tool, its translation into clinical use is vital. Presently, there is no single imaging method suitable for drug-release studies. However, hybrid imaging has the potential to provide the desired imaging system. PMID- 22235964 TI - Total synthesis of oxidized welwitindolinones and (-)-N-methylwelwitindolinone C isonitrile. AB - We report the total synthesis of (-)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies. PMID- 22235967 TI - In vitro antimycobacterial activity and HPLC-DAD screening of phenolics from Ficus benjamina L. and Ficus luschnathiana (Miq.) Miq. leaves. AB - The total phenolic content (Folin-Ciocalteu) of the leaves of Ficus benjamina and Ficus luschnathiana was evaluated and screened by HPLC-DAD. Ficus luschnathiana crude extract (CE) presented phenolic content higher than that of F. benjamina (149.92 +/- 3.65 versus 122.63 +/- 2.79 mg of GAE). Kaempferol (1.63 +/- 0.16 mg g(-1) dry weight of CE) and chlorogenic acid (17.77 +/- 0.57 mg g(-1) of butanolic fraction) were identified and quantified in F. benjamina, whereas rutin (1.39 +/- 0.20 mg g(-1)), caffeic (1.14 +/- 0.13 mg g(-1)) and chlorogenic (3.73 +/- 0.29 mg g(-1)) acids were quantified in the CE of F. luschnathiana. Additionaly, rutin (15.55 +/- 1.92 mg g(-1)) and quercetin (3.53 +/- 0.12 mg g( 1)) were quantified in ethyl acetate and butanolic fractions, respectively. Antimycobacterial activity of CEs and fractions was evaluated against Mycobacterium smegmatis by broth microdilution method. Ethyl acetate fraction from F. benjamina and n-butanol fraction from F. luschnathiana displayed the highest inhibitory activity (MIC = 312.50 ug mL(-1) and 156.25 ug mL(-1), respectively). Further studies are required to identify the compounds directly related to antimycobacterial activity. PMID- 22235968 TI - Use of CD9 and CD61 for the characterization of AML-M7 by flow cytometry in a dog*. AB - Acute megakaryoblastic leukaemia (AML-M7) is a rare myeloproliferative disorder in domestic animals. Recently, thanks to the greater availability of immunophenotype techniques, precise diagnosis is more easily made. The morphological evaluation has its limitations, especially in the study of poorly differentiated cells. Few reports have described AML-M7 in dogs using flow cytometry. This clinical case points out the utility of flow cytometry in the characterization of AML-M7 in a 3-year-old German Shepherd dog. Flow cytometry investigation has established megakaryocytic lineage involvement by showing the presence of two megakaryocyte/platelet associated antigens (CD9 and CD61). In human medicine CD9 may be used as a platelet and megakaryocyte marker. There is an evidence of cross-reactivity of human anti-CD9 monoclonal antibody with canine samples. To our knowledge, the use of CD9 has never been described before, for this purpose in the dog. PMID- 22235969 TI - Low-level laser therapy improves visual acuity in adolescent and adult patients with amblyopia. AB - OBJECTIVE: The purpose of this study was to examine the effects of low-level laser therapy (LLLT) on visual acuity in adolescent and adult patients with amblyopia. BACKGROUND DATA: Currently, amblyopia can be treated successfully only in children. METHODS: In this single-blinded, placebo-controlled study, 178 patients (mean age 46.8 years) with amblyopia caused by ametropia (110 eyes) or strabismus (121 eyes) were included. For LLLT, the area of the macula was irradiated through the conjunctiva from 1 cm distance for 30 sec with laser light (780 nm, 292 Hz, 1:1 duty cycle; average power 7.5 mW; spot area 3 mm(2)). The treatment was repeated on average 3.5 times, resulting in a mean total dose of 0.77 J/cm(2). No occlusion was applied, and no additional medication was administered. Best corrected distant visual acuity was determined using Snellen projection optotypes. In 12 patients (12 eyes), the multifocal visual evoked potential (M-VEP) was recorded. A control group of 20 patients (20 eyes) received mock treatment. RESULTS: Visual acuity improved in ~90% of the eyes treated with LLLT (p<0.001), increasing by three or more lines in 56.2% and 53.6% of the eyes with amblyopia caused by ametropia and strabismus, respectively. The treatment effect was maintained for at least 6 months. The mean M-VEP amplitude increased by 1207 nV (p<0.001) and mean latency was reduced by 7 msec (p=0.14). No changes were noted in the control group. CONCLUSIONS: LLLT led to a significant improvement in visual acuity in adolescent and adult patients with amblyopia caused by ametropia or strabismus. PMID- 22235970 TI - Effects of a therapeutic laser and passive stretching program for treating tendon overuse. AB - OBJECTIVE: This study investigated the effects of a therapeutic laser, passive stretching, and their combined treatment on the strength of Achilles tendons with overuse pathologies. BACKGROUND DATA: Tendinopathy involving overuse is usually treated with exercise and stretching, but there has been no report on the treatment effect of a therapeutic laser combined with passive stretching on managing this condition. Despite the beneficial effect of a therapeutic laser on healing tendons that have had traumatic injury, its effect on degenerative tendons is not known. METHODS: Twenty-five mature Sprague-Dawley (SD) rats were used, with 20 subjected to daily bipedal downhill running for 8 weeks, to induce Achilles overuse, and 5 as normal controls. The exercised rats were divided into four groups: 1, laser treatment; 2, passive stretching; 3, combined laser and stretching; and 4, no treatment, running controls. GaAlAs laser with 660 nm wavelength was applied to both Achilles tendons for 50 sec for Groups 1 and 3. Passive stretching of 20 times/10 sec of maximum ankle plantar flexion was applied to Groups 2 and 3. Treatments were applied after each running session for a a total of 56 treatment sessions. On week 9, the tendons were tested for load relaxation, stiffness, and ultimate strength. RESULTS: Stiffness was different (p=0.01), difference in ultimate strength was marginally insignificant (p=0.07), and load-relaxation difference was not significant among groups. Post-hoc analyses revealed that the mean stiffness of all the four exercise groups was lower than the normal control, whereas the ultimate strength from the laser and combined laser and stretching was not different from that of the normal control group, but was higher than that of the passive stretching and no treatment groups. CONCLUSIONS: We conclude that a therapeutic laser and combined laser with passive stretching might slow down the decrease in Achilles tendon strength but would not be able to stop the pathological changes of overuse from developing. PMID- 22235971 TI - Low-level laser irradiation affects the release of basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and receptor of IGF-I (IGFBP3) from osteoblasts. AB - OBJECTIVE: It was the aim of the present study to evaluate whether the laser irradiation of osteoblasts could enhance the release of growth factors including basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and receptor of IGF-I (IGFBP3). BACKGROUND DATA: Low-level laser therapy (LLLT) has been shown to have biostimulatory effects on various cell types by enhancing production of some cytokines and growth factors. MATERIALS AND METHODS: Human mesenchymal stem cells (MSCs) were seeded in osteogenic medium and differentiated into osteoblasts. Three groups were formed: in the first group (single dose group), osteoblasts were irradiated with laser (685 nm, 25 mW, 14.3 mW/cm(2), 140 sec, 2 J/cm(2)) for one time; and in the second group, energy at the same dose was applied for 2 consecutive days (double dose group). The third group was not irradiated with laser and served as the control group. Proliferation, viability, bFGF, IGF-I, and IGFBP3 levels were compared between groups. RESULTS: Both of the irradiated groups revealed higher proliferation, viability, bFGF, IGF-I, and IGFBP3 expressions than did the nonirradiated control group. There was increase in bFGF and IGF-I expressions and decrease in IGFBP3 in the double dose group compared to single dose group. CONCLUSIONS: The results of the present study indicate that LLLT increases the proliferation of osteoblast cells and stimulates the release of bFGF, IGF-I, and IGFBP3 from these cells. The biostimulatory effect of LLLT may be related to the enhanced production of the growth factors. PMID- 22235972 TI - An interstitial granulomatous pattern in localized lichen myxedematosus with associated monoclonal gammopathy. PMID- 22235974 TI - Analysis of ADP-glucose pyrophosphorylase expression during turion formation induced by abscisic acid in Spirodela polyrhiza (greater duckweed). AB - BACKGROUND: Aquatic plants differ in their development from terrestrial plants in their morphology and physiology, but little is known about the molecular basis of the major phases of their life cycle. Interestingly, in place of seeds of terrestrial plants their dormant phase is represented by turions, which circumvents sexual reproduction. However, like seeds turions provide energy storage for starting the next growing season. RESULTS: To begin a characterization of the transition from the growth to the dormant phase we used abscisic acid (ABA), a plant hormone, to induce controlled turion formation in Spirodela polyrhiza and investigated their differentiation from fronds, representing their growth phase, into turions with respect to morphological, ultra-structural characteristics, and starch content. Turions were rich in anthocyanin pigmentation and had a density that submerged them to the bottom of liquid medium. Transmission electron microscopy (TEM) of turions showed in comparison to fronds shrunken vacuoles, smaller intercellular space, and abundant starch granules surrounded by thylakoid membranes. Turions accumulated more than 60% starch in dry mass after two weeks of ABA treatment. To further understand the mechanism of the developmental switch from fronds to turions, we cloned and sequenced the genes of three large-subunit ADP-glucose pyrophosphorylases (APLs). All three putative protein and exon sequences were conserved, but the corresponding genomic sequences were extremely variable mainly due to the invasion of miniature inverted-repeat transposable elements (MITEs) into introns. A molecular three-dimensional model of the SpAPLs was consistent with their regulatory mechanism in the interaction with the substrate (ATP) and allosteric activator (3-PGA) to permit conformational changes of its structure. Gene expression analysis revealed that each gene was associated with distinct temporal expression during turion formation. APL2 and APL3 were highly expressed in earlier stages of turion development, while APL1 expression was reduced throughout turion development. CONCLUSIONS: These results suggest that the differential expression of APLs could be used to enhance energy flow from photosynthesis to storage of carbon in aquatic plants, making duckweeds a useful alternative biofuel feedstock. PMID- 22235973 TI - Plasticity of mouse enteric synapses mediated through endocannabinoid and purinergic signaling. AB - BACKGROUND: The enteric nervous system (ENS) possesses extensive synaptic connections which integrate information and provide appropriate outputs to coordinate the activity of the gastrointestinal tract. The regulation of enteric synapses is not well understood. Cannabinoid (CB)(1) receptors inhibit the release of acetylcholine (ACh) in the ENS, but their role in the synapse is not understood. We tested the hypothesis that enteric CB(1) receptors provide inhibitory control of excitatory neurotransmission in the ENS. METHODS: Intracellular microelectrode recordings were obtained from mouse myenteric plexus neurons. Interganglionic fibers were stimulated with a concentric stimulating electrode to elicit synaptic events on to the recorded neuron. Differences between spontaneous and evoked fast synaptic transmission was examined within preparations from CB(1) deficient mice (CB(1)(-/-)) and wild-type (WT) littermate controls. KEY RESULTS: Cannabinoid receptors were colocalized on terminals expressing the vesicular ACh transporter and the synaptic protein synaptotagmin. A greater proportion of CB(1)(-/-) neurons received spontaneous fast excitatory postsynaptic potentials than neurons from WT preparations. The CB(1) agonist WIN55,212 depressed WT synapses without any effect on CB(1)(-/-) synapses. Synaptic activity in response to depolarization was markedly enhanced at CB(1)(-/ ) synapses and after treatment with a CB(1) antagonist in WT preparations. Activity-dependent liberation of a retrograde purine messenger was demonstrated to facilitate synaptic transmission in CB(1)(-/-) mice. CONCLUSIONS & INFERENCES: Cannabinoid receptors inhibit transmitter release at enteric synapses and depress synaptic strength basally and in an activity-dependent manner. These actions help explain accelerated intestinal transit observed in the absence of CB(1) receptors. PMID- 22235975 TI - Immobilized streptavidin gradients as bioconjugation platforms. AB - Surface density gradients of streptavidin (SAV) were created on solid surfaces and demonstrated functionality as a bioconjugation platform. The surface density of immobilized streptavidin steadily increased in one dimension from 0 to 235 ng cm(-2) over a distance of 10 mm. The density of coupled protein was controlled by its immobilization onto a polymer surface bearing a gradient of aldehyde group density, onto which SAV was covalently linked using spontaneous imine bond formation between surface aldehyde functional groups and primary amine groups on the protein. As a control, human serum albumin was immobilized in the same manner. The gradient density of aldehyde groups was created using a method of simultaneous plasma copolymerization of ethanol and propionaldehyde. Control over the surface density of aldehyde groups was achieved by manipulating the flow rates of these vapors while moving a mask across substrates during plasma discharge. Immobilized SAV was able to bind biotinylated probes, indicating that the protein retained its functionality after being immobilized. This plasma polymerization technique conveniently allows virtually any substrate to be equipped with tunable protein gradients and provides a widely applicable method for bioconjugation to study effects arising from controllable surface densities of proteins. PMID- 22235977 TI - Effect of gauche molecular conformations and molecular flexibility on the rotator phase transitions of alkanes. AB - Experimental studies have shown that the gauche molecular conformations and the chain configurations play an important role in determining the structures and the phase transitions of the different rotator phases of n-alkanes. We extend our previous phenomenological theory to describe the effect of gauche defects and molecular flexibility on the various rotator phase transitions of n-alkanes. The roles of gauche defects and molecular flexibility are discussed by means of phenomenological theory. The effect of gauche defects and molecular flexibility is to modify the Landau coefficients and to shift the transition lines in the phase diagram. The theoretical predictions are found to be in good qualitative agreement with available experimental results. PMID- 22235976 TI - Growth hormone receptor (GHR) RNAi decreases proliferation and enhances apoptosis in CMT-U27 canine mammary carcinoma cell line. AB - Canine mammary gland has been identified as a major site of the extrapituitary growth hormone (GH) production. This finding is linked to its role in tumourigenesis of the mammary gland. Our previous studies indicated the role of GH and GH receptor (GHR) in regulation of proliferation and apoptosis. Thus, we have optimized the ghr RNA interference method in canine mammary carcinoma cell line CMT-U27. We have analysed the effect of GHR reduction on the intracellular signalling and the cell cycle and apoptosis. The results showed that GHR reduction decreased the p-ERK1/2 expression and caused increase of apoptosis and decrease in number of cells at S and G2M phases. This study indicates that GHR besides proliferative effect promotes growth by increasing cell survival. It can tilt the balance between proliferation and death in cancer cells. PMID- 22235978 TI - Early onset of endothelial cell proliferation in coronary thrombi of patients with an acute myocardial infarction: implications for plaque healing. AB - AIMS: Coronary thrombotic occlusion in ST-segment elevation myocardial infarction (STEMI) patients is often preceded by episodes of progressive growth of the thrombus mass. Similar to wound healing, the organization of thrombus could depend on ingrowth of microvessels in order to stabilize its structure. We investigated the patterns of neovascularization in different stages of coronary thrombus evolution. MATERIAL AND METHODS: Thrombectomy materials obtained from STEMI patients were histologically classified according to thrombus age in three groups: fresh (< 1 day), lytic (1-5 days) or organized (> 5 days) thrombi. Forty thrombi of each group were randomly collected. Neovascularization in the thrombi was evaluated histomorphologically and with immunodouble stains to visualize various differentiation antigens of endothelial cells (ECs) and primitive cells. RESULTS: Morphologically, ECs in the coronary thrombi manifested as: single cells, cell clusters or microvessels. CD31+/CD34+ ECs were present in 98% of all the thrombi. In addition, endothelial clusters were found in 63% of the fresh thrombi (< 1 day). CD105+, Ki67+, or C-kit+ ECs (active, proliferating cells) were observed in all the stages, but significantly more in organized thrombi (> 5 days) compared with fresh and lytic ones (< 5 days), and mainly as cell clusters (P <= 0.05 for all). CD133+ primitive cells were found only sporadically in 11% of all the samples. CONCLUSION: EC proliferation is initiated very early, and gradually progresses during the organization process of thrombus after coronary plaque disruption, with only a limited contribution of primitive cells in this process. PMID- 22235979 TI - Selective and sustained attention in children with spina bifida myelomeningocele. AB - Spina bifida myelomeningocele (SBM) is a neural tube defect that has been related to deficits in several cognitive domains including attention. Attention function in children with SBM has often been studied using tasks that are confounded by complex motor demands or tasks that do not clearly distinguish perceptual from response-related components of attention. We used a verbal-report paradigm based on the Theory of Visual Attention (Bundesen, 1990) and a new continuous performance test, the Dual Attention to Response Task (Dockree et al., 2006), for measuring parameters of selective and sustained attention in 6 children with SBM and 18 healthy control children. The two tasks had minimal motor demands, were functionally specific and were sensitive to minor deficits. As a group, the children with SBM were significantly less efficient at filtering out irrelevant stimuli. Moreover, they exhibited frequent failures of sustained attention and response control in terms of omission errors, premature responses, and prolonged inhibition responses. All 6 children with SBM showed deficits in one or more parameters of attention; for example, three patients had elevated visual perception thresholds, but large individual variation was evident in their performance patterns, which highlights the relevance of an effective case-based assessment method in this patient group. Overall, the study demonstrates the strengths of a new testing approach for evaluating attention function in children with SBM. PMID- 22235980 TI - Effects of age on female reproductive success in Drosophila bipectinata. AB - Female age influence on mating success, courtship activities, mating latency, copulation duration, fecundity, ovarioles number, and wing length has been studied using isofemale lines of Drosophila bipectinata collected at three different localities. It was observed that in all localities, middle-aged D. bipectinata females had significantly greater mating success, showed less rejection responses to courting male, mated faster, copulated longer, and had greater fecundity and ovariole number than young and old-aged females. Further, old-aged females had comparatively less fitness traits than young age females. This research suggests the occurrence of age specific female reproductive success as follows: middle-aged > young > old-aged. PMID- 22235981 TI - The status of the contralateral ear in children with acquired cholesteatoma. AB - CONCLUSION: The high prevalence of pathological changes in the contralateral ear (CLE) among children treated because of middle ear cholesteatoma (MEC) was observed. Evolution of many retraction pockets into cholesteatoma points to the need for early intervention in those patients, especially those with concomitant attic retraction pockets and secretory otitis media (SOM). OBJECTIVES: The aim of the study was to assess the frequency of pathological changes in the CLE of children operated because of MEC, and to determine their clinical evolution. METHODS: Retrospective analysis was performed on the basis of medical records of 202 patients treated surgically for MEC in the years 1998-2011. The mean age of included patients was 11 years and the mean observation period was 54 months. Otoscopic findings before surgery were compared with the latest examination. RESULTS: At the time of surgery for MEC, 54.5% of CLEs presented with abnormalities. The most frequent findings were retraction of the tympanic membrane (30%) and SOM, 22.4%. Also, 7% of patients presented with bilateral MEC. Thirty-four percent (20 cases) of retraction pockets diagnosed at the beginning of the observation period required surgical intervention. During the intervention in 20% of cases (12/59 cases) diagnosis of cholesteatoma was confirmed. At the end of the observation period bilateral cholesteatoma was diagnosed in 12.9% of children. PMID- 22235982 TI - Responding in a test of decision-making under risk is under moderate genetic control in the rat. AB - BACKGROUND: Risk-taking, measured with laboratory tasks such as the Balloon Analog Risk Task (BART), is associated with real-life manifestations of risky behaviors, which may be an important component of inherited liability to alcohol use disorders. To identify genomic factors that influence these traits, the current study (i) characterized performance of a rodent version of the BART in multiple inbred rat strains, (ii) tested the degree to which performance was under genetic control, (iii) explored sex differences in performance, and (iv) evaluated the risk-taking behavior of F1 progeny of high-risk- and low-risk taking strains to examine modes of inheritance. METHODS: Male and female rats (N = 100) from 5 inbred strains (Wistar-Furth, Fischer-344, Lewis, Spontaneously Hypertensive, Brown Norway) and Wistar-Furth * Fischer-344 hybrids were tested in the rat-BART, as well as in tests of locomotor activity, sucrose preference, and general motivation. RESULTS: About 55% of the variance in risk-taking behavior was attributable to heritable factors. The Fischer-344 strain was the most risk taking and the most variable in responding. The mating of low-risk-taking Wistar Furth and Fischer-344 rats produced progeny that behaved most like the Fischer 344 strain. Consistent with prior research in this laboratory (Jentsch et al., 2010), all rats were sensitive to changes in both risk and reinforcement parameters in the rat-BART; rats decreased voluntary risk-taking in the face of increasing risk and increased lever pressing when reinforcement probabilities were reduced. CONCLUSIONS: Our results endorse a moderately heritable pattern of risk-taking behavior in rats. The behavior of the hybrid progeny suggests a polygenic model with most gene effects transmitted by mode of dominant inheritance. The identification of high-risk and low-risk strains allows for isolation of quantitative trait loci associated with task performance and for probing the relationships between risk-taking and dimensions of alcohol use disorders. PMID- 22235983 TI - Putting a bifunctional motor to work: insights into the role of plant KCH kinesins. PMID- 22235984 TI - The first glance into the Glomus genome: an ancient asexual scandal with meiosis? PMID- 22235985 TI - Computational models of plant development and form. AB - The use of computational techniques increasingly permeates developmental biology, from the acquisition, processing and analysis of experimental data to the construction of models of organisms. Specifically, models help to untangle the non-intuitive relations between local morphogenetic processes and global patterns and forms. We survey the modeling techniques and selected models that are designed to elucidate plant development in mechanistic terms, with an emphasis on: the history of mathematical and computational approaches to developmental plant biology; the key objectives and methodological aspects of model construction; the diverse mathematical and computational methods related to plant modeling; and the essence of two classes of models, which approach plant morphogenesis from the geometric and molecular perspectives. In the geometric domain, we review models of cell division patterns, phyllotaxis, the form and vascular patterns of leaves, and branching patterns. In the molecular-level domain, we focus on the currently most extensively developed theme: the role of auxin in plant morphogenesis. The review is addressed to both biologists and computational modelers. PMID- 22235986 TI - Assessment of arterial stiffness in women with gestational diabetes. AB - AIMS: Gestational diabetes mellitus may precede development of Type 2 diabetes and may be related to cardiovascular disease. Pulse wave velocity measurement is the gold-standard method to evaluate arterial stiffness, a preclinical cardiovascular risk marker. However, the relationship between aortic stiffness and gestational diabetes is unclear. The aim of this study was to evaluate aortic pulse wave velocity in women with gestational diabetes in comparison with a matched control group of healthy pregnant women. METHODS: This case-control study included 24 women with gestational diabetes and 27 matched control subjects. Clinical, demographic and laboratory variables were obtained and aortic pulse wave velocity were measured. RESULTS: Both groups had similar age, gestational age, BMI, ethnicity, smoking status and blood pressure levels. Women with gestational diabetes had aortic pulse wave velocity comparable with control subjects: 7.2 +/- 0.9 vs. 7.3 +/- 1.2 m/s (P = 0.79). When categorized according to the median value of pulse wave velocity (7.3 m/s), age (P < 0.001), diastolic blood pressure (P = 0.03) and heart rate (P = 0.02) were associated with increased arterial stiffness. In the group with gestational diabetes, there was a non-significant trend towards higher 1-h postprandial glycaemia in patients with higher (above the median) pulse wave velocity (6.5 +/- 0.8 vs. 7.1 +/- 1.3 mmol/l, P = 0.22) and a lower prevalence of patients with good glycaemic control (38.5 vs. 72.7%, P = 0.09). CONCLUSIONS: Although gestational diabetes may be a risk factor for development of cardiovascular disease, women with gestational diabetes do not have higher aortic stiffness than healthy pregnant women. Time of exposure to hyperglycaemia may have been insufficient to increase central arterial stiffness in women with gestational diabetes. PMID- 22235988 TI - JACS Spotlights--highlights of recent publications in the Journal. PMID- 22235989 TI - Nanoreactors for studying single nanoparticle coarsening. AB - The ability to observe intermediate structures as part of coarsening processes that lead to the formation of single nanoparticles (NPs) is important in gaining fundamental insight pertaining to nanostructure growth. Here, we use scanning probe block copolymer lithography (SPBCL) to create "nanoreactors" having attoliter volumes, which confine Au NP nucleation and growth to features having diameters <150 nm on a substrate. With this technique, one can use in situ TEM to directly observe and study NP coarsening and differentiate Ostwald ripening from coalescence processes. Importantly, the number of metal atoms that can engage in coarsening can be controlled with this technique, and TEM "snapshots" of particle growth can be taken. The size of the resulting nanostructures can be controlled in the 2-10 nm regime. PMID- 22235990 TI - Correlation of platelet growth factor release in jawbone defect repair--a study in the dog mandible. AB - BACKGROUND: Platelet concentrate/platelet-rich plasma (PRP) has been studied extensively in various experimental models and there is some agreement among workers to its early effect in bone regeneration and healing. We have earlier showed in vitro that titanium in whole blood activates the thrombogenic response to a higher degree than PRP and that a fluoridated test surface augmented the effect compared with control. PURPOSE: We designed this study to evaluate the effect of PRP and whole blood on bone regeneration in a dog implant defect model and, in addition, the effect of a test surface modified in hydrofluoric acid. A correlation attempt between platelet count, release of growth factors, and bone regeneration was made. MATERIALS AND METHODS: Six dogs were used and simultaneously with the experimental surgery and implant installation, autologous PRP was prepared. Defects were prepared (6 mm in diameter and 5 mm deep), and implants were installed (TiO2 gritblasted and hydrofluoric acid treated [test] or TiO2 gritblasted [control], 5 mm in diameter and 9 mm long) in defects filled with either PRP or whole blood. Randomization of sides between PRP and whole blood, and sites for test and control implants were made. Blood samples were collected from PRP and whole blood. The dogs were killed after 5 weeks of healing, and samples with implants and surrounding bone were collected and processed for analysis. Enzyme linked immunosorbent assays were used for detection of growth factors in PRP. RESULTS: The mean increase of platelet count was 424% in PRP. A correlation for platelet counts and transforming growth factor beta was found in each dog (r(2) = 0.857). Approximately 50% of the region of interest (ROI) in the defects was filled with new bone after 5 weeks. No difference could be observed in ROI by using PRP or whole blood in the defects regarding new bone formation, bone in contact with implant, or distance to first bone contact. However, the fluoridated implants exhibited more new bone formation (p = .03) compared with control, regardless of comparing PRP or whole blood, and also displayed a shorter distance from first bone contact to the margin of the bone envelope (p = .05). CONCLUSIONS: Platelet concentrate/PRP failed to show more new bone regeneration in a peri-implant defect model compared with whole blood. Implants treated with hydrofluoric acid displayed higher percentages of bone fill in the defect. PMID- 22235991 TI - S-1 as a core anticancer fluoropyrimidine agent. AB - INTRODUCTION: 5-FU is a core anticancer agent for GI and other malignancies, and infusional 5-FU regimens have been widely utilized. Orally administrable fluoropyrimidine prodrugs have been developed to enhance the anticancer efficacy of 5-FU and to reduce its adverse reactions. AREAS COVERED: S-1 is an FT-based oral 5-FU prodrug in combination with a DPD inhibitor (CDHP) and an OPRT inhibitor (Oxo), which exerts the following effects: i) maintaining normal gut immunity, Oxo can decrease GI toxicities of 5-FU; ii) sustaining high plasma 5-FU concentrations, Cmax of FBAL after S-1 administration is extremely low, which dramatically decreases adverse reactions such as HFS, neurotoxicities and cardiotoxicities; iii) plasma 5-FU concentrations vary less extensively after S-1 administration and iv) S-1 can be safely administered to patients with DPD deficiency. Furthermore, the alternate-day S-1 administration can reduce the GI toxicities and myelotoxicities of 5-FU without reducing its anticancer efficacy, enabling patients to continue the oral administration for 6 - 12 months. EXPERT OPINION: Replacement of regimens with infusional 5-FU and other fluoropyrimidines by the alternate-day S-1 administration may be recommended because the latter procedure is efficient for patients while sustaining the enhanced anticancer efficacy of 5-FU and without reducing its dose intensity. PMID- 22235992 TI - Cyclodextrin polymer nanoassemblies: strategies for stability improvement. AB - The main goal of this work was to develop two strategies for stabilization of nanoassemblies made of beta-cyclodextrin polymer and amphiphilic dextran associated through host-guest complexes. The first strategy was to coat the nanoassemblies with a dextran derivative bearing adamantyl anchoring groups and hydrophilic poly(ethylene oxide-co-propylene oxide) side chains to increase the steric repulsion between the nanoassemblies. The second strategy developed was to post-reticulate the nanoassemblies upon UV irradiation. Photo-cross-linkable nanoassemblies have been prepared from new host or guest polymers bearing allylether or methacrylate groups. The modified nanoassemblies have been characterized by dynamic light scattering as a function of time and for various salt and competitor concentrations. The results of the first strategy show an improvement of shelf stability and resistance at relatively low concentrations of competitors. The second strategy is the most efficient in providing good shelf stability, much larger than with the first strategy, together with a large resistance to dissociation in presence of competitors. PMID- 22235993 TI - Therapeutic potential of carbon monoxide in multiple sclerosis. AB - Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle. In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response. The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems. This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation. The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease modifying properties in multiple sclerosis. PMID- 22235994 TI - Immunology in the clinic review series; focus on cancer: multiple roles for the immune system in oncogene addiction. AB - Despite complex genomic and epigenetic abnormalities, many cancers are irrevocably dependent on an initiating oncogenic lesion whose restoration to a normal physiological activation can elicit a dramatic and sudden reversal of their neoplastic properties. This phenomenon of the reversal of tumorigenesis has been described as oncogene addiction. Oncogene addiction had been thought to occur largely through tumour cell-autonomous mechanisms such as proliferative arrest, apoptosis, differentiation and cellular senescence. However, the immune system plays an integral role in almost every aspect of tumorigenesis, including tumour initiation, prevention and progression as well as the response to therapeutics. Here we highlight more recent evidence suggesting that oncogene addiction may be integrally dependent upon host immune-mediated mechanisms, including specific immune effectors and cytokines that regulate tumour cell senescence and tumour-associated angiogenesis. Hence, the host immune system is essential to oncogene addiction. PMID- 22235995 TI - Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. AB - Mononuclear phagocytes are cells of the innate immunity that defend the host against harmful pathogens and heal tissues after injury. Contrary to expectations, in malignancies, tumour-associated macrophages (TAM) promote disease progression by supporting cancer cell survival, proliferation and invasion. TAM and related myeloid cells [Tie2(+) monocytes and myeloid-derived suppressor cells (MDSC)] also promote tumour angiogenesis and suppress adaptive immune responses. These divergent biological activities are mediated by macrophages/myeloid cells with distinct functional polarization, which are ultimately dictated by microenvironmental cues. Clinical and experimental evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of macrophages in tumours is considered a promising therapeutic strategy: depletion of TAM or their 're-education' as anti-tumour effectors is under clinical investigation and will hopefully contribute to the success of conventional anti cancer treatments. PMID- 22235996 TI - Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy. AB - Research into aberrant glycosylation and over-expression of glycolipids on the surface of the majority of cancers, coupled with a knowledge of glycolipids as functional molecules involved in a number of cellular physiological pathways, has provided a novel area of targets for cancer immunotherapy. This has resulted in the development of a number of vaccines and monoclonal antibodies that are showing promising results in recent clinical trials. PMID- 22235998 TI - Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes. AB - Up-regulation of interleukin (IL)-17 in small intestinal mucosa has been reported in coeliac disease (CD) and in peripheral blood in type 1 diabetes (T1D). We explored mucosal IL-17 immunity in different stages of CD, including transglutaminase antibody (TGA)-positive children with potential CD, children with untreated and gluten-free diet-treated CD and in children with T1D. Immunohistochemistry was used for identification of IL-17 and forkhead box protein 3 (FoxP3)-positive cells and quantitative polymerase chain reaction (qPCR) for IL-17, FoxP3, retinoic acid-related orphan receptor (ROR)c and interferon (IFN)-gamma transcripts. IL-1beta, IL-6 and IL-17 were studied in supernatants from biopsy cultures. Expression of the apoptotic markers BAX and bcl-2 was evaluated in IL-17-stimulated CaCo-2 cells. The mucosal expression of IL-17 and FoxP3 transcripts were elevated in individuals with untreated CD when compared with the TGA-negative reference children, children with potential CD or gluten-free diet-treated children with CD (P < 0.005 for all IL-17 comparisons and P < 0.01 for all FoxP3 comparisons). The numbers of IL-17-positive cells were higher in lamina propria in children with CD than in children with T1D (P < 0.05). In biopsy specimens from patients with untreated CD, enhanced spontaneous secretion of IL-1beta, IL-6 and IL-17 was seen. Activation of anti-apoptotic bcl 2 in IL-17-treated CaCo-2 epithelial cells suggests that IL-17 might be involved in mucosal protection. Up-regulation of IL-17 could, however, serve as a biomarker for the development of villous atrophy and active CD. PMID- 22235997 TI - Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies. AB - Cancer is one of the most important pathological conditions facing mankind in the 21st century, and is likely to become the most important cause of death as improvements continue in health, diet and life expectancy. The immune response is responsible for controlling nascent cancer through immunosurveillance. If tumours escape this control, they can develop into clinical cancer. Although surgery and chemo- or radiotherapy have improved survival rates significantly, there is a drive to reharness immune responses to treat disease. As T cells are one of the key immune cells in controlling cancer, research is under way to enhance their function and improve tumour targeting. This can be achieved by transduction with tumour-specific T cell receptor (TCR) or chimaeric antigen receptors (CAR) to generate redirected T cells. Virus-specific cells can also be transduced with TCR or CAR to create bi-functional T cells with specificity for both virus and tumour. In this review we outline the development and optimization of redirected and bi-functional T cells, and outline the results from current clinical trials using these cells. From this we discuss the challenges involved in generating effective anti-tumour responses while avoiding concomitant damage to normal tissues and organs. PMID- 22235999 TI - Immune complexes and late complement proteins trigger activation of Syk tyrosine kinase in human CD4(+) T cells. AB - In systemic lupus erythematosus (SLE), the autoantibodies that form immune complexes (ICs) trigger activation of the complement system. This results in the formation of membrane attack complex (MAC) on cell membrane and the soluble terminal complement complex (TCC). Hyperactive T cell responses are hallmark of SLE pathogenesis. How complement activation influences the T cell responses in SLE is not fully understood. We observed that aggregated human gamma-globulin (AHG) bound to a subset of CD4(+) T cells in peripheral blood mononuclear cells and this population increased in the SLE patients. Human naive CD4(+) T cells, when treated with purified ICs and TCC, triggered recruitment of the FcRgamma chain with the membrane receptor and co-localized with phosphorylated Syk. These events were also associated with aggregation of membrane rafts. Thus, results presented suggest a role for ICs and complement in the activation of Syk in CD4(+) T cells. Thus, we propose that the shift in signalling from zeta-chain ZAP70 to FcRgamma chain-Syk observed in T cells of SLE patients is triggered by ICs and complement. These results demonstrate a link among ICs, complement activation and phosphorylation of Syk in CD4(+) T cells. PMID- 22236000 TI - Galectin-3 in cord blood of term and preterm infants. AB - In recent years galectin-3 has gained attention as a signalling molecule, mainly in inflammatory diseases. Data on galectin-3 expression in neonates, however, are limited, and expression of this lectin in cord blood has not yet been reported. The aim of this study was to determine galectin-3 levels in cord blood of term and preterm neonates as well as galectin-3 levels in cord blood of term neonates after stimulation with the prevalent pathogen Streptococcus agalactiae. Cord blood samples were incubated for 24 h and galectin-3 levels were assessed by enzyme-linked immunosorbent assay. There is a positive correlation between gestational age and galectin-3 levels in cord blood. Expression of galectin-3 is significantly higher in cord blood of small-for-gestational-age infants compared to appropriate-for-gestational-age infants. Stimulation with an invasive but not with a colonizing strain of S. agalactiae induced expression of galectin-3. Galectin-3 is expressed constitutively in cord blood of neonates and seems to play a role in the innate immunity of this population. PMID- 22236001 TI - Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells. AB - Insulin resistance and metabolic syndrome are chronic inflammatory conditions that lead to hepatic injury and non-alcoholic steatohepatitis (NASH). Bovine colostrum has therapeutic effects in a variety of chronic infections. However its effectiveness in NASH was never studied. Natural killer T (NKT) cells have been shown to be associated with some of the pathological and metabolic abnormalities accompanying NASH in leptin-deficient (ob/ob) mice. In the present study, we used hyperimmune bovine colostrum to treat hepatic injury and insulin resistance and we also assessed the effects on NKT cells. We used ob/ob mice that were fed for 6 weeks with either 0.1 mg bovine colostrum prepared from non-immunized cows, 0.1 mg hyperimmune colostrum raised against a bacterial lipopolysaccharide (LPS) extract or 0.001, 0.1 or 1 mg of immunoglobulin (Ig)G purified from hyperimmune colostrum (IgG-LPS). NKT cells were phenotyped by flow cytometry, and hepatic injury and insulin resistance were assessed by measuring fasting glucose levels, glucose tolerance tests and liver enzymes. Fat accumulation was measured in the liver and plasma. Oral administration of hyperimmune colostrums decreased alanine aminotransferase (ALT) serum levels and serum triglycerides compared to controls. Glucose intolerance was also improved by the hyperimmune colostrum preparations. These results were accompanied by a decrease in serum tumour necrosis factor (TNF)-alpha levels following oral treatment with 0.1 or 1 mg of IgG-LPS. The beneficial effects of hyperimmune colostrums were associated with an increase in the number of splenic NKT cells. These data suggest that oral administration of hyperimmune colostrum preparations can alleviate chronic inflammation, liver injury and insulin resistance associated with NASH. PMID- 22236003 TI - Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells. AB - The activation of nuclear factor-kappa B (NF-kappaB) in vascular endothelial cells may be involved in vascular pathogeneses such as vasculitis or atherosclerosis. Recently, it has been reported that some amino acids exhibit anti-inflammatory effects. We investigated the inhibitory effects of a panel of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases in various cell types. The activation of NF kappaB was determined in human coronary arterial endothelial cells (HCAECs) because NF-kappaB modulates the production of many cytokines and the expression of adhesion molecules. We examined the inhibitory effects of the amino acids cysteine, histidine and glycine on the induction of NF-kappaB activation, expression of CD62E (E-selectin) and the production of interleukin (IL)-6 in HCAECs stimulated with tumour necrosis factor (TNF)-alpha. Cysteine, histidine and glycine significantly reduced NF-kappaB activation and inhibitor kappaBalpha (IkappaBalpha) degradation in HCAECs stimulated with TNF-alpha. Additionally, all the amino acids inhibited the expression of E-selectin and the production of IL-6 in HCAECs, and the effects of cysteine were the most significant. Our results show that glycine, histidine and cysteine can inhibit NF-kappaB activation, IkappaBalpha degradation, CD62E expression and IL-6 production in HCAECs, suggesting that these amino acids may exhibit anti-inflammatory effects during endothelial inflammation. PMID- 22236002 TI - Hypochlorous acid regulates neutrophil extracellular trap release in humans. AB - Neutrophil extracellular traps (NETs) comprise extracellular chromatin and granule protein complexes that immobilize and kill bacteria. NET release represents a recently discovered, novel anti-microbial strategy regulated non exclusively by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generation of reactive oxygen intermediates (ROIs), particularly hydrogen peroxide. This study aimed to characterize the role of ROIs in the process of NET release and to identify the dominant ROI trigger. We employed various enzymes, inhibitors and ROIs to record their effect fluorometrically on in vitro NET release by human peripheral blood neutrophils. Treatment with exogenous superoxide dismutase (SOD) supported the established link between hydrogen peroxide and NET production. However, treatment with myeloperoxidase inhibitors and direct addition of hypochlorous acid (HOCl; generated in situ from sodium hypochlorite) established that HOCl was a necessary and sufficient ROI for NET release. This was confirmed by the ability of HOCl to stimulate NET release in chronic granulomatous disease (CGD) patient neutrophils which, due to the lack of a functional NADPH oxidase, also lack the capacity for NET release in response to classical stimuli. Moreover, the exogenous addition of taurine, abundantly present within the neutrophil cytosol, abrogated NET production stimulated by phorbol myristate acetate (PMA) and HOCl, providing a novel mode of cytoprotection by taurine against oxidative stress by taurine. PMID- 22236004 TI - Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency. AB - Abnormalities in peripheral blood B cell subsets have been identified in common variable immunodeficiency (CVID) patients and classification systems based upon their numbers have been proposed to predict the clinical features. We analysed B lymphocyte subsets by multi-colour flow cytometry (MFC) in a cohort of well characterized CVID patients to look at their clinical relevance and validate the published association of different classification criteria (Freiburg, Paris and Euroclass) with clinical manifestations. CVID patients had a reduced proportion of total and switched memory B cells (MBC, swMBC) compared to normal controls (P < 0.0006). Patients classified in Freiburg Ia had a higher prevalence of granulomatous diseases (P = 0.0034). The previously published associations with autoimmune diseases could not be confirmed. The Euroclass classification was not predictive of clinical phenotypes. The absolute numbers of all B cell subsets were reduced in CVID patients compared to controls. There was a significant linear correlation between low absolute total B cells and MBC with granulomatous disease (P < 0.05) and a trend towards lower B cells in patients with autoimmune diseases (P = 0.07). Absolute number of different B cell subsets may be more meaningful than their relative percentages in assessing the risk of granulomatous diseases and possibly autoimmunity. PMID- 22236005 TI - Cytokine profile and induction of T helper type 17 and regulatory T cells by human peripheral mononuclear cells after microbial exposure. AB - The immunomodulatory effects of probiotics were assessed following exposure of normal peripheral blood mononuclear cells (PBMC), cord blood cells and the spleen derived monocyte/macrophage cell line CRL-9850 to Lactobacillus acidophilus LAVRI A1, Lb. rhamnosus GG, exopolysaccharides (EPS)-producing Streptococcus thermophilus St1275, Bifidobacteriun longum BL536, B. lactis B94 and Escherichia coli TG1 strains. The production of a panel of pro- and anti-inflammatory cytokines by PBMC following bacterial stimulation was measured, using live, heat killed or mock gastrointestinal tract (GIT)-exposed bacteria, and results show that (i) all bacterial strains investigated induced significant secretion of pro- and anti-inflammatory cytokines from PBMC-derived monocytes/macrophages; and (ii) cytokine levels increased relative to the expansion of bacterial cell numbers over time for cells exposed to live cultures. Bifidobacteria and S. thermophilus stimulated significant concentrations of transforming growth factor (TGF)-beta, an interleukin necessary for the differentiation of regulatory T cells (T(reg) )/T helper type 17 (Th17) cells and, as such, the study further examined the induction of Th17 and T(reg) cells after PBMC exposure to selected bacteria for 96 h. Data show a significant increase in the numbers of both cell types in the exposed populations, measured by cell surface marker expression and by cytokine production. Probiotics have been shown to induce cytokines from a range of immune cells following ingestion of these organisms. These studies suggest that probiotics' interaction with immune-competent cells produces a cytokine milieu, exerting immunomodulatory effects on local effector cells, as well as potently inducing differentiation of Th17 and T(reg) cells. PMID- 22236006 TI - Carriage of the EGF rs4444903 A>G functional polymorphism associates with disease progression in chronic HBV infection. AB - Because epidermal growth factor (EGF) up-regulation is characteristic of the cirrhotic liver, we hypothesised that the EGF rs4444903 A > G functional polymorphism might be associated with a worse disease course in patients with chronic HBV infection. To verify this hypothesis, 170 HBV-positive patients (125 males) with a median age of 52 years were studied. Sixty-two of these patients were followed longitudinally for a median time of 21 years. Genotyping for the EGF rs4444903 A > G polymorphism was performed by the polymerase chain reaction based restriction fragment length polymorphism assay. In the cross-sectional study, the EGF rs4444903 A > G polymorphism genotypic frequencies significantly differed between transplant patients (A/A = 20.4%, A/G = 52.3%, G/G = 27.3%) and HBsAg+ carriers (active and inactive: A/A = 35.7%, A/G = 47.6%, G/G = 16.7%, P = 0.036 for the linear trend). In the longitudinal study, the EGF rs4444903 A > G polymorphism was found to be an independent predictor of cirrhosis development (O.R. 7.73, 95% C.I. 1.21-49.5, P = 0.007). Three groups of patients were identified: A/A female homozygotes (n = 9), A/A male homozygotes (n = 13) and carriers of the G allele of either gender (n = 40). Cirrhosis did not occur among A/A females (n = 0/9), seldom occurred among A/A males (n = 2/13) and reached the highest frequency among G/* patients (n = 13/40, P = 0.026). In conclusion, the EGF rs4444903 A > G polymorphism appears to be associated with an unfavourable disease course of chronic HBV infection and cirrhosis development. This effect might be modulated, at least in part, by the gender of the patient. PMID- 22236007 TI - M-ficolin levels are associated with the occurrence of severe infections in patients with haematological cancer undergoing chemotherapy. AB - The pattern recognition molecules H-ficolin, L-ficolin and M-ficolin bind to micro-organisms. They activate the lectin pathway of complement through mannan binding lectin (MBL)-associated serine proteases (MASPs). Association between low MBL levels and infections in patients undergoing chemotherapy for haematological diseases has been observed previously. We now examine for MASP-2, MASP-3 and ficolin levels. We assessed the concentration of lectin pathway molecules as risk factors for infection in patients with haematological malignancy undergoing chemotherapy. Samples taken before the initiation of chemotherapy covering 117 chemotherapy cycles in 105 patients were available. MASPs and ficolins were measured by time-resolved immunoflourometric assays and the levels related to parameters of infections. End-points included febrile neutropenia, documented infections, bacteraemia or severe infections. Lower M-ficolin concentrations were found in patients who developed a severe infection: median 0.27 ug/ml compared to 0.47 ug/ml in patients who did not develop a severe infection (P = 0.01). Conversely, MASP-2 was higher in these patients: median 0.53 ug/ml compared to 0.37 ug/ml, respectively (P = 0.008). When considering M-ficolin levels below 0.36 ug/ml as deficient, the time to development of severe infection was shorter in the M-ficolin deficient group: the hazard ratio was 2.60 (95% confidence interval: 1.23-5.49). No associations were revealed between infections and H ficolin, L-ficolin or MASP-3. Patients with low M-ficolin are more likely to develop severe infections, whereas MASP-2 showed the opposite. PMID- 22236008 TI - Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study. AB - Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flow-mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24-39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P < 0.001) and systolic (P = 0.053) and diastolic (P = 0.002) blood pressure elevation, and associated inversely with flow-mediated dilation (P = 0.014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0.029) and diastolic (P = 0.004) blood pressure elevation and flow-mediated dilation (P = 0.014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age. PMID- 22236009 TI - Comparison of interferon-gamma-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection. AB - In this study, we investigated the role and expression of T helper type 17 (Th17) cells and Th17 cytokines in human tuberculosis. We show that the basal proportion of interferon (IFN)-gamma-, interleukin (IL)-17- and IL-22-expressing CD4(+) T cells and IL-22-expressing granulocytes in peripheral blood were significantly lower in latently infected healthy individuals and active tuberculosis patients compared to healthy controls. In contrast, CD4(+) T cells expressing IL-17, IL 22 and IFN-gamma were increased significantly following mycobacterial antigens stimulation in both latent and actively infected patients. Interestingly, proinflammatory IFN-gamma and tumour necrosis factor (TNF)-alpha were increased following antigen stimulation in latent infection. Similarly, IL-1beta, IL-4, IL 8, IL-22 and TNF-alpha were increased in the serum of latently infected individuals, whereas IL-6 and TNF-alpha were increased significantly in actively infected patients. Overall, we observed differential induction of IL-17-, IL-22- and IFN-gamma-expressing CD4(+) T cells, IL-22-expressing granulocytes and proinflammatory cytokines in circulation and following antigenic stimulation in latent and active tuberculosis. PMID- 22236010 TI - Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4alpha senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A. AB - Renal allograft survival is related directly to cell senescence. In the transplantation scenario many cellular events - participating as immunological and non-immunological factors - could contribute to accelerate this biological process, responsible for the ultimate fate of the graft. Mechanisms concerned in tolerance versus rejection are paramount in this outcome. For this reason, immunosuppressive treatment constitutes an extremely important decision to prevent organ dysfunction and, finally, graft loss. This study was conducted to document the proportion of CD4(+) /interleukin (IL)-17A(+) -, CD16(+) /indoleamine 2, 3-dioxygenase (IDO(+) )-, forkhead box protein P3 (FoxP3(+)) expressing cells, senescent cells (p16(INK) (4alpha)) and the percentage of interstitial fibrosis (IF) in graft biopsies of kidney transplant recipients participating in the BENEFIT (Bristol-Myers Squibb IM103008) study. CD4(+) /IL 17A(+) , CD16(+) /IDO(+), FoxP3(+) and p16(INK) (4alpha+) cells were evaluated by immunohistochemistry, and the percentage of IF by morphometry on graft biopsies obtained at time 0 (pre-implantation) and at 12 months post-transplant. Senescent cells and CD4(+) /IL-17A(+) cells were increased among graft biopsies in subjects receiving cyclosporin A (CsA) compared to those under belatacept treatment. Meanwhile, CD16(+) /IDO(+) and FoxP3(+) -expressing cells were lower in biopsies from CsA treatment compared to patients treated with Belatacept. Histological morphometric analyses disclosed more IF in 12-month CsA-treated patients in comparison to pre-implantation biopsy findings. Summing up, renal biopsies from patients receiving belatacept showed greater amounts of FoxP3(+) cells and lower amounts of CD4(+) /IL-17A(+) and senescent cells compared to patients under CsA treatment. Along with these findings, an increase in IF in annual CsA-treated patients biopsies compared to pre-implantation and belatacept-treated patients were observed. PMID- 22236011 TI - Selective clinical and immune response of the oligoclonal autoreactive T cells in Omenn patients after cyclosporin A treatment. AB - The immunological hallmark of Omenn syndrome (OS) is the expansion and activation of an oligoclonal population of autoreactive T cells. These cells should be controlled rapidly by immunosuppressive agents, such as cyclosporin A (CsA), to avoid tissue infiltration and to improve the general outcome of the patients. Here we studied the clinical and the immune response to CsA in two Omenn patients and also examined the gene expression profile associated with good clinical response to such therapy. T cell receptor diversity was studied in cells obtained from OS patients during CsA therapy. Characterization of gene expression in these cells was carried out by using the TaqMan low-density array. One patient showed complete resolution of his symptoms after CsA therapy. The other patient showed selective response of his oligoclonal T cell population and combination therapy was required to control his symptoms. Transcriptional profile associated with good clinical response to CsA therapy revealed significant changes in 26.6% of the tested genes when compared with the transcriptional profile of the cells before treatment. Different clinical response to CsA in two OS patients is correlated with their immunological response. Varying clonal expansions in OS patients can cause autoimmune features and can respond differently to immunosuppressive therapy; therefore, additional treatment is sometimes indicated. CsA for OS patients causes regulation of genes that are involved closely with self-tolerance and autoimmunity. PMID- 22236012 TI - T cell receptor (TCR) signal strength controls arthritis severity in proteoglycan specific TCR transgenic mice. AB - T cell receptor transgenic (TCR-Tg) mice specific for the arthritogenic 5/4E8 epitope in the G1 domain of cartilage proteoglycan were generated and back crossed into arthritis-prone BALB/c background. Although more than 90% of CD4(+) T cells of all TCR-Tg lines were 5/4E8-specific, one (TCR-TgA) was highly sensitive to G1-induced or spontaneous arthritis, while another (TCR-TgB) was less susceptible. Here we studied whether fine differences in TCR signalling controlled the onset and severity of arthritis. Mice from the two TCR-Tg lines were immunized side by side with purified recombinant human G1 (rhG1) domain for G1 domain of cartilage proteoglycan (PG)-induced arthritis (GIA). TCR-TgA mice developed severe and early-onset arthritis, whereas TCR-TgB mice developed weaker arthritis with delayed onset, although TCR-TgB CD4(+) T cells expressed approximately twice more TCR-Vbeta4 chain protein. The more severe arthritis in TCR-TgA mice was associated with higher amounts of anti-G1 domain-specific antibodies, larger numbers of B cells and activated T helper cells. Importantly, TCR-TgB CD4(+) T cells were more sensitive to in vitro activation-induced apoptosis, correlating with their higher TCR and CD3 expression and with the increased TCR signal strength. These findings indicate that TCR signal strength determines the clinical outcome of arthritis induction: 'optimal' TCR signal strength leads to strong T cell activation and severe arthritis in TCR-TgA mice, whereas 'supra-optimal' TCR signal leads to enhanced elimination of self-reactive T cells, resulting in attenuated disease. PMID- 22236016 TI - Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells. AB - Dysregulation of platelet-derived growth factor receptor (PDGFR) may play a role in feline injection-site sarcoma (ISS) cell growth and viability. Masitinib, a tyrosine kinase inhibitor approved for treatment of canine mast cell tumours, is highly selective for the PDGFR signalling pathway and may offer a new therapeutic approach for this disease. The in vitro effects of masitinib on growth, apoptosis and PDGFR signalling in two novel ISS cell lines were investigated. PDGFR expression was confirmed by Western blot in cell lines derived from a primary ISS tumour (JB) and a corresponding, histologically confirmed ISS lung metastasis (JBLM). Masitinib inhibited cell growth and PDGFR phosphorylation in both cell lines. Higher drug concentrations were required to inhibit growth than to modulate ligand-induced autophosphorylation of PDGFR. These in vitro data suggest that masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS. PMID- 22236017 TI - Volatile compound in cut and un-cut flowers of tetraploid Freesia hybrida. AB - The flower volatile compounds (FVCs) of two tetraploid Freesia hybrida (pink yellow and yellow) cultivars and their cut flowers were analysed by headspace solid-phase microextraction combined with gas chromatography-mass spectrometry. Twelve FVCs were identified in the pink-yellow cultivar, with linalool as the major compound; 30 FVCs were identified in the yellow cultivar, with linalool and terpineol as the two major compounds. The FVCs (>1%) of the two cut flower cultivars were very similar to that of the un-cut flowers, and no significant difference was observed. PMID- 22236013 TI - Protective effect of Clostridium tyrobutyricum in acute dextran sodium sulphate induced colitis: differential regulation of tumour necrosis factor-alpha and interleukin-18 in BALB/c and severe combined immunodeficiency mice. AB - One of the promising approaches in the therapy of ulcerative colitis is administration of butyrate, an energy source for colonocytes, into the lumen of the colon. This study investigates the effect of butyrate producing bacterium Clostridium tyrobutyricum on dextran sodium sulphate (DSS)-induced colitis in mice. Immunocompetent BALB/c and immunodeficient severe combined immunodeficiency (SCID) mice reared in specific-pathogen-free (SPF) conditions were treated intrarectally with C. tyrobutyricum 1 week prior to the induction of DSS colitis and during oral DSS treatment. Administration of DSS without C. tyrobutyricum treatment led to an appearance of clinical symptoms - bleeding, rectal prolapses and colitis-induced increase in the antigen CD11b, a marker of infiltrating inflammatory cells in the lamina propria. The severity of colitis was similar in BALB/c and SCID mice as judged by the histological damage score and colon shortening after 7 days of DSS treatment. Both strains of mice also showed a similar reduction in tight junction (TJ) protein zonula occludens (ZO)-1 expression and of MUC-2 mucin depression. Highly elevated levels of cytokine tumour necrosis factor (TNF)-alpha in the colon of SCID mice and of interleukin (IL)-18 in BALB/c mice were observed. Intrarectal administration of C. tyrobutyricum prevented appearance of clinical symptoms of DSS-colitis, restored normal MUC-2 production, unaltered expression of TJ protein ZO-1 and decreased levels of TNF-alpha and IL-18 in the descending colon of SCID and BALB/c mice, respectively. Some of these features can be ascribed to the increased production of butyrate in the lumen of the colon and its role in protection of barrier functions and regulation of IL-18 expression. PMID- 22236018 TI - New clinical approach for use of Er:YAG laser in the surgical treatment of oral lichen planus: a report of two cases. AB - The aim of this clinical report is to demonstrate the efficiency of Er:YAG laser in reducing symptoms and lymphoplasmocytic infiltrate in case of oral lichen planus (OLP). In addition to medical therapy and conventional surgery, laser has been proposed for the treatment of this disease, but currently, use of Er:YAG laser (2940 nm) has not been reported. Two clinical cases of female patients who came to our clinic with lesions in the internal portion of the cheek and in the hard palate mucosa close to the upper right molars, surgically treated by Er:YAG laser, are described. The parameters used were as follows: energy, 80-120 mJ; frequency, 6-15 Hz; non-contact hand piece; spot size diameter, 0.9 mm; pulse duration, 100 MUsec (VSP) to 300 MUsec (SP) ; fluences, 12.6-18.9 J/cm(2); and air/water spray (ratio: 6/5). In the two patients, the peeling of the lesions was completed with much less discomfort (<25% in visual analogue scale). A very small recurrence was observed in one case (cheeks) after 15 months, and the same protocol was applied successfully. The use of this wavelength offers several advantages including, a good and fast healing process, a very low level of discomfort during and after intervention, and a rapid disappearance of symptoms. Even if this methodology seems to be an interesting new surgical approach in the management of non-erosive OLP, this clinical report has to be considered as a preliminary one because of the limited number of cases. As a consequence, further studies and long-term follow-up will be necessary. PMID- 22236019 TI - Context and uncertainty in narratives: stories of sickness among the Beja of Northeastern Sudan. AB - The present paper deals with the parents' narratives of sickness and misfortune of their children among the Beja people in the Red Sea Hills, Northeastern Sudan. Drawing on fieldwork focusing parents' health-seeking behavior related to child sicknesses through 1993-95, and combining participant observation and interviews, the aim is firstly to elucidate how markers of uncertainty is a pronounced trait of Beja sickness narratives, inviting listeners to actively engage in the stories, adding to a still scarce but growing literature on narration and uncertainty. Secondly, it aims at relating this narrative style to wider contexts of Beja culture and society, a type of analysis seldom undertaken within the field of medical anthropology. It is argued that although some facets of the lives of Beja people have changed since the time of the fieldwork, the changes are not pronounced and have not changed the cultural environment so as to make the analysis and conclusions of this paper less valid. PMID- 22236021 TI - MRI features of cervical articular process degenerative joint disease in Great Dane dogs with cervical spondylomyelopathy. AB - Cervical spondylomyelopathy or Wobbler syndrome commonly affects the cervical vertebral column of Great Dane dogs. Degenerative changes affecting the articular process joints are a frequent finding in these patients; however, the correlation between these changes and other features of cervical spondylomyelopathy are uncertain. We described and graded the degenerative changes evident in the cervical articular process joints from 13 Great Danes dogs with cervical spondylomyelopathy using MR imaging, and evaluated the relationship between individual features of cervical articular process joint degeneration and the presence of spinal cord compression, vertebral foraminal stenosis, intramedullary spinal cord changes, and intervertebral disc degenerative changes. Degenerative changes affecting the articular process joints were common, with only 13 of 94 (14%) having no degenerative changes. The most severe changes were evident between C4-C5 and C7-T1 intervertebral spaces. Reduction or loss of the hyperintense synovial fluid signal on T2-weighted MR images was the most frequent feature associated with articular process joint degenerative changes. Degenerative changes of the articular process joints affecting the synovial fluid or articular surface, or causing lateral hypertrophic tissue, were positively correlated with lateral spinal cord compression and vertebral foraminal stenosis. Dorsal hypertrophic tissue was positively correlated with dorsal spinal cord compression. Disc-associated spinal cord compression was recognized less frequently. PMID- 22236023 TI - Sex-gender differences in diabetes vascular complications and treatment. AB - Diabetes mellitus and cardiovascular diseases act as two sides of the same coin: diabetes is an important risk factor for cardiovascular disease while patients with ischemic cardiovascular diseases often have diabetes or pre-diabetes. As firstly shown by Framingham study, diabetic women have an increased cardiovascular risk about 3.5 fold higher than non diabetic women, against an increase of "only" 2.1 fold found in male subjects. In view of the impact of sexual hormones on glucose homeostasis, the molecular pathways involved in insulin resistance suggest a sex-gender specificity mechanism in the development of diabetic complications leading to the unmet need of sex-gender therapeutic approaches. This has also been seen in other diabetic complications such as renal diseases, which seems to progress at a faster rate in females compared with males and women benefit less from treatment than do men. Of note, none of the trials done so far are primarily designed to assess sex-gender differences in the benefit from a specific intervention strategy, de facto excluding fertile women from experimentation. In order to provide a more evidence based medicine for women and to reach equity between men and women, sex-gender epidemiological reports, preclinical and clinical research are mandatory to evaluate the impact of gender on the outcomes and to improve sex-gender awareness and competency in the health care system. Future studies should consider sex-gender differences in the setting of randomized controlled trials with drugs. PMID- 22236024 TI - Bone marrow microenvironment: a newly recognized target for diabetes-induced cellular damage. AB - Diabetes mellitus is considered a cardiovascular disease owing to its prevalent association with cardiovascular morbidity and mortality. Cardiovascular events are not only more frequent but also complicated with more severe outcomes in diabetic patients as compared with non-diabetic patients. One mechanism accounting for this difference consists of the impairment of the regenerative cellular machinery, which contributes to tissue healing. Recent evidence indicates the contribution of resident progenitor cells in post-ischemic tissue remodeling. In addition, a wide spectrum of cells from distant sources, including the bone marrow, is attracted and home to the healing tissue. Diabetes affects the process of mobilization and recruitment as well as intrinsic functional properties of bone marrow-derived progenitor cells. This review highlights current evidence for diabetes-induced damage of bone marrow hematopoietic progenitor cells in the endosteal and vascular niches. PMID- 22236022 TI - Cerebrovascular complications of diabetes: focus on stroke. AB - Cerebrovascular complications make diabetic patients 2-6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature. PMID- 22236025 TI - Cardiac effects of HDL and its components on diabetic cardiomyopathy. AB - Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease and hypertension under diabetes mellitus. Hyperglycemia, hyperinsulinemia, and hyperlipidemia, characteristic metabolic disturbances evident in diabetes mellitus, all three lead to a specific altered cardiac structure and function. Recently, it has been demonstrated that altered HDL, be it low HDL or dysfunctional HDL is not only a consequence of diabetes mellitus, but can also contribute to the development of diabetes mellitus, and therefore also of diabetic cardiomyopathy. This review summarizes how HDL can indirectly affect diabetic cardiomyopathy via their influence on the metabolic triggers hyperglycemia, hyperinsulinemia, and hyperlipidemia, and how they can directly influence the cardiac cellular consequences, typical for diabetic cardiomyopathy, including inflammation, oxidative stress, apoptosis, fibrosis, Ca2+ handling, glucose homeostasis, and endothelial dysfunction. PMID- 22236026 TI - Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin. AB - Type 2 diabetes mellitus (T2DM) is a disease characterized by inadequate beta cell response due to progressive insulin resistance that typically accompanies physical inactivity and weight gain. T2DM is associated with substantial morbidity and mortality related to the associated atherosclerotic cardiovascular risks and diabetic vasculopathies, including microangiopathies (e.g., blindness and renal failure) and macroangiopathies (atherosclerosis). The increasing global prevalence of T2DM is linked to the rising rates of obesity, especially abdominal obesity. Visceral fat accumulation is upstream of obesity-related disorders including atherosclerotic cardiovascular disease (ACVD), and is associated with impaired insulin sensitivity and atherosclerosis through dysregulated production of adipocytokines, especially hypoadiponectinemia. This review article discusses the pathophysiological mechanisms responsible for T2DM and atherosclerosis, focusing on adiponectin. Clinical and experimental studies have shown that hypoadiponectinemia contributes to a variety of life style-related diseases including T2DM and atherosclerosis. It is likely that life-style modification, visceral fat reduction and use of medications that increase serum adiponectin levels (e.g., rimonabant, thiazolidinediones, fibrates, angiotensin receptor blocker and mineralocorticoid receptor blockade) when provided in combination can improve hypoadiponectinemia and thus prevent the development of life style related diseases including T2DM and ACVD. PMID- 22236027 TI - Diabetes-induced epigenetic signature in vascular cells. AB - Vascular dysfunction is a common consequence of diabetes mellitus. Stable propagation of gene expression from cell to cell generation during development of diseases (like diabetes) is regulated by epigenetic mechanisms. These are heritable patterns of gene expression that cannot solely be explained by changes in DNA sequence. Recent evidence shows that diabetes-induced epigenetic changes can affect gene expression in vascular endothelial cells and vascular smooth muscles cells. Such effects further influence inflammatory and insulin production pathways in these cells and thus ensure a long-term memory, whereby epigenetic changes are maintained even long after restoring normo-glycaemic conditions by appropriate therapeutic approaches. This review focuses on the epigenetic marks, which endure on the vascular chromatin under diabetic conditions. PMID- 22236029 TI - Traditional medicinal practices of a Sardar healer of the Sardar (Dhangor) community of Bangladesh. PMID- 22236030 TI - Urut Melayu for poststroke patients: a qualitative study. AB - BACKGROUND: Urut Melayu, the traditional Malay massage, had been introduced into three pioneer hospitals in Malaysia, as part of the integrated hospital program. It was introduced primarily for the rehabilitation of poststroke patients. After almost 3 years since it was first implemented, there are currently plans to extend it to other hospitals in the country. Information from this study will contribute toward a better future implementation plan. OBJECTIVES: This study was conducted to gain an insight into the experiences and views of poststroke patients and their urut Melayu practitioners. METHODS: A qualitative study design was adopted. A total of 17 semistructured in-depth interviews were carried out with poststroke patients who were undergoing urut Melayu treatment at one of the three integrated hospitals. Information was solicited from their accompanying caregivers whenever necessary. The 2 urut Melayu practitioners at the hospital were also interviewed. All the interviews were carried out in Malay by the authors, at the Traditional and Complementary Medicine unit of the relevant hospital. The interviews were audiotaped, transcribed, and coded into categories through a constant-comparison method of data analysis. Illustrative quotations were identified to supplement the narrative descriptions of the themes. RESULTS: It was found that urut Melayu was sought by patients who had experienced stroke brought about by hypertension and postdelivery complications. They reported the unique characteristics of urut Melayu and their positive experiences with it. CONCLUSIONS: Urut Melayu has potential as a complementary therapy for poststroke patients. It is recommended that the number of practitioners at the Traditional and Complementary Medicine unit be increased to provide the optimum care for poststroke patients. PMID- 22236028 TI - Emerging therapy for diabetic neuropathy: cell therapy targeting vessels and nerves. AB - Diabetic neuropathy (DN), the most common complication of diabetes, frequently leads to foot ulcers and may progress to limb amputations. Despite continuous increase in incidence, there is no clinical therapy to effectively treat DN. Pathogenetically, DN is characterized by reduced vascularity in peripheral nerves and deficiency in angiogenic and neurotrophic factors. We will briefly review the pathogenetic mechanism of DN and address the effects and the mechanisms of cell therapies for DN. To reverse the changes of DN, studies have attempted to deliver neurotrophic or angiogenic factors for treatment in the form of protein or gene therapy; however, the effects turned out to be very modest if not ineffective. Recent studies have demonstrated that bone marrow (BM)-derived cells such as mononuclear cells or endothelial progenitor cells (EPCs) can effectively treat various cardiovascular diseases through their paracrine effects. As BM-derived cells include multiple angiogenic and neurotrophic cytokines, these cells were used for treating experimental DN and found to reverse manifestations of DN. Particularly, EPCs were shown to exert favorable therapeutic effects through enhanced neural neovascularization and neuro-protective effects. These findings clearly indicate that DN is a complex disorder with pathogenetic involvement of both vascular and neural components. Studies have shown that cell therapies targeting both vascular and neural elements are shown to be advantageous in treating DN. PMID- 22236031 TI - Use of Ayurvedic diagnostic criteria in Ayurvedic clinical trials: a literature review focused on research methods. AB - OBJECTIVES: The objective of this literature review is to evaluate whether Ayurvedic diagnostic criteria or Western medicine diagnostic criteria have been used in published clinical trials testing an Ayurvedic intervention/treatment. DESIGN: The PubMed, Embase, and Allied and Complementary Medicine databases were searched to identify Ayurvedic clinical trials published from 1980 to 2009. A total of 45 Ayurvedic clinical trials were identified and grouped into two time periods: pre- and post-2000 periods. Each article was independently reviewed by two calibrated reviewers. RESULTS: Analysis revealed that not 1 of these 45 studies, in either time period, reported "only-and-full" use of the 23 available Ayurvedic diagnostic criteria. In fact, 24.4% of these 45 articles never specified any diagnostic criteria at all. While the percentage of articles using Ayurvedic diagnostic criteria (either as "only use" or "combined use with Western Medicine diagnostic criteria") doubled over the two time periods (27.7% to 59%), rarely were more than 2 of the 23 Ayurvedic diagnostic criteria ever used. CONCLUSIONS: To improve confidence in their findings, future studies should strive to correct this observed inappropriate and gross underuse of Ayurvedic diagnostic criteria in the designing of clinical studies that aim to rigorously test the effectiveness of Ayurvedic treatments. PMID- 22236032 TI - Arabidopsis plants grown in the field and climate chambers significantly differ in leaf morphology and photosystem components. AB - BACKGROUND: Plants exhibit phenotypic plasticity and respond to differences in environmental conditions by acclimation. We have systematically compared leaves of Arabidopsis thaliana plants grown in the field and under controlled low, normal and high light conditions in the laboratory to determine their most prominent phenotypic differences. RESULTS: Compared to plants grown under field conditions, the "indoor plants" had larger leaves, modified leaf shapes and longer petioles. Their pigment composition also significantly differed; indoor plants had reduced levels of xanthophyll pigments. In addition, Lhcb1 and Lhcb2 levels were up to three times higher in the indoor plants, but differences in the PSI antenna were much smaller, with only the low-abundance Lhca5 protein showing altered levels. Both isoforms of early-light-induced protein (ELIP) were absent in the indoor plants, and they had less non-photochemical quenching (NPQ). The field-grown plants had a high capacity to perform state transitions. Plants lacking ELIPs did not have reduced growth or seed set rates, but their mortality rates were sometimes higher. NPQ levels between natural accessions grown under different conditions were not correlated. CONCLUSION: Our results indicate that comparative analysis of field-grown plants with those grown under artificial conditions is important for a full understanding of plant plasticity and adaptation. PMID- 22236034 TI - A sense of presentation: Hotta's maxims. PMID- 22236033 TI - Radiotherapy in the management of localized mucocutaneous oral lymphoma in dogs: 14 cases. AB - Oral mucocutaneous lymphoma is rare in dogs. Surgery and chemotherapy do not usually provide effective long-term control. The objective of this study was to retrospectively evaluate survival of dogs with localized oral lymphoma treated with radiation therapy. The medical database of three institutions was searched for dogs with diagnosis of oral lymphoma treated with radiotherapy. Dogs with evidence of systemic disease were excluded. Survival was calculated with the Kaplan-Meier method and prognostic variables analysed with log-rank test. Fourteen dogs were included in the study. Mean survival was 1129 days [95% confidence interval (CI) 711-1546] with median survival of 770 days. The overall response of radiotherapy was 67% (five complete and three partial responses). A survival advantage was seen in dogs with no evidence of lymph node metastasis (P = 0.002) and that achieved a complete response to radiation therapy (P = 0.013). Radiation therapy was a well-tolerated and effective treatment for localized oral lymphoma. PMID- 22236036 TI - Mesoscale simulation of the effect of a lactide segment on the nanostructure of star poly(ethylene glycol-co-lactide)-acrylate macromonomers in aqueous solution. AB - The distribution of reactive groups and micelle formation in amphiphilic macromonomers and the extent of network formation in aqueous solution depend on the segment length of the hydrophobic monomer. The objective of this work was to simulate by dissipative particle dynamics (DPD) the structure of the four-arm star poly(ethylene glycol-co-lactide)-acrylate (SPELA) macromonomer in aqueous solution. The effect of lactide segment length (n) in each arm and macromonomer concentration on the distribution and size of the micelles was investigated. In the absence of lactide, the reactive acrylate groups were uniformly distributed in the aqueous solution. With the addition of lactide segments, micelles formed with a hydrophobic core containing lactide and acrylate beads and a hydrophilic corona of ethylene oxide beads. The size and average number of macromonomers (aggregation number) of the micelles increased with n while the number density of micelles decreased. Furthermore, the fraction of macromonomer arms incorporated in the micelles as either loops or intermicellar bridges increased with increasing n. The macromonomer bridge fraction showed a biphasic behavior with a maximum at n = 4. The accumulation of water beads around acrylates decreased with increasing n. The aggregation of acrylates initially increased with n, and then, it decreased for n > 4 due to the decrease in size and distance between the micelles. The fraction of acrylates in the core surface layer of the micelles decreased from 66 to 19% when n increased from 4 to 16 with a higher fraction of acrylates trapped in the micelles' core. Macromonomer concentration increased the number density of micelles, but it did not have a significant effect on the micelle size or distribution of the acrylates. The simulation results indicate that SPELA macromers with <4 lactide segment length can potentially produce degradable PEG-based hydrogels with the highest network density. PMID- 22236035 TI - Exogenous activated protein C inhibits the progression of diabetic nephropathy. AB - BACKGROUND: Activated protein C (APC) can regulate immune and inflammatory responses and apoptosis. Protein C transgenic mice develop less diabetic nephropathy but whether exogenous administration of APC suppresses established diabetic nephropathy is unknown. OBJECTIVES: We investigated the therapeutic potential of APC in mice with streptozotocin-induced diabetic nephropathy. METHODS: Diabetes was induced in unilaterally nephrectomized C57/Bl6 mice using intraperitoneal (i.p.) injection of streptozotocin. Four weeks later, the mice were treated with i.p. exogenous APC every other day for 1 month. RESULTS: APC treated mice had a significantly improved blood nitrogen urea-to-creatinine ratio, urine total protein to creatinine ratio and proteinuria, and had significantly less renal fibrosis as measured by the levels of collagen and hydroxyproline. The renal tissue concentration of monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and the RNA expression of platelet-derived growth factor (PDGF), transforming growth factor beta1 and connective tissue growth factor (CTGF) were significantly lower in APC treated mice than in untreated animals. The percentage of apoptotic cells was reduced and the expression of podocin, nephrin and WT-1 in the glomeruli was significantly improved in mice treated with APC compared with untreated mice. The levels of coagulation markers were not affected by APC treatment. CONCLUSION: Exogenous APC improves renal function and mitigates pathological changes in mice with diabetic nephropathy by suppressing the expression of fibrogenic cytokines, growth factors and apoptosis, suggesting its potential usefulness for the therapy of this disease. PMID- 22236037 TI - A method for distinctly marking honey bees, Apis mellifera, originating from multiple apiary locations. AB - Inexpensive and non-intrusive marking methods are essential to track natural behavior of insects for biological experiments. An inexpensive, easy to construct, and easy to install bee marking device is described in this paper. The device is mounted at the entrance of a standard honey bee Apis mellifera L. (Hymenoptera: Apidae) hive and is fitted with a removable tube that dispenses a powdered marker. Marking devices were installed on 80 honey bee colonies distributed in nine separate apiaries. Each device held a tube containing one of five colored fluorescent powders, or a combination of a fluorescent powder (either green or magenta) plus one of two protein powders, resulting in nine unique marks. The powdered protein markers included egg albumin from dry chicken egg whites and casein from dry powdered milk. The efficacy of the marking procedure for each of the unique markers was assessed on honey bees exiting each apiary. Each bee was examined, first by visual inspection for the presence of colored fluorescent powder and then by egg albumin and milk casein specific enzyme-linked immunosorbent assays (ELISA). Data indicated that all five of the colored fluorescent powders and both of the protein powders were effective honey bee markers. However, the fluorescent powders consistently yielded more reliable marks than the protein powders. In general, there was less than a 1% chance of obtaining a false positive colored or protein-marked bee, but the chance of obtaining a false negative marked bee was higher for "protein-marked" bees. PMID- 22236038 TI - Various presentations of fourth branchial pouch sinus tract during surgery. AB - CONCLUSION: A recurrent neck abscess or acute suppurative thyroiditis should arouse suspicion of fourth branchial pouch sinus. Complete surgical excision is usually curative. The classification of sinus tract according to the area where it is emerging from the larynx may be helpful in identifying the tract during surgery. OBJECTIVE: To describe our experience of the diagnosis and management of fourth branchial pouch sinus and elucidate three different emerging pathways of the sinus tract during surgery. METHODS: Retrospective case series with eight patients who were diagnosed with fourth branchial pouch sinus between January 2007 and July 2011 at the First Affiliated Hospital of Zhengzhou University. RESULTS: Six patients presented with recurrent neck abscess, two presented with acute suppurative thyroiditis. All patients had barium swallow and sinus tract was delineated in six cases. All eight patients underwent surgical excision of the sinus tract. Three different emerging pathways of the sinus tract were identified during surgery. The tract could penetrate the thyroid cartilage near the inferior horn, the inferior pharyngeal constrictor muscle or the cricothyroid membrane when it emerged from the larynx. The recurrent laryngeal nerve was commonly dissected to avoid inadvertent damage. Hemithyroidectomy was performed in six patients. All eight are currently asymptomatic. PMID- 22236039 TI - Roles of the locus coeruleus and adrenergic receptors in brain-mediated hypothalamic-pituitary-adrenal axis responses to intracerebroventricular alcohol. AB - BACKGROUND: Alcohol activates the hypothalamic-pituitary-adrenal (HPA) axis through its actions in both the periphery and the central nervous system (CNS). The studies presented here were designed to test the CNS-specific noradrenergic mechanisms by which alcohol stimulates HPA activity in the male rat. METHODS: We used an experimental paradigm in which a small, nontoxic amount (5 MUl) of alcohol was slowly microinfused intracerebroventricularly (icv). Alcohol was administered icv to animals with lesions of the locus coeruleus (LC) or in animals pretreated with alpha- or beta-adrenergic receptor antagonists. Hormonal HPA activation was determined by measuring secretion of the pituitary stress hormone adrenocorticotropin (ACTH). Neuronal activation was determined by quantification of the expression of the transcription factor c-fos (Fos). RESULTS: As expected, icv alcohol stimulated ACTH secretion from the pituitary and Fos expression in the paraventricular nucleus of the hypothalamus (PVN). Bilateral electrolytic LC lesions blocked the ability of icv alcohol to stimulate ACTH secretion. Pretreatment with icv propranolol increased basal ACTH secretion levels, but icv alcohol did not increase this effect. Propranolol also blunted icv alcohol-induced PVN Fos expression. A low dose of phenoxybenzamine, an alpha adrenergic receptor antagonist, did not affect the ability of icv alcohol to stimulate ACTH release. However, a higher dose of the drug was able to block the ACTH response to icv alcohol. Despite this, phenoxybenzamine did not inhibit alcohol-induced Fos expression. Icv pretreatment with corynanthine, a selective alpha-1 adrenergic receptor antagonist, modestly raised basal ACTH levels and blocked the icv alcohol-induced secretion of this hormone. CONCLUSIONS: These results indicate that the LC and norepinephrine play important roles in HPA activation caused by icv alcohol administration, but that the specific adrenergic receptor subtypes involved in this phenomenon still need to be identified. PMID- 22236040 TI - The Class II KNOX gene KNAT7 negatively regulates secondary wall formation in Arabidopsis and is functionally conserved in Populus. AB - * The formation of secondary cell walls in cell types such as tracheary elements and fibers is a defining characteristic of vascular plants. The Arabidopsis transcription factor KNAT7 is a component of a transcription network that regulates secondary cell wall biosynthesis, but its function has remained unclear. * We conducted anatomical, biochemical and molecular phenotypic analyses of Arabidopsis knat7 loss-of-function alleles, KNAT7 over-expression lines and knat7 lines expressing poplar KNAT7. * KNAT7 was strongly expressed in concert with secondary wall formation in Arabidopsis and poplar. Arabidopsis knat7 loss of-function alleles exhibited irregular xylem phenotypes, but also showed increased secondary cell wall thickness in fibers. Increased commitment to secondary cell wall biosynthesis was accompanied by increased lignin content and elevated expression of secondary cell wall biosynthetic genes. KNAT7 over expression resulted in thinner interfascicular fiber cell walls. * Taken together with data demonstrating that KNAT7 is a transcriptional repressor, we hypothesize that KNAT7 is a negative regulator of secondary wall biosynthesis, and functions in a negative feedback loop that represses metabolically inappropriate commitment to secondary wall formation, thereby maintaining metabolic homeostasis. The conservation of the KNAT7 regulatory module in poplar suggests new ways to manipulate secondary cell wall deposition for improvement of bioenergy traits in this tree. PMID- 22236044 TI - Randomized controlled trial to compare two bone substitutes in the treatment of bony dehiscences. AB - AIM: This in vivo split-mouth randomized controlled trial compared a synthetic bone substitute with a bovine bone mineral to cover bone dehiscences after implant insertion. MATERIALS AND METHODS: Fourteen patients received four to six implants to support an overdenture. Two comparable dehiscences within the same patient were first covered with a layer of autogenous bone, followed by a layer of either Bio-Oss(r) (group 1; Geistlich Pharma AG, Wolhusen, Switzerland) or Straumann BoneCeramic(r) (group 2; Institut Straumann AG, Basel, Switzerland) and sealed by a resorbable membrane. The change in vertical dimension of the defect was measured at implant placement and at abutment connection (6.5 months). Clinical and radiological parameters were evaluated up to 1 year of loading. RESULTS: The vertical size of the defect at surgery was 6.4 +/- 1.6 mm for group 1 and 6.4 +/- 2.2 mm for group 2 sites, measured from the implant shoulder. After 6.5 months, the depth of the defect was reduced to 1.5 +/- 1.2 mm and 1.9 +/- 1.2 mm for group 1 and group 2 sites, respectively (p > 0.05). No implants failed during follow-up. Mean marginal bone loss over the SLActive surface was 0.94 mm (group 1), 0.81 mm (group 2), and 0.93 mm (group 3, no dehiscence) after 1 year of loading. CONCLUSION: Both bone substitutes behaved equally effectively. PMID- 22236046 TI - Introduction to the quantum chemistry 2012 issue. PMID- 22236045 TI - In vitro and in vivo evaluation of Assam Bora rice starch-based bioadhesive microsphere as a drug carrier for colon targeting. AB - OBJECTIVE: The aim of this study is to develop, characterize and evaluate (in vitro and in vivo) a novel colon-targeted bioadhesive microsphere (BAM) containing metronidazole (MTZ). METHODS: BAMs are prepared using Assam Bora rice starch as a natural bioadhesive polymer by a double emulsion solvent evaporation method. RESULTS: The prepared microspheres showed a uniform spherical shape, with excellent retention time. The in vitro drug release study of the optimized formulations, in different physiological environments, confirmed the insignificant release of metronidazole in the physiological conditions of the stomach (10 - 12.5%) and small intestine (< 25%). Further, fast and major drug release in cecal content (> 90) indicated that the release of the drug was unaffected by the hostile environment of the gastrointestinal tract (GIT). In vitro bacterial inhibition studies illustrated that MTZ loaded BAMs, inhibiting metronidazole-sensitive Bacteroides fragilis and selected BAMs (F1 - F7), have an equivalent or higher zone of inhibition than the marketed formulation. An in vivo organ distribution study of MTZ revealed that Assam Bora rice starch-based microspheres were relatively intact in the upper part of GIT, and the drug was released only after reaching the colon, owing to the microbial degradation of Assam Bora rice starch by microflora residing in the colon. CONCLUSION: MTZ release patterns exhibited slow and extended release over longer periods of time, which shows the potential of Assam Bora rice starch microspheres as a drug carrier for an effective colon-targeted delivery system. PMID- 22236047 TI - Recent advances in wave function-based methods of molecular-property calculations. PMID- 22236048 TI - Primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with carboplatin or toceranib. AB - In human medicine, primary frontal sinus squamous cell carcinoma (pFS-SCC) is not frequently reported. In veterinary medicine, frontal sinus SCC is exclusively described as an extension of nasal cavity SCC. To our knowledge, this is the first publication concerning canine pFS-SCC, diagnosed using histology or cytology and medical imaging, in three dogs. The tumours extended into the orbit or brain cavity, without nasal involvement. Treatment was initiated with piroxicam-carboplatin. Prolongation of carboplatin delivery with a low dose intensity was performed on dogs with a favourable initial response. Dog 1 achieved a complete remission (CR), but was euthanized 344 days after start of therapy. Dog 2, still alive 3 years after start of therapy and in CR, received 14 carboplatin deliveries. In dog 3, after changing the treatment protocol into piroxicam-toceranib, a significant tumour reduction occurred, but the dog was euthanized after 195 days because of a relapse. PMID- 22236049 TI - Comparison of fatty acid profile and antioxidant potential of extracts of seven Citrus rootstock seeds. AB - The extracts of seven Citrus rootstock seeds have been compared regarding fatty acid profile and antioxidant potential. Sour orange (Citrus aurantium L.) was found to contain the highest oil amount (34%), while the Poncirus trifoliata cultivars contained the highest percentage of unsaturated fatty acids (84-87%). In addition, the antioxidant properties of the extracts from defatted seeds have been evaluated by measuring their radical scavenging activity against 2,2' diphenyl-1-picrylhydrazyl. The highest antioxidant activities were observed in the case of the acetone extract of sour orange and Citrumelo Swingle (76% and 75%, respectively), at a concentration of 0.17 mg mL(-1). Moreover, the total phenolic content of the extracts, determined using the Folin-Ciocalteau reagent, was found to be correlated with the radical scavenging activity results. The acetone extracts of sour orange and Citrumelo Swingle exhibited the highest phenolic content [112.3 and 103.4 mg gallic acid equivalent g(-1) dry sample weight, respectively]. PMID- 22236050 TI - A real-time PCR assay for detection and quantification of Verticillium dahliae in spinach seed. AB - Verticillium dahliae is a soilborne fungus that causes Verticillium wilt on multiple crops in central coastal California. Although spinach crops grown in this region for fresh and processing commercial production do not display Verticillium wilt symptoms, spinach seeds produced in the United States or Europe are commonly infected with V. dahliae. Planting of the infected seed increases the soil inoculum density and may introduce exotic strains that contribute to Verticillium wilt epidemics on lettuce and other crops grown in rotation with spinach. A sensitive, rapid, and reliable method for quantification of V. dahliae in spinach seed may help identify highly infected lots, curtail their planting, and minimize the spread of exotic strains via spinach seed. In this study, a quantitative real-time polymerase chain reaction (qPCR) assay was optimized and employed for detection and quantification of V. dahliae in spinach germplasm and 15 commercial spinach seed lots. The assay used a previously reported V. dahliae specific primer pair (VertBt-F and VertBt-R) and an analytical mill for grinding tough spinach seed for DNA extraction. The assay enabled reliable quantification of V. dahliae in spinach seed, with a sensitivity limit of ~1 infected seed per 100 (1.3% infection in a seed lot). The quantification was highly reproducible between replicate samples of a seed lot and in different real-time PCR instruments. When tested on commercial seed lots, a pathogen DNA content corresponding to a quantification cycle value of >=31 corresponded with a percent seed infection of <=1.3%. The assay is useful in qualitatively assessing seed lots for V. dahliae infection levels, and the results of the assay can be helpful to guide decisions on whether to apply seed treatments. PMID- 22236051 TI - The importance of multilocus sequence typing: cautionary tales from the bacterium Xylella fastidiosa. AB - Microbial identification methods have evolved rapidly over the last few decades. One such method is multilocus sequence typing (MLST). MLST is a powerful tool for understanding the evolutionary dynamics of pathogens and to gain insight into their genetic diversity. We illustrate the importance of accurate typing by reporting on three problems that have arisen in the study of a single bacterial species, the plant pathogen Xylella fastidiosa. Two of these were particularly serious since they concerned contamination of important research material that has had detrimental consequences for Xylella research: the contamination of DNA used in the sequencing of an X. fastidiosa genome (Ann-1) with DNA from another X. fastidiosa strain, and the unrecognized mislabeling of a strain (Temecula1) distributed from a culture collection (ATCC). We advocate the routine use of MLST to define strains maintained in culture collections and emphasize the importance of confirming the purity of DNA submitted for sequencing. We also present a third example that illustrates the value of MLST in guiding the choice of taxonomic types. Beyond these situations, there is a strong case for MLST whenever an isolate is used experimentally, especially where genotypic differences are suspected to influence the outcome. PMID- 22236052 TI - What is the cause of retraction spaces associated with basal cell carcinoma? PMID- 22236053 TI - Ethnic differences in utilization of youth mental health care. AB - OBJECTIVES: There is an overall underutilization of youth mental health care (YMHC). It is unknown whether underutilization differs per ethnic group. Therefore, this study is aimed at gaining insight into the effects of ethnicity, age and gender on this utilization. DESIGN: The sample consisted of outpatient children (age 5-10) (n=1940) and adolescents (age 11-19) (n=2484) admitted to a Dutch YMHC centre. Ethnic background of the patients (patient registration system) was compared to that of the general population (municipality files). Relative risks (RRs) on utilization for non-native groups were calculated with natives as the reference group. RESULTS: With regard to children, female children from Moroccan, Turkish and other non-native western descent were less likely to enter mental health care than native Dutch female children. The RR was 0.24 for Moroccan girls, 0.53 for Turkish girls, and 0.60 for girls from other non-native western countries. Male children from almost all non-native groups were also less likely to enter mental health care than native Dutch male children, with the RRs being between 0.43 and 0.65. With regard to adolescents, most non-native adolescents, were as likely as native adolescents to enter mental health care. An exception were males and females from Morocco and males from Turkey and non native western countries, who were less likely than Dutch adolescents to enter mental health care (RRs between 0.61 and 0.80). CONCLUSION AND DISCUSSION: Results imply that YMHC is less accessible for children from a minority background than for children from a native background. With adolescents, there is no difference in accessibility between natives and non-natives. Future research should focus on the reasons for this difference in accessibility. Potential mediators such as socioeconomic status, discrimination, acculturation processes, language barriers should be taken into account. PMID- 22236056 TI - Radiotherapy-induced myelosuppression in dogs: 103 cases (2002-2006). AB - Definitive radiotherapy refers to delivery of large doses, typically 48-62 Gray, of ionizing radiation over several weeks using a daily or alternate-day fractionation schedule. The impact of definitive radiotherapy alone on haematopoiesis in tumour-bearing dogs is unknown. Medical records from 103 dogs receiving definitive (60) Cobalt teletherapy for cancer over a 5-year period were reviewed for signalment, tumour type and location, total radiotherapy dose and fractionation scheme. Complete blood count data were collected before, halfway through, and at the end of radiation treatment, and analysed for changes associated with patient variables. The results demonstrate significant reductions in haematocrit, total white blood cell count, neutrophils, eosinophils, monocytes, lymphocytes and platelets occurred during definitive radiotherapy but remained within laboratory reference intervals. These data are important for anticipation of toxicity associated with combinations of radiotherapy and chemotherapy in dogs but do not support the routine monitoring of haematology parameters during definitive radiotherapy. PMID- 22236055 TI - Drug resistance mutations of HIV type 1 non-B viruses to integrase inhibitors in treatment-naive patients from sub-saharan countries and discordant interpretations. AB - The routine use of integrase inhibitors in sub-Saharan Africa where HIV-1 non-B viruses predominate is limited, but evaluating their effectiveness on HIV-1 subtypes and CRFs that circulate in this region is essential. We here analyzed 97 integrase sequences from HIV-1 non-B-infected individuals from African countries. Using currently available interpretation algorithms (ANRS, HIVdb, and Rega), we identified the presence of mutations at nine resistance-associated positions including L74M (3.1%), T97A (9.3%), K156N (2.1%), E157Q (5.2%), G163K (1.0%), T206S (48.5%), S230N (1.0%), D232N (1.0%), and R236K (1.0%). All but one (E157Q) were considered as accessory resistant mutation by the algorithms. E157Q identified in 5% of patients tested (5/97) was selected by the ANRS algorithm as a primary mutation, which alone can confer resistance to raltegravir. These results illustrated the need of further in vitro and clinical studies involving non-B viruses to better understand the real significance of observed mutations and harmonize interpretations. PMID- 22236057 TI - Plasma-derived human antithrombin attenuates ventilator-induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats. AB - BACKGROUND: Mechanical ventilation exaggerates pneumonia-associated pulmonary coagulopathy and inflammation. We hypothesized that the administration of plasma derived human antithrombin (AT), one of the natural inhibitors of coagulation, prevents ventilator-induced pulmonary coagulopathy, inflammation and bacterial outgrowth in a Streptococcus pneumoniae pneumonia model in rats. METHODS: Forty eight hours after induction of S. pneumoniae pneumonia rats were subjected to mechanical ventilation (tidal volume 12 mL kg(-1), positive end-expiratory pressure 0 cmH(2)O and inspired oxygen fraction 40%). Rats were randomized to systemic treatment with AT (250 IU administered intravenously (i.v.) before the start of mechanical ventilation) or placebo (saline). Non-ventilated, non infected rats and non-ventilated rats with pneumonia served as controls. The primary endpoints were pulmonary coagulation and inflammation in bronchoalveolar lavage fluid (BALF). RESULTS: Pneumonia was characterized by local activation of coagulation and inhibition of fibrinolysis, resulting in increased levels of fibrin degradation products and fibrin deposition in the lung. Mechanical ventilation exaggerated pulmonary coagulopathy and inflammation. Systemic administration of AT led to supra-normal BALF levels of AT and decreased ventilator-associated activation of coagulation. AT neither affected pulmonary inflammation nor bacterial outgrowth from the lungs or blood. CONCLUSIONS: Plasma derived human AT attenuates ventilator-induced coagulopathy, but not inflammation and bacterial outgrowth in a S. pneumoniae pneumonia model in rats. PMID- 22236058 TI - New directions of EvoDevo: revisiting ideas of professor Hotta. PMID- 22236059 TI - Irradiation of ethylene/styrene copolymers: evidence of sensitization of the aromatic moiety as counterpart of the radiation protection effect. AB - Molecules containing aromatics systems are more stable in the presence of ionizing radiations than alkanes. In the same way, introducing aromatic rings into aliphatic compounds increases their stability. The protective effect is nonlocal and likely results from the transfer of energy and species from the aliphatic moiety to the aromatic one. For years, it was commonly assumed that the aromatic moiety, which is very radiation resistant, accommodates the extra energy remaining unaffected. The use of Fourier transform infrared spectroscopy, online with high energy ion beam irradiation of ethylene/styrene random copolymers, allows us to bring experimental evidence that the benzene rings are sensitized by transfer reactions and consequently that this effect is more important in polymers with low benzene ring molar content. PMID- 22236060 TI - Chemical evaluation of African palm weevil, Rhychophorus phoenicis, larvae as a food source. AB - The chemical properties of the African palm weevil, Rhychophorus phoenicis (F.) (Coleoptera: Curculionidae), larvae were evaluated using standard methodology. The chloroform-methanol extract yielded 37.12% on a dry basis. The oil was liquid at room temperature with a flash point of 36.0 degrees C. Analysis of the physical constants indicated values of 192.25 Wijs and 427.70 mg KOH/g as iodine and saponification, respectively. Fatty acid analysis of the extracted oil showed the presence of unsaturated fatty acids at low levels. Palmitic acid and stearic acid constituted 35.3 and 60.5% of the oil, respectively. The usual behaviour of the oil at room temperature, irrespective of the level of unsaturation of its constituent fatty acid was noted. The total protein content of the defatted palm weevil larva (dry basis) was estimated at 66.3%. The amino acid values compared favourably to FAO reference protein, except for tryptophan, which was limiting. All the other essential amino acids were adequate. Mineral analysis revealed high levels of potassium (1025 mg/100 g) and phosphorus (685 mg/100 g). The dried and defatted palm weevil lava represents a very good source of protein, and a good complement of essential amino acids. PMID- 22236062 TI - Comment on the paper by Suffoletto et al. entitled: Text-message-based assessments and brief intervention for young adults discharged from the emergency department. AB - BACKGROUND: This commentary discusses the importance of the recent article by Suffoletto and colleagues (in press), from the perspective of the developing role that technology such as text-messaging is serving as a means of increasing the reach of brief interventions for harmful alcohol use. RESULTS: This study is important as it offers evidence from a well-designed study that text-messaging can be used to survey young adults about their alcohol use shows promising results for the potential efficacy of this technology to reduce alcohol use, including risky heavy episodic use. There are ethical and clinical considerations around text-messaging that need to be examined. CONCLUSIONS: Future adequately powered randomized studies are needed to show the comparative effect of new technologies, such as text-messaging, in comparison with more traditional methods of providing interventions in reducing harmful alcohol use. PMID- 22236063 TI - Inputs from the basolateral amygdala to the nucleus accumbens shell control opiate reward magnitude via differential dopamine D1 or D2 receptor transmission. AB - The basolateral amygdala (BLA), ventral tegmental area and nucleus accumbens (NAc) form a functionally connected neural circuit involved in the processing of opiate-related reward and memory. Dopamine (DA) projections from the ventral tegmental area to the BLA modulate associative plasticity mechanisms within the BLA. However, the role of DA receptor signaling in the BLA and its functional outputs to the NAc during opiate reward processing is not currently understood. Using an unbiased place conditioning procedure, we measured the rewarding effects of morphine following intra-BLA microinfusions of specific DA D1 or D2 receptor agonists in either opiate-naive or opiate-dependent/withdrawn rats. Activation of intra-BLA D1 receptors strongly potentiated the behaviorally rewarding effects of opiates, only in the opiate-naive state. However, once opiate dependence and withdrawal occurred, the intra-BLA DA-mediated potentiation of opiate reward salience switched to a D2 receptor-dependent substrate. We next performed single unit, in-vivo extracellular neuronal recordings in the NAc shell (NA shell), to determine if intra-BLA D1/D2 receptor activation may modulate the NA shell neuronal response patterns to morphine. Consistent with our behavioral results, intra-BLA D1 or D2 receptor activation potentiated NAc 'shell' (NA shell) neuronal responses to sub-reward threshold opiate administration, following the same functional boundary between the opiate-naive and opiate-dependent/withdrawn states. Finally, blockade of N-methyl-d-aspartate transmission within the NA shell blocked intra-BLA DA D1 or D2 receptor-mediated opiate reward potentiation. Our findings demonstrate a novel and functional DA D1/D2 receptor-mediated opiate reward memory switch within the BLA->NA shell circuit that controls opiate reward magnitude as a function of opiate exposure state. PMID- 22236064 TI - The study protocol of a cluster-randomised controlled trial of family-mediated personalised activities for nursing home residents with dementia. AB - BACKGROUND: Following admission to a nursing home, the feelings of depression and burden that family carers may experience do not necessarily diminish. Additionally, they may experience feelings of guilt and grief for the loss of a previously close relationship. At the same time, individuals with dementia may develop symptoms of depression and agitation (BPSD) that may be related to changes in family relationships, social interaction and stimulation. Until now, interventions to alleviate carer stress and BPSD have treated carers and relatives separately rather than focusing on maintaining or enhancing their relationships. One-to-one structured activities have been shown to reduce BPSD and also improve the caring experience, but barriers such as a lack of resources impede the implementation of activities in aged care facilities. The current study will investigate the effect of individualised activities based on the Montessori methodology administered by family carers in residential care. METHODS/DESIGN: We will conduct a cluster-randomised trial to train family carers in conducting personalised one-to-one activities based on the Montessori methodology with their relatives. Montessori activities derive from the principles espoused by Maria Montessori and subsequent educational theorists to promote engagement in learning, namely task breakdown, guided repetition, progression in difficulty from simple to complex, and the careful matching of demands to levels of competence. Persons with dementia living in aged care facilities and frequently visiting family carers will be included in the study. Consented, willing participants will be randomly assigned by facility to a treatment condition using the Montessori approach or a control waiting list condition. We hypothesise that family carers conducting Montessori-based activities will experience improvements in quality of visits and overall relationship with the resident as well as higher self-rated mastery, fewer depressive symptoms, and a better quality of life than carers in the waiting list condition. DISCUSSION: We hypothesise that training family carers to deliver personalised activities to their relatives in a residential setting will make visits more satisfying and may consequently improve the quality of life for carers and their relatives. These beneficial effects might also reduce nursing staff burden and thus impact positively on residential facilities. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12611000998943. PMID- 22236066 TI - Phytosphingosine-phosphate is a signal for AtMPK6 activation and Arabidopsis response to chilling. AB - * Long-chain bases (LCBs) are pleiotropic sphingolipidic signals in eukaryotes. We investigated the source and function of phytosphingosine-1-phosphate (PHS-P), a phospho-LCB rapidly and transiently formed in Arabidopsis thaliana on chilling. * PHS-P was analysed by thin-layer chromatography following in vivo metabolic radiolabelling. Pharmacological and genetic approaches were used to identify the sphingosine kinase isoforms involved in cold-responsive PHS-P synthesis. Gene expression, mitogen-activated protein kinase activation and growth phenotypes of three LCB kinase mutants (lcbk1, sphk1 and lcbk2) were studied following cold exposure. * Chilling provoked the rapid and transient formation of PHS-P in Arabidopsis cultured cells and plantlets. Cold-evoked PHS-P synthesis was reduced by LCB kinase inhibitors and abolished in the LCB kinase lcbk2 mutant, but not in lcbk1 and sphk1 mutants. lcbk2 presented a constitutive AtMPK6 activation at 22 degrees C. AtMPK6 activation was also triggered by PHS-P treatment independently of PHS/PHS-P balance. lcbk2 mutants grew comparably with wild-type plants at 22 and 4 degrees C, but exhibited a higher root growth at 12 degrees C, correlated with an altered expression of the cold-responsive DELLA gene RGL3. * Together, our data indicate a function for LCBK2 in planta. Furthermore, they connect PHS-P formation with plant response to cold, expanding the field of LCB signalling in plants. PMID- 22236067 TI - Relative decay of fecal indicator bacteria and human-associated markers: a microcosm study simulating wastewater input into seawater and freshwater. AB - Fecal contaminations of inland and coastal waters induce risks to human health and economic losses. To improve water management, specific markers have been developed to differentiate between sources of contamination. This study investigates the relative decay of fecal indicator bacteria (FIB, Escherichia coli and enterococci) and six human-associated markers (two bacterial markers: Bacteroidales HF183 (HF183) and Bifidobacterium adolescentis (BifAd); one viral marker: genogroup II F-specific RNA bacteriophages (FRNAPH II); three chemical markers: caffeine and two fecal stanol ratios) in freshwater and seawater microcosms seeded with human wastewater. These experiments were performed in darkness, at 20 degrees C and under aerobic conditions. The modeling of the decay curves allows us (i) to compare FIB and markers and (ii) to classify markers according to their persistence in seawater (FRNAPH II < HF183, stanol ratios < BifAd, caffeine) and in freshwater (HF183, stanol ratios < FRNAPH II < BifAd < caffeine). Although those results depend on the experimental conditions, this study represents a necessary step to develop and validate an interdisciplinary toolbox for the investigation of the sources of fecal contaminations. PMID- 22236068 TI - The early-life social environment and DNA methylation. AB - DNA methylation is a chemical modification of DNA that confers, upon identical sequences, different identities that are reflected in different gene expression programming. DNA methylation has a well-established role in cellular differentiation by providing a mechanism for one genome to express multiple phenotypes in a multicellular organism. Recent data point however to the possibility that in addition to the innate process of cellular differentiation, DNA methylation can serve as a genome adaptation mechanism, adapting genome function to changing environmental contexts including social environments. A critical time point for this process is early life when cues from the social and physical environments define lifelong trajectories of physical and mental health. DNA methylation and additional epigenetic modifications could therefore serve as molecular links between 'nurture' and 'nature'. Data that are consistent with this new role for DNA methylation as a mechanism for conferring an 'environment' specific identity to DNA will be discussed. PMID- 22236070 TI - White light emission and second harmonic generation from secondary group participation (SGP) in a coordination network. AB - We describe a white emitting coordination network solid that can be conveniently applied as a thin film onto a commercial UV-LED lamp for practical white lighting applications. The solid state material was discovered in an exercise of exploring molecular building blocks equipped with secondary groups for fine-tuning the structures and properties of coordination nets. Specifically, CH(3)SCH(2)CH(2)S- and (S)-CH(3)(OH)CHCH(2)S- (2-hydroxylpropyl) were each attached as secondary groups to the 2,5- positions of 1,4-benzenedicarboxylic acid (bdc), and the resultant molecules (L1 and L2, respectively) were crystallized with Pb(II) into the topologically similar 3D nets of PbL1 and PbL2, both consisting of interlinked Pb-carboxyl chains. While the CH(3)S- groups in PbL1 are not bonded to the Pb(II) centers, the hydroxy groups in PbL2 participate in coordinating to Pb(II) and thus modify the bonding features around the Pb(II), but only to a slight and subtle degree (e.g., Pb-O distances 2.941-3.116 A). Interestingly, the subtle change in structure significantly impacts the properties, i.e., while the photoluminescence of PbL1 is yellowish green, PbL2 features bright white emission. Also, the homochiral side group in PbL2 imparts significant second harmonic generation, in spite of its seemingly weak association with the main framework (the NLO-phore). In a broad perspective, this work showcases the idea of secondary group participation (SGP) in the construction of coordination networks, an idea that parallels that of hemilabile ligands in organometallics and points to an effective strategy in developing advanced functions in solid state framework materials. PMID- 22236072 TI - Recasting biomolecules for function. PMID- 22236071 TI - Generation of a cholangiocyte-specific cDNA expression library for the identification of B and T cell autoantigens in murine biliary disease. AB - AIM: Several mouse models of inflammatory cholangiopathies exist, including biliary atresia, primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. In an ongoing effort to identify the target antigens of both infiltrating autoreactive T cells and serum autoantibodies, we aimed to generate a cholangiocyte-derived cDNA library capable of expressing a wide variety of proteins. METHODS: mRNA was isolated from a normal mouse cholangiocyte cell line and reverse transcribed into cDNA. After initial cloning of the cDNA into a transfer vector (pDONR222), the entire library was shuttled into an Escherichia coli expression vector (pDEST160). RESULTS: The library contains 2.3 * 10(6) independent clones and expresses proteins up to 100 kD in molecular weight. Using a variety of techniques, including western blot analysis, mass spectrometry of individual clones, and direct DNA sequencing of plasmids, a number of both ubiquitously expressed and cholangiocyte-specific proteins (e.g. cytokeratin 19) have been identified within. CONCLUSION: A comprehensive mouse cholangiocyte cDNA expression library has been generated and is available for use as a source of multiple cholangiocyte-specific antigens for immunological studies. The library can be used to screen for specificity of T cell lines or hybridomas. Furthermore, this library has potential uses in SEREX analysis of autoantibody reactivity. The cholangiocyte-specific cDNA library is a powerful tool for the identification of target antigens in murine inflammatory cholangiopathies and is available as a shared resource. PMID- 22236073 TI - Cytokeratin 10-negative nested pattern enables sure distinction of clonal seborrheic keratosis from pagetoid Bowen's disease. AB - BACKGROUND: The histopathologic pattern of clonal seborrheic keratosis (SK) is quite similar to the nested pattern of pagetoid Bowen's disease [squamous cell carcinoma in situ (SCCIS)], and differentiation between the two can be challenging, especially when only small pieces are available for interpretation. METHODS: Eleven examples of clonal SK and 13 examples of pagetoid SCCIS were examined histopathologically (tabulating necrotic keratinocytes, suprabasal mitoses, infiltrate, parakeratosis housing plump nuclei, crowding of nuclei) and immunohistochemically (using Ki-67, bcl-2, cytokeratin 7 and cytokeratin 10). Sensitivity, specificity, p-values (Fisher's exact test, two-tailed) and positive/negative likelihood ratios (+LR/-LR) were calculated. RESULTS: Significant differences were seen with regard to crowding (p = 0.0009) and mitoses (p = 0.0006); however, only complete absence of necrotic keratinocytes or of crowding appeared to be diagnostically convincing for a diagnosis of clonal SK (-LR < 0.01). Significant differences were also seen with bcl-2 (p = 0.0005) and cytokeratin 10 antibodies (p < 0.00001). Both markers displayed a typical nested pattern in clonal SK, nests being bcl-2-positive and cytokeratin 10-negative. Cytokeratin 10-negative nests were the most convincing criterion for differentiation between clonal SK and pagetoid SCCIS (+LR > 10, -LR < 0.01). CONCLUSIONS: The most reliable marker to distinguish clonal SK from pagetoid SCCIS is cytokeratin 10 when it spares nests. Other criteria that assist in the differential diagnosis are bcl-2 expression, absence of crowding and of mitoses. PMID- 22236074 TI - Heavy metal content of a medicinal moss tea for hypertension. AB - The content of various heavy metals (arsenic, cadmium, chromium, copper, iron, lead, mercury, nickel, manganese and zinc) in the moss species Rhodobryum ontariense (Kindb.) Kindb. and its tea are presented in this study. Pursuant to the use of this tea in traditional Chinese medicine for hypertension, the aim of this study was to examine its safety in regard to the metals. All heavy metals were determined by adequate EPA methods. The concentrations of all metals for daily intake in its tea were below the safety levels for human consumption. These results indicate the importance of manganese in R. ontariense tea traditionally used for hypertension and other heart disorders. PMID- 22236075 TI - AHL signals induce rubrifacine production in a bruI mutant of Brenneria rubrifaciens. AB - Several members of the bacterial genus Brenneria are pathogenic on different tree species. Cell-free extracts from the bacterial phytopathogens Brenneria rubrifaciens, B. salicis, and B. nigrifluens induced production of the red pigment rubrifacine in the B. rubrifaciens bruI insertional mutant Br-212. Analysis of the bruI locus identified an adjacent open reading frame, designated bruR, with homology to luxR. High-performance liquid chromatography and mass spectrometry analysis of ethyl acetate extracts from wild-type B. rubrifaciens and Escherichia coli expressing the bruI gene identified two acyl homoserine lactone (AHL) peaks, N-(3-oxohexanoyl)-homoserine lactone (3OC6HSL) and N hexanoyl-homoserine lactone (C6HSL). Addition of synthetic 3OC6HSL and C6HSL at 10 MUM to the bruI mutant, strain Br-212, induced rubrifacine production and the ability to elicit a hypersensitive reaction (HR) in tobacco leaves. Synthetic C6HSL was less effective at inducing pigment production than 3OC6HSL at 10 MUM. The bruI mutant Br-212 did not produce detectable AHLs, indicating that C6HSL and 3OC6HSL are the major AHLs produced by this species. The AHLs N-heptanoyl-DL homoserine lactone (C7HSL), N-octanoyl-DL-homoserine lactone (C8HSL), and N-(3 oxooctanoyl)-DL-homoserine lactone (3OC8HSL) also induced pigment production in Br-212 and restored its ability to elicit an HR in tobacco, suggesting that cross talk with other bacterial species may be possible. PMID- 22236076 TI - Flow cytometric techniques for detection of candidate cancer stem cell subpopulations in canine tumour models. AB - The cancer stem cell (CSC) hypothesis proposes that tumour growth is maintained by a distinct subpopulation of 'CSC'. This study applied flow cytometric methods, reported to detect CSC in both primary and cultured cancer cells of other species, to identify candidate canine subpopulations. Cell lines representing diverse canine malignancies, and cells derived from spontaneous canine tumours, were evaluated for expression of stem cell-associated surface markers (CD34, CD44, CD117 and CD133) and functional properties [Hoecsht 33342 efflux, aldehyde dehydrogenase (ALDH) activity]. No discrete marker-defined subsets were identified within established cell lines; cells derived directly from spontaneous tumours demonstrated more heterogeneity, although this diminished upon in vitro culture. Functional assays produced variable results, suggesting context dependency. Flow cytometric methods may be adopted to identify putative canine CSC. Whilst cell lines are valuable in assay development, primary cells may provide a more rewarding model for studying tumour heterogeneity in the context of CSC. However, it will be essential to fully characterize any candidate subpopulations to ensure that they meet CSC criteria. PMID- 22236077 TI - Twenty-fold difference in evolutionary rates between the mitochondrial and plastid genomes of species with secondary red plastids. AB - Within plastid-bearing species, the relative rates of evolution between mitochondrial and plastid genomes are poorly studied, but for the few lineages in which they have been explored, including land plants and green algae, the mitochondrial DNA mutation rate is nearly always estimated to be lower than or equal to that of the plastid DNA. Here, we show that in protists from three distinct lineages with secondary, red algal-derived plastids, the opposite is true: their mitochondrial genomes are evolving 5-30 times faster than their plastid genomes, even when the plastid is nonphotosynthetic. These findings have implications for understanding the origins and evolution of organelle genome architecture and the genes they encode. PMID- 22236078 TI - 'Walk with your head high': African and African-Caribbean fatherhood, children's mental well-being and social capital. AB - OBJECTIVES: The findings presented in this article were unanticipated and came to light during a study which investigated African and African-Caribbean fathers' views about preventive primary care services. This article reports findings which indicate that African and African-Caribbean fathers strive to enable and protect children's mental well-being and create social, cultural and symbolic forms of capital. It also seeks to identify implications for health and social care policy and practice in England. DESIGN: There is limited literature examining African and African-Caribbean fathers' health experiences in England. Consequently an exploratory research approach was required. This involved nine, in-depth, semi structured qualitative group interviews undertaken with 46 African and African Caribbean fathers. The data were analysed thematically using abductive reasoning, informed by Bourdieu's theoretical work. RESULTS: Fathers were striving to enable and protect children's mental well-being through providing authoritative, loving, affectionate fatherhood involving reasoning, good communication and promoting self-esteem. These practices were seen to be necessary if children were to prosper in a harsh social world characterised by structural hazards including racism, negative stereotypes and limited opportunities. The fathers reported their efforts to develop what Bourdieu has termed symbolic, cultural and social capital as means of promoting the mental well-being of their children and the children of others. CONCLUSION: The implications for theory, future research, public health policy and practice, in relation to the needs of African and African-Caribbean fathers and families, are also discussed, with specific focus on how to realise the potential of African and African-Caribbean fathers' positive contributions to family and community health. PMID- 22236080 TI - Isolation, characterization, and sequence analysis of a novel HIV type 1 subtype A1 strain from Russia. AB - A new syncytia-inducing human immunodeficiency virus type 1 (HIV-1) strain designated PokA79 was first isolated from a peripheral blood mononuclear cells (PBMC) pool from 24 HIV-1-infected patients from Russia and adapted to growth in MT2, MT4, and U937 cell cultures. The full-length genome of this isolate was amplified by RT-two-round PCR and sequenced. The obtained sequence belongs to the A1 subtype and clustered with other A1 former Soviet Union (FSU) strains. Full length genome analysis showed that some of the PokA79 genes contain insertions and frame shifts, and the gp120 V3 loop has the three amino acid insertion inside its apex, which is rare for subtype A1 sequences. Nonidentical insertions of the same size are also present in the V3 apex region of several HIV-1 sequences from Central Africa. PMID- 22236079 TI - Patterns of early transmission of pandemic influenza in London - link with deprivation. AB - BACKGROUND: During the early containment phase in England from April to June 2009, the national strategy for H1N1 pandemic influenza involved case investigation and treatment, and tracing and prophylaxis of contacts. OBJECTIVE: To describe the relationship between early transmission of H1N1 pandemic influenza in London and age and socio-economic status. METHODS: Epidemiological data on cases of pandemic flu in London reported to the London Flu Response Centre were analysed to determine patterns of transmission. RESULTS: There were 3487 reported cases (2202 confirmed, 1272 presumed and 14 probable) from 20 April to 28 June 2009, during the 'containment' period. The highest report rate of 206 per 100 000 (95% CI 195-218) was seen in primary school-age children (5-11 years) followed by 129 (95% CI 119-139) in secondary school-age children (12-18 years). Reports of cases were initially concentrated in affluent areas but overall showed a clear trend with deprivation and risk ratio of 2.32 (95% CI 1.94-2.78) between the most deprived and the least deprived. CONCLUSION: Early transmissions were highest amongst school-aged children but linked with socio-economic deprivation across all age groups. PMID- 22236081 TI - Blockade of the nuclear factor kappa B pathway prolonged islet allograft survival. AB - Nuclear factor kappa B (NF-kappaB) pathway is known for its important role in the upregulation of various inflammatory mediators and its "switch regulator" functionality for transcription factor gene networks which control cytokine induced beta-cell dysfunction and death. In this study, the islets were divided into the control group, Ad-green fluorescent protein, and the adenovirus transfected with inhibitor kappa B group. The proliferation index of peripheral blood mononuclear cells and the islets apoptosis index were examined after mixed lymphocyte-islet reaction with inverted fluorescence microscopy. Moreover, mRNA expression of inflammatory cytokines was measured by reverse transcription polymerase chain reaction. The islet graft survival time in diabetic rats, insulin in grafts, and cytokine concentrations in the supernatant were determined by immunohistochemistry and enzyme-linked immunosorbent assay. We found that blocking of NF-kappaB activation in beta-cells significantly downregulated inflammatory chemokine production by islets cells in vitro and in vivo, inhibited T-cell recruitment into the pancreatic islets, inhibited beta-cell dysfunction, and effectively prolonged the survival time of islet grafts. The results presented in this work highlight a novel mechanism of blocking NF-kappaB activation in beta-cells for the treatment of islet cell transplantation. PMID- 22236082 TI - Monitoring of plasma levels of activated protein C using a clinically applicable oligonucleotide-based enzyme capture assay. AB - BACKGROUND: Human-activated protein C (APC) is a serine protease with anticoagulant, anti-inflammatory and cytoprotective functions. This feature renders APC to be a promising vascular-inflammatory biomarker. OBJECTIVE: The aim of the present study was the development and validation of a technique that allows the measurement of APC plasma levels under practical laboratory conditions. METHODS/PATIENTS: Based on the APC-binding ssDNA aptamer HS02-52G we developed an oligonucleotide-based enzyme capture assay (OECA) that quantifies aptamer-captured APC through hydrolysis rates of a fluorogenic peptide substrate. After optimization of pre-analytical conditions, plasma APC levels were measured in healthy individuals and patients undergoing hip replacement surgery. RESULTS AND CONCLUSION: A combination of APC-OECA with an aprotinin-based quenching strategy allowed APC analysis with a limit of detection as low as 0.022 +/- 0.005 ng mL(-1) (0.39 +/- 0.10 pmol L(-1)) and a limit of quantification of 0.116 +/- 0.055 ng mL(-1) (2.06 +/- 0.98 pmol L(-1)). While APC plasma levels in healthy individuals fell below the quantifiable range of the APC-OECA platform, levels substantially increased in patients undergoing hip replacement surgery reaching peak values of up to 12 ng mL(-1) (214 pmol L(-1)). When normalized to the amount of thrombin generated, interindividual variabilities in the APC generating capacity were observed. In general, with a turn-around time from blood sampling to generation of test results of < 7 h, the APC-OECA platform allows sensitive and rapid determination of circulating APC levels under pathological conditions. PMID- 22236084 TI - Coleopterans associated with plants that form phytotelmata in subtropical and temperate Argentina, South America. AB - A list of the most common plants that form phytotelmata and their associated coleopterans (aquatic, semi-aquatic and terrestrial) from the northeastern subtropical and temperate area of Argentina, South America with biological and behavioral observations is presented in this study. Species of Poaceae (n = 3), Bromeliaceae (5), Apiaceae (6), Araceae (2), Urticaceae (1), Marantaceae (1), Arecaceae (1), Dipsacaceae (1) and Cyperaceae (1) were identified as phytotelmata. Aquatic species of Scirtidae (2), Dytiscidae (2), and Hydrophilidae (4), semi-aquatic Chelonariidae (2), and terrestrial species of Carabidae (3), Staphylinidae (5), Histeridae (1), Elateridae (1), Cantharidae (1), Cleridae (1), Tenebrionidae (1), Meloidae (1), Anthicidae (1), Chrysomelidae (3), Curculionidae (7) and Apionidae (1) were identified from six species of Eryngium L. (Apiales: Apiaceae), two species of Guadua Kunth (Poales: Poaceae), Aechmea distichantha Lemaire (Poales: Bromeliaceae), and from fallen leaves of Euterpe edulis Martius (Arecales: Arecaceae) from the temperate and subtropical area. The highest species richness was recorded in Eryngium phytotelmata. Fifteen species of beetles inhabit Eryngium cabrerae Pontiroli, 11 in E. horridum Malme, 7 in E. stenophyllum Urban, 4 in E. aff. serra Chamisso and Schlechtendal., 3 in E. elegans Chamisso and Schlechtendal, 2 in E. eburneum Decne and E. pandanifolium Chamisso and Schlechtendal. From bamboo, 6 species of coleopterans were collected from Guadua trinii (Nees) Nees ex Ruprecht and 4 from G. chacoensis (Rojas) Londono and Peterson. Three species of aquatic coleopterans were recorded from A. distichantha and only one from E. edulis. PMID- 22236085 TI - Immediate postextractive dental implant placement with immediate loading on four implants for mandibular-full-arch rehabilitation: a retrospective analysis. AB - BACKGROUND: To date, only few studies have reported on the clinical outcomes of immediate postextraction implant placement and immediate loading. PURPOSE: The purpose of this retrospective study was to report the results of immediately loading four implants placed in fresh extraction sockets in the mandible after a follow-up of 24 months. MATERIALS AND METHODS: Between January 2001 and January 2009, 50 patients (28 women and 22 men, average age 54 years), had 347 teeth extracted and a total of 200 dental implants placed in the mandible. The patients received a provisional fixed bridge the same day and a permanent one 3 months later. Clinical checkups were performed after 1, 2, 3, 6, 12, and 24 months. Marginal bone measurements were made in intraoral radiographs taken 1 day after surgery and after 1 year. A questionnaire was used to evaluate self-perceived factors related to comfort, aesthetics, and function. RESULTS: All bridges were stable and no implant failures were recorded during the follow-up, giving a survival rate of 100%, at 2 years. The marginal bone loss amounted to 1.33 +/- 0.36 mm after 1 year and 1.48 +/- 0.39 mm after 2 years. Ten patients showed prosthetic complications with the provisional bridge, but all the definitive prostheses remained stable throughout the study period without any complications. The patients reported satisfaction with the treatment. CONCLUSIONS: The present retrospective study showed that immediate loading of four implants immediately placed in extraction sockets is a valid treatment modality for the totally edentulous mandible. PMID- 22236086 TI - Synthesis and evaluation of 18F-labeled styryltriazole and resveratrol derivatives for beta-amyloid plaque imaging. AB - In the present study, a styryltriazole and four resveratrol derivatives were synthesized as candidates for beta-amyloid (Abeta) plaque imaging. On the basis of their binding affinities to Abeta(1-42) aggregates, the styryltriazole (1, K(i) = 12.8 nM) and one resveratrol derivative (5, K(i) = 0.49 nM) were labeled with (18)F. In normal mice, tissue distribution of [(18)F]5 showed good initial brain uptake (3.26% ID/g at 2 min) but slow wash-out from brains (2-to-60 min uptake ratio: 2.9). Furthermore, it underwent in vivo metabolic defluorination (1.88% ID/g at 2 min and 9.73% ID/g at 60 min). In contrast, [(18)F]1 displayed high initial brain uptake (5.38% ID/g at 2 min) with rapid wash-out from brains (0.52% ID/g at 60 min; 2-to-60 min uptake ratio: 10.3). These results indicate that [(18)F]1 has in vivo kinetics comparable to PET radiopharmaceuticals currently under commercial development, demonstrating that [(18)F]1 is a desirable PET radioligand for Abeta plaque imaging. PMID- 22236088 TI - De novo synthesis of PERIOD initiates circadian oscillation in cultured mouse suprachiasmatic nucleus after prolonged inhibition of protein synthesis by cycloheximide. AB - The circadian oscillation is known to stop with prolonged inhibition of protein synthesis and to restart from a particular phase after the removal of inhibition. In order to know the underlying molecular mechanisms, the mouse suprachiasmatic nucleus was cultured and treated with a protein synthesis inhibitor, cycloheximide (CHX), for various durations. Circadian rhythms in Bmal1 expression and PER2 protein were monitored by means of bioluminescence reporters. Bmal1-LUC and PER2::LUC bioluminescence decreased to basal levels after CHX application. CHX washout restarted the circadian rhythms from a fixed phase when CHX treatment exceeded 18 h. mRNA of Per1, Per2 and Rev-erbalpha increased and reached high plateau levels in 18 h after CHX application, which continued for 48 h; whereas Bmal1 mRNA increased for the first 18 h but then decreased to the basal level. Immunoblot analysis showed a decreased PER2::LUC level at 24 h after CHX application, indicating that the transcription of Pers and Rev-erbalpha was disinhibited by CHX. CHX washout increased PER2::LUC bioluminescence and protein level in a few hours. High Per mRNA levels induced the rapid increases of their proteins, which might trigger the restarting of circadian oscillation. These findings indicate that the circadian oscillation is stopped by disinhibition of Per1 and Per2 transcriptions, and restarted upon the recovery of the PER mediated auto-feedback loop. De novo synthesis of PER protein is a key factor to initiate the circadian oscillation after prolonged inhibition of protein synthesis. PMID- 22236089 TI - Silver-based intermetallic heterostructures in Sb2Te3 thick films with enhanced thermoelectric power factors. AB - In this work, Ag(x)Te(y)-Sb(2)Te(3) heterostructured films are prepared by ligand exchange using hydrazine soluble metal chalcogenide. Because of the created interfacial barrier, cold carriers are more strongly scattered than hot ones and thereby an over 50% enhanced thermoelectric power factor (~2 MUW/(cm.K(2))) is obtained at 150 degrees C. This shows the possibility of engineering multiphases to further improve thermoelectric performance beyond phonon scattering through a low-temperature solution processed route. PMID- 22236090 TI - Mapping neural circuits with activity-dependent nuclear import of a transcription factor. AB - Abstract: Nuclear factor of activated T cells (NFAT) is a calcium-responsive transcription factor. We describe here an NFAT-based neural tracing method-CaLexA (calcium-dependent nuclear import of LexA)-for labeling active neurons in behaving animals. In this system, sustained neural activity induces nuclear import of the chimeric transcription factor LexA-VP16-NFAT, which in turn drives green fluorescent protein (GFP) reporter expression only in active neurons. We tested this system in Drosophila and found that volatile sex pheromones excite specific neurons in the olfactory circuit. Furthermore, complex courtship behavior associated with multi-modal sensory inputs activated neurons in the ventral nerve cord. This method harnessing the mechanism of activity-dependent nuclear import of a transcription factor can be used to identify active neurons in specific neuronal population in behaving animals. PMID- 22236091 TI - Disability outcomes and dose escalation with etanercept, adalimumab, and infliximab in rheumatoid arthritis patients: a US-based retrospective comparative effectiveness study. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease that if left untreated may substantially impair physical functioning. Etanercept, infliximab, and adalimumab are tumor necrosis factor (TNF) blockers whose FDA-approved indications in the US include moderate to severe RA. TNF-blocker dose escalation has been well documented in the literature; however, the comparative effectiveness of these agents remains uncertain. OBJECTIVE: To compare the effectiveness and dose escalation rates of etanercept, adalimumab, and infliximab in US community settings. We hypothesized that etanercept would be equivalent to infliximab and adalimumab in patient-reported disability 9-15 months after therapy initiation, and that fewer etanercept patients would experience dose escalation. METHODS: This is a retrospective analysis of the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). Adult patients with no biologic use 6 months before TNF-blocker initiation (index) and with Health Assessment Questionnaire Disability Index (HAQ-DI) scores at index and 9-15 months after index were analyzed (218 etanercept, 93 infliximab, and 40 adalimumab). RESULTS: HAQ-DI change scores at 9-15 months did not differ by treatment (-0.12, -0.10, and -0.08 points for etanercept, infliximab, and adalimumab, respectively; p = 0.52). Dose increases were observed in 1.4% of etanercept, 10.8% of infliximab (p < 0.001), and 12.5% of adalimumab patients (p = 0.004). HAQ-DI change was associated with pre-index HAQ-DI score (p < 0.0001) and disease duration (p = 0.001). CONCLUSIONS: Fewer etanercept patients escalated dose than infliximab or adalimumab patients, but improvements in functional disability were similar. These differences may have been influenced by package labeling, mode of administration, or other factors. RA treatment with infliximab and adalimumab in community settings, characterized by dose escalation, did not yield greater disability improvements compared to etanercept, which remained at a relatively stable dose. Uncontrolled treatment selection in this observational design may have influenced outcomes, and prior methotrexate treatment may partly explain disability improvements smaller than typically observed in clinical trials. PMID- 22236092 TI - Azathioprine-induced EBV-positive mucocutaneous ulcer. AB - Epstein-Barr virus (EBV)-positive mucocutaneous ulcer was recently described as a clinicopathologic entity occurring secondary to iatrogenic or age-related immune suppression. The histopathology of EBV-positive mucocutaneous ulcer reveals a polymorphous infiltrate including atypical large B-cells and Reed-Sternberg-like cells which are CD20-positive, CD30-positive and EBV-positive. The disorder follows an indolent and self-limited course. We report a case of EBV-positive mucocutaneous ulcer secondary to prolonged use of azathioprine for the treatment of pemphigoid and highlight the need for recognition of this disorder by dermatopathologists and dermatologists. PMID- 22236093 TI - Volatile organic compounds of Schenella pityophilus. AB - Volatile organic compounds of Schenella pityophilus have been identified via solid-phase microextraction-gas chromatography-mass spectrometry analysis. Ten compounds have been identified, in which 3-methylthio-1-propene was the most significant component. Some other components were previously identified in Tuber aestivum and Tuber melanosporum. PMID- 22236094 TI - Dynamic trajectories of growth and nitrogen capture by competing plants. AB - Although dynamic, plant competition is usually estimated as biomass differences at a single, arbitrary time; resource capture is rarely measured. This restricted approach perpetuates uncertainty. To address this problem, we characterized the competitive dynamics of Dactylis glomerata and Plantago lanceolata as continuous trajectories of biomass production and nitrogen (N) capture. Plants were grown together or in isolation. Biomass and N content were measured at 17 harvests up to 76 d after sowing. Data were fitted to logistic models to derive instantaneous growth and N capture rates. Plantago lanceolata was initially more competitive in terms of cumulative growth and N capture, but D. glomerata was eventually superior. Neighbours reduced maximum biomass, but influenced both maximum N capture and its rate constant. Timings of maximal instantaneous growth and N capture rates were similar between species when they were isolated, but separated by 16 d when they were competing, corresponding to a temporal convergence in maximum growth and N capture rates in each species. Plants processed N and produced biomass differently when they competed. Biomass and N capture trajectories demonstrated that competitive outcomes depend crucially on when and how 'competition' is measured. This potentially compromises the interpretation of conventional competition experiments. PMID- 22236095 TI - Outcome in dogs with surgically resected oral fibrosarcoma (1997-2008). AB - Oral fibrosarcoma (FSA) is a common oral tumour in dogs, and historically reported survival times after surgical excision range from 7.0 to 12.2 months with local recurrence rates of 32-57%. The purpose of this retrospective study was to report outcome in a cohort of dogs with oral FSA treated with surgical excision with or without adjuvant radiation therapy. Twenty-nine dogs with a histological diagnosis of FSA arising from the oral cavity that underwent surgical resection of their oral FSA were included in this study. Twenty-one dogs were treated with surgical excision alone and eight dogs with both surgery and radiation therapy. The median progression-free interval was >653 days. The median survival time was 743 days. The 1- and 2-year survival rates were 87.7 and 57.8%, respectively. Seven (24.1%) dogs developed local recurrence. Seven dogs (24.1%) developed metastasis. PMID- 22236096 TI - Rational design of surface/interface chemistry for quantitative in vivo monitoring of brain chemistry. AB - To understand the molecular basis of brain functions, researchers would like to be able to quantitatively monitor the levels of neurochemicals in the extracellular fluid in vivo. However, the chemical and physiological complexity of the central nervous system (CNS) presents challenges for the development of these analytical methods. This Account describes the rational design and careful construction of electrodes and nanoparticles with specific surface/interface chemistry for quantitative in vivo monitoring of brain chemistry. We used the redox nature of neurochemicals at the electrode/electrolyte interface to establish a basis for monitoring specific neurochemicals. Carbon nanotubes provide an electrode/electrolyte interface for the selective oxidation of ascorbate, and we have developed both in vivo voltammetry and an online electrochemical detecting system for continuously monitoring this molecule in the CNS. Although Ca(2+) and Mg(2+) are involved in a number of neurochemical signaling processes, they are still difficult to detect in the CNS. These divalent cations can enhance electrocatalytic oxidation of NADH at an electrode modified with toluidine blue O. We used this property to develop online electrochemical detection systems for simultaneous measurements of Ca(2+) and Mg(2+) and for continuous selective monitoring of Mg(2+) in the CNS. We have also harnessed biological schemes for neurosensing in the brain to design other monitoring systems. By taking advantage of the distinct reaction properties of dopamine (DA), we have developed a nonoxidative mechanism for DA sensing and a system that can potentially be used for continuously sensing of DA release. Using "artificial peroxidase" (Prussian blue) to replace a natural peroxidase (horseradish peroxidase, HRP), our online system can simultaneously detect basal levels of glucose and lactate. By substituting oxidases with dehydrogenases, we have used enzyme-based biosensing schemes to develop a physiologically relevant system for detecting glucose and lactate in rat brain. Because of their unique optical properties and modifiable surfaces, gold nanoparticles (Au-NPs) have provided a platform of colorimetric assay for in vivo cerebral glucose quantification. We designed and modified the surfaces of Au-NPs and then used a sequence of reactions to produce hydroxyl radicals from glucose. PMID- 22236097 TI - Women's views on consent, counseling and confidentiality in PMTCT: a mixed methods study in four African countries. AB - BACKGROUND: Ambitious UN goals to reduce the mother-to-child transmission of HIV have not been met in much of Sub-Saharan Africa. This paper focuses on the quality of information provision and counseling and disclosure patterns in Burkina Faso, Kenya, Malawi and Uganda to identify how services can be improved to enable better PMTCT outcomes. METHODS: Our mixed-methods study draws on data obtained through: (1) the MATCH (Multi-country African Testing and Counseling for HIV) study's main survey, conducted in 2008-09 among clients (N = 408) and providers at health facilities offering HIV Testing and Counseling (HTC) services; 2) semi-structured interviews with a sub-set of 63 HIV-positive women on their experiences of stigma, disclosure, post-test counseling and access to follow-up psycho-social support; (3) in-depth interviews with key informants and PMTCT healthcare workers; and (4) document study of national PMTCT policies and guidelines. We quantitatively examined differences in the quality of counseling by country and by HIV status using Fisher's exact tests. RESULTS: The majority of pregnant women attending antenatal care (80-90%) report that they were explained the meaning of the tests, explained how HIV can be transmitted, given advice on prevention, encouraged to refer their partners for testing, and given time to ask questions. Our qualitative findings reveal that some women found testing regimes to be coercive, while disclosure remains highly problematic. 79% of HIV-positive pregnant women reported that they generally keep their status secret; only 37% had disclosed to their husband. CONCLUSION: To achieve better PMTCT outcomes, the strategy of testing women in antenatal care (perceived as an exclusively female domain) when they are already pregnant needs to be rethought. When scaling up HIV testing programs, it is particularly important that issues of partner disclosure are taken seriously. PMID- 22236099 TI - Weak epitaxy growth of phthalocyanine on inducing layers of fluorinated 5,5" bis(biphenyl-4-yl)-2,2':5',2"-terthiophene. AB - Weak epitaxy growth (WEG) is an effective method in the preparation of high mobility thin films of disk-like organic semiconductors. The growth behavior and quality of the epitaxial thin film are closely related to the inducing layers. Here, a series of fluorinated molecules, 5,5"-bis(3'-fluoro-biphenyl-4-yl) 2,2':5',2"-terthiophene (m-F2BP3T), 5,5"-bis(3',5'-difluoro-biphenyl-4-yl) 2,2':5',2"-terthiophene (F4BP3T), and 5,5"-bis(4'-fluoro-biphenyl-4-yl) 2,2':5',2"-terthiophene (p-F2BP3T) as well as a referenced molecule 5,5" bis(biphenyl-4-yl)-2,2':5',2"-terthiophene (BP3T), are introduced to serve as inducing layers for the epitaxy growth of phthalocyanine. Compared to the nonfluorinated inducing layer, the interactions between the fluorinated inducing layer and phthalocyanine might be relatively strong due to the potential existence of C-H...F weak hydrogen bonds. The growth behavior and mechanism of phthalocyanine on the fluorinated inducing layers are investigated by atomic force microscopy (AFM), grazing incidence X-ray diffraction (GIXD), selected area electron diffraction (SAED). According to the AFM and SAED, H(2)Pc presents a selective epitaxy growth depending on the position of fluorine: epitaxy growth on m-F2BP3T and F4BP4T, and nonepitaxy growth on p-F2BP3T. Comparison of CuPc with F(16)CuPc on monolayer p-F2BP3T further revealed that the uncommon nonepitaxy growth behavior of H(2)Pc (CuPc) on p-F2BP3T mainly originates from the enhanced interactions between the two types of molecules. As a consequence, the capability of molecules orienting themselves along the surface channel is decreased; meanwhile, the demand of the upper limit of the lattice mismatch is more rigorous for commensurate epitaxy. Finally, the oriented nucleation of H(2)Pc (CuPc) on monolayer p-F2BP3T is affected, and netlike crystals are formed. The sudden change of H(2)Pc (CuPc) from multiorientation on monolayer to just one orientation on double-layer p-F2BP3T suggests that there is a critical lattice mismatch value for commensurate epitaxy in WEG when the molecule-substrate interactions are enhanced. PMID- 22236098 TI - Bioamplification and the selective depletion of persistent organic pollutants in Chinook salmon larvae. AB - The maternal provisioning of yolk to eggs transfers significant quantities of persistent organic pollutants (POPs). As yolk utilization progresses via metabolic activity, there is a potential to realize further increases in POP concentrations if yolk lipids are depleted at a faster rate than POPs, a condition referred to as bioamplification. This study investigated the bioamplification of POPs in Chinook salmon ( Oncorhynchus tshawytscha ) eggs and larvae. Chinook eggs were sampled from the Credit River, ON, Canada, and brought to an aquaculture facility where they were fertilized, incubated, and maintained posthatch until maternally derived lipid reserves became depleted (approximately 168 days). The loss of chemicals having an octanol-water partition coefficient (log K(OW)) greater than 5.8 was slow to negligible from days 0-135. However, during the increase in water temperatures in early spring, K(OW)-dependent elimination of POPs was observed. Bioamplification was maximized for the highest log K(OW) POPs, with an approximate 5-fold increase in lipid equivalents concentrations in 168 day old larvae as compared to newly fertilized eggs. This study demonstrates that later yolk-sac Chinook larvae (before exogenous feeding) are exposed to higher lipid equivalents POP concentrations than predicted by maternal deposition, which could lead to underestimates in the toxicity of critical life stages. PMID- 22236100 TI - Membrane recruitment of autophagy proteins in selective autophagy. AB - Autophagy is a stress response that is upregulated in response to signals such as starvation, growth factor deprivation, endoplasmic reticulum stress, and pathogen infection. Defects in this pathway are the underlying cause of a number of diseases, including metabolic aberrations, infectious diseases, and cancer, which are closely related to hepatic disorders. To date, more than 30 human ATG (autophagy) genes have been reported to regulate autophagosome formation. In this review, we summarize the current understanding of how ATG proteins behave during autophagosome formation in both non-selective and selective autophagy. PMID- 22236101 TI - Boys' and girls' involvement in science learning and their self-efficacy in Taiwan. AB - This cross-sectional study investigated the significant differences in students' self-efficacy and their involvement in learning science. Nine hundred and twenty two elementary school fifth graders, 499 junior high school eighth graders, and 1455 senior or vocational high school eleventh graders completed the students' questionnaire. Analyses of variance (ANOVAs) and independent t-tests compared the significant similarities and differences across school levels and genders. The initial findings were as follows: A sharp decline in boys' and girls' self efficacy scores from elementary to secondary school levels; boys have significantly higher self-efficacy scores than girls at vocational and senior high school levels; students with more involvement in science learning presented significantly higher self-efficacy scores than those with less involvement. The significant discrepancies in terms of gender and age in students' self-efficacy and involvement in learning science need to be addressed. Implications and limitations are provided. PMID- 22236102 TI - Comparing the hyper-variable V4 and V9 regions of the small subunit rDNA for assessment of ciliate environmental diversity. AB - The hyper-variable V4 and V9 regions of the small subunit (SSU) rDNA have been targeted for assessing environmental diversity of microbial eukaryotes using next generation sequencing technologies. Here, we explore how the genetic distances among these short fragments compare with the distances obtained from near full length SSU-rDNA sequences by comparing all pairwise estimates, as well as within and among species of ciliates. Results show that pairwise distances from V4 more closely match the near full-length SSU-rDNA and are more comparable with previous studies based on much longer SSU-rDNA fragments, then pairwise distances from V9. Thus, studies that use the V4 will estimate similar values of phylotype richness and community structure as would have been estimated using the full-length SSU rDNA. PMID- 22236104 TI - Effects of transplantation sites on tumour growth, pulmonary metastasis and ezrin expression of canine osteosarcoma cell lines in nude mice. AB - To determine the influence of the transplantation site of canine osteosarcoma (OS) cell lines on tumour growth and pulmonary metastasis, three OS cell lines were transplanted into nude mice via subcutaneous (SC), intratibial (IT) or intravenous (IV) injection. IT-xenografts exhibited greater potential for developing primary masses and pulmonary metastasis than SC-xenografts. In IT and IV xenografts, lung micrometastases along with phosphorylated ezrin-radixin moesin (p-ERM) overexpression were found in mice xenografted with HMPOS and OOS cells after 1 week and metastasis was found with decreased p-ERM expression at later time points. The expression of ezrin and p-ERM in the primary tumours of IT xenografted mice was higher than those in SC-xenografted mice with HMPOS and OOS cells. The results suggest that the orthotopic transplantation site plays an important role in the spontaneous metastasis of canine OS and that ezrin phosphorylation may be involved in the early metastatic mechanism of canine OS cells. PMID- 22236105 TI - Epitope specificity of anti-HA2 antibodies induced in humans during influenza infection. AB - BACKGROUND: The conserved, fusion-active HA2 glycopolypeptide (HA2) subunit of influenza A hemagglutinin comprises four distinct antigenic sites. Monoclonal antibodies (MAbs) recognizing three of these sites are broadly cross-reactive and protective. OBJECTIVES: This study aimed to establish whether antibodies specific to these three antigenic sites were elicited during a natural influenza infection or by vaccination of humans. METHODS: Forty-five paired acute and convalescent sera from individuals with a confirmed influenza A (subtype H3) infection were examined for the presence of HA2-specific antibodies. The fraction of antibodies specific to three particular antigenic sites (designated IIF4, FC12, and CF2 here) was investigated using competitive enzyme immunoassay. RESULTS: Increased levels of antibodies specific to an ectodomain of HA2 (EHA2: N-terminal residues 23-185 of HA2) were detected in 73% of tested convalescent sera (33/45), while an increased level of antibodies specific to the HA2 fusion peptide (N-terminal residues 1-38) was induced in just 15/45 individuals (33%). Competitive assays confirmed that antibodies specific to the IIF4 epitope (within HA2 residues 125 175) prevailed in 86% (13/15) over those specific to the other two epitopes during infection. However, only a negligible increase in HA2-specific antibodies was detectable following vaccination with a current subunit vaccine. CONCLUSIONS: We observed that the antigenic site localized within N-terminal HA2 residues 125 175 was more immunogenic than that within residues 1-38 (HA2 fusion protein), although both are weak natural immunogens. We suggest that new anti-influenza vaccines should include HA2 (or specific epitopes localized within this glycopolypeptide) to enhance their cross-protective efficacy. PMID- 22236106 TI - Simian foamy virus prevalence in Macaca mulatta and zookeepers. AB - The simian foamy virus (SFV) has been reported to be transmissible among humans occupationally exposed to nonhuman primates. Nevertheless, epidemiological and genotypic data on the SFV in Macaca mulatta and zookeepers in China are limited. In the present study, SFV proviral DNA was detected in 74 blood samples from M. mulatta and 12 saliva specimens from zookeepers by nested polymerase chain reaction. A total of 29 blood samples from M. mulatta (29/74, 39.19%) and two saliva specimens from zookeepers (2/12, 16.67%) were positive. The phylogenetic analysis indicated that these SFV strains shared the highest homology with Macaca fascicularis (93.4%). The two SFV strains infected human beings, and shared the highest homology of 98.6% with each other as well as 90.8-99.5% with M. mulatta. The investigation revealed the high prevalence of the SFV in M. mulatta in China and its zoonotic transmission to humans. PMID- 22236107 TI - Characterization of lipophorin receptor (LpR) mediating the binding of high density lipophorin (HDLp) in the silkworm, Bombyx mori. AB - In an earlier report, we described the gene encoding a lipophorin receptor (LpR) of the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), and recombinant expression of the protein. The present study was performed to characterize the corresponding native BmLpR and its binding characteristics. Polyclonal anti-LpR antibody prepared against the cloned receptor fragment from the cytoplasmic domain specifically detected the receptor. Through immunoblotting, ovary and brain membrane protein samples of BmLpR have shown an apparent molecular mass of 105 kDa and 120 kDa under nonreducing and reducing conditions, respectively. Ligand binding of LpR supported the immunoblot results. It bound to high density lipophorin (HDLp) and has shown requirement of Ca(2+) in binding. Further, a dose dependent inhibition by EDTA was observed in receptor ligand binding. The characteristics of the BmLpR protein confirm the properties of a ligand-receptor interaction similar to that of vertebrate low density lipoprotein receptor (LDLR). PMID- 22236108 TI - A dual-chambered hemodialyzer for convection-enhanced hemodialysis. AB - Convective clearance during hemodialysis (HD) improves dialysis outcomes in kidney failure patients, and, thus, trials have been undertaken to increase convective mass transfer, which is directly related to internal filtration rates. The authors designed a new hemodialyzer to increase the internal filtration rates, and here describe the hemodialytic efficacy of the devised unit. The developed dual-chambered hemodialyzer (DCH) contains two separate chambers for dialysate flow within a single housing. By placing a flow restrictor on the dialysate stream between these two chambers, dialysate pressures are regulated independently. Dialysate is maintained at a higher pressure than blood pressure in one chamber, and at a lower pressure in the other chamber. The dialysis performance of the DCH was investigated using an acute canine renal failure model. Urea and creatinine reductions and albumin loss were monitored, and forward and backward filtration rates were measured. No procedurally related malfunction was encountered, and animals remained stable without any complications. Urea and creatinine reductions after 4-h dialysis treatments were 75.2 +/- 6.5% and 67.7 +/- 8.9%, respectively. Post-treatment total protein and albumin levels remained at pretreatment values. Total filtration volume was 4.98 +/- 0.5 L over 4 h, whereas the corresponding backfiltration (BF) volume was 4.77 +/- 0.6 L. The developed dual-chamber dialyzer has the benefit of providing independent control of forward filtration and BF rates. HD using this dialyzer provides a straightforward means of increasing the internal filtration and convective dose. PMID- 22236109 TI - Neonatal treatment with a pegylated leptin antagonist has a sexually dimorphic effect on hypothalamic trophic factors and neuropeptide levels. AB - It is clear that the prenatal and early neonatal environments are important for determining the metabolic equilibrium in the adult animal, with prenatal/neonatal leptin levels being at least one of the factors involved. Leptin modulates hypothalamic development and, in particular, the neuronal circuits involved in metabolic control. We have recently reported that maternal deprivation (MD) for 24 h on postnatal day (PND) 9 modifies trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus, as well as body weight and circulating leptin levels at PND13, with long- term effects on weight gain and circulating metabolic hormones in the adult. Moreover, these responses are sexually dimorphic. During MD, a dramatic decline in leptin levels is observed; thus, we aimed to determine which of the previously observed changes in markers of hypothalamic development might be attributed to the decline in this metabolic signal. Accordingly, male and female rats were treated with a pegylated leptin antagonist on PND9. In both sexes, hypothalamic signal transducer and activator of transcription 3 activation in response to acute leptin treatment was blocked by the antagonist. In females, hypothalamic mRNA levels for brain-derived neurotrophic factor, cocaine- and amphetamine-regulated transcript and the leptin receptor were increased, as were nestin and vimentin levels. There was also an increase in cell death in the hypothalamus, with a shift towards an anti apoptotic balance in the Bcl2/BAX ratio. No hypothalamic effects were seen in males. Because antagonism of the actions of leptin at this specific neonatal stage affects hypothalamic cell turnover and maturation in a sex-specific manner, changes in this hormone, at least at this postnatal age, may differentially affect hypothalamic development in males and females, and may explain some of the reported sexually dimorphic responses to modifications in the early nutritional environment. PMID- 22236112 TI - Phase, morphology, and hygroscopicity of mixed oleic acid/sodium chloride/water aerosol particles before and after ozonolysis. AB - Aerosol optical tweezers are used to probe the phase, morphology, and hygroscopicity of single aerosol particles consisting of an inorganic component, sodium chloride, and a water insoluble organic component, oleic acid. Coagulation of oleic acid aerosol with an optically trapped aqueous sodium chloride droplet leads to formation of a phase-separated particle with two partially engulfed liquid phases. The dependence of the phase and morphology of the trapped particle with variation in relative humidity (RH) is investigated by cavity enhanced Raman spectroscopy over the RH range <5% to >95%. The efflorescence and deliquescence behavior of the inorganic component is shown to be unaffected by the presence of the organic phase. Whereas efflorescence occurs promptly (<1 s), the deliquescence process requires both dissolution of the inorganic component and the adoption of an equilibrium morphology for the resulting two phase particle, occurring on a time-scale of <20 s. Comparative measurements of the hygroscopicity of mixed aqueous sodium chloride/oleic acid droplets with undoped aqueous sodium chloride droplets show that the oleic acid does not impact on the equilibration partitioning of water between the inorganic component and the gas phase or the time response of evaporation/condensation. The oxidative aging of the particles through reaction with ozone is shown to increase the hygroscopicity of the organic component. PMID- 22236111 TI - Four modalities of single implant treatment in the anterior maxilla: a clinical, radiographic, and aesthetic evaluation. AB - PURPOSE: To document the outcome of single implants in the anterior maxilla following four routine treatment modalities when performed by experienced clinicians in daily practice using the same implant system and biomaterials. MATERIAL AND METHODS: A retrospective study in patients who had been treated by two periodontists and two prosthodontists in 2006 and 2007 was conducted. The four treatment modalities practically covered every clinical situation and included standard implant treatment (SIT), immediate implant treatment (IIT), implant treatment in conjunction with guided bone regeneration (GBR), and implant treatment in grafted bone (BGR) harvested from the chin. All implants were installed via flap surgery. Patients were clinically and radiographically examined. Complications were registered and the aesthetic outcome (pink esthetic score [PES] and white esthetic score [WES]) was rated. A blinded clinician who had not been involved in the treatment performed all evaluations. Patient's aesthetic satisfaction was also registered. RESULTS: One hundred four out of 115 eligible patients (44 SIT, 28 IIT, 18 GBR, and 14 BGR) received at least one single NobelReplace tapered TiUnite(r) (Nobel Biocare, Goteborg, Sweden) implant in the anterior maxilla and were available for evaluation. Clinical parameters (implant survival: 93%, mean plaque level: 24%, mean bleeding on probing: 33%, and mean probing depth: 3.2 mm) and mean bone level (1.19 mm) did not differ significantly between treatment modalities. Postoperative complications were more common following GBR/BGR (>61%) when compared with SIT/IIT (<18%) (p < .001). BGR was in 4/14 patients associated with permanent sensory complications at the donor site. Technical complications occurred in 9/104 patients. SIT and IIT showed similar soft tissue aesthetics (PES: 10.07 and 10.88, respectively), however major alveolar process deficiency was common (>15%). PES was 9.65 for GBR. BGR showed inferior soft tissue aesthetics (PES: 9.00; p = .045) and shorter distal papillae were found following GBR/BGR (p = .009). Periodontal disease (odds ratio [OR]: 13.0, p < .001), GBR/BGR (OR: 4.3, p = .004), and a thin-scalloped gingival biotype (OR: 3.7, p = .011) increased the risk for incomplete distal papillae. WES was 7.98 for all patients considered. Poor agreement was found between objective and subjective aesthetic ratings. CONCLUSIONS: All treatment modalities were predictable from a clinical and radiographic point of view. However, advanced reconstructive surgery, especially BGR, increased the risk for complications and compromised aesthetics. Research is required on the prevention and minimally invasive treatment of buccal bone defects at the time of tooth loss to avoid complex therapy. PMID- 22236114 TI - Acute New World cutaneous leishmaniasis presenting as tuberculoid granulomatous dermatitis. AB - Acute primary cutaneous leishmaniasis typically presents microscopically with a lymphohistiocytic infiltrate containing admixed plasma cells, parasitized macrophages and abundant organisms. Tuberculoid granulomatous changes may occur in the later phases of primary infection. A 23-year-old male presented 1 month after visiting Peru with classic clinical findings of acute primary cutaneous leishmaniasis, while histopathology showed a tuberculoid granulomatous process that lacked any organisms in hematoxylin-eosin and fungal stains. Polymerase chain reaction (PCR) analysis and tissue cultures confirmed the diagnosis of cutaneous leishmaniasis with Leishmania (Viannia) panamensis infection. A pauci organism tuberculoid granulomatous process may uncommonly be the presenting histopathology in the acute infectious phase of cutaneous leishmaniasis. Clinicians and dermatopathologists should be aware of this atypical presentation, which may cause diagnostic confusion and delay proper treatment. PCR testing should be employed in cases with high clinical suspicion when histopathology is not definitive. PMID- 22236115 TI - Treatment of Atherosclerosis as an inflammatory disease. PMID- 22236116 TI - Anti-inflammatory effects of anti-platelet treatment in atherosclerosis. AB - Atherosclerosis is considered an inflammatory disease. T-cells, macrophages, and mast cells infiltrate atherosclerotic plaques and platelets play an essential role releasing inflammatory mediators that stimulate plaque progression. This is important in acute coronary syndromes but it is also the mechanism involved in plaque progresion and endothelial dysfunction. Antiplatelet drugs exert their effects not only by inhibition of platelet aggregation but also through their antiinflammatory effect. Aspirin, thyenopiridines and GPIIb/IIIa inhibitors have antiinflammatory properties that involve different mechanisms of action, especially related to the blockade of platelet activation and platelet-leukocyte interactions. Testing platelet function in addition to assessing levels of inflammatory markers, and not only the risk of bleeding, could help in decision making to balance the risk-benefit of anti-thrombotic treatment. Different clinical settings are associated with variable inflammatory states, and this could be, in part, responsible for variable response to treatment. PMID- 22236118 TI - Recent progress in small molecule CCR5 antagonists as potential HIV-1 entry inhibitors. AB - Currently the long-term usage of traditional anti-HIV drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), eventually leads to the emergence of drug resistance and severe side effects. Thus it is imperative to design and develop more promising HIV-1 inhibitors to overcome these drawbacks. Fortunately, with the identification of some fascinating targets in the entry process of viral life cycle, HIV-1 entry inhibitors (EIs) with low cytotoxicity and mild side effects turned out as novel and effective anti-HIV agents. Especially, of these potent EIs, small molecule CCR5 antagonist maraviroc was approved by US FDA in 2007, which significantly increased the therapeutic options for the clinical treatment of HIV-infected patients. Subsequently, as promising anti-HIV drug candidates, kinds of small molecule CCR5 antagonists have been synthesized and evaluated in clinical trials. In this article, current progress in the development of novel small molecule CCR5 antagonists will be reviewed on the basis of their chemical structures with a special attention to their discovery stories. Simultaneously, binding mode analysis based on molecular modeling studies will also be introduced. PMID- 22236119 TI - Editorial: Peptides in diagnosis and therapy. PMID- 22236117 TI - "Liking" and "wanting" linked to Reward Deficiency Syndrome (RDS): hypothesizing differential responsivity in brain reward circuitry. AB - In an attempt to resolve controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluate the three main competing explanatory categories: "liking,""learning," and "wanting" [1]. That is, DA may mediate (a) the hedonic impact of reward (liking), (b) learned predictions about rewarding effects (learning), or (c) the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting). We evaluate these hypotheses, especially as they relate to the Reward Deficiency Syndrome (RDS), and we find that the incentive salience or "wanting" hypothesis of DA function is supported by a majority of the evidence. Neuroimaging studies have shown that drugs of abuse, palatable foods, and anticipated behaviors such as sex and gaming affect brain regions involving reward circuitry, and may not be unidirectional. Drugs of abuse enhance DA signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Addictive drugs have in common that they are voluntarily selfadministered, they enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens (NAC), and they stimulate the functioning of brain reward circuitry (producing the "high" that drug users seek). Although originally believed simply to encode the set point of hedonic tone, these circuits now are believed to be functionally more complex, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms of dopaminergic genes and other neurotransmitter genetic variants, may have a cumulative effect on vulnerability to addiction. The RDS model of etiology holds very well for a variety of chemical and behavioral addictions. PMID- 22236120 TI - Mining PeptideAtlas for biomarkers and therapeutics in human disease. AB - Mass spectrometry information has long offered the potential of discovering biomarkers that would enable clinicians to diagnose disease, and treat it with targeted therapies. PeptideAtlas currently provides access to large-scale spectra data and identification information. This data, and the generation of targeted peptide information, represents the first step in the process of locating disease biomarkers. Reaching the goal of clinical proteomics requires that this data be integrated with additional information from disease literature and genomic studies. Here we describe PeptideAtlas and associated methods for mining the data, as well as the software tools necessary to support large-scale integration and mining. PMID- 22236122 TI - Ghrelin and the brain-gut axis as a pharmacological target for appetite control. AB - Appetite regulation is highly complex and involves a large number of orexigenic and anorexigenic peptide hormones. These are small, processed, secreted peptides derived from larger prepropeptide precursors. These peptides are important targets for the development of therapeutics for obesity, a global health epidemic. As a case study, we consider the ghrelin axis. The ghrelin axis is likely to be a particularly useful drug target, as it also plays a role in energy homeostasis, adipogenesis, insulin regulation and reward associated with food intake. Ghrelin is the only known circulating gut orexigenic peptide hormone. As it appears to play a role in diet-induced obesity, blocking the action of ghrelin is likely to be effective for treating and preventing obesity. The ghrelin peptide has been targeted using a number of approaches, with ghrelin mirror-image oligonucleotides (Spiegelmers) and immunotherapy showing some promise. The ghrelin receptor, the growth hormone secretagogue receptor, may also provide a useful target and a number of antagonists and inverse agonists have been developed. A particularly promising new target is the enzyme which octanoylates ghrelin, ghrelin O-acyltransferase (GOAT), and drugs that inhibit GOAT are likely to circumvent pharmacological issues associated with approaches that directly target ghrelin or its receptor. PMID- 22236121 TI - Peptides for therapy and diagnosis of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with devastating effects. The greatest risk factor to develop AD is age. Today, only symptomatic therapies are available. Additionally, AD can be diagnosed with certainty only post mortem, whereas the diagnosis "probable AD" can be established earliest when severe clinical symptoms appear. Specific neuropathological changes like neurofibrillary tangles and amyloid plaques define AD. Amyloid plaques are mainly composed of the amyloid-betapeptide (Abeta). Several lines of evidence suggest that the progressive concentration and subsequent aggregation and accumulation of Abeta play a fundamental role in the disease progress. Therefore, substances which bind to Abeta and influence aggregation thereof are of great interest. An enormous number of organic substances for therapeutic purposes are described. This review focuses on peptides developed for diagnosis and therapy of AD and discusses the pre- and disadvantages of peptide drugs. PMID- 22236123 TI - Short peptide modules for enhancing intestinal barrier function. AB - The intestinal epithelial barrier is indispensable to our immune system. Defects in this barrier function have been observed in intestinal disorders such as inflammatory bowel diseases, food allergies, and celiac diseases. Therefore, the modulation of the barrier function is currently viewed as a potentially positive pharmacological outcome. This review describes a unique peptide, Asn-Pro-Trp- Asp Gln (NPWDQ), which can finely adjust the intestinal barrier. It is obtained by the hydrolysis of casein, a major milk protein, and considerably inhibits the permeation of ovalbumin, one of the food allergens, in Caco-2, a human intestinal cell line. Using DNA microarray, we observed that NPWDQ only up-regulated expression of the occludin gene, whereas the levels of other genes, such as those of the claudin and zonula occludens families, remained unchanged. Increased protein expression of occludin was also observed. The fact that milk-derived peptide(s) can enhance intestinal barrier function gives a new significance to lactation because it plays an important role in promoting the maturation of the intestinal barrier. In this context, it is highly probable and worthy of considerable attention that various bioactive peptides with this type of activity are yet to be observed in the bovine and/or human casein sequence. Moreover, milkderived peptides could be considered as potential candidates for the prevention of certain intestinal disorders. PMID- 22236124 TI - Peptides in oral diseases. AB - The oral cavity is home to numerous viruses and micro-organisms recognized as having a role in various oral diseases as well as in infections in other parts of the body. Indeed, in general a microbial infection underlies or is believed to underlie the ample spectrum of oral diseases, from tooth enamel decay to periodontal lesions, from candidiasis to virus-induced oral squamous cell carcinomas, and bullous autoimmune oral disorders. This clinico-pathological context stresses the need of targeted therapies to specifically kill infectious agents in a complex environment such as the oral cavity, and explains the current interest in exploring peptide-based therapeutic approaches in oral and dental research. Here, we review the therapeutic potential of antimicrobial peptides such as LL-37, beta defensins, adrenomedullin, histatins, and of various peptides modulating gene expression and immuno-biological interaction(s) in oral diseases. PMID- 22236125 TI - Apelin in the control of body fluid homeostasis and cardiovascular functions. AB - The discovery of apelin, an endogenous ligand of the orphan APJ receptor is an important advance for fundamental research and clinical medicine. Apelin and its receptor have a wide tissue distribution not only in the brain but also in peripheral organs including kidney, heart, vessels, and adipose tissue. Apelin is implicated in many physiological and pathophysiological processes such as the regulation of body fluid homeostasis, cardiovascular functions, glucose homeostasis, cell proliferation, and angiogenesis. This review focuses on, i) the various signaling cascades evoked upon stimulation of the apelin receptor by the different molecular forms of apelin found in vivo, ii) the distribution of apelin and its receptor in the brain and the cardiovascular system, iii) the opposing actions of vasopressin and apelin in the regulation of water balance at the central and kidney levels, and on the cardiovascular system regarding regulation of arterial blood pressure, vascular tone, and cardiac function. PMID- 22236126 TI - Thymosin beta4 protein therapy for cardiac repair. AB - Clinical interventions leading to improved survival in patients with acute myocardial infarction have, paradoxically, increased the need for cardiac regenerative strategies as more people are living with heart failure. Over the last 10-15 years there have been significant advances in our understanding of cell-based therapy for cardiac repair. Evidence that paracrine stimulation largely underlies the functional benefits in cell transplantation has led to a paradigm shift in regenerative medicine: from cell therapy to factor/protein based therapy. Although, future regenerative approaches may likely involve a synergistic protein cocktail, this review will focus on the role of a promising candidate, thymosin beta 4 (Tbeta4) in cardioprotection, neovascularization, tissue regeneration and inflammation - all essential components in cardiac repair. PMID- 22236127 TI - Therapeutic potential of host defense peptides in antibiotic-resistant infections. AB - The emergence of infections caused by multi-drug resistant (MDR) pathogens pose a major burden to modern healthcare. Exacerbating this issue is the substantial decline in development of new classes of antibiotics by pharmaceutical companies. This has led to renewed interest in the therapeutic potential of natural anti infective agents such as host defense peptides (HDPs). The broad antimicrobial and immunomodulatory activities of HDPs and their synthetic derivatives, coupled with the fact that they do not readily induce microbial resistance, makes them extremely valuable leads in the development of new treatment strategies for MDR infections. This review examines our knowledge of the mechanisms behind multi drug resistance as well as the properties of HDPs and their therapeutic potential, especially in the case of MDR infections. Challenges to their development as new therapeutics are also discussed. PMID- 22236128 TI - Peptides in melanoma therapy. AB - Peptides derived from tumor associated antigens can be utilized to elicit a therapeutically effective immune response against melanoma in experimental models. However, patient vaccination with peptides - although it is often followed by the induction of melanoma- specific T lymphocytes - is rarely associated with tumor response of clinical relevance. In this review I summarize the principles of peptide design as well as the results so far obtained in the clinical setting while treating cutaneous melanoma by means of this active immunotherapy strategy. I also discuss some immunological and methodological issues that might be helpful for the successful development of peptide-based vaccines. PMID- 22236129 TI - Circumscribing the conformational peptide epitope landscape. AB - The development of vaccines for new and re-emerging pathologies and infections is based on the ability to define immunogenic epitopes. An immunogenic B-cell peptide epitope is a specific restricted antigen region that is capable of eliciting a humoral immune response and of combining with a specific site on antibodies. Using a number of experimental models and based on data from several literature reports, we identified low levels of sequence similarity to the host proteome as one of the main factors modulating the B-cell epitope repertoire in the humoral immune response. In point of fact, a low level of sequence identity to the host proteins is a common denominator unifying the composite, disparate assembly of linear peptide B-cell epitopes that has been experimentally validated and described in the literature. Here, we explore the proteomic similarity of conformational epitopes experimentally validated and described in published reports. Again, discontinuous epitopic structures formed by non-contiguous amino acid residues were found to define peptide sequences with a low level of similarity to the host. The present meta-analysis adds further significance to the immunological low-similarity theory and its clinical implications. Potentially, low-similarity peptide epitopes pave the way for novel effective vaccines in cancer, autoimmunity, and infectious diseases. PMID- 22236130 TI - A stable "flat" form of two-dimensional crystals: could graphene, silicene, germanene be minigap semiconductors? AB - The discovery of a flat two-dimensional crystal known as graphene has contradicted Landau-Peierls-Mermin-Wagner arguments that there is no stable flat form of such crystals. Here, we show that the "flat" shape of graphene arises due to a microscopic buckling at the smallest possible interatomic scale. We show that the graphene, silicene, and other two-dimensional crystals are stable due to transverse short-range displacements of appropriate atoms. The distortions are small and form various patterns, which we describe in a framework of Ising model with competing interactions. We show that when temperature decreases, two transitions, disorder into order and order into disorder, arise. The ordered state has a form of stripes where carbon atoms are shifted regularly with respect to the plane. The flat graphene, silicene, or germanene planes look like a microscopic "washboard" with the wavelength of about couple of interatomic spacing of appropriate sublattices, which for graphene is about 1.8-3.6 A. At lower temperatures, the ordered state transforms into a glass. Because of up-down asymmetry in buckled graphene, silicene and other two-dimensional crystals deposited on substrate, a minibandgap may arise. We derive a criterion for the minigap formation and show how it is related to the buckling and to the graphene substrate interaction. Because of the bandgap, there may arise new phenomena and in particular a rectification of ac current induced by microwave or infrared radiation. We show that the amplitude of direct current arising at wave mixing of two harmonics of microwave electromagnetic radiation is huge. Moreover, we predict the existence of miniexcitons and a new type of fermionic minipolaritons whose behavior can be controlled by the microwave and terahertz radiation. PMID- 22236131 TI - In vitro antioxidant activity of extracts of Sybaris liquorice roots from Southern Italy. AB - The antioxidant properties of extracts of Sybaris liquorice roots have been assessed using 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay. The extracts, obtained by Soxhlet extraction (Et(2)O, AcOEt, MeOH and BuOH) of the yellow (inner part) and brown (cortex) root powders ensuing from decortication of the raw dry roots, followed by separation and powderisation, were analysed for their scavenging activity by evaluating the colourimetric decrease in the absorbance of DPPH. The highest antioxidant activity (98.39 +/- 0.56%) was observed in the case of the Et(2)O extract of the brown powder, at a concentration of 3.33 mg mL(-1). Moreover, the total phenolic content of the extracts was determined using the Folin-Ciocalteu reagent and expressed as milligram gallic acid equivalent per gram of dry extract. Our results show that the Et(2)O extract of the liquorice root cortex could be used as an attractive natural source of antioxidant additives for food, cosmetic or pharmaceutical applications. PMID- 22236132 TI - Partial anomalous pulmonary vein connection. PMID- 22236133 TI - pH-responsive nanoparticles shelled with chitosan for oral delivery of insulin: from mechanism to therapeutic applications. AB - Despite advances in drug-delivery technologies, successful oral administration of protein drugs remains an elusive challenge. When protein drugs are administered orally, they can rapidly denature or degrade before they reach their targets. Such drugs also may not absorb adequately within the small intestine. As a protein drug for treating diabetes, insulin is conventionally administered via subcutaneous (SC) injection, yet often fails to achieve the glucose homeostasis observed in nondiabetic subjects. Some of this difference may relate to insulin transport: normally, endogenously secreted insulin moves to the liver via portal circulation. When administered subcutaneously, insulin moves through the body via peripheral circulation, which can produce a peripheral hyperinsulinemia. In addition, because SC treatment requires multiple daily injections of insulin, patients often do not fully comply with treatment. Oral administration of exogenous insulin would deliver the drug directly into the liver through portal circulation, mimicking the physiological fate of endogenously secreted insulin. This characteristic may offer the needed hepatic activation, while avoiding hyperinsulinemia and its associated long-term complications. This Account demonstrates the feasibility of using chitosan nanoparticles for oral insulin delivery. Nanoparticle (NP) delivery systems may provide an alternative means of orally administering protein drugs. In addition to protecting the drugs against a harmful gastric environment, the encapsulation of protein drugs in particulate carriers can avert enzymatic degradation, while controlling the drug release and enhancing their absorption in the small intestine. Our recent study described a pH-responsive NP system composed of chitosan (CS) and poly(gamma-glutamic acid) for oral delivery of insulin. As a nontoxic, soft-tissue compatible, cationic polysaccharide, CS also adheres to the mucosal surface and transiently opens the tight junctions (TJs) between contiguous epithelial cells. Therefore, drugs made with CS NPs would have delivery advantages over traditional tablet or powder formulations. This Account focuses on the premise that these CS NPs can adhere to and infiltrate the mucus layer in the small intestine. Subsequently, the infiltrated CS NPs transiently open the TJs between epithelial cells. Because they are pH-sensitive, the nanoparticles become less stable and disintegrate, releasing the loaded insulin. The insulin then permeates through the opened paracellular pathway and moves into the systemic circulation. PMID- 22236136 TI - The Bowel Function Index: a new validated scale for assessing opioid-induced constipation. AB - BACKGROUND: The management of opioid-induced constipation (OIC) is often complicated by the fact that clinical measures of constipation do not always correlate with patient perception. As the discomfort associated with OIC can lead to poor compliance with the opioid treatment, a shift in focus towards patient assessment is often advocated. SCOPE: The Bowel Function Index * (BFI) is a new patient-assessment scale that has been developed and validated specifically for OIC. It is a physician-administered, easy-to-use scale made up of three items (ease of defecation, feeling of incomplete bowel evacuation, and personal judgement of constipation). An extensive analysis has been performed in order to validate the BFI as reliable, stable, clinically valid, and responsive to change in patients with OIC, with a 12-point change in score constituting a clinically relevant change in constipation. FINDINGS: The results of the validation analysis were based on major clinical trials and have been further supported by data from a large open-label study and a pharmaco-epidemiological study, in which the BFI was used effectively to assess OIC in a large population of patients treated with opioids. Although other patient self-report scales exist, the BFI offers several unique advantages. First, by being physician-administered, the BFI minimizes reading and comprehension difficulties; second, by offering general and open ended questions which capture patient perspective, the BFI is likely to detect most patients suffering from OIC; third, by being short and easy-to-use, it places little burden on the patient, thereby increasing the likelihood of gathering accurate information. CONCLUSION: Altogether, the available data suggest that the BFI will be useful in clinical trials and in daily practice. PMID- 22236137 TI - Effects of olanzapine long-acting injection on levels of functioning among acutely ill patients with schizophrenia. AB - OBJECTIVE: To assess the effects of olanzapine long-acting injection (olanzapine LAI) on levels of functioning in acutely ill patients with schizophrenia. RESEARCH DESIGN AND METHODS: During this 8-week randomized, double-blind, placebo controlled trial, 404 inpatients were randomized to four treatment arms (olanzapine-LAI 210 mg/2 weeks = 106; olanzapine-LAI 300 mg/2 weeks = 100; olanzapine-LAI 405 mg/4 weeks = 100; placebo = 98). Also, data from the three active dosing arms were combined and compared to placebo data. CLINICAL TRIAL REGISTRATION: NCT00088478. MAIN OUTCOME MEASURES: The treatment group comparison of mean change from baseline to endpoint in the total score and four subdomains of the Heinrichs-Carpenter Quality of Life Scale (QLS) and in the 2 summary scores and 8 subscale scores of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were assessed using an ANOVA model. RESULTS: All three olanzapine-LAI treatment groups and the combined olanzapine-LAI group were superior to placebo on the QLS total score (all p-values < 0.01) and the Intrapsychic Foundations subdomain (all p-values < 0.02). Olanzapine-LAI 210 mg/2 weeks (p < 0.001), 300 mg/2 weeks (p = 0.006), and the combined olanzapine-LAI group (p = 0.003) were superior to placebo on the Interpersonal Relations subdomain. The 300 mg/2 weeks group (p = 0.027) and the combined olanzapine-LAI group (p = 0.014) were also superior to placebo on the Instrumental Role subdomain. For the SF-36, the 300 mg/2 weeks and 405 mg/4 weeks olanzapine-LAI groups and the combined olanzapine-LAI group were superior to placebo on the Mental component score (all p-values < 0.05). Each olanzapine-LAI group and the combined group were superior on the Mental Health scale (all p-values < 0.05). Significant negative correlations between PANSS scores and measures of functioning indicate that as symptoms decreased, functioning increased. CONCLUSION: These results suggest that olanzapine-LAI may improve level of functioning in acutely ill patients with schizophrenia within 8 weeks of initiating treatment. PMID- 22236138 TI - The vascular-disrupting agent combretastatin impairs splitting and sprouting forms of physiological angiogenesis. AB - OBJECTIVE: Vascular-disrupting agents like combretastatin (CA-4-P), used to attenuate tumor blood flow in vivo, exert anti-mitotic and anti-migratory effects on endothelial cells in vitro. We tested whether anti-vascular or anti-angiogenic effects of CA-4-P are evident with physiological angiogenesis in skeletal muscle (EDL) due to sustained hyperemia (intraluminal splitting) and chronic muscle overload (abluminal sprouting). METHODS: CA-4-P was given i.v. (25 mg/kg on alternate days for 14 days) to mice subjected to angiogenic stimuli (prazosin or synergist extirpation). The responses of femoral artery blood flow as well as capillarity, capillary ultrastructure, and levels of Rho GTPase were measured. RESULTS: Blood flow was unaffected in the sprouting angiotype, but decreased in the splitting angiotype, by CA-4-P. In contrast, CA-4-P attenuated the capillarity increase in both models, associated with reduced lamellipodia and filopodia formation. Muscle overload, but not hyperemia, was accompanied by an increase in Rho GTPase with CA-4-P. CONCLUSIONS: CA-4-P impaired the angiogenic response in both experimental models. This inhibitory effect was associated with a lower increase in femoral blood flow in splitting, whereas sprouting angiogenesis was accompanied by higher Rho activity consistent with the interruption of actin polymerization. Thus, CA-4-P may exert context-dependent anti-vascular and anti-angiogenic effects in vivo under physiological conditions. PMID- 22236139 TI - Efficacy of cosmetic formulations containing dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid and kinetin. AB - The present study aimed to evaluate the photoprotective effects of cosmetic formulations containing a dispersion of liposome with magnesium ascorbyl phosphate (MAP), alpha-lipoic acid (ALA) and kinetin, as well as their effects on the hydration and viscoelastic skin properties. The photoprotection was determined in vitro (antioxidant activity) and in vivo on UV-irradiated hairless mouse skin. The hydration effects were performed with the application of the formulations under study on the forearm of human volunteers and skin conditions were analyzed before and after a single application and daily applications during 4 weeks in terms of transepidermal water loss (TEWL), skin moisture and viscoelastic properties. The raw material under study possessed free-radical scavenging activity and the formulation with it protected hairless mouse skin barrier function against UV damage. After 4 weeks of application on human skin, the formulation under study enhanced stratum corneum skin moisture and also showed hydration effects in deeper layers of the skin. Thus, it can be concluded that the cosmetic formulation containing a dispersion of liposome with MAP, ALA and kinetin under study showed photoprotective effects in skin barrier function as well as pronounced hydration effects on human skin, which suggests that this dispersion has potential antiaging effects. PMID- 22236140 TI - Bisphosphonates significantly increase the activity of doxorubicin or vincristine against canine malignant histiocytosis cells. AB - Canine malignant histiocytosis (MH) is an aggressive neoplasm of macrophages and dendritic cells. It carries a poor prognosis because of the development of widespread metastasis and poor sensitivity to chemotherapy. Thus, there is a large need for new treatments for MH. We hypothesized that bisphosphonates might be useful to increase the effectiveness of cytotoxic chemotherapy against MH. To address this question, we conducted in vitro screening studies using MH cell lines and a panel of 6 chemotherapy and 5 bisphosphonate drugs. The combination of clodronate with vincristine was found to elicit synergistic killing which was associated with a significant increase in cell cycle arrest. Second, zoledronate combined with doxorubicin also significantly increased cell killing. Zoledronate significantly increased the uptake of doxorubicin by MH cells. On the basis of these findings, we conclude that certain bisphosphonate drugs may increase the overall effectiveness of chemotherapy for MH in dogs. PMID- 22236143 TI - The Journal of Physical Chemistry. Editorial for January 2012 for JPC A/B/C. PMID- 22236142 TI - Nutritional status of Palestinian preschoolers in the Gaza Strip: a cross sectional study. AB - BACKGROUND: The authors examined factors associated with nutritional resilience/vulnerability among preschoolers in the Gaza Strip in 2007, where political violence and deprivation are widespread. METHODS: This cross-sectional study was carried out in 2007 using random sampling of kindergartens in order to select 350 preschoolers. Binary logistic regression was used to compare resilient (adequate nutrition) and vulnerable (stunted) groups with those with moderate nutrition. RESULTS: Approximately 37% of the subjects demonstrated nutritional resilience and 15% were vulnerable. Factors associated with nutritional resilience were child younger age, normal birth weight, actively hand- or spoon feeding when the child was below two years, and residential stability in the past two years. The only factor associated with nutritional vulnerability was lower total score on the mother's General Health Questionnaire, which we interpret as a marker of maternal mental health. CONCLUSIONS: Children with low-birth weight and older children had worse nutritional resiliency outcomes. Further, poorer outcomes for children were associated with lower maternal mental health status, as well as increased family residential instability. Our results add to the large literature on the pervasive effects of violence and instability on children and underscore the need for resources for early intervention and for the urgent resolution of the Palestinian and other armed conflicts. PMID- 22236141 TI - Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release. AB - Oxidized low-density lipoprotein (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to the formation of lipid-laden macrophages (foam cells). Fcgamma receptors mediate uptake of oxLDL-IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL-IC, but not free oxLDL, activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyses sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L-ASMase) and secretory (S-ASMase). In this study we examined whether oxLDL and oxLDL-IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. The oxLDL-IC, but not oxLDL, induced early and consistent release of catalytically active S-ASMase. The oxLDL-IC also consistently stimulated L-ASMase activity, whereas oxLDL induced a rapid transient increase in L-ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L-ASMase activity; however, activity remained significantly lower than that induced by oxLDL-IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL-IC, heat-shock protein 70B' (HSP70B') was up-regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL-IC induced the formation and release of HSP70-containing and IL-1beta-containing exosomes via an ASMase-dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL-IC differentially regulate ASMase activity, and the pro-inflammatory responses to oxLDL-IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis. PMID- 22236144 TI - Opposing effects of age and calorie restriction on molecular determinants of myocardial ischemic tolerance. AB - We test the hypothesis that moderate calorie restriction (CR) reverses negative influences of age on molecular determinants of myocardial stress resistance. Postischemic contractile dysfunction, cellular damage, and expression of regulators of autophagy/apoptosis and of prosurvival and prodeath kinases were assessed in myocardium from young adult (YA; 2- to 4-month-old) and middle-aged (MA; 12-month-old) mice, and MA mice subjected to 14 weeks of 40% CR (MA-CR). Ventricular dysfunction after 25%+/-2%), as was cell death indicated by troponin I (TnI) efflux (1,701+/-214 ng vs. 785+/-102 ng in YA). MA hearts exhibited 30% and 65% reductions in postischemic Beclin1 and Parkin, respectively, yet 50% lower proapoptotic Bax and 85% higher antiapoptotic Bcl2, increasing the Bcl2/Bax ratio. Age did not influence Akt or p38-mitogen-activated protein kinase (MAPK) expression; reduced expression of increasingly phosphorylated ribosomal protein S6 kinase (p70S6K), increased expression of dephosphorylated glycogen synthase kinase 3beta (GSK3beta) and enhanced postischemic p38-MAPK phosphorylation. CR countered the age-related decline in ischemic tolerance, improving contractile recovery (60%+/-4%) and reducing cell death (123+/-22 ng of TnI). Protection was not associated with changes in Parkin or Bax, whereas CR partially limited the age-related decline in Beclin1 and further increased Bcl2. CR counteracted age related changes in p70S6K, increased Akt levels, and reduced p38-MAPK (albeit increasing preischemic phosphorylation), and paradoxically reduced postischemic GSK3beta phosphorylation. In summary, moderate age worsens cardiac ischemic tolerance; this is associated with reduced expression of autophagy regulators, dysregulation of p70S6K and GSK3beta, and postischemic p38-MAPK activation. CR counters age effects on postischemic dysfunction/cell death; this is associated with reversal of age effects on p70S6K, augmentation of Akt and Bcl2 levels, and preischemic p38-MAPK activation. Age and CR thus impact on distinct determinants of ischemic tolerance, although p70S6K signaling presents a point of convergence. PMID- 22236146 TI - Prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhosis with fasting plasma glucose level of <126 mg/dL. AB - AIM: The aim of this study was to evaluate the prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhotic patients with fasting plasma glucose (FPG) level of <126 mg/dL. METHODS: A total of 263 patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) positive liver cirrhosis, FPG level of <126 mg/dL, and had diabetes status evaluated by the use of 75-g oral glucose tolerance test (OGTT), were enrolled in this study. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. Diabetes was defined as a 2-h post-load glucose on the OGTT of >=200 mg/dL. The prevalence of diabetes by use of OGTT and predictive factors for diabetes were evaluated by the use of the Mann-Whitney U-test, Fisher's exact probability test or multivariate analysis by logistic regression. Hypoalbuminemia was defined as serum albumin level of <3.9 g/dL. Elevated indocyanine green retention rate at 15 min (ICG( R) 15) was regarded as >= 25%. RESULTS: Out of 263 patients, 44 (16.7%) were diagnosed as having diabetes. Multivariate analysis showed that diabetes occurred when patients had hypoalbuminemia of <3.9 g/dL (odds ratio [OR] 2.33; 95% confidential interval [CI] = 1.04-5.24; P = 0.040) and ICG( R) 15 of <25% (OR 2.36; 95%CI = 1.01-5.58). CONCLUSIONS: Hypoalbuminemia and elevated ICG( R) 15 in hepatitis virus related cirrhotic patients with FPG level of <126 mg/day enhance diabetes pattern after OGTT with significant difference. PMID- 22236145 TI - A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. AB - A Mediterranean diet rich in olive oil has been associated with health benefits in humans. It is unclear if and to what extent olive oil phenolics may mediate these health benefits. In this study, we fed senescence-accelerated mouse-prone 8 (SAMP8, n=11 per group) semisynthetic diets with 10% olive oil containing either high (HP) or low amounts of olive oil phenolics (LP) for 4.5 months. Mice consuming the HP diet had significantly lower concentrations of the oxidative damage markers thiobarbituric acid-reactive substances and protein carbonyls in the heart, whereas proteasomal activity was similar in both groups. Nrf2 dependent gene expression may be impaired during the aging process. Therefore, we measured Nrf2 and its target genes glutathione-S-transferase (GST), gamma glutamyl cysteine synthetase (gamma-GCS), nicotinamide adenine dinucleotide phosphate [NAD(P)H]:quinone oxidoreductase (NQO1), and paraoxonase-2 (PON2) in the hearts of these mice. Nrf2 as well as GST, gamma-GCS, NQO1, and PON2 mRNA levels were significantly higher in heart tissue of the HP as compared to the LP group. The HP-fed mice had significantly higher PON1 activity in serum compared to those receiving the LP diet. Furthermore, HP feeding increased relative SIRT1 mRNA levels. Additional mechanistic cell culture experiments were performed, and they suggest that the olive oil phenolic hydroxytyrosol present in the HP oil may be responsible for the induction of Nrf2-dependent gene expression and the increase in PON activity. In conclusion, a diet rich in olive oil phenolics may prevent oxidative stress in the heart of SAMP8 mice by modulating Nrf2-dependent gene expression. PMID- 22236147 TI - Successful hydraulic strategies to start up OLAND sequencing batch reactors at lab scale. AB - Oxygen-limited autotrophic nitrification/denitrification (OLAND) is a one-stage combination of partial nitritation and anammox, which can have a challenging process start-up. In this study, start-up strategies were tested for sequencing batch reactors (SBR), varying hydraulic parameters, i.e. volumetric exchange ratio (VER) and feeding regime, and salinity. Two sequential tests with two parallel SBR were performed, and stable removal rates > 0.4 g N l(-1) day(-1) with minimal nitrite and nitrate accumulation were considered a successful start up. SBR A and B were operated at 50% VER with 3 g NaCl l(-1) in the influent, and the influent was fed over 8% and 82% of the cycle time respectively. SBR B started up in 24 days, but SBR A achieved no start-up in 39 days. SBR C and D were fed over 65% of the cycle time at 25% VER, and salt was added only to the influent of SBR D (5 g NaCl l(-1)). Start-up of both SBR C and D was successful in 9 and 32 days respectively. Reactor D developed a higher proportion of small aggregates (0.10-0.25 mm), with a high nitritation to anammox rate ratio, likely the cause of the observed nitrite accumulation. The latter was overcome by temporarily including an anoxic period at the end of the reaction phase. All systems achieved granulation and similar biomass-specific nitrogen removal rates (141-220 mg N g(-1) VSS day(-1)). FISH revealed a close juxtapositioning of aerobic and anoxic ammonium-oxidizing bacteria (AerAOB and AnAOB), also in small aggregates. DGGE showed that AerAOB communities had a lower evenness than Planctomycetes communities. A higher richness of the latter seemed to be correlated with better reactor performance. Overall, the fast start-up of SBR B, C and D suggests that stable hydraulic conditions are beneficial for OLAND while increased salinity at the tested levels is not needed for good reactor performance. PMID- 22236148 TI - Phase II clinical evaluation of lomustine chemotherapy for feline vaccine associated sarcoma. AB - Treatment of feline vaccine-associated sarcoma (VAS) is challenging, in part due to the high likelihood of tumour recurrence despite aggressive local therapy. Lomustine is potentially an attractive agent to add to the current treatment armamentarium. In this de-escalating phase I/II prospective trial, 28 cats with measurable VAS were treated at target dosages of 38-60 mg m(-2) every 3 weeks until disease progression. The overall response rate was 25%, with a median progression-free survival and median duration of response of 60.5 and 82.5 days, respectively. Haematologic toxicity, specifically cumulative neutropenia, was significant, and dose reductions and treatment delays were common. Although these data support further investigation of lomustine for the treatment of VAS, safe, multidosing protocols must first be determined. PMID- 22236149 TI - Multiple introductions of HIV into men who have sex with men were found in Zhengzhou City, China. AB - Zhengzhou is the capital of Henan province, where severe HIV prevalence was found in former paid plasma donors. In recent years, the HIV epidemic in men who have sex with men (MSM) increased rapidly in the city. To explore the subtype distribution and genetic characterization of HIV in MSM in Zhengzhou city, phylogenetic analysis was fulfilled based on the full-length gag, pol, and partial env gene. A total of 31 HIV-1-seropositive MSM individuals were enrolled. The full length gag, pol, and partial env gene were amplified and sequenced. Multiple subtypes, including CRF01_AE (45.2%), subtype B (38.7%), and CRF07_BC (16.1%), were identified. Close phylogenetic relationships among our strains with strains from the Henan local area, Hebei MSM population, Beijing area, and Liaoning area were found, suggesting a multiple introduction of HIV into the population. The results will provide clues for prevention and for changes in behavior in the Henan MSM population and also detailed sequence data for vaccine design. PMID- 22236150 TI - Root surface treatment using diode laser in delayed tooth replantation: radiographic and histomorphometric analyses in rats. AB - BACKGROUND AIM: The aim of this study was to evaluate, by radiographic and histomorphometric analyses, the effects of high-power diode laser irradiation on the root surfaces of delayed replanted rat teeth. MATERIAL AND METHODS: Maxillary right incisors were extracted from 60 Wistar rats and kept dry for 60 min. Subsequently, the root canals were prepared and filled with calcium hydroxide paste. According to the root surface treatment before the replantation, the teeth were assigned to four groups (n = 15): G1 (negative control) - no root surface treatment; G2 (positive control) - treated with 2% sodium fluoride solution; G3 - irradiated with a high-power diode laser (810 nm, continuous mode, 1.0 W, 30 s); and G4 - irradiated with a diode laser using the same parameters as those used for G3 but in pulsed mode. The rats were euthanized after 15, 30, and 60 days of replantation. The specimens were digitally radiographed and processed for histomorphometric analysis to determine the average root resorption areas and to evaluate the histological events. RESULTS: The percentage of root resorption was in the following order: G1 > G2 > G4 > G3. Both histomorphometric and radiographic analyses showed significantly lower means (P < 0.05) of the occurrence of root resorption in the irradiated groups (G3 and G4) when compared to the control groups (G1 and G2). Replacement resorption and ankylosis were observed in histological sections only after 30 and 60 days; however, such events were not observed in G3. CONCLUSION: Root surface treatments with high-powered diode laser irradiation prior to delayed replantation reduced the occurrence of external root resorption compared to no treatment or sodium fluoride treatment at up to 60 days. PMID- 22236151 TI - Management of single-ventricle patients with Berlin Heart EXCOR Ventricular Assist Device: single-center experience. AB - There are minimal data regarding chronic management of single-ventricle ventricular assist device (VAD) patients. This study aims to describe our center's multidisciplinary team management of single-ventricle patients supported long term with the Berlin Heart EXCOR Pediatric VAD. Patient #1 was a 4-year-old with double-outlet right ventricle with aortic atresia, L-looped ventricles, and heart block who developed heart failure 1 year after Fontan. She initially required extracorporeal membrane oxygenation support and was transitioned to Berlin Heart systemic VAD. She was supported for 363 days (cardiac intensive care unit [CICU] 335 days, floor 28 days). The postoperative course was complicated by intermittent infection including methicillin-resistant Staphylococcus aureus, intermittent hepatic and renal insufficiencies, and transient antithrombin, protein C, and protein S deficiencies resulting in multiple thrombi. She had a total of five pump changes over 10 months. Long-term medical management included anticoagulation with enoxaparin, platelet inhibition with aspirin and dipyridamole, and antibiotic prophylaxis using trimethoprim/sulfamethoxazole. She developed sepsis of unknown etiology and subsequently died from multiorgan failure. Patient #2 was a 4-year-old with hypoplastic left heart syndrome who developed heart failure 2 years after bidirectional Glenn shunt. At systemic VAD implantation, he was intubated with renal insufficiency. Post-VAD implantation, his renal insufficiency resolved, and he was successfully extubated to daytime nasal cannula and biphasic positive airway pressure at night. He was supported for 270 days (CICU 143 days, floor 127 days). The pump was upsized to a 50-mL pump in May 2011 for increased central venous pressures (29 mm Hg). Long-term medical management included anticoagulation with warfarin and single-agent platelet inhibition using dipyridamole due to aspirin resistance. He developed increased work of breathing requiring intubation, significant anasarca, and bleeding from the endotracheal tube. The family elected to withdraw support. Although both patients died prior to heart transplantation, a consistent specialized multidisciplinary team approach to the medical care of our VAD patients, consisting of cardiothoracic surgeons, heart transplant team, hematologists, pharmacists, infectious disease physicians, psychiatrists, specialty trained bedside nursing, and nurse practitioners, allowed us to manage these patients long term while awaiting heart transplantation. PMID- 22236152 TI - The temporal pattern of mating behavior of the fruit fly, Anastrepha zenildae in the laboratory. AB - The state of Rio Grande do Norte is an important fruit-producing and exporting area in northeastern Brazil. The success of this industry depends on fruit fly population control, especially in fly-free exporting zones. However, many fruits are not exported because of quarantine restrictions imposed by importing countries. A survey in the state has detected a considerable increase of the fruit fly, Anastrepha zenildae Zucchi (Diptera: Tephritidae), probably a result of the introduction of irrigated guava orchards that make fruit available all year. Knowledge of the sexual behavior of Tephritidae has great importance to pest control programs, particularly those that employ the Sterile Insect Technique. In order to characterize the reproductive behavior of A. zenildae, 32 individuals (16 males; 16 females) in each of six generations were submitted to an artificial 12:12 L:D cycle (750: < 1 lux, lights on 07:00-19:00) and observed over their lifetimes. The courtship and copulation occurred in leks and the episodes varied with the time of day, courtship being most frequent between Zeitgeber time (ZT) 3 and ZT 7, peaking at ZT 5-6. Copulations occurred between ZT 2 and ZT 8, with a higher frequency between ZT 5-7 and a peak at ZT 6. Mean duration was 0.28 +/- 0.03 min/male (range: 5-163 min). Males in the leks attempted to copulate mainly between ZT 3 and ZT 7 with a peak at ZT 6, and males outside leks peaked at ZT 7. The different timing of sexual behaviors among related sympatric species, including A. zenildae, may contribute to species isolation. PMID- 22236153 TI - Metal based agents with potential for therapeutic and diagnostic applications. PMID- 22236154 TI - Development of sugar-based materials for biological devices. AB - Recent progresses of our group dealing with newly developed sugar-based ligands and their metal complexes have been reviewed. Carbohydrate moiety affects on the stereochemistry around the metal center and controls the biological activity of the complex. PMID- 22236155 TI - Improvement of tumor localization of photosensitizers for photodynamic therapy and its application for tumor diagnosis. AB - Photodynamic therapy (PDT) and photodynamic diagnosis of cancer are widely used in clinical fields. These are performed using photosensitizers. Many metalloporphyrin-related compounds have been developed as photosensitizers for use in PDT, and these tumor localization ability have been improved in recent research. Moreover, the precursor of porphyrin 5-aminolevulinic acid is used in fluorescence diagnosis using its tumor localization ability. In this review, these applications of photosensitizers in cancer therapy and diagnosis are summarized. PMID- 22236156 TI - Zinc complexes developed as metallopharmaceutics for treating diabetes mellitus based on the bio-medicinal inorganic chemistry. AB - Biological trace metals such as iron, zinc, copper, and manganese are essential to life and health of humans, and the success of platinum drugs in the cancer chemotherapy has rapidly grown interest in developing inorganic pharmaceutical agents in medicinal chemistry, that is, medicinal inorganic chemistry, using essential elements and other biological trace metals. Transition metal complexes with unique chemical structures may be useful alternatives to the drugs available to address some of the incurable diseases. In this review, we emphasize that metal complexes are an expanding of interest in the research field of treatment of diabetes mellitus. Especially, orally active anti-diabetic and anti-metabolic syndrome zinc complexes have been developed and progressed since the discovery in 2001, where several highly potent anti-diabetic zinc complexes with different coordination structures have quite recently been disclosed, using experimental diabetic animals. In all of the complexes discussed, zinc is found to be biologically active and function by interacting with some target proteins related with diabetes mellitus. The design and screening of zinc complexes with higher activity is not efficient without consideration of the translational research. For the development of a clinically useful metallopharmaceutics, the research of zinc complexes on the long-term toxicity including side effects, clear-cut evidence of target molecule for the in vivo pharmacological action, and good pharmacokinetic property are essential in the current and future studies. PMID- 22236157 TI - What does the future hold for photo-oxidizing Ru(II) complexes with polyazaaromatic ligands in medicinal chemistry? AB - Since the discovery of cisplatin, the search for diagnostic or therapeutic agents based on other metals, has expanded intensively owing to the numerous possibilities offered by coordination chemistry. This mini-review focuses on recent advances in the search for Ru(II) polyazaaromatic complexes of potential interest as molecular tools applied to cellular diagnostics or as specific cellular photo-reagents for future biomedical applications. The interaction of Ru(II) polyazaaromatic complexes with living cells is reported, as well as the photo-reaction mechanisms of photo-oxidizing Ru(II) complexes with nucleic acids. The novel strategies currently developed to improve their reactivity and specificity towards DNA, more particularly in the gene-silencing framework, are also discussed. PMID- 22236158 TI - Next-generation anticancer metallodrugs. AB - More than 99% of currently approved clinical drugs are organic compounds. In contrast, the percentage of metal-containing drugs (metallodrugs) is very low. In cancer chemotherapy, however, platinum coordination compounds represented by cisplatin and derivatives thereof are essential anticancer agents with proven effects against a variety of tumors. Because of the proven clinical applications of these platinum-based drugs, the number of research initiatives to identify other metallodrugs that can be used for cancer therapy has increased considerably in the field of inorganic biochemistry. Anticancer platinum compounds continue to be designed and synthesized through several different approaches in order to improve the therapeutic effects and to overcome the disadvantages of current platinum-based drugs. The use of transition metal compounds other than platinum has also attracted attention. Gold coordination complexes, for instance, demonstrate outstanding cytotoxic properties, and certain ruthenium complexes possess a strong ability to inhibit metastases of solid invasive tumors. In this review, the potential of anticancer metallodrugs is described and representative examples from the most recent families of Pt-, Ru-, and Au-based compounds are discussed with respect to their possible modes of action and most probable biomolecular targets. PMID- 22236159 TI - Multifunctional ligands in medicinal inorganic chemistry--current trends and future directions. AB - This review will highlight recent advances in ligand design for innovative applications in medicinal inorganic chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy. Increasing the potency of therapeutic compounds, while limiting side effects, is a common goal in medicinal chemistry. In an effort to achieve this goal, compounds are being developed that either target a disease site, or are activated by a disease specific biological process. Metal complexes containing targeting functions and/or bioactive ligands, as well as agents that are activated by specific enzymes, or changes in pH and pO2, provide new avenues for drug development. Radiodiagnostic compounds, magnetic resonance imaging agents, and optical probes containing transition metals offer versatility unavailable to organic imaging agents. In certain cases, dual modality agents have been developed, and will be highlighted. Finally, we will discuss targeted metal binding compounds for treatment of metal overload disorders, and the recent application to neurodegenerative disease. PMID- 22236160 TI - Terpyridines and their complexes with first row transition metal ions: cytotoxicity, nuclease activity and self-assembly of biomacromolecules. AB - Transition metal complexes with terpyridine ligands have attracted a widespread interest with respect to biomedical applications: [(tpy)PtCl]Cl and [(tpy)RuCl(3)] are potent anti-tumor agents with activities comparable to those of cisplatin and carboplatin. The Ru(II) complexes feature a high potential as reactive probes for DNA oxidation; whereas, luminescent Ir(III), Pt(II) or Eu(III) complexes have been utilized in biolabeling applications. Besides complexes based on heavy second or third row transition metal ions, remarkable results have been obtained with respect to the development of new types of metallodrugs, based on the naturally more abundant and intrinsically less toxic first row transition metal ions (e.g. Fe(II), Cu(I/II), Zn(II)). The perspective of these complexes in particular with respect to future biomedical applications in chemotherapy and cleavage of nucleic acids is evaluated in this review. PMID- 22236161 TI - Therapeutic potential of photochemically active metal complexes based on interaction with enzymes. AB - Transition metal complexes with oligopyridine ligands and ruthenium or rhenium centers have attracted a widespread interest with respect to biomedical applications as they are luminescent and form triplet excited states which may form (1)O(2). These complexes have been shown to enter living cells and even cellular nuclei. In addition detailed investigations of their interaction with proteins/enzymes have shown that they are capable of binding to these biomolecules, alter the redox state of the enzyme metal centre and induce different reactivity. The application of these complexes as photoactive metallodrugs will depend on their photophysical and photochemical properties. The potential of these complexes together with relevant aspects of their chemistry will be discussed in this review. PMID- 22236162 TI - Use of proliferation rate, p53 staining and perforating elastic fibers in distinguishing keratoacanthoma from hypertrophic lichen planus: a pilot study. AB - BACKGROUND: Distinguishing keratoacanthoma (KA) and hypertrophic lichen planus (LP) histopathologically can be difficult, and the challenge is compounded by the tendency of KA to arise in association with hypertrophic LP. METHODS: In this pilot study, we compared 18 cases each of KA and hypertrophic LP for proliferation index (MIB-1), p53 staining and the presence of perforating elastic fibers (elastic Verhoeff-van Gieson) to determine the utility of these staining modalities in distinguishing KA from hypertrophic LP. RESULTS: Proliferation index in KA compared to hypertrophic LP is 88.2 (mean positive MIB-1 cells/*100 field), SD = 56.6 and 47.3, SD = 68.4, respectively. p53 staining in KA compared to hypertrophic LP is 251 (mean positive cells/*100 field), SD = 117 and 158, SD = 119, respectively. Fifteen of eighteen (83%) keratoacanthomata demonstrate perforating elastic fibers compared to 1/18 (6%) for hypertrophic LP. CONCLUSION: Proliferation index is not significantly different between KA and hypertrophic LP (p = 0.059). Expression of p53 is increased in KA over hypertrophic LP (p = 0.024). The presence of perforating elastic fibers in KA is significantly different from hypertrophic LP (p < 0.0001) and suggests that elastic Verhoeff van Gieson staining may be of practical benefit in distinguishing KA from hypertrophic LP in difficult cases. PMID- 22236163 TI - Comparison of fracture resistance and fit accuracy of customized zirconia abutments with prefabricated zirconia abutments in internal hexagonal implants. AB - BACKGROUND: Customized zirconia abutments are increasingly applied for the fabrication of esthetic implant restorations aimed at imitating the natural situation. These abutments are individually shaped according to the anatomical needs of the respective implant site. PURPOSE: This study sought to compare the fracture resistance and fit accuracy of prefabricated and customized zirconia abutments using an internal hexagonal implant system (TSV(r), Zimmer, Carlsbad, CA, USA). MATERIALS AND METHODS: Two zirconia abutment groups were tested: prefabricated zirconia abutments (ZirAce, Acucera, Seoul, Korea) and customized zirconia abutments milled by the Zirkonzahn milling system. Twenty zirconia abutments per group were connected to implants on an acrylic resin base with 30 Ncm torque. The fracture resistance of zirconia abutments was measured with an angle of 30 degrees at a crosshead speed of 1 mm/min using the universal testing machine (Z020, Zwick, Ulm, Germany). Marginal and internal gaps between implants and zirconia abutments were measured after sectioning the embedded specimens using a digital microhardness tester (MXT70, Matsuzawa, Tokyo, Japan). RESULTS: The customized abutments were significantly stronger (1,430.2 N) than the prefabricated abutments (1,064.1 N). The mean marginal adaptation of customized abutments revealed a microgap that was increased (11.5 um) over that in prefabricated abutments (4.3 um). CONCLUSION: Within the limitations of this study, the customized abutments are significantly stronger than prefabricated abutments, but the fit is less accurate. The strength and fit of both abutments are within clinically acceptable limit. PMID- 22236168 TI - Comment on "Frequency upshift in BO2 and CO2+ upon electronic excitation: a twin state model rationalization". PMID- 22236166 TI - Promoting fit bodies, healthy eating and physical activity among Indigenous Australian men: a study protocol. AB - BACKGROUND: Overall the physical health of Indigenous men is among the worst in Australia. Research has indicated that modifiable lifestyle factors, such as poor nutrition and physical inactivity, appear to contribute strongly to these poor health conditions. To effectively develop and implement strategies to improve the health of Australia's Indigenous peoples, a greater understanding is needed of how Indigenous men perceive health, and how they view and care for their bodies. Further, a more systematic understanding of how sociocultural factors affect their health attitudes and behaviours is needed. This article presents the study protocol of a community-based investigation into the factors surrounding the health and body image of Indigenous Australian men. METHODS AND DESIGN: The study will be conducted in a collaborative manner with Indigenous Australian men using a participatory action research framework. Men will be recruited from three locations around Australia (metropolitan, regional, and rural) and interviewed to understand their experiences and perspectives on a number of issues related to health and health behaviour. The information that is collected will be analysed using modified grounded theory and thematic analysis. The results will then be used to develop and implement community events in each location to provide feedback on the findings to the community, promote health enhancing strategies, and determine future action and collaboration. DISCUSSION: This study will explore both risk and protective factors that affect the health of Indigenous Australian men. This knowledge will be disseminated to the wider Indigenous community and can be used to inform future health promotion strategies. The expected outcome of this study is therefore an increased understanding of health and health change in Indigenous Australian men, the development of strategies that promote healthy eating and positive patterns of physical activity and, in the longer term, more effective and culturally-appropriate interventions to improve health. PMID- 22236169 TI - Influence of calcium hydroxide intracanal medication on bond strength of two endodontic resin-based sealers assessed by micropush-out test. AB - AIM: To evaluate the influence of calcium hydroxide (CH) paste used as intracanal medication on the bond strength of AH Plus (AH) and Epiphany (EP) sealers to root dentin. METHODOLOGY: Sixty palatal canals were prepared in human maxillary first molars, using a rotary system. Half of the specimens received distilled water, and the other ones received intracanal medication with CH for 14 days. Thereafter, the CH was removed and both groups were further divided into two subgroups, filled with either AH or EP. The test specimens were submitted to the micropush-out test at a speed of 0.5 mm min(-1) . Results were statistically analyzed with anova and Tukey's test at a 95% confidence level. RESULTS: The use of CH had statistically significant (P < 0.05) influence on AH only, increasing its bond strength from 19.7 +/- 4.5 to 23.8 +/- 2.5 (mean +/- SD in MPa). In both EP groups, with (1.8 +/- 0.5 MPa) and without (1.5 +/- 0.9 MPa) CH, the bond strength values were statistically significantly lower than in either of the AH groups (P < 0.05). CONCLUSION: Calcium hydroxide used as intracanal medication for 14 days had a positive influence on the bond strength of AH to root dentin whereas the effect on EP was insignificant. Regardless of the intracanal medication used, AH showed considerably higher bond strength values compared with EP sealer. PMID- 22236171 TI - Hierarchical nanoflake surface driven by spontaneous wrinkling of polyelectrolyte/metal complexed films. AB - A mechanical or physical change observed in nanocomposite thin films has recently offered new opportunities to generate intriguing nanostructures. In this study, we present a novel means of creating a hierarchically developed nanoflake structure by exploiting surface wrinkles that occur during the incorporation process of metallic nanoparticles into layer-by-layer assembled polyelectrolyte multilayer (PEM) thin films. The PEM film composed with linear polyethylenimine (LPEI) and poly(acrylic acid) (PAA) allows for facilitated cationic exchange reaction within the film even after the electrostatic complexation and chemical cross-linking reaction. The subsequent reduction process induces an in situ complexation of metallic nanoparticles with a PEM matrix, causing an accumulation of lateral compressive stress for surface wrinkling. The wrinkling characteristics of the complexed films can be theoretically interpreted by employing the gradationally swollen film model, whereby a gradual change in the elastic property along the axial direction of the film can be appropriately reflected. In addition, wrinkled surfaces are further processed to form vertically aligned and hierarchically ordered nanoflakes after selective removal of the PEM matrix with plasma ashing. Consequently, superhydrophobic surface properties (water contact angle = 170 degrees , sliding angle <1 degrees ) can be attained from the hierarchical nanoflake structure. The method presented here is advantageous in that large-scale preparation can be readily implemented by a stepwise dipping process without resorting to specific patterning or a serially applied complex structuring process, which can provide a promising platform technique for various surface engineering applications. PMID- 22236172 TI - Use of patient health records in research. PMID- 22236173 TI - Pharmaceutical care R.I.P? PMID- 22236174 TI - Clozapine repackaged into dose administration aids: a common practice in Australian hospitals. AB - OBJECTIVES: Clozapine is an atypical antipsychotic used in the treatment of schizophrenia. Due to the patient profile there is a high rate of repackaging of clozapine into dose administration aids (DAAs). Because of reports from hospital pharmacists about discoloration of returned clozapine tablets that have been repackaged into DAAs, the aim of this study was to evaluate the chemical, physical and photostability of these tablets repackaged into a DAA. METHOD: Clozapine tablets were repackaged into DAAs and evaluated for physicochemical stability over a 6-week period at a controlled room temperature (25+/-1 degrees C; 60+/-1.5% relative humidity (RH)) and accelerated conditions (40+/-1 degrees C; 75+/-1.5% RH). In addition, photostability studies were performed according to the International Committee on Harmonisation (ICH) guidelines. KEY FINDINGS: Chemical stability was confirmed for all storage conditions, including for those photostability (ICH conditions), with the clozapine content occurring within the British Pharmacopoeial (BP) range of 90-110%. Although the physical stability was confirmed for all tests at room temperature (weight uniformity, hardness, friability, disintegration and dissolution), under accelerated conditions the disintegration test did not meet BP requirements. However, the subsequent dissolution test was successful with 85% of clozapine dissolving in 45min. CONCLUSIONS: This study illustrates that clozapine, when correctly repackaged, maintains its physical and chemical stability for 6 weeks. As no discoloration of the tablets was observed, it is assumed that the reports received were as a result of improper handling by patients. Based on these findings, it is recommended that patients be advised on the correct handling and storage of their DAAs. PMID- 22236175 TI - Determinants and frequency of pharmaceutical compounding in pharmacy practice in Palestine. AB - OBJECTIVES: The aims of this study were to determine the frequency of prescription compounding by community pharmacists, identify factors that influence pharmacists' decisions to provide compounding services, and evaluate physicians' perspectives on prescribing medications that require compounding. METHODS: The study was a cross-sectional survey administered via face-to-face structured interviews with randomly selected community pharmacists and physicians from different areas of the West Bank. KEY FINDINGS: Of the 260 community pharmacists who were contacted, 212 agreed to participate in the survey, giving a response rate of 81.5%. Overall, 153 (72.2%) of respondent pharmacists provided compounding services. Compounded prescriptions accounted for 1973 (1.55%) of 126,840 prescriptions dispensed in a typical month. Among the compounders, 112 (73.2%) pharmacists reported that their goal in providing full pharmaceutical care to their patients was the most important motivator. The most frequently reported reason for not providing compounding was 'I do not receive prescriptions that require compounding' by 43 out of 59 (72.9%) pharmacists. A total of 179 out of 220 physicians consented to participate in this study giving a response rate of 81.4%. The majority of physicians (142, 79.3%) did not prescribe compounded medicines. The most important reason for their decision to prescribe compounded medicines was the unavailability of the required dosage forms. The most commonly cited reason for not prescribing them was a lack of trust in the quality of the compounded formulations. CONCLUSION: While most respondent pharmacists provide a compounding service this represents only a small percentage of the total volume of dispensed prescriptions. Most responding physicians do not prescribe medications that require compounding because they lack trust in the quality of the compounded formulations. PMID- 22236176 TI - Adapting the US Institute for Safe Medication Practices' Medication Safety Self Assessment tool for community pharmacies in Finland. AB - OBJECTIVES: To adapt a US Institute for Safe Medication Practices' Medication Safety Self Assessment (MSSA) tool to, and test its usefulness in, Finnish community pharmacies. METHODS: A three-round Delphi survey was used to adapt self-assessment characteristics of the US MSSA tool to Finnish requirements, and to obtain a consensus on the feasibility and significance of these characteristics in assessing the safety of medication practices in community pharmacies. The Delphi modified self-assessment tool was piloted in 18 community pharmacies in order to refine the tool, using a questionnaire containing structured and open-ended questions. KEY FINDINGS: A total of 211 self-assessment characteristics were accepted to the self-assessment tool for pilot use by expert panellists in the Delphi rounds. Most pilot users considered the tool as useful in: identifying medication safety targets for development; medication safety assessment; and identifying the strengths of medication safety. The substance of the self-assessment tool was considered as comprehensive and essential for medication safety. Most criticism was regarding: the multiplicity of self assessment characteristics; interpretation of some characteristics; and that all the characteristics were not yet available. After the modification, according to the pilot users' comments, the final Finnish tool consisted of 230 medication safety characteristics. CONCLUSIONS: The study indicated the feasibility of adapting a US medication safety self-assessment tool for use in community pharmacy practice in Finland. More efforts should be made to familiarise Finnish community pharmacists with the self-assessment tool and its benefits, and get them to use the tool as part of their long-term quality improvement. PMID- 22236178 TI - Pharmacists' awareness of Australia's health care reforms and their beliefs and attitudes about their current and future roles. AB - OBJECTIVE: To explore pharmacists' awareness of Australia's health care reforms and their beliefs and attitudes about their current and future roles. METHODS: Four focus groups were conducted with 32 South Australian pharmacists: two groups included community pharmacists and pharmacy owners; one included hospital pharmacists and another, consultant pharmacists. KEY FINDINGS: Four themes emerged: (1) poor awareness of health care reform agenda; (2) strong adherence to the supply model; (3) lack of appreciation of alternative models; and (4) communication barriers. CONCLUSIONS: Participants' low awareness of Australia's health care reforms and their expressed beliefs and attitudes to their current role in the health system suggest that they are not well prepared for the potential future roles expected of health professionals in the health care reform agenda. PMID- 22236177 TI - Experiences of a nationwide web-based system: reporting dispensing errors in Swedish pharmacies. AB - OBJECTIVES: To design and evaluate a national web-based dispensing error reporting system for all Swedish pharmacies, replacing the currently used paper based system. METHODS: A working group designed the new system. The number of reports before (1999-2003) and after (2004-2005) introduction was studied in a descriptive analysis. The completeness of reports was evaluated through the study of 100 randomly selected reports from the third quarter of 2003 and 2004 from each system. Evaluation was done by chi-square analysis; P>0.05. Perceptions on introduction were collected in semi-structured interviews (working group and one assistant) and subjected to descriptive analysis. KEY FINDINGS: Reported error rate per 100,000 dispensed items was 12.9 pre- and 21.4 post implementation. Completeness-analysis revealed that information was more comprehensively reported in the new system. A significant difference existed in the extent to which incidents were described as well as details provided of the medicine and the patient. According to the interviewees, users initially found the web-based system difficult to handle. It took more than 6 months to change this perception. CONCLUSIONS: Introducing a web-based system for reporting dispensing errors had an impact on quantity of reports and completeness. Time and patience was needed to implement the changes. PMID- 22236179 TI - A cost-consequences analysis of an adherence focused pharmacist-led medication review service. AB - OBJECTIVES: The aim of this project was to conduct an economic evaluation of the Norfolk Medicines Support Service (NMSS), a pharmacist-led medication review service for patients identified in primary care as non-adherent. METHODS: The cost-consequences analysis was based on a before and after evaluation of the NMSS. Participants completed a self-reported adherence and health-related quality of life questionnaire prior to the review, at 6 weeks and 6 months. Service provision, prescribing and secondary care costs were considered and the mean cost before and after the intervention was calculated. KEY FINDINGS: One-hundred and seventeen patients were included in the evaluation. The mean cost per patient of prescribing and hospital admissions in the 6 months prior to the intervention was L2190 and in the 6 months after intervention L1883. This equates to a mean cost saving of L307 per patient (parametric 95% confidence interval: L1269 to L655). The intervention reduced emergency hospital admissions and increased medication adherence but no significant change in health-related quality of life was observed. CONCLUSION: The costs of providing this medication review service were offset by the reduction in emergency hospital admissions and savings in medication cost, assuming the findings of the evaluation were real and the regression to the mean phenomenon was not involved. This cost-consequences approach provides a transparent descriptive summary for decision-makers to use as the basis for resource allocation decisions. PMID- 22236180 TI - Analysis of enquiries to the National Pharmacy Association following major changes to controlled drug legislation in the UK. AB - OBJECTIVES: The National Pharmacy Association (NPA) provides an advice service to community pharmacists in the UK, and keeps a database of the enquiries it receives. The aim of this research was to analyse the database for the period of October 2007 to March 2008 to gain an insight into how well pharmacists coped with legislative changes directly affecting pharmacy by identifying which changes generated the most enquiries during these 6 months and ascertaining in which months these queries were at their highest levels. METHODS: Anonymised telephone enquiries regarding controlled drugs (CDs) received by the NPA from pharmacists during a 6-month period were reviewed and categorised according to the legislative change or other CD issue to which they related. A Poisson model was applied to determine whether there was a significant difference in the total number of CD queries generated each month. KEY FINDINGS: Altogether 6082 queries regarding CDs were received, of which 57% related to legislative changes. The three legislative changes that took place during the 6-month period all generated a significant increase in numbers of queries around the time of the change. Queries regarding the new form of CD register comprised the largest single category. CONCLUSIONS: Community pharmacists seek information regarding legislative changes when such changes come into force to a greater degree than when the legislation is drafted, consulted upon or enacted. The high number of queries received by the NPA does reflect that there was a difficulty in applying the various legislative changes in practice. PMID- 22236181 TI - Pharmacists' perceptions of their practice: a comparison between Alberta and Northern Ireland. AB - OBJECTIVE: To explore how community pharmacists from Alberta, Canada, and Northern Ireland, UK, describe what a pharmacist does and to compare their responses. METHODS: Two hundred community pharmacists were interviewed using the telephone. The interviewer who introduced himself as a researcher asked two questions about the period over which the participants had been practising pharmacy and the way they describe what a pharmacist does. Responses were categorised into three categories: patient-centred, product-focused and ambiguous. Word-cloud analysis was used to assess the use of patient-care-related terms. KEY FINDINGS: Of the responses from community pharmacists in Alberta, 29% were categorised as patient-centred, 45% as product-focused and 26% as ambiguous. In Northern Ireland, 40% of the community pharmacists' responses were categorised as patient-centred, 39% as product-focused and 21% as ambiguous. Community pharmacists in Northern Ireland provided more patient-centred responses than community pharmacists in Alberta (P=0.013). The word-cloud analysis showed that 'medicine' and 'dispense' were the most frequently reported terms. It also highlighted a relative lack of patient-care-related terms. CONCLUSIONS: The findings of the present study are suggestive of some movement towards patient centredness; however, product-focused practice still predominates within the pharmacy profession in Alberta and Northern Ireland. The relative lack of patient care-related terms suggests that patient care is still not the first priority for pharmacists in both Alberta and Northern Ireland. PMID- 22236182 TI - Role of pharmacists in the management of patients with epilepsy. AB - OBJECTIVES: The aim of this article is to highlight the roles that pharmacists currently have in the management of patients with epilepsy and the opportunities and challenges associated with these roles. KEY FINDINGS: There are many opportunities for pharmacists in the management of patients with epilepsy owing to the accessibility and extensive knowledge of drug therapy. The role of pharmacists extends beyond dispensing medications. The pharmacists have a significant role in the education of patients about the disease and therapy, encouraging adherence and explaining side effects and providing information on potential drug-drug interactions, resulting in improved clinical outcomes and decreased costs. Physicians prefer pharmacists as information sources for medication profile and drug interaction screening for patients with epilepsy. However, there are certain challenges which the pharmacists should overcome if effective medication therapy management services are to be provided on a routine basis. Educational interventions are required to improve the knowledge and skills of pharmacists. The gap between patients' and pharmacists' views of the pharmacist's role has to be narrowed to ensure enhanced role of the pharmacists in this patient group. CONCLUSIONS: There are a lot of opportunities and challenges for pharmacists to provide medication therapy management services for patients with epilepsy. Evidence in the literature provides justification for such services. However more research is required to provide foundation for routine provision of such services in all healthcare facilities. PMID- 22236183 TI - Year-long presence of Eimeria echidnae and absence of Eimeria tachyglossi in captive short-beaked echidnas ( Tachyglossus aculeatus ). AB - The short-beaked echidna ( Tachyglossus aculeatus ) is 1 of 5 extant species of monotreme, found only in Australia and Papua New Guinea. The aim of this study was to identify the species of coccidia present and establish a range of subclinical Eimeria spp. (Coccidia: Apicomplexa) oocyst shedding in echidnas from eastern Australia over 18 mo. The coccidia were detected in 89% (49/55) of fecal samples from 12 long-term monitored and healthy captive echidnas, 75% (3/4) of 4 healthy long-term captive echidnas, 83% (5/6) of 6 short-term captive echidnas, and 60% (6/10) of 10 wild echidnas. Echidnas captive for 4 to 23 yr shed 100 46,000 oocysts g(-1) of E. echidnae and remained clinically healthy during this study. Sub-adult and adult wild, and short-term captive, echidnas shed oocysts of both E. echidnae and E. tachyglossi . The lack of coccidia in juvenile short beaked echidnas suggests these animals are probably non-immune and should not be placed in environments heavily contaminated with oocysts. In addition, no oocysts were found in captive long-beaked echidnas ( Zaglossus bartoni bartoni , n = 2) housed at Taronga Zoo. This study represents an important step in understanding the host-parasite interaction between coccidia and short-beaked echidnas. PMID- 22236184 TI - Quality of life associated with treatment of castration-resistant prostate cancer: a review of the literature. AB - The development of new therapies for castration-resistant prostate cancer (CRPC) has increasingly focused on improving patient quality of life, mainly because of limited survival gains and continuing high morbidity burden from disease progression or the adverse effects of treatments. However, there is no generally accepted quality of life instrument for use with this patient group. This paper objectively reviews the existing literature and assesses the impact of CRPC treatments on patients' quality of life. The review also provides a narrative description of the evolving role of quality of life measures in clinical trials, and critiques the most widely used instruments. PMID- 22236185 TI - GPC5 rs2352028 polymorphism and risk of lung cancer in Han Chinese. AB - rs2352028 in GPC5 has been reported to be associated with the risk of lung cancer in never-smokers. We performed a replication study in 1,045 lung cancer patients and 1,094 controls of Han Chinese origin. We found no association between rs2352028 and lung cancer/adenocarcinoma in never-smokers, but a p value of .04 (under the recessive model) was obtained between this SNP and overall lung cancer/adenocarcinoma. Our data and a recent meta-analysis suspected the possibility of rs2352028 being a risk variant of lung cancer risk in never smokers. Our findings suggested that rs2352028 might confer a slight risk to lung cancer/adenocarcinoma. PMID- 22236186 TI - Relationship between advanced oxidation protein products, advanced glycation end products, and S-nitrosylated proteins with biological risk and MDR-1 polymorphisms in patients affected by B-chronic lymphocytic leukemia. AB - The aim of our study was to analyze the serum levels of advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEs), and protein nitrosylation in patients with B-chronic lymphocytic leukemia (B-CLL). AOPPs, AGEs, and S-nitrosylated were increased in B-CLL patients. The mutation of IgVH gene, CD 38, and Zap 70 expression were not associated with increased oxidative stress. The mutant 2677GT genotype was found to be associated with higher AGEs levels with respect to wild-type genotype, while as far the C3435T MDR1 polymorphism is concerned, subjects presenting wild-type genotype showed higher values of AOPPs with respect to heterozygous genotype. Our results suggest that B CLL is associated with oxidative stress. PMID- 22236187 TI - Glucosylceramide synthase protects glioblastoma cells against autophagic and apoptotic death induced by temozolomide and Paclitaxel. AB - Glioblastoma is a deadly cancer with intrinsic chemoresistance. Understanding this property will aid in therapy. Glucosylceramide synthase (GCS) is associated with resistance and poor outcome; little is known about glioblastomas. In glioblastoma cells, temozolomide and paclitaxel induce ceramide increase, which in turn promotes cytotoxicity. In drug-resistant cells, both drugs are unable to accumulate ceramide, increased expression and activity of GCS is present, and its inhibitors hinder resistance. Resistant cells exhibit cross-resistance, despite differing in marker expression, and cytotoxic mechanism. These findings suggest that GCS protects glioblastoma cells against autophagic and apoptotic death, and contributes to cell survival under chemotherapy. PMID- 22236188 TI - Differential expression and function of peroxiredoxin 1 and peroxiredoxin 6 in cancerous MCF-7 and noncancerous MCF-10A breast epithelial cells. AB - Peroxiredoxins are thiol-specific antioxidant proteins whose expression is elevated in several cancers. We compared the expression and function of Prdx1 and Prdx6 between the MCF-7 mammary adenocarcinoma cell line and the noncancerous MCF 10A cell line. We found elevated Prdx1 expression in MCF-7 cells and comparable expression of Prdx6. Suppression of Prdx1 and/or Prdx6 resulted in a modest increase in peroxide-induced cytotoxicity of MCF-7 cells, and a dramatic increase in MCF-10A cytotoxicity with and without hydrogen peroxide treatment. Our data confirm a cytoprotective role for peroxiredoxins and suggest a synergistic role for Prdx1 and Prdx6 in MCF-10A cells. PMID- 22236190 TI - Direct short-term cytotoxic effects of BIBR 1532 on acute promyelocytic leukemia cells through induction of p21 coupled with downregulation of c-Myc and hTERT transcription. AB - Acute promyelocytic leukemia (APL) is characterized by specific t(15;17), distinct morphologic picture, and clinical coagulopathy that contribute to the morbidity and mortality of the disease. This study aims to investigate the effects of antitelomerase compound BIBR1532 on APL cells (NB4). BIBR 1532 exerts a direct short-term growth suppressive effect in a concentration-dependent manner probably through downregulation of c-Myc and hTERT expression. Our results also suggest that induction of p21 and subsequent disturbance of Bax/Bcl-2 balanced ratio as well as decreased telomerase activity may be rational mechanisms for the potent/direct short-term cytotoxicity of high doses of BIBR1532 against NB4 cells. PMID- 22236192 TI - Secreted clusterin in colon tumor cell models and its potential as diagnostic marker for colorectal cancer. AB - We studied the specific changes of the secreted protein clusterin and its cytoplasmic precursor regarding colorectal tumorigenesis, using in vitro differentiation of Caco-2 cells. In tumor-like stage, we observed an overexpression of both precursor and secreted clusterin, corroborated in the cell line SW-480. Noticeably, SW-620 cells (from a tumoral node, thus with metastatic capacity) did not show overexpression of either precursor or secreted clusterin, suggesting a downregulation related to local metastasis. We further investigated clusterin in serum, finding a significant increase in colorectal cancer patients, with 81% sensitivity, 79% specificity, and an area under the ROC curve of 0.85. PMID- 22236191 TI - CEA and CA19.9 as early predictors of progression in advanced/metastatic colorectal cancer patients receiving oxaliplatin-based chemotherapy and bevacizumab. AB - We evaluated the changes of the tumor markers CEA and CA19.9 as early predictors of progression in metastatic colorectal cancer (mCRC) patients participating in a clinical study and receiving chemotherapy and bevacizumab (Bev). Seventy-two patients had high baseline CEA or CA19.9 serum levels. By ROC analyses, the areas under the curves were 0.83 for variable CEA cutoff values for distinguishing progressive disease (PD) versus stable disease (SD)/partial remission (PR)/complete remission (CR), and 0.80 for variable CA19.9 cutoff values for distinguishing PD versus SD/PR/CR. Rises in CEA and CA19.9 may early signal the occurrence of progression in mCRC patients receiving chemotherapy and Bev. PMID- 22236189 TI - Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. AB - Glioblastoma multiforme (GBM) is the most malignant and aggressive type of brain tumor with an average life expectancy of less than 15 months. This is mostly due to the highly mutated genome of GBM, which is characterized by the deregulation of many key signaling pathways involving growth, proliferation, survival, and apoptosis. It is critical to explore novel diagnostic and therapeutic strategies that target these pathways to improve the treatment of malignant glioma in the future. This review summarizes the most common and important pathways that are highly mutated or deregulated in GBM and discusses potential therapeutic strategies targeting these pathways. PMID- 22236193 TI - Prognostic significance of SOX2 expression in nasopharyngeal carcinoma. AB - The significance of SOX2 in nasopharyngeal carcinoma (NPC), a tumor associated with Epstein-Barr virus (EBV), remains unclear. Here, we reported that, in the univariate analysis, SOX2 expression was correlated with a poorer distant metastasis-free survival (DMFS). The EBV-VCA/IgA titers in patients with NPC were also associated with a poorer overall survival (OS). Patients with NPC, who had both strong staining of SOX2 and high titers of EBV-VCA/IgA, had the poorest prognoses. Therefore, SOX2 or the combination of the SOX2 expression level and EBV-VCA/IgA titers could be valuable to predict distant metastasis or the prognosis of NPC. PMID- 22236195 TI - All heat, no light--the states' Medicaid claims before the Supreme Court. PMID- 22236194 TI - Preliminary evidence for biologic activity of toceranib phosphate (Palladia((r))) in solid tumours. AB - The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia(r), Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity. PMID- 22236197 TI - The fate of health care reform--what to expect in 2012. PMID- 22236199 TI - Tissue-specific differences in inflammatory infiltrate and matrix metalloproteinase expression in adipose tissue and liver of mice with diet induced obesity. AB - AIM: While low grade inflammation persists in both visceral fat and hepatic tissue in obesity, these changes often result in progressive disease and fibrosis only in the liver and not in adipose tissue. We hypothesized that a tissue specific difference in obesity-induced inflammatory cell infiltrate may be responsible for such organ difference in susceptibility to fibrosis. METHODS: Mice were fed either standard chow or a high fat diet over 19 weeks. Hepatic steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. Immunohistochemistry staining for macrophage subsets and quantitative reverse transcription-polymerase chain reaction for matrix metalloproteinase (MMP)- and fibrosis-related gene expression was performed in paired livers and visceral (epididymal) fat pads at early (9 weeks) and advanced (19 weeks) stages of progressive diet-induced obesity. RESULTS: Up to 19 weeks of high fat feeding led to the development of obesity and hepatic steatosis, as well as increased gene expression of Mmp12, Mmp13 and Timp1 in predominantly adipose tissue, and to a lesser extent of liver tissue. In contrast to visceral fat, cell counts for macrophages as well as profibrogenic gene signaling in liver tissue during development of diet-induced obesity remained largely unchanged. CONCLUSIONS: Development of diet-induced obesity in the mouse increased inflammatory macrophages counts in adipose tissue rather than the liver. This was associated with greater increases in MMP expression in adipose tissue compared with liver. We propose that attenuated hepatic MMP expression in livers and adipose tissue of obese mice shifts the balance of fibrogenesis/fibrolysis and predispose the liver to development of fibrosis. PMID- 22236198 TI - Concise and highly stereoselective synthesis of the C20-C26 building block of halichondrins and Eribulin. AB - A concise, stereoselective, and scalable synthesis of the C20-C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective S(N)2' substitution, and selective conversion of a C-Si to C-I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20 C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1. PMID- 22236196 TI - Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. AB - BACKGROUND: Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. METHODS: We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. RESULTS: Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cgamma(2) (PLCgamma(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37 degrees C but enhanced signaling at subphysiologic temperatures. CONCLUSIONS: Genomic deletions in PLCG2 cause gain of PLCgamma(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.). PMID- 22236200 TI - Is tamoxifen alone adequate therapy in very young Chinese women with operable breast cancer? AB - Breast cancer occurs earlier in Chinese women than in Caucasian women. We have compared the clinicopathologic characteristics and prognosis in very young and older premenopausal women with breast cancer in south China. We separated 905 consecutive premenopausal patients with first diagnosis of breast cancer, surgically treated at the Sun Yat-sen University Cancer Center from October 2003 to December 2006, into a very young group (189 [13.7%]; <35 years old) and an older group (716 [52.0%]; 35-57 years old). Approximately, 90% of patients received adjuvant chemotherapy and hormonal therapy with tamoxifen for hormone receptor (HR)-positive breast cancer. We retrospectively compared the clinicopathologic factors and survival rates of these two groups. The 3-year disease-free survival rate (78.0% versus 89.1%, p < 0.001) was poorer in the very young group, and 3-year overall survival rate (94.3% versus. 96.8%, p = 0.10) was similar. Moreover, the 3-year overall survival rate (p = 0.020) and disease-free survival rate (p < 0.001) were significantly poorer in HR-positive patients in the very young group whereas there was no significant difference in outcomes between the HR-negative groups. In China, age younger than 35 years is an independent predictor of breast cancer recurrence. In very young women with HR positive breast cancer, chemotherapy plus tamoxifen alone may not be adequate standard treatment. PMID- 22236202 TI - Thymidine kinase assay in canine lymphoma. AB - The aim of the study was to evaluate if thymidine kinase (TK) correlated with duration of first remission (DFR) or survival in dogs with lymphoma and if initial TK levels correlated with stage and substage; and also to assess if TK level at diagnosis correlated with immunophenotype. TK was assayed in 73 dogs with treatment naive lymphoma, then again after treatment; 47% had an initial TK above the reference interval. Dogs with B-cell lymphoma had higher initial TK activities than dogs with T-cell lymphoma. TK levels were not higher in dogs with higher stage disease and TK activity prior to treatment was not associated with DFR or survival. Where TK was elevated at diagnosis, it fell into the reference range during remission. TK was normal in 53% dogs at diagnosis, which is higher than previously reported. Further studies are warranted to assess the utility of TK in dogs with lymphoma. PMID- 22236201 TI - Genetic characterization of HIV type 1 Tat exon 1 from a southern Indian clinical cohort: identification of unique epidemiological signature residues. AB - The trans-activator of transcription (Tat) of HIV-1 plays an important role in viral infection and pathogenesis. We examined the genetic characteristics of exon 1 of the tat gene derived from 102 seropositive subjects from southern India. Database-derived Indian (n=105) and global (n=413) HIV-1C sequences were also used for viral epidemiological signature pattern analysis in the Tat open reading frame (ORF). We identified HIV-1C as the most predominant genetic subtype (99%) and the presence of a novel A1C recombinant strain in one study participant. After examining all the available HIV-1C Indian sequences from primary clinical isolates and database-derived sequences, we found a high level of sequence conservation (92.6 +/- 12%) within Tat amino acid residues. Furthermore, signature pattern analysis identified five amino acid positions in Tat that contained signature residues unique for Indian HIV-1C consisting of 21A, 24N, 29K, 40K, and 60Q. Our data have direct relevance for subunit-based Tat HIV-1 vaccine development. PMID- 22236203 TI - Captivating titles and award-winning labels to promote premium products of microbiology. PMID- 22236204 TI - Coronary artery fistula with giant aneurysm. PMID- 22236205 TI - Performers' responses to stressors encountered in sport organisations. AB - We investigated athletes' responses to organisational stressors. Ten sport performers (five males and five females) were interviewed with regard to the organisational-related demands they had encountered and their responses to these stressors. The main emotional responses that were revealed were anger, anxiety, disappointment, distress, happiness, hope, relief, reproach and resentment. The main attitudinal responses were beliefs, motivation and satisfaction. The main behavioural responses were categorised as verbal and physical. The data indicate that performers generally respond to organisational stressors with a wide range of emotions, attitudes and behaviours. The findings are discussed in relation to the extant literature and in terms of their implications for applied practice and future research. Consultants should employ reactive strategies alongside proactive approaches to ensure that performers are psychologically prepared to manage and cope with any demands that are not eliminated. Future research should focus on performers' cognitive appraisals of the organisational stressors they encounter. PMID- 22236206 TI - A critical tyrosine residue determines the uncoupling protein-like activity of the yeast mitochondrial oxaloacetate carrier. AB - The mitochondrial Oac (oxaloacetate carrier) found in some fungi and plants catalyses the uptake of oxaloacetate, malonate and sulfate. Despite their sequence similarity, transport specificity varies considerably between Oacs. Indeed, whereas ScOac (Saccharomyces cerevisiae Oac) is a specific anion-proton symporter, the YlOac (Yarrowia lipolytica Oac) has the added ability to transport protons, behaving as a UCP (uncoupling protein). Significantly, we identified two amino acid changes at the matrix gate of YlOac and ScOac, tyrosine to phenylalanine and methionine to leucine. We studied the role of these amino acids by expressing both wild-type and specifically mutated Oacs in an Oac-null S. cerevisiae strain. No phenotype could be associated with the methionine to leucine substitution, whereas UCP-like activity was dependent on the presence of the tyrosine residue normally expressed in the YlOac, i.e. Tyr-ScOac mediated proton transport, whereas Phe-YlOac lost its protonophoric activity. These findings indicate that the UCP-like activity of YlOac is determined by the tyrosine residue at position 146. PMID- 22236207 TI - Proteomic analysis of formalin-fixed, paraffin-embedded melanoma. PMID- 22236208 TI - Multicenter randomized clinical trial: early loading of implants in maxillary bone. AB - PURPOSE: The aim of this study was to show prognostic equivalence between implant loading in the maxilla after 12 weeks versus 4 weeks. MATERIALS AND METHODS: One hundred four patients, from four centers in this open-labeled randomized multicenter prospective controlled clinical trial, were assigned to either 12 weeks or 4 weeks of unloaded healing. Two hundred sixty-nine implants (sand blasted large-grid, acid etched [SLA] surface, >= 4.1 mm diameter; >= 10 mm length) were inserted and evaluated during an individual 5-year follow-up. Primary outcome was implant success after 12 months; prognostic equivalence was characterized by a maximum difference of +/- 5% in implant failure rates. RESULTS: Implant-wise 1-year failure rates were estimated 3.1% (5/163 implants) in the 4 weeks group versus 3.6% (4/112 implants) in the 12 weeks group (95% confidence interval [CI] for the difference -3.2 -+4.2%); implant-wise evaluation demonstrated statistically significant prognostic equivalence of 4 and 12 weeks loading. Patient-wise 1-year failure rates were estimated 6.7% (n = 4 patients) in the 4 weeks group versus 5.1% (n = 2 patients) in the 12 weeks group (95% CI for the difference -9.6 -+6.5%). All implant failures occurred within the first 3 months of the individual observation period. Prior bone augmentation, underdimensioned drilling, bone quality, implant type, implant length, implant diameter, residual teeth, and fixing of the restoration did not reveal associations with the implant outcome: trial site, posterior jaw region, and splinting were associated with a higher failure rate. Resonance frequency analysis did not serve as a predictor of implant failures at the time of implant insertion. CONCLUSION: Loading of standard SLA implants in the maxilla 4 weeks versus 12 weeks after insertion resulted in statistically equivalent failure patterns within a 1-year follow-up period; nevertheless, the observed patient wise failure patterns of the interim analysis requires further understanding of patient-individual aspects of the early loading concept. PMID- 22236209 TI - Assessing trends and predictors of tuberculosis in Taiwan. AB - BACKGROUND: Variety of environmental and individual factors can cause tuberculosis (TB) incidence change. The purpose of this study was to assess the characteristics of TB trends in the period 2004 - 2008 in Taiwan by month, year, gender, age, temperature, seasonality, and aborigines. METHODS: The generalized regression models were used to examine the potential predictors for the monthly TB incidence in regional and national scales. RESULTS: We found that (i) in Taiwan the average TB incidence was 68 per 100,000 population with mortality rate of 0.036 person-1 yr-1, (ii) the highest TB incidence rate was found in eastern Taiwan (116 per 100,000 population) with the largest proportion of TB relapse cases (8.17%), (iii) seasonality, aborigines, gender, and age had a consistent and dominant role in constructing TB incidence patterns in Taiwan, and (iv) gender, time trend, and 2-month lag maximum temperature showed strong association with TB trends in aboriginal subpopulations. CONCLUSIONS: The proposed Poisson regression model is capable of forecasting patterns of TB incidence at regional and national scales. This study suggested that assessment of TB trends in eastern Taiwan presents an important opportunity for understanding the time-series dynamics and control of TB infections, given that this is the typical host demography in regions where these infections remain major public health problems. PMID- 22236211 TI - Post-natal anaemia and iron deficiency in HIV-infected women and the health and survival of their children. AB - Prenatal iron supplementation may improve pregnancy outcomes and decrease the risk of child mortality. However, little is known about the importance of post natal maternal iron status for child health and survival, particularly in the context of HIV infection. We examined the association of maternal anaemia and hypochromic microcytosis, an erythrocyte morphology consistent with iron deficiency, with child health and survival in the first two to five years of life. Repeated measures of maternal anaemia and hypochromic microcytosis from 840 HIV-positive women enrolled in a clinical trial of vitamin supplementation were prospectively related to child mortality, HIV infection and CD4 T-cell count. Median duration of follow-up for the endpoints of child mortality, HIV infection and CD4 cell count was 58, 17 and 23 months, respectively. Maternal anaemia and hypochromic microcytosis were associated with greater risk of child mortality [hazard ratio (HR) for severe anaemia = 2.58, 95% confidence interval (CI): 1.66 4.01, P trend < 0.0001; HR for severe hypochromic microcytosis = 2.36, 95% CI: 1.27-4.38, P trend = 0.001]. Maternal anaemia was not significantly associated with greater risk of child HIV infection (HR for severe anaemia = 1.46, 95% CI: 0.91, 2.33, P trend = 0.08) but predicted lower CD4 T-cell counts among HIV uninfected children (difference in CD4 T-cell count/uL for severe anaemia: -93, 95% CI: -204-17, P trend = 0.02). The potential child health risks associated with maternal anaemia and iron deficiency may not be limited to the prenatal period. Efforts to reduce maternal anaemia and iron deficiency during pregnancy may need to be expanded to include the post-partum period. PMID- 22236212 TI - Increased survival and reduced renal injury in MRL/lpr mice treated with a human Fcgamma receptor II (CD32) peptide. AB - Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease affecting many organs. The deposition in kidney tissue of immune complexes and their interaction with macrophages is thought to trigger the inflammatory response leading to glomerulonephritis. It has been demonstrated that inhibition of this interaction in murine models can alleviate the disease. Six synthetic peptides were derived from the membrane-proximal extracellular domain (EC2) of human Fcgamma receptor II (huFcgammaRII). Of these, one peptide, huRII6, was shown to be a potent competitive inhibitor of IgG binding to recombinant FcgammaRII in vitro. To examine the possible therapeutic impact of huRII6 in vivo, this peptide, or a control, was given by subcutaneous injection to female MRL/lpr mice from weeks 7 to 36, resulting in an enhanced survival rate compared with control-treated animals and a reduction of proteinuria. Histopathological examination of the kidneys showed a reduction in deposition of immune complexes and preservation of structure. Such a functional peptide should prove useful for examining the role of IgG-FcgammaR interactions in experimental models of disease and may provide for the development of FcR-targeting drugs to treat autoimmune disorders. PMID- 22236213 TI - Toxicity of the essential oil of Illicium difengpi stem bark and its constituent compounds towards two grain storage insects. AB - During our screening program for new agrochemicals from Chinese medicinal herbs, the essential oil of Illicium difengpi stem bark was found to possess strong insecticidal activities against the maize weevil, Sitophilus zeamais (Motschulsky) (Coleoptera: Curculionidae) and red flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae). A total of 37 components of the essential oil of I. difengpi were identified. The main components of the essential oil were safrole (23.61%), linalool (12.93%), and germacrene D (5.35%). Bioactivities-directed chromatographic separation on repeated silica gel columns led to the isolation of two compounds: safrole and linalool. Safrole showed pronounced contact toxicity against both insect species and (LD50 = 8.54 for S. zeamais; 4.67 ug/adult for T. castaneum) and was more toxic than linalool (LD50 = 24.88 for S. zeamais; 8.12 ug/adult for T. castaneum). The essential oil acting against the two species of insects showed LD50 values of 13.83 and 6.33 ug/adult, respectively. Linalool also possessed strong fumigant toxicity against both insect species (LC50 = 10.02 for S. zeamais; 9.34 mg/L for T. castaneum) and was more toxic than safrole (LD50 = 32.96 and 38.25 mg/L), while the crude essential oil acting against the two species of insects showed LC50 values of 14.62 and 16.22 mg/L, respectively. These results suggest that the essential oil of I. difengpi stem bark and the two compounds may be used in grain storage to combat insect pests. PMID- 22236216 TI - Co-occurrence of sexual risk behaviors and substance use across emerging adulthood: evidence for state- and trait-level associations. AB - AIMS: Prior research has suggested that problematic alcohol and drug use are related to risky sexual behaviors, either due to trait-level associations driven by shared risk factors such as sensation seeking or by state-specific effects, such as the direct effects of substance use on sexual behaviors. Although the prevalence of both high-risk sexual activity and alcohol problems decline with age, little is known about how the associations between substance use disorder symptoms and high-risk sexual behaviors change across young adulthood. DESIGN, SETTING AND PARTICIPANTS: Using a community sample (n = 790) interviewed every 3 years from age 21 to age 30 years, we tested trait- and state-level associations among symptoms of alcohol and drug abuse and dependence and high risk sexual behaviors across young adulthood using latent growth curve models. MEASUREMENTS: We utilized diagnostic interviews to obtain self-report of past year drug and alcohol abuse and dependence symptoms. High-risk sexual behaviors were assessed with a composite of four self-reported behaviors. FINDINGS: Results showed time-specific associations between alcohol disorder symptoms and risky sexual behaviors (r = 0.195, P < 0.001), but not associations between their trajectories of change. Conversely, risky sexual behaviors and drug disorder symptoms were associated only at the trait level, not the state level, such that the levels and rate of change over time of both were correlated (r = 0.35, P < 0.001). CONCLUSIONS: High-risk sexual behaviors during young adulthood seem to be driven both by trait and state factors, and intervention efforts may be successful if they are either aimed at high-risk individuals or if they work to disaggregate alcohol use from risky sexual activities. PMID- 22236217 TI - Stereophotogrammetric analysis of nasolabial morphology among Asian Malays: influence of age and sex. AB - OBJECTIVE: It is clear that population-specific norms should be used when planning plastic and reconstructive surgery for selected patients. In this study, we aimed to generate nasal and labial reference values by applying a stereophotogrammetric technique. A further aim was to investigate the effect of sexual dimorphism, age-related changes, and the interrelation between nasal and labial morphology. DESIGN: Cross-sectional study. SETTING: The data were collected from different locations on the Malaysian peninsula. PARTICIPANTS: A total of 276 Asian Malays (138 males and 138 females) were included in this study, and a three-dimensional system was used for capturing data. The sample was divided into three age groups: 13 to 14, 15 to 17, and 18 to 36 years. MAIN OUTCOME MEASURE(S): Twenty-five dimensions of the nose and lips were measured and analyzed separately in males and females. RESULTS: Significant differences between males and females were identified in 11 distances, and significant effects of age were found in most of the dimensions (p < .05). Significant correlations between the nasal and labial dimensions were recorded, particularly between lateral lip height and width of the ala insertion. A principal component analysis showed interrelationships between the nasal width distances and upper lip height. CONCLUSION: This study has provided a new three-dimensional database for nose and lip morphology in Malays and demonstrated patterns of variation that can be used by surgeons to make comparisons within and between different human populations and also to develop treatment plans for their patients. PMID- 22236218 TI - Description of a new Capillariinae (Nematoda: Trichuridae) from Scapteromys aquaticus (Cricetidae: Sigmodontinae) from Buenos Aires, Argentina. AB - A new species of Capillaria is described on the basis of specimens recovered from the intestine of the swamp rat Scapteromys aquaticus (Cricetidae: Sigmodontinae) from Argentina. Capillaria alainchabaudi n. sp. and a peculiar species from Australian marsupials are the only 2 species of Capillaria sensu stricto parasitic in mammals. A comparison with the Australian species and with the 18 species of this genus described from other vertebrates from the Western Hemisphere is given. The separation of the new species is based on morphologic and morphometrical features, such as intestine ending in cloaca beside ejaculatory duct, 2 lateral nonmembranous caudal lobes, 2 pairs of caudal non pedunculated papillae, terminal part of cylindrical cirrus ornamented with thin and thick spines, spicule with apex not well sclerotized in the males, a conspicuous vulvar appendage in the females, and 2 bacillary bands. A survey of the literature revealed that the species of Capillariinae from rodents belong to 9 genera, and the total number of species is low compared to the high diversity and abundance of the hosts, particularly if the modern Muroidea are considered. PMID- 22236220 TI - The blame frame: media attribution of culpability about the MMR-autism vaccination scare. AB - Scholars have examined how news media frame events, including responsibility for causing and fixing problems, and how these frames inform public judgment. This study analyzed 281 newspaper articles about a controversial medical study linking the measles, mumps, and rubella (MMR) vaccination with autism. Given criticism of the study and its potential negative impact on vaccination rates across multiple countries, the current study examined actors to whom news media attributed blame for the MMR-vaccine association, sources used to support those attributions, and what solutions (e.g., mobilizing information), if any, were offered. This study provides unique insight by examining the evolution of these attributions over the lifetime of the controversy. Findings emphasize how news media may attribute blame in health risk communication and how that ascription plays a potentially vital role in shaping public behavior. Theoretical and practical implications are discussed. PMID- 22236219 TI - Mild reaction conditions for the terminal deuteration of alkynes. AB - Routinely employed syntheses of terminally deuterated alkynes often utilize strong bases (i.e., LDA, n-BuLi, or Grignard reagents) or low (i.e., -78 degrees C) or elevated (i.e., 56 degrees C) reaction temperatures; furthermore many of these procedures afford average yields and in some cases less than optimum deuterium incorporation. Herein we report the application of alternative extremely mild reaction conditions that readily afford quantitative yields of terminally deuterated alkynes in a matter of minutes with exceptional isotope incorporation at ambient temperature. PMID- 22236221 TI - Outcome of 19 dogs with parathyroid carcinoma after surgical excision. AB - Parathyroid carcinoma (PTC) is rare in dogs and there is little information documenting its treatment and prognosis. The objective of this study was to describe the outcome of dogs with PTC treated with surgical excision. Medical records of 19 dogs undergoing surgical excision of PTC between 1990 and 2010 were reviewed retrospectively. Dogs were presented for clinical hypercalcaemia or incidental hypercalcaemia noted by referring veterinarians on routine serum chemistry profiles. A parathyroid nodule was identified with cervical ultrasound in 17/17 dogs. Hypercalcaemia resolved in 18/19 dogs within 4 days postoperatively. Nine developed hypocalcaemia. None were confirmed to develop recurrent or metastatic PTC. The only death associated with PTC was a dog that was euthanized for intractable hypocalcaemia 9 days after surgery. Estimated 1-, 2- and 3-year survival rates were 72, 37 and 30%, respectively. Excision of PTC results in resolution of hypercalcaemia and excellent tumour control. PMID- 22236223 TI - Cardiac arrest during long-distance running races. AB - BACKGROUND: Approximately 2 million people participate in long-distance running races in the United States annually. Reports of race-related cardiac arrests have generated concern about the safety of this activity. METHODS: We assessed the incidence and outcomes of cardiac arrest associated with marathon and half marathon races in the United States from January 1, 2000, to May 31, 2010. We determined the clinical characteristics of the arrests by interviewing survivors and the next of kin of nonsurvivors, reviewing medical records, and analyzing postmortem data. RESULTS: Of 10.9 million runners, 59 (mean [+/-SD] age, 42-13 years; 51 men) had cardiac arrest (incidence rate, 0.54 per 100,000 participants; 95% confidence interval [CI], 0.41 to 0.70). Cardiovascular disease accounted for the majority of cardiac arrests. The incidence rate was significantly higher during marathons (1.01 per 100,000; 95% CI, 0.72 to 1.38) than during half marathons (0.27; 95% CI, 0.17 to 0.43) and among men (0.90 per 100,000; 95% CI, 0.67 to 1.18) than among women (0.16; 95% CI, 0.07 to 0.31). Male marathon runners, the highest-risk group, had an increased incidence of cardiac arrest during the latter half of the study decade (2000-2004, 0.71 per 100,000 [95% CI, 0.31 to 1.40]; 2005-2010, 2.03 per 100,000 [95% CI, 1.33 to 2.98]; P=0.01). Of the 59 cases of cardiac arrest, 42 (71%) were fatal (incidence, 0.39 per 100,000; 95% CI, 0.28 to 0.52). Among the 31 cases with complete clinical data, initiation of bystander-administered cardiopulmonary resuscitation and an underlying diagnosis other than hypertrophic cardiomyopathy were the strongest predictors of survival. CONCLUSIONS: Marathons and half-marathons are associated with a low overall risk of cardiac arrest and sudden death. Cardiac arrest, most commonly attributable to hypertrophic cardiomyopathy or atherosclerotic coronary disease, occurs primarily among male marathon participants; the incidence rate in this group increased during the past decade. PMID- 22236224 TI - Germline mutations in HOXB13 and prostate-cancer risk. AB - BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate cancer susceptibility gene. METHODS: We screened more than 200 genes in the 17q21 22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS: Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.). PMID- 22236226 TI - Clinical practice. Hidradenitis suppurativa. PMID- 22236225 TI - Fitness memberships and favorable selection in Medicare Advantage plans. AB - BACKGROUND: Because Medicare Advantage plans must pay for covered services, they may design insurance benefits to appeal to healthier beneficiaries. METHODS: We identified 11 Medicare Advantage plans that offered new fitness-membership benefits in 2004 or 2005 and matched these plans to 11 Medicare Advantage control plans that did not offer coverage for fitness memberships. Using a difference-in differences approach, we compared the self-reported health status of persons who enrolled after the fitness benefit was added to the plan with the self-reported health status of persons entering the same plan before the fitness benefit was offered. RESULTS: The proportion of enrollees reporting excellent or very good health was 6.1 percentage points higher (95% confidence interval [CI], 2.6 to 9.7) among the 755 new enrollees in plans that added fitness benefits than among the 4097 earlier enrollees. The proportion of new enrollees reporting activity limitation was 10.4 percentage points lower (95% CI, 6.6 to 14.3) and the proportion reporting difficulty walking was 8.1 percentage points lower (95% CI, 4.4 to 11.7), as compared with earlier enrollees. Within control plans, the differences between the 1154 new enrollees and the 3910 earlier enrollees were 1.5 percentage points or less for each measure. The adjusted differences between the fitness-benefit plans and the control plans were 4.7 percentage points higher for general health (95% CI, 0.2 to 9.2), 9.2 percentage points lower for activity limitation (95% CI, 5.1 to 13.3), and 7.4 percentage points lower for difficulty walking (95% CI, 4.5 to 10.4). These differences persisted at 2 years for activity limitation and difficulty walking. CONCLUSIONS: Medicare Advantage plans offering coverage for fitness memberships may attract and retain a healthier subgroup of the Medicare population. (Funded by the National Institute on Aging.). PMID- 22236227 TI - Images in clinical medicine. Paragonimiasis. PMID- 22236228 TI - Case records of the Massachusetts General Hospital. Case 1-2012. An 82-year-old man with persistent ulcers on the hands. PMID- 22236222 TI - Subclinical atrial fibrillation and the risk of stroke. AB - BACKGROUND: One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. METHODS: We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. RESULTS: By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. CONCLUSIONS: Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT ClinicalTrials.gov number, NCT00256152.). PMID- 22236229 TI - How much atrial fibrillation is too much atrial fibrillation? PMID- 22236230 TI - Diet and intestinal immunity. PMID- 22236231 TI - Acute coronary thrombosis in Boston marathon runners. PMID- 22236233 TI - An impedance threshold device in out-of-hospital cardiac arrest. PMID- 22236234 TI - An impedance threshold device in out-of-hospital cardiac arrest. PMID- 22236236 TI - Breast-cancer adjuvant therapy with zoledronic acid. PMID- 22236238 TI - Breast-cancer screening. PMID- 22236239 TI - Breast-cancer screening. PMID- 22236240 TI - Breast-cancer screening. PMID- 22236242 TI - Inflammatory bowel disease and ADAM17 deletion. PMID- 22236243 TI - Generalizing lung-cancer screening results. PMID- 22236244 TI - Images in clinical medicine. Jugular venous C-V wave in severe tricuspid regurgitation. PMID- 22236247 TI - 'Quake brain': coping with the series of earthquakes in Christchurch. PMID- 22236248 TI - Nurses' conception of patients' family participation in any psychiatric set up: important facts. PMID- 22236246 TI - Age-related changes in oxidative capacity differ between locomotory muscles and are associated with physical activity behavior. AB - There is discrepancy in the literature regarding the degree to which old age affects muscle bioenergetics. These discrepancies are likely influenced by several factors, including variations in physical activity (PA) and differences in the muscle group investigated. To test the hypothesis that age may affect muscles differently, we quantified oxidative capacity of tibialis anterior (TA) and vastus lateralis (VL) muscles in healthy, relatively sedentary younger (8 YW, 8 YM; 21-35 years) and older (8 OW, 8 OM; 65-80 years) adults. To investigate the effect of physical activity on muscle oxidative capacity in older adults, we compared older sedentary women to older women with mild-to-moderate mobility impairment and lower physical activity (OIW, n = 7), and older sedentary men with older active male runners (OAM, n = 6). Oxidative capacity was measured in vivo as the rate constant, k(PCr), of postcontraction phosphocreatine recovery, obtained by (31)P magnetic resonance spectroscopy following maximal isometric contractions. While k(PCr) was higher in TA of older than activity-matched younger adults (28%; p = 0.03), older adults had lower k(PCr) in VL (23%; p = 0.04). In OIW compared with OW, k(PCr) was lower in VL (~45%; p = 0.01), but not different in TA. In contrast, OAM had higher k(PCr) than OM (p = 0.03) in both TA (41%) and VL (54%). In older adults, moderate-to-vigorous PA was positively associated with k(PCr) in VL (r = 0.65, p < 0.001) and TA (r = 0.41, p = 0.03). Collectively, these results indicate that age-related changes in oxidative capacity vary markedly between locomotory muscles, and that altered PA behavior may play a role in these changes. PMID- 22236249 TI - Performance characteristics of a conformal ultra-wideband multilayer applicator (CUMLA) for hyperthermia in veterinary patients: a pilot evaluation of its use in the adjuvant treatment of non-resectable tumours. AB - Performance and clinical characteristics of a novel hyperthermia antenna operating at 434 MHz were evaluated for the adjuvant treatment of locally advanced superficial tumours in cats, dogs and horses. Electromagnetic simulations were performed to determine electric field characteristics and compared to simulations for a flat microwave antenna with similar dimensions. Simulation results show a reduced skin surface and backfield irradiation and improved directional irradiation (at broadside) compared to a flat antenna. Radiated power and penetration is notably increased with a penetration depth of 4.59 cm compared to 2.74 cm for the flat antenna. Clinical use of the antenna was then evaluated in six animals with locoregionally advanced solid tumours receiving adjuvant chemotherapy. During clinical applications, therapeutic temperatures were achieved at depths >=4 cm. Objective responses were seen in all patients; tissue toxicity in one case limited further therapy. This antenna provides compact, efficient, focused and deep-penetrating clinical hyperthermia for the treatment of solid tumours in veterinary patients. PMID- 22236250 TI - Exploring activity cliffs in medicinal chemistry. PMID- 22236251 TI - Creative cross-organizational collaboration: coming to a project near you. AB - Historically, the pharmaceutical industry has provided investors with robust growth and patients with a range of life-enhancing treatments; academic institutions conducted early-stage research largely supported by the government; disease foundations funded projects in their areas of interest; and venture capital built exciting new startups with bold ambitions. Today, those institutions are all facing scientific, economic and operating challenges. As a result, they are experimenting with new organizational and funding models. We consider some of those models in the life sciences in general, as well as in the development and delivery of novel regenerative medicines. In particular, the changing roles of the venture capital and disease foundation communities are considered in the context of academic and commercial collaborations. PMID- 22236252 TI - Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA. AB - AIMS: To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. METHODS: Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. RESULTS: All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. CONCLUSIONS: Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE. PMID- 22236254 TI - Amino-modified and lipid-conjugated dicer-substrate siRNA enhances RNAi efficacy. AB - The development of Dicer-substrate small interfering RNAs (DsiRNAs) has been pursued in recent years because these molecules exhibit a much more potent gene silencing effect than 21-nucleotide (nt) siRNAs. In the present study, we designed eight different types of amino-modified DsiRNAs and a palmitic acid conjugated DsiRNA expected to result in improved biological properties of siRNAs, including their stability against nuclease degradation, membrane permeability, and RNAi efficacy. The DsiRNAs were modified with an amine at the 5'- and/or 3' end of the sense and/or antisense strand. Dicer enzyme cleaved most of the amino modified DsiRNAs to lead to the release of 21-nt siRNA; some of them, however, were not or partly cleaved. All amino-modified DsiRNAs exhibited strong resistance against nuclease degradations. Among the amino-modified DsiRNAs, the DsiRNA modified with an amine restricted at the 3'-end of the sense strand showed the most enhanced gene-silencing effect and maintained its potent gene suppression after one week of cell transfection against Renilla luciferase activity. For further improvement, palmitic acid was conjugated to DsiRNA at the 3'-end of the sense strand (C16-DsiRNA) to facilitate the membrane permeability and potent gene-silencing activity. The C16-DsiRNA showed enhanced membrane permeability to HeLa cells. The C16-DsiRNA exhibited extremely high inhibition of Renilla luciferase activity. PMID- 22236253 TI - Identifying work ability promoting factors for home care aides and assistant nurses. AB - BACKGROUND: In workplace health promotion, all potential resources needs to be taken into consideration, not only factors relating to the absence of injury and the physical health of the workers, but also psychological aspects. A dynamic balance between the resources of the individual employees and the demands of work is an important prerequisite. In the home care services, there is a noticeable trend towards increased psychosocial strain on employees at work. There are a high frequency of work-related musculoskeletal disorders and injuries, and a low prevalence of sustainable work ability. The aim of this research was to identify factors promoting work ability and self-efficacy in care aides and assistant nurses within home care services. METHODS: This study is based on cross-sectional data collected in a municipality in northern Sweden. Care aides (n = 58) and assistant nurses (n = 79) replied to a self-administered questionnaire (response rate 46%). Hierarchical multiple regression analyses were performed to assess the influence of several independent variables on self-efficacy (model 1) and work ability (model 2) for care aides and assistant nurses separately. RESULTS: Perceptions of personal safety, self-efficacy and musculoskeletal wellbeing contributed to work ability for assistant nurses (R2adj of 0.36, p < 0.001), while for care aides, the safety climate, seniority and age contributed to work ability (R2adj of 0.29, p = 0.001). Self-efficacy was associated with the safety climate and the physical demands of the job in both professions (R2adj of 0.24, p = 0.003 for care aides), and also by sex and age for the assistant nurses (R2adj of 0.31, p < 0.001). CONCLUSIONS: The intermediate factors contributed differently to work ability in the two professions. Self-efficacy, personal safety and musculoskeletal wellbeing were important for the assistant nurses, while the work ability of the care aides was associated with the safety climate, but also with the non-changeable factors age and seniority. All these factors are important to acknowledge in practice and in further research. Proactive workplace interventions need to focus on potentially modifiable factors such as self efficacy, safety climate, physical job demands and musculoskeletal wellbeing. PMID- 22236256 TI - The roles of climate, phylogenetic relatedness, introduction effort, and reproductive traits in the establishment of non-native reptiles and amphibians. AB - We developed a method to predict the potential of non-native reptiles and amphibians (herpetofauna) to establish populations. This method may inform efforts to prevent the introduction of invasive non-native species. We used boosted regression trees to determine whether nine variables influence establishment success of introduced herpetofauna in California and Florida. We used an independent data set to assess model performance. Propagule pressure was the variable most strongly associated with establishment success. Species with short juvenile periods and species with phylogenetically more distant relatives in regional biotas were more likely to establish than species that start breeding later and those that have close relatives. Average climate match (the similarity of climate between native and non-native range) and life form were also important. Frogs and lizards were the taxonomic groups most likely to establish, whereas a much lower proportion of snakes and turtles established. We used results from our best model to compile a spreadsheet-based model for easy use and interpretation. Probability scores obtained from the spreadsheet model were strongly correlated with establishment success as were probabilities predicted for independent data by the boosted regression tree model. However, the error rate for predictions made with independent data was much higher than with cross validation using training data. This difference in predictive power does not preclude use of the model to assess the probability of establishment of herpetofauna because (1) the independent data had no information for two variables (meaning the full predictive capacity of the model could not be realized) and (2) the model structure is consistent with the recent literature on the primary determinants of establishment success for herpetofauna. It may still be difficult to predict the establishment probability of poorly studied taxa, but it is clear that non-native species (especially lizards and frogs) that mature early and come from environments similar to that of the introduction region have the highest probability of establishment. PMID- 22236257 TI - Characterization of particulate emissions from municipal wastewater sludge incinerators. PMID- 22236255 TI - Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition. AB - CypD (cyclophilin D) has been established as a critical regulator of the MPT (mitochondrial permeability transition) pore, and pharmacological or genetic inhibition of CypD attenuates MPT in numerous systems. However, it has recently been suggested that the inhibitory effects of CypD inhibition only manifest when P(i) (inorganic phosphate) is present, and that inhibition is lost when P(i) is replaced by As(i) (inorganic arsenate) or V(i) (inorganic vanadate). To test this, liver mitochondria were isolated from wild-type and CypD-deficient (Ppif-/ ) mice and then incubated in buffer containing P(i), As(i) or V(i). MPT was induced under both energized and de-energized conditions by the addition of Ca2+, and the resultant mitochondrial swelling was measured spectrophotometrically. For pharmacological inhibition of CypD, wild-type mitochondria were pre-incubated with CsA (cyclosporin A) before the addition of Ca2+. In energized and de energized mitochondria, Ca2+ induced MPT regardless of the anion present, although the magnitude differed between P(i), As(i) and V(i). However, in all cases, pre-treatment with CsA significantly inhibited MPT. Moreover, these effects were independent of mouse strain, organ type and rodent species. Similarly, attenuation of Ca2+-induced MPT in the Ppif-/- mitochondria was still observed irrespective of whether P(i), As(i) or V(i) was present. We conclude that the pharmacological and genetic inhibition of CypD is still able to attenuate MPT even in the absence of P(i). PMID- 22236258 TI - Removal of trace chlorinated organic compounds by activated carbon and fixed-film bacteria. PMID- 22236260 TI - Modification of pollutant hydrolysis kinetics in the presence of humic substances. PMID- 22236259 TI - Rates and temperature dependences of the reaction of hydroxyl radical with isoprene, its oxidation products, and selected terpenes. PMID- 22236261 TI - Kinetics of decomposition of tetrathionate, trithionate, and thiosulfate in alkaline media. PMID- 22236262 TI - A photoreactor for investigations of the degradation of particle-bound polycyclic aromatic hydrocarbons under simulated atmospheric conditions. PMID- 22236264 TI - Copper(II) complexing capacities of natural waters by fluorescence quenching. PMID- 22236263 TI - Nitrated polycyclic aromatic hydrocarbons in urban air particles. PMID- 22236265 TI - Distribution of selected gaseous organic mutagens and suspect carcinogens in ambient air. PMID- 22236266 TI - Ozone-precursor relationships from EKMA diagrams. PMID- 22236267 TI - Gas chromatography/mass spectrometry identification of organic volatiles contributing to rendering odors. PMID- 22236268 TI - Correction. Accumulation by fish of contaminants released from dredged sediments. PMID- 22236270 TI - Associations between oxidative parameters in pregnancy and birth anthropometry in a cohort of women and children in rural Bangladesh: the MINIMat-cohort. AB - Oxidative stress is suggested as a potential mechanism in impaired foetal growth, smaller birth size and thus subsequently adult chronic diseases. We have investigated associations between oxidative stress in pregnancy and birth anthropometry (weight, height, head and chest circumferences). In the MINIMat trial (Maternal and Infant Nutrition Interventions, Matlab) in rural Bangladesh, free 8-iso-prostaglandin F(2alpha) (lipid peroxidation) was analysed in pregnancy week 14 and 30 and 8-Hydroxy-2 -Deoxyguanosine (DNA oxidation) in week 19. We found that higher levels of lipid peroxidation in early pregnancy were associated with larger infant size (birth length and chest circumference). In late pregnancy, no clear pattern of associations was found. Increasing level of DNA oxidation was associated with lower birth length in girls but no other associations were found. In conclusion, a higher level of lipid peroxidation in early (but not late) pregnancy was associated with a favourable larger birth size suggesting that timing of lipid peroxidation is of importance. PMID- 22236271 TI - The cleft-columellar angle: a useful variable to describe the unilateral cleft lip-associated nasal deformity. AB - Objective : To study a method for quantification of the severity of either the unilateral cleft lip deformity or the associated cleft nasal deformity. A standard method would be useful for defining surgical outcomes. Design : Using a developed rating questionnaire and patient photographs, 26 nonexpert volunteers rated 14 children with untreated unilateral cleft lip according to the severity of their overall deformity, as well as the individual lip and nose deformities. The cleft-columellar angle was measured as defined by the intersection of a line in the parasagittal plane and a line perpendicular to the columellar base along the midcolumellar line. The association between deformity ratings and the cleft columellar angle was modeled using mixed-model regression analysis. Setting : Tertiary care academic medical center. Results : After accounting for within rater and within-child effects, the cleft-columellar angle explained a statistically significant portion of the variance in the rated severity for lip deformity (49%, p = .0012), nasal deformity (57%, p = .0001), and overall deformity (57%, p = .0005). Conclusions : Measurement of the cleft-columellar angle in two-dimensional digital photography is simple and correlative, capturing a substantial portion of nonexpert severity ratings of the constellation of deformities seen with the unilateral cleft lip deformity. Given its ease of application, the cleft-columellar angle is a useful variable in the description of the unilateral cleft lip deformity and may find utility across institutions as cleft surgeons seek to advance surgical care through outcomes research. PMID- 22236273 TI - Organic peracids: a structural puzzle for 17O NMR and ab initio chemical shift calculations. AB - We have applied (17)O NMR spectroscopy to investigate the structure of the organic peracids formed by reaction of acetic acid (AA) or lactic acid (LA) with aqueous hydrogen peroxide (HP), which are used in several "green chemistry" applications. The interpretation of the experimental spectra has been supported by ab initio calculations of the (17)O chemical shifts for several possible species, using a continuum representation of the solvent. The combined use of these tools has also allowed us to discuss the decomposition mechanism of LA/HP solutions. The calculated electric field gradients for water, HP, and CO(2) (a decomposition product of LA) correlate well with the experimental (17)O line widths. PMID- 22236274 TI - A new species of Pterygodermatites (Nematoda: Rictulariidae) from the Incan shrew opossum, Lestoros inca. AB - Pterygodermatites ( Paucipectines ) hymanae n. sp. (Rictulariidae) collected from the Incan shrew opossum, Lestoros inca , from Peru is described herein. These nematodes show a subapical, slightly dorsal oral opening and a laterally compressed buccal capsule with 2 conspicuous lateral walls and a dorsal wall. Each lateroventral wall possesses 4 relatively large denticles, and the dorsal wall has 6 denticles. Females are characterized by a conspicuously large postvulvar 37th spine, which may reach 1 mm. This is the first record of endoparasites in the Incan shrew opossum and the fifth species of Pterygodermatites recorded in New World marsupials. PMID- 22236275 TI - "Above the influence": how college students communicate about the healthy deviance of alcohol abstinence. AB - Consumption of alcohol is widespread in U.S. culture, particularly among college students. Using a communication privacy management framework ( Petronio, 2002 ), this study examined how college students who abstain from alcohol negotiate communication of their nondrinking status and establish meaning in a culture in which drinking is the norm. Through 25 face-to-face interviews, this article explores the experiences of "healthy deviants"-individuals who engage in healthy behavior that violates traditional norms. Interviews identified that participants relied on privacy rules when determining whether and how to disclose their nondrinking status. If participants perceived more costs from the disclosure than rewards, they did not disclose. Participants enacted specific strategies to manage (non)disclosure of their abstinence from alcohol, providing practical ways for people who engage in healthy deviance to avoid or manage stigma. PMID- 22236276 TI - Highly efficient and stereoselective construction of dispiro-[oxazolidine-2 thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles. AB - An efficient and stereoselective reaction between 3-isothiocyanato oxindoles and isatins/isatinimines has been developed to afford structurally diverse dispiro[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2 thione]bisoxindoles in excellent results under mild conditions. The potential of asymmetric induction by means of a chiral auxiliary was explored. The isomers are separable, and products could be isolated as single diastereomers by column chromatography. Further synthetic transformations of the reaction product were also successfully realized. PMID- 22236277 TI - Phenology drives mutualistic network structure and diversity. AB - Several network properties have been identified as determinants of the stability and complexity of mutualistic networks. However, it is unclear which mechanisms give rise to these network properties. Phenology seems important, because it shapes the topology of mutualistic networks, but its effects on the dynamics of mutualistic networks have scarcely been studied. Here, we study these effects with a general dynamical model of mutualistic and competitive interactions where the interaction strength depends on the temporal overlap between species resulting from their phenologies. We find a negative complexity-stability relationship, where phenologies maximising mutualistic interactions and minimising intraguild competitive interactions generate speciose, nested and poorly connected networks with moderate asymmetry and low resilience. Moreover, lengthening the season increases diversity and resilience. This highlights the fragility of real mutualistic communities with short seasons (e.g. Arctic environments) to drastic environmental changes. PMID- 22236279 TI - Current status of canine cancer registration - report from an international workshop. AB - This is a report from a workshop on canine cancer registration hosted at the Norwegian School of Veterinary Science in Oslo in August 2010. The aim is to present a summary of the current efforts to gather data on canine (and feline) cancer based on information from participants at the workshop. A definition and classification of cancer registries is provided together with an inventory of the databases presented. Particular focus is placed on the distinction between population-based and hospital-based cancer registries. Future challenges are discussed and issues relating to harmonization of diagnostic coding, defining the population-at-risk, individual animal identification and data quality are included. Finally, other groups working within the field of cancer registration in companion animals are encouraged to contact the authors for future collaboration. PMID- 22236278 TI - Multi-level analysis of alcohol-related injury and drinking pattern: emergency department data from 19 countries. AB - Aim While drinking in the event is an important factor in injury occurrence, the pattern of usual drinking may also be important in risk of injury. Explored here is the relationship of an alcohol-related injury with an individual usual drinking pattern. Design Alcohol-related injury is examined using hierarchical linear models, taking into account individual usual volume of consumption over the past 12 months, as well as aggregate-level detrimental drinking pattern (DDP) and alcohol policy measures. Setting Data analyzed are from emergency departments (EDs) in 19 countries, comprising three collaborative studies on alcohol and injury, all of which used a similar methodology. Participants The sample comprised 14 132 injured drinkers across 46 emergency room (ER) studies. Measurements Alcohol-related injury was measured, separately, by any self reported drinking prior to injury, a blood alcohol concentration (BAC) >= 0.08 and self-reported causal attribution of injury to drinking. Findings While individual usual volume strongly predicted an alcohol-related injury for all three measures, usual drinking pattern also predicted an alcohol-related injury (controlling for volume), with episodic heavy and frequent heavy drinking both more predictive of alcohol-related injury than other drinking patterns. When individual usual volume and drinking pattern were controlled, DDP was no longer a significant predictor of alcohol-related injury. Alcohol policy measures were predictive of both BAC and causal attribution (the stronger the policy the lower the rates of alcohol-related injury). Conclusions Volume of alcohol typically consumed and occurrence of heavy drinking episodes are associated independently with incidence of alcohol-related injury. The stronger the anti-alcohol policies in a country, the lower the rates of alcohol-related injury. PMID- 22236280 TI - Elevated serum thymidine kinase activity in canine splenic hemangiosarcoma*. AB - Thymidine kinase 1 (TK1) is a soluble biomarker associated with DNA synthesis. This prospective study evaluated serum TK1 activity in dogs presenting with hemoabdomen and a splenic mass. An ELISA using azidothymidine as a substrate was used to evaluate TK1 activity. Sixty-two dogs with hemoabdomen and 15 normal controls were studied. Serum TK1 activity was significantly higher in dogs with hemangiosarcoma (HSA) than in normal dogs (mean +/- SEM = 17.0 +/- 5.0 and 2.01 +/- 0.6, respectively), but not dogs with benign disease (mean +/- SEM = 10.0 +/- 3.3). Using a cut-off of 6.55 U/L, TK activity demonstrated a sensitivity of 0.52, specificity of 0.93, positive predictive value of 0.94 and negative predictive value of 0.48 for distinguishing HSA versus normal. When interval thresholds of <1.55 and >7.95 U/L were used together, diagnostic utility was increased. Serum TK1 evaluation may help to discriminate between benign disease and HSA in dogs with hemoabdomen and a splenic mass. PMID- 22236281 TI - Association of hypoalbuminemia with severe anemia in patients with diabetic nephrosclerosis. AB - BACKGROUND: Anemia in patients with early diabetes mellitus nephrosclerosis (DMN) is more severe than in patients with kidney disease of other origins, and the mechanism for this remains unclear. In this study, we carried out a retrospective study in order to identify the factors associated with anemia in patients with DMN. METHODS: To elucidate the factors that influence the severity of anemia in patients with DMN, we carried out a retrospective follow-up study of 124 biopsy proven DMN cases [mean (SE) age, 55.3 (1.2) years; range, 18-78 years; male/female, 80/44]. First, a cluster analysis was performed using red blood cell counts and hemoglobin (Hb) and hematocrit levels. We then divided the clusters with regard to renal prognosis and survival and carried out simple and multifactorial analysis of clinical data, including the body mass index, age, systolic blood pressure (BP), diastolic BP, duration after the diagnosis of diabetes mellitus, serum albumin levels, blood urea nitrogen (BUN) concentrations, serum creatinine concentrations, the estimated glomerular filtration rate (eGFR) validated in the Japanese population, iron levels, total cholesterol levels, triglyceride levels, fasting blood sugar levels, HbA1c levels, urinary protein secretion, and pathohistological parameters. RESULTS: The factors that were significantly associated with the cluster group that showed severe anemia were sex (p = 0.0162), hypoalbuminemia (p < 0.0001), high BUN concentrations (p = 0.0020), low eGFR (p = 0.0104), and Kimmelstiel-Wilson nodules (p = 0.0022). In addition, hypoalbuminemia (p = 0.0277), high BUN concentrations (p = 0.0338), and a low eGFR (p = 0.0417) were significantly associated with this group in a multifactorial analysis. CONCLUSION: Our data strongly suggest that hypoalbuminemia is associated with severe anemia in DMN patients. PMID- 22236282 TI - Delta9-tetrahydrocannabinol (Delta9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease. AB - AIMS: Delta9-tetrahydrocannabinol (Delta9-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Delta9-THC. METHODS: Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. RESULTS: We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Delta9-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants alpha-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Delta9-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Delta9-THC, while the PPARgamma agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Delta9-THC increased PPARgamma expression in MPP+ treated SH-SY5Y cells, another indicator of PPARgamma activation. CONCLUSIONS: We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Delta9-THC that may be mediated through PPARgamma activation. PMID- 22236283 TI - Use of vitamin and mineral supplements in long-term care home residents. AB - Vitamin-mineral supplementation may offer older adults health and cognition related benefits but overuse may contribute to polypharmacy. We examined the prevalence of supplement usage in long-term care facility (LTC) residents (>= 65 years of age). As cognition may be affected by nutrition, we also examined use in those with diagnosis of dementia and those with no dementia diagnosis. The prevalence of supplement usage and overall "pill count" from pharmaceutical use was assessed in 189 LTC residents and a subsample of 56 older adults with dementia diagnosis, respectively. Participants were residing in an LTC facility of a mid-size metropolitan area during 2009. The average use of supplements was 1.0 per day for all residents, with 35% taking vitamin D supplements, 20% multivitamins, and 26% calcium. Supplement use was similar (p >= 0.05) for those with dementia diagnosis (53%, average 2.0 per day) and for those without such diagnosis (45%, average 2.2 per day). Usage ranged between 1-6 supplements per day. In both of these groups, ~73% of users were taking vitamin D. The number of prescribed medications ranged from 4 to 24 (average 10.2) in a subsample of residents whose supplement intake was 0 to 6 (average 2). These findings suggest an overall low rate of supplement use, with no significant differences (p >= 0.05) in use between residents with and without dementia diagnosis. However, some residents were at risk for supplement overuse. PMID- 22236284 TI - Glucose tolerance is affected by visceral adiposity and sex, but not birth weight, in Yucatan miniature pigs. AB - Epidemiological studies have linked small birth weight and lack of breastfeeding to type 2 diabetes mellitus. This study aimed to determine if (i) small birth weight promotes and (ii) suckling prevents the development of adiposity and diabetes biomarkers in a Yucatan miniature pig model. At 3 days of age, the intrauterine growth-restricted (IUGR) piglet (n = 6) was paired with a normal weight (NW), same-sex littermate (n = 6) and fed milk replacer for 4 weeks. A sow fed normal weight littermate (n = 6) was also compared with the NW littermate to assess the effects of suckling. All pigs were fed a standard diet ad libitum for 5 h.day(-1) from week 4. At 9.5 months, pigs underwent intravenous glucose tolerance (IVGTT) and insulin sensitivity tests (IST). At 10 months, tissues were harvested for fat analysis and pancreas histology. IUGR pigs demonstrated compensatory growth before sexual maturity and had greater subcutaneous fat depth; birth weight also negatively correlated with visceral fat content. Visceral and subcutaneous adiposity were greater in females than males. IVGTT and IST outcomes were not different due to birth weight or suckling. However, visceral adiposity was associated with several glucose tolerance outcomes and females were more glucose intolerant due to their greater adiposity. Pancreas insulin content or histology outcomes were not different. This model did not develop markers of type 2 diabetes mellitus because of small birth weight or formula feeding. However, visceral adiposity and sex were associated with glucose intolerance, which is consistent with data in humans. PMID- 22236285 TI - Measuring sunscreen protection against solar-simulated radiation-induced structural radical damage to skin using ESR/spin trapping: development of an ex vivo test method. AB - The in vitro star system used for sunscreen UVA-testing is not an absolute measure of skin protection being a ratio of the total integrated UVA/UVB absorption. The in vivo persistent-pigment-darkening method requires human volunteers. We investigated the use of the ESR-detectable DMPO protein radical adduct in solar-simulator-irradiated skin substitutes for sunscreen testing. Sunscreens SPF rated 20+ with UVA protection, reduced this adduct by 40-65% when applied at 2 mg/cm(2). SPF 15 Organic UVA-UVB (BMDBM-OMC) and TiO(2)-UVB filters and a novel UVA-TiO(2) filter reduced it by 21, 31 and 70% respectively. Conventional broad-spectrum sunscreens do not fully protect against protein radical-damage in skin due to possible visible-light contributions to damage or UVA-filter degradation. Anisotropic spectra of DMPO-trapped oxygen-centred radicals, proposed intermediates of lipid-oxidation, were detected in irradiated sunscreen and DMPO. Sunscreen protection might be improved by the consideration of visible-light protection and the design of filters to minimise radical leakage and lipid-oxidation. PMID- 22236286 TI - Validation of an LC-MS/MS method to determine five immunosuppressants with deuterated internal standards including MPA. AB - BACKGROUND: Therapeutic drug monitoring of immunosuppressive drugs in organ transplanted patients is crucial to prevent intoxication or transplant rejection due to inadequate dosage. The commonly used immunoassays have been gradually undergoing replacement by mass spectrometry, since this physical method offers both a higher sensitivity and specificity. However, a switch should be carefully considered because it is a challenging procedure and needs to be thoroughly validated. From an economic perspective it is reasonable to include mycophenolic acid into the assay, because this saves the necessity for an additional measurement. However, to date very few validation protocols for the measurement of immunosuppressants, including mycophenolic acid, are available. In order to adequately compensate for matrix effects, the use of stable isotope labeled internal standards is advisable. Here, the authors describe a single method suitable for the quantification of cyclosporine A, tacrolimus, sirolimus, everolimus and mycophenolic acid, based on deuterated internal standards. METHODS: Plasma proteins were precipitated with zinc-sulfate, followed by an online solid phase extraction in the flow-through direction. Chromatographic separation was performed by a c18-phenyl-hexyl column. For subsequent mass spectrometric analysis stable-isotope-labeled internal standards were used. Results were available after 3.5 minutes. RESULTS: Low quantification limits (accuracy: 104 - 118%) and linearity resulted in 2 -1250 ng/ml for cyclosporine A; 0.5 - 42.2 ng/ml for tacrolimus; 0.6 - 49.2 ng/ml for sirolimus; 0.5 - 40.8 ng/ml for everolimus and 0.01 - 7.5 MUg/ml for mycophenolic acid. Intra-assay precision revealed a coefficient of variation (CV) of 0.9 - 14.7%, with an accuracy of 89 - 138%. The CV of inter-assay precision was 2.5 - 12.5%, with an accuracy of 90 - 113%. Recovery ranged from 76.6 to 84%. Matrix effects were well compensated by deuterated internal standards. CONCLUSIONS: The authors present a fast, economical and robust method for routine therapeutic drug monitoring comprising five immunosuppressants including mycophenolic acid. PMID- 22236287 TI - Catalytic activity control of restriction endonuclease--triplex forming oligonucleotide conjugates. AB - Targeting of individual genes in complex genomes requires endonucleases of extremely high specificity. To direct cleavage at the unique site(s) in the genome, both naturally occurring and artificial enzymes have been developed. These include homing endonucleases, zinc-finger nucleases, transcription activator-like effector nucleases, and restriction or chemical nucleases coupled to a triple-helix forming oligonucleotide (TFO). The desired cleavage has been demonstrated both in vivo and in vitro for several model systems. However, to limit cleavage strictly to unique sites and avoid undesired reactions, endonucleases with controlled activity are highly desirable. In this study we present a proof-of-concept demonstration of two strategies to generate restriction endonuclease-TFO conjugates with controllable activity. First, we combined the restriction endonuclease caging and TFO coupling procedures to produce a caged MunI-TFO conjugate, which can be activated by UV-light upon formation of a triple helix. Second, we coupled TFO to a subunit interface mutant of restriction endonuclease Bse634I which shows no activity due to impaired dimerization but is assembled into an active dimer when two Bse634I monomers are brought into close proximity by triple helix formation at the targeted site. Our results push the restriction endonuclease-TFO conjugate technology one step closer to potential in vivo applications. PMID- 22236289 TI - Editorial. But Dad, how will you get to work? PMID- 22236291 TI - Letters. Phosphorus in runoff. PMID- 22236290 TI - Letters. Filtration theory. PMID- 22236293 TI - Outlook. PMID- 22236292 TI - Environmental currents. PMID- 22236294 TI - Air pollution affects community health. PMID- 22236295 TI - Curtailing pollution from metal finishing. PMID- 22236296 TI - Conference on science in the control of smog. PMID- 22236297 TI - Formation of hydrocarbons and oxides of nitrogen in automobile engines. PMID- 22236298 TI - Characterization of particulate matter in vehicle exhaust. PMID- 22236299 TI - Chemical element balances and identification of air pollution sources. PMID- 22236300 TI - Growth mechanisms and size spectra of photochemical aerosols. PMID- 22236301 TI - Vertical distribution of photochemical smog in Los Angeles basin. PMID- 22236303 TI - Industry trends. PMID- 22236302 TI - Mathematical modeling of urban air pollution. General theory. PMID- 22236305 TI - New literature. PMID- 22236308 TI - Unleashing the Nation's Nurse Practitioners. PMID- 22236309 TI - Leveraging health information technology and health information management in rural america: a health summit commentary. PMID- 22236307 TI - Blood-borne macrophage-neural cell interactions hitchhike on endosome networks for cell-based nanozyme brain delivery. AB - BACKGROUND: Macrophage-carried nanoformulated catalase ('nanozyme') attenuates neuroinflammation and protects nigrostriatal neurons from 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine intoxication. This is facilitated by effective enzyme transfer from blood-borne macrophages to adjacent endothelial cells and neurons leading to the decomposition of reactive oxygen species. MATERIALS & METHODS: We examined the intra- and inter-cellular trafficking mechanisms of nanozymes by confocal microscopy. Improved neuronal survival mediated by nanozyme-loaded macrophages was demonstrated by fluorescence-activated cell sorting. RESULTS: In macrophages, nanozymes were internalized mainly by clathrin-mediated endocytosis then trafficked to recycling endosomes. The enzyme is subsequently released in exosomes facilitated by bridging conduits. Nanozyme transfer from macrophages to adjacent cells by endocytosis-independent mechanisms diffusing broadly throughout the recipient cells. In contrast, macrophage-free nanozymes were localized in lysosomes following endocytic entry. CONCLUSION: Facilitated transfer of nanozyme from cell to cell can improve neuroprotection against oxidative stress commonly seen during neurodegenerative disease processes. PMID- 22236310 TI - Differences in readiness between rural hospitals and primary care providers for telemedicine adoption and implementation: findings from a statewide telemedicine survey. AB - PURPOSE: Published advantages of and challenges with telemedicine led us to examine the scope of telemedicine adoption, implementation readiness, and barriers in a southern state where adoption has been historically low. We hypothesized that rural hospitals and primary care providers (RPCPs) differ on adoption, readiness, and implementation barriers. We examined the degree to which they differ on (a) telemedicine adoption or readiness; (b) telemedicine training needs; (c) current use of technology for patient care; and (d) environmental concerns in facilities for telemedicine. METHODS: Paper surveys were sent to rural hospitals and RPCPs with response rates of 50% (n = 38) and 25.9% (n = 339), respectively. Three of 4 hospitals were represented. Chi-square analyses were used to test for differences between rural hospitals and RPCPs. FINDINGS: Compared to RPCPs, rural hospitals were significantly more likely to report higher rates of telemedicine knowledge (P= .0007); planning for or implementing telemedicine (P < .0001); and reporting their disaster recovery data systems (P= .0002) and availability and location of outlets and connections (P= .03) as adequate for telemedicine. Rural hospitals were less likely to report having no telemedicine education needs (P= .04). CONCLUSIONS: Telemedicine continues to be a viable solution for bridging geographic access gaps to a variety of specialty care. Users need assistance in understanding legal implications, care coordination, billing for services, and disaster data recovery. In rural areas, hospitals appear to best embody characteristics of facilities that successfully implement telemedicine and have the greatest degree of readiness. PMID- 22236311 TI - The adoption and use of health information technology in rural areas: results of a national survey. AB - CONTEXT: Health information technology (HIT) is a national policy priority. Knowledge about the special needs, if any, of rural health care providers should be taken into account as policy is put into action. Little is known, however, about rural-urban differences in HIT adoption at the national level. PURPOSE: To conduct the first national assessment of HIT in rural primary care offices, with particular attention to electronic medical record (EMR) adoption, range of capabilities in use, and plans for adoption. METHODS: A national mail survey of 5,200 primary care offices, stratified by rurality using Rural-Urban Commuting Area categories, was conducted in 2007-2008. Regression analyses were used to assess the relationship between office characteristics and EMR adoption, capabilities used, and future adoption plans. RESULTS: A commercial EMR system was present in 31% of offices, with no significant differences by rurality. Of offices with EMRs, 12% reported using a full range of EMR capabilities, with 51% using a basic range and 37% using less than the basic range. Large Rural (adjusted OR = 3.71, P= .022) and Small Rural (aOR = 3.75, P= .049) offices were more likely than Urban offices to use a broader range of EMR capabilities. Among offices without EMRs, those in Isolated areas were less likely to have more immediate plans to adopt (aOR = 0.19, P= .02). CONCLUSIONS: HIT adoption and use in rural primary care offices does not appear to be lower than in urban offices. The situation, however, is dynamic and warrants further monitoring. PMID- 22236312 TI - Factors influencing electronic clinical information exchange in small medical group practices. AB - PURPOSE: The purpose of this study was to identify the organizational factors that influence electronic health information exchange (HIE) by medical group practices in rural areas. METHODS: A purposive sample of 8 small medical group practices in 3 experimental HIE regions were interviewed to determine the extent of clinical information exchange with other health care providers and to identify the factors influencing those patterns. FINDINGS: HIE was found to be largely limited to exchanging immunization data through the state health department and exchanging clinical information within owned provider systems. None of the clinics directly exchange clinical information with non-owned clinics or hospitals. CONCLUSIONS: While regional HIE networks may be a laudable goal, progress is slow and significant technical, political, and financial obstacles remain. Limiting factors include data protection concerns, competition among providers, costs, and lack of compatible electronic health record (EHR) systems. PMID- 22236313 TI - EMRs and clinical IS implementation in hospitals: a statewide survey. AB - PURPOSE: Present an overview of clinical information systems (IS) in hospitals and analyze the level of electronic medical records (EMR) implementation in relation to clinical IS capabilities and organizational characteristics. METHODS: We developed a survey instrument measuring clinical IS implementation and classified clinical IS across 5 EMR levels. The survey was administered to hospitals in a state with a large number of rural hospitals (84% response rate). FINDINGS: Clinical IS were classified across 5 EMR levels, a useful approach for understanding the gaps in clinical IS in hospitals. Almost half (43%) of hospitals in Iowa were at EMR Level 0, with at least 1 of the ancillary systems still absent; 12% were at Level 1 with all 3 ancillary systems in place; 16% were at Level 2 corresponding to an early EMR system; 18% were at Level 3 corresponding to an intermediate EMR system; and 10% were at Level 4 corresponding to an advanced EMR system. In contrast, 22% had no plans for EMR implementation at all. EMR level was lower in critical access hospitals and positively associated with more slack resources and staffed beds. Over a 3-year period, there were increases in ancillary systems and clinical documentation implementation. CONCLUSIONS: The survey performed well. There was agreement with published estimates of EMR penetration, sensitivity to change over time, and association with known organizational factors. It is well designed and can be used to map onto a comprehensive classification scheme capturing the EMR level and evaluating progress toward meaningful use. PMID- 22236314 TI - Development and testing of emergency department patient transfer communication measures. AB - PURPOSE: Communication problems are a major contributing factor to adverse events in hospitals.(1) The contextual environment in small rural hospitals increases the importance of emergency department (ED) patient transfer communication quality. This study addresses the communication problems through the development and testing of ED quality measurement of interfacility patient transfer communication. METHODS: Input from existing measures, measurement and health care delivery experts, as well as hospital frontline staff was used to design and modify ED quality measures. Three field tests were conducted to determine the feasibility of data collection and the effectiveness of different training methods and types of partnerships. Measures were evaluated based on their prevalence, ease of data collection, and usefulness for internal and external improvement. FINDINGS: It is feasible to collect ED quality measure data. Different data sources, data collection, and data entry methods, training and partners can be used to examine hospital ED quality. There is significant room for improvement in the communication of patient information between health care facilities. CONCLUSION: Current health care reform efforts highlight the importance of clear communication between organizations held accountable for patient safety and outcomes. The patient transfer communication measures have been tested in a wide range of rural settings and have been vetted nationally. They have been endorsed by the National Quality Forum, are included in the National Quality Measurement Clearinghouse supported by the Agency for Health Care Research and Quality (AHRQ), and are under consideration by the Centers for Medicare and Medicaid Services for future payment determinations beginning in calendar year 2013. PMID- 22236315 TI - Is distance to provider a barrier to care for medicaid patients with breast, colorectal, or lung cancer? AB - PURPOSE: Distance to provider might be an important barrier to timely diagnosis and treatment for cancer patients who qualify for Medicaid coverage. Whether driving time or driving distance is a better indicator of travel burden is also of interest. METHODS: Driving distances and times from patient residence to primary care provider were calculated for 3,917 breast, colorectal (CRC) and lung cancer Medicaid patients in Washington State from 1997 to 2003 using MapQuest.com. We fitted regression models of stage at diagnosis and time-to treatment (number of days between diagnosis and surgery) to test the hypothesis that travel burden is associated with timely diagnosis and treatment of cancer. FINDINGS: Later stage at diagnosis for breast cancer Medicaid patients is associated with travel burden (OR = 1.488 per 100 driving miles, P= .037 and OR = 1.270 per driving hour, P= .016). Time-to-treatment after diagnosis of CRC is also associated with travel burden (14.57 days per 100 driving miles, P= .002 and 5.86 days per driving hour, P= .018). CONCLUSIONS: Although travel burden is associated with timely diagnosis and treatment for some types of cancer, we did not find evidence that driving time was, in general, better at predicting timeliness of cancer diagnosis and treatment than driving distance. More intensive efforts at early detection of breast cancer and early treatment of CRC for Medicaid patients who live in remote areas may be needed. PMID- 22236316 TI - Receipt of cancer screening services: surprising results for some rural minorities. AB - BACKGROUND: Evidence suggests that rural minority populations experience disparities in cancer screening, treatment, and outcomes. It is unknown how race/ethnicity and rurality intersect in these disparities. The purpose of this analysis is to examine the cancer screening rates among minorities in rural areas. METHODS: We utilized the 2008 Behavioral Risk Factor Surveillance System (BRFSS) to examine rates of screening for breast, cervical, and colorectal cancer. Bivariate analysis estimated screening rates by rurality and sociodemographics. Multivariate analysis estimated the factors that contributed to the odds of screening. RESULTS: Rural residents were less likely to obtain screenings than urban residents. African Americans were more likely to be screened than whites or Hispanics. Race/ethnicity and rurality interacted, showing that African American women continued to be more likely than whites to be screened for breast or cervical cancer, but the odds decreased with rurality. CONCLUSIONS: This analysis confirmed previous research which found that rural residents were less likely to obtain cancer screenings than other residents. We further found that the pattern of disparity differed according to race/ethnicity, with African Americans having favorable odds of receipt of service regardless of rurality. These results have the potential to create better targeted interventions to those groups that continue to be underserved. PMID- 22236318 TI - Does the universal health insurance program affect urban-rural differences in health service utilization among the elderly? Evidence from a longitudinal study in taiwan. AB - PURPOSE: To assess the impact of the introduction of Taiwan's National Health Insurance (NHI) on urban-rural inequality in health service utilization among the elderly. METHODS: A longitudinal data set of 1,504 individuals aged 65 and older was constructed from the Survey of Health and Living Status of the Elderly. A difference-in-differences model was employed and estimated by the random-effect probit method. FINDING: The introduction of universal NHI in Taiwan heterogeneously affected outpatient and inpatient health service utilization among the elderly in urban and rural areas. The introduction of NHI reduced the disparity of outpatient (inpatient) utilization between the previously uninsured and insured older urban residents by 12.9 (22.0) percentage points. However, there was no significant reduction in the utilization disparity between the previously uninsured and insured elderly among rural residents. CONCLUSIONS: Our study on Taiwan's experience should provide a valuable lesson to countries that are in an initial stage of proposing a universal health insurance system. Although NHI is designed to ensure the equitable right to access health care, it may result in differential impacts on health service utilization among the elderly across areas. The rural elderly tend to confront more challenges in accessing health care associated with spatial distance, transportation, social isolation, poverty, and a lack of health care providers, especially medical specialists. PMID- 22236317 TI - Prevalence estimates of health risk behaviors of immigrant latino men who have sex with men. AB - PURPOSE: Little is known about the health status of rural immigrant Latino men who have sex with men (MSM). These MSM comprise a subpopulation that tends to remain "hidden" from both researchers and practitioners. This study was designed to estimate the prevalence of tobacco, alcohol, and drug use, and sexual risk behaviors of Latino MSM living in rural North Carolina. METHODS: A community based participatory research (CBPR) partnership used respondent-driven sampling (RDS) to identify, recruit, and enroll Latino MSM to participate in an interviewer-administered behavioral assessment. RDS-weighted prevalence of risk behaviors was estimated using the RDS Analysis Tool. Data collection occurred in 2008. RESULTS: A total of 190 Latino MSM was reached; the average age was 25.5 years and nearly 80% reported being from Mexico. Prevalence estimates of smoking everyday and past 30-day heavy episodic drinking were 6.5% and 35.0%, respectively. Prevalence estimates of past 12-month marijuana and cocaine use were 56.0% and 27.1%, respectively. Past 3-month prevalence estimates of sex with at least one woman, multiple male partners, and inconsistent condom use were 21.2%, 88.9%, and 54.1%, respectively. CONCLUSIONS: Respondents had low rates of tobacco use and club drug use, and high rates of sexual risk behaviors. Although this study represents an initial step in documenting the health risk behaviors of immigrant Latino MSM who are part of a new trend in Latino immigration to the southeastern United States, a need exists for further research, including longitudinal studies to understand the trajectory of risk behavior among immigrant Latino MSM. PMID- 22236319 TI - Adoption and perceived effectiveness of financial improvement strategies in critical access hospitals. AB - PURPOSE: To ascertain the use and perceived success of strategies to improve the financial performance of Critical Access Hospitals (CAHs). METHODS: Information about the use and perceived effectiveness of 44 specific strategies to improve financial performance was collected from an online survey of 291 CAH Chief Executive Officers and Chief Financial Officers. Responses were merged with financial and operational characteristics of the respondents' hospitals obtained from Medicare cost reports. Use rates and perceived success and failure were calculated for each strategy. A cluster analysis was applied to classify strategies based on their use and success. Finally, CAH characteristics were examined to predict the use of individual strategies. FINDINGS: Financial improvement strategies are pervasive among CAHs. The administrators who responded to the survey in this study reported using an average of 17.0 of the maximum 44 strategies listed in the survey questionnaire. Revenue/cost, human resource, and capital strategies were more frequently used than service expansion and reduction strategies. Overall, CAH characteristics did not explain the use or perceived success of specific strategies, but they did partially predict the number of strategies attempted. CONCLUSIONS: CAH administrators have used multiple strategies to improve financial performance with a wide variety of reported success. More research into the effectiveness of specific interventions is needed to help administrators select evidence-based strategies. PMID- 22236320 TI - Complementary and alternative medicine in rural communities: current research and future directions. AB - CONTEXTS: The consumption of complementary and alternative medicine (CAM) in rural areas is a significant contemporary health care issue. An understanding of CAM use in rural health can provide a new perspective on health beliefs and practice as well as on some of the core service delivery issues facing rural health care generally. PURPOSE: This article presents the first review and synthesis of research findings on CAM use and practice in rural communities. METHODS: A comprehensive search of literature from 1998 to 2010 in CINAHL, MEDLINE, AMED, and CSA Illumina (social sciences) was conducted. The search was confined to peer-reviewed articles published in English reporting empirical research findings on the use or practice of CAM in rural settings. FINDINGS: Research findings are grouped and examined according to 3 key themes: "prevalence of CAM use and practice,""user profile and trends of CAM consumption," and "potential drivers and barriers to CAM use and practice." CONCLUSIONS: Evidence from recent research illustrates the substantial prevalence and complexity of CAM use in rural regions. A number of potential gaps in our understanding of CAM use and practice in rural settings are also identified. PMID- 22236321 TI - Identification of 23 novel MHC class I alleles in cynomolgus macaques of Philippine and Philippine/Mauritius origins. AB - We report here novel Mafa-A, -AG and -B alleles identified in two groups of cynomolgus macaques. PMID- 22236322 TI - A new Haemocystidium (Apicomplexa: Plasmodiidae) species of the dhub lizard, Uromastyx aegyptia microlepis , in Abu Dhabi, distinguished by the absence of pigment. AB - The spiny-tailed lizard, Uromastyx aegyptia microlepis , in Abu Dhabi is parasitized by Haemocystidium apigmentada n. sp., and 2 species of Hepatozoon . The elongate gametocytes of H. apigmentada are 13-19 * 6-9 um, with length * width (LW) 90-133 um(2), and L/W ratio 1.56-3.17. Gametocyte dimensions do not differ by sex. Gametocytes are unpigmented. Hepatozoon species 1 has gamonts with a consistently terminal nucleus, with dimensions of 13-16 * 4.5-7 um, LW of 58 104 um(2), and L/W ratio of 2.00-3.22. Hepatozoon species 2 gamonts have a broad nucleus at the midbody, and dimensions of 13-15.5 * 5-7 um, LW of 71-109 um(2), and L/W ratio of 1.93-3.00. PMID- 22236323 TI - Oral health-related quality of life in children with orofacial clefts. AB - Objectives : To determine the impact of orofacial clefts on the oral health related quality of life of affected children and whether the oral health-related quality of life of children with orofacial clefts differs among different age groups. To assess whether the responses of children with orofacial clefts differ from the caregivers' perceptions of their child's oral health-related quality of life and compare with data from a control group. Design : Cross-sectional study. Patients/Setting : A total of 75 subjects with cleft lip and/or cleft palate (mean age, 13.0 years) from the Nationwide Children's Hospital Craniofacial Anomalies Clinic, as well as their caregivers, and 75 control subjects (mean age, 13.9 years). Main Outcome Measure : Self-reported oral health-related quality of life measured with the Child Oral Health Impact Profile, a reliable and valid questionnaire designed for use with children and teenagers. Results : Children with orofacial clefts had statistically significant lower quality of life scores than control subjects had for overall oral health-related quality of life, Functional Well-being, and Social Emotional Well-being. There was a statistically significant difference in the interaction of age group and Social-Emotional Well being between children with orofacial clefts and control children. No statistically significant differences were found between the responses of children with orofacial clefts and their caregivers' reports. Conclusions : Presence of an orofacial cleft significantly decreases overall oral health related quality of life, Functional Well-being, and Social-Emotional Well-being in children and adolescents. The negative impact of orofacial clefts on Social Emotional Well-being is greater in 15- to 18-year-olds than in younger age groups. Children with orofacial clefts and their caregivers had very similar evaluations of the child's oral health-related quality of life. PMID- 22236324 TI - Network news coverage of obesity in two time periods: an analysis of issues, sources, and frames. AB - Obesity is an epidemic plaguing American society. The current study adds to a growing body of framing research as it examines the portrayal of obesity on television network news in two 5-year time periods, 1995-1999 and 2005-2009. Through content analysis of TV news transcripts from three networks (ABC, NBC, and CBS), this study analyzed episodic-thematic frames, issues, and sources. Results revealed the amount of obesity-related news coverage increased along with thematically framed stories. The use of politicians, affected others, supporters, and others as sources increased, but experts and those struggling with obesity remained primary sources. Changes in the proportion of issues discussed revealed significant decreases in the discussion of genetic causes and personal stories. Results reflect the societal impact of obesity and indicate the ways in which obesity is perceived by the public through network news. Findings provide insight for media advocacy opportunities and contribute to research on framing and obesity. PMID- 22236325 TI - Studies of impulsive vibrational influence on ultrafast electronic excitation transfer. AB - We investigated electronic energy-transfer dynamics in three model dimers within which coherent intramonomer nuclear motion had been induced by impulsive Raman excitation using an optimized, electronically preresonant control pulse. Calculations of the donor-survival probability, the ultrafast pump-probe signal, and the pump-probe difference signal are presented for dithia-anthracenophane and homodimers of 2-difluoromethylanthracene and 2-trifluoromethylanthracene. Survival probabilities and signals, along with phase-space analyses, elucidated the mechanisms, extent, and spectroscopic manifestations of external vibrational or torsional control over electronic excitation transfer. PMID- 22236326 TI - Synthesis of N-azolylindoles by copper-catalyzed C-H/N-H coupling-annulation sequence of o-alkynylanilines. AB - A wide range of o-alkynylanilines undergo a copper-catalyzed direct C-H/N-H coupling with azoles followed by benzannulation to form the corresponding N azolylindoles in good yields. The domino reaction proceeds effectively with molecular oxygen as the sole oxidant and provides a new dehydrogenative access to the titled compounds of interest in pharmaceutical and material sciences. PMID- 22236328 TI - Life and applications of extremophiles. PMID- 22236327 TI - Prescribing of nicotine replacement therapy to cardiovascular disease patients in England. AB - AIMS: In November 2005 the indications for nicotine replacement therapy (NRT) were broadened in the United Kingdom, making all forms available to patients with stable cardiovascular disease (CVD). This study aimed to estimate the effects of this change on prescribing of NRT to CVD patients in England. DESIGN: Segmented regression analysis of time series of monthly rates of prescribing of NRT. SETTING: A total of 350 general practices in England included in The Health Improvement Network (THIN), a database of UK electronic primary care records. PARTICIPANTS: All adult patients with coronary heart disease (CHD) or stroke registered with a THIN practice in England. MEASUREMENTS: The number of patients per 100,000 with CHD and stroke that received a prescription for NRT each month between January 2002 and June 2009. FINDINGS: Approximately 1500 per 100,000 smokers with CVD were prescribed NRT per month. Prescribing of NRT to CHD and stroke patients increased until the end of 2005 and subsequently decreased, with no immediate change following the Medicines and Healthcare Regulatory Authority (MHRA) licensing change. CONCLUSIONS: Broadening the marketing licence in the United Kingdom for nicotine replacement therapy to allow it to be prescribed to patients with CVD did not increase prescribing rates for this group of patients. PMID- 22236329 TI - Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. AB - The purpose of this study was to assess the toxicoses and antitumor activity of metronomic chlorambucil at a dosage of 4 mg m(-2) daily in dogs with naturally occurring cancer. Thirty-six dogs were enrolled in the study. The protocol was well tolerated with no grade 3 or 4 toxicoses noted. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumour, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration) for an overall remission rate of 11% (4 of 36). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. Chlorambucil given in a metronomic protocol showed antitumor activity in dogs with a variety of naturally occurring cancers. PMID- 22236330 TI - Scalable fabrication of multifunctional freestanding carbon nanotube/polymer composite thin films for energy conversion. AB - Translating the unique properties of individual single-walled carbon nanotubes (SWNTs) to the macroscale while simultaneously incorporating additional functionalities into composites has been stymied by inadequate assembly methods. Here we describe a technique for developing multifunctional SWNT/polymer composite thin films that provides a fundamental engineering basis to bridge the gap between their nano- and macroscale properties. Selected polymers are infiltrated into a Mayer rod coated conductive SWNT network to fabricate solar cell transparent conductive electrodes (TCEs), fuel cell membrane electrode assemblies (MEAs), and lithium ion battery electrodes. Our TCEs have an outstanding optoelectronic figure of merit sigma(dc)/sigma(ac) of 19.4 and roughness of 3.8 nm yet are also mechanically robust enough to withstand delamination, a step toward scratch resistance necessary for flexible electronics. Our MEAs show platinum utilization as high as 1550 mW/mg(Pt), demonstrating our technique's ability to integrate ionic conductivity of the polymer with electrical conductivity of the SWNTs at the Pt surface. Our battery anodes, which show reversible capacity of ~850 mAh/g after 15 cycles, demonstrate the integration of electrode and separator to simplify device architecture and decrease overall weight. Each of these applications demonstrates our technique's ability to maintain the conductivity of SWNT networks and their dispersion within a polymer matrix while concurrently optimizing key complementary properties of the composite. Here, we lay the foundation for the assembly of nanotubes and nanostructured components (rods, wires, particles, etc.) into macroscopic multifunctional materials using a low-cost and scalable solution-based processing technique. PMID- 22236332 TI - Reading between the lines: molecular characterization of five widely used canine lymphoid tumour cell lines. AB - Molecular characterization of tumour cell lines is increasingly regarded as a prerequisite for defining their validity as models of in vivo neoplasia. We present the first comprehensive catalogue of genomic and transcriptional characteristics of five widely used canine lymphoid tumour cell lines. High resolution microarray-based comparative genomic hybridization defined their unique profiles of genomic DNA copy number imbalance. Multicolour fluorescence in situ hybridization identified aberrant gains of MYC, KIT and FLT3 and deletions of PTEN and CDKN2 in individual cell lines, and also revealed examples of extensive structural chromosome reorganization. Gene expression profiling and RT PCR analyses defined the relationship between genomic imbalance and transcriptional dysregulation in each cell line, clarifying their relevance as models of discrete functional pathways with biological and therapeutic significance. In combination, these data provide an extensive resource of molecular data for directing the appropriate use of these cell lines as tools for studying canine lymphoid neoplasia. PMID- 22236331 TI - Twilight zone sponges from Guam yield theonellin isocyanate and psammaplysins I and J. AB - From the organic extracts of two Guam sponges, Rhaphoxya sp. and Suberea sp., determined to have cytotoxic and chemopreventive activities, three new compounds, theonellin isocyanate (1) and psammaplysins I and J (5, 6), and six previously reported compounds (2-4, 7-9) were isolated and characterized spectroscopically ((1)H and (13)C NMR, MS, IR, UV, [alpha](D)). The two new metabolites (5 and 6) isolated from the Suberea sp. sponge are rare examples of compounds containing a bromotyramine moiety rather than the more usual dibromo analogue. For the compounds isolated from the Rhaphoxya sp., this is the first report of the known compounds 2-4 being found in a single sponge. For previously reported compounds 2 4 complete unambiguous (1)H and (13)C NMR data are provided. PMID- 22236334 TI - ALK status in a primary lung tumour and metachronous metastases. PMID- 22236335 TI - Host cell and expression engineering for development of an E. coli ketoreductase catalyst: enhancement of formate dehydrogenase activity for regeneration of NADH. AB - BACKGROUND: Enzymatic NADH or NADPH-dependent reduction is a widely applied approach for the synthesis of optically active organic compounds. The overall biocatalytic conversion usually involves in situ regeneration of the expensive NAD(P)H. Oxidation of formate to carbon dioxide, catalyzed by formate dehydrogenase (EC 1.2.1.2; FDH), presents an almost ideal process solution for coenzyme regeneration that has been well established for NADH. Because isolated FDH is relatively unstable under a range of process conditions, whole cells often constitute the preferred form of the biocatalyst, combining the advantage of enzyme protection in the cellular environment with ease of enzyme production. However, the most prominent FDH used in biotransformations, the enzyme from the yeast Candida boidinii, is usually expressed in limiting amounts of activity in the prime host for whole cell biocatalysis, Escherichia coli. We therefore performed expression engineering with the aim of enhancing FDH activity in an E. coli ketoreductase catalyst. The benefit resulting from improved NADH regeneration capacity is demonstrated in two transformations of technological relevance: xylose conversion into xylitol, and synthesis of (S)-1-(2 chlorophenyl)ethanol from o-chloroacetophenone. RESULTS: As compared to individual expression of C. boidinii FDH in E. coli BL21 (DE3) that gave an intracellular enzyme activity of 400 units/g(CDW), co-expression of the FDH with the ketoreductase (Candida tenuis xylose reductase; XR) resulted in a substantial decline in FDH activity. The remaining FDH activity of only 85 U/g(CDW) was strongly limiting the overall catalytic activity of the whole cell system. Combined effects from increase in FDH gene copy number, supply of rare tRNAs in a Rosetta strain of E. coli, dampened expression of the ketoreductase, and induction at low temperature (18 degrees C) brought up the FDH activity threefold to a level of 250 U/g(CDW) while reducing the XR activity by just 19% (1140 U/g(CDW)). The E. coli whole-cell catalyst optimized for intracellular FDH activity showed improved performance in the synthesis of (S)-1-(2 chlorophenyl)ethanol, reflected in a substantial, up to 5-fold enhancement of productivity (0.37 g/g(CDW)) and yield (95% based on 100 mM ketone used) as compared to the reference catalyst. For xylitol production, the benefit of enhanced FDH expression was observed on productivity only after elimination of the mass transfer resistance caused by the cell membrane. CONCLUSIONS: Expression engineering of C. boidinii FDH is an important strategy to optimize E. coli whole cell reductase catalysts that employ intracellular formate oxidation for regeneration of NADH. Increased FDH-activity was reflected by higher reduction yields of D-xylose and o-chloroacetophenone conversions provided that mass transfer limitations were overcome. PMID- 22236333 TI - A molecular signature for purified definitive endoderm guides differentiation and isolation of endoderm from mouse and human embryonic stem cells. AB - Embryonic definitive endoderm (DE) generates the epithelial compartment of vital organs such as liver, pancreas, and intestine. However, purification of DE in mammals has not been achieved, limiting the molecular "definition" of endoderm, and hindering our understanding of DE development and attempts to produce endoderm from sources such as embryonic stem (ES) cells. Here, we describe purification of mouse DE using fluorescence-activated cell sorting (FACS) and mice harboring a transgene encoding enhanced green fluorescent protein (eGFP) inserted into the Sox17 locus, which is expressed in the embryonic endoderm. Comparison of patterns of signaling pathway activation in native mouse DE and endoderm-like cells generated from ES cells produced novel culture modifications that generated Sox17-eGFP+ progeny whose gene expression resembled DE more closely than achieved with standard methods. These studies also produced new FACS methods for purifying DE from nontransgenic mice and mouse ES cell cultures. Parallel studies of a new human SOX17-eGFP ES cell line allowed analysis of endoderm differentiation in vitro, leading to culture modifications that enhanced expression of an endoderm-like signature. This work should accelerate our understanding of mechanisms regulating DE development in mice and humans, and guide further use of ES cells for tissue replacement. PMID- 22236336 TI - Ethnic diversity outpatient clinic in paediatrics. AB - BACKGROUND: The health status of chronic sick ethnic minority children in the Netherlands is unequal compared with indigenous Dutch children. In order to optimize the health care for these children a specific patient-oriented clinic in ethnic-cultural diversity: the Mosaic Outpatient Clinic (MOC) was integrated in the general Paediatric Outpatient Departments (POPD) of three hospitals in Amsterdam. METHODS: Feasibility of the MOC, factors influencing the health care process and encountered bottlenecks in health care were studied in ethnic minority children with asthma, diabetes type 1 or metabolic disease originating from Morocco, Turkey and Surinam. Feasibility was determined by the number of patients attended, support from the paediatric medical staff and willingness of the patients to participate. Influences on the health care process comprised parents' level of knowledge of disease, sense of disease severity, level of effort, linguistic skills, health literacy, adherence to treatment and encountered bottlenecks in the health care process. Moreover, the number of admissions and visits to the POPD in the years before, during and after the MOC were analysed. RESULTS: In 2006 a total of 189 ethnic minority children were seen. Integration of the MOC within the general POPD of the hospital is feasible. The ability of the parents to speak and understand Dutch was found to be 58%, functional health literacy was 88%; sufficient knowledge of disease and sense of disease severity were 59% and 67%, respectively. The main bottlenecks in the healthcare process: poor knowledge of disease, limited sense of disease severity and low health literacy in the parents proved to be the best predictors for decreased adherence. After attending the MOC there was a decrease in the number of admissions and visits to the POPD for asthma while the number of visits increased in patients with diabetes and the amount of no-shows decreased in patients with a metabolic disease. CONCLUSION: Integration of a MOC in the general POPD is feasible and appreciated by the parents, provides more insight in the problems ethnic minority children and their parents face and shows promising directions for optimizing adherence in these children. PMID- 22236337 TI - Hsp70 alters tau function and aggregation in an isoform specific manner. AB - Tauopathies are characterized by abnormal aggregation of the microtubule associated protein tau. This aggregation is thought to occur when tau undergoes shifts from its native conformation to one that exposes hydrophobic areas on separate monomers, allowing contact and subsequent association into oligomers and filaments. Molecular chaperones normally function by binding to exposed hydrophobic stretches on proteins and assisting in their refolding. Chaperones of the heat shock protein 70 (Hsp70) family have been implicated in the prevention of abnormal tau aggregation in adult neurons. Tau exists as six alternatively spliced isoforms, and all six isoforms appear capable of forming the pathological aggregates seen in Alzheimer's disease. Because tau isoforms differ in primary sequence, we sought to determine whether Hsp70 would differentially affect the aggregation and microtubule assembly characteristics of the various tau isoforms. We found that Hsp70 inhibits tau aggregation directly and not through inducer mediated effects. We also determined that Hsp70 inhibits the aggregation of each individual tau isoform and was more effective at inhibiting the three repeat isoforms. Finally, all tau isoforms robustly induced microtubule formation while in the presence of Hsp70. The results presented herein indicate that Hsp70 affects tau isoform dysfunction while having very little impact on the normal function of tau to mediate microtubule assembly. This indicates that targeting Hsp70 to tau may provide a therapeutic approach for the treatment of tauopathies that avoids disruption of normal tau function. PMID- 22236338 TI - Echocardiogram utilization among rural and urban veterans. AB - PURPOSE: To compare echocardiography use among urban and rural veterans and whether differences could be accounted for by distance. METHODS: We used Veterans Administration (VA) administrative data from 1999 to 2007 to identify regular users of the VA Healthcare System (VA users) who did and did not receive echocardiography. Each veteran was categorized as residing in urban, rural or highly rural areas using RUCA codes. Poisson regression was used to compare echocardiography utilization rates among veterans residing in each area after adjusting for demographics, comorbidities, clustering of patients within VA networks and distance to the nearest VA medical center offering echocardiography. FINDINGS: Our study included 22.7 million veterans of whom 1.3 million (5.7%) received at least 1 echocardiogram. Of echocardiography recipients, 69.2% lived in urban, 22.0% in rural and 8.8% in highly rural areas. In analyses adjusting for patient demographics, comorbidities, and clustering, utilization of echocardiography was modestly lower for highly rural and rural veterans compared with urban veterans (42.0 vs 40.1 vs 43.1 echocardiograms per 1,000 VA users per year for highly rural, rural and urban, respectively; P< .001). After further adjusting for distance, echocardiography utilization was somewhat higher for veterans in highly rural and rural areas than it was for urban areas (44.9 vs 41.8 vs 40.8 for highly rural, rural and urban, respectively; P< .001). CONCLUSIONS: Echocardiography utilization among rural and highly rural veterans was marginally lower than for urban veterans, but these differences can be accounted for by the greater distance of more rural veterans from facilities offering echocardiograms. PMID- 22236339 TI - Dealing efficiently with emotions: acceptance-based coping with negative emotions requires fewer resources than suppression. AB - Previous studies have consistently shown that changing or avoiding emotions requires resources and therefore leads to impaired performance on a subsequent self-control task. The aim of the present study was to investigate the extent to which acceptance-based coping requires regulatory resources. Participants who accepted their emotions during exposure to a sad video performed better on a subsequent self-control task than participants who were instructed to suppress their emotions and a control group who received no instructions. These findings suggest that acceptance is an efficient strategy in terms of resources. PMID- 22236341 TI - Local strategies to address health needs of individuals with orofacial clefts in alagoas, Brazil. AB - Objective : To describe demographic and clinical-genetic characteristics of patients from a poor area of Brazil and to share experience on how the local genetic unit has addressed their major health needs. Design : Descriptive cohort. Setting : A clinical-genetic unit, a cytogenetics unit, and a regional cleft team located in the northeast and southeast of Brazil. Participants : A total of 133 individuals with orofacial clefts who attended the surgical call of a nongovernmental organization. From this group, 125, 77, and 13 patients completed phases 1, 2, and 3, respectively. Methods : Phase 1 comprised a description of demographic characteristics recorded through interviews. Phase 2 included a clinical-genetic evaluation using a pretested form, as well as cytogenetic analyses of selected patients. Phase 3 comprised collaborative action to address major health needs of patients without primary surgery. The Fisher test was used for statistics with p value < .05. Results : A majority of patients were rural residents with isolated cleft lip with cleft palate. Ages ranged between 0 and 30 years. Fifty percent had never undergone surgery; whereas, 100% had never attended a genetic evaluation. Isolated cleft was diagnosed in 77.9%, syndromes in 14.3%, and multiple congenital abnormalities in 7.8%. Positive familial history of clefts occurred in 28%; whereas, parental consanguinity was present in 7.8% cases. A total of 23 individuals without cleft surgery were registered for multidisciplinary treatment. Conclusions : Findings revealed high levels of unmet medical needs and provided an evidence base for health care planning. Collaborative action was crucial and might be applied to other regions in Brazil. PMID- 22236342 TI - Influence of oral sex and oral cancer information on young adults' oral sexual risk cognitions and likelihood of HPV vaccination. AB - Public health information and educational interventions regarding human papillomavirus (HPV) have focused on the link between vaginal sex and cervical cancer among women. Many people are unaware that HPV can be transmitted through oral sex or that HPV causes oral cancers. Given that HPV infections and unprotected oral sex are increasing, research on oral sex-related HPV risk is important. This study examined the effect of a brief informational intervention regarding HPV and oral sex on the sexual risk cognitions of young adults. College students (N = 238) read information on HPV, oral sex, and oral cancer or no information. Participants then completed measures of oral sex and HPV knowledge, oral sex willingness, HPV vaccination likelihood, and risk perceptions. Participants who read the information on HPV and oral sex and cancer (compared to those who did not) reported greater knowledge, perceived risk and concern, and lower willingness to engage in oral sex. These effects were only significant among women. However, men reported a higher likelihood of future HPV vaccination compared to women who had not yet received the vaccine. Focusing on oral sex and cancer, this study adds to research investigating ways to reduce HPV infections. PMID- 22236343 TI - Pre-hospital care and hazardous environments. PMID- 22236344 TI - Feasibility of cerebral near-infrared spectroscopy monitoring in the pre-hospital environment. AB - BACKGROUND: Traumatic brain injury (TBI) is a significant cause of death and severe disability from trauma. Pre-hospital care of patients with TBI may be aided by non-invasive monitoring of cerebral tissue oxygenation. This pilot observational study was designed to assess if cerebral tissue oximetry using near infrared spectroscopy (NIRS) is feasible in the pre-hospital and transport environment. METHODS: After ethics committee review, we undertook a feasibility trial in healthy volunteers, transported by road ambulance or helicopter, to assess if monitoring signals could be obtained in the outside environment and during patient transport. RESULTS: A total of 33 road ambulance transports and 32 helicopter transports were undertaken. For monitoring commenced outdoors, 33 of 66 probes applied (50%) provided adequate monitoring signal. For road transports, 33 out of 33 transports (100%) resulted in successful bilateral monitoring for more than 70% of the sampling period. For helicopter transports, four transports were cut short by battery failure during the mission and 24 of 28 transports (85.7%) resulted in successful bilateral monitoring for more than 70% of the sampling period. While patient and transport platform movement did not impact on monitoring signals, exposure to ambient light provided a challenge in obtaining monitoring signals that is nevertheless manageable with increased probe shielding. CONCLUSIONS: NIRS monitoring is feasible in the pre-hospital environment, opening up the possibility for further research of the role of this modality in this setting. PMID- 22236345 TI - The analgesic effect of continuous subacromial bupivacaine infusion after arthroscopic shoulder surgery: a randomized controlled trial. AB - BACKGROUND: The benefits of subacromial local anesthetic infusion are controversial. The aim of this study was to evaluate the efficacy of subacromial bupivacaine infusion after arthroscopic acromionplasty and rotator cuff procedures. METHODS: Ninety patients with subacromial impingement disease scheduled for elective shoulder arthroscopy were enrolled in this randomized, prospective and placebo-controlled study. The patients received subacromially either 5.0 mg/ml bupivacaine or 9.0 mg/ml saline at the rate of 2 ml/h post operatively for 48 h. The primary outcome measure was the use of rescue oxycodone. The consumption of opioids, ibuprofen, paracetamol and codeine, and the intensity of pain were recorded. RESULTS: Patients receiving bupivacaine infusion used significantly less oxycodone compared with patients receiving saline [15 vs. 20 mg (median) oxycodone intravenously on the day of surgery, 0 vs. 10 mg (median) perorally on the first post-operative day]. There was no significant difference in the use of ibuprofen, paracetamol and codeine, except that paracetamol was used more in patients receiving saline during the day of surgery (P = 0.009). The pain scores of patients receiving bupivacaine were lower at 18 h (P = 0.008). Average pain scores for the worst pain experienced did not differ between the groups. There were three (4%) premature discontinuations because of technical problems. CONCLUSIONS: Considering the low need of opioids, expenses and technical problems in these patients, subacromial 5.0 mg/ml bupivacaine infusion 2 ml/h confers only moderate and probably clinically insignificant efficacy compared with placebo. This efficacy might be overweighed by the disadvantages. PMID- 22236346 TI - Selective spinal anesthesia for outpatient transurethral prostatectomy (TURP): randomized controlled comparison of chloroprocaine with lidocaine. AB - BACKGROUND: This is a study comparing two short-acting local anesthetics lidocaine and 2-chloroprocaine in combination with fentanyl, to provide selective spinal anesthesia for outpatient transurethral resection of the prostate (TURP). METHODS: In this prospective, randomized double-blind study, selective spinal anesthesia was performed in 40 American Society of Anesthesiologists I-III outpatients undergoing TURP using either 40 mg of chloroprocaine mixed with 12.5 MUg of fentanyl (n = 20) or 35 mg of lidocaine mixed with 12.5 MUg of fentanyl (n = 20). The primary outcome was duration of spinal block. Secondary outcomes were time to reach T10 (onset), time to maximal level, duration above T10 and lidocaine 3, maximal level of block, and adverse effects. RESULTS: The median (minimum, maximum) onset time was 4 (1, 16) and 3 (2, 10) min for chloroprocaine and lidocaine, respectively. Time to maximal level was 20 (17, 29) and 22 (16, 26) min for chloroprocaine and lidocaine, respectively. Mean maximal level was T7 T8 for both agents. Duration of block above T10 was 54 (28, 88) and 63 (31, 87) min for chloroprocaine and lidocaine, respectively. Duration of block above lidocaine 3 was 93 (56, 218) and 98 (58, 151) min for chloroprocaine and lidocaine, respectively. There was no statistical difference between the two groups with respect to these clinical end points. Four patients in the lidocaine group developed transient neurological symptoms. One patient in the chloroprocaine group developed a cauda equina-like syndrome but recovered fully after several weeks. CONCLUSIONS: Selective spinal anesthesia with chloroprocaine and lidocaine for TURP yielded comparable results for clinical characteristics. Further research on transient neurological symptom and cauda equina risk with chloroprocaine is warranted. PMID- 22236347 TI - The effects of age on maintenance of intense neuromuscular block with rocuronium. AB - BACKGROUND: Increasing age is associated with a longer duration of action of neuromuscular block. The aim of this study was to determine the influence of ageing on the recovery of the post-tetanic count (PTC) from rocuronium-induced neuromuscular block. METHODS: Twenty-two younger (20-60 years) and 22 older (> 70 years) patients were enrolled in this study. After induction of anaesthesia with fentanyl and propofol, all patients initially received 1 mg/kg rocuronium and neuromuscular block were evaluated by contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation using an acceleromyograph. Subsequently, intense rocuronium-induced block was determined every 6 min using the PTC during 1.0-1.5% sevoflurane and remifentanil anaesthesia. When the first response to the PTC stimulus was detected, 0.2 mg/kg rocuronium was additionally administered, and again, spontaneous recovery of neuromuscular function was monitored until the first response to the PTC reappeared. RESULTS: Median values (range) of the times from the administration of 1 mg/kg and 0.2 mg/kg rocuronium until recovery of the first detectable PTC were significantly longer in the older [51.0 (27-100) min, P < 0.0001 and 30.0 (12-66) min, P = 0.0036, respectively] than the younger patients [31.5 (21-45) min and 18.0 (12-36) min, respectively]. CONCLUSION: The times from rocuronium injection to reappearance of the first response to PTC stimulation are approximately twofold longer and more variable in older than younger patients. Hence, the dosing interval of rocuronium should be adjusted using neuromuscular monitoring when maintaining intense neuromuscular block, especially in older patients. PMID- 22236348 TI - Anaphylaxis to atracurium - a non-QAI-dependent reaction? PMID- 22236350 TI - Outlook on the phase equilibria of the innovative system of "protected glycerol": 1,4-dioxaspiro[4.5]decane-2-methanol and alternative solvents. AB - Fundamental data on 1,4-dioxaspiro[4.5]decane-2-methanol are scarce. This work presents the foremost systematic data on the solubility of 1,4 dioxaspiro[4.5]decane-2-methanol in sustainable solvents such as water and ionic liquids accompanied by the interpretation of interactions occurring in such binary systems. 1,4-Dioxaspiro[4.5]decane-2-methanol, here called protected glycerol, has been synthesized in order to protect the two hydroxyl groups of glycerol, thus avoiding the formation of side products in a specific process. A series of imidazolium salts accompanied by pyridinium, phosphonium, and ammonium ones with various types of counterions were used in this study. The liquid-liquid and solid-liquid equilibrium measurements in binary systems were carried out by using a dynamic method at atmospheric pressure over the temperature range from 273.00 to 378.30 K or below the boiling point of the solvent. Among all tested sustainable solvents, protected glycerol exhibited limited solubility, with only a few of them in the temperature range studied. The majority of the examined ionic liquids, either hydrophilic or hydrophobic, showed complete miscibility with this monohydroxyol. The Fourier-transform infrared (FTIR) spectroscopy studies of solute and solvents showing a miscibility gap and of their mixtures were performed to obtain insight into major inter- and intramolecular interactions in the investigated systems. Furthermore, the differential scanning calorimetry was used for the first time to determine the melting point, the enthalpy of melting, and the temperature and enthalpy of the solid-solid phase transition of 1-allyl-3-methylimidazolium chloride [Amim][Cl]. The results for the solubility of protected glycerol in sustainable solvents can be used to design future alternative reactions, such as telomerization with protected glycerol in ionic liquids for more specific building blocks and extraction/or separation that involves these mixtures. PMID- 22236351 TI - Reactivity of long conjugated systems: selectivity of Diels-Alder cycloaddition in oligofurans. AB - Taking advantage of the synthetic availability and solubility of long oligofurans, their reactivity toward dienophiles was studied as a model for the rarely investigated reactivity of long conjugated systems. Unlike oligoacenes, the reactivity of oligofurans decreases or remains constant with increasing chain length. Terminal ring cycloadducts of oligofurans are kinetically and thermodynamically favored, whereas central ring cycloadducts are preferred in oligoacenes, because of the different driving forces in the two reactions: pi conjugation in oligofurans and aromatization/dearomatization in oligoacenes. PMID- 22236352 TI - Quantitative genetics of behavioural reaction norms: genetic correlations between personality and behavioural plasticity vary across stickleback populations. AB - Behavioural ecologists have proposed various evolutionary mechanisms as to why different personality types coexist. Our ability to understand the evolutionary trajectories of personality traits requires insights from the quantitative genetics of behavioural reaction norms. We assayed > 1000 pedigreed stickleback for initial exploration behaviour of a novel environment, and subsequent changes in exploration over a few hours, representing their capacity to adjust their behaviour to changes in perceived novelty and risk. We found heritable variation in both the average level of exploration and behavioural plasticity, and population differences in the sign of the genetic correlation between these two reaction norm components. The phenotypic correlation was not a good indicator of the genetic correlation, implying that quantitative genetics are necessary to appropriately evaluate evolutionary hypotheses in cases such as these. Our findings therefore have important implications for future studies concerning the evolution of personality and plasticity. PMID- 22236353 TI - Toxicity associated with epirubicin treatments in a large case series of dogs. AB - Epirubicin is a stereoisomer of doxorubicin that is widely used in human oncology. The purpose of this study was to evaluate the toxicity associated with epirubicin administration in dogs. Three hundred and fifteen treatments were administered to 139 dogs. Patients received between one and seven doses. One hundred and sixteen treatments were associated with toxicity in 81 patients (50 episodes of lethargy, 49 of diarrhoea, 42 of vomiting, 40 of anorexia, 2 hypersensitivity reactions and 2 suspected extravasations). Thirty-six (11%) adverse events resulted in hospitalization in 33 (24%) patients, of which 15 were neutropenic and 9 pyrexic. Mean duration of hospitalization was 3.4 days and 33 patients recovered uneventfully. Owners of 11 patients declined further treatment after toxicity occurred. After 25 treatments associated with toxicity, dose reductions reduced toxicity. The use of prophylactic anti-emetics, gastroprotectants and antibiotics did not reduce the frequency of gastrointestinal toxicity. PMID- 22236354 TI - Narratives of HIV disclosure and masculinity in a South African village. AB - This paper describes men's experiences of disclosing their HIV status, arguing that disclosure restored their social respect, which was previously undermined by an illness from AIDS. Results are from a 14-month ethnographic study conducted in rural South African health facility, among a group of 25 men attending an AIDS support group. The men included in this study tested while they were critically ill and some were negatively labelled as 'already dead' because of their poor state of health. The majority voluntarily disclosed their HIV status to the public after recovering from the physical symptoms of AIDS. This elicited positive reaction from the community, who treated them with admiration for disclosing their HIV status. The paper emphasises the fact that the good response received by participants from the community was predicated mainly on having healthy physical looks that men gained from using antiretroviral medication. This paper then further analyses the ways in which a 'healthy appearance' facilitates disclosure of HIV status and also disrupts the stigma attached to HIV in the studied community. PMID- 22236355 TI - Fascin-1 expression in canine cutaneous and oral melanocytic tumours. AB - Fascin-1 expression was examined in 9 cutaneous melanocytomas and 47 oral melanomas. The cases were scored on the basis of extent and intensity of staining, and combined scores were calculated. Fascin-1 expression was observed in 5/9 (56%) melanocytomas and 46/47 (98%) melanomas. The combined score for fascin-1 was significantly greater in stage III/IV melanomas than in stage I/II melanomas (P < 0.05). In addition, strong fascin-1 staining was associated with a significantly shortened survival time (P < 0.05). The results of this study suggest that fascin-1 overexpression correlates with the malignancy of canine melanoma and has the potential to be a new immunohistochemical marker to predict the clinical course of canine melanoma. In addition, targeted therapy for fascin 1 may represent a new strategy for the treatment of canine melanoma. PMID- 22236356 TI - Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross reactivity with long-term treatment. AB - AIMS: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety. METHODS: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52 weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30 weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52 weeks) were analysed. RESULTS: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody positive; 31.7% exhibited low titres (<=125) and 5.0% had higher titres (>=625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. CONCLUSIONS: Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide. PMID- 22236357 TI - Determinants of condom uptake among HIV voluntary counselling and testing clients: experiences from a hospital-based study in south India. AB - BACKGROUND: HIV voluntary counselling and testing was a key HIV prevention strategy brought to scale by India's National AIDS Control Organization. Condom uptake is an essential metric of intervention impact given the expansion of the epidemic into an increasingly diverse population. With only 20% of first-time counselling and testing clients at the largest HIV treatment hospital in south India reporting previous condom use, the question of intervention impact on condom use deserves investigation. In this study, we track intervention impact across various demographic groups and identify the added value of more thorough counselling. METHODS: Data were collected from 8,865 individuals who attended counselling multiple times at the Tamil Nadu Government Hospital of Thoracic Medicine over the years 2004-2009. Counsellors recorded client demographic characteristics, HIV risk behaviours reported, and counselling services provided after each counselling session. Matching and regression methods were used to determine the probability of condom uptake by serostatus, gender, and receipt of personalized risk reduction counselling while controlling for other characteristics. RESULTS: HIV counselling and testing was associated with condom uptake among 29.2% of HIV positive women (CI 24.5-34.4%), 31.7% of HIV positive men (CI 27.8-35.4%), 15.5% of HIV negative women (CI 11.2-20.8%), and only 3.6% of HIV negative men (CI 1.9-5.9%) who had previously never used condoms. Personalized risk reduction counselling increased impact in some groups; for example an additional 18% of HIV negative women (CI 11.3-24.4%) and 17% of HIV positive men (CI 10.9-23.4%) started using condoms. The number of sexual partners was not associated with the impact of counselling completeness. CONCLUSIONS: Because the components of testing and counselling impact the condom use habits of men and women differently, understanding the dynamics of condom use negotiation between partners is essential to optimizing impact on Indian couples. Clients' predicted condom uptake ranged between 4% and 47% depending on factors like gender, serostatus, and services provided. Personalized risk reduction counselling is associated with increased chance of condom use, with larger gains in HIV negative women and HIV positive men. HIV negative men are least likely to start using condoms and least impacted by additional counselling. PMID- 22236358 TI - The evil circle of poverty: a qualitative study of malaria and disability. AB - BACKGROUND: This article discusses the link between disability and malaria in a poor rural setting. Global malaria programmes and rehabilitation programmes are organized as vertical and separate programmes, and as such they focus on prevention, cure and control, and disability respectively. When looking at specific conditions and illnesses, the impairing long-term consequences of illness incidents during childhood are not questioned. METHODS: The study design was ethnographic with an open, exploratory approach. Data were collected in Mangochi District in Malawi through qualitative in-depth interviews and participant observation. RESULTS: Despite a local-based health service system, people living in poor rural areas are confronted with a multitude of barriers when accessing malaria prevention and treatment. Lack of skilled health personnel and equipment add to the general burden of poverty: insufficient knowledge about health care, problems connected to accessing the health facility in time, insufficient initiatives to prevent malaria attacks, and a general lack of attention to the long term disabling effects of a malaria attack. CONCLUSIONS: This study points to the importance of building malaria programmes, research and statistics that take into consideration the consequences of permanent impairment after a malaria attack, as well as the context of poverty in which they often occur. In order to do so, one needs to develop methods for detecting people whose disabilities are a direct result of not having received health services after a malaria episode. This may be done through qualitative approaches in local communities and should also be supplemented by suitable surveys in order to estimate the problem on a larger scale. PMID- 22236359 TI - Epidemiology of out-of hospital pediatric cardiac arrest due to trauma. AB - OBJECTIVE: To determine the epidemiology and survival of pediatric out-of hospital cardiac arrest (OHCA) secondary to trauma. METHODS: The CanAm Pediatric Cardiac Arrest Study Group is a collaboration of researchers in the United States and Canada sharing a common goal to improve survival outcomes for pediatric cardiac arrest. This was a prospective, multicenter, observational study. Twelve months of consecutive data were collected from emergency medical services (EMS), fire, and inpatient records from 2000 to 2003 for all OHCAs secondary to trauma in patients aged <=18 years in 36 urban and suburban communities supporting advanced life support (ALS) programs. Eligible patients were apneic and pulseless and received chest compressions in the field. The primary outcome was survival to discharge. Secondary measures included return of spontaneous circulation (ROSC), survival to hospital admission, and 24-hour survival. RESULTS: The study included 123 patients. The median patient age was 7.3 years (interquartile range [IQR] 6.0 17.0). The patient population was 78.1% male and 59.0% African American, 20.5% Hispanic, and 15.7% white. Most cardiac arrests occurred in residential (47.1%) or street/highway (37.2%) locations. Initial recorded rhythms were asystole (59.3%), pulseless electrical activity (29.1%), and ventricular fibrillation/tachycardia (3.5%). The majority of cardiac arrests were unwitnessed (49.5%), and less than 20% of patients received chest compressions by bystanders. The median (IQR) call-to-arrival interval was 4.9 (3.1-6.5) minutes and the on scene interval was 12.3 (8.4-18.3) minutes. Blunt and penetrating traumas were the most common mechanisms (34.2% and 25.2%, respectively) and were associated with poor survival to discharge (2.4% and 6.5%, respectively). For all OHCA patients, 19.5% experienced ROSC in the field, 9.8% survived the first 24 hours, and 5.7% survived to discharge. Survivors had triple the rate of bystander cardiopulmonary resuscitation (CPR) than nonsurvivors (42.9% vs. 15.2%). Unlike patients sustaining blunt trauma or strangulation/hanging, most post-cardiac arrest patients who survived the first 24 hours after penetrating trauma or drowning were discharged alive. Drowning (17.1% of cardiac arrests) had the highest survival-to-discharge rate (19.1%). CONCLUSIONS: The overall survival rate for OHCA in children after trauma was low, but some trauma mechanisms are associated with better survival rates than others. Most OHCA in children is preventable, and education and prevention strategies should focus on those overrepresented populations and high-risk mechanisms to improve mortality. PMID- 22236360 TI - Emotional or evidence-based medicine--is there a moral tragedy in haemostatic therapy? PMID- 22236361 TI - Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template bleeding time in a single-center prospective study. AB - BACKGROUND: Patients with heightened platelet reactivity in response to antiplatelet agents are at an increased risk of recurrent ischemic events. However, there is a lack of diagnostic criteria for increased response to combined aspirin/clopidogrel therapy. The challenge is to identify patients at risk of bleeding. This study sought to characterize bleeding tendency in patients treated with aspirin and clopidogrel. PATIENTS/METHODS: In a single-center prospective study, 100 patients under long-term aspirin/clopidogrel treatment, the effect of therapy was assayed by template bleeding time (BT) and the inhibition of platelet aggregation (IPA) by light transmission aggregometry (LTA). Arachidonic acid (0.625 mmol/L) and adenosine diphosphate (ADP; 2, 4, and 8 MUmol/L) were used as platelet agonists. RESULTS: Bleeding episodes (28 nuisance, 2 hematuria [1 severe], 1 severe proctorrhagia, 1 severe epistaxis) were significantly more frequent in patients with longer BT. Template BT >= 24 min was associated with bleeding episodes (28 of 32). Risk of bleeding increased 17.4% for each 1 min increase in BT. Correlation was found between BT and IPAmax in response to ADP 2 MUmol/L but not to ADP 4 or 8 MUmol/L. CONCLUSION: In patients treated with dual aspirin/clopidogrel therapy, nuisance and internal bleeding were significantly associated with template BT and with IPAmax in response to ADP 2 MUmol/L but not in response to ADP 4 MUmol/L or 8 MUmol/L. PMID- 22236362 TI - Diffuse large B cell lymphoma presenting as Horner's syndrome in a patient diagnosed with neurofibromatosis type 1: a case report and review of the literature. AB - INTRODUCTION: Horner's syndrome has a variety of etiologies ranging from benign to serious life-threatening conditions and has been infrequently reported as a presenting symptom of patients with lymphoid neoplasms. Only one case of Burkitt's lymphoma presenting with toothache, paresthesia, and Horner's syndrome has been described and no case reports of diffuse large B-cell lymphoma as the etiology of Horner's syndrome currently exist in the literature. In addition, lymphoid neoplasms have rarely been reported to occur in patients with neurofibromatosis type 1 despite an increased risk of many types of cancer in such cases. CASE PRESENTATION: A 28-year-old Thai man presented with a progressively enlarged left supraclavicular mass together with a significant weight loss and night sweating for four months. He also noticed hoarseness and ptosis of his left eye associated with double vision for two months. Physical examination revealed large supraclavicular lymphadenopathy and Horner's syndrome (ptosis, miosis, and anhydrosis) on the left side of his face. A large mediastinal mass was clearly detected by chest X-ray and computed tomography and subsequent lymph node biopsy provided a diagnosis of diffuse large B-cell lymphoma. Interestingly, the patient was also definitely diagnosed with neurofibromatosis type 1 from multiple cafe au lait macules, axillary freckles, three neurofibromas, multiple Lisch nodules, and a history of affected family members. He subsequently received chemotherapy with a good response. Twenty-seven cases of various types of lymphoid neoplasms previously reported to occur in neurofibromatosis type 1 patients were also extracted from the literature. All cases were non-Hodgkin lymphoma and the major subtype was T-cell. Only nine cases were B-cell lymphoma. The majority of cases were young with a median age at lymphoma diagnosis of 9.4 years (range 1.1 to 77 years). Two-thirds of the cases were boys or men. Other concomitant malignancies were brain tumor, colorectal cancer, pheochromocytoma, and acute lymphoblastic leukemia. CONCLUSIONS: We describe for the first time a case of diffuse large B-cell lymphoma that occurred in a neurofibromatosis type 1 patient with Horner's syndrome. Horner's syndrome can be an initial manifestation of diffuse large B-cell lymphoma. Patients who present with a classical triad of Horner's syndrome should always be fully investigated for lymphomatous involvement, especially in the thorax. The exact molecular mechanism for diffuse large B-cell lymphoma development in neurofibromatosis type 1 cases remains to be elucidated. PMID- 22236363 TI - Dental and maxillofacial characteristics of six Japanese individuals with ectrodactyly-ectodermal dysplasia-clefting syndrome. AB - Objective : Ectrodactyly-ectodermal dysplasia-clefting syndrome is a congenital anomaly characterized by ectodermal dysplasia, ectrodactyly, cleft lip and palate, and lacrimal duct anomalies. Because this syndrome is frequently accompanied by a congenital lack of teeth, narrow palate, and malocclusion, comprehensive orthodontic intervention is required. Design : To highlight the specific dental and maxillofacial characteristics of ectrodactyly-ectodermal dysplasia-clefting syndrome, six Japanese individuals diagnosed with the syndrome are described here. Patients : The subjects consisted of two boys and four girls (age range, 6.0 to 13.9 years) diagnosed with ectrodactyly-ectodermal dysplasia clefting syndrome by medical and dental specialists. Their conditions included ectodermal dysplasia (hypodontia, microdontia, enamel hypoplasia, and abnormalities in hair and nails), cleft lip and/or palate, and ectrodactyly. Cephalograms, panoramic x-rays, and dental casts were taken; systemic complications were recorded at the first visit to our dental hospital. Results : All individuals had severe oligodontia with 9 to 18 missing teeth. The missing teeth were mainly maxillary and mandibular incisors and second bicuspids, arranged in a symmetrical manner. Cephalometric analysis showed retruded and short maxilla due to cleft lip and/or palate. It is interesting that all individuals showed a characteristically shaped mandibular symphysis with a retruded point B. It is likely that this unusual symphyseal morphology is due to the lack of mandibular incisors. Conclusions : This study demonstrates the presence of severe oligodontia in the incisal and premolar regions and describes a characteristic maxillary and mandibular structure in Japanese individuals with ectrodactyly-ectodermal dysplasia-clefting syndrome. PMID- 22236364 TI - A domino palladium-catalyzed C-C and C-O bonds formation via dual O-H bond activation: synthesis of 6,6-dialkyl-6H-benzo[c]chromenes. AB - An efficient Pd-catalyzed domino reaction of alpha,alpha-dialkyl-(2 bromoaryl)methanols to 6,6-dialkyl-6H-benzo[c]chromenes is presented. Their formation can be explained via a five membered Pd(II)-cycle that efficiently involves a domino homocoupling with the second molecule, beta-carbon cleavage, and finally intramolecular Buchwald-Hartwig cyclization. This domino process effectively involves breaking of five sigma-bonds (2C-Br, 2O-H, and a C-C) and formation of two new sigma-bonds (C-C and C-O). This mechanistic pathway is unprecedented and further illustrates the power of transition metal catalysis. PMID- 22236365 TI - The use of neural networks and texture analysis for rapid objective selection of regions of interest in cytoskeletal images. AB - Understanding cytoskeletal dynamics in living tissue is prerequisite to understanding mechanisms of injury, mechanotransduction, and mechanical signaling. Real-time visualization is now possible using transfection with plasmids that encode fluorescent cytoskeletal proteins. Using this approach with the muscle-specific intermediate filament protein desmin, we found that a green fluorescent protein-desmin chimeric protein was unevenly distributed throughout the muscle fiber, resulting in some image areas that were saturated as well as others that lacked any signal. Our goal was to analyze the muscle fiber cytoskeletal network quantitatively in an unbiased fashion. To objectively select areas of the muscle fiber that are suitable for analysis, we devised a method that provides objective classification of regions of images of striated cytoskeletal structures into "usable" and "unusable" categories. This method consists of a combination of spatial analysis of the image using Fourier methods along with a boosted neural network that "decides" on the quality of the image based on previous training. We trained the neural network using the expert opinion of three scientists familiar with these types of images. We found that this method was over 300 times faster than manual classification and that it permitted objective and accurate classification of image regions. PMID- 22236366 TI - Changes in surgical workload at the JF Med Gp Role 3 Hospital, Camp Bastion, Afghanistan, November 2008-November 2010. AB - INTRODUCTION: The operative workload at the surgical facility in Camp Bastion, Afghanistan, has previously been reported for the two-year period 1 May 2006 to 1 May 2008. There have since been considerable changes not only in the casualty rates, but also in the injury patterns encountered. Severe wounds from improvised explosive devices (IEDs) have become the signature injury of the insurgency. We present recent data for the surgical activity at the Joint Forces Medical Group Role 3 Hospital, Camp Bastion, for the two-year period 1 November 2008 to 1 November 2010. PATIENTS AND METHODS: A retrospective analysis of the operating theatre logbooks was undertaken for the period 1 November, 2008 to 1 November, 2010. RESULTS: During the study period a total of 4276 cases required 5737 surgical procedures. Compared with the previously reported series from May 2006 to 2008, this represents a 2.6-fold increase in the surgical workload of the hospital. There has been a 5.7-fold increase in the number of amputations (483 during this study period, 8.4% all operative procedures), and for the lower limbs these have become increasingly proximal (48% all amputations were above-knee lower limb amputations). During the study period there were also significant increases in the frequency of perineal injuries as well as the numbers of cases involving 5 or more surgeons. DISCUSSION: The surgical workload at the Role 3 Hospital, Camp Bastion, Afghanistan is increasing. This is a result not only of increasing casualty numbers but also of increasingly severe injury patterns. With the growing use of powerful IEDs, traumatic lower limb amputations in particular are becoming more common, and are increasingly associated with significant pelvic and perineal injury. These complex injury patterns necessitate a multi-surgeon approach, and it is important these trends are noted for future planning of medical support to military operations in Afghanistan. PMID- 22236367 TI - Modification of percutaneous vertebroplasty for painful old osteoporotic vertebral compression fracture in the elderly: preliminary report. AB - OBJECTIVE: To study the clinical efficacy of modified percutaneous vertebroplasty (PVP) in the treatment of painful old osteoporosis vertebral compression fractures (OVCF). METHODS: From April 2007 to October 2009, 16 cases (23 vertebrae) of symptomic old OVCF were treated with a modified PVP. Before operation, all the patients were examined by standing anteroposterior and lateral X-Ray and MRI. The pain level of each patient was assessed before operation and 1 week, 6, 12 months after the operation using visual analogue scale (VAS) and Oswestry disability index (ODI). The middle line vertebral body height and local sagittal Cobb's angle were also measured. RESULTS: Postoperative average VAS, Oswestry disability index (ODI), the local sagittal Cobb's angle decreased from 7.8, 72.3%, and 38.2 degrees to 3.1, 26.8%, and 21.5 degrees respectively before and after surgery (p<0.05). The mean midline vertebral height increased from 13.8mm to 26.6mm before and after surgery (p<0.05). There was no infection, nerve injury, pulmonary embolism, or death after operation. CONCLUSIONS: The modified PVP can increase the space for bone cement filling and is good for the restoration of vertebral body height. It is an optimal procedure for the treatment of painful old OVCF. PMID- 22236368 TI - Routine blood tests as predictors of mortality in hip fracture patients. AB - OBJECTIVE: The aim of this study was to assess the evidence for the association between different biochemical markers at admission and mortality through a meta analysis. DATA SOURCES: PubMed-, Embase-, Cochran Library and the Web of Knowledge were searched for cohort studies. STUDY SELECTION: Eligible studies were observational studies with a study population larger than 150 subjects, a mean age above 60 years and a study duration below 730 days. DATA EXTRACTION: Characteristics of studies and outcomes of all-cause mortality were extracted from the retrieved articles. Data were pooled across studies for the individual biomarker using random- or fixed-effect analysis. DATA SYNTHESIS: 15 eligible studies of 5 different markers on mortality were studied. The following markers were found to be of prognostic value on mortality in hip fracture patients: low haemoglobin (odds ratio, 2.78; 95% confidence interval, 2.17-3.55; P<0.00001, 3148 subjects included), low total lymphocyte count, TLC (odds ratio, 2.60; 95% confidence interval, 1.61-4.20; P<0.00001, 1689 subjects included), low albumin (odds ratio, 1.83; 95% confidence interval, 1.31-2.56; P=0.0004, 1680 subjects included), low albumin/low TLC (odds ratio, 3.00; 95% confidence interval, 1.81 4.99; P<0.0001, 704 subjects included), low albumin/high TLC (odds ratio, 3.39; 95% confidence interval, 1.83-6.29; P=0.0001, 704 subjects included), high creatinine (odds ratio, 1.58; 95% confidence interval, 1.25-1.99; P=0.0001, 3761 subjects included), and high PTH (odds ratio, 15.43; 95% confidence interval, 3.60-66.14; P=0.0002, 525 subjects included). CONCLUSION: Biochemical markers at admission are valid predictors of mortality in hip fracture patients. PMID- 22236370 TI - The transcriptome of the adenovirus infected cell. AB - Alternations of cellular gene expression following an adenovirus type 2 infection of human primary cells were studied by using superior sensitive cDNA sequencing. In total, 3791 cellular genes were identified as differentially expressed more than 2-fold. Genes involved in DNA replication, RNA transcription and cell cycle regulation were very abundant among the up-regulated genes. On the other hand, genes involved in various signaling pathways including TGF-beta, Rho, G-protein, Map kinase, STAT and NF-kappaB stood out among the down-regulated genes. Binding sites for E2F, ATF/CREB and AP2 were prevalent in the up-regulated genes, whereas binding sites for SRF and NF-kappaB were dominant among the down-regulated genes. It is evident that the adenovirus has gained a control of the host cell cycle, growth, immune response and apoptosis at 24 h after infection. However, efforts from host cell to block the cell cycle progression and activate an antiviral response were also observed. PMID- 22236371 TI - Clinical outcome in 94 cases of dermal haemangiosarcoma in dogs treated with surgical excision: 1993-2007*. AB - Canine dermal haemangiosarcoma (HSA) is believed to have a better prognosis compared to HSA in other organs, but outcome has only been reported in a small number of dogs. The purpose of this study was to assess outcome and prognostic factors in a larger cohort of dogs with dermal HSA. Clinical data was collected retrospectively for 94 dogs and histopathology was reviewed in 53 dogs. Median overall survival time was 987 days. Dogs of predisposed breed with ventral location and histologic solar changes had longer survivals. Loco-regional recurrence occurred in 72/94 (77%) dogs. Predisposed breeds with ventral location and multiple masses were more likely to develop recurrence. Non-predisposed breeds with invasive tumours were more likely to develop metastasis. Results suggest that dogs with solar-induced dermal HSA may have high recurrence rates, but prolonged survivals. Dogs with non-solar tumours may be at increased risk for metastasis and shorter survival. PMID- 22236369 TI - Analysis of the interactions of viral and cellular factors with human cytomegalovirus lytic origin of replication, oriLyt. AB - Human cytomegalovirus transient lytic DNA replication relies on the cis-acting element oriLyt, six viral-encoded core proteins, the proposed DNA replication initiator protein UL84, IE2, IRS1 and the gene products from the UL112/113 loci. In an effort to elucidate cellular and viral-encoded factors that may play a role in oriLyt-dependent replication we used DNA-affinity purification and mass spectrometry to isolate and identify several previously unknown cellular and viral factors that interact with HCMV oriLyt DNA. These proteins include the multifunctional hnRNP-K, BUB3, HMGB1, PTB-1, UL83, UL112/113, and IRS1. Chromatin immunoprecipitation (ChIP) assays confirmed an interaction of several of these factors with oriLyt. Co-immunoprecipitation experiments detected an interaction between UL84 and hnRNP-K in infected and transfected cells. Knockdown of hnRNP K expression by siRNA inhibited the amplification of oriLyt in the transient assay. Together, these data suggest a possible regulatory role in DNA replication for several previously unidentified viral and cellular factors. PMID- 22236372 TI - Development of large-scale functional networks over the lifespan. AB - The development of large-scale functional organization of the human brain across the lifespan is not well understood. Here we used magnetoencephalographic recordings of 53 adults (ages 18-89) to characterize functional brain networks in the resting state. Slow frequencies engage larger networks than higher frequencies and show different development over the lifespan. Networks in the delta (2-4 Hz) frequency range decrease, while networks in the beta/gamma frequency range (> 16 Hz) increase in size with advancing age. Results show that the right frontal lobe and the temporal areas in both hemispheres are important relay stations in the expanding high-frequency networks. Neuropsychological tests confirmed the tendency of cognitive decline with older age. The decrease in visual memory and visuoconstructive functions was strongly associated with the age-dependent enhancement of functional connectivity in both temporal lobes. Using functional network analysis this study elucidates important neuronal principles underlying age-related cognitive decline paving mental deterioration in senescence. PMID- 22236373 TI - Investigating channel blockers for the treatment of multiple sclerosis: considerations with mefloquine and carbenoxolone. PMID- 22236374 TI - The effect of TNF-alpha, FcgammaR and CD1 polymorphisms on Guillain-Barre syndrome risk: evidences from a meta-analysis. AB - BACKGROUND AND OBJECTIVES: The findings on the associations between potential genetic variants and risk of Guillain-Barre syndrome (GBS) are controversial. We conducted a meta-analysis for candidate genes to provide the evidences for the current understanding of the genetic association with GBS. METHODS: We searched relevant studies without language restriction in PubMed, Embase and Cochrane library through May 2011. The strengths of the associations between genetic variants and GBS risk were estimated by odds ratios (ORs) with 95% confidence intervals (CIs). Random-effects models or fixed effects model was applied based on the heterogeneity test. RESULTS: We identified 12 case-control studies involving 1,590 GBS cases and 2,154 controls for the analysis. Because of limited eligible data, our meta-analysis specifically focused on 6 genetic variants of 3 candidate genes, TNF-alpha, FcgammaR and CD1. We found that TNF-alpha 308 G/A polymorphism was significantly associated with the risk of GBS in the overall population (GG+GA vs. AA: OR=0.32, 95%CI=0.16-0.62; GG vs. AA: OR=0.36, 95%CI=0.19-0.68). Subgroup analysis further provided evidence of significant association between TNF-alpha 308 G/A and risk of the GBS in Asian population (GG+GA vs. AA: OR=32, 95%CI=0.11-0.93; GG vs. AA: OR=0.32, 95%CI=0.15-0.68). In addition, we did not observe significant associations between FcgammaRIIA R/H, FcgammaRIIIA F/V, FcgammaRIIIB NA1/NA2, CD1A 1/2 and CD1E 1/2 polymorphisms and susceptibility for developing GBS. CONCLUSIONS: Our findings showed that TNF alpha 308A allele might be a moderate risk factor for GBS. However, the results should be interpreted with caution due to the limited number of studies available. PMID- 22236375 TI - Cancer stem cell sorting from colorectal cancer cell lines by sedimentation field flow fractionation. AB - Recently, cancer stem cells (CSCs) have been identified in many types of cancers, such as colorectal cancer (CRC). CSCs seem to be involved in initiation, growth, and tumor metastasis, as well as in radio- and chemotherapy failures. CSCs appears as new biological targets for cancer therapy, requiring the development of noninvasive cell sorting methods. In this study, we used sedimentation field flow fractionation (SdFFF) to prepare enriched populations of CSCs from eight cell lines corresponding to different CRC grades. On the basis of phenotypic and functional characterizations, "hyperlayer" elution resulted in a fraction overexpressing CSC markers (CD44, CD166, EpCAM) for all cell lines. CSCs were eluted in the last fraction for seven out of eight cell lines, but in the first for HCT116. These results suggest, according to the literature, that two different pools of CSCs exist, quiescent and activated, which can both be sorted by SdFFF. Moreover, according to CSC properties, enriched fractions are able to form colonies. PMID- 22236377 TI - Duration of antibiotic therapy in bacteraemia. PMID- 22236376 TI - Mutant pfcrt "SVMNT" haplotype and wild type pfmdr1 "N86" are endemic in Plasmodium vivax dominated areas of India under high chloroquine exposure. AB - BACKGROUND: Chloroquine resistance (CQR) phenotype in Plasmodium falciparum is associated with mutations in pfcrt and pfmdr-1 genes. Mutations at amino acid position 72-76 of pfcrt gene, here defined as pfcrt haplotype are associated with the geographic origin of chloroquine resistant parasite. Here, mutations at 72-76 and codon 220 of pfcrt gene and N86Y pfmdr-1 mutation were studied in blood samples collected across 11 field sites, inclusive of high and low P. falciparum prevalent areas in India. Any probable correlation between these mutations and clinical outcome of CQ treatment was also investigated. METHODS: Finger pricked blood spotted on Whatman No.3 papers were collected from falciparum malaria patients of high and low P. falciparum prevalent areas. For pfcrt haplotype investigation, the parasite DNA was extracted from blood samples and used for PCR amplification, followed by partial sequencing of the pfcrt gene. For pfmdr-1 N86Y mutation, the PCR product was subjected to restriction digestion with AflIII endonuclease enzyme. RESULTS: In 240 P. falciparum isolates with reported in vivo CQ therapeutic efficacy, the analysis of mutations in pfcrt gene shows that mutant SVMNT-S (67.50%) and CVIET-S (23.75%) occurred irrespective of clinical outcome and wild type CVMNK-A (7.91%) occurred only in adequate clinical and parasitological response samples. Of 287 P. falciparum isolates, SVMNTS 192 (66.89%) prevailed in all study sites and showed almost monomorphic existence (98.42% isolates) in low P. falciparum prevalent areas. However, CVIETS-S (19.51%) and CVMNK-A (11.84%) occurrence was limited to high P. falciparum prevalent areas. Investigation of pfmdr-1 N86Y mutation shows no correlation with clinical outcomes. The wild type N86 was prevalent in all the low P. falciparum prevalent areas (94.48%). However, mutant N86Y was comparably higher in numbers at the high P. falciparum prevalent areas (42.76%). CONCLUSIONS: The wild type pfcrt gene is linked to chloroquine sensitivity; however, presence of mutation cannot explain the therapeutic efficacy of CQ in the current scenario of chloroquine resistance. The monomorphic existence of mutant SVMNT haplotype, infer inbreeding and faster spread of CQR parasite in areas with higher P. vivax prevalance and chloroquine exposure, whereas, diversity is maintained in pfcrt gene at high P. falciparum prevalent areas. PMID- 22236378 TI - Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy. AB - BACKGROUND: Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. METHODS: Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. RESULTS: We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. CONCLUSION: Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects. PMID- 22236379 TI - Neuroethologically delineated differences in the seizure behavior of synapsin 1 and synapsin 2 knock-out mice. AB - The highly homologous nerve terminal phosphoproteins synapsin I and synapsin II have been linked to the pathogenesis of epilepsy through associations between synapsin gene mutations and epileptic disease in humans and to the observation of handling induced seizures in mice genetically depleted of one or both of these proteins. Whereas seizure behavior in mice lacking both synapsin I and synapsin II is well characterized, the seizure behavior in mice lacking either is less well studied. Through so called neuroethologically based analyses of fully established seizure behavior in Synapsin 1 and 2 knock-out mice (Syn1KO and Syn2KO mice) aged 4 1/2 months, this study reveals significant differences in the seizure behavior of the two genotypes: whereas Syn1KO mice show both partial and generalized forebrain seizure activity, Syn2KO mice show only fully generalized forebrain seizures. Analysis of seizure behavior at earlier stages shows that the mature seizure pattern in Syn2KO mice establishes rapidly from the age of ~2 months, when Syn1KO partial seizures are rare, and Syn1KO generalized seizures are almost absent. The specific behavioral phenotypes of the two strains suggest that the slight differences in structure, function and expression of these highly related proteins could be important factors during seizure generating neural activity. PMID- 22236381 TI - Helicobacter pylori has an unprecedented nitric oxide detoxifying system. AB - AIMS: The ability of pathogens to cope with the damaging effects of nitric oxide (NO), present in certain host niches and produced by phagocytes that support innate immunity, relies on multiple strategies that include the action of detoxifying enzymes. As for many other pathogens, these systems remained unknown for Helicobacter pylori. This work aimed at identifying and functionally characterizing an H. pylori system involved in NO protection. RESULTS: In the present work, the hp0013 gene of H. pylori is shown to be related to NO resistance, as its inactivation increases the susceptibility of H. pylori to nitrosative stress, and significantly decreases the NADPH-dependent NO reduction activity of H. pylori cells. The recombinant HP0013 protein is able to complement an NO reductase-deficient Escherichia coli strain and exhibits significant NO reductase activity. Mutation of hp0013 renders H. pylori more vulnerable to nitric oxide synthase-dependent macrophage killing, and decreases the ability of the pathogen to colonize mice stomachs. INNOVATION: Phylogenetic studies reveal that HP0013, which shares no significant amino acid sequence similarity to the other so far known microbial NO detoxifiers, belongs to a novel family of proteins with a widespread distribution in the microbial world. CONCLUSION: H. pylori HP0013 represents an unprecedented enzymatic NO detoxifying system for the in vivo microbial protection against nitrosative stress. PMID- 22236382 TI - Connection tubing causing small bowel obstruction and colonic erosion as a rare complication after laparoscopic gastric banding: a case report. AB - INTRODUCTION: Laparoscopic adjustable gastric banding is the most frequently performed bariatric procedure for the treatment of morbid obesity and is associated with low morbidity and mortality. Complications related to obesity surgery are rare and their presentation is often non-specific. Thus, it is highly important for physicians who are practising bariatric surgery to be aware of complications described in single-case studies or series when they come across similar complications even years after the primary bariatric operation. CASE PRESENTATION: We report the case of a 47-year-old Malay woman who was admitted with symptoms and signs suggesting intestinal obstruction five years after gastric band placement. CONCLUSIONS: In our patient, the band connection wire tube was the cause of both small bowel obstruction and colonic erosion. Computed axial tomography is the cornerstone of the investigation of such patients. After surgical removal of the connecting tube, our patient recovered without sequelae. PMID- 22236383 TI - Neurorepair with mesenchymal stem cells: hope or hype? PMID- 22236384 TI - Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. AB - BACKGROUND: More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. METHODS: Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5.5-6.5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200. FINDINGS: We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1.6*10(6) cells per kg bodyweight (range 1.1-2.0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0.02 logMAR units, 95% CI -0.03 to -0.01; p=0.003) and visual evoked response latency (-1.33 ms, -2.44 to -0.21; p=0.020), with an increase in optic nerve area (difference in monthly rates of change 0.13 mm(2), 0.04 to 0.22; p=0.006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. INTERPRETATION: Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. FUNDING: Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust. PMID- 22236385 TI - The worship to abbreviations: idolatry or virtue. PMID- 22236387 TI - Knowledge is power: studying critical incidents in intensive care. AB - Despite their difficult definition and taxonomy, it is imperative to study critical incidents in intensive care, since they may be followed by adverse events and compromised patient safety. Identifying recurring patterns and factors contributing to critical incidents constitutes a prerequisite for developing effective preventive strategies. Self-reporting methodology, although widely used for studying critical incidents, has been criticized in terms of reliability and may considerably underestimate both overall frequency and specific types of them. Promotion of non-blaming culture, analysis of critical incident reports and development of clinical recommendations are expected to minimize critical incidents in the future. PMID- 22236389 TI - Mapping right ventricular myocardial mechanics using 3D cine DENSE cardiovascular magnetic resonance. AB - BACKGROUND: The mechanics of the right ventricle (RV) are not well understood as studies of the RV have been limited. This is, in part, due to the RV's thin wall, asymmetric geometry and irregular motion. However, the RV plays an important role in cardiovascular function. This study aims to describe the complex mechanics of the healthy RV using three dimensional (3D) cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR). METHODS: Whole heart 3D cine DENSE data were acquired from five healthy volunteers. Tailored post-processing algorithms for RV mid-wall tissue tracking and strain estimation are presented. A method for sub-dividing the RV into four regions according to anatomical land marks is proposed, and the temporal evolution of strain was assessed in these regions. RESULTS: The 3D cine DENSE tissue tracking methods successfully capture the motion and deformation of the RV at a high spatial resolution in all volunteers. The regional Lagrangian peak surface strain and time to peak values correspond with previous studies using myocardial tagging, DENSE and strain encoded CMR. The inflow region consistently displays lower peak strains than the apical and outflow regions, and the time to peak strains suggest RV mechanical activation in the following order: inflow, outflow, mid, then apex. CONCLUSIONS: Model-free techniques have been developed to study the myocardial mechanics of the RV at a high spatial resolution using 3D cine DENSE CMR. The consistency of the regional RV strain patterns across healthy subjects is encouraging and the techniques may have clinical utility in assessing disrupted RV mechanics in the diseased heart. PMID- 22236388 TI - Target product profiles for protecting against outdoor malaria transmission. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) and indoor residual sprays (IRS) have decimated malaria transmission by killing indoor-feeding mosquitoes. However, complete elimination of malaria transmission with these proven methods is confounded by vectors that evade pesticide contact by feeding outdoors. METHODS: For any assumed level of indoor coverage and personal protective efficacy with insecticidal products, process-explicit malaria transmission models suggest that insecticides that repel mosquitoes will achieve less impact upon transmission than those that kill them outright. Here such models are extended to explore how outdoor use of products containing either contact toxins or spatial repellents might augment or attenuate impact of high indoor coverage of LLINs relying primarily upon contact toxicity. RESULTS: LLIN impact could be dramatically enhanced by high coverage with spatial repellents conferring near complete personal protection, but only if combined indoor use of both measures can be avoided where vectors persist that prefer feeding indoors upon humans. While very high levels of coverage and efficacy will be required for spatial repellents to substantially augment the impact of LLINs or IRS, these ambitious targets may well be at least as practically achievable as the lower requirements for equivalent impact using contact insecticides. CONCLUSIONS: Vapour-phase repellents may be more acceptable, practical and effective than contact insecticides for preventing outdoor malaria transmission because they need not be applied to skin or clothing and may protect multiple occupants of spaces outside of treatable structures such as nets or houses. PMID- 22236390 TI - Endobronchial valve deployment in severe alpha-1 antitrypsin deficiency emphysema: a case series. AB - INTRODUCTION: Patients with end-stage emphysema because of alpha-1 antitrypsin (AAT) deficiency represent a challenging clinical management problem, and studies of volume reduction therapy to date have largely excluded these patients. We report the outcome of bronchoscopic volume reduction with the insertion of Emphasys endobronchial valves (Emphasys Medical, Redwood City, CA, USA) in six patients with end-stage emphysema because of AAT deficiency. CASE SERIES: Of 51 patients with end stage emphysema referred for transplantation, we studied six patients with AAT deficiency and utilized the BODE index and lung allocation score for survival estimation. MEASUREMENTS AND MAIN RESULTS: The forced expiratory volume in 1s improved from a median of 0.575L to 0.905L (P=0.028). There was a median reduction in total lung capacity (TLC) of 0.61L. The residual volume /TLC fell from 74.0% to 58.4%. Before treatment, four patients had a BODE index of greater than eight units, which correlates with a 4-year survival of 18%. After treatment, two patients improved their BODE index to below seven units, which correlates with an estimated 4-year survival of over 50%. CONCLUSIONS: The data from this case series suggest that this intervention may provide bridging therapy to subsequent transplantation for younger AAT patients with end-stage emphysema. PMID- 22236386 TI - Animal models of the non-motor features of Parkinson's disease. AB - The non-motor symptoms (NMS) of Parkinson's disease (PD) occur in roughly 90% of patients, have a profound negative impact on their quality of life, and often go undiagnosed. NMS typically involve many functional systems, and include sleep disturbances, neuropsychiatric and cognitive deficits, and autonomic and sensory dysfunction. The development and use of animal models have provided valuable insight into the classical motor symptoms of PD over the past few decades. Toxin induced models provide a suitable approach to study aspects of the disease that derive from the loss of nigrostriatal dopaminergic neurons, a cardinal feature of PD. This also includes some NMS, primarily cognitive dysfunction. However, several NMS poorly respond to dopaminergic treatments, suggesting that they may be due to other pathologies. Recently developed genetic models of PD are providing new ways to model these NMS and identify their mechanisms. This review summarizes the current available literature on the ability of both toxin-induced and genetically-based animal models to reproduce the NMS of PD. PMID- 22236391 TI - Verrucous skin lesions on the feet in diabetic neuropathy successfully treated with topical maxacalcitol. PMID- 22236392 TI - A two-session psychological intervention for siblings of pediatric cancer patients: a randomized controlled pilot trial. AB - BACKGROUND: Since siblings of pediatric cancer patients are at risk for emotional, behavioral, and social problems, there is considerable interest in development of early psychological interventions. This paper aimed at evaluating the effectiveness of a two-session psychological intervention for siblings of newly diagnosed pediatric cancer patients. METHODS: Thirty siblings age 6-17 years were randomly assigned to an intervention group or an active control group with standard psychosocial care. The manualized intervention provided to siblings in the first 2 months after the cancer diagnosis of the ill child included medical information, promotion of coping skills, and a psychoeducational booklet for parents. At 4 to 6 weeks, 4 months, and 7 months after the diagnosis, all siblings and their parents completed measures (from standardized instruments) of social support, quality of life, medical knowledge, posttraumatic stress symptoms, and anxiety. RESULTS: At follow-up siblings in the intervention group showed better psychological well-being, had better medical knowledge, and reported receiving social support from more people. However, the intervention had no effects on posttraumatic stress symptoms and anxiety. CONCLUSIONS: The results of this pilot trial suggest that a two-session sibling intervention can improve siblings' adjustment, particularly psychological well-being, in the early stage after a cancer diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00296907. PMID- 22236393 TI - Red cell microparticle enumeration: validation of a flow cytometric approach. AB - BACKGROUND AND OBJECTIVES: There is growing interest in the clinical application of red blood cell (RBC) microparticle (MP) enumeration as they have been postulated to be effectors of coagulation and inflammation following transfusion and in sickle cell disease. No uniform approach in MP enumeration exists and a key limitation is the lack of an internal validation process. We present and validate a flow cytometric approach where an internal standard is utilized. MATERIALS AND METHODS: Glycophorin A(+) Annexin V(+) events were enumerated using MPs isolated from RBC units or plasma samples obtained from volunteers. A mixture of absolute counting (7.6 MUm) and calibration beads (0.5, 0.9 and 3 MUm) at a fixed ratio was added to each sample. RESULTS: RBC MPs were initially selected based upon a fluorescence threshold, and the 0.5- and 0.9-MUm beads defined the upper and lower light scatter distribution of MPs. The ratio of 7.6:3-MUm bead events was used as an internal standard to validate the precision of MP enumeration across samples (coefficient of variation = 2.5-7.2%) and remained constant in both platelet-rich plasma (PRP) and platelet-free plasma (PFP). RBC MP counts increased in both PRP and PFP obtained from whole blood stimulated with ionophore and increasing calcium concentrations, with PRP showing higher MP counts than PFP at every concentration studied. CONCLUSION: This method is a useful strategy to detect RBC MP counts across bio-samples provided that the flow cytometer can reliably discriminate the size of the calibration beads. PMID- 22236394 TI - Copeptin in aneurysmal subarachnoid hemorrhage. AB - Copeptin is a peptide derived from pre-provasospression along with arginine vasospressin. In the setting of aneurysmal subarachnoid hemorrhage (SAH), elevated serum copeptin levels correlate with vasospasm, inpatient mortality, mortality at 1 year, and poor functional outcome at 1 year. The potential role of serum copeptin levels in the management of patients with aneurysmal SAH is promising and should be explored further. PMID- 22236395 TI - Distance to health services influences insecticide-treated net possession and use among six to 59 month-old children in Malawi. AB - BACKGROUND: Health ministries and providers are rapidly scaling up insecticide treated nets (ITN) distribution to control malaria, yet possession and proper use typically remain below targeted levels. In Malawi, health facilities (HFs) are currently the principal points of ITN distribution, making it important to understand how access to these ITN sources affects ownership, possession, and use. The authors evaluated the association between proximity to HFs and ITN possession or use among Malawian children six to 59 months of age. METHODS: A household malaria survey undertaken in eight districts of Malawi during 2007 was used to characterize ITN possession and use. The location of each respondent's household was geocoded as was those of Ministry of Health (MoH) HFs and other health centres. Euclidean distance from each household to the nearest HF was calculated. Patterns of net possession and use were determined through descriptive methods. The authors then analysed the significance of distance and ITN possession/use through standard statistical tests, including logistic regression. RESULTS: Median distance to HFs was greater among households that did not possess ITNs and did not use an ITN the previous evening. Descriptive statistical methods confirmed a pattern of decreasing ITN possession and use with increasing distance from HFs. Logistic regression showed the same statistically significant association of distance to HFs, even when controlling for age and gender of the child, ratio of nets to children in household, community net possession and use, and household material wealth. CONCLUSIONS: Strategies that exclusively distribute ITNs through HFs are likely to be less effective in increasing possession and use in communities that are more distant from those health services. Health providers should look towards community-based distribution services that take ITNs directly to community members to more effectively scale up ITN possession and regular use aimed at protecting children from malaria. PMID- 22236396 TI - Decreased blood pressure with a corresponding decrease in adhesive molecules in diabetic rats caused by vitamin E administration. AB - BACKGROUND: Hypertension is one of the important clinical problems of diabetic cardiovascular disease. The aim of this study was to determine the effect of vitamin E on blood pressure parameters and adhesive molecule amounts in diabetic rats. METHODS: Twenty-four male Wistar rats were divided into three groups (each of n = 8): the controls (C), non-treated diabetic (NTD), and vitamin E treated diabetic (VETD) groups. A single intraperitoneal injection of buffered streptozotocin (60 mg/kg) in cold sodium citrate (pH 4.5) was used to induce diabetes. The VETD group received 300 mg of vitamin E daily intragastrically for 6 weeks. Systolic and diastolic blood pressure, mean arterial pressure, as well as the dicrotic pressure, crest time, systolic and diastolic periods, and plasma levels of intercellular adhesion molecule-1 and E-selectin were measured after 6 weeks. RESULTS: The results revealed that there was a significant increase in systolic and diastolic blood pressures, mean arterial pressure, crest time, systolic duration, and the amount of sICAM-1 and E-selectin in diabetic rats. There was no significant difference in the heart rate or cardiac cyclic duration among the different groups. Significant improvement of blood pressure parameters as well as attenuation of the elevated ICAM-1 and E-selectin amounts was found in the vitamin E treated group. CONCLUSIONS: These findings indicate that vitamin E significantly improved blood pressure elevation in diabetic rats and that these effects could be associated with reducing adhesive molecule and antioxidant properties of vitamin E. PMID- 22236398 TI - Blocking of CTLA-4 on lymphocytes improves the sensitivity of lymphocyte transformation tests in a patient with nickel allergy. PMID- 22236397 TI - Frailty in primary care: a review of its conceptualization and implications for practice. AB - Frail, older patients pose a challenge to the primary care physician who may often feel overwhelmed by their complex presentation and tenuous health status. At the same time, family physicians are ideally suited to incorporate the concept of frailty into their practice. They have the propensity and skill set that lends itself to patient-centred care, taking into account the individual subtleties of the patient's health within their social context. Tools to identify frailty in the primary care setting are still in the preliminary stages of development. Even so, some practical measures can be taken to recognize frailty in clinical practice and begin to address how its recognition may impact clinical care. This review seeks to address how frailty is recognised and managed, especially in the realm of primary care. PMID- 22236399 TI - Evaluation of objective and subjective indicators of death in a period of one year in a sample of prevalent patients under regular hemodialysis. AB - BACKGROUND: To identify objective and subjective indicators of death in prevalent hemodialysis (HD) patients in a follow-up study of 12 months. METHODS: The study included end-stage renal disease patients undergoing HD and analyzed demographic and laboratory data from the dialysis unit's records. Baseline data concerning socioeconomic status, comorbidity, quality of life level, coping style and depression were also assessed. For variables that differed in the comparison between survivors and non-survivors, Cox proportional hazards for death were calculated. RESULTS: The mortality rate was 13.0%. Non-survivors differed in age, comorbidity, inclusion on the transplant waiting list and physical functioning score. The hazard ratios of death were 8.958 (2.843-28.223; p < 0.001) for comorbidity, 3.992 (1.462-10.902; p = 0.007) for not being on the transplant waiting list, 1.038 (1.012-1.066; p = 0.005) for age, and 0.980 (0.964-0.996; p = 0.014) for physical functioning. CONCLUSIONS: Comorbidity, not being on the transplant waiting list, age and physical functioning, which reflects physical status, must be seen as risk indicators of death among patients undergoing HD. PMID- 22236400 TI - Supramandibular canal portion superior to the fossa of the submaxillary gland: a tomographic evaluation of the cross-sectional dimension in the molar region. AB - PURPOSE: Within the fossa of the submaxillary gland (FSG), there is a portion superior to the mandibular canal (SMCP) that can affect implant placement. Our study evaluated this specific portion's prevalence and its average dimensional difference between the first and the second molar regions in a dental implant population. MATERIALS AND METHODS: From 112 patients' mandibular cone beam computerized tomography scans, the SMCPs of the FSG's horizontal and vertical dimensions in the first and second molar positions on both sides were digitally measured. RESULTS: The SMCP of the FSG is larger in the second molar region than in the first molar region in >90% of cases. Average differences were 2.3 mm horizontally and 2.7 mm vertically. Gender difference and intraindividual's left/right variation were both clinically less significant in magnitude than the difference between the molar regions. Taking the 2-mm safety margin above the mandibular canal into consideration, the SMCP of the FSG remained high in prevalence. CONCLUSIONS: The SMCP of the FSG may complicate implant placement more in the second molar region than in the first. Implant planning in the posterior mandibular molar regions should include a SMCP of the FSG evaluation using computer tomography especially in the second molar region. PMID- 22236401 TI - Development of the breast milk expression experience measure. AB - Exclusive breastfeeding provides optimal nutrition through 6 months. Recent research has shown that milk expression may affect breastfeeding duration. A woman's experience with milk expression might mediate the effect of milk expression on breastfeeding duration. The objective of this study was to develop a measure to evaluate women's experiences of expressing milk. Based on the available literature, we developed a brief measure of the Breast Milk Expression Experience (BMEE) assessing three dimensions: (1) social support for milk expression; (2) ease of learning how to express milk; and (3) personal experiences of milk expression. All items used 1-5 Likert scales, with higher scores indicating better experiences. We administered the items immediately after expression to 68 mothers who expressed milk post-partum. We evaluated this measure for reliability using Cronbach's alpha. Mothers completing the BMEE were 57% primiparous with 75% vaginal births. The BMEE demonstrated appropriate reliability with a Cronbach's alpha of 0.703 for the summary index and 0.719 0.763 for social support, learning experience and personal experience subscales. The BMEE also indicated good predictive validity; of the six mothers who had a mean score <3 on the 11-item scale post-partum, two (33.3%) were expressing breast milk at 1 month, compared with 37 (80.4%) of the 46 mothers who had a mean score >=3 on the 11-item scale post-partum (P = 0.012). The BMEE is a promising measure of milk expression experience in this population. Use of this measure may allow improved understanding of women's experiences expressing milk. PMID- 22236402 TI - Effect of meal content on heart rate variability and cardiovascular reactivity to mental stress. AB - Little is known about transient effects of foods and nutrients on reactivity to mental stress. In a randomized crossover study of healthy adults (n=20), we measured heart rate variability (respiratory sinus arrhythmia), blood pressure, and other hemodynamic variables after three test meals varying in type and amount of fat. Measurements were collected at rest and during speech and cold pressor tasks. There were significant postmeal changes in resting diastolic blood pressure (-4%), cardiac output (+18%), total peripheral resistance (-17%), and interleukin-6 (-27%). Heart rate variability and hemodynamic reactivity to stress was not affected by meal content. We recommend that future studies control for time since last meal and continue to examine effects of meal content on heart rate variability. PMID- 22236403 TI - Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. AB - Dendritic cells (DCs) are known as antigen-presenting cells and play a central role in both innate and acquired immunity. Peripheral blood monocytes give rise to resident and recruited DCs in lymph nodes and non-lymphoid tissues. The ligands of nuclear hormone receptors can modulate DC differentiation and so influence various biological functions of DCs. The role of bile acids (BAs) as signalling molecules has recently become apparent, but the functional role of BAs in DC differentiation has not yet been elucidated. We show that DCs derived from human peripheral blood monocytes cultured with a BA produce lower levels of interleukin-12 (IL-12) and tumour necrosis factor-alpha in response to stimulation with commensal bacterial antigens. Stimulation through the nuclear receptor farnesoid X (FXR) did not affect the differentiation of DCs. However, DCs differentiated with the specific agonist for TGR5, a transmembrane BA receptor, showed an IL-12 hypo-producing phenotype. Expression of TGR5 could only be identified in monocytes and was rapidly down-regulated during monocyte differentiation to DCs. Stimulation with 8-bromoadenosine-cyclic AMP (8-Br-cAMP), which acts downstream of TGR5 signalling, also promoted differentiation into IL 12 hypo-producing DCs. These results indicate that BAs induce the differentiation of IL-12 hypo-producing DCs from monocytes via the TGR5-cAMP pathway. PMID- 22236404 TI - Carboxyhemoglobin levels in medical intensive care patients: a retrospective, observational study. AB - INTRODUCTION: Critical illness leads to increased endogenous production of carbon monoxide (CO) due to the induction of the stress-response enzyme, heme oxygenase 1 (HO-1). There is evidence for the cytoprotective and anti-inflammatory effects of CO based on animal studies. In critically ill patients after cardiothoracic surgery, low minimum and high maximum carboxyhemoglobin (COHb) levels were shown to be associated with increased mortality, which suggests that there is an 'optimal range' for HO-1 activity. Our study aimed to test whether this relationship between COHb and outcome exists in non-surgical ICU patients. METHODS: We conducted a retrospective, observational study in a medical ICU at a university hospital in Vienna, Austria involving 868 critically ill patients. No interventions were undertaken. Arterial COHb was measured on admission and during the course of treatment in the ICU. The association between arterial COHb levels and ICU mortality was evaluated using bivariate tests and a logistic regression model. RESULTS: Minimum COHb levels were slightly lower in non-survivors compared to survivors (0.9%, 0.7% to 1.2% versus 1.2%, 0.9% to 1.5%; P=0.0001), and the average COHb levels were marginally lower in non-survivors compared to survivors (1.5%, 1.2% to 1.8% versus 1.6%, 1.4% to 1.9%, P=0.003). The multivariate logistic regression analysis revealed that the association between a low minimum COHb level and increased mortality was independent of the severity of illness and the type of organ failure. CONCLUSIONS: Critically ill patients surviving the admission to a medical ICU had slightly higher minimum and marginally higher average COHb levels when compared to non-survivors. Even though the observed differences are statistically significant, the minute margins would not qualify COHb as a predictive marker for ICU mortality. PMID- 22236405 TI - LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia. AB - ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants (n = 1,250) in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Multivariate linear regression and two-way ANOVA for percent change in apoC-III level were performed. SNPs in the lipoprotein lipase (LPL) gene region, rs1801177 (P = 4.7 * 10(-8)), rs7016529 (P = 1.2 * 10(-6)), and rs249 (P = 4.1 * 10(-5)), were associated with apoC-III response to combination therapy. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoC-III increase in response to statins and FA. This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy. PMID- 22236406 TI - Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. AB - Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases. PMID- 22236407 TI - Nutritional status and growth of indigenous Xavante children, Central Brazil. AB - BACKGROUND: The aim of this study was to characterize the nutritional status of Xavante Indian children less than 10 years of age in Central Brazil and to evaluate the hypothesis of an association between child nutrition and socioeconomic differentiation in this population. METHODS: A cross-sectional study was conducted in July 2006 that included all children under the age of 10 from the Xavante village Pimentel Barbosa in Mato Grosso, Brazil. The data collected included weight, height, and sociodemographic information. Sociodemographic data were used to generate two indices ("income" and "wealth") and to determine the proportion of adults in each household. Descriptive analyses were performed for weight-for-age (W/A), height-for-age (H/A), and weight-for height (W/H) using the NCHS and the WHO growth references. Univariate and multivariate analyses were conducted using H/A and W/A as a response variables. RESULTS: Of a total of 246 children under the age of ten residing in the village, 232 (94.3%) were evaluated. Following the NCHS reference, 5.6% of children under the age of ten presented low W/A and 14.7% presented low H/A. Among children under the age of five, deficit percentages for weight and height were 4.5% and 29.9%, respectively, following the WHO curves. Among children < 2 years of age, H/A index variability was found to be directly related to child's age and inversely related to the proportion of adults in the household. Maternal BMI was positively associated with growth for children from 2 to 4 years of age, explaining 11.5% of the z-score variability for the H/A index. For children 5 years of age and older, the wealth index and maternal height were positively associated with H/A. No significant associations were found using W/A as the dependent variable. CONCLUSION: This study demonstrated that undernutrition, in particular linear growth deficit, is a notable health issue for Xavante children. These findings contrast with the nutritional profile observed among Brazilian children nationally, which is characterized by a sharp decline in child undernutrition in recent decades, even in the poorest regions of the country. This discrepancy calls attention to the persistent health disparities that exist between indigenous and non-indigenous people in Brazil. PMID- 22236408 TI - Targeting sphingosine kinase-1 to inhibit melanoma. AB - Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage-dependent and -independent growth as well as sensitized melanoma cells to apoptosis-inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID- 22236410 TI - Glucagon-like peptide-1 agonists. PMID- 22236409 TI - Interactions between prostaglandins, leukotrienes and HIV-1: possible implications for the central nervous system. AB - In HIV-1-infected individuals, there is often discordance between viremia in peripheral blood and viral load found in the central nervous system (CNS). Although the viral burden is often lower in the CNS compartment than in the plasma, neuroinflammation is present in most infected individuals, albeit attenuated by the current combined antiretroviral therapy. The HIV-1-associated neurological complications are thought to result not only from direct viral replication, but also from the subsequent neuroinflammatory processes. The eicosanoids - prostanoids and leukotrienes - are known as potent inflammatory lipid mediators. They are often present in neuroinflammatory diseases, notably HIV-1 infection. Their exact modulatory role in HIV-1 infection is, however, still poorly understood, especially in the CNS compartment. Nonetheless, a handful of studies have provided evidence as to how these lipid mediators can modulate HIV-1 infection. This review summarizes findings indicating how eicosanoids may influence the progression of neuroAIDS. PMID- 22236411 TI - Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. AB - OBJECTIVE: To determine whether treatment with agonists of glucagon-like peptide 1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus. DESIGN: Systematic review with meta-analyses. DATA SOURCES: Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin. DATA EXTRACTION: Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors. RESULTS: 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference -2.9 kg, 95% confidence interval -3.6 to -2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (-3.2 kg, -4.3 to -2.1; three trials) as well as patients with diabetes (-2.8 kg, -3.4 to -2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia. CONCLUSIONS: The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus. PMID- 22236414 TI - [Quality assurance and quality improvement in medical practice. Part 1. Definition and importance of quality in medical practice]. AB - In Hungary, financing of healthcare has decreased relative to the GDP, while the health status of the population is still ranks among the worst in the European Union. Since healthcare financing is not expected to increase, the number of practicing doctors per capita is continuously decreasing. In the coming years, it is an important question that in this situation what methods can be used to prevent further deterioration of the health status of the Hungarian population, and within this is the role of the quality approach, and different methods of quality management. In the present and the forthcoming two articles those standpoints will be summarized which support the need for the integration of quality assurance in the everyday medical practice. In the first part the importance of quality thinking, quality management, quality assurance, necessity of quality measurement and improvement, furthermore, advantages of the quality systems will be discussed. PMID- 22236413 TI - New data on the presence of hemocyanin in Plecoptera: recomposing a puzzle. AB - The specific role of hemocyanin in Plecoptera (stoneflies) is still not completely understood, since none of the hypotheses advanced have proven fully convincing. Previous data show that mRNA hemocyanin sequences are not present in all Plecoptera, and that hemocyanin does not seem to be uniformly distributed within the order. All species possess hexamerins, which are multifunction proteins that probably originated from hemocyanin. In order to obtain an increasingly detailed picture on the presence and distribution of hemocyanin across the order, this study presents new data regarding nymphs and adults of selected Plecoptera species. Results confirm that the hemocyanin expression differs among nymphs in the studied stonefly species. Even though previous studies have found hemocyanin in adults of two stonefly species it was not detected in the present study, even in species where nymphs show hemocyanin, suggesting that the physiological need of this protein can change during life cycle. The phylogenetic pattern obtained using hemocyanin sequences matches the accepted scheme of traditional phylogeny based on morphology, anatomy, and biology. It is remarkable to note that the hemocyanin conserved region acts like a phylogenetic molecular marker within Plecoptera. PMID- 22236415 TI - [Diagnostic endoscopic ultrasonography in the gastrointestinal tract]. AB - Endoscopic ultrasonography is a relatively new technology that combines the use of flexible fiberoptic endoscopes with high-resolution ultrasound technology. It proved to be highly accurate and useful in the staging of gastrointestinal malignancies, as well as in characterizing the nature of subepithelial lesions and disorders of the pancreaticobiliary system. In this overview the variety of current evidence based diagnostic options of endoscopic ultrasonography are discussed. PMID- 22236416 TI - [Study of incidence and treatment of acute myocardial infarction by evaluating the financing database: 2004-2009]. AB - In Hungary we have no comprehensive data on hospital care and short and long term prognosis of patients with myocardial infarction. AIMS: To collect data on number, hospital care and prognosis of patients treated for myocardial infarction in all Hungarian hospitals. METHODS: Authors studied the number of patients treated in hospital for acute myocardial infarction, the frequency of revascularization by coronary angioplasty during treatment, as well as the 30 and 365 day mortality of patients by the evaluation of the financing database of the National Health Insurance Fund for 6 years (2004-2009). RESULTS: There has been no major change during the observation period in the number of patients treated in hospital for myocardial infarction (approximately 16,500 cases/year). The incidence in males (calculated by the number of patients treated in hospital) is higher in any age group compared to females; this difference is lower in older age groups. During the observation period the 30 and 365 day mortality has decreased by 1.8% (18.9% vs. 17.1% and 29.9% vs. 28.1%, respectively), which was caused by a decrease in the mortality of patients above age 70. The percentage of revascularization by coronary angioplasty during the treatment of myocardial infarction has significantly increased (18.2% vs. 49.8%). The International Classification of Diseases does not differentiate between the different forms of myocardial infarction, therefore the prognostic effects of coronary angioplasty cannot be evaluated in this respect. CONCLUSIONS: Authors conclude that the financing database is suitable to evaluate the major aspects of care and to support healthcare management decisions, while the appropriateness of treatment and the effectiveness of different interventions can be assessed by prospective databases satisfying the needs of special aspects and can therefore be used for detailed assessments. PMID- 22236412 TI - Influence of experience on performance of individual surgeons in thyroid surgery: prospective cross sectional multicentre study. AB - OBJECTIVE: To determine the association between surgeons' experience and postoperative complications in thyroid surgery. DESIGN: Prospective cross sectional multicentre study. SETTING: High volume referral centres in five academic hospitals in France. PARTICIPANTS: All patients who underwent a thyroidectomy undertaken by every surgeon in these hospitals from 1 April 2008 to 31 December 2009. MAIN OUTCOME MEASURES: Presence of two permanent major complications (recurrent laryngeal nerve palsy or hypoparathyroidism), six months after thyroid surgery. We used mixed effects logistic regression to determine the association between length of experience and postoperative complications. RESULTS: 28 surgeons completed 3574 thyroid procedures during a one year period. Overall rates of recurrent laryngeal nerve palsy and hypoparathyroidism were 2.08% (95% confidence interval 1.53% to 2.67%) and 2.69% (2.10% to 3.31%), respectively. In a multivariate analysis, 20 years or more of practice was associated with increased probability of both recurrent laryngeal nerve palsy (odds ratio 3.06 (1.07 to 8.80), P=0.04) and hypoparathyroidism (7.56 (1.79 to 31.99), P=0.01). Surgeons' performance had a concave association with their length of experience (P=0.036) and age (P=0.035); surgeons aged 35 to 50 years had better outcomes than their younger and older colleagues. CONCLUSIONS: Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further. PMID- 22236417 TI - [Nondetectable prostate cancer in radical prostatectomy specimens]. AB - Since the widespread use of prostate-specific antigen, early diagnosis of prostate cancer at an early stage has been increased. Consequently, a greater frequency of low-volume disease or no tumor has been found in radical prostatectomy specimen. AIMS: In the present study authors analyzed patients classified as pT0 after radical prostatectomy at their center. METHODS: 1134 radical prostatectomies were evaluated retrospectively at the author's center between 1996 and 2010. If there was no evidence of prostate cancer in the specimen, patient was staged as pT0. Patients were divided into two groups: received neoadjuvant hormonal therapy or not. RESULTS: Overall 32 (2.8%) patients were staged as pT0. The rate of pT0 staging was 9.3% and 1.2% in the hormonally treated group and non-hormonally treated group. False-positive prostate biopsy was found in 2 cases. The rate of pT0 staging was higher in patients with incidental prostate cancer, low Gleason score and enlarged prostate. Biochemical relapse was observed in 3 pT0 patients in the hormonally treated group, among them there was one clinical relapse. In non-hormonally treated group no recurrence was detected. CONCLUSION: The rate of pT0 staging was higher in the hormonally treated group. Because of biochemical and clinical relapse despite vanishing prostate cancer phenomenon, these cases are considered not to be true pT0. On the basis of present study and other reports the rate of pT0 staging is about one percentage in non-hormonally treated patients. Prognosis of these patients is excellent. PMID- 22236419 TI - Lymphatic filariasis mapping by immunochromatographic test cards and baseline microfilaria survey prior to mass drug administration in Sierra Leone. AB - BACKGROUND: National mapping of lymphatic filariasis (LF) was conducted using immunochromatographic tests (ICT) in 2005 to determine endemicity and geographic spread of the disease. A baseline microfilaria survey was then conducted to determine LF prevalence and microfilaria intensity. METHODS: In 2005 1,982 persons of 15 years and over from 14 health districts were selected and fingertip blood samples were tested with ICT cards. In 2007-8 blood samples were taken between 10 p.m. and 2 a.m. and examined for microfilaria (mf) from 9,288 persons from 16 sentinel sites representing each district and 2 additional sites for districts with populations over 500,000 (Bo and Kenema). RESULTS: The overall LF prevalence by ICT cards was 21% (males 28%, females 15%). All districts had a prevalence of Wuchereria bancrofti antigen > 1%. Distribution of LF prevalence showed a strong spatial correlation pattern with high prevalence in a large area in the northeast gradually decreasing to a relatively low prevalence in the southwest coast. High prevalence was found in the northeast, Bombali (52%), Koinadugu (46%), Tonkolili (37%) and Kono (30%). Low prevalence was found in the southwest, Bonthe (3%) and Pujehun (4%). The mf prevalence was higher in the northeast: Bombali, 6.7%, Koinadugu 5.7%, Port Loko 4.4% and Kono 2.4%. Overall there was a significant difference in mf prevalence by gender: males 2.9%, females 1.8% (p = 0.0002) and within districts in Kailahun, Kono, Port Loko, Moyamba and Koinadugu (all p < 0.05). The mf prevalence was higher in people > 20 years (2.5%) than in people <= 20 years (1.7%) (p = 0.043). The overall arithmetic mean mf density was 50.30 mf/ml among mf-positive individuals and 1.19 mf/ml in the population examined which varied significantly between districts. CONCLUSIONS: The ICT results showed that LF was endemic nationwide and that preventive chemotherapy (PCT) was justified across the country. Both the ICT and microfilaraemia surveys found that prevalence was greater in males than females. The increase in microfilaraemia prevalence by age was evident when grouped as <= 20 versus > 20 years demonstrating early exposure. Baseline LF microfilaria load will be used to monitor PCT program progress. PMID- 22236420 TI - Abutment rotational freedom evaluation of external hexagon single-implant restorations after mechanical cycling. AB - PURPOSE: The purpose of this study was to evaluate the rotational freedom between implant and abutment counterpart of two abutments types over external hexagon implants submitted to mechanical cycling. MATERIALS AND METHODS: Ten implants with external hexagon (3.75 mm * 13 mm), five cast abutments, and five premachined abutments both with 4.1 mm plataform size were used in this study. Ten metallic crowns were fabricated using the two types of abutments and were fixed to each implant using titanium screws (Ti6Al4V). Rotational freedom measurements were made before and after the cast procedure and after the mechanical cycling. Groups were classified according to the rotational misfit register using University of California, Los Angeles abutment and implants as new (group 1 = G1); using crowns and implants after crown casting (group 2 = G2); and using crowns and implants after mechanical cycling (group 3 = G3). Oblique loading of 120N at 1.8 Hz and 5 * 10(5) cycles was applied on specimen. RESULTS: Statistical analysis (p < .05) showed that no significant difference was observed when cast abutment was compared with premachined abutment after casting (p = .390) and mechanical cycling (p = .439); however, significant difference was noted before the casting (p = .005) with higher values for the cast abutments. CONCLUSIONS: Within the limitations of this in vitro study, it could be concluded that the abutment type used do not influenced the rotational freedom after casting and the amount of applied cycles (500,000 cycles) was not sufficient to significantly alter the values of rotational freedom at the implant/abutment joint. PMID- 22236421 TI - Giant thoracoabdominal esophageal bronchogenic cyst. PMID- 22236422 TI - Measuring patients' views: between enthusiasm and reality. PMID- 22236423 TI - Congenital tracheal diverticulum seen in adult age. PMID- 22236424 TI - Multiple aortopathy phenotypes with bicuspid aortic valve: the importance of terminology and definition criteria. PMID- 22236426 TI - Checkpoints of B cell differentiation: visualizing Ig-centric processes. AB - The generation of antibody responses and B cell memory can only take place following multiple steps of differentiation. Key molecular processes during precursor B cell differentiation in bone marrow generate unique antibodies. These antibodies are further optimized via molecular modifications during immune responses in peripheral lymphoid organs. Multiple checkpoints ensure proper differentiation of precursor and mature B lymphocytes. Many of these checkpoints have been found disrupted in patients with a primary immunodeficiency. Based on studies in these patients and in mouse models, new insights have been generated in B cell differentiation and antibody responses. Still, in many patients with impaired antibody formation, it remains unclear how B cells are affected. In this perspective, we present 11 critical processes in B cell differentiation. We discuss how defects in these processes can result in impaired checkpoint selection and how they can be visualized in healthy subjects and patients with immunodeficiency or other immunological disease. PMID- 22236425 TI - The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. AB - Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II-deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions. PMID- 22236427 TI - DOCK8 deficiency. AB - The discovery that loss-of-function mutations in the gene DOCK8 are responsible for most forms of autosomal recessive hyper-IgE syndrome and some forms of combined immunodeficiency without elevated serum IgE has led to studies into the immunopathogenesis of this disease. In this review, we relate the clinical features of this disease to studies using patients' cells and a mouse model of Dock8 deficiency, which have revealed how DOCK8 regulates T and B cell numbers and functions. The results of these studies help to explain how the absence of DOCK8 contributes to patients' susceptibility to viral, fungal, and bacterial infections. However, unanswered questions remain regarding how the absence of DOCK8 also leads to high IgE and allergic disease, predisposition for malignancy, and unusual clinical features, such as CNS abnormalities and autoimmunity, observed in some patients. PMID- 22236428 TI - Molecular mechanisms of the immunological abnormalities in hyper-IgE syndrome. AB - Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic dermatitis associated with extremely high serum IgE levels and susceptibility to staphylococcal skin abscesses and pneumonia. Recent studies have identified dominant negative mutations in the signal transducer and activator of transcription 3 gene (STAT3) as a major molecular cause of classical hyper-IgE syndrome, but the molecular mechanisms underlying this syndrome remain unclear. We recently showed that the impaired development of interleukin 17 (IL-17) producing T helper cells (Th17 cells) due to defective IL-6 and IL-23 signaling in T cells, and the impaired generation of induced regulatory T (iT(reg) ) cells from defective IL-10 signaling in dendritic cells, may account for the immunological abnormalities of hyper-IgE syndrome. These findings open up possibilities for exploring new approaches to the treatment of HIES patients. PMID- 22236430 TI - DNA repair: the link between primary immunodeficiency and cancer. AB - The adaptive component of the immune system depends greatly on the generation of genetic diversity provided by lymphocyte-specific genomic rearrangements. V(D)J recombination, class switch recombination (CSR), and somatic hypermutation (SHM) constitute complex and vulnerable processes that are orchestrated by a multitude of DNA repair pathways. When inherited defects in certain DNA repair proteins are present, lymphocyte development can be compromised and, consequently, patients can develop primary immunodeficiencies (PIDs). PID patients often have a strong predisposition for cancer development as a result of genomic instability generated from defective DNA repair mechanisms. Tumors of lymphoid origin are one of the most common PID-associated cancers, likely due to DNA lesions resulting from defective V(D)J, CSR, and SHM. In this review, we describe PID syndromes that confer an increased risk for cancer development. Furthermore, we discuss the role of the affected proteins in tumorigenesis/lymphomagenesis. PMID- 22236429 TI - Perspectives on common variable immune deficiency. AB - Common variable immunodeficiency (CVID) is considered to be a collection of genetic immune defects with complex inheritance patterns. While the main phenotype is loss of B cell function, the majority of the genetic mechanisms leading to CVID remain elusive. In the past two decades there have been increasing efforts to unravel the genetic defects in CVID. Here, we provide an overview of our current understanding of the genetic basis of these defects, as revealed over time by earlier linkage studies in large cohorts, analysis of families with recessive inheritance, targeted gene approaches, and genome-wide association studies using single nucleotide polymorphism arrays and copy number variation, and whole genome studies. PMID- 22236431 TI - Inherited defects causing hemophagocytic lymphohistiocytic syndrome. AB - Hemophagocytic lymphohistiocytosis (HLH) manifests as the uncontrolled activation of T lymphocytes and macrophages infiltrating multiple organs. Molecular studies of individuals with HLH have demonstrated in most of these conditions a critical role of granule-dependent cytotoxic activity in the regulation of lymphocyte homeostasis, and have allowed the characterization of key effectors regulating cytotoxic granule release. The cytolytic process may now be considered a multistep process, including cell activation; the polarization of cytotoxic granules toward the conjugated target cell; the tethering, priming, and fusion of the cytotoxic granules with the plasma membrane; and the release of their contents (perforin and granzymes) into the intercellular cleft, leading to target cell death. Cytolytic cells have a second effector function involving the production of cytokines, principally gamma-interferon, which is secreted independently of the exocytosis cytotoxic granule pathway. An analysis of the mechanisms underlying HLH has identified gamma-interferon as a key cytokine inducing uncontrolled macrophage activation, and thus represents a potential therapeutic target. PMID- 22236432 TI - Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome. AB - Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene and, as a syndrome, is characterized by chronic mucocutaneous candidiasis and the presentation of various autoimmune diseases. During the last decade, research on APECED and AIRE has provided immunologists with several invaluable lessons regarding tolerance and autoimmunity. This review describes the clinical and immunological features of APECED and discusses emerging alternative models to explain the pathogenesis of the disease. PMID- 22236434 TI - IL-10 and IL-10 receptor defects in humans. AB - Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is chronic in nature and is characterized by abdominal pain, diarrhea, bleeding, and malabsorption. It is considered a complex multigenic and multifactorial disorder that results from disturbed interactions between the immune system and commensal bacteria of the gut. Recent work has demonstrated that IBD with an early-onset within the first months of life can be monogenic: mutations in IL-10 or its receptor lead to a loss of IL-10 function and cause severe intractable enterocolitis in infants and small children. Both IL 10 and IL-10 receptor deficiency can be successfully treated by hematopoietic stem cell transplantation. PMID- 22236433 TI - Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. AB - Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria, such as Mycobacterium bovis Bacille Calmette Guerin (BCG) vaccines and nontuberculous, environmental mycobacteria (EM). Since 1996, MSMD-causing mutations have been found in six autosomal genes involved in IL-12/23-dependent, IFN-gamma-mediated immunity. The aim of this review is to provide the description of the two described forms of X-linked recessive (XR) MSMD. Germline mutations in two genes, NEMO and CYBB, have long been known to cause other human diseases incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (NEMO/IKKG), and X-linked chronic granulomatous disease (CGD) (CYBB)-but specific mutations in either of these two genes have recently been shown to cause XR-MSMD. NEMO is an essential component of several NF-kappaB dependent signaling pathways. The MSMD-causing mutations in NEMO selectively affect the CD40-dependent induction of IL-12 in mononuclear cells. CYBB encodes gp91(phox) , which is an essential component of the NADPH oxidase in phagocytes. The MSMD-causing mutation in CYBB selectively affects the respiratory burst in macrophages. Mutations in NEMO and CYBB may therefore cause MSMD by selectively exerting their deleterious impact on a single signaling pathway (CD40-IL-12, NEMO) or a single cell type (macrophages, CYBB). These experiments of Nature illustrate how specific germline mutations in pleiotropic genes can dissociate signaling pathways or cell lineages, thereby resulting in surprisingly narrow clinical phenotypes. PMID- 22236435 TI - The case for newborn screening for severe combined immunodeficiency and related disorders. AB - Early detection of primary immunodeficiency is recognized as important for avoiding infectious complications that compromise outcomes. In particular, severe combined immunodeficiency (SCID) is fatal in infancy unless affected infants can be diagnosed before the onset of devastating infections and provided with an immune system through allogenic hematopoietic cell transplantation, enzyme replacement, or gene therapy. A biomarker of normal T cell development, T cell receptor excision circles (TRECs), can be measured in DNA isolated from the dried blood spots routinely obtained for newborn screening; infants identified as lacking TRECs can thus receive confirmatory testing and prompt intervention. Early results of TREC testing of newborns in five states indicate that this addition to the newborn screening panel can be successfully integrated into state public health programs. A variety of cases with typical SCID genotypes and other T lymphocytopenic conditions have been detected in a timely manner and referred for appropriate early treatment. PMID- 22236436 TI - Newborn screening for primary immunodeficiencies: beyond SCID and XLA. AB - Primary immunodeficiencies (PID) encompass more than 250 disease entities, including phagocytic disorders, complement deficiencies, T cell defects, and antibody deficiencies. While differing in clinical severity, early diagnosis and treatment is of considerable importance for all forms of PID to prevent organ damage and life-threatening infections. During the past few years, neonatal screening assays have been developed to detect diseases hallmarked by the absence of T or B lymphocytes, classically seen in severe combined immunodeficiencies (SCID) and X-linked agammaglobulinemia (XLA). As described in this review, a reduction or lack of T and B cells in newborns is also frequently found in several other forms of PID, requiring supplemental investigation and involving the development of additional technical platforms in order to help classify abnormal screening results. PMID- 22236437 TI - Homologous recombination-based gene therapy for the primary immunodeficiencies. AB - The devastating nature of primary immunodeficiencies, the ability to cure primary immunodeficiencies by bone marrow transplantation, the ability of a small number of gene-corrected cells to reconstitute the immune system, and the overall suboptimal results of bone marrow transplantation for most patients with primary immunodeficiencies make the development of gene therapy for this class of diseases important. While there has been clear clinical benefit for a number of patients from viral-based gene therapy strategies, there have also been a significant number of serious adverse events, including the development of leukemia, from the approach. In this review, I discuss the development of nuclease-stimulated, homologous recombination-based approaches as a novel gene therapy strategy for the primary immunodeficiencies. PMID- 22236438 TI - Copper(I)-assembled [3]rotaxane whose two rings act as flapping wings. AB - A new copper-complexed [3]rotaxane consisting of two coordinating 30-membered rings threaded by a two-binding-site axis has been prepared in good yield from relatively simple organic fragments. The main specificity of the system originates from the stoppering reaction, based on "click" chemistry, and thus from the presence of two triazole groups at positions next to the bidentate chelates of the axis central part. The geometry of the coordinating atoms belonging to the axis is such that the triazole groups can either be part of the coordinating fragments when the metal center is 5-coordinate or be not at all involved in coordination to the metal when the latter is 4-coordinate. To be more specific, when the two complexed metal centers are monovalent copper(I) centers, the triazoles are not included in the metal coordination sphere, whereas when the metal centers are Cu(II) or Zn(2+), the triazole groups are bound to the metals. This is easily explained by the fact that Cu(I) is preferably 4-coordinate and Cu(II) and Zn(2+) are 5-coordinate. The interconversion between both situations (4- or 5-coordinate) can be quantitatively induced by metal exchange (Cu(I)/Zn(2+)) or by a redox process (Cu(II)/Cu(I)). It leads to important geometrical changes and in particular to a strong modification of the angle between the two rings. As a consequence, the two threaded rings undergo a motion which is reminiscent of a wing-flapping movement similar to that of birds. This flapping motion is fast and quantitative. It should lead to new functional molecular machines in the future. PMID- 22236439 TI - Current state of US breastfeeding laws. AB - This study systematically examined state-level laws protecting breastfeeding, including their current status and historical development, as well as identified gaps across US states and regions. The National Conference of State Legislatures summarised breastfeeding laws for 50 states and DC as of September 2010, which we updated through May 2011. We then searched LexisNexis and Westlaw to find the full text of laws, recording enactment dates and definitions. Laws were coded into five categories: (1) employers are encouraged or required to provide break time and private space for breastfeeding employees; (2) employers are prohibited from discriminating against breastfeeding employees; (3) breastfeeding is permitted in any public or private location; (4) breastfeeding is exempt from public indecency laws; and (5) breastfeeding women are exempt from jury duty. By May 2011, 1 state had enacted zero breastfeeding laws, 10 had one, 22 had two, 12 had three, 5 had four and 1 state had laws across all five categories. While 92% of states allowed mothers to breastfeed in any location and 57% exempted breastfeeding from indecency laws, 37% of states encouraged or required employers to provide break time and accommodations, 24% offered breastfeeding women exemption from jury duty and 16% prohibited employment discrimination. The Northeast had the highest proportion of states with breastfeeding laws and the Midwest had the lowest. Breastfeeding outside the home is protected to varying degrees depending on where women live; this suggests that many women are not covered by comprehensive laws that promote breastfeeding. PMID- 22236440 TI - Scavenging behavior of Lynx rufus on human remains during the winter months of Southeast Texas. AB - Animal-scavenging alterations on human remains can be mistaken as human criminal activity. A 32-day study, documenting animal scavenging on a human cadaver, was conducted at the Southeast Texas Applied Forensic Science facility, Sam Houston State University, Huntsville, Texas. A Stealth Cam Rogue IR was positioned near the cadaver to capture scavenging activity. An atypical scavenger, the bobcat, Lynx rufus, was recorded feeding on the cadaver. Scavenging by bobcats on human remains is not a predominant behavior and has minimal documentation. Scavenging behaviors and destruction of body tissues were analyzed. Results show that the bobcat did not feed on areas of the body that it does for other large animal carcasses. Results also show the bobcat feeds similarly during peak and nonpeak hours. Understanding the destruction of human tissue and covering of the body with leaf debris may aid forensic anthropologists and pathologists in differentiating between nefarious human activity and animal scavenging. PMID- 22236441 TI - Automatic filtering of outliers in RR intervals before analysis of heart rate variability in Holter recordings: a comparison with carefully edited data. AB - BACKGROUND: Undetected arrhythmic beats seriously affect the power spectrum of the heart rate variability (HRV). Therefore, the series of RR intervals are normally carefully edited before HRV is analysed, but this is a time consuming procedure when 24-hours recordings are analysed. Alternatively, different methods can be used for automatic removal of arrhythmic beats and artefacts. This study compared common frequency domain indices of HRV when determined from manually edited and automatically filtered RR intervals. METHODS AND RESULTS: Twenty-four hours Holter recordings were available from 140 healthy subjects of age 1-75 years. An experienced technician carefully edited all recordings. Automatic filtering was performed using a recursive procedure where RR intervals were removed if they differed from the mean of the surrounding RR intervals with more than a predetermined limit (ranging from 10% to 50%). The filtering algorithm was evaluated by replacing 1% of the beats with synthesised ectopic beats. Power spectral analysis was performed before and after filtering of both the original edited data and the noisy data set. The results from the analysis using the noisy data were used to define an age-based filtering threshold. The age-based filtration was evaluated with completely unedited data, generated by removing all annotations from the series of RR intervals, and then comparing the resulting HRV indices with those obtained using edited data. The results showed equivalent results after age-based filtration of both the edited and unedited data sets, where the differences in HRV indices obtained by different preprocessing methods were small compared to the mean values within each age group. CONCLUSIONS: The study showed that it might not be necessary to perform the time-consuming careful editing of all detected heartbeats before HRV is analysed in Holter recordings.In most subjects, it is sufficient to perform the regular editing needed for valid arrhythmia analyses, and then remove undetected ectopic beats and artefacts by age-based filtration of the series of RR intervals, particularly in subjects older than 30 years. PMID- 22236442 TI - Asthma incidence among children and adults: findings from the Behavioral Risk Factor Surveillance system asthma call-back survey--United States, 2006-2008. AB - BACKGROUND: Asthma, a chronic respiratory condition affecting 8.2% of the US population (2009), causes significant societal and economic burden, resulting in missed school/work days, activity limitations, and increased healthcare utilization. Annual asthma prevalence estimates are available from national surveys, but these surveys have not routinely collected asthma incidence data that are important for identifying risk factors and trends in rates of disease onset. The Asthma Call-back Survey (ACBS), implemented in 2006, provides detailed asthma data that supplement Behavioral Risk Factor Surveillance System (BRFSS) data. We analyzed BRFSS and ACBS data to estimate annual asthma incidence and to determine whether these rates differed by age group, sex, and race/ethnicity. METHODS: BRFSS and ACBS data from the participating states during 2006-2008 (24 states and District of Columbia [DC] in 2006; 34 states and DC in 2007 and 2008) were analyzed to calculate 12-month incidence rates. Incident cases of asthma were defined as people diagnosed with asthma by a healthcare provider within 12 months prior to survey participation. RESULTS: Estimated asthma incidence among at-risk adults was 3.8/1000, whereas that among at-risk children was 12.5/1000. Incidence among children aged 0-4 years was 23.4/1000, more than five times greater than that among youth aged 12-17 years (4.4/1000). Adult females had 1.8 times greater asthma incidence than adult males (4.9/1000 vs. 2.8/1000, respectively). Incidence among non-Hispanic (NH) White adults was 3.9/1000, among NH non-White adults was 3.2/1000, and among Hispanic adults was 4.0/1000. CONCLUSIONS: This is the first successful application of the BRFSS-ACBS during 2006-2008 to estimate asthma incidence rates from participating states and DC. As with known patterns in asthma prevalence, we found that asthma incidence was higher in children than adults, higher in younger children than older children and adolescents, and higher in adult females than adult males. However, we were unable to identify statistically significant differences in asthma incidence among most race/ethnic groups. As additional data on asthma incidence become available from the ACBS, these rates, coupled with ACBS data on symptoms, asthma self-management practices, and healthcare utilization, may help asthma control programs identify risk factors for disease development and target asthma prevention and control measures to populations most affected. PMID- 22236444 TI - Genetic and molecular characterization of uveal melanoma cell lines. AB - The recent identification of frequent activating mutations in GNAQ or GNA11 in uveal melanoma provides an opportunity to better understand the pathogenesis of this melanoma subtype and to develop rational therapeutics to target the cellular effects mediated by these mutations. Cell lines from uveal melanoma tumors are an essential tool for these types of analyses. We report the mutation status of relevant melanoma genes, expression levels of proteins of interest, and DNA fingerprinting of a panel of uveal melanoma cell lines used in the research community. PMID- 22236445 TI - Analysis of EBNA-1 and LMP-1 variants in diseases associated with EBV infection in Chinese children. AB - BACKGROUND: In China, primary EBV infection occurs during childhood with seroprevalence reaching about 100% by 10 years of age. There are few studies on EBV variants in diseases associated with EBV infection in Chinese children. In this study, we investigated the diversity of the EBV genes (EBNA-1 and LMP-1) and the relationship between EBV variants and the clinical phenotypes in diseases associated with EBV infections in Chinese pediatric cases. RESULTS: The frequencies of EBV type I in the IM, HLH and HL samples were 98.4%, 100% and 95.8%, respectively. Three known EBNA-1 variants were identified, including V-val (all were V-val-v1 sub-variant), P-thr' and V-Leu (MT). The frequency of V-val-v1 was 98.6% in the IM samples, 100% in the HLH samples and 97.1% in the HL samples. There were no significant differences of the distribution of EBNA-1 variants between IM, HLH and HL samples (P > 0.05). Three known LMP-1 variants, including China 1, China 2 and Med, were identified and China 1 was predominant in all groups (IM 88.6%, HLH 100% and HL 100%). The frequency of del-LMP-1 was 88.6% in the IM samples, 100% in the HLH samples and 96.0% in the HL samples. There were no significant differences in the frequency of del-LMP-1 between the IM, HLH and HL samples (P > 0.05). The frequency of XhoI loss was 90.6% in the IM samples, 100% in the HLH samples and 100% in the HL samples, with no significant difference in frequency (P > 0.05). In the EBV type I strain, V-val-v1 variant (EBNA-1) was linked with China1 variant (LMP-1) in 88.9% of the IM samples, 100% of the HLH samples and 80.0% of the HL samples in this study. CONCLUSIONS: Type I EBV was the most prevalent subtype EBV in Chinese pediatric cases and V-val-v1 (EBNA-1) and China1 (LMP-1) variants were the most dominant variants. There was a strong linkage between V-val-v1 (EBNA-1) variant and China1 (LMP-1) variant in type I EBV. The sequence variation in EBV genes may represent a geographic polymorphism since no preferential associations were found between specific EBV variants and specific diseases in this study. PMID- 22236446 TI - Transplanted fibroblasts prevents dysfunctional repair in a murine CXCR3 deficient scarring model. AB - In skin, the regeneration of the ontogenically distinct mesenchymal and epithelial compartments must proceed in a coordinated manner orchestrated by extracellular signaling networks. We have recently found that the switch from regeneration to remodeling during repair is modulated by chemokines that bind CXCR3 receptor. If this signaling is disrupted wounds continue to be active, resulting in a chronic hypercellular and hypertrophic state characterized by an immature matrix composition. As healing is masterminded in large part by fibroblasts and their synthesis of the extracellular matrix, the question arose as to whether this ongoing scarring can be modulated by transplanted fibroblasts. We examined wounds in the CXCR3-/- mouse scarring model. These wounds exhibited a significant delay in healing in all areas compared to young and aged wild-type mice. Full-thickness wounds were transplanted with fibroblasts derived from newborn CXCR3-/- or wild-type mice. The transplanted fibroblasts were labeled with fluorescent dye (CM-DiI) and suspended in hyaluronic acid gel; by 30 days, these transplanted cells comprised some 30% of the dermal stromal cells regardless of the host or source of transplanted cells. Wild-type fibroblasts transplanted into CXCR3-/- mice wounds reversed the delay and dysfunction previously seen in CXCR3-/- wounds; this correction was not noted with transplanted CXCR3-/- fibroblasts. Additionally, transplant of CXCR3-/- cells into wounds in wild-type animals did not adversely affect those wounds. The transplanted fibroblasts exhibited strong survival and migration patterns and led to an increase in tensile strength. Expression of matrix proteins and collagen in CXCR3-/- wounds transplanted with wild-type fibroblasts resembled normal wild type healing, and the wound matrix in wild-type mice transplanted with CXCR3-/- cells also presented a mature matrix. These suggest that the major determinant of healing versus scarring lies with the nature of the matrix. These findings have intriguing implications for rational cellular interventions aimed at promoting wound healing via cell therapy. PMID- 22236448 TI - Treatment of systemic lupus erythematosus: new advances in targeted therapy. AB - Treatment for systemic lupus erythematosus (SLE) has traditionally been restricted to broad-based immunosuppression, with glucocorticoids being central to care. Recent insights into lupus pathogenesis promise new, selective therapies with more favorable side effect profiles. The best example of this is belimumab, which targets the B cell cytokine BLyS and has now received Food and Drug Administration (FDA) approval for its use in SLE. Strategies targeting other cytokines, such as interleukin 6 (IL-6) and interferon (IFN)-alpha, are also on the horizon. Blockade of costimulatory interactions between immune cells offers another opportunity for therapeutic intervention, as do small molecule inhibitors that interfere with cell signaling pathways. We review here the current strategies for SLE treatment, with particular focus on therapies now in active pharmaceutical development. We will also discuss new understandings in lupus pathogenesis that may lead to future advances in therapy. PMID- 22236447 TI - Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma. AB - In the light of increasing evidence supporting cancer stem cells (CSCs) theory, the expression of two stem cell markers, CD133 and adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2), in esophageal squamous cell carcinoma (ESCC) was investigated, and their prognostic values were evaluated. Paraffin embedded tissue sections of 110 ESCC patients were investigated using Immunohistochemistry. The association of CD133 and ABCG2 expression with clinicopathologic characteristics was analyzed by chi(2) test. Survival analysis was carried out using Kaplan-Meier method and Cox proportional hazards model. CD133 and ABCG2 expression were detected in 27.3% and 15.5% of ESCC patients, respectively. The presence of CD133-positive cancer cells was associated with tumor cell differentiation (P= 0.008) but not significantly related to the survival of ESCC patients (P= 0.085). ABCG2 expression was not associated with clinicopathologic characteristics but was a significant prognostic factor for adverse overall survival of ESCC patients (P= 0.005). The median overall survival time for ESCC patients with and without ABCG2 expression were 21.8 and >49.3 months, respectively. A combined analysis of CD133 and ABCG2 expression did not show that ESCC patients with coexpression of these two markers had a worse prognosis than those with only ABCG2 expression (P= 0.934). Moreover, ABCG2 expression was revealed to be an independent prognostic factor along with tumor node metastasis stage in multivariate analysis (hazard ratio of ABCG2, 3.38; 95% confidence interval, 1.61~7.09; P= 0.001). By survival analysis based on tumor node metastasis stage of ESCC, the association between ABCG2 expression and the patients' prognosis was found significant in the group of relatively early stage (P= 0.005) and marginally significant in the group of relatively late stage (P= 0.058). This is the first time to report the presence of CD133-positive cancer cells in ESCC but not supporting its prognostic value and validity as a CSC marker for ESCC. ABCG2 expression was found to correlate with the survival of ESCC patients, especially those at relatively early stage, suggesting that ABCG2 positive cancer cells may represent a pool of CSCs in ESCC, and relatively early stage patients with ABCG2 expression may deserve more intensive or targeted therapy. PMID- 22236450 TI - Laparoscopic management of abdominal ectopic pregnancy using FLOSEAL Hemostatic Matrix. PMID- 22236449 TI - Multi-region analysis of longitudinal FDG-PET for the classification of Alzheimer's disease. AB - Imaging biomarkers for Alzheimer's disease are desirable for improved diagnosis and monitoring, as well as drug discovery. Automated image-based classification of individual patients could provide valuable diagnostic support for clinicians, when considered alongside cognitive assessment scores. We investigate the value of combining cross-sectional and longitudinal multi-region FDG-PET information for classification, using clinical and imaging data from the Alzheimer's Disease Neuroimaging Initiative. Whole-brain segmentations into 83 anatomically defined regions were automatically generated for baseline and 12-month FDG-PET images. Regional signal intensities were extracted at each timepoint, as well as changes in signal intensity over the follow-up period. Features were provided to a support vector machine classifier. By combining 12-month signal intensities and changes over 12 months, we achieve significantly increased classification performance compared with using any of the three feature sets independently. Based on this combined feature set, we report classification accuracies of 88% between patients with Alzheimer's disease and elderly healthy controls, and 65% between patients with stable mild cognitive impairment and those who subsequently progressed to Alzheimer's disease. We demonstrate that information extracted from serial FDG-PET through regional analysis can be used to achieve state-of-the-art classification of diagnostic groups in a realistic multi-centre setting. This finding may be usefully applied in the diagnosis of Alzheimer's disease, predicting disease course in individuals with mild cognitive impairment, and in the selection of participants for clinical trials. PMID- 22236451 TI - Clinical and anatomic features of female genital tuberculosis in 28 patients. PMID- 22236452 TI - Mathematical modelling and evaluation of the different routes of transmission of lumpy skin disease virus. AB - Lumpy skin disease (LSD) is a severe viral disease of cattle. Circumstantial evidence suggests that the virus is transmitted mechanically by blood-feeding arthropods. We compared the importance of transmission via direct and indirect contact in field conditions by using mathematical tools. We analyzed a dataset collected during the LSD outbreak in 2006 in a large dairy herd, which included ten separated cattle groups. Outbreak dynamics and risk factors for LSD were assessed by a transmission model. Transmission by three contact modes was modelled; indirect contact between the groups within a herd, direct contact or contact via common drinking water within the groups and transmission by contact during milking procedure. Indirect transmission was the only parameter that could solely explain the entire outbreak dynamics and was estimated to have an overall effect that was over 5 times larger than all other possible routes of transmission, combined. The R0 value induced by indirect transmission per the presence of an infectious cow for 1 day in the herd was 15.7, while the R0 induced by direct transmission was 0.36. Sensitivity analysis showed that this result is robust to a wide range of assumptions regarding mean and standard deviation of incubation period and regarding the existence of sub-clinically infected cattle. These results indicate that LSD virus spread within the affected herd could hardly be attributed to direct contact between cattle or contact through the milking procedure. It is therefore concluded that transmission mostly occurs by indirect contact, probably by flying, blood-sucking insects. This has important implications for control of LSD. PMID- 22236453 TI - Kinematic and kinetic characteristics of Masai Barefoot Technology footwear. AB - The Masai Barefoot Technology (MBT) shoe was developed as a walking device to improve gait stability and reduce the joint load. Kinematic changes with MBT shoes have been reported; however, kinetic characteristics with MBT shoes have not been adequately assessed. The purpose of this study was to investigate the immediate effects of using MBT footwear on the kinetic and kinematic changes in the lower extremity in healthy males. Fourteen healthy male subjects (mean age: 25.6 +/- 5.1 years) underwent three-dimensional gait analysis. Ground reaction forces (GRF) during the shock absorption phase were significantly decreased with MBT shoes compared with stable shoes. Gait with the MBT shoes showed significantly decreased knee extension angle in the early stance phase, a decreased hip extension angle, and an increased ankle dorsiflexion angle in the late stance phase. The peak value of the ankle planter moment, ankle negative power, and vertical component of the GRF significantly decreased with MBT shoes in the late stance phase compared with stable shoes. Therefore, MBT shoes could assist with shock absorption in the early stance phase and maintain the progression force while reducing joint moment and power. The results of this study suggest that MBT shoes might be effective to improve shock absorption, increase knee extensor muscle activity, and assist ankle push-off. PMID- 22236455 TI - Carbapenem-resistant Pseudomonas aeruginosa pneumonia with intermediate minimum inhibitory concentrations to doripenem: combination therapy with high-dose, 4-h infusion of doripenem plus fosfomycin versus intravenous colistin plus fosfomycin. PMID- 22236456 TI - Thionium ion initiated medium-sized ring formation: the total synthesis of asteriscunolide D. AB - The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a gamma-hydroxy propiolate as a handle for butenolide formation via Ru catalyzed alkene-alkyne coupling. PMID- 22236457 TI - Automatically evaluated degree of intelligibility of children with different cleft type from preschool and elementary school measured by automatic speech recognition. PMID- 22236458 TI - Population variability in CD38 activity: correlation with age and significant effect of TNF-alpha -308G>A and CD38 184C>G SNPs. AB - CD38 (EC 3.2.2.6, NAD(+)-glycohydrolase) is a multifunctional enzyme catalyzing the synthesis and hydrolysis of cyclic ADP-ribose from NAD(+) to ADP-ribose. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications. Notably, it has been linked to HIV infection, leukemias, myelomas, solid tumors, Type II Diabetes mellitus, bone metabolism, as well as Autism Spectrum Disorder. Taking into account the crucial role played by CD38 in many diseases and in clinical practice, here we assessed the distribution of CD38 NADase activity in a healthy population (104 sex-matched unrelated individuals, 12-98 years) and determined its main predictors among genetic and physiological factors (age and sex). The mean value of CD38 NADase activity was 0.051+/-0.023 mU/mg (0.010-0.099 mU/mg), following a normal distribution in the study population (Kolmogorov-Smirnov test P=0.200). The TNF alpha -308G>A (rs1800629) resulted the main predictor (beta=0.364, P=0.00008), followed by Age (beta=0.280, P=0.002) and the CD38 184C>G (rs6449182) (beta=0.193, P=0.033). Our study contributes to understanding CD38 enzyme physiological functions, by reporting, for the first time, its activity distribution in healthy individuals and demonstrating a significant positive correlation with age. Moreover, the possible use of TNF-alpha -308G>A (rs1800629) and the CD38 184C>G (rs6449182) SNPs as predictive genetic markers of CD38 activity, clearly point toward possible pharmacogenomic applications and to a more refined use of CD38 in clinical settings. PMID- 22236459 TI - The integrated model of serotonin transporter gene variation (5HTTLPR) and the glial cell transporter in stress vulnerability and depression. AB - The serotonin transporter gene (SLC6A4) promoter polymorphism (5HTTLPR) has been associated with individual stress responses such that individuals with childhood abuse history have higher rates of depression in later life if they are homozygous short (s/s) of the gene. It is hypothesized that these findings could be explained by an integrated model of a role of the glial cell transporter and a functional difference of 5HTTLPR in the capacity of absorbing serotonin from the synapse. A hypothetical integrated model of the SLC6A4 function and the role of glial cells are put forward to explain accumulating results of recent investigations exploring the relationship between the gene and the diverse mental activities including depression and stress response. A model based on SLC6A4 variation is proposed to explain individual differences in stress vulnerability/resilience. The role of the glial cell transporter surrounding the synapse is integrated in the model to understand the modulation of the neurotransmission. It is hypothesized that a synapse with less serotonin transporter contributes to unstable processing in neurotransmission as compared to a synapse with more serotonin transporter. As such, based on functional differences of 5HTTLPR in the expression of the serotonin transporter, it is asserted that individuals with the s/s genotype process neurotransmission differently and in a reactive way. This integrated model of 5HTTLPR and glial cells suggests that the efficacy of serotonin reuptake in the synapse may play a crucial role in variability of neurotransmission, which can lead to differences in the stress response and the pathophysiology of depression. PMID- 22236460 TI - Improving automatic face recognition with user interaction. AB - Face recognition systems aim to recognize the identity of a person depicted in a photograph by comparing it against a gallery of prerecorded images. Current systems perform quite well in controlled scenarios, but they allow for none or little interaction in case of mistakes due to the low quality of images or to algorithmic limitations. Following the needs and suggestions of investigators, we present a guided user interface that allows to adjust from a fully automatic to a fully assisted modality of execution, according to the difficulty of the task and to amount of available information (gender, age, etc.): the user can generally rely on automatic execution and intervene only on a limited number of examples when a failure is automatically detected or when the quality of intermediate results is deemed unsatisfactory. The interface runs on top of a preexistent automatic face recognition algorithm in such a way to guarantee full control over the execution flow and to exploit the peculiarities of the underlying image processing techniques. The viability of the proposed solution is tested on a classic face identification task run on a standard publicly available database (the XM2VTS), assessing the improvement to user interaction over the automatic system performance. PMID- 22236462 TI - Comparison of the Diamond-Forrester method and Duke Clinical Score to predict obstructive coronary artery disease by computed tomographic angiography. AB - We sought to evaluate the ability of the Diamond and Forrester method (DFM) and the Duke Clinical Score (DCS) to predict obstructive coronary artery disease (CAD) on coronary computed tomographic angiography (CCTA) and the effect of these different risk scores on the appropriateness level using the 2010 Appropriate Use Criteria. Consecutive symptomatic patients who underwent CCTA for evaluation of CAD (n = 114) were classified as having a low, intermediate, or high pretest probability using the DFM and DCS. Using the Appropriate Use Criteria, the indications for CCTA were classified according to the pretest probability and previous testing. The CCTA results were classified as revealing obstructive (>=70% stenosis), nonobstructive (<70%), or no CAD. When the patients' risk was classified using the DFM, 18% were low, 65% intermediate, and 17% high risk. When using the DCS, 53% of patients had a reclassification of their risk, most of whom changed from intermediate to either low or high risk (50% low, 19% intermediate, 35% high risk). The net reclassification improvement for the prediction of obstructive CAD was 51% (p = 0.01). Of the 37 patients who were reclassified as low risk, 36 (97%) lacked obstructive CAD. Appropriateness for CCTA was reclassified for 13% of patients when using the DCS instead of the DFM, and the number of appropriate examinations was significantly fewer (68% vs 55%, p <0.001). In conclusion, reclassification of risk using the DCS instead of the DFM resulted in improved prediction of obstructive CAD on CCTA, especially in low risk patients. More patients were categorized as having a high pretest probability of CAD, resulting in reclassification of their examination indications as uncertain or inappropriate. These results identify the need for improved pretest risk scores for noninvasive tests such as CCTA and suggest that the method of risk assessment could have important implications for patient selection and quality assurance programs. PMID- 22236461 TI - Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states. AB - BACKGROUND: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaValpha2delta-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects. RESULTS: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaValpha2delta-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaValpha2delta-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaValpha2delta-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaValpha2delta-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation. CONCLUSIONS: Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaValpha2delta-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states. PMID- 22236463 TI - Use and outcomes of multivessel percutaneous coronary intervention in patients with acute myocardial infarction complicated by cardiogenic shock (from the EHS PCI Registry). AB - The value of multivessel percutaneous coronary intervention (MV-PCI) in patients with cardiogenic shock (CS) and multivessel disease (MVD) is still unclear because randomized controlled trials are missing. Therefore, we sought to evaluate the impact of MV-PCI on in-hospital outcomes of patients with MVD presenting with CS: 336 patients with acute myocardial infarction complicated by CS and >=70% stenoses in >=2 major epicardial vessels were included in this analysis of the Euro Heart Survey PCI registry. Patients undergoing MV-PCI (n = 82, 24%) were compared to those with single-vessel PCI (n = 254, 76%). The rate of 3-vessel disease (60% vs 57%, p = 0.63) was similar in the 2 cohorts. Presentation with resuscitation (48 vs 46%, p = 0.76) and ST-segment elevation myocardial infarction (83 vs 87%, p = 0.31) was frequent in patients with MV-PCI and single-vessel PCI. Patients with ventilation were more likely to receive MV PCI (30% vs 19%, p = 0.05). There was a tendency toward a higher hospital mortality in patients with MV-PCI (48.8% vs 37.4%, p = 0.07). After adjustment for confounding variables, no significant difference for in-hospital mortality (odd ratio [OR] 1.28, 95% confidence interval [CI] 0.72 to 2.28) could be observed between the 2 groups. Age (OR 1.41, 95% CI 1.13 to 1.77), 3-vessel disease (OR 1.78, 95% CI 1.04 to 3.03), ventilation (OR 3.01, 95% CI 1.59 to 5.68), and previous resuscitation (OR 2.55, 95% CI 1.48 to 4.39) were independent predictors of hospital death. In conclusion, MV-PCI is currently used in only 1/4 of patients with CS and MVD. An additional nonculprit PCI was not associated with a survival benefit in these high risk patients. PMID- 22236464 TI - A dysflagellar mutant of Leishmania (Viannia) braziliensis isolated from a cutaneous leishmaniasis patient. AB - BACKGROUND: Parasites of the Leishmania genus alternate between the flagellated extracellular promastigote stage and intracellular amastigotes. Here we report the characterization of a Leishmania isolate, obtained from a cutaneous leishmaniasis patient, which presents peculiar morphological features. METHODS: The parasite was cultured in vitro and characterized morphologically using optical and electron microscopy. Identification was performed based on monoclonal antibodies and internal ribosomal spacer typing. In vitro macrophage cultures, murine experimental models and sand fly infections were used to evaluate infectivity in vitro and in vivo. RESULTS: The isolate was identified as Leishmania (Viannia) braziliensis. In the atypical promastigotes grown in culture, a short flagellum surrounded or interrupted by a protuberance of disorganized material was observed. A normal axoneme was present close to the basal body but without elongation much further outside the flagellar pocket. A disorganized swelling at the precocious end of the axoneme coincided with the lack of a paraflagellar rod structure. The isolate was able to infect macrophages in vitro, induce lesions in BALB/c mice and infect Lutzomyia longipalpis. CONCLUSIONS: Notwithstanding the lack of an extracellular flagellum, this isolate infects macrophages in vitro and produces lesions when inoculated into mice. Moreover, it is able to colonize phlebotomine sand flies. Considering the importance attributed to the flagellum in the successful infection and survival of Leishmania in the insect midgut and in the invasion of macrophages, these findings may bring new light into the infectious mechanisms of L. (V.) braziliensis. PMID- 22236465 TI - Automatic small bowel tumor diagnosis by using multi-scale wavelet-based analysis in wireless capsule endoscopy images. AB - BACKGROUND: Wireless capsule endoscopy has been introduced as an innovative, non invasive diagnostic technique for evaluation of the gastrointestinal tract, reaching places where conventional endoscopy is unable to. However, the output of this technique is an 8 hours video, whose analysis by the expert physician is very time consuming. Thus, a computer assisted diagnosis tool to help the physicians to evaluate CE exams faster and more accurately is an important technical challenge and an excellent economical opportunity. METHOD: The set of features proposed in this paper to code textural information is based on statistical modeling of second order textural measures extracted from co occurrence matrices. To cope with both joint and marginal non-Gaussianity of second order textural measures, higher order moments are used. These statistical moments are taken from the two-dimensional color-scale feature space, where two different scales are considered. Second and higher order moments of textural measures are computed from the co-occurrence matrices computed from images synthesized by the inverse wavelet transform of the wavelet transform containing only the selected scales for the three color channels. The dimensionality of the data is reduced by using Principal Component Analysis. RESULTS: The proposed textural features are then used as the input of a classifier based on artificial neural networks. Classification performances of 93.1% specificity and 93.9% sensitivity are achieved on real data. These promising results open the path towards a deeper study regarding the applicability of this algorithm in computer aided diagnosis systems to assist physicians in their clinical practice. PMID- 22236466 TI - Biomechanical and bone histomorphological evaluation of two surfaces on tapered and cylindrical root form implants: an experimental study in dogs. AB - PURPOSE: The aim of this study was to evaluate the early bone response of tapered and cylindrical root form implants with two different surface treatments in fresh extraction sockets after 4 and 8 weeks. MATERIALS AND METHODS: Surface treatments and implant design comprised (n = 9 each): tapered with dual acid-etched surface; tapered with dual acid-etched and sandblasted surface (T DAE SB); cylindrical with dual acid-etched surface (C DAE); and cylindrical with dual acid-etched and sandblasted surface (C DAE SB). Implants were placed in the distal sockets of mandibular premolars (2 P2, 3 P3, 4 P4 ) of six beagle dogs, remaining in vivo for 4 and 8 weeks. After sacrifice, the implants were subjected to torque to the point of interface fracture and subsequently nondecalcified for histomorphological study. Statistical analysis was performed by a General Linear Model (GLM) analysis of variance model with a significance level of 5%. RESULTS: Torque to interface fracture was significantly greater for the C DAE SB group than for the other groups (p < .001). Histomorphological analysis showed woven bone formation around all implant surfaces at 4 weeks and its replacement by lamellar bone at 8 weeks. Study time (4 or 8 weeks) did not affect torque measures. CONCLUSIONS: The double acid-etched and sandblasted sample surface increased early bone biomechanical fixation of both cylindrical and tapered root form implants. The cylindrical root form implants showed higher torque to interface fracture values when compared with the tapered root form implants. The C DAE SB surface group showed the highest biomechanical fixation values (p < .001). PMID- 22236467 TI - Distal ureteral diameter measurement objectively predicts vesicoureteral reflux outcome. AB - OBJECTIVE: Vesicoureteral reflux (VUR) grading may be difficult when discrepancies exist between the degree of dilation of the pyelocalyceal system and the ureter. Resolution may be more accurately predicted by the appearance of the distal ureter. We analyzed a novel, objective method of evaluating VUR based on the diameter of the distal ureter. METHODS: Seventy-nine voiding cystourethrograms were reviewed (18 boys; 61 girls; aged 1 month to 7.5 years). The largest ureteral diameter within the false pelvis was measured and normalized by dividing by the distance from the L1-L3 vertebral body to give the distal ureteral diameter: L1-L3 ratio (UDR). Clinical outcome was defined as spontaneous resolution or surgical correction. RESULTS: A significant association between grade and UDR existed (p < 0.0001). Mean UDR was significantly greater in those who underwent surgical correction (0.34 +/- 0.02 vs 0.18 +/- 0.02; p < 0.0001). Logistic regression analysis demonstrated a significant association of UDR with outcome controlling for grade (p = 0.001). Grade effect on outcome when controlling for UDR was not significant (p = 0.76). Odds ratio for surgical correction corresponding to a 0.1 increase in UDR equaled 2.25 (95% CI: 1.39, 3.64). CONCLUSION: UDR provides an objective measurement of VUR and appears more predictive of clinical outcome than grade in this series. PMID- 22236468 TI - Urinary incontinence and quality of life in children. AB - OBJECTIVE: Urinary incontinence (UI) negatively affects children's quality of life (QOL). It is not known if parents are reliable informants on impact and QOL nor if lower urinary tract symptoms (LUTS) are related to QOL. We wished to determine the association between LUTS measured by the Dysfunctional Voiding Symptom Score (DVSS) and QOL measured by the Pediatric Urinary Incontinence QOL tool (PIN-Q), and to test the relationship between parent and patient's responses. SUBJECTS AND METHOD: Forty children (10 males, 30 females), aged 5-11 years with non-neurogenic daytime wetting, and their parents completed DVSS and PIN-Q as well as responding to open-ended questions about the effect of incontinence. RESULTS: Child DVSS: mean 12.6 (3 (very mild) to 21 (severe)); parent DVSS: mean 12.8 (3-20). Child PIN-Q: mean 37.6 (8 (no effect) to 70 (severe effect)); parent PIN-Q: mean 38.7 (15-61). Parents indicated a major effect of UI on family function and dynamics, as well as on the child. CONCLUSIONS: UI has a major effect on the child and the family. The PIN-Q and DVSS are complementary and provide a clinically appropriate picture of LUTS and impact on QOL. Parents understood the effect of incontinence and could act as proxy for the child. PMID- 22236469 TI - Synthesis and evaluation of platelet aggregation inhibitory activity of some 3 phenyl-pyrroloquinazolinones. AB - A series of 3-phenyl-2,7-dihydro-1H-pyrrolo[3,2-f]quinazolin-1-one derivatives (3 PPyQZ) was synthesized starting from 5-amino-indoles, via condensation with N ethoxycarbonylthiobenzamides followed by thermal cyclization. On the basis of their structural analogy with reported anti-thrombin pyrroloquinazolines, the derivatives were first tested for their capacity to inhibit platelet aggregation. Some of them had in vitro inhibitory effects on collagen and thrombin-induced aggregation in the micromolar range, and much higher inhibition than that shown by some phenyl-pyrroloquinolinones. Experiments to determine the mechanism of action of the most potent inhibitor (compound 18) indicated that it acts in at least two sites: one preceding the agonist-induced increase of cytosolic [Ca(2+)], and one following this step of the platelet activation cascade. The compound also inhibited thrombin-evoked protein-Tyr-phosphorylation. Although it is premature to draw definitive conclusions, the present results indicate that 3 PPyQZ structure, with the quite potent inhibitor of platelet aggregation compound 18, might constitute a starting point for the synthesis of potential anti thrombosis agents. PMID- 22236470 TI - Probing the antiamoebic and cytotoxicity potency of novel tetrazole and triazine derivatives. AB - A series of compounds bearing a Tetrazole and Triazine ring motif conjugated with a SO(2)NH function were synthesized and investigated for their antiamoebic potency. Cytotoxicity of the compounds was checked on human hepatocellular carcinoma cell line HepG2. Incorporation of Triazine ring in place of tetrazole resulted in a precipitous increase in the antiamoebic activity of the compounds. Antiamoebic activity of the investigated compounds was found to be position and substituent dependent. In vitro cytotoxicity results revealed noncytotoxic nature of all the tested compounds up to a concentration of 25 MUM. Compound 5c and 5d were obtained as least cytotoxic (IC(50) > 100 MUM) and excellent Entamoeba histolytica inhibitors with IC(50) values of 1.05 MUM and 1.02 MUM respectively. PMID- 22236471 TI - Synthesis and anticonvulsant activity of 1-(8-(benzyloxy)quinolin-2-yl)-6 substituted-4,6-diazaspiro[2,4]heptane-5,7-diones. AB - In the present study on the development of new anticonvulsants, 16 new1-(8 (benzyloxy)quinolin-2-yl-6-substituted-4,6-diazaspiro[2,4]heptane-5,7-diones were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 8e and 8j showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 8e showed the MES-induced seizures with ED(50) value of 8.6 mg/kg and TD(50) value of 365.3 mg/kg after intraperitoneally injection to mice, which provided compound 8e with a protective index (TD(50)/ED(50)) of 26.8 in the MES test. PMID- 22236472 TI - Design, synthesis and evaluation of caffeic acid phenethyl ester-based inhibitors targeting a selectivity pocket in the active site of human aldo-keto reductase 1B10. AB - Inhibitors of a human aldo-keto reductase, AKR1B10, are regarded as promising therapeutics for the treatment of cancer, but those with both high potency and selectivity compared to the structurally similar aldose reductase (AKR1B1) have not been reported. In this study, we have found that, among honeybee propolis products, caffeic acid phenethyl ester (CAPE) inhibited AKR1B10 (IC(50) = 80 nM) with 7-fold selectivity over AKR1B1. Based on a model of docked CAPE in AKR1B10, its derivatives were designed, synthesized and evaluated for inhibitory potency. Among them, 3-(4-hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester (10c) was the most potent competitive inhibitor (K(i) = 2.6 nM) with 790 fold selectivity for AKR1B10 over AKR1B1. Molecular docking of 10c and site directed mutagenesis of AKR1B10 residues suggested that the interactions between the 2-methoxy and 3-hydroxy groups of 10c and the enzyme's Val301 and Gln114, respectively, are important for the inhibitor's selectivity. Additionally, the sub-MUM concentration of 10c significantly suppressed the farnesal metabolism and cellular proliferation in AKR1B10-overexpressing cells. PMID- 22236473 TI - Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys. AB - CONTEXT: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. OBJECTIVE: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. METHODS: This is a multicenter retrospective study. RESULTS: Mean age at study was 25.6+/ 2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9+/-2 cm, regardless of GH treatment. CONCLUSIONS: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients. PMID- 22236474 TI - Lymphocyte signaling: regulation of FoxO transcription factors by microRNAs. AB - The Forkhead box O (FoxO) family of transcription factors is important for the maintenance of immunological homeostasis and tolerance by controlling the development and function of B and T lymphocytes. Because dysregulation in FoxO activity can result in chronic inflammation and autoimmunity, the transcriptional activity of FoxO proteins is tightly controlled and generally dependent on complex posttranslational modifications that lead either to their nuclear entry and subsequent activation or, alternatively, to their nuclear export. The phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt) axis represents the major pathway phosphorylating and thereby inactivating FoxO proteins. However, recent results have revealed an additional posttranscriptional mechanism of FoxO inactivation by microRNAs. The discovery of this molecular pathway may provide a new therapeutic avenue for the modulation of FoxO activity in immune mediated diseases using either microRNA targeting antagomirs or synthetic microRNA mimics, a topic that is addressed in this review. PMID- 22236475 TI - Complications of ear rings. AB - In this paper the complications of ear piercing are considered and the treatment of resultant deformities is described. PMID- 22236476 TI - The methodology of negative pressure wound therapy: separating fact from fiction. AB - BACKGROUND: Negative pressure wound therapy (NPWT) is a technique that has gained such rapid acceptance for such a diversity of wound management problems that the evidence for optimal use has struggled to keep up. While clinical studies have sought to evaluate its effectiveness for a variety of acute and chronic wounds, preclinical studies have suggested that features such as the magnitude and periodicity of negative pressure, the wound filler and interface materials and the drainage conduit might introduce key pathophysiological variations at the wound bed influencing healing. Optimising the methodological approach is the key to achieving the best outcomes with NPWT. The aim of the present study was to evaluate and summarise the clinical and experimental evidence for how these methodological variations influence wound healing when using NPWT. METHODS: A literature review was conducted to evaluate each component of NPWT inciting methodological variation with reference to clinical and preclinical variables including wound volume reduction, blood flow, granulation and growth factor stimulation. RESULTS: Fourteen commercially available NPWT systems are currently available. Both foam and gauze transmit NP efficiently. While some preclinical evidence suggests foam may preferentially promote cell proliferation, there is no clear evidence to favour one wound filler. Most wound contraction occurs within the first -50 mmHg and physiological optimisation may be achieved within -80 mmHg. Cyclical NP-mediated cell mechanotransduction may alter the healing characteristics of the wound bed but no definitive clinical protocol has been established. There is insufficient evidence to credit NPWT with reduced bacterial wound colonisation. CONCLUSION: There is an urgent need to develop evidence-based NPWT regimes, tailoring the methodological aspects of therapy to the clinical need. An individualised strategy may yield improved outcomes and realise the potential of this powerful therapeutic intervention. PMID- 22236477 TI - Type IV hypersensitivity to a textured silicone breast implant. AB - We present a case of hypersensitivity to a breast implant in a 57-year old female with breast cancer and hypersensitivity to adhesive dressings. A mastectomy, axillary node clearance, latissimus dorsi flap and silicone implant-based reconstruction were performed. The mammary wound dehisced within three weeks and the implant required removal. No pus was present, and cultures were negative. Three years later, a further silicone implant was inserted. Within three weeks from insertion, the patient required readmission with serous discharge from the wound, flu-like symptoms, low-grade pyrexia and painful swelling at the operative site. The implant was removed. Capsule biopsies demonstrated a large lymphoid cell reaction, in keeping with a delayed hypersensitivity reaction. Patch testing to samples of the implant was positive. PMID- 22236478 TI - Chitosan-coated anisotropic silver nanoparticles as a SERS substrate for single molecule detection. AB - Surface-enhanced Raman spectroscopy (SERS) is a technique that has become widely used for identifying and providing structural information about molecular species in low concentration. There is an ongoing interest in finding optimum particle size, shape and spatial distribution for optimizing the SERS substrates and pushing the sensitivity toward the single-molecule detection limit. This work reports the design of a novel, biocompatible SERS substrate based on small clusters of anisotropic silver nanoparticles embedded in a film of chitosan biopolymer. The SERS efficiency of the biocompatible film is assessed by employing Raman imaging and spectroscopy of adenine, a significant biological molecule. By combining atomic force microscopy with SERS imaging we find that the chitosan matrix enables the formation of small clusters of silver nanoparticles, with junctions and gaps that greatly enhance the Raman intensities of the adsorbed molecules. The study demonstrates that chitosan-coated anisotropic silver nanoparticle clusters are sensitive enough to be implemented as effective plasmonic substrates for SERS detection of nonresonant analytes at the single molecule level. PMID- 22236479 TI - Thioredoxin interacting protein genetic variation is associated with diabetes and hypertension in the Brazilian general population. AB - OBJECTIVE: To investigate the relationship between TXNIP polymorphisms, diabetes and hypertension phenotypes in the Brazilian general population. METHODS: Five hundred seventy-six individuals randomly selected from the general urban population according to the MONICA-WHO project guidelines were phenotyped for cardiovascular risk factors. A second, independent, sample composed of 487 family trios from a different site was also selected. Nine TXNIP polymorphisms were studied. The potential association between TXNIP variability and glucose phenotypes in children was also explored. TXNIP expression was quantified by real time PCR in 53 samples from human smooth muscle cells primary culture. RESULTS: TXNIP rs7211 and rs7212 polymorphisms were significantly associated with glucose and blood pressure related phenotypes. In multivariate logistic regression models the studied markers remained associated with diabetes even after adjustment for covariates. TXNIP rs7211 T/rs7212 G haplotype (present in approximately 17% of individuals) was significantly associated to diabetes in both samples. In children, the TXNIP rs7211 T/rs7212 G haplotype was associated with fasting insulin concentrations. Finally, cells harboring TXNIP rs7212 G allele presented higher TXNIP expression levels compared with carriers of TXNIP rs7212 CC genotype (p=0.02). CONCLUSION: Carriers of TXNIP genetic variants presented higher TXNIP expression, early signs of glucose homeostasis derangement and increased susceptibility to chronic metabolic conditions such as diabetes and hypertension. Our data suggest that genetic variation in the TXNIP gene may act as a "common ground" modulator of both traits: diabetes and hypertension. PMID- 22236480 TI - Impaired coronary flow reserve in young patients affected by severe psoriasis. AB - OBJECTIVE: Our study aimed to evaluate the effects of psoriasis (Pso) on coronary microvascular function and whether there is a relationship between disease activity scores and coronary blood flow abnormalities. METHODS: 56 young patients (pts) with Pso (42 M, aged 37+/-3 years) without clinical evidence of cardiovascular diseases, and 56 controls matched for age and gender were studied. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic echocardiography at rest and during adenosine infusion. Coronary flow reserve (CFR) was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR<=2.5 was considered abnormal. RESULTS: In pts with Pso, CFR was lower than in controls (3.2+/-0.9 vs. 3.7+/-0.7, p=0.02). CFR was abnormal (<=2.5) in 12 pts (22% vs. 0% controls, p<0.0001). Moreover, in pts with CFR<=2.5, Psoriasis Area Severity Index (PASI), a clinical score for Pso severity, was higher (11+/-6 vs. 7+/-3, p=0.006) compared to pts with CFR>2.5. At multivariable analysis PASI remained the only determinant of CFR<=2.5 (p=0.02). CONCLUSION: CFR in young pts with severe Pso without coronary disease is reduced suggesting a coronary microvascular dysfunction, independently related to the severity and extension of Pso. This early microvascular impairment might be hypothesized as the consequence of prolonged and sustained systemic inflammation and might explain the increased cardiovascular risk conferred by Pso. PMID- 22236481 TI - Adrenalectomy stimulates the formation of initial atherosclerotic lesions: reversal by adrenal transplantation. AB - Long-term changes in the secretion of immunosuppressive adrenal-derived glucocorticoid hormones influence cardiovascular disease risk. Here we determined the consequences of changes in adrenal steroid metabolism for the development of atherosclerotic lesions in mice. Atherosclerosis-susceptible low-density lipoprotein (LDL) receptor knockout mice were subjected to adrenalectomy (ADX) or a control (SHAM) operation and subsequently fed an atherogenic diet for 4 weeks. Atherogenic diet feeding raised plasma corticosterone levels in SHAM mice, but not adrenalectomized mice, resulting in an 83% lower (P<0.01) corticosterone level in adrenalectomized mice. Adrenalectomy was associated with a respectively 22% and 29% lower plasma level of cholesterol and triglycerides. In contrast, white blood cell counts were increased 2-fold (P<0.01) in adrenalectomized mice, which could be attributed to a significant 2.1- to 2.6-fold rise in lymphocyte (P<0.05) and monocyte (P<0.05) numbers. Probably as a result of the enhanced systemic inflammatory status, adrenalectomy was associated with a higher susceptibility for diet-induced atherosclerosis (321+/-18*10(3) MUm(2) for ADX vs 240+/-31*10(3) MUm(2) for SHAM; P<0.05) not withstanding the lowered cholesterol levels. Restoring adrenocortical steroid secretion - but not adrenal medulla function - and the associated downstream glucocorticoid receptor signaling in adrenalectomized mice through adrenal transplantation induced a reversal of the adrenalectomy-associated rise in white blood cell numbers, plasma monocyte chemoattractant protein 1 (MCP-1) levels, and atherosclerotic lesion development (lesion size in transplanted mice: 258+/-34*10(3) MUm(2); P<0.05 vs ADX). In conclusion, our studies show that adrenal-derived steroids protect against the development of initial atherosclerotic lesions in LDL receptor knockout mice. PMID- 22236482 TI - Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice. AB - OBJECTIVES: Interleukin (IL)-1 produced by vascular and bone marrow-derived cells exerts proinflammatory effects in these cell types by binding to IL-1 receptor type-1 (IL-1R1). We have previously shown that bone marrow-derived IL-1alpha and IL-1beta are critical for atherogenesis in apoE knockout (KO) mice. The aim of the present study was to investigate whether IL-1R1 on vascular wall resident or bone marrow-derived cells mediates IL-1's effects in atherogenesis. METHODS AND RESULTS: We generated apoE-/-/IL-1R1-/- double knockout (DKO) mice and created radiation chimeras. Aortic sinus lesion area was 20-47% lower in DKO compared to apoE KO mice with similar plasma lipids. The production of IL-1alpha and IL-1beta upon stimulation with LPS was not altered in IL-1R1-/- compared to IL-1R1+/+ peritoneal macrophages. DKO mice transplanted with IL-1R1+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE KO mice while specific deficiency of IL-1R1 in bone marrow-derived cells did not attenuate atherosclerosis. The mRNA levels of genes that promote macrophage recruitment to the vascular wall, namely CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aortas from DKO compared to apoE KO mice. Finally, blockade of IL-1R1 with IL-1R antagonist (IL-1Ra) resulted in complete abrogation of IL-1beta-induced expression of adhesion and chemotactic molecules and IL-1alpha, in isolated human umbilical vein endothelial cells (HUVEC). CONCLUSIONS: Vascular wall resident cells are the main targets for the pro-atherogenic effects of bone marrow-derived IL-1 through IL-1R1, partly by induction of adhesion and chemotactic molecules in endothelial cells. PMID- 22236483 TI - Trends in early and late diagnosis of HIV-1 infections in Tokyoites from 2002 to 2010. AB - OBJECTIVE: The objective of this study was to delineate the trends in early and late diagnosis of HIV-1 infection in newly diagnosed Tokyoites. METHODS: The BED assay was used to identify cases diagnosed at an early stage of infection. BED positive non-AIDS cases with a CD4 cell count >= 200/MUl were defined as cases with recent infection. The rates of AIDS and recent infection in 809 newly diagnosed Tokyoites during 2002-2010 were analyzed. RESULTS: The AIDS rate was 22.5%. AIDS patients were older (40.4 years) than non-AIDS patients (35.0 years), and a smaller proportion were men who have sex with men (MSM) in AIDS patients (81.7%) than in non-AIDS patients (89.9%). The AIDS rate was persistently lower (<= 14.3%) in <= 29-year-old than in >= 30-year-old MSM. The rate of recent infection was 24.4%. Individuals with recent infection (33.0 years old) were younger than the others (37.2 years). The rate of recent infection was lower (<= 18.5%) in MSM aged >= 40 years than in those aged <= 39 years during the study period, except for 2007 and 2008. CONCLUSIONS: Younger MSM Tokyoites appear to be aware of the risk of their sexual behavior, sufficient to take voluntary HIV testing repeatedly, resulting in early diagnosis. Older MSM did not take HIV testing frequently enough and may be a good target for campaigns promoting testing. PMID- 22236484 TI - Group B Streptococcus infections in non-pregnant adults: the role of immunosuppression. AB - BACKGROUND: Group B Streptococcus (GBS) is a known causative pathogen of neonatal sepsis, but the epidemiology in non-pregnant adults is less studied. METHODS: Retrospective case-control and cohort analyses of risk factors and outcomes of GBS infections among non-pregnant adults were conducted at the Detroit Medical Center from January 2005 to May 2010. Uninfected controls were matched to cases in a 3:1 ratio. Data were obtained from charts and pharmacy records. Identification of the bacteria and antimicrobial susceptibility testing were determined by MicroScan. Cox regression was used for matched multivariate analyses. RESULTS: Thirty-two patients with GBS infections were identified and were matched and compared to 96 controls. Compared to controls, patients with GBS infection were significantly younger. Immunosuppression, attributable mainly to neutropenia and recent use of glucocorticoids, was an independent predictor for GBS infection (odds ratio 2.7, p=0.03). Nine (28%) of the patients with GBS infection had bacteriological failure despite the administration of appropriate antimicrobial therapy. Of the 10 patients with bloodstream infections (BSI), three had endocarditis and four had central nervous system (CNS) infections. During the study period the incidence of infections decreased, but the rates of resistance to erythromycin and clindamycin increased. CONCLUSIONS: GBS, previously considered a genitourinary pathogen, has emerged as a non-nosocomial opportunistic pathogen causing BSI, endocarditis, and CNS infections. Immunosuppression, particularly transient immunosuppressed states, was an independent predictor for GBS BSI. Resistance rates to macrolides and clindamycin continue to increase, and should be closely monitored. PMID- 22236485 TI - Molecular cloning, expression, bioinformatics analysis and bioactivity characterization of TNF13B (BAFF) gene in bat (Vespertilio superans Thomas). AB - B cell activating factor (BAFF) belonging to the tumor necrosis factor (TNF) family is critical to B cell survival, proliferation, maturation, and immunoglobulin secretion and to T cell activation. In the present study, the full length cDNA of BAFF (designated bBAFF) from the bat (Vespertilio superans Thomas) was cloned using RT-PCR and rapid amplification of cDNA ends (RACE) techniques. The full-length cDNA of bBAFF consists of 986 bases including an 873 bp open reading frame encoding 290 amino acids. Sequence comparison indicated that the amino acid of bBAFF possessed the TNF signature, a transmembrane domain, a putative furin protease cleavage site and three cysteine residues. The predicted three-dimensional (3D) structure of the bsBAFF monomer, analyzed by comparative protein modeling, revealed that it was very similar to its counterparts. Real time quantitative PCR (qPCR) analysis indicated that bBAFF mRNA was predominantly expressed in bat lymphoid tissue spleen. The SUMO (Small Ubiquitin-like Modifier) bsBAFF was efficiently expressed in Escherichia coliBL21 (DE3) and confirmed by SDS-PAGE and Western blotting analysis. Laser scanning confocal microscopy analysis showed that bsBAFF could bind to its receptors on B cells. In vitro, the MTT assays indicated that SUMO-bsBAFF was not only able to promote survival/proliferation of bat lymphocytes but also able to stimulate survival/proliferation of mouse B cells. These findings indicate that bsBAFF plays an important role in the survival/proliferation of B cells and has functional cross-reactivity among mammalians. The present findings may provide valuable information for research into the immune system of the bat. PMID- 22236486 TI - A comparison of perioperative charges and outcome between open and mini-open approaches for anterior lumbar discectomy and fusion. AB - The objectives of this study were to examine charge data and long-term outcomes of two approaches for anterior lumbar interbody fusion: a mini-open lateral approach (extreme lateral interbody fusion, XLIF) and an open anterior approach (anterior lumbar interbody fusion, ALIF) through retrospective chart review. A total of 202 patients underwent surgery: 87 with ALIF (Open) and 115 with XLIF (Mini-open) procedures, all with transpedicular fixation. Complications occurred in 16.7% of Open, and 8.2% of Mini-open, procedures (p = 0.041). The mean charges ($US) for one-level Mini-open and Open procedures were $91,995 and $102,146, and for two-level procedures were $124,540 and $144,183, respectively. All differences were statistically significant (p < 0.05). This represents a 10% cost savings, based on charges, for one-level and 13.6% for two-level Mini-open compared to Open procedures. Functional outcomes improved significantly at two years for both cohorts, although the difference between groups was not statistically significant. In conclusion, the Mini-open approach, compared to the Open, resulted in clinical as well as cost benefits with similar long-term outcomes. PMID- 22236487 TI - [Doctor Google: use of Internet during pregnancy in France in 2009]. AB - OBJECTIVES: To determine the profile of pregnant women who use Internet during pregnancy as well as their motivations. PATIENTS AND METHODS: We conducted a transversal prospective survey with questionnaires distributed to women during pregnancy and in the postpartum period in a regional hospital in the Yvelines from July 13th to November 28th, 2009. The same questionnaire was posted for pregnant women on Internet websites and forums dedicated to pregnancy from October 1st, 2009 to January 6th, 2010. Qualitative variables were compared by Chi(2) or Fisher tests. RESULTS: We obtained 791 answers, with 83 and 97% using Internet during pregnancy in the hospital and on-line population respectively. Their motivations to use Internet are the easy access (85% of the population, n=606) and the anonymity afforded by this media (49.1%, n=351). The profile of the patient using Internet was: primiparous, less than 35 years, higher education and having a profession. The most popular information searched was on the delivery (49.1%). CONCLUSION: The population using Internet during pregnancy seems homogeneous and represented by young, educated, and working women. PMID- 22236489 TI - How to think about interprofessional competence: a metacognitive model. AB - Different professions meet and work together in teams every day in health and social care. To identify and deliver the best quality of care for the patient, teamwork should be both professionally and interprofessionally competent. How can enhanced education prepare teamworkers to be both professionally and interprofessionally competent? To achieve interprofessional skills and design effective interprofessional curricula, there is a need for metacognitive frameworks focusing on the relationship between theories and the problem-solving process as well as the structure and content of professional competence. The aim of this article is to discuss the need for shared metacognitive structures/models as a tool for securing successful interprofessional learning and developing personal, professional and interprofessional competence to improve the quality of care. A metacognitive model for interprofessional education and practice is presented in this article. This model has been developed as a tool for analyzing professional competence on three levels: individual, team and organization. The model comprises seven basic components of professional competence and the way they are related and interact. Examples of how this metacognitive model can be used in the early, middle and late stages in interprofessional education are given. PMID- 22236488 TI - Managing co-morbid depression and anxiety in primary care patients with asthma and/or chronic obstructive pulmonary disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma are common chronic diseases that are frequently accompanied by depression and/or anxiety. However, symptoms of depression and anxiety are often not recognized and therefore not treated. Currently, only a few studies have tested new clinical approaches that could improve the treatment of co-morbid depression and anxiety in these groups of patients. METHODS/DESIGN: The present randomized controlled study will be conducted within the framework of PoZoB (Praktijk Ondersteuning Zuid-Oost Brabant), a large primary care organization in the Netherlands. Patients with asthma/COPD and co-morbid anxiety/depression will be included in order to test the effectiveness of a disease management approach to treat these co-morbid disorders. Important elements of this approach are: 1) systematic screening to improve detection of anxiety and depression 2) treatment in case of positive screening 3) monitoring of anxiety and depression 4) intensified treatment in case of non-remission (stepped care). DISCUSSION: The present study is a large primary care study on the treatment of co-morbid depression and anxiety in patients with asthma and COPD. Strengths of this study are its randomized design, the focus on implementation in primary care and the fact that it applies the latest findings on the treatment of depression and anxiety. First results are expected in 2012/2013. PMID- 22236490 TI - Households' perception of climate change and human health risks: a community perspective. AB - BACKGROUND: Bangladesh has been identified as one of the most vulnerable countries in the world concerning the adverse effects of climate change (CC). However, little is known about the perception of CC from the community, which is important for developing adaptation strategies. METHODS: The study was a cross sectional survey of respondents from two villages--one from the northern part and the other from the southern part of Bangladesh. A total of 450 households were selected randomly through multistage sampling completed a semi-structure questionnaire. This was supplemented with 12 focus group discussions (FGDs) and 15 key informant interviews (KIIs). RESULTS: Over 95 percent of the respondents reported that the heat during the summers had increased and 80.2 percent reported that rainfall had decreased, compared to their previous experiences. Approximately 65 percent reported that winters were warmer than in previous years but they still experienced very erratic and severe cold during the winter for about 5-7 days, which restricted their activities with very destructive effect on agricultural production, everyday life and the health of people. FGDs and KIIs also reported that overall winters were warmer. Eighty point two percent, 72.5 percent and 54.7 percent survey respondents perceived that the frequency of water, heat and cold related diseases/health problems, respectively, had increased compared to five to ten years ago. FGDs and KIIs respondents were also reported the same. CONCLUSIONS: Respondents had clear perceptions about changes in heat, cold and rainfall that had occurred over the last five to ten years. Local perceptions of climate variability (CV) included increased heat, overall warmer winters, reduced rainfall and fewer floods. The effects of CV were mostly negative in terms of means of living, human health, agriculture and overall livelihoods. Most local perceptions on CV are consistent with the evidence regarding the vulnerability of Bangladesh to CC. Such findings can be used to formulate appropriate sector programs and interventions. The systematic collection of such information will allow scientists, researchers and policy makers to design and implement appropriate adaptation strategies for CC in countries that are especially vulnerable. PMID- 22236491 TI - Insulin induces production of new elastin in cultures of human aortic smooth muscle cells. AB - Diabetes mellitus accelerates atherosclerotic progression, peripheral angiopathy development, and arterial hypertension, all of which are associated with elastic fiber disease. However, the potential mechanistic links between insulin deficiency and impaired elastogenesis in diabetes have not been explored. Results of the present study reveal that insulin administered in therapeutically relevant concentrations (0.5 to 10 nmol/L) selectively stimulates formation of new elastic fibers in cultures of human aortic smooth muscle cells. These concentrations of insulin neither up-regulate collagen type I and fibronectin deposition nor stimulate cellular proliferation. Further, the elastogenic effect of insulin occurs after insulin receptor activation, which triggers the PI3K downstream signaling pathway and activates elastin gene transcription. In addition, the promoter region of the human elastin gene contains the CAAATAA sequence, consistent with the FoxO-recognized element, and the genomic effects of insulin occur after removal of the FoxO1 transcriptional inhibitor from the FoxO recognized element in the elastin gene promoter. In addition, insulin signaling facilitates the association of tropoelastin with its specific 67-kDa elastin binding protein/spliced form of beta-galactosidase chaperone, enhancing secretion. These results are crucial to understanding of the molecular and cellular mechanisms of diabetes-associated vascular disease, and, in particular, endorse use of insulin therapy for treatment of atherosclerotic lesions in patients with type 1 diabetes, in which induction of new elastic fibers would mechanically stabilize the developing plaques and prevent arterial occlusions. PMID- 22236492 TI - Managing clustered data using hierarchical linear modeling. AB - Researchers in nutrition research often use cluster or multistage sampling to gather participants for their studies. These sampling methods often produce violations of the assumption of data independence that most traditional statistics share. Hierarchical linear modeling is a statistical method that can overcome violations of the independence assumption and lead to correct analysis of data, yet it is rarely used in nutrition research. The purpose of this viewpoint is to illustrate the benefits of hierarchical linear modeling within a nutrition research context. PMID- 22236493 TI - Food deserts in Leon County, FL: disparate distribution of Supplemental Nutrition Assistance Program-accepting stores by neighborhood characteristics. AB - OBJECTIVE: Examine whether neighborhood characteristics of racial composition, income, and rurality were related to distribution of Supplemental Nutrition Assistance Program (SNAP)-accepting stores in Leon County, Florida. DESIGN: Cross sectional; neighborhood and food store data collected in 2008. SETTING AND PARTICIPANTS: Forty-eight census tracts as proxy of neighborhoods in Leon County, Florida. All stores and SNAP-accepting stores were identified from a commercial business directory and a United States Department of Agriculture SNAP-accepting store list, respectively (n = 288). MAIN OUTCOME MEASURES: Proportion of SNAP accepting stores across neighborhoods. ANALYSIS: Descriptive statistics to describe distribution of SNAP-accepting stores by neighborhood characteristics. Proportions of SNAP-accepting stores were compared by neighborhood characteristics with Wilcoxon-Mann-Whitney and Kruskal-Wallis tests. RESULTS: Of 288 available stores, 45.1% accepted SNAP benefits. Of the 48 neighborhoods, 16.7% had no SNAP-accepting stores. Proportions of SNAP-accepting grocery stores were significantly different by neighborhood racial composition and income. Primarily black neighborhoods did not have any supermarkets. Results were mixed with regard to distribution of food stores and SNAP-accepting stores by neighborhood racial composition, income, and rurality. CONCLUSIONS AND IMPLICATIONS: This study suggests disparities in distribution of SNAP-accepting stores across neighborhood characteristics of racial composition, income, and rurality. PMID- 22236494 TI - A qualitative study to explore how parental expectations and rules influence beverage choices in early adolescence. AB - OBJECTIVE: To understand parent beverage expectations for early adolescents (EAs) by eating occasion at home and in various settings. METHODS: Descriptive study using focus group interviews and the constant comparative method for qualitative data analysis. RESULTS: Six focus groups were completed, and 2 were conducted in Spanish. Participants (n = 49) were mostly female (86%) and non-Hispanic white (49%) and Hispanic (33%). Parent expectations for EA beverage intake were based on health beliefs, EA preferences, and cost, whereas those related to portion sizes and frequency varied by beverage type. Parents managed beverage expectations at home and away from home by making healthful beverages available and accessible, or by offering or allowing only specific beverages. CONCLUSIONS AND IMPLICATIONS: Results from this qualitative study involving a small sample of parents showed that expectations were influenced by practical concerns and managed primarily through availability practices. These issues could be addressed to improve EA beverage consumption. PMID- 22236495 TI - Factors contributing to a school's decision to apply for the California Instructional School Garden Program. AB - OBJECTIVE: To compare the applicant schools (AS) to non-applicant schools (NAS) residing in the same school districts for the California Instructional School Garden Program and identify barriers to the application process. METHODS: A case control, cross-sectional study design was used to compare resources and school environments. Pearson chi-square and logistic regression were conducted. RESULTS: Public schools throughout California participated (n = 1,662). The response rates for AS and NAS were 43.2% and 48.2%, respectively. Applicant schools had greater access to garden coordinators and parent/community volunteers dedicated to school gardens, and they had other sources of funds/grants to support school gardens compared to NAS (P < .001). CONCLUSIONS AND IMPLICATIONS: Access to certain garden resources played a significant role in predicting whether schools would decide to participate in the California Instructional School Garden Program. PMID- 22236496 TI - Associations of built food environment with dietary intake among youth with diabetes. AB - OBJECTIVE: To evaluate the associations of supermarket and fast-food outlet accessibility and availability with dietary intake among youth with diabetes. DESIGN: Subjects' residential location and dietary intake was obtained from the SEARCH for Diabetes in Youth study. Food outlet data obtained from the South Carolina Department of Health and Environmental Control and InfoUSA were merged based on names and addresses of the outlets. The comprehensive data were then used to construct accessibility and availability measures for each participant. SETTING: State of South Carolina. PARTICIPANTS: Three hundred fifty-nine youths with diabetes (10 years old and older) from the SEARCH for Diabetes in Youth study. PHENOMENA OF INTEREST: Supermarket and fast-food outlet accessibility and availability; dietary intake represented by Dietary Approaches to Stop Hypertension (DASH) score. ANALYSIS: Generalized estimating equations analyses. RESULTS: Increased availability and accessibility of supermarkets were significantly associated with higher DASH score, even after adjusting for individual-level correlates, urbanicity, and fast-food outlet accessibility or availability. Fast-food accessibility, however, was associated only with specific food groups (meat, sweets, and low-fat dairy intake), not with the DASH score. CONCLUSIONS AND IMPLICATIONS: Efforts to promote environments conducive to healthful eating may significantly improve the overall dietary intake and reduce diet-related health complications among youth with diabetes. PMID- 22236497 TI - Retarded Onchocerca volvulus L1 to L3 larval development in the Simulium damnosum vector after anti-wolbachial treatment of the human host. AB - BACKGROUND: The human parasite Onchocerca volvulus harbours Wolbachia endosymbionts essential for worm embryogenesis, larval development and adult survival. In this study, the development of Wolbachia-depleted microfilariae (first stage larvae) to infective third stage larvae (L3) in the insect vector Simulium damnosum was analysed. METHODS: Infected volunteers in Cameroon were randomly and blindly allocated into doxycycline (200 mg/day for 6 weeks) or placebo treatment groups. After treatment, blackflies were allowed to take a blood meal on the volunteers, captured and dissected for larval counting and DNA extraction for quantitative real-time PCR analysis. RESULTS: PCR results showed a clear reduction in Wolbachia DNA after doxycycline treatment in microfilariae from human skin biopsies with > 50% reduction at one month post-treatment, eventually reaching a reduction of > 80%. Larval stages recovered from the insect vector had similar levels of reduction of endosymbiotic bacteria. Larval recoveries were analysed longitudinally after treatment to follow the kinetics of larval development. Beginning at three months post-treatment, significantly fewer L3 were seen in the blackflies that had fed on doxycycline treated volunteers. Concomitant with this, the proportion of second stage larvae (L2) was significantly increased in this group. CONCLUSIONS: Doxycycline treatment and the resulting decline of Wolbachia endobacteria from the microfilaria resulted in retarded development of larvae in the insect vector. Thus, anti-wolbachial treatment could have an additive effect for interrupting transmission by reducing the number of L3 that can be transmitted by blackflies. PMID- 22236499 TI - Characteristics of false allegation adult crimes. AB - The purpose of this study was to identify common factors in false allegation adult crimes, by examining the dynamics involved in 30 confirmed false allegation cases. The authors conducted a comprehensive review of these adjudicated cases and then completed a collection instrument to capture offender demographics, offense characteristics, and motive. The results indicated that most false allegation crimes were committed by women (73.3%) and Caucasians (93.3%). Data indicated that more interpersonally violent allegations were primarily motivated by attention/sympathy needs (50.0%), whereas more impersonal offenses involved other motivations such as providing an alibi (16.7%) or profit (13.3%). Offenders tended to be younger, high school graduates with no higher education (43.3%). A total of 23.3% of offenders had a prior criminal history. Male offenders appeared as likely as women to be motivated by attention/sympathy; however, men tended to select more violent, nonsexual offenses (e.g., attempted murder) than women. PMID- 22236498 TI - Expanding the multipotent profile of huprine-tacrine heterodimers as disease modifying anti-Alzheimer agents. AB - BACKGROUND: Multifactorial diseases such as Alzheimer's disease (AD) should be more efficiently tackled by drugs which hit multiple biological targets involved in their pathogenesis. We have recently developed a new family of huprine-tacrine heterodimers, rationally designed to hit multiple targets involved upstream and downstream in the neurotoxic cascade of AD, namely beta-amyloid aggregation and formation as well as acetylcholinesterase catalytic activity. OBJECTIVE: In this study, the aim was to expand the pharmacological profiling of huprine-tacrine heterodimers investigating their effect on muscarinic M(1) receptors as well as their neuroprotective effects against an oxidative insult. METHODS: Sprague Dawley rat hippocampus homogenates were used to assess the specific binding of two selected compounds in competition with 1 nM [(3)H]pirenzepine (for M(1) receptors) or 0.8 nM [(3)H]quinuclidinyl benzilate (for M(2) receptors). For neuroprotection studies, SHSY5Y cell cultures were subjected to 250 MUM hydrogen peroxide insult with or without preincubation with some huprine-tacrine heterodimers. RESULTS: A low nanomolar affinity and M(1)/M(2) selectivity has been found for the selected compounds. Huprine-tacrine heterodimers are not neurotoxic to SHSY5Y cells at a range of concentrations from 1 to 0.001 MUM, and some of them can protect cells from the oxidative damage produced by hydrogen peroxide at concentrations as low as 0.001 MUM. CONCLUSION: Even though it remains to be determined if these compounds act as agonists at M(1) receptors, as it is the case of the parent huprine Y, their low nanomolar M(1) affinity and neuroprotective effects expand their multitarget profile and increase their interest as disease-modifying anti-Alzheimer agents. PMID- 22236500 TI - [Recurrent atypical mycobacterial infections in the adult: think of autoantibodies against interferon-gamma !]. AB - INTRODUCTION: Disseminated non-tuberculosis mycobacterial infections are associated with a defect of the cellular immune response. They have been mainly reported in AIDS patients. Cases related to the presence of anti-interferon-gamma autoantibodies are rare. CASE REPORT: We report a non HIV-infected 45-year-old Thai woman, with a past medical history of Graves' disease. She presented with recurrent disseminated and severe non-tuberculous mycobacterial infections that were related to the production of anti-interferon-gamma autoantibody. The diagnosis was suspected in the presence of a negative interferon-gamma release assay (IGRA) including with the positive control, and evidenced by the identification of specific antibodies. CONCLUSION: Anti-interferon-gamma autoantibody production is a rare cause of non tuberculous mycobacterial infection. Such a mechanism should be suspected in non HIV-infected patients and especially in those having an Asiatic ethnicity or an associated immune disorder. A negative IGRA (including with the positive control) is a reliable diagnostic tool and should be completed with the identification of specific autoantibodies. PMID- 22236501 TI - Impact of antisecretory treatment on respiratory symptoms of gastroesophageal reflux disease in children. AB - The effect of antisecretory treatment on extraesophageal symptoms of gastroesophageal reflux disease was evaluated. Seventy-eight children presenting with typical and extraesophageal symptoms of gastroesophageal reflux disease underwent a multichannel intraluminal impedance and pH monitoring (MII/pH). Children with a positive MII/pH were randomly treated with proton pump inhibitors (PPIs) or histamine H(2) -receptor antagonists (H(2) RAs) during 3 months. At the end of the treatment period, all patients were recalled. A second treatment period of 3 months was given to those patients who were not symptom-free after 3 months. Thirty-five of the forty-one (85.4%) children with a pathologic MII/pH presented with extraesophageal symptoms and were treated with PPIs (omeprazole; n:19) or H(2) RAs (ranitidine; n:16) for 12 weeks. After 3 months, 11/19 (57.9%) PPI-treated patients had a complete resolution of symptoms; 6/8 nonresponders were treated with PPI for another 3 months and became all symptom-free. The other two underwent a Nissen fundoplication. Only 5/16 (31.2 %) patients treated with H(2) RAs had a complete resolution of symptoms after 3 months; 1/11 was treated again with H(2) RAs during 3 months, and 10/11 were changed to PPIs. In 3/10, a partial resolution of symptoms was achieved, while in 7/10, a complete remission was obtained (P < 0.05). Antisecretory reflux treatment improves extraesophageal reflux symptoms. The efficacy of PPIs is superior to that of H(2) RAs in these children. PMID- 22236502 TI - Analytical expressions for pH-regulated electroosmotic flow in microchannels. AB - We derived analytical expressions for the pH-regulated electroosmotic flow in a microchannel for arbitrary level of surface potential and type of electrolyte solution; previous results are almost always based on the conditions of low, constant surface potential, which are inaccurate and unrealistic. In addition, an analytical expression for the dependence of the surface potential on the electrolyte concentration and solution pH is obtained, which is capable of explaining the behavior of the empirical relation used in the literature. The analytical results derived are readily applicable to further electrokinetic analyses, and to interpret experimental observations and/or design devices involving electroosmosis such as biosensors and lab-on-a-chip. PMID- 22236503 TI - Recombinant human TSH for thyroid remnant ablation with (131)I in children and adolescents with papillary carcinoma. AB - BACKGROUND: The objective of this study was to report the results of a series of 12 patients with papillary carcinoma aged 16 years or younger, who were prepared with recombinant human TSH (rhTSH) for remnant ablation with (131)I. The TSH levels achieved and the safety of 24 cycles of rhTSH administration (ablation and control assessment) are reported. METHODS: All patients were prepared using the same protocol as recommended for adults. Eight to 12 months after initial therapy, the patients were submitted to neck ultrasound, measurement of stimulated Tg and anti-Tg antibodies (TgAb), and diagnostic whole-body scanning (DxWBS). RESULTS: TSH levels >50 mIU/l were achieved in all patients. An adverse reaction (mild nausea and headache) was observed in 1/24 cycles (4.1%). Eight (88.8%) of 9 patients with uptake in the thyroid bed in post-therapy whole-body scanning (RxWBS) achieved complete remission. One patient presented TgAb in the absence of apparent disease. In addition, imaging methods showed no apparent disease in the 2 patients with lymph node metastases in RxWBS. Elevated Tg persisted in 1 patient with pulmonary micrometastases. CONCLUSION: The present results demonstrate the efficacy and safety of rhTSH in children and adolescents. PMID- 22236504 TI - Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study. AB - Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted. PMID- 22236505 TI - The hidden third: improving outcome in treatment-resistant depression. AB - Treatment-resistant depression (TRD) presents many challenges for both patients and physicians. This review aims to evaluate the current status of the field of TRD and reflects the main findings of a consensus meeting held in September 2009. Literature searches were also conducted using PubMed and EMBASE. Abstracts of the retrieved articles were reviewed independently by the authors for inclusion. Evaluation of the clinical evidence in TRD is complicated by the absence of a validated definition, and there is a need to move away from traditional definitions of remission based on severity of symptoms to one that includes normalisation of functioning. One potential way of improving treatment of TRD is through the use of predictive biomarkers and clinical variables. The advent of new treatments may also help by focusing on neurotransmitters other than serotonin. Strategies such as the switching of antidepressants, use of combination therapy with lithium, atypical antipsychotics and other pharmacological agents can improve outcomes, and techniques such as deep brain stimulation and vagus nerve stimulation have shown promising early results. Despite consistent advances in the pharmacotherapy of mood disorders in the last decade, high rates of TRD are still a challenging aspect of overall management. PMID- 22236506 TI - How do plants feel the heat? AB - In plants, the heat stress response (HSR) is highly conserved and involves multiple pathways, regulatory networks and cellular compartments. At least four putative sensors have recently been proposed to trigger the HSR. They include a plasma membrane channel that initiates an inward calcium flux, a histone sensor in the nucleus, and two unfolded protein sensors in the endoplasmic reticulum and the cytosol. Each of these putative sensors is thought to activate a similar set of HSR genes leading to enhanced thermotolerance, but the relationship between the different pathways and their hierarchical order is unclear. In this review, we explore the possible involvement of different thermosensors in the plant response to warming and heat stress. PMID- 22236507 TI - Sonochemical synthesis of versatile hydrophilic magnetite nanoparticles. AB - Hydrophilic magnetite nanoparticles in the size range 30-10nm are easily and rapidly prepared under ultrasonic irradiation of Fe(OH)(2) in di- and tri ethylene glycol/water solution with volume ratio varying between 7:3 and 3:7. Structural (XRD) and morphological (SEM) characterization reveal good crystalline and homogeneous particles whereas, when solvothermally prepared, the particles are inhomogeneous and aggregated. The sonochemically prepared particles are versatile, i.e. well suited to covalently bind molecules because of the free glycol hydroxylic groups on their surface or exchange the diethylene or triethylene glycol ligand. They can be easily transferred in hydrophobic solvents too. Room-temperature magnetic hysteresis properties measured by means of Vibrating Sample Magnetometer (VSM) display a nearly superparamagnetic character. The sonochemical preparation is easily scalable to meet industrial demand. PMID- 22236508 TI - Invasive findings in patients with angina equivalent symptoms but no coronary artery disease; results from the heart quest cohort study. AB - BACKGROUND: The cause of angina in patients presenting at coronary angiography without significant coronary artery disease (CAD) has not been systematically assessed in a large prospective cohort. This study is aimed to identify the cause of angina in these patients. METHODS: This prospective cohort comprised 718 consecutive patients with angina equivalent symptoms and no CAD (defined as no coronary stenosis >= 50%) between January 1st 1997 and July 31st 2008. All patients underwent additional invasive testing (intracoronary acetylcholine administration, fast atrial pacing). Small vessel and vasospastic diseases were diagnosed according to symptoms and vessel reaction during testing. RESULTS: Mean age was 56.3 +/- 11.0 years (range 15 to 81 years). A majority of 431 patients (60.0%) had small vessel and/or vasospastic disease (233 patients had small vessel disease, 145 vasospastic disease and 53 a combination of both). Additional 87 patients (12.1%) had another cardiac disease. Only in a minority of 200 study participants (27.9%) that the symptoms were attributed to an extracardiac problem. Patients with small vessel disease were more likely to be female, to have hypertension, to have a family history of CAD and to have effort-related symptoms. Patients with vasospastic disease were more likely to be current smokers, to have angina at rest or to present as myocardial infarction, and to have coronary sclerosis and/or endothelial dysfunction. CONCLUSIONS: In a majority of patients with angina but no significant CAD, a cardiac cause of their symptoms can be found. Systematical invasive testing may help optimizing the medical management of these patients. PMID- 22236509 TI - Soluble epoxide hydrolase inhibition exerts beneficial anti-remodeling actions post-myocardial infarction. AB - BACKGROUND: A contributory role for soluble epoxide hydrolase (sEH) in cardiac remodeling post-myocardial infarction (MI) has been suggested; however effects of sEH inhibition following MI have not been evaluated. In this study, we examined in vivo post-MI anti-remodeling effects of a novel sEH inhibitor (GSK2188931B) in the rat, and evaluated its direct in vitro effects on hypertrophy, fibrosis and inflammation. METHODS AND RESULTS: Post-MI administered GSK2188931B (80 mg/kg/d in chow) for 5 weeks improved left ventricular (LV) ejection fraction compared to vehicle-treated (Veh) rats (P<0.01; Sham 65 +/- 2%, MI+Veh 30 +/- 2%, MI+GSK 43 +/- 2%) without affecting systolic blood pressure. Percentage area of LV tissue sections stained positive for picrosirius red (PS) and collagen I (CI) were elevated in LV non-infarct zone (P<0.05; NIZ; PS: Sham 1.46 +/- 0.13%, MI+Veh 2.14 +/- 0.22%, MI+GSK 1.28 +/- 0.14%; CI: Sham 2.57 +/- 0.17%, MI+Veh 5.06 +/- 0.58%, MI+GSK 2.97 +/- 0.34%) and peri-infarct zone (P<0.001; PIZ; PS: Sham 1.46 +/- 0.13%, MI+Veh 9.06 +/- 0.48%, MI+GSK 6.31 +/- 0.63%; CI: Sham 2.57+/-0.17%, MI+Veh 10.51 +/- 0.64%, MI+GSK 7.77 +/- 0.57%); GSK2188931B attenuated this increase (P<0.05). GSK2188931B reduced macrophage infiltration into the PIZ (P<0.05). GSK2188931B reduced AngII- and TNFalpha-stimulated myocyte hypertrophy, AngII- and TGFbeta-stimulated cardiac fibroblast collagen synthesis, including markers of gene expression ANP, beta-MHC, CTGF and CI (P<0.05). GSK2188931B reduced TNFalpha gene expression in lipopolysaccharide (LPS)-stimulated monocytes (P<0.05). CONCLUSION: sEH inhibition exerts beneficial effects on cardiac function and ventricular remodeling post-MI, and direct effects on fibrosis and hypertrophy in cardiac cells. These findings suggest that sEH is an important contributor to the pathological remodeling following MI, and may be a useful target for therapeutic blockade in this setting. PMID- 22236510 TI - Functional electrical stimulation for chronic heart failure: a meta-analysis. AB - INTRODUCTION: We conducted a meta-analysis of randomized, controlled trials of combined electrical stimulation versus conventional exercise training or placebo control in heart failure patients. METHODS: A systematic search was conducted of Medline (Ovid) (1950-September 2011), Embase.com (1974-September 2011), Cochrane Central Register of Controlled Trials and CINAHL (1981-September 2011). The search strategy included a mix of MeSH and free text terms for the key concepts heart failure, exercise training and functional electrical stimulation (FES). RESULTS: FES produced inferior improvements in peak VO2 when compared to cycle training: mean difference (MD) -0.32 ml.kg(-1).min(-1) (95% C.I. -0.63 to -0.02 ml.kg(-1).min(-1), p=0.04), however FES elicited superior improvements in peak VO2: MD 2.30 ml.kg(-1).min(-1) (95% C.I. 1.98 to 2.62 ml.kg(-1).min(-1), p<0.00001); and six minute walk distance to sedentary care or sham FES; MD 46.9 m (95% C.I. 22.5 to 71.3m, p=0.0002). There was no difference in change in quality of life between cycling and FES, but FES elicited significantly larger improvements in Minnesota Living with Heart Failure score than placebo or sham treatment; MD 1.15 (95% C.I. 0.69 to 1.61, p<0.00001). Moreover, the total FES intervention hours were strongly correlated with change in peak VO2, (r=0.80, p=0.02). CONCLUSIONS: Passive or active exercise is beneficial for patients with moderate to severe heart failure, but active cycling, or other aerobic/resistance activity is preferred in patients with heart failure who are able to exercise, and FES is the preferred modality in those unable to actively exercise. The benefits of FES may however, be smaller than those observed in conventional exercise training. Aggregate hours of electrical stimulation therapy were associated with larger improvements in cardio-respiratory fitness. PMID- 22236511 TI - Long-term hemodynamic performance of bileaflet prostheses versus tilting-disc prostheses in the aortic position. AB - BACKGROUND: The aim of this study was to compare the long-term hemodynamic performances of Medtronic-Hall (MH) and ATS medical bileaflet (ATS) valves in the aortic position. METHODS: We reviewed 249 patients that underwent AVR using MH or ATS valves between October 1994 and February 2004. MH valves were implanted in 117 patients (the MH group) and ATS valves in 132 patients (the ATS group). Serial changes in echocardiographic findings and clinical outcomes were analyzed. RESULTS: No early mortality occurred, and the late valve-related mortality was 11.2% (28/249). The transaortic mean pressure gradient (TMPG) in the MH group increased more rapidly than that in the ATS group during follow-up. Concomitant mitral valve replacement (double valve replacement, DVR) and placement of small aortic prostheses (indexed effective orifice area less than 0.85 cm(2)/m(2)) were found to contribute to a postoperative increase in TMPG. No inter-group difference in cumulative survival was observed at 10 years (88.2 +/- 3.1% vs. 84.7 +/- 3.1%, p=0.847). Cox regression analysis revealed that old age and DVR were predictors of late death, and that female gender, inclusion in the MH group and DVR were predictive of major adverse valve-related events (MAVREs). CONCLUSIONS: The MH group showed higher MAVREs than the ATS group and a relatively rapid increase in TMPG. Furthermore, DVR and placement of small prostheses were related to a late increase in TMPG irrespective of valve type. PMID- 22236512 TI - ARB may be superior to ACEI on treatment of Marfan's syndrome by blocking TGF beta mediated activation of ERK. PMID- 22236513 TI - Renalguard system: a dedicated device to prevent contrast-induced acute kidney injury. PMID- 22236514 TI - Urokinase receptor surface expression regulates monocyte migration and is associated with accelerated atherosclerosis. AB - BACKGROUND: The urokinase receptor (uPAR) is a key regulator of pericellular proteolysis, cell adhesion and migration, all of which are fundamental processes in atherogenesis. We hypothesized that increased monocytic uPAR expression in circulation is associated with the formation and development of atherosclerosis. METHODS: A total of 42 male apoE-/- mice were ramdonly divided into high-fat (HF) diet and normal diet (n=21 per group). The percentage of uPAR expressing monocytes (PUEM) and the expression of uPAR within different types of atherosclerotic plaques were measured at an interval of 3 weeks from week 10 to week 16. In vitro, uPAR expression upon ox-LDL stimulation and the migration of monocytes were examined. RESULTS: PUEM in circulation was significantly higher in animals with HF diet compared with those having normal diet (p<0.03). The augmented levels of PUEM were associated with body weight, visceral fat weight and numbers of uPAR+macrophages within atherosclerotic lesions. Accumulation of uPAR+macrophages increased with the progression of atherosclerosis. Monocytes upon ox-LDL stimulation exhibited an increased uPAR expression and uPAR antibody markedly suppressed monocyte migration induced by monocyte chemotactic protein-1. uPAR modulated monocyte migration was accelerated by uPA and was suppressed by amino terminal fragment of uPA dependent. CONCLUSIONS: Over-expression of uPAR both in circulating monocytes and in atherosclerotic lesions is associated with the development of atherosclerotic plaques. uPAR and its interaction with uPA may contribute to enhanced monocyte migration. Thus, uPAR may be a novel target for prevention of uncontrolled monocyte recruitment in inflammatory atherogenic process. PMID- 22236515 TI - Prevalence of asymptomatic and electrically undetectable intracardiac inside-out abrasion in silicon-coated Riata(r) and Riata(r) ST implantable cardioverter defibrillator leads. AB - BACKGROUND: Recently, several cases of symptomatic and/or electrically detectable intracardiac inside-out abrasions in silicon-coated Riata(r) and Riata(r) ST leads have been described. However, the prevalence in asymptomatic patients with unremarkable implantable cardioverter defibrillator (ICD) interrogation is unknown. The aim of this study was to determine the prevalence of asymptomatic and electrically undetectable intracardiac inside-out abrasion in silicon-coated Riata(r) and Riata(r) ST leads. METHODS: All 52 patients with an active silicone coated Riata(r) and Riata(r) ST lead followed up in our outpatient clinic were scheduled for a premature ICD interrogation and a biplane chest radiograph. When an intracardiac inside-out abrasion was suspected, this finding was confirmed by fluoroscopy. RESULTS: Mean time since implantation was 71 +/- 18 months. An intracardiac inside-out abrasion was confirmed by fluoroscopy in 6 patients (11.5%). Mean time from lead implantation to detection of intracardiac inside-out abrasion was 79 +/- 14 months. In all patients with an intracardiac inside-out abrasion, ICD interrogation showed normal and stable electrical parameters. Retrospectively, in 4 of these 6 patients, a coronary angiography performed 25 +/ 18 months before diagnosis of intracardiac inside-out abrasion already showed the defect. Despite undetected intracardiac inside-out abrasion, 2 of these 4 patients experienced adequate antitachycardia pacing and ICD-shocks. ICD leads were replaced in all 6 patients. CONCLUSIONS: The prevalence of asymptomatic intracardiac inside-out abrasion in silicon-coated Riata(r) and Riata(r) ST leads is higher than 10% when assessed by fluoroscopy, and most intracardiac inside-out abrasions are not detectable by ICD interrogation. PMID- 22236516 TI - Fabrication of tunable silica-mineralized nanotubes using flagella as bio templates. AB - Bacterial flagella are particularly attractive bio-templates for nanotubes due to their tubular structures and small inner and outer diameters. In this work, flagella isolated from Salmonella typhimurium were used as templates for silica mineralized nanotubes. The process involved pretreatment of flagella with aminopropyltriethoxysilane (APTES), followed by the addition of tetraethoxysilane (TEOS). By controlling the concentration of TEOS and the reaction time, we developed a simple and precise method for creating silica-mineralized flagella nanotubes (SMFNs) with various thicknesses of the silica layer. It is demonstrated that flagella can be utilized for the fabrication of SMFNs with tunable thickness. A thicker silica layer was obtained as the concentration ratio of TEOS and reaction time was increased. The present experimental evidence has shown the feasibility of using such fabrication techniques to manufacture nanotubes without genetic modification of flagella which retain the original morphology. PMID- 22236517 TI - Proteomic analysis of a multi-resistant clinical Escherichia coli isolate of unknown genomic background. AB - Horizontal transfer of gene clusters occurs in Escherichia coli (E. coli), which could lead to evolution of new pathovars and improve survival fitness. However, this genetic event results in genomic plasticity which is a hindrance for proteomic characterization of strains with unknown genetic backgrounds. To characterize such isolate with many specific genetic variations we used the recently in-house designed MSMSpdbb software which merges protein databases from several sources of E. coli including type strains and other commensal and pathogenic isolates. We selected a multidrug resistant clinical isolate in order to check the capacity of our approach to identify selected protein markers. From the 1596 identified proteins, we found important virulence factors such as IutA, OmpA, TraT and selected enzymes conferring antibiotic resistance, such as CTX-M 15 (Extended-Spectrum Beta Lactamase--ESBL) and AAC(6')-Ib-cr (to aminoglycoside+fluoroquinolone). In addition, we compared the protein identifications with E. coli gene annotation and found that 27% of the proteins identified in the present study corresponded to the pan-genome of E. coli species and are only present in a subset of strains. This demonstrates the ability of our approach to characterize the proteome of bacterial strains with complex genomic plasticity even without its genomic information. PMID- 22236518 TI - Multiplexed quantification of 63 proteins in human urine by multiple reaction monitoring-based mass spectrometry for discovery of potential bladder cancer biomarkers. AB - Three common urological diseases are bladder cancer, urinary tract infection, and hematuria. Seventeen bladder cancer biomarkers were previously discovered using iTRAQ - these findings were verified by MRM-MS in this current study. Urine samples from 156 patients with hernia (n=57, control), bladder cancer (n=76), or urinary tract infection/hematuria (n=23) were collected and subjected to multiplexed LC-MRM/MS to determine the concentrations of 63 proteins that are normally considered to be plasma proteins, but which include proteins found in our earlier iTRAQ study. Sixty-five stable isotope-labeled standard proteotypic peptides were used as internal standards for 63 targeted proteins. Twelve proteins showed higher concentrations in the bladder cancer group than in the hernia and the urinary tract infection/hematuria groups, and thus represent potential urinary biomarkers for detection of bladder cancer. Prothrombin had the highest AUC (0.796), with 71.1% sensitivity and 75.0% specificity for differentiating bladder cancer (n=76) from non-cancerous (n=80) patients. The multiplexed MRM-MS data was used to generate a six-peptide marker panel. This six peptide panel (afamin, adiponectin, complement C4 gamma chain, apolipoprotein A II precursor, ceruloplasmin, and prothrombin) can discriminate bladder cancer subjects from non-cancerous subjects with an AUC of 0.814, with a 76.3% positive predictive value, and a 77.5% negative predictive value. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. PMID- 22236519 TI - The network interaction of the human cytosolic 90 kDa heat shock protein Hsp90: A target for cancer therapeutics. AB - In the cell, proteins interact within a network in which a small number of proteins are highly connected nodes or hubs. A disturbance in the hub proteins usually has a higher impact on the cell physiology than a disturbance in poorly connected nodes. In eukaryotes, the cytosolic Hsp90 is considered to be a hub protein as it interacts with molecular chaperones and co-chaperones, and has key regulatory proteins as clients, such as transcriptional factors, protein kinases and hormone receptors. The large number of Hsp90 partners suggests that Hsp90 is involved in very important functions, such as signaling, proteostasis and epigenetics. Some of these functions are dysregulated in cancer, making Hsp90 a potential target for therapeutics. The number of Hsp90 interactors appears to be so large that a precise answer to the question of how many proteins interact with this chaperone has no definitive answer yet, not even if the question refers to specific Hsp90s as one of the human cytosolic forms. Here we review the major chaperones and co-chaperones that interact with cytosolic Hsp90s, highlighting the latest findings regarding client proteins and the role that posttranslational modifications have on the function and interactions of these molecular chaperones. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22236520 TI - Proteomics analysis reveals multiple regulatory mechanisms in response to selenium in rice. AB - Selenium (Se) shows both beneficial and toxic effects on plant growth. Rice (Oryza sativa L.) seedlings cultivated under lower concentrations of sodium selenite showed enhanced growth, whereas higher concentrations of sodium selenite repressed seedling growth. To acquire detailed regulatory mechanisms underlying these effects, a comparative proteomics study using 2-dimensional gel electrophoresis and MALDI-TOF/TOF MS was performed. By comparison of gel images between Se treatments and control, 66 and 97 differentially expressed proteins were identified in shoot and root, respectively under at least one of the Se treatment concentrations. Gene Ontology and Clustering analysis reveal primary metabolism, photosynthesis and redox homeostasis are the most highly affected biological processes by Se treatments. Lower Se treatments (2 and 6 mg/L sodium selenite) activated antioxidative system, enhanced photosynthesis and primary metabolism. However, higher Se treatment (10mg/L sodium selenite) damaged photosynthesis apparatus, inhibited photosynthesis and primary metabolism. Protein ubiquitination and phosphorylation may also play important roles in Se response in rice. In conclusion, our study provided novel insights into Se response in rice at the proteome level, which are expected to be highly useful for dissecting the Se response pathways in higher plants and for producing Se enriched rice cultivars in the future. PMID- 22236522 TI - Cephalometric norms for a Moroccan population. AB - This is a descriptive cephalometric study aimed at contributing to the establishment of Steiner analysis cephalometric norms for a patient population from the Center for Dental Treatment and Consultation (CCTD) at the Ibn Rochd Hospital Center in Casablanca, Morocco. Teleradiography was used to obtain lateral cephalograms of 71 young adults (47 women; 24 men) aged on average 22.73 +/- 1.69 years. All subjects presented good facial harmony, an acceptable profile, and dental class I with no history of orthodontic treatment. Tracing and analysis followed. The resulting means and standard deviations were compared to Steiner's norms and norms from similar studies. This revealed certain particularities in our sample, the most notable being a greater skeletal sagittal discrepancy (indicating a class II tendency), labial crown tipping of the lower incisors, and a retruded position of the maxillary and mandibular bony bases. These features should be taken into account when diagnosing and treating patients at the CCTD. However, more exhaustive studies must be performed before these results can be generalized to the Casablancan or Moroccan populations as a whole. PMID- 22236523 TI - The minimum required muscle force for a sit-to-stand task. AB - The purpose of this study was to reveal the minimum required muscle force for a sit-to-stand task. Combining experimental procedures and computational processing, movements of various sit-to-stand patterns were obtained. Muscle forces and activations during a movement were calculated with an inverse dynamics method and a static numerical optimization method. The required muscle force for each movement was calculated with peak muscle activation, muscle physiological cross sectional area and specific tension. The robustness of the results was quantitatively evaluated with sensitivity analyses. From the results, a distinct threshold was found for the total required muscle force of the hip and knee extensors. Specifically, two findings were revealed: (1) the total force of hip and knee extensors is appropriate as the index of minimum required muscle force for a sit-to-stand task and (2) the minimum required total force is within the range of 35.3-49.2 N/kg. A muscle is not mechanically independent from other muscles, since each muscle has some synergetic or antagonistic muscles. This means that the mechanical threshold of one muscle varies with the force exertion abilities of other muscles and cannot be evaluated independently. At the same time, some kinds of mechanical threshold necessarily exist in the sit-to-stand task, since a muscle force is an only force to drive the body and people cannot stand up from a chair without muscles. These indicate that the existence of the distinct threshold in the result of the total required muscle force is reasonable. PMID- 22236524 TI - Osmotic swelling and residual stress in cardiovascular tissues. AB - Osmotic swelling (OS) and residual stress (RS) significantly affect the function of cardiovascular (CVS) tissues and organs. The physical mechanisms of OS and RS are reviewed and analyzed with focus on the theoretical background and related experimental evidence. It will be shown that swelling of CVS tissues stems from the presence of charged proteoglycan macro-molecules in these tissues, and that this swelling is a key determinant of RS. In view of OS and RS functional significance in mechanical function, modeling attempts which incorporate them in CVS stress analysis will be presented and discussed. PMID- 22236525 TI - Nonlinear viscoelasticty plays an essential role in the functional behavior of spinal ligaments. AB - Despite the significant role ligament viscoelasticity plays in functional spinal biomechanics, relatively few studies have been performed to develop constitutive models that explicitly characterize this complex behavior. Unfortunately, the application and interpretation of these previous models are limited due to the use of simplified (quasi-linear) viscoelastic formulations or characterization techniques that have been shown to affect the predictive accuracy of the fitted coefficients. In order to surmount these previous limitations, the current study presents the application of a novel fitting technique (applied to stress relaxation experiments) and nonlinear viscoelastic constitutive formulation to human cervical spine anterior longitudinal ligament (ALL), posterior longitudinal ligament (PLL) and ligamentum flavum (LF). The fitted coefficients were validated by quantifying the ability of the constitutive equation to predict an independent cyclic data set across multiple physiologic strain amplitudes and frequencies. The resulting validated constitutive formulation indicated that the strain dependent viscoelastic behavior of the longitudinal ligaments (ALL and PLL) was dominated by both the short-term (t=0.1s) and the steady-state (as t->infinity) behavior. Conversely, the LF exhibited consistent relaxation behavior across the investigated temporal spectrum. From these data, it can be hypothesized that the unique strain-dependent temporal behavior of these spinal ligaments may be a functional adaptation that minimizes muscular expenditure during quasi-static postures while maximizing structural stability of the spine during transient loading events. PMID- 22236526 TI - Considerations for reporting finite element analysis studies in biomechanics. AB - Simulation-based medicine and the development of complex computer models of biological structures is becoming ubiquitous for advancing biomedical engineering and clinical research. Finite element analysis (FEA) has been widely used in the last few decades to understand and predict biomechanical phenomena. Modeling and simulation approaches in biomechanics are highly interdisciplinary, involving novice and skilled developers in all areas of biomedical engineering and biology. While recent advances in model development and simulation platforms offer a wide range of tools to investigators, the decision making process during modeling and simulation has become more opaque. Hence, reliability of such models used for medical decision making and for driving multiscale analysis comes into question. Establishing guidelines for model development and dissemination is a daunting task, particularly with the complex and convoluted models used in FEA. Nonetheless, if better reporting can be established, researchers will have a better understanding of a model's value and the potential for reusability through sharing will be bolstered. Thus, the goal of this document is to identify resources and considerate reporting parameters for FEA studies in biomechanics. These entail various levels of reporting parameters for model identification, model structure, simulation structure, verification, validation, and availability. While we recognize that it may not be possible to provide and detail all of the reporting considerations presented, it is possible to establish a level of confidence with selective use of these parameters. More detailed reporting, however, can establish an explicit outline of the decision-making process in simulation-based analysis for enhanced reproducibility, reusability, and sharing. PMID- 22236527 TI - Activation and aponeurosis morphology affect in vivo muscle tissue strains near the myotendinous junction. AB - Hamstring strain injury is one of the most common injuries in athletes, particularly for sports that involve high speed running. The aims of this study were to determine whether muscle activation and internal morphology influence in vivo muscle behavior and strain injury susceptibility. We measured tissue displacement and strains in the hamstring muscle injured most often, the biceps femoris long head muscle (BFLH), using cine DENSE dynamic magnetic resonance imaging. Strain measurements were used to test whether strain magnitudes are (i) larger during active lengthening than during passive lengthening and (ii) larger for subjects with a relatively narrow proximal aponeurosis than a wide proximal aponeurosis. Displacement color maps showed higher tissue displacement with increasing lateral distance from the proximal aponeurosis for both active lengthening and passive lengthening, and higher tissue displacement for active lengthening than passive lengthening. First principal strain magnitudes were averaged in a 1cm region near the myotendinous junction, where injury is most frequently observed. It was found that strains are significantly larger during active lengthening (0.19 SD 0.09) than passive lengthening (0.13 SD 0.06) (p<0.05), which suggests that elevated localized strains may be a mechanism for increased injury risk during active as opposed to passive lengthening. First principal strains were higher for subjects with a relatively narrow aponeurosis width (0.26 SD 0.15) than wide (0.14 SD 0.04) (p<0.05). This result suggests that athletes who have BFLH muscles with narrow proximal aponeuroses may have an increased risk for BFLH strain injuries. PMID- 22236528 TI - Elastic modulus of hard tissues. AB - This work aims at evaluating the elastic modulus of hard biological tissues by considering their staggered platelet micro-structure. An analytical expression for the effective modulus along the stagger direction is formulated using three non-dimensional structural variables. Structures with a single staggered hierarchy (e.g. collagen fibril) are first studied and predictions are compared with the experimental results and finite element simulations from the literature. A more complicated configuration, such as an array of fibrils, is analyzed next. Finally, a mechanical model is proposed for tooth dentin, in which variations in the multi-scale structural hierarchy are shown to significantly affect the macroscopic mechanical properties. PMID- 22236529 TI - The influence of acetabular cup material on pelvis cortex surface strains, measured using digital image correlation. AB - Acetabular cup loosening is a late failure mode of total hip replacements, and peri-prosthetic bone deterioration may promote earlier failure. Preservation of supporting bone quality is a goal for implant design and materials selection, to avoid stress shielding and bone resorption. Advanced polymer composite materials have closer stiffness to bone than metals, ceramics or polymers, and have been hypothesised to promote less adverse bone adaptation. Computer simulations have supported this hypothesis, and the present study aimed to verify this experimentally. A composite hemi-pelvis was implanted with Cobalt Chromium (CoCr), polyethylene (UHMWPE) and MOTIS((r))carbon-fibre-reinforced polyether etherketone (CFR-PEEK) acetabular cups. In each case, load was applied to the implanted pelvis and Digital Image Correlation (DIC) was used for surface strain measurement. The test was repeated for an intact hemi-pelvis. Trends in implanted vs. intact bone principal strains were inspected to assess the average principal strain magnitude change, allowing comparison of the potential bone responses to implantation with the three cups. The CFR-PEEK cup was observed to produce the closest bone strain to the intact hip in the main load path, the superior peri acetabular cortex (+12% on average, R(2)=0.84), in comparison to CoCr (+40%, R(2)=0.91) and UHWMPE cups (-26%, R(2)=0.94). Clinical observations have indicated that increased periacetabular cortex loading may result in reduced polar cancellous bone loading, leading to longer term losses in periprosthetic bone mineral density. This study provides experimental evidence to verify previous computational studies, indicating that cups produced using materials with stiffness closer to cortical bone recreate physiological cortical bone strains more closely and could, therefore, potentially promote less adverse bone adaptation than stiffer press-fitted implants in current use. PMID- 22236530 TI - Planar biaxial characterization of diseased human coronary and carotid arteries for computational modeling. AB - Computational models have the potential to provide precise estimates of stresses and strains associated with sites of coronary plaque rupture. However, lack of adequate mathematical description of diseased human vessel wall mechanical properties is hindering computational accuracy. The goal of this study is to characterize the behavior of diseased human coronary and carotid arteries using planar biaxial testing. Diseased coronary specimens exhibit relatively high stiffness (50-210 kPa) and low extensibility (1-10%) at maximum equibiaxial stress (250 kPa) compared to human carotid specimens and values commonly reported for porcine coronary arteries. A thick neointimal layer observed histologically appears to be associated with heightened stiffness and the direction of anisotropy of the specimens. Fung, Choi-Vito and modified Mooney-Rivlin constitutive equations fit the multiaxial data from multiple stress protocols well, and parameters from representative coronary specimens were utilized in a finite element model with fluid-solid interactions. Computed locations of maximal stress and strain are substantially altered, and magnitudes of maximum principal stress (48-65 kPa) and strain (6.5-8%) in the vessel wall are lower than previously predicted using parameters from uniaxial tests. Taken together, the results demonstrate the importance of utilizing disease-matched multiaxial constitutive relationships within patient-specific computational models to accurately predict stress and strain within diseased coronary arteries. PMID- 22236531 TI - Modeling of cardiac muscle thin films: pre-stretch, passive and active behavior. AB - Recent progress in tissue engineering has made it possible to build contractile bio-hybrid materials that undergo conformational changes by growing a layer of cardiac muscle on elastic polymeric membranes. Further development of such muscular thin films for building actuators and powering devices requires exploring several design parameters, which include the alignment of the cardiac myocytes and the thickness/Young's modulus of elastomeric film. To more efficiently explore these design parameters, we propose a 3-D phenomenological constitutive model, which accounts for both the passive deformation including pre stretch and the active behavior of the cardiomyocytes. The proposed 3-D constitutive model is implemented within a finite element framework, and can be used to improve the current design of bio-hybrid thin films and help developing bio-hybrid constructs capable of complex conformational changes. PMID- 22236532 TI - Acute mechanical effects of elastase on the infrarenal mouse aorta: implications for models of aneurysms. AB - Intraluminal exposure of the infrarenal aorta to porcine pancreatic elastase represents one of the most commonly used experimental models of the development and progression of abdominal aortic aneurysms. Morphological and histological effects of elastase on the aortic wall have been well documented in multiple rodent models, but there has been little attention to the associated effects on mechanical properties. In this paper, we present the first biaxial mechanical data on, and associated nonlinear constitutive descriptors of, the effects of elastase on the infrarenal aorta in mice. Quantification of the dramatic, acute effects of elastase on wall behavior in vitro is an essential first step toward understanding the growth and remodeling of aneurysms in vivo, which depends on both the initial changes in the mechanics and the subsequent inflammation mediated turnover of cells and extracellular matrix that contributes to the evolving mechanics. PMID- 22236534 TI - Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice. METHODS/DESIGN: The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7 14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs. DISCUSSION: The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2666. PMID- 22236533 TI - Enteric alpha defensins in norm and pathology. AB - Microbes living in the mammalian gut exist in constant contact with immunity system that prevents infection and maintains homeostasis. Enteric alpha defensins play an important role in regulation of bacterial colonization of the gut, as well as in activation of pro- and anti-inflammatory responses of the adaptive immune system cells in lamina propria. This review summarizes currently available data on functions of mammalian enteric alpha defensins in the immune defense and changes in their secretion in intestinal inflammatory diseases and cancer. PMID- 22236535 TI - Diversification and trends in biliary tree cancer among the three major ethnic groups in the state of New Mexico. AB - BACKGROUND: New Mexico's population is composed of 45% non-Hispanic whites, 42% Hispanics, 10% American Indians, and 3% other minorities. The purpose of this study was to compare the trends of biliary tract cancer among these groups over the past 3 decades. METHODS: The state's tumor registry was used to ascertain the incidence of gallbladder cancer, extrahepatic bile duct cancer, and intrahepatic bile duct cancer. RESULTS: A total of 1,449 new biliary cancers were diagnosed between 1981 and 2008. The contemporary incidence of gallbladder cancer remains several times higher among American Indians than in other ethnicities: for men, 4.1%, 1.1%, and .8% for American Indians, Hispanics, and non-Hispanic whites, respectively, and for women, 8.1%, 2.1%, and 1.0%, respectively. CONCLUSIONS: Biliary malignancies are more prevalent among American Indians. Despite a decline in the incidence of gallbladder cancer among American Indians and Hispanics, it remains higher compared with the state's non-Hispanic white population. PMID- 22236536 TI - Gender differences in the factor structure of the Alcohol Use Disorders Identification Test in multinational general population surveys. AB - BACKGROUND: Most gender-specific studies of the Alcohol Use Disorders Identification Test (AUDIT) have focused on gender differences in thresholds for hazardous drinking. This study examines gender differences in the factor structure of the AUDIT in general-population surveys. METHODS: General-population surveys from 15 countries provided 27,478 current drinkers' responses to the AUDIT and related measures. We used single-group confirmatory factor analysis (CFA) to evaluate goodness-of-fit of three hypothesized models for responses to the AUDIT by men and women in each country. Bayesian Information Criteria (BIC) using a maximum likelihood robust (MLR) estimator was evaluated to identify the best fitted model. We then assessed factorial invariance within country surveys where fit indices were acceptable for both genders. Gender-specific internal consistency and concurrent validity were also evaluated in all 15 countries. RESULTS: CFA revealed that the fit indices of 2-factor or 3-factor models were consistently better than fit indices for a 1-factor model in 14 of 15 countries. Comparisons of BIC values indicated that the 2-factor solution was the best fitted model. Factorial invariance tests in data from 3 countries indicated that the factor loadings and thresholds of the AUDIT were invariant across gender. The internal reliability and concurrent validity of AUDIT and its subscales were acceptable in both genders. CONCLUSIONS: A two-factor model best describes AUDIT responses across general-population surveys in 12 of 15 countries, with acceptable internal reliability and concurrent validity, and supports a gender invariant structure in at least three of those countries. PMID- 22236538 TI - Laparoscopic exploration versus intraoperative endoscopic sphincterotomy for common bile duct stones: a prospective randomized trial. AB - BACKGROUND/AIMS: Laparoscopic cholecystectomy (LC) combined with intraoperative endoscopic sphincterotomy (IOES) was compared to LC with laparoscopic common bile duct exploration (LCBDE) to define the best single-session minimally invasive treatment for cholecystocholedocholithiasis. METHODS: Between June 2009 and December 2010, patients with gallstones and common bile duct (CBD) stones diagnosed by preoperative ultrasonography and magnetic resonance cholangiopancreatography were randomized to LC-LCBDE or LC-IOES. The primary end point was complete clearance of CBD of stones. The secondary end points were operation time, conversion rate, length of hospital stay, complications and mortality. RESULTS: Two hundred and twenty-six patients were eligible. They were randomized to LC-LCBDE (n = 115) and LC-IOES (n = 111). There was no statistically significant difference in the success rate of CBD clearance between the two interventions (92% for LC-LCBDE vs. 97.2% for LC-IOES with a p value >0.05). There were no differences between the two groups in terms of surgical time and postoperative length of stay. Pancreatitis and bleeding sphincterotomy were significantly more prevalent in the LC-IOES group, while bile leakage and retained CBD stones were significantly more prevalent in the LC-LCBDE group. CONCLUSION: Both LC-IOES and LC-LCBDE were shown to be safe, effective, minimally invasive treatments for cholecystocholedocholithiasis, but the former option may be preferred when facilities and experience in endoscopic therapy exist. PMID- 22236537 TI - DSM-IV alcohol abuse and dependence criteria characteristics for recent onset adolescent drinkers. AB - BACKGROUND: Little is known about the psychometric properties of alcohol abuse and dependence criteria among recent-onset adolescent drinkers, particularly for those who consume alcohol infrequently. This study evaluated how well DSM-IV alcohol dependence criteria measure an alcohol use disorder (AUD) construct for recent onset adolescent drinkers at different levels of drinking frequency. METHOD: Data were drawn from the National Survey on Drug Use and Health, a nationally representative sample of 9356 recent-onset adolescent drinkers, aged 12-21, who began drinking within the past year. Multiple group item response theory analysis was conducted to assess the 11 DSM-IV alcohol abuse and dependence criteria. RESULTS: Criteria most likely to be endorsed at lower AUD severity included "withdrawal," "problems at home, school or work" and "tolerance." The criteria "drinking larger amounts/longer period of time," "unsuccessful efforts to cut down" and "continuing to drink despite related health problems" were more likely to be endorsed at higher AUD severity. Two criteria, "tolerance" and "time spent getting, using or recovering from alcohol" showed differential item functioning between drinking frequency groups (<7 vs. >= 7 days in past month), with lower discrimination and severity for more frequent drinkers. DSM-IV criteria were most precise for intermediate levels of AUD severity. CONCLUSIONS: All but two DSM-IV criteria had consistent psychometric properties across drinking frequency groups. Symptoms were most precise for a narrow, intermediate range of AUD severity. Those assessing AUD in recent onset adolescent drinkers might consider additional symptoms to capture the full AUD continuum. PMID- 22236539 TI - High seroprevalence of Toxoplasma gondii infection in a subset of Mexican patients with work accidents and low socioeconomic status. AB - BACKGROUND: Toxoplasma gondii has been associated with reflex impairment and traffic accidents. It is unknown whether Toxoplasma infection might be associated with work accidents. Therefore, using a case-control seroprevalence study design, 133 patients with a recent work accident and 266 control subjects of the general population from the same region were examined with enzyme-linked immunoassays for the presence and levels of anti-Toxoplasma IgG antibodies and anti-Toxoplasma IgM antibodies. Socio-demographic, work, clinical and behavioral characteristics from each worker were obtained. RESULTS: Eleven (8.3%) of 133 patients, and 14 (5.3%) of 266 controls had anti-T. gondii IgG antibodies. Anti-T. gondii IgG levels were higher than 150 IU/ml in 8 (6%) patients and 10 (3.8%) controls. Anti-T. gondii IgM antibodies were found in one (0.8%) of the workers, and in 6 (2.3%) of the controls. No statistically significant differences in the IgG seroprevalences, frequencies of high IgG levels, and IgM seroprevalences among patients and controls were found. In contrast, a low socio-economic level in patients with work accidents was associated with Toxoplasma seropositivity (P = 0.01). Patients with work accidents and low socioeconomic status showed a significantly (OR = 3.38; 95% CI: 0.84-16.06; P = 0.04) higher seroprevalence of T. gondii infection than controls of the same socioeconomic status (15.1% vs. 5%, respectively). Multivariate analysis showed a positive association of T. gondii infection with boar meat consumption (OR = 3.04; 95% CI: 1.03-8.94; P = 0.04). In contrast, a negative association between T. gondii infection and national trips (OR = 0.40; 95% CI: 0.17-0.96; P = 0.04), sausage consumption (OR = 0.20; 95% CI: 0.05-0.68; P = 0.01), and ham consumption (OR = 0.16; 95% CI: 0.05-0.51; P = 0.002) was found. CONCLUSIONS: In the study described here seropositivity to T. gondii was associated to work accidents in a subset of patients with low socioeconomic status. This is the first report of an association of T. gondii infection and work accidents. Further studies to confirm our results are needed. Results may help in designing optimal prevention strategies to avoid T. gondii infection. PMID- 22236540 TI - Screening for gynaecological cancers. Preface. PMID- 22236541 TI - Postural function of the diaphragm in persons with and without chronic low back pain. AB - STUDY DESIGN: A case-control study. OBJECTIVES: To examine the function of the diaphragm during postural limb activities in patients with chronic low back pain and healthy controls. BACKGROUND: Abnormal stabilizing function of the diaphragm may be an etiological factor in spinal disorders. However, a study designed specifically to test the dynamics of the diaphragm in chronic spinal disorders is lacking. METHODS: Eighteen patients with chronic low back pain due to chronic overloading, as ascertained via clinical assessment and magnetic resonance imaging, and 29 healthy subjects were examined. Both groups presented with normal pulmonary function test results. A dynamic magnetic resonance imaging system and specialized spirometric readings were used with subjects in the supine position. Measurements during tidal breathing (TB) and isometric flexion of the upper and lower extremities against external resistance with TB were performed. Standard pulmonary function tests, including respiratory muscle drive (PI(max) and PE(max)), were also assessed. RESULTS: Using multivariate analysis of covariance, smaller diaphragm excursions and higher diaphragm position were found in the patient group (P<.05) during the upper extremity TB and lower extremity TB conditions. Maximum changes were found in costal and middle points of the diaphragm. A 1-way analysis of covariance showed a steeper slope in the middle posterior diaphragm in the patient group both in the upper extremity TB and lower extremity TB conditions (P<.05). CONCLUSION: Patients with chronic low back pain appear to have both abnormal position and a steeper slope of the diaphragm, which may contribute to the etiology of the disorder. PMID- 22236542 TI - Expression of caveolin-1, caveolin-2 and caveolin-3 in thyroid cancer and stroma. AB - OBJECTIVE: To study the expression status of caveolin-1, caveolin-2 and caveolin 3 in the epithelial and stromal compartments of conventional papillary thyroid carcinoma (PTC), diffuse sclerosing variant of papillary carcinoma (DSVPC) and anaplastic carcinoma (AC). METHODS: Tissue microarrays were constructed from 70 PTC, 41 DSVPC and 12 AC, and immunohistochemical stains were performed with caveolin-1, caveolin-2, caveolin-3, cytokeratin, vimentin and E-cadherin. The expression status of these markers in the epithelial and stromal cells was evaluated, and the results were correlated with the clinicopathologic variables. RESULTS: Epithelial caveolin-3 expression was absent in the majority of PTC and DSPVC, and was significantly increased in AC (p < 0.001). The stromal expression of caveolin-1, caveolin-2 and caveolin-3 increased in frequency from PTC to DSVPC to AC, and was significantly increased in the stroma of AC (p < 0.001). Cytokeratin and E-cadherin were more frequently negative in AC compared to PTC (p = 0.003) and DSVPC (p < 0.001), while vimentin was more frequently expressed in AC compared to PTC and DSVPC (both p < 0.001). CONCLUSION: Epithelial caveolin-3 expression is increased in AC compared to PTC and DSVPC, and this may be linked to the epithelial-mesenchymal transition process of AC. In addition, stromal caveolin-1, caveolin-2 and caveolin-3 expression was more frequent in AC compared to PTC and DSVPC, and the specific expression of caveolin-3 in the stroma of AC could suggest a possible role of myofibroblasts. PMID- 22236543 TI - Prolyl hydroxylase domain 2 protein is a strong prognostic marker in human gastric cancer. AB - OBJECTIVE: According to recent research, prolyl hydroxylase domain 2 protein (PHD2) plays an important role in human carcinogenesis by inducing neovascularization and tumor growth. The aim of this study was to evaluate PHD2 expression patterns in primary gastric adenocarcinoma and to test for a potential predictive value of PHD2 expression in gastric cancer patients. METHODS: In a total of 121 patients, PHD2 expression was investigated by immunohistochemistry in paraffin-embedded tissue and correlated with clinicopathological parameters and patient survival. RESULTS: 64 of 121 gastric carcinomas (52.9%) showed PHD2 expression in tumor cell cytoplasm. In univariate analysis, PHD2-negative patients had a significantly shortened survival in comparison with PHD2-postive patients (19.5 vs. 32.7 months, p = 0.02). Independent prognostic significance could be shown in multivariate analysis for PHD2 expression (p = 0.005), age at diagnosis (p = 0.012), lymph node status (p = 0.016) and R status (p = 0.026). CONCLUSION: Cytoplasmic PHD2 expression has a strong impact on survival in gastric cancer patients. Therefore, PHD2 represents a useful predictive biomarker in the evaluation of high-risk patients. Furthermore, these results underline the importance of PHD2 in gastric carcinogenesis and may identify PHD2 as a putative target for future gastric cancer therapy. PMID- 22236544 TI - DNMT3B (C46359T) polymorphisms and immunoexpression of DNMT3b and DNMT1 proteins in oral lichen planus. AB - OBJECTIVE: To investigate the DNMT3B (C46359T) polymorphism and immunoexpression of DNMT3b and DNMT1 in oral lichen planus (OLP) compared to a control group. METHODS: We aimed to investigate the DNMT3B (C46359T) polymorphism and immunoexpression of DNMT3b and DNMT1 in OLP (n = 32), comparing it with oral mucosa (control; n = 24). The DNMT3B (C46359T) polymorphism was analyzed using the RFLP-PCR and DNMT1, and DNMT3a proteins were identified using immunohistochemistry. We also compared the DNMT3B expression in OLP and oral inflammatory fibrous hyperplasia (OIFH), another oral inflammatory disease. Differences between the groups were determined by specific statistical analyses. RESULTS: The CT genotype of DNMT3B was associated with OLP development (p = 0.012). Increased expression of DNMT3B and DNMT1 was observed in OLP compared to the control group (p = 0.014 and p = 0.001, respectively). A significant increase in DNMT3B protein levels was observed in the genotype CT in DNMT3B (C46359T) polymorphisms (p = 0.045). No DNMT3B expression differences between OLP and OIFH were observed. CONCLUSIONS: Our data show that the DNMT3B (C46359T) polymorphism is associated with OLP development. Furthermore, increased expression of the enzyme DNMT3B, an epigenetic-associated protein, is present in OLP. PMID- 22236545 TI - Interferon (alpha, beta and omega) receptor 2 is a prognostic biomarker for lung cancer. AB - OBJECTIVES: It has been reported that the type I interferon receptor subunit, interferon (alpha, beta and omega) receptor 2 (IFNAR2), is overexpressed in several malignancies, primarily adenocarcinomas (ADCs); however, the biological significance of IFNAR2 in human lung cancer has not yet been studied. METHODS: Immunohistochemical analysis of 113 surgically resected lung specimens was performed, and the results were evaluated in association with clinical variables, including survival. Serum concentrations of IFNAR2 were also determined by an enzyme-linked immunosorbent assay in 157 lung cancer patients and 164 healthy volunteers. RESULTS: IFNAR2 overexpression was observed in all histological types of lung cancer examined. Furthermore, strong IFNAR2 expression was associated with shorter progression-free survival (PFS) and overall survival (OS) (p < 0.0001 and p = 0.0110, respectively) in non-small cell lung cancer patients. Multivariate analyses confirmed its independent prognostic value for PFS and OS (p < 0.0001 and p = 0.0222, respectively). IFNAR2 serum levels were also significantly higher in lung cancer patients than in healthy volunteers (p < 0.0001). CONCLUSIONS: IFNAR2 overexpression was observed in various histological types of lung cancer, and appears to be associated with lung cancers that behave aggressively. The results of this study strongly support the potential of IFNAR2 to be a prognostic biomarker for lung cancer. PMID- 22236546 TI - Immunolocalization of sprouty-1 and sprouty-2 in developing rat lung. AB - OBJECTIVE: Sprouty, a common antagonist of fibroblast growth factor (FGF) and epidermal growth factor signaling, is a key player regulating tracheal branching and eye development in Drosophila. Four Sprouty homologs have been identified in vertebrates and all share a cysteine-rich region. However, the physiological function(s) of the individual Sprouty homologs is unknown. mRNA of Sprouty homologs is expressed during mouse lung development. In the present study, we investigated the immunolocalization of Sprouty proteins in rat lung at different stages of development. METHODS: Rabbit antibodies were raised against peptides derived from rat Sprouty-1 and Sprouty-2 and were used in Western blot analysis to determine Sprouty distribution in subcellular fractions (pellets and supernatant centrifuged at 5,000 and 20,000 g) and bronchoalveolar lavage fluid (BAL) from adult rat lungs or used in immunohistochemistry. RESULTS: Western blot analysis revealed a 30-kDa Sprouty-1 band and a 34-kDa Sprouty-2 band in the supernatant and pellet fractions centrifuged at 20,000 g. BAL contained a band of approximately 16 kDa with Sprouty-1 antibody derived from proteolytic fragmentation of Sprouty-1. In embryonic day (E) 14 and E16 lungs, Sprouty-1 and Sprouty-2 were expressed both in epithelial and peripheral mesenchymal cells. In adult rat lung, bronchiolar and alveolar type II epithelial cells showed staining for both Sprouty-1 and Sprouty-2. Sprouty-1 expression was also seen in alveolar type I epithelial cells. CONCLUSION: In light of the proximity of the distribution of Sprouty to that of FGF-10 (peripheral mesenchyme) and its receptor FGFR2IIIb (distal tubular epithelium) in lung development, and the finding that FGF-9, which is expressed in mesothelial cells, upregulates FGF-10, it appears that Sprouty expression in epithelial and mesenchymal cells during branching morphogenesis is closely related to signaling by FGF-9 and FGF-10. PMID- 22236547 TI - Leptin, MUC2 and mTOR in appendiceal mucinous neoplasms. AB - OBJECTIVE: Leptin contributes to mucin production in colonic epithelium and regulates carcinogenesis via various signalling pathways. We evaluated the proteins involved in mucin-producing carcinogenesis and putative targets for molecular therapy in appendiceal mucinous neoplasms. METHODS: Immunohistochemistry and fluorescence in situ hybridization were performed in 22 cases of appendiceal mucinous adenoma, 20 mucinous neoplasms of uncertain malignant potential and 14 mucinous adenocarcinomas. RESULTS: Leptin, MUC2, MUC5AC, mTOR and ERK were more frequently immunopositive in mucinous adenocarcinomas compared with mucinous adenomas or mucinous neoplasms of uncertain malignant potential (p < 0.05). STAT3 revealed immunopositivity in 82% of tumours, regardless of tumour category. MUC2 immunopositivity was associated with pseudomyxoma peritonei (p < 0.05). None of the tumours exhibited c kitimmunoexpression, amplification of Her2 or EGFR, or translocation of ALK. The mTOR-immunopositive group of patients had a lower rate of disease-free survival compared with the mTOR-immunonegative group (p < 0.05). CONCLUSIONS: Leptin may collaborate with MUC2 and MUC5AC in mucin-producing carcinogenesis in an mTOR-, STAT3- and ERK-dependent manner. STAT3 may be activated early during tumorigenesis. MUC2 and mTOR (but not c-kit, Her2, EGFR and ALK) may represent targets for molecular therapy in pseudomyxoma peritonei and appendiceal mucinous adenocarcinoma, respectively. PMID- 22236548 TI - side-chain-oxidized oxysterols upregulate ACE2 and Mas receptor in rat primary neurons. AB - BACKGROUND: Disturbances in cholesterol metabolism have been associated with hypertension and Alzheimer's disease (AD). We recently reported increased angiotensin-converting enzyme (ACE) activity and angiotensinogen (AGT) levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. ACE activity positively correlated with plasma and CSF 27-hydroxycholesterol (27 OH) levels, an oxysterol that passes to the brain from the blood. Additionally, we showed that 27-OH and 24(S)-hydroxycholesterol (24S-OH) enhance AGT synthesis and modulate renin and ACE activities in brain cells. OBJECTIVES: To gain insight into how oxysterols affect the brain renin-angiotensin system (RAS), we analyzed the effects of 24S-OH and 27-OH on two other proteins in this system: ACE2 and Mas receptor (MasR). METHODS: RT-PCR and Western blot analysis in rat primary neurons treated with either 24S-OH or 27-OH. RESULTS: The levels of ACE2 and MasR were increased by a physiological concentration (1 MUM) of these oxysterols after 24 h. CONCLUSIONS: 24S-OH and 27-OH enhance the brain RAS by acting on different levels, from the precursor to several downstream enzymes. Our results support the idea that disturbances in cholesterol metabolism would contribute to alterations in the brain RAS, which further suggest mechanistic links between two well-known risk factors for AD: hypercholesterolemia and hypertension. PMID- 22236549 TI - [Genetic disorders of surfactant]. AB - Lung diseases associated with surfactant metabolism disorders represent a significant but heterogeneous group of rare disorders. Intra-alveolar accumulation of protein related to surfactant dysfunction leads to cough, hypoxemia and radiological diffuse infiltration. Inherited deficiency of pulmonary surfactant protein B (SP-B) was initially described in term newborns who develop severe respiratory failure at birth. More recently, mutations in surfactant protein C (SP-C) or in proteins required for surfactant synthesis such as ATP-binding cassette, sub-family A, member 3 (ABCA3) or NK2 homeobox 1 (NKX2 1) were identified in newborns with respiratory distress but also in children with diffuse infiltrative pneumonia. The aim of this review is to describe the clinical presentation of these diseases but also the diagnostic tools and the treatments options available. PMID- 22236550 TI - [Enriched-enrollment randomized-withdrawal trials]. AB - A clinical trial's power depends on the probability of observing an effect of the tested drug in the trial population, on the size of this effect, and on the heterogeneousness of the judgment criterion in the population. Enriched enrollment randomized-withdrawal trials are clinical trials which comprise a first period in which subjects are selected depending on whether they respond to the tested drug or not. The responding patients are subsequently randomized into 2 groups: in one of them the treatment is pursued, in the other group a placebo is substituted. These designs are very useful in pediatrics, decreasing the number of subjects needed, on condition that the effect of the treatment is only suspensive in a setting of chronic disease. Here we discuss the advantages and disadvantages of such trials. PMID- 22236551 TI - Dermatological signs and symptoms of measles: a prospective case series and comparison with the literature. AB - BACKGROUND/AIMS: Because of high vaccination rates, population immunity against measles increased in the western world. Nevertheless, outbreaks are still observed. The aim of this article is to document and describe the natural course of dermatological manifestations and compare it with the literature. METHODS: After detecting a measles index case, the dermatological onset of the disease in the non-vaccinated siblings was prospectively monitored and documented with a digital camera. RESULTS: Our findings show that dermatological symptoms are only limited consistently from one case to another and described heterogeneously in the literature as well. CONCLUSION: Dermatological manifestations do not seem conclusive in our clinical data set as well as in the literature. Especially the exact onset of the Koplik spots should be further explored in detail. In future, a larger population should be observed and clinical diagnostics for measles defined. PMID- 22236552 TI - The contribution of cat owners' attitudes and behaviours to the free-roaming cat overpopulation in Tel Aviv, Israel. AB - The attitudes and behaviours of cat owners in regard to treatment of cats may have a cumulative effect on the food availability, reproduction, density and welfare of the free-roaming cat population and thus also on the extent of cat overpopulation. Understanding this is thus a vital step in the a priori planning of cat management programs on any scale, as well as in developing public education programs on this issue. Although recent years have seen an accumulation of knowledge in regard to cat owners' attitudes and behaviours, the findings vary among countries and locations and in Israel this has never been investigated systematically. Using a questionnaire provided to cat owners in veterinary clinics, this study aimed at identifying those attitudes and behaviours that may be contributing to cat overpopulation in Tel Aviv, Israel, and at exploring the socio-economic factors that influence this problem. The findings show that the influential factors can be predicted from the cat owners' socio-economic status, mainly education and income, as well as gender and age. A consistency in those cat owner behaviours that contribute to cat overpopulation was also uncovered, revealing a sub-population of individuals who persist in the undesirable behaviours. Finally, a strong relationship between attitude and consequent behaviour was demonstrated, indicating the importance of education and targeted publicity as a means to influence attitudes and thereby change behaviours in this respect. We propose several measures by which to reduce the current extent of cat owners' contribution to the cat overpopulation: discouraging unwanted owner behaviours such as abandonment of their cats and allowing them to breed; promoting awareness of the neutering option among cat caretakers; and increasing pre-adoption neutering rates in shelters. Regional and national laws promoting responsible pet ownership need to be enacted. By improving the current level of knowledge and awareness among cat owners regarding cat overpopulation issues, and encouraging a more responsible attitude, cat owners' bond with their cats could be strengthened, as well as their bond with and contribution to their environment. PMID- 22236553 TI - A new method for the evaluation of dental implant stability using an inductive sensor. AB - We developed a new method for the measurement of dental implant stability by analyzing the impulse response of the implant. The movement of the implant was measured by an inductive sensor with a dedicated adaptor. The large inductance of the adapter amplified the small displacement signal of the implant. The Periotest (Siemens, Bensheim, Germany) was used as a source of excitation force to acquire the impact response of the implant. Power spectrum analysis was applied to the impact response of the implant. The peak frequency of the spectrum was used as a measure of the implant stability. The performance of the system was tested and verified through simulation of the implant-bone interface in an in vitro model. Various implant-bone interfacial conditions were assessed. Holes of varying depth and diameter were drilled into a dental implantation model. Two types of impression materials (EXAMIXFINE, Regisil Rigid) with different degrees of hardness were used to fix the implant into the hole. The implant stability was also measured using the ISQ (implant stability quotient) by resonance frequency analysis on the Osstell Mentor (Integration Diagnostics AB, Goteborgsvagen, Sweden) for comparison. Linear regression analysis of the peak frequency as a stability parameter showed a linear relationship with both the depth and the diameter of the hole (p<0.05). When EXAMIXFINE was used, the peak frequency was linearly associated with the depth (R(2)=0.443) and diameter (R(2)=0.396) of the hole. When Regisil Rigid was used, the peak frequency also showed a linear relationship with the depth (R(2)=0.555) and diameter (R(2)=0.350) of the hole. The peak frequency also increased as the hardness of the impression material increased. Differentiability of the system was evaluated by an ANOVA test. A statistically significant difference (p<0.01) was found between all implantation conditions, except in one case using the Regisil Rigid material. In contrast, the ISQ value did not consistently differentiate under several implantation conditions. The developed method could differentiate the stability changes in simulated implantation conditions with a wider dynamic range and with higher resolution than the ISQ value. PMID- 22236554 TI - Synthesis of iron nanoparticles from hemoglobin and myoglobin. AB - Stable iron nanoparticles have been synthesized from naturally occurring and abundant Fe-containing bio-precursors, namely hemoglobin and myoglobin. The formation of stable iron nanoparticles was achieved through a one-pot, single phase chemical reduction approach. The reduction of iron ions present in the bio precursors was carried out at room temperature and avoids the use of harsh chemical reagents. The size distribution of the product falls into the narrow 2-5 nm range and the particles were found to be crystalline. This method can be a valuable synthetic approach for producing bio-conjugated nanoparticle systems for biological applications. PMID- 22236555 TI - Transport of two metal oxide nanoparticles in saturated granular porous media: role of water chemistry and particle coating. AB - The growing use of nanosized titanium dioxide (nTiO2) and zinc oxide (nZnO) in a large number of commercial products raises concerns regarding their release and subsequent mobility in natural aquatic environments. Laboratory-scale sand-packed column experiments were conducted with bare and polymer-coated nTiO2 and nZnO to improve our understanding of the mobility of these nanoparticles in natural or engineered water saturated granular systems. The nanoparticles are characterized over a range of environmentally relevant water chemistries using multiple complimentary techniques: dynamic light scattering, nanoparticle tracking analysis, transmission electron microscopy, and scanning electron microscopy. Overall, bare (uncoated) nanoparticles exhibit high retention within the water saturated granular matrix at solution ionic strengths (IS) as low as 0.1 mM NaNO3 for bare nTiO2 and 0.01 mM NaNO3 for bare nZnO. Bare nTiO2 and nZnO also display dynamic (time-dependent) deposition behaviors under selected conditions. In contrast, the polymer-coated nanoparticles are much less likely to aggregate and exhibit significant transport potential at IS as high as 100 mM NaNO3 or 3 mM CaCl2. These findings illustrate the importance of considering the extent and type of surface modification when evaluating metal oxide contamination potential in granular aquatic environments. PMID- 22236556 TI - Physical therapy in a value-based healthcare world. AB - Musculoskeletal conditions are important contributors to United States healthcare spending and are certain to play an important role in the future as the population continues to age. Almost half of the population of the United States experiences a musculoskeletal condition annually. Meeting the needs of these individuals within a changing healthcare delivery and reimbursement environment prompted a recent Summit sponsored by the United States Bone and Joint Initiative (USBJI). The Summit dealt with a topic critical to the future of healthcare for clinicians, consumers, and payers alike: value. We do not operate within a value based healthcare system. Our current delivery system continues to reward volumes, not value. Failure to focus on value has had devastating consequences. The challenge of shifting from a volume-based to a value-based system is central to the future of healthcare. Discussion and action will be critical for the physical therapy profession moving into the future. PMID- 22236558 TI - Radioactivity from Fukushima Dai-ichi in air over Europe; part 2: what can it tell us about the accident? AB - It is shown which information can be extracted from the monitoring of radionuclides emitted from the Fukushima Dai-ichi nuclear power plant and transported to Europe. In this part the focus will be on the analysis of the concentration ratios. While (131)I, (134)Cs and (137)Cs were reported by most stations, other detected radionuclides, reported by some, are (95)Nb, (129m)Te, (132)Te, (132)I, (136)Cs and (140)La. From their activity ratios a mean burn-up of 26.7 GWd/t of the fuel from which they originated is estimated. Based on these data, inventories of radionuclides present at the time of the accident are calculated. The caesium activity ratios indicate emissions from the core of unit 4 which had been unloaded into the fuel storage pool prior to the accident. PMID- 22236557 TI - Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. AB - AIMS: We compared neurodevelopmental outcomes of extremely low birth weight (ELBW) infants with and without bronchopulmonary dysplasia (BPD), using the physiologic definition. STUDY DESIGN: ELBW (birth weights<1000 g) infants admitted to the Neonatal Research Network centers and hospitalized at 36 weeks postmenstrual age (n=1189) were classified using the physiologic definition of BPD. Infants underwent Bayley III assessment at 18-22 months corrected age. Multivariable logistic regression was used to determine the association between physiologic BPD and cognitive impairment (score<70). RESULTS: BPD by the physiologic definition was diagnosed in 603 (52%) infants, 537 of whom were mechanically ventilated or on FiO(2)>30% and 66 who failed the room air challenge. Infants on room air (n=505) and those who passed the room air challenge (n=51) were classified as "no BPD" (n=556). At follow up, infants with BPD had significantly lower mean weight and head circumference. Moderate to severe cerebral palsy (7 vs. 2.1%) and spastic diplegia (7.8 vs. 4.1%) and quadriplegia (3.9 vs. 0.9%) phenotypes as well as cognitive (12.8 vs. 4.6%) and language scores<70 (24.2 vs. 12.3%) were significantly more frequent in those with BPD compared to those without BPD. BPD was independently associated (adjusted OR 2.4; 95% CI 1.40-4.13) with cognitive impairment. CONCLUSIONS: Rates of adverse neurodevelopmental outcomes in early childhood were significantly higher in those with BPD. BPD by the physiologic definition was independently associated with cognitive impairment using Bayley Scales III. These findings have implications for targeted post-discharge surveillance and early intervention. PMID- 22236559 TI - The evidence on the degradation processes in the midgut epithelial cells of the larval antlion Euroleon nostras (Geoffroy in Fourcroy, 1785) (Myrmeleontidae, Neuroptera). AB - We analysed structural differences between midgut epithelial cells of fed instar antlions' larvae Euroleon nostras and starved ones. In starved larvae the presence of autophagolysosome-like structures was observed, which are characteristic structures associated with autophagy. The results presented here provide insight supporting the role of autophagy as a cell survival mechanism for the periods of food deprivation. Additional structural changes in the cytoplasm were seen in the spherites. The ultrastructure and chemical composition of spherites in the midgut epithelial cells of first, second and third instar larvae were observed with light microscopy and transmission electron microscopy (TEM). A detailed characterization of the elemental composition of the spherites was studied using analytical electron microscopy; a combination of energy dispersive X-ray spectroscopy (EDXS), electron energy-loss spectroscopy (EELS) and energy filtering TEM (EFTEM) was applied. The structure and elemental composition of the spherites changed during the period of larval life. Moreover, changes in chemical composition were found between spherites from fed and starved E. nostras. In fed first instar larvae, the spherites contained an organic matrix, composed of C, N and O. In this matrix, P, Cl, Ca and Fe were detected. In starved first instar larvae, only C, N and P were present. The spherites of fed second instar larvae were rich in organic and inorganic elements and were composed of C, N, O, Na, Mg, P, S, Cl, K, Ca, Mn, Fe and Zn. In starved second instar larvae, the chemical elements N, O, P, Ca and Fe were found. In fed third instar larvae, the spherites contained C, N, O, Na, Mg, P, Cl, K, Ca, Mn, Fe, Co and Zn. In starved third larvae, C, O, Si, Ca, and Fe were detected. Generally, the spherites are exploited in starved larvae. These results suggest that the elemental supply of spherites may provide crucial support for physiological processes during starvation periods amongst E. nostras instar larvae. In some cases in fed second and fed third instar larvae, spherites were seen in the lumen of the midgut. Such spherites could serve as reservoirs for nontoxic waste material that cannot be metabolized. PMID- 22236560 TI - Molecular detection of Setaria tundra (Nematoda: Filarioidea) and an unidentified filarial species in mosquitoes in Germany. AB - BACKGROUND: Knowledge of the potential vector role of Culicidae mosquitoes in Germany is very scanty, and until recently it was generally assumed that they are not involved in the transmission of anthroponotic or zoonotic pathogens in this country. However, anticipated changes in the course of global warming and globalization may alter their status. METHODS: We conducted a molecular mass screening of mosquitoes for filarial parasites using mitochondrial 12S rRNA-based real-time PCR. RESULTS: No parasites causing disease in humans such as Dirofilaria spp. were detected in about 83,000 mosquitoes tested, which had been collected in 2009 and 2010 in 16 locations throughout Germany. However, minimum infection rates of up to 24 per 1000 mosquitoes were revealed, which could be attributed to mosquito infection with Setaria tundra and a yet unidentified second parasite. Setaria tundra was found to be widespread in southern Germany in various mosquito species, except Culex spp. In contrast, the unidentified filarial species was exclusively found in Culex spp. in northern Baden Wurttemberg, and is likely to be a bird parasite. CONCLUSIONS: Although dirofilariasis appears to be emerging and spreading in Europe, the absence of Dirofilaria spp. or other zoonotic filariae in our sample allows the conclusion that the risk of autochthonous infection in Germany is still very low. Potential vectors of S. tundra in Germany are Ochlerotatus sticticus, Oc. cantans, Aedes vexans and Anopheles claviger. Technically, the synergism between entomologists, virologists and parasitologists, combined with state-of-the-art methods allows a very efficient near-real-time monitoring of a wide spectrum of both human and veterinary pathogens, including new distribution records of parasite species and the incrimination of their potential vectors. PMID- 22236561 TI - Use of health systems and policy research evidence in the health policymaking in eastern Mediterranean countries: views and practices of researchers. AB - BACKGROUND: Limited research exists on researchers' knowledge transfer and exchange (KTE) in the eastern Mediterranean region (EMR). This multi-country study explores researchers' views and experiences regarding the role of health systems and policy research evidence in health policymaking in the EMR, including the factors that influence health policymaking, barriers and facilitators to the use of evidence, and the factors that increase researchers' engagement in KTE. METHODS: Researchers who published health systems and policy relevant research in 12 countries in the EMR (Bahrain, Egypt, Iran, Jordan, Lebanon, Libya, Morocco, Oman, Palestine, Sudan, Syria, and Yemen) were surveyed. Descriptive analysis and Linear Mixed Regression Models were performed for quantitative sections and the simple thematic analysis approach was used for open-ended questions. RESULTS: A total of 238 researchers were asked to complete the survey (response rate 56%). Researchers indicated transferring results to other researchers (67.2%) and policymakers in the government (40.5%). Less than one-quarter stated that they produced policy briefs (14.5%), disseminated messages that specified possible actions (24.4%), interacted with policymakers and stakeholders in priority setting (16%), and involved them in their research (19.8%). Insufficient policy dialogue opportunities and collaboration between researchers and policymakers and stakeholders (67.9%), practical constraints to implementation (66%), non receptive policy environment (61.3%), and politically sensitive findings (57.7%) hindered the use of evidence. Factors that increase researchers' engagement in KTE activities in the region were associated with involving policymakers and stakeholders at various stages such as priority-setting exercises and provision of technical assistance. CONCLUSIONS: Researchers in the EMR recognize the importance of using health systems evidence in health policymaking. Potential strategies to improve the use of research evidence emphasize two-way communication between researchers and policymakers. Findings are critical for the upcoming World Health Report 2012, which will emphasize the significance of conducting and translating health research to inform health policies. PMID- 22236562 TI - Ion-exchange resins facilitate like-charged protein refolding: effects of porous solid phase properties. AB - We have previously found that addition of charged particles in a refolding solution can greatly increase the refolding yield of like-charged proteins. Herein, porous anion exchangers of different charged group densities, ligand chemistries, pore sizes and particle sizes were prepared with Sepharose FF gel for studying their effects on the oxidative refolding of like-charged lysozyme. We found that charge density had significant contribution to the enhancing effects on lysozyme refolding. At low resin concentration range (<0.04-0.1g/mL), the refolding yield increased with increasing charged group density and resin concentration. The yield then reached a plateau at a critical resin concentration; the higher the charge density, the lower the critical resin concentration. This implies that gel particles of higher charge density were favorable to offer higher refolding yield at lower added concentrations. In the gel concentration range in which refolding yield has reached plateau, there existed an optimum charge density that gave the highest refolding yield. It was attributed to the electrostatic repulsion effect of the charged groups on the like-charged protein, which reduced the accessible pore volume for the protein. At the same charge density, the refolding yield was independent of ligand chemistry, but a polyelectrolyte group of higher molecular weight was more suitable for grafting the gel to prepare matrices of high charge density. The resins of smaller size exhibited better facilitating effect, and the microporous resin was better than that with superpores. The research is expected to help design more effective charged materials for facilitating protein refolding. PMID- 22236564 TI - Chemically bonded cationic beta-cyclodextrin derivatives and their applications in supercritical fluid chromatography. AB - Cationic beta-cyclodextrin (CD) perphenylcarbamoylated derivatives were chemically bonded onto vinylized silica using a radical co-polymerization reaction. The derived materials were used as chiral stationary phases (CSP) in supercritical fluid chromatography (SFC). Enantioseparations were successfully demonstrated on 14 racemates encompassing flavanones, thiazides and amino acid derivatives. The electrostatic force between the analytes and the cationic moiety on beta-CD derivative was found to be important for retention and enantioseparation of the racemates. Aromatic cationic moiety on beta-CD enabled better enantioseparations than aliphatic cationic moiety. It was also found that the presence of acid additives would result in lower retention of the analytes but often assist the chiral resolutions. PMID- 22236563 TI - Disaccharide analysis of glycosaminoglycan mixtures by ultra-high-performance liquid chromatography-mass spectrometry. AB - Glycosaminoglycans are a family of polysaccharides widely distributed in all eukaryotic cells. These polyanionic, linear chain polysaccharides are composed of repeating disaccharide units that are often differentially substituted with sulfo groups. The diversity of glycosaminoglycan structures in cells, tissues and among different organisms reflect their functional an evolutionary importance. Glycosaminoglycan composition and structure also changes in development, aging and in disease progression, making their accurate and reliable analysis a critical, albeit, challenging endeavor. Quantitative disaccharide compositional analysis is one of the primary ways to characterize glycosaminoglycan composition and structure and has a direct relationship with glycosaminoglycan biological functions. In this study, glycosaminoglycan disaccharides, prepared from heparan sulfate/heparin, chondroitin sulfate/dermatan sulfate and neutral hyaluronic acid using multiple polysaccharide lyases, were fluorescently labeled with 2 aminoacridone, fractionated into 17 well-resolved components by reverse-phase ultra-performance liquid chromatography, and analyzed by electrospray ionization mass spectrometry. This analysis was successfully applied to cell, tissue, and biological fluid samples for the picomole level detection of glycosaminoglycan composition and structure. PMID- 22236565 TI - Calculation of the geometrical three-point parameter constant appearing in the second order accurate effective medium theory expression for the B-term diffusion coefficient in fully porous and porous-shell random sphere packings. AB - Using computational fluid dynamics (CFD), the effective B-term diffusion constant gamma(eff) has been calculated for four different random sphere packings with different particle size distributions and packing geometries. Both fully porous and porous-shell sphere packings are considered. The obtained gamma(eff)-values have subsequently been used to determine the value of the three-point geometrical constant (zeta2) appearing in the 2nd-order accurate effective medium theory expression for gamma(eff). It was found that, whereas the 1st-order accurate effective medium theory expression is accurate to within 5% over most part of the retention factor range, the 2nd-order accurate expression is accurate to within 1% when calculated with the best-fit zeta2-value. Depending on the exact microscopic geometry, the best-fit zeta2-values typically lie in the range of 0.20-0.30, holding over the entire range of intra-particle diffusion coefficients typically encountered for small molecules (0.1 <= D(pz)/D(m) <= 0.5). These values are in agreement with the zeta2-value proposed by Thovert et al. for the random packing they considered. PMID- 22236566 TI - Rational design of heteropolyacid-based nanosorbent for hollow fiber solid phase microextraction of organophosphorus residues in hair samples. AB - A novel heteropolyacid-based supported ionic liquid (IL) mediated sol-gel hybrid organic-inorganic material is presented for effective use in hollow fiber solid phase microextraction (HF-SPME). We examined a Keggin-based IL that was evaluated in conjunction with sol-gel. This study shows that Keggin-based IL sol-gel generated porous morphology pro effective extraction media. The method was developed for the extraction of the organophosphorus pesticides (OPs); diazinon, fenitrothion and malathion from human hair samples. The OPs were subsequently analyzed with high performance liquid chromatography and photodiode array detection (HPLC-PDA). In the basic condition (pH 10-11), the gel growth process in the presence of IL was initiated. Afterward, this sol was injected into a polypropylene hollow fiber segment for in situ-gelation process. Parameters affecting the efficiency of HF-SPME were thoroughly investigated. Linearity was observed over a range of 0.02-50,000 MUg/g and 0.0001-25,000 ng/mL with detection limits between 0.0074-1.3000 MUg/g and 0.00034-0.84 ng/mL for the OPs in hair and aqueous matrices, respectively. The relative recoveries in the real samples, for OPs in the storekeeper hair ranged from 86 to 95.2%. PMID- 22236567 TI - Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion. AB - BACKGROUND: Carcinoma cells must circumvent the normally suppressive signals to disseminate. While often considered 'stop' signals for adherent cells, CXCR3 binding chemokines have recently been correlated positively with cancer progression though the molecular basis remains unclear. RESULTS: Here, we examined the expression and function of two CXCR3 variants in human prostate cancer biopsies and cell lines. Globally, both CXCR3 mRNA and protein were elevated in localized and metastatic human cancer biopsies compared to normal. Additionally, CXCR3A mRNA level was upregulated while CXCR3B mRNA was downregulated in these prostate cancer specimens. In contrast to normal prostate epithelial cells (RWPE-1), CXCR3A was up to half the receptor in the invasive and metastatic DU-145 and PC-3 prostate cancer cells, but not in the localized LNCaP cells. Instead of inhibiting cell migration as in RWPE-1 cells, the CXCR3 ligands CXCL4/PF4 and CXCL10/IP10 promoted cell motility and invasiveness in both DU-145 and PC-3 cells via PLCbeta3 and MU-calpain activation. CXCR3-mediated diminution of cell motility in RWPE-1 cells is likely a result of cAMP upregulation and m calpain inhibition via CXCR3B signal transduction. Interestingly, overexpression of CXCR3B in DU-145 cells decreased cell movement and invasion. CONCLUSION: These data suggest that the aberrant expression of CXCR3A and down-regulation of CXCR3B may switch a progression "stop" to a "go" signal to promote prostate tumor metastasis via stimulating cell migration and invasion. PMID- 22236568 TI - Invited commentary. PMID- 22236569 TI - Efficacious treatment of non-dermatophyte mould onychomycosis with topical amphotericin B. AB - BACKGROUND: Dermatophytes are the main cause of onychomycosis, but various non dermatophyte moulds (NDMs) are often the infectious agents in abnormal nails. In particular, Fusarium spp. and other NDMs are mostly insensitive to standard onychomycosis treatment with topical agents as well as with oral terbinafine and itraconazole. OBJECTIVE: The aim of this work is to report the efficacy of a topical amphotericin B solution on NDM onychomycosis in a series of 8 patients resistant to multiple conventional topical and systemic treatments. METHODS: Treatment consisted in the application of an optimized amphotericin B solution once daily to the affected nails and surrounding tissue. No mechanical debridement or medications were allowed except for trimming excessively long nails or in some cases occasionally applying urea-based cream to soften thickened nail plates. RESULTS: Onychomycosis was clinically cured in all patients after a 12-month treatment. Mycological cure was obtained in all but 1 patient. CONCLUSIONS: Topical amphotericin B is an efficacious, safe, cheap and easy-to apply treatment which should be considered as first-line therapy for NDM onychomycosis. PMID- 22236570 TI - GPR35 is a target of the loop diuretic drugs bumetanide and furosemide. AB - We report that the loop diuretic drugs bumetanide and furosemide used in the treatment of hypertension are GPR35 agonists. We utilized calcium flux, inositol phosphate accumulation, and dynamic redistribution assays to examine the pharmacology of these compounds on the human, mouse and rat GPR35. While potent on human GPR35, neither bumetanide nor furosemide were active against mouse or rat GPR35. Furthermore, the Na(+)-Cl(-) cotransporter inhibi- tors chlorothiazide and hydrochlorothiazide were inactive against GPR35 in all three species. We also demonstrate that GPR35 is expressed in human skin where it has been shown that loop diuretics inhibit histamine-induced flare and itch response. These findings suggest that GPR35 may play an important role in skin cell biology and be a potential target for the treatment of a variety of immune disorders. PMID- 22236571 TI - Using personality disorders to distinguish between patients with psychogenic nonepileptic seizures and those with epileptic seizures. AB - Identifying psychiatric disorders rather than psychiatric symptoms might help to distinguish patients with psychogenic nonepileptic seizures (PNES) from those with epileptic seizures (ES). Patients with PNES (n=35), patients with ES (n=35), and healthy controls (n=37) were compared with respect to the prevalence of psychiatric disorders in this study. We tested the predictive power of having axis I psychiatric disorders, as well as personality disorders, in distinguishing ES from PNES. There was no significant difference between the patient groups in the prevalence of axis I psychiatric disorders. Personality disorders were more prevalent in the PNES group than in the ES group (P<0.05). Having a personality disorder was the only predictor for the PNES group. Having a personality disorder seems to be a more significant predictor for PNES than having an axis I psychiatric disorder. Greater attention should be paid to personality disorders in the differentiation of PNES and ES and the provision of effective treatment. PMID- 22236572 TI - The assessment of consciousness during partial seizures. AB - A wide range of controversial definitions and dynamic components surround the multi-dimensional concept of consciousness, with important reflections on the phenomenological description of ictal states relevant to epileptic seizures. The inadequacies of terminology, the insufficient emphasis on the subjective nature of consciousness, as well as the intrinsic limitations of the simple versus complex dichotomy for partial seizures, are to be considered in view of a modern definition of consciousness. In this paper, we review the difficulties encountered by clinicians in assessing the ictal conscious state in patients with epilepsy, and illustrate how a more sophisticated bi-dimensional model of consciousness can prove a valuable conceptual tool for the clinical assessment of ictal consciousness and the categorization of seizures. PMID- 22236573 TI - Epilepsy-related employment prevalence and retirement incidence in the German working population: 1994-2009. AB - Epilepsy-related employment prevalence and retirement incidence were investigated in the German working population from 1994 to 2009. The overall mean prevalence of employment of people with epilepsy was 5.1+/-0.2 per 1000 workers. The employment rate among people with epilepsy increased from 63.5% in 1994 to 65.9% in 2000 (0.4% annually) and then more steeply from 66.8% in 2001 to 76.9% in 2009 (1.4% annually). A prominent increase in rate of employment of people with epilepsy since 2001 was temporarily associated with approval of leviteracetam in 2000 (P<0.001, OR=8.3, CI=6.45-10.12). The overall mean employment rate of people with epilepsy was lower than that of the general population (68.5% vs 90.1%, P<0.001). The overall mean incidence of epilepsy-related retirement (RI) during the study was 4.6+/-1.6/1000, similar to the RI for people with other illnesses (5.1+/-0.8/1000), and the risk of retiring because of epilepsy was not higher than that for other illnesses over the entire study period (P=0.52, OR=1.11, CI=0.86-1.43). The RI among workers with epilepsy, however, sharply declined from 8.3/1000 in 1994 to 2.9/1000 in 2000 (-65%, < 0.001), followed by a slight increase and stabilization at 3.9/1000 workers between 2001 and 2009. The decline in RI among people with epilepsy was temporarily associated with legislation of the Law on Support of Employment in 1996 (P=0.032, OR=2.15, CI=1.17-2.89) and approval of lamotrigine in 1993 (P=0.024, OR=2.64, CI=2.17-3.88). These patterns suggest that drug treatment and legislative laws may have led to increased employment and reduced retirement rates for people with epilepsy. PMID- 22236574 TI - The effect of rosmarinic acid on 1,2-dimethylhydrazine induced colon carcinogenesis. AB - This study was carried out to investigate the chemopreventive potential of rosmarinic acid (RA) against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the effect of RA on tumour formation, antioxidant enzymes, cytochrome P450 content, p-nitrophenol hydroxylase and GST activities. Rats were divided into six groups and fed modified pellet diet for the entire experimental period. Group 1 served as control, group 2 received RA (10 mg/kgb.w.). Groups 3-6 were induced colon cancer by injecting DMH (20 mg/kgb.w.) subcutaneously once a week for the first four weeks (groups 3-6). In addition, RA was administered at the doses of 2.5, 5 and 10 mg/kgb.w. to groups 4-6 respectively. DMH treated rats showed large number of colonic tumours; decreased lipid peroxidation; decreased antioxidant status; elevated CYP450 content and PNPH activities; and decreased GST activity in the liver and colon. Supplementation with RA (5 mgkg/b.w.) to DMH treated rats significantly decreased the number of polyps (50%); reversed the markers of oxidative stress (21.0%); antioxidant status (38.55%); CYP450 content (29.41%); and PNPH activities (21.9%). RA at the dose of 5 mg/kgb.w. showed a most pronounced effect and could be used as a possible chemopreventive agent against colon cancer. PMID- 22236575 TI - Anger in PTSD: is there a need for a concept of PTSD-related posttraumatic anger? AB - Despite extensive research on posttraumatic stress disorder (PTSD), anger in PTSD has received little attention. This is surprising, given anger is a key predictor of treatment outcome in PTSD. This paper seeks to build an argument for investigating anger in PTSD as a discrete entity. A key argument is that the capacity to image visual mental phenomena is crucial to the aetiology and maintenance of anger in PTSD. Evidence is reviewed for the influence of visual imagery in anger in PTSD from the perspectives of neuropsychology, psychopathology, anger and PTSD. An argument is advanced for including visual imagery in an integrated (visual-linguistic) cognitive model of anger in PTSD. Directions for research on visual imagery in anger in PTSD and its treatment implications are discussed. PMID- 22236576 TI - CREB-regulated transcription coactivator 1-dependent transcription in Alzheimer's disease mice. AB - BACKGROUND/AIMS: Long-term memory requires fine-tuning regulation of gene expression in specific neural circuits of the brain. Transcriptional regulation of gene programs is a key mechanism for memory storage and its deregulation may contribute to synaptic and cognitive dysfunction in memory disorders. The molecular mechanisms underlying changes on activity-dependent gene expression in Alzheimer's disease (AD) are largely unknown. METHODS: We analyzed the expression of activity-dependent genes regulated by the cAMP response element binding protein (CREB) and activation of CREB and its coactivator CREB-regulated transcription coactivator 1 (CRTC1) in control and mutant beta-amyloid precursor protein (APP(Sw,Ind); Swedish and Indiana mutations) transgenic mice. RESULTS: Gene expression analyses revealed specific downregulation of a subset of well known activity-induced CREB-dependent genes, including c-fos, Bdnf and Nr4a2, in the hippocampus of memory-impaired APP(Sw,Ind) transgenic mice. Activity dependent CREB transcription induced by calcium/cAMP signals is disrupted through a mechanism involving deregulation of calcium/calcineurin-mediated dephosphorylation and activation of CRTC1. Expression of CRTC1 and pharmacological activation of L-type voltage-gated calcium channels reverse the deficits in CRTC1-mediated transcription in APP(Sw,Ind) neurons. CONCLUSION: Our results suggest that CRTC1 dysfunction caused by Abeta accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice. PMID- 22236577 TI - Combined mesenchymal stem cell sheets and rhBMP-2-releasing calcium sulfate-rhBMP 2 scaffolds for segmental bone tissue engineering. AB - Repair of segmental bone defects remains a major challenge for orthopedic surgeons. This study aimed to investigate whether recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded calcium sulfate (CS) combined with mesenchymal stem cell (MSC) sheets could accelerate bone regeneration in ulnar segmental defects of rabbits. In vitro, the osteogenic differentiation of MSCs cultured on rhBMP-2-loaded CS was investigated. Forty complete 1.2-cm bone defects were treated with CS (group A), rhBMP-2-loaded CS (group B), MSC sheet wrapped CS (group C), and MSC sheet-wrapped rhBMP-2-loaded CS (group D). At 4 and 8 weeks after implantation, the samples were treated by X-ray, microcomputed tomography, and histological observation. The rhBMP-2 could be released from the rhBMP-2-loaded CS scaffolds and maintain its bioactivity. The alkaline phosphatase (ALP) of MSCs cultured on rhBMP-2-loaded CS was significantly higher than that of CS at both 7 and 14 days (p < 0.05). The defects treated with MSC sheet-wrapped rhBMP-2-loaded CS showed significantly higher scores by X-ray analysis and more bone formation determined by both histology and microcomputed tomography than the other three groups at both 4 and 8 weeks after implantation (p < 0.05). No significant difference in X-ray score and bone formation was found between groups B and C, both significantly higher than group A (p < 0.05). The results suggested that MSC sheet-wrapped rhBMP-2-loaded CS may be an effective approach to promote the repair of segmental bone defects and has great potential for repairing large segmental bone defects in clinic. PMID- 22236578 TI - Acetylcholinesterase is associated with apoptosis in beta cells and contributes to insulin-dependent diabetes mellitus pathogenesis. AB - Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic beta-cell apoptosis. Here, we investigated the role of AChE in the development of IDDM and analyzed protective effects of AChE inhibitors. Multiple low-dose streptozotocin (MLD-STZ) administration resulted in IDDM in a mouse model. Western blot analysis, cytochemical staining, and immunofluorescence staining were used to detect AChE expression in MIN6 cells, primary beta cells, and apoptotic pancreatic beta cells of MLD-STZ-treated mice. AChE inhibitors were administered intraperitoneally to the MLD-STZ mice for 30 days. Blood glucose, plasma insulin, and creatine levels were measured, and glucose tolerance tests were performed. The effects of AChE inhibitors on MIN6 cells were also evaluated. AChE expression was induced in the apoptotic MIN6 cells and primary beta cells in vitro and pancreatic islets in vivo when treated with STZ. Induction and progressive accumulation of AChE in the pancreatic islets were associated with apoptotic beta cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels and plasma creatine clearance in the MLD-STZ mice. AChE inhibitors partially protected MIN6 cells from the damage caused by STZ treatment. Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM. PMID- 22236579 TI - Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth. AB - The human transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein (TM4SF4/il-TMP) was originally cloned as an intestinal and liver tetraspan membrane protein and mediates density-dependent cell proliferation. The rat homolog of TM4SF4 was found to be up-regulated in regenerating liver after two-thirds hepatectomy and overexpression of TM4SF4 could enhance liver injury induced by CCl(4). However, the expression and significance of TM4SF4/il-TMP in liver cancer remain unknown. Here, we report that TM4SF4/il-TMP is frequently and significantly overexpressed in hepatocellular carcinoma (HCC). Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that TM4SF4/il-TMP mRNA and protein levels were up-regulated in ~80% of HCC tissues. Immunohistochemical analysis of a 75 paired HCC tissue microarray revealed that TM4SF4/il-TMP was significantly overexpressed in HCC tissues (P< 0.001), and high immunointensity of TM4SF4/il-TMP tended to be in well-to-moderately differentiated HCC compared with poorly differentiated tumors. Functional studies showed that overexpression of TM4SF4/il-TMP in QGY-7701 and BEL-7404 HCC cell lines through stable transfection of TM4SF4 expression plasmid significantly promoted both cell growth and colony formation of HCC cells. Reduction of TM4SF4/il-TMP expression in QGY-7701 and BEL-7404 cells by stably transfecting TM4SF4 antisense plasmid caused great inhibition of cell proliferation. Our findings suggest that TM4SF4/il-TMP has the potential to be biomarker in HCC and plays a crucial role in promotion of cancer cell proliferation. PMID- 22236580 TI - The combined influence of surface modification, size distribution, and interaction time on the cytotoxicity of CdTe quantum dots in PANC-1 cells. AB - Mercaptopropionic acid (MPA) and cysteamine (Cys) capped CdTe quantum dots (QDs) were successfully prepared and used to investigate the combined influence of surface modification, size distribution, and interaction time on their cytotoxicity in human pancreatic carcinoma (PANC-1) cells. Results indicated that the smaller the size of MPA-CdTe QDs, the higher the cytotoxicity, which could be partly due to the difference of their distribution inside cells. Comparing with MPA-CdTe QDs, Cys-CdTe QDs had better cellular metabolizability and lower cytotoxicity. These QDs' cellular distribution and cytotoxicity were closely related to their interaction time with cells. Their cytotoxicity was found to be significantly enhanced with the increase of incubation time in medium. After QD treatments, the influence of recover time on the final cell viability was also dependent on the concentration and surface modification of QDs used in pretreatment. The combined influence of these factors discussed here might provide useful information for understanding and reducing the cytotoxicity of QDs in future biomedical applications. PMID- 22236581 TI - Assessment of appropriate medication administration for hospitalized patients with Parkinson's disease. AB - BACKGROUND: For Parkinson's disease (PD) patients, adherence to a regular PD medication schedule is important in achieving optimal symptom control. There are few published studies quantifying PD medication administrations in hospitalized PD patients. METHODS: Hospitalization records for 100 veterans with idiopathic PD and admitted to our center were reviewed to determine the on time rate and contraindicated medication doses. A barcode based computerized medication administration system within the electronic medical record provided information of the exact time the medication was given to a patient. RESULTS: Eighty-nine idiopathic PD patients met study inclusion criteria. Among them, 87 were on levodopa monotherapy or in combination with other PD medications. Two patients were on dopamine agonists only. A total of 3873 doses of PD medications were prescribed during hospitalization. Among 675 incorrect medication administrations, 322 doses were omitted, 300 doses late by >= 30 min, and 53 doses given early by >= 30 min. Contraindicated medications were prescribed for 19 patients. The correct administration percentage was lower during the first 2 days post-admission compared to subsequent days (mean 74.6% vs. 82.8%) and higher for patients who had neurological consultations (mean 85.5% vs. 76.5%). Correct administration rates were better for patient-based medication schedules (85.6%) than with hospital-based schedules (77.5%), but did not achieve statistical significance. CONCLUSION: Adherence to regular PD medication dosing schedules during hospitalization is problematic, but improves with specialist consultation. Staff involved in the admission process for PD patients should work to safeguard against disruption of the prescribed home dosing schedule. PMID- 22236582 TI - Assessment of the Scopa-Aut questionnaire in multiple system atrophy: relation to UMSARS scores and progression over time. AB - Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression - that is the Unified MSA Rating Scale (UMSARS) - were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials. PMID- 22236583 TI - Pregnancy in patients with Sydenham's Chorea. AB - BACKGROUND: Sydenham's Chorea is a frequent cause of chorea during pregnancy, chorea gravidarum. The aim of this article is to describe the effect of pregnancy in a consecutive series of patients with diagnosis of Sydenham's Chorea. METHODS: A chart review was performed of all patients with the diagnosis of Sydenham's Chorea followed up at our institution from 07/1993 through 08/2010 and who became pregnant. RESULTS: From 66 patients, 20 became pregnant. Of these 20 patients, 15 (75%) developed chorea gravidarum. Generalized chorea was found in 67% of these 15 patients, focal or multifocal chorea was identified in 20% and 13.4% developed hemichorea. In 80% of cases chorea began in the first 6 months of gestation. Three women with previous persistent chorea experienced worsening of the movement disorder during pregnancy. Remission occurred after delivery in 11 patients whereas the other four remained with non-disabling chorea during the first 12 months after delivery. Abortion occurred in two patients (13%). All patients with chorea gravidarum subsequently treated with oral contraceptives developed recurrence of chorea. CONCLUSIONS: Chorea gravidarum is a frequent complication of pregnancy in patients with previous history of Sydenham's Chorea and an increased risk of miscarriage should be considered. Our findings confirm the notion that chorea gravidarum results from hormonal changes acting on previously dysfunctional basal ganglia. PMID- 22236584 TI - Osteochondral angiogenesis in rat mandibular condyles with osteoarthritis-like changes. AB - OBJECTIVE: To investigate angiogenesis at the osteochondral junction and changes in expression of pro- and anti-angiogenic factors in rat mandibular condyles with osteoarthritis-like changes. METHODS: In order to evoke osteoarthritis-like lesions in mandibular condyles, disordered occlusion was created experimentally in rats. Osteochondral vascularity was assessed histologically at 20 and 24 weeks. Protein and mRNA levels of pro-angiogenic factors including vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and matrix metalloproteases 9 (MMP9), and anti-angiogenic factor chondromodulin-I (CHM-I) were investigated by means of immunohistochemical staining and real-time PCR. RESULTS: Osteochondral angiogenesis was demonstrated as increased numbers of vascular channels terminating in the calcified cartilage and non-calcified cartilage in 20- and 24-week experimental groups compared with controls (all P<0.05). In the experimental groups, VEGF, CTGF and MMP9 were highly expressed in the tissues adjacent to the osteochondral junction. However, CHM-I was more expressed in the superior but not deep hypertrophic chondrocytes. Compared to their age-matched controls, the protein levels of VEGF and CTGF were higher in 20 week experimental group, and the protein and mRNA levels of CTGF, MMP-9, and CHM I increased in the 24-week experimental group (all P<0.05). CONCLUSION: In the present rat model, osteochondral angiogenesis was observed in mandibular condyles with osteoarthritis-like changes, accompanied with local upregulation of VEGF, CTGF and MMP9. Although the increase in CHM-I may moderate pro-angiogenic factors effects in the superior cartilage, the deficiency of deep hypertrophic chondrocytes to express CHM-I may permit vascular invasion into condylar cartilage. PMID- 22236585 TI - JOSPT: the way ahead. AB - Last Fall, JOSPT conducted an extensive environmental survey that attracted 560 respondents. The survey represented the Journal's many stakeholder groups, including authors, reviewers, editors, Orthopaedic and Sports Sections members, individual and institutional subscribers, and international partners. The Journal also held a strategic planning meeting and adopted a plan for the next 2 years. Among other findings, the survey showed that journals remain the most important means by which professionals stay current in the field of musculoskeletal rehabilitation. The survey also highlighted the technological sea change in publishing today. The expansion of JOSPT's online features in recent years, the need to select the "right" technologies, the plethora of content delivery options already available, and the growing demand to read and access the Journal anytime, anywhere, dominated the survey's results. Based on this survey, existing initiatives, and discussion at the planning meeting, JOSPT's plan for the future has at its heart technology as means of developing and disseminating clinically relevant information to improve patient care. PMID- 22236586 TI - A novel synthesis of graphene nanoscrolls with tunable dimension at a large scale. AB - Graphene nanoscrolls which could overcome the chirality dependence of metallic or semiconducting behavior in carbon nanotubes have been recently investigated and proposed for a wide variety of applications. In order to further improve their practical applications, a variety of synthetic approaches have been widely explored but with various limitations. For instance, it remains challenging to produce graphene nanoscrolls with tunable dimensions and high quantity, which greatly hinders their potential applications. Herein, we report a new and general approach to synthesize graphene nanoscrolls with accurately tunable widths and lengths at a large scale. The resulting high-quality graphene nanoscrolls show promising applications in a wide variety of electronic devices. PMID- 22236587 TI - Comparisons of polybrominated diphenyl ethers levels in paired South Korean cord blood, maternal blood, and breast milk samples. AB - Polybrominated diphenyl ethers (PBDEs), commonly used flame retardants, have been reported as potential endocrine disruptor and neurodevelopmental toxicants, thus giving rise to the public health concern. The goal of this study was to investigate the relationship between umbilical cord blood, maternal blood, and breast milk concentrations of PBDEs in South Korean. We assessed PBDE levels in paired samples of umbilical cord blood, maternal blood, and breast milk. The levels of seven PBDE congeners were measured in 21 paired samples collected from the Cheil Woman's Hospital (Seoul, Korea) in 2008. We also measured thyroid hormones levels in maternal and cord blood to assess the association between PBDEs exposure and thyroid hormone levels. However, there was no correlation between serum thyroxin (T4) and total PBDEs concentrations. The total PBDEs concentrations in the umbilical cord blood, maternal blood, and breast milk were 10.7+/-5.1 ng g(-1) lipid, 7.7+/-4.2 ng g(-1) lipid, and 3.0+/-1.8 ng g(-1) lipid, respectively. The ranges of total PBDE concentrations observed were 2.28 30.94 ng g(-1) lipid in umbilical cord blood, 1.8-17.66 ng g(-1) lipid in maternal blood, and 1.08-8.66 ng g(-1) lipid in breast milk. BDE-47 (45-73% of total PBDEs) was observed to be present dominantly in all samples, followed by BDE-153. A strong correlation was found for major BDE-congeners between breast milk and cord blood or maternal blood and cord blood samples. The measurement of PBDEs concentrations in maternal blood or breast milk may help to determine the concentration of PBDEs in infant. PMID- 22236588 TI - The effects of aging time on the fraction distribution and bioavailability of PAH. AB - Understanding the effects of aging time on the fraction distribution and bioavailability of PAH, such as phenanthrene (PHE) and pyrene (PYR), has considerable benefits for risk assessment, food security and remediation strategies for contaminated soil. The results of the present study show that the proportion of the desorbed PHE decreased from ca. 82% at day 0 to ca. 65% at day 150. In addition, non-desorbed PHE increased from ca. 18% at day 0 to ca. 31% at day 150, whereas the changes of desorbed and non-desorbed PYR showed no significant trend during this aging period. The proportion of desorbed PYR was lower than that of PHE, whereas the opposite occurred with the non-desorbed fraction. After 150 d of aging, the proportion of bound residues (PHE and PYR) increased significantly with the cultivating time from ca. 0.2% to ca. 4.7% and ca. 0.1% to ca. 1.2% for PHE and PYR, respectively. In addition, the bioavailability of PAH (PHE and PYR) to earthworms was also assessed over 0-150 d. The results showed that the uptake rate and bioconcentration factor (BCF) of pollutants by earthworms displayed the following biphasic character: a rapid decrease over the first 15 d followed by a slow decrease over the next 135 d. Moreover, the earthworm uptake rate of PHE was greater than that of PYR throughout the incubation period, indicating that PHE has a higher bioavailability than PYR. In addition, the positive correlation between the uptake rate of earthworms and PAH extractability suggested that a three-step extraction is a reliable approach to predict PHE bioavailability in soil. However, a limit was observed for PYR. PMID- 22236589 TI - Efficient bio-deodorization of aniline vapor in a biotrickling filter: metabolic mineralization and bacterial community analysis. AB - A biotrickling filter inoculated with commercial mixed microorganisms B350 was employed to treat N-containing odorous vapor - aniline. Results indicated no aniline could be detected when empty bed residence time (EBRT) was larger than 110s at inlet concentration of 0.30 g m(-3). The variation of inlet concentration did not change removal efficiencies when concentration is less than 0.21 g m(-3) at fixed EBRT 110s. Biodegradation mechanism of aniline was tentatively proposed based on identified intermediates and predicted biodegradation pathway as well as final mineralized products. Aniline was firstly biodegraded to catechol, and then to levulinic acid and subsequently to succinic acid. Finally, about 62% aniline carbon was completely mineralized to CO(2), while about 91% aniline nitrogen was converted into ammonia and nitrate. Bacterial community in biotrickling filter was found that at least seven bands microbes were identified for high efficiencies of bioreactor at stable state. In all, biotrickling filter seeded with B350 would be a better choice for the purification odorous gas containing high concentration aniline. PMID- 22236590 TI - Water extractable organic carbon in untreated and chemical treated biochars. AB - Biochar, as a soil amendment, can increase concentrations of soil organic matter, especially water-extractable organic carbon (WEOC). This can affect the adsorption-desorption equilibrium between the dissolved solid phases in soil organic matter. Dissolved organic carbon (DOC) represents a small proportion of soil organic matter, but is of significant importance in the soil ecosystem due to its mobility and reactivity. Here, water extracts obtained from twelve non herbaceous biochars (before, and after, chemical treatment with either H(3)PO(4) or KOH), were tested by Liquid Chromatography - Organic Carbon Detection (LC-OCD) to identify the effects of both pyrolysis conditions and chemical treatments on WEOC content. LC-OCD has the capacity to provide a fingerprint of WEOC, which allows analysis of the various fractions present. WEOC content was affected by both the pyrolysis temperature and the feedstock used. High mineral ash contents deriving from the feedstock can prompt thermochemical reactions of lignocelluloses to produce a relatively high WEOC content, which includes low molecular weight neutrals and humic acids as dominant components. A significant change in WEOC occurred during pyrolysis due to secondary reactions which resulted in a much lower WEOC in the high temperature biochars where fractions of low molecular weight acids and neutrals are dominant. Chemical treatments with H(3)PO(4) or KOH increased WEOC concentration, possibly by promoting hydrolysis reactions on biochar surfaces. These observations assist in assessing the contribution of biochar additions to the soil ecosystem and demonstrate the utility of LC-OCD in providing an understanding of how biochar additions to soil can alter DOC. PMID- 22236591 TI - Tolerance, uptake and removal of nitrobenzene by a newly-found remediation species Mirabilis jalapa L. AB - The growth, photosynthesis rate, and ultrastructure of Mirabilis jalapa L. as a newly-found remediation species under stress of nitrobenzene (NB) and its uptake and removal of NB by the plants were investigated. The results showed that M. jalapa plants could endure contaminated soils by lower than 10.0 mg NB kg(-1) because there was no decrease in the total length of the plant roots, the maximum length of the hypocotyle, the length of the first seminal root, the height of the shoots and the dry biomass of the seedlings as well as the photosynthesis rate of the plants compared with those in the control. In particular, the growth of the plants could be significantly (P<0.01) enhanced by 0.1 mg NB kg(-1) under unautoclaved and autoclaved soils. Ultrastructural observations on leaf cells of the plants found that these cells had smooth, clean and continuous cell membranes and cell walls, indicating that there was no obvious damage by NB in comparison with those in the control. Although the absorption of NB in shoots and roots of M. jalapa was weak, plant-promoted biodegradation of NB was considerable and the dominant contribution in the removal of NB from contaminated soils, suggesting the feasibility of M. jalapa applied to phytoremediation of NB contaminated soils. PMID- 22236592 TI - Responses of juvenile sea bass, Dicentrarchus labrax, exposed to acute concentrations of crude oil, as assessed by molecular and physiological biomarkers. AB - In the present study, juvenile sea bass were exposed for 48 and 96 h to an Arabian light crude oil and their responses were assessed at the molecular and physiological levels. The aim of the study was therefore to assess (i) the short term effects of crude oil exposure by the measurement of several molecular biomarkers, (ii) the consequences of this short term exposure on fish health by using growth and condition indices measured after a decontamination period of 28 and 26 d in seawater. Hydrocarbon petroleum concentrations was monitored during the 96 h experiments and an increase of PAH concentrations were found in fish following both exposure times. An 7-ethoxyresorufin-O-deethylase (EROD) induction was observed after 48 h of exposure, while a significant decrease in the sea bass specific growth rate in length and for the RNA:DNA ratio was observed 28 d after that exposure ceased. The EROD induction doubled after the 96 h exposure, and a significant increase in GST activities was observed. A significant decrease in the specific growth rates, the otolith recent growth, the RNA:DNA ratio and the Fulton's K condition index were then observed in sea bass 26 d after the 96 h exposure to mechanically dispersed crude oil compared to the control. The present study shows that growth and condition indices can prove useful in assessing fish health status following an oil spill. Their complementary analysis with sensitive molecular biomarkers as EROD could improve the determination of oil spill impact on fish populations. PMID- 22236593 TI - Hormonal activities of new brominated flame retardants. AB - After the phase-out of two commercial mixtures of brominated flame retardants, an increasing number of alternative flame retardants have been introduced in commercial applications. None of them, however, has been thoroughly tested for its hormonal activity. We used two yeast reporter-gene assays to determine the potential of eleven compounds to interfere with estrogenic and androgenic pathways. Our data demonstrate the ability of 2,4,6-tribromophenol to lower the transcriptional activity of human estrogen and androgen receptors. A nominal IC(50) value of 14.1 MUM for anti-estrogenic and 3.9 MUM for anti-androgenic activity was obtained using the luciferase reporter. An IC(50) value of 9.2 MUM was calculated for the anti-estrogenic activity measured by the beta galactosidase assay. Of the tested chemicals, this study highlights the endocrine disrupting effects of 2,4,6-tribromophenol whose occurrence in the environment should be monitored. PMID- 22236594 TI - Cervical epidural abscess presenting as giant cell arteritis. AB - Maxillofacial surgeons may be involved in the initial investigation and management of temporal arteritis. We present a case of a cervical epidural abscess with clinical features of temporal arteritis. PMID- 22236595 TI - Applying aviation factors to oral and maxillofacial surgery--the human element. AB - There are many similarities between flying commercial aircraft and surgery, particularly in relation to minimising risk, and managing potentially fatal or catastrophic complications, or both. Since 1979, the development of Crew Resource Management (CRM) has improved air safety significantly by reducing human factors that are responsible for error. Similar developments in the operating theatre have, to a certain extent, lagged behind aviation, and it is well recognised that we can learn much from the industry. An increasing number of publications on aviation factors relate to surgery but to our knowledge there is a lack of research in our own specialty. We discuss how aviation principles related to human factors can be translated to the operating theatre to improve teamwork and safety for patients. Clinical research is clearly needed to develop this fascinating area more fully. PMID- 22236596 TI - The diagnosis and management of aortic dissection. PMID- 22236597 TI - Consultant cover and mortality among hospital patients. PMID- 22236598 TI - Commercialisation is bad for public health. PMID- 22236599 TI - Why do single event probabilities confuse patients? PMID- 22236600 TI - Out of hours care: a call for continuity. PMID- 22236601 TI - Faith, hype, and charity. PMID- 22236602 TI - Big tits. PMID- 22236603 TI - Nuclear reactor pulse calibration using a CdZnTe electro-optic radiation detector. AB - A CdZnTe electro-optic radiation detector was used to calibrate nuclear reactor pulses. The standard configuration of the Pockels cell has collimated light passing through an optically transparent CdZnTe crystal located between crossed polarizers. The transmitted light was focused onto an IR sensitive photodiode. Calibrations of reactor pulses were performed using the CdZnTe Pockels cell by measuring the change in the photodiode current, repeated 10 times for each set of reactor pulses, set between 1.00 and 2.50 dollars in 0.50 increments of reactivity. PMID- 22236604 TI - Implementation of a tree algorithm in MCNP code for nuclear well logging applications. AB - The goal of this paper is to develop some modeling capabilities that are missing in the current MCNP code. Those missing capabilities can greatly help for some certain nuclear tools designs, such as a nuclear lithology/mineralogy spectroscopy tool. The new capabilities to be developed in this paper include the following: zone tally, neutron interaction tally, gamma rays index tally and enhanced pulse-height tally. The patched MCNP code also can be used to compute neutron slowing-down length and thermal neutron diffusion length. PMID- 22236605 TI - Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis. AB - BACKGROUND: Praziquantel (PZQ) is an isoquinoline derivative (2 cyclohexylcarbonyl-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino{2,1-a}-isoquinoline-4 one), and is currently the drug of choice for all forms of schistosomiasis. Silymarin, a standardized milk thistle extract, of which silibinin is the main component, is known for its hepatoprotective, anti-inflammatory, antioxidant activities, and hepatocyte regeneration. This study investigates the anti inflammatory/anti-fibrotic effects of silymarin and/or PZQ on schistosomal hepatic fibrosis. METHODS: Schistosoma mansoni-infected mice were divided into two large groups (I & II), each with four subgroups and were run in parallel. (i) Infected untreated; (ii) treated with silymarin, starting from the 4th (3 weeks before PZQ therapy) or 12th (5 weeks after PZQ therapy) weeks post infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with silymarin, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice run in parallel with the infected groups. Mice of groups I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), transforming growth factor-beta1 (TGF-beta1) and number of mast cells were determined. In addition, parasitological, biochemical and histological parameters that reflect disease severity and morbidity were examined. RESULTS: Silymarin caused a partial decrease in worm burden; hepatic tissue egg load, with an increase in percentage of dead eggs; modulation of granuloma size, with significant reduction of hepatic HYP content; tissue expression of MMP-2, TGF-beta1; number of mast cells, with conservation of hepatic reduced glutathione (GSH). PZQ produced complete eradication of worms, eggs and alleviated liver inflammation and fibrosis. The best results were obtained, in most parameters studied, in groups of mice treated with silymarin in addition to PZQ. CONCLUSIONS: Our results point to silymarin as a promising anti-inflammatory and anti-fibrotic agent; it could be introduced as a therapeutic tool with PZQ in the treatment of schistosomal liver fibrosis, but further studies on mechanisms of silymarin and PZQ in chronic liver diseases may shed light on developing therapeutic methods in clinical practice. PMID- 22236607 TI - Thermo-responsive Hercosett/Poly(N-isopropylacrylamide) films: a new, fast, optically responsive coating. AB - Poly(N-isopropylacrylamide) (PNIPAM) is a common thermo-responsive, water-soluble polymer, while Hercosett is a cationic resin commonly employed in the paper industry. In this paper, HercosettTM and poly(N-isopropylacrylamide) (PNIPAM) nanoparticles were used to prepare composite films that show thermo-responsive behavior and swelling-shrinking properties in water. First, size-controlled PNIPAM hydrogel nanoparticles were synthesized. These were then embedded within a matrix of the cationic resin Kymene 577H by film casting. The distribution of nanoparticles in the resin film was investigated. The thermo-responsive properties of the as-synthesized PNIPAM hydrogel nanoparticles and of the composite films were characterized together with the repeatability of the swelling-shrinking cycles. The presence of nanoparticles endowed the film with highly enhanced water retention (in comparison with resin-only films) and, most importantly, thermo-responsiveness. A very fast optical and morphological response was in fact observed. Due to the dual (optical and morphological) response, this new system is suitable for applications in optical or morphological actuation and gating. PMID- 22236606 TI - A review of clinical trials of cetuximab combined with radiotherapy for non-small cell lung cancer. AB - Treatment of non-small cell lung cancer (NSCLC) is challenging in many ways. One of the problems is disappointing local control rates in larger volume disease. Moreover, the likelihood of both nodal and distant spread increases with primary tumour (T-) stage. Many patients are elderly and have considerable comorbidity. Therefore, aggressive combined modality treatment might be contraindicated or poorly tolerated. In many cases with larger tumour volume, sufficiently high radiation doses can not be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents, which increase tumour cell kill, might improve the therapeutic ratio. If such agents have a favourable toxicity profile, even elderly patients might tolerate concomitant treatment. Based on sound preclinical evidence, several relatively small studies have examined radiotherapy (RT) with cetuximab in stage III NSCLC. Three different strategies were pursued: 1) RT plus cetuximab (2 studies), 2) induction chemotherapy followed by RT plus cetuximab (2 studies) and 3) concomitant RT and chemotherapy plus cetuximab (2 studies). Radiation doses were limited to 60-70 Gy. As a result of study design, in particular lack of randomised comparison between cetuximab and no cetuximab, the efficacy results are difficult to interpret. However, strategy 1) and 3) appear more promising than induction chemotherapy followed by RT and cetuximab. Toxicity and adverse events were more common when concomitant chemotherapy was given. Nevertheless, combined treatment appears feasible. The role of consolidation cetuximab after RT is uncertain. A large randomised phase III study of combined RT, chemotherapy and cetuximab has been initiated. PMID- 22236608 TI - Comprehensive study of mesoporous carbon functionalized with carboxylate groups and magnetic nanoparticles as a promising adsorbent. AB - Highly ordered mesoporous carbon functionalized with carboxylate groups and magnetic nanoparticles has been successfully synthesized. By oxidative treatment using (NH(4))(2)S(2)O(8) and H(2)SO(4) mixed solution, numerous hydrophilic groups were created in the mesopores without destroying the ordered mesostructure of CMK-3. Through the in situ reduction in Fe(3+), magnetic nanoparticles were successfully introduced into the mesopores, resulting in the multifunctional mesoporous carbon Fe-CMK-3. The obtained hybrid carbon material possesses ordered mesostructure, high Brunauer-Emmett-Teller (BET) surface area up to 1013 m(2)/g, large pore volume of about 1.16 cm(3)/g, carboxylic surface, and excellent magnetic property. When used as an adsorbent, Fe-CMK-3 exhibits excellent performances for removing toxic organic compounds from waster-water, with a high adsorption capacity, an extremely rapid adsorption rate, and an easy magnetically separable process. In the case of requiring emergency removal of large amount of organic pollutants in aqueous, the hybrid carbon adsorbent would be an ideal choice. PMID- 22236609 TI - Leucine supplementation combined with resistance exercise improves the plasma lipid profile of dexamethasone-treated rats. AB - The impact of leucine supplementation and resistance exercise (RE) on plasma lipid profile was evaluated in adult rats treated with dexamethasone, an experimental model of dyslipidemia. Total cholesterol did not differ among groups. Furthermore, leucine supplementation did not promote improvement in the plasma total cholesterol and LDL-c of the animals. However, plasma TG and VLDL-c were significantly decreased and HDL-c increased after 7 days of leucine supplementation combined with RE. In conclusion, leucine supplementation combined with RE, but not isolated, improved the plasma lipid profile of dexamethasone induced dyslipidemic rats. PMID- 22236611 TI - Quality-of-care processes in geriatric assessment units: principles, practice, and outcomes. AB - OBJECTIVES: To assess quality-of-care processes and to examine whether care processes are associated with short-term postdischarge outcomes in older vulnerable hospitalized patients. DESIGN: Retrospective study. SETTING: Forty nine Geriatric Assessment Units. PARTICIPANTS: Patients aged 65 and older who were admitted to a Geriatric Assessment Unit for a fall with trauma. MEASUREMENTS: Three care processes (comprehensiveness, informational continuity, patient-centered care) assessed through chart audit; three-month postdischarge outcomes (emergency department visit, hospital readmission, and death) obtained from national databases. RESULTS: A total of 934 hospitalization records were included. Mean comprehensiveness and informational continuity scores were 55% +/- 12% and 42% +/- 16%, respectively. Items related to geriatric global assessment (eg, functional autonomy) were particularly overlooked. Patient-centered care was poorly provided, with only 24% of hospitalization records showing evidence of advance care directives and at least one patient/family meeting with the physician to discuss clinical evolution. For the three care processes, a large variability among Geriatric Assessment Units was observed. Better comprehensiveness of care was associated with lowered short-term mortality (OR = 0.73, 95% CI = 0.55-0.96, P = .023), whereas higher scores on informational continuity was associated with fewer emergency department visits (OR = 0.91, 95% CI = 0.82-1.00, P = .046), hospital readmissions (OR = 0.84, 95% CI = 0.74-0.94, P = .003), and mortality (OR = 0.72, 95% CI = 0.59-0.88, P = .002). Patient centered care was not associated with any of the postdischarge outcomes. CONCLUSION: A large gap between geriatric care principles and practice in Geriatric Assessment Units has been observed. Our results show that improvement in care processes may be translated to decreased short-term health services use and mortality. PMID- 22236612 TI - Topical mannitol reduces inflammatory edema in a rat model of arthritis. AB - The hexahydric alcohol mannitol is widely used to shift fluids from the intracellular to the extracellular compartments, to increase diuresis and improve mucus clearance in the airways. In principle, because of its physicochemical properties, topical mannitol might also draw fluids out of epidermis or mucosa. Here, we report that topical mannitol applications on the hind paws of rats with adjuvant-induced arthritis reduced paw thickness and tissue edema without affecting the inflammatory infiltrates. Of note, the anti-edema effects of acute (4 h) mannitol application occurred earlier than those prompted by a similar treatment with classic anti-inflammatory drugs such as diclofenac or ketoprofen. Yet, the extent of edema reduction was higher with diclofenac or ketoprofen than with mannitol when the drugs were applied in a chronic (16 h) paradigm. Together, data demonstrate that topical application of mannitol exerts potent and fast anti edema effects in a rat model of joint inflammation, suggesting a possible utilization in patients affected by osseo-arthritic disorders. PMID- 22236613 TI - Primary metastatic neuroendocrine small cell bladder cancer: a case report and literature review. AB - Small cell carcinoma of the urinary bladder (SCCUB) is a rare variant of neuroendocrine nonepithelial tumor. Clinically, SCCUB appears like a flat or ulcerated lesion and microscopically can cause microvascular invasion and necrosis. Small cell cancer, rarely found in the urogenital tract in a primitive form, usually coexists with urothelial bladder cancers. It has an incidence of 0.35-0.7% of all bladder neoplasms and survival at 5 years is estimated to be around 8%. A 60-year-old man who was a smoker was referred to our department with episodes of gross hematuria and pain in the lumbar region. After an extensive transurethral resection of the bladder, including of the muscular layer, the diagnosis of small cell carcinoma of the bladder was made. The neoplastic cells were positive with immunohistochemical staining for chromogranin A, paranuclear reactivity to cytokeratin and neuron-specific enolase. A total-body CT scan revealed lymph node involvement and hepatic, adrenal and lung metastases. Because of the advanced stage it was decided to avoid radical cystectomy and perform chemotherapy. The patient underwent two different cycles of cisplatin chemotherapy following international recommendations, but unfortunately without any response. After palliative therapy, the patient died in January 2010. PMID- 22236614 TI - Volumetric modulated arc therapy for nasopharyngeal carcinoma: a dosimetric comparison with TomoTherapy and step-and-shoot IMRT. AB - PURPOSE: Volumetric modulated arc therapy (VMAT), a novel technique, employs a linear accelerator to conduct dynamic modulation rotation radiotherapy. The goal of this study was to compare VMAT with helical tomotherapy (HT) and step-and shoot intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with regard to the sparing effect on organs at risk (OARs), dosimetric quality, and efficiency of delivery. MATERIALS AND METHODS: Twenty patients with NPC treated by HT were re-planned by VMAT (two arcs) and IMRT (7-9 fields) for dosimetric comparison. The target area received three dose levels (70, 60, and 54 Gy) in 33 fractions using simultaneous integrated boosts technique. The Philips Pinnacle Planning System 9.0 was adopted to design VMAT, using SmartArc as the planning algorithm. For a fair comparison, the planning target volume (PTV) coverage of the 3 plans was normalized to the same level. Dosimetric comparisons between VMAT, HT, and IMRT plans were analyzed to evaluate (1) coverage, homogeneity, and conformity of PTV, (2) sparing of OARs, (3) delivery time, and (4) monitor units (MUs). RESULTS: The VMAT, HT, and IMRT plans had similar PTV coverage with an average of 96%. There was no significant difference between VMAT and HT in homogeneity, while the homogeneity indices of VMAT (1.06) and HT (1.06) were better than IMRT plans (1.07, p<0.05). HT plans provided a better conformity index (1.17) than VMAT (1.28, p=0.01) and IMRT (1.36, p=0.02). When compared with IMRT, VMAT and HT had a better sparing effect on brain stem and spinal cord (p<0.05). The effect of parotid sparing was similar between VMAT (mean=26.3 Gy) and HT (mean=27.5 Gy), but better than IMRT (mean=31.3 Gy, p<0.01). The delivery time per fraction for VMAT (5.7 min) were much lower than for HT (9.5 min, p<0.01) and IMRT (9.2 min, p<0.01). CONCLUSIONS: Our results indicate that VMAT provides better sparing of normal tissue, homogeneity, and conformity than IMRT, and shorter delivery time than HT. PMID- 22236615 TI - [Malignant sacrococcygeal teratoma in an adult woman]. AB - BACKGROUND: Sacrococcygeal teratomas are neoplasms that are ordinarily diagnosed intrauterinely. In case of complete or partial intrapelvic sacrococcygeal teratoma, it may happen that it is only ascertained at a later age. CASE DESCRIPTION: During a regular monitoring visit for breast cancer a 58-year-old female reported that she had discovered a swelling at the level of her coccyx. MRI imagery appeared to indicate an ectopic ovary. After resection, it appeared that it was a mature teratoma from which mucinous adenocarcinoma had developed. CONCLUSION: Given the risk of malignant deterioration, it is important that sacrococcygeal teratoma be recognized and treated by means of complete resection, including resection of the coccygeal bone. PMID- 22236616 TI - [High mortality in patients with idiopathic pulmonary fibrosis on Dutch lung transplant waiting list]. AB - OBJECTIVE: To describe patients diagnosed with idiopathic pulmonary fibrosis (IPF) registered for lung transplantation and to evaluate the current referral guidelines for lung transplantation in the Netherlands. DESIGN: Retrospective study. METHOD: All patients diagnosed with interstitial lung disease and registered for lung transplantation from September 1989-June 2010 were included in this study. Patients who had been diagnosed with IPF according to the American Thoracic Society-European Respiratory Society criteria were included. Clinical data of these patients at the time of screening for lung transplantation and survival data were collected. RESULTS: In total, 289 patients with IPF were registered for lung transplantation. After a first waiting list. During the waiting period, 30 patients (33%) died, 7 were taken off the list due to newly developed comorbidity and excessive physical deterioration, 51 underwent transplantation and 2 were still on the waiting list at the time of study closure. At the time of screening, the mean FVC% predicted of these patients was 51% (SD: 19.0) and the mean diffusing capacity was 27% of predicted (SD: 9.3). CONCLUSION: One-third of the IPF patients on the waiting list died before donor lungs became available. The mean diffusing capacity of 27% of predicted at the time of screening was considerably lower than advised in the international guidelines for placement on the waiting list. This study, therefore, shows that the timing of screening IPF patients for lung transplantation can be improved in the Netherlands. PMID- 22236617 TI - [Thoracoscopic treatment of atrial fibrillation]. AB - Atrial fibrillation (AF) is the most common arrhythmia in humans. The majority of patients with AF can function reasonably well on a daily basis with anti arrhythmic drugs. A small proportion of patients with AF remain symptomatic despite anti-arrhythmic drugs. They might have an indication for invasive treatment for AF, such as endovascular catheter ablation (effective particularly in paroxysmal AF) or the Cox-Maze procedure (open heart surgery), in which the conductivity between the pulmonary veins and the left atrium is blocked. Hybrid thoracoscopic pulmonary vein isolation (VATS-PVI) is a new minimally invasive treatment for AF where the cardiothoracic surgeon and cardiologist work closely together. During this procedure the cardiologist performs electrophysiological measurements to verify whether the blockade of conductivity is successful. This approach has a success rate of 86% at a follow-up of 12 months. PMID- 22236618 TI - [Insufficient evidence supporting iron supplementation in anaemia during pregnancy]. AB - The Royal Dutch Organization of Midwives (KNOV) recently presented their practice guideline 'Anaemia in midwifery practice'. The guideline identified available evidence on diagnosis, prognosis and treatment of anaemia in pregnancy. Anaemia based on iron deficiency and subsequent treatment with iron supplementation are probably the most frequent aspects of care for pregnant women. However, there is surprisingly enough no evidence of the efficacy of iron supplementation treatment on relevant clinical outcomes in pregnant women with anaemia. We plead to make the next guideline a multidisciplinary one. Such a guideline may lead to a large pragmatic trial evaluating the efficacy of iron supplementation treatment for patients with anaemia. PMID- 22236619 TI - [Screening for thyroid dysfunction in dyslipidaemia patients]. AB - We describe 2 patients, a 49-year-old man presenting with dyspnoea and fatigue, and a 50-year-old woman referred for hypercholesterolaemia and hypertension. Both patients appeared to have hypothyroidism-induced dyslipidaemia. The lipid abnormalities resolved completely following thyroid hormone replacement therapy. Hypothyroidism is a well-known cause of secondary dyslipidaemia and may therefore predispose to the development of atherosclerotic disease. Measurement of thyroid hormone levels are, however, often not included in the screening of dyslipidaemia patients. The cases presented illustrate the insidious and diverse clinical presentations and diagnostic challenges of hypothyroidism. In addition, these cases demonstrate that clinical and biochemical screening for thyroid dysfunction is of paramount importance in all dyslipidaemia patients to prevent inappropriate initiation of lipid-lowering therapy. PMID- 22236620 TI - [Dutch College of General Practitioners' practice guideline 'Diverticulitis' from a surgical perspective]. AB - Diverticulitis is a common disease which, in the Netherlands, leads to approximately 13,500 hospitalizations annually. This figure represents merely 12% of actual cases encountered by general practitioners. The combined factors of older age, pain in the left lower abdomen which increases on movement, an elevated C-reactive protein level, the absence of vomiting and a prior episode of diverticulitis are highly predictive for this clinical diagnosis. This prediction model has been developed in secondary care centres. Its diagnostic value has yet to be proven in general practice. PMID- 22236621 TI - Clearance, distribution volume, and dialyzer mass area transport coefficient of glucose in whole blood. AB - The extracorporeal transport of glucose was studied to determine the dialyzer mass transfer coefficient K(0)A for glucose in whole blood under conditions of glucose delivery and glucose removal. Glucose was removed from blood or delivered to blood using glucose-free dialysate or dialysate with a glucose concentration of 200 mg/dl (11.1 mmol/L). FX8 dialyzers (Fresenius Medical Care, Bad Homburg, Germany) were studied at constant dialysate flow Q(d) (500 ml/min) and variable blood flows Q(b) (200, 300, and 400 ml/min) under countercurrent flow conditions in a series of laboratory bench studies. Glucose clearance K(d) and glucose distribution volume flow rate Q(e) were determined from glucose mass balance. In 32 studies done with bovine blood at different hematocrit levels glucose was calculated to distribute in plasma water and to be excluded from red cell water when passing the FX8 dialyzer. The dialyzer mass transfer area coefficient K(0)A for glucose computed from Q(e), Q(d), and K(d) was 301.6 +/- 45.2 ml/min and not different between modes of glucose delivery or glucose removal but lower than expected from the diffusivity of glucose estimated for aqueous solutions. PMID- 22236622 TI - Microbubbles of air may occur in the organs of hemodialysis patients. AB - During hemodialysis (HD), blood that passes the dialysis device gets loaded with microbubbles (MB) of air that are returned to the patient without inducing an alarm. The aim with this study was to clarify if these signals are due to microembolies of air, clots, or artifacts, by histopathology of autopsy material of HD patients. These first results are from a patient on chronic HD. Due to pulmonary edema he was ultrafiltered. Within 30 minutes after the start, he suffered from a cardiac arrest and died. Autopsy verified the clinical findings. Microscopic investigation verified microembolies of air that were surrounded by fibrin in the lungs, brain, and heart. The study verified that MBs can enter the blood during HD and are trapped in the lungs. In addition, MBs pass the pulmonary capillaries and enter the arterial part of the body and are dispersed throughout the body. This can contribute to organ damage and be part of the poor prognoses seen in HD patients. Data support the importance to reduce MBs in the dialysis circuit. PMID- 22236623 TI - Optimal timing algorithms of para-aortic counterpulsation device: an animal study. AB - Para-aortic counterpulsation device (PACD) is a promising therapy for severe heart failure (HF). However, the lack of knowledge about mechanisms has limited its clinical application. The aim of this study was to investigate the optimal timing algorithms. At the following four triggering algorithms, pre-R-wave deflation and dicrotic notch-inflation (PD), pre-R-wave-deflation and postdicrotic notch-inflation (PP), R-wave-deflation and dicrotic notch-inflation (RD), and R-wave-deflation and postdicrotic notch-inflation (RP), hemodynamic effects of PACD were assessed in vivo. There was more significant promotion of left mean coronary artery flow (Q(LM)), carotid artery flow (Q(CA)), cardiac output (CO), pulmonary artery flow/LA pressure ratio (Q(PA)/LAP), left ventricular myocardial oxygen consumption (LVVO(2)), external LV work (ELVW), and cardiac mechanical efficiency (CME) at RD and RP models than PD and PP models. R wave-deflation and postdicrotic notch-inflation model provided further benefits. There was significant correlation between LV functional parameters and carotid arterial reflux, but aortic pressure-related parameters. Filling at beginning of LV systolic phase and ejection at the end of isovolumic relaxation phase were the optimal triggering algorithms of PACD. It is suggested that carotid artery reflows and ventricular pressure-related parameters should be used as reference standard to adjust the timing of balloon inflation or deflation. PMID- 22236624 TI - In vitro testing of a novel blood pump designed for temporary extracorporeal support. AB - Extracorporeal blood pumps are used as temporary ventricular assist devices or for extracorporeal membrane oxygenation. The ideal pump would be intrinsically self-regulating, carry no risk of cavitation or excessive inlet suction, be afterload insensitive, and valveless thus reducing thrombogenicity. Currently used technology, including roller, centrifugal, and pneumatic pulsatile pumps, does not meet these requirements. We studied a nonocclusive peristaltic pump (M Pump) in two mock circulatory loops and compared the performance to a frequently used centrifugal pump and a modified prototype of the M-Pump (the BioVAD). The simple resistance loop consisted of the investigated pump, a fixed height reservoir at 150 mm Hg, and a variable inflow reservoir. The pulsatile circulation used a mock patient simulator with adjustable resistance elements connected to a pneumatic pulsatile pump. The M-Pump intrinsically regulated flow with changing preload, was afterload insensitive, and did not cavitate, unlike the centrifugal pump. The BioVAD also demonstrated these features and could augment output with the use of vacuum assistance. A nonocclusive peristaltic pump may be superior for short-term extracorporeal circulatory assist by mitigating risks of excessive inlet suction, afterload sensitivity, and thrombosis. PMID- 22236625 TI - In vivo performance evaluation of the innovamedica pneumatic ventricular assist device. AB - We evaluated the short- and mid-term in vivo performance of the Innovamedica ventricular assist device (VAD), a new, low-cost, paracorporeal, pneumatically actuated, pulsatile blood pump. We implanted the VAD in six healthy sheep by inserting the stainless-steel inflow cannula into the left ventricular apex and suturing the outflow graft to the descending thoracic aorta. The anesthetized animals were supported for 6 hours, and pump performance, hemodynamic parameters, and hemolysis were monitored. The pump maintained a blood flow of 4.4 +/- 0.8 L/min and an arterial blood pressure of 76 +/- 15 mm Hg. At 6 hours, the plasma free hemoglobin concentration was 5.11 +/- 0.6 mg/dl (baseline value, 4.52 +/- 0.7 mg/dl). The VAD was easy to implant and deair and performed well during the 6 hour period. After successful short-term results, we similarly implanted the VAD in two healthy sheep for 30 days. The animals reached the scheduled end point without device-related problems. Postmortem examination of the explanted organs revealed small infarcted areas in the kidneys of one animal, but renal function was unaffected; the animal also had two thrombi (3 and 7 mm) on the outlet valve. This device may offer a simple, economical alternative to currently available VADs. PMID- 22236626 TI - Evaluation of a ventricular assist device: stability under x-rays and therapeutic beam attenuation. AB - Improved outcomes and quality of life of heart failure patients have been reported with the use of left ventricular assist devices (LVADs). However, little information exists regarding devices in patients undergoing radiation cancer treatment. Two HeartWare Ventricular Assist Device (HVAD) pumps were repeatedly irradiated with high intensity 18 MV x-rays to a dosage range of 64-75 Gy at a rate of 6 Gy/min from a radiation oncology particle accelerator to determine operational stability. Pump parameter data was collected through a data acquisition system. Second, a computerized tomography (CT) scan was taken of the device, and a treatment planning computer estimated characteristics of dose scattering and attenuation. Results were then compared with actual radiation measurements. The devices exhibited no changes in pump operation during the procedure, though the titanium components of the HVAD markedly attenuate the therapy beam. Computer modeling indicated an 11.8% dose change in the absorbed dosage that was distinctly less than the 84% dose change measured with detectors. Simulated and measured scattering processes were negligible. Computer modeling underestimates pretreatment dose to patients when the device is in the field of radiation. Future x-ray radiation dosimetry and treatment planning in HVAD patients should be carefully managed by radiation oncology specialists. PMID- 22236627 TI - Follow-up of the sagittal spine by optical technique. AB - OBJECTIVES: Report the use of an optical technique for individual monitoring of the sagittal morphology of the spine in an upright position while avoid irradiation. SUBJECTS AND METHODS: The series consists of 15 asymptomatic subjects and 326 cases with spinal disorders. Sagittal analysis is expressed by the global trunk tilt (GTT), the intensity of the curves and their level of inflection. RESULTS: The confidence interval is 2 to 3 degrees and 3 to 6mm according to the parameters. A significant correlation was observed for the global axis measured by optical or radiological techniques. Variations in intensity and proportion of thoracic and lumbar sagittal curves were observed according to the disease, as well as their evolution over a period of 5 to 30 months. Various "strategies" of adaptation have been observed during repeated examinations. DISCUSSION: This non-radiating technique allows to be repeated after initial X-rays, for regular monitoring of a disturbance or a therapeutic effect. Its understandable imaging allows the patient to be aware of his situation. CONCLUSION: This optical technique is reliable and safe for monitoring the sagittal balance while helping further therapeutic target. PMID- 22236628 TI - Accuracy and precision of desktop spirometers in general practices. AB - BACKGROUND: Spirometry has become an essential tool for general practices to diagnose and monitor chronic airways diseases, but very little is known about the performance of the spirometry equipment that is being used in general practice settings. The use of invalid spirometry equipment may have consequences on disease diagnosis and management of patients. OBJECTIVES: To establish the accuracy and precision of desktop spirometers that are routinely used in general practices. METHODS: We evaluated a random sample of 50 spirometers from Dutch general practices by testing them on a certified waveform generator using 8 standard American Thoracic Society waveforms to determine accuracy and precision. Details about the brand and type of spirometers, year of purchase, frequency of use, cleaning and calibration were inquired with a study-specific questionnaire. RESULTS: 39 devices (80%) were turbine spirometers, 8 (16%) were pneumotachographs, and 1 (2%) was a volume displacement spirometer. Mean age of the spirometers was 4.3 (SD 3.7) years. Average deviation from the waveform generator reference values (accuracy) was 25 ml (95% confidence interval 12-39 ml) for FEV(1) and 27 ml (10-45 ml) for FVC, but some devices showed substantial deviations. FEV(1) deviations were larger for pneumotachographs than for turbine spirometers (p < 0.0031), but FVC deviations did not differ between the two types of spirometers. In the subset of turbine spirometers, no association between age and device performance was observed. CONCLUSIONS: On average, desktop spirometers in general practices slightly overestimated FEV(1) and FVC values, but some devices showed substantial deviations. General practices should pay more attention to the calibration of their spirometer. PMID- 22236629 TI - Attention deficit hyperactivity disorder and sensory modulation disorder: a comparison of behavior and physiology. AB - Children with attention deficit hyperactivity disorder (ADHD) are impulsive, inattentive and hyperactive, while children with sensory modulation disorder (SMD), one subtype of Sensory Processing Disorder, have difficulty responding adaptively to daily sensory experiences. ADHD and SMD are often difficult to distinguish. To differentiate these disorders in children, clinical ADHD, SMD, and dual diagnoses were assessed. All groups had significantly more sensory, attention, activity, impulsivity, and emotional difficulties than typical children, but with distinct profiles. Inattention was greater in ADHD compared to SMD. Dual diagnoses had more sensory-related behaviors than ADHD and more attentional difficulties than SMD. SMD had more sensory issues, somatic complaints, anxiety/depression, and difficulty adapting than ADHD. SMD had greater physiological/electrodermal reactivity to sensory stimuli than ADHD and typical controls. Parent-report measures identifying sensory, attentional, hyperactive, and impulsive difficulties varied in agreement with clinician's diagnoses. Evidence suggests ADHD and SMD are distinct diagnoses. PMID- 22236630 TI - Coping of siblings of children with developmental disabilities in the Bedouin community. AB - This is the first study that examines the coping of siblings of children with developmental disabilities in comparison with siblings of children without disabilities in the Bedouin community in Israel. For this purpose, the study examines the components of self-esteem, stress, and growth. Data were collected from 200 adolescents. The findings of this study show that siblings to children with developmental disabilities have a similar degree of self-esteem to those siblings to children without disabilities, whereas siblings to children with developmental disabilities have higher levels of stress perception and growth compared to siblings f children without developmental disabilities. In addition, a negative correlation was found between perception of stress and growth and a positive correlation between self-esteem and growth. PMID- 22236631 TI - Maternal-reported behavioral and emotional problems in Taiwanese preschool children. AB - There has been limited epidemiologic information concerning preschoolers' behavioral and emotional problems in Eastern societies. This study was therefore aimed to investigate behavioral and emotional problems in a large sample of Taiwanese preschoolers using the Child Behavior Checklist for Ages 1.5-5 (CBCL/1.5-5). The CBCL/1.5-5 was scored by mothers of 645 Taiwanese preschoolers aged 24-71 months. Psychometric features of the scale as well as the raw scores and prevalence rates of behavioral problems of Taiwanese preschoolers were compared with those of American counterparts. Several demographic variables with the Total Problems and syndromes scores were also examined. The CBCL/1.5-5 was found to have good to excellent levels of reliability (internal consistency, test retest reliability and inter-parent agreement) and an acceptable model fit of seven-syndrome factor structure (root mean square error of approximation=0.055) when used with Taiwanese preschoolers. The prevalence rate of Total Problems, Internalizing syndrome and Externalizing syndrome score in the clinical range was 25.1%, 11.2% and 25.4%, respectively. Cross-cultural comparisons showed that Taiwanese preschoolers had higher scores in six narrow-band syndromes (effect size d=0.17-0.43, all p's<0.005) and prevalence rates of four Internalizing related syndromes and Sleep Problems than American sample (odds ratio=2.4-4.9, all p's<0.005). Analyses of behavioral correlates revealed associations of first birth order with higher Internalizing, Externalizing and Total Problems scores (all p's<0.05). Furthermore, younger ages (24-47 months) and male gender were associated with higher Externalizing and Total Problems scores (all p's<0.05). Our data have provided important epidemiologic information to assist in clinical assessment and management of preschoolers' behavioral and emotional problems in an Eastern society. PMID- 22236632 TI - The advantage of reading over listening text comprehension in Down syndrome: what is the role of verbal memory? AB - The current study was designed to investigate the role played by verbal memory in the advantage shown by individuals with Down syndrome in reading over listening text comprehension (Roch & Levorato, 2009). Two different aspects of verbal memory were analyzed: processing load and coding modality. Participants were 20 individuals with Down syndrome, aged between 11 and 26 years who were matched for reading comprehension with a group of 20 typically developing children aged between 6;3 and 7;3 years. The two groups were presented with a listening comprehension test and four verbal memory tasks in which the degree of processing load and the coding modality were manipulated. The results of the study confirmed the advantage of reading over listening comprehension for individuals with Down syndrome. Furthermore, it emerged that different aspects of verbal memory were related respectively to reading and to listening comprehension: visual memory with low processing load was related to the former and oral memory with high processing load to the latter. Finally, it was demonstrated that verbal memory contributed to explain the advantage of reading over listening comprehension in Down syndrome. The results are discussed in light of their theoretical relevance and practical implications. PMID- 22236633 TI - JOSPT perspectives for patients. Neck pain: manipulation of your neck and upper back leads to quicker recovery. AB - Neck pain is very common and fortunately resolves quickly in most individuals. However, in certain cases neck pain can last longer and result in chronic pain, limited neck motion, and disability. In fact, chronic neck pain is the second leading cause of workers' compensation claims in the United States. Treatments that can quickly reduce pain, increase motion, and improve the ability of the muscles to protect the neck may help decrease long-term disability associated with neck pain. A variety of manual therapy treatments are currently used to manage neck pain. These treatments include mobilization, which slowly and repeatedly moves the neck joints and muscles, and manipulation, which delivers a single, small, quick movement to the joints and muscles. A research report published in the January 2012 issue of JOSPT examines the outcomes of these 2 treatment methods and draws conclusions about which one is best. PMID- 22236634 TI - An investigation of modifying effects of single nucleotide polymorphisms in metabolism-related genes on the relationship between peripheral nerve function and mercury levels in urine and hair. AB - Mercury (Hg) is a potent neurotoxicant. We hypothesized that single nucleotide polymorphisms (SNPs) in genes coding glutathione-related proteins, selenoproteins and metallothioneins may modify the relationship of mercury biomarkers with changes in peripheral nerve function. Dental professionals (n=515) were recruited in 2009 and 2010. Sensory nerve function (onset latency, peak latency and amplitude) of the median, ulnar and sural nerves was recorded. Samples of urine, hair and DNA were collected. Covariates related to demographics, nerve function and elemental and methyl-mercury exposure were also collected. Subjects included 244 dentists (47.4%) and 269 non-dentists (52.2%; mostly dental hygienists and dental assistants). The mean mercury levels in urine (1.06 MUg/L) and hair (0.51 MUg/g) were not significantly different from the US general population (0.95 MUg/L and 0.47 MUg/g, respectively). In multivariate linear models predicting nerve function adjusting for covariates, only 3 out of a total of 504 models showed stable and statistically significant interaction of SNPs with mercury biomarkers. Overall, given the possibility of false positives, the results suggested little evidence of effect modification of the SNPs on the relationship between mercury biomarkers with peripheral nerve function at exposure levels that are relevant to the general US population. PMID- 22236635 TI - Concentrations and speciation of polybrominated diphenyl ethers in human amniotic fluid. AB - Polybrominated diphenyl ethers (PBDEs) are persistent organic chemicals used as flame retardants in textiles, plastics, and consumer products. Although PBDE accumulation in humans has been noted since the 1970s, few studies have investigated PBDEs within the gestational compartment, and none to date has identified levels in amniotic fluid. The present study reports congener-specific brominated diphenyl ether (BDE) concentrations in second-trimester clinical amniotic fluid samples collected in 2009 from fifteen women in southeast Michigan, USA. Twenty-one BDE congeners were measured by GC/MS/NCI. The average total PBDE concentration was 3795 pg/ml amniotic fluid (range: 337-21,842 pg/ml). BDE-47 and BDE-99 were identified in all samples. Based on median concentrations, the dominant congeners were BDE-208, 209, 203, 206, 207, and 47 representing 23, 16, 12, 10, 9 and 6%, respectively, of the total detected PBDEs. PBDE concentrations were identified in all amniotic fluid samples from southeast Michigan, supporting a need for further investigations of fetal exposure pathways and potential impacts on perinatal health. PMID- 22236636 TI - Anthropogenic atmospheric nickel emissions and its distribution characteristics in China. AB - Nickel and its compounds are considered as potential human carcinogens, and atmospheric nickel is one of the major routes for human exposure. By applying the best available fuel-based or product-based emission factors and annual activity levels, a multiple-year comprehensive inventory of anthropogenic atmospheric nickel emissions in China is presented with temporal trend and spatial resolutions for the period of 1980-2009 from both fuels combustion sources and industrial producing processes. We estimate that the total atmospheric nickel emissions from all the sources have increased from 1096.07 t in 1980 to 3933.71 t in 2009, at an average annual growth rate of 4.5%. Therein, coal combustion is the leading source, attributing 63.4% of the national total nickel emissions in 2009; liquid fuels consumption ranks the second, contributing 12.4% of the totals; biofuels burning accounts for 8.4% and the remaining sources together contribute 15.8% of the totals. Significant spatial variations are demonstrated among provincial emissions and the most concentrated regions are the highly industrialized and densely populated areas like the Yangtze River Delta, the Pearl River Delta and the Beijing-Tianjin-Hebei region. Moreover, the overall uncertainties are estimated at -32.6%-37.7% by using Monte Carlo simulation, most of which come from non-ferrous metals smelting category, implying the urgent need for further investigation and field tests. This article may help to combat the increasing stress on air heavy metals pollution in China and provide useful information to calculate global mass balance models for hazardous trace elements. PMID- 22236637 TI - Muscle precursor cells for the restoration of irreversibly damaged sphincter function. AB - Multiple modalities, including injectable bulking agents and surgery, have been used to treat stress urinary incontinence. However, none of these methods is able to fully restore normal striated sphincter muscle function. In this study, we explored the possibility of achieving functional recovery of the urinary sphincter muscle using autologous muscle precursor cells (MPCs) as an injectable, cell-based therapy. A canine model of striated urinary sphincter insufficiency was created by microsurgically removing part of the sphincter muscle in 24 dogs. Autologous MPCs were obtained, expanded in culture, and injected into the damaged sphincter muscles of 12 animals. The animals were followed for up to 6 months after injection, and urodynamic studies, functional organ bath studies, ultrastructural and histological examinations were performed. Animals receiving MPC injections demonstrated sphincter pressures of approximately 80% of normal values, while the pressures in the control animals without cells dropped and remained at 20% of normal values. Histological analysis indicated that the implanted cells survived and formed tissue, including new innervated muscle fibers, within the injected region of the sphincter. These results indicate that autologous muscle precursor cells may be able to restore otherwise irreversibly damaged urinary sphincter function clinically. PMID- 22236638 TI - Synthesis of vertically aligned ultra-long ZnO nanowires on heterogeneous substrates with catalyst at the root. AB - The synthesis of ultra-long high-quality ZnO nanowires with uniform size and orientation on heterogeneous substrates is highly desirable, not only for investigating the fundamental properties of ZnO nanowires, but also for fabricating integrated functional nanodevices. Here we present a novel and general technique for growing vertically aligned ultra-long ZnO nanowires on various substrates. More importantly, the metal catalyst is experimentally determined not at the tip ends of the nanowires but at the junction area between the nanowires and the underlying substrate. Based on detailed analysis and control group results, we then propose a three-stage growth mechanism, in which vapor-liquid-solid growth and vapor-solid growth compete with each other to become dominant. PMID- 22236639 TI - Effectiveness of myofascial release in the management of lateral epicondylitis in computer professionals. AB - OBJECTIVE: To investigate whether myofascial release (MFR) reduces the pain and functional disability of lateral epicondylitis (LE) in comparison with a control group receiving sham ultrasound therapy in computer professionals. DESIGN: Randomized, controlled, single blinded trial. SETTING: Nonprofit research foundation clinic in Kerala, India. PARTICIPANTS: Computer professionals (N=68) with LE. INTERVENTIONS: MFR group or control group. The techniques were administered by certified MFR practitioners and consisted of 12 sessions per client over 4 weeks. MAIN OUTCOME MEASURE: The Patient-Rated Tennis Elbow Evaluation (PRTEE) scale was used to assess pain severity and functional disability. The primary outcome measure was the difference in PRTEE scale scores between week 1 (pretest score), week 4 (posttest score), and follow-up at week 12 after randomization. RESULTS: The simple main effects analysis showed that the MFR group performed better than the control group in weeks 4 and 12 (P<.005). Patients in the MFR and control groups reported a 78.7% and 6.8% reduction, respectively, in their pain and functional disability in week 4 compared with that in week 1, which persisted as 63.1% in the follow-up at week 12 in the MFR group. CONCLUSIONS: This study provides evidence that MFR is more effective than a control intervention for LE in computer professionals. PMID- 22236640 TI - Prognostic factors for upper urinary tract urothelial carcinoma after nephroureterectomy. AB - INTRODUCTION: The purpose of this study was to evaluate prognostic factors for patients with upper urinary tract urothelial carcinoma (UUT-UC) after nephroureterectomy and to seek a better way of finding more favorable clinical results for these patients. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 121 UUT-UC patients who underwent a nephroureterectomy at our institution, and analyzed the prognostic significance of various clinicopathological parameters for progression-free and disease-specific survival rates by using univariate and multivariate analysis. RESULTS: A Cox proportional hazards model showed that extravesical tumor recurrence after surgery was an independent prognostic factor for disease-specific survival (p < 0.0001). An additional model showed that lymphovascular invasion (LVI) was one of the independent predictors of lower extravesical-recurrence-free survival rates (p = 0.0004). Our final finding was that pathological tumor stage and positive surgical margin were significantly associated with the presence of LVI (p < 0.0001 and p = 0.0029, respectively). CONCLUSIONS: We conclude that there is a high possibility of LVI in patients with large tumors. Our findings should be helpful in terms of determining whether or not to perform neoadjuvant chemotherapy for patients with large tumors, given the fact that we frequently find a severe reduction in renal function after nephroureterectomy. PMID- 22236641 TI - Women at war: understanding how women veterans cope with combat and military sexual trauma. AB - The wars in Iraq (Operation Iraqi Freedom, OIF) and Afghanistan (Operation Enduring Freedom, OEF) have engendered a growing population of US female veterans, with women now comprising 15% of active US duty military personnel. Women serving in the military come under direct fire and experience combat related injuries and trauma, and are also often subject to in-service sexual assaults and sexual harassment. However, little is known regarding how women veterans cope with these combat and military sexual trauma experiences once they return from deployment. To better understand their experiences, we conducted semi structured interviews with nineteen OEF/OIF women veterans between January November 2009. Women veterans identified stressful military experiences and post deployment reintegration problems as major stressors. Stressful military experiences included combat experiences, military sexual trauma, and separation from family. Women had varying abilities to address and manage stressors, and employed various cognitive and behavioral coping resources and processes to manage their stress. PMID- 22236642 TI - Understanding the outcomes of multi-centre clinical trials: a qualitative study of health professional experiences and views. AB - All trials use protocols to standardize practice within and between trial centres and to enable replication of an experiment across space and time. However, while 'centre effects' have been noted in the literature, the processes and mechanisms by which trial staff convert a protocol into practice, and create 'evidence', is a relatively understudied phenomenon. We undertook a qualitative investigation of a multi-centre, UK-based, insulin trial, where differences were found between participating centres in their attainment of the trial's primary clinical endpoint (HbA(1c)), a measure of patients' average blood glucose control. In depth interviews were conducted with 12 research nurses and nine clinicians recruited from 11 centres in 2009, and explored their views about trial participation and experiences of trial delivery from inception to closeout. Staff accounts highlighted mixed agendas and/or ambivalent views about involvement in pharmaceutically funded trials, and discursive and temporal strategies by which they attempted to separate research from clinical practice and to convert commercially funded work into better patient care. Staff in different centres also reported divergent practices by which they recruited patients into the trial and 'enacted' the protocol to enhance trial outcomes and/or to individualise and improve patient care. By exploring, and comparing, the experiences of staff who worked on the same trial but in different centres, this study highlights the importance of understanding, and exploring, the enactment of protocols in ways which situate individual practices within both local (institutional) and global contexts. PMID- 22236643 TI - Key concepts relevant to quality of complex and shared decision-making in health care: a literature review. AB - High-quality provider-patient decision-making is key to quality care for complex conditions. We performed an analysis of key elements relevant to quality and complex, shared medical decision-making. Based on a search of electronic databases, including Medline and the Cochrane Library, as well as relevant articles' reference lists, reviews of tools, and annotated bibliographies, we developed a list of key concepts and applied them to a decision-making example. Key concepts identified included provider competence, trustworthiness, and cultural competence; communication with patients and families; information quality; patient/surrogate competence; and roles and involvement. We applied this concept list to a case example, shared decision-making for live donor kidney transplantation, and identified the likely most important concepts as provider and cultural competence, information quality, and communication with patients and families. This concept list may be useful for conceptualizing the quality of complex shared decision-making and in guiding research in this area. PMID- 22236644 TI - Inflammation mobilizes local resources to control hyperalgesia: the role of endogenous opioid peptides. AB - The aim of the present study was to investigate the mechanisms underlying the endogenous control of nociception at a peripheral level during inflammation. Using a pharmacological approach and the rat paw pressure test, we assessed the effect of an intraplantar injection of naloxone, an opioid receptor antagonist, and bestatin, an aminopeptidase inhibitor, on hyperalgesia induced by carrageenan, which mimics an inflammatory process, or prostaglandin E(2) (PGE(2)), which directly sensitizes nociceptors. Naloxone induced a significant and dose-dependent (25, 50 or 100 MUg) increase in carrageenan-induced hyperalgesia, but not PGE(2)-induced hyperalgesia. Bestatin (400 MUg/paw) significantly counteracted carrageenan-induced hyperalgesia, inducing an increase in the nociceptive threshold compared to control, but it did not modify hyperalgesia induced by PGE(2) injection into the rat paw. Positive beta endorphin immunoreactivity was increased in paw inflammation induced by carrageenan in comparison with the control group. However, PGE(2) did not significantly alter the immunostained area. These results provide evidence for activation of the endogenous opioidergic system during inflammation and indicate that this system regulates hyperalgesia through a negative feedback mechanism, modulating it at a peripheral level. PMID- 22236645 TI - Bilateral maxillary mucoceles: an unusual presentation of cystic fibrosis. AB - OBJECTIVE: We report a rare case of bilateral maxillary mucoceles. This was the primary presentation in a child with an underlying diagnosis of cystic fibrosis. CASE REPORT: A five-month-old infant presented with isolated symptoms of nasal congestion. Initial examination and investigation with computed tomography identified the cause to be bilateral maxillary mucoceles. The child was investigated for cystic fibrosis and found to be positive. Given the young age and anatomy, a modified surgical approach was used to treat the mucoceles, comprising endoscopic and bilateral uncapping of the maxillary mucocele, uncinectomy, and middle meatal antrostomy. The child was then followed up with appropriate treatment for cystic fibrosis. At six-week follow up, there was no recurrence of symptoms. CONCLUSION: Maxillary mucoceles are extremely rare but can present in patients with chronic sinusitis or cystic fibrosis. To our knowledge, there are no prior reports of this condition being the primary indicator of underlying cystic fibrosis in the absence of upper respiratory tract symptoms. Doctors should be aware that mucoceles can present in very young individuals and may indicate an underlying diagnosis of cystic fibrosis. A high index of clinical suspicion will avoid delays in diagnosis and long-term management. PMID- 22236646 TI - Making SharePoint(r) Chemically AwareTM. AB - BACKGROUND: The use of SharePoint(r) collaboration software for content management has become a critical part of today's drug discovery process. SharePoint 2010 software has laid a foundation which enables researchers to collaborate and search on various contents. The amount of data generated during a transition of a single compound from preclinical discovery to commercialization can easily range in terabytes, thus there is a greater demand of a chemically aware search algorithm that supplements SharePoint which enables researchers to query for information in a more intuitive and effective way. Thus by supplementing SharePoint with Chemically AwareTM features provides a great value to the pharmaceutical and biotech companies and makes drug discovery more efficient. Using several tools we have integrated SharePoint with chemical, compound, and reaction databases, thereby improving the traditional search engine capability and enhancing the user experience. RESULTS: This paper describes the implementation of a Chemically AwareTM system to supplement SharePoint. A Chemically Aware SharePoint (CASP) allows users to tag documents by drawing a structure and associating it with the related content. It also allows the user to search SharePoint software content and internal/external databases by carrying out substructure, similarity, SMILES, and IUPAC name searches. Building on traditional search, CASP takes SharePoint one step further by providing a intuitive GUI to the researchers to base their search on their knowledge of chemistry than textual search. CASP also provides a way to integrate with other systems, for example a researcher can perform a sub-structure search on pdf documents with embedded molecular entities. CONCLUSION: A Chemically AwareTM system supplementing SharePoint is a step towards making drug discovery process more efficient and also helps researchers to search for information in a more intuitive way. It also helps the researchers to find information which was once difficult to find by allowing one to tag documents with molecular entities and integrating with image recognition software to find information from pdf documents. PMID- 22236647 TI - Hook plate fixation of acute displaced lateral clavicle fractures: mid-term results and a brief literature overview. AB - BACKGROUND: The clavicle hook plate achieves like most other operative techniques, a high percentage of union and a low percentage of complications however concerns about long term complications still exist, particularly the involvement of the acromioclavicular joint. METHODS: To evaluate the results and long term effects in use of this plate we performed a retrospective analysis with a mean follow up of 65 months (5.4 years) of 28 consecutive patients with acute displaced lateral clavicle fractures, treated with the clavicle hook plate. RESULTS: Short term functional results in all patients were good to excellent. All but one patient had a united fracture (96%). Nine patients (32%) developed impingement symptoms and in 7 patients (25%) subacromial osteolysis was found. These findings resolved after plate removal. Twenty-four patients were re evaluated at a mean follow-up period of 5.4 years. The Constant-Murley score was 97 and the DASH score was 3.5. Four patients (14%) developed acromioclavicular joint arthrosis of which one was symptomatic. Three patients (11%) had extra articular ossifications of which one was symptomatic. There was no relation between the impingement symptoms, subacromial osteolysis and development of acromioclavicular joint arthrosis or extra articular ossifications. CONCLUSIONS: The clavicle hook plate is a good primary treatment option for the acute displaced lateral clavicle fracture with few complications. At mid term the results are excellent and no long term complications can be addressed to the use of the plate. PMID- 22236648 TI - Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk. AB - Alterations in the nucleotide sequences of folate-metabolizing genes can increase the risk of malignant transformation. The aim of our study was to investigate the association of three single-nucleotide polymorphisms (SNPs) in the folate metabolizing genes - A2756G MTR, A66G MTRR, and 844ins68 CBS - which have putative functional significance in breast cancer risk. The allele and genotype frequencies of the SNPs were determined in a case group (840 women with sporadic breast cancer) and a control group (770 women). No statistically significant association of studied SNPs with breast cancer was revealed. A meta-analysis, which included data obtained from the literature and the present research, did not reveal any statistically significant associations of these SNPs with breast cancer. The results obtained provide evidence that these SNPs are not involved in the development of breast cancer. PMID- 22236649 TI - Comparative incidence of cancer in HIV-AIDS patients and transplant recipients. AB - BACKGROUND: Studies have found a relationship between decreased immunity and increased incidence of cancer. METHODS: A systematic review of observational studies evaluating the incidence of cancer in both organ recipients and people with HIV/AIDS compared with the general population. Eligible studies were searched up to March 2011 in the following databases: Pubmed, Embase, Scielo, Cancerlit and Google scholar. In this study, the standardized incidence ratios (SIR) of cancer in people with HIV/AIDS and of organ transplant recipients were compared with those found among the general population. RESULTS: Twenty-five studies of transplant and HIV-associated cancer risk, involving 866776 people with HIV/AIDS or organ recipients and 21260 new cases of cancer, were included. The risk for the development of new cancer cases was higher among people with HIV/AIDS (SIR=4, IC95% 3.78-4.24) and who received organs (SIR=3.28, IC95% 3.06 3.52) when compared with the general population. CONCLUSION: Similar SIR in both immunocompromised populations suggests that the weakened immune system is responsible for the increased risk of new cases of cancer among these groups. Research investments are needed to develop effective cancer prevention strategies in these populations. PMID- 22236650 TI - Age effects on rotational hand action. AB - We investigated age-related differences in finger coordination during rotational hand actions. Two hypotheses based on earlier studies were tested: higher safety margins and lower synergy indices were expected in the elderly. Young and elderly subjects held a handle instrumented with five six-component force sensors and performed discrete accurate pronation and supination movements. The weight of the system was counterbalanced with another load. Indices of synergies stabilizing salient performance variables, such as total normal force, total tangential force, moments produced by these forces, and total moment of force were computed at two levels of a hypothetical control hierarchy, at the virtual finger-thumb level and at the individual finger level. At each level, synergy indices reflected the normalized difference between the sum of the variances of elemental variables and variance of their combined output, both computed at comparable phases over repetitive trials. The elderly group performed the task slower and showed lower safety margins for the thumb during the rotation phase. Overall, the synergy indices were not lower in the elderly group. In several cases, these indices were significantly higher in the elderly than in the younger participants. Hence, both main hypotheses have been falsified. We interpret the unexpectedly low safety margins in the elderly as resulting from several factors such as increased force variability, impaired feed-forward control, and the fact that there was no danger of dropping the object. Our results suggest that in some natural tasks, such as the one used in this study, healthy elderly persons show no impairment, as compared to younger persons, in their ability to organize digits into synergies stabilizing salient performance variables. PMID- 22236651 TI - A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy. AB - BACKGROUND: Calstabins 1 and 2 bind to Ryanodine receptors regulating muscle excitation-contraction coupling. Mutations in Ryanodine receptors affecting their interaction with calstabins lead to different cardiac pathologies. Animal studies suggest the involvement of calstabins with dilated cardiomyopathy. RESULTS: We tested the hypothesis that calstabins mutations may cause dilated cardiomyopathy in humans screening 186 patients with idiopathic dilated cardiomyopathy for genetic alterations in calstabins 1 and 2 genes (FKBP12 and FKBP12.6). No missense variant was found. Five no-coding variations were found but not related to the disease. CONCLUSIONS: These data corroborate other studies suggesting that mutations in FKBP12 and FKBP12.6 genes are not commonly related to cardiac diseases. PMID- 22236652 TI - Benserazide dosing regimen affects the response to L-3,4-dihydroxyphenylalanine in the 6-hydroxydopamine-lesioned rat. AB - Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4 dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We now assess the effect of dose, timing, and supplemental administration of benserazide on the rotational response induced by L-DOPA in unilateral 6-hydroxydopamine-lesioned rats. L-DOPA (12.5 mg/kg, p.o.) concomitant with benserazide (3.125-15 mg/kg, p.o.) produced a dose-dependent increase in contraversive rotation compared with the effects of L-DOPA alone. The optimal L-DOPA response was achieved with 10 mg/kg of benserazide and this dose was used in subsequent experiments. When L DOPA treatment was delayed for 1, 2, or 3 h after benserazide, the rotational response declined suggesting loss of AADC inhibition. Unexpectedly, there was also a progressive decline in response when benserazide and L-DOPA were given together but at increasingly later time points of 08.00, 09.00, 10.00, and 11.00 h. To assess supplemental administration of benserazide, an additional dose was given 2 h after the initial benserazide/L-DOPA treatment. This produced a further increase in the number of contralateral rotations indicating that the effect of benserazide declines while plasma levels of L-DOPA are maintained. Therefore, optimization of the dose and timing of benserazide administration is essential to achieve a consistent L-DOPA response in 6-hydroxydopamine-lesioned rats. These findings may have implications for the way in which peripheral AADC inhibitors are used in the treatment of PD. PMID- 22236653 TI - Anti-cytokine auto-vaccinations as tools for the analysis of cytokine function in vivo. AB - Braking B cell tolerance to generate antibodies against autologous cytokines or chemokines offers an alternative to gene inactivation for functional analysis of these factors in vivo. It is clearly less potent than the genetic approach but offers the advantage of extreme flexibility. The basic principle is to enable a self-reactive B cell to attract T cell help by presenting foreign peptides, a process we called "deceptive" antigen presentation. We here review the different auto-vaccine procedures that are currently used and provide several examples of functional information acquired by this procedure or by mAbs derived from auto vaccinated mice. PMID- 22236654 TI - Mixed epithelial and stromal tumor of the kidney in a 14-year-old boy. PMID- 22236655 TI - Depression in older people in the general hospital: a systematic review of screening instruments. AB - BACKGROUND: depression is common in later life, particularly in people with poor physical health. In the acute hospital setting this is associated with poor outcomes, increased length of stay and compromised care. The recognition and diagnosis of depression is therefore a key first step in managing depression in the general hospital, and this may be facilitated by the use of an appropriate screening instrument. OBJECTIVE: the aim of this study is to review all relevant literature on rating scales used to detect depression in older people in general hospitals so as to identify the most appropriate tool and cut-off score with optimal performance. METHOD: an electronic search was conducted applying key search terms. Selection of articles was conducted in a staged manner and by utilising predetermined quality criteria. When appropriate pooled analysis was undertaken. FINDINGS: only 14 studies satisfied the inclusion criteria and only one instrument-the Geriatric Depression Scale (GDS)-has been studied to an adequate extent in older people in the acute general hospital setting. Best performance for the GDS was for a cut-off of 5/6 for the GDS-15 and 10/11 for the GDS-30. CONCLUSION: further research is required before recommending the use of brief depression screening instruments (single or two items) in the acute hospital setting. The GDS would appear the most validated instrument currently (in either 15 or 30 item versions), though other tools such as the BASDEC show promise. PMID- 22236656 TI - Transient reduced diffusion in the cortex in a child with prolonged febrile seizures. AB - We report on a 4-year-old boy with transient reduced diffusion in the cortex, thalamus, and hippocampus on diffusion-weighted imaging (DWI) performed after prolonged febrile seizures (PFS). He had experienced intermittent right hemiconvulsions lasting about 90 min during the febrile illness, but his neurological symptom resolved completely after several hours. DWI performed immediately after the PFS showed abnormally high signal intensities in the left extended cortex and pulvinar of the ipsilateral thalamus. Two days later, these DWI lesions resolved completely, but abnormally high signal intensities were observed in the left hippocampus. Three months later, the DWI was normal, and no atrophy or gliosis was seen. This patient had unique lesions on DWI after PFS, but it is nevertheless important to attend to such lesions on the DWI of patients with PFS. PMID- 22236658 TI - Unicameral bone cyst of the calcaneus. PMID- 22236659 TI - Immobilization of monolayer protected lipophilic gold nanorods on a glass surface. AB - We present a novel process of immobilization of gold nanorods (GNRs) on a glass surface. We demonstrate that by exploiting monolayer protection of the GNRs, their unusual optical properties can be completely preserved. UV-visible spectroscopy and atomic force microscopy analysis are used to reveal the optical and morphological properties of monolayer protected immobilized lipophilic GNRs, and molecular dynamics simulations are used to elucidate their surface molecule arrangements. PMID- 22236660 TI - Robotic-assisted laparoscopic sacrocolpopexy: temporary phenomenon or a new consolidated technique. PMID- 22236661 TI - Pirandello's analogy: a source for a better understanding of the social impact of stroke. AB - BACKGROUND: Suffering a stroke has major implications for the patient. To understand human suffering, one should understand society. Pirandello described society as a higher entity than the individual, thereby justifying human adaptability to society. We explore a qualitative finding that suggests that social trends may influence how stroke patients prioritize aspects of their rehabilitation. METHODS: We compare a contemporary patient's experience of stroke recovery with that of a fictional character from the works of Luigi Pirandello. Both patients had two main residual symptoms: hemiparesis and aphasia. RESULTS: The rehabilitation priorities of the two patients differed, and appeared to reflect the contemporaneous demands of society. Mobility was prioritized in 1910; communication was prioritized in 2010. However, essential aspects of 'being a stroke patient' remained unchanged; both patients retained a sense of self and both coped emotionally by being hopeful. CONCLUSIONS: We conclude that stroke patients respond to society's contemporaneous demands and expectations. Currently, society demands participation in a large social environment and this is reflected in stroke patients' priorities. This analogy could enable medical professionals to better understand the social impact of stroke, and consequently offer appropriate interventions to improve rehabilitation outcomes for individual patients. PMID- 22236662 TI - Endothelial progenitor cells and thrombosis. AB - The remodelling of existing vessels (i.e. angiogenesis) and the "de novo" vessel formation (i.e. vasculogenesis) occur not only during the embryonic development but also over the entire postnatal life. In 1997, the Asahara group first reported that endothelial progenitor cells circulate in peripheral blood and that they are recruited at sites of ischemia, thus proving that these cells are able to promote vasculogenesis. Since then, several different approaches have been set up to investigate endothelial progenitor cells. This review summarizes the different modalities utilized to enumerate these cells, delineates their involvement in the haemostatic pathways, and depicts their altered trafficking during cardiovascular diseases. Finally, recent observations suggesting a primary role for endothelial progenitors in particular situations such as pulmonary arterial hypertension or Philadelphia negative-myeloproliferative neoplasms are discussed. PMID- 22236663 TI - Use of bilateral suture lateralisation technique in severe paradoxical vocal fold movement, allowing removal of long-term tracheostomy: case report. AB - OBJECTIVE: We report a novel bilateral suture lateralisation technique that allowed permanent tracheostomy decannulation in a patient with severe paradoxical vocal fold movement. CASE REPORT: A 45-year-old woman presented to the accident and emergency department with worsening shortness of breath. Flexible nasoendoscopy revealed limited vocal fold abduction and an emergency tracheostomy was sited; this was subsequently changed to a long-term Silver Negus tube. Her tracheostomy care was complicated by discomfort and dislodgement. The diagnosis of paradoxical vocal fold movement was only made when the patient presented to our department. Cognitive behaviour therapy and botulinum toxin injection were tried without success. A right vocal fold lateralisation procedure was performed, which enabled temporary tracheostomy decannulation. A left vocal fold lateralisation procedure was subsequently performed and the patient was successfully decannulated, with significant improvement in quality of life. CONCLUSION: Paradoxical vocal fold movement is a rare condition that is most commonly managed by biofeedback sessions, relaxation manoeuvres or botulinum toxin injection. However, in cases similar to ours in which these treatments are unsuccessful, we suggest a 'last resort' technique to manage this rare condition. PMID- 22236664 TI - Historical background. AB - Surgery, radiation therapy, chemotherapy, steroid therapy and radiosurgery have been the mainstream of management of brain metastasis and the trend has been continuously changed along with the advancement of cancer management, development of new technology and changing in perception of quality of life. A glance at the historical perspective on brain metastasis management clearly shows two major shifts which have been made in last two decades. One is the changes of leading treatment modalities from whole-brain radiation therapy to multimodal management focusing on radiosurgery, and the other is changes of the attitude of the treatment from palliative purpose to disease control. The epoch-making change in the understanding of brain metastasis is that brain metastasis is no longer a death sentence as considered in the past. PMID- 22236665 TI - Epidemiology of central nervous system metastases. AB - Brain metastases are overwhelmingly the most common type of brain tumor, out numbering primary brain tumors in incidence by more than four-to-one. They are associated with poor prognosis both from a length-of-life as well as a quality-of life standpoint. Once the brain metastasis is detected, without treatment, most patients die within months, either from widespread systemic disease, or due to the brain metastasis itself. The complications of brain metastases are also devastating. Patients can suffer from seizures, weakness or paralysis, language and communication deficits, as well as cognitive decline. These complications negatively impact on quality of life through effects on functional independence, impairment of capacity to participate in activities and relationships, as well as distortion of individual personality and identity. At the same time, there are great financial burdens associated with both the care and treatment of patients with brain metastases. Early detection of brain metastases in cancer patients is critical for limiting these complications, minimizing these burdens and improving the outlook regarding both survival and quality of life. Understanding the epidemiology of brain metastases can lead to the development of new strategies for the early identification and successful treatment of these patients. PMID- 22236666 TI - Histopathology of brain metastases after radiosurgery. AB - Histopathological investigations revealed acute-, subacute-, and chronic-type tissue responses, accompanied by inflammatory cell reaction in radiosurgery treated cerebral metastases originating from different primary cancers. Immunohistochemistry demonstrated that the preponderance of CD68-positive macrophages and CD3-positive T lymphocytes in the inflammatory infiltration developed in better controlled metastases ( > 5 months). In contrast, it was sparse or absent in poorly controlled neoplasms ( < 5 months) after radiosurgery. This inflammatory reaction may be stimulated by the ionizing energy, probably influenced by the general condition of the patients' immune system as well, and seems to play a role in local tumor control after focused radiation. PMID- 22236667 TI - Radiobiological principles: their application to gamma knife therapy. AB - Gamma Knife treatments are regarded as single dose exposures, however, in reality the total dose delivered is the addition of a variable number of individual smaller doses from the variable number of iso-centres or shots, selected to cover a lesion. The dose prescription, in terms of dose and dose rate, to different points on a given physical iso-surface, will vary according to location. In radiobiological terms this treatment pattern does not represent a single exposure, but a schedule with a variable number of different sized dose fractions given at different dose rates with multiple incompletes repair intervals (the time between shots). Using the concept of biologically effective dose (BED), incorporating a fast and a slow component of repair, the biological effectiveness of a 12-shot protocol was found to vary with the decay in the activity of the (60)Co sources and the time interval between shots. However, the largest effect was found when this standard protocol was compared with one involving only 2 shots. It should be recognised in individual Gamma Knife treatments that there are many variables which have the potential to influence the biological effective of the treatment and thus the importance of a single variable may be difficult to determine in isolation. Reports in the literature support the results of these simulated calculations into the factors likely to change the biologically effective dose with the use of the Gamma Knife. PMID- 22236668 TI - Imaging diagnosis of brain metastasis. AB - Hematogeneous spread of primary neoplasm can result in central nervous system (CNS) disease burden in various anatomically distinct regions; calvarial, pachymeningeal, leptomeningeal, and intraparenchymal. The choice of imaging modality is dependent on the individual clinical situation, but, largely depends on the patients overall clinical status and the information needed to make treatment decisions. Contrast-enhanced magnetic resonance (MR) imaging is the preferred imaging modality of choice; however, computed tomography (CT) is often utilized as the first-pass screening modality for CNS disease. Despite the superior soft tissue resolution, multiplanar capability, and noninvasive nature of MR imaging, T(1)- and T(2)-weighted sequences are limited to delineating morphologic anatomical deraignment of tissues by tumor. Several physiology based MR imaging sequences have been developed which compliment anatomic MR imaging. Proton magnetic resonance spectroscopic and dynamic susceptibility contrast enhanced perfusion-weighted imaging are two physiologic sequences which add additional diagnostic information allowing for improved tumor characterization. Common pitfalls in evaluating for metastatic disease burden include the misidentification of non-neoplastic hematomas, remote microvascular ischemia, and acute onset of ischemic stroke. In the pediatric population, CNS metastases are rare; however, the onset of acute neurological symptoms in a child with known primary tumor should prompt imaging of the neuroaxis. PMID- 22236669 TI - Surgical treatment of solitary brain metastases. AB - Brain metastases are the most common form of brain tumors and are diagnosed in about 40% of all patients with systemic malignancies. Although the percentage of solitary brain metastases has dropped in recent estimates from about 50-30% of all patients with brain metastases, this percentage still represents a significant number of patients, and the overall incidence of brain metastases is still on the rise. Historically, brain metastases carried a grim prognosis with a median survival of only a few weeks. The utilization of whole-brain radiation therapy (WBRT) and steroids improved the prognosis to few months. However, it was not until the advent of advanced surgical techniques in conjunction with other treatment modalities such as WBRT and stereotactic radiosurgery that patients became less likely to succumb to neurological complications. In the last few decades, surgical resection has evolved from a mere emergent palliative treatment to a standard treatment modality that has led to improved clinical outcomes in carefully selected patients with brain metastases. This positive contribution has been made possible by randomized clinical trials, advancement of surgical techniques and tools, imaging modalities, and better understanding of the pathophysiology and perioperative care. PMID- 22236670 TI - Whole-brain radiation therapy of brain metastasis. AB - The purpose of this report was to review the role of whole brain radiotherapy (WBRT) in the management of brain metastases. In particular, we review the role of WBRT as a prophylactic therapy, and the role of surgery and stereotactic radiousurgery (SRS) with respect to WBRT, by discussing the relevant randomized controlled trials. WBRT is associated with toxicities and this may influence the decision to use WBRT and, therefore, we review both the acute side effects of WBRT and the more serious late side effects of neurocognitive impairment and leukoencephalopathy. As patients are living longer with brain metastases the role of WBRT is moving forward; however, using modern radiation technology we may be able to reduce the morbidity of this therapy. We present an extreme case of re-re treatment WBRT with hippocampal sparing and simultaneous integrated boosts to multiple lesions as one of the future directions under evaluation. PMID- 22236671 TI - Advances in radiation therapy of brain metastasis. AB - The traditional treatment for brain metastases is to administer whole-brain radiation therapy using two-dimensional techniques. Owing to the short survival duration of patients historically treated, most patients with brain metastases did not survive long enough to manifest neurologic/neuropsychologic complications. With improved systemic therapy, and more aggressive focal treatment options, longer survival times are now becoming observed along with late effects of cancer treatment. Recently, advances in radiation therapy for brain metastases have taken shape in an attempt to improve the therapeutic ratio of improving intracranial disease control while reducing neurotoxicities. This review provides an overview of advances in the radiotherapeutic management of brain metastases. PMID- 22236672 TI - Role of chemotherapy on brain metastasis. AB - Cytotoxic chemotherapy has been considered ineffective for brain metastasis, traditionally because of poor penetration across the blood-brain barrier. However, cytotoxic chemotherapy could be effective in some specific situation, e.g. macroscopic brain metastasis of chemosensitive disease, such as small cell lung cancer, germ cell tumor and breast cancer. Recently, tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR) (gefitinib and erlotinib) or human epidermal growth factor receptor 2 (HER2) (lapatinib) have a promising activity to brain metastasis of lung cancer with activating EGFR mutations or breast cancer with HER2 over expression. More molecular targeting agents will also be used against brain metastasis with the advance of understanding of molecular mechanism of cancer. PMID- 22236673 TI - Radiosurgery for brain metastases. AB - We discuss the current literature on the role of stereotactic radiosurgery in the multidisciplinary management of brain metastases and focus on the level of evidence that addresses key management questions. We reviewed the literature on the different roles of radiosurgery, radiotherapy, and resection, and in particular the 2009 Guidelines project of the Joint Section on Tumors of the AANS/CNS. Retrospective case series, matched cohort studies, and randomized trials show specific survival and local tumor control benefits after radiosurgery. Radiosurgery is an effective and safe minimally invasive option for patients with brain metastases. Randomized trials include tumors of different histologies which can detract from their relevance to specific tumor types. PMID- 22236674 TI - Stereotactic radiosurgery for patients with metastatic brain tumors: development of a consensus radiosurgery guideline recommendation. AB - Our objective was to provide guidelines about the use of stereotactic radiosurgery in patients with imaging identified metastatic tumors of the brain. The working group consisted of physicians and medical physicists from the staff of major medical centers that provide radiosurgery. Computerized and hand searches of published literature electronic clinical databases were performed. Members of a working group reviewed published literature and clinical experience on metastatic brain tumor radiosurgery to develop a draft guideline and provide scientific foundation for patients and physicians. The optimal dose range for volumetric conformal brain metastases radiosurgery has been largely established based on location and volume of the tumor. The relationship to whole brain radiation therapy has been evaluated. A clinical algorithm for the potential role of stereotactic radiosurgery for metastatic brain tumors was defined. The recommendations developed by this consensus guidelines methodology provide a framework for professional judgment and treatment selection alternatives. PMID- 22236675 TI - Radiosurgical dose selection for brain metastasis. AB - Dose selection for brain metastasis radiosurgery is based largely upon clinical data obtained over a half century of radiosurgical treatments for various benign and malignant conditions. It is expected that within the entire radiosurgical process, the step of dose selection will occur within a framework of accurate calibration of dose delivery and accurate and detailed imaging for planning the radiosurgical treatment. Brain metastasis radiosurgery should seek lifelong, uncomplicated control. A low radiosurgery dose that will not control the tumor will not achieve this therapeutic goal, and neither will a radiosurgery dose that controls the tumor but causes symptomatic brain radiation necrosis. The volume of the metastasis being targeted and the volume of normal tissues receiving substantial radiosurgical doses are of paramount importance in dose selection. A high degree of conformality of the high-dose radiosurgical treatment volume to the metastasis has been shown to decrease complications, as does a steep dose gradient between the metastasis and adjacent normal brain tissue. A dose escalation trial conducted by the Radiation Therapy Oncology Group that differentially dose-escalated radiosurgical doses for tumors of different sizes established that single-fraction doses between 15 and 24 Gy are relatively safe in patients who have received prior fractionated radiation therapy to the brain. Corresponding data do not exist for patients who are treated with primary radiosurgery and no whole brain radiation therapy. A dose-escalation trial for three-fraction radiosurgical treatment of brain metastases is being conducted at Stanford. Knowledge of prior whole brain radiation therapy treatment details, including the dose delivered and the time interval since that treatment was given may affect the choice of radiosurgical dose, as may recent administration of systemic, radiation-potentiating chemotherapy. Physician knowledge and careful judgment, together with careful treatment planning and delivery can minimize the risks associated with brain metastasis radiosurgery. PMID- 22236676 TI - Treatment of brain metastasis from lung cancer. AB - Brain metastasis from lung cancer occupies a significant portion of all brain metastases. About 15-20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis during the course of the disease. The prognosis of brain metastasis is poor with median survival of less than 1 year. Whole-brain radiation therapy (WBRT) is widely used for the treatment of brain metastasis. WBRT can also be used as adjuvant treatment along with surgery and stereotactic radiosurgery (SRS).Surgery provides a rapid relief of mass effects and may be the best choice for a large single metastasis. SRS confers local control rates comparable to those for surgery with minimal toxicities and versatility that makes it applicable to multiple lesions, deep-seated lesions, and to patients with poor medical conditions. Recursive partitioning analysis (RPA) classes are widely used for prognostic stratification. However, the validity of RPA classes, especially for NSCLC, has been questioned and other scoring systems are being developed. Synchronous presentation of primary NSCLC and brain metastases is a special situation in which surgery for the lung lesion and surgery or SRS for brain lesions are recommended if the thoracic disease is in early stages. Small cell lung cancer (SCLC) has a higher likelihood for brain metastasis than NSCLC and prophylactic cranial irradiation and subsequent WBRT are usually recommended. Recently, SRS for brain metastasis from SCLC has been tried, but requires further verification. PMID- 22236677 TI - gamma knife radiosurgery of brain metastasis from breast cancer. AB - The incidence of brain metastasis in patients with metastatic breast cancer ranges from 14 to 16%.Age, number of metastatic sites, short disease-free survival and molecular subtypes are associated with the occurrence of brain metastasis. Patients classified in the triple-negative group more frequently presented brain metastasis as the first site (26%) than those in the human epidermal growth factor receptor 2 (HER2)-positive (6%) or luminal (12%) subtypes. Whole brain radiation therapy (WBRT) is still the standard treatment for breast cancer patients with brain metastasis. The 1- and 2-year survival rates of patients with brain metastasis were 25 and 10%, respectively, with a median survival of 6 months. In selected patients with single brain metastasis, majority of lung cancer, three randomized controlled trials underlined the significant survival benefit in adding local treatment such as surgery or stereotactic radio surgery to WBRT. Similarly, the upfront stereotactic radiosurgery (SRS) alone did not affect survival rate in three other randomized studies and represents an alternative treatment for patients with stage 1-4. Metastatic breast cancer patients with Karnofsky Performance Scale >=70, single or oligometastatic brain metastases and well-controlled extracranial disease or favorable disease-specific graded prognostic assessment group presented a median overall survival of 16 months. Delaying WBRT could spare patients of neurocognitive toxicity due to full-dose whole brain irradiation. Nevertheless, the real WBRT neurocognitive impact is still unclear. These patients should be followed with serial magnetic resonance image every 3 months and treated with WBRT or additional SRS at recurrence to control brain disease. PMID- 22236678 TI - Brain metastasis from renal cell carcinoma. AB - Renal cell carcinoma (RCC) is one of primary cancers which metastasis to the brain frequently, although RCC accounts for only 1% of all cancer. The metastatic tumor from RCC has the propensity of intratumoral hemorrhage and relatively massive surrounding edema compared with other metastatic tumors. These characteristics make an emphasis on the surgical resection in the management of metastatic tumor. However, the surgery is not always possible due to the characteristics of tumor and patient. The outcome of conventional whole brain radiotherapy is unsatisfactory due to the resistant feature of RCC to the radiation, although it plays an important role in other malignancies. The stereotactic radiosurgery (SRS) including various modalities have showed the excellent outcomes in the control of tumor itself and surrounding edema. The repeatability of SRS is also attractive merit, because the new brain metastasis can be encountered in anytime regardless of the first-line treatment modalities. A few adverse effects following SRS have been reported however, incidence and severity could be acceptable without severe morbidity. Therefore, SRS must be emphasized in the management of brain metastasis from RCC and individual various combined treatment strategies could be suggested. PMID- 22236679 TI - Stereotactic radiosurgery of brain metastasis from melanoma. AB - Brain metastasis represents the most common intracranial neoplasm in adult patients. Melanoma is the third most frequent cancer histology and consequently comprises a significant portion of brain metastasis patients. Unlike the more frequent lung and breast cancers, melanoma represents a particularly challenging entity because of its radioresistant nature. Stereotactic radiosurgery appears to overcome the inherent radioresistance of brain metastasis from melanoma and, thereby, affords a high rate of local tumor control. Reports from leading centers indicate a favorable benefit to risk profile for radiosurgery in melanoma patients. Local tumor control after radiosurgery generally exceeds 80%, and neurological complications as a result of radiosurgery are infrequent. A higher performance status and lower intracranial tumor burden in melanoma patients at the time of radiosurgery are associated with longer survival. Radiosurgery may be used in conjunction upfront with radiotherapy, resection, and chemotherapy or as a salvage therapy in selected melanoma patients. Careful radiological and neurological follow-up is required to assess local tumor control and distant intracranial disease progression. Further clinical studies will be required to better define the role of upfront and salvage radiosurgery in selected cohorts of patients with brain metastasis from melanoma. However, it appears likely that radiosurgery will play an expanded role in the overall management of these patients. PMID- 22236681 TI - CyberKnife radiosurgery for brain metastases. AB - Classic radiosurgery is a neurosurgical treatment concept for single-fraction irradiation of cerebral lesions not amenable to open surgery. Until recently it has been realized mainly by frame-based technologies (Gamma Knife; stereotactic linear accelerators). The CyberKnife described in 1997 is an image-guided frameless robotic technology for whole-body radiosurgery. It can be used for classic single-fraction radiosurgery and for hypofractionated treatments. The CyberKnife treatment procedure is completely non-invasive and can be repeated throughout the body if necessary. Brain metastases are an important and frequently treated indication of modern radiosurgery. Data concerning radiosurgical treatment of brain metastases with the CyberKnife are reviewed. Scientific evidence shows that the full-body applicability of the CyberKnife is not at the expense of an inferior intracranial treatment quality when compared to standard frame-based technology. The clinical results of CyberKnife single fraction radiosurgery are in line with the published literature. The attractive therapeutic profile of CyberKnife radiosurgery is reflected by a high tumor control and a low toxicity and the repeatability of the treatments for recurrent metastases. Although hypofractionated treatments (in 3-5 fractions) of brain metastases have been performed with the CyberKnife to treat large metastases, the clinical significance of this new radiosurgical concept is unclear and requires further study. A new approach is to treat the resection cavity with radiosurgery after surgical removal of brain metastases. In this concept radiosurgery replaces fractionated radiation therapy as an adjunct to surgery. The initial results are very promising. The CyberKnife has been established as a modern non-invasive technology for intra- and extracranial radiosurgery. It adds to the oncological armamentarium and confers upon radiosurgery a greater emphasis as an oncological treatment concept. PMID- 22236680 TI - gamma knife radiosurgery of other brain metastases. AB - We evaluated the role of Gamma Knife stereotactic radiosurgery in the multidisciplinary management of brain metastases ovarian and endometrial, prostate, thyroid, sarcoma, or unknown primary cancers. From a series of over 3,000 patients who had Gamma Knife radiosurgery for brain metastases we reviewed indications and outcomes in patients with less common cancer types. All tumor types responded favorably to radiosurgery. Patients with male and female genitourinary primaries tended to develop brain metastases late in their course and did worse. Patients with thyroid metastases appear to live much longer with a more indolent course. Radiosurgery is an effective and safe minimally invasive option for patients with brain metastases from these less common primary origins. PMID- 22236682 TI - Management of adverse radiation effects after radiosurgery. AB - Stereotactic radiosurgery (SRS) is a well-established tool in the armamentarium for the treatment of metastatic tumors to the brain. Although SRS has proven to be highly effective in the management of brain metastases, it is not without risk. Despite selective targeting of lesions and the sharp dose fall-off associated with radiosurgical treatments, adverse radiation effects (AREs) can and do occur, albeit at a low rate, just as has been reported after conventional fractionated radiation therapy. One of the most vexing clinical scenarios for SRS practitioners is the distinction between ARE and tumor recurrence or progression after radiosurgery. Differentiation of these two entities is critical, as further treatment options range from oral medications to invasive surgical resection. In this review, we define AREs and discuss the possible mechanisms that produce them. Efforts to distinguish between ARE and tumor progression also are explored. Finally, a management algorithm for AREs is proposed. PMID- 22236683 TI - Radiosurgery after craniotomy. AB - Adjuvant irradiation of the resection cavity after craniotomy is a newer application of stereotactic radiosurgery. This technique has been proposed to avoid long-term neurotoxicity of whole-brain radiation therapy, and seems to afford comparable local control rates in the multiple published retrospective series so far. Currently, many questions remain to be answered to define the optimal patients who are candidate for tumor bed radiosurgery. The optimal timing after craniotomy, the volume of tissue to include in the treatment isodose and the radiation dose required to provide long-term local control are parameters which remain controversial at the moment. PMID- 22236684 TI - Combined role of whole-brain radiation therapy and radiosurgery for the treatment of brain metastasis. AB - While the optimal treatment of brain metastases remains controversial, there is a clear role for radiotherapy in the management of this disease. Herein, we discuss, based upon the prospective randomized trials, the interplay of surgical resection, whole-brain radiation therapy and stereotactic radiosurgery. Specific treatment recommendations depend on various clinical parameters and patient preference. Consistently, multiple trials of whole-brain radiation therapy have demonstrated improved local control, decreased progression elsewhere in the brain, but no overall survival benefit and concern for worse neurocognitive outcome. However, both new medications and technological advancements in the delivery of radiation therapy aim to reduce the neurocognitive sequelae of whole brain radiation therapy. Stereotactic radiosurgery has been demonstrated to improve overall survival in patients with a single brain metastasis when delivered in conjunction with whole-brain radiation therapy. Unfortunately, there is no current role to the addition of chemotherapy to radiation therapy for brain metastases. PMID- 22236685 TI - Modern radiosurgery equipment for treating brain metastases. AB - Radiosurgery plays an important role in the management of brain metastases, which are the most common indication for such treatment in many centers. Because brain metastases are well enhanced on magnetic resonance images and show clear margins from the surrounding normal brain, they are suitable for radiosurgery. The dedicated radiosurgery machines used for treating brain metastases have different characteristics from the conventional external beam radiotherapy machines, although the same gamma rays are used in both methods. In a radiosurgery procedure, highly concentrated radiation is given to a predefined target so that every cell inside it is affected. To achieve this, a radio-surgery machine should provide a highly accurate and precise delivery of radiation to the target with a steep dose gradient relative to surrounding tissues. Among the diverse dedicated machines that are in clinical use for radiosurgery of brain metastases, three - the Gamma Knife((r)), CyberKnife((r)), and Novalis(TM) - will be reviewed in this report. The basic principles of each machine for achieving a high convergence of radiation and for adjusting the radiation beam to conform to the target are described. The mechanical accuracy and characteristics of treatment plans are discussed briefly. PMID- 22236686 TI - Stereotactic radiosurgery for large brain metastases. AB - Surgical resection still remains the mainstay of treatments for large brain metastases if feasible. Recently, stereotactic radiosurgery (SRS) using low-dose, 11- to 12-Gy marginal prescription dose, was tried to document the benefit for patients with large brain metastases when it was used as a primary or salvage treatment. Many large brain metastases responded promptly and showed favorable outcome after SRS. More than half of the patients recovered from their neurological deficits within 1 month after SRS. However, not negligible portion of patients were suffered from the adverse radiation effects and the final outcome was not same as that of optimal sized tumors for SRS. The safety of the current dose scheme for large brain metastases should be reevaluated in the near future, considering the relatively high rate of radiation-related injuries observed. Even with modern technology, SRS alone may not have any benefit in tumor volume reduction and survival for brain metastases larger than 26 cm(3) (an approximate maximum diameter of 3.5 cm). PMID- 22236687 TI - How many metastases can be treated with radiosurgery? AB - We describe postradiosurgical treatment outcomes of our consecutive series of 1,676 patients (654 females and 1,022 males, mean age 63 years, range 19-92 years) who underwent Gamma Knife radiosurgery (GKRS) for brain metastases, focusing particularly on GKRS for multiple lesions. The most common primary cancer was lung (1,057; 63.1%), followed by alimentary tract (198; 11.8%), breast (180; 10.7%), uro-genital (113; 6.7%) and others (128; 7.6%). Mean and median lesion numbers were 7 and 3, respectively, range 1-85. The overall median survival times were 9.0 months in females and 5.9 in males after GKRS (p < 0.0001). The Kaplan-Meier method was used to assess tumor numbers by group: 1-4, 5-9, 10-14, 15-19, 20-24, 25-29, 30-39 and >=40. The post-GKRS median survival times were 8.3, 5.3, 6.9, 5.2, 5.6, 3.0, 5.3 and 4.3 months, respectively (p < 0.0001). Also, the Kaplan-Meier method was used to compare 15 pairs of groups based on tumor numbers: 1 vs. >=2, <=2 vs. >=3, <=3 vs. >=4, ---, and <=15 vs. >=16. In each of the 15 pairs, the median survival times of patients with lower tumor numbers were significantly longer than those of patients with higher tumor numbers (p < 0.0001). Furthermore, 14 other pairs of groups, based on tumor numbers, were also assessed by this method: 1 vs. 2, 2 vs. 3, 3 vs. 4, ---, and 14 vs. 15. Among the 14 pairs, only the 1 vs. 2 pair showed a significant median survival time difference (p = 0.0002); no significant differences were detected for the other 13 pairs. Although tumor number was demonstrated to have a significant impact on the duration of survival, approximately 85% of patients with brain metastasis died of causes other than brain disease progression, regardless of tumor number. PMID- 22236688 TI - Management of recurrent brain metastasis after radiosurgery. AB - Stereotactic radiosurgery (SRS) has become a first-line treatment option for brain metastases, both as a boost following whole-brain radiation therapy (WBRT), and as stand-alone treatment. When SRS is used as a single modality treatment, the local and distant brain recurrence rates range from 73 to 76.4%. When used in combination with WBRT, recurrence rates range from 27 to 46.8%. As systemic therapies improve, the number of patients who develop new or recurrent brain metastases after SRS is likely to increase. The evidence regarding the safety and efficacy of salvage therapies is very limited, making options for treatment unclear and controversial. In this report, we review current diagnostic challenges regarding local recurrence after SRS and the development of new brain metastases after SRS. Potential therapeutic strategies and the patients for who each is recommended are discussed, including repeat SRS, surgical resection, WBRT, fractionated stereotactic radiosurgery, chemotherapy, and supportive care. PMID- 22236689 TI - Future perspectives on brain metastasis management. AB - Brain metastases are the most common intracranial tumors encountered by physicians. Historically, the mainstays of therapy were limited to surgery and whole brain radiation. Surgery is typically reserved for safely accessible and symptomatic tumors in patients well enough to tolerate a procedure. Whole-brain radiation therapy has proven to have limited efficacy and concerns have arisen regarding its toxicity. Advances in the treatment of systemic cancers have yielded improved long-term survival and quality of life for patients. To parallel these efforts in systemic treatment, continual improvement of the treatment of brain metastases is a must. The last two decades have seen a paradigm shift in the thinking about metastatic brain tumor treatment as a result of the advent of stereotactic radiosurgery. Radiosurgery has proven to be an efficacious, minimally invasive, and highly selective treatment for metastatic brain tumors. In this review, we discuss the evolution of metastatic brain tumor management, the appropriately diminished role for reflexive whole brain radiation, and the growing importance of stereotactic radiosurgery as an upfront treatment modality in conjunction with surgery and subsequent salvage radiosurgery. PMID- 22236690 TI - The effects of digestion enzymes on islet viability and cellular composition. AB - The choice of enzyme blend is critical for successful islet isolation. Islet yield, viability, integrity, and function are important factors that influence the outcome of islet transplantation. Liberase HI has been used as a standard enzyme for pancreas digestion and has successfully produced islets that reversed diabetes. However, the replacement of Liberase HI with collagenase NB1 has significantly influenced the process outcome, both in quality and quantity of the isolated islets. The assessment of islet cells by Flow Cytometry (FC) has been reported to be useful for evaluating islet quality. The aim of this study was to assess the isolation outcomes and islet quality when comparing human islet cell processed with Liberase HI and NB1. A total of 66 islet isolations, 46 processed using Liberase HI and 20 using Serva NB1, were retrospectively analyzed. Islet yield, function in vitro, islet cell viability by FC, as well as isolation related factors were compared. There was no significant difference in donor characteristics such as age and height; however, body mass index (BMI) in the Liberase HI group was significantly higher. There was also no significant difference in prepurification, postisolation, or postculture IEQ or percent recovery between the two groups. Flow data showed Liberase HI preparations had a significantly higher percent of live cells (DAPI(-)) and NG(+)/TMRE(+) when compared to NB1. Stimulation Indices (SI) for Liberase HI (n = 45) showed 3.17 and NB1 (n = 18) 2.71 (p = NS). The results of Annexin V/DAPI staining for live, apoptotic, and necrotic cells were 50.7 +/- 2.24%, 14.4 +/- 1.02%, and 27.8 +/- 1.92% for Liberase HI versus 48.1 +/- 1.93%, 12.3 +/- 0.92%, and 33.9 +/- 2.28% for NB1. Islets isolated using Liberase HI showed higher viable beta cells by NG/TMRE staining and decreased necrosis by Annexin V/DAPI staining. FC assessment may be useful for determining the choice of digestion enzyme to maximize viable islets. PMID- 22236692 TI - Acute post-cardiopulmonary bypass left atrial thrombosis after mitral valvuloplasty and left atrial thrombectomy. AB - A patient with mitral stenosis and multiple left atrial thrombi underwent valvuloplasty and thrombectomy. While closing the sternum after completing the cardiopulmonary bypass, a new left atrial thrombus was detected by transesophageal echocardiography. We used heparin for the prevention of new thrombus formation and closed the wound after meticulous bleeding control. Three months later, there was no residual thrombus in the left atrium according to the echocardiographic study. PMID- 22236691 TI - Resting state functional MRI in Alzheimer's Disease. AB - Resting-state functional magnetic resonance imaging (fMRI) is emerging as an interesting biomarker for measuring connectivity of the brain in patients with Alzheimer's disease (AD). In this review, we discuss the origins of resting-state fMRI, common methodologies used to extract information from these four dimensional fMRI scans, and important considerations for the analysis of these scans. Then we present the current state of knowledge in this area by summarizing various AD resting-state fMRI studies presented in the first section and end with a discussion of future developments and open questions in the field. PMID- 22236693 TI - Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease. AB - BACKGROUND: Loss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies. METHODS: This was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency>=5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD. RESULTS: Variant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE epsilon4 non-carriers (P(interaction) < 0.05). CONCLUSION: Inherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM. PMID- 22236694 TI - Technical considerations for measurement of the fetal left modified myocardial performance index. PMID- 22236695 TI - Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. AB - Genetic alterations and epigenetic dysregulation in cancer cells create a vast array of neoepitopes potentially recognizable by the immune system. Immune checkpoint blockade has the capacity to enhance and sustain endogenous immunity against non-mutated tumor-associated antigens as well as uniquely mutant antigens, establishing durable tumor control. Recent evidence from preclinical models highlights the pivotal role of the Programmed Death-1 (PD-1) T cell co receptor and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, in maintaining an immunosuppressive tumor microenvironment. Encouraging early clinical results using blocking agents against components of the PD-1 pathway have validated its importance as a target for cancer immunotherapy. PMID- 22236696 TI - Replenishing B lymphocytes in health and disease. AB - The path from hematopoietic stem cells (HSCs) to functional B lymphocytes has long been appreciated as a basic model of differentiation, but much clinically relevant information has also been obtained. It is now possible to conduct single cell studies with increasingly high resolution, revealing that individual stem and progenitor cells differ from each other with respect to differentiation potential and fates. B lymphopoiesis is now seen as a gradual and unsynchronized process where progenitors eventually become B lineage restricted. Major milestones have been identified, but a precise sequence need not be followed and oscillation between states is possible. It is not yet clear if this versatility has survival value, but information is accumulating about infections and age related changes. PMID- 22236697 TI - Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. AB - Intestinal epithelial cells provide an essential line of defense for Caernohabditis elegans against ingested pathogens. Because nematodes consume microorganisms as their food source, there has presumably been selection pressure to evolve and maintain immune defense mechanisms within the intestinal epithelium. Here we review recent advances that further define the immune signaling network within these cells and suggest mechanisms used by the nematode to monitor for infection. In reviewing studies of pathogenesis that use this simple model system, we hope to illustrate some of the basic principles of epithelial immunity that may also be of relevance in higher order hosts. PMID- 22236698 TI - Cytokinins: metabolism and function in plant adaptation to environmental stresses. AB - In plants, the cytokinin (CK) phytohormones regulate numerous biological processes, including responses to environmental stresses, via a complex network of CK signaling. By an unknown mechanism, stress signals are perceived and transmitted through the His-Asp phosphorelay, an important component of the CK signal transduction pathway, triggering CK-responsive genes. Because of the intensive crosstalk between CKs and abscisic acid (ABA), modulation of CK levels and their signal transduction affects both ABA-dependent and ABA-independent pathways, enabling plant adaptation to adverse conditions. This review presents our current understanding of the functions of CKs and CK signaling in the regulation of plant adaptation to stress. Biotechnological strategies based on the modulation of CK levels have been examined with the aim of stabilizing agriculture yields. PMID- 22236700 TI - Toward a new era in prosthodontic medicine. PMID- 22236699 TI - The trihelix family of transcription factors--light, stress and development. AB - GT factors are the founding members of the trihelix transcription factor family. They bind GT elements in light regulated genes, and their nature was uncovered in a burst of activity in the 1990s. Study of the trihelix family then slowed. However, interest is now re-awakening. Genomic studies have revealed 30 members of this family in Arabidopsis and 31 in rice, falling into five clades. Newly discovered functions involve responses to salt and pathogen stresses, the development of perianth organs, trichomes, stomata and the seed abscission layer, and the regulation of late embryogenesis. Thus the time is ripe for a review of the genomic and functional information now emerging for this neglected family. PMID- 22236701 TI - The importance of radiographic imaging in the microscopic assessment of bone tumors. AB - INTRODUCTION: Primary bone tumors are rare and require a multidisciplinary approach. Diagnosis involves primarily the radiologist and the pathologist. Bone lesions are often heterogeneous and the microscopic diagnostic component(s) may be in the minority, especially on core needle biopsies. Reactive processes, benign, and malignant tumors may have similar microscopic aspects. For these challenging cases, the correlation of microscopic and radiologic information is critical, or diagnostic mistakes may be made with severe clinical consequences for the patient. The purpose of this article is to explain how pathologists can best use imaging studies to improve the diagnostic accuracy of bone lesions. DIAGNOSIS: Many bone lesions are microscopically and/or radiographically heterogeneous, especially those with both lytic and matrix components. Final diagnosis may require specific microscopic diagnostic features that may be present in the lesion, but not the biopsy specimen. A review of the imaging helps assess if sampling was adequate. The existence of a pre-existing bone lesion, syndrome (such as Ollier disease or multiple hereditary exostosis), or oncologic history may be of crucial importance. Finally, imaging information is very useful for the pathologist to perform accurate local and regional staging during gross examination. CONCLUSION: Close teamwork between pathologists, radiologists, and clinicians is of utmost importance in the evaluation and management of bone tumors. These lesions can be very difficult to interpret microscopically; imaging studies therefore play a crucial role in their accurate diagnosis. PMID- 22236702 TI - Virtual non-contrast in second-generation, dual-energy computed tomography: reliability of attenuation values. AB - PURPOSE: To evaluate the reliability of attenuation values in virtual non contrast images (VNC) reconstructed from contrast-enhanced, dual-energy scans performed on a second-generation dual-energy CT scanner, compared to single energy, non-contrast images (TNC). MATERIALS AND METHODS: Sixteen phantoms containing a mixture of contrast agent and water at different attenuations (0 1400 HU) were investigated on a Definition Flash-CT scanner using a single-energy scan at 120 kV and a DE-CT protocol (100 kV/SN140 kV). For clinical assessment, 86 patients who received a dual-phase CT, containing an unenhanced single-energy scan at 120 kV and a contrast enhanced (110 ml Iomeron 400 mg/ml; 4 ml/s) DE-CT (100 kV/SN140 kV) in an arterial (n=43) or a venous phase, were retrospectively analyzed. Mean attenuation was measured within regions of interest of the phantoms and in different tissue types of the patients within the corresponding VNC and TNC images. Paired t-tests and Pearson correlation were used for statistical analysis. RESULTS: For all phantoms, mean attenuation in VNC was 5.3+/-18.4 HU, with respect to water. In 86 patients overall, 2637 regions were measured in TNC and VNC images, with a mean difference between TNC and VNC of 3.6+/-8.3 HU. In 91.5% (n=2412) of all cases, absolute differences between TNC and VNC were under 15HU, and, in 75.3% (n=1986), differences were under 10 HU. CONCLUSIONS: Second-generation dual-energy CT based VNC images provide attenuation values close to those of TNC. To avoid possible outliers multiple measurements are recommended especially for measurements in the spleen, the mesenteric fat, and the aorta. PMID- 22236703 TI - Improved radiograph measurement inter-observer reliability by use of statistical shape models. AB - Pre- and post-operative radiographs of patients undergoing joint arthroplasty are often examined for a variety of purposes including preoperative planning and patient assessment. This work examines the feasibility of using active shape models (ASM) to semi-automate measurements from post-operative radiographs for the specific case of the OxfordTM Unicompartmental Knee. Measurements of the proximal tibia and the position of the tibial tray were made using the ASM model and manually. Data were obtained by four observers and one observer took four sets of measurements to allow assessment of the inter- and intra-observer reliability, respectively. The parameters measured were the tibial tray angle, the tray overhang, the tray size, the sagittal cut position, the resection level and the tibial width. Results demonstrated improved reliability (average of 27% and 11.2% increase for intra- and inter-reliability, respectively) and equivalent accuracy (p>0.05 for compared data values) for all of the measurements using the ASM model, with the exception of the tray overhang (p=0.0001). Less time (15s) was required to take measurements using the ASM model compared with manual measurements, which was significant. These encouraging results indicate that semi automated measurement techniques could improve the reliability of radiographic measurements. PMID- 22236704 TI - Comparison of neuroendocrine tumor detection and characterization using DOTATOC PET in correlation with contrast enhanced CT and delayed contrast enhanced MRI. AB - PURPOSE: We evaluated the rate of successful characterization of gastroenteropancreatic neuroendocrine tumors (NETs) present with an increased somatostatin receptor, comparing CE-CT with CE-MRI, each in correlation with DOTATOC-PET. METHODS AND MATERIALS: 8 patients with GEP-NET were imaged using CE MRI (Gd-EOB-DTPA), CE-CT (Imeron 400) and DOTATOC-PET. Contrast-enhancement of normal liver-tissue and metastasis was quantified with ROI-technique. Tumor delineation was assessed with visual-score in blind-read-analysis by two experienced radiologists. RESULTS: Out of 40 liver metastases in patients with NETs, all were detected by CE-MRI and the lesion extent could be adequately assessed, whereas CT failed to detect 20% of all metastases. The blind-read-score of CT in arterial and portal phase was median -0.65 and -1.4, respectively, and 2.7 for delayed-MRI. The quantitative ROI-analysis presented an improved contrast enhancement-ratio with a median of 1.2, 1.6 and 3.3 for CE-CT arterial, portal phase and delayed-MRI respectively. CONCLUSION: Late CE-MRI was superior to CE-CT in providing additionally morphologic characterization and exact lesion extension of hepatic metastases from neuroendocrine tumor detected with DOTATOC-PET. Therefore, late enhanced Gd-EOB-DTPA-MRI seems to be the adequate imaging modality for combination with DOTATOC-PET to provide complementary (macroscopic and molecular) tumor characterization in hepatic metastasized NETs. PMID- 22236705 TI - Normal CT characteristics of the thymus in adults. AB - BACKGROUND: The thymus changes with age. Its shape and the proportion of solid tissue and fat vary between individuals, yet there is no comprehensive work describing the size and morphology of the normal thymus on CT. As a result, many adults with some preserved soft tissue in the thymus may undergo extensive work up to exclude mediastinal tumor. Our aim was to quantify CT characteristics of the normal thymus in an adult population. METHODS: CT chest scans of 194 trauma patients aged 14-78 years (mean 52.6 years), were retrospectively reviewed. The density, volume, shape and predominant side of the thymus were recorded for 56 patients in whom some solid tissue was preserved. Statistical analysis of these characteristics according to the patient age and gender was performed. RESULTS: Thymic density and volume decreased progressively with age. No solid tissue component was seen in the thymus in patients older than 54 years. In the majority of patients, the thymus had an arrowhead shape, with middle position. However, great variability in thymic shape and border were noted. There was a highly significant relationship between density and patient age (p<0.0001). CONCLUSION: We hope that our work will help in the definition of normal thymic CT parameters in adults, help to prevent unnecessary and expensive imaging procedures, and reduce patient exposure to ionizing radiation. PMID- 22236706 TI - Detecting event-related changes of multivariate phase coupling in dynamic brain networks. AB - Oscillatory phase coupling within large-scale brain networks is a topic of increasing interest within systems, cognitive, and theoretical neuroscience. Evidence shows that brain rhythms play a role in controlling neuronal excitability and response modulation (Haider B, McCormick D. Neuron 62: 171-189, 2009) and regulate the efficacy of communication between cortical regions (Fries P. Trends Cogn Sci 9: 474-480, 2005) and distinct spatiotemporal scales (Canolty RT, Knight RT. Trends Cogn Sci 14: 506-515, 2010). In this view, anatomically connected brain areas form the scaffolding upon which neuronal oscillations rapidly create and dissolve transient functional networks (Lakatos P, Karmos G, Mehta A, Ulbert I, Schroeder C. Science 320: 110-113, 2008). Importantly, testing these hypotheses requires methods designed to accurately reflect dynamic changes in multivariate phase coupling within brain networks. Unfortunately, phase coupling between neurophysiological signals is commonly investigated using suboptimal techniques. Here we describe how a recently developed probabilistic model, phase coupling estimation (PCE; Cadieu C, Koepsell K Neural Comput 44: 3107-3126, 2010), can be used to investigate changes in multivariate phase coupling, and we detail the advantages of this model over the commonly employed phase-locking value (PLV; Lachaux JP, Rodriguez E, Martinerie J, Varela F. Human Brain Map 8: 194-208, 1999). We show that the N-dimensional PCE is a natural generalization of the inherently bivariate PLV. Using simulations, we show that PCE accurately captures both direct and indirect (network mediated) coupling between network elements in situations where PLV produces erroneous results. We present empirical results on recordings from humans and nonhuman primates and show that the PCE-estimated coupling values are different from those using the bivariate PLV. Critically on these empirical recordings, PCE output tends to be sparser than the PLVs, indicating fewer significant interactions and perhaps a more parsimonious description of the data. Finally, the physical interpretation of PCE parameters is straightforward: the PCE parameters correspond to interaction terms in a network of coupled oscillators. Forward modeling of a network of coupled oscillators with parameters estimated by PCE generates synthetic data with statistical characteristics identical to empirical signals. Given these advantages over the PLV, PCE is a useful tool for investigating multivariate phase coupling in distributed brain networks. PMID- 22236707 TI - Contributions of excitation and suppression in shaping spatial frequency selectivity of V1 neurons as revealed by binocular measurements. AB - Neurons in the early visual cortex are generally highly sensitive to stimuli presented to the two eyes. However, the majority of studies on spatial and temporal aspects of neural responses were based on monocular measurements. To study neurons under more natural, i.e., binocular, conditions, we presented sinusoidal gratings of a variety of spatial frequencies (SF) dichoptically in rapid sequential flashes and analyzed the data using a binocular reverse correlation technique for neurons in cat area 17. The resulting set of data represents a frequency-domain binocular receptive field from which detailed selectivities, both monocular and binocular, could be obtained. Consistent with previous studies, the responses could generally be explained by linear summation of inputs from the two eyes. Suppressive responses were also observed and were delayed typically by 5-15 ms relative to excitatory responses. However, we have found more diverse nature of suppressive responses than those reported previously. The optimal suppressive frequency could be either higher or lower than that of the excitatory responses. The bandwidth of SF tuning of the suppressive responses was usually broader than that of the excitatory responses. Cells with lower optimal SFs for suppression tended to show high optimal SFs and sharp tuning curves. The dynamic shift of optimal SF from low to high SF was accompanied by suppression with earlier onset and higher peak SF or later onset and lower peak SF than excitation. These results suggest that the suppression plays an essential role in generating the temporal dynamics of SF selectivity. PMID- 22236708 TI - Selective optogenetic stimulation of cholinergic axons in neocortex. AB - Acetylcholine profoundly affects neocortical function, being involved in arousal, attention, learning, memory, sensory and motor function, and plasticity. The majority of cholinergic afferents to neocortex are from neurons in nucleus basalis. Nucleus basalis also contains projecting neurons that release other transmitters, including GABA and possibly glutamate. Hence, electrical stimulation of nucleus basalis evokes the release of a mixture of neurotransmitters in neocortex, and this lack of selectivity has impeded research on cholinergic signaling in neocortex. We describe a method for the selective stimulation of cholinergic axons in neocortex. We used the Cre-lox system and a viral vector to express the light-activated protein channelrhodopsin-2 in cholinergic neurons in nucleus basalis and their axons in neocortex. Labeled neurons depolarized on illumination with blue light but were otherwise unchanged. In anesthetized mice, illumination of neocortex desynchronized the local field potential, indicating that light evoked release of ACh. This novel technique will enable many new studies of the cellular, network, and behavioral physiology of ACh in neocortex. PMID- 22236709 TI - Somatosensory control of balance during locomotion in decerebrated cat. AB - Postmammillary decerebrated cats can generate stepping on a moving treadmill belt when the brain stem or spinal cord is stimulated tonically and the hindquarters are supported both vertically and laterally. While adequate propulsion seems to be generated by the hindlimbs under these conditions, the ability to sustain equilibrium during locomotion has not been examined extensively. We found that tonic epidural spinal cord stimulation (5 Hz at L5) of decerebrated cats initiated and sustained unrestrained weight-bearing hindlimb stepping for extended periods. Detailed analyses of the relationships among hindlimb muscle EMG activity and trunk and limb kinematics and kinetics indicated that the motor circuitries in decerebrated cats actively maintain equilibrium during walking, similar to that observed in intact animals. Because of the suppression of vestibular, visual, and head-neck-trunk sensory input, balance-related adjustments relied entirely on the integration of somatosensory information arising from the moving hindquarters. In addition to dynamic balance control during unperturbed locomotion, sustained stepping could be reestablished rapidly after a collapse or stumble when the hindquarters switched from a restrained to an unrestrained condition. Deflecting the body by pulling the tail laterally induced adaptive modulations in the EMG activity, step cycle features, and left right ground reaction forces that were sufficient to maintain lateral stability. Thus the brain stem-spinal cord circuitry of decerebrated cats in response to tonic spinal cord stimulation can control dynamic balance during locomotion using only somatosensory input. PMID- 22236710 TI - Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation. AB - Transcranial direct current stimulation (tDCS) can produce a lasting polarity specific modulation of cortical excitability in the brain, and it is increasingly used in experimental and clinical settings. Recent studies suggest that the after effects of tDCS are related to molecular mechanisms of activity-dependent synaptic plasticity. Here we investigated the effect of DCS on the induction of one of the most studied N-methyl-d-aspartate receptor-dependent forms of long term potentiation (LTP) of synaptic activity at CA3-CA1 synapses in the hippocampus. We show that DCS applied to rat brain slices determines a modulation of LTP that is increased by anodal and reduced by cathodal DCS. Immediate early genes, such as c-fos and zif268 (egr1/NGFI-A/krox24), are rapidly induced following neuronal activation, and a specific role of zif268 in the induction and maintenance of LTP has been demonstrated. We found that both anodal and cathodal DCS produce a marked subregion-specific increase in the expression of zif268 protein in the cornus ammonis (CA) region, whereas the same protocols of stimulation produce a less pronounced increase in c-fos protein expression in the CA and in dentate gyrus regions of the hippocampus. Brain-derived neurotrophic factor expression was also investigated, and it was found to be reduced in cathodal-stimulated slices. The present data demonstrate that it is possible to modulate LTP by using DCS and provide the rationale for the use of DCS in neurological diseases to promote the adaptive and suppress the maladaptive forms of brain plasticity. PMID- 22236711 TI - Effect of a nonspiking neuron on motor patterns of the leech. AB - Premotor and motoneurons could play regulatory roles in motor control. We have investigated the role of a premotor nonspiking (NS) neuron of the leech nervous system in two locomotive patterns: swimming and crawling. The NS neuron is coupled through rectifying electrical junctions to all the excitatory motoneurons examined. In addition, activation of motoneurons evokes chemically mediated inhibitory responses in NS. During swimming and crawling, the NS membrane potential (Vm(NS)) oscillated phase locked to the motor output. Hyperpolarization or depolarization of NS had no effect on swimming, but hyperpolarization of NS slowed down the crawling activity and decreased the motoneuron firing frequency. Depolarization of NS increased the motoneuron activity, and, at stages where the crawling pattern was fading, depolarization of NS reinstated it. Future work should determine if NS is actually a member of the central pattern generator or a regulatory element. PMID- 22236712 TI - Short-interval intracortical inhibition blocks long-term potentiation induced by paired associative stimulation. AB - Paired associative stimulation (PAS) of the motor cortex leads to increased motor evoked potential (MEP) amplitudes in the stimulated hand muscles. We hypothesized that evoking GABA(A) receptor-mediated short-interval intracortical inhibition (SICI) simultaneously with excitatory PAS would depress long-term potentiation plasticity in motor cortex. Four different PAS paradigms were tested, standard PAS (PAS25) and three conditioned PAS protocols (CS2-PAS25, CS2-PAS25adj, and CS10-PAS25adj). A subthreshold conditioning stimulus 2 ms (CS2) or 10 ms (CS10) before the test stimuli was added to the conditioned PAS protocols. Since CS2 has inhibitory and CS10 has facilitatory effect on cortical excitability, in the CS2 PAS25adj and CS10-PAS25adj protocols, TS intensity was adjusted to produce a 1-mV MEP in the presence of CS2 or CS10 to control for the degree of corticospinal excitation. As expected, MEP amplitudes after PAS25 were higher compared with that at baseline, but importantly, MEP amplitudes did not change after PAS was induced in the presence of SICI in either the CS2-PAS25 or CS2-PAS25adj condition. Furthermore, the CS10-PAS25adj protocol showed significantly increased MEP amplitude at 60 min after PAS compared with baseline. These results show that SICI blocked the induction of long-term potentiation-like plasticity in the motor cortex, indicating that GABAergic circuits play an important role in the regulation of cortical plasticity. The study demonstrates a noninvasive and nonpharmacological way to achieve focal modulation of plasticity. PMID- 22236713 TI - Tonic NMDA receptor-mediated current in prefrontal cortical pyramidal cells and fast-spiking interneurons. AB - Tonically activated neuronal currents mediated by N-methyl-d-aspartate receptors (NMDARs) have been hypothesized to contribute to normal neuronal function as well as to neuronal pathology resulting from excessive activation of glutamate receptors (e.g., excitotoxicity). Whereas cortical excitatory cells are very vulnerable to excitotoxic insult, the data regarding resistance of inhibitory cells (or interneurons) are inconsistent. Types of neurons with more pronounced tonic NMDAR current potentially associated with the activation of extrasynaptic NMDARs could be expected to be more vulnerable to excessive activation by glutamate. In this study, we compared tonic activation of NMDARs in excitatory pyramidal cells and inhibitory fast-spiking interneurons in prefrontal cortical slices. We assessed tonic NMDAR current by measuring holding current shift as well as noise reduction following NMDAR blockade after removal of spontaneous glutamate release. In addition, we compared NMDAR miniature excitatory postsynaptic currents (EPSCs) in both cell types. We have demonstrated for the first time that tonic NMDAR currents are present in inhibitory fast-spiking interneurons. We found that the magnitude of tonic NMDAR current is similar in pyramidal cells and fast-spiking interneurons, and that quantal release of glutamate does not significantly impact tonic NMDAR current. PMID- 22236714 TI - Similarity of superior colliculus involvement in microsaccade and saccade generation. AB - The characteristics of microsaccades, or small fixational saccades, and their influence on visual function have been studied extensively. However, the detailed mechanisms for generating these movements are less understood. We recently found that the superior colliculus (SC), a midbrain structure involved in saccade generation, also plays a role in microsaccade generation. Here we compared the dynamics of neuronal activity in the SC associated with microsaccades to those observed in this structure in association with larger voluntary saccades. We found that microsaccade-related activity in the SC is characterized by a gradual increase in firing rate starting ~100 ms prior to microsaccade onset, a peak of neuronal discharge just after movement onset, and a subsequent gradual decrease in firing rate until ~100 ms after movement onset. These properties were shared with saccade-related SC neurons, recorded from the same monkeys but preferring larger eye movements, suggesting that at the level of the SC the neuronal control of microsaccades is similar to that for larger voluntary saccades. We also found that neurons exhibiting microsaccade-related activity often also exhibited saccade-related activity for slightly larger movements of similar direction, suggesting a continuity of the spatial representation in the SC, in both amplitude and direction, down to the smallest movements. Our results indicate that the mechanisms controlling microsaccades may be fundamentally the same as those for larger saccades, and thus shed new light on the functional role of these eye movements and their possible influence on sensory and sensory-motor processes. PMID- 22236715 TI - Stability limits modulate whole-body motor learning. AB - Our daily movements exert forces upon the environment and also upon our own bodies. To control for these forces, movements performed while standing are usually preceded by anticipatory postural adjustments (APAs). This strategy is effective at compensating for an expected perturbation, as it reduces the need to compensate for the perturbation in a reactive manner. However, it can also be risky if one anticipates the incorrect perturbation, which could result in movements outside stability limits and a loss of balance. Here, we examine whether the margin for error defined by these stability limits affects the amount of anticipation. Specifically, will one rely more on anticipation when the margin for error is lower? Will the degree of anticipation scale with the margin for error? We took advantage of the asymmetric stability limits (and margins for error) present in the sagittal plane during upright stance and investigated the effect of perturbation direction on the magnitude of APAs. We also compared anticipatory postural control with the anticipatory control observed at the arm. Standing subjects made reaching movements to multiple targets while grasping the handle of a robot arm. They experienced forward or backward perturbing forces depending on the target direction. Subjects learned to anticipate the forces and generated APAs. Although subjects had the biomechanical capacity to adapt similarly in the forward and backward directions, APAs were reduced significantly in the backward direction, which had smaller stability limits and a smaller margin for error. Interestingly, anticipatory control produced at the arm, where stability limits are not as relevant, was not affected by perturbation direction. These results suggest that stability limits modulate anticipatory control, and reduced stability limits lead to a reduction in anticipatory postural control. PMID- 22236716 TI - Pyramidal tract neurons receptive to different forelimb joints act differently during locomotion. AB - During locomotion, motor cortical neurons projecting to the pyramidal tract (PTNs) discharge in close relation to strides. How their discharges vary based on the part of the body they influence is not well understood. We addressed this question with regard to joints of the forelimb in the cat. During simple and ladder locomotion, we compared the activity of four groups of PTNs with somatosensory receptive fields involving different forelimb joints: 1) 45 PTNs receptive to movements of shoulder, 2) 30 PTNs receptive to movements of elbow, 3) 40 PTNs receptive to movements of wrist, and 4) 30 nonresponsive PTNs. In the motor cortex, a relationship exists between the location of the source of afferent input and the target for motor output. On the basis of this relationship, we inferred the forelimb joint that a PTN influences from its somatosensory receptive field. We found that different PTNs tended to discharge differently during locomotion. During simple locomotion shoulder-related PTNs were most active during late stance/early swing, and upon transition from simple to ladder locomotion they often increased activity and stride-related modulation while reducing discharge duration. Elbow-related PTNs were most active during late swing/early stance and typically did not change activity, modulation, or discharge duration on the ladder. Wrist-related PTNs were most active during swing and upon transition to the ladder often decreased activity and increased modulation while reducing discharge duration. These data suggest that during locomotion the motor cortex uses distinct mechanisms to control the shoulder, elbow, and wrist. PMID- 22236717 TI - Atypical subtrochanteric femoral fracture. AB - The patient was a 72-year-old woman who presented to an emergency department with a chief complaint of severe right thigh pain following a fall. Prior to the fall, the patient reported an 8-month history of worsening right thigh pain. The patient had a 4-year history of alendronate and calcium use to manage her osteoporosis. Dual X-ray absorptiometry (DXA) hip images taken 1 month prior to the patient's fracture demonstrated lateral cortical thickening in the subtrochanteric region of the femur. In retrospect, this finding was concerning for impending complete fracture. J Orthop Sports Phys Ther 2012;42(1):44. doi:10.2519/jospt.2012.0402. PMID- 22236718 TI - Formation of a 3,4-diol-1,2-epoxide metabolite of benz[a]anthracene with cytotoxicity and genotoxicity in a human in vitro hepatocyte culture system. AB - Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that require metabolic activation to exert their carcinogenic effects. This study investigated the 3,4-diol-1,2-epoxide formation of benz[a]anthracene (BA) and its toxic effects in a human in vitro hepatocyte culture system. Both mRNA and protein expression of metabolic enzymes which can activate PAHs to carcinogenic forms increased after BA exposure in HepG2 cells and our quantitative analysis showed that the formation of BA-3,4-diol-1,2-epoxide in medium extracts increased in a time-dependent manner. We also performed several comparative studies which show that much lower concentrations of BA-3,4-diol-1,2-epoxide had stronger cytotoxicity and genotoxicity than higher doses of BA. These results suggest that BA is activated as the major carcinogenic metabolite 3,4-diol-1,2-epoxide, in human in vitro culture systems by metabolic enzymes and that this metabolite has stronger cytotoxic and genotoxic effects than its parent compound. PMID- 22236719 TI - The relationship among IL-13, GSTP1, and CYP1A1 polymorphisms and environmental tobacco smoke in a population of children with asthma in Northern Mexico. AB - Exposure to environmental tobacco smoke (ETS) during early childhood increases the risk of developing asthma. The intention of this study was to genotype a population of children from Coahuila state in Northern Mexico and to determine whether polymorphisms of the CYP1A1, GSTP1, and IL13 genes are associated with exposure to ETS and subsequently a higher risk for asthma. IL13 plays an important role in the development of allergic response, particularly those related with airway inflammation. CYP1A1 and GSTP1 are xenobiotic-metabolizing enzymes induced by repeated exposure to toxicants. Polymorphisms of these genes have been related with ETS exposure and increased risk for asthma. To assess the effect of IL13 (-1112 C>T and Arg110Gln), GSTP1 (Ile105Val), and CYP1A1 (Ile462Val) on asthma risk and ETS exposure, we recruited 201 unrelated children and classified them into four groups: (1) control without ETS exposure; (2) control with ETS exposure; (3) with asthma and with ETS exposure and (4) with asthma and without ETS exposure. No association among ETS exposure, asthma, and the studied polymorphisms was denoted by multivariate analysis of this population. PMID- 22236720 TI - Effects of atrazine and chlorpyrifos on activity and transcription of glutathione S-transferase in common carp (Cyprinus carpio L.). AB - Glutathione S-transferase isoenzymes (GSTs) play a critical role in detoxification pathways. Here we report the tissue distribution of four antioxidant GSTs gene in common carp, and their expression profiles. We also investigated the GSTs activity in different tissues after exposure to the agricultural chemicals atrazine (ATR), chlorpyrifos (CPF), and their mixture. Relative changes in the mRNA abundance of the GST isoforms were examined by real time PCR in liver, brain, kidney and gill of common carp. After exposure and recovery, we observed a statistically significant decrease in the GSTs activity in animals exposed to high concentrations of ATR (428 MUg/L), CPF (116 MUg/L), and their mixture (113 MUg/L). At basal levels of tissue expression, four GSTs transcript were detected in liver, brain, kidney, and gill. High expression levels were found in all examined tissues. Transcription of some GST isoforms, GST kappa (GSTK), GST theta (GSTT) and GST rho (GSTR), decreased after exposure to CPF and ATR for the entire experimental period in both the kidney and gill. However, increased transcription of GST mu (GSTM) was observed in the kidney or gill 20 d after exposure to ATR or CPF, respectively. Transcription of both GSTT and GSTR was inhibited for the entire experimental period in the brain, kidney and gill of animals exposed to the ATR/CPF mixture, but transcription of GSTM was induced in the liver after 40 d of exposure. In summary, changes in the GSTs activity and their transcription varied within each organ and among organs of common carp after exposure to ATR, CPF, and their mixture. PMID- 22236721 TI - Subacute arsenic exposure through drinking water reduces the pharmacodynamic effects of ketoprofen in male rats. AB - We evaluated the modulatory role of the groundwater contaminant arsenic on the pharmacodynamic responses of the nonsteroidal analgesic-antipyretic drug ketoprofen and the major pro-inflammatory mediators linked to the mechanism of ketoprofen's therapeutic effects. Rats were pre-exposed to sodium arsenite (0.4, 4 and 40 ppm) through drinking water for 28 days. The pharmacological effects of orally administered ketoprofen (5 mg/kg) were evaluated the following day. Pain, inflammation and pyretic responses were, respectively, assessed through formalin induced nociception, carrageenan-induced inflammation and lipopolysaccharide induced pyrexia. Arsenic inhibited ketoprofen's analgesic, anti-inflammatory and antipyretic effects. Further, arsenic enhanced cyclooxygenase-1 and cyclooxygenase-2 activities and tumor necrosis factor-alpha, interleukin-1beta and prostaglandin-E(2) production in hind paw muscle. These results suggest a functional antagonism of ketoprofen by arsenic. This may relate to arsenic mediated local release of tumor necrosis factor-alpha and interleukin-1beta, which causes cyclooxygenase induction and consequent prostaglandin-E(2) release. In conclusion, subacute exposure to environmentally relevant concentrations of arsenic through drinking water may aggravate pain, inflammation and pyrexia and thereby, may reduce the therapeutic efficacy of ketoprofen. PMID- 22236722 TI - Configuration of microbially synthesized Pd-Au nanoparticles studied by STEM based techniques. AB - Bimetallic Pd-Au particles synthesized using Desulfovibrio desulfuricans bacteria are characterized using scanning transmission electron microscopy (STEM) with a high-angle annular dark field (HAADF) detector combined with energy dispersive x ray (EDX) silicon drift detector (SDD) elemental mapping and plasmon electron energy-loss spectroscopy (EELS). When combined with EDX, theoretical considerations or EELS, the atomic-number contrast (Z-contrast) provided by HAADF STEM is effective in characterizing the compositional configuration of the bimetallic nanoparticles. Homogeneous mixing and complex segregations have been found for different particles in this work. The EELS study has also found different behaviours corresponding to surface plasmon resonances in different regions of a single particle due to its heterogeneity and anisotropy. HAADF-STEM tomography has been performed to obtain three-dimensional (3D) visualization of the nanoparticles. PMID- 22236723 TI - Correlation between 3D ultrasound appearance and postnatal findings in bilateral malformations of the fetal hands. AB - Malformations of the hand have an incidence of 1 in about 1,500 births. Ultrasound diagnosis and classification of the anomaly is not always easy because of the various positions taken by the hand. We describe the case of a 23-year-old patient with a fetus affected by a symmetrical and bilateral hand oligodactyly associated with deformities of the other fingers. 3D ultrasound evaluation allowed an exact prediction of the malformation and showed perfect correspondence with postnatal findings. The case illustrates the contribution of 3D ultrasound to the evaluation of fetal limb anomalies. PMID- 22236724 TI - Effects of relative low-frequency bilateral globus pallidus internus stimulation for treatment of cervical dystonia. AB - OBJECTIVE: To assess the effect of relative lower amplitude and frequency for globus pallidus internus (GPi) deep brain stimulation (DBS) of cervical dystonia (CD). MATERIALS AND METHODS: Between February 2005 and October 2008, 14 patients diagnosed with CD underwent bilateral GPi DBS and all the patients received low frequency stimulation and were followed for more than 2 years. We activated the implantable pulse generator 3-4 days postoperatively and initial amplitude, pulse width, and frequency were set at 1.5 V, 120 MUs, and 70 Hz. The Toronto Western Spasmodic Torticolis Rating Scale (TWSTRS) was applied preoperatively and at 1, 6, 12 and 24 months postoperatively. RESULTS: The overall TWSTRS scores improved 71.2% 2 years postoperatively (p = 0.001). The mean improvement was 78.4% in severity subscores, 68.4% in disability, and 66.8% in pain scores for the 2-year follow-up period. The TWSTRS scores were significantly reduced (p < 0.05), suggesting that the most significant improvement of the TWSTRS scores occurred within 1 month. The final amplitude was 2.9/2.7 V with the pulse width of 147.9/147.9 MUs and the frequency of 101.1/100 Hz. CONCLUSION: According to our results, the initial settings of low amplitude and especially relatively low frequency are safe and effective for treatment of CD. PMID- 22236725 TI - Possible eosinophilic esophagitis induced by milk oral immunotherapy. PMID- 22236726 TI - Administration of influenza vaccine to pediatric patients with egg-induced anaphylaxis. PMID- 22236727 TI - Pancreatitis as a novel complication of aspirin therapy in patients with aspirin exacerbated respiratory disease. PMID- 22236728 TI - Allergen-induced IgE-dependent gut inflammation in a human PBMC-engrafted murine model of allergy. AB - BACKGROUND: Humanized murine models comprise a new tool to analyze novel therapeutic strategies for allergic diseases of the intestine. OBJECTIVE: In this study we developed a human PBMC-engrafted murine model of allergen-driven gut inflammation and analyzed the underlying immunologic mechanisms. METHODS: Nonobese diabetic (NOD)-scid-gammac(-/-) mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or not. Three weeks later, mice were challenged with the allergen orally or rectally, and gut inflammation was monitored with a high-resolution video miniendoscopic system, as well as histologically. RESULTS: Using the aeroallergens birch or grass pollen as model allergens and, for some donors, also hazelnut allergen, we show that allergen-specific human IgE in murine sera and allergen-specific proliferation and cytokine production of human CD4(+) T cells recovered from spleens after 3 weeks could only be measured in mice treated with PBMCs plus allergen. Importantly, these mice had the highest endoscopic scores evaluating translucent structure, granularity, fibrin, vascularity, and stool after oral or rectal allergen challenge and a strong histologic inflammation of the colon. Analyzing the underlying mechanisms, we demonstrate that allergen associated colitis was dependent on IgE, human IgE receptor-expressing effector cells, and the mediators histamine and platelet-activating factor. CONCLUSION: These results demonstrate that allergic gut inflammation can be induced in human PBMC-engrafted mice, allowing the investigation of pathophysiologic mechanisms of allergic diseases of the intestine and evaluation of therapeutic interventions. PMID- 22236729 TI - Recurrent severe exacerbations in early life and reduced lung function at school age. PMID- 22236730 TI - Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients. AB - BACKGROUND: Blood tests are needed to identify steroid-resistant (SR) asthmatic patients early so that they can be managed with alternative anti-inflammatory therapy. OBJECTIVE: We sought to assess the usefulness of peripheral blood to predict steroid response in asthmatic patients. METHODS: Nineteen asthmatic patients with FEV(1) of less than 80% of predicted value were classified as SR or steroid sensitive (SS) based on change in lung FEV(1) percentage after 7 days of oral prednisone. Blood was collected at baseline (visit 1) and 30 days after prednisone administration (visit 3). PBMCs were cultured for 4 hours with or without 10(-7) mol/L dexamethasone, and cellular response to dexamethasone was determined by using real-time PCR based on expression analysis of steroid regulated genes. Suppression of PHA-induced T-cell proliferation by dexamethasone was assessed. RESULTS: Prednisone significantly improved FEV(1) percentages in SS asthmatic patients (mean +/- SE: 17.5% +/- 2.4%) but not SR asthmatic patients (0.8% +/- 2.0%, P < .001). Before prednisone treatment, mitogen-induced kinase phosphatase 1 (P = .01) and IL-8 mRNA (P < .05) levels were significantly higher in PBMCs from SR asthmatic patients. TNF-alpha (P < .05) and IL-8 fold suppression by dexamethasone (P < .05) were significantly reduced in PBMCs from SR asthmatic patients. The expression of glucocorticoid receptor (GCR) beta, but not GCR-alpha, was significantly increased in PBMCs of SR asthmatic patients (P = .01). The dexamethasone inhibitory concentration of 50% for PBMC proliferation was significantly higher for SR asthmatic patients (P < .05). These markers no longer differed between groups in PBMCs 30 days after prednisone administration. The composite score of assays at baseline before prednisone was significantly different between SR and SS asthmatic patients (P < .001). CONCLUSIONS: PBMCs from SR asthmatic patients have higher baseline mitogen-induced kinase phosphatase 1, IL-8, and GCR-beta mRNA levels; have a lower GCR-alpha/GCR-beta mRNA ratio; are less responsive to suppression of TNF-alpha and IL-8 by dexamethasone; and require more dexamethasone to suppress T-cell proliferation compared with SS asthmatic patients. PMID- 22236731 TI - Age-related differences in the pathogenesis of chronic rhinosinusitis. PMID- 22236732 TI - Increased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy. PMID- 22236733 TI - Diagnostic tools assessing airway remodelling in asthma. AB - Asthma is an inflammatory disease of the lower airways characterised by the presence of airway inflammation, reversible airflow obstruction and airway hyperresponsiveness and alterations on the normal structure of the airways, known as remodelling. Remodelling is characterised by the presence of metaplasia of mucous glands, thickening of the lamina reticularis, increased angiogenesis, subepithelial fibrosis and smooth muscle hypertrophy/hyperplasia. Several techniques are being optimised at present to achieve a suitable diagnosis for remodelling. Diagnostic tools could be divided into two groups, namely invasive and non-invasive methods. Invasive techniques bring us information about bronchial structural alterations, obtaining this information directly from pathological tissue, and permit measure histological modification placed in bronchi layers as well as inflammatory and fibrotic cell infiltration. Non invasive techniques were developed to reduce invasive methods disadvantages and measure airway remodelling-related markers such as cytokines, inflammatory mediators and others. An exhaustive review of diagnostic tools used to analyse airway remodelling in asthma, including the most useful and usually employed methods, as well as the principal advantages and disadvantages of each of them, bring us concrete and summarised information about all techniques used to evaluate alterations on the structure of the airways. A deep knowledge of these diagnostic tools will make an early diagnosis of airway remodelling possible and, probably, early diagnosis will play an important role in the near future of asthma. PMID- 22236734 TI - Effect of high dose inhaled corticosteroids on cell mediated immunity in patients with asthma. AB - BACKGROUND: Cell mediated immunity is suppressed by systemic corticosteroids. Inhaled corticosteroids have been shown to affect parameters including bone metabolism, hypothalamus-pituitary adrenal axis, linear growth, and lead to the development of cataracts. However, it is unclear if high dose inhaled corticosteroid therapy affects cell mediated immunity. STUDY OBJECTIVES: To evaluate if asthma patients taking high dose inhaled corticosteroids chronically have reduced cell mediated immunity compared to asthma patients not taking inhaled corticosteroids. METHODS: Eighteen asthmatic subjects participated in this cross-sectional study. Cell mediated immunity was evaluated in nine patients who had been taking high dose inhaled corticosteroids for >6 months and nine patients not taking inhaled corticosteroids. Cell mediated immunity was evaluated by delayed type hypersensitivity (DTH) skin testing with intradermal placement of candida and tetanus antigens. RESULTS: There was no significant difference in DTH skin test results between the high dose inhaled corticosteroid and no corticosteroid treated asthma group. CONCLUSION: Patients with asthma taking high dose inhaled corticosteroids chronically (>6 months) did not have significantly greater impaired cell mediated immunity than patients not taking inhaled corticosteroids in this study. PMID- 22236735 TI - Transcranial direct current stimulation in the treatment of major depression: a meta-analysis. AB - BACKGROUND: So far, no comprehensive answer has emerged to the question of whether transcranial direct current stimulation (tDCS) can make a clinically useful contribution to the treatment of major depression. We aim to present a systematic review and meta-analysis of tDCS in the treatment of depression. METHOD: Medline and Embase were searched for open-label and randomized controlled trials of tDCS in depression using the expressions ('transcranial direct current stimulation' or 'tDCS') and ('depression' or 'depressed'). Study data were extracted with a standardized data sheet. For randomized controlled trials, effect size (Hedges' g) was calculated and the relationships between study variables and effect size explored using meta-regression. RESULTS: A total of 108 citations were screened and 10 studies included in the systematic review. Six randomized controlled trials were included in the meta-analysis, with a cumulative sample of 96 active and 80 sham tDCS courses. Active tDCS was found to be more effective than sham tDCS for the reduction of depression severity (Hedges' g=0.743, 95% confidence interval 0.21-1.27), although study results differed more than expected by chance (Q=15.52, df=6, p=0.017, I2=61.35). Meta regression did not reveal any significant correlations. CONCLUSIONS: Our study was limited by the small number of studies included, which often had small sample size. Future studies should use larger, if possible representative, health service patient samples, and optimized protocols to evaluate the efficacy of tDCS in the treatment of depression further. PMID- 22236736 TI - Interactions between herbs and conventional drugs: overview of the clinical data. AB - This article provides an overview of the clinical evidence of interactions between herbal and conventional medicines. Herbs involved in drug interactions- or that have been evaluated in pharmacokinetic trials--are discussed in this review. While many of the interactions reported are of limited clinical significance and many herbal products (e.g. black cohosh, saw palmetto, echinacea, hawthorn and valerian) seem to expose patients to minor risk under conventional pharmacotherapy, a few herbs, notably St. John's wort, may provoke adverse events sufficiently serious to endanger the patients' health. Healthcare professionals should remain vigilant for potential interactions between herbal medicines and prescribed drugs, especially when drugs with a narrow therapeutic index are used. PMID- 22236737 TI - A case of Charcotian grande hysterie: observation by Julien Offray de La Mettrie in 1738. AB - Julien Offray de La Mettrie (1709-1751) is a French philosopher who owes his fame to his materialist ideas. He was also a provocative atheist who used his scathing pen to defend the first concept of a theory of mind. We offer here one of his little-known works, reporting on a case of grande hysterie, as Jean-Martin Charcot (1825-1893) and his student Paul Richer (1849-1933) would describe the condition 150 years later. After discussing how La Mettrie interpreted this observation, we will compare it to interpretations developed during the 19th century, in particular by the La Salpetriere school. PMID- 22236738 TI - Ulcerative colitis practice guidelines in adults. PMID- 22236739 TI - Beyond amyloid: a diverse portfolio of novel drug discovery programs for Alzheimer's disease and related dementias. AB - Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 http://www.worldeventsforum.com/addf/addrugdiscovery. PMID- 22236740 TI - A review of the cytomorphology of Epstein-Barr virus-associated malignancies. AB - The Epstein-Barr virus (EBV) is a member of the herpes family of viruses and is very common in humans. EBV is most often associated with infectious mononucleosis. However, it is estimated that 1% of tumors including lymphoproliferative, epithelial and mesenchymal are linked to EBV infection. EBV has a tropism for certain epithelial cells, lymphocytes and myocytes. Like other herpesviruses, EBV has both lytic and latent phases of infection. In the latent form, EBV-encoded genes ensure the survival of the viral genome, allowing it to circumvent the host's immune surveillance by limited expression of viral proteins and carries with it the risk of neoplastic transformation. Cytologists are likely to encounter EBV-associated malignancies in cytology material but unlike other herpesviruses, EBV does not evoke a viral cytopathic effect. The manifestation of EBV-related tumors is also often variable depending upon the patient's immune status. Therefore, knowledge of the patient's EBV status and immune competence (e.g. HIV-infection or transplant-related immunosuppression) combined with the cytomorphology and results of ancillary studies are often all required to make a diagnosis of EBV-associated malignancy. This review discusses the unique cytomorphology and ancillary studies required to diagnose EBV-related neoplasms. PMID- 22236741 TI - Myxofibrosarcoma: cytomorphologic findings and differential diagnosis on fine needle aspiration. AB - OBJECTIVE: To analyze the cytomorphologic findings of myxofibrosarcoma (MFS) on fine needle aspiration (FNA) and examine the differential diagnoses. STUDY DESIGN: A retrospective review was undertaken of material from 22 patients with an FNA procedure of their tumor prior to resection. A tally was performed of all the features known in the literature, including myxoid matrix, spindle cells, nuclear pleomorphism, curvilinear vessels, and multinucleated cells. A review of the literature was also performed to elucidate any advances in the use of morphology and other modalities to deconvolute the challenging differential diagnosis. Clinicoradiologic characteristics and immunostaining were also analyzed and correlated. RESULTS: FNA diagnoses included high-grade sarcoma (32%), recurrent MFS (23%), spindle cell neoplasm (18%), indeterminate-grade sarcoma (14%), low-grade sarcoma (9%), and pleomorphic adenoma (4%). Of the cases available for morphologic review, myxoid matrix was the most frequent observation (88%), followed by spindle cells (82%), nuclear pleomorphism (76%), multinucleated cells (71%), and curvilinear vessels (65%). Myxoid matrix, spindle cells, and nuclear pleomorphism were very often concomitant observations. CONCLUSION: MFS demonstrates characteristic albeit nonspecific morphological findings and can overlap morphologically with other clinically significant entities based on FNA material. PMID- 22236742 TI - Cytopathologic analysis of stroma-poor salivary gland epithelial/myoepithelial neoplasms on fine needle aspiration. AB - OBJECTIVE: Fine needle aspiration (FNA) diagnosis of salivary gland neoplasms with epithelial/myoepithelial cells but rare or no stroma is usually difficult. Our aim was to study the cytomorphology of this cohort of FNA cases and evaluate the clinical follow-up. STUDY DESIGN: The diagnostic terminology for this group of aspirates was 'favor an epithelial/myoepithelial neoplasm of the salivary gland'. The cytologic smears of 32 such cases were retrieved and showed cellular smears with bland-appearing or mildly atypical epithelial and myoepithelial cells without typical chondromyxoid stroma seen in pleomorphic adenoma (PA). RESULTS: Twenty of the 32 cases had histologic follow-up. Ten of these 20 cases were PAs, including 8 cellular PAs. Two cases were basal cell adenomas, 1 case myoepithelioma and 1 case benign adenoma, not otherwise specified. Among the 6 malignant tumors on surgical resections, there were 3 epithelial-myoepithelial carcinomas, 1 myoepithelial carcinoma, 1 basal cell adenocarcinoma and 1 adenoid cystic carcinoma. CONCLUSIONS: Although 14 of the 20 (70%) cases were benign neoplasms, a substantial amount of cases (30%) were malignant salivary gland neoplasms. The generic diagnostic terminology of 'epithelial/myoepithelial neoplasm of the salivary gland' and appropriate clinical follow-up are recommended for these cases. PMID- 22236743 TI - Pancreatic cystic lesions without overt cytologic atypia: proposed diagnostic categories for endoscopic ultrasound-guided fine-needle aspiration cytology with utilization of fluid carcinoembryonic antigen level. AB - OBJECTIVES: It was the aim of this study to examine pancreatic cyst cases that lack markedly atypical or malignant epithelium on endoscopic ultrasound-guided fine-needle aspirations. STUDY DESIGN: We conducted a retrospective case review study, including 24 cases that were either acellular or lacked cytologic atypia and were subsequently resected. The cases were retrospectively divided into 3 categories: (1) non-diagnostic, (2) cyst contents only, and (3) cyst contents with bland-appearing epithelium. The cyst contents were subdivided into mucinous and non-mucinous types. The cytologic diagnoses were correlated with cyst fluid carcinoembryonic antigen (CEA) levels and subsequent histologic diagnoses. RESULTS: Category 1 comprised 4 cases: 2 cases (CEA >800 ng/ml) with mucin producing neoplasms and 2 cases (CEA not determined) with microcystic serous cystadenomas. Category 2 included 4 cases with non-mucinous and 4 with mucinous contents. In the first subgroup, 2 cases (CEA >800 ng/ml) showed mucinous cystic neoplasms and 2 cases (CEA negligible or not determined) pseudocysts. In the second subgroup, there were 3 cases with neoplastic mucinous cysts (1 CEA >800 ng/ml, 2 not determined) and 1 case with a lymphoepithelial cyst with mucinous metaplasia (CEA >800 ng/ml). Almost all cases (10/11) in category 3 had neoplastic mucinous cysts regardless of the CEA levels. CONCLUSIONS: The proposed 3 cytologic categories of pancreatic cystic lesion combined with cyst fluid CEA levels provide useful clinical information. PMID- 22236744 TI - The accuracy of the 'triple test' in the diagnosis of papillary lesions of the breast. AB - BACKGROUND AND OBJECTIVE: The literature on fine-needle aspiration (FNA) cytology for papillary lesions presents a very mixed picture. Many authors advocate mandatory excision of these lesions. This recommendation is largely based on the 'atypical' nature of the FNA report. The aim of this work is to see if breast papillomas can be treated conservatively. STUDY DESIGN: We report a retrospective study of outcomes for patients with a provisional diagnosis of a 'papillary breast lesion' based on assessment by palpation (no clinically suspicious features), sonography (benign or probably benign according to the Breast Imaging Reporting and Data System 'BI-RADS(r)'), and FNA (benign cytological category with a papillary architecture) findings from one integrated breast service. RESULTS: Thirty-six cases were identified over a period of 6 years. Thirty-four of the patients had surgical excision. All of the 34 surgical cases were confirmed to be benign in nature on histopathology (intraduct papilloma). The remaining 2 cases were stable on follow-up. CONCLUSION: We believe that a policy of mandatory excision of papillary lesions of the breast is unnecessarily cautious. PMID- 22236745 TI - World wide web-based cytological analysis of atypical squamous cells cannot exclude high-grade intraepithelial lesions. AB - OBJECTIVE: It has been reported that the low level of consistency of diagnosis of atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions (ASC-H) in uterine cervical cancer screening using the Bethesda System, indicating the necessity of a large-scale survey. We presented cases cytologically judged as ASC-H on our website and invited our members to give their opinions regarding the diagnosis by voting online. The Web voting results were analyzed and ASC-H was cytologically investigated. STUDY DESIGN: Virtual slides of atypical cells in cytology preparations of 53 cases were prepared and presented on a website. ASC-H cases were divided into 42 cases sampled by brush scraping and 11 cases sampled by cotton swab scraping. Fifty-three cases cytologically judged as ASC-H were classified into benign and CIN2/3, and their patterns of arrangement of atypical cells and 8 cytological parameters were morphologically investigated. RESULTS: The frequency of ASC-H diagnosis in the Web votes was low: 29.2% for brush-scraped and 26.2% for cotton swab-scraped cases. Three-dimensionality, coarse chromatin and irregular nuclei were significantly different between high-grade squamous intraepithelial lesions and benign cases. CONCLUSION: Web-based surveys showed the difference of cytological findings between high-grade squamous intraepithelial lesions and benign cases. To increase interobserver consistency, it may be useful to share information online, which avoids geographical and temporal limitations. PMID- 22236746 TI - p16(INK4a) and ProEx C immunostains facilitate differential diagnosis of hyperchromatic crowded groups in liquid-based Papanicolaou tests with menstrual contamination. AB - OBJECTIVE: Evaluation of hyperchromatic crowded groups in Papanicolaou (Pap) tests from women during menstruation can be a diagnostic pitfall due to similar morphological appearances with significant cervical lesions. We studied the results of p16(INK4a) and ProEx C on cell blocks from Pap tests during menstruation in an attempt to facilitate the differentiation. STUDY DESIGN: Immunohistochemical stains for p16(INK4a) and ProEx C were performed on 25 cell blocks prepared from residual liquid-based cervical material with menstrual contamination. RESULTS: Strong, diffuse, and full thickness staining pattern for p16(INK4a) and ProEx C was observed in cases of high-grade squamous intraepithelial lesion (HSIL) and small cell carcinoma of the cervix. The low grade squamous intraepithelial lesion cases and cases negative for intraepithelial lesion or malignancy were negative for ProEx C, with focal staining for p16(INK4a). The benign endometrial cells had either negative or focal patchy staining, which is often associated with tubal metaplasia. CONCLUSION: p16(INK4a) and ProEx C are sensitive markers for identifying significant lesions in Pap test specimens with menstrual contamination. Patchy/mosaic staining may be seen in benign endometrial tissue with tubal metaplasia, but strong, diffuse staining likely indicates HSIL or carcinoma. These findings can be helpful in interpreting hyperchromatic crowded groups in menstrual Pap specimens. Further study may be prudent, being aware of the small study group. PMID- 22236747 TI - Histopathologic outcomes and clinical correlations for high-risk patients screened with anal cytology. AB - OBJECTIVE: Anal cytologic testing is being increasingly used as a preventive screening test in high-risk populations. We document anal cytology results, correlating HIV test results, and histopathologic follow-up outcomes from a large integrated health system which recently implemented anal screening. STUDY DESIGN: Anal Pap tests between May 2007 and August 2009 were studied and correlated with HIV test histories and follow-up histopathologic diagnoses. RESULTS: 688 anal cytologic tests were identified with 7.4% reported as unsatisfactory; 72% of anal cytologic tests were abnormal; 91% of patients were HIV positive. The HIV positive rate and likelihood of high viral load were both significantly greater among patients with abnormal anal cytology than among patients with negative anal cytology, but did not vary significantly among patients with different categories of abnormal anal cytology. For 459 patients with abnormal anal cytology, 198 had anal biopsies. For patients with abnormal anal cytology findings of ASC-US (atypical squamous cells of undetermined significance), LSIL (low-grade squamous intraepithelial neoplasia), ASC-H (atypical squamous cells, cannot exclude high grade squamous lesion), and HSIL (high-grade squamous intraepithelial neoplasia), histopathologic intraepithelial neoplasia (AIN)2/3 or 2/3+ diagnoses were established in 46.5, 56.6, 65, and 80.8%, respectively. CONCLUSIONS: Patients with any level of abnormal anal cytology result are at significant risk of the presence of histopathologically verifiable high-grade anal intraepithelial lesions. More specific markers for identifying patients at highest risk of progression to invasive anal carcinoma are needed. PMID- 22236748 TI - Exfoliative cytology and cytocentrifuge preparation of oral premalignant and malignant lesions. AB - OBJECTIVE: Oral exfoliative cytology is a sensitive and reliable diagnostic tool for the early diagnosis of oral cancer. Traditional exfoliative cytology, though popular, has limitations which could be overcome using cytocentrifuge preparations. The purpose of this study was to compare the efficacy of cytocentrifuged specimens with that of conventionally prepared smears in the diagnosis of oral premalignancy and malignancy. STUDY DESIGN: Exfoliative cytology was performed on 30 patients with oral premalignant and malignant lesions. The yield was smeared immediately onto a slide for conventional exfoliative cytology (group A). The lesion was then scraped again and the yield was suspended in a bottle containing a fixative solution for cytocentrifuge apparatus-assisted smearing (group B). Both smears were stained with rapid Papanicolaou stain and assessed for cellularity, cellular and nuclear morphology, evaluation of mitosis and background. RESULT: All the criteria assessed were statistically significant (p value of <0.001) in group B except for mitosis, which was significant in group A. CONCLUSION: Cytocentrifuge preparations can preserve the cellular details and reduce the overlapping of cells, enabling precise interpretation and thus aiding in the diagnosis of premalignant and malignant lesions of the oral cavity. PMID- 22236749 TI - Application of a new liquid-based procedure (TACAS) for the screening of cervical cancer: a preliminary study. AB - OBJECTIVE: To evaluate the usefulness of a new liquid-based cytological procedure in a population screening program for cervix cancer. SUBJECTS AND METHODS: Subjects were 1,000 women who underwent primary screening at the Kanagawa Health Service Association. The cytological specimens obtained by either cotton stick and Cytobrush(r) or Cervex-Brush(r) were processed using the Thinlayer Advanced Cytology Assay System (TACASTM), following the manufacturer's instructions. RESULTS: (1) Cells were evenly distributed on specimens and stained evenly; (2) shrinkage of cells was 5% based on measurement of the nuclear diameters of granulocytes in comparison with those of the conventional procedure; (3) incidences of cells that occupied the whole area, 1/20<=, 1/4<=, 1/4> of the observation fields were 58.8, 26.2, 12.0 and 3.0%, respectively; (4) number of the squamous cells in cases with 1/4> was <5,000, in which specimen cells were correctly obtained from the squamocolumnar junction except in 3 cases (0.3%); (5) bleeding at cellular sampling was 5%, but did not disturb cell analysis; (6) inflammation caused by organisms was easily diagnosed; (7) detection rate of abnormal cytology was 4.3%, including ASC-US in 2.8% and ASC-H in 0.1%. CONCLUSION: TACAS is a feasible and useful cytological procedure. PMID- 22236750 TI - Prevalence of human papilloma virus in esophageal carcinomas: a polymerase chain reaction-based study. AB - OBJECTIVES: Human papilloma virus (HPV) has been repeatedly found in esophageal carcinoma tissues. However, detection rates of HPV DNA in these tumors have varied markedly. Differences in detection methods, sample types and geographic regions of the sample origin have been suggested as potential causes of this discrepancy. This study was undertaken to analyze the prevalence of HPV in esophageal carcinoma. STUDY DESIGN: HPV L1 DNA was evaluated in a total of 49 esophageal carcinoma samples, including 44 cases of squamous cell carcinoma (SCC) and 5 cases of adenocarcinoma. Seventeen control samples of esophageal brushings were also analyzed. The HPV L1 fragment was detected using MY09/MY11 primers. RESULTS: In test samples, 17/49 (34.7%) were positive for HPV L1 and, in comparison, none of the control samples were positive. HPV DNA was identified in 17/37 (46%) cases of non-keratinizing SCC and was not identified in any case of esophageal keratinizing SCC and adenocarcinoma. CONCLUSION: This study defines a significant association of HPV with esophageal non-keratinizing SCC. Our findings raise the possibility that HPV is involved in esophageal carcinogenesis, especially the non-keratinizing type of SCC. Further investigation with a larger sample size over broader geographic areas may be warranted. PMID- 22236751 TI - Lymphoepithelioma-like carcinoma of the breast: cytological and histological features and review of the literature. AB - OBJECTIVE: We present, for the first time, the cytological features of lymphoepithelioma-like carcinoma (LELC) of the breast in preoperative fine-needle aspiration (FNA) and touch imprints from secondary deposits in the sentinel lymph node (SLN). STUDY DESIGN: We report a case of a 53-year-old woman who was diagnosed with breast carcinoma on preoperative FNA and was subjected to SLN biopsy, partial mastectomy and axillary lymph node dissection. The final diagnosis was LELC of the breast. Cytological and histological features were analyzed. RESULTS: The smears from preoperative FNA contained cohesive clusters and isolated tumour cells in a haemorrhagic background with scattered lymphocytes. Some of the clusters were infiltrated by the inflammatory cells. The cells had large, pleomorphic nuclei and scanty, ill-defined cytoplasm. The intraoperative touch imprints from the SLN were highly cellular, comprising abundant scattered lymphoid cells, among which were tight clusters of indistinct cells, about 3 times larger than the lymphocyte population. CONCLUSION: In our case, LELC shares many cytological features with LELC described in other organs. Immunostains with epithelial markers play an important role in establishing the epithelial nature of the neoplastic cells. LELC should be borne in mind in the evaluation of breast lesions with prominent lymphoid cell infiltration. Its cytological features, as presented, could contribute to its preoperative evaluation on cytological grounds. PMID- 22236752 TI - Vaginal stump metastasis from sigmoid colon cancer. AB - BACKGROUND: Vaginal metastasis from organs other than the uterus is rare. Generally, patients with vaginal metastasis from colorectal cancer have a dismal prognosis. Although biopsy is the best method to make the diagnosis, massive bleeding may occur. On the other hand, liquid-based cytology (LBC) has the utility to perform immunocytochemistry on additional unstained slides: we can make a diagnosis with several immunocytochemical findings. CASE: A 67-year-old postmenopausal female presented to our hospital with vaginal bleeding. The patient had undergone colectomy because of her stage III sigmoid colon cancer 3 years earlier. The patient had also undergone hysterectomy for cervical cancer 30 years earlier. LBC from the vaginal stump revealed adenocarcinoma. Immunocytochemically, cancer cells were negative for cytokeratin 7 and positive for cytokeratin 20, which suggested metastasis from the sigmoid colon cancer; the diagnosis was made without a biopsy. CONCLUSION: When the patient has a metastatic lesion from colon adenocarcinoma, LBC with immunocytochemistry is useful in making a diagnosis. PMID- 22236753 TI - Fine-needle aspiration cytology of metastatic oligodendroglioma: case report and literature review. AB - BACKGROUND: Systemic metastasis of a glial tumor is a rare event. However, metastatic cases are anticipated to increase due to prolongation of survival as a result of the development of new treatment modalities. The possibility of metastasis should be considered in patients with a history of a glial tumor rather than a second primary tumor. Fine-needle aspiration cytology is one of the diagnostic procedures primarily applied for confirmation of metastasis in cases with a known primary focus. Therefore, comprehensive knowledge of diagnostic cytomorphologic findings is required in these cases. CASE REPORT: We report a young woman with oligodendroglioma metastasizing to the cervical lymphatic chain 5 years after initial diagnosis. Fine-needle aspiration cytology revealed a highly cellular smear with dispersed single cells and loosely cohesive cell clusters showing rosette-like features on a clean background. The relatively monotonous tumor cells were small sized and had round nuclei with moderate anisonucleosis and scant cytoplasm without extensions. Diagnostic confirmation was made by excisional biopsy and demonstration of 1p19q codeletion on tissue section by fluorescence in situ hybridization. CONCLUSION: A brief review of the literature with an emphasis on the cytologic features of metastatic oligodendroglioma and differential diagnosis with respect to other metastatic small round cell tumors is provided. PMID- 22236754 TI - The chance identification of unusual-appearing bacteria in bronchoalveolar lavage fluid. AB - BACKGROUND: A well-known indication for the cytologic examination of bronchoalveolar lavage (BAL) fluid is the identification of infectious organisms. However, an important distinction must be made as to whether the organisms seen represent a true opportunistic lower respiratory tract infection or a non pathologic contamination. CASE: We describe herein the case of a 13-month-old male infant who presented with persistent chest congestion and tracheobronchitis and who underwent BAL as part of his clinical work-up. On cytological examination of the BAL fluid, the Romanowsky-stained cytospin slides contained numerous squamous epithelial cells with some showing rare striated rod-like structures on their surfaces. The peculiar structures also had rounded ends and were very large when compared to adjacent known bacterial cocci. CONCLUSION: We have determined that the striated rod-like structures in the infant's BAL fluid were indeed bacteria, Simonsiella sp. Simonsiella has reportedly been found in up to 32% of oral swabs in normal humans and it is considered a commensal and non-pathogenic organism. The characteristically large size, the association with normal oral derived squamous cells and the striated appearance is diagnostic and will hopefully eliminate any possibility of confusion with a truly pathogenic organism. PMID- 22236755 TI - Familial adenomatous polyposis-associated papillary thyroid carcinoma shows an indolent course and usually, but not always, belongs to the cribriform-morular variant of papillary thyroid carcinoma. PMID- 22236756 TI - From feathers to syngas - technologies and devices. AB - The poultry waste produced by industrial slaughterhouses typically contains not only feathers, but also a mixture of animal entrails, nails, blood, beaks and whole carcasses. Economical utilisation of this mixture, varying strongly in composition and moisture content, is, in general, difficult. We demonstrate that this awkward material can be successfully used for gasification in a simple, fixed-bed gasifier. The method of gasification, which we developed, enables control of the gasification process and ensures its stability in the operational regime of a working poultry processing plant. The installation, which has been working in Poland for 2 years, utilises 2 tons of feathers per hour and produces syngas of stable composition and fairly high quality. The syngas is burnt in the combustion chamber adjacent to the gasifier. Heat is recuperated in a boiler producing 3.5 tons per hour of technological steam continuously used for the operation of the slaughterhouse. The whole process complies with the stringent emission standards. In the paper we present the end-use device for feather utilisation and describe the underlying gasification and syngas combustion processes. Key elements of the whole installation are briefly discussed. The environmental impacts of the installation are summarized. PMID- 22236757 TI - Advanced aspects of thermal treatment of solid wastes: from a flue gas to a fuel gas technology? PMID- 22236758 TI - Low-force AFM nanomechanics with higher-eigenmode contact resonance spectroscopy. AB - Atomic force microscopy (AFM) methods for quantitative measurements of elastic modulus on stiff (>10 GPa) materials typically require tip-sample contact forces in the range from hundreds of nanonewtons to a few micronewtons. Such large forces can cause sample damage and preclude direct measurement of ultrathin films or nanofeatures. Here, we present a contact resonance spectroscopy AFM technique that utilizes a cantilever's higher flexural eigenmodes to enable modulus measurements with contact forces as low as 10 nN, even on stiff materials. Analysis with a simple analytical beam model of spectra for a compliant cantilever's fourth and fifth flexural eigenmodes in contact yielded good agreement with bulk measurements of modulus on glass samples in the 50-75 GPa range. In contrast, corresponding analysis of the conventionally used first and second eigenmode spectra gave poor agreement under the experimental conditions. We used finite element analysis to understand the dynamic contact response of a cantilever with a physically realistic geometry. Compared to lower eigenmodes, the results from higher modes are less affected by model parameters such as lateral stiffness that are either unknown or not considered in the analytical model. Overall, the technique enables local mechanical characterization of materials previously inaccessible to AFM-based nanomechanics methods. PMID- 22236759 TI - Response to--Blood Pressure Monitoring 2011; 16: 67-73. PMID- 22236760 TI - Modeling of Clostridium perfringens vegetative cell inactivation in beef-in-sauce products: a meta-analysis using mixed linear models. AB - The aim of the present study was to predict Clostridium perfringens vegetative cell inactivation during the final reheating step of two beef-in-sauce products prepared and distributed in a French hospital for exposure in risk assessment. In order to account for variability according to experts and international organization recommendations, published data were used to estimate the thermal inactivation parameters of a probabilistic model. Mixed effects models were proposed to describe variability on D(ref) the decimal reduction time at temperature T(ref). Many models differing by their description of variability on D(ref) were tested. Based on goodness-of-fit and parsimony of the model, the one including three random effects was chosen. That model describes random effects of vegetative cell culture conditions, strains and other uncontrolled experimental factors. In order to check the ability of the model to predict inactivation under dynamic thermal conditions, model validation was carried out on published non isothermal data. This model was then used to predict C. perfringens vegetative cell inactivation using temperature profiles inside beef-in-sauce products registered in a French hospital and to explore control measures easier to apply than French regulations. PMID- 22236761 TI - Maple sap predominant microbial contaminants are correlated with the physicochemical and sensorial properties of maple syrup. AB - Maple sap processing and microbial contamination are significant aspects that affect maple syrup quality. In this study, two sample sets from 2005 and 2008 were used to assess the maple syrup quality variation and its relationship to microbial populations, with respect to processing, production site and harvesting period. The abundance of maple sap predominant bacteria (Pseudomonas fluorescens group and two subgroups, Rahnella spp., Janthinobacterium spp., Leuconostoc mesenteroides) and yeast (Mrakia spp., Mrakiella spp.,Guehomyces pullulans) was assessed by quantitative PCR. Maple syrup properties were analyzed by physicochemical and sensorial methods. Results indicate that P. fluorescens, Mrakia spp., Mrakiella spp. G. pullulans and Rahnella spp. are stable contaminants of maple sap, as they were found for every production site throughout the flow period. Multiple factor analysis reports a link between the relative abundance of P. fluorescens group and Mrakia spp. in maple sap with maple and vanilla odor as well as flavor of maple syrup. This evidence supports the contribution of these microorganisms or a consortium of predominant microbial contaminants to the characteristic properties of maple syrup. PMID- 22236762 TI - In vitro and in situ antimicrobial action and mechanism of glycinin and its basic subunit. AB - Glycinin, basic subunit and beta-conglycinin were isolated from soybean protein isolate and tested for their antimicrobial action against pathogenic and spoilage bacteria as compared to penicillin. The three fractions exhibited antibacterial activities equivalent to or higher than penicillin in the next order; basic subunit>glycinin>beta-conglycinin with MIC of 50, 100 and 1000 MUg/mL, respectively. The IC(50%) values of the basic subunit, glycinin and beta conglycinin against Listeria?monocytogenes were 15, 16 and 695 MUg/mL, against Bacillussubtilis were 17, 20, and 612 MUg/mL, and against S. Enteritidis were 18, 21 and 526 MUg/mL, respectively. Transmission electron microscopy images of L. monocytogenes and S. Enteritidis exhibited bigger sizes and separation of cell wall from cell membrane when treated with glycinin or basic subunit. Scanning electron microscopy of B. subtilis indicated signs of irregular wrinkled outer surface, fragmentation, adhesion and aggregation of damaged cells or cellular debris when treated with glycinin or the basic subunits but not with penicillin. All tested substances particularly the basic subunit showed increased concentration-dependent cell permeation assessed by crystal violet uptake. The antimicrobial action of glycinin and basic subunit was swifter than that of penicillin. The cell killing efficiency was in the following descending order; basic subunit>glycinin>penicillin>beta-conglycinin and the susceptibility of the bacteria to the antimicrobial agents was in the next order: L. monocytogenes>B. Subtilis>S. Enteritidis. Adding glycinin and the basic subunit to pasteurized milk inoculated with the three bacteria; L. monocytogenes, B. Subtilis and S. Enteritidis (ca. 5 log CFU/mL) could inhibit their propagation after 16-20 days storage at 4 degrees C by 2.42-2.98, 4.25-4.77 and 2.57-3.01 log and by 3.22 3.78, 5.65-6.27 and 3.35-3.72 log CFU/mL, respectively. PMID- 22236763 TI - Intraparenchymal papillary meningioma of brainstem: case report and literature review. AB - Both intraparenchymal papillary meningioma and papillary meningioma with cyst formation of brainstem have never been reported. The authors present an extremely rare case of patient with intraparenchymal papillary meningioma of brainstem. A 23-year-old Chinese male presented with a 4-month history of progressive left upper limb and facial nerve palsy. Magnetic resonance imaging revealed a cystic solid, heterogeneously enhancing mass in pons and right cerebral peduncle with no dural attachment. The tumor was totally removed via subtemporal approach. During surgery, the lesion was found to be completely intraparenchymal. Histological and immunohistochemical examinations were compatible with the diagnosis of papillary meningioma. The lesion recurred nine months after primary surgery, a second surgery followed by radiotherapy was performed. Till to now (nearly 2 years after the treatment), the patient is tumor free survival. Intraparenchymal meningioma of brainstem with cystic formation is very rare, however, it should be considered as a differential diagnosis of a brainstem neoplasm. The present case strongly recommended that postoperative radiotherapy was essential for the patients with papillary meningiomas. PMID- 22236764 TI - Chewing pattern and muscular activation in open bite patients. AB - Different studies have indicated, in open bite patients, that masticatory muscles tend to generate a small maximum bite force and to show a reduced cross-sectional area with a lower EMG activity. The aim of this study was to evaluate the kinematics parameters of the chewing cycles and the activation of masseters and anterior temporalis muscles of patients with anterior dental open bite malocclusion. There have been no previous reports evaluating both kinematic values and EMG activity of patients with anterior open bite during chewing. Fifty two young patients (23 boys and 29 girls; mean age+/-SD 11.5+/-1.2 and 10.2+/ 1.6years, respectively) with anterior open bite malocclusion and 21 subjects with normal occlusion were selected for the study. Kinematics parameters and surface electromyography (EMG) were simultaneously recorded during chewing a hard bolus with a kinesiograph K7-I Myotronics-Usa. The results showed a statistically significant difference between the open bite patients and the control group for a narrower chewing pattern, a shorter total and closing duration of the chewing pattern, a lower peak of both the anterior temporalis and the masseter of the bolus side. In this study, it has been observed that open bite patients, lacking the inputs from the anterior guidance, that are considered important information for establishing the motor scheme of the chewing pattern, show narrower chewing pattern, shorter lasting chewing cycles and lower muscular activation with respect to the control group. PMID- 22236765 TI - A method for identifying the origin of chondroitin sulfate with near infrared spectroscopy. AB - The object of this study was to explore the feasibility of support vector machine (SVM) to identify the origin of chondroitin sulfate (CS) by near infrared spectroscopy. 96 batches CS from three different origins were collected in this research, 66 batches of which were chosen for training set by Kennard-Stone (KS) method and the rest were used for testing. Through the comparison of pretreatment methods of standard normal variate transformation (SNV), multiplicative scatter correction (MSC), Savitzky-Golay (SG) smoothing and derivative with SG smoothing, a SVM discrimination model was constructed, of which the prediction result is 100% accurate with the pretreatment of first derivative and SG smoothing with 15 points. The result indicated that it had great potential using SVM to identify the origin of CS. PMID- 22236766 TI - Rate of recurrence following stereotactic aspiration of colloid cysts of the third ventricle. AB - BACKGROUND: The rate of recurrence following stereotactic aspiration of colloid cysts is not defined in the literature. AIMS: To study the long-term imaging and clinical outcome in patients who had stereotactic aspiration of colloid cysts of the third ventricle. METHODS: Between 1987 and 1994, computerized tomography guided stereotactic aspiration was attempted in 26 consecutive patients with colloid cysts of the third ventricle. RESULTS: There was no mortality or permanent morbidity. A complete aspiration of the cyst was possible in 17 patients, a partial aspiration of the cyst was achieved in 6 and the aspiration failed in 3 patients. On long-term follow-up, symptomatic recurrence was noted in 5/6 patients after partial aspiration and 4/17 patients after complete aspiration (mean follow-up 84.8 months). Kaplan-Meier analysis revealed that after complete aspiration of the cyst, median time to recurrence on imaging is 42 months (95% CI 23.0-60.9 months) but median time to symptomatic recurrence is much later at 184 months (95% CI 88.2-279.7 months). CONCLUSIONS: Stereotactic aspiration of colloid cysts remains a valid surgical option as complete aspiration leads to a good long-term outcome in several patients. Partial aspiration of the cyst should be followed by excision of the cyst, due to the high rate of symptomatic recurrence. However, periodic follow-up imaging is mandatory even after complete aspiration as delayed recurrences are possible. PMID- 22236767 TI - The effect of growth factors and soluble Nogo-66 receptor protein on transplanted neural stem/progenitor survival and axonal regeneration after complete transection of rat spinal cord. AB - Adult central mammalian axons show minimal regeneration after spinal cord injury due to loss of oligodendrocytes, demyelination of surviving axons, absence of growth-promoting molecules, and inhibitors of axonal outgrowth. In the present study, we attempted to address these impediments to regeneration by using a combinatory strategy to enhance cell survival and regeneration after complete spinal cord transection (SCT) in adult rats. The strategy comprised: 1) adult rat brain-derived neural stem/progenitor cells (NSPCs) preseeded on laminin-coated chitosan channels; 2) extramedullary chitosan channels to promote axonal regrowth and reduce the barrier caused by scarring; 3) local delivery of a novel rat soluble Nogo-66 receptor protein [NgR(310)ecto-Fc, referred to as NgR] to block the inhibitory effect of myelin-based inhibitors; and 4) local delivery of basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor to enhance survival and promote differentiation of transplanted cells. Compared with our previous studies where brain-derived NSPCs preseeded in extramedullary chitosan channels were implanted in the same SCT model but without growth factors and NgR, the present channel-growth factor combination produced greater numbers of surviving NSPCs after SCT. Also, the growth factors promoted preferential differentiation of NSPCs toward oligodendrocytes, while NgR significantly decreased astrocytic differentiation of NSPCs. NgR alone or in combination with NSPCs significantly enhanced the total number of myelinated fibers in the bridge and increased the area of the bridging tissue between the cord stumps. The combination of NgR, growth factors, and NSPCs had synergistic effect on bridge formation. However, only a small number of descending corticospinal tract axons grew into the central portions of the bridges as shown by anterograde tracing of the corticospinal tract with BDA. The majority of the regenerated axons in the channels originated from local host neurons adjacent to the tissue bridges. In conclusion, we showed that growth factors increased survival of transplanted NSPCs whereas NgR enhanced axonal regeneration, but the combination did not have additive effects on functional recovery or regeneration. PMID- 22236768 TI - Electron beam radiotherapy for tongue cancer using an intra-oral cone. AB - To explain the adaptation technique using an intra-oral cone (IOC) for radiation therapy, and to determine the optimal schedule resulting in a high local control rate and an acceptable complication rate using direct electron beam radiation for the treatment of tongue cancer. Thirty patients with the tongue cancer (T1:T2:T3=16:11:3) were treated with 6-15 MeV electron radiation using an IOC. Twenty-six patients were treated with electron radiation using an IOC with or without an excisional biopsy. The other four patients were treated with a combination of the external beam radiation and electron radiation using the IOC. In order to formulate a safe and effective treatment program, we calculated the biologically effective dose (BED). The two- and five-year local control rates for all patients were 63% and 52%, respectively. The two- and five-year overall survival rates for all patients were 73% and 69%, respectively. Local control was achieved in 12 of 15 patients who were irradiated with a BED of 90.9 Gy(10) or more, whereas it was not achieved in nine of the 15 patients who were treated with less than a BED of 90.9 Gy(10) (p=0.03). The application of electron radiation using an IOC for the treatment of tongue cancer provides acceptable local control and adverse effect rates, especially for elderly patients considered to be high risk for complications from anesthesia. The optimum BED(10) value for the treatment of early tongue cancer using the IOC technique appears to be at least 90.9 Gy(10). PMID- 22236769 TI - Conformation of poly-L-glutamate is independent of ionic strength. AB - CD and UV resonance Raman measurements surprisingly find that the charge screening of even 2 M concentrations of NaCl and KCl does not alter the unfolded PPII and 2.5(1)-helix conformations of poly-L-glutamate. These salts appear to be excluded from the region between the side chain charges and the peptide backbone. Furthermore, no direct ion pairing occurs between these salts and the side chain carboxylates. PMID- 22236770 TI - Leucite-reinforced glass ceramic inlays luted with self-adhesive resin cement: a 2-year in vivo study. AB - OBJECTIVES: Aim of the present prospective controlled clinical study was to compare the clinical performances of two different cementation procedures to lute IPS Empress inlays and onlays. METHODS: Eighty-three IPS Empress restorations (70 class-II inlays, 13 onlays/47 premolars, 36 molars) were placed in 30 patients (19 females/11 males, mean age=39 years). Two cementation procedures were tested: group 1: forty-three restorations were luted with a self-adhesive resin cement (RelyX Unicem, RX, 3M ESPE); group 2: forty restorations were luted with an etch and-rinse multistep adhesive (Syntac Classic, Ivoclar-Vivadent) and Variolink II low (SV, Ivoclar-Vivadent). All restorations were evaluated after 2 weeks (baseline=1st recall=R1, n=83), 6 months (R2, n=83), 1 year (R3, n=82), and 2 years (R4, n=82) by two independent blinded calibrated examiners using modified USPHS criteria. RESULTS: From R1 to R4, one failure occurred in the SV group (at R2) due to marginal enamel chipping. After 2 years of clinical service (R4), better marginal and tooth integrity (p<0.05) was found in group 2 (SV) compared to the use of the self-adhesive cement (RX, group 1), while no differences were found for all remaining investigated criteria (p>0.05). The absence of enamel in proximal boxes (10% with no enamel and 51% of the restorations with less than 0.5mm enamel width at the bottom of the proximal box) did not affect marginal performance (p>0.05). SIGNIFICANCE: The self-adhesive resin cement RelyX Unicem showed clinical outcomes similar to a conventional multi-step cementation procedure after 2 years of clinical service for most of the tested criteria. PMID- 22236772 TI - Child maltreatment and adult violent offending: population-based twin study addressing the 'cycle of violence' hypothesis. AB - BACKGROUND: Associations between child maltreatment and adult violence, often termed the 'cycle of violence', are well documented. However, the nature of such links after appropriate control for confounding remains uncertain. We aimed to determine whether child maltreatment causes adult violent offending or whether suggested links are due to genetic or family environment confounding. METHOD: A total of 18 083 20- to 47-year-old twins from the Swedish population-based Study of Twin Adults: Genes and Environment (STAGE) participated. We linked information on self-reported child maltreatment with national register data on convictions for adult crime. We used a case-control design to elucidate associations among unrelated individuals and also conducted within-discordant twin pair analyses to estimate the influence of familial confounding on this association. RESULTS: The odds ratio (OR), adjusted for age, sex and education, for violent offending in maltreated children grown up versus unrelated controls was 1.98 [95% confidence interval (CI) 1.52-2.57]. However, the association decreased to 1.18 (95% CI 0.62 2.25) when maltreated children were compared to their non-maltreated twins, suggesting substantial confounding by genetic or family environmental factors (within-twin OR<1.98) and a weak, non-significant causal effect (within-twin OR>1.00). Familial confounding was also pronounced for the association between child maltreatment and any offending. CONCLUSIONS: Childhood maltreatment was found to be a weak causal risk factor for adult violent offending; hence, reducing maltreatment might decrease violent crime less than previously expected. Instead, considerable familial confounding of the link between child maltreatment and adult violent offending suggests that prevention strategies need to address overlapping genetic and/or family environmental liability for abusive and violent behavior. PMID- 22236771 TI - Delineation and diagnostic criteria of Oral-Facial-Digital Syndrome type VI. AB - Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma. PMID- 22236773 TI - Pulmonary hypertension and macrocephaly in a newborn. PMID- 22236774 TI - Conformations, dynamics and interactions of di-, tri- and pentamannoside with mannose binding lectin: a molecular dynamics study. AB - The binding of serum mannose-binding protein A (MBP-A) to high mannose N-linked glycoproteins, present on the surface of microorganism, activates the complement system. It is very important to explore the overall conformations of these ligands in the binding site of the MBP-A, which is very much dependent on the conformation of the manno-di-, tri- and the penta-saccharides that represent the component structures of these high-mannose type oligosaccharides. Herein, we report the possible conformations of alpha-(1->6)-linked dimannoside, benzyl substituted trimannoside and core pentamannoside of the N-linked glycan in the binding site of MBP-A, with the help of molecular dynamics simulations. The results indicate that for all three ligands in addition to the non-reducing terminal mannose moiety the reducing moieties also interact with protein. Binding free energy calculations also indicate that the benzyl-substituted trisaccharide has higher affinity in comparison to the methyl substituted one. We have also found some conformers of the pentasaccharide, which have higher binding affinity than the monosaccharide. PMID- 22236775 TI - Characteristics of muscle fibers in rats with limb movements during sleep after spinal cord injury. AB - BACKGROUND/AIMS: Previous studies have demonstrated that spinal cord injury (SCI) results in changes in sleep patterns through increased arousals and limb movements during sleep. Dramatic changes in muscle myosin heavy-chain isoforms have also been reported. The aim of this study was to investigate the characteristics of muscle fibers after SCI in rats with limb movements during sleep. METHODS: Forty male Wistar rats were divided into four groups: SHAM, SCI 3, 7 and 15 days. Animals were subjected to electrode insertion surgery, 24-hour baseline sleep recording, SCI, and subsequent sleep recording for 3, 7, or 15 consecutive days. In addition, the gastrocnemius muscle and spinal cord were collected for histopathological/histochemical analyses. RESULTS: Our results indicate a rapid and progressive decrease in the cross-sectional area of type I fibers in the gastrocnemius muscle (35.76-24.74 MUm(2)) after SCI. Additionally, we found SCI-induced changes in sleep patterns. Following SCI, we also observed limb movements in sleeping rats, as well as significant negative moderate correlations between type I fibers and limb movement. CONCLUSION: Our study strengthened the hypothesis by correlation between changes in types of muscle fiber (decline in type I fibers) and an increase in limb movements during sleep after SCI. PMID- 22236776 TI - Clonogenic assays are of limited value in discriminating patients with myelodysplastic syndrome and patients with megaloblastic anemia. PMID- 22236777 TI - Steps solidifying a role for SEPT9 in breast cancer suggest that greater strides are needed. AB - Septins comprise a conserved family of GTPase proteins. Of these, human SEPT9 has been widely implicated in cancers of epithelial origin, including breast cancer, as well as leukemia. In a previous issue of Breast Cancer Research, Connolly and colleagues present compelling data further supporting a role for SEPT9 isoforms in early breast cancer development as well as evidence suggesting that cellular localization patterns of SEPT9 isoforms may contribute to oncogenesis. PMID- 22236778 TI - Bimetallic PtM (M=Pd, Ir) nanoparticle decorated multi-walled carbon nanotube enzyme-free, mediator-less amperometric sensor for H2O2. AB - A new highly catalytic and intensely sensitive amperometric sensor based on PtM (where M=Pd, Ir) bimetallic nanoparticles (NPs) for the rapid and accurate estimation of hydrogen peroxide (H(2)O(2)) by electrooxidation in physiological conditions is reported. PtPd and PtIr NPs-decorated multiwalled carbon nanotube nanocatalysts (PtM/MWCNTs) were prepared by a modified Watanabe method, and were characterized by XRD, TEM, ICP, and XAS. The sensors were constructed by immobilizing PtM/MWCNTs nanocatalysts in a Nafion film on a glassy carbon electrode. Both PtPd/MWCNTs and PtIr/MWCNTs assemblies catalyzed the electrochemical oxidation of H(2)O(2). Cyclic voltammetry characterization measurements revealed that both the PtM (M=Pd, Ir)/MWCNTs/GCE possessed similar electrochemical surface areas (~0.55 cm(2)), and electron transfer rate constants (~1.23 * 10(-3)cms(-1)); however, the PtPd sensor showed a better performance in H(2)O(2) sensing than did the PtIr counterpart. Explanations were sought from XAS measurements to explain the reasons for differences in sensor activity. When applied to the electrochemical detection of H(2)O(2), the PtPd/MWCNTs/GC electrode exhibited a low detection limit of 1.2 MUM with a wide linear range of 2.5-125 MUM (R(2)=0.9996). A low working potential (0V (SCE)), fast amperometric response (<5s), and high sensitivity (414.8 MUA mM(-1)cm(-2)) were achieved at the PtPd/MWCNTs/GC electrode. In addition, the PtPd/MWCNTs nanocatalyst sensor electrode also exhibited excellent reproducibility and stability. Along with these attractive features, the sensor electrode also displayed very high specificity to H(2)O(2) with complete elimination of interference from UA, AA, AAP and glucose. PMID- 22236779 TI - Electrochemical growth of gold nanoparticles on horizontally aligned carbon nanotubes: a new platform for ultrasensitive DNA sensing. AB - A new platform based on electrochemical growth of Au nanoparticles on horizontally aligned single walled carbon nanotube (SWCNT) array was developed for ultrasensitive DNA detection. The as-prepared DNA-functionalized SWCNT-Au platform, in which every gold-coated SWCNT acts as an isolated micro electrode, could detect lower than 10 zmol complimentary 10-base DNA, which corresponded to having 6 DNA molecules in a 1 mL sample solution. For a 1-base mismatched DNA, the experimental detection limit was 100 amol. A linear relationship between the change of charge transfer resistance and target DNA concentration was achieved at low concentration range. Over the extended DNA concentration range, the change of charge transfer resistance was found to have a linear relationship with respect to the logarithm of the target DNA concentration. The sensor also showed great stability and could be conveniently regenerated via dehybridization in hot water. The significant improvement in sensitivity illustrates that combining Au nanoparticles with the on-site fabricated SWCNT array represents a promising platform for achieving ultrasensitive biosensor. PMID- 22236780 TI - DNA-directed capture of primary cells from a complex mixture and controlled orthogonal release monitored by SPR imaging. AB - Many biological samples are composed of several cell types. Qualitative and quantitative analysis of these complex mixtures is of major interest for both diagnostic and biomedical applications. Because large amounts of biological material are often challenging to collect, tremendous efforts have been made for a decade to design miniaturized platforms-such as lab-on-a-chip or microarrays-to run sensitive and reliable analysis from tiny quantities of starting material. Although barely explored so far, the release of resolved cellular samples constitutes an exciting strategy for further cell analysis. Herein, we propose a DNA-based biochip suitable for cell-type analysis in a label-free manner. The DNA array is firstly converted into antibody-array using antibody-DNA conjugates. These protein-DNA hybrid molecules are chemically synthesized by covalent coupling of short oligonucleotides to antibodies directed against cell-type specific markers. We show not only specific capture of primary spleen cells on protein-DNA microarray spots but also their fast and specific orthogonal release according to the antibody-DNA combinations by incorporating restriction sites in DNA. Both molecular and cellular interactions occurring on the biochip are monitored by surface plasmon resonance (SPR) imaging. This optical technique turns out to be a powerful way to monitor, in real-time, biological interactions occurring on the microarrayed features. PMID- 22236781 TI - Impact of keratoconus, cross-linking and cross-linking combined with photorefractive keratectomy on self-reported quality of life. AB - PURPOSE: To assess the effect of stage 1 keratoconus (KC) and of the 2 prevalent KC therapeutic options: (1) corneal collagen cross-linking (CXL) and (2) CXL combined with topography-guided photorefractive keratectomy (t-PRK) on self reported quality of life (QOL) by means of the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25). METHODS: Thirty-two patients with bilateral KC stage 1 (KC group) and best-corrected visual acuity of 20/20 in both eyes were prospectively recruited. Of them, 19 KC patients underwent typical CXL treatment (CXL group), whereas 13 underwent CXL combined with t-PRK treatment (tCXL group). Only the eye with the most advanced condition received the treatment. Subjects responded to the NEI-VFQ 25 1 day before the treatment and 1 year postoperatively. Thirty-nine age-matched contact lens users formed the control group. NEI-VFQ 25 subscale and total scores were associated with spherical equivalent, mean keratometry, and a series of Scheimpflug imaging derived corneal variance indexes by means of the Spearman correlation coefficient and multivariate linear regression analysis. RESULTS: Preoperatively, significant differences were detected between the KC group and the control group in VFQ 25 total and all subscale scores (P < 0.05), except "general health," "color vision," and "peripheral vision" domains. According to the multivariate linear regression analysis, the index of height decentration was the most significant predictor of VFQ 25 total score (b = 0.943; P = 0.016). Postoperatively, significant differences were detected in "mental health" and "dependency" VFQ 25 domains for both the CXL and tCXL groups (P = 0.05). Furthermore, the tCXL group demonstrated significant differences in the "near activities" (P = 0.04), "role limitations" (P = 0.02), and "driving" (P < 0.01) subscale scores. CONCLUSIONS: Our results suggest that KC exerts a significant impact on KC patients' QOL, even in its early stages with normal best-spectacle-corrected visual acuity. Moreover, both CXL and CXL combined with t-PRK seem to exert a beneficial impact on self reported QOL, suggesting that they should be applied as soon as possible. PMID- 22236783 TI - Long-term outcomes of penetrating keratoplasty for keratoconus with resolved corneal hydrops. AB - PURPOSE: To address the controversial issue of whether the occurrence of corneal hydrops adversely affects the fate of subsequent penetrating keratoplasty (PK), this study compared the long-term outcomes of PK in keratoconic eyes with resolved corneal hydrops with those without prior corneal hydrops. METHODS: This was a retrospective chart review of 102 eyes of 102 patients with keratoconus who underwent PK. The primary outcome measure was endothelial rejection-free allograft survival and the secondary outcomes were vision, postoperative complications, and histopathologic findings of corneal buttons obtained during PK. RESULTS: The mean follow-up after PK was 5.5 +/- 3.3 years. The Kaplan-Meier endothelial rejection-free allograft survival at 1 and 5 years post-PK were 93.7% +/- 4% and 82.6% +/- 7%, respectively, in 32 eyes with hydrops and 100% and 98% +/- 2%, respectively, in 70 eyes without hydrops (P = 0.04). Multivariate analysis showed that the risk of endothelial rejection episodes was greater in eyes with longer duration of corneal hydrops (P = 0.019) and coexistent ocular allergy (P = 0.012). All rejection episodes were reversed medically and only 1 allograft failed because of postoperative endophthalmitis. More than 90% of eyes achieved a visual acuity of better than 20/40. Common postoperative complications were cataract and graft infiltrate. Histopathology in cases of resolved hydrops after intracameral gas showed unique compression artifacts like folding and burial of the broken ends of Descemet membrane in the stroma. CONCLUSIONS: Although endothelial rejection episodes are more common in eyes with resolved corneal hydrops, long-term allograft survival and visual results after PK in eyes with keratoconus are excellent, irrespective of prior corneal hydrops. PMID- 22236784 TI - Intraocular lens opacifications in Descemet stripping endothelial keratoplasty patients. AB - PURPOSE: To report 3 cases of unexplained intraocular lens (IOL) opacification in patients who previously underwent Descemet stripping endothelial keratoplasty (DSEK). METHODS: Case series. Three pseudophakic eyes of 3 patients, who developed a membraneous opacification of the IOL after uneventful DSEK are presented. RESULTS: In 2 eyes, the opacification interfered with visual acuity. In 1 case, an attempt was made to remove the opacification with the aid of YAG laser and surgically, to no avail, necessitating an IOL explantation. CONCLUSIONS: IOL opacification can occur in eyes previously subjected to DSEK. The majority of patients subjected to DSEK are pseudophakic; surgeons should be aware of this possible complication. To the best of our knowledge, this has not been described in the literature to date. Further research is required to elucidate the nature of such IOL opacifications and possible ways to prevent them. PMID- 22236785 TI - Outcomes of Boston keratoprosthesis implantation for failed keratoplasty after keratolimbal allograft. AB - PURPOSE: To evaluate factors that contribute to keratoplasty failure after keratolimbal allograft (KLAL) and report the outcomes of Boston keratoprosthesis type I (KPro) as salvage therapy. METHODS: Retrospective noncomparative case series of 7 eyes in 7 consecutive patients with ocular surface disease and limbal stem cell deficiency treated with KPro after failed KLAL. Mechanisms of graft failure, KPro device retention rate, and preoperative and postoperative best corrected visual acuities were studied. RESULTS: In the studied cohort, keratoplasty graft failure occurred at an average of 9.9 months (range, 1-17 months) after KLAL. Among the 7 eyes reviewed, 4 had tube shunts, 3 of which contributed directly to endothelial graft failure. One eye failed due to fungal keratitis, 1 eye failed due to immune-mediated endothelial rejection, and 2 eyes failed due to recurrent surface disease. During an average follow-up of 585 days (19.5 months) after KPro, best-corrected visual acuity improved from a median of counting fingers CF@2ft (range, hand motions to 20/400) to a median of 20/400 (range, CF@3ft to 20/25). There was 85.7% (6 of 7) retention of implanted devices at the last follow-up, with 1 eye requiring repeat KPro for corneal melt and implant extrusion after abrupt cessation of immunosuppression. CONCLUSIONS: Despite successful KLAL outcomes and systemic immunosuppression, patients who undergo ocular surface reconstruction with KLAL are still at risk for subsequent keratoplasty failure. Keratoprosthesis is a viable salvage therapy for visual rehabilitation in these patients. Adequate immunosuppression is important in postoperative management of these patients. PMID- 22236786 TI - Treatment of early Acanthamoeba keratitis with alcohol-assisted epithelial debridement. AB - PURPOSE: To study the safety and efficacy of treating early-stage Acanthamoeba keratitis (AK) with 20% alcohol-assisted epithelial debridement. METHODS: Four consecutive patients (2 wearing orthokeratology lenses and 2 wearing soft contact lenses) presented with pseudodendrites, radial keratoneuritis, and epithelial irregularities. Using a technique similar to laser-assisted subepithelial keratomileusis, we performed alcohol-assisted full-thickness debridement of the corneal epithelium and sent portions for smears, histopathologic and ultrastructural examinations, and culture for evidence of Acanthamoeba. Patients were then started on topical propamidine isethionate and 0.02% polyhexamethylene biguanide. RESULTS: Immediately after debridement, minimal underlying anterior stromal infiltrate or haze was seen. Dosages of antiamoebic agents were tapered as corneal defects reepithelialized (in 1-3 weeks) with no evidence of post debridement corneal infection. At the final follow-up, 1 cornea was transparent and the other 3 corneas had very faint subepithelial haze. Cultures of all epithelial debridement specimens yielded Acanthamoeba trophozoites and cysts, and histopathologic and electron microscopic examinations revealed Acanthamoeba organisms within corneal epithelial layers. CONCLUSIONS: Alcohol-assisted epithelial debridement facilitates detachment of the full-thickness corneal epithelial layer in a controlled manner and seems to be effective in the treatment of early-stage AK. Unlike the fragile fragmented specimens obtained by mechanical scraping without alcohol soaking, epithelial sheets detached easily and the architectures were well preserved, permitting histopathologic and ultrastructural examinations. Most importantly, 20% alcohol-assisted epithelial debridement did not prevent culturing of Acanthamoeba from the removed epithelial specimens. PMID- 22236787 TI - Postoperative complications of conjunctival limbal autograft surgery. AB - PURPOSE: To report postoperative complications of conjunctival limbal autograft in patients with unilateral total limbal stem cell deficiency (LSCD). METHODS: In this retrospective observational case series, medical charts of 34 patients with unilateral total LSCD with at least 6 months of follow-up were reviewed. Main outcome measure was postoperative complications. RESULTS: The mean follow-up period was 17.2 +/- 6.3 (range, 6-33) months. The postoperative complications observed included conjunctival encroachment over the graft, small graft, graft dislodging, thick graft, improper position, graft edema, ocular surface exposure, progressive horizontal conjunctivalization, and pyogenic granuloma. Persistent epithelial defect occurred in 5 eyes because of ocular surface exposure (n = 2), conjunctival encroachment (n = 1), and small graft size (n = 2). Epithelial defects healed in 4 of them with sectoral vascularization of the cornea. Optical penetrating keratoplasty was performed on 18 eyes with dense corneal opacification. Persistent epithelial defect occurred in 6 eyes with inadvertent cut limbal graft (n = 2), small limbal graft (n = 2), and ocular surface exposure (n = 2). CONCLUSIONS: Conjunctival limbal autograft is an effective procedure for anatomical and visual rehabilitation of eyes with unilateral total LSCD. However, it may be complicated by several adverse events. The most common complications are related to the transplanted grafts (size, thickness, position, and alignment) and chronic ocular surface exposure, which may later lead to epithelial breakdown and corneal conjunctivalization. PMID- 22236788 TI - Prevalence and risk factors of meibomian gland dysfunction: the Singapore Malay eye study. AB - PURPOSE: To describe the prevalence and associations of meibomian gland dysfunction (MGD) in an urban Malay population in Singapore. METHODS: Population based cross-sectional study of 3280 (78.7% response rate) Malay persons aged 40 to 80 years, living in Singapore. MGD was defined by a slit-lamp clinical examination as either lid margin telangiectasia or meibomian gland orifice plugging in at least one eye. Participants underwent a standardized questionnaire and clinical examination, including laboratory investigations. Data were analyzed for 3271 persons. RESULTS: The age-standardized prevalence of MGD was 56.3% [95% confidence interval (CI), 53.3-59.4]. A higher MGD prevalence was found in male participants across all age groups [odds ratio (OR), 1.30; 95% CI, 1.35-1.79], postmenopausal women (OR, 1.64; 95% CI, 1.19-2.33), and all participants with pinguecula (OR, 2.43; 95% CI, 2.08-2.85), high diastolic blood pressure (OR, 1.32; 95% CI, 1.08-1.62), and use of angiotensin II receptor blockers (OR, 4.02; 95% CI, 1.74-9.27). CONCLUSIONS: MGD was highly prevalent in this Asian population and associated with various systemic and ocular conditions. PMID- 22236789 TI - Repeatability of pachymetric mapping using fourier domain optical coherence tomography in corneas with opacities. AB - PURPOSE: To evaluate the repeatability of Fourier domain optical coherence tomography (OCT) pachymetric mapping in patients with corneal opacities and to assess the reliability of Fourier domain OCT with 830 nm wavelength as a pachymetric measurement tool in opaque corneas. METHODS: A Fourier domain OCT system was used to map the corneal thickness of patients with corneal scars or dystrophy. A retrospective study of a consecutive series was conducted. The repeatability was measured using pooled standard deviation of repeated measurements. A slit-scanning tomography device provided pachymetric mapping for comparison. RESULTS: Seventeen eyes of 12 patients with corneal scars (7 trauma and 3 post infection) or dystrophy (2 Reis-Bucklers and 5 granular dystrophy) were included. The posterior corneal boundary was detectable in all cases. The average corneal thickness measured by OCT was 536 +/- 89 MUm in central 2 mm area, 553 +/- 76 MUm in pericentral 2- to 5-mm area, and 508 +/- 93 MUm for the minimum corneal thickness. The slit-scanning tomography central corneal thickness, 433 +/- 111 MUm, was significantly lower than OCT readings (mean difference -91.1 +/- 33.3 MUm, P = 0.002). Repeatability of the OCT measurements was 2.1 MUm centrally and 1.2 MUm pericentrally. CONCLUSION: Pachymetric mapping with Fourier domain OCT was highly repeatable. Fourier domain OCT is a reliable pachymetric tool in opaque corneas. In comparison, corneal thickness measured by the slit-scanning tomography is significantly thinner than those measured by the Fourier domain OCT in the presence of corneal opacities. PMID- 22236790 TI - Diphosphonium ionic liquids as broad-spectrum antimicrobial agents. AB - PURPOSE: One of the most disturbing trends in recent years is the growth of resistant strains of bacteria with the simultaneous dearth of new antimicrobial agents. Thus, new antimicrobial agents for the use on the ocular surface are needed. METHODS: We synthesized a variety of ionic liquid compounds, which possess 2 positively charged phosphonium groups separated by 10 methylene units in a "bola"-type configuration. We tested these compounds for antimicrobial activity versus a variety of ocular pathogens, as well as their cytoxicity, in vitro in a corneal cell line and in vivo in mice. RESULTS: The ionic liquid Di Hex C10 demonstrated broad in vitro antimicrobial activity at low micromolar concentrations versus gram-negative and gram-positive organisms, including methicillin-resistant Staphylococcus aureus strains and ocular fungal pathogens. Treatment with Di-Hex C10 resulted in bacterial killing in as little as 15 minutes in vitro. Di-Hex C10 showed little cytotoxicity at 1 MUM versus a corneal epithelial cell line or at 10 MUM in a mouse corneal wound model. We also show that this bis-phosphonium ionic liquid structure is a key because a comparable monophosphonium ionic liquid is cytotoxic to both bacteria and corneal epithelial cells. CONCLUSIONS: Here, we report the first use of dicationic bis-phosphonium ionic liquids as antimicrobial agents. Our data suggest that diphosphonium ionic liquids may represent a new class of broad-spectrum antimicrobial agents for the use on the ocular surface. PMID- 22236791 TI - Meta-analysis of randomized controlled trials comparing excimer laser and phakic intraocular lenses for myopia between 6.0 and 20.0 diopters. AB - PURPOSE: Meta-analysis of randomized controlled trials (RCTs) comparing excimer laser refractive surgery and phakic intraocular lenses (pIOLs) for the correction of myopia between 6.0 and 20.0 diopters (D). pIOLs are an alternative surgical option to excimer laser for these patients. The evidence base comparing these 2 methods has never been assessed systematically. METHODS: Cochrane Eyes and Vision Group, International. We performed a comprehensive literature search using the Cochrane Collaboration methodology to identify RCTs. A meta-analysis on the results of RCTs was performed. We analyzed data for efficacy outcomes, accuracy outcomes, safety outcomes, adverse effects, and quality-of-life measures. RESULTS: This review included 3 RCTs with a total of 228 eyes. The range of myopia was 6.0 to 20.0 D with up to 4.0 D of astigmatism. The pIOL group was less likely to lose 2 or more lines of best spectacle-corrected visual acuity at 12 months (odds ratio, 0.35; 95% confidence interval, 0.19-0.66, P = 0.001). PIOL surgery scored more highly on patient satisfaction/preference questionnaires. CONCLUSIONS: The results of this systematic review show that pIOLs are safer within 1 year of follow-up compared with excimer laser surgical correction for myopia between 6 and 20 D. There is weaker evidence for superior visual quality in pIOL recipients. Further RCTs adequately powered for subgroup analysis with long-term follow-up are necessary to establish the ideal myopic range for excimer laser and pIOL treatments. PMID- 22236792 TI - Effects of inter-tube distance and alignment on tunnelling resistance and strain sensitivity of nanotube/polymer composite films. AB - A model for carbon nanotube (CNT)/polymer composite conductivity is developed, considering the effect of inter-tube tunnelling through the polymer. The statistical effects of inter-tube distance and alignment on the tunnelling are investigated through numerical modelling, to highlight their role in the conductance and piezoresistance of the composite film. The impact of critical parameters, including the concentration, alignment and aspect ratio of the CNTs and the tunnelling barrier height of the polymer is statistically evaluated using a large number of randomly generated CNT/polymer composite films. A numerical model is presented for the tunnelling resistance as a function of CNT concentration and polymer properties, which provides good agreement with the reported conductance in the literature. In particular, for a low concentration of CNTs close to the percolation threshold, we demonstrate how tunnelling dominates the conductance properties and leads to significant increase in the piezoresistance of the composite. This is important for gaining insight into the optimum concentration and alignment of the CNTs in the composite film for applications such as strain sensors, anisotropic conductive films, transparent electrodes and flexible electronics. PMID- 22236793 TI - Left ventricular thrombus during cardiopulmonary bypass as the primary manifestation of heparin-induced thrombocytopenia. PMID- 22236794 TI - A new case of primary signet-ring cell carcinoma of the cervix with prominent endometrial and myometrial involvement: Immunohistochemical and molecular studies and review of the literature. AB - BACKGROUND: As a rule, endocervical tumours with signet-ring cell are classed as metastatic extra-genital neoplasms. In a patient aged 45 years, we describe primary cervical signet-ring cell carcinoma (PCSRCC) characterized by prominent endometrial and myometrial involvement, simulating primary endometrial adenocarcinoma with cervical extension. In addition, a review was made of the literature to identify the clinical and pathological features of this rare malignancy. CASE PRESENTATION: A 45-year-old woman was referred to our Gynaecology Department due to persistent abnormal vaginal bleeding. Transvaginal ultrasonography showed slight endometrial irregularities in the whole uterine cavity suggestive of endometrial neoplasms. Pelvic magnetic resonance imaging revealed diffuse enlargement of the cervix, which had been replaced by a mass. Induration extended to the parametria and sigmoid colon fat.Histological examination of endometrial curettage and a cervical biopsy revealed a neoplasm characterized by neoplastic signet-ring cells and trabecular structures. Immunohistochemical analysis and molecular studies showed certain findings consistent with a cervical neoplasm, such as positivity to CEA, keratin 7, Ca-125 and p16 and the presence of HPV (Human Papilloma Virus) DNA 18.On examination of the hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy, the lesion replacing the cervix, endometrium and myometrium, revealed the same immunohistochemical findings observed on endometrial curettage and cervical biopsy specimens. Metastases were found in an ovarian cystic lesion and the lymph nodes. CONCLUSION: With this report the authors have demonstrated that the spread of cervical adenocarcinoma to the uterine corpus, although rare, may be observed, and that in this instance immunohistochemical and molecular studies can provide sufficient information for accurate diagnosis even on small biopsy specimens. PMID- 22236795 TI - Differences in susceptibility to oxidative stress in the skin of Japanese and French subjects and physiological characteristics of their skin. AB - BACKGROUND: Many researchers have studied differences in conditions of ethnic skin using biophysical measurements. However, few studies to date have focused on the antioxidative capacity of the skin. METHODS: We measured two parameters of oxidative stress in the stratum corneum, catalase activity and protein carbonylation of the stratum corneum (SCCP), in two ethnic groups, Japanese and French subjects, to characterize the susceptibility to oxidative stress. We also measured several physiological parameters at three different skin sites, two sun exposed sites (cheek and dorsal aspect of the hand) and a sun-protected site (inner upper arm), in both ethnic groups. RESULTS: Transepidermal water loss (TEWL), the size of corneocytes and skin color showed differences between sun exposed and sun-protected sites regardless of ethnicity. Regarding ethnic differences, catalase activities and parameters of skin hydration and barrier function of Japanese subjects were higher than those of French subjects. However, SCCP values showed a trend contrary to catalase activity. The difference in the b* value indicated that the melanin content of Japanese skin was higher than that of French skin. Pearson's correlation analyses showed that catalase activity and SCCP values had weak relationships with water content, TEWL and skin color in both ethnic groups. CONCLUSION: Differences in susceptibility to oxidative stress, namely melanin content and catalase activity in the skin, induce the better skin condition of Japanese compared with French subjects. PMID- 22236797 TI - Patient reported outcome measures: how are we feeling today? PMID- 22236796 TI - Botulinum toxin a versus placebo for refractory detrusor overactivity in women: a randomised blinded placebo-controlled trial of 240 women (the RELAX study). AB - BACKGROUND: Emerging data suggest botulinum toxin is an effective treatment for detrusor overactivity (DO), but large studies confirming efficacy and safety are lacking. OBJECTIVE: Study the efficacy and safety of onabotulinumtoxinA (onaBoNTA) for the treatment of DO. DESIGN, SETTING, AND PARTICIPANTS: A double blind placebo-controlled randomised trial in eight UK urogynaecology centres was conducted between 2006 and 2009. A total of 240 women with refractory DO were randomised to active or placebo treatment and followed up for 6 mo. INTERVENTION: Treatment consisted of 200 IU onaBoNTA or placebo injected into the bladder wall (20 sites; 10 IU per site in 1ml saline). MEASUREMENTS: Primary outcome was voiding frequency per 24h at 6 mo. Secondary outcomes included urgency and incontinence episodes and quality-of-life data. Intention-to-treat analysis was used with imputation of missing data. RESULTS AND LIMITATIONS: A total of 122 women received onaBoNTA and 118 received the placebo. Median (interquartile range) voiding frequency was lower after onaBoNTA compared with placebo (8.3 [6.83-10.0] vs 9.67 [8.37-11.67]; difference: 1.34; 95% confidence interval [CI], 1.00-2.33; p=0.0001). Similar differences were seen in urgency episodes (3.83 [1.17-6.67] vs 6.33 [4.0-8.67]; difference: 2.50; 95% CI, 1.33-3.33; p<0.0001) and leakage episodes (1.67 [0-5.33] vs 6.0 [1.33-8.33]; difference: 4.33; 95% CI, 3.33-5.67; p<0.0001). Continence was more common after botulinum toxin type A (BoNTA; 31% vs 12%; odds ratio [OR]: 3.12; 95% CI, 1.49-6.52; p=0.002). Urinary tract infection (UTI; 31% vs 11%; OR: 3.68; 95% CI, 1.72-8.25; p=0.0003) and voiding difficulty requiring self-catheterisation (16% vs 4%; OR: 4.87; 95% CI, 1.52-20.33; p=0.003) were more common after onaBoNTA. CONCLUSIONS: This randomised controlled trial of BoNTA for refractory DO, the largest to date, confirms efficacy and safety of the compound. UTI (31%) and self-catheterisation (16%) are common. A third of women achieved continence. TRIAL REGISTRATION: The study received ethical committee approval from the Scottish Multicentre Research Ethics Committee (reference: 04/MRE10/67). The trial has a EudraCT number (2004 002981-39), a clinical trial authorisation from the UK Medicines and Healthcare Regulatory Agency, and it was registered on Current Controlled Trials (ISRCTN26091555) on May 26, 2005. PMID- 22236798 TI - Exertional dyspnoea and syncope. PMID- 22236799 TI - The saga of Poly Implant Prosthese breast implants. PMID- 22236800 TI - Doctors told to collaborate with community pharmacists to improve pain management. PMID- 22236801 TI - Modest increase seen in US health spending in 2010. PMID- 22236803 TI - Improving Alzheimer's disease outcomes in Down's syndrome. PMID- 22236802 TI - Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome. METHODS: In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS: We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4.1 (95% CI -13.1 to 4.8) in DAMES scores, -8.5 (-20.1 to 3.1) in ABS I scores, and 2.0 (-7.2 to 11.3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0.33). Five participants in the memantine group and four controls died from serious adverse events (p=0.77). INTERPRETATION: There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients. FUNDING: Lundbeck. PMID- 22236804 TI - Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. AB - BACKGROUND: Omalizumab may inhibit allergic inflammation and could contribute to decreasing airway remodeling in patients with asthma. OBJECTIVE: The aim of this study was to assess the effects of omalizumab on airway wall thickness using computed tomography (CT). METHODS: Thirty patients with severe persistent asthma were randomized to conventional therapy with (n = 14) or without omalizumab (n = 16) for 16 weeks. The following airway dimensions were assessed by a validated CT technique: airway wall area corrected for body surface area (WA/BSA), percentage wall area (WA%), wall thickness (T)/?BSA, and luminal area (Ai)/BSA at the right apical segmental bronchus. The percentage of eosinophils in induced sputum, pulmonary function and the Asthma Quality of Life Questionnaire (AQLQ) were assessed as well. RESULTS: Treatment with omalizumab significantly decreased WA/BSA (p < 0.01), WA% (p < 0.01), and T/?BSA (p < 0.01), and increased Ai/BSA (p < 0.05), whereas conventional therapy resulted in no change. In the omalizumab group (n = 14), a significant decrease in the percentage of sputum eosinophils (p < 0.01), improved forced expiratory volume in 1 s (FEV(1)), and an improved AQLQ score were recorded. The changes in FEV(1)% predicted and sputum eosinophils were significantly correlated with changes in WA% (r = 0.88, p < 0.001, and r = 072, p < 0.01, respectively). CONCLUSIONS: These findings suggest that omalizumab reduced airway wall thickness and airway inflammation. Larger patient studies with longer-term follow-up are needed to show whether omalizumab can truly maintain improved airway wall dimensions. PMID- 22236805 TI - Coordinate regulation of Gram-positive cell surface components. AB - The cell surface of Gram-positive pathogens represents a complex association of glycopolymers that control cell division, homeostasis, immune evasion, tissue invasion, and resistance to antimicrobials. These glycopolymers include the peptidoglycan cell wall, wall-teichoic acids, lipoteichoic acids, and capsular polysaccharide. Disruption of individual factors often results in pleiotropic effects, making it difficult to discern regulation and function. In this review we collate recent work describing these pleiotropic phenotypes, and propose that this is due to coordinated regulation of biosynthesis or modification of these cell surface components. A better understanding of the regulatory networks that control the relative prevalence of each factor on the cell surface or their modulated functions may help facilitate the identification of new targets for antimicrobial therapy. PMID- 22236806 TI - Structural studies on bovine heart cytochrome c oxidase. AB - Among the X-ray structures of bovine heart cytochrome c oxidase (CcO), reported thus far, the highest resolution is 1.8A. CcO includes 13 different protein subunits, 7 species of phospholipids, 7 species of triglycerides, 4 redox-active metal sites (Cu(A), heme a (Fe(a)), Cu(B), heme a(3) (Fe(a3))) and 3 redox inactive metal sites (Mg(2+), Zn(2+) and Na(+)). The effects of various O(2) analogs on the X-ray structure suggest that O(2) molecules are transiently trapped at the Cu(B) site before binding to Fe(a3)(2+) to provide O(2)(-). This provides three possible electron transfer pathways from Cu(B), Fe(a3) and Tyr244 via a water molecule. These pathways facilitate non-sequential 3 electron reduction of the bound O(2)(-) to break the OO bond without releasing active oxygen species. Bovine heart CcO has a proton conducting pathway that includes a hydrogen-bond network and a water-channel which, in tandem, connect the positive side phase with the negative side phase. The hydrogen-bond network forms two additional hydrogen-bonds with the formyl and propionate groups of heme a. Thus, upon oxidation of heme a, the positive charge created on Fe(a) is readily delocalized to the heme peripheral groups to drive proton-transport through the hydrogen-bond network. A peptide bond in the hydrogen-bond network and a redox coupled conformational change in the water channel are expected to effectively block reverse proton transfer through the H-pathway. These functions of the pathway have been confirmed by site-directed mutagenesis of bovine CcO expressed in HeLa cells. PMID- 22236807 TI - Adapted timed up and go: a rapid clinical test to assess gait and cognition in multiple sclerosis. AB - BACKGROUND/AIMS: To measure the Timed Up and Go (TUG), imagined TUG (iTUG), and the difference of time between these two tests (delta time) in 20 patients with relapsing-remitting multiple sclerosis (RRMS) and 20 healthy age-matched controls and to examine whether an association with cognitive functions, motor impairment, and behavioral changes can be determined. METHODS: The mean +/- SD of TUG, iTUG and delta time were used as outcomes. Spatiotemporal gait parameters were recorded by a 12-camera optoelectronic system during straight walking at usual self-selected speed. Cognitive functions were assessed by a standardized neuropsychological examination. RESULTS: Patients performed the TUG slower than the controls (10.00 +/- 1.70 s vs. 8.71 +/- 1.04 s, p = 0.01, respectively). The TUG was correlated with gait parameters, cognitive functions, and behavior, whereas delta time was correlated only with cognitive functions. CONCLUSION: TUG represents an interesting test to reveal subtle deficits in RRMS patients with low disability and is related to motor, cognitive, and behavioral functioning. Combining with the TUG, delta time could easily give additional information on specific cognitive functions in the assessment of patients with RRMS. PMID- 22236808 TI - Updating clinical practice recommendations: is it worthwhile and when? AB - BACKGROUND: Keeping clinical practice recommendations up-to-date with a continually evolving evidence base presents challenges. Resources required to update recommendations compete with those needed to evaluate newer treatments. METHODS: We describe an approach developed by the UK National Institute for Health and Clinical Excellence (NICE) for updating clinical practice recommendations for new interventional procedures and we evaluate relevant initial experience of using this system. Depending on whether evidence for a procedure is judged adequate or inadequate for safety and efficacy, use in clinical practice is usually recommended with either "normal" or "special" arrangements for patient consent, data collection and institutional oversight, respectively. We examined whether differences in the state of the evidence at the initial and the updated appraisal of procedures were associated with changed recommendations. RESULTS: Since 2008, updating of recommendations focuses on procedures with initially inadequate evidence. "Special arrangements" recommendations about eleven procedures were updated after 3.3-6.5 years (median, 5.3 years), and recommendations for six were changed to "normal arrangements." Overall, procedures with changed ("special-to-normal") recommendations had a greater increase in the number of patients included in observational studies published since the initial guidance. CONCLUSIONS: Procedures with changed ("special-to-normal") recommendations generally had greater increases in their evidence base. Although uncertainties about optimal methods for keeping evidence based recommendations up-to-date remain, this experience should be useful to policy makers in developing processes for prioritizing scarce resources for updating clinical practice recommendations. Further studies are needed about the value placed on "updated" recommendations by clinicians, policy-makers, and patients. PMID- 22236809 TI - Biomarker robustness reveals the PDGF network as driving disease outcome in ovarian cancer patients in multiple studies. AB - BACKGROUND: Ovarian cancer causes more deaths than any other gynecological cancer. Identifying the molecular mechanisms that drive disease progress in ovarian cancer is a critical step in providing therapeutics, improving diagnostics, and affiliating clinical behavior with disease etiology. Identification of molecular interactions that stratify prognosis is key in facilitating a clinical-molecular perspective. RESULTS: The Cancer Genome Atlas has recently made available the molecular characteristics of more than 500 patients. We used the TCGA multi-analysis study, and two additional datasets and a set of computational algorithms that we developed. The computational algorithms are based on methods that identify network alterations and quantify network behavior through gene expression.We identify a network biomarker that significantly stratifies survival rates in ovarian cancer patients. Interestingly, expression levels of single or sets of genes do not explain the prognostic stratification. The discovered biomarker is composed of the network around the PDGF pathway. The biomarker enables prognosis stratification. CONCLUSION: The work presented here demonstrates, through the power of gene expression networks, the criticality of the PDGF network in driving disease course. In uncovering the specific interactions within the network, that drive the phenotype, we catalyze targeted treatment, facilitate prognosis and offer a novel perspective into hidden disease heterogeneity. PMID- 22236810 TI - A model for chromosome condensation based on the interplay between condensin and topoisomerase II. AB - The compaction of chromatin that occurs when cells enter mitosis is probably the most iconic process of dividing cells. Mitotic chromosomal compaction or 'condensation' is functionally linked to resolution of chromosomal intertwines, transcriptional shut-off and complete segregation of chromosomes. At present, understanding of the molecular events required to convert interphase chromatin into mitotic chromosomes is limited. Here, we review recent advances in the field, focusing on potential chromosomal compaction mechanisms and their importance to chromosome segregation. We propose a model of how metaphase chromosomes could be shaped based on the enzymatic activities of condensin and topoisomerase II in overwinding and relaxation of the DNA fiber during mitosis. We suggest that condensin overwinding is an important requirement for intertwine resolution by topoisomerase II and, together with the inhibition of transcription, contributes to cytological mitotic chromosome appearance or 'condensation'. PMID- 22236811 TI - Submicroscopic deletion of FGFR1 gene is recurrently detected in myeloid and lymphoid neoplasms associated with ZMYM2-FGFR1 rearrangements: a case study. PMID- 22236812 TI - Critical care in pregnancy. AB - Childbirth is a major event in the lives of mothers and their families. Critical illness in pregnancy is uncommon but may arise from conditions unique to pregnancy, conditions exacerbated by pregnancy and coincidental conditions. According to the latest Confidential Enquiry into Maternal Deaths in the UK, haemorrhage remains a leading direct cause of mortality; however, there has been an increase in mortality due to indirect causes. The obstetric population has changed over the past decade and we are caring for much older mothers with pre existing disorders and advanced chronic medical conditions. It is therefore essential to adopt an early multidisciplinary approach for the care of these women. With birth rates increasing, complex caseloads and changes in training of both medical and midwifery staff, the challenge of caring for critically ill obstetric patients requires urgent attention. PMID- 22236814 TI - Perceived quality of life of children after successful bridging to heart transplantation. AB - BACKGROUND: Mechanical circulatory support is increasingly used to bridge children with end-stage heart failure to transplant. Quality of life (QoL) has not been systematically evaluated in children bridged to heart transplant. METHODS: All children transplanted for cardiomyopathy during 2001 to 2008 and currently being followed at our center (n = 84) had QoL assessed during 2006 to 2009, at a median of 3 years post-transplant, using a validated generic measure (PedsQL4.0). RESULTS: Twenty-six children, aged 2.7 to 18 (median 7.4) years who were bridged to transplant, were compared with 58 children, aged 2.0 to 18.0 (median 13.0) years, who were transplanted in the same era without bridging. There were no significant differences between the 2 groups on any domains of QoL assessed by children or parents, although the small number of bridged patients increases the likelihood of a Type II error. Bridged children who were younger (r = 0.48, p = 0.02) or more recently transplanted (r = 0.42, p = 0.04) were scored by their parents as having poorer emotional QoL. Regression analysis indicated that age at transplant was the only medical or demographic variable associated with parent-reported total QoL scores (beta = 0.27, p = 0.01). With few links between QoL scores and medical or demographic factors, other subjective psychologic factors may be of greater salience in determining QoL. CONCLUSIONS: Despite greater severity of illness, children who required mechanical bridging to transplantation report a QoL comparable to that of other children undergoing heart transplantation. Younger children may require greater psychologic support to reach their full potential in terms of QoL. PMID- 22236813 TI - The value of mastectomy flap fixation in reducing fluid drainage and seroma formation in breast cancer patients. AB - BACKGROUND: Prolonged and excessive drainage of serous fluid and seroma formation constitute the most common complications after mastectomy for breast carcinoma. Seroma formation delays wound healing, increases susceptibility to infection, skin flap necrosis, persistent pain and prolongs convalescence. For this, several techniques have been investigated to improve primary healing and minimize seroma formation. MATERIALS AND METHODS: Between June 2009 and July 2010 forty patients with breast carcinoma, scheduled for modified radical mastectomy, were randomly divided into 2 groups, the study group (20) and the control group (20). In the study group; the mastectomy flaps were fixed to the underlying muscles in raws, at various parts of the flap and at the wound edge using fine absorbable sutures. In the control group; the wound was closed in the conventional method at the edges. Closed suction drains were used in both groups. Patients, tumor characteristics and operative related factors were recorded. The amount and color of drained fluid were recorded daily. The drains were removed when the amount become less than 50 cc. The total amount and duration of drained fluid and the formation of seroma were recorded and the results were compared between the two groups. RESULTS: In the flap fixation group, the drain was removed in significantly shorter time compared to the control group (p < 0.001). Also, the total amount of fluid drained was significantly lower in the flap fixation group (p < 0.001). The flap fixation group showed a significantly lower frequency of seroma formation compared to the control group, both clinically (p = 0.028) and ultrasonographically (p = 0.047). CONCLUSIONS: The mastectomy flap fixation technique is a valuable procedure that significantly decreases the incidence of seroma formation, and reduces the duration and amount of drained fluid. However, it should be tried on a much wider scale to prove its validity. PMID- 22236815 TI - ACSM clinician profile. Per Renstrom, MD, PhD. PMID- 22236816 TI - Exertional maladies: lessons and questions from recurring events. PMID- 22236818 TI - If athletes will not adopt preventive measures, effective measures must adopt athletes. PMID- 22236819 TI - Ocular injuries in sports. AB - Eye injuries are common in sports. Team physicians need to be able to recognize and treat common injuries and know when to refer other problems. This article highlights the current treatment of common sports-related eye injuries and reviews some of the new literature. Nearly 90% of all sports-related eye injuries can be prevented with adequate eye protection and will be discussed in some detail in the article. PMID- 22236820 TI - Athletes with seizure disorders. AB - Individuals with seizure disorders have long been restricted from participation in certain sporting activities. Those with seizure disorders are more likely than their peers to have a sedentary lifestyle and to develop obesity. Regular participation in physical activity can improve both physical and psychosocial outcomes for persons with seizure disorders. Seizure activity often is reduced among those patients who regularly engage in aerobic activity. Recent literature indicates that the diagnosis of seizure disorders remains highly stigmatizing in the adolescent population. Persons with seizure disorders may be more accepted by peer groups if they are allowed to participate in sports and recreational activities. Persons with seizure disorders are encouraged to participate in regular aerobic activities. They may participate in team sports and contact or collision activities provided that they utilize appropriate protective equipment. There seems to be no increased risk of injury or increasing seizure activity as the result of such participation. Persons with seizure disorders still are discouraged from participating in scuba diving and skydiving. The benefits of participation in regular sporting activity far outweigh any risk to the athlete with a seizure disorder who chooses to participate in sports. PMID- 22236821 TI - Second impact syndrome or cerebral swelling after sporting head injury. AB - Second impact syndrome is believed to be the catastrophic consequence of repeated head injury in sport. The scientific evidence to support this concept is nonexistent, and belief in the syndrome is based upon the interpretation of anecdotal cases more often than not, lacking sufficient clinical detail to make definitive statements. The fear of this condition has driven many of the current return-to-play guidelines following concussion. Diffuse cerebral swelling (DCS) following a head injury is a well-recognized condition, more common in children than in adults, and usually has a poor outcome. PMID- 22236822 TI - Osteoblastoma as the cause of persistent lumbosacral pain in a female high school athlete. PMID- 22236823 TI - Radiating upper limb pain in the contact sport athlete: an update on transient quadriparesis and stingers. AB - Participation in contact sports exposes the athlete to a risk of cervical spine injury. Temporary neurological injuries manifesting as radiating arm pain or paresthesias, such as transient quadriparesis and stingers, present unique challenges for the sports medicine physician and will be reviewed in detail. The initial management of these conditions must recognize signs and symptoms of spinal cord injury and prevent further neurological sequelae. Evaluation will often include advanced imaging of the cervical spine in addition to serial neurological examinations. This review concludes with rational return-to-play guidelines for contact sport athletes. PMID- 22236824 TI - Evaluation of the athlete with buttock pain. AB - Buttock (gluteal) pain is commonly experienced by athletes of all ages and activity levels. Evaluation of buttock pain can be challenging because the differential diagnoses are extensive. Symptoms may originate from the pelvis or hip or be referred from the lumbosacral spine or neurovascular structures. Few articles in the literature are dedicated to the primary complaint of buttock pain. The purpose of this article is to provide a clinical algorithm to assist the sports clinician in reaching an accurate diagnosis and initiating the appropriate treatment. PMID- 22236825 TI - Challenges of the pregnant athlete and low back pain. AB - Low back pain during pregnancy is a common problem with a high prevalence among pregnant athletes. The etiology of pregnancy-related low back pain remains unclear, although more evidence is supporting a biomechanical/musculoskeletal origin. This article will review the causes of low back pain in athletes and pregnant women, differentiate low back from pelvic girdle pain, and discuss the treatment and prevention of pregnancy-related low back and pelvic girdle pain. PMID- 22236826 TI - Graphene growth on a Pt(111) substrate by surface segregation and precipitation. AB - We report on the fabrication of a sizable graphene sheet on a carbon-doped Pt(111) substrate through surface segregation and precipitation. Scanning Auger electron spectroscopy (AES) reveals that the graphene covered more than 98% of the substrate surface. Our graphene consists of single-layer graphene across the substrate with fractions of several micrometer wide bi- and tri-layer graphene islands. We also show that the number of graphene layers can be precisely determined by analyzing AES data. While Raman spectroscopy is usually used to study graphene on SiO2, we show that AES is a powerful tool to characterize graphene grown on metal substrates. PMID- 22236827 TI - Long-term health-related quality of life after decompressive hemicraniectomy in stroke patients with life-threatening space-occupying brain edema. AB - BACKGROUND: Although randomized clinical trials have reported significant improvement in mortality and functional outcome as measured with modified Rankin Scale (mRS) or Barthel index (BI) in stroke patients with space-occupying anterior circulation infarctions treated with hemicraniectomy, many clinicians are still concerned about the long-term health-related quality of life (HRQoL). AIM: Assessment of HRQoL after hemicraniectomy to holistically reevaluate clinical outcome. METHODS: Eleven patients (6 men, 5 women; mean age 48 (SD 5.8) years) were examined at 9-51 months after hemicraniectomy. Test batteries comprised NIH stroke scale, BI, mRS, neuropsychological tests (Visual Object and Space Perception Battery and clock test), and HRQoL-scales (Short Form 36 Health Survey (SF-36), Nottingham Health Profile (NHP), Questions on Life Satisfaction, Hospital Anxiety and Depression Scale and EQ-5D). RESULTS: Median values for NIHSS, BI and mRS were 11.5, 55 and 3.5. In HRQoL-scales, subscales related to physical mobility and functioning were consistently severely impaired, while subscales related to psychological well-being were impaired to a lesser extent. Mean scores for physical functioning and physical role were 10.5 and 12.5 in the SF-36, and 61.3 and 43.3 for physical mobility and energy in the NHP; emotional role and mental health scored 63.3 and 66.4 (SF-36), scores for emotional reaction and social isolation were 18.9 and 16.0 (NHP), respectively. CONCLUSION: Although, physical components of HRQoL are highly impaired, these stroke patients achieved a satisfying level of psychological well-being which was endorsed by a nearly unanimous retrospective appraisal of life-saving hemicraniectomy. PMID- 22236828 TI - Cysteamine improves growth performance and gastric ghrelin expression in preweaning piglets. AB - The aim of the present study was to investigate the effect of cysteamine on growth performance of preweaning piglets and gastric expression of ghrelin mRNA in vivo and in vitro. Twelve litters of newborn piglets were allocated randomly to control and treatment groups. From 15 d of age, piglets in the control group were fed basal creep diet, whereas the treatment group received basal diet supplemented with 120 mg cysteamine per kg of diet until weaning on 35 d of age. Body weight gain, creep feed consumption, and diarrhea rates were recorded, and gastric mucosal tissues were collected for quantifying mRNA expression. To evaluate the direct effect of cysteamine on gastric ghrelin expression, primary cultures of gastric mucosal cells isolated from 35-d-old piglets were exposed to cysteamine for 20 h at 0, 1, 10, and 100 MUg/mL, respectively. Dietary cysteamine increased (P < 0.05) average daily creep feed consumption and BW gain in preweaning pigs, which was accompanied by reduction in diarrhea rates. At 35 d of age, piglets treated with cysteamine showed increased (P < 0.05) ghrelin and gastrin and decreased (P < 0.05) somatostatin mRNA expression in gastric mucosa. Moreover, dietary cysteamine treatment increased serum concentration of gastrin (P < 0.05). In vitro, cysteamine significantly increased ghrelin mRNA expression in gastric mucosal cells at the concentration of 10 MUg/mL. In conclusion, dietary cysteamine is effective in improving the growth performance and health condition of preweaning piglets, which is associated with its stimulatory effects on gastric ghrelin mRNA expression both in vivo and in vitro. PMID- 22236829 TI - The degradation and biocompatibility of pH-sensitive biodegradable polyurethanes for intracellular multifunctional antitumor drug delivery. AB - To obtain controllable stepwise biodegradable polymer for multifunctional antitumor drug carriers, pH-sensitive biodegradable polyurethanes were firstly synthesized using poly(epsilon-caprolactone) (PCL) and pH-sensitive poly(epsilon caprolactone)-hydrazone-poly(ethylene glycol)-hydrazone-poly(epsilon caprolactone) macrodiol (PCLH) as soft segment; l-lysine ethyl ester diisocyanate (LDI), l-lysine derivative tripeptide and 1,4-butandiol (BDO) as hard segment; and hydrazone-linked methoxyl-poly(ethylene glycol)(m-PEG-Hyd) as end-capper. Then, an extensive degradation process of the prepared pH-sensitive polyurethanes was investigated in vitro with proton nuclear magnetic resonance spectra ((1)H NMR), gel permeation chromatograph (GPC), scanning electron microscopy (SEM), and weight loss. It was found that the degradation of these polyurethanes occurred via the random hydrolytic ester cleavage along the PCL segments close to PEG segments in enzymatic solutions while the hydrazone bond in the polymer chain was more easily cleaved in acidic media, which was accelerated with decreasing pH value. Furthermore, the biocompatibility in vivo was evaluated in an intramuscular implantation model on Sprague-Dawley rats, using SEM and light microscopy. The result showed that the prepared polyurethanes can be easily degraded and the degradation products do not induce any adverse response from surrounding muscle tissues. Our work suggests that the prepared pH-sensitive polyurethanes could be promising materials as controllable biodegradable and non cyctotoxic multifunctional carriers for active intracellular drug delivery. PMID- 22236831 TI - Genetic analysis reveals population structuring and a bottleneck in the black faced lion tamarin (Leontopithecus caissara). AB - The ability of a population to evolve in a changing environment may be compromised by human-imposed barriers to gene flow. We investigated the population structure and the possible occurrence of a genetic bottleneck in two isolated populations of the black-faced lion tamarin (Leontopithecus caissara), a species with very reduced numbers (less than 400) in a very restricted range in the Atlantic Forest of southeast Brazil. We determined the genotypes of 52 individuals across 9 microsatellite loci. We found genetic divergence between the populations, each exhibiting low genetic diversity. Analysis revealed broad- and fine-scale population structuring. Both populations have evidently experienced population reduction and a genetic bottleneck without presenting any apparent detrimental effect. Anyway, measures should be taken to effectively protect the forests where L. caissara occurs in order to allow its populations to increase and counteract the eventual effects of genetic impoverishment. PMID- 22236830 TI - Reconstruction of 3D stacked hepatocyte tissues using degradable, microporous poly(d,l-lactide-co-glycolide) membranes. AB - There is great demand for constructing well-organized three-dimensional (3D) tissues in vitro. Here, we developed a 3D stacked culture method using biodegradable poly(d,l-lactide-co- glycolide) (PLGA) membranes with defined topography. Pore size and porosity of the membranes can be controlled by changing the moisture content during fabrication. The optimized membrane served as a scaffold to manipulate small hepatocyte (SH) layers when they were stacked, while it degraded after stacking, resulting in the reorganization of the cells into a 3D stacked structure. Immunofluorescent staining for domain markers of cell polarity and electron microscopy confirmed that the cells in the 3D stacked structures recovered polarity. Furthermore, the cells exhibited improved liver specific function as compared with cells in a monolayer. This 3D stacked culture may enable reconstruction of multilayered hepatic tissues with highly differentiated functions in vitro. PMID- 22236832 TI - Fibroblast activation protein: A potential therapeutic target in cancer. AB - The concept of targeting antigens selectively expressed on the surface of tumor capillary endothelial cells or in tumor stroma has emerged as a promising strategy for cancer therapeutics. Identification of stromal targets for anticancer therapy and development of selective inhibitors of these targets are of great clinical interest. Fibroblast activation protein (FAP), a member of the serine protease family, selectively expressed in the stromal fibroblasts associated with epithelial cancers, whereas with low or undetectable expression in the resting fibroblasts of normal adult tissues. The proteolytic activity of FAP has been shown to support tumor growth and proliferation, making it a potential target for novel anticancer therapies, such as those by immune-based approaches. PMID- 22236833 TI - [Endometrial cancer: place for adjuvant chemotherapy]. AB - Endometrial cancer is the most common gynaecological cancer in western countries. Radiotherapy remains the mainstay of postoperative management, but accumulating data show that adjuvant chemotherapy may display promising results after surgery. Characteristic features of the patients and disease, type of treatment including modality of surgery, radiation and chemotherapy are different from studies reported. The results from these trials are inconsistent but certain groups of patients with high-risk features could have advantage to adjuvant chemotherapy. The indication of adjuvant chemotherapy must be discussed in this situation taking into account the patient's profile with potential comorbidities and risk of toxicities. PMID- 22236834 TI - Development of a clinical global impression scale for fatigue. AB - Physical, cognitive, and affective components of fatigue are often associated with depression and other Axis I psychiatric disorders. We developed two, single item global assessment scales to specifically evaluate symptoms of fatigue. 101 subjects visiting a clinical trial site consented to participate in this reliability and validity study. Diagnoses included Major Depressive Disorder, Bipolar disorder, and schizophrenia. There were two clinic visits during which the modified Clinician and Patient Impressions of Fatigue rating instruments were administered in conjunction with the MGH cognitive and physical functioning questionnaire (MGH-CPFQ), a validated patient-rated 7-item scale. CGI-Severity and PGI-Severity for fatigue were well correlated at two separate visits (p < 0.00005). At visit 1, the mean CGI-S for fatigue was 3.33 +/- 1.53 (SD) and the PGI-S for fatigue was 3.57 +/- 1.70 (r = 0.75; p = 0.000). At visit 1, the total MGH-CPFQ was 21.66 +/- 6.92. Both CGI-S and PGI-S measures for fatigue were highly correlated with the MGH-CPFQ: CGI-S (r = 076; p < 0.00005); PGI-S (r = 0.62; p < 0.00005). Both the PGI-S and CGI-S for fatigue revealed temporal stability and convergent validity for the MGH-CPFQ (r = 0.83 for CGI-S and 0.73 for PGI-S). There was high internal consistency between the two independent CGI raters at visit 2 as demonstrated by a kappa statistic = 0.971 (CGI-S) and 0.868 (CGI-I) and Cronbach's alpha = 0.998 (CGI-S) and 0.941 (CGI-I). As shown here, the modified CGI and PGI instruments for fatigue are reliable measures of fatigue and both measures are validated with the MGH-CPFQ instrument. PMID- 22236835 TI - Audit of physicians' adherence to the antibiotic policy guidelines in Kuwait. AB - OBJECTIVE: To audit physicians' adherence to the local antibiotic policy guidelines in government hospitals in Kuwait. MATERIALS AND METHODS: The study was a retrospective review of patient records in nine hospitals between July 1 and December 31, 2008. Clinical notes and medication charts of the latest hospital admissions were checked for antibiotic prescribing. On the audit form, aspects of the prescribed antibiotic were benchmarked to the hospital antibiotic policy guidelines to evaluate adherence. RESULTS: Of 2,232 reviewed records, 1,112 (49.8%) patients had 1,528 antibiotic prescriptions. Patients who received antibiotics were significantly younger than those who did not (median age: 26.3 vs. 29.8 years, p < 0.001) and their hospital stay was significantly longer (median: 4 vs. 2 days, p < 0.001). The choice of an antibiotic was appropriate and matched the policy in 806 (52.7%) prescriptions. Of such appropriate antibiotics, adherence to route of administration was observed in 768/806 (95.3%), to dose in 758 (94%), to frequency in 746 (92.6%) and to duration in 608 (75.4%). Full adherence to all aspects of antibiotic choice, dose, route, frequency and duration was achieved in 464 (30.4%) prescriptions. In 382 (25%), the antibiotics administered were not indicated. CONCLUSION: There was low adherence to the local antibiotic policy guidelines. Physicians' antibiotic prescribing practices should be optimized. Adherence to, and update of, the policy is recommended. PMID- 22236836 TI - VDAC blockage by phosphorothioate oligonucleotides and its implication in apoptosis. AB - Apoptosis is a crucial process that regulates the homeostasis of multicellular organisms. Impaired apoptosis contributes to cancer development, while enhanced apoptosis is detrimental in neurodegenerative diseases. The intrinsic apoptotic pathway is initiated by cytochrome c release from mitochondria. Research published in the recent decade has suggested that cytochrome c release can be influenced by the conducting states of VDAC, the channel in the mitochondrial outer membrane (MOM) responsible for metabolite flux. This review will describe the evidence that VDAC gating or blockage and subsequent changes in MOM permeability influence cytochrome c release and the onset of apoptosis. The blockage of VDAC by G3139, a proapoptotic phosphorothioate oligonucleotide, provides strong evidence for the role of VDAC in the initiation of apoptosis. The proapoptotic activity and VDAC blockage are linked in that both require the PS (phosphorothioate) modification, both are enhanced by an increase in oligonucleotide length, and both are insensitive to the nucleotide sequence. Thus, the mitochondrial outer membrane permeability regulated by VDAC gating may play an important role in mitochondrial function and in the control of apoptosis. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism. PMID- 22236837 TI - Progress in understanding the role of lipids in membrane protein folding. AB - Detailed investigations of membrane protein folding present a number of serious technical challenges. Most studies addressing this subject have emphasized aspects of protein amino acid sequence and structure. While it is generally accepted that the interplay between proteins and lipids plays an important role in membrane protein folding, the role(s) played by membrane lipids in this process have only recently been explored in any detail. This review is intended to summarize recent studies in which particular lipids or membrane physical properties have been shown to play a role in the folding of intact, functionally competent integral membrane proteins. This article is part of a Special Issue entitled: Protein Folding in Membranes. PMID- 22236840 TI - Will molecular diagnosis of drug-resistant tuberculosis improve patient outcomes? PMID- 22236841 TI - The TDR Tuberculosis Strain Bank: a resource for basic science, tool development and diagnostic services. AB - BACKGROUND: The Special Programme for Research and Training in Tropical Diseases recently launched a Mycobacterium tuberculosis strain bank (TDR-TB Strain Bank). OBJECTIVE: To describe the TDR-TB Strain Bank, the characterisation of strains, bank management and the procedure for releasing materials. RESULTS: The TDR-TB Strain Bank consists of 229 clinical M. tuberculosis isolates (single-colony derived cultures) plus five mycobacterial reference strains for purposes of identification. These are available as freeze-dried, viable strains or as heat inactivated bacterial suspensions, quality controlled for purity, viability and authenticity. Isolates originated from diverse geographical settings and were selected for their resistance profiles against first- and second-line drugs. Low and high levels of resistance were determined by the minimum inhibitory concentrations of isoniazid, rifampicin, ethambutol, streptomycin, ofloxacin, kanamycin, capreomycin, ethionamide and para-aminosalicylic acid. Sequencing for drug resistance mutations was performed on the relevant sections of the rpoB, katG, inhA, embB, rpsL, rrs, gyrA and gyrB genes. Typing using lineage-defining loci of mycobacterial interspersed repetitive unit-variable number tandem repeats indicated that the most important genetic lineages were represented. CONCLUSIONS: The TDR-TB Strain Bank is a high quality bioresource for basic science, supporting the development of new diagnostics and drug-resistant detection tools and providing reference materials for laboratory quality management programmes. PMID- 22236842 TI - Seasonality of tuberculosis in New York City, 1990-2007. AB - SETTING: Several non-US-based studies have found seasonal fluctuations in the incidence of tuberculosis (TB). OBJECTIVE: The current study examined patterns of TB seasonality for New York City verified TB cases from January 1990 to December 2007. DESIGN: Autocorrelation functions and Fourier analysis were used to detect a cyclical pattern in monthly incidence rates. Analysis of variance was used to compare seasonal mean case proportions. RESULTS: A cyclical pattern was detected every 12 months. Of the 34,004 TB cases included, 21.9% were in the fall (September-November), 24.7% in winter (December-February), 27.3% in spring (March May), and 26.1% in the summer (June-August). The proportion of cases was lowest in fall (P < 0.0001) and highest in the spring (P < 0.0002). CONCLUSION: Possible explanations for seasonal variations in TB incidence include lower vitamin D levels in winter, leading to immune suppression and subsequent reactivation of latent TB; indoor winter crowding, increasing the likelihood of TB transmission; and providers attributing TB symptoms to other respiratory illnesses in winter, resulting in a delay in TB diagnosis until spring. Understanding TB seasonality may help TB programs better plan and allocate resources for TB control activities. PMID- 22236843 TI - Mortality trends for tuberculosis and sarcoidosis in English populations, 1979 2008. AB - SETTING: Analysis of data sets that included both underlying and all contributing causes of death (together termed 'mentions'): the Oxford Record Linkage Study, 1979-2008, and England national data, 1995-2008. OBJECTIVE: To determine mortality trends for the granulomatous lung conditions tuberculosis (TB) and sarcoidosis in the Oxford region (1979-2008) and England (1995-2008). RESULTS: Mortality for mentions of TB in the Oxford region declined from 39.7 deaths per million population in 1979 to 9.0 in 2008. The corresponding rates for underlying cause were 17.1, falling to 4.5. In England, mortality rates from TB fell from 18.5/million in 1995 to 12.2 in 2008 (mentions), and from 9.3 in 1995 to 6.5 in 2008 (underlying cause). Numbers of deaths from sarcoidosis in Oxford were very small, and showed no significant trend. For the much larger England population, mortality rates based on mentions were 3.6/million in 1995 and 4.2 in 2008; the corresponding rates for sarcoidosis as underlying cause were 2.1 and 2.3. CONCLUSION: TB mortality is still declining in England, despite a recent resurgence in the prevalence of the disease. Mortality from sarcoidosis has been largely stable. The conventional statistic of underlying cause of death missed almost half of all certified TB and sarcoidosis deaths. PMID- 22236844 TI - A population-based study of tuberculosis epidemiology and innovative service delivery in Canada. AB - OBJECTIVE: To compare and interpret tuberculosis (TB) incidence rates in a Canadian population across two decennials (1989-1998 and 1999-2008) as a benchmark for World Health Organization targets and the long-term goal of TB elimination. The population under study was served by two urban clinics in the first decennial and two urban and one provincial clinic in the second. METHODS: TB rates among Status Indians, Canadian-born 'others' and the foreign-born were estimated using provincial and national databases. Program performance was measured in on-reserve Status Indians in each decennial. RESULTS: In each decennial, the incidence rate in Status Indians and the foreign-born was greater than that in the Canadian-born 'others'; respectively 27.7 and 33.0 times in Status Indians, and 8.0 and 20.9 times in the foreign-born. Between decennials, the rate fell by 56% in Status Indians, 58% in Canadian-born 'others', and 18% in the foreign-born. On-reserve Status Indians had higher rates than off-reserve Status Indians, and the three-clinic model out-performed the two-clinic model among those on-reserve. Rates in the foreign-born varied by World Bank region, and were highest among those from Africa and Asia. CONCLUSION: Status Indians and the foreign-born are at increased risk of TB in Canada. Significant progress towards TB elimination has been made in Status Indians but not in the foreign born. PMID- 22236845 TI - Post-migration screening for active tuberculosis in Victoria, Australia. AB - SETTING: Tuberculosis (TB) screening clinic. OBJECTIVE: To determine TB prevalence at entry, screening yield and incidence in immigrants on a TB health undertaking (TBU) who were selected for post-migration screening due to an abnormal chest radiograph (CXR) in Victoria, Australia, in the years 1996-2006. METHOD: Rates of notified TB calculated from linkage of a screening programme database with the Victorian TB database. RESULTS: Prevalence at entry (cases notified between arrival in Australia and 6 months after the screening registration date) was 505 per 100,000 population; yield at entry (prevalent cases detected by the screening programme) was 420/100,000, and incidence (cases notified between 6 and 12 months after screening registration date) was 160/100,000 person-years. Persons issued a TBU after applying from within Australia (on-shore) had a prevalence of 1876/100,000, seven-fold higher than those issued a TBU outside Australia (off-shore, 254/100,000). The combination of an abnormal CXR and a tuberculin skin test >= 15 mm carried a prevalence of notified TB of 2907/100,000. CONCLUSION: Selective post-migration screening can achieve a high yield of notified TB. PMID- 22236846 TI - Improving tuberculosis contact tracing: the role of evaluations in the home and workplace. AB - SETTING: In 2004, the tuberculosis (TB) contact screening strategy in Vila Nova de Gaia, Portugal, was changed from targeting only close contacts identified by interviews with the index patient (reflecting national policy) to include visits to the patient?s home and workplace. OBJECTIVE: To find out 1) whether the new strategy increased adherence to TB screening procedures, 2) whether the strategy identified more at-risk contacts and 3) whether the strategy increased prevention of TB. METHODS: We compared TB contact tracing during the periods 2001-2003 and 2004-2006. The numbers of identified and screened contacts and the results of screening procedures (number of patients with active TB and latent TB infection [LTBI] detected per index case) were analysed. The number of instances of active TB prevented and the numbers of contacts that had to be screened to prevent one such instance were calculated and compared for both screening strategies. RESULTS: Home and workplace visits helped to identify more at-risk contacts (8.4 per index patient) than interview (2.5 per index patient), and improved adherence (87.3% of identified contacts were screened compared to 67.6% previously). More patients with active TB and LTBI were detected (1.4 per index patient compared with 0.75 per index patient previously), and more TB cases were prevented. CONCLUSION: The newly implemented contact screening programme, featuring home and workplace evaluation of TB patient contacts, improved adherence to screening procedures, identified more at-risk contacts and should prevent more TB cases in the future. PMID- 22236847 TI - Prevalence of latent tuberculosis infection in inmates recently incarcerated in a men's prison in Barcelona. AB - OBJECTIVE: To study the prevalence of latent tuberculosis infection (LTBI) in prisoners. METHODS: Among inmates admitted to a men's preventive detention prison in Barcelona during May-June 2009, without a previous positive tuberculin skin test (TST), a >= 10 mm TST was considered positive (5 mm in human immunodeficiency virus [HIV] infected persons). A multivariate logistic regression was performed, calculating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 221 individuals were included. The average age was 33.5 years (+/- 8.9 SD); 61.6% were foreigners and 45.2% were heroine and/or cocaine users; 40.3% had LTBI. The infection was associated with age >40 years (OR 3.10, 95%CI 1.51-6.35) and having been born in Eastern Europe (OR 4.3, 95%CI 1.4-12.8), North Africa (OR 2.2, 95%CI 1.01-4.7), sub-Saharan Africa (OR 7.6, 95%CI 1.3-44) or Latin America (OR 3.8, 95%CI 1.5-9.3). Subjects infected with HIV had a lower risk of a positive TST (OR 0.22, 95%CI 0.04-1.07). Only 31 (14%) did not present any of these risk factors, and 8 (25.8%) had LTBI. CONCLUSIONS: The prevalence of LTBI was very high in this study, and systematic screening of all inmates at the time of entry into the prison is therefore recommended. Excluding those who do not fall in any of the high-risk prevalence groups from the evaluation complicates the screening and is not very effective. PMID- 22236848 TI - Prevalence of positive tuberculosis skin tests during 5 years of screening in a Swiss remand prison. AB - BACKGROUND: Tuberculosis (TB) screening in prisons is recommended, but the appropriate methods remain controversial. Studies evaluating screening in remand prisons are scarce. METHOD: Between 1997 and 2001, voluntary screening based on the tuberculin skin test (TST) was offered to all prisoners on entry into the largest remand prison in Switzerland. Prisoners with positive results underwent chest X-rays. We analysed this information collected in an anonymous database. RESULTS: A total of 4890 prisoners entered the prison and were eligible for screening; 3779 (77.3%) had TST performed on average 9 days after arrival: 46.9% were positive (induration >= 10 mm). Positive TST rates were similar over the 5 years. Women were more likely to have a negative TST (60.4%) than men (47.7%; P < 0.001, Pearson's (2) 16.5). Positive TSTs varied according to the prisoner's country of origin (64% for sub-Saharan Africa, 57% for Eastern Europe, 56% for North Africa, 51% for Asia and 34% for North and West Europe). CONCLUSION: The percentage of TST-positive subjects was high, and most did not receive preventive treatment for latent TB. The usefulness of systematic TST for all prisoners on entry is limited, as diagnosis of TB disease usually remains the priority in prisons. PMID- 22236849 TI - Intervention to increase detection of childhood tuberculosis in Bangladesh. AB - BACKGROUND: Despite a well-functioning adult tuberculosis (TB) control programme, children with TB remain grossly under-detected in Bangladesh. It is conservatively estimated that annually around 21,000 children with TB go undetected, due to an almost exclusive focus on sputum smear-positive TB and the absence of training or guidelines in paediatric TB. OBJECTIVE: To double child TB detection by increasing general awareness and training of health care workers at microscopy centres supported by the Damien Foundation (DF) Bangladesh. METHODS: A cluster-randomised trial was carried out with provision of child TB guidelines, training and logistics support to staff of 18 microscopy centres, while 18 non adjacent microscopy centres continued their usual practice and served as controls. Paediatric data on TB suspect referral and case detection were collected at baseline and during the intervention at both control and intervention sites. RESULTS: Child TB case detection increased in both intervention and control microscopy centres, but the increase was three times the baseline in the intervention centres (from 3.8% to 12%) in comparison to less than double the baseline in the control centres (from 4.3% to 7%, P = 0.001). CONCLUSION: Simple guidelines and training on child TB case detection, together with basic logistics support, can be integrated into the existing National TB Control Programme and improve service delivery to children in TB-endemic areas. PMID- 22236850 TI - Rifampicin-monoresistant Mycobacterium tuberculosis disease among children in Cape Town, South Africa. AB - SETTING: Tygerberg Children's Hospital (TCH) and Brooklyn Chest Hospital (BCH), South Africa. OBJECTIVES: To describe paediatric cases of rifampicin (RMP) monoresistant tuberculosis (RMR-TB) disease. DESIGN: Records of children with culture-confirmed RMR-TB between 1 March 2003 and 28 February 2009 were identified from a prospectively recorded database of drug-resistant TB at TCH and BCH. Mutation analysis was performed on available specimens. RESULTS: Eighteen children with a median age of 6.9 years (range 2 months-12.8 years) were identified. Nine (50%) were human immunodeficiency virus (HIV) infected and four (22%) were HIV-exposed but non-infected. Eleven (61%) had had previous TB treatment or prophylaxis. Nine children (50%) had cavitary disease and five children (22%) had extra-pulmonary disease. Twelve (67%) had adult TB source cases, including five (42%) adults with known RMR-TB. Primary transmission occurred among 11 children (61%) and acquisition of RMR-TB was possible in seven (39%) with prior RMP exposure. Median delay to specific RMR-TB treatment was 70 days (range 23-188). One child died from RMR-TB meningitis. Gene mutations consistent with RMR-TB were confirmed in five available samples. CONCLUSION: RMR TB disease is increasingly encountered, particularly among HIV-infected and HIV exposed non-infected children. Delay in commencing appropriate treatment for RMR TB and high rates of cavitary disease could be a source of RMR-TB transmission. PMID- 22236851 TI - A national infection control evaluation of drug-resistant tuberculosis hospitals in South Africa. AB - BACKGROUND: The importance of infection control (IC) in health care settings with tuberculosis (TB) patients has been highlighted by recent health care-associated outbreaks in South Africa. OBJECTIVE: To conduct operational evaluations of IC in drug-resistant TB settings at a national level. METHODS: A cross-sectional descriptive study was conducted from June to September 2009 in all multidrug resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB) facilities in South Africa. Structured interviews with key informants were completed, along with observation of IC practices. Health care workers (HCWs) were asked to complete an anonymous knowledge, attitudes and practices (KAP) questionnaire. Multilevel modeling was used to take into consideration the relationship between center and HCW level variables. RESULTS: Twenty-four M(X)DR-TB facilities (100%) were enrolled. Facility infrastructure and staff adherence to IC recommendations were highly varied between facilities. Key informant interviews were incongruent with direct observation of practices in all settings. A total of 499 HCWs were enrolled in the KAP evaluation. Higher level of clinical training was associated with greater IC knowledge (P < 0.001), more appropriate attitudes (P < 0.001) and less time spent with coughing patients (P < 0.001). IC practices were poor across all disciplines. CONCLUSION: These findings demonstrate a clear need to improve and standardize IC infrastructure in drug-resistant TB settings in South Africa. PMID- 22236853 TI - Patterns of pncA mutations in drug-resistant Mycobacterium tuberculosis isolated from patients in South Korea. AB - BACKGROUND: Pyrazinamide (PZA), one of the most effective anti-tuberculosis drugs, becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by pyrazinamidase (PZase). PZA resistance is caused mainly by the loss of enzyme activity by mutation. OBJECTIVE: To investigate the patterns of pncA mutations in PZA-resistant mycobacteria isolated from South Korean patients. METHODS: Mycobacterial isolates with clinically proven drug resistance were cultured to determine susceptibility to anti-tuberculosis agents. pncA mutations were recognised by sequencing and compared with the relevant wild-type DNA sequence. RESULTS: Among 108 isolates, 102 were successfully cultured and underwent drug susceptibility testing; all were multidrug-resistant (MDR). pncA mutations were found in 86 cultured isolates (85.1%): 55 (84.6%) in MDR and 31 (86.1%) in extensively drug-resistant isolates. Substitution of a single nucleotide was most common. The most frequent mutations were a deletion that caused a frameshift at nucleotide (nt) 71, a substitution at nt 403 and a substitution at nt 11. Combined, these accounted for ~ 40% of all mutations. However, 15 samples (14.9%) with defective PZase activity showed no mutation. CONCLUSION: pncA mutation in M. tuberculosis is a major mechanism of PZA resistance in MDR isolates from patients in South Korea. The patterns of mutation might be more scattered and diverse. DNA-based diagnosis of PZA resistance has potential for the rapid detection of drug resistance. PMID- 22236852 TI - Risk factors for mortality among MDR- and XDR-TB patients in a high HIV prevalence setting. AB - SETTING: Recent studies suggest that the prevalence of drug-resistant tuberculosis (TB) in sub-Saharan Africa may be rising. This is of concern, as human immunodeficiency virus (HIV) co-infection in multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has been associated with exceedingly high mortality rates. OBJECTIVE: To identify risk factors associated with mortality in MDR- and XDR-TB patients co-infected with HIV in South Africa. DESIGN: Case control study of patients who died of all causes within 2 years of diagnosis with MDR- or XDR-TB. RESULTS: Among 123 MDR-TB patients, 78 (63%) died following diagnosis. CD4 count <= 50 (HR 4.64, P = 0.01) and 51-200 cells/mm(3) (HR 4.17, P = 0.008) were the strongest independent risk factors for mortality. Among 139 XDR TB patients, 111 (80%) died. CD4 count <= 50 cells/mm(3) (HR 4.46, P = 0.01) and resistance to all six drugs tested (HR 2.54, P = 0.04) were the principal risk factors. Use of antiretroviral therapy (ART) was protective (HR 0.34, P = 0.009). CONCLUSIONS: Mortality due to MDR- and XDR-TB was associated with greater degree of immunosuppression and drug resistance. Efforts to reduce mortality must focus on preventing the amplification of resistance by strengthening TB treatment programs, as well as reducing the pool of immunosuppressed HIV-infected patients through aggressive HIV testing and ART initiation. PMID- 22236854 TI - Evaluation of the GenoType(r) MTBDRsl assay for susceptibility testing of second line anti-tuberculosis drugs. AB - BACKGROUND: The GenoType(r) MTBDRsl assay is a new rapid assay for the detection of resistance to second-line anti-tuberculosis drugs. OBJECTIVE: To evaluate the MTBDRsl assay on 342 multidrug-resistant tuberculosis isolates for resistance to ofloxacin (OFX), kanamycin (KM), capreomycin (CPM) and ethambutol (EMB), to compare the results to the agar proportion method, and to test discrepant results using DNA sequencing. RESULT: The sensitivity and specificity of the MTBDRsl assay were respectively 70.3% and 97.7% for OFX, 25.0% and 98.7% for KM, 21.2% and 98.7% for CPM and 56.3% and 56.0% for EMB. DNA sequencing identified mutations that were not detected by the MTBDRsl assay. The 8/11 phenotypically OFX-resistant isolates had mutations in gyrA (2/8 had an additional mutation in the gyrB gene), 1/11 had mutations only in the gyrB gene, 6/21 phenotypically KM resistant isolates had mutations in the rrs gene, and 7/26 and 20/26 phenotypically CPM-resistant isolates had mutations in the rrs and tlyA genes. CONCLUSION: The MTBDRsl assay showed lower sensitivity than previous studies. The assay performed favourably for OFX; however, it was less sensitive in the detection of KM/CPM resistance and demonstrated low sensitivity and specificity for EMB resistance. It is recommended that the MTBDRsl assay include additional genes to achieve better sensitivity for all the drugs tested. PMID- 22236855 TI - Integrated detection of multi- and extensively drug-resistant tuberculosis using the nitrate reductase assay. AB - It currently takes 2-3 months to obtain a diagnosis for multidrug-resistant (MDR ) and extensively drug-resistant tuberculosis (XDR-TB). We evaluated the rapid non-commercial nitrate reductase assay (NRA), which is capable of the simultaneous detection of MDR- and XDR-TB, and compared the results with the proportion method (PM). The sensitivity was respectively 97%, 99%, 100% and 94.6% for rifampicin (RMP), isoniazid (INH), ofloxacin (OFX) and kanamycin (KM). The specificity was respectively 100%, 95%, 95.7% and 99% for RMP, INH, OFX and KM. The turnaround time for NRA was 10-14 days, compared to 4-6 weeks for the PM. Our study showed that NRA provided sensitive and specific detection of resistance to first- and second-line drugs. PMID- 22236856 TI - HIV-related bronchiectasis in children: an emerging spectre in high tuberculosis burden areas. AB - BACKGROUND: Human immunodeficiency virus (HIV) infected children have an eleven fold risk of acute lower respiratory tract infection. This places HIV-infected children at risk of airway destruction and bronchiectasis. OBJECTIVE: To study predisposing factors for the development of bronchiectasis in a developing world setting. METHODS: Children with HIV-related bronchiectasis aged 6-14 years were enrolled. Data were collected on demographics, induced sputum for tuberculosis, respiratory viruses (respiratory syncytial virus), influenza A and B, parainfluenza 1-3, adenovirus and cytomegalovirus), bacteriology and cytokines. Spirometry was performed. Blood samples were obtained for HIV staging, immunoglobulins, immunoCAP(r)-specific immunoglobulin E (IgE) for common foods and aeroallergens and cytokines. RESULTS: In all, 35 patients were enrolled in the study. Of 161 sputum samples, the predominant organisms cultured were Haemophilus influenzae and parainfluenzae (49%). The median forced expiratory volume in 1 second of all patients was 53%. Interleukin-8 was the predominant cytokine in sputum and serum. The median IgE level was 770 kU/l; however, this did not seem to be related to atopy; 36% were exposed to environmental tobacco smoke, with no correlation between exposure and CD4 count. CONCLUSION: Children with HIV-related bronchiectasis are diagnosed after the age of 6 years and suffer significant morbidity. Immune stimulation mechanisms in these children are intact despite the level of immunosuppression. PMID- 22236857 TI - Prevalence of asthma and associated factors among schoolchildren in rural South India. AB - OBJECTIVES: 1) To estimate the prevalence of asthma among secondary school children in a rural area in Karnataka, South India, and 2) to identify risk factors associated with asthma among asthma patients. MATERIALS AND METHODS: A cross-sectional study was undertaken among 588 secondary school children in a rural area in South India. A locally adapted version of the questionnaire used in an asthma prevalence study in Iowa, USA, was administered. RESULTS: The prevalence of asthma in the study group was 4.9%. In a multivariate model, significant association was found with sex (male predominance) and exposure to dust in the house. Place of residence, farm dwelling, household pets (cats or dogs), smokers in the family, type of cooking fuel used and the use of firewood without chimneys did not show any significant association. CONCLUSION: In the present study, the prevalence of questionnaire-diagnosed asthma in the study group was 4.9%. Of the total number of schoolchildren with asthma, 17 (58.6%) were detected who had not been diagnosed previously. One third of the children with asthma had visited emergency departments in the last 12 months, indicative of poor asthma control. Another third suffered limitation of activity at home and or at school, which could indicate poor quality of life. PMID- 22236858 TI - Patient and doctor perspectives on incorporating smoking cessation into tuberculosis care in Beijing, China. AB - SETTING: Tuberculosis (TB) hospital in Beijing, China. OBJECTIVE: To describe perspectives of patients and physicians regarding the incorporation of smoking cessation interventions as part of TB treatment. DESIGN: Seven focus groups were conducted with 39 patients and 17 physicians. RESULTS: Patients were more receptive to physicians' advice to quit smoking due to increased concerns about their health after becoming ill with TB. However, patients indicated that they might start smoking again after they recovered from TB. Patients' attempts to quit smoking may have been inhibited by exposure to smoking at the TB facility. Physicians had low levels of knowledge regarding the effect of smoking on TB. Many doctors, particularly those who smoked, did not view smoking cessation as an integral part of TB treatment. CONCLUSION: Despite the presence of a 'teachable moment', TB patients experience significant barriers to quitting smoking. Patient education in TB treatment programs should address the specific effects of smoking on TB and the general health benefits of cessation. Smoke-free policies should be strictly enforced in TB facilities. Successful integration of smoking cessation interventions within TB treatment regimens may require that providers adopt smoking cessation as an essential part of TB treatment. PMID- 22236859 TI - Assessment of tobacco dependence in waterpipe smokers in Egypt. AB - SETTING: Waterpipe smoking is increasing worldwide. Nevertheless, little is known about nicotine dependence in tobacco smokers who use waterpipes. OBJECTIVE: To assess evidence of dependence among non-cigarette smoking waterpipe smokers in Egypt. METHODS: A total of 154 male exclusive current waterpipe smokers were enrolled for the present study. We adapted the Fagerstrom test for nicotine dependence and the Reasons for Smoking (RFS) scales and related these to smoking behavior. RESULTS: The mean age of the subjects was 47 +/- 14 years, the mean age at smoking initiation was 22 +/- 9 years, and average daily consumption was 4 +/ 8 hagars (tobacco units). The time to the first smoke of the day (P < 0.001), smoking even when ill (P = 0.003), time to tobacco craving (P < 0.001), and hating to give up the first smoke of the day (P = 0.033) were each significantly associated with the number of hagars smoked per day. The RFS subscales of addictive smoking, smoking to relieve negative affect, and smoking for stimulation were also associated with these variables. CONCLUSION: The overall findings suggest that waterpipe smokers exhibit many of the same features of nicotine dependency attributed to cigarette smokers. PMID- 22236860 TI - A 38-year-old hairdresser with irritant-associated vocal cord dysfunction. AB - The present case study reports the first case of a 38-year-old hairdresser with irritant-associated vocal cord dysfunction (VCD) due to alkaline persulfate, who was referred on suspicion of occupational asthma. Several tests were performed, including specific inhalation challenge and upper airway endoscopy. During the specific inhalation challenge to alkaline persulfate, the patient experienced dysphonia and a non-significant decrease in forced expiratory volume in 1 second on spirometry. Upper airway endoscopy was then performed and revealed VCD. A specific inhalation challenge test is therefore essential in cases of VCD to exclude possible concomitant occupational asthma. PMID- 22236861 TI - Severe hypercalcaemia following vitamin D replacement for tuberculosis-associated hypovitaminosis D. PMID- 22236862 TI - Ethionamide-induced hypothyroidism. PMID- 22236863 TI - Etanercept in the treatment of recalcitrant enteropathic arthritis: a case report. AB - INTRODUCTION: Enteropathic arthritis is one of the recognized extraintestinal manifestations of inflammatory bowel disease and affects up to 25% of patients. The treatment options for refractory disease were rather limited and ineffective until the arrival of biologic therapy in the last few years. The use of etanercept was unique for this disease. CASE PRESENTATION: In this case report, a 58-year-old Malay woman with a 17-year history of ulcerative colitis had persistent left knee effusion and synovitis for seven years, despite remission of the primary disease. She had had multiple courses of systemic and intra-articular steroid that caused significant systemic side effects such as impaired fasting glucose, hypertension, cataract, and weight gain. She also had a total left knee replacement for secondary osteoarthritis. But the left knee synovitis and effusion recurred a month after the total knee replacement, and she was subjected to a total synovectomy the following year. In view of failure of remission despite multiple immunosuppressants (100 mg of azathioprine daily, 1 g of sulfasalazine twice a day, 10 mg of prednisolone daily, and 10 mg of methotrexate weekly), 25 mg of subcutaneous etanercept twice weekly was started. After 5 weeks of treatment, complete resolution of left knee effusion and normalization of the inflammatory markers were shown. This continued up to 12 months of follow-up while our patient was on etanercept and 10 mg of methotrexate weekly. No relapse or serious side effects were noted. CONCLUSIONS: This case demonstrates the efficacy of etanercept in recalcitrant enteropathic arthritis with no relapse of the underlying colitis while on treatment. The usage of this tumor necrosis factor inhibitor was unique in this case of rheumatology and gastroenterology. PMID- 22236864 TI - Hospitals have no excuse for cutting services, says Nuffield Trust. PMID- 22236865 TI - Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma. AB - BACKGROUND: The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses. METHODS: The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed. RESULTS: Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results. CONCLUSIONS: Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC. PMID- 22236866 TI - MO19390 (SAiL): bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC. AB - INTRODUCTION: The clinical benefit and safety profile associated with first-line bevacizumab with doublet chemotherapy in patients with advanced non-squamous non small cell lung cancer (NSCLC) was established in two large phase III studies, E4599 and AVAiL. SAiL, a single-arm phase IV study, was conducted to evaluate bevacizumab with a range of first-line chemotherapy regimens in a routine oncology practice setting. METHODS: This analysis of the SAiL data was undertaken to specifically evaluate bleeding adverse events (AEs) in this study, and to explore potential associations between bleeding and baseline patient and disease characteristics. RESULTS: In total, 2212 patients were evaluated. Bleeding AEs (any grade) occurred in 38.2% of patients (grade >= 3 bleeding AEs: 3.6%). Grade >= 3 pulmonary hemorrhage and central nervous system bleeding events were observed in 0.7% and 0.1% of patients, respectively. The incidence of grade >= 3 bleeding AEs was comparable across patient subgroups defined by central tumor location, tumor cavitation, histology, concomitant anticoagulation therapy and age. The majority (88.6%) of bleeding events resolved or improved, 10.2% persisted and 1.3% led to death; 10.2% of bleeding events required bevacizumab interruption or discontinuation. CONCLUSIONS: This analysis from the SAiL trial reaffirms a comparable incidence of clinically significant bleeding associated with first-line bevacizumab and chemotherapy as previous phase III studies in NSCLC patients despite less stringent first-line selection criteria. Grade >= 3 bleeding appears to be comparable when analyzed for patient and tumor characteristics, including tumor cavitation and concomitant anticoagulation therapy. Most bleeding events resolved or improved, and interruption/discontinuation of bevacizumab was infrequent in a standard oncology practice setting. PMID- 22236867 TI - Elevated expression of eukaryotic translation initiation factor 4E is associated with proliferation, invasion and acquired resistance to erlotinib in lung cancer. AB - Eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting factor for cap-dependent translation initiation, which is known to regulate oncogenesis. Elevated eIF4E and its negative impact on prognosis in human non-small cell lung cancer (NSCLC) have been reported previously. However, its potential as a therapeutic target and role in regulation of sensitivity to EGFR inhibitors is an area of ongoing investigations. In this study, we detected increased levels of eIF4E in 16 human NSCLC cell lines compared with their normal bronchial epithelial cells. Consistently, human tissue array analysis showed that eIF4E expression was significantly higher in human NSCLC tissues than normal tissues. Inhibition of eIF4E using eIF4E siRNA inhibited the growth and invasion of NSCLC cells. These data suggest that eIF4E overexpression plays a crucial role in positive regulation of the growth and invasion of NSCLC cells. By proteomics, we found that eIF4E levels were elevated in erlotinib-resistant cell lines compared with the sensitive parental cell line. In agreement, assembly of the eIF4F cap complex and several oncogenic proteins regulated by the cap-dependent translation mechanism, were also increased in erlotinib-resistant cells. Thus, erlotinib resistant cells exhibit elevated eIF4E expression and cap-dependent translation. Inhibition of eIF4F with different means (e.g., gene knockdown) downregulated c Met expression and partially restored cell sensitivity to erlotinib, suggesting that elevated eIF4E contributes to development of erlotinib resistance, likely through positive regulation of c-Met expression. Taken together, we suggest that elevated eIF4E in NSCLC cells is associated with proliferation, invasion and acquired erlotinib resistance. PMID- 22236869 TI - Preparation and characterization of stable aqueous higher-order fullerenes. AB - Stable aqueous suspensions of nC60 and individual higher fullerenes, i.e. C70, C76 and C84, are prepared by a calorimetric modification of a commonly used liquid-liquid extraction technique. The energy requirement for synthesis of higher fullerenes has been guided by molecular-scale interaction energy calculations. Solubilized fullerenes show crystalline behavior by exhibiting lattice fringes in high resolution transmission electron microscopy images. The fullerene colloidal suspensions thus prepared are stable with a narrow distribution of cluster radii (42.7 +/- 0.8 nm, 46.0 +/- 14.0 nm, 60 +/- 3.2 nm and 56.3 +/- 1.1 nm for nC60, nC70, nC76 and nC84, respectively) as measured by time-resolved dynamic light scattering. The zeta-potential values for all fullerene samples showed negative surface potentials with similar magnitude ( - 38.6 +/- 5.8 mV, - 39.1 +/- 4.2 mV, - 38.9 +/- 5.8 mV and - 41.7 +/- 5.1 mV for nC60, nC70, nC76 and nC84, respectively), which provide electrostatic stability to the colloidal clusters. This energy-based modified solubilization technique to produce stable aqueous fullerenes will likely aid in future studies focusing on better applicability, determination of colloidal properties, and understanding of environmental fate, transport and toxicity of higher-order fullerenes. PMID- 22236868 TI - The importance of diagnostic testing in the management of community-acquired respiratory infection during influenza season. PMID- 22236870 TI - Blastic plasmacytoid dendritic cell neoplasm without cutaneous lesion at presentation: case report and literature review. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy derived from precursors of plasmacytoid dendritic cells. This disease typically presents with cutaneous involvement as the first manifestation, with subsequent or simultaneous spread to bone marrow and peripheral blood. It is exceedingly rare to diagnose BPDCN without a cutaneous lesion. Here, we report a 21-year-old male who was diagnosed with BPDCN in the absence of cutaneous symptoms. Clinically, left inguinal nodules were noticed for 4 months. The diagnosis of BPDCN was established based on histological and immunohistochemical study of a lymph node biopsy. The patient was classified as stage IVA with bone marrow involvement and underwent three cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine. A complete response was established after one cycle; however, the patient relapsed with disseminated cutaneous lesions and bone marrow involvement following a response duration of 10 months. This case is significant for BPDCN presenting with lymph node and bone marrow involvement in the absence of characteristic cutaneous manifestations. PMID- 22236871 TI - Autoimmune pancreatitis mimicking carcinoma of the head of the pancreas: a case report. AB - INTRODUCTION: We report on a case of autoimmune pancreatitis presenting as pancreatic head cancer, which is extremely rare in Iran. Currently, on the PubMed database, no such cases exist. CASE PRESENTATION: A 70-year-old Iranian man presented with recurrent abdominal pain, jaundice and elevated bilirubin and alkaline phosphatase levels. An abdominal computed tomography scan revealed a heterogeneous presence in the pancreatic head as well as dilated intra- and extrahepatic bile ducts. A common bile duct stent had been inserted. Our patient was subsequently diagnosed with pancreatic head cancer.Due to his continued recurrent abdominal pain, our patient returned to the hospital. His levels of bilirubin, alkaline phosphatase and tumor markers were all normal but his immunoglobulin G4 and antinuclear antibodies were extremely high. A biopsy of the pancreatic head heterogeneity by endoscopic ultrasonography was performed.Pathologic samples showed fibrosis associated with lymphoplasmacytic infiltration and no evidence of malignancy. A diagnosis of autoimmune pancreatitis was confirmed, the bile duct stent removed, and an appropriate treatment plan was undertaken. CONCLUSION: Autoimmune pancreatitis should be considered in suspected cases of pancreatic cancer. In these instances, a biopsy of the pancreas will help to differentiate between the two and prevent complications due to disease progression as well as unnecessary surgery. PMID- 22236872 TI - Habitat separation of sympatric Microcebus spp. in the dry spiny forest of south eastern Madagascar. AB - We investigated whether or not habitat structure contributes to the separation of two sister species of lemurs and their hybrids. For this, we studied Microcebus murinus and M. griseorufus along a continuous vegetation gradient where populations of the two species occur in sympatry or in allopatry. In allopatry, the two species are generalists without any sign of microhabitat selectivity. In sympatry, both species differed significantly and discriminated against certain habitat structures: M. murinus was found in microhabitats with larger trees than average while M. griseorufus utilized microhabitats with smaller trees. Hybrids between the two species did not show any significant discrimination for or against microhabitat structure and did not differ in their habitat utilization from either parent species. Both species can go into torpor and hibernation. M. griseorufus is seen more frequently during the cool dry season than M. murinus. We assume that M. murinus goes into extended torpor or hibernation more frequently than M. griseorufus. We interpret the different occurrence of large sized trees in microhabitats of M. murinus as a prerequisite for M. murinus to be able to spend extended periods of time in tree holes that are isolated and allow hibernation at reduced temperature levels. PMID- 22236873 TI - Glutamine and the tumor microenvironment: understanding the mechanisms that fuel cancer progression. PMID- 22236874 TI - Reuben Lotan, Ph.D. (1946-2011): in memoriam. PMID- 22236876 TI - Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells: implications for preventing chemotherapy resistance. AB - Glutamine metabolism is crucial for cancer cell growth via the generation of intermediate molecules in the tricarboxylic acid (TCA) cycle, antioxidants and ammonia. The goal of the current study was to evaluate the effects of glutamine on metabolism in the breast cancer tumor microenvironment, with a focus on autophagy and cell death in both epithelial and stromal compartments. For this purpose, MCF7 breast cancer cells were cultured alone or co-cultured with non transformed fibroblasts in media containing high glutamine and low glucose (glutamine +) or under control conditions, with no glutamine and high glucose (glutamine -). Here, we show that MCF7 cells maintained in co-culture with glutamine display increased mitochondrial mass, as compared with control conditions. Importantly, treatment with the autophagy inhibitor chloroquine abolishes the glutamine-induced augmentation of mitochondrial mass. It is known that loss of caveolin-1 (Cav-1) expression in fibroblasts is associated with increased autophagy and an aggressive tumor microenvironment. Here, we show that Cav-1 downregulation which occurs in fibroblasts maintained in co-culture specifically requires glutamine. Interestingly, glutamine increases the expression of autophagy markers in fibroblasts, but decreases expression of autophagy markers in MCF7 cells, indicating that glutamine regulates the autophagy program in a compartment-specific manner. Functionally, glutamine protects MCF7 cells against apoptosis, via the upregulation of the anti-apoptotic and anti-autophagic protein TIGAR. Also, we show that glutamine cooperates with stromal fibroblasts to confer tamoxifen-resistance in MCF7 cancer cells. Finally, we provide evidence that co-culture with fibroblasts (1) promotes glutamine catabolism, and (2) decreases glutamine synthesis in MCF7 cancer cells. Taken together, our findings suggest that autophagic fibroblasts may serve as a key source of energy-rich glutamine to fuel cancer cell mitochondrial activity, driving a vicious cycle of catabolism in the tumor stroma and anabolic tumor cell expansion. PMID- 22236877 TI - PERP gene therapy attenuates lung cancer xenograft via inducing apoptosis and suppressing VEGF. AB - Inducing apoptosis is an attractive antitumor strategy. PERP is an apoptosis associated target of p53, and its activation alone is sufficient to induce apoptotic pathway leading to cell death. We have previously demonstrated that overexpression of PERP in tumor cell lines with low intrinsic PERP activity suppressed cancer cell growth and enhanced sensitivity to chemotherapeutical agents. We further identified that PERP was present in surgical normal lung tissue, but absent in cancerous tissue of the same patient. Here, we sought to investigate the anti-tumor effects of PERP gene therapy in vivo. Then nude mice were transplanted with p53-mutanted Anip973 human lung cancer xenografts and treated with normal saline, pcDNA3.1 (vector) and pcDNA3.1-PERP, respectively. Successful transfection and robust expression of PERP was detected. Treatment with pcDNA3.1-PERP increased apoptosis and retarded growth in the xenografts, which contributed to a 55% decrease in tumor volume compared with controls. Furthermore, PERP gene therapy activated pro-apoptotic Caspase-3 cascade and upregulated the expression of the second mitochondria-derived activator of caspase (Smac) and human TNF-related apoptosis-inducing ligand (TRAIL), while suppressed vascular endothelial growth factor (VEGF) expression, indicating apoptosis and anti-angiogenesis are involved in the inhibitory effect of the PERP gene therapy. Taken together, our results suggest PERP gene therapy may supply an alternative strategy for lung adenocarcinoma management. Furthermore, Anip973 is a p53-mutanted cell line and the findings of this study provide reference value for other p53-mutanted cancers which is common among malignant tumors. PMID- 22236875 TI - Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. AB - We have previously demonstrated that enhanced aerobic glycolysis and/or autophagy in the tumor stroma supports epithelial cancer cell growth and aggressive behavior, via the secretion of high-energy metabolites. These nutrients include lactate and ketones, as well as chemical building blocks, such as amino acids (glutamine) and nucleotides. Lactate and ketones serve as fuel for cancer cell oxidative metabolism, and building blocks sustain the anabolic needs of rapidly proliferating cancer cells. We have termed these novel concepts the "Reverse Warburg Effect," and the "Autophagic Tumor Stroma Model of Cancer Metabolism." We have also identified a loss of stromal caveolin-1 (Cav-1) as a marker of stromal glycolysis and autophagy. The aim of the current study was to provide genetic evidence that enhanced glycolysis in stromal cells favors tumorigenesis. To this end, normal human fibroblasts were genetically-engineered to express the two isoforms of pyruvate kinase M (PKM1 and PKM2), a key enzyme in the glycolytic pathway. In a xenograft model, fibroblasts expressing PKM1 or PKM2 greatly promoted the growth of co-injected MDA-MB-231 breast cancer cells, without an increase in tumor angiogenesis. Interestingly, PKM1 and PKM2 promoted tumorigenesis by different mechanism(s). Expression of PKM1 enhanced the glycolytic power of stromal cells, with increased output of lactate. Analysis of tumor xenografts demonstrated that PKM1 fibroblasts greatly induced tumor inflammation, as judged by CD45 staining. In contrast, PKM2 did not lead to lactate accumulation, but triggered a "pseudo-starvation" response in stromal cells, with induction of an NFkappaB-dependent autophagic program, and increased output of the ketone body 3-hydroxy-buryrate. Strikingly, in situ evaluation of Complex IV activity in the tumor xenografts demonstrated that stromal PKM2 expression drives mitochondrial respiration specifically in tumor cells. Finally, immuno-histochemistry analysis of human breast cancer samples lacking stromal Cav 1 revealed PKM1 and PKM2 expression in the tumor stroma. Thus, our data indicate that a subset of human breast cancer patients with a loss of stromal Cav-1 show profound metabolic changes in the tumor microenvironment. As such, this subgroup of patients may benefit therapeutically from potent inhibitors targeting glycolysis, autophagy and/or mitochondrial activity (such as metformin). PMID- 22236879 TI - HDAC inhibitor sodium butyrate sensitizes E1A+Ras-transformed cells to DNA damaging agents by facilitating formation and persistence of gammaH2AX foci. AB - HDAC inhibitors (HDACi) suppress the growth of tumor cells due to induction of cell cycle arrest, senescence or apoptosis. Recent data demonstrate that HDACi can interfere with DNA Damage Response (DDR) thereby sensitizing the cells to DNA damaging agents. Here, we show that HDACi sodium butyrate (NaBut) potentiates the formation of gammaH2AX foci predominantly in S-phase E1A+Ras cells. Accumulation of gammaH2AX foci sensitizes the cells toward such DNA damaging agents as irradiation (IR) and adriamycin. In fact, NaBut potentiates the persistence of gammaH2AX foci induced by genotoxic agents. The synergizing effects depend on DNA damaging factors and on the order of NaBut treatment. Indeed, NaBut treatment for 24 h leads to an accumulation of G 1-phase cells and a lack of S-phase cells, therefore, adriamycin, a powerful S-phase-specific inhibitor, when added to NaBut treated cells, is unable to substantially add gammaH2AX foci. In contrast, IR produces both single- and double-strand DNA breaks at any stage of the cell cycle and was shown to increase gammaH2AX foci in NaBut-treated cells. Further, a lifetime of IR-induced gammaH2AX foci depends on the subsequent presence of HDACi. Correspondingly, NaBut withdrawal leads to the extinction of IR-induced gammaH2AX foci. This necessitates HDACi to hold the IR-induced gammaH2AX foci unrepaired. However, the IR-induced gammaH2AX foci persist after long-term NaBut treatment (72 h) even after washing the drug. Thus, although signaling pathways regulating H2AX phosphorylation in NaBut-treated cells remain to be investigated, the obtained results show that NaBut potentiates effects of DNA damaging agents by facilitating formation and persistence of gammaH2AX foci. PMID- 22236878 TI - The heat shock proteins as targets for radiosensitization and chemosensitization in cancer. AB - The heat shock proteins (HSPs) represent a class of proteins which are induced under physiologic stress to promote cell survival in the face of endogenous or exogenous injury. HSPs function predominantly as molecular chaperones, maintaining their "client" proteins in the correct conformational state in order to withstand a biologic stressor. Elevated HSP expression is also found in a range of pathologic conditions, notably malignancy. Cancer cells exploit the pro survival phenotype endowed by HSPs to bolster their proliferative potential. Consequently, developing means of abrogating HSP expression may provide a way to render cancer cells more susceptible to radiation or chemotherapy. Here, we review the members of the HSP class and their roles in malignancy. We focus on attempts to target these proteins, particularly the small HSPs, in developing potent radiation and chemotherapy sensitizers, as well as proposed mechanisms for this sensitization effect. PMID- 22236880 TI - The role of cytokine signaling in the pathogenesis of cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) displays immunosuppressive properties and phenotypic plasticity. The malignant T cells in CTCL can possess features of immunomodulating regulatory T cells (Treg) and IL-17-producing helper T cells (Th17) depending on the stimuli they receive from antigen presenting cells and other sources. IL-2-type cytokines activate STAT5 to promote expression of Treg related FoxP3, while various cytokines can activate STAT3 to induce synthesis of IL-10 and IL-17. When the Treg phenotype is activated in the early stages of CTCL, "immune evasion" can occur, allowing the clonal T cells to expand. Late stages of CTCL lose the FoxP3 expression but continue to express an immunosuppressive cell-surface ligand PD-L1 suggesting that this and possibly other immunosuppressive proteins rather than FoxP3 are critical for the immunosuppressive state in the advanced stages of CTCL. Novel therapeutic agents may potentially exploit the phenotypic plasticity of CTCL such that the malignant T cells become vulnerable to antitumor immunity. PMID- 22236881 TI - Urinary survivin mRNA expression and urinary nuclear matrix protein 22 BladderChek(r) and urine cytology in the detection of transitional cell carcinoma of the bladder. AB - OBJECTIVE: To compare the diagnostic performance of urine cytology (UC), survivin mRNA expression, and the NMP22 BladderChek(r) (NMP22BC) test for the detection, grading and staging of transitional cell carcinoma (TCC) of the bladder. MATERIALS AND METHODS: Voided urine samples collected from 25 healthy controls and 80 patients diagnosed with TCC of the bladder were subjected to UC, the NMP22BC test and reverse-transcription real-time PCR for survivin mRNA expression. RESULTS: Survivin mRNA expression showed the highest sensitivity (87.5%) followed by the NMP22BC test (61.3%) while UC exhibited the lowest sensitivity (40%). All three urine markers had a similar specificity of 96% (95% CI 80.5-99.3%). Survivin mRNA expression was the only urine marker that showed a significant difference in relation to tumour histological grade (chi(2) 8.5, p = 0.015). None of the three urine markers was significantly related to tumour pathological stages. CONCLUSION: The diagnostic sensitivity of urinary survivin mRNA expression was superior to that of UC and the NMP22BC test and correlates with tumour pathological grade but not stage. PMID- 22236882 TI - Screening serum biomarker of knee osteoarthritis using a phage display technique. AB - OBJECTIVES: To screen serum biomarker of knee osteoarthritis (OA) using a phage random peptide library. DESIGN AND METHODS: A phage random peptide library of random peptide 12-mers was screened with purified immunoglobulin G (IgG) from sera of knee OA patients. Patients with knee rheumatoid arthritis (RA), hip OA, non-erosive hand OA or erosive hand OA, and healthy volunteers were used as controls. RESULTS: A phage clone with inserted peptide TGLESGHGPGDS (named KOA1) showed 90% positive reaction rate with the knee OA patients, significantly higher than that with the knee RA patients (27.8%), the non-erosive hand OA patients (34.3%), the erosive hand OA patients (31.3%) and the healthy controls (12.0%), but not the hip OA patients (82.5%). CONCLUSIONS: The novel knee OA mimic peptide KOA1 identified with a random phage display peptide library and sera from knee OA patients could be a potential serum biomarker for knee OA. PMID- 22236883 TI - The chimney graft technique for preserving visceral vessels during endovascular treatment of aortic pathologies. AB - OBJECTIVE: Patients with juxtarenal, pararenal, or thoracoabdominal aneurysms require complex surgical open repair, which is associated with increased mortality and morbidity. The "chimney graft" or "snorkel" technique has evolved as a potential alternative to fenestrated and side-branched endografts. The purpose of this study is to review all published reports on chimney graft (CG) technique involving visceral vessels and investigate the safety and efficacy of the technique. METHODS: Studies were included in the present review if visceral revascularization during endovascular treatment of aortic pathologies was achieved via a CG implantation. Reports on the chimney technique for aortic arch branches revascularization were excluded. A multiple electronic health database search was performed on all articles published until April 2011. RESULTS: The electronic literature search yielded 15 reports that fulfilled the inclusion criteria. A total of 93 patients (81.3% male; mean age, 71.9 +/- 0.9 years) were analyzed. In 77.4% of the patients, the CG procedure was applied for the treatment of abdominal aortic aneurysms. Out of the 93 patients, 24.7% were operated on in an urgent setting (symptomatic or ruptured aneurysm). A total of 134 CGs were implanted: 108 to the renal arteries, 20 to the superior mesenteric artery, five to the celiac trunk, and one to the inferior mesenteric artery. In 57 patients, a single CG was deployed; in 32 patients, two CGs; in three patients, three CGs; and in one patient, four CGs were deployed. Ninety-four percent of CGs were directed proximally, whereas 6.0% were directed caudally. Primary technical success was achieved in all patients. A total of 13 patients (14.0%) developed a type I endoleak. Three were detected and treated intraoperatively. Postoperatively, 10 type I endoleaks were revealed, four of which required secondary intervention. During a mean follow-up period of 9.0 +/- 1.0 months, 131 of 134 (97.8%) CGs remained patent. Two CGs to the renal arteries and one to the superior mesenteric artery occluded. Postoperatively, 11.8% of patients suffered renal function impairment and 2.1% a myocardial infarction. Ischemic stroke presented in 3.2% of patients. The 30-day in-hospital mortality was 4.3%. CONCLUSIONS: The role of the chimney technique in the management of complex abdominal aortic aneurysms is still unclear. This technique has relatively good results, considering the anatomic limitations of the aortic neck. However, long-term endograft durability and proximal fixation remains a significant concern. Thus, there is a reasonable hesitation to embrace the method for widespread use in the absence of long-term data. PMID- 22236884 TI - The importance of antegrade completion angiography in aortobifemoral bypass limb revision. AB - Aortobifemoral bypass is a durable arterial reconstruction with well-defined failure modes. Management of graft limb thrombosis requires restoration of inflow and correction of any causative outflow lesions. Successful, minimally invasive inflow restoration with catheter thrombectomy can become problematic if assessment of technical adequacy is deficient or reveals causal lesions within the graft body. We describe a case illustrating the potential shortfall of retrograde graft limb completion angiography in depicting neointimal flaps, the benefit of antegrade angiography in depicting these flaps, and a novel utilization of a standard endovascular method to correct flaps that involve the graft body. PMID- 22236885 TI - Results of carotid artery stenting with distal embolic protection with improved systems: Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy (PROTECT) trial. AB - OBJECTIVE: The Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy (PROTECT) study was performed to evaluate the safety and effectiveness of two devices for carotid artery stenting (CAS) in the treatment of carotid artery stenosis in patients at high risk for carotid endarterectomy (CEA): (1) a new embolic protection device, the Emboshield Pro (Abbott Vascular, Abbott Park, Ill), using the periprocedural composite end point of 30-day death, stroke, and myocardial infarction (DSMI), and (2) a carotid stent in conjunction with an embolic protection device (EPD) using the DSMI periprocedural composite end point plus ipsilateral stroke at up to 3 years for long-term evaluation. METHODS: This prospective, multicenter clinical trial enrolled 220 consecutive participants between November 29, 2006, and January 14, 2008, followed by a second cohort of 102 participants between January 14 and June 18, 2008. Enrolled participants had carotid stenosis (symptomatic >50% or asymptomatic >80%). The first 220 subjects underwent distal EPD placement with a new large-diameter filter, and the second cohort of 102 underwent placement of an older EPD that is no longer manufactured. All 322 participants were to be treated with a dedicated carotid stent with a tapered, small, closed-cell design (Xact; Abbott Vascular) and were to be included in the long-term evaluation. Independent neurologic assessment was performed before CAS and at 1 day, 30 days, and annually after CAS. All primary end point events were independently adjudicated by a central committee. RESULTS: The periprocedural composite end point of DSMI (95% confidence interval) in the first 220 participants was 2.3% (0.74%, 5.22%), with a combined death and stroke rate of 1.8% (0.50%, 4.59%) and a rate of death and major stroke of 0.5% (0.01%, 2.51%). As of January 3, 2011, the median follow-up for the entire 322-subject cohort for the long-term evaluation was 2.8 years. Freedom from the periprocedural composite of DSMI plus ipsilateral stroke thereafter was 95.4%, with an annualized ipsilateral stroke rate of 0.4%. CONCLUSIONS: CAS outcomes in patients at high risk for CEA have improved from earlier carotid stent trials. With periprocedural rates of DSMI of 2.3%, death or stroke at 1.8%, and death or major stroke rate of 0.5%, PROTECT has the lowest rate of periprocedural complications among other comparable single-arm CAS trials in patients at high risk for CEA. PMID- 22236886 TI - [Systemic therapy for advanced endometrial cancer]. AB - Endometrial cancer has generally a good prognosis when it is diagnosed at an early stage but remains incurable at an advanced stage (recurrent or metastatic) with only few therapeutic options. Hormone therapy is the treatment of choice in case of slowly progressive disease with a tumor expressing hormonal receptors due to its favorable safety profile. Taxanes, anthracyclines and platinum compounds are the most active chemotherapy agents with greater response rates when they are combined at the price of a significant toxicity. Targeted therapies based on a better understanding of tumor biology are being evaluated with some promising results. PMID- 22236887 TI - Aphasia induced by gliomas growing in the ventrolateral frontal region: assessment with diffusion MR tractography, functional MR imaging and neuropsychology. AB - INTRODUCTION: Lesions in the ventrolateral region of the dominant frontal lobe have been historically associated with aphasia. Recent imaging results suggest that frontal language regions extend beyond classically defined Broca's area to include the ventral precentral gyrus (VPCG) and the arcuate fasciculus (AF). Frontal gliomas offer a unique opportunity to identify structures that are essential for speech production. The aim of this prospective study was to investigate the correlation between language deficits and lesion location in patients with gliomas. METHODS: Nineteen patients with glioma and 10 healthy subjects were evaluated with diffusion tensor imaging magnetic resonance (MR) tractography, functional MR (verb generation task) and the Aachener Aphasie Test. Patients were divided into two groups according to lesion location with respect to the ventral precentral sulcus: (i) anterior (n=8) with glioma growing in the inferior frontal gyrus (IFG) and underlying white matter; (ii) posterior (n=11) with glioma growing in the VPCG and underlying white matter. Virtual dissection of the AF, frontal intralobar tract, uncinate fasciculus (UF) and inferior frontal occipital fasciculus (IFOF) was performed with a deterministic approach. RESULTS: Seven posterior patients showed aphasia classified as conduction (4), Broca (1), transcortical motor (1) and an isolated deficit of semantic fluency; one anterior patient had transcortical mixed aphasia. All posterior patients had invasion of the VPCG, however only patients with aphasia had also lesion extension to the AF as demonstrated by tractography dissections. All patients with language deficits had high grade glioma. Groups did not differ regarding tumour volume. A functional pars opercularis was identified with functional MR imaging (fMRI) in 17 patients. CONCLUSIONS: Gliomas growing in the left VPCG are much more likely to cause speech deficits than gliomas infiltrating the IFG, including Broca's area. Lesion extension to the AF connecting frontal to parietal and temporal regions is an important mechanism for the appearance of aphasia. PMID- 22236888 TI - Postural control in multiple sclerosis: effects of disability status and dual task. AB - Persons with Multiple Sclerosis (PwMS) have postural control impairments. The simultaneous performance of a cognitive task while maintaining an upright posture (i.e. dual task) negatively influences postural control in PwMS with mild disability. This investigation compares the effect of simultaneous cognitive task performance on postural control in PwMS with mild and moderate disability. Forty five PwMS were divided into groups based on Expanded Disability Status Scale (EDSS) scores: mild (EDSS: 2.0-3.5) and moderate (EDSS: 4.0-6.5) disbaility. Each participant underwent posturography testing during a quiet baseline condition and a cognitive task condition (i.e. dual task). The cognitive task was a word list generation (WLG) task. Median sway velocity, root mean square displacement, and sway area were calculated for each condition. The moderate disability group had significantly worse postural control than the mild disability group. There was an increase in postural sway in the dual task condition. There were no significant task-by-group interactions on postural control. Postural control declines with disability status and is negatively affected by a concurrent cognitive task in PwMS. The dual task cost during a balance task is not different between disability levels and this conflicts with findings for the effect of dual tasking during walking in PwMS. PMID- 22236889 TI - Fludarabine may overcome resistance to rituximab in IgM-related neuropathy. AB - Rituximab, a monoclonal antibody directed against CD20, became widely used for the treatment of immunoglobulin M (IgM)-related neuropathy. However, response rate by rituximab monotherapy is no more than 30%. Previous studies revealed that fludarabine acts synergistically with rituximab in vitro and that fludarabine also ameliorates IgM-related neuropathy in a subset of patients. Here we present two cases of IgM-related neuropathy in the background of Waldenstrom macroglobulinaemia, including one with rituximab resistance. They showed marginal to high titres of both anti-myelin associated glycoprotein and anti-sulphate-3 glucuronyl paragloboside antibodies, and their symptoms were featured by prominent motor deterioration. The combination therapy with rituximab and fludarabine stabilised or improved neuropathic symptoms with tolerable adverse events. Fludarabine may have a potential to overcome rituximab resistance. In conclusion, combination therapy with rituximab and fludarabine should be considered for IgM-related neuropathy, especially when efficacy of rituximab monotherapy is insufficient. PMID- 22236890 TI - Publication of RadioGraphics manuscripts: guidelines for authors and description of solicitation process and peer review. PMID- 22236891 TI - Pulmonary hypertension: how the radiologist can help. AB - Pulmonary hypertension is defined as an abnormal elevation of pressure in pulmonary circulation, with a mean pulmonary arterial pressure higher than 25 mmHg, regardless of the underlying mechanism. The clinical classification system for pulmonary hypertension was updated at the fourth World Symposium on Pulmonary Hypertension in Dana Point, California, in 2008. In patients with suspected pulmonary hypertension, the diagnostic approach includes four stages: suspicion, detection, classification, and functional evaluation. It is crucial to understand the advantages and disadvantages of the different imaging tools available for the diagnostic work-up and follow-up of patients with pulmonary hypertension. Many conditions that cause pulmonary hypertension have suggestive findings at multidetector computed tomography or magnetic resonance imaging; some causes may be surgically treatable, whereas others may demonstrate adverse reactions to vasodilator therapies used during the course of treatment. Therefore, the radiologist plays an important role in evaluating patients with this disease. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.321105232/-/DC1. PMID- 22236892 TI - Thoracic manifestations of collagen vascular diseases. AB - Collagen vascular diseases are a diverse group of immunologically mediated systemic disorders that often lead to thoracic changes. The collagen vascular diseases that most commonly involve the lung are rheumatoid arthritis, progressive systemic sclerosis, systemic lupus erythematosus, polymyositis and dermatomyositis, mixed connective tissue disease, and Sjogren syndrome. Interstitial lung disease and pulmonary arterial hypertension are the main causes of mortality and morbidity among patients with collagen vascular diseases. Given the broad spectrum of possible thoracic manifestations and the varying frequency with which different interstitial lung diseases occur, the interpretation of thoracic images obtained in patients with collagen vascular diseases can be challenging. The task may be more difficult in the presence of treatment-related complications such as drug toxicity and infections, which are common in this group of patients. Although chest radiography is most often used for screening and monitoring of thoracic alterations, high-resolution computed tomography can provide additional information about lung involvement in collagen vascular diseases and may be especially helpful for differentiating specific disease patterns in the lung. General knowledge about the manifestations of thoracic involvement in collagen vascular diseases allows radiologists to provide better guidance for treatment and follow-up of these patients. PMID- 22236893 TI - Common and uncommon manifestations of Wegener granulomatosis at chest CT: radiologic-pathologic correlation. AB - Wegener granulomatosis is an uncommon necrotizing vasculitis that classically manifests as a clinical triad consisting of upper and lower airway involvement and glomerulonephritis. Other less frequently involved organ systems include the central and peripheral nervous system and large joints. The diagnosis is based on a combination of clinical and laboratory findings. Because thoracic involvement often predominates, chest radiographic findings are often the first to suggest the diagnosis. However, chest computed tomography (CT) has superior sensitivity and specificity for evaluation of the airways, lung parenchyma, and mediastinum, particularly with the use of multiplanar reformatted and three-dimensional images. Common pulmonary radiologic findings include waxing and waning nodules, masses, ground-glass opacities, and consolidation. Airway involvement is usually characterized by circumferential tracheobronchial thickening, which can be smooth or nodular. Pleural effusions are the most common manifestation of pleural disease and can result from primary involvement or be secondary to renal failure. Mediastinal lymphadenopathy is a nonspecific finding and is usually reactive. Uncommon thoracic radiologic manifestations include involvement of the heart and great vessels. CT is the imaging modality of choice for diagnosis, surveillance, and follow-up in patients with Wegener granulomatosis. PMID- 22236894 TI - Thoracic paracoccidioidomycosis: radiographic and CT findings. AB - Paracoccidioidomycosis (PCM) is the most common systemic mycosis in Latin America. Although most cases occur in developing countries, recent immigration patterns and an increase in travel have led to a growing number of PCM cases in the United States and Europe. PCM is caused by the dimorphic fungus Paracoccidioides brasiliensis, and the chronic form may progress to severe pulmonary involvement. Several radiologic patterns have been described for pulmonary PCM, including linear and reticular opacities, variable-sized nodules, patchy ill-defined opacities, airspace consolidation, and cavitary lesions. Fibrosis and paracicatricial emphysema are common associated findings. Chest computed tomography (CT) is the method of choice for evaluating pulmonary PCM, with the most common CT findings being ground-glass attenuation, consolidation, small or large nodules, masses, cavitations, interlobular septal thickening, emphysema, and fibrotic lesions. PCM is also an important cause of the "reversed halo" sign at high-resolution CT and should be considered in the differential diagnosis. Awareness of the multiple radiologic manifestations of PCM as well as its epidemiologic and clinical characteristics may permit early diagnosis and initiation of specific treatment, thereby reducing associated morbidity and mortality. PMID- 22236895 TI - MR imaging and CT evaluation of congenital pulmonary vein abnormalities in neonates and infants. AB - Magnetic resonance (MR) imaging and computed tomography (CT) are increasingly being used in diagnosis and follow-up of congenital pulmonary vein anomalies in neonates and infants. Such anomalies include total or partial anomalous pulmonary venous return, sinus venosus defect, malposition of the septum primum, cor triatriatum, pulmonary vein atresia or stenosis, and abnormal number or course of the pulmonary veins. MR imaging provides a wealth of anatomic and functional data that are valuable in case management and planning intervention. Gadolinium enhanced MR angiography is the mainstay of anatomic evaluation. Ventricular volumetry with two-dimensional steady-state free-precession sequences and flow analysis with cine phase-contrast imaging provide physiologic information that may be used to calculate the degree of right heart enlargement and the shunt fraction, allowing the cardiologist to determine the functional importance of the lesion. CT provides superior spatial resolution and short imaging times but at the expense of exposure to ionizing radiation. PMID- 22236896 TI - AIRP best cases in radiologic-pathologic correlation: congenital mesoblastic nephroma. PMID- 22236897 TI - Imaging features of therapeutic drug-induced musculoskeletal abnormalities. AB - Increasing use of a wide variety of therapeutic drugs with known musculoskeletal side-effect profiles necessitates a rigorous understanding and approach when evaluating imaging features suggestive of drug-induced musculoskeletal abnormalities. The etiology of such abnormalities is diverse, and the clinical and imaging manifestations may be nonspecific. The recognition of adverse effects depends, first, on the physician's vigilant review of clinical information for relevant drug history and indicative signs, and second, on the radiologist's ability to detect musculoskeletal changes consistent with known potential effects of specific drugs. Musculoskeletal abnormalities induced by therapeutic drugs may be broadly categorized as embryopathic, juvenile, or postmaturation. Embryopathic skeletal abnormalities result from the teratogenic effects of drugs administered to pregnant women (eg, thalidomide, anticonvulsants). Other therapeutic agents characteristically lead to abnormalities during postnatal skeletal maturation (eg, high-dose vitamins or prostaglandin) either because they are used exclusively in children or because they have idiosyncratic effects on immature musculoskeletal structures. Many drugs (eg, statins) may have musculoskeletal side effects that, although independent of the stage of skeletal maturation, are most often seen in adults or elderly people because they are commonly prescribed for people in these age groups. Drug-induced musculoskeletal abnormalities may be further characterized according to the predominant skeletal manifestations as osteomalacic, proliferative, or osteoporotic and according to the involvement of soft tissues as musculotendinous or chondral. PMID- 22236898 TI - Radiologic review of total elbow, radial head, and capitellar resurfacing arthroplasty. AB - The use of metal and pyrolytic carbon radial head implants, capitellar resurfacing, and total elbow arthroplasty has become common in contemporary orthopedic surgery practice. The goal of total elbow arthroplasty is to decrease pain and restore an acceptable range of motion to the elbow joint. Rheumatoid arthritis is the primary indication for total elbow arthroplasty; newer indications include primary or posttraumatic osteoarthritis, fracture nonunion, acute comminuted fractures of the elbow, and postoperative resection of a neoplasm. Unlike total elbow arthroplasty, radial head replacement is most commonly performed in patients with trauma. Radial head fractures account for 33% of all elbow fractures in adults and are often associated with ligament disruption and valgus instability at the elbow. The goals of capitellar resurfacing arthroplasty include prevention of secondary osteoarthritis of the radiocapitellar joint and erosion in patients with radial head arthroplasty. Effective postoperative radiologic assessment of these different types of elbow reconstructions requires an understanding of their basic component design, physiologic purpose, and normal postoperative appearance, as well as the appearance of complications. Radiologists may have little training and experience with these new orthopedic devices. PMID- 22236899 TI - Lesions of the petrous apex: classification and findings at CT and MR imaging. AB - The petrous apex is a complex region of the central skull base that is surrounded by a number of important vascular and neural structures and can be home to a wide range of disease processes. Lesions arising in or spreading to the petrous apex cause varied and occasionally severe clinical sequelae, which typically result from mass effect or direct invasion of the cranial nerves, brainstem, or internal carotid artery. Because the petrous apex is not amenable to direct examination, cross-sectional imaging with computed tomography and magnetic resonance (MR) imaging plays an important role in diagnosis and characterization of lesions occurring there. Petrous apex lesions can be classified on the basis of their origin into the following categories: developmental lesions, inflammatory lesions, benign tumors, malignant tumors, vascular lesions, and osseous dysplasias. The most common lesions arising in the petrous apex are cholesterol granulomas, which can be reliably diagnosed with MR imaging due to their high signal intensity on both T1-weighted images and T2-weighted images. In addition, one should also be familiar with anatomic variants or pseudolesions in the petrous apex that can be mistaken for pathologic conditions. PMID- 22236900 TI - MR imaging evaluation of perianal fistulas: spectrum of imaging features. AB - Perianal fistulization is an inflammatory condition that affects the region around the anal canal, causing significant morbidity and often requiring repeated surgical treatments due to its high tendency to recur. To adopt the best surgical strategy and avoid recurrences, it is necessary to obtain precise radiologic information about the location of the fistulous track and the affected pelvic structures. Until recently, imaging techniques played a limited role in evaluation of perianal fistulas. However, magnetic resonance (MR) imaging now provides more precise information on the anatomy of the anal canal, the anal sphincter complex, and the relationships of the fistula to the pelvic floor structures and the plane of the levator ani muscle. MR imaging allows precise definition of the fistulous track and identification of secondary fistulas or abscesses. It provides accurate information for appropriate surgical treatment, decreasing the incidence of recurrence and allowing side effects such as fecal incontinence to be avoided. Radiologists should be familiar with the anatomic and pathologic findings of perianal fistulas and classify them using the St James's University Hospital MR imaging-based grading system. PMID- 22236901 TI - Orthotopic liver transplantation: reversible Doppler US findings in the immediate postoperative period. AB - Orthotopic liver transplantation (OLT) is the only definitive treatment for irreversible acute liver failure and chronic liver disease. In the immediate postoperative period after OLT, patients are closely monitored with Doppler ultrasonography (US) to detect treatable vascular complications and ensure graft survival. The first postoperative Doppler US examination is performed fairly early on the first postoperative day, before surgical wound closure has been performed. The immediate postoperative images, obtained when the effects of surgery are very recent, often reveal an array of findings that may appear alarming but that tend to normalize within a few days and are compatible with changes related to the surgery itself. These findings include a starry-sky appearance of reperfusion hepatic edema, transient foci of increased echogenicity, pneumobilia, small fluid collections, perihepatic hematomas, pleural effusion, temporary elevation of hepatic arterial velocity, transient elevation of resistive index (RI), decreased RI with tardus parvus waveform, increased portal venous flow and mono- or biphasic waveforms of the hepatic veins. Most of these changes revert to normal in the first postoperative week; deterioration atypical of transient changes requires further evaluation. PMID- 22236902 TI - AIRP best cases in radiologic-pathologic correlation: Brunner gland hamartoma. PMID- 22236903 TI - MR imaging assessment of the breast after breast conservation therapy: distinguishing benign from malignant lesions. AB - Dynamic contrast material-enhanced magnetic resonance (MR) imaging has emerged as a valuable tool in evaluation of women who have undergone lumpectomy and whole breast radiation therapy for breast cancer. Early diagnosis of local recurrence by means of close clinical and imaging follow-up is an important component of a breast-conserving strategy, as it may improve survival. In the post-breast conservation therapy (BCT) breast, resolving edema, fat necrosis, a small focal area of non-masslike enhancement (NMLE), and thin linear NMLE at the lumpectomy site can all be expected findings. In contrast, masslike enhancement or NMLE of ductal or segmental distribution can indicate recurrence. Therefore, at MR imaging of the post-BCT breast, it is important to identify lesions that are benign or appropriate for short-interval imaging surveillance to minimize unnecessary intervention, as well as to discern suspicious lesions and optimize the diagnosis of recurrence. PMID- 22236904 TI - Relative importance of metaphor in radiology versus other medical specialties. AB - The acquisition of competence in radiology often entails referring to other realms of knowledge, by which insights are acquired through the use of metaphor. One way in which compelling associations are made and retained is by linking anatomic structures and pathologic conditions with objects, places, and concepts, and codifying these relationships as metaphoric signs. An aggregate of specialty specific signs were obtained from two general medical dictionaries and from encyclopedic texts in radiology and six other specialties: internal medicine, dermatology, pathology, general surgery, orthopedics, and pediatrics. The signs were then separated into two categories: eponymous (bearing the name of an individual or place) and metaphoric (extending meaning from one context to another). A total of 375 metaphoric signs were collected from citations in the researched dictionaries and texts, the overwhelming majority (66%) of which were radiologic in reference. In every other specialty, eponymous signs outnumbered metaphoric signs. In contrast, eponymous signs were comparatively infrequent in radiology. The striking difference observed in the data highlights the importance of metaphors for discourse and instruction in radiology. In image interpretation, the meaning of perceptual input is often discerned through associations with pictures previously encountered and understood both concretely and metaphorically. The inherent nature of radiologic images as simulacra of both normal anatomy and disease entities makes imaging findings well suited to explanation by means of named patterns borrowed from other realms of knowledge. PMID- 22236905 TI - FIGO staging system for endometrial cancer: added benefits of MR imaging. AB - Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. This pathologic condition is staged with the International Federation of Gynecology and Obstetrics (FIGO) system. The FIGO staging system recently underwent significant revision, which has important implications for radiologists. Key changes incorporated into the 2009 FIGO staging system include simplification of stage I disease and removal of cervical mucosal invasion as a distinct stage. Magnetic resonance (MR) imaging is essential for the preoperative staging of endometrial cancer because it can accurately depict the depth of myometrial invasion, which is the most important morphologic prognostic factor and correlates with tumor grade, presence of lymph node metastases, and overall patient survival. Diffusion-weighted MR imaging and dynamic contrast medium enhanced MR imaging are useful adjuncts to standard morphologic imaging and may improve overall staging accuracy. PMID- 22236906 TI - Interventional radiology in pregnancy complications: indications, technique, and methods for minimizing radiation exposure. AB - Complications of pregnancy, whether they occur during gestation or postpartum, often pose complex challenges because they affect two patients (mother and fetus or infant) and because both short- and long-term outcomes must be considered in management decision making. Interventional radiologists play a critical role in treating complications such as ectopic implantation, postpartum hemorrhage, symptomatic ovarian cyst, post-cesarean section fluid collection, obstructive uropathy, and vesicouterine fistula. Interventional radiology offers therapeutic options that obviate surgery, thereby minimizing morbidity and mortality and maximizing the potential for fertility preservation. Such options include chemical injection of an ectopic gestational sac, uterine artery embolization, aspiration and drainage, percutaneous nephrostomy, and suprapubic cystostomy catheter placement. All these procedures are performed with the use of radiologic imaging for guidance. The levels of radiation to which the mother and fetus may be exposed during such procedures are of concern because of potential negative effects on long-term health. However, various methods can be used to lower maternal and fetal radiation dose levels to the minimum needed to accomplish the clinical objective. PMID- 22236907 TI - Coronary veins: comprehensive CT-anatomic classification and review of variants and clinical implications. AB - Recent developments in cardiac pacing and trans-coronary vein ablations have demonstrated the increasing value of imaging of the cardiac venous system (CVS), especially computed tomographic (CT) mapping of the coronary veins. In contrast to that for coronary arteries, the literature for coronary veins is scarce. Moreover, a complete, highly efficient, and clinically useful classification of the CVS is not as straightforward as for the coronary arteries. The CVS comprises polymorphous types of venous conduits with notable anatomic variations. Recent anatomic classification divides the cardiac veins into two main groups: tributaries of the greater CVS and tributaries of the lesser CVS, consisting of the thebesian vessels. The greater CVS is subdivided into two groups: coronary sinus and non-coronary sinus tributaries. Imaging information about the CVS in this review is useful for a better understanding of the spatial orientation of the CVS and furthers proper use of the correct nomenclature for this important system. The authors describe the clinical implications of the different imaging techniques for assessment of the coronary veins, where cardiac CT venous mapping has major advantages. The role of CT in anatomic classification, assessment of anatomic variants, and diagnosis of pathologic changes of the CVS is discussed. The authors also underscore the particular role of CT venous mapping for cardiac interventions, especially for left ventricular pacing in cardiac resynchronization therapy and in percutaneous mitral annuloplasty. PMID- 22236908 TI - Between a rock and a hard place: clinical and imaging features of vascular compression syndromes. AB - Vascular compression syndromes are caused by the entrapment of vessels between rigid or semirigid surfaces in a confined anatomic space. Chronic entrapment may lead to arterial ischemia and embolism, venous stasis and thrombosis, and hematuria. These syndromes are usually seen in otherwise healthy young patients, among whom underdiagnosis is common. Most occurrences of vascular compression are associated with an underlying anatomic abnormality. In a small percentage of cases, other contributing factors, including repetitive microtrauma, may cause pathologic changes leading to the onset of pain and other symptoms of vascular and neural compression. Hence, the diagnosis must be based on both clinical and radiologic findings. Because some cases of vascular entrapment become symptomatic only when specific physical maneuvers are performed, dynamic diagnostic imaging methods are especially useful. Digital subtraction angiography has been the mainstay of imaging-based diagnosis for most vascular compression syndromes, but other methods (eg, color Doppler ultrasonography, computed tomographic angiography, and magnetic resonance angiography) are used with increasing frequency for initial diagnostic evaluation. Because vascular compression syndromes are caused by the external compression of vessels, endoluminal treatment alone is rarely adequate and surgical decompression is likely to be required for optimal and durable clinical benefit. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.321115011/ /DC1. PMID- 22236909 TI - Association study of C1qA polymorphisms with systemic lupus erythematosus in a Han population. AB - OBJECTIVE: The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the C1qA gene region with systemic lupus erythematosus (SLE) in a Chinese Han population. METHODS: Chinese SLE patients (n = 748) and ethnically- and geographically-matched healthy controls (n = 750) were genotyped for the C1qA region SNPs, rs172378 and rs665691, by using the Sequenom MassArray system. RESULTS: The Chinese Han SLE patients and controls had statistically similar frequencies of alleles, genotypes, and haplotypes of C1qA polymorphisms. Moreover, no association signal was detected on different genetic models (additive, dominant, and recessive) or in SLE subgroups stratified by various clinical manifestations. CONCLUSIONS: The C1qA SNPs, rs172378 and rs665691, confer no genetic predisposition to SLE in a Chinese Han population. PMID- 22236910 TI - Familial SLE: sustained drug-free remission in a mother successfully treated for anal cancer, but development of SLE in a 16-year old daughter. AB - The immunopathogenesis of systemic lupus erythematosus has been thoroughly investigated recently, and genome-wide association studies have identified genes statistically associated with lupus. However, the progression to overt disease is dependent on the activation of environmental factors ('triggers'), among which oestrogen stimulation is prominent. Here we report the case of a mother with long standing SLE entering into long term drug-free remission following intensive, menopause-inducing chemoradiotherapy for cancer, and the opposite case of her daughter, who developed SLE following the initiation of her menstrual cycle. PMID- 22236911 TI - Should we stop doing blind transversus abdominis plane blocks? AB - BACKGROUND: Any landmark-based regional anaesthetic technique raises two important issues. The first is the accuracy of placement of the needle and thus the local anaesthetic in a 'blind' technique and the second is the potential for damage to adjacent structures. We designed a prospective, blinded study in an adult general surgical population to evaluate with ultrasound the placement of the needle tip and local anaesthetic during transversus abdominis plane (TAP) blocks using the landmark-based 'double-pop' technique. METHODS: After induction of general anaesthesia, 36 adult patients had a TAP block performed bilaterally using the standard landmark-based technique. Ultrasonography was then used to record the actual needle position and local anaesthetic spread. The anaesthetist performing the block was blinded to the ultrasound images. RESULTS: Thirty-six adult patients were included in the study, which was terminated early due to what was considered an unacceptably high level of peritoneal needle placements. The needle tip and local anaesthetic spread were in the correct plane in only 17 (23.6%) of the injections. In the remaining 55 (76.4%), the needle was in the subcutaneous tissue 1 (1.38%), external oblique muscle 1 (1.38%), plane between the external and internal oblique muscles 5 (6.94%), internal oblique muscle 26 (36.1%), transversus abdominis muscle 9 (12.5%), and peritoneum 13 (18%). CONCLUSIONS: We conclude that the needle and local anaesthetic placement using the standard landmark-based approach to the TAP block is inaccurate, and the incidence of peritoneal placement is unacceptably high. PMID- 22236912 TI - Needles, haystacks and grails: the challenges and promise of tuberculosis vaccine trials. PMID- 22236913 TI - Managing malaria in tuberculosis patients on fluoroquinolone-containing regimens: assessing the risk of QT prolongation. AB - The role of fluoroquinolones (FQs) in the management of drug-susceptible and drug resistant tuberculosis (TB) is under investigation. They are currently being used off-licence to treat TB patients who develop hepatotoxicity on standard therapy, and in patients with drug-resistant disease. Prolongation of ventricular repolarisation, recorded as lengthening of the QT interval on an electrocardiogram, is a recognised adverse effect associated with FQs. Significant prolongation of the QT interval may precipitate torsades de pointe, a potentially fatal tachyarrhythmia. Currently licensed FQs are considered safe, and there are very few reports of associated arrhythmias, but most labels contraindicate concomitant administration of other agents that prolong QT. In many high TB burden countries, malaria is also endemic. Many antimalarials, and possibly malaria infection itself, may prolong QT; under current licence, co administration of FQs with these antimalarials is contraindicated due to potential risk of additive QT prolongation. This poses significant challenges in planning future policy on FQ use for first-line anti-tuberculosis treatment; the duration of TB treatment makes concomitant malaria treatment inevitable, and options without FQ contraindications are limited. Furthermore, malaria diagnosis is often poor and access to treatment uncontrolled, with many patients buying 'over-the-counter' and/or 'traditional' remedies; concomitant use with anti tuberculosis treatment is thus likely to be unregulated. Drug interaction studies are urgently required to assess the safety of managing patients with TB and malaria within endemic, resource-poor settings where programmatic management and low-cost monitoring are essential for effective implementation of public health strategies. PMID- 22236914 TI - Tuberculosis contact investigation in a high-burden setting: house or household? AB - SETTING: A high tuberculosis (TB) burden setting, South Africa. Two frequently used definitions for 'household' are 1) 'all dwellings on the same plot of land that share the same residential address'; and 2) 'a group of persons who live together in the same dwelling unit and who have the same eating arrangements'. OBJECTIVE: To characterise a household and the outcome of investigations in household child contacts using definition 1 compared to definition 2 during a TB contact investigation. DESIGN: Access to a household (definition 1) was gained via an adult TB case. Children were assessed for TB infection and disease. RESULTS: Household enumeration indicated 25 members of three families living in a main house and a fourth family living in an adjacent structure. Three children were diagnosed with TB and two referred for isoniazid preventive therapy. Families living in the main house shared the main kitchen, while the yard house family used its own kitchen. This household would have been classified as two separate households if definition 2 had been used, and children with TB disease and infection would have been missed. CONCLUSION: The definition of household in TB contact investigation should provide a framework that is broad enough to capture the majority of children at risk. PMID- 22236915 TI - Serial testing of Malaysian health care workers with QuantiFERON(r)-TB Gold In Tube. AB - BACKGROUND: Serial testing for tuberculosis (TB) exposure has been advocated among health care workers (HCWs) at risk of nosocomial infection. OBJECTIVE: To determine the incidence and factors associated with TB infection among selected HCWs in Malaysia and to determine interferon-gamma response in serial testing. DESIGN: A cohort of 769 HCWs were retested after 1 year using QuantiFERON(r)-TB Gold In-Tube. Incidence of TB infection was determined among HCWs who previously tested negative. Conversion and reversion rates using several definitions were explored. RESULTS: Incidence of TB infection was 9.9 per 100 workers per year (95%CI 7.9-12.3). Working in the Emergency Department (ED; RR 2.18, 95%CI 1.07 4.43) was significantly associated with risk of TB infection. Reversion and conversion occurred frequently, with 46.7% reversion among HCWs with baseline interferon-gamma (IFN-gamma) levels of 0.35-0.70 international units (IU)/ml, and 23.8% conversion among HCWs with baseline IFN-gamma levels of 0.20-0.34 IU/ml. CONCLUSIONS: TB infection control measures need to be strengthened, particularly in the ED, as the incidence of TB was high. Conversion and reversion rates in serial testing were high, and further studies are needed to facilitate its interpretation. PMID- 22236916 TI - Factors influencing sex differences in numbers of tuberculosis suspects at diagnostic centres in Pakistan. AB - SETTING: DOTS-reporting tuberculosis (TB) diagnostic centres across Pakistan. OBJECTIVES: To quantitatively investigate the influence of diagnostic centre characteristics on the number of female and male TB suspects registered at diagnostic centres. DESIGN: Ten districts were selected across the four provinces of Pakistan. Data were collected on male and female TB suspects in all diagnostic centres within each district. A structured questionnaire was used to collect data on characteristics of the diagnostic centres. Multiple linear regression analysis was conducted to evaluate the influence of each characteristic on sex differences in the numbers of suspects. RESULTS: Two diagnostic centre characteristics were associated with higher numbers of female than male TB suspects: catering to the local catchment area (P = 0.001) and being accessible on foot (P = 0.002). The following characteristics were associated with higher numbers of male than female TB suspects: being open after 2 pm (P = 0.041), having more than five doctors working at the centre (P = 0.019), and having more than 100 suspects registered per quarter (P = 0.008). CONCLUSIONS: Smaller, local diagnostic centres that are accessible on foot registered more female than male TB suspects. More centralised facilities located further from homes, larger facilities and those with evening opening hours registered more male than female suspects. PMID- 22236917 TI - DOT associated with reduced all-cause mortality among tuberculosis patients in Taipei, Taiwan, 2006-2008. AB - OBJECTIVE: To determine whether patients receiving directly observed treatment (DOT) had lower all-cause mortality than those treated with self-administered treatment (SAT) and to identify factors associated with mortality among tuberculosis (TB) patients. DESIGN: All TB patients in Taipei, Taiwan, diagnosed between 2006 and 2008 were included in a retrospective cohort study. RESULTS: Among 3624 TB patients, 45.5% received DOT, which was disproportionately offered to older patients and those with more underlying illness and severe TB disease. After controlling for patients' sociodemographic factors, clinical findings and underlying comorbidities, the odds of death were 40% lower (aOR 0.60, 95%CI 0.5 0.8) among patients treated with DOT than those on SAT. After adjusting for DOT, independent predictors of death included non-Taiwan birth, increasing age, male, unemployment, end-stage renal disease requiring dialysis, malignancy, acid-fast bacilli smear positivity and pleural effusion. CONCLUSION: DOT was associated with lower all-cause mortality after controlling for confounding factors. DOT should be expanded in Taiwan to improve critical treatment outcomes among TB patients. PMID- 22236918 TI - Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial. AB - SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guerin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. RESULTS: A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. CONCLUSION: Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups. PMID- 22236919 TI - High prevalence of drug resistance amongst HIV-exposed and -infected children in a tuberculosis prevention trial. AB - An emergence of drug-resistant tuberculosis (DR-TB) in settings affected by human immunodeficiency virus (HIV) and tuberculosis (TB) has been observed. We investigated the prevalence of DR-TB in P1041, a multicentered, randomised, double-blind trial which compared the administration of isoniazid (INH) to placebo, in HIV-exposed, non-infected and -infected African infants in the absence of any documented TB exposure. The prevalence of multidrug-resistant TB (MDR-TB) was 22.2% (95%CI 8.5-45.8) and INH monoresistance 5.6% (95%CI 0.1-27.6) among culture-confirmed cases, with all MDR-TB occurring in a single site. There was no association between INH treatment or placebo group, or between HIV infection status, and DR-TB prevalence. There was a high prevalence of DR-TB among HIV-exposed and -infected children. Surveillance of DR-TB among children in high-burden TB-HIV settings should be routine. PMID- 22236921 TI - False-positive rifampicin resistance on Xpert(r) MTB/RIF: case report and clinical implications. AB - The World Health Organization had endorsed Xpert(r) MTB/RIF (Xpert) as the initial diagnostic for multidrug-resistant tuberculosis (TB) or TB suspects co infected with the human immunodeficiency virus. We investigated an unexpected case of rifampicin (RMP) resistance on Xpert using repeat Xpert, smear microscopy, MTBDRplus assay, culture, drug susceptibility testing, spoligotyping and rpoB gene sequencing. A false-positive result was most likely, given the wild type rpoB gene sequence and exclusion of both mixed infection and mixture of drug susceptible and drug-resistant populations. When decentralising Xpert, test performance characteristics need to be understood by health care workers and methods of confirmation of RMP resistance need to be accessible. PMID- 22236920 TI - Rise in rifampicin-monoresistant tuberculosis in Western Cape, South Africa. AB - SETTING: Brewelskloof Hospital, Western Cape, South Africa. OBJECTIVES: To verify the perceived increase in rifampicin monoresistant tuberculosis (RMR-TB) in the Cape Winelands-Overberg region and to identify potential risk factors. DESIGN: A retrospective descriptive study of trends in RMR-TB over a 5-year period (2004 2008), followed by a case-control study of RMR and isoniazid (INH) monoresistant TB cases, diagnosed from April 2007 to March 2009, to assess for risk factors. RESULTS: The total number of RMR-TB cases more than tripled, from 31 in 2004 to 98 in 2008. The calculated doubling time was 1.63 years (95%CI 1.18-2.66). For the assessment of risk factors, 95 RMR-TB cases were objectively verified on genotypic and phenotypic analysis. Of 108 specimens genotypically identified as RMR cases, 13 (12%) were misidentified, multidrug-resistant TB. On multivariate analysis, previous use of antiretroviral therapy (OR 6.4, 95%CI 1.3-31.8), alcohol use (OR 4.8, 95%CI 2.0-11.3) and age >= 40 years (OR 5.8, 95%CI 2.4-13.6) were significantly associated with RMR-TB. CONCLUSION: RMR-TB is rapidly increasing in the study setting, particularly among patients with advanced human immunodeficiency virus (HIV) disease. Routine drug susceptibility testing should be considered in all TB-HIV co-infected patients, and absence of INH resistance should be confirmed phenotypically if genotypic RMR-TB is detected. PMID- 22236922 TI - Comparing early treatment outcomes of MDR-TB in decentralised and centralised settings in KwaZulu-Natal, South Africa. AB - SETTING: In KwaZulu-Natal, South Africa, a setting endemic for tuberculosis (TB) and the human immunodeficiency virus (HIV), prolonged hospitalisation for the treatment of the growing number of multidrug-resistant TB (MDR-TB) patients is neither possible nor effective. OBJECTIVE: To compare early treatment outcomes in patients with MDR-TB with and without HIV co-infection at four decentralised rural sites with a central urban referral hospital. DESIGN: This is an operational, prospective cohort study of patients between 1 July 2008 and 30 November 2009, where culture conversion, time to culture conversion, survival and predictors of these outcomes were analysed. RESULTS: Of 860 patients with MDR TB, 419 were at the decentralised sites and 441 at the central hospital. Overall, 71% were HIV co-infected. In the 17-month study period, there was a higher proportion of culture conversion at the decentralised sites compared with the centralised hospital (54% vs. 24%, P < 0.001, OR 3.76, 95%CI 2.81-5.03). The median time to treatment initiation was significantly shorter at the decentralised sites compared with the centralised hospital (72 vs. 93 days, P < 0.001). There was no significant difference in survival following treatment initiation. CONCLUSION: In this study, early treatment outcomes suggest that decentralised care for MDR-TB patients is superior to that in a centralised setting. PMID- 22236923 TI - Fluoroquinolone and pyrazinamide resistance in multidrug-resistant tuberculosis. AB - In a study performed in Cambodia, a higher number of tuberculosis (TB) strains with mutations in the pncA gene associated with pyrazinamide resistance (PZA-R) was found in fluoroquinolone-resistant (FQ-R) multidrug-resistant (MDR) strains (93%), compared with 47% in MDR and 3% in non-MDR strains. This emphasises the need for easy and rapid tests for identification of PZA-R for efficient treatment of MDR-TB. PMID- 22236924 TI - Recovery of Mycobacterium tuberculosis from Lowenstein-Jensen media contaminated with other organisms. AB - Growth of contaminating organisms along with Mycobacterium tuberculosis on Lowenstein-Jensen (LJ) medium is common. However, there is no documented evidence on the decontamination procedure adopted in mycobacteriology laboratories to recover M. tuberculosis from the contaminants grown on LJ medium. At the National Institute for Research in Tuberculosis, of 1048 LJ slopes with M. tuberculosis received from intermediate reference laboratories, 98 (9%) were contaminated. Of these, 87 (89%) M. tuberculosis cultures were retrieved after decontamination with 1% cetrimide. The use of cetrimide as a decontaminating agent to retrieve M. tuberculosis cultures grown with contaminants is documented. PMID- 22236925 TI - In vitro reaction phenotyping studies on rifamycins to explain the auto-induction of rifabutin metabolism. AB - A study was carried out to establish the relative contribution of human cytochrome P450 (CYP450) enzymes in the metabolism of rifampicin (RMP), rifapentine (RPT) and rifabutin (RFB). It involved the incubation of the three drugs in five major CYP450 isoforms. Both RMP and RPT showed minimal metabolism by CYP450 enzymes, whereas RFB showed extensive metabolic degradation by CYP3A4. A known inducer of CYP3A4, RFB was shown in this study to be also a substrate for the same enzyme. The latter might be one of the reasons for the auto-induction of RFB metabolism and the consequent lower bioavailability of the drug on repeated administration. PMID- 22236926 TI - Real-time PCR and Amplified MTD(r) for rapid detection of Mycobacterium tuberculosis in pulmonary specimens. AB - SETTING: Patients with suspected pulmonary tuberculosis (PTB) in the First Affiliated Hospital, College of Medicine, Zhejiang University. OBJECTIVE: To evaluate the 'Care TB(r)' real-time polymerase chain reaction (PCR) assay in comparison with the Amplified MTD(r) Test (AMTD) for the rapid diagnosis of TB. DESIGN: Self-expectorated sputum was collected for direct smear microscopy, culture, real-time PCR and AMTD assay. Performance of the 'Care TB' real-time PCR and AMTD assay were compared using a combination of culture and clinical diagnosis as a reference standard. RESULTS: Of the 178 sputum specimens, 83 were culture-positive; of these, 74 were Mycobacterium tuberculosis complex and 9 strains were non-tuberculous mycobacteria. The overall sensitivities and specificities were respectively 91.6% and 100% for real-time PCR, and 95.2% and 97.9% for AMTD. In the smear-positive specimens, the sensitivities and specificities were respectively 97% and 100% for real-time PCR, and 98.5% and 100% for AMTD. In the smear-negative specimens, the sensitivities and specificities were 70.6% and 100% for real-time PCR, and 82.4% and 97.7% for AMTD. CONCLUSIONS: Both real-time PCR and AMTD are rapid and specific tests for detecting M. tuberculosis complex; however, 'Care TB' real-time PCR is more convenient and economical. PMID- 22236927 TI - Using likelihood ratios to estimate diagnostic accuracy of a novel multiplex nested PCR in extra-pulmonary tuberculosis. AB - SETTING: A tertiary care centre in Mumbai with a referral bias towards treatment failures. OBJECTIVE: To standardise and evaluate a novel single tube multiplex nested polymerase chain reaction (PCR) targeting insertion sequence (IS) 6110, mpb64, rrs and rpoB genes for rapid diagnosis of extra-pulmonary tuberculosis (EPTB). METHODS: The PCR assay was evaluated among 489 consecutive consenting patients, and results were compared against a composite reference standard comprising smear microscopy, culture, clinical symptoms, radiological scan and histology. RESULTS: PCR assay reported a pooled sensitivity of 94.5% (242/256, 95%CI 91-97): 91.9% (125/136, 95%CI 86-96) for smear-negative composite reference standard (CRS) positive cases and 97.5% (117/120, 95%CI 93-99) for smear-positive CRS-positive cases. The PCR positivity rate increased from 91.7% (235/256, 95%CI 88-95) when presence of IS6110 was considered alone for reporting a test as positive to 94.5% (242/256, 95%CI 91-97) when used in combination with other three gene targets, with a specificity of 96.4% (212/220, 95%CI 93-98). A positive likelihood ratio of 26 (95%CI 13-51) and a negative likelihood ratio of 0.06 (95%CI 0.03-0.09) makes the test useful for ruling out and ruling in the disease. CONCLUSION: Culture should not be replaced by PCR as a gold standard; however, PCR can be used as a rapid, accurate tool in the diagnosis of EPTB. PMID- 22236928 TI - Pre-transplant risk factors for tuberculosis after kidney transplant in an intermediate burden area. AB - OBJECTIVE: To examine pre-transplant risk factors for the development of post kidney transplant tuberculosis (TB) in an intermediate TB burden country, as this is important for early detection and prophylaxis to prevent post-transplant TB. DESIGN: A retrospective, longitudinal cohort study of 1097 kidney transplant patients was performed at the Severance Hospital, Seoul, South Korea, between January 2000 and March 2010. The standardised incidence ratio (SIR) of post transplant TB compared to the general population was calculated and pre transplant risk factors were analysed. RESULTS: Among the 1097 kidney transplant patients, 2.1% (23/1097) developed post-transplant TB, with an incidence of 445.2 cases per 100,000 patients per year. The SIR of TB in kidney transplant patients compared with the general population was 4.26 (95%CI 2.6-6.45). A positive tuberculin skin test (TST; RR 3.54, 95%CI 1.13-11.11, P = 0.03) and previously healed TB on chest radiograph (CXR; RR 8.71, 95%CI 1.00-75.84, P = 0.05) were significant pre-transplant risk factors for post-transplant TB on multivariate analysis. CONCLUSION: The incidence of TB in kidney transplant patients was higher than in the general population. Positive TST results and previously healed TB lesions visible on pre-transplant CXR were significant pre-transplant risk factors for post-kidney transplant TB. PMID- 22236929 TI - Dairy food, calcium and vitamin D intake and prevalence of allergic disorders in pregnant Japanese women. AB - SETTING: Epidemiological evidence for the associations between intake of dairy products, calcium and vitamin D and allergic disorders has been inconsistent. OBJECTIVES: To examine such associations in Japan. DESIGN: This cross-sectional study enrolled 1745 pregnant women. The definitions of wheeze and asthma were based on European Community Respiratory Health Survey criteria, whereas those of eczema and rhinoconjunctivitis were based on International Study of Asthma and Allergies in Childhood criteria. Information on dietary factors was collected using a validated self-administered diet history questionnaire. RESULTS: Intake of total dairy products, milk, yoghurt, cheese and calcium was not related to the prevalence of wheeze, asthma, eczema or rhinoconjunctivitis. After adjustment for potential confounders, vitamin D intake was found to be independently positively associated with the prevalence of asthma: the adjusted ORs for asthma in the first, second, third and fourth quartiles were respectively 1.00 (reference), 1.26 (95%CI 0.65-2.50), 2.08 (95%CI 1.13-3.94), and 1.82 (95%CI 0.97-3.51, P for trend = 0.03). There were no relationships between vitamin D consumption and the prevalence of wheeze, eczema or rhinoconjunctivitis. CONCLUSIONS: These findings suggest that vitamin D intake may be positively related to the prevalence of asthma in young adult Japanese women. PMID- 22236930 TI - Clinical features of subjects with an isolated FEV1 reduction. AB - BACKGROUND: The clinical significance of an isolated reduction in forced expiratory volume in 1 second (FEV(1); i.e., low FEV(1), but normal forced vital capacity [FVC] and FEV(1)/FVC) has not been established. OBJECTIVE: To examine the clinical features of subjects with an isolated FEV(1) reduction. METHODS: Clinical, spirometry and radiological data were retrospectively collected from 15,192 subjects attending a medical check-up at the Health Promotion Center of the Asan Medical Center, Korea. Predicted spirometry values were calculated from the Korean reference equations, and the lower limit of normal was set at the 5th percentile. Subjects were divided into four groups: isolated FEV(1) reduction, normal (normal FVC, FEV(1) and FEV(1)/FVC), obstructive (low FEV(1)/FVC) and restrictive (low FVC and normal FEV(1)/FVC). The groups were compared in terms of clinical characteristics. RESULTS: Of the 15,192 subjects, 323 (2.1%) had an isolated FEV(1) reduction, 10,591 (69.7%) were normal, 951 obstructive (6.3%) and 3327 (22.0%) restrictive. The isolated FEV(1) reduction group had a higher proportion of subjects with smoking history (63.2% vs. 45.7%), radiology abnormalities (15.5% vs. 4.3%) and history of respiratory disease (8.4% vs. 3.0%) than the normal group (all P < 0.001). CONCLUSION: An isolated FEV(1) reduction suggests abnormal spirometry, and further study is needed to evaluate whether these cases belong to the obstructive or restrictive group. PMID- 22236931 TI - Quitting smoking with varenicline: parallel, randomised efficacy trial in Iran. AB - BACKGROUND: Smoking cessation programmes were first introduced in Iran in 1997. To date a number of types of nicotine replacement therapy have been prescribed. OBJECTIVE: To evaluate the effectiveness of varenicline for tobacco cessation. METHODS: This was a randomised parallel clinical study conducted in 2010. Participants were smokers willing to quit who were visiting a smoking cessation clinic for the first time and were randomly divided into three groups: all three groups received brief counselling on cessation, Group 2 received nicotine patches and Group 3 was prescribed varenicline for 8 weeks. RESULTS: There were 272 participants in the study: 91 in Group 1, 92 in Group 2 and 89 in Group 3. At the end of the first month, 128 of the 272 subjects (47.1%) succeeded in quitting: 17 (18.7%) in Group 1, 60 (65.2%) in Group 2 and 51 (57.3%) in Group 3 (P = 0.000). At follow-up after 12 months, 58 subjects (21.3%) remained smoke-free, of whom 6 (6.6%) were in Group 1, 23 (25%) in Group 2 and 29 (32.6%) in Group 3 (P = 0.000). CONCLUSION: In the study, varenicline treatment was slightly more effective than but not significantly different from nicotine replacement therapy. PMID- 22236932 TI - Smoking cessation in older adults. AB - BACKGROUND: Older smokers are often not encouraged to quit smoking due to the erroneous idea that it is too late for such interventions. OBJECTIVE: To compare smoking cessation rates among older and younger treatment seekers, and to evaluate whether age is an obstacle to smoking cessation. DESIGN AND METHODS: Smokers (n = 987) were submitted to the same behavioural programme plus pharmacotherapy at the Smoking Cessation Clinic of Hospital Sao Lucas, in Porto Alegre, Brazil, from July 2004 to June 2009. Quit rates were evaluated at 2, 6 and 12 months. Abstinence was confirmed by exhaled carbon monoxide < 10 ppm. Volunteers were grouped by age <60 and >= 60 years. RESULTS: Abstinence rates (+/ SD) in the younger group were respectively 57.1% (+/- 1.9), 46.8% (+/- 2.1) and 43.5% (+/- 2.7) at 2, 6 and 12 months of follow-up. Rates for the >= 60 year group were respectively 67.4% (+/- 4.3), 52.3% (+/- 5.4) and 53.3% (+/- 5.4; log rank test, P = 0.073). The difference was also not statistically significant using Cox regression (adjusted HR 0.90, 95%CI 0.66-1.22, P = 0.48). CONCLUSIONS: In this real-world setting, treatment for smoking cessation led to similar abstinence rates in older and younger smokers. These results may have implications for clinical practice and smoking cessation policies for low- and middle-income countries such as Brazil. PMID- 22236933 TI - Tuberculin skin test conversions in hospital housekeepers. PMID- 22236934 TI - Empirical tuberculosis treatment or improved diagnostics? PMID- 22236936 TI - Interferon-gamma release assay T-SPOT(r).TB and HIV-related tuberculosis. PMID- 22236937 TI - Tolerance of moxifloxacin-containing regimens in the treatment of tuberculosis. PMID- 22236938 TI - Efficacy of utilising patient self-report of auditory complaints to monitor aminoglycoside ototoxicity. PMID- 22236939 TI - The key to advanced airways during cardiac arrest: well trained and early. AB - Airway management during cardiac arrests is a controversial area. There are advantages to the provision of a patent airway with an airway adjunct, especially as this can optimize oxygenation and carbon dioxide clearance as well as facilitate continuous compressions. These advantages come at a potential cost, in particular errors in placement of the devices and interruption to compressions necessitated for insertion. The widespread availability of supraglottic airways (SGAs), their ease of insertion, and their ability to be inserted without interruptions to compressions have meant that the role of the definitive airway device - the endotracheal tube - is being challenged. In the previous issue of Critical Care, a study from Japan reported the use of advanced airways in more than 5,000 victims of cardiac arrests. The authors were not able to demonstrate a survival advantage with either SGAs or endotracheal intubation (ETI). They did, however, demonstrate improved outcomes when the emergency life-saving technicians had been trained to perform ETI and when the advanced airway device was inserted earlier. PMID- 22236940 TI - Offspring outcomes after maternal BPD: euphenics for the epidemic? PMID- 22236941 TI - Comment on: Dietary assessment of adolescents undergoing laparoscopic Roux-en-Y gastric bypass surgery: macro- and micronutrient, fiber and supplement intake. PMID- 22236942 TI - Endoscopic findings in mantle cell lymphoma with gastrointestinal tract involvement. AB - BACKGROUND AND AIMS: Mantle cell lymphoma (MCL) of the gastrointestinal (GI) tract is a rare disease with a poor prognosis. The aim of this study was to determine clinical and endoscopic characteristics of patients with GI MCL. METHODS: Clinical features of 19 patients with GI MCL were reviewed along with the endoscopic findings on 27 anatomical lesions. RESULTS: The initial presenting symptoms were abdominal pain (n = 7, 36.8%), GI tract bleeding (n = 5, 26.3%), dyspnea (n = 2, 10.5%), indigestion (n = 1, 5.3%), diarrhea (n = 1, 5.3%), cervical lymphadenopathy (n = 1, 5.3%), tonsilar mass (n = 1, 5.3%), and no symptoms (n = 1, 5.3%). On endoscopy, in 19 patients with 27 lesions, the anatomic locations of the lesions were: stomach, n = 2 (10.5%); stomach and colon, n = 7 (36.8%); terminal ileum and colon, n = 1 (5.3%); colon, n = 9 (47.4%). There was 1 fungating case (3.7%), 4 ulcerative cases (14.8%), 9 infiltrative cases (33.3%), and 13 polypoid cases (48.1%). CONCLUSIONS: The endoscopic findings in GI MCL are variable, with common presenting manifestations of abdominal pain and GI bleeding. PMID- 22236944 TI - Quasiparticle scattering off phase boundaries in epitaxial graphene. AB - We investigate the electronic structure of terraces of single layer graphene (SLG) by scanning tunnelling microscopy (STM) on samples grown by thermal decomposition of 6H-SiC(0001) crystals in ultra-high vacuum. We focus on the perturbations of the local density of states (LDOS) in the vicinity of edges of SLG terraces. Armchair edges are found to favour intervalley quasiparticle scattering, leading to the (?3 x ?3)R30 degrees LDOS superstructure already reported for graphite edges and more recently for SLG on SiC(0001). Using the Fourier transform of LDOS images, we demonstrate that the intrinsic doping of SLG is responsible for a LDOS pattern at the Fermi energy which is more complex than for neutral graphene or graphite, since it combines local (?3 x ?3)R30 degrees superstructure and long range beating modulation. Although these features have already been reported by Yang et al (2010 Nano Lett. 10 943-7) we propose here an alternative interpretation based on simple arguments classically used to describe standing wave patterns in standard two-dimensional systems. Finally, we discuss the absence of intervalley scattering off other typical boundaries: zig-zag edges and SLG/bilayer graphene junctions. PMID- 22236945 TI - Aqueductal developmental venous anomaly as an unusual cause of congenital hydrocephalus: a case report and review of the literature. AB - INTRODUCTION: Aqueductal stenosis may be caused by a number of etiologies including congenital stenosis, tumor, inflammation, and, very rarely, vascular malformation. However, aqueductal stenosis caused by a developmental venous anomaly presenting as congenital hydrocephalus is even more rare, and, to the best of our knowledge, has not yet been reported in the literature. In this study, we review the literature and report the first case of congenital hydrocephalus associated with aqueductal stenosis from a developmental venous anomaly. CASE PRESENTATION: The patient is a three-day-old, African-American baby girl with a prenatal diagnosis of hydrocephalus. She presented with a full fontanelle, splayed sutures, and macrocephaly. Postnatal magnetic resonance imaging showed triventricular hydrocephalus, suggesting aqueductal stenosis. Examination of the T1-weighted sagittal magnetic resonance imaging enhanced with gadolinium revealed a developmental venous anomaly passing through the orifice of the aqueduct. We treated the patient with a ventriculoperitoneal shunt. CONCLUSIONS: Ten cases of aqueductal stenosis due to venous lesions have been reported and, although these venous angiomas and developmental venous anomalies are usually considered congenital lesions, all 10 cases became symptomatic as older children and adults. Our case is the first in which aqueductal stenosis caused by a developmental venous anomaly presents as congenital hydrocephalus. We hope adding to the literature will improve understanding of this very uncommon cause of hydrocephalus and, therefore, will aid in treatment. PMID- 22236946 TI - Improvement of visible light photocatalytic acetaldehyde decomposition of bismuth vanadate/silica nanocomposites by cocatalyst loading. AB - Photocatalytic activity of bismuth vanadate (BiVO(4)) for acetaldehyde decomposition under visible light irradiation was improved by inclusion of a nanocomposition of silica as an adsorbent material and loading of platinum (Pt) or trivalent iron ion (Fe(3+)) as reduction cocatalysts. Addition of silica enhanced photocatalytic activity due to improvement of adsorption ability, but total decomposition of acetaldehyde was not observed within 24h of visible light irradiation. For further improvement of photocatalytic activity, BiVO(4) with an optimized amount of silica composition were modified with Pt or Fe(3+). Photodeposition of Pt greatly increased photocatalytic activity, and acetaldehyde was totally decomposed within 24h of visible light irradiation. PMID- 22236943 TI - Clinical correlates of apathy in patients recently diagnosed with Parkinson's disease: the ANIMO study. AB - OBJECTIVE: Little is known about apathy in the early stages of Parkinson's disease (PD). We determined the clinical correlates of apathy in a large representative sample of patients recently diagnosed with PD (ANIMO study). METHODS: PD patients, diagnosed within 2 years of inclusion, were recruited in 102 outpatient clinics situated in 82 populations throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale (LARS). Clinical comparisons and correlations were performed using nonparametric tests. Regression analyses were used to test the association of clinical variables with apathy. RESULTS: We recruited 557 PD patients (60.3% men) with a mean age of 68.8 +/- 9.7 years, and UPDRS motor score of 21.1 +/- 10.8. Apathy only was diagnosed in 186 (33.4%), and apathy and depression in 215 patients (38.6%). Patients with higher comorbidity (OR = 1.10, 95% CI 1.01-1.20, p = 0.001), motor impairment (OR = 1.07, 95% CI 1.03-1.10, p < 0.0001), and lower education (OR = 2.16, 95% CI 1.21-3.85, p = 0.009) had higher odds of having apathy, in contrast to patients living in a rural environment (OR = 0.35, 95% CI 0.32-0.85, p = 0.01), and left predominant PD motor laterality (OR = 0.34, 95% CI 0.13-0.88, p = 0.01). LARS scores were significantly correlated with UPDRS motor scores (r(s) = 0.44, p < 0.001), predominantly with axial score (r(s) = 0.43, p < 0.001). CONCLUSIONS: In PD, apathy is a very common and disabling nonmotor symptom separable from depression. Patients living in a rural environment, with lower comorbidity and motor impairment, higher education background, and left predominant PD motor laterality are at lower risk of suffering from apathy. PMID- 22236947 TI - Biosorption of the metal-complex dye Acid Black 172 by live and heat-treated biomass of Pseudomonas sp. strain DY1: kinetics and sorption mechanisms. AB - The ability of Pseudomonas sp. strain DY1 to adsorb Acid Black 172 was studied to determine the kinetics and mechanisms involved in biosorption of the dye. Kinetic data for adsorption fit a pseudo-second-order model. Increased initial dye concentration could significantly enhance the amount of dye adsorbed by heat treated biomass in which the maximum amount of dye adsorbed was as high as 2.98 mmol/g biomass, whereas it had no significant influence on dye sorption by live biomass. As treated temperature increased, the biomass showed gradual increase of dye sorption ability. Experiments using potentiometric titration and Fourier transform infrared spectroscopy (FTIR) indicated that amine groups (NH2) played a prominent role in biosorption of Acid Black 172. Scanning electron microscopy (SEM), atomic force microscopy (AFM) and transmission electron microscopy (TEM) analysis indicated that heat treatment of the biomass increased the permeability of the cell walls and denatured the intracellular proteins. The results of biosorption experiments by different cell components confirmed that intracellular proteins contributed to the increased biosorption of Acid Black 172 by heat treated biomass. The data suggest that biomass produced by this strain may have application for removal of metal-complex dyes from wastewater streams generated from the dye products industry. PMID- 22236948 TI - Degradation of brominated flame retardant in computer housing plastic by supercritical fluids. AB - The degradation process of brominated flame retardant (BFR) and BFR-containing waste computer housing plastic in various supercritical fluids (water, methanol, isopropanol and acetone) was investigated. The results showed that the debromination and degradation efficiencies, final products were greatly affected by the solvent type. Among the four tested solvents, isopropanol was the most suitable solvent for the recovery of oil from BFR-containing plastic for its (1) excellent debromination effectiveness (debromination efficiency 95.7%), (2) high oil production (60.0%) and (3) mild temperature and pressure requirements. However, in this case, the removed bromine mostly existed in the oil. Introduction of KOH into the sc-isopropanol could capture almost all the inorganic bromine from the oil thus bromine-free oil could be obtained. Furthermore, KOH could enhance the depolymerization of the plastic. The obtained oil mainly consisted of single- and duplicate-ringed aromatic compounds in a carbon range of C9-C17, which had alkyl substituents or aliphatic bridges, such as butyl-benzene, (3-methylbutyl)-benzene, 1,1'-(1,3-propanediyl)bis benzene. Phenol, alkyl phenols and esters were the major oxygen-containing compounds in the oil. This study provides an efficient approach for debromination and simultaneous recovering valuable chemicals from BFR-containing plastic in e waste. PMID- 22236949 TI - Degradation of high concentration 2,4-dichlorophenol by simultaneous photocatalytic-enzymatic process using TiO2/UV and laccase. AB - Removal of 2,4-dichlorophenol (2,4-DCP) by TiO2/UV photocatalytic, laccase, and simultaneous photocatalytic-enzymatic treatments were investigated. Coupling of native laccase with TiO2/UV showed a negative synergetic effect due to the rapid inactivation of laccase. Immobilizing laccase covalently to controlled porous glass (CPG) effectively enhanced the stability of laccase against TiO2/UV induced inactivation. By coupling CPG-laccase with the TiO2/UV the degradation efficiency of 2,4-DCP was significantly increased as compared with the results obtained when immobilized laccase or TiO2/UV were separately used. Moreover, the enhancement was more remarkable for the degradation of 2,4-DCP with high concentration, such that for the degradation of 5mM 2,4-DCP, 90% removal percentage was achieved within 2h with the coupled degradation process. While for the TiO2/UV and CPG laccase process, the removal percentage of 2,4-DCP at 2h were only 26.5% and 78.1%, respectively. The degradation kinetics were analyzed using a intermediate model by taking into account of the intermediates formed during the degradation of 2,4-DCP. The high efficiency of the coupled degradation process therefore provided a novel strategy for degradation of concentrated 2,4-DCP. Furthermore, a thermometric biosensor using the immobilized laccase as biorecognition element was constructed for monitoring the degradation of 2,4-DCP, the result indicated that the biosensor was precise and sensitive. PMID- 22236950 TI - Synthesis of 4-vinylpyridine-divinylbenzene copolymer adsorbents for microwave assisted desorption of benzene. AB - Reports on the development of polymer adsorbents for microwave-assisted desorption of nonpolar volatile organic compounds (VOCs) are rare. In this study, we synthesized macroporous polymeric adsorbents with hydrophilic methyl pyridinium units for microwave-assisted desorption of nonpolar VOCs. The benzene adsorption and desorption properties of the adsorbents were investigated under both dry and humid conditions. Under humid conditions, as the content of the hydrophilic methyl pyridinium units in the adsorbents increased from 0 to 20%, the adsorption capacity of benzene decreased from about 21 to 7 mg/g, while the desorption efficiency of benzene increased significantly from 48 to 87%. The maximum concentration of desorbate also increased significantly as the content of the hydrophilic units was increased under humid conditions. We attributed the enhanced desorption efficiency mainly to more adsorbed moisture, which indirectly allowed heating of the polymer adsorbents to higher temperatures upon irradiation with 600 W microwaves. PMID- 22236951 TI - Effects of a salsa dance training on balance and strength performance in older adults. AB - BACKGROUND: Deficits in static and particularly dynamic postural control and force production have frequently been associated with an increased risk of falling in older adults. OBJECTIVE: The objectives of this study were to investigate the effects of salsa dancing on measures of static/dynamic postural control and leg extensor power in seniors. METHODS: Twenty-eight healthy older adults were randomly assigned to an intervention group (INT, n = 14, age 71.6 +/- 5.3 years) to conduct an 8-week progressive salsa dancing programme or a control group (CON, n = 14, age 68.9 +/- 4.7 years). Static postural control was measured during one-legged stance on a balance platform and dynamic postural control was obtained while walking on an instrumented walkway. Leg extensor power was assessed during a countermovement jump on a force plate. RESULTS: Programme compliance was excellent with participants of the INT group completing 92.5% of the dancing sessions. A tendency towards an improvement in the selected measures of static postural control was observed in the INT group as compared to the CON group. Significant group * test interactions were found for stride velocity, length and time. Post hoc analyses revealed significant increases in stride velocity and length, and concomitant decreases in stride time. However, salsa dancing did not have significant effects on various measures of gait variability and leg extensor power. CONCLUSION: Salsa proved to be a safe and feasible exercise programme for older adults accompanied with a high adherence rate. Age related deficits in measures of static and particularly dynamic postural control can be mitigated by salsa dancing in older adults. High physical activity and fitness/mobility levels of our participants could be responsible for the nonsignificant findings in gait variability and leg extensor power. PMID- 22236952 TI - Potential toxicity and affinity of triphenylmethane dye malachite green to lysozyme. AB - Malachite green is a triphenylmethane dye that is used extensively in many industrial and aquacultural processes, generating environmental concerns and health problems to human being. In this contribution, the complexation between lysozyme and malachite green was verified by means of computer-aided molecular modeling, steady state and time-resolved fluorescence, and circular dichroism (CD) approaches. The precise binding patch of malachite green in lysozyme has been identified from molecular modeling and ANS displacement, Trp-62, Trp-63, and Trp-108 residues of lysozyme were earmarked to possess high-affinity for this dye, the principal forces in the lysozyme-malachite green adduct are hydrophobic and pi-pi interactions. Steady state fluorescence proclaimed the complex of malachite green with lysozyme yields quenching through static type, which substantiates time-resolved fluorescence measurements that lysozyme-malachite green conjugation formation has an affinity of 10(3)M(-1). Moreover, via molecular modeling and also CD data, we can safely arrive at a conclusion that the polypeptide chain of lysozyme partially destabilized upon complexation with malachite green. The data emerged here will help to further understand the toxicological action of malachite green in human body. PMID- 22236953 TI - Effects of di-(2-ethylhexyl) phthalate and four of its metabolites on steroidogenesis in MA-10 cells. AB - Phthalate plasticizers are used in the plastics industry to aid in processing and impart flexibility to plastics. Due to the broad use of plastics, and the tendency of plasticizers to leach out of polymers, plasticizers have become ubiquitous in the environment. Concerns about the testicular toxicity of phthalate plasticizers, in particular di-(2-ethylhexyl) phthalate (DEHP), have arisen due to their ability to cause male reproductive tract abnormalities in animal models. It has been assumed that the DEHP metabolite, mono-(2-ethylhexyl) phthalate (MEHP), is the active compound, however, metabolites such as 2 ethylhexanol, 2-ethylhexanal and 2-ethylhexanoic acid, have not been thoroughly investigated. The aim of this study was to evaluate the anti-androgenic potential of these metabolites in vitro with a mouse Leydig tumor cell line, MA-10 cells. DEHP, MEHP and 2-ethylhexanal were found to decrease cell viability, as well as steroidogenic potential. The latter was assessed using an enzyme-linked immunosorbent assay (ELISA) to quantify steroid production and quantitative real time polymerase chain reaction (qRT-PCR) to assess gene expression analysis of key steroidogenic enzymes. 2-Ethylhexanal proved to be the most potent steroidogenic disruptor, offering intriguing implications in the search for the mechanism of phthalate testicular toxicity. Overall, the study suggests the involvement of multiple active metabolites in the testicular toxicity of DEHP. PMID- 22236954 TI - A standardization of Amphibalanus (Balanus) amphitrite (Crustacea, Cirripedia) larval bioassay for ecotoxicological studies. AB - A series of 10 intra-laboratory bioassays and an inter-laboratory assay involving nine laboratories, were performed to validate the use of Amphibalanus amphitrite larvae as test organisms for ecotoxicological studies. The standardization protocol utilized Cadmium Nitrate as a reference toxicant and larval immobilization (after 24 and 48 h) as the end-point. The statistical data analysis showed high homogeneity in intra-laboratory EC(50) values among bioassay repetitions (coefficient of variation (CV)=15.8% after 24 h and 16.9% after 48 h); also CV values obtained in inter laboratory comparison exercise were not higher than the 50%, variation coefficient mentioned in the ISO standards for the precision of inter-laboratory assays. The results demonstrated that the protocol implemented for the balanus larval bioassay comply with the international standards both for intra- and inter-laboratory precision. PMID- 22236956 TI - Oesophageal cancer: how radical should surgery be? AB - INTRODUCTION: Oesophagectomy for carcinoma can be viewed as comprising two components: resection of the oesophagus and resection of the enveloping lymphatics. Controversy exists regarding how extensive these two components should be. METHODS: Through a literature overview, the aim of this educational article is to provide surgeons with arguments to understand which operation is the most oncologically sound according to patient and tumour parameters. RESULTS: Non-randomised comparative studies evaluating radical lymphadenectomy have reported controversial survival benefit. Independent association found between the number of surgically removed lymph nodes and overall survival is an indirect evidence supporting radical lymphadenectomy. The only phase III trial comparing non-radical transhiatal oesophagectomy with transthoracic oesophagectomy for patients with oesophageal adenocarcinoma found 5-year survival rates of 29% vs. 39%, respectively. Although not statistically significant due to underpowered study, specialists would consider less of an increase in survival to be clinically relevant. For squamous OC, the first small randomised controlled trial comparing 2-field lymphadenectomy to 3-field lymphadenectomy did not found significant 5-year survival difference (48% vs. 66%) and the second one comparing 2-field lymphadenectomy to lymph node sampling identified a survival benefit favoring radical resection (36% vs. 25%). CONCLUSION: Radical transthoracic oesophagectomy with two-field lymphadenectomy appears to offer an optimal balance between benefits and risks to a majority of OC patients, especially in the growing area of neoadjuvant treatments. Non-radical resection should be probably reserved for patients with a poor general status whereas 3-field lymphadenectomy may be reserved to selected patients with loco-regional disease in experienced hands, surely for patients with upper OC. PMID- 22236955 TI - The prognostic factors of resected non-small cell lung cancer with chest wall invasion. AB - BACKGROUND: We retrospectively reviewed the clinical features and surgical outcomes of patients with a surgically resected NSCLC invading chest wall in order to identify prognostic factors that impact long term survival. METHODS: Between January 1990 and December 2009, 107 patients who underwent surgical resection for chest wall invading NSCLC were reviewed. Tumors invading only the parietal pleura were defined as superficial invasions, and those involving the soft tissue or ribs were defined as deep invasions. RESULTS: There were 91 men and 16 women; median age was 64 years (range 30 to 80 years). Overall 5 year survival rate was 26.3%. The univariate prognostic factors for survival included gender, extent of resection (pneumonectomy vs lobectomy), tumor size(> 5 cm vs <= 5 cm), nodal status (N0 or N1 vs N2), completeness of resection (complete vs incomplete) and completeness of adjuvant chemotherapy. At multivariate analysis, five independent prognostic factors were shown; depth of invasion (superficial vs deep), tumor size, nodal status, completeness of resection, and completeness of adjuvant chemotherapy. In patients with completely resected T3N0 NSCLC, completion of chemotherapy is the only prognostic factor for long term survival. CONCLUSIONS: Completeness of resection, nodal status, depth of invasion, tumor size, and adjuvant chemotherapy were prognostic factors for long-term survival in NSCLC patients with chest wall invasion. Because of poor prognosis in cases with chest wall invasion that have N2 positive LN, that is difficult to achieve complete resection and that need pneumonectomy, definite chemoradiotherapy or neoadjuvant chemoradiotherapy should be considered first in these cases. PMID- 22236957 TI - Qualitative and quantitative evaluation of EHR-integrated mobile patient questionnaires regarding usability and cost-efficiency. AB - OBJECTIVES: The objective of this evaluation study is to assess a web-based application, currently available on iPad, to document questionnaires regarding patient reported outcomes such as quality of life. Based on the single source approach, the results of these questionnaires are available in the electronic health record to be used for treatment and research purposes. The assessment focuses on the usability and efficiency of the system. METHODS: The system usability scale questionnaire with seven additional items was used to rate the usability by the patients. It was formally validated by a Cronbach Alpha test. In addition, semi-structured interviews were conducted with patients and medical staff. Time and cost measures, based on official tables of costs, were taken through workflow observations. This study was conducted in the department of dermatology at the University Hospital of Munster, Germany from April to June 2011. RESULTS: Using the web-based application questionnaire, results about patient reported outcomes like quality of life are immediately available in the electronic health record and can be used for treatment or research purposes. 118 patients and four staff members participated in the study. The usability score reached 80 from 100 points and patients as well as medical staff stated in the interviews that the usability of the web-based system was high, and they preferred it to the previously used paper-based questionnaires. In the setting of our pilot department the mobile devices amortized their costs after 6.7 months. In general, depending on the professional group who are going to post process the paper-based forms, the earliest break-even point to use mobile questionnaires is at 1737 paper sheets per year. CONCLUSION: The mobile patient questionnaires, integrated into the electronic health record, were well accepted in our pilot setting with high usability scores from patients and medical staff alike. The system has also proved to be cost-efficient compared to the paper-based workflow, given that a certain number of questionnaires is used per year. PMID- 22236958 TI - The preoperative activity of Th1 and Th17 cytokine axes in prediction of sepsis after radical cystectomy. AB - The aim of the study was to correlate the preoperative activity of Th1 and Th17 cytokine axes with the development of sepsis after radical cystectomy. The study involved twenty patients with the infiltrative transitional cell carcinoma of the urinary bladder without previous radiotherapy/chemotherapy, who underwent open radical cystectomy with urinary diversion. Preoperative plasma concentrations of Th1 cytokines interleukin 12 (IL-12) and interferon gamma (IFN-gamma), and Th17 cytokines IL-23 and IL-17, were measured using ELISA. Preoperative expression of mRNA for IL-12p35, IFN-gamma, IL-23p19 and IL-17 was quantified by real-time RT PCR using mRNA extracted from peripheral blood mononuclear cells. Eight patients developed postoperative sepsis, diagnosed within two weeks post-operation as systemic inflammatory response syndrome in the presence of local or systemic infection. The preoperative basal plasma concentrations of Th1 and Th17 cytokines were slightly above the detection limits, with a tendency toward lower concentrations in patients who developed sepsis, but the difference was not significant (p>0.05). The preoperative expression of mRNA encoding IL-12p35 and IL-17 was significantly lower in patients who developed sepsis (p=0.003 and p=0.028, respectively). The similar trend was observed for IL-23p19 and IFN gamma, but the differences did not reach the statistical significance (p=0.051 and p=0.172, respectively). These data suggest that determination of preoperative Th1 and Th17 cytokine mRNA levels might be useful in predicting sepsis development after radical cystectomy. PMID- 22236960 TI - [Dry pulpitis and fissured fingers in patients with hepatitis c combination therapy]. PMID- 22236959 TI - Elevated ammonium concentrations from wastewater discharge depress primary productivity in the Sacramento River and the Northern San Francisco Estuary. AB - Primary production in the Northern San Francisco Estuary (SFE) has been declining despite heavy loading of anthropogenic nutrients. The inorganic nitrogen (N) loading comes primarily from municipal wastewater treatment plant (WTP) discharge as ammonium (NH(4)). This study investigated the consequences for river and estuarine phytoplankton of the daily discharge of 15 metric tons NH(4)-N into the Sacramento River that feeds the SFE. Consistent patterns of nutrients and phytoplankton responses were observed during two 150-km transects made in spring 2009. Phytoplankton N productivity shifted from NO(3) use upstream of the WTP to productivity based entirely upon NH(4) downstream. Phytoplankton NH(4) uptake declined downstream of the WTP as NH(4) concentrations increased, suggesting NH(4) inhibition. The reduced total N uptake downstream of the WTP was accompanied by a 60% decline in primary production. These findings indicate that increased anthropogenic NH(4) may decrease estuarine primary production and increase export of NH(4) to the coastal ocean. PMID- 22236961 TI - HoxB8 in noradrenergic specification and differentiation of the autonomic nervous system. AB - Different prespecification of mesencephalic and trunk neural crest cells determines their response to environmental differentiation signals and contributes to the generation of different autonomic neuron subtypes, parasympathetic ciliary neurons in the head and trunk noradrenergic sympathetic neurons. The differentiation of ciliary and sympathetic neurons shares many features, including the initial BMP-induced expression of noradrenergic characteristics that is, however, subsequently lost in ciliary but maintained in sympathetic neurons. The molecular basis of specific prespecification and differentiation patterns has remained unclear. We show here that HoxB gene expression in trunk neural crest is maintained in sympathetic neurons. Ectopic expression of a single HoxB gene, HoxB8, in mesencephalic neural crest results in a strongly increased expression of sympathetic neuron characteristics like the transcription factor Hand2, tyrosine hydroxylase (TH) and dopamine-beta hydroxylase (DBH) in ciliary neurons. Other subtype-specific properties like RGS4 and RCad are not induced. HoxB8 has only minor effects in postmitotic ciliary neurons and is unable to induce TH and DBH in the enteric nervous system. Thus, we conclude that HoxB8 acts by maintaining noradrenergic properties transiently expressed in ciliary neuron progenitors during normal development. HoxC8, HoxB9, HoxB1 and HoxD10 elicit either small and transient or no effects on noradrenergic differentiation, suggesting a selective effect of HoxB8. These results implicate that Hox genes contribute to the differential development of autonomic neuron precursors by maintaining noradrenergic properties in the trunk sympathetic neuron lineage. PMID- 22236964 TI - Self-assembled iron oxide nanoparticle multilayer: x-ray and polarized neutron reflectivity. AB - We have investigated the structure and magnetism of self-assembled, 20 nm diameter iron oxide nanoparticles covered by an oleic acid shell for scrutinizing their structural and magnetic correlations. The nanoparticles were spin-coated on an Si substrate as a single monolayer and as a stack of 5 ML forming a multilayer. X-ray scattering (reflectivity and grazing incidence small-angle scattering) confirms high in-plane hexagonal correlation and a good layering property of the nanoparticles. Using polarized neutron reflectivity we have also determined the long range magnetic correlations parallel and perpendicular to the layers in addition to the structural ones. In a field of 5 kOe we determine a magnetization value of about 80% of the saturation value. At remanence the global magnetization is close to zero. However, polarized neutron reflectivity reveals the existence of regions in which magnetic moments of nanoparticles are well aligned, while losing order over longer distances. These findings confirm that in the nanoparticle assembly the magnetic dipole-dipole interaction is rather strong, dominating the collective magnetic properties at room temperature. PMID- 22236965 TI - Cytokine network in psoriasis revisited. AB - Psoriasis is a chronic genetically determined, erythemato-squamous disease associated with many comorbidities. Evidence from clinical studies and experimental models support the concept that psoriasis is a T cell-mediated inflammatory skin disease and T helper (Th) cells - Th1, Th17 and Th22 - play an important role in the pathogenesis. Th1 cytokines IFNgamma, IL-2, as well as Th17 cytokines IL-17A, IL-17F, IL-22, IL-26, and TNFalpha (Th1 and Th17 cytokine) are increased in serum and lesional skin. IL-22 produced by Th17 and new subset of T helper cells, Th22, is also increased within psoriatic lesions and in the serum. Other recently recognized cytokines of significant importance in psoriasis are IL 23, IL-20 and IL-15. The IL-23/Th17 pathway plays a dominant role in psoriasis pathogenesis. Currently due to enormous methodological progress, more and more clinical and histopathological psoriatic features could be explained by particular cytokine imbalance, which still is one of the most fascinating dermatological research fields stimulating new and new generations of researchers. PMID- 22236962 TI - Nerve repulsion by the lens and cornea during cornea innervation is dependent on Robo-Slit signaling and diminishes with neuron age. AB - The cornea, the most densely innervated tissue on the surface of the body, becomes innervated in a series of highly coordinated developmental events. During cornea development, chick trigeminal nerve growth cones reach the cornea margin at embryonic day (E)5, where they are initially repelled for days from E5 to E8, instead encircling the corneal periphery in a nerve ring prior to entering on E9. The molecular events coordinating growth cone guidance during cornea development are poorly understood. Here we evaluated a potential role for the Robo-Slit nerve guidance family. We found that Slits 1, 2 and 3 expression in the cornea and lens persisted during all stages of cornea innervation examined. Robo1 expression was developmentally regulated in trigeminal cell bodies, expressed robustly during nerve ring formation (E5-8), then later declining concurrent with projection of growth cones into the cornea. In this study we provide in vivo and in vitro evidence that Robo-Slit signaling guides trigeminal nerves during cornea innervation. Transient, localized inhibition of Robo-Slit signaling, by means of beads loaded with inhibitory Robo-Fc protein implanted into the developing eyefield in vivo, led to disorganized nerve ring formation and premature cornea innervation. Additionally, when trigeminal explants (source of neurons) were oriented adjacent to lens vesicles or corneas (source of repellant molecules) in organotypic tissue culture both lens and cornea tissues strongly repelled E7 trigeminal neurites, except in the presence of inhibitory Robo-Fc protein. In contrast, E10 trigeminal neurites were not as strongly repelled by cornea, and presence of Robo-Slit inhibitory protein had no effect. In full, these findings suggest that nerve repulsion from the lens and cornea during nerve ring formation is mediated by Robo-Slit signaling. Later, a shift in nerve guidance behavior occurs, in part due to molecular changes in trigeminal neurons, including Robo1 downregulation, thus allowing nerves to find the Slit-expressing cornea permissive for growth cones. PMID- 22236967 TI - Reflections on determinants of augmentation index. PMID- 22236966 TI - HIPK2 downregulates vimentin and inhibits breast cancer cell invasion. AB - Vimentin, a mesenchymal marker, is frequently overexpressed in epithelial carcinomas undergoing epithelial to mesenchymal transition (EMT), a condition correlated with invasiveness and poor prognosis. Therefore, vimentin is a potential molecular target for anticancer therapy. Emerging studies in experimental models underscore the functions of homeodomain-interacting protein kinase 2 (HIPK2) as potential oncosuppressor by acting as transcriptional corepressor or catalytic activator of molecules involved in apoptosis and response to antitumor drugs. However, an involvement of HIPK2 in limiting tumor invasion remains to be elucidated. This study, by starting with a microarray analysis, demonstrates that HIPK2 downregulates vimentin expression in invasive, vimentin-positive, MDA-MB-231 breast cancer cells and in the non-invasive MCF7 breast cancer cells subjected to chemical hypoxia, a drive for mesenchymal shift and tumor invasion. At functional level, vimentin downregulation by HIPK2 correlates with inhibition of breast tumor cell invasion. Together, these data show that vimentin is a novel target for HIPK2 repressor function and that HIPK2 mediated vimentin downregulation can contribute to inhibition of breast cancer cells invasion that might be applied in clinical therapy. PMID- 22236968 TI - The threat of ethnicity for cardiovascular disease risk. PMID- 22236969 TI - Effect of treatment on cardiac small resistance arteries in hypertension and diabetes: trick or treat. PMID- 22236970 TI - Systolic and diastolic pulse wave velocity: a confusing parameter or a new frontier? PMID- 22236971 TI - The relationship between hypertension and obesity across different ethnicities. AB - BACKGROUND AND OBJECTIVE: Hypertension and obesity are major contributors to cardiovascular disease, and the relationship between these conditions is known to vary among ethnicities. However, this relationship has not previously been examined in aboriginal populations. The present investigation aimed to identify and compare this relationship among white (n = 3566), aboriginal (n = 850), East Asian (n = 446), and South Asian (n = 222) individuals from the province of British Columbia, Canada. METHODS: Blood pressure, BMI, and waist circumference were directly measured along with self-reported antihypertensive medication usage. Relative risk ratios were calculated to evaluate the risk of hypertension among individuals of varying BMI and waist circumference measurements. The relative risks of hypertension were compared both within and between four ethnic groups. RESULTS: Greater relative risks for hypertension were observed among individuals with increased BMI or increased waist circumference among all four ethnic groups. Aboriginal individuals appear to experience the greatest increases in relative risk for hypertension with increased BMI or waist circumference compared to other ethnic groups. The differences in the risk of developing hypertension between aboriginal and white populations appear to be largely associated with differences in body composition (i.e., BMI or waist circumference). East Asian and South Asian populations experience greater relative risk for hypertension than white populations at the same level of BMI or waist circumference. CONCLUSION: Hypertension prevention and treatment strategies among aboriginal, East Asian, and South Asian populations should target reducing fat mass and abdominal fat. PMID- 22236972 TI - Pulse wave encephalopathy. PMID- 22236973 TI - Validation of carotid blood pressure assessment by tonometry. PMID- 22236975 TI - The history of primary hyperaldosteronism with simultaneous hypercortisolism. PMID- 22236976 TI - Adrenal venous sampling crucial in primary aldosteronism? PMID- 22236977 TI - Supracentrimetric nodule on computed tomography does not exclude adrenal venous sampling before surgery for primary aldosteronism. PMID- 22236978 TI - Meta-analysis supports ACCORD blood pressure but effect of excessive DBP lowering uncertain. PMID- 22236979 TI - Blood pressure lowering in diabetic patients. PMID- 22236980 TI - Functional characterization of aromatic amino acid aminotransferase involved in 2 phenylethanol biosynthesis in isolated rose petal protoplasts. AB - In rose flowers, 2-phenylethanol (2PE) is biosynthesized from l-phenylalanine (l Phe) via phenylacetaldehyde (PAld) by the actions of two enzymes, pyridoxal-5' phosphate (PLP)-dependent aromatic amino acid decarboxylase (AADC) and phenylacetaldehyde reductase (PAR). We here report that Rosa 'Yves Piaget' aromatic amino acid aminotransferase produced phenylpyruvic acid (PPA) from l-Phe in isolated petal protoplasts. We have cloned three full length cDNAs (RyAAAT1-3) of aromatic amino acid aminotransferase families based on rose EST database and homology regions. The RyAAATs enzymes were heterogeneously expressed in Escherichia coli and characterized biochemically. The recombinant RyAAAT3 showed the highest activity toward l-Phe in comparison with l-tryptophan, l-tyrosine, d Phe, glycine, and l-alanine, and showed 9.7-fold higher activity with l-Phe rather than PPA as a substrate. RyAAAT3 had an optimal activity at pH 9 and at 45 55 degrees C with alpha-ketoglutaric acid, and was found to be a PLP dependent enzyme based on the inhibition test using Carbidopa, an inhibitor of PLP dependent enzymes. The transcript of RyAAAT3 was expressed in flowers as well as other organs of R. 'Yves Piaget'. RNAi suppression of RyAAAT3 decreased 2PE production, revealing the involvement of RyAAAT3 in 2PE biosynthesis in rose protoplasts and indicating that rose protoplasts have potentially two different 2PE biosynthetic pathways, the AADC route and the new route via PPA from l-Phe. PMID- 22236981 TI - Fertile transgenic Brachiaria ruziziensis (ruzigrass) plants by particle bombardment of tetraploidized callus. AB - We have produced transgenic plants of the tropical forage crop Brachiaria ruziziensis (ruzigrass) by particle bombardment-mediated transformation of multiple-shoot clumps and embryogenic calli. Cultures of multiple-shoot clumps and embryogenic calli were induced on solidified MS medium supplemented with 0.5mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) and 2mg/L 6-benzylaminopurine (BAP) or 4mg/L 2,4-D and 0.2mg/L BAP, respectively. Both cultures were bombarded with a vector containing an herbicide resistance gene (bar) as a selectable marker and the beta-glucuronidase (GUS) reporter gene. Sixteen hours after bombardment, embryogenic calli showed a significantly higher number of transient GUS expression spots per plate and callus than multiple-shoot clumps, suggesting that embryogenic callus is the more suitable target tissue. Following bombardment and selection with 10mg/L bialaphos, herbicide-resistant embryogenic calli regenerated shoots and roots in vitro, and mature transgenic plants have been raised in the greenhouse. Polymerase chain reaction (PCR) and DNA gel blot analysis verified that the GUS gene was integrated into the genome of the two regenerated lines. In SacI digests, the two transgenic lines showed two or five copies of GUS gene fragments, respectively, and integration at different sites. Histochemical analysis revealed stable expression in roots, shoots and inflorescences. Transgenic plants derived from diploid target callus turned out to be sterile, while transgenics from colchicine-tetraploidized callus were fertile. PMID- 22236982 TI - Do we need an assessment of the nutrition risk in the critically ill patient? AB - The description of a new score of nutrition risk in critically ill patients in the previous issue of Critical Care is very appropriate and timely. However, the use of this score will probably not help the clinician to improve the prescription of nutrition therapy, especially when major uncertainties are raised about the definition of adequate nutrition. The validation of the score will require the use of outcome variables susceptible to influence by nutrition, such as surrogate markers of muscle function. Meanwhile the educational value of a score of nutrition risk is undisputed in settings where the use of scores is incorporated into the usual practice. PMID- 22236983 TI - Birth cohort effects in neurological diseases: amyotrophic lateral sclerosis, Parkinson's disease and multiple sclerosis. AB - BACKGROUND: Generational differences in disease rates are the main subject of age period-cohort (APC) analysis, which is mostly applied in cancer and suicide research. This study applied APC analysis to selected neurological diseases: amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and multiple sclerosis (MS). METHODS: The analyses were based on Swiss mortality data. Age stratified data has been available for MS, PD and ALS since 1901, 1921, and 1942, respectively. APC analysis was performed within the framework of logit models. Main effect models were extended by implementing nested effects, i.e. age effects nested in subperiods, in order to account for the fact that age profiles may change for reasons other than generational influences. RESULTS: In preliminary analyses, APC analysis yielded noteworthy birth cohort effects in all three diseases. After implementing nested effects, the birth cohort effects disappeared in ALS, and smoothed out in PD, where they were greater for the generations born before the 1920s. In MS, the birth cohort effects remained stable, and exhibited a peak in cohorts born in the 1910s and 1920s. CONCLUSIONS: APC analysis yielded some evidence for birth cohort effects, i.e. predisposing risk factors that may change in historical terms, in MS and PD, but probably not in ALS. PMID- 22236985 TI - Letter from the editor. PMID- 22236984 TI - Risk factors for complications of endoscopic sinus surgery for chronic rhinosinusitis. AB - BACKGROUND: Patients undergoing endoscopic sinus surgery (ESS) are at risk of complications because of the close proximity of the sinuses to the orbit and anterior skull base. The aim of this study was to evaluate the complications of ESS and to identify patient characteristics that were risk factors for the complications. METHODS: We conducted a prospective study of 706 patients who underwent ESS for chronic rhinosinusitis. Patients completed preoperative examinations that included computed tomography, endoscopic observation for nasal polyps, and tests for comorbidities including asthma and vascular disease. Perioperative complications were evaluated based on information provided by the surgeons. Multivariate analysis was performed to identify patient characteristics that were risk factors for complications. RESULTS: Overall, perioperative complications occurred in 41 patients (5.8%). A major complication, cerebrospinal fluid leakage, occurred in one patient (0.1%). Minor complications occurred in 40 patients (5.7%), with the most common being intraoperative hemorrhage (n = 18). Multivariate analysis indicated that presence of asthma and the total polyp score correlated significantly with the occurrence of complications. CONCLUSION: The risk factors for perioperative complications were asthma and the polyp score. We conclude that the surgeon should confirm whether the patient has lower airway disease, especially asthma, before operating. The surgeon should also determine the grade of nasal polyps. PMID- 22236986 TI - Heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a growing complication of a common medication used to prevent deep vein thrombosis (DVT) in hospitalized patients. The purpose of this article is to review the mechanism that causes paradoxical thrombus formation in HIT and ways to recognize this important complication with various testing modalities and to discuss the approaches to treatment once a diagnosis has been made. HIT is a clinical diagnosis that can be further supported by utilizing the "4 Ts": thrombocytopenia, timing of platelet count fall, thrombosis or other complications, and other causes for thrombocytopenia. Diagnosis of HIT can be established using an HIT antibody test. Once a drop in platelet count is observed in a patient, it is important to rule out HIT. When HIT is first suspected, it is important to discontinue all heparin products. The gold standard in diagnosing HIT is the 14C-serotonin release assay (14C-SRA) assay, which has high sensitivity and specificity but is technically demanding and more time consuming than other antibody-detecting immunoassays. Anticoagulation in HIT patients is essential due to the increased risk of thrombosis. Treatment consists of utilizing alternative, nonheparin anticoagulants like lepirudin, argatroban, bivalirudin, or fondaparinux (although fondaparinux is not formally approved by the US Food and Drug Administration for this condition). Each of these agents should be individually formulated based on the patient and the presence/absence of liver or renal failure. Treatment duration has yet to be determined. However, in patients requiring long-term anticoagulation (pulmonary embolism, DVT, stroke), the transition to warfarin can be made once the platelet count recovers and there has been at least 5 days of overlap with a nonheparin anticoagulant. PMID- 22236987 TI - Next generation clinical trials. PMID- 22236988 TI - B-cell receptor inhibitors in chronic lymphocytic leukemia. PMID- 22236989 TI - The safety of the blood supply. PMID- 22236990 TI - Adjuvant chemotherapy for stage II and III colorectal cancer. PMID- 22236991 TI - Chronic myeloid leukemia following heart transplantation and immunosuppression with tacrolimus. PMID- 22236992 TI - Post-transplantation chronic myeloid leukemia. PMID- 22236993 TI - Multiple myeloma with multiple extramedullary plasmacytomas. PMID- 22236994 TI - Plasma cell myeloma with multiple plasmacytomas. PMID- 22236995 TI - Prognostic value of arterial pulse wave velocity in peritoneal dialysis patients. AB - BACKGROUND: Cardiovascular disease is the most common cause of mortality in chronic peritoneal dialysis (PD) patients. Increased arterial stiffness may be related to a high peritoneal permeability, resulting in fluid overload of PD patients. We examined the prognostic value and factors that govern the longitudinal change of arterial pulse wave velocity (PWV) in Chinese PD patients. METHOD: We enrolled 155 new PD patients. PWV was measured at baseline and then repeated after 2 years of follow-up. RESULTS: At 24 months, the survival of patients with baseline carotid-femoral (CF)-PWV above 10 m/s was significantly worse than that of those with CF-PWV below 10 m/s (76.1 vs. 88.6%, p = 0.006). However, after adjusting for confounding factors, CF-PWV was not an independent predictor of survival. Amongst the 100 patients who had repeated PWV measurement after 2 years, the average CF-PWV increased from 9.92 +/- 2.04 to 11.00 +/- 2.30 m/s (p < 0.0001). The change in CF-PWV over 2 years significantly correlated with systolic blood pressure (r = 0.241, p = 0.036), serum calcium level (r = 0.231, p = 0.044), and normalized protein nitrogen appearance (NPNA) (r = -0.337, p = 0.001). CONCLUSIONS: A high baseline CF-PWV was associated with a lower overall survival of Chinese PD patients, but the prognostic value of CF-PWV disappeared after adjusting for confounding factors. After 2 years of PD, most patients had progressive increase in CF-PWV; the magnitude of increase is related to systolic blood pressure, serum calcium level, and baseline NPNA. Further study is needed to determine whether serial measurement of CF-PWV provides additional prognostic information. PMID- 22236996 TI - Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16. AB - Toll-like receptors (TLRs) are innate sentinels required for clearance of bacterial and fungal infections of the cornea, but their role in viral immunity is currently unknown. We report that TLR signaling is expendable in herpes simplex virus (HSV)-1 containment as depicted by plaque assays of knockout mice (MyD88(-/-), Trif(-/-) and MyD88(-/-) Trif(-/-) double knockout) resembling wild type controls. To identify the key sentinel in viral recognition of the cornea, in vivo knockdown of the DNA sensor IFI-16/p204 in the corneal epithelium was performed and resulted in a loss of IFN-regulatory factor-3 (IRF-3) nuclear translocation, interferon-alpha production, and viral containment. The sensor seems to have a similar function in other HSV clinically relevant sites such as the vaginal mucosa in which a loss of p204/IFI-16 results in significantly more HSV-2 shedding. Thus, we have identified an IRF-3-dependent, IRF-7- and TLR independent innate sensor responsible for HSV containment at the site of acute infection. PMID- 22236997 TI - Dendritic cells produce TSLP that limits the differentiation of Th17 cells, fosters Treg development, and protects against colitis. AB - Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and keratinocytes, and is involved in immune homeostasis or inflammation. The mechanism through which TSLP regulates intestinal inflammation is unclear. Here, we report that mouse dendritic cells (DCs) express TSLP both in vitro and in vivo in response to Toll-like receptor ligation in a MyD88-dependent fashion. TSLP is produced by the CD103(+) subset of tolerogenic gut DCs and is downregulated during experimental colitis. TSLP produced by DCs acts directly on T cells by reducing their capacity to produce interleukin (IL)-17 and fostering the development of Foxp3(+) T cells. Consistently, TSLP protects against colitis development through a direct action on T cells, as adoptive transfer of naive T cells from TSLPR(-/-) to SCID mice results in a more severe colitis, with increased frequency of IL-17-producing T cells and inflammatory cytokines. Hence, we describe a new anti-inflammatory role of TSLP in the gut. PMID- 22236998 TI - Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. AB - The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described "depletion of regulatory T cell" (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation. PMID- 22236999 TI - A systematic literature review of 10 years of research on sex/gender and pain perception - part 2: do biopsychosocial factors alter pain sensitivity differently in women and men? AB - This systematic review summarizes the results of 10 years of laboratory research on pain and sex/gender. An electronic search strategy was designed by a medical librarian to access multiple databases. A total of 172 articles published between 1998 and 2008 were retrieved, analyzed, and synthesized. The second set of results presented in this review (129 articles) examined various biopsychosocial factors that may contribute to differences in pain sensitivity between healthy women and men. The results revealed that the involvement of hormonal and physiological factors is either inconsistent or absent. Some studies suggest that temporal summation, allodynia, and secondary hyperalgesia may be more pronounced in women than in men. The evidence to support less efficient endogenous pain inhibitory systems in women is mixed and does not necessarily apply to all pain modalities. With regard to psychological factors, depression may not mediate sex differences in pain perception, while the role of anxiety is ambiguous. Cognitive and social factors appear to partly explain some sex-related differences. Finally, past individual history may be influential in female pain responses. However, these conclusions must be treated with much circumspection for various methodological reasons. Furthermore, some factors/mechanisms remain understudied in the field. There is also a need to assess and improve the ecological validity of findings from laboratory studies on healthy subjects, and perhaps a change of paradigm needs to be considered at this point in time to better understand the factors that influence the experience of women and men who suffer from acute or chronic pain. PMID- 22237000 TI - Evoked bursting in injured Abeta dorsal root ganglion neurons: a mechanism underlying tactile allodynia. AB - Chronic compression of rat dorsal root ganglion (CCD) produced tactile allodynia accompanied with hyperexcitability of the myelinated Abeta dorsal root ganglion (DRG) neurons. The Abeta DRG neuron hyperexcitability exhibits as bursting discharges in response to peripherally evoked action potentials (evoked bursting [EB]). The incidence of EB was significantly increased after chronic compression of DRG (CCD) (43.3%) vs control (13.3%). EB was maintained by oscillation of the membrane potential, and its duration was increased when the membrane potential was depolarized. EB was found to coexist in some neurons with spontaneous bursting (SB), but EB always occurred at a more negative membrane potential than SB. Afterdischarges of the wide dynamic range neurons of the dorsal horn in the spinal cord in response to electrical stimulation of Abeta afferent nerve fibers were suppressed by blocking EB of the DRG neurons. CCD neurons with EB exhibited increased current density of persistent sodium current (I(Nap)) and hyperpolarization-activated cation current (I(h)) and decreased alpha-dendrotoxin (alpha-DTX) sensitive current (I(DTX)). The increased I(h) activated by afterhyperpolarization of peripheral afferent action potential was necessary for EB generation and a balance between I(DTX) and I(Nap) might be necessary for EB maintenance. This study may suggest a role of EB of myelinated DRG neurons in development of allodynia after nerve injury and a potential pharmaceutical therapy in treating neuropathic allodynia. PMID- 22237001 TI - Sequential changes in pathophysiology of systemic inflammatory response in a disseminated neonatal herpes simplex virus (HSV) infection. AB - BACKGROUND: Disseminated neonatal herpes simplex virus (HSV) infection causes a typical systemic inflammatory response syndrome and has a high mortality rate. However, the validity of anti-inflammatory intervention against this condition remains unknown. OBJECTIVES: We sought to demonstrate the sequential changes in the pathophysiology of disseminated neonatal HSV infections. STUDY DESIGN: The HSV serum copy number as well as high-mobility group box 1 (HMGB1) and cytochrome c concentrations, which predict the severity and mortality rate of sepsis, were sequentially evaluated in a patient with disseminated neonatal HSV infection caused by HSV-2. RESULTS: As the patient presented with evidence of hyper inflammation and severe illness, we empirically undertook anti-inflammatory intervention that included the administration of prednisolone, high-dose immunoglobulin, and blood exchange therapy in addition to high-dose acyclovir (ACV) therapy. The patient survived without significant neurological sequela. We found that (1) the serum concentrations of both HMGB1 and cytochrome c were extremely high, (2) temporal increases in these biomarkers were observed after admission, and (3) interestingly, the increase in HMGB1 level preceded that of cytochrome c. These results suggested that the pathophysiology of this condition changed sequentially in a dramatic manner, and the timing of our anti inflammatory intervention was prior to the transition of pathological status from hyper-inflammation to massive apoptosis. CONCLUSIONS: Anti-inflammatory intervention may only be effective if it is undertaken during the early phase of disseminated neonatal HSV infections. PMID- 22237002 TI - Helminthic infection and the risk of neurologic disease progression in HTLV-1. AB - BACKGROUND: Infection with the human T-cell lymphotropic virus, type 1 (HTLV-1) has been associated with an increased Th1 response. Interestingly, a higher prevalence of helminthic coinfection has been observed among infected individuals, and subsequent modulation of the immune response typically associated with helminths may influence clinical outcomes among HTLV-1 coinfected individuals. OBJECTIVE: This study was conducted to elucidate the association between helminthic coinfection and the development of clinically characterized neurologic disease that occurs in HTLV-1 infection. STUDY DESIGN: In a cohort analysis, incidence of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was recorded. Incidence of clinical outcomes and disease-free survival of several neurologic outcomes associated with HTLV-1 were estimated using the Kaplan-Meier method with log-rank tests. The relationships between helminthic infection and risk of HTLV-1 neurologic outcomes were assessed by Cox proportional hazard modeling. RESULTS: Seventy-four coinfected and 79 non coinfected patients were followed, with 92 helminthic infections observed in the coinfected group. One patient per group developed HAM/TSP and the risk of progression to neurologic disease outcomes did not differ among those with and without helminthic coinfection (p>0.45). A significant difference was noted in the prevalence of neurologic disease outcomes among all patients at the conclusion of the study (p<0.01). CONCLUSIONS: These data suggest that treated helminthic infection does not affect risk of development of neurologic disease in HTLV-1 infection, and reinforce that treatment of helminths does not adversely affect patients with HTLV-1. Importantly, among all patients, an overall progression of neurologic disease was observed. PMID- 22237003 TI - Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis. AB - BACKGROUND: The IMPACT study was a randomized, double-blind study comparing 100 to 200 days of VGCV prophylaxis (900 mg once daily) in D+/R- kidney transplant recipients. Although extending the duration of prophylaxis resulted in a significant reduction in confirmed cytomegalovirus (CMV) disease (100-day: 36.8% vs 200-day: 16.1%(1)), the consequence of extending the duration of prophylaxis on the development of viral resistance remains unknown. OBJECTIVE: To determine whether extending valganciclovir prophylaxis from 100 days to 200 days increased the incidence of ganciclovir resistance. STUDY DESIGN: Genotypic analysis of CMV UL97 and UL54 was conducted on virus isolated from patients meeting the predefined resistance analysis criteria (RAC). RESULTS: A greater number of patients met the RAC in the 100 day prophylaxis arm (50/163; 31%) compared to the 200 day prophylaxis arm (22/155; 14%). Sequence data were successfully generated for all 200-day patients and 48/50 100-day patients. Three patients in each treatment arm (100 day: 3/163 (1.8%) vs 200 day: 3/155 (1.9%)) had a single known valganciclovir resistance mutation detected (100 day: UL97 gene: M460V, C592G twice; 200 day: UL97 gene: C603W, M460V and UL54 gene: P522S). Overall, a resistance mutation was more likely to be detected if the patient met the RAC during prophylaxis (5/12 (42%)) compared to post-prophylaxis (1/58 (2%)). All six patients with known ganciclovir resistance mutations cleared the virus; three cleared virus without treatment and three cleared virus following treatment. CONCLUSIONS: Extending valganciclovir prophylaxis from 100 days to 200 days did not significantly affect the incidence of ganciclovir resistance. PMID- 22237005 TI - [Hypertension and exercise]. AB - Levels of physical activity in modern urbanized society are clearly insufficient to maintain good health, and to prevent cardiovascular and other disease. Aerobic exercise is almost completely free of secondary effects, and is a useful adjunctive therapy in treating hypertension. There are several possible mechanisms to account for the beneficial effects of exercise in reducing blood pressure, the resulting physiological effects usually being classified as acute, post-exercise or chronic. Variations in genetic background, hypertension etiology, pharmacodynamics and pharmacokinetics may explain the different blood pressure responses to exercise among hypertensive patients. The present review discusses the different pathophysiological aspects of the response to exercise in hypertensives, including its modulators and diagnostic and prognostic usefulness, as well as the latest guidelines on prescribing and monitoring exercise regimes and drug therapy in the clinical follow-up of active hypertensive patients. PMID- 22237006 TI - The primary brain vesicles revisited: are the three primary vesicles (forebrain/midbrain/hindbrain) universal in vertebrates? AB - It is widely held that three primary brain vesicles (forebrain, midbrain, and hindbrain vesicles) develop into five secondary brain vesicles in all vertebrates (von Baer's scheme). We reviewed previous studies in various vertebrates to see if this currently accepted scheme of brain morphogenesis is a rule applicable to vertebrates in general. Classical morphological studies on lamprey, shark, zebrafish, frog, chick, Chinese hamster, and human embryos provide only partial evidence to support the existence of von Baer's primary vesicles at early stages. Rather, they suggest that early brain morphogenesis is diverse among vertebrates. Gene expression and fate map studies on medaka, chick, and mouse embryos show that the fates of initial brain vesicles do not accord with von Baer's scheme, at least in medaka and chick brains. The currently accepted von Baer's scheme of brain morphogenesis, therefore, is not a universal rule throughout vertebrates. We propose here a developmental hourglass model as an alternative general rule: Brain morphogenesis is highly conserved at the five-brain vesicle stage but diverges more extensively at earlier and later stages. This hypothesis does not preclude the existence of deep similarities in molecular prepatterns at early stages. PMID- 22237007 TI - MiRNA-21: a biomarker predictive for platinum-based adjuvant chemotherapy response in patients with non-small cell lung cancer. AB - PURPOSE: To investigate the possible role of microRNAs in the resistance to platinum based chemotherapy in non-small cell lung cancer (NSCLC), explore their potential role and find potential biomarkers for prediction of the response to platinum. RESULTS: 21 miRNAs were deregulated in A549/CDDP. Increased miR-21 expression significantly increased the resistance of A549 cell to platinum, whereas reduced miR-21 decreased the resistance of A549/CDDP cell. This finding was further validated in the tissue samples of 58 patients and it was found that miR-21 expression was significantly increased in platinum based chemotherapy resistant patients (n = 58, p = 0.000). And increased miR-21 expression was associated with the shorter DFS (p = 0.008). Among these 58 patients, 32 had the corresponding plasma samples and similar tendencies were detected in 68.75% patients. Finally, transfection of A549/CDDP with anti-miR-21 increased the expression of PTEN and decreased Bcl-2. In contrast, pre-miR-21 decreased the expression of PTEN and increased Bcl-2 in A549. PATIENTS AND METHODS: Microarray was employed to compare the expression of miRNAs between A549 and A549/CDDP cells. The effect of a differently expressed miRNA (miR-21) was examined on the sensitivity of cells to platinum. MiR-21 expression in NSCLC tumor tissues and matched plasma sample was also analyzed by Real-time PCR. CONCLUSION: Our data suggests that the expression level of miR-21 in tumor tissue and plasma might be used as a biomarker to predict adjuvant platinum based chemotherapy response and disease free survival in patients with NSCLC. Thus, it may serve as a novel therapeutic target to modulate platinum-based chemotherapy. PMID- 22237008 TI - Effects of age-related differences in empathy on social economic decision-making. AB - BACKGROUND: The ways in which aging affects social economic decision-making is a central issue in the psychology of aging. To examine age-related differences in social economic decision-making as a function of empathy, 80 healthy volunteers participated in the Repeated Fixed Opponent Ultimatum Game (UG-R). Previous economic decision-making research has shown that in younger adults empathy is associated with prosocial behavior. The effects of empathy on older adult social economic decision-making are not well understood. METHODS: On each of 20 consecutive trials in the UG-R, one player ("Proposer") splits $10 with another player ("Responder") who chooses either to accept (whereby both receive the proposed division) or reject (whereby neither receives anything). Trait cognitive and emotional empathy were measured using the Interpersonal Reactivity Index. RESULTS: UG-R data were examined as a function of age and cognitive empathy. For "unfair" offers (i.e. offers less than $5), older Responders with high cognitive empathy showed less prosocial behavior and obtained greater payoffs than younger Responders with high cognitive empathy. CONCLUSIONS: High levels of cognitive empathy may differentially affect economic decision-making behavior in younger and older adults. For older adults, high cognitive empathy may play a role in obtaining high financial payoffs while for younger adults it may instead be involved in facilitating social relationships. PMID- 22237009 TI - Up-regulation of 12(S)-lipoxygenase induces a migratory phenotype in colorectal cancer cells. AB - 12(S)-Lipoxygenase (LOX) and its product 12(S)-hydroxyeicosatetraenic (HETE) acid have been implicated in angiogenesis and tumour invasion in several tumour types while their role in colorectal cancer progression has not yet been studied. We have analysed 12(S)-LOX expression in colorectal tumours and found gene expression up-regulated in colorectal cancer specimens for which the pathology report described involvement of inflammation. Using cell line models exposed to 12(S)-HETE or over-expressing 12(S)-LOX malignant cell growth as well as tumour cell migration was found to be stimulated. Specifically, Caco2 and SW480 cells over-expressing 12(S)-LOX formed fewer colonies from sparse cultures, but migrated better in filter-migration assays. SW480 LOX cells also had higher anchorage-independent growth capacity and a higher tendency to metastasise in vivo. Knock-down or inhibition of 12(S)-LOX inhibited cell migration and anchorage-independent growth in both 12(S)-LOX transfectants and SW620 cells that express high endogenous levels of 12(S)-LOX. On the cell surface E-cadherin and integrin-beta1 expression were down-regulated in a 12(S)-LOX-dependent manner disturbing cell-cell interactions. The results demonstrate that 12(S)-LOX expression in inflammatory areas of colorectal tumours has the capacity to induce an invasive phenotype in colorectal cancer cells and could be targeted for therapy. PMID- 22237010 TI - Increased cancer risks in myotonic dystrophy. AB - OBJECTIVE: To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested in several studies but the risks of cancers have not been quantified. PATIENTS AND METHODS: A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method. RESULTS: A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval [CI], 1.80-12.93; P=.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; P<.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; P=.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; P=.05). The estimated cumulative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma. CONCLUSION: Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers. PMID- 22237011 TI - TonB is essential for virulence in avian pathogenic Escherichia coli. AB - Avian pathogenic Escherichia coli (APEC) strains have multiple iron-uptake systems that facilitate adaptation to iron-restricted environments and are believed to assist in colonisation of the host. These systems include several TonB-dependent transporters of ferri-siderophores encoded by the chromosome and the large virulence plasmid common to APECs. The tonB gene of the virulent APEC strain E956 was replaced with a selectable antibiotic resistance marker using Lambda Red recombinase mutagenesis. The phenotype of the DeltatonB E956 mutant was compared to the parent strain under various culture conditions and in chickens experimentally infected via the respiratory route. The mutant was resistant to streptonigrin, impaired in its ability to adapt to growth in iron depleted medium and had greater tolerance of oxidative stress than the parental strain. The mutant was avirulent in chickens, did not affect the growth of chicks and colonisation was mostly limited to the trachea. This study has demonstrated that TonB is essential for virulence in APEC. PMID- 22237012 TI - Small ruminant lentiviruses: immunopathogenesis of visna-maedi and caprine arthritis and encephalitis virus. AB - The small ruminant lentiviruses include the prototype for the genus, visna-maedi virus (VMV) as well as caprine arthritis encephalitis virus (CAEV). Infection of sheep or goats with these viruses causes slow, progressive, inflammatory pathology in many tissues, but the most common clinical signs result from pathology in the lung, mammary gland, central nervous system and joints. This review examines replication, immunity to and pathogenesis of these viruses and highlights major differences from and similarities to some of the other lentiviruses. PMID- 22237013 TI - Activation of boron nitride nanotubes and their polymer composites for improving mechanical performance. AB - Boron nitride nanotubes (BNNTs) are inappropriate for further chemical derivatization because of their chemical inertness. We demonstrate covalent activation of chemically inert BNNTs by isophorone diisocyanate (IPDI) to form isocyanate group (NCO)-terminated BNNT precursors with an 'NCO anchor' ready for further functionalization. As identified by Fourier transform infrared spectroscopy, a number of molecules or polymers with -COOH, -OH or -NH2 groups are readily attached to the activated IPDI-BNNTs. The IPDI-BNNT-involving polymer composites have shown mechanical properties are considerably improved due to the good dispersibility of IPDI-BNNTs in the polymer matrix and the strong interfacial interactions between BNNTs and polymers. The methodology reported here provides a promising method to promote the chemical reactivity of BNNTs and covalently modify polymer nanocomposites with improved mechanical performance. PMID- 22237014 TI - XPB helicase regulates DNA incision by the Thermoplasma acidophilum endonuclease Bax1. AB - Bax1 has recently been identified as a novel binding partner for the archaeal helicase XPB. We previously characterized Bax1 from Thermoplasma acidophilum as a Mg2+-dependent structure-specific endonuclease. Here we directly compare the endonuclease activity of Bax1 alone or in combination with XPB. Using several biochemical and biophysical approaches, we demonstrate regulation of Bax1 endonuclease activity by XPB. Interestingly, incision assays with Bax1 and XPB/Bax1 clearly demonstrate that Bax1 produces different incision patterns depending on the presence or absence of XPB. Using atomic force microscopy (AFM), we directly visualize and compare binding of Bax1 and XPB/Bax1 to different DNA substrates. Our AFM data support enhanced DNA binding affinity of Bax1 in the presence of XPB. Taken together, the DNA incision and binding results suggest that XPB is able to load and position Bax1 on the scissile DNA substrate, thus increasing the DNA substrate range of Bax1. PMID- 22237015 TI - DNA-based assembly lines and nanofactories. AB - With the invention of the DNA origami technique, DNA self-assembly has reached a new level of sophistication. DNA can now be used to arrange molecules and other nanoscale components into almost arbitrary geometries-in two and even three dimensions and with nanometer precision. One exciting prospect is the realization of dynamic systems based on DNA, in which chemical reactions are precisely controlled by the spatial arrangement of components, ultimately resulting in nanoscale analogs of molecular assembly lines or 'nanofactories'. This review will discuss recent progress toward this goal, ranging from DNA-templated synthesis over artificial DNA-based enzyme cascades to first examples of 'molecular robots'. PMID- 22237016 TI - Recent advances in genetic code engineering in Escherichia coli. AB - The expansion of the genetic code is gradually becoming a core discipline in Synthetic Biology. It offers the best possible platform for the transfer of numerous chemical reactions and processes from the chemical synthetic laboratory into the biochemistry of living cells. The incorporation of biologically occurring or chemically synthesized non-canonical amino acids into recombinant proteins and even proteomes via reprogrammed protein translation is in the heart of these efforts. Orthogonal pairs consisting of aminoacyl-tRNA synthetase and its cognate tRNA proved to be a general tool for the assignment of certain codons of the genetic code with a maximum degree of chemical liberty. Here, we highlight recent developments that should provide a solid basis for the development of generalist tools enabling a controlled variation of chemical composition in proteins and even proteomes. This will take place in the frame of a greatly expanded genetic code with emancipated codons liberated from the current function or with totally new coding units. PMID- 22237017 TI - Expanding the synthetic biology toolbox: engineering orthogonal regulators of gene expression. AB - Despite substantial progress in synthetic biology, we still lack the ability to engineer anything as complex as Nature has. One of the many reasons is that we lack the requisite tools for independently controlling the expression of multiple genes in parallel. While our toolbox is still spare, the situation is rapidly changing. This opinion discusses some recent approaches and open challenges in designing orthogonal regulators of gene expression in bacteria. PMID- 22237018 TI - A profile of skin cancer prevention media coverage in 2009. AB - BACKGROUND: Little is known about the coverage of skin cancer prevention messages in news print media. OBJECTIVE: To perform a content analysis of mass-media articles from newspaper and magazines pertaining to skin cancer prevention in 4 specific months (January, May, July, and October) in 2009 and assess the extent of coverage of skin cancer prevention messages. METHODS: We conducted a content analysis of 144 articles related to skin cancer prevention extracted from strategic media scans of selected months in 2009. We sought to provide the frequency of mass-media content categorized by theme and focus related to ultraviolet radiation (UVR) protection and risk-reducing behaviors. RESULTS: The audience for the vast majority (78%) of the articles was the general public. Among the assessed articles, more were published in May (49%) and July (35%) than in the remaining other months. The two most frequent themes focused on 'protection of the skin' (32%) and on 'skin cancer prevention' (23%) via risk reduction behavioral practices. Analysis of message content regarding UVR reduction practices showed that many mentioned 'use of sunscreen' (65% of messages) with the least-often mentioned behaviors being 'seek shade' (6.3%) and 'do not burn' (1.4%). In addition, a quarter of the articles lacked any content mentioning recommended UVR reduction behaviors. LIMITATIONS: This study was limited to the narrow scope of articles published in 2009 and for selected months. CONCLUSIONS: This profile of mass-media content regarding skin cancer prevention revealed gaps in coverage of UVR reduction behaviors with possible room for improvement. Strategies for improving and comprehensiveness of coverage of recommended skin cancer prevention behaviors in the media are discussed. PMID- 22237019 TI - Nanostructure and beta1-integrin distribution analysis of pig's spermatogonial stem cell by atomic force microscopy. AB - Spermatogonial stem cells (SSCs) provide the foundation for spermatogenesis and male fertility. However, spermatogenesis has direct links with some adhesion molecules on SSCs membrane. Beta1-integrin (CD29) is such a kind of adhesion molecule and a biomarker of pig's SSCs. Therefore, quantitative characteristics of beta1-integrin expression level in a single cell could help us to capture the signal switch and understand the mechanism of spermatogenesis. In this study, atomic force microscopy (AFM) was used to obtain the morphology and ultrastructure of SSCs at nanometer level, and the CD29 Ab-functionalized AFM tip was used to examine beta1-integrin distribution on the cell membrane. There were many force-binding spots on about 50% of cell membrane binding to the CD29 Ab functionalized AFM tip, and the mean bind rupture force was 283.63+/-12.56PN which was much larger than the non-specific average force 70.75+/-10.95PN. Meanwhile, beta1-integrin on SSCs membrane was distributed non-uniformly, and there were some beta1-integrins appeared to be expressed as 150-350 nm nanoclusters on the membrane. Our results discovered the structure of SSCs at nanometer level by AFM. The force between beta1-integrin antigen-antibody interactions and the distribution of beta1-integrin protein on SSCs membrane were also firstly demonstrated. PMID- 22237020 TI - Polymorphism T->C of gene CYP17 promoter and polycystic ovary syndrome risk: a meta-analysis. AB - The T->C polymorphism of CYP17 gene has been inconsistently associated with polycystic ovary syndrome (PCOS) risk. We examined the association by performing a meta-analysis. Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP17 polymorphism and PCOS were calculated in a fixed-effects model and a random-effects model when appropriate. The pooled ORs were performed for co-dominant model (CC vs. TT, TC vs. TT), dominant model (CC+TC vs. TT), and recessive model (CC vs. TC+TT). Subgroup analyses were performed by ethnicity, country, Hardy-Weinberg equilibrium (HWE) in controls and study sample size. This meta-analysis included 10 case-control studies, which included 1321 PCOS cases and 1017 controls. Overall, the variant genotypes (CC and TC) were not associated with PCOS risk, compared with the wild-type TT homozygote. Similarly, no associations were found in the dominant and recessive models. Stratified analyses by ethnicity/country also detected no significant association. However, limiting the analysis to the studies within HWE, a significantly increased risk was observed (TC vs. TT, OR=1.44, 95% CI=1.10-1.88; dominant model, OR=1.41, 95% CI=1.10-1.81). Moreover, when stratifying by study sample size, a significantly elevated risk was found among small sample studies (<=200 subjects), but not among large sample studies (> 200 subjects). This meta analysis suggests that the CYP17 T/C polymorphism may be not associated with PCOS risk, while the observed increase in risk of PCOS may be due to small-study bias. PMID- 22237021 TI - Transiting circumbinary planets Kepler-34 b and Kepler-35 b. AB - Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars (binaries). Although long anticipated, the existence of a 'circumbinary planet' orbiting such a pair of normal stars was not definitively established until the discovery of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289 days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131 days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than ~1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million. PMID- 22237022 TI - A novel retinoblastoma therapy from genomic and epigenetic analyses. AB - Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss. PMID- 22237023 TI - A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. AB - Exercise benefits a variety of organ systems in mammals, and some of the best recognized effects of exercise on muscle are mediated by the transcriptional co activator PPAR-gamma co-activator-1 alpha (PGC1-alpha). Here we show in mouse that PGC1-alpha expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise. PMID- 22237025 TI - Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. AB - Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions. PMID- 22237026 TI - The month of birth and the incidence of multiple sclerosis in the Israeli population. AB - BACKGROUND: Recent studies on date of birth of multiple sclerosis (MS) patients showed a spring peak and an autumn nadir. We examined the effect of date of birth in a large group of MS patients and non-MS patients, compared to the general population in Israel. METHODS: A retrospective analysis was performed in a large cohort of MS patients and patients with other neurological disorders. The date of birth, gender, and country of birth were identified for each patient. The results were compared to a national database. RESULTS: There were 2,264 MS patients and 1,758 patients with other diagnoses. No significant peak or nadir in the date of birth was identified in either group, both in patients born in Israel or in immigrants. No difference was found compared to the national birth rate. When we controlled for the country of birth, there was no difference. CONCLUSION: An increased frequency of MS patients born in the months of April and May was considered as a proof of maternal influence. The results of our study show that this finding is not consistent worldwide. The month of birth was not found to be a significant factor in Israeli MS patients. PMID- 22237027 TI - Understanding elder abuse: a social rights perspective. PMID- 22237024 TI - Complete subunit architecture of the proteasome regulatory particle. AB - The proteasome is the major ATP-dependent protease in eukaryotic cells, but limited structural information restricts a mechanistic understanding of its activities. The proteasome regulatory particle, consisting of the lid and base subcomplexes, recognizes and processes polyubiquitinated substrates. Here we used electron microscopy and a new heterologous expression system for the lid to delineate the complete subunit architecture of the regulatory particle from yeast. Our studies reveal the spatial arrangement of ubiquitin receptors, deubiquitinating enzymes and the protein unfolding machinery at subnanometre resolution, outlining the substrate's path to degradation. Unexpectedly, the ATPase subunits within the base unfoldase are arranged in a spiral staircase, providing insight into potential mechanisms for substrate translocation through the central pore. Large conformational rearrangements of the lid upon holoenzyme formation suggest allosteric regulation of deubiquitination. We provide a structural basis for the ability of the proteasome to degrade a diverse set of substrates and thus regulate vital cellular processes. PMID- 22237028 TI - Postneonatal mortality among Alaska Native infants - Alaska, 1989-2009. AB - Alaska's postneonatal mortality rate of 3.4 deaths per 1,000 live births during 2006-2008 was 48% higher than the 2007 U.S. rate of 2.3 per 1,000. Among American Indian/Alaska Native (AI/AN) infants, the Alaska rate of 8.0 per 1,000 was 70% higher than the U.S. rate of 4.7. The Alaska Division of Public Health analyzed a linked birth-infant death file for 1989-2009 to examine temporal trends in postneonatal mortality in Alaska, specifically in the Alaska Native (AN) population. Overall and non-Alaska Native (non-AN) rates declined during the entire period, but no significant trends in AN-specific mortality were apparent. Infant mortality review committee findings indicated a decline during 1992-2007 among all postneonatal deaths attributed to sudden infant death syndrome (SIDS) or sudden unexplained infant death (SUID), but not for other causes. Lack of progress in reducing postneonatal mortality, particularly among AN infants, indicates a need for renewed emphasis within the Alaska health-care community. Current initiatives to reduce preventable causes of postneonatal mortality should be evaluated and successful models more widely implemented. PMID- 22237029 TI - Surveillance for chronic hepatitis B virus infection - New York City, June 2008 November 2009. AB - Chronic hepatitis B virus (HBV) infection is a leading cause of cirrhosis and liver cancer worldwide; the estimated prevalence in the United States is 0.3% 0.5%. Each year, approximately 11,500-13,000 persons are newly reported with a positive HBV test to the New York City (NYC) Department of Health and Mental Hygiene (DOHMH). To characterize chronic HBV patients, DOHMH began ongoing enhanced chronic HBV surveillance, selecting a random sample of newly reported cases and collecting more detailed information from the patients' clinicians. This report summarizes investigations of 180 randomly selected HBV cases reported during June 2008-November 2009. Approximately two thirds (67%) of patients were Asian, and the most commonly reported reason for HBV testing was the patient's birth country or race/ethnicity (27%). In 70% of cases, the clinician did not know of any patient risk factors. Sixty-nine percent of clinicians stated that they counseled their patients about notifying close contacts about their infection, and 75% counseled about transmission and prevention. Sixty-two percent did not know their patient's hepatitis A vaccination status despite recommendations. This surveillance effort provided quantitative data on health disparities useful for identifying opportunities for outreach and education, and it showed that not all patients received recommended prevention and treatment services. In response to these findings, DOHMH now routinely distributes HBV patient education materials to populations in need. PMID- 22237030 TI - CDC grand rounds: prescription drug overdoses - a U.S. epidemic. AB - In 2007, approximately 27,000 unintentional drug overdose deaths occurred in the United States, one death every 19 minutes. Prescription drug abuse is the fastest growing drug problem in the United States. The increase in unintentional drug overdose death rates in recent years has been driven by increased use of a class of prescription drugs called opioid analgesics. Since 2003, more overdose deaths have involved opioid analgesics than heroin and cocaine combined. In addition, for every unintentional overdose death related to an opioid analgesic, nine persons are admitted for substance abuse treatment, 35 visit emergency departments, 161 report drug abuse or dependence, and 461 report nonmedical uses of opioid analgesics. Implementing strategies that target those persons at greatest risk will require strong coordination and collaboration at the federal, state, local, and tribal levels, as well as engagement of parents, youth influencers, health-care professionals, and policy-makers. PMID- 22237031 TI - Vital signs: binge drinking prevalence, frequency, and intensity among adults - United States, 2010. AB - BACKGROUND: Binge drinking accounts for more than half of the estimated 80,000 average annual deaths and three quarters of $223.5 billion in economic costs resulting from excessive alcohol consumption in the United States. METHODS: CDC analyzed data collected in 2010 on the prevalence of binge drinking (defined as four or more drinks for women and five or more drinks for men on an occasion during the past 30 days) among U.S. adults aged >=18 years in 48 states and the District of Columbia; and on the frequency (average number of episodes per month) and intensity (average largest number of drinks consumed on occasion) among binge drinkers. RESULTS: The overall prevalence of binge drinking was 17.1%. Among binge drinkers, the frequency of binge drinking was 4.4 episodes per month, and the intensity was 7.9 drinks on occasion. Binge drinking prevalence (28.2%) and intensity (9.3 drinks) were highest among persons aged 18-24 years. Frequency was highest among binge drinkers aged >=65 years (5.5 episodes per month). Respondents with household incomes >=$75,000 had the highest binge drinking prevalence (20.2%), but those with household incomes <$25,000 had the highest frequency (5.0 episodes per month) and intensity (8.5 drinks on occasion). The age-adjusted prevalence of binge drinking in states ranged from 10.9% to 25.6%, and the age-adjusted intensity ranged from 6.0 to 9.0 drinks on occasion. CONCLUSIONS: Binge drinking is reported by one in six U.S. adults, and those who binge drink tend to do so frequently and with high intensity. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: More widespread implementation of Community Guide recommended interventions (e.g., measures controlling access to alcohol and increasing prices) could reduce the frequency, intensity, and ultimately the prevalence of binge drinking, as well as the health and social costs related to it. PMID- 22237032 TI - Tinnitus before and 6 months after cochlear implantation. AB - In this prospective multicenter study, tinnitus loudness and tinnitus-related distress were investigated in 174 cochlear implant (CI) candidates who underwent CI surgery at a Swiss cochlear implant center. All subjects participated in two session, one preoperatively and one 6 months after device activation. In both sessions, tinnitus loudness was assessed using a visual analogue scale and tinnitus distress using a standardized tinnitus questionnaire. The data were compared with unaided pre- and postoperative pure tone thresholds, and postoperative speech reception scores. 71.8% of the subjects reported tinnitus preoperatively. Six months after CI surgery 20.0% of these reported abolition of their tinnitus, 51.2% a subjective improvement, 21.6% no change and 7.2% a deterioration. Of the 49 (28.2%) subjects with no tinnitus preoperatively, 5 developed tinnitus 6 months after CI. These 5 had poorer speech understanding after CI surgery with their device than the group who remained tinnitus free. We found no correlation between tinnitus improvement, age, duration of tinnitus, or change in unaided hearing thresholds between the two sessions. PMID- 22237033 TI - Occupational health and safety surveillance and research using workers' compensation data. AB - OBJECTIVE: Examine uses of US workers' compensation (WC) data for occupational safety and health purposes. METHODS: This article is a summary of the proceedings from an invitational workshop held in September 2009 to discuss the use of WC data for occupational safety and health prevention purposes. RESULTS: Workers' compensation data systems, although limited in many ways, contain information such as medical treatments, their costs and outcomes, and disability causes that are unavailable from national occupational surveillance sources. CONCLUSIONS: Despite their limitations, WC records are collected in a manner consistent with many occupational health and safety surveillance needs. Reports are available on the use of WC data for surveillance and research purposes such as estimating the frequency, magnitude, severity, and cost of compensated injuries. Inconsistencies in WC data can limit generalization of research results. PMID- 22237034 TI - Poultry processing work and respiratory health of Latino men and women in North Carolina. AB - OBJECTIVE: To evaluate associations between poultry processing work and respiratory health among working Latino men and women in North Carolina. METHODS: Between May 2009 and November 2010, 402 poultry processing workers and 339 workers in a comparison population completed interviewer-administered questionnaires. Of these participants, 279 poultry processing workers and 222 workers in the comparison population also completed spirometry testing to provide measurements of forced expiratory volume in 1 second and forced vital capacity. RESULTS: Nine percent of poultry processing workers and 10% of workers in the comparison population reported current asthma. Relative to the comparison population, adjusted mean forced expiratory volume in 1 second and forced vital capacity were lower in the poultry processing population, particularly among men who reported sanitation job activities. CONCLUSIONS: Despite the low prevalence of respiratory symptoms reported, poultry processing work may affect lung function. PMID- 22237035 TI - The effect of body mass index on recovery and return to work after onset of work related low back pain. AB - OBJECTIVE: To assess the effect of body mass index (BMI) on pain and function outcomes in the acute and subacute stages of work-related low back pain (LBP). METHODS: A prospective cohort of working-age patients (410 male, 197 female) with recent onset LBP (<=14 days' duration) provided height and weight as part of a study of prognostic factors for back disability. Self-reported pain, functional limitation, and work status were assessed at 1- and 3-month follow-ups. RESULTS: BMI (kg/m) was used to categorize participants as normal (31%), overweight (40%), or obese (29%). In prediction analyses, outcomes of pain, functional limitation, and return to work showed no significant variation (P > 0.05) by BMI, with or without controlling for potential confounds. CONCLUSIONS: BMI is not a useful prognostic factor during the acute and subacute stages of work-related LBP. PMID- 22237036 TI - Lichenoid red tattoo reaction: histological and immunological perspectives. AB - As tattooing practices increase, delayed-type inflammatory reactions represent an uncommon adverse event to tattoo pigments. Different reaction patterns, such as eczematous, lichenoid, granulomatous and pseudolymphomatous reactions, have been previously reported, especially in association with metals contained in red tattoo pigments. We report a lichenoid papular reaction to an organic red tattoo ink, characterized by an intense mononuclear infiltrate dominated by CD8(+) T cells and CD56(+) lymphocytes and distributed in the superficial dermis around the red pigment and in the epidermis. Cytofluorimetric analysis of the lesional skin infiltrate confirmed the high frequency of cytotoxic CD8(+ )T cells and CD56(+)CD16(-) lymphocytes, most of which release type 1 cytokines. Chemical analysis of the red tattoo pigment confirmed its organic nature and the presence of intermediate reactive compounds. The lichenoid tissue reaction to red organic tattoo pigment showed the prototypical features of a cytotoxic inflammatory response to foreign substances (xenobiotics). The chemically unstable and reactive nature of modern tattoo pigments has to be taken into account by the clinician as well by the tattoo recipients. PMID- 22237037 TI - Detecting plasma Epstein-Barr virus DNA to diagnose postradiation nasopharyngeal skull base lesions in nasopharyngeal carcinoma patients: a prospective study. AB - The diagnosis of postradiation nasopharyngeal skull base lesions in petients with nasopharyngeal carcinoma (NPC) is still a tough problem in clinical practice. An early and accurate diagnosis is important for subsequent management. We prospectively evaluated the diagnostic value of plasma Epstein-Barr virus(EBV) DNA in detecting postradiation nasopharyngeal skull base lesions in NPC patients. From July 2006 to September 2010, 90 patients with postradiation NPC (34 women and 56 men; median age: 42 years) met the selection criteria and were recruited in this study. All postradiation nasopharyngeal skull base lesions were found in the latest magnetic resonance imaging (MRI) examinations before endoscopic surgery, and the nasopharyngeal cavity was normal under flexible nasopharyngoscopy. Plasma EBV DNA detection was performed within 2 weeks before endoscopic surgery. A total of 90 endoscopic operations were successfully performed without any postoperative complications. Recurrences confirmed by postoperative pathology were found in 30 patients. The specificity, positive and negative predictive values of plasma EBV DNA detection were better than those of MRI. In addition, combining plasma EBV DNA detection with MRI improved the specificity and positive predictive values of MRI. Plasma EBV DNA detection followed by MRI would help to diagnose recurrence whereas MRI was unable. These results indicate that plasma EBV DNA is an effective and feasible biomarker for detecting postradiation nasopharyngeal skull base lesions in NPC patients. PMID- 22237038 TI - Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells. AB - Niclosamide, an oral antihelminthic drug, has been used to treat tapeworm infection for about 50 years. Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs. Recently, several groups have independently discovered that niclosamide is also active against cancer cells, but its precise mechanism of antitumor action is not fully understood. Evidence supports that niclosamide targets multiple signaling pathways (NF kappaB, Wnt/beta-catenin, Notch, ROS, mTORC1, and Stat3), most of which are closely involved with cancer stem cells. The exciting advances in elucidating the antitumor activity and the molecular targets of this drug will be discussed. A method for synthesizing a phosphate pro-drug of niclosamide is provided. Given its potential antitumor activity, clinical trials for niclosamide and its derivatives are warranted for cancer treatment. PMID- 22237039 TI - Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. AB - Multidrug resistance (MDR), which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence, has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades. Several mechanisms of overcoming drug resistance have been postulated. Well known P glycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure. Innovative theranostic (therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits. In this review, we discuss the mechanisms of drug efflux mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome. PMID- 22237040 TI - Increased pretreatment levels of serum LDH and ALP as poor prognostic factors for nasopharyngeal carcinoma. AB - Serum enzymes that play potential roles in tumor growth have recently been reported to have prognostic relevance in a diverse array of tumors. However, prognosis-related serum enzymes are rarely reported for nasopharyngeal carcinoma(NPC). To clarify whether the level of serum enzymes is linked to the prognosis of NPC, we reviewed the pretreatment data of lactate dehydrogenase(LDH), alkaline phosphatase (ALP), and glutamyl transferase (GGT) in 533 newly diagnosed NPC patients who underwent radical radiotherapy between May 2002 and October 2003 at Sun Yat-sen University Cancer Center. Patients were grouped according to the upper limit of normal values of LDH, ALP, and GGT. The Kaplan-Meier method and log-rank test were used for selecting prognostic factors from clinical characteristics and serum enzymes, and the chi-square test was applied to analyze the relationships of clinical characteristics and serum enzymes. Finally, a Cox proportional hazards model was used to identify the independent prognostic factors. We found that increased levels of LDH had poor effects on both overall survival and distant metastasis-free survival (P = 0.009 and 0.035, respectively), and increased pretreatment level of serum ALP had poor effects on both overall survival and local recurrence-free survival (P = 0.037 and 0.039, respectively). In multivariate analysis, increased LDH level was identified as an independent prognostic factor for overall survival. Therefore, we conclude that increased pretreatment serum LDH and ALP levels are poor prognostic factors for NPC. PMID- 22237041 TI - Reversing multidrug resistance by tyrosine kinase inhibitors. AB - Recently, a large number of tyrosine kinase inhibitors(TKIs) have been developed as anticancer agents. These TKIs can specifically and selectively inhibit tumor cell growth and metastasis by targeting various tyrosine kinases and thereby interfering with cellular signaling pathways. The therapeutic potential of TKIs has been hindered by multidrug resistance(MDR), which is commonly caused by overexpression of ATP-binding cassette(ABC) membrane transporters. Interestingly, some TKIs have also been found to reverse MDR by directly inhibiting the function of ABC transporters and enhancing the efficacy of conventional chemotherapeutic drugs. In this review, we discuss ABC transporter-mediated MDR to TKIs and MDR reversal by TKIs. PMID- 22237043 TI - [Effectiveness of endovascular prostheses as initial treatment for superior vena cava syndrome of malignant cause]. AB - BACKGROUND AND OBJECTIVE: Superior vena cava syndrome (SVCS) is caused by venous return obstruction often originated by an invading mediastinal tumour. Our objective was to evaluate the usefulness of stents as initial treatment for SVCS of malignant origin. PATIENTS AND METHODS: From December 1996 to August 2010, 120 patients with SVCS were referred for percutaneous treatment. Seventy-six were under oncological follow-up cases and in 44 cases the tumour was unknown. A non concurrent prospective study was made of 113 patients without prior chemotherapy or radiotherapy, who opted for endovascular treatment as first option. RESULTS: One hundred and two men and 11 women were treated, mean age 61.18 years old (range 45-85). SVCS causes included lung cancer (100), lung metastases (6), compression by enlarged lymph nodes (6), and an embryonic tumour. One hundred and fifty-five prostheses were implanted. One stent was enough in 75 patients, 2 stents in 34, and 3 in 4. Technical success rate was 98.2%. Symptoms disappeared completely in 97 patients and partially in 13. Complications were stent migration (5), epistaxis (1), and post-procedure groin hematoma (1). Seventy-three asymptomatic patients had a mean survival of 210 days (75% primary permeability and 52.9% secondary permeability). CONCLUSIONS: The use of stents in malignant SVCS is a safe and effective procedure for venous obstruction, leading to the immediate disappearance of symptoms, allowing the underlying tumour staging, facilitating the establishment of the best treatment and improving life quality. PMID- 22237044 TI - Lorentz force actuation of a heated atomic force microscope cantilever. AB - We report Lorentz force-induced actuation of a silicon microcantilever having an integrated resistive heater. Oscillating current through the cantilever interacts with the magnetic field around a NdFeB permanent magnet and induces a Lorentz force that deflects the cantilever. The same current induces cantilever heating. With AC currents as low as 0.2 mA, the cantilever can be oscillated as much as 80 nm at resonance with a DC temperature rise of less than 5 degrees C. By comparison, the AC temperature variation leads to a thermomechanical oscillation that is about 1000 times smaller than the Lorentz deflection at the cantilever resonance. The cantilever position in the nonuniform magnetic field affects the Lorentz force-induced deflection, with the magnetic field parallel to the cantilever having the largest effect on cantilever actuation. We demonstrate how the cantilever actuation can be used for imaging, and for measuring the local material softening temperature by sensing the contact resonance shift. PMID- 22237045 TI - Work disability rates in RA. Results from an inception cohort with 24 years follow-up. AB - OBJECTIVE: To explore rates of and reasons for work disability in an early RA cohort with median 10 years follow-up. METHODS: One thousand four hundred and sixty patients with early RA (<2 years symptom duration) and no prior DMARD therapy were recruited from nine rheumatology outpatient departments across the UK between 1986 and 1998. Standard clinical, laboratory and radiological assessments were recorded at 6-monthly and yearly intervals. Assessment of employment included details of type and hours of paid work. The main outcomes investigated were rates of and main reasons for work cessation, analysed by age of onset of RA (<45, 45-60 years) and year of recruitment to the study (before or after 1992). RESULTS: Maximum follow-up was 24 years, median 10 years. Of 647 patients in paid work at baseline, the majority were <60 years old (91%). The estimated probability of stopping work due to RA was highest in patients with older age of onset (45-60 years) who were recruited before 1992, but improved in those recruited from 1992 to 1998 (P < 0.01). There was no difference seen over the study recruitment years in younger age of onset patients. CONCLUSION: Work loss related to RA occurred much earlier than for other reasons, especially in the first 5 years of RA, but improved in the later recruitment period. Work disability is multifactorial, and the gradual changes in therapies used over time in this cohort may be one explanation for the secular differences seen. PMID- 22237046 TI - PTPN22 R620W polymorphism in the ANCA-associated vasculitides. AB - OBJECTIVES: PTPN22 is involved in T-cell activation and its R620W single nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. METHODS: PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. RESULTS: The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, chi(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, chi(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, chi(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, chi(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, chi(2 )= 16.567, OR = 3.73). CONCLUSION: The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset. PMID- 22237047 TI - Is there an association between advanced stage of renal cell carcinoma and paraneoplastic syndrome? AB - OBJECTIVE: To investigate any association between renal cell carcinoma (RCC) and paraneoplastic syndromes (PNS). SUBJECTS AND METHODS: The retrospective analysis included 1,028 patients of Chinese Han nationality with resectable RCC and PNS. The PNS included elevated erythrocyte sedimentation rate (ESR), hypertension, cachexia, anemia, pyrexia, abnormal liver function, hypercalcemia, polycythemia, varicocele and neuromyopathy. Staging was categorized as local (T1-2N0M0) and locally advanced (T3-4NxM0). RESULTS: Among patients with at least one PNS, elevated ESR (p = 0.008), cachexia (p = 0.000), varicocele (p = 0.000) and pyrexia (p = 0.021) were related to advanced stage of RCC. Among patients with only one PNS, hypertension (p = 0.012) and hypercalcemia (p = 0.000) were related to advanced stage. The remaining PNS were not associated with tumor stage. CONCLUSION: Pyrexia, elevated ESR, cachexia and varicocele were related to advanced RCC. Hypertension and hypercalcemia occurring as single PNS, although also correlated with advanced stage, require further investigation. PMID- 22237048 TI - Functional imaging in freely moving animals. AB - Uncovering the relationships between animal behavior and cellular activity in the brain has been one of the key aims of neuroscience research for decades, and still remains so. Electrophysiological approaches have enabled sparse sampling from electrically excitable cells in freely moving animals that has led to the identification of important phenomena such as place, grid and head-direction cells. Optical imaging in combination with newly developed labeling approaches now allows minimally invasive and comprehensive sampling from dense networks of electrically and chemically excitable cells such as neurons and glia during self determined behavior. To achieve this two main imaging avenues have been followed: Optical recordings in head-restrained, mobile animals and miniature microscope bearing freely moving animals. Here we review progress made toward functional cellular imaging in freely moving rodents, focusing on developments over the past few years. We discuss related challenges and biological applications. PMID- 22237049 TI - Determinants of ochratoxin A exposure--a one year follow-up study of urine levels. AB - Dietary exposure to the ochratoxin A (OTA) occurring in Portugal is characterized by a high frequency of contamination of the consumed foodstuffs, although at low levels. The exposure bears significance for the total food consumed, and not for a particular one. Biomonitoring studies are thus fundamental in simplifying the evaluation of exposure, with no need to examine the entire range of consumed foodstuffs. Biomonitoring studies further allow the identification of host factors as predictors of OTA exposure in epidemiologic studies, the results of which are merited for targeting intervention strategies by public health authorities and advising official regulatory decisions. Using a longitudinal approach, this study examined factors related to OTA exposure in the adult population over a one-year period. Anthropometric measures, season of the year and region were the selected factors correlated with OTA exposure biomarker. Urine samples from 95 inhabitants from six Portuguese main geographical areas were assayed through spectrofluorimetric detection. Exposure to OTA proved to markedly increase in winter, and gender differences were observed only in summer, which might be related to different dietary patterns not only between seasons, but also between genders. The same rationale may also serve the observed statistically significant differences between some regions. No other strong association upon the remaining determinants under testing was observed. These observations reinforce the need for OTA exposure evaluation, possibly specifically targeting the staple foods or dietary habits that sustain potential predictors or determinants of exposure. PMID- 22237050 TI - Histone deacetylase in chronic lymphocytic leukemia. AB - BACKGROUND: Elevated histone deacetylase (HDAC) isoenzyme levels have been described in patients with carcinomas and leukemias. HDAC inhibitors (HDACi) have shown promise in the treatment of carcinomas and are currently under intense research. To make better use of HDACi in treating chronic lymphocytic leukemia (CLL), HDAC isoenzyme levels were studied. METHODS: Quantitative reverse transcriptase polymerase chain reaction for HDAC isoenzyme was measured in 32 patients with CLL and compared with 17 normal volunteer controls. ZAP-70, CD38 and CD44 were also assayed and correlated to HDAC isoenzyme levels. RESULTS: The results showed: (1) HDAC isoenzyme levels in CLL were significantly increased in class I including HDAC1 and HDAC3, in class II including HADC6, HDAC7, HDAC9 and HDAC10, and in class III including SIRT1 and SIRT6; (2) higher expression of HDAC isoenzyme levels was found in ZAP-70+ compared to ZAP-70- patients, and CD44 expression levels were correlated with HDAC isoenzyme expression levels in the majority of HDAC classes. CONCLUSIONS: These results suggest: (1) in CLL, elevated HDAC isoenzyme activity is not restricted to one class, and therefore, HDACi therapy may need to be directed to more than one specific class of HDAC; (2) higher HDAC expression activity may indicate a poor prognosis and more advanced disease stage (through indirect evidence), since higher values were found in patients with ZAP-70+ and higher CD44 expression levels. PMID- 22237052 TI - Skin burns after laser exposure: histological analysis and predictive simulation. AB - Thermal effects of laser irradiation on skin are investigated in this paper. The main purpose is to determine the damage level induced by a laser exposure. Potential burns induced by two lasers (wavelength 808nm and 1940nm) are studied and animal experimentations are performed. Several exposure durations and laser powers are tested. Based on previous works, a mathematical model dedicated to temperature prediction is proposed and finite-element method is implemented. This numerical predictive tool based on the bioheat equation takes into account heat losses due to the convection on skin surface, blood circulatory and also evaporation. Thermal behavior of each skin layer is also described considering distinct thermal and optical properties. Since the mathematical model is able to estimate damage levels, histological analyses were also carried through. It is confirmed that the mathematical model is an efficient predictive tool for estimation of damage caused by lasers and that thermal effects sharply depend on laser wavelength. PMID- 22237053 TI - Evaluation of wound healing activities of kefir products. AB - Kefirs are natural probiotic compounds with antibacterial and anti-inflammatory properties which were tested in experimental burn injury. Kefir gels were prepared from an extract of continuously cultured kefir grains in MRS Broth medium for 24, 48 and 96h. Similar burn injuries were made on dorsal skin surface of 56 rats. After 24h the wounds were infected with Pseudomonas aeruginosa. The infected rats were divided in to 7 groups of 8 rats each. The base gel, silver sulfadiazine ointment, kefir 24h gel, kefir 48h gel, kefir 96h gel and kefir grains 96h gel were applied twice a day. Burn wound area was measured at baseline, one and two weeks. After two weeks the animals in all groups were sacrificed and whole skin wound areas were removed and percentage of epithelization, scar formation, inflammation and angiogenesis were evaluated. Results indicated that at the end of the 2nd week the percentage of wound size were lowest in order of kefir 96h gelA) and vitamin B-12 in Europe and West Africa. AB - BACKGROUND: Genomewide association studies have shown a relation between plasma vitamin B-12 concentration and the 461G->A polymorphism of fucosyltransferase 2 (FUT2), a gene associated with susceptibility to Helicobacter pylori infection. OBJECTIVE: We evaluated in 2 populations the association of FUT2 461 G->A polymorphism with vitamin B-12 and related metabolic markers and investigated whether the influence of FUT2 on H. pylori serology is part of the mechanisms that underlie these associations. DESIGN: The study included 1282 ambulatory subjects from Europe and West Africa. Blood concentrations of vitamin B-12, folate, homocysteine, and methylmalonic acid were measured. Genotyping was performed by real-time polymerase chain reaction. H. pylori serology testing was performed by using ELISA. RESULTS: In univariate analysis, FUT2 461 A/A genotype was associated with higher plasma vitamin B-12 concentration in the total population (P = 0.0007) as well as in Europe (P = 0.0009) and in West Africa (P = 0.0015). Positivity for H. pylori serology was higher in West Africa (P < 0.0001) and was not associated with low plasma vitamin B-12. The prevalence of H. pylori positive patients did not differ among FUT2 461 G->A genotypes (P = 0.2068). In multivariate analysis, FUT2 461 G->A genotype (P = 0.0008), but not positive H. pylori serology, was an independent predictor of plasma vitamin B-12 concentration. CONCLUSION: This study confirms the influence of FUT2 461 G->A polymorphism on plasma vitamin B-12 concentration and showed no influence of H. pylori serologic status on this association in ambulatory subjects from Europe and West Africa. PMID- 22237058 TI - Cesarean section and risk of obesity in childhood, adolescence, and early adulthood: evidence from 3 Brazilian birth cohorts. AB - BACKGROUND: The number of cesarean sections (CSs) is increasing in many countries, and there are concerns about their short- and long-term effects. A recent Brazilian study showed a 58% higher prevalence of obesity in young adults born by CS than in young adults born vaginally. Because CS-born individuals do not make contact at birth with maternal vaginal and intestinal bacteria, the authors proposed that this could lead to long-term changes in the gut microbiota that could contribute to obesity. OBJECTIVE: We assessed whether CS births lead to increased obesity during childhood, adolescence, and early adulthood in 3 birth cohorts. DESIGN: We analyzed data from 3 birth-cohort studies started in 1982, 1993, and 2004 in Southern Brazil. Subjects were assessed at different ages until 23 y of age. Poisson regression was used to estimate prevalence ratios with adjustment for <=15 socioeconomic, demographic, maternal, anthropometric, and behavioral covariates. RESULTS: In the crude analyses, subjects born by CS had ~50% higher prevalence of obesity at 4, 11, and 15 y of age but not at 23 y of age. After adjustment for covariates, prevalence ratios were markedly reduced and no longer significant for men or women. The only exception was an association for 4-y-old boys in the 1993 cohort, which was not observed in the other 2 cohorts or for girls. CONCLUSION: In these 3 birth cohorts, CSs do not seem to lead to an important increased risk of obesity during childhood, adolescence, or early adulthood. PMID- 22237059 TI - Exclusive breastfeeding duration and cardiorespiratory fitness in children and adolescents. AB - BACKGROUND: Breastfeeding has been associated with a protective effect against cardiovascular disease. Higher cardiorespiratory fitness during childhood is associated with healthier cardiovascular profile later in life. OBJECTIVES: The objective was to examine the association of exclusive breastfeeding duration with fitness in children and adolescents and to test the role of body composition and sociodemographic factors in this relation. DESIGN: At the time of the study, exclusive breastfeeding duration was reported by mothers and grouped into 4 categories: exclusively formula fed or breastfed for <3, 3-6, or >6 mo. Fitness was determined by a maximal cycle-ergometer test in 1025 children (aged 9.5 +/- 0.4 y) and in 971 adolescents (aged 15.5 +/- 0.5 y) from Estonia and Sweden. RESULTS: Longer duration of breastfeeding was associated with higher fitness regardless of confounders [+5.1% L/min; country, sex, age, pubertal status, and BMI (adjusted P < 0.001) or fat mass and fat-free mass (FFM) (+3.3%; adjusted P < 0.001)]. Further adjustment for birth weight, physical activity, and maternal educational level did not change the results (P = 0.001). The results were consistent in children and adolescents with low (P < 0.001) or high (P = 0.013) FFM, in nonoverweight (P < 0.001) or overweight (P = 0.002) children and adolescents, in offspring of nonoverweight (P < 0.001) or overweight (P = 0.003) mothers, in mothers with a low (P = 0.004) or high (P < 0.001) educational level, and in participants born within upper (P = 0.001), middle (P = 0.017), or lower (P = 0.007) tertiles of birth weight. CONCLUSIONS: Longer exclusive breastfeeding has a beneficial effect on cardiorespiratory fitness in children and adolescents. Because early infant-feeding patterns are potentially modifiable, a better understanding of the possible programming effect of exclusive breastfeeding on cardiorespiratory fitness is of public health interest. PMID- 22237060 TI - Caffeinated beverage intake and reproductive hormones among premenopausal women in the BioCycle Study. AB - BACKGROUND: Caffeinated beverages are widely consumed among women of reproductive age, but their association with reproductive hormones, and whether race modifies any such associations, is not well understood. OBJECTIVE: We assessed the relation between caffeine and caffeinated beverage intake and reproductive hormones in healthy premenopausal women and evaluated the potential effect modification by race. DESIGN: Participants (n = 259) were followed for up to 2 menstrual cycles and provided fasting blood specimens for hormonal assessment at up to 8 visits per cycle and four 24-h dietary recalls per cycle. Weighted linear mixed models and nonlinear mixed models with harmonic terms were used to estimate associations between caffeine and hormone concentrations, adjusted for age, adiposity, physical activity, energy and alcohol intakes, and perceived stress. On the basis of a priori assumptions, an interaction between race and caffeine was tested, and stratified results are presented. RESULTS: Caffeine intake >=200 mg/d was inversely associated with free estradiol concentrations among white women (beta = -0.15; 95% CI: -0.26, -0.05) and positively associated among Asian women (beta = 0.61; 95% CI: 0.31, 0.92). Caffeinated soda intake and green tea intake >=1 cup/d (1 cup = 240 mL) were positively associated with free estradiol concentrations among all races: beta = 0.14 (95% CI: 0.06, 0.22) and beta = 0.26 (95% CI: 0.07, 0.45), respectively. CONCLUSIONS: Moderate consumption of caffeine was associated with reduced estradiol concentrations among white women, whereas caffeinated soda and green tea intakes were associated with increased estradiol concentrations among all races. Further research is warranted on the association between caffeine and caffeinated beverages and reproductive hormones and whether these relations differ by race. PMID- 22237062 TI - Food consumption and advanced beta cell autoimmunity in young children with HLA conferred susceptibility to type 1 diabetes: a nested case-control design. AB - BACKGROUND: Evidence for the role of food consumption during childhood in the development of beta cell autoimmunity is scarce and fragmentary. OBJECTIVE: We set out to study the associations of longitudinal food consumption in children with the development of advanced beta cell autoimmunity. DESIGN: Children with advanced beta cell autoimmunity (n = 232) (ie, with repeated positivity for antibodies against islet cells) together with positivity for at least one of the other 3 antibodies analyzed or clinical type 1 diabetes were identified from a prospective birth cohort of 6069 infants with HLA-DQB1-conferred susceptibility to type 1 diabetes who were born in 1996-2004, with the longest follow-up to the age of 11 y. Repeated 3-d food records were completed by the families and daycare personnel. Diabetes-associated autoantibodies and diets were measured at 3-12-mo intervals. Four control subjects, who were matched for birth date, sex, area, and genetic risk, were randomly selected for each case. RESULTS: In the main food groups, only intakes of cow-milk products (OR: 1.05; 95% CI: 1.00, 1.10) and fruit and berry juices (OR: 1.09; 95% CI: 1.02, 1.12) were significantly, although marginally, associated with advanced beta cell autoimmunity. The consumption of fresh milk products and cow milk-based infant formulas was related to the endpoint, whereas no evidence was shown for consumption of sour milk products and cheese. The intake of fat from all milk products and protein from fresh milk products was associated with risk of advanced beta cell autoimmunity. CONCLUSION: Intakes of cow milk and fruit and berry juices could be related to the development of advanced beta cell autoimmunity. This trial was registered at clinicaltrials.gov as number NCT00223613. PMID- 22237061 TI - Efficacy and safety of a short course of very-high-dose cholecalciferol in hemodialysis. AB - BACKGROUND: Vitamin D deficiency is highly prevalent among hemodialysis patients, but little data exist in support of an optimal repletion regimen. OBJECTIVE: The objective was to ascertain the efficacy of weekly very-high-dose cholecalciferol (vitamin D(3)) in correcting vitamin D insufficiency and deficiency in patients with stage 5D chronic kidney disease. DESIGN: We conducted a prospective, double blind, randomized controlled pilot study that compared placebo with very high doses of oral cholecalciferol for 3 wk (200,000 IU/wk) in hemodialysis patients. We examined the rate of correction of vitamin D insufficiency or deficiency and the effect of treatment on markers of mineral metabolism and routine laboratory variables. RESULTS: Twenty-seven subjects received placebo, and 25 received cholecalciferol. The majority (94%) of subjects had serum 25-hydroxyvitamin D [25(OH)D] concentrations <30 ng/mL. Study groups were similar with respect to baseline clinical characteristics, with the exception of hemoglobin concentrations, which were lower in the cholecalciferol-treated group (P < 0.04). At follow-up, 90.5% of subjects treated with cholecalciferol achieved serum 25(OH)D concentrations >=30 ng/mL in contrast to 13.6% of the placebo group. There were no significant changes in serum calcium, phosphate, or intact parathyroid hormone during the study. CONCLUSION: Short-term, high-dose oral cholecalciferol treatment of vitamin D deficiency in hemodialysis patients appears to be effective and with no evidence of toxic effects. This trial was registered at clinicaltrials.gov as NCT00912782. PMID- 22237063 TI - Leptin reverses declines in satiation in weight-reduced obese humans. AB - BACKGROUND: Individuals who are weight-reduced or leptin deficient have a lower energy expenditure coupled with higher hunger and disinhibition and/or delayed satiation compared with never-weight-reduced control subjects. Because exogenous leptin inhibits feeding in congenitally leptin-deficient humans, reduced leptin signaling may reduce the expression of feeding inhibition in humans. OBJECTIVE: The objective was to test the hypothesis that reduced leptin signaling may reduce the expression of feeding inhibition (ie, blunt satiation) in humans by examining the effects of leptin repletion on feeding behavior after weight loss. DESIGN: Ten obese humans (4 men, 6 women) were studied as inpatients while they received a weight-maintaining liquid-formula diet. Satiation was studied by measuring intake and ratings of appetite-related dispositions 3 h after ingestion of 300 kcal of the liquid-formula diet. The subjects were studied at each of 3 time periods: 1) while they maintained their usual weight (Wt(initial)) and then after weight reduction and stabilization at 10% below initial weight and while they received 5 wk of either 2) twice-daily injections of placebo (Wt(-10%placebo)) or 3) "replacement doses" of leptin (Wt(-10%leptin)) in a single-blind crossover design with a 2-wk washout period between treatments. Energy expenditure was also measured at each study period. RESULTS: Both energy expenditure and visual analog scale ratings that reflect satiation were significantly lower at Wt(-10%placebo) than at Wt(initial) and Wt(-10%leptin). CONCLUSION: The results are consistent with the hypothesis that the absence of leptin signaling after weight loss may blunt the expression of feeding inhibition in humans. PMID- 22237066 TI - A long stretch. PMID- 22237064 TI - Weight-loss diets modify glucose-dependent insulinotropic polypeptide receptor rs2287019 genotype effects on changes in body weight, fasting glucose, and insulin resistance: the Preventing Overweight Using Novel Dietary Strategies trial. AB - BACKGROUND: Glucose-dependent insulinotropic polypeptide [also known as gastric inhibitory polypeptide (GIP)] and its receptor (GIPR) may link overnutrition to obesity, insulin resistance, and type 2 diabetes. A GIPR variant rs2287019 was recently associated with obesity and glucose metabolism. OBJECTIVE: We aimed to examine whether weight-loss diets that vary in fat content may modify the effect of this variant on changes in body weight, fasting glucose, and insulin resistance in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial. DESIGN: We genotyped the GIPR rs2287019 in 737 overweight adults who were randomly assigned to 1 of 4 weight-loss diets that varied in macronutrient contents for 2 y. We assessed the percentage changes in body weight, fasting glucose, and insulin resistance (HOMA-IR) across genotypes by the low-fat and high-fat diets. RESULTS: At 6 mo of diet intervention, the T allele of rs2287019 was associated with greater weight loss (beta +/- SE: -1.05 +/- 0.56%; P = 0.06) and greater decreases in fasting glucose (beta +/- SE: -2.33 +/- 0.86%; P = 0.006), fasting insulin (beta +/- SE: -8.76 +/- 4.13%; P = 0.03), and HOMA-IR (beta +/- SE: -10.52 +/- 4.39%; P = 0.01) in participants who were assigned to low-fat diets, whereas there was no significant genotype effect on changes in these traits in the group assigned to the high-fat diet (all P > 0.44; P interaction = 0.08, 0.04, 0.10, and 0.07, respectively). After correction for multiple tests (significant P = 0.008), the genotype effect on changes in fasting glucose remained significant. Sensitivity analysis in white participants showed that the interactions were more evident on changes in insulin and HOMA-IR (P interaction < 0.008). CONCLUSION: The T allele of GIPR rs2287019 is associated with greater improvement of glucose homeostasis in individuals who choose a low fat, high-carbohydrate, and high-fiber diet. The POUNDS LOST trial was registered at clinicaltrials.gov as NCT00072995. PMID- 22237067 TI - Get tough on nuclear safety. PMID- 22237068 TI - Whales for sale. PMID- 22237065 TI - Energy intake and leukocyte telomere length in young adults. AB - BACKGROUND: Dietary energy restriction in mammals, particularly at a young age, extends the life span. Leukocyte telomere length (LTL) is thought to be a bioindicator of aging in humans. High n-6 (omega-6) PUFA intake may accelerate LTL attrition. OBJECTIVE: We determined whether lower energy and higher PUFA intakes in young adulthood are associated with shorter LTL in cross-sectional and longitudinal analyses. DESIGN: In a longitudinal observational study (405 men, 204 women), diet was determined at baseline by a semiquantitative food-frequency questionnaire, and LTL was determined by Southern blots at mean ages of 30.1 y (baseline) and 43.2 y (follow-up). Spearman correlations and multivariable linear regression were used. RESULTS: Baseline energy intake was inversely associated with follow-up LTL in men (standardized beta = -0.171, P = 0.0005) but not in women (P = 0.039 for sex interaction). The difference in men between the highest and lowest quintiles of energy was 244 base pairs (bp) (95% CI: 59, 429 bp) and between extreme quintiles of LTL was 440 kcal (95% CI: 180, 700 kcal). Multivariable adjustment modestly attenuated the association (beta = -0.157, P = 0.002). Inverse associations, which were noted for all macronutrients, were strongest for the unsaturated fatty acids. In multivariable models including energy and the macronutrients (as percentage of energy), the significant inverse energy-LTL association (but not the PUFA-LTL association) persisted. The energy LTL association was restricted to never smokers (standardized beta = -0.259, P = 0.0008; P = 0.050 for the smoking * calorie interaction). CONCLUSIONS: The inverse calorie intake-LTL association is consistent with trial data showing beneficial effects of calorie restriction on aging biomarkers. Further exploration of energy intake and LTL dynamics in the young is needed. PMID- 22237069 TI - Don't censor life-saving science. PMID- 22237081 TI - France 'imagines the unimaginable'. PMID- 22237082 TI - Greek science on the brink. PMID- 22237083 TI - Disaster toll tallied. PMID- 22237084 TI - Rules tighten on use of antibiotics on farms. PMID- 22237085 TI - Radio array starts work. PMID- 22237088 TI - US translational-science centre gets under way. PMID- 22237089 TI - Stem-cell research: Never say die. PMID- 22237090 TI - Research ethics: Zero tolerance. PMID- 22237091 TI - Climate policy: Deadline 2015. PMID- 22237092 TI - Conservation science: A market approach to saving the whales. PMID- 22237097 TI - Scientific misconduct: Latest MMR 'dispute' is a straw man. PMID- 22237098 TI - Nuclear power: India should exploit renewable energy. PMID- 22237099 TI - Water management: Reduce urban flood vulnerability. PMID- 22237100 TI - Sequencing data: A genomic network to monitor Earth. PMID- 22237101 TI - Astrophysics: Progenitors of type Ia supernovae. PMID- 22237103 TI - Applied physics: Nanowire electronics comes of age. PMID- 22237104 TI - Earth science: Limits of the power law. PMID- 22237105 TI - Cognition: Your face looks familiar. PMID- 22237107 TI - An absence of ex-companion stars in the type Ia supernova remnant SNR 0509-67.5. AB - A type Ia supernova is thought to begin with the explosion of a white dwarf star. The explosion could be triggered by the merger of two white dwarfs (a 'double degenerate' origin), or by mass transfer from a companion star (the 'single degenerate' path). The identity of the progenitor is still controversial; for example, a recent argument against the single-degenerate origin has been widely rejected. One way to distinguish between the double- and single-degenerate progenitors is to look at the centre of a known type Ia supernova remnant to see whether any former companion star is present. A likely ex-companion star for the progenitor of the supernova observed by Tycho Brahe has been identified, but that claim is still controversial. Here we report that the central region of the supernova remnant SNR 0509-67.5 (the site of a type Ia supernova 400 +/- 50 years ago, based on its light echo) in the Large Magellanic Cloud contains no ex companion star to a visual magnitude limit of 26.9 (an absolute magnitude of M(V) = +8.4) within a region of radius 1.43 arcseconds. (This corresponds to the 3sigma maximum distance to which a companion could have been 'kicked' by the explosion.) This lack of any ex-companion star to deep limits rules out all published single-degenerate models for this supernova. The only remaining possibility is that the progenitor of this particular type Ia supernova was a double-degenerate system. PMID- 22237106 TI - The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. AB - Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL. PMID- 22237108 TI - One or more bound planets per Milky Way star from microlensing observations. AB - Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002 07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(?) and M(?) is Earth's mass). Cool Neptunes (10 30 M(?)) and super-Earths (5-10 M(?)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception. PMID- 22237109 TI - Modelling the rheology of MgO under Earth's mantle pressure, temperature and strain rates. AB - Plate tectonics, which shapes the surface of Earth, is the result of solid-state convection in Earth's mantle over billions of years. Simply driven by buoyancy forces, mantle convection is complicated by the nature of the convecting materials, which are not fluids but polycrystalline rocks. Crystalline materials can flow as the result of the motion of defects--point defects, dislocations, grain boundaries and so on. Reproducing in the laboratory the extreme deformation conditions of the mantle is extremely challenging. In particular, experimental strain rates are at least six orders of magnitude larger than in nature. Here we show that the rheology of MgO at the pressure, temperature and strain rates of the mantle is accessible by multiscale numerical modelling starting from first principles and with no adjustable parameters. Our results demonstrate that extremely low strain rates counteract the influence of pressure. In the mantle, MgO deforms in the athermal regime and this leads to a very weak phase. It is only in the lowermost lower mantle that the pressure effect could dominate and that, under the influence of lattice friction, a viscosity of the order of 10(21) 10(22) pascal seconds can be defined for MgO. PMID- 22237112 TI - Guidelines for field triage of injured patients: recommendations of the National Expert Panel on Field Triage, 2011. AB - In the United States, injury is the leading cause of death for persons aged 1-44 years. In 2008, approximately 30 million injuries were serious enough to require the injured person to visit a hospital emergency department (ED); 5.4 million (18%) of these injured patients were transported by Emergency Medical Services (EMS). On arrival at the scene of an injury, the EMS provider must determine the severity of injury, initiate management of the patient's injuries, and decide the most appropriate destination hospital for the individual patient. These destination decisions are made through a process known as "field triage," which involves an assessment not only of the physiology and anatomy of injury but also of the mechanism of the injury and special patient and system considerations. Since 1986, the American College of Surgeons Committee on Trauma (ACS-COT) has provided guidance for the field triage process through its "Field Triage Decision Scheme." This guidance was updated with each version of the decision scheme (published in 1986, 1990, 1993, and 1999). In 2005, CDC, with financial support from the National Highway Traffic Safety Administration, collaborated with ACS COT to convene the initial meetings of the National Expert Panel on Field Triage (the Panel) to revise the decision scheme; the revised version was published in 2006 by ACS-COT (American College of Surgeons. Resources for the optimal care of the injured patient: 2006. Chicago, IL: American College of Surgeons; 2006). In 2009, CDC published a detailed description of the scientific rationale for revising the field triage criteria (CDC. Guidelines for field triage of injured patients: recommendations of the National Expert Panel on Field Triage. MMWR 2009;58[No. RR-1]). In 2011, CDC reconvened the Panel to review the 2006 Guidelines in the context of recently published literature, assess the experiences of states and local communities working to implement the Guidelines, and recommend any needed changes or modifications to the Guidelines. This report describes the dissemination and impact of the 2006 Guidelines; outlines the methodology used by the Panel for its 2011 review; explains the revisions and modifications to the physiologic, anatomic, mechanism-of-injury, and special considerations criteria; updates the schematic of the 2006 Guidelines; and provides the rationale used by the Panel for these changes. This report is intended to help prehospital-care providers in their daily duties recognize individual injured patients who are most likely to benefit from specialized trauma center resources and is not intended as a mass casualty or disaster triage tool. The Panel anticipates a review of these Guidelines approximately every 5 years. PMID- 22237114 TI - Atopic dermatitis: impact on quality of life and patients' attitudes toward its management. AB - This work studies atopic dermatitis in the following terms: impact on patients' life; patients' satisfaction and attitudes toward topical pharmacological treatment and medical recommendations (regarding hygienic and preventive strategies) and patients' and dermatologists' impressions of severity at the moment of consultation. To this end, an epidemiological, multicentre, cross sectional study was carried out. In total, 191 dermatologists collected data from 322 patients (163 children, 159 adults). Poor agreement between specialists' and patients' criteria was found and patients with higher severity of affectation showed higher impacts on sleep/rest, emotional and school/ professional fulfillment (p<0.001). Moreover, reported compliance with pharmacological treatment and medical recommendations was high but patients' satisfaction with these recommendations was lower than with respect to pharmacological treatment. These results highlight that although reported compliance was high, there were still non-compliance attitudes and concerns about treatments that should be answered. Finally, a significant impact on patients' life was confirmed. PMID- 22237115 TI - Diabetes, insulin use, and non-Hodgkin lymphoma mortality in Taiwan. AB - The objective was to evaluate non-Hodgkin lymphoma (NHL) mortality trends and mortality rate ratios between diabetes patients and the general population, and to study NHL risk factors among diabetes patients in Taiwan. A cohort of 80 397 patients with type 2 diabetes mellitus older than 45 years was recruited in 1995 1998 and followed up until 2006. Age-standardized NHL mortality in 1995-2006 was calculated. Non-Hodgkin lymphoma risk factors in diabetes patients were evaluated using Cox regression. Age-standardized NHL mortality trend was steady. Eighty-two male and 69 female diabetes patients died of NHL (crude mortality rates, 35.1 and 23.0 per 100 000 person-years, respectively; corresponding overall mortality rate ratios comparing diabetes patients to the general population, 2.06 and 2.14). The mortality rate ratios were 1.47, 2.33, and 2.78 for men aged at least 65, 55 to 64, and 45 to 54 years, respectively; the corresponding ratios for women were 1.48, 2.22, and 2.79. Age and male sex were significant risk factors, whereas insulin use, diabetes duration, smoking, body mass index, and area of residence were not. Diabetes duration became a significant factor after excluding patients who died of NHL within 5 years of diabetes diagnosis. Patients with diabetes have a higher risk of mortality from NHL, but insulin use is not associated with NHL mortality. Future studies are needed to fully elucidate any association between increased mortality rate ratio and younger age as well as the lack of association between NHL and insulin use demonstrated herein. PMID- 22237116 TI - [Phase II trial of improved regimen with gemcitabine in patients with advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Gemcitabine-platinum-combined with chemotherapy is the most common treatment for advanced non-small cell lung cancer (NSCLC). Gemcitabine is administered once a week in a general three-week schedule. In the present study, gemcitabine is administered on d1 and d5 to improve compliance, and the efficacy and safety of the improved regimen is evaluated in untreated patients with advanced NSCLC. METHODS: A total of 83 patients were enrolled between October 2007 and October 2009. In each cycle, gemcitabine was administered at a dose of 1,000 mg/m2-1,250 mg/m2 via a 30 min intravenous infusion on d1 and d5 followed by cisplatin at a dose of 75 mg/m2 or carboplatin (AUC=5) on d1 every three weeks. At least two cycles of chemotherapy were completed in each case, and clinical response and toxicity of the regimen were observed. RESULTS: The objective response rate was 37.3%. The median progression free survival and overall survival time were 6.1 months and 15.0 months, respectively. The one-year and two-year survival rates were 57.8% and 16.2%, respectively. Myelosuppression and gastrointestinal responses were the main toxicities. The incidence of grade 3/4 of leucopenia, hypohemia, and thrombocytopenia were 26.5%, 10.8% and 7.2%, respectively. A total of 27.5% of the patients in the cisplatin group had grade 3/4 gastrointestinal responses. Treatment related deaths were not observed in this study. CONCLUSION: The regimen is active and well-tolerated in untreated patients with advanced NSCLC. Further randomized controlled studies are necessary. PMID- 22237117 TI - [Evaluation of efficacy and safety of bevacizumab combined with chemotherapy for Chinese patients with advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: The current study reported the result of bevacizumab treatment administered to 25 Chinese patients with advanced non-small cell lung cancer (NSCLC) who were treated at the Peking Union Medical College Hospital as a part of the SAiL (MO19390) trial. This trial is an open, international multicenter, single-arm clinical study that assesses the safety and efficacy of first-line bevacizumab-based therapy in advanced NSCLC. METHODS: Twenty-five Chinese patients with advanced non-squamous NSCLC received bevacizumab (15 mg/kg) combined with chemotherapy (carboplatin plus paclitaxel) treatment from August 2007 to February 2008. Adverse effects (AEs), objective response rate (ORR), median time to progression (TTP), and overall survival (OS) were measured. RESULTS: AEs were generally mild and reversible. The most frequent AEs were alopecia, peripheral neuropathy, rash, proteinuria, nausea/vomitting, fatigue, myalgia, bleeding, and hypertension. The partial remission and stable disease rates were 68% and 28%, respectively. The median TTP and OS of all patients were 11.2 and 19.3 months, respectively. CONCLUSION: Bevacizumab combined with carboplatin-based chemotherapy may be well tolerated and beneficial for Chinese patients with non-squamous NSCLC. PMID- 22237118 TI - [Evaluation of serum cytokines in small cell lung cancer and its clinical significance]. AB - BACKGROUND AND OBJECTIVE: It has been proven that serum cytokines could be changed in the early stage of patients with small cell lung cancer (SCLC). The current research investigates the different changes of cytockines and searches for potential biomarkers to improve the situation of the early diagnosis of SCLC. METHODS: The differential expression cytokines were detected using Reybiotech G6/G7 analysis of microarrays in the serum of 4 SCLC patients, 4 normal controls, and 4 phlegmonosis controls. The differential cytokines were confirmed by enzyme linked immunosorbentassay (ELISA) in 197 SCLC patients, 180 normal controls, and 97 phlegmonosis controls. RESULTS: The levels of the 4 most valuable biomarkers in SCLC, including Leptin, MSP-alpha, uPAR, and MIP-1beta, were significantly higher than that in the other groups with microaaray screening (P<0.05). The ELISA results showed that the uPAR are much higher in SCLC patients than that in the controls, in which the diagnostic sensitivity and specificity were 52.93% and 83.36%, respectively. The Leptin level was significantly higher in SCLC patients who do not have obvious body weight lost, whereas no difference were found in the SCLC who have obvious body weight lost compared with control groups. The diagnostic sensitivity and specificity of Leptin are 50.11% and 86.77%. The MSP alpha and MIP-1beta level have no significant difference among the three groups. CONCLUSION: The uPAR elevated level is significant in indicating SCLC diagnoses. The Leptin may be associated with SCLC in patients who do not have a change in weight. PMID- 22237119 TI - [Expression and its clinical significance of SLC22A18 in non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: It has been proven that multidrug resistance (MDR) is the main cause of chemotherapy failure in lung cancer. Research on emergence mechanisms of MDR has great clinical significance in improving the curative efficiency of lung cancer chemotherapy. Proteins encoded by the SLC22A18 gene, which is similar to the transmembrane transporter, may influence the sensitivity of chemotherapeutics as well as the metabolism and growth of cells. In addition, these proteins probably have some effect on the development of lung cancer MDR. The aim of the present study is to investigate the expression of SLC22A18 protein in non-small cell lung cancer (NSCLC) as well as in corresponding normal lung tissue. Furthermore, the relationship between SLC22A18 expression and pathological grade and TNM stage is analyzed. METHODS: The expression of SLC22A18 was detected by EnVinsion in 96 cases with NSCLC and in corresponding normal lung tissue. Statistical analysis was performed using SPSS 17.0 statistical software. RESULTS: SLC22A18 was mainly located in cell membrane and cytoplasm. The expression level of SLC22A18 in NSCLC was significantly higher than that in normal tissue (P<0.01). The positive rates in squamous cell lung cancer and lung adenocarcinoma were 68% and 78.2%, respectively (P<0.05). Moreover, the higher expression of SLC22A18 was associated with lower histological grade and later TNM stage (P<0.05). CONCLUSION: SLC22A18 protein is overexpressed in NSCLC, and its expression is correlated with pathological grade and TNM stage. These findings provide the experimental basis for investigating the role of tumor and chemoresistance. PMID- 22237120 TI - [Application of 18F-FDG PET/CT in pulmonary disease: a report of 419 cases]. AB - BACKGROUND AND OBJECTIVE: The application and the value of PET/CT in lung cancer are on the way to development. The aim of this study is to summarize the data from 419 patients with pulmonary tumor or tumor-like disease and to explore the appliance of PET/CT. METHODS: From Dec 2007 to Aug 2011, 594 patients with pulmonary tumor or tumor-like disease underwent PET/CT examination during the different course of treatment, which were treated by single surgery team from Peking University Cancer Hospital. Of these patients, 419 cases diagnosed pathologically were included into study. The clinicapathological and follow-up data were collected to analyze the value of PET/CT in diagnosis, TNM staging, therapy response evaluation and posttherapy monitoring. RESULTS: Four hundred and nineteen cases comprised of 63 benign and 356 malignant, of which, 338 were primary lung cancer, and 18 were metastases. The SUVmax cutoff was defined as 2.5 to differentiate the benign and malignant disease. PET/CT obtained the role of diagnosis with sensitivity as 85.0%, specificity as 52.4%, accuracy rate as 79.2%, positive predictive value as 89.2% and negative predictive value as 42.9%, respectively. Of 338 primary cases, 275 underwent PET/CT at initial diagnosis, in which, 46 (16.7%) distant metastasis were found, including 8 additional metastasis not found by conventional utilities. Six of 43 recurrences were found by PET/CT following conventional examination. In T staging, SUVmax is positively correlated with diameter of tumors (P<0.05). In N staging, 610 stations of lymph nodes were resected from 168 cases, with 37 stations predicted as positive by PET/CT and 102 stations pathologically proven positive, therefore, calculating the sensitivity as 36.3%, specificity as 93.9%, accuracy rate as 84.3%, positive predictive value as 54.4% and negative predictive value as 88.0%, respectively. Ten patients underwent PET/CT scan for chemotherapy response evaluation, with SUVmax changing following T downstaging. CONCLUSION: PET/CT is one optional method for diagnosis of pulmonary tumors. In TNM staging, PET/CT showed the superiority than conventional utilities in M staging, but possesses the high specificity but inferior sensitivity in N staging. Therefore, PET/CT should be used as routine examination for postoperation follow-up. Furthermore, PET/CT performed the outstanding role in chemotherapy response evaluation. PMID- 22237121 TI - [Effects of Feiji decoction for soothing the liver combined with psychotherapy on quality of life in primary lung cancer patients]. AB - BACKGROUND AND OBJECTIVE: Primary lung cancer is one of the most common malignant tumors. It causes great pain and mood disorders to patients, and significantly reduces their quality of life. The aim of the current study is to evaluate the effect of Feiji Decoction for soothing the liver combined with psychotherapy on quality of life (QoL) and physical status of patients with primary lung cancer. METHODS: A total of 118 patients with primary non-small cell lung cancer were randomly divided into two groups. The 57 patients in the combined therapy group were treated with Feiji Decoction for soothing the liver and psychotherapy combined with chemotherapy, whereas the 61 patients in the control group were treated with chemotherapy only. Both groups were observed for the two treatment courses. The European Organization for Research and Treatment of Cancer QoL Questionnaire LC-43 (EORTC QLQ-LC43) was used to assess the QoL of every patient in both groups before and after treatment scales. At the same time, physical status was assessed using the Karnofsky performance status (KPS) and East Cooperative Oncology Group performance status (ECOG). RESULTS: The scores of physiology function, role function, emotion function, cognize function, society function, and general health in the therapy group were higher than that of the control group. The therapy group also showed better QoL results than the contol group. Significant differences were observed between the two groups (P<0.01). Meanwhile, the scores of fatigue, vomit, pain, polypnea, insomnia, anorexia, constipation, and specific manifestation of lung cancer in the therapy group were obviously lower than that of the control group; more patients were observed to be relieved. Significant differences between the two groups were observed (P<0.01). The KPS and ECOG scores of the patients were observed to have improved and stabilized in the therapy group than that of the control group; the differences were statistically significant (P<0.01). CONCLUSION: Feiji Decoction for soothing the liver combined with psychotherapy can alleviate the clinical symptoms, elevate the physical status, and improve the QOL of patients with primary lung cancer. Thus, this therapy has a good clinical therapeutic effect. PMID- 22237122 TI - [Correlation between podoplanin-positive lymphatic microvessel density and CT characteristics of non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: It has been proven that ymphatic microvessel density (LMVD) was closely correlated with the lymphatic metastasis of non-small cell lung cancer (NSCLC). The aim of the present study is to explore the relationship between podoplanin-LMVD and multi-slice spiral computed tomography (MSCT) characteristics of NSCLC. METHODS: MSCT scanning was performed on 34 cases of NSCLC (squamous carcinoma, 15 cases; adenocarcinoma, 15 cases; and adenosquamous carcinoma, 4 cases) prior to operation. Clinical pathology results, including lymph node metastasis, were obtained. CT characteristics, such as shape of the edge, internal structure, and adjacent structures, were described. LMVD in the central and peripheral areas examined respectively using SP immunohistochemical technique were analyzed. RESULTS: Lymph node metastasis was found to be associated with LMVD in the peripheral areas. LMVD in the peripheral areas of the resected lesions, the MSCT findings of which included spinous process, pleural indentation, and carcinomatous lymphangitis, was higher than that of the lesions without these MSCT characteristics (P<0.05). CONCLUSION: MSCT findings of spinous process, pleural indentation, or carcinomatous lymphangitis of NSCLC may suggest a higher level of tumor lymphangiogenesis with a higher risk of lymph node metastasis. PMID- 22237123 TI - [Clinical experiences of bronchopleural fistula-related fatal hemoptysis after the resection of lung cancer: a report of 7 cases]. AB - BACKGROUND AND OBJECTIVE: Massive hemoptysis was a rare but severe postoperative complication of lung cancer. The aim of the present study is to investigate the mechanisms, risk factors, early symptoms, prevention, and treatment options for fatal hemoptysis. METHODS: From April 2007 to May 2011, 1,737 patients with lung cancer were surgically treated in the West China Hospital of Sichuan University. Twenty patients died during the perioperative period, seven of whom died of massive hemoptysis. These seven cases were analyzed, and their clinical data, as well as related literatures, were reviewed. RESULTS: Massive hemoptysis is the second cause of death after lung cancer surgery. Six patients died directly of massive hemoptysis. One patient underwent secondary surgery because of massive hemoptysis, but eventually died because of lung infection and respiratory failure. Early symptoms of hemorrhage were observed in four cases, and the overall incidence rate of massive hemoptysis was 0.4% (7/1,737). CONCLUSION: Bronchovascular fistula (BVF) caused by bronchopleural fistula (BPF) is the mechanism for massive hemoptysis. Diabetes is a high risk factor. Early diagnosis and surgical treatment of BPF or BVF can prevent the occurrence of death as a result of massive hemoptysis. PMID- 22237124 TI - [Clinical response to gefitinib retreatment of lung adenocarcinoma patients who benefited from an initial gefitinib therapy: a retrospective analysis]. AB - BACKGROUND AND OBJECTIVE: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has been widely used for the treatment of non-small cell lung cancer (NSCLC). It is most effective in women, as well as in patients who have never smoked, have pulmonary adenocarcinomas, or are of Asian origin. Several treatment options are available for NSCLC patients who responded to initial gefitinib therapy but demonstrated tumor progression, of which gefitinib readministration is the chosen therapeutic option. The present study aims to evaluate the efficacy and toxicity of gefitinib readministration. METHODS: The clinical data of 18 patients with NSCLC who had shown partial response (PR) or achieved a stable disease (SD) status after gefitinib administration and were retreated with gefitinib due to failure of the initial therapy were reviewed and retrospectively analyzed. RESULTS: Of the 18 patients studied, 1 (6%) showed partial remission (PR), 11 (61%) achieved SD, and 6 (33%) experienced disease progression. The disease control rate was 67%, and the median progression-free survival was 5.16 months (range, 1 to 24.8 months). The median overall survival from the start of the gefitinib therapy was 39.4 months (range, 15.38 to 52.44 months). Moreover, the median overall survival from the beginning of the 2nd therapy was 12.41 months (range, 3.98 to 38.24 months). Mild toxicity was observed with the 2nd gefitinib therapy. CONCLUSION: The results of the present study indicate that patients with NSCLC may still be expected to achieve prolonged survival through gefitinib readministration if they initially responded to gefitinib and underwent various subsequent treatments. PMID- 22237125 TI - [Effect of VATS wedge resection and mediastinal lymph node sampling in elderly patients with early peripheral lung cancer]. AB - BACKGROUND AND OBJECTIVE: The treatment for early-stage non-small cell lung cancer is primarily surgical. However, the optimal extent of mediastinal lymph node resection remains to be determined. The aim of the current study is to investigate the effect of a pulmonary wedge resection on aged patients with lung cancer. METHODS: A total of 15 lung cancer patients aged over 70 years were treated via video-assisted thoracoscopic surgery (VATS) wedge resection and mediastinal lymph node sampling from June 2004 to February 2008. Mediastinal lymph node sampling included stations 2R, 4R, 8 and 9 for the right-sided cancers and stations 5, 6, 8 and 9 for the left-sided cancers. RESULTS: VATS wedge resection and mediastinal lymph node sampling for aged patients with peripheral lung cancer are minimally invasive treatments with a short operative time and low postoperative morbidity. The 1-year and 3-year survival rates were 100% and 86.6%, respectively. CONCLUSION: VATS wedge resection and mediastinal lymph node sampling can be an alternative treatment for aged patients with early peripheral lung cancer. PMID- 22237126 TI - [Serum/plasma microRNAs as biomarkers for lung cancer]. PMID- 22237127 TI - [A case report of benign metastasizing lung leiomyoma]. PMID- 22237128 TI - [Rare solitary fibrous tumor of diaphragmatic pleura: a case report]. PMID- 22237129 TI - [Pourfour du petit syndrome caused by lung cancer and it's infrared thermal imaging: a case report]. PMID- 22237130 TI - A large exposure to Brucella melitensis in a diagnostic laboratory. AB - BACKGROUND: Brucella species are easily transmitted by aerosols and can be acquired in the laboratory. AIM: To report the management of a large exposure to Brucella melitensis that occurred over six days in a hospital diagnostic laboratory. METHODS: Fifty-one exposed staff were managed according to Centers for Disease Control and Prevention guidelines. A further 96 non-exposed laboratory staff were tested for seroprevalence. Testing was carried out using the Brucella sp. serum agglutination test. FINDINGS: Twenty-seven people had high risk exposure and 24 had low-risk exposure. High-risk staff were offered post exposure prophylaxis. Twelve (44.4%) agreed to this, of whom eight (66.7%) completed the course. Overall compliance with serological follow-up at baseline, 2, 4, 6 weeks and 8 months was 45.9%. Despite this poor compliance there were no clinical brucellosis cases and no seroconversion in the 47.1% of staff tested at 8 months. Brucella sp. seroprevalence among all staff tested was 3/147 (2.0%). CONCLUSION: Lack of experience with Brucella spp. and lack of policies for handling potentially hazardous organisms contributed to this prolonged exposure. As compliance with current recommendations may be poor, the optimum frequency of serological follow-up and target groups for prophylaxis should be reassessed. Laboratories in low- or non-endemic areas must prepare for potential isolation of Brucella spp. The impact of human brucellosis in Malaysia requires further study. PMID- 22237131 TI - Fine tuning of the redox function of Pseudomonas aeruginosa cytochrome c551 through structural properties of a polypeptide loop bearing an axial Met residue. AB - Pseudomonas aeruginosa cytochrome c(551) (PA) possesses a long polypeptide loop near its heme, and a unique hydrogen bond network among Ser52, axial Met61, and the heme 13-propionate side chain, i.e., Ser52 amide NH is hydrogen bonded to axial Met61 carbonyl CO, Met61 amide NH to Ser52 carbonyl CO, and Ser52 side chain OH to the heme 13-propionate side chain, contributes to stabilization of the structure of the loop [Y. Matsuura, T. Takano, R.E. Dickerson, J. Mol. Biol. 156 (1982) 389-409]. In this study, the structure and redox function of S52N and S52G mutants were characterized in order to elucidate the role of Ser52 in functional regulation of the protein. We found that the redox function of PA was hardly affected by an S52N mutation, but was slightly by an S52G one. The functional similarity between the wild-type protein and the S52N mutant demonstrated that Asn52 in the mutant plays a similar pivotal role in the formation of the unique hydrogen bond network that stabilizes the structure of the loop as Ser52 in the wild-type protein does. On the other hand, the functional alteration induced by the S52G mutation can be attributed to a structural change of the loop due to the lack of the hydrogen bond between the Gly52 and heme 13-propionate side chain in the mutant. Thus, this study demonstrated that the function of the protein can be tuned through the structural properties of the polypeptide loop near its heme. PMID- 22237132 TI - Determination of caprolactam and 6-aminocaproic acid in human urine using hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - A simple and rapid assay based on hydrophilic interaction liquid chromatography with tandem mass spectrometry has been first developed and validated for simultaneous determination of caprolactam (CA) and 6-aminocaproic acid (6-ANCA) in human urine using 8-aminocaprylic acid as internal standard. A 20MUL aliquot of urine was injected directly into the liquid chromatography tandem mass spectrometry (LC-MS-MS) system. The analytes were separated on a Phenomenex Luna HILIC column with gradient elution. Detection was performed on Triple Quadrupole LC-MS in positive ions multiple reaction monitoring mode using electrospray ionization. The calibration curves were linear (r(2)>=0.995) over the concentration range from 62.5 to 1250ng/mL for CA and 31.25 to 1000ng/mL for 6 ANCA. The detection limits of CA and 6-ANCA were 62.5 and 15.6ng/mL, respectively. The intra-day and inter-day precisions were within 8.7% and 9.9%, respectively. The intra-day and inter-day accuracy were between 5.3% and 3.5%, and between 6.1% and 6.6%, respectively. The method proved to be simple and time efficient, and was successfully applied to evaluate the kinetics of caprolactam in one unusual case of caprolactam poisoning. PMID- 22237133 TI - Determination of atomoxetine metabolites in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study. AB - 4-Hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (N-DAT) are major metabolites of atomoxetine, a potent and selective inhibitor of the presynaptic norepinephrine transporter that is used for the treatment of attention deficit/hyperactivity disorder. The pharmacological activity of 4-HAT is similar to that of atomoxetine. We have developed and validated a simple, rapid and sensitive liquid chromatography analytical method with tandem mass spectrometry (LC-MS/MS) for the determination of 4-HAT and N-DAT in human plasma. After liquid liquid extraction with methyl t-butyl ether, chromatographic separation of analytes was performed using a reversed-phase Luna C(18) column (2.0mm*100mm, 3MUm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.5) methanol (10:90, v/v) and quantified by MS/MS detection in ESI positive ion mode. The flow rate of the mobile phase was 250MUL/min and the retention times of 4 HAT, N-DAT and internal standard (IS, metoprolol) were 0.9, 1.0 and 1.0min, respectively. The calibration curves were linear over the range of 0.05-20ng/mL for 4-HAT and 0.1-20ng/mL for N-DAT. The lower limits of quantification, using 200MUL human plasma, were 0.05 and 0.1ng/mL for 4-HAT and N-DAT, respectively. The mean accuracy and precision for intra- and inter-day validation of 4-HAT and N-DAT were both within the acceptable limits. This LC-MS/MS method showed improved sensitivity for quantification of the two main metabolites of atomoxetine in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans. PMID- 22237134 TI - Benchmarking: applications to transfusion medicine. AB - Benchmarking is as a structured continuous collaborative process in which comparisons for selected indicators are used to identify factors that, when implemented, will improve transfusion practices. This study aimed to identify transfusion medicine studies reporting on benchmarking, summarize the benchmarking approaches used, and identify important considerations to move the concept of benchmarking forward in the field of transfusion medicine. A systematic review of published literature was performed to identify transfusion medicine-related studies that compared at least 2 separate institutions or regions with the intention of benchmarking focusing on 4 areas: blood utilization, safety, operational aspects, and blood donation. Forty-five studies were included: blood utilization (n = 35), safety (n = 5), operational aspects of transfusion medicine (n = 5), and blood donation (n = 0). Based on predefined criteria, 7 publications were classified as benchmarking, 2 as trending, and 36 as single-event studies. Three models of benchmarking are described: (1) a regional benchmarking program that collects and links relevant data from existing electronic sources, (2) a sentinel site model where data from a limited number of sites are collected, and (3) an institutional-initiated model where a site identifies indicators of interest and approaches other institutions. Benchmarking approaches are needed in the field of transfusion medicine. Major challenges include defining best practices and developing cost-effective methods of data collection. For those interested in initiating a benchmarking program, the sentinel site model may be most effective and sustainable as a starting point, although the regional model would be the ideal goal. PMID- 22237135 TI - Primary focal hyperhidrosis in a new family not linked to known loci. AB - BACKGROUND: Primary focal hyperhidrosis (PFH) is a disabling disorder. A first locus has been mapped in families with only palmar involvement, raising the question whether other unknown genes are responsible for more diffuse phenotypes. OBJECTIVE: We investigated a PFH family with a new phenotype, providing evidence that PFH is a clinically and genetically heterogeneous condition. METHODS: Family members were examined by autonomic tests, skin biopsy and genetic analysis, and followed up for 4 years. RESULTS: Age at onset was early, involving the axillae, palms and soles. Affected members had dysautonomic features also at onset. Cardiovascular dysautonomia was present in affected and unaffected members. Skin biopsy revealed impairment of intraepidermal nerve fibers and reduced innervation of sweat glands. There was no linkage to PFH and aquaporin-5 loci. CONCLUSION: This pedigree may serve as a basis for identifying a novel unmapped gene. Skin biopsy and cardiovascular autonomic tests provide important additions to the characterization of PFH. PMID- 22237136 TI - Radiofrequency catheter ablation for ventricular tachycardia. AB - The management of ventricular tachycardia (VT) has evolved considerably in recent times. The majority of patients with VT have structural heart disease and often implantable defibrillators. Implantable defibrillators can terminate ventricular arrhythmias and prevent sudden death but do not prevent these arrhythmias from occurring. Ventricular tachycardia may also occur in patients without structural heart disease and although these patients generally have a benign prognosis, the symptoms can be significant. Radiofrequency catheter ablation has a definite role as an alternative to anti-arrhythmic therapy in both groups of patients. This review outlines the indications, techniques and outcomes of catheter ablation in the management of patients with ventricular tachycardia. PMID- 22237138 TI - Clinical characteristics and outcome of apical ballooning syndrome in Auckland, New Zealand. AB - BACKGROUND: Apical ballooning syndrome (ABS) mimics myocardial infarction but is characterised by transient left ventricular (LV) dysfunction without significant coronary artery obstruction. METHODS: We prospectively identified 100 consecutive patients presenting in the Auckland region between March 2004 and July 2010 and obtained clinical, laboratory, electrocardiography, echocardiography, coronary angiography and long-term follow-up data. RESULTS: Chest pain or dyspnoea were the most common presenting symptom, 95% were women (mean age 65 +/- 11 years). An associated stressor was identified in two-thirds of patients, troponin was elevated in all patients, and one-third had ECG ST-elevation. There was a similar range of initial LV ejection fraction (EF), myocardial damage, LV recovery and prognosis in those with and without ST-elevation, and with and without identifiable stressors. One-quarter had a complicated in-hospital course. Lower admission LVEF, but not peak troponin level or ECG ST-elevation, was associated with a complicated in-hospital course. The mean follow-up was 3.0 +/- 1.7 years. One patient died in hospital. Four died late after discharge, all from non cardiac causes. Seven had recurrent ABS. CONCLUSION: In this large, prospective, New Zealand ABS cohort a quarter of patients had a complicated in-hospital course, but almost all recovered, recurrence was infrequent and long-term prognosis dependent on associated non-cardiac disease. PMID- 22237139 TI - Electromyographical analysis of lower extremity muscle activation during variations of the loaded step-up exercise. AB - The loaded step-up exercise allows strength and conditioning practitioners to incorporate a unilateral resistance for athletes while performing extension at the hip, knee, and plantar flexion at the ankle. This study evaluated the activation of the biceps femoris (BF), gluteus maximus (GMx), gluteus medius (GMe), rectus femoris, semitendinosus (ST), vastus lateralis, and vastus medialis during 4 variations of the step-up exercise to assess the specific muscle training stimulus of each exercise variation. The exercises included the step-up, crossover step-up, diagonal step-up, and lateral step-up. Fifteen women who regularly engaged in lower body resistance training performed the 4 exercises with 6 repetition maximum loads on a 45.72-cm (18-in.) plyometric box. Data were collected with a telemetered electromyography (EMG) system, and root mean square values were calculated for EMG data for eccentric and concentric phases. Results of a repeated-measures analysis of variance revealed a variety of differences in muscle activation between the exercises (p <= 0.05). The results indicated that the crossover step-up elicited the greatest concentric muscle activation for the GMe, whereas the step-up elicited greatest eccentric activation for the GMe and greatest activation for the GMx, BF, and ST in both concentric and eccentric phases. These findings can be used by practitioners to inform exercise selection to best target and maximally activate a variety of hip and thigh musculature. PMID- 22237140 TI - Longitudinal follow-up of biochemical markers of fatigue throughout a sporting season in young elite rugby players. AB - The aims of this study were to evaluate links between biochemical markers and competition and training conditions, overtraining questionnaire scores, and anthropometric characteristics of young elite rugby players and to identify evolving profiles of fatigue during the sports season. Twelve elite rugby players were included in the study. The tests were carried out every 15 days over the course of one sporting season from July until March, including the interseason. Changes in body composition parameters, blood biochemistry, and scores on various questionnaires were examined. The majority of the biochemical parameters and subjective variables showed significant variations over time. There were significant positive correlations between overtraining scores and alanine amino transferase (ALAT; r = 0.24, p < 0.05) and creatine phosphokinase (CK; r = 0.3, p < 0.01) levels. In addition, game time was significantly correlated with changes in CK (r = 0.46, p < 0.01), whereas difficult training sessions were significantly correlated with changes in both CK (r = 0.27, p < 0.05) and ALAT (r = 0.33, p < 0.01). We suggest that regular monitoring of these biochemical parameters may provide important information for the coach on the fatigue of rugby players and their perceived difficulty of training. PMID- 22237141 TI - Effects of different types of warm-up on swimming performance, reaction time, and dive distance. AB - The purpose of this study was to evaluate the effects of 3 types of warm-up (WU) on swimming performance, reaction time, and dive distance. In repeated-measures counterbalanced design, National Collegiate Athletic Association Division I swimmers (n = 16) used 3 WUs before performing 50-yd (45.7-m) freestyle swim trials. The WU consisted of (a) no WU, (b) short WU (50-yd at 40% of swimmers' maximal effort and 50-yd at 90%), and (c) regular WU (usual precompetition WU). The mean 50-yd time was significantly faster (p = 0.01) after the regular WU (24.95 +/- 1.53 seconds) when compared with that of the short WU (25.26 +/- 1.61 seconds). However, individual data indicated that 19% of the participants performed their best in the 50-yd category after short, 37% after no, and 44% after regular WU. Heart rate was significantly higher (p = 0.01) after regular WU (100 +/- 13 b.min(-1)) when compared with that of the no WU category (88 +/- 18 b.min(-1)). However, no significant differences among WUs were found for reaction time (p = 0.96), rating of perceived exertion post 50-yd time trial (p = 0.11), dive distance (p = 0.67), or stroke count (p = 0.23). In conclusion, the average regular WU was better than short or noWU to achieve the fastest mean time in the 50-yd freestyle; however, some individual performances were faster after WUs different from their regular approach. PMID- 22237142 TI - miR-34a expression, cell cycle arrest and cell death of malignant mesothelioma cells upon treatment with radiation, docetaxel or combination treatment. AB - OBJECTIVE: Malignant mesothelioma (MM) is a highly aggressive tumour related to asbestos exposure. Histopathologically, the tumour is classified as epithelial, sarcomatoid or biphasic. To date, MM is still an incurable disease. METHODS: To evaluate treatment strategies on MM cells, the effects of radiotherapy, docetaxel or a combination of both on MM cells derived from the sarcomatoid type ZL34 and the epithelial type M28K were investigated. The TP53 gene, micro-RNA expression, cell cycle distribution and cell death were assessed as indicators of treatment effects. RESULTS: Despite the normal TP53 gene sequences in these cell lines, radiation-induced miR-34a expression was detected only in the M28K cells. Increasing G0/G1 cell numbers were detected in irradiated M28K and ZL34 cells. There was more radiation-induced cell death in M28K compared to ZL34 cells. The highest degree of cell cycle arrest at G2 and cell death in both cell types was obtained in the presence of docetaxel. The combination of docetaxel and radiation did not show any additive effects on miR-34a expression, cell cycle arrest or cell death in either the M28K or ZL34 cells. CONCLUSION: Microtubule formation and other related functions by docetaxel might be the most suitable treatment modulation in both sarcomatoid and epithelial types of MM. PMID- 22237143 TI - Sentinel lymph node biopsy in breast cancer: a history and current clinical recommendations. AB - The advent of sentinel lymph node biopsy changed the way the surgical community treated breast cancer. It also reduced the post operative morbidity for millions of patients. Now that sentinel lymph node biopsy has become the mainstay of treatment, new clinical questions have arisen and continued research is being done to answer these questions. This report details a brief history of sentinel lymph node biopsy and how it was applied in the treatment a breast cancer. This report also includes a review of the current literature regarding unique clinical scenarios involving sentinel lymph node biopsy in breast cancer including the ACOSOG Z011 trial. PMID- 22237144 TI - Stimulation of neo-angiogenesis by combined use of irradiated and vascularized living bone graft for oncological reconstruction. AB - Reconstruction for large bone and osteochondral defects following musculoskeletal tumor excision remains challenging. Mega-prosthesis is clearly a useful reconstructive tool. Because the survival time of tumor patients has been increasing due to better treatment options, the aim of our group is to achieve complete biological reconstruction without using any artificial materials. With this approach, durability would not be a limitation. In the present study, we reviewed the biological reconstructive procedures currently available for large bone defects after tumor excision. Devitalized bone autograft is particularly well suited in the region where allografts are not readily available. However, the complication rate, such as infection and spontaneous bone resorption, was unexpectedly high due to non-viable graft. In an attempt to reduce these complications, we have used irradiated bone autograft in combination with free vascularized viable bone graft. In an experimental study, we demonstrated a neo vascularization effect of vascularized bone graft with devitalized bone autograft, i.e. to convert dead bone into living bone. Clinically, this technique is best indicated for reconstruction of intercalary bone defect, especially tibial shaft. Some degree of articular change occurs after irradiation and cannot be prevented, even with the combined use of vascularized bone graft. In our experience, secondary procedures such as surface replacement prosthesis are necessary to treat the osteoarthritis in such cases, even if the radiological finding is severe. The rationale for a combined vascularized and irradiated bone autograft is the cumulative advantage provided by the biological properties of the former with the mechanical endurance of the latter. PMID- 22237145 TI - Phase II trial of cetuximab in patients with metastatic or locally advanced soft tissue or bone sarcoma. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) tyrosine kinase is overexpressed in many sarcoma subtypes. In vitro studies suggest a role of the EGFR pathway in growth and differentiation in some sarcomas. We conducted a phase II trial of cetuximab, a monoclonal antibody to EGFR, in patients with advanced sarcomas. METHODS: Cetuximab was administered intravenously as a loading dose on 400 mg/m on day 1, cycle 1 and subsequently 250 mg/m on days 1, 8, 15, and 21 of a 28 day cycle. Using a Simon 2-stage design, 21 EGFR patients were to be accrued in the first stage, with an additional 11 patients if >3 patients met the primary endpoint of 4-month progression-free survival (PFS). An exploratory subgroup of EGFR patients was also included. RESULTS: Twenty-one and 15 evaluable patients enrolled in the EGFR and EGFR subgroup, respectively. One of 21 EGFR patients (4.8%) achieved 4-month PFS. Median PFS and overall survival were 1.7 months [95% confidence interval (CI), 1.6-1.8] and 7.7 months (95% CI, 4.2-10.7), respectively. Three of 15 EGFR patients (20%) achieved 4-month PFS. Median PFS and overall survival were 1.8 months (95% CI, 0.8-2.5) and 15.7 months (95% CI, 7.7-25.3), respectively. No responses were seen in either group. There was no correlation between clinical outcomes and expression of MAP-K, PTEN, and phospho EGFR. CONCLUSIONS: Cetuximab is not an active as a single agent in advanced sarcoma. Further study of anti-EGFR therapy in sarcoma should only be considered after identification of molecular abnormalities predictive of benefit. PMID- 22237146 TI - Can serum be used for analyzing the EGFR mutation status in patients with advanced non-small cell lung cancer? AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutations as prognostic or predictive marker in patients with non-small cell lung cancer (NSCLC) have been used widely. However, it may be difficult to get tumor tissue for analyzing the status of EGFR mutation status in large proportion of patients with advanced disease. PATIENTS AND METHODS: We obtained pairs of tumor and serum samples from 57 patients with advanced NSCLC, between March 2006 and January 2009. EGFR mutation status from tumor samples was analyzed by genomic polymerase chain reaction and direct sequence and EGFR mutation status from serum samples was determined by the peptide nucleic acid locked nucleic acid polymerase chain reaction clamp. RESULTS: EGFR mutations were detected in the serum samples of 11 patients and in the tumor samples of 12 patients. EGFR mutation status in the serum and tumor samples was consistent in 50 of the 57 pairs (87.7%). There was a high correlation between the mutations detected in serum sample and the mutations detected in the matched tumor sample (correlation index 0.62; P<0.001). Twenty two of 57 patients (38.5%) received EGFR-tyrosine kinase inhibitors as any line therapy. The response for EGFR-tyrosine kinase inhibitors was significantly associated with EGFR mutations in both tumor samples and serum samples (P<0.05). There was no significant differences in overall survival according to the status of EGFR mutations in both serum and tumor samples (P>0.05). CONCLUSIONS: Serum sample might be alternatively used in the difficult time of getting tumor tissue for analyzing the status of EGFR mutation status in patients with advanced NSCLC. PMID- 22237147 TI - A pragmatic contouring guideline for salivary gland structures in head and neck radiation oncology: the MOIST target. AB - OBJECTIVES: One of the main normal tissue toxicities in head and neck radiation oncology is xerostomia. In several studies, reduced radiation dose to the salivary glands has been shown to diminish the effects of gland dysfunction. However, no clear guidelines exist to define the anatomic location of the involved glands on cross-sectional imaging in a pragmatic manner. This study presents an anatomic, computed tomography (CT)-based definition of the major and minor salivary glands. METHODS: On the basis of information from normal structure anatomy, the location of major and minor salivary glands was identified and translated into a cross-sectional CT-based description of the salivary glands. RESULTS: The major salivary glands include the parotids and submandibular glands. The minor salivary glands are presented as a part of a surrogate structure (the Minor Oral Including Sublingual Salivary Tissue target), including the minor glands located in the oral mucosa of the tongue, hard and soft palate, buccal mucosa, and inner surface of the lips. CONCLUSIONS: Clinical implementation of CT based delineations of the salivary glands according to the proposed guideline should reduce interobserver variability. This may lead to an improved understanding of the relationship between radiation dose and volume and effects on salivary function. PMID- 22237148 TI - Supportive care considerations during concurrent chemoradiotherapy for pancreatic adenocarcinoma: lessons learned from clinical experience. AB - Concurrent chemotherapy and radiotherapy (chemoradiotherapy) for the management of pancreatic adenocarcinoma in either adjuvant or locally regional advanced settings produces predictable acute toxicities that are proportional in severity to the intensity and type of systemic therapy and to the parameters of radiotherapy. In addition, relevant to the adjuvant setting, surgery for pancreatic cancer often produces physiologic alterations that may impact a patient's ability to tolerate chemoradiotherapy. Failures to anticipate, monitor, and proactively manage the effects of surgery and toxicities of chemoradiotherapy can result in the need for unplanned treatment interruptions and/or inability to complete all planned therapy. In this review, complications of pancreatic cancer itself and of pancreatic resection as well as toxicities of chemoradiotherapy are delineated, and approaches to their management before, during, and after chemoradiotherapy are presented. Planning for the treatment of side effects before the anticancer therapy begins facilitates therapy administration and improves patient tolerance. PMID- 22237149 TI - When is elective pelvic lymph node irradiation indicated in definitive radiotherapy for localized prostate cancer? AB - The objective is to define the role of elective pelvic node irradiation (EPNI) in patients treated with definitive radiotherapy for clinically localized prostate cancer. Review of the pertinent literature revealed few prospective randomized trials that evaluated the efficacy of EPNI. Although EPNI may reduce the risk of regional recurrence, its impact on biochemical progression-free survival and overall survival is unclear. Depending on the extent of the radiotherapy fields, EPNI may result in a modest increase in acute toxicity and an even smaller increase in late toxicity. EPNI may reduce the risk of regional failure in patients with high-risk prostate cancer with a likelihood of lymph node positivity of >=15%. Although it may result in improved biochemical progression free survival, its impact is likely modest, at best. However, EPNI should be considered for patients with a high risk of regional disease. PMID- 22237150 TI - Known and novel post-transcriptional regulatory sequences are conserved across plant families. AB - The sequence elements that mediate post-transcriptional gene regulation often reside in the 5' and 3' untranslated regions (UTRs) of mRNAs. Using six different families of dicotyledonous plants, we developed a comparative transcriptomics pipeline for the identification and annotation of deeply conserved regulatory sequences in the 5' and 3' UTRs. Our approach was robust to confounding effects of poor UTR alignability and rampant paralogy in plants. In the 3' UTR, motifs resembling PUMILIO-binding sites form a prominent group of conserved motifs. Additionally, Expansins, one of the few plant mRNA families known to be localized to specific subcellular sites, possess a core conserved RCCCGC motif. In the 5' UTR, one major subset of motifs consists of purine-rich repeats. A distinct and substantial fraction possesses upstream AUG start codons. Half of the AUG containing motifs reveal hidden protein-coding potential in the 5' UTR, while the other half point to a peptide-independent function related to translation. Among the former, we added four novel peptides to the small catalog of conserved peptide uORFs. Among the latter, our case studies document patterns of uORF evolution that include gain and loss of uORFs, switches in uORF reading frame, and switches in uORF length and position. In summary, nearly three hundred post transcriptional elements show evidence of purifying selection across the eudicot branch of flowering plants, indicating a regulatory function spanning at least 70 million years. Some of these sequences have experimental precedent, but many are novel and encourage further exploration. PMID- 22237152 TI - Vascular endothelial function is not related to serum uric acid in healthy adults. AB - BACKGROUND: Some experimental evidence suggests that uric acid impairs endothelial function. It is controversial if high uric acid levels and impaired endothelial function are related in healthy adults. In addition, the effect of uric acid on endothelial cells (ECs) of humans is unexplored. METHODS: Data of 107 healthy adult volunteers were analyzed. The association between serum uric acid and endothelial-dependant dilation (EDD) and endothelial-independent dilation (EID) was evaluated by linear regression models. We also examined the relations between uric acid and systemic and cellular markers of inflammation and oxidative stress in all or subsets of participants. RESULTS: Uric acid levels and EDD were not related in unadjusted or adjusted models. There was a significant negative correlation between uric acid and EID in the pooled sample (r = -0.34, P = 0.005). This correlation remained significant after adjusting for demographics (P = 0.04) and was attenuated after adjusting for other cardiac risk factors (P = 0.12). Higher serum uric acid levels were found to correlate significantly with C reactive protein (CRP) (r = 0.31, P = 0.002). Serum uric acid levels were not associated with brachial artery EC nuclear factor-kappaB (NF-kappaB) p65 or NADPH oxidase p47(phox) expression or with nitrotyrosine staining, but were inversely associated with EC manganese superoxide dismutase (MnSOD) expression (r = -0.5, P = 0.01, n = 25). CONCLUSION: Elevated serum uric acid is not associated with endothelial dysfunction among healthy adults, but is inversely related to EID and EC MnSOD, and positively related to systemic inflammation. These findings may have implications for cardiovascular risk in healthy adults. PMID- 22237151 TI - Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. AB - T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation. PMID- 22237153 TI - Microalbuminuria is independently associated with deep or infratentorial brain microbleeds in hypertensive adults. AB - BACKGROUND: Brain microbleeds (BMBs) detected on gradient echo T2*-weighted magnetic resonance imaging (GE-MRI) may be pathophysiologically linked to ischemic cerebral small-vessel disease (SVD) and increased risk of future hemorrhagic stroke. Chronic kidney disease (CKD) has been associated with the presence of BMBs in stroke patients. However, the relationship between CKD markers and BMBs in stroke-free populations is unknown. METHODS: Two hundred and eighty-five hypertensive subjects (mean age 68.6 years) without neurological symptoms were enrolled from a hospital-based outpatient clinic and all participants underwent GE-MRI. We calculated urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Multivariate logistic regression analysis was used to evaluate the association between these kidney biomarkers and the presence and location of BMBs, controlling for age, sex, use of antihypertensive or antithrombotic drugs, and MRI findings. RESULTS: BMBs were observed in 48 (16.8%) patients. Median UACRs were significantly higher in patients with deep or infratentorial BMBs than in patients with pure lobar BMBs (54 vs. 17 mg/g creatinine, P = 0.04). No significant differences were found between eGFR levels and the location of BMBs. Microalbuminuria (UACR >30- <=300 mg/g creatinine), but not low eGFR level was significantly associated with higher prevalence of deep or infratentorial BMBs (odds ratio (OR): 3.16, 95% confidence interval (CI): 1.34 7.44, P = 0.009) even after adjustment for potential confounding factors. CONCLUSIONS: Microalbuminuria is closely associated with the prevalence of deep or infratentorial BMBs in hypertensive patients. Our findings provide new insights into the association between risk factors and the distribution of BMBs. PMID- 22237154 TI - Health literacy associated with blood pressure but not other cardiovascular disease risk factors among dialysis patients. AB - BACKGROUND: Limited health literacy is prevalent and has been linked to adverse patient outcomes. We examined the relationship between health literacy and cardiovascular disease (CVD) risk factors, including blood pressure (BP) parameters, lipids, waist-to-hip ratio (WHR), body mass index (BMI), and tobacco utilization among dialysis patients. METHODS: We conducted a cross-sectional study of 72 participants in a prospective cohort study of vascular calcification in newly initiated dialysis patients. Health literacy was assessed using the Short Test of Functional Health Literacy (S-TOFHLA) in Adults. The study population was dichotomized into those with and without adequate literacy. Linear and logistic regression analyses were used to predict continuous and dichotomous cardiovascular risk factor variables, respectively. RESULTS: Twenty-one percent had limited health literacy. Compared to limited health literacy, adequate health literacy was associated with lower BP parameters in multivariable analyses (systolic blood pressure (SBP): beta -16.8, s.e. 6.7, P = 0.01; diastolic blood pressure (DBP): beta -13.8, s.e. 4.1, P = 0.001; mean arterial pressure (MAP): beta -14.8, s.e. 4.6, P = 0.002). Health literacy was not a statistically significant predictor of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, WHR, BMI, or tobacco utilization. CONCLUSIONS: Limited health literacy is common in individuals on dialysis. Individuals with adequate health literacy skills had DBP readings that were on average 13.8 mm Hg lower and MAP that was 14.8 mm Hg lower than those with inadequate health literacy. Prospective studies to elucidate if improvements in health literacy skills will lead to improvement in BP control are needed. PMID- 22237155 TI - Increased expression of Na,K-ATPase and a selective increase in phosphorylation at Ser-11 in the cortex of the 2-kidney, 1-clip hypertensive rat. AB - BACKGROUND: The mechanism by which blood pressure increases during renovascular hypertension is incompletely understood. We, therefore, tested the hypothesis that in the 2-kidney, 1-clip (2K-1C) rat, in which hypertension develops due to increased angiotensin II (Ang II) levels, there is increased expression and phosphorylation of Na,K-ATPase at Ser-11 and Ser-18 in the kidney cortex. The rationale is Ang II is reported to directly stimulate Na,K-ATPase activity in proximal tubules, which reabsorb 2/3 of filtered sodium, via increased phosphorylation at Ser-11 and Ser-18 and the Na,K-ATPase drives sodium reabsorption. METHODS: Five-week-old Sprague-Dawley rats underwent unilateral or sham clipping of the right renal artery and placement of telemetry transmitters. Six weeks later blood pressure and plasma Ang II were measured and kidneys harvested. The amount of Na,K-ATPase, phosphorylation at Ser-11 and Ser-18, and the expression of beta-actin in each kidney cortex were measured by quantitative immunoblotting. RESULTS: Clipping significantly increased mean arterial pressure from 110 +/- 3 to 148 +/- 13 mm Hg, plasma Ang II, cortical Na,K-ATPase in the unclipped kidney of 2K-1C compared to sham-clipped rats, the total cortical Na,K ATPase in both kidneys compared to sham-clipped rats, and the extent to which the Na,K-ATPase was phosphorylated at Ser-11. Clipping did not significantly change phosphorylation at Ser-18, beta-actin, or the total protein in the cortexes of both kidneys. CONCLUSIONS: Thus, in the kidney cortex of rats with renovascular hypertension there is increased expression of Na,K-ATPase and a selective increase in its phosphorylation at Ser-11 that could increase the capacity to reabsorb sodium and water. PMID- 22237156 TI - Association of left ventricular mass with the AGTR1 A1166C polymorphism. AB - BACKGROUND: The A1166C polymorphism is located within the microRNA-155 binding site of the human angiotensin II (Ang II) type-1 receptor (AGTR1) gene. The C allele interferes with the base-pairing complementariness between AGTR1 mRNA and microRNA-155 and thereby increases AGTR1 protein expression in vitro. We hypothesized that left ventricular (LV) mass is associated with the AGTR1 A1166C polymorphism. METHODS: Among 708 individuals (mean age, 49.4 years; 51.8% women) randomly recruited in a white European population, we measured LV structure by two-dimensional guided M-mode echocardiography, the AGTR1 A1166C polymorphism and the 24-h urinary aldosterone. We applied a mixed model to assess phenotype genotype associations while adjusting for covariables and accounting for relatedness. RESULTS: The AA (49.1%), AC (42.8%), and CC (8.1%) genotypes were in Hardy-Weinberg equilibrium. Using a recessive model, CC homozygotes compared to A allele carriers showed significant increases (P < 0.021) in LV mass index (+5.78 +/- 2.25 g/m(2)), mean wall thickness (MWT) (+0.48 +/- 0.15 mm), interventricular septum (IVS) (+0.60 +/- 0.18 mm) and posterior wall thickness (PWT) (+0.34 +/- 0.15 mm), but lower 24-h urinary aldosterone excretion (geometric mean, 22.4 vs. 19.0 nmol; P = 0.050). Sensitivity analyses in 552 participants untreated for hypertension were confirmatory. CONCLUSIONS: LV mass index is associated with the AGTR1 A1166C polymorphism. Further research should clarify to what extent this association might be mediated via different expression of AGTR1 as modulated by microRNA-155. PMID- 22237157 TI - Body mass index, exercise capacity, and mortality risk in male veterans with hypertension. AB - BACKGROUND: Overweight and obesity are associated with increased risk of chronic diseases and mortality. Exercise capacity is inversely associated with mortality risk. However, little is known on the interaction between fitness, fatness, and mortality risk in hypertensive individuals. Thus, we assessed the interaction between exercise capacity, fatness, and all-cause mortality in hypertensive males. METHODS: A graded exercise test was performed in 4,183 hypertensive veterans (mean age +/- s.d.; 63.3 +/- 10.5 years) at the Veterans Affairs Medical Center, Washington, DC. We defined three body weight categories based on body mass index (BMI): normal weight (BMI <25); overweight (BMI 25-29.9); and obese (BMI >=30); and three fitness categories based on peak metabolic equivalents (METs) achieved: low-fit (<=5 METs); moderate-fit (5.1-7.5 MET); and high-fit (>7.5 METs). RESULTS: During a median follow-up period of 7.2 years, there were 1,000 deaths. The association between exercise capacity and mortality risk was strong, inverse, and graded. For each 1-MET increase in exercise capacity the adjusted risk was 20% for normal weight, 12% for overweight, and 25% for obese (P < 0.001). When compared to normal weight but unfit individuals, mortality risks were 60% lower in the overweight/high-fit and 78% lower in the obese/high-fit individuals (P < 0.001). CONCLUSIONS: Increased exercise capacity is associated with lower mortality risk in hypertensive males regardless of BMI. The risk for overweight and obese but fit individuals was significantly lower when compared to normal weight but unfit. These findings suggest that in older hypertensive men, it may be healthier to be fit regardless of standard BMI category than unfit and normal weight. PMID- 22237158 TI - Control of renin synthesis and secretion. AB - The aspartyl protease renin is the rate limiting activity of the renin angiotensin-aldosterone system (RAAS). Renin is synthesized as an enzymatically inactive proenzyme which is constitutively secreted from several tissues. Only renin-expressing cells in the kidney are capable of generating active renin from prorenin, which is stored in prominent vesicles and which is released into the circulation upon demand. The acute release of renin is controlled by cyclic adenosine monophosphate (cAMP) and by calcium signaling pathways, which in turn are activated by a number of systemic and local factors. Longer lasting challenges of renin secretion lead to changes in the number of renin-producing cells, which occur by a metaplastic transformation of renin cell precursors such as preglomerular vascular smooth muscle or extraglomerular mesangial cells. This review aims to briefly address the state of knowledge of these various aspects of renin synthesis and secretion and attempts to relate them to the in vivo situation, in particular in men. PMID- 22237162 TI - Effect of acidulated phosphate fluoride gel application time on enamel demineralization of deciduous and permanent teeth. AB - Although the effect of acidulated phosphate fluoride gel (APF gel) on caries reduction in permanent teeth is based on evidence, the relevance of the clinical application time is still under debate. Also, the effect of 4- versus 1-min application has not been evaluated in deciduous enamel. In a blind, crossover, in situ study of 14 days, 16 adult volunteers wore palatal appliances containing slabs of human permanent and deciduous enamel. At the beginning of each phase, the slabs were submitted to one of the following treatments: no APF application (negative control); APF gel (1.23% F) application for 1 or 4 min. Biofilm accumulation on the slab surface was allowed and the slabs were subjected eight times a day to 20% sucrose, simulating a high cariogenic challenge condition. On the 15th day of each phase, fluoride retained as CaF(2) and fluorapatite (FAp) was determined on the enamel of the slabs and demineralization was assessed by cross-sectional microhardness. Fluoride as CaF(2) and FAp, formed by APF gel application on the enamel slabs not subjected to the cariogenic challenge, was also determined. APF gel reduced demineralization in both enamel types (p < 0.05), but the difference between 1 and 4 min was not statistically significant (p > 0.05). CaF(2) and FAp formed and retained on deciduous and permanent enamel was significantly higher in APF gel groups (p < 0.05), but no significant difference was found between 1 and 4 min (p > 0.05). The findings suggest that 1 min of APF gel application provides a similar effect on inhibition of demineralization as 4 min, for both permanent and deciduous enamel. PMID- 22237159 TI - BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFbeta receptor to promote invasion. AB - Coronary vessel development depends on a subpopulation of epicardial cells that undergo epithelial to mesenchymal transformation (EMT) and invade the subepicardial space and myocardium. These cells form the smooth muscle of the vessels and fibroblasts, but the mechanisms that regulate these processes are poorly understood. Mice lacking the Type III Transforming Growth Factor beta Receptor (TGFbetaR3) die by E14.5 due to failed coronary vessel development accompanied by reduced epicardial cell invasion. BMP2 signals via TGFbetaR3 emphasizing the importance of determining the relative contributions of the canonical BMP signaling pathway and TGFbetaR3-dependent signaling to BMP2 responsiveness. Here we examined the role of TGFbetaR3 in BMP2 signaling in epicardial cells. Whereas TGFbeta induced loss of epithelial character and smooth muscle differentiation, BMP2 induced an ALK3-dependent loss of epithelial character and modestly inhibited TGFbeta-stimulated differentiation. Tgfbr3(-/-) cells respond to BMP2 indicating that TGFbetaR3 is not required. However, Tgfbr3( /-) cells show decreased invasion in response to BMP2 and overexpression of TGFbetaR3 in Tgfbr3(-/-) cells rescued invasion. Invasion was dependent on ALK5, ALK2, ALK3, and Smad4. Expression of TGFbetaR3 lacking the 3 C-terminal amino acids required to interact with the scaffolding protein GIPC (GAIP-interacting protein, C terminus) did not rescue. Knockdown of GIPC in Tgfbr3(+/+) or Tgfbr3( /-) cells rescued with TGFbetaR3 decreased BMP2-stimulated invasion confirming a requirement for TGFbetaR3/GIPC interaction. Our results reveal the relative roles of TGFbetaR3-dependent and TGFbetaR3-independent signaling in the actions of BMP2 on epicardial cell behavior and demonstrate the critical role of TGFbetaR3 in mediating BMP2-stimulated invasion. PMID- 22237163 TI - Gender identification in younger and older adults: use of spectral and temporal cues in noise-vocoded speech. AB - OBJECTIVE: The aim of this study was to investigate potential effects of age on the ability of normal-hearing (NH) adult listeners to utilize spectral and temporal cues when performing a voice gender identification task. DESIGN: Ten younger and 10 older NH adult listeners were measured on their ability to correctly identify the speaker gender of six different vowel tokens (H-/vowel/-D) when spoken by eight speakers (four male and four female). Spectral (number of channels) and temporal cues (low-pass cut-off frequency for temporal envelope extraction) were systematically manipulated using noiseband vocoding techniques; stimuli contained 1, 4, 8, 16, or 32 spectral channels, while the low-pass cut off frequency of the temporal envelope filter was 20, 50, 100, 200, or 400 Hz. Furthermore, the fundamental frequencies (F0s) of the vowel tokens were manipulated to create two conditions: "Expanded" (large range of F0 values) and "Compressed" (small range of F0 values). RESULTS: In general, younger listeners performed better than the older listeners but only when stimuli were spectrally degraded. For both the Expanded and Compressed conditions, the overall performance of the younger listeners was better than that of the older listeners, suggesting age-related deficits in both spectral and temporal processing. Furthermore, a significant interaction between age group and temporal envelope cues revealed that older listeners received less benefit from increasing temporal envelope information compared with the benefit observed among younger listeners. In particular, the performance of the younger NH group (collapsed across number of channels), but not the older NH group, improved as the temporal envelope cut off frequency was increased from 50 to 400 Hz. CONCLUSIONS: The results reported here support previous findings of senescent declines in perceiving spectrally reduced speech and temporal amplitude modulation processing. These results suggest that when F0 values are similar to one another, younger listeners can use temporal cues alone to glean voice-pitch information but older listeners exhibit a lessened ability to use such cues. Previous studies have demonstrated the importance of temporal envelope cues in periodicity perception (e.g., gender recognition) by cochlear implant listeners. The results of this study suggest that aging affects the use of such cues, and consequently gender recognition might be poorer among older cochlear implant recipients. PMID- 22237164 TI - Effects of age and hearing impairment on the ability to benefit from temporal and spectral modulation. AB - OBJECTIVES: At poor signal-to-noise ratios, speech understanding may depend on the ability to combine speech fragments that are distributed across time and frequency. The goal of this study was to determine the effects of development and hearing impairment on this ability. DESIGN: Listeners in the present study included adults and children with normal hearing and with hearing impairment. The children with normal hearing included a younger group (aged 4.6-6.9 yr, N = 10) and an older group (aged 7.3-11.1 yr, N = 11). The adults with normal hearing were aged 19 to 27 yr (N = 10). Adults (aged 19-54 yr, N = 9) and children (aged 7.2-10.7 yr, N = 8) with hearing impairment were also tested. The two groups with hearing impairment had comparable mild/moderate bilateral sensorineural hearing impairment. Masked speech reception thresholds for sentences were determined in a baseline condition of steady speech-shaped noise and in noise that was temporally modulated, spectrally modulated, or both temporally and spectrally modulated. RESULTS: The results of normal-hearing listeners indicated higher masked speech reception thresholds for children than adults in steady noise. Adults and children showed the same magnitude of masking release for spectral modulation. Adults showed more masking release than the younger children for temporal modulation and showed more masking release than both the younger and older children for combined temporal/spectral modulation. Comparing normal-hearing and hearing-impaired listeners, the hearing-impaired listeners had higher masked speech reception thresholds in the steady noise condition and reduced masking release in the modulated noise conditions. Neither the two-way interaction between age and hearing impairment nor the three-way interaction between age, hearing impairment, and masking configuration was significant. CONCLUSIONS: Although the reduced masking release for temporal modulation shown by the younger children with normal hearing could be a result of poor temporal resolution, it more likely reflects inefficient use of speech cues in temporal gaps or factors stemming from higher signal-to-noise ratios required by children in the baseline condition. The reduced masking release for combined temporal/spectral modulation demonstrated by both the younger and older children with normal hearing may indicate that children in the age range tested here have some difficulty in combining speech information that is distributed across temporal and spectral gaps. Hearing impairment was associated with higher thresholds and reduced masking release in all modulation conditions. Children with hearing impairment showed the poorest performance of any group, consistent with additive effects of hearing loss and development. PMID- 22237165 TI - Serotonin syndrome associated with MDPV use: a case report. AB - Serotonin syndrome is associated with use of certain street drugs, including methamphetamine, cocaine, and ecstasy. We describe a case of a woman who developed clinical findings consistent with serotonin syndrome after insufflation of 3,4-methylenedioxypyrovalerone (MDPV), a synthetic amphetamine. MDPV belongs to a group of substances called phenylethylamines, which are beta-ketone analogs of other drugs of abuse, such as amphetamines and 3,4 methylenedioxymethamphetamine. She also received fentanyl initially during her hospitalization, which has also been associated with serotonin syndrome. In addition to benzodiazepines and supportive care, she was treated with cyproheptadine for 8 days, with slow resolution of her symptoms. PMID- 22237166 TI - Ketamine-like effects after recreational use of methoxetamine. AB - Methoxetamine, the N-ethyl derivative of ketamine, is a novel recreational drug that is not at present subject to restrictive regulations in most countries. To our knowledge, no case of methoxetamine abuse has been published to date in the scientific literature, and the only sources of information are illegal drug users' Web discussion forums. We report the first case of analytically confirmed intravenous methoxetamine abuse in a 19-year-old man. Observed signs and symptoms such as tachycardia, hypertension, confusion, agitation, stupor, ataxia, mydriasis, and nystagmus were consistent with ketamine-induced adverse effects and resolved with symptomatic treatment. According to this case report, user Web reports, and the chemical structure, methoxetamine produces ketamine-like effects. Complete recovery can be expected with supportive care. PMID- 22237167 TI - Skin tags: a useful clinical sign for insulin resistance? PMID- 22237168 TI - Information flow, dynamical systems theory and the human brain: Comment on "Information flow dynamics in the brain" by M.I. Rabinovich et al. PMID- 22237169 TI - Consciousness: distinguishing two types of level and of causation: Comment on "Neuroontology, neurobiological naturalism, and consciousness: a challenge to scientific reduction and a solution" by Todd E. Feinberg. PMID- 22237170 TI - Value-added oil and animal feed production from corn-ethanol stillage using the oleaginous fungus Mucor circinelloides. AB - This study highlights the potential of oleaginous fungus, Mucor circinelloides in adsorbing/assimilating oil and nutrients in thin stillage (TS), and producing lipid and protein-rich fungal biomass. Fungal cultivation on TS for 2 days in a 6 L airlift bioreactor, resulted in a 92% increase in oil yield from TS, and 20 g/L of fungal biomass (dry) with a lipid content of 46% (g of oil per 100g dry biomass). Reduction in suspended solids and soluble chemical oxygen demand (SCOD) in TS were 95% and 89%, respectively. The polyunsaturated fatty acids in fungal oil were 52% of total lipids. Fungal cells grown on Yeast Malt (YM) broth had a higher concentration of gamma-linolenic acid (17 wt.%) than those grown on TS (1.4 wt.%). Supplementing TS with crude glycerol (10%, v/v) during the stationary growth phase led to a further 32% increase (from 46% to 61%) in cellular oil content. PMID- 22237171 TI - Nitrogen removal from opto-electronic wastewater using the simultaneous partial nitrification, anaerobic ammonium oxidation and denitrification (SNAD) process in sequencing batch reactor. AB - Simultaneous partial nitrification, anaerobic ammonium oxidation and denitrification (SNAD) system was applied to treat the opto-electronic industrial wastewater in a 2.5L sequencing batch reactor. The characteristics of wastewater were low C/N ratio (~ 0.2) with 100mg-COD/L and 567 mg NH(4)(+)-N/L. The experiment was carried out over 8 months in six different stages, where nitrogen loading rate was gradually increased from 16 g-N/m(3)d in stage I to 230 g N/m(3)d in stage VI. The COD and nitrogen removal rates by the SNAD system reached to 28 g COD/m(3)d and 197 g NH(4)(+)-N/m(3)d, respectively in stage VI. These results showed that the SNAD system is suitable to treat wastewater containing high nitrogen pollutants with low COD level. Presence of ammonium oxidizing bacteria and anammox bacteria were confirmed by polymerase chain reaction (PCR). PCR results also indicated that Candidatus Kuenenia stuttgartiensis may be one of the dominant species in the reactor. PMID- 22237172 TI - Enzymatic accessibility of fiber hemp is enhanced by enzymatic or chemical removal of pectin. AB - Pectinolytic enzymes, steam explosion and alkaline treatment were used to assess the role of pectin for the accessibility of hydrolytic enzymes in the enzymatic hydrolysis of biomass. Hemp (Cannabis sativa L.), a potential energy crop especially in boreal climate with a low need of fertilizers, was used in the study either as untreated or anaerobically preserved raw material. Addition of pectinases increased the hydrolysis yield by 26%, 54%, and 64% from the theoretical carbohydrates of untreated, acid, and alkali-preserved materials, respectively. Steam explosion and hot alkali treatment increased the conversion of the total carbohydrates by 78% and 60%, respectively, compared to the untreated hemp. Elevated separation of cells within the hemp stalk tissues and an increased surface area was revealed after hot alkali or pectinase treatments, contributing to the increased conversion to sugars by commercial enzymes. PMID- 22237173 TI - Impact of pyrolysis temperature and manure source on physicochemical characteristics of biochar. AB - While pyrolysis of livestock manures generates nutrient-rich biochars with potential agronomic uses, studies are needed to clarify biochar properties across manure varieties under similar controlled conditions. This paper reports selected physicochemical results for five manure-based biochars pyrolyzed at 350 and 700 degrees C: swine separated-solids; paved-feedlot manure; dairy manure; poultry litter; and turkey litter. Elemental and FTIR analyses of these alkaline biochars demonstrated variations and similarities in physicochemical characteristics. The FTIR spectra were similar for (1) turkey and poultry and (2) feedlot and dairy, but were distinct for swine biochars. Dairy biochars contained the greatest volatile matter, C, and energy content and lowest ash, N, and S contents. Swine biochars had the greatest P, N, and S contents alongside the lowest pH and EC values. Poultry litter biochars exhibited the greatest EC values. With the greatest ash contents, turkey litter biochars had the greatest biochar mass recoveries, whereas feedlot biochars demonstrated the lowest. PMID- 22237174 TI - Determination of effective moisture diffusivity and drying kinetics for poplar sawdust by thermogravimetric analysis under isothermal condition. AB - The current study presents a thermogravimetric method to determine the effective moisture diffusivity and drying kinetics of biomass. Drying experiments on poplar sawdust were performed at four temperatures (60, 70, 80, and 90 degrees C) by a thermogravimetric analyzer (TGA). The major assumption in experimentally determining effective diffusivity by Fick's diffusion equation is that drying is mass transfer limited and temperature remains isothermal during drying. The results indicated that TGA could well achieve these determining conditions. The drying process of sawdust mostly took place in the falling rate period. Midilli Kucuk model showed the best fit for all experimental data. The effective diffusivity values changed from 9.38 * 10(-10)m(2)/s to 1.38 * 10(-9)m(2)/s within the given temperature range, and the activation energy was calculated to be 12.3 kJ/mol. PMID- 22237175 TI - A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. AB - BACKGROUND: Cytomegalovirus reactivation occurs within 6 months in 60-70% of cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a cytomegalovirus therapeutic DNA vaccine compared with placebo. METHODS: In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor-recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were cytomegalovirus-seropositive, 18-65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor recipient HLA matching status, and donor's cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of cytomegalovirus-specific antiviral therapy in the per protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov, number NCT00285259. FINDINGS: We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0.145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups. INTERPRETATION: We show proof of concept for an immunotherapeutic cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial. FUNDING: Vical and US National Institute of Allergy and Infectious Diseases. PMID- 22237176 TI - Cytomegalovirus vaccine: light on the horizon. PMID- 22237177 TI - Characteristic genes in luminal subtype breast tumors with CD44+CD24-/low gene expression signature. AB - OBJECTIVE: Breast cancer cells with CD44+CD24-/low gene expression signature have been suggested to have stem cell-like tumor-initiating properties. The purpose of this study is to clarify the gene expression profiling of cells with CD44+CD24 /low gene expression signature in the luminal subtype. METHODS: Laser capture microdissection was used to select the isolation of cancer cells in 35 frozen tissues of breast cancer, and RNA extracted from these cells was examined by real time RT-PCR to quantify CD44 and CD24 expressions. Human stem cell RT(2) Profiler PCR Array was used for gene expression analysis in the groups of CD44+CD24-/low and CD44+CD24+ gene expression signature. RESULTS: Thirty-five tumors were divided into 3 groups. Group A was composed of the CD44+CD24-/low type, in which the ratio of CD44/CD24 was >10.0. Group B was composed of the CD44+CD24+ type, in which the ratio was >0.1 and <=10.0. In group C, composed of the CD44-/lowCD24+ type, the ratio was <0.1. The number of tumors in groups A, B, and C were 5, 28, and 2, respectively. Regarding the correlation of CD44/CD24 status with tumor characteristics, the tumors of group A were significantly associated with axillary lymph node metastasis compared with those of group B (p = 0.033). There were no significant differences in tumor size, nuclear grade, or HER2 status between the two groups. According to signaling pathways, the number of expression genes for the Notch pathway in group A was significantly greater than in group B (p = 0.028). Overexpressed genes for ALDH1 (p = 0.021) and SOX2 (p = 0.018) were noted in group A compared to group B. CONCLUSION: This study suggests that the Notch pathway may be an important signaling pathway in luminal subtype with CD44+CD24-/low gene expression signature. In addition, either ALDH1 or SOX2 may be a candidate marker for cancer stem cells in luminal subtype breast cancer. PMID- 22237179 TI - Golden jubilee of CPSP: achievements of JCPSP. PMID- 22237178 TI - Reliability analysis of a smartphone-aided measurement method for the Cobb angle of scoliosis. AB - STUDY DESIGN: A comparison between the smartphone-aided measurement method and the manual measurement method for the Cobb angle in adolescent idiopathic scoliosis. OBJECTIVE: To evaluate the reliability and measurement error for the smartphone-aided Cobb angle measurement method and compare its reliability and measurement error with those of the manual method. SUMMARY OF BACKGROUND DATA: The development of smartphones has provided new opportunities that integrate mobile technology into daily clinical practice. Smartphone applications can provide quick assistance in the diagnosis and treatment of disease. Cobbmeter is a smartphone application designed for the measurement of Cobb angle on Apple iPhone smartphones. There is no study on the reliability and measurement error of this smartphone-aided measurement method. METHODS: : Fifty-three posteroanterior radiographs of adolescent idiopathic scoliosis patients with thoracic scoliosis were used for the standard Cobb method of measurement (manual set) and the smartphone-aided Cobb method of measurement (smartphone set). Five spinal surgeons measured the Cobb angle with the use of both the manual method and the smartphone-aided method. The measurement time was recorded for every measurement. The frequency and the cumulative percent distribution for intraobserver differences were tabulated, both for the individual examiners and for the overall results for the 5 examiners. The intraclass correlation coefficient (ICC) 2-way mixed model on absolute agreement was used to analyze measurement reliability. Summary statistics from analyses of variance calculations were used to provide 95% prediction limits for the error in measurements. A paired t test was used to compare the time consumed for the measurement between both sets. RESULTS: The intraobserver and interobserver ICCs were excellent in the smartphone set and in the manual set. Both the intraobserver ICC and the interobserver ICC were better in the smartphone set than in the manual set. The mean Cobb angle of all measured x-rays was 29.3 degrees (range, 17-58 degrees) in the manual set and 29.1 degrees (range, 18-56 degrees) in the smartphone set. The mean time consumed was 13.7 seconds (range, 8.6-18.5 s) for the smartphone set, whereas it was 37.9 seconds (range, 30.1-46.9 s) for the manual set, and the mean time consumed for the smartphone set was significantly shorter than that of the manual set (P<0.05). CONCLUSIONS: Smartphone-aided measurement for Cobb angle showed excellent reliability and efficiency. It is suggested to popularize the use of this method in clinical practice. PMID- 22237180 TI - Reviewing personal bacteria - the human microbiome project. PMID- 22237182 TI - Effect of stress on biofilm formation by icaA positive and negative strains of methicillin resistant Staphylococcus aureus. AB - OBJECTIVE: To determine the effect of physical and chemical stress factors e.g. antibiotics, NaCl, glucose, heat shock, cold shock and sonic waves on biofilm formation by icaA positive and negative strains of Methicillin resistant Staphylococcus (S.) aureus. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Microbiological Analytical Centre, Pakistan Council of Scientific and Industrial Research (PCSIR) Laboratories Complex, Karachi, from January to December 2010. METHODOLOGY: One strain of Staphylococcus aureus labelled as FA was isolated from a food sample and the other strain labelled as CL was a clinical strain. Biofilm assays were performed in brain-heart infusion (BHI) medium and in BHI supplemented with 7% NaCl, 5% glucose, or sub-inhibitory concentrations of Vancomycin, Oxacillin, Ampicillin, Tetracycline, Erythromycin, Rifampicin and Ciprofloxacin. Polymerase chain reaction (PCR) was used for screening of the icaA and mecA genes. RESULTS: The FA and CL were identified as MRSA carrying mecA gene. The strain FA showed biofilm formation without any treatment and was found to carry icaA gene contrary to CL, that does not contain this gene therefore, is unable to produce biofilm under normal conditions without any stress. The use of sub-lethal doses of cell wall active antibiotics, exposure to 7% NaCl, sonication, and heat shock were found to augment biofilm quantity in FA, an icaA positive strain and induce biofilm mode of growth in CL, an icaA negative strain. Anti-protein synthesis antibiotics did not show any effect on biofilm formation process in icaA positive or negative strains. CONCLUSION: There is a role of anti-cell wall factors i.e. sonication, heat shock, NaCl and antibiotics in the induction of biofilm mode of growth in MRSA and Methicillin sensitive S. aureus. The factors which partially damage bacterial cell wall, equally, induce biofilm formation in icaA positive or negative S. aureus. PMID- 22237181 TI - Dentoalveolar heights in skeletal class I normodivergent facial patterns. AB - OBJECTIVE: To determine the dentoalveolar heights (mm) in skeletal class I normodivergent facial pattern and compare the same heights in male and female subjects. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Orthodontics Clinic, The Aga Khan University Hospital, Karachi, from July to October 2009. METHODOLOGY: Eighty one subjects were selected from the orthodontic record at the Aga Khan University Hospital Karachi. The inclusion criteria were an age range of 12 to 30 years and skeletal class I normodivergent facial pattern with exclusion criteria of prior orthodontic treatment, restored teeth and craniofacial anomalies/syndromes. The pre-treatment cephalographs of the patients were traced manually on acetate paper by the principal investigator. The various land marks were marked and the parameters were recorded. Mean and standard deviations were determined. Independent sample t-test was used to find gender dimorphism. RESULTS: The mean age of the sample was 15.8 +/- 3.4 years. Mean ANB angle for the entire sample was 2.6 degrees +/- 1.2 degrees and for angle SN-MP was 31.5 degrees +/- 2.5 degrees . Descriptive analysis presented mean value of upper anterior, upper posterior, lower anterior and lower posterior dentoalveolar heights to be 28.5 +/- 2.7 mm, 22.9 +/- 2.6 mm, 41.3 +/- 2.9 mm and 31.5 +/- 3.2 mm respectively. Male subjects had significantly greater mean values for lower anterior and posterior dentoalveolar heights (p=0.02 and 0.05 respectively). CONCLUSION: The mean dentoalveolar heights for the skeletal class I normodivergent sample were established. No gender dimorphism was found for upper dentoalveolar heights however, lower anterior and lower posterior were significantly greater in males as compared to females. All the values of dentoalveolar heights for male subjects were greater than female subjects. PMID- 22237183 TI - Blood glucose levels in neonatal sepsis and probable sepsis and its association with mortality. AB - OBJECTIVE: To determine the blood glucose levels among patients with neonatal sepsis and probable sepsis and evaluate their association with the mortality rate. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: Fazle Omar Hospital, Rabwah, Pakistan from July 2007 to December 2008. METHODOLOGY: Neonates with culture proven and probable neonatal sepsis were included. The glucose levels at the time of admission and outcomes were recorded. The patients were divided in four groups according to their glucose levels i.e. < 40 mg/dl, 40-100 mg/dl, 101-200 mg/dl and > 200 mg/dl. The patients were divided in two groups according to weight i.e. < 2.5 kg and 3 2.5 kg. RESULTS: There were a total of 502 cases. The glucose levels were below 40 mg/dl in 50 patients (9.9%), between 40 mg/dl to 100 mg/dl in 322 (64.1%), between 101 mg/dl to 200 mg/dl in 95 (18.9%) and above 200 mg/dl in 35 patients (6.9%). Among these four groups, 16 (32%), 32 (9.9%), 22 (23.2%) and 17 (48.6%) neonates died respectively (p < 0.001). The difference in glucose levels among the two groups according to weight was significant (p=0.002). CONCLUSION: Majority of patients with neonatal sepsis and probable sepsis had glucose levels between 40 and 100 mg/dl at admission. Those with the levels below 40 mg/dl and above 200 mg/dl had higher mortality rates. PMID- 22237184 TI - The clinical significance of perilimbal conjunctival pigmentation in vernal conjunctivitis. AB - OBJECTIVE: To compare the extent of perilimbal conjunctival pigmentation and limbal palisadal pigmentation in patients with vernal conjunctivitis and controls and correlate it with the duration of disease. STUDY DESIGN: Case control study. PLACE AND DURATION OF STUDY: Eye Department, Combined Military Hospital, Abbottabad, from May 2009 to March 2010. METHODOLOGY: One hundred subjects including 50 patients with vernal conjunctivitis and 50 controls were studied. Demographic data, family and personal history, disease duration, symptoms, signs, complications and extent of perilimbal and palisadal conjunctival pigmentation were recorded among patients and controls. Mann Whitney-U test and Spearman's rho test were used for statistical analysis. RESULTS: The extent of perilimbal conjunctival pigmentation in patients with vernal conjunctivitis was more than controls (p < 0.0001). Similarly, limbal palisadal pigmentation was also more extensive than controls (p = 0.004). There was no correlation between the duration of disease and severity of conjunctival pigmentation (r = 0.24) (p = 0.086). CONCLUSION: The presence of increased perilimbal and limbal palisadal conjunctival pigmentation among patients with vernal conjunctivitis is a specific sign of vernal conjunctivitis. PMID- 22237185 TI - Modified suture anchors for open bankart repair. AB - OBJECTIVE: To evaluate the efficacy of cancellous screws as suture anchors, in open Bankart repair. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Orthopaedics, Combined Military Hospital, Rawalpindi, from March 2009 to October 2010. METHODOLOGY: Fourteen patients with recurrent anterior dislocation were included in the study. Through anterior approach three 4 mm partially threaded cancellous screws were placed at the anterior Glenoid rim. Prolene-1 suture was tied around these screws which acted as anterior anchors and was used to re-attach the capsule and labrum back to bone. The mean duration of follow-up was 8 months. The patients were evaluated at 3 monthly intervals with a physical examination, radiographs, the modified shoulder rating scale of Rowe and Zarins and American Shoulder and Elbow Surgeons score. RESULTS: The mean operating time was 58 minutes. There was no immediate/early postoperative complication. At the last follow-up none of the patients had recurrence or radiological evidence of hardware failure/complication. Eleven patients (79%) had a score of 90 points on the scale of Rowe and Zarins and 12 patients (85.7%) had a score of at least 90 points on the scale of the American Shoulder and Elbow Surgeons scale. Ten patients (71%) had full range of motion in all planes. CONCLUSION: Use of cancellous screws as a suture anchor is a safe and cost effective substitute of commercially available suture anchors in open Bankart repair. PMID- 22237186 TI - Paediatric Halitosis and Helicobacter pylori Infection. AB - OBJECTIVE: To compare the presence of Helicobacter pylori (H. pylori) infection by stool antigen test in children with and without halitosis. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Department of Paediatrics, Fatih University Hospital, Ankara, Turkey, between December 2008 and June 2009. METHODOLOGY: Fifty-three patients aged between 3-15 years who presented to paediatrics outpatient clinic with halitosis and 55 healthy children aged between 4-15 years without halitosis were included in the study. Halitosis was confirmed with organoleptic test. Stool antigen test was performed in both groups. Intergroup proportions were compared using chisquare and Fisher exact tests with significance at p < 0.05. RESULTS: The H. pylori stool antigen test was positive in 11 out of 53 patients (20.8%) with halitosis and 12 of 55 healthy controls (21.8%). The rate of positive H. pylori stool antigen test results were similar between two groups (p > 0.05). Twoweeks eradication treatment was administered to 11 patients with H. pylori infection and halitosis. After treatment, the symptoms of 8 patients with halitosis (72.7%) completely resolved and persisted in 3 patients (27.3%). Seven of the 11 patients who were administered eradication treatment also had abdominal pain along with halitosis. Both symptoms completely resolved in all those patients after treatment. CONCLUSION: Although no statistically significant difference existed between the rate of H. pylori infections among those with and without halitosis. Eradication treatment was found beneficial in the treatment of children with halitosis and positive H. pylori stool antigen test. PMID- 22237188 TI - Elective hemi transurethral resection of prostate: a safe and effective method of treating huge benign prostatic hyperplasia. AB - OBJECTIVE: To evaluate the safety and efficacy of elective hemi-resection of prostate in patients with huge gland, weighing more than 120 grams. STUDY DESIGN: Multicentric, analytical comparative study. PLACE AND DURATION OF STUDY: Department of Urology, Karachi Medical and Dental College, Abbasi Shaheed Hospital and Dr. Ziauddin Hospital, Karachi, from August 2006 to July 2009. METHODOLOGY: All benign cases were included in this study and divided into two groups. In group A, patients having hugeprostate (> 120 grams) were placed and hemi TURP was performed. In group B, patients having 60 to 100 grams prostate were placed and conventional Blandy's TURP was performed. Results of both groups were compared in terms of duration of surgery, amount of tissue resected, operative bleeding, postoperative complications, duration of postoperative catheterization, re-admission and re-operations. Effectiveness of procedure was assessed by a simple questionnaire filled by the patients at first month, first year and second year. Patients satisfaction in terms of their ability to void, control urination, frequency, urgency, urge incontinence, haematuria, recurrent UTI, re-admission and re-operations were also assessed. Fisher exact test was applied to compare the safety and efficacy of variables. RESULTS: In group A and B, average age range was 72 and 69 years, average weight of prostate was 148 and 70 grams, average duration of surgery was 102 and 50 minutes respectively. Average weight of resected tissue was 84 and 54 grams and haemoglobin loss was two grams and one gram respectively. Total hospital stay was 5 and 4 days. Total duration of indwelling Foley's catheter (postoperative) was 5 days and 2 days. Patient satisfaction in term of urine flow, urinary control, improvement in frequency and nocturia were comparable in both groups. UTI and re-admission was more in hemiresection group. At the end of 2 years follow-up, there is no statistical difference between the safety and efficacy of two methods of treatment. CONCLUSION: In selected population, elective hemi TURP for huge obstructed prostate is a safe treatment. It's safety and short terms efficacy is comparable with the results of conventional TURP. PMID- 22237187 TI - Clinical spectrum of infantile spasm at presentation. AB - OBJECTIVE: To determine the clinical and EEG findings in children with infantile spasms at their initial presentation to the Neurophysiology Department, Children's Hospital, Lahore, Pakistan. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: The Neurophysiology Department, Children's Hospital, Lahore, Pakistan, from January 2008 to December 2010. METHODOLOGY: Children aged < 24 months, referred for their first EEG test was assessed for the diagnosis of infantile spasms. Clinical manifestation, EEG finding and anti-epileptic drugs being administered on presentation were analyzed by the paediatric neurologists. RESULTS: Among the total 2050, 410 children (20%) had infantile spasms. Mean age at presentation was 4.6 + 3.5 months. Three hundred and twenty eight presented due to infantile spasms / seizures (80%) and 82 due to psychomotor delay / regression (20%). Seventy-two percent patients presented at the age < 6 month and no patient presented after the age of 18 months. Spasm types were mixed (56%), flexors (24%), extensor (12%) and asymmetric (8%). Etiology classification was symptomatic in 58% and cryptogenic in 42%. Autonomic disturbance, impaired consciousness and abnormal eye movements were the dominant initial clinical presentations. EEG records showed hypsarrhythmic/modified hypsarrhythmic in 82% and other forms of epileptic discharges in 18%. Hormonal therapy was being administered in 12%, 40% were receiving Phenobarbitone and 34% were not being treated with any anti-epileptic agent. CONCLUSION: Patients with infantile spasms have abnormal EEG findings predominantly the hypsarrhythmic modified hypsarrhythmic discharge. To avoid improper treatment, such patients should be referred to the specialized centres. PMID- 22237189 TI - Nicolau syndrome following intramuscular penicillin injection. AB - Nicolau Syndrome (NS) is a rare but severe localized adverse reaction at the site of intramuscular drug injection. The typical presentation is intense pain around the injection site soon after injection, followed by erythema, purplish network discolouration of the skin, haemorrhagic patch, and finally tissue necrosis. Here in, we report a 9 years old boy, the third Nicolau Syndrome (NS) reported from Iran after a single intramuscular injection of penicillin. PMID- 22237190 TI - Milliary tuberculosis with unusual paradoxical response at 3 weeks of antituberculous treatment. AB - Milliary Tuberculosis (TB) occurs through lymphohaematogenous dissemination of M. tuberculosis and paradoxical response (PR) is a recognized feature. Respiratory failure, choroid tubercles and brain tuberculomas are some of the complications. Brain tuberculomas mainly occur in the cerebrum, cerebellum, where as involvement of the brainstem is rare. A 31 years old female presented with history of ill health, easy fatigability, excessive sweating and fever of one month duration, dry cough for one week and shortness of breath for 3 days. Provisional diagnosis was disseminated TB complicated by hypoxemic respiratory failure and bilateral choroid tubercles. She was started on anti-TB treatment with adjuvant steroids. The initial response to treatment was remarkable but after about 3 weeks of anti TB therapy, she suddenly deteriorated developing spastic ataxia. After exclusion of other possible causes she was successfully treated under the impression of having PR. PMID- 22237191 TI - Non-communicating extradural arachnoid cyst of dorsal spine. AB - Extradural arachnoid cyst in the spine is an uncommon cause of spinal cord compression in the paediatric population. Most reported cysts have communication with the intrathecal subarachnoid space through a small defect in the dura. The reported child had spinal cord compression caused by a large spinal extradural arachnoid cyst in dorsal spine that did not communicate with the intradural subarachnoid space. Surgical excision of cyst was done with recovery of neurological deficit postoperatively. PMID- 22237192 TI - Intramedullary spinal tuberculoma. AB - Spinal intradural intramedullary tuberculoma is extremely rare entity of tuberculosis involving the nervous system. Because of its atypical symptomatology, it must be considered in differential diagnosis of spinal cord lesions, especially where prevalence of tuberculosis is high. In this case report this atypical disease is described where good outcome was achieved by surgical excision of the intramedullary lesion followed by antituberculous therapy. PMID- 22237193 TI - Squamous inclusion cyst in a sentinel axillary lymph node associated with breast malignancy. AB - Axillary intranodal squamous inclusion cyst is a rare benign histological finding that may be confused with malignant diseases. A 52 years old female presented with a painless lump in the left breast for one and a half month. The mammogram was reported as being suspicious of carcinoma. Left breast lumpectomy and histology revealed infiltrating ductal carcinoma. After a month, modified radical mastectomy was done. Frozen section of axillary sentinel lymph nodes revealed benign histology with squamous inclusion cyst in one of the nodes. All lymph nodes recovered from mastectomy specimen were also benign. PMID- 22237194 TI - Hypermetropia as a presentation of diffuse choroidal haemangioma in sturge-weber syndrome. AB - A 16 years old male patient of Sturge-Weber syndrome was referred to glaucoma clinic for the management of unilateral glaucoma. There was also an ipsilateral hypermetropic shift. On detailed investigations, a diffuse choroidal haemangioma was diagnosed which induced this hypermetropic shift. Anisometropia in Sturge Weber syndrome can give us clue regarding some underlying pathology, so unilateral myopia or hypermetropia should be thoroughly evaluated in such patients. PMID- 22237195 TI - Congenital epulis. AB - Epulis is a rare tumour, with female preponderance that is only seen in the newborns. It arises from the mucosa of the gingiva and protrudes out of the infant's mouth. It can potentially obstruct the airways and may require an EXIT (ex-utero intrapartum treatment) procedure which involves establishing an airway before the feto-maternal circulation is interrupted. We present a female newborn with such a mass, which was diagnosed antenatally. A multidisciplinary team including the neonatologist, anaesthesiologist and ENT specialist should be present in the delivery room to establish the airways, which may require an EXIT procedure. Recommended treatment is early surgical resection. Recurrences of the tumour and damage to future dentition have not been reported, suggesting that radical excision is not warranted. PMID- 22237196 TI - Finger prosthesis with an alternative approach. AB - This report describes the case of a 42 years old male patient whose one right hand finger was partially lost as a result of occupational trauma. A modified impression technique was used for impression making and wax pattern was fabricated using the normal hand of the same patient. A special type of wax was formulated to make a pattern which was easily molded and carved. Two indexed casts were used to determine the length of fingers. Intrinsic and extrinsic staining was also done to match the adjacent skin colour. A ring was used as a retentive method. The patient was highly appreciative of the social acceptance after he started wearing the finger prosthesis. PMID- 22237197 TI - Clinical pattern of vitiligo. AB - All new cases of vitiligo reporting to Dermatology Outpatient of Combined Military Hospital, Panu Aqil, were included in the study. Of the 230 patients, 124 were male (53.9%) and 106 were female (46.1%). Males were more commonly affected. The disease affected all age groups. Mean age at presentation was 27.02 + 18.34 years and age at presentation ranged from 5.5 months to 82 years. The mean age at onset was 22.03 + 16.97 years with majority 30.4% (n=70), developing vitiligo in first decade of life. Generalized vitiligo was the most common type (n=132, 57.4%) followed by focal (n=53, 23%) and acro-facial vitiligo (n=16, 7%). Head and neck was the most common initial site of onset (n=100, 43.48%). Koebner phenomenon was observed in 72 patietns (31.3%), family history was present in 64 patients (27.8%) and 16 patients (7%) had associated diseases. PMID- 22237198 TI - Frequency and physical factors associated with gender-based violence in the internally displaced people of Pakistan. AB - Gender-based violence frequency and associated physical factors were determined in internally displaced people camp of Jalozai (Pakistan). Majority of families reported that security conditions were lacking and washrooms were neither illuminated (68%, n=29) nor locked (82%, n=31). Reported incidents of emotional violence were 56% (n=35), physical violence 42% (n=26) and sexual violence 18% (n=11). Health facilities reported 12 cases of gender-based violence/ month. No health education on prevention of gender-based violence (93%, n=56) neither psychologist was provided by any health facility. There was no refugee committee (95%, n=59) for women protection and health education (93%, n=56) for prevention of gender-based violence was done. To safeguard women and children proper lightening of passage, lock facilities in washrooms and timely reporting of gender-based violence cases should be ensured. This can be established by creating women protection committees and by conducting health education programs for gender-based violence. PMID- 22237199 TI - Mental health in the wake of flooding in pakistan: an ongoing humanitarian crisis. PMID- 22237200 TI - Physician satisfaction survey on continuing medical education. PMID- 22237201 TI - Why is the sustained virological response rate among HCV genotype 3 infected patients in Pakistan low? PMID- 22237202 TI - Pyknodysostosis. PMID- 22237204 TI - Role of the promyelocytic leukaemia protein in cell death regulation. AB - The promyelocytic leukaemia gene PML was originally identified at the t(15;17) translocation of acute promyelocytic leukaemia, which generates the oncogene PML retinoic acid receptor alpha. PML epitomises a subnuclear structure called PML nuclear body. Current models propose that PML through its scaffold properties is able to control cell growth and survival at many different levels. Here we discuss the current literature and propose new avenues for investigation. PMID- 22237205 TI - Cancer metabolism: current perspectives and future directions. AB - Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how 'metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer's 'Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells. PMID- 22237206 TI - DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway. AB - The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage. PMID- 22237207 TI - Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis. AB - Within the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic apoptotic pathway accompanied by activation of caspase-2 under hyperoxic conditions in the neonatal brain still remains elusive. Inhibition of caspases appears a promising strategy for neuroprotection. In order to assess the influence of specific caspases on the developing brain, we applied a recently developed pentapeptide-based group II caspase inhibitor (5-(2,6-difluoro-phenoxy)-3(R,S)-(2(S)-(2(S)-(3-methoxycarbonyl 2(S)-(3-methyl-2(S)-((quinoline-2-carbonyl)-amino)-butyrylamino)propionylamino)3 methylbutyrylamino)propionylamino)-4-oxo-pentanoic acid methyl ester; TRP601). Here, we report that elevated oxygen (hyperoxia) triggers a marked increase in active caspase-2 expression, resulting in an initiation of the intrinsic apoptotic pathway with upregulation of key proteins, namely, cytochrome c, apoptosis protease-activating factor-1, and the caspase-independent protein apoptosis-inducing factor, whereas BH3-interacting domain death agonist and the anti-apoptotic protein B-cell lymphoma-2 are downregulated. These results coincide with an upregulation of caspase-3 activity and marked neurodegeneration. However, single treatment with TRP601 at the beginning of hyperoxia reversed the detrimental effects in this model. Hyperoxia-mediated neurodegeneration is supported by intrinsic apoptosis, suggesting that the development of highly selective caspase inhibitors will represent a potential useful therapeutic strategy in prematurely born infants. PMID- 22237208 TI - A novel radioresistant mechanism of galectin-1 mediated by H-Ras-dependent pathways in cervical cancer cells. AB - Galectin-1 is a lectin recognized by galactoside-containing glycoproteins, and is involved in cancer progression and metastasis. The role of galectin-1 in radiosensitivity has not previously been investigated. Therefore, this study tests whether galectin-1 is involved in the radiosensitivity mediated by the H Ras signaling pathway using cervical carcinoma cell lines. A knockdown of galectin-1 expression in HeLa cells decreased clonogenic survival following irradiation. The clonogenic survival increased in both HeLa and C33A cells with galectin-1 overexpression. The overexpression or knockdown of galectin-1 did not alter radiosensitivity, whereas H-Ras was silenced in both cell lines. Whereas K Ras was knocked down, galectin-1 restored the radiosensitivity in HeLa cells and C33A cells. The knockdown of galectin-1 increased the high-dose radiation-induced cell death of HeLa cells transfected by constitutively active H-Ras. The knockdown of galectin-1 inhibited the radiation-induced phosphorylation of Raf-1 and ERK in HeLa cells. Overexpression of galectin-1 enhanced the phosphorylation of Raf-1 and ERK in C33A cells following irradiation. Galectin-1 decreased the DNA damage detected using comet assay and gamma-H2AX in both cells following irradiation. These findings suggest that galectin-1 mediates radioresistance through the H-Ras-dependent pathway involved in DNA damage repair. PMID- 22237210 TI - Extracorporeal management of poisonings. AB - Extracorporeal methods have been an integral part in the management of poisonings. The elimination of a drug or toxin by extracorporeal techniques (ECT) is governed by the properties of the toxin and the chosen extracorporeal therapy. The various ECT include hemodialysis, hemoperfusion, hemofiltration, continuous renal replacement therapy and peritoneal dialysis, all of which have been used some time or another for the management of poisonings. This review highlights the concepts forming the basis for selecting one modality over the others. PMID- 22237209 TI - Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair. AB - Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG(+/+)/UDG(-/-)). UDG(-/-) cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG(+/+) cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG(+/+) cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIalpha, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism. PMID- 22237211 TI - Screening for latent tuberculosis in refugees with renal failure. AB - Refugee camps are prone for easy spread of infections of various kinds and tuberculosis (TB) is no exception. Refugees with renal failure are often a vulnerable group because they are immunocompromised due to reasons such as poor nutrition, overcrowding and immune suppression due to renal failure. Latent pulmonary TB is a particular problem in this patient population as it is not easily diagnosed and has immense potential for spread. Tuberculin Skin Test (TST), although easy to perform and is cost-effective, suffers from the limitations of giving false positive results due to cross-reaction with the vaccination. Chest radiography though cheap, has not yet been validated in refugee populations for this purpose. Sputum analysis shows promise due to ease of performing but again has not been validated in refugees. Newer assays such as IF-gamma show great promise but needs large scale studies for validation and cheaper assays need to be developed for use in resource poor refugee setting. In short, an ideal tool for effective screening of latent TB in refugees with renal failure is lacking. Future studies are required to identify this ideal tool. PMID- 22237212 TI - Insomnia and limb pain in hemodialysis patients: what is the share of restless leg syndrome? AB - Insomnia and limb pain are common problems in dialysis patients. In addition, restless leg syndrome (RLS) as a specific cause of insomnia and limb pain has been reported in many studies. The purpose of this study was to estimate incidence of insomnia and RLS as a cause of insomnia in these patients. Twenty six patients undergoing hemodialysis were investigated for insomnia, limb pain and RLS as per the defined criteria. They were evaluated for dialysis quality, dialysis duration, hemoglobin, serum phosphorous, ionized calcium, iron and ferritin levels. These variables between patients with insomnia and those with normal sleep were evaluated by independent "t" test. Without considering the etiology or pathogenesis of insomnia, we evaluated the occurrence of insomnia and limb pain in these patients, and specifically, restless leg syndrome. Insomnia and limb pain were common in dialytic patients. 46% of patients had insomnia. 91% of sleepless group had limb pain as a persistent, annoying complaint. Limb pain was not seen in groups with a normal sleep pattern. Restless leg syndrome was found in 8% of total cases (2 out of 26) and 17% among the insomnia group (2 out of 12). In spite of high incidence of insomnia among patients undergoing regular hemodialysis, role of RLS is trivial. There is a strong relationship between hemoglobin levels and duration of renal replacement therapy to insomnia occurrence. PMID- 22237213 TI - Correlation of serum magnesium with dyslipidemia in patients on maintenance hemodialysis. AB - This study was performed to determine the correlation between serum magnesium (Mg) and dyslipidemia in patients on maintenance hemodialysis (MHD). This hospital-based cross-sectional observational study was conducted at the Department of Nephro-Urology, Liaquat University Hospital, Hyderabad, Pakistan, from April 2008 to June 2008. Fifty patients with end-stage kidney disease on MHD treatment (33 males and 17 females) were studied. The mean duration on HD was 7.58 +/- 2.05 years, with frequency being two to three sessions/week, and each session lasted for four hours. After obtaining informed written consent, the general information of each patient was recorded on a proforma. After overnight fasting, blood samples was drawn from the arterio-venous fistula for lipid profile, lipoprotein, serum Mg, serum creatinine, blood urea, serum calcium and serum phosphorus. Dyslipidemia was defined as presence of total cholesterol (TC), triglyceride (TG) or low-density lipoprotein (LDL) levels more then 95 th percentile for age and gender or high-density lipoprotein (HDL) levels less then 35 mg/dL. Descriptive and inferential statistical analyses were performed using SPSS version 16.0. The mean age of the study patients was 45.68 +/- 13.97 years. There was a significant positive correlation between serum Mg and serum lipoprotein-a (LP-a) (r = 0.40, P < 0.007), serum HDL (r = 0.31, P < 0.01) and serum TG (r = 0.35, P < 0.005). There was no significant correlation between serum Mg and serum LDL-c and serum TC. The serum TG and LP-a levels were significantly increased while HDL-c was significantly lower in MHD patients. The serum TC, LDL-c and very low-density lipoprotein-c were not significantly elevated. We conclude that patients with chronic kidney disease undergoing MHD show positive correlation between serum Mg and serum HDL, LP-a and TG. The abnormalities of lipid metabolism, such as hyper-triglyceridemia, elevated LP-a and low HDL-c, could contribute to atherosclerosis and cardiovascular disease in these patients. PMID- 22237214 TI - The impact of education on nutrition on the quality of life in patients on hemodialysis: a comparative study from teaching hospitals. AB - Patients on maintenance hemodialysis (MHD) experience decreased quality of life (QoL) and significantly higher rates of malnutrition, inflammation, hospitalization and mortality when compared with the normal population. The dietary approach in the different phases of chronic renal failure is one of the most important, and yet controversial, topics in the whole history of nephrology, even when dialysis facilities were not easily available. Although much progress has been made in recent years in recognizing the link between malnutrition, different diseases and increased mortality, no consensus has yet been reached concerning the ideal assessment and management of nutritional status in dialysis patients in Iran. In this study, 70 patients on MHD in the teaching hospitals in Urmia were divided into two groups and were requested to fill in the validated SF 36 QoL questionnaire. One group of 35 patients received dietary counseling while the other did not and acted as controls. The SF-36, a short-form QoL scoring system consists of 36 questions that are compressed into eight multi-item scales covering all aspects of QoL. The two groups studied were similar in age, level of education, gender and duration of dialysis treatment; 46.8% of the patients were female and 52% were male. The total SF-36 score was slightly higher in males compared with females, but this difference was not statistically significant (P = 0.05). The scores were higher in the group counseled about diet. Overall, the difference in physical health, in work activities and QoL as a whole, between the two groups, was statistically significant (t = 2.04, df = 34, P = 0.049; t = 2.04, df = 34, P = 0.049; t = 2.28, df = 1.96, P = 0.043, respectively). The QoL was considerably diminished in HD patients, but less so in the group that was educated about their nutrition. Improvement in QoL is achievable in patients if their discomfort is more effectively treated medically. One of the methods for this is education about their nutritional program, which can be used for other chronic diseases too. More research is needed to assess whether interventions help to improve QoL and lower heath risks among patients on HD. PMID- 22237215 TI - Evaluation of association between intima-media thickness of the carotid artery and risk factors for cardiovascular disease in patients on maintenance hemodialysis. AB - Cardiovascular disease is the most common cause of mortality and morbidity in patients with end-stage renal disease (ESRD). Atherosclerosis is a systemic disease, and carotid and coronary vessels are at comparable risk for developing pathologic changes. For this reason, increase in the thickness of the intima media layers of carotid arteries can be a harbinger of coronary atherosclerosis and also a prognostic factor for cardiovascular accidents. In this study, we evaluated the status of carotid intima-media thickness (CIMT) in patients with ESRD on dialysis and analyzed its association with other risk factors for cardiovascular diseases. This cross-sectional study was conducted on patients referred for hemodialysis (HD) to the Taleghani Hospital (Shahid Beheshti University of Medical Sciences, Tehran, Iran) during 2007-2008. At the beginning, biochemical parameters and common cardiovascular risk factors were extracted from the patients' files, and then CIMT was measured by using B-Mode high-resolution ultrasonography, 1 cm proximal to the carotid bulb in the posterior wall. Finally, correlation between other risk factors and CIMT was made. One hundred patients with chronic and advanced renal disease were evaluated, including 46% females and 54% males. The mean age of these patients was 59.2 +/- 13.1 years, with a range of 26-81 years. Correlations between CIMT and age (P = 0.023, r = 0.478), dialysis duration (P = 0.017, r = 0.435), number of cigarettes smoked (P = 0.026, r = 0.429), diastolic blood pressure (P = 0.013, r = 0.455) and fasting blood sugar (P = 0.045, r = 0.346) were significant. Risk factors for cardiovascular disease in patients on HD are of significant interest because of the high prevalence and frequency of the disease in this group of patients. However, in the present study, we were not able to find a very consistent and definite role for some risk factors in our patients. More studies are required to make clear the role of these factors in patients on HD. PMID- 22237216 TI - Hemodialysis for methyl alcohol poisoning: a single-center experience. AB - Methanol is a cheap and potent adulterant of illicit liquors. Hemodialysis (HD) is the best method to rapidly remove both toxic acid metabolites and parent alcohols, and it plays a fundamental role in treating severely poisoned patients. This retrospective study was carried out on 91 patients with detectable serum methanol levels who underwent HD. Because toxic alcohol levels were not immediately available, the initial diagnosis and treatment was based on clinical history with evidence of toxic alcohol intake, presence of high anion metabolic acidosis and/or end organ damage. Patients received bicarbonate, ethanol, according to clinical features and blood gases. Patients underwent HD in the setting of known methanol ingestion with high anion gap metabolic acidosis, or evidence of end-organ damage, regardless of methanol level. HD prescription included large surface area dialyzer (>= 1.5 m2), blood flow rate of 250-350 mL/min and dialysate flow rate of 500 mL/min for 4-6 h. Between 9 and 11 July 2009, 91 males with mean age 40 +/- 8.5 years underwent HD, and 13 patients required a second HD session. Patients consumed 100-500 mL illicit liquors, and symptoms appeared six and 60 h later. Clinical features were gastro-intestinal symptoms (83.5%), visual disturbances (60.4%), central nervous system symptoms (59.3%) and dyspnea (43.9%). Before HD, mean pH was 7.11 +/- 0.04 (range 6.70- 7.33) and mean bicarbonate levels were 8.5 +/- 4.9 mmol/L (range 2-18). Three patients died due to methanol intoxication. Mortality was associated with severe metabolic acidosis (pH <= 6.90), ventilator requirement and coma/seizure on admission (P < 0.001). Timely HD, bicarbonate, ethanol and supportive therapy can be life-saving in methanol intoxication. PMID- 22237217 TI - Tuberculous peritonitis associated with peritoneal dialysis. AB - Even though rare, tuberculous peritonitis (TBP) in patients on continuous ambulatory peritoneal dialysis (CAPD) is a perilous condition. Physicians worry about continuing treatment of their patients, whether to continue this modality of dialysis or switch to hemodialysis. A retrospective cohort study of 89 patients undergoing CAPD over a 12-year period was carried out for any episode of peritonitis with the objectives to find out the incidence of TBP in these patients, evaluation of patients' 3-year survival, possibility of retention of Tenckhoff catheter, and modality of dialysis post-infection. One hundred and three episodes of peritonitis occurred in our patients. Most of them were bacterial and occasionally fungal. We identified four cases of TBP, with one patient having concurrent bacterial infection in the peritoneal fluid. The clinical presentation was insidious with cloudy fluid in all cases. The diagnosis was established by the polymerase chain reaction (PCR) technique in one case, by positive peritoneal fluid culture for Mycobacterium tuberculosis in two cases, and clinically in the fourth one that responded well to anti-tuberculous therapy. All four patients survived their mycobacterial infection. Removal of catheter was necessary in all four patients and all were converted to hemodialysis. Three patients remained on hemodialysis thereafter, and one patient had to be re implanted with a new catheter and was restarted on CAPD. TBP in patients undergoing CAPD in Jeddah remains a real concern, especially with the evidence of high prevalence of tuberculosis and with the emergence of drug-resistant tuberculosis. We recommend early initiation of anti-tuberculous therapy and removal of the Tenckhoff catheter for better survival. Most of these patients probably will require conversion to hemodialysis, but in a selected few CAPD can be restarted. PMID- 22237218 TI - Endoscopic correction of vesicoureteric reflux: 10-year experience of a tertiary care center. AB - Endoscopic treatment (ET) of vesicoureteric reflux (VUR) is becoming the new gold standard for surgical correction. ET for VUR using newly available bulking agents is a reliable and safe alternative procedure to open ureteral reimplantation for the treatment of VUR in children. We retrospectively reviewed our experience over 10 years of patients with primary VUR who underwent ET and had at least one year of follow-up at our center from 1998 to 2008. We looked at laterality, success rate, need for a second procedure and complication rate. We observed 321 patients with ET for VUR during this period; 115 (35.8%) of them were males and the total intervened ureters were 480. Correction of VUR was defined as either the resolution of reflux or a downgrading to grade 1 revealed with a follow-up voiding cystourethrogram and no ipsilateral renal or ureteric dilatation detected on renal ultrasound. At two to three months of follow-up, VUR was corrected in 393/480 (81.8%) refluxing ureters after a single endoscopic injection. With a second, repeated injection in the failed cases, VUR was corrected in a total of 418 (87.1%) refluxing ureters. Only three patients had post-operative complications (<1%). We conclude that our study suggests that the majority of patients will be cured after undergoing, as out-patients, this endoscopic procedure. We believe that the widely reported safety of bulking agents and the short learning curve will make ET the standard treatment for VUR once surgical correction is warranted. PMID- 22237219 TI - Role of viruses in renal cell carcinoma. AB - To determine whether viral infections are related to renal cell carcinoma (RCC), we studied 49 patients with RCC (29 patients were males with age ranging from 30 to 81 years and a mean of 57.5 years; 20 patients were females with age ranging from 36 to 70 years with a mean of 58.4 years) and 16 non-neoplastic kidney patients as controls. Tissues specimens from study patients and controls were examined by nested polymerase chain reaction (PCR) to determine the presence of DNA of several viruses including human papilloma virus (HPV), Epstein-Barr virus (EBV), and polyoma viruses (BKV and JCV). Our results revealed that 7 of 49 (14.29%) RCC tissue specimens had HPV DNA compared with none of 16 non-cancer control subjects. Regarding the HPV types, all the positive results were high risk HPV types (type 16 in three and 18 in four patients). The present study suggests that HPV infection, especially high-risk types, is associated with RCC. However, more studies are necessary to demonstrate the molecular oncogenic processes involved in this association. PMID- 22237220 TI - Acid-base and electrolyte disorders in patients with diabetes mellitus. AB - Diabetes mellitus is the most common metabolic disorder in the community. The diabetics may suffer from acid-base and electrolyte disorders due to complications of diabetes mellitus and the medication they receive. In this study, acid-base and electrolyte disorders were evaluated among outpatient diabetics in our hospital. The study consisted of patients with diabetes mellitus who visited the hospital as outpatients between the period January 1, 2004 to December 31, 2006. The patients' medical history, age and type of diabetes were noted, including whether they were taking diuretics and calcium channel blockers or not. Serum creatinine, proteins, sodium, potassium and chloride and blood gases were measured in all patients. Proteinuria was measured by 24-h urine collection. Two hundred and ten patients were divided in three groups based on the serum creatinine. Group A consisted of 114 patients that had serum creatinine < 1.2 mg/dL, group B consisted of 69 patients that had serum creatinine ranging from 1.3 to 3 mg/dL and group C consisted of 27 patients with serum creatinine > 3.1 mg/dL. Of the 210 patients, 176 had an acid-base disorder. The most common disorder noted in group A was metabolic alkalosis. In groups B and C, the common disorders were metabolic acidosis and alkalosis, and metabolic acidosis, respectively. The most common electrolyte disorders were hypernatremia (especially in groups A and B), hyponatremia (group C) and hyperkalemia (especially in groups B and C). It is concluded that: (a) in diabetic outpatients, acid-base and electrolyte disorders occurred often even if the renal function is normal, (b) the most common disorders are metabolic alkalosis and metabolic acidosis (the frequency increases with the deterioration of the renal function) and (c) the common electrolyte disorders are hypernatremia and hypokalemia. PMID- 22237221 TI - Inappropriate use of urinary catheters and its common complications in different hospital wards. AB - Inappropriate use of indwelling urinary catheters (IUCs) and their related complications is one of the most important problems in hospital wards. The aim of this study was to evaluate inappropriate use of IUCs and their complications among patients in Tehran, Iran. Two hundred and six consecutive patients hospitalized in the intensive care unit (ICU) as well as medical and surgical wards at the Shahid Mohammadi Hospital in Bandarabbas from September 1 to 30, 2005 and in whom IUCs were used, were studied. Data collected included age of the patients, diagnoses, reason for use of IUC and the complications related to it. Overall, 164 patients (79.6%) had IUCs used appropriately while 42 of them (20.6%) were catheterized unjustifiably. Inappropriate use of IUCs in the ICU, medical and surgical wards was reported in 12 (18.5%), 16 (19.0%) and 14 patients (24.6%), respectively. The most common complication of IUCs was urinary tract infection, which occurred in 91 patients (44.2%) and hematuria, which was seen in 3.9% of the patients. Our study suggests that inappropriate use of IUCs is prevalent, particularly in the surgical wards, and the most common complication observed was catheter-associated urinary tract infection. PMID- 22237223 TI - The cost of hemodialysis in a large hemodialysis center. AB - To assess the cost of hemodialysis (HD) delivered at our center according to the treatment protocols based on the current Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines, we analyzed our cost data during the period from 1st of January 2007 to 30th of June 2010. The methods were used to determine both direct costs (related to dialysis treatment such as dialysis disposables, dialysis related drugs, medical personnel, out-patient medications, laboratory and other ancillary services) and overhead costs (building, maintenance and engineering costs, housekeeping, and administrative personnel). During the study period, an average of 2,500 HD sessions per month were performed for 200 patients. The mean total cost per HD session was calculated as 297 US dollars (USD) [1,114 Saudi Riyals (SR)], and the mean total cost of dialysis per patient per year was 46,332 USD (173,784 SR). Direct costs contributed to 81.15% of the total cost from which the personnel cost represented 41.11% and dialysis disposables represented 13.64%, while medications (outpatient and intravenous dialysis related medications including albumin, erythropoiesis stimulating agents, iron and vitamin D3) accounted for 12.47% of the total cost. Our total cost level is well below the average cost in the industrialized countries. PMID- 22237222 TI - Hospital-acquired acute kidney injury in critically ill children and adolescents. AB - This study determined the (1) hospital incidence, prevalence and etiology; (2) frequency of each of the acute kidney injury (AKI) stages and (3) the 60-day outcome. Retrospective analysis of clinico-laboratory data of Nigerian children/adolescents with hospital-acquired acute kidney injury (hAKI) was performed. AKI occurred in 103 (3.13%) of 3,286 childhood and adolescent admissions. Twenty-eight (27.2%) were hAKI while 72.8% were community-acquired AKI (cAKI). Annual hAKI incidence and prevalence rates were 0.17% (or 3.7 per million children population [pmcp]/year) and 0.84% (or 18.3 pmcp), respectively. Male (20):female (8) ratio was 2.5:1. In the hAKI group, median age was 5 (0.063 15.0) years. AKI stages 1, 2 and 3 accounted for 14.3%, 25.0% and 60.7%, respectively. AKI stage 3 was most anuric, with high dialysis requirement (P = 0.0329). Nephrotoxics (42.87%) were a leading cause of hAKI. Seventy-five percent of the recorded deaths were in the first 28 hAKI days. Median survival time was 23.5 admission (11-52) days. The means values of maximum serum creatinine (Scr) for survivors (486.0 +/- 382.0 MUmol/L or 5.5 +/- 4.3 mg/dL) and for non survivors (353.0 +/- 160.0 MUmol/L or 4.0 +/- 1.8 mg/dL) were similar (P > 0.20). The 60-day cumulative mortality was 36.7%. Scr severity may not be a reliable mortality determinant among AKI patients. The maximal mortality in the first 28 days of hAKI onset and overall high mortality rate indicate that high level of clinical vigilance and informed therapeutic intervention will be critical to survival during this period. Cause of death was multi-factorial. PMID- 22237224 TI - Predictors of early vascular-access failure in patients on hemodialysis. AB - Vascular access management is key and critical in the successful management of hemodialysis patients, and an arteriovenous fistula (AVF) is considered the access of choice. This study was conducted between January 2007 and October 2009 at the Military Hospital in Rabat. Data on 115 patients who underwent 138 AVFs were retrospectively studied. Wrist AVF was the most common site of use. The primary course was uncomplicated in 63% of the patients, while primary failure occurred in 23.9% of the patients. Presence of diabetes was the most important risk factor for primary failure. PMID- 22237225 TI - Comparison of diagnostic quality of kidney biopsy obtained using 16G and 18G needles in patients with diffuse renal disease. AB - To determine the diagnostic quality and complication rates of 16G and 18G needles in biopsy of the kidney, we performed renal biopsy using a biopsy gun under ultrasound guidance in 50 patients who were prospectively and evenly assigned to one of the two needle biopsy methods from April 2007 until May 2008. Two cores of renal biopsy specimen were obtained in each case and subjected to histopathological and immunoflourescence (IF) examination. Pain associated with the procedure was assessed using a visual analog scale. The number of glomeruli retrieved using the 16G needle ranged from 0 to 30 (mean 9.42 +/- 5.5) and those retrieved using 18G needle ranged from 0 to 19 (mean 7.72 +/- 4.4), P <0.05. The quality of biopsy was poorer with 18G needle as compared with 16G needles because of a higher amount of fragmentation and crushing artifact. There was no difference in the complication rates between the two needles (2% each). The 16G needle was associated with significantly more pain than the 18G needle. We conclude that our study demonstrates the benefit of the larger 16G needle in providing more tissue and glomeruli, which is more diagnostically useful. However, the use of 16G needle was associated with significantly more pain than the 18G needle, and may be a better compromise for diagnostic usefulness and patient acceptability. PMID- 22237226 TI - Teaching of the renal system in an integrated, problem-based curriculum. AB - To assess teaching in the Renal System Block of an integrated problem-based learning (PBL) undergraduate medical curriculum by the students' and tutors' according to their perceptions of relevance, stimulation and amount learned from the problems, a 16-item questionnaire focusing on these issues was distributed to a group of 1st year medical students in Riyadh, Saudi Arabia (n = 17) and their tutors (n = 3). Group ratings on Likert-type rating scales and open-ended comments were analyzed to determine median and qualitative differences. Students' and tutors had favorable, congruent perceptions of amount learned, stimulation and relevance of renal medicine problems to the Saudi Arabian healthcare context. Open-ended comments of both groups were highly supportive of the Block objectives, content and integrated teaching. It is concluded that exploring the congruence of students' and tutors' perspectives has been helpful in determining the necessity for renal medicine block modifications; emulating a PBL collaborative knowledge-building approach in curriculum development. PMID- 22237227 TI - Residual amoebic liver abscess in a prospective renal transplant recipient. AB - Amoebic liver abscess (ALA) is by far the most common extraintestinal manifestation of invasive amoebiasis. The vast majority of these resolve with treatment; however, a small percentage of the treated ALAs are known to persist asymptomatically. Herein, we present a prospective renal allograft recipient with a residual liver abscess who had a successful renal transplant after treatment. In our opinion, persistence of a radiological finding of residual abscess in the absence of clinical disease does not appear to be a contraindication to renal transplantation. PMID- 22237228 TI - Primary cutaneous cryptococcosis due to Cryptococcous laurentii in a renal transplant recipient. AB - We report a patient with primary cutaneous cryptococcosis caused by Cryptococcous laurentii following renal transplantation, probably due to repeated insulin and heparin subcutaneous injections on his thigh. Although cutaneous cryptococcosis due to C. neoformans is well known, reports of skin infections due to non neoformans cryptococci are uncommon. PMID- 22237229 TI - Unilateral recurrent pleural effusion in a renal transplant patient. AB - Pleural effusion is a frequent complication in patients undergoing hemodialysis (HD). We report a patient on HD with a novel cause of recurrent unilateral pleural effusion. A 45-year-old female patient on long-term maintenance HD presented to us with recurrent unilateral pleural effusion. She had a history of poor quality dialysis, severe anemia and severe hypertension. Despite correcting these factors and even after undergoing successful renal transplantation, she continued to have recurrent effusion. Left upper extremity venography demonstrated severe stenosis of the subclavian vein and an increased venous flow in the ipsilateral arteriovenous (AV) fistula. Ligation of the AV fistula led to dramatic resolution of the pleural effusion. Hemodialysis patients who develop unexplained pleural effusions ipsilateral to a functioning AV fistula should be investigated for stenosis in the brachiocephalic vein, particularly those patients who have had previous catheterizations of the jugular or subclavian veins on the same side as the effusion. Correcting the stenosis by venous angioplasty and/or ligation of the ipsilateral fistula can dramatically resolve the pleural effusion. A high index of suspicion is required to diagnose this complication for meaningful intervention. PMID- 22237230 TI - Catastrophic antiphospholipid syndrome presenting as fever of unknown origin. AB - Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies with characteristic clinical manifestation, which include venous, arterial thrombosis, thrombotic microangiopathy, and recurrent fetal loss. The syndrome can be secondary to many causes including systemic lupus erythematosus (SLE) or "primary" antiphospholipid syndrome (APLS). We report a case of a man with catastrophic antiphospholipid syndrome (CAPS), which occurs when three or more organ systems are affected by thrombosis in less than a week. Catastrophic antiphospholipid syndrome is uncommon but often fatal. The patient received a successful treatment that controlled this disease and included intravenous heparin, antiplatelet, intravenous corticosteroid, and plasmapheresis. PMID- 22237231 TI - Primary renal osteosarcoma with systemic dissemination. AB - Primary renal osteosarcoma is an uncommon disease, which, unlike its skeletal counterpart, presents mostly in adults, and is generally diagnosed late due to its non-specific features and intra-abdominal location. Even if the disease is localized at diagnosis, it follows an aggressive course despite radical surgery and adjuvant treatment. We report a case of renal osteosarcoma in a 65-year-old female, who developed regional recurrence, and lung and bone metastases soon after radical nephrectomy for localized disease. Chemotherapy was ineffective in controlling systemic disease. PMID- 22237232 TI - Acute renal failure as an initial manifestation of multiple endocrine neoplasia (MEN) type 1. AB - Multiple endocrine neoplasia (MEN) is a group of heritable syndromes characterized by aberrant growth of benign or malignant tumors in a subset of endocrine tissues. There are three major syndromes: MEN1, 2A and 2B. We describe a 60-year-old woman who initially manifested acute renal failure due to hypercalcemia and dehydration and, finally, was diagnosed as a sporadic MEN1 case. PMID- 22237233 TI - Squamous cell carcinoma in exstrophic unreconstructed urinary bladder in an adult. AB - Bladder exstrophy is rare and associated with an increased incidence of bladder cancer. Unreconstructed bladder extrophy presenting in an adult is very rare as most of the patients undergo repair in childhood. Most of the cancers are adenocarcinomas. We report a rare case of squamous cell carcinoma occurring in exstrophic unreconstructed bladder in a 58-year-old male patient. PMID- 22237234 TI - Hypernatremic dehydration due to lactation failure in an exclusively breastfed neonate. AB - We report a 13-day-old exclusively breastfed neonate, admitted with a history of fever, poor feeding, lethargy and decreased urine output. The mother had history of lactation failure. The neonate had severe hypernatremia, acute renal failure and metabolic acidosis. Renal ultrasound was normal, but the sodium level in mother's milk was 96 mEq/L (normal 7 +/- 2 mEq/L). The neonate required peritoneal dialysis on the second day of admission. The biochemical investigations gradually returned to normal and the neonate was discharged on day 12 of admission. We highlight the importance of lactation management and supportive counseling to prevent complications like hypernatremic dehydration due to lactation failure. PMID- 22237235 TI - Prevalence of microalbuminuria in a population of healthy blood donors: a single center experience. PMID- 22237236 TI - A successful renal transplant after cytomegalovirus colitis in a dialysis patient. PMID- 22237237 TI - A comparative study of impact of infusion of Ringer's Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation. PMID- 22237238 TI - Eliminating the chronic problem of false positive HCV testing from hemodialysis units at lowest cost. PMID- 22237239 TI - A rare complication of pegylated interferon Alfa 2a in a hepatitis C-positive patient on maintenance hemodialysis. PMID- 22237240 TI - Mutation analysis of PKD1 gene in Indian population. PMID- 22237241 TI - Tenofovir-induced nephrotoxicity: myths and facts. PMID- 22237242 TI - C1q nephropathy presenting as nephritic-nephrotic syndrome. PMID- 22237243 TI - Outcomes of arteriovenous fistula for hemodialysis in Sudanese patients: single center experience. AB - A well-functioning arteriovenous fistula (AVF) is essential for the maintenance of hemodialysis (HD) in patients with chronic renal failure. Our aim is to review our experience of creating AVF and to asses its success rate and common complication. A prospective, hospital-based study was conducted on 73 patients (48 males and 25 females) on chronic HD in Gezira Hospital for Renal Diseases and Surgery, from January to July 2007. Their mean age was 43.9 years (range from 18 to 72 years). Seventy-one (97.3%) of the study subjects had been dialyzed before creation of the AVF, 67 (91.8%) of them having undergone HD with temporary access. All patients (n=73) had a native AVF as the permanent vascular access (VA). A primary radiocephalic AVF was created in 78.1% of the patients, cubital fossa in 20.5% and one case had left snuff box AVF (1.4%). Percentage of AVF maturation was reported in 67.1% of the cases within the first six weeks and in 9.6% of the cases AVF never matured. Failure of AVF function occurred in 26% of the cases, due to thrombosis in 20.5% (n=15) and aneurysm in 5.5% of the cases. We conclude that an optimum outcome is likely when there is a multidisciplinary team approach, and early referral to vascular surgery is paramount. PMID- 22237244 TI - Etiology of chronic renal failure in Jenin district, Palestine. AB - A study was conducted on chronic renal failure patients treated by medications or by hemodialysis at The Martyr Dr. Khalil Sulaiman Hospital in Jenin city, Palestine, from 1/8/2005 to 1/8/2006 to know the underlying etiology of chronic renal failure. The subjects included were 84 patients. The information was obtained from files of the patients. The diagnosis was based on medical history, laboratory tests, X-rays, CT scans, ultrasound and renal biopsies. The results showed that the three most common causes of chronic renal failure in Jenin district were diabetes mellitus (33.32%), hypertension (16.7%), and chronic glomerulonephritis (13.1%). Inherited kidney diseases formed an important percentage (17.85%) and included primary hyperoxaluria (10.71%), Alport's syndrome (5.95%), and adult polycystic kidney disease (1.19%). These results differ from what is found in most developing countries including many Arab countries where the principal causes of chronic renal failure are chronic glomerulonephritis and interstitial nephritis. The high prevalence of inherited kidney diseases in some families (primary hyperoxaluria and Alport's) syndrome may be explained by the very high prevalence of consanguineous marriage especially among cousins in these families. PMID- 22237245 TI - Childhood urolithiasis in north-western Libya. AB - The study reviews causes of urolithiasis and its manifestations in North-West (NW) Libya. Libyan childhood urolithiasis accounted for 3.6% of nephrology out patient work load. There were 59 children with urolithiasis, including 34 boys and 25 girls with a mean age of 2.8 +/- 2.42 years. Urolithiasis was more common among younger age groups (P = 0.001) and in boys with primary oxaluria and infective etiology. The causes of urolithiasis included metabolic stones in 64%, infective in 26%, and it was idiopathic in 10%. Overall, family history of renal stone disease was elicited in 59%; it was 92% in patients with primary oxaluria. The main presenting features were abdominal pain (27%), gross hematuria (22%), associated urinary tract infection (UTI; 24%), and stone release in 19%. Stone location was bilateral in 64%, multiple in 68%, and in the upper tract in 93% (P = 0.05). Important complications encountered included chronic renal failure (13%), hydronephrosis (34%), systemic hypertension (8%), and rickets in 17%. Calcium oxalate was the most prominent constituent, seen in 41% of the calculi, followed by struvite (21%), uric acid (10%), carbapatite (7%), and cystine (3.5%). Diagnostically helpful findings were family history, age at presentation, UTI by urease producing organisms, rickets, imaging and chemical analysis of calculi. Early detection and prompt treatment helps in preventing long-term sequelae in patients with urolithiasis. PMID- 22237246 TI - Renal disease in adult Nigerians with sickle cell anemia: a report of prevalence, clinical features and risk factors. AB - Renal abnormalities in adult Nigerians with sickle cell anemia (SCA) have not been extensively studied. To determine the prevalence, pattern and the associated risk factors of renal disease, 72 subjects with SCA from two centers in the southwestern Nigeria were investigated. Socio-demographic data, body mass index and clinical findings were documented. The urine analysis, serum bio-chemistry, hemogram and renal factors attributable to SCA were determined. Presence of albuminuria of at least 1+ or microalbuminuria in those negative with dipstick; and the estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula categorized subjects to various stages of chronic kidney disease (CKD). Subjects with and without albuminuria were compared to determine the relative risk associated with renal disease. Four (5.6%) subjects had macro-albuminuria, while 32 (44.4%) had micro-albuminuria and 30 (41.7%) had hemoglobinuria. In the subjects with albuminuria, age, hematocrit, systolic blood pressure, serum creatinine, urea and creatinine clearance were numerically higher while the eGFR was numerically lower. There was no significant difference in the clinical parameters studied in the two groups of subjects. The diastolic blood pressure was significantly higher in the albuminuric group. Based on eGFR, 22 (30.6%) subjects had hyperfiltration (GFR > 140 mL/min/1.73 m2), of whom 36.4% had albuminuria, 18 (25.0%) had stage 1 CKD, 30 (41.7%) had stage 2 CKD and two (2.7%) subjects had stage 3 CKD with albuminuria. None had stage 4 and 5 CKD. We conclude that renal abnormalities, importantly albuminuria, is common in adult Nigerians with SCA and the pattern and incidence are similar to those reported from other parts of the world. Regular blood pressure monitoring, early diagnosis and active intervention are advocated to delay progression to end-stage kidney disease in view of poor outcomes of renal replacement therapy in SCA patients with nephropathy. PMID- 22237251 TI - Synthesis and interaction with midkine of biotinylated chondroitin sulfate tetrasaccharides. AB - Regiospecifically sulfated chondroitin sulfate repeating tetrasaccharides, CS-OO, GlcAbeta-GalNAcbeta-GlcAbeta-GalNAcbeta;CS-EE, GlcAbeta-GalNAc(4S6S)beta-GlcAbeta GalNAc(4S6S)beta; and CS-AA, GlcAbeta-GalNAc(4S)beta-GlcAbeta-GalNAc(4S)beta, having biotin linked with a hydrophilic linker at the reducing terminal were synthesized effectively by a coupling of the corresponding disaccharide units and regioselective sulfation. CS-EE showed greater affinity for midkine than CS-AA and CS-OO. PMID- 22237252 TI - First theophylline-based ratiometric fluorescent synthetic receptor for selective recognition of dihydrogenphosphate and biological phosphate ions. AB - We have developed a new ratiometric fluorescent chemosensor 1 based on xanthine alkaloid theophylline moiety for the detection of dihydrogen phosphate and ATP. The chemosensor 1 selectively recognizes tetrabutylammonium dihydrogen phosphate in CH(3)CN/H(2)O (9:1) by exhibiting a significant decrease in the emission of naphthalene and its sensing properties regarding ATP and other related phosphate species were evaluated. The anion binding properties of 1 were evaluated by (1)H NMR, UV-vis, and fluorescence spectroscopic methods. PMID- 22237253 TI - Dynamic nuclear polarization of quadrupolar nuclei using cross polarization from protons: surface-enhanced aluminium-27 NMR. AB - The surface of gamma-alumina nanoparticles can be characterized by dynamic nuclear polarization (DNP) surface-enhanced NMR of (27)Al. DNP is combined with cross-polarization and MQ-MAS to determine local symmetries of (27)Al sites at the surface. PMID- 22237254 TI - The possibility of postoperative cognitive dysfunction in obstetric anaesthesia following caesarean section. PMID- 22237255 TI - Memantine in everyday clinical practice: a comparison of studies in Germany and Greece. AB - BACKGROUND/AIMS: Results from German and Greek non-interventional studies were compared to investigate possible differences concerning efficacy, tolerability and compliance between both countries. METHODS: In two open-label, multicentre, non-interventional studies, 4,305 patients with mild to severe Alzheimer's disease (AD) were treated with daily doses of 20 mg memantine for 6 months. Efficacy was assessed using the Mini-Mental State Examination (MMSE) and instrumental activities of daily living (IADL) scales. Safety and tolerability were recorded. RESULTS: After 6 months, the patients showed an improvement of their cognitive performance by 2 MMSE points compared to baseline (p < 0.001). MMSE values were improved in 67.4% of the patients, while 15.1% remained stable, and MMSE deteriorated in 17.5% only. The ability to perform IADL increased, as is indicated by lower values (baseline: 70.5; after 6 months: 66.6 points). Improvement of cognition and IADL was nearly identical in both countries. Treatment discontinuation was significantly more frequent in the Greek population, mainly due to non-adherence (9.4% of the safety population). 345 adverse events were recorded in 245 patients (6.3%), and they were significantly associated with country and age. CONCLUSION: The results correspond to those of clinical trials and support the efficacy and good tolerability of memantine in a realistic setting. Differences between the countries were observed regarding the baseline characteristics of patients (more female, older and more severe patients in Germany as well as less pretreatment with cholinesterase inhibitors) and regarding premature discontinuation and reported adverse drug reactions, which were both higher in Greece. PMID- 22237256 TI - Oral flurbiprofen metabolic ratio assessment using a single-point dried blood spot. AB - We investigated whether a single blood measurement using the minimally invasive technique of a finger prick to draw a blood sample of 5 ul (to yield a dried blood spot (DBS)) is suitable for the assessment of flurbiprofen (FLB) metabolic ratio (MR). Ten healthy volunteers who had been genotyped for CYP2C9 were recruited as subjects. They received FLB alone in session 1 and FLB with fluconazole in session 2. In session 3, the subjects were pretreated for 4 days with rifampicin and received FLB with the last dose of rifampicin on day 5. Plasma and DBS samples were obtained between 0 and 8 h after FLB administration, and urine was collected during the 8 h after administration. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. FLB's apparent clearance values decreased by 35% in plasma and DBS during session 2 and increased by 75% in plasma and by 30% in DBS during session 3. Good correlations were observed between MRs calculated from urine, plasma, and DBS samples. PMID- 22237257 TI - Detection of adverse drug reaction signals using an electronic health records database: Comparison of the Laboratory Extreme Abnormality Ratio (CLEAR) algorithm. AB - Electronic health records (EHRs) are expected to be a good source of data for pharmacovigilance. However, current quantitative methods are not applicable to EHR data. We propose a novel quantitative postmarketing surveillance algorithm, the Comparison of Laboratory Extreme Abnormality Ratio (CLEAR), for detecting adverse drug reaction (ADR) signals from EHR data. The methodology involves calculating the odds ratio of laboratory abnormalities between a specific drug exposed group and a matched unexposed group. Using a 10-year EHR data set, we applied the algorithm to test 470 randomly selected drug-event pairs. It was found possible to analyze a single drug-event pair in just 109 +/- 159 seconds. In total, 120 of the 150 detected signals corresponded with previously reported ADRs (positive predictive value (PPV) = 0.837 +/- 0.113, negative predictive value (NPV) = 0.659 +/- 0.180). By quickly and efficiently identifying ADR signals from EHR data, the CLEAR algorithm can significantly contribute to the utilization of EHR data for pharmacovigilance. PMID- 22237258 TI - CT contrast enhancement of the pancreas: patterns of enhancement, pitfalls and clinical implications. PMID- 22237259 TI - Pharmacogenetic analysis of BR.21, a placebo-controlled randomized phase III clinical trial of erlotinib in advanced non-small cell lung cancer. AB - BACKGROUND: BR.21 is a double-blind, placebo-controlled trial of second-/third line erlotinib in stage IIIB/IV non-small cell lung cancer patients. Predictive and prognostic analyses of epidermal growth factor receptor (EGFR), ABCG2, and AKT1 genetic polymorphisms were performed. METHODS: Two hundred forty-two patients were genotyped for EGFR-216G>T (EGFR216), EGFR-191C>A (EGFR191), EGFR intron 1 CA-dinucleotide-repeat (CADR), ABCG2+421C>A (ABCG2), and AKT1-SNP4G>A (AKT1). Cox proportional hazard and logistic regression models compared genotypes with overall survival (OS), progression-free survival (PFS), and presence/absence of skin toxicity. RESULTS: Prognostic evaluation was based on the placebo arm: patients carrying at least one CADR long allele (>16 repeats) had a trend toward worse PFS: the adjusted hazard ratio was 1.7 (95% confidence interval [CI]: 1.0 3.0; p = 0.07). EGFR216, EGFR191, ABCG2, and AKT1 were not prognostic. Polymorphisms were not predictive for erlotinib effect (OS/PFS): no treatment polymorphism interactions were demonstrated. Individuals carrying the rare T/T genotype of EGFR216 had an adjusted odds ratio of 8.8 (95% CI: 1.1-72; p = 0.04) of developing skin toxicity; no other significant polymorphic relationships with skin toxicity were found. CONCLUSIONS: In contrast to previous publications, carrying shorter alleles of the EGFR CADR polymorphism was not predictive of OS or PFS. EGFR216 homozygous variants were associated with greater skin toxicity from erlotinib. PMID- 22237260 TI - Physician preferences for management of patients with stage IIIA NSCLC: impact of bulk of nodal disease on therapy selection. AB - INTRODUCTION: Stage IIIA non-small cell lung cancer (NSCLC) constitutes a heterogeneous group of patients with predominant ipsilateral mediastinal (N2) disease. The spectrum of lymph node presentation has lead to a host of trials involving various therapeutic combinations, and optimal management has been unclear. METHODS: In 2007 and 2008, 10 live research events surveyed the practice preferences of American medical oncologists using two hypothetical scenarios. The first scenario was of a stage IIIA NSCLC in the right upper lobe with a single enlarged (>1 cm) 4R lymph node found to be malignant by mediastinoscopy. The second was of a bulky stage IIIA NSCLC with multistation N2 pathologically positive nodes. RESULTS: In the first scenario, 373 (92%) of the oncologists incorporated surgery into their treatment plan. Only 34 (8%) offered chemoradiotherapy alone. Neoadjuvant chemotherapy, followed by surgery and then additional chemoradiotherapy (32%), was the most commonly offered treatment strategy. In the second scenario, 209 (52%) medical oncologists chose definitive chemoradiation. A total of 193 (48%) included surgery as part of the treatment plan. CONCLUSIONS: The current standard of care for IIIA N2 NSCLC recognized before treatment is concurrent chemoradiotherapy. This study demonstrated that a significant proportion of oncologists treating locally advanced lung cancer include surgery as part of the treatment plan more so in single versus multinodal station disease. Since node positive locally advanced disease is such a common presentation for patients with lung cancer, well-designed clinical trials are needed to define the most advantageous treatment strategy for individual subsets of patients with stage IIIA disease. PMID- 22237261 TI - A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer. AB - INTRODUCTION: This phase I/II study evaluated the safety and antitumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non small cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3). RESULTS: Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21-432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors. CONCLUSIONS: The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low. PMID- 22237262 TI - Correlation between MET gene copy number by silver in situ hybridization and protein expression by immunohistochemistry in non-small cell lung cancer. AB - PURPOSE: The MET receptor is involved in the pathogenesis and progression of non small cell lung cancer (NSCLC). Clinical trials with MET inhibitors in NSCLC are planned with patient selection based on immunohistochemistry (IHC) and/or gene copy number assessment. Therefore, a detailed understanding of relationship between these markers and prognosis is essential. METHODS: This study included tumors from 189 patients with NSCLC who underwent pulmonary resection (median follow-up, 5.3 years). MET expression was evaluated by IHC on tissue microarrays and scored according to hybrid (H) score (range: 0-400) and by scoring system used in the MetMAb trial (>= 50% of cells with moderate or strong staining). MET gene copy number was assessed by silver in situ hybridization (n =140 patients). RESULTS: Median MET IHC H score was 60 (range: 0-400; n =174). There were no associations between clinical and pathological characteristics, disease-free survival, and overall survival according to median value (p =0.36 and p =0.38, respectively), or other cut-points. According to MetMAb scoring criteria, IHC positivity rate was 25%, again with no associations to clinicopathological features or survival. In 140 tumors evaluable for MET copy number, 3 (2.1%) showed gene amplification and 14 (10%) had tumors with average of 5 or more copies per nucleus. There were no associations of MET copy number with clinical characteristics, disease-free survival, or overall survival with any analyzed cut points. Correlation between MET copy number and protein expression was significant (Pearson's r =0.42, p < 0.0001). CONCLUSIONS: There is a significant correlation between MET protein expression and MET gene copy number in operable NSCLC, but neither is associated with prognosis. PMID- 22237263 TI - MET signaling: novel targeted inhibition and its clinical development in lung cancer. AB - MET is a versatile receptor tyrosine kinase within the human kinome which is activated by its specific natural ligand hepatocyte growth factor (HGF). MET signaling plays an important physiologic role in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. Studies have shown that MET pathway is activated in many solid and hematological malignancies, including lung cancer, and can be altered through ligand or receptor overexpression, genomic amplification, MET mutations, and alternative splicing. The MET signaling pathway is known to be an important novel target for therapeutic intervention in human cancer. A number of novel therapeutic agents that target the MET/HGF pathway have been tested in early-phase clinical studies with promising results. Phase 3 studies of MET targeting agents have just been initiated. We will review the MET signaling pathway and biology in lung cancer and the recent clinical development and advances of MET/HGF targeting agents with emphasis on discussion of issues and strategies needed to optimize the personalized therapy and further clinical development. PMID- 22237264 TI - High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) mutation has been known to be associated with adenocarcinoma with bronchioloalveolar carcinoma (BAC; lepidic) feature. This study was aimed to characterize the frequency of EGFR mutations and their association with histologic subtypes in Korean nonsmall cell lung cancer (NSCLC) patients. METHODS: Three hundred eighty-two (88 biopsies and 294 resections) NSCLC patients were investigated for EGFR mutations (exons 18-21) by polymerase chain reaction and direct sequencing method. For the resected adenocarcinoma specimens, histologic subtypes were classified according to both 2004 World Health Organization classification and 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The results were correlated with EGFR mutation and clinicopathologic features. RESULTS: EGFR mutations were detected in 196 of 382 NSCLCs (51.3%) and were more frequent in women than in men (65.7% versus 34.3%, p < 0.001) and in nonsmokers than in smokers (63.4% versus 32.0%, p < 0.001). Regarding histologic subtypes of adenocarcinoma, mixed acinar and BAC pattern showed the most frequent EGFR mutation (67.6%), followed by mixed papillary and acinar (65.2%), mixed solid and acinar (38.2%), micropapillary and acinar (30.4%), and acinar and mucinous BAC (13.3%). In addition, EGFR mutations were more frequently observed in tumors with BAC or papillary components than those with mucinous BAC or solid components. Identical EGFR mutations were detected in a single tumor showing mixed histological features. EGFR protein expression was seen more frequently in tumors with EGFR mutations than those without EGFR mutations (75.3% versus 24.7%, p=0.003). EGFR mutations were significantly more common in tumors with thyroid transcription factor-1 (TTF-1) expression than those without TTF-1 (p < 0.001), and almost all (92.7%) mutated adenocarcinomas were TTF-1 positive. CONCLUSIONS: The incidence of EGFR mutations is variable according to histologic subtypes, gender, and smoking history. The mixed acinar and BAC and papillary and acinar subtypes, the presence of BAC (lepidic) or papillary components, EGFR, and TTF-1 protein expression can predict higher EGFR mutation in lung adenocarcinoma. However, intratumoral heterogeneity of EGFR mutation was not found. In addition, relatively high incidence of EGFR mutations in Korean men who smoked with adenocarcinoma histology suggests that these patients should not be left behind EGFR mutation test. PMID- 22237266 TI - MAGE qPCR improves the sensitivity and accuracy of EBUS-TBNA for the detection of lymphatic cancer spread. AB - INTRODUCTION: Microscopic examination of histologic slides or cytologic specimens of mediastinal lymph node samples obtained by diagnostic mediastinoscopy or endobronchial ultrasound-guided fine-needle aspiration (EBUS-TBNA) is routinely used for the staging of lung cancer patients. Therefore, we explored whether the detection of tumor-associated mRNA in lymph node samples from patients with suspected lung cancer adds diagnostic accuracy to conventional histopathological staging. METHODS: We examined 202 lymph nodes obtained by EBUS-TBNA or mediastinoscopy from 89 patients with lung cancer. Lymph node samples from patients with nonmalignant disease were available as controls (60 samples from 31 patients). Real-time quantitative mRNA analysis was performed for melanoma antigen-A genes (MAGE-A 1-6, MAGE-A 12) using a LightCycler 480 instrument. RESULTS: MAGE transcript levels in control and cancer patients differed widely, and the 95% confidence interval served to define the threshold between negative and positive samples. MAGE 1 to 6 transcripts were detected in 35 of 122 (28.7%) lymph nodes obtained by EBUS-TBNA and 16 of 80 (20.0%) lymph nodes obtained by mediastinoscopy. MAGE 12 transcripts were detected in 10 of 122 (8.2%) lymph nodes obtained by EBUS-TBNA and 9 of 80 (11.3%) lymph nodes obtained by mediastinoscopy. Although the accuracy of histopathological diagnosis after EBUS TBNA and mediastinoscopy was 69.6% and 84.1%, respectively, it increased to 81.2% and 86.4%, respectively, when combined with MAGE-quantitative polymerase chain reaction. CONCLUSIONS: The combination of EBUS-TBNA and MAGE-quantitative polymerase chain reaction increases the accuracy of tumor cell detection to the level seen with mediastinoscopy. PMID- 22237267 TI - [Central neurobiological mechanism of liver depression and spleen deficiency syndrome based on chronic stress: a review]. AB - Some researchers focus on research of the nature of syndromes. The methods of combining traditional Chinese medicine syndrome and diseases and the correspondence between formulas and syndromes may be used in research of the nature of syndromes. According to combined theories of zang-organ state and seven emotions in traditional Chinese medicine with stress theory in modern medicine, the authors applied the methods of chronic immobilization stress to induce liver depression and spleen deficiency syndrome in rats based on the thinking of relativity on formula and syndrome. The research showed that the central neurobiology mechanism of liver depression and spleen deficiency syndrome closely correlates to the hypothalamic-pituitary-adrenal axis, brain-gut axis, myriad central neurotrophic factors, neurotransmitters, neuropeptides and hormones and their receptors, involving in many encephalic regions such as the hypothalamus, hippocampus, cortex, amygdale, etc. The authors will combine their previous work with multi-disciplinary research, such as genomics, proteomics, metabolomics and bioinformatics in future studies, to reveal the scientific connotations of liver depression and spleen deficiency syndrome. PMID- 22237268 TI - [Research advances in the relationship between prolactin and spontaneous abortion]. AB - Spontaneous abortion is one of the most common gestational conditions, with the morbidity of 1% to 5% in married women. It is a serious problem troubling women at the reproductive age. There are many factors causing spontaneous abortion, among them, spontaneous abortion resulting from endocrine abnormalities can be detected and treated. Prolactin is a major endocrine hormone participating in reproductive regulation and playing an important role in early pregnancy implantation and pregnancy maintenance. When there are unusual levels it is closely related to spontaneous abortion, leading to a necessity to further study the relationship between them. International and domestic research developments in recent years about the correlation between prolactin and spontaneous abortion are discussed in this paper. PMID- 22237269 TI - [The relationship between hypoxia-inducible factor-1alpha and cartilage degeneration in osteoarthritis: a review]. AB - Osteoarthritis is one of the most common diseases seen in clinical practice. Cartilage survives in the hypoxic microenvironment. Hypoxia-inducible factor 1alpha (HIF-1alpha) is a key nuclear transcription factor which mediates the hypoxic response of cells. HIF-1alpha gene is an important regulator for the adaptation of articular cartilage to the hypoxic environment. It is important for formation of articular cartilage, energy metabolism and matrix synthesis. If the HIF-1alpha gene is knocked out, the cartilage can not maintain their normal morphology and function, which may lead to cartilage degeneration, and result in diseases such as osteoarthritis. Chinese herbal medicines can regulate the expression of HIF-1alpha gene and supply a therapy method for osteoarthritis. In this paper, the authors review the situation of the correlation between HIF 1alpha and osteoarthritis cartilage degeneration examined in recent years. PMID- 22237270 TI - Research advances in treatment of cerebral ischemic injury by acupuncture of conception and governor vessels to promote nerve regeneration. AB - Cerebral ischemia is one of the most common diseases treated by acupuncture therapeutics. Recent studies indicated that acupuncture treatment by needling the conception and governor vessels had positive effects in promoting neural regeneration in patients after cerebral ischemia injury. Acupuncture intervention could continuously promote the proliferation and differentiation of the neural stem cells in the brain, obviously up-regulate expression of growth factors, accelerate angiogenesis and inhibit apoptosis. Hence, it is necessary to present an exhaustive review on the mechanisms. The present review gives a detailed description of pathological changes of cerebral ischemia and acupuncture intervention applied to the conception and governor vessels, and proposes research prospects in the future. PMID- 22237271 TI - [Systematic review and meta-analysis of randomized controlled trials comparing Chinese patent medicines Compound Danshen Dripping Pills and Di'ao Xinxuekang in treating angina pectoris]. AB - BACKGROUND: Chinese patent medicines Compound Danshen Dripping Pills (DSP) and Di'ao Xinxuekang (DXK) capsules were both found effective in treating angina pectoris. However, there is no systematic review comparing their efficacy. OBJECTIVE: This systematic review aims to compare the efficacy of DSP and DXK in treating angina pectoris based on randomized controlled trials (RCTs) comparing their efficacy. SEARCH STRATEGY: RCT reports published between 1994 and 2011 were retrieved from databases including China Doctoral Dissertations Full-text Database, Chinese Journal Full-text Database, China Master's Theses Full-text Database, Wanfang Data, Cochrane Library, Excerpts Medica Database, ScienceDirect, MEDLINE (EBSCOhost) and PubMed. The last retrieval was performed on April 7, 2011. INCLUSION CRITERIA: RCT reports comparing the effects of DSP and DXK were included, regardless publishing language. DATA EXTRACTION AND ANALYSIS: Included RCT reports were assessed for their study quality by using the Jadad scale and the Cochrane risk of bias tool. Data including overall effect and electrocardiography (ECG) improvements were extracted from the included RCTs for meta-analysis. The effect sizes based on overall and ECG diagnosis were measured by odds ratio (OR) and 95% confidence interval (CI). Subgroup analysis and sensitivity analysis were also performed. RESULTS: Nine RCT reports with 926 participants were included. Eight were scored 2 and the other one was scored 4 by using the Jadad scale. The OR between DSP and DXK based on overall diagnosis was 2.06 (95% CI: 1.03-4.12; P(overall)=0.04). Six out of the nine included RCTs reported ECG data. The OR between DSP and DXK based on the ECG diagnosis was 1.92 (95% CI: 1.23-3.00; P(ECG)=0.004). The OR results were stable under subgroup analysis and sensitivity analysis. CONCLUSION: DSP was consistently more effective than DXK according to meta-analysis, which was verified by subgroup analysis and sensitivity analysis. However, more RCTs of higher quality are needed for further confirmation. PMID- 22237272 TI - Estimation of sample size and testing power (Part 4). AB - Sample size estimation is necessary for any experimental or survey research. An appropriate estimation of sample size based on known information and statistical knowledge is of great significance. This article introduces methods of sample size estimation of difference test for data with the design of one factor with two levels, including sample size estimation formulas and realization based on the formulas and the POWER procedure of SAS software for quantitative data and qualitative data with the design of one factor with two levels. In addition, this article presents examples for analysis, which will play a leading role for researchers to implement the repetition principle during the research design phase. PMID- 22237273 TI - [Effects of summer acupoint application therapy in reducing exacerbation frequency of chronic lung diseases: protocol of a retrospective and prospective study]. AB - BACKGROUND: Chronic lung diseases, including bronchial asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, allergic rhinitis and repeated respiratory tract infection (RRTL) in infants, exacerbate frequently in winter because of respiratory viral infections and low temperature. Summer acupoint application therapy (SAAT) is thought to be effective in reducing exacerbation frequency of chronic lung diseases in winter. It is a kind of therapy using a herbal mixture for external application on special acupoints during summer. The herbal mixture basically contains Semen Sinapis Albae, Herba Asari, Radix Euphorbiae Kansui and Rhizoma Corydalis. The acupoints include Feishu (BL13), Dazhui (GV14) and Danzhong (CV17). Through a large-scale multicenter trial based on three years of clinical observation, and retrospective and prospective analyses, this study aims to explore the efficacy of SAAT. METHODS AND DESIGN: In this clinical observation trial, patients who have been diagnosed with bronchial asthma, COPD, chronic bronchitis, allergic rhinitis or RRTL will be enrolled from 13 centers. All patients enrolled will be treated with SAAT over a two-year period by medical practitioners. After this, an initial case report form (CRF) will be completed and forwarded to the central study site (China Academy of Chinese Medical Sciences, Beijing, China). The CRF is designed to investigate patients' history of medical treatment (including SAAT) and chronic lung disease exacerbation, also self-reported health condition. For retrospective analyses, the authors will focus on those who have accepted SAAT before enrollment and will collect their SAAT history and chronic lung disease exacerbation history, to evaluate the effects of SAAT. For prospective analyses, medical students will follow up with patients by phone interviews in winter once a year. The primary outcome is frequency of chronic lung disease exacerbation in winter. The secondary outcomes include conditions of lung disease recovery, non SAAT therapy, and a self health report. DISCUSSION: The authors aim to collect 7 400 patients from July 2008 to August 2009. The final follow-up has been completed in December 2010. To reduce the selection bias, a total of 13 clinical centers from different areas of China have participated in this study. The results from this study will provide a high-quality evidence base for evaluating the efficacy of SAAT in reducing exacerbation frequency of chronic lung diseases in winter. TRIAL REGISTRATION NUMBER: This trial has been registered in Chinese Clinical Trial Registry (Identifier: ChiCTR-TNRC-10001292). PMID- 22237274 TI - [Effects of acupuncture at Shenmen (HT7) or Taiyuan (LU9) on P3a and P3b of event related potentials in healthy young adults]. AB - OBJECTIVE: To investigate the effects of manual acupuncture at Shenmen (HT7) or Taiyuan (LU9) on the attention function of the brain, and to lay an experimental foundation for researching brain function and integration mechanisms of the human brain in relation to acupuncture stimulation. METHODS: Ten healthy young college students were selected as experimental subjects. P3a and P3b potentials were induced by novel stimulation and target stimulation with vision and were observed using Neuroscan event-related potentials system at time windows of ms 330-430 or 400-600 ms for observing the change of intensity distribution of P300 after manual acupuncture at HT7 or LU9. RESULTS: The amplitude of P3a and P3b decreased significantly after manual acupuncture at HT7 or LU9, but the degree of decreases affected by the acupoints was different. The decrease of the amplitude of P3a due to acupuncture at HT7 was more significant than acupuncture at LU9 (P<0.05). CONCLUSION: The attention function of the brain is affected by manual acupuncture at HT7 or LU9 and manual acupuncture at HT7 has a greater influence on the attention function of the brain. PMID- 22237275 TI - [Efficacy of cervical fixed-point traction manipulation for cervical spondylotic radiculopathy: a randomized controlled trial]. AB - BACKGROUND: Cervical spondylotic radiculopathy is a commonly encountered and frequently occurring disease. Traditional Chinese osteopathic manipulations may have better therapeutic efficacy than that of other methods in treating patients with cervical spondylotic radiculopathy. OBJECTIVE: To evaluate the clinical therapeutic effects of cervical fixed-point traction manipulation in treating patients with cervical spondylotic radiculopathy. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A prospective, randomized controlled trial was adopted. Eighty four patients with cervical spondylotic radiculopathy were randomly divided into treatment group (n=42) and control group (n=42). All patients were enrolled from the outpatient service of Department of Rehabilitation of Chinese PLA General Hospital of China. Patients received oral and written information about clinical procedures before giving their written informed consent. The patients were treated with cervical fixed-point traction manipulation (treatment group) or cervical computer traction (control group). Cervical fixed-point traction was performed once every other day for a total of seven treatment periods and cervical computer traction was performed 30 min, once per day for 14 d. MAIN OUTCOME MEASURES: Before and after treatment, visual analogue scale (VAS) score and temperature of upper limb skin (normal limb and abnormal limb) detected by infrared thermal imaging system were contrastively analyzed. RESULTS: Five patients were lost to follow-up, one patient in the treatment group and four patients in the control group. There were significant differences in VAS score and temperature difference between the normal and abnormal upper limbs of infrared thermal imaging in the treatment group (t=28.652, P<0.01; t=64.214, P<0.01) or in the control group (t=14.484, P<0.05; t=84.425, P<0.05) compared between before and after treatment. After treatment, the changes in VAS score and temperature difference of normal and abnormal upper limbs in the treatment group were more obvious compared with the control group (t=7.494, P<0.01; t=5.321, P<0.01). CONCLUSION: Cervical fixed-point traction manipulation has better efficacy than cervical computer traction in treating patients with cervical spondylotic radiculopathy. PMID- 22237276 TI - [Facial spectrum and color characteristics of five viscera reflecting on the face in sub-health status]. AB - OBJECTIVE: To observe the facial spectrum and color of different points, the positions of heart, liver, spleen, lung and kidney of traditional Chinese medicine reflecting on the face, in healthy participants and those with a sub health status, so as to provide an objective basis for health evaluation. METHODS: The health condition of 470 subjects without acute and chronic conditions was assessed using the Health Evaluating Questionnaire H20 V2009. The subjects were diagnosed with health (more than 80 score) or sub-health (score between 60 and 80) status according to the questionnaire score. The subjects with a subhealth status were also analyzed using the five-viscera syndrome differentiation of traditional Chinese medicine using the form for collecting information according to the four examinations. Then for gathering the facial color information, CIE L*a*b and C values and reflections of wavelengths ranged from 400 to 700 nm were measured using a CM-2600D spectrophotometer on 8 points of the face, including the frontal part, glabella, nose, mandible, two cheeks and eyelids. RESULTS: L value of the sub-health group was higher than that of the health group (P<0.05), and a, b and C values were lower than those of the health group (P<0.05), suggesting that the facial complexion of the sub-health group was pale/whiter than the health group. The reflectance rates of wavelengths (from 400 to 550 nm) of the sub-health group were higher than those of the health group (P<0.05), which suggested that the facial complexion of the sub-health group was partially green. The a, b and C values of the forehead, glabella and nose of subjects in the sub-health group were apparently different from the health subjects. L values of five-viscera types were significantly different from people of a health status (P<0.05). There were some differences in color values among the five-viscera groups: lung group's color values were significantly different from the others in terms of a, b and C values. The spectral reflectance of different viscera groups of the sub-health group also showed certain differences: reflectance of wavelengths at 400 to 490 nm in the lung group and at 520 to 580 nm in the spleen group showed significant difference from the other groups, and the lung group was lower and the spleen group was higher than the others. CONCLUSION: There are some differences in facial spectrum and color in different sites of the face in sub-health status of different viscera syndrome types, which can provide an objective basis for health evaluation. PMID- 22237277 TI - [Effects of platycodin D in combination with different active ingredients of Chinese herbs on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines]. AB - OBJECTIVE: To investigate the effects of platycodin D in combination with different active ingredients of Chinese herbs under different therapeutic principles on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines. METHODS: The effective doses of platycodin D, Ophiopogon total saponins, curcumenol and osthole in inhibiting proliferation of breast cancer cell lines 4T1 and MDA-MB-231 were detected by methyl thiazolyl tetrazolium (MTT) assay, respectively. Optimized combinations of platycodin D with Ophiopogon total saponins, curcumenol, or osthole were determined by uniform design method. Effects of the optimized combinations of platycodin D with the three ingredients on proliferation and invasion of 4T1 and MDA-MB-231 cells were verified and evaluated by MTT assay and Transwell chamber test, respectively. RESULTS: Verifying study showed that the inhibitory effects of platycodin D in combination with curcumenol or osthole on proliferation of 4T1 and MDA-MB-231 cells were better than those of platycodin D in combination with Ophiopogon total saponins and each ingredient used alone (P<0.05 or P<0.01). The inhibitory effect of platycodin D in combination with Ophiopogon total saponins or osthole on invasion of 4T1 cells was significantly better than those of platycodin D in combination with curcumenol and each ingredient used alone (P<0.05 or P<0.01). Moreover, the inhibitory effect of platycodin D in combination with curcumenol or osthole on invasion of MDA-MB-231 cells was significantly better than that of platycodin D in combination with Ophiopogon total saponins (P<0.01). CONCLUSION: The optimized combinations of platycodin D with three different active ingredients of Chinese herbs under different therapeutic principles can significantly inhibit the proliferation and decrease the invasion of 4T1 and MDA-MB-231 cells. Different platycodin D combinations have different potency in suppressing breast cancer cell proliferation and invasion. PMID- 22237278 TI - [Effects of extracts from Panax ginseng, Panax notoginseng and Ligusticum chuanxiong on expression of beta-galactosidase and signal pathway p16-cyclin D/CDK-Rb in vascular smooth muscle cells]. AB - OBJECTIVE: To observe the pathological changes of vascular aging in spontaneously hypertensive rats (SHRs), and the effects of extracts from Panax ginseng, Panax notoginseng (Burk.) and Ligusticum chuanxiong on vascular aging. METHODS: Vascular smooth muscle cells (VSMCs) isolated from thoracic aorta of Wistar-Kyoto (WKY) rats and SHRs were primarily cultured and divided into WKY group, SHR group, valsartan group, low-dose extract group and high-dose extract group. Aging situation of VSMCs was detected by senescence-associated beta-galactosidase (SA beta-gal) staining; the cell cycle was analyzed by flow cytometry; mRNA and protein expressions of p16, cyclin D1, cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (Rb) were detected by real-time fluorescence quantitative polymerase chain reaction (PCR) and Western blotting. RESULTS: SA-beta-gal stain showed that compared with the WKY group, number of SA-beta-gal-positive cells in the SHR group was increased significantly (P<0.01); extracts from Panax ginseng, Panax notoginseng (Burk.) and Ligusticum chuanxiong reduced the number of SA-beta gal-positive cells in the SHR group (P<0.01). Flow cytometry analysis showed that the number of VSMCs in G1 phase was reduced and in S phase was increased significantly (P<0.05) in the SHR group compared with the WKY group, and the number of VSMCs in G(1) phase was increased and in S phase was reduced significantly in the extracts groups (P<0.05). PCR result showed that compared with the WKY group, the mRNA expressions of p16 and Rb in the SHR group were reduced and those of cyclin D1 and CDK4 were increased significantly, the mRNA expressions of p16 and Rb in the extracts group were increased and mRNA expressions of cyclin D1 and CDK4 were reduced significantly. Western blotting result showed that compared with the WKY group, the protein expression of p16 in the SHR group was reduced and the protein expressions of cyclin D1, CDK4 and phospho-Rb were increased significantly (P<0.05), while the protein expression of p16 in the extracts group was increased and the protein expressions of cyclin D1, CDK4 and phospho-Rb were reduced significantly (P<0.05). CONCLUSION: The extracts from Panax ginseng, Panax notoginseng (Burk.) and Ligusticum chuanxiong can delay vascular aging of SHRs, which works by p16-cyclin D/CDK-RB pathways to inhibit VSMC proliferation. PMID- 22237279 TI - [Chinese herbal medicine Lingqi Huangban Granule protects retinal pigment epithelial cells against oxidative stress-induced injury in vitro]. AB - OBJECTIVE: To observe the protective effects of drug-contained serum of Lingqi Huangban Granule (LQHBG), a compound traditional Chinese herbal medicine, on oxidative stress-induced injury in rabbit retinal pigment epithelial (RPE) cells in vitro. METHODS: The oxidative stress of rabbit RPE cells in vitro was induced with hydrogen peroxide (500MUmol/L) and different concentrations of LQHBG were administered to rats to prepare medicated serum. RPE cells were randomized into normal control group (no hydrogen peroxide), model group (hydrogen peroxide), model plus serum group (hydrogen peroxide and 10% control serum), model plus low dose LQHBG group (hydrogen peroxide and low-dose LQHBG-medicated serum) and model plus high-dose LQHBG group (hydrogen peroxide and high-dose LQHBG-medicated serum). Teminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and flow cytometry (FCM) were used to measure apoptosis of cultured rabbit RPE cells. Protein expressions of caspase-3 and Bcl-X(L) were observed by Western blot method. RESULTS: FCM results showed that the apoptotic rates of the normal control group, model group, control serum group and serum containing low- and high-dose LQHBG groups were (4.85+/-0.26)%, (20.02+/-1.37)%, (21.84+/-0.94)%, (13.56+/-0.55)%, and (8.58+/-0.39)%, respectively; compared with the model group, the apoptotic rates of RPE cells in the low- and high-dose LQHBG groups were obviously reduced in a dose-related manner (P<0.05). TUNEL results showed that nuclei of apoptotic cells were stained brown; the number of apoptotic cells in the low- and high-dose LQHBG groups was obviously less than that in the model group. The protein expression of caspase-3 was up-regulated in the model and control serum groups, which was higher than that in the high-dose LQHBG group (P<0.05). The protein expression of Bcl-X(L) was down-regulated in the model and control serum groups, which was lower than that in the low- and high-dose LQHBG groups (P<0.01). CONCLUSION: Drug-contained serum of LQHBG obviously reduces apoptosis and partly protects rabbit RPE cells from oxidative stress-induced injury. The protective function is due to an improvement in antioxidant abilities, down-regulation of the expression of caspase-3 and up-regulation of the expression of Bcl-X(L). PMID- 22237280 TI - [Effects of the active components of Chinese herbal medicine Xiaoxuming Decoction on memory behavior and brain injury in rats with chronic cerebral ischemia]. AB - OBJECTIVE: To study the effects of the active components of Xiaoxuming Decoction (XXM), a compound traditional Chinese herbal medicine, on chronic cerebral ischemia in rats. METHODS: Chronic cerebral ischemia was induced in rats by occlusion of bilateral common carotid arteries. Then, the rats with chronic cerebral ischemia were randomly divided into five groups: model group, extract of Ginkgo biloba group and low-, medium- and high-dose active components of XXM groups. Another 11 rats without occlusion of common carotid arteries were used as the sham-operation group. Memory behavior was investigated by Morris water maze test. The structure of hippocampus and cortex neurons was observed with Nissel staining. The white matter lesion was stained with Kluver-Barrera stain method to observe the pathological changes. The astrocyte activation was observed using immunohistochemical method with glial fibrillary acidic protein (GFAP) antibody. RESULTS: The active components of XXM could significantly improve the impairment of learning and memory induced by chronic cerebral ischemia in rats. Compared with the model group, the time to reach the platform for rats was shortened by treating with the active components of XXM in Morris water maze test, particularly in the medium-dose group (P<0.05). In addition, the low- and medium dose active components of XXM improved the decrease of cerebrovascular reactivity induced by chronic cerebral ischemia. The results of the pathological analysis also suggested that the active components of XXM could ameliorate the pathological damage induced by chronic cerebral ischemia in rats with the number of neurons increased, and the morphology and distribution of neurons recovered to normal levels. The low-dose active components of XXM significantly reduced the white matter lesions (P<0.05, P<0.01). Active components of XXM treatment could also reduce the activation of astrocytes. CONCLUSION: The active components of XXM may attenuate the chronic cerebral ischemic injury in rats. PMID- 22237281 TI - [Dynamic changes of laboratory parameters of rats with type 2 diabetes and insulin resistance: defining their role in development of traditional Chinese medicine syndrome]. AB - OBJECTIVE: To observe the development of Chinese medicine syndromes of rats with type 2 diabetes and insulin resistance by detecting dynamic changes of laboratory parameters. METHODS: A total of 110 male Sprague-Dawley rats were randomly divided into control group (n=50) and model group (n=60) to observe the correlation between laboratory parameter changes and development of Chinese medicine syndromes. A rat model of type 2 diabetes and insulin resistance was established by feeding rats with high-calorie and high-fat diet together with peritoneal injection of streptozocin (30 mg/kg, once). At the end of 0, 6, 8, 10 and 12 weeks, 10 rats were randomly selected form each group and blood was taken from common carotid artery to detect contents of total cholesterol (TC), triacylglycerol (TAG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and leptin in serum, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) contents in plasma and whole blood and plasma viscosities. RESULTS: Compared with the control group, concentrations of TNF-alpha, IL-6, leptin and cAMP and ratio of cAMP/cGMP increased and content of cGMP decreased markedly from the 6th week to the 12th week. Concentrations of TC, TAG and LDL-C increased from the 8th week to the 12th week, while HDL-C decreased from the 10th week to the 12th week. Whole blood and plasma viscosity values under different shear rates increased significantly from the 10th week to the 12th week. CONCLUSION: Based on the understanding of markers which have close relationship with Chinese medicine syndromes of dual deficiency of qi and yin, turbid phlegm and blood stasis, combining with the dynamic changes of appearance behavior and laboratory parameters of this animal experiment, the authors speculate the development characteristics of Chinese medicine syndromes in rats with type 2 diabetes. The dynamic progress of Chinese medicine syndromes and pathology varies from dual deficiency of qi and yin to dual deficiency of qi and yin with turbid phlegm, and at last to the combination of dual deficiency of qi and yin, turbid phlegm and blood stasis. PMID- 22237282 TI - Isolation, characterization and thin-layer chromatography method development of clerosterol palmityl ester: a chemical marker for standardization of leaves of Clerodendrum phlomidis. AB - OBJECTIVE: Clerosterol palmityl ester (CPE) is a unique clerosterol derivative isolated and characterized from the leaves of Clerodendrum phlomidis. Considering the uniqueness of this compound, the present study was planned to use CPE as a specific chemical marker and develop a new validated thin-layer chromatography (TLC) method for standardisation of C. phlomidis. METHODS: Separation and quantification of CPE were achieved by TLC using a mobile phase of petroleum ether (60 to 80 degrees centigrade) and ethyl acetate (95:5, volume ratio) (Rf 0.64) on precoated silica gel 60F(254) aluminium plates. Densitometric determination was carried out after derivatization with anisaldehyde sulphuric acid reagent in absorption mode at 527 nm. RESULTS: The calibration curve was linear in the concentration range of 100 to 500 ng/spot. The method was validated for precision, repeatability and accuracy. The proposed method was found to be simple, specific, precise, accurate, rapid and cost-effective. CONCLUSION: This TLC procedure may be used effectively for quantitative determination of CPE, identification of the plant and standardization of this plant or its derived products. PMID- 22237283 TI - [Some suggestions on WHO/ICTM terminologies]. PMID- 22237284 TI - Interrelations among immune defense indexes reflect major components of the immune system in a free-living vertebrate. AB - Understanding the relationships among immune components in free-living animals is a challenge in ecoimmunology, and it is important not only for selecting the immune assays to be used but also for more knowledgeable interpretation of results. In this study, we investigated the relationships among six immune defense indexes commonly used by ecoimmunologists and measured simultaneously in individual free-living tree swallows. Three main axes of variation in immune function were identified using a principal components analysis, representing variation in T-cell, B-cell, and innate immunity. Measures within each axis tended to be positively correlated among individuals, while measures in different axes were uncorrelated. A trade-off between T-cell function and B-cell function became apparent only when variation among individuals in body condition, age, and general quality was taken into account. Interestingly, the level of natural antibodies, a component of innate immunity, showed the strongest association with components of acquired B-cell function, possibly reflecting a common underlying genetic mechanism, as has been documented in poultry. Our results indicate that despite the complexity of the immune system, important insights can be gained by using the currently available assays but in a more comprehensive approach than has generally been used in the field of ecoimmunology. PMID- 22237285 TI - Impact of body reserves on energy expenditure, water flux, and mating success in breeding male northern elephant seals. AB - In capital breeders, individual differences in body size and condition can impact mating effort and success. In addition to the collateral advantages of large body size in competition, large nutrient reserves may offer advantages in endurance rivalry and enable the high rates of energy expenditure associated with mating success. We examined the impacts of body reserves and dominance rank on energy expenditure, water flux, mating success, and breeding tenure in the adult male northern elephant seal, a polygynous, capital breeder. Adult males expended energy at a rate of 159 +/- 49 MJ d (-1), which is equivalent to 3.1 times the standard metabolic rate predicted by Kleiber's equation. Despite high rates of energy expenditure and a long fasting duration, males spared lean tissue effectively, deriving a mean of 7% of their metabolism from protein catabolism. Body composition had a strong impact on the ability to spare lean tissue during breeding. When controlling for body size, energy expenditure, depletion of blubber reserves, and water efflux were significantly greater in alpha males than in subordinate males. Large body size was associated with increased reproductive effort, tenure on shore, dominance rank, and reproductive success. Terrestrial locomotion and topography appeared to strongly influence energy expenditure. Comparisons with conspecific females suggest greater total seasonal reproductive effort in male northern elephant seals when controlling for the effects of body mass. In polygynous capital breeding systems, male effort may be strongly influenced by physiological state and exceed that of females. PMID- 22237286 TI - No effect of carotenoid supplementation on phytohemagglutinin response or body condition of nestling house wrens. AB - Carotenoids are an essential and often limiting resource in animals and play important roles in immune system function. In birds, the period shortly after hatching is an energetically demanding stage characterized by rapid growth in body size and organ systems, including the immune system. Availability of carotenoids for the growing nestlings may be of particular importance and potentially limiting at this stage of development. We tested the hypothesis that the availability of carotenoids for the embryo in the egg and in the diet of nestlings limits the condition and immune responses of nestling house wrens (Troglodytes aedon Vieillot 1809), a species with melanin-based plumage pigments. In one experiment, nestlings within females' second broods were randomly assigned to receive either a control or a lutein supplement (2008); in a second experiment, females, before their first broods, were either induced to lay additional eggs or not induced, and nestlings within both kinds of broods were supplemented as in the first experiment (2009). There were no significant effects of lutein supplementation on nestling condition or phytohemagglutinin response. There was a significant effect of lutein supplementation on nestling mass in 2008, but the difference was opposite to that predicted. Moreover, even when breeding females were stressed by inducing them to lay supernumerary eggs, lutein supplementation of nestlings had no effect on the size or condition of nestlings hatching from these eggs. These results suggest that maternally derived lutein in the egg and that provided in the diet of nestlings are not limiting to normal development and to the components of the immune system involved in the phytohemagglutinin response of nestling house wrens. PMID- 22237287 TI - Neural thermal performance in porcelain crabs, genus Petrolisthes. AB - Neurons are highly temperature sensitive. Temperature-induced nerve failure may play an important role in determining organismal thermal tolerance limits and distribution patterns. To expand our understanding of the role of neuronal thermal performance in setting thermal limits, we compared the thermal performance of neurons from five porcelain crab (genus Petrolisthes) congeners that differ in thermal habitat. In experiment 1, neuronal performance of sensory neurons was determined by extracellular recording of spontaneous action potentials during thermal ramps. Arrhenius break temperatures of action potential generation were used to calculate maximum critical temperature (CT(max)) and minimum critical temperature (CT(min)) for neuronal performance. CT(max) and CT(min) were related to habitat temperature across the five species and were found to respond to acclimation temperature. In experiment 2, we assessed the performance of neurons from Petrolisthes cinctipes acclimated at 8 degrees , 18 degrees , and 25 degrees C when placed at 30 degrees C (near the whole-organism CT(max) of this species) and demonstrated that neural performance near whole organism CT(max) increases with increasing acclimation temperature. In experiment 3, we compared the thermal limits of sensory afferents and pacemaker efferents and found that they were correlated, although pacemaker efferents tended to have a higher CT(max) and reduced plasticity. Our final analysis, which was of transcriptomic data in cardiac tissue, leads us to hypothesize that nerve membrane K(+) conductance may underlie variation in nerve thermal tolerance. PMID- 22237288 TI - Cocoon and epidermis of Australian Cyclorana frogs differ in composition of lipid classes that affect water loss. AB - For amphibians to survive in environments that experience annual droughts, they must minimize evaporative water loss. One genus of Australian hylid frogs, Cyclorana, prevents desiccation by burrowing in the soil and forming cocoons composed of alternating layers of shed epidermis and glandular secretions. Previous data are inconclusive about the role that lipids play in reducing evaporative water loss through skin (cutaneous water loss [CWL]) when Cyclorana spp. are within cocoons. In this study, we measured CWL and lipids in the epidermis and in cocoons of five species of Cyclorana. CWL was significantly lower in frogs within cocoons than in frogs without cocoons. Surface-area specific CWL for the three small species was significantly higher than that of the two larger species of Cyclorana, but this difference was not apparent in frogs within cocoons. Although lipids were responsible for more of the dry mass of the epidermis (approximately 20%) than of the cocoons (approximately 7%) we found that cerebrosides and ceramides, two polar lipid classes, were almost exclusively found in cocoons. This suggests that these lipid classes are in the glandular secretions rather than in the epidermis. Because these polar lipids are the types that reduce water loss in birds (cerebrosides and ceramides) and mammals (ceramides), we conclude that they are important not only for holding together the shed layers of skin but also for contributing to the barrier against water loss. PMID- 22237289 TI - Effect of dietary restriction on immune response of laboratory mice divergently selected for basal metabolic rate. AB - To study whether dietary restriction (DR; 70% of ad lib. feeding)-elicited immunosuppression results from the trade-off between the costs of mounting an immune response and the metabolic costs of maintenance, we subjected mice from two divergent lines selected for high basal metabolic rate (H-BMR) and low BMR (L BMR) to 4 wk of DR and then challenged them with keyhole limpet hemocyanin (KLH) antigen. Those line types differ genetically with respect to BMR and to the mass of metabolically expensive internal organs, which are larger in H-BMR mice. In mice of both line types, DR resulted in a significant reduction of body mass, an immune response, and the downsizing of spleen, lymph nodes, thymus, heart, and kidneys but not small intestines. DR resulted in a greater reduction of the spleen and lymph nodes in mice of the H-BMR line type, whereas the thymus was more affected in L-BMR line type. In contrast, immunization resulted in an increase of liver mass in DR mice of both line types. A comparison of the results of current and earlier studies on the same mouse line types suggests that metabolic trade-offs involving the costs of an immune response are more apparent when animals are forced to increase energy demands (e.g., by cold exposure) compared to when energy demands are decreased through DR. Our findings also suggest that divelrgent selection on BMR resulted in between-line-type differences in T-cell- and B-cell-mediated types of an immune response. More generally, our results indicate that production of a wide repertoire of antibodies is not correlated with high BMR. PMID- 22237290 TI - Sex and proximity to reproductive maturity influence the survival, final maturation, and blood physiology of Pacific salmon when exposed to high temperature during a simulated migration. AB - Some Pacific salmon populations have been experiencing increasingly warmer river temperatures during their once-in-a-lifetime spawning migration, which has been associated with en route and prespawn mortality. The mechanisms underlying such temperature-mediated mortality are poorly understood. Wild adult pink (Oncorhynchus gorbuscha) and sockeye (Oncorhynchus nerka) salmon were used in this study. The objectives were to investigate the effects of elevated water temperature on mortality, final maturation, and blood properties under controlled conditions that simulated a "cool" (13 degrees C) and "warm" (19 degrees C) freshwater spawning migration. After 10 d at 13 degrees C, observed mortality was 50%-80% in all groups, which suggested that there was likely some mortality associated with handling and confinement. Observed mortality after 10 d at 19 degrees C was higher, reaching >=98% in male pink salmon and female pink and sockeye salmon. Thus, male sockeye salmon were the most thermally tolerant (54% observed mortality). Model selection supported the temperature- and sex-specific mortality patterns. The pink salmon were closer to reproductive maturation and farther along the senescence trajectory than sockeye salmon, which likely influenced their survival and physiological responses throughout the experiment. Females of both species held at 19 degrees C had reduced plasma sex steroids compared with those held at 13 degrees C, and female pink salmon were less likely to become fully mature at 19 degrees than at 13 degrees C. Male and female sockeye salmon held at 19 degrees C had higher plasma chloride and osmolality than those held at 13 degrees C, indicative of a thermally related stress response. These findings suggest that sex differences and proximity to reproductive maturity must be considered when predicting thermal tolerance and the magnitude of en route and prespawn mortality for Pacific salmon. PMID- 22237291 TI - Expression analysis of glycerol synthesis-related liver transcripts in rainbow smelt (Osmerus mordax) exposed to a controlled decrease in temperature. AB - Rainbow smelt (Osmerus mordax) accumulate high glycerol levels to avoid freezing at subzero temperatures. Glyceroneogenesis is activated by low temperature and occurs in liver via a branch in glycolysis and gluconeogenesis. In this study, carbohydrate and liver transcript levels of 21 genes potentially associated with glycerol production were assessed during a controlled warm to cold transition. Smelt were held at 8 degrees C (warm smelt; non-glycerol accumulating) or subjected to a controlled decrease in water temperature from 8 degrees to 0 degrees C (cold smelt; glycerol accumulating) and sampled at the end of the temperature decrease and 1 mo later. In cold smelt compared with warm smelt, liver glycogen levels were lower and phosphoglucomutase transcript levels were higher. Plasma glycerol levels were higher and increased over time in cold smelt; in cold smelt, liver phosphofructokinase and pyruvate dehydrogenase kinase transcript levels increased over time. These findings imply that glycerol production is being fueled by glycogen degradation and inhibition of pyruvate oxidation serves to channel metabolic flux toward glycerol as opposed to complete glycolysis. Plasma glucose and liver glucose-6-phosphatase transcript levels were higher. Lipoprotein lipase transcript levels were higher, suggesting enhanced lipid breakdown to fuel energy metabolism. Glutamine synthetase transcript levels were higher, perhaps to store nitrogen for biosynthesis in spring. PMID- 22237292 TI - Determining seabird body condition using nonlethal measures. AB - Energy stores are critical for successful breeding, and longitudinal studies require nonlethal methods to measure energy stores ("body condition"). Nonlethal techniques for measuring energy reserves are seldom verified independently. We compare body mass, size-corrected mass (SCM), plasma lipids, and isotopic dilution with extracted total body lipid content in three seabird species (thick billed murres Uria lomvia, all four measures; northern fulmars Fulmarus glacialis, three measures; and black-legged kittiwakes Rissa tridactyla, two measures). SCM and body mass were better predictors of total body lipids for the species with high percent lipids (fulmars; R2 = 0.5-0.6) than for the species with low percent lipids (murres and kittiwakes; R2 = 0.2-0.4). The relationship between SCM and percent body lipids, which we argue is often a better measure of condition, was also poor (R2 < 0.2) for species with low lipids. In a literature comparison of 17 bird species, percent lipids was the only predictor of the strength of the relationship between mass and total body lipids; we suggest that SCM be used as an index of energy stores only when lipids exceed 15% of body mass. Across all three species we measured, SCM based on the ordinary least squares regression of mass on the first principal component outperformed other measures. Isotopic dilution was a better predictor of both total body lipids and percent body lipids than were mass, SCM, or plasma lipids in murres. Total body lipids decreased through the breeding season at both sites, while total and neutral plasma lipid concentrations increased at one site but not another, suggesting mobilization of lipid stores for breeding. A literature review showed substantial variation in the reliability of plasma markers, and we recommend isotopic dilution (oxygen-18, plateau) for determination of energy reserves in birds where lipid content is below 15%. PMID- 22237293 TI - Tissue carbon incorporation rates and diet-to-tissue discrimination in ectotherms: tortoises are really slow. AB - Abstract Understanding carbon incorporation rates and diet-to-tissue discrimination (Delta(13)C(tissue-diet)) in animals is necessary to interpret stable isotope data collected from animals in the field. Our current understanding of the carbon dynamics in terrestrial ectotherms such as snakes, lizards, and turtles is poorly developed. Here we use a diet switch experiment to estimate carbon incorporation rates and diet-to-tissue discrimination factors in growing desert tortoises (Gopherus agassizii). Average carbon retention times for red blood cells (RBCs) and plasma were 126.7 +/- 40.3 and 32.9 +/- 14.5 days, respectively. Tissue carbon incorporation rates were affected by both growth and metabolism, with growth accounting for 50% of the carbon turnover in RBCs and 13% of carbon turnover in plasma. At equilibrium, scute keratin (0.8 +/- 0.1) and plasma (1.0 +/- 0.2) showed enriched discrimination values (Delta(13)C) compared to the test diet, but RBC Delta(13)C values were indistinguishable from diet (0.2 +/- 0.3). We also found that new keratin continued to contribute significant material to previously grown keratin rings on the tortoise's shell. Changes in the delta(13)C of previously laid down growth rings indicated that the old rings closest to the region of new growth received about 73% of the carbon from the current diet; these data suggest that the interpretation of dietary history using growth rings must recognize that each ring may represent the weighted average of the diet over several seasons. These results continue to highlight the importance of laboratory experiments in interpreting isotopic data derived from field studies. PMID- 22237294 TI - The Neoadjuvant Net: a patient- and surgeon-friendly device to facilitate safe breast-conserving surgery in patients who underwent neoadjuvant treatment. AB - The primary goal of the study was to describe an innovative and helpful tool in defining the minimal surgical margins necessary during breast-conserving surgery (BCS) after neoadjuvant treatment: the Neoadjuvant Net (NN). The secondary endpoint was to assess its usefulness in achieving postoperative disease-free margins and reducing Ipsilateral Breast Tumor Recurrences (IBRTs). The breast conserving surgical technique together with the use of the Neoadjuvant Net is herein reported. Age, stage at diagnosis, clinical and pathological response, lymph node status, type of surgery, margin status, and incidence of local and distant recurrence were retrospectively analyzed. Seventy-five patients underwent BCS following medical treatment from 2000 to 2011. The majority of the patients had significant size reduction (63/75, 84%). Twenty-two had a complete clinical response but only 11 (11/75, 14.7%) showed a complete pathological response. Two patients (2/75, 2.67%) had infiltrated surgical margins. After a mean follow-up of seventy months, 3 patients (3/75, 4%) had IBRTs and 4 women had distant metastases (4/75, 5.34%). The NN is an easy-to-use, non-invasive instrument designed with the purpose of facilitating the surgeon's task of reducing infiltrated margins and IBTRs. PMID- 22237296 TI - Completion node dissection in patients with sentinel node-positive melanoma of the head and neck. AB - OBJECTIVE: Determine if completion lymph node dissection (CLND) is associated with improved survival in sentinel lymph node (SLN)-positive cutaneous melanoma of the head and neck (CMHN) patients. STUDY DESIGN: Retrospective analysis of large population database. SETTING: Surveillance, Epidemiology and End Results (SEER) database/multiple settings. SUBJECTS AND METHODS: Using the SEER database, the authors identified patients with SLN-positive CMHN. Clinicopathologic data and 5-year disease-specific survival (DSS) were examined for patients who underwent sentinel lymph node biopsy (SLNB) alone vs SLNB + CLND. RESULTS: Among 350 SLN-positive patients, 210 (60%) had SLNB + CLND, and 140 (40%) had SLNB only. Patients in the SLNB-only group were significantly older (median age 62 vs 53 years, P < .0001). The cohort as a whole did not significantly benefit from CLND; however, CLND was associated with improved DSS for a subgroup of patients age <60 years with nonulcerated tumors <= 2 mm thick (P = .03). Relative to SLNB alone, CLND did not improve survival for patients age >= 60 years or those with thicker (>2 mm) or ulcerated tumors. CONCLUSIONS: Compared with SLNB alone, CLND does not seem to be associated with improved survival for most patients with SLN positive CMHN. CLND likely improves survival for patients age <60 years with thin (<= 2 mm) nonulcerated tumors and when there is a low risk of identifying positive non-SLNs. PMID- 22237297 TI - Augmentation of ocular vestibular-evoked myogenic potentials via bone-conducted vibration stimuli in Meniere disease. AB - OBJECTIVE: The asymmetry ratio of ocular vestibular-evoked myogenic potential (oVEMP) >40% is interpreted as augmented or reduced response depending on whether the nI-pI amplitude of the lesion ear is larger or smaller than that of the opposite ear, respectively. This study compared unilateral Meniere disease patients with augmented oVEMPs vs reduced oVEMPs to elucidate the mechanism of augmented oVEMP. STUDY DESIGN: Case series with chart review. SETTING: University hospital. METHODS: Forty patients with unilateral definite Meniere disease were enrolled in this study, including 20 patients with augmented oVEMPs and another 20 patients with reduced oVEMPs in the hydropic side. All patients underwent audiometry, caloric test, and oVEMP and cervical VEMP (cVEMP) tests via bone conducted vibration stimuli. Then, the oVEMP and cVEMP test results were compared with the stage of Meniere disease, respectively. RESULTS: The augmented group had earlier nI and pI latencies and larger nI-pI amplitude of oVEMPs compared with the reduced group. Caloric test also revealed a significant difference in abnormal responses between the augmented and reduced groups. However, both groups did not differ significantly in the abnormal percentage of cVEMP test results. A significant trend to decline in the prevalence of augmented oVEMPs was noted from stages I to III-IV but not in that of abnormal cVEMPs. CONCLUSION: The augmented oVEMPs have earlier latencies and larger amplitudes compared with the reduced oVEMPs, indicating that a relatively larger population of intact utricular afferents is activated during the early stage of Meniere disease. PMID- 22237295 TI - Air pollution and markers of coagulation, inflammation, and endothelial function: associations and epigene-environment interactions in an elderly cohort. AB - BACKGROUND: Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states. METHODS: We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short- and intermediate-term air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-like receptor 2 (TLR-2), and ICAM-1. RESULTS: We found effects of particle number, black carbon, nitrogen dioxide (NO(2)), and carbon monoxide (CO) on fibrinogen. Ozone was a predictor of C reactive protein and ICAM-1. Particle number, black carbon, NO(2), CO, PM(2.5), and sulfates were associated with ICAM-1 and VCAM-1. An interquartile range increase in 24-hour exposure for NO(2) was associated with a 1.7% (95% confidence interval = 0.2%-3.3%) increase in fibrinogen for ozone; a 10.8% (2.2%-20.0%) increase in C-reactive protein for particle number; a 5.9% (3.6%-8.3%) increase in ICAM-1; and for PM(2.5), a 3.7% (1.7%-5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status. CONCLUSION: We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution. PMID- 22237298 TI - Calcium management after thyroidectomy: a simple and cost-effective method. AB - OBJECTIVE: Hypocalcemia is one of the principal complications of total or completion thyroidectomy. A number of different protocols for managing this potential complication have been published. Our simple postoperative regimen is described and the safety and cost-effectiveness assessed. STUDY DESIGN: Case series with planned data collection. SETTING: Academic medical center. SUBJECTS AND METHODS: All patients undergoing total or completion thyroidectomy from January 2008 through June 2010 were evaluated. Data collected included age; gender; procedure performed; levels of ionized calcium, parathyroid hormone, and vitamin D; complications; and need for readmission. Standard descriptive statistics were used to summarize these data. RESULTS: In total, 526 patients had thyroid surgery during the 30-month study period. Of these, 307 underwent completion or total thyroidectomy and were prescribed a 3-week tapering course of calcium carbonate postoperatively. Twenty-three patients (7.5%) experienced symptoms of hypocalcemia that were managed on an outpatient basis with additional doses of oral calcium. Two patients (0.7%) required readmission. The cost of a 3 week regimen of calcium carbonate is approximately $15. This is considerably less expensive than either the cost of overnight admission or published laboratory protocols that are designed to predict the risk of hypocalcemia. CONCLUSIONS: Prophylactic calcium supplementation without routine laboratory assessment proved to be a safe and cost-effective method of preventing and managing postoperative hypocalcemia following total or completion thyroidectomy. PMID- 22237299 TI - Preliminary report of vocal fold augmentation with cross-linked porcine collagen. AB - OBJECTIVE: To evaluate the short-term outcomes of using cross-linked porcine collagen for vocal fold augmentation. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral hospital. SUBJECTS AND METHODS: Twenty consecutive patients of unilateral vocal fold paralysis (UVFP) were recruited, including 10 males and 10 females. All the subjects received videolaryngostroboscopic (VLS) evaluation for the glottic closure pattern, perceptual grading using the GRB scale (grade, roughness, breathiness), acoustic analysis, maximal phonation time (MPT), and Voice Handicap Index (VHI) questionnaire. Purified telopeptide-free, glutaraldehyde cross-linked porcine collagen was injected under local anesthesia with fiberscopic guidance. RESULTS: Treatment outcomes were evaluated 3 months after the injection. Fifteen (75%) of 20 patients reported complete resolution of symptoms, whereas the other 5 (25%) patients had substantial improvements. The median score of perceptual analysis of voice quality showed significant improvements from G2/R2/B2 to G1/R1/B0 (P < .001). Glottic closure pattern under stroboscopy had improved from "predominantly open" before the procedure to a "half-open and half-close" pattern after the procedure (P < .001). Acoustic analysis demonstrated significant improvements of jitter and normalized noise energy (P < .05). Maximal phonation time revealed a significant improvement from 7.5 +/- 3.2 seconds to 13.1 +/- 3.9 seconds (P < .01). The VHI had also decreased from 53 +/- 25 points to 27 +/- 20 points (P < .01). No patients had serious adverse events during the follow-up period. CONCLUSION: This case series demonstrated that porcine collagen may be a suitable material for temporary vocal fold augmentation. PMID- 22237300 TI - Low-cost LED annular illuminator for intraoral photography. PMID- 22237301 TI - Cigarette smoke inhibits dynamic ciliary beat frequency in pediatric adenoid explants. AB - OBJECTIVE: Environmental tobacco smoke exposure in children increases the incidence of upper respiratory infections, chronic sinusitis, and chronic otitis media. This study investigated the effects of ex vivo and in vitro smoke exposure on dynamic ciliary beat frequency (CBF) in pediatric adenoid explants. STUDY DESIGN: Blinded and controlled prospective study. SETTING: Tertiary care pediatric hospital. SUBJECTS AND METHODS: Fifty-five children undergoing adenoidectomy for obstructive sleep apnea and adenotonsillar hypertrophy were enrolled in this study. Adenoids were surgically removed using currettage. Hair was collected for nicotine analysis. Tissue was sectioned into 1-mm strips and allowed to equilibrate in DMEM/F12 with 2% fetal bovine serum for 24 hours. Cilia bearing explant tissues were treated with either DMEM/F12 media, 5% cigarette smoke extract (CSE), or 10% CSE for 24 hours. Cilia were then stimulated using either isoproterenol (10(-9) M) or methacholine (10(-6)M), and CBF was serially recorded using the Sisson-Ammons Video Analysis (SAVA) software. RESULTS: Children with hair nicotine levels >= 1 ng/mg consistent with secondhand smoke exposure display blunted dynamic CBF response ex vivo. Explants incubated with CSE in vitro demonstrate significant impairment of isoproterenol and methacholine induced CBF. CONCLUSION: CBF of adenoid explants increases when stimulated with isoproterenol and methacholine. Ex vivo and in vitro smoke exposure blunted ciliostimulation of CBF in adenoid explants. Smoke exposure impairs ciliary function in the pediatric airway and could potentially contribute to disorders such as chronic rhinosinusitis and chronic otitis media. PMID- 22237303 TI - Divergence of larval resource acquisition for water conservation and starvation resistance in Drosophila melanogaster. AB - Laboratory selection experiments have evidenced storage of energy metabolites in adult flies of desiccation and starvation resistant strains of D. melanogaster but resource acquisition during larval stages has received lesser attention. For wild populations of D. melanogaster, it is not clear whether larvae acquire similar or different energy metabolites for desiccation and starvation resistance. We tested the hypothesis whether larval acquisition of energy metabolites is consistent with divergence of desiccation and starvation resistance in darker and lighter isofemale lines of D. melanogaster. Our results are interesting in several respects. First, we found contrasting patterns of larval resource acquisition, i.e., accumulation of higher carbohydrates during 3rd instar larval stage of darker flies versus higher levels of triglycerides in 1st and 2nd larval instars of lighter flies. Second, 3rd instar larvae of darker flies showed ~40 h longer duration of development at 21 degrees C; and greater accumulation of carbohydrates (trehalose and glycogen) in fed larvae as compared with larvae non-fed after 150 h of egg laying. Third, darker isofemale lines have shown significant increase in total water content (18%); hemolymph (86%) and dehydration tolerance (11%) as compared to lighter isofemale lines. Loss of hemolymph water under desiccation stress until death was significantly higher in darker as compared to lighter isofemale lines but tissue water loss was similar. Fourth, for larvae of darker flies, about 65% energy content is contributed by carbohydrates for conferring greater desiccation resistance while the larvae of lighter flies acquire 2/3 energy from lipids for sustaining starvation resistance; and such energy differences persist in the newly eclosed flies. Thus, larval stages of wild-caught darker and lighter flies have evolved independent physiological processes for the accumulation of energy metabolites to cope with desiccation or starvation stress. PMID- 22237302 TI - Carotenoid supplementation and GnRH challenges influence female endocrine physiology, immune function, and egg-yolk characteristics in Japanese quail (Coturnix japonica). AB - Androgens and carotenoids circulating in plasma affect the physiology and behavior of vertebrates. Much is known about control mechanisms and functions of each of these substances, yet their interactive effects are not well understood. Here we examine possible additive, multiplicative, and interactive effects of testosterone and carotenoids on female endocrine physiology, immunocompetence, and investment in eggs by simultaneously manipulating levels of testosterone [via gonadotropin releasing hormone (GnRH) challenges] and carotenoids (via diet supplementation) in captive female Japanese quail (Coturnix japonica). Females were randomly assigned to one of four treatments: carotenoid supplementation, GnRH challenge, GnRH challenge + carotenoid supplementation, or control. Carotenoid supplementation significantly increased circulating plasma carotenoid levels and acquired immune system performance, but not innate immunity. GnRH challenges elevated circulating testosterone and carotenoid levels, and induced immunosuppression in females. However, females in the GnRH challenge + carotenoid supplementation treatment had higher cell-mediated immune responses than control females and similar responses to those of carotenoid-supplemented females. Hence, availability of carotenoids in female quail seemed to counteract immunosuppressive effects of GnRH challenges. Our results provide further evidence for synergistic effects of carotenoids and testosterone on endocrine physiology and immune function in female birds. Elevated plasma testosterone or carotenoids levels resulted in increased deposition of those compounds to eggs, respectively. Furthermore, because we found that concentrations of testosterone and carotenoids in yolks were correlated within each treatment group, differential deposition of hormones and carotenoids in eggs may not only respond to surrounding social and environmental conditions, but also to other components of the egg. PMID- 22237307 TI - Variability of CT contrast enhancement in the pancreas: a cause for concern? AB - BACKGROUND: Multidetector CT is a valuable technique for diagnosis/staging in several pancreatic pathologies. Diagnosis is usually based on tissue density measurements. Recently, newer functional CT techniques have been introduced. The aim of this study was to assess variability in perfusion and dual-energy CT data, and to compare these data with density measurements in the pancreas of a healthy population. METHODS: Two groups were included: 20 patients underwent perfusion CT imaging, and 10 patients were scanned using a dual-energy protocol. In both groups, tissue density [Hounsfield units (HU)] was measured in the pancreatic head, body and tail. Functional data were calculated (blood flow/blood volume in the perfusion CT group, iodine concentration in the dual-energy group), and variability was assessed. RESULTS: Density measurements were comparable for the perfusion and dual-energy CT groups, and ranged from 14 to 60 HU. Maximal enhancement differences between the head/body/tail of the pancreas ranged between 2 and 21 HU. Considerable variability was observed, both in density measurements (ranging from 3 to 34%) and in functional parameters (mean variability in perfusion CT parameters blood flow and blood volume was 21.3 and 10% respectively; mean variability in dual-energy iodine-mapping results was 24.4%). CONCLUSION: This study demonstrated the presence of important intraindividual variability in pancreatic tissue contrast enhancement, regardless of the CT technique used. Considering the variability observed in this study, the use of cut-off values to characterize pancreatic pathologies seems troublesome, and morphologic primary and secondary changes will remain important, even when using novel functional imaging techniques. and IAP. PMID- 22237308 TI - Relationship between urinary tract infection categorization and pathogens' antimicrobial susceptibilities. AB - BACKGROUND: Urinary tract infections (UTIs) can be hard to treat and treatment plans need to include accurate categorization such as uncomplicated or complicated UTI, or catheterized or uncatheterized UTI. We investigated the antibiotic susceptibilities of representative uropathogens in UTI categories. METHODS: We isolated uropathogens and analyzed their antimicrobial susceptibilities according to UTI categorization such as: (1) urology outpatients, urology inpatients, or other department inpatients; (2) uncomplicated or complicated UTIs; (3) upper or lower UTIs, and (4) non catheterized or catheterized UTIs. RESULTS: Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa were representative uropathogens. Susceptibilities to levofloxacin (LVFX) in E. coli in urology outpatients (p = 0.0179), those to ceftadizime in E. coli in other department inpatients (p = 0.0327), and those to LVFX in E. faecalis in complicated UTI (p = 0.0137) significantly decreased in these 3 years compared with the previous 3 years. Susceptibilities of upper UTI to LVFX in E. coli were significantly lower in the recent 4 years compared to lower UTI (p = 0.0452) and those of catheterized UTI to LVFX in E. faecalis were significantly lower than in non-catheterized UTI (p = 0.0153). CONCLUSIONS: Data demonstrated different tendencies of uropathogens' antibiotic susceptibilities according to UTI categorizations and they could be useful for planning UTI treatments. PMID- 22237309 TI - Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients. AB - Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies using baseline gene expression profiles have provided mixed results, our approach was to use an in vivo dexamethasone challenge test and to compare glucocorticoid receptor (GR)-mediated changes in gene expression between depressed patients and healthy controls. Whole genome gene expression data (baseline and following GR stimulation with 1.5 mg dexamethasone p.o.) from two independent cohorts were analyzed to identify gene expression pattern that would predict case and control status using a training (N=18 cases/18 controls) and a test cohort (N=11/13). Dexamethasone led to reproducible regulation of 2670 genes in controls and 1151 transcripts in cases. Several genes, including FKBP5 and DUSP1, previously associated with the pathophysiology of major depression, were found to be reliable markers of GR-activation. Using random forest analyses for classification, GR-stimulated gene expression outperformed baseline gene expression as a classifier for case and control status with a correct classification of 79.1 vs 41.6% in the test cohort. GR-stimulated gene expression performed best in dexamethasone non-suppressor patients (88.7% correctly classified with 100% sensitivity), but also correctly classified 77.3% of the suppressor patients (76.7% sensitivity), when using a refined set of 19 genes. Our study suggests that in vivo stimulated gene expression in peripheral blood cells could be a promising molecular marker of altered GR-functioning, an important component of the underlying pathology, in patients suffering from depressive episodes. PMID- 22237313 TI - Re: immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. PMID- 22237310 TI - Social fear conditioning: a novel and specific animal model to study social anxiety disorder. AB - Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1 s, 0.7 mA) during the investigation of a con specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches. PMID- 22237311 TI - Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia. AB - Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABA(A) receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB-6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB-6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25-11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB 649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB 649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem. PMID- 22237314 TI - Re: prognosis and characteristics of renal cell carcinoma in hemodialysis patients: bilateral occurrence does not influence cancer-specific survival. PMID- 22237315 TI - Re: tumour diameter and decreased preoperative estimated glomerular filtration rate are independently correlated in patients with renal cell carcinoma. PMID- 22237316 TI - Re: antegrade perfusion with bacillus Calmette-Guerin in patients with non-muscle invasive urothelial carcinoma of the upper urinary tract: who may benefit? PMID- 22237317 TI - Re: long-term outcomes of immediate versus delayed nephroureterectomy for upper tract urothelial carcinoma. PMID- 22237318 TI - Re: bladder preservation multimodality therapy as an alternative to radical cystectomy for treatment of muscle invasive bladder cancer. PMID- 22237319 TI - Re: international phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. PMID- 22237320 TI - Re: surgery-related complications of robot-assisted radical cystectomy with intracorporeal urinary diversion. PMID- 22237321 TI - Re: readaptation of the peritoneum following extended pelvic lymphadenectomy and cystectomy has a significant beneficial impact on early postoperative recovery and complications: results of a prospective randomized trial. PMID- 22237322 TI - Re: should intervening benign tissue be included in the measurement of discontinuous foci of cancer on prostate needle biopsy? Correlation with radical prostatectomy findings. PMID- 22237323 TI - Re: suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study. PMID- 22237324 TI - Re: stepwise approach for nerve sparing without countertraction during robot assisted radical prostatectomy: technique and outcomes. PMID- 22237325 TI - Re: orgasm-associated urinary incontinence and sexual life after radical prostatectomy. PMID- 22237326 TI - Re: presence of teratoma in orchiectomy specimen increases the need for postchemotherapy RPLND. PMID- 22237327 TI - Re: population structure and uropathogenic virulence-associated genes of faecal Escherichia coli from healthy young and elderly adults. PMID- 22237328 TI - Re: origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. PMID- 22237329 TI - Re: antimicrobial resistance in more than 100,000 Escherichia coli isolates according to culture site and patient age, gender, and location. PMID- 22237333 TI - Re: twenty-year prevalence of diabetes mellitus and hypertension in patients receiving shock-wave lithotripsy for urolithiasis. PMID- 22237334 TI - Re: repeat retrourethral transobturator sling in the management of recurrent postprostatectomy stress urinary incontinence after failed first male sling. PMID- 22237335 TI - Re: urethral rest: role and rationale in preparation for anterior urethroplasty. PMID- 22237336 TI - Re: buccal mucosal graft urethroplasty for penile stricture: only dorsal or combined dorsal and ventral graft placement? PMID- 22237337 TI - Re: the "7-flap" perineal urethrostomy. PMID- 22237338 TI - Re: radiological treatment of renal artery occlusion after blunt abdominal trauma in a pediatric patient: is it never too late? PMID- 22237339 TI - Re: intermediate-term follow-up of patients treated with percutaneous embolization for grade 5 blunt renal trauma. PMID- 22237341 TI - Re: complications of hand-assisted laparoscopic renal surgery: single-center ten year experience. PMID- 22237340 TI - Re: what are the specific computed tomography scan criteria that can predict or exclude the need for renal angioembolization after high-grade renal trauma in a conservative management strategy? PMID- 22237343 TI - Re: management of intraoperative splenic injury during laparoscopic urological surgery. PMID- 22237345 TI - Re: a small-scale clinical trial to determine the safety and efficacy of testosterone replacement therapy in hypogonadal men with spinal cord injury. PMID- 22237346 TI - Re: mixed incontinence: comparing definitions in non-surgical patients. PMID- 22237347 TI - Re: national community prevalence of overactive bladder in the United States stratified by sex and age. PMID- 22237348 TI - Re: patient satisfaction with the benefits of overactive bladder treatment: exploration of influencing factors and development of a satisfaction assessment instrument. PMID- 22237349 TI - Re: clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial. PMID- 22237350 TI - Re: comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). PMID- 22237351 TI - Re: progression of null or mild lower urinary tract symptoms indicative of benign prostatic hyperplasia after 2 years of follow-up in non-treated men aged 40 years or older. PMID- 22237352 TI - Re: effect of obesity on the outcome of kidney transplantation: a 20-year follow up. PMID- 22237353 TI - Re: laparoscopic kidney transplantation: an initial experience. PMID- 22237355 TI - Re: association between smoking cessation and sexual health in men. PMID- 22237354 TI - Re: the relationships between sex hormones and sexual function in middle-aged and older European men. PMID- 22237356 TI - Re: total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. PMID- 22237358 TI - Re: does metabolic syndrome impair sexual function in middle- to old-aged women? PMID- 22237359 TI - Re: do the effects of testosterone on muscle strength, physical function, body composition, and quality of life persist six months after treatment in intermediate-frail and frail elderly men? PMID- 22237360 TI - Re: frailty in relation to variations in hormone levels of the hypothalamic pituitary-testicular axis in older men: results from the European Male Aging Study. PMID- 22237361 TI - Re: low testosterone concentrations and the symptoms of testosterone deficiency according to the Androgen Deficiency in Ageing Males (ADAM) and Ageing Males' Symptoms rating scale (AMS) questionnaires. PMID- 22237362 TI - Re: varicocele repair: does it still have a role in infertility treatment? PMID- 22237363 TI - Re: a meta-analysis of meta-analyses. PMID- 22237364 TI - Re: varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. PMID- 22237365 TI - Re: role of tissue digestion and extensive sperm search after microdissection testicular sperm extraction. PMID- 22237366 TI - Re: heat shock factor Y chromosome (HSFY) mRNA level predicts the presence of retrievable testicular sperm in men with nonobstructive azoospermia. PMID- 22237367 TI - Re: asymmetric spermatic cord vessel enhancement and enlargement on contrast enhanced MDCT as indicators of ipsilateral scrotal pathology. PMID- 22237368 TI - Are costs for robotic assisted sacrocolpopexy lower than those for open sacrocolpopexy? PMID- 22237369 TI - Re: today's 'meaningful use' standard for medication orders by hospitals may save few lives; later stages may do more. PMID- 22237370 TI - Re: higher fees paid to us physicians drive higher spending for physician services compared to other countries. PMID- 22237371 TI - Re: US physician practices versus Canadians: spending nearly four times as much money interacting with payers. PMID- 22237372 TI - Re: crisis checklists for the operating room: development and pilot testing. PMID- 22237373 TI - Re: simple, age-based formula for predicting renal length in children. PMID- 22237375 TI - Re: ureteral stents do not cause bacterial infections in children after ureteral reimplantation. PMID- 22237374 TI - Re: peritoneal metastases after laparoscopic nephron-sparing surgery for localized Wilms tumor. PMID- 22237376 TI - Re: licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells. PMID- 22237377 TI - Re: beta-catenin is essential for Mullerian duct regression during male sexual differentiation. PMID- 22237380 TI - Re: clinical practice guidelines for the management of patients with endometrial cancer in France. PMID- 22237379 TI - Breast and abdominal adipose multipotent mesenchymal stromal cells and stage specific embryonic antigen 4 expression. AB - We assessed human mesenchymal stem cells (MSCs) harvested from breast and abdominal adipose tissues enriched in embryonic stage-specific antigen (SSEA-4) expression for osteogenic and adipogenic differentiation in comparison to a mixed cell population. Human adipose was obtained from abdominal and breast tissues of females undergoing gastric bypass and breast reduction, respectively. SSEA-4 expressing cells were enriched from the mixed cell population by magnetic cell sorting and expanded in culture. The results showed that freshly isolated cells from breast and abdominal tissues based on adipose from 3 patients comprised 12 and 10% SSEA-4+ cells, respectively. At passage 0, 48% of the cells from breast adipose tissue were positive for SSEA-4 while 12% of the cells from abdominal adipose tissue were positive for this antigen. The level of SSEA-4-expressing cells remained relatively constant with passaging; SSEA-4-expressing cells from breast tissue comprised 45% of the total while 27% of the cells from abdominal adipose tissue expressed SSEA-4 at passage 5. Cells sorted for SSEA-4 expression exhibited a higher potential for differentiation toward osteogenic and adipogenc cell lineages in vitro when compared to a mixed population. Interestingly, SSEA-4 expression was lost upon differentiation, suggesting that the antigen marks a subpopulation of MSCs. Taken together, the data demonstrate that breast adipose tissue is highly enriched in a subpopulation of MSCs expressing SSEA-4 and suggest that SSEA-4 may be a marker of a subpopulation of MSCs with high potential for osteogenic and adipogenic differentiation. PMID- 22237381 TI - Fertility-sparing surgery for early cervical cancer-approach to less radical surgery. AB - OBJECTIVE: To evaluate whether certain patients with early-stage cervical cancer are candidates for less radical surgery when considering fertility-sparing surgery. DESIGN: Prospective cohort study. SETTING: Two gynecologic cancer centers (St Thomas' Hospital, London; and West Kent Gynaecological Cancer Centre, Maidstone). POPULATION: Women with early-stage cervical cancer (n = 66) undergoing fertility-sparing surgery, either simple (SVT) or radical vaginal trachelectomy (RVT). METHODS: Prospective clinical data collection and review of patient notes, pathology and radiology data, and pregnancy outcomes. MAIN OUTCOME MEASURES: Postoperative complications, surgical specimen histologic analysis, follow-up data, and obstetric outcome. RESULTS: A total of 66 women underwent either SVT (n = 15) or RVT (n = 51), with pelvic lymphadenectomy, for stage IA2 or IB1 cervical cancer. There was no residual disease in the SVT specimen in 53% versus 29% after RVT. Clear surgical margins in 100% of SVT specimens with residual disease versus 94% after RVT. Two patients had positive lymph nodes after RVT; one of these declined adjuvant treatment until after egg harvesting and subsequently died of disease (1.5%). Median follow-up was 96 months (range, 12-120 months). One patient had a mid vaginal recurrence (1.5%). Twenty-four women have tried to conceive to date, with 14 women having 17 live births. Live birth pregnancy rate was 70.8%. CONCLUSIONS: It is possible to select patients for a less radical fertility-sparing procedure through identification of measurable low-risk factors and thus reduce the morbidity caused by conventional RVT. The selection criteria should be stringent and applied within the setting of a cancer center. PMID- 22237382 TI - Value of magnetic resonance and 18FDG PET-CT in predicting tumor response and resectability of primary locally advanced cervical cancer after treatment with intensity-modulated arc therapy: a prospective pathology-matched study. AB - OBJECTIVE: To report on the value of magnetic resonance imaging (MRI) and 2-deoxy 2-[18] fluoro-D-glucose positron emission tomography computed tomography (18FDG PET-CT) in predicting resectability and pathological response of primary locally advanced cervical cancer after neoadjuvant intensity-modulated arc therapy (IMAT) with or without cisplatin (C). METHODS AND MATERIALS: Twenty-seven patients with International Federation of Gynecology and Obstetrics stages IB2 to IVA cervical cancer were treated with IMAT-C followed by extrafascial hysterectomy (EH). All patients received MRI and 18FDG PET-CT after IMAT-C. The end points of this study were to: 1. Assess the ability of MRI to predict negative surgical margins (R0). 2. Assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MRI in predicting the following situation at the EH specimen: "no residual disease or minimal microscopically visible residual tumor." 3. Assess the sensitivity, specificity, PPV, and NPV value of 18FDG PET CT in predicting "no residual viable tumor cells" at the EH specimen. RESULTS: An R0 resection was obtained in all patients. None of the EH specimens contained macroscopically visible tumor. In 13 patients, no viable tumor cells were found and only 14 had residual microscopic disease. Twenty-four of 27 MRIs were able to correctly predict R0 resection. A negative MRI was 100% predictive for the end point "R0 resection." The specificity and NPV of MRI (end point 2) were 74% and 100%, respectively. No sensitivity or PPV could be calculated. The sensitivity, specificity, PPV, and NPV of 18FDG PET-CT were 29%, 62%, 44%, and 44%, respectively (end point 3). CONCLUSIONS: A negative MRI after IMAT-C predicts 100% correctly for R0 resection. The role of FDG PET-CT in predicting viable tumor cells at EH specimen is at least debatable. PMID- 22237383 TI - Prognostic determinants in patients with stage I uterine papillary serous carcinoma: a 15-year multi-institutional review. AB - OBJECTIVE: The aim of this retrospective, multi-institutional study was to evaluate the importance of surgical staging for stage I uterine papillary serous carcinomas (UPSCs) to determine optimal management of this rare tumor. METHODS: With institutional review board approval from both participating institutions, all patients with 2009 International Federation of Gynecology and Obstetrics stage I mixed serous and UPSC diagnosed between January 1, 1992, and December 31, 2007, were identified at the 2 institutions. Clinical factors were correlated using Spearman correlation coefficients, Kaplan-Meier survival estimates and a Cox proportional hazards model. RESULTS: Of the 204 UPSC patients treated during this period, 84 were classified as stage I, with substages as follows: stage IA, n = 71; stage IB, n = 13. Thirty-seven patients (44%) had a history of a second cancer (22 breast tumors, 9 synchronous mullerian cancers). Surgical staging with at least hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and bilateral pelvic lymph node dissection was performed in 60 (71%) of 84 patients. The median survival for all patients was 10 years. Univariate analysis revealed surgical staging (P < 0.001), normal preoperative CA-125 (P < 0.001), and absence of additional cancers (P < 0.01) to be associated with improved survival. Age adjusted multivariate analysis incorporating these factors revealed that advancing substage (hazard ratio, 4.59; P < 0.05), a second malignancy (hazard ratio, 2.75; P < 0.04), and surgical staging (hazard ratio, 0.18; P < 0.001) were independent factors associated with overall survival. In a subset analysis excluding patients with a second malignancy, substage (hazard ratio, 3.52; P < 0.05), and surgical staging (hazard ratio, 0.16; P < 0.001) were independent factors affecting overall survival. CONCLUSIONS: Independent of adjuvant chemotherapy or radiation, stage of disease, comprehensive surgical staging, and the presence of a second malignancy were predictors of overall survival. PMID- 22237384 TI - Survival rates for international federation of gynecology and obstetrics stage III ovarian carcinoma by cell type: a study of 262 unselected patients with uniform pathologic review. AB - OBJECTIVE: Published data are conflicting on the influence of cell type on prognosis in ovarian cancer. The recent separation of low-grade serous carcinoma as a distinctive cell type of ovarian cancer with an indolent behavior, in retrospect, suggests that survival in studies that have not separated this group may be inaccurate. METHODS: An unselected series of 262 International Federation of Gynecology and Obstetrics stage III ovarian carcinomas was studied. Diagnostic classification of each tumor was made with particular attention to recent refinements in cell-type classification. Survival curves were constructed according to Kaplan-Meier and compared with the log-rank test. RESULTS: The 5 year survival for 207 high-grade serous carcinomas was 40%, as compared with 71% for 18 patients with low-grade serous carcinoma (P = 0.0113). Low-grade serous carcinoma was significantly more likely to be optimally debulked (P = 0.0039) and significantly less likely to be substage IIIC (P < 0.0001). The survival for carcinosarcoma was significantly inferior to all serous carcinomas (P = 0.0322). The significance of this latter comparison was lost when carcinosarcomas were compared with only high-grade serous carcinoma (P > 0.05). CONCLUSIONS: Low-grade serous carcinoma has a significantly better prognosis than high-grade serous carcinoma and also differs with regard to substage distribution and proportion of patients optimally debulked. Because of its excellent prognosis, failure to separate low-grade serous carcinomas, notwithstanding its infrequent occurrence, can change the results of survival analyses that do not make this separation. PMID- 22237385 TI - Site-specific incorporation of diamondoids on DNA using click chemistry. AB - A simple and robust solid phase synthetic method for the ligation of diamondoids on the phosphate backbone of DNA with "click" chemistry using [Cu(CH(3)CN)(4)]PF(6) without a stabilizing ligand is reported. It was found that as the size of dimondoid increased, a corresponding increase in melting temperature was observed. PMID- 22237386 TI - Bullous leukaemia cutis. PMID- 22237387 TI - 18F-Fluorodeoxyglucose positron emission tomography/computed tomography finds answers in cancer patients with increasing tumor markers and negative or equivocal conventional imaging modalities. AB - BACKGROUND: The increase in tumor markers with negative or equivocal conventional imaging modalities represents a serious dilemma in the follow-up of previously treated cancer patients. Positron emission tomography/computed tomography (PET/CT) has emerged as a useful tool in oncological imaging in staging and restaging of most cancers. OBJECTIVE: This study explored the potential role of 18F-fluorodeoxyglucose (FDG) PET/CT in the detection and localization of tumor recurrence in cancer patients with increasing serum tumor markers and negative or equivocal conventional imaging modalities. MATERIALS AND METHODS: This prospective study was conducted on 105 previously diagnosed and treated cancer patients with different pathologies. All patients were referred for 18F-FDG PET/CT scans because of increasing tumor markers with negative or equivocal conventional imaging modalities. All patients underwent whole-body 18F-FDG PET/CT scans. The findings were confirmed by clinical and/or radiological follow-up of at least 12 months and histopathologically whenever possible. RESULTS: PET/CT detected recurrence and/or metastases in 90 patients (85.7%), including 17 recurrences, 50 metastases, and 23 recurrences and metastases. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT scans were 95.7, 100, 100, 73.3, and 96.2%, respectively. These parameters were 95, 100, 100, 69, and 95% for PET scans alone and were 91.5, 100, 100, 57.9, and 92.3% for CT scans alone. CONCLUSION: 18F-FDG PET/CT is a powerful diagnostic tool in restaging of cancer patients. In most cases, PET/CT provides accurate results and helps resolve the clinical dilemma encountered in oncological patients with increasing serum tumor markers and negative or equivocal findings in conventional imaging modalities. PMID- 22237388 TI - Trends in death attributed to heart failure over the past two decades in Europe. AB - AIMS: Little is known regarding temporal trends in mortality attributed to heart failure (HF) from a population perspective. The aim of this study was to assess the mortality related to HF as an underlying cause during the last 20 years in seven European countries. METHODS AND RESULTS: The number of deaths with HF as the underlying cause was collected in seven European states: Germany, Greece, England and Wales, Spain, France, Finland, and Sweden from 1987 to 2008. Disease coding for HF was based on the International Classification of Diseases (ICD 9th and 10th versions). We computed age-standardized death rates (SDRs) per 100 000 inhabitants. Mean age at death from HF was also calculated for the same period. In the seven studied countries, the HF SDR decreased continuously from 54.2 (1987) to 32.6 (2008). Despite differences in the early 1990s, SDRs related to HF seemed to converge, in these seven European countries, to ~30 deaths per 100 000 population in the near future, for both men and women. During the study period, the mean age at death increased from 80.0 to 82.7 years. Half of the deaths from HF occurred in hospital, without change over time. CONCLUSION: There has been a 40% reduction of the SDR due to HF in seven European countries during two decades and a concomitant increase in the mean age at death from HF. We hypothesize that these results may be related to a better management of chronic and acute HF patients over the past 20 years. PMID- 22237390 TI - Treatment of gastroenteropancreatic neuroendocrine tumors with peptide receptor radionuclide therapy. AB - The primary treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs) is surgery with curative intent or debulking of the tumor mass. In case of metastatic disease, cytoreductive options are limited. A relatively new therapeutic modality, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, is currently available in a number of mostly European centers. Complete and partial responses obtained after treatment with [90Y-DOTA0,Tyr3]octreotide are in the same range as after treatment with [177Lu DOTA0,Tyr3]octreotate (i.e. 10-30%). However, significant nephrotoxicity has been observed after treatment with [90Y-DOTA0,Tyr3]octreotide. Options to improve PRRT may include combinations of radioactive labeled somatostatin analogs, intra arterial administration, and the use of radiosensitizing drugs combined with PRRT. Other therapeutic applications of PRRT may include additional therapy cycles in patients with progressive disease after benefit from initial therapy, PRRT in adjuvant or neoadjuvant setting, or PRRT combined with new targeted therapies, such as sunitinib or everolimus. Randomized clinical trials comparing PRRT with other treatment modalities, or comparing various radioactive labeled somatostatin analogs should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs. PMID- 22237391 TI - [Radiological findings in Currarino syndrome]. AB - OBJECTIVE: To describe the clinical, radiological and genetic findings of a family affected by Currarino syndrome (CS) (agenesis of the sacrum, presacral mass, and anal-rectal anomalies), and to familiarise the radiologist with this condition that, although uncommon, could be suspected by its characteristic images. MATERIAL AND METHODS: A study was made of 8 out of 9 family members (the parents, 7 siblings; 4 males and 3 females) suspected of having CS. The clinical and genetic findings are described. Using simple X-rays, ultrasound and magnetic resonance imaging, the presence of agenesis of the sacrum, a presacral mass and anal-rectal anomalies were investigated. Furthermore, a genetic analysis of the HLBX9 gene was performed. Permission by the Ethics Committee was not requested as all the family members gave their consent by signing a document. RESULTS: The mother with a scimitar-shaped sacrum confirmed that she was the transmitter of the genetic mutation. One of the seven siblings had complete CS (sacral agenesis, anorectal stenosis, and anterior meningocele). Four siblings had an incomplete CS: 3 with sacral agenesis and a presacral mass (two anterior meningoceles and one teratoma) and the fourth with sacral agenesis and anorectal stenosis. One sibling had no anomalies. The mother, as well as four siblings, did not have the HLXB9 gene mutation. CONCLUSION: When there is sacral agenesis, the possibility of presacral masses and anorectal changes should be investigated. Likewise, if there is familial association, they should be investigated for a CS. PMID- 22237393 TI - Signalling: SRC and survival. PMID- 22237392 TI - Cancer stem cells: an evolving concept. AB - The cancer stem cell (CSC) concept derives from the fact that cancers are dysregulated tissue clones whose continued propagation is vested in a biologically distinct subset of cells that are typically rare. This idea is not new, but has recently gained prominence because of advances in defining normal tissue hierarchies, a greater appreciation of the multistep nature of oncogenesis and improved methods to propagate primary human cancers in immunodeficient mice. As a result we have obtained new insights into why the CSC concept is not universally applicable, as well as a new basis for understanding the complex evolution, phenotypic heterogeneity and therapeutic challenges of many human cancers. PMID- 22237394 TI - Therapeutics: Keeping one step ahead. PMID- 22237396 TI - Angiogenesis: What's the alternative? PMID- 22237397 TI - Comparison of cryoglobulinemia in children and adults. AB - BACKGROUND/PURPOSE: Cryoglobulinemic vasculitis is a systemic vasculitis resulting from circulating immune complex deposition in the small vessels and is characterized by variable clinical features, including purpura, Raynaud's syndrome, ulcerations, arthralgia, glomerulonephritis, and peripheral neuropathy. Cryoglobulinemia can also result from hepatitis C virus (HCV) infection. The clinical spectrum and associated or underlying diseases of cryoglobulinemia in different age groups is not well understood. This study investigated the demographic, clinical, serologic features, and associated or underlying diseases in children and adult patients with cryoglobulinemia. METHODS: The retrospective study included 114 patients (18 children, 96 adults) who presented with cryoglobulinemia between 2000 and 2010 at the Chang Gung Memorial Hospital. Their medical records were reviewed and serological and virologic assessments were analyzed. RESULTS: In this group of patients, children had a significantly higher prevalence of prolonged fever (16.7% vs. 3.13%; p=0.018), arthralgia (66.67% vs. 16.67%; p<0.001), arthritis (66.67% vs. 15.63%; p<0.001) and cutaneous involvement (77.78% vs. 50%; p=0.03) compared with adults. Both the adult and children groups had a greater frequency of hepatitis B virus (HBV) infection (20.8% and 5.6%, respectively), than HCV infection (12.5% and 0%, respectively). CONCLUSIONS: Children with cryoglobulinemia had a significantly higher prevalence of prolonged fever, arthralgia, arthritis and cutaneous involvement compared with adults. PMID- 22237398 TI - A novel clonality assay for the assessment of canine T cell proliferations. AB - Polymerase chain reaction (PCR) based clonality assays are an important tool to differentiate neoplastic from reactive lymphocyte populations. A recent description of the canine T cell receptor gamma locus identified a large number of formerly unknown genes, and determined the locus topology consisting of 8 cassettes with up to 3 variable (V) genes, 2 joining (J) genes and one constant (C) gene each. Given that these data were not available when existing canine T cell clonality assays were developed, it is likely that they will fail to detect a subset of clonal lymphocyte populations. The objective of this study was to gauge the potential of canine T cell clonality assays to detect all rearranged T cell receptor gamma genes and to develop an improved clonality assay. The primer sequences of existing clonality assays were aligned to the reference sequences of all rearranged genes and genes were scored as to the likelihood of being recognized by a primer. All four assays likely recognized subgroup Vgamma2 and Vgamma6 genes but 3 out of 4 assays were unlikely to detect subgroup Vgamma3 and Vgamma7 genes. All assays likely recognized Jgammax-2 genes, but only two assays were likely to detect most Jgammax-1 genes. Two assays had forward primers located as close as four nucleotides to the junctional region. A new multiplex PCR was designed with all primers combined in a single tube. An alternative primer set allowed identification of variable gene usage through gene specific forward primers. The coverage of all rearranged genes facilitated the detection of multiple clonal rearrangements per neoplastic sample. The new assay detected clonal DNA at a concentration of 5% within polyclonal background but detection thresholds were dependent on the gene usage of clonal rearrangements as well as the position of the clonal peak in respect to the polyclonal background. The new multiplex assay recognized 12/12 (100%) of confirmed neoplastic samples as compared to 2/12 (17%) by an existing assay. On a series of 60 diagnostic samples the concordance rate of both assays was 41/60 (68.3%). In 14/60 (23.3%) of the cases, the new multiplex assay yielded a clonal result while the existing assay gave a non-clonal result. In 5/60 (8.3%) of cases, the new assay yielded a non clonal result while the existing primer set gave a clonal result. These findings suggest that the new multiplex assay has an improved sensitivity over traditional assays and is suited to reduce the rate of false-negative results. PMID- 22237395 TI - Balancing repair and tolerance of DNA damage caused by alkylating agents. AB - Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity. PMID- 22237399 TI - Educational paper: the podocytopathies. AB - In the recent past, hereditary podocytopathies have increasingly been recognized to be involved in the development of steroid-resistant nephrotic syndrome (SRNS). Mutations in podocyte genes substantially alter the development and structural architecture of the podocyte including its interdigitating foot processes. These constitute the basis of the slit diaphragm which is an essential part of the glomerular filtration barrier. Depending on the affected protein, the clinical course is variable with respect to onset and severity of the disease as well as treatment options. In general, hereditary podocytopathies are associated with a poorer renal outcome than the non-genetic variants. In addition, they require a different approach with respect to the applied therapeutic strategies as most patients do not respond to immunosuppressive agents. Therefore, genetic testing of podocyte genes should be considered as a routine diagnostic tool for patients with SRNS because the identification of a genetic origin has a direct implication on clinical course, renal outcome, and genetic counseling. In this educational paper, we will give an overview over the podocyte genes identified so far to be involved into the pathophysiology of hereditary podocytopathies. PMID- 22237400 TI - From sleep duration to childhood obesity--what are the pathways? AB - Sleep duration has been identified as risk factor for obesity already in children. Besides investigating the role of fat mass (FM), this study addressed the question whether endocrine mechanisms act as intermediates in the association between sleep duration and overweight/obesity. Within the framework of the IDEFICS study, the present research was conducted in 609 German resident children aged 2-9 years with information on fasting insulin, C-reactive protein and cortisol levels next to anthropometric measurements and parental questionnaires. Emphasising methodological aspects, an age-specific measure of sleep duration was derived to account for alteration in sleep duration during childhood/period of growth. Multivariate linear regression and quantile regression models confirmed an inverse relationship between sleep duration and measures of overweight/obesity. The estimate for the association of sleep duration and body mass index (BMI) was approximately halved after adjustment for FM, but remained significant. The strength of this association was also markedly attenuated when adjusting for insulin mainly for the upper BMI quantiles (Q80, beta = -0.36 vs. beta = -0.26; Q95, beta = -0.87 vs. beta = -0.47). Adjustment for cortisol and CrP did not yield this attenuation. CONCLUSION: The inverse relationship between sleep duration and BMI is mainly explained by the association between sleep duration and FM. Insulin may explain part of this association, in particular at the upper tail of the BMI distribution. PMID- 22237402 TI - From stress specificity to basal necessity: ATF6 uprising. Focus on "Pancreatic beta-cells depend on basal expression of active ATF6alpha-p50 for cell survival even under nonstress conditions". PMID- 22237401 TI - Clostridium difficile toxins: mediators of inflammation. AB - Clostridium difficile is a significant problem in hospital settings as the most common cause of nosocomial diarrhea worldwide. C. difficile infections (CDIs) are characterized by an acute intestinal inflammatory response with neutrophil infiltration. These symptoms are primarily caused by the glucosylating toxins, TcdA and TcdB. In the past decade, the frequency and severity of CDIs have increased markedly due to the emergence of so-called hypervirulent strains that overproduce cytotoxic glucosylating toxins relative to historical strains. In addition, these strains produce a third toxin, binary toxin or C. difficile transferase (CDT), that may contribute to hypervirulence. Both the glucosylating toxins and CDT covalently modify target cell proteins to cause disassembly of the actin cytoskeleton and induce severe inflammation. This review summarizes our current knowledge of the mechanisms by which glucosylating toxins and CDT disrupt target cell function, alter host physiology and stimulate immune responses. PMID- 22237404 TI - The interplay of multiple molecular and cellular components is necessary for compartmentalization of cAMP. Focus on "Assessment of cellular mechanisms contributing to cAMP compartmentalization in pulmonary microvascular endothelial cells". PMID- 22237403 TI - Regulation of acid-base transporters by reactive oxygen species following mitochondrial fragmentation. AB - Mitochondrial morphology is determined by the balance between the opposing processes of fission and fusion, each of which is regulated by a distinct set of proteins. Abnormalities in mitochondrial dynamics have been associated with a variety of diseases, including neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and dominant optic atrophy. Although the genetic determinants of fission and fusion are well recognized, less is known about the mechanism(s) whereby altered morphology contributes to the underlying pathophysiology of these disease states. Previous work from our laboratory identified a role for mitochondrial dynamics in intracellular pH homeostasis in both mammalian cell culture and in the genetic model organism Caenorhabditis elegans. Here we show that the acidification seen in mutant animals that have lost the ability to fuse their mitochondrial inner membrane occurs through a reactive oxygen species (ROS)-dependent mechanism and can be suppressed through the use of pharmacological antioxidants targeted specifically at the mitochondrial matrix. Physiological approaches examining the activity of endogenous mammalian acid-base transport proteins in rat liver Clone 9 cells support the idea that ROS signaling to sodium-proton exchangers contributes to acidification. Because maintaining pH homeostasis is essential for cell function and viability, the results of this work provide new insight into the pathophysiology associated with the loss of inner mitochondrial membrane fusion. PMID- 22237405 TI - Lactic acid restores skeletal muscle force in an in vitro fatigue model: are voltage-gated chloride channels involved? AB - High interstitial K(+) concentration ([K(+)]) has been reported to impede normal propagation of electrical impulses along the muscle cell membrane (sarcolemma) and then also into the transverse tubule system; this is one considered underlying mechanism associated with the development of muscle fatigue. Interestingly, the extracellular buildup of lactic acid, once considered an additional cause for muscle fatigue, was recently shown to have force-restoring effects in such conditions. Specifically, it was proposed that elevated lactic acid (and intracellular acidosis) may lead to inhibition of voltage-gated chloride channels, thereby reestablishing better excitability of the muscle cell sarcolemma. In the present study, using an in vitro muscle contractile experimental setup to study functionally viable rectus abdominis muscle preparations obtained from normal swine, we examined the effects of 20 mM lactic acid and 512 MUM 9-anthracenecarboxylic acid (9-AC; a voltage-gated chloride channel blocker) on the force recovery of K(+)-depressed (10 mM K(+)) twitch forces. We observed a similar muscle contractile restoration after both treatments. Interestingly, at elevated [K(+)], myotonia (i.e., hyperexcitability or afterdepolarizations), usually present in skeletal muscle with inherent or induced chloride channel dysfunctions, was not observed in the presence of either lactic acid or 9-AC. In part, these data confirm previous studies showing a force restoring effect of lactic acid in high-[K(+)] conditions. In addition, we observed similar restorative effects of lactic acid and 9-AC, implicating a beneficial mechanism via voltage-gated chloride channel modulation. PMID- 22237406 TI - Resolvin D1 prevents TNF-alpha-mediated disruption of salivary epithelial formation. AB - Sjogren's syndrome is a chronic autoimmune disorder characterized by inflammation of salivary glands resulting in impaired secretory function. Our present studies indicate that chronic exposure of salivary epithelium to TNF-alpha and/or IFN gamma alters tight junction integrity, leading to secretory dysfunction. Resolvins of the D-series (RvDs) are endogenous lipid mediators derived from DHA that regulate excessive inflammatory responses leading to resolution and tissue homeostasis. In this study, we addressed the hypothesis that activation of the RvD1 receptor ALX/FPR2 in salivary epithelium prevents and/or resolves the TNF alpha-mediated disruption of acinar organization and enhances monolayer formation. Our results indicate that 1) the RvD1 receptor ALX/FPR2 is present in fresh, isolated cells from mouse salivary glands and in cell lines of salivary origin; and 2) the agonist RvD1 (100 ng/ml) abolished tight junction and cytoskeletal disruption caused by TNF-alpha and enhanced cell migration and polarity in salivary epithelium. These effects were blocked by the ALX/FPR2 antagonist butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe. The ALX/FPR2 receptor signals via modulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways since, in our study, blocking PI3K activation with LY294002, a potent and selective PI3K inhibitor, prevented RvD1-induced cell migration. Furthermore, Akt gene silencing with the corresponding siRNA almost completely blocked the ability of Par-C10 cells to migrate. Our findings suggest that RvD1 receptor activation promotes resolution of inflammation and tissue repair in salivary epithelium, which may have relevance in the restoration of salivary gland dysfunction associated with Sjogren's syndrome. PMID- 22237408 TI - Parenting: the forgotten role of women living with systemic lupus erythematosus. AB - This study investigates parenting and the impact of symptoms, such as pain and fatigue, on the parenting abilities of mothers with systemic lupus erythematosus (SLE). Participants were 68 mothers with SLE who had children 18 years of age and younger. The mothers completed surveys consisting of a demographic questionnaire and self-report instruments such as the Parenting Disability Index (PDI), Health Assessment Questionnaire, Pain Visual Analog Scale, and Multidimensional Assessment of Fatigue Scale. Analysis of variance was used to compare parenting abilities for women with younger children (birth -5 years) and women with older children (6-18 years) and women with children in both age groups. There were no significant differences between the three groups. However, having more fatigue, functional disability, and less education resulted in higher PDI scores in all groups. Mothers with children younger than age 5 reported that having energy to talk/listen to a child was the most difficult parenting task. Mothers with children between 6 and 18 years of age reported the most difficulties with maintaining discipline, playing games, shopping, and doing household chores. Symptoms of lupus have a significant influence on mothering roles. In daily practice, health care providers may want to consider inquiring about the impact SLE may be having on their patients' parenting roles. PMID- 22237407 TI - The role of calcium-independent phospholipase A2gamma in modulation of aqueous humor drainage and Ca2+ sensitization of trabecular meshwork contraction. AB - The contractile and relaxation characteristics of trabecular meshwork (TM) are presumed to influence aqueous humor (AH) drainage and intraocular pressure. The mechanisms underlying regulation of TM cell contractile properties, however, are not well understood. This study investigates the role of calcium-independent phospholipase A(2) (iPLA(2)), which controls eicosanoid synthesis, in regulation of TM cell contraction and AH outflow using mechanism-based isoform specific inhibitors (R)-bromoenol lactone (R-BEL, iPLA(2)gamma specific) and (S)-bromoenol lactone (S-BEL, iPLA(2)beta specific). Immunohistochemical analysis revealed intense staining for both iPLA(2)beta and gamma isoforms throughout the TM, juxtacanalicular tissue, and Schlemm's canal of human eye. Inhibition of iPLA(2)gamma by R-BEL or small interfering RNA-mediated silencing of iPLA(2)gamma expression induced dramatic changes in TM cell morphology, and decreased actin stress fibers, focal adhesions, and myosin light-chain (MLC) phosphorylation. AH outflow facility increased progressively and significantly in enucleated porcine eyes perfused with R-BEL. This response was associated with a significant decrease in TM tissue MLC phosphorylation and alterations in the morphology of aqueous plexi in R-BEL-perfused eyes. In contrast, S-BEL did not affect either of these parameters. Additionally, R-BEL-induced cellular relaxation of the TM was associated with a significant decrease in the levels of active Rho GTPase, phospho-MLC phosphatase, phospho-CPI-17, and arachidonic acid. Taken together, these observations demonstrate that iPLA(2)gamma plays a significant and isoform specific role in regulation of AH outflow facility by altering the contractile characteristics of the TM. The effects of iPLA(2)gamma on TM contractile status appear to involve arachidonic acid and Rho GTPase signaling pathways. PMID- 22237409 TI - New lithium-zincate approaches for the selective functionalisation of pyrazine: direct dideprotozincation vs. nucleophilic alkylation. AB - Comparing the reactivity of the related lithium zincates [(THF)LiZn(TMP)(t)Bu(2)] (1) and [(PMDETA)LiZn(t)Bu(3)] (2) towards pyrazine discloses two new bimetallic approaches for the selective 2,5-dideprotonation and room temperature C-H alkylation of this sensitive heterocycle. PMID- 22237410 TI - Effect of hydroalcoholic extract from Copaifera langsdorffii leaves on urolithiasis induced in rats. AB - Copaifera langsdorffii Desf. commonly known as "copaiba", produce a commercially valuable oil-resin that is extensively used in folk medicine for anti inflammatory, antimicrobial and antiseptic purposes. We have found the hydroalcoholic extract of this plant leaf has the potential to treat urolithiasis, a problem affecting ~7% of the population. To isolate the functional compounds C. langsdorffii leaves were dried, ground, and macerated in a hydroalcoholic solution 7:3 to produce a 16.8% crude extract after solvent elimination. Urolithiasis was induced by introduction of a calcium oxalate pellet (CaOx) into the bladders of adult male Wistar rats. The treated groups received the crude extract by oral gavage at 20 mg/kg body weight daily for 18 days. Extract treatment started 30 days after CaOx seed implantation. To monitor renal function sodium, potassium and creatinine concentrations were analyzed in urine and plasma, and were found to be in the normal range. Analyses of pH, magnesium, phosphate, calcium, uric acid, oxalate and citrate levels were evaluated to determine whether the C. langsdorffii extract may function as a stone formation prevention agent. The HPLC analysis of the extract identified flavonoids quercitrin and afzelin as the major components. Animals treated with C. langsdorffii have increased levels of magnesium and decreased levels of uric acid in urinary excretions. Treated animals have a significant decrease in the mean number of calculi and a reduction in calculi mass. Calculi taken from extract treated animals were more brittle and fragile than calculi from untreated animals. Moreover, breaking calculi from untreated animals required twice the amount of pressure as calculi from treated animals (6.90 +/- 3.45 vs. 3.00 +/- 1.51). The extract is rich in flavonoid heterosides and other phenolic compounds. Therefore, we hypothesize this class of compounds might contribute significantly to the observed activity. PMID- 22237411 TI - Reducing radiation exposure from computed tomography of the brain in children- report of a practical approach. AB - PURPOSE: To reduce radiation exposure to paediatric neurosurgical patients from computed tomography (CT), a CT scanning protocol - lower radiation dose and selective scan segment (LDSS) protocol was used for CT brain at the authors' hospital. To evaluate the amount of reduction in radiation exposure by using this LDSS protocol compared to their usual protocol, the authors prospectively documented their findings. METHODS: From May 2010 to June 2011, paediatric neurosurgical patients requiring CT brain, and when it was not a clinical emergency and there was baseline CT or MRI brain available, were evaluated for the LDSS protocol. The LDSS protocol used a lower tube current-time product and a shorter scan length to attain a lower total radiation dose. The CT scanning parameters of the patients' usual CT brain and LDSS CT were recorded and compared. Adverse events were also recorded. RESULTS: A total of 24 paediatric patients were included. Using the LDSS protocol, the effective doses were between 9% and 80% of the usual protocol and, in 20 patients, <=50% of the usual protocol. The tube voltage was 120 kV. For patients below 10 years old, 100 mA s was adequate for the purposes of their CTs; in some patient categories, it was lower than 100 mA s. For patients aged 10 or above, 150 mA s was used. The scan length varied. CONCLUSIONS: Radiation exposure from CT brain in paediatric neurosurgical patients could be reduced by adopting a CT scanning protocol, which aimed dynamically at a lower tube current-time product and a shorter scan length than the usual settings at a hospital. PMID- 22237412 TI - Subcutaneous cervical emphysema associated with mastoid fracture. PMID- 22237413 TI - Molecular characterization of Ethiopian indigenous goat populations. AB - Six Ethiopian indigenous goat populations viz. Gumuz, Agew, Begia-Medir, Bati, Abergelle, and Central Abergelle were genotyped for 15 microsatellite markers recommended by Food and Agriculture Organization of the United Nations and International Society for Animal Genetics. A total of 158 individual goats were tested to assess genetic variations within and between the goat populations in the Amhara Region of Ethiopia. The markers revealed 100% polymorphism across six goat populations indicating the presence of genetic diversity, which is an important variable to measure genetic variability within and between populations. The mean observed and expected heterozygosity values ranged from 0.56 (Central Abergelle) to 0.68 (Bati) and 0.59 (Abergelle) to 0.69 (Agew goat), respectively. The lowest genetic distance was observed between Begia-Medir and Central Abergelle (0.039), and the largest distances between Agew and Abergelle (0.140) and Gumuz and Abergelle (0.169). Neighbor-joining and the unweighted pair group method with arithmetic mean methods with bootstrap value of 1,000 was used which grouped the six goat populations into two major groups viz. the Abergelle goat cluster as one group and the Agew, Gumuz, Bati, Begia-Medir, and Central Abergelle goats as the second group. In our study, the obtained higher total variation within the goat populations (95%) confirms a close relatedness of the studied goat ecotypes, which might have happened due to the existence of uncontrolled animal breeding strategies resulting from uncontrolled movement of animals through various market routes and agricultural extension systems. The study contributed to the genetic characterization of Ethiopian indigenous goat populations and demonstrated the usefulness of the 15 microsatellite makers for biodiversity studies in goats. PMID- 22237415 TI - Experimentally altered navigational demands induce changes in the cortical forebrain of free-ranging northern pacific rattlesnakes (Crotalus o. oreganus). AB - The hippocampus of birds and mammals plays a crucial role in spatial memory and navigation. The hippocampus exhibits plasticity in adulthood in response to diverse environmental factors associated with spatial demands placed on an animal. The medial and dorsal cortices of the telencephalon of squamate reptiles have been implicated as functional homologues to the hippocampus. This study sought to experimentally manipulate the navigational demands placed on free ranging northern Pacific rattlesnakes (Crotalus o. oreganus) to provide direct evidence of the relationship between spatial demands and neuroplasticity in the cortical telencephalon of the squamate brain. Adult male rattlesnakes were radio tracked for 2 months, during which time 1 of 3 treatments was imposed weekly, namely 225-meter translocation in a random direction, 225-meter walk and release at that day's capture site (handling control) or undisturbed (control). Snakes were then sacrificed and the brains were removed and processed for histological analysis of cortical features. The activity range was larger in the translocated (Tr) group compared to the handled (Hd) and undisturbed control (Cn) groups when measured via 95% minimum convex polygon (MCP). At the 100% MCP level, Tr snakes had larger activity ranges than the Cn snakes only. The volume of the medial cortex (MC) was larger in the Tr group compared to the Cn group. The MC of Hd snakes was not significantly different from that of either of the other groups. No differences in dorsal cortex (DC) or lateral cortex volumes were detected among the groups. Numbers of 5-bromo-2'-deoxyuridine (BrdU)-labeled cells in the MC and DC 3 weeks after BrdU injection were not affected by treatment. This study establishes a causal relationship between navigational demands and greater MC volume in a free-ranging reptile. PMID- 22237414 TI - Nucleotide sequence and chromosomal localization of the gene for pierisin-1, a DNA ADP-ribosylating protein, in the cabbage butterfly Pieris rapae. AB - Cabbage butterfly, Pieris rapae, contains a unique DNA ADP-ribosylating protein, pierisin-1, which transfers ADP-ribose moiety of NAD to guanine bases of DNA. Pierisin-like proteins are only distributed in subtribes Pierina, Aporiina and Appiadina of the family Pieridae. In this study, we obtained genomic clones carrying the pierisin-1 gene from adult samples of P. rapae by plaque hybridization. The pierisin-1 gene was found to consist of two exons, 0.1-kb exon 1 and 3.9-kb exon 2, and a 2.3-kb intron. In addition, we could demonstrate that the putative promoter in the about 3-kb upstream region from the transcription start site of the gene include a transcriptional activating motif involved in immune pathways and hormonal regulation. We also examined chromosomal localization of the pierisin-1 gene. Fluorescence in situ hybridization (FISH) analysis using Cy3-labeled pierisin-1 genomic clone demonstrated the localization of the gene near the kinetochore in chromosome 9. Thus, we confirmed that the pierisin-1 gene is located in the genome of P. rapae. PMID- 22237416 TI - A novel isoform of the orphan receptor RORgammat suppresses IL-17 production in human T cells. AB - T helper (Th)17 cells constitute a distinct subset of CD4(+) helper T cells that is mainly characterized by abundant interleukin (IL)-17 production and is involved in the host defence against bacteria and fungi as well as in the pathogenesis of autoimmune diseases. The retinoic orphan receptor (ROR)gammat directs the transcriptional activation of the IL17 gene. Here, we report the presence of a novel RORgammat isoform, RORgammat-Delta(5-8), which lacks the hinge-encoding exons 5-8 and represses potently IL17 and IL21 gene transcription. It thereby reduces the expression of multiple Th17-assigned cytokines. We propose that RORgammat-Delta(5-8) acts as a dominant-negative regulator of RORgammat mediated gene regulation and the balance between the full-length RORgammat and the novel repressor isoform may arbitrate IL-17 production in human T cells. PMID- 22237417 TI - Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg(689) (MSP(wt)) and Cys(689) (MSP(mut)) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP(mut) significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC. PMID- 22237418 TI - Object-based attention occurs regardless of object awareness. AB - In this study, we investigated whether awareness of objects is necessary for object-based guidance of attention. We used the two-rectangle method (Egly, Driver, & Rafal, 1994) to probe object-based attention and adopted the continuous flash suppression technique (Tsuchiya & Koch, 2005) to control for the visibility of the two rectangles. Our results show that object-based attention, as indexed by the same-object advantage--faster response to a target within a cued object than within a noncued object--was obtained regardless of participants' awareness of the objects. This study provides the first evidence of object-based attention under unconscious conditions by showing that the selection unit of attention can be at an object level even when these objects are invisible--a level higher than the previous evidence for a subliminally cued location. We suggest that object based attentional guidance plays a fundamental role of binding features in both the conscious and unconscious mind. PMID- 22237419 TI - Use of a photographic manipulation tool to assess corneal vascular response. AB - PURPOSE: Corneal vasculature change in contact lens wearers has been linked to the level of hypoxia within the cornea.To assess the impact a treatment has on limbal vessels, a sensitive method of measurement and quantification is required. METHODS: A group of 21 highly myopic, hydrogel wearers, with preexisting signs of corneal hypoxia, were enrolled into a study where they wore sifilcon A penetrated hydrogel lenses (Dk/t +/- 117), on a daily wear basis for 9 months. At all scheduled visits, photographs were taken of the superior, inferior, temporal, and nasal limbal regions which were then imported into Adobe Photoshop. A red-free filter was applied to enhance the contrast of the blood columns. In each quadrant, the length of the longest visible blood column was measured and the blood columns that penetrated 0.5 mm into the cornea were counted. A control group of 11 non-lens wearers was recruited. Their photographs were taken at the beginning of the study and 9 months later. An independent, masked observer assessed the photographs. RESULTS: There was a significant decrease in the maximum penetration of the blood column in all quadrants (p = 0.001) from baseline to the 9-month visit (e.g., superior: baseline 0.84 +/- 0.39 mm; 9 months 0.63 +/- 0.20 mm). There was also significant reduction in the number of visible blood columns longer than 0.5 mm in each quadrant (p = 0.001) from baseline to 9 months in all quadrants (e.g., superior: baseline 14.0 +/- 8.2; 9 months 6.5 +/- 6.0). The control group showed no change over time for the maximum blood column length (p = 0.638) or the number of columns 0.5 mm (p = 0.341). CONCLUSIONS: A group of highly myopic subjects exhibited reduction in the maximum length and number of blood columns in the cornea when ref it with a highly permeable silicone hydrogel material. The use of photography, along with Adobe Photoshop software, provides a reliable way of measuring corneal vascular responses over time. PMID- 22237420 TI - The protection of selenium on adriamycin-induced mitochondrial damage in rat. AB - Although adriamycin (ADR) exhibits high anti-tumor efficacy in vitro, its clinical use in cancer chemotherapy is limited due to its high renal toxicity. This study investigated the mechanism of ADR nephropathy and the protective effect of selenium on ADR-induced kidney damage by analyzing of the relationship between selenium and mitochondria. Rats were divided into four groups. The first group was injected with saline i.p. for 21 days, the second group received the 4 mg/kg i.p. ADR every alternate day for 8 days, the third group received the 50 MUg/kg i.p. Se for 21 days, and the fourth group received the Se. ADR co administration i.p. blood pressures were assessed, the mitochondrial membrane potential (MMP) was assessed, and the adenosine triphosphate (ATP) levels were determined. The total antioxidant (TAS) and oxidant status (TOS) in cytosol, the mitochondria of kidney cells, and plasma were measured. Mitochondrial TAS decreased and TOS increased in the ADR group compared to the Se group. ADR treated rats showed significantly lower MMP than did the control and Se groups. MMP was significantly restored in the Se + ADR group through selenium treatment compared to the ADR group (p < 0.01). In the ADR group, a reduction in ATP content was seen compared to the control and Se groups (p < 0.01). ATP level was significantly restored through treatment with selenium in the Se + ADR group compared to the ADR group (p < 0.01). We concluded that selenium is effective in vivo against ADR-induced kidney damage via the restoration of TAS and TOS, which prevented mitochondrial damage. PMID- 22237421 TI - Effect of dietary supplementation of organic chromium on performance, carcass traits, oxidative parameters, and immune responses in commercial broiler chickens. AB - An experiment was conducted to study effect of supplementing graded concentrations (0, 100, 200, 300, or 400 MUg/kg diet) of organic chromium (Cr) on performance, carcass traits, oxidative stress, and immune responses in commercial broiler chickens reared in open-sided poultry house under tropical climatic conditions. Each diet was fed ad libitum to eight replicates consisting of six birds in each pen from 1 to 42 days of age. Body mass gain and feed efficiency at 21 and 42 days of age and relative mass of liver, abdominal fat, and ready to cook yields at 42 days of age were not affected (P > 0.05) by supplementing organic Cr in broiler diet. Body mass loss during pre-slaughter holding period (12 h) reduced and relative breast mass increased nonlinearly (P < 0.01) with concentration of Cr in diet. Lipid peroxidation decreased, while activities of glutathione peroxidase and glutathione reductase in plasma increased nonlinearly with Cr supplementation. The ratio between heterophyl and lymphocyte was not affected (P > 0.05) with Cr supplementation in broiler diet. Relative mass of lymphoid organs (bursa, spleen, and thymus) and antibody production to Newcastle disease vaccination were not affected (P > 0.05) by the treatments employed. The cell-mediated immunity (lymphocyte proliferation ratio) increased nonlinearly with dietary Cr concentration. The results of the present study indicated that supplementation of organic Cr did not influence body mass and feed efficiency. However, supplementation of the Cr reduced pre-slaughter holding losses, increased the relative mass of breast, and increased antioxidant status and lymphocyte proliferation in broilers reared in tropics. PMID- 22237422 TI - Influence of incubation conditions on hydrolysis efficiency and iodine enrichment in baker's yeast. AB - The influence of incubation conditions, enzyme type, hydrolysis time, and potassium iodide concentration on hydrolysis and iodine enrichment were studied in supernatant and pellets of Saccharomyces cervisiae hydrolysates. The type of enzyme used and incubation time significantly influence hydrolysis efficiency and protein concentration in supernatant and pellet. The highest protein hydrolysis efficiency was obtained by 24-h incubation with papain. Significantly lower values were observed for pepsin and autolysis. The potassium iodide concentration influences the iodine content of supernatant and pellet, but not hydrolysis. Iodide enrichment of supernatant and pellet depends on the concentration of iodide using during incubation. High concentration of iodide and long incubation times were the conditions for optimal iodide enrichment and high-protein hydrolysates. The optimal hydrolysis efficiency and iodine enrichment were obtained during 24-h incubation with papain in a 4.5-mM potassium iodide medium. The efficiency reached 98.22% with iodine concentrations of 2,664.91 and 9,200.67 MUg/g iodine in pellet and supernatant, respectively. PMID- 22237424 TI - Immune response in the barrier epithelia: lessons from the fruit fly Drosophila melanogaster. AB - The barrier epithelia of multicellular organisms frequently come into direct contact with microorganisms and thus need to fulfill the important task of preventing the penetration of pathogens that could cause systemic infections. A functional immune defence in the epithelial linings of the digestive, respiratory and reproductive organs as well as the epidermis/skin of animals is therefore of crucial importance for survival. Epithelial defence reactions are likely to be evolutionarily ancient, and the use of invertebrate animal models, such as insects and nematodes, has been crucial in unravelling the mechanisms underlying epithelial immunity. This review addresses basic questions of epithelial immunity in animals and humans. It focuses on recent developments in the understanding of the immune responses in the fruit fly Drosophila melanogaster and how the innate immune system acts locally in the epidermis and cuticle, tracheae, gut and genital organs. Both basal immune activities in epithelia that are constantly exposed to microbes as well as positive and negative regulation in response to pathogenic organisms are covered. Important immuno-physiological aspects of epithelial defence mechanisms are also discussed, such as wound healing, re epithelialization and intestinal homeostasis. PMID- 22237425 TI - GSTM1 and GSTT1 polymorphisms and colorectal cancer risk in Chinese population: a meta-analysis. AB - PURPOSE: Studies investigating the associations between GSTM1 and GSTT1 polymorphisms and colorectal cancer (CRC) risk in Chinese population have reported controversial results. Thus, a meta-analysis was performed. METHODS: Four hundred and seven relevant records were identified through a literature search up to September 7, 2011, and 19 studies were finally included, involving a total of 3,130 CRC cases and 6,423 controls. Subgroup analyses were performed by language and study design. Statistical analysis was performed with the software programs Review Manager (version 5.1.2) and STATA (version 11.0). RESULTS: For the GSTM1 polymorphism, the null genotype of GSTM1 was not associated with CRC risk in Chinese population (OR = 1.12, 95% CI = 0.97-1.28). Similar associations were found for GSTT1 polymorphism (OR = 1.10, 95% CI = 0.94-1.29) and the dual null genotype of GSTM1/GSTT1 (OR = 1.26, 95% CI = 0.93-1.71). For subgroup analyses, studies published in English and population-based studies further identified these associations for the three aspects above in Chinese population. CONCLUSIONS: This meta-analysis suggests that the null genotypes of GSTM1 and GSTT1 and the dual null genotype of GSTM1/GSTT1 were all not risk factors in CRC in Chinese population. PMID- 22237427 TI - The family history: the first genetic test, and still useful after all those years? AB - The family history has its origins in genealogy and over the past century has become embedded in clinical practice. Its importance in specialized circumstances is unquestioned but largely untested. Moreover, the relevance of the family history to common diseases, especially in an era of genomic markers that convey risk and the emphasis on "personalized medicine," must be given careful scrutiny. Given the time and expertise needed to obtain and interpret the family history, without a clearer sense of clinical validity and utility, its role will likely diminish. The time to perform the requisite investigations is now. PMID- 22237428 TI - Prader-Willi syndrome. AB - Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (1-3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available. PMID- 22237429 TI - Decision to abort after a prenatal diagnosis of sex chromosome abnormality: a systematic review of the literature. AB - We performed a systematic review of factors affecting parental decisions to continue or terminate a pregnancy after prenatal diagnosis of a sex chromosome abnormality, as reported in published studies from 1987 to May 2011. Based on the Matrix Method for systematic reviews, 19 studies were found in five electronic databases, meeting specific inclusion/exclusion criteria. Abstracted data were organized in a matrix. Alongside the search for factors influencing parental decisions, each study was judged on its methodological quality and assigned a methodological quality score. Decisions either to terminate or to continue a sex chromosome abnormality-affected pregnancy shared five similar factors: specific type of sex chromosome abnormality, gestational week at diagnosis, parents' age, providers' genetic expertise, and number of children/desire for (more) children. Factors unique to termination decisions included parents' fear/anxiety and directive counseling. Factors uniquely associated with continuation decisions were parents' socioeconomic status and ethnicity. The studies' average methodological quality score was 10.6 (SD = 1.67; range, 8-14). Findings from this review can be useful in adapting and modifying guidelines for genetic counseling after prenatal diagnosis of a sex chromosome abnormality. Moreover, improving the quality of future studies on this topic may allow clearer understanding of the most influential factors affecting parental decisions. PMID- 22237430 TI - Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. AB - Women with recurrent pregnancy loss are offered Factor V Leiden (F5) and/or prothrombin G20210A (F2) testing to identify candidates for anticoagulation to improve outcomes. A systematic literature review was performed to estimate test performance, effect sizes, and treatment effectiveness. Electronic searches were performed through April 2011, with review of references from included articles. English-language studies addressed analytic validity, clinical validity, and/or clinical utility and satisfied predefined inclusion criteria. Adequate evidence showed high analytic sensitivity and specificity for F5 and F2 testing. Evidence for clinical validity was adequate. The summary odds ratio for association of recurrent pregnancy loss with F5 in case-controlled studies was 2.02 (95% confidence interval, 1.60-2.55), with moderate heterogeneity and suggestion of publication bias. Longitudinal studies in women with recurrent pregnancy loss or unselected cohorts showed F5 carriers were more likely to have a subsequent loss than noncarriers (odds ratios: 1.93 and 2.03, respectively). Results for F2 testing were similar. For clinical utility, evidence was adequate that anticoagulation treatments were ineffective (except in antiphospholipid antibody syndrome) and had treatment-associated harms. The certainty of evidence is moderate (high, moderate, and low) that anticoagulation of women with recurrent pregnancy loss and F5/F2 variants would currently lead to net harms. PMID- 22237431 TI - The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. AB - PURPOSE: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. METHODS: Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. RESULTS: Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. CONCLUSION: The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup. PMID- 22237432 TI - Incidence and predictors of positive and negative effects of BRCA1/2 genetic testing on familial relationships: a 3-year follow-up study. AB - PURPOSE: Little is known about the long-term impact of BRCA1/2 testing on the relationships between family members. We assessed the incidence of positive and negative family relationship effects of BRCA1/2 testing in the 3 years after result disclosure and identified predictors of these effects. METHODS: A total of 485 women and 67 men who had undergone BRCA1/2 testing were asked 3 years later whether having been tested had improved and/or disrupted relationships with their relatives. The associations with sociodemographic, medical, and psychosocial characteristics were assessed. RESULTS: Globally, 85.1% did not report any positive or negative effects of genetic testing on family relationships. Positive and negative effects were reported by 13.2% and 3.7% of participants, respectively. Reporting positive relationship effects was associated with older age, intolerance for uncertainty, cancer-specific distress, and more social support. Low education, positive attitude toward prophylactic mastectomy, and low social support increased the likelihood of negative effects. CONCLUSION: Our findings do not support the belief that family relationships are frequently disrupted by BRCA1/2 testing. Understanding that most family relationships are unchanged long term by genetic testing may help genetic service providers encourage those considering testing to overcome hesitancy related to potential difficulties of communicating results to relatives. PMID- 22237433 TI - Assessing the analytic validity of molecular testing for Huntington disease using data from an external proficiency testing survey. AB - PURPOSE: Documenting high analytic validity of the molecular diagnostic test for Huntington disease is important because of counseling implications. This dominantly inherited adult onset disorder (prevalence of three or more per 100,000) is characterized by chorea, ataxia, and personality changes. The molecular basis is excessive CAG repeats in the HTT gene. METHODS: External proficiency testing survey results for Huntington disease were extracted (2003 2010). Analytic interpretations and CAG repeat lengths were compared with published performance criteria. RESULTS: Between 2008 and 2010, 33 US participating laboratories reported clinical test interpretations. Analytic validity was high (sensitivity: 99.5%, 95% confidence interval: 97.1-99.9%; specificity: 99.2%, 95% confidence interval: 97.1-99.9%). Repeat length errors occurred in 2.6% (95% confidence interval: 1.8-3.8%) of 1,060 allelic challenges, with most being minor or from a single participant. Past performance (2003-2007) was similar. The 23 international participants had more total repeat length errors (17.5%, 95% confidence interval: 14.6-20.7%). Further analyses indicated that assessment criteria can be relaxed without jeopardizing analytic validity. CONCLUSION: Analytic validity is high for Huntington disease testing among US laboratories. International survey participants had lower analytic validity and a higher proportion of poorly performing laboratories. The reasons for this are unclear. PMID- 22237434 TI - The impact of false-positive newborn screening results on families: a qualitative study. AB - PURPOSE: Newborn screening leads to improved treatment and disease outcomes, but false-positive newborn screening results may cause distress for parents. The purpose of this study was to describe the experiences of families who receive a false-positive newborn screening result in an attempt to discover ways to help improve the newborn screening communication process for families. METHODS: This was a qualitative study using two methods of data collection: in-depth, semistructured interviews and focus groups. Participants (N = 27) were parents whose children (ages 6-16 months) underwent follow-up testing after newborn screening and whose follow-up test results indicated that the newborn screening result was a false-positive. RESULTS: Our analysis found that parents who have a false-positive newborn screening result experience five distinct stages. Most parents did not report long-term negative impacts of the experience, but some experienced some residual worry. Participants described effective provider communication as key in mitigating stress. Some parents identified the experience as leading to positive outcomes. CONCLUSION: Identifying best practices for communication between the health care providers and parents is an essential component in improving the newborn screening process. Further research is needed to discover best practices for communication to minimize potential harm and maximize the benefits of newborn screening. PMID- 22237435 TI - Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal transducing death domain: molecular mechanisms and clinical penetrance. AB - PURPOSE: Autoimmune lymphoproliferative syndrome is a disorder of lymphocyte apoptosis. Although FAS molecules bearing mutations in the signal-transducing intracellular death domain exhibit dominant-negative interference with FAS mediated apoptosis, mechanisms for pathology of non-death domain FAS mutations causing autoimmune lymphoproliferative syndrome are poorly defined. METHODS: RNA stability, protein expression, ligand binding, and ability to transmit apoptosis signals by anti-FAS antibody or FAS ligand were determined for a cohort of 39 patients with non-death domain autoimmune lymphoproliferative syndrome. Correlations between mutation type and disease penetrance were established in mutation-positive family members. RESULTS: Frameshifts or transcriptional stop mutations before exon 7 resulted in messenger RNA haploinsufficiency, whereas an amino-terminal signal sequence mutation and certain intracellular truncations prevented cell surface localization of FAS. All resulted in decreased FAS localization, inability to bind FAS ligand, and reduced FAS ligand-induced apoptosis. Extracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis. Mutation-positive relatives with haploinsufficient or extracellular mutations had lower penetrance of autoimmune lymphoproliferative syndrome clinical phenotypes than did relatives with death domain mutations. CONCLUSION: We have defined molecular mechanisms by which non death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with autoimmune lymphoproliferative syndrome, and demonstrated that FAS haploinsufficiency can lead to autoimmune lymphoproliferative syndrome. PMID- 22237437 TI - Testing for variants in CYP2C19: population frequencies and testing experience in a clinical laboratory. AB - PURPOSE: We sought to determine the genotype frequencies for cytochrome p450 enzyme 2C19 variant alleles both in the US pan-ethnic population and various US ethnic groups and to establish the frequency of clinically actionable genotypes. METHODS: Analytical results were obtained from 1,396 consecutive samples submitted for cytochrome p450 enzyme 2C19 genotyping tests and stored in a proprietary database. This database was queried and genotypes and predicted phenotypes established. Anonymized samples were obtained from specimens submitted for cystic fibrosis genotyping that contained ethnicity information. Samples from 357, 149, and 346 individuals self-identified as white, African American, and Hispanic, respectively, were analyzed. In addition, 342 anonymized samples submitted for Ashkenazi Jewish panel testing were analyzed. RESULTS: Significant ethnic differences were observed in the frequencies of the *17 ultrarapid allele among the various groups studied. In the pan-ethnic population, 3.8% of tested patients were classified as ultrarapid metabolizers, 24% as extensive metabolizers heterozygous for a *17 ultrarapid allele, 27% as intermediate metabolizers, and 3.5% as poor metabolizers. Using stringent criteria, 7.3% of individuals would have clinically actionable genotypes. In addition, we detected two individuals with a haplotype of *2/*17 and a single individual with a haplotype of *4/*17 indicating that the *17 hypermetabolic allele can occur on a *1, *2, or *4 background. PMID- 22237436 TI - Cardiovascular findings in duplication 17p11.2 syndrome. AB - PURPOSE: Cardiovascular abnormalities are newly recognized features of duplication 17p11.2 syndrome. In a single-center study, we evaluated subjects with duplication 17p11.2 syndrome for cardiovascular abnormalities. METHODS: Twenty-five subjects with 17p11.2 duplication identified by chromosome analysis and/or array-based comparative genomic hybridization were enrolled in a multidisciplinary protocol. In our clinical evaluation of these subjects, we performed physical examinations, echocardiography, and electrocardiography. Three of these subjects were followed up longitudinally at our institution. RESULTS: Cardiovascular anomalies, including structural and conduction abnormalities, were identified in 10 of 25 (40%) of subjects with duplication 17p11.2 syndrome. The most frequent abnormality was dilated aortic root (20% of total cohort). Bicommissural aortic valve (2/25), atrial (3/25) and ventricular (2/25) septal defects, and patent foramen ovale (4/25) were also observed. CONCLUSION: Duplication 17p11.2 syndrome is associated with structural heart disease, aortopathy, and electrocardiographic abnormalities. Individuals with duplication 17p11.2 syndrome should be evaluated by electrocardiography and echocardiography at the time of diagnosis and monitored for cardiovascular disease over time. Further clinical investigation including longitudinal analysis would likely determine the age of onset and characterize the progression (if any) of vasculopathy in subjects with duplication 17p11.2 syndrome, so that specific guidelines can be established for cardiovascular management. PMID- 22237438 TI - Noninvasive fetal sex determination in maternal plasma: a prospective feasibility study. AB - PURPOSE: To prospectively validate a protocol for noninvasive fetal sex determination in maternal plasma and demonstrate its applicability to clinical practice. METHODS: Peripheral blood from 404 pregnant women undergoing prenatal invasive testing was collected from 6 to 23 weeks of gestation. Real-time PCR was performed for the SRY gene and multicopy DYS14 marker sequence located within the TSPY gene by the TaqMan minor groove binder probe assay as a first-line test. Owing to a false-positive result, amplification of repetitive motifs of the DAZ gene region was also tested as a second-line test performed in the last 232 patients enrolled in our series. A diagnostic algorithm was designed using a combination of these three markers. Fetal gender determined by noninvasive prenatal diagnosis (NIPD) was compared with that diagnosed by quantitative fluorescent PCR after invasive testing or ultrasound. RESULTS: A single false positive result was obtained in the first 172 pregnancies. Reporting criteria were modified in the subsequent 232 pregnancies, giving an overall sensitivity and specificity of 100% (95% CI 99.8-100%) and 99.5% (95% CI 98.1-100%), respectively. Pregnancy outcome was obtained in all cases, including 221 male bearing and 183 female-bearing pregnancies. CONCLUSION: NIPD for fetal sex determination in maternal plasma is highly accurate and clinically applicable if robust reporting criteria are applied. PMID- 22237439 TI - A comprehensive survey of cancer risks in extended families. AB - PURPOSE: Cancer is familial; yet known cancer predisposition genes, as well as recognized environmental factors, explain only a small percentage of familial cancer clusters. This population-based description of cancer clustering describes patterns of cancer coaggregation suggestive of a genetic predisposition. METHODS: Using a computerized genealogy of Utah families linked to a statewide cancer registry, we estimated the relative risks for 36 different cancer sites in first , second-, and third-degree relatives of cancer cases, for each cancer site individually, and between cancer sites. We estimated the sex- and birth-year specific rates for cancer using 1 million individuals in the resource. We applied these rates to groups of cases or relatives and compared the observed and expected numbers of cancers to estimate relative risks. RESULTS: Many cancer sites show significantly elevated relative risks among distant relatives for cancer of the same site, strongly supporting a heritable contribution. Multiple combinations of cancer sites were observed among first-, second-, and third degree relatives, suggesting the existence of heritable syndromes involving more than one cancer site. CONCLUSION: This complete description of coaggregation of cancer by site in a well-defined population provides a set of observations supporting heritable cancer predispositions and may support the existence of genetic factors for many different cancers. PMID- 22237440 TI - Caregiver opinions about fragile X population screening. AB - PURPOSE: We sought to determine caregiver perceptions about population screening for fragile X and to examine factors potentially associated with support for screening. METHODS: We asked 1,099 caregivers of a child with fragile X syndrome or a fragile X carrier to rate whether free, voluntary screening should be offered preconception, prenatally, neonatally, or when problems occur. Caregivers chose a preferred time for screening, reported whether screening would affect parent-child bonding, indicated preferences for carrier detection, and gave reasons for their choices. RESULTS: Caregivers endorsed all forms of screening, but prenatal screening was less strongly endorsed than preconception or postnatal screening. Most (79%) preferred preconception carrier testing, allowing more options when making reproductive decisions. Most thought that screening should also disclose carrier status and believed a positive screen would not negatively affect parent-child bonding. Maternal education, caregiver depression, family impact, and severity of disability were not associated with screening opinions, but parents who only had carrier children were less likely to endorse prenatal screening. CONCLUSION: Caregivers of children with fragile X widely endorse screening. However, because different parents will make different choices, screening may need to be offered at multiple times with careful consideration of consent and informed decision-making. PMID- 22237441 TI - An audit of clinical service examining the uptake of genetic testing by at-risk family members. AB - PURPOSE: The aim of this study was to investigate the uptake of genetic testing by at-risk family members for four genetic conditions: chromosomal translocations, fragile X syndrome, Huntington disease, and spinal muscular atrophy. METHODS: A clinical audit was undertaken using genetics files from Genetic Health Services Victoria. Data were extracted from the files regarding the number of at-risk family members and the proportion tested. Information was also collected about whether discussion of at-risk family members and family communication during the genetic consultation was recorded. RESULTS: The proportion of at-risk family members who had genetic testing ranged from 11% to 18%. First-degree family members were most frequently tested and the proportion of testing decreased by degree of relatedness to the proband. Smaller families were significantly more likely to have genetic testing for all conditions except Huntington disease. Female at-risk family members were significantly more likely to have testing for fragile X syndrome. CONCLUSION: The majority of at-risk family members do not have genetic testing. Family communication is likely to influence the uptake of genetic testing by at-risk family members and therefore it is important that families are supported while communicating to ensure that at risk family members are able to make informed decisions about genetic testing. PMID- 22237442 TI - Revisiting the Wilson-Jungner criteria: how can supplemental criteria guide public health in the era of genetic screening? AB - PURPOSE: Advances in technology have made newborn screening for more than 50 inborn errors of metabolism possible using a dried blood sample. A framework is proposed that public health practitioners may use when considering candidate disorders for newborn screening panels. METHODS: The framework expands on the 10 Wilson-Jungner criteria with the addition of 11 criteria specific to newborn screening. A calculation, the "pNBS Decision Score," is used to quantify results and rank candidate disorders. RESULTS: The pNBS Decision Scores that were calculated for phenylketonuria (OMIM# 261600), cystic fibrosis (OMIM# 219700), Pompe disease (OMIM# 232300), and severe combined immunodeficiency (OMIM# 102700) support their inclusion as newborn screening disorders. The pNBS Decision Score suggests that Krabbe disease (OMIM# 245200) is not a candidate disorder for inclusion at this time. CONCLUSION: The proposed framework adds to the ability of policy makers to quantify an essential portion of the process for adding disorders to newborn screening panels. Other factors such as ethical, legal, and social issues, clinical utility, and advocacy are also part of the policy process. The framework is not intended to replace existing nomination processes but rather to enhance those processes by encouraging iterative review of newborn screening-specific criteria. The use of the framework will provide consistency across a portion of the decision process. The public health community should take the opportunity to revisit the screening determinants of the Wilson-Jungner criteria from a 21st century perspective. The results suggest that this framework provides the public health practitioner with a consistent process for making an evidence-based decision. PMID- 22237443 TI - Successful immune tolerance induction to enzyme replacement therapy in CRIM negative infantile Pompe disease. AB - PURPOSE: Infantile Pompe disease resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients. METHODS: Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA. RESULTS: In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts. CONCLUSION: The combination of rituximab with methotrexate +/- intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naive setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy. PMID- 22237444 TI - Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations. AB - PURPOSE: Hereditary spastic paraplegias compose a group of neurodegenerative disorders with a large clinical and genetic heterogeneity. Among the autosomal recessive forms, spastic paraplegia type 11 is the most common. METHODS: To better understand the spastic paraplegia type 11 mutation spectrum, we studied a group of 54 patients with hereditary spastic paraplegia. Mutation screening was performed by PCR amplification of SPG11 coding regions and intron boundaries, followed by sequencing. For the detection of large gene rearrangements, we performed multiplex ligation-dependent probe amplification. RESULTS: We report 13 families with spastic paraplegia type 11 carrying either novel or previously identified mutations. We describe a complex entire SPG11 rearrangement and show that large gene rearrangements are frequent among patients with spastic paraplegia type 11. Moreover, we mapped the deletion breakpoints of three different large SPG11 deletions and provide evidence for Alu microhomology mediated exon deletion. CONCLUSION: Our analysis shows that the high number of repeated elements in SPG11 together with the presence of recombination hotspots and the high intrinsic instability of the 15q locus all contribute toward making this genomic region more prone to large gene rearrangements. These findings enlarge the amount of data relating repeated elements with neurodegenerative disorders and highlight their importance in human disease and genome evolution. PMID- 22237446 TI - Enhancing exposure to genetics and genomics through an innovative medical school curriculum. AB - PURPOSE: Physicians entering medical practice in the 21st century will require more than a basic understanding of human genetics because of rapid progress in the field of genetics and genomics. The current undergraduate medical curriculum at most institutions is not adequate to prepare medical students for these challenges. Enhancing exposure to genetics throughout the medical school curriculum should help prepare the next generation of physicians to use genetic and genomic information for optimal patient care. METHODS: We have introduced a Genetics Track Curriculum to the undergraduate medical curriculum at Baylor College of Medicine. RESULTS: This track runs in parallel to the existing 4-year curriculum and includes didactic sessions, small group discussions, longitudinal clinical experiences, clinical and laboratory rotations, community outreach, and scholarly projects related to genetics. It also provides the students a means to network and discuss topics and career paths in medical genetics. CONCLUSION: We have developed a novel curriculum that enhances genomic education for medical students with the ultimate goal of enabling our graduates to deliver more effective and personalized medical care. We believe that the Genetics Track Curriculum at Baylor College of Medicine can serve as a prototype for other medical schools across the country and abroad. PMID- 22237445 TI - Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting. AB - Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships. PMID- 22237447 TI - Toward better counseling for Down syndrome. PMID- 22237448 TI - How can we stimulate translational research in cancer genomics beyond bench to bedside? PMID- 22237449 TI - Evaluation of the adolescent or adult with some features of Marfan syndrome. AB - ACMG standards and guidelines are designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticists should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these standards and guidelines.Individuals who are suspected of having Marfan syndrome are often referred to a medical geneticist for further evaluation and diagnosis. However, there are a number of conditions that share physical manifestations with those of Marfan syndrome; therefore, an approach to diagnosis and evaluation is crucial to the proper long-term follow-up of these individuals. This practice guideline provides guidance for the approach to this cadre of individuals. PMID- 22237451 TI - Performance of SLS/MWCNTs/PANI capacitor electrodes in a physiological electrolyte and in serum. AB - We report a stainless steel/multi walled carbon nanotubes/polyaniline (SLS/MWCNTs/PANI) capacitor electrode capable of operating in a physiological electrolyte and in serum. The specific capacitance of SLS/MWCNTs/PANI reaches 401 F g(-1) in the physiological electrolyte and 326 F g(-1) in serum. The capacity loss at 6.4 MUA mm(-2) over 2000 cycles is 10% in the physiological electrolyte and 21% in serum. PMID- 22237452 TI - Overexpression of tumor suppressor TSLC1 by a survivin-regulated oncolytic adenovirus significantly inhibits hepatocellular carcinoma growth. AB - PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Oncolytic viruses represent a promising therapeutic agent or vehicle to human cancers due to their ability of selectively lysing cancer cells but not in normal cells. TSLC1, a novel tumor suppressor gene, was loss in many human cancers including HCC, not in normal cells. The current study is focused on the antitumor effect of TSLC1-armed survivin-regulated oncolytic adenovirus for HCC and to explore their molecular mechanism. METHODS: The expression of tumor suppressor TSLC1 and survivin was detected by quantitative PCR. The recombinant virus Ad.SP-E1A-E1B((Delta55))-TSLC1 (brief name as SD55-TSLC1) was constructed by inserting TSLC1 gene into the dual-regulated oncolytic adenovirus vector Ad.SP E1A-E1B((Delta55)). Then, we performed the antitumor experiments of SD55-TSLC1 in vitro and in nude mice xenografted with Huh7 liver cancer. RESULTS: The expression of TSLC1 was lower in HCC cells than in normal cells, which implied TSLC1 is a tumor suppressor of liver cancer. Survivin expression is higher in detected HCC cells than in normal cells. The SD55-TSLC1 exhibited an excellent antitumor effect on HCC cell growth in vitro but does no or little damage to normal liver cells. Animal experiment further confirmed that SD55-TSLC1 achieved significant inhibition of Huh7 liver cancer xenografted growth. Furthermore, the mechanism of antitumor efficacy by SD55-TSLC1 was elucidated to be due to the activation of caspase apoptotic pathway including the inducement of caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage. This is the first report of TSLC1 by oncolytic adenovirus with an excellent antitumor effect to liver cancer growth. CONCLUSION: These data suggest that an oncolytic adenovirus expressing TSLC1 is effective and support that SD55-TSLC1 may be a potent antitumoral agent for future clinical trials of liver cancer. PMID- 22237453 TI - Inducible expression of tissue factor in small-cell lung cancer: impact on morphology and matrix metalloproteinase secretion. AB - PURPOSE: Tissue factor (TF), the transmembrane receptor for factor VIIa (FVIIa), has key regulatory functions in coagulation as well as in tumour progression and metastasis. Small-cell lung cancer (SCLC) metastasises more aggressively than non small-cell lung cancer (NSCLC). Previously, we described the transition of SCLC cell line H69 to adherent growth and TF expression. Here, we explored the differential expression of TF and its functional impact on morphology and matrix metalloproteinase (MMP) secretion. METHODS: The constitutional TF expression was evaluated in a panel of established NSCLC and SCLC cell lines. Furthermore, in three stress-selected adherent SCLC H69 cells, TF and MMP expressions were determined by mRNA, protein, and activity measurements. RNA interference-mediated TF down-regulation and FVIIa stimulation were used to study the impact of TF on cellular functions. RESULTS: NSCLC cells expressed high TF antigen (median 3.75 ng/mg; range 0.31-65.2 ng/mg protein, n = 8), while SCLC expressed none or low TF (median 0.07 ng/mg; range 0-0.39 ng/mg protein, n = 6). However, selected H69 adherent cells markedly expressed TF (range: 4.8-44.3 ng/mg protein, n = 3) and secreted MMP-2 and MMP-9. FVIIa stimulated MMP-2 and MMP-9 secretion in H69adh cells, whereas TF down-regulation diminished MMP-2 and MMP-9 expression and promoted reversion to suspension growth. CONCLUSIONS: Our data show the significance of TF expression in the reversible growth phenotype of H69. Because TF, MMP expression, and adherence are highly relevant to cancer metastasis, this study suggests a novel mechanism of adaptation, thereby adding to the understanding of SCLC biology and its aggressiveness. PMID- 22237454 TI - Comparison of clinicopathological characteristics and prognoses between bilateral and unilateral breast cancer. AB - PURPOSE: The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We compared the characteristics and prognosis of bilateral breast cancer and unilateral breast cancer. METHODS: Our study included 4,183 patients with breast cancer who were treated at Sun Yat-sen University Cancer Center between January 1, 2000, and December 31, 2007. Bilateral breast cancer was categorized as synchronous (within 3 months) or metachronous (diagnosed after 3 months of first cancer). SPSS was used for data analysis. RESULTS: 106 (2.5%) and 31 (0.7%) patients were diagnosed with metachronous and synchronous bilateral cancer. Women with bilateral cancer had more frequent postmenopause, HER-2 negativity, and advanced disease than in patients with unilateral cancer. Young age at diagnosis, invasive lobular carcinoma, ER/PR negativity, HER-2 positivity, radiation, large tumor size (T > 5 cm), and stage III disease of the first cancer were risk factors for contralateral cancer. The 5-year disease-free survival and overall survival rates were 76 and 83% for unilateral cancer, while 32 and 72% for bilateral cancer (P = 0.000 for both). CONCLUSIONS: Bilateral cancer was associated with shorter disease-free survival and overall survival than unilateral cancer. The prognosis of metachronous bilateral cancer, especially those diagnosed within 2 years after the first cancer was significantly worse than synchronous bilateral cancer. PMID- 22237455 TI - Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties. AB - PURPOSE: Prostate cancer (PCa) becomes lethal when cancer cells develop into castration-resistant PCa, which remains incurable because of the poor understanding of their cell origin and characteristics. We aim to investigate the potential role of cancer stem cells (CSCs) in PCa progression. METHODS: Human PCa cell lines (LNCaP, 22RV1, DU145 and PC-3) were plated in serum-free suspension culture system allowed for tumorsphere forming. To evaluate the CSC characteristics of tumorspheres, the self-renewal, chemoresistance, tumorigenicity of the PCa tumorsphere cells, and the expression levels of stemness-related proteins in the PCa tumorsphere cells were assessed, comparing with the parental adherent cells. RESULTS: Tumorsphere cells from PCa cell lines displayed enhanced self-renewal, chemoresistance and tumor-initiating capacity when compared with the adherent cells. Additionally, these cells overexpressed CSC marker CD44. Also, the tumorsphere cells expressed high levels of "stemness" genes Gli1, ABCG2 and Bmi-1. CONCLUSIONS: Collectively, these data demonstrated that tumorspheres derived from PCa cells possess chemoresistant and CSC properties. Our study suggests that the identification of PCa CSCs could provide new insight into the lethal phenotype of PCa and therapeutic implications. PMID- 22237456 TI - Circulating microRNA-218 was reduced in cervical cancer and correlated with tumor invasion. AB - BACKGROUNDS: microRNA-218 was proved to be a tumor-suppressor microRNA in several cancers, but its status in cervical cancer patients has not been established. In this study, we investigated the expression of microRNA-218 in the sera from cervical cancer patients and its relationships with clinico-pathological characteristics. METHODS: The expression of microRNA-218 was detected in the sera of 90 cervical cancer patients and 50 normal age-matched women by quantitative real-time PCR. The clinical data were collected and analyzed by statistical software. RESULTS: In the cancer group, microRNA-218 was reduced significantly in the sera (P < 0.001). Moreover, decreased microRNA-218 was associated with later stages, cervical adenocarcinoma, and lymphatic node metastasis. CONCLUSIONS: microRNA-218 was deregulated in most cervical cancer patients and associated with tumor invasion. PMID- 22237457 TI - Efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma and poor risk features. AB - BACKGROUND: Temsirolimus is a standard of care in patients with metastatic renal cell carcinoma (mRCC) with poor risk factors. The role of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) remains poorly defined in this setting. METHODS: Records of our center were examined to identify patients with mRCC and 3 or more poor prognosis factors, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, who had been treated with VEGFR TKIs. Their baseline characteristics, radiologic response, adverse events, and survival status were assessed. RESULTS: The 88 patients who met our inclusion criteria had a median age of 56 years (range 17-83 years). We observed clear cell histology in 71 (81%) patients, and 52 (59%) underwent prior nephrectomy. Seventy-six patients (86%) were treated with sunitinib and 10 (11%) with sorafenib. Of 85 patients with measurable lesions, 19 (22%) showed objective response, with disease control achieved in 49 (56%). At a median follow-up of 29.6 months, the median time to progression was 5.0 months (95% CI, 3.5-6.5 months) and the median overall survival (OS) was 9.3 months (95% CI, 7.1-11.5 months). Neutrophil count (>ULN), bone metastasis, and lymph node metastasis were independent prognostic factors for OS, whereas prior nephrectomy was not. CONCLUSIONS: VEGFR TKIs, especially sunitinib, are active and tolerated by mRCC patients with poor risk features. PMID- 22237458 TI - blaKPC and rmtB on a single plasmid in Enterobacter amnigenus and Klebsiella pneumoniae isolates from the same patient. AB - Enterobacter amnigenus (EA76) and Klebsiella pneumoniae (KP76) isolates with multidrug-resistant (MDR) patterns were identified from the same patient in the neurosurgery department of our hospital. An outbreak of MDR K. pneumoniae had also occurred in this department. To characterize the resistance mechanism and molecular epidemiology of these isolates, sequential experiments including antimicrobial susceptibility testing, polymerase chain reaction (PCR), plasmid analysis, pulsed field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. EA76 and KP76 were resistant to all of the antibiotics tested, except colistin and tigecycline. blaKPC-2, blaTEM-1, blaSHV-12, blaCTX-M 3, blaCTX-M-14, and rmtB genes were identified in both isolates, with blaKPC-2, blaTEM-1, blaCTX-M-14, and rmtB being co-carried on one plasmid in each isolate. Further analysis showed different restriction patterns between the two KPC carrying plasmids. Of the 11 carbapenem-resistant isolates found in the outbreak, all were resistant to all of the beta-lactams tested, with 63.64% (7/11) also exhibiting resistance to aminoglycosides and 72.73% (8/11) exhibiting resistance to quinolones. PCR analysis and molecular typing of the 11 K. pneumoniae strains revealed that the seven aminoglycoside-resistant isolates shared the same antibiotic-resistant gene pattern and identical or one-band-difference PFGE profiles relative to KP76. In addition, all of the eight aminoglycoside-resistant isolates, including KP76, belonged to the national epidemic clone ST11. The overall results indicate the emergence of E. amnigenus and outbreak of ST11 K. pneumoniae, with both co-harboring blaKPC and rmtB genes on a single plasmid in our neurosurgery wards. PMID- 22237459 TI - The epidemiology of the first described carbapenem-resistant Klebsiella pneumoniae outbreak in a tertiary care hospital in Saudi Arabia: how far do we go? AB - The purpose of this investigation was to describe the first documented carbapenem resistant Klebsiella pneumoniae (CRKP) outbreak in a tertiary care facility in Saudi Arabia. We initiated a prospective study to follow all cases of CRKP as well as the active surveillance of patients in areas where cases were identified. We also conducted a retrospective review of the microbiology database for any missed cases of CRKP. Pulsed field gel electrophoresis (PFGE) was conducted for the available CRKP isolates. During March 2010, a cluster of eight CRKPs was detected primarily in the adult intensive care unit (ICU). Patients with CRKPs were put under strict contact isolation, along with appropriate infection control measures. A retrospective review of K. pneumoniae isolates over the previous 6 months revealed two more CRKPs. The PFGE results during the outbreak period showed that the majority of strains were genetically indistinguishable or closely related. The majority of patients had prolonged hospital stay (91%), indwelling devices (81%), surgical procedures (74%), carbapenem use (62%), and colonization/infection with other multiple drug-resistant organisms (MDROs) (57%). Two-fifths of patients with CRKP had clinical infection and 38% died during the current hospitalization. Contact isolation, hand hygiene, environmental cleaning, and staff education may control CRKP outbreak in the acute care setting, but did not prevent endemicity. PMID- 22237460 TI - Mechanical circulatory support for elderly heart failure patients. AB - End-stage systolic heart failure is an increasingly common problem in elderly patients and is associated with high cost, poor quality of life, and poor outcomes. Mechanical circulatory support is a promising therapy as both a bridge to transplantation and destination therapy. Elderly patients are frequently ineligible for heart transplantation because of their age and comorbidities, and the application of mechanical circulatory support for destination therapy in this population is not well defined. A review of the literature was undertaken to better characterize our experience to date with mechanical circulatory support in older heart failure populations. Mechanical circulatory support is being employed increasingly for destination therapy indications in older patients. The newer continuous flow devices appear to have disproportionate advantage in elderly patients, which has translated into marked improvement in 1- and 2-year survival. The rational implementation of MCS devices in elderly heart failure patients needs to focus on (1) continuous flow devices that appear to have particular benefit in this population, (2) extensive pre-MCS assessment including variables relating to frailty, and (3) intervening before these patients develop cardiogenic shock. More data are needed on the cost-benefit analysis of routine use of CF devices as destination therapy in elderly patients with heart failure. PMID- 22237461 TI - Mercury concentrations in nestling wading birds relative to diet in the southeastern United States: a stable isotope analysis. AB - Mercury (Hg) is a ubiquitous environmental contaminant that is transferred trophically through aquatic and terrestrial food webs. To better understand the routes of Hg uptake in organisms that rely on both aquatic and terrestrial food resources, we analyzed feather and down samples from nestling wading birds of varying trophic positions in both inland and coastal colonies. We used stable nitrogen and carbon isotope analyses to evaluate trophic positions of individual species (delta(15)N) and differences in foraging habitat use (delta(13)C). Inland, aquatic species had higher trophic status than the single terrestrial species examined, and the expected positive relationship between delta(15)N and Hg content of feathers was observed. However, the same was not true for all species from coastal colonies. Feathers from species that primarily consumed saltwater prey were relatively high in delta(15)N value and low in Hg content, which is opposite of the trend expected due to Hg biomagnification in food chains. In contrast, coastal species foraging in freshwater or a combination of freshwater and saltwater habitats displayed greater Hg contents in feathers. The apparent differential use of the two aquatic systems (freshwater and saltwater) in coastal environments by wading bird species results in variations in delta(15)N values and Hg contents in nestling feathers not found in species associated with only freshwater systems. PMID- 22237462 TI - Effects of triclosan and triclocarban, two ubiquitous environmental contaminants, on anatomy, physiology, and behavior of the fathead minnow (Pimephales promelas). AB - Triclosan (TCS) and triclocarban (TCC) are two common antimicrobial agents found in many personal care products and subsequently are detected ubiquitously in wastewater effluent and receiving waters. Both compounds are of recent regulatory interest due to their omnipresence in the environment, including in humans. Although TCS and TCC have been suggested to be endocrine active, little information exists about their effects on organismal end points in development (growth, escape performance), anatomy (morphological indices, histology), physiology (vitellogenin), and behavior of exposed aquatic organisms. In this study, newly hatched fathead minnows were exposed for 12 days, and mature male and female fathead minnows (Pimephales promelas) were exposed for 21 days to environmentally realistic concentrations (nanograms per liter) of these two compounds singularly and in mixtures. At the end of the exposure, larvae were assessed for growth and predator-avoidance performance, and a subset of mature fish was assessed for plasma vitellogenin induction, expression of secondary sexual characteristics, relative size of liver and gonads, and histopathological changes to both organs. The remaining exposed mature fish were placed in breeding pairs of one male and one female minnow from the same treatment to assess their ability to defend a nest site and reproduce. Exposure to either antimicrobial compound, alone or as a mixture, caused no changes to larval fish, gonad size, or vitellogenin concentrations in mature fathead minnows. In contrast, decreased aggression was seen in adult male fathead minnows exposed to TCC (1.6 MUg/l) or a mixture (560 ng/l TCS + 179 ng/l TCC and 1.6 MUg/l TCS + 450 ng/l TCC). Decreased aggression would likely decrease their ability to defend and hold a nest site needed for spawning and reproduction. Substantial variability was found in the severity of observed effects within treatments, suggesting that environmentally realistic concentrations of these compounds may only affect particularly sensitive individuals. PMID- 22237463 TI - Effect size of ticagrelor over clopidogrel in the Platelet Inhibition and Patient Outcomes (PLATO) trial: from statistics to clinical judgment. PMID- 22237465 TI - Letter to the Editor: Mastrevirus sequences in a begomovirus-infected plant. AB - Recombination is a major driver of diversification of geminiviruses and is believed to be, for a large part, responsible for the present taxonomic structure of the family Geminiviridae. Examples of recent intergeneric recombination between viruses of the genera Begomovirus and Mastrevirus remain to be identified. Here, we show that one of the prerequisites for begomovirus mastrevirus intergeneric recombination, co-infection of a single plant, does occur. The lack of reported recombination between viruses of these two genera may suggest that there are constraints to viable intergeneric recombinant viruses being produced, possibly due to the extreme genetic distances between extant begomo- and mastreviruses. PMID- 22237464 TI - Identification and characterization of monoclonal antibodies against the ORFV059 protein encoded by Orf virus. AB - Recent outbreaks of orf in China have been attributed to a novel strain of Orf virus (ORFV) designated ORFV-Jilin. Currently, monoclonal antibodies (Mabs) have not yet been developed against this specific pathogen even though such entities could have potential applications regarding the diagnosis and characterization of ORFV-Jilin. Therefore, the current study was undertaken to generate Mab against the immunodominant ORFV059 protein of this virus. For this purpose, the ORFV Jilin ORFV059 protein was expressed in Escherichia coli and subsequently used as an antigen to immunize mice and for the initial screening of hybridomas prepared from the mice for their ability to produce anti-ORFV059 protein Mabs via an indirect ELISA. Ten, positive hybridomas were identified in this manner and verified based on the ability of their released Mab to react specifically with both naturally and artificially expressed ORFV059 protein in Western blots. The two hybridomas with the greatest propensity to secrete Mab were subcloned three times before being introduced intraperitoneally into mice. Afterwards, both Mab were separately purified from the mice's ascetic fluids and found to successfully recognize the ORFV-Jilin ORFV059 protein in a variety of immunological assays. Thus, the widespread utility of these Mab as a diagnostic core reagent should prove invaluable for further investigations regarding the mechanisms of orf pathogenesis and the control of this disease. In this regard, it should be noted that Mab A3 was used to confirm the predicted late expression of the ORFV-Jilin ORFV059 protein during virus replication. PMID- 22237466 TI - Natural history of untreated renal cell carcinoma with venous tumor thrombus. AB - OBJECTIVES: The natural history of untreated renal cell carcinoma (RCC) with venous tumor thrombus (VTT) is poorly characterized. We aimed to describe the natural history of this disease, and to identify prognostic factors associated with disease-specific survival. MATERIALS AND METHODS: We identified patients in the Surveillance, Epidemiology, and End Results (SEER) database with untreated renal cell carcinoma and venous tumor thrombi. Disease-specific median and 1-year survival rates were determined, and disease-free survival curves were plotted using the Kaplan-Meier method. Multivariable Cox regression analyses were performed to identify factors associated with disease-specific and overall survival in this patient group. RESULTS: Of 2,265 patients with RCC and VTT, 390 (17%) underwent no treatment; 278 (71%) patients died during follow-up; of these, 243 deaths (87%) were due to RCC. Median and 1-year disease-specific survival for this group was 5 months and 29%, respectively. On multivariable analysis, the extent of tumor thrombus (HR 1.7 for T3c vs. T3b, 95% CI 1.0-2.7) and the presence of metastases (HR 3.1 for M+ vs. M0, 95% CI 1.7-5.5) were most strongly associated with disease-specific mortality. CONCLUSIONS: Prognosis is poor for the majority of untreated patients with RCC and VTT. Supradiaphragmatic thrombi and distant metastases are adverse prognostic factors in this patient group. This information is important when counseling patients as to the risk and benefits of surgical vs. nonoperative management of RCC and VTT. PMID- 22237467 TI - Randomized clinical trial of omega-3 fatty acid-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing oesophagogastric cancer surgery. AB - BACKGROUND: Oesophagogastric cancer surgery is immunosuppressive. This may be modulated by omega-3 fatty acids (O-3FAs). The aim of this study was to assess the effect of perioperative O-3FAs on clinical outcome and immune function after oesophagogastric cancer surgery. METHODS: Patients undergoing subtotal oesophagectomy and total gastrectomy were recruited and allocated randomly to an O-3FA enteral immunoenhancing diet (IED) or standard enteral nutrition (SEN) for 7 days before and after surgery, or to postoperative supplementation alone (control group). Clinical outcome, fatty acid concentrations, and HLA-DR expression on monocytes and activated T lymphocytes were determined before and after operation. RESULTS: Of 221 patients recruited, 26 were excluded. Groups (IED, 66; SEN, 63; control, 66) were matched for age, malnutrition and co morbidity. There were no differences in morbidity (P = 0.646), mortality (P = 1.000) or hospital stay (P = 0.701) between the groups. O-3FA concentrations were higher in the IED group after supplementation (P < 0.001). The ratio of omega-6 fatty acid to O-3FA was 1.9:1, 4.1:1 and 4.8:1 on the day before surgery in the IED, SEN and control groups (P < 0.001). There were no differences between the groups in HLA-DR expression in either monocytes (P = 0.538) or activated T lymphocytes (P = 0.204). CONCLUSION: Despite a significant increase in plasma concentrations of O-3FA, immunonutrition with O-3FA did not affect overall HLA-DR expression on leucocytes or clinical outcome following oesophagogastric cancer surgery. REGISTRATION NUMBER: ISRCTN43730758 (http://www.controlled-trials.com). PMID- 22237469 TI - Pro-atrial natriuretic peptide (pro-ANP) level in patients with severe sepsis and septic shock: prognostic and diagnostic significance. AB - BACKGROUND: To establish the prognostic and discriminative value of the pro atrial natriuretic peptide (pro-ANP) level in patients with severe sepsis or septic shock. PATIENTS AND METHODS: An observational and prospective study was conducted on 50 critically ill patients with severe sepsis or septic shock. Measurements of the level of procalcitonin (PCT) and mid-regional pro-ANP were determined in the serum of patients with commercially available immunoluminometric tests. RESULTS: The median pro-ANP level was significantly higher in non-survivors than in survivors (P < 0.05) on all consecutive days. No significant differences in the pro-ANP levels were observed in patients with severe sepsis and septic shock. There was a strong correlation between the PCT and pro-ANP levels on admission in non-survivors and in septic shock patients (r = 0.56, P = 0.007 and r = 0.43, P = 0.02, respectively). CONCLUSIONS: pro-ANP evaluated in severe sepsis and septic shock patients is a valuable prognostic biomarker, but, in contrast to PCT, which is routinely used as a diagnostic marker of severe sepsis and septic shock, it does not possess diagnostic and discriminative value. PMID- 22237468 TI - Multipotent mesenchymal stromal cell therapy and risk of malignancies. AB - Cell therapy with Multipotent Mesenchymal Stromal Cells (MSC) holds enormous promise for the treatment of a large number of degenerative and immune/inflammatory diseases. Their multilineage differentiation potential, immunoprivilege and capacity of promoting recovery of damaged tissues coupled with anti-inflammatory and immunosuppressive properties are the focus of a multitude of clinical studies currently underway. The recognized clinical potential of MSC repairing/immunomodulatory effects now encompasses graft-versus host disease, hematologic malignancies, cardiovascular diseases, neurologic and inherited diseases, autoimmune diseases, organ transplantation, refractory wounds, and bone/cartilage defects among others. However, it has been suggested that both the need of extensive ex vivo culture for MSC clinical use, and their proangiogenic, anti-apoptotic and immunomodulatory properties may act together as tumor promoters, raising significant safety concerns. This paper will review the available data on in vitro MSC maldifferentiation and the ability of MSC to sustain tumor growth in vivo, with the aim to clarify whether MSC-based therapeutic approaches may carry actual risk of malignancies. PMID- 22237472 TI - Tuberculosis among drug users and homeless persons: impact of voluntary X-ray investigation on active case finding. AB - BACKGROUND: Illicit drug use and homelessness are major contributors to the incidence of tuberculosis (TB) among inhabitants of major cities. OBJECTIVE: The primary objective of this study was to establish a sustainable low-threshold chest X-ray screening programme for pulmonary TB among illicit drug users and homeless persons and to integrate this into the existing public health programme for active case finding. A secondary objective was to estimate the coverage of the programme, assess other risk factors and determine TB rates and treatment outcome in these two groups. METHODS: Illicit drug users and homeless persons were asked to voluntarily participate in an X-ray screening programme. The coverage of the intervention, total number and characteristics of cases and the follow-up of treatment were assessed. RESULTS: A total of 4,529 chest radiographs were made from 3,477 persons, of whom 66% were homeless and 34% were illicit drug users, between May 2002 and April 2007. Coverage for screening once every 2 years ranged between 18 and 26%. Thirty-nine TB cases (14 drug users, 25 homeless persons) were identified, representing 8.7% of the total case load of 448 notified cases of pulmonary TB in Frankfurt during this period. Among the drug users, human immunodeficiency virus coinfection (10/14) seemed to play a key role in the development of TB. The case-finding rate of 861/100,000 radiographs (1,122/100,000 persons) is as high as that in routine contact investigations (1,078/100,000). Among all individuals with TB, 76% completed treatment. CONCLUSION: A novel targeted TB screening approach with voluntary radiographic examination of illicit drug users and homeless persons can be integrated into the existing public TB prevention programme and provides a high case-finding rate. PMID- 22237470 TI - Hepatitis C virus infection in the Middle East and North Africa "MENA" region: injecting drug users (IDUs) is an under-investigated population. AB - PURPOSE: Investigation of the injecting drug users (IDUs) population is becoming extremely critical and timely in light of the recent evidence that IDUs now act as the core of hepatitis C virus (HCV) epidemics in developed countries. The purpose of this article, therefore, is not only to review the epidemiology of HCV in the Middle East and North Africa (MENA) region, but also to see whether IDUs were adequately studied and whether harm reduction strategies to be applied for their protection have been set. METHODS: A literature review was carried out of articles published within the last decade on HCV infection. RESULTS: The gathered data showed that the population of IDUs is severely under-investigated throughout the whole region, possibly due to religious and cultural impediments. CONCLUSION: In order to reduce the risk of HCV infection in IDUs, a set of recommendations are advanced emphasizing the urgent need for bio-behavioral studies in this population in order to help identify the source and mode of transmission and the genotypes of HCV involved. These results may allow the development of effective and, yet, socially acceptable intervention strategies. We believe that the role which IDUs play in sustaining HCV infection is also an under-investigated topic in many developing countries. Similar reviews and, hence, interventions should be initiated in these regions. PMID- 22237471 TI - Genotypic resistance profiles associated with virological failure to darunavir containing regimens: a cross-sectional analysis. AB - INTRODUCTION: This study aimed at defining protease (PR) resistance mutations associated with darunavir (DRV) failure and PR resistance evolution at DRV failure in a large database of treatment-experienced human immunodeficiency virus (HIV) patients. RESULTS: Overall, 1,104 patients were included: 118 (10.7%) failed at a median observation time of 16 months. The mean number of PR mutations at baseline was 2.7, but it was higher in patients who subsequently failed DRV. In addition, the number of PR mutations increased at failure. The increase in the mean number of mutations was completely related to mutations considered to be associated with DRV resistance following the indications of the main DRV clinical trials. DISCUSSION: The higher statistical difference at baseline between failing versus non-failing patients was observed for the V32I and I84V mutations. At DRV failure, the major increase was still observed for V32I; I54L, V11I, T74P and I50V also increased. Despite the increment in the mean number of mutations per patient between baseline and failure, in 21 patients (17.8%) at baseline and 36 (30.5%) at failure, no PR mutation was detected. CONCLUSION: The HIV-DB interpretation algorithm identified few patients with full DRV resistance at baseline and few patients developed full resistance at DRV failure, indicating that complete resistance to DRV is uncommon. PMID- 22237473 TI - The clinical differences between dengue and scrub typhus with acute respiratory failure in southern Taiwan. AB - BACKGROUND: For both dengue and scrub typhus, acute respiratory failure (ARF) is a serious complication. The present study was carried out in order to investigate the clinical courses and outcomes of adult dengue and scrub typhus patients with ARF, and to identify the clinical differences between adult dengue and scrub typhus patients with ARF. METHODS: We conducted a retrospective study of the serologically confirmed adult dengue or scrub typhus patients admitted between 1998 and 2008 at Kaohsiung Chang Gung Memorial Hospital. A total of 980 dengue and 102 scrub typhus adult patients were included in our study. RESULTS: Eighteen of the 980 adult dengue patients and 8 of the 102 adult scrub typhus patients had ARF. There were significant differences that existed for eschar (P = 0.001; dengue 0%; scrub 62.5%), cough (P = 0.016; dengue 55.6%; scrub typhus 100%), white blood cell (WBC) count [P = 0.026; dengue 7.40 +/- 5.74; scrub typhus 11.84 +/- 4.95 (*10(3)/MUL)], platelet count [P = 0.008; dengue 42.2 +/- 33.9; scrub typhus 104.1 +/- 93.3 (*10(9)/L)], prothrombin time (PT) [P = 0.007; dengue 12.82 +/- 1.36; scrub typhus 10.74 +/- 0.98 (s)], activated partial thromboplastin time (APTT) [P = 0.002; dengue 50.81 +/- 10.08; scrub typhus 37.44 +/- 4.06 (s)], blood urea nitrogen (BUN) [P < 0.001; dengue 64.6 +/- 43.2; scrub typhus 20.9 +/- 9.1 (mg/dL)], creatinine [P < 0.001; dengue 3.77 +/- 3.37; scrub typhus 1.05 +/- 0.37 (mg/dL)], admission day (A-day) [P = 0.027; dengue 2.9 +/- 1.3; scrub typhus 5.4 +/- 2.6 (days)], and ventilator duration [P = 0.022; dengue 9.4 +/- 14.0; scrub typhus 14.8 +/- 10.4 (days)] between both groups. CONCLUSIONS: This study provides relatively rare data regarding the clinical differences between adult dengue and scrub typhus patients with ARF. PMID- 22237474 TI - Hepatitis B in the United States: ongoing missed opportunities for hepatitis B vaccination, evidence from the Behavioral Risk Factor Surveillance Survey, 2007. AB - PURPOSE: In the USA, the burden of hepatitis B disproportionately affects high risk adults who alone account for more than 75% of newly reported hepatitis B virus infections each year. Despite the localization of new infections in identifiable high-risk groups, vaccination rates in this subgroup, with the exception of health care workers, remain consistently low. The purpose of this study was to characterize those at risk for hepatitis B transmission and quantify the association between missed opportunities and hepatitis B vaccination. METHODS: Data from the 2007 Behavioral Risk Factor Surveillance Survey (BRFSS) of adults aged 18 years and older who were at high risk for hepatitis B infection (n = 15,432) were analyzed. Multivariate regression analysis was conducted to determine factors independently associated with vaccination. RESULTS: In a nationally representative sample, 51.4% of high-risk adults remained unvaccinated against hepatitis B and more than 50% had a missed opportunity for vaccination. High-risk adults who were vaccinated against pneumonia and influenza had a higher odds ratio of being vaccinated against hepatitis B than those not vaccinated against pneumonia and influenza (OR 2.27 and 1.67, respectively). Also, high-risk adults tested for human immunodeficiency virus (HIV) at a counseling and testing site or a drug treatment facility had a higher OR of being vaccinated than those who had not been tested for HIV (OR 1.78 and 1.73, respectively). The opposite relationship was true among individuals tested for HIV at a correctional facility (OR 0.60). CONCLUSIONS: The findings of this study underscore the inadequacy of vaccination coverage in high-risk adults and highlight advantageous opportunities to bridge gaps in vaccination coverage. PMID- 22237475 TI - Blockade of acid-sensing ion channels protects articular chondrocytes from acid induced apoptotic injury. AB - OBJECTIVE: Acid-sensing ion channels (ASICs) are members of the degenerin/epithelial sodium channel (DEG/ENaC) protein superfamily and play a critical role in acid-induced cell injury. In this study, we examined whether drugs such as amiloride that block ASICs could attenuate acid-induced apoptotic injury to articular chondrocytes. METHODS: Articular chondrocytes were isolated from Sprague-Dawley rats, and their phenotype was determined by toluidine blue and immunocytochemical staining. Articular chondrocyte viability assay was performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). Apoptosis of chondrocytes was observed by the terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling method as well as propidium iodide labeling methods. Intracellular calcium ([Ca(2+)](i)) was analyzed by a Ca(2+)-imaging method. In addition, the expression levels of calpain and calcineurin in articular chondrocytes were examined by real-time PCR and immunocytochemical staining. The activity of caspase-3 was evaluated by spectrophotometric assays. RESULTS: Positive staining for glycosaminoglycan and collagen II was seen in articular chondrocytes. Blocking acid-sensing ion channels significantly decreased the cell death percentage and increased cell viability following acid exposure. After pretreated with amiloride, acid-induced [Ca(2+)](i) rises were reduced. Amiloride also inhibited calpain and calcineurin expression levels in acid-induced chondrocytes, and inhibited caspase-3 activity. CONCLUSION: The data presented in this study provided some experimental evidence that blocking ASICs could protect acid-induced apoptotic injury to chondrocytes. PMID- 22237476 TI - Barrier protective activities of curcumin and its derivative. AB - AIM AND OBJECTIVE: Curcumin, a poly-phenolic compound, possesses diverse pharmacologic activities. However, the barrier protective functions of curcumin or its derivative have not yet been studied. The objective of this study was to investigate the barrier protective activities of curcumin and its derivative (bisdemethoxycurcumin, BDMC) on lipopolysaccharide (LPS) barrier disruption in human umbilical vein endothelial cells (HUVECs) were investigated. METHODS: The barrier protective effects of curcumin and BDMC such as permeability, expression of cell adhesion molecules, monocytes adhesion and migration toward HUVECs were tested. RESULTS: Curcumin and BDMC inhibited LPS-induced barrier permeability, monocyte adhesion and migration; inhibitory effects were significantly correlated with inhibitory functions of curcumin and BDMC on LPS-induced cell adhesion molecules (vascular cell adhesion molecules, intracellular cell adhesion molecule, E-selectin). Furthermore, LPS-induced nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor-alpha (TNF-alpha) release from HUVECs were inhibited by curcumin and BDMC. Surprisingly, the barrier protective activities of BDMC were better than those of curcumin, indicating that the methoxy group in curcumin negatively regulated barrier protection function of curcumin. CONCLUSION: Given these results, curcumin or its derivative, BDMC, showed barrier protective activities and they could be a therapeutic candidates for various systemic inflammatory diseases. PMID- 22237478 TI - Bone age in the 21st century: is Greulich and Pyle's atlas accurate for Israeli children? AB - BACKGROUND: The applicability today of Greulich and Pyle's Radiographic Atlas of Skeletal Development of the Hand and Wrist (G&P) is uncertain. OBJECTIVE: The purpose of this study was to determine whether G&P is accurate in Israeli children today. MATERIALS AND METHODS: Left-hand radiographs of 679 children (375 boys) ranging in age from 1 day to 18 years old were obtained for trauma in the period 2001-2009 and were evaluated for bone age according to G&P. Individual bone age was plotted against calendar age and smoothed to obtain the association between calendar age and bone age. Any difference was assessed with Wilcoxon signed-rank test. RESULTS: In girls, there was no significant difference between bone age and calendar age (P = 0.188). G&P underestimated bone age in boys <15 years old (median difference, 2.3 months; P < 0.0001) and overestimated bone age in boys >=15 years old (median difference, 2.9 months; P = 0.0043). The largest median difference (5.4 months; P = 0.0003) was seen in boys 6-10 years old. CONCLUSION: The differences between calendar age and bone age according to G&P were relatively small compared with normal variance and are unlikely to be of clinical importance. PMID- 22237480 TI - Absence of the spleen(s) in conjoined twins: a diagnostic clue of laterality defects? Radiological study of historical specimens. AB - BACKGROUND: Laterality defects are quite common in thoracoileopagus and parapagus dicephalus but rare in other types of conjoined twins. OBJECTIVE: To present the presumed laterality defects in cephalothoracoileopagus and prosopothoracoileopagus conjoined twins, based on the unilateral or bilateral absence or duplication of the spleen. MATERIALS AND METHODS: Three human anatomical specimens of craniothoracoileopagus (CTIP) twins and one of prosopothoracoileopagus (PTIP) twins were investigated. The specimens were part of the Museum Vrolik collection of the Department of Anatomy and Embryology of the Academic Medical Centre, University of Amsterdam, The Netherlands. The specimens were taken out of their jars and scanned with multidetector CT and volumetric T2-weighted MRI at 1.5 T. RESULTS: The internal anatomy of the specimens was largely in accordance with previous reports. However, there was no recognisable spleen in the right twin in one CTIP specimen, in the left twin in one other CTIP specimen, and in both twins in the third CTIP specimen and in the PTIP specimen. CONCLUSION: Asplenia and polysplenia are considered reliable indicators of right and left isomerism, respectively. However, three of our four specimens had laterality patterns that did not correspond with those previously reported. Since no other parameters of laterality defects could be verified in these specimens, we concluded that asplenia was unlikely to be caused by laterality defects. PMID- 22237479 TI - Primary aneurysmal bone cysts in children: percutaneous sclerotherapy with absolute alcohol and proposal of a vascular classification. AB - BACKGROUND: Percutaneous sclerotherapy is an effective treatment for aneurysmal bone cysts (ABCs). OBJECTIVE: The purpose of this study was to demonstrate the safety and efficacy of sclerotherapy with absolute alcohol and to propose a vascular classification of ABCs based on a retrospective review. MATERIALS AND METHODS: This was a review of children treated with absolute alcohol sclerotherapy for ABC at a single institution from January 1995 until November 2009. Treatment response was evaluated radiographically and clinically. Cyst fluid was classified as clear, partially bloody, or bloody. Presence of any venous drainage of the cyst was assessed by injection of contrast medium into the cyst cavity. RESULTS: Twenty-nine children with ages ranging from 2 to 16 years were included. Treatment response was good in 17 (59%), partial in 9 (31%), and poor in 3 (10%) children. Venous drainage was absent in six out of seven clear fluid cysts, which we classified as lymphatic. Drainage was present in all seven bloody-fluid cysts, which we classified as venous. In seven partially bloody fluid cysts, venous drainage was seen in three. CONCLUSION: Sclerotherapy with absolute alcohol is a safe and effective treatment of ABC. We propose classifying ABC as lymphatic or venous and suggest considering ABC intraosseous slow-flow vascular malformations. PMID- 22237481 TI - Blood pressure and body mass index: a comparison of the associations in the Caucasian and Asian populations. AB - A strong association between blood pressure (BP) and body mass index (BMI) has been observed in developed and developing countries. Whether there are differences in these associations between Caucasians and Asians remains unknown. Our objective was to compare the associations of BP with fatness measures in the Caucasian and Asian samples. The study used data from two population-based cross sectional studies conducted using similar methodology: a survey in Australia in 1998-1999 (n = 832 adults aged 25-64 years; 47% male) and a survey in Vietnam in 2005 (n = 1978 adults aged 25-64 years; 46% male). Participants completed questionnaires and attended clinics for physical measurements including BP and anthropometry. Linear regression was used for analysis. Independent of age, there were strong associations between BP indices and BMI in each sample, but the patterns of associations were different. Among Caucasians, pulse pressure (PP) increased with increasing BMI because the slope of systolic pressure with BMI exceeded the slope of diastolic pressure with BMI (P<0.001 for both sexes). In contrast, among Asians, PP decreased with increasing BMI. Associations between BMI and BP are different between Caucasian and Asian populations. Among Asians, the stronger association of increasing BMI and diastolic BP, but not PP, suggests a different pathophysiology related to hypertension. PMID- 22237482 TI - Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats. AB - Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na(+)-rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serum- and glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na(+)-rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na(+) rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP. PMID- 22237483 TI - Activation of phosphorus by group 14 elements in low oxidation states. AB - The activation of phosphorus remains a popular and competitive area of research driven by the dual goals of finding ways to avoid the environmentally questionable P-Cl compounds applied in many industrial processes and the target of catalytic functionalization of P(4). In recent years the activation, degradation, fragmentation, and functionalization of white phosphorus by compounds with heavier main group elements have become a fertile area of research. The isolation of various carbenes and functionalized silylenes has prompted chemists to investigate their reactions with white phosphorus. The most intriguing fact in these reactions is the subtle change in the substituents may afford strikingly different compounds. For example, from the reaction of P(4) with PhC(NtBu)(2)SiCl a cyclic Si(2)P(2) derivative is obtained, whereas the analogous reaction with PhC(NtBu)(2)SiN(SiMe(3))(2) resulted in an acyclic Si(2)P(4) framework. Similar phenomena have also been observed in the carbene mediated P(4) activation. Apart from these, a new entry point into phosphorus chemistry is the gentle activation of P(4) by an alkyne analogue of tin. In this feature article we have covered the activation of phosphorus by compounds with low valent group 14 elements with special concern to the recent developments in this topic. PMID- 22237485 TI - Obesity and knee osteoarthritis. AB - BACKGROUND: The association between obesity and knee osteoarthritis, and specifically the role of obesity as a risk factor for knee osteoarthritis has been well documented. A systematic review and meta-analysis by Blagojevic et al. in Osteoarthr Cartil 18(1):24-33, (2010) examined 36 papers reporting on BMI and found that all studies demonstrated obesity and being overweight to be risk factors for knee osteoarthritis. The effect size for obesity as a risk factor for knee OA was reported to be I2 = 97%, and the random effects pooled odds ratio for obesity compared to normal weight was 2.63 with a 95% CI of 2.28-3.05. OBJECTIVE: This review summarises recent findings involving the association between knee osteoarthritis and obesity: the potential mechanisms of the link between the two disease states; and the potential benefits of weight loss on obese, knee osteoarthritis patients. METHODS: Studies for inclusion in our report were identified using: MEDLINE; EMBASE; PUBMED; Cochrane Central Register of Controlled Trials; CINAHL; and reference lists of relevant articles. MAIN RESULTS: A number of recent studies involving the association between obesity and knee osteoarthritis have since been published. A large, population-based prospective study (n = 823) conducted by Toivanen et al. with a follow-up of 22 years found that the risk for knee osteoarthritis was 7 times greater for people with BMI >= 30 compared to the control of people with BMI <25. A prospective cohort study of the Norwegian population by Grotle et al. that followed 1,675 patients reported that BMI >30 was significantly associated with osteoarthritis of the knee, with odds ratio of 2.81, and 95% CI of 1.32-5.96. Lohmander et al. found that in a large cohort study of 27,960 patients from the Swedish population, the relative risk for knee osteoarthritis (fourth quartile compared to first quartile) was 8.1, with a 95% CI of 5.3-12.4. Finally, a case-control study from Holliday et al. with 1,042 knee osteoarthritis patients and 1,121 matched controls reported that the adjusted odds ratio for knee osteoarthritis in patients with BMI >30 was 7.48 with 95% CI of 5.45-10.27. CONCLUSION: Recent prospective studies demonstrate obesity as a primary risk factor for incident knee osteoarthritis. The potential mechanisms to link obesity and knee osteoarthritis, as both a biomechanical and metabolic condition are strongly linked. It has been established that weight loss for obese patients with knee osteoarthritis is clinically beneficial, for pain reduction, and for improved function. The exact mechanism linking obesity and osteoarthritis is complex; however, it is our opinion that further evidence supporting the link between the two diseases will be useful in providing clinicians and researchers with targets for physical therapy and pharmacological management of obese patients with knee osteoarthritis. PMID- 22237484 TI - Effects of antidepressants and cyclooxygenase-2 inhibitor on cytokines and kynurenines in stimulated in vitro blood culture from depressed patients. AB - BACKGROUND: Immune activation induces a pro-inflammatory state, which enhances the tryptophan degradation into kynurenine (KYN). The involvement of kynurenines has been shown in patients with major depression. Here, the effects of anti inflammatory medication and antidepressants on cytokines and tryptophan metabolite changes in blood culture with immune challenge [bacterial mimetic lipopolysaccharide (LPS)] were investigated. MATERIALS AND METHODS: A total of 21 depressed patients and 38 matched controls were recruited. Whole blood cultures were stimulated with LPS and drugs were added (celecoxib, venlafaxine, reboxetine, imipramine and fluoxetine). Cytokines and kynurenines were analysed. RESULTS: After stimulation with LPS, the interferon-gamma and interleukin (IL)-10 secretions were significantly higher in controls than in patients (p = 0.045, p = 0.032), respectively. Adding imipramine and celecoxib abolished the significance for IL-10. Challenge with LPS induced the kynurenine pathway in each group. Regarding the ratio KYNA/KYN, which indicated how much of KYN formed is further catabolised into the neuroprotective arm, the controls' blood cultures showed a significantly higher ratio (p = 0.045). DISCUSSION: Stimulation with LPS induced increased production of pro-inflammatory and anti-inflammatory cytokines in both groups, but higher responses in controls. This lower production of cytokine responses in depressed patients indicates that their immune cells are in a refractory phase, induced by a pre-existing pro-inflammatory state. For kynurenines, the whole metabolism was enhanced by LPS; however, an imbalance to neuroprotective metabolites was observed just in control blood. A drug effect could only be shown for imipramine and celecoxib, which were beneficial in terms of re-balancing the immune function but not in re-balancing neuroactive metabolites. PMID- 22237486 TI - Risk of erectile dysfunction and retrograde ejaculation associated with thulium laser vaporesection of the prostate for bladder outflow obstruction: a retrospective study. AB - OBJECTIVE: The aim of this study was to determine the incidence of erectile dysfunction and retrograde ejaculation following thulium:yttrium-aluminium-garnet (Tm:YAG) laser prostate vaporesection (ThuVaRP). PATIENTS AND METHODS: Between January 2009 and June 2010, 113 consecutive patients underwent ThuVaRP for bladder outflow obstruction. Of these, 54 (48%) were included in the study as they were able to maintain an erection for sexual intercourse prior to undergoing ThuVaRP. All patients had benign pathology and had not undergone previous bladder neck surgery. The incidence of erectile dysfunction and retrograde ejaculation was reported at a mean follow-up period of 12 months post-operatively. RESULTS: The mean patient age was 71 years (range 46-90). The mean follow-up period was 12 months (range 4-21). 11 (20%) patients experienced worsening erectile function with 3 (6%) noticing an improvement. A total of 30 patients (56%) experienced some degree of retrograde ejaculation. 4 patients (7%) noticed an improvement in their ejaculation. Retrograde ejaculation was more common in patients with an indwelling catheter in situ for refractory urinary retention (43 vs. 17%, p = 0.04) and in diabetic patients (27 vs. 4%, p = 0.03). There was an increased trend of erectile dysfunction in men aged >=70 years, with hypertension and with hypercholesterolaemia, but this was not significant. CONCLUSION: Our retrospective study has demonstrated that the overall risk of erectile dysfunction and retrograde ejaculation associated with ThuVaRP is 20 and 56%, respectively. PMID- 22237489 TI - Inhibition of neointimal proliferation after bare metal stent implantation with low-pressure drug delivery using a paclitaxel-coated balloon in porcine coronary arteries. AB - A variety of mechanical and laser-based methods remove or shift atherosclerotic plaques and reopen the artery to its original lumen. Subsequent treatment with drug-coated balloons (DCB) may smooth the vessel wall but does not require high pressure inflation. We investigated the efficacy of paclitaxel-coated balloons inflated with only 2 atm after bare metal stent implantation in coronary arteries of 24 pigs. Angiography and histomorphometry was performed on day 28. DCB inflated with 2 atm caused similar reduction of late lumen loss (LLL) as high pressure inflation with 12 atm (0.89 +/- 0.58 vs. 0.72 +/- 0.39 mm, p = 0.34). Both DCB treatments significantly (p < 0.01) reduced LLL versus uncoated balloons (1.50 +/- 0.51 mm). Treatment with low-pressure DCB resulted in less maximal intimal thickness (0.45 +/- 0.15 vs. 0.67 +/- 0.25 mm) and neointimal area (2.93 +/- 0.73 vs. 3.82 +/- 1.27 mm(2)) than treatment with uncoated balloons (p < 0.05). In conclusion, low-pressure treatment with DCB was similarly effective as high-pressure treatment justifying clinical trials in vessels which will benefit from inhibition of neointimal proliferation but may not tolerate high inflation pressure. PMID- 22237490 TI - Tight junctions in neurological diseases. AB - Tight junction, one of the type of cell-cell junctions, controls the paracellular permeability across the lateral intercellular space and maintains the cell polarity. Tight junctions consist of transmembrane proteins: members of tight junction-associated MARVEL protein (TAMP) family, claudins and junctional adhesion molecules (JAMs), and various cytoplasmic proteins that are necessary for the correct organization of the integral membrane components of the junction. Alterations in expression or localization of proteins of tight junctions have been described in several neurological disorders including multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease and epilepsy. In this review, we summarize the most recent data on components of tight junctions and focus on the implication of tight junction dysfunction in neurological diseases. PMID- 22237491 TI - Introduction to spiking neural networks: Information processing, learning and applications. AB - The concept that neural information is encoded in the firing rate of neurons has been the dominant paradigm in neurobiology for many years. This paradigm has also been adopted by the theory of artificial neural networks. Recent physiological experiments demonstrate, however, that in many parts of the nervous system, neural code is founded on the timing of individual action potentials. This finding has given rise to the emergence of a new class of neural models, called spiking neural networks. In this paper we summarize basic properties of spiking neurons and spiking networks. Our focus is, specifically, on models of spike based information coding, synaptic plasticity and learning. We also survey real life applications of spiking models. The paper is meant to be an introduction to spiking neural networks for scientists from various disciplines interested in spike-based neural processing. PMID- 22237492 TI - Testosterone and its metabolites--modulators of brain functions. AB - Testosterone is a steroid sex hormone with an important role in the physiology in both sexes. It is involved in the development of morphological and functional parameters of the body via multiple molecular mechanisms. Intensive research focused on testosterone reveals associations with cognitive abilities and behavior and its causative role in sex differences in cognition. Testosterone modulates brain structure and the differentiation of neurons during intrauterine development with profound effects on brain functions during postnatal life. In this review we summarize the effects of testosterone on brain physiology and cognition with respect to the underlying molecular mechanisms. PMID- 22237493 TI - Modeling the meaning of words: neural correlates of abstract and concrete noun processing. AB - We present a model relating analysis of abstract and concrete word meaning in terms of semantic features and contextual frames within a general framework of neurocognitive information processing. The approach taken here assumes concrete noun meanings to be intimately related to sensory feature constellations. These features are processed by posterior sensory regions of the brain, e.g. the occipital lobe, which handles visual information. The interpretation of abstract nouns, however, is likely to be more dependent on semantic frames and linguistic context. A greater involvement of more anteriorly located, perisylvian brain areas has previously been found for the processing of abstract words. In the present study, a word association test was carried out in order to compare semantic processing in healthy subjects (n=12) with subjects with aphasia due to perisylvian lesions (n=3) and occipital lesions (n=1). The word associations were coded into different categories depending on their semantic content. A double dissociation was found, where, compared to the controls, the perisylvian aphasic subjects had problems associating to abstract nouns and produced fewer semantic framebased associations, whereas the occipital aphasic subject showed disturbances in concrete noun processing and made fewer semantic feature based associations. PMID- 22237494 TI - A role for the right prefrontal and bilateral parietal cortex in four-term transitive reasoning: an fMRI study with abstract linear syllogism tasks. AB - Previous imaging studies have identified many brain regions activated during reasoning, but there are differences among the findings concerning specific regions engaged in reasoning and the contribution of language areas. Also, little is known about the relation between task complexity and neural activation during reasoning. The present fMRI study investigated brain activity during complex four term transitive reasoning with abstract material (determinate or partially indeterminate) and compared the resulting images to those obtained during a memorization task. The memory condition required subjects to memorize unrelated elements whereas the reasoning conditions required them to integrate information from premises and to infer relations between elements. After contrasting the two kinds of reasoning conditions with the memory condition we found that right prefrontal and bilateral parietal regions are specifically activated during reasoning. We also demonstrated that different reasoning requirements--the possibility of constructing one (determined reasoning) versus several (undetermined reasoning) models of a situation during task solving--lead to different patterns of brain activity, with higher prefrontal (PFC) activity accompanying undetermined reasoning. We interpret the PFC activity as a reflection of simultaneous maintenance and manipulation of information in reasoning. These findings provide new evidence that specific forms of reasoning (abstract and undetermined) demand recruitment of right PFC and hemispheric coordination and lend new support to the mental model theory of relational reasoning. PMID- 22237495 TI - Galanin and vasopressin response to hyperosmotic stimulation: in vitro study. AB - Galanin (Gal)--a neuropeptide present in the nervous system and peripheral tissues--may be involved in the regulation of hypothalamo-neurohypophysial system function. It was shown that centrally injected galanin inhibits osmotically stimulated vasopressin (VP) secretion into the blood and reduces VP mRNA level in the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. The aim of the present study in vitro was to investigate the influence of Gal on vasopressin release from isolated rat hypothalamus (Hth), neurohypophysis (NH) or hypothalamo neurohypophysial explants (Hth-NH). The effect of Gal on VP secretion was studied under conditions of direct osmotic (i.e., Na+-evoked) (series 1) as well as nonosmotic (i.e., K+-evoked) (series 2) stimulation. In series 3, vasopressin response to Gal was studied using the neural tissues obtained from animals drinking 2 percent NaCl solution for eight days (indirect osmotic stimulation). Gal in a concentration of 10-10 M and 10-8 M inhibited basal VP release from Hth, NH and Hth-NH explants isolated from euhydrated rats as well as from Hth-NH complex of osmotically challenged animals. When the neural tissues obtained from previously salt-loaded rats were incubated in K+-enriched medium the inhibitory effect of Gal was completely blocked. It may be concluded that the effect of Gal is depending on the current functional status of the hypothalamo-neurohypophysial system. PMID- 22237496 TI - Direct MRI-guided stereotaxic viral mediated gene transfer of alpha-synuclein in the Gottingen minipig CNS. AB - The aim was to establish a non-primate large animal PD model by lentiviral vector mediated mutant alpha-synuclein overexpression in the substantia nigra. Lentivirus encoding A53T alpha-synuclein (6 x 2.5 MUl) was stereotaxically injected into the substantia nigra of six adult female Gottingen minipigs. Contralateral control injections encoding enhanced green fluorescent protein (EGFP) were performed. Gait-analysis was performed pre- and postoperatively. PCR of the transgenes and immunohistochemical staining against alpha-synuclein, EGFP, GFAP and TH was performed after 20 weeks. Gait analysis revealed a significant increase in step length and height, and a decrease in the double stand phase. PCR verified the mesencephalic presence of transgenes. IHC analysis showed alpha synuclein expression in nigral neurons, around the injection tract and in related nigrostriatal projections. The alpha-synuclein positive neurons appeared swollen and vacuolated, in contrast to the EGFP-injected control side. To transduct all nigrostriatal cells with few microinjections, wider dissemination of the transgene must be achieved. PMID- 22237497 TI - Lipopolysaccharide injected to pregnant mice affects behavior of their offspring in adulthood. AB - We studied consequences of maternal immune response on the course of pregnancy and the behavior of adult offspring. Mice in late gestation (day 16-17) were injected with lipopolysaccharide (LPS). Treatment of pregnant mice with high doses of LPS resulted in fetal resorption or stillbirths. Pregnant mice treated with low doses (100 or 300 micrograms/kg) of LPS gave birth to normal numbers of pups. However, behavior of the offspring was altered. Adult offspring of dams injected at a dose of 300 micrograms/kg of LPS traveled longer distances in the open field and spent more time in the central part of the arena, than mice in the control group. Female mice of this group spent more time in open arms of the elevated plus maze, in comparison to female control mice. Results of the Morris water maze test showed impairment of spatial learning and memory in male offspring born to LPS-injected dams. Furthermore, in the nest building test adult mice born from LPS challenged pregnancies constructed worse quality nests, which points to the presence of hippocampal dysfunction. These findings indicate that maternal bacterial infections during pregnancy may alter offspring behavior in adult life. PMID- 22237498 TI - Impact of excess body weight on walking at the preferred speed. AB - The implications of a long-lasting mechanical load on the locomotor activity are poorly understood. The objective of the present studies was to determine an impact of excess body weight on basic spatiotemporal gait measures and to test the hypothesis that leg swing phase may account for a load-related adaptation of the stride characteristics. To this end the basic spatial and temporal stride measures were assessed in 100 obese and 36 lean women (age range between 18 and 67 years) walking with their self-selected pace on a 10-meter long and 1 meter wide instrumented pathway. Among the subjects there were: 44 with class I obesity, 27 with class II obesity, and 29 with class III. Subjects' stance and swing times as well as the stride lengths were recorded by means of contact copper-film electrodes attached to a sole of subject' footwear. The acquired gait measures were used then to compute: a mean velocity of walking, double support times and a mean velocity of a foot during swing phase. Data analysis showed that subjects from every experimental groups walked with a very similar speed (1.08 +/ 0.2 m/s) and cadence (106 +/- 10 steps/min). Their stance time was not affected by body weight and it remained at the mean level of 746 +/- 90 ms for all groups. The temporal stride characteristics and the stance-to-swing ratio were, however, substantially modified in obese individuals due to attenuation of the swing time. As a consequence, the remaining normalized (i.e., expressed as percentage of gait cycle time) phases of stride: the stance and the double support were relatively longer. While the swing time negatively correlated with the body mass index (BMI), the normalized stance and the double support exhibited strong positive correlation (r=0.46) with the BMI. The increase of leg swing velocity seems the main and unique adaptation mechanism that is utilized in the preferred walking gait in obese women. PMID- 22237499 TI - Structural neuroplasticity induced by melatonin in entorhinal neurons of rats exposed to toluene inhalation. AB - Several clinical studies have shown that abusing volatile solvents, mainly toluene, produces neurological, neuropathological and neuropsychiatric disorders. Symptoms of these disorders include loss in impulse control, distractibility and memory deficits, which are associated with mild brain atrophy. The entorhinal cortex is critically involved in mnemonic processes, and memory disorders are the major symptom detected in chronic solvent abusers. Therefore, in the present study, we evaluated (1) whether the entorhinal neuronal morphology was impaired by subchronic toluene exposure and (2) if melatonin protected the neuronal cytoarchitecture, as has been demonstrated in neocortical neurons. Consistent with our previous findings, the present study indicates that the entorhinal cell dendritic arborization was significantly reduced in toluene exposed animals, and melatonin administration significantly rescued the reduced dendritic branching induced by toluene neurotoxicity. PMID- 22237501 TI - Inbreeding affects sexual signalling in males but not females of Tenebrio molitor. AB - In many species of animals, individuals advertise their quality with sexual signals to obtain mates. Chemical signals such as volatile pheromones are species specific, and their primary purpose is to influence mate choice by carrying information about the phenotypic and genetic quality of the sender. The deleterious effects of consanguineous mating on individual quality are generally known, whereas the effect of inbreeding on sexual signalling is poorly understood. Here, we tested whether inbreeding reduces the attractiveness of sexual signalling in the mealworm beetle, Tenebrio molitor, by testing the preferences for odours of inbred and outbred (control) individuals of the opposite sex. Females were more attracted to the odours produced by outbred males than the odours produced by inbred males, suggesting that inbreeding reduces the attractiveness of male sexual signalling. However, we did not find any difference between the attractiveness of inbred and outbred female odours, which may indicate that the quality of females is either irrelevant for T. molitor males or quality is not revealed through female odours. PMID- 22237502 TI - Hotter nests produce smarter young lizards. AB - A hatchling reptile's sex, body size and shape, and locomotor performance can be influenced not only by its genes, but also by the temperature that it experiences during incubation. Can incubation temperature also affect a hatchling's cognitive skills? In the scincid lizard Bassiana duperreyi, higher incubation temperatures enhanced the resultant hatchling's learning performance. Hence, factors such as maternal nest-site selection and climate change affect not only the size, shape and athletic abilities of hatchling reptiles, but also their ability to learn novel tasks. PMID- 22237503 TI - Convergence and divergence in Diana monkey vocalizations. AB - Individually distinct vocalizations are widespread among social animals, presumably caused by variation in vocal tract anatomy. A less-explored source of individual variation is due to learned movement patterns of the vocal tract, which can lead to vocal convergence or divergence in social groups. We studied patterns of acoustic similarity in a social call produced by 14 female Diana monkeys (Cercopithecus diana) in two free-ranging groups. Calls showed variability in fundamental frequency contours owing to individual identity and external context. Vocal divergence increased significantly between females during poor visibility and tended to increase in the presence of neighbours. In contrast, vocal convergence increased significantly between females during vocal interactions, because females matched the frequency contour of their own call with another female's preceding call. Our findings demonstrate that these primates have some control over the acoustic fine structure of their most important social vocalization. Vocal convergence and divergence are two opposing processes that enable callers to ensure spatial proximity and social cohesion with other group members. PMID- 22237504 TI - Do females preferentially associate with males given a better start in life? AB - A poor start in life owing to a restricted diet can have readily detectable detrimental consequences for many adult life-history traits. However, some costs such as smaller adult body size are potentially eliminated when individuals modify their development. For example, male mosquitofish (Gambusia holbrooki) that have reduced early food intake undergo compensatory growth and delay maturation so that they eventually mature at the same size as males that develop normally. But do subtle effects of a poor start persist? Specifically, does a male's developmental history affect his subsequent attractiveness to females? Females prefer to associate with larger males but, controlling for body length, we show that females spent less time in association with males that underwent compensatory growth than with males that developed normally. PMID- 22237505 TI - Letter to editor re: Ling et al. 2011 (Environ Sci Pollut Res Int 18(6): 877 889). PMID- 22237506 TI - Proteomic analysis of dimethoate-responsive proteins in the oyster (Saccostrea cucullata) gonad. AB - INTRODUCTION: The organophosphorus pesticide dimethoate (DM) has been widely used in agriculture, and its extensive use could still have left many environmental problems. METHODS: In the present study, the oyster (Saccostrea cucullata) was subjected to acute DM toxicity (2 mg/L), and gas chromatographic analysis revealed and quantified residues of DM in the oyster gonad. RESULTS: Two dimensional gel electrophoresis showed 12 differentially expressed proteins in the DM-exposed oyster gonad in comparison to the control. Among these 12 protein spots, nine were down-regulated, and three were up-regulated. Both matrix assisted laser desorption/ionization time-of-flight tandem mass spectrometry and database searching were utilized to identify these differential proteins, and revealed five proteins previously described as being related to DM toxicity. In addition, the levels of mRNA expression corresponding to these differential proteins were further proved in part by real-time PCR. The functions of these proteins were summarized as: carrying out energy metabolism, DNA repair, DNA transcriptional regulation, and oxidative protection. The remaining seven protein spots were of particular interest in terms of their responses to DM, which have seldom been reported. CONCLUSION: These data might point to a number of novel and significant biomarkers for evaluating the contamination levels of DM and provide useful insight into the mechanisms of DM toxicity in vivo. PMID- 22237507 TI - Heterogeneous photocatalytic degradation of methyl orange in schwertmannite/oxalate suspension under UV irradiation. AB - INTRODUCTION: Schwertmannite was synthesized through an oxidation of FeSO(4) by Acidithiobacillus ferrooxidans LX5 cell suspension at an initial pH 2.5 and 28 degrees C for 3 days and characterized using X-ray diffraction spectroscopy and scanning electron microscope. The schwertmannite photocatalytic degradation of methyl orange (MO) by oxalate was investigated at different initial pH values, concentrations of schwertmannite, oxalate, and MO. RESULTS: The results demonstrated that photodegradation of MO in the presence of schwertmannite or oxalate alone was very weak. However, the removal of MO was significantly enhanced when schwertmannite and oxalate coexisted in the reaction system. Low pH (4 or less) was beneficial to the degradation of MO. The optimal doses of schwertmannite and oxalate were 0.2 g L(-1) and 2 mM, respectively. Hydroxyl radicals (.OH) and Fe(II), the intermediate products, were also examined during the reaction to explore their correlation with the degradation of MO. CONCLUSION: A possible mechanism for the photocatalytic decomposition of MO in the study was proposed. The formation of Fe(III)-oxalate complexes on the surface of schwertmannite was a precursor of H(2)O(2) and Fe(II) production, further leading to the yield of .OH responsible for the decomposition of MO. PMID- 22237508 TI - Efficient biosorption of chromium(VI) ion by dry Araucaria leaves. AB - BACKGROUND: In this paper, batch removal of hexavalent chromium from aqueous solutions by Araucaria heterophylla leaves was investigated. The batch experiments were conducted to study the adsorption of metal species and effect of different pH, contact time, metal concentration, biosorbent concentration, and adsorption capacity. METHOD: Freundlich and Langmuir's isotherm model were used to describe the adsorption behavior, and the experimental results fitted Freundlich model well. RESULTS: The adsorption efficiency observed for all chromium concentrations, i.e., 1, 3, 5, and 10 mg/L was 100% and the equilibrium was achieved in 30 min for 1 and 3 mg/L, whereas for 5 and 10 mg/L, it was less than 60 min. FTIR spectra was taken to identify functional groups involved in the biosorption. CONCLUSION: Thus, Araucaria leaves can be considered as one of the cheap and efficient biosorbent for toxic hexavalent chromium removal from natural or wastewaters. PMID- 22237509 TI - Factors influencing wound healing of critical ischaemic foot after bypass surgery: is the angiosome important in selecting bypass target artery? AB - OBJECTIVES: The aim of the study is to determine factors affecting ischaemic wound healing and role of the angiosome concept in bypass surgery. DESIGN: Single centre, retrospective clinical study. MATERIALS AND METHODS: A total of 249 consecutive critical ischaemic limbs with tissue loss in 228 patients who underwent distal bypasses from 2003 to 2009 were reviewed. A total of 81% of patients were diabetic, and 49% of patients had dialysis-dependent renal disease (end-stage renal disease, ESRD). Distal targets of bypasses were the crural artery (57%) and the pedal artery (43%). RESULTS: The complete healing of ischaemic wounds was achieved in 211 limbs (84.7%). ESRD (odds ratio (OR) 0.127, p < 0.001), diabetes (OR 0.216, p = 0.030), Rutherford category 6 (R6) with heel ulcer/gangrene (OR 0.134, p < 0.001), R6 except heel (OR 0.336, p = 0.025) and low albuminaemia (OR 0.387, p = 0.049) were negative predictors of wound healing. Regarding the angiosome, the healing rate in the indirect revascularisation (IR) group was slower than in the direct revascularisation (DR) group, especially in patients with ESRD (p < 0.001). However, the healing rates of the DR and IR groups were similar after minimising background differences with propensity score methods (p = 0.185). CONCLUSIONS: In the field of bypass surgery, the angiosome concept seems unimportant, at least in non-ESRD cases. The location and extent of ischaemic wounds as well as co-morbidities may be more relevant than the angiosome in terms of wound healing. PMID- 22237510 TI - Catheter-based radiofrequency renal-nerve ablation in patients with resistant hypertension. AB - This review aims to describe the role and the results of catheter-based renal nerve ablation for the treatment of resistant hypertension. Despite the availability of multiple classes of orally active antihypertensive treatments, resistant hypertension remains an important public health issue in 2012 due to its prevalence and association with target-organ damage and poor prognosis. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments based on old concepts. In the absence of orally active antihypertensive agents, patients with severe and complicated hypertension were widely treated by surgical denervation of the kidney until the 1960s, but this approach was associated with a high incidence of severe adverse events and a high mortality rate. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients with resistant hypertension with a new therapeutic option that is less invasive than surgery and can be performed rapidly under local anaesthesia. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected resistant hypertensive patients with suitable renal artery anatomy. The available evidence suggests a favourable blood pressure-lowering effect in the short term (6 months) and a low incidence of immediate local and endovascular complications. This follow-up period is, however, too short for the detection of rare or late-onset adverse events. For the time being, the benefit/risk ratio of this technique remains to be evaluated, precluding its uncontrolled and widespread use in routine practice. PMID- 22237511 TI - Total endovascular repair for thoraco-abdominal aneurysms: not for all, not for now. PMID- 22237512 TI - The strange relationship between diabetes and abdominal aortic aneurysm. AB - In a 1997 report of a large abdominal aortic aneurysm (AAA) screening study, we observed a negative association between diabetes and AAA. Although this was not previously described and negative associations between diseases are rare, the credibility of the finding was supported by consistent results in several previous studies and by the absence of an obvious artifactual explanation. Since that time, a variety of studies of AAA diagnosis, both by screening and prospective clinical follow-up, have confirmed the finding. Other studies have reported slower aneurysm enlargement and fewer repairs for rupture in diabetics. The seeming protective effect of diabetes for AAA contrasts with its causal role in occlusive vascular disease and so provides a strong challenge to the traditional view of AAA as a manifestation of atherosclerosis. Research focused on a protective effect of diabetes has already increased our understanding of the etiology of AAA, and might eventually pave the way for new therapies to slow AAA progression. PMID- 22237513 TI - Local but not systemic capillary lactate is a reperfusion biomarker in experimental acute limb ischaemia. AB - INTRODUCTION: Systemic capillary lactate, an end product of cellular anaerobic metabolism, has not established credibility in monitoring limb reperfusion. We assessed, in mice, whether local capillary lactate, arising from the reperfused limb, might be a relevant biomarker of reperfusion. REPORT: Systemic and local capillary lactate were sampled in the non-ischaemic and in the ischaemic limb. Only local lactate concentrations significantly increased after 2 h of ischaemia and decreased after reperfusion. DISCUSSION: Local, but not systemic, capillary lactate appeared as a potential reperfusion biomarker in this experimental acute limb ischaemia model. PMID- 22237515 TI - Setting up an ancient DNA laboratory. AB - Entering into the world of ancient DNA research is nontrivial. Because the DNA in most ancient specimens is degraded to some extent, the potential for contamination of ancient samples and DNA extracts with modern DNA is considerable. To minimize the risk associated with working with ancient DNA, experimental protocols specific to handling ancient specimens have been introduced. Here, I outline the challenges associated with working with ancient DNA and describe guidelines for setting up a new ancient DNA laboratory. I also discuss steps that can be taken at the sample collection and preparation stage to minimize the potential for contamination with exogenous sources of DNA. PMID- 22237516 TI - A phenol-chloroform protocol for extracting DNA from ancient samples. AB - The myriad downstream applications of ancient DNA (aDNA) analysis all ultimately require that sequence data are generated from extracts of ancient material. DNA extraction from tissues known to contain preserved biomolecules (e.g. teeth, hair, tissue, bone) relies on subtle modifications of a basic technique that has been in use for nearly two decades. Multiple DNA extraction protocols have been introduced, with varying levels of success depending on tissue type and the long term preservation environment to which the ancient tissue was exposed. Here, we describe the phenol-chloroform method for extracting aDNA from any tissue type. This commonly employed method allows for the recovery of total nucleic acid content with minimal loss of low molecular weight double-stranded DNA. PMID- 22237514 TI - Thalidomide inhibits adipogenesis of orbital fibroblasts in Graves' ophthalmopathy. AB - The expansion of orbital adipose tissue is a main pathophysiology of Graves' ophthalmopathy (GO), which is an inflammatory autoimmune disease in the orbital region. The effects of immunosuppressive drugs on adipogenesis of orbital fibroblasts have not been determined. Thalidomide, as an immunosuppressive drug, has recently been used in the therapy of many autoimmune diseases. In this study, we analyzed the effects of thalidomide on adipogenesis and found that adipocyte differentiation from preadipocytes in the orbital region was enhanced, which was demonstrated by enhanced expression of peroxisome proliferator activated receptor gamma (PPARgamma), ap2, and thyroid-stimulating hormone receptor (TSHR). The expression of inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) was also increased in GO. Thalidomide dose-dependently inhibited adipogenesis of 3T3-L1 preadipocytes and orbital fibroblasts from GO patients. Along with the inhibited adipogenesis, the expression of TSHR, TNFalpha, and IL-6 was also down-regulated. We discovered that the mechanism for thalidomide inhibiting adipogenesis was the down-regulation of PPARgamma, rather than C/EBPbeta and C/EBPdelta. We suggest that, besides its canonical anti TNFalpha effect, thalidomide plays a role in inhibiting adipogenesis of orbital fibroblasts in GO patients. PMID- 22237517 TI - DNA extraction of ancient animal hard tissue samples via adsorption to silica particles. AB - A large number of subfossil and more recent skeletal remains, many of which are stored in museums and private collections, are potentially accessible for DNA sequence analysis. In order to extract the small amount of DNA preserved in these specimens, an efficient DNA release and purification method is required. In this chapter, I describe an efficient and straightforward purification and concentration method that uses DNA adsorption to a solid surface of silica particles. Comparative analysis of extraction methods has shown that this method works reliably for ancient as well as younger, museum-preserved specimens. PMID- 22237518 TI - Case study: recovery of ancient nuclear DNA from toe pads of the extinct passenger pigeon. AB - A variety of DNA extraction methods have been employed successfully to extract DNA from museum specimens. Toe pads are a common source of ancient DNA in birds, as they are generally not an informative character and can be removed without significant destruction of precious specimens. However, the DNA in these tissues is often highly degraded, both by natural postmortem decay and due to treatment by preservatives. In this case study chapter, we describe the use of both a commercial DNA extraction method and a silica-based method to extract ancient DNA from desiccated toe pads from the extinct passenger pigeon, Ectopistes migratorius. Successful amplification of nuclear DNA was achieved from both methods, representing the first nuclear DNA sequence recovered from this extinct species. We describe simple modifications to both protocols that we employed during the DNA extraction process. PMID- 22237519 TI - Extraction of DNA from paleofeces. AB - Paleofeces are the nonmineralized remains of dung from extant and extinct fauna. They represent a surprisingly large proportion of fossil remains recovered from cave sites across the world. Paleofeces contain the DNA of the defecator as well as the DNA of ingested plant and animal remains. To successfully extract DNA from paleofeces, a balance must be achieved between the minimization of DNA loss during extraction and the removal of coeluates that would otherwise inhibit the Taq DNA polymerase during downstream applications. Here we present a simplified version of a protocol to extract DNA from paleofecal remains. PMID- 22237520 TI - DNA extraction from keratin and chitin. AB - DNA extracted from keratinous and chitinous materials can be a useful source of genetic information. To effectively liberate the DNA from these materials, buffers containing relatively high levels of DTT, proteinase K, and detergent are recommended, followed by purification using either silica-column or organic methods. PMID- 22237521 TI - Case study: ancient sloth DNA recovered from hairs preserved in paleofeces. AB - Ancient hair, which has proved to be an excellent source of well-preserved ancient DNA, is often preserved in paleofeces. Here, we separate and wash hair shafts preserved in a paleofecal specimen believed to be from a Darwin's ground sloth, Mylodon darwinii. After extracting DNA from the recovered and cleaned hair using a protocol optimized for DNA extraction from keratinous substrates, we amplify 12S and 16S rDNA sequences from the DNA extract. As expected, the recovered sequences most closely match previously published sequences of M. darwinii. Our results demonstrate that hair preserved in paleofeces, even from temperate cave environments, is an effective source of ancient DNA. PMID- 22237522 TI - Ancient DNA extraction from soils and sediments. AB - DNA contained in soils and sediments can provide novel insights into past environments and ecosystems. In this chapter, I describe an efficient and effective technique to extract total DNA from sediments in a manner that minimizes the coextraction of PCR-inhibitory compounds. I describe two different approaches: one that is suitable for large (up to 10 g wet weight) amounts of substrate, and a second that is more appropriate for small (up to 0.5 g) amounts of substrate. Finally, I discuss some of the obstacles that may be encountered in the process of extracting DNA from soils and sediments and suggest approaches to circumvent some common problems. PMID- 22237523 TI - DNA extraction from fossil eggshell. AB - Avian eggshell fragments recovered from both paleontological and archaeological deposits contain a cache of well-preserved ancient DNA. Here, we describe an extraction protocol that has been optimized to maximize the recovery of ancient DNA from fossil eggshell and minimize the co-purification of PCR inhibitors. In this method, fossil eggshell fragments are powdered, then digested and heated to release DNA from the calcite matrix. The digest then undergoes a concentration step before purification and washing using silica columns. The method has been used to recover aDNA from the eggshell of many avian species including moa, elephant birds, and emu, up to 19,000 years old. PMID- 22237524 TI - Ancient DNA extraction from plants. AB - A variety of protocols for DNA extraction from archaeological and paleobotanical plant specimens have been proposed. This is not surprising given the range of taxa and tissue types that may be preserved and the variety of conditions in which that preservation may take place. Commercially available DNA extraction kits can be used to recover ancient plant DNA, but modifications to standard approaches are often necessary to improve yield. In this chapter, I describe two protocols for extracting DNA from small amounts of ancient plant tissue. The CTAB protocol, which I recommend for use with single seeds, utilizes an incubation period in extraction buffer and subsequent chloroform extraction followed by DNA purification and suspension. The PTB protocol, which I recommend for use with gourd rind and similar tissues, utilizes an overnight incubation of pulverized tissue in extraction buffer, removal of the tissue by centrifugation, and DNA extraction from the buffer using commercial plant DNA extraction kits. PMID- 22237526 TI - Case study: ancient DNA recovered from pleistocene-age remains of a Florida armadillo. AB - Warm, humid regions are not ideal for long-term DNA preservation. Consequently, little ancient DNA research has been carried out involving taxa that lived in, for example, tropical and subtropical regions. Those studies that have isolated ancient DNA from warm environments have mostly been limited to the most recent several thousand years. Here, we discuss an ancient DNA experiment in which we attempt to amplify mitochondrial DNA from remains of armadillo, glyptodont, and pampathere from sites in Florida, USA, all believed to be around 10,000-12,000 years old. We were successful in recovering DNA from only one of these samples. However, based on the amount and distribution of DNA damage, the ancient DNA recovered was well-preserved despite the age and preservation environment. In this case study chapter, we discuss the experimental procedure we used to characterize the DNA from the Floridian samples, focusing on challenges of working with ancient specimens from warm environments and steps taken to confirm the authenticity of the recovered sequence. PMID- 22237525 TI - DNA extraction from formalin-fixed material. AB - The principal challenges facing PCR-based analyses of DNA extracted from formalin fixed materials are fragmentation of the DNA and cross-linked protein-DNA complexes. Here, we present an efficient protocol to extract DNA from formalin fixed or paraffin-embedded tissues (FFPE). In this protocol, protein-DNA cross links are reversed using heat and alkali treatment, yielding significantly longer fragments and larger amounts of PCR-amplifiable DNA than standard DNA extraction protocols. PMID- 22237527 TI - Nondestructive DNA extraction from museum specimens. AB - Natural history museums around the world hold millions of animal and plant specimens that are potentially amenable to genetic analyses. With more and more populations and species becoming extinct, the importance of these specimens for phylogenetic and phylogeographic analyses is rapidly increasing. However, as most DNA extraction methods damage the specimens, nondestructive extraction methods are useful to balance the demands of molecular biologists, morphologists, and museum curators. Here, I describe a method for nondestructive DNA extraction from bony specimens (i.e., bones and teeth). In this method, the specimens are soaked in extraction buffer, and DNA is then purified from the soaking solution using adsorption to silica. The method reliably yields mitochondrial and often also nuclear DNA. The method has been adapted to DNA extraction from other types of specimens such as arthropods. PMID- 22237528 TI - Case study: using a nondestructive DNA extraction method to generate mtDNA sequences from historical chimpanzee specimens. AB - A major challenge for ancient DNA (aDNA) studies using museum specimens is that sampling procedures usually involve at least the partial destruction of each specimen used, such as the removal of skin, pieces of bone, or a tooth. Recently, a nondestructive DNA extraction method was developed for the extraction of amplifiable DNA fragments from museum specimens without appreciable damage to the specimen. Here, we examine the utility of this method by attempting DNA extractions from historic (older than 70 years) chimpanzee specimens. Using this method, we PCR-amplified part of the mitochondrial HVR-I region from 65% (56/86) of the specimens from which we attempted DNA extraction. However, we found a high incidence of multiple sequences in individual samples, suggesting substantial cross-contamination among samples, most likely originating from storage and handling in the museums. Consequently, reproducible sequences could be reconstructed from only 79% (44/56) of the successfully extracted samples, even after multiple extractions and amplifications. This resulted in an overall success rate of just over half (44/86 of samples, or 51% success), from which 39 distinct HVR-I haplotypes were recovered. We found a high incidence of C to T changes, arguing for both low concentrations of and substantial damage to the endogenous DNA. This chapter highlights both the potential and the limitations of nondestructive DNA extraction from museum specimens. PMID- 22237529 TI - PCR amplification, cloning, and sequencing of ancient DNA. AB - PCR amplification of DNA is routine in modern molecular biology. However, the application of PCR to ancient DNA (aDNA) experiments often requires significant modification to standard protocols. The degraded nature of most aDNA fragments requires targeting shorter fragments, performing replicate amplifications, incorporating multiple negative controls, combating PCR inhibition, using specific DNA polymerases to deal with damaged bases, working in a separate aDNA facility, and modifying the PCR recipe to deal with damaged and low copy-number target DNA. In this chapter, we describe how and why these procedures are implemented, discuss aDNA-specific troubleshooting methodology, and suggest modifications to commercial cloning and sequencing procedures to reduce the expense of PCR product cloning. PMID- 22237530 TI - Quantitative real-time PCR in aDNA research. AB - Quantitative real-time PCR (qPCR) is a technique that is widely used in the field of ancient DNA (aDNA). Quantitative PCR can be used to optimize aDNA extraction methodologies, to detect PCR inhibition, and to quantify aDNA libraries for use in high-throughput sequencing. In this chapter, we outline factors that need to be considered when developing efficient SYBR Green qPCR assays. We describe how to setup qPCR standards of known copy number and provide some useful tips regarding interpretation of qPCR data generated from aDNA templates. PMID- 22237531 TI - Multiplex PCR amplification of ancient DNA. AB - Multiplex PCR allows the simultaneous amplification of up to dozens of target fragments in a single PCR. It is therefore a powerful tool to obtain many kilobases of continuous sequence from minute amounts of ancient DNA (aDNA), which usually must be amplified in multiple short and overlapping fragments. Because significantly less template is required compared to amplifying each fragment separately, multiplex PCR is particularly beneficial when the fossil material itself, or access to the fossil material, is limited. The recently refined two step multiplex PCR protocol consists of a first-step reaction (the actual multiplex PCR) that then acts as the template for the second-step PCR. During the second step, nested primers are used in individual amplification reactions. Although the same set of primers can be used in both steps, using a nested set in the second step adds an additional level of selectivity and specificity, minimizing PCR artifacts. This is particularly important when complex mixtures of template DNA, such as aDNA extracts, are amplified. PMID- 22237532 TI - Preparation of next-generation sequencing libraries from damaged DNA. AB - Next-generation sequencing (NGS) has revolutionized ancient DNA research, especially when combined with high-throughput target enrichment methods. However, attaining high sequencing depth and accuracy from samples often remains problematic due to the damaged state of ancient DNA, in particular the extremely low copy number of ancient DNA and the abundance of uracil residues derived from cytosine deamination that lead to miscoding errors. It is therefore critical to use a highly efficient procedure for conversion of a raw DNA extract into an adaptor-ligated sequencing library, and equally important to reduce errors from uracil residues. We present a protocol for NGS library preparation that allows highly efficient conversion of DNA fragments into an adaptor-ligated form. The protocol incorporates an option to remove the vast majority of uracil miscoding lesions as part of the library preparation process. The procedure requires only two spin column purification steps and no gel purification or bead handling. Starting from an aliquot of DNA extract, a finished, highly amplified library can be generated in 5 h, or under 3 h if uracil removal is not required. PMID- 22237533 TI - Generating barcoded libraries for multiplex high-throughput sequencing. AB - Molecular barcoding is an essential tool to use the high throughput of next generation sequencing platforms optimally in studies involving more than one sample. Various barcoding strategies allow for the incorporation of short recognition sequences (barcodes) into sequencing libraries, either by ligation or polymerase chain reaction (PCR). Here, we present two approaches optimized for generating barcoded sequencing libraries from low copy number extracts and amplification products typical of ancient DNA studies. PMID- 22237534 TI - Case study: targeted high-throughput sequencing of mitochondrial genomes from extinct cave bears via direct multiplex PCR sequencing (DMPS). AB - Here I describe the use of a recently developed technique for targeted high throughput sequencing of highly degraded DNA by direct multiplex PCR sequencing (DMPS) that was used to amplify 31 near-complete mitochondrial genomes of the extinct cave bear (Ursus spelaeus). DMPS couples multiplex PCR with the generation of barcoded sequencing libraries to be sequenced in parallel on a high throughput sequencing platform. DMPS makes it possible to generate large amounts of targeted DNA sequence data simultaneously from multiple degraded samples such as fossil remains. In this chapter, I describe an experiment that uses DMPS with different primer sets and on both modern and ancient DNA templates. PMID- 22237535 TI - Target enrichment via DNA hybridization capture. AB - Recent advances in high-throughput DNA sequencing technologies have allowed entire nuclear genomes to be shotgun sequenced from ancient DNA (aDNA) extracts. Nonetheless, targeted analyses of specific genomic loci will remain an important tool for future aDNA studies. DNA capture via hybridization allows the efficient exploitation of current high-throughput sequencing for population genetic analyses using aDNA samples. Specifically, hybridization capture allows larger data sets to be generated for multiple target loci as well as for multiple samples in parallel. "Bait" molecules are used to select target regions from DNA libraries for sequencing. Here we present a brief overview of the currently available hybridization capture protocols using either an in-solution or a solid phase (immobilized) approach. While it is possible to purchase ready-made kits for this purpose, I present a protocol that allows users to generate their own custom bait to be used for hybridization capture. PMID- 22237536 TI - Case study: enrichment of ancient mitochondrial DNA by hybridization capture. AB - In ancient DNA studies focusing on estimating population histories, genetic markers are sequenced from a large number of samples belonging to the same species. Targeting loci of interest using traditional PCR can be time-consuming, in particular when samples are not well preserved and multiple overlapping fragments are required. Here, I describe the process of generating DNA libraries from ancient DNA (aDNA) extracts for high-throughput sequencing. I use a serial in-solution DNA hybridization approach with subsequent bead capture to enrich libraries for the target locus, in this case the mitochondrial control region of ancient beavers (Castor fiber). The resulting sequencing reads are run through quality control filters to obtain reliable consensus sequences. Using these sequences, I construct a phylogenetic tree, which agrees with previously published data regarding phylogeographic relationships among beavers. PMID- 22237537 TI - Analysis of high-throughput ancient DNA sequencing data. AB - Advances in sequencing technologies have dramatically changed the field of ancient DNA (aDNA). It is now possible to generate an enormous quantity of aDNA sequence data both rapidly and inexpensively. As aDNA sequences are generally short in length, damaged, and at low copy number relative to coextracted environmental DNA, high-throughput approaches offer a tremendous advantage over traditional sequencing approaches in that they enable a complete characterization of an aDNA extract. However, the particular qualities of aDNA also present specific limitations that require careful consideration in data analysis. For example, results of high-throughout analyses of aDNA libraries may include chimeric sequences, sequencing error and artifacts, damage, and alignment ambiguities due to the short read lengths. Here, I describe typical primary data analysis workflows for high-throughput aDNA sequencing experiments, including (1) separation of individual samples in multiplex experiments; (2) removal of protocol-specific library artifacts; (3) trimming adapter sequences and merging paired-end sequencing data; (4) base quality score filtering or quality score propagation during data analysis; (5) identification of endogenous molecules from an environmental background; (6) quantification of contamination from other DNA sources; and (7) removal of clonal amplification products or the compilation of a consensus from clonal amplification products, and their exploitation for estimation of library complexity. PMID- 22237538 TI - Phylogenetic analysis of ancient DNA using BEAST. AB - Under exceptional circumstances, it is possible to obtain DNA sequences from samples that are up to hundreds of thousands of years old. These data provide an opportunity to look directly at past genetic diversity, to trace the evolutionary process through time, and to infer demographic and phylogeographic trends. Ancient DNA (aDNA) data sets have some degree of intrinsic temporal structure because the sequences have been obtained from samples of different ages. When analyzing these data sets, it is usually necessary to take the sampling times into account. A number of phylogenetic methods have been designed with this purpose in mind. Here I describe the steps involved in Bayesian phylogenetic analysis of aDNA data. I outline a procedure that can be used to co-estimate the genealogical relationships, mutation rate, evolutionary timescale, and demographic history of the study species in a single analytical framework. A number of modifications to the methodology can be made in order to deal with complicating factors such as postmortem damage, sequences from undated samples, and data sets with low information content. PMID- 22237539 TI - Unraveling assembly of stream biofilm communities. AB - Microbial biofilms assemble from cells that attach to a surface, where they develop into matrix-enclosed communities. Mechanistic insights into community assembly are crucial to better understand the functioning of natural biofilms, which drive key ecosystem processes in numerous aquatic habitats. We studied the role of the suspended microbial community as the source of the biofilm community in three streams using terminal-restriction fragment length polymorphism and 454 pyrosequencing of the 16S ribosomal RNA (rRNA) and the 16S rRNA gene (as a measure for the active and the bulk community, respectively). Diversity was consistently lower in the biofilm communities than in the suspended stream water communities. We propose that the higher diversity in the suspended communities is supported by continuous inflow from various sources within the catchment. Community composition clearly differed between biofilms and suspended communities, whereas biofilm communities were similar in all three streams. This suggests that biofilm assembly did not simply reflect differences in the source communities, but that certain microbial groups from the source community proliferate in the biofilm. We compared the biofilm communities with random samples of the respective community suspended in the stream water. This analysis confirmed that stochastic dispersal from the source community was unlikely to shape the observed community composition of the biofilms, in support of species sorting as a major biofilm assembly mechanism. Bulk and active populations generated comparable patterns of community composition in the biofilms and the suspended communities, which suggests similar assembly controls on these populations. PMID- 22237541 TI - First evidence for the existence of pennate diatom viruses. AB - Diatoms are considered the most successful and widespread group of photosynthetic eukaryotes. Their contribution to primary production is remarkably significant to the earth's ecosystems. Diatoms are composed of two orders: Centrales and Pennales. Thus far, viruses infecting centric diatom species have been isolated and characterized; however, viruses infecting pennates have not been reported. Here, we describe the first isolations and preliminary characterizations of two distinct pennate diatom viruses, AglaRNAV (31 nm in diameter, accumulates in the host cytoplasm) and TnitDNAV (35 nm in diameter, accumulates in the host nuclei) infecting Asterionellopsis glacialis and Thalassionema nitzschioides, respectively. Their genomes contain a single-stranded RNA of approximately 9.5 kb, and a closed, circular single-stranded DNA of approximately 5.5 kb harboring a partially double-stranded region, respectively. Further analysis of these viruses may elucidate many aspects of diatom host-virus relationships. PMID- 22237540 TI - Proteus mirabilis interkingdom swarming signals attract blow flies. AB - Flies transport specific bacteria with their larvae that provide a wider range of nutrients for those bacteria. Our hypothesis was that this symbiotic interaction may depend on interkingdom signaling. We obtained Proteus mirabilis from the salivary glands of the blow fly Lucilia sericata; this strain swarmed significantly and produced a strong odor that attracts blow flies. To identify the putative interkingdom signals for the bacterium and flies, we reasoned that as swarming is used by this bacterium to cover the food resource and requires bacterial signaling, the same bacterial signals used for swarming may be used to communicate with blow flies. Using transposon mutagenesis, we identified six novel genes for swarming (ureR, fis, hybG, zapB, fadE and PROSTU_03490), then, confirming our hypothesis, we discovered that fly attractants, lactic acid, phenol, NaOH, KOH and ammonia, restore swarming for cells with the swarming mutations. Hence, compounds produced by the bacterium that attract flies also are utilized for swarming. In addition, bacteria with the swarming mutation rfaL attracted fewer blow flies and reduced the number of eggs laid by the flies. Therefore, we have identified several interkingdom signals between P. mirabilis and blow flies. PMID- 22237542 TI - Pseudomonas syringae naturally lacking the canonical type III secretion system are ubiquitous in nonagricultural habitats, are phylogenetically diverse and can be pathogenic. AB - The type III secretion system (T3SS) is an important virulence factor of pathogenic bacteria, but the natural occurrence of variants of bacterial plant pathogens with deficiencies in their T3SS raises questions about the significance of the T3SS for fitness. Previous work on T3SS-deficient plant pathogenic bacteria has focused on strains from plants or plant debris. Here we have characterized T3SS-deficient strains of Pseudomonas syringae from plant and nonplant substrates in pristine nonagricultural contexts, many of which represent recently described clades not yet found associated with crop plants. Strains incapable of inducing a hypersensitive reaction (HR(-)) in tobacco were detected in 65% of 126 samples from headwaters of rivers (mountain creeks and lakes), snowpack, epilithic biofilms, wild plants and leaf litter and constituted 2 to 100% of the P. syringae population associated with each sample. All HR(-) strains lacked at least one gene in the canonical hrp/hrc locus or the associated conserved effector locus, but most lacked all six of the genes tested (hrcC, hrpL, hrpK1, avrE1 and hrpW1) and represented several disparate phylogenetic clades. Although most HR(-) strains were incapable of causing symptoms on cantaloupe seedlings as expected, strains in the recently described TA-002 clade caused severe symptoms in spite of the absence of any of the six conserved genes of the canonical T3SS according to PCR and Southern blot assays. The phylogenetic context of the T3SS variants we observed provides insight into the evolutionary history of P. syringae as a pathogen and as an environmental saprophyte. PMID- 22237543 TI - Identification of a novel cyanobacterial group as active diazotrophs in a coastal microbial mat using NanoSIMS analysis. AB - N(2) fixation is a key process in photosynthetic microbial mats to support the nitrogen demands associated with primary production. Despite its importance, groups that actively fix N(2) and contribute to the input of organic N in these ecosystems still remain largely unclear. To investigate the active diazotrophic community in microbial mats from the Elkhorn Slough estuary, Monterey Bay, CA, USA, we conducted an extensive combined approach, including biogeochemical, molecular and high-resolution secondary ion mass spectrometry (NanoSIMS) analyses. Detailed analysis of dinitrogenase reductase (nifH) transcript clone libraries from mat samples that fixed N(2) at night indicated that cyanobacterial nifH transcripts were abundant and formed a novel monophyletic lineage. Independent NanoSIMS analysis of (15)N(2)-incubated samples revealed significant incorporation of (15)N into small, non-heterocystous cyanobacterial filaments. Mat-derived enrichment cultures yielded a unicyanobacterial culture with similar filaments (named Elkhorn Slough Filamentous Cyanobacterium-1 (ESFC-1)) that contained nifH gene sequences grouping with the novel cyanobacterial lineage identified in the transcript clone libraries, displaying up to 100% amino-acid sequence identity. The 16S rRNA gene sequence recovered from this enrichment allowed for the identification of related sequences from Elkhorn Slough mats and revealed great sequence diversity in this cluster. Furthermore, by combining (15)N(2) tracer experiments, fluorescence in situ hybridization and NanoSIMS, in situ N(2) fixation activity by the novel ESFC-1 group was demonstrated, suggesting that this group may be the most active cyanobacterial diazotroph in the Elkhorn Slough mat. Pyrotag sequences affiliated with ESFC-1 were recovered from mat samples throughout 2009, demonstrating the prevalence of this group. This work illustrates that combining standard and single-cell analyses can link phylogeny and function to identify previously unknown key functional groups in complex ecosystems. PMID- 22237544 TI - Acyl homoserine lactone-based quorum sensing in a methanogenic archaeon. AB - Acyl homoserine lactone (AHL)-based quorum sensing commonly refers to cell density-dependent regulatory mechanisms found in bacteria. However, beyond bacteria, this cell-to-cell communication mechanism is poorly understood. Here we show that a methanogenic archaeon, Methanosaeta harundinacea 6Ac, encodes an active quorum sensing system that is used to regulate cell assembly and carbon metabolic flux. The methanogen 6Ac showed a cell density-dependent physiology transition, which was related to the AHL present in the spent culture and the filI gene-encoded AHL synthase. Through extensive chemical analyses, a new class of carboxylated AHLs synthesized by FilI protein was identified. These carboxylated AHLs facilitated the transition from a short cell to filamentous growth, with an altered carbon metabolic flux that favoured the conversion of acetate to methane and a reduced yield in cellular biomass. The transcriptomes of the filaments and the short cell forms differed with gene expression profiles consistent with the physiology. In the filaments, genes encoding the initial enzymes in the methanogenesis pathway were upregulated, whereas those for cellular carbon assimilation were downregulated. A luxI-luxR ortholog filI-filR was present in the genome of strain 6Ac. The carboxylated AHLs were also detected in other methanogen cultures and putative filI orthologs were identified in other methanogenic genomes as well. This discovery of AHL-based quorum sensing systems in methanogenic archaea implies that quorum sensing mechanisms are universal among prokaryotes. PMID- 22237545 TI - Dinitrogen fixation in a unicellular chlorophyll d-containing cyanobacterium. AB - Marine cyanobacteria of the genus Acaryochloris are the only known organisms that use chlorophyll d as a photosynthetic pigment. However, based on chemical sediment analyses, chlorophyll d has been recognized to be widespread in oceanic and lacustrine environments. Therefore it is highly relevant to understand the genetic basis for different physiologies and possible niche adaptation in this genus. Here we show that unlike all other known isolates of Acaryochloris, the strain HICR111A, isolated from waters around Heron Island, Great Barrier Reef, possesses a unique genomic region containing all the genes for the structural and enzymatically active proteins of nitrogen fixation and cofactor biosynthesis. Their phylogenetic analysis suggests a close relation to nitrogen fixation genes from certain other marine cyanobacteria. We show that nitrogen fixation in Acaryochloris sp. HICR111A is regulated in a light-dark-dependent fashion. We conclude that nitrogen fixation, one of the most complex physiological traits known in bacteria, might be transferred among oceanic microbes by horizontal gene transfer more often than anticipated so far. Our data show that the two powerful processes of oxygenic photosynthesis and nitrogen fixation co-occur in one and the same cell also in this branch of marine microbes and characterize Acaryochloris as a physiologically versatile inhabitant of an ecological niche, which is primarily driven by the absorption of far-red light. PMID- 22237546 TI - Selection of primers for optimal taxonomic classification of environmental 16S rRNA gene sequences. AB - Microbial community profiling using 16S rRNA gene sequences requires accurate taxonomy assignments. 'Universal' primers target conserved sequences and amplify sequences from many taxa, but they provide variable coverage of different environments, and regions of the rRNA gene differ in taxonomic informativeness- especially when high-throughput short-read sequencing technologies (for example, 454 and Illumina) are used. We introduce a new evaluation procedure that provides an improved measure of expected taxonomic precision when classifying environmental sequence reads from a given primer. Applying this measure to thousands of combinations of primers and read lengths, simulating single-ended and paired-end sequencing, reveals that these choices greatly affect taxonomic informativeness. The most informative sequence region may differ by environment, partly due to variable coverage of different environments in reference databases. Using our Rtax method of classifying paired-end reads, we found that paired-end sequencing provides substantial benefit in some environments including human gut, but not in others. Optimal primer choice for short reads totaling 96 nt provides 82-100% of the confident genus classifications available from longer reads. PMID- 22237547 TI - In situ proteo-metabolomics reveals metabolite secretion by the acid mine drainage bio-indicator, Euglena mutabilis. AB - Euglena mutabilis is a photosynthetic protist found in acidic aquatic environments such as peat bogs, volcanic lakes and acid mine drainages (AMDs). Through its photosynthetic metabolism, this protist is supposed to have an important role in primary production in such oligotrophic ecosystems. Nevertheless, the exact contribution of E. mutabilis in organic matter synthesis remains unclear and no evidence of metabolite secretion by this protist has been established so far. Here we combined in situ proteo-metabolomic approaches to determine the nature of the metabolites accumulated by this protist or potentially secreted into an AMD. Our results revealed that the secreted metabolites are represented by a large number of amino acids, polyamine compounds, urea and some sugars but no fatty acids, suggesting a selective organic matter contribution in this ecosystem. Such a production may have a crucial impact on the bacterial community present on the study site, as it has been suggested previously that prokaryotes transport and recycle in situ most of the metabolites secreted by E. mutabilis. Consequently, this protist may have an indirect but important role in AMD ecosystems but also in other ecological niches often described as nitrogen-limited. PMID- 22237548 TI - A discriminative analytical method for detection of CES1A1 and CES1A2/CES1A3 genetic variants. AB - Human carboxylesterase 1 (hCES1), encoded by the CES1 gene, is the predominant hepatic hydrolase responsible for the metabolism of many therapeutic agents, toxins, and endogenous substances. Genetic variants of CES1 can affect hCES1 function and expression and ultimately influence clinical response to drugs serving as hCES1 substrates. The CES1 gene consists of three isoforms including the functional CES1A1 and CES1A2 genes and the nonfunctional pseudogene CES1A3. Natural variants of these isoforms exert differing impacts on hCES1 function. However, the existing CES1 genotyping methods are incapable of determining whether these variants belong to CES1A1, CES1A2, or CES1A3 because of the high similarity among these three genes, as a consequence they are unable to discriminate between heterozygotes and homozygotes. We report the development of a novel long-range PCR-based, discriminative genotyping assay capable of specifically detecting the variants among CES1A1, CES1A2, and CES1A3 genes. The comparison of the genotyping results between this novel assay and those previously reported methods highlighted the necessity of applying the discriminative genotyping assay in pharmacogenetic studies involving CES1 gene. PMID- 22237551 TI - FRET spectral unmixing: a ratiometric fluorescent nanoprobe for hypochlorite. AB - A specific ratiometric nanoprobe for hypochlorite was constructed as a paradigm of FRET spectral unmixing. The separation of FRET pairs' emissions reaches 175 nm, which ensures that the FRET probing is more accurate. This new nanoprobe shows high selectivity and potential in biological systems. PMID- 22237549 TI - PharmGKB summary: very important pharmacogene information for G6PD. PMID- 22237554 TI - Empty follicle syndrome after GnRHa triggering versus hCG triggering in COS. AB - PURPOSE: This study aimed to explore the incidence of empty follicle syndrome (EFS) in oocyte donors who had final oocyte maturation triggered with GnRHa and to compare the incidence of EFS in this group of patients with IVF patients who had final oocyte maturation with hCG. METHODS: Data including 2034 oocyte donation cycles and 1433 IVF cycles performed between years 2009 and 2010 was retrospectively analyzed to identify cases of EFS in each group. RESULTS: The incidence of EFS in the two groups did not differ significantly, 3.5% versus 3.1%, (n.s.). CONCLUSIONS: This large retrospective analysis indicates that the incidence of EFS is not increased after GnRHa triggering as compared to hCG triggering. PMID- 22237555 TI - Decreased echogenicity of the embryo is correlated with absence of cardiac activity. AB - PURPOSE: The purpose of this study was to investigate whether the sonographic echogenicity of embryos is associated with cardiac activity in utero. METHODS: The present study reviewed a total of 164 embryos having a gestational age between 6 and 8 weeks. These embryos were examined by transvaginal ultrasonography and a comparison of their echogenicity was made with respect to those of the placenta and the myometrium. Grade II embryos were less echogenic than the placenta or had similar echogenicity with the myometrium, whereas grade I embryos shared the same echogenicity as the placenta. In contrast, grade III embryos were less echogenic than the myometrium. RESULTS: Most of the embryos with cardiac activity were detected to have grade II echogenicity (78/130, 60.0%), whereas the remaining embryos had grade I echogenicity (52/130, 40.0%). In contrast, most of the embryos without cardiac activity had grade III echogenicity (20/34, 58.8%), whereas the remaining embryos had either grade II (8/34, 23.5%) or grade I (6/34, 17.7%) echogenicity. CONCLUSIONS: Decreased echogenicity of embryos on grayscale ultrasound in the early first trimester is correlated with an absence of cardiac activity. PMID- 22237556 TI - Impact of gender, maternal education, and birth order on the development of language comprehension: a longitudinal study from 18 to 36 months of age. AB - OBJECTIVE: To investigate the impact of child gender, maternal education, and birth order on language comprehension (LC) status at 18 and 36 months of age and on the change in LC between these time points. Gender interactions and interactions between maternal education and birth order are also examined. METHODS: This study is based on data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Maternal report data on education, birth order, and child language in a sample of 44,921 children were used in linear regression analyses. RESULTS: At 18 and 36 months of age, first born girls of mothers with high educational attainment had the highest level of LC. Between 18 and 36 months of age, first-born boys of mothers with high educational attainment had the highest increase in LC. Having a highly educated mother contributed more to the increase in LC in boys than in girls. The boys whose mothers had the highest education level had lower scores than the girls whose mothers had the lowest educational level, at both ages. Although significant, the considerable effect of high maternal education was not substantially dependent on birth-order status. CONCLUSIONS: Boys develop LC at a faster rate than girls between 18 and 36 months, but girls still remain superior in their level of LC at 36 months of age. Being firstborn or having a highly educated mother does not compensate for this lag. PMID- 22237557 TI - Adherence to Mediterranean diet and close dietetic supervision increase total dietary antioxidant intake and plasma antioxidant capacity in subjects with abdominal obesity. AB - PURPOSE: To determine the effect of Mediterranean-type diet and close dietetic supervision on dietary antioxidant intake and plasma total antioxidant capacity (TAC) in patients with abdominal obesity. METHODS: Ninety subjects with abdominal obesity, 46 in intervention group, 44 in control group, participated in a 2 month, randomized, parallel dietary intervention. All participants were counseled on Greek Mediterranean diet. The intervention group was under close dietetic supervision, followed a specific relevant daily and weekly food plan consuming antioxidant-rich foods and food products. Total dietary antioxidant intake was calculated from the volunteers' food diaries, and plasma TAC using plasma ORAC assay and plasma ferric-reducing antioxidant power (FRAP) assay, both at baseline and at 2 months. RESULTS: Following the 2-month period, total dietary antioxidant intake was increased in the intervention group compared to the control group (P = 0.000). In addition, increased intake of total fat, due to higher consumption of monounsaturated fatty acids, as well as increased intakes of dietary fiber, vitamin C and alcohol was also observed in the intervention group compared to the control group (P < 0.05). Plasma TAC was increased in the intervention group compared to the control group (P = 0.039) using the ORAC assay, while there was a trend toward a TAC increase (P = 0.077) using the FRAP assay. CONCLUSION: Adherence to a Mediterranean-type diet, with emphasis on an increase in foods rich in antioxidants and close dietetic supervision, can increase total dietary antioxidant intake and plasma TAC in patients with abdominal obesity. PMID- 22237559 TI - Diet mediates the relationship between longevity and reproduction in mammals. AB - The disposable soma hypothesis posits a negative correlation between longevity and reproduction, presumably because these aspects of fitness compete for a limited pool of nutrients. However, diet, which varies widely among animals, could affect the availability of key nutrients required for both reproduction and longevity, especially protein. We used a comparative database of mammal life history data to test the hypothesis that carnivores experience less of a negative relationship between reproduction and longevity than herbivores. Annual reproduction and adult mass were significant predictors of longevity among all mammals; although, the relative importance of reproduction and mass for explaining longevity varied among trophic levels. In herbivores, reproduction was a stronger predictor of longevity than mass. Carnivores showed the opposite pattern with reproduction explaining much less of the variation in longevity. Omnivores showed an intermediate pattern with mass and reproduction explaining similar amounts of variation in longevity. In addition, longevity and reproduction were significantly higher in omnivores than herbivores and carnivores, which were not different from each other. Higher dietary protein at higher trophic levels may allow mammals to avoid potential conflicts between reproduction and longevity. However, there may be potential costs of carnivorous diets that limit the overall performance of carnivores and explain the peak in reproduction and longevity for omnivores. PMID- 22237558 TI - Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. AB - With aging and Alzheimer's disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brain-derived neurotrophic factor in AD. We have replicated this aging phenotype in cultured neurons from aged mice despite being grown in the same environmental conditions as young neurons. This led us to hypothesize that age-related differences in epigenetic acetylation and methylation of histones are associated with age related gene regulation. We cultured hippocampal/cortical neurons from the 3xTg AD mouse model and from non-transgenic mice to quantify single cell acetylation and methylation levels across the life span. In non-transgenic neurons, H3 acetylation was unchanged with age, while H4 acetylation decreased with age of the donor. Compared to non-transgenic neurons, 3xTg-AD neurons had higher levels of H3 and H4 acetylation beginning at 4 months of age. In contrast to non transgenic neurons, 3xTg-AD neurons increased acetylation with age; 3xTg-AD neurons also responded differently to inhibition of histone deacetylases at an early age. Importantly, treatment of non-transgenic neurons with the AD peptide Abeta also elevated levels of acetylation. We also examined the repressive function of histone H3 lysine 9 (H3K9) methylation. H3K9 methylation increased with age in non-transgenic neurons, which was amplified further in 3xTg-AD neurons. The dominant effect of higher H3K9 methylation was supported by lower Bdnf gene expression in non-transgenic and 3xTg-AD mice. These data show that the epigenetic states of non-transgenic and 3xTg-AD brain neurons are profoundly different and reversible, beginning at 4 months of age when the first memory deficits are reported. PMID- 22237560 TI - Phenotypic and genotypic variability in Alpers syndrome. AB - BACKGROUND: Alpers syndrome is one of the most common phenotypes of mitochondrial disorders in early childhood and has been associated with pathogenic mutations in POLG1. AIMS: To investigate the phenotypic-genotypic correlations in Alpers syndrome and to identify potential differences among patients with Alpers syndrome with or without pathogenic POLG1 mutations. METHODS: Patients with the phenotype of Alpers syndrome who were referred to our pediatric hospital during 1984-2007 and were diagnosed with mitochondrial encephalomyopathy underwent further biochemical, morphological and genetic investigations. RESULTS: A total of 19 patients were included in the study, of whom six had pathogenic POLG1 mutations including a novel mutation (c.907 G>A, p.Gly303Arg). Complete mtDNA sequencing in the subgroup without POLG1 mutations showed 5 novel and 5 very rare mtDNA variants considered as rare polymorphisms. Compared to POLG1(-) patients, the POLG1(+) patients more frequently had seizures at onset, which often became refractory. Ataxia and stroke-like episodes were much more common, while microcephaly and spasticity were encountered almost solely in the POLG1(-) group. Hepatic and ophthalmological involvement developed in 79% and 88% of patients, respectively. Most of the patients in both groups had predominant deficiency of complex I. In addition to the major degenerative changes in the cerebral cortex, the basal ganglia, thalamus and white matter were also involved to variable extent. CONCLUSION: Alpers syndrome is a heterogeneous syndrome that should be considered in patients with early-onset progressive cortical encephalopathy regardless of liver involvement. The phenotype is different depending on the presence or absence of POLG1 mutations. PMID- 22237561 TI - Diversion of emergency acute workload to primary care: an attractive private sector alternative to public hospital emergency departments? PMID- 22237562 TI - Non-contact first specialist appointments are safe. PMID- 22237563 TI - Classification controversies in relation to fibromyalgia syndrome. PMID- 22237564 TI - Deaths and hospital admissions as a result of home injuries among young and middle-aged New Zealand adults. AB - AIM: New Zealand lacks a comprehensive national profile of home injuries, this information is necessary to develop effective targeted injury prevention initiatives. This study describes the epidemiology of unintentional home injuries resulting in death or admission to hospital among young and middle-age New Zealanders. METHOD: Cases were selected from Ministry of Health public hospital discharge (2000-2009) and mortality data (1998-2007), and included all 20-64 year olds where the place of injury occurrence was classified as 'home'. Only initial hospitalisations with a stay of 24 hours or longer were included. The circumstances of injury were coded according to the ICD-10 external cause categories. Mean annual rates of death or hospitalisation were calculated using census and intercensal denominator data. RESULTS: On average 4000 young and middle-age adults are admitted to hospital and 60 die annually as a result of unintentional injuries sustained at home. Overall, mortality rates were highest amongst males, older adults (50 to 64 years), and Maori. The leading causes of unintentional home injury deaths were poisoning, falls, and burns. Hospitalisation rates were highest among males, the older age groups (> 40 years), and Maori. As age increased so did the incidence of hospital admission. The leading contributors resulting in admission to hospital were falls, cutting or piercing, overexertion, and poisoning. Injuries due to falls had the highest median length of hospital stay and in-hospital mortality rate. As deprivation increased so did the frequency of hospital admissions due to fall and cutting or piercing injuries. CONCLUSION: Poisonings and falls are the leading causes of unintentional home injury death among young and middle-aged New Zealanders. In addition, falls are a significant contributor to home injury resulting in admission to hospital. The large numbers of home injuries occurring each year in New Zealand, mean that even moderately successful injury prevention interventions could have large impacts at the population level. PMID- 22237565 TI - Smoking outdoors at pubs and bars: is it a problem? An air quality study. AB - AIMS: (i) To measure air quality in semi-enclosed outdoor smoking areas of pubs and bars in New Zealand. (ii) To evaluate evidence of drift of fine particulates of secondhand smoke (SHS) from semi-enclosed outdoor smoking areas to indoor (smoke-free) areas. (iii) To evaluate evidence that the degree of communication between the outdoor smoking area and indoor areas influences the level of particulates indoors. METHODS: We measured fine particulate levels (PM(2.5)) using portable real-time aerosol monitors in a convenience sample of seven pubs and bars in central Wellington City. This was on one to three occasions (12 measurements in total) over four different nights. RESULTS: On the first two nights, when there was no or infrequent communication between the outdoor and indoor areas, the mean level of PM(2.5) varied from 32 to 109 MUg/m3 in the outdoor smoking area, and from 14 to 79 MUg/m3 in the adjacent indoor areas. On nights three and four, communicating doors were generally open most of the time. The mean level of PM(2.5) varied from 29 to 192 MUg/m3 in the smoking areas, from 36 to 117 MUg/m3 in adjacent indoor areas, and from 23 to 104 MUg/m3 in more distant indoor areas. Levels of PM(2.5) in adjacent indoor areas were highest in pubs where communicating doors were open all the time (mean 117 MUg/m3), intermediate where communicating doors were open intermittently (mean 85 MUg/m3), and lowest when they were wholly or mainly closed (mean 25 MUg/m3). CONCLUSIONS: Air quality in semi-enclosed outdoor smoking areas was variable, and in some pubs was very poor. Where free communication exists between outdoor smoking areas and indoor areas, SHS drift can often greatly reduce indoor air quality throughout the pub or bar. Regulations to restrict the degree of communication and proximity of smoking areas to indoor areas may be justified to maintain indoor air quality and to protect health, particularly that of workers. PMID- 22237566 TI - Women with fibromyalgia syndrome in New Zealand: the symptom experience. AB - AIMS: Diagnosis and treatment of fibromyalgia syndrome (FMS) currently focuses on the experience of widespread pain. However, the symptom experience described by patients with FMS in clinical practice is far more diverse. This study aims identify the most common and severe symptoms in female patients diagnosed with FMS. METHODS: This study interviewed 56 patients diagnosed with fibromyalgia syndrome about their symptoms using the Clinical Interview Schedule--Revised. RESULTS: The most frequent and disabling symptoms reported by participants were fatigue, sleep disturbance and cognitive difficulties. CONCLUSIONS: These findings highlight the need for a range of symptoms to be considered in the assessment and treatment of FMS to help improve patient outcomes. PMID- 22237567 TI - Safety and efficiency of non-contact first specialist assessment in neurology. AB - AIM: To investigate safety and efficiency of non-contact first specialist assessments (NCFSA) in neurology. METHODS: Out of a cohort of 1107 patients referred to a neurology clinic, a total of 222 (20%) was triaged into NCFSA and investigated with a 6 months observational study of safety and efficiency indicators. RESULTS: There were three (1.35%) adverse events (delay in diagnosis) recorded, one of which with actual detriment to the patient. After 6 months the rate of re-referrals was 11.26%, and inpatient admission rate 5.86%. CONCLUSIONS: There is a potential for NCFSAs to optimise the use of available resources in a neurology outpatient setting with low risk of delay in diagnosis. PMID- 22237568 TI - Poor oral health in patients with coronary heart disease: a case-control study of Indian adults. AB - AIM: The present study was conducted to quantitate the oral health of coronary heart disease patients and compare them with controls for a valid inference METHOD: A total of 100 medically diagnosed coronary heart disease patients were compared with 100 controls using the World Health Organization (WHO) oral health assessment form. Statistical analysis was done using SPSS (version 10) software. RESULTS: Statistically higher mean sextant value for shallow pockets 4-5 mm, CPI (Community Periodontal Index) score 3 and LOA (Loss of attachment) score 1,2 was found for cases as compared to controls (p<=0.05). Similarly, higher mean DMFT (Decayed-Missing-Filled Teeth) and missing teeth were observed for cases as compared to controls (p>0.05). CONCLUSION: The present study shows a slight increase in the level of mild periodontal disease in coronary heart disease patients as compared to controls, with a non-significant difference in dental caries. PMID- 22237569 TI - Two New Zealand outbreaks of norovirus gastroenteritis linked to commercially farmed oysters. AB - AIM: We report on the investigations of two gastroenteritis outbreaks, which were linked to a common source. METHODS: Retrospective cohort studies were conducted for two gastroenteritis outbreaks which occurred in Auckland and in Waikato. Faecal samples and samples of oyster meat were analysed. Environmental surveys of implicated areas were conducted. RESULTS: 10 out of 16 people who had eaten at a catered event in Auckland, and 3 out of 15 people who had eaten at a Waikato restaurant, experienced gastroenteritis. The symptoms, duration of illness and incubation periods were consistent with norovirus gastroenteritis in both outbreaks. The consumption of oysters was strongly associated with an increased risk of illness. Faecal samples were positive for norovirus. Oysters from both outbreaks were traced back to the same growing area. Samples of oyster meat from one of the restaurants and from the growing area were positive for norovirus. The growing area was closed for further investigation. A pipe from a waste water treatment plant was later found to be leaking partially treated effluent into a stream discharging near the implicated growing area. CONCLUSION: Investigation of these two outbreaks led to the discovery of a common source of norovirus at a commercial oyster growing area. PMID- 22237570 TI - The Hui Process: a framework to enhance the doctor-patient relationship with Maori. AB - AIM: To describe a method of integrating cultural competency practice, specific to Maori, in the doctor-patient relationship. METHOD: The Hauora Maori curriculum at University of Otago, Christchurch has developed the 'Hui Process', a framework to guide clinical interaction with Maori derived from engagement and relationship building principles of Te Ao Maori. RESULTS: The current consensus from Maori health leaders, student feedback and anecdotal Maori patient feedback indicates the 'Hui Process' is easily learnt, well received by patients and can enhance the doctor-patient relationship. CONCLUSION: The introduction of the 'Hui Process' as a framework for building effective relationships between doctors and Maori patients has been well received in medical education. Clinicians should consider utilising the 'Hui Process'. PMID- 22237571 TI - Health equity: what does it mean for child health? AB - The concept of 'health equity' has become increasingly central to discussions around social determinants of health, and the resultant disparities in health outcomes. It has particular pertinence to paediatric populations in New Zealand: some of our most alarming disparities relate to child health, and there is increasing recognition of the need to reduce these inequities. Effective 'health equity' approaches in child health demand that clinicians broaden their roles to become strong advocates for social justice: in order to achieve progress in this area, it is essential that child health is prioritised at our most fundamental policy levels. PMID- 22237572 TI - Medical image. Horse tick in a human ear. PMID- 22237573 TI - Medical image. The shepherd's swollen arm. PMID- 22237574 TI - Medical image. Small bowel diverticulosis: a rare cause of iron deficiency anaemia. PMID- 22237575 TI - Medical image. Cruveilhier-Baumgarten syndrome with caput medusae. PMID- 22237576 TI - Response to PHARMAC on Access to new medicines in New Zealand compared to Australia. PMID- 22237577 TI - PSA testing--who should decide when it is performed? PMID- 22237578 TI - Invasive meningococcal disease in Northland, New Zealand. PMID- 22237579 TI - Public funding of bariatric surgery. PMID- 22237580 TI - Synthetic cannabinoid use in New Zealand: a brief evaluation of inquiries to the New Zealand National Poisons Centre. PMID- 22237581 TI - Early ketamine to treat refractory status epilepticus. AB - BACKGROUND: Management of refractory status epilepticus (SE) involves administration of intravenous gamma-aminobutyric acid (GABA(A)) receptor agonists, such as benzodiazepines, barbiturates, or propofol. Animal models suggest that reductions in synaptic GABA(A) receptors may cause these drugs to become less effective as the duration of SE increases. This may explain the large doses that are commonly required to control seizures, which in turn contributes to a high incidence of complications, including hypotension and the need for vasopressors. In contrast, expression of excitatory N-methyl-D-aspartate (NMDA) receptors increases with prolonged SE and their stimulation by glutamate may propagate seizure activity. Ketamine is a NMDA-receptor antagonist that is considered promising as treatment for refractory SE. Compared with other anaesthetic drugs, ketamine produces less hypotension. METHODS: This report describes a patient who developed worsening hypotension with escalating doses of midazolam and propofol in the context of non-convulsive SE. He was therefore treated with ketamine within hours of being diagnosed. RESULTS: Ketamine was immediately efficacious at reducing the frequency, amplitude, and duration of seizures. The dose was rapidly titrated upwards using quantitative continuous EEG monitoring, until seizures were completely abolished. SE did not recur with weaning of sedatives and he went on to have an excellent recovery. A small number of previous reports have found ketamine to abort late SE. In most cases, ketamine was administered several days into the course, and outcomes were poor even though seizures were controlled. CONCLUSION: Larger series and phase I clinical trial(s) of ketamine for treatment of refractory SE seem warranted. PMID- 22237582 TI - Socioeconomic correlates of inpatient spending for patients with type 2 diabetes mellitus in China: evidence from Hangzhou. AB - AIMS: We evaluated the factors associated with inpatient costs including total costs, pharmaceutical costs and laboratory costs for diabetes-related admissions. PATIENTS AND METHODS: Using data for 960 adult patients admitted between May 2005 and April 2008 with a primary or secondary diagnosis of type 2 diabetes mellitus (DM) at Sir Run Run Shaw Hospital affiliated with Zhejiang University Medical School (SRRSH) in Hangzhou, China, we evaluate the association between patient characteristics and inpatient costs with multivariable regression analyses. RESULTS: Total inpatient costs were positively associated with age, higher UKPDS stroke risk score, and presence of any complication. A regression that included patient socioeconomic and clinical characteristics explained 21.5% of the variation in total inpatient costs; regression estimates indicate that patients with coronary artery disease, retinopathy, nephropathy, neuropathy, and diabetic foot had inpatient costs that were respectively 93.7%, 14.0%, 17.5%, 11.5% and 89.0% higher than otherwise similar patients without those complications. Pharmaceutical costs did not differ by insurance coverage. Insured patients spent 7-16% more on laboratory tests than otherwise similar patients did. CONCLUSIONS: Clinical factors, especially presence of diabetes-related complications, appear to be the primary determinants of variation in inpatient costs for patients with type 2 DM in China. To mitigate the health costs increases associated with China's DM epidemic, policymakers should focus on cost-effective ways to manage patients in outpatient settings to prevent the complications associated with diabetes. PMID- 22237583 TI - Extracellular matrix alterations in the atria: insights into the mechanisms and perpetuation of atrial fibrillation. AB - Atrial fibrillation is the most common arrhythmia in clinical practice and is associated with increased cardiovascular morbidity and mortality. Atrial fibrosis, a detrimental process that causes imbalance in extracellular matrix deposition and degradation, has been implicated as a substrate for atrial fibrillation, but the precise mechanisms of structural remodelling and the relationship between atrial fibrosis and atrial fibrillation are not completely understood. A large number of experimental and clinical studies have shed light on the mechanisms of atrial fibrosis at the molecular and cellular level, including interactions between matrix metalloproteinases and their endogenous tissue inhibitors, and profibrotic signals through specific molecules and mediators such as angiotensin II, transforming growth factor-beta1, connective tissue growth factor, and platelet-derived growth factor. This review focuses on the mechanisms of atrial fibrosis and highlights the relationship between atrial fibrosis and atrial fibrillation. PMID- 22237584 TI - Do patients with electrocardiographic Brugada type 1 pattern have associated right bundle branch block? A comparative vectorcardiographic study. AB - AIMS: Previous studies have reported right bundle branch block in Brugada syndrome. Subsequent analysis of electrocardiograms (ECGs) found one-third of cases classified as right bundle branch block did not meet criteria of a wide final S wave in the left leads. We aimed to study the role of the vectorcardiogram to characterize Brugada type 1 ECG pattern. METHODS AND RESULTS: Compare Frank-method vectorcardiogram in 11 patients with Brugada type 1 ECG pattern (BrS group) with vectorcardiogram of 20 healthy individuals with ECGs depicting incomplete right bundle branch block (IRBBB group) and 12 patients with complete right bundle branch block (CRBBB group). Initial 10-20 ms vector of the QRS loop in the horizontal plane (HP): BrS and IRBBB groups: Vector heading anterior and leftward. CRBBB group: Vector directed anterior and rightward. Right end conduction delay of the QRS loop: BrS group: Upper right quadrant of the frontal plane, right posterior quadrant of the HP. IRBBB group: Upper right quadrant of the frontal plane (30%) and right anterior quadrant of the HP (90%). CRBBB group: Upper right quadrant on the frontal plane (30%); all cases in the right anterior quadrant of the HP. 0 point (onset of QRS loop) and J point (end of QRS loop) relationship: BrS group: Not coincidental. IRBBB and CRBBB groups: Coincidental. T loop morphology, size, and appearance: BrS group: Circular, with symmetrical afferent and efferent limbs in 10 cases (90%). IRBBB and CRBBB groups: Elliptical or linear with slow inscription of efferent limb and rapid inscription of afferent limb. CONCLUSIONS: Vectorcardiograms in patients with Brugada type 1 ECG pattern have distinctive characteristics compared with healthy individuals with incomplete and CRBBB. These differences relate to the spatial location of the end conduction delay (right superior and posterior quadrant in the BrS group) and the morphology, size, and velocity of inscription of afferent and efferent limbs of the T loop (circular, small, of symmetrical limbs) and with a 1:1 length/width ratio. PMID- 22237585 TI - Safe magnetic resonance image scanning of the pacemaker patient: current technologies and future directions. AB - Magnetic resonance imaging (MRI) is the imaging modality of choice in many clinical situations, and its use is likely to grow due to expanding indications and an ageing population. Many patients with implantable devices are denied MRI except in cases of urgent need, and when scans must be performed they are complicated by the need for burdensome and costly personnel and monitoring requirements that have the net effect of restricting access to scans. Several small studies, enrolling a total of 344 patients, suggest that some patients with conventional systems may undergo MR examinations without clinically overt adverse events. However, a number of potential interactions exist between implantable cardiac devices and the static and gradient magnetic fields and modulated radio frequency (RF) fields generated during MR scans; nearly all studies have reported pacing capture threshold changes, troponin elevations, ectopy, unpredictable reed switch behaviour, and other 'subclinical' issues with pacemakers and implantable cardioverter-defibrillators (ICDs) in patients who have undergone MRI. Attention has turned to devices that are specifically designed to be safe in the MRI environment. A clinical study of one such device documented its ability to be exposed to MRI in a 1.5 T scanner without adverse impact on patient outcomes or pacemaker system function. Such new technologies may enable scanning of pacemaker and ICD patients with reduced concerns regarding the short- and long-term effects of MRI. As importantly, these devices may increase the number of centres that are able to safely perform MRI and, thus, expand access to scans for patients with these devices. PMID- 22237586 TI - Role of inflammation in early atrial fibrillation recurrence. AB - AIMS: Outcome of rhythm control in atrial fibrillation (AF) is still poor due to various mechanisms involved in the initiation and perpetuation of AF. Differences in timing of AF recurrence may depend on different types of mechanisms. The aim of this study was to assess the mechanisms involved in early AF recurrence in patients with short-lasting AF. METHODS AND RESULTS: Patients with short-lasting persistent AF undergoing rhythm control (n= 100) were included. Markers of mechanisms involved in the initiation and perpetuation of AF were assessed, including clinical factors, echocardiographic parameters, and biomarkers. Primary endpoint was early AF recurrence (recurrence <1 month). Secondary endpoint was progression to permanent AF. Median total AF history was short: 4.2 months. Early AF recurrences occurred in 30 patients (30%) after a median of 6 (inter-quartile range 2-14) days. Baseline log(2) interleukin (IL)-6 [adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI) 1.0-1.7, P= 0.02] and present or previous smoking (adjusted HR 3.6, 95% CI 1.2-10.9, P= 0.03) were independently associated with early AF recurrence, suggesting that inflammation played an important role in early recurrences. Atrial fibrillation became permanent in 29 patients (29%). Baseline transforming growth factor-beta1, left ventricular ejection fraction, and early AF recurrence were independently associated with progression to permanent AF. CONCLUSION: In patients with short-lasting AF, early AF recurrence seemed to be associated with inflammation as represented by IL-6. Treatment aimed against inflammation may therefore prevent early AF recurrences, which can improve rhythm control outcome. PMID- 22237587 TI - Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis. AB - Matrix metalloproteinase 9 (MMP9) gene has been shown to be involved in the pathogenesis of allergic rhinitis (AR) and asthma. Previous studies suggested that single-nucleotide polymorphisms (SNPs) of the MMP9 gene conferred a risk for childhood asthma. However, whether the SNPs confer a risk for AR has not been previously investigated. The objective of this study was to investigate whether SNPs of the MMP9 gene are associated with risk of seasonal AR (pollinosis), perennial AR and allergen sensitization. A total of 670 school children were recruited in Japan and genotyped for functional polymorphism in the promoter ( 1590C/T: rs3918242) and three amino-acid substitutions (R297Q: rs17576; P574R: rs2250889; R668Q: rs17577). Serum levels of total and specific IgE were determined. Disease status and other clinical characteristics of the subjects were investigated using a questionnaire. Associations between the MMP9 SNPs and both AR and serum IgE levels were evaluated. -1590C/T showed significant association with cedar pollinosis (corrected P (Pcor)=0.039). R668Q was in strong linkage disequilibrium (LD) with -1590C/T and showed significant association with cedar pollinosis (Pcor=0.023) and serum cedar pollen-specific IgE level (Pcor=0.022). A haplotype associated with -1590T and 668Q showed a significant association with cedar pollinosis, orchard grass pollinosis and cedar pollen specific IgE (Pcor=0.0012, Pcor=0.0059 and Pcor=0.0041, respectively). R297Q and P574R were in weak LD with the rest of the SNPs and did not show significant association with disease. Compared with wild-type MMP9 protein (279R-574P-668R), a variant enzyme (279R-574P-668Q) that showed association with pollinosis had lower activity. However, lower enzyme activity was not associated with disease risk because another variant (279Q-574R-668R) showed lower enzyme activity but was not associated with pollinosis. The -1590T allele and its corresponding haplotype was associated with higher promoter activity and with pollen-specific IgE levels and pollinosis, suggesting that -1590C/T may have more impact on sensitization and disease development than R668Q. Our results suggest that the MMP9 gene confers susceptibility to cedar pollinosis in Japanese children. The MMP9 gene may be associated with pollinosis through sensitization processes. PMID- 22237588 TI - Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell. AB - Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders. PMID- 22237589 TI - Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations. AB - The enzyme 6-pyruvoyl-tetrahydropterin synthase (PTPS, gene symbol: PTS) is involved in the second step of the de novo biosynthesis of tetrahydrobiopterin (BH4), which is a vital cofactor of nitric oxide synthases and three types of aromatic amino acid hydroxylases; the latter are important enzymes in the production of neurotransmitters. We conducted a study of PTS mutations in East Asia, including Taiwan, Mainland China, Japan, South Korea, the Philippines, Thailand and Malaysia. A total of 43 mutations were identified, comprising 22 previously reported mutations and 21 new discovered mutations. Among these, the c.155A>G, c.259C>T, c. 272A>G, c.286G>A and c.84-291A>G mutations were the most common PTS mutations in East Asia, while the c.58T>C and c.243G>A mutations were, respectively, specific to Filipinos and Japanese originating from Okinawa. Further studies demonstrated that each of the mutations listed above was in linkage disequilibrium to a specific allele of polymorphic microsatellite marker, D11S1347. These results suggest the presence of founder effects that have affected these frequent mutations in East Asia populations. In this context, D11S1347 should become one of the most reliable polymorphic markers for use in prenatal diagnosis among PTPS deficient families, especially where mutations are yet to be identified. PMID- 22237590 TI - Non-hypoxic stabilization of HIF-Ialpha during coordinated interaction between Akt and angiopoietin-1 enhances endothelial commitment of bone marrow stem cells. AB - We previously reported that mesenchymal stem cells (MSC) co-expressing Akt and angiopoietin-1 (Ang-1) preserved infarcted heart function via angiomyogenesis. The present study determined the mechanism of co-overexpression of Akt and Ang-1 in promoting endothelial commitment of MSC. The cells were transduced with vectors encoding for Akt ((Akt)MSC), Ang-1 ((Ang-1)MSC), and both Akt and Ang-1 ((AA)MSC) using Empty vector transduced MSC ((Emp)MSC) as control. Molecular studies indicated a coordinated interaction between Akt and Ang-1 in (AA)MSC and led to non-hypoxic stabilization of hypoxia inducible factor-1alpha (HIF-Ialpha) which accentuated under 4-h anoxia. We also observed HIF-Ialpha dependent induction of hemeoxygenase-1, endothelial specific markers and VEGF in (AA)MSC. Vascular commitment of (AA)MSC was confirmed by immunostaining, Western blotting and flow cytometry for endothelial specific early and late markers including Flt1, Flk1, Tie2, VCAM-1, and von Willebrand Factor-VIII (vWF-VIII) in HIF-Ialpha dependent fashion besides exhibiting higher emigrational activity and angiogenesis in vitro. (AA)MSC transplanted into rat model of myocardial infarction showed higher Flk1 and Flt1 positivity and also promoted intrinsic Flk1(+) and Flt1(+) cell mobilization into the infarcted heart. Given the ease of availability of MSC and simplicity of approach to co-overexpress Ang-1 and Akt to enhance their endothelial commitment, the strategy will be significant for cellular angiogenesis to treat ischemic heart. PMID- 22237591 TI - Induction of heme oxygenase-1 shifts the balance from proinjury to prosurvival in the placentas of pregnant rats with reduced uterine perfusion pressure. AB - Placental hypoxia/ischemia has been implicated as a central factor in the development of preeclampsia. One particularly useful animal model to study the impact of placental ischemia is the reduced uterine perfusion pressure (RUPP) model. We have previously demonstrated that RUPP animals exhibit elevated placental oxidative stress, which plays an important role in the development of the associated maternal hypertension. Recently, we have demonstrated that cobalt protoporphyrin (CoPP)-mediated induction of heme oxygenase-1 (HO-1) attenuates RUPP-induced oxidative stress and consequent hypertension. However, signaling pathways that are involved in this process are virtually unknown. Here, we show that placentas from RUPP animals exhibit increased phosphorylation of JNK, STAT1, STAT3, and p52shc with a concomitant increase in caspase-3 activation and depletion of intracellular ATP. Treatment with CoPP decreased RUPP-induced phosphorylation of JNK and STAT1, while it increased phosphorylation of ERK and STAT3, leading to decreased caspase-3 activation and restoration of intracellular ATP content. Our data imply that RUPP induces oxidative stress and the consequent injurious state by increasing phosphorylation of mediators of injury (STAT1, JNK) and, to a lesser extent, survival (STAT3, p52shc) in placentas of pregnant rats. HO-1 induction shifts this balance to a prosurvival phenotype by augmenting phosphorylation of the prosurvival ERK and STAT3, while suppressing phosphorylation of JNK and STAT1. This attenuates the resulting injury, as indicated by caspase-3 activation and ATP depletion. These results demonstrate a novel therapeutic activity of HO-1 induction in placental cell survival during ischemia and support the HO-1 pathway as a promising therapeutic target for the management of preeclampsia. PMID- 22237592 TI - Architecture of kangaroo rat inner medulla: segmentation of descending thin limb of Henle's loop. AB - We hypothesize that the inner medulla of the kangaroo rat Dipodomys merriami, a desert rodent that concentrates its urine to more than 6,000 mosmol/kgH(2)O water, provides unique examples of architectural features necessary for production of highly concentrated urine. To investigate this architecture, inner medullary nephron segments in the initial 3,000 MUm below the outer medulla were assessed with digital reconstructions from physical tissue sections. Descending thin limbs of Henle (DTLs), ascending thin limbs of Henle (ATLs), and collecting ducts (CDs) were identified by immunofluorescence using antibodies that label segment-specific proteins associated with transepithelial water flux (aquaporin 1 and 2, AQP1 and AQP2) and chloride flux (the chloride channel ClC-K1); all tubules and vessels were labeled with wheat germ agglutinin. In the outer 3,000 MUm of the inner medulla, AQP1-positive DTLs lie at the periphery of groups of CDs. ATLs lie inside and outside the groups of CDs. Immunohistochemistry and reconstructions of loops that form their bends in the outer 3,000 MUm of the inner medulla show that, relative to loop length, the AQP1-positive segment of the kangaroo rat is significantly longer than that of the Munich-Wistar rat. The length of ClC-K1 expression in the prebend region at the terminal end of the descending side of the loop in kangaroo rat is about 50% shorter than that of the Munich-Wistar rat. Tubular fluid of the kangaroo rat DTL may approach osmotic equilibrium with interstitial fluid by water reabsorption along a relatively longer tubule length, compared with Munich-Wistar rat. A relatively shorter length prebend segment may promote a steeper reabsorptive driving force at the loop bend. These structural features predict functionality that is potentially significant in the production of a high urine osmolality in the kangaroo rat. PMID- 22237594 TI - Editorial focus: Myoglobin-2, an adaptation for life at low oxygen pressure. Focus on: "Functional differentiation of myoglobin isoforms in the hypoxia tolerant carp". PMID- 22237593 TI - Hyperthermia induces injury to the intestinal mucosa in the mouse: evidence for an oxidative stress mechanism. AB - Loss of the intestinal barrier is critical to the clinical course of heat illness, but the underlying mechanisms are still poorly understood. We tested the hypothesis that conditions characteristic of mild heatstroke in mice are associated with injury to the epithelial lining of the intestinal tract and comprise a critical component of barrier dysfunction. Anesthetized mice were gavaged with 4 kDa FITC-dextran (FD-4) and exposed to increasing core temperatures, briefly reaching 42.4 degrees C, followed by 30 min recovery. Arterial samples were collected to measure FD-4 concentration in plasma (in vivo gastrointestinal permeability). The small intestines were then removed to measure histological evidence of injury. Hyperthermia resulted in a ~2.5-fold elevation in plasma FD-4 and was always associated with significant histological evidence of injury to the epithelial lining compared with matched controls, particularly in the duodenum. When isolated intestinal segments from control animals were exposed to >=41.5 degrees C, marked increases in permeability were observed within 60 min. These changes were associated with release of lactate dehydrogenase, evidence of protein oxidation via carbonyl formation and histological damage. Coincubation with N-acetylcysteine protected in vitro permeability during hyperthermia and reduced histological damage and protein oxidation. Chelation of intracellular Ca(2+) to block tight junction opening during 41.5 degrees C exposure failed to reduce the permeability of in vitro segments. The results demonstrate that hyperthermia exposure in mouse intestine, at temperatures at or below those necessary to induce mild heatstroke, cause rapid and substantial injury to the intestinal lining that may be attributed, in part, to oxidative stress. PMID- 22237596 TI - A rotating disk electrode study of the particle size effects of Pt for the hydrogen oxidation reaction. AB - By using a catalyst-lean thin-film RDE method, the fast kinetics of the hydrogen oxidation reaction (HOR) on highly dispersed Pt nanoparticle electrocatalysts can be determined, free from the interference of the mass transport of H(2) molecules in solution. Measurements with carbon-supported Pt nanoparticles of different sizes thus allow revealing the particle size effect of Pt for the HOR. It is shown that there is a "negative" particle size effect of Pt on the kinetics of HOR, i.e., the exchange current density j(0) decreases with the increased dispersion (i.e. decreased mean particle size). A maximum mass activity of Pt for the HOR is found at particle sizes of 3-3.5 nm. The observed particle size effect is interpreted in terms of the size dependent distribution of surface atoms on the facets and edges, which is implied by the voltammetric responses of Pt/C catalysts with differently sized Pt particles. The accompanied decrease in the HOR activity with the increase in the edge atom fraction suggests that the edge atoms on the surface of Pt nanoparticles are less active for the HOR than those on the facets. PMID- 22237597 TI - Comprehensive national analysis of emergency and essential surgical capacity in Rwanda. AB - BACKGROUND: Disparities in the global availability of operating theatres, essential surgical equipment and surgically trained providers are profound. Although efforts are ongoing to increase surgical care and training, little is known about the surgical capacity in developing countries. The aim of this study was to create a baseline for surgical development planning at a national level. METHODS: A locally adapted World Health Organization survey was conducted in November 2010 to assess emergency and essential surgical capacity and volumes, with on-site interviews at 44 district and referral hospitals in Rwanda. Results were compiled for education and capacity development discussions with the Rwandan Ministry of Health and the Rwanda Surgical Society. RESULTS: Among 10.1 million people, there were 44 hospitals and 124 operating rooms (1.2 operating rooms per 100,000 persons). There was a total of 50 surgeons practising full- or part-time in Rwanda (0.49 total surgeons per 100,000 persons). The majority of consultant surgeons worked in the capital (covering 10 per cent of the population). Anaesthesia was performed primarily by anaesthesia technicians, and six of 44 hospitals had no trained anaesthesia provider. Continuous availability of electricity, running water and generators was lacking in eight hospitals, and 19 reported an absence or shortage in the availability of pulse oximetry. Equipment for life-saving surgical airway procedures, particularly in children, was lacking. A dedicated emergency area was available in only 19 hospitals. In 2009 and 2010 over 80,000 surgical procedures (major and minor) were recorded annually in Rwanda. CONCLUSION: A comprehensive countrywide assessment of surgical capacity in resource-limited settings found severe shortages in available resources. Immediate local feedback is a useful tool for creating a baseline of surgical capacity to inform country-specific surgical development. PMID- 22237598 TI - Different classes of input and output neurons reveal new features in microglomeruli of the adult Drosophila mushroom body calyx. AB - To investigate how sensory information is processed, transformed, and stored within an olfactory system, we examined the anatomy of the input region, the calyx, of the mushroom bodies of Drosophila melanogaster. These paired structures are important for various behaviors, including olfactory learning and memory. Cells in the input neuropil, the calyx, are organized into an array of microglomeruli each comprising the large synaptic bouton of a projection neuron (PN) from the antennal lobe surrounded by tiny postsynaptic neurites from intrinsic Kenyon cells. Extrinsic neurons of the mushroom body also contribute to the organization of microglomeruli. We employed a combination of genetic reporters to identify single cells in the Drosophila calyx by light microscopy and compared these with cell shapes, synapses, and circuits derived from serial section electron microscopy. We identified three morphological types of PN boutons, unilobed, clustered, and elongated; defined three ultrastructural types, with clear- or dense-core vesicles and those with a dark cytoplasm having both; reconstructed diverse dendritic specializations of Kenyon cells; and identified Kenyon cell presynaptic sites upon extrinsic neurons. We also report new features of calyx synaptic organization, in particular extensive serial synapses that link calycal extrinsic neurons into a local network, and the numerical proportions of synaptic contacts between calycal neurons. All PN bouton types had more ribbon than nonribbon synapses, dark boutons particularly so, and ribbon synapses were larger and with more postsynaptic elements (2-14) than nonribbon (1-10). The numbers of elements were in direct proportion to presynaptic membrane area. Extrinsic neurons exclusively had ribbon synapses. PMID- 22237599 TI - Characteristic magnetic resonance features of focal autoimmune pancreatitis useful for differentiation from pancreatic cancer. AB - PURPOSE: To identify characteristic magnetic resonance (MR) features of focal autoimmune pancreatitis (f-AIP) useful for differentiation from pancreatic cancer (PC). METHODS: We retrospectively analyzed MR imaging findings of 20 f-AIP lesions and 40 PC lesions smaller than 40 mm in diameter. On fat-suppressed T2 weighted images and dynamic contrast-enhanced fat-suppressed T1-weighted images (DCE-T1WI), we classified MR features of internal signal intensity for each lesion into homogeneous, speckled, or target type. We assessed the sensitivity, specificity, and accuracy of these findings in the diagnosis of f-AIP. We also investigated the incidence of previously reported findings for differentiation between f-AIP and PC. RESULTS: Speckled enhancement within a hypointense or isointense lesion on pancreatic phase DCE-T1WI (speckled type) was observed more frequently in f-AIP than in PC, with high sensitivity, high specificity, and high accuracy. Hypointensity to hyperintensity surrounding a less enhanced focal area on DCE-T1WIs (target type) and upper stream main pancreatic duct dilatation were observed more frequently in PC than in f-AIP. CONCLUSION: Speckled enhancement inside an f-AIP lesion on pancreatic phase DCE-T1WI was useful for differentiation from PC. PMID- 22237600 TI - Measurement of paraben concentrations in human breast tissue at serial locations across the breast from axilla to sternum. AB - The concentrations of five esters of p-hydroxybenzoic acid (parabens) were measured using HPLC-MS/MS at four serial locations across the human breast from axilla to sternum using human breast tissue collected from 40 mastectomies for primary breast cancer in England between 2005 and 2008. One or more paraben esters were quantifiable in 158/160 (99%) of the tissue samples and in 96/160 (60%) all five esters were measured. Variation was notable with respect to individual paraben esters, location within one breast and similar locations in different breasts. Overall median values in nanograms per gram tissue for the 160 tissue samples were highest for n-propylparaben [16.8 (range 0-2052.7)] and methylparaben [16.6 (range 0-5102.9)]; levels were lower for n-butylparaben [5.8 (range 0-95.4)], ethylparaben [3.4 (range 0-499.7)] and isobutylparaben 2.1 (range 0-802.9). The overall median value for total paraben was 85.5 ng g(-1) tissue (range 0-5134.5). The source of the paraben cannot be identified, but paraben was measured in the 7/40 patients who reported never having used underarm cosmetics in their lifetime. No correlations were found between paraben concentrations and age of patient (37-91 years), length of breast feeding (0-23 months), tumour location or tumour oestrogen receptor content. In view of the disproportionate incidence of breast cancer in the upper outer quadrant, paraben concentrations were compared across the four regions of the breast: n propylparaben was found at significantly higher levels in the axilla than mid (P = 0.004 Wilcoxon matched pairs) or medial (P = 0.021 Wilcoxon matched pairs) regions (P = 0.010 Friedman ANOVA). PMID- 22237601 TI - The effects of DBS patterns on basal ganglia activity and thalamic relay : a computational study. AB - Thalamic neurons receive inputs from cortex and their responses are modulated by the basal ganglia (BG). This modulation is necessary to properly relay cortical inputs back to cortex and downstream to the brain stem when movements are planned. In Parkinson's disease (PD), the BG input to thalamus becomes pathological and relay of motor-related cortical inputs is compromised, thereby impairing movements. However, high frequency (HF) deep brain stimulation (DBS) may be used to restore relay reliability, thereby restoring movements in PD patients. Although therapeutic, HF stimulation consumes significant power forcing surgical battery replacements, and may cause adverse side effects. Here, we used a biophysical-based model of the BG-Thalamus motor loop in both healthy and PD conditions to assess whether low frequency stimulation can suppress pathological activity in PD and enable the thalamus to reliably relay movement-related cortical inputs. We administered periodic pulse train DBS waveforms to the sub thalamic nucleus (STN) with frequencies ranging from 0-140 Hz, and computed statistics that quantified pathological bursting, oscillations, and synchronization in the BG as well as thalamic relay of cortical inputs. We found that none of the frequencies suppressed all pathological activity in BG, though the HF waveforms recovered thalamic reliability. Our rigorous study, however, led us to a novel DBS strategy involving low frequency multi-input phase-shifted DBS, which successfully suppressed pathological symptoms in all BG nuclei and enabled reliable thalamic relay. The neural restoration remained robust to changes in the model parameters characterizing early to late PD stages. PMID- 22237602 TI - Towards the realization of label-free biosensors through impedance spectroscopy integrated with IDES technology. AB - Impedance spectroscopy (IS) is a powerful technique for analysis of the complex electrical impedance of a large variety of biological systems, because it is sensitive both to surface phenomena and to changes of bulk properties. A simple and convenient method of analysis of cell properties by IS is described. An interdigitated electrodes configuration was used for the measurements; human epithelial cells were grown on the device to investigate the complex dielectric response as a function of frequency, in order to test the suitability of the device for use as a label-free biosensor. To test the ability of the device to detect channels in the cell membrane, the effect of drugs known to affect membrane integrity was also investigated. The frequency response of the admittance (i.e. the reciprocal of the impedance) can be well fitted by a model based on very simple assumptions about the cells coating the device surface and the current flow; from the calculations, membrane-specific capacitance and information about cell adhesion can be inferred. These preliminary efforts have shown that our configuration could lead to a label-free non-invasive technique for biosensing and cellular behavior monitoring which might prove useful in investigation of the basic properties of cells and the effect of drugs by estimation of some fundamental properties and modification of the electrical characteristics of the device. PMID- 22237604 TI - [Magic, chemistry and psychiatry]. PMID- 22237605 TI - [The journal in 2011]. PMID- 22237603 TI - Impairment of the biomechanical compliance of P pili: a novel means of inhibiting uropathogenic bacterial infections? AB - Gram-negative bacteria often initiate their colonization by use of extended attachment organelles, so called pili. When exposed to force, the rod of helix like pili has been found to be highly extendable, mainly attributed to uncoiling and recoiling of its quaternary structure. This provides the bacteria with the ability to redistribute an external force among a multitude of pili, which enables them to withstand strong rinsing flows, which, in turn, facilitates adherence and colonization processes critical to virulence. Thus, pili fibers are possible targets for novel antibacterial agents. By use of a substance that compromises compliance of the pili, the ability of bacteria to redistribute external forces can be impaired, so they will no longer be able to resist strong urine flow and thus be removed from the host. It is possible such a substance can serve as an alternative to existing antibiotics in the future or be a part of a multi-drug. In this work we investigated whether it is possible to achieve this by targeting the recoiling process. The test substance was purified PapD. The effect of PapD on the compliance of P pili was assessed at the single organelle level by use of force-measuring optical tweezers. We showed that the recoiling process, and thus the biomechanical compliance, in particular the recoiling process, can be impaired by the presence of PapD. This leads to a new concept in the search for novel drug candidates combating uropathogenic bacterial infections -"coilicides", targeting the subunits of which the pilus rod is composed. PMID- 22237606 TI - [Is there adequate discussion between psychiatrists and their patients regarding patients' sexual problems?]. AB - BACKGROUND: Sexual problems arise frequently among psychiatric patients, either as a symptom of psychiatric disorders or as a side effect of psychotropic medication. However, it is questionable whether in daily practice psychiatrists and trainee psychiatrists give enough attention to patients' sexual problems. GOAL: To investigate how much attention psychiatrists and trainees give to patients' sexual problems and to discover what factors influence the amount of attention they give. METHODS: All psychiatrists and trainees working at two academic psychiatric centres and three mental health institutes in the province of North Holland were asked to complete an online questionnaire about the discussion of sexual problems. RESULTS: 164 psychiatrists and trainee psychiatrists completed the questionnaire (response rate 44%). About 50% of the respondents stated that they spent less than five minutes per week discussing sexual problems with their patients. When prescribing antidepressants and antipsychotics, psychiatrists and trainees often failed to inform patients about sexual side effects (33% in the case of antidepressants and 50% for antipsychotics). CONCLUSIONS: The investigation reveals that psychiatrists and trainees give little attention to sexuality problems of patients. The main reason for this seems to be feelings of shame and incompetence. Lack of time was not identified as a significant factor. We believe that the situation will improve considerably if psychiatrists and trainees involved in training programmes and supervisory activities give more attention to sexual problems. PMID- 22237607 TI - [Design of the general population study NEMESIS-2: Netherlands Mental Health Survey and Incidence Study-2]. AB - BACKGROUND: The longitudinal epidemiological population study NEMESIS-2 (Netherlands Mental Health Survey and Incidence Study-2) replicates the first study conducted from 1996 to 1999, and expands it by adding new subjects such as impulse-control disorders. AIM: To describe the aims and design of nemesis-2, particularly of its first round of measurements, to provide up-to-date figures on prevalence, incidence, course and consequences of mental disorders and associated factors, and to study trends in the mental health of the population aged 18-64 years and the use these people make of psychiatric services. METHOD: Face-to-face interviews were conducted (November 2007-July 2009) by means of the Composite International Diagnostic Interview 3.0. RESULTS: The response was 65.1% (n = 6646). Respondents were reasonably representative for the population, but young persons were somewhat underrepresented. Two follow-up rounds of measurements are planned with three year intervals between the rounds. The second round of measurements began in November 2010. CONCLUSION: A qualitatively good dataset was built up. This will allow several mental health topics to be studied in the future. PMID- 22237608 TI - [Prevalence of mental disorders, and trends from 1996 to 2009. Results from NEMESIS-2]. AB - BACKGROUND: Little is known about the prevalence and trends of mental disorders in the Dutch population. AIM: To present the prevalences of lifetime and 12-month DSM-IV mood disorders, anxiety disorders, and substance use disorders and impulse control disorders reported in NEMESIS-2 (Netherlands Mental Health Survey and Incidence Study), and to compare the 12-month prevalence of mood disorders, anxiety disorders and substance use disorders with estimates from the first study (NEMESIS-1). METHOD: Between November 2007 and July 2009, face-to-face interviews were conducted among 6646 subjects aged 18-64 by means of the Composite International Diagnostic Interview 3.0. Trends in mental disorders were examined with these data and NEMESIS-1 data from 1996 (n = 7076). RESULTS: The lifetime prevalence in NEMESIS-2 was 20.2% for mood disorder, 19.6% for anxiety disorder, 19.1% for substance use disorder and 9.2% for impulse-control or behaviour disorder. For the 12-month disorders, the prevalences were 6.1%, 10.1%, 5.6% and 2.1%, respectively. Between 1996 and 2007-2009, there was no change in the 12 month prevalence of anxiety disorder and substance use disorder. The 12-month prevalence of mood disorder decreased slightly but was no longer significant after differences in the sociodemographic variables between the two studies had been taken into account. CONCLUSION: This study shows that in the Netherlands mental disorders occur fairly frequently. Over about a decade, no clear change was found in the mental health status of the population. PMID- 22237609 TI - [The decision-making process in obsessive compulsive disorder]. AB - BACKGROUND: The extremely intrusive and repetitive nature of the symptoms of patients with obsessive-compulsive disorder (OCD) is suggestive of abnormalities in the decision-making process. This could explain why such patients realise how exaggerated and unreasonable their symptoms are, but time after time they become entrapped by them. AIM: To review the available research results relating to the underlying mechanisms of decision making and to link these to the characteristics of OCD. METHOD: We studied the literature on the decision-making process in OCD with the help of PubMed. RESULTS: There is a correlation between abnormalities in the decision-making process and dysfunction in the prefrontal cortex, more specifically in the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC). The activity in these areas in the course of functional imaging is different in OCD patients and in healthy persons. Evaluation of abnormal decision making in OCD patients performed with the help of the Iowa Gambling Task (IGT) is a possible predictor of the prognosis for pharmacological treatment. CONCLUSION: The concept of 'OCD as an abnormality in the decision-making process' generates new hypotheses concerning the etiology and pathophysiology of OCD. Abnormal decision-making may be an endophenotype, which could have important implications for treatment. PMID- 22237610 TI - [Disulfiram as a treatment for cocaine dependency]. AB - BACKGROUND: Cocaine abuse and dependency have a considerable impact on society and health issues. Current treatment of cocaine dependency consists primarily of psychosocial and therapeutic interventions. There is a marked need for effective pharmacological treatments in addition to the currently available treatment options. Recently, there is some evidence that disulfiram (DSF) might reduce use of cocaine in patients presenting with cocaine dependency. AIM: To explore the efficacy of disulfiram as a treatment for cocaine dependency. METHOD: We performed a Medline search for randomised controlled trials (RCTs) relating to disulfiram as a treatment for cocaine dependency. RESULTS: We found six RCT's for this review. Disulfiram seemed to have a positive effect on the primary cocaine outcomes. In addition, a positive effect of disulfiram seemed to be independent of alcohol abuse. However, the quality of these studies was extremely variable both in terms of sample size and composition. A possible neurobiological explanation for this would be an inhibitory effect of disulfiram on dopamine beta hydroxylase, thus generating lower levels of norepinefrine. CONCLUSION: Disulfiram seems to be a valuable drug for the treatment of cocaine dependency. Due to the limited number and quality of the published studies, further research is needed in order to support the early positive results. PMID- 22237611 TI - [Frailty; a fragile concept]. AB - BACKGROUND: Frailty can be regarded as a condition in which the reserve capacity of various physical systems has sunk to a critical low, at which point minor disturbances can develop into serious health problems. AIM: To review the various operationalisations of the concept of frailty and describe the relationship between frailty and psychopathology. METHOD: We searched the literature up to October 2010 using PubMed, PsycINFO and CINAHL. RESULTS: We found 35 operationalisations of the concept of frailty; 4 single measurements as a proxy for frailty (e.g. muscle strength), 18 syndrome diagnoses which can be subdivided into single (n = 5) and multiple syndrome diagnoses (n = 13) and 13 dimensional operationalisations for which measurement instruments were used. Only 6 studies reported the relationship between frailty and psychopathology. The studies revealed an association between depression and psychopathology. An important finding was the association between depression and frailty, but the direction of the association is unknown. CONCLUSION: No consensus has been reached regarding the operationalisation of the concept of frailty. For the purpose of gerontopsychiatric research we recommend the inclusion of a syndrome diagnosis based on physical criteria (physical frailty) because this should make it possible to unravel the relationship between psychopathology and underlying ageing mechanisms. PMID- 22237612 TI - ['Frailty' in gerontopsychiatry: useful and multicoloured innovation source]. PMID- 22237613 TI - [Key points for the treatment of the elderly with bipolar disorder]. AB - BACKGROUND: There is a lack of research into the treatment of the elderly with bipolar disorder. The Dutch guidelines for the treatment of older persons with bipolar disorder are based primarily on research relating to younger adults. AIM: To define key points for the treatment of bipolar disorder in later life. METHOD: The working group on the elderly of the Dutch Foundation for Bipolar Disorder defined key points in several consensus meetings based on clinical experience and research literature. RESULTS: Recommendations were drawn up for the treatment of the elderly with bipolar disorder relating to somatic comorbidity, pharmacotherapy, cognitive dysfunctions and psychosocial support. CONCLUSIONS: In general the Dutch Guidelines for the treatment of Bipolar Disorder are applicable for the elderly, provided the key points are taken into consideration. PMID- 22237614 TI - [Psychotropic drugs dispensed on the island of Bonaire]. AB - BACKGROUND: Up till now little is known about psychiatric disorders in relation to the use of psychotropics drugs on the Dutch Antilles, with the exception of Curacao. AIM: To map the quantity and type of psychotropics prescribed for Bonairians in 2009. METHOD: We performed a retrospective data analysis of the antipsychotics dispensed by the pharmacies on Bonaire in 2009. Our analysis focused on the benzodiazepines and related compounds, antipsychotics, lithium, antidepressants and ADHD- and narcolepsy-medication. With regard to antipsychotics and antidepressants, we also investigated 'the age distribution of the persons to whom the psychotropics were dispensed'. In addition, we mapped the frequency with which the drugs were dispensed: once only, infrequently, regularly. RESULTS: At least one psychotropic drug was delivered to 18.37% of (N=2365) Bonairians in 2009. Benzodiazepines and related compounds in particular were the most commonly dispensed drugs. CONCLUSION: One in five Bonairians received at least one prescription for psychotropic drugs in 2009. PMID- 22237615 TI - [ADD psychosis: treatment with antipsychotics and methylphenidate?]. AB - Two patients with a psychotic disorder who also met the diagnostic criteria for attention deficit hyperactivity disorder ADHD were treated with antipsychotics and methylphenidate. The first patient remained stable for many years with this combination treatment, whereas the second became psychotic several months after he had increased the dose of methylphenidate and had started to use cocaine. In the light of these two case studies, we have reviewed the literature on ADD psychosis, and we formulate recommendations regarding the specialised treatment needed for this uncommon disorder. PMID- 22237616 TI - [Reaction on 'Getting better at home, not in the hospital']. PMID- 22237617 TI - [Reaction on 'Getting better at home, not in the hospital']. PMID- 22237618 TI - [Reaction on 'Contact with the child and adolescent psychiatric services is determined by cultural and socio-economic differences']. PMID- 22237619 TI - [Reaction on 'Rapid tranquillisation; review of the literature and recommendations']. PMID- 22237623 TI - Twenty-third annual Pezcoller Symposium: engineering influences in cancer research. AB - The cross-disciplinary focus of the meeting highlighted recent progress in physical and genetic analysis and engineering of cancer disease models. As the central theme, mechanical forces affecting cell signaling, growth, differentiation, and metastasis were discussed with emphasis on the tumor microenvironment and cellular immunity, taking into account novel nanotechnology, biosensing, and intravital microscopy tools to monitor animal cancer models and human cancer. Emerging themes were the role of extracellular matrix imposing mechanical mechanisms on tumor cell function, including microenvironmental cues controlling the movement of tumor and immune cells, advanced genetic animal models for cancer that better recapitulate human disease, and preclinical and clinical molecular imaging of tumor architecture and stiffness, as well as novel nanotechnologies for anticancer drug delivery. PMID- 22237624 TI - Kaposi sarcoma herpesvirus promotes endothelial-to-mesenchymal transition through Notch-dependent signaling. AB - Endothelial-to-mesenchymal transition (EndMT) is now widely considered a pivotal contributor to cancer progression. In this study, we show that the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a sufficient cause of EndMT, potentially helping to explain the aggressiveness of KS that occurs commonly in AIDS patients. Upon KSHV infection, primary dermal microvascular endothelial cells lost expression of endothelial markers and acquired expression of mesenchymal markers, displaying new invasive and migratory properties along with increased survival. KSHV activated Notch-induced transcription factors Slug and ZEB1, and canonical Notch signaling was required for KSHV-induced EndMT. In contrast, KSHV did not utilize the TGFbeta signaling pathway, which has also been linked to EndMT. Within KS lesions, KSHV-infected spindle cells displayed features compatible with KSHV-induced EndMT including a complex phenotype of endothelial and mesenchymal properties, Notch activity, and nuclear ZEB1 expression. Our results show that KSHV engages the EndMT program to increase the invasiveness and survival of infected endothelial cells, traits that likely contribute to viral persistence and malignant progression. One important implication of our findings is that therapeutic approaches to disrupt the Notch pathway may offer novel approaches for KS treatment. PMID- 22237625 TI - Pocket proteins suppress head and neck cancer. AB - Head and neck squamous cell carcinomas (HNSCC) is a common cancer in humans long known to be caused by tobacco and alcohol use, but now an increasing percentage of HNSCC is recognized to be caused by the same human papillomaviruses (HPV) that cause cervical and other anogenital cancers. HPV-positive HNSCCs differ remarkably from HPV-negative HNSCCs in their clinical response and molecular properties. From studies in mice, we know that E7 is the dominant HPV oncoprotein in head and neck cancer. E7 is best known for its ability to inactivate pRb, the product of the retinoblastoma tumor susceptibility gene. However, loss of pRb function does not fully account for potency of E7 in causing head and neck cancer. In this study, we characterized the cancer susceptibility of mice deficient in the expression of pRb and either of two related "pocket" proteins, p107 and p130, that are also inactivated by E7. pRb/p107-deficient mice developed head and neck cancer as frequently as do HPV-16 E7 transgenic mice. The head and neck epithelia of the pRb/p107-deficient mice also displayed the same acute phenotypes and biomarker readouts as observed in the epithelia of E7 transgenic mice. Mice deficient for pRb and p130 in their head and neck epithelia showed intermediate acute and tumor phenotypes. We conclude that pRb and p107 act together to efficiently suppress head and neck cancer and are, therefore, highly relevant targets of HPV-16 E7 in its contribution to HPV-positive HNSCC. PMID- 22237626 TI - Exploiting the mutanome for tumor vaccination. AB - Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult. The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination. Here, we used next generation sequencing exome resequencing to identify 962 nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with 563 of those mutations in expressed genes. Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis. Aim1 and Trrap mutations known to be altered in human melanoma were included among those found. The immunogenicity and specificity of 50 validated mutations was determined by immunizing mice with long peptides encoding the mutated epitopes. One-third of these peptides were found to be immunogenic, with 60% in this group eliciting immune responses directed preferentially against the mutated sequence as compared with the wild-type sequence. In tumor transplant models, peptide immunization conferred in vivo tumor control in protective and therapeutic settings, thereby qualifying mutated epitopes that include single amino acid substitutions as effective vaccines. Together, our findings provide a comprehensive picture of the mutanome of B16F10 melanoma which is used widely in immunotherapy studies. In addition, they offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations. Lastly, they argue that the use of deep sequencing to systematically analyze immunogenicity mutations may pave the way for individualized immunotherapy of cancer patients. PMID- 22237627 TI - VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. AB - In metronomic chemotherapy, frequent drug administration at lower than maximally tolerated doses can improve activity while reducing the dose-limiting toxicity of conventional dosing schedules. Although the antitumor activity produced by metronomic chemotherapy is attributed widely to antiangiogenesis, the significance of this mechanism remains somewhat unclear. In this study, we show that a 6-day repeating metronomic schedule of cyclophosphamide administration activates a potent antitumor immune response associated with brain tumor recruitment of natural killer (NK) cells, macrophages, and dendritic cells that leads to marked tumor regression. Tumor regression was blocked in nonobese diabetic/severe combined immunodeficient (NOD/SCID-gamma) mice, which are deficient or dysfunctional in all these immune cell types. Furthermore, regression was blunted by NK cell depletion in immunocompetent syngeneic mice or in perforin-deficient mice, which are compromised for NK, NKT, and T-cell cytolytic functions. Unexpectedly, we found that VEGF receptor inhibitors blocked both innate immune cell recruitment and the associated tumor regression response. Cyclophosphamide administered at a maximum tolerated dose activated a transient, weak innate immune response, arguing that persistent drug-induced cytotoxic damage or associated cytokine and chemokine responses are required for effective innate immunity-based tumor regression. Together, our results reveal an innate immunity-based mechanism of tumor regression that can be activated by a traditional cytotoxic chemotherapy administered on a metronomic schedule. These findings suggest the need to carefully evaluate the clinical effects of combination chemotherapies that incorporate antiangiogenesis drugs targeting VEGF receptor. PMID- 22237628 TI - RNAi-mediated targeting of noncoding and coding sequences in DNA repair gene messages efficiently radiosensitizes human tumor cells. AB - Human tumor cell death during radiotherapy is caused mainly by ionizing radiation (IR)-induced DNA double-strand breaks (DSB), which are repaired by either homologous recombination repair (HRR) or nonhomologous end-joining (NHEJ). Although siRNA-mediated knockdown of DNA DSB repair genes can sensitize tumor cells to IR, this approach is limited by inefficiencies of gene silencing. In this study, we show that combining an artificial miRNA (amiR) engineered to target 3'-untranslated regions of XRCC2 (an HRR factor) or XRCC4 (an NHEJ factor) along with an siRNA to target the gene coding region can improve silencing efficiencies to achieve more robust radiosensitization than a single approach alone. Mechanistically, the combinatorial knockdown decreased targeted gene expression through both a reduction in mRNA stability and a blockade to mRNA translation. Together, our findings establish a general method of gene silencing that is more efficient and particularly suited for suppressing genes that are difficult to downregulate by amiR- or siRNA-based methods alone. PMID- 22237629 TI - Antigen-specific CD4(+) T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. AB - Myeloid-derived suppressor cells (MDSC) play a major role in cancer-related immune suppression, yet the nature of this suppression remains controversial. In this study, we evaluated the ability of MDSCs to elicit CD4(+) T-cell tolerance in different mouse tumor models. In contrast to CD8(+) T-cell tolerance, which could be induced by MDSCs in all the tumor models tested, CD4(+) T-cell tolerance could be elicited in only one of the models (MC38) in which a substantial level of MHC class II was expressed on MDSCs compared with control myeloid cells. Mechanistic investigations revealed that MDSCs deficient in MHC class II could induce tolerance to CD8(+) T cells but not to CD4(+) T cells. Unexpectedly, antigen-specific CD4(+) T cells (but not CD8(+) T cells) could dramatically enhance the immune suppressive activity of MDSCs by converting them into powerful nonspecific suppressor cells. This striking effect was mediated by direct cell cell contact through cross-linking of MHC class II on MDSCs. We also implicated an Ets-1 transcription factor-regulated increase in expression of Cox-2 and prostaglandin E2 in MDSCs in mediating this effect. Together, our findings suggest that activated CD4(+) T cells that are antigen specific may enhance the immune suppressive activity of MDSCs, a mechanism that might serve normally as a negative feedback loop to control immune responses that becomes dysregulated in cancer. PMID- 22237630 TI - pCEST: Positive contrast using Chemical Exchange Saturation Transfer. AB - Chemical Exchange Saturation Transfer (CEST) contrast utilizes selective pre saturation of a small pool of exchanging protons and subsequent detection of the decrease in bulk water signal. The CEST contrast is negative and requires detection of small signal change in the presence of a strong background signal. Here we develop a Positive CEST (pCEST) detection scheme utilizing the analogous nature of the CEST and off-resonance T(1)(rho) experiments and exploring increased apparent relaxation rates in the presence of the selective pre saturation. pCEST leads to the positive contrast, i.e., increased signal intensity as the result of the presence of the agent and RF pre-saturation. Simultaneously substantial background suppression is achieved. The contrast can be switched "ON" and "OFF", similar to the original CEST. PMID- 22237631 TI - Isolating chemical exchange saturation transfer contrast from magnetization transfer asymmetry under two-frequency rf irradiation. AB - Chemical exchange saturation transfer (CEST), arising from mobile groups, and magnetization transfer (MT) contrast arising from immobile protons, have enjoyed wide popularity recently in MRI applications. It is often difficult to separate genuine CEST signatures from MT effects, which are asymmetric with respect to the water resonance. A two-pool model for magnetization transfer (MT) is established based on Provotorov's theory of saturation, and then extended to the situation of simultaneous two-frequency rf irradiation. Numerical simulations and experimental results demonstrate that two-frequency rf irradiation can flatten out MT asymmetry when both frequency components lie within the spectrum of an MT pool. Based on this result, we propose a strategy to isolate chemical exchange saturation transfer (CEST) contrast from MT asymmetry contrast by using the two frequency rf irradiation technique. PMID- 22237632 TI - Different pattern of carotid and myocardial changes according to left ventricular geometry in hypertensive patients. AB - The relation between left ventricular (LV) hypertrophy and LV function is well known. However, less is known about the vascular changes influenced by LV geometry. We sought to investigate the relationship of LV geometry to carotid arterial and LV function. A total of 476 hypertensive patients were prospectively recruited. All subjects underwent echocardiography and carotid ultrasound. LV geometry is categorized into four groups according to relative wall thickness (RWT) and LV mass index (LVMI). Concentric LV geometry was associated with increased carotid intima-media thickness (IMT), beta-stiffness, and lower strain. All of the carotid parameters showed a stepwise change according to RWT of LV, whereas LV function was worse in hypertrophic geometry, as reflected by significantly lower systolic mitral annular velocity, higher left atrial volume index and E/E' ratio (P<0.001). By multivariate analysis after adjustment for clinical and laboratory parameters, IMT was independently associated with RWT, whereas myocardial function was independently associated with LVMI. Carotid arterial function and IMT showed worse values in concentric geometry, whereas LV systolic and diastolic function were worse in hypertrophic geometry, suggesting a discrepancy between carotid arterial and LV function in hypertensive patients. PMID- 22237633 TI - Inflammatory markers are associated with left ventricular hypertrophy and diastolic dysfunction in a population-based sample of elderly men and women. AB - Markers of inflammation have previously been related to left ventricular (LV) hypertrophy (LVH) in uremic and hypertensive patients. The present study investigated inflammatory markers in relation to LV geometry and diastolic function in a population of elderly persons. In the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (1016 men and women 70 years of age), echocardiograms to determine relative wall thickness (RWT), LV mass index (LVMI) and the E/A-ratio were obtained. Based on RWT and LVMI, four geometric subgroups were defined; normal, concentric remodeling, eccentric and concentric LVH. In all, 10 circulating inflammatory markers were measured. Higher levels of high sensitive C-reactive protein (hsCRP) and E-selectin were seen in the three abnormal geometry groups than in the normal group adjusting for gender, body mass index, systolic and diastolic blood pressure and use of antihypertensive medication. Higher level of inter-cellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1) and P-selectin were only seen in concentric LVH. Levels of tumor necrosis factor-alpha, interleukin-6, l selectin, monocyte chemotactic protein-1 and leukocyte count did not differ between the LV groups. l-selectin and hsCRP were related to the E/A-ratio. The adhesion molecules; E-selectin, ICAM-1, VCAM-1, P-selectin and hsCRP were elevated in elderly persons with abnormal LV geometry, especially in concentric LVH, after adjusting for hypertension and obesity. l-selectin and hsCRP were related to LV diastolic function. Further studies are motivated to investigate a pathogenetic role of inflammation for abnormal LV geometry and function. PMID- 22237634 TI - Chemical speciation studies on DU contaminated soils using flow field flow fractionation linked to inductively coupled plasma mass spectrometry (FlFFF-ICP MS). AB - Flow field flow fractionation (FlFFF) in combination with inductively coupled plasma mass spectrometry (ICP-MS) was used to study the chemical speciation of U and trace metals in depleted uranium (DU) contaminated soils. A chemical extraction procedure using sodium pyrophosphate, followed by isolation of humic and fulvic substances was applied to two dissimilar DU contaminated sample types (a sandy soil and a clay-rich soil), in addition to a control soil. The sodium pyrophosphate fractions of the firing range soils (Eskmeals and Kirkcudbright) were found to contain over 50% of the total U (measured after aqua regia digestion), compared to approximately 10% for the control soil. This implies that the soils from the contaminated sites contained a large proportion of the U within more easily mobile soil fractions. Humic and fulvic acid fractions each gave characteristic peak maxima for analytes of interest (Mn, Fe, Cu, Zn, Pb and U), with the fulvic acid fraction eluting at a smaller diameter (approximately 2.1 nm on average) than the humic fraction (approximately 2.4 nm on average). DU in the fulvic acid fraction gave a bimodal peak, not apparent for other trace elements investigated, including natural U. This implies that DU interacts with the fulvic acid fraction in a different way to all other elements studied. PMID- 22237635 TI - Unusual metallic foreign bodies in the larynx: two case reports. AB - Impaction of a foreign body (FB) in the larynx is a rare situation. It is more common in children then older age group. The authors report two cases of unusual foreign bodies in the larynx which presented with complaints of sudden onset of change of voice without any respiratory difficulty. One was of 9 y and other was a 7-y-old boy with foreign body in the glottis. In both cases there was accidental inhalation of the FB which was immediately followed by difficulty of speech. Metallic foreign bodies were removed successfully by direct laryngoscopy under general anesthesia (GA) which is followed by recovery of the symptoms. PMID- 22237636 TI - Idiopathic periscapular tumoral calcinosis mimicking and presenting as extraskeletal chondromatous tumor. AB - Tumoral calcinosis is a rare, benign condition of extra-osseous calcification. The term tumoral calcinosis has been liberally and imprecisely used to describe any massive collection of periarticular calcification.It is important to diagnose and differentiate it from other similar conditions causing extra-osseous calcification. The authors report here one such case having tumoral calcinosis around scapula mimicking as chondromatous tumor. PMID- 22237637 TI - Unilateral pulmonary hypoplasia with abdominal situs inversus. AB - A case of unilateral pulmonary hypoplasia in association with abdominal situs inversus (Situs Inversus Partialis) is described here in a 2-mo-old baby. The normally related heart (levocardia) is dextroposed due to the hypoplastic right lung and compensatory hyper-inflation of the opposite lung which clinically mimicked a mirror-image situs inversus totalis. Such a combination, to the best of authors' knowledge, has never been reported in the world literature. PMID- 22237638 TI - Hypothyroidism in children beyond 5 y of age: delayed diagnosis of congenital hypothyroidism. AB - OBJECTIVE: To determine the frequency of undiagnosed congenital hypothyroidism (CH) and its manifestations in hypothyroid children presenting beyond 5 y of age. METHODS: Retrospective analysis of records of children with hypothyroidism more than 5 y of age at presentation between October 1997 and April 2010. RESULTS: Three hundred twenty children were diagnosed with hypothyroidism. Ninety-four (29.3%) were >=5 y at presentation. Of these, CH was diagnosed in 34 (36.1%) and acquired hypothyroidism (AH) in 60 (63.9%). Symptoms of CH were noted at a mean age of 35.3+/-25.9 mo (range 12-132 mo) while the mean age at presentation was 86.6+/-35.3 mo (range 60-216 mo). The mean interval between onset of symptoms and diagnosis was nearly 51 mo. The mean duration of symptoms before diagnosis in children with AH was significantly shorter (8 mo, p<0.001). The main presenting complaints in children with CH and AH were growth delay (100%) and thyroid swelling (65%) respectively. Mean fT4 values in CH and AH at presentation were 0.23 and 0.34 ng/dL respectively (p=0.019). Children with CH had significantly higher TSH values (377.4 mIU/L) as compared to those with AH (151.4 mIU/L) (p=0.002) and had significantly delayed bone age (mean difference in chronological age and bone age 4.9 y in CH vs. 2.0 y in AH, p<0.01). Most common cause of CH in this group was thyroid dysgenesis (51.8%), followed by agenesis (25.9%) and dyshormonogenesis (22.2%). CONCLUSIONS: In absence of a universal screening program, diagnosis of CH, an important cause of preventable mental retardation is often delayed in India. PMID- 22237639 TI - Homochiral oligopeptides by chiral amplification: interpretation of experimental data with a copolymerization model. AB - We present a differential rate equation model of chiral polymerization based on a simple copolymerization scheme in which the enantiomers are added to, or removed from, the homochiral or heterochiral chains (reversible stepwise isodesmic growth or dissociation). The model is set up for closed systems and takes into account the corresponding thermodynamic constraints implied by the reversible monomer attachments, while obeying a constant mass constraint. In its simplest form, the model depends on a single variable rate constant, the maximum chain length N, and the initial concentrations. We have fit the model to the experimental data from the Rehovot group on lattice-controlled chiral amplification of oligopeptides. We find in all the chemical systems employed, except for one, that the model fits the measured relative abundances of the oligopeptides with higher degrees of correlation than from a purely random polymerization process. PMID- 22237640 TI - Context for WOC practice: evidence-based research. PMID- 22237642 TI - CAET feature section. PMID- 22237643 TI - Selecting instruments: reliability and validity considerations. PMID- 22237646 TI - Identifying and managing fecal incontinence. PMID- 22237647 TI - Curative treatment without surgical reconstruction after perineal debridement of Fournier's gangrene. AB - BACKGROUND: Fournier's gangrene (necrotizing fasciitis) is an acute life threatening disease of the perineal area that requires urgent medical intervention. Once the affected area is surgically debrided and the patient is stabilized, surgical management typically involves 1 or more additional procedures that may include split-thickness skin grafts, flaps, or an elective diverting urostomy and/or colostomy. The professional literature discussing nonsurgical approaches to healing for Fournier's gangrene after surgical debridement is sparse. CASE: We present 3 cases of male patients with Fournier's gangrene from our facility who healed uneventfully with negative pressure wound therapy placed after extensive debridement without further surgical intervention. An added benefit was a satisfactory aesthetic effect. CONCLUSION: Expert wound management including negative pressure wound therapy after surgical debridement of Fournier's gangrene eliminated the need for further operative procedures and prolonged hospitalizations in these cases. We believe that surgical teams should consider using negative pressure wound therapy as part of the initial curative plan of care after debridement, and that plans for restorative plastic surgery should be restricted to patients who do not exhibit adequate improvement with conservative wound management. PMID- 22237649 TI - [Epilepsy surgery]. AB - Epilepsy surgery is an important therapeutic option for patients with epilepsy since one third of all epilepsy patients will still not be become seizure free despite newly developed antiepileptic drugs. Anterior temporal lobe resection is the most common procedure. Extratemporal resections require more complex diagnostics and often invasive evaluation which is not the case in most temporal epilepsy patients due to improved imaging (MRI, PET, SPECT). Electrical stimulation of the anterior thalamus has been available as a treatment option since last year. PMID- 22237650 TI - [Differential diagnosis of epileptic seizures]. AB - The differential diagnoses of epileptic seizures depend on the different semiologies of the respective seizures. Patient history and history of witnesses are of foremost importance in the differentiation. When seizures recur, they are more easily distinguished than single seizures. Diagnostic methods like EEG and eventually EEG video monitoring will help in the differentiation when clinical information and patient history do not allow a clear diagnosis. We present the most common differential diagnoses and their differences compared to epileptic seizures. PMID- 22237652 TI - Recruiting patients into randomized clinical trials in surgery. PMID- 22237651 TI - Cell-to-cell variability in troponin I phosphorylation in a porcine model of pacing-induced heart failure. AB - We tested the hypothesis that myocardial contractile protein phosphorylation and the Ca(2+) sensitivity of force production are dysregulated in a porcine model of pacing-induced heart failure (HF). The level of protein kinase A (PKA)-dependent cardiac troponin I (TnI) phosphorylation was lower in the myocardium surrounding the pacing electrode (pacing site) of the failing left ventricle (LV) than in the controls. Immunohistochemical assays of the LV pacing site pointed to isolated clusters of cardiomyocytes exhibiting a reduced level of phosphorylated TnI. Flow cytometry on isolated and permeabilized cardiomyocytes revealed a significantly larger cell-to-cell variation in the level of TnI phosphorylation of the LV pacing site than in the opposite region in HF or in either region in the controls: the interquartile range (IQR) on the distribution histogram of relative TnI phosphorylation was wider at the pacing site (IQR = 0.53) than that at the remote site of HF (IQR = 0.42; P = 0.0047) or that of the free wall of the control animals (IQR = 0.36; P = 0.0093). Additionally, the Ca(2+) sensitivities of isometric force production were higher and appeared to be more variable in single permeabilized cardiomyocytes from the HF pacing site than in the healthy myocardium. In conclusion, the level of PKA-dependent TnI phosphorylation and the Ca(2+) sensitivity of force production exhibited a high cell-to-cell variability at the LV pacing site, possibly explaining the abnormalities of the regional myocardial contractile function in a porcine model of pacing-induced HF. PMID- 22237653 TI - Bayesian approach to predicting cancer incidence for an area without cancer registration by using cancer incidence data from nearby areas. AB - This paper compares three different methods for performing cancer incidence prediction in an area without a cancer registry under a Bayesian framework, using linear and log-linear age-period models with either age-specific slopes or a common slope across age groups. The three methods assume that a nearby area with a cancer registration has similar incidence and mortality patterns as the area of interest without a cancer registry where the cancer incidence prediction is carried out. The three methods differ in modeling strategies: (i) modeling the incidence rate directly; (ii) modeling the ratio of the number of incident cases to that of mortality cases; and (iii) modeling the difference between the incidence rate and the mortality rate. Strategy (iii) is a new approach in this type of projection. Empirical assessment is made using real data from the cancer registry of Tarragona, Spain, to predict cancer incidence in Girona, Spain, and vice versa. Predictions of short-term (3-4 years) incidence were made for 2001 in Tarragona using observed cancer incidence and mortality data for 1994-1998 from Girona. Short-term predictions were made for 2002 in Girona using Tarragona's 1994-1998 data. Additionally, long-term (10 years) incidence rate predictions were made for 2002 in Girona using data from Tarragona for the period 1985-1992. Our results suggest that extrapolating time-trends of incidence rates minus mortality rates may have the best predictive performance overall. These methods of population-level disease-incidence prediction are highly relevant to health care planning and policy decisions. PMID- 22237654 TI - A systematic review and meta-analysis of the utility of EUS for preoperative staging for gastric cancer. AB - BACKGROUND: Accurate preoperative staging is important in determining the appropriate treatment of gastric cancer. Recently, endoscopic ultrasound (EUS) has been introduced as a staging modality. However, reported test characteristics for EUS in gastric cancer vary. Our purpose in this study was to identify, synthesize, and evaluate findings from all articles on the performance of EUS in the preoperative staging of gastric cancer. METHODS: Electronic literature searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1 January 1998 to 1 December 2009. All search titles and abstracts were independently rated for relevance by a minimum of two reviewers. Meta-analysis for the performance of EUS was analyzed by calculating agreement (Kappa statistic), and pooled estimates of accuracy, sensitivity, and specificity for all EUS examinations, using histopathology as the reference standard. Subgroup analyses were also performed. RESULTS: Twenty-two articles met our inclusion criteria and were included in the review. EUS pooled accuracy for T staging was 75% with a moderate Kappa (0.52). EUS was most accurate for T3 disease, followed by T4, T1, and T2. EUS pooled accuracy for N staging was 64%, sensitivity was 74%, and specificity was 80%. There was significant heterogeneity between the included studies. Subgroup analyses found that annual EUS volume was not associated with EUS T and N staging accuracy (P = 0.836, 0.99, respectively). CONCLUSION: EUS is a moderately accurate technique that seems to describe advanced T stage (T3 and T4) better than N or less advanced T stage. Stratifying by EUS annual volume did not affect EUS performance in staging gastric cancer. PMID- 22237655 TI - Adenovirus-mediated expression of p33(ING1b) induces apoptosis and inhibits proliferation in gastric adenocarcinoma cells in vitro. AB - BACKGROUND: Inhibitor of growth 1b (ING1b) is considered to be a class II tumor suppressor gene. Although reduced expression of p33(ING1b) has been reported in many human malignancies, including gastric cancers, the effect of p33(ING1b) on gastric cancer cells has yet to be investigated. METHODS: Expression of p33(ING1b) in gastric adenocarcinoma tissues and their adjacent non-malignant gastric mucosa, as well as in gastric adenocarcinoma cell lines and normal gastric epithelial cells, was detected by using Western blotting. Recombinant adenoviruses were prepared to mediate the ectopic expression of p33(ING1b) (Ad ING1b) and green fluorescent protein (GFP)(Ad-GFP) in the gastric adenocarcinoma cell lines, SGC-7901, MKN28, and MKN45 and the normal gastric epithelial cell line GES-1. Alterations in the proliferation and apoptosis of the cells after adenoviral infection were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively, and cell cycle distribution was analyzed in a fluorescence-activated cell sorter. RESULTS: Western blotting confirmed the reduced expression of p33(ING1b) in gastric adenocarcinoma tissues and gastric adenocarcinoma cell lines. The ectopic expression of p33(ING1b) mediated by Ad-ING1b resulted in decreased growth, increased apoptosis, and cell cycle arrest at the G1 phase in both benign and malignant gastric epithelial cells regardless of their p53 status. Addition of a p53 inhibitor, pifithrin-alpha, did not abolish the pro-apoptotic and cell cycle arresting effects of p33(ING1b) in p53 wild-type cells. CONCLUSIONS: Down regulation of p33(ING1b) might play an important role in the development of gastric adenocarcinoma. Targeted local expression of p33(ING1b) may offer a promising alternative therapeutic measure for gastric cancer. PMID- 22237656 TI - A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach. AB - BACKGROUND: Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily. METHODS: Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C). RESULTS: In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (>=5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, >=75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2). CONCLUSIONS: The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers. PMID- 22237657 TI - Identification of gastric cancer risk markers that are informative in individuals with past H. pylori infection. AB - BACKGROUND: Epigenomic damage induced by Helicobacter pylori infection is accumulated in gastric mucosae before the development of malignancy. In individuals without current H. pylori infection, DNA methylation levels of specific CpG islands (CGIs) are associated with gastric cancer risk. Because risk estimation in individuals with past infection is clinically important, we here aimed to identify the risk markers that reflect epigenomic damage induced by H. pylori infection, and that are informative in these individuals. METHODS: Gastric mucosae were obtained from 55 gastric cancer patients (GC-Pt) (21 with current infection and 34 with past infection) and 55 healthy volunteers (HV) (7 never infected, 21 with current infection, and 27 with past infection). Hypermethylated CGIs were searched for by methylated DNA immunoprecipitation-CGI microarray, and methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction (PCR). RESULTS: By microarray analysis of a pool of three samples from GC-Pt with past infection and another pool of samples from HV with past infection, 15 hypermethylated CGIs in the former pool were isolated. Seven of them had significantly higher methylation levels in GC-Pt with past infection (n = 10) than in HV with past infection (n = 10) (P < 0.001). In a validation cohort (21 GC-Pt with past infection and 14 HV with past infection), the seven new markers had large areas under the receiver-operating characteristic curves (0.78 0.84) and high odds ratios (12.7-36.0) compared with two currently available markers (0.60-0.65, 5.0-5.7). CONCLUSIONS: We identified seven novel gastric cancer risk markers that are highly informative in individuals with past infection. PMID- 22237658 TI - Comparative analysis of the efficacy and safety of chemotherapy with oxaliplatin plus fluorouracil/leucovorin between elderly patients over 65 years and younger patients with advanced gastric cancer. AB - BACKGROUND: A chemotherapy regimen with oxaliplatin, fluorouracil, and leucovorin is commonly used to treat advanced gastric cancer (AGC). This study was designed to compare the efficacy and the safety of oxaliplatin plus fluorouracil/leucovorin administered biweekly (mFOLFOX6) between elderly patients aged over 65 years and younger counterparts with AGC. METHODS: This analysis included 82 AGC patients (>=65:31, <65:51). Patients with previously untreated chemo-naive advanced adenocarcinoma of the stomach received oxaliplatin 85 mg/m(2), 5-FU bolus 400 mg/m(2) on day 1 and 5-FU 1,500 mg/m(2), leucovorin 75 mg/m(2) 22 h infusion on days 1 and 2 every 2 weeks. The aim of the study was to compare efficacy and safety, including response rate (RR), progression-free survival (PFS), overall survival, and grade >=3 adverse events, between patients aged >=65 years and patients aged <65 years. RESULTS: Median progression-free survival (PFS) was not significantly different between both groups (>=65: 5.8 months, <65: 5.7 months, respectively, HR 0.77, 95% CI: 0.44-1.16, P = 0.18). Median overall survival was not significantly different between both groups (>=65: 10.3 months, <65: 9.5 months HR 0.83, 95% CI: 0.50-1.37, P = 0.46). The rate of grade 3 or 4 neutropenia did not differ with age group (>=65: 51.6%, <65: 43.1%); nor did the rates of neutropenic fever (>=65: 16.1%, <65: 5.9%), and infection without neutropenia (>=65: 3.2%, <65: 3.9%). Rates of grade >=3 toxicities such as thrombocytopenia, nausea/vomiting, or peripheral neuropathy were not significantly different between the two groups. CONCLUSIONS: mFOLFOX6 maintains its efficacy and safety in elderly patients aged over 65 years in comparison with AGC patients aged <65 years. Its judicious use should be considered regardless of age. PMID- 22237659 TI - Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study. AB - BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients. METHODS: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks). RESULTS: Thirty-four patients were enrolled, with an average age of 64 years (range 34 69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9 54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively. CONCLUSIONS: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU. PMID- 22237660 TI - Evidence of variant intra- and interspecific scaling of tree crown structure and relevance for allometric theory. AB - General scaling rules or constants for metabolic and structural plant allometry as assumed by the theory of Euclidian geometric scaling (2/3-scaling) or metabolic scaling (3/4-scaling) may meet human's innate propensity for simplicity and generality of pattern and processes in nature. However, numerous empirical works show that variability of crown structure rather than constancy is essential for a tree's success in coping with crowding. In order to link theory and empiricism, we analyzed the intra- and inter-specific scaling of crown structure for 52 tree species. The basis is data from 84 long-term plots of temperate monospecific forests under survey since 1870 and a set of 126 yield tables of angiosperm and gymnosperm forest tree species across the world. The study draws attention to (1) the intra-specific variation and correlation of the three scaling relationships: tree height versus trunk diameter, crown cross-sectional area versus trunk diameter, and tree volume versus trunk diameter, and their dependence on competition, (2) the inter-specific variation and correlation of the same scaling exponents ([Formula: see text] and [Formula: see text]) across 52 tree species, and (3) the relevance of the revealed variable scaling of crown structure for leaf organs and metabolic scaling. Our results arrive at suggesting a more extended metabolic theory of ecology which includes variability and covariation between allometric relationships as prerequisite for the individual plant's competitiveness. PMID- 22237662 TI - Observation of metal ion dependent packing structures and magnetic behaviors of metal-bis-1, 2-dithiolene complexes. AB - The crystal structures and magnetic properties were investigated experimentally and theoretically for two S = 1/2 spin chain complexes, which consist of [M(mnt)(2)](-) (M = Pt for 1 or Pd for 2) with 1-(4'-bromo-2'-flurobenzyl)-4 aminopyridinium (1-BrFBz-4-NH(2)Py(+)). The 1-BrFBz-4-NH(2)Py(+) cations exhibit different molecular conformations and arrangements in 1 and 2; the [M(mnt)(2)](-) anions form regular stacks in 1, whereas they form irregular stacks in 2. In addition, the intermolecular interactions between the [M(mnt)(2)](-) anions and cations are also different from each other in the crystals of 1 and 2. Complex 1 shows the magnetic characteristics of a low-dimensional antiferromagnetic coupling spin system with a spin-Peierls-type transition around 7 K, and complex 2 exhibits diamagnetism over the temperature range of 5-300 K. Theoretical analyses, based on the calculations for the charge density distributions of [Pt(mnt)(2)](-) and [Pd(mnt)(2)](-) anions and the magnetic exchange constants within the anion spin chains, addressed the diverse molecular alignments in the crystals of 1 and 2 and distinct magnetic behaviors between 1 and 2. PMID- 22237661 TI - Synaptic plasticity in the medial superior olive of hearing, deaf, and cochlear implanted cats. AB - The medial superior olive (MSO) is a key auditory brainstem structure that receives binaural inputs and is implicated in processing interaural time disparities used for sound localization. The deaf white cat, a proven model of congenital deafness, was used to examine how deafness and cochlear implantation affected the synaptic organization at this binaural center in the ascending auditory pathway. The patterns of axosomatic and axodendritic organization were determined for principal neurons from the MSO of hearing, deaf, and deaf cats with cochlear implants. The nature of the synapses was evaluated through electron microscopy, ultrastructure analysis of the synaptic vesicles, and immunohistochemistry. The results show that the proportion of inhibitory axosomatic terminals was significantly smaller in deaf animals when compared with hearing animals. However, after a period of electrical stimulation via cochlear implants the proportion of inhibitory inputs resembled that of hearing animals. Additionally, the excitatory axodendritic boutons of hearing cats were found to be significantly larger than those of deaf cats. Boutons of stimulated cats were significantly larger than the boutons in deaf cats, although not as large as in the hearing cats, indicating a partial recovery of excitatory inputs to MSO dendrites after stimulation. These results exemplify dynamic plasticity in the auditory brainstem and reveal that electrical stimulation through cochlear implants has a restorative effect on synaptic organization in the MSO. PMID- 22237663 TI - Impact of comorbidity on colorectal cancer screening cost-effectiveness study in diabetic populations. AB - BACKGROUND: Although comorbidity has been shown to affect the benefits and risks of colorectal cancer (CRC) screening, it has not been accounted for in prior cost effectiveness analyses of CRC screening. OBJECTIVE: To evaluate the impact of diagnosis of diabetes mellitus, a highly prevalent comorbidity in U.S. adults aged 50 and older, on health and economic outcomes of CRC screening. DESIGN: Cost effectiveness analysis using an integrated modeling framework. DATA SOURCES: Derived from basic and epidemiologic studies, clinical trials, cancer registries, and a colonoscopy database. TARGET POPULATION: U.S. 50-year-old population. TIME HORIZON: Lifetime. PERSPECTIVE: Costs are based on Medicare reimbursement rates. INTERVENTIONS: Colonoscopy screening at ten-year intervals, beginning at age 50, and discontinued after age 50, 60, 70, 80 or death. OUTCOME MEASURES: Health outcomes and cost effectiveness. RESULTS OF BASE-CASE ANALYSIS: Diabetes diagnosis significantly affects cost-effectiveness of CRC screening. For the same CRC screening strategy, a person without diabetes at age 50 gained on average 0.07-0.13 life years more than a person diagnosed with diabetes at age 50 or younger. For a population of 1,000 patients diagnosed with diabetes at baseline, increasing stop age from 70 years to 80 years increased quality-adjusted life years (QALYs) gained by 0.3, with an incremental cost-effectiveness ratio of $206,671/QALY. The corresponding figures for 1,000 patients without diabetes are 2.3 QALYs and $46,957/QALY. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness results are sensitive to cost of colonoscopy and adherence to colonoscopy screening. LIMITATIONS: Results depend on accuracy of model assumptions. CONCLUSION: Benefits of CRC screening differ substantially for patients with and without diabetes. Screening for CRC in patients diagnosed with diabetes at age 50 or younger is not cost-effective beyond age 70. Screening recommendations should be individualized based on the presence of comorbidities. PMID- 22237665 TI - The man who would be doctor. PMID- 22237664 TI - The need for safeguards in advance care planning. AB - The recent uproar about Medicare "death panels" draws attention to public and professional concerns that advance care planning might restrict access to desired life-sustaining care. The primary goal of advance care planning is to promote the autonomy of a decisionally incapacitated patient when choices about life sustaining treatments are encountered, but the safety of this procedure has not received deserved scrutiny. Patients often do not understand their decisions or they may change their mind without changing their advance care directives. Likewise, concordance between patients' wishes and the understanding of the physicians and surrogate decision makers who need to represent these wishes is disappointingly poor. A few recent reports show encouraging outcomes from advance care planning, but most studies indicate that the procedure is ineffective in protecting patients from unwanted treatments and may even undermine autonomy by leading to choices that do not reflect patient values, goals, and preferences. Safeguards for advance care planning should be put in place, such as encouraging physicians to err on the side of preserving life when advance care directives are unclear, requiring a trained advisor to review non-emergent patient choices to limit life-sustaining treatment, training of clinicians in conducting such conversations, and structured discussion formats that first address values and goals rather than particular life-sustaining procedures. Key targets for research include: how to improve completion rates for person wanting advance care directives, especially among minorities; more effective and standardized approaches to advance care planning discussions, including how best to present prognostic information to patients; methods for training clinicians and others to assist patients in this process; and systems for assuring that directives are available and up-to-date. PMID- 22237666 TI - Bias in the reporting of family history: implications for clinical care. AB - Family history of cancer is critical for identifying and managing patients at risk for cancer. However, the quality of family history data is dependent on the accuracy of patient self reporting. Therefore, the validity of family history reporting is crucial to the quality of clinical care. A retrospective review of family history data collected at a community hospital between 2005 and 2009 was performed in 43,257 women presenting for screening mammography. Reported numbers of breast, colon, prostate, lung, and ovarian cancer were compared in maternal relatives vs. paternal relatives and in first vs. second degree relatives. Significant reporting differences were found between maternal and paternal family history of cancer, in addition to degree of relative. The number of paternal family histories of cancer was significantly lower than that of maternal family histories of cancer. Similarly, the percentage of grandparents' family histories of cancer was significantly lower than the percentage of parents' family histories of cancer. This trend was found in all cancers except prostate cancer. Self-reported family history in the community setting is often influenced by both bloodline of the cancer history and the degree of relative affected. This is evident by the underreporting of paternal family histories of cancer, and also, though to a lesser extent, by degree. These discrepancies in reporting family history of cancer imply we need to take more care in collecting accurate family histories and also in the clinical management of individuals in relation to hereditary risk. PMID- 22237667 TI - Surface-active solid lipid nanoparticles as Pickering stabilizers for oil-in water emulsions. AB - Oil-in-water (O/W) emulsions solely stabilized by surface-active solid lipid nanoparticles (SLNs) were developed. The SLNs were generated by quench-cooling hot O/W nanoemulsions consisting of 7.5% glyceryl stearyl citrate (GSC) dispersed in water. Their initial volume-weighted mean particle diameter (~152 nm) and zeta potential (ca.-49 mV) remained unchanged for 24 weeks. O/W emulsions (oil phase volume fraction: 0.2) containing 7.5% (w/w) GSC SLNs in the aqueous phase were kinetically-stable for 12 weeks and did not visually phase-separate over 24 weeks. The O/W emulsions generated with solid-state GSC SLNs had a volume weighted mean oil droplet diameter of ~459 nm and a zeta potential of ca.-43 mV. Emulsion microstructure evaluated with TEM revealed dispersed oil droplets sparsely covered with adsorbed Pickering-type SLNs as well aggregated SLNs present in the continuous phase. Gradual emulsion destabilization resulted from GSC SLN dissolution during the experimental timeframe. Overall, surface-active SLNs developed via nanoemulsions effectively kinetically stabilized O/W emulsions. PMID- 22237668 TI - Urgent percutaneous transcatheter embolization of hemorrhagic hepatic lesions with N-butyl cyanoacrylate. AB - PURPOSE: To report on our clinical experience with and the success rate and safety of percutaneous transcatheter embolization with N-butyl cyanoacrylate (NBCA) as the lone primary embolic agent used for arterial embolization of hemorrhagic liver lesions. MATERIALS AND METHODS: This retrospective study enrolled all patients who presented to the emergency room with hemorrhagic liver lesions during a two-year period and were treated by percutaneous transcatheter embolization with NBCA. RESULTS: Eight consecutive patients were evaluated, and 13 lesions were embolized exclusively with NBCA: eight pseudoaneurysms and five active bleeds. All patients were treated successfully using percutaneous transcatheter embolization with NBCA without re-bleedings or major complications. CONCLUSION: Percutaneous transcatheter embolization with NBCA is a safe and effective method for treating hemorrhagic lesions. PMID- 22237669 TI - Bevacizumab (Avastin) for retinopathy of prematurity: wrong dose, wrong drug, or both? PMID- 22237670 TI - Accuracy of referrals from an orthoptic vision screening program for 3- to 4-year old preschool children. AB - PURPOSE: To determine the accuracy of orthoptist referrals from a preschool-based vision screening program for children 3-4 years of age and to report the outcomes of referred children. METHODS: This was a retrospective review of records of participants in the preschool vision screening program in the Walsall, United Kingdom, area for the 2006-2007 school year. Screening examinations were performed by orthoptists and included assessment of visual acuity, ocular alignment, ocular motility, and stereoacuity. RESULTS: For the 2006-2007 school year, 2,830 of 3,623 children (78%) were screened, Of these, 413 were referred to the Hospital Eye Service. Comparison of the screening results and the Hospital Eye Service examination revealed that recorded visual acuities were similar in 81% of subjects and ocular alignment in 94%. Visual acuity was 6/9 or better at the hospital examination in 87% of referred children, with 46% requiring spectacle use only; 17% of referrals were diagnosed with amblyopia. CONCLUSIONS: Although the Walsall vision screening program diverged from UK national guidelines by testing at an earlier age, there was no evidence that earlier screening led to a large number of incorrect referrals, and early screening may allow for better outcomes. Sensitivity of screening was not tested, and orthoptist screening in the United Kingdom is likely to be more accurate in this age group than nonspecialist or lay screening that is performed in many other areas. PMID- 22237671 TI - Molecular dynamics calculation of molecular volumes and volumes of activation. AB - Experimentally, the effects of pressure on reaction rates are described by their pressure derivatives, known as volumes of activation. Transition state theory directly links activation volumes to partial molar volumes of reactants and transition states. We discuss a molecular dynamics method for the accurate calculation of molecular volumes, within which the volumes of molecular species are obtained as a difference between the volumes of pure solvent and solvent with a single molecule inserted. The volumes thus obtained depend on the molecular geometry, the strength and type of the solute-solvent interactions, as well as temperature and pressure. The partial molar volumes calculated using this approach agree well with experimental data. Since this method can also be applied to transition state species, it allows for quantitative analysis of experimental volumes of activation in terms of structural parameters of the corresponding transition states. The efficiency of the approach is illustrated by calculation of volumes of activation for three nonpolar reactions in nonpolar solvents. The results agree well with the experimental data. PMID- 22237672 TI - Preparation and characterization of a thermostable enzyme (Mn-SOD) immobilized on supermagnetic nanoparticles. AB - Superoxide dismutase (SOD) has been widely applied in medical treatments, cosmetic, food, agriculture, and chemical industries. In industry, the immobilization of enzymes can offer better stability, feasible continuous operations, easy separation and reusing, and significant decrease of the operation costs. However, little attention has focused on the immobilization of the SOD, as well as the immobilization of thermostable enzymes. In this study, the recombinant thermostable manganese superoxide dismutase (Mn-SOD) of Thermus thermophilus wl was purified and covalently immobilized onto supermagnetic 3 APTES-modified Fe(3)O(4)@SiO(2) nanoparticles using glutaraldehyde method to prepare the Mn-SOD bound magnetic nanoparticles. The Mn-SOD nanoparticles were characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, X-ray diffraction, transmission electron microscopy, and vibrating sample magnetometer analysis. The results indicated that the diameter of Mn-SOD nanoparticles was 40 (+/- 5) nm, and its saturation magnetization value was 27.9 emu/g without remanence or coercivity. By comparison with the free Mn-SOD, it was found that the immobilized Mn-SOD on nanoparticles exhibited better resistance to temperature, pH, metal ions, enzyme inhibitors, and detergents. The results showed that the immobilized Mn-SOD on nanoparticles could be reused ten times without significant decrease of enzymatic activity. Therefore, our study presented a novel strategy for the immobilization of thermostable Mn-SOD and for the application of thermostable enzymes. PMID- 22237673 TI - Developing fungal pigments for "painting" vascular plants. AB - The use of fungal pigments as color additives to wood as a method to increase forest revenue is a relatively new, but quickly developing field. Sugar maple (Acer saccharum) is currently the primary utilized hardwood for spalting and appears to be the best suited North American hardwood for such purposes. The combination of Trametes versicolor and Bjerkandera adusta has been identified in several instances as a strong fungal pairing for zone line production; however, Xylaria polymorpha is capable of creating zone lines without the antagonism of a secondary fungus. Few fungal pigments have been developed for reliable use; Scytalidium cuboideum is capable of producing a penetrating pink/red stain, as well as a blue pigment after extended incubation, and Chlorociboria sp. produces a blue/green pigment if grown on aspen (Populus tremuloides). Several opportunities exist for stimulation of fungal pigments including the use of copper sulfate and changes in wood pH. PMID- 22237674 TI - Interobserver variability, and visual and quantitative parameters of (123)I-FP CIT SPECT (DaTSCAN) studies. AB - OBJECTIVE: To evaluate the degree of interobserver agreement in the visual interpretation of (123)I-FP-CIT studies and to investigate for potential associations between visual and semi-quantitative parameters. METHODS: Eighty nine (123)I-FP-CIT studies were blindly reviewed by 3 independent observers: a consultant, a resident doctor and a radiographer. They classified every study as either "normal" or "abnormal" and assigned visual (123)I-FP-CIT uptake scores (2: normal, 1: reduced and 0: no uptake) in basal ganglia nuclei (right and left putamina and caudate nuclei) on every scan. Striatal (123)I-FP-CIT binding ratios were calculated using crescent-ROI software. The interobserver agreement for the interpretation of studies and for visual score assignment was evaluated by means of kappa statistics. We investigated for associations of binding ratios with visual scores and clinical parameters; patients' clinical diagnoses served as the reference standard. RESULTS: There was excellent interobserver agreement (kappa 0.89-0.93) in classifying studies as "normal" or "abnormal" and fine agreement in assignment of visual scores (kappa 0.71-0.80 for putamina and 0.50-0.79 for caudate nuclei). Nuclei with scores of 1 and 0 showed significantly reduced binding ratios (about 30 and 50%, respectively) compared with the nuclei scored as 2. ROC analysis indicated the optimal cutoff point of striatal binding ratio at 3.8 (sensitivity 98.5%, specificity 95%) for the detection of parkinsonian syndromes. Striatal binding ratios were negatively associated with age in normal subjects and disease duration in Parkinson's disease patients. CONCLUSION: Visual interpretation of (123)I-FP-CIT studies showed very good interobserver agreement. We found significant associations among visual, semi-quantitative and clinical parameters. PMID- 22237675 TI - Comparison of animal studies between interstitial magnetic resonance lymphography and radiocolloid SPECT/CT lymphoscintigraphy in the head and neck region. AB - OBJECTIVE: To comparatively assess two techniques, radiocolloid SPECT/CT lymphoscintigraphy and interstitial MR lymphography using SPIO and gadoxetate disodium, in animal models. MATERIALS AND METHODS: We used twenty one 8-week-old male nude mice of strain BALB/c Slc-nu/nu, weighing 23-27 g. The 4.7-T MRI equipment was used to detect the SNs. T2*WI of gradient-echo sequences was acquired sequentially up to 24 h after administering SPIO, ferucarbotran. T1WI was acquired sequentially up to 80 min after administering gadoxetate disodium. (99m)Tc-phytate SPECT/CT lymphoscintigraphy was taken at 30 min after the injection to detect the SNs using animal-dedicated whole-body SPECT/CT hybrid scanner. The injection was submucosally performed in the right tongue margin of each mouse. Reading performances concerning SN visualization and its quality on interstitial MR lymphogram and SPECT/CT lymphoscintigram were performed by 3 radiologists. RESULTS: The SN intensities were 0.43 for the right, 0.61 for the left at 30 min after ferucarbotran injection, with gradual decrease in intensity, and 1.43 for the right, 1.33 for the left at 10 min after gadoxetate disodium injection with a fast decrease in intensity. The base value of 1.0 was at pre examination. The mean numbers of lymph nodes visualized were 4.00 nodes for on SPECT/CT lymphoscintigram and 2.0 for interstitial MR lymphogram. There was a statistically significant difference in the mean scores between SPECT/CT lymphoscintigraphy and interstitial MR lymphography (two factor mixed design with repeated measures on one factor: p < 0.0002). CONCLUSIONS: In our comparative study using mice, the results of radiocolloid SPECT/CT lymphoscintigraphy were superior to those of interstitial MR lymphography, while both SPIO and gadoxetate disodium have a potential of being employed for sentinel node navigation surgery by interstitial MR lymphography in the head and neck region. PMID- 22237676 TI - Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with (99m)Tc-DTPA-glipizide. AB - OBJECTIVE: This study was aimed to assess pancreas beta cell activity using (99m)Tc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated. METHODS: DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30-120 min after injection of (99m)Tc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given (99m)Tc-DTPA. To demonstrate pancreas beta cell uptake of (99m)Tc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, i.v.) and the images were acquired at immediately-65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h. RESULTS: The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. (99m)Tc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas (99m)Tc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with (99m)Tc-DTPA-GLP in normal rat, however, (99m)Tc-DTPA has poor uptake suggesting the specificity of (99m)Tc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug. CONCLUSIONS: It is feasible to use (99m)Tc-DTPA-GLP to assess pancreas beta cell receptor recognition. (99m)Tc DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors. PMID- 22237677 TI - Modelling the lymphatic system: challenges and opportunities. AB - The lymphatic system is a vital part of the circulatory and immune systems, and plays an important role in homeostasis by controlling extracellular fluid volume and in combating infection. Nevertheless, there is a notable disparity in terms of research effort expended in relation to the treatment of lymphatic diseases in contrast to the cardiovascular system. While similarities to the cardiovascular system exist, there are considerable differences in their anatomy and physiology. This review outlines some of the challenges and opportunities for those engaged in modelling biological systems. The study of the lymphatic system is still in its infancy, the vast majority of the models presented in the literature to date having been developed since 2003. The number of distinct models and their variants are few in number, and only one effort has been made thus far to study the entire lymphatic network; elements of the lymphatic system such as the nodes, which act as pumps and reservoirs, have not been addressed by mathematical models. Clearly, more work will be necessary in combination with experimental verification in order to progress and update the knowledge on the function of the lymphatic system. As our knowledge and understanding of its function increase, new and more effective treatments of lymphatic diseases are bound to emerge. PMID- 22237679 TI - Meta-DNA: synthetic biology via DNA nanostructures and hybridization reactions. AB - Can a wide range of complex biochemical behaviour arise from repeated applications of a highly reduced class of interactions? In particular, can the range of DNA manipulations achieved by protein enzymes be simulated via simple DNA hybridization chemistry? In this work, we develop a biochemical system which we call meta-DNA (abbreviated as mDNA), based on strands of DNA as the only component molecules. Various enzymatic manipulations of these mDNA molecules are simulated via toehold-mediated DNA strand displacement reactions. We provide a formal model to describe the required properties and operations of our mDNA, and show that our proposed DNA nanostructures and hybridization reactions provide these properties and functionality. Our meta-nucleotides are designed to form flexible linear assemblies (single-stranded mDNA (ssmDNA)) analogous to single stranded DNA. We describe various isothermal hybridization reactions that manipulate our mDNA in powerful ways analogous to DNA-DNA reactions and the action of various enzymes on DNA. These operations on mDNA include (i) hybridization of ssmDNA into a double-stranded mDNA (dsmDNA) and heat denaturation of a dsmDNA into its component ssmDNA, (ii) strand displacement of one ssmDNA by another, (iii) restriction cuts on the backbones of ssmDNA and dsmDNA, (iv) polymerization reactions that extend ssmDNA on a template to form a complete dsmDNA, (v) synthesis of mDNA sequences via mDNA polymerase chain reaction, (vi) isothermal denaturation of a dsmDNA into its component ssmDNA, and (vii) an isothermal replicator reaction that exponentially amplifies ssmDNA strands and may be modified to allow for mutations. PMID- 22237678 TI - Stochastic steady state gain in a gene expression process with mRNA degradation control. AB - Recent analyses with high-resolution single-molecule experimental methods have shown highly irregular and variable bursting of mRNA in a wide range of organisms. Noise in gene expression is thought to be beneficial in cell fate specifications, as it can lay a foundation for phenotypic diversification of isogenetic cells in the homogeneous environment. However, because the stability of proteins is, in many cases, higher than that of mRNAs, noise from transcriptional bursting can be considerably buffered at the protein level, limiting the effect of noisy mRNAs at a more global regulation level. This raises a question as to what constructive role noisy mRNAs can play in the system-level dynamics. In this study, we have addressed this question using the computational models that extend the conventional transcriptional bursting model with a post transcriptional regulation step. Surprisingly, by comparing this stochastic model with the corresponding deterministic model, we find that intrinsic fluctuations can substantially increase the expected mRNA level. Because effects of a higher mRNA level can be transmitted to the protein level even with slow protein degradation rates, this finding suggests that an increase in the protein level is another potential effect of transcriptional bursting. Here, we show that this striking steady state increase is caused by the asynchronous nature of molecular reactions, which allows the transcriptional regulation model to create additional modes of qualitatively distinct dynamics. Our results illustrate non-intuitive effects of reaction asynchronicity on system dynamics that cannot be captured by the traditional deterministic framework. Because molecular reactions are intrinsically stochastic and asynchronous, these findings may have broad implications in modelling and understanding complex biological systems. PMID- 22237680 TI - A new prenylated flavanone from Derris trifoliata Lour. AB - A new flavanone, 4',5,7-trihydroxy-6,8-di-(2-hydroxy-3-methylbut-3-enyl)- flavanone, was isolated from the aerial parts of Derris trifoliate, together with eleven known compounds: rotenone, tephrosin, 12a-hydroxyrotenone, deguelin, 6a,12a-dehydro-rotenone, dehydrodeguelin, 7a-O-methyldeguelol, 7a-O methylelliptonol, 5,7,3',4'-tetra-hydroxy-6,8-diprenylisoflavone, daidzein and 4' hydroxy-7-methoxyflavanone. 7a-O-Methylelliptonol was isolated for the first time from the genus Derris. Their structures were characterized on the basis of spectral data. Eight of the isolated compounds were found to be significantly toxic to brine shrimp (LC(50) range 0.06-9.95 MUg/mL). The new compound showed weak toxicity (LC(50) = 211.31 MUg/mL). PMID- 22237681 TI - Induction of apoptosis in human breast adenocarcinoma cells MCF-7 by monapurpyridine A, a new azaphilone derivative from Monascus purpureus NTU 568. AB - A new azaphilonidal derivative, monapurpyridine A (MPA), has recently been isolated from the fermented products of Monascus purpureus NTU 568. The structure of MPA was elucidated by nuclear magnetic resonance (1H-NMR, 13C-NMR, COSY, HMQC, and HMBC) and other spectroscopic analyses. Biological evaluation revealed that MPA could induce cell death in human breast adenocarcinoma cells MCF-7, and it has no significant toxicity to normal mammary epithelial cells M10. The MTT assay and flow cytometric analysis were employed to investigate cell viability and cell cycle influenced by MPA. Moreover, we used Western blot and caspase activity assay to demonstrate the activation of caspase-3, -8 and -9 resulted from MPA. All evidence supported that MPA was suitable for developing into a chemotherapeutic or chemopreventive agent against breast cancer. PMID- 22237682 TI - Gamma irradiation increases the antioxidant properties of Tualang honey stored under different conditions. AB - This study was conducted to evaluate the effects of evaporation, gamma irradiation and temperature on the total polyphenols, flavonoids and 1,1-diphenyl 2-picrylhydrazyl (DPPH) radical-scavenging activities of Tualang honey samples (n = 14) following storage over three, six or twelve months. The mean polyphenol concentrations of the six gamma irradiated honey samples at three, six and twelve months, respectively, were 96.13%, 98.01% and 102.03% higher than the corresponding values of the eight non-gamma irradiated samples. Similarly, the mean values for flavonoids at three, six and twelve months were 111.52%, 114.81% and 110.04% higher, respectively, for the gamma irradiated samples. The mean values for DPPH radical-scavenging activities at three, six and twelve months were also 67.09%, 65.26% and 44.65% higher, respectively, for the gamma irradiated samples. These data indicate that all gamma irradiated honey samples had higher antioxidant potential following gamma irradiation, while evaporation and temperature had minor effects on antioxidant potential. PMID- 22237683 TI - A process for extracellular thermostable lipase production by a novel Bacillus thermoamylovorans strain. AB - A lipolytic enzyme-producing thermophilic microorganism, recently isolated from a hot spring in Galicia (North Western Spain), has been investigated. First, the strain was genetically identified and tentatively named Bacillus thermoamylovorans CH6B. It produced significant levels (around 450 U/L) of extracellular lipolytic activity in shake flask cultures, and the most suitable conditions for this biological process were found at temperatures between 50 and 55 degrees C, and an initial pH value around 7.0. Next, a preliminary scaling up of the process was carried out in a 5-L stirred tank bioreactor, and it was concluded that operation at agitation and aeration rates of 300 rpm and 0.33 vvm, respectively, were advisable. In both type of cultures, the results were successfully fitted to logistic equations, and the relationship between lipase production and cell growth was investigated. Furthermore, some relevant properties of the crude lipolytic enzyme extracts were assessed. The crude biocatalyst preferentially hydrolysed p-nitrophenyl esters of medium and long chain fatty acids. Thermal stability in aqueous solution of the produced enzyme was also promising, and the deactivation profiles were fitted to a series-type deactivation model. PMID- 22237684 TI - Evaluation of nutrient uptake and physical parameters on cell biomass growth and production of spilanthol in suspension cultures of Spilanthes acmella Murr. AB - Spilanthes acmella Murr. has a plethora of highly valuable biologically active compounds and has been listed as one of the important medicinal plants of the world. However, no perceptible biotechnological advances have been made for this genus to exploit or enhance its utility. To nullify the effect of seasonal variations, the present report is the first attempt to establish in vitro cell suspension cultures and to evaluate the production of spilanthol from them, a key component of the plant responsible for most of its pharmaceutical activities. The study examined the biomass growth in relation to the consumption of major nutrients and sucrose, agitation speed and dynamic change in pH. Results indicated that the consumption of phosphate resulted in the onset of decline phase in cultures. Spilanthol production was observed to be growth associated and maximum production occurred on the 15th day. Among the carbon sources, the highest production of spilanthol as 91.4 ug g(-1) DW was recorded in the medium supplemented with sucrose, followed by glucose which produced 56.8 ug g(-1) DW of spilanthol. Spilanthol could not be detected in fructose containing medium. Maximum viable cultures were obtained at a rotation speed of cells at 120 rpm. This study signifies the utility of Spilanthes suspension cultures for biosynthesis and constant production of spilanthol, throughout the year. The results of present study are useful for further scale-up process. PMID- 22237685 TI - Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance. AB - AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance. METHODS: Metabolic studies were performed in Chop ( -/- ) and wild-type C57Bl/6 mice, and included euglycaemic-hyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. RESULTS: Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop ( -/- ) mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. CONCLUSIONS/INTERPRETATION: These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance. PMID- 22237686 TI - Impact of maternal diabetes on birthweight is greater in non-Hispanic blacks than in non-Hispanic whites. AB - AIMS/HYPOTHESIS: To determine the impact of maternal diabetes during pregnancy on racial disparities in fetal growth. METHODS: Using linked birth certificate, inpatient hospital and prenatal claims data we examined live singleton births of mothers resident in South Carolina who self-reported their race as non-Hispanic white (NHW; n = 140,128) or non-Hispanic black (NHB; n = 82,492) and delivered at 28-42 weeks' gestation between 2004 and 2008. RESULTS: Prepregnancy diabetes prevalence was higher in NHB (3.0%) than in NHW (1.7%), while the prevalence of gestational diabetes mellitus (GDM) was similar in NHB (6.1%) and NHW (6.3%). At a delivery BMI of 35 kg/m(2), GDM exposure was associated with an average birthweight only 17 g (95% CI 4, 30) higher in NHW, but 78 g (95% CI 61, 95) higher in NHB (controlling for gestational age, maternal age, infant sex and availability of information on prenatal care). Figures for prepregnancy diabetes were 58 g (95% CI 34, 81) in NHW and 60 g (95% CI 37, 84) in NHB. GDM had a greater impact on birthweight in NHB than in NHW (60 g racial difference [95% CI 39, 82]), while prepregnancy diabetes had a large but similar impact. Similarly, the RR for GDM of having a large- relative to a normal-weight-for-gestational-age infant was lower in NHW (RR 1.41 [95% CI 1.34, 1.49]) than in NHB (RR 2.24 [95% CI 2.05, 2.46]). CONCLUSIONS/INTERPRETATION: These data suggest that the negative effects of GDM combined with obesity during pregnancy may be greater in NHB than in NHW individuals. PMID- 22237687 TI - Hedgehog signals inhibit postnatal beta cell neogenesis from adult rat exocrine pancreas in vitro. AB - AIMS/HYPOTHESIS: Transdifferentiation of pancreatic exocrine cells into insulin producing beta cells may represent an important alternative to islets required for diabetes cell therapy. Rat pancreatic acinar cells are known to transdifferentiate into functional beta cells, with recapitulation of several pancreas developmental features. Considering the inhibitory functions of hedgehog signalling in early and mid-stage pancreatic development, we questioned whether it also operates in transdifferentiating acinar cells and whether its modulation would influence postnatal beta cell neogenesis in vitro. METHODS: Rat exocrine cells were precultured in suspension for 4 days and then incubated with EGF and leukaemia inhibitory factor (LIF) for 72 h. The hedgehog signalling pathway was modulated during this, and its effects analysed by RT-PCR, immunocytochemistry and western blot. RESULTS: Our data indicate induction of Dhh and Ihh, but not Shh, expression during acinar cell culture, resulting in activation of hedgehog targets (Ptc1, Gli1). Exposure of the metaplastic cells to EGF and LIF induced beta cell differentiation without affecting endogenous hedgehog activity. Whereas blocking endogenous hedgehog only slightly increased beta cell neogenesis, exposure to embryoid body-conditioned medium activated hedgehog signalling as well as other pathways such as Notch, resulting in severe blockade of beta cell neogenesis. Interestingly, this effect was partially rescued by treatment with the hedgehog inhibitor, 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), alone. CONCLUSIONS/INTERPRETATION: We report here Dhh/Ihh-dependent activation of hedgehog targets during pancreatic exocrine cell metaplasia in vitro and a persistent inhibitory function of hedgehog signalling in a model of postnatal beta cell differentiation. PMID- 22237688 TI - Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases IGF-I bioactivity similarly. AB - AIMS/HYPOTHESIS: The aim of this study was to compare IGF-I bioactivity 36 weeks after the addition of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) or NPH insulin to metformin therapy in type 2 diabetic patients who had poor glucose control under metformin monotherapy. METHODS: In the Lantus plus Metformin (LANMET) study, 110 poorly controlled insulin-naive type 2 diabetic patients were randomised to receive metformin with either insulin glargine (G+MET) or NPH insulin (NPH+MET). In the present study, IGF-I bioactivity was measured, retrospectively, in 104 out of the 110 initially included LANMET participants before and after 36 weeks of insulin therapy. IGF-I bioactivity was measured using an IGF-I kinase receptor activation assay. RESULTS: After 36 weeks of insulin therapy, insulin doses were comparable between the G+MET (68 +/- 5.7 U/day) and NPH+MET (71 +/- 6.2 U/day) groups (p = 0.68). Before insulin therapy, circulating IGF-I bioactivity was similar between the G+MET (134 +/- 9 pmol/l) and NPH+MET (135 +/- 10 pmol/l) groups (p = 0.83). After 36 weeks, IGF-I bioactivity had decreased significantly (p = 0.001) and did not differ between the G+MET (116 +/- 9 pmol/l) and NPH+MET (117 +/- 10 pmol/l) groups (p = 0.91). At baseline and after insulin therapy, total IGF-I concentrations were comparable in both groups (baseline: G+MET 13.3 +/- 1.0 vs NPH+MET 13.3 +/- 1.0 nmol/l, p = 0.97; and 36 weeks: 13.4 +/- 1.0 vs 13.1 +/- 0.9 nmol/l, p = 0.71). Total IGF-I concentration did not change during insulin therapy (13.3 +/- 0.7 vs 13.3 +/- 0.7 nmol/l, baseline vs 36 weeks, p = 0.86). CONCLUSIONS/INTERPRETATION: Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases serum IGF-I bioactivity in a similar manner. PMID- 22237689 TI - How much does screening bring forward the diagnosis of type 2 diabetes and reduce complications? Twelve year follow-up of the Ely cohort. AB - AIMS: There are continuing uncertainties about how much screening for type 2 diabetes brings forward the clinical diagnosis and the impact that earlier diagnosis has on health outcomes. We compared the duration of diabetes and health outcomes in a population invited for diabetes screening at 5-yearly intervals from 1990 (screened population) with those in a similar population not invited for screening (unscreened population). METHODS: This was a parallel-group, cohort study of people aged 40-65 years, free of known diabetes, identified from the population register of a general practice in Ely, Cambridgeshire, UK (n = 4,936). In 1990-1992, one-third (n = 1,705), selected randomly, received an invitation for screening for diabetes and cardiovascular risk factors at 5-yearly intervals (screened population). From the remainder of the sampling frame, 1,705 randomly selected individuals were invited to diabetes screening 10 years later (unscreened population). Patients with diabetes from both populations were invited for a health assessment, including biochemical, anthropometric and questionnaire measures, and testing for the presence of diabetic complications RESULTS: Of the 199 eligible individuals with diabetes diagnosed during follow up, 152 (76%) attended for health assessment. The median duration of clinically recognised diabetes was significantly longer in cases arising in the screened (5.0 years) compared with the unscreened population (1.7 years; p = 0.006). Clinical measures, prescribed medication and functional status were similar between screened and unscreened populations. CONCLUSIONS: Diabetes screening resulted in cases being identified on average 3.3 years earlier, a difference significantly shorter than previous estimates. Earlier diagnosis did not appear to impact on health outcomes. Further evidence is needed to justify the introduction of population-based screening. PMID- 22237690 TI - Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study. AB - AIMS/HYPOTHESIS: Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG) rich lipoproteins in type 2 diabetes before and following a high-fat meal. METHODS: Seventy-one patients (age 18-70 years), who did not reach HbA(1c) 6.5% (48 mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16 week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7-5.0 mmol/l was among the entry criteria. Patients received a high fat mixed meal before and 4 and 16 weeks after randomisation (allocation by central office) to Alo (n = 25), Alo/Pio (n = 22) or Pbo (n = 24). Blood was sampled at pre-specified intervals, starting at 15 min before and ending 8 h after meal ingestion. RESULTS: At week 16, Alo (n = 25) and Alo/Pio (n = 21) vs Pbo (n = 24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p < 0.001), as well as in chylomicron TG (p < 0.001) and VLDL1 TG iAUCs (p < 0.001 and p = 0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment (p = 0.028), and a non-significant trend towards a decrease with Alo/Pio (p = 0.213). The incidence of adverse events was low and consistent with previous studies. CONCLUSIONS/INTERPRETATION: Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00655863. PMID- 22237692 TI - Blood tests may predict early primary myelofibrosis in patients presenting with essential thrombocythemia. AB - According to World Health Organization (WHO)-defined criteria, patients presenting clinically as essential thrombocythemia (ET) may show early primary myelofibrosis (PMF) with accompanying thrombocythemia [1]. Previous clinicopathological studies revealed that laboratory parameters like gender matched hemoglobin (Hb), white blood cell (WBC) count, and particularly lactate dehydrogenase (LDH) values are significantly different in PMF [2]. By strictly applying the WHO criteria, our investigation was aimed to study sensitivity and specificity of these features in an exploratory cohort of 536 patients and to validate the results on an independently recruited series of 321 strictly corresponding patients. The discriminatory power of these parameters (Hb, WBC, and LDH) was tested by plotting their receiver operating characteristic curves. The best performance was found for LDH (areas under the curve, AUC 5 0.7059). WBC and Hb had superimposable curves, with AUC of 0.6279 and 0.6257, respectively. A diagnostic algorithm was generated by applying these parameters in a stepwise fashion. Nearly half of the patients could be correctly allocated to WHO-defined ET or early PMF in both cohorts investigated. It is important to note that this result does not substitute bone marrow morphology with hematological parameters, however, in clinical practice may alert physicians to get more suspicious of early PMF in a patient presumably presenting with ET. PMID- 22237693 TI - Predictive factors for postoperative constipation and continence after stapled transanal rectal resection. AB - BACKGROUND: Although stapled transanal rectal resection (STARR) has become an important surgical option in the treatment of obstructive defaecation syndrome, objective data about parameters that predict its success or failure are not yet available. METHODS: Medical history, clinical and radiomorphological data were obtained prospectively from a multi-institutional STARR registry. Predictive factors for postoperative constipation (Cleveland Clinic Constipation Score, CCS) and incontinence (Cleveland Clinic Incontinence Score, CCIS) were identified using univariable and multivariable analysis. RESULTS: Data were obtained for 181 of 201 patients in the STARR registry, with completed median follow-up of 19.4 (range 12-41) months. Although the CCS decreased significantly overall (from mean(s.d.) 16.3(4.9) to 6.7(4.1); P < 0.001), 31 patients (17.1 per cent) complained about persisting constipation. CCIS levels remained unchanged overall, but 16 patients (8.8 per cent) had new-onset faecal incontinence. Multivariable analysis revealed that rectocele (beta = -0.302, P < 0.001) and intussusception (beta = -0.392, P < 0.001) were independent predictors of low CCS levels, and intussusception (beta = -0.216, P = 0.001) and enterocele (beta = -0.171, P = 0.012) were independent predictors of low CCIS levels. In contrast, small rectal diameter (beta = -0.293, P < 0.001), low squeeze pressure (beta = -0.188, P = 0.005) and increased pelvic floor descent at rest (beta = 0.264, P < 0.001) predicted high CCIS levels. CONCLUSION: Factors for a favourable outcome after STARR included rectocele, intussusception and enterocele, whereas small rectal diameter, low sphincter pressure and increased pelvic floor descent were unfavourable. These findings should be integrated into the therapy algorithm for STARR. PMID- 22237694 TI - Systematic review of the complications of plate fixation of clavicle fractures. AB - BACKGROUND: The number of displaced midshaft clavicle fractures treated surgically is increasing and plate fixation is often the treatment modality of choice. The study quality and scientific levels of evidence at which possible complications of this treatment are presented vary greatly in literature. PURPOSES: The purpose of this systematic review is to assess the prevalence of complications concerning plate fixation of dislocated midshaft clavicle fractures. METHODS: A computer-based search was carried out using EMBASE and PUBMED/MEDLINE. Studies included for review reported complications after plate fixation alone or in comparison to either treatment with intramedullary pin fixation and/or nonoperative treatment. Two quality assessment tools were used to assess the methodological quality of the studies. Included studies were ranked according to their levels of evidence. RESULTS: After study selection and reading of the full texts, 11 studies were eligible for final quality assessment. Nonunion and malunion rates were less than 10% in all analysed studies but one. The vast majority of complications seem to be implant related, with irritation or failure of the plate being consistently reported on in almost every study, on average ranging from 9 to 64%. CONCLUSION: The quantity of relevant high evidence studies is low. With low nonunion and malunion rates, plate fixation can be a safe treatment option for acute dislocated midshaft clavicle fractures, but complications related to the implant material requiring a second operation are frequent. Future prospective trials are needed to analyse the influence of various plate types and plate position on implant-related complications. PMID- 22237695 TI - Reversible delayed posthypoxic leukoencephalopathy after drug overdose: MRI findings in a collection of patients. PMID- 22237696 TI - Case report: lethal fetal head injury and placental abruption in a pregnant trauma patient. AB - Fetal trauma in blunt abdominal trauma is uncommon, but traumatic fetal head injury is almost universally fatal to the fetus. Placental abruption is the most common injury to the gravid uterus in trauma, and when the mother survives, it is the most common cause of fetal death. The imaging diagnosis of these conditions may be difficult since there are only three cases reported in the literature of intrauterine skull fractures on plain films [3, 8, 10], ultrasound is in sensitive in the diagnosis of placental abruption [24], and the most sensitive test to diagnose placental abruption is external fetal monitoring with devices that measure uterine tone and contractility and fetal heart rate [23]. The diagnosis of fetal trauma and placental abruption may be made on contrast enhanced CT performed through the abdomen and pelvis of pregnant trauma patients. For these reasons, it is useful for the radiologist interpreting the CT scan to recognize fetal head injuries and placental abruption in pregnant trauma patients.Fig. 7 Axial scans through the bony pelvis demonstrate an unstable pelvic fracture with posterior pelvic ring disruption.There is a zone 2 fracture of the left sacrum and a fracture of the left obturator ring (arrowheads) PMID- 22237698 TI - Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. AB - Adenosine 5'-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term 'purinergic' was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. PMID- 22237697 TI - Physiological and anatomical evidence for an inhibitory trigemino-oculomotor pathway in the cat. AB - During blink down-phase, the levator palpebrae superioris (levator) muscle is inactivated, allowing the orbicularis oculi muscle to act. For trigeminal reflex blinks, the excitatory connections from trigeminal sensory nuclei to the facial nucleus have been described, but the pathway whereby the levator is turned off have not. We examined this question by use of both physiological and anatomical approaches in the cat. Intracellular records from antidromically activated levator motoneurons revealed that periorbital electrical stimulation produced bilateral, long latency inhibitory postsynaptic potentials (IPSPs). Central electrical stimulation of the principal trigeminal nucleus produced shorter latency IPSPs. Intracellular staining revealed that these motoneurons reside in the caudal central subdivision and have 10 or more poorly branched dendrites, which extend bilaterally into the surrounding supraoculomotor area. Axons penetrated in this region could be activated from periorbital and central electrodes. Neurons labeled from tracer injections into the caudal oculomotor complex were distributed in a crescent-shaped band that lined the ventral and rostral aspects of the pontine trigeminal sensory nucleus. Double-label immunohistochemical procedures demonstrated that these cells were not tyrosine hydroxylase-positive cells in the Kolliker-Fuse area. Instead, supraorbital nerve afferents displayed a similar crescent-shaped distribution, suggesting they drive these trigemino-oculomotor neurons. Anterograde labeling of the trigemino oculomotor projection indicates that it terminates bilaterally, in and above the caudal central subdivision. These results characterize a trigemino-oculomotor pathway that inhibits levator palpebrae motoneurons in response to blink producing periorbital stimuli. The bilateral distributions of trigemino oculomotor afferents, levator motoneurons, and their dendrites supply a morphological basis for conjugate lid movements. PMID- 22237699 TI - Dipolar 3-methoxychromones as bright and highly solvatochromic fluorescent dyes. AB - Herein, three environment-sensitive (solvatochromic) fluorescent dyes presenting a strong electron acceptor 3-methoxychromone unit and varied electron donor 2 aryl were developed. All three dyes showed remarkable polarity-dependent shifts of the emission maximum, which increase with extension of the dye conjugation. For the 3-methoxychromone bearing a 7-(diethylamino)-9,9-dimethylfluoren-2-yl donor group the difference between the excited and the ground state dipole moments, estimated from the Lippert-Mataga expression, reached 20 D, which is among the largest reported for neutral dipolar fluorophores. Moreover, the new dyes are characterized by significant two-photon absorption cross-section (up to 450 GM) and large fluorescence quantum yields. The strong decrease in the fluorescence quantum yields of the dyes in polar protic solvents was observed together with the increase in the non-radiative deactivation rates, which can originate from twisted intramolecular charge transfer and intermolecular proton transfer phenomena. In comparison to the parent 3-hydroxychromone derivatives, the new dyes presented significantly improved photostability, which confirms that photodegradation of 3-hydroxychromones occurs from a product of the excited-state intramolecular proton transfer (phototautomer). Finally, an application of the new dyes for probing local binding site polarity of serum albumin was shown. This new class of fluorescent dyes may serve as attractive building blocks for future molecular sensors utilizing environment-sensitive fluorophores. PMID- 22237700 TI - Risk assessment of heavy metals in road and soil dusts within PM2.5, PM10 and PM100 fractions in Dongying city, Shandong Province, China. AB - 15 road and 14 soil dust samples were collected from an oilfield city, Dongying, from 11/2009-4/2010 and analyzed by inductively coupled plasma-mass spectroscopy (ICP-MS) for V, Cr, Mn, Co, Ni, Cu, Zn, As, Cd and Pb within PM(2.5), PM(10) and PM(100) fractions synchronously. Metal concentrations, sources and human health risk were studied. Results showed that both soil and road dust exhibited higher values for Mn and Zn and lower values for Co and Cd for the three fractions. Mass concentration ratios of PM(2.5)/PM(10) and PM(10)/PM(100) for metals in road and soil dust indicate that most of the heavy metals tend to concentrate in fine particles. Geoaccumulation index and enrichment factors analysis showed that Cu, Zn and Cd exhibited moderate or heavy contamination and significant enrichment, indicating the influence of anthropogenic sources. Vanadium, Cr, Mn and Co were mostly not enriched and were mainly influenced by crustal sources. For Ni, As and Pb, they ranged from not enriched to moderately enriched and were influenced by both crustal materials and anthropogenic sources. The conclusions were confirmed by multivariate analysis methods. Principle component analysis revealed that the major sources were vehicle emission, industrial activities, coal combustion, agricultural activities and crustal materials. The risk assessment results indicated that metal ingestion appeared to be the main exposure route followed by dermal contact. The most likely cause for cancer and other health risks are both the fine particles of soil and road dusts. PMID- 22237701 TI - Genetics and epigenetics of the skin meet deep sequence. AB - Rapid advances in next-generation sequencing technology are revolutionizing approaches to genomic and epigenomic studies of skin. Deep sequencing of cutaneous malignancies reveals heavily mutagenized genomes with large numbers of low-prevalence mutations and multiple resistance mechanisms to targeted therapies. Next-generation sequencing approaches have already paid rich dividends in identifying the genetic causes of dermatologic disease, both in heritable mutations and the somatic aberrations that underlie cutaneous mosaicism. Although epigenetic alterations clearly influence tumorigenesis, pluripotent stem cell biology, and epidermal cell lineage decisions, labor and cost-intensive approaches long delayed a genome-scale perspective. New insights into epigenomic mechanisms in skin disease should arise from the accelerating assessment of histone modification, DNA methylation, and related gene expression signatures. PMID- 22237702 TI - Old and new: recent innovations in vaccine biology and skin T cells. AB - Memory is the hallmark of the adaptive immune system, and the observation that infectious diseases often lead to lifelong immunity in individuals who survive a first infection became the genesis for the development of vaccines. Immunization, which is the iatrogenic engineering of a protective memory immune response to a pathogen, became a standard part of medical care in the twentieth century, and has had an almost incalculable positive effect on human health and wellness. Vaccines to many, but by no means all, infectious diseases have been developed and are in common use. Smallpox vaccine, arguably the most effective vaccine in human history, was (and still is) delivered through disrupted epidermis in a process called scarification. Virtually all vaccines today are delivered by means of a hypodermic needle and syringe into muscle, in a process that bypasses the epidermis and dermis and their attendant innate and adaptive immune attributes. This article discusses vaccines in the context of the newly appreciated paradigm of tissue-resident memory T cells, and specifically discusses the role of these cells in skin and other epithelial interfaces with the environment in the maintenance of protective immunity. PMID- 22237703 TI - BAG3: a new therapeutic target of human cancers? AB - Bcl-2-associated athanogene (BAG) family proteins share the BAG domain, which is characterized by their interaction with a variety of partners (heat shock proteins, steroid hormone receptors, Raf-1 and others) and is involved in regulating a number of cellular processes. BAG3, also known as CAIR-1 or Bis, mediates protein delivery to proteasome and modulates apoptosis by interfering with cytochrome c release, apoptosome assembly and other events in the cellular death program. Moreover, it takes part in the processes of cell adhesion and migration. It has been shown that, in human cancer cells, including lymphocytic and myeloblastic leukemic cells, BAG3 sustains cell survival and underlies resistance to chemotherapy, through down-modulation of apoptosis. BAG3 knocking down could enhance the effectiveness of chemotherapy. This review summarizes the physiological and pathological roles of BAG3 in cancer cells and its potential as a therapeutic target of human malignancies. PMID- 22237704 TI - An insight into the role of autophagy in cell responses in the aging and neurodegenerative brain. AB - Oxidative stress, inflammation and the aggregation of oxidized, misfolded or aberrant proteins in the brain induces deregulations in programmed cell death: apoptosis and autophagy. Apoptosis is one of processes implicated in aging and neurodegenerative pathologies, and for the last decade, has been one of the most studied processes due to its essential role, not only in aging, but also in many neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington's. However, autophagy being the major intracellular pathway for the degradation and recycling of long-live proteins and organelles is widely involved in the pathogenesis or prevention of many age-related diseases, including neurodegenerative conditions. Recently, autophagy activation has been considered as part of the cellular responses to elevated oxidative stress, eliminating unwanted, damaged and oxidative structures; thus favouring, in this way, the key anti-aging mechanism associated with the caloric restriction. Longevity factors, such as sirtuins, and redox-sensitive transcriptional factors, such as NF-kappaB and p53, can also regulate basal autophagy in cells, with a direct impact on longevity and the development of inflammation and neurodegeneration. Here, we reviewed the critical changes of autophagy in the aging and neuro-degenerative brain and the role of key regulators of autophagy, which are directly related to oxidative stress, inflammation and longevity pathways. PMID- 22237705 TI - Multiple sclerosis - remyelination failure as a cause of disease progression. AB - Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS) that affects worldwide about 2.5 million people. The morphological correlates of the disease are multiple lesions in brain and spinal cord which are characterized by demyelination, inflammation, gliosis and axonal damage. The underlying cause for the permanent neurological deficits in MS patients is axonal loss. Demyelinated axons are prone to damage due to the lack of trophic support by myelin sheaths and oligodendrocytes, as well as the increased vulnerability to immune mediated attacks. Remyelination occurs, but especially in chronic lesions is frequently limited to a small rim at the lesion border. Current treatment strategies are based on anti-inflammatory or immunomodulatory drugs and have the potential to reduce the numbers of newly evolving lesions, although as yet no treatment strategy exists to influence or prevent the progressive disease phase. Therefore, the development of neuroprotective treatment options, such as the promotion of endogenous remyelination is an attractive strategy. A prerequisite for the development of such new treatments is the understanding of the mechanisms leading to remyelination and the reasons for insufficient endogenous repair in chronic MS. This review will therefore provide an overview of the current concepts regarding remyelination in the rodent and human CNS. We will also summarize a selected number of inhibitory pathways and non-disease related factors which may contribute to remyelination failure in chronic MS. PMID- 22237706 TI - Predictive pathology in routine diagnostics of solid tumors. AB - For decades, macroscopic and microscopic analysis of human tissue specimens by pathologists has been the basis for disease classification. In recent years, there has been an increasingly better understanding of molecular alterations underlying the pathogenesis of cancers as well as the establishment and integration of novel molecular analyses into a histomorphological-based workflow. This has dramatically extended the possibilities of diagnostic pathology - from its descriptive role to a clinical advisory role on cancer classification including prognostic and predictive molecular pathological information. This review will focus on the recent developments of molecular pathological techniques and the current tools and applications of predictive pathology in view of targeted therapies in solid cancers. PMID- 22237707 TI - Protein expression and gene mutation status of KIT and PDGFRA in renal cell carcinoma. AB - The author investigated protein expression and gene mutations of KIT and PDGFRA in 61 consecutive surgical cases of renal cell carcinoma (RCC). The cases of RCC consisted of 43 clear cell RCC (CCRCC), 9 chromophobe RCC (ChrRCC), or 9 papillary RCC (PaRCC). Normal distribution of KIT and PDGFRA protein was also examined in non-tumorous normal parenchyma (n=10). In normal kidneys, KIT was expressed in distal convoluted tubules and collecting ducts, and PDGFRA in distal and proximal convoluted tubules and collecting ducts. KIT expression was recognized in 9 ChrRCC (100%, 9/9), but not in 43 CCRCC (0%, 0/43) and 9 PaRCC (0%, 0/9). PDGFRA expression was recognized in 7 CCRCC (16%, 7/43) and 2 PaRCC (28%, 2/9), but not in ChrRCC (0%, 0/9). A molecular genetic analysis using PCR direct sequencing was performed in selected 30 cases (ChrRCC=9, CCRCC=12, PaRCC=9): it revealed no mutations in KIT (exons 9, 11, 13, and 17) or PDGFRA (exons 12 and 18) genes in any cases examined. These results suggest that in normal renal parenchyma KIT is expressed in distal convoluted tubules and collecting ducts, and PDGFRA in proximal and distal convoluted tubules and collecting ducts, that KIT is expressed exclusively in ChrRCC and its incidence is 100%, that KIT-positive ChrRCC was negative for PDGFRA, that PDGFRA is expressed in a small percentage in CCRCC and PaRCC, and that mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) are absent in RCC. PMID- 22237708 TI - Endogenous neurogenesis after intracerebral hemorrhage. AB - Currently, it is accepted that brain injury promotes endogenous neurogenesis in mammals, primarily in the subventricular zone (SVZ), and newborn cells can migrate to the injured area. We examined the pattern of endogenous neurogenesis in adult rats after intracerebral hemorrhage (ICH) that was caused by intrastrial administration of collagenase type IV. Our results showed that ICH induced strong endogenous neurogenesis between 72 hours and 7 days after injury, but that the majority of newborn cells did not survive longer than 3 weeks due to apoptosis mediated cell death. Furthermore, endogenous neurogenesis remained into a small extent at least 1 year after ICH. Because of the growing interest in new strategies for brain regeneration, these data suggest endogenous neurogenesis and inhibiting apoptosis of newborn neuroblasts as potential strategies to improve the consequences of hemorrhagic stroke in humans. PMID- 22237709 TI - ABCA17 mediates sterol efflux from mouse spermatozoa plasma membranes. AB - Mammalian spermatozoa lose plasma membrane cholesterol during maturation in the epididymis and during capacitation in the female reproductive tract. While cholesterol acceptors such as high-density lipoproteins (HDL) and apolipoproteins A-I (apoA-I) and J (Apo J) have been found in male and female reproductive tracts, transporters that mediate cholesterol efflux from plasma membranes of spermatozoa to acceptors are not well defined. Candidates include members of the ATP-binding cassette (ABC) transporter superfamily including ABCA1, ABCA7, ABCA17, and ABCG1. In this study, we utilize immunocytochemistry on sections of adult mouse testis and epididymis and RT-PCR on isolated germ cells. The data reveal that ABCA17 is expressed by steps 12-16 elongated spermatids in the mouse in testis and by spermatozoa in the lumen of the epididymis where ABCA17 localizes to the sperm head and tail midpiece. It also localizes on these areas of mouse sperm isolated from the epididymis. Moreover, ABCA17 antibody interferes with cholesterol efflux from spermatozoa to lipid acceptors apoA-I. Taken together, these results suggest that ABCA17 plays an important role in the process of sterol efflux which renders spermatozoa capable of fertilizing an oocyte. PMID- 22237710 TI - Neutrophil gelatinase-associated lipocalin (NGAL) immunohistochemical expression in follicular cell-derived thyroid tumors: a novel diagnostic tool? AB - Discrimination of follicular cell-derived benign and malignant tumors of the thyroid is one of the major problems encountered in surgical pathology. In the present study, we evaluated the immunohistochemical expression of NGAL, an iron binding protein involved in the infiltrative potential of cancer cells, in a cohort of tumors including 8 follicular adenomas (FA), 2 Hurthle cell adenomas (HA), 2 atypical adenomas (AA), 8 minimally invasive follicular carcinomas (MIFC), 9 widely invasive follicular carcinomas (WIFC), 3 Hurthle cell carcinomas (HC) and 8 papillary carcinomas (PC) with 5 follicular-variant PC (FVPC) and 3 not otherwise specified (PC-NOS). Our goal was to test whether evaluation of NGAL immunoexpression may be of use in the differential diagnosis of benign and malignant thyroid neoplasias. 92% of benign tumors (specificity) were negative for NGAL, whereby NGAL immuno-expression was found in 82% (sensitivity) of malignant tumors, and, specifically, in 100% of MIFC, in 87% of WIFC, in 100% of HC, in 80% of FVPC. None of the PC-NOS displayed NGAL staining. When only tumors with a follicular architecture were considered, NGAL specificity for malignant lesions was 92%; sensitivity, positive predictive value and negative predictive value were 92%, 96% and 85%. Diagnostic accuracy of NGAL expression in the differential diagnosis between benign and malignant follicular tumors was 92%. In conclusion, NGAL protein seems to represent a marker of malignant follicular cell derived thyroid tumors, and especially of those with follicular architecture. Hence assessment of its expression might be of use with respect to differential diagnosis from follicular benign neoplasias. PMID- 22237711 TI - Differential expression of FGF family members in a progestin-dependent BT-474 human breast cancer xenograft model. AB - Members of the fibroblast growth factor (FGF) family have been associated with tumor progression and angiogenesis, though the mechanism through which they affect the progression of breast cancer remains elusive. We recently showed that progestins increase the production of the potent angiogenic factor VEGF in an in vivo BT-474 human breast cancer cell-derived xenograft model. In this study we sought to determine the effect of progesterone (P) on regulation of specific FGF family members (FGF-2, FGF-4 and FGF-8) in the same model. Using immunohistochemistry we found that treatment with P significantly reduced FGF-2 and FGF-8 levels, while modestly increasing the levels of FGF-4 in tumors collected at the termination of the study or soon after P treatment began. The in vivo observations with FGF-2 were confirmed in cultured BT-474 cells, though the P-mediated reduction in FGF-2 was not blocked by the anti-progestin RU-486, suggesting that classical progesterone receptors (PR) are not involved in FGF-2 down-regulation. Also, P did not affect levels of FGF-2 mRNA in BT-474 cells, indicating that P exerts its effects on FGF-2 post-transcriptionally. Our observations suggest that the in vivo stimulation of BT-474 cell growth by P is associated with down-regulation of FGF-2 and FGF-8. Furthermore, since FGF-4 levels increased during P-treatment, FGF-4 may be required for tumor growth and maintenance and might therefore be a potential therapeutic target through which to suppress P-dependent tumor growth. PMID- 22237712 TI - Keratin 20 - a diagnostic and prognostic marker in colorectal cancer? AB - Colorectal cancer cells characteristically show strong expression of keratin 20 (K20) and lack expression of keratin 7 (K7). The biological significance of reduced K20 expression, however, is unclear. 381 colorectal cancers with 148 corresponding metastases were evaluated for K20 and K7 expression by immunohistochemistry using a tissue microarray technique. K20 immunoreactivity was assessed semiquantitatively as either negative, low (<50% of cancer cells) or high (>=50% of cancer cells). Progression-free and cancer-specific survivals were determined using the Kaplan-Meier method. Expression of K20 was observed in 348 out of 372 (94%) evaluable primary tumors, with 135 (36%) cases showing low K20 and 213 (57%) cases high K20 expression, while 24 (6%) tumors completely lacked K20 immunoreactivity. Reduced K20 expression (lack of staining or low expression) was significantly associated with poor differentiation, large tumor size and mismatch repair deficiency, but did not significantly affect patients' outcome. Immunoreactivity of K20 and K7 in metastatic tissues matched well with that of corresponding primary tumors, with high concordance for lymph node (p<0.001) and distant metastases (p<0.001), respectively. In conclusion, our data illustrate the value of keratin subtyping in carcinoma of unknown primary (CUP) syndrome: K20 expression is common in colorectal cancer and the K20 high / K7 negative immunoprofile represents the predominant phenotype. Reduced K20 expression may, however, lead to false-negative assessment of metastatic deposits if only small amounts of tissue are obtained (e.g. in needle biopsies), particularly in poorly differentiated cancers. Reduced expression of K20 may be used to select tumors for microsatellite instability testing. PMID- 22237713 TI - Immunohistochemical localization of complement regulatory proteins in the human retina. AB - Age-related macular degeneration (AMD) is a complex disease. Genetic studies have found strong associations between AMD and variants of several complement pathway associated genes. The regulation of the complement cascade seems to be critical in the pathogenesis of AMD. In 45 human donor eyes immunohistochemistry was performed using antibodies directed against major regulators of the complement system: complement factor H (CFH), decay accelerating factor (DAF/CD55), complement receptor 1 (CR1/CD35), and membrane cofactor protein (MCP/CD46). All eyes were classified in AMD and controls. 11 eyes were graded as early AMD. 34 eyes were controls. In all eyes staining was found in intercapillary pillars of choroid adjacent to Bruch's membrane for CFH, at the basal surface of RPE cells for MCP, and at the apical side of the retinal pigment epithelium for CR1. DAF immunoreactivity was increased along the inner segments of rod and cone photoreceptor cells at the level of the external limiting membrane Labeling of soft drusen was found for CFH and CR1. In addition, DAF and CR1 showed staining of ganglion cells in all eyes. CFH and particularly MCP showed decreased or absent staining in eyes with early AMD adjacent to Bruch's membrane. The overlapping expression of regulators at the level of Bruch's membrane and the retinal pigment epithelium shows the importance of this site for control of the complement system. Decreased and therefore unbalanced expression of regulators, as shown in this study for CFH and MCP, may ultimately lead to AMD. PMID- 22237714 TI - Thyroid hormone and anti-Mullerian hormone (AMH) on Leydig cell differentiation: studies using C57BL/6 mice and AMH over expressing mice. AB - Although the thyroid hormone has stimulatory effects and anti-Mullerian hormone (AMH) has inhibitory effects on prepubertal Leydig cell (LC) differentiation, it is important to find out whether the stimulatory effect of thyroid hormone could overcome the inhibitory effect of AMH on postnatal LC differentiation. Therefore, the objective of the present study was to use the anti-Mullerian hormone overexpressing mouse (AMH++) model to understand the simultaneous effects of AMH and thyroid hormone on postnatal LC differentiation, proliferation, maturation and function and to test whether the inhibitory effect of AMH could be overcome by the stimulatory effect of the thyroid hormone. Four age groups (7, 21, 40, 90 days) of control (C57BL/6; C) and AMH++ were used. Mice received either saline or triiodothyronine (T3) SC injections daily from birth to 21days. The four experimental groups were C, C+T3, AMH++ and AMH+T3. Body and testis weights of both C+T3 and AMH+T3 mice were significantly reduced at days 21, 40 and 90, compared to their age-matched saline-treated mice (C and AMH++). BrdU studies revealed the absence of LC proliferation in AMH++ mice at day7, however, same aged mice of C+T3 and AMH+T3 mice showed increased LC proliferation; the rate was highest in C+T3 at day21. C+T3 mice of day 21 had more LC than C mice as well as AMH+T3 and AMH++ mice. At days 40 and 90, LC number/testis in C+T3 was lower than C, however, AMH+T3 had higher LC numbers than AMH++ mice. Cellular apoptosis was not seen as the cause of reduced LC numbers. Serum testosterone was not different among groups at day 21, but significantly higher levels were seen in AMH+T3 compared to AMH++ mice at days 40 and 90. Similar pattern was seen for luteinizing hormone (LH)-stimulated testicular testosterone and androstenedione production in vitro. Findings suggest that T3-treatment for the first postnatal 21 days was able to partially counteract the inhibitory effect of AMH on prepubertal LC differentiation. Whether continuation of the T3-treatment beyond 21 days would have resulted in complete removal of this inhibition, is a question that needs to be addressed. PMID- 22237715 TI - Negative/low HER2 expression alone or combined with E-cadherin positivity is predictive of better prognosis in patients with breast carcinoma. AB - The loss of E-cadherin expression leads to absence of tissue integrity, an essential step in tumor progression. Methylation of CpG islands in the promoter region of the CDH1 gene coding E-cadherin might be an alternative for gene silencing. In the present study, we investigate the expression of E-cadherin and hormone receptors in invasive ductal breast carcinoma (IDCs). Protein expression was analysed immunohistochemically in 87 cases, including 26 familial tumors. The most interesting results revealed a significantly reduced E-cadherin expression in cases with familial history compared to sporadic tumors (p=0.009), as well as with tumors <=5 cm (p=0.022). Moreover, HER2 over-expression was associated with distant metastasis (p=0.011) and overall survival (p log rank=0.028). Tumors displaying negative/low HER2 expression combined with E-cadherin positivity confer better patient survival (p=0.052). Triple Negative tumors (TN) were more frequently found in patients with advanced grade (GIII) (p=0.001) and TNM (III+IV) (p=0.018) which supports the aggressive behavior of TN tumors. On the other hand, hypermethylation of CDH1 gene promoter was observed in 46% of hereditary cases and strongly associated with loss of E-cadherin expression (p=0.002). Furthermore, patients with unmethylated CDH1 pattern have a better 5 year disease free survival (p=0.021). In conclusion, in patients with hereditary breast cancer, the CpG methylation event contributes to the loss of E-cadherin expression. On the other hand, HER2 over-expression is predictive of worse prognosis, either alone or combined with loss of E-cadherin expression in Tunisian patients with breast cancer. PMID- 22237716 TI - Visualizing TGF-beta and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation. AB - BACKGROUND: The TGF-beta superfamily members transforming growth factor-beta (TGF beta/Activin) and bone morphogenetic proteins (BMP) have been implicated in the pathogenesis of atherosclerosis. However, their role in human disease remains controversial. In this study we used Smad phosphorylation as a read out for TGF beta and BMP signaling during the initiation, progression and (de)stabilization of human atherosclerotic disease. MATERIAL AND METHODS: A systematic analysis was performed in 114 peri-renal aortic patches (stained with Movat Pentachrome, H&E, pSmad2, pSmad1,5,8 and PAI-1) covering the entire atherosclerotic spectrum (van Dijk, 2010). Immunostaining against T-cells (CD3) and monocytes and macrophages (CD68) was used to explore a putative association between TGF-beta and BMP signaling and vascular inflammation. RESULTS: Smad phosphorylation was present within the normal arterial wall in approximately 10% of the endothelial cells and intimal smooth muscle cells. A significant increase in pSmad2 and pSmad1,5,8 positivity was found in non-progressive lesions (>50% positivity). No further increase or decrease was found in the progressive atherosclerotic lesions, vulnerable and stabilized lesions. No association was found between TGF-beta and BMP signaling and CD3 and CD68 expression, nor cap thickness. CONCLUSION: Activation of the TGF-beta and BMP pathways is an early event in atherosclerotic lesion formation. No significant relationships were found between Smad phosphorylation and vessel wall inflammation or plaque vulnerability. PMID- 22237717 TI - Antenatal depressive symptoms among Canadian-born and immigrant women in Quebec: differential exposure and vulnerability to contextual risk factors. AB - PURPOSE: To examine the distribution of contextual risk factors for antenatal depression according to immigrant status and the length of stay in Canada, to assess the association between these risk factors and antenatal depression (AD) for Canadian-born and immigrant women, and to compare the vulnerability of Canadian-born and immigrant women to risk factors in relation to antenatal depression. METHODS: Women were recruited at routine ultrasound examinations (16 20 weeks), at antenatal blood sampling (8-12 weeks), or in antenatal care clinics. Cross-sectional analysis was performed on the baseline sample consisting of 5,162 pregnant women. CES-D scale was used to investigate depression. Levels of exposure to the selected risk factors according to immigrant status and length of stay were assessed using Chi-square-test or the t test. All measures of association were assessed using logistic regression. Multiplicative interaction terms were constructed between each of the risk factors and immigrant status to reveal differential vulnerability between Canadian-born and immigrant women. RESULTS: Prevalence of AD (CES-D >=16 points) was higher in immigrants (32% [29.6 34.4]) than in Canadian-born women (22.8% IC 95% [21.4-24.1]). Immigrant women were significantly more exposed than Canadian-born women to adverse contextual risk factors such as high marital strain, lack of social support, poverty, and crowding. At the same level of exposure to risk factors, Canadian-born women presented higher vulnerability to AD when lacking social support (OR = 4.14 IC 95% [2.69; 6.37]) while immigrant women presented higher vulnerability to AD when lacking money for basic needs (OR = 2.98 IC 95% [2.06; 4.32]). CONCLUSIONS: Important risk factor exposure inequalities exist between Canadian-born and immigrant pregnant women. Interventions should target poverty and social isolation. The observed high frequency of AD highlights the need to evaluate the effectiveness of preventive interventions of antenatal depression. PMID- 22237718 TI - High prevalence of eating disorders not otherwise specified in northwestern Spain: population-based study. AB - PURPOSE: To determine the incidence and prevalence of eating disorder and its clinical forms. METHODS: All new ED cases of both genders, >=15 years old, diagnosed from January 2005 to December 2009 were included. All patients who suffered from ED in December 2009 were included in the prevalence study. This is a prospective, population-based study. Cumulative incidence rates and 20-year prevalence were calculated. RESULTS: The ED incidence was 14.1 (95% CI 11.4-16.1) cases per 100,000 inhabitants per year, for AN, BN and EDNOS 3.1 (95% CI 2.00 4.1), 4.4 (95% CI 3.0-8.00) and 6.5 (95% CI 4.8-7.9), respectively. The incidence of ED at the four age-intervals, 15-24, 25-34, 35-45 and >45 years, revealed that the 25-34-year interval had the highest incidence; moreover, new cases were observed even in the >45-year interval. The prevalence of ED was 82.8 (95% CI 69.4-94.5) per 100,000 inhabitants, being for AN, BN and EDNOS 18.6 (95% CI 12.5 24.4), 25.7 (95% CI 18.5-32.5) and 38.3 (95% CI 29.4-46.5), respectively. CONCLUSIONS: The incidence and prevalence of EDNOS are the highest in the ED cases; furthermore, new cases of ED are observed above the age of 45, which are remarkable data. PMID- 22237719 TI - Biomarkers of calcification and atherosclerosis in patients with degenerative aortic stenosis in relation to concomitant coronary artery disease. AB - INTRODUCTION: There is an ongoing debate regarding aortic valve degenerative processes. Some markers of calcification and atherosclerosis may be potentially useful in establishing their etiology. OBJECTIVES: The aim of the study was to assess the biochemical markers of calcification and atherosclerosis in patients with degenerative aortic stenosis (AS) in relation to the aortic valve calcium score (AVCS) and concomitant coronary artery disease (CAD). PATIENTS AND METHODS: The study involved 88 patients: 68 patients with degenerative AS (group A), including 44 patients with severe AS (A1; 25 patients with CAD) and 24 patients with moderate AS (A2; 13 patients with CAD) and 20 matched subjects as controls (18 patients with CAD). In all patients, clinical data were assessed, laboratory tests were done (including the analysis of serum interleukin4 [IL-4], osteoprotegerin [OPG], and fetuin-A levels), coronary angiography was performed, and the AVCS was measured. RESULTS: Study groups and subgroups had comparable serum IL-4, OPG, and fetuin-A levels. There were significant differences in the AVCS between patients with severe AS, moderate AS, and controls (3605 +/- 2542 Agatston units [AU], 1390 +/- 1143 AU, 100 +/- 194 AU, respectively; P <0.001). There were no significant correlations between the AVCS and serum IL-4, OPG, or fetuin-A levels. In moderate AS, serum OPG levels were higher in subjects with concomitant CAD (5.84 +/- 1.4 vs. 4.03 +/- 1.3 pmol/l, P = 0.036). In severe AS, the mean AVCS was similar in patients with and without CAD. Higher AVCS was observed only in patients with moderate AS and coexisting CAD compared with patients without CAD (1644 +/- 1285 vs. 902 +/- 789 AU, P = 0.038). CONCLUSIONS: There were no significant differences between patients with and without degenerative AS in selected biochemical markers. The presence of CAD in moderate AS was associated with increased AVCS and serum OPG levels suggesting the effect of atherosclerosis on early valve calcification. In patients with severe AS, there were no correlations between calcification and atherosclerotic markers. PMID- 22237720 TI - Education: a microfluidic platform for university-level analytical chemistry laboratories. AB - We demonstrate continuous flow acid-base titration reactions as an educational microfluidic platform for undergraduate and graduate analytical chemistry courses. A series of equations were developed for controlling and predicting the results of acid-base neutralisation reactions conducted in a microfluidic format, including the combinations of (i) a strong base and a strong acid, (ii) a strong base and a weak acid, and (iii) a strong base and a multiprotic acid. Microfluidic titrations yielded excellent repeatability. The small experimental footprint is advantageous in crowded teaching laboratories, and it offers limited waste and exposure to potentially hazardous acids and bases. This platform will help promote the utilisation of microfluidics at an earlier stage of students' careers. PMID- 22237721 TI - An uncommon cause of Dysphagia. PMID- 22237722 TI - The effect of surface electrical stimulation on swallowing in dysphagic Parkinson patients. AB - Surface electrical stimulation has been applied on a large scale to treat oropharyngeal dysphagia. Patients suffering from oropharyngeal dysphagia in the presence of Parkinson's disease have been treated with surface electrical stimulation. Because of controversial reports on this treatment, a pilot study was set up. This study describes the effects of a single session of surface electrical stimulation using different electrode positions in ten patients with idiopathic Parkinson's disease (median Hoehn and Yahr score: II) and oropharyngeal dysphagia compared to ten age- and gender-matched healthy control subjects during videofluoroscopy of swallowing. Three different electrode positions were applied in random order per subject. For each electrode position, the electrical current was respectively turned "on" and "off" in random order. Temporal, spatial, and visuoperceptual variables were scored by experienced raters who were blinded to the group, electrode position, and status (on/off) of the electrical current. Interrater and interrater reliabilities were calculated. Only a few significant effects of a single session of surface electrical stimulation using different electrode positions in dysphagic Parkinson patients could be observed in this study. Furthermore, significant results for temporal and spatial variables were found regardless of the status of the electrical current in both groups suggesting placebo effects. Following adjustment for electrical current status as well as electrode positions (both not significant, P > 0.05) in the statistical model, significant group differences between Parkinson patients and healthy control subjects emerged. Further studies are necessary to evaluate the potential therapeutic effect and mechanism of electrical stimulation in dysphagic patients with Parkinson's disease. PMID- 22237723 TI - Guidelines for pediatric management of severe chronic neutropenia. PMID- 22237724 TI - Reduced expression of microtubule-associated protein 1 light chain 3 in hypertrophic scars. AB - Autophagy is a tightly regulated physiological process essential for cellular maintenance, differentiation, development, and homeostasis. Aberration of this process associates with the pathogeneses of several diseases in mammals. Hypertrophic scar (HS) is characterized by an abundance of collagenous tissue with hypercellularity. However, the molecular mechanism in HS formation is poorly understood. We compared the autophagic capacity in HS and its normal skin (NS) counterparts and explored the molecular mechanism of autophagy during the formation of HS. Microtubule-associated protein 1 light chain 3 (LC3) proteins in HS and NS were detected by immunohistochemistry, Western blot and quantitative real-time PCR (qPCR). The data showed that LC3 positive staining in HS was less intensive relative to NS group (p < 0.05). Three forms of LC3, with molecular weights of about 19 kDa (proLC3), 18 kDa (LC3-I) and 16 kDa (LC3-II), respectively, expressed in NS by Western blot. In contrast, only proLC3 expressed while both LC3-I and LC3-II were significantly downregulated in HS. The protein level of beclin 1 in HS was significantly lower compared with NS (p < 0.05). LC3 and beclin 1 mRNA levels in HS were significantly lower than that in NS (p < 0.05). These results suggest that the generation of LC3-I and LC3-II are interrupted in HS, and that the resultant decrease of autophagic capacity may associate with the pathogenesis of HS. PMID- 22237725 TI - Protective effects of beta-glucan against oxidative injury induced by 2.45-GHz electromagnetic radiation in the skin tissue of rats. AB - In recent times, there is widespread use of 2.45-GHz irradiation-emitting devices in industrial, medical, military and domestic application. The aim of the present study was to investigate the effect of 2.45-GHz electromagnetic radiation (EMR) on the oxidant and antioxidant status of skin and to examine the possible protective effects of beta-glucans against the oxidative injury. Thirty-two male Wistar albino rats were randomly divided into four equal groups: control; sham exposed; EMR; and EMR + beta-glucan. A 2.45-GHz EMR emitted device from the experimental exposure was applied to the EMR group and EMR + beta-glucan group for 60 min daily, respectively, for 4 weeks. beta-glucan was administered via gavage at a dose of 50 mg/kg/day before each exposure to radiation in the treatment group. The activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), as well as the concentration of malondialdehyde (MDA) were measured in tissue homogenates of the skin. Exposure to 2.45-GHz EMR caused a significant increase in MDA levels and CAT activity, while the activities of SOD and GSH-Px decreased in skin tissues. Systemic beta-glucan significantly reversed the elevation of MDA levels and the reduction of SOD activities. beta-glucan treatment also slightly enhanced the activity of CAT and prevented the depletion of GSH-Px activity caused by EMR, but not statistically significantly. The present study demonstrated the role of oxidative mechanisms in EMR-induced skin tissue damages and that beta-glucan could ameliorate oxidative skin injury via its antioxidant properties. PMID- 22237726 TI - Practical approaches to diagnose and treat for T0 malignant pleural mesothelioma: a proposal for diagnostic total parietal pleurectomy. AB - Malignant pleural mesothelioma (MPM) remains suffering poor prognosis in spite of recent diagnostic and therapeutic progress. Although there is currently no established evidence, early diagnosis and early intervention may play a key role to improve prognosis of MPM, similarly to other malignancies. As pleural effusion is usually the first clinical sign of MPM, pleural effusion cytology is often the first diagnostic examination to be carried out. Since the sensitivity of pleural effusion cytology is approximately 60%, however, false-negative diagnosis is given to almost half of true MPM patients at this clinical step. One practical way to reduce the number of misdiagnosed MPM is to encourage performing thoracoscopic pleural biopsy unless definitive diagnosis other than MPM is established. There still remain a considerable number of patients with radiological/thoracoscopic T0 MPM who are misdiagnosed with nonspecific pleuritis after a complete investigation including thoracoscopic biopsies. Such patients will turn out to be malignant during follow-up period, although they have the best opportunity for long-term survival if only early therapeutic intervention is given. Currently, we are performing diagnostic total parietal pleurectomy in highly selected patients, who are characterized with strong clinical suspicion, positive pleural effusion cytology but uncertain pathological diagnosis, excellent cardiopulmonary reserve, and with written informed consent for highly invasive diagnostic surgery for pathologically unproven disease. PMID- 22237728 TI - Intermolecular acetaldehyde and dimethoxymethane formation mechanisms via ethenol and methoxymethylene precursors in reactions of atomic carbon with methanol: a computational study. AB - Atomic carbon, a reactive intermediate abundant in the interstellar medium (ISM) can participate in various energetically demanding reactions in its extremely long living (69 min) first excited singlet state ((1)D). Several studies on reactions of oxygen containing species with carbon atoms have been reported, however mechanistic details of the title reaction remain obscure. We report here quantum chemical studies on reactions of methanol with (3)P and (1)D carbon atoms at the CCSD(T)/cc-pVTZ level of theory, with which experimentally well known facile CO production, intermolecular acetaldehyde formation, and intermolecular dimethoxymethane production mechanisms are explained. Energetics of the fragmentation, O-H insertion, C-H insertion, and O-C insertion channels on the triplet and singlet surfaces are studied. The CO production mechanism by C ((1)D) is identified as an oxygen abstraction and a triplet PES seems non-operative. Presenting novel features for the intermolecular reaction channels, current findings may be applicable to C + ROR reactions. PMID- 22237727 TI - Pathological and molecular biological approaches to early mesothelioma. AB - Malignant mesothelioma is an asbestos-related malignancy that arises primarily from mesothelial cells on the serosal surfaces of the pleural, peritoneal, and pericardial cavities. Malignant pleural mesothelioma (MPM) is most common, and its incidence is dramatically increasing worldwide as a result of widespread use of asbestos. Morphological discrimination between MPM and reactive mesothelial hyperplasia is difficult, and the most reliable pathological criterion for malignancy is mesothelial proliferation invading deeply into subpleural adipose tissues. To establish radical cure of MPM, it is crucial to find early-stage MPM of epithelial type, in which mesothelial proliferation is localized on the serosal surface of parietal pleura or limited within the submesothelial fibrous tissues of parietal pleura. The initial clinical presentation for patients with MPM is frequently dyspnea and/or chest pain due to large pleural effusion, and cytological analysis of pleural effusions is valuable to find patients with early stage MPM of epithelial type. Recently, cytological features of MPM in pleural effusion, molecular markers for MPM, and genetic alternations of MPM have been reported. In this review, we discuss major issues on pathological and molecular biological approaches for diagnosis of early-stage MPM of epithelial type. PMID- 22237729 TI - Evidences for viral strain selection in late stages of HIV infection: an analysis of Vpu alleles. AB - One of the most studied topics about AIDS disease is the presence of different progression levels in patients infected by HIV. Several studies have shown that this progression is directly associated with host genetics, although viral factors are also known to play a role. Here we explore the contribution of Vpu protein in the evolution of viral population. The sequence variation of Vpu was analyzed during HIV infection in peripheral blood monocyte cells of 12 patients in different clinical stages of HIV-1 infection early and late stages of infections, separated by at least 4 years. The clustering analysis of Vpu sequences showed higher diversity of early alleles, non-random distribution of sequences, and viral evolution strains selection. Forty-two amino acid modifications were found in the multiple alignments of the 57 different alleles found for early stage were 23 modifications were found in the late stage dataset. Interestingly fourteen alteration of early stage were located in conserved site related with Vpu functions alterations while these alterations appear with less frequency in the late stage of infection. Moreover, late stage alleles tend to be similar with the Vpu wild type sequence, suggesting viral selection toward populations harboring more efficient variants during the course of infection. This would contribute to higher infectivity and viral replication actually observed at the aggressive late stages of infection. These data, in conjunction with in vitro experiments, will be important to elucidation of the physiological relevance of Vpu protein in the pathogenic mechanisms of AIDS. PMID- 22237731 TI - Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. AB - BACKGROUND: The impact of nationwide centralization of pancreaticoduodenectomy (PD) on mortality is largely unknown. The aim of this study was to analyse changes in hospital volumes and in-hospital mortality after PD in the Netherlands between 2004 and 2009. METHODS: Nationwide data on International Classification of Diseases, ninth revision (ICD-9) code 5-526 (PD, including Whipple), patient age, sex and mortality were retrieved from the independent nationwide KiwaPrismant registry. Based on established cut-off points of annually performed PDs, hospitals were categorized as very low (fewer than 5), low (5-10), medium (11-19) or high (at least 20) volume. A subgroup analysis based on a cut-off age of 70 years was also performed. RESULTS: Some 2155 PDs were included. The number of hospitals performing PD decreased from 48 in 2004 to 30 in 2009 (P = 0.011). In these specific years, the proportion of patients undergoing PD in a medium- or high-volume centre increased from 52.9 to 91.2 per cent (P < 0.001). Nationwide mortality rates after PD decreased from 9.8 to 5.1 per cent (P = 0.044). The mortality rate during the 6-year period was 14.7, 9.8, 6.3 and 3.3 per cent in very low-, low-, medium- and high-volume hospitals respectively (P < 0.001). The difference in mortality between medium- and high-volume centres was statistically significant (P = 0.004). The volume-outcome relationship was not influenced by age (P = 0.467). The mortality rate after PD in patients aged at least 70 years was 10.4 per cent compared with 4.4 per cent in younger patients (P < 0.001). CONCLUSION: With nationwide centralization of PD, the in-hospital mortality rate after this procedure decreased. Further centralization of PD is likely to decrease mortality further, especially in the elderly. PMID- 22237730 TI - Molecular bioelectricity in developmental biology: new tools and recent discoveries: control of cell behavior and pattern formation by transmembrane potential gradients. AB - Significant progress in the molecular investigation of endogenous bioelectric signals during pattern formation in growing tissues has been enabled by recently developed techniques. Ion flows and voltage gradients produced by ion channels and pumps are key regulators of cell proliferation, migration, and differentiation. Now, instructive roles for bioelectrical gradients in embryogenesis, regeneration, and neoplasm are being revealed through the use of fluorescent voltage reporters and functional experiments using well-characterized channel mutants. Transmembrane voltage gradients (V(mem) ) determine anatomical polarity and function as master regulators during appendage regeneration and embryonic left-right patterning. A state-of-the-art recent study reveals that they can also serve as prepatterns for gene expression domains during craniofacial patterning. Continued development of novel tools and better ways to think about physical controls of cell-cell interactions will lead to mastery of the morphogenetic information stored in physiological networks. This will enable fundamental advances in basic understanding of growth and form, as well as transformative biomedical applications in regenerative medicine. PMID- 22237732 TI - A 100-year sedimentary record of natural and anthropogenic impacts on a shallow eutrophic lake, Lake Chaohu, China. AB - In this study, the sediment profiles of total organic carbon, total nitrogen, C/N ratios, total phosphorus, N/P ratios, C/P ratios, particle sizes, and stable carbon and nitrogen isotopes (delta(13)C and delta(15)N) were used to investigate natural and anthropogenic impacts on Lake Chaohu over the past 100 years. Before 1960, Lake Chaohu experienced low productivity and a relatively steady and low nutrient input. The increasing concentration and fluxes of total organic carbon, total nitrogen, total phosphorus, together with changes in the delta(13)C and delta(15)N of organic material in the sediment cores, suggested that the anthropogenic effects on trophic status first started because of an increase in nutrient input caused by a population increase in the drainage area. With the construction of the Chaohu Dam, an increase in the utilization of fertilizer and the population growth which occurred since 1960, stable depositional conditions and increasing nutrient input resulted in a dominantly algae-derived organic matter source and high productivity. Nutrient input increased most significantly around 1980 following the rapidly growing population, with concomitant urbanization, industrial and agricultural development. This study also revealed that the concentration and distribution of nutrients varied between different areas of sediment within Lake Chaohu because of the influence of different drainage basins and pollution sources. PMID- 22237734 TI - Surgery for atrial fibrillation: recent progress and future perspective. AB - Development and introduction of radiofrequency ablation devices allowed the maze procedures to be performed safely and easily, further enabling off-pump pulmonary vein isolation through a mini-thoracotomy or thoracoscope. The effects of the maze procedure include prevention of stroke and other complications related to atrial fibrillation, improved cardiac performance, and relief of symptoms. Indications for the maze procedure have been discussed on the basis of the evidence. Pulmonary vein isolation has been shown to be effective in most patients with paroxysmal atrial fibrillation and can be performed with endocardial catheter ablation and minimally invasive epicardial ablation. These two modalities should be compared in terms of the success rate, occurrence of cerebral microembolic signals, capability of additional lesions indicated for persistent or long-standing persistent atrial fibrillation, and closure of the left atrial appendage. Noncontinuous or nontransmural lines of conduction block as a result of incomplete ablation can result in recurrence of atrial fibrillation and induction of atrial tachycardia. Intraoperative verification of conduction block across the ablation lines is recommended to prevent these complications. Volume reduction of the enlarged left atrium or a boxlesion to isolate the entire posterior left atrium may be effective in patients with a dilated left atrium, but the potentially impaired atrial transport function should be considered. Mapping of active ganglionated plexi and their ablation may improve the outcome of the procedure, but the long-term effect on atrial fibrillation and autonomic nerve activities should be examined. PMID- 22237733 TI - Thymoma and thymic carcinoma. AB - Thymic tumors comprise a heterogeneous group of neoplasms with a wide spectrum of clinical presentations. The evolution of the disease is often unpredictable, ranging from an indolent attitude to the possibility of intra- and extrathoracic spread. From the histological point of view, thymoma and thymic carcinoma are the most frequent subtypes and arise only from thymic epithelial cells. Other histological types are even more rare and are usually considered separately. A number of prognostic factors have been validated as predictors of outcome: staging, World Health Organization histological classification, diameter of the tumor, associated paraneoplastic syndromes, completeness of resection, and early onset of recurrence. Complete surgical resection is the key factor for cure and should be considered the gold standard at any stage. Especially for more aggressive lesions, surgery should be considered with a multimodality approach, involving induction and adjuvant therapy according to the stage. Multimodality therapy protocols have been designed based on the integration of clinical staging and histology. Neoadjuvant therapy is now administered before surgical resection in patients with tumors considered inoperable as it improves resectability and survival and reduces the risk of recurrence. Adjuvant treatment has been extensively reported after both complete or partial resection. New targeted therapies are in the developmental stage, and in the future they will be part of the standard protocols. Integrated treatment modalities require strict cooperation between medical and radiation oncologists, thoracic surgeons, and pathologists. PMID- 22237735 TI - Multicenter trial of carperitide in patients with renal dysfunction undergoing cardiovascular surgery. AB - PURPOSE: The aim of this study was to evaluate the efficacy of carperitide in maintaining renal function during intraoperative and postoperative management of patients with renal dysfunction undergoing elective cardiovascular surgery. METHODS: The subjects were 88 patients with a preoperative serum creatinine level >=1.2 mg/dl who underwent elective cardiovascular surgery using cardiopulmonary bypass. They were prospectively divided into a group that received carperitide from the start of surgery (carperitide group, n = 44) and a group that was not given carperitide (control group, n = 44). Carperitide infusion was initiated at the beginning of surgery and was continued for >=5 days, with the central dose being 0.02 g/kg/min. The primary endpoint was the serum creatinine level on postoperative day (POD) 3. RESULTS: The serum creatinine levels on PODs 3, 4, and 7 were significantly lower, and creatinine clearance on PODs 2 and 3 was significantly higher in the carperitide group than in the controls. One patient in the control group and no patient in the carperitide group required continuous hemodiafiltration, but the difference was not statistically significant. CONCLUSION: Continuous low-dose infusion of carperitide from the start of cardiovascular surgery maintained renal function in patients with preoperative renal dysfunction. PMID- 22237736 TI - Morphological evaluation of areas of damage in blunt cardiac injury and investigation of traffic accident research. AB - PURPOSE: This study investigated the relation between the cause of blunt cardiac injury and areas of damage. For the purpose of injury prevention, we also examined traffic accident cases in a micro study using engineering-based medicine. METHODS: Among the 2673 patients transported to our facility within the 15-month period from February 2009 to April 2010, there were 12 cases of cardiac perforation. We studied these cases anatomically to evaluate the morphology of the damaged cardiac areas. We conducted a detailed micro-study in two cases regarding the circumstances surrounding the traffic accident and the vehicular damage. RESULTS: Subjects were nine men (mean age 64 years). The mean Injury Severity Score was 54.0 +/- 19.6, and the probability of survival was 0.147. The actual survival rate was 16.7% (2 survivors, 10 deaths). Lesion sites in the 12 cases (21 sites in total) were the right atrium in 8 cases, superior and inferior vena cava in 5 cases, right ventricle in 4 cases, pulmonary artery and left atrium in 1 case each, and pulmonary vein in 2 cases, excluding the left ventricle and ascending aorta. In three cases, the aortic isthmus was also injured. CONCLUSION: Blunt cardiac injury was more common on the right side chamber. The survival rate was extremely close to the calculated survival probability. Proper seatbelt usage is important for the prevention of blunt cardiac injury due to traffic accidents. Increased severity of injury may be associated with accidents involving light motor vehicles. PMID- 22237737 TI - Efficacy of functional operability algorithm for octogenarians with primary lung cancer. AB - PURPOSE: The number of lung cancer patients is increasing in association with the aging of society, and age is associated with the risk of undergoing a thoracotomy procedure. We prospectively investigated the efficacy of a functional operability algorithm that included pulmonary function and exercise test results for determining the indication for surgery in octogenarians. METHODS: From April 2001 to October 2008, surgical indications for a total of 45 octogenarians were assessed using our algorithm, including forced expiratory volume in 1 s/forced vital capacity ratio, predicted postoperative percent of forced expiratory volume in 1 s, Hugh-Jones dyspneic index, and empirical anaerobic threshold obtained during an exercise test. Then the surgical results were reviewed. RESULTS: Thoracotomy was contraindicated in one patient; the remaining 44 patients underwent surgery. Axilloanterior thoracotomy (75%), lobectomy (84%), and mediastinal lymph node dissection (73%) were the major procedures. Altogether, 37 postthoracotomy complica-Received: 13 February 2011 / Accepted: 30 May 2011 (c) The Japanese Association for Thoracic Surgery 2012 tions occurred in 29 (65.9%) patients. The 30-day and hospital mortality rates were 2.3% and 4.5%, respectively, and overall and disease-specific 5-year survival rates for the 42 patients were 54.5% and 79.6%, respectively. CONCLUSION: Following careful selection with our functional operability algorithm, octogenarians were able to tolerate a standard lung resection for primary lung cancer with acceptable morbidity and mortality. Their survival was consistent with that of younger cancer patients. PMID- 22237738 TI - Role of pulmonary resection in the diagnosis and treatment of limited-stage small cell lung cancer: revision of clinical diagnosis based on findings of resected specimen and its influence on survival. AB - PURPOSE: Our aims were to evaluate (1) the result of surgical treatment of limited-stage small cell lung cancer (SCLC) by examining long-term survival and prognostic factors, (2) the diagnostic role of surgery by comparing clinical and histopathological diagnoses and staging, and (3) the impact of preoperative diagnostic accuracy on survival. METHODS: We retrospectively reviewed the clinical profiles of 37 patients treated at our institution between January 1990 and December 2007 for SCLC diagnosed using surgical specimens. RESULTS: The median follow-up period was 41.2 months, and the 5-year survival rate was 57.5%. Lobectomy or wider resection was performed alone in 33 cases and with mediastinal dissection in 29 cases. Fifteen patients did not receive chemotherapy. SCLC was diagnosed preoperatively or intraoperatively in 75% and non-SCLC in 25%. Clinical stage 1 disease was diagnosed in 29 patients; however, pathological stage 1 was seen in only 20. Patients at pathological stage 1 disease showed better survival than those at stage 2, but a similar result was not obtained in the case of clinical stage of the disease. Tumor size and nodal stage were the only significant factors influencing survival in a multivariate analysis. The adequacy of preoperative clinical diagnosis of tumor extensiveness, nodal involvement, and clinical stage did not significantly influence survival. CONCLUSION: Surgery for limited-stage SCLC was associated with a favorable survival rate and provided important pathological information that can help predict survival. Accuracy of preoperative diagnoses showed no apparent impact on survival for surgically treated SCLC patients. PMID- 22237739 TI - Hammock mitral valve in an adult patient. AB - We describe a case of hammock mitral valve in an adult. A 38-year-old woman presented with recently acquired dyspnea. Echocardiography showed severe mitral stenosis related to a hammock mitral valve characterized by the presence of an overdeveloped papillary muscle that gives short chordae to both mitral leaflets. No other valve insufficiency was noted. At operation, we observed direct continuity accompanying several fenestrations between both leaflets and the huge abnormal muscular band just underneath the mural leaflet. Resection of the anterior leaflet and was successfully replaced with a bioprosthetic valve. Her postoperative course was unremarkable. PMID- 22237740 TI - One-stage operation for esophageal perforation of a thoracic aortic aneurysm. AB - The patient was a 65-year-old man. Preoperative computed tomography showed a ruptured thoracic aortic aneurysm that formed a submucosal hematoma in the thoracic esophagus with perforation near the esophageal-cardiac junction. A one stage operation was performed. The aortic arch and proximal descending aorta were replaced with rifampicin-soaked synthetic grafts, followed by subtotal esophagectomy with primary reconstruction using a gastric tube. His early postoperative course was uneventful, and he started oral intake on postoperative day (POD) 15; however, dysphagia occurred on POD 20, and an esophageal fistula and mediastinitis developed more than 1 month after the operation. The patient recovered from mediastinitis after 4 months of mediastinal drainage and administration of antibiotics. Thus, a one-stage operation for esophageal perforation of a ruptured thoracic aortic aneurysm with primary esophageal reconstruction is possible in selected patients. Care must be taken to avoid postoperative compression of the reconstructed esophagus by a mediastinal hematoma. PMID- 22237741 TI - Muscle plombage for extensive bronchial necrosis after right lower lobectomy. AB - Bronchial stump necrosis is a lethal complication after pulmonary resection. We report a patient who had extensive necrosis of the intermediate bronchus after right lower lobectomy. The large bronchial defect was successfully fixed with latissimus dorsi muscle and replaced by bronchial epithelialization. PMID- 22237742 TI - Micro-immunohistochemistry using a microfluidic probe. AB - A flexible method to extract more high-quality information from tissue sections is critically needed for both drug discovery and clinical pathology. Here, we present micro-immunohistochemistry (MUIHC), a method for staining tissue sections at the micrometre scale. Nanolitres of antibody solutions are confined over micrometre-sized areas of tissue sections using a vertical microfluidic probe (vMFP) for their incubation with primary antibodies, the key step in conventional IHC. The vMFP operates several micrometres above the tissue section, can be interactively positioned on it, and even enables the staining of individual cores of tissue microarrays with multiple antigens. MUIHC using such a microfluidic probe is preservative of tissue samples and reagents, alleviates antibody cross reactivity issues, and allows a wide range of staining conditions to be applied on a single tissue section. This method may therefore find broad use in tissue based diagnostics and in research. PMID- 22237743 TI - Structural plasticity of hippocampal mossy fiber synapses as revealed by high pressure freezing. AB - Despite recent progress in fluorescence microscopy techniques, electron microscopy (EM) is still superior in the simultaneous analysis of all tissue components at high resolution. However, it is unclear to what extent conventional fixation for EM using aldehydes results in tissue alteration. Here we made an attempt to minimize tissue alteration by using rapid high-pressure freezing (HPF) of hippocampal slice cultures. We used this approach to monitor fine-structural changes at hippocampal mossy fiber synapses associated with chemically induced long-term potentiation (LTP). Synaptic plasticity in LTP has been known to involve structural changes at synapses including reorganization of the actin cytoskeleton and de novo formation of spines. While LTP-induced formation and growth of postsynaptic spines have been reported, little is known about associated structural changes in presynaptic boutons. Mossy fiber synapses are assumed to exhibit presynaptic LTP expression and are easily identified by EM. In slice cultures from wildtype mice, we found that chemical LTP increased the length of the presynaptic membrane of mossy fiber boutons, associated with a de novo formation of small spines and an increase in the number of active zones. Of note, these changes were not observed in slice cultures from Munc13-1 knockout mutants exhibiting defective vesicle priming. These findings show that activation of hippocampal mossy fibers induces pre- and postsynaptic structural changes at mossy fiber synapses that can be monitored by EM. PMID- 22237745 TI - Renalase, kidney function, and markers of endothelial dysfunction in renal transplant recipients. AB - INTRODUCTION: Renalase is an enzyme released by the kidneys, which breaks down catecholamines in the blood and thus may regulate blood pressure. In kidney transplant recipients, endothelial dysfunction is often present. OBJECTIVES: The aim of the study was to assess associations between renalase, blood pressure, and kidney function in kidney allograft recipients. PATIENTS AND METHODS: We studied 62 kidney allograft recipients. Complete blood count, urea and creatinine levels, serum lipids, and fasting glucose were measured by standard laboratory methods. We also assessed markers of coagulation: prothrombin fragments 1+2; fibrinolysis: tissue plasminogen activator (tPA), plasminogen activator inhibitor, plasmin antiplasmin complexes; endothelial function/injury: von Willebrand factor (vWF), thrombomodulin, intercellular adhesion molecule, vascular cell adhesion molecule (VCAM); and inflammation: high-sensitivity C-reactive protein and interleukin 6. Renalase levels were assessed using a commercially available kit. RESULTS: Mean serum renalase levels in kidney allograft recipients correlated with age, time after transplantation, soluble CD44 (sCD44), VCAM, serum creatinine, estimated glomerular filtration rate (eGFR; measured by CKD-EPI, MDRD, and Cockcroft-Gault formulas), serum phosphate, urea, sCD146, vWF, and thrombomodulin and tended to correlate with tPA. In patients with eGFR above 60 ml/min, renalase was lower than in those with lower eGFR. In hypertensive allograft recipients, renalase was significantly higher than in normotensives. A multiple regression analysis showed that renalase was predicted in 58% by serum creatinine. CONCLUSIONS: Renalase, which is highly elevated in kidney transplant recipients, is dependent primarily on kidney function, which deteriorates with age and time after transplantation. Further studies are needed to establish the putative role of renalase in the pathogenesis of hypertension after transplantation and its possible use in novel targeted therapies. PMID- 22237746 TI - Acute kidney injury following acute liver failure: potential role of systemic cadmium mobilization? AB - OBJECTIVE: A significant fraction of patients with acute liver failure (ALF) suffer from a concomitant acute kidney injury (AKI), the mechanism of which is probably multifactorial. Cadmium (Cd) is a widespread environmental pollutant and a tubulotoxic metal that accumulates in the liver. We tested the hypothesis that a release of Cd during ALF may cause a redistribution of Cd from the liver to the kidneys and play a role in the occurrence of ALF-associated AKI. METHODS: Twenty patients with ALF (ALF-patients), 20 patients from the ICU with no liver damage at admission (ICU-controls) and 20 healthy controls were recruited to compare the 24-h urinary excretion rate of Cd with that of lead (Pb), a nephrotoxic metal that does not accumulate in the liver, and zinc (Zn), a non-nephrotoxic element found in high amounts in the liver. The excretion rates of the low-molecular weight proteins (LMWPs) were monitored. RESULTS: ALF-patients excreted markedly more Cd than the healthy controls and ICU-controls. In ALF-patients, the four urinary LMWPs (RBP, beta2-MG, CC16 and alpha1-MG) increased as a function of Cd excretion, with high correlation coefficients. The prevalence of patients excreting a high amount of LMWPs also increased with increasing Cd excretion. No relationship was found between the other elements investigated and the LMWPs, with the exception of copper, which shares close toxicokinetic similarities with Cd. CONCLUSIONS: This study shows a strong association between urinary Cd levels and the excretion rates of LMWPs in patients with ALF. A causal relationship is possible but could not be fully demonstrated in this study. PMID- 22237747 TI - In-line filter included into the syringe infusion pump assembly reduces flow irregularities. AB - PURPOSE: To evaluate whether an in-line filter inserted in the syringe pump infusion line assembly influences start-up times and flow irregularities during vertical pump displacement at low infusion rates. METHODS: Fluid delivery after syringe pump start-up and after vertical displacement of the syringe pump by -50 cm was determined gravimetrically at flow rates of 0.5, 1.0 and 2.0 ml h(-1). Measurements were repeated for each flow rate four times with two different syringe pumps with and without an in-line filter incorporated. Data are shown as median and range. RESULTS: Start-up times were reduced by an in-line filter at 0.5 ml h(-1) flow rate from 355.5 s (0-660) to 115 s (0-320), whereas the effect was attenuated at higher flow rates. Pooling of fluid into the infusion system after lowering the infusion syringe pump was halved in all flow rates tested. Amount of infusion bolus after elevating the syringe pump by 50 cm was not affected by an in-line filter. CONCLUSION: In the evaluated model in-line filters help to reduce flow irregularities and delay in drug delivery of syringe pumps at low flow rates and represent an option to optimize continuous administration of highly concentrated short-acting drugs at very small infusion rates. PMID- 22237748 TI - Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. AB - We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan-Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed 'familial benign hematuria.' Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension. PMID- 22237749 TI - Role of microRNAs in kidney homeostasis and disease. AB - MicroRNAs (miRNAs) are endogenous short (20-22 nucleotides) non-coding RNA molecules that mediate gene expression. This is an important regulatory mechanism to modulate fundamental cellular processes such as differentiation, proliferation, death, metabolism, and pathophysiology of many diseases. The miRNA expression profile of the kidney differs greatly from that of other organs, as well as between the different regions in the kidney. In kidneys, miRNAs are indispensable for development and homeostasis. In this review, we explore the involvement of miRNAs in the regulation of blood pressure, hormone, water, and ion balance pertaining to kidney homeostasis. We also highlight their importance in renal pathophysiology, such as in polycystic disease, diabetic nephropathy, nephrogenic diabetes insipidus, hypertension, renal cancer, and kidney fibrosis (epithelial-mesenchymal transition). In addition, we highlight the need for further investigations on miRNA-based studies in the development of diagnostic, prognostic, and therapeutic tools for renal diseases. PMID- 22237750 TI - Renal BOLD-MRI does not reflect renal function in chronic kidney disease. AB - Renal blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) is a noninvasive fast technique to characterize renal function. Here we evaluated the impact of renal function on the relaxation rate (R2(*)) in the cortex and medulla to provide baseline data for further use of renal BOLD-MRI. This parameter was evaluated in 400 patients scheduled for abdominal imaging who underwent transversal blood oxygen level-dependent measurements with a multi-echo gradient echo sequence with 12 echo times. The loss of phase coherence (T2(*)) maps were generated in which kidney regions of interest were selected to differentiate the medulla and cortex, and R2(*) was equated to 1/T2(*). Individual R2(*) values were, in turn, correlated to the eGFR (MDRD formula of 280 patients with available serum creatinine measurements), age, and gender each for 1.5 and 3.0 T field-strength scans of 342 patients. At both the field strengths, no significant differences in R2(*) of the cortex and medulla were found between patient gender, age, eGFR, or between different stages of chronic kidney disease determined using the KDOQI system. Thus, BOLD-MRI of a non-specific patient population failed to discriminate between the patients with various stages of chronic kidney disease. PMID- 22237751 TI - Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. AB - Loss of kidney function in renal ischemia/reperfusion injury is due to programmed cell death, but the contribution of necroptosis, a newly discovered form of programmed necrosis, has not been evaluated. Here, we identified the presence of death receptor-mediated but caspase-independent cell death in murine tubular cells and characterized it as necroptosis by the addition of necrostatin-1, a highly specific receptor-interacting protein kinase 1 inhibitor. The detection of receptor-interacting protein kinase 1 and 3 in whole-kidney lysates and freshly isolated murine proximal tubules led us to investigate the contribution of necroptosis in a mouse model of renal ischemia/reperfusion injury. Treatment with necrostatin-1 reduced organ damage and renal failure, even when administered after reperfusion, resulting in a significant survival benefit in a model of lethal renal ischemia/reperfusion injury. Unexpectedly, specific blockade of apoptosis by zVAD, a pan-caspase inhibitor, did not prevent the organ damage or the increase in urea and creatinine in vivo in renal ischemia/reperfusion injury. Thus, necroptosis is present and has functional relevance in the pathophysiological course of ischemic kidney injury and shows the predominance of necroptosis over apoptosis in this setting. Necrostatin-1 may have therapeutic potential to prevent and treat renal ischemia/reperfusion injury. PMID- 22237752 TI - Tubular epithelial syndecan-1 maintains renal function in murine ischemia/reperfusion and human transplantation. AB - Syndecan-1, a heparan sulfate proteoglycan, has an important role in wound healing by binding several growth factors and cytokines. As these processes are also crucial in damage and repair after renal transplantation, we examined syndecan-1 expression in human control kidney tissue, renal allograft protocol biopsies, renal allograft biopsies taken at indication, and non-transplant interstitial fibrosis. Syndecan-1 expression was increased in tubular epithelial cells in renal allograft biopsies compared with control. Increased epithelial syndecan-1 in allografts correlated with low proteinuria and serum creatinine, less interstitial inflammation, less tubular atrophy, and prolonged allograft survival. Knockdown of syndecan-1 in human tubular epithelial cells in vitro reduced cell proliferation. Selective binding of growth factors suggests that syndecan-1 may promote epithelial restoration. Bilateral renal ischemia/reperfusion in syndecan-1-deficient mice resulted in increased initial renal failure and tubular injury compared with wild-type mice. Macrophage and myofibroblast numbers, tubular damage, and plasma urea levels were increased, and tubular proliferation reduced in the kidneys of syndecan-1 deficient compared with wild-type mice 14 days following injury. Hence syndecan-1 promotes tubular survival and repair in murine ischemia/reperfusion injury and correlates with functional improvement in human renal allograft transplantation. PMID- 22237753 TI - Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. AB - The expression of the renoprotective antiaging gene Klotho is decreased in uremia. Recent studies suggest that Klotho may be a tumor suppressor, and its expression may be repressed by DNA hypermethylation in cancer cells. Here we investigated the effects and possible mechanisms by which Klotho expression is regulated during uremia in uninephrectomized B-6 mice given the uremic toxins indoxyl sulfate or p-cresyl sulfate. Cultured human renal tubular HK2 cells treated with these toxins were used as an in vitro model. Injections of indoxyl sulfate or p-cresyl sulfate increased their serum concentrations, kidney fibrosis, CpG hypermethylation of the Klotho gene, and decreased Klotho expression in renal tubules of these mice. The expression of DNA methyltransferases 1, 3a, and 3b isoforms in HK2 cells treated with indoxyl sulfate or p-cresyl sulfate was significantly increased. Specific inhibition of DNA methyltransferase isoform 1 by 5-aza-2'-deoxycytidine caused demethylation of the Klotho gene and increased Klotho expression in vitro. Thus, inhibition of Klotho gene expression by uremic toxins correlates with gene hypermethylation, suggesting that epigenetic modification of specific genes by uremic toxins may be an important pathological mechanism of disease. PMID- 22237754 TI - Urinary secretion and extracellular aggregation of mutant uromodulin isoforms. AB - Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein. PMID- 22237755 TI - Apathy in Parkinson's disease: diagnostic and etiological dilemmas. AB - About one-third of patients with Parkinson's disease (PD) are diagnosed with apathy in cross-sectional studies. However, once patients with concomitant depression and dementia are excluded, the frequency of apathy drops to 5% to 10%. Several scales have been recommended to rate apathy in PD, but specific psychiatric interviews have not been developed, and recently proposed standardized diagnostic criteria are still in the validation process. Most studies assessing the association between subthalamic deep brain stimulation (STN DBS) and apathy have reported a relative increase in the frequency and severity of apathy, although discrepant findings have also been reported. Several mechanisms to explain apathy in PD have been proposed, from dopaminergic imbalances in frontal-basal ganglia circuits to dysfunction of nondopaminergic circuits and the cingulate gyrus. Future studies should provide reliable and valid instruments to diagnose apathy in PD, and should examine the mechanism of apathy accounting for relevant confounders, such as depression and cognitive deficits, and important contextual factors. Finally, treatment for apathy in PD should not be restricted to psychoactive drugs, but should also include nonpharmacological techniques such as psychotherapy and occupational therapy. PMID- 22237756 TI - Pylorus- and spleen-preserving total pancreatoduodenectomy with resection of both whole splenic vessels: feasibility and laparoscopic application to intraductal papillary mucin-producing tumors of the pancreas. AB - BACKGROUND: Total pancreatectomy is recommended for intraductal papillary mucinous tumors with widespread involvement of the entire pancreas. Organ preserving and minimally invasive surgery should be applied in benign and borderline pancreatic lesions. METHODS: Pylorus- and spleen-preserving total pancreatoduodenectomy (PpSpTPD) with segmental resection of both splenic vessels was attempted for five patients. The technique was based on the concepts of two surgical procedures: pylorus-preserving pancreatoduodenectomy and distal pancreatectomy with segmental resection of splenic vessels ("extended" Warshaw's procedure). RESULTS: Three patients underwent laparoscopic-assisted PpSpTPD and two underwent open surgery. No mortality was noted. Short-term follow-up (median, 28 months) suggested that all patients tolerated the insulin therapy and showed relatively good nutritional status. Only minimal to moderate perigastric fundal varices were noted without gastrointestinal bleeding. CONCLUSIONS: PpSpTPD with segmental resection of both splenic vessels is feasible and safe. Even a minimally invasive approach can be indicated in selected patients. PMID- 22237758 TI - Laparoscopic colorectal resection for cancer: effects of conversion on long-term oncologic outcomes. AB - BACKGROUND: The effects of conversion to open surgery during laparoscopic resection for colorectal cancer on long-term oncologic outcomes still are unclear. METHODS: All 450 laparoscopic colorectal resections for cancer performed at a single center between 1994 and 2008 and included in a prospectively maintained database were considered. Patients who required conversion to open surgery (CONV) were matched 1:2 with laparoscopically completed cases (LAP) and 1:5 with open surgery cases (OPEN) for age, American Society of Anesthesiologists (ASA) score, year of surgery, tumor location, and tumor stage. Fisher's exact, chi-square, and Wilcoxon tests were used as appropriate. Kaplan-Meier curves were compared to analyze survival. RESULTS: In this study, 31 CONV cases were independently compared with 62 LAP and 155 OPEN cases. Compared with the LAP and OPEN patients, the CONV patients were characterized by a numerically higher rate of preoperative comorbidity (61.3% vs LAP, 51.6; P = 0.4 and OPEN, 48.4%; P = 0.2), male gender (77.4% vs LAP, 59.7%; P = 0.09 and OPEN, 58.1%; P = 0.05), and a significantly higher mean body mass index (29.6 vs LAP, 26.8; P = 0.012 and OPEN, 28.8; P = 0.3). The pathologic tumor stage, location, and chemotherapy and radiotherapy rates were comparable among the groups. After a median follow-up period of 4.1, 4.2, and 4.6 years, the 5-year disease-free survival rate was significantly lower for the CONV patients (40.2%) than for the LAP (70.7%, P = 0.01) or the OPEN (63.3%, P = 0.04) patients. However, the 5-year cancer-specific survival rates were similar among the CONV (94.4%), LAP (86.1%, P = 0.36), and OPEN (84.9%, P = 0.14) patients. CONCLUSIONS: Conversion to open surgery does not affect oncologic outcomes, although CONV patients have increased comorbidity rates affecting long-term mortality. PMID- 22237759 TI - Postural responses without versus with acute external cervical spine fixation: a comparative study in healthy subjects and patients with acute unilateral vestibular loss. AB - Using a diagnostic prospective cohort single center study design, the influence of a cervical collar on standing balance during dynamic postural perturbations in healthy adults and patients with acute unilateral vestibular dysfunction was measured in 31 healthy subjects and 27 patients with acute unilateral vestibular loss. The main outcome measures were completed standard protocols on the Sensory Organization Test (SOT) and Motor Control Test (MCT) of the NeuroCom Equitest((r)) computerized posturography platform measured without and with acute cervical fixation, respectively. Paired t test showed no significant difference during the six conditions of neither the SOT scores nor analyzing the SOT strategies or during the MCT between the non-fixed and fixed neck in healthy subjects and in the patients (all p > 0.05). Older healthy subjects showed decreased SOT scores but equal MCT results. The age effect was more dominant in the patients when wearing the collar. Gender had no influence whether in healthy individuals nor in patients. In almost all conditions of the SOT but only in some MCT subtests patients had significantly lower scores than healthy subjects without collar and with collar (all p < 0.05). In conclusion, the SOT but only some subtest of the MCT could clearly distinguish between healthy adults and patient with acute unilateral vestibular loss. Equilibrium scores did not change significantly when the cervical spine was fixed with a collar. Acute fixation of the neck with a collar seems not to affect standing balance, even not when vestibular, visual and/or somatosensory input are also reduced. PMID- 22237757 TI - Pure natural orifice transluminal endoscopic surgery (NOTES) with ultrasonography guided transgastric access and over-the-scope-clip closure: a porcine feasibility and survival study. AB - BACKGROUND: Most natural orifice transluminal endoscopic surgery (NOTES) procedures to date rely on the hybrid technique with simultaneous laparoscopic access to protect against access-related complications and to achieve adequate triangulation for dissection. This is done at the cost of the potential benefits of this new minimally invasive technique. This study aimed to evaluate the feasibility and safety of a transgastric (TG) pure-NOTES procedure in a diagnostic setting. METHODS: A TG pure-NOTES procedure with endoscopic ultrasonograpy (EUS)-guided access and over-the-scope-clip (OTSC) closure was performed for 10 pigs in a survival and feasibility study. A full macroscopic necropsy with subsequent histologic evaluation was performed on postoperative day (POD) 14. The outcome parameters were uncomplicated follow-up assessment, survival, intraoperative complications, intraabdominal pathology, macroscopic full-thickness closure, and histology-proven full-thickness healing of the gastrotomy. RESULTS: An uncomplicated postoperative course was reported for 9 of the 10 pigs, and survival was reported for all 10 pigs. For all the pigs, EUS guided access was performed successfully with a median duration of 25 min (range, 12-62 min) and without intraoperative complications or access-related lesions at necropsy. An OTSC closure was achieved with a median duration of 11 min (range, 3 28 min). The OTSC provided immediate closure, but according to the authors' definition of a full-thickness healing evaluated by histologic examination, this was not achieved in any of the cases. Although all the animals survived until POD 14, intraabdominal chronic abscesses were present in 3 of the 10 pigs at necropsy. CONCLUSIONS: The EUS-guided TG access proved to be feasible without access-related complications. Although OTSC provided an immediate closure, the histopathology raised concerns regarding the risk of perforation. Together with the high risk of intraabdominal infection, TG pure-NOTES is not yet ready for routine clinical practice. PMID- 22237760 TI - Short tone bursts are better than clicks for cervical vestibular-evoked myogenic potentials in clinical practice. AB - Our aim is to compare short tone burst (STB)--and clicks--stimuli to evoke vestibular-evoked myogenic potentials (VEMPs) in healthy controls. A cross sectional study in which VEMPs were measured in two sets of 185 and 55 normal volunteers by an air-conducted 500 Hz STBs and clicks, respectively. The test retest reliability between different sessions was assessed in two subsets of 35 individuals. Moreover, 53 individuals were examined with both stimuli within the same session. Intraclass correlation coefficients (ICC) were used to assess reliability for P1 and N1 latencies, corrected amplitude and asymmetry ratio (AR). The results included that STBs produced a reliable response between different sessions (N = 35; [ICC] = 0.61-0.94, all p < 0.0001). Although clicks produced a reliable response for P1 and N1 latencies and corrected amplitudes (ICC = 0.62-0.74, all p < 0.0001), the amplitude ratio showed a lower reliability [ICC = 0.32 (-0.10 to 0.59)]. The amplitude of VEMP was consistently larger with 500 Hz STBs than clicks for a given sound pressure level. Within the same session, STBs evoked a response in 52/53 subjects (98%) whereas clicks evoked VEMPs only in 44/53 individuals (83%). Conclusions revealed that a 500 Hz STBs elicited consistently larger amplitudes, better reliability across recording sessions and fewer missing responses compared with click-induced VEMPs. PMID- 22237761 TI - Endoscopic transnasal intraorbital surgery: our experience with 16 cases. AB - The objective of the study is to present our multicentric experience on intraorbital lesions managed by means of an endonasal endoscopic approach. The study design used was multi-institutional retrospective review. We collected data on 16 intraorbital medially-located lesions, all managed by means of an endonasal route, treated in four different skull base centers. We retrospectively reviewed the technical details, complications, histology, and general outcome. The endoscopic endonasal approach was effective in removing completely intraorbital extra-intraconal tumors in 8 cases, in performing biopsies for histological diagnosis in 6 intraorbital intraconal tumors, and in draining 1 extraconal abscess. No major complications were observed; in particular, there was no optic nerve damage. Minor, temporary complications (diplopia) were seen in 3 cases; only 2 patients experienced a permanent diplopia related to medial rectus muscle impairment, in 1 case associated with enophthalmos. Our preliminary multi-centric clinical experience suggests that medially located intraorbital lesions, and in particular the infero-medial ones, can be successfully and safely managed by such an approach. The well-known advantages of the endoscopic techniques, namely the lack of external scars, less bleeding, shorter hospital stay, and fewer complications, are confirmed. PMID- 22237762 TI - New cochlear implant technologies improve performance in post-meningitic deaf patients. AB - The objective of the study was to compare the performance of cochlear implantation between post-meningitic and non-meningitic patients, and to evaluate the impact on hearing outcome of technical advances in cochlear implant technology. Retrospective chart review was used as the study design. Twenty adults with post-meningitic profound hearing loss receiving unilateral or bilateral cochlear implants between 1990 and 2008 were tested. Results were compared to a control group of 46 adults implanted for a non-meningitic hearing loss, with the same pre-operative speech scores. Speech scores were poorer in post-meningitic patients compared to those of control group, whatever the duration after implantation (p < 0.0001). Speech scores of subjects implanted and fitted before 2001 were compared to those of subjects implanted after 2001, with the same duration of hearing loss. Performance improved with implants and processors available after 2001, with a magnitude of improvement higher in post meningitic patients (p < 0.0001 and p < 0.05 in post-meningitic and control groups, respectively, two-way ANOVA). Consequently, speech scores of post meningitic patients implanted after 2001 achieved those of control subjects (two way ANOVA). Advances in cochlear implant technology and coding strategy improve hearing outcome in post-meningitic adult patients, who now achieve similar performance as those of non-meningitic patients. PMID- 22237763 TI - Prognostic value of Helicobacter pylori sinonasal colonization for efficacy of endoscopic sinus surgery. AB - Compared with rhinologic patients without chronic rhinosinusitis (CRS), a higher prevalence of sinonasal Helicobacter pylori (HP) in patients with CRS was found. This study investigated if HP sinonasal colonization has a prognostic value for efficacy of functional endoscopic sinus surgery (FESS). Nasal polyps of 40 patients with CRS, undergoing FESS, were analyzed for presence of HP using immunohistochemistry (IHC). Patients were categorized as to whether the IHC was positive (HP+ group) or negative (HP- group). HP+ group and HP- group were compared according to the nasal polyp eosinophil density, and to the improvement (difference between pre- and post-operative scores) of the subjective symptom scores, and the nasal endoscopic scores. Nasal polyps in 28 (70%) patients were positive for HP. There were no significant differences between HP+ group and HP- group comparing the eosinophils, and the improvement of the single symptom and the total symptom scores. HP+ group had significantly greater improvement of the nasal endoscopic scores (F[1.38] = 6.212; P = 0.017). There is no influence of sinonasal HP on tissue eosinophilia and on CRS symptoms. There is a prognostic value for endonasal findings: CRS patients with HP have statistically significant greater improvement of the postoperative endoscopic scores. PMID- 22237764 TI - Current strategies for microRNA research. AB - The short ribonucleic acid molecules (20-24 nucleotides) known as microRNAs (miRNAs) are non-coding RNAs that disrupt translation or degrade target mRNAs posttranscriptionally in a sequence-specific manner, and the miRNA may not be completely complementary to its targets. This class of RNAs is thought to be functionally important because many individual miRNAs are evolutionally conserved across widely diverse phyla. Further, miRNAs are associated with diverse biological phenomena, such as cell growth, apoptosis, development, differentiation, cancer, and arthritis. MicroRNA research is one of a number of rapidly evolving fields of basic and biomedical science, with many new techniques being developed. However, miRNA experiments require modifications of preexisting molecular techniques or specialized methods, given the difficulties stemming from their small size. In this review, we summarize current in-silico and biochemical strategies for miRNA research to outline the current status of the research techniques now being employed to find a new direction in the field. PMID- 22237766 TI - Potential-induced phase transition of low-index Au single crystal surfaces in propylene carbonate solution. AB - In situ scanning tunneling microscopy (STM) was employed to examine the surface structures of Au(111), Au(100), and Au(110) single crystals in propylene carbonate (PC) containing tetrabutylammonium perchlorate (TBAP). All three electrodes exhibited potential-induced phase transition between the reconstructed and unreconstructed (1 * 1) structures at negative and positive potentials, respectively. The potential-induced phase transition of the Au electrode surfaces is attributed to the interaction of the TBA cation and the perchlorate anion at the electrode surface, which is similar to that which takes place in aqueous solutions. In addition to static atomic structures, dynamic processes of both the reconstruction and the lifting of the reconstruction were investigated by means of in situ STM. The lifting of reconstructed Au(111)-(?3 * 22) on Au(111) to the (1 * 1) structure is completed within 1 min at a positive potential. The diffusion of Au atoms on the Au(100) plane in the PC solution proceeds more rapidly than that in the aqueous solution, suggesting that the PC solvent plays an important role in accelerating the diffusion of Au atoms. PMID- 22237765 TI - Simultaneous quantitative analysis of the expression of CD64 and CD35 on neutrophils as markers to differentiate between bacterial and viral infections in patients with rheumatoid arthritis. AB - OBJECTIVES: The expression level of CD64 on neutrophils can be used to differentiate between an infection and a disease flare in rheumatoid arthritis (RA) patients. However, the CD64 expression is elevated by both bacteria and viruses, so it cannot be used to distinguish the type of infection. We herein investigated the results of a simultaneous quantitative analysis of the expression of CD64 and CD35 on neutrophils to determine whether these molecules can be used to distinguish between bacterial and viral infections in RA patients. METHODS: We collected blood from 22 RA patients with pathogen-proven infections (15 bacterial and 7 viral infections). Blood samples were stained with QuantiBRITE CD64PE/CD45PerCP and CD35PE, and the mean fluorescence intensities were assessed by a flow cytometer. The mean numbers of molecules were calculated using QuantiBrite PE beads. RESULTS: We calculated the ratio of CD64 to the CD35 level (CD35/CD64), and used a cut-off value of 2.8 for the CD35/CD64 ratio. At this value, the sensitivity for diagnosing a bacterial infection was 87%, and the specificity was 86%. CONCLUSIONS: Simultaneous quantitative analysis of CD64 and CD35 expression on neutrophils might be useful to distinguish between bacterial and viral infections in RA patients. PMID- 22237767 TI - Plasma vitamin C concentrations in patients on routine hemodialysis and its relationship to patients' morbidity and mortality. AB - BACKGROUND: Some studies have hypothesized the protective role of vitamin C against cardiovascular disorders (CVD) in patients with end-stage renal disease (ESRD). This study was designed to assess plasma vitamin C concentration and its relationship to hemodialysis (HD) patients' morbidity and mortality. METHODS: Plasma vitamin C concentrations were assessed in HD patients using spectrophotometry and subjects were prospectively followed for up eighteen months for all-cause mortality. Any association between vitamin C concentration and patients' demographic data, co-morbidities, or the cause of ESRD were investigated using the Chi-square test. RESULTS: Ninety-one patients with a mean age of 56.7 +/- 15.7 years were included in this study. The most frequent cause of ESRD was simultaneous hypertension and diabetes in 30 % of patients, followed by hypertension in 25.6 %, and diabetes in 11.1 %, respectively. About 34 % of patients had CVD as the most prevalent co-morbidity. Forty-nine patients (53.8 %) had low levels of vitamin C concentration. There was a significant relationship between vitamin C insufficiency and presence of any co-morbidity in HD patients (p < 0.05). There was a significant difference in vitamin C concentrations between patients without co-morbidities and those with cardiovascular ones (F[2,88]=3.447, p = 0.036). Twenty-two (24.2 %) patients died over a median duration of 227 days. There was a significant difference in time to death of patients with and without low levels of vitamin C concentration (p = 0.04). CONCLUSIONS: The results showed lower plasma vitamin C levels in HD patients who suffered any co-morbidity and sooner time to death in these patients. PMID- 22237768 TI - Vitamin D status and cytokine levels in patients with Crohn's disease. AB - OBJECTIVE: There is growing evidence that vitamin D may have immunomodulatory properties in Crohn's disease (CD). The aim of this study was to determine if serum 25-hydroxy-vitamin D [25(OH)D] was associated with inflammatory cytokines, IL-10, and TNF-alpha levels in patients with inactive CD. METHODS: This was a prospective study of 75 adults with quiescent CD. Serum 25(OH)D was measured by radioimmunoassay and serum IL-10 and TNF-alpha by ELISA. Disease activity was assessed by the Crohn's disease activity index (CDAI) and C-reactive protein (CRP). RESULTS: IL-10 levels were significantly lower in patients with vitamin D insufficiency compared with the vitamin D replete group (mean and SE 2.48 +/- 0.51 v 6.77 +/- 2.49 pg/mL, p < 0.001). There were, however, no differences in serum TNF-alpha or CRP levels based on vitamin D status. The use of a vitamin D supplement at a low dose (200 IU) did not significantly influence IL-10 levels. CONCLUSION: Circulating levels of IL-10, but not TNF-alpha, were significantly lower in CD patients with inadequate serum 25(OH)D. This suggests that poor vitamin D status may be linked to reduced anti-inflammatory capacity in this group. PMID- 22237769 TI - Serum antioxidant vitamin levels in patients with coronary heart disease. AB - The aim of this study was to investigate anthropometric measurements, body composition, and serum antioxidant vitamin levels in men with coronary heart disease (CHD). Thirty-five men with CHD and 31 men without CHD, aged 40 - 65 years, were included this study. Dietary records and anthropometric measurements of each participant were recorded by researchers and serum antioxidant vitamin levels and lipid profiles were analyzed. Fat mass (FM) and the percentage of fat mass (FM%) in men with CHD was higher than in men without CHD (p < 0.05). Lipid profiles were found to be similar in both groups, with the exception of high density lipoprotein cholesterol (HDL-C). Men with CHD had lower HDL-C levels than men without CHD (p < 0.05). When the antioxidant vitamin intake of participants was investigated, vitamin E intake in men without CHD was found to be less than in men with CHD (p < 0.05). However, serum vitamin A, vitamin E, and vitamin C levels in men with CHD were found to be lower than in men without CHD (p < 0.05). Based on the results of this study, we propose that high FM, low HDL-C, and low serum antioxidant vitamin levels could be important risk factors for CHD. PMID- 22237770 TI - Estimation of the 25(OH) vitamin D threshold below which secondary hyperparathyroidism may occur among African migrant women in Paris. AB - PURPOSE: It has previously been shown that there is a threshold of serum 25 hydroxy vitamin D below which secondary hyperparathyroidism may occur. Our purpose was to estimate this threshold in a population of migrant African women living in Paris. METHODS: Between February 2008 and December 2009, measurements of 25-hydroxy vitamin D and parathormone were performed in 165 African migrant women living in Paris. The estimation of 25-hydroxy vitamin D and parathormone marginal distributions as Gaussian mixtures, combined with a nonparametric kernel estimation method of the regression function of parathormone on 25-hydroxy vitamin D, provided the desired estimate of serum 25-hydroxy vitamin D threshold. RESULTS: In our sample of African women, our method has shown that serum 25 hydroxy vitamin D levels below 48 +/- 2 nmol/L may induce an increase in parathormone concentrations. CONCLUSION: In this sample, our method provided a reliable estimate (95 % confidence interval) of the serum 25-hydroxy vitamin D level below which an increase in parathormone concentrations can be observed. PMID- 22237771 TI - Nutritional status of 8- to 12-year-old children with height below or at 25th percentile associated with height in the Seoul metropolitan area. AB - BACKGROUND: Childhood is the best time to establish healthful dietary habits through adulthood. However, as of yet, there is relatively little research on the nutritional status of children with low height. This study aimed to evaluate the nutritional status of school-aged children with low height. METHODS: This study was implemented in the Seoul metropolitan area with 8- to 12-year-old Korean children (n = 93) who fall below the 25th percentile (<= P25) for height. Nutritional status was assessed using anthropometry and dietary assessment. Dietary assessment was carried out using a 24-hour recall on a typical and quantitative food frequency questionnaire. The Pearson' s correlation analysis was conducted to determine associations between height and nutrient intake. RESULTS: The mean percentiles of height were 19.5(th) for boys, and 19.0(th) for girls, respectively. Nutrients ingested below the Estimated Average Requirement (EAR) of the Dietary Reference Intakes for Koreans (KDRIs), considered inadequate, were folic acid, calcium, vitamin C, and iron. Significant differences between recommended and consumed servings of food groups were observed in the meat, fish, egg, and legume group (p = 0.039), vegetable group (p < 0.001), and fruit group (p = 0.044). The height percentiles of the subjects were negatively correlated with calories derived from carbohydrates (p < 0.001). CONCLUSIONS: School-aged children living in the Seoul metropolitan area, with height <= P25, consumed inadequate nutrients and insufficient food groups, which may put the children in a low height percentile. More efforts to provide education on adequate dietary intake and to monitor the nutritional status of children are needed to improve dietary adequacy based on food groups and to increase the growth of children with low height. PMID- 22237772 TI - Emerging nutrition gaps in a world of affluence - micronutrient intake and status globally. AB - Nutrition is important for human health in all stages of life - from conception to old age. Today we know much more about the molecular basis of nutrition. Most importantly, we have learnt that micronutrients, among other factors, interact with genes, and new science is increasingly providing more tools to clarify this interrelation between health and nutrition. Sufficient intake of vitamins is essential to achieve maximum health benefit. It is well established that in developing countries, millions of people still suffer from micronutrient deficiencies. However, it is far less recognized that we face micronutrient insufficiencies also in developed countries. PMID- 22237773 TI - B-vitamins, methylenetetrahydrofolate reductase (MTHFR) and hypertension. AB - Hypertension is a leading risk factor for cardiovascular disease (CVD) and stroke. A common polymorphism in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR), previously identified as the main genetic determinant of elevated homocysteine concentration and also recognized as a risk factor for CVD, appears to be independently associated with hypertension. The B-vitamin riboflavin is required as a cofactor by MTHFR and recent evidence suggests it may have a role in modulating blood pressure, specifically in those with the homozygous mutant MTHFR 677 TT genotype. If studies confirm that this genetic predisposition to hypertension is correctable by low-dose riboflavin, the findings could have important implications for the management of hypertension given that the frequency of this polymorphism ranges from 3 to 32 % worldwide. PMID- 22237776 TI - Vitamin D effects on bone and muscle. AB - Increasing data suggest that higher 25-hydroxyvitamin D [25(OH)D] serum concentrations are advantageous for health. At present, strong evidence for causality is available for fracture and fall prevention, while promising epidemiologic and mechanistic studies suggest a key role of vitamin D in the preservation of cardiovascular health, and the prevention of cancer and other common chronic disease. For lower extremity function, fall prevention, hip bone density, and for fracture prevention optimal benefits are observed with 25(OH)D levels of at least 75 nmol/L to 100 nmol/L [1]. This threshold may be reached in 50 % of adults with 800 to 1000 IU vitamin D per day. This manuscript will discuss the evidence of vitamin D in fall and fracture prevention and how these data transfer to the most recent recommendations by the IOF (International Osteoporosis Foundation) and the IOM (Institute of Medicine). PMID- 22237775 TI - EURRECA's approach for estimating micronutrient requirements. AB - In Europe, micronutrient dietary reference values have been established by (inter)national committees of experts and are used by public health policy decision-makers to monitor and assess the adequacy of diets within population groups. The approaches used to derive dietary reference values (including average requirements) vary considerably across countries, and so far no evidence-based reason has been identified for this variation. Nutrient requirements are traditionally based on the minimum amount of a nutrient needed by an individual to avoid deficiency, and is defined by the body's physiological needs. Alternatively the requirement can be defined as the intake at which health is optimal, including the prevention of chronic diet-related diseases. Both approaches are confronted with many challenges (e. g., bioavailability, inter and intra-individual variability). EURRECA has derived a transparent approach for the quantitative integration of evidence on Intake-Status-Health associations and/or Factorial approach (including bioavailability) estimates. To facilitate the derivation of dietary reference values, EURopean micronutrient RECommendations Aligned (EURRECA) is developing a process flow chart to guide nutrient requirement-setting bodies through the process of setting dietary reference values, which aims to facilitate the scientific alignment of deriving these values. PMID- 22237778 TI - Does the speciation clock tick more slowly in the absence of heteromorphic sex chromosomes? AB - Squamates may be an attractive group in which to study the influence of sex chromosomes on speciation rates because of the repeated evolution of heterogamety (both XY and ZW), as well as an apparently large number of taxa with environmental sex-determination. PMID- 22237777 TI - Renal salt-wasting syndrome in children with intracranial disorders. AB - Hypotonic hyponatremia, a serious and recognized complication of any intracranial disorder, results from extra-cellular fluid volume depletion, inappropriate anti diuresis or renal salt-wasting. The putative mechanisms by which intracranial disorders might lead to renal salt-wasting are either a disrupted neural input to the kidney or the elaboration of a circulating natriuretic factor. The key to diagnosis of renal salt-wasting lies in the assessment of extra-cellular volume status: the central venous pressure is currently considered the yardstick for measuring fluid volume status in subjects with intracranial disorders and hyponatremia. Approximately 110 cases have been reported so far in subjects <=18 years of age (male: 63%; female: 37%): intracranial surgery, meningo-encephalitis (most frequently tuberculous) or head injury were the most common underlying disorders. Volume and sodium repletion are the goals of treatment, and this can be performed using some combination of isotonic saline, hypertonic saline, and mineralocorticoids (fludrocortisone). It is worthy of a mention, however, that some authorities contend that cerebral salt wasting syndrome does not exist, since this diagnosis requires evidence of a reduced arterial blood volume, a concept but not a measurable variable. PMID- 22237779 TI - What can we learn from international comparisons of costs by DRG? AB - OBJECTIVES: The objective of this study was to compare costs data by diagnosis related group (DRG) between Belgium and Switzerland. Our hypotheses were that differences between countries can probably be explained by methodological differences in cost calculations, by differences in medical practices and by differences in cost structures within the two countries. METHODS: Classifications of DRG used in the two countries differ (AP-DRGs version 1.7 in Switzerland and APR-DRGs version 15.0 in Belgium). The first step of this study was to transform Belgian summaries into Swiss AP-DRGs. Belgian and Swiss data were calculated with a clinical costing methodology (full costing). Belgian and Swiss costs were converted into US$ PPP (purchasing power parity) in order to neutralize differences in purchasing power between countries. RESULTS: The results of this study showed higher costs in Switzerland despite standardization of cost data according to PPP. The difference is not explained by the case-mix index because this was similar for inliers between the two countries. The length of stay (LOS) was also quite similar for inliers between the two countries. The case-mix index was, however, higher for high outliers in Belgium, as reflected in a higher LOS for these patients. Higher costs in Switzerland are thus probably explained mainly by the higher number of agency staff by service in this country or because of differences in medical practices. CONCLUSIONS: It is possible to make international comparisons but only if there is standardization of the case-mix between countries and only if comparable accountancy methodologies are used. Harmonization of DRGs groups, nomenclature and accountancy is thus required. PMID- 22237774 TI - Antioxidant vitamin status (A, E, C, and beta-carotene) in European adolescents - the HELENA Study. AB - BACKGROUND: An adequate nutritional status of antioxidant vitamins (vitamins A, C, E) and b-carotene is essential especially during childhood and adolescence, because of their important roles in cell growth and development. Currently, there are no physiological reference values for blood concentration of these vitamins and b-carotene in apparently healthy European adolescents. The aim of the current study was to obtain reliable and comparable data of antioxidant vitamins and b carotene in a cross-sectional study, within HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence), which was conducted in a representative sample of adolescents from ten European cities. MATERIAL AND METHODS: From a subsample of 1,054 adolescents (males= 501) of the HELENA Cross Sectional Study with an age range of 12.5 to 17.49 years, fasting blood samples were taken and analyzed for vitamins A, E, C, and b-carotene status. As specific reference values for adolescents are missing, percentile distribution by age and sex is given. RESULTS: Mean concentrations were the following: Retinol: 356.4 +/- 107.9 cm/mL; alpha-tocopherol: 9.9 +/- 2.1 microg/mL; vitamin C: 10.3 +/- 3.3 mg/L; and b carotene: 245.6 +/- 169.6 cm/mL. Females showed higher alpha-tocopherol and vitamin C values compared with males and 17-year-old boys had higher retinol levels than the same-aged girls (p = 0.018). Retinol serum concentrations increased significantly according to age in both gender, but girls had also significantly increasing b-carotene levels by age. CONCLUSIONS: For the first time, concentrations of antioxidant vitamins and pro-vitamin beta-carotene have been obtained in a representative sample of apparently healthy European adolescents. These data can contribute to the establishment of reference ranges in adolescents. PMID- 22237780 TI - Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL). PMID- 22237781 TI - Cancer statistics, 2012. AB - Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in the United States in 2012. During the most recent 5 years for which there are data (2004-2008), overall cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.6% per year in women. Over the past 10 years of available data (1999-2008), cancer death rates have declined by more than 1% per year in men and women of every racial/ethnic group with the exception of American Indians/Alaska Natives, among whom rates have remained stable. The most rapid declines in death rates occurred among African American and Hispanic men (2.4% and 2.3% per year, respectively). Death rates continue to decline for all 4 major cancer sites (lung, colorectum, breast, and prostate), with lung cancer accounting for almost 40% of the total decline in men and breast cancer accounting for 34% of the total decline in women. The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket. PMID- 22237783 TI - A healthy diet and physical activity help reduce your cancer risk. PMID- 22237782 TI - American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. AB - The American Cancer Society (ACS) publishes Nutrition and Physical Activity Guidelines to serve as a foundation for its communication, policy, and community strategies and, ultimately, to affect dietary and physical activity patterns among Americans. These Guidelines, published approximately every 5 years, are developed by a national panel of experts in cancer research, prevention, epidemiology, public health, and policy, and they reflect the most current scientific evidence related to dietary and activity patterns and cancer risk. The ACS Guidelines focus on recommendations for individual choices regarding diet and physical activity patterns, but those choices occur within a community context that either facilitates or creates barriers to healthy behaviors. Therefore, this committee presents recommendations for community action to accompany the 4 recommendations for individual choices to reduce cancer risk. These recommendations for community action recognize that a supportive social and physical environment is indispensable if individuals at all levels of society are to have genuine opportunities to choose healthy behaviors. The ACS Guidelines are consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes, as well as for general health promotion, as defined by the 2010 Dietary Guidelines for Americans and the 2008 Physical Activity Guidelines for Americans. PMID- 22237784 TI - Efferent projections of C3 adrenergic neurons in the rat central nervous system. AB - C3 neurons constitute one of three known adrenergic nuclei in the rat central nervous system (CNS). While the adrenergic C1 cell group has been extensively characterized both physiologically and anatomically, the C3 nucleus has remained relatively obscure. This study employed a lentiviral tracing technique that expresses green fluorescent protein behind a promoter selective to noradrenergic and adrenergic neurons. Microinjection of this virus into the C3 nucleus enabled the selective tracing of C3 efferents throughout the rat CNS, thus revealing the anatomical framework of C3 projections. C3 terminal fields were observed in over 40 different CNS nuclei, spanning all levels of the spinal cord, as well as various medullary, mesencephalic, hypothalamic, thalamic, and telencephalic nuclei. The highest densities of C3 axon varicosities were observed in Lamina X and the intermediolateral cell column of the thoracic spinal cord, as well as the dorsomedial medulla (both commissural and medial nuclei of the solitary tract, area postrema, and the dorsal motor nucleus of the vagus), ventrolateral periaqueductal gray, dorsal parabrachial nucleus, periventricular and rhomboid nuclei of the thalamus, and paraventricular and periventricular nuclei of the hypothalamus. In addition, moderate and sparse projections were observed in many catecholaminergic and serotonergic nuclei, as well as the area anterior and ventral to the third ventricle, Lamina X of the cervical, lumbar, and sacral spinal cord, and various hypothalamic and telencephalic nuclei. The anatomical map of C3 projections detailed in this survey hopes to lay the first steps toward developing a functional framework for this nucleus. PMID- 22237785 TI - Incontinence during intercourse: myths unravelled. AB - INTRODUCTION AND HYPOTHESIS: This study aimed to establish the prevalence of urinary leakage during intercourse, the extent to which urinary leakage impacts on sex life and the correlation between different urodynamic diagnosis and coital leakage. METHODS: Four hundred eighty women attending between 1 January 2006 and December 2010 with urinary incontinence and subsequently undergoing urodynamic assessment were included. Data were collected as part of routine clinical care using the electronic Pelvic floor Assessment Questionnaire and correlated with urodynamic findings. RESULTS: Sixty percent of women with urinary incontinence reported leakage during intercourse. Overall quality of life in women with urinary incontinence was strongly correlated to the impact of urinary symptoms on sex life. Parameters of sexual function were no different in women with different urodynamic diagnosis. CONCLUSION: Worsening urinary incontinence has a deleterious effect on sexual function. Urodynamic diagnosis does not correlate with the nature of underlying sexual problems, orgasm or penetration incontinence. PMID- 22237786 TI - Laparoscopic mesh explantation and drainage of sacral abscess remote from transvaginal excision of exposed sacral colpopexy mesh. AB - Sacral colpopexy may be complicated by mesh exposure, and the surgical treatment of mesh exposure typically results in minor postoperative morbidity and few delayed complications. A 75-year-old woman presented 7 years after a laparoscopic sacral colpopexy, with Mersilene mesh, with an apical mesh exposure. She underwent an uncomplicated transvaginal excision and was asymptomatic until 8 months later when she presented with vaginal drainage and a sacral abscess. This was successfully treated with laparoscopic enterolysis, drainage of the abscess, and explantation of the remaining mesh. Incomplete excision of exposed colpopexy mesh can lead to ascending infection and sacral abscess. Laparoscopic drainage and mesh removal may be considered in these patients. PMID- 22237788 TI - Analgesia and sedation in high-risk critically ill patients: still waiting for evidence about remifentanil. PMID- 22237787 TI - Vaginal repair of neobladder-vaginal fistula: a case report and review of the literature. AB - Neobladder substitution after radical cystectomy for invasive cancer has become commonplace as it preserves normal volitional voiding through the native urethra and avoids urinary diversion. Neobladder-vaginal fistula (NVF) is a rare postoperative complication of this procedure that results in decreased quality of life. We describe a case of vaginal repair of a NVF and present a review of the literature. PMID- 22237789 TI - Pneumomediastinum and emphysema of the neck after a suicide attempt by hanging. PMID- 22237790 TI - Prolonged neuromuscular block associated to non-alcoholic steatohepatitis in morbidly obese patient: neostigmine versus sugammadex. PMID- 22237791 TI - A year in review in Minerva Anestesiologica 2011. Critical care. Experimental and clinical studies. PMID- 22237792 TI - No correlation of substantia nigra echogenicity and nigrostriatal degradation in Parkinson's disease. AB - BACKGROUND: Substantia nigra hyperechogenicity assessed by transcranial sonography is a typical finding in up to 90% of patients with idiopathic Parkinson's disease, although its value as a surrogate marker for disease progression in Parkinson's disease is controversial. (123) I-FP-CIT-single photon emission computed tomography (SPECT) represents an established paraclinical surrogate marker to quantify the nigrostriatal dopaminergic deficit in Parkinson's disease. Whereas most studies found no correlation between extent of substantia nigra echogenicity and the putaminal FP-CIT binding ratio, a more recent analysis reported opposite results. METHODS: In 92 patients with Parkinson's disease the substantia nigra echogenicity was compared with the putaminal FP-CIT binding ratio using an investigator-independent SPECT analysis protocol and with several clinical parameters. RESULTS: No correlation was found between the substantia nigra hyperechogenicity and the FP-CIT binding ratio or the disease severity. CONCLUSIONS: Substantia nigra hyperechogenicity does not reflect the degree of the nigrostriatal degeneration or the clinical state of the disease progression. PMID- 22237793 TI - Camphor-based Schiff base ligand SBAIB: an enantioselective catalyst for addition of phenylacetylene to aldehydes. AB - A series of Schiff base ligands were synthesized from (1R)-camphor. Under the optimal conditions, (+)-SBAIB-a, 10 was found to be an excellent catalyst for the enantioselective addition of phenylacetylene to various aldehydes without utilizing either achiral additives or Ti(O(i)Pr)(4). This approach yielded (R) propargylic alcohols in extremely high yields (up to 99%) and excellent enantioselectivities (up to 92%). The corresponding (S)-propargylic alcohols were synthesized in good to high enantioselectivities (up to 91%) and excellent yields (up to 99%) using (-)-SBAIB-a, 41. PMID- 22237794 TI - Interplay of transcriptional and proteolytic regulation in driving robust cell cycle progression. AB - Complex biological systems, such as the cell cycle control network, are shown to be robust against various perturbations. It is crucial to identify the interactions of the network that can contribute towards robust cell cycle behaviour. The proteins in the cell cycle control network are regulated at the level of synthesis, degradation and activity. A closer examination of the network reveals that most of the proteins are subjected to all three types of regulation. Such multiple layers of regulation most probably contribute towards the robust cell cycle behaviour against perturbations. In this work, we investigate such a hypothesis by subjecting our budding yeast cell cycle model to global parameter perturbations using pre-defined viability criteria. We systematically tested the global role of regulated transcription and targeted degradation of proteins in driving robust cell cycle oscillations. We demonstrate that targeted degradation of proteins in the budding yeast cell cycle model makes the cell cycle oscillations robust against perturbations even in the absence of regulated transcription. We show that regulated transcription plays a major role in controlling the period of the cell cycle oscillations which is argued to be important for balanced cell growth and division. We show that both regulated transcription and degradation are part of feedback loops in the network which ensure robust function against parametric variations that can arise from the mutations and/or variations in protein levels. PMID- 22237795 TI - Non-attendance at counselling therapy in cocaine-using methadone-maintained patients: lessons learnt from an abandoned randomised controlled trial. AB - BACKGROUND: Recently, the authors commenced a randomised controlled trial to study the effectiveness of cognitive behavioural coping skills (CBCS) to reduce cocaine usage in methadone-maintained patients' in a clinical setting by assessing attendance at treatment sessions and outcomes in terms of cocaine use. However, recruitment into the study stopped when it became apparent that attendance at counselling sessions was poor. AIMS: The aim of the current study was to determine the reasons for both non-attendance and attendance from a patient's perspective at counselling sessions. METHODS: A cross-sectional design was employed whereby participants who were recruited for the original study were interviewed utilising a semi-structured interview format. RESULTS: Motivational inconsistencies were most frequently cited as the reason for dropping out of counselling, whereas a good relationship with staff was cited by attenders as the most important factors which aided their attendance at counselling sessions. CONCLUSIONS: Selecting opiate-dependent methadone-maintained cocaine abusers on the basis of their urine toxicology and offering them counselling as a way of reducing their harmful drug use did not prove efficacious. Attempting to address cocaine misuse within this cohort may need a more stepped approach including brief interventions, such as motivational interviewing, or other enhancers of motivation before we can test the effectiveness of CBCS in this population. PMID- 22237796 TI - A real-time PCR-based amelogenin Y allele dropout assessment model in gender typing of degraded DNA samples. AB - Allelic dropout due to stochastic variation in degraded small quantity DNA appears to be one of the most serious genotyping errors. Most methods require PCR replication to address this problem. The small amounts of valuable samples are often a limitation for such replications. We report a real-time PCR-based amelogonin Y (AMELY) allele dropout estimation model in an AMEL-based gender typing. We examined 915 replicates of AMELY-positive modern male DNA with varying amounts of DNA and humic acid. A male-specific AMEL fragment (AMELy) dropped out in 143 genuine male replicates, leading to gender typing errors. By graphing a scatter plot of the crossing point versus the end cycle fluorescence of the male replicates, a standard graph model for the estimation of the AMELy allele dropout was constructed with the dropout-prone and dropout-free zones. This model was then applied to ancient DNA (aDNA) samples. Nine samples identified as female were found in the dropout-prone zone; with higher DNA concentrations, six were shifted to the dropout-free zone. Among them, two female identifications were converted to male. All the aDNA gender was confirmed by sex-determination region Y marker amplification. Our data suggest that this model could be a basic approach for securing AMELy allele dropout-safe data from the stochastic variation of degraded inhibitory DNA samples. PMID- 22237797 TI - mPGES-1 deletion potentiates urine concentrating capability after water deprivation. AB - PGE(2) plays an important role in the regulation of fluid metabolism chiefly via antagonizing vasopressin-induced osmotic permeability in the distal nephron, but its enzymatic sources remain uncertain. The present study was undertaken to investigate the potential role of microsomal PGE synthase (mPGES)-1 in the regulation of urine concentrating ability after water deprivation (WD). Following 24-h WD, wild-type (WT) mice exhibited a significant reduction in urine volume, accompanied by a significant elevation in urine osmolality compared with control groups. In contrast, in response to WD, mPGES-1 knockout (KO) mice had much less urine volume and higher urine osmolality. Analysis of plasma volume by measurement of hematocrit and by using a nanoparticle-based method consistently demonstrated that dehydrated WT mice were volume depleted, which was significantly improved in the KO mice. WD induced a twofold increase in urinary PGE(2) output in WT mice, which was completely blocked by mPGES-1 deletion. At baseline, the KO mice had a 20% increase in V(2) receptor mRNA expression in the renal medulla but not the cortex compared with WT controls; the expression was unaffected by WD irrespective of the genotype. In response to WD, renal medullary aquaporin-2 (AQP2) mRNA exhibited a 60% increase in WT mice, and this increase was greater in the KO mice. Immunoblotting demonstrated increased renal medullary AQP2 protein abundance in both genotypes following WD, with a greater increase in the KO mice. Similar results were obtained by using immunohistochemistry. Paradoxically, plasma AVP response to WD seen in WT mice was absent in the KO mice. Taken together, these results suggest that mPGES-1-derived PGE(2) reduces urine concentrating ability through suppression of renal medullary expression of V(2) receptors and AQP2 but may enhance it by mediating the central AVP response. PMID- 22237798 TI - Natriuretic effect of bufalin in isolated rat kidneys involves activation of the Na+-K+-ATPase-Src kinase pathway. AB - Bufadienolides are structurally related to the clinically relevant cardenolides (e.g., digoxin) and are now considered as endogenous steroid hormones. Binding of ouabain to Na(+)-K(+)-ATPase has been associated, in kidney cells, to the activation of the Src kinase pathway and Na(+)-K(+)-ATPase internalization. Nevertheless, whether the activation of this cascade also occurs with other cardiotonic steroids and leads to diuresis and natriuresis in the isolated intact kidney is still unknown. In the present work, we perfused rat kidneys for 120 min with bufalin (1, 3, or 10 MUM) and measured its vascular and tubular effects. Thereafter, we probed the effect of 10 MUM 3-(4-chlorophenyl)1-(1,1 dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4amine (PP2), a Src family kinase inhibitor, and 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (UO126), a highly selective inhibitor of both MEK1 and MEK2, on bufalin-induced renal alterations. Bufalin at 3 and 10 MUM profoundly increased several parameters of renal function in a time- and/or concentration-dependent fashion. At a concentration that produced similar inhibition of the rat kidney Na(+)-K(+) ATPase, ouabain had a much smaller diuretic and natriuretic effect. Although bufalin fully inhibited the rat kidney Na(+)-K(+)-ATPase in vitro, its IC(50) (33 +/- 1 MUM) was threefold higher than the concentration used ex vivo and all its renal effects were blunted by PP2 and UO126. Furthermore, the phosphorylated (activated) ERK1/2 expression was increased after bufalin perfusion and this effect was totally prevented after PP2 pretreatment. The present study shows for the first time the direct diuretic, natriuretic, and kaliuretic effects of bufalin in isolated rat kidney and the relevance of Na(+)-K(+)-ATPase-mediated signal transduction. PMID- 22237799 TI - Mechanisms of p53 activation and physiological relevance in the developing kidney. AB - The tumor suppressor protein p53 is a short-lived transcription factor due to Mdm2-mediated proteosomal degradation. In response to genotoxic stress, p53 is stabilized via posttranslational modifications which prevent Mdm2 binding. p53 activation results in cell cycle arrest and apoptosis. We previously reported that tight regulation of p53 activity is an absolute requirement for normal nephron differentiation (Hilliard S, Aboudehen K, Yao X, El-Dahr SS Dev Biol 353: 354-366, 2011). However, the mechanisms of p53 activation in the developing kidney are unknown. We show here that metanephric p53 is phosphorylated and acetylated on key serine and lysine residues, respectively, in a temporal profile which correlates with the maturational changes in total p53 levels and DNA binding activity. Site-directed mutagenesis revealed a differential role for these posttranslational modifications in mediating p53 stability and transcriptional regulation of renal function genes (RFGs). Section immunofluorescence also revealed that p53 modifications confer the protein with specific spatiotemporal expression patterns. For example, phos-p53(S392) is enriched in maturing proximal tubular epithelial cells, whereas acetyl p53(K373/K382/K386) are expressed in nephron progenitors. Functionally, p53 occupancy of RFG promoters is enhanced at the onset of tubular differentiation, and p53 loss or gain of function indicates that p53 is necessary but not sufficient for RFG expression. We conclude that posttranslational modifications are important determinants of p53 stability and physiological functions in the developing kidney. We speculate that the stress/hypoxia of the embryonic microenvironment may provide the stimulus for p53 activation in the developing kidney. PMID- 22237800 TI - Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-kappaB and upregulating endothelial nitric oxide synthase. AB - The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-kappaB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham operated); CLP; and CLP+EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-l-arginine methyl ester (l NAME) simultaneously with EPO administration (CLP+EPO+l-NAME). A fifth group (CLP+EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP+EPO rats presented significantly higher inulin clearance than did CLP and CLP+EPO+l-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP+EPO rats; and inulin clearance was significantly higher in CLP+EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-alpha activation, NF-kappaB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-kappaB downregulation. PMID- 22237801 TI - Smad3 mediates ANG II-induced hypertensive kidney disease in mice. AB - Although Smad3 is a key mediator for fibrosis, its functional role and mechanisms in hypertensive nephropathy remain largely unclear. This was examined in the present study in a mouse model of hypertension induced in Smad3 knockout (KO) and wild-type (WT) mice by subcutaneous angiotensin II infusion and in vitro in mesangial cells lacking Smad3. After angiotensin II infusion, both Smad3 KO and WT mice developed equally high levels of blood pressure. However, disruption of Smad3 prevented angiotensin II-induced kidney injury by lowering albuminuria and serum creatinine (P < 0.01), inhibiting renal fibrosis such as collagen type I and IV, fibronectin, and alpha-SMA expression (all P < 0.01), and blocking renal inflammation including macrophage and T cell infiltration and upregulation of IL 1beta, TNF-alpha, and monocyte chemoattractant protein-1 in vivo and in vitro (all P < 0.001). Further studies revealed that blockade of angiotensin II-induced renal transforming growth factor (TGF)-beta1 expression and inhibition of Smurf2 mediated degradation of renal Smad7 are mechanisms by which Smad3 KO mice were protected from angiotensin II-induced renal fibrosis and NF-kappaB-driven renal inflammation in vivo and in vitro. In conclusion, Smad3 is a key mediator of hypertensive nephropathy. Smad3 promotes Smurf2-dependent ubiquitin degradation of renal Smad7, thereby enhancing angiotensin II-induced TGF-beta/Smad3-mediated renal fibrosis and NF-kappaB-driven renal inflammation. Results from this study suggest that inhibition of Smad3 or overexpression of Smad7 may be a novel therapeutic strategy for hypertensive nephropathy. PMID- 22237802 TI - Mice with targeted disruption of the acyl-CoA binding protein display attenuated urine concentrating ability and diminished renal aquaporin-3 abundance. AB - The acyl-CoA binding protein (ACBP) is a small intracellular protein that specifically binds and transports medium to long-chain acyl-CoA esters. Previous studies have shown that ACBP is ubiquitously expressed but found at particularly high levels in lipogenic cell types as well as in many epithelial cells. Here we show that ACBP is widely expressed in human and mouse kidney epithelium, with the highest expression in the proximal convoluted tubules. To elucidate the role of ACBP in the renal epithelium, mice with targeted disruption of the ACBP gene (ACBP(-/-)) were used to study water and NaCl balance as well as urine concentrating ability in metabolic cages. Food intake and urinary excretion of Na(+) and K(+) did not differ between ACBP(-/-) and (+/+) mice. Interestingly, however, water intake and diuresis were significantly higher at baseline in ACBP( /-) mice compared with that of (+/+) mice. Subsequent to 20-h water deprivation, ACBP(-/-) mice exhibited increased diuresis, reduced urine osmolality, elevated hematocrit, and higher relative weight loss compared with (+/+) mice. There were no significant differences in plasma concentrations of renin, corticosterone, and aldosterone between mice of the two genotypes. After water deprivation, renal medullary interstitial fluid osmolality and concentrations of Na(+), K(+), and urea did not differ between genotypes and cAMP excretion was similar. Renal aquaporin-1 (AQP1), -2, and -4 protein abundances did not differ between water deprived (+/+) and ACBP(-/-) mice; however, ACBP(-/-) mice displayed increased apical targeting of pS256-AQP2. AQP3 abundance was lower in ACBP(-/-) mice than in (+/+) control animals. Thus we conclude that ACBP is necessary for intact urine concentrating ability. Our data suggest that the deficiency in urine concentrating ability in the ACBP(-/-) may be caused by reduced AQP3, leading to impaired efflux over the basolateral membrane of the collecting duct. PMID- 22237803 TI - Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats. AB - Naloxone (an opioid receptor antagonist) was used to examine the role of opioid mechanisms in bladder reflexes and in somatic afferent inhibition of these reflexes by tibial nerve stimulation (TNS). Experiments were conducted in alpha chloralose-anesthetized cats when the bladder was infused with saline or 0.25% acetic acid (AA). The bladder volume was measured at the first large-amplitude (>30 cmH(2)O) contraction during a cystometrogram and termed "estimated bladder capacity" (EBC). AA irritated the bladder, induced bladder overactivity, and significantly (P < 0.0001) reduced EBC to 14.3 +/- 1.9% of the saline control. TNS (5 Hz, 0.2 ms) at 4 and 8 times the threshold (T) intensity for inducing an observable toe movement suppressed AA-induced bladder overactivity and significantly increased EBC to 41.5 +/- 9.9% (4T, P < 0.05) and 46.1 +/- 7.9% (8T, P < 0.01) of the saline control. Naloxone (1 mg/kg iv) completely eliminated TNS inhibition of bladder overactivity. Naloxone (0.001-1 mg/kg iv) did not change EBC during AA irritation. However, during saline infusion naloxone (1 mg/kg iv) significantly (P < 0.01) reduced EBC to 66.5 +/- 8.1% of the control EBC. During saline infusion, TNS induced an acute increase in EBC and an increase that persisted following the stimulation. Naloxone (1 mg/kg) did not alter either type of inhibition. However, naloxone administered during the poststimulation inhibition decreased EBC. These results indicate that opioid receptors have different roles in modulation of nociceptive and nonnociceptive bladder reflexes and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders. PMID- 22237804 TI - Superficially porous particles columns for super fast HPLC separations. AB - Superficially porous silica particles columns (SPSPCs) are manufactured by different companies. The most common have the brand names Halo, Ascentis Express and Kinetex. These columns provide super fast, sharp peaks and moderate sample loading and back pressure. These are available in different chemistries such as C8, C18, RP Amide and Hilic. Normally, the silica gel particles have 2.7 and 1.7 um total and inner solid core diameters with 0.5 um thick outer porous layer, 90 A pore size and 150 m2/g surface area. They have been used for the separation and identification of low and high molecular weight compounds. The present article describes the state of the art of superficially porous silica particles based columns with special emphasis on their structures, mechanisms of separation, applications and comparison. PMID- 22237805 TI - Hippocratic, religious, and secular ethics: the points of conflict. AB - The origins of professional ethical codes and oaths are explored. Their legitimacy and usefulness within the profession are questioned and an alternative ethical source is suggested. This source relies on a commonly shared, naturally knowable set of principles known as common morality. PMID- 22237806 TI - A comparison of quality of life and satisfaction of women with early-stage breast cancer treated with breast conserving therapy vs. mastectomy in southern China. AB - BACKGROUND: The purpose of this study was to compare the quality of life (QoL) and overall satisfaction with treatment of women with stage T1-2N0M0 breast cancer treated with breast conserving therapy (BCT) or mastectomy (MAS) in southern China. METHODS: Functional assessment of cancer therapy-breast, traditional Chinese version 4 (FACT-B), was administered to 180 patients with stage T1-2N0M0 breast cancer (82 BCT and 98 MAS) treated between July 2000 and July 2008. RESULTS: The two groups differed in tumor pathology and how axillary lymph nodes were treated (sentinel node biopsy vs. dissection), while other disease and socioeconomic characteristics were similar. The median follow-up after completion of radiotherapy was 60 months in the BCT group, and 65 months in the MAS group. The scores of the physical, functional, and emotional domains and breast-specific concerns of FACT-B were not significantly different between the groups. The social domain score of the BCT group was significantly greater than those of the MAS group. CONCLUSIONS: Patients who underwent BCT did not report better QoL than those who received MAS, but BCT patients experienced easier social adjustment. PMID- 22237807 TI - Sprouting of colonic afferent central terminals and increased spinal mitogen activated protein kinase expression in a mouse model of chronic visceral hypersensitivity. AB - Visceral pain following infection or inflammation is a major clinical problem. Although we have knowledge of how peripheral endings of colonic afferents change in disease, their central projections have been overlooked. With neuroanatomical tracing and colorectal distension (CRD), we sought to identify colonic afferent central terminals (CACTs), the dorsal horn (DH) neurons activated by colonic stimuli in the thoracolumbar (T10-L1) DH, and determine how they are altered by postinflammatory chronic colonic mechanical hypersensitivity. Retrograde tracing from the colon identified CACTs in the DH, whereas immunohistochemistry for phosphorylated MAP kinase ERK 1/2 (pERK) identified DH neurons activated by CRD (80 mmHg). In healthy mice, CACTs were located primarily in DH laminae I (LI) and V (LV) and projected down middle and lateral DH collateral pathways. CRD evoked pERK immunoreactivity in DH neurons, the majority of which were located in LI and LV, the same regions as CACTs. In postinflammatory mice, CACTs were significantly increased in T12-L1 compared with healthy mice. Although CACTs remained abundant in LI, they were more widespread and were now present in deeper laminae. After CRD, significantly more DH neurons were pERK-IR postinflammation (T12-L1), with abundant expression in LI and deeper laminae. In both healthy and postinflammatory mice, many pERK neurons were in close apposition to CACTs, suggesting that colonic afferents can stimulate specific DH neurons in response to noxious CRD. Overall, we demonstrate that CACT density and the number of responsive DH neurons in the spinal cord increase postinflammation, which may facilitate aberrant central representation of colonic nociceptive signaling following chronic peripheral hypersensitivity. PMID- 22237808 TI - [Overactive bladder syndrome: the social and economic perspective]. AB - Overactive bladder syndrome (OAB) is a highly prevalent condition associated with a significant impairment of patients' Quality of Life (QoL) because of its adverse effects on social, sexual, interpersonal, and professional functions. Cost-of-illness analyses showed the huge economic burden related to OAB for patients, public healthcare systems, and society, secondary to both direct and indirect costs. These types of cost analyses, however, exclude intangible costs related to QoL impairment. Recently, many novel therapies have been introduced, arising the need to apply the modern methodology of Health Technology Assessment (HTA) to new therapies in order to evaluate objectively their value in terms of both improvement in length/Quality of Life and costs. By producing information on the clinical, economic, organizational, social and ethical impact of health technologies, HTA has been used worldwide to inform decision makers at different levels in health systems. The HTA approach demonstrated, worldwide, to be a useful approach to increase the level of appropriateness in the use of medical technology and, as a consequence of that, of resources. Health utilities are instruments that allow a measurement of QoL and its integration in the economic evaluation using the Quality-of-life-Adjusted-Life-Years (QALYs) model and cost utility analysis. The development of suitable instruments for quantifying utility in the specific group of OAB patients is vitally important to extend the application of cost-utility analysis in OAB and to guide healthcare resources allocation for this disorder. Studies are required to define the cost effectiveness of available pharmacological and non-pharmacological therapy options. PMID- 22237809 TI - Human semen study around and away from gold mine area. AB - Gold was first detected in human semen in 1981. The entry of gold into semen was hypothesized through food items. Earlier reports identified gold in semen as important for good quality of semen. The infertility rate could be low around gold mine area when compared to other places. The aim of the study was to verify this. Towards this, the quality of human semen around a gold mine (Kolar, India) was evaluated and compared to that from a place which was 2000 km away from a gold mine (Jamnagar, India). A total number of 254 semen samples from Kolar and 437 from Jamnagar were evaluated. The fertility rate was higher in Kolar region. The semen samples studied for both places showed that the semen quality was superior in Kolar gold field area. PMID- 22237810 TI - An effective approach of lesion segmentation within the breast ultrasound image based on the cellular automata principle. AB - In this paper, a novel lesion segmentation within breast ultrasound (BUS) image based on the cellular automata principle is proposed. Its energy transition function is formulated based on global image information difference and local image information difference using different energy transfer strategies. First, an energy decrease strategy is used for modeling the spatial relation information of pixels. For modeling global image information difference, a seed information comparison function is developed using an energy preserve strategy. Then, a texture information comparison function is proposed for considering local image difference in different regions, which is helpful for handling blurry boundaries. Moreover, two neighborhood systems (von Neumann and Moore neighborhood systems) are integrated as the evolution environment, and a similarity-based criterion is used for suppressing noise and reducing computation complexity. The proposed method was applied to 205 clinical BUS images for studying its characteristic and functionality, and several overlapping area error metrics and statistical evaluation methods are utilized for evaluating its performance. The experimental results demonstrate that the proposed method can handle BUS images with blurry boundaries and low contrast well and can segment breast lesions accurately and effectively. PMID- 22237811 TI - Tri- and pentacalix[4]pyrroles: synthesis, characterization and their use in the extraction of halide salts. AB - Calixpyrrole-based oligomeric compounds were synthesized by "click chemistry" from the corresponding alkyne- and azide-functionalized calix[4]pyrroles. Calix[4]pyrrole 3, possessing an alkyne functional group, was prepared through a mixed condensation of pyrrole with acetone and but-3-ynyl 4-oxopentanoate. Another alkyne-group-containing calix[4]pyrrole 5 was obtained by treatment of 4' hydroxyphenyl-functionalized calixpyrrole 4 with propargyl bromide. Tetrakis(azidopentyl)-functionalized calix[4]pyrrole 7 was synthesized by reacting NaN(3) with tetrabromopentyltetraethylcalix[4]pyrrole 6, which was prepared through a condensation reaction of pyrrole and 7-bromohept-2-one. Oligomeric calixpyrrole compounds were found to be capable of extracting tetrabutylammonium chloride and fluoride salts from aqueous media. Extraction abilities of the oligomeric compounds were monitored by NMR and UV/Vis spectroscopy and thermogravimetric analysis. PMID- 22237812 TI - Growth from birth to adulthood and peak bone mass and density data from the New Delhi Birth Cohort. AB - Growth in early life may predict adult bone health. Our data showed that greater height and body mass index (BMI) gain in utero and infancy are associated with higher peak bone mass, and greater BMI gain in childhood/adolescence with higher peak bone density. These associations are mediated by attained adult height and BMI. INTRODUCTION: To study the relationship of height and BMI during childhood with adult bone mineral content (BMC), areal density (aBMD) and apparent density (BMAD, estimated volumetric density). METHODS: Participants comprised 565 men and women aged 33-39 years from the New Delhi Birth Cohort, India, whose weight and height were recorded at birth and annually during infancy (0-2 years), childhood (2-11 years) and adolescence (11 years-adult). Lumbar spine, femoral neck and forearm BMC and aBMD were measured using dual X-ray absorptiometry; lumbar spine and femoral neck BMAD were calculated. RESULTS: Birth length, and height and height gain during infancy, childhood and adolescence were positively correlated with adult BMC (p<=0.01 all sites except birth length with femoral neck). Correlations increased with height from birth to 6 years, then remained constant for later height measurements. There were no associations with BMAD. BMI at birth, and during childhood and adolescence was also positively correlated with BMC (p < 0.01 all sites). BMI at 11 years, and BMI gain in childhood and adolescence, were correlated with aBMD and BMAD (p < 0.001 for all); these correlations strengthened with increasing age of BMI measurement. The associations with height and BMI in early life became non-significant after adjustment for adult height and BMI. CONCLUSIONS: Greater skeletal growth and BMI gain in utero and during infancy are associated with higher peak BMC, and greater BMI gain in childhood and adolescence is associated with higher peak aBMD and BMAD. These associations are mediated by the attainment of adult height and BMI, respectively. PMID- 22237813 TI - The 25(OH)D level needed to maintain a favorable bisphosphonate response is >=33 ng/ml. AB - Why only some osteoporotic patients maintain response to prolonged bisphosphonate therapy is unknown. We examined bisphosphonate response and its association with serum 25 hydroxy vitamin D (25(OH)D) level in a "real world" setting. Serum 25(OH)D level was strongly associated with maintaining bisphosphonate response arguing that vitamin D may be involved in optimizing prolonged bisphosphonate therapy. INTRODUCTION: This study examined the maintenance of bisphosphonate response in the "real world" setting and the association between 25(OH)D and bisphosphonate response using an established composite definition of response. METHODS: Postmenopausal women with low bone mineral density (BMD) treated with bisphosphonates were identified from two New York City practices. Patients were excluded for a history of chronic steroid use, metabolic bone disease, or bisphosphonate non-adherence. Patients were categorized as bisphosphonate non responders if they had a T-score < -3 that persisted between dual-energy X-ray absorptiometry (DEXA) scans, a >3% decrease in BMD, or an incident fracture on bisphosphonate therapy, criteria based on the EUROFORS trial. Demographic and clinical data including mean 25(OH)D levels between DEXA scans were obtained. Mean 25(OH)D levels were compared between responders and non-responders and multiple logistic regression analysis was performed to identify factors associated with non-response. RESULTS: A total of 210 patients were studied. A favorable response to bisphosphonate therapy was seen in 47% (N = 99/210). Patients with a mean 25(OH)D >=33 ng/ml had a ~4.5-fold greater odds of a favorable response (P < 0.0001). 25(OH)D level was significantly associated with response - a 1 ng/ml decrease in 25(OH)D was associated with ~5% decrease in odds of responding (odds ratio = 0.95; 95% confidence interval, 0.92-0.98; P = 0.0006). CONCLUSIONS: Patients with a mean 25(OH)D >=33 ng/ml had a substantially greater likelihood of maintaining bisphosphonate response. This threshold level of 25(OH)D is higher than that considered adequate by the Institute of Medicine, arguing that higher levels may be required for specific therapeutic outcomes. PMID- 22237815 TI - Three years of alendronate treatment does not continue to decrease microstructural stresses and strains associated with trabecular microdamage initiation beyond those at 1 year. AB - The effects of a 3-year alendronate treatment on trabecular stresses/strains associated with microdamage initiation were investigated using finite element modeling (FEM). Severely damaged trabeculae in the low-dose treatment group were associated with increased stresses compared with the high-dose treatment group (p = 0.006) and approached significance in the control group (p = 0.02). INTRODUCTION: Alendronate, a commonly prescribed anti-remodeling agent, decreases fracture risk in the vertebrae, hip, and wrist of osteoporotic individuals. However, evaluation of microdamage accumulation in animal and human studies shows increased microdamage density relative to controls. Microstructural von Mises stresses associated with severe and linear damage have been found to decrease after 1 year of alendronate treatment. In the present study, stresses/strains associated with damage were assessed after 3 years of treatment to determine whether they continued to decrease with increased treatment duration. METHODS: Microdamaged trabeculae visualized with fluorescent microscopy were associated with stresses and strains obtained using image-based FEM. Stresses/strains associated with severe, diffuse, and linearly damaged and undamaged trabeculae were compared among groups treated for 3 years with an osteoporotic treatment dose of alendronate, a Paget's disease treatment dose of alendronate, or saline control. Architectural characteristics and mineralization were also analyzed from three-dimensional microcomputed tomography reconstructed images. RESULTS: Severely damaged trabeculae in the osteoporotic treatment dose group were associated with increased stress compared with the Paget's disease treatment dose group (p = 0.006) and approached significance compared to the control group (p = 0.02). Trabecular mineralization in severely damaged trabeculae of the low-dose treatment group was significantly greater compared to severely damaged trabeculae in the high-dose treatment and control group, suggesting that changes at the tissue level may play a role in these findings. CONCLUSIONS: Trabecular level stresses associated with microdamage do not continue to decrease with prolonged alendronate treatment. Changes in mineralization may account for these findings. PMID- 22237814 TI - Iron excess limits HHIPL-2 gene expression and decreases osteoblastic activity in human MG-63 cells. AB - In order to understand mechanisms involved in osteoporosis observed during iron overload diseases, we analyzed the impact of iron on a human osteoblast-like cell line. Iron exposure decreases osteoblast phenotype. HHIPL-2 is an iron-modulated gene which could contribute to these alterations. Our results suggest osteoblast impairment in iron-related osteoporosis. INTRODUCTION: Iron overload may cause osteoporosis. An iron-related decrease in osteoblast activity has been suggested. METHODS: We investigated the effect of iron exposure on human osteoblast cells (MG-63) by analyzing the impact of ferric ammonium citrate (FAC) and iron citrate (FeCi) on the expression of genes involved in iron metabolism or associated with osteoblast phenotype. A transcriptomic analysis was performed to identify iron modulated genes. RESULTS: FAC and FeCi exposure modulated cellular iron status with a decrease in TFRC mRNA level and an increase in intracellular ferritin level. FAC increased ROS level and caspase 3 activity. Ferroportin, HFE and TFR2 mRNAs were expressed in MG-63 cells under basal conditions. The level of ferroportin mRNA was increased by iron, whereas HFE mRNA level was decreased. The level of mRNA alpha 1 collagen type I chain, osteocalcin and the transcriptional factor RUNX2 were decreased by iron. Transcriptomic analysis revealed that the mRNA level of HedgeHog Interacting Protein Like-2 (HHIPL-2) gene, encoding an inhibitor of the hedgehog signaling pathway, was decreased in the presence of FAC. Specific inhibition of HHIPL-2 expression decreased osteoblast marker mRNA levels. Purmorphamine, hedgehog pathway activator, increased the mRNA level of GLI1, a target gene for the hedgehog pathway, and decreased osteoblast marker levels. GLI1 mRNA level was increased under iron exposure. CONCLUSION: We showed that in human MG-63 cells, iron exposure impacts iron metabolism and osteoblast gene expression. HHIPL-2 gene expression modulation may contribute to these alterations. Our results support a role of osteoblast impairment in iron-related osteoporosis. PMID- 22237817 TI - Precision of 18F-fluoride PET skeletal kinetic studies in the assessment of bone metabolism. AB - We assessed the precision of lumbar spine (18)F-PET measurements based on 58 scans performed on 20 postmenopausal women. The percentage coefficient of variation (%CV) (95% confidence interval) was 9.2% (7.5-11.8) for standardised uptake values, 11.7% (9.5-14.9) for plasma clearance measurements using the Patlak method and 14.5% (11.7-18.5) for plasma clearance measurements using the Hawkins three-compartment model. INTRODUCTION: (18)F-Fluoride positron emission tomography ((18)F-PET) is a non-invasive technique that allows the assessment of regional bone turnover in patients with metabolic bone disease. Knowledge of the precision errors of (18)F-PET measurements is important for planning the number of subjects required for research studies. METHODS: Twenty osteoporotic postmenopausal women had (18)F-PET scans of the lumbar spine at 0, 6 and 12 months after stopping long-term bisphosphonate treatment. No significant changes in the PET measurements were seen over the 12-month period, and the data were deemed suitable for a precision study. Precision errors were evaluated for standardised uptake values (SUVs) and for the fluoride plasma clearance to bone mineral (K (i)) determined using the Patlak and Hawkins methods. Precision errors were expressed as the %CV and were calculated for the mean L1-L4 region and for individual vertebrae. RESULTS: %CV (95% confidence interval) for the L1-L4 region was 9.2% (7.5-11.8) for SUV, 11.7% (9.5-14.9) for K (i) measured using the Patlak method and 14.5% (11.7-18.5) for K (i) measured using the Hawkins method. There was no significant difference between precision errors obtained for the L1-L4 region and those obtained for a single vertebra. CONCLUSIONS: SUV measurements showed the smallest precision error followed by the Patlak method, while the Hawkins method gave the largest error. Measuring a smaller region of interest did not increase the precision error, suggesting that the factor determining the errors may be scanner calibration. PMID- 22237818 TI - Painless legs and moving toes from parasagittal meningioma. PMID- 22237820 TI - The case of the Marquis de Causan (1804): an early account of visual loss associated with spinal cord inflammation. AB - The recent discovery of disease specific and pathogenic autoantibodies in neuromyelitis optica (NMO, Devic's disease) has revived the interest in this intriguing yet often devastating condition. While the history of classic multiple sclerosis has been studied extensively, only very little is known so far about the early history of NMO. Here we discuss a now forgotten report by the famous French anatomist and pathologist Antoine Portal (1742-1832), first physician to Louis XVIII and founding and lifelong president of the Academie Nationale de Medecine. Portal's report, which fascinated some of the most renowned 19th century pioneers in the field of neurology but fell into oblivion later, represents the first account of visual loss in a patient with spinal cord inflammation but no brain pathology in the Western literature known so far- published more than 60 years prior to Thomas Clifford Allbutt's much cited note on a patient with myelitis and a "sympathetic eye disorder". PMID- 22237819 TI - Increased cerebral activation after behavioral treatment for memory deficits in MS. AB - Deficits in new learning and memory are common in persons with multiple sclerosis (MS), though few studies have examined the efficacy of memory retraining in MS. Previous research from our laboratory has demonstrated that the modified Story Memory Technique (mSMT) significantly improves new learning and memory in MS. The present double-blind, placebo-controlled, randomized clinical trial was designed to examine changes in cerebral activation following mSMT treatment. Sixteen individuals with clinically definite MS were randomly assigned to treatment (n = 8) or placebo-control (n = 8) groups, matched for age, education, and disease characteristics. Baseline and follow-up fMRI was collected during performance of learning and memory tasks. No baseline activation differences on fMRI were seen between groups. After treatment, greater activation was evident in the treatment group during performance of a memory task within a widespread cortical network involving frontal, parietal, precuneus, and parahippocampal regions. All participants in the treatment group showed increased activation in frontal and temporal regions in particular. In contrast, the control group showed no significant changes in cerebral activation at follow-up. A significant association was found between increased activation in the right middle frontal gyrus and improved memory performance post-treatment. The increased activation seen likely reflects increased use of strategies taught during treatment when learning new information. This study is the first to demonstrate a significant change in cerebral activation resulting from a behavioral memory intervention in an MS sample. Behavioral interventions can show significant changes in the brain, validating clinical utility. PMID- 22237821 TI - Rating papilloedema: an evaluation of the Frisen classification in idiopathic intracranial hypertension. AB - The appearance of the optic disc is a key measure of disease status in idiopathic intracranial hypertension (IIH). The Frisen classification describes stages of optic disc swelling (grades 0-5). It is the only classification of papilloedema, and is used internationally in clinical and research practice. Despite this, there has been very limited evaluation of the scale. We assessed the inter-rater reproducibility and ability to discriminate optic disc changes over time using the Frisen classification compared with a system of ranking papilloedema severity in patients with IIH. Paired disc photographs (before and after treatment) were obtained from 47 patients with IIH (25 acute and 22 chronic). Six neuro ophthalmologists blinded to patient identity, clinical information and chronology of the photographs reviewed the discs and allocated a Frisen grade and ranked the paired discs in order of papilloedema severity (disc ranking). A total of 188 optic disc photographs were reviewed. All six reviewers agreed in only three comparisons (1.6%) when using the Frisen classification, compared with 42 comparisons (45.2%) when using disc ranking. The probability of agreement between any two reviewers was 36.1% for Frisen grade and 70.0% for disc ranking. Disc ranking had significantly greater sensitivity for finding differences in degree of disc oedema, identifying a difference in 75.3% of paired photographs compared to 53.2% detected using the Frisen classification (p < 0.001). This study demonstrated the limited reproducibility and discriminative ability of the Frisen classification in identifying changes in serial optic disc photographs in IIH. Simple optic disc ranking appears to be a more sensitive and reliable tool to monitor changes in optic disc appearance. The use of disc ranking in clinical practice and research studies is recommended to monitor alterations in optic disc appearance until alternative schemes, specific to IIH, have been developed. PMID- 22237816 TI - Vitamin D status and physical activity interact to improve bone mass in adolescents. The HELENA Study. AB - The effects of vitamin D concentrations on bone mineral content in adolescents are still unclear. Vitamin D and physical activity (PA) may interact to determine bone mineral content (BMC) in two possible directions; 25(OH)D sufficiency levels improve BMC only in active adolescents, or PA increases BMC in individuals with replete vitamin D levels. INTRODUCTION: The effects of suboptimal 25 hydroxycholecalciferol (25(OH)D) concentrations on BMC in adolescents are still unclear. The main aim of this study was to evaluate the influence of 25(OH)D on BMC in adolescents, considering the effect of body composition, sex, age, Tanner stage, season, calcium and vitamin D intakes, physical fitness and PA. METHODS: Serum 25(OH)D concentrations, anthropometric measurements, dual energy X-ray absorptiometry measurements, calcium and vitamin D intakes, PA and physical fitness were obtained in 100 Spanish adolescents (47 males), aged 12.5-17.5 years, within the framework of the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study. Relations were examined using ANCOVA and regression analyses including BMC as dependent variable. RESULTS: Linear regression of BMC suggested that 25(OH)D concentrations independently influenced total and leg BMC after controlling for age, sex, lean mass, seasonality and calcium intake (B = 0.328, p < 0.05, and B = 0.221, p < 0.05, respectively) in the physically active group. No significant influence of 25(OH)D concentrations on BMC was observed in the inactive group. Significant effect was shown between the interaction of 25(OH)D and PA on BMC for the total body and legs (both p < 0.05). CONCLUSIONS: Vitamin D and PA may interact to determine BMC. 25(OH)D sufficiency levels improve bone mass only in active adolescents, or PA has a positive influence on BMC in individuals with replete vitamin D levels. PMID- 22237822 TI - Gender-related differences in the burden of non-motor symptoms in Parkinson's disease. AB - Differences in the expression of non-motor symptoms (NMS) by Parkinson's disease (PD) patients may have important implications for their management and prognosis. Gender is a basic epidemiological variable that could influence such expression. The present study evaluated the prevalence and severity of NMS by gender in an international sample of 951 PD patients, 62.63% males, using the non-motor symptoms scale (NMSS). Assessments for motor impairment and complications, global severity, and health state were also applied. All disease stages were included. No significant gender differences were found for demographic and clinical characteristics. For the entire sample, the most prevalent symptoms were Nocturia (64.88%) and Fatigue (62.78%) and the most prevalent affected domains were Sleep/Fatigue (84.02%) and Miscellaneous (82.44%). Fatigue, feelings of nervousness, feelings of sadness, constipation, restless legs, and pain were more common and severe in women. On the contrary, daytime sleepiness, dribbling saliva, interest in sex, and problems having sex were more prevalent and severe in men. Regarding the NMSS domains, Mood/Apathy and Miscellaneous problems (pain, loss of taste or smell, weight change, and excessive sweating) were predominantly affected in women and Sexual dysfunction in men. No other significant differences by gender were observed. To conclude, in this study significant differences between men and women in prevalence and severity of fatigue, mood, sexual and digestive problems, pain, restless legs, and daytime sleepiness were found. Gender-related patterns of NMS involvement may be relevant for clinical trials in PD. PMID- 22237823 TI - Metabonomics study of the acute graft rejection in rat renal transplantation using reversed-phase liquid chromatography and hydrophilic interaction chromatography coupled with mass spectrometry. AB - Acute graft rejection is one of the most common and serious post complications in renal transplantation, noninvasive diagnosis of acute graft rejection is essential for reducing risk of surgery and timely treatment. In this study, a non targeted metabonomics approach based on ultra performance liquid chromatography (UPLC) coupled with quadrupole time-of-flight mass spectrometry (MS) is used to investigate the effect of acute graft rejection in rat renal transplantation on metabolism. To collect more metabolite information both hydrophilic interaction chromatography and reversed-phase liquid chromatography were used. Using the partial least squares-discriminant analysis, we found that the change of metabonome in a sham-operated group and a non-graft rejection group had a similar trend, while that of the acute graft rejection group was clearly different. Several discriminating metabolites of the acute graft rejection were identified, including creatinine, phosphatidyl-cholines, lyso-phosphatidylcholines, carnitine C16:0, free fatty acids and indoxyl sulfate etc. These discriminating metabolites suggested that acute graft rejection in renal transplantation can lead to the accumulation of creatinine in the body, and also the abnormal metabolism of phospholipids. These findings are useful to understand the mechanisms of the rejection, it also means that a UPLC-MS metabonomic approach is a suitable tool to investigate the metabolic abnormality in the acute graft rejection in renal transplantation. PMID- 22237824 TI - Painless groin mass and multiple erythematous to violaceous skin lesions: diagnosis and discussion. PMID- 22237825 TI - Photolysis of ortho-nitrobenzylic derivatives: the importance of the leaving group. AB - Quantum yields for the photoinduced release of seven different commonly used leaving groups (LGs) from the o-nitroveratryl protecting group were measured. It was found that these quantum yields depend strongly on the nature of the LGs. We show that the quantum efficiency with which the LGs are released correlates with the stabilization that these LGs provide to o-nitrobenzyl-type radicals because radical stabilizing groups weaken the C-H bond that is cleaved in the photoinduced hydrogen atom transfer step, and hence lower the barrier for this process. At the same time these substituents lower the endothermicity of the thermal hydrogen atom transfer and thus increase the barrier for the reverse process, thereby enhancing the part of the initially formed aci-nitro intermediates which undergo cyclization (which ultimately leads to LG release). Radical stabilization energies computed by DFT methods are thus a useful predictor of the relative efficiency with which LGs are photoreleased from o nitrobenzyl protecting groups. PMID- 22237826 TI - Association between type D personality and prognosis in patients with cardiovascular diseases: a systematic review and meta-analysis. AB - BACKGROUND: Since 1995, the association of type D personality and mortality in patients with cardiovascular diseases has been increasingly investigated. PURPOSE: The aim of this meta-analysis was to integrate conflicting results and to examine possible moderators of this association. METHODS: Prospective studies assessing type D personality and hard endpoints were selected and pooled in meta analyses. Cardiovascular diagnosis, type and quality of adjustment, and publication date were examined in moderator analyses. RESULTS: Twelve studies on patients with cardiovascular diseases (N = 5,341) were included. Pooled crude and adjusted effects demonstrated a significant association of type D personality and hard endpoints (odds ratio (OR) of 2.28 (95% CI [1.43-3.62]), adjusted hazard ratio (HR) of 2.24 (95% CI [1.37-3.66])). The OR decreased over time (OR 5.02 to OR 1.54). There was no association in congestive heart failure patients. CONCLUSIONS: More recent methodologically sound studies suggest that early type D studies had overestimated the prognostic relevance. PMID- 22237827 TI - Videolaryngoscopy offers advantages over classic laryngoscopy in a patient with seriously limited lip opening. PMID- 22237828 TI - Auditory evoked potential index does not correlate with observer assessment of alertness and sedation score during 0.5% bupivacaine spinal anesthesia with nitrous oxide sedation alone. AB - PURPOSE: The aim of this study was to evaluate the auditory evoked potential (AEP) index as a hypnosis monitor during nitrous oxide (N(2)O) sedation added to spinal analgesia. METHODS: Forty-five patients scheduled to undergo surgery under spinal anesthesia were recruited after giving informed consent. Adequate anesthesia levels were confirmed, and a disposable AEP index sensor (aepEX, Medical Device Management) was placed. A tight facemask was fitted, and a fresh gas flow of 100% oxygen 10 L/min was provided. AEP index monitoring was then initiated, and measurements and observer assessment of alertness/sedation (OAA/S) scores were recorded manually. N(2)O was administered in stepwise increases in the end-tidal concentration of 33%, 50%, and 67%. Paired AEP index and OAA/S scores were obtained immediately before each change in N(2)O concentration. RESULTS: Sixteen patients were excluded from final analysis because of nausea, vomiting, or abnormal excitatory behaviors. The increases in N(2)O concentration induced significant decreases in OAA/S scores and no substantial AEP index changes. Although OAA/S scores of 1 and 2 were observed in only two and five patients, respectively, a reduction in the OAA/S score from 5 to 1 was associated with a significant decrease in AEP index to the level indicative of moderate sedation. CONCLUSION: The AEP index might not be a suitable indicator of light hypnosis as defined by an OAA/S score of >=3 during sedation with N(2)O alone. PMID- 22237829 TI - Minimally invasive heart valve surgery: how and why in 2012. AB - Cardiac surgical procedures via traditional sternotomy are safe and effective operations performed by cardiothoracic surgeons worldwide. However, postoperative limitations in upper extremity activity during bone healing are seen as undesirable by some. Percutaneous catheter-based attempts to emulate the outcomes of traditional cardiac surgical procedures have largely fallen short of established standards of efficacy and durability. The field of minimally invasive heart valve surgery thus developed out of a need to offer smaller, better tolerated incisions to patients while maintaining high-quality clinical outcomes. These operations are safe and effective when performed by proficient surgical teams, allowing patients to resume normal activities more rapidly. We explore current evidence supporting the practice of minimally invasive heart valve surgery in 2012 and analyze the clinical impact of these nascent surgical platforms. PMID- 22237831 TI - Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. AB - Recent data suggest that the chemokine receptor CXCR3 is functionally involved in fibroproliferative disorders, including liver fibrosis. Neoangiogenesis is an important pathophysiological feature of liver scarring, but a functional role of angiostatic CXCR3 chemokines in this process is unclear. We therefore investigated neoangiogenesis in carbon tetrachloride (CCl(4))-induced liver fibrosis in Cxcr3(-/-) and wildtype mice by histological, molecular, and functional imaging methods. Furthermore, we assessed the direct role of vascular endothelial growth factor (VEGF) overexpression on liver angiogenesis and the fibroproliferative response using a Tet-inducible bitransgenic mouse model. The feasibility of attenuation of angiogenesis and associated liver fibrosis by therapeutic treatment with the angiostatic chemokine Cxcl9 was systematically analyzed in vitro and in vivo. The results demonstrate that fibrosis progression in Cxcr3(-/-) mice was strongly linked to enhanced neoangiogenesis and VEGF/VEGFR2 expression compared with wildtype littermates. Systemic VEGF overexpression led to a fibrogenic response within the liver and was associated with a significantly increased Cxcl9 expression. In vitro, Cxcl9 displayed strong antiproliferative and antimigratory effects on VEGF-stimulated endothelial cells and stellate cells by way of reduced VEGFR2 (KDR), phospholipase Cgamma (PLCgamma), and extracellular signal-regulated kinase (ERK) phosphorylation, identifying this chemokine as a direct counter-regulatory molecule of VEGF signaling within the liver. Accordingly, systemic administration of Cxcl9 led to a strong attenuation of neoangiogenesis and experimental liver fibrosis in vivo. CONCLUSION: The results identify direct angiostatic and antifibrotic effects of the Cxcr3 ligand Cxcl9 in a model of experimental liver fibrosis. The amelioration of liver damage by systemic application of Cxcl9 might offer a novel therapeutic approach for chronic liver diseases associated with increased neoangiogenesis. PMID- 22237830 TI - Impact of chorda tympani nerve injury on cell survival, axon maintenance, and morphology of the chorda tympani nerve terminal field in the nucleus of the solitary tract. AB - Chorda tympani nerve transection (CTX) has been useful to study the relationship between nerve and taste buds in fungiform papillae. This work demonstrated that the morphological integrity of taste buds depends on their innervation. Considerable research focused on the effects of CTX on peripheral gustatory structures, but much less research has focused on the central effects. Here, we explored how CTX affects ganglion cell survival, maintenance of injured peripheral axons, and the chorda tympani nerve terminal field organization in the nucleus of the solitary tract (NTS). After CTX in adult rats, the chorda tympani nerve was labeled with biotinylated dextran amine at 3, 7, 14, 30, and 60 days post-CTX to allow visualization of the terminal field associated with peripheral processes. There was a significant and persistent reduction of the labeled chorda tympani nerve terminal field volume and density in the NTS following CTX. Compared with controls, the volume of the labeled terminal field was not altered at 3 or 7 days post-CTX; however, it was significantly reduced by 44% and by 63% at 30 and 60 days post-CTX, respectively. Changes in the density of labeled terminal field in the NTS paralleled the terminal field volume results. The dramatic decrease in labeled terminal field size post-CTX cannot be explained by a loss of geniculate ganglion neurons or degeneration of central axons. Instead, the function and/or maintenance of the peripheral axonal process appear to be affected. These new results have implications for long-term functional and behavioral alterations. PMID- 22237832 TI - Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis benzimidazole-dihydroquinoxalines. AB - Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity. PMID- 22237833 TI - Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study. AB - To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At-Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40-item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty-six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration. PMID- 22237835 TI - Adjuvant PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) or gemcitabine followed by chemoradiation in pancreatic cancer: a randomized phase II trial. AB - BACKGROUND: Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. METHODS: Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, alpha=.05 and beta=.10, the study was to enroll 51 patients per arm. RESULTS: A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. CONCLUSIONS: The 4-drug regimen deserves further assessment in resectable pancreatic cancer. PMID- 22237834 TI - Loss of adenosine A2B receptor mediated relaxant responses in the aged female rat bladder; effects of dietary phytoestrogens. AB - This study examined the effect of age, ovariectomy and dietary phytoestrogen ingestion on adenosine A(2B) receptor mediated relaxant responses and mRNA expression of adenosine receptor subtypes in the rat isolated bladder. Female Wistar rats (8 weeks) were anaesthetised and the ovaries were removed (ovx) or left intact (sham). Rats were fed either normal rat chow (soy, phytoestrogens) or a non-soy (phytoestrogen free) diet. Isolated bladder from rats aged 12, 24 or 52 weeks were pre-contracted with 3 MUM carbachol prior to a concentration response curve to 5'-(N-ethylcarboxamido) adenosine (NECA) being obtained. In 12-week-old rats, the bladder exhibited enhanced relaxant responses to NECA in soy-fed rats (P < 0.05), whilst at 24 weeks of age, the relaxant responses to NECA were attenuated in all the groups studied except soy-treated sham rat bladders in which the relaxant responses were enhanced. At 52 weeks of age, no relaxant effects were observed in any of the treatment groups and NECA-induced contractile responses occurred. In all bladders, the adenosine A(2B) receptor was the most abundantly expressed. In bladders from young and mature female rats, the mRNA expression of adenosine receptors (A(1), A(2A) and A(2B)) was lowest in the bladder from non-soy-fed ovariectomised animals and the use of phytoestrogens in the diet increased the mRNA expression of these receptors (P < 0.05). While a soy diet improves the relaxant effects to the adenosine analogue via adenosine A(2B) receptors in bladders from younger rats, the benefits are lost with advancing age. PMID- 22237836 TI - Large-scale honeycomb microstructures constructed by platinum-acetylide gelators through supramolecular self-assembly. AB - A series of new platinum-acetylide complexes 4a-4c and 6a-6c were synthesized and characterized. The gelation properties of these compounds were investigated by the "stable-to-inversion-of-test-tube" method. Unlike compounds 4a-4c, amides 6b and 6c can gelate a variety of nonpolar alkyl solvents; this result indicates that the hydrogen bonds between amide groups play an important role in the formation of metallic organogels. Interestingly, compared to the typical morphologies of known organogels or metallic organogels, compounds 6b and 6c exhibited highly ordered honeycomb patterns on a large-scale (determined by SEM analysis). To investigate the driving forces for the self-assembly process, concentration-dependent (1)H NMR spectroscopy and a competitive experiment between hydrogen bonds were used to confirm that intermolecular hydrogen bonding play an essential role during the formation of supramolecular aggregates. PMID- 22237838 TI - Radial intrastromal femtosecond laser incisions for myopia correction. PMID- 22237837 TI - The chemical ecology of cyanobacteria. AB - This review covers the literature on the chemically mediated ecology of cyanobacteria, including ultraviolet radiation protection, feeding-deterrence, allelopathy, resource competition, and signalling. To highlight the chemical and biological diversity of this group of organisms, evolutionary and chemotaxonomical studies are presented. Several technologically relevant aspects of cyanobacterial chemical ecology are also discussed. PMID- 22237840 TI - Total hip replacement fifteen years after pelvic support osteotomy (PSO): a case report and review of the literature. AB - Treatment of chronic hip instability in children and young adults is challenging. Proximal femoral osteotomy had been suggested to provide pelvic stability and improved abductor function. Total hip replacement after pelvic support osteotomy can be challenging due to altered anatomy due to angulation of the proximal femur in both frontal and sagittal planes. This is a 29-year-old woman who had total hip replacement after pelvic support osteotomy. The patient had pelvic support at the age of 14 years. Pelvic support osteotomy delayed the need for total hip replacement for 15 years. Preoperative planning for total hip replacement with model was used for proper understanding of the anatomy of the proximal femur. Revision of femoral component was necessary due to penetration of the proximal femur. In conclusion, total hip replacement after pelvic support osteotomy is a technically demanding procedure, and careful attention to surgical details is necessary for successful outcome. PMID- 22237839 TI - Restoration of the photoreceptor layer and improvement of visual acuity in successfully treated optic disc pit maculopathy: a long follow-up study by optical coherence tomography. AB - PURPOSE: To investigate by optical coherence tomography (OCT) the evolution of the photoreceptor layer and its association with best-corrected visual acuity (BCVA) in optic disc pit (ODP) maculopathy after successful surgical treatment. METHODS: Fourteen eyes of 14 patients were included in this study, and followed up from 36 to 95 months (mean 57.36 +/- 18.32 months). The follow-up period started at the time of complete subretinal fluid absorption. Examination was performed by time-domain OCT before and after treatment. Spectral-domain OCT was used after treatment. Parameters assessed were type of elevation, central foveal thickness, time elapsed from onset to treatment, type of treatment, BCVA, and inner segment outer segment (IS/OS) junction line. The IS/OS junction was characterized after treatment as intact, interrupted, or absent (not distinguishable). RESULTS: Significant restoration of the IS/OS junction line was first noticed between 6 and 12 months after fluid absorption (p = 0.02; Wilcoxon signed rank test). Restoration was continuous up to the 24th month of postoperative examination after fluid absorption (p = 0.14; Wilcoxon signed rank test). BCVA was 0.99 +/- 0.38 logMar before treatment, 0.81 +/- 0.26 logMar (p = 0.011; paired t-test) immediately after fluid absorption and 0.61 +/- 0.33 logMar (p = 0.026; one-way ANOVA) 24 months after fluid resolution. BCVA was significantly positively correlated with the integrity of the IS/OS junction line during follow-up (Pearson r = 0.775; p < 0.001). CONCLUSIONS: The IS/OS junction restoration cannot be detected immediately after fluid resolution in the majority of cases. It became evident 6-12 months later and was completed 24 months after fluid absorption. Improvement in BCVA was noticed only during the first 2 years of follow-up. No significant changes were noticed in BCVA or the IS/OS line after 2 years. Among the studied variables, the final photoreceptor layer condition and BCVA immediately after fluid absorption are the main factors predicting final BCVA after successful surgical treatment of ODP maculopathy. PMID- 22237841 TI - Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3 octreotide positron emission tomography and 123I-metaiodobenzylguanidine: a clarification. PMID- 22237842 TI - Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour homing peptides in a preclinical mouse model of peritoneal carcinomatosis. AB - PURPOSE: Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with (225)Ac and (213)Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of (225)Ac-DOTA-F3 in comparison with that of (213)Bi-DTPA-F3. METHODS: ID(50) values of (213)Bi-DTPA-F3 and (225)Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology. RESULTS: ID(50) values of (213)Bi-DTPA-F3 and (225)Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 * 10(7) MDA-MB-435 cells. Therapy with 6 * 1.85 kBq of (225)Ac-DOTA-F3 or 6 * 1.85 MBq of (213)Bi DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived (213)Bi (t (1/2) 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of (225)Ac DOTA-F3 (t (1/2) 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with (225)Ac-DOTA-F3 (43%) and with (213)Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10-30% of animals after treatment with (225)Ac-DOTA-F3 or (213)Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. CONCLUSION: Therapy with both (225)Ac-DOTA-F3 and (213)Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application. PMID- 22237843 TI - Imaging of inflamed carotid artery atherosclerotic plaques with the use of 99mTc HYNIC-IL-2 scintigraphy in end-stage renal disease patients. AB - PURPOSE: Identification of vulnerable plaques remains crucial for better cardiovascular risk assessment. At least 20% of inflammatory cells within unstable (vulnerable) plaques comprise T lymphocytes, which contain receptors for interleukin-2 (IL-2); those receptors can be identified by scintigraphy with radiolabelled IL-2.The aim of this study was to identify the "inflamed" (vulnerable) plaques by scintigraphy using IL-2 labelled with (99m)Tc in the selected, high cardiovascular risk group of end-stage renal disease (ESRD) patients. METHODS: A total of 28 patients (18 men, 10 women, aged 55.2 +/- 9.6 years, 17 on peritoneal dialysis, 11 on haemodialysis) underwent common carotid artery (CCA) scintigraphy with the use of (99m)Tc-hydrazinonicotinamide (HYNIC) IL-2. In all cases, ultrasound examination of the CCA was performed and levels of selected proinflammatory factors, atherogenic markers and calcium-phosphate balance parameters were measured. Finally, the target to non-target (T/nT) ratio of IL-2 uptake in atherosclerotic plaques with intima-media thickness (IMT), classic cardiovascular risk factors and concentrations of the measured factors were compared. RESULTS: Increased (99m)Tc-HYNIC-IL-2 uptake in atherosclerotic plaques in 38/41 (91%) cases was detected. The median T/nT ratio of focal (99m)Tc HYNIC-IL-2 uptake in atherosclerotic plaques was 2.35 (range 1.23-3.63). The mean IMT value on the side of plaques assessed by scintigraphy was 0.79 +/- 0.18 mm (median 0.8, range 0.5-1.275). Correlations between T/nT ratio and homocysteine (R = 0.22, p = 0.037), apolipoprotein B (apoB) (R = 0.31, p = 0.008), apoB to apoA-I ratio (R = 0.29, p = 0.012) and triglyceride concentration (R = 0.26, p = 0.021) were detected. A lower T/nT ratio in patients with better parameters of nutritional status (haemoglobin, albumin, adiponectin) in comparison with patients with worse nutritional parameters (3.20 +/- 0.5 vs 2.16 +/- 0.68, p = 0.025) was revealed as well as a difference between values of T/nT ratio in groups of patients with values of apoB, soluble CD40 ligand and asymmetric dimethylarginine above and below median (3.18 +/- 0.52 vs 2.16 +/- 0.68, p = 0.031). No statistically significant association was found between T/nT ratio and mean value of either IMT or classic cardiovascular risk factors. CONCLUSION: Scintigraphy with the use of (99m)Tc-HYNIC-IL-2 can be a tool for inflamed atherosclerotic (vulnerable) plaque visualization within CCA in ESRD patients. Quantitative results of carotid artery scintigraphy with (99m)Tc-HYNIC-IL-2 correlate with serum concentration of selected cardiovascular risk markers. PMID- 22237844 TI - Usefulness and pitfalls of MAA SPECT/CT in identifying digestive extrahepatic uptake when planning liver radioembolization. AB - PURPOSE: Identifying gastroduodenal uptake of (99m)Tc-macroaggregated albumin (MAA), which is associated with an increased risk of ulcer disease, is a crucial part of the therapeutic management of patients undergoing radioembolization for liver tumours. Given this context, the use of MAA single photon emission computed tomography (SPECT)/CT may be essential, but the procedure has still not been thoroughly evaluated. The aim of this retrospective study was to determine the effectiveness of MAA SPECT/CT in identifying digestive extrahepatic uptake, while determining potential diagnostic pitfalls. METHODS: Overall, 139 MAA SPECT/CT scans were performed on 103 patients with different hepatic tumour types. Patients were followed up for at least 6 months according to standard requirements. RESULTS: Digestive, or digestive-like, uptake other than free pertechnetate was identified in 5.7% of cases using planar imaging and in 36.6% of cases using SPECT/CT. Uptake sites identified by SPECT/CT included the gastroduodenal region (3.6%), gall bladder (12.2%), portal vein thrombosis (6.5%), hepatic artery (6.5%), coil embolization site (2.1%) as well as falciform artery (5.0%). For 2.1% of explorations, a coregistration error between SPECT and CT imaging could have led to a false diagnosis by erroneously attributing an uptake site to the stomach or gall bladder, when the uptake actually occurred in the liver. CONCLUSION: SPECT/CT is more efficacious than planar imaging in identifying digestive extrahepatic uptake sites, with extrahepatic uptake observed in one third of scans using the former procedure. However, more than half of the uptake sites in our study were vascular in nature, without therapeutic implications. The risk of coregistration errors must also be kept in mind. PMID- 22237845 TI - SPECT/CT versus MRI in patients with nonspecific pain of the hand and wrist - a pilot study. AB - BACKGROUND: Hand and wrist pain is a diagnostic challenge for hand surgeons and radiologists due to the complex anatomy of the involved small structures. The American College of Radiology recommends MRI as the study of choice in patients with chronic wrist pain if radiographs are negative. Lately, state-of-the-art SPECT/CT systems have been introduced and may help in the diagnosis of this selected indication. MATERIALS AND METHODS: This retrospective study included 21 patients with nonspecific pain of the hand/wrist. The diagnosis of nonspecific wrist pain was made by the referring hand surgeon based on patient history, clinical examination, plain radiography and clinical guidelines. All patients received planar early-phase imaging and late-phase SPECT/CT imaging as well as MRI. Lesions were divided into major (causative) and minor (not causative) pathologies according to clinical follow-up. Furthermore, oedema-like bone marrow changes seen on MRI were compared with focally increased tracer uptake seen on SPECT/CT images. RESULTS: MRI yielded a quite high sensitivity (0.86), but a low specificity (0.20). In contrast, SPECT/CT yielded a high specificity (1.00) and a low sensitivity (0.71). Oedema-like bone marrow changes were detected in 15 lesions in 11 patients. In ten lesions with bone marrow oedema on MRI, foci of elevated tracer uptake were detected on SPECT/CT. Overall, MRI was more sensitive, but SPECT/CT was more specific in the evaluation of causative pathologies. CONCLUSION: In this initial comparison, SPECT/CT showed higher specificity than MRI in the evaluation of causative pathologies in patients with nonspecific wrist pain. However, MRI was more sensitive. Thus, SPECT/CT was shown to be a useful problem-solving tool in the diagnostic work-up of these patients. PMID- 22237846 TI - Feasibility of bremsstrahlung dosimetry for direct dose estimation in patients undergoing treatment with 90Y-ibritumomab tiuxetan. AB - PURPOSE: Radioimmunotherapy with (90)Y-ibritumomab tiuxetan has been used successfully used in the treatment of CD20-positive non-Hodgkin's lymphoma (NHL). Pretherapy imaging with (111)In-ibritumomab tiuxetan has been used in provisional dosimetry studies. Posttherapy imaging of (90)Y-ibritumomab tiuxetan for clinical use is appealing as it would simplify the data acquisition process and allow measurements of actual doses absorbed during treatment. METHODS: The study included 29 patients with non-Hodgkin's lymphoma, of whom 16 (group I) received a pretherapy (111)In-ibritumomab tiuxetan diagnostic study and (90)Y-ibritumomab tiuxetan treatment 1 week later, and 13 (group II) received only (90)Y ibritumomab tiuxetan treatment. Planar imaging and blood sampling were performed in all patients. The doses absorbed by organs at risk were calculated using a whole-body average attenuation correction factor (relative dosimetry approach) and, in the case of the (111)In-ibritumomab tiuxetan image sets, also using organ specific attenuation correction factors (absolute dosimetry method). Red marrow absorbed doses were based on gamma counting of blood samples. RESULTS: The estimated red marrow absorbed doses from (111)In and (90)Y data were equivalent. In all cases, the doses absorbed by organs at risk were found to be within prescribed limits. The relative dosimetry approach applied to both the (90)Y and (111)In data significantly underestimated the doses relative to those obtained with the (111)In absolute dosimetry method which is generally accepted as the reference method (MIRD 16). In the case of (111)In, the relative dosimetry approach values were highly correlated (R(2) = 0.61) with the reference method values. Relative dosimetry estimates may be adjusted multiplying by a correction factor of 2.8. The (90)Y-ibritumomab tiuxetan relative dosimetry data correlated poorly with the reference method values (R (2) = 0.02). CONCLUSION: Based on patient-specific dosimetry, the administered activity may be increased by an average factor of 2.4, indicating that most patients could be undertreated. The relative dosimetry approach based on planar imaging largely underestimates doses relative to reference values. Dosimetry based on planar bremsstrahlung imaging is not a dependable alternative to (111)In dosimetry. PMID- 22237847 TI - Highlights of the EANM Congress 2011: Birmingham, UK. AB - The EANM Congress 2011 took place in Birmingham between the 15th and 19th October 2011 under the presidency of Professor Werner Langsteger. The attendance was reassuringly high, in line with other EANM congresses, despite the current 'Eurozone Crisis'. Participants from 87 countries came along, met old friends and made new ones. They were presented with a massive programme of 1,480 abstracts, symposia, and CME, scientific, plenary and featured sessions. The industry made a substantial contribution to the success of the congress with 109 hardware, software and radiopharmaceutical companies demonstrating the latest technology and innovations in the field. A feature in this year's congress was the emphasis on the role of the young generation. The highlight lecture was presented and this article was compiled by three young EANM members chosen from the young investigator project of the EANM. They review the most highly rated presentations in clinical and preclinical imaging in oncology, neuroendocrine tumours, cardiology, paediatrics and neurology, and provide an update on radionuclide therapy, physics, instrumentation, innovative tracers and techniques. PMID- 22237848 TI - Probing gunshot residue, sweat and latent human fingerprints with capillary-scale ion chromatography and suppressed conductivity detection. AB - An investigation into capillary-scale ion chromatography with suppressed conductivity detection is presented for the identification of low molecular weight anions in samples of limited size. Both particle-packed and polymer monolith capillary ion exchange resins were compared with respect to their chromatographic efficiencies, operating back-pressures and thermal selectivities. Using a multistep hydroxide gradient, it was possible to separate a large selection of inorganic and organic anions in <23 mins using both phases with an injection volume of only 0.4 MUL. Method performance was tested with respect to linearity, range, reproducibility and sensitivity and compared to a micro-bore (2 mm) IC method. Limits of mass sensitivity improved by factors up to 1,800-fold using the capillary IC system and lay in the range 0.3-26.2 pg. The finalised analytical method was applied to the determination of both endogenous and exogenous species in sweat and fingermark deposits. It was possible to determine presence of elevated levels of thiocyanate and benzoate in the sweat of three moderate smokers (5-10 cigarettes/day) in comparison to non-smokers. A controlled firing experiment was also conducted to assess the transfer of gunshot residue into fingerprints of a firer. Similarly, identification of direct contact with a black powder substitute is presented via analysis of latent fingermarks. To the best of our knowledge, this represents the first study of sweat and fingerprints using capillary-scale suppressed ion chromatography. PMID- 22237849 TI - Can prognostic factors be used to direct therapy in chronic lymphocytic leukemia? AB - Chronic lymphocytic leukemia (CLL) shows a heterogeneous clinical course, which can be explained in part by prognostic factors. Most patients do not need treatment at the time of first diagnosis. The identification of prognostic factors is of major interest if strategies can be devised to treat patients according to their individual risk profile or biological subgroup. Currently, in spite of a wealth of prognostic factors, individualized treatment approaches in different genetic or risk groups are the exemption in CLL. This review summarizes the most important prognostic and predictive factors in CLL, with particular emphasis on factors affecting treatment decisions in clinical trials and routine practice. PMID- 22237850 TI - Bilateral vasculopexy of anomalous vertebral arteries causing cervicomedullary compression: case report and technical note. AB - INTRODUCTION: The authors report an extremely rare cause of cervicomedullary cord compression by anomalous ectatic vertebral arteries. MATERIAL: A 50-year-old male patient presented with a 9 month history of progressive quadriparesis. Investigations revealed that the vertebral arteries on both sides had a mirror like course and caused a deep indentation into the high cervical cord. Bilateral vasculopexy was done using Teflon slings. The treatment resulted in rapid recovery from symptoms. CONCLUSIONS: Anomalous course of the vertebral artery can result in symptoms of high cervical cord compression. Vasculopexy can result in lasting cure from symptoms. PMID- 22237851 TI - Spinous process-splitting open pedicle screw fusion provides favorable results in patients with low back discomfort and pain compared to conventional open pedicle screw fixation over 1 year after surgery. AB - INTRODUCTION: The conventional open pedicle screw fusion (PSF) requires an extensive detachment of the paraspinal muscle from the posterior aspect of the lumbar spine, which can cause muscle injury and subsequently lead to "approach related morbidity". The spinous process-splitting (SPS) approach for decompression, unilateral laminotomy for bilateral decompression, and the Wiltse approach for pedicle screw insertion are considered to be less invasive to the paraspinal musculature. We investigated whether SPS open PSF combined with the abovementioned techniques attenuates the paraspinal muscle damage and yields favorable clinical results, including alleviation in the low back discomfort, in comparison to the conventional open PSF. METHODS: We studied 53 patients who underwent single-level PSF for the treatment of degenerative spondylolisthesis (27 patients underwent SPS open PSF and the other 26 underwent the conventional open PSF). The clinical outcomes were assessed using the Japanese Orthopedic Association (JOA) score, the Roland-Morris disability questionnaire (RDQ), and the visual analog scale (VAS) for low back pain and low back discomfort (heavy feeling or stiffness). Postoperative multifidus (MF) atrophy was evaluated using MRI. Follow-up examinations were performed at 1 and 3 years after the surgery. RESULTS: Although there was no significant difference in the JOA and RDQ score between the two groups, the VAS score for low back pain and discomfort after the surgery were significantly lower in the SPS open PSF group than in the conventional open PSF group. The extent of MF atrophy after SPS open PSF was reduced more significantly than after the conventional open PSF during the follow up. The MF atrophy ratio was found to correlate with low back discomfort at the 1 year follow-up examination. CONCLUSION: In conclusion, SPS open PSF was less damaging to the paraspinal muscle than the conventional open PSF and had a significant clinical effect, reducing low back discomfort over 1 year after the surgery. PMID- 22237852 TI - Lack of early pattern stimulation prevents normal development of the alpha (Y) retinal ganglion cell population in the cat. AB - Binocular deprivation of pattern vision (BD) early in life permanently impairs global motion perception. With the SMI-32 antibody against neurofilament protein (NFP) as a marker of the motion-sensitive Y-cell pathway (Van der Gucht et al. [2001] Cereb. Cortex 17:2805-2819), we analyzed the impact of early BD on the retinal circuitry in adult, perceptually characterized cats (Burnat et al. [2005] Neuroreport 16:751-754). In controls, large retinal ganglion cells exhibited a strong NFP signal in the soma and in the proximal parts of the dendritic arbors. The NFP-immunoreactive dendrites typically branched into sublamina a of the inner plexiform layer (IPL), i.e., the OFF inner plexiform sublamina. In the retina of adult BD cats, however, most of the NFP-immunoreactive ganglion cell dendrites branched throughout the entire IPL. The NFP-immunoreactive cell bodies were less regularly distributed, often appeared in pairs, and had a significantly larger diameter compared with NFP-expressing cells in control retinas. These remarkable differences in the immunoreactivity pattern were typically observed in temporal retina. In conclusion, we show that the anatomical organization typical of premature Y-type retinal ganglion cells persists into adulthood even if normal visual experience follows for years upon an initial 6-month period of BD. Binocular pattern deprivation possibly induces a lifelong OFF functional domination, normally apparent only during development, putting early high-quality vision forward as a premise for proper ON-OFF pathway segregation. These new observations for pattern-deprived animals provide an anatomical basis for the well-described motion perception deficits in congenital cataract patients. PMID- 22237853 TI - Patient handling and musculoskeletal disorders among hospital workers: analysis of 7 years of institutional workers' compensation claims data. AB - OBJECTIVES: Musculoskeletal disorders (MSDs) are the most common occupational injuries and illnesses among hospital workers in the United States. To date, there is little in the literature examining the principal effect of patient handling on MSDs. The primary objective of this study was to investigate and confirm the principal effect of patient handling on hospital worker MSDs. METHODS: Workers' Compensation (WC) claims related to MSDs filed during 2003-2009 by employees in a large US healthcare system were classified using ICD-9. Patient handling, demographic, work, and injury characteristics were obtained. Two multivariable Poisson regression models were compared to evaluate association between risk factors and MSDs. One model contained all risk factors, excluding patient handling; the other model included patient handling. RESULTS: Among 3,452 claims from 24,824 FTEs, 76% were MSDs. About half of the MSDs involved patient handling. In the regression model without patient handling, EMS workers, women, 50-59 years of age, union members, evening shift workers, and fulltime workers showed associations with MSDs. However, all the observed associations disappeared when patient handling was included in the second regression model; patient handling was the only factor showing an association with MSDs, although the effect was not strong (RR = 1.2, 95% CI = 1.2-1.3). CONCLUSIONS: All the observed associations of risk factors disappeared and were further away from patient handling on the causal pathway to MSDs. Patient handling involves numerous work elements and dynamic physical activities. Understanding the work elements of patient handling and conducting interventions based on specific patient handling tasks can substantially reduce MSDs among hospital workers. PMID- 22237856 TI - One-dimensional SDS gel electrophoresis of proteins. AB - One-dimensional gel electrophoresis of proteins provides information about the molecular size, amount, and purity of a protein sample. Separated proteins can be recovered from polyacrylamide gels for subsequent characterization by a variety of secondary techniques, such as mass spectrometry to determine post translational modifications and the amino acid sequence. In addition, one dimensional electrophoresis is the standard first step in immunoblotting and immunodetection. Protein separations in vertical slab gels are performed in a variety of formats. Most recently, small format minigels are typical due to their ease of use, low relative cost, and ready commercial availability. Larger gels provide more separation area and thus better resolution for complex samples and continue to be in use for specialized analysis. PMID- 22237855 TI - Probabilistic classification and gambling in patients with schizophrenia receiving medication: comparison of risperidone, olanzapine, clozapine and typical antipsychotics. AB - RATIONALE: We have previously shown that patients with schizophrenia treated with typical antipsychotics were impaired on the weather prediction probabilistic classification learning (PCL) task that relies on striatal function, and that similar patients treated with atypical antipsychotics were impaired on the Iowa gambling task (IGT) that depends on medial prefrontocortical function. OBJECTIVES: We tested the hypothesis that test performance of patients treated with risperidone will be more similar to those treated with typical rather than atypical antipsychotics. RESULTS: Groups of schizophrenia patients treated with risperidone, olanzapine, clozapine or typical antipsychotics did not differ on the Positive and Negative Syndrome Scale or the Mini Mental State Exam (MMSE) but scored lower than controls on the MMSE. For the PCL task, patients treated with clozapine improved over trials while those treated with typical antipsychotics, olanzapine, or risperidone did not. For the IGT, patients treated with typical antipsychotics or risperidone improved over trials while those treated with clozapine or olanzapine did not. CONCLUSIONS: Results generally supported the hypothesis that patients treated with risperidone perform more like those treated with typical antipsychotics than those treated with other atypical antipsychotics. PMID- 22237854 TI - Striatal and extrastriatal dopamine D2 receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: a positron emission tomography study with [11C]raclopride and [11C]FLB457. AB - RATIONALE: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D2 receptors have reported inconsistent results regarding regional differences of dopamine D2 receptor occupancy by aripiprazole. OBJECTIVE: To test the hypothesis of preferential binding to extrastriatal dopamine D2 receptors by aripiprazole, we investigated its regional dopamine D2 receptor occupancies in healthy young subjects. MATERIALS AND METHODS: Using PET and two radioligands with different affinities for dopamine D2 receptors, [11C]raclopride and [11C]FLB457, striatal and extrastriatal dopamine D2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. RESULTS: Our data showed that dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [11C]FLB457 ranging from 46.6% to 58.4%. CONCLUSIONS: In the present study, preferential extrastriatal dopamine D2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole. PMID- 22237857 TI - In vitro transcription and immobilized template analysis of preinitiation complexes. AB - In the study of gene regulation, it is often necessary to employ functional assays that investigate the action or mechanism of specific promoters or enhancer binding factors and their role in transcription by RNA polymerase II. Although many assays measure the transcription of a gene under the control of an endogenous or model activator in vivo, it is often useful to recreate transcription in vitro in order to study specific regulatory mechanisms. In this unit, protocols are presented that will allow the investigator to perform in vitro transcription using preinitiation complexes assembled from cellular extracts on either naked DNA or chromatin templates. PMID- 22237858 TI - Protein databases on the Internet. AB - Protein databases have become a crucial part of modern biology. Huge amounts of data for protein structures, functions, and particularly sequences are being generated. Searching databases is often the first step in the study of a new protein. Comparison between proteins or between protein families provides information about the relationship between proteins within a genome or across different species, and hence offers much more information than can be obtained by studying only an isolated protein. In addition, secondary databases derived from experimental databases are also widely available. These databases reorganize and annotate the data or provide predictions. The use of multiple databases often helps researchers understand the structure and function of a protein. Although some protein databases are widely known, they are far from being fully utilized in the protein science community. This unit provides a starting point for readers to explore the potential of protein databases on the Internet. PMID- 22237859 TI - Reprogramming of mouse, rat, pig, and human fibroblasts into iPS cells. AB - The induction of pluripotency in somatic cells by transcription-factor overexpression has been widely regarded as one of the major breakthroughs in stem cell biology within this decade. The generation of these induced pluripotent stem cells (iPSCs) has enabled investigators to develop in vitro disease models for biological discovery and drug screening, and in the future, patient-specific therapy for tissue or organ regeneration. While new technologies for reprogramming are continually being discovered, the availability of iPSCs from different species is also increasing rapidly. Comparison of iPSCs across species may provide new insights into key aspects of pluripotency and early embryonic development. iPSCs from large animals may enable the generation of genetically modified large animal models or potentially transplantable donor tissues or organs. This unit describes the procedure for the generation of iPSCs from mouse, rat, pig and human fibroblasts. PMID- 22237860 TI - Strontium ranelate prevents bone loss in a rat model of localized muscle paralysis. AB - Twenty-one 3.5-month-old female Sprague-Dawley rats were randomly assigned to three groups: BTX group, in which each rat received a single intramuscular injection of 2 U of Clostridium botulinum toxin (BTX) in the quadriceps femoris muscle of the right hind limb; BTX + SR group, in which each rat received a BTX injection and a dose of strontium ranelate (dose level of 625 mg/kg/day); and the control group. All the rats were killed at 9 weeks post-treatment. It was showed that BTX-induced rats a rapid loss of body weight in the first 3 weeks, after which their body weight showed a slow increase similar to that observed in the control rats. The net body weight loss was mainly attributed to muscle atrophy. BTX caused remarkable bone degradation in either the trabecular bone or the cortical bone of the disuse femur. The deteriorations in the bone mass and bone microstructure were locally limited and could be prevented by strontium ranelate treatment. Biomechanical analysis showed that strontium ranelate treatment improved the mechanical performance of the tibia in BTX-treated rats. It was showed that a clinical-corresponding dose of strontium ranelate could prevent bone loss in long-term immobilized rats. PMID- 22237861 TI - Impact of residual stretch and remodeling on collagen engagement in healthy and pulmonary hypertensive calf pulmonary arteries at physiological pressures. AB - Understanding the mechanical behavior of proximal pulmonary arteries (PAs) is crucial to evaluating pulmonary vascular function and right ventricular afterload. Early and current efforts focus on these arteries' histological changes, in vivo pressure-diameter behavior and mechanical properties under in vitro mechanical testing. However, the in vivo stretch and stress states remain poorly characterized. To further understand the mechanical behavior of the proximal PAs under physiological conditions, this study computed the residual stretch and the in vivo circumferential stretch state in the main pulmonary arteries in both control and hypertensive calves by using in vitro and in vivo artery geometry data, and modeled the impact of residual stretch and arterial remodeling on the in vivo circumferential stretch distribution and collagen engagement in the main pulmonary artery. We found that the in vivo circumferential stretch distribution in both groups was nonuniform across the vessel wall with the largest stretch at the outer wall, suggesting that collagen at the outer wall would engage first. It was also found that the circumferential stretch was more uniform in the hypertensive group, partially due to arterial remodeling that occurred during their hypoxic treatment, and that their onset of collagen engagement occurred at a higher pressure. It is concluded that the residual stretch and arterial remodeling have strong impact on the in vivo stretch state and the collagen engagement and thus the mechanical behavior of the main pulmonary artery in calves. PMID- 22237862 TI - Expression pattern of embryonic stem cell markers in DFAT cells and ADSCs. AB - Mature adipocytes can revert to a more primitive phenotype and gain cell proliferative ability under the condition of ceiling method, named dedifferentiated fat cells (DFAT cells). These cells exhibit multilineage potential as adipose tissue-derived stromal cells (ADSCs). However, the stem molecular signature of DFAT cells and the difference distinct from ADSCs are still not sure. To study the molecular signature of DFAT cells better, highly purified mature adipocytes were obtained from rats and the purity was more than 98%, and about 98.6% were monocytes. These mature adipocytes dedifferentiated into fibroblast-like cells spontaneously by the ceiling culture method, these cells proliferated rapidly in vitro, grew in the same direction and formed vertex, and expressed extensively embryonic stem cell markers such as Oct4, Sox2, c-Myc, and Nanog, surface antigen SSEA-1, CD105, and CD31, moreover, these cells possessed ALP and telomerase activity. The expression level was Oct4 1.3%, Sox2 1.3%, c-Myc 1.2%, Nanog 1.2%, CD105 0.6%, CD31 0.6% and SSEA-1 0.4%, respectively, which was lower than that in ADSCs, but the purity of DFAT cells was much higher than that of ADSCs. In conclusion, DFAT cells is a highly purified stem cell population, and expressed some embryonic stem cell markers like ADSCs, which seems to be a good candidate source of adult stem cells for the future cell replacement therapy. PMID- 22237863 TI - Expression and glucocorticoid-regulation of "Bam", a novel BH3-only transcript in acute lymphoblastic leukemia. AB - Apoptosis is a morphologically defined form of cell death that plays a major role in cell physiology, pathology and cancer therapy. The Bcl-2 family of pro- and anti-apoptotic molecules is a key regulator of this phenomenon, with the sub family of BH3-only molecules serving as activators and/or facilitators. Apoptosis induced by glucocorticoids (GC) is a central component in the therapy of acute lymphoblastic leukemia (ALL), and defining its molecular basis and that of GC resistance is crucial for therapeutic improvements. We recently identified a novel transcript from the BCL2L11/Bim locus, termed "Bam", by affymetrix based whole genome expression profiling performed on 27 children (13 were already published) with ALL and many additional biological systems. Most children that induced Bam also induced Bim as well, in some cases Bam induction was more pronounced than that of Bim and in one patient only the Bam, but not Bim was induced. In C7H2, PreB697, Jurkat-GR(wt) and GC-sensitive (S-lines), this transcript was induced by GC in a translation-independent manner, suggesting that direct transcriptional induction of this BH3-only molecule by GC might cause apoptosis in at least ALL children and other biological systems. PMID- 22237864 TI - Simultaneous measurement of extracellular dopamine and dopamine transporter occupancy by cocaine analogs in squirrel monkeys. AB - Several classes of drugs bind to the dopamine transporter (DAT) with high affinity, but some are weaker positive reinforcers than cocaine, suggesting that affinity for and occupancy of the DAT is not the only determinant of a drug's reinforcing effectiveness. Other factors such as the rate of onset have been positively and strongly correlated with the reinforcing effects of DAT inhibitors in nonhuman primates. In the current studies, we examined the effects of acute systemic administration of cocaine and three cocaine analogs (RTI-150, RTI-177, and RTI-366) on binding to DAT in squirrel monkey brain using positron emission tomography (PET) neuroimaging. During the PET scan, we also measured drug effects on dopamine (DA) levels in the caudate using in vivo microdialysis. In general, our results suggest a lack of concordance between drug occupancy at DAT and changes in DA levels. These studies also indicate that acute cocaine administration decreases the availability of plasma membrane DAT for binding, even after cocaine is no longer blocking DA uptake as evidence by a return to basal DA levels. PMID- 22237865 TI - Automated identification of extreme-risk events in clinical incident reports. AB - OBJECTIVES: To explore the feasibility of using statistical text classification to automatically detect extreme-risk events in clinical incident reports. METHODS: Statistical text classifiers based on Naive Bayes and Support Vector Machine (SVM) algorithms were trained and tested on clinical incident reports to automatically detect extreme-risk events, defined by incidents that satisfy the criteria of Severity Assessment Code (SAC) level 1. For this purpose, incident reports submitted to the Advanced Incident Management System by public hospitals from one Australian region were used. The classifiers were evaluated on two datasets: (1) a set of reports with diverse incident types (n=120); (2) a set of reports associated with patient misidentification (n=166). Results were assessed using accuracy, precision, recall, F-measure, and area under the curve (AUC) of receiver operating characteristic curves. RESULTS: The classifiers performed well on both datasets. In the multi-type dataset, SVM with a linear kernel performed best, identifying 85.8% of SAC level 1 incidents (precision=0.88, recall=0.83, F measure=0.86, AUC=0.92). In the patient misidentification dataset, 96.4% of SAC level 1 incidents were detected when SVM with linear, polynomial or radial-basis function kernel was used (precision=0.99, recall=0.94, F-measure=0.96, AUC=0.98). Naive Bayes showed reasonable performance, detecting 80.8% of SAC level 1 incidents in the multi-type dataset and 89.8% of SAC level 1 patient misidentification incidents. Overall, higher prediction accuracy was attained on the specialized dataset, compared with the multi-type dataset. CONCLUSION: Text classification techniques can be applied effectively to automate the detection of extreme-risk events in clinical incident reports. PMID- 22237866 TI - Evaluation of computer-based medical histories taken by patients at home. AB - The authors developed a computer-based general medical history to be taken by patients in their homes over the internet before their first visit with their primary care doctor, and asked six doctors and their participating patients to assess this history and its effect on their subsequent visit. Forty patients began the history; 32 completed the history and post-history assessment questionnaire and were for the most part positive in their assessment; and 23 continued on to complete their post-visit assessment questionnaire and were for the most part positive about the helpfulness of the history and its summary at the time of their visit with the doctor. The doctors in turn strongly favored the immediate, routine use of two modules of the history--the family and social histories--for all their new patients. The doctors suggested further that the summaries of the other modules of the history be revised and shortened to make it easier for them to focus on clinical issues in the order of their preference. PMID- 22237867 TI - Translational informatics: an industry perspective. AB - Translational informatics (TI) is extremely important for the pharmaceutical industry, especially as the bar for regulatory approval of new medications is set higher and higher. This paper will explore three specific areas in the drug development lifecycle, from tools developed by precompetitive consortia to standardized clinical data collection to the effective delivery of medications using clinical decision support, in which TI has a major role to play. Advancing TI will require investment in new tools and algorithms, as well as ensuring that translational issues are addressed early in the design process of informatics projects, and also given higher weight in funding or publication decisions. Ultimately, the source of translational tools and differences between academia and industry are secondary, as long as they move towards the shared goal of improving health. PMID- 22237869 TI - Organocatalytic enantioselective pyrazol-3-one addition to maleimides: reactivity and stereochemical course. AB - The enantioselective synthesis of pyrazol-3-ones has not been extensively studied in organic synthesis. Here in we report the first asymmetric addition of pyrazolones to maleimides catalyzed by bifunctional thiourea catalysts. PMID- 22237868 TI - Evidence for alkene cis-aminocupration, an aminooxygenation case study: kinetics, EPR spectroscopy, and DFT calculations. AB - Alkene difunctionalization reactions are important in organic synthesis. We have recently shown that copper(II) complexes can promote and catalyze intramolecular alkene aminooxygenation, carboamination, and diamination reactions. In this contribution, we report a combined experimental and theoretical examination of the mechanism of the copper(II)-promoted olefin aminooxygenation reaction. Kinetics experiments revealed a mechanistic pathway involving an equilibrium reaction between a copper(II) carboxylate complex and the gamma-alkenyl sulfonamide substrate and a rate-limiting intramolecular cis-addition of N-Cu across the olefin. Kinetic isotope effect studies support that the cis aminocupration is the rate-determining step. UV/Vis spectra support a role for the base in the break-up of copper(II) carboxylate dimer to monomeric species. Electron paramagnetic resonance (EPR) spectra provide evidence for a kinetically competent N-Cu intermediate with a Cu(II) oxidation state. Due to the highly similar stereochemical and reactivity trends among the Cu(II)-promoted and catalyzed alkene difunctionalization reactions we have developed, the cis aminocupration mechanism can reasonably be generalized across the reaction class. The methods and findings disclosed in this report should also prove valuable to the mechanism analysis and optimization of other copper(II) carboxylate promoted reactions, especially those that take place in aprotic organic solvents. PMID- 22237870 TI - Bifidobacterium lactis Bb12 enhances intestinal antibody response in formula-fed infants: a randomized, double-blind, controlled trial. AB - BACKGROUND: Addition of probiotics to infant formula may positively affect immune function in nonexclusively breastfed infants. This study aimed to investigate the effect of infant starter formula containing the probiotic Bifidobacterium animalis subspecies lactis (Bb12) on intestinal immunity and inflammation. METHODS: Six-week-old healthy, full-term infants (n = 172) were enrolled in a prospective, randomized, double-blind, controlled clinical trial with 2 groups studied in parallel to a breastfed comparison group. Formula-fed (FF) infants were randomized to partially hydrolyzed whey formula (CON) or the same formula containing 10(6) colony-forming units (CFU) Bb12/g (PRO) for 6 weeks. Fecal secretory IgA (sIgA), calprotectin, lactate, and stool pH were assessed at baseline, 2 weeks, and 6 weeks. Anti-poliovirus-specific IgA and anti-rotavirus specific IgA were assessed at 2 and 6 weeks. RESULTS: Among vaginally delivered FF infants, PRO consumption increased (P < .05) fecal sIgA compared to CON. Anti poliovirus-specific IgA concentration increased (P < .05) in all infants consuming PRO, whereas anti-rotavirus-specific IgA tended to increase (P = .056) with PRO consumption in cesarean-delivered infants. Anthropometrics and tolerance did not differ significantly between FF infants. CONCLUSIONS: Infants consuming formula with Bb12 produced feces with detectable presence of Bb12 and augmented sIgA concentration. Furthermore, cesarean-delivered infants consuming Bb12 had heightened immune response, as evidenced by increased anti-rotavirus- and anti poliovirus-specific IgA following immunization. These results demonstrate that negative immune-related effects of not breastfeeding and cesarean delivery can be mitigated by including Bb12 in infant formula, thereby providing infants a safe, dietary, immune-modulating bacterial introduction. PMID- 22237871 TI - Whey- vs casein-based enteral formula and gastrointestinal function in children with cerebral palsy. AB - OBJECTIVES: Children with severe cerebral palsy (CP) commonly have gastrointestinal (GI) dysfunction. Whey-based enteral formulas have been postulated to reduce gastroesophageal reflux (GOR) and accelerate gastric emptying (GE). The authors investigated whether whey-based (vs casein-based) enteral formulas reduce GOR and accelerate GE in children who have severe CP with a gastrostomy and fundoplication. METHODS: Thirteen children received a casein based formula for 1 week and either a 50% whey whole protein (50% WWP) or a 100% whey partially hydrolyzed protein (100% WPHP) formula for 1 week. Reflux episodes, gastric half-emptying time (GE t(1/2)), and reported pain and GI symptoms were measured. RESULTS: Whey formulas emptied significantly faster than casein (median [interquartile range (IQR)] GE t(1/2), 33.9 [25.3-166.2] min vs 56.6 [46-191] min; P = .033). Reflux parameters were unchanged. GI symptoms were lower in children who received 50% WWP (visual analog symptom score, median [IQR], 0 [0-11.8]) vs 100% WPHP (13.0 [2.5-24.8]) (P = .035). CONCLUSION: This pilot study shows that in children who have severe CP with a gastrostomy and fundoplication, GE of the whey-based enteral formula is significantly faster than casein. The acceleration in GE does not alter GOR frequency, and there appears to be no effect of whey vs casein in reducing acid, nonacid, and total reflux episodes. The results indicate that enteral formula selection may be particularly important for children with severe CP and delayed GE. PMID- 22237872 TI - Feeding premature infants: why, when, and what to add to human milk. PMID- 22237873 TI - Mother's milk, feeding strategies, and lactoferrin to prevent necrotizing enterocolitis. PMID- 22237874 TI - Recent developments in necrotizing enterocolitis. PMID- 22237875 TI - Nonalcoholic fatty liver disease in pediatric patients. AB - Nonalcoholic fatty liver disease is a spectrum of liver disease ranging from simple hepatic steatosis to steatohepatitis, hepatic fibrosis, and cirrhosis. It is highly associated with obesity and insulin resistance, and with the dramatic increase in childhood and adolescent obesity, it has become the most common form of chronic liver disease in these age groups. Genetic and environmental factors both appear to play a role in the development of nonalcoholic fatty liver disease. There is currently no established effective therapy, and decreasing the prevalence of this disorder will require a reduction in the current obesity epidemic. PMID- 22237876 TI - Infant food allergy: where are we now? AB - For many years, the prevailing maxim for prevention of food allergy in at-risk infants was to reduce allergic sensitization by avoiding exposure to highly allergenic foods until the baby's immune and digestive systems were sufficiently developed to cope with the allergen. Current thinking is completely different: exposure to food in the early stages of development may be the way to induce tolerance. Exclusive breastfeeding until 4-6 months, followed by introduction of complementary foods individually, is recommended. Any restrictions on mother's diet, other than avoidance of her own allergens during pregnancy and breastfeeding, are contraindicated. If a baby at high risk for allergy (defined as having 1 first-degree relative with diagnosed allergy) cannot be exclusively breastfed to 4-6 months of age, the preferred method of feeding for the prevention of atopic disease is an extensively hydrolyzed formula. There appears to be no value in delaying the introduction of any food beyond 6 months of age. Most food allergy is outgrown in childhood, but allergy to some foods tends to persist. Induction of tolerance to foods to which a child is allergic may be achieved by low-dose exposure in a process known as specific oral tolerance induction (SOTI). Early results indicate that some probiotic strains of bacteria, such as Lactobacillus rhamnosus GG or Lactobacillus F19, may reduce allergic sensitization. PMID- 22237877 TI - The Stanford nutrition course. PMID- 22237878 TI - Nutritional management of cystic fibrosis. PMID- 22237879 TI - Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad. AB - As the gluten-free diet (GFD) gains in popularity with the general public, health practitioners are beginning to question its real health benefits. For those patients with celiac disease (CD), the GFD is considered medical nutrition therapy, as well as the only proven treatment that results in improvements in symptomatology and small bowel histology. Those with wheat allergy also benefit from the GFD, although these patients often do not need to restrict rye, barley, and oats from their diet. Gluten sensitivity is a controversial subject, where patients who have neither CD nor wheat allergy have varying degrees of symptomatic improvement on the GFD. Conditions in this category include dermatitis herpetiformis (DH), irritable bowel syndrome (IBS), and neurologic diseases such as gluten-sensitive ataxia and autism. It is important for patients and healthcare practitioners to understand the differences between these conditions, even though they may all respond to a GFD. Patients with CD can experience comorbid nutrition deficiencies and are at higher risk for the development of cancers and other autoimmune conditions. Those with wheat allergy and gluten sensitivity are thought not to be at higher risk for these complications. Defining the symptoms and biochemical markers for gluten-sensitive conditions is an important area for future investigations, and high-quality, large-scale randomized trials are needed to prove the true benefits of the GFD in this evolving field. PMID- 22237880 TI - Are probiotics ready for prime time? PMID- 22237881 TI - Pediatric obesity: preventive measures in early childhood. AB - This article reviews the factors contributing to early childhood obesity and the options for recognition and early intervention. The role for developing preschool wellness programs that incorporate nutrition education and physical activity is presented with a model under development in the state of Maryland. PMID- 22237882 TI - Nonalcoholic fatty liver disease in pediatric patients--a problem that is "enormous" and "growing"! PMID- 22237884 TI - Effects of prebiotic-containing infant formula on gastrointestinal tolerance and fecal microbiota in a randomized controlled trial. AB - BACKGROUND: Prebiotic-containing infant formula may beneficially affect gastrointestinal tolerance and commensal microbiota composition. OBJECTIVE: Assess gastrointestinal tolerance and fecal microbiota, pH, and short-chain fatty acid (SCFA) concentrations of infants consuming formula with or without prebiotics. DESIGN: Full-term formula-fed infants were studied to a breastfed comparison group (BF). Formula-fed infants (FF) were randomized to consume a partially hydrolyzed whey formula with (PRE) or without (CON) 4 g/L of galacto oligosaccharides and fructo-oligosaccharides (9:1). Fecal bacteria, pH, and SCFA were assessed at baseline, 3 weeks, and 6 weeks. Caregivers of patients recorded stool characteristics and behavior for 2 days before the 3- and 6-week visits. RESULTS: Feces from infants fed PRE had a higher absolute number (P = .0083) and proportion (P = .0219) of bifidobacteria than CON-fed infants and did not differ from BF. BF had a higher proportion of bifidobacteria than CON (P = .0219) and lower number of Clostridium difficile than FF (P = .0087). Feces from formula-fed infants had higher concentrations of acetate (P < .001), butyrate (P < .001), propionate (P < .001), and total SCFAs (P = .0230) than BF; however, fecal pH was lower (P = .0161) in PRE and BF than CON. Prebiotic supplementation did not alter stool patterns, tolerance, or growth. BF had more frequent stools that were yellow (P < .0001) and more often liquid than FF (P < .0001). CONCLUSIONS: Infant formula containing the studied oligosaccharides was well tolerated, increased abundance and proportion of bifidobacteria, and reduced fecal pH in healthy infants. PMID- 22237883 TI - Short-term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain triglycerides, and fish oil: a randomized double-blind study in preterm infants. AB - BACKGROUND: For premature neonates needing parenteral nutrition (PN), a balanced lipid supply is crucial. The authors hypothesized that a lipid emulsion containing medium-chain triglycerides (MCTs) and soybean, olive, and fish oils would be as safe and well tolerated as a soybean emulsion while beneficially influencing the fatty acid profile. METHODS: Double-blind, controlled study in 53 neonates (<34 weeks' gestation) randomized to receive at least 7 days of PN containing either an emulsion of MCTs and soybean, olive, and fish oils or a soybean oil emulsion. Target lipid dosage was 1.0 g fat/kg body weight [BW]/d on days 1-3, 2 g/kg BW/d on day 4, 3 g/kg BW/d on day 5, and 3.5 g/kg BW/d on days 6 14. RESULTS: Test emulsion vs control, mean +/- SD: baseline triglyceride concentrations were 0.52 +/- 0.16 vs 0.54 +/- 0.19 mmol/L and increased similarly in both groups to 0.69 +/- 0.38 vs 0.67 +/- 0.36 on day 8 of treatment (P = .781 for change). A significantly higher decrease in total and direct bilirubin vs baseline was seen in the test group compared with the control group P < .05 between groups). In plasma and red blood cell phospholipids, eicosapentaenoic acid and docosahexaenoic acid were higher, and the n-6/n-3 fatty acid ratio was lower in the test group (P < .05 vs control). CONCLUSIONS: The lipid emulsion, based on a mixture of MCTs and soybean, olive, and fish oils, was safe and well tolerated by preterm infants while beneficially modulating the fatty acid profile. PMID- 22237885 TI - Neuropilin-1 is upregulated in Sjogren's syndrome and contributes to pathological neovascularization. AB - Neuropilin-1 (NRP1) is a transmembrane co-receptor for members of the vascular endothelial growth factor family. Recent studies revealed an important role of NRP1 in angiogenesis and progression of many diseases. The role of NRP1 in the development of Sjogren's syndrome (SS), one of the most common rheumatic diseases, has not yet been investigated. Molecular studies and protein expression techniques were performed to elucidate the gene and protein expression profile of NRP1 in human salivary gland epithelial cells (SGEC) from primary SS. We used human microarrays and transient transfection with a mutant form of the negative inhibitory kappaBalpha proteins (IkappaBalphaDN) to investigate whether selective inhibition of nuclear Factor-kappaB (NF-kappaB) improves NRP1-mediated pro angiogenic factors release from SS SGEC. The selective NRP1 function inhibition with an antibody to human NRP1, was employed to evaluate the therapeutic potential of targeting NRP1. We demonstrate that NRP1 is expressed in SGEC of both human healthy biopsies and in SS samples, and increased NRP1 expression in SS SGEC is significantly associated with pro-angiogenic factors release. Neutralizing anti-NRP1 antibody decreased pro-angiogenic factor production from SS SGEC and blocking NF-kappaB activation could be a way to inhibit NRP1-mediated angiogenesis in Sjogren's syndrome. PMID- 22237886 TI - Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells. AB - Tumors are composed of heterogeneous populations of cells including tumor initiating cells (TICs) and metastatic precursors. While the origin of these cells is unknown, there is evidence that tumor cells can transdifferentiate from an epithelial to a mesenchymal phenotype, a property referred to as epithelial-to mesenchymal transition (EMT). This cellular plasticity may explain the heterogeneous nature of tumors and differences in the tumorigenic and invasive properties of cells. Understanding the origin of these cells and the contribution of external factors that influence the acquisition of cellular properties is critical for the development of therapeutics to eradicate cancer. In this study, we show that primary murine tumor cells harvested from FVB/N Tg (MMTV/Neu) spontaneous mammary tumors possess differentiation plasticity and can be enriched to be epithelial or mesenchymal-like using selected culture media conditions, and we show evidence of EMT in a clonal population of primary epithelial tumor cells when cultured in fibroblast growth factor-1 (FGF-1) or transforming growth factor beta (TGF-beta). We also determined that in contrast to the identification of mesenchymal-like tumor cells as TICs in orthotopic xenograph models of tumorigenicity, epithelial-enriched murine mammary tumor cells were more tumorigenic as compared to mesenchymal-enriched cells when transplanted back subcutaneously into syngeneic immune competent mice. Together, these data suggest that EMT plasticity can be induced in primary murine mammary tumor cells, and that tumorigenicity of epithelial or mesenchymal-like cells may be influenced by factors such as the site of tumor inoculation or the immune state of the host (xenogenic immune compromised versus syngeneic immune competent). PMID- 22237887 TI - Immune suppression in the tumor microenvironment: a role for dendritic cell mediated tolerization of T cells. AB - Immune suppression remains a consistent obstacle to successful anti-tumor immune responses. As tumors develop, they create a microenvironment that not only supports tumor growth and metastasis but also reduces potential adaptive immunity to tumor antigens. Among the many components of this tumor microenvironment is a population of dendritic cells which exert profound immune suppressive effects on T cells. In this review, we discuss our recent findings related to these tumor associated dendritic cells and how targeting them may serve to generate more durable anti-tumor immune responses. PMID- 22237888 TI - Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion. AB - Adoptive cell transfer (ACT) of in vitro expanded autologous tumor-infiltrating lymphocytes (TIL) has been shown to exert therapeutic efficacy in melanoma patients. We aimed to develop an ACT protocol based on tumor-specific T cells isolated from peripheral blood and in vitro expanded by Dynabeads(r) ClinExVivoTMCD3/CD28. We show here that the addition of an in vitro restimulation step with relevant peptides prior to bead expansion dramatically increased the proportion of tumor-specific T cells in PBMC-cultures. Importantly, peptide pulsed dendritic cells (DCs) as well as allogeneic tumor lysate-pulsed DCs from the DC vaccine preparation could be used with comparable efficiency to peptides for in vitro restimulation, to increase the tumor-specific T-cell response. Furthermore, we tested the use of different ratios and different types of Dynabeads(r) CD3/CD28 and CD3/CD28/CD137 T-cell expander, for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads(r) CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells that were both cytotoxic and effective cytokine producers upon antigen recognition. Dynabeads(r)-expanded T-cell cultures shows phenotypical characteristics of memory T cells with potential to migrate and expand in vivo. In addition, they possess longer telomeres compared to TIL cultures. Taken together, we demonstrate that in vitro restimulation of tumor-specific T cells prior to bead expansion is necessary to achieve high numbers of tumor-specific T cells. This is effective and easily applicable in combination with DC vaccination, by use of vaccine-generated DCs, either pulsed with peptide or tumor-lysate. PMID- 22237889 TI - Postvaccination increase in serotype 19A pneumococcal disease in Norway is driven by expansion of penicillin-susceptible strains of the ST199 complex. AB - Serotype replacement in invasive pneumococcal disease has been observed after widespread use of the 7-valent pneumococcal conjugate vaccine (PCV7). Replacement is dominated by penicillin-nonsusceptible serotype 19A in several countries. Antibiotic selection pressure has been proposed to interact with immunization, leading to rapid replacement. In Norway, where prescription of antibiotics is limited, post-PCV7 replacement by serotype 19A is dominated by penicillin susceptible clones. Hence, serotype 19A replacement occurs, although it is not driven by antibiotic selection pressure. PMID- 22237890 TI - Evaluation of biological sample preparation for immunosignature-based diagnostics. AB - To address the need for a universal system to assess health status, we previously described a method termed "immunosignaturing" which splays the entire humoral antibody repertoire across a peptide microarray. Two important issues relative to the potential broad use of immunosignatures are sample preparation and stability. In the present study, we compared the immunosignatures developed from serum, plasma, saliva, and antibodies eluted from blood dried onto filter paper. We found that serum and plasma provide identical immunosignatures. Immunosignatures derived from dried blood also correlated well with those from nondried serum from the same individual. Immunosignatures derived from dried blood were capable of distinguishing naive mice from those infected with influenza virus. Saliva was applied to the arrays, and the IgA immunosignature correlated strongly with that from dried blood. Finally, we demonstrate that dried blood retains immunosignature information even when exposed to high temperature. This work expands the potential diagnostic uses for immunosignatures. These features suggest that different forms of archival samples can be used for diagnosis development and that in prospective studies samples can be easily procured. PMID- 22237891 TI - Evaluation of gamma interferon (IFN-gamma)-induced protein 10 responses for detection of cattle infected with Mycobacterium bovis: comparisons to IFN-gamma responses. AB - Gamma interferon (IFN-gamma)-induced protein 10 (IP-10) has recently shown promise as a diagnostic biomarker of Mycobacterium tuberculosis infection of humans. The aim of the current study was to compare IP-10 and IFN-gamma responses upon Mycobacterium bovis infection in cattle by using archived samples from two aerosol inoculation studies. In the first study (10(4) CFU M. bovis by aerosol, n = 7), M. bovis purified protein derivative (PPDb)-specific IP-10 and IFN-gamma gene expression was detected as early as 29 days after challenge. PPDb-specific IP-10 and IFN-gamma mRNA responses followed a similar pattern of expression over the course of this study and were highly correlated (r = 0.87). In the second study (10(5) CFU M. bovis by aerosol, n = 5), IP-10 and IFN-gamma (protein) responses to mycobacterial antigens were compared following challenge. IFN-gamma responses to mycobacterial antigens were detected at 29 days after challenge and were sustained during the remainder of the study. IFN-gamma responses to mycobacterial antigens exceeded corresponding responses in nonstimulated cultures. IP-10 responses to mycobacterial antigens exceeded preinfection responses at 7, 29, and 63 days after challenge. In contrast to IFN-gamma responses, IP-10 responses to mycobacterial antigens generally did not exceed the respective responses in nonstimulated cultures. IP-10 responses to medium alone and to mycobacterial antigens followed a similar pattern of response. Correlations between IP-10 and IFN-gamma (protein) responses were modest (r ~ 0.50 to 0.65). Taken together, these findings do not support the use of IP-10 protein as a biomarker for bovine tuberculosis using the current testing protocol and reagents; however, mRNA-based assays may be considered for further analysis. PMID- 22237892 TI - Monitoring of peptide-specific and gamma interferon-productive T cells in patients with active and convalescent tuberculosis using an enzyme-linked immunosorbent spot assay. AB - To establish a high-efficiency gamma interferon-specific enzyme-linked immunosorbent spot assay (IFN-gamma ELISPOT assay) for detection of tuberculosis (TB), peptides (E6, E7, and C14) and peptide mixtures (E6 plus E7 and E6 plus E7 plus C14) were used to monitor peripheral blood (PBL) samples from patients with pulmonary TB (PTB), as well as control samples. The positive detection rates of the five IFN-gamma ELISPOT assays were 78.38%, 74.86%, 55.83%, 90.43%, and 91.51%, respectively, and there were similar detection rates between the two combined peptide mixture IFN-gamma ELISPOT assays and the tuberculin skin test (TST) (90.62% versus 95.59%). No significant difference was found between the detection rates of the two combined peptide mixture IFN-gamma ELISPOT assays and the T-SPOT.TB assay for 86 patients with PTB (P > 0.05), but the median number of spot-forming cells/10(6) cells (SFP value) for positive results was higher by the former than by the latter assay (P < 0.05). In contrast, the 29.93% positive detection rate and median SFP value of 482 by the two combined peptide mixture IFN-gamma ELISPOT assays were significantly higher than the corresponding values of 14.29% and 152 by T-SPOT.TB assay for the same 147 community donors (P < 0.05). For nine PTB patients tracked, the SFP value of 7 for the two peptide mixture IFN-gamma ELISPOT assays began to decrease from the second month after regular treatment. A relatively low, almost normal, SFP level was reached and maintained after the third or fourth month. Two in-house IFN-gamma ELISPOT assays and the T-SPOT.TB assay could reduce the false-positive and false-negative detection rates of TST and sputum acid-fast staining. Therefore, these two combined peptide mixture IFN-gamma ELISPOT assays have a potential advantage, beyond their greater specificity and sensitivity, for use in screening and detection of active TB infection (TBI) and latent TB infection (LTBI) in China. PMID- 22237893 TI - Flagellin from recombinant attenuated Salmonella enterica serovar Typhimurium reveals a fundamental role in chicken innate immunity. AB - Recombinant attenuated Salmonella vaccines have been extensively studied, with a focus on eliciting specific immune responses against foreign antigens. However, very little is known about the innate immune responses, particularly the role of flagellin, in the induction of innate immunity triggered by recombinant attenuated Salmonella in chickens. In the present report, we describe two Salmonella enterica serovar Typhimurium vaccine strains, wild-type (WT) or flagellin-deficient (flhD) Salmonella, both expressing the fusion protein (F) gene of Newcastle disease virus. We examined the bacterial load and spatiotemporal kinetics of expression of inflammatory cytokine, chemokine, and Toll-like receptor 5 (TLR5) genes in the cecum, spleen, liver, and heterophils following oral immunization of chickens with the two Salmonella strains. The flhD mutant exhibited an enhanced ability to establish systemic infection compared to the WT. In contrast, the WT strain induced higher levels of interleukin-1beta (IL 1beta), CXCLi2, and TLR5 mRNAs in cecum, the spleen, and the heterophils than the flhD mutant at different times postinfection. Collectively, the present data reveal a fundamental role of flagellin in the innate immune responses induced by recombinant attenuated Salmonella vaccines in chickens that should be considered for the rational design of novel vaccines for poultry. PMID- 22237894 TI - Comparison of immunoglobulin G subclass concentrations in severe community acquired pneumonia and severe pandemic 2009 influenza A (H1N1) infection. AB - We compared immunoglobulin G (IgG) subclasses in patients with severe noninfluenza community-acquired pneumonia (CAP) to those in patients with severe pandemic 2009 influenza (H1N1) virus infection. Low IgG1 and IgG2 levels occurred often in the CAP group; however, H1N1 patients had lower IgG1 and IgG2 levels (5.4 versus 3.3 g/liter [P = 0.008] and 2.5 versus 1.2 g/liter [P < 0.001], respectively). Low IgG2 levels may be specifically linked to severe H1N1; however, it is not clear whether this association is related to H1N1 or to other features of severity. PMID- 22237895 TI - Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency. AB - Staphylococcus aureus alpha toxin (AT) is an important virulence determinant and may be a valid target for immunoprophylaxis against staphylococcal disease. Here we report the identification of potent inhibitory anti-AT monoclonal antibodies (MAbs) derived using B-cell hybridoma technology from VelocImmune mice engineered to produce IgG with a human variable domain. A small panel of inhibitory MAbs blocked AT-mediated lysis of rabbit red blood cells, A549 human lung epithelial cells, and THP-1 human monocytic cells, in a dose-dependent manner. Binding studies indicated that these MAbs recognize a similar epitope on AT and exhibit dissociation constants (K(D)) ranging from 0.50 to 15 nM. In an S. aureus dermonecrosis model, mice passively immunized with anti-AT inhibitory MAbs exhibited significant reductions of lesion size relative to mice treated with an irrelevant IgG control. Interestingly, there was a correlation between MAb affinity for a single epitope, the 50% inhibitory concentration (IC(50)) in the AT hemolytic assay, and lesion size reduction in the dermonecrosis model. A representative high-affinity MAb, 2A3.1, was demonstrated to significantly reduce lesion size following infection with three different clinical isolates (USA300, CC30, and CC5). Taken together, these results indicate that in vitro potency of anti-AT MAbs predicts in vivo potency in this model, supporting their continued preclinical evaluation as molecules for immunoprophylaxis against staphylococcal skin and soft tissue infections caused by diverse clinical isolates. PMID- 22237896 TI - Development of a bead-based multiplex immunoassay for simultaneous quantitative detection of IgG serum antibodies against measles, mumps, rubella, and varicella zoster virus. AB - Enzyme-linked immunosorbent assay (ELISA) is normally used to quantify the amount of serum IgG antibodies against measles, mumps, rubella, and varicella-zoster virus (MMRV). However, this method is time- and material-consuming. Therefore, a multiplex immunoassay for the simultaneous quantitative detection of antibodies against MMRV was developed. In-house as well as commercially available antigens can be used, making the assay available for all laboratories. The multiplex assay is much more sensitive than the separate ELISAs and has a high specificity, and only 5 MUl of serum is needed. Heterologous inhibition did not exceed 11.5%, while homologous inhibition varied between 91.3 and 97.9%. Good correlations with the in-house ELISAs for measles (R(2) = 0.98), mumps (R(2) = 0.97), and rubella (R(2) = 0.97) virus as well as with the ELISA kit for varicella-zoster virus (R(2) = 0.95) were obtained. In conclusion, the MMRV multiplex assay is a good alternative to the conventional ELISAs and suitable for use in serosurveillance and vaccine studies. PMID- 22237898 TI - Effects of North American porcine reproductive and respiratory syndrome virus (PRRSV)-based modified live vaccines on preimmunized sows artificially inseminated with European PRRSV-spiked semen. AB - The objective of the present study was to determine if the European porcine reproductive and respiratory syndrome virus (PRRSV) can be transmitted via spiked semen to preimmunized sows and induce reproductive failure. Sows were immunized with the North American PRRSV-based modified live vaccine (Ingelvac PRRS MLV; Boehringer Ingelheim Animal Health, St. Joseph, MO) and were artificially inseminated. The sows were randomly divided into three groups. The vaccinated (group 2) and nonvaccinated (group 3) sows developed a PRRSV viremia at 7 to 28 days postinsemination with the European PRRSV-spiked semen. The number of genomic copies of the European PRRSV in serum samples was not significantly different between vaccinated and nonvaccinated sows. All negative-control sows in group 1 farrowed at the expected date. The sows in groups 2 and 3 farrowed between 103 and 110 days after the first insemination. European PRRSV RNA was detected in the lungs of 8 out of 11 live-born piglets and 46 out of 54 stillborn fetuses. In addition, PRRSV RNA was detected using in situ hybridization in other tissues from vaccinated sows that had been inseminated with European PRRSV-spiked semen (group 2). The present study has demonstrated that vaccinating sows with the North American PRRSV-based modified live vaccine does not prevent reproductive failure after insemination with European PRRSV-spiked semen. PMID- 22237897 TI - Antibodies to a novel leptospiral protein, LruC, in the eye fluids and sera of horses with Leptospira-associated uveitis. AB - Screening of an expression library of Leptospira interrogans with eye fluids from uveitic horses resulted in identification of a novel protein, LruC. LruC is located in the inner leaflet of the leptospiral outer membrane, and an lruC gene was detected in all tested pathogenic L. interrogans strains. LruC-specific antibody levels were significantly higher in eye fluids and sera of uveitic horses than healthy horses. These findings suggest that LruC may play a role in equine leptospiral uveitis. PMID- 22237900 TI - Management of obstructive colorectal cancer: evaluation of preoperative bowel decompression using ileus tube drainage. AB - PURPOSE: This study evaluated a better treatment for patients with obstructive colorectal cancer (CRC) that have a poor prognosis. METHOD: This study compared the outcomes of 138 patients with obstructive CRC, including 70 primary resections, 50 resections after bowel decompression using an ileus tube, and 18 delayed resections after colostomy. RESULTS: The ileus tube and delayed resection groups included more left-sided primary lesions. The physiologic POSSUM, types 3 4, tumor size, CEA, and hospital stay of the delayed resection group were different, in comparison to both the primary resection and ileus tube groups. The histopathological type and depth of invasion of the delayed resection group included less well types and more T4 than those of the ileus tube group. The operative blood loss of the delayed resection group was more than that of the ileus tube group. There were no differences in the overall and disease-free survival among the three groups. CONCLUSION: Separately analyzing the data of the right-sided cancer group and the left-sided cancer group demonstrated that primary resection might be acceptable for right-sided obstructive CRC and delayed resection might be done for patients with poorer general conditions (high PPS) and poorer oncological prognostic factors such as more type 3/type 4 cases, a larger tumor size, a less well-differentiated histopathological type, more T4 cases, and a higher CEA level. PMID- 22237899 TI - The HIV-1 env protein: a coat of many colors. AB - HIV-1 is completely dependent upon the Env protein to enter cells. The virus typically replicates in activated CD4+ T cells due to viral entry requirements for the CCR5 coreceptor and for high surface levels of the CD4 receptor. This is the case for the transmitted virus and for most of the virus sampled in the blood. Over the course of infection, the env gene can evolve to encode a protein with altered receptor and coreceptor usage allowing the virus to enter alternative host cells. In about 50% of HIV-1 infections, the viral population undergoes coreceptor switching, usually late in disease, allowing the virus to use CXCR4 to enter a different subset of CD4+ T cells. Neurocognitive disorders occur in about 10% of infections, also usually late in disease, but caused (ultimately) by viral replication in the brain either in CD4+ T cells or macrophage and/or microglia. Expanded host range is significantly intertwined with pathogenesis. Identification and characterization of such HIV-1 variants may be useful for early detection which would allow intervention to reduce viral pathogenesis in these alternative cell types. PMID- 22237901 TI - Mucocele-like tumor associated with ductal carcinoma in situ diagnosed as mucinous carcinoma by fine-needle aspiration cytology: report of a case. AB - Mucocele-like tumors (MLTs) of the breast are rare, with only 11 cases reported from Japan and 35 cases from other countries. MLTs of the breast were first described by Rosen in 1986. They are believed to be related to atypical ductal hyperplasia, ductal carcinoma, or mucinous carcinoma. It is difficult to diagnose this tumor preoperatively, and especially difficult to differentiate between benign and malignant forms. We report a case of MLT associated with ductal carcinoma in situ, which was initially diagnosed as fibroadenoma by mammography and ultrasonography, and as mucinous carcinoma by fine-needle aspiration cytology. We discuss the characteristic findings of imaging and the appropriate clinical treatment of this tumor. The characteristic image first signals the possibility of this tumor, following which the diagnosis can be confirmed by pathological examination of a fully excised tumor specimen. Breast-conserving surgery is recommended because of the low risk of high-grade malignancy, even when malignancy is confirmed, and lymph node dissection may be avoided. PMID- 22237902 TI - Choice of rating method for assessing occupational asbestos exposure: study for compensation purposes in France. AB - BACKGROUND: In the course of setting up the National Mesothelioma Surveillance Program (PNSM), established in France in 1998, the question arose as to the most suitable method of assessing occupational exposure. The aim of this study was to define the most suitable rating method for assessing occupational asbestos exposure in order to assess medico-social care. METHOD: The study included 100 subjects-50 cases of mesothelioma and 50 controls-randomly selected and representing 457 jobs held. Job asbestos exposure was assessed by a six-expert panel using two methods: "by job" rating, where all the jobs in were assessed regardless of the subjects; and "by subject" rating, where all the jobs of a subject were assessed at the same time. Consensus was obtained and subjects' exposure was calculated for each rating. Then, two internal experts assessed job asbestos exposure with the "by subject" rating. Kappa coefficients were used to measure agreement between the ratings. RESULTS: Agreement between "by job" and "by subject" ratings was very good for subject probability of exposure (kappa = 0.84) and cumulative exposure index (kappa = 0.80). Agreement between the six expert panel and the two internal experts was good for subject exposure (kappa for probability = 0.71; kappa for cumulative exposure index= 0.68). CONCLUSION: This study shows that the two rating systems have good or very good agreement. These results validate the routine use in the PNSM of the "by subject" rating, with the advantage of being convenient and quick to provide feedback on occupational asbestos exposure to mesothelioma cases for compensation. PMID- 22237903 TI - Quantitative analysis of neocortical gyrencephaly in African elephants (Loxodonta africana) and six species of cetaceans: comparison with other mammals. AB - This study provides quantitative data on the extent of gyrencephaly in the large brained African elephant and several species of cetaceans (from smaller to larger brained) in comparison with other mammals. Across three mammalian orders (primates, carnivores, and artiodactyls), the species with the larger brains are more gyrencephalic with each order, exhibiting a specific negative allometry. The African elephant, with a 5-kg brain, has a gyrencephalic index (GI) of 3.89, which, though highly gyrencephalic, is not more so than would be predicted for a mammal with a 5-kg brain. The cetaceans had an average GI of 5.43, are the most gyrencephalic mammals studied to date, and are more gyrencephalic than one would predict based on comparison with other mammals. No relationship between brain mass and GI was evident in the cetaceans as seen in other mammals, with all cetaceans showing similar GIs irrespective of brain mass (range of GI 5.23-5.70, range of brain mass 577-5617 g). This is yet another parameter indicating cetaceans to be neuroanatomical outliers. Two species of pinnipeds studied had GIs that were well above those seen for terrestrial carnivores, and the aquatic manatee was close to lissencephalic. Thus, all three groups of marine mammals showed unusual extents of cortical gyrencephaly, indicating a morphological alteration of the telencephalon associated with the return to the marine environment. The analysis suggests that cortical thickness and neuronal density are important factors in determining the extent of gyrencephaly across mammalian species. PMID- 22237904 TI - Learn and live: predator experience and feeding history determines prey behaviour and survival. AB - Determining how prey learn the identity of predators and match their vigilance with current levels of threat is central to understanding the dynamics of predator-prey systems and the determinants of fitness. Our study explores how feeding history influences the relative importance of olfactory and visual sensory modes of learning, and how the experience gained through these sensory modes influences behaviour and survival in the field for a juvenile coral reef damselfish. We collected young fish immediately prior to their settlement to benthic habitats. In the laboratory, these predator-naive fish were exposed to a high- or low-food ration and then conditioned to recognize the olfactory cues (odours) and/or visual cues from two common benthic predators. Fish were then allowed to settle on reefs in the field, and their behaviour and survival over 70 h were recorded. Feeding history strongly influenced their willingness to take risks in the natural environment. Conditioning in the laboratory with visual, olfactory or both cues from predators led fish in the field to display risk averse behaviour compared with fish conditioned with sea water alone. Well-fed fish that were conditioned with visual, chemical or a combination of predator cues survived eight times better over the first 48 h on reefs than those with no experience of benthic predator cues. This experiment highlights the importance of a flexible and rapid mechanism of learning the identity of predators for survival of young fish during the critical life-history transition between pelagic and benthic habitats. PMID- 22237905 TI - Universal scaling rules predict evolutionary patterns of myogenesis in species with indeterminate growth. AB - Intraspecific phenotypic variation is ubiquitous and often associated with resource exploitation in emerging habitats. For example, reduced body size has evolved repeatedly in Arctic charr (Salvelinus alpinus L.) and threespine stickleback (Gasterosteus aculeatus L.) across post-glacial habitats of the Northern Hemisphere. Exploiting these models, we examined how body size and myogenesis evolve with respect to the 'optimum fibre size hypothesis', which predicts that selection acts to minimize energetic costs associated with ionic homeostasis by optimizing muscle fibre production during development. In eight dwarf Icelandic Arctic charr populations, the ultimate production of fast-twitch muscle fibres (FN(max)) was only 39.5 and 15.5 per cent of that in large-bodied natural and aquaculture populations, respectively. Consequently, average fibre diameter (FD) scaled with a mass exponent of 0.19, paralleling the relaxation of diffusional constraints associated with mass-specific metabolic rate scaling. Similar reductions in FN(max) were observed for stickleback, including a small bodied Alaskan population derived from a larger-bodied oceanic stock over a decadal timescale. The results suggest that in species showing indeterminate growth, body size evolution is accompanied by strong selection for fibre size optimization, theoretically allowing resources saved from ionic homeostasis to be allocated to other traits affecting fitness, including reproduction. Gene flow between small- and large-bodied populations residing in sympatry may counteract the evolution of this trait. PMID- 22237906 TI - Adaptive evolution of facial colour patterns in Neotropical primates. AB - The rich diversity of primate faces has interested naturalists for over a century. Researchers have long proposed that social behaviours have shaped the evolution of primate facial diversity. However, the primate face constitutes a unique structure where the diverse and potentially competing functions of communication, ecology and physiology intersect, and the major determinants of facial diversity remain poorly understood. Here, we provide the first evidence for an adaptive role of facial colour patterns and pigmentation within Neotropical primates. Consistent with the hypothesis that facial patterns function in communication and species recognition, we find that species living in smaller groups and in sympatry with a higher number of congener species have evolved more complex patterns of facial colour. The evolution of facial pigmentation and hair length is linked to ecological factors, and ecogeographical rules related to UV radiation and thermoregulation are met by some facial regions. Our results demonstrate the interaction of behavioural and ecological factors in shaping one of the most outstanding facial diversities of any mammalian lineage. PMID- 22237907 TI - Context-dependent symbioses and their potential roles in wildlife diseases. AB - It is well known in ecology, evolution and medicine that both the nature (commensal, parasitic and mutualistic) and outcome (symbiont fitness, survival) of symbiotic interactions are often context-dependent. Less is known about the importance of context-dependence in symbioses involved in wildlife disease. We review variable symbioses, and use the amphibian disease chytridiomycosis to demonstrate how understanding context-dependence can improve the understanding and management of wildlife diseases. In chytridiomycosis, the host-pathogen interaction is context-dependent; it is strongly affected by environmental temperature. Skin bacteria can also modify the interaction; some bacteria reduce amphibians' susceptibility to chytridiomycosis. Augmentation of protective microbes is being considered as a possible management tool, but informed application of bioaugmentation requires understanding of how the interactions between host, beneficial bacteria and pathogen depend upon environmental context. The community-level response of the amphibian skin microbiota to environmental conditions may explain the relatively narrow range of environmental conditions in which past declines have occurred. Environmental context affects virulence and the protection provided by mutualists in other host-pathogen systems, including threatened bats and corals. Increased focus on context-dependence in interactions between wildlife and their symbionts is likely to be crucial to the future investigation and management of emerging diseases of wildlife. PMID- 22237908 TI - Prey community structure affects how predators select for Mullerian mimicry. AB - Mullerian mimicry describes the close resemblance between aposematic prey species; it is thought to be beneficial because sharing a warning signal decreases the mortality caused by sampling by inexperienced predators learning to avoid the signal. It has been hypothesized that selection for mimicry is strongest in multi-species prey communities where predators are more prone to misidentify the prey than in simple communities. In this study, wild great tits (Parus major) foraged from either simple (few prey appearances) or complex (several prey appearances) artificial prey communities where a specific model prey was always present. Owing to slower learning, the model did suffer higher mortality in complex communities when the birds were inexperienced. However, in a subsequent generalization test to potential mimics of the model prey (a continuum of signal accuracy), only birds that had foraged from simple communities selected against inaccurate mimics. Therefore, accurate mimicry is more likely to evolve in simple communities even though predator avoidance learning is slower in complex communities. For mimicry to evolve, prey species must have a common predator; the effective community consists of the predator's diet. In diverse environments, the limited diets of specialist predators could create 'simple community pockets' where accurate mimicry is selected for. PMID- 22237909 TI - Spatial reorientation by geometry with freestanding objects and extended surfaces: a unifying view. AB - The macroscopic, three-dimensional surface layout geometry of an enclosure apparently provides a different contribution for spatial reorientation than the geometric cues associated with freestanding objects arranged in arrays with similar geometric shape. Here, we showed that a unitary spatial representation can account for the capability of animals to reorient both by extended surfaces and discrete objects in a small-scale spatial task. We trained domestic chicks to locate a food-reward from an opening on isolated cylinders arranged either in a geometrically uninformative (square-shaped) or informative (rectangular-shaped) arrays. The arrays were located centrally within a rectangular-shaped enclosure. Chicks trained to access the reward from a fixed position of openings proved able to reorient according to the geometric cues specified by the shape of the enclosure in all conditions. Chicks trained in a fixed position of opening with geometric cues provided both by the arena and the array proved able to reorient according to each shape separately. However, chicks trained to access the reward from a variable position of openings failed to reorient. The results suggest that the physical constrains associated with the presence of obstacles in a scene, rather than their apparent visual extension, are crucial for spatial reorientation. PMID- 22237910 TI - Optimal foraging for specific nutrients in predatory beetles. AB - Evolutionary theory predicts that animals should forage to maximize their fitness, which in predators is traditionally assumed equivalent to maximizing energy intake rather than balancing the intake of specific nutrients. We restricted female predatory ground beetles (Anchomenus dorsalis) to one of a range of diets varying in lipid and protein content, and showed that total egg production peaked at a target intake of both nutrients. Other beetles given a choice to feed from two diets differing only in protein and lipid composition selectively ingested nutrient combinations at this target intake. When restricted to nutritionally imbalanced diets, beetles balanced the over- and under-ingestion of lipid and protein around a nutrient composition that maximized egg production under those constrained circumstances. Selective foraging for specific nutrients in this predator thus maximizes its reproductive performance. Our findings have implications for predator foraging behaviour and in the structuring of ecological communities. PMID- 22237911 TI - Egg phenotype matching by cuckoos in relation to discrimination by hosts and climatic conditions. AB - Although parasites and their hosts often coexist in a set of environmentally differentiated populations connected by gene flow, few empirical studies have considered a role of environmental variation in shaping correlations between traits of hosts and parasites. Here, we studied for the first time the association between the frequency of adaptive parasitic common cuckoo Cuculus canorus phenotypes in terms of egg matching and level of defences exhibited by its reed warbler Acrocephalus scirpaceus hosts across seven geographically distant populations in Europe. We also explored the influence of spring climatic conditions experienced by cuckoos and hosts on cuckoo-host egg matching. We found that between-population differences in host defences against cuckoos (i.e. rejection rate) covaried with between-population differences in degree of matching. Between-population differences in host egg phenotype were associated with between-population differences in parasitism rate and spring climatic conditions, but not with host level of defences. Between-population differences in cuckoo egg phenotype covaried with between-population differences in host defences and spring climatic conditions. However, differences in host defences still explained differences in mimicry once differences in climatic conditions were controlled, suggesting that selection exerted by host defences must be strong relative to selection imposed by climatic factors on egg phenotypes. PMID- 22237915 TI - Synthesis of amphiphilic azo-anion-radical complexes of chromium(III) and the development of ultrathin redox-active surfaces by the Langmuir-Schaefer technique. AB - Neutral tris-chelated chromium complex [Cr(L(a))(3)] (1a), and its surfactant derivatives [Cr(L(b))(3)] (1b), [Cr(L(c))(3)] (1c), and [Cr(L(d))(3)] (1d) (where L(a)=2-(4'-methoxyphenylazo)pyridine, L(b)=2-(4'-butyloxyphenylazo)pyridine, L(c =2-(4'-octyloxyphenylazo)pyridine, and L(d)=2-(4'-dodecyloxyphenylazo)pyridine) were synthesized. The molecular structure of compound 1a, determined by X-ray diffraction, showed that the local geometry around the metal center is a distorted octahedral with meridional coordination of the ligands. The structural parameters, spectroscopic data, and density functional theory (DFT) calculations on representative complex 1a suggest that ligand L(a) is predominantly an azo anion-radical-type, and so the complex can be represented as [Cr(III)(L(a. ))(3)]. An assessment of their physicochemical and surface properties was performed with the aim of using these triple-tailed metallosurfactants as precursors for redox-responsive films. The surface-pressure-molecular-area isotherm measurement for compound 1d shows that the complex forms a stable Langmuir film at the air/water interface. The monolayer and multilayers were successfully transferred onto the quartz substrate and the platinum working electrode at a surface pressure of 10 mN m(-1) by the Langmuir-Schaefer (LS) technique. The LS films were studied by UV/Vis spectrometry, infrared spectroscopy, field-emission scanning electron microscopy, and atomic force microscopy. A good linear relationship between the absorbance at 370 nm and the thickness of the layers against the number of deposited layers indicated the uniformity and reproducibility of this transfer process. Voltammograms for platinum-surface-bound LS film of compound 1d showed that the redox response owing to the first oxidation is stable and reproducible after many cycles (>300 cycles). Spectroscopic studies and electrochemical measurements of compound 1d on the LS films revealed that these complexes are potential candidates for molecular devices. PMID- 22237914 TI - Investigation of some biologically relevant redox reactions using electrochemical mass spectrometry interfaced by desorption electrospray ionization. AB - Recently we have shown that, as a versatile ionization technique, desorption electrospray ionization (DESI) can serve as a useful interface to combine electrochemistry (EC) with mass spectrometry (MS). In this study, the EC/DESI-MS method has been further applied to investigate some aqueous phase redox reactions of biological significance, including the reduction of peptide disulfide bonds and nitroaromatics as well as the oxidation of phenothiazines. It was found that knotted/enclosed disulfide bonds in the peptides apamin and endothelin could be electrochemically cleaved. Subsequent tandem MS analysis of the resulting reduced peptide ions using collision-induced dissociation (CID) and electron-capture dissociation (ECD) gave rise to extensive fragment ions, providing a fast protocol for sequencing peptides with complicated disulfide bond linkages. Flunitrazepam and clonazepam, a class of nitroaromatic drugs, are known to undergo reduction into amines which was proposed to involve nitroso and N hydroxyl intermediates. Now in this study, these corresponding intermediate ions were successfully intercepted and their structures were confirmed by CID. This provides mass spectrometric evidence for the mechanism of the nitro to amine conversion process during nitroreduction, an important redox reaction involved in carcinogenesis. In addition, the well-known oxidation reaction of chlorpromazine was also examined. The putative transient one-electron transfer product, the chlorpromazine radical cation (m/z 318), was captured by MS, for the first time, and its structure was also verified by CID. In addition to these observations, some features of the DESI-interfaced electrochemical mass spectrometry were discussed, such as simple instrumentation and the lack of background signal. These results further demonstrate the feasibility of EC/DESI-MS for the study of the biology-relevant redox chemistry and would find applications in proteomics and drug development research. PMID- 22237916 TI - First kinetic evidence for the CH/pi and pi/pi solute-solvent interaction of C60 in the Diels-Alder reaction with cyclohexadiene. AB - The first CH/pi solute-solvent interaction of C(60) was evidenced by the kinetic solvent effects in the Diels-Alder reaction with 1,3-cyclohexadiene based on the evaluation of linear free energy relationship of log k(2) with empirical solvent polarity and basicity parameters, E(T)(30) and D(pi), respectively. PMID- 22237918 TI - Locomotor behavior of bonnet monkeys after spinal contusion injury: footprint study. AB - Analysis of gait functions following spinal cord injury has been widely studied in rats, mice but limited in primates. This investigation was performed to quantitatively analyze the degree of functional recovery in bipedal locomotion in bonnet monkeys after induced spinal cord contusion. The degree of locomotor recovery was examined by measuring four gait variables, viz., tip of opposite foot (TOF), print-length (PL), toe-spread (TS), and intermediary toe-spread (IT) from the recorded hindlimb prints of monkeys using ink and paper technique. Contusion was induced in spinal cord at T12-L1 level in anaesthetized monkeys by using the Allen's weight drop technique. Postoperatively, all spinal contused animals initially showed a significant decrease in TOF, which then gradually increased for longer duration and attained the near normal values by the sixth month. On the other hand, PL, TS, and IT variables in hindlimb prints of contused animals were found to dramatically increase initially and then slowly decrease subsequently. Later there was a recovery to insignificant levels which differed from the corresponding preoperative values by the fifth month. The observations of this study suggest that the functional contributions of the spared fibers, especially in ventral and ventrolateral funiculi, through collateral sprouts or synaptic plasticity that were formed in the contused spinal cord may be responsible for substantial recovery of hindlimb movements. Moreover, based on analysis of footprint variables observed in locomotion in these subjected monkeys, we understand that spinal automatism and development of responses by afferent stimuli from outside the cord could possibly contribute to recovery of the paralyzed hindlimbs. PMID- 22237917 TI - Genome-wide association for fear conditioning in an advanced intercross mouse line. AB - Fear conditioning (FC) may provide a useful model for some components of post traumatic stress disorder (PTSD). We used a C57BL/6J * DBA/2J F(2) intercross (n = 620) and a C57BL/6J * DBA/2J F(8) advanced intercross line (n = 567) to fine map quantitative trait loci (QTL) associated with FC. We conducted an integrated genome-wide association analysis in QTLRel and identified five highly significant QTL affecting freezing to context as well as four highly significant QTL associated with freezing to cue. The average percent decrease in QTL width between the F(2) and the integrated analysis was 59.2%. Next, we exploited bioinformatic sequence and expression data to identify candidate genes based on the existence of non-synonymous coding polymorphisms and/or expression QTLs. We identified numerous candidate genes that have been previously implicated in either fear learning in animal models (Bcl2, Btg2, Dbi, Gabr1b, Lypd1, Pam and Rgs14) or PTSD in humans (Gabra2, Oprm1 and Trkb); other identified genes may represent novel findings. The integration of F(2) and AIL data maintains the advantages of studying FC in model organisms while significantly improving resolution over previous approaches. PMID- 22237919 TI - Long-term results of cementless femoral reconstruction following intertrochanteric osteotomy. AB - PURPOSE: The objective of this retrospective cohort study was to assess the long term outcome of cementless femoral reconstruction in patients with previous intertrochanteric osteotomy (ITO). METHODS: We evaluated the clinical and radiographic results of a consecutive series of 45 patients (48 hips, mean age 50 years) who had undergone conversion hip replacement following ITO with a cementless, grit-blasted, double-tapered femoral component. Clinical outcome was determined using the Harris hip score. Stem survival for different end points was assessed using Kaplan-Meier survivorship analysis. RESULTS: At a mean follow-up of 20 (range, 16-24) years, 11 patients (12 hips) had died, and no patient was lost to follow-up. Six patients (six hips) underwent femoral revision, two for infection, three for aseptic loosening and one for periprosthetic fracture. Mean Harris hip score at final follow-up was 78 points (range, 23-100 points). Stem survival for all revisions was 89% (95%CI, 75-95) at 20 years, and survival for aseptic loosening was 93% (95%CI, 80-98). CONCLUSIONS: The long-term results with this type of cementless femoral component in patients with previous intertrochanteric osteotomy are encouraging and compare well to those achieved in patients with normal femoral anatomy. PMID- 22237920 TI - Cartilage labelling for mechanical testing in T-peel configuration. AB - PURPOSE: The purpose of this study was to find a suitable method of labelling cartilage samples for the measurement of distraction distances in biomechanical testing. METHODS: Samples of bovine cartilage were labelled using five different methods: hydroquinone and silver nitrate (AgNO3), potassium permanganate (KMnO4) with sodium thiosulphate (Na2S2O3), India ink, heat, and laser energy. After the labelling, we analysed the cartilage samples with regard to cytotoxity by histochemical staining with ethidiumbromide homodimer (EthD-1) and calcein AM. Furthermore, we tested cartilages labelled with India ink and heat in a T-peel test configuration to analyse possible changes in the mechanical behaviour between marked and unlabelled samples. RESULTS: Only the labelling methods with Indian ink or a heated needle showed acceptable results in the cytotoxity test with regard to labelling persistence, accuracy, and the influence on consistency and viability of the chondrocytes. In the biomechanical T-peel configuration, heat-labelled samples collapsed significantly earlier than unlabelled samples. CONCLUSION: Labelling bovine cartilage samples with Indian ink in biomechanical testing is a reliable, accurate, inexpensive, and easy-to-perform method. This labelling method influenced neither the biomechanical behaviour nor the viability of the tissue compared to untreated bovine cartilage. PMID- 22237921 TI - Intervertebral focal surgery for the treatment of non-contiguous multifocal spinal tuberculosis. AB - PURPOSE: The purpose of this study was to assess the clinical efficacy of intervertebral focal surgery by complete debridement, deformity correction, graft fusion, and internal fixation for patients with non-contiguous multifocal spinal tuberculosis. METHODS: A total of 29 cases with non-contiguous multifocal spinal tuberculosis admitted to the hospital from January 2000 to January 2007 were treated by intervertebral focal surgery. There were 63 foci in 29 cases, averaging 2.2 foci per case, and 146 affected vertebral bodies, averaging 2.3 vertebral bodies per focus. Three cases had one normal intervertebral disc between two foci, and the other 26 cases had two or more normal intervertebral discs between two foci. RESULTS: All cases were followed-up for an average of five years. The kyphosis showed a mean correction rate of 67.7% after surgery. A mean loss rate of correction of 8.2% was observed at the final follow-up. The levels of erythrocyte sedimentation rate and C-reactive protein returned to normal in 27 cases on average at 5.8 months and bone union could be observed at five months after surgery. Eleven cases with nerve damage recovered to E grade at the final follow-up. CONCLUSIONS: Intervertebral focal surgery by complete debridement, deformity correction, graft fusion, and internal fixation for patients with non-contiguous multifocal spinal tuberculosis was feasible and effective. PMID- 22237922 TI - Maturation of the gastric microvasculature in Xenopus laevis (Lissamphibia, Anura) occurs at the transition from the herbivorous to the carnivorous lifestyle, predominantly by intussuceptive microvascular growth (IMG): a scanning electron microscope study of microvascular corrosion casts and correlative light microscopy. AB - The microvascular bed of the stomach of Xenopus laevis and the changes it undergoes when the herbivorous tadpole becomes a carnivorous adult were studied by scanning electron microscopy of vascular corrosion casts and light microscopy of stained tissue sections. In tadpoles an upper and a lower gastric artery supplied, and upper, middle and lower medial and lateral gastric veins drained the vertically extending stomach. During metamorphosis, the stomach gained a horizontal cranio-caudal extension and vessels accordingly become dorsal and ventral gastric arteries, and anterior, middle and posterior gastric veins, respectively. Up to stage 64 (late climax) mucosal capillaries formed a polygonal network of wide immature-looking capillaries ensheathing gastric glands in a basket-like manner. From stage 64 onwards, blood vessels of the stomach appeared mature, revealed a clear hierarchy and were correlated closely with the histomorphology of the stomach, which had also gained the adult pattern. Within the gastric mucosa, ascending arterioles branched in a fountain-like pattern into wide subepithelial capillaries establishing a centripetal blood flow along the gastric glands, which makes an ultrashort control loop of glandular cells within the branched tubular gastric glands very unlikely. Formation of the stomach external muscular layer started at stage 57 when smooth muscle cells locally formed a single longitudinal and one-to-two single circular layers. Abundant signs of intussusceptive microvascular growth and rare vascular sprouts in vascular corrosion casts indicated that the larval-to-adult microvascular pattern formation of the stomach of Xenopus laevis Daudin occurs predominantly by non sprouting angiogenesis. PMID- 22237923 TI - Absence of musculocutaneous nerve with variations in course and distribution of the median nerve. AB - Variations in the brachial plexus and its terminal branches are not uncommon. A communicating branch arising from the musculocutaneous nerve to the median nerve is a frequent variation, but complete merging of musculocutaneous nerve into the median nerve is very rare. Here, we observed variations in the origin, course and distribution of the median nerve in the left upper limb. The musculocutaneous nerve was absent. The median nerve was formed in the upper part of the arm, in front of the brachial artery. The median nerve supplied the biceps, coracobrachialis and brachialis muscles and gave the lateral cutaneous nerve of the forearm. The present report provides evidence of variation in important nerves of the anterior compartment of the arm. PMID- 22237924 TI - Mesenchymal cell populations: development of the induction systems for Schwann cells and neuronal cells and finding the unique stem cell population. AB - Mesenchymal cell populations, referred to as mesenchymal stem cells or multipotent stromal cells (MSCs), which include bone marrow stromal cells (BMSCs), umbilical cord stromal cells and adipose stromal cells (ASCs), participate in tissue repair when transplanted into damaged or degenerating tissues. The trophic support and immunomodulation provided by MSCs can protect against tissue damage, and the differentiation potential of these cells may help to replace lost cells. MSCs are easily accessible and can be expanded on a large scale. In addition, BMSCs and ASCs can be harvested from the patient himself. Thus, MSCs are considered promising candidates for cell therapy. In this review, I will discuss recently discovered high-efficiency induction systems for deriving Schwann cells and neurons from MSCs. Other features of MSCs that are important for tissue repair include the self-renewing property of stem cells and their potential for differentiation. Thus, I will also discuss the stemness of MSCs and describe the discovery of a certain stem cell type among adult MSCs that can self renew and differentiate into cells of all three germ layers. Furthermore, I will explore the prospects of using this cell population for cell therapy. PMID- 22237926 TI - Iron(II) complexes of new hexadentate 1,1,1-tris-(iminomethyl)ethane podands, and their 7-methyl-1,3,5-triazaadamantane rearrangement products. AB - New iron(II) podand complexes have been prepared, by condensation of 2 (aminomethyl)-2-methyl-1,3-diaminopropane with 3 equiv of a heterocyclic aldehyde in the presence of hydrated Fe[BF(4)](2) or Fe[ClO(4)](2) as templates. The 2 (aminomethyl)-2-methyl-1,3-diaminopropane is prepared in situ by deprotonation of its trihydrochloride salt. The chloride must be removed from these reactions by precipitation with silver, to avoid the formation of the alternative 2,4,6 trisubstituted-7-methyl-1,3,5-triazaadamantane condensation products, or their FeCl(2) adducts. The crystal structures of two 2,4,6-tri(pyridyl)-7-methyl-1,3,5 triazaadamantane-containing species are presented, and contain two different geometric isomers of this tricyclic ring with three equatorial, or two equatorial and one axial, pyridyl substituents. Both structures feature strong C-HX (X = Cl or F) hydrogen bonding from the aminal C-H groups in the triazaadamantane ring. Five iron(II) podand complexes were successfully obtained, all of which contain low-spin iron centres. PMID- 22237925 TI - Chemical composition and antifungal activity of essential oils and supercritical CO2 extracts of Apium nodiflorum (L.) Lag. AB - Aerial parts of Apium nodiflorum collected in Portugal and Italy were submitted to hydrodistillation; also a supercritical fluid extract was obtained from Italian plants. The extracts were analyzed by GC and GC/MS. Both essential oils, obtained from Portuguese and Italian plants, posses high content of phenylpropanoids (51.6 vs. 70.8%); in the former, the percentage split in myristicin (29.1%) and dillapiol (22.5%), whereas in the latter, the total percentage is only of dillapiol (70.8%). The co-occurrence of myristicin and dillapiol is frequent because dillapiol results from enzymatic methoxylation of myristicin. Antimicrobial activity of phenylpropanoids has been patented, what suggest the potential of plants with high amounts of these compounds. Minimal inhibitory concentration (MIC) and minimal lethal concentration, determined according to NCCLS, were used to evaluate the antifungal activity of the essential oils against yeasts, Aspergillus species and dermatophytes. Essential oils exhibited higher antifungal activity than other Apiaceae against dermatophytes, with MIC ranging from 0.04 to 0.32 MUl/ml. These results support the potential of A. nodiflorum oil in the treatment of dermatophytosis and candidosis. PMID- 22237927 TI - Co-administration of statins with cytochrome P450 3A4 inhibitors in a UK primary care population. AB - PURPOSE: The co-administration of cytochrome P450 3A4 (CYP3A4) inhibitors with simvastatin or atorvastatin (CYP3A4-metabolised statins) is associated with increased statin exposure and can increase the risk of adverse drug reactions. The aim of this study was to measure the concomitant exposure of patients to CYP3A4-metabolised statins and CYP3A4 inhibitors in the UK primary care population. METHODS: The co-administration of statins and CYP3A4 inhibitors during 2008 was examined in the General Practice Research Database, a large nationally representative UK primary care database. All known inhibitors were included with labelled inhibitors identified using the Medicines and Healthcare products Regulatory Agency Drug Safety Update and UK summary of product characteristics for statins. Exposure was examined in patients overall, patients 65 years and older and those prescribed higher doses of statins. RESULTS: There were 364,574 patients included in the analyses. Ninety-three percent of the patients were prescribed CYP3A4-metabolised statins, most whom received simvastatin (72%) and atorvastatin (24%). Approximately one third (30%) of the patients prescribed a CYP3A4-metabolised statin had also been prescribed a concomitant CYP3A4 inhibitor during the study period, including 11% prescribed a concomitant labelled inhibitor, with an annualised median days of concomitant use of 173 days, predominantly involving macrolide antibiotics and calcium channel blockers co-prescriptions. Rates were higher in the subgroup aged 65 and over and in those on high dose statins. CONCLUSIONS: The co-prescription of CYP3A4 metabolised statins and CYP3A4 inhibitors is common in UK primary care. This co prescription suggests the limited appreciation of potential interactions and Medicines and Healthcare products Regulatory Agency safety advice, with the potential to increase likelihood for side effects amongst patients. Strategies to reduce drug interactions with potential adverse effects should be targeted at prescribers and pharmacists. PMID- 22237929 TI - Posterior reversible encephalopathy syndrome: a case following reversible cerebral vasoconstriction syndrome masquerading as subarachnoid haemorrhage. AB - Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic clinico radiological diagnosis typically presenting with headache, encephalopathy and visual disturbance accompanied by a unique neuroradiological pattern of symmetrical parieto-occipital vasogenic oedema. Here we present the case of a 51 year-old woman who presented to hospital following a thunderclap headache, initially thought to be secondary to a subarachnoid haemorrhage (SAH). A tiny anterior choroidal artery aneurysm was demonstrated on cerebral angiogram. At surgical clipping, no evidence of haemorrhage was observed. Post-operatively, the patient developed delayed right-sided hemiparesis, managed with aggressive hypertensive treatment, and later, with onset of septicaemia, central visual loss. Computed tomography (CT) brain scans demonstrated oedematous changes within the parieto-occipital regions bilaterally and later areas of infarction. The initial diagnosis of SAH was revised to reversible cerebral vasoconstriction syndrome (RCVS), which gave rise to PRES. To our knowledge, this is the first reported case of RCVS with concomitant PRES and cerebral infarction. PMID- 22237928 TI - Impact of molecular biology studies on the understanding of brain tumors in childhood. AB - Pediatric brain tumors are the second most common form of childhood malignancy. Brain tumors are a very heterogenous group of tumors and the pathogenesis of many of these tumors is yet to be clearly elucidated. Current diagnostic tools include histopathology and immunohistochemistry, but classification based on these means has significant limitations. As our understanding of the molecular biology of individual tumors continues to increase it has led to the identification of reliable and increasingly available molecular biomarkers. Molecular techniques are likely to complement current standard means of investigation and help not only overcome diagnostic challenges but may also result in better disease classification and risk stratification, leading to more personalized therapeutic approaches. PMID- 22237930 TI - Lung cancer risk among construction workers in California, 1988-2007. AB - BACKGROUND: Although lung cancer risks can vary by race/ethnicity and by construction occupation, these risks have not been examined extensively. METHODS: This study analyzed 110,937 lung cancer cases identified from the California Cancer Registry between 1988 and 2007. Mean age at diagnosis, proportion diagnosed at an advanced stage, and proportion with 3-year survival were calculated for lung cancer cases employed in the construction industry. Case control methodology was also used to assess the risk of lung cancer. Morbidity odds ratios (MORs) were estimated by conditional logistic regression. RESULTS: Construction workers were found to have a significantly elevated risk for all lung cancer combined (MOR = 1.57) and for each lung cancer histologic subtype examined. All construction occupations, except managers/engineers and supervisors, had a significantly elevated risk for all lung cancer combined. Roofers and welders had the highest risks for total lung cancer and for each of the histologic subtypes. Construction workers in each of the four race/ethnicity groups also had significantly increased lung cancer risks. Compared to non construction workers, construction workers were diagnosed at an earlier age, at a more advanced stage, and had significantly lower 3-year survival, though differences were modest. CONCLUSION: These findings justify additional reductions in carcinogenic exposures in construction, and increased support for smoking cessation programs at construction sites. PMID- 22237932 TI - The accuracy or inaccuracy of affective forecasts depends on how accuracy is indexed: a meta-analysis of past studies. PMID- 22237931 TI - (+/-)3,4-methylenedioxymethamphetamine ("ecstasy") treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain. AB - (+/-)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg * 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment. PMID- 22237933 TI - Assessing metal-metal multiple bonds in Cr-Cr, Mo-Mo, and W-W compounds and a hypothetical U-U compound: a quantum chemical study comparing DFT and multireference methods. AB - To gain insights into the trends in metal-metal multiple bonding among the Group 6 elements, density functional theory has been employed in combination with multiconfigurational methods (CASSCF and CASPT2) to investigate a selection of bimetallic, multiply bonded compounds. For the compound [Ar-MM-Ar] (Ar=2,6 (C(6)H(5))(2)-C(6)H(3), M=Cr, Mo, W) the effect of the Ar ligand on the M(2) core has been compared with the analogous [Ph-MM-Ph] (Ph=phenyl, M=Cr, Mo, W) compounds. A set of [M(2)(dpa)(4)] (dpa=2,2'-dipyridylamide, M=Cr, Mo, W, U) compounds has also been investigated. All of the compounds studied here show important multiconfigurational behavior. For the Mo(2) and W(2) compounds, the sigma(2)pi(4)delta(2) configuration dominates the ground-state wavefunction, contributing at least 75%. The Cr(2) compounds show a more nuanced electronic structure, with many configurations contributing to the ground state. For the Cr, Mo, and W compounds the electronic absorption spectra have been studied, combining density functional theory and multireference methods to make absorption feature assignments. In all cases, the main features observed in the visible spectra may be assigned as charge-transfer bands. For all compounds investigated the Mayer bond order (MBO) and the effective bond order (EBO) were calculated by density functional theory and CASSCF methods, respectively. The MBO and EBO values share a similar trend toward higher values at shorter normalized metal metal bond lengths. PMID- 22237935 TI - Microparticles as autoantigens: making immune complexes big. PMID- 22237936 TI - Posterior reversible encephalopathy syndrome (PRES) during induction chemotherapy for acute myeloblastic leukemia (AML). PMID- 22237938 TI - Enantioselective synthesis of C-linked spiroacetal-triazoles as privileged natural product-like scaffolds. AB - The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective enzymatic kinetic resolution. PMID- 22237937 TI - Cyclophosphamide-containing regimen (TCD) is superior to melphalan-containing regimen (MPT) in elderly multiple myeloma patients with renal impairment. AB - Renal impairment (RI) is a frequent complication with higher incidence of infections and an important prognostic factor for survival. Melphalan clearance is renal function dependent whereas cyclophosphamide is renal function independent. We investigated which combination regimen should be selected between melphalan-combining regimen (MPT) or cyclophosphamide-combining regimen (TCD) in elderly multiple myeloma (MM) patients with RI. Between 2005 and 2009, 157 newly diagnosed MM patients with RI were included comparing MPT with TCD therapy as initial treatment. Seventy-four patients were given MPT regimen, and 83 patients were given TCD regimen. Baseline characteristics were similar between the MPT and TCD groups. Analysis of different cutoff levels between 25% and 75% quartiles using log-rank test determined that glomerular filtration rate (GFR), 40 ml/min/1.73 m(2) as the cutoff point, yielded the highest difference in event free survival (EFS) and overall survival (OS). The MPT subgroup with low GFR (GFR <40 ml/min/1.73 m(2)) had poorer response rates than others. The incidence of neutropenia and infection with febrile neutropenia were higher in the MPT subgroup with low GFR than the others (p = 0.016, p < 0.001). Furthermore, mortality due to the infection was higher in the MPT subgroup with low GFR than the others (p < 0.001). EFS was lower in the MPT subgroup with low GFR than the others (p < 0.001). OS was lower in the MPT subgroup with low GFR than the others (p < 0.001). In newly diagnosed elderly MM patients with RI, TCD regimen would be an effective and tolerable treatment option due to the combination of cyclophosphamide independent to renal function and dexamethasone effective for RI. PMID- 22237939 TI - Applying the principles of knowledge translation and exchange to inform dissemination of HIV survey results to adolescent participants in South Africa. AB - It is widely accepted that researchers have an obligation to inform survey participants of research results. However, there is little evidence on the effectiveness of various dissemination strategies. The emerging field of knowledge transfer and exchange (KTE) may offer insight given its focus on techniques to enhance the effectiveness of communicating evidence-based information. To date, KTE has focused primarily on information exchange between researchers and policy-makers as opposed to study participants; however, there are principles that may be relevant in this new context. This gap in the literature becomes even more salient in the context of public health research where research results can reveal particular misunderstandings or shortcomings in knowledge that threaten to severely compromise participants' health. The objective of this article is to describe how KTE principles were used to inform dissemination of results of a self-administered sexual health survey to adolescent study participants in a resource-deprived, peri-urban area of South Africa. Strategies for enhancing two-way information exchange included constructing interactive dissemination sessions led by young, isiZulu fieldworkers. We also employed techniques to create a safe space for dialogue, encouraged the shared ownership of results and crafted targeted messages. Particularly noteworthy was the benefit accrued by the research team through this process of exchange, including novel explanations for study findings and new ideas for future research. PMID- 22237941 TI - Holo and apo-transferrins interfere with adherence to abiotic surfaces and with adhesion/invasion to HeLa cells in Staphylococcus spp. AB - Staphylococcus aureus and Staphylococcus epidermidis are the major cause of infections associated with implanted medical devices. Colonization on abiotic and biotic surfaces is often sustained by biofilm forming strains. Human natural defenses can interfere with this virulence factor. We investigated the effect of human apo-transferrin (apo-Tf, the iron-free form of transferrin, Tf) and holo transferrin (holo-Tf, the iron-saturated form) on biofilm formation by CA-MRSA S. aureus USA300 type (ST8-IV) and S. epidermidis (a clinical isolate and ATCC 35984 strain). Furthermore S. aureus adhesion and invasion assays were performed in a eukaryotic cell line. A strong reduction in biofilm formation with both Tfs was obtained albeit at very different concentrations. In particular, the reduction in biofilm formation was higher with apo-Tf rather than obtained with holo-Tf. Furthermore, while S. aureus adhesion to eukaryotic cells was not appreciably affected, their invasion was highly inhibited in the presence of holo-Tf, and partially inhibited by the apo form. Our results suggest that Tfs could be used as antibacterial adjuvant therapy in infection sustained by staphylococci to strongly reduce their virulence related to adhesion and cellular invasion. PMID- 22237940 TI - Production of finely graded forces in humans: effects of simulated weightlessness by water immersion. AB - We have shown before that subjects exposed to a changed gravitoinertial environment produce exaggerated manual forces. From the observed pattern of findings, we argued that initial forces were exaggerated because of abnormal vestibular activity and peak forces because of degraded proprioceptive feedback. If so, only peak but not initial forces should be affected by water immersion, an environment that influences proprioceptive feedback but not vestibular activity. The present study was undertaken to scrutinize this prediction. Twelve subjects sat in a chair once immersed in water and once on dry land, while producing pre trained isometric forces with a joystick. In a control experiment, subjects performed a four-choice reaction-time task. During the joystick task, produced initial forces were comparable in water and on land, while peak (+24%) and end forces (+22%) were significantly higher in water, as was their reaction time (+6%). During the control task, reaction time was comparable in water and on land. Our findings corroborate the above notion that initial forces increase when the vestibular system is stimulated (gravitoinertial change, visual field motion, but not water immersion), while peak forces increase when proprioceptive feedback is degraded (probably all three scenarios) and are not corrected until response end. Our findings further confirm the absence of cognitive slowing in simple choice reaction tasks under shallow-water immersion conditions. PMID- 22237942 TI - Influence of socioeconomic factors on the adherence of alendronate treatment in incident users in Norway. AB - PURPOSE: To examine whether socioeconomic factors influence adherence to alendronate drug treatment among incident users in Norway during 2005-2009. METHODS: The study included 7610 incident alendronate users in 2005 (40-79 years), followed until 31 December 2009. Mean age was 66.6 years, and 86.7% of the patients were women. Data were drawn from the Norwegian Prescription Database and linked to marital status, education and income. Adherence was measured by the medication possession ratio (MPR). MPR was defined as the number of dispensed defined daily doses divided by the number of days each patient was included in the study. A patient was adherent if MPR >= 80%. ORs with 95%CI were estimated using logistic regression. RESULTS: Among all patients, 45.5% was adherent throughout 4.2 years. A slightly higher proportion of women than men were adherent. Adjusted for all covariates, women aged 70-79 years had an OR of 1.27 (95%CI 1.10-1.45) for adherence compared with those 40-59 years. In women, high household income predicted adherence of alendronate use. In men, a middle educational level compared with a low level, predicted adherence (adjusted OR = 1.47 (95%CI 1.10-1.96)). After adjustments, previous marriage reduced the odds of being adherent compared with present marriage, in both men and women. CONCLUSIONS: In women, the most important factors for being adherent were high age and high income. In men, a middle educational level predicted adherence. Previous marriage reduced the odds of being adherent in both women and men. PMID- 22237943 TI - Abeta potentiates inflammatory activation of glial cells induced by scavenger receptor ligands and inflammatory mediators in culture. AB - Alzheimer disease (AD) is a neurodegenerative disorder characterized by the accumulation of beta amyloid (Abeta) aggregates. Abeta induces the inflammatory activation of glia, inducing secretion of Interleukin 1beta (IL1beta), nitric oxide (NO) and superoxide radicals. The specific receptor responsible for the induction of inflammatory activation by Abeta, is still an open question. We propose that scavenger receptors (SR) participate in the activation of glia by Abeta. We assessed production of NO, synthesis of IL1beta and activation of ERK, JNK and NF-kappaB signaling pathways by Western blot, in primary rat glial cultures exposed to SR ligands (fucoidan and Poly I), LPS + IFNgamma (LI), and Abeta. Poly I but not fucoidan nor fibrillar Abeta increased threefold NO production by astrocytes in a time-dependent manner. Fucoidan and Poly I increased 5.5- and 3.5-fold NO production by microglia, and co-stimulation with Abeta increased an additional 60% NO induced by SR ligands. Potentiation by Abeta was observed later for astrocytes than for microglia. In astrocytes, co stimulation with Abeta potentiated ERK and JNK activation in response to Fucoidan and Poly I, whereas it reduced induction of JNK activation by LI and left unaffected NF-kappaB activation induced by LI. Levels of pro-IL1beta in astrocytes increased with Abeta, SR ligands and LI, and were potentiated by co stimulation with Abeta. Our results suggest that SRs play a role on inflammatory activation, inducing production of NO and IL1beta, and show potentiation by Abeta. Potentiation of the inflammatory response of Abeta could be meaningful for the activation of glia observed in AD. PMID- 22237945 TI - A nickel thiolate catalyst for the long-lived photocatalytic production of hydrogen in a noble-metal-free system. PMID- 22237944 TI - Dexamethasone enhances oxidative stress-induced cell death in murine neural stem cells. AB - Glucocorticoids (GCs) are essential for normal brain development; however, there is consistent evidence that prenatal exposure of the fetal brain to excess GCs permanently modifies the phenotype of neuronal cells. In this paper, the murine derived multipotent stem cell line C17.2 was used, as an in vitro model, to investigate the impact of GCs on neural stem cell survival. Our results indicate that dexamethasone (Dex) increases the sensitivity of murine neural stem cells (NSCs) to 2,3-methoxy-1,4-naphthoquinone-induced apoptosis, and this effect could be blocked by the glucocorticoid-receptor (GR) antagonist mifepristone, strongly suggesting the involvement of the GR. Furthermore, our results show that Dex decreases cell number and induces a G1-arrest. We hypothesized that the mitochondria are the main target of Dex. Interestingly, after treatment with Dex, 72% of the investigated genes involved in the mitochondrial respiratory chain are down-regulated, as well as 29% of the genes encoding for antioxidant enzymes. In conclusion, using the C17.2 cell line as a model to study developmental neurotoxicity in vitro, we have shown that GCs can increase cellular sensitivity to oxidative stress and alter the phenotype of NCSs. PMID- 22237947 TI - Cytotoxic activity of new racemic and optically active N-phosphonoalkyl bicyclic beta-amino acids against human malignant cell lines. AB - The cytotoxic effects of novel racemic and optically active constrained N phosphonoalkyl bicyclic beta-amino acids were tested against a panel of human tumor cell lines. All of the compounds investigated exhibited different concentration-dependent antiproliferative effects against the HT-29, MDA-MB-231, HepG2 and HeLa cell lines after 24 h treatment. The most sensitive cells were the HeLa cells at various concentrations of the four compounds tested. The aminophosphonate 3 exerted the most pronounced antiproliferative effect against the HeLa cells (inhibition of the cell vitality up to 70% at 0.5 mg/ml) and was not toxic to the normal Lep3 cells at lower concentration. Furthermore, the N phosphonophenyl derivatives 1 and 2 displayed antiproliferative effect against mainly the MDA-MB-231 tumour cells at higher concentration. PMID- 22237946 TI - Expression of the affinity tags, glutathione-S-transferase and maltose-binding protein, in tobacco chloroplasts. AB - Chloroplast transformation offers an exciting platform for the safe, inexpensive and large-scale production of recombinant proteins in plants. An important advantage for the isolation of proteins produced in the chloroplast would be the use of affinity tags for rapid purification by affinity chromatography. To date, only His-tags have been used. In this study, we have tested the feasibility of expressing two additional affinity tags: glutathione-S-transferase (GST) and a His-tagged derivative of the maltose-binding protein (His6-MBP). By using the chloroplast 16S rRNA promoter and 5' untranslated region of phage T7 gene 10, GST and His6-MBP were expressed in homoplastomic tobacco plants at approximately 7% and 37% of total soluble protein, respectively. GST could be purified by one-step affinity purification using a glutathione column. Much better recoveries were obtained for His6-MBP by using a twin-affinity purification procedure involving first immobilised nickel followed by binding to amylose. Interestingly, expression of GST led to cytoplasmic male sterility. Overall, our work expands the tools available for purifying recombinant proteins from the chloroplast. PMID- 22237948 TI - Characterization and outcomes of optic nerve gliomas: a population-based analysis. AB - Optic nerve gliomas (ONG) are rare astrocytic neoplasms. A paucity of literature exists on the epidemiology and outcomes of ONG. Here, we present a series of 445 cases of ONG obtained from the Surveillance, epidemiology and end results (SEER) database. Data on patient and tumor characteristics as well as initial treatment with surgery or radiation were extracted from the SEER Database. Survival rates were calculated using the Kaplan-Meier method. A multivariate analysis was performed to determine independent prognostic factors predicting mortality hazard ratios (HRs) using Cox proportional hazards modeling. The median age range at diagnosis was 5-9 years. Twenty percent of patients were over the age of 20 years. Amongst patients with information available on tumor grade (n = 131), 83% had a low-grade tumors and 17% had a high-grade tumors. Sixteen percent of patients received radiation therapy and 18.4% of patient underwent a sub- or gross total resection. The 5 year overall survival was 96% and 20% for patients with low- and high-grade tumors, respectively. In a multivariate analysis, grade was the only significant predictor of overall survival (HR 29.3, CI: 4.3, 205.4, P < 0.001). Age at diagnosis, receipt of radiation therapy, and extent of surgical resection were not significantly correlated with overall survival. In conclusion, ONG are rare tumors seen predominantly in children. The overall prognosis of high-grade tumors remains poor in all age groups despite multi modality treatment. PMID- 22237952 TI - Discovery of an entropically-driven small molecule streptavidin binder from nucleic acid-encoded libraries. AB - Dehydrocholic acid was identified as a selective streptavidin binder from a PNA tagged library. Isothermal calorimetry titration measurements showed this interaction to be entropically driven. Peptides tagged with dehydrocholic acid can be captured on a streptavidin resin and released under thermal conditions. PMID- 22237949 TI - Spurious progression in pediatric brain tumors. AB - In this study, we sought to characterize post-therapy MRI changes mimicking progression, which we refer to as "spurious progression" (SP) in children with brain tumors. We analyzed whether SP is associated with particular tumor types or therapeutic modalities. Between 2000 and 2009, we identified 181 consecutive children <21 years of age at our center who were treated for brain tumors and had at least three MRI scans within a year after completing therapy. SP was defined as MRI abnormalities characterized by increase in size, enhancement, edema, or cystic changes within 12 months following therapy, and stabilization or improvement on subsequent imaging. One-hundred forty-one patients with brain tumors were evaluable. Fifty-six (40%) had imaging abnormalities initially suggestive of disease progression; of these, 34 (24%) had true disease progression (TP). The remaining 22 (16%) had SP based on either stability, decrease in enhancement, edema, size, or disappearance of these cystic or non cystic abnormalities. SP occurred in patients with low grade (n = 20) and high grade lesions (n = 2). Median time to SP was 2.4 months (range, 0.7-8.3 months), with time to stability, decrease, or disappearance at a median of 4 months (range 1.4-7.7 months). Five patients were clinically symptomatic from SP and were treated with steroids, cyst drainage, and/or surgery. Therefore, SP occurs more commonly in children with low grade tumors, but can also occur with high grade brain tumors, regardless of therapeutic approach. PMID- 22237953 TI - Immunosuppression induction with rabbit anti-thymocyte globulin with or without rituximab in 1000 liver transplant patients with long-term follow-up. AB - Rabbit anti-thymocyte globulin (rATG)-based immunosuppression induction is being increasingly used in liver transplantation (LT) in conjunction with steroid-free protocols to delay the initiation of calcineurin inhibitors. This study reports a single-center comparison of transplant outcomes and complications in 3 immunosuppression eras. Data were obtained retrospectively from a center research database, and the analysis included LT patients from 2001 to 2008. The immunosuppression consisted of rATG induction in 3 doses (6 mg/kg in all): (1) the first dose was administered perioperatively [the rabbit anti-thymocyte globulin in the operating room (rATG-OR) era]; (2) the first dose was delayed until 48 hours after transplantation [the rabbit anti-thymocyte globulin after a delay (rATG-D) era]; or (3) the first dose was delayed until 48 hours after transplantation, and a single dose of rituximab was added 72 hours after transplantation [the rabbit anti-thymocyte globulin after a delay plus rituximab (rATG-D-Ritux) era]. The initial maintenance immunosuppression was tacrolimus monotherapy, which was started on postoperative day 2. There were 166 patients (16%) in the rATG-OR era, 259 patients (26%) in the rATG-D era, and 588 patients (58%) in the rATG-D-Ritux era (1013 patients in all). Demographically, the latter eras were characterized by higher recipient and donor ages; greater percentages of liver-kidney transplants, hepatocellular carcinoma (HCC), donation after cardiac death (DCD), and imported organs; and shorter graft ischemia times. There were no significant differences between the 3 immunosuppression groups in unadjusted patient survival 3 and 5 years after transplantation (80% and 75% for the rATG-OR era, 75% and 67% for the rATG-D era, and 79% and 71% for the rATG-D Ritux era, P = 0.15). The 5-year survival rates for patients with hepatitis C virus (HCV) and HCC were 65% and 68%, respectively. The factors included in the Cox regression model for patient death included the Model for End-Stage Liver Disease score [hazard ratio (HR) = 1.03, P = 0.001], HCV (HR = 1.28, P = 0.04), donor age (HR = 1.01, P = 0.001), recipient age (HR = 1.01, P = 0.05), and DCD (HR = 1.55, P = 0.11). rATG-based induction immunosuppression can be safely used in adult LT recipients with excellent survival and low rejection rates and without increases in immunosuppression-related side effects. PMID- 22237954 TI - Effects of increasing age, dosage, and duration of PTH treatment on BMD increase- a meta-analysis. AB - We studied the effects of increasing age, dosage, and duration of parathyroid hormone (PTH) treatment on changes in bone mineral density (BMD). Randomized placebo controlled trials on PTH treatment in men or women were retrieved from PubMed (1951 to present), Web of Science (1945 to present), or Embase (1974 to present). The search date was November 16, 2010. All studies comparing PTH treatment to either placebo or antiresorptive drugs--for example, bisphosphonates or hormone replacement therapy--were included. A total of 214 studies were identified in the initial search, and 15 of these trials were included. By metaregression analysis, we found that the increase in spine BMD (Z-score) after PTH treatment was blunted by increasing age (R(2) = 0.27; 2p = 0.01, slope -0.023 Z-scores per year, 11 studies). By increasing PTH dosage (MUg/d), spine BMD increased significantly (2p = 0.002) with a slope of +0.011 Z-scores/MUg/d of teriparatide. Furthermore, the duration of treatment was positively correlated to spine BMD (P < 0.001) with a slope of +0.043 Z-score for each extra month of treatment. We evaluated the BMD effect in hips and found no age dependency (R(2) = 0.04; P = 0.66; 8 studies). However, for the spine, we found a significant relation to daily dosage (P = 0.011), Z-score coefficient 0.0051 +/- 0.0020 (2p < 0.01). The treatment duration also correlated positively by a Z-score coefficient of 0.0170 +/- 0.0053, 2p < 0.01 per extra month of treatment. PTH treatment alone seems to be able to improve BMD significantly. However, the BMD increase was significantly lower with increasing age in the spine. No age dependency was observed in the hips. In general the effect of treatment was improved with increasing dosage and duration of treatment from 6 to 36 months. PMID- 22237955 TI - Photocatalytic reversible amination of alpha-keto acids on a ZnS surface: implications for the prebiotic metabolism. AB - We report the enzyme-like reversible amination of four intermediates pertinent to the reductive tricarboxylic acid cycle on a photo-irradiated surface of mineral sphalerite (ZnS). Given its prevalence in the waters of early Earth, we suggest that the mineral-based photochemistry might have catalyzed the homeostasis of prebiotic metabolic systems. PMID- 22237956 TI - Inhibition of Csn3 expression induces growth arrest and apoptosis of hepatocellular carcinoma cells. AB - PURPOSE: Csn3 (or CSN3) encodes the third subunit of an eight-subunit complex, the COP9 signalosome (CSN), which acts as a protein kinase and a deneddylase in mammalian cells. Previous studies have shown that Csn3 is essential for maintenance of cell proliferation in the mouse embryonic epiblast and associated with the tumorigenesis process in osteosarcoma. However, its correlation with hepatocellular carcinoma (HCC) has not been explored yet. METHODS: The expression of Csn3 in HCC (n = 30), cirrhosis (n = 30), and normal tissues (n = 30) was detected using immunohistochemical analysis. The impacts of lentivirus-mediated inhibition of Csn3 on HCC cells were detected using MTT, BrdU incorporation assay, and flow cytometric analysis. In addition, the colony formation and tumor growth ability in nude mice were detected to define the role of Csn3 in tumorigenesis. RESULTS: Knockdown of Csn3 expression in HCC cell lines (SMMC-7721 and Hep3B) significantly inhibits the tumor growth both in vitro and in vivo. Further investigation indicates that this growth inhibition effect may be mediated through cell cycle arrest in G0/G1 phase and inductions of pro-apoptotic proteins BIK and Caspase-8. In addition, knockdown of Csn3 expression evidently suppresses tumor growth in a xenograft nude mice model. CONCLUSION: Collectively, this study demonstrates Csn3 as an oncogene that regulates the tumorigenesis process in HCC cells. PMID- 22237957 TI - Phase I and pharmacologic study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial. AB - PURPOSE: To evaluate the safety and tolerability of amrubicin (AMR), determine its maximum tolerated dose (MTD), its dose-limiting toxicities (DLTs), and its recommended dose (RD), and to conduct a pharmacokinetic study of weekly AMR administrations in patients with chemotherapy-refractory or recurrent small cell or non-small cell lung cancer. PATIENTS AND METHODS: Patients with refractory or relapsed non-small cell and small cell lung cancer after 1 or 2 regimens of chemotherapy were eligible. AMR was initiated at 45 mg/m(2) weekly (repetition of dose on 1st and 8th day with a rest on day 15). The dose level was increased by 5 mg/m(2) by modified Fibonacci dose escalation scheme. RESULTS: Seven patients had small cell lung cancer and 9 had non-small cell lung cancer. Fifty-four courses (median: 3, range: 1-6) were administered at 5 dose levels. At 65 mg/m(2), 3 patients had DLTs as follows: 1 was grade 3 (CTCAE v3.0) in AST/ALT, 1 was grade 3 febrile neutropenia, and 1 was grade 4 neutropenia. Leukocytopenia and neutropenia were correlated with amrubicinol (AMR-OH) C (max) (P = 0.042, P = 0.047, respectively). The AUC (area under the curve of plasma concentration versus time extrapolated to concentration zero) of AMR and AMR-OH did not depend on the dose levels. CONCLUSION: In the present phase I study of AMR administered weekly to previously treated lung cancer patients, the maximum tolerated dose and RD were 65 and 60 mg/m(2), respectively. The best response rate was 15.4%, and adverse events with this schedule were tolerable. PMID- 22237958 TI - Phase I trial of oral S-1 combined with gemcitabine and cisplatin for advanced biliary tract cancer (KHBO1002). AB - PURPOSE: We aimed to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the addition of S-1, an oral fluorouracil derivative, to gemcitabine and cisplatin combination therapy, which is the current standard treatment for advanced biliary tract cancer. METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were eligible for inclusion. The planned dosages of gemcitabine (mg/m(2))/cisplatin (mg/m(2))/S-1 (mg/m(2)/day) were as follows: level 0, 800/25/60; level 1, 1,000/25/60; and levels 2 and 3, 1,000/25/80. In each cycle, gemcitabine and cisplatin were intravenously administered on day 1 (or days 1 and 8 at level 3), and S-1 was orally administered twice daily on days 1-7 (or days 1 14 at level 3); this was repeated every 14 days (or 21 days at level 3). RESULTS: Seventeen patients were enrolled, and level 1 was chosen as the starting dose. Two of six patients developed DLTs (grade 4 neutropenia and grade 3 febrile neutropenia) at level 1, and the dose was escalated to level 2. DLTs (grade 3 rashes and grade 3 vasovagal reactions) occurred in two of six assessable patients at level 2; we then proceeded to level 3. The first three assessable patients enrolled at level 3 developed DLTs (two cases of grade 4 neutropenia, one of grade 4 leucopenia, two of grade 3 fatigue, one of grade 3 anorexia, and one of grade 3 febrile neutropenia) during their first cycle, and this dose was determined to be the MTD. Therefore, we selected level 2 as the recommended dose (RD) for a subsequent phase II study. CONCLUSIONS: We determined the RD of gemcitabine/cisplatin/S-1 combination therapy for advanced biliary tract cancer; we are proceeding to a phase II study to investigate the efficacy of this combination therapy for advanced biliary tract cancer. PMID- 22237959 TI - Ugt1a is required for the protective effect of selenium against irinotecan induced toxicity. AB - PURPOSE: Irinotecan (CPT-11) is widely used for the treatment of patients with colorectal cancer. However, the adverse effects associated with the treatment have hindered the efficacies of irinotecan. We have shown that organic selenium compounds could significantly attenuate irinotecan-associated toxicity and enhance antitumor activity in xenograft tumor models. The objective of this study is to determine the role of a specific group of uridine diphosphate glucuronosyltransferases, which is coded by UGT1A, in detoxification process of irinotecan as well as selenium-associated protective effect against irinotecan induced toxicity. METHODS: In this study, the toxicities of irinotecan, docetaxel and cisplatin in the Ugta1 mutant rats and their wild-type controls were compared. The plasma concentrations of irinotecan and SN-38 were measured. The modulatory effect of a selenium compound on irinotecan-induced toxicity was analyzed in these rats. RESULTS: We demonstrated that the maximum tolerated doses of irinotecan in the homozygous mutant rats were significantly lower than those in wild-type rats, 25 mg/kg * 1 versus 200 mg/kg * 1 and 3 mg/kg/day * 3 versus 100 mg/kg/day * 3, respectively. The enhanced sensitivity was specific to irinotecan and was not observed with other chemotherapeutic agents, such as docetaxel and cisplatin, where Ugt1a is not required for their metabolism. Our results also showed that selective protection against irinotecan-induced toxicity by 5-methylselenocysteine was achieved in the wild-type rats but not in the Ugt1a null rats. CONCLUSION: These data support the hypothesis that expression of UGT1A is critical for 5-methylselenocysteine to exert its protective effect against irinotecan-induced toxicity. PMID- 22237960 TI - Copper(II)-catalyzed monoarylation of vicinal diols with diaryliodonium salts. PMID- 22237961 TI - Migrant farmworker housing regulation violations in North Carolina. AB - BACKGROUND: The quality of housing provided to migrant farmworkers is often criticized, but few studies have investigated these housing conditions. This analysis examines housing regulation violations experienced by migrant farmworkers in North Carolina, and the associations of camp characteristics with the presence of housing violations. METHODS: Data were collected in183 eastern North Carolina migrant farmworker camps in 2010. Housing regulation violations for the domains of camp, sleeping room, bathroom, kitchen, laundry room, and general housing, as well as total violations were assessed using North Carolina Department of Labor standards. RESULTS: Violations of housing regulations were common, ranging from 4 to 22 per camp. Housing regulation violations were common in all domains; the mean number of camp violations was 1.6, of sleeping room violations was 3.8, of bathroom violations was 4.5, of kitchen violations was 2.3, of laundry room violations was 1.2, and of general housing violations was 3.1. The mean number of total housing violations was 11.4. Several camp characteristics were consistently associated with the number of violations; camps with workers having H-2A visas, with North Carolina Department of Labor Certificates of Inspection posted, and assessed early in the season had fewer violations. CONCLUSIONS: These results argue for regulatory changes to improve the quality of housing provided to migrant farmworkers, including stronger regulations and the more vigorous enforcement of existing regulations. PMID- 22237963 TI - Ultra-low concentration monitoring of catalytic reactions in photonic crystal fiber. PMID- 22237962 TI - Electron-transfer reduction of dinuclear copper peroxo and bis-MU-oxo complexes leading to the catalytic four-electron reduction of dioxygen to water. AB - The four-electron reduction of dioxygen by decamethylferrocene (Fc*) to water is efficiently catalyzed by a binuclear copper(II) complex (1) and a mononuclear copper(II) complex (2) in the presence of trifluoroacetic acid in acetone at 298 K. Fast electron transfer from Fc* to 1 and 2 affords the corresponding Cu(I) complexes, which react at low temperature (193 K) with dioxygen to afford the eta(2):eta(2)-peroxo dicopper(II) (3) and bis-MU-oxo dicopper(III) (4) intermediates, respectively. The rate constants for electron transfer from Fc* and octamethylferrocene (Me(8)Fc) to 1 as well as electron transfer from Fc* and Me(8)Fc to 3 were determined at various temperatures, leading to activation enthalpies and entropies. The activation entropies of electron transfer from Fc* and Me(8)Fc to 1 were determined to be close to zero, as expected for outer sphere electron-transfer reactions without formation of any intermediates. For electron transfer from Fc* and Me(8)Fc to 3, the activation entropies were also found to be close to zero. Such agreement indicates that the eta(2):eta(2)-peroxo complex (3) is directly reduced by Fc* rather than via the conversion to the corresponding bis-MU-oxo complex, followed by the electron-transfer reduction by Fc* leading to the four-electron reduction of dioxygen to water. The bis-MU-oxo species (4) is reduced by Fc* with a much faster rate than the eta(2):eta(2) peroxo complex (3), but this also leads to the four-electron reduction of dioxygen to water. PMID- 22237964 TI - Structural requirements in lithium cobalt oxides for the catalytic oxidation of water. PMID- 22237965 TI - What do cytokine profiles tell us about subsets of juvenile idiopathic arthritis? AB - Classification of juvenile idiopathic arthritis is an ongoing process and up to now has been predominantly based on clinical manifestations--mainly number of joints at onset of disease. In the meantime, basic studies have advanced our knowledge regarding the disease pathogenesis. Unfortunately, studies of cytokines and cytokine polymorphisms have not followed the predominantly clinical International League of Associations for Rheumatology classification in that no significant biological differences among the different disease categories have been demonstrated with robust associations. Only systemic-onset disease seems to be quite different from other disease categories with regard to biologic mechanisms; indeed, it now seems closer to autoinflammatory than to classic autoimmune diseases. New players in the immunologic basis of juvenile idiopathic arthritis (eg, interleukin-17 and regulatory T cells) are also discussed in this review. PMID- 22237966 TI - Fenugreek attenuation of diabetic nephropathy in alloxan-diabetic rats: attenuation of diabetic nephropathy in rats. AB - Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. To prevent the development of this disease and to improve advanced kidney injury, effective therapies directed toward the key molecular target are required. In this paper, the efficacy of fenugreek to restore the kidney function of diabetic rats via its antioxidant and anti-inflammatory activities has been studied. Novel data showing the efficacy of fenugreek to attenuate progression of diabetic nephropathy and production of interleukin-6 (IL-6) in rats compared with a diabetic untreated group were obtained. Rats were classified into five groups; control, diabetic untreated, and three diabetic groups treated with fenugreek, rosiglitazone, and metformin. Treatment with fenugreek has been continued for 12 weeks. Fenugreek was found to significantly reduce the high levels of glucose, urea, creatinine, sodium, potassium, and IL-6 in serum compared with the diabetic untreated group. In addition, levels of malondialdehyde and IL-6 in the kidney homogenate were significantly reduced as a result of the fenugreek treatment compared with the diabetic untreated group. Moreover, concentration of GSH and the activity of both superoxide dismutase and catalase were considerably increased in the diabetic treated groups compared with the diabetic untreated group. Furthermore, glomerular mesangial expansion was reduced in the treated animal groups. These findings suggest a therapeutic potential of fenugreek against diabetic nephropathy, explain its antioxidative/anti-inflammatory properties and provide a direction for future research. PMID- 22237967 TI - Lack of robust LGN label following transneuronal rabies virus injections into macaque area V4. AB - In primates, retinal inputs are relayed through the magno- and parvocells of the lateral geniculate nucleus (LGN) indirectly to extrastriate visual cortex. The most direct pathway identified to the extrastriate cortex is a disynaptic one that provides robust magno- and parvocellular inputs to the middle temporal area (MT). The inclusion of parvocells in this projection is somewhat surprising because of their importance for color and form vision, whereas MT is more strictly tuned to velocity. This raises the question of whether areas more involved in color and form processing, such as V4, receive similar projections. We report here on experiments that use rabies virus injections into V4 to retrogradely label mono- and disynaptic inputs. We find only a small number of labeled neurons in the LGN in a pattern consistent with monosynaptic labeling of koniocells, rather than disynaptic labeling of magno- and parvocells. The lack of robust magno- and parvocellular label was not due to ineffective viral transport because in the same cases we find hundreds of neurons labeled in the thalamic reticular nucleus, a structure that can only be labeled disynaptically from the cortex. We also find a complete absence of neurons labeled in V1, but thousands in adjacent areas V2 and V3. This result helps explain the absence of labeled magno- and parvocells in the LGN because disynaptic transport from an extrastriate visual area should require a relay through V1. Taken together, these results suggest that ascending magno/parvocellular inputs to V4 are more hierarchically organized than the relatively direct inputs to MT. PMID- 22237968 TI - Angiomatoid change in polyps of the nasal and paranasal regions: an underrecognized and commonly misdiagnosed lesion--report of 45 cases. AB - We present 45 patients with angiomatoid polyps of the nasal and paranasal regions (APNPRs), which are underrecognized lesions which may cause considerable diagnostic difficulties. There were 32 men and 13 women in our series. The average age at diagnosis was 49 years in men and 54.3 years in women. Locations were known in 41 cases and included the nasal septum (14), maxillary sinus (12), ethmoid sinuses (5), lateral wall of the nasal cavity (5), sphenoid sinus (1), and nasal cavity, not otherwise specified (4). X-ray or computed tomography was performed in 19 cases and revealed bone erosions/deviations in four cases. Initial misdiagnoses submitted by referring pathologists were reported in 20/32 of the consultation cases. Our study confirms that APNPRs are benign lesions which often recur and sometimes multiple recurrences are seen. APNPRs sometimes cause severe changes of the skeletal bones especially in recurrent lesions. Awareness of the above described features and familiarity with the clinical presentation of APNPRs is the best way to avoid a misdiagnosis. PMID- 22237969 TI - The roles of neutral sphingomyelinases in neurological pathologies. AB - The neutral sphingomyelinases (N-SMases) are a group of Mg2+-dependent enzymes with a pH optimum in the neutral range. N-SMases catalyze the conversion of sphingomyelin to ceramide and have been found particularly enriched in brain tissue. N-SMase activity has been implicated in many physiological and pathological processes affecting the brain and nervous system. In this review, we discuss the proposed functions of N-SMase with a particular emphasis on its role in neurological disorders, such as age-related neurodegeneration, Alzheimer's disease, HIV-associated dementia, atherosclerosis, ischemia-reperfusion injury, and cancer. PMID- 22237971 TI - A case of selective arterial embolization for recurrent hemarthrosis after total knee arthroplasty. PMID- 22237970 TI - Administration of histidine to female rats induces changes in oxidative status in cortex and hippocampus of the offspring. AB - Histidinemia is an inherited metabolic disorder biochemically characterized by high concentrations of histidine in biological fluids. Usually affected patients are asymptomatic although some individuals have mental retardation and speech disorders. Considering the high prevalence of histidinemia and the scarce information on the effects of maternal histidinemia on their progeny, we investigated various parameters of oxidative stress in brain cortex and hippocampus of the offspring from female rats that received histidine (0.5 mg/g of body weight) in the course of pregnancy and lactation. At 21 days of age we found a significant increase of thiobarbituric acid reactive substances (TBARS), 2',7'-dihydrodichlorofluorescein oxidation, superoxide dismutase (SOD) activity, catalase (CAT) activity, total sulfhydryls and glutathione (GSH) content in cerebral cortex and hippocampus. We also verified that at 60 days of age, GSH, SOD and total sulfhydryls returned to normal levels in brain cortex, while the other parameters decreased in the same structure. In the hippocampus, at 60 days of age GSH returned to normal levels, CAT persisted elevated and the other parameters decreased. These results indicate that histidine administration to female rats can induce oxidative stress in the brain from the offspring, which partially recovers 40 days after breastfeeding stopped. PMID- 22237972 TI - What should we do as orthopedic surgeons in catastrophic disasters? PMID- 22237973 TI - Human alpha-enolase is immunogenic, but not arthritogenic, in HLA-DR4-transgenic mice: comment on the article by Kinloch et al. PMID- 22237976 TI - Treatment of varicose veins: does each technique have a formal indication? AB - Nowadays, various surgical and endovenous methods are available to treat varicose veins. Theoretically, every technique is applicable to treat any kind of patient. However, it seems appropriate to consider the specific indications and limitations of each of the techniques. To choose the most appropriate treatment method, several issues have to be taken into account. The patient's reason for consulting and clinical condition will define the aim of the treatment. Anatomical and hemodynamic characterization of the varicose veins by means of duplex ultrasound will define the technical feasibility. Although a definitive algorithm still remains to be developed, some of the most important questions that should be included in a decision tree can already be proposed: Is high ligation necessary or at least justified? Is stripping or ablation necessary or at least justified, and in that case, what is the most appropriate technique to be used? All this should help us define a reasonable "a la carte" treatment for each patient. PMID- 22237975 TI - Extended and sequential delivery of protein from injectable thermoresponsive hydrogels. AB - Thermoresponsive hydrogels are attractive for their injectability and retention in tissue sites where they may serve as a mechanical support and as a scaffold to guide tissue remodeling. Our objective in this report was to develop a thermoresponsive, biodegradable hydrogel system that would be capable of protein release from two distinct reservoirs--one where protein was attached to the hydrogel backbone, and one where protein was loaded into biodegradable microparticles mixed into the network. Thermoresponsive hydrogels consisting of N isopropylacrylamide (NIPAAm), 2-hydroxyethyl methacrylate (HEMA), and biodegradable methacrylate polylactide were synthesized along with modified copolymers incorporating 1 mol % protein-reactive methacryloxy N hydroxysuccinimide (MANHS), hydrophilic acrylic acid (AAc), or both. In vitro bovine serum albumin (BSA) release was studied from hydrogels, poly(lactide-co glycolide) microparticles, or microparticles mixed into the hydrogels. The synthesized copolymers were able to gel below 37 degrees C and release protein in excess of 3 months. The presence of MANHS and AAc in the copolymers was associated with higher loaded protein retention during thermal transition (45% vs. 22%) and faster release (2 months), respectively. Microspheres entrapped in the hydrogel released protein in a delayed fashion relative to microspheres in saline. The combination of a protein-reactive hydrogel mixed with protein-loaded microspheres demonstrated a sequential release of specific BSA populations. Overall the described drug delivery system combines the advantages of injectability, degradability, extended release, and sequential release, which may be useful in tissue engineering applications. PMID- 22237977 TI - The efficiency of pain control using a thigh pad under the elastic stocking in patients following venous stripping: results of a case-control study. AB - BACKGROUND: The use of a specific thigh foam pad placed under compression stockings increases interface pressure. The interface pressure obtained under 2 medical compression stockings of 15 to 20 mm Hg at the ankle, is 14 +/- 2.2 mm Hg in the middle of the thigh in the horizontal position and rises to 49.2 +/- 4.7 mm Hg when an appropriate thigh foam pad is interposed. Thigh compression could be useful in relieving pain after surgery of the great saphenous vein. OBJECTIVE: The aim of this study was to compare pain intensity on day 1 and day 7 and global mean pain during the week after stripping of the great saphenous vein between patients to whom a pad has been added at the thigh level under the compression stocking (case) and patients wearing a compression stocking only (control). METHODS: Case-control study conducted in daily surgical practice by patients having undergone surgical stripping. Main criteria: pain self-evaluation on visual analogue scale from day 1 to day 7 adjusted for analgesic consumption. No pain evaluation was conducted on Day 0 because of the fact that the elastic compression was applied in the operating room on a patient still under anesthesia. Results. A total of 53 patients were included in the study: 36 in the pad group and 17 in the control group. Patients were similar in respect of age, sex ratio, body mass index, professional status, and CEAP (clinical, etiologic, anatomic, and pathophysiologic) classification. On day 1, pain was 40.8 +/- 20.8 in the control group and 27.4 +/- 24.2 in the pad group (P = .05). On day 7, pain was 15.3 +/- 13.4 in the control group and 3.7 +/- 5.5 in the pad group (P < .0001). Global mean pain during the week after stripping surgery was 156.5 +/- 80.6 in the control group and 80.1 +/- 82.01 in the pad group (P < .0001). CONCLUSION: The results of this case-control study show that the addition of a pad at thigh level under the elastic compression stocking significantly reduces pain experienced by patients during the week after stripping surgery by 49%. PMID- 22237978 TI - Predictors of von Willebrand disease in children. AB - BACKGROUND: Bleeding and bruising are common symptoms for which children are referred to a pediatric hematologist. Although bleeding scores have been validated to quantify bleeding risk in adults, there are no similar definitive data in children. The aim was to describe presenting bleeding symptoms in children and evaluate if these bleeding symptoms were predictive of von Willebrand disease (VWD) or low von Willebrand factor (VWF). PROCEDURE: We performed a retrospective chart review of consecutive pediatric patients referred for perceived bleeding symptoms to the coagulation clinic at The Children's Hospital of Pittsburgh of UPMC. All underwent a uniform bleeding symptom inventory and hemostatic testing. Single and multiple variable logistic regression models were created to predict either VWD, low VWF, or nonspecific defective platelet aggregation, using the predictor variables of family bleeding history, mucocutaneous bleeding, cutaneous bleeding, and surgical bleeding, based on The International Society on Thrombosis and Hemostasis (ISTH) bleeding definitions. RESULTS: Of 298 pediatric patients evaluated, 8% had VWD (VWF:RCo and VWF:Ag <= 30 IU/dl) and 34% had low VWF (VWF:RCo and VWF:Ag 30-50 IU/dl). Further, 16% had a nonspecific platelet aggregation disorder, 41% had normal hemostatic testing, and 1% had factor VIII or IX deficiency. In single and multiple variable logistic regression analysis, neither a personal or family bleeding history at presentation, nor the presence of two or more bleeding symptoms were predictive of VWD, low VWF, or nonspecific defective platelet aggregation. CONCLUSIONS: These findings suggest that qualitative assessment of bleeding symptoms alone is not useful in children. PMID- 22237979 TI - Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts. AB - The main biological active substance secreted by the pineal gland, melatonin (MLT), counteracts the effects of estrogens in breast cancer via exerting a number of its own oncostatic properties. Recent studies of postmenopausal women have identified that the major metabolite of MLT is statistically significantly associated with a lower risk of developing breast cancer. While MLT production decreases with age, breast cancer risk, however, increases with age and obesity. We hypothesize that MLT inhibits estrogen production in breast adipose fibroblasts (BAFs), the main local source of estrogen in breast tumors of postmenopausal women, by inhibiting transcription of the CYP19A1 gene that encodes the key enzyme aromatase. Normal BAFs were cultured from women undergoing breast reduction surgery, while breast cancer-associated fibroblasts (CAFs) were isolated from three women with estrogen receptor (ER) positive invasive ductal carcinomas. MTNR1A and MTNR1B receptor expression and CYP19A1 mRNA expression following MLT treatments were determined by qRT-PCR. BAFs express the G-protein coupled MLT receptors MTNR1A and MTNR1B with elevated levels of MTNR1A found in CAFs. Treatment of BAFs and CAFs with MLT resulted in significant suppression of CYP19A1 transcription and aromatase activity at pharmacological, physiological and sub-physiological concentrations. MLT suppression occurred through promoter specific PI.4-, PI.3- and PII-derived CYP19A1 mRNA. Stimulation of CYP19A1 PII mRNA and aromatase activity by prostaglandin E(2) (PGE(2)) were significantly attenuated by physiological doses of MLT. Lower levels of MLT in aging women may increase the risk of progressing ER-positive breast cancer through a decreased ability to suppress CYP19A1 expression and subsequent local estrogen production in BAFs/CAFs. PMID- 22237980 TI - Risk perception, prevention and diagnostic tests. AB - The objective of this paper is to study the impact of risk perception and diagnostic information on medical prevention decisions. The intertemporal preferences of individuals are represented by a model of recursive rank dependent utility, which has the advantage of allowing risk perceptions to vary over time and with health status. The main results of the paper are the following. Concerning the impact of risk perception on prevention, two types of pessimists have to be distinguished: the moderate pessimists and the fatalists. Both types overestimate the probability of disease, but the fatalists underestimate the reduction of the disease probability by prevention. Risk perception modification after the occurrence of the disease influences prevention decisions. Indeed, we show that moderate pessimists often choose a high level of primary and tertiary prevention, but a moderate pessimist who becomes fatalist after the occurrence of the disease may choose a high level of primary prevention and a low level of tertiary prevention. PMID- 22237981 TI - Reversible piezochromic behavior of two new cationic iridium(III) complexes. AB - We demonstrate that two new cationic Ir(III) complexes exhibit an interesting piezochromism, and their emission color can be smartly switched by grinding and heating. This is the first example that the Ir(III) complexes display piezochromic phosphorescence. PMID- 22237982 TI - Phylogenetic analysis of Cronobacter isolates based on the rpoA and 16S rRNA genes. AB - The reclassification of the genus Cronobacter (previously known as Enterobacter sakazakii) was based on a polyphasic analysis that led to the description of five species. These bacteria are opportunistic pathogens that can cause neonatal meningitis and other infections in immuno-compromised individuals. Cronobacter species have been reported to show differences in sensitivity to antibiotics, heat and chemicals, as well as differences in virulence. The objective of this study was to classify Cronobacter isolates from infant formula milk, the food processing environment and fresh produce in South Africa and to evaluate the phylogenetic placement of these isolates based on the rpoA and 16S ribosomal RNA (rRNA) gene sequences. All the South African strains were identified as Cronobacter sakazakii despite the wide variety of isolation sources. No relation between the phylogenetic placement and strain origin could be determined. Strains of C. sakazakii, Cronobacter dublinensis, Cronobacter turicensis and Cronobacter muytjensii could be differentiated from each other, but it was not possible to differentiate between C. sakazakii and Cronobacter malonaticus based on the rpoA and 16S rRNA gene sequences alone. However, sequence data of these two genes can be used to differentiate between C. sakazakii and C. malonaticus when used in combination with biochemical analysis based on the utilisation of malonate. PMID- 22237983 TI - The construction of a new integrative vector with a new selective marker of copper resistance for glycerol producer Candida glycerinogenes. AB - Candida glycerinogenes WL2002-5 has been used for industrial-scale fermentation of glycerol and may be a promising genetic host due to its tolerance to high osmotic pressure and fast growth. It resists many kinds of drugs, such as G418/hygromycin/cycloheximide. In previous studies, only Zeocin was used as a drug-resistant marker. But Zeocin is so expensive that it largely limits the genetic and molecular study. Here, we constructed a eukaryotic integrative vector pGAPZU, based on pGAPZB, to gain a new selectable marker of copper resistance for this strain. The results showed that the CUP1 gene of Saccharomyces cerevisiae elevated copper resistance of C. glycerinogenes. The C. glycerinogenes transformed with recombinant vector pGUC, obtained from introducing CUP1 gene into plasmid pGAPZU, could resist 21 mM copper, while the minimum inhibitory concentration (MIC) of wild type was 18 mM in solid YEPD medium. With copper resistance as a selective marker, research cost was largely reduced from 114.0 $/L with Zeocin as selective marker to 0.1 $/L. The new expression vector pGUC and selective marker of copper resistance gene establish a good foundation for further study on this industrial strain. PMID- 22237984 TI - Determinants of sickness absence duration after an occupational back injury in the Belgian population. AB - BACKGROUND: This study aimed at assessing factors associated to the duration of sickness absence after a back injury in the Belgian working population, with a special emphasis on cultural factors. METHODS: The data were retrieved from the Belgian Fund for Work Accidents database over a 3-year period (2001-2003). The population source involved all Belgian workers under a job contract in the private sector registered as compensated cases for an accident that occurred at the workplace (n = 558,276). From that database, all back injury cases involving a complete data set and registered during the first 6 months of each year (n = 11,262) were selected and eight factors (gender, age, seniority in the current job, job category, accident regional location, enterprise size, sector of activity, and accident circumstances) were analyzed in relation to the outcome variable, sick leave duration recorded as ordered time intervals between 0 and 183-366 days. RESULTS: Sick leave duration was strongly associated in a multivariate model to age (>=40 years: OR = 2.18), blue-collar job (1.55), work in building industry (1.32), and enterprise size (>100: 0.85), and to a less extent to seniority (>10y: 0.88), and circumstance of accident (falls: 1.26). Injuries occurring in the French-speaking part of the country were associated to a longer sick leave (1.07; P = 0.034). CONCLUSIONS: This study shows that besides well-known risk factors, subtle cultural language-linked factors and/or regional differences in economic climate may significantly influence the length of disability period after a back injury. PMID- 22237985 TI - Common genetic variants in prostate cancer risk prediction--results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). AB - BACKGROUND: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age. METHODS: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data. RESULTS: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile). CONCLUSIONS: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening. IMPACT: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. PMID- 22237986 TI - Genetic susceptibility to type 2 diabetes and breast cancer risk in women of European and African ancestry. AB - BACKGROUND: Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight. METHODS: We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies. RESULTS: We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk. CONCLUSION: The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist. IMPACT: The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk. PMID- 22237987 TI - Underreporting of myeloid malignancies by United States cancer registries. AB - BACKGROUND: The recent decrease in myeloid leukemia incidence may be directly attributed to changes in the population-based cancer registries 2001 guidelines, which required the capture of only one malignancy in the myeloid lineage per person and the simultaneous adoption of myelodysplastic syndrome registration in the United States. METHODS: We constructed four claims-based algorithms to assess myeloid leukemia incidence, applied the algorithms to the 1999-2008 Surveillance Epidemiology and End Results (SEER)-Medicare database, and assessed algorithm validity using SEER-registered cases. RESULTS: Each had moderate sensitivities (75%-94%) and high specificities (>99.0%), with the 2+BCBM algorithm showing the highest specificity. On the basis of the 2+BCBM algorithm, SEER registered only 50% of the acute myelogenous leukemia cases and a third of the chronic myelogenous leukemia (CML) cases. The annual incidence of myeloid leukemia in 2005 was 26 per 100,000 persons 66 years or older, much higher than the 15 per 100,000 reported by SEER using the same sample. CONCLUSION: Our findings suggest underreporting of myeloid leukemias in SEER by a magnitude of 50% to 70% as well as validate and support the use of the 2+BCBM claims algorithm in identifying myeloid leukemia cases. Use of this algorithm identified a high number of uncaptured myeloid leukemia cases, particularly CML cases. IMPACT: Our results call for the commitment of more resources for centralized cancer registries so that they may improve myeloid leukemia case ascertainment, which would empower policy makers with ability to properly allocate limited health care resources. PMID- 22237988 TI - Tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's associated esophageal adenocarcinoma. AB - BACKGROUND: Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC). METHODS: Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum. RESULTS: Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03-3.77 nmol/L), but not in patients with acid reflux and/or BE. CONCLUSIONS: Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483). IMPACT: Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation. PMID- 22237989 TI - Combined oxypalladation/C-H functionalization: palladium(II)-catalyzed intramolecular oxidative oxyarylation of hydroxyalkenes. PMID- 22237990 TI - Effect of seating forces on cement-ceramic adhesion in microtensile bond tests. AB - OBJECTIVES: The aim of this study was to evaluate the effect of different seating forces during cementation in cement-ceramic microtensile bond strength (MUTBS). MATERIALS AND METHODS: Forty-five blocks (5 * 5 * 4 mm(3)) of a glass-infiltrated alumina-based ceramic (In-Ceram Alumina) were fabricated according to the manufacturer's instructions and duplicated in resin composite. Ceramic surfaces were polished, cleaned for 10 min in an ultrasonic bath, silica coated using a laboratory type of air abrasion device, and silanized. Each treated ceramic block was then randomly assigned to five groups (n = 9) and cemented to a composite block under five seating forces (10 g, 50 g, 100 g, 500 g, and 750 g) using a dual-cured resin cement (Panavia F). The ceramic-cement-composite assemblies were cut under coolant water to obtain bar specimens (1 mm * 0.8 mm(2)). The MUTBS tests were performed in a universal testing machine (1 mm/min). The mean bond strengths values were statistically analyzed using one-way ANOVA (alpha <= 0.05). RESULTS: Different seating forces resulted in no significant difference in the MUTBS results ranging between 13.1 +/- 4.7 and 18.8 +/- 2.1 MPa (p = 0.13) and no significant differences among cement thickness. CONCLUSIONS: Excessive seating forces during cementation seem not to affect the MUTBS results. CLINICAL RELEVANCE: Excessive forces during the seating of single all-ceramic restorations cementation seem to display the same tensile bond strength to the resin cement. PMID- 22237991 TI - The impact of a recent relapse on patient-reported outcomes in subjects with multiple sclerosis. AB - PURPOSE: In this study, we estimate the impact of a recent relapse on physical and mental health in subjects with relapsing-remitting multiple sclerosis (RRMS) using validated patient-reported outcome (PRO) measures. METHODS: Subjects enrolled in the Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital with RRMS were eligible for enrollment. Subjects with a clinical visit within 45 days of a relapse were identified and divided into groups based on whether the relapse occurred before (recent relapse) (n = 59) or after the visit (pre-relapse) (n = 31). A group of subjects with no relapses was also identified (remission) (n = 336). PRO measures in these three groups were compared. All outcomes were compared using a t test and linear regression controlling for age, disease duration, sex, and EDSS. RESULTS: Subjects with a recent relapse had significantly worse functioning on several physical and mental health scales compared to subjects in remission even after adjusting for potential confounders. Subjects with a recent relapse also showed significant deterioration on PRO measures over 1 year compared to subjects in remission (P < 0.05 for each comparison). Subjects in the pre-relapse group were not significantly different than subjects in remission. CONCLUSIONS: Clinical relapses have a measurable effect on PRO in subjects with RRMS. PMID- 22237993 TI - Increased expression of HMGB1 is associated with poor prognosis in human bladder cancer. AB - BACKGROUND AND OBJECTIVE: High-mobility group box 1 (HMGB1) is a versatile protein with intranuclear and extracellular functions that is involved in numerous biological and pathological processes, such as transcription, DNA repair, and response to infection and inflammation. HMGB1 overexpression has been reported in a variety of human cancers. However, the clinical significance of HMGB1 expression in bladder cancer (BC) remains unclear. This study is aimed to investigate the correlations between HMGB1 expression and prognosis in patients with BC. METHODS: HMGB1 protein expression in 164 primary BC tissue specimens was analyzed by immunohistochemistry, and its association with clinicopathologic factors and prognosis was also analyzed. RESULTS: HMGB1 protein had high expression in 87 of 164 cases of BC (53%). HMGB1 overexpression was significantly associated with tumor grade (P < 0.001), and stage (P = 0.001). The Kaplan-Meier survival analysis demonstrated that HMGB1 expression was significantly associated with shorter disease-free survival and overall survival (both P < 0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with BC. CONCLUSIONS: HMGB1 might be a new molecular marker to predict the prognosis of patients with BC. PMID- 22237992 TI - Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. AB - OBJECTIVE: To estimate the prevalence, types, and sociodemographic and biobehavioral correlates of antinuclear antibodies (ANAs) in the US. METHODS: We conducted a cross-sectional analysis of 4,754 individuals from the National Health and Nutrition Examination Survey 1999-2004. ANAs were assessed by indirect immunofluorescence. In ANA-positive individuals, cellular staining patterns were determined, and specific autoantibody reactivities were assessed by immunoprecipitation. RESULTS: The ANA prevalence in the US population of individuals ages 12 years and older was 13.8% (95% confidence interval [95% CI] 12.2-15.5%). ANA prevalence increased with age (P=0.01), and ANAs were more prevalent among females than males (17.8% versus 9.6%; P<0.001), with the female to-male ratio peaking at 40-49 years of age. ANA prevalence was modestly higher in African Americans compared with whites (age-adjusted prevalence odds ratio [POR] 1.30, 95% CI 1.00-1.70). Remarkably, ANAs were less common in overweight and obese individuals (age-adjusted POR 0.74) than in persons of normal weight. No significant associations of ANA with education, family income, alcohol use, smoking history, serum levels of cotinine, or C-reactive protein were observed. In ANA-positive individuals, nuclear patterns were seen in 84.6%, cytoplasmic patterns were seen in 21.8%, and nucleolar patterns were seen in 6.1%; the most common specific autoantibodies were anti-Ro (3.9%) and anti-Su (2.4%). CONCLUSION: These findings suggest that more than 32 million persons in the US have ANAs, and that the prevalence is higher among females, older individuals, African Americans, and those with a normal body weight. These data will serve as a useful baseline for future investigations of predictors and changes in ANA prevalence over time. PMID- 22237994 TI - Healthy eating index in southern Brazilian older adults and its association with socioeconomic, behavioral and health characteristics. AB - OBJECTIVE: The objective of this study was to assess factors associated with the diet quality of brazilian older adults. DESIGN: Cross-sectional study. SETTING: City of Carlos Barbosa, Brazil. PARTICIPANTS: 228 participants aged 60 and older. MEASUREMENTS: A questionnaire with questions on socioeconomic and behavioral variables and health characteristics was used. The body mass index was calculated and the waist circumference was measured to provide information in respect to abdominal fat accumulation. Dietary data were collected via 24-hour recall and the diet quality was assessed using the Healthy Eating Index, an instrument that attributes scores to the diet according to the adequacy of intake of the main food and nutrient groups. Participants were divided into three categories, according to the Healthy Eating Index scores: under 51--poor diet; between 51 and 80--diet that needs improvement; over 80--good diet. The evaluation employed the analysis of variance, t test and non-conditional logistic regression to assess the association between the Healthy Eating Index and the other variables. RESULTS: Most participants (80.9%) presented diet that needs improvement and the marital status showed an independent association with the Healthy Eating Index- married individuals showed higher odds of presenting good diet. CONCLUSION: The results of this study suggest that, in general, the diet quality of this group needs improvement and that the marital status is a factor that can be considered for the development of activities to promote health and healthy food intake habits. PMID- 22237995 TI - Genome-wide linkage scan for quantitative trait loci underlying normal variation in heel bone ultrasound measures. AB - Quantitative ultrasound (QUS) traits are correlated with bone mineral density (BMD), but predict risk for future fracture independent of BMD. Only a few studies, however, have sought to identify specific genes influencing calcaneal QUS measures. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing normal variation in QUS traits. QUS measures were collected from a total of 719 individuals (336 males and 383 females) from the Fels Longitudinal Study who have been genotyped and have at least one set of QUS measurements. Participants ranged in age from 18.0 to 96.6 years and were distributed across 110 nuclear and extended families. Using the Sahara (r) bone sonometer, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI) were collected from the right heel. Variance components based linkage analysis was performed on the three traits using 400 polymorphic short tandem repeat (STR) markers spaced approximately 10 cM apart across the autosomes to identify QTL influencing the QUS traits. Age, sex, and other significant covariates were simultaneously adjusted. Heritability estimates (h2) for the QUS traits ranged from 0.42 to 0.57. Significant evidence for a QTL influencing BUA was found on chromosome 11p15 near marker D11S902 (LOD = 3.11). Our results provide additional evidence for a QTL on chromosome 11p that harbors a potential candidate gene(s) related to BUA and bone metabolism. PMID- 22237996 TI - Overweight and obesity as markers for the evaluation of disease risk in older adults. AB - OBJECTIVES: To explore disease risk through the measurement of BMI scores and waist circumferences in older Mexican adults with favorable health statuses and to determine how this risk is associated with sociodemographic characteristics. METHODS: Using data from the National Health and Nutrition Survey of 2006, we created a cross-sectional design and selected 878 participants (60 years or older) who had favorable health statuses. The demographic data, health status, body mass index (BMI), waist circumference (WC), and an estimation of disease risk (arterial hypertension, diabetes type 2, and metabolic syndrome) were obtained through the survey. RESULTS: The prevalence of overweight, obesity, and abdominal obesity were 42.1%, 29.7%, and 80.9%, respectively. Disease risks, which were classified as least, increased, high, or very high, were 14.7%, 17.5%, 38.7%, and 29.1%, respectively. We observed that younger age has a higher risk for disease and that this decreases as age increases until it becomes minimal. After controlling for some risk factors such as tobacco, alcohol, and physical activity, we observed that being female, younger, and married are all factors significantly associated with a high and very high risk for disease. On the other hand, being indigenous, having a low education level, living in a rural setting are all protective factors with a minimum disease risk. CONCLUSIONS: The prevalence rates of overweight, obesity, and abdominal obesity are high among older Mexican adults. We observed that as age increases, disease risk decreases, which also occurs with some lifestyle factors such as living in a rural setting, being indigenous, having a low education level, and being married. PMID- 22237997 TI - Antioxidant biomarkers and food intake in elderly women. AB - OBJECTIVE: To investigate the relationship between antioxidant biomarkers and food intake in elderly women. DESIGN: Cross-sectional study. SETTING: Recreation Center for the Elderly in the city of Itajai, Santa Catarina, Brazil. PARTICIPANTS: 73 elderly women with an average age of 71 years, 93% caucasian, average body weight 68.7 +/- 13.1 kg and average BMI 28.5 +/- 2.3 kg/m2. MEASUREMENTS: Nutritional status was assessed based on the Body Mass Index (BMI). Data on food intake were obtained by applying the 24h diet recall method in three non-consecutive days, including Sunday. The assessment of antioxidant biomarkers was performed based on tests for total plasma thiols and phenolic compounds. The linear regression analysis was used to assess the effect of the consumption of food groups on antioxidant biomarkers. RESULTS: A positive association was found between thiols and intake of carotenoid-rich vegetables (p=0.03), oils, fats and oilseeds (p=0.03); a negative association was observed between total concentrations of phenolic compounds and intake of cereals (p=0.04). CONCLUSION: The intake of foods from the carotenoid-rich vegetables, oils, fats and oilseeds food groups increased the levels of plasma thiols, and the intake of foods from the group of cereals decreased the plasma concentration of phenols. Studies should be conducted to investigate the association between the intake of antioxidant-rich foods and the plasma antioxidant profile, as a way to protect against the aging process. PMID- 22237998 TI - Comparing measures of fat-free mass in overweight older adults using three different bioelectrical impedance devices and three prediction equations. AB - OBJECTIVES: To compare measures of fat-free mass (FFM) by three different bioelectrical impedance analysis (BIA) devices and to assess the agreement between three different equations validated in older adult and/or overweight populations. DESIGN: Cross-sectional study. SETTING: Orthopaedics ward of Brisbane public hospital, Australia. PARTICIPANTS: Twenty-two overweight, older Australians (72 yr +/- 6.4, BMI 34 kg/m2 +/- 5.5) with knee osteoarthritis. MEASUREMENTS: Body composition was measured using three BIA devices: Tanita 300 GS (foot-to-foot), Impedimed DF50 (hand-to-foot) and Impedimed SFB7 (bioelectrical impedance spectroscopy (BIS)). Three equations for predicting FFM were selected based on their ability to be applied to an older adult and/ or overweight population. Impedance values were extracted from the hand-to-foot BIA device and included in the equations to estimate FFM. RESULTS: The mean FFM measured by BIS (57.6 kg +/- 9.1) differed significantly from those measured by foot-to-foot (54.6 kg +/- 8.7) and hand-to-foot BIA (53.2 kg +/- 10.5) (P < 0.001). The mean +/- SD FFM predicted by three equations using raw data from hand to-foot BIA were 54.7 kg +/- 8.9, 54.7 kg +/- 7.9 and 52.9 kg +/- 11.05 respectively. These results did not differ from the FFM predicted by the hand-to foot device (F = 2.66, P = 0.118). CONCLUSIONS: Our results suggest that foot-to foot and hand-to-foot BIA may be used interchangeably in overweight older adults at the group level but due to the large limits of agreement may lead to unacceptable error in individuals. There was no difference between the three prediction equations however these results should be confirmed within a larger sample and against a reference standard. PMID- 22237999 TI - Tea and cognitive health in late life: current evidence and future directions. AB - This review summarizes the literature on the association between tea consumption and cognitive health in late life. Population-based studies reviewed in this article suggest that tea drinking has beneficial effects on cognitive function of elderly persons. However, a cause-effect relationship between tea consumption and cognitive decline and dementia could not be drawn given inconsistent findings from only two longitudinal cohort studies. The neuroprotective effects of tea consumption could be due to catechins, L-theanine and other compounds in tea leaves. More longitudinal observational study is needed. Information on life-time tea consumption and blood concentrations of catechins and L-theanine could be collected in future studies. PMID- 22238000 TI - Water homeostasis, frailty and cognitive function in the nursing home. AB - OBJECTIVE: - To develop and test a practical clinical method to assess frailty in nursing homes; - To investigate the relationship between cognitive status of the elderly and the balance between water compartments of their body composition. DESIGN AND SUBJECTS: Cross-sectional study, conducted at two nursing homes in Boston-MA. METHODS: Body mass and height (Ht) were evaluated to calculate BMI (body mass index, in Kg/m2). The cognitive decline was evaluated based on the scores obtained from the Mini-Mental State Examination (MMSE); The extracellular to total body water ratio (ECW/TBW) was calculated after the analysis of TBW from deuterium and tritium dilution and ECW from bromide dilution. Single-frequency BIA analysis data were investigated for resistance (R) and reactance (Xc), plotted in an R/Ht Xc/Ht graph (vectorial analysis-BIVA). The BIVA results of nursing home residents were compared against the data obtained from the NHANES III study. TBW and ECW values were compared with a group of free-living elderly volunteers. RESULTS: The ECW/TBW was significantly higher in nursing home residents than in the free-living individuals. BIVA analysis showed significantly higher Xc/Ht values in the reference subjects. The MMSE did not present a significant correlation with ECW/TBW for either gender. CONCLUSION: We proposed the ECW/TBW ratio and BIVA as surrogate methods for the clinical assessment of frailty. We tested successfully both approaches with nursing home patients and free-living volunteers and compared them to a national data base. The advent of new, portable instruments will enable field tests to further validate our proposed "Frailty Factor" in future studies. We found no correlation between frailty and cognitive decline in the nursing home. PMID- 22238002 TI - Frailty criteria and cognitive performance are related: data from the FIBRA study in Ermelino Matarazzo, Sao Paulo, Brazil. AB - OBJECTIVES: To assess the relationship between the CHS frailty criteria (Fried et al., 2001) and cognitive performance. DESIGN: Cross sectional and population based. SETTING: Ermelino Matarazzo, a poor sub district of the city of Sao Paulo, Brazil. PARTICIPANTS: 384 community dwelling older adults, 65 and older. MEASUREMENTS: Assessment of the CHS frailty criteria, the Brief Cognitive Screening Battery (memorization of 10 black and white pictures, verbal fluency animal category, and the Clock Drawing Test) and the Mini-Mental State Examination (MMSE). RESULTS: Frail older adults performed significantly lower than non-frail and pre frail elderly in most cognitive variables. Grip strength and age were associated to MMSE performance, age was associated to delayed memory recall, gait speed was associated to verbal fluency and CDT performance, and education was associated to CDT performance. CONCLUSION: Being frail may be associated with cognitive decline, thus, gerontological assessments and interventions should consider that these forms of vulnerability may occur simultaneously. PMID- 22238003 TI - Physical function predicts improvement in quality of life in elderly Icelanders after 12 weeks of resistance exercise. AB - BACKGROUND: Little is known about the effects of resistance training on health related quality of life (HRQL) in the elderly. AIM: The main purpose of the study was to investigate the effects of resistance training on strength, body composition, functional capacity and HRQL in independent living elderly people. We hypothesised that resistance training would improve lean mass, muscle strength, physical function and HRQL. METHODS: Subjects (N = 237, 73.7+/-5.7 yrs, 58.2% female) participated in a 12-week resistance exercise program (3 times/week; 3 sets, 6-8 repetitions at 75-80% of the 1-repetition maximum) designed to increase strength and muscle mass of major muscle groups. Body composition, quadriceps- and grip strength, timed up and go test (TUG), six minute walk for distance (6MW) and HRQL were measured at baseline and endpoint. RESULTS: Two hundred-and-four participants completed the study. Although the increase in lean mass was small (+0.8 kg, P<0.01), quadriceps strength (+53.5 N), grip strength (+3.0 lb), TUG (-0.6 sec), 6MW (+33.6 m) and HRQL (+1.2 t-score) improved significantly (all P<0.01). Changes in 6MW predicted improvement in HRQL after 12 weeks. CONCLUSIONS: Our study shows that a 12-week resistance exercise program significantly improves lean mass, muscle strength, physical function and HRQL in elderly individuals, and that improvements in physical function predict improvements in HRQL. Our study indicates that resistance training should be promoted for the elderly as it has the potential to improve physical performance, thereby prolonging healthy, independent aging. PMID- 22238001 TI - The hormonal pathway to cognitive impairment in older men. AB - In older men there is a multiple hormonal dysregulation with a relative prevalence of catabolic hormones such as thyroid hormones and cortisol and a decline in anabolic hormones such as dehydroepiandrosterone sulphate, testosterone and insulin like growth factor 1 levels. Many studies suggest that this catabolic milieu is an important predictor of frailty and mortality in older persons. There is a close relationship between frailty and cognitive impairment with studies suggesting that development of frailty is consequence of cognitive impairment and others pointing out that physical frailty is a determinant of cognitive decline. Decline in cognitive function, typically memory, is a major symptom of dementia. The "preclinical phase" of cognitive impairment occurs many years before the onset of dementia. The identification of relevant modifiable factors, including the hormonal dysregulation, may lead to therapeutic strategies for preventing the cognitive dysfunction. There are several mechanisms by which anabolic hormones play a role in neuroprotection and neuromodulation. These hormones facilitate recovery after brain injury and attenuate the neuronal loss. In contrast, elevated thyroid hormones may increase oxidative stress and apoptosis, leading to neuronal damage or death. In this mini review we will address the relationship between low levels of anabolic hormones, changes in thyroid hormones and cognitive function in older men. Then, giving the contradictory data of the literature and the multi-factorial origin of dementia, we will introduce the hypothesis of multiple hormonal derangement as a better determinant of cognitive decline in older men. PMID- 22238004 TI - How to assess functional status: a new muscle quality index. AB - Aging is associated with decreases in muscle mass, muscle strength and muscle power, with muscle strength declining at a higher rate than muscle mass, but at a lower rate than muscle power. This progressive mismatch suggests a deterioration of muscle "quality" that may lead to functional incapacities. Although it may be difficult to synthesize the concept of muscle quality, the aim of the present paper was to propose a clinical definition of muscle quality in regard to the functional status. Accordingly, the muscle strength or muscle power per unit of muscle mass ratios appear to be clinically relevant markers of muscle quality. Several mechanisms susceptible to influence these ratios have been described, among which age, gender, sex hormones, obesity, physical activity and fibrosis. Various methods to assess muscle quality in both the clinical and research fields have also been listed, with a particular interest for the tests used to measure muscle power. Finally, we proposed a clinical screening tool to detect individuals at risk of functional incapacities. Briefly, the muscle quality score is based on handgrip strength assessment by hand dynamometer, muscle mass measurement by bioelectrical analysis, and leg muscle power estimation using a chair stand test. PMID- 22238005 TI - Effects of anorexia on mortality among older adults receiving home care: an observation study. AB - PURPOSE: We describe the prevalence of secondary anorexia in a population of older people living in community and receiving home care. In addition, we examined the relationship between secondary anorexia and mortality. METHODS: We analyzed data from a large collaborative observational study group, the Italian Silver Network Home Care project, that collected data on patients admitted to home care programs. A total of twelve Home Health Agencies participated in such project evaluating the implementation of the Minimum Data Set for Home Care (MDS HC) instrument. A total of 2757 patients were enrolled in the present study. The main outcome measures were the prevalence of anorexia, weight loss and survival. RESULTS: More than 25% (744 subjects) of the study sample suffered from anorexia. During a mean follow-up of 10 months from initial MDS-HC assessment, 468 patients (17%) died. There was uneven distribution of the risk. After adjusting for age, gender and for all other possible risk factors for death (living alone, physical and cognitive disability, behavior problems, urinary incontinence, pressure ulcer, hearing impairment, congestive heart failure, hypertension, depression, diabetes, renal failure, cancer), subjects with anorexia were more likely to die relative to patients without anorexia (RR, 1.83; 95% CI 1.45-2.31). Even though the risk of mortality was higher among subjects suffering from anorexia and weight loss, the anorexia per se was associated with higher risk compared with subjects without anorexia (RR, 1.45; 95% CI 1.01-2.19). CONCLUSIONS: Anorexia is associated with a significant higher risk of all-cause mortality. The present findings support the possibility that anorexia has an independent effect on survival even among old people receiving home care. PMID- 22238006 TI - Adverse systemic arterial function in patients with selenium deficiency. AB - BACKGROUND: Experimental studies have shown that selenium is involved in the synthesis of selenoproteins which might contribute to cardiovascular protection. However, the relationship between selenium deficiency and vascular function in clinical context remains unknown. OBJECTIVE: To investigate for any relationship between selenium deficiency and systemic arterial function in patients with high risk of vascular events. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: 306 consecutive patients with high risk for cardiovascular events (coronary artery disease 35%, acute/ recurrent ischemic stroke 40%, diabetes mellitus 54%) followed up at internal medicine outpatient clinics. MEASUREMENTS: Non-invasive brachial-ankle pulse wave velocity (PWV) was determined using vascular profiling system (VP-2000). Long-term intake of selenium was determined by a validated food frequency questionnaire. RESULTS: Mean daily selenium intake was 59.5 +/- 52.1 mcg/day, and mean PWV was 1782.4 +/- 418.4 cm/s. Patients with selenium intake <10th percentile had significantly higher PWV as compared to patients with intake >= 10th percentile (1968.2 +/- 648.9 cm/s versus 1762.2 +/- 381.6 cm/s, P=0.010). After adjusting for potential confounders including age, gender, history of hypertension, hyperlipidemia, diabetes and cardiovascular disease, smoking status, use of cardiovascular medications, waist-hip ratio, education/ financial status, physical activity, calorie intake and intake of antioxidant vitamins, deficient selenium intake <10th percentile remained independently predictive of increased PWV by +363.4 cm/s [95% CI: 68.1 to 658.6, P=0.016, relative increase 21%]. CONCLUSIONS: Selenium deficiency is associated with adverse arterial function in patients with high risk for vascular events. PMID- 22238007 TI - A systematic review of the literature concerning the relationship between obesity and mortality in the elderly. AB - INTRODUCTION: Obesity is a risk factor for chronic diseases and premature mortality, but the extent of these associations among the elderly is under debate. The aim of this systematic literature review (SR) is to collate and critically assess the available information of the impact of obesity on mortality in the elderly. METHODS: In PubMed, there are three-hundred twelve papers on the relationship between obesity and mortality among older adults. These papers were analysed on the basis of their abstracts, and sixteen studies were considered suitable for the purpose of the study. It was possible to perform a pooled estimate for aggregated data in three different studies. CONCLUSION: The results of this SR document that an increased mortality in obese older adults. The limitation of BMI to index obesity and the noted protective action of a moderate increase in BMI on mortality are highlighted. Waist circumference is an indicator of central adiposity and potentially as good a risk factor for mortality as BMI in obese elderly adults. PMID- 22238008 TI - The impact of body mass index in old age on cause-specific mortality. AB - OBJECTIVES: To assess the association between Body Mass Index (BMI) and cause specific mortality in older adults and to assess which BMI was associated with lowest mortality. DESIGN: Prospective study. SETTING: European towns. PARTICIPANTS: 1,980 older adults, aged 70-75 years from the SENECA (Survey in Europe on Nutrition and the Elderly: a concerted action) study. MEASUREMENTS: BMI, examined in 1988/1989, and mortality rates and causes of death during 10 years of follow-up. RESULTS: Cox proportional hazards model including both BMI and BMI2, accounting for sex, smoking status, educational level and age at baseline showed that BMI was associated with all-cause mortality (p<0.01), cardiovascular mortality (p<0.01) and mortality from other causes (p<0.01), but not with cancer or respiratory mortality (p>0.3). The lowest all-cause mortality risk was found at 27.1 (95%CI 24.1, 29.3) kg/m2, and this risk was increased with statistical significance when higher than 31.4 kg/m2 and lower than 21.1 kg/m2. The lowest cardiovascular mortality risk was found at 25.6 (95%CI 17.1, 28.4) kg/m2, and was increased with statistical significance when higher than 30.9 kg/m2. CONCLUSION: In this study, BMI was associated with all-cause mortality risk in older people. This risk was mostly driven by an increased cardiovascular mortality risk, as no association was found for mortality risk from cancer or respiratory disease. Our results indicate that the WHO cut-off point of 25 kg/m2 for overweight might be too low in old age, but more studies are needed to define specific cut-off points. PMID- 22238009 TI - Evaluation of nutritional status and skin condition among elderly residents in a long-term care hospital. AB - OBJECTIVE: The availability of nutritional screening tools for older adults is limited, depending on their physical characteristics or the setting. We investigated the relationships between various nutritional indicators and skin conditions as possible screening indicators. DESIGN: Cross-sectional study. SETTING: A long-term care hospital in Japan. PARTICIPANTS: 90 elderly residents who were aged >=65 years old. MEASUREMENTS: The nutritional status of the residents was assessed by body mass index (BMI), involuntary weight loss, arm muscle area, and serum albumin and prealbumin levels. Leg skin condition was evaluated by: 1) functional factors including pH, hydration and transepidermal water loss; 2) skin color including L*, a*, b* and individual typology angle (ITA degrees ) using a tristimulus colorimetric instrument; and 3) skin morphology. Repeated measures analysis of variance was employed, adjusted for demographic characteristics and room temperature, with measurement site as the repeated variable. RESULTS: Among the skin indicators, b* was significantly correlated with BMI (p=0.018), and weight loss over the previous month (p=0.042) and 6 months (p=0.002). Additionally, ITA degrees was associated with weight loss over 1 month (p=0.013). Both b* and ITA degrees showed the area under the receiver operating characteristic curve of 0.64 to 0.80 for weight loss >2% over 1 month. CONCLUSIONS: Residents with poorer nutritional status had yellower and darker skin color. PMID- 22238010 TI - Sequential anaerobic/aerobic treatment of dye-containing wastewaters: colour and COD removals, and ecotoxicity tests. AB - Colour and COD removals of the azo dyes Congo Red (CR) and Reactive Black 5 (RB5) were individually evaluated in a sequential anaerobic/aerobic treatment system. Additionally, dye toxicity was assessed by using acute ecotoxicity tests with Daphnia magna as the indicator-organism. The anaerobic reactor was operated at approximately 27 degrees C and with hydraulic retention times of 12 and 24 h. The aerobic reactor was operated in batch mode with a total cycle of 24 h. During anaerobic step, high colour removals were obtained, 96.3% for CR (400 mg/L) and 75% for RB5 (200 mg/L). During the aerobic phase, COD effluent was considerably reduced, with an average removal efficiency of 52% for CR and 85% for RB5, which resulted in an overall COD removal of 88% for both dyes. Ecotoxicity tests with CR revealed that the anaerobic effluent presented a higher toxicity compared with the influent, and an aerobic post-treatment was not efficient in reducing toxicity. However, the results with RB5 showed that both anaerobic and aerobic steps could decrease dye toxicity, especially the aerobic phase, which removed completely the toxicity in D. magna. Therefore, the anaerobic/aerobic treatment is not always effective in detoxifying dye-containing wastewaters, sometimes even increasing dye toxicity. PMID- 22238011 TI - ANCUT2, an extracellular cutinase from Aspergillus nidulans induced by olive oil. AB - Cutinases are versatile carboxylic ester hydrolases with great potential in many biocatalytic processes, including biodiesel production. Genome sequence analysis of the model organism Aspergillus nidulans reveals four genes encoding putative cutinases. In this work, we purified and identified for the first time a cutinase (ANCUT2) produced by A. nidulans. ANCUT2 is a 29-kDa protein which consists of 255 amino acid residues. Comparison of the amino acid sequence of ANCUT2 with other microbial cutinase sequences revealed a high degree of homology with other fungal cutinases as well as new features, which include a serine-rich region and conserved cysteines. Cutinase production with different lipidic and carbon sources was also explored. Enzyme activity was induced by olive oil and some triacylglycerides and fatty acids, whereas it was repressed by glucose (1%) and other sugars. In some conditions, a 22-kDa post-translational processing product was also detected. The cutinase nature of the enzyme was confirmed after degradation of apple cutin. PMID- 22238012 TI - Biofouling potential reductions using a membrane hybrid system as a pre-treatment to seawater reverse osmosis. AB - Biofouling on reverse osmosis (RO) membranes is the most serious problem which affects desalination process efficiency and increases operation cost. The biofouling cannot be effectively removed by the conventional pre-treatment traditionally used in desalination plants. Hybrid membrane systems coupling the adsorption and/or coagulation with low-pressure membranes can be a sustainable pre-treatment in reducing membrane fouling and at the same time improving the feed water quality to the seawater reverse osmosis. The addition of powder activated carbon (PAC) of 1.5 g/L into submerged membrane system could help to remove significant amount of both hydrophobic compounds (81.4%) and hydrophilic compounds (73.3%). When this submerged membrane adsorption hybrid system (SMAHS) was combined with FeCl(3) coagulation of 0.5 mg of Fe(3+)/L, dissolved organic carbon removal efficiency was excellent even with lower dose of PAC (0.5 g/L). Detailed microbial studies conducted with the SMAHS and the submerged membrane coagulation-adsorption hybrid system (SMCAHS) showed that these hybrid systems can significantly remove the total bacteria which contain also live cells. As a result, microbial adenosine triphosphate (ATP) as well as total ATP concentrations in treated seawater and foulants was considerably decreased. The bacteria number in feed water prior to RO reduced from 5.10E(+06) cells/mL to 3.10E(+03) cells/mL and 9.30E(+03) cells/mL after SMAHS and SMCAHS were applied as pre-treatment, respectively. These led to a significant reduction of assimilable organic carbon (AOC) by 10.1 MUg/L acetate-C when SMCAHS was used as a pre-treatment after 45-h RO operation. In this study, AOC method was modified to measure the growth of bacteria in seawater by using the Pseudomonas P.60 strain. PMID- 22238013 TI - Cloning, expression, and characterization of a wide-pH-range stable phosphite dehydrogenase from Pseudomonas sp. K in Escherichia coli. AB - A phosphite dehydrogenase gene (ptdhK) consisting of 1,011-bp nucleotides which encoding a peptide of 336 amino acid residues was cloned from Pseudomonas sp. K. gene ptdhK was expressed in Escherichia coli BL21 (DE3) and the corresponding recombinant enzyme was purified by metal affinity chromatography. The recombinant protein is a homodimer with a monomeric molecular mass of 37.2 kDa. The specific activity of PTDH-K was 3.49 U mg(-1) at 25 degrees C. The recombinant PTDH-K exhibited maximum activity at pH 3.0 and at 40 degrees C and displayed high stability within a wide range of pHs (5.0 to 10.5). PTDH-K had a high affinity to its natural substrates, with K (m) values for sodium phosphite and NAD of 0.475 +/- 0.073 and 0.022 +/- 0.007 mM, respectively. The activity of PTDH-K was enhanced by Na(+), NH (4) (+) , Mg(2+), Fe(2+), Fe(3+), Co(2+), and EDTA, and PTDH-K exhibited different tolerance to various organic solvents. PMID- 22238014 TI - Kinetic study of empty fruit bunch using hot liquid water and dilute acid. AB - Empty fruit bunch (EFB), a residual product of the palm plantation, is an attractive biomass for biorefinery. As xylan is susceptible to high temperature pretreatment, it is important to setup a proper pretreatment condition to maximize the sugar recovery from EFB. Kinetic parameters of mathematical models were obtained in order to predict the concentration of xylose, glucose, furfural, and acetic acid in the hydrolysate and to find production conditions of xylose. We investigated the kinetics of hot liquid water and dilute sulfuric acid hydrolysis over a 40-min period using a self-designed setup by measuring the concentrations of released sugars (xylose, glucose) and degradation products (acetic acid and furfural). The reaction was performed within the range 160~180 degrees C, under reaction conditions of various concentration of sulfuric acid (0.1~0.2%) and 1:7 solid-liquid ratio in a batch reactor. The kinetic constants can be expressed by the Arrhenius equation with the activation energy for the hydrolysis of sugar and decomposition of sugar. The activation energy of xylose was determined to be 136.2187 kJ mol(-1). PMID- 22238016 TI - Enhanced ammonia content in compost leachate processed by black soldier fly larvae. AB - Black soldier fly (BSF) larvae (Hermetia illucens), feeding on leachate from decaying vegetable and food scrap waste, increase ammonia (NH (4) (+) ) concentration five- to sixfold relative to leachate unprocessed by larvae. NH (4) (+) in larva-processed leachate reached levels as high as ~100 mM. Most of this NH (4) (+) appears to have come from organic nitrogen within the frass produced by the larvae as they fed on leachate. In nitrate-enriched solutions, BSF larvae also facilitate dissimilatory nitrate reduction to ammonia. The markedly higher concentration of NH (4) (+) recovered in leachates processed with BSF larvae and concomitant diversion of nutrients into insect biomass (itself a valuable feedstock) indicate that the use of BSF larvae in processing leachate of decaying organic waste could be advantageous in offsetting capital and environmental costs incurred in composting. PMID- 22238015 TI - Novel copper-based therapeutic agent for anti-inflammatory: synthesis, characterization, and biochemical activities of copper(II) complexes of hydroxyflavone Schiff bases. AB - Four hydroxyflavone derivatives have been synthesized with the aim of obtaining a good model of superoxide dismutase. Better to mimic the natural metalloenzyme, copper complexes have been designed. The Cu(II) complexes of general formulae, [CuL] where L = 5-hydroxyflavone-o-phenylenediamine (L1H2)/m-phenylenediamine (L2H2) and 3-hydroxyflavone-o-phenylenediamine (L3H2)/m-phenylenediamine (L4H2) have been synthesized. The structural features have been determined from their analytical and spectral data. All the Cu(II) complexes exhibit square planar geometry. Redox behavior of copper complexes was studied and the present ligand systems stabilize the unusual oxidation state of the copper ion during electrolysis. The in vitro antimicrobial activities of the investigated compounds were tested against the bacterial species Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa and fungal species Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola, and Candida albicans. Superoxide dismutase and anti inflammatory activities of the copper complexes have also been measured and discussed. PMID- 22238017 TI - Improved mass multiplication of Rhodiola crenulata shoots using temporary immersion bioreactor with forced ventilation. AB - A temporary immersion bioreactor system was found to be suitable for mass shoot proliferation of Rhodiola crenulata. The shoot multiplication ratio and hyperhydration rate reached 46.8 and 35.4%, respectively, at a temporary immersion cycle of 3-min immersion every 300 min. Forced ventilation was employed in the temporary immersion bioreactor culture in order to decrease the hyperhydration rate, improve shoot quality and enhance the multiplication ratio. The highest multiplication ratio of 55.7 was obtained under a temporary immersion cycle of 3-min immersion every 180 min with the forced ventilation at an air flow rate of 40 l/h, and the hyperhydration rate was reduced to 26.1%. Forced ventilation also improved the subsequent elongation and rooting rate of these proliferated shoots, and the shoot cultures from the temporary immersion bioreactor formed complete plantlets when subcultured onto a rooting medium containing 5 MUmol/l indole-3-acetic acid. PMID- 22238018 TI - 153Sm-HM for arthritic knee pain. Estimated dosimetry. AB - Osteoarthritis is the most common type of arthropathy and after cardiovascular diseases is the most disabling disease in developing countries. The dosimetry for the clinical application of 153-samarium-hydroxymacroaggregates (153Sm-HM) for radiation synovectomy (RSV) and palliative treatment for arthritic pain, as far as we know, has not been reported. The aim of this research was to estimate the radiation dose necessary for synovial ablation and pain palliation with minimum risk to the patient. 153Sm-HM (370 MBq) was administered intra-articularly in a patient with severe knee pain and hindered motility. Regions of interest drawn on sequential, conjugated, anterior and posterior scintigraphy images were used to obtain the respective activity. The data was entered into a knee joint histological-geometric model designed with micrometric dimensions to represent the synovial cell layers. The Monte Carlo code was used to calculate the absorbed dose in each of the 12 model-cells representing the distance from the synovial liquid to the cartilage or bone. The absorbed dose in the synovial cavity was 114 Gy which is sufficient energy for RSV. The treated patient referred little pain and higher motility with no adverse reactions. 153Sm-HM is a potentially valid radiopharmaceutical for RSV, which effectively palliates knee pain. PMID- 22238020 TI - Constrained digold(I) diaryls: syntheses, crystal structures, and photophysics. AB - A series of di(gold(I) aryls), L(AuR)(2) (L = DPEphos, DBFphos, or Xantphos; R = 1-naphthyl, 2-naphthyl, 9-phenanthryl, or 1-pyrenyl), have been prepared. The complexes were characterized by multinuclear NMR spectroscopy, static and time dependent optical spectroscopy, mass spectrometry, microanalysis, and X-ray crystallography. In addition, DFT calculations on model dinuclear gold complexes have been used to examine the electronic structures. Photophysical properties of the dinuclear complexes have been compared to mononuclear analogues. Low temperature excited-state lifetimes for both the mononuclear and dinuclear complexes in toluene indicate triplet-state emission. Time-resolved DFT calculations suggest that emission originates from aryl-ligand transitions, even if the LUMO resides elsewhere. PMID- 22238019 TI - Mechanical properties of tyramine substituted-hyaluronan enriched fascia extracellular matrix. AB - Naturally occurring biomaterial scaffolds derived from extracellular matrix (ECM) have been the topic of recent investigation in the context of rotator cuff tendon repair. We previously reported a method to treat fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) for use as a tendon augmentation scaffold. The presence of crosslinked TS-HA in fascia was associated with an increased macrophage and giant cell response compared to water-treated controls after implantation in a rat abdominal wall model. The objective of this study was to determine the extent to which TS-HA treatment was associated with mechanical property changes of fascia after implantation in the rat model. Fascia samples in all groups demonstrated time-dependent decreases in mechanical properties. TS-HA treated fascia with crosslinking exhibited a lower toe modulus, a trend toward lower toe stiffness, and a higher transition strain than water-treated controls not only after implantation, but also at time zero. TS-HA treatment, with or without crosslinking, had no significant effect on time-zero or post-implantation load relaxation ratio, load relaxation rate, linear-region stiffness, or linear region modulus. Our findings demonstrated that the particular TS-HA treatment employed in this study decreased the low-load elastic mechanical properties of fascia ECM, in keeping with the heightened macrophage and giant cell host response seen previously. This work provides a starting point and guidance for investigating alternative HA treatment strategies. PMID- 22238021 TI - The role of multi-modality imaging for sinus of Valsalva aneurysms. AB - Sinus of Valsalva aneurysms (SVAs) are uncommon but important entities. They are most often congenital in origin, resulting from incomplete fusion of the aortic media to the aortic valve annulus. Less frequently, they may be acquired, usually secondary to infective endocarditis. Unruptured aneurysms may be clinically silent and diagnosed incidentally, but can also produce symptoms as a consequence of mass effect on related structures. Rupture may present with sudden hemodynamic collapse but can have a more insidious onset depending upon the site and size of the perforation. Early diagnosis is imperative and can usually be made reliably by transthoracic echocardiography. However, transesophageal echocardiography may sometimes be required for confirmation. Cardiovascular magnetic resonance imaging (CMRI) and multi-detector computed tomography are being increasingly utilized for evaluation of SVAs and can offer valuable complimentary information. CMRI in particular enables a comprehensive assessment of anatomy, function and flow in a single sitting. Surgical repair forms the mainstay of treatment for both ruptured and unruptured aneurysms and has low complication rates. This article provides an overview of the pathological and clinical aspects of SVAs and discusses in detail the role of advanced imaging modalities in their evaluation. PMID- 22238023 TI - On the uses of routine patient-reported health outcome data. AB - It has long been standard practice to ask patients in clinical trials about their health status, but the practice is now being extended to patients receiving treatment on a routine basis. In this paper, we examine four types of analyses that these health data might inform: comparisons of alternative treatments for the same condition, of health care providers, of changes in performance over time and of treatments of different types of condition. Analytical challenges arise because counterfactuals cannot be observed and because health status cannot be measured continuously. The implications of these challenges and the ability to meet them vary according to the comparative exercise. We argue that, provided with a sufficient number of health status measures for each patient and proper risk adjustment, health status measurement has great potential to inform the first three types of comparison. However, we believe that it is not yet possible to use such data to make secure comparative judgements about the outcomes from treatment for different types of condition. PMID- 22238022 TI - Evaluation of postmortem MDCT and MDCT-angiography for the investigation of sudden cardiac death related to atherosclerotic coronary artery disease. AB - The goal of this study was to evaluate the diagnostic value of postmortem multi computed tomography (MDCT) and MDCT-angiography for sudden cardiac deaths related to ischemic heart disease. Twenty three cases were selected based on clinical history and the results of native MDCT, multiphase post-mortem CT-angiography and conventional autopsy were compared. Radiological examination showed calcification of coronary arteries in 78% of the cases, most of which were not detailed at autopsy. MDCT-angiography allowed better visualization of the coronary arteries than MDCT and permitted the evaluation of stenoses and occlusions. Of the 14 cases of coronary thrombosis detected at conventional autopsy, 11 were visible as stop of perfusion with CT-angiography and three were found to be partly perfused. One case had an old thrombosis with collateral circulation. One case had a coronary artery postmortem clot found with MDCT-angiography. Coronary artery calcifications are more easily detected and documented with radiological examination than with conventional autopsy. MDCT is of limited diagnostic value for ischemic heart disease. MDCT-angiography, when correctly interpreted, is a reasonable tool to view the morphology of coronary arteries, rule out significant coronary artery stenoses, identify occlusions and direct sampling for histological examination. PMID- 22238024 TI - Type II collagen fragment HELIX-II is a marker for early cartilage lesions but does not predict the progression of cartilage destruction in human knee joint synovial fluid. AB - To determine whether there is a direct correlation between the concentration of type II collagen fragment HELIX-II in synovial fluid and the severity of cartilage damage at the knee joint, 83 patients who had undergone knee arthroscopy or total knee replacement were enrolled in this study (49% women, mean +/- SD age 49.5 +/- 19). The content of HELIX-II in the synovial fluid samples was measured by enzyme-linked immunosorbent assay (ELISA). Cartilage damage at the knee joint was classified during arthroscopy or direct surgical observation, using the Outerbridge cartilage damage scoring system. The maximum damage score was defined as the highest score among the six areas of the knee joint, and the cumulative score was defined as the sum of the scores of the six areas of the knee joint. The intra-assay and inter-assay variations of the HELIX II ELISA were lower than 13 and 15%, respectively. The level of HELIX-II in the severely damaged cartilage groups (cumulative scores = 11-24 or maximum score = 2 4) was much higher than in the slightly damaged cartilage groups (cumulative scores = 0-10 or maximum score = 0-1). The level of HELIX-II in cartilage from severely damaged cartilage groups was significantly higher than in the slightly damaged groups, but no significant difference was detected in the level of HELIX II among the severely damaged cartilage sub-groups. There was a significant correlation between the HELIX-II concentration in the synovial fluid and the cumulative (r = 0.807) and maximum scores (r = 0.794). Thus, elevated HELIX-II level is correlated with early cartilage lesions, but does not have the sensitivity to predict the progression of severity of cartilage damage in the knee joint. PMID- 22238025 TI - Chondrogenesis from umbilical cord blood cells stimulated with BMP-2 and BMP-6. AB - Umbilical cord blood contains undifferentiated mesenchymal stem cells (MSCs) with chondrogenic potential that may be used for the repair of joint damage. The role of growth factors during the process of chondrogenesis is still not entirely understood. The objective of this study was to evaluate the formation of chondrocytes, cartilaginous matrix and type II collagen from human umbilical cord blood stem cells exposed to two different growth factors, BMP-6 and BMP-2, while being cultured as a micromass or a monolayer. Umbilical cord blood was obtained from full-term deliveries, and then, mononuclear cells were separated and cultured for expansion. Afterward, these cells were evaluated by flow cytometry using antibodies specific for MSCs and induced to chondrogenic differentiation in micromass and monolayer cultures supplemented with BMP-2 and BMP-6. Cellular phenotype was evaluated after 7, 14 and 21 days by RT-PCR and Western blot analysis to identify the type II collagen and aggrecan. The expanded cells displayed surface antigens characteristic of mesenchymal progenitor cells and were negative for hematopoietic differentiation antigens. Type II collagen and aggrecan mRNAs were expressed from day 14 in cells stimulated with BMP-2 or BMP 6. Type II collagen was demonstrated by Western blotting in both groups, and the greatest expression was observed 21 days after the cells were stimulated with BMP 2 cultured in micromass. BMP-2 in micromass culture was more efficient to induce the chondrogenesis. PMID- 22238027 TI - Diffused systemic sclerosis due to occupational solvent exposure. PMID- 22238026 TI - Prescription for antiresorptive therapy in Mexican patients with rheumatoid arthritis: is it time to reevaluate the strategies for osteoporosis prevention? AB - Glucocorticoids are frequently used in rheumatoid arthritis (RA) in order to alleviate symptoms of joint inflammation, retard erosions and to treat extra articular manifestations, although these drugs may increase the risk of bone mineral loss and osteoporotic fractures. To date, in Mexico there are no studies that identify the frequency of patients with RA with corticosteroids, receiving therapy for osteoporosis. Therefore, we evaluated the prevalence and factors related to the prescription of antiresorptives in 520 Mexican patients with RA. We used a multivariate model to identify variables associated with antiresorptives prescription. We identified that although 79% of patients were under treatment with glucocorticoids, only 13% received antiresorptive agents as preventive therapy for osteoporosis. The multivariate analysis identified that higher proportions of antiresorptive drugs prescriptions were associated with female patients (OR 11.40, 95% CI: 1.5-84.3, P = 0.02), an age of 40 years or more (OR 3.22, 95% CI: 1.3-8.3, P = 0.02) and to consume a lower number of cointerventions with other drugs (OR 1.09, 95% CI: 1.0-1.2, P = 0.03). Corticosteroid treatment was not associated with the prescription of antiresorptives (P = 0.31). In conclusion, a low proportion of Mexicans with RA receive antiresorptive therapy independently regardless of whether they consume or not chronically corticosteroids. Additional strategies should be evaluated to encourage the prevention and early treatment for osteoporosis in patients with RA. PMID- 22238030 TI - A versatile Ru catalyst for the asymmetric transfer hydrogenation of both aromatic and aliphatic sulfinylimines. AB - A highly efficient Ru catalyst based on an achiral, very simple, and inexpensive amino alcohol ligand (2-amino-2-methylpropan-1-ol) has been developed for the asymmetric transfer hydrogenation (ATH) of chiral N-(tert-butylsulfinyl)imines. This complex is able to catalyze the ATH of both aromatic and the most challenging aliphatic sulfinylimines by using isopropyl alcohol as the hydrogen source. The diastereoselective reduction of aromatic, heteroaromatic, and aliphatic sulfinylketimines, including sterically congested cases, over short reaction times (1-4 h), followed by desulfinylation of the nitrogen atom, affords the corresponding highly enantiomerically enriched (ee up to >99 %) alpha branched primary amines in excellent yields. The same ligand was equally effective for the synthesis of both (R)- and (S)-amines by using the appropriate absolute configuration in the iminic substrate. DFT mechanistic studies show that the hydrogen-transfer process is stepwise. Moreover, the origin of the diastereoselectivity has been rationalized. PMID- 22238028 TI - Gene expression patterns in peripheral blood cells associated with radiographic severity in African Americans with early rheumatoid arthritis. AB - Gene expression profiling may be used to stratify patients by disease severity to test the hypothesis that variable disease outcome has a genetic component. In order to define unique expression signatures in African American rheumatoid arthritis (RA) patients with severe erosive disease, we undertook a gene expression study using samples of RNA from peripheral blood mononuclear cells (PBMCs). RNA from baseline PBMC samples of 96 African American RA patients with early RA (<2 years disease duration) was hybridized to cDNA probes of the Illumina Human HT-V3 expression array. Expression analyses were performed using the ca. 25,000 cDNA probes, and then expression levels were compared to the total number of erosions in radiographs of the hands and feet at baseline and 36 months. Using a false discovery rate cutoff of Q = 0.30, 1,138 genes at baseline and 680 genes at 36 months significantly correlated with total erosions. No evidence of a signal differentiating disease progression, or change in erosion scores between baseline and 36 months, was found. Further analyses demonstrated that the differential gene expression signature was localized to the patients with the most erosive disease (>10 erosions). Ingenuity Pathway Analysis demonstrated that genes with fold change greater than 1.5 implicated immune pathways such as CTLA signaling in cytotoxic T lymphocytes. These results demonstrate that CLEAR patients with early RA having the most severe erosive disease, as compared to more mild cases (<10 erosions), may be characterized by a set of differentially expressed genes that represent biological pathways with relevance to autoimmune disease. PMID- 22238029 TI - ANCA-associated vasculitis in systemic sclerosis report of 3 cases. AB - The aim of the study was to describe the occurrence of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in systemic sclerosis (SSc) patients. SSc patients who developed biopsy-proven AAV were identified. Their clinical manifestations, autoantibodies, presentation with vasculitis, treatment and outcome were described and compared with previously reported patients with these two conditions. Of 985 patients, 3 were identified. All patients had interstitial lung disease, and all presented with acute renal failure, proteinuria and hematuria, and were P-ANCA- and anti-Scl-70-positive. One required hemodialysis. Two were hypertensive; additionally, one patient had sinusitis, and another had monoarthritis and a macular rash. All were treated with high-dose corticosteroids and responded to therapy and attained remission at 6 months. At 1 year, one patient died of pneumonia. ANCA-associated vasculitis is a rare but serious finding in SSc patients. Positive anti-Scl-70 antibody is found commonly in these patients. Different treatment modalities are effective. Serious infections can complicate therapy and lead to death. PMID- 22238032 TI - Occupational contact allergens: are they also associated with occupational asthma? AB - BACKGROUND: Workplace exposures that can potentially cause both allergic occupational contact dermatitis (AOCD) and occupational asthma (OA) are not clearly identified. METHODS: Occupational contact allergens (OCAs) were identified using North American Contact Dermatitis Group (NACDG) data. Reference documents and systematic reviews were used to determine whether each OCA had been reported to potentially cause OA. The presence or absence of a sensitizer notation in occupational hygiene reference documents was also examined. RESULTS: The 10 most common OCAs were: epoxy resin*, thiuram, carba mix, nickel sulfate*, cobalt chloride*, potassium dichromate*, glyceryl thioglycolate, p phenylenediamine*, formaldehyde* and glutaraldehyde*. Seven (indicated by *) were determined to be possible causes of OA. Information on sensitizing potential from OH reference materials contained conflicting information. CONCLUSIONS: Several common OCAs can also potentially cause OA. Inhalation and dermal exposures to these agents should be controlled and both OA and AOCD should be considered as possible health outcomes. Increased consistency in sensitizer notations is needed. PMID- 22238033 TI - Perioperative medicine: innovations and challenges. PMID- 22238034 TI - Integrating perioperative information from divergent sources. AB - The enormous diversity of physician practices, including specialists, and patient requirements and comorbidities make integration of appropriate perioperative information difficult. Lack of communicating computer systems adds to the difficulty of assembling data. Meta analysis and evidence-based studies indicate that far too many tests are performed perioperatively. Guidelines for appropriate perioperative management have been formulated by several specialties. Education as to current findings and requirements should be better communicated to surgeons, consultants, and patients to improve healthcare needs and at the same time decrease costs. Means to better communication by interpersonal collaboration are outlined. PMID- 22238031 TI - Isolation and study of insulin activated nitric oxide synthase inhibitory protein in acute myocardial infarction subjects. AB - Insulin inhibits platelet aggregation through nitric oxide synthesis by stimulating platelet insulin activated nitric oxide synthase. Impaired platelet insulin activated nitric oxide synthase in acute myocardial infarction (AMI) patients had been reported and thus our aim was to identify and isolate the factors impairing insulin activated nitric oxide in acute myocardial infarction patients' plasma and study its effect on platelets aggregation in vitro. The insulin activated nitric oxide synthase inhibitor was identified as a protein and was purified from the plasma of AMI subjects using DEAE cellulose and Sephadex G 50 column, molecular weight determined by SDS-PAGE, nitric oxide quantified by methaemoglobin method, inhibitor protein quantified in plasma by immunoblot and ELISA, platelet aggregation studies done using an aggregometer, thromboxane-A2 in the platelets determined by radioimmunoassay, (125)I-insulin radioligand binding studies done using normal subject platelets. The purified nitric oxide synthase inhibitor protein was ~66 kDa, concentration in AMI subjects' plasma varied from 114 to 9,090 MUM and was undetected in normal subjects' plasma. The inhibitor protein competes with insulin for insulin receptor binding sites. The Incubation of the normal subject PRP with 5.0 MUM inhibitor for 30 min followed by 0.4 MUM ADP addition caused platelet aggregation in vitro, 130 MUM aspirin or 400 MUU insulin/ml addition was able to abrogate 0.4 MUM ADP induced platelet aggregation even in the presence of 5.0 MUM inhibitor. A potent inhibitory protein against insulin activated nitric oxide synthase in platelets appears in circulation of AMI subjects impairing nitric oxide production, potentiating ADP induced platelet aggregation and increasing the thromboxane-A2 level in platelets. PMID- 22238035 TI - Value of specialized preanesthetic clinic for cardiac and major vascular surgery patients. AB - In a complicated and specialized population, such as patients undergoing cardiac and major vascular procedures, patients, clinicians, and hospitals may be best served and resources conserved with a specialized preanesthesia clinic. A specialized preanesthesia clinic for cardiac and major vascular procedures has a focused staff usually consisting of practitioners with cardiac and major vascular surgical care experience designed to address the patient evaluation, the information gathering, the necessary consultations, the required testing, and specific needs for the day of cardiac and major vascular surgery. Specialized preanesthesia clinics increase patient satisfaction and may also provide cost containment by decreasing the amount of indiscriminate ordering of expensive preoperative tests and potentially may decrease patient litigation. Resident trainee education can also be enhanced by a specialized preanesthesia clinic for cardiac and major vascular rotations. The ultimate goal of a specialized preanesthesia clinic is to ensure a safe and efficient perioperative cardiac and major vascular surgical experience in complicated patients undergoing complex procedures. PMID- 22238036 TI - Perioperative assessment of patients with cardiac implantable electronic devices. AB - Worldwide, nearly 4 million patients currently have cardiac implantable electronic devices. Due to the increasing number of candidates to receive either pacemakers or implantable cardiac defibrillators, there is no doubt that primary care physicians or anesthesiologists are very likely to interact and deal with this particular patient population. However, besides technologic advancements, several factors have been frequently reported to cause confusion regarding their perioperative care. Therefore, it has become extremely valuable to understand the basic functions and operation of these devices, as well as their functional limitations, to prevent iatrogenic complications and detect potential failure in an early stage. PMID- 22238037 TI - Perioperative dental evaluation. AB - Typically, a patient's intraoral condition is not a chief perioperative concern. The need for proper dental care is often unmet prior to a surgical procedure. Consequently, patients presenting for surgery may possess untreated decayed teeth and/or periodontal disease. These individuals may be harboring a quiescent and potent odontogenic infection. In the perioperative period, the deleterious effects of such an infection can not only compromise surgical outcome, but also magnify treatment and expenses. This article will elaborate on the connection between oral health and systemic disease, and discuss the barriers that exist with improving oral health. It will review pertinent dental nomenclature and anatomy, as well as emphasize the practice and value of a preoperative dental evaluation. Various compromised intraoral conditions are presented among a range of patient populations. The importance of treating an acute odontogenic infection before surgery is also discussed. Healthcare providers who recognize significant perioperative dental conditions can implement effective and preventive actions that can contain costs and achieve optimal patient care. PMID- 22238038 TI - Prediction of rate and severity of adverse perioperative outcomes: "normal accidents" revisited. AB - The American Society of Anesthesiologists Physical Status classification system has been shown to predict the frequency of perioperative morbidity and mortality despite known subjectivity, inconsistent application, and exclusion of many perioperative confounding variables. The authors examined the relationship between the American Society of Anesthesiologists Physical Status and both the frequency and the severity of adverse events over a 10-year period in an academic anesthesiology practice. The American Society of Anesthesiologists Physical Status is predictive of not only the frequency of adverse perioperative events, but also the severity of adverse events. These nonlinear mathematical relationships can provide meaningful information on performance and risk. Calculated odds ratios allow discussion about individualized anesthesia risks based on the American Society of Anesthesiologists Physical Status because the added complexity of the surgical or diagnostic procedure, and other perioperative confounding variables, is indirectly factored into the Physical Status classification. The ability of the American Society of Anesthesiologists Physical Status to predict adverse outcome frequency and severity in a nonlinear relationship can be fully explained by applying the Normal Accident Theory, a well-known theory of system failure that relates the interactive complexity of system components to the frequency and the severity of system failures or adverse events. PMID- 22238039 TI - From bloodless surgery to patient blood management. AB - Safety and efficacy concerns of allogeneic blood transfusions and their impact on patient outcomes and associated staggering costs and restricted supply have fueled the quest for other modalities and strategies to reduce use of blood components. Patient blood management focuses on multidisciplinary and multimodal preventive measures to reduce or obviate the need for transfusions and ultimately to improve the clinical outcomes of patients. Patient blood management strategies can be applied at every stage of care to surgical and nonsurgical patients, and they generally fall under one of these three categories (the so-called pillars of blood management): optimizing hematopoiesis and appropriate management of anemia, minimizing bleeding and blood loss, and harnessing and optimizing physiological tolerance of anemia through employing all available modalities while treatment is initiated. Several tools and modalities are available to address each of these pillars. Examples include hematinic agents, systemic and topical hemostatic agents, autotransfusion, and blood-sparing perfusion and surgical techniques. Additionally, changes in practice of clinicians (e.g., adherence to restrictive, evidence-based transfusion strategies with emphasis on physiologic indications for transfusion, minimization of iatrogenic blood loss, and adequate planning) play an important role in patient blood management. Emerging evidence supports that appropriate use of these strategies as part of a multimodal program is a safe and effective way of reducing allogeneic transfusions and improving patient outcomes. PMID- 22238040 TI - Impact of red blood cell transfusion on global and regional measures of oxygenation. AB - Anemia is common in critically ill patients. Although the goal of transfusion of red blood cells is to increase oxygen-carrying capacity, there are contradictory results about whether red blood cell transfusion to treat moderate anemia (e.g., hemoglobin 7-10 g/dL) improves tissue oxygenation or changes outcomes. Whereas increasing levels of anemia eventually lead to a level of critical oxygen delivery, increased cardiac output and oxygen extraction are homeostatic mechanisms the body uses to prevent a state of dysoxia in the setting of diminished oxygen delivery due to anemia. In order for cardiac output to increase in the face of anemia, normovolemia must be maintained. Transfusion of red blood cells increases blood viscosity, which may actually decrease cardiac output (barring a state of hypovolemia prior to transfusion). Studies have generally shown that transfusion of red blood cells fails to increase oxygen uptake unless oxygen uptake/oxygen delivery dependency exists (e.g., severe anemia or strenuous exercise). Recently, near-infrared spectroscopy, which approximates the hemoglobin saturation of venous blood, has been used to investigate whether transfusion of red blood cells increases tissue oxygenation in regional tissue beds (e.g., brain, peripheral skeletal muscle). These studies have generally shown increases in near-infrared spectroscopy derived measurements of tissue oxygenation following transfusion. Studies evaluating the effect of transfusion on the microcirculation have shown that transfusion increases the functional capillary density. This article will review fundamental aspects of oxygen delivery and extraction, and the effects of red blood cell transfusion on tissue oxygenation as well as the microcirculation. PMID- 22238041 TI - Developmental disability in the young and postoperative cognitive dysfunction in the elderly after anesthesia and surgery: do data justify changing clinical practice? AB - The assumption that anesthesia has no serious, long-term, adverse central nervous system consequences may be true for most patients between 6 months and 60 years of age. However, for patients younger than 6 months or older than 60 years, that status quo assumption is under challenge from a growing body of evidence. Fetuses and newborns appear to be at risk because systems that would enable them to fully recover from the effects of more than 2 hours of anesthesia are still in development. In distinction, the elderly appear to be at risk because systems that once enabled them to fully recover have ever-diminishing capacity. Even for those between the age of 6 months and 60 years, full recovery may require replacing apoptosed neurons and pruning overabundant dendritic spines...perhaps leaving patients not quite the same person that they were before they were anesthetized. PMID- 22238043 TI - Types of office-based anesthetics. AB - Over the past several decades, there have been evolutionary changes in both surgery and anesthesia. Newer anesthetics have excellent safety profiles and are associated with fewer hemodynamic side effects and rapid elimination from the body. Innovative surgical techniques are less invasive and cause less perioperative patient pain. These developments have fueled the growth of office based surgery and anesthesia. All types of anesthesia, including local, monitored anesthesia care, general, and regional anesthesia, have been used safely within the private practitioner's office. Because of the remote nature of the private surgeon's office, the proper selection of both patient and procedure to be performed is of utmost importance. It is likewise imperative that the practitioner assures that the patient does not experience excessive postoperative pain and/or nausea and vomiting. It is of the utmost importance that the practicing anesthesiologist assure that every location in which procedures and surgeries are performed is a safe anesthetizing location. PMID- 22238042 TI - Long-term outcomes in elderly surgical patients. AB - Anesthesia has developed to the point where long-term outcomes are important endpoints. Elderly patients are becoming an increasingly large part of most surgical practices, consistent with demographic shifts. Long-term outcomes are particularly important for this group. In this review, we discuss functional outcomes in the elderly. We describe the areas of cognitive change and frailty, both of which are specific to the elderly. We also discuss prevention of surgical infections and emerging evidence around hemodynamic alterations in the operating room and their impact on long-term outcomes. PMID- 22238044 TI - Lungs in critical care: new look at old practices. AB - There has been a marked increase in the volume of critical care services throughout the world in the last few years with the wide addition of intensive care units in developing nations. Despite extensive efforts in research and some progress in treatment, mortality and morbidity have not significantly decreased. Recent research has demonstrated that modifying standard practices of mechanical ventilation and sedation may contribute to improved patient outcomes. This article discusses how new aspects of physiologically based mechanical ventilation with minimal intravenous sedation may help decrease the incidence of nosocomial pneumonia, modulate systemic inflammatory response, and reduce the incidence of delirium. These interlinked modalities may someday contribute to decreased length of stay and a reduction in treatment-related complications. These concepts may also open new avenues to improve patient care and stimulate ongoing investigation in other areas related to physiologically based critical care practices. PMID- 22238045 TI - Managing chronic pain with spinal cord stimulation. AB - Since its introduction as a procedure of last resort in a terminally ill patient with intractable cancer-related pain, spinal cord stimulation has been used to effectively treat chronic pain of varied origins. Spinal cord stimulation is commonly used for control of pain secondary to failed back surgery syndrome and complex regional pain syndrome, as well as pain from angina pectoris, peripheral vascular disease, and other causes. By stimulating one or more electrodes implanted in the posterior epidural space, the patient feels paresthesias in their areas of pain, which reduces the level of pain. Pain is reduced without the side effects associated with analgesic medications. Patients have improved quality of life and improved function, with many returning to work. Spinal cord stimulation has been shown to be cost effective as compared with conservative management alone. There is strong evidence for efficacy and cost effectiveness of spinal cord stimulation in the treatment of pain associated with intractable angina, failed back surgery syndrome, and complex regional pain syndrome. In this article, we review the history and pathophysiology of spinal cord stimulation, and the evidence (or lack thereof) for efficacy in common clinical practice. PMID- 22238046 TI - Preventing post-thoracotomy pain syndrome. AB - This article provides a concise overview of post-thoracotomy pain syndrome, describes anesthetic and surgical factors that have been investigated to reduce the incidence of the syndrome, and explores the effectiveness of various treatments for this condition. Although some interventions (both procedural and pharmacologic) have been investigated in both preventing and treating post thoracotomy pain syndrome, definitive studies are lacking and firm conclusions regarding the benefit of any intervention cannot be drawn. The problem is compounded further by our lack of understanding of the pathophysiologic mechanisms underlying the development of chronic pain after surgery. Going forward, it will be important to elucidate these mechanisms and conduct well designed trials involving novel therapeutic agents for both prevention and treatment of post-thoracotomy pain syndrome. PMID- 22238047 TI - Role of simulation in U.S. physician licensure and certification. AB - The evolution of simulation from an educational tool to an emerging evaluative tool has been rapid. Physician certification has a long history and serves an important role in assuring that practicing physicians are competent and capable of providing a high level of safe care to patients. Traditional assessment methods have relied mostly on multiple-choice exams or continuing medical education exercises. These methods may not be adequate to assess all competencies necessary for excellence in medical practice. Simulation enables assessment of physician competencies in real time and represents the next step in physician certification in the modern age of healthcare. PMID- 22238048 TI - Anesthesia information management systems: past, present, and future of anesthesia records. AB - Documenting a patient's anesthetic in the medical record is quite different from summarizing an office visit, writing a surgical procedure note, or recording other clinical encounters. Some of the biggest differences are the frequent sampling of physiologic data, volume of data, and diversity of data collected. The goal of the anesthesia record is to accurately and comprehensively capture a patient's anesthetic experience in a succinct format. Having ready access to physiologic trends is essential to allowing anesthesiologists to make proper diagnoses and treatment decisions. Although the value provided by anesthesia information management systems and their functions may be different than other electronic health records, the real benefits of an anesthesia information management system depend on having it fully integrated with the other health information technologies. An anesthesia information management system is built around the electronic anesthesia record and incorporates anesthesia-relevant data pulled from disparate systems such as laboratory, billing, imaging, communication, pharmacy, and scheduling. The ability of an anesthesia information management system to collect data automatically enables anesthesiologists to reliably create an accurate record at all times, regardless of other concurrent demands. These systems also have the potential to convert large volumes of data into actionable information for outcomes research and quality-improvement initiatives. Developing a system to validate the data is crucial in conducting outcomes research using large datasets. Technology innovations outside of healthcare, such as multitouch interfaces, near-instant software response times, powerful but simple search capabilities, and intuitive designs, have raised the bar for users' expectations of health information technology. PMID- 22238049 TI - Highly regioselective migration of the sulfonyl group: easy access to functionalized pyrroles. PMID- 22238050 TI - Endothelial cell adhesion and proliferation to PEGylated polymers with covalently linked RGD peptides. AB - A nonfouling peptide grafted polymer was synthesized that can promote endothelial cell (EC) binding. The polymer was composed of hexyl methacrylate, methyl methacrylate, poly(ethylene glycol) methacrylate, and CGRGDS peptide. The peptide was incorporated into the polymer system either by a chain transfer reaction or by coupling to an acrylate-PEG-N-hydroxysuccinimide (NHS) comonomer. The introduction of PEG chains minimizes protein adsorption. Human umbilical vein ECs and endothelial colony forming cells were cultured on these surfaces in short term and long-term studies. A difference in number and morphology of ECs was observed depending on the method of peptide incorporation. Both cell types adhered better to polymer films containing NHS coupled RGD peptide after 2 h even in the presence of albumin but significant cell detachment occurred after 4 days. Polymer solutions were electrospun into fibrous scaffolds. Both nonfouling and peptide binding characteristics were retained after processing. PMID- 22238051 TI - Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. AB - OBJECTIVE: To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in patients with systemic lupus erythematosus (SLE) and to determine whether immunoglobulin and C1q levels are correlated with clinical and serologic parameters. METHODS: Sixty-eight clinically well-characterized SLE patients, 38 healthy controls, 6 patients with systemic sclerosis (SSc), and 6 patients with rheumatoid arthritis (RA) were included. The numbers of annexin V binding MPs displaying IgG, IgM, or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP IgG load was determined by flow cytometric analysis of all samples from SLE patients and healthy controls. RESULTS: SLE patients had significantly increased total and relative numbers of IgG-positive MPs (P = 0.0004), with a much higher average IgG load per MP (P < 0.0001) than healthy controls. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q levels in SLE patients. In RA and SSc patients, the average IgG load per MP was significantly lower than in SLE patients (P = 0.006 and P = 0.05, respectively). Also, the IgM load and C1q load per MP were significantly higher in SLE patients than in the control groups (P < 0.05), except for IgM in the RA group. IgG-positive MPs were significantly associated with the presence of anti-double-stranded DNA, anti-extractable nuclear antigen, and antihistone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG load per MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and complement consumption. CONCLUSION: Our findings indicate that circulating cell-derived MPs in SLE patients carry increased loads of IgG, IgM, and C1q and that IgG MPs are associated with autoantibodies and complement activation. The findings link immunologic reactions on MPs with the etiology of SLE. PMID- 22238052 TI - DNA methylation biomarker candidates for early detection of colon cancer. AB - Promoter CpG island hypermethylation of tumor suppressor genes is a common hallmark of all human cancers. Many researchers have been looking for potential epigenetic therapeutic targets in cancer using gene expression profiling with DNA microarray approaches. Our recent genome-wide platform of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that FBN2 and TCERG1L gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. In this study, promoter DNA hypermethylation of FBN2 and TCERG1L in CRC occurs as an early and cancer specific event in colorectal cancer. Both genes showed high frequency of methylation in colon cancer cell lines (>80% for both of genes), adenomas (77% for FBN2, 90% for TCERG1L, n = 39), and carcinomas (86% for FBN2, 99% for TCERG1L, n = 124). Bisulfite sequencing confirmed cancer-specific methylation of FBN2 and TCERG1L of promoters in colon cancer cell line and cancers but not in normal colon. Methylation of FBN2 and TCERG1L is accompanied by downregulation in cell lines and in primary tumors as described in the OncomineTM website. Together, our results suggest that gene silencing of FBN2 and TCERG1L is associated with promoter DNA hypermethylation in CRC tumors and may be excellent biomarkers for the early detection of CRC. PMID- 22238054 TI - Hindfoot joint pressure in supination sprains. AB - BACKGROUND: Hindfoot trauma including ankle and subtalar sprains may be followed by osteochondral lesions and persisting pain originating from posttraumatic arthritis. HYPOTHESIS: "Acute severe" supination sprains and "mild supination sprains with increasing ligamentous incompetence" of the hindfoot lead to medial ankle and subtalar stress concentrations that may contribute to osteochondral lesions (OCLs) and subsequent arthritis. STUDY DESIGN: Controlled laboratory study. METHODS: "Acute severe" sprains and "mild sprains with increasing ligamentous incompetence" (consecutive anterior talofibular ligament [ATFL], calcaneofibular ligament [CFL], and lateral talocalcaneal ligament [LTCL] transections) were simulated in human lower leg specimens (7 different specimens for each condition). The effect on the migration of the center of force (COF) and on the tibiotalar and subtalar pressures at 700-N (acute severe) and 150-N (mild sprain with increasing ligamentous incompetence) axial static and dynamic loads, respectively, was recorded using pressure sensors. RESULTS: In the "acute severe" sprain, the peak pressure increase reached the level of significance in the ankle (P = .042) and in the subtalar medial facet (P = .046). The ankle COF migrated significantly toward the medial (P = .001) and posterior (P = .023) directions. In the "mild sprain with increasing ligamentous incompetence" condition, the ankle (P = .018) and subtalar (medial facet, P = .022) peak pressure increased significantly with intact ligaments and with all ligaments cut. The ankle COF migrated significantly toward the medial direction when the ATFL and CFL or when all 3 ligaments were severed. The anteroposterior ankle COF migration was anterior when all ligaments were intact or when only the ATFL was severed but posterior when the CFL or when the CFL and the LTCL were severed in addition. CONCLUSION: Next to chronic inhomogeneous load distribution in the unstable hindfoot and shear stress during sprains, intra-articular pressure elevation (impact) in the ankle and subtalar joint during hindfoot supination sprains with intact ligaments or incompetent ligaments likely contributes to OCLs of the medial talar dome and the medial subtalar facet. CLINICAL RELEVANCE: Intra articular hindfoot pressure elevation (impact) in "acute severe" and in "mild hindfoot supination sprains with increasing ligamentous incompetence" is substantial for the development of OCLs at the medial midtalar dome and the medial facet of the subtalar joint. PMID- 22238053 TI - Quantitative expression analysis of the apoptosis-related genes BCL2, BAX and BCL2L12 in gastric adenocarcinoma cells following treatment with the anticancer drugs cisplatin, etoposide and taxol. AB - The BCL2 family of proteins includes apoptosis-related molecules involved in normal physiology, as well as cancer pathology. Members of our team have discovered and cloned the novel gene BCL2L12, which codes for a protein member of the BCL2 family. The BCL2L12 expression has been studied extensively in various types of cancer and its important clinical value has been underlined. The main objective of this study is the relative quantification of the mRNA expression of the apoptosis-related genes BCL2, BAX and BCL2L12 in gastric cancer cells, following treatment with anticancer drugs. Gastric adenocarcinoma cells AGS were treated with various concentrations of the chemical substances cisplatin, etoposide and taxol for three time periods. Cell viability was examined by using the MTT assay. Total RNA was extracted and reverse transcribed into cDNA. A highly sensitive, quantitative real-time PCR method was developed based on the SYBR Green chemistry, for the proper mRNA quantification. GAPDH was used as a housekeeping gene. Relative quantification analysis was performed by using the comparative C(T) method ([Formula: see text]). Treatment of AGS cells with 10 MUM cisplatin, 0.5 MUM etoposide and 10 nM taxol affected the BCL2, BAX and BCL2L12 mRNA levels, compared to the untreated cells. Cisplatin and etoposide induced a major down-regulation in the BCL2 mRNA levels after 72 h of treatment, while the BAX mRNA levels were slightly up-regulated. Moreover, taxol had an up-regulating effect on both BCL2 and BAX transcript levels after 48 h of incubation. Chemotherapy had a much smaller effect on the BCL2L12 expression levels, eventually characterised by a small down-regulation. PMID- 22238055 TI - Prospective analysis of failure rate and predictors of failure after anatomic anterior cruciate ligament reconstruction with allograft. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is one of the most frequently performed orthopaedic procedures. Failures are a reality of surgery; to limit failures, we must first understand and quantify them. PURPOSE: The purposes of this study were to determine the rate and factors associated with graft failure after anatomic ACL reconstruction performed with allograft. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All consecutive subjects who underwent anatomic single- or double-bundle ACL reconstruction with allograft between January 2007 and December 2009 were included and followed clinically. Graft failure was defined as patient-reported instability, pathological laxity during the physical examination, or evidence of a failed graft on magnetic resonance imaging or during arthroscopy. Potential predictors of graft failure that were explored included subject age, sex, height, weight, body mass index, meniscus injury, and time of return to preinjury sports. RESULTS: There were 206 subjects included in this study: 168 double-bundle and 38 single-bundle reconstructions. Overall, 27 (13%) subjects experienced graft failure. Twenty three (13%) double-bundle subjects failed. The characteristics associated with double-bundle graft failure were younger age (19 vs 25 years, P < .001) and earlier return to sports (at 222 vs 267 days, P = .007). Four (11%) of the single bundle subjects failed. The characteristics associated with single-bundle graft failure were younger age (19 vs 24 years, P = .049) and increased body mass (83 vs 65 kg, P = .031). CONCLUSION: The overall graft failure rate after anatomic ACL reconstruction with allograft was 13%. Younger age, earlier return to sports, and a higher body weight were associated with graft failure. PMID- 22238056 TI - Representative baseline values on the Sport Concussion Assessment Tool 2 (SCAT2) in adolescent athletes vary by gender, grade, and concussion history. AB - BACKGROUND: To improve and standardize the sideline evaluation of sports-related concussion, the Sport Concussion Assessment Tool 2 (SCAT2) was developed. This tool assesses concussion-related signs and symptoms, cognition, balance, and coordination. This newly published assessment tool has not established representative baseline data on adolescent athletes. HYPOTHESIS: Representative baseline SCAT2 scores in adolescent athletes will differ by gender, grade in school, and self-reported concussion history. STUDY DESIGN: Descriptive epidemiology study. METHODS: Interscholastic athletes were administered the SCAT2 during a preseason concussion baseline testing session. The SCAT2 total score ranges from 0 to 100 points, with lower scores indicating poorer performance. Overall, representative values were calculated using descriptive statistics. Separate independent-samples t tests, with gender and concussion history as the independent variables, and a 1-way analysis of variance, with grade as the independent variable, were conducted to assess differences in SCAT2 total score (P < .05). RESULTS: There were 1134 high school athletes (872 male and 262 female) who participated. The SCAT2 total score across all participants was 88.3 +/- 6.8 (range, 58-100); skewness was -0.86 +/- 0.07, and kurtosis was 0.73 +/- 0.14. Male athletes scored significantly lower on the SCAT2 total score (P = .03; 87.7 +/- 6.8 vs 88.7 +/- 6.8), and 9th graders (86.9 +/- 6.8) scored significantly lower than 11th (88.7 +/- 7.0) and 12th (89.0 +/- 6.6) graders (P < .001). Athletes with a self-reported concussion history scored significantly lower on the SCAT2 total score than those with no concussion history (P < .001; 87.0 +/- 6.8 vs 88.7 +/- 6.5). CONCLUSION: These data provide representative scores on the SCAT2 in adolescent athletes and show that male athletes, 9th graders, and those with a self-reported concussion history scored significantly lower than their female, upperclassmen, or nonconcussed peers. CLINICAL RELEVANCE: These results suggest that healthy adolescent athletes display variability on the SCAT2 at baseline. Therefore, clinicians should administer baseline assessments of the SCAT2 because assuming a perfect baseline score of 100 points is not appropriate in an adolescent athlete population. PMID- 22238057 TI - Observer agreement on the Dejour trochlear dysplasia classification: a comparison of true lateral radiographs and axial magnetic resonance images. AB - BACKGROUND: Trochlear dysplasia is known to be an important cause of patellofemoral instability. D. Dejour's radiographic and magnetic resonance imaging (MRI) classifications are widely used in clinical practice and in the orthopaedic literature to assess the severity of trochlear dysplasia. The indication for deepening trochleoplasty to treat trochlear dysplasia is also mainly based on the severity of trochlear dysplasia according to Dejour's criteria. PURPOSE: To our knowledge, there is no study evaluating the efficacy of the Dejour classification. The aim of this study was to assess the intraobserver and interobserver agreements of the radiographic and MRI-based classification as described by Dejour. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: From 50 patients, 50 lateral radiographs as well as 50 MRI scans were read twice independently within 4 weeks by 4 surgeons (2 senior and 2 junior examiners). Analysis was made according to Dejour's 4 grades of radiological criteria of trochlear dysplasia as well as differentiating between 2 grades: low grade (type A) and high-grade trochlear dysplasia (types B-D). RESULTS: The 4 grade analysis showed fair intraobserver and interobserver agreements (24%-78%), while the 2-grade analysis showed good to excellent agreement (56%-96%). The best overall agreement was found for the 2-grade analysis on MRI scans (62%-96%). The lateral radiographs tended to underestimate the severity of trochlear dysplasia compared with axial MRI. CONCLUSION: D. Dejour's classification is valid for typing trochlear dysplasia and is particularly useful in separating low-grade from high-grade dysplasia. PMID- 22238058 TI - Ultrasound-guided sclerosis of neovessels in patellar tendinopathy: a prospective study of 101 patients. AB - BACKGROUND: A randomized controlled study has shown promising clinical results after treatment with sclerosing injections in a group of patients with patellar tendinopathy, but no study has investigated medium- or long-term outcome in a large and unselected group of patients. PURPOSE: To investigate if sclerosing treatment would affect the level of patellar tendon pain and knee function after 24 months in a large group of patients with patellar tendinopathy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This prospective study recruited patients with a clinical diagnosis of jumper's knee and visible neovascularization corresponding to the painful area on power Doppler ultrasound. They received up to a maximum of 5 ultrasound-guided sclerosing injections using polidocanol at 4- to 6-week intervals. Knee pain and function were recorded using the Victorian Institute of Sport Assessment-Patella (VISA-P) score before treatment and 6, 12, and 24 months after the first injection. RESULTS: In total, 101 patients (15 women and 86 men) with 120 tendons were included and given from 1 to 5 sclerosing injections (mean [SD], 2.5 [0.9]). The patients reported a significantly improved VISA-P score from baseline (mean, 39; 95% confidence interval [CI], 36-42) to the 24-month follow-up (mean, 65; 95% CI, 60-70) (range, 21-100; P < .001, paired t test). However, a VISA-P score of >95 points was reported in only 22 cases (20%), whereas 37 cases (36%) reported a VISA-P score of <50 at 24 months. CONCLUSION: Sclerosing treatment with polidocanol resulted in a moderate improvement in knee function and reduced pain in a heterogeneous group of patients with patellar tendinopathy. Nevertheless, few of the patients were cured, and the majority still had reduced function and substantial pain after 24 months of follow-up. PMID- 22238059 TI - Haploidentical stem cell transplantation for children with high-risk leukemia. AB - BACKGROUND: The Chilean population is ethnically diverse, and more than 50% of children referred for hematopoietic stem cell transplantation (HSCT) lack a suitable donor. PROCEDURE: To expand the donor pool, we assessed the feasibility, tolerance, and efficacy of using a haploidentical (HI) donor and a reduced intensity conditioning regimen for high-risk pediatric leukemia. This study was facilitated by technology transfer from St. Jude Children's Research Hospital over the 2 preceding years. RESULTS: Between March 2006 and April 2009, 10 patients (median age, 9.8 years) received T cell-depleted grafts at Calvo Mackenna Hospital in Santiago. Median cell doses were CD34+: 7.45 * 10(6)/kg (range, 4.00-20.20 * 10(6)/kg); CD3+: 0.88 * 10(5)/kg (0.11-1.35 * 10(5)/kg); and CD56+: 71.30 * 10(6)/kg (31.50-131.80 * 10(6)/kg). Nine patients experienced complete engraftment; six of the nine remain alive and clinically well 13-50 months post-HSCT. Three patients died after bone marrow relapse, while only one died of transplant-related causes. Virus reactivation was the main post transplant complication: 5/10 had positive CMV PCR but none had CMV disease. One patient developed acute GvHD > grade II and only one had chronic GvHD. CONCLUSIONS: HI-HSCT is feasible in our setting, offers a rational treatment option, and expands the donor pool significantly for children with high-risk leukemia in a developing country. This information is especially relevant to other ethnically diverse populations that are poorly represented in international donor registries. PMID- 22238060 TI - A systematic review of the associations between empathy measures and patient outcomes in cancer care. AB - OBJECTIVE: Despite a call for empathy in medical settings, little is known about the effects of the empathy of health care professionals on patient outcomes. This review investigates the links between physicians' or nurses' empathy and patient outcomes in oncology. METHOD: With the use of multiple databases, a systematic search was performed using a combination of terms and subject headings of empathy or perspective taking or clinician-patient communication, oncology or end-of-life setting and physicians or nurses. Among the 394 hits returned, 39 studies met the inclusion criteria of a quantitative measure of empathy or empathy-related constructs linked to patient outcomes. RESULTS: Empathy was mainly evaluated using patient self-reports and verbal interaction coding. Investigated outcomes were mainly proximal patient satisfaction and psychological adjustment. Clinicians' empathy was related to higher patient satisfaction and lower distress in retrospective studies and when the measure was patient-reported. Coding systems yielded divergent conclusions. Empathy was not related to patient empowerment (e.g. medical knowledge, coping). CONCLUSION: Overall, clinicians' empathy has beneficial effects according to patient perceptions. However, in order to disentangle components of the benefits of empathy and provide professionals with concrete advice, future research should apply different empathy assessment approaches simultaneously, including a perspective-taking task on patients' expectations and needs at precise moments. Indeed, clinicians' understanding of patients' perspectives is the core component of medical empathy, but it is often assessed only from the patient's point of view. Clinicians' evaluations of patients' perspectives should be studied and compared with patients' reports so that problematic gaps between the two perspectives can be addressed. PMID- 22238061 TI - Engineering gibberellin metabolism in Solanum nigrum L. by ectopic expression of gibberellin oxidase genes. AB - Gibberellins (GAs) control many aspects of plant development, including seed germination, shoot growth, flower induction and growth and fruit expansion. Leaf explants of Solanum nigrum (Black Nightshade; Solanaceae) were used for Agrobacterium-mediated delivery of GA-biosynthetic genes to determine the influence of their encoded enzymes on the production of bioactive GAs and plant stature in this species. Constructs were prepared containing the neomycin phosphotransferase (nptII) gene for kanamycin resistance as a selectable marker, and the GA-biosynthetic genes, their expression under the control of the CaMV 35S promoter. The GA-biosynthetic genes comprised AtGA20ox1, isolated from Arabidopsis thaliana, the product from which catalyses the formation of C(19) GAs, and MmGA3ox1 and MmGA3ox2, isolated from Marah macrocarpus, which encode functionally different GA 3-oxidases that convert C(19)-GAs to biologically active forms. Increase in stature was observed in plants transformed with AtGA20ox1, MmGA3ox2 and MmGA3ox1 + MmGA3ox2, their presence and expression being confirmed by PCR and RT-PCR, respectively, accompanied by an increase in GA(1) content. Interestingly, MmGA3ox1 alone did not induce a sustained increase in plant height, probably because of only a marginal increase in bioactive GA(1) content in the transformed plants. The results are discussed in the context of regulating plant stature, since this strategy would decrease the use of chemicals to promote plant growth. PMID- 22238062 TI - Molecular cloning and characterization of seven class III peroxidases induced by overexpression of the agrobacterial rolB gene in Rubia cordifolia transgenic callus cultures. AB - Here, seven new class III peroxidase genes of Rubia cordifolia L., RcPrx01 RcPrx07, were isolated and characterized. Expression of the Prx genes was studied in R. cordifolia aerial organs as well as in cells transformed with the rolB and rolC genes of Agrobacterium rhizogenes and cells transformed with the wild-type A. rhizogenes A4 strain. In rolC- and rolB-transformed cells, the rol genes were expressed under the control of the 35S promoter, whereas in A. rhizogenes A4 transformed cells the rol genes were expressed under the control of their native promoters. All studied peroxidase genes were greatly upregulated in rolB overexpressing cells. In contrast, overexpression of the rolC gene and expression of the rol genes under the control of their native promoters had little effect on the abundance of peroxidase transcripts. In accordance with this observation, peroxidase activity was substantially increased in rolB cells and was slightly affected in other transformed cells. Our results indicate that rolB strictly affects the regulation of a set of seven R. cordifolia class III peroxidases. PMID- 22238063 TI - Characterization and genetic analysis of an EIN4-like sequence (CaETR-1) located in QTL(AR1) implicated in ascochyta blight resistance in chickpea. AB - Two alleles of a chickpea (Cicer arietinum L.) ethylene receptor-like sequence (CaETR-1) were sequence-characterized using synteny analysis with genome sequences of Medicago truncatula L. The full length of the sequence obtained in the accession FLIP84-92C resistant to ascochyta blight (CaETR-1a) span 4,428 bp, including the polyadenylation signal in the 3'-untranslated region (UTR), whereas it has a 730 bp deletion in the 3'-UTR region in the susceptible accession PI359075 (CaETR-1b). The deduced protein belongs to subfamily II of the ethylene receptors and contains all the domains that define EIN4 homologs in Arabidopsis. The EIN4-like sequence (CaETR-1) has been mapped using a recombinant inbred line (RIL) population derived from an intraspecific cross between ILC3279 and WR315, resistant and susceptible to blight, respectively. The locus was located in LGIVa of the genetic map, flanked by markers NCPGR91 and GAA47 (at distances of 11.3 and 17.9 cM, respectively). This is the first potentially functional sequence identified under a QTL peak for ascochyta blight resistance in chickpea (QTL(AR1)). This EIN4-like (CaETR-1) sequence explained up to 33.8% of the total phenotypic variation. This sequence could be directly related to blight resistance, together with other QTLs that have been found to be involved in resistance to this major chickpea disease. PMID- 22238064 TI - Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis. AB - Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic. PMID- 22238066 TI - The basic theory, diagnostic, and therapeutic system of traditional Chinese medicine and the challenges they bring to statistics. AB - Traditional Chinese medicine (TCM) has an unique theory system and abundant preventative and therapeutic methods. In recent years, TCM has gradually become the hot topic of application and research around the world. This paper introduces how TCM uses the theory of yin-yang and five-phase to explain the mechanism of balancing the function of human body, the methods of diagnosing, abundant therapeutic methods and technologies, and treating principles, analyzes the features of TCM, and points out some of the problems waitiing to be solved in TCM scientific researches and statistical analysis. PMID- 22238065 TI - Production of different glycosylation variants of the tumour-targeting mAb H10 in Nicotiana benthamiana: influence on expression yield and antibody degradation. AB - We previously described the expression of a tumour-targeting antibody (mAb H10) in Nicotiana benthamiana by vacuum-agro-infiltration and the remarkable yields of highly pure protein achieved. The objective of the present work was to investigate different strategies for transient overexpression of the mAb H10 in which glycan configuration was modulated and assess how these strategies affect the accumulation yield and stability of the antibody. To this aim, three procedures have been assayed: (1) Site-directed mutagenesis to abolish the glycosylation site; (2) endoplasmic reticulum retention (C-terminal SEKDEL fusion) to ensure predominantly high-mannose type glycans; and (3) expression in a N. benthamiana RNAi down-regulated line in which beta1,2-xylosyltransferase and alpha1,3-fucosyltransferase gene expression is silenced. The three antibody variants (H10-Mut) (H10-SEKDEL) (H10(XylT/FucT)) were transiently expressed, purified and characterised for their glycosylation profile, expression/purification yield and antibody degradation pattern. Glycosylation analysis of H10(XylT/FucT) demonstrated the absence of plant complex-type sugars, while H10-SEKDEL, although substantially retained in the ER, revealed the presence of beta1,2-xylose and alpha1,3-fucose residues, indicating a partial escape from the ER retrieval system. Antibody accumulation and purification yields were not enhanced by ER retention. All H10 antibody glyco-forms revealed greater degradation compared to the original, resulting mostly in the formation of Fab fragments. In the case of aglycosylated H10-Mut, more than 95% of the heavy chain was cleaved, confirming the pivotal role of the sugar moiety in protein stability. Identification of possible 'fragile' sites in the H10 antibody hinge region could be of general interest for the development of new strategies to reduce antibody degradation and increase the yield of intact IgGs in plants. PMID- 22238067 TI - Inter- versus intra-molecular cyclization of tripeptides containing tetrahydrofuran amino acids: a density functional theory study on kinetic control. AB - Density functional B3LYP method was used to investigate the preference of intra- and inter-molecular cyclizations of linear tripeptides containing tetrahydrofuran amino acids. Two distinct model pathways were conceived for the cyclization reaction, and all possible transition states and intermediates were located. Analysis of the energetics indicate intermolecular cyclization being favored by both thermodynamic and kinetic control. Geometric and NBO analyses were performed to explain the trends obtained along both the reaction pathways. Conceptual density functional theory-based reactive indices also show that reaction pathways leading to intermolecular cyclization of the tripeptides are relatively more facile compared to intramolecular cyclization. PMID- 22238068 TI - Theoretical investigation of the enzymatic phosphoryl transfer of beta phosphoglucomutase: revisiting both steps of the catalytic cycle. AB - Enzyme catalyzed phosphate transfer is a part of almost all metabolic processes. Such reactions are of central importance for the energy balance in all organisms and play important roles in cellular control at all levels. Mutases transfer a phosphoryl group while nucleases cleave the phosphodiester linkages between two nucleotides. The subject of our present study is the Lactococcus lactis beta phosphoglucomutase (beta-PGM), which effectively catalyzes the interconversion of beta-D-glucose-1-phosphate (beta-G1P) to beta-D-glucose-6-phosphate (beta-G6P) and vice versa via stabile intermediate beta-D-glucose-1,6-(bis)phosphate (beta G1,6diP) in the presence of Mg(2+). In this paper we revisited the reaction mechanism of the phosphoryl transfer starting from the bisphosphate beta-G1,6diP in both directions (toward beta-G1P and beta-G6P) combining docking techniques and QM/MM theoretical method at the DFT/PBE0 level of theory. In addition we performed NEB (nudged elastic band) and free energy calculations to optimize the path and to identify the transition states and the energies involved in the catalytic cycle. Our calculations reveal that both steps proceed via dissociative pentacoordinated phosphorane, which is not a stabile intermediate but rather a transition state. In addition to the Mg(2+) ion, Ser114 and Lys145 also play important roles in stabilizing the large negative charge on the phosphate through strong coordination with the phosphate oxygens and guiding the phosphate group throughout the catalytic process. The calculated energy barrier of the reaction for the beta-G1P to beta-G1,6diP step is only slightly higher than for the beta G1,6diP to beta-G6P step (16.10 kcal mol(-1) versus 15.10 kcal mol(-1)) and is in excellent agreement with experimental findings (14.65 kcal mol(-1)). PMID- 22238069 TI - Transthoracic echocardiography visualization of bicaval dual lumen catheters for veno-venous extracorporeal membrane oxygenation. AB - Bicaval dual lumen catheters improve the efficiency of veno-venous extracorporeal membrane oxygenation by minimizing recirculation with an innovative design, which requires precise placement of three catheter ports in the superior vena cava, right atrium, and inferior vena cava, respectively. However, the exact position of these catheter ports is usually not known during placement because they cannot be visualized with conventional radiography. We performed a retrospective review of our experience over the past year using transthoracic echocardiography to evaluate the position of the catheter ports. From a subcostal, sagittal imaging approach, we were able to identify all three catheter ports in 11 of 11 studies. At least one of the catheter ports was incorrectly positioned in 5 of 11 studies. Further prospective evaluation is necessary to determine if catheter repositioning based on transthoracic echocardiography findings can further improve the clinical efficiency of veno-venous extracorporeal membrane oxygenation. PMID- 22238070 TI - Stacked platinum complexes of the magnus' salt type inside a coordination cage. AB - Neatly wrapped up: alternately stacked square-planar platinum(II) complexes inside a dinuclear coordination cage were prepared to give a discrete and soluble Pt(5) -array of the Magnus' salt type. Characterization of the complex in solution was complemented by an X-ray crystal structure of {[Pt(pyridine)(4)]? [PtCl(4)](2) @Cage}; this structure showed the linear, pentanuclear array within the cages and their circular packing into a hollow tubular superstructure. PMID- 22238071 TI - Interferon-gamma release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. AB - OBJECTIVE: To evaluate the performance of an interferon-gamma release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti-tumor necrosis factor therapy in patients with autoimmune inflammatory diseases. METHODS: This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test. RESULTS: In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157-0.279; P=0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guerin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P=0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P=0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported. CONCLUSION: In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST. PMID- 22238072 TI - A cell-delivered and cell-activated SN38-dextran prodrug increases survival in a murine disseminated pancreatic cancer model. AB - Enzyme-activated prodrugs have been investigated and sought after as highly specific, low-side-effect treatments, especially for cancer therapy. Unfortunately, excellent targets for enzyme-activated therapy are rare. Here a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site is demonstrated. Raw264.7 cells (mouse monocyte/macrophage-like cells, Mo/Ma) are engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression is regulated by the TetOn(r) system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan-like prodrug, which is conjugated to dextran and can be loaded into the cytoplasm of Mo/Ma, is synthesized. To test the system, a murine pancreatic cancer model is generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma are loaded with the prodrug and are injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrates that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system, which is self-contained within tumor-homing cells and can prolong the life of i.p. pancreatic tumor bearing mice, is demonstrated. PMID- 22238073 TI - SOCS1 is significantly up-regulated in Nutlin-3-treated p53wild-type B chronic lymphocytic leukemia (B-CLL) samples and shows an inverse correlation with miR 155. AB - The basal SOCS1 mRNA levels were significantly lower in p53(mutated) BJAB and MAVER leukemic cell lines with respect to p53(wild-type) SKW6.4 and JVM-2 leukemic cell lines, p53(wild-type) primary B chronic lymphocytic leukemia (B CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53(wild-type) B-CLL cells as well as in p53(wild-type) B leukemic cell lines, but not in p53(mutated) B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important therapeutic target of Nutlin-3 in B-CLL. PMID- 22238074 TI - Bouveret's syndrome: endoscopic or surgical treatment. PMID- 22238075 TI - The role of beta-frequency neural oscillations in motor control. PMID- 22238077 TI - Genetic analysis of DSCAM's role as a Netrin-1 receptor in vertebrates. AB - Down syndrome cell adhesion molecule (DSCAM) has mainly been characterized for its function as an adhesion molecule in axon growth and in self-recognition between dendrites of the same neuron. Recently, it has been shown that DSCAM can bind to Netrin-1 and that downregulation of DSCAM expression by siRNAs in chick and rodent spinal cords leads to impaired growth and turning response of commissural axons to Netrin-1. To investigate the effect of complete genetic ablation of DSCAM on Netrin-1-induced axon guidance, we analyzed spinal commissural neurons in DSCAM-null mice and found that they extend axons that reach and cross the floor plate and express apparently normal levels of the Netrin receptors DCC (deleted in colorectal carcinoma) and Neogenin. In vitro, commissural neurons in dorsal spinal cord explants of DSCAM-null embryos show normal outgrowth in response to Netrin-1. We therefore conclude that DSCAM is not required for Netrin-induced commissural axon outgrowth and guidance in mice. PMID- 22238076 TI - Inner hair cells are not required for survival of spiral ganglion neurons in the adult cochlea. AB - Studies of sensorineural hearing loss have long suggested that survival of spiral ganglion neurons (SGNs) depends on trophic support provided by their peripheral targets, the inner hair cells (IHCs): following ototoxic drugs or acoustic overexposure, IHC death is rapid whereas SGN degeneration is always delayed. However, recent noise-trauma studies show that SGNs can die even when hair cells survive, and transgenic mouse models show that supporting cell dysfunction can cause SGN degeneration in the absence of IHC pathology. To reexamine this issue, we studied a model of IHC loss that does not involve noise or ototoxic drugs. Mice lacking the gene for the high-affinity thiamine transporter (Slc19a2) have normal cochlear structure and function when fed a regular (thiamine-rich) diet. However, dietary thiamine restriction causes widespread, rapid (within 10 d) loss of IHCs. Using this model, we show that SGNs can survive for months after IHC loss, indicating that (1) IHCs are not necessary for neuronal survival, (2) neuronal loss in the other hearing loss models is likely due to effects of the trauma on the sensory neurons or other inner ear cells, and (3) that other cells, most likely supporting cells of the organ of Corti, are the main source of SGN survival factors. These results overturn a long-standing dogma in the study of sensorineural hearing loss and highlight the importance of cochlear supporting cells in neuronal survival in the adult inner ear. PMID- 22238078 TI - Central adaptation to odorants depends on PI3K levels in local interneurons of the antennal lobe. AB - We have previously shown that driving PI3K levels up or down leads to increases or reductions in the number of synapses, respectively. Using these tools to assay their behavioral effects in Drosophila melanogaster, we showed that a loss of synapses in two sets of local interneurons, GH298 and krasavietz, leads to olfaction changes toward attraction or repulsion, while the simultaneous manipulation of both sets of neurons restored normal olfactory indexes. We show here that olfactory central adaptation also requires the equilibrated changes in both sets of local interneurons. The same genetic manipulations directed to projection (GH146) or mushroom body (201Y, MB247) neurons did not affect adaptation. Also, we show that the equilibrium is a requirement for the glomerulus-specific size changes which are a morphological signature of central adaptation. Since the two sets of local neurons are mostly, although not exclusively, inhibitory (GH298) and excitatory (krasavietz), we interpret that the normal phenomena of sensory perception, measured as an olfactory index, and central adaptation rely on an inhibition/excitation ratio. PMID- 22238079 TI - Cross-frequency phase-phase coupling between theta and gamma oscillations in the hippocampus. AB - Neuronal oscillations allow for temporal segmentation of neuronal spikes. Interdependent oscillators can integrate multiple layers of information. We examined phase-phase coupling of theta and gamma oscillators in the CA1 region of rat hippocampus during maze exploration and rapid eye movement sleep. Hippocampal theta waves were asymmetric, and estimation of the spatial position of the animal was improved by identifying the waveform-based phase of spiking, compared to traditional methods used for phase estimation. Using the waveform-based theta phase, three distinct gamma bands were identified: slow gamma(S) (gamma(S); 30-50 Hz), midfrequency gamma(M) (gamma(M); 50-90 Hz), and fast gamma(F) (gamma(F); 90 150 Hz or epsilon band). The amplitude of each sub-band was modulated by the theta phase. In addition, we found reliable phase-phase coupling between theta and both gamma(S) and gamma(M) but not gamma(F) oscillators. We suggest that cross-frequency phase coupling can support multiple time-scale control of neuronal spikes within and across structures. PMID- 22238080 TI - Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments. AB - Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific gene environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes. PMID- 22238081 TI - Saccadic interception of a moving visual target after a spatiotemporal perturbation. AB - Animals can make saccadic eye movements to intercept a moving object at the right place and time. Such interceptive saccades indicate that, despite variable sensorimotor delays, the brain is able to estimate the current spatiotemporal (hic et nunc) coordinates of a target at saccade end. The present work further tests the robustness of this estimate in the monkey when a change in eye position and a delay are experimentally added before the onset of the saccade and in the absence of visual feedback. These perturbations are induced by brief microstimulation in the deep superior colliculus (dSC). When the microstimulation moves the eyes in the direction opposite to the target motion, a correction saccade brings gaze back on the target path or very near. When it moves the eye in the same direction, the performance is more variable and depends on the stimulated sites. Saccades fall ahead of the target with an error that increases when the stimulation is applied more caudally in the dSC. The numerous cases of compensation indicate that the brain is able to maintain an accurate and robust estimate of the location of the moving target. The inaccuracies observed when stimulating the dSC that encodes the visual field traversed by the target indicate that dSC microstimulation can interfere with signals encoding the target motion path. The results are discussed within the framework of the dual-drive and the remapping hypotheses. PMID- 22238082 TI - Adaptation of binaural processing in the adult brainstem induced by ambient noise. AB - Interaural differences in stimulus intensity and timing are major cues for sound localization. In mammals, these cues are first processed in the lateral and medial superior olive by interaction of excitatory and inhibitory synaptic inputs from ipsi- and contralateral cochlear nucleus neurons. To preserve sound localization acuity following changes in the acoustic environment, the processing of these binaural cues needs neuronal adaptation. Recent studies have shown that binaural sensitivity adapts to stimulation history within milliseconds, but the actual extent of binaural adaptation is unknown. In the current study, we investigated long-term effects on binaural sensitivity using extracellular in vivo recordings from single neurons in the dorsal nucleus of the lateral lemniscus that inherit their binaural properties directly from the lateral and medial superior olives. In contrast to most previous studies, we used a noninvasive approach to influence this processing. Adult gerbils were exposed for 2 weeks to moderate noise with no stable binaural cue. We found monaural response properties to be unaffected by this measure. However, neuronal sensitivity to binaural cues was reversibly altered for a few days. Computational models of sensitivity to interaural time and level differences suggest that upregulation of inhibition in the superior olivary complex can explain the electrophysiological data. PMID- 22238083 TI - Perceptual learning reduces crowding in amblyopia and in the normal periphery. AB - Amblyopia is a developmental visual disorder of cortical origin, characterized by crowding and poor acuity in central vision of the affected eye. Crowding refers to the adverse effects of surrounding items on object identification, common only in normal peripheral but not central vision. We trained a group of adult human amblyopes on a crowded letter identification task to assess whether the crowding problem can be ameliorated. Letter size was fixed well above the acuity limit, and letter spacing was varied to obtain spacing thresholds for central target identification. Normally sighted observers practiced the same task in their lower peripheral visual field. Independent measures of acuity were taken in flanked and unflanked conditions before and after training to measure crowding ratios at three fixed letter separations. Practice improved the letter spacing thresholds of both groups on the training task, and crowding ratios were reduced after posttest. The reductions in crowding in amblyopes were associated with improvements in standard measures of visual acuity. Thus, perceptual learning reduced the deleterious effects of crowding in amblyopia and in the normal periphery. The results support the effectiveness of plasticity-based approaches for improving vision in adult amblyopes and suggest experience-dependent effects on the cortical substrates of crowding. PMID- 22238084 TI - Predicting conceptual processing capacity from spontaneous neuronal activity of the left middle temporal gyrus. AB - Conceptual processing is a crucial brain function for humans. Past research using neuropsychological and task-based functional brain-imaging paradigms indicates that widely distributed brain regions are related to conceptual processing. Here, we explore the potential contribution of intrinsic or spontaneous brain activity to conceptual processing by examining whether resting-state functional magnetic resonance imaging (rs-fMRI) signals can account for individual differences in the conceptual processing efficiencies of healthy individuals. We acquired rs-fMRI and behavioral data on object conceptual processing tasks. We found that the regional amplitude of spontaneous low-frequency fluctuations in the blood oxygen level-dependent signal in the left (posterior) middle temporal gyrus (LMTG) was highly correlated with participants' semantic processing efficiency. Furthermore, the strength of the functional connectivity between the LMTG and a series of brain regions-the left inferior frontal gyrus, bilateral anterior temporal lobe, bilateral medial temporal lobe, posterior cingulate gyrus, and ventromedial and dorsomedial prefrontal cortices-also significantly predicted conceptual behavior. The regional amplitude of low-frequency fluctuations and functionally relevant connectivity strengths of LMTG together accounted for 74% of individual variance in object conceptual performance. This semantic network, with the LMTG as its core component, largely overlaps with the regions reported in previous conceptual/semantic task-based fMRI studies. We conclude that the intrinsic or spontaneous activity of the human brain reflects the processing efficiency of the semantic system. PMID- 22238085 TI - Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons. AB - Motor neurons that control limb movements are organized as a neuronal nucleus in the developing ventral horn of the spinal cord called the lateral motor column. Neuronal migration segregates motor neurons into distinct lateral and medial divisions within the lateral motor column that project axons to dorsal or ventral limb targets, respectively. This migratory phase is followed by an aggregation phase whereby motor neurons within a division that project to the same muscle cluster together. These later phases of motor neuron organization depend on limb regulated differential cadherin expression within motor neurons. Initially, all motor neurons display the same cadherin expression profile, which coincides with the migratory phase of motor neuron segregation. Here, we show that this early, pan-motor neuron cadherin function drives the divisional segregation of spinal motor neurons in the chicken embryo by controlling motor neuron migration. We manipulated pan-motor neuron cadherin function through dissociation of cadherin binding to their intracellular partners. We found that of the major intracellular transducers of cadherin signaling, gamma-catenin and alpha-catenin predominate in the lateral motor column. In vivo manipulations that uncouple cadherin-catenin binding disrupt divisional segregation via deficits in motor neuron migration. Additionally, reduction of the expression of cadherin-7, a cadherin predominantly expressed in motor neurons only during their migration, also perturbs divisional segregation. Our results show that gamma-catenin-dependent cadherin function is required for spinal motor neuron migration and divisional segregation and suggest a prolonged role for cadherin expression in all phases of motor neuron organization. PMID- 22238087 TI - Alteration of synaptic network dynamics by the intellectual disability protein PAK3. AB - Several gene mutations linked to intellectual disability in humans code for synaptic molecules implicated in small GTPase signaling. This is the case of the Rac/Cdc42 effector p21-activated kinase 3 (PAK3). The mechanisms responsible for the intellectual defects and the consequences of the mutation on the development and wiring of brain networks remain unknown. Here we show that expression of PAK3 mutants, suppression of PAK3, or inhibition of PAK3 function in rat hippocampal slice cultures interfere with activity-mediated spine dynamics. Inhibition of PAK3 resulted in two main alterations: (1) an increased growth of new, unstable spines, occurring in clusters, and mediated by activity; and (2) an impairment of plasticity-mediated spine stabilization interfering with the formation of persistent spines. Additionally, we find that PAK3 is specifically recruited by activity from dendrites into spines, providing a new mechanism through which PAK3 could participate in the control of both spine stabilization and local spine growth. Together, these data identify a novel function of PAK3 in regulating activity-mediated rearrangement of synaptic connectivity associated with learning and suggest that defects in spine formation and refinement during development could account for intellectual disability. PMID- 22238086 TI - Neural correlation is stimulus modulated by feedforward inhibitory circuitry. AB - Correlated variability of neural spiking activity has important consequences for signal processing. How incoming sensory signals shape correlations of population responses remains unclear. Cross-correlations between spiking of different neurons may be particularly consequential in sparsely firing neural populations such as those found in layer 2/3 of sensory cortex. In rat whisker barrel cortex, we found that pairs of excitatory layer 2/3 neurons exhibit similarly low levels of spike count correlation during both spontaneous and sensory-evoked states. The spontaneous activity of excitatory-inhibitory neuron pairs is positively correlated, while sensory stimuli actively decorrelate joint responses. Computational modeling shows how threshold nonlinearities and local inhibition form the basis of a general decorrelating mechanism. We show that inhibitory population activity maintains low correlations in excitatory populations, especially during periods of sensory-evoked coactivation. The role of feedforward inhibition has been previously described in the context of trial-averaged phenomena. Our findings reveal a novel role for inhibition to shape correlations of neural variability and thereby prevent excessive correlations in the face of feedforward sensory-evoked activation. PMID- 22238089 TI - Action reprogramming in Parkinson's disease: response to prediction error is modulated by levels of dopamine. AB - Humans are able to use knowledge of previous events to estimate the probability of future actions. Consequently, an unexpected event will elicit a prediction error as the prepared action has to be replaced by an unprepared option in a process known as "action reprogramming" (AR). Here we show that people with Parkinson's disease (PD) have a dopamine-sensitive deficit in AR that is proportional to the size of the prediction error. Participants performed a probabilistic reaction time (RT) task in the context of either a predictable or unpredictable environment. For an overall predictable sequence, PD patients, on and off dopamine medication, and healthy controls showed similar improvements in RT. However, in the context of a generally predictable sequence, PD patients off medication were impaired in reacting to unexpected events that elicit large prediction errors and require AR. Critically, this deficit in AR was modulated by the prediction error associated with the upcoming event. The prolongation of RT was not observed during an overall unpredictable sequence, in which relatively unexpected events evoke little prediction error and the requirement for AR should be minimal, given the context. The data are compatible with recent theoretical accounts suggesting that levels of dopamine encode the reliability, i.e., precision, of sensory information. In this scheme, PD patients off medication have low dopamine levels and may therefore be less confident about incoming sensory information and more reliant on top-down predictions. Consequently, when these internal predictions are incorrect, PD patients take longer to respond appropriately to unexpected sensory information. PMID- 22238090 TI - Neural prediction errors reveal a risk-sensitive reinforcement-learning process in the human brain. AB - Humans and animals are exquisitely, though idiosyncratically, sensitive to risk or variance in the outcomes of their actions. Economic, psychological, and neural aspects of this are well studied when information about risk is provided explicitly. However, we must normally learn about outcomes from experience, through trial and error. Traditional models of such reinforcement learning focus on learning about the mean reward value of cues and ignore higher order moments such as variance. We used fMRI to test whether the neural correlates of human reinforcement learning are sensitive to experienced risk. Our analysis focused on anatomically delineated regions of a priori interest in the nucleus accumbens, where blood oxygenation level-dependent (BOLD) signals have been suggested as correlating with quantities derived from reinforcement learning. We first provide unbiased evidence that the raw BOLD signal in these regions corresponds closely to a reward prediction error. We then derive from this signal the learned values of cues that predict rewards of equal mean but different variance and show that these values are indeed modulated by experienced risk. Moreover, a close neurometric-psychometric coupling exists between the fluctuations of the experience-based evaluations of risky options that we measured neurally and the fluctuations in behavioral risk aversion. This suggests that risk sensitivity is integral to human learning, illuminating economic models of choice, neuroscientific models of affective learning, and the workings of the underlying neural mechanisms. PMID- 22238088 TI - Preservation of cone photoreceptors after a rapid yet transient degeneration and remodeling in cone-only Nrl-/- mouse retina. AB - Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor neural retina leucine zipper (NRL). The loss of Nrl (Nrl(-/-)) in mice results in a retina with predominantly S-opsin-containing cones that exhibit molecular and functional characteristics of wild-type cones. Here, we report that Nrl(-/-) retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by 4 months of age, resulting in a thinner but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic electroretinogram. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of genes related to stress response and inflammation, implying their involvement in cone death. The Nrl(-/-) mouse illustrates the long-term viability of cones in the absence of rods and retinal pigment epithelium defects in a rodless retina. We propose that Nrl(-/-) retina may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone dominant human macula. PMID- 22238091 TI - Improved outcome after peripheral nerve injury in mice with increased levels of endogenous omega-3 polyunsaturated fatty acids. AB - Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. omega-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and pro-regenerative potential of omega-3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for omega-3 fatty acid desaturase, which leads to an increase in endogenous omega-3 PUFAs and a concomitant decrease in omega-6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat 1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous omega 3 PUFA could lead to beneficial effects after a PNI. PMID- 22238092 TI - GABA is excitatory in adult vasopressinergic neuroendocrine cells. AB - Neuronal excitability in the adult brain is controlled by a balance between synaptic excitation and inhibition mediated by glutamate and GABA, respectively. While generally inhibitory in the adult brain, GABA(A) receptor activation is excitatory under certain conditions in which the GABA reversal potential is shifted positive due to intracellular Cl(-) accumulation, such as during early postnatal development and brain injury. However, the conditions under which GABA is excitatory are generally either transitory or pathological. Here, we reveal GABAergic synaptic inputs to be uniformly excitatory in vasopressin (VP) secreting magnocellular neurons in the adult hypothalamus under normal conditions. The GABA reversal potential (E(GABA)) was positive to resting potential and spike threshold in VP neurons, but not in oxytocin (OT)-secreting neurons. The VP neurons lacked expression of the K(+)-Cl(-) cotransporter 2 (KCC2), the predominant Cl(-) exporter in the adult brain. The E(GABA) was unaffected by inhibition of KCC2 in VP neurons, but was shifted positive in OT neurons, which express KCC2. Alternatively, inhibition of the Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1), a Cl(-) importer expressed in most cell types mainly during postnatal development, caused a negative shift in E(GABA) in VP neurons, but had no effect on GABA currents in OT neurons. GABA(A) receptor blockade caused a decrease in the firing rate of VP neurons, but an increase in firing in OT neurons. Our findings demonstrate that GABA is excitatory in adult VP neurons, suggesting that the classical excitation/inhibition paradigm of synaptic glutamate and GABA control of neuronal excitability does not apply to VP neurons. PMID- 22238093 TI - Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities. AB - Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types, but its role in neurons remains unclear. In a proteomic screen of rat brains in which ischemic tolerance was induced by electrical stimulation of the cerebellar fastigial nucleus, we found that prohibitin is upregulated in mitochondria. This observation prompted us to investigate the role of prohibitin in neuronal death and survival. We found that prohibitin is upregulated also in the ischemic tolerance induced by transient ischemia in vivo, or oxygen-glucose deprivation in neuronal cultures. Cell fractionation and electron-microscopic immunolabeling studies demonstrated that prohibitin is localized to neuronal mitochondria. Upregulation of prohibitin in neuronal cultures or hippocampal slices was markedly neuroprotective, whereas prohibitin gene silencing increased neuronal vulnerability, an effect associated with loss of mitochondrial membrane potential and increased mitochondrial production of reactive oxygen species. Prohibitin upregulation was associated with reduced production of reactive oxygen species in mitochondria exposed to the complex I inhibitor rotenone. In addition, prohibitin protected complex I activity from the inhibitory effects of rotenone. These observations, collectively, establish prohibitin as an endogenous neuroprotective protein involved in ischemic tolerance. Prohibitin exerts beneficial effects on neurons by reducing mitochondrial free radical production. The data with complex I activity suggest that prohibitin may stabilize the function of complex I. The protective effect of prohibitin has potential translational relevance in diseases of the nervous system associated with mitochondrial dysfunction and oxidative stress. PMID- 22238094 TI - Kinases SPAK and OSR1 are upregulated by estradiol and activate NKCC1 in the developing hypothalamus. AB - In immature neurons the amino acid neurotransmitter, GABA provides the dominant mode for neuronal excitation by inducing membrane depolarization due to Cl(-) efflux through GABA(A) receptors (GABA(A)Rs). The driving force for Cl(-) is outward because the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) elevates the Cl(-) concentration in these cells. GABA-induced membrane depolarization and the resulting activation of voltage-gated Ca(2+) channels is fundamental to normal brain development, yet the mechanisms that regulate depolarizing GABA are not well understood. The neurosteroid estradiol potently augments depolarizing GABA action in the immature hypothalamus by enhancing the activity of the NKCC1 cotransporter. Understanding how estradiol controls NKCC1 activity will be essential for a complete understanding of brain development. We now report that estradiol treatment of newborn rat pups significantly increases protein levels of two kinases upstream of the NKCC1 cotransporter, SPAK (STE20/SPS1-related proline alanine rich kinase) and OSR1 (oxidative stress response kinase). The estradiol induced increase is transcription dependent, and its time course parallels that of estradiol-enhanced phosphorylation of NKCC1. Antisense oligonucleotide mediated knockdown of SPAK, and to a lesser degree of OSR1, precludes estradiol mediated enhancement of NKCC1 phosphorylation. Functionally, knockdown of SPAK or OSR1 in embryonic hypothalamic cultures diminishes estradiol-enhanced Ca(2+) influx induced by GABA(A)R activation. Our data suggest that SPAK and OSR1 may be critical factors in the regulation of depolarizing GABA-mediated processes in the developing brain. It will be important to examine these kinases with respect to sex differences and developmental brain anomalies in future studies. PMID- 22238097 TI - Tune it down to live it up? Rapid, nongenomic effects of cortisol on the human brain. AB - The stress hormone cortisol acts on the brain, supporting adaptation and time adjusted coping processes. Whereas previous research has focused on slow emerging, genomic effects of cortisol, we addressed the rapid, nongenomic cortisol effects on in vivo neuronal activity in humans. Three independent placebo-controlled studies in healthy men were conducted. We observed changes in CNS activity within 15 min after intravenous administration of a physiological dose of 4 mg of cortisol (hydrocortisone). Two of the studies demonstrated a rapid bilateral thalamic perfusion decrement using continuous arterial spin labeling. The third study revealed rapid, cortisol-induced changes in global signal strength and map dissimilarity of the electroencephalogram. Our data demonstrate that a physiological concentration of cortisol profoundly affects the functioning and perfusion of the human brain in vivo via a rapid, nongenomic mechanism. The changes in neuronal functioning suggest that cortisol acts on the thalamic relay of background as well as on task-specific sensory information, allowing focus and facilitation of adaptation to challenges. PMID- 22238095 TI - RNA binding proteins accumulate at the postsynaptic density with synaptic activity. AB - Neuronal activity elicits changes in synaptic composition that play an important role in experience-dependent plasticity (Choquet and Triller, 2003; Lisman and Raghavachari, 2006; Bourne and Harris, 2008; Holtmaat and Svoboda, 2009). We used a modified version of stable isotope labeling by amino acids in cell culture to identify activity-dependent modifications in the composition of postsynaptic densities (PSDs) isolated from rat primary neuronal cultures. We found that synaptic activity altered ~2% of the PSD proteome, which included an increase in diverse RNA binding proteins (RNABPs). Indeed, 12 of the 37 identified proteins whose levels changed with synaptic activity were RNABPs and included the heterogeneous nuclear ribonucleoproteins (hnRNPs) G, A2/B1, M, and D. Knockdown of hnRNPs M and G using shRNAs resulted in altered numbers of dendritic spines, suggesting a crucial role for these proteins in spine density. Synaptic activity also resulted in a concomitant increase in dendritic and synaptic poly(A) mRNA. However, this increase was not affected by knockdown of hnRNPs M or G. Our results suggest that hnRNP proteins regulate dendritic spine density and may play a role in synaptodendritic mRNA metabolism. PMID- 22238096 TI - A conditioning lesion protects axons from degeneration via the Wallenda/DLK MAP kinase signaling cascade. AB - Axons are vulnerable components of neuronal circuitry, and neurons are equipped with mechanisms for responding to axonal injury. A highly studied example of this is the conditioning lesion, in which neurons that have been previously injured have an increased ability to initiate new axonal growth (Hoffman, 2010). Here we investigate the effect of a conditioning lesion on axonal degeneration, which occurs in the distal stump after injury, and also occurs in neuropathies and neurodegenerative disorders (Coleman, 2005). We found that Drosophila motoneuron axons that had been previously injured had an increased resiliency to degeneration. This requires the function of a conserved axonal kinase, Wallenda (Wnd)/DLK, and a downstream transcription factor. Because axonal injury leads to acute activation of Wnd (Xiong et al., 2010), and overexpression studies indicate that increased Wnd function is sufficient to promote protection from degeneration, we propose that Wnd regulates an adaptive response to injury that allows neurons to cope with axonal stress. PMID- 22238098 TI - Why do axons differ in caliber? AB - CNS axons differ in diameter (d) by nearly 100-fold (~0.1-10 MUm); therefore, they differ in cross-sectional area (d(2)) and volume by nearly 10,000-fold. If, as found for optic nerve, mitochondrial volume fraction is constant with axon diameter, energy capacity would rise with axon volume, also as d(2). We asked, given constraints on space and energy, what functional requirements set an axon's diameter? Surveying 16 fiber groups spanning nearly the full range of diameters in five species (guinea pig, rat, monkey, locust, octopus), we found the following: (1) thin axons are most numerous; (2) mean firing frequencies, estimated for nine of the identified axon classes, are low for thin fibers and high for thick ones, ranging from ~1 to >100 Hz; (3) a tract's distribution of fiber diameters, whether narrow or broad, and whether symmetric or skewed, reflects heterogeneity of information rates conveyed by its individual fibers; and (4) mitochondrial volume/axon length rises >=d(2). To explain the pressure toward thin diameters, we note an established law of diminishing returns: an axon, to double its information rate, must more than double its firing rate. Since diameter is apparently linear with firing rate, doubling information rate would more than quadruple an axon's volume and energy use. Thicker axons may be needed to encode features that cannot be efficiently decoded if their information is spread over several low-rate channels. Thus, information rate may be the main variable that sets axon caliber, with axons constrained to deliver information at the lowest acceptable rate. PMID- 22238100 TI - Vision modulates corticospinal suppression in a functionally specific manner during movement of the opposite limb. AB - The effect of vision on the excitability of corticospinal projections to the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of right human forearm was investigated before and during discrete movement of the opposite limb. An external force opposed the initial phase of the movement (wrist flexion) and assisted the reverse phase, so that recruitment of the wrist extensors was minimized. Three conditions were used as follows: viewing the inactive right limb (Vision), viewing the mirror image of the moving left limb (Mirror), and with vision of the right limb occluded (No Vision). Transcranial magnetic stimulation was delivered to the left motor cortex: before, at the onset of, or during the left limb movement to obtain motor evoked potentials (MEPs) in the muscles of the right forearm. At and following movement onset, MEPs obtained in the right FCR were smaller in the Vision condition than in the Mirror and No Vision conditions. A distinct pattern of variation was obtained for the ECR. In all conditions, MEPs in this muscle were elevated upon or following movement of the opposite limb. An additional analysis of ipsilateral silent periods indicated that interhemispheric inhibition plays a role in mediating these effects. Activity-dependent changes in corticospinal output to a resting limb during discrete actions of the opposite limb are thus directly contingent upon where one looks. Furthermore, the extent to which vision exerts an influence upon projections to specific muscles varies in accordance with the functional contribution of their homologs to the intended action. PMID- 22238099 TI - Disruption of NMDA receptors in oligodendroglial lineage cells does not alter their susceptibility to experimental autoimmune encephalomyelitis or their normal development. AB - Pharmacological studies have suggested that oligodendroglial NMDA glutamate receptors (NMDARs) mediate white matter injury in a variety of CNS diseases, including multiple sclerosis (MS). We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), a model of human MS, by timed conditional disruption of oligodendroglial NR1, an essential subunit of functional NMDARs, using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system. We found that selective ablation of oligodendroglial NR1 did not alter the clinical severity of EAE elicited in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide), nor were there significant differences between the oligodendroglial NR1 KO and non-KO mice in numbers of axons lost in spinal cord dorsal funiculi or severity of spinal cord demyelination. Similarly, constitutive deletion of NR3A, a modulatory subunit of oligodendroglial NMDARs, did not alter the course of MOG peptide EAE. Furthermore, conditional and constitutive ablation of NR1 in neonatal oligodendrocyte progenitor cells did not interrupt their normal maturation and differentiation. Collectively, our data suggest that oligodendroglial lineage NMDARs are neither required for timely postnatal development of the oligodendroglial lineage, nor significant participants in the pathophysiology of MOG-peptide EAE. PMID- 22238101 TI - Intermittent visual feedback can boost motor learning of rhythmic movements: evidence for error feedback beyond cycles. AB - Movement error is a driving force behind motor learning. For motor learning with discrete movements, such as point-to-point reaching, it is believed that the brain uses error information of the immediately preceding movement only. However, in the case of continuous and repetitive movements (i.e., rhythmic movements), there is a ceaseless inflow of performance information. Thus, an accurate temporal association of the motor commands with the resultant movement errors is not necessarily guaranteed. We investigated how the brain overcomes this challenging situation. Human participants adapted rhythmic movements between two targets to visuomotor rotations, the amplitudes of which changed randomly from cycle to cycle (the duration of one cycle was ~400 ms). A system identification technique revealed that the motor adaptation was affected not just by the preceding movement error, but also by a history of errors from the previous cycles. Error information obtained from more than one previous cycle tended to increase, rather than decrease, movement error. This result led to a counterintuitive prediction: providing visual error feedback for only a fraction of cycles should enhance visuomotor adaptation. As predicted, we observed that motor adaptation to a constant visual rotation (30 degrees ) was significantly enhanced by providing visual feedback once every fourth or fifth cycle rather than for every cycle. These results suggest that the brain requires a specific processing time to modify the motor command, based on the error information, and so is unable to deal appropriately with the overwhelming flow of error information generated during rhythmic movements. PMID- 22238102 TI - Subsynaptic AMPA receptor distribution is acutely regulated by actin-driven reorganization of the postsynaptic density. AB - AMPA receptors (AMPARs) mediate synaptic transmission and plasticity during learning, development, and disease. Mechanisms determining subsynaptic receptor position are poorly understood but are key determinants of quantal size. We used a series of live-cell, high-resolution imaging approaches to measure protein organization within single postsynaptic densities in rat hippocampal neurons. By photobleaching receptors in synapse subdomains, we found that most AMPARs do not freely diffuse within the synapse, indicating they are embedded in a matrix that determines their subsynaptic position. However, time lapse analysis revealed that synaptic AMPARs are continuously repositioned in concert with plasticity of this scaffold matrix rather than simply by free diffusion. Using a fluorescence correlation analysis, we found that across the lateral extent of single PSDs, component proteins were differentially distributed, and this distribution was continually adjusted by actin treadmilling. The C-terminal PDZ ligand of GluA1 did not regulate its mobility or distribution in the synapse. However, glutamate receptor activation promoted subsynaptic mobility. Strikingly, subsynaptic immobility of both AMPARs and scaffold molecules remained essentially intact even after loss of actin filaments. We conclude that receptors are actively repositioned at the synapse by treadmilling of the actin cytoskeleton, an influence which is transmitted only indirectly to receptors via the pliable and surprisingly dynamic internal structure of the PSD. PMID- 22238104 TI - L-DOPA impairs proteasome activity in parkinsonism through D1 dopamine receptor. AB - Aberrant membrane localization of dopamine D(1) receptor (D1R) is associated with L-DOPA-induced dyskinesia (LID), a major complication of L-DOPA treatment in Parkinson's disease (PD). Since the proteasome plays a central role in modulating neuronal response through regulation of neurotransmitter receptor intraneuronal fate, we hypothesized that the ubiquitine-proteasome proteolytic pathway could be impaired in LID. Those LIDs are actually associated with a striatum-specific decrease in proteasome catalytic activity and accumulation of polyubiquitinated proteins in experimental rodent and monkey parkinsonism. We then demonstrated that such decreased proteasome catalytic activity (1) results from D1R activation and (2) feed-back the D1R abnormal trafficking, i.e., its exaggerated cell surface abundance. We further showed that the genetic invalidation of the E3 ubiquitin-protein ligase parkin PD gene leads to exaggerated abnormal involuntary movements compared with wild-type mice. We thus established in an unprecedented series of experimental models that impairment of the ubiquitine-proteasome system at specific nodes (E3 ligase parkin, polyubiquitination, proteasome catalytic activity) leads to the same phenomenon, i.e., aberrant behavioral response to dopamine replacement therapy in PD, highlighting the intimate interplay between dopamine receptor and proteasome activity in a nondegenerative context. PMID- 22238103 TI - Fetal testosterone influences sexually dimorphic gray matter in the human brain. AB - In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain. PMID- 22238105 TI - Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex. AB - Patterned neuronal activity such as spindle bursts in the neonatal cortex is likely to promote the maturation of cortical synapses and neuronal circuits. Previous work on cats has shown that removal of subplate neurons, a transient neuronal population in the immature cortex, prevents the functional maturation of thalamocortical and intracortical connectivity. Here we studied the effect of subplate removal in the neonatal rat primary somatosensory cortex (S1). Using intracortical EEG we show that after selective removal of subplate neurons in the limb region of S1, endogenous and sensory evoked spindle burst activity is largely abolished. Consistent with the reduced in vivo activity in the S1 limb region, we find by in vitro recordings that thalamocortical inputs to layer 4 neurons are weak. In addition, we find that removal of subplate neurons in the S1 barrel region prevents the development of the characteristic histological barrel like appearance. Thus, subplate neurons are crucially involved in the generation of particular types of early network activity in the neonatal cortex, which are an important feature of cortical development. The altered EEG pattern following subplate damage could be applicable in the neurological assessment of human neonates. PMID- 22238106 TI - Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. AB - The neurotrophin nerve growth factor (NGF) regulates neuronal growth, differentiation, and survival during development. However, the precursor of NGF, proNGF, is a potent apoptotic ligand for the p75 neurotrophin receptor (p75(NTR)) sortilin complex. The mechanisms that regulate cleavage of proNGF, therefore, are critical determinants of whether this factor promotes neuronal survival or death. In this study, we demonstrate that, following kainic acid-induced seizures, the proNGF processing enzyme matrix metalloproteinase 7 (MMP-7) and its inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) are regulated in a manner that prevents proneurotrophin cleavage and leads to increased proNGF in the extracellular milieu. Furthermore, we demonstrate both in vitro and in vivo that exogenous MMP-7 enhances proNGF cleavage and provides neuroprotection following kainic acid treatment. These data demonstrate that increased extracellular proNGF levels following seizures are stabilized by altered MMP-7 enzymatic activity, leading to increased neuronal death via activation of p75(NTR). PMID- 22238107 TI - Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury. AB - In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI), and epilepsy. The coupling of neurons by gap junctions (electrical synapses) increases during neuronal injury. We report here that the ischemic increase in neuronal gap junction coupling is regulated by glutamate via group II metabotropic glutamate receptors (mGluRs). Specifically, using electrotonic coupling, Western blots, and siRNA in the mouse somatosensory cortex in vivo and in vitro, we demonstrate that activation of group II mGluRs increases background levels of neuronal gap junction coupling and expression of connexin 36 (Cx36) (neuronal gap junction protein), and inactivation of group II mGluRs prevents the ischemia-mediated increases in the coupling and Cx36 expression. We also show that the regulation is via cAMP/PKA (cAMP-dependent protein kinase)-dependent signaling and posttranscriptional control of Cx36 expression and that other glutamate receptors are not involved in these regulatory mechanisms. Furthermore, using the analysis of neuronal death, we show that inactivation of group II mGluRs or genetic elimination of Cx36 both dramatically reduce ischemia-mediated neuronal death in vitro and in vivo. Similar results are obtained using in vitro models of TBI and epilepsy. Our results indicate that neuronal gap junction coupling is a critical component of glutamate-dependent neuronal death. They also suggest that causal link among group II mGluR function, neuronal gap junction coupling, and neuronal death has a universal character and operates in different types of neuronal injuries. PMID- 22238108 TI - Prefrontal cortex mediates extinction of responding by two distinct neural mechanisms in accumbens shell. AB - Suppression of ill-timed or competing actions optimizes goal-directed behaviors. Diminished inhibitory control over such actions is a central feature of such disorders as impulsivity, obesity, and drug addiction. The ventromedial prefrontal cortex (vmPFC) is involved in suppression of unreinforced actions. Using reversible inactivation in rats, we demonstrate that vmPFC activity is also required for inhibition of unreinforced actions extinguished during learning of a cued appetitive task and that behavioral disinhibition following vmPFC inactivation depends on dopamine signaling in nucleus accumbens shell (NAcS). Combining electrophysiological recording in NAcS with vmPFC inactivation in rats reveals two neural mechanisms by which vmPFC inhibits unreinforced actions. The first is by suppressing phasic excitations that promote behavioral cue responding. The second is by increasing the basal firing of NAcS neurons that tonically inhibit reward seeking. These results identify the vmPFC and the NAcS as critical elements of the circuits relevant to suppression of inappropriate actions. PMID- 22238109 TI - Disrupted-in-Schizophrenia 1 (DISC1) is necessary for the correct migration of cortical interneurons. AB - Disrupted-in-Schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder. PMID- 22238110 TI - Axonal transport of neurofilaments: a single population of intermittently moving polymers. AB - Studies on mouse optic nerve have led to the controversial proposal that only a small proportion of neurofilaments are transported in axons and that the majority are deposited into a persistently stationary and extensively cross-linked cytoskeletal network that remains fixed in place for months without movement. We have used computational modeling to address this issue, taking advantage of the wealth of published kinetic and morphometric data available for neurofilaments in the mouse visual system. We show that the transport kinetics and distribution of neurofilaments in mouse optic nerve can all be explained fully by a "stop-and-go" model of neurofilament transport, in which axons contain a single population of neurofilaments that all move stochastically in a rapid, intermittent, and bidirectional manner. Importantly, we find that the transport kinetics are not consistent with deposition of neurofilaments into a persistently stationary phase, and that deposition models cannot account for the observed distribution of neurofilaments along mouse optic nerve axons. Finally, we show that the apparent existence of a stationary neurofilament network in mouse optic nerve is most likely an experimental artifact due to contamination of the neurofilament transport kinetics with cytosolic proteins that move at faster rates. Thus, there is no evidence for the deposition of axonally transported neurofilaments into a persistently stationary neurofilament network in optic nerve axons. We conclude that all of the neurofilaments move and that they do so with a single broad and continuous distribution of average rates that is dictated by their intermittent and stochastic motile behavior. PMID- 22238111 TI - The effect of the swim-up and hyaluronan-binding methods on the frequency of abnormal spermatozoa detected by FISH and SCSA in carriers of balanced chromosomal translocations. AB - BACKGROUND: The swim-up and hyaluronan (HA)-binding methods are used for the selection of good quality spermatozoa to improve pregnancy rates and embryo quality and to reduce the number of miscarriages after IVF. We evaluated whether the processing of sperm by these methods reduces the frequency of spermatozoa with abnormal karyotypes and altered chromatin quality in balanced translocation carriers. METHODS: Semen samples of 12 carriers of balanced chromosomal translocations were analysed for the frequency of spermatozoa, which are chromosomally unbalanced due to the segregation of balanced translocations, aneuploidies for chromosomes 7, 8, 13, 18, 21, X or Y, diploid sperm or sperm with fragmented DNA and poorly condensed chromatin. Results obtained by fluorescence in situ hybridization (FISH) and sperm chromatin structure assay were compared between ejaculated (n = 12), swim-up (n = 12) and HA-binding processed (n = 6) semen samples of the translocation carriers and with the control group (n = 10). RESULTS: The mean frequencies of unbalanced segregation products were 17.5 and 16.5% in neat and swim-up processed samples from Robertsonian translocation carriers, and 55.4, 54.5 and 50.9% in neat, swim-up and HA-bound sperm samples from reciprocal translocation carriers. Significant decreases in the frequency of sperm showing chromosome 18 and XY disomy and of diploidy, and in the rates of high-density staining sperm were observed in the motile swim-up fractions. There were significantly more sperm showing fragmented chromatin in the group of translocation carriers than in the control group, but no differences in the aneuploidy and diploidy rates were observed. CONCLUSIONS: The swim-up method is suitable for selection of sperm with condensed chromatin and a lower frequency of some aneuploidies and of diploidy. The frequency of spermatozoa chromosomally unbalanced due to the segregation of reciprocal (but not Robertsonian) translocations is significantly lower in HA-bound sperm. However, the advantages of either method for selecting normal sperm are limited. PMID- 22238112 TI - Anti-Mullerian hormone: clairvoyance or crystal clear? AB - The clinical use of anti-Mullerian hormone (AMH) has increased exponentially due to its unique relationship with the ovarian reserve and ability to predict ovarian response, facilitate pretreatment counselling and individualize treatment strategies to minimize the risk of ovarian hyperstimulation syndrome. There is now a rapidly increasing literature examining additional possibilities for AMH, all of which suggest that its reach extends far beyond the assisted conception clinic. The recognition that it is a significantly more accurate and reliable measure of ovarian reserve than the antral follicle count or FSH has led to its adoption by physicians to counsel women on their reproductive lifespan, the impact of gonadotoxic chemotherapy, radiotherapy and surgery on the ovarian reserve and allow polycystic ovarian syndrome to be diagnosed by primary care physicians. We propose that there is an adequate literature base to embrace this technology while continuing to develop and refine how AMH can optimize patient care. PMID- 22238113 TI - Robotic treatment of colorectal endometriosis: technique, feasibility and short term results. AB - BACKGROUND: Deep infiltrating endometriosis (DIE) is a complex disease that impairs the quality of life and the fertility of women. Since a medical approach is often insufficient, a minimally invasive approach is considered the gold standard for complete disease excision. Robotic-assisted surgery is a revolutionary approach, with several advantages compared with traditional laparoscopic surgery. METHODS: From March 2010 to May 2011, we performed 22 consecutive robotic-assisted complete laparoscopic excisions of DIE endometriosis with colorectal involvement. All clinical data were collected by our team and all patients were interviewed preoperatively and 3 and 6 months post-operatively and yearly thereafter regarding endometriosis-related symptoms. Dysmenorrhoea, dyschezia, dyspareunia and dysuria were evaluated with a 10-point analog rating scale. RESULTS: There were 12 patients, with a median larger endometriotic nodule of 35 mm, who underwent segmental resection, and 10 patients, with a median larger endometriotic nodule of 30 mm, who underwent complete nodule debulking by colorectal wall-shaving technique. No laparotomic conversions were performed, nor was any blood transfusion necessary. No intra-operative complications were observed and, in particular, there were no inadvertent rectal perforations in any of the cases treated by the shaving technique. None of the patients had ileostomy or colostomy. No major post-operative complications were observed, except one small bowel occlusion 14 days post-surgery that was resolved in 3 days with medical treatment. Post-operatively, a statistically significant improvement of patient symptoms was shown for all the investigated parameters. CONCLUSIONS: To our knowledge, this is the first study reporting the feasibility and short-term results and complications of laparoscopic robotic-assisted treatment of DIE with colorectal involvement. We demonstrate that this approach is feasible and safe, without conversion to laparotomy. PMID- 22238114 TI - Array comparative genomic hybridization in male infertility. AB - BACKGROUND: Male infertility caused by a maturation arrest of spermatogenesis is a condition with an abrupt stop in spermatogenesis, mostly at the level of primary spermatocytes. The etiology remains largely unknown. METHODS: We focused on patients with a complete arrest at the spermatocyte level (n = 9) and used array comparative genomic hybridization to screen for deletions or duplications that might be associated with maturation arrest. Interesting copy number variations (CNVs) were further examined by using quantitative PCR. Where appropriate, the expression pattern was analyzed in multiple human tissues including the testis. RESULTS: A total of 227 CNVs were detected in the patient group. After the elimination of CNVs that were also present in the control group or that were not likely to be involved in male infertility, the remaining 11 regions were investigated more in detail. We first determined the expression pattern of seven genes, for which expression had not been reported to be investigated in testicular tissue, after which one region could be eliminated. Next, all 10 promising candidate regions were analyzed by quantitative PCR in a control population. CONCLUSIONS: Eight deletions/duplications were absent in our control group, and therefore might be linked with the male infertility in our patients. One of these alterations, however, has been detected in a proven fertile father group. Further research is necessary to determine the relationship between the observed genomic alterations and maturation arrest of spermatogenesis. Furthermore, several of the above genes have not been studied at the functional level and consequently, more research is required to determine their role in spermatogenesis. PMID- 22238115 TI - Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards. AB - BACKGROUND: Genetic examination of childhood leukemia has not been available in Iraq. We here report the frequency of TEL-AML1, E2A-PBX1, MLL-AF4, and BCR-ABL chimeric transcripts in 264 Iraqi children newly diagnosed with acute lymphoblastic leukemia (ALL), using FTA cards impregnated with bone marrow aspirate or whole blood. PATIENTS AND METHODS: The diagnosis of ALL was made according to standard French-American-British morphologic criteria. Based on the results of storage temperature and duration, most of the FTA samples were preserved at 4 degrees C for up to 6 weeks in five Iraqi hospitals and then transferred to Japan for molecular analysis. Nested reverse transcription polymerase chain reaction was adopted for the analysis. RESULTS: TEL-AML1 chimeric transcript product was found in 32 (12.1%) of 264 ALL patients. Eleven (4.2%) patients, 4 (1.5%) patients, and 11 (4.2%) patients had E2A-PBX1 mRNA, MLL AF4 mRNA, and BCR-ABL mRNA, respectively. One patient had both TEL-AML1 and E2A PBX1 fusion genes. The incidence of TEL-AML1 in Iraqi ALL children appears to be similar to or slightly higher than those of Jordan (12%) and Kuwait (7%). The prevalence and clinical findings of ALL patients with either E2A-PBX1 or BCR-ABL were comparable to the data reported elsewhere. CONCLUSION: International collaboration via FTA cards may be helpful to improve diagnosis and management of patients with hematological malignancies in low-income and underdeveloped countries. PMID- 22238116 TI - Strain-specific colitis susceptibility in IL10-deficient mice depends on complex gut microbiota-host interactions. AB - BACKGROUND: Colitis susceptibility in Il10(-/-) mice depends on genetic background and microbiota composition. A major genetic locus mediating colitis susceptibility, Cdcs1, was transferred from susceptible C3Bir-Il10(-/-) to resistant B6-Il10(-/-) mice, resulting in susceptible congenic BC-R3-Il10(-/-) mice. The aim of this study was to determine the impact of microbiota on this differential colitis susceptibility using a Helicobacter hepaticus infection model. METHODS: Parental C3Bir-Il10(-/-) , B6-Il10(-/-) , and congenic BC-R3 Il10(-/-) mice were inoculated with H. hepaticus and analyzed for inflammation. In parental Il10(-/-) mice, microbiota composition was determined by terminal restriction fragment length polymorphism (T-RFLP) and quantitative polymerase chain reaction (qPCR). RESULTS: Most severe inflammation was observed in C3Bir Il10(-/-) in the cecum, in BC-R3-Il10(-/-) in cecum and colon, and, unexpectedly, in B6-Il10(-/-) in the colon. C3Bir-Il10(-/-) and BC-R3-Il10(-/-) secreted significantly more interferon-gamma (IFNgamma) and interleukin (IL)17 than B6 Il10(-/-) . T-RFLP analyses in C3Bir-Il10(-/-) and B6-Il10(-/-) mice revealed 1) a significant impact of H. hepaticus infection on species richness and diversity, and 2) strain differences in microbiota composition only after H. hepaticus infection. qPCR revealed higher numbers of Clostridia leptum and Bacteroides spp. in the cecum of infected C3Bir-Il10(-/-) mice, and Lactobacillus spp. in B6-Il10( /-) mice. CONCLUSIONS: Cdcs1 modifies the response to H. hepaticus infection. However, this infection alone does not reflect the original response to a complex colitogenic biota. H. hepaticus-induced inflammation altered intestinal microbiota in a mouse strain-specific manner. Bacteroides spp. became more abundant in susceptible C3Bir-Il10(-/-) , lactobacilli in B6-Il10(-/-) mice. Therefore, both host immune response and differential compositional changes of microbiota play a role in strain-specific colitis susceptibility in Il10(-/-) mice. PMID- 22238117 TI - Conditional estimation after a two-stage diagnostic biomarker study that allows early termination for futility. AB - Many biomarkers identified in marker discovery are shown to have inadequate performance in validation studies. This motivates the use of group sequential designs that allow early termination for futility. However, an option for early termination will lead to biased estimates for studies that reach full enrollment. We propose conditional estimators and confidence intervals that correct for this bias assuming that an unadjusted estimator exists that has an independent increments covariance structure. The proposed estimators and confidence intervals are applied to conditional estimation of the receiver operating characteristic curve and the positive predictive value curve after a two-stage study that allows early termination for futility, and their performance is evaluated by simulation. PMID- 22238118 TI - Functionalization and dispersion of hexagonal boron nitride (h-BN) nanosheets treated with inorganic reagents. AB - A mixture of bulk hexagonal boron nitride (h-BN) with hydrazine, 30% H(2)O(2), HNO(3)/H(2)SO(4), or oleum was heated in an autoclave at 100 degrees C to produce functionalized h-BN. The product formed stable colloid solutions in water (0.26-0.32 g L(-1)) and N,N-dimethylformamide (0.34-0.52 g L(-1)) upon mild ultrasonication. The yield of "soluble" h-BN reached about 70 wt%. The dispersions contained few-layered h-BN nanosheets with lateral dimensions in the order of several hundred nanometers. The functionalized dispersible h-BN was characterized by IR spectroscopy, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, UV/Vis spectroscopy, X-ray diffraction (XRD), dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM). It is shown that h-BN preserves its hexagonal structure throughout the functionalization procedure. Its exfoliation into thin platelets upon contact with solvents is probably owing to the attachment of hydrophilic functionalities. PMID- 22238119 TI - Estrogen receptor beta (ERbeta) is a novel prognostic marker of recurrence survival in non-muscle-invasive bladder cancer potentially by inhibiting cadherin switch. AB - OBJECTIVE: The function and significance of estrogen receptor beta (ERbeta) in bladder cancer remains a field of hot debate. In this study, we aimed to (a) evaluate ERbeta as a novel prognostic marker of recurrence-free survival and (b) digest the underlying mechanism by elucidating the relationship between ERbeta expression and cadherin switch. METHODS: We examined the expression levels of ERbeta, E-cadherin and N-cadherin in 42 initial non-muscle-invasive urothelial bladder carcinomas via immunohistochemistry. Correlation analysis was performed among ERbeta expression, cadherin switch, and recurrence-free survival. Moreover, in vitro studies were performed to validate the identified correlation using two bladder cancer cell lines RT4 and 253 J. Upon stimulation with an ERbeta selective agonist diarylpropionitrile, E-cadherin, N-cadherin expressions; cell migration, and invasion capacity were assessed. RESULTS: Expression of ERbeta protein was seen in 34 bladder cancer cases (80.9%), and 21 (50%) specimens showed non-cadherin switch (positive E-cadherin and negative N-cadherin). ERbeta expression and the non-cadherin switch are both accompanied with better recurrence-free survival. Also, the least ERbeta expression was observed in specimens that undergo cadherin switch. Moreover, these results were consistent with our observations in bladder cancer RT4 and 253 J cell lines studies. Diarylpropionitrile stimulation resulted in an increase in E-cadherin, a decrease in N-cadherin expressions and abolished cell migration and invasion. CONCLUSION: ERbeta is a prognostic marker of recurrence-free rate in non-muscle-invasive bladder cancer, potentially through suppressing cadherin switch, and may act as a potential target for bladder cancer therapy. PMID- 22238120 TI - Chemoprevention of prostate cancer: an updated view. AB - OBJECTIVES: To place chemoprevention of prostate cancer in current clinical context. METHODS: Review of recently published updates of large, randomized, controlled trials of primary chemoprevention of prostate cancer. RESULTS: With extended post-intervention follow-up, SELECT demonstrated a 17% increased risk of prostate cancer relative to placebo in the vitamin E alone arm. Two other trials in men with high-grade PIN demonstrated no effect of selenium alone or in combination with soy and lycopene. Trials of 5alpha-reductase inhibitors show an approximate 25% relative risk reduction in men at average risk and in those with an "elevated" PSA and prior negative biopsy, but adoption of these agents in clinical practice has been limited by concerns over an apparently increased risk of high-grade disease. CONCLUSIONS: Primary prevention of prostate cancer remains an attractive goal because of its prevalence and treatment-related morbidity. Neither selenium nor vitamin E prevents prostate cancer. The benefit/risk ratio for 5alpha-reductase inhibitors can be improved by limiting their use to men at high risk. PMID- 22238121 TI - Genome-scale methylation analysis of Parkinson's disease patients' brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1. AB - Multiple lines of evidence suggest a link between environmental toxins and Parkinson's disease (PD). Although numerous studies reported associations of genetic variants in de-toxifying enzymes, i.e. cytochrome genes, with PD. Epigenetic modifications of genes and subsequent altered expression may confer a yet unappreciated level of susceptibility. We present a genome-wide methylation analysis of PD with quantitative DNA methylation levels of 27.500 CpG sites representing 14.495 genes. We found decreased methylation of the cytochrome P450 2E1 gene and increased expression of CYP2E1 messenger RNA in PD patients' brains, suggesting that epigenetic variants of this cytochrome contribute to PD susceptibility. PMID- 22238122 TI - Exploring rock fissures: does a specialized root morphology explain endemism on granite outcrops? AB - BACKGROUND AND AIMS: Worldwide, many plant species are confined to open, shallow soil, rocky habitats. Although several hypotheses have been proposed to explain this habitat specificity, none has been convincing. We suggest that the high level of endemism on shallow soils is related to the edaphic specialization needed to survive in these often extremely drought-prone habitats. Previous research has shown that species endemic to ironstone communities in SW Australia have a specialized root morphology that enhances their chance to access fissures in the underlying rock. Here we test the generality of these findings for species that are confined to a shallow-soil habitat that is of much greater global significance: granite outcrops. METHODS: We compared temporal and spatial root growth and allocation of three endemic woody perennials of SW Australian granite outcrop communities with those of congeners occurring on nearby deeper soils. Seedlings of all species were grown in 1.2 m long custom-made containers with a transparent bottom that allowed monitoring of root growth over time. KEY RESULTS: The granite outcrop endemics mostly differed in a predictable way from their congeners from deeper soils. They generally invested a larger portion of their biomass in roots, distributed their roots faster and more evenly over the container and had a lower specific root length. In different species pairs the outcrop endemics achieved their apparent advantage by a different combination of the aforementioned traits. CONCLUSIONS: Our results are consistent with earlier work, indicating that species restricted to different types of drought-prone shallow-soil communities have undergone similar selection pressures. Although adaptive in their own habitat in terms of obtaining access to fissures in the underlying rock, these root system traits are likely to be maladaptive in deeper soil habitats. Therefore, our results may provide an explanation for the narrow endemism of many shallow-soil endemics. PMID- 22238123 TI - Subclavian and pulmonary artery steal phenomenon in a patient with isolated left subclavian artery and right aortic arch. AB - We describe a patient with an isolated left subclavian artery associated with right aortic arch, patent ductus arteriosus, and ventricular septal defect. As the isolated left subclavian artery is supplied by the left vertebral artery in which blood flows in the retrograde direction, this anomaly is usually responsible for a congenital subclavian steal phenomenon. Atrophy of the left cerebral hemisphere and inverted left vertebral arterial flow were clearly depicted by echoencephalography in this patient, whose subclavian artery was connected to the main pulmonary artery by a patent ductus arteriosus. PMID- 22238124 TI - Feasibility of neurobehavioral screening following diagnosis of pediatric cancer. AB - BACKGROUND: Neurobehavioral deficits will affect up to 50% of pediatric cancer survivors treated with central nervous system (CNS)-directed therapies. Guidelines suggest assessment of neurobehavioral skills at diagnosis be extended from patients with brain tumors to include all patients requiring CNS-directed therapies. However, comprehensive neuropsychological assessment at diagnosis is difficult to implement and resource intensive. A screening assessment targeted at the neurobehavioral domains known to be impacted by cancer treatments may be more feasible. This study aimed to assess the feasibility of implementing baseline neurobehavioral screening following childhood cancer diagnosis. PROCEDURE: A consecutive sample of 59 recently diagnosed patients requiring CNS-directed therapies, and 49 healthy controls were assessed using a targeted neurobehavioral screen, which included measures of developmental, cognitive, academic, behavioral, and psychosocial functioning. Feasibility was assessed using a formal feasibility framework, with criteria of brevity, simplicity, relevance, acceptability, and value. Neurobehavioral assessment was compared to standard care to determine the quality of information acquired from the screen. RESULTS: Mean time from diagnosis to assessment was 5.17 weeks. Assessments were completed within 1 hour for 87% of patients. Participant and researcher evaluation indicated the screen was acceptable across a range of criteria, with no differences between clinical and control groups. Compared to standard medical record documentation, the screen provided significant additional information on developmental and neurobehavioral status of patients at diagnosis. CONCLUSION: A brief neurobehavioral screen in the early period following cancer diagnosis is feasible and provides valuable baseline data for children at risk of neurobehavioral late-effects of cancer treatments. PMID- 22238125 TI - Synthesis and photophysical properties of fullerene-phthalocyanine-porphyrin triads and pentads. AB - The synthesis and photophysical properties of several fullerene-phthalocyanine porphyrin triads (1-3) and pentads (4-6) are described. The three photoactive moieties were covalently connected in an one-step synthesis through 1,3-dipolar cycloaddition to C(60) of the corresponding azomethine ylides generated in situ by condensation reaction of a substituted N-porphyrinylmethylglycine derivative and an appropriated formyl phthalocyanine or a diformyl phthalocyanine derivative, respectively. ZnP-C(60)-ZnPc (3), (ZnP)(2)-ZnPc-(C(60))(2) (6), and (H(2)P)(2)-ZnPc-(C(60))(2) (5) give rise upon excitation of their ZnP or H(2)P components to a sequence of energy and charge-transfer reactions with, however, fundamentally different outcomes. With (ZnP)(2)-ZnPc-(C(60))(2) (6) the major pathway is an highly exothermic charge transfer to afford (ZnP)(ZnP(.+))-ZnPc (C(60)(.-))(C(60)). The lower singlet excited state energy of H(2)P (i.e., ca. 0.2 eV) and likewise its more anodic oxidation (i.e., ca. 0.2 V) renders the direct charge transfer in (H(2)P)(2)-ZnPc-(C(60))(2) (5) not competitive. Instead, a transduction of singlet excited state energy prevails to form the ZnPc singlet excited state. This triggers then an intramolecular charge transfer reaction to form exclusively (H(2)P)(2)-ZnPc(.+)-(C(60)(.-))(C(60)). A similar sequence is found for ZnP-C(60)-ZnPc (3). PMID- 22238126 TI - Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors. AB - Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). We solved the crystal structure of PR2 with APV at 1.5 A resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR1 mutant (PR(1M) ) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR2. PR(1M) more closely resembled PR2 than PR1 in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR(1M) with APV, DRV, and SQV were compared with available PR1 and PR2 complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR(1M) and PR1, however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR(1M). Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR1 (M) and PR2 relative to the strong hydrogen bonds observed in PR1, consistent with 15- and 19-fold weaker inhibition, respectively. Overall, PR(1M) partially replicates the specificity of PR2 and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2. PMID- 22238129 TI - Carbodiphosphorane analogues E(PPh3)2 with E=C-Pb: a theoretical study with implications for ligand design. AB - Quantum-chemical calculations at the BP86/TZVPP level have been carried out for the heavy Group 14 homologues of carbodiphosphorane E(PPh(3))(2), where E=Si, Ge, Sn, Pb, which are experimentally unknown so far. The results of the theoretical investigation suggest that the tetrelediphosphoranes E(PPh(3))(2) (1E) are stable compounds that could become isolated in a condensed phase. The molecules possess donor-acceptor bonds Ph(3)P->E<-PPh(3) to a bare tetrele atom E, which retains its four valence electrons as two electron lone pairs. The analysis of the bonding situation and the calculation of the chemical reactivity indicate that the molecules 1E belong to the class of divalent E(0) compounds (ylidones). All molecules 1C-1Pb have very large first but also very large second proton affinities, which distinguishes them from the N-heterocyclic carbene homologues, in which the donor atom is a divalent E(II) species that possesses only one electron lone pair. Compounds 1E are powerful double donors that strongly bind Lewis acids such as BH(3) and AuCl in the complexes 1E(BH(3))(n) and 1E(AuCl)(n) (n=1, 2). The bond dissociation energies (BDEs) of the second BH(3) and AuCl molecules are only slightly less than the BDE of the first BH(3) and AuCl. The results of this work are a challenge for experimentalists. PMID- 22238128 TI - Cooperative ligand effects in phase-switching homogeneous catalysts. PMID- 22238127 TI - A new approach to high sensitivity liquid chromatography-mass spectrometry of peptides using nanoflow solvent assisted inlet ionization. AB - Liquid chromatography (LC) solvent assisted inlet ionization (SAII) mass spectrometry (MS) was previously reported to give good chromatographic resolution and MS detection injecting 66 ng of a BSA tryptic digest. In analogy to nano electrospray ionization (nESI), we extend SAII LC/MS to nano-SAII (nSAII) operating at nL min(-1) flow rates and demonstrate good quality ion chromatograms and mass spectra from injection of as little as 0.7 ng of BSA digest onto a capillary LC column. Data dependent fragmentation is demonstrated for injection of 7 ng of a BSA digest. This method has advantages over nESI in ease of use and low cost as it requires no voltage and is operational without the necessity of connectors or fragile nESI emitters, although similar constricted tips can be helpful in nSAII to stabilize the signal at low nanoliter flow. At a flow rate of 0.8 MUL min(-1), the only requirement for nSAII is that the exit-end of the capillary LC column be adjusted near the aperture of the heated inlet of the mass spectrometer. PMID- 22238130 TI - Biomimetic graphene surfaces with superhydrophobicity and iridescence. PMID- 22238131 TI - Restricted mean models for transplant benefit and urgency. AB - The US lung allocation policy estimates each individual's urgency and transplant benefit in defining a lung allocation score (LAS). Transplant benefit, as defined by the Organ Procurement and Transplantation Network Thoracic Committee, is the days of life gained over the following year if transplanted versus not transplanted. Urgency is measured by days of life during the next year without transplant. In both definitions, accurate estimation of wait list days lived, or a wait list restricted mean lifetime, is required. Risk factors are available to estimate patient urgency when listed, with more urgent patients removed from the wait list upon death or transplant. As a patient progresses, priority for transplant (censoring) changes accordingly. Therefore, it is crucial to adjust for dependent censoring in modeling days of life. We develop a model for the restricted mean as a function of covariates, by using pseudo-observations that account for dependent censoring linked to a series of longitudinal measures (LAS). Simulation results show that our method performs well in situations comparable with the LAS setting. Applying wait list and post-transplant model results that account for dependent censoring to wait list patients, we obtain estimates of transplant benefit that are larger for many of the more urgent patients in need of transplant. The difference in LAS for an individual, when properly accounting for dependent censoring, has high impact on the priority and timing of an organ offer for these patients. PMID- 22238132 TI - Estimation of fan beam and parallel beam parameters in a wire mesh design. AB - Special collimators used in imaging systems play an important part in obtaining qualified images to improve diagnosis in medicine. METHODS: The primary aim of this study was to compare resolution between fan beam and parallel beam collimators using Monte Carlo simulation in the shape of cubic holes. Also, parameters such as geometric efficiency, geometric resolution, scatter, penetration, and full width at half maximum were studied to compare their special characteristics. RESULTS: The simulation results demonstrated that the geometry efficiency of a fan beam collimator increased as the angle of the slant hole increased, and the geometric resolution decreased as the angle of the slant hole increased, at a distinct distance from a monoenergetic source of gamma-rays. In contrast, at a distinct angle, geometric resolution increased as the distance between the source and the collimator surface increased. For both collimators, scatter and penetration decreased as the distance increased. These results were in agreement with ADAC company data. Finally, fan beam collimators were found to have better resolution than parallel beam collimators with a cubic hole shape in a wire mesh design. CONCLUSION: Estimation of the fan beam by parallel beam parameters as cubic holes can be suitable in collimator design to improve resolution and efficiency. PMID- 22238133 TI - Surgical repair after ineffective device closure of an inferior sinus venosus defect. AB - A young woman presented with severe heart failure symptoms 4 years after percutaneous device closure of an atrial septal defect (ASD). There was residual left-to-right shunting, and the device was obstructing the inferior caval vein and tricuspid valve flow. Intraoperatively, the ASD was shown to be an inferior sinus venosus defect, and reconstruction of the mitral valve and the posterior wall of the left atrium was required. This case emphasizes the importance of appropriate patient selection for interventional ASD closure and demonstrates that patients with less-than-optimal results should be referred for surgical correction early, before the device produces secondary damage to atrial structures and atrioventricular valves. PMID- 22238134 TI - Neonatal candiduria: does it jeopardize the outcome of infants at risk in Cairo University Neonatal Intensive Care Units (NICUs)? PMID- 22238135 TI - The use of comic drama in improving hand hygiene compliance. PMID- 22238136 TI - Assessment of the prognostic value of the World Health Organization clinical staging system for HIV/AIDS in HIV-infected children and adolescents in a cohort in Belo Horizonte, Brazil. AB - This study aimed to evaluate the prognostic value of WHO clinical staging system in HIV-infected children and adolescents in Belo Horizonte, Brazil. WHO clinical stages were evaluated for risk of disease progression in 335 patients admitted from 1989 to 2003. In Kaplan-Meier analysis, age, clinical stage, CD4% <15% and viral load >5 log(10) were statistically significant. In Cox proportional hazards model, the relative risk of disease progression for Stage 4 at admission and in the worst moment were 3.47 [confidence interval (CI) 95% CI = 1.92-6.26] and 2.89 (95% CI = 1.44-5.79). Stages 2 and 3 were neutral as predictors of risk either of disease progression. CD4% <15% and viral load > 5 log(10) remained statistically significant in multivariate analysis. WHO clinical Stage 4 was a good predictor of risk of progression in this cohort. The findings support WHO proposition to start antiretroviral treatment for patients at a more advanced clinical stage. PMID- 22238137 TI - Pneumococcal nasopharyngeal carriage in infants of mothers immunized with 23V non conjugate pneumococcal polysaccharide vaccine. AB - To assess the effects of maternal immunization on pneumococcal colonization in infants, pregnant women were assigned into three groups. The group Pregn Vac received the Pn23V during pregnancy, the group Puerp Vac received vaccine during immediate puerperium and the group No Vac received no vaccine. Nasopharyngeal samples were collected at 3 and 6 months. A total of 150 pregnant women were selected during the prenatal period. The proportion of pneumococcal carriage in at least one evaluation was in group Pregn Vac 22.2% (10/45), group Puerp Vac 23.4% (11/47) and group No Vac 21.2% (10/47), respectively. The most frequently isolated serotype in group Puerp Va and group No Vac was 6B and 6A. In the Pregn Vac, the most important serotype was 19F. Although this study was unable to demonstrate any effect of maternal vaccination in reducing pneumococcal colonization, reduction of colonization for serotype 6B in infants may be an important effect. PMID- 22238138 TI - Fecal calprotectin in predicting relapse of inflammatory bowel diseases: a meta analysis of prospective studies. AB - BACKGROUND: Fecal calprotectin (FC) is a relatively new marker of intestinal inflammation. Recently, many studies have extended its role in predicting relapse of quiescent inflammatory bowel disease (IBD), but the reported results have been inconsistent. We aimed to perform a meta-analysis of the predictive capacity of FC in IBD relapse. METHODS: We systematically searched the Medline, Web of Science, Cochrane Library, and EMBASE databases for prospective studies that used FC concentrations at remission in predicting relapse of Crohn's disease (CD) and ulcerative colitis (UC). Pooled sensitivity, specificity, and other diagnostic indices were evaluated. RESULTS: A total of 672 IBD patients (318 UC and 354 CD) from six different studies were analyzed. The pooled sensitivity and specificity of FC to predict relapse of quiescent IBD was 78% (95% confidence interval [CI]: 72-83) and 73% (95% CI: 68-77), respectively. The area under the summary receiver operating characteristic (sROC) curve was 0.83 and the diagnostic odds ratio was 10.31 (95% CI: 5.05-21.06). The capacity of FC to predict relapse was comparable between UC and CD. In CD patients the predictive value of FC in isolated small bowel CD was not assessed due to insufficiency of available data. Compared with all enrolled CD patients, FC appeared to be more accurate in ileocolonic and colonic CD. CONCLUSIONS: As a simple and noninvasive marker, FC is useful to predict relapse in quiescent IBD patients. PMID- 22238139 TI - Sonographic appearance of an advanced invasive mole and associated metastatic thrombus in the inferior vena cava. AB - We present a case of an advanced invasive mole with a metastatic thrombus in the inferior vena cava in which sonography clearly showed vesicles in the myometrium, ovaries, and metastatic thrombus leading to a diagnosis of invasive mole rather than choriocarcinoma. PMID- 22238140 TI - Evaluation of partial and total splenectomy in children with sickle cell disease using an Internet-based registry. AB - BACKGROUND: Clinical outcomes of children with sickle cell disease (SCD) who undergo total or partial splenectomy (PS) are poorly defined. The purpose of this retrospective study was to initiate an Internet-based registry to facilitate analysis of clinical outcomes for these children. We hypothesized that both surgical procedures would be well tolerated and would eliminate risk of splenic sequestration. METHODS: We developed a web-based registry using the Research Electronic Data Capture (REDCap) platform. Children were included if they had SCD and underwent total splenectomy (TS) or PS between 2003 and 2010. Clinical outcomes were compared between cohorts, with follow-up to 1 year. RESULTS: Twenty four children were included, TS (n = 15) and PS (n = 9). There were no differences in surgical time or intraoperative blood loss. The length of stay was longer after PS (4.1 +/- 1.7 days) compared to TS, (2.4 +/- 1.2 days, P = 0.02). Within 30 days of surgery, 2 (20%) patients had acute chest syndrome (ACS) following TS and 2 (15%) patients had ACS after PS. During 1-year follow-up, no patient in either cohort had recurrent splenic sequestration, venous thrombosis or overwhelming postsplenectomy sepsis. All children who were transfused preoperatively to prevent recurrent splenic sequestration successfully discontinued transfusions. CONCLUSIONS: Both TS and PS result in favorable hematologic outcomes and low risk of adverse events for children with SCD. A REDCap-based registry may facilitate data entry and analysis of clinical outcomes to allow for comparison between different types of splenectomy. PMID- 22238141 TI - Expression of a soluble form of iodotyrosine deiodinase for active site characterization by engineering the native membrane protein from Mus musculus. AB - Reductive deiodination is critical for thyroid function and represents an unusual exception to the more common oxidative and hydrolytic mechanisms of dehalogenation in mammals. Studies on the reductive processes have been limited by a lack of convenient methods for heterologous expression of the appropriate proteins in large scale. The enzyme responsible for iodide salvage in the thyroid, iodotyrosine deodinase, is now readily generated after engineering its gene from Mus musculus. High expression of a truncated derivative lacking the membrane domain at its N-terminal was observed in Sf9 cells, whereas expression in Pichia pastoris remained low despite codon optimization. Ultimately, the desired expression in Escherichia coli was achieved after replacing the two conserved Cys residues of the deiodinase with Ala and fusing the resulting protein to thioredoxin. This final construct provided abundant enzyme for crystallography and mutagenesis. Utility of the E. coli system was demonstrated by examining a set of active site residues critical for binding to the zwitterionic portion of substrate. PMID- 22238144 TI - The 2-oxoglutarate-dependent oxygenase JMJD6 catalyses oxidation of lysine residues to give 5S-hydroxylysine residues. AB - Amino acid analyses reveal that JMJD6-catalysed hydroxylation of RNA-splicing regulatory protein fragments occurs to give hydroxylysine products with 5S stereochemistry. This contrasts with collagen lysyl hydroxylases, which give 5R hydroxylated products. The work suggests that more than one subfamily of lysyl hydroxylases has evolved and illustrates the importance of stereochemical assignments in proteomic analyses. PMID- 22238143 TI - IspG-catalyzed positional isotopic exchange in methylerythritol cyclodiphosphate of the deoxyxylulose phosphate pathway: mechanistic implications. AB - H(2)(18)O under the bridge: Recently, the deoxyxylulose phosphate (DXP) pathway was discovered to be a second pathway supplying isoprenoid biosynthetic precursors. One of steps is an IspG-catalyzed reductive deoxygenation of methylerythritol cyclodiphosphate (MEcPP) to 4-hydroxyl-3-methyl-2-(E)-1 diphosphate (HMBPP). Using [2-(13) C,(18) O]-MEcPP, we detected the positional isotopic exchange for the bridging oxygen in MEcPP. PMID- 22238145 TI - Synthetic caged DAG-lactones for photochemically controlled activation of protein kinase C. AB - Switching on kinases: Synthetic caged DAG-lactones have been developed and showed decreases of two orders of magnitude, relative to the corresponding parent compounds, in their binding affinities towards PKC. The caged compounds had no effect on the translocation of PKC until after photoactivation. This approach is a potentially powerful tool for probing the PKC signaling cascade. PMID- 22238146 TI - Mutational biosynthesis of ansamitocin antibiotics: a diversity-oriented approach to exploit biosynthetic flexibility. AB - New ansamitocin derivatives were prepared by feeding aminobenzoic acid derivatives to cultures of Actinosynnema pretiosum HGF073, a mutant strain blocked in the biosynthesis of the required 3-amino-5-hydroxybenzoic acid (AHBA) starter unit. Use of several aminobenzoic acids as precursors led to a spectrum of products, reflecting the sequence of post-PKS tailoring steps involved in the generation of ansamitocins and adding novel aspects to the published suggestion model of post-PKS tailoring logic and flexibility. The studies provide insights into the substrate flexibility of the enzymes required for ansamitocin biosynthesis in A. pretiosum, whereas preliminary biological testing of the derivatives isolated and fully characterized by NMR spectroscopy allowed structure-activity relationship assignments to be made for a variety of intermediates occurring during the post-PKS tailoring sequence in ansamitocin biosynthesis. PMID- 22238147 TI - Live cell luminescence imaging as a function of delivery mechanism. AB - Mitochondria in live cells can be imaged with a ruthenium(II) complex that usually binds and images nuclear DNA. The cellular uptake mechanism of this probe was changed by using a biocompatible pH-sensitive polymersome vector. This change in delivery route, determines the final cellular location of the probe and thus modulates its imaging properties. PMID- 22238148 TI - Expanding and engineering the genetic code in a single expression experiment. AB - Expanding and engineering the code simultaneously: This concept was experimentally realized in a single in vivo expression experiment whereby residue specific, sense codon reassignments Met->Nle/Pro->(4S-F)Pro (code engineering) were combined with position-specific STOP->Bpa read-through by an amber suppressor tRNA (code expansion). PMID- 22238151 TI - A two-stage Bayesian design for co-development of new drugs and companion diagnostics. AB - Most new drug development in oncology is based on targeting specific molecules. Genomic profiles and deregulated drug targets vary from patient to patient making new treatments likely to benefit only a subset of patients traditionally grouped in the same clinical trials. Predictive biomarkers are being developed to identify patients who are most likely to benefit from a particular treatment; however, their biological basis is not always conclusive. The inclusion of marker negative patients in a trial is therefore sometimes necessary for a more informative evaluation of the therapy. In this paper, we present a two-stage Bayesian design that includes both marker-positive and marker-negative patients in a clinical trial. We formulate a family of prior distributions that represent the degree of a priori confidence in the predictive biomarker. To avoid exposing patients to a treatment to which they may not be expected to benefit, we perform an interim analysis that may stop accrual of marker-negative patients or accrual of all patients. We demonstrate with simulations that the design and priors used control type I errors, give adequate power, and enable the early futility analysis of test-negative patients to be based on prior specification on the strength of evidence in the biomarker. PMID- 22238149 TI - Morphological differences between beta(2) -microglobulin in fibrils and inclusion bodies. AB - Over expression of proteins in E. coli frequently results in the production of inclusion bodies. Although beta(2) -microglobulin frequently forms fibrillar structures, our studies reveal significant differences between the protein in fibrils and inclusion bodies. This suggests that the formation of fibrils in inclusion bodies is dependent on the propensity of the protein to form fibrillar structures. PMID- 22238153 TI - Bilateral Wilms tumors (WT) treated with the SIOP 93 protocol in France: epidemiological survey and patient outcome. AB - BACKGROUND: The treatment of bilateral Wilms tumors (WT) requires multimodality therapy with individualized decision to ensure cure while preserving as much renal parenchyma as possible. PROCEDURE: We analyzed the clinical records of 49 children with bilateral WT treated in France between 1993 and 2001, according to the SIOP-93 guidelines (individual treatment program: Treatment was continued as long as there was imaging evidence of tumor regression). Pathology reports, duration of preoperative chemotherapy and surgical records were also reviewed. Overall Survival (OS) and Event-Free Survival (EFS) rates were studied and relationships between possible prognostic factors and survival were assessed. RESULTS: Imaging studies revealed bilateral involvement in 98% of the cases. Whatever the response to preoperative chemotherapy, the mean duration of neoadjuvant chemotherapy was 80 days (Q1-Q3: 47-89 days). Forty-eight children underwent nephron sparing surgery (NSS) at least for one kidney and 19 for both. Five-year EFS and OS rates were, respectively, 83.4 and 89.5%. Only the most advanced stages were shown to affect OS (P = 0.03). At study endpoint, end-stage renal disease (ESRD) was reported in seven children, associated with a predisposing phenotype in three. CONCLUSIONS: Results of this study demonstrate a favorable outcome of patients with bilateral WT receiving an individual treatment program. With a tailored approach to treatment according to the tumor response, 77% of our patients were operated before the third month of preoperative chemotherapy. In spite of good survival, 14% of our patients have ESRD. PMID- 22238155 TI - Intramyocardial hematoma with epicardial rupture following percutaneous coronary intervention. AB - Intramyocardial (or subepicardial) hematomas are uncommon conditions that occur mostly after myocardial infarction, percutaneous coronary intervention (PCI), coronary artery bypass surgery, cardiac surgery, or chest trauma. Coronary perforation is a rare complication of PCI and the subset of patients developing an intramyocardial hematoma, usually considered a catastrophic event, is even rarer. We describe here the case of 63-year-old man in whom an intramyocardial hematoma with epicardial rupture occurred after PCI. The patient was treated conservatively with a successful outcome. PMID- 22238154 TI - Pediatric ulcerative colitis associated with autoimmune diseases: a distinct form of inflammatory bowel disease? AB - BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) is multifactorial, with some patients presenting additional autoimmune symptoms. Inflammatory colitis associated with autoimmune (AI) liver disease appears to have clinical features different from those of "classical" ulcerative colitis (CUC). The aim of this study was to describe these features, in order to differentiate a subgroup of colitis associated with autoimmunity (CAI) from CUC. METHODS: Twenty-eight consecutive children with inflammatory colitis associated with primary sclerosing cholangitis (PSC), celiac disease, or AI hepatitis were compared with a matched control group of 27 children with isolated UC. Clinical course, histology, as well as inflammatory profile in the colonic mucosa based on real-time polymerase chain reaction (PCR) were analyzed. RESULTS: In CAI the main digestive symptoms at disease onset were abdominal pain (12/28) and bloody strings in the stool (12/28), along with a high prevalence of autoimmune diseases in relatives, as compared with bloody diarrhea in the CUC group (26/27). At diagnosis, pancolitis was seen in 18/28 CAI patients compared with 8/27 in UC. In CAI, the pathological findings were different from CUC: 1) major lesions predominantly located in the right colon; 2) pseudo-villous appearance of the mucosa, and strong infiltration with eosinophils; 3) mild glandular lesions; and 4) differing inflammatory infiltrate with reduced FOXP3, interleukin (IL)-2, and thymic stromal lymphopoietin (TSLP) levels. Evolution in CAI was less aggressive, requiring less corticosteroids/immunomodulators. CONCLUSIONS: Precise clinical, histological, and molecular analyses reveal marked differences between patients with CUC and those with associated AI phenomena, supporting the hypothesis of a distinct AI presentation of IBD. PMID- 22238156 TI - Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. AB - Animal studies and clinical observations suggest that epilepsy is associated with inflammation. Translocator protein (TSPO) (18 kDa), a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. TSPO can be measured in the living human brain with PET and the novel radioligand (11)C-PBR28. In this study, we sought to determine whether in vivo expression of TSPO is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy. METHODS: Sixteen patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with (11)C-PBR28 PET and MRI. Uptake of radioactivity after injection of (11)C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired-samples t test. RESULTS: We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. CONCLUSION: We found increased uptake of radioactivity after injection of (11)C-PBR28 ipsilateral to the seizure focus in patients with temporal lobe epilepsy, suggesting increased expression of TSPO. Studies in larger samples are required to confirm this finding and determine the clinical utility of imaging TSPO in temporal lobe epilepsy. PMID- 22238157 TI - The role of the oligosaccharide binding cleft of rice BGlu1 in hydrolysis of cellooligosaccharides and in their synthesis by rice BGlu1 glycosynthase. AB - Rice BGlu1 beta-glucosidase nucleophile mutant E386G is a glycosynthase that can synthesize p-nitrophenyl (pNP)-cellooligosaccharides of up to 11 residues. The X ray crystal structures of the E386G glycosynthase with and without alpha-glucosyl fluoride were solved and the alpha-glucosyl fluoride complex was found to contain an ordered water molecule near the position of the nucleophile of the BGlu1 native structure, which is likely to stabilize the departing fluoride. The structures of E386G glycosynthase in complexes with cellotetraose and cellopentaose confirmed that the side chains of N245, S334, and Y341 interact with glucosyl residues in cellooligosaccharide binding subsites +2, +3, and +4. Mutants in which these residues were replaced in BGlu1 beta-glucosidase hydrolyzed cellotetraose and cellopentaose with k(cat) /K(m) values similar to those of the wild type enzyme. However, the Y341A, Y341L, and N245V mutants of the E386G glycosynthase synthesize shorter pNP-cellooligosaccharides than do the E386G glycosynthase and its S334A mutant, suggesting that Y341 and N245 play important roles in the synthesis of long oligosaccharides. X-ray structural studies revealed that cellotetraose binds to the Y341A mutant of the glycosynthase in a very different, alternative mode not seen in complexes with the E386G glycosynthase, possibly explaining the similar hydrolysis, but poorer synthesis of longer oligosaccharides by Y341 mutants. PMID- 22238158 TI - Tuning the activity of mitochondria-penetrating peptides for delivery or disruption. AB - Mitochondrially targeted agents have the capacity to be both vehicles for the delivery of bioactive agents and mitochondrial disrupters and show promise for the treatment of various diseases. Engineering these agents to specifically accumulate or disrupt the mitochondrion is challenging, as there is a fine line between characteristics of the molecules that accomplish each task. Here, we assess the physicochemical properties governing mitochondrial matrix accumulation or membrane disruption caused by mitochondria-penetrating peptides. Increases in peptide length and hydrophobicity were uncovered as the dominant factors in deriving membrane disruptive activity. Shorter, less hydrophobic peptides did not disrupt the mitochondrial membrane, but rather accumulated in the mitochondrial matrix without interfering with cellular activity. These shorter peptides, however, can trigger cytochrome c release through activation of the permeability transition pore complex (PTPC), but only at very high concentrations. This study illustrates that the activity of a mitochondria-localizing agent can be controlled through alterations in peptide hydrophobicity and dosing concentrations. PMID- 22238160 TI - Detection of human bocavirus in the cerebrospinal fluid of children with encephalitis. AB - We report 4 children with encephalitis associated with human bocavirus (HBoV) 1 or 2. All children were severely underweight, and 2 died; 1 of them had a matching HBoV2 nucleotide sequence isolated from serum and bocavirus like particles in the cerebrospinal fluid that were observed with electron microscopy. No further pathogens were detected in the cerebrospinal fluid of these patients. PMID- 22238161 TI - Oral transmission of Chagas disease. AB - Chagas disease is now an active disease in the urban centers of countries of nonendemicity and endemicity because of congenital and blood and/or organ transplantation transmissions and the reactivation of the chronic disease in smaller scale than vectorial transmission, reported as controlled in countries of endemicity. Oral transmission of Chagas disease has emerged in unpredictable situations in the Amazon region and, more rarely, in areas of nonendemicity where the domiciliary triatomine cycle was under control because of exposition of the food to infected triatomine and contaminated secretions of reservoir hosts. Oral transmission of Chagas disease is considered when >1 acute case of febrile disease without other causes is linked to a suspected food and should be confirmed by the presence of the parasite after direct microscopic examination of the blood or other biological fluid sample from the patient. PMID- 22238162 TI - Plasma HIV-1 RNA levels during antiretroviral therapy: how low is low enough? PMID- 22238163 TI - Life-threatening respiratory pasteurellosis associated with palliative pet care. AB - Pasteurella multocida is a zoonotic Gram-negative cocco-bacillus often associated with soft tissue infections due to dog and cat bites. Here we report 3 patients who developed life-threatening P. multocida respiratory tract infections after providing palliative care to their dying pets. PMID- 22238164 TI - Hepatitis a epidemiology goes global. PMID- 22238165 TI - Persistence of pneumolysin in the cerebrospinal fluid of patients with pneumococcal meningitis is associated with mortality. AB - Poor prognosis in Pneumococcal meningitis may be associated with high pneumolysin levels in cerebrospinal fluid (CSF). In patient samples we showed that pneumolysin levels in CSF remained high after 48 hours in nonsurvivors of meningitis compared with survivors. Selective antipneumolysin treatment may present a novel therapeutic option. PMID- 22238166 TI - A multistate outbreak of hepatitis A associated with semidried tomatoes in Australia, 2009. AB - BACKGROUND: A large outbreak of hepatitis A affected individuals in several Australian states in 2009, resulting in a 2-fold increase in cases reported to state health departments compared with 2008. Two peaks of infection occurred (April-May and September-November), with surveillance data suggesting locally acquired infections from a widely distributed food product. METHODS: Two case control studies were completed. Intensive product trace-back and food sampling was undertaken. Genotyping was conducted on virus isolates from patient serum and food samples. Control measures included prophylaxis for close contacts, public health warnings, an order by the chief health officer under the Victorian Food Act 1984, and trade-level recalls on implicated batches of semidried tomatoes. RESULTS: A multijurisdictional case-control study in April-May found an association between illness and consumption of semidried tomatoes (odds ratio [OR], 3.0; 95% CI 1.4-6.7). A second case-control study conducted in Victoria in October-November also implicated semidried tomatoes as being associated with illness (OR, 10.3; 95% CI, 4.7-22.7). Hepatitis A RNA was detected in 22 samples of semidried tomatoes. Hepatitis A virus genotype IB was identified in 144 of 153 (94%) patients tested from 2009, and partial sequence analysis showed complete identity with an isolate found in a sample of semidried tomatoes. CONCLUSIONS: The results of both case-control studies and food testing implicated the novel vehicle of semidried tomatoes as the cause of this hepatitis A outbreak. The outbreak was extensive and sustained despite public health interventions, the design and implementation of which were complicated by limitations in food testing capability and complex supply chains. PMID- 22238167 TI - Plasma HIV-1 RNA detection below 50 copies/ml and risk of virologic rebound in patients receiving highly active antiretroviral therapy. AB - BACKGROUND: Plasma human immunodeficiency virus type 1 (HIV-1) RNA suppression <50 copies/mL is regarded as the optimal outcome of highly active antiretroviral therapy (HAART). Current viral load (VL) assays show increased sensitivity, but the significance of RNA detection <50 copies/mL is unclear. METHODS: This study investigated the virologic outcomes of 1247 patients with VL <50 copies/mL at an arbitrary time point during HAART (= T0), according to whether the actual, unreported (T0)VL was 40-49 copies/mL, RNA detected <40 copies/mL (RNA(+)), or RNA not detected (RNA(-)), as measured by the Abbott Real Time assay. Predictors of rebound >50 and >400 copies/mL over 12 months following T0 were analyzed with Cox proportional hazards models incorporating the (T0)VL and demographic and clinical data. RESULTS: Rebound rates >50 copies/mL were 34.2% for (T0)VL 40-49 copies/mL, 11.3% for RNA(+), and 4.0% for RNA(-); rebound rates >400 copies/mL were 13.0%, 3.8%, and 1.2%, respectively. The adjusted hazard ratios for rebound >50 copies/mL were 4.67 (95% confidence interval, 2.91-7.47; P < .0001) and 1.97 (1.25-3.11; P < .0001) with (T0)VL 40-49 copies/mL and RNA(+), respectively, relative to RNA(-), and 6.91 (2.90-16.47; P < .0001) and 2.88 (1.24-6.69; P < .0001), respectively, for rebound >400 copies/mL. The association was independent of adherence levels. CONCLUSIONS: In treated patients monitored by RealTime, a VL of 40-49 copies/mL and, to a lesser extent, RNA detection <40 copies/mL predict rebound >50 and >400 copies/mL independently of other recognized determinants. The goal of HAART may need to be revised to a lower cutoff than 50 copies/mL. PMID- 22238168 TI - Role of neutralizing antibodies in adults with community-acquired pneumonia by respiratory syncytial virus. AB - BACKGROUND: Respiratory syncytial virus (RSV) has been implicated in the etiology of adult community-acquired pneumonia (CAP). We investigated RSV infection in Chilean adults with CAP using direct viral detection, real-time reverse transcription polymerase chain reaction (rtRT-PCR), and serology (microneutralization assay). METHODS: RSV, other respiratory viruses, and bacteria were studied by conventional and molecular techniques in adults aged >=18 years presenting with CAP to the healthcare facilities in Santiago, Chile from February 2005 through December 2007. RESULTS: All 356 adults with CAP enrolled had an acute blood sample collected at enrollment, and 184 had a convalescent blood sample. RSV was detected in 48 cases (13.4%). Immunofluorescence assay and viral isolation each detected only 1 infection (0.2%), whereas rtRT-PCR was positive in 32 (8.9%) cases and serology was positive in 20 (10.8%) cases. CAP clinical characteristics were similar in RSV infected and non-RSV-infected cases. RSV-specific geometric mean serum neutralizing antibody titer (GMST) was significantly lower at admission in the 48 RSV-infected cases compared with 308 non-RSV-infected adults (GMST in log(2): RSV/A 8.1 vs 8.9, and RSV/B 9.3 vs 10.4; P < .02). CONCLUSIONS: RSV infection is frequent in Chilean adults with CAP. Microneutralization assay was as sensitive as rtRT-PCR in detecting RSV infection and is a good adjunct assay for diagnostic research. High RSV-specific serum-neutralizing antibody levels were associated with protection against common and severe infection. The development of a vaccine could prevent RSV-related CAP in adults. PMID- 22238170 TI - Fatal Naegleria fowleri infection acquired in Minnesota: possible expanded range of a deadly thermophilic organism. AB - BACKGROUND: Primary amebic meningoencephalitis (PAM), caused by the free-living ameba Naegleria fowleri, has historically been associated with warm freshwater exposures at lower latitudes of the United States. In August 2010, a Minnesota resident, aged 7 years, died of rapidly progressive meningoencephalitis after local freshwater exposures, with no history of travel outside the state. PAM was suspected on the basis of amebae observed in cerebrospinal fluid. METHODS: Water and sediment samples were collected at locations where the patient swam during the 2 weeks preceding illness onset. Patient and environmental samples were tested for N. fowleri with use of culture and real-time polymerase chain reaction (PCR); isolates were genotyped. Historic local ambient temperature data were obtained. RESULTS: N. fowleri isolated from a specimen of the patient's brain and from water and sediment samples was confirmed using PCR as N. fowleri genotype 3. Surface water temperatures at the times of collection of the positive environmental samples ranged from 22.1 degrees C to 24.5 degrees C. August 2010 average air temperature near the exposure site was 25 degrees C, 3.6 degrees C above normal and the third warmest for August in the Minneapolis area since 1891. CONCLUSIONS: This first reported case of PAM acquired in Minnesota occurred 550 miles north of the previously reported northernmost case in the Americas. Clinicians should be aware that N. fowleri-associated PAM can occur in areas at much higher latitude than previously described. Local weather patterns and long term climate change could impact the frequency of PAM. PMID- 22238169 TI - A comparison of 2 strategies to prevent infection following pertussis exposure in vaccinated healthcare personnel. AB - BACKGROUND: Antibiotic postexposure prophylaxis (PEP) following pertussis exposure is recommended but has never been evaluated in healthcare personnel (HCP) vaccinated with acellular pertussis vaccine (Tdap). METHODS: Tdap vaccinated HCP were randomized to receive azithromycin PEP or no PEP following pertussis exposure. Acute and convalescent nasopharyngeal swabs and sera were obtained for pertussis testing by polymerase chain reaction (PCR) and anti pertussis toxin (PT) immunoglobulin G, respectively. A nasopharyngeal aspirate was also collected for PCR and culture from subjects who reported respiratory symptoms within 21 days following identification of the exposure. Pertussis infection was defined as a positive culture or PCR, a 2-fold rise in anti-PT titer, or a single anti-PT titer of >=94 enzyme-linked immunosorbent assay units/mL. Daily symptom monitoring without PEP was considered noninferior to PEP after pertussis exposure if the lower limit of the 1-sided 95% confidence interval (CI) for the reduction in pertussis was greater than -7%. RESULTS: During 30 months of study, 86 subjects were randomized following a pertussis exposure. Using the predefined definition of infection, pertussis infection did not develop in 41 (97.6%) of 42 subjects who received azithromycin PEP and 38 (86.4%) of 44 subjects who did not receive PEP (absolute risk difference, -11.3%; lower bound of the 1-sided 95% CI, -20.6%; P = .81). However, no subject developed symptomatic pertussis confirmed with culture or a specific PCR assay, and possibly no subject developed subclinical pertussis infection based upon additional serologic testing. CONCLUSIONS: Using the predefined definition of pertussis infection, noninferiority for preventing pertussis following exposure was not demonstrated for daily symptom monitoring of Tdap-vaccinated HCP without PEP when compared with antibiotic PEP. However, the small number of exposed HCP warrants further study of this approach. CLINICAL TRIAL REGISTRATION: NCT00469274. PMID- 22238171 TI - The risk of tuberculosis disease among persons with diabetes mellitus: a prospective cohort study. AB - BACKGROUND: Evidence suggests a causal link between diabetes mellitus and tuberculosis risk. However, to date, few studies have used a prospective design to estimate the impact of diabetes on tuberculosis in a general population. In this study, we prospectively investigated the risk of tuberculosis among persons with diabetes stratified by severity. METHODS: A cohort study was performed that involved 17,715 Taiwanese persons on whom baseline data were collected during Taiwan's 2001 National Health Interview Survey. Participants' subsequent medical care until December 2004 was captured from the National Health Insurance database. The diagnosis and severity of diabetes were established using self report, International Classification of Diseases, Ninth Revision, Clinical Modification codes, and pharmacy records; incident tuberculosis disease was identified using these codes and pharmacy records. Covariates were obtained through in-person interviews. We used Cox proportional hazards regression analyses to measure the association between tuberculosis and both diabetes and diabetes severity. RESULTS: Diabetes in general and treated diabetes were significantly associated with tuberculosis (adjusted hazard ratio, 2.09 [95% confidence interval {CI}, 1.10-3.95] and 2.60 [95% CI, 1.34-5.03], respectively). Compared with persons without treated diabetes, participants' risk of tuberculosis increased as the number of complications of diabetes mellitus increased (P = .0016), with >3-fold risk among those with >= 2 diabetes-related complications (odds ratio, 3.45; 95% CI, 1.59-7.50). Similarly, the risk increased among those with higher Diabetes Complications Severity Index scores (P = .0002). CONCLUSIONS: The risk of developing tuberculosis increased among those with increasing diabetes severity. PMID- 22238172 TI - Role of serum cytokine profile in ulcerative colitis assessment. AB - BACKGROUND: Several cytokines are overexpressed in the colonic mucosa of patients with ulcerative colitis (UC). The measurement of these parameters in plasma could be useful in diagnosis and disease assessment. METHODS: In all, 67 UC patients and 21 healthy controls were enrolled. At inclusion, clinical, endoscopic, and histological disease activity were assessed using the Ulcerative Colitis Activity Index (UCAI) and the Baron and Geboes scales, respectively. Serum cytokine concentrations were analyzed with a multiplex system (Bio-Plex pro, Bio-Rad) measuring interleukin (IL)-1-beta, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17, interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Multiple logistic regression was used to design a serum cytokines profile. RESULTS: In the UC group the disease activity was moderate to severe based on clinical evaluation in 35 patients (52.2%), by endoscopic appearance in 45 (67.2%), and in 53 patients (81.6%) using histology. With respect to controls, the multivariate analysis identified that UC patients had higher IL-8 (odds ratio [OR] = 1.37; P = 0.002) and IL-10 concentrations (OR = 3.88; P = 0.012) with lower levels of IFN-gamma (OR = 0.95; P = 0.002). The model had an accuracy of 77.3%, which increased to 94.6% when only newly diagnosed patients were considered. Patients with moderate to severe disease according to their clinical score showed a higher concentration of IL-8 (OR = 1.16; P = 0.012) and IL-10 (OR = 1.76; P = 0.039) with lower levels of IL-17 (OR = 0.97; P = 0.021). The IL-8 serum concentration was also related to endoscopic and histological severity (OR = 1.10; P = 0.026 and OR = 1.33, P = 0.017, respectively). CONCLUSIONS: A serum cytokine profile may be an auxiliary tool for the diagnosis and severity assessment of UC. IL-8 seems to be a reliable biomarker, closely related to disease activity. PMID- 22238173 TI - Beyond diversity: reducing racial health care disparities. PMID- 22238174 TI - Natural and engineered plasmin inhibitors: applications and design strategies. AB - The serine protease plasmin is ubiquitously expressed throughout the human body in the form of the zymogen plasminogen. Conversion to active plasmin occurs through enzymatic cleavage by plasminogen activators. The plasminogen activator/plasmin system has a well-established function in the removal of intravascular fibrin deposition through fibrinolysis and the inhibition of plasmin activity; this has found widespread clinical use in reducing perioperative bleeding. Increasing evidence also suggests diverse, although currently less defined, roles for plasmin in a number of physiological and pathological processes relating to extracellular matrix degradation, cell migration and tissue remodelling. In particular, dysregulation of plasmin has been linked to cancer invasion/metastasis and various chronic inflammatory conditions; this has prompted efforts to develop inhibitors of this protease. Although a number of plasmin inhibitors exist, they commonly suffer from poor potency and/or specificity of inhibition that either results in reduced efficacy or prevents clinical use. Consequently, there is a need for further development of high-affinity plasmin inhibitors that maintain selectivity over other serine proteases. This review summarises clearly defined and potential applications for plasmin inhibition. The properties of naturally occurring and engineered plasmin inhibitors are discussed in the context of current knowledge regarding plasmin structure, specificity and function. This includes design strategies to obtain the potency and specificity of inhibition in addition to controlled temporal and spatial distribution tailored for the intended use. PMID- 22238175 TI - Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers. AB - The polypeptide hormone Islet Amyloid Polypeptide (IAPP, amylin) is responsible for islet amyloid formation in type-2 diabetes and in islet cell transplants, where it may contribute to graft failure. Human IAPP is extremely amyloidogenic and fewer inhibitors of IAPP amyloid formation have been reported than for the Alzheimer's Abeta peptide or for alpha-synuclein. The ability of a set of hydroxyflavones to inhibit IAPP amyloid formation was tested. Fluorescence detected thioflavin-T-binding assays are the most popular methods for measuring the kinetics of amyloid formation and for screening potential inhibitors; however, we show that they can lead to false positives with hydroxyflavones. Several of the compounds inhibit thioflavin-T fluorescence, but not amyloid formation; a result which highlights the hazards of relying solely on thioflavin T assays to screen potential inhibitors. Transmission electron microscopy (TEM) and right-angle light scattering show that Morin hydrate (2',3,4',5,7 Pentahydroxyflavone) inhibits amyloid formation by human IAPP and disaggregates preformed IAPP amyloid fibers. In contrast, Myricetin, Kaempferol, and Quercetin, which differ only in hydroxyl groups on the B-ring, are not effective inhibitors. Morin hydrate represents a new type of IAPP amyloid inhibitor and the results with the other compounds highlight the importance of the substitution pattern on the B-ring. PMID- 22238176 TI - Oxidative trifluoromethylation of arylboronates with shelf-stable potassium (trifluoromethyl)trimethoxyborate. PMID- 22238178 TI - Postoperative morbidity and perioperative anti-TNF treatment: should we blame the drugs? PMID- 22238179 TI - The bleeding edge of symptom assessment. PMID- 22238180 TI - Comparative study of the semiconducting properties of benzothiadiazole and benzobis(thiadiazole) derivatives using computational techniques. AB - Recent literature reports indicate that derivatives of benzothiadiazole (BT) and benzobis(thiadiazole) (BBT), which differs from BT by an extra thiadiazole ring, exhibit good semiconducting properties, such as high electron mobility and low lying lowest unoccupied molecular-orbital (LUMO) levels. In this study herein, computational techniques like density functional theory (DFT), spin-flip DFT and valence-bond methods are used to analyze the semiconducting properties of these molecules. Calculations at the B3LYP/cc-pVTZ level reveal that all the BBT molecules, including the bare BBT ring, have lower lying LUMO energies (3.70-4.11 eV) compared to the BT derivatives (2.56-3.41 eV) with similar substitution. The reorganization energies (lambda(+)/lambda(-)) obtained at this level of theory of the BT derivatives are around (225-333)/(246-315) meV, while BBT derivatives have much smaller reorganization energies and these are in the range of (129-259)/(150 230) meV. We observe that the different behavior of BBT is due to the inherited biradicaloid character from the parent molecule tetramethylenebenzene (TMB), a disjoint non-Kekule biradical having non-bonding molecular orbitals (NBMOs) as the highest occupied molecular orbital (HOMO) and LUMO. Additionally, the perturbation of the orbitals of the biradical TMB to obtain BBT is the major cause for the BBT derivatives to have a larger electron affinity (EA) and a smaller HOMO-LUMO gap (HLG) compared to BT derivatives. PMID- 22238182 TI - A facile synthesis of dynamic supramolecular aggregates of cucurbit[n]uril (n=5 8) capped with gold nanoparticles in aqueous media. AB - Supramolecular capping of cucurbit[n]uril (CB[n]), where n=5-8, by narrowly dispersed gold nanoparticles has been achieved through a facile synthetic route with metastable gold nanoparticles as a labile intermediate. The resultant assemblies were stable in solution, and were found to form dynamic aggregates consisting of a controllable ratio of singly and doubly capped CB[n]. The stability of the system was attributed to the presence of sodium cations bound on the vacant carbonyl portals of the singly capped CB[n] molecules. These dynamically capped CB[n] systems can find potential use in a range of applications varying from ultrasensitive multiplexed in situ sensing to photocatalysis. PMID- 22238181 TI - Simulations of the p97 complex suggest novel conformational states of hydrolysis intermediates. AB - The vitally important AAA (ATPases associated with various cellular activities) protein p97 is involved in cellular functions ranging from replication to degradation of misfolded proteins and has recently been proposed as a novel chemotherapeutic target. p97 is a large molecular machine that has been shown to hexamerize in vitro, with each monomer consisting of an N domain responsible for binding to effector proteins and two AAA repeats (D1 and D2). However, structural studies are inconclusive or in disagreement with one another on several important features such as the locations of the N domains, the relative orientations of the D1 and D2 rings, and the dimensions of the central pore. Here, we present atomic scale simulations of the p97 hexamer in the prehydrolysis, transition, and post hydrolysis states. To improve the agreement between low- and high-resolution experimental studies, we first use a biased simulation technique, molecular dynamics flexible fitting (MDFF), to improve the correlation between the structures described in these experiments. We follow this with extended, classical molecular dynamics simulations, which not only show that structures generated in the MDFF phase are stable, but reveal insights into the dynamics important to each state. Simulation results suggest a hybrid model for hydrolysis, in which the N and D2 domains are dynamic while the D1 domains are relatively static, salt bridges stabilize the position of the N domains in the pre-hydrolysis state, and the rings formed by D1 and D2 rotate relative to one another. PMID- 22238183 TI - Eye movement patterns during the recognition of three-dimensional objects: preferential fixation of concave surface curvature minima. AB - This study used eye movement patterns to examine how high-level shape information is used during 3D object recognition. Eye movements were recorded while observers either actively memorized or passively viewed sets of novel objects, and then during a subsequent recognition memory task. Fixation data were contrasted against different algorithmically generated models of shape analysis based on: (1) regions of internal concave or (2) convex surface curvature discontinuity or (3) external bounding contour. The results showed a preference for fixation at regions of internal local features during both active memorization and passive viewing but also for regions of concave surface curvature during the recognition task. These findings provide new evidence supporting the special functional status of local concave discontinuities in recognition and show how studies of eye movement patterns can elucidate shape information processing in human vision. PMID- 22238184 TI - Infants and adults use line junction information to perceive 3D shape. AB - Two experiments investigated infants' and adults' perception of 3D shape from line junction information. Participants in both experiments viewed a concave wire half-cube frame. In Experiment 1, adults reported that the concave wire frame appeared to be convex when it was viewed monocularly (with one eye covered) and that it appeared to be concave when it was viewed binocularly. In Experiment 2, 5 and 7-month-old infants were shown the concave wire frame under monocular and binocular viewing conditions, and their reaching behavior was recorded. The infants in both age groups reached preferentially toward the center of the wire frame in the monocular condition and toward its edges in the binocular condition. Because infants typically reach to what they perceive to be closest to them, these reaching preferences provide evidence that they perceived the wire frame as convex when they viewed it monocularly and as concave when they viewed it binocularly. These findings suggest that, by 5 months of age, infants, like adults, use line junction information to perceive depth and object shape. PMID- 22238185 TI - Predictors of health-related quality of life in children and adolescents with juvenile idiopathic arthritis. PMID- 22238186 TI - Various types of stem cells, including a population of very small embryonic-like stem cells, are mobilized into peripheral blood in patients with Crohn's disease. AB - BACKGROUND: Developmentally early cells, including hematopoietic stem progenitor cells (HSPCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs), are mobilized into peripheral blood (PB) in response to tissue/organ injury. We sought to determine whether these cells are mobilized into PB in patients with Crohn's disease (CD). METHODS: Twenty-five patients with active CD, 20 patients in clinical remission, and 25 age-matched controls were recruited and PB samples harvested. The circulating CD133+/Lin-/CD45+ and CD34+/Lin-/CD45+ cells enriched for HSPCs, CD105+/STRO-1+/CD45- cells enriched for MSCs, CD34+/KDR+/CD31+/CD45-cells enriched for EPCs, and small CXCR4+CD34+CD133+ subsets of Lin-CD45- cells that correspond to the population of VSELs were counted by fluorescence-activated cell sorting (FACS) and evaluated by direct immunofluorescence staining for pluripotency embryonic markers and by reverse-transcription polymerase chain reaction (RT-PCR) for expression of messenger (m)RNAs for a panel of genes expressed in intestine epithelial stem cells. The serum concentration of factors involved in stem cell trafficking, such as stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data indicate that cells expressing markers for MSCs, EPCs, and small Oct-4+Nanog+SSEA 4+CXCR4+lin-CD45- VSELs are mobilized into PB in CD. The mobilized cells also expressed at the mRNA level genes playing a role in development and regeneration of gastrointestinal epithelium. All these changes were accompanied by increased serum concentrations of VEGF and HGF. CONCLUSIONS: CD triggers the mobilization of MSCs, EPCs, and VSELs, while the significance and precise role of these mobilized cells in repair of damaged intestine requires further study. PMID- 22238187 TI - Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate. AB - BACKGROUND: High dose methotrexate (HD-MTX), used in the treatment of children with acute lymphoblastic leukemia (ALL), is moderately emetogenic. First generation 5-HT(3) receptor antagonists are effective prophylactic agents but require multiple administrations. Palonosetron has a half life of 36-42 hours and has higher affinity and selectivity to the 5-HT(3) receptor. Adult studies have demonstrated that palonosetron is both more effective and require fewer administrations than first generation 5-HT(3) receptor antagonists. The purpose of this study was to examine the effect of a single dose of palonosetron (5 ug/kg) for the prevention of chemotherapy-induced nausea and vomiting in children 18 years of age with ALL treated with HD-MTX, 5 g/m(2). PROCEDURE: Between January 2010 and December 2010, 138 courses, originating from 53 children, were included from four Danish Childhood Cancer Centers. Information regarding emetic episodes, rescue therapy, and nausea were recorded prospectively on questionnaires. RESULTS: Complete response (no emesis and no rescue therapy) was achieved in 84.1% of courses during the acute (0-24 hours post-chemotherapy) and in 60.1% during the delayed phase (24-66 hours post-chemotherapy). 92.0% of courses were free of emesis during the acute, and 86.2% were free of emesis during the delayed phase. 76.8% of courses were free of nausea during the acute, and 78.3% were free of nausea during the delayed phase. CONCLUSIONS: A single dose of palonosetron--without concomitant corticosteroid--was effective in preventing both acute and delayed phase CINV in majority of children with ALL treated with HD-MTX. PMID- 22238188 TI - Dating bloodstains with fluorescence lifetime measurements. PMID- 22238189 TI - General and disease-specific psychosocial adjustment in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy with implantable cardioverter defibrillators: a large cohort study. AB - BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by frequent life-threatening ventricular arrhythmias, diagnosed on average in the teens to mid-50s and commonly treated by implantable cardioverter defibrillators (ICDs). As younger age and high frequency of ICD discharges are risk factors for difficulties in psychosocial adjustment, we developed a study to assess psychosocial adjustment among patients with ARVD/C and to determine risk factors for poor adjustment in this high-risk population. METHODS AND RESULTS: Eighty-six adults enrolled in the Johns Hopkins ARVD Registry (38 male; mean age, 45.4+/-12.9 years), with an ICD in place for a median 3.2 years (range, 0.2 to 20.1 years), completed a set of questionnaires measuring ICD-specific anxiety (Florida Shock Anxiety Scale), device acceptance (Florida Patient Acceptance Survey), anxiety and depression (Hospital Anxiety and Depression Scale), and functional capacity (Duke Activity Status Index). Although overall device acceptance (Florida Patient Acceptance Survey mean, 76.7+/-15.3) was normative, patients with ARVD/C had substantially elevated body image concerns (Florida Patient Acceptance Survey subscale mean, 17.9+/-23.5) and device-related distress (subscale mean, 26.5+/-19.2), particularly among younger patients (P<0.01). Patients with ARVD/C had elevated ICD-specific (Florida Shock Anxiety Scale mean, 22.9+/-7.8) and general clinical anxiety (Hospital Anxiety and Depression Scale anxiety subscale mean, 6.2+/-3.9). Device-specific anxiety (Florida Shock Anxiety Scale) was predicted by younger age (P<0.0001), poorer functional capacity (P=0.016), having an ICD shock (P=0.003), and shorter time since ICD implant (P=0.007). Participants with poor device adjustment had an increased likelihood of clinically significant anxiety (P=0.006) and depression (P=0.008). CONCLUSIONS: Patients with ARVD/C are at elevated risk for anxiety, and young patients face challenges with device acceptance. Risk factors for poor device adjustment may be used clinically to identify patients at high-risk of psychological distress. PMID- 22238191 TI - Acetylene adsorption on CPO-27-M metal-organic frameworks (M=Fe, Co and Ni). PMID- 22238190 TI - Elevated CD14++CD16- monocytes predict cardiovascular events. AB - BACKGROUND: Although monocytes in peripheral blood are no longer considered to be a homogeneous population, associations between distinct monocyte subsets and cardiovascular disease have not been highlighted in large epidemiological studies. METHODS AND RESULTS: The study included 700 randomly selected subjects from the cardiovascular arm of the Malmo Diet and Cancer study. Among these, 123 subjects experienced ischemic cardiovascular events during the follow-up until December 2008. Mononuclear leukocytes frozen at the baseline investigation in 1991 to 1994 were thawed and analyzed with flow cytometry to enumerate monocyte subsets, based on CD14 and CD16 expression. The percentage and number of classical CD14(++)CD16(-) monocytes were increased in the cardiovascular-event group compared with the event-free subjects (median, 69% [interquartile range, 62% to 76%] versus 67% [59% to 72%], P=0.017; 344 [251 to 419] cells/MUL versus 297 [212 to 384] cells/MUL, P=0.003). The hazard ratio was 1.66 for suffering a cardiovascular event in the highest tertile of the number of CD14(++)CD16(-) monocytes compared with the lowest tertile, even after adjustment for common risk factors (HR, 1.66; 95% CI: 1.02 to 2.72). CD14(++)CD16(-) monocytes did not, however, associate with the extent of atherosclerosis at baseline. In contrast, the percentage of monocytes expressing CD16 was negatively associated to the extent of carotid atherosclerosis measured as intima-media thickness at baseline. The chemokine receptors CCR2, CX3CR1, and CCR5 were not differentially expressed between cases and controls on any of the monocyte subsets, but CCR5 expression on CD14(+)CD16(++) monocytes was negatively associated to carotid intima-media thickness. CONCLUSIONS: This study shows that classical CD14(++)CD16(-) monocytes can predict future cardiovascular risk independently of other risk factors in a randomly selected population. PMID- 22238193 TI - Mitochondrial myopathy in rheumatology: comment on the article by Albert et al. PMID- 22238192 TI - Structure-function relationship of assimilatory nitrite reductases from the leaf and root of tobacco based on high-resolution structures. AB - Tobacco expresses four isomers of assimilatory nitrite reductase (aNiR), leaf type (Nii1 and Nii3), and root-type (Nii2 and Nii4). The high-resolution crystal structures of Nii3 and Nii4, determined at 1.25 and 2.3 A resolutions, respectively, revealed that both proteins had very similar structures. The Nii3 structure provided detailed geometries for the [4Fe-4S] cluster and the siroheme prosthetic groups. We have generated two types of Nii3 variants: one set focuses on residue Met175 (Nii3-M175G, Nii3-M175E, and Nii3-M175K), a residue that is located on the substrate entrance pathway; the second set targets residue Gln448 (Nii3-Q448K), a residue near the prosthetic groups. Comparison of the structures and kinetics of the Nii3 wild-type (Nii3-WT) and the Met175 variants showed that the hydrophobic side-chain of Met175 facilitated enzyme efficiency (k(cat) /K(m) ). The Nii4-WT has Lys449 at the equivalent position of Gln448 in Nii3-WT. The enzyme activity assay revealed that the turnover number (k(cat) ) and Michaelis constant (K(m) ) of Nii4-WT were lower than those of Nii3-WT. However, the k(cat) /K(m) of Nii4-WT was about 1.4 times higher than that of Nii3-WT. A comparison of the kinetics of the Nii3-Q448K and Nii4-K449Q variants revealed that the change in k(cat) /K(m) was brought about by the difference in Residue 448 (defined as Gln448 in Nii3 and Lys449 in Nii4). By combining detailed crystal structures with enzyme kinetics, we have proposed that Nii3 is the low-affinity and Nii4 is the high-affinity aNiR. PMID- 22238197 TI - Effects of an intravenous bolus of alfaxalone versus propofol on intraocular pressure in sheep. AB - The objective of this prospective study was to determine the effects of a single intravenous bolus of alfaxalone in 2-hydroxypropyl-beta-cyclodextrin and propofol on the intraocular pressure (IOP) in sheep. Ten Ripollesa sheep with a bodyweight of 48.5 (6.8) kg (mean [sd]) were used in the study. Twenty-four hours before the experimental procedure, a complete ophthalmic examination was performed in all animals. The day of the study, intravenous alfaxalone (2 mg/kg) or propofol (6 mg/kg) was randomly administered in a cross-over design, with a washout period of two weeks. Measurements of IOP, globe position and pupil size were obtained at basal time, before induction (time 0) and at two, five, 10, 15, 20, 30, 45, 60, 90 and 120 minutes after drug administration. Occasional side effects and time to standing were also noted. Intravenous administration of alfaxalone and propofol in sheep resulted in no alteration of IOP. Nevertheless, a decrease in the pupil size was observed in both groups. This present study shows that alfaxalone and propofol, administrated as a single intravenous bolus, are good options for maintaining IOP during anaesthesia in sheep, although marked miosis was observed after administration. PMID- 22238194 TI - 18F-FDG microPET imaging detects early transient response to an IGF1R inhibitor in genetically engineered rhabdomyosarcoma models. AB - BACKGROUND: Alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) are among the most common and most treatment resistant soft tissue sarcomas of childhood. Here, we evaluated the potential of (18)F Fluorodeoxyglucose (FDG) as a marker of therapeutic response to picropodophyllin (PPP), an IGF1R inhibitor, in a conditional mouse model of ARMS and a conditional model of ERMS/undifferentiated pleomorphic sarcoma (UPS). PROCEDURE: Primary tumor cell cultures from Myf6Cre,Pax3:Fkhr,p53 and Pax7CreER,Ptch1,p53 conditional models of ARMS and ERMS/UPS were found to be highly sensitive to PPP (IC(50) values 150 and 200 nM, respectively). Animals of each model were then treated with 80 mg/kg/day PPP by intraperitoneal injection for 12 days and imaged by (18)F-FDG microPET. RESULTS: Tumor volumes on day 4 for PPP-treated ARMS and ERMS mice were lower than untreated control mouse tumor volumes, although treated tumors were larger than day 0. However, tumor FDG uptake was significantly reduced on day 4 for PPP-treated mice compared to pretreatment baseline or untreated control mice on day 4 (P < 0.05). Nevertheless, by day 12 tumor volumes and FDG uptake for treated mice had increased significantly, indicating rapidly evolving resistance to therapy. CONCLUSIONS: (18)F-FDG PET imaging is a potential imaging biomarker of molecular susceptibility to targeted agents early in treatment for this aggressive form of sarcoma, but may find best use serially for Phase I/II studies where chemotherapy and targeted agents are combined to cytoreduce tumors and abrogate Igf1r inhibitor resistance. PMID- 22238198 TI - Association of gammaherpesviruses and bacteria with clinical metritis in a dairy herd. PMID- 22238199 TI - Farmers' confidence in vaccinating badgers against bovine tuberculosis. AB - This paper examines UK farmers' levels of confidence in vaccinating badgers against bovine tuberculosis (bTB) and their trust in the Government's ability to deal with bTB. In 2010, a badger vaccine based on the BCG vaccine was licensed following field trials and used as part of the UK Government's Badger Vaccination Deployment Project. A stratified random sample of cattle farmers in five different locations of England was surveyed using a telephone survey to elicit their views of badger vaccination. The survey provided a total of 341 responses with a response rate of 80 per cent. Results suggest that the farmers are cautious about badger vaccination, appearing to be neither overly confident nor unconfident in it. However, the farmers did not reveal high levels of trust in the Government to manage bTB policy or badger vaccination. There were no differences in the levels of confidence or trust between farms that were under bTB restrictions at the time of the survey and those that were not or between farms with historically high levels of bTB. Analysis of principal components suggests that 33 per cent of the farmers accepted badger vaccination, but that acceptance is dependent on the wider social and political environment. PMID- 22238200 TI - Haemolytic disease in sheep attributed to a Babesia lengau-like organism. PMID- 22238201 TI - Economic analysis of outbreaks of porcine reproductive and respiratory syndrome virus in nine sow herds. AB - The economic losses due to porcine reproductive and respiratory syndrome virus (PRRSv) outbreaks are reported in the literature to be substantially high, but recent figures are not available. The aim of this study was to quantify the economic effects of epidemic PRRSv outbreaks in Dutch sow herds. Nine sow herds were selected based on a confirmed PRRSv outbreak within those populations. The economic impact during the first 18 weeks after the outbreak was estimated by comparing the overall costs between pre- and postoutbreak periods, using different factors (production data, medication, diagnostics, labour, etc.). An outbreak of PRRSv resulted in a reduced number of sold pigs per sow of 1.7. The economic loss varied between ?59 and ?379 for one sow per 18-week period outbreak. The mean loss per sow per outbreak was ?126. The costs after the outbreak varied significantly from ?3 to 160 per sow, due to the different methods used by farmers to tackle PRRSv outbreaks. The calculated costs in this study correlate with the costs of the initial outbreak in The Netherlands of 98 per sow. PMID- 22238202 TI - Impact of a high-phosphorus diet on the sonographic and CT appearance of kidneys in degus, and possible concurrence with dental problems. AB - The main aim of this study was to investigate the impact of pelleted diet of different mineral composition on the sonographic and CT appearance of kidneys in degus (Octodon degus). A total of 35 animals were randomly divided into five groups, fed diets containing different calcium and phosphorus contents (13.5 g/kg calcium and 6.3 g/kg phosphorus, or 9.1 g/kg calcium and 9.5 g/kg phosphorus) and given different amounts of exposure to UV light. Endoscopic examination of the oral cavity as well as renal ultrasonography and CT was performed four times at four-month intervals throughout the study. After 14 months of feeding an experimental diet, all degus were euthanased and subsequently all kidneys were collected for histopathological examination. Animals fed a diet with high dietary phosphate and improper calcium to phosphorus ratio showed severe nephrocalcinosis. Ultrasonographic and CT kidney abnormalities presented as hyperechogenicity and hyperdensity (interpreted as nephrocalcinosis), respectively. The most striking changes were seen at the corticomedullary zone. Ultrasonography and CT correlated in all cases with histopathological findings. Dental disease developed quickly in groups fed diets with an improper calcium and phosphorus content, with obvious apical and coronal elongation of all the teeth. A possible influence of UV light access could not be proved in this study. PMID- 22238203 TI - Surveillance for antibodies to West Nile virus in Ireland. PMID- 22238204 TI - A study on the association of serum 1,5-anhydroglucitol levels and the hyperglycaemic excursions as measured by continuous glucose monitoring system among people with type 2 diabetes in China. AB - BACKGROUND: Blood glucose excursion is an important component of the glycaemic burden, but there are no indexes that can directly reflect them. The aim was to evaluate the values and significance of serum 1,5-anhydroglucitol (1,5-AG) in people with type 2 diabetes mellitus in China and to elucidate the relationship between 1,5-AG and traditional indexes of glycaemic excursions by continuous glucose monitoring. METHODS: A total of 576 healthy adults and 292 patients were included, and their 1,5-AG, fasting blood glucose and postprandial blood glucose and glycated haemoglobin were measured. For the 34 patients, their mean blood glucose, standard deviation of blood glucose, mean amplitude of glucose excursion, mean of daily differences, low blood glucose M-value index and the area under the curve for blood glucose above 180 mg/dL were calculated by use of a continuous glucose monitoring system. RESULTS: Serum levels of 1,5-AG among healthy adults were 28.44 +/- 8.76 ug/mL with a significant gender bias rather than age bias. The 1,5-AG levels in people with type 2 diabetes mellitus were 4.57 +/- 3.71 ug/mL, which were lower than those seen in the healthy adults. There was a correlation between 1,5-AG and glycated haemoglobin, fasting blood glucose, and postprandial blood glucose (r = -0.251, -0.195 and -0.349, respectively; all had p < 0.05). The continuous glucose monitoring system demonstrated that 1,5-AG presents a negative correlation with mean blood glucose, standard deviation of blood glucose, mean amplitude of glucose excursion and mean of daily differences for 7 days and with the area under the curve for blood glucose above 180 mg/dL on the third, fourth and seventh days. CONCLUSIONS: 1,5 AG may serve as a marker of hyperglycaemia and 7-day hyperglycaemic excursions as well as being a useful adjunct to glycated haemoglobin for blood glucose monitoring in patients with diabetes. PMID- 22238205 TI - Transition metal hydrazide-based hydrogen-storage materials: the first atoms-in molecules analysis of the Kubas interaction. AB - Molecular models of the M-H(2) binding sites of experimentally characterised amorphous vanadium hydrazide gels are studied computationally using gradient corrected density functional theory, to probe the coordination number of the vanadium in the material and the nature of the interaction between the metal and the H(2) molecules. The H(2) is found to bind to the vanadium through the Kubas interaction, and the first quantum theory of atoms-in-molecules analysis of this type of interaction is reported. Strong correlation is observed between the electron density at the H-H bond critical point and the M-H(2) interaction energy. Four coordinate models give the best reproduction of the experimental data, suggesting that the experimental sites are four coordinate. The V-H(2) interaction is shown to be greater when the non-hydrazine based ligand, THF, of the experimental system is altered to a poorer pi-acceptor ligand. Upon altering the metal to Ti or Cr the M-H(2) interaction energy changes little but the number of H(2) which may be bound decreases from four (Ti) to two (Cr). It is proposed that changing the metal from V to Ti may increase the hydrogen storage capacity of the experimental system. A 9.9 wt% maximum storage capacity at the ideal binding enthalpy for room temperature performance is predicted when the Ti metal is combined with a coordination sphere containing 2 hydride ligands. PMID- 22238206 TI - Transfusion medicine problems and solutions for the pediatric hematologist/oncologist. AB - Blood component transfusion is an integral part of the care of children with oncologic and hematologic conditions. The complexity of transfusion medicine may however lead to challenges for pediatric hematologists/oncologists. In this review, three commonly encountered areas of transfusion medicine are explored. The approach to the investigation and management of suspected platelet refractoriness is reviewed. The unique transfusion related challenges encountered by children undergoing stem cell transplantation are also discussed. Finally, issues arising out of the care of children with hemoglobinopathies are explored, with an emphasis on the incidence of allo- and autoimmunization. PMID- 22238207 TI - Bidentate and tridentate metal-ion coordination states within ternary complexes of RB69 DNA polymerase. AB - Two divalent metal ions are required for primer-extension catalyzed by DNA polymerases. One metal ion brings the 3'-hydroxyl of the primer terminus and the alpha-phosphorus atom of incoming dNTP together for bond formation so that the catalytically relevant conformation of the triphosphate tail of the dNTP is in an alpha,beta,gamma-tridentate coordination complex with the second metal ion required for proper substrate alignment. A probable base selectivity mechanism derived from structural studies on Dpo4 suggests that the inability of mispaired dNTPs to form a substrate-aligned, tridentate coordination complex could effectively cause the mispaired dNTPs to be rejected before catalysis. Nevertheless, we found that mispaired dNTPs can actually form a properly aligned tridentate coordination complex. However, complementary dNTPs occasionally form misaligned complexes with mutant RB69 DNA polymerases (RB69pols) that are not in a tridentate coordination state. Here, we report finding a beta,gamma-bidentate coordination complex that contained the complementary dUpNpp opposite dA in the structure of a ternary complex formed by the wild type RB69pol at 1.88 A resolution. Our observations suggest that several distinct metal-ion coordination states can exist at the ground state in the polymerase active site and that base selectivity is unlikely to be based on metal-ion coordination alone. PMID- 22238208 TI - Patterns of compartment involvement in tibiofemoral osteoarthritis in men and women and in whites and African Americans. AB - OBJECTIVE: We conducted a cross-sectional study to describe the prevalence of tibiofemoral joint space narrowing (JSN) in medial and lateral compartments and assess whether it differs by sex and ethnic groups, and, if it does, to what extent such a difference is accounted for by knee malalignment. METHODS: The Multicenter Osteoarthritis Study is an observational study of persons ages 50-79 years with either symptomatic knee osteoarthritis or high risk of disease. Knee radiographs were assessed for JSN in each tibiofemoral compartment. Mechanical axis angle was measured using full-extremity films. We compared the proportion of knees with medial compartment JSN and with lateral JSN between men and women, as well as between whites and African Americans, using a logistic regression model adjusting for covariates (race or sex and body mass index, age, education, and clinic site). We used generalized estimating equations to account for correlation between 2 knees within a person. RESULTS: Of 5,202 knees (2,652 subjects), 1,532 (29.5%) had medial JSN and 427 (8.2%) had lateral JSN. Lateral JSN was more prevalent in the knees of women than in men (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.5-2.4) and was also higher in the knees of African Americans than in whites (OR 2.4, 95% CI 1.7-3.3). Further adjustment for malalignment attenuated the OR for sex but not the OR for race. CONCLUSION: Women and African Americans are more likely to have lateral JSN than men and whites, respectively. Valgus malalignment may contribute to the higher prevalence in women. PMID- 22238209 TI - Water-soluble, donor-acceptor biphenyl derivatives in the 2-(o-nitrophenyl)propyl series: highly efficient two-photon uncaging of the neurotransmitter gamma aminobutyric acid at lambda = 800 nm. PMID- 22238210 TI - A novel small molecule, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5 ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-bibenzo[d][1,3]dioxole-5,5' dicarboxylate (7k), alleviates the development of D galactosamine/lipopolysaccharide-induced acute liver failure by inhibiting macrophage infiltration and regulating cytokine expression. AB - Acute liver failure (ALF) is a relatively rare liver disorder that leads to the massive death of hepatocytes. Our previous study reported that a novel small molecule agent, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5 ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-bibenzo[d][1,3]dioxole-5,5' dicarboxylate (7k), possessed potent anti-inflammatory activity. In the present study, we further evaluated the therapeutic effects of 7k on lipopolysaccharide (LPS)-induced ALF and investigated the mechanisms of action. Our results demonstrated that 7k inhibited the migration of RAW264.7 macrophages, blocked the activity of nuclear factor-kappaB protein, and dose-dependently down-regulated the production of interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 as well as their corresponding mRNAs in RAW264.7 cells. Oral administration of 7k at a dose of 50 mg/kg significantly suppressed the serum level of enzyme activity and prevented the damage of liver tissue in D-galactosamine/LPS-induced ALF. Treatment with 7k also remarkably blocked the increase in the number of CD11b(+)- and CD68(+)-positive cells in the liver, and in vivo nuclear factor-kappaB activity, known to regulate inflammatory responses in many cell types, was effectively inhibited. The serum concentrations and hepatic mRNA expression of proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and IL-6 were markedly down-regulated in mice by the treatment of 7k. In summary, 7k alleviated the development and progression of D-galactosamine/LPS-induced ALF by inhibiting macrophage infiltration and regulating the expression of cytokines. PMID- 22238212 TI - A humanized glycoprotein VI (GPVI) mouse model to assess the antithrombotic efficacies of anti-GPVI agents. AB - Glycoprotein VI (GPVI) has been proposed as a promising antiplatelet target, because its blockade prevents experimental thrombosis without impairing hemostasis. The objective of this study was to develop a preclinical tool to evaluate the role of human GPVI (hGPVI) in various models of thrombosis and to screen anti-GPVI compounds. A genetically modified mouse strain expressing hGPVI has been developed using a knockin strategy. The mice were viable and fertile and did not present any hematological defects. Approximately 3700 copies of human GPVI were detected at the platelet surface. Platelet aggregation, fibrinogen binding, and P-selectin exposure were normal in response to various agonists. The 9O12.2 Fab fragment directed against human GPVI bound to hGPVI platelets in vitro and ex vivo and markedly reduced collagen- and collagen-related peptide-induced responses. Injection of 9O12.2 into hGPVI animals did not prolong the tail bleeding time but provided protection against lethal thromboembolism induced by a collagen/adrenaline mixture. In addition, 9O12.2 reduced arterial thrombus growth by 44% after superficial laser injury, 43% after deep laser injury in mice pretreated with hirudin, and 48% after mechanical injury. In conclusion, we have developed a humanized mouse model that could be used in preclinical studies to evaluate the effects of anti-GPVI compounds. PMID- 22238213 TI - P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict brain accumulation of the active sunitinib metabolite N-desethyl sunitinib. AB - N-desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N-desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N-desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N-desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine Abcg2, but not ABCC2 or Abcc2. At 5 MUM, ABCB1 and ABCG2 contributed almost equally to N-desethyl sunitinib transport. In vivo, the systemic exposure of N desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or Abcg2 were absent. However, brain accumulation of N-desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a/1b(-/-)/Abcg2(-/-) mice, but not in Abcb1a/1b(-/-) or Abcg2(-/-) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N-desethyl sunitinib were detectable only in Abcb1a/1b(-/-)/Abcg2(-/-) mice after sunitinib administration. Combined elacridar plus N-desethyl sunitinib treatment increased N-desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N-desethyl sunitinib is effectively restricted by both Abcb1 and Abcg2. The effect of elacridar treatment in improving brain accumulation of N-desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation. PMID- 22238211 TI - Microinjection of glycine into the ventral tegmental area selectively decreases ethanol consumption. AB - The mechanisms of ethanol addiction are not completely understood. The mesolimbic dopaminergic system is involved in many drug-related behaviors, including ethanol self-administration. The dopaminergic neurons in this system originate in the ventral tegmental area (VTA) and are under the control of GABAergic transmission. Our previous in vitro electrophysiological data indicate that glycine receptors (GlyRs) exist on the GABAergic terminals, which make synapses on VTA dopaminergic neurons, and activation of these GlyRs reduces GABAergic transmission and increases the activity of VTA dopaminergic neurons. In the current study, we tested the hypothesis that the activation of the presynaptic GlyRs in the VTA might interfere with ethanol self-administration. Glycine and strychnine, the selective antagonist of GlyRs, were injected, either alone or in combination, into the VTA of rats. Ethanol self-administration by rats was evaluated by using three different drinking models: intermittent access, continuous access, and operant self-administration. We found that the infusion of glycine into the VTA selectively reduced the intake of ethanol but not sucrose or water in rats chronically exposed to ethanol under the intermittent-access and continuous access procedures and decreased lever-press responding for ethanol under an operant self-administration procedure. The effects of glycine probably were mediated by strychnine-sensitive GlyRs, because the coinjection of glycine and strychnine reduced neither ethanol intake in the home cages nor lever-press responding for ethanol in the operant chambers. Thus, GlyRs in the VTA may play a critical role in ethanol self-administration in animals chronically exposed to ethanol. Therefore, drugs targeting GlyRs may be beneficial for alcoholics. PMID- 22238214 TI - When and why do retrieval attempts enhance subsequent encoding? AB - Unsuccessful retrieval attempts can enhance subsequent encoding and learning. In three experiments, subjects either attempted to retrieve word pairs prior to studying them (e.g., attempting to recall tide-? before studying tide-beach) or did not attempt retrieval and retention of the studied targets was assessed on a subsequent cued recall test. Experiment 1 showed that attempting retrieval enhanced subsequent encoding and recall relative to not attempting retrieval when the word pairs were semantically related, but not when the pairs were unrelated. In Experiment 2, studying a different word pair prior to the correct pair (e.g., studying tide-wave prior to tide-beach) did not produce the same effect as attempting retrieval prior to studying. Constraining retrieval to a particular candidate word prior to study (e.g., recalling tide-wa__ before studying tide beach) produced a negative effect on subsequent recall. Experiment 3 showed that attempting retrieval did not enhance encoding when a brief delay occurred between the retrieval attempt and the subsequent study trial. The results support the idea that a search set of candidates related to the retrieval cue is activated during retrieval and that this retrieval-specific activation can enhance subsequent encoding of those candidates. PMID- 22238216 TI - Metabolic syndrome, physical activity and cardiac autonomic function. AB - BACKGROUND: Our primary aim was to investigate the associations that components of metabolic syndrome and physical activity have with cardiac autonomic nervous system activity as estimated by heart rate variability (HRV) in young adults free of metabolic abnormalities. We also aimed to identify predictors of 3-year changes in HRV. METHODS: Physical activity was assessed annually in 163 healthy participants over 3 years (2008-2010). Components of metabolic syndrome measured annually were; waist circumference, systolic blood pressure, high-density lipoprotein, triglycerides, glucose, and C-reactive protein. A linear mixed regression model was used to assess associations between HRV, metabolic syndrome components and physical activity. Linear regression was used to identify predictors of changes in HRV. RESULTS: Metabolic syndrome components were negatively associated with HRV indices and higher heart rate, while physical activity was associated with higher HRV and lower heart rate. Physical activity and inflammation were predictors of positive and negative changes in HRV indices, respectively. CONCLUSIONS: In participants without significant metabolic abnormalities, metabolic syndrome components were still associated with less favourable HRV profiles. Physical activity and inflammation were both able to predict changes in HRV, albeit in different directions. It appears that the process of autonomic dysfunction starts at a young age and may be mediated in part by inflammation. Metabolic syndrome prevalence is increasing in younger populations; promoting the metabolic and autonomic benefits of exercise remains imperative. PMID- 22238215 TI - The cycling of acetyl-coenzyme A through acetylcarnitine buffers cardiac substrate supply: a hyperpolarized 13C magnetic resonance study. AB - BACKGROUND: Carnitine acetyltransferase catalyzes the reversible conversion of acetyl-coenzyme A (CoA) into acetylcarnitine. The aim of this study was to use the metabolic tracer hyperpolarized [2-(13)C]pyruvate with magnetic resonance spectroscopy to determine whether carnitine acetyltransferase facilitates carbohydrate oxidation in the heart. METHODS AND RESULTS: Ex vivo, following hyperpolarized [2-(13)C]pyruvate infusion, the [1-(13)C]acetylcarnitine resonance was saturated with a radiofrequency pulse, and the effect of this saturation on [1-(13)C]citrate and [5-(13)C]glutamate was observed. In vivo, [2-(13)C]pyruvate was infused into 3 groups of fed male Wistar rats: (1) controls, (2) rats in which dichloroacetate enhanced pyruvate dehydrogenase flux, and (3) rats in which dobutamine elevated cardiac workload. In the perfused heart, [1 (13)C]acetylcarnitine saturation reduced the [1-(13)C]citrate and [5 (13)C]glutamate resonances by 63% and 51%, respectively, indicating a rapid exchange between pyruvate-derived acetyl-CoA and the acetylcarnitine pool. In vivo, dichloroacetate increased the rate of [1-(13)C]acetylcarnitine production by 35% and increased the overall acetylcarnitine pool size by 33%. Dobutamine decreased the rate of [1-(13)C]acetylcarnitine production by 37% and decreased the acetylcarnitine pool size by 40%. CONCLUSIONS: Hyperpolarized (13)C magnetic resonance spectroscopy has revealed that acetylcarnitine provides a route of disposal for excess acetyl-CoA and a means to replenish acetyl-CoA when cardiac workload is increased. Cycling of acetyl-CoA through acetylcarnitine appears key to matching instantaneous acetyl-CoA supply with metabolic demand, thereby helping to balance myocardial substrate supply and contractile function. PMID- 22238217 TI - Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: a pilot study. AB - BACKGROUND: Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction. PROCEDURE: A single institution open-label pilot study was conducted in childhood BT survivors: >=1 year from cancer treatment; and who received >23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug. RESULTS: From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9-11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (P < 0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (P = 0.007), and the Number/Letter task (P = 0.018). CONCLUSIONS: Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction. PMID- 22238218 TI - Self-assembly of amphiphilic molecules in droplet compartments: an approach toward discrete submicrometer-sized one-dimensional structures. PMID- 22238219 TI - Prediction of protein-protein binding free energies. AB - We present an energy function for predicting binding free energies of protein protein complexes, using the three-dimensional structures of the complex and unbound proteins as input. Our function is a linear combination of nine terms and achieves a correlation coefficient of 0.63 with experimental measurements when tested on a benchmark of 144 complexes using leave-one-out cross validation. Although we systematically tested both atomic and residue-based scoring functions, the selected function is dominated by residue-based terms. Our function is stable for subsets of the benchmark stratified by experimental pH and extent of conformational change upon complex formation, with correlation coefficients ranging from 0.61 to 0.66. PMID- 22238220 TI - Trends in hip fracture incidence and in the prescription of antiosteoporosis medications during the same time period in Belgium (2000-2007). AB - OBJECTIVE: To examine the secular trend of hip fracture incidence in Belgium between 2000 and 2007 and the concomitant change in the prescriptions of antiosteoporosis medications. METHODS: The incidence of hip fractures and the number of prescriptions were determined using national databases. A logistic regression including years and 5-year age range was performed to assess the secular trend of hip fracture incidence, and Pearson's correlation coefficient was calculated to examine the relationship between hip fracture incidence and the prescriptions of antiosteoporosis medications. RESULTS: The annual number of hip fractures increased in Belgium from 13,512 in 2000 to 14,744 in 2007, with a more marked increased in men (20.4%) than in women (5.7%). The age-adjusted incidence of hip fractures was significantly decreased by 1.12% per year in women, but declined nonsignificantly by 0.34% per year in men. An increase in the prescriptions of antiosteoporosis medications in women was observed during the same time period. CONCLUSION: Despite an increase in the number of hip fractures in Belgium between 2000 and 2007, there was a significant decrease in age adjusted incidence in women but not in men. Although our results suggest that the decrease may be related to the extent of antiosteoporosis medications, a causal relationship cannot be ascertained and many other factors may have contributed to the decrease in age-adjusted incidence. PMID- 22238221 TI - Investigation on the chemiluminescence reaction of the phenylhydrazine-luminol peroxide system. AB - We studied the chemiluminescence (CL) oxidation of phenyl hydrazine-luminol with various organic and inorganic peroxides. Maximum CL intensity for this system was obtained for t-butylhydroperoxide. The enhancement in CL depended strongly on pH and was greatest at pH 12.5. The solvent drastically enhanced the CL intensity. DMSO was found to increase the CL intensity many-fold as compared to acetonitrile and water. The effect of temperature on CL intensity has also been studied. The CL spectra revealed a broad peak at 425 nm, which suggests excited 3 aminophthalate ion as the luminophor. A mechanism to explain the reactions is suggested. PMID- 22238222 TI - 2011 panel on developing a biomaterials curriculum. AB - This article provides the transcript for the Panel on Developing a Biomaterials Curriculum held at the 2011 annual meeting of the Society for Biomaterials in Orlando, FL. The panelists were Thomas R. Harris of Vanderbilt University, Jack Lemons of the University of Alabama, Birmingham, Antonios G. Mikos of Rice University, David A. Puleo on the University of Kentucky, Frederick J. Schoen of Harvard Medical School, and Johnna S. Temenoff of Georgia Tech/Emory. The panelists, each an expert in engineering education and textbook author, presented their perspectives on key issues of developing undergraduate and graduate curricula that contain a biomaterials focus. The presentations were followed by a lively and informative discussion with the audience. A redacted portion of this discussion is included. PMID- 22238223 TI - C-H...O hydrogen bonding induced triazole foldamers: efficient halogen bonding receptors for organohalogens. PMID- 22238224 TI - The impact of CRISPR repeat sequence on structures of a Cas6 protein-RNA complex. AB - The repeat-associated mysterious proteins (RAMPs) comprise the most abundant family of proteins involved in prokaryotic immunity against invading genetic elements conferred by the clustered regularly interspaced short palindromic repeat (CRISPR) system. Cas6 is one of the first characterized RAMP proteins and is a key enzyme required for CRISPR RNA maturation. Despite a strong structural homology with other RAMP proteins that bind hairpin RNA, Cas6 distinctly recognizes single-stranded RNA. Previous structural and biochemical studies show that Cas6 captures the 5' end while cleaving the 3' end of the CRISPR RNA. Here, we describe three structures and complementary biochemical analysis of a noncatalytic Cas6 homolog from Pyrococcus horikoshii bound to CRISPR repeat RNA of different sequences. Our study confirms the specificity of the Cas6 protein for single-stranded RNA and further reveals the importance of the bases at Positions 5-7 in Cas6-RNA interactions. Substitutions of these bases result in structural changes in the protein-RNA complex including its oligomerization state. PMID- 22238225 TI - Disease severity and knee extensor force in knee osteoarthritis: data from the Osteoarthritis Initiative. AB - OBJECTIVE: To determine whether the method of disease severity measurement influences the magnitude of knee extensor force deficits in knee osteoarthritis (OA). METHODS: Data from the Osteoarthritis Initiative (n = 659) were analyzed. Knee extensor force was assessed with isometric contractions. Clinical severity was measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Patients were stratified into tertiles of severity (i.e., moderate, mild, and severe OA) based on the lowest, middle, and highest WOMAC scores, respectively. Kellgren/Lawrence (K/L) grading was used to assess radiographic severity of the tibiofemoral compartment and patients were again stratified into mild (K/L grade <2), moderate (K/L grade 2), and severe (K/L grade >2) knee OA. RESULTS: When stratifying with the WOMAC, force was significantly lower in the severe group compared to the mild (~18% lower; P < 0.001) and moderate groups (~9% lower; P = 0.03), and in the moderate group compared to the mild group (~10% lower; P = 0.03). When stratifying with K/L grade, small nonsignificant differences were observed in the severe (~7% lower; P = 0.19) and moderate groups (~8% lower; P = 0.08) compared to the mild group. Large intragroup variability was observed when comparing WOMAC scores across radiographic severity (coefficients of variation were 79.3%, 74.6%, and 61.6% for K/L grade <2, K/L grade 2, and K/L grade >2, respectively). CONCLUSION: The method of disease severity stratification influences the magnitude of knee extensor force deficits because no difference in force between disease subgroups was observed when stratifying with K/L grade. Furthermore, there was large variability in the WOMAC score within each radiographic subgroup, highlighting the limitations in using radiographic measures to reflect symptom severity. PMID- 22238226 TI - Scavenging of hydroxyl radical by catecholamines. AB - The direct effects of the four catecholamines (CATs), adrenaline (A), noradrenaline (NA), dopamine (D) and isoproterenol (I), on free radicals were investigated using the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH(*)) and hydroxyl radial (HO(*)). The CATs examined were found to inhibit the ESR signal intensity of DPPH(*) in a dose-dependent manner over the range 0.1-2.5 mmol/L in the following order: NA > A > I > D, with IC50= 0.30 +/- 0.03 for noradrenaline and IC50= 0.86 +/- 0.02 for dopamine. Hydroxyl radicals were produced using a Fenton reaction in the presence of the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO), and ESR technique was applied to detect the CATs reactivity toward the radicals. The reaction rates constant (k(r)) of CATs with HO(*) were found to be in the order of 10(9) L/mol/s, and the k(r) value for noradrenaline was the highest (k(r)= 8.4 * 10(9) L/mol/s). The CATs examined exhibited also a strong decrease in the light emission (62-73% at 1 mmol/L concentration and 79-89% at 2 mmol/L concentration) from a Fenton-like reaction. These reactions may be relevant to the biological action of these important polyphenolic compounds. PMID- 22238227 TI - Relationship between vein graft failure and subsequent clinical outcomes after coronary artery bypass surgery. AB - BACKGROUND: Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes. METHODS AND RESULTS: Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21-2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71-1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77-1.53; P=0.65). CONCLUSIONS: VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery. PMID- 22238228 TI - Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism. AB - BACKGROUND: Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen ovale (PFO) are at risk for recurrent cerebrovascular events. Differences in long-term clinical outcome were investigated among patients with percutaneous PFO closure and those who received medical treatment. METHODS AND RESULTS: Between 1994 and 2000, 308 consecutive patients with cerebrovascular events presumably related to PFO underwent either percutaneous PFO closure (150 patients) or medical treatment (158 patients). Patients were followed up prospectively for up to 15 years. Seven patients were lost during follow-up. The primary outcome was a composite of stroke, transient ischemic attack, or peripheral embolism. We analyzed 103 propensity score-matched pairs of patients who underwent percutaneous PFO closure or medical treatment. At a median follow-up of 9 years, the primary composite outcome occurred in 11 patients slated to PFO closure (11%) and 22 patients slated to medical treatment (21%; hazard ratio=0.43; 95% confidence interval=0.20-0.94; P=0.033). The treatment effect was driven by a decrease in the risk of transient ischemic attack of 5% versus 14%, respectively (hazard ratio=0.31; 95% confidence interval=0.10-0.94; P=0.039). The risk of all-cause (6% in both groups) and cardiovascular (3% in both groups) mortality appeared to be identical. CONCLUSION: In this long-term observational, propensity score-matched study, percutaneous PFO closure was more effective than medical treatment for the secondary prevention of recurrent cerebrovascular events among patients with PFO-related transient ischemic attack or stroke. PMID- 22238229 TI - Two-photon confocal imaging study: cell uptake of two photon dyes-labeled PAMAM dendrons in HeLa cells. AB - A two-photon excitation difluoroboron dye activated in the near infrared region for biological image analysis was synthesized in this study. Cell affinity, membrane interaction, and the endocytosis pathway of PAMAM dendrons were investigated using only covalent two-photon dyes (TPD) at the periphery of the PAMAM dendrons. Generation 3 TPD-labeled PAMAM dendrons (BG3) exhibited multivalency binding on the HeLa cell membranes from the cell affinity study in the fixation of HeLa cells. Photo-stimulation on the membrane of the living HeLa cell was observed by confocal optical imaging in situ, using the two-photon model, when incubated with BG3. Analyses of cell membrane integrity via lactate dehydrogenase (LDH) assay confirmed membrane damage at two photon excitation model. However, no variation in the cell was observed using the one-photon excitation model. These results indicated a high degree of dendrons uptake by cells through binding to the cell membrane following the endocytotic pathway. Furthermore, the wide excitation fluorescence spectrum of difluoroboron dye provides dual imaging with which to study the endocytosis of TPD-labeled PAMAM dendrons using a single near infrared laser. PMID- 22238230 TI - Role of enhancin in Mamestra configurata nucleopolyhedrovirus virulence: selective degradation of host peritrophic matrix proteins. AB - To infect per os, baculovirus virions cross the peritrophic matrix (PM) to reach the midgut epithelium. Insect intestinal mucins (IIMs) are PM proteins that protect the PM and aid passage of the food bolus through the gut. Some baculoviruses, including Mamestra configurata nucleopolyhedrovirus (MacoNPV-A), encode metalloproteases, known as enhancins, that facilitate infection by degrading IIMs. We examined the interaction between MacoNPV-A enhancin and M. configurata IIMs both in vivo and in vitro. Per os inoculation of M. configurata larvae with MacoNPV-A occlusion bodies (OBs) resulted in the degradation of McIIM4 within 4 h of OB ingestion, while McIIM2 was unaffected. The PM recovered by 8 h post-inoculation. To investigate whether enhancin was responsible for the degradation of IIM, a recombinant Autographa californica multiple nucleopolyhedrovirus expressing MacoNPV enhancin (AcMNPV-enMP2) was constructed. Enhancin was found to be a component of occlusion-derived virions in AcMNPV-enMP2 and MacoNPV-A. In in vitro assays, McIIM4 was degraded after MacoNPV-A and AcMNPV enMP2 treatments. Degradation of McIIM4 was inhibited by EDTA, a metalloprotease inhibitor, indicating that the degradation was due to enhancin activity. Thus, MacoNPV-A enhancin is able to degrade major structural PM proteins, but exhibits target substrate specificity. PMID- 22238231 TI - Binding of cellular p32 protein to the rubella virus P150 replicase protein via PxxPxR motifs. AB - A proline-rich region (PRR) within the rubella virus (RUBV) P150 replicase protein that contains three SH3 domain-binding motifs (PxxPxR) was investigated for its ability to bind cell proteins. Pull-down experiments using a glutathione S-transferase-PRR fusion revealed PxxPxR motif-specific binding with human p32 protein (gC1qR), which could be mediated by either of the first two motifs. This finding was of interest because p32 protein also binds to the RUBV capsid protein. Binding of p32 to P150 was confirmed and was abolished by mutation of the first two motifs. When mutations in the first two motifs were introduced into a RUBV cDNA infectious clone, virus replication was significantly impaired. However, virus RNA synthesis was found to be unaffected, and subsequent immunofluorescence analysis of RUBV-infected cells revealed co-localization of p32 and P150 but little overlap of p32 with RNA replication complexes, indicating that p32 does not participate directly in virus RNA synthesis. Thus, the role of p32 in RUBV replication remains unresolved. PMID- 22238233 TI - The recombinant origin of emerging human norovirus GII.4/2008: intra-genotypic exchange of the capsid P2 domain. AB - GII.4 noroviruses are a major cause of acute gastroenteritis in humans. A new variant of GII.4, the 2008 variant, has recently increased its prevalence on a global scale. A previous study of this variant in Japan suggested that it might be of recombinant origin, with a breakpoint at the ORF1-ORF2 junction. Here, examination of the evolutionary origin of the 2008 variant based on a larger sample of worldwide GII.4 norovirus sequences revealed a more complex pattern of recombination between the 2006a- and 2006b-like variants of genotype GII.4, involving the P2 antigenic domain. Double (termed '2008i') and triple (termed '2008ii') recombinant forms of 2008 variants were identified. This study highlights the possible importance of intra-genotypic recombination over antigenic regions in driving norovirus evolution, and is suggestive of a process analogous to the antigenic shift of influenza A virus by reassortment. PMID- 22238234 TI - Inhibition of infectious bursal disease virus infection by artificial microRNAs targeting chicken heat-shock protein 90. AB - Infectious bursal disease virus (IBDV) causes an important disease in young chickens. Chicken heat-shock protein 90 (cHsp90) has been shown to be a functional component of the cellular receptor complex for IBDV infection. This study demonstrates the inhibitory effect of vector-expressed anti-cHsp90alpha microRNA (miRNA) on IBDV infection. The reporter vectors pcHsp90alpha-EGFP and pcHsp90beta-EGFP were constructed to facilitate effective miRNA selection. Two anti-cHsp90alpha and one anti-cHsp90beta miRNA-expression vectors were constructed for a stable transfection study. Poly(A)-tailed RT-PCR detected sequence-specific miRNA transcription in transfected cells. Semiquantitative RT PCR showed inhibition of cHsp90 transcription in transfected cells. A virus titration assay showed that the anti-cHsp90alpha miRNA, but not the anti cHsp90beta miRNA, had inhibitory effects on IBDV infection. These results suggest that cHsp90alpha is a functional component of the cellular receptor complex for IBDV infection, and that anti-cHsp90alpha miRNA could be used as an anti-IBDV reagent. PMID- 22238232 TI - Cyclophilin A is required for efficient human cytomegalovirus DNA replication and reactivation. AB - Human cytomegalovirus (HCMV) is a large DNA virus belonging to the subfamily Betaherpesvirinae. Haematopoietic cells of the myeloid lineage have been shown to harbour latent HCMV. However, following terminal differentiation of these cells, virus is reactivated, and in an immunocompromised host acute infection can occur. It is currently unknown which viral and cellular factors are involved in regulating the switch between lytic and latent infections. Cyclophilin A (CyPA) is a cellular protein that acts as a major factor in virus replication and/or virion maturation for a number of different viruses, including human immunodeficiency virus, hepatitis C virus, murine cytomegalovirus, influenza A virus and vaccinia virus. This study investigated the role of CyPA during HCMV infection. CyPA expression was silenced in human foreskin fibroblast (HF) and THP 1 cells using small interfering RNA (siRNA) technology, or the cells were treated with cyclosporin A (CsA) to inhibit CyPA activity. Silencing CyPA in HF cells with siRNA resulted in an overall reduction in virus production characterized by delayed expression of immediate-early (IE) proteins, decreased viral DNA loads and reduced titres. Furthermore, silencing of CyPA in THP-1 cells pre- and post differentiation prevented IE protein expression and virus reactivation from a non productive state. Interestingly, it was observed that treatment of THP-1 cells with CsA prevented the cells from establishing a fully latent infection. In summary, these results demonstrate that CyPA expression is an important factor in HCMV IE protein expression and virus production in lytically infected HF cells, and is a major component in virus reactivation from infected THP-1 cells. PMID- 22238235 TI - Two palmitylated cysteine residues of the severe acute respiratory syndrome coronavirus spike (S) protein are critical for S incorporation into virus-like particles, but not for M-S co-localization. AB - The endodomain of several coronavirus (CoV) spike (S) proteins contains palmitylated cysteine residues and enables co-localization and interaction with the CoV membrane (M) protein. Depalmitylation of mouse hepatitis virus S proteins abolished this interaction, resulting in the failure of S incorporation into virions. In contrast, an immunofluorescence assay (IFA) showed that depalmitylated severe acute respiratory syndrome coronavirus (SCoV) S proteins still co-localized with the M protein in the budding site. Here, we determined the ability of depalmitylated SCoV S mutants to incorporate S into virus-like particles (VLPs). IFA confirmed that all SCoV S mutants co-localized with the M protein intracellularly. However, the mutants lacking two cysteine residues (C(1234/1235)) failed to incorporate S into VLPs. This indicated that these palmitylated cysteines are essential for S incorporation, but are not involved in S co-localization mediated by the M protein. Our findings suggest that M-S co localization and S incorporation occur independently of one another in SCoV virion assembly. PMID- 22238237 TI - Mutagenesis of the palmitoylation site in vaccinia virus envelope glycoprotein B5. AB - The outer envelope of vaccinia virus extracellular virions is derived from intracellular membranes that, at late times in infection, are enriched in several virus-encoded proteins. Although palmitoylation is common in vaccinia virus envelope proteins, little is known about the role of palmitoylation in the biogenesis of the enveloped virus. We have studied the palmitoylation of B5, a 42 kDa type I transmembrane glycoprotein comprising a large ectodomain and a short (17 aa) cytoplasmic tail. Mutation of two cysteine residues located in the cytoplasmic tail in close proximity to the transmembrane domain abrogated palmitoylation of the protein. Virus mutants expressing non-palmitoylated versions of B5 and/or lacking most of the cytoplasmic tail were isolated and characterized. Cell-to-cell virus transmission and extracellular virus formation were only slightly affected by those mutations. Notably, B5 versions lacking palmitate showed decreased interactions with proteins A33 and F13, but were still incorporated into the virus envelope. Expression of mutated B5 by transfection into uninfected cells showed that both the cytoplasmic tail and palmitate have a role in the intracellular transport of B5. These results indicate that the C terminal portion of protein B5, while involved in protein transport and in protein-protein interactions, is broadly dispensable for the formation and egress of infectious extracellular virus and for virus transmission. PMID- 22238236 TI - Structure of the dengue virus glycoprotein non-structural protein 1 by electron microscopy and single-particle analysis. AB - The flavivirus non-structural protein 1 (NS1) is a glycoprotein that is secreted as a soluble hexameric complex during the course of natural infection. Growing evidence indicates that this secreted form of NS1 (sNS1) plays a significant role in immune evasion and modulation during infection. Attempts to determine the crystal structure of NS1 have been unsuccessful to date and relatively little is known about the macromolecular organization of the sNS1 hexamer. Here, we have applied single-particle analysis to images of baculovirus-derived recombinant dengue 2 virus NS1 obtained by electron microscopy to determine its 3D structure to a resolution of 23 A. This structure reveals a barrel-like organization of the three dimeric units that comprise the hexamer and provides further insights into the overall organization of oligomeric sNS1. PMID- 22238238 TI - Combining coordination chemistry and catalysis to tie a knot by an active-metal template strategy. AB - Collar and tie men: the smallest trefoil knot reported to date has been prepared by an active metal template synthesis. Copper(I) ions are able to constrain the well-designed structure so that it can form the loops by complexing to the bipyridine moieties in the core of the thread and the two ends of the entangled lace on opposite faces of the loop, before acting as a catalyst to close the lace. PMID- 22238239 TI - Inaccuracy of self-reported low sodium diet. AB - OBJECTIVES: This study evaluates how often the self-report of a low sodium (Na) intake is reflected by a low 24-h urinary sodium excretion and examines the influence of incomplete urinary collections on this comparison. METHODS: In a study in which 24-h urine collections were obtained for measurement of Na and creatinine excretion, 120 participants were asked whether their Na intake was low, medium, or high. A 24-h urine collection was considered complete if creatinine excretion was >=20 mg/kg in men or >=15 mg/kg in women, and incomplete if below those amounts. The kappa statistic was computed to assess the level of agreement between 24-h Na excretion, dichotomized at 100 meq and self-report responses. RESULTS: Agreement between self-reported and actual Na excretion was poor. The kappa statistic was 0.18 for the total sample, 0.04 for complete collectors, and 0.51 for incomplete collectors, respectively. Overall, 24-h Na excretion exceeded 100 meq among 75% of those reporting an average or high Na intake, but it also exceeded 100 meq among 57% of those reporting a low sodium intake. Further, among those reporting a low sodium intake, Na excretion exceeded 100 meq in 80% of those who submitted a complete collection, but in only 29% of those who submitted an incomplete collection. CONCLUSIONS: These findings suggest that many individuals who report a low salt diet actually excrete >=100 meq/day. Na intake is also frequently underestimated because many 24-h urine collections are incomplete. PMID- 22238240 TI - Predictors of health-related quality of life in children and adolescents with juvenile idiopathic arthritis: results from a Web-based survey. AB - OBJECTIVE: Children with juvenile idiopathic arthritis (JIA) experience functional impairment due to joint manifestations of the disease. The aim of our present study was to assess health-related quality of life (HRQOL) and its predictors in a group of children and adolescents with JIA. METHODS: The study sample includes all JIA patients (ages 6-18 years) who consulted a pediatric rheumatologist in Amsterdam, The Netherlands, between February 2009 and March 2010. HRQOL was measured using the Paediatric Quality of Life Inventory 4.0 (ages 6-18 years). Functional ability was measured using the Childhood Health Assessment Questionnaire, and medical and sociodemographic parameters were assessed. The study sample was compared to a Dutch youth norm population including children with other chronic health conditions. The proportion of children with JIA with an impaired HRQOL (<1 SD) was evaluated and multivariate regression analyses were performed to predict HRQOL outcome. RESULTS: Of the eligible patients, 64.1% (n = 152) participated. Both children (ages 6-12 years) and adolescents (ages 13-18 years) with JIA reported a significantly lower HRQOL in almost all domains compared to either healthy controls or children with other chronic health conditions. Approximately half of the children with JIA showed an impaired HRQOL. The main predictors of HRQOL were functional ability, pain, subjective burden of medication use, and school absence. CONCLUSION: The HRQOL is severely affected in children and adolescents with JIA. These findings underline the necessity to systematically monitor HRQOL in daily clinical practice. PMID- 22238242 TI - Low-temperature electrospun silk scaffold for in vitro mucosal modeling. AB - Electrospinning is often used to create scaffolding as a biomimetic of the extracellular matrix of tissues. A frequent limitation of this technique for three-dimensional tissue modeling is poor cell infiltration throughout the void volume of scaffolds. Here, we generated low-temperature electrospun silk scaffolds and compared these with conventional electrospun silk scaffolds in terms of mechanical properties, void volume, cell infiltration, cell viability, and potential to support mucosal models under three-dimensional culture conditions. Low-temperature electrospun silk scaffolds supported fibroblast attachment and infiltration throughout the volume of the scaffolds, while conventional electrospun scaffolds exhibited limited cell infiltration with fibroblasts attaching exclusively to the seeding surface of the scaffolds. The porosity of low-temperature electrospun scaffolds was 93% compared with 88% of conventional electrospun silk scaffolds. Uniaxial tensile testing showed a 3.5 fold reduction in strength of low-temperature electrospun silk compared with the conventional in terms of peak stress and modulus but no significant change in strain at break. Mucosal modeling with fibroblast-keratinocyte or fibroblast carcinoma cocultures showed similar results, with cell infiltration occurring only in low-temperature electrospun scaffolds. Cell viability was confirmed using live/dead staining after 21 days in culture. Furthermore, low-temperature electrospun silk scaffolds were able to support keratinocyte differentiation, as judged by involucrin immunoreactivity. The low-temperature electrospun silk scaffold that we have developed eliminates the limitation of electrospun silk scaffolds in terms of cell infiltration and, therefore, can potentially be used for a wide range of tissue engineering purposes ranging from in vitro tissue modeling to in vivo tissue regeneration purposes. PMID- 22238243 TI - Exposure to inhibitors of the renin-angiotensin system is a major independent risk factor for acute renal failure induced by sucrose containing intravenous immunoglobulins. A case-control study. PMID- 22238245 TI - 4,4'-Azobis(halopyridinium) derivatives: strong multidentate halogen-bond donors with a redox-active core. PMID- 22238244 TI - Primary Sjogren's syndrome as a systemic disease: a study of participants enrolled in an international Sjogren's syndrome registry. AB - OBJECTIVE: To study the prevalence of extraglandular manifestations in primary Sjogren's syndrome (SS) among participants enrolled in the Sjogren's International Collaborative Clinical Alliance (SICCA) Registry. METHODS: A total of 1,927 participants in the SICCA registry were studied, including 886 participants who met the 2002 American-European Consensus Group (AECG) criteria for primary SS, 830 "intermediate" cases who had some objective findings of primary SS but did not meet AECG criteria, and 211 control individuals. We studied the prevalence of immunologic and hematologic laboratory abnormalities, specific rheumatologic examination findings, and physician-confirmed thyroid, liver, and kidney disease, as well as lymphoma among SICCA participants. RESULTS: Laboratory abnormalities, including hematologic abnormalities, hypergammaglobulinemia, and hypocomplementemia, frequently occurred among primary SS cases and were more common among the intermediate cases than among control participants. Cutaneous vasculitis and lymphadenopathy were also more common among primary SS cases. In contrast, the frequency of physician-confirmed diagnoses of thyroid, liver, and kidney disease and lymphoma was low and only primary biliary cirrhosis was associated with primary SS case status. Rheumatologic and neurologic symptoms were common among all SICCA participants, regardless of case status. CONCLUSION: Data from the international SICCA registry support the systemic nature of primary SS, manifested primarily in terms of specific immunologic and hematologic abnormalities. The occurrence of other systemic disorders among this cohort is relatively uncommon. Previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of certain neurologic, rheumatologic, or other systemic manifestations. PMID- 22238246 TI - Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. AB - PURPOSE: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment. EXPERIMENTAL DESIGN: Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability. RESULTS: Forty-six patients were treated. Best responses to treatment with brivanib (N = 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension. CONCLUSION: Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib. PMID- 22238247 TI - Duration of red blood cell storage and outcomes following orthotopic liver transplantation. AB - Liver transplantation may be complicated by massive intraoperative bleeding, and red blood cell (RBC) transfusions may be required. The storage duration or age of transfused RBCs has been shown to affect the morbidity and mortality of critically ill, trauma, and cardiac surgery patients. Here we investigate the effect of RBC age on the outcomes of liver transplant patients. Five hundred thirty-one patients underwent orthotopic liver transplantation between January 1, 2000 and August 15, 2010. The patient demographics, the Model for End-Stage Liver Disease-sodium (MELD-Na) score, and the number and age of RBC units were evaluated with univariate and multivariate models of outcomes, which included mortality rates 2 years after transplantation, postoperative infections, and organ rejection. In a univariate analysis, the number of RBC units (but not the RBC age) was associated with increased 2-year mortality, an increased risk of infection, and a decreased risk of organ rejection. Only the number of RBC units was associated with increased 2-year mortality in a multivariate Cox regression model. The mortality risk was decreased by two-thirds for patients who received <10 U of RBCs versus those who received >=10 U (hazard ratio = 0.33, 95% confidence interval = 0.16-0.69, P = 0.003). The number of transfused RBC units was not associated with the risk of infection or organ rejection in a multivariate logistic regression model. In conclusion, the RBC age is not associated with infection, organ rejection, or death in liver transplant patients. Patients who receive more blood have an increased risk of death. In a multivariate model, the MELD-Na score was not associated with increased mortality, and this is consistent with previous studies demonstrating that the MELD-Na score is a poor predictor of long-term survival after transplantation. PMID- 22238248 TI - Adhesion, activation, and aggregation of blood platelets and biofilm formation on the surfaces of titanium alloys Ti6Al4V and Ti6Al7Nb. AB - Titanium alloys are still on the top list of fundamental materials intended for dental, orthopedics, neurological, and cardiovascular implantations. Recently, a special attention has been paid to vanadium-free titanium alloy, Ti6Al7Nb, that seems to represent higher biocompatibility than traditional Ti6Al4V alloy. Surprisingly, these data are not thoroughly elaborated in the literature; particularly there is a lack of comparative experiments conducted simultaneously and at the same conditions. Our study fills these shortcomings in the field of blood contact and microbiological colonization. To observe platelets adhesion and biofilm formation on the surfaces of compared titanium alloys, fluorescence microscope Olympus GX71 and scanning electron microscope HITACHI S-3000N were used. Additionally, flow cytometry analysis of platelets aggregation and activation in the whole blood after contact with sample surface, as an essential tool for biomaterial thrombocompatibility assessment, was proposed. As a result of our study it was demonstrated that polished surfaces of Ti6Al7Nb and Ti6Al4V alloys after contact with whole citrated blood and E. coli bacterial cells exhibit a considerable difference. Overall, it was established that Ti6Al4V has distinct tendency to higher thrombogenicity, more excessive bacterial biofilm formation and notable cytotoxic properties in comparison to Ti6Al7Nb. However, we suggest these studies should be extended for other types of cells and biological objects. PMID- 22238249 TI - Quantum Hall effects in graphene-based two-dimensional electron systems. AB - In this article we review the quantum Hall physics of graphene-based two dimensional electron systems, with a special focus on recent experimental and theoretical developments. We explain why graphene and bilayer graphene can be viewed respectively as J D 1 and 2 chiral two-dimensional electron gases (C2DEGs), and why this property frames their quantum Hall physics. The current status of experimental and theoretical work on the role of electron-electron interactions is reviewed at length with an emphasis on unresolved issues in the field, including the role of disorder in current experiments. Special attention is given to the interesting low magnetic field limit, and to the relationship between quantum Hall effects and the spontaneous anomalous Hall effects that might occur in bilayer graphene systems in the absence of a magnetic field. PMID- 22238250 TI - Potential impact on patient residence to hospital travel distance and access to care under a policy of preferential referral to high-volume knee replacement hospitals. AB - OBJECTIVE: To examine the potential impact of a policy of selective referral to high-volume knee replacement hospitals on patients' travel distance to hospitals and access to care for patients seeking total knee replacement (TKR) in urban and rural settings. METHODS: The travel distance required for patients to reach their hospital of service and the additional travel distance required to reach the nearest high-volume hospital were analyzed using a 100% sample of Medicare fee for-service patients undergoing TKR in 2001. RESULTS: Of the 183,174 TKRs performed in the US during 2001, 95% of the patients selected underwent TKR at a hospital that was located within 50 miles of their residence. There were 11,550 patients who had their TKR performed at a low-volume hospital (LVH) where there was no nearer high-volume hospital. The impact of a policy that would direct patients to high-volume hospitals varied by region. In urban areas, the nearest high-volume hospital was a median of 3.8 miles further than the LVH of service. The patient factors race and poverty were associated with selection of LVHs in urban areas. In rural areas and urban clusters, 1,506 patients would have had to travel >50 miles and 259 patients would have had to travel >100 miles to reach a high-volume hospital. CONCLUSION: A policy to direct patients away from LVHs could increase patients' travel time to hospitals in rural areas and restrict access for minority and low-income patients in urban areas. Any implementation of selective referral to high-volume centers should address access to hospitals for rural patients and urban minority and low-income patients. PMID- 22238251 TI - Implications of changing the minimal survival benefit in liver transplantation. AB - The limited availability of livers donated by deceased donors for transplantation means that not everyone who might benefit from the procedure can receive a graft, so any selection and allocation system must have clearly defined goals. The United Kingdom, in common with many other countries, has adopted a minimum benefit criterion of a greater than 50% probability of survival 5 years after transplantation. We investigated the impact of changing this minimum benefit criterion on a case mix of listed patients. The analysis was based on 5330 adult elective patients who underwent transplantation with livers from donation after brain death donors between January 1994 and December 2007. We examined the impact of balancing the number of registrations on the list with the number of available donor livers while allowing a 10% mortality rate and found that this would require a survival threshold of at least 74% at 5 years. According to historical data, the application of this more stringent criterion would significantly reduce the eligibility of older and nonwhite patients and patients with hepatocellular carcinoma or hepatitis C virus infections. Thus, if such undesirable restrictions on access to liver transplantation are to be avoided, we must consider alternative strategies such as the acceptance of higher transplant list mortality. PMID- 22238252 TI - Depolymerization of insulin amyloid fibrils by albumin-modified magnetic fluid. AB - Pathogenesis of amyloid-related diseases is associated with the presence of protein amyloid deposits. Insulin amyloids have been reported in a patient with diabetes undergoing treatment by injection of insulin and causes problems in the production and storage of this drug and in pplication of insulin pumps. We have studied the interference of insulin amyloid fibrils with a series of 18 albumin magnetic fluids (MFBSAs) consisting of magnetite nanoparticles modified by different amounts of bovine serum albumin (w/w BSA/Fe3O4 from 0.005 up to 15). We have found that MFBSAs are able to destroy amyloid fibrils in vitro. The extent of fibril depolymerization was affected by nanoparticle physical-chemical properties (hydrodynamic diameter, zeta potential and isoelectric point) determined by the BSA amount present in MFBSAs. The most effective were MFBSAs with lower BSA/Fe3O4 ratios (from 0.005 to 0.1) characteristic of about 90% depolymerizing activity. For the most active magnetic fluids (ratios 0.01 and 0.02) the DC50 values were determined in the range of low concentrations, indicating their ability to interfere with insulin fibrils at stoichiometric concentrations. We assume that the present findings represent a starting point for the application of the active MFBSAs as therapeutic agents targeting insulin amyloidosis. PMID- 22238254 TI - 25-hydroxyvitamin D: a difficult analyte. PMID- 22238255 TI - Advancing laboratory medicine through innovation: a tale of six inventors. PMID- 22238256 TI - Cytotoxicity of cadmium-containing quantum dots based on a study using a microfluidic chip. AB - There is a lack of reliable nanotoxicity assays available for monitoring and quantifying multiple cellular events in cultured cells. In this study, we used a microfluidic chip to systematically investigate the cytotoxicity of three kinds of well-characterized cadmium-containing quantum dots (QDs) with the same core but different shell structures, including CdTe core QDs, CdTe/CdS core-shell QDs, and CdTe/CdS/ZnS core-shell-shell QDs, in HEK293 cells. Using the microfluidic chip combined with fluorescence microscopy, multiple QD-induced cellular events including cell morphology, viability, proliferation, and QD uptake were simultaneously analysed. The three kinds of QDs showed significantly different cytotoxicities. The CdTe QDs, which are highly toxic to HEK293 cells, resulted in remarkable cellular and nuclear morphological changes, a dose-dependent decrease in cell viability, and strong inhibition of cell proliferation; the CdTe/CdS QDs were moderately toxic but did not significantly affect the proliferation of HEK293 cells; while the CdTe/CdS/ZnS QDs had no detectable influence on cytotoxicity with respect to cell morphology, viability, and proliferation. Our data indicated that QD cytotoxicity was closely related to their surface structures and specific physicochemical properties. This study also demonstrated that the microfluidic chip could serve as a powerful tool to systematically evaluate the cytotoxicity of nanoparticles in multiple cellular events. PMID- 22238253 TI - Inactive disease and remission in childhood-onset systemic lupus erythematosus. AB - OBJECTIVE: To define inactive disease (ID) and clinical remission (CR) and to delineate variables that can be used to measure ID/CR in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Delphi questionnaires were sent to an international group of pediatric rheumatologists. Respondents provided information about variables to be used in future algorithms to measure ID/CR. The usefulness of these variables was assessed in 35 children with ID and 31 children with minimally active lupus (MAL). RESULTS: While ID reflects cSLE status at a specific point in time, CR requires the presence of ID for >6 months and considers treatment. There was consensus that patients in ID/CR can have <2 mild nonlimiting symptoms (i.e., fatigue, arthralgia, headaches, or myalgia) but not Raynaud's phenomenon, chest pain, or objective physical signs of cSLE; antinuclear antibody positivity and erythrocyte sedimentation rate elevation can be present. Complete blood count, renal function testing, and complement C3 all must be within the normal range. Based on consensus, only damage-related laboratory or clinical findings of cSLE are permissible with ID. The above parameters were suitable to differentiate children with ID/CR from those with MAL (area under the receiver operating characteristic curve >0.85). Disease activity scores with or without the physician global assessment of disease activity and patient symptoms were well suited to differentiate children with ID from those with MAL. CONCLUSION: Consensus has been reached on common definitions of ID/CR with cSLE and relevant patient characteristics with ID/CR. Further studies must assess the usefulness of the data-driven candidate criteria for ID in cSLE. PMID- 22238257 TI - CHROMATRA: a Galaxy tool for visualizing genome-wide chromatin signatures. AB - CHROMATRA (CHROmatin Mapping Across TRAnscripts) is a visualization tool available as plug-in for the Galaxy platform. It allows detailed yet concise presentations of data derived from ChIP-chip or ChIP-seq experiments by visualizing enrichment scores across genes or other genomic features while accounting for their length and additional characteristics such as gene expression. It integrates into typical analysis workflows and enables rapid graphical assessment and comparison of genome-wide data at a glance. AVAILABILITY: https://github.com/cmmt/chromatra. PMID- 22238258 TI - IMID: integrated molecular interaction database. AB - MOTIVATION: Molecular interaction information, such as protein-protein interactions and protein-small molecule interactions, is indispensable for understanding the mechanism of biological processes and discovering treatments for diseases. Many databases have been built by manual annotation of literature to organize such information into structured form. However, most databases focus on only one type of interactions, which are often not well annotated and integrated with related functional information. RESULTS: In this study, we integrate molecular interaction information from literature by automatic information extraction and from manually annotated databases. We further integrate the relationships between protein/gene and other bio-entity terms including gene ontology terms, pathways, species and diseases to build an integrated molecular interaction database (IMID). Interactions can be selected by their associated probabilities. IMID allows complex and versatile queries for context-specific molecular interactions, which are not available currently in other molecular interaction databases. AVAILABILITY: The database is located at www.integrativebiology.org. PMID- 22238259 TI - RIBER/DIBER: a software suite for crystal content analysis in the studies of protein-nucleic acid complexes. AB - Co-crystallization experiments of proteins with nucleic acids do not guarantee that both components are present in the crystal. We have previously developed DIBER to predict crystal content when protein and DNA are present in the crystallization mix. Here, we present RIBER, which should be used when protein and RNA are in the crystallization drop. The combined RIBER/DIBER suite builds on machine learning techniques to make reliable, quantitative predictions of crystal content for non-expert users and high-throughput crystallography. PMID- 22238260 TI - PHACTS, a computational approach to classifying the lifestyle of phages. AB - MOTIVATION: Bacteriophages have two distinct lifestyles: virulent and temperate. The virulent lifestyle has many implications for phage therapy, genomics and microbiology. Determining which lifestyle a newly sequenced phage falls into is currently determined using standard culturing techniques. Such laboratory work is not only costly and time consuming, but also cannot be used on phage genomes constructed from environmental sequencing. Therefore, a computational method that utilizes the sequence data of phage genomes is needed. RESULTS: Phage Classification Tool Set (PHACTS) utilizes a novel similarity algorithm and a supervised Random Forest classifier to make a prediction whether the lifestyle of a phage, described by its proteome, is virulent or temperate. The similarity algorithm creates a training set from phages with known lifestyles and along with the lifestyle annotation, trains a Random Forest to classify the lifestyle of a phage. PHACTS predictions are shown to have a 99% precision rate. AVAILABILITY AND IMPLEMENTATION: PHACTS was implemented in the PERL programming language and utilizes the FASTA program (Pearson and Lipman, 1988) and the R programming language library 'Random Forest' (Liaw and Weiner, 2010). The PHACTS software is open source and is available as downloadable stand-alone version or can be accessed online as a user-friendly web interface. The source code, help files and online version are available at http://www.phantome.org/PHACTS/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238261 TI - SSuMMo: rapid analysis, comparison and visualization of microbial communities. AB - MOTIVATION: Next-generation sequencing methods are generating increasingly massive datasets, yet still do not fully capture genetic diversity in the richest environments. To understand such complicated and elusive systems, effective tools are needed to assist with delineating the differences found in and between community datasets. RESULTS: The Small Subunit Markov Modeler (SSuMMo) was developed to probabilistically assign SSU rRNA gene fragments from any sequence dataset to recognized taxonomic clades, producing consistent, comparable cladograms. Accuracy tests predicted >90% of genera correctly for sequences downloaded from public reference databases. Sequences from a next-generation sequence dataset, sampled from lean, overweight and obese individuals, were analysed to demonstrate parallel visualization of comparable datasets. SSuMMo shows potential as a valuable curatorial tool, as numerous incorrect and outdated taxonomic entries and annotations were identified in public databases. AVAILABILITY AND IMPLEMENTATION: SSuMMo is GPLv3 open source Python software, available at http://code.google.com/p/ssummo/. Taxonomy and HMM databases can be downloaded from http://bioltfws1.york.ac.uk/ssummo/. SUPPLEMENTARY INFORMATION: Supplemental materials are available at Bioinformatics Online. PMID- 22238262 TI - The evolution of nitrogen fixation in cyanobacteria. AB - MOTIVATION: Fixed nitrogen is an essential requirement for the biosynthesis of cellular nitrogenous compounds. Some cyanobacteria can fix nitrogen, contributing significantly to the nitrogen cycle, agriculture and biogeochemical history of Earth. The rate and position on the species phylogeny of gains and losses of this ability, as well as of the underlying nif genes, are controversial. RESULTS: We use probabilistic models of trait evolution to investigate the presence and absence of cyanobacterial nitrogen-fixing ability. We estimate rates of change on the species phylogeny, pinpoint probable changes and reconstruct the state and nif gene complement of the ancestor. Our results are consistent with a nitrogen fixing cyanobacterial ancestor, repeated loss of nitrogen fixation and vertical descent, with little horizontal transfer of the genes involved. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238263 TI - MetExtract: a new software tool for the automated comprehensive extraction of metabolite-derived LC/MS signals in metabolomics research. AB - MOTIVATION: Liquid chromatography-mass spectrometry (LC/MS) is a key technique in metabolomics. Since the efficient assignment of MS signals to true biological metabolites becomes feasible in combination with in vivo stable isotopic labelling, our aim was to provide a new software tool for this purpose. RESULTS: An algorithm and a program (MetExtract) have been developed to search for metabolites in in vivo labelled biological samples. The algorithm makes use of the chromatographic characteristics of the LC/MS data and detects MS peaks fulfilling the criteria of stable isotopic labelling. As a result of all calculations, the algorithm specifies a list of m/z values, the corresponding number of atoms of the labelling element (e.g. carbon) together with retention time and extracted adduct-, fragment- and polymer ions. Its function was evaluated using native (12)C- and uniformly (13)C-labelled standard substances. AVAILABILITY: MetExtract is available free of charge and warranty at http://code.google.com/p/metextract/. Precompiled executables are available for Windows operating systems. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238264 TI - Interactome-transcriptome integration for predicting distant metastasis in breast cancer. AB - MOTIVATION: High-throughput gene expression profiling yields genomic signatures that allow the prediction of clinical conditions including patient outcome. However, these signatures have limitations, such as dependency on the training set, and worse, lack of generalization. RESULTS: We propose a novel algorithm called ITI (interactome-transcriptome integration), to extract a genomic signature predicting distant metastasis in breast cancer by superimposition of large-scale protein-protein interaction data over a compendium of several gene expression datasets. Training on two different compendia showed that the estrogen receptor-specific signatures obtained are more stable (11-35% stability), can be generalized on independent data and performs better than previously published methods (53-74% accuracy). AVAILABILITY: The ITI algorithm source code from analysis are available under CeCILL from the ITI companion website: http://bioinformatique.marseille.inserm.fr/iti. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238265 TI - Estimating abundances of retroviral insertion sites from DNA fragment length data. AB - MOTIVATION: The relative abundance of retroviral insertions in a host genome is important in understanding the persistence and pathogenesis of both natural retroviral infections and retroviral gene therapy vectors. It could be estimated from a sample of cells if only the host genomic sites of retroviral insertions could be directly counted. When host genomic DNA is randomly broken via sonication and then amplified, amplicons of varying lengths are produced. The number of unique lengths of amplicons of an insertion site tends to increase according to its abundance, providing a basis for estimating relative abundance. However, as abundance increases amplicons of the same length arise by chance leading to a non-linear relation between the number of unique lengths and relative abundance. The difficulty in calibrating this relation is compounded by sample-specific variations in the relative frequencies of clones of each length. RESULTS: A likelihood function is proposed for the discrete lengths observed in each of a collection of insertion sites and is maximized with a hybrid expectation-maximization algorithm. Patient data illustrate the method and simulations show that relative abundance can be estimated with little bias, but that variation in highly abundant sites can be large. In replicated patient samples, variation exceeds what the model implies-requiring adjustment as in Efron (2004) or using jackknife standard errors. Consequently, it is advantageous to collect replicate samples to strengthen inferences about relative abundance. PMID- 22238266 TI - Detecting genomic indel variants with exact breakpoints in single- and paired-end sequencing data using SplazerS. AB - MOTIVATION: The reliable detection of genomic variation in resequencing data is still a major challenge, especially for variants larger than a few base pairs. Sequencing reads crossing boundaries of structural variation carry the potential for their identification, but are difficult to map. RESULTS: Here we present a method for 'split' read mapping, where prefix and suffix match of a read may be interrupted by a longer gap in the read-to-reference alignment. We use this method to accurately detect medium-sized insertions and long deletions with precise breakpoints in genomic resequencing data. Compared with alternative split mapping methods, SplazerS significantly improves sensitivity for detecting large indel events, especially in variant-rich regions. Our method is robust in the presence of sequencing errors as well as alignment errors due to genomic mutations/divergence, and can be used on reads of variable lengths. Our analysis shows that SplazerS is a versatile tool applicable to unanchored or single-end as well as anchored paired-end reads. In addition, application of SplazerS to targeted resequencing data led to the interesting discovery of a complete, possibly functional gene retrocopy variant. AVAILABILITY: SplazerS is available from http://www.seqan.de/projects/ splazers. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238267 TI - De novo motif discovery facilitates identification of interactions between transcription factors in Saccharomyces cerevisiae. AB - MOTIVATION: Gene regulation involves complicated mechanisms such as cooperativity between a set of transcription factors (TFs). Previous studies have used target genes shared by two TFs as a clue to infer TF-TF interactions. However, this task remains challenging because the target genes with low binding affinity are frequently omitted by experimental data, especially when a single strict threshold is employed. This article aims at improving the accuracy of inferring TF-TF interactions by incorporating motif discovery as a fundamental step when detecting overlapping targets of TFs based on ChIP-chip data. RESULTS: The proposed method, simTFBS, outperforms three naive methods that adopt fixed thresholds when inferring TF-TF interactions based on ChIP-chip data. In addition, simTFBS is compared with two advanced methods and demonstrates its advantages in predicting TF-TF interactions. By comparing simTFBS with predictions based on the set of available annotated yeast TF binding motifs, we demonstrate that the good performance of simTFBS is indeed coming from the additional motifs found by the proposed procedures. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238269 TI - GROMACS molecule & liquid database. AB - MOTIVATION: The molecular dynamics simulation package GROMACS is a widely used tool used in a broad range of different applications within physics, chemistry and biology. It is freely available, user friendly and extremely efficient. The GROMACS software is force field agnostic, and compatible with many molecular dynamics force fields; coarse-grained, unified atom, all atom as well as polarizable models based on the charge on a spring concept. To validate simulations, it is necessary to compare results from the simulations to experimental data. To ease the process of setting up topologies and structures for simulations, as well as providing pre-calculated physical properties along with experimental values for the same we provide a web-based database, containing 145 organic molecules at present. RESULTS: Liquid properties of 145 organic molecules have been simulated using two different force fields, OPLS all atom and Generalized Amber Force Field. So far, eight properties have been calculated (the density, enthalpy of vaporization, surface tension, heat capacity at constant volume and pressure, isothermal compressibility, volumetric expansion coefficient and the static dielectric constant). The results, together with experimental values are available through the database, along with liquid structures and topologies for the 145 molecules, in the two force fields. AVAILABILITY: The database is freely available under http://virtualchemistry.org. PMID- 22238268 TI - Predicting folding free energy changes upon single point mutations. AB - MOTIVATION: The folding free energy is an important characteristic of proteins stability and is directly related to protein's wild-type function. The changes of protein's stability due to naturally occurring mutations, missense mutations, are typically causing diseases. Single point mutations made in vitro are frequently used to assess the contribution of given amino acid to the stability of the protein. In both cases, it is desirable to predict the change of the folding free energy upon single point mutations in order to either provide insights of the molecular mechanism of the change or to design new experimental studies. RESULTS: We report an approach that predicts the free energy change upon single point mutation by utilizing the 3D structure of the wild-type protein. It is based on variation of the molecular mechanics Generalized Born (MMGB) method, scaled with optimized parameters (sMMGB) and utilizing specific model of unfolded state. The corresponding mutations are built in silico and the predictions are tested against large dataset of 1109 mutations with experimentally measured changes of the folding free energy. Benchmarking resulted in root mean square deviation = 1.78 kcal/mol and slope of the linear regression fit between the experimental data and the calculations was 1.04. The sMMGB is compared with other leading methods of predicting folding free energy changes upon single mutations and results discussed with respect to various parameters. AVAILABILITY: All the pdb files we used in this article can be downloaded from http://compbio.clemson.edu/downloadDir/mentaldisorders/sMMGB_pdb.rar. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238271 TI - Surrogate variable analysis using partial least squares (SVA-PLS) in gene expression studies. AB - MOTIVATION: In a typical gene expression profiling study, our prime objective is to identify the genes that are differentially expressed between the samples from two different tissue types. Commonly, standard analysis of variance (ANOVA)/regression is implemented to identify the relative effects of these genes over the two types of samples from their respective arrays of expression levels. But, this technique becomes fundamentally flawed when there are unaccounted sources of variability in these arrays (latent variables attributable to different biological, environmental or other factors relevant in the context). These factors distort the true picture of differential gene expression between the two tissue types and introduce spurious signals of expression heterogeneity. As a result, many genes which are actually differentially expressed are not detected, whereas many others are falsely identified as positives. Moreover, these distortions can be different for different genes. Thus, it is also not possible to get rid of these variations by simple array normalizations. This both way error can lead to a serious loss in sensitivity and specificity, thereby causing a severe inefficiency in the underlying multiple testing problem. In this work, we attempt to identify the hidden effects of the underlying latent factors in a gene expression profiling study by partial least squares (PLS) and apply ANCOVA technique with the PLS-identified signatures of these hidden effects as covariates, in order to identify the genes that are truly differentially expressed between the two concerned tissue types. RESULTS: We compare the performance of our method SVA-PLS with standard ANOVA and a relatively recent technique of surrogate variable analysis (SVA), on a wide variety of simulation settings (incorporating different effects of the hidden variable, under situations with varying signal intensities and gene groupings). In all settings, our method yields the highest sensitivity while maintaining relatively reasonable values for the specificity, false discovery rate and false non-discovery rate. Application of our method to gene expression profiling for acute megakaryoblastic leukemia shows that our method detects an additional six genes, that are missed by both the standard ANOVA method as well as SVA, but may be relevant to this disease, as can be seen from mining the existing literature. PMID- 22238270 TI - BESC knowledgebase public portal. AB - The BioEnergy Science Center (BESC) is undertaking large experimental campaigns to understand the biosynthesis and biodegradation of biomass and to develop biofuel solutions. BESC is generating large volumes of diverse data, including genome sequences, omics data and assay results. The purpose of the BESC Knowledgebase is to serve as a centralized repository for experimentally generated data and to provide an integrated, interactive and user-friendly analysis framework. The Portal makes available tools for visualization, integration and analysis of data either produced by BESC or obtained from external resources. AVAILABILITY: http://besckb.ornl.gov. PMID- 22238272 TI - A scalable and portable framework for massively parallel variable selection in genetic association studies. AB - The deluge of data emerging from high-throughput sequencing technologies poses large analytical challenges when testing for association to disease. We introduce a scalable framework for variable selection, implemented in C++ and OpenCL, that fits regularized regression across multiple Graphics Processing Units. Open source code and documentation can be found at a Google Code repository under the URL http://bioinformatics.oxfordjournals.org/content/early/2012/01/10/bioinformatics. ts015.abstract. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22238273 TI - Theoretical study on the possible use of SiC microparticles as photothermal agents for the heating of bacteria. AB - Gold nanoparticles exhibiting surface plasmon resonances have been considered as photothermal agents for the selective destruction of bacteria by visible to near infrared radiation. Here, we consider theoretically the possible complementary use of sub-micron silicon carbide (SiC) particles as photothermal agents for the heating of bacteria by pulsed mid-infrared (MIR) radiation. A SiC microparticle can exhibit surface phonon resonances in the MIR. Similar to the effect of surface plasmon resonances in gold nanoparticles, this could lead to enhanced absorption at the resonant wavelength and strong heating of the microparticle locally. If the heating is sufficient, this might lead to damage of bacterial cells adjacent to SiC particles. We estimate the heating of sub-micron SiC particles in a water medium under various pulse lengths of radiation at wavelength 10.6 MUm. Noting that SiC is being investigated as a biocompatible material that could be functionalized for biomedical applications, and that an appropriately roughened SiC surface could be expected to exhibit similar surface phonon resonances, we speculate that enhanced heating under MIR radiation may be useful for in vitro sterilization of such surfaces. PMID- 22238274 TI - Intra-particle coupling and plasmon tuning of multilayer Au/dielectric/Au nanocrescents adhered to a dielectric cylinder. AB - A 3D numerical study on surface plasmon resonance is presented for a multilayer Au/dielectric/Au nanocrescent structure adhered to a dielectric cylinder. Investigations are carried out on the structure's coupling modes, local field enhancement (LFE) and plasmon tuning capability. The cavity coupling via the cylinder is found to be dominant in tuning the plasmon wavelength. This provides the possibility of tailoring the device's plasmon band by adjusting the cylinder's size and material. By using a cylinder with higher permittivity, the plasmon peak significantly shifts to the near- or mid-infrared regime without increasing the size of the crescents, thus increase of radiation loss can be fully avoided. Extra crescent layers can also be added to the structure to induce intra-particle couplings among Au crescents and enlarge the areas of the hot spots, without shifting the plasmon band. The LFE of the multiple-layer structure is shown to be dramatically increased through the intra-particle coupling among the Au crescents, compared with a single layer Au nanocrescent structure. Further increase of LFE can be achieved by substituting semiconductors for the dielectrics in the structure due to the charge transport at metal-semiconductor interfaces. PMID- 22238275 TI - Tumor detection strategy using ZnO light-emitting nanoprobes. AB - Traditional methods of detecting cancer cells, such as fluorescence, have their limits and can hardly be used for identification during tumor resection. Here we report an alternative tumor detection technology using ZnO nanorods bonded to antibodies as cancer cell probes. Our experiment shows that antibodies toward epidermal growth factor receptor (EGFR) can be connected to ZnO nanorods and to EGFR receptors of SCC (squamous cell carcinoma). The cancer cell can be recognized by the naked eye or an optical microscope with the help of purple light emission from ZnO/EGFR antibody probes. On the other hand, for cells with less EGFR expression, in our case Hs68, no purple light was observed as the probes were washed off. From the photoluminescent spectra, the peak intensity ratio between the purple light (from ZnO at the wavelength 377 nm) and the green band (from the autofluorescence of cells) is much higher with the presence in SCC, as compared with Hs68. The ZnO/EGFR antibody probes have the potential to be applied to surgery for real-time tumor cell identification. The cancer cells will be excised with the help of purple light emission. PMID- 22238276 TI - Diabetes, its treatment, and catastrophic medical spending in 35 developing countries. AB - OBJECTIVE: To assess the individual financial impact of having diabetes in developing countries, whether diabetic individuals possess appropriate medications, and the extent to which health insurance may protect diabetic individuals by increasing medication possession or decreasing the risk of catastrophic spending. RESEARCH DESIGN AND METHODS: Using 2002-2003 World Health Survey data (n = 121,051 individuals; 35 low- and middle-income countries), we examined possession of medications to treat diabetes and estimated the relationship between out-of-pocket medical spending (2005 international dollars), catastrophic medical spending, and diabetes. We assessed whether health insurance modified these relationships. RESULTS: Diabetic individuals experience differentially higher out-of-pocket medical spending, particularly among individuals with high levels of spending (excess spending of $157 per year [95% CI 130-184] at the 95th percentile), and a greater chance of incurring catastrophic medical spending (17.8 vs. 13.9%; difference 3.9% [95% CI 0.2-7.7]) compared with otherwise similar individuals without diabetes. Diabetic individuals with insurance do not have significantly lower risks of catastrophic medical spending (18.6 vs. 17.7%; difference not significant), nor were they significantly more likely to possess diabetes medications (22.8 vs. 20.6%; difference not significant) than those who were otherwise similar but without insurance. These effects were more pronounced and significant in lower-income countries. CONCLUSIONS: In low-income countries, despite insurance, diabetic individuals are more likely to experience catastrophic medical spending and often do not possess appropriate medications to treat diabetes. Research into why policies in these countries may not adequately protect people from catastrophic spending or enhance possession of critical medications is urgently needed. PMID- 22238277 TI - Mortality experience of a low-income population with young-onset diabetes. AB - OBJECTIVE: In young-onset diabetes, insulin therapy status is a rough marker of diabetes type. We describe the mortality experience of a low-income, predominantly minority population with diabetes diagnosed before age 30 years, stratified by insulin therapy. RESEARCH DESIGN AND METHODS: A total of 1,098 adults aged 40-79 years (median 49) diagnosed with diabetes before age 30 years and 49,914 without diabetes were recruited from community health centers. Individuals with diabetes were categorized by insulin therapy at baseline: group A, insulin therapy only; group B, insulin therapy and an oral hypoglycemic agent; and group C, no insulin therapy. Cox models were used to compute hazard ratios (HRs) and 95% CI for cause-specific mortality based on both underlying and contributing causes of death from death certificates. RESULTS: During follow-up (mean 3.9 years), 15.0, 12.5, and 7.3% of groups A, B, and C, respectively, and 4.6% without diabetes died. Compared with individuals without diabetes, HRs (CI) for all-cause mortality were 4.3 (3.4-5.6), 4.2 (2.8-6.3), and 2.0 (1.4-2.8) in groups A, B, and C, respectively. The leading cause of death was renal failure (end-stage renal disease [ESRD]) in group A, ESRD and coronary artery disease (CAD) in group B, and CAD in group C and individuals without diabetes. HRs for these conditions were at least twice as high as the HRs for all-cause mortality, reaching 17.3 (10.2-29.3), 17.9 (8.3-38.7), and 5.1 (2.3-11.7) in groups A, B, and C, respectively, for ESRD. CONCLUSIONS: Excess mortality persists among people with young-onset diabetes of long duration, with ESRD and CAD as the leading contributors to mortality. PMID- 22238278 TI - Imager evaluation of diabetic retinopathy at the time of imaging in a telemedicine program. AB - OBJECTIVE: To evaluate the ability of certified retinal imagers to identify presence versus absence of sight-threatening diabetic retinopathy (stDR) (moderate nonproliferative diabetic retinopathy or worse or diabetic macular edema) at the time of retinal imaging in a telemedicine program. RESEARCH DESIGN AND METHODS: Diabetic patients in a primary care setting or specialty diabetes clinic received Joslin Vision Network protocol retinal imaging as part of their care. Trained nonphysician imagers graded the presence versus absence of stDR at the time of imaging. These gradings were compared with masked gradings of certified readers. RESULTS: Of 158 patients (316 eyes) imaged, all cases of stDR (42 eyes [13%]) were identified by the imagers at the time of imaging. Six eyes with mild nonproliferative diabetic retinopathy were graded by the imagers to have stDR (sensitivity 1.00, 95% CI 0.90-1.00; specificity 0.97, 0.94-0.99). CONCLUSIONS: Appropriately trained imagers can accurately identify stDR at the time of imaging. PMID- 22238279 TI - Novel urinary protein biomarkers predicting the development of microalbuminuria and renal function decline in type 1 diabetes. AB - OBJECTIVE: To define a panel of novel protein biomarkers of renal disease. RESEARCH DESIGN AND METHODS: Adults with type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes study who were initially free of renal complications (n = 465) were followed for development of micro- or macroalbuminuria (MA) and early renal function decline (ERFD, annual decline in estimated glomerular filtration rate of >=3.3%). The label-free proteomic discovery phase was conducted in 13 patients who progressed to MA by the 6-year visit and 11 control subjects, and four proteins (Tamm-Horsfall glycoprotein, alpha-1 acid glycoprotein, clusterin, and progranulin) identified in the discovery phase were measured by enzyme-linked immunosorbent assay in 74 subjects: group A, normal renal function (n = 35); group B, ERFD without MA (n = 15); group C, MA without ERFD (n = 16); and group D, both ERFD and MA (n = 8). RESULTS: In the label-free analysis, a model of progression to MA was built using 252 peptides, yielding an area under the curve (AUC) of 84.7 +/- 5.3%. In the validation study, ordinal logistic regression was used to predict development of ERFD, MA, or both. A panel including Tamm-Horsfall glycoprotein (odds ratio 2.9, 95% CI 1.3-6.2, P = 0.008), progranulin (1.9, 0.8-4.5, P = 0.16), clusterin (0.6, 0.3-1.1, P = 0.09), and alpha-1 acid glycoprotein (1.6, 0.7-3.7, P = 0.27) improved the AUC from 0.841 to 0.889. CONCLUSIONS: A panel of four novel protein biomarkers predicted early renal damage in type 1 diabetes. These findings require further validation in other populations for prediction of renal complications and treatment monitoring. PMID- 22238281 TI - Transient invasive migration in mouse cumulus oocyte complexes induced at ovulation by luteinizing hormone. AB - Ovulation, the release of the oocyte from the ovarian follicle, is initiated by the luteinizing hormone surge. It is clear that highly controlled degradation of the follicle and ovarian wall is required for passage of the oocyte and accompanying cumulus cells from the follicle, but the mechanism has not yet been elucidated. Here we show that cumulus oocyte complexes (COCs) adopt transient adhesive, migratory, and matrix-invading capacities at the time of ovulation. We characterized cell adhesion, migration, and invasion in preovulatory and postovulatory mouse COCs collected over a time course post-human chorionic gonadotropin (hCG) administration. Adhesion of dispersed cumulus cells and intact COCs to extracellular matrix proteins present in the ovarian wall (collagens, laminin, and fibronectin) increased significantly after hCG treatment and declined immediately after ovulation. Cumulus cell migration was low in unexpanded, equine chorionic gonadotropin-only treated COCs, but increased 4, 8, and 10 h post-hCG, reaching a peak at 12 h post-hCG that coincided with ovulation. The ability of cumulus cells to migrate was rapidly diminished in COCs isolated from the oviduct within 2 h postovulation. Cell migration was cumulus cell specific and was not observed in granulosa cells. Invasion through three dimensional collagen I and matrigel barriers by preovulatory expanded COCs was equivalent to that of a known invasive breast cancer cell line (MB-231). Cumulatively, these results demonstrate that cumulus cells in the expanded COC transition to an adhesive, motile, and invasive phenotype in the periovulatory period that may be required for successful release of the oocyte from the ovary at ovulation. PMID- 22238280 TI - 25-hydroxyvitamin D concentrations and in vivo insulin sensitivity and beta-cell function relative to insulin sensitivity in black and white youth. AB - OBJECTIVE: To examine the relationships between plasma 25-hydroxyvitamin D [25(OH)D] and in vivo insulin sensitivity and beta-cell function relative to insulin sensitivity, disposition index (DI), in black and white youth. RESEARCH DESIGN AND METHODS: Plasma 25(OH)D concentrations were analyzed in banked specimens in healthy youth aged 8 to 18 years who had existing data on hyperinsulinemic-euglycemic and hyperglycemic clamp to assess insulin sensitivity and secretion, and measurements of body composition, and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). RESULTS: A total of 183 research volunteers (mean +/- SD; age, 12.6 +/- 2.2 years; 98 white, 98 male, 92 obese) were studied. Analysis of HbA(1c), fasting glucose and insulin, insulin sensitivity, and DI across quartiles of plasma 25(OH)D revealed no differences among whites. In blacks, the observed significance of higher insulin sensitivity and DI in the highest quartile of 25(OH)D disappeared after adjusting for any of the adiposity measures (BMI or fat mass or VAT or SAT). The difference in insulin sensitivity (9.4 +/- 1.2 vs. 5.6 +/- 0.5 mg/kg/min per MUU/mL; P = 0.006) between 25(OH)D nondeficient (>=20 ng/mL) versus deficient (<20 ng/mL) black youth also was negated when adjusted for adiposity. CONCLUSIONS: In healthy youth, plasma 25(OH)D concentrations bear no independent relationship to parameters of glucose homeostasis and in vivo insulin sensitivity and beta-cell function relative to insulin sensitivity. It remains to be determined whether in youth with dysglycemia the relationships are different and whether vitamin D optimization enhances insulin sensitivity and beta-cell function. PMID- 22238282 TI - The molecular role of connexin 43 in human trophoblast cell fusion. AB - Connexin expression and gap junctional intercellular communication (GJIC) mediated by connexin 43 (Cx43)/gap junction A1 (GJA1) are required for cytotrophoblast fusion into the syncytium, the outer functional layer of the human placenta. Cx43 also impacts intracellular signaling through protein-protein interactions. The transcription factor GCM1 and its downstream target ERVW 1/SYNCYTIN-1 are key players in trophoblast fusion and exert their actions through the ERVW-1 receptor SLC1A5/ASCT-2/RDR/ATB(0). To investigate the molecular role of the Cx43 protein and its interaction with this fusogenic pathway, we utilized stable Cx43-transfected cell lines established from the choriocarcinoma cell line Jeg3: wild-type Jeg3, alphahCG/Cx43 (constitutive Cx43 expression), JpUHD/Cx43 (doxycyclin-inducible Cx43 expression), or JpUHD/trCx43 (doxycyclin-inducible Cx43 carboxyterminal deleted). We hypothesized that truncation of Cx43 at its C-terminus would inhibit trophoblast fusion and protein interaction with either ERVW-1 or SLC1A5. In the alphahCG/Cx43 and JpUHD/Cx43 lines, stimulation with cAMP caused 1) increase in GJA1 mRNA levels, 2) increase in percentage of fused cells, and 3) downregulation of SLC1A5 expression. Cell fusion was inhibited by GJIC blockade using carbenoxylone. Neither Jeg3, which express low levels of Cx43, nor the JpUHD/trCx43 cell line demonstrated cell fusion or downregulation of SLC1A5. However, GCM1 and ERVW-1 mRNAs were upregulated by cAMP treatment in both Jeg3 and all Cx43 cell lines. Silencing of GCM1 prevented the induction of GJA1 mRNA by forskolin in BeWo choriocarcinoma cells, demonstrating that GCM1 is upstream of Cx43. All cell lines and first trimester villous explants also demonstrated coimmunoprecipitation of SLC1A5 and phosphorylated Cx43. Importantly, SLC1A5 and Cx43 gap junction plaques colocalized in situ to areas of fusing cytotrophoblast, as demonstrated by the loss of E-cadherin staining in the plasma membrane in first-trimester placenta. We conclude that Cx43-mediated GJIC and SLC1A5 interaction play important functional roles in trophoblast cell fusion. PMID- 22238283 TI - Elastic fiber assembly in the adult mouse pubic symphysis during pregnancy and postpartum. AB - Impairment of pelvic organ support has been described in mice with genetic modifications of the proteins involved in elastogenesis, such as lysyl oxidase like 1 (LOXL1) and fibulin 5. During pregnancy, elastic fiber-enriched pelvic tissues are modified to allow safe delivery. In addition, the mouse pubic symphysis is remodeled in a hormone-controlled process that entails the modification of the fibrocartilage into an interpubic ligament (IpL) and the relaxation of this ligament. After first parturition, recovery occurs to ensure pelvic tissue homeostasis. Because ligaments are the main supports of the pelvic organs, this study aimed to evaluate elastogenesis in the IpL during mouse pregnancy and postpartum. Accordingly, virgin, pregnant, and postpartum C57BL/6 mice were studied using light, confocal, and transmission electron microscopy as well as Western blots and real-time PCR. Female mice exhibited the separation of the pubic bones and the formation, relaxation, and postpartum recovery of the IpL. By the time the IpL was formed, the elastic fibers had increased in profile length and diameter, and they consisted of small conglomerates of amorphous material distributed among the bundles of microfibrils. Our analyses also indicated that elastin/tropoelastin, fibrillin 1, LOXL1/Loxl1, and fibulin 5 were spatially and temporally regulated, suggesting that these molecules may contribute to the synthesis of new elastic fibers during IpL development. Overall, this work revealed that adult elastogenesis may be important to assure the elasticity of the pelvic girdle during preparation for parturition and postpartum recovery. This finding may contribute to our understanding of pathological processes involving elastogenesis in the reproductive tract. PMID- 22238284 TI - Identification of goat mammary stem/progenitor cells. AB - Goat mammary gland epithelial cells have been used to establish primary and permanent cell lines, but to date, no data have been available regarding mammary stem cells (MaSCs) in this species. The detection and characterization of goat MaSCs is an important task for a better understanding of the cyclic character of mammary gland development, which will also offer the potential for manipulation of lactation yield and persistency. The objective of the present study was to demonstrate that a subpopulation of goat MaSCs resides in the goat mammary gland. Mammary tissue from lactating Saanen goats (Capra hircus) was dissociated and processed to a single-cell suspension. Using an in vitro colony-forming assay, we demonstrated that distinct colony types, which expressed specific lineage markers, arose from unipotent progenitors. Using two different growth media, we showed that the frequencies of caprine clonogenic progenitors differed according to growth conditions. Goat epithelial cells were transplanted under the kidney capsule of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, where they formed organized, bilayered structures. Our results indicate the presence of goat MaSCs in the caprine mammary gland. To our knowledge, these data represent the first description of the tissue hierarchy of the goat mammary gland and demonstrate the regenerative potential of adult goat MaSCs. PMID- 22238285 TI - Progesterone inhibits uterine gland development in the neonatal mouse uterus. AB - Uterine glands and their secretions are required for conceptus (embryo/fetus and associated placenta) survival and development. In most mammals, uterine gland morphogenesis or adenogenesis is a uniquely postnatal event; however, little is known about the mechanisms governing the developmental event. In sheep, progestin treatment of neonatal ewes permanently ablated differentiation of the endometrial glands. Similarly, progesterone (P4) inhibits adenogenesis in neonatal mouse uterus. Thus, P4 can be used as a tool to discover mechanisms regulating endometrial adenogenesis. Female pups were treated with sesame vehicle alone as a control or P4 from Postnatal Day 2 (PD 2) to PD 10, and reproductive tracts were examined on PD 5, 10, or 20. Endometrial glands were fully developed in control mice by PD 20 but not in P4-treated mice. All other uterine cell types appeared normal. Treatment with P4 stimulated proliferation of the stroma but suppressed proliferation of the luminal epithelium. Microarray analysis revealed that expression of genes were reduced (Car2, Fgf7, Fgfr2, Foxa2, Fzd10, Met, Mmp7, Msx1, Msx2, Wnt4, Wnt7a, Wnt16) and increased (Hgf, Ihh, Wnt11) by P4 in the neonatal uterus. These results support the idea that P4 inhibits endometrial adenogenesis in the developing neonatal uterus by altering expression of morphoregulatory genes and consequently disrupting normal patterns of cell proliferation and development. PMID- 22238288 TI - Three-dimensional dynamic force spectroscopy measurements on KBr(001): atomic deformations at small tip-sample separations. AB - Three-dimensional dynamic force spectroscopy measurements were carried out above KBr(001) at low temperature in order to investigate the distance dependence of the tip-sample interactions. In particular, the recorded 3D frequency shift data as well as the extracted interaction force and potential energy fields were analysed with respect to influences of tip and/or sample deformations. We found that a postprocessing correction of the observed deformations significantly modifies the magnitude of the extracted interaction forces and also the image contrast. PMID- 22238287 TI - Insulin resistance induces medial artery calcification in fructose-fed rats. AB - Osteogenic differentiation of vascular smooth muscle cells (VSMCs) results in medial artery calcification, which is common in diabetes, but the pathogenesis is poorly understood. We aimed to explore the pathophysiological roles of insulin resistance (IR) on medial artery calcification in rats with 10% fructose in drinking water. After 12 weeks of fructose feeding, rats showed severe IR, with increased levels of fasting blood glucose, serum insulin and oral glucose tolerance test (OGTT). Fructose-fed rats showed aortic calcification, increased aortic calcium deposition and irregular elastic fibers in the medial layer of the vessel wall. Moreover, plasma phosphorus concentration, calcium * phosphorus product and alkaline phosphatase (ALP) activity, and aortic calcium content and ALP activity were significantly increased. Fructose feeding increased mRNA levels of osteopontin, type III sodium-dependent phosphate co-transporter, bone morphogenetic protein-2 and the key transcription factor core binding factor alpha 1 in aortic tissue and downregulated mRNA levels of osteoprotegerin and matrix gamma-carboxyglutamic acid protein. Fructose feeding decreased protein levels of smooth-muscle lineage markers and induced severe lipid peroxidation injury. IR induced by high fructose feeding could evoke osteogenic transdifferentiation of VSMCs and promote vascular calcification. PMID- 22238286 TI - Alcoholic liver disease and the potential role of plasminogen activator inhibitor 1 and fibrin metabolism. AB - Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury. PMID- 22238289 TI - Glucuronidation of edaravone by human liver and kidney microsomes: biphasic kinetics and identification of UGT1A9 as the major UDP-glucuronosyltransferase isoform. AB - Edaravone was launched in Japan in 2001 and was the first neuroprotectant developed for the treatment of acute cerebral infarction. Edaravone is mainly eliminated as glucuronide conjugate in human urine (approximately 70%), but the mechanism involved in the elimination pathway remains unidentified. We investigated the glucuronidation of edaravone in human liver microsomes (HLM) and human kidney microsomes (HKM) and identified the major hepatic and renal UDP glucuronosyltransferases (UGTs) involved. As we observed, edaravone glucuronidation in HLM and HKM exhibited biphasic kinetics. The intrinsic clearance of glucuronidation at high-affinity phase (CL(int1)) and low-affinity phase (CL(int2)) were 8.4 +/- 3.3 and 1.3 +/- 0.2 MUl . min(-1) . mg(-1), respectively, for HLM and were 45.3 +/- 8.2 and 1.8 +/- 0.1 MUl . min(-1) . mg( 1), respectively, for HKM. However, in microsomal incubations contained with 2% bovine serum albumin, CL(int1) and CL(int2) were 16.4 +/- 1.2 and 3.7 +/- 0.3 MUl . min(-1) . mg(-1), respectively, for HLM and were 78.5 +/- 3.9 and 3.6 +/- 0.5 MUl . min(-1) . mg(-1), respectively, for HKM. Screening with 12 recombinant UGTs indicated that eight UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17) produced a significant amount of glucuronide metabolite. Thus, six UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A9, UGT2B7, and UGT2B17) expressed in human liver or kidney were selected for kinetic studies. Among them, UGT1A9 exhibited the highest activity (CL(int1) = 42.4 +/- 9.5 MUl . min(-1) . mg(-1)), followed by UGT2B17 (CL(int) = 3.3 +/- 0.4 MUl . min(-1) . mg(-1)) and UGT1A7 (CL(int) = 1.7 +/- 0.2 MUl . min(-1) . mg(-1)). Inhibition study found that inhibitor of UGT1A9 (propofol) attenuated edaravone glucuronidation in HLM and HKM. In addition, edaravone glucuronidation in a panel of seven HLM was significantly correlated (r = 0.9340, p = 0.0021) with propofol glucuronidation. Results indicated that UGT1A9 was the main UGT isoform involved in edaravone glucuronidation in HLM and HKM. PMID- 22238290 TI - Hollow CoFe2O4 nanospheres as a high capacity anode material for lithium ion batteries. AB - Hollow structured CoFe2O4 nanospheres were synthesized by a hydrothermal method. The uniform hollow nanosphere architecture of the as-prepared CoFe2O4 has been confirmed by field emission scanning electron microscopy and transmission electron microscopy analysis, which give an outer diameter of 200-300 nm and a wall thickness of about 100 nm. CoFe2O4 nanospheres exhibited a high reversible capacity of 1266 mA h g-1 with an excellent capacity retention of 93.6% over 50 cycles and an improved rate capability. CoFe2O4 could be a promising high capacity anode material for lithium ion batteries. PMID- 22238291 TI - Effects of intraperitoneal administration of gabapentin on the minimum alveolar concentration of isoflurane in adult male rats. AB - Gabapentin has been used to treat a variety of conditions in both human and veterinary medicine, including seizures, neuropathies and chronic pain. However, little information is known about the effects of gabapentin on the minimum alveolar concentration (MAC) of volatile anaesthetics. In this study, we investigated the effect of intraperitoneal administration of gabapentin on isoflurane MAC in adult male rats and hypothesized that gabapentin would decrease MAC in a dose-dependent manner. Using a standard MAC study protocol, we compared five treatment groups (G) receiving 0 (G(0)), 30 (G(30)), 100 (G(100)), 300 (G(300)) and 1000 (G(1000)) mg/kg gabapentin intraperitoneally and compared post drug MAC values among groups and with corresponding baseline MAC values determined in each group prior to drug testing. The average baseline isoflurane MAC value was 1.45 +/- 0.17%, which did not differ significantly between groups (1.47 +/- 0.23% [G(30)], 1.46 +/- 0.23% [G(100)], 1.48 +/- 0.18% [G(300)] and 1.42 +/- 0.2% [G(1000)]). In the G(300) and G(1000) groups, the isoflurane MAC value decreased significantly by 19% and 18%, respectively, from corresponding baseline values (P< 0.05, when compared with G(0)). Linear regression analysis revealed a negative correlation between blood gabapentin concentration and percent change in MAC (R(2) = 0.43; P< 0.05) but not dose. In conclusion, high dose intraperitoneal gabapentin decreased isoflurane MAC. However, the effect was small and not dose-dependent, and is unlikely to be clinically significant. PMID- 22238292 TI - Premedication with meloxicam exacerbates intracranial haemorrhage in an immature swine model of non-impact inertial head injury. AB - Meloxicam is a cyclo-oxygenase-2 (COX-2) preferential non-steroidal anti inflammatory drug with very effective analgesic and anti-inflammatory effects in swine. Previous reports in piglets have demonstrated that meloxicam also inhibits COX-1 and reduces production of thromboxane significantly. We use preinjury analgesia in our immature swine (3-5-day-old piglets) model of brain injury using rapid head rotations without impact. In 23 consecutive subjects we found that premedication with meloxicam (n = 6) produced a significantly higher mortality rate (5/6 or 83%) than buprenorphine (n = 17, 1/17 or 6%, P < 0.02). On gross neuropathological examination of the meloxicam-treated swine, we observed massive subdural and subarachnoid bleeding which were not present in buprenorphine premedicated animals. To our knowledge there are no previous reports in swine of increased bleeding or platelet inhibition associated with meloxicam administration and further research is needed to define mechanisms of action in piglets. We caution the use of meloxicam in swine when inhibition of platelet aggregation might adversely affect refinement of experimental research protocols, such as in stroke, trauma and cardiac arrest models. PMID- 22238293 TI - Mast cell-induced lung injury in mice infected with H5N1 influenza virus. AB - Although an important role for mast cells in several viral infections has been demonstrated, its role in the invasion of highly pathogenic H5N1 influenza virus is unknown. In the present study, we demonstrate that mast cells were activated significantly by H5N1 virus (A/chicken/Henan/1/2004) infection both in vivo and in vitro. Mast cells could possibly intensify the lung injury that results from H5N1 infection by releasing proinflammatory mediators, including histamine, tryptase, and gamma interferon (IFN-gamma). Lung lesions and apoptosis induced by H5N1 infection were reduced dramatically by treatment with ketotifen, which is a mast cell degranulation inhibitor. A combination of ketotifen and the neuraminidase inhibitor oseltamivir protected 100% of the mice from death postinfection. In conclusion, our data suggest that mast cells play a crucial role in the early stages of H5N1 influenza virus infection and provide a new approach to combat highly pathogenic influenza virus infection. PMID- 22238294 TI - Luria-delbruck estimation of turnip mosaic virus mutation rate in vivo. AB - A potential drawback of recent antiviral therapies based on the transgenic expression of artificial microRNAs is the ease with which viruses may generate escape mutations. Using a variation of the classic Luria-Delbruck fluctuation assay, we estimated that the spontaneous mutation rate in the artificial microRNA (amiR) target of a plant virus was ca. 6 * 10(-5) per replication event. PMID- 22238296 TI - Detection of murine leukemia virus in the Epstein-Barr virus-positive human B cell line JY, using a computational RNA-Seq-based exogenous agent detection pipeline, PARSES. AB - Many cell lines commonly used for biological studies have been found to harbor exogenous agents such as the human tumor viruses Epstein-Barr virus (EBV) and human papillomavirus. Nevertheless, broad-based, unbiased approaches to globally assess the presence of ectopic organisms within cell model systems have not previously been available. We reasoned that high-throughput sequencing should provide unparalleled insights into the microbiomes of tissue culture cell systems. Here we have used our RNA-seq analysis pipeline, PARSES (Pipeline for Analysis of RNA-Seq Exogenous Sequences), to investigate the presence of ectopic organisms within two EBV-positive B-cell lines commonly used by EBV researchers. Sequencing data sets from both the Akata and JY B-cell lines were found to contain reads for EBV, and the JY data set was found to also contain reads from the murine leukemia virus (MuLV). Further investigation revealed that MuLV transcription in JY cells is highly active. We also identified a number of MuLV alternative splicing events, and we uncovered evidence of APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G)-dependent DNA editing. Finally, reverse transcription-PCR analysis showed the presence of MuLV in three other human B-cell lines (DG75, Ramos, and P3HR1 Cl.13) commonly used by investigators in the Epstein-Barr virus field. We believe that a thorough examination of tissue culture microbiomes using RNA-seq/PARSES-like approaches is critical for the appropriate utilization of these systems in biological studies. PMID- 22238297 TI - A human antibody recognizing a conserved epitope of H5 hemagglutinin broadly neutralizes highly pathogenic avian influenza H5N1 viruses. AB - Influenza A virus infection is a persistent threat to public health worldwide due to its ability to evade immune surveillance through rapid genetic drift and shift. Current vaccines against influenza A virus provide immunity to viral isolates that are similar to vaccine strains. High-affinity neutralizing antibodies against conserved epitopes could provide immunity to diverse influenza virus strains and protection against future pandemic viruses. In this study, by using a highly sensitive H5N1 pseudotype-based neutralization assay to screen human monoclonal antibodies produced by memory B cells from an H5N1-infected individual and molecular cloning techniques, we developed three fully human monoclonal antibodies. Among them, antibody 65C6 exhibited potent neutralization activity against all H5 clades and subclades except for subclade 7.2 and prophylactic and therapeutic efficacy against highly pathogenic avian influenza H5N1 viruses in mice. Studies on hemagglutinin (HA)-antibody complexes by electron microscopy and epitope mapping indicate that antibody 65C6 binds to a conformational epitope comprising amino acid residues at positions 118, 121, 161, 164, and 167 (according to mature H5 numbering) on the tip of the membrane-distal globular domain of HA. Thus, we conclude that antibody 65C6 recognizes a neutralization epitope in the globular head of HA that is conserved among almost all divergent H5N1 influenza stains. PMID- 22238298 TI - Genome-wide networks of amino acid covariances are common among viruses. AB - Coordinated variation among positions in amino acid sequence alignments can reveal genetic dependencies at noncontiguous positions, but methods to assess these interactions are incompletely developed. Previously, we found genome-wide networks of covarying residue positions in the hepatitis C virus genome (R. Aurora, M. J. Donlin, N. A. Cannon, and J. E. Tavis, J. Clin. Invest. 119:225 236, 2009). Here, we asked whether such networks are present in a diverse set of viruses and, if so, what they may imply about viral biology. Viral sequences were obtained for 16 viruses in 13 species from 9 families. The entire viral coding potential for each virus was aligned, all possible amino acid covariances were identified using the observed-minus-expected-squared algorithm at a false discovery rate of <=1%, and networks of covariances were assessed using standard methods. Covariances that spanned the viral coding potential were common in all viruses. In all cases, the covariances formed a single network that contained essentially all of the covariances. The hepatitis C virus networks had hub-and spoke topologies, but all other networks had random topologies with an unusually large number of highly connected nodes. These results indicate that genome-wide networks of genetic associations and the coordinated evolution they imply are very common in viral genomes, that the networks rarely have the hub-and-spoke topology that dominates other biological networks, and that network topologies can vary substantially even within a given viral group. Five examples with hepatitis B virus and poliovirus are presented to illustrate how covariance network analysis can lead to inferences about viral biology. PMID- 22238301 TI - Varicella-zoster virus infects human embryonic stem cell-derived neurons and neurospheres but not pluripotent embryonic stem cells or early progenitors. AB - Pluripotent human stem cells are a powerful tool for the generation of differentiated cells that can be used for the study of human disease. We recently demonstrated that neurons derived from pluripotent human embryonic stem cells (hESC) can be infected by the highly host-restricted human alphaherpesvirus varicella-zoster virus (VZV), permitting the interaction of VZV with neurons to be readily evaluated in culture. In the present study, we examine whether pluripotent hESC and neural progenitors at intermediate stages of differentiation are permissive for VZV infection. We demonstrate here that VZV infection is blocked in naive hESC. A block to VZV replication is also seen when a bacterial artificial chromosome (BAC) containing the VZV genome is transfected into hESC. In contrast, related alphaherpesviruses herpes simplex virus 1 (HSV-1) and pseudorabies virus (PrV) productively infect naive hESC in a cell-free manner, and PrV replicates from a BAC transfected into hESC. Neurons differentiate from hESC via neural progenitor intermediates, as is the case in the embryo. The first in vitro stage at which permissiveness of hESC-derived neural precursors to VZV replication is observed is upon formation of "neurospheres," immediately after detachment from the inductive stromal feeder layer. These findings suggest that hESC may be useful in deciphering the yet enigmatic mechanisms of specificity of VZV infection and replication. PMID- 22238299 TI - Residues in the hendra virus fusion protein transmembrane domain are critical for endocytic recycling. AB - Hendra virus is a highly pathogenic paramyxovirus classified as a biosafety level four agent. The fusion (F) protein of Hendra virus is critical for promoting viral entry and cell-to-cell fusion. To be fusogenically active, Hendra virus F must undergo endocytic recycling and cleavage by the endosomal/lysosomal protease cathepsin L, but the route of Hendra virus F following internalization and the recycling signals involved are poorly understood. We examined the intracellular distribution of Hendra virus F following endocytosis and showed that it is primarily present in Rab5- and Rab4-positive endosomal compartments, suggesting that cathepsin L cleavage occurs in early endosomes. Hendra virus F transmembrane domain (TMD) residues S490 and Y498 were found to be important for correct Hendra virus F recycling, with the hydroxyl group of S490 and the aromatic ring of Y498 important for this process. In addition, changes in association of isolated Hendra virus F TMDs correlated with alterations to Hendra virus F recycling, suggesting that appropriate TMD interactions play an important role in endocytic trafficking. PMID- 22238295 TI - Deep sequencing identifies viral and wasp genes with potential roles in replication of Microplitis demolitor Bracovirus. AB - Viruses in the genus Bracovirus (BV) (Polydnaviridae) are symbionts of parasitoid wasps that specifically replicate in the ovaries of females. Recent analysis of expressed sequence tags from two wasp species, Cotesia congregata and Chelonus inanitus, identified transcripts related to 24 different nudivirus genes. These results together with other data strongly indicate that BVs evolved from a nudivirus ancestor. However, it remains unclear whether BV-carrying wasps contain other nudivirus-like genes and what types of wasp genes may also be required for BV replication. Microplitis demolitor carries Microplitis demolitor bracovirus (MdBV). Here we characterized MdBV replication and performed massively parallel sequencing of M. demolitor ovary transcripts. Our results indicated that MdBV replication begins in stage 2 pupae and continues in adults. Analysis of prereplication- and active-replication-stage ovary RNAs yielded 22 Gb of sequence that assembled into 66,425 transcripts. This breadth of sampling indicated that a large percentage of genes in the M. demolitor genome were sequenced. A total of 41 nudivirus-like transcripts were identified, of which a majority were highly expressed during MdBV replication. Our results also identified a suite of wasp genes that were highly expressed during MdBV replication. Among these products were several transcripts with conserved roles in regulating locus-specific DNA amplification by eukaryotes. Overall, our data set together with prior results likely identify the majority of nudivirus-related genes that are transcriptionally functional during BV replication. Our results also suggest that amplification of proviral DNAs for packaging into BV virions may depend upon the replication machinery of wasps. PMID- 22238300 TI - Characterization of the RNA silencing suppression activity of the Ebola virus VP35 protein in plants and mammalian cells. AB - Ebola virus (EBOV) causes a lethal hemorrhagic fever for which there is no approved effective treatment or prevention strategy. EBOV VP35 is a virulence factor that blocks innate antiviral host responses, including the induction of and response to alpha/beta interferon. VP35 is also an RNA silencing suppressor (RSS). By inhibiting microRNA-directed silencing, mammalian virus RSSs have the capacity to alter the cellular environment to benefit replication. A reporter gene containing specific microRNA target sequences was used to demonstrate that prior expression of wild-type VP35 was able to block establishment of microRNA silencing in mammalian cells. In addition, wild-type VP35 C-terminal domain (CTD) protein fusions were shown to bind small interfering RNA (siRNA). Analysis of mutant proteins demonstrated that reporter activity in RSS assays did not correlate with their ability to antagonize double-stranded RNA (dsRNA)-activated protein kinase R (PKR) or bind siRNA. The results suggest that enhanced reporter activity in the presence of VP35 is a composite of nonspecific translational enhancement and silencing suppression. Moreover, most of the specific RSS activity in mammalian cells is RNA binding independent, consistent with VP35's proposed role in sequestering one or more silencing complex proteins. To examine RSS activity in a system without interferon, VP35 was tested in well characterized plant silencing suppression assays. VP35 was shown to possess potent plant RSS activity, and the activities of mutant proteins correlated strongly, but not exclusively, with RNA binding ability. The results suggest the importance of VP35-protein interactions in blocking silencing in a system (mammalian) that cannot amplify dsRNA. PMID- 22238302 TI - Beyond anchoring: the expanding role of the hendra virus fusion protein transmembrane domain in protein folding, stability, and function. AB - While work with viral fusion proteins has demonstrated that the transmembrane domain (TMD) can affect protein folding, stability, and membrane fusion promotion, the mechanism(s) remains poorly understood. TMDs could play a role in fusion promotion through direct TMD-TMD interactions, and we have recently shown that isolated TMDs from three paramyxovirus fusion (F) proteins interact as trimers using sedimentation equilibrium (SE) analysis (E. C. Smith, et al., submitted for publication). Immediately N-terminal to the TMD is heptad repeat B (HRB), which plays critical roles in fusion. Interestingly, addition of HRB decreased the stability of the trimeric TMD-TMD interactions. This result, combined with previous findings that HRB forms a trimeric coiled coil in the prefusion form of the whole protein though HRB peptides fail to stably associate in isolation, suggests that the trimeric TMD-TMD interactions work in concert with elements in the F ectodomain head to stabilize a weak HRB interaction. Thus, changes in TMD-TMD interactions could be important in regulating F triggering and refolding. Alanine insertions between the TMD and HRB demonstrated that spacing between these two regions is important for protein stability while not affecting TMD-TMD interactions. Additional mutagenesis of the C-terminal end of the TMD suggests that beta-branched residues within the TMD play a role in membrane fusion, potentially through modulation of TMD-TMD interactions. Our results support a model whereby the C-terminal end of the Hendra virus F TMD is an important regulator of TMD-TMD interactions and show that these interactions help hold HRB in place prior to the triggering of membrane fusion. PMID- 22238304 TI - Varicella-Zoster virus ORF12 protein triggers phosphorylation of ERK1/2 and inhibits apoptosis. AB - Mitogen-activated protein kinases (MAPKs) are a family of serine-threonine protein kinases involved in many cellular processes, including cell proliferation, differentiation, inflammation, and cell death. Activation of several MAPKs, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), results in stimulation of activator protein 1 (AP-1), which promotes gene transcription. Previous studies have demonstrated that varicella-zoster virus (VZV) infection activates ERK1/2, p38, and JNK to promote viral replication, but the underlying mechanism(s) is unclear. To identify viral proteins responsible for the activation of MAPK, we used a proteomic approach to screen viral proteins for AP-1 promoter activation by an AP 1-luciferase reporter assay. We found that VZV ORF12 protein, located in the tegument of virions, enhances AP-1 reporter activity. This effect of ORF12 protein was markedly inhibited by a MAPK/ERK kinase 1 and 2 (MEK1/2) inhibitor (U0126), partially blocked by a p38 inhibitor (SB202190), but not inhibited by a JNK inhibitor (SP600125). Expression of VZV ORF12 protein in cells resulted in phosphorylation of ERK1/2 and p38 but not JNK. Infection of cells with a VZV ORF12 deletion mutant resulted in reduced levels of phosphorylated ERK1/2 (p ERK1/2) compared to infection with wild-type VZV. Furthermore, deletion of ORF12 rendered VZV-infected cells more susceptible to staurosporine-induced apoptosis. In conclusion, VZV ORF12 protein activates the AP-1 pathway by selectively triggering the phosphorylation of ERK1/2 and p38. Cells infected with a VZV ORF12 deletion mutant have reduced levels of p-ERK1/2 and are more susceptible to apoptosis than cells infected with wild-type VZV. PMID- 22238305 TI - Endogenous lentiviruses in the ferret genome. AB - By screening 74 chordate genomes for endogenous lentiviruses using Pol sequences of exogenous lentiviruses as a reference, we identified a novel endogenous lentivirus in the genome of the ferret (Mustela putorius furo). Phylogenetic analysis suggested that the ferret endogenous lentivirus, denoted ELVmpf, diverged early in the evolution of the mammalian lentiviruses, although with a lack of resolution at key nodes. These data support the notion that lentiviruses have evolved on timescales of millions of years. PMID- 22238303 TI - Human metapneumovirus (HMPV) binding and infection are mediated by interactions between the HMPV fusion protein and heparan sulfate. AB - Human metapneumovirus (HMPV) is a major worldwide respiratory pathogen that causes acute upper and lower respiratory tract disease. The mechanism by which this virus recognizes and gains access to its target cell is still largely unknown. In this study, we addressed the initial steps in virus binding and infection and found that the first binding partner for HMPV is heparan sulfate (HS). While wild-type CHO-K1 cells are permissive to HMPV infection, mutant cell lines lacking the ability to synthesize glycosaminoglycans (GAGs), specifically, heparan sulfate proteoglycans (HSPGs), were resistant to binding and infection by HMPV. The permissiveness to HMPV infection was also abolished when CHO-K1 cells were treated with heparinases. Importantly, using recombinant HMPV lacking both the G and small hydrophobic (SH) proteins, we report that this first virus-cell binding interaction is driven primarily by the fusion protein (HMPV F) and that this interaction is needed to establish a productive infection. Finally, HMPV binding to cells did not require beta1 integrin expression, and RGD-mediated interactions were not essential in promoting HMPV F-mediated cell-to-cell membrane fusion. Cells lacking beta1 integrin, however, were less permissive to HMPV infection, indicating that while beta1 integrins play an important role in promoting HMPV infection, the interaction between integrins and HMPV occurs after the initial binding of HMPV F to heparan sulfate proteoglycans. PMID- 22238306 TI - The viral protein Tat can inhibit the establishment of HIV-1 latency. AB - The establishment of HIV-1 latency can result from limiting levels of transcription initiation or elongation factors, restrictive chromatin modifications, transcriptional interference, and insufficient Tat activity. Since the viral protein Tat can counteract many of these factors, we hypothesized that the presence of exogenous Tat during infection might inhibit the establishment of latency. This was explored using a Jurkat model of latency establishment and reactivation. PCR and reverse transcriptase PCR (RT-PCR) confirmed the latent state in this model and showed evidence of transcriptional interference. To address our hypothesis, cells undergoing infection were first exposed to either purified recombinant Tat or a transactivation-negative mutant. Only the former resulted in a modest inhibition of the establishment of latency. Next, Jurkat cells stably expressing intracellular Tat were used in our latency model to avoid limitations of Tat delivery. Experiments confirmed that intracellular Tat expression did not affect the susceptibility of these cells to viral infection. Eight weeks after infection, Jurkat cells expressing Tat harbored up to 1,700 fold fewer (P < 0.01) latent viruses than Jurkat cells that did not express Tat. Additionally, Tat delivered by a second virus was sufficient to reactivate most of the latent population. Our results suggest that inhibition of the establishment of latent infection is theoretically possible. In a hypothetical scenario of therapy that induces viral gene expression during acute infection, activation of viruses which would otherwise have entered latency could occur while concurrent highly active antiretroviral therapy (HAART) would prevent further viral spread, potentially decreasing the size of the established latent reservoir. PMID- 22238307 TI - Filoviruses require endosomal cysteine proteases for entry but exhibit distinct protease preferences. AB - Filoviruses are enveloped viruses that cause sporadic outbreaks of severe hemorrhagic fever [CDC, MMWR Morb. Mortal. Wkly. Rep. 50:73-77, 2001; Colebunders and Borchert, J. Infect. 40:16-20, 2000; Colebunders et al., J. Infect. Dis. 196(Suppl. 2):S148-S153, 2007; Geisbert and Jahrling, Nat. Med. 10:S110-S121, 2004]. Previous studies revealed that endosomal cysteine proteases are host factors for ebolavirus Zaire (Chandran et al., Science 308:1643-1645, 2005; Schornberg et al., J. Virol. 80:4174-4178, 2006). In this report, we show that infection mediated by glycoproteins from other phylogenetically diverse filoviruses are also dependent on these proteases and provide additional evidence indicating that they cleave GP1 and expose the binding domain for the critical host factor Niemann-Pick C1. Using selective inhibitors and knockout-derived cell lines, we show that the ebolaviruses Zaire and Cote d'Ivoire are strongly dependent on cathepsin B, while the ebolaviruses Sudan and Reston and Marburg virus are not. Taking advantage of previous studies of cathepsin B inhibitor resistant viruses (Wong et al., J. Virol. 84:163-175, 2010), we found that virus specific differences in the requirement for cathepsin B are correlated with sequence polymorphisms at residues 47 in GP1 and 584 in GP2. We applied these findings to the analysis of additional ebolavirus isolates and correctly predicted that the newly identified ebolavirus species Bundibugyo, containing D47 and I584, is cathepsin B dependent and that ebolavirus Zaire-1995, the single known isolate of ebolavirus Zaire that lacks D47, is not. We also obtained evidence for virus-specific differences in the role of cathepsin L, including cooperation with cathepsin B. These studies strongly suggest that the use of endosomal cysteine proteases as host factors for entry is a general property of members of the family Filoviridae. PMID- 22238308 TI - Vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma. AB - Vesicular stomatitis virus (VSV) is a promising oncolytic agent against a variety of cancers. However, it has never been tested in any pancreatic cancer model. Pancreatic ductal adenocarcinoma (PDA) is the most common and aggressive form of pancreatic cancer. In this study, the oncolytic potentials of several VSV variants were analyzed in a panel of 13 clinically relevant human PDA cell lines and compared to conditionally replicative adenoviruses (CRAds), Sendai virus and respiratory syncytial virus. VSV variants showed oncolytic abilities superior to those of other viruses, and some cell lines that exhibited resistance to other viruses were successfully killed by VSV. However, PDA cells were highly heterogeneous in their susceptibility to virus-induced oncolysis, and several cell lines were resistant to all tested viruses. Resistant cells showed low levels of very early VSV RNA synthesis, indicating possible defects at initial stages of infection. In addition, unlike permissive PDA cell lines, most of the resistant cell lines were able to both produce and respond to interferon, suggesting that intact type I interferon responses contributed to their resistance phenotype. Four cell lines that varied in their permissiveness to VSV DeltaM51 and CRAd dl1520 were tested in mice, and the in vivo results closely mimicked those in vitro. While our results demonstrate that VSV is a promising oncolytic agent against PDA, further studies are needed to better understand the molecular mechanisms of resistance of some PDAs to oncolytic virotherapy. PMID- 22238309 TI - The Simian virus 40 late viral protein VP4 disrupts the nuclear envelope for viral release. AB - Simian virus 40 (SV40) appears to initiate cell lysis by expressing the late viral protein VP4 at the end of infection to aid in virus dissemination. To investigate the contribution of VP4 to cell lysis, VP4 was expressed in mammalian cells where it was predominantly observed along the nuclear periphery. The integrity of the nuclear envelope was compromised in these cells, resulting in the mislocalization of a soluble nuclear marker. Using assays that involved the cellular expression of VP4 or the treatment of cells with purified VP4, we found that the central hydrophobic domain and a proximal C-terminal nuclear localization signal of VP4 were required for (i) cytolysis associated with prolonged expression; (ii) nuclear envelope accumulation; and (iii) disruption of the nuclear, red blood cell, or host cell membranes. Furthermore, a conserved proline within the hydrophobic domain was required for membrane perforation, suggesting that this residue was crucial for VP4 cytolytic activity. These results indicate that VP4 forms pores in the nuclear membrane leading to lysis and virus release. PMID- 22238311 TI - Functional interferon system is required for clearance of lassa virus. AB - Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever (LF) in humans, a deadly disease endemic to West Africa that results in 5,000 to 10,000 deaths annually. Here we present results demonstrating that functional type I and type II interferon (IFN) signaling is required for efficient control of LASV dissemination and clearance. PMID- 22238310 TI - Entry of human T-cell leukemia virus type 1 is augmented by heparin sulfate proteoglycans bearing short heparin-like structures. AB - Three molecules have been identified as the main cellular factors required for binding and entry of human T-cell leukemia virus type 1 (HTLV-1): glucose transporter 1 (GLUT1), heparan sulfate (HS), and neuropilin 1 (NRP-1). However, the precise mechanism of HTLV-1 cell tropism has yet to be elucidated. Here, we examined the susceptibilities of various human cell lines to HTLV-1 by using vesicular stomatitis virus pseudotypes bearing HTLV-1 envelope proteins. We found that the cellular susceptibility to HTLV-1 infection did not correlate with the expression of GLUT1, HS, or NRP-1 alone. To investigate whether other cellular factors were responsible for HTLV-1 susceptibility, we conducted expression cloning. We identified two HS proteoglycan core proteins, syndecan 1 and syndecan 2, as molecules responsible for susceptibility to HTLV-1. We found that treatment of syndecan 1-transduced cells (expressing increased HS) with heparinase, a heparin-degradative enzyme, reduced HTLV-1 susceptibility without affecting the expression levels of HS chains. To further elucidate these results, we characterized the expression of HS chains in terms of the mass, number, and length of HS in several syndecan 1-transduced cell clones as well as human cell lines. We found a significant correlation between HTLV-1 susceptibility and the number of HS chains with short chain lengths. Our findings suggest that a combination of the number and the length of HS chains containing heparin-like regions is a critical factor which affects the cell tropism of HTLV-1. PMID- 22238312 TI - The E1 protein of human papillomavirus type 16 is dispensable for maintenance replication of the viral genome. AB - Papillomavirus genomes are thought to be amplified to about 100 copies per cell soon after infection, maintained constant at this level in basal cells, and amplified for viral production upon keratinocyte differentiation. To determine the requirement for E1 in viral DNA replication at different stages, an E1 defective mutant of the human papillomavirus 16 (HPV16) genome featuring a translation termination mutation in the E1 gene was used. The ability of the mutant HPV16 genome to replicate as nuclear episomes was monitored with or without exogenous expression of E1. Unlike the wild-type genome, the E1-defective HPV16 genome became established in human keratinocytes only as episomes in the presence of exogenous E1 expression. Once established, it could replicate with the same efficiency as the wild-type genome, even after the exogenous E1 was removed. However, upon calcium-induced keratinocyte differentiation, once again amplification was dependent on exogenous E1. These results demonstrate that the E1 protein is dispensable for maintenance replication but not for initial and productive replication of HPV16. PMID- 22238313 TI - Neutralizing epitopes in the membrane-proximal external region of HIV-1 gp41 are influenced by the transmembrane domain and the plasma membrane. AB - Failure to elicit broadly neutralizing (bNt) antibodies (Abs) against the membrane-proximal external region of HIV-1 gp41 (MPER) reflects the difficulty of mimicking its neutralization-competent structure (NCS). Here, we analyzed MPER antigenicity in the context of the plasma membrane and identified a role for the gp41 transmembrane domain (TM) in exposing the epitopes of three bNt monoclonal Abs (MAbs) (2F5, 4E10, and Z13e1). We transiently expressed DNA constructs encoding gp41 ectodomain fragments fused to either the TM of the platelet-derived growth factor receptor (PDGFR) or the gp41 TM and cytoplasmic tail domain (CT). Constructs encoding the MPER tethered to the gp41 TM followed by a 27-residue CT fragment (MPER-TM1) produced optimal MAb binding. Critical binding residues for the three Nt MAbs were identified using a panel of 24 MPER-TM1 mutants bearing single amino acid substitutions in the MPER; many were previously shown to affect MAb-mediated viral neutralization. Moreover, non-Nt mutants of MAbs 2F5 and 4E10 exhibited a reduction in binding to MPER-TM1 and yet maintained binding to synthetic MPER peptides, indicating that MPER-TM1 better approximates the MPER NCS than peptides. Replacement of the gp41 TM and CT of MPER-TM1 with the PDGFR TM reduced binding by MAb 4E10, but not 2F5, indicating that the gp41 TM plays a pivotal role in orienting the 4E10 epitope, and more globally, in affecting MPER exposure. PMID- 22238314 TI - Control of innate immune signaling and membrane targeting by the Hepatitis C virus NS3/4A protease are governed by the NS3 helix alpha0. AB - Hepatitis C virus (HCV) infection is sensed in the host cell by the cytosolic pathogen recognition receptor RIG-I. RIG-I signaling is propagated through its signaling adaptor protein MAVS to drive activation of innate immunity. However, HCV blocks RIG-I signaling through viral NS3/4A protease cleavage of MAVS on the mitochondrion-associated endoplasmic reticulum (ER) membrane (MAM). The multifunctional HCV NS3/4A serine protease is associated with intracellular membranes, including the MAM, through membrane-targeting domains within NS4A and also at the amphipathic helix alpha(0) of NS3. The serine protease domain of NS3 is required for both cleavage of MAVS, a tail-anchored membrane protein, and processing the HCV polyprotein. Here, we show that hydrophobic amino acids in the NS3 helix alpha(0) are required for selective cleavage of membrane-anchored portions of the HCV polyprotein and for cleavage of MAVS for control of RIG-I pathway signaling of innate immunity. Further, we found that the hydrophobic composition of NS3 helix alpha(0) is essential to establish HCV replication and infection. Alanine substitution of individual hydrophobic amino acids in the NS3 helix alpha(0) impaired HCV RNA replication in cells with a functional RIG-I pathway, but viral RNA replication was rescued in cells lacking RIG-I signaling. Therefore, the hydrophobic amphipathic helix alpha(0) of NS3 is required for NS3/4A control of RIG-I signaling and HCV replication by directing the membrane targeting of both viral and cellular substrates. PMID- 22238315 TI - Postexposure treatment with the live-attenuated rabies virus (RV) vaccine TriGAS triggers the clearance of wild-type RV from the Central Nervous System (CNS) through the rapid induction of genes relevant to adaptive immunity in CNS tissues. AB - Postexposure treatment (PET) of wild-type rabies virus (RV)-infected mice with a live-attenuated triple-glycoprotein RV variant (TriGAS) promotes survival but does not prevent the pathogenic RV from invading and replicating in the brain. Successful PET is associated with the induction of a robust virus-neutralizing antibody response and clearance of the wild-type RV from brain tissues. Comparison of the transcriptomes of normal mouse brain with those of wild-type-RV infected mice that had received either mock or TriGAS PET treatment revealed that many of the host genes activated in the mock-treated mice represent type I interferon (IFN) response genes. This indicates that RV infection induces an early type I IFN response that is unable to control the infection. In contrast, most of the activated genes in the brain of the RV-infected, TriGAS-treated mouse play a role in adaptive immunity, including the regulation of T cell activation, T cell differentiation, and the regulation of lymphocyte and mononuclear cell proliferation. These findings were confirmed by quantitative PCR (qPCR) array studies, which showed that 3 genes in particular, encoding chemokine ligand 3 (Ccl3), natural killer cell activator 2 (interleukin 12B [IL-12B]), and granzyme A (GzmA), were activated earlier and to a greater extent in the brains of RV infected mice treated with TriGAS than in the brains of mock-treated mice. The activation of these genes, known to play key roles in the regulation of lymphocyte and mononuclear cell proliferation, is likely an important part of the mechanism by which TriGAS mediates its PET activity. PMID- 22238316 TI - Restricted replication of xenotropic murine leukemia virus-related virus in pigtailed macaques. AB - Although xenotropic murine leukemia virus-related virus (XMRV) has been previously linked to prostate cancer and myalgic encephalomyelitis/chronic fatigue syndrome, recent data indicate that results interpreted as evidence of human XMRV infection reflect laboratory contamination rather than authentic in vivo infection. Nevertheless, XMRV is a retrovirus of undefined pathogenic potential that is able to replicate in human cells. Here we describe a comprehensive analysis of two male pigtailed macaques (Macaca nemestrina) experimentally infected with XMRV. Following intravenous inoculation with >10(10) RNA copy equivalents of XMRV, viral replication was limited and transient, peaking at <=2,200 viral RNA (vRNA) copies/ml plasma and becoming undetectable by 4 weeks postinfection, though viral DNA (vDNA) in peripheral blood mononuclear cells remained detectable through 119 days of follow-up. Similarly, vRNA was not detectable in lymph nodes by in situ hybridization despite detectable vDNA. Sequencing of cell-associated vDNA revealed extensive G-to-A hypermutation, suggestive of APOBEC-mediated viral restriction. Consistent with limited viral replication, we found transient upregulation of type I interferon responses that returned to baseline by 2 weeks postinfection, no detectable cellular immune responses, and limited or no spread to prostate tissue. Antibody responses, including neutralizing antibodies, however, were detectable by 2 weeks postinfection and maintained throughout the study. Both animals were healthy for the duration of follow-up. These findings indicate that XMRV replication and spread were limited in pigtailed macaques, predominantly by APOBEC-mediated hypermutation. Given that human APOBEC proteins restrict XMRV infection in vitro, human XMRV infection, if it occurred, would be expected to be characterized by similarly limited viral replication and spread. PMID- 22238317 TI - Impact of HLA-B*81-associated mutations in HIV-1 Gag on viral replication capacity. AB - HIV-1 attenuation resulting from immune escape mutations selected in Gag may contribute to slower disease progression in HIV-1-infected individuals expressing certain HLA class I alleles. We previously showed that the protective allele HLA B*81 and the HLA-B*81-selected Gag T186S mutation are strongly associated with a lower viral replication capacity of recombinant viruses encoding Gag-protease derived from individuals chronically infected with HIV-1 subtype C. In the present study, we directly tested the effect of this mutation on viral replication capacity. In addition, we investigated potential compensatory effects of various polymorphisms, including other HLA-B*81-associated mutations that significantly covary with the T186S mutation. Mutations were introduced into a reference subtype B backbone and into patient-derived subtype C sequences in subtype B and C backbones by site-directed mutagenesis. The exponential-phase growth of mutant and wild-type viruses was assayed by flow cytometry of a green fluorescent protein reporter T cell line or by measurement of HIV-1 reverse transcriptase activity in culture supernatants. Engineering of the T186S mutation alone into all patient-derived subtype C sequences failed to yield replication competent viruses, while in the subtype B sequence, the T186S mutation resulted in impaired replication capacity. Only the T186S mutation in combination with the T190I mutation yielded replication-competent viruses for all virus backbones tested; however, these constructs replicated slower than the wild type, suggesting that only partial compensation is mediated by the T190I mutation. Constructs encoding the T186S mutation in combination with other putative compensatory mutations were attenuated or defective. These results suggest that the T186S mutation is deleterious to HIV-1 subtype C replication and likely requires complex compensatory pathways, which may contribute to the clinical benefit associated with HLA-B*81. PMID- 22238318 TI - Rapid and massive virus-specific plasmablast responses during acute dengue virus infection in humans. AB - Humoral immune responses are thought to play a major role in dengue virus-induced immunopathology; however, little is known about the plasmablasts producing these antibodies during an ongoing infection. Herein we present an analysis of plasmablast responses in patients with acute dengue virus infection. We found very potent plasmablast responses that often increased more than 1,000-fold over the baseline levels in healthy volunteers. In many patients, these responses made up as much 30% of the peripheral lymphocyte population. These responses were largely dengue virus specific and almost entirely made up of IgG-secreting cells, and plasmablasts reached very high numbers at a time after fever onset that generally coincided with the window where the most serious dengue virus-induced pathology is observed. The presence of these large, rapid, and virus-specific plasmablast responses raises the question as to whether these cells might have a role in dengue immunopathology during the ongoing infection. These findings clearly illustrate the need for a detailed understanding of the repertoire and specificity of the antibodies that these plasmablasts produce. PMID- 22238319 TI - Mutating conserved cysteines in the alphavirus e2 glycoprotein causes virus specific assembly defects. AB - There are 80 trimeric, glycoprotein spikes that cover the surface of an alphavirus particle. The spikes, which are composed of three E2 and E1 glycoprotein heterodimers, are responsible for receptor binding and mediating fusion between the viral and host-cell membranes during entry. In addition, the cytoplasmic domain of E2 interacts with the nucleocapsid core during the last stages of particle assembly, possibly to aid in particle stability. During assembly, the spikes are nonfusogenic until the E3 glycoprotein is cleaved from E2 in the trans-Golgi network. Thus, a mutation in E2 potentially has effects on virus entry, spike assembly, or spike maturation. E2 is a highly conserved, cysteine-rich transmembrane glycoprotein. We made single cysteine-to-serine mutations within two distinct regions of the E2 ectodomain in both Sindbis virus and Ross River virus. Each of the E2 Cys mutants produced fewer infectious particles than wild-type virus. Further characterization of the mutant viruses revealed differences in particle morphology, fusion activity, and polyprotein cleavage between Sindbis and Ross River virus mutants, despite the mutations being made at corresponding positions in E2. The nonconserved assembly defects suggest that E2 folding and function is species dependent, possibly due to interactions with a virus-specific chaperone. PMID- 22238320 TI - Wild-type measles virus with the hemagglutinin protein of the edmonston vaccine strain retains wild-type tropism in macaques. AB - A major difference between vaccine and wild-type strains of measles virus (MV) in vitro is the wider cell specificity of vaccine strains, resulting from the receptor usage of the hemagglutinin (H) protein. Wild-type H proteins recognize the signaling lymphocyte activation molecule (SLAM) (CD150), which is expressed on certain cells of the immune system, whereas vaccine H proteins recognize CD46, which is ubiquitously expressed on all nucleated human and monkey cells, in addition to SLAM. To examine the effect of the H protein on the tropism and attenuation of MV, we generated enhanced green fluorescent protein (EGFP) expressing recombinant wild-type MV strains bearing the Edmonston vaccine H protein (MV-EdH) and compared them to EGFP-expressing wild-type MV strains. In vitro, MV-EdH replicated in SLAM(+) as well as CD46(+) cells, including primary cell cultures from cynomolgus monkey tissues, whereas the wild-type MV replicated only in SLAM(+) cells. However, in macaques, both wild-type MV and MV-EdH strains infected lymphoid and respiratory organs, and widespread infection of MV-EdH was not observed. Flow cytometric analysis indicated that SLAM(+) lymphocyte cells were infected preferentially with both strains. Interestingly, EGFP expression of MV-EdH in tissues and lymphocytes was significantly weaker than that of the wild type MV. Taken together, these results indicate that the CD46-binding activity of the vaccine H protein is important for determining the cell specificity of MV in vitro but not the tropism in vivo. They also suggest that the vaccine H protein attenuates MV growth in vivo. PMID- 22238321 TI - Alpha interferon and HIV infection cause activation of human T cells in NSG-BLT mice. AB - The development of small animal models for the study of HIV transmission is important for evaluation of HIV prophylaxis and disease pathogenesis. In humanized bone marrow-liver-thymus (BLT) mice, hematopoiesis is reconstituted by implantation of human fetal liver and thymus tissue (Thy/Liv) plus intravenous injection of autologous liver-derived hematopoietic stem progenitor cells (HSPC). This results in reconstitution of human leukocytes in the mouse peripheral blood, lymphoid organs, and mucosal sites. NOD-scid interleukin-2 receptor-negative (IL 2Rgamma(-/-)) (NSG)-BLT mice were inoculated intravaginally with HIV and were monitored for plasma viremia by a branched DNA assay 4 weeks later. T-cell activation was determined by expression of CD38 and HLA-DR on human CD4(+) and CD8(+) T cells in mouse peripheral blood at the time of inoculation and 4 weeks later. Additional BLT mice were treated with human alpha interferon 2b (IFN alpha2b) (intron A) and assessed for T-cell activation. Productive HIV infection in BLT mice was associated with T-cell activation (increases in CD38 mean fluorescence intensity and both the frequency and absolute number of CD38(+) HLA DR(+) T cells) that correlated strongly with plasma viral load and was most pronounced in the CD8(+) T-cell compartment. This T-cell activation phenotype was recapitulated in NSG-BLT mice treated with intron A. HIV susceptibility correlated with the number of HSPC injected, yet a number of mice receiving the Thy/Liv implant alone, with no HSPC injection, were also susceptible to intravaginal HIV. These results are consistent with studies linking T-cell activation to progressive disease in humans and lend support for the use of NSG BLT mice in studies of HIV pathogenesis. PMID- 22238322 TI - Simian virus 40 strains with novel properties generated by replacing the viral enhancer with synthetic oligonucleotides. AB - Typical enhancers of viral or cellular genes are approximately 100 to 400 bp long and contain several transcription factor binding sites. Previously, we have shown that simian virus 40 (SV40) genomic DNA that lacks its own enhancer can be used as an "enhancer trap" since it reacquires infectivity upon incorporation of heterologous enhancers. Here, we show that SV40 infectivity can be restored with synthetic enhancers that are assembled by the host cell. We found that several oligonucleotides, cotransfected with enhancerless SV40 DNA into host cells, were incorporated into the viral genome via cellular DNA end joining. The oligonucleotides tested included metal response elements (MREs), the binding sites for the transcription factor MTF-1, which induces gene activity in response to heavy metals. These recombinant SV40 strains showed preferential growth on cells overloaded with zinc or cadmium. We also cotransfected enhancerless SV40 DNA with oligonucleotides corresponding to enhancer motifs of human and mouse cytomegalovirus (HCMV and MCMV, respectively). In contrast to SV40 wild type, the viruses with cytomegalovirus-derived patchwork enhancers strongly expressed T antigen in human HEK293 cells, accompanied by viral DNA replication. Occasionally, we also observed the assembly of functional viral genomes by incorporation of fragments of bovine DNA, an ingredient of the fetal calf serum in the medium. These fragments contained, among other sites, binding sites for AP 1 and CREB transcription factors. Taken together, our studies show that viruses with novel properties can be generated by intracellular incorporation of synthetic enhancer DNA motifs. PMID- 22238323 TI - Abeta delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin. AB - Alzheimer disease is characterized by the presence of increased levels of the beta-amyloid peptide (Abeta) in the brain parenchyma and cerebral blood vessels. This accumulated Abeta can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that Abeta(42) specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, Abeta(42)-induced structural changes cannot be the sole mechanism of delayed lysis because Abeta overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that Abeta interferes with the binding of plasminogen to fibrin, which could impair plasmin generation and fibrin degradation. Indeed, plasmin generation by tissue plasminogen activator (tPA), but not streptokinase, is slowed in fibrin clots containing Abeta(42), and clot lysis by plasmin, but not trypsin, is delayed. Notably, plasmin and tPA activities, as well as tPA-dependent generation of plasmin in solution, are not decreased in the presence of Abeta(42). Our results indicate the existence of 2 mechanisms of Abeta(42) involvement in delayed fibrinolysis: (1) through the induction of a tighter fibrin network composed of thinner fibers, and (2) through inhibition of plasmin(ogen)-fibrin binding. PMID- 22238325 TI - Regulation of CXCR4 conformation by the small GTPase Rac1: implications for HIV infection. AB - The chemokine receptor CXCR4 is a critical regulator of cell migration and serves as a coreceptor for HIV-1. The chemokine stromal cell derived factor-1, also known as CXCL12, binds to CXCR4 and exerts its biologic functions partly through the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). We show in different cell types, including CD34(+) hematopoietic stem and progenitor cells, that inhibition of Rac1 causes a reversible conformational change in CXCR4, but not in the related receptors CXCR7 or CCR5. Biochemical experiments showed that Rac1 associates with CXCR4. The conformational change of CXCR4 on Rac1 inhibition blocked receptor internalization and impaired CXCL12-induced Galpha(i) protein activation. Importantly, we found that the conformation adopted by CXCR4 after Rac1 inhibition prevents HIV-1 infection of both the U87-CD4-CXCR4 cell line and of primary peripheral blood mononuclear cells. In conclusion, our data show that Rac1 activity is required to maintain CXCR4 in the responsive conformation that allows receptor signaling and facilitates HIV-1 infection; this implies that Rac1 positively regulates CXCR4 function and identifies the Rac1-CXCR4 axis as a new target for preventing HIV-1 infection. PMID- 22238324 TI - IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors. AB - While most blood lineages are assumed to mature through a single cellular and developmental route downstream of HSCs, dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors differentiate into common DC progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that IFN regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8(-/-) BM demonstrated cell-intrinsic defects in the formation of CDPs and all splenic DC subsets. Irf8(-/-) common myeloid progenitors and, unexpectedly, Irf8(-/-) ALPs produced more neutrophils in vivo than their wild-type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context. PMID- 22238326 TI - Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma is the most frequent type of B-cell lymphoma in adult patients but also occurs in children. Patients are currently assigned to therapy regimens based on arbitrarily chosen age limits only (eg, 18 or 60 years) and not biologically justified limits. A total of 364 diffuse large B-cell lymphomas and related mature aggressive B-cell lymphomas other than Burkitt lymphoma from all age groups were analyzed by comprehensive molecular profiling. The probability of several biologic features previously reported to be associated with poor prognosis in diffuse large B-cell lymphoma, such as ABC subtype, BCL2 expression, or cytogenetic complexity, increases with age at diagnosis. Similarly, various genetic features, such as IRF4 translocations, gains in 1q21, 18q21, 7p22, and 7q21, as well as changes in 3q27, including gains and translocations affecting the BCL6 locus, are significantly associated with patient age, but no cut-offs between age groups could be defined. If age was incorporated in multivariate analyses, genetic complexity lost its prognostic significance, whereas the prognostic impact of ABC subtype and age were additive. Our data indicate that aging is a major determinant of lymphoma biology. They challenge current concepts regarding both prognostic biomarkers and treatment stratification based on strict age cut-offs. PMID- 22238327 TI - Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. AB - Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia cases and in 1 child with systemic mastocytosis with MDS. In 1 juvenile myelomonocytic leukemia patient, the SRSF2 mutation that initially coexisted with an oncogenic NRAS mutation was absent at relapse, whereas the NRAS mutation persisted and a second, concomitant NRAS mutation later emerged. The patient with systemic mastocytosis and MDS carried both mutated U2AF35 and KIT in a single clone as confirmed by clonal sequencing. In the adult MDS patients sequenced for control purposes, we detected previously reported mutations in 7/30 and a novel SRSF2 deletion (c.284_307del) in 3 of 30 patients. These findings implicate that spliceosome mutations are rare in pediatric MDS and juvenile myelomonocytic leukemia and are unlikely to operate as driver mutations. PMID- 22238328 TI - Molecular imaging of inflammation for detection of vulnerable atheromatous plaques. PMID- 22238329 TI - On cars, TVs, and other alibis to globalize sedentarism. PMID- 22238330 TI - Physical activity levels, ownership of goods promoting sedentary behaviour and risk of myocardial infarction: results of the INTERHEART study. AB - AIMS: To evaluate the association between occupational and leisure-time physical activity (PA), ownership of goods promoting sedentary behaviour, and the risk of myocardial infarction (MI) in different socio-economic populations of the world. Studies in developed countries have found low PA as a risk factor for cardiovascular disease; however, the protective effect of occupational PA is less certain. Moreover, ownership of goods promoting sedentary behaviour may be associated with an increased risk. METHODS: In INTERHEART, a case-control study of 10 043 cases of first MI and 14 217 controls who did not report previous angina or physical disability completed a questionnaire on work and leisure-time PA. RESULTS: Subjects whose occupation involved either light [multivariable adjusted odds ratio (OR) 0.78, confidence interval (CI) 0.71-0.86] or moderate (OR 0.89, CI 0.80-0.99) PA were at a lower risk of MI, whereas those who did heavy physical labour were not (OR 1.02, CI 0.88-1.19), compared with sedentary subjects. Mild exercise (OR 0.87, CI 0.81-0.93) as well as moderate or strenuous exercise (OR 0.76, CI 0.69-0.82) was protective. The effect of PA was observed across countries with low, middle, and high income. Subjects who owned both a car and a television (TV) (multivariable-adjusted OR 1.27, CI 1.05-1.54) were at higher risk of MI compared with those who owned neither. CONCLUSION: Leisure-time PA and mild-to-moderate occupational PA, but not heavy physical labour, were associated with a reduced risk, while ownership of a car and TV was associated with an increased risk of MI across all economic regions. PMID- 22238331 TI - Magnetic resonance metabolic imaging of glioma. AB - 2-Hydroxyglutarate (2-HG) is a potential oncometabolite involved in gliomagenesis that has been identified as an aberrant product of isocitrate dehydrogenase (IDH) mutated glial tumors. Recent genomics studies have shown that heterozygous mutation of IDH genes 1 and 2, present in up to 86% of grade II gliomas, is associated with a favorable outcome. Two reports in this issue describe both ex vivo and in vivo methods that could noninvasively detect the presence of 2-HG in glioma patients. This approach could have valuable implications for diagnosis, prognosis, and stratification of brain tumors, as well as for monitoring of treatment in glioma patients. PMID- 22238332 TI - Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. AB - Mutations in the gene isocitrate dehydrogenase 1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. Arginine 132 (R132) mutations in the enzyme IDH1 result in excess production of the metabolite 2 hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized in vivo spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG noninvasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG was also detected using 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting mutated IDH1. PMID- 22238333 TI - Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas. AB - Recent studies have indicated that a significant survival advantage is conferred to patients with gliomas whose lesions harbor mutations in the genes isocitrate dehydrogenase 1 and 2 (IDH1/2). IDH1/2 mutations result in aberrant enzymatic production of the potential oncometabolite D-2-hydroxyglutarate (2HG). Here, we report on the ex vivo detection of 2HG in IDH1-mutated tissue samples from patients with recurrent low-grade gliomas using the nuclear magnetic resonance technique of proton high-resolution magic angle spinning spectroscopy. Relative 2HG levels from pathologically confirmed mutant IDH1 tissues correlated with levels of other ex vivo metabolites and histopathology parameters associated with increases in mitotic activity, relative tumor content, and cellularity. Ex vivo spectroscopic measurements of choline-containing species and in vivo magnetic resonance measurements of diffusion parameters were also correlated with 2HG levels. These data provide extensive characterization of mutant IDH1 lesions while confirming the potential diagnostic value of 2HG as a surrogate marker of patient survival. Such information may augment the ability of clinicians to monitor therapeutic response and provide criteria for stratifying patients to specific treatment regimens. PMID- 22238338 TI - International Committee on Systematics of Prokaryotes. Subcommittee on the taxonomy of Pasteurellaceae: minutes of the meetings, 25 August 2011, Elsinore, Denmark. PMID- 22238334 TI - Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens. AB - Excessive consumption of alcohol is among the leading causes of preventable death worldwide. Although ethanol modulates a variety of molecular targets, including several neurotransmitter receptors, the neural mechanisms that underlie its rewarding actions and lead to excessive consumption are unknown. Studies in animals suggest that release of endogenous opioids by ethanol promotes further consumption. To examine this issue in humans and to determine where in the brain endogenous opioids act to promote alcohol consumption, we measured displacement of a radiolabeled MU opioid receptor agonist, [11C]carfentanil, before and immediately after alcohol consumption in both heavy drinkers and control subjects. Drinking alcohol induced opioid release in the nucleus accumbens and orbitofrontal cortex, areas of the brain implicated in reward valuation. Opioid release in the orbitofrontal cortex and nucleus accumbens was significantly positively correlated. Furthermore, changes in orbitofrontal cortex binding correlated significantly with problem alcohol use and subjective high in heavy drinkers, suggesting that differences in endogenous opioid function in these regions contribute to excessive alcohol consumption. These results also suggest a possible mechanism by which opioid antagonists such as naltrexone act to treat alcohol abuse. PMID- 22238339 TI - A two-year observational study assessing the safety of DepoFoam bupivacaine after augmentation mammaplasty. AB - BACKGROUND: Two-year safety outcomes in patients who received DepoFoam bupivacaine during two prior breast augmentation studies were evaluated. OBJECTIVES: The authors assess the clinical sequelae observed during follow-up examination with respect to the integrity of the breast implants. METHODS: In Study 1, patients received bupivacaine HCl (75 mg) in one breast pocket and DepoFoam bupivacaine (133 or 266 mg) in the other. In Study 2, patients received either bupivacaine HCl (200 mg) or DepoFoam bupivacaine (532 mg), divided equally into each breast pocket. Investigators and patients remained blinded to the treatment administered. Patients completed a questionnaire regarding breast pain, tenderness, tingling, numbness, burning, changes in sensation, and any relevant life events potentially affecting the implants. Patients were also assessed for postoperative healing and implant integrity. RESULTS: Ninety-four women were evaluated. Most patients in all groups had no change in breast size or shape and no changes in the skin or nipple. There were no reports of palpable hard knots or swelling. There was one report of irritation/implant leakage (in a patient who received bupivacaine HCl [75 mg] in the relevant breast). Most patients reported no breast pain, tenderness, tingling, numbness, burning, other changes in sensation, chest wall surgery or trauma, or life events affecting the implant. CONCLUSIONS: At a two-year follow-up assessment, DepoFoam bupivacaine was not associated with any complications that would compromise the integrity of the breast implants. There was no indication of an association between DepoFoam bupivacaine or bupivacaine HCl and changes in sensation or other abnormal findings in these patients. LEVEL OF EVIDENCE: 2. PMID- 22238340 TI - Look back and talk openly: responding to and communicating about the risk of large-scale error in pathology diagnoses. AB - QUALITY PROBLEM OR ISSUE: In 2005 we were informed about the possibility of a systemic error in pathology diagnoses of ~7400 histological tests done between 4 and 6 years earlier. INITIAL ASSESSMENT: We determined to undertake a lookback and apply principles of open disclosure to inform the affected community of ~200,000 people. CHOICE OF SOLUTION: The lookback included subjecting all cases to independent pathology review. The public announcement of the review included an unreserved apology and took place before the results of the re-examination of the pathology specimens were known. IMPLEMENTATION: The lookback involved the simultaneous implementation of five critical elements: leadership and governance, risk assessment and planning, implementation of the independent review, procedures for patient care and communication and open disclosure. Protocols were developed to care for those patients whose original test results were found to be incorrect. EVALUATION: The original result for >200 patients was incorrect, and 38 had experienced clinical consequences. There was no public panic as a result of the wide open disclosure. Few related legal claims or complaints were made. The impact of the pathology diagnostic error has continued to 2011 for some patients. LESSONS LEARNED: Openly disclosing a risk of widespread error meant the community could be supported with information and medical management as needed. Credentialing and peer-review processes for senior staff must be precise and collegiate. Sometimes action has to take place even when the risk is ill defined. There are five critical elements in planning and implementing a large-scale lookback. PMID- 22238341 TI - New tricks of an old pattern: structural versatility of scorpion toxins with common cysteine spacing. AB - Scorpion venoms are a rich source of K(+) channel-blocking peptides. For the most part, they are structurally related small disulfide-rich proteins containing a conserved pattern of six cysteines that is assumed to dictate their common three dimensional folding. In the conventional pattern, two disulfide bridges connect an alpha-helical segment to the C-terminal strand of a double- or triple-stranded beta-sheet, conforming a cystine-stabilized alpha/beta scaffold (CSalpha/beta). Here we show that two K(+) channel-blocking peptides from Tityus scorpions conserve the cysteine spacing of common scorpion venom peptides but display an unconventional disulfide pattern, accompanied by a complete rearrangement of the secondary structure topology into a CS helix-loop-helix fold. Sequence and structural comparisons of the peptides adopting this novel fold suggest that it would be a new elaboration of the widespread CSalpha/beta scaffold, thus revealing an unexpected structural versatility of these small disulfide-rich proteins. Acknowledgment of such versatility is important to understand how venom structural complexity emerged on a limited number of molecular scaffolds. PMID- 22238342 TI - Identification of residues that underpin interactions within the eukaryotic initiation factor (eIF2) 2B complex. AB - Eukaryotic initiation factor 2B (eIF2B) plays a key role in protein synthesis and in its control. It comprises five different subunits, alpha-epsilon, of which eIF2Bepsilon contains the catalytic domain. Formation of the complete complex is crucial for full activity and proper control of eIF2B. Mutations in the genes for eIF2B cause an often severe neurological disorder, "vanishing white matter." eIF2Bgamma and eIF2Bepsilon contain homologous and conserved domains with sequence similarity to nucleotidyl transferases (NTs) and acyl transferases and can form a binary complex. The latter contain a hexad repeat that mainly comprises isoleucyl residues (hence termed the "I-patch" region). These data reveal that certain residues in the NT domains of eIF2Bgamma/epsilon, which are highly conserved throughout eukaryotes, play key roles in the interactions between subunits in the eIF2B complex. Our data show that the I-patch regions are important in the interactions between the catalytic eIF2Bgammaepsilon complex and the other subunits. We also studied the functional effects of vanishing white matter mutations in the NT and I-patch domains. Lastly, our data show that eIF2Bgamma promotes the expression of eIF2Bepsilon, providing a mechanism for achieving correct stoichiometry of these eIF2B subunits in the cell. PMID- 22238343 TI - Identification of intersubunit domain interactions within eukaryotic initiation factor (eIF) 2B, the nucleotide exchange factor for translation initiation. AB - In eukaryotic translation initiation, eIF2B is the guanine nucleotide exchange factor (GEF) required for reactivation of the G protein eIF2 between rounds of protein synthesis initiation. eIF2B is unusually complex with five subunits (alpha-epsilon) necessary for GEF activity and its control by phosphorylation of eIF2alpha. In addition, inherited mutations in eIF2B cause a fatal leukoencephalopathy. Here we describe experiments examining domains of eIF2Bgamma and epsilon that both share sequence and predicted tertiary structure similarity with a family of phospho-hexose sugar nucleotide pyrophosphorylases. Firstly, using a genetic approach, we find no evidence to support a significant role for a potential nucleotide-binding region within the pyrophosphorylase-like domain (PLD) of eIF2Bepsilon for nucleotide exchange. These findings are at odds with one mechanism for nucleotide exchange proposed previously. By using a series of constructs and a co-expression and precipitation strategy, we find that the eIF2Bepsilon and -gamma PLDs and a shared second domain predicted to form a left handed beta helix are all critical for interprotein interactions between eIF2B subunits necessary for eIF2B complex formation. We have identified extensive interactions between the PLDs and left-handed beta helix domains that form the eIF2Bgammaepsilon subcomplex and propose a model for domain interactions between eIF2B subunits. PMID- 22238344 TI - Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport. AB - The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (DeltaN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. DeltaN-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and DeltaN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD. PMID- 22238345 TI - Net proton uptake is preceded by multiple proton transfer steps upon electron injection into cytochrome c oxidase. AB - Cytochrome c oxidase (COX), the last enzyme of the respiratory chain of aerobic organisms, catalyzes the reduction of molecular oxygen to water. It is a redox linked proton pump, whose mechanism of proton pumping has been controversially discussed, and the coupling of proton and electron transfer is still not understood. Here, we investigated the kinetics of proton transfer reactions following the injection of a single electron into the fully oxidized enzyme and its transfer to the hemes using time-resolved absorption spectroscopy and pH indicator dyes. By comparison of proton uptake and release kinetics observed for solubilized COX and COX-containing liposomes, we conclude that the 1-MUs electron injection into Cu(A), close to the positive membrane side (P-side) of the enzyme, already results in proton uptake from both the P-side and the N (negative)-side (1.5 H(+)/COX and 1 H(+)/COX, respectively). The subsequent 10-MUs transfer of the electron to heme a is accompanied by the release of 1 proton from the P-side to the aqueous bulk phase, leaving ~0.5 H(+)/COX at this side to electrostatically compensate the charge of the electron. With ~200 MUs, all but 0.4 H(+) at the N-side are released to the bulk phase, and the remaining proton is transferred toward the hemes to a so-called "pump site." Thus, this proton may already be taken up by the enzyme as early as during the first electron transfer to Cu(A). These results support the idea of a proton-collecting antenna, switched on by electron injection. PMID- 22238346 TI - Adenine aminohydrolase from Leishmania donovani: unique enzyme in parasite purine metabolism. AB - Adenine aminohydrolase (AAH) is an enzyme that is not present in mammalian cells and is found exclusively in Leishmania among the protozoan parasites that infect humans. AAH plays a paramount role in purine metabolism in this genus by steering 6-aminopurines into 6-oxypurines. Leishmania donovani AAH is 38 and 23% identical to Saccharomyces cerevisiae AAH and human adenosine deaminase enzymes, respectively, catalyzes adenine deamination to hypoxanthine with an apparent K(m) of 15.4 MUM, and does not recognize adenosine as a substrate. Western blot analysis established that AAH is expressed in both life cycle stages of L. donovani, whereas subcellular fractionation and immunofluorescence studies confirmed that AAH is localized to the parasite cytosol. Deletion of the AAH locus in intact parasites established that AAH is not an essential gene and that Deltaaah cells are capable of salvaging the same range of purine nucleobases and nucleosides as wild type L. donovani. The Deltaaah null mutant was able to infect murine macrophages in vitro and in mice, although the parasite loads in both model systems were modestly reduced compared with wild type infections. The Deltaaah lesion was also introduced into a conditionally lethal Deltahgprt/Deltaxprt mutant in which viability was dependent on pharmacologic ablation of AAH by 2'-deoxycoformycin. The Deltaaah/Deltahgprt/Deltaxprt triple knock-out no longer required 2'-deoxycoformycin for growth and was avirulent in mice with no persistence after a 4-week infection. These genetic studies underscore the paramount importance of AAH to purine salvage by L. donovani. PMID- 22238347 TI - Substrate specificities and intracellular distributions of three N-glycan processing enzymes functioning at a key branch point in the insect N glycosylation pathway. AB - Man(alpha1-6)[GlcNAc(beta1-2)Man(alpha1-3)]ManGlcNAc(2) is a key branch point intermediate in the insect N-glycosylation pathway because it can be either trimmed by a processing beta-N-acetylglucosaminidase (FDL) to produce paucimannosidic N-glycans or elongated by N-acetylglucosaminyltransferase II (GNT II) to produce complex N-glycans. N-acetylglucosaminyltransferase I (GNT-I) contributes to branch point intermediate production and can potentially reverse the FDL trimming reaction. However, there has been no concerted effort to evaluate the relationships among these three enzymes in any single insect system. Hence, we extended our previous studies on Spodoptera frugiperda (Sf) FDL to include GNT-I and -II. Sf-GNT-I and -II cDNAs were isolated, the predicted protein sequences were analyzed, and both gene products were expressed and their acceptor substrate specificities and intracellular localizations were determined. Sf-GNT-I transferred N-acetylglucosamine to Man(5)GlcNAc(2), Man(3)GlcNAc(2), and GlcNAc(beta1-2)Man(alpha1-6)[Man(alpha1-3)]ManGlcNAc(2), demonstrating its role in branch point intermediate production and its ability to reverse FDL trimming. Sf-GNT-II only transferred N-acetylglucosamine to Man(alpha1-6)[GlcNAc(beta1 2)Man(alpha1-3)]ManGlcNAc(2), demonstrating that it initiates complex N-glycan production, but cannot use Man(3)GlcNAc(2) to produce hybrid or complex structures. Fluorescently tagged Sf-GNT-I and -II co-localized with an endogenous Sf Golgi marker and Sf-FDL co-localized with Sf-GNT-I and -II, indicating that all three enzymes are Golgi resident proteins. Unexpectedly, fluorescently tagged Drosophila melanogaster FDL also co-localized with Sf-GNT-I and an endogenous Drosophila Golgi marker, indicating that it is a Golgi resident enzyme in insect cells. Thus, the substrate specificities and physical juxtapositioning of GNT-I, GNT-II, and FDL support the idea that these enzymes function at the N-glycan processing branch point and are major factors determining the net outcome of the insect cell N-glycosylation pathway. PMID- 22238350 TI - Echocardiographic epicardial adipose tissue predicts subclinical atherosclerosis: epicardial adipose tissue and atherosclerosis. AB - We examined the relationship between coronary flow rate and epicardial adipose tissue (EAT) in patients with slow coronary flow (SCF) and normal coronary arteries. The study included 40 consecutive patients with stable angina pectoris who had normal coronary arteries. All patients underwent echocardiography. To determine the SCF, thrombolysis in myocardial infarction (TIMI) frame count method was used. Half of the patients had SCF at least in 1 coronary artery. Thrombolysis in myocardial infarction frame counts, the mean TIMI frame count, and EAT thickness were significantly higher in patients with SCF. Slow coronary flow showed a significantly positive correlation with EAT thickness. Epicardial adipose tissue thickness was the only independent predictor of SCF. Our findings suggest that there is a significant correlation between the SCF and EAT. Therefore, echocardiographic EAT may become a predictor of subclinical atherosclerosis in patients with stable angina pectoris. PMID- 22238348 TI - Neutralization of macrophage migration inhibitory factor (MIF) by fully human antibodies correlates with their specificity for the beta-sheet structure of MIF. AB - The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a beta-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this beta-sheet structure is a crucial region for MIF activity and a promising target for anti MIF antibody therapy. PMID- 22238351 TI - Ankle-brachial index and coronary artery lesion complexity in patients with acute coronary syndromes. AB - We investigated the relationship between peripheral artery disease (PAD) and coronary artery disease (CAD) complexity in patients with acute coronary syndromes (ACS). Consecutive patients with first time diagnosis of ACS (n = 150) were enrolled. SYNTAX score (SS), a marker of CAD complexity, was assessed by dedicated computer software and diagnosis of PAD was established by ankle brachial index (ABI) value. SYNTAX score was higher in patients with overt and borderline PAD (ABI <= 0.99) than normal participants (ABI 1-1.29; 16.7 +/- 8.2 vs 10.1 +/- 5.5; P < .001). In addition, there was a strong negative correlation between ABI and SS (r = -.46; P < .001).We have demonstrated increased CAD complexity in patients with ACS and PAD and strong correlation between degree of PAD and coronary lesion complexity. PMID- 22238352 TI - Clinical outcome after saphenous vein stenting with Taxus Liberte stent: results from the OLYMPIA Registry (TAXUS Liberte Postapproval Global Program). AB - We evaluated the incidence of clinical events after implantation of the TAXUS Liberte paclitaxel-eluting stent in saphenous vein graft (SVG) lesions in an unselected patient population. The OLYMPIA (TAXUS Liberte Post-Approval Global Registry) program gathered data on 21 954 patients receiving at least 1 TAXUS Liberte stent, including 345 patients with SVG lesions. All cardiac events were monitored with independent adjudication of end points. Patients enrolled at procedure started with no mandated inclusion/exclusion criteria. In SVG-OLYMPIA (n = 345), baseline comorbidities/complex disease were more frequent than the rest of the OLYMPIA (n = 21 560). SVG-OLYMPIA had similar cardiac death, target vessel revascularization, and definitive stent thrombosis rates than the rest of OLYMPIA. Despite higher baseline risk, the SVG-OLYMPIA had similar 12-month clinical outcome than the rest of the OLYMPIA registry, confirming the safety and efficacy of the TAXUS Liberte stent in this high-risk group. PMID- 22238349 TI - Studies of the pattern recognition molecule H-ficolin: specificity and purification. AB - Ficolins are pattern recognition molecules of the innate immune system. H-ficolin is found in plasma associated with mannan-binding lectin-associated serine proteases (MASPs). When H-ficolin binds to microorganisms the MASPs are activated, which in turn activate the complement system. H-ficolin is the most abundant ficolin in humans, yet its ligand binding characteristics and biological role remain obscure. We examined the binding of H-ficolin to Aerococcus viridans as well as to a more defined artificial target, i.e. acetylated bovine serum albumin. A strict dependence for calcium ions and inhibition at high NaCl concentration was found. The binding to acetylated bovine serum albumin was inhibited by acetylsalicylic acid and sodium acetate as well as by N-acetylated glucosamine and galactosamine (GlcNAc and GalNAc) and glycine (GlyNAc). The binding to A. viridans was sensitive to the same compounds, but, importantly, higher concentrations were needed for inhibition. N-Acetylated cysteine was also inhibitory, but this inhibition was parallel with reduction in the oligomerization of H-ficolin and thus represents structural changes of the molecule. Based on our findings, we developed a procedure for the purification of H-ficolin from serum, involving PEG precipitation, affinity chromatography on Sepharose derivatized with acetylated serum albumin, ion exchange chromatography, and gel permeation chromatography. The purified H-ficolin was observed to elute at 700 kDa, similar to what we find for H-ficolin in whole serum. MASP-2 was co purified with H-ficolin, and the purified H-ficolin.MASP-2 complex could activate complement as measured by cleavage of complement factor C4. This study extends our knowledge of the specificity of this pattern recognition molecule, and the purified product will enable further studies. PMID- 22238353 TI - Atherosclerotic risk factors and premature atherosclerosis in acromegaly before and after 48 months of octreotide-LAR treatment. AB - We studied premature atherosclerosis with carotid Doppler ultrasonography in active acromegaly before and after treatment. Patients (n = 27) with active acromegaly and 12 age-, gender-, and body mass index-matched healthy individuals were included in the study. Carotid intima-media thickness was decreased significantly in the inactive group after treatment (median: 0.6 mm, interquartile range [IQR]: 0.55-0.80]) when compared with the active group (median: 0.9 mm [IQR: 0.75-1.15], P < .0001), but there was no significant difference between the inactive and control groups. There was a correlation between homeostasis model of assessment-insulin resistance (P = .01, r = .41) and growth hormone (GH; P < .0001, r = .46). In conclusion, premature atherosclerosis was demonstrated in active acromegaly patients probably as a consequence of insulin resistance and direct vascular effects of GH and/or insulin-like growth factor 1. PMID- 22238354 TI - Bromenshenk et al (PLoS One, 2011, 5(10):e13181) have claimed to have found peptides from an invertebrate iridovirus in bees. PMID- 22238355 TI - Cavernous sinus dural fistula 'mimicking' SUNCT. PMID- 22238356 TI - Aquaporin-4 antibodies are not present in patients with idiopathic intracranial hypertension. AB - OBJECTIVES: We aimed to investigate anti-aquaporin-4 (AQP-4) water channel antibodies, affecting cerebrospinal fluid (CSF) secretion and absorption, in idiopathic intracranial hypertension (IIH) patients. METHODS: Patients fulfilling the modified Dandy's diagnostic criteria for IIH were included and their clinical features and CSF findings were reviewed. Their serum samples and control groups were investigated by immunofluorescence and a cell-based assay for anti-AQP-4 antibodies and by immunohistochemistry for IgG binding patterns. RESULTS: Twenty nine patients diagnosed with IIH were investigated. We could not detect any anti AQP-4 antibodies in our series. However, we identified different serum IgG binding patterns in 11 IIH patients. CONCLUSION: There is only one report investigating the anti-AQP4 antibodies in IIH. Our study with a larger sample confirmed the results of this report and indicated that AQP4 antibodies did not have a primary role in IIH pathogenesis, but provided some support for the contribution of inflammatory mechanisms in IIH. PMID- 22238357 TI - Coexistence of hemiplegic migraine with SUNCT or SUNA: a case series. AB - BACKGROUND: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that includes transient hemiparesis of different degrees. The dominantly inherited type, called familial hemiplegic migraine, along with the sporadic type, in which no family history of similar attacks exists, have been recently recognized by the revised International Classification of Headache Disorders (ICHD-2). Short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are also very rare conditions that are classified as trigeminal autonomic cephalalgias. This report provides the first description of an association between HM and SUNCT/SUNA. CASES: Eight females and two males with both these disorders were identified between 2007 and 2010. CONCLUSION: The coexistence of such rare primary headache disorders is probably due to a common underlining mechanism, with a sodium channelopathy being an attractive potential candidate. PMID- 22238358 TI - Fer kinase regulates cell migration through alpha-dystroglycan glycosylation. AB - Glycans of alpha-dystroglycan (alpha-DG), which is expressed at the epithelial cell-basement membrane (BM) interface, play an essential role in epithelium development and tissue organization. Laminin-binding glycans on alpha-DG expressed on cancer cells suppress tumor progression by attenuating tumor cell migration from the BM. However, mechanisms controlling laminin-binding glycan expression are not known. Here, we used small interfering RNA (siRNA) library screening and identified Fer kinase, a non-receptor-type tyrosine kinase, as a key regulator of laminin-binding glycan expression. Fer overexpression decreased laminin-binding glycan expression, whereas siRNA-mediated down-regulation of Fer kinase increased glycan expression on breast and prostate cancer cell lines. Loss of Fer kinase function via siRNA or mutagenesis increased transcription levels of glycosyltransferases, including protein O-mannosyltransferase 1, beta3-N acetylglucosaminyltransferase 1, and like-acetylglucosaminyltransferase that are required to synthesize laminin-binding glycans. Consistently, inhibition of Fer expression decreased cell migration in the presence of laminin fragment. Fer kinase regulated STAT3 phosphorylation and consequent activation, whereas knockdown of STAT3 increased laminin-binding glycan expression on cancer cells. These results indicate that the Fer pathway negatively controls expression of genes required to synthesize laminin-binding glycans, thus impairing BM attachment and increasing tumor cell migration. PMID- 22238359 TI - Cell-free reconstitution of vacuole membrane fragmentation reveals regulation of vacuole size and number by TORC1. AB - Size and copy number of organelles are influenced by an equilibrium of membrane fusion and fission. We studied this equilibrium on vacuoles-the lysosomes of yeast. Vacuole fusion can readily be reconstituted and quantified in vitro, but it had not been possible to study fission of the organelle in a similar way. Here we present a cell-free system that reconstitutes fragmentation of purified yeast vacuoles (lysosomes) into smaller vesicles. Fragmentation in vitro reproduces physiological aspects. It requires the dynamin-like GTPase Vps1p, V-ATPase pump activity, cytosolic proteins, and ATP and GTP hydrolysis. We used the in vitro system to show that the vacuole-associated TOR complex 1 (TORC1) stimulates vacuole fragmentation but not the opposing reaction of vacuole fusion. Under nutrient restriction, TORC1 is inactivated, and the continuing fusion activity then dominates the fusion/fission equilibrium, decreasing the copy number and increasing the volume of the vacuolar compartment. This result can explain why nutrient restriction not only induces autophagy and a massive buildup of vacuolar/lysosomal hydrolases, but also leads to a concomitant increase in volume of the vacuolar compartment by coalescence of the organelles into a single large compartment. PMID- 22238360 TI - Dissection of the NUP107 nuclear pore subcomplex reveals a novel interaction with spindle assembly checkpoint protein MAD1 in Caenorhabditis elegans. AB - Nuclear pore complexes consist of several subcomplexes. The NUP107 complex is important for nucleocytoplasmic transport, nuclear envelope assembly, and kinetochore function. However, the underlying molecular mechanisms and the roles of individual complex members remain elusive. We report the first description of a genetic disruption of NUP107 in a metazoan. Caenorhabditis elegans NUP107/npp-5 mutants display temperature-dependent lethality. Surprisingly, NPP-5 is dispensable for incorporation of most nucleoporins into nuclear pores and for nuclear protein import. In contrast, NPP-5 is essential for proper kinetochore localization of NUP133/NPP-15, another NUP107 complex member, whereas recruitment of NUP96/NPP-10C and ELYS/MEL-28 is NPP-5 independent. We found that kinetochore protein NUF2/HIM-10 and Aurora B/AIR-2 kinase are less abundant on mitotic chromatin upon NPP-5 depletion. npp-5 mutants are hypersensitive to anoxia, suggesting that the spindle assembly checkpoint (SAC) is compromised. Indeed, NPP 5 interacts genetically and physically with SAC protein MAD1/MDF-1, whose nuclear envelope accumulation requires NPP-5. Thus our results strengthen the emerging connection between nuclear pore proteins and chromosome segregation. PMID- 22238361 TI - Matrix rigidity regulates a switch between TGF-beta1-induced apoptosis and epithelial-mesenchymal transition. AB - The transforming growth factor-beta (TGF-beta) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF beta acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-beta switches to promote tumorigenic cell functions, such as epithelial-mesenchymal transition (EMT) and increased cell motility. Dramatic changes in the cellular microenvironment are also correlated with tumor progression, including an increase in tissue stiffness. However, it is unknown whether these changes in tissue stiffness can regulate the effects of TGF-beta. To this end, we examined normal murine mammary gland cells and Madin-Darby canine kidney epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-beta1. Varying matrix rigidity switched the functional response to TGF-beta1. Decreasing rigidity increased TGF-beta1-induced apoptosis, whereas increasing rigidity resulted in EMT. Matrix rigidity did not change Smad signaling, but instead regulated the PI3K/Akt signaling pathway. Direct genetic and pharmacologic manipulations further demonstrated a role for PI3K/Akt signaling in the apoptotic and EMT responses. These findings demonstrate that matrix rigidity regulates a previously undescribed switch in TGF-beta-induced cell functions and provide insight into how changes in tissue mechanics during disease might contribute to the cellular response to TGF-beta. PMID- 22238362 TI - Desmoplakin controls microvilli length but not cell adhesion or keratin organization in the intestinal epithelium. AB - Maintaining proper cell-cell adhesion in the intestine is essential for tissue homeostasis and barrier function. This adhesion is thought to be mediated by cell adhesion structures, including tight junctions, adherens junctions, and desmosomes, which concentrate in the apical junctional region. While clear roles for adherens and tight junctions have been established in simple epithelia, the function of desmosomes has not been addressed. In stratified epithelia, desmosomes impart mechanical strength to tissues by organizing and anchoring the keratin filament network. In this paper, we report that the desmosomal protein desmoplakin (DP) is not essential for cell adhesion in the intestinal epithelium. Surprisingly, when DP is lacking, keratin filament localization is also unperturbed, although keratin filaments no longer anchor at desmosomes. Unexpectedly, DP is important for proper microvillus structure. Our study highlights the tissue-specific functions of desmosomes and reveals that the canonical functions for these structures are not conserved in simple epithelium. PMID- 22238363 TI - Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content. AB - Caveolin-1 is an integral membrane protein of plasma membrane caveolae. Here we report that caveolin-1 collects at the cytosolic surface of lysosomal membranes when cells are serum starved. This is due to an elevation of the intralysosomal pH, since ionophores and proton pump inhibitors that dissipate the lysosomal pH gradient also trapped caveolin-1 on late endosome/lysosomes. Accumulation is both saturable and reversible. At least a portion of the caveolin-1 goes to the plasma membrane upon reversal. Several studies suggest that caveolin-1 is involved in cholesterol transport within the cell. Strikingly, we find that blocking cholesterol export from lysosomes with progesterone or U18666A or treating cells with low concentrations of cyclodextrin also caused caveolin-1 to accumulate on late endosome/lysosomal membranes. Under these conditions, however, live-cell imaging shows cavicles actively docking with lysosomes, suggesting that these structures might be involved in delivering caveolin-1. Targeting of caveolin-1 to late endosome/lysosomes is not observed normally, and the degradation rate of caveolin-1 is not altered by any of these conditions, indicating that caveolin-1 accumulation is not a consequence of blocked degradation. We conclude that caveolin-1 normally traffics to and from the cytoplasmic surface of lysosomes during intracellular cholesterol trafficking. PMID- 22238364 TI - Derlin-1 and UBXD8 are engaged in dislocation and degradation of lipidated ApoB 100 at lipid droplets. AB - Apolipoprotein B-100 (ApoB) is the principal component of very low density lipoprotein. Poorly lipidated nascent ApoB is extracted from the Sec61 translocon and degraded by proteasomes. ApoB lipidated in the endoplasmic reticulum (ER) lumen is also subjected to proteasomal degradation, but where and how it dislocates to the cytoplasm remain unknown. In the present study, we demonstrate that ApoB after lipidation is dislocated to the cytoplasmic surface of lipid droplets (LDs) and accumulates as ubiquitinated ApoB in Huh7 cells. Depletion of UBXD8, which is almost confined to LDs in this cell type, decreases recruitment of p97 to LDs and causes an increase of both ubiquitinated ApoB on the LD surface and lipidated ApoB in the ER lumen. In contrast, abrogation of Derlin-1 function induces an accumulation of lipidated ApoB in the ER lumen but does not increase ubiquitinated ApoB on the LD surface. UBXD8 and Derlin-1 bind with each other and with lipidated ApoB and show colocalization around LDs. These results indicate that ApoB after lipidation is dislocated from the ER lumen to the LD surface for proteasomal degradation and that Derlin-1 and UBXD8 are engaged in the predislocation and postdislocation steps, respectively. PMID- 22238365 TI - (212)Pb-radioimmunotherapy induces G(2) cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease. AB - In preclinical studies, targeted radioimmunotherapy using (212)Pb-TCMC trastuzumab as an in vivo generator of the high-energy alpha-particle emitting radionuclide (212)Bi is proving an efficacious modality for the treatment of disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T intraperitoneal xenografts were treated with (212)Pb-TCMC-trastuzumab and compared with the nonspecific control (212)Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. (212)Pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double-strand breaks (DSB) at 24 hours. Rad51 protein expression was downregulated, indicating delayed DNA double-strand damage repair compared with (212)Pb-TCMC-HuIgG, the nonspecific control. (212)Pb-TCMC-trastuzumab treatment also caused G(2)-M arrest, depression of the S phase fraction, and depressed DNA synthesis that persisted beyond 120 hours. In contrast, the effects produced by (212)Pb-TCMC-HuIgG seemed to rebound by 120 hours. In addition, (212)Pb-TCMC trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 hours, suggesting a correlation between induction of p21 protein and modification in chromatin structure of p21 in response to (212)Pb-TCMC trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G(2)-M arrest, and chromatin remodeling were associated with (212)Pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T intraperitoneal xenograft model for disseminated intraperitoneal disease. PMID- 22238366 TI - Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. AB - Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR mediated signaling and viability with IC(50) values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC(50) values <40 nmol/L and inhibited cell growth with GI(50) (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC(50) values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR driven cancers. PMID- 22238367 TI - DLK1 as a potential target against cancer stem/progenitor cells of hepatocellular carcinoma. AB - Delta-like 1 homolog (DLK1; Drosophila) is a hepatic stem/progenitor cell marker in fetal livers that plays a vital role in oncogenesis of hepatocellular carcinoma (HCC). The aim of this study is to investigate whether DLK1 could serve as a potential therapeutic target against cancer stem/progenitor cells of HCC. DLK1(+) and DLK1(-) cells were sorted by fluorescence-activated cell sorting and magnetic-activated cell sorting, respectively, and then were evaluated by flow cytometry. The biological behaviors of these isolated cells and those with DLK1 knockdown were assessed by growth curve, colony formation assay, spheroid colony formation, chemoresistance, and in vivo tumorigenicity. Adenovirus-mediated RNA interference was used to knockdown the endogenous DLK1. We found that DLK1(+) population was less than 10% in almost all 17 HCC cell lines examined. DLK1(+) HCC cells showed stronger ability of chemoresistance, colony formation, spheroid colony formation, and in vivo tumorigenicity compared with DLK1(-) cells. The DLK1(+) HCC cells could generate the progeny without DLK1 expression. Furthermore, DLK1 knockdown could suppress the ability of proliferation, colony formation, spheroid colony formation, and in vivo tumorigenicity of Hep3B and Huh 7 HCC cells. Our data suggested that DLK1(+) HCC cells have characteristics similar to those of cancer stem/progenitor cells. RNA interference against DLK1 can suppress the malignant behaviors of HCC cells, possibly through directly disrupting cancer stem/progenitor cells, which suggested that DLK1 could be a potential therapeutic target against the HCC stem/progenitor cells. PMID- 22238369 TI - An ex post facto evaluation framework for place-based police interventions. AB - BACKGROUND: A small but growing body of research evidence suggests that place based police interventions generate significant crime control gains. While place based policing strategies have been adopted by a majority of U.S. police departments, very few agencies make a priori commitments to rigorous evaluations. OBJECTIVE: Recent methodological developments were applied to conduct a rigorous ex post facto evaluation of the Boston Police Department's Safe Street Team (SST) hot spots policing program. RESEARCH DESIGN: A nonrandomized quasi-experimental design was used to evaluate the violent crime control benefits of the SST program at treated street segments and intersections relative to untreated street segments and intersections. Propensity score matching techniques were used to identify comparison places in Boston. Growth curve regression models were used to analyze violent crime trends at treatment places relative to control places. UNITS OF ANALYSIS: Using computerized mapping and database software, a micro level place database of violent index crimes at all street segments and intersections in Boston was created. MEASURES: Yearly counts of violent index crimes between 2000 and 2009 at the treatment and comparison street segments and intersections served as the key outcome measure. RESULTS: The SST program was associated with a statistically significant reduction in violent index crimes at the treatment places relative to the comparison places without displacing crime into proximate areas. CONCLUSIONS: To overcome the challenges of evaluation in real-world settings, evaluators need to continuously develop innovative approaches that take advantage of new theoretical and methodological approaches. PMID- 22238368 TI - MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. AB - HER2 amplification is found in more than 15% of gastric cancers and is associated with poor clinical outcome. Lapatinib, a dual HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown promising in vitro results in treating HER2(+) cancer cells. However, several studies have shown that activation of alternative receptor tyrosine kinases can mediate resistance to HER targeted therapy. Here, we investigated whether activated MET can confer resistance to lapatinib inhibition of gastric cancer cells. A panel of gastric cancer cell lines was treated with lapatinib, and we observed that cell proliferation was reduced by 70% and that the degree of HER2 amplification corresponds to sensitivity to lapatinib. Immunoblotting analysis indicated that phosphorylation of HER2, EGFR, MET, AKT, and extracellular signal-regulated kinase was inhibited by lapatinib and presumably led to cell-cycle arrest as observed with flow cytometry. Hepatocyte growth factor (HGF) activation of MET receptors rescued cells from lapatinib-induced growth inhibition by restimulating the downstream pathways and restoring normal cell-cycle progression. This rescue effect could be abrogated by inhibiting MET with PHA-665752 (a highly specific MET inhibitor) or downregulating MET expression with short interfering RNA. No synergy in growth inhibition was observed when cells were treated with a combination of lapatinib and PHA-665752. Repeat studies using insulin-like growth factor 1 and fibroblast growth factor 3 could not uniformly rescue the lapatinib treated gastric cancer cells. In conclusion, HGF/MET-mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in gastric cancer cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation. PMID- 22238370 TI - Global gene analysis of oocytes from early stages in human folliculogenesis shows high expression of novel genes in reproduction. AB - The pool of primordial follicles in humans is laid down during embryonic development and follicles can remain dormant for prolonged intervals, often decades, until individual follicles resume growth. The mechanisms that induce growth and maturation of primordial follicles are poorly understood but follicles once activated either continue growth or undergo atresia. We have isolated pure populations of oocytes from human primordial, intermediate and primary follicles using laser capture micro-dissection microscopy and evaluated the global gene expression profiles by whole-genome microarray analysis. The array data were confirmed by qPCR for selected genes. A total of 6301 unique genes were identified as significantly expressed representing enriched specific functional categories such as 'RNA binding', 'translation initiation' and 'structural molecule activity'. Several genes, some not previously known to be associated with early oocyte development, were identified with exceptionally high expression levels, such as the anti-proliferative transmembrane protein with an epidermal growth factor-like and two follistatin-like domains (TMEFF2), the Rho-GTPase activating protein oligophrenin 1 (OPHN1) and the mitochondrial-encoded ATPase6 (ATP6). Thus, the present study provides not only a technique to capture and perform transcriptome analysis of the sparse material of human oocytes from the earliest follicle stages but further includes a comprehensive basis for our understanding of the regulatory factors and pathways present during early human folliculogenesis. PMID- 22238371 TI - Association study of CYP17 and HSD11B1 in polycystic ovary syndrome utilizing comprehensive gene coverage. AB - Cytochrome P450-C17 enzyme (CYP17) is an important component of the androgen synthesis pathway, a pathway that is dysfunctional in polycystic ovary syndrome (PCOS). Variation in 11-beta hydroxysteroid dehydrogenase (HSD11B1) is associated with cortisone reductase deficiency, a condition with a phenotype similar to PCOS. Both CYP17 and HSD11B1 genes have been previously studied for their possible relationship with PCOS, yielding inconsistent results. In this study, we evaluated the association between variation in these genes and PCOS. Two-hundred and eighty-seven Caucasian PCOS women and 187 Caucasian controls were genotyped for single nucleotide polymorphisms (SNPs) that were specifically chosen to allow full coverage of CYP17 and HSD11B1, including four SNPs in CYP17 and eight SNPs in HSD11B1. SNP and haplotype association analyses were conducted. Our results indicate that variants in the two genes are not associated with PCOS, or with the quantitative traits characteristic of PCOS, suggesting that these genes are not major risk factors for the syndrome. PMID- 22238372 TI - Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4 dependent, cholesterol-sensitive activation of NF-kappaB. AB - Oxidized cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25 hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved. Treatment of primary trophoblasts in culture with 25-OHC and 7-ketoC increased the production of proinflammatory cytokines (interleukin-6, macrophage inflammatory protein 1beta and tumour necrosis factor-alpha) in a concentration-dependent fashion. Inhibition of TLR4 activation using selective inhibitors of TLR4 complex formation (OxPAPC) or signalling transmission (CLI095) prevented lipopolysaccharide (LPS)- and oxysterol-induced inflammatory cytokine production. Pretreatment of trophoblasts with selective inhibitors of I-kB kinase activity (parthenolide and TPCA-1) reduced oxysterol- and LPS-stimulated inflammatory responses, consistent with the involvement of the nuclear factor kappa B (NF kappaB) pathway downstream of TLR4 signalling. Both oxysterols also increased the phosphorylation and nuclear localization of NF-kappaB subunit p65/RelA. Oxysterols are also known to activate liver X receptors (LXRs) which can inhibit inflammatory signalling, either directly or indirectly via membrane cholesterol reduction. Treatment with the LXR agonist, T0901317, exerted significant anti inflammatory effects, reducing LPS- and oxysterol-driven cytokine production. Treatment with methyl-beta-cyclodextrin to deplete membrane microdomain cholesterol and thereby disrupt TLR4 signalling, similarly abrogated their effects. Together, these findings indicate that although oxysterols likely activate both pro- and anti-inflammatory pathways in the placenta, the predominant effect is the promotion of placental inflammation via TLR4-dependent activation of NF-kappaB. PMID- 22238373 TI - Contemporary issues in intellectual disability practice, policy and research. PMID- 22238374 TI - BC1-FMRP interaction is modulated by 2'-O-methylation: RNA-binding activity of the tudor domain and translational regulation at synapses. AB - The brain cytoplasmic RNA, BC1, is a small non-coding RNA that is found in different RNP particles, some of which are involved in translational control. One component of BC1-containing RNP complexes is the fragile X mental retardation protein (FMRP) that is implicated in translational repression. Peptide mapping and computational simulations show that the tudor domain of FMRP makes specific contacts to BC1 RNA. Endogenous BC1 RNA is 2'-O-methylated in nucleotides that contact the FMRP interface, and methylation can affect this interaction. In the cell body BC1 2'-O-methylations are present in both the nucleus and the cytoplasm, but they are virtually absent at synapses where the FMRP-BC1-mRNA complex exerts its function. These results strongly suggest that subcellular region-specific modifications of BC1 affect the binding to FMRP and the interaction with its mRNA targets. We finally show that BC1 RNA has an important role in translation of certain mRNAs associated to FMRP. All together these findings provide further insights into the translational regulation by the FMRP BC1 complex at synapses. PMID- 22238375 TI - C7orf30 specifically associates with the large subunit of the mitochondrial ribosome and is involved in translation. AB - In a comparative genomics study for mitochondrial ribosome-associated proteins, we identified C7orf30, the human homolog of the plant protein iojap. Gene order conservation among bacteria and the observation that iojap orthologs cannot be transferred between bacterial species predict this protein to be associated with the mitochondrial ribosome. Here, we show colocalization of C7orf30 with the large subunit of the mitochondrial ribosome using isokinetic sucrose gradient and 2D Blue Native polyacrylamide gel electrophoresis (BN-PAGE) analysis. We co purified C7orf30 with proteins of the large subunit, and not with proteins of the small subunit, supporting interaction that is specific to the large mitoribosomal complex. Consistent with this physical association, a mitochondrial translation assay reveals negative effects of C7orf30 siRNA knock-down on mitochondrial gene expression. Based on our data we propose that C7orf30 is involved in ribosomal large subunit function. Sequencing the gene in 35 patients with impaired mitochondrial translation did not reveal disease-causing mutations in C7orf30. PMID- 22238376 TI - C7orf30 is necessary for biogenesis of the large subunit of the mitochondrial ribosome. AB - Defects of the translation apparatus in human mitochondria are known to cause disease, yet details of how protein synthesis is regulated in this organelle remain to be unveiled. Here, we characterize a novel human protein, C7orf30 that contributes critically to mitochondrial translation and specifically associates with the large subunit of the mitochondrial ribosome (mt-LSU). Inactivation of C7orf30 in human cells by RNA interference results in respiratory incompetence owing to reduced mitochondrial translation rates without any appreciable effects on the steady-state levels of mitochondrial mRNAs and rRNAs. Ineffective translation in C7orf30-depleted cells or cells overexpressing a dominant-negative mutant of the protein results from aberrant assembly of mt-LSU and consequently reduced formation of the monosome. These findings lead us to propose that C7orf30 is a human assembly and/or stability factor involved in the biogenesis of the large subunit of the mitochondrial ribosome. PMID- 22238378 TI - A novel phage-encoded transcription antiterminator acts by suppressing bacterial RNA polymerase pausing. AB - Gp39, a small protein encoded by Thermus thermophilus phage P23-45, specifically binds the host RNA polymerase (RNAP) and inhibits transcription initiation. Here, we demonstrate that gp39 also acts as an antiterminator during transcription through intrinsic terminators. The antitermination activity of gp39 relies on its ability to suppress transcription pausing at poly(U) tracks. Gp39 also accelerates transcription elongation by decreasing RNAP pausing and backtracking but does not significantly affect the rates of catalysis of individual reactions in the RNAP active center. We mapped the RNAP-gp39 interaction site to the beta flap, a domain that forms a part of the RNA exit channel and is also a likely target for lambda phage antiterminator proteins Q and N, and for bacterial elongation factor NusA. However, in contrast to Q and N, gp39 does not depend on NusA or other auxiliary factors for its activity. To our knowledge, gp39 is the first characterized phage-encoded transcription factor that affects every step of the transcription cycle and suppresses transcription termination through its antipausing activity. PMID- 22238377 TI - Structural insights into the redox-switch mechanism of the MarR/DUF24-type regulator HypR. AB - Bacillus subtilis encodes redox-sensing MarR-type regulators of the OhrR and DUF24-families that sense organic hydroperoxides, diamide, quinones or aldehydes via thiol-based redox-switches. In this article, we characterize the novel redox sensing MarR/DUF24-family regulator HypR (YybR) that is activated by disulphide stress caused by diamide and NaOCl in B. subtilis. HypR controls positively a flavin oxidoreductase HypO that confers protection against NaOCl stress. The conserved N-terminal Cys14 residue of HypR has a lower pK(a) of 6.36 and is essential for activation of hypO transcription by disulphide stress. HypR resembles a 2-Cys-type regulator that is activated by Cys14-Cys49' intersubunit disulphide formation. The crystal structures of reduced and oxidized HypR proteins were resolved revealing structural changes of HypR upon oxidation. In reduced HypR a hydrogen-bonding network stabilizes the reactive Cys14 thiolate that is 8-9 A apart from Cys49'. HypR oxidation breaks these H-bonds, reorients the monomers and moves the major groove recognition alpha4 and alpha4' helices ~4 A towards each other. This is the first crystal structure of a redox-sensing MarR/DUF24 family protein in bacteria that is activated by NaOCl stress. Since hypochloric acid is released by activated macrophages, related HypR-like regulators could function to protect pathogens against the host immune defense. PMID- 22238379 TI - Young intragenic miRNAs are less coexpressed with host genes than old ones: implications of miRNA-host gene coevolution. AB - MicroRNAs (miRNAs) have emerged as key regulators of gene expression. Intragenic miRNAs account for ~50% of mammalian miRNAs. Classic studies reported that they are usually coexpressed with host genes. Here, using genome-wide miRNA and gene expression profiles from five sample sets, we show that evolutionarily conserved ('old') intragenic miRNAs tend to be coexpressed with host genes, but non conserved ('young') ones rarely do so. This result is robust: in all sample sets, the coexpression rate of young miRNAs is significantly lower than that of conserved ones even after controlling for abundance. As a result, although young miRNAs dominate in human genome, the majority of intragenic miRNAs that show coexpression with host genes are phylogenetically old ones. For younger miRNAs, extrapolation of their expression profiles from those of their host genes should be treated with caution. We propose a model to explain this phenomenon in which the majority of young miRNAs are unlikely to be coexpressed with host genes; however, for some fraction of young miRNAs coexpression with their host genes, initially imbued by chromatin level effects, is advantageous and these are the ones likely to embed into the system and evolve ever higher levels of coexpression, possibly by evolving piggybacking mechanisms. PMID- 22238380 TI - The RNA helicase RHAU (DHX36) unwinds a G4-quadruplex in human telomerase RNA and promotes the formation of the P1 helix template boundary. AB - Human telomerase RNA (hTR) contains several guanine tracts at its 5'-end that can form a G4-quadruplex structure. Previous evidence suggests that a G4-quadruplex within this region disrupts the formation of an important structure within hTR known as the P1 helix, a critical element in defining the template boundary for reverse transcription. RNA associated with AU-rich element (RHAU) is an RNA helicase that has specificity for DNA and RNA G4-quadruplexes. Two recent studies identify a specific interaction between hTR and RHAU. Herein, we confirm this interaction and identify the minimally interacting RNA fragments. We demonstrate the existence of multiple quadruplex structures within the 5' region of hTR and find that these regions parallel the minimal sequences capable of RHAU interaction. We confirm the importance of the RHAU-specific motif in the interaction with hTR and demonstrate that the helicase activity of RHAU is sufficient to unwind the quadruplex and promote an interaction with 25 internal nucleotides to form a stable P1 helix. Furthermore, we have found that a 5' terminal quadruplex persists following P1 helix formation that retains affinity for RHAU. Finally, we have investigated the functional implications of this interaction and demonstrated a reduction in average telomere length following RHAU knockdown by small interfering RNA (siRNA). PMID- 22238381 TI - Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals. AB - Non-canonical guanine quadruplex structures are not only predominant but also conserved among bacterial and mammalian promoters. Moreover recent findings directly implicate quadruplex structures in transcription. These argue for an intrinsic role of the structural motif and thereby posit that single nucleotide polymorphisms (SNP) that compromise the quadruplex architecture could influence function. To test this, we analysed SNPs within quadruplex motifs (Quad-SNP) and gene expression in 270 individuals across four populations (HapMap) representing more than 14,500 genotypes. Findings reveal significant association between quadruplex-SNPs and expression of the corresponding gene in individuals (P < 0.0001). Furthermore, analysis of Quad-SNPs obtained from population-scale sequencing of 1000 human genomes showed relative selection bias against alteration of the structural motif. To directly test the quadruplex-SNP transcription connection, we constructed a reporter system using the RPS3 promoter-remarkable difference in promoter activity in the 'quadruplex destabilized' versus 'quadruplex-intact' promoter was noticed. As a further test, we incorporated a quadruplex motif or its disrupted counterpart within a synthetic promoter reporter construct. The quadruplex motif, and not the disrupted-motif, enhanced transcription in human cell lines of different origin. Together, these findings build direct support for quadruplex-mediated transcription and suggest quadruplex-SNPs may play significant role in mechanistically understanding variations in gene expression among individuals. PMID- 22238382 TI - Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. AB - CONTEXT: Little is known about the long-term health of subjects treated with GH in childhood, and Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) is a study addressing this question. OBJECTIVE: The objective of the study was to evaluate the long-term mortality of patients treated with recombinant GH in childhood in France. DESIGN: This was a population-based cohort study. SETTING: The setting of the study was a French population-based register. PARTICIPANTS: A total of 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), idiopathic short stature (n = 871), or born short for gestational age (n = 335) who started treatment between 1985 and 1996 participated in the study. Follow-up data on vital status were available in September 2009 for 94.7% of the patients. MAIN OUTCOME MEASURES: All cause and cause-specific mortality was measured in the study. RESULTS: All-cause mortality was increased in treated subjects [standardized mortality ratio (SMR) 1.33, 95% confidence interval (CI) 1.08-1.64]. In a multivariate analysis adjusted for height, the use of GH doses greater than 50 MUg/kg . d was associated with mortality rates using external and internal references (SMR 2.94, 95% CI 1.22-7.07, hazard ratio 2.79, 95% CI 1.14-6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95% CI 1.01-14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95% CI 1.40-5.83) or subarachnoid or intracerebral hemorrhage (SMR 6.66, 95% CI 1.79-17.05) was observed. CONCLUSIONS: Mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood. PMID- 22238384 TI - Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves' ophthalmopathy. AB - PURPOSE: Platelet-derived growth factors (PDGF) are regulators of fibroblast activity that may be involved in the pathophysiology of Graves' ophthalmopathy (GO). We unraveled the expression and origin of PDGF family members in GO orbital tissue and investigated the effect of PDGF isoforms on IL-6 and hyaluronan production and proliferation by orbital fibroblasts. METHODS: PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGF-Ralpha, and PDGF-Rbeta expression was determined by real time quantitative PCR and PDGF-A and PDGF-B protein expression was determined by Western blot in orbital tissues. Orbital tissues were immunohistochemically stained for PDGF-A and PDGF-B expression, together with stainings for T cells, monocytes, B cells, macrophages, and mast cells. Effects of PDGF-AA, PDGF-AB, and PDGF-BB on orbital fibroblast proliferation and IL-6 and hyaluronan production were examined. Finally, effects of PDGF-BB- and PDGF-AA-neutralizing antibodies on IL-6 and hyaluronan production in GO whole orbital tissue cultures were tested. RESULTS: GO orbital tissue showed increased PDGF-A and PDGF-B mRNA and protein levels. Increased numbers of PDGF-A- and PDGF-B-positive monocytes, macrophages, and mast cells were present in GO orbital tissue. PDGF-BB stimulated proliferation and hyaluronan and IL-6 production by orbital fibroblasts the most, followed by PDGF-AB and PDGF-AA. Finally, in particular imatinib mesylate and PDGF-BB-neutralizing antibodies reduced IL-6 and hyaluronan production by whole orbital tissue cultures from GO patients. CONCLUSIONS: In GO, mast cells, monocytes, and macrophages may activate orbital fibroblasts via secretion of especially PDGF-AB and PDGF-BB. Preclinical studies with whole orbital tissue cultures show that blocking PDGF-B chain containing isoforms can be a promising treatment for GO. PMID- 22238383 TI - Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. AB - Osteoporosis is defined as low bone mineral density associated with skeletal fractures secondary to minimal or no trauma, most often involving the spine, the hip, and the forearm. The decrease in bone mineral density is the consequence of an unbalanced bone remodeling process, with higher bone resorption than bone formation. Osteoporosis affects predominantly postmenopausal women, but also older men. This chronic disease represents a considerable medical and socioeconomic burden for modern societies. The therapeutic options for the treatment of osteoporosis have so far comprised mostly antiresorptive drugs, in particular bisphosphonates and more recently denosumab, but also calcitonin and, for women, estrogens or selective estrogen receptor modulators. These drugs have limitations, however, in particular the fact that they lead to a low turnover state where bone formation decreases with the decrease in bone-remodeling activity. In this review, we discuss the alternative class of osteoporosis drugs, i.e. bone anabolics, their biology, and the perspectives they offer for our therapeutic armamentarium. We focus on the two main osteoanabolic pathways identified as of today: PTH, the only anabolic drug currently on the market; and activation of canonical Wnt signaling through inhibition of the endogenous inhibitors sclerostin and dickkopf1. Each approach is based on a different molecular mechanism, but most recent evidence suggests that these two pathways may actually converge, at least in part. Whereas recombinant human PTH treatment is being revisited with different formulations and attempts to regulate endogenous PTH secretion via the calcium-sensing receptor, antibodies to sclerostin and dickkopf1 are currently in clinical trials and may prove to be even more efficient at increasing bone mass, possibly independent of bone turnover. Each of these anabolic approaches has its own limitations and safety issues, but the prospects of effective anabolic therapy for osteoporosis are indeed bright. PMID- 22238385 TI - Mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy. AB - OBJECTIVE: Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle. RESEARCH DESIGN AND METHODS: Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls. RESULTS: The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P<0.001). This substantial (~35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates. CONCLUSIONS: Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance. PMID- 22238386 TI - 25-hydroxyvitamin D assay variations and impact on clinical decision making. AB - CONTEXT: Laboratories are increasingly shifting to new automated 25 hydroxyvitamin D (25-OHD) assays, with subsequent variability in results. OBJECTIVE/SETTING: We describe the experience at our center with such a shift and illustrate its clinical implications. METHODS: 25-OHD levels were measured in 494 patients using Immunodiagnostic Systems RIA (IDS-RIA) and DiaSorin Liaison assays. Sources of variability between the assays were investigated in a subset of 83 samples, retested in the reference laboratory in the United States, and by reviewing the performance reports issued by the International Vitamin D External Quality Assessment Scheme, DEQAS. 25-OHD cut-points for target levels were used to compare the two assays. RESULTS: 25-OHD concentrations were significantly lower when measured with Liaison as compared to IDS-RIA: mean bias was -5 ng/ml, range was -38.1 to 18.7 ng/ml, P<0.001; the absolute bias was independent of 25 OHD value. Interassay variability was also detected in values obtained in the reference laboratory and in DEQAS reports. Using 20 ng/ml as the target 25-OHD level, 52% of patients required treatment when tested by Liaison, as opposed to 36% by IDS-RIA (P<0.001). Using 30 ng/ml as the desirable level, the proportions were 79 and 64%, respectively (P<0.001). The two assays agreed in only 41-68% of subjects, proportions that depended on criteria used to define agreement. CONCLUSION: A change in 25-OHD assays has a significant impact on results, patient classification, and treatment recommendations. Such variability cannot be ignored when deriving and applying vitamin D guidelines. It also renders universal assay standardization a pressing call. PMID- 22238387 TI - Cavernous carotid artery aneurysm, a rare cause of intrasellar mass and hyperprolactinemia. PMID- 22238388 TI - Circulating levels of TNF-alpha are associated with impaired glucose tolerance, increased insulin resistance, and ethnicity: the Insulin Resistance Atherosclerosis Study. AB - OBJECTIVE: Although several epidemiological studies have investigated associations between TNF-alpha and insulin resistance, results have been inconsistent. We studied the relationship between TNF-alpha and glucose tolerance status as part of the Insulin Resistance Atherosclerosis Study. RESEARCH DESIGN AND METHODS: Serum concentrations of TNF-alpha were measured in 1558 individuals in a triethnic population across a spectrum of glucose tolerance. Insulin sensitivity and insulin secretion were assessed by a frequently sampled iv glucose tolerance test (FSIGT). RESULTS: Compared with those with normal glucose tolerance, circulating levels of TNF-alpha were elevated in individuals with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2D) after adjusting for age, gender, ethnicity, clinic site, and body mass index (3.3, 3.5, and 3.7 pg/ml in subjects with normal glucose tolerance, IGT, and T2D, respectively; P<0.05). Age-, sex-, and body mass index-adjusted levels of TNF alpha differed by ethnicity, with Hispanics having the highest levels and African Americans having the lowest (4.1, 3.6, and 3.0 pg/ml in Hispanics, non-Hispanic whites, and African-Americans, respectively; P<0.05). TNF-alpha was correlated with waist circumference, high-density lipoprotein, triglycerides, plasminogen activator inhibitor-1 and insulin sensitivity index (SI) (r=0.22, -0.30, 0.35, 0.31, and -0.25; P<0.0001); however, correlations varied by ethnicity. After adjusting for demographics and adiposity, individuals characterized by increased insulin resistance (lower SI), had higher levels of TNF-alpha than subjects characterized by high insulin sensitivity (3.8 and 3.3 pg/ml in subjects with an SI below/above the median at baseline; P<0.0001). No differences were found for acute insulin response. CONCLUSIONS: We confirm that TNF-alpha is associated with IGT and T2D in a large, multiethnic population, independent of measures of adiposity. Adjusted values of TNF-alpha, as well as relationships between TNF alpha and variables related to T2D, varied by ethnicity. Increased TNF-alpha levels were predominantly associated with insulin resistance but not with primary defects in beta-cell function. PMID- 22238389 TI - Evidence for calcitonin-producing cells in human lingual thyroids. AB - CONTEXT: The thyroid contains two types of cells, the thyroid follicular cells and the calcitonin-producing cells. The site of origin of the thyroid follicular cells is the median thyroid anlage, an endothelial diverticulum in the midline of the ventral pharynx between the first and the second pharyngeal pouches. The ultimobranchial bodies (UBB), a pair of transient embryonic structures evaginated from the fourth pharyngeal pouch and located symmetrically on the sides of the developing neck, are the source of calcitonin-producing cells. In human embryos, the thyroid bud starts its migration at embryonic day 24 and reaches its final location in front of the trachea at embryonic day 45-50. The UBB fuse with the primitive thyroid when thyroid migration is completed. Lingual thyroids result from the failure of the thyroid precursor cells to migrate from the primordial pharynx to the anterior part of the neck. Therefore, calcitonin-producing cells are not expected to be present in lingual thyroids. OBJECTIVE: Our objective was to determine whether calcitonin-producing C cells are present in ectopic lingual thyroids. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: We performed calcitonin immunolabeling and transcript detection on four flash-frozen ectopic lingual thyroids. Additional calcitonin immunolabeling was performed on two other paraffin-embedded ectopic lingual thyroids. RESULTS: We report evidence of calcitonin-producing cells in six independent cases of ectopic lingual thyroids. CONCLUSION: The UBB are not the only source of calcitonin-producing cells in humans. Interactions between calcitonin-producing and thyroid follicular cells occur earlier than previously accepted. PMID- 22238390 TI - Update: consequences of abnormal fetal growth. AB - Intrauterine growth restriction (IUGR) is prevalent worldwide and affects children and adults in multiple ways. These include predisposition to type 2 diabetes mellitus, the metabolic syndrome, cardiovascular disease, persistent reduction in stature, and possibly changes in the pattern of puberty. A review of recent literature confirms that the metabolic effects of being born small for gestational age are evident in the very young, persist with age, and are amplified by adiposity. Furthermore, the pattern of growth in the first few years of life has a significant bearing on a person's later health, with those that show increasing weight gain being at the greatest risk for future metabolic dysfunction. Treatment with exogenous human GH is used to improve height in children who remain short after being small for gestational age at birth, but the response of individuals remains variable and difficult to predict. The mechanisms involved in the metabolic programming of IUGR children are just beginning to be explored. It appears that IUGR leads to widespread changes in DNA methylation and that specific "epigenetic signatures" for IUGR are likely to be found in various fetal tissues. The challenge is to link such alterations with modifications in gene expression and ultimately the metabolic abnormalities of adulthood, and it represents one of the frontiers for research in the field. PMID- 22238391 TI - Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk. AB - CONTEXT: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. OBJECTIVE: Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people. SETTING AND DESIGN: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is an prospective cohort study. PATIENTS: Patients included men and women aged 70-82 yr (n=5316) with known cardiovascular risk factors or previous cardiovascular disease. MAIN OUTCOME MEASURES: Incidence rate of heart failure hospitalization, atrial fibrillation, and cardiovascular events and mortality according to baseline thyroid status were evaluated. Euthyroid participants (TSH=0.45-4.5 mIU/liter) were compared with those with subclinical hyperthyroidism (TSH<0.45 mIU/liter) and those with subclinical hypothyroidism (TSH>=4.5 mIU/liter, both with normal free T4). RESULTS: Subclinical hyperthyroidism was present in 71 participants and subclinical hypothyroidism in 199 participants. Over 3.2 yr follow-up, the rate of heart failure was higher for subclinical hyperthyroidism compared with euthyroidism [age- and sex-adjusted hazard ratio (HR)=2.93, 95% confidence interval (CI)=1.37-6.24, P=0.005; multivariate-adjusted HR=3.27, 95% CI=1.52-7.02, P=0.002). Subclinical hypothyroidism (only at threshold>10 mIU/liter) was associated with heart failure (age- and sex-adjusted HR=3.01, 95% CI=1.12-8.11, P=0.029; multivariate HR=2.28, 95% CI=0.84-6.23). There were no strong evidence of an association between subclinical thyroid dysfunction and cardiovascular events or mortality, except in those with TSH below 0.1 or over 10 mIU/liter and not taking pravastatin. CONCLUSION: Older people at high cardiovascular risk with low or very high TSH along with normal free T4 appear at increased risk of incident heart failure. PMID- 22238392 TI - Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. AB - CONTEXT: Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. OBJECTIVES: Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. DESIGN AND SETTING: This was a 24-wk, international, multicenter, randomized, parallel-group, double blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. PATIENTS: Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. INTERVENTION: Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. MAIN OUTCOME MEASURES: Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. RESULTS: At wk 24, placebo corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. CONCLUSIONS: Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin. PMID- 22238393 TI - Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study. AB - CONTEXT: The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment. OBJECTIVE: To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden. DESIGN: Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands). PATIENTS: All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation. MAIN OUTCOME MEASURE: Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed. RESULTS: Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect. CONCLUSIONS: In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease. PMID- 22238394 TI - Giant bilateral myelolipomas in a man with congenital adrenal hyperplasia. PMID- 22238395 TI - Genomic imprinting effects on cognitive and social abilities in prepubertal girls with Turner syndrome. AB - CONTEXT: Recent evidence suggests that the cognitive and social manifestations associated with Turner syndrome (TS) might be influenced by epigenetic factors in the form of genomic imprinting. However, due to small and heterogeneous samples, inconsistent results have emerged from these studies. OBJECTIVE: The objective of this prospective study was to establish the impact of genomic imprinting on neurocognitive abilities and social functioning in young girls with TS. DESIGN, SETTING, AND PARTICIPANTS: An extensive battery of neuropsychological assessments was administered to 65 children with TS who had never been exposed to estrogen treatment, 24 of whom had an X-chromosome from paternal origin (Xpat) and 41 from maternal origin (Xmat). MAIN OUTCOME MEASURES: The Wechsler scales of intelligence, the Motor-Free Visual Spatial test-3, the Wide Range Assessment of Visual Motor Ability, and the attention/executive domain of the NEPSY were used to assess cognitive abilities. Social functioning was assessed with the Social Responsiveness Scale and the Behavior Assessment System for Children-2. RESULTS: Results showed that although individuals with Xpat obtained lower scores than their counterparts with Xmat on most cognitive and social measures, only the Perceptual Reasoning Index of the intelligence scale yielded significant differences after correction for multiple comparisons. CONCLUSION: Overall, these results suggest that although some aspects of the neuropsychological profile of TS may be influenced by epigenetic factors, the sociocognitive phenotype associated with the disorder is not modulated by genomic imprinting. PMID- 22238396 TI - Thyroid function and mortality in older men: a prospective study. AB - CONTEXT: Mild abnormalities of thyroid function have been associated with both beneficial and detrimental effects on mortality. OBJECTIVE: Our objective was to determine the association between continuous TSH as well as categories of thyroid function with total and cause-specific mortality in a cohort of older men. DESIGN, SETTING, AND PARTICIPANTS: Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community-dwelling U.S. men aged 65 yr and older. A total of 1587 participants randomly selected for thyroid function testing were included in this analysis. TSH and free T4 were measured at baseline, and four categories of thyroid function were defined. (subclinical hyperthyroid; euthyroid; subclinical hypothyroid TSH<10 mIU/liter; and subclinical hypothyroid, TSH>=10 mIU/liter.) MAIN OUTCOME MEASURE: Total mortality, cardiovascular (CV) and cancer deaths were confirmed by review of death certificates. RESULTS: There were 432 deaths over a mean follow-up of 8.3 yr. In fully adjusted models, there was no association between baseline TSH and any death [relative hazard (RH)=1.01 per mIU/liter, 95% confidence interval (CI)=0.95-1.06], CV death (RH=1.05 per mIU/liter, 95% CI 0.96-1.15), or cancer death (RH=0.96 per mIU/liter, 95% CI=0.85-1.07). There was also no statistically significant association between thyroid function category and total or cause specific mortality, but few men (n=8) had subclinical hypothyroidism with TSH levels of 10 mIU/liter or higher. CONCLUSIONS: A single measurement of thyroid function did not predict total or cause-specific mortality in this cohort. These data support neither a beneficial nor a detrimental effect of subclinical thyroid dysfunction in older men. SUMMARY: Subclinical thyroid dysfunction is not associated with an increased risk of all-cause or CV mortality in older men. PMID- 22238397 TI - Subclinical hypothyroidism and hyperthyroidism have opposite effects on hepatic very-low-density lipoprotein-triglyceride kinetics. AB - CONTEXT: Clinically overt thyroid dysfunction is associated with alterations in triglyceride (TG) metabolism. The effect of subclinical thyroid disease on very low-density lipoprotein (VLDL) kinetics is not known. OBJECTIVE: Our objective was to investigate whether subclinical thyroid disease is associated with alterations in hepatic VLDL metabolism. DESIGN AND OUTCOMES: We measured VLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics by infusing stable isotopically labeled tracers, in conjunction with mathematical modeling. SETTING AND PARTICIPANTS: Ten women with subclinical hypothyroidism, 10 women with subclinical hyperthyroidism, and 25 euthyroid women, matched on age, body mass index, and percent body fat, were studied in the Clinical Research Unit at Washington University School of Medicine. RESULTS: Plasma VLDL-TG concentrations were 0.75+/-0.13, 0.51+/-0.06, and 0.37+/-0.07 mmol/liter (P=0.029), and hepatic VLDL-TG secretion rates were 6.5+/-0.7, 5.0+/-0.4, and 4.1+/-0.6 MUmol/liter.min (P=0.026) in hypothyroid, euthyroid, and hyperthyroid women, respectively. The differences in VLDL-TG secretion rates were due to differences in the incorporation of systemic plasma free fatty acids into VLDL-TG (4.3+/-0.3, 3.1+/ 0.3, and 2.5+/-0.3 MUmol/liter.min in hypothyroid, euthyroid, and hyperthyroid women, respectively; P=0.005). Plasma VLDL-apoB-100 concentration and hepatic secretion rate did not differ among groups (P>0.400), so the molar ratios of VLDL TG to VLDL-apoB-100 secretion rates were 21,469+/-3,477, 16,025+/-1,273, and 11,889+/-1,319 in hypothyroid, euthyroid, and hyperthyroid women, respectively (P=0.019). CONCLUSIONS: Subclinical thyroid disease affects hepatic VLDL-TG but not VLDL-apoB-100 metabolism: subclinical hypothyroidism increases, whereas subclinical hyperthyroidism decreases, hepatic VLDL-TG secretion rate compared with the euthyroid state. Plasma VLDL-TG concentration is greater in subclinical hypothyroid than euthyroid and hyperthyroid subjects, due to greater secretion of large, TG-rich VLDL particles from the liver. PMID- 22238398 TI - Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects. AB - CONTEXT: Aging is associated with deteriorating glucose tolerance. Studies assessing glucose tolerance and subsequent insulin and incretin hormone release often fail to take into account the rate of gastric emptying when evaluating these responses. OBJECTIVE: Our objective was to determine the comparative effects of variations in the small intestinal glucose load on the glycemic, insulinemic, and incretin responses in healthy young and older subjects. MATERIALS AND METHODS: Twelve healthy young (six males, six females; age 22.2+/ 2.3 yr) and 12 older (six males, six females; age 68.7+/-1.0 yr) subjects had measurements of blood glucose, serum insulin and plasma incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] and calculations of insulin resistance (homeostatic model assessment) and beta-cell function corrected for insulin sensitivity, before and during intraduodenal infusions of glucose at 1, 2, or 3 kcal/min or saline for 60 minutes. The study was double-blinded and randomized, and performed in the Discipline of Medicine at the Royal Adelaide Hospital. RESULTS: At baseline, blood glucose and serum insulin were slightly higher in the older subjects (P<0.001), whereas GLP-1 and GIP were comparable between groups. In both groups, the glycemic, insulinemic, and GLP-1 responses were dependent on the duodenal glucose load in a nonlinear fashion (P<0.001). The glycemic response was greater (P<0.001) in the older subjects, whereas GLP-1 and GIP responses were comparable between groups. The older subjects were more insulin resistant (P<0.001) and had impaired beta-cell function, particularly at higher glucose loads (P<0.05). CONCLUSION: When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance. PMID- 22238399 TI - Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate. AB - CONTEXT: Phthalates are ubiquitous environmental chemicals. Fetal exposure to certain phthalates [e.g. di-n-butyl phthalate (DBP)] causes masculinization disorders in rats, raising concern for similar effects in humans. We investigated whether DBP exposure impairs steroidogenesis by the human fetal testis. OBJECTIVE: The aim of the study was to determine effects of DBP exposure on testosterone production by normally growing human fetal testis xenografts. DESIGN: Human fetal testes (14-20 wk gestation; n=12) were xenografted into castrate male nude mice that were treated for 4-21 d with vehicle, or 500 mg/kg.d DBP, or monobutyl phthalate (active metabolite of DBP); all mice were treated with human chorionic gonadotropin to mimic normal human pregnancy. Rat fetal testis xenografts were exposed for 4 d to DBP as a positive control. MAIN OUTCOME MEASURES: Testosterone production was assessed by measuring host serum testosterone and seminal vesicle (SV) weights at termination, plus testis gene expression (rats). RESULTS: Human fetal testis xenografts showed similar survival (~80%) and total graft weight (8.6 vs. 10.1 mg) in vehicle and DBP-exposed hosts, respectively. Serum testosterone (0.56 vs. 0.64 ng/ml; P>0.05) and SV weight (67.2 vs. 81.9 mg; P>0.05) also did not differ. Exposure to monobutyl phthalate gave similar results. In contrast, exposure of rat fetal xenografts to DBP significantly reduced SV weight and testis Cyp11a1/StAR mRNA expression and lowered testosterone levels, confirming that DBP exposure can inhibit steroidogenesis in xenografts, further validating the negative findings on testosterone production in the human. CONCLUSIONS: Exposure of human fetal testes to DBP is unlikely to impair testosterone production as it does in rats. This has important safety and regulatory implications. PMID- 22238400 TI - Outpatient thyroid remnant ablation using repeated low 131-iodine activities (740 MBq/20 mCix2) in patients with low-risk differentiated thyroid cancer. AB - CONTEXT: In low-risk differentiated thyroid cancer (DTC), postoperative (131)I remnant ablation should employ a minimum effective activity; reports increasingly suggest efficacy of low activities, e.g. 1110 MBq/30 mCi. OBJECTIVES, DESIGN, PATIENTS, AND INTERVENTIONS: We retrospectively studied the ablation capability and diagnostic utility of the Minidose protocol, two 740-MBq/20 mCi outpatient administrations, 6-18 months apart, plus related diagnostic procedures, in 160 consecutive (near-) totally thyroidectomized low-risk DTC (pT1/N0-Nx) patients. Successful ablation comprised negative 740-MBq whole-body scintigraphy with cervical uptake below 0.1%, negative stimulated thyroglobulin (STg) (<1 ng/ml, negative thyroglobulin antibodies), and negative Doppler ultrasonography (performed around Minidose 2). SETTING: The study took place at a referral center. RESULTS: Minidose imaging found unsuspected nodal or distant metastases in nine of 160 patients (5.6%). Ablation success rates after one (two) 740-MBq activity (activites) were 75.9% (90.2%) in 145 (132) evaluable imaging-negative patients. Compared with thyroid hormone withdrawal, recombinant human TSH stimulation was associated with higher urinary iodine excretion/creatinine, lower cervical uptake, and more frequent ablation success after the first 740 MBq; success rates no longer differed significantly after both administrations. Patients with STg below 10 ng/ml at Minidose 1 were oftener ablated at Minidose 2 (odds ratio=13.9, 95% confidence interval=2.5-76.4, P<0.003), attaining 92.0% final ablation success after recombinant human TSH preparation, suggesting that one 740-MBq activity should suffice in this subgroup. All 81 evaluable patients with prolonged follow-up (mean 41.8+/-21.9 months after Minidose 1) had no evidence of disease at the last visit. CONCLUSIONS: The Minidose outpatient ablation protocol is effective and diagnostically useful in low-risk DTC. PMID- 22238402 TI - EGF receptor (ERBB1) abundance in adipose tissue is reduced in insulin-resistant and type 2 diabetic women. AB - CONTEXT: Indications of adipose tissue dysfunction correlate with systemic insulin resistance and type 2 diabetes. It has been suggested that a defect in adipose tissue turnover may be involved in the development of these disorders. Whether this dysfunction causes or exacerbates systemic insulin resistance is not fully understood. OBJECTIVES, PARTICIPANTS, AND MEASURES: We tested whether the expression of members of the mitogenic ErbB family was reduced in adipose tissue of insulin-resistant individuals and whether ErbB1 and ErbB2 were involved in adipogenesis. Thirty-two women covering a wide range of body mass index values and insulin sensitivity participated in the cross-sectional portion of this study. We also studied preadipocytes isolated from 12 insulin-sensitive individuals to evaluate the impact of ErbB1 or ErbB2 inhibition on adipogenesis in vitro. For this purpose, we measured phospho-ErbB1 and phospho-ErbB2 levels using ELISA and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma-regulated genes by real-time PCR. RESULTS: Among the ErbB family members, only ErbB1 expression was correlated with insulin sensitivity. Additionally, ErbB1 levels correlated positively with PPARgamma and several PPARgamma-regulated genes including acyl-coenzyme A synthetase long-chain family member 1 (ACSL1), adiponectin, adipose tissue triacylglycerol lipase (ATGL), diacylglycerol acyl transferase 1 (DGAT1), glycerol-3-phosphate dehydrogenase 1 (GPD1), and lipoprotein lipase (LPL), but negatively with CD36 and fatty acid-binding protein 4 (FABP4). In preadipocyte culture, ErbB1, but not ErbB2, inhibition was associated with a reduction in the expression of all the above-mentioned genes. CONCLUSIONS: These findings demonstrate a key role for ErbB1 in adipogenesis and suggest that lower ErbB1 protein abundance may lead to adipose tissue dysfunction. PMID- 22238401 TI - Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. AB - CONTEXT: Obesity has emerged as one of the leading medical challenges of the 21st century. The resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority is to delineate how mechanisms governing food intake and body fat content are altered in an obesogenic environment. EVIDENCE ACQUISITION: We considered all relevant published research and cited references that represented the highest quality evidence available. Where space permitted, primary references were cited. EVIDENCE SYNTHESIS: The increase of energy intake that has fueled the U.S. obesity epidemic is linked to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in genetically susceptible individuals and involves the biological defense of an elevated body fat mass, which may result in part from interactions between brain reward and homeostatic circuits. Inflammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypothalamic neurons may also contribute to the development of obesity and offer a plausible mechanism to explain the biological defense of elevated body fat mass. CONCLUSIONS: Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Breakthroughs in this area may be required for the development of effective new obesity prevention and treatment strategies. PMID- 22238403 TI - Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect? AB - CONTEXT: In fertile patients the endometrial Wilms tumor suppressor gene (WT1) is expressed during the window of implantation. Polycystic ovary syndrome (PCOS) patients suffer from hyperandrogenemia and infertility and have elevated endometrial androgen receptor (AR) expression. WT1 is known to be down-regulated by AR. Therefore, the expression of WT1 and its targets may be altered in PCOS endometrium. OBJECTIVE: The objective of the study was to assess the expression and regulation of WT1 and selected downstream targets in secretory endometrium from ovulatory PCOS (ovPCOS) and fertile women. DESIGN AND PATIENTS: Endometrial samples were obtained from 25 ovPCOS and 25 fertile patients. MAIN OUTCOME MEASURE: Endometrial expression of WT1 and selected downstream targets were assessed by immunohistochemistry and RT-PCR. The androgen effect on WT1 expression was determined in vitro by immunoblots and RT-PCR. The expression of WT1 and its targets was quantified in fertile and ovPCOS stromal cells in the presence of androgens by RT-PCR. Caspase-3/7 activity was measured to evaluate sensitivity to drug-induced apoptosis. RESULTS: WT1 expression was down-regulated in secretory-phase ovPCOS endometrium. Stromal expression of Bcl-2 and p27 was higher, and epidermal growth factor receptor was lower in ovPCOS than in fertile patients. Endometrial stromal expression of WT1, Bcl-2, Bcl-2-associated X protein, and beta-catenin was regulated by androgens. Apoptosis levels were reduced in ovPCOS samples and androgen-treated fertile samples. CONCLUSION: WT1 expression is down-regulated in ovPCOS endometrium during the window of implantation. Androgens regulate the expression of WT1 and its targets during endometrial decidualization. The altered balance between WT1 and AR in the endometrium of PCOS patients may jeopardize the success of decidualization and endometrial receptivity. PMID- 22238404 TI - Atypical celiac disease as cause of increased need for thyroxine: a systematic study. AB - OBJECTIVE: Replacement T4 dose in hypothyroid patients bearing both chronic autoimmune thyroiditis and atypical celiac disease (CD) has been analyzed. DESIGN: Replacement T4 dose has been analyzed in 35 hypothyroid patients with Hashimoto's thyroiditis (HT) and atypical CD, as defined by the American Gastroenterological Association. We have evaluated the ability of the same dose of T4 to reach target TSH in 21 patients before and during gluten-free diet (GFD). In the remaining 14 patients, noncompliant with GFD, we analyzed replacement T4 dose and compared it with that in a similar group consisting of 68 patients with hypothyroid HT but no evidence of celiac sprue or other conditions interfering with T4 absorption. RESULTS: In patients with isolated HT, the desired serum TSH (median=1.02 mU/liter) was reached in all patients after 5+/-2 months of treatment at a median T4 dose of 1.31 MUg/kg.d. After a similar period and dose of T4, higher levels of TSH (median=4.20 mU/liter) were observed in patients with HT and CD. In 21 CD patients, target TSH (median TSH=1.25 mU/liter) has been attained after 11+/-3 months of GFD without increasing T4 dose (1.32 MUg/kg.d). In the remaining 14 patients, who were noncompliant with GFD, target TSH has also been achieved but at a higher T4 dose (median=1.96 MUg/kg.d; +49%; P=0.0002) than in hypothyroid patients without CD. CONCLUSIONS: Atypical CD increases the need for T4. The effect was reversed by GFD or by increasing T4 dose. Malabsorption of T4 may provide the opportunity to detect CD that was overlooked until the patients were put under T4 therapy. PMID- 22238405 TI - Primary hyperparathyroidism and celiac disease: a population-based cohort study. AB - CONTEXT: Celiac disease (CD) has been linked to several endocrine disorders, including type 1 diabetes and thyroid disorders, but little is known regarding its association to primary hyperparathyroidism (PHPT). OBJECTIVE: The aim of the study was to examine the risk of PHPT in patients with CD. DESIGN AND SETTING: We conducted a two-group exposure-matched nonconcurrent cohort study in Sweden. A Cox regression model estimated hazard ratios (HR) for PHPT. PARTICIPANTS: We identified 17,121 adult patients with CD who were diagnosed through biopsy reports (Marsh 3, villous atrophy) from all 28 pathology departments in Sweden. Biopsies were performed in 1969-2008, and biopsy report data were collected in 2006-2008. Statistics Sweden then identified 85,166 reference individuals matched with the CD patients for age, sex, calendar period, and county. MAIN OUTCOME MEASURE: PHPT was measured according to the Swedish national registers on inpatient care, outpatient care, day surgery, and cancer. RESULTS: During follow up, 68 patients with CD and 172 reference individuals developed PHPT (HR=1.91; 95% confidence interval=1.44-2.52). The absolute risk of PHPT was 42/100,000 person-years with an excess risk of 20/100,000 person-years. The risk increase for PHPT only occurred in the first 5 yr of follow-up; after that, HR were close to 1 (HR=1.07; 95% confidence interval=0.70-1.66). CONCLUSIONS: CD patients are at increased risk of PHPT, but the absolute risk is small, and the excess risk disappeared after more than 5 yr of follow-up. PMID- 22238406 TI - Symptomatic heterozygotes and prenatal diagnoses in a nonconsanguineous family with syndromic combined pituitary hormone deficiency resulting from two novel LHX3 mutations. AB - CONTEXT: Only 11 mutations have been reported in the transcription factor LHX3, known to be important for the development of the pituitary and motor neurons. All patients were homozygous, with various syndromic forms of combined pituitary hormone deficiency (CPHD), hampering to allocate, in these consanguineous patients, the respective contribution of LHX3 and additional genes to each symptom. OBJECTIVE: The aim of the study was to report the family history and the molecular basis of a nonconsanguineous patient with syndromic CPHD. PATIENT: The patient, who presented at birth with respiratory distress, had a syndromic CPHD, including severe scoliosis, and normal intelligence. His father and paternal grandmother displayed limited head rotation. RESULTS: Two new LHX3 defects were identified. The paternally inherited c.252-3C>G mutation, which disrupts an acceptor splice site, would lead to severely truncated proteins containing a single LIM domain, resembling LIM-only proteins. Coexpression studies revealed the dominant-negative effect of this LIM-only protein over the wild-type LHX3. The maternally inherited p.Cys118Tyr mutation results in partial loss of transcriptional activity and synergy with POU1F1. Given the severity of the patient's phenotype, two prenatal diagnoses were performed: the first led to pregnancy interruption, the second to the birth of a healthy boy. CONCLUSIONS: This study of the first nonconsanguineous patient with LHX3 mutations demonstrates the pleiotropic roles of LHX3 during development and its full involvement in the complex disease phenotype. Isolated limitation of head rotation may exist in heterozygous carriers and would result from a dominant negative effect. These data allowed the first prenatal diagnoses of this severe condition to be performed. PMID- 22238407 TI - 18-hydroxycorticosterone, 18-hydroxycortisol, and 18-oxocortisol in the diagnosis of primary aldosteronism and its subtypes. AB - CONTEXT: Diagnosis of primary aldosteronism (PA) is made by screening, confirmation testing, and subtype diagnosis (computed tomography scan and adrenal vein sampling). However, some tests are costly and unavailable in most hospitals. OBJECTIVE: The aim of the study was to evaluate the role of serum 18 hydroxycorticosterone (s18OHB), urinary and serum 18-hydroxycortisol (u- and s18OHF), and urinary and serum 18-oxocortisol (u- and s18oxoF) in the diagnosis of PA and its subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). PATIENTS: The study included 62 patients with low-renin essential hypertension (EH), 81 patients with PA (20 APA, 61 BAH), 24 patients with glucocorticoid-remediable aldosteronism, 16 patients with adrenal incidentaloma, and 30 normotensives. INTERVENTION AND MAIN OUTCOME MEASURES: We measured s18OHB, s18OHF, and s18oxoF before and after saline load test (SLT) and 24-h u18OHF and u18oxoF. RESULTS: PA patients displayed significantly higher levels of s18OHB, u18OHF, and u18oxoF compared to EH and normal subjects; APA patients displayed s18OHB, u18OHF, and u18oxoF levels significantly higher than BAH patients. Similar results were obtained for s18OHF and s18oxoF. SLT significantly reduced s18OHB, s18OHF, and s18oxoF in all groups, but steroid reduction was much less for APA patients compared to BAH and EH. The s18OHB/aldosterone ratio after SLT more than doubled in EH but remained unchanged in APA patients. CONCLUSIONS: u18OHF, u18oxoF, and s18OHB measurements in patients with a positive aldosterone/plasma renin activity ratio correlate with confirmatory tests and adrenal vein sampling in PA patients. If verified, these steroid assays would refine the diagnostic workup for PA. PMID- 22238408 TI - Racial and ethnic differences in the relationship between HbA1c and blood glucose: implications for the diagnosis of diabetes. AB - Hemoglobin A1c (HbA1c) is widely used as an index of mean glycemia in diabetes, as a measure of risk for the development of diabetic complications, and as a measure of the quality of diabetes care. In 2010, the American Diabetes Association recommended that HbA1c tests, performed in a laboratory using a method certified by the National Glycohemoglobin Standardization Program, be used for the diagnosis of diabetes. Although HbA1c has a number of advantages compared to traditional glucose criteria, it has a number of disadvantages. Hemoglobinopathies, thalassemia syndromes, factors that impact red blood cell survival and red blood cell age, uremia, hyperbilirubinemia, and iron deficiency may alter HbA1c test results as a measure of average glycemia. Recently, racial and ethnic differences in the relationship between HbA1c and blood glucose have also been described. Although the reasons for racial and ethnic differences remain unknown, factors such as differences in red cell survival, extracellular intracellular glucose balance, and nonglycemic genetic determinants of hemoglobin glycation are being explored as contributors. Until the reasons for these differences are more clearly defined, reliance on HbA1c as the sole, or even preferred, criterion for the diagnosis of diabetes creates the potential for systematic error and misclassification. HbA1c must be used thoughtfully and in combination with traditional glucose criteria when screening for and diagnosing diabetes. PMID- 22238409 TI - Ocular signs of multiple endocrine neoplasia type 2B (MEN2B). PMID- 22238410 TI - Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease? AB - OBJECTIVE: To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD). METHODS: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment. Both patients had increased glycogen levels in muscle and PHK activity <11% of normal. Two novel pathogenic nonsense mutations were found in the PHKA1 gene. The metabolic response to anaerobic forearm exercise and aerobic cycle exercise was studied in the patients and 5 healthy subjects. RESULTS: Ischemic exercise showed a normal 5-fold increase in plasma lactate (peak 5.7 and 6.9 mmol/L) but an exaggerated 5-fold increase in ammonia (peak 197 and 171 MUmol/L; control peak range 60-113 MUmol/L). An incremental exercise test to exhaustion revealed a blunted lactate response (5.4 and 4.8 mmol/L) vs that for control subjects (9.6 mmol/L; range 7.1-14.3 mmol/L). Fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. None of the patients developed a second wind phenomenon or improved their work capacity with an IV glucose infusion. CONCLUSION: Our findings demonstrate that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis is probably explained by an alternative activation of myophosphorylase by AMP and P(i) at high exercise intensities. PMID- 22238411 TI - Prestroke/poststroke fMRI in aphasia: perilesional hemodynamic activation and language recovery. PMID- 22238412 TI - Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke: a randomized trial. AB - OBJECTIVE: To investigate the long-term behavioral and neurophysiologic effects of combined time-locked repetitive transcranial magnetic stimulation (rTMS) and physical therapy (PT) intervention in chronic stroke patients with mild motor disabilities. METHODS: Thirty patients were enrolled in a double-blind, randomized, single-center clinical trial. Patients received 10 daily sessions of 1 Hz rTMS over the intact motor cortex. In different groups, stimulation was either real (rTMS(R)) or sham (rTMS(S)) and was administered either immediately before or after PT. Outcome measures included dexterity, force, interhemispheric inhibition, and corticospinal excitability and were assessed for 3 months after the end of treatment. RESULTS: Treatment induced cumulative rebalance of excitability in the 2 hemispheres and a reduction of interhemispheric inhibition in the rTMS(R) groups. Use-dependent improvements were detected in all groups. Improvements in trained abilities were small and transitory in rTMS(S) patients. Greater behavioral and neurophysiologic outcomes were found after rTMS(R), with the group receiving rTMS(R) before PT (rTMS(R)-PT) showing robust and stable improvements and the other group (PT-rTMS(R)) showing a slight improvement decline over time. CONCLUSION: Our findings indicate that priming PT with inhibitory rTMS is optimal to boost use-dependent plasticity and rebalance motor excitability and suggest that time-locked rTMS is a valid and promising approach for chronic stroke patients with mild motor impairment. CLASSIFICATION OF EVIDENCE: This interventional study provides Class I evidence that time-locked rTMS before or after physical therapy improves measures of dexterity and force in the affected limb in patients with chronic deficits more than 6 months poststroke. PMID- 22238413 TI - What T-cell receptors can tell us about neurologic disease. PMID- 22238414 TI - Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease. AB - OBJECTIVE: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). METHODS: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. RESULTS: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Abeta(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. CONCLUSIONS: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria. PMID- 22238416 TI - CD8+ T-cell immunity in chronic inflammatory demyelinating polyradiculoneuropathy. AB - OBJECTIVE: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease. METHODS: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies. RESULTS: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients' peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve infiltrating CD8+ T-cell clones was visualized by immunohistochemistry. CONCLUSIONS: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP. PMID- 22238415 TI - FLNA genomic rearrangements cause periventricular nodular heterotopia. AB - OBJECTIVE: To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNA sequencing is negative. METHODS: Screening of 35 patients from 33 pedigrees on an Affymetrix 6.0 microarray led to the identification of one individual bearing a CNV that disrupted FLNA. FLNA-disrupting CNVs were also isolated in 2 other individuals by multiplex ligation probe amplification. These 3 cases were further characterized by high-resolution oligo array comparative genomic hybridization (CGH), and the precise junctional breakpoints of the rearrangements were identified by PCR amplification and sequencing. RESULTS: We report 3 cases of PNH caused by nonrecurrent genomic rearrangements that disrupt one copy of FLNA. The first individual carried a 113-kb deletion that removes all but the first exon of FLNA. A second patient harbored a complex rearrangement including a deletion of the 3' end of FLNA accompanied by a partial duplication event. A third patient bore a 39 kb deletion encompassing all of FLNA and the neighboring gene EMD. High resolution oligo array CGH of the FLNA locus suggests distinct molecular mechanisms for each of these rearrangements, and implicates nearby low copy repeats in their pathogenesis. CONCLUSIONS: These results demonstrate that FLNA is prone to pathogenic rearrangements, and highlight the importance of screening for CNVs in individuals with PNH lacking FLNA point mutations. PMID- 22238417 TI - Alzheimer disease: can the exam predict the pathology? PMID- 22238418 TI - Cerebral hemodynamics and cognitive impairment: baseline data from the RECON trial. AB - OBJECTIVE: To determine whether unihemispheral hemodynamic failure is independently associated with cognitive impairment among participants in the National Institute of Neurological Disorders and Stroke-sponsored, multicenter, randomized clinical trial, Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON). METHODS: Forty-three patients were randomized into RECON after recent symptomatic carotid artery occlusion and asymmetrically increased oxygen extraction fraction (OEF) by PET (OEF ratio >1.13), indicating stage II hemodynamic failure on the side of occlusion. The PET-positive patients were compared with 28 RECON-enrolled patients who met all clinical and radiographic inclusion/exclusion criteria but had no OEF asymmetry. A multivariable regression compared patients with PET OEF >1.13 or <=1.13, stratifying by TIA vs. stroke as the qualifying event. The dependent variable was a composite neurocognitive score derived from averaging age-normalized z scores on a test battery that included global and internal carotid artery (ICA) side-relevant hemisphere-specific tests. RESULTS: There were no differences in demographic, clinical, or radiologic characteristics between the PET-positive and PET-negative patients except for PET OEF asymmetry. The unadjusted average neurocognitive z score was -1.45 for the PET-positive and -1.25 for the PET-negative patients, indicating cognitive impairment in both groups but no difference between them (p = 0.641). After adjustment for age, education, side of occlusion, depression, and previous stroke, there was a significant difference between PET-positive and PET-negative patients among those with TIA as a qualifying event (average z score = -1.41 vs. 0.76, p = 0.040). Older age and right ICA side were also significant in this model. CONCLUSION: Hemodynamic failure is independently associated with cognitive impairment in patients with carotid occlusion. This finding establishes the physiologic parameter upon which the extracranial-intracranial bypass will be tested. PMID- 22238419 TI - Functional recovery after ischemic stroke--a matter of age: data from the Austrian Stroke Unit Registry. AB - OBJECTIVE: To analyze the association between patient age and good functional outcome after ischemic stroke with special focus on young patients who were numerically underrepresented in previous evaluations. METHODS: Of 43,163 ischemic stroke patients prospectively enrolled in the Austrian Stroke Unit Registry, 6,084 (14.1%) were <=55 years old. Functional outcome was available in a representative subsample of 14,256 patients free of prestroke disability, 2,223 of whom were 55 years or younger. Herein we analyzed the effects of age on good functional outcome 3 months after stroke (modified Rankin Scale score <=2). RESULTS: Good outcome was achieved in 88.2% (unadjusted probability) of young stroke patients (<=55 years). In multivariable analysis, age emerged as a significant predictor of outcome independent of stroke severity, etiology, performance of thrombolysis, sex, risk factors, and stroke complications. When the age stratum 56-65 years was used as a reference, odds ratios (95% confidence interval [95% CI]) of good outcome were 3.4 (1.9-6.4), 2.2 (1.6-3.2), and 1.5 (1.2-1.9) for patients aged 18-35, 36-45, and 46-55 years and 0.70 (0.60-0.81), 0.32 (0.28-0.37), and 0.18 (0.14-0.22) for those aged 66-75, 76-85, and >85 years (p < 0.001). In absolute terms, the regression-adjusted probability of good outcome was highest in the age group 18-35 years and gradually declined by 3.1% 4.2% per decade until age 75 with a steep drop thereafter. Findings applied equally to sexes and patients with and without IV thrombolysis or diabetes. CONCLUSIONS: Age emerged as a highly significant inverse predictor of good functional outcome after ischemic stroke independent of stroke severity, characteristics, and complications with the age-outcome association exhibiting a nonlinear scale and extending to young stroke patients. PMID- 22238420 TI - TsHKT1;2, a HKT1 homolog from the extremophile Arabidopsis relative Thellungiella salsuginea, shows K(+) specificity in the presence of NaCl. AB - Cellular Na(+)/K(+) ratio is a crucial parameter determining plant salinity stress resistance. We tested the function of plasma membrane Na(+)/K(+) cotransporters in the High-affinity K(+) Transporter (HKT) family from the halophytic Arabidopsis (Arabidopsis thaliana) relative Thellungiella salsuginea. T. salsuginea contains at least two HKT genes. TsHKT1;1 is expressed at very low levels, while the abundant TsHKT1;2 is transcriptionally strongly up-regulated by salt stress. TsHKT-based RNA interference in T. salsuginea resulted in Na(+) sensitivity and K(+) deficiency. The athkt1 mutant lines overexpressing TsHKT1;2 proved less sensitive to Na(+) and showed less K(+) deficiency than lines overexpressing AtHKT1. TsHKT1;2 ectopically expressed in yeast mutants lacking Na(+) or K(+) transporters revealed strong K(+) transporter activity and selectivity for K(+) over Na(+). Altering two amino acid residues in TsHKT1;2 to mimic the AtHKT1 sequence resulted in enhanced sodium uptake and loss of the TsHKT1;2 intrinsic K(+) transporter activity. We consider the maintenance of K(+) uptake through TsHKT1;2 under salt stress an important component supporting the halophytic lifestyle of T. salsuginea. PMID- 22238422 TI - Visual tracking of plant virus infection and movement using a reporter MYB transcription factor that activates anthocyanin biosynthesis. AB - Insertion of reporter genes into plant virus genomes is a common experimental strategy to research many aspects of the viral infection dynamics. Their numerous advantages make fluorescent proteins the markers of choice in most studies. However, the use of fluorescent proteins still has some limitations, such as the need of specialized material and facilities to detect the fluorescence. Here, we demonstrate a visual reporter marker system to track virus infection and movement through the plant. The reporter system is based on expression of Antirrhinum majus MYB-related Rosea1 (Ros1) transcription factor (220 amino acids; 25.7 kD) that activates a series of biosynthetic genes leading to accumulation of colored anthocyanins. Using two different tobacco etch potyvirus recombinant clones tagged with Ros1, we show that infected tobacco (Nicotiana tabacum) tissues turn bright red, demonstrating that in this context, the sole expression of Ros1 is sufficient to induce pigment accumulation to a level readily detectable to the naked eye. This marker system also reports viral load qualitatively and quantitatively by means of a very simple extraction process. The Ros1 marker remained stable within the potyvirus genome through successive infectious passages from plant to plant. The main limitation of this marker system is that color output will depend on each particular plant host-virus combination and must be previously tested. However, our experiments demonstrate accurate tracking of turnip mosaic potyvirus infecting Arabidopsis (Arabidopsis thaliana) and either tobacco mosaic virus or potato X virus infecting Nicotiana benthamiana, stressing the general applicability of the method. PMID- 22238421 TI - Laticifer-specific cis-prenyltransferase silencing affects the rubber, triterpene, and inulin content of Taraxacum brevicorniculatum. AB - Certain Taraxacum species, such as Taraxacum koksaghyz and Taraxacum brevicorniculatum, produce large amounts of high-quality natural rubber in their latex, the milky cytoplasm of specialized cells known as laticifers. This high molecular mass biopolymer consists mainly of poly(cis-1,4-isoprene) and is deposited in rubber particles by particle-bound enzymes that carry out the stereospecific condensation of isopentenyl diphosphate units. The polymer configuration suggests that the chain-elongating enzyme (rubber transferase; EC 2.5.1.20) is a cis-prenyltransferase (CPT). Here, we present a comprehensive analysis of transgenic T. brevicorniculatum plants in which the expression of three recently isolated CPTs known to be associated with rubber particles (TbCPT1 to -3) was heavily depleted by laticifer-specific RNA interference (RNAi). Analysis of the CPT-RNAi plants by nuclear magnetic resonance, size-exclusion chromatography, and gas chromatography-mass spectrometry indicated a significant reduction in rubber biosynthesis and a corresponding 50% increase in the levels of triterpenes and the main storage carbohydrate, inulin. Transmission electron microscopy revealed that the laticifers in CPT-RNAi plants contained fewer and smaller rubber particles than wild-type laticifers. We also observed lower activity of hydroxymethylglutaryl-coenzyme A reductase, the key enzyme in the mevalonate pathway, reflecting homeostatic control of the isopentenyl diphosphate pool. To our knowledge, this is the first in planta demonstration of latex specific CPT activity in rubber biosynthesis. PMID- 22238423 TI - Sampling protein motion and solvent effect during ligand binding. AB - An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one. PMID- 22238424 TI - Classification of protein functional surfaces using structural characteristics. AB - Protein structure and function are closely related, especially in functional surfaces, which are local spatial regions that perform the biological functions. Also, protein structures tend to evolve more slowly than amino acid sequences. We have therefore developed a method to classify proteins using the structures of functional surfaces; we call it protein surface classification (PSC). PSC may reflect functional relationships among proteins and may detect evolutionary relationships among highly divergent sequences. We focused on the surfaces of ligand-bound regions because they represent well-defined structures. Specifically, we used structural attributes to measure similarities between binding surfaces and constructed a PSC library of ~2,000 binding surface types from the bound forms. Using flavin mononucleotide-binding proteins and glycosidases as examples, we show how the evolutionary position of an uncharacterized protein can be defined and its function inferred from the characterized members of the same surface subtype. We found that proteins with the same enzyme nomenclature may be divided into subtypes and that two proteins in the same CATH (Class, Architecture, Topology, Homologous superfamily) fold may belong to two different surface types. In conclusion, our approach complements the sequence-based and fold-domain classifications and has the advantage of associating the shape of a protein with its biological function. As an expandable library, PSC provides a resource of spatial patterns for studying the evolution of protein structure and function. PMID- 22238425 TI - Glycogen synthase kinase 3beta transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K+ channels. AB - Despite compelling evidence supporting key roles for glycogen synthase kinase 3beta (GSK3beta), mitochondrial adenosine triphosphate-sensitive K(+) (mitoK(ATP)) channels, and mitochondrial connexin 43 (Cx43) in cytoprotection, it is not clear how these signaling modules are linked mechanistically. By patch clamping the inner membrane of murine cardiac mitochondria, we found that inhibition of GSK3beta activated mitoK(ATP). PKC activation and protein phosphatase 2a inhibition increased the open probability of mitoK(ATP) channels through GSK3beta, and this GSK3beta signal was mediated via mitochondrial Cx43. Moreover, (i) PKC-induced phosphorylation of mitochondrial Cx43 was reduced in GSK3beta-S9A mice; (ii) Cx43 and GSK3beta proteins associated in mitochondria; and (iii) SB216763-mediated reduction of infarct size was abolished in Cx43 KO mice in vivo, consistent with the notion that GSK3beta inhibition results in mitoK(ATP) opening via mitochondrial Cx43. We therefore directly targeted mitochondrial Cx43 by the Cx43 C-terminal binding peptide RRNYRRNY for cardioprotection, circumventing further upstream pathways. RRNYRRNY activated mitoK(ATP) channels via Cx43. We directly recorded mitochondrial Cx43 channels that were activated by RRNYRRNY and blocked by the Cx43 mimetic peptide (43)GAP27. RRNYRRNY rendered isolated cardiomyocytes in vitro and the heart in vivo resistant to ischemia/reperfusion injury, indicating that mitochondrial Cx43 and/or mitoK(ATP)-mediated reduction of infarct size was not undermined by RRNYRRNY-related opening of sarcolemmal Cx43 channels. Our results demonstrate that GSK3beta transfers cytoprotective signaling through mitochondrial Cx43 onto mitoK(ATP) channels and that Cx43 functions as a channel in mitochondria, being an attractive target for drug treatment against cardiomyocyte injury. PMID- 22238426 TI - Synthetic in vivo validation of gene network circuitry. AB - Embryonic development is controlled by networks of interacting regulatory genes. The individual linkages of gene regulatory networks (GRNs) are customarily validated by functional cis-regulatory analysis, but an additional approach to validation is to rewire GRN circuitry to test experimentally predictions derived from network structure. Here we use this synthetic method to challenge specific predictions of the sea urchin embryo endomesoderm GRN. Expression vectors generated by in vitro recombination of exogenous sequences into BACs were used to cause elements of a nonskeletogenic mesoderm GRN to be deployed in skeletogenic cells and to detect their effects. The result of reengineering the regulatory circuitry in this way was to divert the developmental program of these cells from skeletogenesis to pigment cell formation, confirming a direct prediction of the GRN. In addition, the experiment revealed previously undetected cryptic repression functions. PMID- 22238427 TI - Characterization of MADS-domain transcription factor complexes in Arabidopsis flower development. AB - Floral organs are specified by the combinatorial action of MADS-domain transcription factors, yet the mechanisms by which MADS-domain proteins activate or repress the expression of their target genes and the nature of their cofactors are still largely unknown. Here, we show using affinity purification and mass spectrometry that five major floral homeotic MADS-domain proteins (AP1, AP3, PI, AG, and SEP3) interact in floral tissues as proposed in the "floral quartet" model. In vitro studies confirmed a flexible composition of MADS-domain protein complexes depending on relative protein concentrations and DNA sequence. In situ bimolecular fluorescent complementation assays demonstrate that MADS-domain proteins interact during meristematic stages of flower development. By applying a targeted proteomics approach we were able to establish a MADS-domain protein interactome that strongly supports a mechanistic link between MADS-domain proteins and chromatin remodeling factors. Furthermore, members of other transcription factor families were identified as interaction partners of floral MADS-domain proteins suggesting various specific combinatorial modes of action. PMID- 22238429 TI - Study on CCR5 analogs and affinity peptides. AB - The G protein-coupled receptor of human chemokine receptor 5 (CCR5) is a key target in the human immunodeficiency virus (HIV) infection process due to its major involvement in binding to the HIV type 1 (HIV-1) envelope glycoprotein gp120 and facilitating virus entry into the cells. The identification of naturally occurring CCR5 mutations (especially CCR5 delta-32) has allowed us to address the CCR5 molecule as a promising target to prevent or resist HIV infection in vivo. To obtain high-affinity peptides that can be used to block CCR5, CCR5 analogs with high conformational similarity are required. In this study, two recombinant proteins named CCR5 N-Linker-E2 and CCR5 mN-E1-E2 containing the fragments of the CCR5 N-terminal, the first extracellular loop or the second extracellular loop are cloned from a full-length human CCR5 cDNA. The recombinant human CCR5 analogs with self-cleavage activity of the intein Mxe or Ssp in the vector pTwinI were then produced with a high-yield expression and purification system in Escherichia coli. Experiments of extracellular epitope activity identification (such as immunoprecipitation and indirective/competitive enzyme-linked immunosorbent assay) confirmed the close similarity between the epitope activity of the CCR5 analogs and that of the natural CCR5, suggesting the applicability of the recombinant CCR5 analogs as antagonists of the chemokine ligands. Subsequent screening of high-affinity peptides from the phage random peptides library acquired nine polypeptides, which could be used as CCR5 peptide antagonists. The CCR5 analogs and affinity peptides elucidated in this paper provide us with a basis for further study of the mechanism of inhibition of HIV-1 infection. PMID- 22238430 TI - Half-life extension of a single-chain diabody by fusion to domain B of staphylococcal protein A. AB - Binding of a therapeutic protein to a long-circulating plasma protein can result in a strongly extended half-life. Among these plasma proteins, albumin and immunoglobulins are of special interest because of their exceptionally long half life, which is to a great extent determined by recycling through the neonatal Fc receptor (FcRn). Many strategies have been established employing reversible binding to albumin, e.g. using an albumin-binding domain from streptococcal protein G. We show here that the half-life of a recombinant antibody molecule can also be prolonged by fusion to a single immunoglobulin-binding domain (IgBD) from staphylococcal protein A. This domain (domain B, SpA(B)) is composed of 56 amino acid residues and was fused to the C-terminus of a bispecific single-chain diabody (scDb). The scDb-SpA(B) fusion protein was produced in HEK293 cells and retained its antigen-binding activity as shown by enzyme-linked immunosorbent assay and flow cytometry. Furthermore, the fusion protein was capable of binding to human and mouse IgG in a pH-dependent manner. In mice, the terminal half-life of the fusion protein was improved from ~1-2 h of the unmodified scDb to 11.8 h. Although the fusion protein did not reach the long half-life seen for IgG, our results established the applicability of a single bacterial IgBD for half-life extension purposes. PMID- 22238431 TI - Endobronchial ultrasound guided transbronchial needle aspiration: a novel way to diagnose metastatic urological cancer. PMID- 22238432 TI - Comparison of commercial extraction systems and PCR assays for quantification of Epstein-Barr virus DNA load in whole blood. AB - The automation of DNA extraction and the use of commercial quantitative real-time PCR assays could help obtain more reliable results for the quantification of Epstein-Barr virus DNA loads (EBV VL). This study compared two automated extraction platforms and two commercial PCRs for measurement of EBV VL in 10 EBV specimens from Quality Control for Molecular Diagnostics (QCMD) and in 200 whole blood (WB) specimens from transplant (n = 137) and nontransplant (n = 63) patients. The WB specimens were extracted using the QIAcube or MagNA Pure instrument; VL were quantified with the EBV R-gene quantification kit (Argene) or the artus EBV RG PCR kit (Qiagen) on the Rotor-Gene 6000 real-time analyzer; and the results were compared with those of a laboratory-developed PCR. DNA was extracted from the QCMD specimens by use of the QIAamp DNA minikit and was quantified by the three PCR assays. The extraction platforms and the PCR assays showed good correlation (R, >0.9; P, <0.0001), but as many as 10% discordant results were observed, mostly for low viral loads (<3 log(10) copies/ml), and standard deviations reached as high as 0.49 log(10) copy/ml. In WB but not in QCMD samples, Argene PCR tended to give higher VL values than artus PCR or the laboratory-developed PCR (mean difference for the 200 WB VL, -0.42 or -0.36, respectively). In conclusion, the two automated extraction platforms and the two PCRs provided reliable and comparable VL results, but differences greater than 0.5 log(10) copy/ml remained between the two commercial PCRs after common DNA extraction. PMID- 22238433 TI - Biological and phylogenetic characterization of a genotype VII Newcastle disease virus from Venezuela: efficacy of field vaccination. AB - Here we report the biological and molecular characterization of a virulent genotype VII Newcastle disease virus (NDV) circulating in Venezuela and the assessment of the vaccination efficacy under field conditions compared to controlled rearing conditions. Biological pathotyping showed a mean embryo dead time of 50 h and an intracerebral pathogenicity index of 1.86. Sequence-based phylogenetic analysis demonstrated that the virus belongs to genotype VII in class II (a genotype often found in Asia and Africa), representing the first report of the presence of this genotype in the continent of South America. A vaccine-challenge trial in commercial broilers reared in fields or in a experimental setting included dual (live/killed) priming of 1-day-old chicks plus two live NDV and infectious bursal disease virus (IBDV) field vaccinations at days 7 and 17, followed by a very stringent genotype VII NDV challenge at day 28. Serology for NDV and IBDV, bursal integrity, and protection against NDV lethal challenge were assessed. At 28 days, field vaccinates showed significantly lower NDV (1,356 versus 2,384) and higher IBD (7,295 versus 1,489) enzyme-linked immunosorbent assay (ELISA) antibody titers than the experimentally reared birds. A lower bursal size and bursa-body weight ratio (P < 0.05) and higher bursa lesion score were also detected in the field set. Only 57.1% of field vaccinates survived the lethal challenge, differing (P < 0.05) from 90.5% survival in the experimental farm. Overall, results confirmed the presence of the genotype VII viruses in South America and suggest that field-associated factors such as immunosuppression compromise the efficacy of the vaccination protocols implemented. PMID- 22238435 TI - Comparative study using phenotypic, genotypic, and proteomics methods for identification of coagulase-negative staphylococci. AB - Five methods were compared to determine the most accurate method for identification of coagulase-negative staphylococci (CoNS) (n = 142 strains). Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) showed the best results for rapid and accurate CoNS differentiation (99.3% of strains correctly identified). An alternative to this approach could be Vitek2 combined with partial tuf gene sequencing (100% of strains correctly identified when both methods are performed simultaneously). PMID- 22238434 TI - Incidence and virulence determinants of verocytotoxin-producing Escherichia coli infections in the Brussels-Capital Region, Belgium, in 2008-2010. AB - The incidence of verocytotoxin-producing Escherichia coli (VTEC) was investigated by PCR in all human stools from Universitair Ziekenhuis Brussel (UZB) and in selected stools from six other hospital laboratories in the Brussels-Capital Region, Belgium, collected between April 2008 and October 2010. The stools selected to be included in this study were those from patients with hemolytic uremic syndrome (HUS), patients with a history of bloody diarrhea, patients linked to clusters of diarrhea, children up to the age of 6 years, and stools containing macroscopic blood. Verocytotoxin genes (vtx) were detected significantly more frequently in stools from patients with the selected conditions (2.04%) than in unselected stools from UZB (1.20%) (P = 0.001). VTEC was detected most frequently in patients with HUS (35.3%), a history of bloody diarrhea (5.15%), or stools containing macroscopic blood (1.85%). Stools from patients up to the age of 17 years were significantly more frequently vtx positive than those from adult patients between the ages of 18 and 65 years (P = 0.022). Although stools from patients older than 65 years were also more frequently positive for vtx than those from patients between 18 and 65 years, this trend was not significant. VTEC was isolated from 140 (67.9%) vtx-positive stools. One sample yielded two different serotypes; thus, 141 isolates could be characterized. Sixty different O:H serotypes harboring 85 different virulence profiles were identified. Serotypes O157:H7/H- (n = 34), O26:H11/H- (n = 21), O63:H6 (n = 8), O111:H8/H- (n = 7), and O146:H21/H- (n = 6) accounted for 53.9% of isolates. All O157 isolates carried vtx2, eae, and a complete O island 122 (COI-122); 15 also carried vtx1. Non-O157 isolates (n = 107), however, accounted for the bulk (75.9%) of isolates. Fifty-nine (55.1%) isolates were positive for vtx1, 36 (33.6%) were positive for vtx2, and 12 (11.2%) carried both vtx1 and vtx2. Pulsed-field gel electrophoresis revealed wide genetic diversity; however, small clusters of O157, O26, and O63:H6 VTEC that could have been part of unidentified outbreaks were identified. Antimicrobial resistance was observed in 63 (44.7%) isolates, and 34 (24.1%) showed multidrug resistance. Our data show that VTEC infections were not limited to patients with HUS or bloody diarrhea. Clinical laboratories should, therefore, screen all stools for O157 and non-O157 VTEC using selective media and a method for detecting verocytotoxins or vtx genes. PMID- 22238436 TI - Bacteriuria screening by automated whole-field-image-based microscopy reduces the number of necessary urine cultures. AB - We evaluated a new automated urine sediment analyzer that provides whole-field images for the screening of urine samples prior to bacterial culture. Sterile urine samples from 1,011 male and female outpatients and inpatients (mean age 54.7) with a urinary tract infection prevalence of 18.3% were studied. Screening rapidly provides negative results. PMID- 22238437 TI - Rapid typing of extended-spectrum beta-lactamase- and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae isolates by use of SpectraCell RA. AB - Enterobacteriaceae are important pathogens of both nosocomial and community acquired infections. In particular, strains with broad-spectrum beta-lactamases increasingly cause problems in health care settings. Rapid and reliable typing systems are key tools to identify transmission, so that targeted infection control measures can be taken. In this study, we evaluated the performance of Raman spectroscopic analysis (RA) for the typing of multiresistant Escherichia coli and Klebsiella pneumoniae isolates using the SpectraCell RA bacterial strain analyzer (River Diagnostics). Analysis of 96 unrelated isolates revealed that RA generated highly reproducible spectra and exhibited a discriminatory power that is comparable to pulsed-field gel electrophoresis. Furthermore, adequate results were obtained for three collections of clinical isolates. RA was able to discriminate outbreak-related isolates from isolates that were not involved in an outbreak or transmission. Furthermore, it was found that the RA approach recognized clones, irrespective of the extended-spectrum beta-lactamase type. It can be concluded that RA is a suitable typing technique for E. coli and K. pneumoniae isolates. Combining high reproducibility, speed, and ease-of-use, this technique may play an important role in monitoring the epidemiology of these important nosocomial species. PMID- 22238438 TI - Time course of prion seeding activity in cerebrospinal fluid of scrapie-infected hamsters after intratongue and intracerebral inoculations. AB - To assess prospects for early diagnosis of prion disease based on prion seeding activity in cerebrospinal fluid (CSF), we measured the activity over time in scrapie-infected hamsters by real-time quaking-induced conversion (RT-QuIC). After intracerebral inoculation, activity appeared in CSF within 1 day and plateaued weeks before the onset of clinical signs. However, after intratongue inoculation, activity first appeared in CSF with the onset of clinical signs, well after higher-level accumulation of seeding activity in brain. PMID- 22238439 TI - First comprehensive evaluation of the M.I.C. evaluator device compared to Etest and CLSI reference dilution methods for antimicrobial susceptibility testing of clinical strains of anaerobes and other fastidious bacterial species. AB - The new M.I.C. Evaluator strip uses test methodology and the recording of results that are similar to those of Etest. For this first assessment, 102 clinical strains of anaerobic bacteria from 12 genera and 155 strains from 7 genera and 8 species of fastidious bacteria were tested by M.I.C. Evaluator, Etest, and agar dilution or broth microdilution as a reference standard. Ampicillin, amoxicillin, amoxicillin-clavulanate, cefotaxime, ciprofloxacin, erythromycin, imipenem, levofloxacin, metronidazole, penicillin, and tetracycline were tested depending on the species. Agar dilution for anaerobes was performed according to CLSI document M11-A7. For the fastidious bacteria, CLSI document M45-A2 was followed. For the anaerobes, essential and categorical agreement between M.I.C. Evaluator and Etest was >90%. Compared to agar dilution, essential agreement was low for both strip tests, and many very major errors were observed for metronidazole (13 to 14%) and penicillin (8 to 9%) with isolates from the Bacteroides fragilis group and Clostridium species. For fastidious species, essential agreements for M.I.C. Evaluator and Etest plus or minus one doubling dilution were >95%. Compared to broth microdilution, essential agreements were low (40 to 90%) plus or minus one dilution and were >90% plus or minus two dilutions, with high overall category agreement (CA). Major and minor errors were within established parameters for all strains tested. The M.I.C. Evaluator strips were equivalent to Etest for anaerobes and fastidious species. These observations require further investigation to determine which methods provide the most accurate MIC for clinical utility. The further evaluation of additional M.I.C. Evaluator agents will be performed as they become available. PMID- 22238440 TI - Characterization of nontypeable and atypical Streptococcus pneumoniae pediatric isolates from 1994 to 2010. AB - Streptococcus pneumoniae is a major cause of bacteremia, meningitis, pneumonia, sinusitis, and acute otitis media in children. Although optochin susceptibility, bile solubility, and Quellung testing are the standards for identifying and differentiating pneumococci, there are several reports of nontypeable pneumococci that give inconsistent results with one or more of these tests. We characterized 52 isolates previously labeled as nontypeable pneumococci. Microbiological methods included repeating the Quellung reaction using a new and expanded group of antisera, optochin susceptibility and bile solubility tests, and automated Vitek 2 identification. Molecular methods included PCR detection of ply and psaA genes, multilocus sequence typing (MLST), 16S rRNA gene sequencing, and pyrosequencing. Of the 52 isolates, 38 (73%) were optochin susceptible, were psaA and ply positive, and could be serotyped by the Quellung reaction. The remaining 14 isolates, isolated from patients with otitis media (n = 6), bacteremia (n = 6), meningitis (n = 1), and pneumonia (n = 1), underwent further analysis. Three of these 14 isolates were nontypeable due to autoagglutination but were pneumococci by all tests and represented pneumococcal sequence types previously recognized by MLST. The 11 remaining isolates were optochin resistant, and 6 of these were bile soluble. Three of 11 were both psaA and ply positive and clustered with pneumococci by MLST (2 were bile soluble); 8 lacked psaA (5 ply positive, 4 bile soluble) and likely belonged to other Streptococcus species. In conclusion, few isolates were truly nontypeable by Quellung reaction, and MLST and the presence of psaA proved useful in distinguishing between atypical pneumococci and other streptococcal species. PMID- 22238441 TI - First comprehensive evaluation of the M.I.C. evaluator device compared to Etest and CLSI broth microdilution for MIC testing of aerobic Gram-positive and Gram negative bacterial species. AB - The M.I.C. Evaluator strip (Thermo Fisher Scientific, Basingstoke, United Kingdom) uses a methodology similar to that of Etest. In this first assessment of the M.I.C. Evaluator device, 409 strains of aerobic Gram-positive bacteria (staphylococci, streptococci, and enterococci) and 325 strains of Enterobacteriaceae, Pseudomonas species, and Acinetobacter species were tested by M.I.C. Evaluator strip, Etest, and broth microdilution as a reference standard. The Gram-positive bacteria included staphylococci (methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, and coagulase-negative staphylococci), Streptococcus pneumoniae, beta-hemolytic streptococci and viridians group strains, vancomycin-resistant enterococci, and other enterococci. The Gram-negative bacteria included 250 strains of 60 Enterobacteriaceae species plus 50 Pseudomonas and 25 Acinetobacter species. A total of 14 antimicrobial agents (depending on the species) were included. The same methodology and reading format were used for M.I.C. Evaluator strips and Etest. Broth microdilution methodology was performed according to CLSI document M07-A8. For the clinical strains, >95% of results were plus or minus one doubling dilution for all species. There were fewer than 5% minor errors, fewer than 3% major errors, and fewer than 1% very major errors. M.I.C. Evaluator strips and Etest often reported higher MICs than the reference broth microdilution method. The M.I.C. Evaluator strips provided results comparable to those of the predicate Etest device and are of value for the accurate testing of MICs for these important pathogens. PMID- 22238442 TI - Multilocus sequence typing of total-genome-sequenced bacteria. AB - Accurate strain identification is essential for anyone working with bacteria. For many species, multilocus sequence typing (MLST) is considered the "gold standard" of typing, but it is traditionally performed in an expensive and time-consuming manner. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available to scientists and routine diagnostic laboratories. Currently, the cost is below that of traditional MLST. The new challenges will be how to extract the relevant information from the large amount of data so as to allow for comparison over time and between laboratories. Ideally, this information should also allow for comparison to historical data. We developed a Web-based method for MLST of 66 bacterial species based on WGS data. As input, the method uses short sequence reads from four sequencing platforms or preassembled genomes. Updates from the MLST databases are downloaded monthly, and the best-matching MLST alleles of the specified MLST scheme are found using a BLAST-based ranking method. The sequence type is then determined by the combination of alleles identified. The method was tested on preassembled genomes from 336 isolates covering 56 MLST schemes, on short sequence reads from 387 isolates covering 10 schemes, and on a small test set of short sequence reads from 29 isolates for which the sequence type had been determined by traditional methods. The method presented here enables investigators to determine the sequence types of their isolates on the basis of WGS data. This method is publicly available at www.cbs.dtu.dk/services/MLST. PMID- 22238443 TI - Genotype MTBDRplus for direct detection of Mycobacterium tuberculosis and drug resistance in strains from gold miners in South Africa. AB - GenoType MTBDRplus is a molecular assay for detection of Mycobacterium tuberculosis and drug resistance. Assay performance as applied directly to consecutive unselected sputum samples has not been established. The objective of this study was to determine the accuracy of the MTBDRplus test for direct detection of M. tuberculosis (in sputum) and for drug resistance in consecutively submitted sputum samples. In this cross-sectional study in South Africa, one sputum specimen from each person suspected of having pulmonary tuberculosis was tested by smear microscopy, direct MTBDRplus, and Mycobacterial Growth Indicator Tube (MGIT) culture with MGIT drug susceptibility testing. MGIT results were the reference standard. We tested 2,510 sputum samples, and 529 (21.1%) were positive for M. tuberculosis by MGIT. Direct MTBDRplus identified M. tuberculosis in 256 of 529 specimens (sensitivity, 48.4%; 95% confidence interval [CI], 44.1, 52.7). The sensitivity of MTBDRplus for M. tuberculosis detection by sputum smear status was as follows: smear negative, 13.7% (95% CI, 9.8, 18.4); smear scanty, 46.2% (95% CI, 19.2, 74.9); smear 1+, 69.1% (95% CI, 55.2, 80.9); smear 2+, 86.3% (95% CI, 73.7, 94.3); smear 3+, 89.8% (95% CI, 83.7, 94.2). Direct MTBDRplus testing was negative for 1,594/1,612 sputum samples that were culture negative for M. tuberculosis (specificity, 98.9%; 95% CI, 98.2, 99.3). For specimens positive for M. tuberculosis by MTBDRplus, this assay's sensitivity and specificity for rifampin resistance were 85.7% (95% CI, 57.2, 98.2) and 96.6% (95% CI, 93.2, 98.6) and for isoniazid resistance they were 62.1% (95% CI, 42.3, 79.3) and 97.9% (95% CI, 94.8, 99.4). For sputum testing, the sensitivity of MTBDRplus is directly related to the specimen's bacillary burden. Our results support recommendations that the MTBDRplus test not be used for direct testing of smear negative or paucibacillary sputum samples. PMID- 22238444 TI - Clinical and laboratory characteristics of Clostridium difficile infection in patients with discordant diagnostic test results. AB - The aim of this study was to compare the clinical and laboratory characteristics of Clostridium difficile infection (CDI) in patients with discordant test results for the cytotoxin assay (CYT) and PCR assays. A retrospective study from May to August 2008 and March to May 2010 was performed. CDI was diagnosed in 128 patients. PCR increased the yield of C. difficile cases by 2-fold compared to that of the CYT assay. Fifty-six cases (44%) were detected by PCR only (CYT negative). Forty-nine percent of patients with non-NAP1 strains were detected by PCR only, compared to 28% of those infected with NAP1 strains (P < 0.05). No significant differences were found in the clinical severity of illness and outcome among patients that tested positive for CDI by both tests (CYT and PCR) compared to those that tested positive by PCR only. PMID- 22238445 TI - Evaluation of the Yeast Traffic Light PNA FISH probes for identification of Candida species from positive blood cultures. AB - The Yeast Traffic Light PNA FISH kit (YTL) correctly identified Candida spp. in 207/216 (96%) positive blood cultures. Discordant results were seen with known cross-reacting species and cultures containing Candida lambica and Rhodotorula mucilaginosa. The YTL provides rapid, reliable identification of the five common Candida species found in blood cultures. PMID- 22238446 TI - A simple, semiselective medium for anaerobic isolation of anginosus group streptococci from patients with chronic lung disease. AB - The anaerobic isolation of anginosus group streptococci (AGS) from respiratory specimens containing diverse microbiota using a semiselective blood agar medium incorporating nalidixic acid and sulfamethazine (NAS) is described. AGS were detected in 60% of tested sputa from patients with cystic fibrosis, chronic obstructive pulmonary disease, and bronchiectasis. This demonstrates NAS to be a diagnostic tool for detecting AGS within the complex microbial communities associated with chronic lung disorders. PMID- 22238447 TI - Genetic analysis of hepatitis A virus strains that induced epidemics in Korea during 2007-2009. AB - Hepatitis A virus is one of the most prominent causes of fecally transmitted acute hepatitis worldwide. In order to characterize the viral agents causing an outbreak in Korea (comprising North and South Korea) from June 2007 to May 2009, we collected specimens and performed genotyping of the VP1/P2A and VP3/VP1 regions of hepatitis A virus. We then used a multiple-alignment algorithm to compare the nucleotide sequences of the 2 regions with those of reference strains. Hepatitis A virus antibodies were detected in 64 patients from 5 reported outbreaks (North Korea, June 2007 [n = 11]; Jeonnam, April 2008 [n = 15]; Daegu, May 2008 [n = 13]; Seoul, May 2009 [n = 22]; and Incheon, May 2009 [n = 3]). We found 100% homology between strains isolated from the Kaesong Industrial Region and Jeonnam. While those strains were classified as genotype IA strains, strains from Seoul and Incheon were identified as genotype IIIA strains and showed 98.9 to 100% homology. Genotype IIIA was also dominant in Daegu, where strains were 95.7 to 100% homologous. All hepatitis A virus strains isolated from the Kaesong Industrial Region, Jeonnam, Seoul, and Incheon belonged to a single cluster. However, strains from Daegu could be classified into 2 clusters, suggesting that the outbreak had multiple sources. This study indicates that hepatitis A virus strains of 2 different genotypes are currently cocirculating in Korea. Moreover, it documents an increasing prevalence of genotype IIIA strains in the country. PMID- 22238448 TI - A highly efficient Ziehl-Neelsen stain: identifying de novo intracellular Mycobacterium tuberculosis and improving detection of extracellular M. tuberculosis in cerebrospinal fluid. AB - Tuberculous meningitis leads to a devastating outcome, and early diagnosis and rapid chemotherapy are vital to reduce morbidity and mortality. Since Mycobacterium tuberculosis is a kind of cytozoic pathogen and its numbers are very few in cerebrospinal fluid, detecting M. tuberculosis in cerebrospinal fluid from tuberculous meningitis patients is still a challenge for clinicians. Ziehl Neelsen stain, the current feasible microbiological method for the diagnosis of tuberculosis, often needs a large amount of cerebrospinal fluid specimen but shows a low detection rate of M. tuberculosis. Here, we developed a modified Ziehl-Neelsen stain, involving cytospin slides with Triton processing, in which only 0.5 ml of cerebrospinal fluid specimens was required. This method not only improved the detection rate of extracellular M. tuberculosis significantly but also identified intracellular M. tuberculosis in the neutrophils, monocytes, and lymphocytes clearly. Thus, our modified method is more effective and sensitive than the conventional Ziehl-Neelsen stain, providing clinicians a convenient yet powerful tool for rapidly diagnosing tuberculous meningitis. PMID- 22238449 TI - A loss-of-function mutation in the nucleoporin AtNUP160 indicates that normal auxin signalling is required for a proper ethylene response in Arabidopsis. AB - As part of a continuing effort to elucidate mechanisms that regulate the magnitude of ethylene signalling, an Arabidopsis mutant with an enhanced ethylene response was identified. Subsequent characterization of this loss-of-function mutant revealed severe hypocotyl shortening in the presence of saturating ethylene along with increased expression in leaves of a subset of ethylene responsive genes. It was subsequently determined by map-based cloning that the mutant (sar1-7) represents a loss-of-function mutation in the previously described nucleoporin AtNUP160 (At1g33410, SAR1). In support of previously reported results, the sar1-7 mutant partially restored auxin responsiveness to roots of an rce1 loss-of-function mutant, indicating that AtNUP160/SAR1 is required for proper expression of factors responsible for the repression of auxin signalling. Analysis of arf7-1/sar1-7 and arf19-1/sar1-7 double mutants revealed that mutations affecting either ARF7 or ARF19 function almost fully blocked manifestation of the sar1-7-dependent ethylene hypersensitivity phenotype, suggesting that ARF7- and ARF19-mediated auxin signalling is responsible for regulating the magnitude of and/or competence for the ethylene response in Arabidopsis etiolated hypocotyls. Consistent with this, addition of auxin to ethylene-treated seedlings resulted in severe hypocotyl shortening, reminiscent of that seen for other eer (enhanced ethylene response) mutants, suggesting that auxin functions in part synergistically with ethylene to control hypocotyl elongation and other ethylene-dependent phenomena. PMID- 22238450 TI - My favourite flowering image. AB - I selected my favourite image from a paper by Professor Friedrich Laibach, the founder of Arabidopsis research. His paper from 1951 is the first paper dealing with natural variation for flowering time in this species, a topic many scientists including myself, have followed up and has resulted in large steps forward in our understanding of flowering time regulation. How this topic came to be of interest in my laboratory in Wageningen is described in this short overview. PMID- 22238451 TI - Introduction of apple ANR genes into tobacco inhibits expression of both CHI and DFR genes in flowers, leading to loss of anthocyanin. AB - Three genes encoding anthocyanidin reductase (ANR) in apple (Malus*domestica Borkh.), designated MdANR1, MdANR2a, and MdANR2b, have been cloned and characterized. MdANR1 shows 91% identity in coding DNA sequences with MdANR2a and MdANR2b, while MdANR2a and MdANR2b are allelic and share 99% nucleotide sequence identity in the coding region. MdANR1 and MdANR2 genes are located on linkage groups 10 and 5, respectively. Expression levels of both MdANR1 and MdANR2 genes are generally higher in yellow-skinned cv. Golden Delicious than in red-skinned cv. Red Delicious. Transcript accumulation of MdANR1 and MdANR2 genes in fruits gradually decreased throughout fruit development. Ectopic expression of apple MdANR genes in tobacco positively and negatively regulates the biosynthesis of proanthocyanidins (PAs) and anthocyanin, respectively, resulting in white, pale pink-coloured, and white/red variegated flowers. The accumulation of anthocyanin is significantly reduced in all tobacco transgenic flowers, while catechin and epicatechin contents in transgenic flowers are significantly higher than those in flowers of wild-type plants. The inhibition of anthocyanin synthesis in tobacco transgenic flowers overexpressing MdANR genes is probably attributed to down regulation of CHALCONE ISOMERASE (CHI) and DIHYDROFLAVONOL-4-REDUCTASE (DFR) genes involved in the anthocyanin pathway. Interestingly, several transgenic lines show no detectable transcripts of the gene encoding leucoanthocyanidin reductase (LAR) in flowers, but accumulate higher levels of catechin in flowers of transgenic plants than those of wild-type plants. This finding suggests that the ANR gene may be capable of generating catechin via an alternative route, although this mechanism is yet to be further elucidated. PMID- 22238452 TI - Frontiers in metabolic reconstruction and modeling of plant genomes. AB - A major goal of post-genomic biology is to reconstruct and model in silico the metabolic networks of entire organisms. Work on bacteria is well advanced, and is now under way for plants and other eukaryotes. Genome-scale modelling in plants is much more challenging than in bacteria. The challenges come from features characteristic of higher organisms (subcellular compartmentation, tissue differentiation) and also from the particular severity in plants of a general problem: genome content whose functions remain undiscovered. This problem results in thousands of genes for which no function is known ('undiscovered genome content') and hundreds of enzymatic and transport functions for which no gene is yet identified. The severity of the undiscovered genome content problem in plants reflects their genome size and complexity. To bring the challenges of plant genome-scale modelling into focus, we first summarize the current status of plant genome-scale models. We then highlight the challenges - and ways to address them in three areas: identifying genes for missing processes, modelling tissues as opposed to single cells, and finding metabolic functions encoded by undiscovered genome content. We also discuss the emerging view that a significant fraction of undiscovered genome content encodes functions that counter damage to metabolites inflicted by spontaneous chemical reactions or enzymatic mistakes. PMID- 22238453 TI - Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. AB - IL-20 is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about its role in breast cancer. We explored the function of IL-20 in tumor growth and metastasis, as well as in clinical outcome. Tumor expression of IL-20 was assessed by immunohistochemical staining among 198 patients with invasive ductal carcinoma of the breast, using available clinical and survival data. IL-20 expression was associated with advanced tumor stage, greater tumor metastasis, and worse survival. Reverse transcription quantitative polymerase chain reaction showed that clinical breast tumor tissue expressed higher levels of IL-20 and its receptors than did nontumorous breast tissue. IL-20 was also highly expressed in breast cancer bone-metastasis tissue. In vitro, IL-20 upregulated matrix metalloproteinase-9, matrix metalloproteinase-12, cathepsin K, and cathepsin G, and enhanced proliferation and migration of breast cancer cells, which were inhibited by anti-IL-20 mAb 7E. In vivo, we generated murine models to evaluate the therapeutic potential of 7E, using luminescence intensity, radiological scans, and micro-computed tomography. 7E reduced tumor growth, suppressed bone colonization, diminished tumor-mediated osteolysis, and lessened bone density decrement in mice injected with breast cancer cells. In conclusion, our results suggest that IL-20 plays pivotal roles in the tumor progression of breast cancer. IL-20 expression in breast cancer tissue is associated with a poor clinical outcome. Anti-IL-20 mAb 7E suppressed bone colonization and decreased osteolytic bone lesions. Therefore, IL-20 may be a novel target in treating breast tumor induced osteolysis. PMID- 22238454 TI - Conventional dendritic cells require IRAP-Rab14 endosomes for efficient cross presentation. AB - Dendritic cells (DCs) use cellular pathways collectively referred to as cross presentation to stimulate CD8(+) T cells with peptide Ags derived from internalized, exogenous Ags. We have recently reported that DCs rely on aminoterminal trimming of cross-presented peptides by insulin-responsive aminopeptidase (IRAP), an enzyme localized in a regulated endosomal storage compartment. Considering a report contending that this role is limited to inflammatory DCs (Segura et al. 2009. Proc. Natl. Acad. Sci. USA 106: 20377 20381), in this study, we examined the role of IRAP in steady-state DC subpopulations. Steady-state conventional DCs (cDCs) and plasmacytoid DCs expressed similar amounts of IRAP. IRAP colocalized with the endosomal markers Rab14 and syntaxin 6, both known to be associated with regulated endosomal storage compartments, in CD8(+) and CD8(-) cDCs-however, to a greater extent in the former population. Likewise, IRAP recruitment to phagosomes was significantly stronger in CD8(+) DCs. IRAP deficiency compromised cross-presentation of soluble and particulate Ag by both CD8(+) and CD8(-) cDCs, again with a stronger effect in the former population. Thus, the requirement of IRAP in cross-presentation extends to steady-state cDCs. Moreover, these data suggest that increased recruitment of an IRAP(+)/Rab14(+) compartment to Ag-containing vesicles contributes to the superior cross-presentation efficacy of CD8(+) cDCs. PMID- 22238456 TI - Temporal predisposition to alphabeta and gammadelta T cell fates in the thymus. AB - How T cell progenitors engage into the gammadelta or alphabeta T cell lineages is a matter of intense debate. In this study, we analyzed the differentiation potential of single thymocytes from wild-type and TCRgammadelta-transgenic mice at two sequential early developmental stages. Double-negative (DN) 3 progenitors from both wild-type and transgenic mice retain the capacity to engage into both pathways, indicating that full commitment is only completed after this stage. More importantly, DN2 and DN3 progenitors from TCRgammadelta transgenic mice have strong biases for opposite fates, indicating that developmentally regulated changes, other than the production of a functional TCR, altered their likelihood to become a gammadelta or an alphabeta T cell. Thus, unlike the differentiation in other hematopoietic lineages, T cell progenitors did not restrict, but rather switch their differentiation potential as they developed. PMID- 22238455 TI - IL-21 can supplement suboptimal Lck-independent MAPK activation in a STAT-3 dependent manner in human CD8(+) T cells. AB - Although both MHC class II/CD8alpha double-knockout and CD8beta null mice show a defect in the development of MHC class I-restricted CD8(+) T cells in the thymus, they possess low numbers of high-avidity peripheral CTL with limited clonality and are able to contain acute and chronic infections. These in vivo data suggest that the CD8 coreceptor is not absolutely necessary for the generation of Ag specific CTL. Lack of CD8 association causes partial TCR signaling because of the absence of CD8/Lck recruitment to the proximity of the MHC/TCR complex, resulting in suboptimal MAPK activation. Therefore, there should exist a signaling mechanism that can supplement partial TCR activation caused by the lack of CD8 association. In this human study, we have shown that CD8-independent stimulation of Ag-specific CTL previously primed in the presence of CD8 coligation, either in vivo or in vitro, induced severely impaired in vitro proliferation. When naive CD8(+) T cells were primed in the absence of CD8 binding and subsequently restimulated in the presence of CD8 coligation, the proliferation of Ag-specific CTL was also severely hampered. However, when CD8-independent T cell priming and restimulation were supplemented with IL-21, Ag-specific CD8(+) CTL expanded in two of six individuals tested. We found that IL-21 rescued partial MAPK activation in a STAT3- but not STAT1-dependent manner. These results suggest that CD8 coligation is critical for the expansion of postthymic peripheral Ag-specific CTL in humans. However, STAT3-mediated IL-21 signaling can supplement partial TCR signaling caused by the lack of CD8 association. PMID- 22238457 TI - IL-1 receptor signaling is required at multiple stages of sensitization and elicitation of the contact hypersensitivity response. AB - Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. The points at which IL-1R signaling is required during this complex, multistep immune response have not been clearly delineated. The role of IL-1R signaling during 2, 4 dinitro-1-fluorobenezene (DNFB) sensitization to induce hapten-specific CD8 effector T cells and in the trafficking of the effector T cells to the DNFB challenge site to elicit the response were investigated using IL-1R deficient mice. DNFB-sensitized IL-1R(-/-) mice had low CHS responses to hapten challenge that were caused in part by marked decreases in hapten-specific CD8 T cell development to IL-17- and IFN-gamma producing cells during sensitization. Hapten-primed wild type CD8 T cell transfer to naive IL-1R(-/-) mice did not result in T cell activation in response to hapten challenge, indicating a need for IL-1R signaling for the localization or activation, or both, of the CD8 T cells at the challenge site. Decreased CD8 T cell priming in sensitized IL-1R(-/-) mice was associated with marked decreases in hapten-presenting dendritic cell migration from the sensitized skin to draining lymph nodes. Transfer of hapten-presenting dendritic cells from wild type donors to naive IL-1R(-/-) mice resulted in decreased numbers of the dendritic cells in the draining lymph nodes and decreased priming of hapten specific CD8 T cells compared with dendritic cell transfer to naive wild type recipients. These results indicate that IL-1R signaling is required at multiple steps during the course of sensitization and challenge to elicit CHS. PMID- 22238458 TI - IL-12Rbeta2 is essential for the development of experimental cerebral malaria. AB - A Th1 response is required for the development of Plasmodium berghei ANKA (PbA) induced experimental cerebral malaria (ECM). The role of pro-Th1 IL-12 in malaria is complex and controversial. In this study, we addressed the role of IL-12Rbeta2 in ECM development. C57BL/6 mice deficient for IL-12Rbeta2, IL-12p40, or IL-12p35 were analyzed for ECM development after blood-stage PbA infection in terms of ischemia and blood flow by noninvasive magnetic resonance imaging and angiography, T cell recruitment, and gene expression. Without IL-12Rbeta2, no neurologic sign of ECM developed upon PbA infection. Although wild-type mice developed distinct brain microvascular pathology, ECM-resistant, IL-12Rbeta2 deficient mice showed unaltered cerebral microcirculation and the absence of ischemia after PbA infection. In contrast, mice deficient for IL-12p40 or IL 12p35 were sensitive to ECM development. The resistance of IL-12Rbeta2-deficient mice to ECM correlated with reduced recruitment of activated T cells and impaired overexpression of lymphotoxin-alpha, TNF-alpha, and IFN-gamma in the brain after PbA infection. Therefore, IL-12Rbeta2 signaling is essential for ECM development but independent from IL-12p40 and IL-12p35. We document a novel link between IL 12Rbeta2 and lymphotoxin-alpha, TNF-alpha, and IFN-gamma expression, key cytokines for ECM pathogenesis. PMID- 22238459 TI - Plac8-dependent and inducible NO synthase-dependent mechanisms clear Chlamydia muridarum infections from the genital tract. AB - Chlamydia trachomatis urogenital serovars replicate predominantly in genital tract epithelium. This tissue tropism poses a unique challenge for host defense and vaccine development. Studies utilizing the Chlamydia muridarum mouse model have shown that CD4 T cells are critical for clearing genital tract infections. In vitro studies have shown that CD4 T cells terminate infection by upregulating epithelial inducible NO synthase (iNOS) transcription and NO production. However, this mechanism is not critical, as iNOS-deficient mice clear infections normally. We recently showed that a subset of Chlamydia-specific CD4 T cell clones could terminate replication in epithelial cells using an iNOS-independent mechanism requiring T cell degranulation. We advance that work using microarrays to compare iNOS-dependent and iNOS-independent CD4 T cell clones. Plac8 was differentially expressed by clones having the iNOS-independent mechanism. Plac8-deficient mice had delayed clearance of infection, and Plac8-deficient mice treated with the iNOS inhibitor N-monomethyl-l-arginine were largely unable to resolve genital tract infections over 8 wk. These results demonstrate that there are two independent and redundant T cell mechanisms for clearing C. muridarum genital tract infections: one dependent on iNOS, and the other dependent on Plac8. Although T cell subsets are routinely defined by cytokine profiles, there may be important subdivisions by effector function, in this case CD4(Plac8). PMID- 22238460 TI - Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway. AB - Enhancement of stem cell Ag-1 (Sca-1) expression by myeloid precursors promotes the granulopoietic response to bacterial infection. However, the underlying mechanisms remain unclear. ERK pathway activation strongly enhances proliferation of hematopoietic progenitor cells. In this study, we investigated the role of Sca 1 in promoting ERK-dependent myeloid lineage proliferation and the effects of alcohol on this process. Thirty minutes after i.p. injection of alcohol, mice received i.v. challenge with 5 * 10(7) Escherichia coli for 8 or 24 h. A subset of mice received i.v. BrdU injection 20 h after challenge. Bacteremia increased Sca-1 expression, ERK activation, and proliferation of myeloid and granulopoietic precursors. Alcohol administration suppressed this response and impaired granulocyte production. Sca-1 expression positively correlated with ERK activation and cell cycling, but negatively correlated with myeloperoxidase content in granulopoietic precursors. Alcohol intoxication suppressed ERK activation in granulopoietic precursors and proliferation of these cells during bacteremia. Granulopoietic precursors in Sca-1(-/-) mice failed to activate ERK signaling and could not increase granulomacrophagic CFU activity following bacteremia. These data indicate that Sca-1 expression promotes ERK-dependent myeloid cell proliferation during bacteremia. Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol abusing hosts with severe bacterial infection. PMID- 22238461 TI - IL-21 promotes the pathologic immune response to pneumovirus infection. AB - IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased Ig production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has antitumor activity. In this study, we investigated the role of IL-21 in host defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4(+) T cells. Following infection, Il21r(-/-) mice exhibited less lung infiltration by neutrophils than did wild-type (WT) mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8(+), CD4(+), and gammadelta T cell numbers were also lower in the lungs of PVM-infected Il21r(-/-) mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r(-/-) mice. Strikingly, Il21r(-/-) mice had enhanced survival following PVM infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections. PMID- 22238462 TI - The living eye "disarms" uncommitted autoreactive T cells by converting them to Foxp3(+) regulatory cells following local antigen recognition. AB - Immune privilege is used by the eye, brain, reproductive organs, and gut to preserve structural and functional integrity in the face of inflammation. The eye is arguably the most vulnerable and, therefore, also the most "privileged" of tissues; paradoxically, it remains subject to destructive autoimmunity. It has been proposed, although never proven in vivo, that the eye can induce T regulatory cells (Tregs) locally. Using Foxp3-GFP reporter mice expressing a retina-specific TCR, we now show that uncommitted T cells rapidly convert in the living eye to Foxp3(+) Tregs in a process involving retinal Ag recognition, de novo Foxp3 induction, and proliferation. This takes place within the ocular tissue and is supported by retinoic acid, which is normally present in the eye because of its function in the chemistry of vision. Nonconverted T cells showed evidence of priming but appeared restricted from expressing effector function in the eye. Pre-existing ocular inflammation impeded conversion of uncommitted T cells into Tregs. Importantly, retina-specific T cells primed in vivo before introduction into the eye were resistant to Treg conversion in the ocular environment and, instead, caused severe uveitis. Thus, uncommitted T cells can be disarmed, but immune privilege is unable to protect from uveitogenic T cells that have acquired effector function prior to entering the eye. These findings shed new light on the phenomenon of immune privilege and on its role, as well as its limitations, in actively controlling immune responses in the tissue. PMID- 22238463 TI - Vancomycin minimum inhibitory concentrations and outcome in patients with severe Staphylococcus aureus infection. PMID- 22238465 TI - Mycobacterium tuberculosis promotes regulatory T-cell expansion via induction of programmed death-1 ligand 1 (PD-L1, CD274) on dendritic cells. PMID- 22238467 TI - Risk factors for incident condyloma in a multinational cohort of men: the HIM study. AB - Identifying factors associated with condyloma are necessary for prevention efforts. Risk factors for incident condyloma were examined in a cohort of 2487 men from the United States, Brazil, and Mexico and were followed up every 6 months (median, 17.9 months). Factors strongly associated with condyloma were incident infection with human papillomavirus (HPV) types 6 and 11 (hazard ratio [HR], 12.42 [95% confidence interval {CI}, 3.78-40.77]), age (HR, 0.43 [95% CI, .26-.77]; 45-70 vs 18-30 years), high lifetime number of female partners (HR, 5.69 [95% CI, 1.80-17.97]; >=21 vs 0 partners), and number of male partners (HR, 4.53 [95% CI, 1.68-12.20]; >=3 vs 0 partners). The results suggest that HPV types 6 and 11 and recent sexual behavior are strongly associated with incident condyloma. PMID- 22238468 TI - Reduction of antimalarial antibodies by HIV infection is associated with increased risk of Plasmodium falciparum cord blood infection. AB - BACKGROUND: Plasmodium falciparum infection in pregnancy can lead to congenital malaria, which has detrimental health consequences for infants. Human immunodeficiency virus (HIV) might increase cord blood P. falciparum infection by decreasing maternal antimalarial-specific antibodies. METHODS: HIV-negative (n=133) and HIV-positive (n=55) Mozambican pregnant women were assessed at delivery for maternal and cord P. falciparum infection by quantitative polymerase chain reaction (qPCR) and P. falciparum-specific antibodies by enzyme-linked immunosorbent assay and flow cytometry. RESULTS: Prevalence of qPCR-detected cord blood infection was 8.0%. Risk of cord infection was increased in presence of HIV (adjusted odds ratio [AOR], 3.80; P=.04) and placental malaria (AOR, 22.08; P=.002) after adjusting for clinical variables. The odds of having a high immunoglobulin G response to chondrotin sulphate A-binding infected erythrocytes, parasite lysate, and erythrocyte-binding antigen-175 were reduced among HIV positive women (P < .001, .048, and .056, respectively) and among women with cord P. falciparum infection (P = .009, .04, and .046, respectively). In multivariate analysis including maternal HIV status, placental malaria, and antibody responses, HIV was no longer associated with cord blood infection (P = .11). CONCLUSIONS: HIV-associated impairment of antibody responses in pregnant women may contribute to a higher transmission of P. falciparum to their infants. PMID- 22238469 TI - New malaria-control policies and child mortality in senegal: reaching millennium development goal 4. AB - BACKGROUND: The Demographic Surveillance System established in 1962 in Niakhar, Senegal, is the oldest in Africa. Here, we analyze trends in overall child mortality, malaria, and other causes of death in Niakhar from the beginning of data collection to 2010. METHODS: After an initial census, demographic data were updated yearly from 1963 through 2010. From 1984, causes of death were determined by the verbal autopsy technique. RESULTS: During 1963-2010, infant and under-5 mortality rates decreased from 2230/00 to 180/00 and from 4850/00 to 410/00, respectively. The decrease was progressive during the entire observation period, except during 1990-2000, when a plateau and then an increase was observed. Malaria-attributable mortality in under-5 children decreased from 13.50/00 deaths per 1000 children per year during 1992-1999 to 2.20/00 deaths per 1000 children per year in 2010. During this period, all-cause mortality among children aged <5 years decreased by 80%. CONCLUSIONS: Inadequate treatment for chloroquine resistant malaria and an epidemic of meningitis during the 1990s were the 2 factors that interrupted a continuous decrease in child mortality. Direct and indirect effects of new malaria-control policies, introduced in 2003 and completed during 2006-2008, are likely to have been the key cause of the recent dramatic decrease in child mortality. PMID- 22238470 TI - Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. AB - BACKGROUND: Children have a lower response rate to antimonial drugs and higher elimination rate of antimony (Sb) than adults. Oral miltefosine has not been evaluated for pediatric cutaneous leishmaniasis. METHODS: A randomized, noninferiority clinical trial with masked evaluation was conducted at 3 locations in Colombia where Leishmania panamensis and Leishmania guyanensis predominated. One hundred sixteen children aged 2-12 years with parasitologically confirmed cutaneous leishmaniasis were randomized to directly observed treatment with meglumine antimoniate (20 mg Sb/kg/d for 20 days; intramuscular) (n = 58) or miltefosine (1.8-2.5 mg/kg/d for 28 days; by mouth) (n = 58). Primary outcome was treatment failure at or before week 26 after initiation of treatment. Miltefosine was noninferior if the proportion of treatment failures was <=15% higher than achieved with meglumine antimoniate (1-sided test, alpha = .05). RESULTS: Ninety five percent of children (111/116) completed follow-up evaluation. By intention to-treat analysis, failure rate was 17.2% (98% confidence interval [CI], 5.7% 28.7%) for miltefosine and 31% (98% CI, 16.9%-45.2%) for meglumine antimoniate. The difference between treatment groups was 13.8%, (98% CI, -4.5% to 32%) (P = .04). Adverse events were mild for both treatments. CONCLUSIONS: Miltefosine is noninferior to meglumine antimoniate for treatment of pediatric cutaneous leishmaniasis caused by Leishmania (Viannia) species. Advantages of oral administration and low toxicity favor use of miltefosine in children. CLINICAL TRIAL REGISTRATION: NCT00487253. PMID- 22238471 TI - Single-nucleotide polymorphism-defined class I and class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection. AB - We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP associated SNPs are ordered in >=4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype. PMID- 22238472 TI - Variants in toll-like receptor 1 and 4 genes are associated with Chlamydia trachomatis among women with pelvic inflammatory disease. AB - BACKGROUND: Toll-like receptors (TLRs) are involved in the innate immune response. We examined whether TLR variants are associated with Chlamydia trachomatis infection among women with pelvic inflammatory disease (PID). METHODS: We tested whether 18 tagging single nucleotide polymorphisms (tagSNPs) assayed in 4 TLR genes (TLR1, TLR2, TLR4, TLR6) and 2 adaptor molecules (TIRAP, MyD88) were associated with C. trachomatis among 205 African American women with clinically suspected PID from the PID Evaluation and Clinical Health Study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). An empirical P value of <.004 was considered significant. RESULTS: Women with PID who carried the TLR4 rs1927911 CC genotype had significantly increased odds of C. trachomatis (OR, 3.7; 95% CI, 1.6-8.8; P = .002). The TLR1 rs5743618TT genotype was also associated with C. trachomatis (OR, 2.8; 95% CI, 1.3-6.2; P = .008). CONCLUSIONS: Among African American women with PID, variants in the TLR1 and TLR4 genes, which may increase signaling, were associated with increased C. trachomatis infection. PMID- 22238473 TI - Circulating endothelial progenitor cell levels are not reduced in HIV-infected men. AB - Reduced levels of endothelial progenitor cells (EPCs) have been associated with increased cardiovascular (CV) risk, but limited data are available on EPC levels in the human immunodeficiency virus (HIV)-infected population. EPCs (CD45(dim)/CD34(+)/kinase domain receptor(+)) from 36 HIV-uninfected and 30 antiretroviral therapy-naive HIV-infected men without known CV risk factors were enumerated using flow cytometry. The mean EPC levels (+/- standard error of the mean) were 1.4 +/- 0.5 cells/MUL in the HIV-infected group and 3.7 +/- 2.2 cells/MUL in the control group (P = .92). EPC levels were not associated with disease parameters, such as CD4 cell count or viral load. Reductions in EPC levels do not seem to explain the increased risk of CV disease among HIV-infected men. PMID- 22238475 TI - The Development and Correlates of Academic Interests from Childhood through Adolescence. AB - Study goals were to assess: (1) the development of academic interests from middle childhood through late adolescence, (2) the degree to which junior high and high school transitions, parents' educational expectations, interests, and education, were related to changes in academic interests, and (3) the longitudinal links between youth's academic interests and school grades. Participants were mothers, fathers, and two siblings from 201, White, working and middle class families who were interviewed in their homes on up to 9 annual occasions. Multi-level model analyses revealed overall declines in youth's interests over time, with boys showing more rapid decline than girls. Mothers' educational expectations were positively related to youth's interests, and youth's interests declined less when fathers had more education. The transition to junior high, but not high school, was linked to decline in interests, but this was buffered by mothers' academic interests. Declines in youth's academic interests were linked to declines in school grades. PMID- 22238474 TI - Study of genotypic and phenotypic HIV-1 dynamics of integrase mutations during raltegravir treatment: a refined analysis by ultra-deep 454 pyrosequencing. AB - BACKGROUND: The dynamics of raltegravir-resistant variants and their impact on virologic response in 23 HIV-1-infected patients, who started a salvage raltegravir-containing regimen, were investigated. METHODS: Integrase population sequencing and Ultra-Deep-454 Pyrosequencing (UDPS) were performed on plasma samples at baseline and at raltegravir failure. All integrase mutations detected at a frequency >=1% were considered to be reliable for the UDPS analyses. Phylogenetic and phenotypic resistance analyses were also performed. RESULTS: At baseline, primary resistance mutations were not detected by both population and UDPS genotypic assays; few secondary mutations (T97A-V151I-G163R) were rarely detected and did not show any statistically association either with virologic response at 24-weeks or with the development of resistant variants at failure. At UDPS, not all resistant variants appearing early during treatment evolved as major populations during failure; only specific resistance pathways (Y143R Q148H/R-N155H) associated with an increased rate of fitness and phenotypic resistance were selected. CONCLUSIONS: Resistance to raltegravir in integrase strand transfer inhibitor-naive patients remains today a rare event, which might be changed by future extensive use of such drugs. In our study, pathways of resistance at failure were not predicted by baseline mutations, suggesting that evolution plus stochastic selection plays a major role in the appearance of integrase-resistance mutations, whereas fitness and resistance are dominant factors acting for the late selection of resistant quasispecies. PMID- 22238476 TI - Extraction, isolation and characterization of bioactive compounds from plants' extracts. AB - Natural products from medicinal plants, either as pure compounds or as standardized extracts, provide unlimited opportunities for new drug leads because of the unmatched availability of chemical diversity. Due to an increasing demand for chemical diversity in screening programs, seeking therapeutic drugs from natural products, interest particularly in edible plants has grown throughout the world. Botanicals and herbal preparations for medicinal usage contain various types of bioactive compounds. The focus of this paper is on the analytical methodologies, which include the extraction, isolation and characterization of active ingredients in botanicals and herbal preparations. The common problems and key challenges in the extraction, isolation and characterization of active ingredients in botanicals and herbal preparations are discussed. As extraction is the most important step in the analysis of constituents present in botanicals and herbal preparations, the strengths and weaknesses of different extraction techniques are discussed. The analysis of bioactive compounds present in the plant extracts involving the applications of common phytochemical screening assays, chromatographic techniques such as HPLC and, TLC as well as non chromatographic techniques such as immunoassay and Fourier Transform Infra Red (FTIR) are discussed. PMID- 22238477 TI - Evaluation of analgesic and anti-inflammatory activity of diospyros cordifolia extract. AB - In this study we evaluated the analgesic and anti-inflammatory activities of the methanol extract of stem bark of Diospyros cordifolia (MEDC) Roxb. The analgesic effects of the stem bark of the plant was assessed in mice using the tail-flick method while carrageenan, histamine and dextran induced paw oedema was used to study the antiinflammatory effects in rats. The MEDC exhibited significant (p<0.01) analgesic effects comparable to the reference drug diclofenac sodium. MEDC also was evaluated for its anti-inflammatory potential against carrageenan, histamine and dextran induced rat paw edema. The methanol extract (25 and 50 mg / kg body weight) exhibited significant (p<0.01) activity against all phlogistic agents used in a dose dependent manner. All these effects were compared with reference drug phenylbutazone (100 mg/kg body weight). PMID- 22238478 TI - In vivo antitrypanosomal effects of some ethnomedicinal plants from Nupeland of north central Nigeria. AB - Four medicinal plants Acacia nilotica, Bombax buonopozense, Terminalia avicennioides and Zanthoxylum zanthoxyloides traditionally used for treatment of sleeping sickness in Nupeland were investigated for in vivo antitrypanosomal activity. Methanol extracts of different parts of each plant (stem barks and fruits) were obtained and evaluated for their in vivo antitrypanosomal activities against Trypanosoma brucei brucei. Phytochemical screening of the methanol extracts of each plant were performed by standard procedures. Methanol extracts of A. nilotica (stem bark), B. buonopozense (stem bark), T. avicennioides (round fruit) and Z. zanthoxyloides (stem bark) were effective on trypanosomes. The extracts of A. nilotica and B. buonopozense exhibited antitrypanosomal effects at 200 and 300 mg/kg body weight respectively. Doses were able to clear the parasites from circulation within 6 and 7 days of treatment respectively with prolonging survival period of up to 30 days. While the extracts of T. avicennioides and Z. zanthoxyloides showed trypanostatic effects and could not clear the parasites completely. The methanol extracts of these plants contain metabolites that are associated with antitrypanosomal effects; therefore, these medicinal plants may be sources of new compounds that may be active against T. b. brucei. This study has also justified the claim that some medicinal plants of Nupeland possess antitrypanosomal activity and could be useful in the management of trypanosomiasis. PMID- 22238479 TI - Effect of aqueous extract of Cochlospermum planchonii rhizome on some kidney and liver functional indicies of albino rats. AB - Aqueous extract of Cochlospermum planchonii Hook. Ef. x Planch rhizome was investigated for its toxic effects in albino rats using some liver and kidney functional indices as 'markers'. Thirty six albino rats weighing 200.08 +/- 10.21 were randomly assinged into six groups (A-F) of six animals each. Animals in groups A-E were orally administered on daily basis with 1 ml of the extract corresponding to 50 mg/kg body weight of the extract for 1, 3, 5, 10 and 15 days while those in the control group received orally 1 ml of distilled water. Rats in all the groups were sacrificed 24 hours after the completion of their respective doses. The extract significantly (P<0.05) decreased alkaline phosphatase (ALP) activities in the liver leading to 80.95% loss by the end of the experimental period. While there was no consistent pattern in the kidney ALP activity and serum bilirubin level, the serum enzyme compared well (P>0.05) with the control value. There was no effect (P>0.05) on the acid phosphatase activity of the tissues and serum of the animals. The extract also reduced the urea, albumin and creatinine content in the serum of the animals. The alterations in the biochemical parameters by the aqueous extract of Cochlospermum planchoni may have consequential effects on the normal functioning of the liver and kidney of the animals. Therefore, the 50 mg/kg body weight of the aqueous extract of Cochlospermum planchoni rhizome may not be completley safe as an oral remedy. PMID- 22238480 TI - Distribution of iridiod glucosides and anti-oxidant compounds in Spathodea campanulata parts. AB - The antioxidant principles isolated from the various parts of the plant are verminoside (leaf, stem bark and flowers; EC(50) = 2.04 ug/ml), Specioside (flowers; EC(50) = 17.44 ug/ml), Kampeferol diglucoside (leaf; EC(50) = 8.87 ug/ml) and Caffeic acid (leaf and fruits). The non anti-oxidant components isolated in the study include ajugol (stem bark and fruits) and phytol (leaf). PMID- 22238481 TI - Effect of Delonix regia leaf extract on glucose tolerance in glucose-induced hyperglycemic mice. AB - Delonix regia (Fabaceae) leaf is used in folk medicine of Bangladesh for the treatment of diabetes, but so far no scientific study has been done which may support its use in traditional medicine. The present study was carried out to evaluate the possible glucose tolerance efficacy of methanolic extract of Delonix regia leaf using glucose-induced hyperglycemic mice. The extract at different doses was administered one hr prior to glucose administration and blood glucose level was measured after two hrs of glucose administration (p.o.) using glucose oxidase method. The statistical data indicated significant oral hypoglycemic activity on glucose-loaded mice at every dose. Maximum anti-hyperglycemic activity was showed at 400 mg/kg which was comparable to that of a standard drug, glibenclamide (10 mg/kg). The methanolic extract of leaf of Delonix regia had beneficial effects in reducing the elevated blood glucose level of hyperglycemic mice. PMID- 22238482 TI - Virologic and immunologic outcome of treatment of HIV infection with a herbal concoction, alpha-Zam, among clients seeking herbal remedy in Nigeria. AB - This study was to determine the effectiveness (CD4 count and viral load) of a safe herbal concoction, alpha-Zam used by clients seeking herbal remedy for treatment of HIV infection in Nigeria. 51 patients taking alpha-Zam as complementary and alternative therapy through the herbal therapist were studied for a period of 16 months. Preliminary medical and laboratory examinations using WHO and CDC criteria were done after confirmation of HIV infection by Western blotting in the nearest teaching hospitals to the residence of the patients. Regular visits were paid to the patients after commencement of the alpha-Zam to assess the side-effects, drug interactions, toxicity and effectiveness of the herbal remedy. There was a statistical significance (P<0.05) between pre treatment and post-treatment CD4 count. 4 (7.8%) of the patients had average increase in CD4 count of 262+/-16 cell/uL, 23 (45.1%) patients with average increase 310+/-16 cell/uL, 16 (31.4%) patients with average increase 456+/-25 cell/uL and 8 (15.7%) patients with average increase 510+/-36 cell/uL( %) were at WHO staging I , II, III and IV respectively within 4 months on herbal therapy. There was very marked reduction in viral (HIV-RNA) load with 41 (80.4%) and10 (19.6%) HIV infected patients had undetectable viral load and <1000 copies/ml respectively after the therapy. All symptoms and signs associated with HIV infection in all patients fully subsided within 4 weeks of commencement of alpha Zam therapy and there was no evidence of negative drug interaction in those HIV patients using both the herbal and highly active anti-retroviral therapy (HAART). The study is in progress to determine periodic immunological outcomes of post therapy in all patients. PMID- 22238483 TI - Herbal remedies and their adverse effects in Tem tribe traditional medicine in Togo. AB - In Africa, up to 80% of the population relies on herbal concoctions for their primarily health care. In Togo, western Africa, Tem tribe is a population with old knowledge of medicinal plants, however, still very little is known about their medical practices. The present study was conducted to access for the apprehension of adverse effects of traditional remedies by Tem traditional healers (TH). Enquiry was performed by interviews with healers from August to October 2007 in Tchaoudjo prefecture (Togo). The study allowed us to interview 54 TH including 41(75.93%) males and 13(24.07%) females, who cited 102 recipes assumed to have adverse effects. The recipes were used alone to cure several diseases including haemorrhoids (22.55%), female sexual disorders and infertility (21.57%), gastrointestinal disorders (18.63%), and malaria (6.86%). A total of 34 plants belonging to 21 families were cited to be components of the recipes. Euphorbiaceae and Mimosaceae families were the most represented, however, Nauclea latifolia, Khaya senegalensis, Pseudocedrela kotschyi and Xeroderris stuhlmannii were the main components of recipes linked to adverse effects. A total of 20 adverse effects were linked to the administration of theses drugs, and among them; diarrhoea, abdominal pains, polyuria, general weakness and vomiting were the most frequently encountered. These findings were in accordance with several reports of the literature concerning medicinal plants, although they were based on empirical observations. Laboratory screenings are needed to access for the effectiveness as well as the possible toxic effects of the recipes. PMID- 22238484 TI - Evaluation of a haemostatic agent in rabbits. AB - Topical hemostatic agents are applied locally to areas of injured vascular endothelium to control local bleeding. Ankaferd Blood Stopper (ABS) has gained approval in Turkey and Bosnia-Herzegovina as a topical haemostatic agent for external post-surgical and post-dental surgery bleeding. The safety of topical use of ABS has been demonstrated in numerous in vitro and in vivo animal models, as well as in a clinical Phase I trial in humans. ABS, besides its haemostatic activity, also has in vitro anti-infectious and anti-neoplastic effects. To assess potential detrimental effects of intravenous administration of ABS into intact systemic circulation in a rabbit experimental model, one milliliter of ABS was administered intravenously into the systemic circulation of twelve rabbits which were included in the study via the marginal ear vein. Animals were observed for 1 hr before euthanasia was performed by administering 40 mg of intracardiac suxamethonium chloride. In the event of death (cardiopulmonary arrest) before the end of the planned observation period of 60 minutes, time of death was recorded and histopathological examination of the liver and spleen was commenced. Ten rabbits were alive by the end of the planned observation period, without showing any clear signs of discomfort, whereas two animals died within five minutes after systemic administration of intravenous ABS. Postmortem histopathological examination of the livers and spleens of all animals' revealed findings consistent with hepatic venous outflow obstruction. Systemic intravascular administration of ABS into intact vascular endothelium should never be performed in any setting. Further experimental and clinical studies on this liquid hemostatic agent should proceed by accepting ABS as purely a topical haemostatic agent, to be applied solely to areas of injured vascular endothelium. PMID- 22238485 TI - In vitro antiplasmodial properties of Flacourtia flavescens Willd. (Flacourtiaceae) and Rytigynia canthioides (Benth.) Robyns (Rubiaceae). AB - The present study was conducted to investigate the in vitro antimalarial activity of Flacourtia flavescens Willd. (Flacourtiaceae) and Rytigynia canthioides (Benth.) Robyns (Rubiaceae). These two plants are used in Benin folk medicine to treat malaria and fever. Antimalarial activity was assayed on fresh clinical isolates of chloroquine resistant Plasmodium falciparum using the in vitro semi microtest. The results revealed that the IC(50) varied from 1.55 to 22.36ug/ml. F. flavescens hydro methanol extract was more active than R. canthioides. The study demonstrated scientific rationale behind the traditional usage of these plants, however further bioactivity guided phytochemical analyses are necessary to identify the active principles. PMID- 22238486 TI - Steroidogenic enzyme histochemistry in the testis of Sprague Dawley rats following the administration the water extracts from Carica papaya seed. AB - Water extracts from pawpaw seed have been reported to reversibly decrease the testicular weight and to suppress spermatogenesis, and fertility of Wistar rats. The reversible changes become evident, 30 - 45 days after the withdrawal of the extract. The possible effect of this extract on the activities of steroidogenic enzymes of the testis has not been investigated. Water extract of papaya seeds was administered to male Sprague Dawley rats ad libitum for 84 days. Following the discontinuation of the extracts, ten rats each were sacrificed on days 0, 10, 20 and 30 after the withdrawal. Their testes were quickly dissected out and frozen. Cryostat sections, 10um thick were cut. These sections were used for immunohistochemical stains for side chain cleavage enzyme and aromatase, and for histochemical stains for 17-beta Hydroxysteroid dehydrogenase, 3-beta Hydroxysteroid dehydrogenase. We conclude that the water extract of papaya seed suppresses the activities of steroidogenic enzymes in the testis of Sprague Dawley rats, and that this may contribute to reversible suppression of spermatogenesis, a property that gives a possible male contraceptive potential. PMID- 22238487 TI - Evaluation of Neolamarckia cadamba (Roxb.) Bosser leaf extract on glucose tolerance in glucose-induced hyperglycemic mice. AB - Neolamarckia cadamba (Rubiaceae) leaf is used in folk medicine of Bangladesh for the treatment of diabetes, but so far no scientific study has been done which may support its use in traditional medicine. The present study was carried out to evaluate the possible glucose tolerance efficacy of methanolic extract of Neolamarckia cadamba leaf using glucose-induced hyperglycemic mice. The extract at different doses was administered one hour prior to glucose administration and blood glucose level was measured after two hours of glucose administration (p.o.) using glucose oxidase method. The statistical data indicated significant oral hypoglycemic activity on glucose-loaded mice at the two highest doses of 200 and 400 mg extract per kg body weight. Maximum anti-hyperglycemic activity was shown at 400 mg per kg body weight, which was comparable to that of, glibenclamide (10 mg/kg). The methanolic extract of leaf of Neolamarckia cadamba had beneficial effects in reducing the elevated blood glucose level of hyperglycemic mice. PMID- 22238488 TI - Effects of Chinese herbs on the hemagglutination and adhesion of Escherichia coli strain in vitro. AB - The aim of this study is to evaluate Chinese herbs' efficacy on adhesive properties of Escherichia coli (E. coli). The effects of Chinese herbal solution on the hemagglutination and adhesion by E. coli strain were studied. E. coli C16 was isolated from a patient with urinary tract infection. The MIC value of herbal solution for the E. coli C16 was 0.1g/ml. The MBC value was 0.2g/ml. The effects of herbal solution on the hemagglutination abilities of E. coli C16 were dependent on the herbal solution used. The strain C16 lost half of its hemagglutination abilities when the herbal solution concentration was at MIC (0.05g/ml). Herbal solution decreased the adherence of strain C16 in a dose dependent way. The numbers of adherent bacteria were reduced to 45% of the control values after growth with herbal solution at MIC. The results show that anti-adhesion is one mode of action for Chinese herbs used against pathogens. PMID- 22238489 TI - Genistein and daidzein, in combination, protect cellular integrity during 7,12 dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in Sprague-Dawley rats. AB - The status of glycoconjugates (protein bound hexose, hexosamine, sialic acid and fucose) in plasma or serum serve as potential biomarkers for assessing tumor progression and therapeutic interventions. Aim of the present study was to investigate the protective effect of two major soy isoflavones, genistein and daidzein, in combination on the status of glycoconjugates in plasma, erythrocyte membrane and mammary tissues during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in female Sprague-Dawley rats. A single subcutaneous injection of DMBA (25 mg rat(-1)) in the mammary gland developed mammary carcinoma in female Sprague-Dawley rats. Elevated levels of plasma and mammary tissue glycoconjugates accompanied by reduction in erythrocyte membrane glycoconjugates were observed in rats bearing mammary tumors. Oral administration of genistein + daidzein (20 mg + 20 mg kg(-1) bw/day) to DMBA treated rats significantly (p< 0.05) brought back the status of glycoconjugates to near normal range. The present study thus demonstrated that genistein and daidzein in combination protected the structural integrity of the cell surface and membranes during DMBA-induced mammary carcinogenesis. PMID- 22238490 TI - Investigation of wound healing activity of methanolic extract of stem bark of Mimusops elengi Linn. AB - The present study was aimed to evaluate the wound healing activity of extract of bark part of Mimusops elengi. It is well-known plant in Indian traditional medicines. On the basis of traditional use and literature references, this plant was selected for wound healing potential. A methanolic extract of bark parts of Mimusops elengi was examined for wound healing activity in the form of ointment in three types of wound models on mice: the excision, the incision and dead space wound model. The extract ointments showed considerable response in all the above said wound models as comparable to those of a standard drug Betadine ointment in terms of wound contracting ability, wound closure time, tensile strength and dry granuloma weight. Histological analysis was also consistent with the proposal that Mimusops elengi bark extract exhibits significant wound healing. PMID- 22238491 TI - Insights into the monomers and single drugs of Chinese herbal medicine on myocardial preservation. AB - Chinese herbal drugs have been proved to be effective agents in myocardial protection by preventing ischemia-reperfusion injury. The underlying mechanisms as to how these agents work were however poorly elucidated. Studies on the monomers or on the single drugs have highlighted the possible rationales, leading to a better understanding of the pharmaceutical effects of the active parts of the herbs. These agents have been found to be structure-sensitive while they play the role of a protective ingredient. Polysaccharides of Chinese herbal medicine have pharmaceutical effects in immune modulation, anti-inflammation, anti-virus, anti-tumor, anti-aging mechanisms, with an anti-oxidative effect being a commonly recognized mechanism. Saponins are prone to alleviate calcium overload. As bioflavonoids commonly contain active phenolic hydroxy group, they have good anti oxidant property. Those containing effective lignanoids and essential oils can result in a reduced nitric oxide secretion of the endothelial cells and an increased intercellular cell adhesion molecule-1 expression. Alkaloids may resist free radical injuries. Most importantly, modern in-depth research revealed that myocardial infarction is typically associated with apoptosis, and herbal medicine containing carbohydrates and glycosides showed cardioprotective effects by way of inhibiting apoptosis of myocytes. As a supplement to cardioplegia, some Chinese herbal drugs have become especially valuable in myocardial protection in open heart surgery by preserving metabolic energy. In conclusion, the classification of Chinese herbal medicine made according to their main active ingredients has facilitated the expression of their functioning mechanisms. Chinese herbal drugs play an important role in cardioprotection via many different mechanisms, the most recent and important finding being the inhibition of apoptosis. PMID- 22238492 TI - The effects of Taraxacum officinale extracts (TOE) supplementation on physical fatigue in mice. AB - The study is to investigate the effect of Taraxacum officinale extracts (TOE) supplementation on physical fatigue based on the forced swimming capacity in mice. Forty Kunming male mice were randomly divided into 4 groups, i.e., normal control (NC) and three doses of TOE treated group (High-dose, Middle-dose and Low dose). Three TOE treated groups were treated by oral TOE with 10, 30 and 100mg/kg b.w respectively for a period of 42 days. The normal control group was given a corresponding volume of sterile distilled water. After 6 weeks, the forced swimming capacity and blood biochemical parameters in mice were measured, and the result showed that TOE had an anti- physical fatigue effect. It enhanced the maximum swimming capacity of mice, effectively delayed the lowering of glucose in the blood, and prevented the increase in lactate and triglyceride concentrations. PMID- 22238493 TI - In vitro anthelmintic effect of Anogeissus leiocarpus (DC.) Guill. & Perr. leaf extracts and fractions on developmental stages of Haemonchus contortus. AB - The anthelmintic effect of acetone leaf extract and fractions of Anogeissus leiocarpus was investigated to determine the relative efficacy of the components as anthelmintic against Haemonchus contortus (Rudolphi). The fractions were obtained by solvent-solvent group separation of the leaf extract. The fractions were evaluated for ovicidal and larvicidal activity by egg hatch inhibition assay and larval development viability assay. Best-fit LC(50) values for egg hatch test were 0.360, 0.316, 0.093, 0.219 and 0.196 mg/ml for the crude acetone extract, hexane, chloroform, butanol, and 35% water in methanol fractions, respectively. While the best-fit LC(50) values for larval development and viability test were 0.509, 0.162, 0.186, 0.288 and 0.130 mg/ml for the crude acetone extract, hexane, chloroform, butanol, and 35% water in methanol fractions, respectively. The 35% water in methanol fractions was the more active on larvae, although differences in activity between fractions were not significant (p>0.05). A. leiocarpus leaf extracts could find application in anthelmintic therapy in veterinary practice. PMID- 22238494 TI - Anthraquinones of Cissus populnea Guill & Perr (Amplidaceae). AB - Cissus populnea has been used locally to treat many ailments such as venereal, stomach and skin infections; and also used as laxative or purgative. Economically it has been used as binder in food and in lining dye pits. This work aims at determining the type of anthraquinones from the stem bark of C. populnea which might be a potential source of drugs (laxative/cathartic) using thin layer chramatograpy (TLC) and senna leaf as reference. The analysis showed the stem bark anthroquinone extract to contain physcion and chrysophanol. PMID- 22238495 TI - Ethnobotanical and antimicrobial studies of some plants used in Kibwezi (Kenya) for management of lower respiratory tract infections. AB - Respiratory tract infections have gained worldwide recognition especially due to the increased incidence of HIV/AIDS. The bacteria responsible for these infections have also become increasingly resistant to chemotherapeutic agents in lower respiratory infections in Kibwezi in Kenya. Interviews were conducted using semi-structured questionnaires and detailed discussions with respondents. During the field surveys direct observations were made on how these plants are used. From the ethnobotanical survey the modes of preparation used included chewing and boiling. The plant parts used were mostly bark and root, which implies that the main methods of harvesting these plants are destructive in nature. Water and methanolic extracts of the three most popular plants, Acacia nilotica, Strychnos heninngsii and Microglossa densiflora were tested against three test organism: Staphylococcus aureus, Streptococcus pneumoniae and Escherichia coli for their antimicrobial properties. The efficacy of the extracts was tested by bioassay method using the disk diffusion test. It was interesting to note that none of the tested water extracts showed any activity against the test organisms. This is despite the fact that about 83% of the local people used water for extraction. Methanolic extracts of Acacia nilotica and Strychnos heninningsii showed efficacy against S. aureus, S. pneumoniae and E. coli. The findings of this research indicate that A. nilotica and S. heninngsii have antimicrobial properties and further work especially using mammalian models is recommended. PMID- 22238496 TI - Antidiabetic and cytotoxicity screening of five medicinal plants used by traditional African health practitioners in the Nelson Mandela Metropole, South Africa. AB - Diabetes mellitus is a growing problem in South Africa and of concern to traditional African health practitioners in the Nelson Mandela Metropole, because they experience a high incidence of diabetic cases in their practices. A collaborative research project with these practitioners focused on the screening of Bulbine frutescens, Ornithogalum longibracteatum, Ruta graveolens, Tarchonanthus camphoratus and Tulbaghia violacea for antidiabetic and cytotoxic potential. In vitro glucose utilisation assays with Chang liver cells and C2C12 muscle cells, and growth inhibition assays with Chang liver cells were conducted. The aqueous extracts of Bulbine frutescens (143.5%), Ornithogalum longibracteatum (131.9%) and Tarchonanthus camphoratus (131.5%) showed significant increased glucose utilisation activity in Chang liver cells. The ethanol extracts of Ruta graveolens (136.9%) and Tulbaghia violacea (140.5%) produced the highest increase in glucose utilisation in C2C12 muscle cells. The ethanol extract of Bulbine frutescens produced the most pronounced growth inhibition (33.3%) on Chang liver cells. These findings highlight the potential for the use of traditional remedies in the future for the management of diabetes and it is recommended that combinations of these plants be tested in future. PMID- 22238497 TI - Detection of the antibacterial effect of Nigella sativa ground seeds with water. AB - Nigella sativa (NS) seeds have been used for medicinal purposes for centuries both as herbs and its oil. In Islam it is regarded as one of the greatest forms of healing medicine included in the medicine of prophet Mohammed. Huge number of studies have been carried out in recent years on the pharmacological effects of these seeds and also the possible relationship with their constituents. A number of these investigations emphasized the antimicrobial effect of them by using different extracts. In our study we have tried to use the normal human mechanism in digestion by using the ground seeds. A modified paper disc diffusion method was used to test the antibacterial effect of NS seeds. Clear inhibition of the growth of Staphylococcus aureus was observed by concentration of 300 mg/ml with distilled water (D.W.) as control , this inhibition was confirmed by using the positive control Azithromycin. The inhibition obtained was higher with Nigella sativa ground seeds from Hadramout (HNSGS) than with Nigella sativa ground seeds from Ethiopia (ENSGS). No inhibition was found in the growth of E.coli and Enterobacter. This was emphasized by using the positive control Ciprofloxacin. The positive inhibition may be attributed to the two important active ingredients of NS, Thymoquinone and melanin. PMID- 22238498 TI - Use of ethnoveterinary remedies in the management of foot and mouth disease lesions in a diary herd. AB - An outbreak of Foot and Mouth Disease (FMD) affecting 95 (57.2%) out of 166 cattle occurred in a medium-scale dairy farm in Kikuyu district, Kenya. Ethnoveterinary remedies of natural Soda ash solution (97% sodium bicarbonate), honey and finger millet flour were used to manage the FMD lesions. The lesions were washed with soda ash solution to remove the necrotic tissue after which raw honey and finger millet flour were applied to the cleaned lesions. The lesions were examined daily and those with necrotic material washed again with the Soda ash solution. Honey and finger millet flour were applied daily for three days. There was rapid healing of the lesions with the animals resuming feeding after three days. The fast healing of the lesions vindicates the use of these cheap, locally available and easy to apply products in the management of FMD lesions. However, more studies are needed to evaluate further their potencies. PMID- 22238499 TI - In-vitro evaluation of anti-trichomonal activities of Eugenia uniflora leaf. AB - Eugenia uniflora, used ethnomedically in some tropical countries as an anti infective, has shown anti-malarial and anti-trypanocidal activities. Therefore using bioactivity guided fractionation, anti-trichomonal activity of E. uniflora leaf was investigated. Anti-trichomonal activities of leaf methanol extract and its fractions against Trichomonas gallinae as well as their cytotoxicities using an in vitro haemaglutination assay were determined. Anti-trichomonacidal activities of the extract improved on purification up to a stage. Subfractions E(2-5) had LC(50) and LC(90) values of 4.77 - 5.28, 18.49 - 25.00 and 4.53 - 5.18, 18.32 - 19.07 ug/ml at 24 and 48 hrs, respectively that were better than those of metronidazole. Further purification of E(2-5) led to loss of activity suggesting that the active components were probably working synergistically and additively. Demonstration of low haemaglutination titre values of 0.00 - 5.33 by methanolic extract and its partition fractions suggested their low toxicity profile. The established safety of the leaf indicated that its anti-trichomonal activity was not due to non-specific cytotoxicity, hence could be used in ethnomedicine as an anti-trichomonal agent. PMID- 22238500 TI - Combination treatment with oxaliplatin and mangiferin causes increased apoptosis and downregulation of NFkappaB in cancer cell lines. AB - Mangiferin-mediated down-regulation of NFkappaB showed potential for chemotherapeutic agent-mediated cell death, suggesting a role in combination therapy for cancer. In this study the combined mechanism of the anticancer action of oxaliplatin and mangiferin was investigated. MTT dose response curves, trypan blue staining, caspase 3 assays as well as DNA cell cycle analyses were performed on HeLa, HT29 and MCF7 cancer cell lines, with and without the addition of 10 ug/ml mangiferin. Mitochondrial membrane potential, DNA fragmentation, resistance induction studies and NFkappaB assays were performed on HT29 cells only. Addition of 10 ug/ml mangiferin reduced oxaliplatin IC(50) values in HT29 (3.4 fold) and HeLa (1.7 fold) cells in the MTT assay while reducing trypan blue staining. This was accompanied by increased caspase 3 activation and DNA fragmentation and a delay in the S-phase of the cell cycle. Mitochondrial membrane permeabilization was not enhanced in the combination treatment. Mangiferin was shown to cause a reduction of NF-kappaB activation in HT29 cells rendered resistant to oxaliplatin. The present study indicates that mangiferin in combination with oxaliplatin favours apoptotic cell death and thereby improves the efficacy of oxaliplatin in vitro. In addition, combination therapy with mangiferin may also counteract the development of resistance in cancer cell lines. PMID- 22238501 TI - Anti-inflammatory and antioxidant activities of the leaves of Wissadula amplissima var Rostrata. AB - The present study determined the anti-inflammatory activity of Wissadula amplissima var rostrata (Schum. & Thonn.), and calculated the total phenolic content and total antioxidant capacity of the plant in an attempt to justify the traditional uses of the plant in the Ashanti region of Ghana for the management of spider,wasps and bee stings. Powdered dried leaves of Wissadula amplissima were Soxhlet extracted with Petroleum Ether (PWA, yield: 1.46% (w)/(w)); Chloroform (CWA, yield: 1.18% (w)/(w)) and Methanol (MWA, yield: 3.39% (w)/(w)). These fractions were tested for anti-inflammatory activity using carrageenan induced foot edema in 7 day old chicks. The effect before the induction of inflammation (pre-emptive protocol) paradigm was used for the assessment. Oral administration of PWA, CWA and MWA (30 - 300 mg/kg) dose dependently reduced edema with maximal effects of 68.25+/-2.03%, 77.83+/-0.81% and 62.21+/-2.61% respectively. Similarly the NSAID, Diclofenac (10 - 100 mg/Kg, i.p) and the steroidal anti-inflammatory drug dexamethasone (0.3 - 3 mg/Kg, i.p) used as positive controls, dose-dependently inhibited the edema with maximal effect of 87.96+/-1.11% and 67.47+/-3.51% respectively. The potencies exhibited by all three extracts were comparable to that shown by Diclofenac but higher than that of Dexamethasone. Phenols were detected in all three extracts with the highest concentration in the MWA. The extracts also scavenged DPPH with EC(50) values of 0.9784, 0.9096 and 0.2767 for PWA, CWA, MWA respectively. The results of this study give scientific credence to the local use of Wissadula amplissima to modulate inflammation induced by stings of animals. PMID- 22238502 TI - Bidirectional function of shenghe powder on repair of radiation-induced DNA damage in glioma and astrocyte. AB - The study assessed the effect of Chinese herbs of Shenghe Powder (SHP) on the repair capacity of gamma-radiation-induced DNA damage in rat glioma cells (C6) compared with normal human astrocytes (NHA). C6 and NHA Cells treated with SHP and irradiated with 2Gy of gamma radiation. Cells growth inhibition were analysed by MTT assay, DNA damage and repair were evaluated using phosphorylated histone H2AX (gammaH2AX) at the appointed time. Apoptosis was observed by flow cytometry, and the expression of DNA-dependent protein kinase (DNA-PK) and surviving proteins were assessed by Western blot analysis. SHP depressed the radiation induced DNA double-strand break and enhanced the DNA repair capacity in NHA, which correlated with promotion of DNA-PK phosphorylation. In contrast, SHP enhanced radiosensitivity of C6 cells, the pre-treatment with SHP resulted in reduced numbers of gammaH2AX foci in irradiated C6 cells, and decreased the expression of DNA-PK and survivn(P<0.005). It significant effect on inhibition of C6 cell proliferation and induced C6 cells apoptosis in a time-depdendent manner than radiation alone (P<0.001). SHP showed a novel bidirectional function to improve the radioresistance of NHA and enhanced radiosensitivity of C6 cells. This implies that SHP can protect the NHA from radiant damage and enhanced the sensitivity of C6 cells to radiation, which could be attributed to the alteration of survivin DNA-PK in DNA repair processes. PMID- 22238503 TI - Satellite Remote Sensing for Developing Time and Space Resolved Estimates of Ambient Particulate in Cleveland, OH. AB - This article empirically demonstrates the use of fine resolution satellite-based aerosol optical depth (AOD) to develop time and space resolved estimates of ambient particulate matter (PM) <=2.5 um and <=10 um in aerodynamic diameters (PM(2.5) and PM(10), respectively). AOD was computed at three different spatial resolutions, i.e., 2 km (means 2 km * 2 km area at nadir), 5 km, and 10 km, by using the data from MODerate Resolution Imaging Spectroradiometer (MODIS), aboard the Terra and Aqua satellites. Multiresolution AOD from MODIS (AOD(MODIS)) was compared with the in situ measurements of AOD by NASA's AErosol RObotic NETwork (AERONET) sunphotometer (AOD(AERONET)) at Bondville, IL, to demonstrate the advantages of the fine resolution AOD(MODIS) over the 10-km AOD(MODIS), especially for air quality prediction. An instrumental regression that corrects AOD(MODIS) for meteorological conditions was used for developing a PM predictive model.The 2-km AOD(MODIS) aggregated within 0.025 degrees and 15-min intervals shows the best association with the in situ measurements of AOD(AERONET). The 2 km AOD(MODIS) seems more promising to estimate time and space resolved estimates of ambient PM than the 10-km AOD(MODIS), because of better location precision and a significantly greater number of data points across geographic space and time. Utilizing the collocated AOD(MODIS) and PM data in Cleveland, OH, a regression model was developed for predicting PM for all AOD(MODIS) data points. Our analysis suggests that the slope of the 2-km AOD(MODIS) (instrumented on meteorological conditions) is close to unity with the PM monitored on the ground. These results should be interpreted with caution, because the slope of AOD(MODIS) ranges from 0.52 to 1.72 in the site-specific models. In the cross validation of the overall model, the root mean square error (RMSE) of PM(10) was smaller (2.04 ug/m(3) in overall model) than that of PM(2.5) (2.5 ug/m(3)). The predicted PM in the AOD(MODIS) data (~2.34 million data points) was utilized to develop a systematic grid of daily PM at 5-km spatial resolution with the aid of spatiotemporal Kriging. PMID- 22238504 TI - Perceived Norms Mediate Effects of a Brief Motivational Intervention for Sanctioned College Drinkers. AB - The present study is a secondary analysis of a randomized trial of brief motivational interventions (BMIs) for 198 college students sanctioned for alcohol related violations of school policy (Carey, Henson, Carey, & Maisto, 2009). Using multivariate latent growth curve models, we evaluated theoretically-derived mediators of the observed BMI effect: motivation to change (readiness-to-change, costs and benefits of drinking), and drinking norms (injunctive norms for peers, and descriptive norms for friends, local peers, and national peers). Results provided partial support for mediation by changes in perceptions of descriptive but not injunctive norms, a pattern that varied by gender and norm type. We found no evidence of a mediating role for any of the motivational variables. PMID- 22238505 TI - RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation. AB - Rosette nanotubes (RNT) are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G?C motif). In this report, the G?C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK G?C) and amino acid Lys (K-G?C) which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as K(x)/RGDSK(y)-RNT, where x and y refer to the molar ratios of K G?C and RGDSK-G?C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous K(x)/RGDSK(y)-RNT on acute lipopolysaccharide (LPS)-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 MUg and/or intravenously with K90/RGDSK10-RNT. Here we provide the first evidence that intravenous administration of K90/RGDSK10-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K90/RGDSK10-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K90/RGDSK10-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1beta, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K90/RGDSK10-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung. PMID- 22238506 TI - Effect of heparan sulfate and gold nanoparticles on muscle development during embryogenesis. AB - PURPOSE: It was hypothesized that heparan sulfate (HS) as an essential compound for myogenesis and nanoparticles of gold (nano-Au) as highly reactive compounds can affect muscle development as a consequence of molecular regulation of muscle cell formation, and that these effects may be enhanced by a complex of HS conjugated with nano-Au. The objective of the present study was to determine the effect of administration of nano-Au, HS, and a nano-Au+HS complex on the morphological and molecular characteristics of breast muscle during embryogenesis. METHODS: Chicken embryos were used as in vivo model. Fertilized chicken eggs (n = 350) were randomly divided into the control group and the groups treated with nano-Au, HS, and nano-Au+HS. The experimental solutions were given in ovo on the first day of incubation and the embryos were evaluated on day 20 of incubation. The methods included biochemical indices in blood, immunohistochemistry, microscopy (transmission electron microscopy, scanning electron microscopy, confocal), and gene expression at the messenger ribonucleic acid and protein levels. RESULTS: The treatments did not adversely affect mortality, organ weight, and homeostasis of the embryos. HS stimulated the development and maturation of breast muscle by increasing the number of nuclei, satellite cells, and muscle fibers and affected the expression of basic fibroblast growth factor-2 and paired-box transcription factor-7. Furthermore, the nano-Au+HS complex contributed to the increased number of myocytes and nuclei in chicken embryo muscles. CONCLUSION: The results indicate that the administration of HS and nano-Au affects muscle development and that this effect is enhanced by conjugating HS with nano-Au. PMID- 22238507 TI - Preparation and characterization of realgar nanoparticles and their inhibitory effect on rat glioma cells. AB - AIM: Our objective was to prepare a new nano-sized realgar particle and characterize its anti-tumor effect on tumor cells. METHODS: Nanoparticles were prepared by coprecipitation and were detected by transmission electron microscopy, scanning electron microscopy, energy dispersive spectrometry (EDS), and dynamic light scattering. An anti-proliferative effect of realgar nanoparticles on rat glioma (C6) cells was determined by the MTT assay. Cell cycle and apoptosis rates were observed by flow cytometry. Apoptosis-related gene expression was detected by immunofluorescence staining. RESULTS: Realgar nanoparticles were successfully prepared. The particles were spherical, with an average diameter of approximately 80 nm, and contained arsenic and sulfur elements. Realgar nanoparticles inhibited C6 cell proliferation and induced apoptosis in a dose- and time-dependent manner. Treatment of C6 cells with realgar nanoparticles significantly increased the proportions of cells in S and G2/M phases, decreased the proportion of cells in G0/G1 phase, downregulated Bcl 2 expression, and substantially upregulated Bax expression. CONCLUSION: Realgar nanoparticles significantly inhibited C6 glioma cell proliferation and promoted cell apoptosis by inducing the upregulation of Bax and downregulation of Bcl-2 expression. Realgar nanoparticles are a promising in vitro anti-cancer strategy and may be applicable for human cancer therapy studies. PMID- 22238508 TI - Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles. AB - Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra(r) product. PMID- 22238509 TI - Oxaliplatin-incorporated micelles eliminate both cancer stem-like and bulk cell populations in colorectal cancer. AB - PURPOSE: The failure of cancer treatments is partly due to the enrichment of cancer stem-like cells (CSLCs) that are resistant to conventional chemotherapy. A novel micelle formulation of oxaliplatin (OXA) encapsulated in chitosan vesicle was developed. The authors postulate that micelle encapsulation of OXA would eliminate both CSLCs and bulk cancer cells in colorectal cancer (CRC). EXPERIMENTAL DESIGN: In this study, using stearic acid-g-chitosan oligosaccharide (CSO-SA) polymeric micelles as a drug-delivery system, OXA-loaded CSO-SA micelles (CSO-SA/OXA) were prepared. Intracellular uptake of CSO-SA/OXA micelles was assessed by confocal microscope. The effects of free OXA, the empty carrier, and CSO-SA/OXA micelles were tested using human CRC cell lines in vitro and in vivo. RESULTS: The micelles showed excellent internalization ability that increased OXA accumulation both in CRC cells and tissues. Furthermore, CSO-SA/OXA micelles could either increase the cytotoxicity of OXA against the bulk cancer cells or reverse chemoresistance of CSLC subpopulations in vitro. Intravenous administration of CSO-SA/OXA micelles effectively suppressed the tumor growth and reduced CD133+/CD24+ cell (putative CRC CSLC markers) compared with free OXA treatment, which caused CSLC enrichment in xenograft tumors (P < 0.05). CONCLUSION: The results of this study indicate that CSO-SA micelle as a drug delivery carrier is effective for eradicating CSLCs and may act as a new option for CRC therapy. PMID- 22238510 TI - Subtle cytotoxicity and genotoxicity differences in superparamagnetic iron oxide nanoparticles coated with various functional groups. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely utilized for the diagnosis and therapy of specific diseases, as magnetic resonance imaging (MRI) contrast agents and drug-delivery carriers, due to their easy transportation to targeted areas by an external magnetic field. For such biomedical applications, SPIONs must have multifunctional characteristics, including optimized size and modified surface. However, the biofunctionality and biocompatibility of SPIONs with various surface functional groups of different sizes have yet to be elucidated clearly. Therefore, it is important to carefully monitor the cytotoxicity and genotoxicity of SPIONs that are surfaced-modified with various functional groups of different sizes. In this study, we evaluated SPIONs with diameters of approximately 10 nm and 100~150 nm, containing different surface functional groups. SPIONs were covered with -O- groups, so-called bare SPIONs. Following this, they were modified with three different functional groups -hydroxyl (-OH), carboxylic (-COOH), and amine (-NH2) groups--by coating their surfaces with tetraethyl orthosilicate (TEOS), (3-aminopropyl)trimethoxysilane (APTMS), TEOS-APTMS, or citrate, which imparted different surface charges and sizes to the particles. The effects of SPIONs coated with these functional groups on mitochondrial activity, intracellular accumulation of reactive oxygen species, membrane integrity, and DNA stability in L-929 fibroblasts were determined by water-soluble tetrazolium, 2',7'-dichlorodihydrofluorescein, lactate dehydrogenase, and comet assays, respectively. Our toxicological observations suggest that the functional groups and sizes of SPIONs are critical determinants of cellular responses, degrees of cytotoxicity and genotoxicity, and potential mechanisms of toxicity. Nanoparticles with various surface modifications and of different sizes induced slight, but possibly meaningful, changes in cell cytotoxicity and genotoxicity, which would be significantly valuable in further studies of bioconjugation and cell interaction for drug delivery, cell culture, and cancer-targeting applications. PMID- 22238511 TI - A dynamical model of oocyte maturation unveils precisely orchestrated meiotic decisions. AB - Maturation of vertebrate oocytes into haploid gametes relies on two consecutive meioses without intervening DNA replication. The temporal sequence of cellular transitions driving eggs from G2 arrest to meiosis I (MI) and then to meiosis II (MII) is controlled by the interplay between cyclin-dependent and mitogen activated protein kinases. In this paper, we propose a dynamical model of the molecular network that orchestrates maturation of Xenopus laevis oocytes. Our model reproduces the core features of maturation progression, including the characteristic non-monotonous time course of cyclin-Cdks, and unveils the network design principles underlying a precise sequence of meiotic decisions, as captured by bifurcation and sensitivity analyses. Firstly, a coherent and sharp meiotic resumption is triggered by the concerted action of positive feedback loops post translationally activating cyclin-Cdks. Secondly, meiotic transition is driven by the dynamic antagonism between positive and negative feedback loops controlling cyclin turnover. Our findings reveal a highly modular network in which the coordination of distinct regulatory schemes ensures both reliable and flexible cell-cycle decisions. PMID- 22238513 TI - VEGF: Potential therapy for renal regeneration. AB - Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. A number of studies have focused on its role in health and disease and discussed the possibility of VEGF as both a therapeutic tool and target based on its specific actions on vascular proliferation and cell survival. On one side, anti VEGF therapies are at the fore-front of treatment of many solid tumors, but blockade of VEGF carries collateral effects such as hypertension and renal damage largely due to abnormalities in the microvasculature. On the other hand, recent clinical and experimental evidence has shown the feasibility of using VEGF administration to protect ischemic tissues such as the myocardium or the kidney via stimulation of microvascular proliferation and repair. In this commentary, we discuss the possibility and potential mechanisms of using intra-renal administration of VEGF to preserve the renal microcirculation and, consequently, decrease progressive renal injury in chronic renovascular disease. Targeted administration of VEGF may constitute a novel stand-alone or co-adjuvant intervention with the potential to become a part of a comprehensive plan to protect renal function. PMID- 22238514 TI - Mesenchymal stem cells - a promising therapy for Acute Respiratory Distress Syndrome. AB - Acute Respiratory Distress Syndrome (ARDS) constitutes a spectrum of severe acute respiratory failure in response to a variety of inciting stimuli that is the leading cause of death and disability in the critically ill. Despite decades of research, there are no therapies for ARDS, and management remains supportive. A growing understanding of the complexity of the pathophysiology of ARDS, coupled with advances in stem cell biology, has lead to a renewed interest in the therapeutic potential of mesenchymal stem cells for ARDS. Recent evidence suggests that mesenchymal stem cells can modulate the immune response to reduce injury and also increase resistance to infection, while also facilitating regeneration and repair of the injured lung. This unique combination of effects has generated considerable excitement. We review the biological characteristics of mesenchymal stem cells that underlie their therapeutic potential for ARDS. We also summarise existing pre-clinical evidence, evaluate the potential and pitfalls of using mesenchymal stem cells for treatment, and examine the likely future directions for mesenchymal stem cells in ARDS. PMID- 22238515 TI - Lessons from the endothelial junctional mechanosensory complex. AB - Mechanotransduction plays a key role in both normal physiology and in diseases such as cancer, atherosclerosis and hypertension. Nowhere is this more evident than in the vascular system, where fluid shear stress from blood flow plays a critical role in shaping the blood vessels and in determining their function and dysfunction. Responses to flow are mediated in part by a complex of proteins comprised of PECAM-1, VE-cadherin and VEGFR2 at endothelial cell-cell junctions; all proteins that clearly have other, non-mechanical functions. We review recent progress toward understanding the functions and mechanisms of mechanotransduction by this complex and suggest some principles that may apply more broadly. PMID- 22238518 TI - Coupled chemo(enzymatic) reactions in continuous flow. AB - This review highlights the state of the art in the field of coupled chemo(enzymatic) reactions in continuous flow. Three different approaches to such reaction systems are presented herein and discussed in view of their advantages and disadvantages as well as trends for their future development. PMID- 22238519 TI - Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes. AB - In a simple procedure, the intramolecular hydroarylation of N-propargyl-pyrrole-2 carboxamides was accomplished with the aid of gold(III) catalysis. The reaction led to differently substituted pyrrolo[2,3-c]pyridine and pyrrolo[3,2-c]pyridine derivatives arising either from direct cyclization or from a formal rearrangement of the carboxamide group. Terminal alkynes are essential to achieve bicyclic pyrrolo-fused pyridinones by a 6-exo-dig process, while the presence of a phenyl group at the C-C triple bond promotes the 7-endo-dig cyclization giving pyrrolo azepines. PMID- 22238520 TI - Directed aromatic functionalization in natural-product synthesis: Fredericamycin A, nothapodytine B, and topopyrones B and D. AB - THIS IS A REVIEW OF OUR EFFORTS TOWARD THE SYNTHESIS OF A GROUP OF NATURAL PRODUCTS THAT DISPLAY NOTEWORTHY BIOLOGICAL ACTIVITY: Fredericamycin A, nothapodytine B, and topopyrones B and D. In each case, directed aromatic functionalization methodology greatly facilitated the assembly of the key molecular subunits. PMID- 22238521 TI - Continuous-flow enantioselective alpha-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline. AB - The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective alpha-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of beta-aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min. PMID- 22238522 TI - Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope. AB - A high-throughput screening protocol for evaluating chimeric, self-sufficient P450 biocatalysts and their mutants against a panel of substrates was developed, leading to the identification of a number of novel biooxidation activities. PMID- 22238523 TI - Pseudo five-component synthesis of 2,5-di(hetero)arylthiophenes via a one-pot Sonogashira-Glaser cyclization sequence. AB - Based upon a consecutive one-pot Sonogashira-Glaser coupling-cyclization sequence a variety of 2,5-di(hetero)arylthiophenes were synthesized in moderate to good yields. A single Pd/Cu-catalyst system, without further catalyst addition, and easily available, stable starting materials were used, resulting in a concise and highly efficient route for the synthesis of the title compounds. This novel pseudo five-component synthesis starting from iodo(hetero)arenes is particularly suitable as a direct access to well-defined thiophene oligomers, which are of peculiar interest in materials science. PMID- 22238524 TI - Synthesis of (-)-julocrotine and a diversity oriented Ugi-approach to analogues and probes. AB - An improved total synthesis of (-)-julocrotine in three steps from Cbz-glutamine, in 51% overall yield, is presented. To demonstrate the potential of the heterocyclic moiety for diversity oriented synthesis, a series of (-)-julocrotine analogues was synthesized by employing the heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1]. PMID- 22238526 TI - Chiral recognition of ephedrine: Hydrophilic polymers bearing beta-cyclodextrin moieties as chiral sensitive host molecules. AB - In this work we demonstrate chiral recognition of (+)- and (-)-ephedrine using a cyclodextrin-containing polymer. The supramolecular structures obtained by complexation of ephedrine and cyclodextrin were verified by 2-D ROESY NMR measurements. Dynamic light scattering showed clear differences in the mean coil size. PMID- 22238525 TI - Ratiometric fluorescent probe for enantioselective detection of D-cysteine in aqueous solution. AB - A ratiometric fluorescent probe based on a Cd(2+)-ACAQ complex was designed and demonstrated for the chemo- and enantioselective detection of cysteine in 99:1 buffered HEPES:ACN solutions. Under the measuring conditions, the sensor demonstrates high selectivity toward Cys against Hcy and GSH, and an enantioselectivity of 3.35 can be achieved for antipodal forms of Cys. PMID- 22238527 TI - Synthesis of fluoranthenes by hydroarylation of alkynes catalyzed by gold(I) or gallium trichloride. AB - Electrophilic gold(I) catalyst 6 competes with GaCl(3) as the catalyst of choice in the synthesis of fluoranthenes by intramolecular hydroarylation of alkynes. The potential of this catalyst for the preparation of polyarenes is illustrated by a synthesis of two functionalized decacyclenes in a one-pot transformation in which three C-C bonds are formed with high efficiency. PMID- 22238528 TI - Synthesis and oxidation of some azole-containing thioethers. AB - Pyrazole and benzotriazole-containing thioethers, namely 1,5-bis(3,5 dimethylpyrazol-1-yl)-3-thiapentane, 1,8-bis(3,5-dimethylpyrazol-1-yl)-3,6 dithiaoctane and 1,3-bis(1,2,3-benzotriazol-1-yl)-2-thiapropane were prepared and fully characterized. Oxidation of the pyrazole-containing thioether by hydrogen peroxide proceeds selectively to provide a sulfoxide or sulfone, depending on the amount of oxidant used. Oxidation of the benzotriazole derivative by hydrogen peroxide is not selective, and sulfoxide and sulfone form concurrently. Selenium dioxide-catalyzed oxidation of benzotriazole thioether by H(2)O(2), however, proceeds selectively and yields sulfoxide only. PMID- 22238529 TI - A novel and facile synthesis of 3-(2-benzofuroyl)- and 3,6-bis(2 benzofuroyl)carbazole derivatives. AB - A facile synthesis of hitherto unreported 3-(2-benzofuroyl)carbazoles 3a-k, 3,6 bis(2-benzofuroyl)carbazoles 5a-k, and naphtho[2,1-b]furoylcarbazoles 3l and 5l is described. The synthesis mainly relies on the ultrasound-assisted Rap-Stoermer reaction of 3-chloroacetyl- (1) or 3,6-dichloroacetyl-9-ethyl-9H-carbazole (4) with various salicylaldehydes 2a-k as well as 2-hydroxy-1-naphthaldehyde (2l) in CH(3)CN with the presence of PEG-400 as catalyst. The procedure offers easy access to benzofuroylcarbazoles in short reaction times and the products are obtained in moderate to good yields. PMID- 22238530 TI - Supramolecular chemistry II. PMID- 22238531 TI - Highly efficient cyclosarin degradation mediated by a beta-cyclodextrin derivative containing an oxime-derived substituent. AB - The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the beta-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native beta-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (-)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents. PMID- 22238532 TI - Impact of the level of complexity in self-sorting: Fabrication of a supramolecular scalene triangle. AB - The impact of the level of complexity in self-sorting was elaborated through the fabrication of various scalene triangles. It turned out that the self-sorting system with a higher level of complexity was far superior to less complex sorting algorithms. PMID- 22238533 TI - Planar-bilayer activities of linear oligoester bolaamphiphiles. AB - Voltage-clamp experiments of eight oligoester bolaamphiphiles in two subclasses are described. Syntheses of three new terephthalate-based compounds were achieved in three linear steps. Together with five previously described, related compounds, the ion transport activity was assessed by means of the voltage-clamp technique. All of the compounds show multiple types of conductance behavior in planar bilayers, a subset of which was exponentially voltage-dependent. The varied and irregular activities were summarized with the aid of a recently developed "activity-grid" method. PMID- 22238534 TI - Asymmetric synthesis of quaternary aryl amino acid derivatives via a three component aryne coupling reaction. AB - A method was developed for the synthesis of alpha-alkyl, alpha-aryl-bislactim ethers in good to excellent yields and high diastereoselectivities, consisting of a facile one-pot procedure in which the aryl group is introduced by means of a nucleophilic addition to benzyne and the alkyl group by alkylation of a resultant benzylic anion. Hydrolysis of the sterically less hindered adducts gave the corresponding quaternary amino acids with no racemization, whereas hydrolytic ring opening gave the corresponding valine dipeptides from bulkier bislactims. PMID- 22238535 TI - Synthesis of dye/fluorescent functionalized dendrons based on cyclotriphosphazene. AB - Functionalized phenols based on tyramine were synthesized in order to be selectively grafted on to hexachlorocyclotriphosphazene, affording a variety of functionalized dendrons of type AB(5). The B functions comprised fluorescent groups (dansyl) or dyes (dabsyl), whereas the A function was provided by either an aldehyde or an amine. The characterization of these dendrons is reported. An unexpected behaviour of a fluorescent and water-soluble dendron based on dansyl groups in mixtures of dioxane/water was observed. PMID- 22238537 TI - Structural conditions required for the bridge lithiation and substitution of a basic calix[4]arene. AB - Lithiation and subsequent reaction with CO(2) was applied to calix[4]arenes with different, equal or mixed, ether functions at the lower-rim site as well as tert butylated or non-tert-butylated upper-rim positions. Whereas this reaction fails for symmetric calix[4]arene ethers with alkoxy residues greater than methoxy, the carboxylation of mixed methoxy-propoxy calixarene ethers is possible. In connection with this, several new monobridge-substituted calix[4]arenes were characterized with respect to their conformational behaviour in solution and the X-ray crystal structure of one key intermediate is taken into consideration. PMID- 22238536 TI - Recent advances in direct C-H arylation: Methodology, selectivity and mechanism in oxazole series. AB - Catalytic direct (hetero)arylation of (hetero)arenes is an attractive alternative to traditional Kumada, Stille, Negishi and Suzuki-Miyaura cross-coupling reactions, notably as it avoids the prior preparation and isolation of (hetero)arylmetals. Developments of this methodology in the oxazole series are reviewed in this article. Methodologies, selectivity, mechanism and future aspects are presented. PMID- 22238538 TI - Dependency of the regio- and stereoselectivity of intramolecular, ring-closing glycosylations upon the ring size. AB - Phenyl 3,4,6-tri-O-benzyl-2-O-(3-carboxypropionyl)-1-thio-beta-D galactopyranoside (1) was condensed via its pentafluorophenyl ester 2 with 5 aminopentyl (4a), 4-aminobutyl (4b), 3-aminopropyl (4c) and 2-aminoethyl 4,6-O benzylidene-beta-D-glucopyranoside (4d), prepared from the corresponding N-Cbz protected glucosides 3a-d, to give the corresponding 2-[3 (alkylcarbamoyl)propionyl] tethered saccharides 5a-d. Intramolecular, ring closing glycosylation of the saccharides with NIS and TMSOTf afforded the tethered beta(1->3) linked disaccharides 6a-c, the alpha(1->3) linked disaccharides 7a-d and the alpha(1->2) linked disaccharide 8d in ratios depending upon the ring size formed during glycosylation. No beta(1->2) linked disaccharides were formed. Molecular modeling of saccharides 6-8 revealed that a strong aromatic stacking interaction between the aromatic parts of the benzyl and benzylidene protecting groups in the galactosyl and glucosyl moieties was mainly responsible for the observed regioselectivity and anomeric selectivity of the ring-closing glycosylation step. PMID- 22238539 TI - Biosynthesis and function of secondary metabolites. PMID- 22238540 TI - Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes. AB - Cyanobacteria are prolific producers of natural products. Investigations into the biochemistry responsible for the formation of these compounds have revealed fascinating mechanisms that are not, or only rarely, found in other microorganisms. In this article, we survey the biosynthetic pathways of cyanobacteria isolated from freshwater, marine and terrestrial habitats. We especially emphasize modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathways and highlight the unique enzyme mechanisms that were elucidated or can be anticipated for the individual products. We further include ribosomal natural products and UV-absorbing pigments from cyanobacteria. Mechanistic insights obtained from the biochemical studies of cyanobacterial pathways can inspire the development of concepts for the design of bioactive compounds by synthetic-biology approaches in the future. PMID- 22238541 TI - Marilones A-C, phthalides from the sponge-derived fungus Stachylidium sp. AB - The marine-derived fungus Stachylidium sp. was isolated from the sponge Callyspongia sp. cf. C. flammea. Culture on a biomalt medium supplemented with sea salt led to the isolation of three new phthalide derivatives, i.e., marilones A-C (1-3), and the known compound silvaticol (4). The skeleton of marilones A and B is most unusual, and its biosynthesis is suggested to require unique biochemical reactions considering fungal secondary metabolism. Marilone A (1) was found to have antiplasmodial activity against Plasmodium berghei liver stages with an IC(50) of 12.1 uM. Marilone B (2) showed selective antagonistic activity towards the serotonin receptor 5-HT(2B) with a K(i) value of 7.7 uM. PMID- 22238542 TI - Tertiary alcohol preferred: Hydroxylation of trans-3-methyl-L-proline with proline hydroxylases. AB - The enzymatic synthesis of tertiary alcohols by the stereospecific oxidation of tertiary alkyl centers is a most-straightforward but challenging approach, since these positions are sterically hindered. In contrast to P450-monooxygenases, there is little known about the potential of non-heme iron(II) oxygenases to catalyze such reactions. We have studied the hydroxylation of trans-3-methyl-L proline with the alpha-ketoglutarate (alpha-KG) dependent oxygenases, cis-3 proline hydroxylase type II and cis-4-proline hydroxylase (cis-P3H_II and cis P4H). With cis-P3H_II, the tertiary alcohol product (3R)-3-hydroxy-3-methyl-L proline was obtained exclusively but in reduced yield (~7%) compared to the native substrate L-proline. For cis-P4H, a complete shift in regioselectivity from C-4 to C-3 was observed so that the same product as with cis-P3H_II was obtained. Moreover, the yields were at least as good as in control reactions with L-proline (~110% relative yield). This result demonstrates a remarkable potential of non-heme iron(II) oxygenases to oxidize substrates selectively at sterically hindered positions. PMID- 22238543 TI - The application of a monolithic triphenylphosphine reagent for conducting Appel reactions in flow microreactors. AB - Herein we describe the application of a monolithic triphenylphosphine reagent to the Appel reaction in flow-chemistry processing, to generate various brominated products with high purity and in excellent yields, and with no requirement for further off-line purification. PMID- 22238544 TI - Efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles from 3-arylsydnones and 2 aryl-1,1-dihalo-1-alkenes. AB - An efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles was achieved. The synthesis involves the [3 + 2] dipolar cycloaddition of 3-arylsydnones and 2-aryl 1,1-dihalo-1-alkenes. The process proceeds smoothly in moderate to excellent yields. 1,3-Diaryl-4-halo-1H-pyrazoles are found to be important intermediates that can easily be converted into 1,2,5-triaryl-substituted pyrazoles via Pd catalyzed C-H bond activation. PMID- 22238545 TI - Photochemical and thermal intramolecular 1,3-dipolar cycloaddition reactions of new o-stilbene-methylene-3-sydnones and their synthesis. AB - New trans- and cis-o-stilbene-methylene-sydnones 3a,b were synthesized by transforming the trans- and cis-o-aminomethylstilbene derivative, obtained by reduction of corresponding o-cyano derivatives, into glycine ester derivatives (43 and 31% yield) followed by hydrolysis (90 and 96% yield), nitrosation and ring closure with acetic acid anhydride (30 and 40% yield). The products were submitted to photochemical and thermal intramolecular [3 + 2] cycloadditions to afford diverse heteropolycyclic compounds. Photochemical reactions afforded cis-3 (4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (11, 12.5% yield) and trans-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (12, 5% yield). Thermal reactions afforded 3-(4-methylphenyl)-3,3a,8,8a-tetrahydroindeno[2,1 c]pyrazole (14, 50% yield) and 11-(4-methylphenyl)-9,10 diazatricyclo[7.2.1.0(2,7)]dodeca-2,4,6,10-tetraene (15, 22% yield). PMID- 22238546 TI - Continuous proline catalysis via leaching of solid proline. AB - Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst precursor. Specifically, we perform continuous proline catalyzed alpha-aminoxylations using a packed-bed of L proline. The system relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably forming a soluble oxazolidinone intermediate. This transports a catalytic amount of proline from the packed-bed into the reactor coil for subsequent combination with a solution of nitrosobenzene, affording the desired optically active alpha aminooxy alcohol after reduction. To our knowledge, this is the first example in which a homogeneous catalyst is produced continuously using a packed-bed. We predict that the method will not only be useful for other L-proline catalyzed reactions, but we also foresee that it could be used to produce other catalytic species in flow. PMID- 22238547 TI - Continuous-flow hydration-condensation reaction: Synthesis of alpha,beta unsaturated ketones from alkynes and aldehydes by using a heterogeneous solid acid catalyst. AB - A simple, practical and efficient continuous-flow hydration-condensation protocol was developed for the synthesis of alpha,beta-unsaturated ketones starting from alkynes and aldehydes by employing a heterogeneous catalyst in a flow microwave. The procedure presents a straightforward and convenient access to valuable differently substituted chalcones and can be applied on multigram scale. PMID- 22238548 TI - Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities. AB - A series of 6,8-diiodocoumarin-3-N-carboxamides (4-11) were prepared. Treatment of ethyl 6,8-diiodocoumarin-3-carboxylate (1) with ethyl cyanoacetate/NH(4)OAc gave ethyl 2-(3-carbamoyl-6,8-diiodocoumarin-4-yl)-2-cyanoacetate (12) and 2 amino-4-hydroxy-7,9-diiodocoumarino[3,4-c]pyridine-1-carbonitrile (13), and treatment with acetone in the presence of NH(4)OAc or methylamine gave the ethyl 4-oxo-2,6-methano-2-methyl-3,4,5,6-tetrahydro-8,10-diiodobenzo[2,1-g]-2H-1,3 oxazocine-5-carboxylate derivatives 14a,b. All compounds were evaluated for their antimicrobial activity and the compounds 12-14a,b exhibited a pronounced effect on all tested microorganisms. PMID- 22238549 TI - Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca. AB - The volatiles released by Micromonospora aurantiaca were collected by means of a closed-loop stripping apparatus (CLSA) and analysed by GC-MS. The headspace extracts contained more than 90 compounds from different classes. Fatty acid methyl esters (FAMEs) comprised the major compound class including saturated unbranched, monomethyl and dimethyl branched FAMEs in diverse structural variants: Unbranched, alpha-branched, gamma-branched, (omega-1)-branched, (omega 2)-branched, alpha- and (omega-1)-branched, gamma- and (omega-1)-branched, gamma- and (omega-2)-branched, and gamma- and (omega-3)-branched FAMEs. FAMEs of the last three types have not been described from natural sources before. The structures for all FAMEs have been suggested based on their mass spectra and on a retention index increment system and verified by the synthesis of key reference compounds. In addition, the structures of two FAMEs, methyl 4,8 dimethyldodecanoate and the ethyl-branched compound methyl 8-ethyl-4 methyldodecanoate were deduced from their mass spectra. Feeding experiments with isotopically labelled [(2)H(10)]leucine, [(2)H(10)]isoleucine, [(2)H(8)]valine, [(2)H(5)]sodium propionate, and [methyl-(2)H(3)]methionine demonstrated that the responsible fatty acid synthase (FAS) can use different branched and unbranched starter units and is able to incorporate methylmalonyl-CoA elongation units for internal methyl branches in various chain positions, while the methyl ester function is derived from S-adenosyl methionine (SAM). PMID- 22238550 TI - Valence isomerization of cyclohepta-1,3,5-triene and its heteroelement analogues. AB - The valence isomerization of the all-carbon and heteroelement analogues of cyclohepta-1,3,5-triene into the corresponding bicyclo[4.1.0]hepta-2,4-dienes is reviewed to show the impact of the heteroatom on the stability of both valence isomers. The focus is on the parent systems and their synthetic applications. PMID- 22238551 TI - Sexithiophenes as efficient luminescence quenchers of quantum dots. AB - Sexithiophenes 1a and 1b, in which a 4-(dimethylamino)phenyl unit is incorporated as an end-capping group, were synthesised and characterised by cyclic voltammetry, absorption spectroscopy and UV-vis spectroelectrochemistry. Additionally, their ability to function as effective luminescence quenchers for quantum dot emission was studied by photoluminescence spectroscopy and compared with the performance of alkyl end-capped sexithiophenes 2a and 2b. PMID- 22238552 TI - Equilibrium constants and protonation site for N-methylbenzenesulfonamides. AB - The protonation equilibria of four substituted N-methylbenzenesulfonamides, X MBS: X = 4-MeO (3a), 4-Me (3b), 4-Cl (3c) and 4-NO(2) (3d), in aqueous sulfuric acid were studied at 25 degrees C by UV-vis spectroscopy. As expected, the values for the acidity constants are highly dependent on the electron-donor character of the substituent (the pK(BH+) values are -3.5 +/- 0.2, -4.2 +/- 0.2, 5.2 +/- 0.3 and -6.0 +/- 0.3 for 3a, 3b, 3c and 3d, respectively). The solvation parameter m* is always higher than 0.5 and points to a decrease in the importance of solvation on the cation stabilization as the electron-donor character of the substituent increases. Hammett plots of the equilibrium constants showed a better correlation with the sigma(+) substituent parameter than with sigma, which indicates that the initial protonation site is the oxygen atom of the sulfonyl group. PMID- 22238553 TI - Synthetic approaches to multifunctional indenes. AB - The synthesis of multifunctional indenes with at least two different functional groups has not yet been extensively explored. Among the plausible synthetic routes to 3,5-disubstituted indenes bearing two different functional groups, such as the [3-(aminoethyl)inden-5-yl)]amines, a reasonable pathway involves the (5 nitro-3-indenyl)acetamides as key intermediates. Although several multistep synthetic approaches can be applied to obtain these advanced intermediates, we describe herein their preparation by an aldol-type reaction between 5-nitroindan 1-ones and the lithium salt of N,N-disubstituted acetamides, followed immediately by dehydration with acid. This classical condensation process, which is neither simple nor trivial despite its apparent directness, permits an efficient entry to a variety of indene-based molecular modules, which could be adapted to a range of functionalized indanones. PMID- 22238554 TI - Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity. AB - A variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1 ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-beta-lactams. In addition, a number of 2 (azidomethyl)aziridines was converted into novel 2-[(1,2,3-triazol-1 yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, followed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3 diaminopropyl)-1,2,3-triazoles. Although most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC(50)-values of <=25 MUM. PMID- 22238555 TI - Acute traumatic coagulopathy in severe injury: incidence, risk stratification, and treatment options. AB - BACKGROUND: Clinical observation and research findings show that acute traumatic coagulopathy (ATC) is a major factor that must be addressed in the care of severely injured patients. In this review article, we discuss the incidence and causes of ATC, the potential means of early risk stratification for it, and recommendations for its treatment. METHODS: We selectively reviewed the pertinent literature and retrospectively analyzed data from the Trauma Registry of the German Trauma Society (Traumaregister der Deutschen Gesellschaft fur Unfallchirurgie, TR-DGU) relating to the incidence, causes, and outcome of ATC. We provide an overview of current treatment recommendations, supplemented by our own findings regarding the ratio of packed red blood cell concentrate (pRBC) to fresh-frozen plasma (FFP) transfusion and regarding coagulation-factor-based treatments for coagulopathy in the acute phase after trauma. RESULTS AND CONCLUSION: ATC, a condition associated with increased morbidity and mortality, is seen on admission in one out of four patients with major trauma. The main causes of ATC are tissue damage, hypoperfusion, hemodilution, hypothermia, acidosis, and inflammation. It may be possible to identify patients at risk for ATC early on through the use of rapidly calculable, predictive numerical scales (McLaughlinScore, TASH, and ABC), laboratory tests, and imaging studies (FAST and CT). Acute treatment is focused on the control of bleeding and support of the coagulation system according to the current guidelines. Patients at high risk may benefit from a balanced transfusion strategy. Innovative strategies currently under study include point-of-care-guided treatment and coagulation-factor concentrate-based treatment. PMID- 22238556 TI - Correspondence (letter to the editor): Clarifications. PMID- 22238557 TI - Correspondence (letter to the editor): Particular characteristics of encapsulated bacteria. PMID- 22238558 TI - Correspondence (letter to the editor): Limitations. PMID- 22238560 TI - Basic medical advice for travelers to high altitudes. AB - BACKGROUND: High-altitude travel, for mountain climbing, trekking, or sightseeing, has become very popular. Therefore, the awareness of its dangers has increased, and many prospective travelers seek medical advice before setting forth on their trip. METHODS: We selectively searched the literature for relevant original articles and reviews about acclimatization to high altitude and about high-altitude-related illnesses, including acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) (search in Medline for articles published from 1960-2010). RESULTS: High-altitude-related illnesses are caused by hypoxia and the resulting hypoxemia in otherwise healthy persons who travel too high too fast, with too little time to become acclimatized. The individual susceptibility to high-altitude-related illness is a further risk factor that can only be recognized in persons who have traveled to high altitudes in the past. In an unselected group of mountain climbers, 50% had AMS at 4500 meters, while 0.5-1% had HACE and 6% had HAPE at the same altitude. Persons with preexisting illnesses, particularly of the heart and lungs, can develop symptoms of their underlying disease at high altitudes because of hypoxia. Thus, medical advice is based on an assessment of the risk of illness in relation to the intended altitude profile of the trip, in consideration of the prospective traveler's suitability for high altitudes (cardiopulmonary performance status, exercise capacity) and individual susceptibility to high altitude-related illnesses, as judged from previous exposures. The symptoms and treatment of high-altitude-related illnesses should be thoroughly explained. CONCLUSION: An understanding of the physiology of adaptation to high altitudes and of the pathophysiology and clinical manifestations of high-altitude-related illnesses provides a basis for the proper counseling of prospective travelers, through which life-threatening conditions can be prevented. PMID- 22238561 TI - A Diet and Exercise Intervention during Chemotherapy for Breast Cancer. AB - Weight gain is an important concern that impacts on breast cancer outcomes and general health in survivorship. This randomized, pilot study evaluated whether or not women could comply with a weight control program that is initiated at the beginning of chemotherapy for breast cancer. The program sought to prevent weight gain using a low-fat, high fruit-vegetable diet combined with moderate physical activity. The intervention was implemented using a telephone counseling approach that blended motivational interviewing with social cognitive theory. A total of 40 women were recruited over 9 months at the University of Michigan Comprehensive Cancer Center. This represents 55% of eligible women referred to the study and indicates that interest in a healthy lifestyle program at the initiation of chemotherapy for breast cancer was high. Subjects who dropped out had significantly lower fruit and vegetable intakes and lower blood carotenoids at baseline than subjects who completed the study. Statistically significant beneficial effects were observed on fruit and vegetable intakes, physical activity and breast cancer-specific well-being by the intervention. Mean body fat from dual energy X-ray absorptiometry increased in the written materials arm and decreased in the intervention arm. Of the enrolled women, 75% completed 12 months on study and satisfaction with study participation was high. These data indicate that lifestyle intervention during breast cancer treatment is feasible during treatment with chemotherapy for breast cancer and benefits women in several domains. PMID- 22238569 TI - Pyrokinin beta-neuropeptide affects necrophoretic behavior in fire ants (S. invicta), and expression of beta-NP in a mycoinsecticide increases its virulence. AB - Fire ants are one of the world's most damaging invasive pests, with few means for their effective control. Although ecologically friendly alternatives to chemical pesticides such as the insecticidal fungus Beauveria bassiana have been suggested for the control of fire ant populations, their use has been limited due to the low virulence of the fungus and the length of time it takes to kill its target. We present a means of increasing the virulence of the fungal agent by expressing a fire ant neuropeptide. Expression of the fire ant (Solenopsis invicta) pyrokinin beta-neuropeptide (beta-NP) by B. bassiana increased fungal virulence six-fold towards fire ants, decreased the LT(50), but did not affect virulence towards the lepidopteran, Galleria mellonella. Intriguingly, ants killed by the beta-NP expressing fungus were disrupted in the removal of dead colony members, i.e. necrophoretic behavior. Furthermore, synthetic C-terminal amidated beta-NP but not the non-amidated peptide had a dramatic effect on necrophoretic behavior. These data link chemical sensing of a specific peptide to a complex social behavior. Our results also confirm a new approach to insect control in which expression of host molecules in an insect pathogen can by exploited for target specific augmentation of virulence. The minimization of the development of potential insect resistance by our approach is discussed. PMID- 22238570 TI - Development of the Respiratory Index of Severity in Children (RISC) score among young children with respiratory infections in South Africa. AB - OBJECTIVE: Pneumonia is a leading cause of death in children worldwide. A simple clinical score predicting the probability of death in a young child with lower respiratory tract infection (LRTI) could aid clinicians in case management and provide a standardized severity measure during epidemiologic studies. METHODS: We analyzed 4,148 LRTI hospitalizations in children <24 months enrolled in a pneumococcal conjugate vaccine trial in South Africa from 1998-2001, to develop the Respiratory Index of Severity in Children (RISC). Using clinical data at admission, a multivariable logistic regression model for mortality was developed and statistically evaluated using bootstrap resampling techniques. Points were assigned to risk factors based on their coefficients in the multivariable model. A child's RISC score is the sum of points for each risk factor present. Separate models were developed for HIV-infected and non-infected children. RESULTS: Significant risk factors for HIV-infected and non-infected children included low oxygen saturation, chest indrawing, wheezing, and refusal to feed. The models also included age and HIV clinical classification (for HIV-infected children) or weight-for-age (for non-infected children). RISC scores ranged up to 7 points for HIV-infected or 6 points for non-infected children and correlated with probability of death (0-47%, HIV-infected; 0-14%, non-infected). Final models showed good discrimination (area under the ROC curve) and calibration (goodness of-fit). CONCLUSION: The RISC score incorporates a simple set of risk factors that accurately discriminate between young children based on their risk of death from LRTI, and may provide an objective means to quantify severity based on the risk of mortality. PMID- 22238571 TI - Motor-cortical interaction in Gilles de la Tourette syndrome. AB - BACKGROUND: In Gilles de la Tourette syndrome (GTS) increased activation of the primary motor cortex (M1) before and during movement execution followed by increased inhibition after movement termination was reported. The present study aimed at investigating, whether this activation pattern is due to altered functional interaction between motor cortical areas. METHODOLOGY/PRINCIPAL FINDINGS: 10 GTS-patients and 10 control subjects performed a self-paced finger movement task while neuromagnetic brain activity was recorded using Magnetoencephalography (MEG). Cerebro-cerebral coherence as a measure of functional interaction was calculated. During movement preparation and execution coherence between contralateral M1 and supplementary motor area (SMA) was significantly increased at beta-frequency in GTS-patients. After movement termination no significant differences between groups were evident. CONCLUSIONS/SIGNIFICANCE: The present data suggest that increased M1 activation in GTS-patients might be due to increased functional interaction between SMA and M1 most likely reflecting a pathophysiological marker of GTS. The data extend previous findings of motor-cortical alterations in GTS by showing that local activation changes are associated with alterations of functional networks between premotor and primary motor areas. Interestingly enough, alterations were evident during preparation and execution of voluntary movements, which implies a general theme of increased motor-cortical interaction in GTS. PMID- 22238572 TI - Evidence for transcript networks composed of chimeric RNAs in human cells. AB - The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network. PMID- 22238573 TI - B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation. AB - B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3(+) T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR)/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK) are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL 2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK. PMID- 22238574 TI - A randomized controlled trial of adjunctive family therapy and treatment as usual following inpatient treatment for anorexia nervosa adolescents. AB - Research on treatments in anorexia nervosa (AN) is scarce. Although most of the therapeutic programs used in 'real world practice' in AN treatment resort to multidisciplinary approaches, they have rarely been evaluated. OBJECTIVE: To compare two multidimensional post-hospitalization outpatients treatment programs for adolescents with severe AN: Treatment as Usual (TAU) versus this treatment plus family therapy (TAU+FT). METHOD: Sixty female AN adolescents, aged 13 to 19 years, were included in a randomized parallel controlled trial conducted from 1999 to 2002 for the recruitment, and until 2004 for the 18 months follow-up. Allocation to one of the two treatment groups (30 in each arm) was randomised. The TAU program included sessions for the patient alone as well as sessions with a psychiatrist for the patient and her parents. The TAU+FT program was identical to the usual one but also included family therapy sessions targeting intra familial dynamics, but not eating disorder symptoms. The main Outcome Measure was the Morgan and Russell outcome category (Good or Intermediate versus Poor outcome). Secondary outcome indicators included AN symptoms or their consequences (eating symptoms, body mass index, amenorrhea, number of hospitalizations in the course of follow-up, social adjustment). The evaluators, but not participants, were blind to randomization. RESULTS: At 18 months follow-up, we found a significant group effect for the Morgan and Russell outcome category in favor of the program with family therapy (Intention-to-treat: TAU+FT :12/30 (40%); TAU : 5/29 (17.2%) p = 0.05; Per Protocol analysis: respectively 12/26 (46.2%); 4/27 (14.8%), p = 0.01). Similar group effects were observed in terms of achievement of a healthy weight (i.e., BMI>=10(th) percentile) and menstrual status. CONCLUSIONS: Adding family therapy sessions, focusing on intra-familial dynamics rather than eating symptomatology, to a multidimensional program improves treatment effectiveness in girls with severe AN. TRIAL REGISTRATION: Controlled trials.com ISRCTN71142875. PMID- 22238575 TI - CATCHprofiles: clustering and alignment tool for ChIP profiles. AB - Chromatin Immuno Precipitation (ChIP) profiling detects in vivo protein-DNA binding, and has revealed a large combinatorial complexity in the binding of chromatin associated proteins and their post-translational modifications. To fully explore the spatial and combinatorial patterns in ChIP-profiling data and detect potentially meaningful patterns, the areas of enrichment must be aligned and clustered, which is an algorithmically and computationally challenging task. We have developed CATCHprofiles, a novel tool for exhaustive pattern detection in ChIP profiling data. CATCHprofiles is built upon a computationally efficient implementation for the exhaustive alignment and hierarchical clustering of ChIP profiling data. The tool features a graphical interface for examination and browsing of the clustering results. CATCHprofiles requires no prior knowledge about functional sites, detects known binding patterns "ab initio", and enables the detection of new patterns from ChIP data at a high resolution, exemplified by the detection of asymmetric histone and histone modification patterns around H2A.Z-enriched sites. CATCHprofiles' capability for exhaustive analysis combined with its ease-of-use makes it an invaluable tool for explorative research based on ChIP profiling data. CATCHprofiles and the CATCH algorithm run on all platforms and is available for free through the CATCH website: http://catch.cmbi.ru.nl/. User support is available by subscribing to the mailing list catch-users@bioinformatics.org. PMID- 22238576 TI - Whole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus. AB - BACKGROUND: Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus. METHODS: Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates. RESULTS: On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol. CONCLUSION: Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus. PMID- 22238577 TI - The dopamine augmenter L-DOPA does not affect positive mood in healthy human volunteers. AB - Dopamine neurotransmission influences approach toward rewards and reward-related cues. The best cited interpretation of this effect proposes that dopamine mediates the pleasure that commonly accompanies reward. This hypothesis has received support in some animal models and a few studies in humans. However, direct assessments of the effect of transiently increasing dopamine neurotransmission have been largely limited to the use of psychostimulant drugs, which elevate brain levels of multiple neurotransmitters in addition to dopamine. In the present study we tested the effect of more selectively elevating dopamine neurotransmission, as produced by administration of the immediate dopamine precursor, L-DOPA (0, 100/25, 200/50 mg, Sinemet), in healthy human volunteers. Neither dose altered positive mood. The results suggest that dopamine neurotransmission does not directly influence positive mood in humans. PMID- 22238578 TI - Cardiac-oxidized antigens are targets of immune recognition by antibodies and potential molecular determinants in chagas disease pathogenesis. AB - Trypanosoma cruzi elicits reactive oxygen species (ROS) of inflammatory and mitochondrial origin in infected hosts. In this study, we examined ROS-induced oxidative modifications in the heart and determined whether the resultant oxidized cardiac proteins are targets of immune response and of pathological significance in Chagas disease. Heart biopsies from chagasic mice, rats and human patients exhibited, when compared to those from normal controls, a substantial increase in protein 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), carbonyl, and 3-nitrotyrosine (3-NT) adducts. To evaluate whether oxidized proteins gain antigenic properties, heart homogenates or isolated cardiomyocytes were oxidized in vitro and one- or two-dimensional gel electrophoresis (2D-GE)/Western blotting (WB) was performed to investigate the proteomic oxidative changes and recognition of oxidized proteins by sera antibodies in chagasic rodents (mice, rats) and human patients. Human cardiomyocytes exhibited LD(50) sensitivity to 30 uM 4-HNE and 100 uM H(2)O(2) at 6 h and 12 h, respectively. In vitro oxidation with 4-HNE or H(2)O(2) resulted in a substantial increase in 4-HNE- and carbonyl-modified proteins that correlated with increased recognition of cardiac (cardiomyocytes) proteins by sera antibodies of chagasic rodents and human patients. 2D-GE/Western blotting followed by MALDI-TOF-MS/MS analysis to identify cardiac proteins that were oxidized and recognized by human chagasic sera yielded 82 unique proteins. We validated the 2D-GE results by enzyme-linked immunosorbent assay (ELISA) and WB and demonstrated that oxidation of recombinant titin enhanced its immunogenicity and recognition by sera antibodies from chagasic hosts (rats and humans). Treatment of infected rats with phenyl-alpha-tert-butyl nitrone (PBN, antioxidant) resulted in normalized immune detection of cardiac proteins associated with control of cardiac pathology and preservation of heart contractile function in chagasic rats. We conclude that ROS-induced, cardiac oxidized antigens are targets of immune recognition by antibodies and molecular determinants for pathogenesis during Chagas disease. PMID- 22238579 TI - Identification of immunogenic proteins of Waddlia chondrophila. AB - Evidence is growing for a role of Waddlia chondrophila as an agent of adverse pregnancy outcomes in both humans and ruminants. This emerging pathogen, member of the order Chlamydiales, is also implicated in bronchiolitis and lower respiratory tract infections. Until now, the serological diagnosis of W. chondrophila infection has mainly relied on manually intensive tests including micro-immunofluorescence and Western blotting. Thus, there is an urgent need to establish reliable high throughput serological assays. Using a combined genomic and proteomic approach, we detected 57 immunogenic proteins of W. chondrophila, of which 17 were analysed by mass spectrometry. Two novel hypothetical proteins, Wim3 and Wim4, were expressed as recombinant proteins in Escherichia coli, purified and used as antigens in an ELISA test. Both proteins were recognized by sera of rabbits immunized with W. chondrophila as well as by human W. chondrophila positive sera but not by rabbit pre-immune sera nor human W. chondrophila negative sera. These results demonstrated that the approach chosen is suitable to identify immunogenic proteins that can be used to develop a serological test. This latter will be a valuable tool to further clarify the pathogenic potential of W. chondrophila. PMID- 22238580 TI - Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways. AB - Normal aging is associated with impairments in cognition, especially learning and memory. However, major individual differences are known to exist. Using the classical Morris Water Maze (MWM) task, we discriminated a population of 24 months old Long Evans aged rats in two groups--memory-impaired (AI) and memory unimpaired (AU) in comparison with 6-months old adult animals. AI rats presented deficits in learning, reverse memory and retention. At the molecular level, an increase in metabotropic glutamate receptors 5 (mGluR5) was observed in post synaptic densities (PSD) in the hippocampus of AU rats after training. Scaffolding Homer 1b/c proteins binding to group 1 mGluR facilitate coupling with its signaling effectors while Homer 1a reduces it. Both Homer 1a and 1b/c levels were up-regulated in the hippocampus PSD of AU animals following MWM task. Using immunohistochemistry we further demonstrated that mGluR5 as well as Homer 1b/c stainings were enhanced in the CA1 hippocampus sub-field of AU animals. In fact mGluR5 and Homer 1 isoforms were more abundant and co-localized in the hippocampal dendrites in AU rats. However, the ratio of Homer 1a/Homer 1b/c bound to mGluR5 in the PSD was four times lower for AU animals compared to AI rats. Consequently, AU animals presented higher PKCgamma, ERK, p70S6K, mTOR and CREB activation. Finally the expression of immediate early gene Arc/Arg3.1 was shown to be higher in AU rats in accordance with its role in spatial memory consolidation. On the basis of these results, a model of successful cognitive aging with a critical role for mGluR5, Homer 1 proteins and downstream signalling pathways is proposed here. PMID- 22238581 TI - Etiology and clinical characteristics of influenza-like illness (ILI) in outpatients in Beijing, June 2010 to May 2011. AB - BACKGROUND: Since May 2009, exposure of the population of Beijing, China to pH1N1 has resulted in an increase in respiratory illnesses. Limited information is available on the etiology and clinical characteristics of the influenza-like illness (ILI) that ensued in adults following the pH1N1 pandemic. METHODS: Clinical and epidemiological data of ILI in adults was collected. A total of 279 throat swabs were tested for twelve respiratory viruses using multiplex RT-PCR. Clinical characteristics of influenza A in outpatients versus test-negative patients were compared using Pearson's chi2 and the Mann-Whitney U test. 190 swabs were tested for pH1N1 by virus isolation. Consultation rates for ILI were compared between 2009 and 2010. RESULTS: One or two virus were detected in 29% of the samples. Influenza A virus (FLU-A) accounted for 22.9% (64/279). Other viruses were present at a frequency less than 3.0%. Cough was significantly associated with Influenza A virus infection (chi2, p<0.001). The positive rate of FLU-A was consistent with changes in the ILI rate during the same period and there was a significant reduction in the incidence of ILI in 2010 when compared to 2009. During the 2010-2011 influenza season, the incidence peaked in January 2011 in Beijing and north China. CONCLUSIONS: Exposure to pH1N1 had no impact on typical influenza seasonal peaks, although FLU-A remained the predominant virus for 2010 in Beijing. Symptomatically, cough was associated with FLU-A infection. The positive rate of influenza virus was consistent with changes in the ILI rate during the same period and there was a significant reduction in the incidence of ILI in 2010 when compared to that of 2009. PMID- 22238582 TI - Modeling the influence of local environmental factors on malaria transmission in Benin and its implications for cohort study. AB - Malaria remains endemic in tropical areas, especially in Africa. For the evaluation of new tools and to further our understanding of host-parasite interactions, knowing the environmental risk of transmission--even at a very local scale--is essential. The aim of this study was to assess how malaria transmission is influenced and can be predicted by local climatic and environmental factors.As the entomological part of a cohort study of 650 newborn babies in nine villages in the Tori Bossito district of Southern Benin between June 2007 and February 2010, human landing catches were performed to assess the density of malaria vectors and transmission intensity. Climatic factors as well as household characteristics were recorded throughout the study. Statistical correlations between Anopheles density and environmental and climatic factors were tested using a three-level Poisson mixed regression model. The results showed both temporal variations in vector density (related to season and rainfall), and spatial variations at the level of both village and house. These spatial variations could be largely explained by factors associated with the house's immediate surroundings, namely soil type, vegetation index and the proximity of a watercourse. Based on these results, a predictive regression model was developed using a leave-one-out method, to predict the spatiotemporal variability of malaria transmission in the nine villages.This study points up the importance of local environmental factors in malaria transmission and describes a model to predict the transmission risk of individual children, based on environmental and behavioral characteristics. PMID- 22238583 TI - Effect of P to A mutation of the N-terminal residue adjacent to the Rgd motif on rhodostomin: importance of dynamics in integrin recognition. AB - Rhodostomin (Rho) is an RGD protein that specifically inhibits integrins. We found that Rho mutants with the P48A mutation 4.4-11.5 times more actively inhibited integrin alpha5beta1. Structural analysis showed that they have a similar 3D conformation for the RGD loop. Docking analysis also showed no difference between their interactions with integrin alpha5beta1. However, the backbone dynamics of RGD residues were different. The values of the R(2) relaxation parameter for Rho residues R49 and D51 were 39% and 54% higher than those of the P48A mutant, which caused differences in S(2), R(ex), and tau(e). The S(2) values of the P48A mutant residues R49, G50, and D51 were 29%, 14%, and 28% lower than those of Rho. The R(ex) values of Rho residues R49 and D51 were 0.91 s(-1) and 1.42 s(-1); however, no R(ex) was found for those of the P48A mutant. The tau(e) values of Rho residues R49 and D51 were 9.5 and 5.1 times lower than those of P48A mutant. Mutational study showed that integrin alpha5beta1 prefers its ligands to contain (G/A)RGD but not PRGD sequences for binding. These results demonstrate that the N-terminal proline residue adjacent to the RGD motif affect its function and dynamics, which suggests that the dynamic properties of the RGD motif may be important in Rho's interaction with integrin alpha5beta1. PMID- 22238584 TI - Small tympanic membrane perforations in the inferior quadrants do not impact the manubrium vibration in guinea pigs. AB - BACKGROUND: It has been believed that location of the perforation has a significant impact on hearing loss. However, recent studies have demonstrated that the perforation sites had no impact on hearing loss. We measured the velocity and pattern of the manubrium vibration in guinea pigs with intact and perforated eardrum using a laser Doppler vibrometer in order to determine the effects of different location perforations on the middle ear transfer functions. METHODS: Two bullas from 2 guinea pigs were used to determine stability of the umbo velocities, and 12 bullas from six guinea pigs to determine the effects of different location perforations on sound transmission. The manubrium velocity was measured at three points on the manubrium in the frequencies of 0.5-8 kHz before and after a perforation was made. The sites of perforations were in anterior inferior (AI) quadrants of left ears and posterior-inferior (PI) quadrants of right ears. RESULTS: The manubrium vibration velocity losses were noticed in the perforated ears only below 1.5 kHz. The maximum velocity loss was about 7 dB at 500 Hz with the PI perforation. No significant difference in the velocity loss was found between AI and PI perforations. The average ratio of short process velocity to the umbo velocity was approximately 0.5 at all frequencies. No significant differences were found before and after perforation at all frequencies (p>0.05) except 7 kHz (p = 0.004) for both AI and PI perforations. CONCLUSIONS: The manubrium vibration velocity losses from eardrum perforation were frequency-dependent and the largest losses occur at low frequencies. Manubrium velocity losses caused by small acute inferior perforations in guinea pigs have no significant impact on middle ear sound transmission at any frequency tested. The manubrium vibration axis may be perpendicular to the manubrium below 8 kHz in guinea pigs. PMID- 22238585 TI - Metatranscriptomics reveals the diversity of genes expressed by eukaryotes in forest soils. AB - Eukaryotic organisms play essential roles in the biology and fertility of soils. For example the micro and mesofauna contribute to the fragmentation and homogenization of plant organic matter, while its hydrolysis is primarily performed by the fungi. To get a global picture of the activities carried out by soil eukaryotes we sequenced 2*10,000 cDNAs synthesized from polyadenylated mRNA directly extracted from soils sampled in beech (Fagus sylvatica) and spruce (Picea abies) forests. Taxonomic affiliation of both cDNAs and 18S rRNA sequences showed a dominance of sequences from fungi (up to 60%) and metazoans while protists represented less than 12% of the 18S rRNA sequences. Sixty percent of cDNA sequences from beech forest soil and 52% from spruce forest soil had no homologs in the GenBank/EMBL/DDJB protein database. A Gene Ontology term was attributed to 39% and 31.5% of the spruce and beech soil sequences respectively. Altogether 2076 sequences were putative homologs to different enzyme classes participating to 129 KEGG pathways among which several were implicated in the utilisation of soil nutrients such as nitrogen (ammonium, amino acids, oligopeptides), sugars, phosphates and sulfate. Specific annotation of plant cell wall degrading enzymes identified enzymes active on major polymers (cellulose, hemicelluloses, pectin, lignin) and glycoside hydrolases represented 0.5% (beech soil)-0.8% (spruce soil) of the cDNAs. Other sequences coding enzymes active on organic matter (extracellular proteases, lipases, a phytase, P450 monooxygenases) were identified, thus underlining the biotechnological potential of eukaryotic metatranscriptomes. The phylogenetic affiliation of 12 full-length carbohydrate active enzymes showed that most of them were distantly related to sequences from known fungi. For example, a putative GH45 endocellulase was closely associated to molluscan sequences, while a GH7 cellobiohydrolase was closest to crustacean sequences, thus suggesting a potentially significant contribution of non-fungal eukaryotes in the actual hydrolysis of soil organic matter. PMID- 22238587 TI - Intraepithelial gammadelta T cells remain increased in the duodenum of AIDS patients despite antiretroviral treatment. AB - Intraepithelial lymphocytes (IELs) bearing the gammadelta T-cell receptor are a unique intestinal subset whose function remains elusive. Here, we examine how they behave in AIDS and during various regimens of antiretroviral treatment in order to obtain mechanistic insight into their adaptive or innate functional in vivo properties. IELs were studied by multimarker two-colour immunofluorescence in situ staining. Consecutive duodenal biopsies were obtained from advanced infection-prone HIV(+) patients (n = 30). The systemic adaptive immune status was monitored by determining T-cell subsets and immunoglobulins in peripheral blood. The gammadelta IEL ratio (median 14.5%, range 1.5-56.3%) was significantly increased (p<0.02) compared with that in clinically healthy HIV(-) control subjects (n = 11, median 2.8%; range 0.3-38%), although the number of gammadelta IELs per mucosal length unit (U) only tended to be increased (4.0/U in HIV(+) versus 3.2/U in HIV(-) subjects). Notably, the total number of CD3(+) IELs was significantly reduced in AIDS (p<0.0001, 39.6/U in HIV(+) versus 86.4/U in HIV(-) subjects). Almost 100% of the gammadelta IELs were CD8(-) and they often expressed the Vdelta1/Jdelta1-encoded epitope (median 65.2%). HIV(+) patients on highly active antiretroviral therapy only tended to have a lower ratio of gammadelta IELs (median 12.8%) than those receiving no treatment (median 14.3%) or 1 nucleoside analogue (NA) (median 23.5%) or 2 NAs (median 13.0%). This minimal variation among therapy groups, contrasting the treatment response of systemic and local adaptive immunity, harmonizes with the novel idea derived from animal experiments that gammadelta T cells are largely innate cells in first-line microbial defence. PMID- 22238586 TI - Class I(A) PI3Kinase regulatory subunit, p85alpha, mediates mast cell development through regulation of growth and survival related genes. AB - Stem cell factor (SCF) mediated KIT receptor activation plays a pivotal role in mast cell growth, maturation and survival. However, the signaling events downstream from KIT are poorly understood. Mast cells express multiple regulatory subunits of class 1(A) PI3Kinase (PI3K) including p85alpha, p85beta, p50alpha, and p55alpha. While it is known that PI3K plays an essential role in mast cells; the precise mechanism by which these regulatory subunits impact specific mast cell functions including growth, survival and cycling are not known. We show that loss of p85alpha impairs the growth, survival and cycling of mast cell progenitors (MCp). To delineate the molecular mechanism (s) by which p85alpha regulates mast cell growth, survival and cycling, we performed microarray analyses to compare the gene expression profile of MCps derived from WT and p85alpha-deficient mice in response to SCF stimulation. We identified 151 unique genes exhibiting altered expression in p85alpha-deficient cells in response to SCF stimulation compared to WT cells. Functional categorization based on DAVID bioinformatics tool and Ingenuity Pathway Analysis (IPA) software relates the altered genes due to lack of p85alpha to transcription, cell cycle, cell survival, cell adhesion, cell differentiation, and signal transduction. Our results suggest that p85alpha is involved in mast cell development through regulation of expression of growth, survival and cell cycle related genes. PMID- 22238588 TI - Social inequalities in height: persisting differences today depend upon height of the parents. AB - BACKGROUND: Substantial increases in height have occurred concurrently with economic development in most populations during the last century. In high-income countries, environmental exposures that can limit genetic growth potential appear to have lessened, and variation in height by socioeconomic position may have diminished. The objective of this study is to investigate inequalities in height in a cohort of children born in the early 1990s in England, and to evaluate which factors might explain any identified inequalities. METHODS AND FINDINGS: 12,830 children from The Avon Longitudinal Study of Parents and Children (ALSPAC), a population based cohort from birth to about 11.5 years of age, were used in this analysis. Gender- and age-specific z-scores of height at different ages were used as outcome variables. Multilevel models were used to take into account the repeated measures of height and to analyze gender- and age-specific relative changes in height from birth to 11.5 years. Maternal education was the main exposure variable used to examine socioeconomic inequalities. The roles of parental and family characteristics in explaining any observed differences between maternal education and child height were investigated. Children whose mothers had the highest education compared to those with none or a basic level of education, were 0.39 cm longer at birth (95% CI: 0.30 to 0.48). These differences persisted and at 11.5 years the height difference was 1.4 cm (95% CI: 1.07 to 1.74). Several other factors were related to offspring height, but few changed the relationship with maternal education. The one exception was mid-parental height, which fully accounted for the maternal educational differences in offspring height. CONCLUSIONS: In a cohort of children born in the 1990s, mothers with higher education gave birth to taller boys and girls. Although height differences were small they persisted throughout childhood. Maternal and paternal height fully explained these differences. PMID- 22238589 TI - Using hydrophilic ionic liquid, [bmim]BF4-ethylene glycol system as a novel media for the rapid synthesis of copper nanoparticles. AB - In this work, we present a novel method for the synthesis of copper nanoparticles. We utilize the charge compensatory effect of ionic liquid [bmim]BF(4) in conjunction with ethylene glycol for providing electro-steric stabilization to copper nanoparticles prepared from copper sulphate using hydrazine hydrate as a reducing agent. The formed copper nanoparticles showed extended stability over a period of one year. Copper nanoparticles thus prepared were characterized by powder X-ray diffraction measurements (pXRD), transmission electron microscopy (TEM) and quasi elastic light scattering (QELS) techniques. Powder X-ray diffraction (pXRD) analysis revealed relevant Bragg's reflection for crystal structure of copper. Powder X-ray diffraction plots also revealed no oxidized material of copper nanoparticles. TEM showed nearly uniform distribution of the particles in methanol and confirmed by QELS. Typical applications of copper nanoparticles include uses in conductive films, lubrication and nanofluids. Currently efforts are under way in our laboratory for using these nanoparticles as catalysts for a variety of organic reactions. PMID- 22238590 TI - Wolfram syndrome: new mutations, different phenotype. AB - BACKGROUND: Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym "DIDMOAD". The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic beta-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. METHODOLOGY/PRINCIPAL FINDINGS: We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. CONCLUSIONS/SIGNIFICANCE: Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA). PMID- 22238591 TI - The effects of climate change on harp seals (Pagophilus groenlandicus). AB - Harp seals (Pagophilus groenlandicus) have evolved life history strategies to exploit seasonal sea ice as a breeding platform. As such, individuals are prepared to deal with fluctuations in the quantity and quality of ice in their breeding areas. It remains unclear, however, how shifts in climate may affect seal populations. The present study assesses the effects of climate change on harp seals through three linked analyses. First, we tested the effects of short term climate variability on young-of-the year harp seal mortality using a linear regression of sea ice cover in the Gulf of St. Lawrence against stranding rates of dead harp seals in the region during 1992 to 2010. A similar regression of stranding rates and North Atlantic Oscillation (NAO) index values was also conducted. These analyses revealed negative correlations between both ice cover and NAO conditions and seal mortality, indicating that lighter ice cover and lower NAO values result in higher mortality. A retrospective cross-correlation analysis of NAO conditions and sea ice cover from 1978 to 2011 revealed that NAO related changes in sea ice may have contributed to the depletion of seals on the east coast of Canada during 1950 to 1972, and to their recovery during 1973 to 2000. This historical retrospective also reveals opposite links between neonatal mortality in harp seals in the Northeast Atlantic and NAO phase. Finally, an assessment of the long-term trends in sea ice cover in the breeding regions of harp seals across the entire North Atlantic during 1979 through 2011 using multiple linear regression models and mixed effects linear regression models revealed that sea ice cover in all harp seal breeding regions has been declining by as much as 6 percent per decade over the time series of available satellite data. PMID- 22238592 TI - IQSeq: integrated isoform quantification analysis based on next-generation sequencing. AB - With the recent advances in high-throughput RNA sequencing (RNA-Seq), biologists are able to measure transcription with unprecedented precision. One problem that can now be tackled is that of isoform quantification: here one tries to reconstruct the abundances of isoforms of a gene. We have developed a statistical solution for this problem, based on analyzing a set of RNA-Seq reads, and a practical implementation, available from archive.gersteinlab.org/proj/rnaseq/IQSeq, in a tool we call IQSeq (Isoform Quantification in next-generation Sequencing). Here, we present theoretical results which IQSeq is based on, and then use both simulated and real datasets to illustrate various applications of the tool. In order to measure the accuracy of an isoform-quantification result, one would try to estimate the average variance of the estimated isoform abundances for each gene (based on resampling the RNA seq reads), and IQSeq has a particularly fast algorithm (based on the Fisher Information Matrix) for calculating this, achieving a speedup of ~ 500 times compared to brute-force resampling. IQSeq also calculates an information theoretic measure of overall transcriptome complexity to describe isoform abundance for a whole experiment. IQSeq has many features that are particularly useful in RNA-Seq experimental design, allowing one to optimally model the integration of different sequencing technologies in a cost-effective way. In particular, the IQSeq formalism integrates the analysis of different sample (i.e. read) sets generated from different technologies within the same statistical framework. It also supports a generalized statistical partial-sample-generation function to model the sequencing process. This allows one to have a modular, "plugin-able" read-generation function to support the particularities of the many evolving sequencing technologies. PMID- 22238595 TI - Colour patterns do not diagnose species: quantitative evaluation of a DNA barcoded cryptic bumblebee complex. AB - Cryptic diversity within bumblebees (Bombus) has the potential to undermine crucial conservation efforts designed to reverse the observed decline in many bumblebee species worldwide. Central to such efforts is the ability to correctly recognise and diagnose species. The B. lucorum complex (Bombus lucorum, B. cryptarum and B. magnus) comprises one of the most abundant and important group of wild plant and crop pollinators in northern Europe. Although the workers of these species are notoriously difficult to diagnose morphologically, it has been claimed that queens are readily diagnosable from morphological characters. Here we assess the value of colour-pattern characters in species identification of DNA barcoded queens from the B. lucorum complex. Three distinct molecular operational taxonomic units were identified each representing one species. However, no uniquely diagnostic colour-pattern character state was found for any of these three molecular units and most colour-pattern characters showed continuous variation among the units. All characters previously deemed to be unique and diagnostic for one species were displayed by specimens molecularly identified as a different species. These results presented here raise questions on the reliability of species determinations in previous studies and highlights the benefits of implementing DNA barcoding prior to ecological, taxonomic and conservation studies of these important key pollinators. PMID- 22238594 TI - betaB1-crystallin: thermodynamic profiles of molecular interactions. AB - BACKGROUND: beta-Crystallins are structural proteins maintaining eye lens transparency and opacification. Previous work demonstrated that dimerization of both betaA3 and betaB2 crystallins (betaA3 and betaB2) involves endothermic enthalpy of association (~8 kcal/mol) mediated by hydrophobic interactions. METHODOLOGY/PRINCIPAL FINDINGS: Thermodynamic profiles of the associations of dimeric betaA3 and betaB1 and tetrameric betaB1/betaA3 were measured using sedimentation equilibrium. The homo- and heteromolecular associations of betaB1 crystallin are dominated by exothermic enthalpy (-13.3 and -24.5 kcal/mol, respectively). CONCLUSIONS/SIGNIFICANCE: Global thermodynamics of betaB1 interactions suggest a role in the formation of stable protein complexes in the lens via specific van der Waals contacts, hydrogen bonds and salt bridges whereas those beta-crystallins which associate by predominately hydrophobic forces participate in a weaker protein associations. PMID- 22238596 TI - The distance between Mars and Venus: measuring global sex differences in personality. AB - BACKGROUND: Sex differences in personality are believed to be comparatively small. However, research in this area has suffered from significant methodological limitations. We advance a set of guidelines for overcoming those limitations: (a) measure personality with a higher resolution than that afforded by the Big Five; (b) estimate sex differences on latent factors; and (c) assess global sex differences with multivariate effect sizes. We then apply these guidelines to a large, representative adult sample, and obtain what is presently the best estimate of global sex differences in personality. METHODOLOGY/PRINCIPAL FINDINGS: Personality measures were obtained from a large US sample (N = 10,261) with the 16PF Questionnaire. Multigroup latent variable modeling was used to estimate sex differences on individual personality dimensions, which were then aggregated to yield a multivariate effect size (Mahalanobis D). We found a global effect size D = 2.71, corresponding to an overlap of only 10% between the male and female distributions. Even excluding the factor showing the largest univariate ES, the global effect size was D = 1.71 (24% overlap). These are extremely large differences by psychological standards. SIGNIFICANCE: The idea that there are only minor differences between the personality profiles of males and females should be rejected as based on inadequate methodology. PMID- 22238597 TI - Implication for functions of the ectopic adipocyte copper amine oxidase (AOC3) from purified enzyme and cell-based kinetic studies. AB - AOC3 is highly expressed in adipocytes and smooth muscle cells, but its function in these cells is currently unknown. The in vivo substrate(s) of AOC3 is/are also unknown, but could provide an invaluable clue to the enzyme's function. Expression of untagged, soluble human AOC3 in insect cells provides a relatively simple means of obtaining pure enzyme. Characterization of enzyme indicates a 6% titer for the active site 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor and corrected k(cat) values as high as 7 s(-1). Substrate kinetic profiling shows that the enzyme accepts a variety of primary amines with different chemical features, including nonphysiological branched-chain and aliphatic amines, with measured k(cat)/K(m) values between 10(2) and 10(4) M(-1) s(-1). K(m)(O(2)) approximates the partial pressure of oxygen found in the interstitial space. Comparison of the properties of purified murine to human enzyme indicates k(cat)/K(m) values that are within 3 to 4-fold, with the exception of methylamine and aminoacetone that are ca. 10-fold more active with human AOC3. With drug development efforts investigating AOC3 as an anti-inflammatory target, these studies suggest that caution is called for when screening the efficacy of inhibitors designed against human enzymes in non-transgenic mouse models. Differentiated murine 3T3-L1 adipocytes show a uniform distribution of AOC3 on the cell surface and whole cell K(m) values that are reasonably close to values measured using purified enzymes. The latter studies support a relevance of the kinetic parameters measured with isolated AOC3 variants to adipocyte function. From our studies, a number of possible substrates with relatively high k(cat)/K(m) have been discovered, including dopamine and cysteamine, which may implicate a role for adipocyte AOC3 in insulin-signaling and fatty acid metabolism, respectively. Finally, the demonstrated AOC3 turnover of primary amines that are non-native to human tissue suggests possible roles for the adipocyte enzyme in subcutaneous bacterial infiltration and obesity. PMID- 22238598 TI - Lateralized kinematics of predation behavior in a Lake Tanganyika scale-eating cichlid fish. AB - Behavioral lateralization has been documented in many vertebrates. The scale eating cichlid fish Perissodus microlepis is well known for exhibiting lateral dimorphism in its mouth morphology and lateralized behavior in robbing scales from prey fish. A previous field study indicated that this mouth asymmetry closely correlates with the side on which prey is attacked, but details of this species' predation behavior have not been previously analyzed because of the rapidity of the movements. Here, we studied scale-eating behavior in cichlids in a tank through high-speed video monitoring and quantitative assessment of behavioral laterality and kinematics. The fish observed showed a clear bias toward striking on one side, which closely correlated with their asymmetric mouth morphologies. Furthermore, the maximum angular velocity and amplitude of body flexion were significantly larger during attacks on the preferred side compared to those on the nonpreferred side, permitting increased predation success. In contrast, no such lateral difference in movement elements was observed in acoustically evoked flexion during the escape response, which is similar to flexion during scale eating and suggests that they share a common motor control pathway. Thus the neuronal circuits controlling body flexion during scale eating may be functionally lateralized upstream of this common motor pathway. PMID- 22238600 TI - Moths behaving like butterflies. Evolutionary loss of long range attractant pheromones in castniid moths: a Paysandisia archon model. AB - BACKGROUND: In the course of evolution butterflies and moths developed two different reproductive behaviors. Whereas butterflies rely on visual stimuli for mate location, moths use the 'female calling plus male seduction' system, in which females release long-range sex pheromones to attract conspecific males. There are few exceptions from this pattern but in all cases known female moths possess sex pheromone glands which apparently have been lost in female butterflies. In the day-flying moth family Castniidae ("butterfly-moths"), which includes some important crop pests, no pheromones have been found so far. METHODOLOGY/PRINCIPAL FINDINGS: Using a multidisciplinary approach we described the steps involved in the courtship of P. archon, showing that visual cues are the only ones used for mate location; showed that the morphology and fine structure of the antennae of this moth are strikingly similar to those of butterflies, with male sensilla apparently not suited to detect female-released long range pheromones; showed that its females lack pheromone-producing glands, and identified three compounds as putative male sex pheromone (MSP) components of P. archon, released from the proximal halves of male forewings and hindwings. CONCLUSIONS/SIGNIFICANCE: This study provides evidence for the first time in Lepidoptera that females of a moth do not produce any pheromone to attract males, and that mate location is achieved only visually by patrolling males, which may release a pheromone at short distance, putatively a mixture of Z,E-farnesal, E,E farnesal, and (E,Z)-2,13-octadecadienol. The outlined behavior, long thought to be unique to butterflies, is likely to be widespread in Castniidae implying a novel, unparalleled butterfly-like reproductive behavior in moths. This will also have practical implications in applied entomology since it signifies that the monitoring/control of castniid pests should not be based on the use of female produced pheromones, as it is usually done in many moths. PMID- 22238599 TI - Rapid generation of microRNA sponges for microRNA inhibition. AB - MicroRNA (miRNA) sponges are transcripts with repeated miRNA antisense sequences that can sequester miRNAs from endogenous targets. MiRNA sponges are valuable tools for miRNA loss-of-function studies both in vitro and in vivo. We developed a fast and flexible method to generate miRNA sponges and tested their efficiency in various assays. Using a single directional ligation reaction we generated sponges with 10 or more miRNA binding sites. Luciferase and AGO2-immuno precipitation (IP) assays confirmed effective binding of the miRNAs to the sponges. Using a GFP competition assay we showed that miR-19 sponges with central mismatches in the miRNA binding sites are efficient miRNA inhibitors while sponges with perfect antisense binding sites are not. Quantification of miRNA sponge levels suggests that this is at least in part due to degradation of the perfect antisense sponge transcripts. Finally, we provide evidence that combined inhibition of miRNAs of the miR-17~92 cluster results in a more effective growth inhibition as compared to inhibition of individual miRNAs. In conclusion, we describe and validate a method to rapidly generate miRNA sponges for miRNA loss of-function studies. PMID- 22238593 TI - A genome-wide association search for type 2 diabetes genes in African Americans. AB - African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5*10(-8)). SNP rs7560163 (P = 7.0*10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5*10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations. PMID- 22238601 TI - Noisy galvanic vestibular stimulation promotes GABA release in the substantia nigra and improves locomotion in hemiparkinsonian rats. AB - BACKGROUND: The vestibular system is connected to spinal, cerebellar and cerebral motor control structures and can be selectively activated with external electrodes. The resulting sensation of disturbed balance can be avoided by using stochastic stimulation patterns. Adding noise to the nervous system sometimes improves function. Small clinical trials suggest that stochastic vestibular stimulation (SVS) may improve symptoms in Parkinson's disease. We have investigated this claim and possible mechanisms using the 6-hydroxydopamine (6 OHDA) hemilesion model of Parkinson's disease. METHODOLOGY/PRINCIPAL FINDINGS: Animals were tested in the accelerating rod test and the Montoya staircase test of skilled forelimb use. In 6-OHDA hemilesioned animals, SVS improved rod performance by 56+/-11 s. At group level L-DOPA treatment had no effect, but positive responders improved time on rod by 60+/-19 s. Skilled forelimb use was not altered by SVS. To investigate how SVS may influence basal ganglia network activity, intracerebral microdialysis was employed in four regions of interest during and after SVS. In presence of the gamma-amino buturic acid (GABA) transporter inhibitor NNC 711, SVS induced an increase in GABA to 150+/-15% of baseline in the substantia nigra (SN) of unlesioned animals, but had no effect in the pedunculopontine nucleus (PPN), the striatum or the ventromedial thalamus (VM). Dopamine release remained stable in all areas, as did GABA and amine concentrations in the SN of unstimulated controls. Following SVS, a sustained increase in GABA concentrations was observed in the ipsilesional, but not in the contralesional SN of 6-OHDA hemilesioned rats. In contrast, L-DOPA treatment produced a similar increase of GABA in the ipsi- and contra-lesional SN. CONCLUSIONS/SIGNIFICANCE: SVS improves rod performance in a rat model of Parkinson's disease, possibly by increasing nigral GABA release in a dopamine independent way. We propose that SVS could be useful for treating symptoms of Parkinson's disease. PMID- 22238602 TI - A role in immunity for Arabidopsis cysteine protease RD21, the ortholog of the tomato immune protease C14. AB - Secreted papain-like Cys proteases are important players in plant immunity. We previously reported that the C14 protease of tomato is targeted by cystatin-like EPIC proteins that are secreted by the oomycete pathogen Phytophthora infestans (Pinf) during infection. C14 has been under diversifying selection in wild potato species coevolving with Pinf and reduced C14 levels result in enhanced susceptibility for Pinf. Here, we investigated the role C14-EPIC-like interactions in the natural pathosystem of Arabidopsis with the oomycete pathogen Hyaloperonospora arabidopsidis (Hpa). In contrast to the Pinf-solanaceae pathosystem, the C14 orthologous protease of Arabidopsis, RD21, does not evolve under diversifying selection in Arabidopsis, and rd21 null mutants do not show phenotypes upon compatible and incompatible Hpa interactions, despite the evident lack of a major leaf protease. Hpa isolates express highly conserved EPIC-like proteins during infections, but it is unknown if these HpaEPICs can inhibit RD21 and one of these HpaEPICs even lacks the canonical cystatin motifs. The rd21 mutants are unaffected in compatible and incompatible interactions with Pseudomonas syringae pv. tomato, but are significantly more susceptible for the necrotrophic fungal pathogen Botrytis cinerea, demonstrating that RD21 provides immunity to a necrotrophic pathogen. PMID- 22238603 TI - BAC-based sequencing of behaviorally-relevant genes in the prairie vole. AB - The prairie vole (Microtus ochrogaster) is an important model organism for the study of social behavior, yet our ability to correlate genes and behavior in this species has been limited due to a lack of genetic and genomic resources. Here we report the BAC-based targeted sequencing of behaviorally-relevant genes and flanking regions in the prairie vole. A total of 6.4 Mb of non-redundant or haplotype-specific sequence assemblies were generated that span the partial or complete sequence of 21 behaviorally-relevant genes as well as an additional 55 flanking genes. Estimates of nucleotide diversity from 13 loci based on alignments of 1.7 Mb of haplotype-specific assemblies revealed an average pair wise heterozygosity (8.4*10(-3)). Comparative analyses of the prairie vole proteins encoded by the behaviorally-relevant genes identified >100 substitutions specific to the prairie vole lineage. Finally, our sequencing data indicate that a duplication of the prairie vole AVPR1A locus likely originated from a recent segmental duplication spanning a minimum of 105 kb. In summary, the results of our study provide the genomic resources necessary for the molecular and genetic characterization of a high-priority set of candidate genes for regulating social behavior in the prairie vole. PMID- 22238604 TI - TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome. AB - PURPOSE: Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9. METHODS AND MATERIALS: Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study. RESULTS: Mice receiving pre WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001). CONCLUSIONS: TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies. PMID- 22238605 TI - Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. AB - We have recently identified conventional B2 cells as atherogenic and B1a cells as atheroprotective in hypercholesterolemic ApoE(-/-) mice. Here, we examined the development of atherosclerosis in BAFF-R deficient ApoE(-/-) mice because B2 cells but not B1a cells are selectively depleted in BAFF-R deficient mice. We fed BAFF-R(-/-) ApoE(-/-) (BaffR.ApoE DKO) and BAFF-R(+/+)ApoE(-/-) (ApoE KO) mice a high fat diet (HFD) for 8-weeks. B2 cells were significantly reduced by 82%, 81%, 94%, 72% in blood, peritoneal fluid, spleen and peripheral lymph nodes respectively; while B1a cells and non-B lymphocytes were unaffected. Aortic atherosclerotic lesions assessed by oil red-O stained-lipid accumulation and CD68+ macrophage accumulation were decreased by 44% and 50% respectively. B cells were absent in atherosclerotic lesions of BaffR.ApoE DKO mice as were IgG1 and IgG2a immunoglobulins produced by B2 cells, despite low but measurable numbers of B2 cells and IgG1 and IgG2a immunoglobulin concentrations in plasma. Plasma IgM and IgM deposits in atherosclerotic lesions were also reduced. BAFF-R deficiency in ApoE(-/-) mice was also associated with a reduced expression of VCAM-1 and fewer macrophages, dendritic cells, CD4+ and CD8+ T cell infiltrates and PCNA+ cells in lesions. The expression of proinflammatory cytokines, TNF-alpha, IL1 beta and proinflammatory chemokine MCP-1 was also reduced. Body weight and plasma cholesterols were unaffected in BaffR.ApoE DKO mice. Our data indicate that B2 cells are important contributors to the development of atherosclerosis and that targeting the BAFF-R to specifically reduce atherogenic B2 cell numbers while preserving atheroprotective B1a cell numbers may be a potential therapeutic strategy to reduce atherosclerosis by potently reducing arterial inflammation. PMID- 22238606 TI - Low density lipoprotein receptor-related protein 1 dependent endosomal trapping and recycling of apolipoprotein E. AB - BACKGROUND: Lipoprotein receptors from the low density lipoprotein (LDL) receptor family are multifunctional membrane proteins which can efficiently mediate endocytosis and thereby facilitate lipoprotein clearance from the plasma. The biggest member of this family, the LDL receptor-related protein 1 (LRP1), facilitates the hepatic uptake of triglyceride-rich lipoproteins (TRL) via interaction with apolipoprotein E (apoE). In contrast to the classical LDL degradation pathway, TRL disintegrate in peripheral endosomes, and core lipids and apoB are targeted along the endocytic pathway for lysosomal degradation. Notably, TRL-derived apoE remains within recycling endosomes and is then mobilized by high density lipoproteins (HDL) for re-secretion. The aim of this study is to investigate the involvement of LRP1 in the regulation of apoE recycling. PRINCIPAL FINDINGS: Immunofluorescence studies indicate the LRP1 dependent trapping of apoE in EEA1-positive endosomes in human hepatoma cells. This processing is distinct from other LRP1 ligands such as RAP which is efficiently targeted to lysosomal compartments. Upon stimulation of HDL-induced recycling, apoE is released from LRP1-positive endosomes but is targeted to another, distinct population of early endosomes that contain HDL, but not LRP1. For subsequent analysis of the recycling capacity, we expressed the full-length human LRP1 and used an RNA interference approach to manipulate the expression levels of LRP1. In support of LRP1 determining the intracellular fate of apoE, overexpression of LRP1 significantly stimulated HDL-induced apoE recycling. Vice versa LRP1 knockdown in HEK293 cells and primary hepatocytes strongly reduced the efficiency of HDL to stimulate apoE secretion. CONCLUSION: We conclude that LRP1 enables apoE to accumulate in an early endosomal recycling compartment that serves as a pool for the intracellular formation and subsequent re-secretion of apoE-enriched HDL particles. PMID- 22238608 TI - Adult male mice emit context-specific ultrasonic vocalizations that are modulated by prior isolation or group rearing environment. AB - Social interactions in mice are frequently analysed in genetically modified strains in order to get insight of disorders affecting social interactions such as autism spectrum disorders. Different types of social interactions have been described, mostly between females and pups, and between adult males and females. However, we recently showed that social interactions between adult males could also encompass cognitive and motivational features. During social interactions, rodents emit ultrasonic vocalizations (USVs), but it remains unknown if call types are differently used depending of the context and if they are correlated with motivational state. Here, we recorded the calls of adult C57BL/6J male mice in various behavioral conditions, such as social interaction, novelty exploration and restraint stress. We introduced a modulator for the motivational state by comparing males maintained in isolation and males maintained in groups before the experiments. Male mice uttered USVs in all social and non-social situations, and even in a stressful restraint context. They nevertheless emitted the most important number of calls with the largest diversity of call types in social interactions, particularly when showing a high motivation for social contact. For mice maintained in social isolation, the number of calls recorded was positively correlated with the duration of social contacts, and most calls were uttered during contacts between the two mice. This correlation was not observed in mice maintained in groups. These results open the way for a deeper understanding and characterization of acoustic signals associated with social interactions. They can also help evaluating the role of motivational states in the emission of acoustic signals. PMID- 22238607 TI - Large-scale pathway-based analysis of bladder cancer genome-wide association data from five studies of European background. AB - Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ~90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P<=0.01. To minimize false positives, we used the I(2) statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [P(GSEA) = 0.0100, P(ARTP) = 0.0020], 'NAD biosynthesis' [P(GSEA) = 0.0018, P(ARTP) = 0.0086], 'NAD salvage' [P(ARTP) = 0.0068], 'Clathrin derived vesicle budding' [P(ARTP) = 0.0018], 'Lysosome vesicle biogenesis' [P(GSEA) = 0.0023, P(ARTP)<0.00012], 'Retrograde neurotrophin signaling' [P(GSEA) = 0.00840], and 'Mitotic metaphase/anaphase transition' [P(GSEA) = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis. PMID- 22238609 TI - Highly dynamic host actin reorganization around developing Plasmodium inside hepatocytes. AB - Plasmodium sporozoites are transmitted by Anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. The nature of the Plasmodium-host cell interface, as well as the interactions occurring between these two organisms, remains largely unknown. Here we show that highly dynamic hepatocyte actin reorganization events occur around developing Plasmodium berghei parasites inside human hepatoma cells. Actin reorganization is most prominent between 10 to 16 hours post infection and depends on the actin severing and capping protein, gelsolin. Live cell imaging studies also suggest that the hepatocyte cytoskeleton may contribute to parasite elimination during Plasmodium development in the liver. PMID- 22238610 TI - Interaction of proliferation cell nuclear antigen (PCNA) with c-Abl in cell proliferation and response to DNA damages in breast cancer. AB - Cell proliferation in primary and metastatic tumors is a fundamental characteristic of advanced breast cancer. Further understanding of the mechanism underlying enhanced cell growth will be important in identifying novel prognostic markers and therapeutic targets. Here we demonstrated that tyrosine phosphorylation of the proliferating cell nuclear antigen (PCNA) is a critical event in growth regulation of breast cancer cells. We found that phosphorylation of PCNA at tyrosine 211 (Y211) enhanced its association with the non-receptor tyrosine kinase c-Abl. We further demonstrated that c-Abl facilitates chromatin association of PCNA and is required for nuclear foci formation of PCNA in cells stressed by DNA damage as well as in unperturbed cells. Targeting Y211 phosphorylation of PCNA with a cell-permeable peptide inhibited the phosphorylation and reduced the PCNA-Abl interaction. These results show that PCNA signal transduction has an important impact on the growth regulation of breast cancer cells. PMID- 22238611 TI - Organically modified silica nanoparticles are biocompatible and can be targeted to neurons in vivo. AB - The application of nanotechnology in biological research is beginning to have a major impact leading to the development of new types of tools for human health. One focus of nanobiotechnology is the development of nanoparticle-based formulations for use in drug or gene delivery systems. However most of the nano probes currently in use have varying levels of toxicity in cells or whole organisms and therefore are not suitable for in vivo application or long-term use. Here we test the potential of a novel silica based nanoparticle (organically modified silica, ORMOSIL) in living neurons within a whole organism. We show that feeding ORMOSIL nanoparticles to Drosophila has no effect on viability. ORMOSIL nanoparticles penetrate into living brains, neuronal cell bodies and axonal projections. In the neuronal cell body, nanoparticles are present in the cytoplasm, but not in the nucleus. Strikingly, incorporation of ORMOSIL nanoparticles into the brain did not induce aberrant neuronal death or interfered with normal neuronal processes. Our results in Drosophila indicate that these novel silica based nanoparticles are biocompatible and not toxic to whole organisms, and has potential for the development of long-term applications. PMID- 22238612 TI - Influenza virus A infection of human monocyte and macrophage subpopulations reveals increased susceptibility associated with cell differentiation. AB - Influenza virus infection accounts for significant morbidity and mortality world wide. Interactions of the virus with host cells, particularly those of the macrophage lineage, are thought to contribute to various pathological changes associated with poor patient outcome. Development of new strategies to treat disease therefore requires a detailed understanding of the impact of virus infection upon cellular responses. Here we report that human blood-derived monocytes could be readily infected with the H3N2 influenza virus A/Udorn/72 (Udorn), irrespective of their phenotype (CD14(++)/CD16(-), CD14(++)/CD16(+) or CD14(dim)CD16(++)), as determined by multi-colour flow cytometry for viral haemagglutinin (HA) expression and cell surface markers 8-16 hours post infection. Monocytes are relatively resistant to influenza-induced cell death early in infection, as approximately 20% of cells showed influenza-induced caspase-dependent apoptosis. Infection of monocytes with Udorn also induced the release of IL-6, IL-8, TNFalpha and IP-10, suggesting that NS1 protein of Udorn does not (effectively) inhibit this host defence response in human monocytes. Comparative analysis of human monocyte-derived macrophages (Mph) demonstrated greater susceptibility to human influenza virus than monocytes, with the majority of both pro-inflammatory Mph1 and anti-inflammatory/regulatory Mph2 cells expressing viral HA after infection with Udorn. Influenza infection of macrophages also induced cytokine and chemokine production. However, both Mph1 and Mph2 phenotypes released comparable amounts of TNFalpha, IL-12p40 and IP-10 after infection with H3N2, in marked contrast to differential responses to LPS stimulation. In addition, we found that influenza virus infection augmented the capacity of poorly phagocytic Mph1 cells to phagocytose apoptotic cells by a mechanism that was independent of either IL-10 or the Mer receptor tyrosine kinase/Protein S pathway. In summary, our data reveal that influenza virus infection of human macrophages causes functional alterations that may impact on the process of resolution of inflammation, with implications for viral clearance and lung pathology. PMID- 22238613 TI - Recombinant R-spondin2 and Wnt3a up- and down-regulate novel target genes in C57MG mouse mammary epithelial cells. AB - R-spondins (Rspos) comprise a family of four secreted proteins that have important roles in cell proliferation, cell fate determination and organogenesis. Rspos typically exert their effects by potentiating the Wnt/beta-catenin signaling pathway. To systematically investigate the impact of Rspo/Wnt on gene expression, we performed a microarray analysis using C57MG mouse mammary epithelial cells treated with recombinant Rspo2 and/or Wnt3a. We observed the up- and down-regulation of several previously unidentified target genes, including ones that encode proteins involved in immune responses, effectors of other growth factor signaling pathways and transcription factors. Dozens of these changes were validated by quantitative real time RT-PCR. Time course experiments showed that Rspo2 typically had little or no effect on Wnt-dependent gene expression at 3 or 6 h, but enhanced expression at 24 h, consistent with biochemical data indicating that Rspo2 acts primarily to sustain rather than acutely increase Wnt pathway activation. Up-regulation of gene expression was inhibited by pre-treatment with Dickkopf1, a Wnt/beta-catenin pathway antagonist, and by siRNA knockdown of beta catenin expression. While Dickkopf1 blocked Rspo2/Wnt3a-dependent down regulation, a number of down-regulated genes were not affected by beta-catenin knockdown, suggesting that in these instances down-regulation was mediated by a beta-catenin-independent mechanism. PMID- 22238614 TI - Convergent differential regulation of parvalbumin in the brains of vocal learners. AB - Spoken language and learned song are complex communication behaviors found in only a few species, including humans and three groups of distantly related birds- songbirds, parrots, and hummingbirds. Despite their large phylogenetic distances, these vocal learners show convergent behaviors and associated brain pathways for vocal communication. However, it is not clear whether this behavioral and anatomical convergence is associated with molecular convergence. Here we used oligo microarrays to screen for genes differentially regulated in brain nuclei necessary for producing learned vocalizations relative to adjacent brain areas that control other behaviors in avian vocal learners versus vocal non-learners. A top candidate gene in our screen was a calcium-binding protein, parvalbumin (PV). In situ hybridization verification revealed that PV was expressed significantly higher throughout the song motor pathway, including brainstem vocal motor neurons relative to the surrounding brain regions of all distantly related avian vocal learners. This differential expression was specific to PV and vocal learners, as it was not found in avian vocal non-learners nor for control genes in learners and non-learners. Similar to the vocal learning birds, higher PV up-regulation was found in the brainstem tongue motor neurons used for speech production in humans relative to a non-human primate, macaques. These results suggest repeated convergent evolution of differential PV up-regulation in the brains of vocal learners separated by more than 65-300 million years from a common ancestor and that the specialized behaviors of learned song and speech may require extra calcium buffering and signaling. PMID- 22238615 TI - Family history and breast cancer hormone receptor status in a Spanish cohort. AB - BACKGROUND: Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. MATERIALS AND METHODS: A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. RESULTS: Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER &PR-. Women with a family history of breast cancer were more likely to have ER &PR- tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91-2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34-5.81). CONCLUSIONS: An increased proportion of ER-&PR- breast cancer was observed among younger Spanish women with a family history of the disease. PMID- 22238617 TI - Mutational analyses of the influenza A virus polymerase subunit PA reveal distinct functions related and unrelated to RNA polymerase activity. AB - Influenza A viral polymerase is a heterotrimeric complex that consists of PA, PB1, and PB2 subunits. We previously reported that a di-codon substitution mutation (G507A-R508A), denoted J10, in the C-terminal half of PA had no apparent effect on viral RNA synthesis but prevented infectious virus production, indicating that PA may have a novel role independent of its polymerase activity. To further examine the roles of PA in the viral life cycle, we have now generated and characterized additional mutations in regions flanking the J10 site from residues 497 to 518. All tested di-codon mutations completely abolished or significantly reduced viral infectivity, but they did so through disparate mechanisms. Several showed effects resembling those of J10, in that the mutant polymerase supported normal levels of viral RNA synthesis but nonetheless failed to generate infectious viral particles. Others eliminated polymerase activity, in most cases by perturbing the normal nuclear localization of PA protein in cells. We also engineered single-codon mutations that were predicted to pack near the J10 site in the crystal structure of PA, and found that altering residues K378 or D478 each produced a J10-like phenotype. In further studies of J10 itself, we found that this mutation does not affect the formation and release of virion-like particles per se, but instead impairs the ability of those particles to incorporate each of the eight essential RNA segments (vRNAs) that make up the viral genome. Taken together, our analysis identifies mutations in the C-terminal region of PA that differentially affect at least three distinct activities: protein nuclear localization, viral RNA synthesis, and a trans-acting function that is required for efficient packaging of all eight vRNAs. PMID- 22238618 TI - A mutation in intracellular loop 4 affects the drug-efflux activity of the yeast multidrug resistance ABC transporter Pdr5p. AB - Multidrug resistance protein Pdr5p is a yeast ATP-binding cassette (ABC) transporter in the plasma membrane. It confers multidrug resistance by active efflux of intracellular drugs. However, the highly polymorphic Pdr5p from clinical strain YJM789 loses its ability to expel azole and cyclohexmide. To investigate the role of amino acid changes in this functional change, PDR5 chimeras were constructed by segmental replacement of homologous BY4741 PDR5 fragments. Functions of PDR5 chimeras were evaluated by fluconazole and cycloheximide resistance assays. Their expression, ATPase activity, and efflux efficiency for other substrates were also analyzed. Using multiple lines of evidence, we show that an alanine-to-methionine mutation at position 1352 located in the predicted short intracellular loop 4 significantly contributes to the observed transport deficiency. The degree of impairment is likely correlated to the size of the mutant residue. PMID- 22238619 TI - Barriers to partnership working in public health: a qualitative study. AB - BACKGROUND: Public health provision in England is undergoing dramatic changes. Currently established partnerships are thus likely to be significantly disrupted by the radical reforms outlined in the Public Health White Paper. We therefore explored the process of partnership working in public health, in order to better understand the potential opportunities and threats associated with the proposed changes. METHODOLOGY/PRINCIPAL FINDINGS: 70 participants took part in an in-depth qualitative study involving 40 semi-structured interviews and three focus group discussions. Participants were senior and middle grade public health decision makers working in Primary Care Trusts, Local Authorities, Department of Health, academia, General Practice and Hospital Trusts and the third sector in England. Despite mature arrangements for partnership working in many areas, and much support for joint working in principle, many important barriers exist. These include cultural issues such as a lack of shared values and language, the inherent complexity of intersectoral collaboration for public health, and macro issues including political and resource constraints. There is particular uncertainty and anxiety about the future of joint working relating to the availability and distribution of scarce and diminishing financial resources. There is also the concern that existing effective collaborative networks may be completely disrupted as the proposed changes unfold. The extent to which the proposed reforms might mitigate or potentiate these issues remains unclear. However the threats currently remain more salient than opportunities. CONCLUSIONS: The current re-organisation of public health offers real opportunity to address some of the barriers to partnership working identified in this study. However, significant threats exist. These include the breakup of established networks, and the risk of cost cutting on effective public health interventions. PMID- 22238616 TI - New insights into the bacterial fitness-associated mechanisms revealed by the characterization of large plasmids of an avian pathogenic E. coli. AB - Extra-intestinal pathogenic E. coli (ExPEC), including avian pathogenic E. coli (APEC), pose a considerable threat to both human and animal health, with illness causing substantial economic loss. APEC strain chi7122 (O78?K80?H9), containing three large plasmids [pChi7122-1 (IncFIB/FIIA-FIC), pChi7122-2 (IncFII), and pChi7122-3 (IncI(2))]; and a small plasmid pChi7122-4 (ColE2-like), has been used for many years as a model strain to study the molecular mechanisms of ExPEC pathogenicity and zoonotic potential. We previously sequenced and characterized the plasmid pChi7122-1 and determined its importance in systemic APEC infection; however the roles of the other pChi7122 plasmids were still ambiguous. Herein we present the sequence of the remaining pChi7122 plasmids, confirming that pChi7122 2 and pChi7122-3 encode an ABC iron transport system (eitABCD) and a putative type IV fimbriae respectively, whereas pChi7122-4 is a cryptic plasmid. New features were also identified, including a gene cluster on pChi7122-2 that is not present in other E. coli strains but is found in Salmonella serovars and is predicted to encode the sugars catabolic pathways. In vitro evaluation of the APEC chi7122 derivative strains with the three large plasmids, either individually or in combinations, provided new insights into the role of plasmids in biofilm formation, bile and acid tolerance, and the interaction of E. coli strains with 3-D cultures of intestinal epithelial cells. In this study, we show that the nature and combinations of plasmids, as well as the background of the host strains, have an effect on these phenomena. Our data reveal new insights into the role of extra-chromosomal sequences in fitness and diversity of ExPEC in their phenotypes. PMID- 22238620 TI - The origin of large molecules in primordial autocatalytic reaction networks. AB - Large molecules such as proteins and nucleic acids are crucial for life, yet their primordial origin remains a major puzzle. The production of large molecules, as we know it today, requires good catalysts, and the only good catalysts we know that can accomplish this task consist of large molecules. Thus the origin of large molecules is a chicken and egg problem in chemistry. Here we present a mechanism, based on autocatalytic sets (ACSs), that is a possible solution to this problem. We discuss a mathematical model describing the population dynamics of molecules in a stylized but prebiotically plausible chemistry. Large molecules can be produced in this chemistry by the coalescing of smaller ones, with the smallest molecules, the 'food set', being buffered. Some of the reactions can be catalyzed by molecules within the chemistry with varying catalytic strengths. Normally the concentrations of large molecules in such a scenario are very small, diminishing exponentially with their size. ACSs, if present in the catalytic network, can focus the resources of the system into a sparse set of molecules. ACSs can produce a bistability in the population dynamics and, in particular, steady states wherein the ACS molecules dominate the population. However to reach these steady states from initial conditions that contain only the food set typically requires very large catalytic strengths, growing exponentially with the size of the catalyst molecule. We present a solution to this problem by studying 'nested ACSs', a structure in which a small ACS is connected to a larger one and reinforces it. We show that when the network contains a cascade of nested ACSs with the catalytic strengths of molecules increasing gradually with their size (e.g., as a power law), a sparse subset of molecules including some very large molecules can come to dominate the system. PMID- 22238621 TI - Surveillance for malaria elimination in Swaziland: a national cross-sectional study using pooled PCR and serology. AB - BACKGROUND: To guide malaria elimination efforts in Swaziland and other countries, accurate assessments of transmission are critical. Pooled-PCR has potential to efficiently improve sensitivity to detect infections; serology may clarify temporal and spatial trends in exposure. METHODOLOGY/PRINCIPAL FINDINGS: Using a stratified two-stage cluster, cross-sectional design, subjects were recruited from the malaria endemic region of Swaziland. Blood was collected for rapid diagnostic testing (RDT), pooled PCR, and ELISA detecting antibodies to Plasmodium falciparum surface antigens. Of 4330 participants tested, three were RDT-positive yet false positives by PCR. Pooled PCR led to the identification of one P. falciparum and one P. malariae infection among RDT-negative participants. The P. falciparum-infected participant reported recent travel to Mozambique. Compared to performing individual testing on thousands of samples, PCR pooling reduced labor and consumable costs by 95.5%. Seropositivity was associated with age >=20 years (11.7% vs 1.9%, P<0.001), recent travel to Mozambique (OR 4.4 [95% CI 1.0-19.0]) and residence in southeast Swaziland (RR 3.78, P<0.001). CONCLUSIONS: The prevalence of malaria infection and recent exposure in Swaziland are extremely low, suggesting elimination is feasible. Future efforts should address imported malaria and target remaining foci of transmission. Pooled PCR and ELISA are valuable surveillance tools for guiding elimination efforts. PMID- 22238622 TI - Estimates of particulate organic carbon flowing from the pelagic environment to the benthos through sponge assemblages. AB - Despite the importance of trophic interactions between organisms, and the relationship between primary production and benthic diversity, there have been few studies that have quantified the carbon flow from pelagic to benthic environments as a result of the assemblage level activity of suspension-feeding organisms. In this study, we examine the feeding activity of seven common sponge species from the Taputeranga marine reserve on the south coast of Wellington in New Zealand. We analysed the diet composition, feeding efficiency, pumping rates, and the number of food particles (specifically picoplanktonic prokaryotic cells) retained by sponges. We used this information, combined with abundance estimates of the sponges and estimations of the total amount of food available to sponges in a known volume of water (89,821 m(3)), to estimate: (1) particulate organic carbon (POC) fluxes through sponges as a result of their suspension-feeding activities on picoplankton; and (2) the proportion of the available POC from picoplankton that sponges consume. The most POC acquired by the sponges was from non-photosynthetic bacterial cells (ranging from 0.09 to 4.69 g C d(-1) with varying sponge percentage cover from 0.5 to 5%), followed by Prochlorococcus (0.07 to 3.47 g C d(-1)) and then Synechococcus (0.05 to 2.34 g C d(-1)) cells. Depending on sponge abundance, the amount of POC that sponges consumed as a proportion of the total POC available was 0.2-12.1% for Bac, 0.4-21.3% for Prochlo, and 0.3-15.8% for Synecho. The flux of POC for the whole sponge assemblage, based on the consumption of prokaryotic picoplankton, ranged from 0.07-3.50 g C m(2) d(-1). This study is the first to estimate the contribution of a sponge assemblage (rather than focusing on individual sponge species) to POC flow from three groups of picoplankton in a temperate rocky reef through the feeding activity of sponges and demonstrates the importance of sponges to energy flow in rocky reef environments. PMID- 22238623 TI - Fur in Magnetospirillum gryphiswaldense influences magnetosomes formation and directly regulates the genes involved in iron and oxygen metabolism. AB - Magnetospirillum gryphiswaldense strain MSR-1 has the unique capability of taking up large amounts of iron and synthesizing magnetosomes (intracellular magnetic particles composed of Fe(3)O(4)). The unusual high iron content of MSR-1 makes it a useful model for studying biological mechanisms of iron uptake and homeostasis. The ferric uptake regulator (Fur) protein plays a key role in maintaining iron homeostasis in many bacteria. We identified and characterized a fur-homologous gene (MGR_1314) in MSR-1. MGR_1314 was able to complement a fur mutant of E. coli in iron-responsive manner in vivo. We constructed a fur mutant strain of MSR-1. In comparison to wild-type MSR-1, the mutant strain had lower magnetosome formation, and was more sensitive to hydrogen peroxide and streptonigrin, indicating higher intracellular free iron content. Quantitative real-time RT-PCR and chromatin immunoprecipitation analyses indicated that Fur protein directly regulates expression of several key genes involved in iron transport and oxygen metabolism, in addition it also functions in magnetosome formation in M. gryphiswaldense. PMID- 22238624 TI - Meningococcal outer membrane protein NhhA triggers apoptosis in macrophages. AB - Phagocytotic cells play a fundamental role in the defense against bacterial pathogens. One mechanism whereby bacteria evade phagocytosis is to produce factors that trigger apoptosis. Here we identify for the first time a meningococcal protein capable of inducing macrophage apoptosis. The conserved meningococcal outer membrane protein NhhA (Neisseria hia/hsf homologue A, also known as Hsf) mediates bacterial adhesion and interacts with extracellular matrix components heparan sulphate and laminin. Meningococci lacking NhhA fail to colonise nasal mucosa in a mouse model of meningococcal disease. We found that exposure of macrophages to NhhA resulted in a highly increased rate of apoptosis that proceeded through caspase activation. Exposure of macrophages to NhhA also led to iNOS induction and nitric oxide production. However, neither nitric oxide production nor TNF-alpha signaling was found to be a prerequisite for NhhA induced apoptosis. Macrophages exposed to wildtype NhhA-expressing meningococci were also found to undergo apoptosis whereas NhhA-deficient meningococci had a markedly decreased capacity to induce macrophage apoptosis. These data provide new insights on the role of NhhA in meningococcal disease. NhhA-induced macrophage apoptosis could be a mechanism whereby meningococci evade immunoregulatory and phagocytotic actions of macrophages. PMID- 22238625 TI - Baseline predictors of sputum culture conversion in pulmonary tuberculosis: importance of cavities, smoking, time to detection and W-Beijing genotype. AB - BACKGROUND: Time to detection (TTD) on automated liquid mycobacterial cultures is an emerging biomarker of tuberculosis outcomes. The M. tuberculosis W-Beijing genotype is spreading globally, indicating a selective advantage. There is a paucity of data on the association between baseline TTD and W-Beijing genotype and tuberculosis outcomes. AIM: To assess baseline predictors of failure of sputum culture conversion, within the first 2 months of antitubercular therapy, in participants with pulmonary tuberculosis. DESIGN: Between May 2005 and August 2008 we conducted a prospective cohort study of time to sputum culture conversion in ambulatory participants with first episodes of smear and culture positive pulmonary tuberculosis attending two primary care clinics in Cape Town, South Africa. Rifampicin resistance (diagnosed on phenotypic susceptibility testing) was an exclusion criterion. Sputum was collected weekly for 8 weeks for mycobacterial culture on liquid media (BACTEC MGIT 960). Due to missing data, multiple imputation was performed. Time to sputum culture conversion was analysed using a Cox-proportional hazards model. Bayesian model averaging determined the posterior effect probability for each variable. RESULTS: 113 participants were enrolled (30.1% female, 10.5% HIV-infected, 44.2% W-Beijing genotype, and 89% cavities). On Kaplan Meier analysis 50.4% of participants underwent sputum culture conversion by 8 weeks. The following baseline factors were associated with slower sputum culture conversion: TTD (adjusted hazard ratio (aHR) = 1.11, 95% CI 1.02; 1.2), lung cavities (aHR = 0.13, 95% CI 0.02; 0.95), ever smoking (aHR = 0.32, 95% CI 0.1; 1.02) and the W-Beijing genotype (aHR = 0.51, 95% CI 0.25; 1.07). On Bayesian model averaging, posterior probability effects were strong for TTD, lung cavitation and smoking and moderate for W-Beijing genotype. CONCLUSION: We found that baseline TTD, smoking, cavities and W-Beijing genotype were associated with delayed 2 month sputum culture. Larger studies are needed to confirm the relationship between the W-Beijing genotype and sputum culture conversion. PMID- 22238626 TI - Testosterone deficiency accelerates neuronal and vascular aging of SAMP8 mice: protective role of eNOS and SIRT1. AB - Oxidative stress and atherosclerosis-related vascular disorders are risk factors for cognitive decline with aging. In a small clinical study in men, testosterone improved cognitive function; however, it is unknown how testosterone ameliorates the pathogenesis of cognitive decline with aging. Here, we investigated whether the cognitive decline in senescence-accelerated mouse prone 8 (SAMP8), which exhibits cognitive impairment and hypogonadism, could be reversed by testosterone, and the mechanism by which testosterone inhibits cognitive decline. We found that treatment with testosterone ameliorated cognitive function and inhibited senescence of hippocampal vascular endothelial cells of SAMP8. Notably, SAMP8 showed enhancement of oxidative stress in the hippocampus. We observed that an NAD(+)-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence. Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS. Finally, we showed, using co-culture system, that senescent endothelial cells promoted neuronal senescence through humoral factors. Our results suggest a critical role of testosterone and SIRT1 in the prevention of vascular and neuronal aging. PMID- 22238627 TI - Long-term impact of war on healthcare costs: an eight-country study. AB - OBJECTIVE: Exposure to war can negatively affect health and may impact on healthcare costs. Estimating these costs and identifying their predictors is important for appropriate service planning. We aimed to measure use of health services in an adult population who had experienced war in the former-Yugoslavia on average 8 years previously, and to identify characteristics associated with the use and costs of healthcare. METHOD: War-affected community samples in Bosnia Herzegovina, Croatia, Kosovo, FYR Macedonia, and Serbia were recruited through a random walk technique. Refugees in Germany, Italy and the UK were contacted through registers, organisations and networking. Current service use was measured for the previous three months and combined with unit costs for each country for the year 2006/7. A two-part approach was used, to identify predictors of service use with a multiple logistic regression model and predictors of cost with a generalised linear regression model. RESULTS: 3,313 participants were interviewed in Balkan countries and 854 refugees in Western European countries. In the Balkan countries, traumatic events and mental health status were related to greater service use while in Western countries these associations were not found. Participants in Balkan countries with post traumatic stress disorder (PTSD) had costs that were 63% higher (p = 0.005) than those without PTSD. Distress experienced during the most traumatic war event was associated with higher costs (p = 0.013). In Western European countries costs were 76% higher if non-PTSD anxiety disorders were present (0.027) and 63% higher for mood disorders (p = 0.006). CONCLUSIONS: War experiences and their effects on mental health are associated with increased health care costs even many years later, especially for those who stayed in the area of conflict. Focussing on the mental health impact of war is important for many reasons including those of an economic nature. PMID- 22238628 TI - Clinical characteristics and outcomes of hospitalized older patients with distinct risk profiles for functional decline: a prospective cohort study. AB - BACKGROUND: The aim of this research was to study the clinical characteristics and mortality and disability outcomes of patients who present distinct risk profiles for functional decline at admission. METHODS: Multicenter, prospective cohort study conducted between 2006 and 2009 in three hospitals in The Netherlands in consecutive patients of >=65 years, acutely admitted and hospitalized for at least 48 hours. Nineteen geriatric conditions were assessed at hospital admission, and mortality and functional decline were assessed until twelve months after admission. Patients were divided into risk categories for functional decline (low, intermediate or high risk) according to the Identification of Seniors at Risk-Hospitalized Patients. RESULTS: A total of 639 patients were included, with a mean age of 78 years. Overall, 27%, 33% and 40% of the patients were at low, intermediate or high risk, respectively, for functional decline. Low-risk patients had fewer geriatric conditions (mean 2.2 [standard deviation [SD] 1.3]) compared with those at intermediate (mean 3.8 [SD 2.1]) or high risk (mean 5.1 [SD 1.8]) (p<0.001). Twelve months after admission, 39% of the low-risk group had an adverse outcome, compared with 50% in the intermediate risk group and 69% in the high risk group (p<0.001). CONCLUSION: By using a simple risk assessment instrument at hospital admission, patients at low, intermediate or high risk for functional decline could be identified, with distinct clinical characteristics and outcomes. This approach should be tested in clinical practice and research and might help appropriately tailor patient care. PMID- 22238629 TI - Combining optimal control theory and molecular dynamics for protein folding. AB - A new method to develop low-energy folding routes for proteins is presented. The novel aspect of the proposed approach is the synergistic use of optimal control theory with Molecular Dynamics (MD). In the first step of the method, optimal control theory is employed to compute the force field and the optimal folding trajectory for the Calpha atoms of a Coarse-Grained (CG) protein model. The solution of this CG optimization provides an harmonic approximation of the true potential energy surface around the native state. In the next step CG optimization guides the MD simulation by specifying the optimal target positions for the Calpha atoms. In turn, MD simulation provides an all-atom conformation whose Calpha positions match closely the reference target positions determined by CG optimization. This is accomplished by Targeted Molecular Dynamics (TMD) which uses a bias potential or harmonic restraint in addition to the usual MD potential. Folding is a dynamical process and as such residues make different contacts during the course of folding. Therefore CG optimization has to be reinitialized and repeated over time to accomodate these important changes. At each sampled folding time, the active contacts among the residues are recalculated based on the all-atom conformation obtained from MD. Using the new set of contacts, the CG potential is updated and the CG optimal trajectory for the Calpha atoms is recomputed. This is followed by MD. Implementation of this repetitive CG optimization-MD simulation cycle generates the folding trajectory. Simulations on a model protein Villin demonstrate the utility of the method. Since the method is founded on the general tools of optimal control theory and MD without any restrictions, it is widely applicable to other systems. It can be easily implemented with available MD software packages. PMID- 22238630 TI - Abnormal activity in the precuneus during time perception in Parkinson's disease: an fMRI study. AB - BACKGROUND: Parkinson's disease (PD) patients are deficient in time estimation. This deficit improves after dopamine (DA) treatment and it has been associated with decreased internal timekeeper speed, disruption of executive function and memory retrieval dysfunction. METHODOLOGY/FINDINGS: The aim of the present study was to explore the neurophysiologic correlates of this deficit. We performed functional magnetic resonance imaging on twelve PD patients while they were performing a time reproduction task (TRT). The TRT consisted of an encoding phase (during which visual stimuli of durations from 5 s to 16.6 s, varied at 8 levels were presented) and a reproduction phase (during which interval durations were reproduced by a button pressing). Patients were scanned twice, once while on their DA medication (ON condition) and once after medication withdrawal (OFF condition). Differences in Blood-Oxygenation-Level-Dependent (BOLD) signal in ON and OFF conditions were evaluated. The time course of activation in the brain areas with different BOLD signal was plotted. There were no significant differences in the behavioral results, but a trend toward overestimation of intervals <=11.9 s and underestimation of intervals >=14.1 s in the OFF condition (p<0.088). During the reproduction phase, higher activation in the precuneus was found in the ON condition (p<0.05 corrected). Time course was plotted separately for long (>=14.1 s) and short (<=11.9 s) intervals. Results showed that there was a significant difference only in long intervals, when activity gradually decreased in the OFF, but remained stable in the ON condition. This difference in precuneus activation was not found during random button presses in a control task. CONCLUSIONS/SIGNIFICANCE: Our results show that differences in precuneus activation during retrieval of a remembered duration may underlie some aspects of time perception deficit in PD patients. We suggest that DA medication may allow compensatory activation in the precuneus, which results in a more accurate retrieval of remembered interval duration. PMID- 22238631 TI - Dense cranial electroacupuncture stimulation for major depressive disorder--a single-blind, randomized, controlled study. AB - BACKGROUND: Previous studies suggest that electroacupuncture possesses therapeutic benefits for depressive disorders. The purpose of this study was to determine whether dense cranial electroacupuncture stimulation (DCEAS) could enhance the antidepressant efficacy in the early phase of selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder (MDD). METHODS: In this single-blind, randomized, controlled study, patients with MDD were randomly assigned to 9-session DCEAS or noninvasive electroacupuncture (n-EA) control procedure in combination with fluoxetine (FLX) for 3 weeks. Clinical outcomes were measured using the 17-item Hamilton Depression Rating Scale (HAMD 17), Clinical Global Impression-severity (CGI-S), and Self-rating Depression Scale (SDS) as well as the response and remission rates. RESULTS: Seventy-three patients were randomly assigned to n-EA (n = 35) and DCEAS (n = 38), of whom 34 in n-EA and 36 in DCEAS group were analyzed. DCEAS-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores at Day 3 through Day 21 and in SDS scores at Day 3 and Day 21 compared to patients receiving n-EA. DCEAS intervention also produced a higher rate of clinically significant response compared to n-EA procedure (19.4% (7/36) vs. 8.8% (3/34)). The incidence of adverse events was similar in the two groups. CONCLUSIONS: DCEAS is a safe and effective intervention that augments the antidepressant efficacy. It can be considered as an additional therapy in the early phase of SSRI treatment of depressed patients. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN88008690. PMID- 22238632 TI - Circadian preference modulates the neural substrate of conflict processing across the day. AB - Human morning and evening chronotypes differ in their preferred timing for sleep and wakefulness, as well as in optimal daytime periods to cope with cognitive challenges. Recent evidence suggests that these preferences are not a simple by product of socio-professional timing constraints, but can be driven by inter individual differences in the expression of circadian and homeostatic sleep-wake promoting signals. Chronotypes thus constitute a unique tool to access the interplay between those processes under normally entrained day-night conditions, and to investigate how they impinge onto higher cognitive control processes. Using functional magnetic resonance imaging (fMRI), we assessed the influence of chronotype and time-of-day on conflict processing-related cerebral activity throughout a normal waking day. Sixteen morning and 15 evening types were recorded at two individually adapted time points (1.5 versus 10.5 hours spent awake) while performing the Stroop paradigm. Results show that interference related hemodynamic responses are maintained or even increased in evening types from the subjective morning to the subjective evening in a set of brain areas playing a pivotal role in successful inhibitory functioning, whereas they decreased in morning types under the same conditions. Furthermore, during the evening hours, activity in a posterior hypothalamic region putatively involved in sleep-wake regulation correlated in a chronotype-specific manner with slow wave activity at the beginning of the night, an index of accumulated homeostatic sleep pressure. These results shed light into the cerebral mechanisms underlying inter individual differences of higher-order cognitive state maintenance under normally entrained day-night conditions. PMID- 22238633 TI - The return on investment of a Medicaid tobacco cessation program in Massachusetts. AB - BACKGROUND AND OBJECTIVE: A high proportion of low-income people insured by the Medicaid program smoke. Earlier research concerning a comprehensive tobacco cessation program implemented by the state of Massachusetts indicated that it was successful in reducing smoking prevalence and those who received tobacco cessation benefits had lower rates of in-patient admissions for cardiovascular conditions, including acute myocardial infarction, coronary atherosclerosis and non-specific chest pain. This study estimates the costs of the tobacco cessation benefit and the short-term Medicaid savings attributable to the aversion of inpatient hospitalization for cardiovascular conditions. METHODS: A cost-benefit analysis approach was used to estimate the program's return on investment. Administrative data were used to compute annual cost per participant. Data from the 2002-2008 Medical Expenditure Panel Survey and from the Behavioral Risk Factor Surveillance Surveys were used to estimate the costs of hospital inpatient admissions by Medicaid smokers. These were combined with earlier estimates of the rate of reduction in cardiovascular hospital admissions attributable to the tobacco cessation program to calculate the return on investment. FINDINGS: Administrative data indicated that program costs including pharmacotherapy, counseling and outreach costs about $183 per program participant (2010 $). We estimated inpatient savings per participant of $571 (range $549 to $583). Every $1 in program costs was associated with $3.12 (range $3.00 to $3.25) in medical savings, for a $2.12 (range $2.00 to $2.25) return on investment to the Medicaid program for every dollar spent. CONCLUSIONS: These results suggest that an investment in comprehensive tobacco cessation services may result in substantial savings for Medicaid programs. Further federal and state policy actions to promote and cover comprehensive tobacco cessation services in Medicaid may be a cost-effective approach to improve health outcomes for low-income populations. PMID- 22238634 TI - Kinome analysis of receptor-induced phosphorylation in human natural killer cells. AB - BACKGROUND: Natural killer (NK) cells contribute to the defense against infected and transformed cells through the engagement of multiple germline-encoded activation receptors. Stimulation of the Fc receptor CD16 alone is sufficient for NK cell activation, whereas other receptors, such as 2B4 (CD244) and DNAM-1 (CD226), act synergistically. After receptor engagement, protein kinases play a major role in signaling networks controlling NK cell effector functions. However, it has not been characterized systematically which of all kinases encoded by the human genome (kinome) are involved in NK cell activation. RESULTS: A kinase selective phosphoproteome approach enabled the determination of 188 kinases expressed in human NK cells. Crosslinking of CD16 as well as 2B4 and DNAM-1 revealed a total of 313 distinct kinase phosphorylation sites on 109 different kinases. Phosphorylation sites on 21 kinases were similarly regulated after engagement of either CD16 or co-engagement of 2B4 and DNAM-1. Among those, increased phosphorylation of FYN, KCC2G (CAMK2), FES, and AAK1, as well as the reduced phosphorylation of MARK2, were reproducibly observed both after engagement of CD16 and co-engagement of 2B4 and DNAM-1. Notably, only one phosphorylation on PAK4 was differentally regulated. CONCLUSIONS: The present study has identified a significant portion of the NK cell kinome and defined novel phosphorylation sites in primary lymphocytes. Regulated phosphorylations observed in the early phase of NK cell activation imply these kinases are involved in NK cell signaling. Taken together, this study suggests a largely shared signaling pathway downstream of distinct activation receptors and constitutes a valuable resource for further elucidating the regulation of NK cell effector responses. PMID- 22238635 TI - Scleral thickness in human eyes. AB - PURPOSE: To obtain information about scleral thickness in different ocular regions and its associations. METHODS: The histomorphometric study included 238 human globes which had been enucleated because of choroidal melanomas or due to secondary angle-closure glaucoma. Using light microscopy, anterior-posterior pupil-optic nerve sections were measured. RESULTS: In the non-axially elongated group (axial length <=26 mm), scleral thickness decreased from the limbus (0.50+/ 0.11 mm) to the ora serrata (0.43+/-0.14 mm) and the equator (0.42+/-0.15 mm), and then increased to the midpoint between posterior pole and equator (0.65+/ 0.15 mm) and to the posterior pole (0.94+/-0.18 mm), from where it decreased to the peri-optic nerve region (0.86+/-0.21 mm) and finally the peripapillary scleral flange (0.39+/-0.09 mm). Scleral thickness was significantly lower in the axially elongated group (axial length >26 mm) than in the non-axially elongated group for measurements taken at and posterior to the equator. Scleral thickness measurements of the posterior pole and of the peripapillary scleral flange were correlated with lamina cribrosa thickness measurements. Scleral thickness measurements at any location of examination were not significantly (all P>0.10) correlated with corneal thickness measurements. Scleral thickness was statistically independent of age, gender and presence of glaucoma. CONCLUSIONS: In non-axially elongated eyes, the sclera was thickest at the posterior pole, followed by the peri-optic nerve region, the midpoint between posterior pole and equator, the limbus, the ora serrata, the equator and finally the peripapillary scleral flange. In axially elongated eyes, scleral thinning occurred at and posterior to the equator, being more marked closer to the posterior pole and the longer the axial length was. Within the anterior and posterior segment respectively, scleral thickness measurements were correlated with each other. Posterior scleral thickness was correlated with lamina cribrosa thickness. Scleral thickness measurements at any location of examination were not significantly correlated with corneal thickness or with age, gender and presence of absolute secondary angler-closure glaucoma. PMID- 22238636 TI - An analysis approach for high-field fMRI data from awake non-human primates. AB - fMRI experiments with awake non-human primates (NHP) have seen a surge of applications in recent years. However, the standard fMRI analysis tools designed for human experiments are not optimal for analysis of NHP fMRI data collected at high fields. There are several reasons for this, including the trial-based nature of NHP experiments, with inter-trial periods being of no interest, and segmentation artefacts and distortions that may result from field changes due to movement. We demonstrate an approach that allows us to address some of these issues consisting of the following steps: 1) Trial-based experimental design. 2) Careful control of subject movement. 3) Computer-assisted selection of trials devoid of artefacts and animal motion. 4) Nonrigid between-trial and rigid within trial realignment of concatenated data from temporally separated trials and sessions. 5) Linear interpolation of inter-trial intervals and high-pass filtering of temporally continuous data 6) Removal of interpolated data and reconcatenation of datasets before statistical analysis with SPM. We have implemented a software toolbox, fMRI Sandbox (http://code.google.com/p/fmri sandbox/), for semi-automated application of these processing steps that interfaces with SPM software. Here, we demonstrate that our methodology provides significant improvements for the analysis of awake monkey fMRI data acquired at high-field. The method may also be useful for clinical applications with subjects that are unwilling or unable to remain motionless for the whole duration of a functional scan. PMID- 22238637 TI - A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant. AB - We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3 associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the 'rescue' role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic. PMID- 22238638 TI - Functional evolution of duplicated odorant-binding protein genes, Obp57d and Obp57e, in Drosophila. AB - Odorant-binding proteins (OBPs) are extracellular proteins found in insect chemosensilla, where they participate in the sensing of odors, tastes, and pheromones. Although a large number of OBP genes have been identified in insect genomes, their molecular functions and biological roles have been clarified in limited cases. Two OBP genes, Obp57d and Obp57e, were involved in the evolution of host-plant preference in Drosophila sechellia. Comparative analyses of the Obp57d/e genomic sequences from 27 closely related species suggested that the two genes arose by tandem gene duplication and functionally diverged from each other. In this study, the functional evolution of Obp57d and Obp57e was examined by in vitro binding assays using recombinant proteins synthesized in a bacterial system. Compared to the ancestral Dpse?OBP57de, Dmel?OBP57d was more specialized to tridecanoic acid while Dmel?OBP57e was generalized regarding their binding affinity, suggesting that the two OBP genes underwent subfunctionalization and neofunctionalization. A behavioral analysis using knockout flies supported that the biological role is different between OBP57d and OBP57e in vivo. Site-directed mutagenesis of the evolutionarily conserved amino acids revealed that these residues play an important role in protein folding. These findings provide a clue to understanding how the repertoire of OBP genes is maintained in a genome under natural selection. PMID- 22238639 TI - Crimean-Congo hemorrhagic fever virus-infected hepatocytes induce ER-stress and apoptosis crosstalk. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed tick-borne member of the Nairovirus genus (Bunyaviridae) with a high mortality rate in humans. CCHFV induces a severe disease in infected patients that includes, among other symptoms, massive liver necrosis and failure. The interaction between liver cells and CCHFV is therefore important for understanding the pathogenesis of this disease. Here, we described the in vitro CCHFV-infection and -replication in the hepatocyte cell line, Huh7, and the induced cellular and molecular response modulation. We found that CCHFV was able to infect and replicate to high titres and to induce a cytopathic effect (CPE). We also observed by flow cytometry and real time quantitative RT-PCR evidence of apoptosis, with the participation of the mitochondrial pathway. On the other hand, we showed that the replication of CCHFV in hepatocytes was able to interfere with the death receptor pathway of apoptosis. Furthermore, we found in CCHFV-infected cells the over-expression of PUMA, Noxa and CHOP suggesting the crosstalk between the ER-stress and mitochondrial apoptosis. By ELISA, we observed an increase of IL-8 in response to viral replication; however apoptosis was shown to be independent from IL-8 secretion. When we compared the induced cellular response between CCHFV and DUGV, a mild or non-pathogenic Nairovirus for humans, we found that the most striking difference was the absence of CPE and apoptosis. Despite the XBP1 splicing and PERK gene expression induced by DUGV, no ER-stress and apoptosis crosstalk was observed. Overall, these results suggest that CCHFV is able to induce ER-stress, activate inflammatory mediators and modulate both mitochondrial and death receptor pathways of apoptosis in hepatocyte cells, which may, in part, explain the role of the liver in the pathogenesis of CCHFV. PMID- 22238640 TI - Darwin Core: an evolving community-developed biodiversity data standard. AB - Biodiversity data derive from myriad sources stored in various formats on many distinct hardware and software platforms. An essential step towards understanding global patterns of biodiversity is to provide a standardized view of these heterogeneous data sources to improve interoperability. Fundamental to this advance are definitions of common terms. This paper describes the evolution and development of Darwin Core, a data standard for publishing and integrating biodiversity information. We focus on the categories of terms that define the standard, differences between simple and relational Darwin Core, how the standard has been implemented, and the community processes that are essential for maintenance and growth of the standard. We present case-study extensions of the Darwin Core into new research communities, including metagenomics and genetic resources. We close by showing how Darwin Core records are integrated to create new knowledge products documenting species distributions and changes due to environmental perturbations. PMID- 22238641 TI - Transcriptional regulation is a major controller of cell cycle transition dynamics. AB - DNA replication, mitosis and mitotic exit are critical transitions of the cell cycle which normally occur only once per cycle. A universal control mechanism was proposed for the regulation of mitotic entry in which Cdk helps its own activation through two positive feedback loops. Recent discoveries in various organisms showed the importance of positive feedbacks in other transitions as well. Here we investigate if a universal control system with transcriptional regulation(s) and post-translational positive feedback(s) can be proposed for the regulation of all cell cycle transitions. Through computational modeling, we analyze the transition dynamics in all possible combinations of transcriptional and post-translational regulations. We find that some combinations lead to 'sloppy' transitions, while others give very precise control. The periodic transcriptional regulation through the activator or the inhibitor leads to radically different dynamics. Experimental evidence shows that in cell cycle transitions of organisms investigated for cell cycle dependent periodic transcription, only the inhibitor OR the activator is under cyclic control and never both of them. Based on these observations, we propose two transcriptional control modes of cell cycle regulation that either STOP or let the cycle GO in case of a transcriptional failure. We discuss the biological relevance of such differences. PMID- 22238642 TI - CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control. AB - Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag specific T cell responses dominate the virus-specific immunity exclusively in HIV 1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control. PMID- 22238643 TI - Knock down of heat shock protein 27 (HspB1) induces degradation of several putative client proteins. AB - Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions. PMID- 22238644 TI - Cholesterol-lowering drugs and incident open-angle glaucoma: a population-based cohort study. AB - BACKGROUND: Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG. METHODOLOGY/PRINCIPAL FINDINGS: Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31-0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81-5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41-1.94; P = 0.77] for use two years or less; 0.46 [0.23-0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP. CONCLUSIONS/SIGNIFICANCE: Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality. PMID- 22238645 TI - Intradermal electroporation of naked replicon RNA elicits strong immune responses. AB - RNA-based vaccines represent an interesting immunization modality, but suffer from poor stability and a lack of efficient and clinically feasible delivery technologies. This study evaluates the immunogenic potential of naked in vitro transcribed Semliki Forest virus replicon RNA (RREP) delivered intradermally in combination with electroporation. Replicon-immunized mice showed a strong cellular and humoral response, contrary to mice immunized with regular mRNA. RREP elicited induction of interferon-gamma secreting CD8+ T cells and antibody responses were significantly increased by electroporation. CD8+ T cell responses remained substantial five weeks post vaccination, and antigen-specific CD8+ T cells with phenotypic characteristics of both effector and central memory cells were identified. The immune response during the contraction phase was further increased by a booster immunization, and the proportion of effector memory cells increased significantly. These results demonstrate that naked RREP delivered via intradermal electroporation constitute an immunogenic, safe and attractive alternative immunization strategy to DNA-based vaccines. PMID- 22238646 TI - Therapeutic targeting of STAT3 (signal transducers and activators of transcription 3) pathway inhibits experimental autoimmune uveitis. AB - Mice with targeted deletion of STAT3 in CD4(+) T-cells do not develop experimental autoimmune uveitis (EAU) or experimental autoimmune encephalomyelitis (EAE), in part, because they cannot generate pathogenic Th17 cells. In this study, we have used ORLL-NIH001, a small synthetic compound that inhibits transcriptional activity of STAT3, to ameliorate EAU, an animal model of human posterior uveitis. We show that by attenuating inflammatory properties of uveitogenic lymphocytes, ORLL-NIH001 inhibited the recruitment of inflammatory cells into the retina during EAU and prevented the massive destruction of the neuroretina caused by pro-inflammatory cytokines produced by the autoreactive lymphocytes. Decrease in disease severity observed in ORLL-NIH001-treated mice, correlated with the down-regulation of alpha4beta1 and alpha4beta7 integrin activation and marked reduction of CCR6 and CXCR3 expression, providing a mechanism by which ORLL-NIH001 mitigated EAU. Furthermore, we show that ORLL NIH001 inhibited the expansion of human Th17 cells, underscoring its potential as a drug for the treatment of human uveitis. Two synthetic molecules that target the Th17 lineage transcription factors, RORgammat and RORalpha, have recently been suggested as potential drugs for inhibiting Th17 development and treating CNS inflammatory diseases. However, inhibiting STAT3 pathways completely blocks Th17 development, as well as, prevents trafficking of inflammatory cells into CNS tissues, making STAT3 a more attractive therapeutic target. Thus, use of ORLL NIH001 to target the STAT3 transcription factor, thereby antagonizing Th17 expansion and expression of proteins that mediate T cell chemotaxis, provides an attractive new therapeutic approach for treatment of posterior uveitis and other CNS autoimmune diseases mediated by Th17 cells. PMID- 22238647 TI - Chromosome 2p14 is linked to susceptibility to leprosy. AB - BACKGROUND: A genetic component to the etiology of leprosy is well recognized but the mechanism of inheritance and the genes involved are yet to be fully established. METHODOLOGY: A genome-wide single nucleotide polymorphism (SNP) based linkage analysis was carried out using 23 pedigrees, each with 3 to 7 family members affected by leprosy. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1. PRINCIPAL FINDINGS: Genome wide significant evidence for linkage was identified on chromosome 2p14 with a heterogeneity logarithm of odds (HLOD) score of 3.51 (rs1106577) under a recessive model of inheritance, while suggestive evidence was identified on chr.4q22 (HLOD 2.92, rs1349350, dominant model), chr. 8q24 (HLOD 2.74, rs1618523, recessive model) and chr.16q24 (HLOD 1.93, rs276990 dominant model). Our study also provided moderate evidence for a linkage locus on chromosome 6q24-26 by non parametric linkage analysis (rs6570858, LOD 1.54, p = 0.004), overlapping a previously reported linkage region on chromosome 6q25-26. CONCLUSION: A genome wide linkage analysis has identified a new linkage locus on chromosome 2p14 for leprosy in Pedigrees from China. PMID- 22238648 TI - A stakeholder-informed approach to the identification of criteria for the prioritization of zoonoses in Canada. AB - BACKGROUND: Zoonotic diseases account for over 60% of all communicable diseases causing illness in humans and 75% of recently emerging infectious diseases. As limited resources are available for the control and prevention of zoonotic diseases, it is necessary to prioritize diseases in order to direct resources into those with the greatest needs. The selection of criteria for prioritization has traditionally been on the basis of expert opinion; however, details of the methods used to identify criteria from expert opinion often are not published and a full range of criteria may not be captured by expert opinion. METHODOLOGY/PRINCIPAL FINDINGS: This study used six focus groups to identify criteria for the prioritization of zoonotic diseases in Canada. Focus groups included people from the public, animal health professionals and human health professionals. A total of 59 criteria were identified for prioritizing zoonotic diseases. Human-related criteria accounted for the highest proportion of criteria identified (55%), followed by animal-related criteria (26%) then pathogen/disease related criteria (19%). Similarities and differences were observed in the identification and scoring of criteria for disease prioritization between groups; the public groups were strongly influenced by the individual-level of disease burden, the responsibility of the scientific community in disease prioritization and the experiences of recent events while the professional groups were influenced by the societal- and population-level of disease burden and political and public pressure. CONCLUSIONS/SIGNIFICANCE: This was the first study to describe a mixed semi-quantitative and qualitative approach to deriving criteria for disease prioritization. This was also the first study to involve the opinion of the general public regarding disease prioritization. The number of criteria identified highlights the difficulty in prioritizing zoonotic diseases. The method presented in this paper has formulated a comprehensive list of criteria that can be used to inform future disease prioritization studies. PMID- 22238649 TI - Early alterations in hippocampal circuitry and theta rhythm generation in a mouse model of prenatal infection: implications for schizophrenia. AB - Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic polyribocytidilic acid (poly I:C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease. PMID- 22238650 TI - Modeling the spread of methicillin-resistant Staphylococcus aureus in nursing homes for elderly. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is endemic in many hospital settings, including nursing homes. It is an important nosocomial pathogen that causes mortality and an economic burden to patients, hospitals, and the community. The epidemiology of the bacteria in nursing homes is both hospital- and community-like. Transmission occurs via hands of health care workers (HCWs) and direct contacts among residents during social activities. In this work, mathematical modeling in both deterministic and stochastic frameworks is used to study dissemination of MRSA among residents and HCWs, persistence and prevalence of MRSA in a population, and possible means of controlling the spread of this pathogen in nursing homes. The model predicts that: (i) without strict screening and decolonization of colonized individuals at admission, MRSA may persist; (ii) decolonization of colonized residents, improving hand hygiene in both residents and HCWs, reducing the duration of contamination of HCWs, and decreasing the resident?staff ratio are possible control strategies; (iii) the mean time that a resident remains susceptible since admission may be prolonged by screening and decolonization treatment in colonized individuals; (iv) in the stochastic framework, the total number of colonized residents varies and may increase when the admission of colonized residents, the duration of colonization, the average number of contacts among residents, or the average number of contacts that each resident requires from HCWs increases; (v) an introduction of a colonized individual into an MRSA-free nursing home has a much higher probability of leading to a major outbreak taking off than an introduction of a contaminated HCW. PMID- 22238652 TI - Coordinated activity of ventral tegmental neurons adapts to appetitive and aversive learning. AB - Our understanding of how value-related information is encoded in the ventral tegmental area (VTA) is based mainly on the responses of individual putative dopamine neurons. In contrast to cortical areas, the nature of coordinated interactions between groups of VTA neurons during motivated behavior is largely unknown. These interactions can strongly affect information processing, highlighting the importance of investigating network level activity. We recorded the activity of multiple single units and local field potentials (LFP) in the VTA during a task in which rats learned to associate novel stimuli with different outcomes. We found that coordinated activity of VTA units with either putative dopamine or GABA waveforms was influenced differently by rewarding versus aversive outcomes. Specifically, after learning, stimuli paired with a rewarding outcome increased the correlation in activity levels between unit pairs whereas stimuli paired with an aversive outcome decreased the correlation. Paired single unit responses also became more redundant after learning. These response patterns flexibly tracked the reversal of contingencies, suggesting that learning is associated with changing correlations and enhanced functional connectivity between VTA neurons. Analysis of LFP recorded simultaneously with unit activity showed an increase in the power of theta oscillations when stimuli predicted reward but not an aversive outcome. With learning, a higher proportion of putative GABA units were phase locked to the theta oscillations than putative dopamine units. These patterns also adapted when task contingencies were changed. Taken together, these data demonstrate that VTA neurons organize flexibly as functional networks to support appetitive and aversive learning. PMID- 22238653 TI - SASqPCR: robust and rapid analysis of RT-qPCR data in SAS. AB - Reverse transcription quantitative real-time PCR (RT-qPCR) is a key method for measurement of relative gene expression. Analysis of RT-qPCR data requires many iterative computations for data normalization and analytical optimization. Currently no computer program for RT-qPCR data analysis is suitable for analytical optimization and user-controllable customization based on data quality, experimental design as well as specific research aims. Here I introduce an all-in-one computer program, SASqPCR, for robust and rapid analysis of RT-qPCR data in SAS. This program has multiple macros for assessment of PCR efficiencies, validation of reference genes, optimization of data normalizers, normalization of confounding variations across samples, and statistical comparison of target gene expression in parallel samples. Users can simply change the macro variables to test various analytical strategies, optimize results and customize the analytical processes. In addition, it is highly automatic and functionally extendable. Thus users are the actual decision-makers controlling RT-qPCR data analyses. SASqPCR and its tutorial are freely available at http://code.google.com/p/sasqpcr/downloads/list. PMID- 22238651 TI - Metabolic regulation of invadopodia and invasion by acetyl-CoA carboxylase 1 and de novo lipogenesis. AB - Invadopodia are membrane protrusions that facilitate matrix degradation and cellular invasion. Although lipids have been implicated in several aspects of invadopodia formation, the contributions of de novo fatty acid synthesis and lipogenesis have not been defined. Inhibition of acetyl-CoA carboxylase 1 (ACC1), the committed step of fatty acid synthesis, reduced invadopodia formation in Src transformed 3T3 (3T3-Src) cells, and also decreased the ability to degrade gelatin. Inhibition of fatty acid synthesis through AMP-activated kinase (AMPK) activation and ACC phosphorylation also decreased invadopodia incidence. The addition of exogenous 16?0 and 18?1 fatty acid, products of de novo fatty acid synthesis, restored invadopodia and gelatin degradation to cells with decreased ACC1 activity. Pharmacological inhibition of ACC also altered the phospholipid profile of 3T3-Src cells, with the majority of changes occurring in the phosphatidylcholine (PC) species. Exogenous supplementation with the most abundant PC species, 34?1 PC, restored invadopodia incidence, the ability to degrade gelatin and the ability to invade through matrigel to cells deficient in ACC1 activity. On the other hand, 30?0 PC did not restore invadopodia and 36?2 PC only restored invadopodia incidence and gelatin degradation, but not cellular invasion through matrigel. Pharmacological inhibition of ACC also reduced the ability of MDA-MB-231 breast, Snb19 glioblastoma, and PC-3 prostate cancer cells to invade through matrigel. Invasion of PC-3 cells through matrigel was also restored by 34?1 PC supplementation. Collectively, the data elucidate the novel metabolic regulation of invadopodia and the invasive process by de novo fatty acid synthesis and lipogenesis. PMID- 22238654 TI - Hearing sensation levels of emitted biosonar clicks in an echolocating Atlantic bottlenose dolphin. AB - Emitted biosonar clicks and auditory evoked potential (AEP) responses triggered by the clicks were synchronously recorded during echolocation in an Atlantic bottlenose dolphin (Tursiops truncatus) trained to wear suction-cup EEG electrodes and to detect targets by echolocation. Three targets with target strengths of -34, -28, and -22 dB were used at distances of 2 to 6.5 m for each target. The AEP responses were sorted according to the corresponding emitted click source levels in 5-dB bins and averaged within each bin to extract biosonar click-related AEPs from noise. The AEP amplitudes were measured peak-to-peak and plotted as a function of click source levels for each target type, distance, and target-present or target-absent condition. Hearing sensation levels of the biosonar clicks were evaluated by comparing the functions of the biosonar click related AEP amplitude-versus-click source level to a function of external (in free field) click-related AEP amplitude-versus-click sound pressure level. The results indicated that the dolphin's hearing sensation levels to her own biosonar clicks were equal to that of external clicks with sound pressure levels 16 to 36 dB lower than the biosonar click source levels, varying with target type, distance, and condition. These data may be assumed to indicate that the bottlenose dolphin possesses effective protection mechanisms to isolate the self produced intense biosonar beam from the animal's ears during echolocation. PMID- 22238655 TI - Chronic rejection pathology after orthotopic lung transplantation in mice: the development of a murine BOS model and its drawbacks. AB - Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50-75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25-50% of the mice from 4-12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV(0.1), TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options. PMID- 22238656 TI - Central action of peripherally applied botulinum toxin type A on pain and dural protein extravasation in rat model of trigeminal neuropathy. AB - BACKGROUND: Infraorbital nerve constriction (IoNC) is an experimental model of trigeminal neuropathy. We investigated if IoNC is accompanied by dural extravasation and if botulinum toxin type A (BoNT/A) can reduce pain and dural extravasation in this model. METHODOLOGY/PRINCIPAL FINDINGS: Rats which developed mechanical allodynia 14 days after the IoNC were injected with BoNT/A (3.5 U/kg) into vibrissal pad. Allodynia was tested by von Frey filaments and dural extravasation was measured as colorimetric absorbance of Evans blue-plasma protein complexes. Presence of dural extravasation was also examined in orofacial formalin-induced pain. Unilateral IoNC, as well as formalin injection, produced bilateral dural extravasation. Single unilateral BoNT/A injection bilaterally reduced IoNC induced dural extravasation, as well as allodynia (lasting more than 2 weeks). Similarly, BoNT/A reduced formalin-induced pain and dural extravasation. Effects of BoNT/A on pain and dural extravasation in IoNC model were dependent on axonal transport through sensory neurons, as evidenced by colchicine injections (5 mM, 2 ul) into the trigeminal ganglion completely preventing BoNT/A effects. CONCLUSIONS/SIGNIFICANCE: Two different types of pain, IoNC and formalin, are accompanied by dural extravasation. The lasting effect of a unilateral injection of BoNT/A in experimental animals suggests that BoNT/A might have a long-term beneficial effect in craniofacial pain associated with dural neurogenic inflammation. Bilateral effects of BoNT/A and dependence on retrograde axonal transport suggest a central site of its action. PMID- 22238657 TI - Poke weed mitogen requires Toll-like receptor ligands for proliferative activity in human and murine B lymphocytes. AB - Poke weed mitogen (PWM), a lectin purified from Phytolacca americana is frequently used as a B cell-specific stimulus to trigger proliferation and immunoglobulin secretion. In the present study we investigated the mechanisms underlying the B cell stimulatory capacity of PWM. Strikingly, we observed that highly purified PWM preparations failed to induce B cell proliferation. By contrast, commercially available PWM preparations with B cell activity contained Toll-like receptor (TLR) ligands such as TLR2-active lipoproteins, lipopolysaccharide and DNA of bacterial origin. We show that these microbial substances contribute to the stimulatory activity of PWM. Additional experimental data highlight the capacity of PWM to enable B cell activation by immunostimulatory DNA. Based on these findings we propose that the lectin sensitizes B cells for TLR stimulation as described for B cell receptor ligation and that B cell mitogenicity of PWM preparations results from synergistic activity of the poke weed lectin and microbial TLR ligands present in the PWM preparations. PMID- 22238659 TI - SNP discovery and development of a high-density genotyping array for sunflower. AB - Recent advances in next-generation DNA sequencing technologies have made possible the development of high-throughput SNP genotyping platforms that allow for the simultaneous interrogation of thousands of single-nucleotide polymorphisms (SNPs). Such resources have the potential to facilitate the rapid development of high-density genetic maps, and to enable genome-wide association studies as well as molecular breeding approaches in a variety of taxa. Herein, we describe the development of a SNP genotyping resource for use in sunflower (Helianthus annuus L.). This work involved the development of a reference transcriptome assembly for sunflower, the discovery of thousands of high quality SNPs based on the generation and analysis of ca. 6 Gb of transcriptome re-sequencing data derived from multiple genotypes, the selection of 10,640 SNPs for inclusion in the genotyping array, and the use of the resulting array to screen a diverse panel of sunflower accessions as well as related wild species. The results of this work revealed a high frequency of polymorphic SNPs and relatively high level of cross species transferability. Indeed, greater than 95% of successful SNP assays revealed polymorphism, and more than 90% of these assays could be successfully transferred to related wild species. Analysis of the polymorphism data revealed patterns of genetic differentiation that were largely congruent with the evolutionary history of sunflower, though the large number of markers allowed for finer resolution than has previously been possible. PMID- 22238658 TI - The prolyl isomerase Pin1 modulates development of CD8+ cDC in mice. AB - BACKGROUND: Pin1 has previously been described to regulate cells that participate in both innate and adaptive immunity. Thus far, however, no role for Pin1 has been described in modulating conventional dendritic cells, innate antigen presenting cells that potently activate naive T cells, thereby bridging innate and adaptive immune responses. METHODOLOGY/PRINCIPAL FINDINGS: When challenged with LPS, Pin1-null mice failed to accumulate spleen conventional dendritic cells (cDC). Analysis of steady-state spleen DC populations revealed that Pin1-null mice had fewer CD8+ cDC. This defect was recapitulated by culturing Pin1-null bone marrow with the DC-instructive cytokine Flt3 Ligand. Additionally, injection of Flt3 Ligand for 9 days failed to induce robust expansion of CD8+ cDC in Pin1 null mice. Upon infection with Listeria monocytogenes, Pin1-null mice were defective in stimulating proliferation of adoptively transferred WT CD8+ T cells, suggesting that decreases in Pin1 null CD8+ cDC may affect T cell responses to infection in vivo. Finally, upon analyzing expression of proteins involved in DC development, elevated expression of PU.1 was detected in Pin1-null cells, which resulted from an increase in PU.1 protein half-life. CONCLUSIONS/SIGNIFICANCE: We have identified a novel role for Pin1 as a modulator of CD8+ cDC development. Consistent with reduced numbers of CD8+ cDC in Pin1-null mice, we find that the absence of Pin1 impairs CD8+ T cell proliferation in response to infection with Listeria monocytogenes. These data suggest that, via regulation of CD8+ cDC production, Pin1 may serve as an important modulator of adaptive immunity. PMID- 22238660 TI - Identifying and characterizing alternative molecular markers for the symbiotic and free-living dinoflagellate genus Symbiodinium. AB - Dinoflagellates in the genus Symbiodinium are best known as endosymbionts of corals and other invertebrate as well as protist hosts, but also exist free living in coastal environments. Despite their importance in marine ecosystems, less than 10 loci have been used to explore phylogenetic relationships in this group, and only the multi-copy nuclear ribosomal Internal Transcribed Spacer (ITS) regions 1 and 2 have been used to characterize fine-scale genetic diversity within the nine clades (A-I) that comprise the genus. Here, we describe a three step molecular approach focused on 1) identifying new candidate genes for phylogenetic analysis of Symbiodinium spp., 2) characterizing the phylogenetic relationship of these candidate genes from DNA samples spanning eight Symbiodinium clades (A-H), and 3) conducting in-depth phylogenetic analyses of candidate genes displaying genetic divergences equal or higher than those within the ITS-2 of Symbiodinium clade C. To this end, we used bioinformatics tools and reciprocal comparisons to identify homologous genes from 55,551 cDNA sequences representing two Symbiodinium and six additional dinoflagellate EST libraries. Of the 84 candidate genes identified, 7 Symbiodinium genes (elf2, coI, coIII, cob, calmodulin, rad24, and actin) were characterized by sequencing 23 DNA samples spanning eight Symbiodinium clades (A-H). Four genes displaying higher rates of genetic divergences than ITS-2 within clade C were selected for in-depth phylogenetic analyses, which revealed that calmodulin has limited taxonomic utility but that coI, rad24, and actin behave predictably with respect to Symbiodinium lineage C and are potential candidates as new markers for this group. The approach for targeting candidate genes described here can serve as a model for future studies aimed at identifying and testing new phylogenetically informative genes for taxa where transcriptomic and genomics data are available. PMID- 22238661 TI - The origin of GPCRs: identification of mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in fungi. AB - G protein-coupled receptors (GPCRs) in humans are classified into the five main families named Glutamate, Rhodopsin, Adhesion, Frizzled and Secretin according to the GRAFS classification. Previous results show that these mammalian GRAFS families are well represented in the Metazoan lineages, but they have not been shown to be present in Fungi. Here, we systematically mined 79 fungal genomes and provide the first evidence that four of the five main mammalian families of GPCRs, namely Rhodopsin, Adhesion, Glutamate and Frizzled, are present in Fungi and found 142 novel sequences between them. Significantly, we provide strong evidence that the Rhodopsin family emerged from the cAMP receptor family in an event close to the split of Opisthokonts and not in Placozoa, as earlier assumed. The Rhodopsin family then expanded greatly in Metazoans while the cAMP receptor family is found in 3 invertebrate species and lost in the vertebrates. We estimate that the Adhesion and Frizzled families evolved before the split of Unikonts from a common ancestor of all major eukaryotic lineages. Also, the study highlights that the fungal Adhesion receptors do not have N-terminal domains whereas the fungal Glutamate receptors have a broad repertoire of mammalian-like N-terminal domains. Further, mining of the close unicellular relatives of the Metazoan lineage, Salpingoeca rosetta and Capsaspora owczarzaki, obtained a rich group of both the Adhesion and Glutamate families, which in particular provided insight to the early emergence of the N-terminal domains of the Adhesion family. We identified 619 Fungi specific GPCRs across 79 genomes and revealed that Blastocladiomycota and Chytridiomycota phylum have Metazoan-like GPCRs rather than the GPCRs specific for Fungi. Overall, this study provides the first evidence of the presence of four of the five main GRAFS families in Fungi and clarifies the early evolutionary history of the GPCR superfamily. PMID- 22238662 TI - Disease-associated mutations prevent GPR56-collagen III interaction. AB - GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown. PMID- 22238663 TI - An optically stabilized fast-switching light emitting diode as a light source for functional neuroimaging. AB - Neuroscience research increasingly relies on optical methods for evoking neuronal activity as well as for measuring it, making bright and stable light sources critical building blocks of modern experimental setups. This paper presents a method to control the brightness of a high-power light emitting diode (LED) light source to an unprecedented level of stability. By continuously monitoring the actual light output of the LED with a photodiode and feeding the result back to the LED's driver by way of a proportional-integral controller, drift was reduced to as little as 0.007% per hour over a 12-h period, and short-term fluctuations to 0.005% root-mean-square over 10 seconds. The LED can be switched on and off completely within 100 MUs, a feature that is crucial when visual stimuli and light for optical recording need to be interleaved to obtain artifact-free recordings. The utility of the system is demonstrated by recording visual responses in the central nervous system of the medicinal leech Hirudo verbana using voltage-sensitive dyes. PMID- 22238664 TI - Stretching of the back improves gait, mechanical sensitivity and connective tissue inflammation in a rodent model. AB - The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy. PMID- 22238665 TI - Impacts of a national strategy to reduce population salt intake in England: serial cross sectional study. AB - BACKGROUND: The UK introduced an ambitious national strategy to reduce population levels of salt intake in 2003. The aim of this study was to evaluate the impact of this strategy on salt intake in England, including potential effects on health inequalities. METHODS: Secondary analysis of data from the Health Survey for England. Our main outcome measure was trends in estimated daily salt intake from 2003-2007, as measured by spot urine. Secondary outcome measures were knowledge of government guidance and voluntary use of salt in food preparation over this time period. RESULTS: There were significant reductions in salt intake between 2003 and 2007 (-0.175 grams per day per year, p<0.001). Intake decreased uniformly across all other groups but remained significantly higher in younger persons, men, ethnic minorities and lower social class groups and those without hypertension in 2007. Awareness of government guidance on salt use was lowest in those groups with the highest intake (semi-skilled manual v professional; 64.9% v 71.0% AOR 0.76 95% CI 0.58-0.99). Self reported use of salt added at the table reduced significantly during the study period (56.5% to 40.2% p<0.001). Respondents from ethnic minority groups remained significantly more likely to add salt during cooking (white 42.8%, black 74.1%, south Asian 88.3%) and those from lower social class groups (unskilled manual 46.6%, professional 35.2%) were more likely to add salt at the table. CONCLUSIONS: The introduction a national salt reduction strategy was associated with uniform but modest reductions in salt intake in England, although it is not clear precisely which aspects of the strategy contributed to this. Knowledge of government guidance was lower and voluntary salt use and total salt intake was higher among occupational and ethnic groups at greatest risk of cardiovascular disease. PMID- 22238666 TI - Using hierarchical clustering of secreted protein families to classify and rank candidate effectors of rust fungi. AB - Rust fungi are obligate biotrophic pathogens that cause considerable damage on crop plants. Puccinia graminis f. sp. tritici, the causal agent of wheat stem rust, and Melampsora larici-populina, the poplar leaf rust pathogen, have strong deleterious impacts on wheat and poplar wood production, respectively. Filamentous pathogens such as rust fungi secrete molecules called disease effectors that act as modulators of host cell physiology and can suppress or trigger host immunity. Current knowledge on effectors from other filamentous plant pathogens can be exploited for the characterisation of effectors in the genome of recently sequenced rust fungi. We designed a comprehensive in silico analysis pipeline to identify the putative effector repertoire from the genome of two plant pathogenic rust fungi. The pipeline is based on the observation that known effector proteins from filamentous pathogens have at least one of the following properties: (i) contain a secretion signal, (ii) are encoded by in planta induced genes, (iii) have similarity to haustorial proteins, (iv) are small and cysteine rich, (v) contain a known effector motif or a nuclear localization signal, (vi) are encoded by genes with long intergenic regions, (vii) contain internal repeats, and (viii) do not contain PFAM domains, except those associated with pathogenicity. We used Markov clustering and hierarchical clustering to classify protein families of rust pathogens and rank them according to their likelihood of being effectors. Using this approach, we identified eight families of candidate effectors that we consider of high value for functional characterization. This study revealed a diverse set of candidate effectors, including families of haustorial expressed secreted proteins and small cysteine rich proteins. This comprehensive classification of candidate effectors from these devastating rust pathogens is an initial step towards probing plant germplasm for novel resistance components. PMID- 22238667 TI - In situ biological dose mapping estimates the radiation burden delivered to 'spared' tissue between synchrotron X-ray microbeam radiotherapy tracks. AB - Microbeam radiation therapy (MRT) using high doses of synchrotron X-rays can destroy tumours in animal models whilst causing little damage to normal tissues. Determining the spatial distribution of radiation doses delivered during MRT at a microscopic scale is a major challenge. Film and semiconductor dosimetry as well as Monte Carlo methods struggle to provide accurate estimates of dose profiles and peak-to-valley dose ratios at the position of the targeted and traversed tissues whose biological responses determine treatment outcome. The purpose of this study was to utilise gamma-H2AX immunostaining as a biodosimetric tool that enables in situ biological dose mapping within an irradiated tissue to provide direct biological evidence for the scale of the radiation burden to 'spared' tissue regions between MRT tracks. Gamma-H2AX analysis allowed microbeams to be traced and DNA damage foci to be quantified in valleys between beams following MRT treatment of fibroblast cultures and murine skin where foci yields per unit dose were approximately five-fold lower than in fibroblast cultures. Foci levels in cells located in valleys were compared with calibration curves using known broadbeam synchrotron X-ray doses to generate spatial dose profiles and calculate peak-to-valley dose ratios of 30-40 for cell cultures and approximately 60 for murine skin, consistent with the range obtained with conventional dosimetry methods. This biological dose mapping approach could find several applications both in optimising MRT or other radiotherapeutic treatments and in estimating localised doses following accidental radiation exposure using skin punch biopsies. PMID- 22238668 TI - An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment. AB - BACKGROUND: Breast to bone metastases frequently induce a "vicious cycle" in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. METHODOLOGY/PRINCIPAL FINDINGS: To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (MUCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFbeta, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays). CONCLUSION/SIGNIFICANCE: Collectively, these studies identify a novel "mini-vicious cycle" between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFbeta would be beneficial for the treatment of bone metastases. PMID- 22238669 TI - Exposure to N-ethyl-N-nitrosourea in adult mice alters structural and functional integrity of neurogenic sites. AB - BACKGROUND: Previous studies have shown that prenatal exposure to the mutagen N ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits. PMID- 22238670 TI - Increased neointimal thickening in dystrophin-deficient mdx mice. AB - BACKGROUND: The dystrophin gene, which is mutated in Duchenne muscular dystrophy (DMD), encodes a large cytoskeletal protein present in muscle fibers. While dystrophin in skeletal muscle has been extensively studied, the function of dystrophin in vascular smooth muscle is less clear. Here, we have analyzed the role of dystrophin in injury-induced arterial neointima formation. METHODOLOGY/PRINCIPAL FINDINGS: We detected a down-regulation of dystrophin, dystroglycan and beta-sarcoglycan mRNA expression when vascular smooth muscle cells de-differentiate in vitro. To further mimic development of intimal lesions, we performed a collar-induced injury of the carotid artery in the mdx mouse, a model for DMD. As compared with control mice, mdx mice develop larger lesions with increased numbers of proliferating cells. In vitro experiments demonstrate increased migration of vascular smooth muscle cells from mdx mice whereas the rate of proliferation was similar in cells isolated from wild-type and mdx mice. CONCLUSIONS/SIGNIFICANCE: These results show that dystrophin deficiency stimulates neointima formation and suggest that expression of dystrophin in vascular smooth muscle cells may protect the artery wall against injury-induced intimal thickening. PMID- 22238671 TI - The neural substrates of memory suppression: a FMRI exploration of directed forgetting. AB - The directed forgetting paradigm is frequently used to determine the ability to voluntarily suppress information. However, little is known about brain areas associated with information to forget. The present study used functional magnetic resonance imaging to determine brain activity during the encoding and retrieval phases of an item-method directed forgetting recognition task with neutral verbal material in order to apprehend all processing stages that information to forget and to remember undergoes. We hypothesized that regions supporting few selective processes, namely recollection and familiarity memory processes, working memory, inhibitory and selection processes should be differentially activated during the processing of to-be-remembered and to-be-forgotten items. Successful encoding and retrieval of items to remember engaged the entorhinal cortex, the hippocampus, the anterior medial prefrontal cortex, the left inferior parietal cortex, the posterior cingulate cortex and the precuneus; this set of regions is well known to support deep and associative encoding and retrieval processes in episodic memory. For items to forget, encoding was associated with higher activation in the right middle frontal and posterior parietal cortex, regions known to intervene in attentional control. Items to forget but nevertheless correctly recognized at retrieval yielded activation in the dorsomedial thalamus, associated with familiarity-based memory processes and in the posterior intraparietal sulcus and the anterior cingulate cortex, involved in attentional processes. PMID- 22238672 TI - The N-terminal DH-PH domain of Trio induces cell spreading and migration by regulating lamellipodia dynamics in a Rac1-dependent fashion. AB - The guanine-nucleotide exchange factor Trio encodes two DH-PH domains that catalyze nucleotide exchange on Rac1, RhoG and RhoA. The N-terminal DH-PH domain is known to activate Rac1 and RhoG, whereas the C-terminal DH-PH domain can activate RhoA. The current study shows that the N-terminal DH-PH domain, upon expression in HeLa cells, activates Rac1 and RhoG independently from each other. In addition, we show that the flanking SH3 domain binds to the proline-rich region of the C-terminus of Rac1, but not of RhoG. However, this SH3 domain is not required for Rac1 or RhoG GDP-GTP exchange. Rescue experiments in Trio-shRNA expressing cells showed that the N-terminal DH-PH domain of Trio, but not the C terminal DH-PH domain, restored fibronectin-mediated cell spreading and migration defects that are observed in Trio-silenced cells. Kymograph analysis revealed that the N-terminal DH-PH domain, independent of its SH3 domain, controls the dynamics of lamellipodia. Using siRNA against Rac1 or RhoG, we found that Trio-D1 induced lamellipodia formation required Rac1 but not RhoG expression. Together, we conclude that the GEF Trio is responsible for lamellipodia formation through its N-terminal DH-PH domain in a Rac1-dependent manner during fibronectin mediated spreading and migration. PMID- 22238673 TI - Automated reporter quantification in vivo: high-throughput screening method for reporter-based assays in zebrafish. AB - Reporter-based assays underlie many high-throughput screening (HTS) platforms, but most are limited to in vitro applications. Here, we report a simple whole organism HTS method for quantifying changes in reporter intensity in individual zebrafish over time termed, Automated Reporter Quantification in vivo (ARQiv). ARQiv differs from current "high-content" (e.g., confocal imaging-based) whole organism screening technologies by providing a purely quantitative data acquisition approach that affords marked improvements in throughput. ARQiv uses a fluorescence microplate reader with specific detection functionalities necessary for robust quantification of reporter signals in vivo. This approach is: 1) Rapid; achieving true HTS capacities (i.e., >50,000 units per day), 2) Reproducible; attaining HTS-compatible assay quality (i.e., Z'-factors of >=0.5), and 3) Flexible; amenable to nearly any reporter-based assay in zebrafish embryos, larvae, or juveniles. ARQiv is used here to quantify changes in: 1) Cell number; loss and regeneration of two different fluorescently tagged cell types (pancreatic beta cells and rod photoreceptors), 2) Cell signaling; relative activity of a transgenic Notch-signaling reporter, and 3) Cell metabolism; accumulation of reactive oxygen species. In summary, ARQiv is a versatile and readily accessible approach facilitating evaluation of genetic and/or chemical manipulations in living zebrafish that complements current "high-content" whole organism screening methods by providing a first-tier in vivo HTS drug discovery platform. PMID- 22238674 TI - Repression of meiotic genes by antisense transcription and by Fkh2 transcription factor in Schizosaccharomyces pombe. AB - In S. pombe, about 5% of genes are meiosis-specific and accumulate little or no mRNA during vegetative growth. Here we use Affymetrix tiling arrays to characterize transcripts in vegetative and meiotic cells. In vegetative cells, many meiotic genes, especially those induced in mid-meiosis, have abundant antisense transcripts. Disruption of the antisense transcription of three of these mid-meiotic genes allowed vegetative sense transcription. These results suggest that antisense transcription represses sense transcription of meiotic genes in vegetative cells. Although the mechanism(s) of antisense mediated transcription repression need to be further explored, our data indicates that RNAi machinery is not required for repression. Previously, we and others used non strand specific methods to study splicing regulation of meiotic genes and concluded that 28 mid-meiotic genes are spliced only in meiosis. We now demonstrate that the "unspliced" signal in vegetative cells comes from the antisense RNA, not from unspliced sense RNA, and we argue against the idea that splicing regulates these mid-meiotic genes. Most of these mid-meiotic genes are induced in mid-meiosis by the forkhead transcription factor Mei4. Interestingly, deletion of a different forkhead transcription factor, Fkh2, allows low levels of sense expression of some mid-meiotic genes in vegetative cells. We propose that vegetative expression of mid-meiotic genes is repressed at least two independent ways: antisense transcription and Fkh2 repression. PMID- 22238675 TI - Trihydrophobin 1 phosphorylation by c-Src regulates MAPK/ERK signaling and cell migration. AB - c-Src activates Ras-MAPK/ERK signaling pathway and regulates cell migration, while trihydrophobin 1 (TH1) inhibits MAPK/ERK activation and cell migration through interaction with A-Raf and PAK1 and inhibiting their kinase activities. Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. Further study reveals that Tyr-6 phosphorylation of TH1 reduces its inhibition on MAPK/ERK signaling, enhances c Src mediated cell migration. Moreover, induced tyrosine phosphorylation of TH1 has been found by EGF and estrogen treatments. Taken together, our findings demonstrate a novel mechanism for the comprehensive regulation of Ras/Raf/MEK/ERK signaling and cell migration involving tyrosine phosphorylation of TH1 by c-Src. PMID- 22238676 TI - Development of a halotolerant community in the St. Lucia Estuary (South Africa) during a hypersaline phase. AB - BACKGROUND: The St. Lucia Estuary, Africa's largest estuarine lake, is currently experiencing unprecedented freshwater deprivation which has resulted in a northward gradient of drought effects, with hypersaline conditions in its northern lakes. METHODOLOGY/PRINCIPAL FINDINGS: This study documents the changes that occurred in the biotic communities at False Bay from May 2010 to June 2011, in order to better understand ecosystem functioning in hypersaline habitats. Few zooplankton taxa were able to withstand the harsh environmental conditions during 2010. These were the flatworm Macrostomum sp., the harpacticoid copepod Cletocamptus confluens, the cyclopoid copepod Apocyclops cf. dengizicus and the ciliate Fabrea cf. salina. In addition to their exceptional salinity tolerance, they were involved in a remarkably simple food web. In June 2009, a bloom of an orange-pigmented cyanobacterium (Cyanothece sp.) was recorded in False Bay and persisted uninterruptedly for 18 months. Stable isotope analysis suggests that this cyanobacterium was the main prey item of F. cf. salina. This ciliate was then consumed by A. cf. dengizicus, which in turn was presumably consumed by flamingos as they flocked in the area when the copepods attained swarming densities. On the shore, cyanobacteria mats contributed to a population explosion of the staphylinid beetle Bledius pilicollis. Although zooplankton disappeared once salinities exceeded 130, many taxa are capable of producing spores or resting cysts to bridge harsh periods. The hypersaline community was disrupted by heavy summer rains in 2011, which alleviated drought conditions and resulted in a sharp increase in zooplankton stock and diversity. CONCLUSIONS/SIGNIFICANCE: Despite the current freshwater deprivation crisis, the False Bay region has shown to be resilient, harboring a unique biodiversity with species that are capable of enduring harsh environmental conditions. However, further freshwater deprivation may extend beyond the physiological thresholds of this community, as well as other unique biodiversity components which this system sustains. PMID- 22238677 TI - Red blood cells protect albumin from cigarette smoke-induced oxidation. AB - Different studies reported the presence of oxidized (carbonylated) albumin in the extravascular pool, but not in the intravascular one of cigarette smokers. In this study we attempted to explain this apparent discrepancy exposing human serum albumin (HSA) to aqueous cigarette smoke extract (CSE). CSE induces HSA carbonylation and oxidation of the HSA Cys34 sulfhydryl group. An antioxidant action of glutathione, cysteine, and its synthetic derivative N-acetylcysteine was observed only at supra-physiological concentrations, suggesting that physiological (plasma) concentrations of glutathione and cysteine in the low micromolar range are ineffective in preventing cigarette smoke-induced oxidation of HSA. Differently, human erythrocytes resulted to be protective towards CSE induced oxidation (carbonylation and thiol oxidation) of both HSA and total human plasma proteins. PMID- 22238678 TI - Influence of molecular noise on the growth of single cells and bacterial populations. AB - During the last decades experimental studies have revealed that single cells of a growing bacterial population are significantly exposed to molecular noise. Important sources for noise are low levels of metabolites and enzymes that cause significant statistical variations in the outcome of biochemical reactions. In this way molecular noise affects biological processes such as nutrient uptake, chemotactic tumbling behavior, or gene expression of genetically identical cells. These processes give rise to significant cell-to-cell variations of many directly observable quantities such as protein levels, cell sizes or individual doubling times. In this study we theoretically explore if there are evolutionary benefits of noise for a growing population of bacteria. We analyze different situations where noise is either suppressed or where it affects single cell behavior. We consider two specific examples that have been experimentally observed in wild type Escherichia coli cells: (i) the precision of division site placement (at which molecular noise is highly suppressed) and (ii) the occurrence of noise induced phenotypic variations in fluctuating environments. Surprisingly, our analysis reveals that in these specific situations both regulatory schemes [i.e. suppression of noise in example (i) and allowance of noise in example (ii)] do not lead to an increased growth rate of the population. Assuming that the observed regulatory schemes are indeed caused by the presence of noise our findings indicate that the evolutionary benefits of noise are more subtle than a simple growth advantage for a bacterial population in nutrient rich conditions. PMID- 22238679 TI - Natural amyloid-beta oligomers acutely impair the formation of a contextual fear memory in mice. AB - Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss. PMID- 22238680 TI - A novel strategy for development of recombinant antitoxin therapeutics tested in a mouse botulism model. AB - Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant 'targeting agent' that binds a toxin at two unique sites and a 'clearing Ab' that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab V(H) (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit. PMID- 22238682 TI - Comparing monofractal and multifractal analysis of corrosion damage evolution in reinforcing bars. AB - Based on fractal theory and damage mechanics, the aim of this paper is to describe the monofractal and multifractal characteristics of corrosion morphology and develop a new approach to characterize the nonuniform corrosion degree of reinforcing bars. The relationship between fractal parameters and tensile strength of reinforcing bars are discussed. The results showed that corrosion mass loss ratio of a bar cannot accurately reflect the damage degree of the bar. The corrosion morphology of reinforcing bars exhibits both monofractal and multifractal features. The fractal dimension and the tensile strength of corroded steel bars exhibit a power function relationship, while the width of multifractal spectrum and tensile strength of corroded steel bars exhibit a linear relationship. By comparison, using width of multifractal spectrum as multifractal damage variable not only reflects the distribution of corrosion damage in reinforcing bars, but also reveals the influence of nonuniform corrosion on the mechanical properties of reinforcing bars. The present research provides a new approach for the establishment of corrosion damage constitutive models of reinforcing bars. PMID- 22238681 TI - Expression patterns of non-coding spliced transcripts from human endogenous retrovirus HERV-H elements in colon cancer. AB - BACKGROUND: Up-regulation of the most abundant H family human endogenous retrovirus (HERV-H), especially env-related transcripts, correlates with colon cancer. However, expression pattern of spliced non-coding transcripts of HERV-H is not clear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, expression of HERV-H spliced transcripts in colon cancer was investigated by a RT-PCR strategy using primers targeting the tRNA(His) primer-binding site and the R region in the 3' long terminal repeat (LTR), followed by cloning and sequencing of the amplicons. Sequences were then assigned to individual HERV-H loci by employing private nucleotide differences between loci. Different expression patterns of HERV-H spliced transcripts from distinct active elements were found in colon cancer cell lines HT29, LS 174T, RKO, SW480 and SW620. Furthermore, the expression patterns in SW480 and RKO were significantly changed by demethylation treatment. Interestingly, more HERV-H elements were found to be transcriptionally active in colon tumor tissues than in adjacent normal tissues (14 vs. 7). CONCLUSIONS/SIGNIFICANCE: This is the first research to study the character of expression of non-coding spliced transcripts of HERV-H elements in colon cancer. Expression patterns of HERV-H spliced transcripts differed among colon cancer cell lines and could be affected by genomic DNA methylation levels. More importantly, besides the commonly accepted view of up-regulation of HERV-H expression in colon tumor tissues, we found more active HERV-H loci in colon tumor as compared with adjacent normal tissues. PMID- 22238683 TI - Bone histology in Dysalotosaurus lettowvorbecki (Ornithischia: Iguanodontia)- variation, growth, and implications. AB - BACKGROUND: Dysalotosaurus lettowvorbecki is a small ornithopod dinosaur known from thousands of bones and several ontogenetic stages. It was found in a single locality within the Tendaguru Formation of southeastern Tanzania, possibly representing a single herd. Dysalotosaurus provides an excellent case study for examining variation in bone microstructure and life history and helps to unravel the still mysterious growth pattern of small ornithopods. METHODOLOGY/PRINCIPAL FINDINGS: Five different skeletal elements were sampled, revealing microstructural variation between individuals, skeletal elements, cross sectional units, and ontogenetic stages. The bone wall consists of fibrolamellar bone with strong variability in vascularization and development of growth cycles. Larger bones with a high degree of utilization have high relative growth rates and seldom annuli/LAGs, whereas small and less intensively used bones have lower growth rates and a higher number of these resting lines. Due to the scarcity of annuli/LAGs, the reconstruction of the life history of Dysalotosaurus was carried out using regularly developed and alternating slow and fast growing zones. Dysalotosaurus was a precocial dinosaur, which experienced sexual maturity at ten years, had an indeterminate growth pattern, and maximum growth rates comparable to a large kangaroo. CONCLUSIONS/SIGNIFICANCE: The variation in the bone histology of Dysalotosaurus demonstrates the influence of size, utilization, and shape of bones on relative growth rates. Annuli/LAGs are not the only type of annual growth cycles that can be used to reconstruct the life history of fossil vertebrates, but the degree of development of these lines may be of importance for the reconstruction of paleobehavior. The regular development of annuli/LAGs in subadults and adults of large ornithopods therefore reflects higher seasonal stress due to higher food demands, migration, and altricial breeding behavior. Small ornithopods often lack regularly developed annuli/LAGs due to lower food demands, no need for migration, and precocial behavior. PMID- 22238684 TI - How noisy does a noisy miner have to be? Amplitude adjustments of alarm calls in an avian urban 'adapter'. AB - BACKGROUND: Urban environments generate constant loud noise, which creates a formidable challenge for many animals relying on acoustic communication. Some birds make vocal adjustments that reduce auditory masking by altering, for example, the frequency (kHz) or timing of vocalizations. Another adjustment, well documented for birds under laboratory and natural field conditions, is a noise level-dependent change in sound signal amplitude (the 'Lombard effect'). To date, however, field research on amplitude adjustments in urban environments has focused exclusively on bird song. METHODS: We investigated amplitude regulation of alarm calls using, as our model, a successful urban 'adapter' species, the Noisy miner, Manorina melanocephala. We compared several different alarm calls under contrasting noise conditions. RESULTS: Individuals at noisier locations (arterial roads) alarm called significantly more loudly than those at quieter locations (residential streets). Other mechanisms known to improve sound signal transmission in 'noise', namely use of higher perches and in-flight calling, did not differ between site types. Intriguingly, the observed preferential use of different alarm calls by Noisy miners inhabiting arterial roads and residential streets was unlikely to have constituted a vocal modification made in response to sound-masking in the urban environment because the calls involved fell within the main frequency range of background anthropogenic noise. CONCLUSIONS: The results of our study suggest that a species, which has the ability to adjust the amplitude of its signals, might have a 'natural' advantage in noisy urban environments. PMID- 22238686 TI - Avian influenza H5N1 transmission in households, Indonesia. AB - BACKGROUND: Disease transmission patterns are needed to inform public health interventions, but remain largely unknown for avian influenza H5N1 virus infections. A recent study on the 139 outbreaks detected in Indonesia between 2005 and 2009 found that the type of exposure to sources of H5N1 virus for both the index case and their household members impacted the risk of additional cases in the household. This study describes the disease transmission patterns in those outbreak households. METHODOLOGY/PRINCIPAL FINDINGS: We compared cases (n = 177) and contacts (n = 496) in the 113 sporadic and 26 cluster outbreaks detected between July 2005 and July 2009 to estimate attack rates and disease intervals. We used final size household models to fit transmission parameters to data on household size, cases and blood-related household contacts to assess the relative contribution of zoonotic and human-to-human transmission of the virus, as well as the reproduction number for human virus transmission. The overall household attack rate was 18.3% and secondary attack rate was 5.5%. Secondary attack rate remained stable as household size increased. The mean interval between onset of subsequent cases in outbreaks was 5.6 days. The transmission model found that human transmission was very rare, with a reproduction number between 0.1 and 0.25, and the upper confidence bounds below 0.4. Transmission model fit was best when the denominator population was restricted to blood-related household contacts of index cases. CONCLUSIONS/SIGNIFICANCE: The study only found strong support for human transmission of the virus when a single large cluster was included in the transmission model. The reproduction number was well below the threshold for sustained transmission. This study provides baseline information on the transmission dynamics for the current zoonotic virus and can be used to detect and define signatures of a virus with increasing capacity for human-to human transmission. PMID- 22238685 TI - Target identification for stereotactic thalamotomy using diffusion tractography. AB - BACKGROUND: Stereotactic targets for thalamotomy are usually derived from population-based coordinates. Individual anatomy is used only to scale the coordinates based on the location of some internal guide points. While on conventional MR imaging the thalamic nuclei are indistinguishable, recently it has become possible to identify individual thalamic nuclei using different connectivity profiles, as defined by MR diffusion tractography. METHODOLOGY AND PRINCIPAL FINDINGS: Here we investigated the inter-individual variation of the location of target nuclei for thalamotomy: the putative ventralis oralis posterior (Vop) and the ventral intermedius (Vim) nucleus as defined by probabilistic tractography. We showed that the mean inter-individual distance of the peak Vop location is 7.33 mm and 7.42 mm for Vim. The mean overlap between individual Vop nuclei was 40.2% and it was 31.8% for Vim nuclei. As a proof of concept, we also present a patient who underwent Vop thalamotomy for untreatable tremor caused by traumatic brain injury and another patient who underwent Vim thalamotomy for essential tremor. The probabilistic tractography indicated that the successful tremor control was achieved with lesions in the Vop and Vim respectively. CONCLUSIONS: Our data call attention to the need for a better appreciation of the individual anatomy when planning stereotactic functional neurosurgery. PMID- 22238687 TI - Increased frequency of pink bollworm resistance to Bt toxin Cry1Ac in China. AB - Transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) kill some key insect pests, but evolution of resistance by pests can reduce their efficacy. The main approach for delaying pest adaptation to Bt crops uses non-Bt host plants as "refuges" to increase survival of susceptible pests. To delay evolution of pest resistance to transgenic cotton producing Bt toxin Cry1Ac, the United States and some other countries have required refuges of non-Bt cotton, while farmers in China have relied on "natural" refuges of non-Bt host plants other than cotton. The "natural" refuge strategy focuses on cotton bollworm (Helicoverpa armigera), the primary target of Bt cotton in China that attacks many crops, but it does not apply to another major pest, pink bollworm (Pectinophora gossypiella), which feeds almost entirely on cotton in China. Here we report data showing field-evolved resistance to Cry1Ac by pink bollworm in the Yangtze River Valley of China. Laboratory bioassay data from 51 field-derived strains show that the susceptibility to Cry1Ac was significantly lower during 2008 to 2010 than 2005 to 2007. The percentage of field populations yielding one or more survivors at a diagnostic concentration of Cry1Ac increased from 0% in 2005-2007 to 56% in 2008-2010. However, the median survival at the diagnostic concentration was only 1.6% from 2008 to 2010 and failure of Bt cotton to control pink bollworm has not been reported in China. The early detection of resistance reported here may promote proactive countermeasures, such as a switch to transgenic cotton producing toxins distinct from Cry1A toxins, increased planting of non-Bt cotton, and integration of other management tactics together with Bt cotton. PMID- 22238688 TI - Concentration-dependent, size-independent toxicity of citrate capped AuNPs in Drosophila melanogaster. AB - The expected potential benefits promised by nanotechnology in various fields have led to a rapid increase of the presence of engineered nanomaterials in a high number of commercial goods. This is generating increasing questions about possible risks for human health and environment, due to the lack of an in-depth assessment of the physical/chemical factors responsible for their toxic effects. In this work, we evaluated the toxicity of monodisperse citrate-capped gold nanoparticles (AuNPs) of different sizes (5, 15, 40, and 80 nm) in the model organism Drosophila melanogaster, upon ingestion. To properly evaluate and distinguish the possible dose- and/or size-dependent toxicity of the AuNPs, we performed a thorough assessment of their biological effects, using two different dose-metrics. In the first approach, we kept constant the total surface area of the differently sized AuNPs (Total Exposed Surface area approach, TES), while, in the second approach, we used the same number concentration of the four different sizes of AuNPs (Total Number of Nanoparticles approach, TNN). We observed a significant AuNPs-induced toxicity in vivo, namely a strong reduction of Drosophila lifespan and fertility performance, presence of DNA fragmentation, as well as a significant modification in the expression levels of genes involved in stress responses, DNA damage recognition and apoptosis pathway. Interestingly, we found that, within the investigated experimental conditions, the toxic effects in the exposed organisms were directly related to the concentration of the AuNPs administered, irrespective of their size. PMID- 22238689 TI - Effects of NK-4 in a transgenic mouse model of Alzheimer's disease. AB - Beta-amyloid (Abeta) peptides are considered to play a major role in the pathogenesis of Alzheimer's disease (AD) and molecules that can prevent pathways of Abeta toxicity may be potential therapeutic agents for treatment of AD. We have previously reported that NK-4, a cyanine photosensitizing dye, displays neurotrophic and antioxidant activities. In this study, we report the effects of NK-4 on the toxicity of Abeta and on cognitive function and Abeta concentration in a transgenic mouse model of AD (Tg2576). In vitro, NK-4 effectively protected neuronal cells from toxicity induced by Abeta. In addition, it displayed profound inhibitory activities on Abeta fibril formation. In vivo, Tg2576 mice received an intraperitoneal injection at 100 or 500 ug/kg of NK-4 once a day, five times a week for 9 months. Administration of NK-4 to the mice attenuated impairment of recognition memory, associative memory, and learning ability, as assessed by a novel object recognition test, a passive avoidance test, and a water maze test, respectively. NK-4 decreased the brain Abeta concentration while increasing the plasma amyloid level in a dose-dependent manner. NK-4 also improved memory impairments of ICR mice induced by direct intracerebroventricular administration of Abeta. These lines of evidence suggest that NK-4 may affect multiple pathways of amyloid pathogenesis and could be useful for treatment of AD. PMID- 22238690 TI - Foxa1 reduces lipid accumulation in human hepatocytes and is down-regulated in nonalcoholic fatty liver. AB - Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid beta oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance. PMID- 22238691 TI - Preattentive extraction of abstract auditory rules in speech sound stream: a mismatch negativity study using lexical tones. AB - BACKGROUND: Extraction of linguistically relevant auditory features is critical for speech comprehension in complex auditory environments, in which the relationships between acoustic stimuli are often abstract and constant while the stimuli per se are varying. These relationships are referred to as the abstract auditory rule in speech and have been investigated for their underlying neural mechanisms at an attentive stage. However, the issue of whether or not there is a sensory intelligence that enables one to automatically encode abstract auditory rules in speech at a preattentive stage has not yet been thoroughly addressed. METHODOLOGY/PRINCIPAL FINDINGS: We chose Chinese lexical tones for the current study because they help to define word meaning and hence facilitate the fabrication of an abstract auditory rule in a speech sound stream. We continuously presented native Chinese speakers with Chinese vowels differing in formant, intensity, and level of pitch to construct a complex and varying auditory stream. In this stream, most of the sounds shared flat lexical tones to form an embedded abstract auditory rule. Occasionally the rule was randomly violated by those with a rising or falling lexical tone. The results showed that the violation of the abstract auditory rule of lexical tones evoked a robust preattentive auditory response, as revealed by whole-head electrical recordings of the mismatch negativity (MMN), though none of the subjects acquired explicit knowledge of the rule or became aware of the violation. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that there is an auditory sensory intelligence in the perception of Chinese lexical tones. The existence of this intelligence suggests that the humans can automatically extract abstract auditory rules in speech at a preattentive stage to ensure speech communication in complex and noisy auditory environments without drawing on conscious resources. PMID- 22238692 TI - A GIS model predicting potential distributions of a lineage: a test case on hermit spiders (Nephilidae: Nephilengys). AB - BACKGROUND: Although numerous studies model species distributions, these models are almost exclusively on single species, while studies of evolutionary lineages are preferred as they by definition study closely related species with shared history and ecology. Hermit spiders, genus Nephilengys, represent an ecologically important but relatively species-poor lineage with a globally allopatric distribution. Here, we model Nephilengys global habitat suitability based on known localities and four ecological parameters. METHODOLOGY/PRINCIPAL FINDINGS: We geo-referenced 751 localities for the four most studied Nephilengys species: N. cruentata (Africa, New World), N. livida (Madagascar), N. malabarensis (S-SE Asia), and N. papuana (Australasia). For each locality we overlaid four ecological parameters: elevation, annual mean temperature, annual mean precipitation, and land cover. We used linear backward regression within ArcGIS to select two best fit parameters per species model, and ModelBuilder to map areas of high, moderate and low habitat suitability for each species within its directional distribution. For Nephilengys cruentata suitable habitats are mid elevation tropics within Africa (natural range), a large part of Brazil and the Guianas (area of synanthropic spread), and even North Africa, Mediterranean, and Arabia. Nephilengys livida is confined to its known range with suitable habitats being mid-elevation natural and cultivated lands. Nephilengys malabarensis, however, ranges across the Equator throughout Asia where the model predicts many areas of high ecological suitability in the wet tropics. Its directional distribution suggests the species may potentially spread eastwards to New Guinea where the suitable areas of N. malabarensis largely surpass those of the native N. papuana, a species that prefers dry forests of Australian (sub)tropics. CONCLUSIONS: Our model is a customizable GIS tool intended to predict current and future potential distributions of globally distributed terrestrial lineages. Its predictive potential may be tested in foreseeing species distribution shifts due to habitat destruction and global climate change. PMID- 22238693 TI - Non-invasive measurement of hemoglobin: assessment of two different point-of-care technologies. AB - BACKGROUND: Measurement of blood hemoglobin (Hb) concentration is a routine procedure. Using a non-invasive point-of-care device reduces pain and discomfort for the patient and allows time saving in patient care. The aims of the present study were to assess the concordance of Hb levels obtained non-invasively with the Pronto-7 monitor (version 2.1.9, Masimo Corporation, Irvine, USA) or with the NBM-200MP monitor (Orsense, Nes Ziona, Israel) and the values obtained from the usual colorimetric method using blood samples and to determine the source of discordance. METHODS AND FINDINGS: We conducted two consecutive prospective open trials enrolling patients presenting in the emergency department of a university hospital. The first was designed to assess Pronto-7TM and the second NBM-200MPTM. In each study, the main outcome measure was the agreement between both methods. Independent factors associated with the bias were determined using multiple linear regression. Three hundred patients were prospectively enrolled in each study. For Pronto-7TM, the absolute mean difference was 0.56 g.L(-1) (95% confidence interval [CI] 0.41 to 0.69) with an upper agreement limit at 2.94 g.L( 1) (95% CI [2.70;3.19]), a lower agreement limit at -1.84 g.L(-1) (95% CI [-2.08; 1.58]) and an intra-class correlation coefficient at 0.80 (95% CI [0.74;0.84]). The corresponding values for the NBM-200MPTM were 0.21 [0.02;0.39], 3.42 [3.10;3.74], -3.01 [-3.32;-2.69] and 0.69 [0.62;0.75]. Multivariate analysis showed that age and laboratory values of hemoglobin were independently associated with the bias when using Pronto-7TM, while perfusion index and laboratory value of hemoglobin were independently associated with the bias when using NBM-200MPTM. CONCLUSION: Despite a relatively limited bias in both cases, the large limits of agreement found in both cases render the clinical usefulness of such devices debatable. For both devices, the bias is independently and inversely associated with the true value of hemoglobin. TRIAL REGISTRATION: ClinicalTrials.gov NCT01321580 and NCT01321593. PMID- 22238694 TI - Customisation of the exome data analysis pipeline using a combinatorial approach. AB - The advent of next generation sequencing (NGS) technologies have revolutionised the way biologists produce, analyse and interpret data. Although NGS platforms provide a cost-effective way to discover genome-wide variants from a single experiment, variants discovered by NGS need follow up validation due to the high error rates associated with various sequencing chemistries. Recently, whole exome sequencing has been proposed as an affordable option compared to whole genome runs but it still requires follow up validation of all the novel exomic variants. Customarily, a consensus approach is used to overcome the systematic errors inherent to the sequencing technology, alignment and post alignment variant detection algorithms. However, the aforementioned approach warrants the use of multiple sequencing chemistry, multiple alignment tools, multiple variant callers which may not be viable in terms of time and money for individual investigators with limited informatics know-how. Biologists often lack the requisite training to deal with the huge amount of data produced by NGS runs and face difficulty in choosing from the list of freely available analytical tools for NGS data analysis. Hence, there is a need to customise the NGS data analysis pipeline to preferentially retain true variants by minimising the incidence of false positives and make the choice of right analytical tools easier. To this end, we have sampled different freely available tools used at the alignment and post alignment stage suggesting the use of the most suitable combination determined by a simple framework of pre-existing metrics to create significant datasets. PMID- 22238695 TI - Contact with domestic dogs increases pathogen exposure in endangered African wild dogs (Lycaon pictus). AB - BACKGROUND: Infectious diseases have contributed to the decline and local extinction of several wildlife species, including African wild dogs (Lycaon pictus). Mitigating such disease threats is challenging, partly because uncertainty about disease dynamics makes it difficult to identify the best management approaches. Serious impacts on susceptible populations most frequently occur when generalist pathogens are maintained within populations of abundant (often domestic) "reservoir" hosts, and spill over into less abundant host species. If this is the case, disease control directed at the reservoir host might be most appropriate. However, pathogen transmission within threatened host populations may also be important, and may not be controllable by managing another host species. METHODOLOGY/PRINCIPAL FINDINGS: We investigated interspecific and intraspecific transmission routes, by comparing African wild dogs' exposure to six canine pathogens with behavioural measures of their opportunities for contact with domestic dogs and with other wild dogs. Domestic dog contact was associated with exposure to canine parvovirus, Ehrlichia canis, Neospora caninum and perhaps rabies virus, but not with exposure to canine distemper virus or canine coronavirus. Contact with other wild dogs appeared not to increase the risk of exposure to any of the pathogens. CONCLUSIONS/SIGNIFICANCE: These findings, combined with other data, suggest that management directed at domestic dogs might help to protect wild dog populations from rabies virus, but not from canine distemper virus. However, further analyses are needed to determine the management approaches--including no intervention- which are most appropriate for each pathogen. PMID- 22238697 TI - Editorial. PMID- 22238696 TI - Presenilin is the molecular target of acidic gamma-secretase modulators in living cells. AB - The intramembrane-cleaving protease gamma-secretase catalyzes the last step in the generation of toxic amyloid-beta (Abeta) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of gamma-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are gamma-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Abeta42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the gamma-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Abeta42 generation with an IC(50) of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the gamma-secretase complex, in living cells. Labeling was not observed for APP or any of the other gamma-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the gamma-secretase complex. PMID- 22238698 TI - Bone-defects healing by high-molecular hyaluronic acid: preliminary results. AB - AIM.: The aim of this study is to evaluate the capability of HyalossTM matrix (Fab - Fidia Advanced Biopolymers - Pd - Italy), a biomaterial based on hyaluronic acid, used as organic scaffold in bone repair in post-extractive defects. MATERIALS AND METHODS: 20 post-extractive sockets were selected, with similar size defects in the same patient and in the same hemiarch. Hyaluronic acid with high molecular weight (HyalossTM matrix, Fab - Pd - Italy) was mixed with autologous bone obtained using Safescraper((r)) curve (Meta - Re - Italy) to repair post-extractive sites. Safescraper((r)) is a cutting edge system that allows to the collection of autologous bone without using traditional, incision based collection techniques, which could cause discomfort to the patient. RESULTS: Clinical and hystological evaluations were performed, four months after grafting, in the maxilla and in the mandible. From a clinical point of view HyalossTM matrix mixed with autologous bone and patient's blood becomes a substance similar to gel, which is easy to insert in to the defect. From a hystological point of view, in the treated site there is the presence of an erosive activity, with accelerated angiogenetic and bone remodelling activities. CONCLUSIONS: The preliminary results show an acceleration of the bone deposit process and of its remodelling due to the presence of HyalossTM matrix, which, from a clinical point of view, improves the handling and application of the bone matrix inside the defects and, from a hystologic point of view makes it possible to obtain bone regeneration in less time when it is used with autologous bone. PMID- 22238699 TI - The arginine-deiminase enzymatic system on gingivitis: preliminary pediatric study. AB - AIM.: The lactic bacteria are Gram-positive microorganisms with coccus or stick shape, which share a number of physiological and biochemical properties. Several experimental evidences suggest the possibility of using lactic acid bacterial as a preventive or therapeutic potential approaches, alternative or complementary to prevention or treatment protocols currently followed in several pathological conditions. Lactobacillus brevis is able, through the arginine-deiminase activity, to subtract the substrate (arginine) to nitric oxide synthase, and to inhibit in vitro generation of nitric oxide from rat's peritoneal macrophages. These data led us to study the in vivo L. brevis anti-inflammatory effect choosing as experimental model the gingivitis. MATERIALS AND METHODS.: In our study were examined 21 subjects, 16 males and 5 females, aged between 5 and 12 years, with marginal gingivitis problems who have been given chewing gum containing the principle to test in measure of three per day. RESULTS.: At the time T1, after treatment, 18 patients no longer showed inflammation; 2 of them had a slight inflammation and only 1 patient still showed a moderate inflammation. CONCLUSIONS.: From our research, as confirmed by clinical and laboratory investigation, results an effective anti-inflammatory action of arginine-deiminase system that some bacteria possessing. PMID- 22238700 TI - The low level laser therapy in the management of neurological burning mouth syndrome. A pilot study. AB - BACKGROUND AND OBJECTIVE: Burning Mouth Syndrome (BMS) is a common disease but still a diagnostic and therapeutic challenge for clinicians. Despite many studies its nature remains obscure and controversial; nowadays there is no consensus about definition, diagnosis and classification. BMS is characterized clinically by burning sensations in the tongue or other oral sites, often without clinical and laboratory findings. According to the etiology, BMS cases should be subdivided into three subtypes: BMS by local factors (lfBMS), BMS by systemic factors (sfBMS) and neurological BMS (nBMS), the most frequent, in which the symptom is caused by central or peripheral neurological malfunctions affecting in particular the taste pathway. To establish the type of BMS, both anamnesis and clinical examination, including laboratory tests, are necessary; nBMS cases will be recognized by exclusion of any other type. In case of lfBMS or sfBMS, the treatment of the main pathology will be resolutive; in nBMS cases many Authors proposed different pharmacological trials without satisfactory results and the current opinion is that a multidisciplinary approach is required to keep the condition under control. This pilot study aimed to investigate whether the biostimulative effect of Low Level Laser Therapy (LLLT) could enhance the symptoms of nBMS cases, improving patients' quality of life. STUDY DESIGN/MATERIALS AND METHODS: Among 160 patients affected by oral burning sensation attending to the Oral Pathology Complex Operative Unit of the Department of Stomatological Sciences of Sapienza University of Rome, 77 resulted affected by nBMS. Twenty-five of these patients, 16 females and 9 males, were randomly selected for low level laser applications. All the patients were irradiated with a double diode laser (Lumix 2 Prodent, Italy) emitting contemporarily at 650 nm and 910 nm, with a fluence of 0.53 J/cm(2) for 15 minutes twice a week for 4 weeks. The areas of irradiation were the sides of the tongue on the path of taste fibers. A NRS (numerical rating scale) evaluation of maximum and minimum pain was registered before and after the treatment. In each case to the total value of NRS rates registered before the treatment was deducted the total NRS rate registered after the treatment. The difference was estimated effective if over two points. The Kruskall-Wallis test revealed the significance of the study (p<0.0001) and the Dunn's Multiple Comparison test, applied to compare NRS rates before and after the treatment, showed that there is not a statistically relevant difference between min NRS ratings before and after treatment, while there are statistically significant differences between max NRS ratings (p<0.05). RESULTS: All the patients agreed the treatment confirming the general good compliance related to laser treatments. No side effects were registered and all the patients completed the therapy without interruption. Seventeen patients (68%) had relevant benefits from the treatment with valid reduction of NRS ratings. In 8 cases the differences of NRS rates were not relevant being under the limit of reliability established in study design. In no case there was a worsening of the symptoms. CONCLUSIONS: According to the results of this pilot study it is reasonable to suppose that LLLT may play an important role in the management of nBMS cases, more investigations are needed to clarify, by a greater number of cases and a placebo control group, the real effectiveness of this innovative LLLT application. PMID- 22238701 TI - Prosthetic rehabilitation in post-oncological patients: Report of two cases. AB - Prosthetic rehabilitation in post-oncologic patients after bone reconstruction are not substantially different than those of patients affected by severe atrophia of upper or lower jaw after bone reconstruction.Aim of this paper is to evaluate the possibilities of prosthetic rehabilitation on these patients and to present our method. Prosthesis-based oral rehabilitation of such tumor cases rapresents a challenge.The report analyses two cases of patients who underwent ablative oral surgery. Both have received a fibula free vascularised flap. The first was rehabilitated with a removable prosthesis fixed on the residual teeth, while the second with an implant supported prosthesis.In case of carcinoma resection of the oral mucosa, the removable prosthesis guarantees a simplification in dental care operations. On the other hand, irradiated mucosa is frequentely unable to tolerate the friction created by the acrylic base. However, the fixed prosthesis can limit the view during follow-up controls.In our school, according to all exposed reasons, we consider the implant supported overdenture prosthesis to be the best choice for those patients. PMID- 22238702 TI - Editorial. PMID- 22238703 TI - Clinical and instrumental treatment of a patient with dysfunction of the stomatognathic system: a case report. AB - This article details a case report of a subject chosen from among patients treated in the author's clinic in the Posturology and Gnathology Section of the University Milano-Bicocca.It shows how the indispensable clinical analysis of the stomatognathic system and the connections between posture can be supported by instrumental analysis, such as the computerized occlusal analysis system and the force platform, to diagnose and treat dysfunctional patients. PMID- 22238705 TI - Ameloblastic fibro-odontoma: a case report. AB - The clinical case of an unusual ameloblastic fibro-odontoma (AFO) was reported. The patient's clinical chart as well as preoperative and postoperative radiographs and histological findings of a 20-year old man that addressed Dental Clinic at University of L'Aquila were thoroughly reviewed. The patient showed a swelling in the oral cavity and radiographic feature of a radiolucent lesion at left second premolar maxillary site. Histologic examination made diagnosis of AFO. AFO is a rare mixed odontogenic tumor with similarities to the ameloblastic fibroma (AF) and ameloblastic dentinoma. The nature and the relationships between mixed odontogenic tumours and related lesions are still controversial. Moreover is not clear if these lesions are separate pathologies or if they are different development stages of the same pathology. PMID- 22238704 TI - Ultrasonics in endodontic surgery: a review of the literature. AB - Currently, although ultrasonics (US) is used in dentistry for therapeutic and diagnostic applications as well as for cleaning of instruments before sterilization, its main use is for scaling and root planing of teeth and in root canal therapy, both for orthograde and retrograde therapy. Both in conventional and surgical treatments, US in endodontics has enhanced quality of clinical procedures and represents an important adjunct in the treatment of difficult cases. More precisely it has become increasingly more useful in applications such as gaining access to canal openings, cleaning and shaping, obturation of root canals, removal of intracanal materials and obstructions, and endodontic surgery. This review of the literature aims at presenting the numerous advantages of US in surgical endodontics and emphasizes its application in a modern-day endodontic practice. PMID- 22238706 TI - Control factors in removable complete dentures: from the articulation quintet to kinetic contact. AB - Hanau's laws and the so-called articulation quintet have contributed greatly to the evolution of the prosthetic dentistry and have been further elaborated by various authors. The main aim of this study was to establish the stability of prosthetic plates by attaining balanced occlusion. Several authors have addressed the problem of removable and fixed prostheses by classifying mandibular movements into functional and parafunctional movements which extends the classical occlusal mechanics for the modern occlusal feedback model. Moreover, they suggest the use of the angle of convergence as a reference plane when manufacturing prosthetic. PMID- 22238707 TI - Editorial. PMID- 22238708 TI - Patient satisfaction with oral implant rehabilitation: evaluation of responses to a questionnaire. AB - AIM: This pilot study evaluated patients' experience of oral surgical and prosthetic procedures as well as their opinions regarding function, aesthetics, comfort, and satisfaction with treatment outcomes. MATERIALS AND METHODS: Forty nine subjects treated with oral implants completed questionnaires comprising 44 questions. Three questionnaires were used related to implant-supported single tooth, fixed implant-supported prostheses and implant-retained overdentures. The questions related to demographic data (age, sex, employment, marital status and educational level), the source of information, the reason they underwent implant treatment, the discomfort related to all phases of treatment, and their functional and aesthetic satisfaction. RESULTS: Most of the patients (53.8%) were employed and had received a high school certificate or a university diploma. Patients heard about implants from various sources, including referring dentists (55.8%), relatives and friends (23.1%), and television, radio and the Internet (17.3%). The main reasons for choosing implant treatment were restoring lost teeth (35,5%), following dentist's advice (33,3%), improving stability of the removable denture (15.4%), eating habits (13.5%) and aesthetics (1.9%). Most patients considered that the procedure took a long time (44.2%) but was not traumatic (62.5%). Pain was almost absent in most cases (64.5%) and swelling, when present, was generally moderate (48.1%) and seldom was marked (17.3%). Patients were very satisfied about the aesthetics (82.7%) and function (94.2%), and considered the implant prosthesis to be part of themselves (84.6%). Most of the patients considered the implant prostheses to be easy to clean (73.1%), and would repeat the treatment if necessary (86.5%) and recommend it to other people (94.2%). CONCLUSIONS: Although the present study is limited by the small sample, the outcomes suggest that oral implant rehabilitation meets patients' needs and aesthetic demands. PMID- 22238709 TI - Implant adaptation of stock abutments versus CAD/CAM abutments: a radiographic and Scanning Electron Microscopy study. AB - INTRODUCTION: The study evaluated a null-hypothesis of no differences of fit between stock abutments and CAD/CAM titanium, gold sputtered and zirconia abutments when examined for radiographic adaptation and Scanning Electron Microcopy (SEM) at their inner aspect. The agreement between microscopic and radiographic fit was also assessed. METHODS: Implants (Osseospeed, Astra Tech, Molndal, Sweden) were connected to titanium abutments (Ti-design, Astra Tech, Molndal, Sweden) (control group n=12), to stock zirconia abutments (Zir-design, Astra Tech) (group 1 n=12) and to third party zirconia abutments (Aadva Zr abutment, GC, Tokyo, Japan) as observed under SEM (JEOL JSM-6060LV, Tokyo, Japan). Two independent operators blindly evaluated the images, according to a three-score scale: perfect adaptation, no complete adaptation, and clear evidence of no adaptation. A Kruskal-Wallis test was applied to assess significant differences in adaptation scores between the groups. RESULTS: All specimens showed precise SEM adaptation at all tested interfaces and no radiographically apparent gaps. No significant differences were found and therefore the null hypothesis tested was accepted. Radiographic and SEM scores were in agreement. DISCUSSION: CAD/CAM titanium, gold sputtered and zirconia abutments and third part CAD/CAM zirconia abutments show an adaptation to Astra Tech implants that is comparable to that of stock titanium and zirconia abutments. Clinicians might be able to verify such adaptation with an x-ray. In-vivo studies would be needed to evaluate the clinical outcome of CAD/CAM abutments. PMID- 22238710 TI - Estrogenicity of bisphenol A released from sealants and composites: a review of the literature. AB - This study aims to critically summarize the literature about bisphenol A (BPA), indicate whether and how those risks are real and emphasize how it is eventually possible to prevent them. With this in mind, we should consider nature, risks and control of BPA, as well as its presence and its role in sealants and composites. It is important to note that we will focus on literature exclusively written about the possible estrogenic activity (and not about the general toxicology profile) of BPA or its possible derivatives released from composites and sealants (without mentioning, or covering just briefly, similar activities performed by their components). PMID- 22238711 TI - Interceptive therapy with elastodontic appliance: case report. AB - Aim of this report is to describe a case of a patient in mixed dentition with dento-skeletal class II malocclusion, deep bite, increased overjet and gummy smile.IN THIS KIND OF CLINICAL CASE THE OBJECTIVES OF TREATMENT WERE: to correct the dento-skeletal malocclusion, to obtain a correct overbite and overjet, to control the permanent teeth in a good eruption, to improve aesthetical conditions and to maintain clinical results.Treatment plan included just Occlus-o guide((r)), the type that is indicated for mixed dentition (G type). The active phase of therapy was conducted in twelve months and the retention time was two years. Then the patient was controlled every three months and she used the appliance nighttime in alternance for one year more.Occlus-o-guide((r)) was the indicated appliance to obtain all the objectives requested to solve the malocclusion. The early therapy with Occlus-o-guide((r)) is easy, short and most of treated cases don't need a second phase of orthodontic therapy. PMID- 22238712 TI - Perceived and measurable performance of daily brushing and rinsing with an essential oil mouthrinse. AB - AIMS: To determine whether the oral health benefits of recommending twice daily brushing and rinsing with an essential oil mouthrinse (EOM) are perceived and measurable by dentists and also perceived by their patients at a 3-month recall visit. METHODS: This is a monadic, open label, uncontrolled study involving 766 generally healthy Italian subjects aged 19-66 years, with mild to moderate levels of gingivitis, no pockets of more than 4 mm, and at least 20 scorable teeth. Eight dentists scored subjects for plaque and gingivitis at baseline and at 90 days using simplified 4-point plaque and gingivitis indices. All subjects brushed twice daily, immediately followed by rinsing for 30 sec with 20 ml of an essential oil mouthrinse (Listerine((r))). RESULTS: 735 subjects completed the study (95.9%). Average score reductions were 51.9% and 45.7% for plaque and gingivitis, respectively. About 62% and 70% were judged by the dentists as improved for plaque control and gingival health. 85% of subjects judged the EOM as efficacious. CONCLUSION: The oral health benefits of brushing and rinsing twice daily with an essential oil mouthrinse are perceived by patients and professionals alike and measurable by dentists at a 3-month recall visit. PMID- 22238713 TI - A comparative study of Magnetic Resonance (MR) and Computed Tomography (CT) in the pre-implant evaluation. AB - AIM: A successful implant therapy is based on an accurate assessment of the anatomy of the jaws. The aim of our study was to evaluate the reliability of magnetic resonance imaging (MR) compared with computed tomography (CT) for dental implant planning in respect to bone measurements and to observe and analyze the differences. METHOD: We have studied 30 cases in which scans were performed with CT and MR. The images provided by the MR and CT examinations were delivered to three specialists in oral and maxillofacial radiology to measure the bone height at the specific sites.The measurements obtained by the specialists in MR and CT images were compared using the ANOVA test with a 0.05 significance level. RESULT: In all 30 cases examined, MR images appeared perfectly comparable to CT images. The differences between the measurements from the MR and CT exams varied from 0.04 to 1.1 mm. There were no statistically significant differences (P=0.9). CONCLUSION: The MR, when compared with CT, shown to be reliable in respect to bone measurements for dental implant planning. However, further studies are necessary to determine the technical advantages of Resonance at lower fields, compared with those of CT and MR with medium or high magnetic field. PMID- 22238714 TI - Editorial. PMID- 22238715 TI - Stem cells from oral niches: a review. AB - AIM: Stem cell research in recent years have been considered the most advanced sort of medical-scientific research and early results have aroused great expectations. Also in dentistry many studies were performed with the final aim of obtaining new bone and new teeth. In this work we describe the state of the art in dental science stem cell research. METHODS: We have performed a web-based research on MEDLINE within (www.pubmed.gov). We have used "stem cells from human exfoliated deciduous teeth" (24 paper found), "periodontal ligament stem cells" (32 paper found), "stem cell apical papilla" (16 paper found), "dental pulp stem cells" (136 paper found) as keywords for research. For each keyword we have performed a complete review focusing on knowledge upgrade. RESULTS: For each topic was created a selection of papers in chronological order of publication date so to give a timetable of the development of the research for each niche. CONCLUSION: Research about stem cell from oral niches began in 2000 and every year papers publicated were more than the precedent. This review analysed about 180 articles most of which in the last 5 years. Dentla pulp from adult as from deciduous teeth seems to be the most valuable font of stem cells due to the pluripotential type of cells. PMID- 22238716 TI - Leiomyoma of oral cavity: case report and literature review. AB - Leiomyoma is a benign smooth muscle tumour, that occurs most frequently in the uterine myometrium, gastrointestinal tract, skin and lower extremities of middle aged women. Leiomyomas are uncommon in the oral cavity, but in this location are usually localized on the tongue, lips and palate. Most lesions are asymptomatic, although occasional tumours can be painful. The diagnosis is mainly determined by histological studies due to its unspecific clinical appearance.The purpose of this article is to present a case report of 49-year-old male patient with a lesion of the lower lip. After surgical resection hematoxylin-eosin staining confirmed the diagnosis of leiomyoma. PMID- 22238717 TI - Experience of dental caries and its effects on early dental occlusion: a descriptive study. AB - AIM: Describe the occurrence of dental caries in a sample of pre-school children and school children, aged 3 and 12, and study the possible association between caries and malocclusion. METHODS: We selected and analyzed the medical records of a sample of 588 patients who had their first dental examination at the Pediatric Dentistry Unit, Department of Oral and Maxillofacial Sciences of Policlinico Umberto I, "Sapienza" University of Rome. RESULTS: In the sample, 55.4% of the children had no decayed deciduous elements, while 44.6% had at least one decayed deciduous element. The prevalence of decayed permanent teeth was 10.2%, while 89.8% had no decayed permanent teeth. In the sample, 9.4% of the children showed advanced carious lesions, that needed tooth extraction and 6.6% needed a space maintainer for post-extractive interceptive treatment. In the sample, 26.7% of the examined patients had increased overjet, while 3.7% had decreased overjet and 25.4% of the sample had an increased overbite, 11, 2% had reduced over-bite values. A percentage over 10% of the sample had an anterior openbite in centric occlusion. The prevalence of posterior crossbite among entire samples was 19.8%. CONCLUSIONS: Although the incidence of caries disease was high in the selected samples, the study did not show a statistically significant association between caries and clinical orthodontic abnormalities, except for the association between the midline deviation and the severe carious diseases, necessitating extraction. PMID- 22238718 TI - A SEM study of canal cleanliness after a new nickel-titanium rotary instrumentation technique. AB - The purpose of this in vitro study was to evaluate the degree of smear layer removal after root canal preparation with TF((r)) instruments, combined with two different irrigating solutions.For the present study twenty-two freshly extracted human roots were selected. All teeth had been extracted for periodontal purpose. Crown were cut off with a separating disk, so all roots were approximately 10-12 mm long.After having chosen the two control roots, the remaining ones were randomly divided into two groups each containing 10 roots. The two experimental groups were prepared as follows.A crown-down instrumentation technique was used, following TF((r)) manufacturer's instructions.Irrigation of Group A consisted of 2 ml of solution: 6% sodium hypochlorite (Chlor-Extra((r)), Vistadental Racine, Mi, USA) after each instrument followed at the end by a 17% EDTA minute (Smear Clear((r)), SybronEndo, Orange, Ca) irrigation for 1 min. Both irrigants contain tensioactive agents.Group B specimens were irrigated with 2 ml of sterile saline solutions after each instrument. Two control roots were not instrumented and irrigated. Teeth were then examined by scanning electron microscopy.Values obtained were tabulated and statistical analyses were carried out using a non parametric tests.RESULTS SHOWS SIGNIFICANT DIFFERENCES IN THE MEAN SCORE BETWEEN THE TWO GROUPS: most experimental group A canals showed clean or minimal debris in the observed areas, especially in the coronal and middle thirds. PMID- 22238719 TI - Self-ligating versus Invisalign: analysis of dento-alveolar effects. AB - AIM: The aim of this study was to evaluate the changes in the transverse dimension and the perimeter of the maxillary arch produced by low friction self ligating brackets TIME 3 compared to the Invisalign technique. MATERIALS AND METHODS: Both the self-ligating sample and the Invisalign group were composed of 20 subjects, evaluated at the beginning (T0) and at the completion of therapy (T1). All subjects presented a Class I malocclusion with mild crowding in a permanent dentition, without craniofacial anomalies, missing teeth or a history of orthodontic treatment. Dento-alveolar measurements were made on the maxillary dental casts at T0 and T1. Significant differences between the treated groups were assessed with Independent Samples t test (p<0.05). RESULTS: Statistically significant differences between self-ligating sample and Invisalign group were recorded for CWC, FPWF, FPWL, SPWF, SPWL, and AP measurements. No significant changes were found for CWL, MWF, MWL, and AD values. There was not a statistically significant difference between the treatment durations of the groups: 1.8 years for both patients. These data suggest that Invisalign treatment cannot be somewhat faster than fixed appliances. Moreover the final occlusion might not be as ideal. CONCLUSIONS: The low fiction self-ligating system produced statistically significant different outcomes in the transverse dento-alveolar width and the perimeter of the maxillary arch during treatment when compared to Invisalign tecnique. PMID- 22238720 TI - Excision of an oral angiolipoma by KTP laser: a case report. AB - MATERIALS AND METHODS: A 66 year old woman was referred to our observation, since the presence of a painless swelling located on the right cheek mucosa. A surgical approach with KTP laser was performed with the mucosal preservation technique. RESULTS: Follow up after seven days, sixty days and four months did not showed any complication and the histological examination reported the diagnosis of AL. DISCUSSION: AL is a relatively rare tumor of the head and neck region, although it occurs more commonly in the extremities and the trunk. This tumor has been rarely reported in the oral cavity and when seen in this area, it involves in the lip, cheek, tongue, mandible, and palate. ALs are also intraosseous in the mandible and intramuscular in the pterygoid fossa. KTP laser excision showed to be resolutive and avoid of complications. CONCLUSIONS: AL of the cheek is a very rare patology, but when it appears, it requires a surgical excision. PMID- 22238722 TI - Research in esthetic dentistry. PMID- 22238721 TI - Positive autoregulation of GDNF levels in the ventral tegmental area mediates long-lasting inhibition of excessive alcohol consumption. AB - Glial cell line-derived neurotrophic factor (GDNF) is an essential growth factor for the survival and maintenance of the midbrain dopaminergic (DA-ergic) neurons. Activation of the GDNF pathway in the ventral tegmental area (VTA), where the GDNF receptors are expressed, produces a long-lasting suppression of excessive alcohol consumption in rats. Previous studies conducted in the DA-ergic-like cells, SHSY5Y, revealed that GDNF positively regulates its own expression, leading to a long-lasting activation of the GDNF signaling pathway. Here we determined whether GDNF activates a positive autoregulatory feedback loop in vivo within the VTA, and if so, whether this mechanism underlies the long-lasting suppressive effects of the growth factor on excessive alcohol consumption. We found that a single infusion of recombinant GDNF (rGDNF; 10 MUg) into the VTA induces a long-lasting local increase in GDNF mRNA and protein levels, which depends upon de novo transcription and translation of the polypeptide. Importantly, we report that the GDNF-mediated positive autoregulatory feedback loop accounts for the long-lasting inhibitory actions of GDNF in the VTA on excessive alcohol consumption. Specifically, the long-lasting suppressive effects of a single rGDNF infusion into the VTA on excessive alcohol consumption were prevented when protein synthesis was inhibited, as well as when the upregulation of GDNF expression was prevented using short hairpin RNA to focally knock down GDNF mRNA in the VTA. Our results could have implications for the development of long-lasting treatments for disorders in which GDNF has a beneficial role, including drug addiction, chronic stress and Parkinson's disease. PMID- 22238723 TI - Rehabilitation of esthetics in advanced periodontal cases using orthodontics for vertical hard and soft tissue regeneration prior to implants - a report of 2 challenging cases treated with an interdisciplinary approach. AB - The esthetic rehabilitation of advanced periodontal cases remains a challenge, despite the numerous advances in treatment of periodontitis and regenerative therapies. Whilst understanding of periodontal diseases deepens with advances in cell biology, cell signaling, and genomic research, the restoration of the gingival tissues to anatomical norms remains a considerable challenge in advanced cases. The improvements in diagnosis and treatment of disease certainly enable successful management of disease and stabilization of the compromised and failing dentition. Nonetheless, effective "esthetic" rehabilitation of patients with advanced disease affecting teeth in the esthetic zone, where significant asymmetrical bone loss and tissue recession are present, still constitutes a significant dilemma. An interdisciplinary approach involving vertical augmentation of bone and soft tissues by means of orthodontic extrusion of severely compromised periodontally involved teeth to reconstitute esthetics, as well as ideal bone and soft tissue volume prior to immediate implant placement and restoration, may be a particularly useful treatment option in patients suffering advanced periodontal disease with asymmetrical bone and tissue loss in the esthetic zone. This paper discusses the concepts and illustrates its use in two complex and demanding cases. PMID- 22238724 TI - Teeth and posture. AB - Esthetics is a topic that has become much discussed both in medicine and in dentistry. However, it should be questioned how reliable and reproducible the guidelines and protocols for esthetic procedures really are. This article will describe in detail the interactions between the musculoskeletal and masticatory systems. Dentists are frequently misled by their false interpretation of existing reference lines, without recognizing the true problem. The close relationship between skeletal and dental problems and their impact on the masticatory and musculoskeletal systems will be explained in this paper. Esthetics and function - not only of the teeth - form an entity that needs to be viewed and treated as a whole. Many of these interactions are thought of as "alternative medicine" and are therefore hardly considered at all in conventional mainstream medicine. This holistic approach will be further explained and discussed with a patient case. PMID- 22238725 TI - Repeatability of color-measuring devices. AB - INTRODUCTION: The objective of this study was to evaluate the intra- and interdevice repeatability in different tooth regions using three color-measuring devices under clinical conditions. MATERIALS AND METHODS: Fifteen shade measurements (cervical, body, incisal) were recorded on 15 patients by one investigator using three color-measuring devices (VITA Easyshade compact, DeguDent Shadepilot, X-Rite ShadeVision). CIE Lab values were determined for all maxillary anterior teeth. Intraclass correlation coefficients (ICCs) were used to statistically analyze intra-and inter-device repeatability for different tooth regions. Color differences (DeltaE) between measurements were also computed to evaluate the clinical acceptability of repeatability values. The data were evaluated using analysis of variance and Bonferroni's adjustment to control for multiple testing. Differences were deemed significant when P < 0.016. RESULTS: The three color-measuring devices generally exhibited high repeatability of color coordinates for all tooth regions (ICC > 0.516-0.986, DeltaE < 3.03). In contrast, inter-device repeatability was lower for all tooth regions (ICC = 0.010 0.922, DeltaE = 4.06-16.04). CONCLUSIONS: High intra-device repeatability of color coordinates could be achieved for all tooth regions when the same color measuring device was used. However, because of low inter-device repeatability, results using different color-measuring devices are not comparable. PMID- 22238726 TI - Efficacy and persistence of tooth bleaching using a diode laser with three different treatment regimens. AB - STATEMENT OF PROBLEM: Studies have measured the effectiveness of tooth bleaching, however there are very few studies that have measured the persistence in color change after a 6-month follow-up. PURPOSE: This study assessed the efficacy of the laser bleaching process using different regimens, and the persistence of color change over a 6-month period. METHOD AND MATERIALS: Sixty patients divided into three equal groups were subjected to bleaching using a diode laser with 34% hydrogen peroxide. Group 1: patients subjected to one session of laser bleaching. Group 2: patients subjected to two sessions of laser bleaching with a 1-week interval. Group 3: the same as Group 2 but followed by home bleaching once a month for 3 months. The color was assessed four times: before bleaching, directly after bleaching, 3 months after bleaching, and 6 months after bleaching. RESULTS: All teeth had a significant color change at 6 months, but all teeth had regressed from the maximum value. There was significantly less regression in color for Group 3, followed by Groups 2 and 1, respectively. CONCLUSION: The combined technique of in-office laser bleaching for two sessions with a 1-week interval, followed by home bleaching once a month for 3 months gave more persistence in color change. CLINICAL SIGNIFICANCE: In-office power bleaching using a laser assisted hydrogen peroxide system repeated after a week, combined with home bleaching once a month for 3 months, is an effective bleaching regimen with less color regression after 6 months compared to a regimen of in-office bleaching alone. PMID- 22238727 TI - Preliminary clinical reports of a novel night-guard tooth bleaching technique modified by casein phosphopeptide-amorphous calcium phosphate (CCP-ACP). AB - Although supervised night-guard bleaching has proved successful for whitening teeth, both mineral loss and tooth sensitivity are still common problems. The present study introduces a novel remineralizer as well as describes the utilization of a possibly low sensitivity supervised night-guard vital tooth bleaching technique. A 22% carbamide peroxide gel was mixed with the casein phosphopeptide-amorphous calcium phosphate-containing MI Paste. The peroxide/MI Paste mixture was prepared with 1 ml of each material until obtaining a homogeneous paste. Five patients were instructed to follow a home bleaching protocol for 3 weeks. The outcome was assessed visually with a Vitapan scale. All subjects presented reduction of at least two Vitapan scale units after bleaching and no sensitivity was reported. The concomitant use of MI Paste and peroxide might not affect the gel effectiveness and still reduce hypersensitivity levels. PMID- 22238728 TI - Influence of chemical or physical catalysts on high concentration bleaching agents. AB - OBJECTIVES: The aim of this in vitro study was to evaluate the bleaching efficacy of high concentration bleaching agents activated by chemical or physical catalysts. MATERIALS AND METHODS: This study was divided into two parts. Part 1 evaluated the efficacy of tooth whitening after treatment with 35% hydrogen peroxide (Whiteness HP Maxx) that was activated by different light-curing units: halogen lamp (conventional and bleach mode) (Optilux 501C, Demetron/Kerr), LED first generation (Ultrablue IV, DMC), LED/diode laser (Ultrablue IV, DMC), LED second generation (Bluephase 16i, Ivoclar Vivadent), and no light source (control group). Part 2 provided an analysis of the effect of chemical and physical catalysts on high concentration bleaching agents: 35% hydrogen peroxide (Whiteness HP Maxx) + 20% sodium hydroxide; 35% hydrogen peroxide + 7% sodium bicarbonate; 38% hydrogen peroxide (Opalescence Xtra Boost); 35% hydrogen peroxide + halogen lamp; 35% hydrogen peroxide + 20% sodium hydroxide + halogen lamp; 35% hydrogen peroxide + 7% sodium bicarbonate + halogen lamp; 38% hydrogen peroxide + halogen lamp; and 35% hydrogen peroxide. Blocks obtained from human molars were randomly divided into groups (n = 5) in accordance with bleaching treatments. The efficacy of bleaching was measured using a spectrophotometer. Three bleaching sessions were performed. The results were submitted to ANOVA followed by the Tukey test (5%). RESULTS: For both parts of the study, activated vs. non-activated bleaching did not differ significantly for all sessions tested. CONCLUSION: Activating systems did not improve the whitening effectiveness of high concentration bleaching agents. PMID- 22238729 TI - Paediatricians' views on dental and oral health and treatment needs in children. AB - PURPOSE: To assess paediatricians' knowledge, attitude and awareness towards dental and oral health and treatment needs of their patients. MATERIALS AND METHODS: Eighty-four paediatricians practicing in four cities of North Karnataka, India, were randomly selected for the study and were requested to fill out an objective questionnaire without providing any oral health information. RESULTS: The present study shows that paediatricians who were surveyed had poor knowledge regarding dental and oral health and treatment needs in children. CONCLUSION: Paediatricians need to update themselves on recent recommendations regarding dental and oral health so as to ensure that all their patients receive timely preventive and restorative dental care. PMID- 22238730 TI - Tooth mortality and prosthetic treatment needs among the urban and rural adult population of Dharwad district, India. AB - PURPOSE: To assess the tooth mortality and prosthetic treatment needs among the urban and rural adult population of Dharwad district. MATERIALS AND METHODS: A total of 1223 subjects (685 urban and 538 rural) were selected using multi-stage cluster random sampling. A form was prepared and data were collected on sociodemographic factors, tooth mortality and its causes and prosthetic treatment needs by the interview method and clinical examination. RESULTS: The rural population compared to urban, increased age and females compared to males had higher tooth mortality rates, which was demonstrated by the multiple logistic regression model. Dental caries and periodontal diseases were the two reasons for increased tooth mortality in the population studied. A proportion of 50.01% of the population required some form of prosthetic treatment. CONCLUSION: Age, gender and location were positive predictors of tooth mortality. Greater prosthetic treatment needs were observed among the rural population. PMID- 22238731 TI - Anxiety and fear of dental treatment among users of public health services. AB - PURPOSE: The aim of the present investigation was to determine the degree of anxiety and fear in patients treated at the dental school clinics of the Universidade Federal de Pernambuco (Brazil) regarding the different types of treatment offered. MATERIALS AND METHODS: The sample was made up of 400 patients from both genders over 18 years of age treated between July and October 2007. Data collection was carried out through the administration of validated questionnaires by a calibrated researcher. The Modified Dental Anxiety Scale (MDAS) and Gatchel's Scale were used to evaluate the degree of anxiety and fear among the patients. RESULTS: There was a 23.0% prevalence of dental anxiety; 9.5% were very anxious, 13.5% were anxious and 77.0% were not anxious. Women were more anxious than men (20.7% and 11.3%, respectively, P = 0.995). The age group that exhibited the highest prevalence of anxiety was 30 to 39 years (29.3%). Regarding fear, 13.5% felt extreme fear; 30.5% felt moderate fear and 56% felt no fear. Schooling was the only significant socioeconomic factor for both anxiety and fear. In the association between fear and anxiety, 38.9% of the patients with extreme fear were classified as very anxious. CONCLUSION: The majority of individuals were classified as non-anxious and without fear regarding dental procedures. PMID- 22238732 TI - Assessment of aesthetic perception of mild and moderate dental fluorosis levels among students from the Federal University of Minas Gerais-UFMG, Brazil. AB - PURPOSE: To verify the aesthetic impact of mild and moderate dental fluorosis on young adult students from the UFMG using pictures with different fluorosis levels simulated in a computer program. MATERIALS AND METHODS: The sample consisted of 396 university students, randomly selected from various courses (except dentistry). These participants were shown three mouth pictures with different rates of dental fluorosis (TFO, TF2 and TF4) according to the Thylstrup-Fejerskov Index (TF). The volunteers gave an individual assessment of the pictures and graded them (from 1 to 10) based on their aesthetics. In addition, they answered if they would feel uncomfortable smiling and if they would seek dental treatment in each case. The results were submitted to a chi-square test (P < 0.05). RESULTS: The students preferred the TF4 picture to the TF2. The picture which presented no fluorosis was more often preferred than the pictures which presented some form of change due to fluorosis. Higher scores were recorded by men for the TF2 picture than by women (P < 0.05). As for the TF0 and TF4 pictures, the scores were similar among males and females. Furthermore, women reported more discomfort in smiling (P = 0.001) and a greater desire to seek out dental treatment than did men. Only 27.5% of all students stated that they knew what dental fluorosis was. CONCLUSION: Mild and moderate dental fluorosis had a negative aesthetic effect on the studied population, leading to a strong desire to seek dental treatment to change the appearance of affected teeth. PMID- 22238733 TI - Self-reported knowledge and practice of American Heart Association 2007 guidelines for prevention of infective endocarditis: a survey among dentists in Hyperabad City, India. AB - PURPOSE: To evaluate the knowledge and practice of the American Heart Association (AHA) 2007 guidelines among dentists in Hyderabad city, India, for the prevention of infective endocarditis (IE). MATERIALS AND METHODS: A survey questionnaire was mailed to the dentists to assess their knowledge with regard to the antibiotic prophylaxis needed for specific cardiac conditions and the prophylaxis reasonable before various dental procedures in high-risk patients and the first-line and second-line antibiotic regimen prescribed. RESULTS: Of the 190 registered dentists, 169 (88.94%) completed the questionnaire. The mean age of the population was 39.17 +/- 8.23 years. The majority of the respondents correctly identified that having prosthetic cardiac valves, a previous history of IE illness and cardiac transplantation with subsequent cardiac valvulopathy are cardiac conditions requiring antibiotic prophylaxis. Prescription of first-line antibiotic drugs and second-line drug regimens corresponding to the current guidelines was correctly answered by only 56.21% dentists and 60.95% dentists, respectively. CONCLUSION: A relatively low level of knowledge of the new guidelines was reported among dentists, reflecting the need for more continuing dental education programmes. PMID- 22238734 TI - Mechanisms and treatment approaches of dentine hypersensitivity: a literature review. AB - PURPOSE: To review major mechanisms of dentine hypersensitivity and the treatment approaches offered. MATERIALS AND METHODS: Medline was used to find relevant literature published up to December 2006. Based on abstracts and full articles, studies (in human and in animals) were identified describing mechanisms and management of dentine hypersensitivity. Additional information was also obtained by using manual library search for relevant topics in standard texts and journals of dentistry. RESULTS: Discussion about the sensitivity of dentine started over a century ago, but it was not until sixty years later that a possible theory was posited. The so-called hydrodynamic theory became popular and was applied to understand the mechanism responsible for hypersensitive dentine. Nevertheless, because of the discrepancies in the pattern by which the dentine responds to various stimuli, several theories of dentine hypersensitivity were proposed which include the hydrodynamic theory, odontoblast transducer mechanism and direct innervation theory. None of these mechanisms was said to fully explain dentine hypersensitivity, thus indicating that as-yet unexplained mechanisms were possibly responsible. A multitude of products were tried and reported to be effective. The efficacy of many was not clearly established and their mechanisms of action were inadequately elucidated. The potential of gene therapy to reduce the burden of dentine hypersensitivity in the future is being examined. CONCLUSIONS: Considerable effort has been made to precisely explain dentine hypersensitivity, but doubt still exists whether any one theory can be applied to understanding this condition. This has led to a constant increase in therapeutic approaches worldwide, but with no conclusive evidence of reliable, successful treatment regimens. PMID- 22238735 TI - White enamel lesions and their progression from childhood to adolescence: a prospective study. AB - PURPOSE: To assess the current situation of white enamel lesions on vestibular surfaces of permanent maxillary incisors, diagnosed 6 years ago, without clinical intervention. MATERIALS AND METHODS: The prospective study reassessed 53 students of both sexes, aged between 13 and 18 years old, all attending the public school system in Natal, Brazil. Data collection was performed by calibrated examiners, and a clinical chart consisting of demographic data on dental caries, oral hygiene and gingival condition was prepared. A tactile-visual examination was conducted using a clinical mirror and periodontal probe. Data compilation and analysis were carried out using SPSS software. In this analysis, the chi-square test was used for qualitative independent variables. To identify the net effect of treatment, multiple logistic analysis with forward stepwise model selection was performed. RESULTS: The final sample was composed of 106 lesions in the 53 individuals, with mean age of 15.02 years, visible plaque index (VPI) of 23.34%, and gingival blood indices (GBI) of 25.92%. A statistically significant relationship (P = 0.003) was found between initial DMFS and the prognosis of white enamel lesions. CONCLUSION: It was observed that past caries experience and dental plaque were the main predictive factors for negative lesion outcomes, demonstrating the need for oral hygiene control through continuing preventive measures. PMID- 22238736 TI - Dental caries experience in preschool children: is it related to a child's place of residence and family income? AB - PURPOSE: To assess the caries prevalence in 3- to 5-year-old children and determine whether urbanisation and income are associated with the dental decay status of these preschool children residing in the district of Lahore, Pakistan. MATERIALS AND METHODS: Multistage random sampling was done to collect the sample of children from urban and rural areas. A list of children 3 to 5 years of age was prepared, and every 2nd child on the list was randomly selected until a total of 700 children were enrolled in the study. Lady Health Workers (LHWs) were trained to conduct this survey after permission from the pertinent authorities. The data of the children and their mothers regarding their age, gender, socioeconomic status (SES) and area of residence were collected. The caries status of children was recorded using the dmft index as per WHO criteria. RESULTS: The prevalence of dental caries in preschool children of Lahore was found to be 40.5%. Within this group, caries prevalence was 33.3% in 3-year-old children, 47.6% in 4-year-old children and 75% in the 5-year-old children. The mean dmft score for the entire child population was 1.85 +/- 3.26. A significant association was found between caries prevalence, low socioeconomic status, female gender and rural residence. CONCLUSION: Preschool children in Lahore, Pakistan have average dmft scores of 1.85 (+/- 3.26), which are mostly related to untreated carious lesions. Lower caries experience was found to be associated with rural residence and low family income. PMID- 22238737 TI - Evaluation of a school-based pit and fissure sealant programme in Iranian children. AB - PURPOSE: This study evaluated sealants placed on permanent molars in first-grade students in Shiraz primary schools during 2008 under a school oral health programme. MATERIALS AND METHODS: A total of 420 sealed first permanent molar teeth in 179 students (mean age 8 years, 6 months) were evaluated for fissure sealant retention, occlusal caries status and Feigal criteria. All teeth were examined 1.5 years after application. The fissure sealants (Conceal F, SDI) were placed on occlusal surfaces after traditional acid etching. Statistical analysis was done with the chi-square test (P < 0.05). RESULTS: 57.5% of the seals were completely retained, 29.6% partially lost and 12.9% completely lost. There were no signs of carious lesions in 77.1% of the teeth. According to the Feigal criteria, success rates based on marginal integrity, marginal discolouration and anatomical form were 98.2%, 95.5% and 58.6%, respectively. The overall success rate with all three criteria was 54.14%. There were no significant relationships between the results and patient gender or tooth position in the arch. CONCLUSION: Although fissure sealants are an effective method for preventing tooth caries, the results of this study indicate that public oral health programmes need to be implemented more carefully and that follow-up programmes are advisable. PMID- 22238738 TI - Assessment of antibacterial efficacy of triphala against mutans streptococci: a randomised control trial. AB - PURPOSE: Triphala is an ayurvedic preparation with known antimicrobial action. This study was carried out to assess the antibacterial efficacy of triphala against salivary mutans streptococci in comparison with the 'gold standard' chlorhexidine. MATERIALS AND METHODS: A double blind randomised control trial was conducted among 57 volunteers who were assessed to be in the high caries risk category. They were randomly allocated into three study groups: 1) 15 ml of 6% triphala mouthwash; 2) 15 ml of 0.2% chlorhexidine (active control); 3) no mouthwash (passive control). Mouthwashes were given twice a day for 15 days. Unstimulated saliva samples were collected at baseline and at 15 and 45 days. Mutans streptococci (MS) were cultured on MSB agar and colony counts obtained. The alpha error was fixed at 5%. ANOVA and post-hoc LSD tests were performed using SPSS version 14. RESULTS: After using mouthwash for 15 days, an 83% and 80% reduction and at 45 days a 67% and 65% reduction in salivary MS colony count was observed in the triphala and chlorhexidine groups, respectively (P = 0.0001). The control group showed an increase of 3% in MS colony count at 15 days and a reduction of 7% at 45 days. (P = 0.116). CONCLUSION: The antimicrobial action of triphala against mutans streptococci closely parallels that of chlorhexidine. It does not have the side effects commonly associated with chlorhexidine and is cost effective. PMID- 22238739 TI - The effect of dental restoration type and material on periodontal health. AB - PURPOSE: To investigate the relationship between the type and material of dental restorations and periodontal health in a sample of Jordanians. MATERIALS AND METHODS: Patients attending the Dental Teaching Clinics of Jordan University of Science and Technology with restored teeth were examined. For every patient, the plaque index, gingival index, probing depth and clinical attachment level were recorded on restored and non-restored tooth surfaces. The restoration types were Classes II, III and V, in addition to crowns and bridge abutments. The restorative materials included amalgam, tooth-coloured materials (resin composite and glass ionomer), non-precious alloys, porcelain and acrylic. RESULTS: Class III restorations were associated with the lowest plaque index (0.62), gingival index (1.13), probing depth (1.62 mm) and clinical attachment level (0.31 mm). Class II restorations had the highest plaque index (0.99) and probing depth values (2.27 mm). Crowns and bridge abutments had the highest gingival index (1.65 and 1.61, respectively), high probing depth (2.01 and 2.15 mm), but a low plaque index (0.69 and 0.66). Class V restorations demonstrated the highest attachment loss (0.92 mm). Resin composite and glass ionomer restorative materials demonstrated the lowest gingival index (1.21) and probing depth (1.75 mm), whereas porcelain demonstrated the lowest plaque index (0.51) and clinical attachment level (0.14 mm). Amalgam was associated with the highest plaque index (1.01) and probing depth (2.29 mm). Non-precious alloys and acrylic covered castings demonstrated the highest gingival index (1.73 and 1.72, respectively) and clinical attachment level (1.00 and 0.88 mm). CONCLUSIONS: Crowns, bridge abutments (especially acrylic and non-precious metals) and Class II amalgam restorations appear to be associated with periodontal breakdown. PMID- 22238740 TI - Child oral health-related quality of life and socioeconomic factors associated with traumatic dental injuries in schoolchildren. AB - PURPOSE: To assess the relationship of child oral health-related quality of life and socioeconomic backgrounds to traumatic dental injuries in schoolchildren. MATERIALS AND METHODS: This study followed a cross-sectional design, with a multistage random sample of 792 12-year-old schoolchildren, representative of Santa Maria, a city in southern Brazil. The participants completed the Brazilian version of the Child Perceptions Questionnaire (CPQ11-14), their parents or guardians answered questions on socioeconomic status, and a dental examination provided information on the prevalence of dental trauma. The assessment of association used Poisson regression models. RESULTS: The prevalence of TDI was 9.7%. The maxillary central incisors were the most frequently traumatised, and the most commonly observed traumatic dental injury was enamel fracture. No association was observed among child oral health-related quality of life and socioeconomic factors with traumatic dental injuries after the adjustment. CONCLUSION: Socioeconomic indicators are not associated with dental trauma in schoolchildren and this oral health condition has no negative impacts on children's quality of life. PMID- 22238741 TI - Role of calcium and potassium channels in effects of hydrogen sulfide on frog myocardial contractility. AB - The effects of sodium hydrosulfide NaHS, a donor of hydrogen sulfide H2S, on the force of muscle contraction were examined on isolated myocardial strips from frog ventricles. NaHS decreased the amplitude of muscle contractions in a dose dependent manner under normal conditions and during inhibition of Ca channels with nifedipine. In contrast, under conditions of blockade of ATP-dependent potassium channels with glibenclamide, NaHS exerted a positive inotropic effect from the first minute of application. Neither blockade, nor activation of ATP dependent K-channels with glibenclamide modulated the negative inotropic effect of NaHS. Inhibition of K-channels with tetraethylammonium (TEA) (3, 5, 10 mM) or 4-aminopyridine increased the amplitude of myocardial contractions. Preliminary application of 4-aminopyridine or TEA (3 mM) did not eliminate NaHS-induced negative inotropic effect, although higher TEA concentrations (5 or 10 mM) prevented it. The data indicate that the targets of H(2)S in frog myocardium are ATP-dependent, Ca-activated, and voltage-dependent K-channels. PMID- 22238742 TI - Induction of caspase cascade as a nonspecific response to myocardial damage. AB - In three experimental series, acute hemodynamic overload of the left ventricle, focal ischemia of the left ventricle, and diphtheritic intoxication were modeled in rabbits. On days 1, 3, and 5 of the experiments, activity of myocardial caspase-3 and caspase-8 were measured separately in the left and right ventricles. In the left ventricle, caspase-3 activity increased in all 3 modeled pathological processes, while in the right ventricle this parameter increased during acute overload and ischemic injury to the left ventricle. Caspase-8 activity increased only in the left ventricle during its hemodynamic overload and remained unchanged in other cases. It was concluded that induction of the caspase cascade can be considered as a nonspecific response to myocardial damage. In this case, specific mechanisms responsible for generation and transmission of apoptotic stimuli in cardiomyocytes have unique features. PMID- 22238743 TI - Monoaminergic regulation of hemopoiesis under extreme conditions. AB - The role of the adrenergic, dopaminergic, and serotoninergic systems in the regulation of hemopoiesis was evaluated on various models of pathological processes (restraint stress, experimental neurosis, and cytostatic treatment). The proliferation, differentiation, and maturation of polypotent, multipotent, partially determined, and oligopotent hemopoietic precursors and functional activity of microenvironmental cells (stromal cells, macrophages, and Thy1,2(+) cells) were shown to be under the control of a complex system of monoaminergic regulation. Central monoamines have a direct or indirect (mediated by microenvironmental cells) regulatory effect on hemopoietic precursors of various classes, which is realized via specific receptors. The system of colony stimulating factors is characterized by selective sensitivity to catecholamines. It should be emphasized that the effects of erythropoietin are mainly associated with serotonin. Irrespective of experimental conditions (hyperplasia of hemopoiesis, myelosuppression, and dysregulation of precursor cell proliferation and differentiation), the erythroid hemopoietic stem is more sensitive to serotoninergic influences. Granulocytopoiesis was revealed to be more sensitive to central catecholamines. PMID- 22238744 TI - Effects of preconditioning on the resistance to acute hypobaric hypoxia and their correction with selective antagonists of nicotinic receptors. AB - Hypobaric hypoxic preconditioning increased the resistance of low resistant and highly resistant rats to acute hypobaric hypoxia at a critical height. Intergroup differences in the resistance of rats to acute hypobaric hypoxia were not observed after hypobaric hypoxia and one variational series with a wide range of resistance (4.5-24.5 min) appeared. Methyllycaconitine, an antagonist of subtype alpha(7) nicotinic cholinergic receptors, abolished the influence of hypobaric hypoxia on low resistant rats, but had no effect on highly resistant animals. Mecamylamine, a preferential antagonist of subtype alpha(4)beta(2) and alpha(3) containing cholinergic receptors, did not modulate the effect of hypobaric hypoxia. By contrast, hypobaric hypoxia abolished the effect of mecamylamine on the resistance of rats that were not trained under conditions of hypobaric hypoxia (low resistant and highly resistant animals with low sensitivity to hypobaric hypoxia). We conclude that the same effect of hypobaric hypoxia is mediated by various mechanisms, which involve different nicotinic cholinergic receptors. They differ from the resistance mechanisms in non-trained rats. PMID- 22238745 TI - Correction of endothelial dysfunction in patients with arterial hypertension. AB - We examined 38 patients (mean age 55.92 +/- 1.56 years) with a 3-5-year history of arterial hypertension. The study showed that hypertension is accompanied by endothelial dysfunction and one of its forming factors is activation of the inflammatory response. Highly sensitive diagnostic tests can verify initiation of inflammation in preclinical manifestations. The use of nonsteroidal anti inflammatory drugs, irrespective of the tropism to cyclooxygenase forms, alleviates manifestations of endothelial dysfunction in patients with arterial hypertension. PMID- 22238746 TI - Hemodynamic changes induced by preventive exposure to terahertz radiation at a frequency range corresponding to molecular emission and absorption spectrum of nitric oxide in animals under conditions of acute stress. AB - We studied the influence of preventive irradiation with terahertz electromagnetic waves at frequencies corresponding to nitric oxide emission and absorption molecular spectrum (150,176-150,664 GHz) on hemodynamic parameters in arteries of albino rats upon acute immobilization stress. We showed that exposure to the specified frequencies can produce adaptogenic effect manifesting in the absence of post-stress changes in the linear, systolic, and diastolic blood flow velocities and pressure gradient in various blood vessels of experimental animals. PMID- 22238747 TI - Study of anti-inflammatory action of aurothiomalate, an inhibitor of NF-kappaB. AB - We compared the effects of NF-kappaB inhibitor aurothiomalate and voltaren on NO production by mouse macrophages in vitro, their ability to cause local edema at the site of injection, and their effect on carrageenan-induced inflammation. High concentrations of aurothiomalate reduced NO production, while in low concentrations both aurothiomalate and voltaren stimulated this process. When injected into mouse footpad, aurothiomalate in a dose >1 mM and voltaren in a dose >1.6 MUM induce paw edema. Both compounds suppressed carrageenan-induced inflammation, but the efficacy of aurothiomalate 2-fold exceeded that of voltaren. PMID- 22238748 TI - Effects of drugs of plant origin on the development of the immune response. AB - The effects of extracts from licorice (Glycyrrhisa glabra), great nettle (Urtica dioica), common burdock (Arctium lappa), and bur marigold (Bidens tripartite) on the humoral and cellular immune response and nonspecific resistance in mice were studied. Burdock and bur marigold extracts stimulated the humoral immune response, nettle and licorice extracts stimulated cellular response and nonspecific resistance, their effects being superior to those of pharmacopoeial Echinacea purpurea tincture. PMID- 22238749 TI - Count of splenic stromal precursor cells in mice and expression of cytokine genes in these cells in primary cultures during different periods after immunization of animals with S. typhimurium antigens. AB - Injection of S. typhimurium antigens significantly (9-fold) increased cloning efficiency and, hence, the content of stromal precursor cells in the spleen as soon as after 24 h. These parameters returned to normal by days 6-15 after immunization. Cultured splenocytes collected from immune (but not intact) animals expressed the genes of proinflammatory cytokines IL-1beta (on days 1, 6, 15) and IL-6 (on days 1 and 6), TNF-alpha (on days 6 and 15), and of IFN-alpha and IL-18 (on days 6 and 15). The expression of IL-4 gene was suppressed on day 6 after immunization, of IL-10 gene on days 1 and 6, of IL-6 gene on day 15. Hence, no signs of immune response suppression by stromal cells were found in this system. The spectrum and dynamics of the expression of pro- and anti-inflammatory cytokine genes in stromal cell cultures from the spleen of immunized mice seemed to correspond to those needed for support of the immune response to S. typhimurium antigens, observed in immunized animals. The results indicate possible involvement of stromal cells in the realization of immune response in vivo. The increase of stromal precursor cells cloning efficiency in response to antigen injection could not be reproduced in vitro: the presence of S. typhimurium antigens in primary cultures of intact mouse bone marrow and spleen throughout the entire period of culturing ~ 20-fold reduced cloning efficiency in cultures. PMID- 22238750 TI - Experimental study of the effects of permafrost microorganisms on the morphofunctional activity of the immune system. AB - The immunobiological potential of a new microorganism species isolated from permafrost specimens (PMO strain 3M) collected from the Mammoth Mountain in Yakutia was studied in laboratory mice. PMO injected intraperitoneally in doses of 2500 to 50 * 10(6) microbial bodies caused characteristic dose-dependent effects on the structure and functions of the immune system (thymus and spleen indexes, functional activity of splenic macrophages, cellular and humoral immunity). Doses of PMO stimulating functional activities of both cellular and humoral immunity were detected. PMID- 22238751 TI - Contribution of dehydroepiandrosterone sulfate and progesterone to in vitro regulation of tolerogenic activity of IFN-alpha-induced dendritic cells. AB - Dehydroepiandrosterone sulfate and progesterone exhibited an immunomodulatory effect on the tolerogenic characteristics of IFN-alpha-induced dendritic cells. The hormone effects depended on the initial level of allostimulatory activity of dendritic cells in mixed lymphocyte culture. However, dehydroepiandrosterone sulfate significantly more often stimulated allostimulatory activity by attenuating the tolerogenic properties of dendritic cells, while progesterone potentiated their tolerogenic potential. The capacity of the hormones (dehydroepiandrosterone sulfate and progesterone) to attenuate tolerogenic activity of dendritic cells was associated with reduction of FasL expression on these cells, while the increase in tolerogenic activity was associated with the increase in the percentage of CD123(+) dendritic cells, and under conditions of modification with dehydroepiandrosterone sulfate it was associated with increased B7-H1 expression. Possible contribution of indolamine-2,3-dioxygenase and prostaglandin E2 to stimulation of tolerogenic characteristics of dendritic cells modified with dehydroepiandrosterone sulfate and progesterone, respectively, was demonstrated. PMID- 22238752 TI - Age-associated reduction of the count and functional activity of stromal precursor cells can be caused by both true reduction (exhaustion) of cell pool and regulatory effects of the organism. AB - The study was carried out on CBA mice using the method of heterotopic transplantation. A fragment of the femoral bone marrow (1/2) or spleen (1/5 of the organ) was transplanted under the renal capsule of a recipient. The following donor-recipient cross-transplantation variants were studied: young-young (Y-Y), young-old (Y-O), old-old (O-O), and old-young (O-Y). Cell suspensions were prepared from 2-month transplants inoculated in monolayer cultures and the cloning efficiency (ECF-F) of stromal precursor cells (CFC-F) was evaluated. The bone marrow transplant ECF-F and the count of CFC-F in the O-O group were 8-fold lower than in the Y-Y group. In the O-Y group, ECF-F was 3-fold higher than in the O-O group, but by 2.5 times lower than in the Y-Y group. ECF-F in Y-O group was 2-fold lower than in Y-Y group. The ECF-F and CFC-F count in spleen transplants in the O-O group were 4- and 6-fold lower, respectively, than in Y-Y group. However, in O-Y group ECF-F was 7-fold higher than in O-O group and higher than even in Y-Y group. The weight of induced ectopic bone tissue after transplantation of the osteoinductor (fragments of the allogenic urinary bladder mucosa) was 2-fold lower in the O-O vs. Y-Y group. However, comparison of the ectopic bone tissue weights in different experimental groups showed that osteoinductor activity of the bladder epithelium did not decrease, but increased 3-fold with age (O-Y:Y-Y). A 5-fold reduction of this proportion in groups where the osteoinductor was transplanted from old donors to old and young recipients (O Y:O-O) could be attributed to age-specific reduction of the count of inducible osteogenic precursor cells (IOPC). The data in general suggest that age-specific reduction of the stromal precursor count and functional activity could be caused by the true reduction (exhaustion) of cell pool (bone marrow CFC-F; presumably, IOPC) and by the regulatory effects of the organism (bone marrow and splenic CFC F, IOPC). These data seem to be significant for understanding of the role of osteogenic stromal precursor cells in the development of age-associated bone tissue defects, for example, senile osteoporosis. PMID- 22238754 TI - Age-specific features of estrous cycles and folliculogenesis in GC female rats selected by catatonic reactivity. AB - A decrease in the total count of follicles in the diestrus and proestrus and higher incidence of permanent estruses were found in 3-month-old females of the catatonic GC rat strain in comparison with Wistar females (control). At the age of 6-12 months, GC females had lower incidence of long estrus and diestrus. The estrous cycle of GC females was shorter than of Wistar rats. With aging (at the age of 18 months), the counts of growing and maturing follicles significantly decreased. Higher counts of growing single-layer and bilayer follicles were found in 18-month-old GC females. Differences in the length of estrus and diestrus and in the incidence of abnormal phases in the two strains also disappeared at this age. Selection by high catatonic reactivity was associated with a decrease in body weight. PMID- 22238753 TI - Expression of thrombospondin-1 gene mRNA and protein in the placenta in gestosis. AB - The expression of TSP-1 gene mRNA and TSP-1 protein in the placental tissue was studied during normal pregnancy and in gestosis. The formation of placental tissue in normal gestation was associated with expression of TSP-1 gene mRNA and of TSP-1 protein. Gestosis was associated with inflammatory reaction in the placenta characterized by increased counts of lymphocytes and macrophages in the villous stroma and involution degenerative changes in tissue. Disorders in placental villi maturation and branching in gestosis were paralleled by hyperexpression of TSP-1 gene mRNA by placental cells and hyperexpression of TSP 1 protein predominating in the stromal elements of terminal villi and near villous vessels. PMID- 22238755 TI - Association of cold receptor TRPM8 gene polymorphism with blood lipid indices and anthropometric parameters in Shorians. AB - We analyzed single nucleotide polymorphisms of the cold receptor TRPM8 gene as genetic markers of blood serum lipid indices in Shorians. Associations were found between rs11562975 (L250L) TRPM8 gene mononucleotide polymorphism with total cholesterol and LDL cholesterol and between rs28901637 (P249P) and HDL cholesterol. No associations of P249P and L250L with triglyceride level were found. L250L polymorphism was associated with anthropometric parameters characterizing lipid metabolism (hip and waist circumferences). The TRPM8 gene is likely to be involved in the regulation of lipid metabolism. PMID- 22238756 TI - Expression of circadian Per1 and Per2 genes in the liver and breast tumor tissues of HER2/neu transgenic mice of different age. AB - The expression of Per1, Per2, and Cry1 circadian genes in the liver and breast tumors were studied by real-time PCR in FVB/N mice of different age transfected with HER-2/neu gene. The expression of Per1 and Per2 genes in breast tumor tissue decreased in comparison with their expression in the lever. The expression of these genes decreased with age in both the liver and tumor tissue. PMID- 22238757 TI - Ultrastructural characteristics of solid pseudopapillary tumors of the pancreas. AB - We carried out an electron microscopic study of solid pseudopapillary tumors of the pancreas (operation material) from 15 patients. Two cell types were distinguished. Type 1 cells had large oval nuclei, little changed mitochondria, and short fragments of the granular cytoplasmic reticulum. These cells formed mainly pseudopapillary structures around the vessels. Type 2 cells were characterized by pronounced nuclear polymorphism with specific "coffee bean" picture. The cytoplasm of these cells contained many large mitochondria with clarified matrix and often destroyed cristae; lipofuchsin granules were seen. The ultrastructural characteristics of the solid pseudopapillary tumor cells attest to their epithelial origin. PMID- 22238758 TI - Detection of minor subpopulations of colorectal adenocarcinoma cells expressing cancer stem cell markers. AB - The expression of puitative surface molecular markers of cancer stem cells on human colorectal adenocarcinoma cells was analyzed by flow cytofluorometry. Cell subpopulations expressing markers of epithelial and malignant cells and stem cell markers were identified. Four minor subpopulations with CD24(+)/CD133(+), CD44(+)/CD133(+), CD90(+)/CD71(+), or CD90(+)/CD24(+) phenotypes meeting this requirement were detected; presumably, those were cancer stem cell subpopulations. These results extend our knowledge on heterogeneity of human colorectal adenocarcinoma cell population and outline new trends of research of cancer stem cell phenotype in these tumors. PMID- 22238759 TI - Peptidergic regulation of thymocyte differentiation, proliferation, and apoptosis during aging of the thymus. AB - The effects of T-31, AB-17, and AB-9 peptides on old (passage 8) thymocyte culture were studied. Only AB-9 peptide exhibited a complex geroprotective effect on thymocytes during their aging. Peptide AB-9 stimulated proliferative activity and differentiation of thymocytes and inhibited their apoptosis. PMID- 22238760 TI - Hemostimulating effects of erythropoietin immobilized by the nanotechnology method of electron-beam synthesis. AB - The hemostimulating effect of erythropoietin immobilized by the nanotechnology method of electron-beam synthesis was studied on the model of carboplatin-induced myelosuppression. Subcutaneous injection or oral administration of immobilized erythropoietin was followed by stimulation of erythropoiesis. The effect was most pronounced after parenteral treatment with this agent. The increase in proliferative activity and maturation of erythroid precursor cells serve as a factor determining acceleration of reparative processes in the hemopoietic tissue. PMID- 22238761 TI - Morphology of endocrine organs in chronic endogenous intoxication. AB - Experimental study of the effects of endogenous toxic compounds on endocrine organs showed that the pathomorphological changes were caused by the cytopathic effects of endogenous toxic compounds involving the development of stereotypical reactions to injury. The severity of these reactions depended on the initial functional status of the gland and its involvement in systemic mechanisms of adaptation to the toxic process. PMID- 22238762 TI - Morphofunctional state of the adrenal glands in albino rats under conditions of toxic stress caused by cadmium salt in winter and summer periods. AB - We studied the morphology and function of the adrenal glands in male and female albino rats in cadmium intoxication during winter and summer periods (January and July). In animals of the control group, sex-related differences in the total area of the adrenal glands and in the size of their zones were revealed. In females, zones of adrenal gland were larger than in males. In winter months, these differences were most pronounced. Analysis of seasonal differences in the area of the adrenal glands in males revealed no significant differences in winter and summer months. Irrespective of the season and gender, cadmium chloride treatment led to an increase in the size of the adrenal glands. Cadmium salts caused more pronounced functional strain in males in winter months and in females in summer. PMID- 22238763 TI - Vascular endothelial growth factor and its receptors in the placenta of pregnant women with obesity. AB - Comparative morphological study of placentas from women with obesity and normal body weight was performed. Expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1, VEGFR-2, VEGFR-3) was detected by immunohistochemical methods. Nonbranching angiogenesis predominated in the placentas from obese women. Immunohistochemical analysis showed reduced intensity of the reaction to VEGF in the syncytiotrophoblast and vascular endothelium of stem villi and enhanced VEGF expression in non-villous cytotrophoblast and endothelial cells of capillaries of mature intermediate and terminal villi; reduced expression of VEGFR-1 and increased levels of VEGFR-2 and VEGFR-3 in the studied structures were also noted. PMID- 22238764 TI - Morphological characteristics of the central compartment of the erythron in aggressive and indolent non-Hodgkin's lymphomas. AB - Structural changes in cells of the central compartment of the erythron depended on tumor infiltration of the bone marrow. Cytostatic therapy was shown to improve quantitative indexes, but had no effect on morphological characteristics of the erythron. Examination of trepanobiopsy specimens from the iliac crest during chemotherapy revealed the existence of specific relationships between the erythron, other cells and tissues of the bone marrow, and tumor. Significant changes in the erythron were found during diffuse tumor infiltration and treatment with anthracycline antibiotics. PMID- 22238765 TI - Effect of epithermal neutrons on viability of glioblastoma tumor cells in vitro. AB - We studied in vitro effect of epithermal neutrons in various doses on viability of glioblastoma U87 tumor cells. Increasing the dose from 1.9 to 4.1 Sv promoted cell death. Cytofluorimetric analysis revealed no activation of apoptosis in the irradiated cells, which attested to necrotic death of the tumor cells exposed to epithermal neutron radiation. PMID- 22238766 TI - Morphological characteristics of the inner medullary zone in the kidneys of Brattleboro and Wistar rats during blockade of prostaglandin synthesis. AB - Morphological characteristics of the inner medullary zone in the kidneys in Brattleboro and Wistar rats were studied during blockade of prostaglandin synthesis. The absence of a diuretic effect of prostaglandins on the kidneys was accompanied by structural changes in the transepithelial and interstitial barriers for an osmotic flow of water. PMID- 22238767 TI - Possibility of microorganism elimination from the blood using modified coal hemosorbents. AB - We studied the possibility of using coal hemosorbents for elimination gram positive and gram-negative microorganisms from the blood. After hemosorption, the number of S. aureus and K. pneumoniae pneumoniae colony-forming units significantly decreased. The obtained results indicate that coal sorbents can bind and probably eliminate gram-positive and gram-negative bacteria from the blood. PMID- 22238768 TI - Integrated separation process for isolation and purification of biosuccinic acid. AB - Biotechnologically produced succinic acid has the potential to displace maleic acid and its uses. Therefore, it is of high interest for the chemical, pharmaceutical, and food industry.In addition to optimized production strains and fermentation processes, an efficient separation of succinic acid from the aqueous fermentation broth is indispensable to compete with the current petrochemical production of succinic acid. Isolation and purification of succinic acid from an Escherichia coli fermentation broth were studied with two amine-based reactive extraction systems: (i) trihexylamine in 1-octanol and (ii) diisooctylamine and dihexylamine in a mixture of 1-octanol and 1-hexanol. Back extraction of succinic acid from the organic phase was carried out using an aqueous trimethylamine solution. The trimethylammonium succinate generated after back extraction was split with an evaporation-based crystallization.The focus was on process integration, for example, reuse of the applied amines for extraction and back extraction. It was shown that the maximum trimethylamine concentration for back extraction should not exceed the stoichiometric amount (2 mol trimethylamine/mol the succinic acid in the organic phase) to ensure maximal extraction yields with the reused organic phase in subsequent extractions. Moreover, mixer-settler extraction and back extraction of succinic acid were scaled up from the milliliter- to the liter-scale making use of liquid-liquid centrifuges. The overall yield was 83.5% of the succinic acid from thefermentation supernatant. The final purity of the succinic acid crystals was 99.5%. Organic phase and amines can easily be recycled and reused. PMID- 22238769 TI - Model-based rational strategy for chromatographic resin selection. AB - A model-based rational strategy for the selection of chromatographic resins is presented. The main question being addressed is that of selecting the most optimal chromatographic resin from a few promising alternatives. The methodology starts with chromatographic modeling,parameters acquisition, and model validation, followed by model-based optimization of the chromatographic separation for the resins of interest. Finally, the resins are rationally evaluated based on their optimized operating conditions and performance metrics such as product purity, yield, concentration, throughput, productivity, and cost. Resin evaluation proceeds by two main approaches. In the first approach, Pareto frontiers from multi-objective optimization of conflicting objectives are overlaid for different resins, enabling direct visualization and comparison of resin performances based on the feasible solution space. The second approach involves the transformation of the resin performances into weighted resin scores, enabling the simultaneous consideration of multiple performance metrics and the setting of priorities. The proposed model-based resin selection strategy was illustrated by evaluating three mixed mode adsorbents (ADH, PPA, and HEA) for the separation of a ternary mixture of bovine serum albumin, ovalbumin, and amyloglucosidase. In order of decreasing weighted resin score or performance, the top three resins for this separation were ADH [PPA[HEA. The proposed model-based approach could be a suitable alternative to column scouting during process development, the main strengths being that minimal experimentation is required and resins are evaluated under their ideal working conditions, enabling a fair comparison. This work also demonstrates the application of column modeling and optimization to mixed mode chromatography. PMID- 22238770 TI - Computational fluid dynamics modeling of mass transfer behavior in a bioreactor for hairy root culture. I. Model development and experimental validation. AB - A two-dimensional axisymmetric computational fluid dynamics (CFD) model based on a porous media model and a discrete population balance model was established to investigate the hydrodynamics and mass transfer behavior in an airlift bioreactor for hairy root culture.During the hairy root culture of Echinacea purpurea, liquid and gas velocity, gas holdup, mass transfer rate, as well as oxygen concentration distribution in the airlift bioreactor were simulated by this CFD model. Simulative results indicated that liquid flow and turbulence played a dominant role in oxygen mass transfer in the growth domain of the hairy root culture. The dissolved oxygen concentration in the hairy root clump increased from the bottom to the top of the bioreactor cultured with the hairy roots, which was verified by the experimental detection of dissolved oxygen concentration in the hairy root clump. This methodology provided insight understanding on the complex system of hairy root culture and will help to eventually guide the bioreactor design and process intensification of large-scale hairy root culture. PMID- 22238771 TI - Effect of needle geometry on flow rate and cell damage in the dispensing-based biofabrication process. AB - Biodispensing techniques have been widely applied in biofabrication processes to deliver cell suspensions and biomaterials to create cell-seeded constructs. Under identical operating conditions,two types of dispensing needles-tapered and cylindrical-can result in different flow rates of material and different cell damage percent induced by the mechanical forces. In this work, mathematical models of both flow rate and cell damage percent in biodispensing systems using tapered and cylindrical needles, respectively, were developed, and experiments were carried out to verify the effectiveness of the developed models. Both simulations and experiments show tapered needles produce much higher flow rates under the same pressure conditions than cylindrical needles. Use of a lower pressure in a tapered needle can therefore achieve the same flow rate as that in a cylindrical needle. At equivalent flow rates, cell damage in a tapered needle is lower than that in a cylindrical one. Both Schwann cells and 3T3 fibroblasts, which have been widely used in tissue engineering, were used to validate the cell damage models. Application of the developed models to specify the influence of process parameters, including needle geometry and air pressure, on the flow rate and cell damage percent represents a significant advance for biofabrication processes.The models can be used to optimize process parameters to preserve cell viability and achieve the desired cell distribution in dispensing-based biofabrication. PMID- 22238772 TI - The author file: Ernst Bamberg. PMID- 22238773 TI - Points of view: the design process. PMID- 22238775 TI - Nanoelectroporation . PMID- 22238774 TI - Human oocytes: still in the game . PMID- 22238776 TI - Sequencing for sugars . PMID- 22238777 TI - High-tech Petri dishes . PMID- 22238778 TI - Noncoding RNA's genomic hangouts . PMID- 22238779 TI - Wholesome proteomics . PMID- 22238780 TI - Who wants a blind breast surgeon? PMID- 22238781 TI - The promise of PROMIS((r)) for addiction. AB - The field of addiction treatment has a measurement problem that pervades efforts to help patients achieve self-sustainable recovery. The impact of using older measurement technology has increased the measurement burden on both service providers and patients, while at the same time limiting the scope and frequency of measurement. The resulting burden can affect provider performance, patient access, and addiction recovery. This paper underscores the need for applying modern measurement theory techniques to reduce the measurement burden currently affecting most if not all major aspects of treatment and recovery. It is currently possible to obtain information more precisely, over a broad spectrum of recovery-oriented domains, faster and at lower cost than current measurement practices allow. However, a persistent research effort will be necessary to achieve that goal. PMID- 22238782 TI - Collegial ethics: what, why and how. AB - Collegial ethics (CE) proposes that we support our colleagues whenever possible. It is more of a focus on the feelings of others rather than on our own. In spite of the importance of collegial interactions, CE is not usually taught. Courses in CE need to be developed, and collegial skills need to be identified, taught and practiced. Such skills would include: use of the golden rule, supportive communication, conflict resolution, and even the development of greater courage in our actions. PMID- 22238783 TI - Neural stem cells for diabetes cell-based therapy. PMID- 22238784 TI - Obituary: Nathan Sharon (1925-2011). PMID- 22238785 TI - Plummer-Vinson syndrome and reactive thrombocytosis mask a JAK2-V617F positive myeloproliferative neoplasm. PMID- 22238786 TI - Climate change, crop yields, and undernutrition, with Sari Kovats by Ashley Ahearn. PMID- 22238788 TI - Bibliography. Systemic disorders with rheumatic manifestations. Current world literature. PMID- 22238787 TI - Introduction of a second dose of measles in national immunization program in India: a major step towards eradication. AB - Measles is a highly infectious, acute respiratory illness that is caused by a virus of the genus Morbillivirus. The disease infects nearly 30 million children each year, and deaths usually occur from complications related to pneumonia, diarrhea and malnutrition. A systematic review of published Indian literature depicts the median case fatality ratio (CFR) of measles to be 1.6%. Through immunization, measles deaths dropped a remarkable 78% from 733,000 in 2000 to 164,000 in 2008. As of 2008, 192 of 193 Member States of WHO use 2 doses of measles vaccine in their national immunization programs, India being the only exception. The Millennium Development Goal (MDG) 4 aims to reduce by two-thirds between 1990 and 2015 the under-five mortality rate (U5MR) in the world. Per the draft comprehensive Multi Year Strategic Plan (cMYP, 2010-17) for immunization of India, the country aims to reduce measles-related mortality by 90% by 2013 when compared to 2000. As recommended by the National Technical Advisory Group on Immunization (NTAGI), the implementation strategy of the second dose of measles vaccine at the state level is determined by the underlying performance of the routine immunization program. The second dose in the national immunization schedule gives extra immunity against measles infection that renders children more susceptible to secondary pneumonia and diarrheal diseases, which are the primary causes of under-5 child mortality in India. PMID- 22238789 TI - The role of vitamin D. Researchers study its potential to stave off type 2 diabetes. PMID- 22238807 TI - [Notes-hybrid: splenectomy (transvaginal/umbilical)]. AB - In the search of less invasive surgery, laparoscopic procedures through natural orifices accesses have begun to be standardized Considering that women have the higher prevalence of idiopathic thrombocytopenic purpura, the purpose of this presentation is to demonstrate our first experience performing a hybrid NOTES (natural orifice transluminal endoscopic surgery) splenectomy, with the transvaginal and umbilical-multi-port access as doors to perform the procedure. We present a 30-year-old woman with body mass index 22 kg/m2 and platelet count 55,000 per microliter-x103/uL. A refractory autoimmune thrombocytopenic purpura was diagnosed. Splenectomy was performed through the umbilical-multi-port and transvaginal accesses, with the use of conventional laparoscopic instruments and video sigmoidosocopy. The surgical specimen was removed vaginally by fragmentation of the piece. The mean operative time was 150 minutes, the blood loss 100 cc, the postoperative pain analog scale 1, and the follow-up 8 weeks. Currently the patient has a platelet count of 450,000 per microliter and she is free of treatment with steroids or any immunosuppressive drugs. We conclude that the transvaginal and umbilical hybrid NOTES constitutes an option to perform splenectomy in selected patients. PMID- 22238808 TI - [The novel stripped bare by photography, even]. PMID- 22238809 TI - Mothering Socialist society: the wife-activists' movement and the Soviet culture of daily life, 1934-41. PMID- 22238810 TI - [Nadar and the "homocidal photograph"]. PMID- 22238811 TI - Nostalgia, gender, and the countryside: placing the "land girl" in First World War Britain. PMID- 22238812 TI - Peasant agriculture in pre-reform Kostroma and Kazan' provinces. PMID- 22238813 TI - [Photography and the representation of exotic societies in the 19th century]. PMID- 22238814 TI - Reconstructing the rural community: village halls and the National Council of Social Service, 1919 to 1939. PMID- 22238815 TI - [Representations of the Orient: photographic projects and cultural mediations]. PMID- 22238816 TI - [The novel of 1900 and photography: the publishers Nilsson/Per Lamm and Offenstadt Freres]. PMID- 22238817 TI - Sobering up the soul of the people: the politics of popular temperance in late Imperial Russia. PMID- 22238818 TI - [Photographic witchcraft from Villiers to Strindberg]. PMID- 22238819 TI - The enigma of married women's control of property in eighteenth-century Russia. PMID- 22238820 TI - The promotion of agricultural education for adults: the Lancashire federation of women's institutes, 1919-45. PMID- 22238821 TI - The rural "middling sort" in early modern England, circa 1640-1740: some economic, political and socio-cultural characteristics. PMID- 22238822 TI - The stone workers of Purbeck. PMID- 22238823 TI - [The role of miR-223 in the acute rejection after kidney transplantation]. AB - AIM: To explore the role of miR-223 in the acute rejection after kidney transplantation. METHODS: 33 patients who received kidney transplantation in our hospital within a year were collected and 12 of them appeared acute rejection within 1 month after surgery. In all the patients, the peripheral blood miR-223 level was collected and detected by blind arrangements. Furthermore, PBMCs from healthy volunteers were also collected and stimulated by PHA and then miR-223 level was measured. RESULTS: In the peripheral blood cell, the miR-223 was increased 2 times after acute rejection, as well as 3. 76 times after PHA treatment.Furthermore, using miR-223 predicts AR had a specificity of 90% and sensitivity of 92%. CONCLUSION: The miR-223 may have significant role in the acute rejection of kidney transplantation. PMID- 22238824 TI - [Establishment of primary Her-2 over- expression human breast cancer cell model]. AB - AIM: Through isolation and purification pri-mary HER2 overexpression human breast cancer cells from malignant pleural effusion and identification the HER2 expression level of the cells to establish the primary HER2 overexpression human breast cancer cell model. METH-ODS: Malignant pleural effusion of HER2 overexpression breast cancer patient was collected. The primary cells were extracted from malignant pleural effusion by Lymphocyte separation medium and the method of density gradient centrifugation. When the primary cells were cultured and spreaded to the 5th generation, the HER2 expression level of the primary cells were detected by the methods of Q-PCR,Western blot and flow cytometry (FCM). Ability of tumor-bearing was detected by tumor-bearing nude mice assay. RESULTS: The primary HER2 overexpression human breast cancer cells were extracted and identified by the methods of Q-PCR, Western blot and tumor-bearing nude mice assay,even though the FCM showed Negative results. CONCLUSION: The primary HER2 overexpression human breast cancer cell model was established; Identification of primary cells need to be confirmed by different methods. PMID- 22238825 TI - [Abstracts of the 58th Meeting of the Japanese Society of Clinical Pathology. November 17-20, 2011. Okayama, Japan]. PMID- 22238826 TI - [Abstracts of the 51st Annual Meeting of the Japanese Society of Nuclear Medicine. October 27-29, 2011. Tsukuba, Japan]. PMID- 22238827 TI - [Proceeding of 41st annual meeting of the Japanese Society of Neuropsychopharmacology. Tokyo, Japan. October 27-29, 2011. Abstracts]. PMID- 22238828 TI - Bringing up baby: for new parents, home visits by trained professionals can make all the difference. PMID- 22238829 TI - The new healthy: lawmakers are cooking up ways to encourage better eating and cultivate local economies. PMID- 22238830 TI - In memoriam: Sigmund S. Socransky. PMID- 22238831 TI - Payment of reimbursement for emergency treatment furnished by non-VA providers in non-VA facilities to certain veterans with service-connected or nonservice connected disabilities. Final rule. AB - This document amends the Department of Veterans Affairs (VA) medical regulations concerning emergency hospital care and medical services provided to eligible veterans at non-VA facilities. The amendments are required by section 402 of the Veterans' Mental Health and Other Care Improvements Act of 2008. Among other things, the amendments authorize VA to pay for emergency treatment provided to a veteran at a non-VA facility up to the time the veteran can be safely transferred to a VA or other Federal facility and such facility is capable of accepting the transfer, or until such transfer was actually accepted, so long as the non-VA facility made and documented reasonable attempts to transfer the veteran to a VA or other Federal facility. PMID- 22238832 TI - Revisions to rules of conduct and standards of responsibility for representatives. Final rules. AB - We are revising our rules of conduct and standards of responsibility for representatives. These revisions further clarify our expectations regarding representatives' obligations to competently represent their clients and constitute official notice concerning our requirements and procedures. We are also updating other rules about the representation of parties. These changes are necessary because our current regulations are insufficient to address some representative conduct that is inappropriate, but has technically fallen outside the scope of our regulations. These changes will allow us to better protect the integrity of our administrative process, ensure that claimants receive competent and effective representation, and further clarify representatives' responsibilities in their dealings with us and with claimants. PMID- 22238833 TI - TRICARE: certified mental health counselors. Interim final rule. AB - This rule is submitted as an interim final rule (IFR) in order to meet the Congressional requirement set forth in the National Defense Authorization Act (NDAA) for Fiscal Year (FY) 2011, Section 724, which required the Department of Defense to prescribe regulations by June 20, 2011, to establish the criteria, as had previously been studied in accordance with Section 717 of the NDAA 2008, that would allow licensed or certified mental health counselors to be able to independently provide care to TRICARE beneficiaries and receive payment for those services. Under current TRICARE requirements, mental health counselors (MHCs) are authorized to practice only with physician referral and supervision. This interim final rule establishes a transition period to phase out the requirement for physician referral and supervision for MHCs and to create a new category of allied health professionals, to be known as certified mental health counselors (CMHCs), who will be authorized to practice independently under TRICARE. During this transition period the MHCs who do not meet the requirements for independent practice as established in this rule, may continue to provide services to TRICARE beneficiaries under the requirements of physician referral and ongoing supervision. This transition period, ending December 31, 2014, will allow time for those MHCs who seek to continue providing services under the TRICARE program to meet the independent practice requirements as outlined in this notice. After December 31, 2014, the Department of Defense will no longer recognize those mental health counselors who do not meet the criteria for a CMHC and will no longer allow them to provide services even upon the referral and supervision of a physician. PMID- 22238834 TI - TRICARE: changes included in the National Defense Authorization Act for Fiscal Year 2010; enhancement of transitional dental care for members of the Reserve Component on active duty for more than 30 days in support of a contingency operation. Final rule. AB - The Department is publishing this final rule to implement section 703 of the National Defense Authorization Act for Fiscal Year 2010 (NDAA for FY10). Specifically, that legislation amends the transitional health care dental benefits for Reserve Component members on active duty for more than 30 days in support of a contingency operation. The legislation entitles these Reserve Component members to dental care in the same manner as a member of the uniformed services on active duty for more than 30 days, thus providing care to the Reserve member in both military dental treatment facilities and authorized private sector dental care. This final rule does not eliminate any medical or dental care that is currently covered as transitional health care for the member. PMID- 22238835 TI - TRICARE: elimination of co-payments for authorized preventive services for certain TRICARE Standard beneficiaries. Final rule. AB - The Department of Defense is publishing this final rule to implement section 711 of the National Defense Authorization Act (NDAA) for Fiscal Year 2009 (FY 2009), Public Law 110-417. Section 711 eliminates copayments for authorized preventive services for TRICARE Standard beneficiaries other than Medicare-eligible beneficiaries. This rule also realigns the covered preventive services listed in the Exclusions section of the regulation to the Special Benefits section in the regulation. PMID- 22238836 TI - A psychosocial evaluation process for living liver donors: the University of Rochester model. AB - OBJECTIVE: The donation of livers by living donors entails complex processes, both surgically and psychosocially, potentially involving risks in both domains. Thorough psychosocial evaluation is necessary to minimize those risks, yet little has been written about the donor assessment process. This article describes one such process, utilized by a transplant program in upstate New York. METHOD: Donor candidates undergo multiple psychosocial interviews early in the overall transplant evaluation process. Evaluators subsequently meet as a group, along with an independent ethicist, to determine psychosocial candidacy prior to final medical/surgical clearance. RESULTS: Between 2003 and 2007, 416 donor candidates initiated and/or underwent full evaluation, resulting in a 17.5% surgery and 55.5% exclusion rate among those individuals. Of those ruled out, 20.8% were for (medical or psychosocial) reasons associated with the recipient, and 8.7% were for donor-related psychosocial issues. CONCLUSION: Given the primacy ofpsychosocial and ethical issues in living liver donor candidate evaluation, the multiple interview process, followed by team discussion and overseen by an ethicist removed from other transplant program functions, has advantages as a donor assessment model. PMID- 22238837 TI - Pilot evaluation of a biopsychosocial integrated standardized patient examination in a family medicine clerkship. AB - OBJECTIVE: A new biopsychosocial Integrated Standardized Patient Examination (ISPE) was implemented to assess communication skills for medical students participating in a family medicine clerkship. METHOD: Mixed method, multi-level evaluation. RESULTS: Pilot ISPE scores were significantly higher than previous Objective Structured Clinical Examination (OSCE) (p < .01). Family Physician and Social/Behavioral Scientist rater scores were correlated (p < .001), and Cronbach's alpha statistics were acceptable (FM: alpha = .837; BH: alpha = .768). Preceptor scores on "relations with professionals" (beta = .694, p = .008) significantly predicted ISPE scores, but other clerkship assignment grades were inversely associated with ISPE. Qualitative focus group themes included lack of readiness, divergence in beliefs on scope of physician practice, and focus on grade. CONCLUSIONS: This pilot project describes the process and demonstrates the possibility of implementing a complex standardized patient case to assess students' management of complicated primary care patients with medical, psychological, and social issues. PMID- 22238838 TI - The prevalence of headache and associated psychosocial factors in an urban biracial sample of older adults. AB - OBJECTIVE: There are limited epidemiological data about headache in urban elderly persons in the United States, especially those from minority backgrounds. This article examines the prevalence of headache and associated psychosocial factors in a biracial sample of older adults in New York City. METHODS: Data from a population-based sample consisting of 214 Caucasians and 859 Blacks aged 55 and over (mean age: 68 years) were analyzed using an adaptation of George's Social Antecedent Model of Psychopathology. The model consisted of 15 independent variables, one interactive variable, and a dependent variable that dichotomized headaches that bothered respondents into "none or little of the time" versus "some, a good part, or most of the time" in the past few weeks. RESULTS: Controlling for design effects, 17.8% of the sample met headache criteria. For the entire sample, logistic regression analysis indicated that headache was significantly associated with anxiety symptoms, depressive symptoms, religiosity, and a smaller proportion of confidantes. When examined separately, headache among blacks was significantly associated with anxiety symptoms, larger social networks, and greater financial strain. Among Caucasians, headache was associated with anxiety symptoms, smaller social networks, religiosity, physical illness, and higher daily functioning. CONCLUSIONS: The study confirms earlier findings that anxiety and depressive symptoms are associated with headache in older adults. The results also identify other psychosocial factors that may differ by race. These findings have important implications with respect to the etiology and management of headache in older adults. PMID- 22238839 TI - The relationship between body mass index, the use of second-generation antipsychotics, and dental caries among hospitalized patients with schizophrenia. AB - OBJECTIVE: Weight gain is common in schizophrenia due to use of the second generation antipsychotic medicines (SGAs). Studies have also shown that body mass index (BMI) and the side effect of SGAs, such as anticholinergic activity, are related to the risk of dental caries. This study aims to investigate the relationship between BMI, the use of the SGAs, and the decayed, missing, and filled tooth index (DMFT) among hospitalized patients with schizophrenia. METHODS: A cross-sectional survey of oral health was conducted in a psychiatric long-term care hospital in Taiwan in 2006. A total of 878 schizophrenic inpatients participated in this survey. The DMFT index was used to assess dental caries, the use of SGAs of subjects were recorded, and the BMI classification was done in accordance with Asian standard scales. Multiple regression models were used to measure the effects of SGAs or BMI on the DMFT index in each subject. RESULTS: Among the subjects with schizophrenia, DMFT is significantly related to independent variables such as age, length of stay, BMI, education, marital status, and grade of disability. Consequent multiple linear regression showed that being underweight (beta = 0.07, p = 0.041) and age were the most significant factors that influence the DMFT score. CONCLUSIONS: We found that the use of SGAs was not significantly associated with the DMFT index. After adjusting for age, being underweight is a significant factor associated with the increased risk of dental caries in hospitalized patients with schizophrenia. Psychologists and dentists should pay more attention to the relation between BMI and dental caries in this population. PMID- 22238840 TI - Disruptive behaviors in the medical setting and borderline personality. AB - OBJECTIVE: Borderline personality disorder (BPD) is characterized in the DSM by anger. While previous studies have examined various types of externalized aggression and violence among individuals with BPD, we are aware of no investigations of disruptive behaviors perpetrated by patients with BPD in medical settings-the focus of the present study. METHOD: Using a cross-sectional, consecutive sample of internal medicine outpatients from a resident provider clinic, we surveyed 397 participants regarding 17 disruptive behaviors related to medical personnel and assessed BPD using two self-report measures, the BPD scale of the Personality Diagnostic Questionnaire-4 (PDQ-4) and the Self-Harm Inventory (SHI). RESULTS: A statistically significantly greater proportion of respondents who exceeded the clinical cut-off scores for BPD on both the PDQ-4 and SHI endorsed at least one form of disruptive behavior. However, there were no differences between participants with versus without BPD symptomatology regarding the number of different forms of disruptive behaviors after that initial threshold of one such behavior was reached. Several specific disruptive behaviors were reported more often in those with BPD symptomatology (i.e., yelling, screaming, verbally threatening, and refusing to talk with medical staff as well as talking badly about medical staff to the patients' friends and family). CONCLUSIONS: BPD appears to be associated with a greater likelihood of disruptive behaviors in the medical setting, but not physical threat. PMID- 22238841 TI - Anxiety disorders, hypertension, and cardiovascular risk: a review. AB - Hypertension, coronary heart disease (CHD), and anxiety disorders all cause substantial morbidity to patients and costs to the healthcare system. Associations between these diseases have been hypothesized and studied for decades. In particular, psychosocial stressors associated with anxiety disorders raise autonomic arousal via the hypothalamic-pituitary axis which increases circulating catecholamines. This heightened arousal is associated with an increased risk of hypertension and a pro-inflammatory state and, consequently, development of coronary heart disease. This association holds across the spectrum of anxiety disorders (generalized anxiety, posttraumatic stress disorder, panic disorder, and obsessive compulsive disorder) and also when controlling for comorbid conditions such as depression and physical ailments. Multiple cross sectional studies reveal a positive association between anxiety and hypertension. These associations are bidirectional, with those with hypertension being more likely to have anxiety and those with anxiety being more likely to have hypertension. However, a few studies have shown no association. Longitudinal studies point to an increased risk of development of hypertension in patients who suffer from anxiety. More convincing studies show links between anxiety symptoms and disorders, including panic disorder and PTSD, and cardiovascular outcomes. Drawing broad conclusions from these studies is challenging, however, given the multiplicity of scales used to measure anxiety disorders. Anxiety, hypertension, and CHD are common conditions seen in primary care, and anxiety may be an important predictor of future CHD outcomes. Better recognition of the association of these conditions and the possible roles of each in development of the other should alert primary care providers to be vigilant in monitoring and treating anxiety, hypertension, and CHD. PMID- 22238842 TI - Barriers to metabolic care for adults with serious mental illness: provider perspectives. AB - This study assessed barriers to metabolic care for persons with serious mental illness (SMI) by surveying experienced healthcare providers. Sixty-eight medical, mental health, and other stakeholders who care for patients with SMI attended a CME conference focused on medical management of SMI patients in 2007. They completed a 27-item survey assessing barriers to and systemic responsibility for metabolic care. The top three ranked barriers were: "separate mental health and primary care systems," "patient's lack of resources," and "[mental health] providers are not trained to do basic primary care." Results indicated that ratings of CMHC responsibility for SMI metabolic care (M = 5.2, SD = 1.5) were significantly lower than ratings of public health (M = 5.7, SD = 1.4), t(66) = 2.3, p = 0.027, and primary care providers (M = 6.3, SD = 1.1), t(67) = 4.7,p <0.001. Experienced providers identified a lack of integrated care and patient characteristics as important barriers to metabolic care and concluded that the primary care and public health systems are primarily responsible for metabolic treatment. PMID- 22238843 TI - Secular IQ increases by epigenesis? The hypothesis of cognitive genotype optimization. AB - The short timescale of massive secular IQ gains ("Flynn Effect") is inconsistent with positive selection of a recent gene mutation, but other genetic mechanisms are possible. Principles of evolutionary psychology, combined with secular trends, suggest an epigenetic explanation: the Cognitive Genome Optimization Hypothesis. Per life-history theory, favorable secular trends may change the phenotypic expression of the genotype which controls the neurophysiology of problem solving. The hypothesis posits two intermediate steps between reliable nutrition (the starting point) and higher IQs (ending point): (1) Earlier cognitive maturation and (2) further calibration of cognitive function by reliable social resources (cultural complexity, mandatory education). Unlike earlier generations, more resources can be deployed to cognitive maturation than to physical survival, and more time is available to calibrate cognitive processing into the upper end of the trait value range for intelligence. The secular trend of earlier puberty timing is critical: data show an association between puberty and higher IQ. PMID- 22238844 TI - Predicting suicidality among psychiatric patients. AB - In a sample of 50 psychiatric patients, suicidality as measured by a 54-item scale was associated with scores on scales to assess the presence of comorbidities, family history, medical factors, clinical ratings of psychiatric diagnosis, psychosocial/environmental factors, and protective factors (multiple R2 = .66). PMID- 22238845 TI - Magical thinking and memory: distinctiveness effect for tv commercials with magical content. AB - The aim of this study was to examine whether memorizing advertised products of television advertisements with magical effects (i.e., talking animals, inanimate objects which turn into humans, objects that appear from thin air or instantly turn into other objects) is easier than memorizing products of advertisements without such effects, by testing immediate and delayed retention. Adolescents and adults viewed two films containing television advertisements and were asked to recall and recognize the films' characters, events, and advertised products. Film 1 included magical effects, but Film 2 did not. On a free-recall test, no differences in the number of items recalled were noted for the two films. On the immediate recognition test, adolescents, but not adults, showed significantly better recognition for the magical than the nonmagical film. When this test was repeated two weeks later, results were reversed: adults, but not adolescents, recognized a significantly larger number of items from the magical film than the nonmagical one. These results are interpreted to accentuate the role of magical thinking in cognitive processes. PMID- 22238846 TI - How task experience influences students' performance expectancies: the role of certainty. AB - The importance of performance expectancies for predicting behavior has long been highlighted in research on expectancy-value models. These models do not take into account that expectancies may vary in terms of their certainty. The study tested the following predictions: task experience leads to a higher certainty of expectancies; certainty and mean expectancies are empirically distinguishable; and expectancies held with high certainty are more accurate for predicting performance. 273 Grade 8 students reported their performance expectancy and the certainty of expectation with regard to a mathematics examination immediately before and after the examination. Actual grades on the examination were also assessed. The results supported the predictions: there was an increase in certainty between the two times of measurement; expectancies and certainty were unrelated at both times of measurement; and for students initially reporting higher certainty, the accuracy of the performance expectancy (i.e., the relation between expectancy and performance) was higher than for students reporting lower certainty. Given lower certainty, the accuracy increased after the students had experience with the examination. The data indicate that it may be useful to include certainty as an additional variable in expectancy-value models. PMID- 22238847 TI - Investment in Personal Development Scale: a preliminary study. AB - Life history theory suggests that reproduction of the species involves three areas of investment: personal development, mating, and nurturing offspring. Using the rational method of test construction, a 29-item scale was constructed to measure investment in personal development, the Investment in Personal Development Scale. Scale scores were statistically significantly correlated with age, year in school, identity commitment, and conscientiousness. PMID- 22238848 TI - Social acceptance of comparative optimism and realism. AB - Studies of optimism and realism (the accuracy of people's outlook on the future) seek to understand the respective effects of these elements on social approbation. Two experiments examined how comparative optimism (vs. pessimism) and realism (vs. unrealism) interacted to influence the targets' social acceptance based on their perceptions about the future. The results showed that realism, or accuracy of prediction, increased the positive social effects of a comparatively optimistic outlook on the future. In contrast, targets who exhibited comparative pessimism were more socially acceptable when their predictions were unrealistic rather than realistic. This phenomenon was examined by also considering the polarity of the events about which judgments were expressed. These results contribute to the body of research about the relationship between optimism and pessimism and the relationship between optimism and realism. PMID- 22238849 TI - The effects of video and nonnegative social feedback on distorted appraisals of bodily sensations and social anxiety. AB - The effects of video feedback and nonnegative feedback from other people were examined as possibly ameliorating distorted appraisals of bodily sensations, as well as subjective and physiological anxiety in socially anxious individuals. Nonnegative feedback from a confederate emphasized the absence of negative outcomes (e.g., did not seem to tremble) rather than the presence of positive outcomes (e.g., looked calm). Socially anxious students were randomly assigned to either the experimental group, which received video and social feedback (n=12), or the control group (n 13). Participants were asked to give a videotaped speech twice. After the first speech, the experimental group watched the videotape of their speech and received feedback from a confederate, whereas the control group watched the video of another person's speech. The intervention improved distorted appraisal of bodily sensations and anticipatory anxiety for the experimental group. However, there were no differential effects on anxiety between the groups during speeches. PMID- 22238850 TI - Skills-demands compatibility as a determinant of flow experience in an inductive reasoning task. AB - The skills-demands fit hypothesis of flow theory was examined. Based on the earlier finding that high demands in a game situation do not reduce the experience of flow, a cognitive task paradigm was used. The effect of skills demands compatibility on the experience of flow but not of other, similar psychological states (i.e., concentration, negative and positive activation) was also investigated. Participants were 89 undergraduate students who worked on a number of inductive reasoning tasks in four successive trials with or without skills-demands compatibility. The results clearly supported the skills-demands fit hypothesis; concentration and activation were affected only by the tasks' difficulty. Inductive reasoning tasks are a useful tool for the experimental analysis of flow, and skills-demands compatibility is a significant and powerful condition of flow, but not of other, similar psychological states. PMID- 22238851 TI - Development of the Mental Clutter Scale. AB - Mental fog is a core symptom of fibromyalgia. Its definition and measurement are central to an understanding of fibromyalgia-related cognitive disability. The Mental Clutter Scale was designed to measure mental fogginess. In an exploratory factor analysis of two different samples (n=128 and n=170), cognitive symptoms of fibromyalgia loaded on 2 dimensions: cognition and mental clarity. The mental clarity factor comprised 8 items with factor loadings greater than .60 and was named the Mental Clutter Scale. The factor stability of the new scale was good, internal consistency was .95, and test-retest reliability over a median of 5 days was .92. The 8-item scale is a quick measure of mental fog that provides clinicians with information about cognitive functioning in fibromyalgia. PMID- 22238852 TI - Leisure-time physical activity and psychological well-being in university students. AB - An analysis of psychological well-being (self-esteem and subjective vitality) of 639 Spanish university students was performed, while accounting for the amount of leisure-time physical activity. The Spanish versions of the Rosenberg Self-Esteem Scale and Subjective Vitality Scale were employed. Participants were divided into four groups (Low, Moderate, High, and Very high) depending on estimation of energy expenditure in leisure-time physical activity. Men and women having higher physical activity rated higher mean subjective vitality; however, differences in self-esteem were observed only in men, specifically between Very high and the other physical activity groups. PMID- 22238853 TI - Brain and psyche in early Christian asceticism. AB - This study is an 11-part investigation of the psychology and neuropsychology of early Christian asceticism as represented by Evagrius Ponticus (AD 345-399), the tradition's first ascetical theologian and possibly its mosfinfluential. Evagrius's biography is reviewed in the first section. The living circuinstaii and perceptual consequences of desert asceticism are considered in the second. Penitence, dispassion, and the mysticism of "pure prayer" are discussed in the third. Austerities are addressed in the fourth section, particularly fasting, prostrations, and prolonged standing. Ascetical perspectives on sleep, dreams, and the hypnogogic state are analyzed in the fifth. The depressive syndrome of acedia is discussed in the sixth. Evagrius's reports of auditory, olfactory, and visual hallucinations are analyzed in the seventh. Multiple complementary interpretations of demonic phenoniena are developed in the eighth section. Evagrius's psychotherapy for anger is reviewed in the ninth. Interpersonal relations among ascetics are considered in the tenth section. The study concludes with a summary. PMID- 22238854 TI - Habitual emotion regulation and the facial grimace. AB - Summary.-Images of pleasant scenes usually produce increased activity over the zygomaticus major muscie, as measured by electromyography (EMG), while less activity is elicited by unpleasant images. However, increases in zygomaticus major EMG activity while viewing unpleasant images have occasionally been reported in the literature on affective facial expression (i.e., "grimacing"). To examine the possibility that individual differences in emotion regulation might be responsible for this inconsistently observed phenomenon, the habitual emotion regulation tendencies of 63 participants (32 women) were assessed and categorized according to their regulatory tendencies. Participants viewed emotionally salient images while zygomaticus major EMG activity was recorded. Participants also provided self-report ratings of their experienced emotional valence and arousal while viewing the pictures. Despite demonstrating intact affective ratings, the "grimacing" pattern of zygomaticus major activity was observed in those who were less likely to use the cognitive reappraisal strategy to regulate their emotions. PMID- 22238855 TI - Schizotypy and hemisphericity. AB - There is considerable evidence that schizophrenia spectrum disorders are associated with a variety of abnormal asymmetries of brain structure, function, and behavior. Schizotypy is a personality trait dimension extending into the normal range, which at its extreme, is associated with a vulnerability to schizophrenia spectrum disorders. Schizotypy in the normal range is also associated with a variety of neurobiological characteristics associated with schizophrenia spectrum disorders, including abnormal brain and behavioral asymmetries. Previous studies have suggested that normal schizotypy (as well as belief in the paranormal) is associated with an increased reliance on the right hemisphere in a variety of tasks. Hemisphericity is a trait-related characteristic preference for the cognitive mode of one or the other cerebral hemispheres, putatively related to hemispheric activation asymmetry. A sample of 256 undergraduates was administered five schizotypy scales, as well as three hemisphericity measures. Higher schizotypy scores were associated with an increase in right hemisphericity and a decrease in integrated hemisphericity. Although the construct of hemisphericity has been criticized, there is evidence to suggest that questionnaire and eye movement measures of hemisphericity may yet have construct validity, and further research on hemisphericity may be warranted. PMID- 22238856 TI - Prejudiced attitude measurement using the Rasch Rating Scale model. AB - There have been two basic approaches for the study of minority group prejudice against the majority: to adapt instruments from the majority group, and to use qualitative techniques by analyzing the content of the discourse of the groups involved. Neither of these procedures solves the problem of measuring intergroup attitudes of majorities and minorities in interaction. This study shows the result of a prejudice scale which was developed to measure the attitude of both the minority and majority groups. Prejudice is conceived as an attitude which requires the beliefs or opinions about the out-group, the emotions it elicits, and the behavior or intentional behavior toward it to be known for its evaluation. The innovation in this work is that the psychometric development of the scale was based on the item response theory, and more specifically, the rating scale model. PMID- 22238857 TI - Treatment of posttraumatic stress disorder in U.S. combat veterans: a meta analytic review. AB - Among U.S. veterans who have been exposed to combat-related trauma, significantly elevated rates of posttraumatic stress disorder (PTSD) are reported. Veterans with PTSD are treated for the disorder at Veterans Affairs (VA) hospitals through a variety of psychotherapeutic interventions. Given the significant impairment associated with PTSD, it is imperative to assess the typical treatment response associated with these interventions. 24 studies with a total sample size of 1742 participants were quantitatively reviewed. Overall, analyses showed a medium between-groups effect size for active treatments compared to control conditions. Thus, the average VA-treated patient fared better than 66% of patients in control conditions. VA treatments incorporating exposure-based interventions showed the highest within-group effect size. Effect sizes were not moderated by treatment dose, sample size, or publication year. Findings are encouraging for treatment seekers for combat-related PTSD in VA settings. PMID- 22238858 TI - Is a multiple self healthy or pathological? AB - In a sample of 144 undergraduate students, scores on Sackeim and Gur's measure of self-deception were associated with neuroticism scores (r = .50) on the Big Five Inventory, while scores on Altrocchi's measure of having a plural self were associated with neuroticism and openness scores (rs = .35 and .18, respectively). A multiple self, therefore, appears to have positive and negative features. PMID- 22238859 TI - A domain-specific validation of the core self-evaluations scale. AB - Core self-evaluations have been recently proposed as indicating positive self concept and as being predictive of various forms of subjective wellbeing. In an effort to further validate the Core Self-Evaluations Scale (CSES), structural equation modeling (SEM) was employed in three independent samples of university students to examine the extent to which scores on the Core Self-Evaluations Scale predicted two measures of university satisfaction. Good fit was found for models that also controlled for status in college, student major, class satisfaction, life satisfaction, college grade point average, and overall grade fairness. Statistically significant relationships corrected for attenuation by SEM between scores on the Core Self-Evaluations Scale and university satisfaction range from .24 to .37. PMID- 22238860 TI - Comparison of the Vineland Adaptive Behavior Scales, Second Edition, and the Bayley Scales of Infant and Toddler Development, Third Edition. AB - The Vineland Adaptive Behavior Scales, Second Edition (Vineland-II), and Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) were administered to 65 children between the ages of 12 and 42 months referred for developmental delays. Standard scores and age equivalents were compared across instruments. Analyses showed no statistical difference between Vineland-II ABC standard scores and cognitive levels obtained from the Bayley-III. However, Vineland-II Communication and Motor domain standard scores were significantly higher than corresponding scores on the Bayley-III. In addition, age equivalent scores were significantly higher on the Vineland-II for the fine motor subdomain. Implications for early intervention are discussed. PMID- 22238861 TI - The effect of women's suggestive clothing on men's behavior and judgment: a field study. AB - Numerous studies have shown that men overestimate the sexual intent of women based on their clothing style; however, this hypothesis has not been assessed empirically in a natural setting. This small field study measured the time it took for men to approach two female confederates sitting in a tavern, one wearing suggestive clothes and one wearing more conservative clothes. The behavior of 108 men was observed over 54 periods on 16 different nights in two different taverns. The time it took for the men to approach after initial eye contact was significantly shorter in the suggestive clothing condition. The men were also asked by male confederates to rate the likelihood of having a date with the women, and having sex on the first date. The men rated their chances to have a date and to have sex significantly higher in the suggestive clothing condition. Results are discussed with respect to men's possible misinterpretation that women's clothing indicates sexual interest, and the risks associated with the misinterpretation. PMID- 22238862 TI - Contact avoidance toward people with stigmatized attributes: mate choice. AB - If contact avoidance is used to avoid harmful people, then this can play an important role when people choose a spouse, by eliminating undesirable people from the list of candidates. The purpose of this study was to reveal the sex difference in contact avoidance toward people with stigmatic attributes, who are therefore disadvantaged as spouse candidates. A total of 228 university students (101 men, 127 women) participated in the survey. Seven types of men and women with stigmatic characteristics were presented and the respondents asked how much they wanted to avoid contact with each type of person in eight physical contact situations. Female respondents wanted to avoid contact with stigmatized men more than with stigmatized women. On the other hand, male respondents showed comparable responses to both stigmatized men and women. The results were considered from the perspective of mate selection based on evolutionary psychology. PMID- 22238863 TI - Patterns of female suicidal behavior in Ghana. AB - The suicidal behavior of African females is a rarely explored topic. The present study is a descriptive analysis of fatal and nonfatal female suicidal behavior in Ghana. Patterns of both fatal and nonfatal female suicidal behavior recorded by the Ghana Police Service during 2006-2008 are examined and described in depth. The data show that during the 3-yr. period, there were 11 fatal and 4 nonfatal suicidal acts by females, out of the total 243 fatal and 44 nonfatal suicidal acts found in the official data. The author describes the ages and occupations of the women and girls who engaged in fatal and nonfatal suicidal behavior, as well as the suicide method, location, circumstances, and police-assigned motives for the suicidal acts. The author concludes that additional research on female suicidal behavior in Africa and other non-Western societies is warranted to develop a more precise understanding of suicidality. PMID- 22238864 TI - A psychometric study of the Drug Use Disorders Identification Test-Extended in a Norwegian sample. AB - Motivation is a widely used concept in substance use treatment, and is commonly seen as a premise for change during treatment. Different measures of motivation have been suggested. A relatively new instrument is the Drug Use Disorders Identification Test-Extended (DUDIT-E), developed in Sweden. This instrument has recently been introduced in Norway. The present study examined the Motivational Index of the Norwegian version of the Drug Use Disorders Identification Test Extended (DUDIT-E). We tested whether the three-factor model ("Positive aspects of substance abuse"; "Negative aspects of substance abuse"; and "Treatment readiness") suggested by previous studies could be replicated in a sample of Norwegian inpatients. Responses to the DUDIT-E were obtained from 105 patients admitted to inpatient substance abuse treatment in Northern Norway. Exploratory common factor analyses were used to compare the factor structure from the current sample with the Swedish sample of mainly detoxification patients and prison inmates. The current sample did not include prison inmates, and it consisted of more women than the Swedish sample. The samples did not differ according to age or substance dependency. The analyses suggested that six primary factors was the most efficient way of combining the item scores, and not 11 as in the Swedish sample. A second-order factor analysis found best support for a two-factor solution, and hence, did not replicate the previously suggested three-factor model either. Several regression analyses comparing the efficiency of the different ways of combining the DUDIT scores in primary or secondary factor scores indicated that the model involving six sum scores had best merit and should be explored further. PMID- 22238865 TI - Flexibility of theory of mind in a matrix game when partner's level is different. AB - The development of theory of mind (ToM) was investigated as flexibility of prediction and decision-making in matrix games with 202 13-, 16-, 19-, and 24 year-old participants. The ToM flexibility of prediction and decision-making showed no significant differences among any age group. The ToM flexibility of prediction and decision-making of the 0th-order partner was better than that of the 1st-order partner. The ToM flexibility of prediction was better than the ToM flexibility of decision making. Matrix games are a feasible, effective, and discriminative way to explore higher levels of theory of mind. PMID- 22238866 TI - Depression and self-focused language in structured interviews with older men. AB - The association between depression and self-focused language has been found to varying extents across studies. The presence or absence of the association may depend on the communicative context. Based on Beck's depression model, a broad, evaluative self-focused question was predicted more likely to elicit a stronger association than a full interview containing a more heterogeneous question set of items. The spontaneous speech obtained during structured interviews of 26 depressed and nondepressed older men, an as-yet little studied population, was analyzed. Results were consistent with the hypothesis that association between self-focused language and depression was demonstrated in the target question but not across the entire interview. The results may explain some of the aforementioned discrepancies in prior studies. PMID- 22238868 TI - Investigation of habitat effects on the spatial distribution of Lutzomyia shannoni across heterogeneous environments, with note of respective mosquito species compositions. AB - Sand flies are small blood feeding dipterans that are primary vectors of numerous human and livestock pathogens. Control efforts are often complex and multidimensional. A fundamental step in the development and implementation of any integrated pest management (IPM) program is the refining of effective surveillance and identification techniques. Before this study, the presence of two species, Lutzomyia shannoni (Dyar) and Lutzomyia vexator (Coquillett) became known in Kentucky and surrounding states. To understand the spatial distribution of these species across heterogeneous landscapes in this region, trapping was conducted at random locations in previously designated habitats. Although a lack of clear data prevented any conclusions to be drawn for the preferences of L. vexator, the species of greater medical and veterinary importance, L. shannoni, was documented to show a strong preference for habitats along the wooded edges of pasture lands. In the region of study, these lands are frequently used in the production of beef cattle and other livestock, reinforcing the veterinary significance of the findings. Because of their familiarity to vector control officials and operators, mosquito species compositions were compared with the recorded abundance of L. shannoni across the varied habitats. The linking of this information should prove useful to management plans for the phlebotomine, if warranted in the future. PMID- 22238867 TI - Genetics and morphology of Aedes aegypti (Diptera: Culicidae) in septic tanks in Puerto Rico. AB - Dengue viruses, primarily transmitted by the mosquito Aedes aegypti (L.), affect an estimated 50-100 million people yearly. Traditional approaches to control mosquito population numbers, such as the use of pesticides, have had only limited success. Atypical mosquito behavior may be one reason why current vector control efforts have been less efficacious than expected. In Puerto Rico, for example, adult Ae. aegypti have been observed emerging from septic tanks. Interestingly, adults emerging from septic tanks are larger on average than adults collected from surface containers. To determine whether adults colonizing septic tanks constitute a separate Ae. aegypti population, we used 12 previously validated microsatellite loci to examine adult mosquitoes collected from both septic tanks and surface containers, but found no evidence to suggest genetic differentiation. Size differences between septic tank and surface mosquitoes were reduced when nutrient levels were held constant across experimental groups. Despite the absence of evidence suggesting a genetic difference between experimental groups in this study, Ae. aegypti emerging from septic tanks may still represent a more dangerous phenotype and should be given special consideration when developing vector control programs and designing public health interventions in the future. PMID- 22238869 TI - When entomological evidence crawls away: Phormia regina en masse larval dispersal. AB - In criminal and civil legal investigations the forensic entomologist usually assists in providing an estimate of the postmortem interval, which closely couples with the time or period of insect activity. A minimum period of insect activity is often interpreted and estimated by dipteran larval developmental age of the oldest specimens collected at a crime scene and/or autopsy. In entomological evidence protocols investigators are recommended to search a 2-10 m perimeter area for the oldest larvae that may have begun to disperse away from the body for burial and pupation. In this study, we described a case of a large aggregate (> 90% larvae) en masse postfeeding dispersal of blow fly larvae away from replicate swine carcasses serving as models of human decomposition. Larval dispersal was evaluated for a spring and a summer trial, with en masse characteristics only occurring during the latter. This en masse dispersal occurred in five out of six replicate carcasses and masses moved from 2 to 26 m away. These data and observations suggest the importance of performing searches > 10 m from human remains for entomological evidence at crime scenes. By missing the oldest larvae at a crime scene, interpretation of entomological evidence can be compromised and erroneous. Based on these data and observations we recommend the crime scene investigators and researchers consider increasing the search radius around crime scene remains to increase the likelihood that the oldest larvae have been collected for analysis. PMID- 22238870 TI - A formulation to encapsulate nootkatone for tick control. AB - Nootkatone is a component of grapefruit oil that is toxic to the disease vectoring tick, Ixodes scapularis Say, but unfortunately causes phytotoxicity to treated plants and has a short residual activity due to volatility. We prepared a lignin-encapsulated nootkatone formulation to compare with a previously used emulsifiable formulation for volatility, plant phytotoxicity, and toxicity to unfed nymphs of I. scapularis. Volatility of nootkatone was measured directly by trapping nootkatone vapor in a closed system and indirectly by measuring nootkatone residue on treated filter paper after exposure to simulated sunlight (Xenon). After 24 h in the closed system, traps collected only 15% of the nootkatone applied as the encapsulated formulation compared with 40% applied as the emulsifiable formulation. After a 1-h light exposure, the encapsulated formulation retained 92% of the nootkatone concentration compared with only 26% retained by the emulsifiable formulation. For plant phytotoxicity, cabbage, Brassica oleracea L., leaves treated with the encapsulated formulation expressed less necrosis, retaining greater leaf weight compared with leaves treated with the emusifiable formulation. The nootkatone in the emulsifiable formulation was absorbed by cabbage and oat, Avena sativa L., plants (41 and 60% recovered 2 h after application, respectively), as opposed to 100% recovery from the plants treated with encapsulated nootkatone. Using a treated vial technique, encapsulated nootkatone was significantly more toxic to I. scapularis nymphs (LC50 = 20 ng/cm2) compared with toxicity of the emulsifiable formulation (LC50 = 35 ng/cm2). Thus, the encapsulation of nootkatone improved toxicity for tick control, reduced nootkatone volatility, and reduced plant phytotoxicity. PMID- 22238871 TI - Impact of house fly salivary gland hypertrophy virus (MdSGHV) on a heterologous host, Stomoxys calcitrans. AB - The effect of Musca domestica salivary gland hypertrophy virus (MdSGHV) on selected fitness parameters of stable flies, Stomoxys calcitrans (L.), was examined in the laboratory. Virus-injected stable flies of both genders suffered substantially higher mortality than control flies. By day 9, female mortality was 59.3 +/- 10.1% in the virus group compared with 23.7 +/- 3.7% in the controls; mortality in virus-injected males was 78.1 +/- 3.1% compared with 33.3 +/- 9.3% for controls. Fecundity of control flies on days 6-9 was 49-54 eggs deposited per live female per day (total, 8,996 eggs deposited), whereas virus-injected flies produced four to five eggs per female on days 6-7 and less then one egg per female per day thereafter (total, 251 eggs). Fecal spot deposition by virus injected flies was comparable to controls initially but decreased to approximately 50% of control levels by day 4 after injection; infected flies produced only 26% as many fecal spots as healthy flies on days 6 and 7. None of the virus-injected stable flies developed symptoms of salivary gland hypertrophy. Quantitative real-time polymerase chain reaction demonstrated virus replication in injected stable flies, with increasing titers of virus genome copies from one to four days after injection. MdSGHV in stable flies displayed tissue tropism similar to that observed in house fly hosts, with higher viral copy numbers in fat body and salivary glands compared with ovaries. Virus titers were approximately 2 orders of magnitude higher in house fly than in stable fly hosts, and this difference was probably due to the absence of salivary gland hypertrophy in the latter species. PMID- 22238872 TI - Discovery of vector mosquitoes (Diptera: Culicidae) in newly installed above- and belowground stormwater treatment systems in San Diego County, California. AB - Stormwater treatment systems (STS) intended to mitigate the potentially negative public health and environmental impact caused by urban runoff are highly conducive to mosquito production. Thirty-one STS, 15 aboveground extended detention basins (EDBs) and 16 proprietary belowground systems newly installed along State Route 125 in San Diego County, CA, were inspected monthly between July 2008 and June 2009 for presence of standing water and mosquitoes. During the 12-mo study, standing water was observed in 66% of the 180 total inspections to EDBs and at least once in each of the 15 basins, whereas belowground systems held water year-round in permanent-water sumps. With the exception of one EDB, immature mosquitoes were observed in all STS, during every month of the year in EDBs and all months except December in belowground systems. Cumulatively, mosquitoes were noted in 44% of the 372 total site inspections, with a nearly equal number of positive observations from EDBs and belowground systems. Four species were identified from EDBs, Culex tarsalis Coquillett, Cx. quinquefasciatus Say, Anopheles hermsi Barr and Guptavanij, and Culiseta incidens (Thompson). Cx. quinquefasciatus was the sole species identified from belowground systems. Results derived from this study provide additional evidence for mosquito production in STS because of structural design or persistent inflows, or both, of dry-weather urban runoff. Interagency collaboration is needed to ensure that STS are designed and maintained in a way that minimizes their potential to produce mosquitoes that can negatively affect public health. PMID- 22238873 TI - Evaluation of ULV applications against Old World sand fly (Diptera: Psychodidae) species in equatorial Kenya. AB - Reducing populations of phlebotomine sand flies in areas prevalent for human leishmaniases is of ongoing importance to United States military operations and civilian populations in endemic regions. However, not enough is known regarding the efficacy of Department of Defense-approved pesticides and equipment against sand flies; specifically, the potential for ultra-low volume (ULV) pesticide applications to control Old World sand fly vectors. In this study we examine two sprayers, the Terminator ULV and the Grizzly ULV, with UV-labeled Duet and Fyfanon in four combinations against caged Phlebotomus duboscqi (Neveu-Lemaire) and wild sand fly populations in a natural environment in western Kenya. All equipment and Fyfanon have United States military National Stock Numbers and both pesticides are registered with the United States Environmental Protection Agency. Caged sand flies were reared from local P. duboscqi and the area has long been studied because of high incidences of human cutaneous and visceral Leishmania. Patterns of mortality across grids of caged sand flies showed greater efficacy from the Grizzly ULV regardless of chemical. The Terminator ULV performed well with Duet but with a less uniform and overall lower rate of mortality across the spray grid. Sampling of wild populations before and after treatments suggested local population suppression from ULV treatments, as well as a possible repellent effect in nearby untreated areas. Surprisingly, ULV active ingredient deposition inferred from patterns of UV-labeled droplets captured on cotton ribbons adjacent to sand fly cages in spray plots did not match patterns of mortality. We discuss the implications of this study, the first of its kind, for future military preventive medicine activities, including relative performance costs and benefits of larger or smaller sprayers, and the relative stability of ULV-induced mortality patterns in varied or sub-optimal conditions. PMID- 22238874 TI - Acute toxicity studies of safer and more effective analogues of N,N-diethyl-2 phenylacetamide. AB - The present work was designed to evaluate the toxicity of various synthesized aromatic amides that are analogs of N,N-diethyl-2-phenylacetamide, a well known insect repellent. The toxicity profile of these compounds was compared with N,N diethyl-2-phenylacetamide as well as other registered insect repellents namely N,N-diethyl-3-methyl benzamide and N,N-diethylbenzamide. The primary skin irritation index values of the compounds, dermal toxicity of the chemicals and acute oral toxicity data to assess the safety of the synthesized aromatic amides are reported in this paper. Results of hematological and biochemical studies of these analogues are reported and discussed. PMID- 22238875 TI - Variability of the susceptibility to deltamethrin in Triatoma infestans: the female factor. AB - We analyzed the variability of susceptibility to deltamethrin in putatively susceptible Triatoma infestans Klug (Hemiptera: Reduviidae), and evaluated the sample size implications on the hypotheses used in the current World Health Organization protocol for the measure of insecticide resistance in Triatominae. Following the protocol, using topical application of deltamethrin to unfed first instar nymphs of T. infestans, we found that susceptibility showed significant differences between offspring from different females, a significant association with female age, and significant interaction female x female age. Considering individual female data, three patterns of nymphal mortality were identified: one showed a strong positive relation between nymphal mortality and their mother's age, another showed high mortality with low variability and the third showed intermediate mortality with high variability along female age. The analysis suggests revision of the World Health Organization protocol for resistance detection in Triatominae, not only to take into consideration the sources of variation in susceptibility, but also the effects of sample size in relation to the significance and power probabilities of the test. PMID- 22238876 TI - Ivermectin acts as a posteclosion nymphicide by reducing blood feeding of human head lice (Anoplura: Pediculidae) that hatched from treated eggs. AB - The 0.5% ivermectin topical cream formulation was not directly ovicidal to treated eggs of head lice, as hatchability was not decreased. Nevertheless, the percent of hatched lice from treated eggs that took a blood meal significantly decreased (80-95%) compared with lice that hatched from untreated eggs and all treated lice died within 48 h of hatching, including those that fed. Dilutions of ivermectin formulation of 0.15 and 0.2 microg/ml, which were topically applied to 0-8 d old eggs, were not lethal to lice at 24 h posteclosion. However, 9 and 16% less lice fed when hatched from these treated eggs, respectively. Total [3H] inulin ingested by untreated first instars significantly increased over a 48 h feeding interval but was significantly less in instars that hatched from eggs receiving the 0.15 (36% less) and 0.2 (55% less) microg/ml ivermectin treatments compared with placebo. The reduced feeding that occurred after the 0.15 and 0.2 microg/ml ivermectin treatments occurred in the absence of mortality and suggests a unique mode of action of ivermectin on feeding that is separate from the mode of action of ivermectin leading to mortality. Failure of hatched instars to take a blood meal after egg treatments with formulated ivermectin is likely responsible for its action as a posteclosion nymphicide. PMID- 22238877 TI - Virulence of a malaria parasite, Plasmodium mexicanum, for its sand fly vectors, Lutzomyia vexator and Lutzomyia stewarti (Diptera: Psychodidae). AB - Evolutionary theory predicts that virulence of parasites for mobile vector insects will be low for natural parasite-host associations that have coevolved. I determined virulence of the malaria parasite of lizards, Plasmodium mexicanum, for its vectors, two species of sand fly (Diptera: Psychodidae), Lutzomyia vexator (Coquillett 1907) and Lutzomyia stewarti (Mangabeira Fo & Galindo 1944), by measuring several life history traits. Developmental rate from egg to eclosion differed for the two species when noninfected. For both sand fly species, developmental rate for each stage (egg to larval hatching, larval period, pupal period) and life span were not altered by infection. Infected sand flies, however, produced fewer eggs. This reduction in fecundity may be a result of lower quality of the blood meal taken from infected lizards (lower concentration of hemoglobin). This report is the first measure of virulence of Plasmodium for an insect vector other than a mosquito and concords with both expectations of theory and previous studies on natural parasite-host associations that revealed low virulence. PMID- 22238878 TI - Strategies for controlling the epizootic amplification of arboviruses. AB - A previously validated, spatially explicit, agent-based model of arbovirus transmission among vector mosquitoes and avian hosts is used to explore the effectiveness of different insecticide control strategies for reducing rates of epizootic transmission and mosquito infection. Mosquito control within the model reduces infection rates among hosts and vectors but generally lengthens the transmission season. Insecticide application focused at oviposition sites is found to be as effective as control applied over the entire model landscape. The findings also indicate that optimum use of insecticide resources would first target areas in which bird activity is collocated with vector mosquito breeding sites, and then, if resources permit and mosquito mortality due to the insecticide is high, target other vector mosquito breeding habitats. More broadly, these experiments demonstrate that model systems provide an economical framework for testing different mosquito and mosquito-borne pathogen control strategies and can ultimately inform field interventions and enable better allocation of intervention resources. PMID- 22238879 TI - Ability of selected Kenyan mosquito (Diptera: Culicidae) species to transmit West Nile virus under laboratory conditions. AB - West Nile virus (WNV) is currently active in Kenya as evidenced by the detection of antibodies in birds bled as part of an avian influenza surveillance program in 2009. Although WNV has been isolated from several mosquito species in Kenya, no studies have ever been conducted to determine which of these species are competent vectors of this virus. Therefore, we allowed Kenyan mosquitoes to feed on 2- or 3-d-old chickens that had been infected with a Lineage one strain of WNV 24-48 h earlier. These mosquitoes were tested approximately 2 wk later to determine infection, dissemination, and transmission rates. All five species [Culex quinquefasciatus Say, Culex univittatus Theobald, Culex vansomereni Edwards, Mansonia africana (Theobald), and Mansonia uniformis (Theobald)] were susceptible to infection, but disseminated infections were detected only in the three Culex, and not the two Mansonia species. Culex mosquitoes with a disseminated infection readily transmitted virus by bite, but even when inoculated with WNV, the two Mansonia failed to transmit virus, indicating a salivary gland barrier. These studies indicate that the three Culex species may play a role in the transmission of WNV in Kenya. PMID- 22238880 TI - Retention of Campylobacter (Campylobacterales: Campylobacteraceae) in the house fly (Diptera: Muscidae). AB - The house fly (Musca domestica L.) may transmit Campylobacter to broiler flocks. We assessed the retention time of house flies for Campylobacter jejuni at five temperatures and three doses. Flies were inoculated individually at their proboscis with 1.6 x 10(7) CFU (colony forming units) of C. jejuni and incubated at 15, 20, 25, 30, and 35 degrees C. Furthermore, a dose experiment was conducted at 25 degrees C where individual flies were inoculated in three series: 6.5 x 10(6), 6.0 x 10(4), and 8.2 x 10(2) C.jejuni CFU. Whole flies were tested for C. jejuni carriage at 0, 6, 12, 18, and 24 h by initial preenrichment in Bolton broth, which afterwards was streaked on modified mCCDA agar plates and incubated under micro-aerobic conditions. The results showed that the time C. jejuni remained in flies declined over time with ascending temperatures and when reducing the inoculation dose. All flies stayed Campylobacter positive 24 h postinoculation at 15 degrees C whereas only one-third of the flies were positive at 20 degrees C and few to none at 25, 30, and 35 degrees C. When combinations of temperature and retention time were expressed as accumulated day-degrees, data could be adequately fitted using a generalized linear mixed model that included a linear effect of day-degrees and the difference between the lowest and the two highest doses. Based on model predictions of selected combinations of temperature and dose, the time for 50% and 1% of flies containing Campylobacter was calculated. It is suggested that house flies are mainly short distance carriers of C. jejuni. PMID- 22238881 TI - Disproportionate mosquito feeding on aggregated hosts. AB - Despite the importance of per-capita feeding rates for mosquito-borne transmission dynamics, the relationship between host aggregation and per-capita feeding rates remains poorly characterized. We conducted indoor experiments to investigate how Culex quinquefasciatus (Say) mosquitoes distribute their blood feeding on variably aggregated domestic chickens (Callus gallus domesticus L.) (one chicken vs. a flock of seven to nine birds). Mosquitoes were always more likely to feed on the larger chicken group; yet, the single chicken tended to be fed on at a higher per-capita rate. When 10 chickens were available the feeding intensity was 4.5 times higher for the single chicken compared with the flock. We conclude that more highly aggregated hosts may experience lower exposure to mosquito bites than less aggregated hosts. PMID- 22238882 TI - Aedes albopictus (Diptera: Culicidae) population size survey in the 2007 Chikungunya outbreak area in Italy. I. Characterization of breeding sites and evaluation of sampling methodologies. AB - The population of Aedes albopictus (Skuse) (Diptera: Culicidae) was measured in four towns in northern Italy by means of Stegomyia indices (house index: percentage of houses with at least one active breeding site; container index: percentage of containers with larvae; and Breteau index: number of active breeding sites per premises), pupae per premises index (PPI), pupae per hectare index (PHI), and ovitrap monitoring. A detailed investigation on types and number of productive or potential larval habitats in the inspected premises was performed. Catch basins were the most productive breeding sites in both private and public areas. The influence of the premises maintenance and premises shading indices (PMI and PSI) on the population indices and the correlations between the latter and egg density were assessed. The highest PPI was found in badly maintained premises, most times combined with shady coverage. Stegomyia indices and PPI were well correlated with each other, but not with the PHI, which also included the pupae collected in public areas. We obtained a highly positive correlation (R = 0.86) between the PHI and weekly mean egg density estimated 7-14 d after inspection of the premises. The number of females per hectare, calculated using the Focks model, was correlated with the mean egg density of the week after sampling (R = 0.79), and we propose that ovitrap monitoring can be used to evaluate the efficiency of the control activities or to determine a mean egg density threshold for epidemic risk evaluation. PMID- 22238883 TI - Altered response to DEET repellent after infection of Aedes aegypti (Diptera: Culicidae) with Sindbis virus. AB - To determine whether a Sindbis virus (family Togaviridae, genus Alphavirus, SINV) infection in Aedes aegypti (L.) (Diptera: Culicidae) affected its response to the repellent DEET, we orally exposed Ae. aegypti to an artificial bloodmeal containing SINV or diluent and then allowed to feed on a 10% sucrose suspension containing 3% DEET. When tested seven or more days after the initial bloodmeal, although none of the diluent-exposed mosquitoes fed on the DEET-sucrose suspension, at least 60% of the SINV-exposed mosquitoes fed on the suspension. When legs from the SINV-exposed mosquitoes were tested to determine dissemination status, 89% of those that fed on the DEET-sucrose suspension contained virus. In contrast, only 34% of the nonfeeders had a disseminated infection. When offered a choice between sucrose with or without DEET, a significantly higher percentage of the SINV-exposed mosquitoes than the control mosquitoes fed on the sucrose containing 3% DEET. Together, these results indicate that mosquitoes with a disseminated SINV infection may be less responsive to DEET than uninfected mosquitoes. Therefore, repellent use may be less effective in deterring infected mosquitoes from biting than previously believed. PMID- 22238884 TI - A comparison of blow fly (Diptera: Calliphoridae) and beetle (Coleoptera) activity on refrigerated only versus frozen-thawed pig carcasses in Indiana. AB - To have large numbers of replicates in forensic entomology research, it is often necessary to freeze carcasses and thaw them before use in experiments. Research on the effects of freezing on decomposition is minimal in the literature and the effect that it has on insect (e.g., blow fly, beetle) activity is virtually unknown. The objective of this study was to compare the differences in insect activity occurring on refrigerated only versus frozen-thawed pig carcasses, and to characterize the associated dipteran fauna. Seven pigs, frozen for 2 mo and then thawed before the experiment, were compared with seven pigs killed and stored in a walk in refrigerator approximately 12 h before the start of the experiment. No significant differences in time to the appearance of adult flies, eggs, larvae, or the initiation and conclusion of larval migration were observed between refrigerated only and frozen-thawed pig carcasses. Beetles from the family Staphylinidae also did not show a significant difference in arrival times. Phormia regina (Meigen), Lucilia coeruleiviridis (Macquart), Cochliomyia macellaria (F.), Pollenia rudis (F.), and Hydrotaea leucostoma (F.) comprised the dipteran taxa present on the carcasses. Results suggest that freezing pigs before exposure in the field does not significantly alter blow fly life events or the appearance of staphylinid beetles. PMID- 22238885 TI - Cadaver wrapping and arrival performance of adult flies in an oil palm plantation in northern Peninsular Malaysia. AB - There is accumulating evidence that criminals wrap dead bodies in an attempt to conceal evidence. To anticipate the forensic implications of this phenomenon, we examined whether flies that are naturally associated with cadavers exhibit a delay in attendance or differ in species composition and abundance patterns because of the presence of wrapping material. Wrapped and exposed carcasses of dead monkeys placed in an oil plantation in Kedah, Malaysia, were visited over 50 d. On daily visits to each of the six carcasses, visiting adult flies were sampled using hand nets. Flies of 12 families were encountered. Calliphoridae (Chrysomya rufifacies Macquart and C. megacephala (F.) was the most prevalent family, followed by Sphaeroceridae. Some families tended to be more abundant in WRCs (i.e., Calliphoridae, Muscidae, and Phoridae), whereas others (i.e., Piophilidae, Sepsidae, and Psychodidae) were more prevalent in exposed carcasses. Wrapping delayed the arrival of all fly species encountered, with delays varying from 1 to 13 d depending on species. Wrapping did not affect species composition of flies, but prolong the occurrence of some species. The results of the current study emphasize the need to take into consideration the presence of a wrap when estimating postmortem interval. PMID- 22238886 TI - Field evaluation of commercial repellents against the floodwater mosquito Psorophora columbiae (Diptera: Culicidae) in St. Johns County, Florida. AB - Three plant-based repellents-REPEL LEMON Eucalyptus Insect Repellent Lotion (active ingredient [AI] 30% oil of eucalyptus), Bite Blocker Xtreme Sportsman Organic Insect Repellent ([AI] 3% soybean oil, 6% geranium oil, and 8% castor oil), and Bite Blocker BioUD Insect Repellent ([AI] 7.75% 2-undecanone)--were evaluated against OFF! ([AI] 15% N,N-diethyl-m-toluamide or N,N-diethyl-3-methyl benzamide, also called DEET) at a field site in Elkton, FL, to determine the mean protection time provided against Psorophora columbiae (Dyar & Knab). These products provided different protection times against biting Ps. columbiae. REPEL provided the longest protection time (330 min) followed by Bite Blocker Xtreme Sportsman (163 min), Bite Blocker BioUD (140 min), and OFF! (130 min). This study provides the first information about plant-based insect repellent protection times against Ps. columbiae. PMID- 22238887 TI - Japanese encephalitis virus in culicine mosquitoes (Diptera: Culicidae) collected at Daeseongdong, a village in the demilitarized zone of the Republic of Korea. AB - In total, 22,846 (17,793 culicines and 5,053 Anopheles spp.) female mosquitoes were captured by a Mosquito Magnet trap at Daeseongdong, a small village adjacent to the military demarcation line (center of the demilitarized zone) in northern Gyeonggi Province, Republic of Korea (ROK). Culicine mosquitoes were identified to species, placed in pools of up to 30 mosquitoes each, and screened for flavivirus using a SYBR Green I-based real-time polymerase chain reaction. In total, 51/660 pools positive for flaviviruses and confirmed by DNA sequencing of the NS5 region, were positive for Japanese encephalitis virus (family Flaviviridae, genus Flavivirus, JEV) (50 Culex tritaeniorhynchus Giles and one Culex bitaeniorhynchus Giles). The JEV maximum likelihood estimations (MLEs) (estimated number of viral RNA-positive mosquitoes per 1,000) for Cx. tritaeniorhynchus and Cx. bitaeniorhynchus were 9.7 and 0.9, respectively. This is the first report of a Cx. bitaeniorhynchus positive for JEV in the ROK. JEV is a local civilian and military health threat and a significant concern for nonimmune (unvaccinated) U.S. soldiers, civilians, and family members deployed to the ROK. PMID- 22238888 TI - Molecular detection of Bartonella species in ticks from Peru. AB - A total of 103 ticks, collected from canines, horses, donkeys, and snakes from Peru, were screened for the presence of Bartonella DNA by polymerase chain reaction analysis. Bartonella DNA was detected in two ticks using Bartonella 16S 23S intergenic spacer region primers and in an additional two ticks using Bartonella NADH dehydrogenase gamma subunit gene (nuoG) primers. Bartonella rochalimae Eremeeva et al., B. quintana Schmincke, and B. elizabethae Daly et al. DNA was detected in a Rhipicephalus sanguineus Latreille (Acari: Ixodidae) female tick removed from a dog and B. quintana DNA was present in a Dermacentor nitens Neumann (Acari: Ixodidae) pool of five larvae, one nymph, and one adult male tick collected from donkeys. This is the first study to report the detection of B. rochalimae, B. quintana, and B. elizabethae DNA in ticks from Peru. Further investigations must be performed to decipher the role ticks may play in the transmission of Bartonella species. PMID- 22238889 TI - Real-life bioethics. PMID- 22238890 TI - Anorexia, authenticity, and the expert perspective. PMID- 22238891 TI - Rationing and reality. PMID- 22238892 TI - Rationing and reality. PMID- 22238893 TI - Rationing and reality. PMID- 22238895 TI - Commercial speech bruises health privacy in the Supreme Court. PMID- 22238894 TI - Compassion. PMID- 22238896 TI - New rules for research with human participants? PMID- 22238897 TI - Confidentiality and its limits. PMID- 22238898 TI - Case study. Confidentiality and its limits. Commentary. PMID- 22238899 TI - Case study. Confidentiality and its limits. Commentary. PMID- 22238900 TI - Bioethics and cancer: when the professional becomes personal. PMID- 22238901 TI - Anorexia nervosa and the language of authenticity. AB - People with anorexia nervosa struggle with questions of authenticity. They thought about whether they were being their authentic selves, and which of their desires, emotions, and choices were authentic. More attention should be paid this important concept and its role and status--both how patients think about it, and how clinicians should think about it. PMID- 22238902 TI - The rationality and morality of dying children. AB - Formal reason is not adequate to explain how we think through real-life problems and make moral decisions about them. A far richer account of rationality is necessary. Interviews conducted with children who have leukemia, and who must figure out by themselves that they are dying and how they should handle that information, illustrate a range on informal tools that must be part of that account. PMID- 22238903 TI - Fetal sentience and women's rights. PMID- 22238904 TI - Human enhancement. Foreword. PMID- 22238905 TI - [Human nature and the enhancement of human beings in the light of the transhumanist program]. AB - There are three main approaches about the question of Human Nature. essentialists consider that there exists a permanent Human Nature, shared by every human being. Existentialists consider that there is no such thing as human nature, but inescapable modes of being in the world. A moderate approach would consider that Human Nature can be modified within the limits of anthropological invariants. Transhumanists are conservative in that they think that there is a Human Nature; but they are radical in that they believe that it can (and must) be transcended by bio-technnologies and computer technologies. This project is evaluated as a caricature of suitable human enhancement. PMID- 22238906 TI - [Human technical enhancement: an introduction to the currents of the debate as well as their fracture lines]. AB - The main objective of this article is to suggest a panel of the different positions active in the human enhancement's debate, to analyze their arguments and to point out the dividing zones. The transhumanist movement is therefore presented in order to highlight the principal thematic of its philosophy, its means of action and the plurality of its subgroups. The purpose is to reassess its complexity in an introductory manner far from the usual, excessive simplifications. In a second time, the "bioconservative" movement is also examined in its foundations to emphasize the norms and principles that are undoubtedly shared by the opponents to the human being's modification. Then, the thinkers of the "liberal ethics" are exemplified as a more moderate alternative, although not flawless. Generally open-minded towards the application of enhancement technologies, they protect as an ultimate guardian, the harm principle, as well as the absolute respect of individual freedom. Once the protagonists are introduced, the true meaning of these positions is replaced in the context of the three main fracture lines: the human nature, the normality criterion and the equality principle. A complex debate indeed that we could summarize by a simple question: what will human do about the human in the 21st century? PMID- 22238907 TI - [Human, transhuman, posthuman. Representations of the body between incompleteness and enhancement]. AB - "Posthuman" is often used to indicate some position, practice, perspective and vision concerning the future of human beings closely related to the use of contemporary technologies. This contribution would like to analyze some conceptions of the notion of posthuman and to present it as a possible form of "non-anthropocentric" thought which considers technological changes as non-human realities strictly involved in the construction and the definition of what constitutes a human being (and his body) and its predicates. Contrary to anthropocentrism which has characterized Western thought from humanism up to the extreme outcomes of transhumanism, non-anthropocentric posthumanism shows how the human being, who has always been the product of hybridization with the non-human (environment, animals and techniques), is built not only by his own strength but always through his partnership and his environment. The idea of enhancement of the body by technology to reach another stage of human evolution is one of the constant elements characterizing transhumanism. Posthumanism suggests no longer considering the interface with technology as an ergonomic relationship with an external tool that just extends the human body, but as a hybrid, or interpenetration that questions the separation of the body and its centrality. In this perspective, the question is not of simply establishing which is a good use of a technology but, every time, of redefining ourselves in our perspectives and our predicates with regard to what a technology allows and opens up to us. PMID- 22238908 TI - [Humanness can be said in many ways]. AB - The recent debates on human enhancement ask the question whether enhancing our capabilities is morally desirable. In a sense, the answer is straightforward: to enhance, that is to make things better, is, by definition, a good thing. However, to enhance has a special meaning in the present debates: it consists in going beyond our "natural" capabilities. Is it then still a good thing? To answer this question, it is necessary to ask what is the value of the goods we pursue through enhancement, and this is only possible in the context of a conception of human flourishing. There exist several conceptions of human flourishing; each demands that we improve ourselves in certain directions, depending on the various excellences and on the ideal of the person they promote. But are all means permissible to this effect? Of course not. A set of normative principles is suggested in order to determine which means are permissible. The result of this is that technological and biotechnological means raise no particular problem. PMID- 22238909 TI - ["Cognitive doping": meaning and stakes]. AB - This article examines the scope and issues specific to using the term "doping" to describe the growing consumption of cognitive enhancers. It traces the history of the taking of substances for the purpose of improving brain functions and discusses the reasons for its negative connotation. In order to evaluate this moral rejection, it sifts through the possible objections that we could emit against the nootropics, at the individual and societal levels. It proposes to restore the concept of "doping" in our cultural heritage, characterized by the conflicting ideals of authenticity and self-improvement, to finally acknowledge the specificity of our time that has to do with personal achievement through performance. Without incensing doping practices, this article suggests that evincing radically intellectual and/or emotional "doping" is sterile, in contradiction with our actions and preventing us from thinking serenely the use of enhancing drugs. PMID- 22238910 TI - [Doping in sport and enhancement medicine]. AB - The reason that gives doping in sport a deeper philosophical and ethical dimension is the emergence of a new medical paradigm: enhancement medicine. The question of enhancing performance in sport has become part of a broader societal debate on human enhancement. The gradual blurriness of the boarders between therapeutic medicine and enhancement medicine constitutes the most spectacular and the most troublesome form of these modifications. In the contemporary biomedicine, the new medicines and technologies can be used not only to cure the patients but also to enhance human capacities. This evolution represents a paradigmatic change in the medical practice: it is not the mere restoration of health which is expected anymore, nor the promotion of health. What is required is the improvement of performance and the perfectibility of the human being, including in the field of sport. Competitive sport could become the main laboratory of enhancement medicine. The intersection of science and sport raises fundamental philosophical, ethical and policy issues that cannot be answered easily. The prohibition and the war on doping is not the only solution. PMID- 22238911 TI - [Bodily excellence and education: ambiguities of performance]. AB - The notion of excellence contains an ambivalence: to aim at the "good" and/or to aim at the "best". This ambivalence exists particularly in the physical effort and in the history of bodily practices, shared between gymnastics, physical education and sports. In the second part of the XXth century, the notion of performance became "worship of performance", "infinite perfectibility". In this context, high level sports became the human improvement laboratory, thanks to the sophistication of its technical means and the its practices intensity. However this "high" questions: about physical and psychological consequences of intensive practices ; about doping and its medical and ethical perspectives; about the increasing precociousness and the potential exploitation of the baby champions. It questions about the nature of familial, social, economical norms transmitted by education: about articulation between constraint and self-government. This is the question about the "price" of excellence. In this sense it appears that the excellence of champion spreads out the margins of an ethics which would be meant to be regulating and universal, indeed this excellence is perhaps, in the same capacity as genius is and in spite of the attachment of sports to a "ethics of the rule", un-ethical. PMID- 22238912 TI - [Enhancement and ethics]. AB - Now suppose we could use genetic engineering, regenerative medicine or drugs - chemical enhancers, or reproductive technology or nanotechnology to produce healthier, fitter and more intelligent individuals, what should our reaction be? Would it be unethical to do so? Would it be ethical not to do so? Our question is this: If the goal of enhanced intelligence, increased powers and capacities and better health is something that we might strive to produce through education, including of course the more general health education of the community; why should we not produce these goals, if we can do so safely, through enhancement technologies or procedures? If these are legitimate aims of education could they be illegitimate as the aims of medical or life science, as opposed to educational science? PMID- 22238913 TI - Cognitive enhancement, human evolution and bioethics. AB - The goal of this article are three-fold. The first is to explore the relations between the properties designated by the terms "human", "post-human," "Transhuman", and to clarify the corresponding "isms". The second is to scrutinize the current techniques for cognitive enhancement in order to assess their relations with the three categories just mentioned, and, with the specific ethical issues that they are raising. The third is to examine whether general ethical principles could be invoked either in favor of or against, the normative proposals of post- and trans-humanism, and to consider how compatible the types of enhancement presently developed are with respect to these principles. PMID- 22238914 TI - Enhancing technologies: transformatio ad quod optimum? AB - The aim of the present paper is to bring out that the way in which we understand the enhancing and genetic interventions is closely related to the notion of health we adopt and this, in turn, to the worldview which underlies it. I explore the two notions of health which have prevailed since antiquity and which continue to co-exist in our era, and I point out that, if either of these makes sense, this is because each presupposes a different worldview with its own normative framework and moral values. As a consequence, when we argue about the enhancing interventions, we are not so much disagreeing about the application of this or that genetic technology as about the different ways in which we conceive our life and place in the world. PMID- 22238915 TI - [Mild brain injuries in emergency medicine]. AB - Diagnostics and correct classification of mild brain injuries is challenging. Problems caused by insufficient documentation at the acute phase become more obvious in situations in which legal insurance issues are to be considered. A small proportion of patients with mild brain injury suffer from prolonged symptoms. Medical recording and classification of the brain injury at the initial phase should therefore be carried out in a structured manner. The review deals with the diagnostic problems of mild brain injuries and presents a treatment protocol for adult patients at the acute phase, aiming at avoiding prolonged problems. PMID- 22238916 TI - [Stem cell transplantation in myelofibrosis]. AB - Allogeneic hematopoietic stem cell transplantation (ASCT) offers the only potentially curative therapy for myelofibrosis, a malignant myeloproliferative disease. The transplant-related mortality is still high, 10-48%, but use of reduced-intensity conditioning is less toxic and allows transplantation to be performed up to 65-70 years of age. Fabourable treatment response will be attained at least in a third of patients, in another third the disease will progress, and nearly one third will succumb due to transplant complications. Thirteen patients with myelofibrosis underwent ASCT at our institution between 1999 and 2009. The outcome of the patients treated with reduced-intensity conditioning corresponds well with those reported in the literature. PMID- 22238917 TI - [Tattoos--what the physician needs to know?]. AB - During the last 20 years needle tattooing has gained great popularity in the Western countries. However, introduction of color pigments or dyes into the skin is not harmless. Local skin problems may be manifested as inflammation, hypersensitivity to dyes, benign or malignant tumors or onset of chronic diseases on tattooed skin areas. Needle tattooing also predisposes to rare but potential blood-borne infections such as hepatitis C and bacterial sepsis. Anyone having a severe primary disease or being under immunosuppressive medication should be aware of the health risks of tattooing. PMID- 22238918 TI - [Neurologic indications of botulin in adults]. AB - Botulin is established as first-line treatment in cervical dystonia, blepharospasm, hemifacial spasm and stroke-related spasticity of the distal parts of the upper limb. In addition, many other motor disorders and muscular hyperactivity states and neurologic symptoms and manifestations, in which temporary muscle paralysis, analgesic properties and effects on the functioning of the autonomic nervous system brought about by botulin can be utilized, have become indications for use. With proper dosage, botulin has proven to be safe even in prolonged use, the effect usually lasting for years. PMID- 22238919 TI - [Botulinum toxin treatment in children]. AB - Botulinum toxin type A treatments in children were started nearly 20 years ago. The first and still most common indication is spastic equinus gait in cerebral palsy, but other indications have emerged, such as idiopathic toe-walking, peri- and post-operative pain, drooling and idiopathic congenital torticollis. The official indication for botulinum toxin treatment is spastic equinus gait in children over 2 years of age. Botulinum toxin is known as the most potent toxin. However, it has proved to be safe and well tolerated among paediatric patients. Adverse events are infrequent, mostly bruising and limited, temporary muscle weakness. With higher doses the risk for generalized adverse events increases. PMID- 22238920 TI - [Botulinum toxins for pain]. AB - We review the evidence of botulinum toxins in the treatment of pain. Main indications of botulinum toxin treatment, dystonia and spasticity, involve pain. Increasing evidence suggests direct analgesic effects of botulinum. Botulinum inhibits release of pain mediators (substance P, CGRP, excitatory amino acids, ATP, noradrenaline). Clinical trials have consistently shown analgesic effect of botulinum toxin in post-stroke shoulder pain, bladder dysfunction, chronic migraine, neuropathic pain, bruxism and lateral epicondylitis. Other pain conditions have been studied with yet uncertain results. It seems that the number of patients who would benefit from botulinum toxin treatment will increase considerably in the future. PMID- 22238921 TI - [Applications of botulin]. AB - Among the ailments of the ocular region, the use of botulin has become established in the treatment of blepharospasm and hemifacial spasm in Finland. Botulin has also been used successfully after peripheral facial palsy to improve facial symmetry, reduce lachrymal flow, treat dribbling of saliva as well as spasmodic dysphonia of laryngeal muscles. It may be effective in dysphagia caused by tightness of the upper esophageal sphincter or in several dyshidroses. Gastroenterologic indications include anal fissure and spasm and achalasia of the lower esophageal sphincter. In urology, botulin is effective in overactive bladder and incomplete voiding. PMID- 22238922 TI - [Strategies of breast cancer treatment based on determination of biological subtype]. PMID- 22238923 TI - [Locally advanced breast cancer (methods of treatment)]. PMID- 22238924 TI - [Breast cancer subtypes and their endocrine-metabolic basis; practical aspects]. PMID- 22238925 TI - [Long-term results of adjuvant endocrine therapy for hormone receptor-positive breast cancer]. PMID- 22238926 TI - [Significance and specifics of surgical treatment in locally advanced breast cancer]. PMID- 22238927 TI - [Diagnosis and treatment of pregnancy-associated breast cancer]. PMID- 22238928 TI - [Novel target therapies used in breast cancer management]. PMID- 22238929 TI - [Is low-dose tamoxifen an effective therapy for breast carcinoma in situ?]. PMID- 22238930 TI - [Pharmacoeconomic aspects of breast cancer management]. PMID- 22238931 TI - [Breast cancer: morbidity, mortality, survival (population study)]. PMID- 22238932 TI - [Lymphoscintigraphy of separate lymph nodes for radiotherapy planning in breast cancer]. AB - Determination of lymph flow from breast cancer can be used as effective tool for individualization of radiation portals for regional radiotherapy. We evaluated this technique in 86 patients with lymph nodes (LN) scintigraphy which was performed 20-240 min after intratumoural injection of 50-100 MBq of 99mTc nanocolloids. After visualisation of lymph flow patterns standard radiation portals were modified in 75% of patients with external and 85%--with internal localisation of primary tumours, In addition we recognised that extent and wideness of radiation portals for internal mammary lymph LN must be arranged in accordance with individual lymph flow pattern. In particularly irradiation of LN on both sides of the sternum was performed only in 3 of 27 (11%) evaluated cases. PMID- 22238933 TI - [Early diagnosis of breast cancer with scintimammography and ultrasound ]. AB - The purpose of this study was to evaluate the role of scintimammography (SMG) and ultrasound (US) in early diagnosis of breast cancer. SMG was administered to 32 women with breast lesions of less than 1 cm in diameter. In addition, all patients underwent high frequency US imaging with digital wide field of view. The following US features were set as diagnostic: heterogeneous echo pattern, irregular morphology, hyperecho, poorly defined edges, posterior acoustic attenuation. SMG was performed in planar and tomography modes 15 min. after i/v injection of 740-860 MBq 99mTc-sestamibi. Images with focal and scattered patchy uptake were discarded. Data on all lesions were verified by biopsy and/or surgery. Thirty-six women revealed lesions of less than 1 cm: 12 out of 14 cases of breast cancer had them, while malignancy was not detected in 16 of 21 women with benign breast lesions. Sensitivity (Sen), Specificity (Sp) and Accuracy (Ac) of SMG in this group was as follows: 86%, 76% and 80%, respectively. US examinations in this group diagnosed benign lesions in 27 out of 35 women: 21- negative, 6--false negative. In the remaining 8 cases, US findings on breast cancer were positive: Sen was low (57%), Sp--high (100%) and Ac--moderate (82%). Taking into account that SMG represents functional status of breast lesions while US--anatomical one, we tested diagnostic value of their combination too (US+SMG). Cancer diagnosis was passed when either SMG or US revealed abnormalities. This diagnostic strategy featured outstanding Sen (100%), moderate Sp (76%) and Ac of 82%. It may be concluded that the combination procedure seems highly promising as far as early diagnosis of small (< 1 cm) breast cancers are concerned. PMID- 22238934 TI - [The risk of local recurrence after breast-conserving surgery for breast cancer]. AB - Recently, the rates of early stage breast cancers involving breast-conserving therapy have increased due to use of mammography screening. Morever, a patient's desire to keep the breast is now considered to be a factor which determines the surgery tactics. However, there has been so far no consensus on optimal extent of surgery capable of preventing local recurrence. In order to precisely estimate such risk it is essential to take into account factors such as tumor size, surgical margin status and age. Besides, correlations between certain subtypes of breast cancer and various associated risks of local recurrence are to be established. Another important factor is to devise the necessary subsequent radiotherapy. PMID- 22238935 TI - [The role of nanotechnology in creating novel antitumor agents]. AB - Nanobiotechnology, defined as an arm of a nano-system is a rapidly developing area of medicine. Nanomaterials ranging from 1 to 1000 nm in size offer unique advantages of interaction with biological systems on the molecular level. Nanobiotechnologies can be used in definition, diagnosis and treatment of cancer thus leading to the new development of a new discipline--nanooncology. The potential of nanoparticles to be used in in-vivo tumor visualization, biomolecular profiling of tumor growth factors and targeted drug delivery is being studied. These methods stemming from nanotechnology may soon find a broad application in oncology. PMID- 22238936 TI - [Endocrine therapy for postmenopausal breast cancer (role of cycline D1)]. PMID- 22238937 TI - [Use of Taxotere in neoadjuvant therapy of breast cancer]. AB - Wide-range research in the efficacy of neoadjuvant therapy of breast cancer has been conducted worldwide for over two decades. Promising end results have been reported on completion of clinical and pathomorpologic response. It has become a standard practice in managing relatively operable and inoperable breast cancer. However, preoperative chemotherapy in operable disease is still a subject of discussion. For many years anthracycline-based treatment has remained a therapy of choice in the neoadjuvant setting. Higher efficacy of its combined use with taxotere and anthracycline was demonstrated. It was followed by higher rates of complete pathomorphologic response and survival. Besides, regimens using taxotere and target therapies are being investigated. Tentative results suggest that better survival may be achieved due to decreased toxicity profiles. PMID- 22238938 TI - [Use of Taxotere in adjuvant chemotherapy of breast cancer]. PMID- 22238939 TI - [Results of single-stage reconstructive surgery in breast cancer patients (a report of 1143 cases)]. AB - Our experience with 1143 single-stage surgeries in breast cancer patients undergoing skin-sparing mastectomies and breast-conserving surgery is presented. Both patients' tissues and silicone implants were used for reconstruction purposes. Latissimus dorsi muscle in combination with endoprothesis was used in 592 patients. The lowest local recurrence rate was reported in the skin-sparing mastectomy group, obviously due to a greater amount of tissues dissected. PMID- 22238940 TI - [Specific features of mammographic visualization of "small" breast tumors developing on the background of fibrocystic disease]. AB - All complications diagnosed at early stages of breast cancer were associated with small tumors, especially with those arising in the aftermath of fibrocystic disease. Hence, our task was to study the XR-semiotics of lesions of less than 15 mm in diameter and of the same origin. 100 mammograms of breast cancer patients with benign disease of the breast were studied. The presence of moderate-to severe fibrocystic disease significantly affected the visualization of lesions of less than 10 mm in diameter. Since the XR-semiotics of small tumors failed to reveal malignancy features, all lesions visualized by mammography required additional diagnostic procedures using ultrasound and invasive radiology. PMID- 22238942 TI - [Brain metastasis in breast cancer]. AB - Brain metastasis is an important issue in modern neurooncology. Our results of combined treatment of brain metastases are presented and available approaches to brain irradiation and chemotherapy are discussed. There is strong evidence to suggest that maximum combinations of approaches might improve treatment efficacy and extend median overall survival to as long as 6 months (p < or = 0.05). PMID- 22238941 TI - [Characteristics of immune status of patients with breast cancer]. PMID- 22238943 TI - [Use of liquid-based endometrial cytology in breast cancer patients receiving tamoxifen]. AB - Fifty-four (54) breast cancer patients, receiving tamoxifen, were enrolled into an evaluation of the status of the endometrium. Liquid-based cytology and immuno cytochemical analysis were used for assessment. Our method proved viable in selective screening for differential diagnosis of endometrial pathology and cancer detection. PMID- 22238944 TI - [Biological active substances of plant origin. Flavanones: dietary sources, biovailability, the influence on xenobiotic metabolizing enzymes]. AB - This review summarizes data concerning distribution, as well as the main food sources and daily consumption of flavanones, a relatively small group of flavonoids exhibiting wide range of biological activities, which are mainly specific for citrus fruits. The questions on their bioavailability and metabolism are discussed. The results of the in vitro and in vivo studies on the effects of flavanones on the activity of I and II phase drug metabolizing enzymes are shown. PMID- 22238945 TI - [Effect of fatty component in ration and coenzyme Q10 on indices of rat lipid metabolism in ontogenesis]. AB - The studies made on rats of 1, 3, 6 and 12 months with fish, palm and linseed oil included in the ration in combination of KoQ10, showed that beginning from young age till 12 months fatty acid composition of liver depended of fat component in the ration. Long-term consumption of fish fat with age results in significant increase in omega 3 fatty acids. In this case the omega 6 fatty acids level remained rather high being indicative of organism adaptation and inclusion of compensatory mechanisms supporting the required level of omega 6. With rat age the content of of KoQ10 in liver of rats of the control group and animals fed by of KoQ10 and palm oil with of KoQ10 decreased by 15-27%, while the consumption of linseed oil and fish fat with tended to increase the content of KoQ10 by 30 and 35%, respectively. PMID- 22238946 TI - [A comparative effect of the experimental diet on growth and development of rats]. AB - There are presented the results of a comparative assessment of the semi-synthetic casein diet, traditionally used by Institute of Nutrition RAMS, and the AIN-93 purified diet, offered by the American Institute of Nutrition, on growth and development of rats. A total of 60 male Wistar rats were used at 90-days experiment, rats were divided into two groups: first group received the semi synthetic casein diet, the second group--AIN-93 diet. Analysis of integral, hematological and biochemical parameters revealed some differences between groups, but values of all studied parameters were within the physiological norm for Wistar rat. Based on the results of this experiment were suggested a new formulation of a diet for laboratory animals. PMID- 22238948 TI - [Hygienic training of the workers occupied in food industry]. AB - The system of professional hygienic training for the workers of enterprises in various branches of food industry needs updating. Suggestions how to improve this work are made. PMID- 22238947 TI - [Efficacy of using zinc oxide nanoparticles in nutrition. Experiments on the laboratory animal]. AB - In experiments on rats there was researched bioavailability of zinc oxide (ZnO) nanoparticles. There were determined the content of Zn in blood serum and tibia, intestinal uptake of macromolecules of egg albumin, some hematological, biochemical and immune indices, liver cells apoptosis. The results obtained show that the uptake of nanoparticles of ZnO enables restoration of this microelement status damaged by zinc deficit diet. PMID- 22238949 TI - [Biologically active food supplements as sources of flavonoids, tannins and dietary fibers]. AB - The content of some biologically active substances such as bioflavonoids, tannins and dietary fiber in various type of biologically active additive was analyzed. The results are shown that the content of bioflavonoids ranger from 26.0 to 3970.0 mg%, tannins--from 1.19 to 857.0 mg%, insoluble dietary fiber--from 4.56 to 67.89% and soluble dietary fiber from 1.0 to 66.8%. PMID- 22238950 TI - [The influence of lactic acid bacteria and yeast on production of staphylococcal enterotoxins]. AB - Research of influence of 10 lactic acid bacteria cultures on staphylococcal growth and production of staphylococcal enterotoxins SEA and SEB has shown that lactic acid bacteria slow down SEA in 5,7 fold and SEB - 1,56 fold. All investigated cultures possessed inhibition action on SEA and SEB production. Has been established, what lactic acid bacteria slow down growth of staphylococcus in 1,48 fold. It has shown that appears, that the most effective inhibitors of SEA and SEB production are strains L. casei, Lactobacillus acidophilus 317/402. PMID- 22238951 TI - [Influence of chitosan on growth rates and protein metabolism in rats]. AB - The results of this experiment indicate that the content of chitosan in the experimental diet of rats influence on the true biological value of protein (BVtr) in the composition of this diet. The change (decrease) BVtr is not directly proportional to the content of chitosan in the diet. The minimum value of BVtr obtained by us has been observed by adding chitosan in an amount of 1.8 grams per 100 grams of dry diet. PMID- 22238952 TI - [To substantiation of vitamin and mineral level in fortified food products]. AB - This review outlines the scientific rationale and commentary for the introduction of sanitary rules and norms governing the enrichment of foods of mass consumption with vitamins and minerals, which were harmonized with EU documents and Codex Alimentarius. PMID- 22238953 TI - [Nutrition management of cancer patients after surgery on the esophagus and stomach: modern view on problem]. AB - The review discusses the problem of cancer patients' nutrition, the data of the nutritional factors role in the restoring the normal functioning of the gastrointestinal tract, the basic principles of the diet after operations on the esophagus and stomach. PMID- 22238954 TI - [The role of the individual nutrition for high sport achievements]. AB - It is established that individual menu, corresponded for personal nutritional need is a key factor for sport success of top athletes. A lot of questions and real approach for formation of the personal menu for top athletes are observed. PMID- 22238955 TI - [Influence of specialized protein food products on functional status of wrestlers]. AB - Influence of system of protein and amino acid rehabilitation on a functional condition of wrestlers is studied. It is established that the offered system has a wide range of adaptogenic. Found that the proposed system and actoprotective activity shows immunoprotective effect on the humoral immune system, accelerates processes of restoration after physical activity, provides a gain of working capacity, and also promotes adaptation of cardiovascular system for physical exercise. PMID- 22238956 TI - [Direct angioplasty of the left main coronary artery with a pericardium flap]. AB - Surgical treatment of stenosis of the left main coronary artery (LMCA) is a special problem, a number of questions of surgical strategy for this lesion still remain unsolved. The question of direct plasty dilatation of LMCA has not lost its actuality. Operations were made on 6 patients in whom direct plasty dilatation of LMCA with a flap from autopericardium was performed for local, not lengthy constriction which was located in the initial and middle part of LMCA. The operations were made under conditions of extracorporeal circulation, moderate general hypothermia (about 32 degrees C), pharmacohypothermic cardioplagia with external cooling of the heart. In all cases there was good restoration of cardiac activity and the absence of myocardium ischemia at the postoperative period. The restoration of the anatomical lumen of LMCA by this method facilitated sufficient blood flow along LMCA. Five years later all the patients are alive, one patient has external angina of the 11 functional class. PMID- 22238957 TI - [Pharmacological correction of free radical disturbances and endotoxicosis in patients with diffuse peritonitis at the postoperative period]. AB - The examination and treatment of 64 patients have shown that inclusion of complex antioxidant cytoflavin in intensive therapy at the postoperative period of diffuse peritonitis allows the hypoxia degree to be decreased that in its turn results in quicker recovery of the antioxidant system and decreased activity of peroxidation and endotoxicosis level. The clinical course of the postoperative period of diffuse peritonitis with cytoflavin included in intensive therapy is characterized by shorter terms of artificial lung ventilation, shorter time of staying in critical condition, more favorable course of complications. PMID- 22238958 TI - [Tumor markers at the preoperative examination and monitoring of surgical treatment of patients with colorectal cancer]. AB - Comparative analysis of using tumor markers in 159 patients with colorectal cancer was made. Carcinoembryonal antigen, skin reaction of hypersensitivity of slow type with autologous modified lymphocytes and a diagnostic test of tumor growth were used as oncomarkers. Each of three markers may be used for preoperative staging of colorectal cancer, postoperative monitoring of patients and determination of the disease prognosis. An individual approach of assessment of the oncomarker level at different stages of examining the patient is recommended. PMID- 22238959 TI - [Clinical parallels of computer tomography and intraoperative findings in benign cystic formations of the pancreas]. AB - A comparative analysis was made of preoperative computer diagnostics and intraoperative findings in 151 patients operated at various periods of chronic pancreatitis (CP) (n=76) with exacerbation of pancreatitis (or relapsed acute against the background of chronic) and 75 patients without exacerbation. Ninety (59.6%) patients have arrived with complications. Sensitivity of the method of computer tomography in patients with pancreatic exacerbation is 97.4%, without exacerbation is 98.7%. Dilatation of the main pancreatic duct is divided into three degrees. The dilatation of the 2nd and 3d degrees was diagnosed in 78 patients. All the patients were operated on the pancreas in the volume of direct interventions including external drainage which was performed in 69, internal in 56, separately resectional operations in 19, isolated cystectomy in 7 patients, In the group of patients operated out of exacerbation a correlation between the degree of the internal pancreas duct hypertension according to the data of preoperative computed diagnostics and the number of operations of internal drainage was followed. The presence of pancreatitis exacerbation (or relapsed acute against the background of chronic) in 27.5% (n=21) did not allow lateral pancreaticojejunostomy to be performed. In 23 patients the presence of exacerbation, complications of CP due to proper cystic formation (suppuration) and from adjoining organs was not considered contraindication to longitudinal and bilateral pancreaticojejunostomy. Low indices of postoperative lethality (0.7%) and of the number of postoperative complications (6%) confirmed the possibility to liquidate intraductal hypertension in complicated CP at earlier terms that protects the patients from many stages of surgical treatment. PMID- 22238960 TI - [Indices of tissue necrosis markers in acute pyo-destructive diseases of organs of the abdominal cavity]. AB - Investigation of indices of lactate dehydrogenase (LDG) and creatine phosphokinase (CPK) in a group of patients with extensive necrotic alterations in organs of the abdominal cavity and in a group of patients without extensive necroses has shown that in the first group there were higher levels of LDG and CPK. It shows that the LDG and CPK indices may be used as markers of tissue necrosis of the abdominal organs. In addition, in patients who died against the background of growing polyorganic insufficiency the LDG and CPK level by the end of treatment was statistically reliably higher than on admission of the same patients that may be an indicator of growing phenomena of dystrophy and micronecroses in vitals, so the indices of LDG and CPK may show the degree of severity of polyorganic insufficiency and determine its prognosis. PMID- 22238961 TI - [Clinico-morphological comparisons in patients with toxic goiter]. AB - The article presents a comparison and analysis of clinical and morphological data obtained in surgical treatment of 743 thyrotoxicosis patients operated in clinical bases of the Saint Petersburg Center of surgery of organs of the endocrine system at the period from 2005 through 2010. Causes of disagreement of the clinical diagnosis and morphological conclusion in patients with different diseases of the thyroid gland resulting in thyrotoxicosis are considered. Great clinical material (743 observations) was used by the authors to demonstrate the diagnostic value of special methods of investigation of the thyroid gland in patients with the toxic goiter. Advantages of subtotal resection of the thyroid gland by the P.Dunhill--E.S.Drachinsky method are stressed for surgical treatment of patients with nodular transformation of the thyroid tissue against the background of diffuse toxic goiter. PMID- 22238962 TI - [Robot-assisted laparoscopic adrenalectomy. The first experience]. PMID- 22238963 TI - [The role of duplex scanning in diagnosing extravasal compression of vertebral arteries in degenerative diseases of the cervical part of the spine]. AB - The method of duplex scanning was used in examination of 210 patients with degenerative-dystrophic diseases of the cervical part of the spine. It allows quantitative and qualitative assessment of the local and systemic hemodynamic value of extravasal compression of vertebral arteries. Local hemodynamic shifts in the area of extravasal influences on the artery were detected in 72.9% of the patients: decreased indices of blood flow and increased indices of peripheral resistance proximal to the compression zone, growing blood velocity in the area of the artery course deformity, in the place of its lumen constriction, decreased blood flow indices and indices of peripheral resistance distally to the compression zone. The assessment of blood flow in the vertebral arteries allows determination of the strategy of treatment of patients with degenerative dystrophic diseases of the cervical part of the spine. PMID- 22238964 TI - [Staged treatment of patient with combined trauma with diffuse peritonitis and numerous complications]. PMID- 22238965 TI - [A differentiated approach to the diagnosis and treatment of portal hypertension in children]. AB - The authors analyze their experience with diagnosis and treatment of 182 children with syndrome of portal hypertension (PH) from 1991 through 2010. Two groups of patients were considered. The first group included 74 newborns with high risk of the development of PH (infants after catheterization of the umbilical vein who endured omphalitis with USI diagnosed thrombosis of the portal vein, patients with cavernous transformation of the portal vein, hepatosplenomegaly). The second group consisted of 108 children aged from 6 months to 14 years with realized syndrome of PH. Investigation of hemostasis (international normalized ratio, fibrinogen, VIII and IX factors) immunogram of the 2nd level, determination of gene polymorphism (prothrombin, V factor, MTHFR, PAI-1), Bonacini index were included in the complex of examination, besides clinical and biochemical analyses of blood. The degree of disturbance of hemodynamics in the portal system was estimated by the data of USI, dopplerography, FEGS. It was established that children with extrahepatic portal hypertension have markers of hereditary thrombophilia in 98% of cases. Bonacini index allows determination of early signs of the development of secondary fibrosis of the liver in children with PH without using liver biopsy. PMID- 22238966 TI - [Long-term results of using mononuclear fraction of autologous bone marrow cells in complex surgical treatment of patients with heart valve failure]. AB - The article is devoted to long-term results of pilot clinical investigation of using mononuclear fraction of autologous bone marrow cells as an additional procedure to standard surgical treatment of heart valve failure in order to improve local perfusion and contractive ability of the myocardium. The article presents results of an analysis of findings of the examination of 7 living patients within 6 years or 7 years after operation as also data of pathologicoanatomical investigation of three dead patients. The data obtained show the safety and effectiveness of this method of cell therapy in patients with heart valve failure. PMID- 22238967 TI - [Changes of intracardiac hemodynamics in plasty of the mitral valve with a synthetic band, early period of observation]. AB - Valve saving interventions have a number of advantages over prostheses of the heart valves. An analysis of early results of annuloplasty of the mitral valve fibrous ring with a synthetic band in mitral failute (MF) did not detect any considerable difference in the indices of postoperative MF both in the main and in the control groups (p = 0.257). At the postoperative period lower mean index of residual MF was noted in the group with mixomatous lesion of the valve as compared with the control group (p = 0.004). PMID- 22238968 TI - [Specific medical strategy for aneurysm of the abdominal aorta]. AB - An analysis of results of treatment of 323 patients with aneurysm of the abdominal and thoraco-abdominal parts of the aorta was made for the period from 1995 through 2010. The patients' age was within the limits from 45 to 88 years and was 67.2 +/- 6.5 at an average. In 65 (24.5%) patients the diagnosis of progressing type aneurysmatic disease of the aorta and other main arteries was made. At the department of surgery of vessels of the Yaroslavl regional clinical hospital (YRCH) planned operations were performed on 102 (31.6%) patients, by emergency indications--on 69 (21.3%), with the clinical picture of rupture on 25 (7.8%) patients. In addition, 58 (17.9%) patients were operated by emergency indications under conditions of the Central regional hospital (CRH). Dynamic follow-up was fulfilled in 69 (21.4%) cases. Results of the operative treatment in greater degree depended on the emergency of surgery and severity of the concomitant pathology. Common lethality after planned operations was 5.9%, emergent--20.3%, aneurysm rupture under conditions of CRH--91.4% of cases. Lethality in YRCH in emergent operations was considerably lower--52% of cases. Use of screening examinations in groups of risk beginning from 50 years of age and the population older than 60, active surgical strategy in small aneurysms, introduction of minimally traumatic operative approaches allow improvement of results of the treatment. PMID- 22238969 TI - [Ways to improve efficacy of emergency operative interventions in patients with cancer of the left flank of the colon complicated by obstruction]. AB - In order to improve radicalism of emergency surgical interventions an appropriate method of total mesocolonectomy and D3-lymph node dissection in the medial lateral direction and the principle of "no-touch technique" were used in 14 patients. This technique is safe, effective, does not prolong the duration of operation and postoperative period, is not followed by increased number of complications and lethality. PMID- 22238970 TI - [Role of selective decontamination in combined treatment of chronic anal fissure]. AB - Effectiveness of selective decontamination in combined treatment of patients with chronic anal fissure and concomitant proctitis was studied in clinical randomized investigation including 103 patients. The etiologically significant flora colonizing the chronic defect of the anoderma does not coincide with the composition of feces microflora and is presented by anaerobic microorganisms or a combination of aerobes and anaerobes. It was established that topical etiotropic antibacterial therapy in combination with medicamentous sphincterotomy in the outpatient treatment resulted in quicker arrest of the pain syndrome, accelerated epithelization of the fissure and made the period of treatment 2 times shorter as compared with control. PMID- 22238971 TI - [Local anesthesia with articain in operative interventions in urology]. AB - The aim of the work was to improve the technique of local anesthesia with "ultrakain D-S" in surgical operations in urology. The research included 50 patients with penis diseases, 70 patients with diseases of the scrotum body, 40 patients with various prostate diseases complicated by acute urinary retention. Operative interventions in the patients were carried out with "ultrakain D-S". The control group consisted of patients with similar pathology and operations under local anesthesia, but with lidocain as anesthesia. The data obtained show that in more pronounced anesthetizing effect of "ultrakain D-S" the quantity of the injected drug was less as well as the time necessary for getting anesthesia was shorter than in the control group. PMID- 22238972 TI - [Mechanical jaundice caused by a forgotten foreign body in the common bile duct]. PMID- 22238973 TI - [Successful nearest outcome of replantation of the upper extremity at the shoulder level in a patient with a severe combined trauma of the chest, abdomen, and extremities]. PMID- 22238975 TI - [Cancer of the thyroid gland: the history of studying at the period from the XIX to the middle of the XX century]. PMID- 22238974 TI - [Simultaneous operation in a patient with ischemic heart disease and gastric cancer]. PMID- 22238976 TI - [Prophylactics of peritoneal commissures--current state of the problem]. PMID- 22238977 TI - [Current state of the problem of surgical treatment of perforating duodenal ulcers]. PMID- 22238978 TI - [Neurotensin-like oligopeptides as potential antipsychotics: effect on dopamine system]. AB - According to published data, peptide neurotensin is considered as endogenous antipsychotic agent. A series of oligopeptides have been synthesized based on the proposed active center of neurotensin. These oligopeptides (called neurotensin like peptides, NLPs) have been studied on behavioral models, in which the functional state of the dopamine system of animals was modified by apomorphine injections. The results of verticalization, stereotypy, and yawning tests revealed NLPs that behave as antagonists of dopamine receptors. Radioligand analysis showed that these peptides compete for specific binding to these receptors with sulpiride, which is a D2-type selective antagonist of dopamine receptors. The high degree of NLPs efficiency manifested in the behavioral tests and radioligand analysis suggests that the their antipsychotic action can be mediated by dopamine receptors. PMID- 22238979 TI - [Effect of GB-115 dipeptide on anxiety in rats with model benzodiazepine withdrawal syndrome]. AB - The effects of GB-115 dipeptide, a retroanalog of endogenous CCK-4, on the behavioral indices in "elevated plus maze" (EPM) test and on the content of biogenic amines in the brain structures after discontinuation of a chronic administration of benzodiazepine (BZ) derivatives phenazepam (2.0 mg/kg, i.p.) and diazepam (4.0 mg/kg, i.p.) have been studied in outbred and inbred MR/MNRA rats. It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal. PMID- 22238980 TI - [Afobazole decreases severity of morphine withdrawal syndrome: experimental evidence]. AB - Effect of afobazole upon morphine dependency has been studied in rats upon the administration of incremental doses of morphine (10-20 mg/kg, i.p.) for 5 days. The state of dependency was evaluated by monitoring sixteen specific behavioral indices of "spontaneous" (24 h after the last morphine injection) or naloxone induced withdrawal syndrome. The effect of afobazole (a single dose of 5 mg/kg injected before the test or subchronically for 5 days) was estimated through its influence upon the total index of withdrawal syndrome, which was calculated using the set of behavioural signs. It is established that afobazole upon either single or subchronic injections significantly decreased the expression of spontaneous morphine withdrawal syndrome. The effect was also statistically significant but less pronounced in the case of naloxone-induced withdrawal syndrome. The obtained data suggest that afobazole can be considered as potential effective drug for the correction of various clinical symptoms of morphine withdrawal syndrome. PMID- 22238981 TI - [Neuroprotector effect of human recombinant erythropoietin sorbed on polymer nanoparticles studied on model of intracerebral post-traumatic hematoma (hemorrhagic stroke)]. AB - The neuroprotective activity of recombinant human erythropoietin (r-HuEpo) sorbed on poly(butyl)cyanoacrilate nanoparticles (EPO-PBCA) and on polylactic-co glycolic acid nanoparticles (EPO-PLGA) has been studied on Wistar rats with intracerebral post-traumatic hematoma (model of hemorrhagic stroke) (IPH-HS) in comparison to native r-HuEpo. It is established that EPO-PBCA produced a protective effect in rats after IPH-HS that was manifested by a decrease in the number of animals with neurological disorders such as circus movement, paresis, and paralysis of hind limbs; the drug also improved coordination (rotating rod test), reduced the number of lost animals, and decreased the loss weight among survived rats. In addition, EPO-PBCA optimized the research behavior of rats with IPH-HS in the open field test and prevented amnesia of passive avoidance reflex (PAR), which was caused by the IPH-HS. These effects were manifested during a two week observation period. EPO-PLGA has a similar but much less pronounced effect on the major disorders caused by IPH-HS. The efficiency of native r-HuEpo as a neuropotective agent was insignificant and only manifested by decrease in the number of lost animals with IPH-HS. PMID- 22238982 TI - [Effect of cardiovascular drugs on vasodilating endothelial function in animals with experimental deficiency of sex hormones]. AB - The influence of various cardiovascular drugs, including ACE inhibitors (lisinopril), beta-adrenoblockers (bisoprolol, nebivolol), calcium inhibitors (nifedipine), cholesterol-lowering drugs (simvastatin), and heparinoids (sulodexide), on the vasodilating endothelial function has been studied in animals with experimental deficiency of sex hormones. According to the expressiveness of a positive effect on endothelium-dependent vasodilatation in castrated rats, the tested drugs can be arranged in the following sequence: sulodexide > lisinopril > or = simvastatin > or = nebivolol > bisoprolol > nifedipine. PMID- 22238983 TI - [Flavonoid correction of functional elasticity of erythrocyte membranes and hemorheological disorders during oxidative stress caused by chronic physical overstrain in mice]. AB - Effect of a course of treatment by bioflavonoids quercetin and diquertin on the physical work capacity, oxidant and antioxidant status of organism, and hemorheological parameters and deformability of erythrocytes have been studied under conditions of chronic physical overstrain in mice caused by sequential extraordinary running load. The drugs effectively prevent the development of oxidative stress, loss of elasticity of erythrocyte membranes and growth in dynamic blood viscosity in microcirculatory link of hemodynamics. It is established that both bioflavonoids significantly increase the physical work capacity of animals and prevent from the development of physical overstrain syndrome. PMID- 22238984 TI - [Effect of cholinesterase reactivator carboxim on T-lymphocyte acetylcholinesterase activity and immune response under conditions of acute intoxication by organophosphorus compounds]. AB - It has been established in experiments on non-inbred rats that the administration of cholinesterase reactivator carboxim in a single dose of 10 mg/kg signifucantly reduces the inactivation of acetylcholinesterase in T-lymphocytes caused by acute intoxication with organophosphorus compounds (sarin, metaphos) in a dose of 1.0 LD50. The drug administration leads to partial or almost complete recovery of the humoral and cellular immune responses. Carboxim does not influence the T independent humoral immune response reduced due to suppression of B-cell (plasmocyte) function by organophosphorus compounds. PMID- 22238985 TI - [Induction of endogenous s-adenosyl-l-methionine in hepatocytes during pharmacological correction of experimental acute toxic and chronic drug-induced liver injury]. AB - The level of endogenous S-adenosyl-L-methionine (SAM) production during pharmacological correction of acute toxic (tetrachloromethane) and chronic drug induced liver injury treated by remaxol, exogenous ademethionine, and reamberin has been studied on 118 outbred male rats. It is established that, upon a single introduction of tetrachlormethane (acute toxic injury model), remaxol and exogenous SAM produced a gain in the endogenous SAM level in hepatocytes. At the same time, in the case of chronic drug-induced injury (antituberculosis drugs), only remaxol caused authentic growth of the endogenous SAM level that was comparable with a compensatory growth of SAM at nontreated animals. Considering the improvement of laboratory indicators and the histological pattern of liver in animals treated by remaxol, it is possible to conclude on the important role of succinic acid along with the induction of SAM, in the hepatoprotective effect of drugs. This is confirmed by the effect of reamberin, which contains only succinic acid without methionine and does not cause induction of endogenous SAM. PMID- 22238986 TI - [Experience of cytoflavin administration for treating acute carbon monoxide poisoning]. AB - Results of an analysis of the efficiency of using cytoflavin, a drug possessing cytoprotective and antihypoxemic properties, in a group of 215 patients with a diagnosis of acute carbon monoxide poisoning in 2004-2010 are compared to analogous data for 215 patients with same diagnosis treated in 1999-2004 without cytoflavin administration. It is established that timely application of cytoflavin (against the standard treatment of CO poisoning) favored lower expressiveness of post-hypoxemic encephalopathythatis characteristic of the given pathology. PMID- 22238987 TI - [Pharmacological modulation of nitrogen oxide system in experimental chronic alcoholic intoxication in rats]. AB - The modeling of chronic alcohol intoxication for 30 days in rats leads to an increase in the level of free metabolites of nitrogen oxide and NO-synthase with simultaneous decrease in the levels of L-arginine, catalase, and superoxide dismutase. The subsequent 14-day treatment with neuropeptide cerebroprotectors cerebrocurin, cortexin, and cerebrolysin led to normalization of the parameters of nitrogen oxide system. The maximum therapeutic activity was shown by cerebrocurin, which can be recommended for inclusion as component of alcoholic encephalopathy treatment. PMID- 22238988 TI - [Metabotropic glutamate receptors as targets for new drug development]. AB - The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered. PMID- 22238989 TI - Me too 2. PMID- 22238990 TI - Minimally invasive cosmetic dentistry: alignment, bleaching and bonding (ABB). AB - This article will outline how combining existing techniques in a new and unique manner can potentially redefine the traditional approach to smile design planning and execution. Alignment, tooth whitening and edge bonding with new highly polishable nano-hybrid composites can make cosmetic dentistry far simpler and less invasive. Patients' perceptions of their end smile result can change dramatically if they are allowed to see their teeth improve gradually. CLINICAL RELEVANCE: This technique will highlight a choice of pathways available in cosmetic dentistry making it much less invasive for the patient and less risky for dentists. PMID- 22238991 TI - Aesthetic composite veneers for an adult patient with amelogenesis imperfecta: a case report. AB - This case has been presented as part of the continual assessment requirement for the MSc in Aesthetic Dentistry, King's College Dental Institute. Amelogenesis imperfecta (AI) is a hereditary disorder of enamel formation, affecting both the permanent and deciduous dentitions. It can be classified into hypoplastic, hypomaturation and hypocalcified types and presents with different hereditary patterns. The aim of this article is to provide an overview of amelogenesis imperfecta, including a detailed case report for an aesthetically concerned adult patient presenting in general practice with a Witkop's Type IA defect managed with the placement of direct, layered resin composite veneers. CLINICAL RELEVANCE: Amelogenesis imperfecta patients are susceptible to the restorative cycle of replacement restorations like any other patient, but start with a distinct disadvantage.This case report demonstrates a minimally invasive, relatively simple and cost-effective option for the aesthetic correction of a case of hypoplastic amelogenesis imperfecta with layered composite veneers. Dent Update 2011; 38:594-603 PMID- 22238992 TI - An in vitro investigation of the initial pH and titratable acidity of a selection of fruit smoothies. AB - Four commercially-available fruit smoothie drinks were assessed for both initial/baseline pH and titratable acidity. A commercially-available smooth orange juice drink was used as a positive control. Baseline pH and titratable acidity were measured by titrating each fruit smoothie with 0.5 mL increments of 1M sodium hydroxide (NaOH), and measuring the pH following the addition of each increment, until pH 7 and pH 10 were reached. Each of the fruit smoothies investigated demonstrated a low baseline pH and had relatively high titratable acidity. Owing to both their low pH and high titratable acidity, it would be advisable to limit the consumption of such fruit smoothies to meal times. CLINICAL RELEVANCE: Fruit smoothies, which are made from pure fruit blended with 100% fruit juice, are a relatively new addition to the soft drinks market. It is recommended that they be consumed through a straw, similar to the advice given for other acidic soft drinks. PMID- 22238993 TI - Indications for surgical endodontics and findings of an audit into referrals. AB - Peri-radicular surgery is a valuable treatment modality allowing thorough treatment of chronic infection of the peri-radicular tissues. It is important that this treatment option is prescribed appropriately and steps are taken to help improve outcomes of surgery. We discuss the indications for peri-radicular surgery, considerations when planning treatment for teeth where orthograde endodontics has failed and present the findings of an audit into the appropriateness of referrals for peri-radicular surgery to the Department of Oral and Maxillofacial Surgery at a District General Hospital. CLINICAL RELEVANCE: This article highlights the indications and contra-indications for peri-radicular surgery to general dental practitioners. PMID- 22238994 TI - A review of root fractures: diagnosis, treatment and prognosis. AB - Tooth fractures (crown or root fractures) are commonly encountered emergencies in a dental clinic. Root fractures are defined as fractures involving the dentine, cementum and pulp. They are broadly classified as horizontal and vertical root fractures. They may be clinically challenging cases to treat as, usually, treatment of such cases requires an interdisciplinary/multidisciplinary approach for complete rehabilitation of teeth. For a successful outcome, it is imperative to arrive at an appropriate diagnosis and design a treatment plan accordingly as soon as possible.This review article discusses the various types of root fractures, their diagnosis and treatment, along with the factors affecting their healing and prognosis. CLINICAL RELEVANCE: Treatment of root fractures depends on a number of factors such as, position of fracture line, mobility of tooth and pulpal status. Thus clinicians must have thorough knowledge and adequate clinical experience to treat them properly. PMID- 22238995 TI - Dislodged lower right third molar tooth into the parapharyngeal space. AB - Lower third molar teeth can be dislodged into fascial tissue spaces when they are extracted or elevated out of their sockets. Thankfully, this rarely occurs. We present a case report on a lower right wisdom tooth dislodged into the right parapharyngeal space on its removal from the socket and the subsequent management of this rare complication. CLINICAL RELEVANCE: Though a rare complication, clinicians have to be aware that lower third molars can be dislodged into tissue spaces and the importance of prompt appropriate management. PMID- 22238996 TI - How well are GIC product labels related to current systematic review evidence? AB - Systematic reviews have been recommended as providing the best source of evidence to guide clinical decisions in dentistry. They appraise evidence from trials focused on investigating clinical effects of dental material categories, such as conventional glass-ionomer cements (GIC) or resin-modified GIC. In contrast, the general dental practitioner is introduced to these categories of materials in the form of branded or private product labels that are marketed during dental conventions or through advertisements. Difficulties may arise in recognizing material categories that have been subjected to systematic reviews, because of the multitude of product labels on the current market. Thus, the value and relevance of published systematic review evidence concerning the material categories represented by these labels may remain obscure. Based on a systematic literature search, this article identifies glass-ionomer cement product labels used during clinical trials which, in turn, were subsequently reviewed in systematic review articles (published between 15 April 2009 and 14 April 2011). This article further clarifies how these product labels relate to the systematic review conclusions. The results show that the conventional and resin-modified glass-ionomer cements that were used in most trials were marketed by GC and 3M ESPE, respectively. The conventional GICs used in most of the reviewed trials were Fuji III and Fuji IX, while Vitremer was the most commonly used resin modified GIC. Evidence from the reviewed trials suggests that GIC provides beneficial effects for preventive and restorative dentistry. However, more trials of higher internal validity are needed in order to confirm (or disprove) these findings. Only GIC products of branded labels and none of private labels were identified, suggesting that private label GIC products have little or no research back-up. CLINICAL RELEVANCE: Dental products, such as glass-ionomers cements (GIC), can only be judged as effective when they are based on sufficient research back-up. Systematic reviews of clinical trials provide such back-up at the highest level. Thus clinicians must be able to identify GIC products for which reliable evidence from systematic reviews of clinical studies is available and know about what such evidence contains. PMID- 22238997 TI - Oral cancer: comprehending the condition, causes, controversies, control and consequences. 11. Surgical complications and adverse effects. PMID- 22238998 TI - Technique tips--modified cheek retractor: 'best from waste'. PMID- 22238999 TI - Physical signs for the General Dental Practitioner. Case 89. Warfarin-induced bruising. PMID- 22239000 TI - [Cytokeratin 18 as an indicator of the activity of liver disease]. AB - Hepatocyte apoptosis plays an important role in a wide range of chronic liver diseases such as: hepatitis C and B, as well as nonalcoholic steatohepatitis. Apoptosis is responsible for removal of damaged and degenerated cells, but also stimulates liver fibrosis, which can lead to cirrhosis. Aminotransferases activity currently used for routine diagnostics and management of liver disease may yield a significant number of false negative values. On the other hand liver biopsy recognized as a gold standard for evaluation hepatic diseases activity--is an invasive technique associated with potential complications and patients' sufferings. The novel biomarker helpful in identifying and monitoring activity of liver disease may be cytokeratin 18. Its fragment levels correlate with the magnitude of hepatocyte apoptosis and independently predict the presence of liver fibrosis and inflammation. This review will focus on potential use of cytokeratin 18 measurement in the diagnosis and management of chronic liver disorders. PMID- 22239001 TI - [Analysis of incidence and clinical picture of pneumothorax in children]. AB - Although pneumothorax has been thoroughly described since the beginning of 19th century there are few studies investigating its epidemiology in pediatric patients. The aim of this study was to evaluate incidence and clinical picture of pneumothorax in pediatric patients. MATERIALS AND METHOD: A retrospective review of medical records of all patients treated in the Department of Pediatric Pulmonology, Allergy and Clinical Immunology of Karol Marcinkowski Medical University from January 1999 to December 2008 with the diagnosis of pneumothorax. Data analyzed include anthropometric parameters, present comorbidities, clinical presentation, treatment, length of hospital stay as well as presence and type of complications. RESULTS: 27 episodes of pneumothorax in 21 patients were treated in the given period. There were 52% of episodes of spontaneous primary pneumothorax, 37% of secondary spontaneous pneumothorax and 11% of pneumothorax due to non-penetrating trauma. 59% of patients were males. Presenting symptoms included dyspnoe (59%), chest pain (48%) and cough (44%). 74% of cases required treatment with chest tube drainage: 80% episodes of primary spontaneous pneumothorax, 67% episodes of non-penetrating trauma pneumothorax and 71% episodes of secondary spontaneous pneumothorax. Mean time of chest tube drainage was 6.2 +/- 5.1 days: 4.5 +/- 0.7 days for non-penetrating trauma pneumothorax, 5.7 +/- 6.4 days for secondary and 7.2 +/- 1.4 days for primary spontaneous pneumothorax. Chest tube drainage was successful in 80% of cases. 4 patients were referred to thoracic surgeons. One child was treated with chemical pleurodesis. Mean hospital stay was 22.2 +/- 13.7 days: 11.1 +/- 0.7 days for patients with non-penetrating trauma pneumothorax and 29.7 +/- 1.4 days for patients with spontaneous secondary pneumothorax. CONCLUSIONS: Primary and secondary spontaneous pneumothorax is a rare event in children and the majority of patients are male. Secondary spontaneous pneumothorax is a complication of underlying chronic pulmonary conditions, most frequently cystic fibrosis and pulmonary infections. Children presenting with spontaneous secondary pneumothorax tended to be younger and required longer hospital stay. PMID- 22239002 TI - [Management of colonoscopic perforations of large bowel]. AB - Perforation of large bowel during elective colonoscopy is rare but serious life threatening complication. Early diagnosis of perforation during or soon after colonoscopy shortens time of peritoneal contamination and allows to get good results of surgical treatment. The aims of this study were to determine the incidence of perforation due to colonoscopy in our hospital and to assess methods and results of surgical treatment. MATERIAL AND METHODS: We reviewed our prospectively collected data of 957 patients operated on because of colorectal diseases in the period from January 2003 to December 2010. Data of 16 patients (1.7%) aged from 22 to 89 years of life (average age 67.5 years) operated on because of colonoscopic perforations were analysed. RESULTS: Perforation of large bowel occurred in 9 patients (0.13%) of 6570 persons colonoscopised in our hospital. All 16 patients were operated on in the period of 0.5-32 hours since colonoscopy was performed. Simple suture of the laesion was the most common procedure performed in 12 patients (4 of them had proximal colostomies performed as well). Postoperative complications occurred in 3 patients (18.7%). Nobody died -mortality 0. Average time of hospital postoperative stay was 8.3 days. CONCLUSIONS: Colonoscopic perforation of large bowel requires surgical treatment. Choice of repair method depends on diameter of perforation, time since onset to operation passed, spread and degree of peritoneal contamination and general patient's condition. PMID- 22239003 TI - [Self-fixating Progrip implant used in the laparoscopic totally extraperitoneal technique for inguinal hernia repair]. AB - Modern tension-free techniques have become standard for inguinal hernia repair. The most highly regarded minimally invasive technique is laparoscopic totally extraperitoneal hernioplasty (TEP) which results in shorter recovery, earlier return to normal activities and better quality of life as compared to open repair techniques. The aim of the study was to evaluate the effects of inguinal hernia management in a von Willebrand (type 2a) patient. For the first time in Poland a partially absorbant mesh with a self-fixating system was implanted in a completely extraperitoneal approach using laparoscopy (TEP technique). MATERIAL AND METHODS: The procedure used was typical for the method; two 5 mm ports and a 10 mm port for the camera were applied below the umbilical line. A 15 x 9 cm synthetic mesh was inserted through the 10 mm port and positioned preperitonealy to close the hernia ring. Substitution therapy was administered for 7 days to control factor VIII activity in plasma at a level of approximately 100% for the first 3 days and 70% until healing of the postoperative wound. RESULTS: Surgery was uneventful with no postoperative complications. The patient was discharged from hospital within 7 days of suture removal. No hernia recurrence nor persisting pain were reported at follow-up examination 6 months after the procedure. CONCLUSIONS: Synthetic mesh with a self-fixating system used in the TEP technique for inguinal hernia repair has been proved safe and fully effective. PMID- 22239004 TI - [Autonomic nervous system activity estimated by heart rate variability in cyclophosphamide-induced overactive bladder experimental model]. AB - Overactive bladder (OAB) is not rarely observed clinical entity affecting lower urinary tract. The OAB pathogenesis is still poorly understood. Two main pathophysiological concepts are postulated: neurogenic theory and miogenic one. The aim of the study was to estimate autonomic nervous system activity by heart rate variability (HRV) assessment in two experimental models: with acute overactive bladder (AOAB) and chronic overactive bladder (COAB) comparing to control. MATERIAL AND METHODS: Study was performed in three groups: control one (10 rats), group with AOAB evoked by i.p. administration of cyclophosphamide (200 mg/kg body weight) (20 rats) and in COAB group caused by 4-times i.p. administration of cyclophosphamide (75 mg/kg body weight). In each case, after urethane anesthesia (1,2 g/kg body weight), 20-minutes ECG recordings were performed with subsequent HRV analysis. Standard time- and spectral (frequency) domain analysis parameters were calculated. RESULTS: Most of differences in time domain analysis parameters were insignificant, except those concerning SDNN and rMSSD. In frequency analysis, a power decrease of all standard spectral components was revealed in both OAB groups, comparing to control. In AOAB, TP and VLF power diminishing were markedly noticed, while COAB group were mostly characterized by LF and HF decrease. In all groups, there were no differences in standardized spectral compounds (nLF, nHF) values. CONCLUSIONS: ANS disturbances, found as standard spectral parameters abnormalities, were demonstrated in both AOAB and COAB. Moreover, the findings of statistically significant differences lack in normalized nLF and nHF powers suggest that VLF changes play essential meaning, reflecting the bladder inflammatory changes progression. Further studies defining precisely ANS disturbances and their reflection in HRV in OAB are required. PMID- 22239005 TI - [Evaluation of tobacco smoking addiction and passive exposure to tobacco smoke in students of medicine]. AB - Active and passive tobacco smoking by students of medical universities show that medical studies cannot be an effective barrier against continuing or even commencing smoking. The aim of the study was an evaluation of tobacco smoking and passive exposure to environmental tobacco smoke in the Physiotherapy students of Faculty of Military Medicine Medical University of Lodz. MATERIAL AND METHODS: There were 565 Physiotherapy students of between 1-5th year of studies, including 394 women and 171 men (mean age 22.41), who were covered by the questionnaire research. The author's form of the questionnaire consisted of closed questions about demographic data and data on active and passive smoking. Prior to completing the questionnaire each student signed an informed consent as well as had an opportunity to get familiar with the patient's information form and could ask additional questions. RESULTS: The results analysis of the questionnaire indicated that 21.42% of the studied subjects are active smokers whereas 78.58% - non-smokers. No statistically significant differences in tobacco smoking due to sex have been noticed. The highest percentage of smokers was found on the 2nd and 3rd year of studies. In the group of 444 non-smokers there were as many as 67.1% of passive smokers. CONCLUSIONS: Tobacco smoking rate among Physiotherapy students amounts to 21.42% and is lower than the rate observed in the Polish population. Among non-smoking physiotherapy students there are 67.1% who are exposed to secondhand tobacco smoke. The obtained result does not largely stray from the result for the adult Polish population. PMID- 22239006 TI - [Self-aggressive behavior in prisons]. AB - In the literature devoted to the phenomenon of self-harm among engaged imprisonment, meets the different views the causes of such behavior and the risk of their occurrence. Views prevail, according to which aggression is considered common phenomenon among people in prisons. Social isolation and lack of close intimate relationships may foster this type of behavior. The aim of this study is to assess the prevalence of self-aggressive behavior among prisoners. MATERIAL AND METHODS: We analyzed 133 cases of self-harm and 151 cases of suicide made a fatal persons deprived of their liberty. THE RESULTS: Among those detained in prisons showing self-aggressive behavior are high rates of mental dysfunction. CONCLUSIONS: In carrying out self-aggressive states embedded high rates of mental dysfunction, mainly disorders Personality and alcohol dependence and/or psychoactive substances. Among those who made a successful suicide bombing found a high rate of personality disorders and disorders depressive. Causes and determinants of self-harm and suicides by persons residing in institutions prisons are in many respects similar. Those embedded in prisons having mental disorders pose a high risk of autoimmunity, and therefore require special supervision and care of individual psycho-psychological one. PMID- 22239007 TI - [Pneumomediastinum as a rare cause of retrosternal chest pain--report of two cases]. AB - Pneumomediastinum (PM) is a rare cause (the rate varies from 1:8500 to 1:30000 patients) of pain in the chest. This is generally a benign entity resulting from alveolar rupture and propagation of the air into the mediastinum that affects mainly young adults. It may appear however as a complication of different procedures within the chest. Asthma, cough, vomiting, illicit drug use and all activities that require the Valsalva maneuver and/or intense breathing work or exercise were identified as predisposing factors of PM. We report cases of two patients admitted within some months to the emergency department due to chest pain. Due to acute onset of symptoms and a presence of a loud murmur along the left border of the sternum the acute pericarditis was suspected. However, after careful and detailed examination acute coronary syndrome and pericarditis were excluded. Radiologic examination and computed tomography of the chest revailed the presence of air in the mediastinum in both cases. After the diagnosis of pneumomediastinum antiinflammatory agents and antibiotics were administered. Recovery was uneventful, within two weeks form the onset a complete resolution of radiologic changes were observed. PMID- 22239008 TI - [Recent clinical picture of Brugada syndrome]. AB - Brugada syndrome is a genetically-based autosomal dominant condition. It occurs as a result of some disorder of ion channels which regulate currents responsible for development of activity potential. Brugada syndrome may appear as a family disease or as a sporadic condition. The syndrome can develop at every age of human life, yet, most frequently in the 3-4th life decade, mostly in men (85%). Its main symptoms include: malignant ventricular arrhythmia leading to fainting, and consequently accounting for, at least 4-12% of all sudden cardiac deaths and for 20-50% of deaths without any confirmed organic heart disease. The purpose of the paper was to present the currently-possessed knowledge about the condition and to highlight the necessity of an indepth ECG analysis, especially with respect to discovery of rare conditions. Due to different clinical symptoms of Brugada syndrome and a possibility of occurrence of changes in the ECG record, it is necessary to regularly monitor and check Brugada syndrome patients. Moreover, it is important to make both patients and first-contact doctors aware of a Brugada syndrome diagnosis and to inform them about a necessity of eliminating certain medicaments and factors (infections, intense physical activity) responsible for sudden cardiac death. Despite possessing great and advanced knowledge about the disorder, the implementation of cardioverter-defibrillator remains the only effective way of treating malignant arrhythmia and of preventing sudden cardiac death. PMID- 22239009 TI - [Recent indications for home oxygen therapy]. AB - Home oxygen therapy is a treating method with an effect on improving the life comfort and long of life in the group of patients suffered from non-neoplasmic lung diseases complicated by partial respiratory failure, proved in many clinical trials according to some estimations the number of patients in Poland who fulfill home oxygen therapy qualification's criteria is twice higher then the number of patients who benefit from this method of therapy. This situation should make pneumonologists concern with problems of patients suffered from the respiratory failure who need this kind of therapy. PMID- 22239010 TI - [Thrombotic complications following the treatment of multiple myeloma with new agents]. AB - Patients with multiple myeloma (MM) are at an increased risk of venous and arterial thrombosis. The risk factors and pathomechanisms for thrombotic complications in multiple myeloma patients can be divided into the disease related and treatment-specific risk factors. With the introduction of novel therapies, including talidomide, lenalidomide and bortezomib, the outcomes of the patients with newly diagnosed or previously treated multiple myeloma have improved, however the treatment affected the prothrombotic and anticoagulant processes. The risk of venous thromboembolism (VTE) in patients receiving immunomodulatory agent-based regimens (thalidomide or lenalidomide), especially when used in combination with high-dose deamethasone- and/or anthracycline-based chemiotherapy is high. The proposed mechanisms for prothrombotic state include changes in von Willebrand factor, factor VIII, thrombomodulin, PAR-1 and COX-2 epression, and some abnormalities in transcription factors and genetic risk factors. Moreover, dysregulation of anticoagulation and impairment of fibrinolysis may also contribute to hypercoagulability state. The incidence of VTE in bortezomib-containing regimens is very low. It may be due to inhibitory effect of bortezomib on platelet aggregation and NF-kappa/beta. This article presents the latest outlook upon the pathogenesis of thrombotic complications in multiple myeloma patients undergoing the therapy with new agents. PMID- 22239011 TI - [The Jung model of active style of schema]. AB - Yung was of an opinion that the borderline personality as a pathology results from the experiences of a frightened and violence-experiencing child who is left to their own devices in the hostile world. In that situation, the child, longing for safety, simultaneously experiences fear of abuse, hurt and rejection and remains distrustful. In order to understand the dramatic changes in the individual's behaviour, in case of the borderline personality disorders, Yung developed the concept, presented by Aaron Beck at the therapeutic workshops in the 1980s. Beck's concept was based upon the assumption that some pathological states expressed strong emotional states, experienced in childhood on the basis of regression. Yung presented them in the form of conceptualization in the categories of the active styles of schema. Apart from the states of regression, he also differentiated less regressive styles of schema. The style of schema should be interpreted as a pattern of experiencing, thinking and behaviour, based upon a determined set of schema, and characterized by independence from other styles. PMID- 22239012 TI - [Pharmacotherapy of patients with the borderline personality disorders]. AB - The American Psychiatric Association (APA) provides guidelines in which it recommends applying pharmacotherapy in order to take under control the symptoms developing in the period of acute decompensation, as well as those connected with the susceptibility of an afflicted individual to an injury resulting from the basic disorder, The guidelines of the APA include in particular what follows: in case of affective deregulation, administering anti-depressive drugs (LDP), mainly SSRLs, as well as IMAOs; in order to take under control the disorders of impulsive-behavioural control, administering SSRIs and normothymic drugs, whilst in the treatment of infirm with perceptive-cognitive disorders, administering antipsychotic medicines (LPP). Currently, upon the basis of existing evidence, one may claim that in the treatment of the borderline personality disorders, psychotherapy is much more effective than pharmacology An obstacle on the road to make psychotherapy more widespread is relatively high cost, which is connected with the necessity of remunerating highly-qualified psychotherapists, involved in the work with the infirm, suffering from the borderline personality disorders, and the time, needed to conduct a successful psychotherapy, as well as the phenomenon of the premature discontinuation of therapy by patients who are emotionally unstable. In turn, pharmacotherapy seems to be necessary in the period of more acute disorders, i.e. in the states of increased affective lability, in dysphoric states, in impulsive behaviours and in the periods of the occurrence of pseudo-psychotic symptoms. PMID- 22239013 TI - [Trazodone in the treatment of addiction]. AB - The problem of addiction to psychoactive substances (SPA) is an important aspect of modem psychiatric treatment. This is due to the increasing number of addicts, and reducing their increasing age. It is estimated that in the United States in 2006, people aged over 12 years of meeting criteria for dependence on SPA was 20 25 million. Other statistics report that in the same age group over the last year contact with these substances were 8-10 percent of the U.S. population. Therefore, it becomes an important issue the appropriate therapeutic treatment of addicts. The result of the search of drugs that help people to alcoholism treatment program, were studies involving trazodone. Counted among the SARI (serotonin reuptake inhibitor and antagonist), shows antagonism to serotonergic receptors (5-HT2 receptors), while an inhibitor of serotonin reuptake. Its performance was analyzed in individuals dependent on alcohol, benzodiazepines and opiates, as well as mixed addictions. Also raised the problem of influence of trazodone on the experience of pain, which maybe helpful in relieving withdrawal symptoms. The data show a positive effect of trazodone in individuals addicted to the SPA, although the mechanism by which trazodone works in the body is very complex and not yet fully understood. Its advantage is the relatively small panel of side effects. Although many of the analyzed studies were not placebo controlled, the results are so promising that you can recommend on the basis of trazodone therapy in individuals addicted to the SPA. PMID- 22239014 TI - Evaluation of arsenic, cadmium, lead, and nickel in biological samples (scalp hair, serum, blood, and urine) of Pakistani viral hepatitis (A - E) patients and controls. AB - BACKGROUND: The aim of present study was to compare the level of arsenic (As), cadmium (Cd), lead (Pb), and nickel (Ni) in biological samples (serum, blood, urine, and scalp hair) of patients suffering from different viral hepatitis (A, B, C, D, and E; n = 521) of both genders, age range 31 - 45 years. For comparative study, 255 age-matched control subjects of both genders residing in the same city were selected as referents. METHODS: The digests of all biological samples were analysed for Cd, Pb, and Ni by electrothermal atomic absorption spectrometry (ETAAS). The validity and accuracy of the methodology was checked by using certified reference materials (CRMs) and with those values obtained by conventional wet acid digestion method on the same CRMs. RESULTS: The results of this study showed that the mean values of As, Cd, Ni, and Pb were higher in blood, serum, and scalp hair samples of hepatitis patients than age-matched control subjects. The urinary levels of these elements were found to be higher in the hepatitis patients than in the age-matched healthy controls (p < 0.001). CONCLUSIONS: These results are consistent with literature-reported data, confirming that the overload of these toxic elements can directly cause lipid peroxidation and eventually hepatic damage. PMID- 22239015 TI - Plasma and urinary HPLC-ED determination of the ratio of 8-OHdG/2-dG in Parkinson's disease. AB - BACKGROUND: Oxidative stress may be directly or indirectly involved in the pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'deoxyguanosine (8-OHdG) is the major product of DNA oxidative damage but its determination in plasma or urine may have controversial significance. The concentration of 8-OHdG not only depends on its oxidation rate but also on the efficacy of the DNA repairing systems. METHODS: We studied the ratio between 8-OHdG and 2-dG (the corresponding not hydroxylated base 2'-deoxyguanosine) in plasma and urine as a marker of oxydative stress in PD. This enabled the determination of the real DNA damage in terms of oxidation rate regardless of the efficacy of the DNA repairing mechanisms. RESULTS: We optimized two different analytical methods: one for 8 OHdG and the other for 2-dG, both based on a common preliminary solid-phase extraction step (SPE) followed by two different HPLC analytical separations with electrochemical detection (HPLC-ED). The reliability of these methods was confirmed by analysing plasma and urine samples collected in parkinsonian patients and in age-matched healthy control subjects. CONCLUSIONS: In urine samples, the measurement of 8-OHdG alone as well as the ratio 8-OHdG/2-dG were significantly different in healthy controls and PD patients. In plasma samples, only the ratio 8-OHdG/2-dG was significantly higher in PD compared to healthy controls showing that the ratio 8-OHdG/2-dG is a reliable diagnostic tool in studies on DNA oxydative damage. PMID- 22239016 TI - Evaluation of arsenic, cadmium, lead, nickel, and zinc in biological samples (scalp hair, blood, and urine) of tuberculosis and diarrhea male human immunodeficiency virus patients. AB - BACKGROUND: The consequence of a deficiency in trace elements has been associated with an increased risk of human immunodeficiency virus type 1 (HIV-1) disease progression and mortality. This study examined the association between high scalp hair and blood arsenic, cadmium, lead, and nickel concentrations and opportunistic infections in hospitalized patients with the acquired immune deficiency syndrome (AIDS). METHODS: The study was performed on sixty two male HIV+ patients (HIV-1) from different cities of Pakistan. The patients were divided in two groups according to secondary infections (tuberculosis, diarrhea, and high fever). The biological samples (scalp hair, blood, and urine) were collected from AIDS patients, and for comparative study 120 healthy subjects (males) of same age group (31 - 45 years), socio-economic status, localities, and dietary habits were also included. The elements in the biological samples were analyzed by electrothermal atomic absorption spectrophotometry, prior to microwave-assisted acid digestion. The validity and accuracy of the methodology was checked using certified reference materials (CRMs) and with values obtained by conventional wet acid digestion method on same CRMs. RESULTS: The results indicated significantly higher levels of As, Cd, Ni, and Pb in the biological samples (scalp hair, blood, and urine) of male HIV-1 patients, compared with control subjects. It was observed that the high levels of these toxic elements may be predictors for secondary infections in HIV-1 patients. There was a significant increase in mean values of As, Cd, Ni, and Pb in whole blood, scalp hair, and urine samples of three groups of AIDS patients as compared to a controlled healthy male group (p < 0.001). CONCLUSIONS: These data present guidance to clinicians and other professionals investigating toxicity of As, Cd, Ni, and Pb in biological samples of AIDS patients. PMID- 22239017 TI - Reduced expression of chemerin is associated with a poor prognosis and a lowed infiltration of both dendritic cells and natural killer cells in human hepatocellular carcinoma. AB - BACKGROUND: Chemerin has been suggested to chemoattract dendritic cells (DC) and natural killer (NK) cells which have the antitumor role. However, no study has been performed to determine the expression of chemerin in tumor tissues. The aim of our study is to investigate chemerin expression in hepatocellular carcinoma (HCC) tumor tissues and to correlate chemerin expression with clinicopathological parameters and prognosis. METHODS: In a random series of 124 HCC patients, the expression of chemerin protein in tumor tissues and matched non-tumor tissues were detected by immunohistochemistry. The infiltration of DC and NK cells was examined by CD11c and CD56 immunostaining to observe whether it correlated with the level of chemerin protein expression. The correlation of chemerin expression levels with clinicopathologic variables and prognosis was also analyzed. RESULTS: The expression of chemerin protein was significantly decreased in HCC of 72 patients compared with paracarcinomatous liver tissue. The level of chemerin expression was significantly correlated with tumor size (p = 0.016), histological grade (p = 0.027) and the infiltration of DC and NK cells (p = 0.027 and p = 0.035, respectively). Survival analysis indicated that HCC patients with lower chemerin expression had poorer survival than those with higher expression (p < 0.001). Multivariable Cox regression analysis revealed that the chemerin expression level was an independent factor for prognosis (HR 3.034, 95% CI 1.017 to 9.053; p = 0.047). CONCLUSIONS: The results suggest that chemerin may play an important role in the development and progression of HCC via the recruitment of DC and NK cells. PMID- 22239018 TI - Effectiveness of a high-throughput genetic analysis in the identification of responders/non-responders to CYP2D6-metabolized drugs. AB - BACKGROUND: Recent studies investigating the single cytochrome P450 (CYP) 2D6 allele *2A reported an association with the response to drug treatments. More genetic data can be obtained, however, by high-throughput based-technologies. Aim of this study is the high-throughput analysis of the CYP2D6 polymorphisms to evaluate its effectiveness in the identification of patient responders/non responders to CYP2D6-metabolized drugs. METHODS: An attempt to compare our results with those previously obtained with the standard analysis of CYP2D6 allele *2A was also made. Sixty blood samples from patients treated with CYP2D6 metabolized drugs previously genotyped for the allele CYP2D6*2A, were analyzed for the CYP2D6 polymorphisms with the AutoGenomics INFINITI CYP4502D6-I assay on the AutoGenomics INFINITI analyzer. RESULTS: A higher frequency of mutated alleles in responder than in non-responder patients (75.38 % vs 43.48 %; p = 0.015) was observed. Thus, the presence of a mutated allele of CYP2D6 was associated with a response to CYP2D6-metabolized drugs (OR = 4.044 (1.348 - 12.154). No difference was observed in the distribution of allele *2A (p = 0.320). CONCLUSIONS: The high-throughput genetic analysis of the CYP2D6 polymorphisms better discriminate responders/non-responders with respect to the standard analysis of the CYP2D6 allele *2A. A high-throughput genetic assay of the CYP2D6 may be useful to identify patients with different clinical responses to CYP2D6-metabolized drugs. PMID- 22239019 TI - Evaluation of anti-CCP antibody for diagnosis of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis is a common, world wide, systemic disease that affects mainly joints. Rheumatoid factor is the only marker to diagnose rheumatoid arthritis; however these antibodies are present in other disorders and even in up to 15% of the healthy population. Many auto antibodies have been reported to diagnose rheumatoid arthritis e.g. APF and AKA, etc. but they are not specific and due to tedious laboratory procedure, they have not been generally adopted. Anti-CCP antibodies have been reported for their high sensitivity and specificity. This study was planed to determine the prevalence of anti-CCP antibodies and RA factor in clinically diagnosed patients of rheumatoid arthritis. METHODS: Anti-CCP antibody was determined by ELISA technique and RA factor was done by latex agglutination method. RESULTS: Forty five patients, 36 female and 9 male, were recruited for this study. Twenty-five (55.6%) patents were positive for anti-CCP antibodies while 20 patients were negative for anti CCP antibodies and comparison between anti-CCP positive and anti-CCP negative was statistically significant (p = < 0.01). Thirty-one (68%) patients were seropositive (SPRA) for RA while 14 (31%) patients were seronegative (SNRA). Among SPRA patients, 18 were positive for anti-CCP antibody and among 14 SNRA patients, 7 patients had anti-CCP antibody and the difference between these two groups was not statistically significant. CONCLUSIONS: Anti-CCP antibody and RA factor should be used concomitantly to diagnose RA. PMID- 22239020 TI - Reduced levels of anti-MDA LDL antibodies in patients with carbohydrate metabolism disorders. AB - BACKGROUND: Diabetic patients undergoing percutaneous coronary intervention (PCI) have a worse prognosis than non-diabetic patients. The anti-oxidized LDL antibodies (anti-LDLox ab) have recently been suggested to be protective against the development of diabetes. The aim of this study was to compare the levels of IgG and IgM anti-oxidized LDL antibodies with reference to the new diagnostic criteria for carbohydrate metabolism disorders after an oral glucose tolerance test (OGTT) in hospitalized patients scheduled to undergo percutaneous coronary intervention. METHODS: We undertook a cross-sectional study of 110 patients undergoing PCI. The patients were classified as being normal (oral glucose test tolerance normal, OGTT-N), or having impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) according to their glucose levels at baseline and after an OGTT. RESULTS: An inverse slope was found in the levels of IgG anti-oxidized LDL antibodies between the OGTT-N patients (optical density (OD) = 0.109) and the patients with IGT (OD = 0.099) or T2DM (OD = 0.084) (p = 0.019). An inverse correlation was also detected between the levels of IgG anti-oxidized LDL antibodies and baseline glycemia (r = -0.23, p = 0.018). CONCLUSIONS: Patients with coronary disease and carbohydrate metabolism disorders have much lower levels of IgG anti-oxidized LDL antibodies than normoglycemic patients. PMID- 22239021 TI - Assessment of intestinal permeability using sugar probes: influence of urinary volume. AB - BACKGROUND: As the accuracy of the "Sugar Test" is currently debated, this study was conducted to focus on how urine volumes may impact the test results. METHODS: Fifty-five subjects, 23 healthy and 32 with Irritable Bowel Syndrome (IBS), were enrolled. Lactulose and D-mannitol dissolved in water were administered to all the participating subjects; the urine excreted was collected and the total urine volume was measured. The urine samples were analyzed by High Performance Liquid Chromatography (HPLC). The results were expressed as percentage of urine recovery of lactulose and D-mannitol and lactulose/D-mannitol ratio (LMR). RESULTS: All subjects were divided into two groups: subjects with urine volume < 500 mL and subjects with urine volume > or = 500 mL. Urine analysis showed that the mean LMR was significantly lower in subjects with urine volume > or = 500 mL than in subjects with urine volume < 500 mL (0.02 +/- 0.02 vs 0.04 +/- 0.04; p < 0.05). A significant increase in D-mannitol recovery was found to be associated with greater urine volumes (p < 0.001). CONCLUSIONS: The urine volume may influence urinary excretion of sugar probes. Intake of liquids should therefore be carefully monitored before and during the test and the volume of urine produced over the period of collection should be precisely measured. PMID- 22239022 TI - Comparison of polymerase chain reaction and conventional methods for diagnosis of Listeria monocytogenes isolated from different clinical specimens and food stuffs. AB - BACKGROUND: Listeria monocytogenes has emerged as a significant food borne pathogen in recent decades. Polymerase chain reaction (PCR) is deemed to be more reliable than conventional methods of identification. This work aimed to evaluate the accuracy of PCR in comparison to conventional methods for the diagnosis of L. monocytegenes from different clinical specimens and food stuffs. METHODS: This study was conducted on 66 clinical specimens and 100 different food stuffs. On the basis of colonial morphology, Gram's stain, catalase test, haemolysis on sheep blood agar, and motility test, Listeria isolates were further identified to species level by 10300 API Listeria strips. PCR was done directly for all specimens to evaluate its accuracy in comparison to conventional methods of diagnosis. RESULTS: A total of 5 (7.6%) same L. monocytogenes isolates were identified both by the conventional method and PCR in different clinical samples. However, PCR identified 6 (6%) L. monocytogenes isolates from food stuffs versus 4 (4%) isolates were identified by conventional methods. CONCLUSIONS: PCR is a rapid procedure with both sensitivity and specificity for quick detection and identification of L. monocytogenes either from clinical specimens or food stuffs. PMID- 22239023 TI - Comparison of serum cardiac specific biomarker release after non-cardiac thoracic surgery. AB - BACKGROUND: The detection of postoperative myocardial infarction can be difficult in patients after lung surgery. The aim of this study was to verify the clinical significance of elevated Troponin I (cTnI), N-terminal pro-natriuretic peptide (NT-pro-BNP), lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB in the perioperative course. METHODS: Between 2007 and 2010, 64 patients (36 men, 28 women) were includeded in this prospective study and underwent thoracotomy and wedge lung resection (n = 20, group I), lobectomy/bilobectomy (n = 24, group II), and pneumonectomy (n = 20, group III). Peri-operative measurements were done for the serum markers: cTnI, NT-pro-BNP, LDH, CK, and CK-MB preoperatively and at 4 hours, 8 hours, and 24 hours postoperatively. Patients were followed over a 90 day period to evaluate postoperative cardiac mortality. RESULTS: No basal troponin I elevation (or CK-MB) was found prior to surgery. Elevation in concentrations of troponin I (> 0.32 ng/mL) occurring after the procedure were seen in 9 patients. However, there was neither association with 90-day survival, postoperative ECG changes, nor with elevated levels of the other cardiac serum markers. cTnI correlated significantly with intrapericardial procedures in 7 out of 20 patients (Spearman's rank correlation coefficient: 0.406; p < 0.0001). Additionally, of the 20 patients within the pneumonectomy group, 8 patients had postoperative elevated serum cTnI. The grouping of patients into groups I through III was significantly associated with cTnI elevation (Spearman's rank correlation coefficient: 0.455; p < 0.0001). CONCLUSIONS: Despite the excellent sensitivity of troponin I for detection of acute myocardial infarction the fact remains that troponin I elevations were common after intrapericardial procedures and pneumonectomies. Thus, to differentiate between cardiac ischemia provoked chest pain and wound pain related to thoracotomy remains most difficult. Patients with only marginally elevated cTnI concentrations after intrapericardial resections or pneumonectomy should remain in the intensive care unit and should be followed-up carefully by cardiologists. PMID- 22239024 TI - Serum homocysteine level and its association with folic acid and vitamin B12 in the third trimester of pregnancies complicated with intrauterine growth restriction. AB - BACKGROUND: Intrauterine growth restriction (IUGR) is a common diagnosis in obstetrics and carries an increased risk of prenatal mortality and morbidity. It is associated with short and long term negative outcome in fetuses, infants, and children. The aim of the study was the determination of serum homocysteine along with folic acid and vitamin B12 concentration in pregnancies complicated with IUGR (intrauterine growth restriction). METHODS: The study was performed in a group of 180 pregnant subjects in the third trimester. Fasting (overnight, at least 12 hour) blood samples were collected from 150 pregnant patients with IUGR and 30 normal pregnant women. Serum total homocysteine (tHcy), serum folic acid, and serum vitamin B12 levels were measured. RESULTS: Mean serum concentration of total homocysteine in the group of pregnant patients with IUGR was 11.14 +/- 4.05 microM/L whereas in the group of normal pregnant women it was 7.42 +/- 2.93 microM/L. The serum folic acid level in the group of pregnant patients with IUGR was 10.24 +/- 3.91 ng/mL while in the group of normal pregnant women it was 15.20 +/- 3.41 ng/mL. The serum vitamin B12 level in the group of pregnant patients with IUGR was 146.99 +/- 43.51 pg/mL where as in the group of normal pregnant women it was 171.96 +/- 25.75 pg/mL. The differences were statistically significant. CONCLUSIONS: The study revealed that increasing serum homocysteine levels in pregnancies complicated with IUGR were accompanied by decreasing levels of serum folic acid and vitamin B12. Treatment with folic acid and vitamin B12 could improve fetal weight in IUGR pregnant patients with increased homocysteine levels. PMID- 22239025 TI - Vitamin A, E, B12, and folic acid in end-stage renal disease Tunisian patients: status and predictive value for overall mortality and cardiovascular events. AB - BACKGROUND: Vitamin status and role in end stage renal disease (ESRD) is controversial. This study was aimed at assessing vitamin A, E, B12, and folic acid status in Tunisian ESRD patients and testing their predictive value for overall mortality and cardiovascular events (CVE). METHODS: We examined plasma vitamin A, E, B12, and folic acid in 115 ESRD patients and looked for any correlation with all-cause mortality and CVE after a six year follow-up. Vitamin A and E were determined by HPLC and vitamin B12 and folic acid were determined by enzyme immunoassay. RESULTS: At enrolment, plasma vitamin A was higher in patients than controls, while plasma vitamin B12 was higher in HD patients. No significant differences were observed for plasma vitamin E and folic acid concentrations between patients and controls. Folic acid and vitamin B12 levels were higher in supplemented patients. During the follow-up period, 17 patients were lost, 15 died, and 36 presented a CVE. Survival analysis showed that mortality and/or CVE trend to be lower for high folic acid levels (Log Rank = 0.098). Cox's regression analysis showed that high levels of folic acid are inversely related to all-cause mortality and/or CVE [Hazard ratio (95% confidence interval), 0.255 (0.08 - 0.740); p = 0.012]. CONCLUSIONS: Plasma vitamins A, E, B12, and folic acid concentrations are usually normal in Tunisian ESRD patients. High folic acid levels are associated with fewer CVE and better survival. However, as uremia could be associated with functional vitamin deficiency, maintaining high plasma vitamin levels by adequate nutrition and tolerable supplementation would be beneficial in ESRD patients. PMID- 22239026 TI - Analysis of clinical and pathological characteristics of 28 cases with renal amyloidosis. AB - BACKGROUND: This study was planned to summarize the clinical and pathological features of renal amyloidosis in order to improve its early and accurate diagnosis. METHODS: The clinical and pathological data were analyzed from 28 patients with renal amyloidosis in the Second Xiangya Hospital from January 2005 to September 2010. RESULTS: Twenty seven out of the 28 (96.4%) cases were over 40 years old and presented with nephrotic syndrome. The initial diagnosis of 23 patients (82.1%) was not renal amyloidosis at their first visit to the local hospital. The pathophysiological finding included diffused deposition of amorphic and eosinophilic amyloid substance in glomerular mesangial, capillary membrane loop, interstitial, vascular, and tubular wall. 26 cases were attributed to the AL type and 2 cases to AA type. 25 patients (89.3%) were found to have monoclonal light chain in serum or urine by protein electrophoresis. CONCLUSIONS: Renal amyloidosis is frequently neglected by local physicians in China. Renal amyloidosis should be highly suspected if the middle-aged nephrotic patient was accompanied by weight loss, organ enlargement, and monoclonal light chains in serum or urine. Renal biopsy, especially with examination under the electron microscopy, is the key to the early diagnosis of renal amyloidosis. Potassium permanganate staining and immunofluorescence examination could help to distinguish primary from secondary amyloidosis. PMID- 22239027 TI - Insulin-like growth factor binding protein-1 and glycodelin levels in uterine flushing before and after hysteroscopic polypectomy. AB - BACKGROUND: Endometrial polyps are one of the most common endometrial abnormalities and it may be associated with infertility and early pregnancy loss. The aim of this study was to investigate the levels of insulin-like growth factor 1 binding protein (IGFBP-1) and glycodelin levels in uterine flushings before and after hysteroscopic polypectomy. METHODS: Two-hundred fifty non pregnant women participated in this prospective interventional study. One-hundred women with a complaint of infertility had endometrial polyps diagnosed by two-dimensional ultrasound scan and confirmed by transvaginal sonohysterography were prepared for hysteroscopic polypectomy, and 150 women with a history of menorrhagia not responding to medical treatment were prepared for hysteroscopic endometrial biopsy. Paired samples of uterine flushings were taken from all patients prior to and post hysteroscopic intervenetion at the midluteal phase. Insulin-like growth factor binding protein-1 was analyzed using an immunoradiometric assay. Enzyme linked immunoassays were performed to analyze glycodelin. Glycodelin and IGFBP-1 levels were compared in both groups prior to and post hysteroscopic intervention. RESULTS: The glycodelin and IGFBP-1 levels are significantly lower in patients with uterine polyps than in patients having menorrhagia preoperatively (p < 0.001 for each). In patients with uterine polyps, both glycodelin and IGFBP-1 were significantly increased postoperatively (p < 0.001 for each), while no significant changes in their values were noted postoperatively in patients with menorrhagia undergoing endometrial biopsy. CONCLUSIONS: Decreased levels of mid secretory IGFBP-1 and glycodelin were associated with the presence of endometrial polyps and both were reversed following hysteroscopic polypectomy. This could explain the pathophysiological mechanisms by which endometrial receptivity is impaired in the presence of endometrial polyps. PMID- 22239028 TI - Detection and characterization of enterovirus associated with herpangina and hand, foot, and mouth disease in Seoul, Korea. AB - BACKGROUND: Human enteroviruses (HEVs) are a major cause of herpangina, HFMD (hand, foot, and mouth disease), and other neurological diseases in Seoul, Korea. METHODS: A total of 56 specimens from hospitalized patients collected from February to December 2009 (37 females and 19 males) in Seoul were tested for HEV from stool, throat swab, and vesicle swab samples taken from patients with herpangina or HFMD using cell culture and RT-PCR in 2009. By the 1D gene, encoding the VP1 capsid protein, seven different HEV genotypes were detected with Coxsackievirus A2, A4, A5, A9, A16 (CA), Coxsackievirus B1 (CB), and Enterovirus 71 (EV71). The most prevalent genotype was CA16 (6, 10.7%), followed by CA2 (4, 7.1%), CA5 (4, 7.1%), EV71 (2, 3.6%), CA4 (1, 1.8%), CA9 (1, 1.8%), and CB1 (1, 1.8%). The 1D gene sequences of two EV71 strains were closely related with one another (98.5% nucleotide similarity) and belonged to the C4 genotype. CONCLUSIONS: It is important to continuously survey the genetic characteristics of EV71 and CA16 from patients, which will provide useful data that aids in our understanding of HFMD infections in Seoul, Korea and may contribute to future control. PMID- 22239029 TI - Allergy to cockroaches: challenges in diagnosis. AB - BACKGROUND: Blattella germanica and Periplaneta americana are the most common domestic species of cockroaches, found all over the world under favorable conditions. Allergen sensitivity can be detected through in vivo tests, such as skin prick tests (SPT) for immediate hypersensitivity and in vitro techniques, represented mainly by the sIgE determination. Nevertheless, there is no gold standard for the detection of hypersensitivity to cockroaches. This study aims to evaluate the agreement between skin prick test to different cockroach allergenic extracts with serum specific IgE determination in the diagnosis of cockroach allergy in asthmatic and non-asthmatic children. METHODS: A case-control study involving 74 asthmatic and 42 non-asthmatic children aged between 6 and 14 years was conducted in Recife, Brazil. All individuals were submitted to a skin prick test (SPT) with Dermatophagoides pteronyssinus, D. farinae, Blomia tropicalis (IPI-ASAC) and three different commercial cockroach extracts (Greer, Hollister Stier, and IPI-ASAC Brasil) of B. germanica and P. americana, and to the quantification of total serum IgE and specific serum IgE to B. germanica and P. americana. RESULTS: The mean diameter of induced papule was considerably greater among the asthmatic patients when compared to non-asthmatic controls, regardless of the species or type of cockroach extract. The correlations between the various types of utilized extracts for the two species studied were not sufficiently strong. Hollister-Stier extract was the most sensible extract among asthmatics in this study for both B. germanica (54.1% [N = 40]) and P. americana (59.5% [N = 44]). A satisfactory correlation was found between the serum levels of specific IgE and total IgE for both species of cockroaches. The correlation of specific IgE serum level from each species with its respective SPT was not considered satisfactory. CONCLUSIONS: The weak correlation between the different extracts clearly indicates a need for standardization of the extracts for SPT for cockroach allergy diagnosis. According to this study, only a patient with high specific IgE serum levels and a positive SPT to a cockroach species should be truly classified as hypersensitive to B. germanica and/or P. americana. PMID- 22239030 TI - Association between angiographically assessed coronary artery disease and serum levels of prostate specific antigen. AB - BACKGROUND: The increased incidence of coronary artery disease (CAD) in patients with conventional cardiovascular risk factors cannot be fully explained by the known risk factors. The aim of the study was to test whether there is an association between the levels of serum total PSA with the presence of CAD and its severity. METHODS: The study population consisted of 151 male patients aged < 55 years admitted at our center for elective coronary angiography. Patients having angiographic evidence of atherosclerosis (Gensini score > 6) in their epicardial coronary tree were categorized as having coronary artery disease (CAD(+) case group). Patients with Gensini score < or = 6 classified as having normal coronary arteries (CAD(-) control group). The presence and severity of CAD was determined by vessel score and Gensini score. The PSA levels were measured by the electrochemoluminescence (ECLIA) method. RESULTS: The mean level of serum PSA was found to be significantly higher in CAD patients than in those without CAD. In a multivariable logistic regression model, after adjusting for covariates, PSA level remained as an independent predictor for CAD occurrence (OR = 2.79; 95% CI: 1.04 - 7.49; p = 0.042). No significant correlation was found between the serum PSA level and the severity of CAD (r = 0.127, p = 0.122) or between PSA level and hsCRP level (r = 0.088, p = 0.282). CONCLUSIONS: It appears that PSA level is significantly associated with the presence of CAD. Further studies with larger sample size are required to confirm this result. PMID- 22239031 TI - Procedure for determination of immunosuppressive drugs in whole blood with liquid chromatography-isotope dilution mass spectrometry. AB - BACKGROUND: Cyclosporin A, sirolimus, tacrolimus, and everolimus are immunosuppressive drugs used for therapy after organ transplantation. There are several analytical procedures for monitoring the drug level in blood, e.g. immunological methods and high-performance liquid chromatography combined with mass spectrometry (MS). From external quality assessment schemes, it became evident that the analytical results show high dispersion and further standardization is required. METHODS: Liquid/liquid extraction of the drugs from whole blood samples was performed using ammonium acetate buffer, pH 9.5, and tert butylmethyl ether/ethyl acetate (1:1 v/v). Separation of the immunosuppressive drugs was achieved by HPLC using a phenyl-hexyl-RP column with a ternary gradient elution profile, consisting of water, methanol, and acetonitrile containing 0.1% v/v formic acid and 0.1 mmol/L Cs+. Quantification of immunosuppressive drugs was performed by isotope-dilution mass spectrometry using [2H12]-Cyclosporin A [13C, 2H3]-Rapamycin, [13C, 2H2]-Tacrolimus, and [13C2, 2H4]-42-O-(2 Hydroxyethyl)rapamycin as internal standards. RESULTS: The recovery of the new procedure was determined by analysis of spiked blood samples. The recovery in spiked EDTA whole blood samples was 100.8 - 102.5% for cyclosporin A, 101.6 - 103.0% for sirolimus, 100.0 - 101.2% for tacrolimus, and 99.5 - 102.4% for everolimus. The imprecision of the new measurement procedure, expressed as the coefficient of variation (CV), was 1.17 - 2.60% for cyclosporin A in the concentration range between 8.1 and 979 microg/L, 0.92 - 1.72% for sirolimus in the concentration range between 2.1 and 33.2 microg/L, 0.44 - 1.06% for tacrolimus in the concentration range between 2.0 and 30.8 microg/L and 0.82 - 4.34% for everolimus in the concentration range between 2.1 and 31.4 microg/L. CONCLUSIONS: An isotope dilution LC-MS/MS procedure for determination of four immunosuppressive drugs was developed to provide a basis for further development toward a reference measurement procedure. PMID- 22239032 TI - Rapid and sensitive detection of Shiga toxin-producing Escherichia coli directly from stool samples by real-time PCR in comparison to culture, enzyme immunoassay and Vero cell cytotoxicity assay. AB - BACKGROUND: From May until July 2011 a large outbreak of infections with Shiga toxin (Stx)-producing Escherichia coli (STEC) occurred in Germany. More than 800 patients suffered from hemolytic uremic syndrome (HUS), and 49 fatal cases were reported. Obviously, a mandatory requirement for such a clinical situation is the availability of rapid and reliable STEC tests from the investigating laboratory. The standard methods like enzyme immunoassay (EIA), vero cell cytotoxicity assay (VCA), and microbiological culture are, however, hampered by a lack of sensitivity and specificity unless a prior, time consuming broth enrichment step is employed. In order to acelerate the laboratory diagnosis, we evaluated an in house real-time PCR assay for the detection of the Stx genes (stx1 and stx2) directly from stool specimens without the need of broth enrichment procedures. METHODS: 754 faecal samples were collected from 481 predominantly hospitalised patients with diarrhea from May 23 to June 10, 2011 at the Medical Laboratory Bremen, Germany. The samples were analysed with a direct stx real-time PCR and compared to EIA, VCA and culturing on enterohemolysin, ESBL, and CPS agar after broth enrichment. In addition, artificial samples (n = 12) from three official EHEC/STEC PCR quality proficiency panels (INSTAND, Germany, September 2006, September 2007, and April 2008) were analysed by real-time PCR only. RESULTS: The real-time PCR produced reliable, distinct melting profiles with characteristic peaks for the stx1 and stx2 PCR products. The quality proficiency panels revealed a detection limit of 10 CFU/PCR per reaction. 112, 86, 99, and 122 of 754 clinical samples were positive for culture, EIA, VCA, and real-time PCR, respectively. 121 of 122 PCR samples were positive only for stx2. Compared to culture as the gold standard, sensitivities of EIA, VCA, and real-time PCR were 76.8 %, 83.9%, and 96.4% and specificities were 99.4%, 99.2%, and 97.8%, respectively. CONCLUSIONS: The direct fecal stx real-time PCR proved superior to enrichment based VCA and EIA and can be recommended as a quick and sensitive tool for the early diagnosis of STEC infection in addition to microbiological culture. PMID- 22239033 TI - Serum matrix Gla protein concentrations in patients with mild and severe acute pancreatitis. AB - BACKGROUND: Acute pancreatitis (AP) causes an increase in proinflammatory cytokine and acute phase protein levels. Our previous studies in AP showed the role of fetuin A as a negative acute phase protein. Matrix Gla protein (MGP), beside fetuin A, is one of the main inhibitors of extraosseous calcification. In the present preliminary study we evaluated the relationship between MGP, lipase, and inflammation in AP patients. METHODS: The study included 40 patients with AP of diverse severity (28 mild, 12 severe), assessed during the early phase of AP (day 1 - day 7 of hospitalization). The concentration of MGP, fetuin A, polymorphonuclear elastase (PMN-elastase), interleukin 6 (IL-6), interleukin 18 (IL-18), hepatocyte growth factor (HGF), high sensitivity tumor necrosis factor alpha (hs TNFalpha), soluble receptor of tumor necrosis factor II (sTNFRII), and neopterin were measured by ELISA kits; albumin, lipase and amylase were measured on a Modular P Chemistry Analyser (Roche Diagnostica, Germany); procalcitonin (PCT) was measured using the LUMItest PCT (Brahms, Germany), and serum amyloid A (SAA) and high sensitivity C-reactive protein (hs CRP) were measured using an immunonephelometric method on a Nephelometer BNII (Siemens Healthcare, Germany). RESULTS: MGP positively correlated with lipase activity (R = 0.64; p < 0.05) on day 1 after admission to hospital. Lower MGP levels were consistent with higher intensity of inflammation, as MGP significantly (p < 0.05) inversely correlated with IL-6 (R = -0.48 on day 3; R = -0.46 on day 5 and R = -0.52 on day 7 after admission), IL-18 (R = - 0.55; R = -0.60; R = -0.48 on day 1, day 3, and day 5, respectively), HGF (R = -0.58 on day 3), hs TNFalpha (R = -0.45 on day 1 and R = 0.64 on day 5), its soluble receptor sTNFRII (R = -0.63; R = -0.61; R = -0.59 on day 3, day 5, and day 7, respectively), hs CRP (R = -0.76 on day 1 and R = -0.83 on day 5), PCT (R = -0.62 on day 1 and R = -0.59 on day 7), SAA (R = -0.45 on day 5) as well as with neopterin (R = -0.52 on day 1 after admission). MGP levels dropped simultaneously with fetuin A (R = 0.50 on day 3; R = 0.60 on day 5 and R = 0.63 on day 7) and albumin concentrations (R = 0.51; R = 0.70; R = 0.94 on day 1, day 5, and day 7 day after admission, respectively). There was a relationship between lipase activity and MGP concentration on day 1 of hospitalization (R = 0.64; p < 0.05). CONCLUSIONS: Our preliminary results indicate that the MGP level correlated negatively with all of the proinflammatory cytokines and acute phase proteins studied in patients with AP, and positively with lipase, fetuin A, and albumin measurements. These findings may indicate the role of MGP in calcium and phosphate metabolism disturbances in the course of AP. PMID- 22239034 TI - Streptococcus bovis isolated in haemoculture a signal of malignant lesion of the colon. AB - S. bovis is known for causing bacteremia and endocarditis as well as accompanying malignant diseases of the gastrointestinal tract. Hence, identification of this species and recognition of the clinical characteristics of infections caused are essential for both therapy and prognosis. S. bovis isolated from haemoculture requires an immediate search for gastrointestinal tract lesions. PMID- 22239035 TI - CYFRA 21-1 as a tool for distant metastasis detection in lung cancer. AB - BACKGROUND: A study to analyse tumor markers (CEA, CA125, CA15.3, CA19.9, CYFRA 21-1, and NSE) for metastasis detection in lung cancer patients. METHODS: Serum tumor markers from 73 lung cancer patients were measured before they were diagnosed. After lung cancer diagnosis, tumor markers were analyzed for the detection of distant metastases. RESULTS: In NSCLC patients CYFRA 21-1 and NSE showed differences between stage IV and any of the other stages, p < 0.05. The accuracy for metastasis detection was AUC = 81.5 % for CYFRA 21-1 and AUC = 78.6 % for < 0.05) were independent predictors for metastasis presence. No tumor marker showed significant differences according to stages in SCLC patients. CONCLUSIONS: CYFRA 21-1 could be used as a screening tool for metastasis detection in lung cancer patients without symptoms of metastasis as well as CYFRA 21-1 and NSE in NSCLC patients. PMID- 22239036 TI - B-type natriuretic peptide measured in serum--calibration using plasma samples for research purposes. AB - BACKGROUND: We aimed to establish an equation for the estimation of the BNP concentration in plasma when only serum is available. METHODS: We enrolled 27 subjects aged at least 45 years, participating in a Portuguese cohort study. Blood samples were collected in plastic whole blood tubes, containing either ethylenediaminetetraacetic acid to obtain plasma or clot activator to obtain serum. The natural logarithm of serum BNP was calibrated with the natural logarithm of plasma BNP using a linear equation. RESULTS: The estimated regression parameters were 0.58 (95 % CI: 0.23 - 0.93) for beta0 and 1.01 (95 % CI: 0.90 - 1.11) for beta1. The absolute agreement between plasma BNP and that predicted by the equation according to the cut-off points 30 and 100 pg/mL were 96.3% (kappa = 0.92) and 96.3% (kappa = 0.91), respectively. CONCLUSIONS: Serum samples cannot be used to estimate absolute plasma concentrations, but serum BNP values and the calibration equation can be used to classify correctly the individuals with the usual cut-offs. PMID- 22239037 TI - Peptidyl-arginine deiminase: an additional marker of rheumatoid arthritis. AB - BACKGROUND: Antibodies against cyclic citrullinated peptide (anti-CCP) were thought to be more specific than rheumatoid factor (RF) for the diagnosis of rheumatoid arthritis (RA). The determination of anti-CCP in addition to RF could be helpful in the serological diagnosis and monitoring of patients with RA. Citrullination of proteins involves the enzymatic conversion of protein containing arginine residues to citrulline residues by the enzyme peptidylarginine deiminase (PAD). The present investigation was undertaken to estimate serum PAD enzyme activity in RA patients with a view to find its importance as a new diagnosis marker in a rheumatology clinic. METHODS: The activity of the PAD enzyme was measured by spectrophotometric method at 530 nm in sera of control subjects and in patients of RA (Group I: RF negative and CCP positive: Group II: both RF and CCP positive) in terms of citrulline formation using benzoyl-arginine ethyl ester (BAEE) as substrate. Anti-CCP and RF were also estimated in two groups by enzyme immunoassay and immunoturbidimetry for comparison. Clinical variables (duration of morning stiffness, swollen and tender joint counts, patient's assessment of pain) and C-reactive protein were also evaluated. RESULTS: A marked increase in PAD enzyme activity (p < 0.001) was noted in RA patients in comparison to controls and the level diminished appreciably along with two known serological markers (anti-CCP and RF) after six months of disease modifying antirheumatic drug (DMARD) treatment. The Group II RA patients showed much higher enzyme activity than Group I RA patients. However, clinical variables did not differ significantly between the two Groups of RA patients. CONCLUSIONS: We conclude that determination of PAD enzyme activity may be used as an additional marker for monitoring disease progression and regression along with anti-CCP and RF in patients with RA. Moreover, this method is rapid, sensitive, and inexpensive and can be adopted in a laboratory having modest facilities. PMID- 22239038 TI - Urine TGF- beta1 assay validation: spinning down urine samples could diminish TGF beta1 signal. AB - BACKGROUND: TGF-beta1 is a mediator of immune and anti-inflammatory responses. The present research was dedicated to the validation of the urine Quantikine Human TGF-beta1 ELISA assay. METHODS: A reference interval was developed utilizing 100 urine samples from healthy donors. Samples containing precipitate were centrifuged and supernatants or un-spun specimens were run with TGF-beta1 assay. RESULTS: Supernatant TGF-beta1 concentrations are only a fraction of the un-spun sample values (77% to 29%, even less for the low concentration samples). Validation involving un-centrifuged urine samples demonstrated the following TGF beta1 assay characteristics: linearity from 23 to 1286 pg/mL, recovery from 95 to 116%; precision: < 17%; analytical specificity 3 pg/mL; reference interval from 0 to 39 pg/mg creatinine; freeze-thaw stability: after first thawing, urine samples could loose from 5 to 40% of TGF-beta1 activity on each following freeze-thaw circle. CONCLUSIONS: For TGF-beta1 assay, urine sample preparation should not include a centrifugation step; repeating freeze-thawing should be avoided. PMID- 22239040 TI - Polymeric forms of light chain: what laboratories and clinicians need to know. PMID- 22239039 TI - Comparison of three single platform methods for CD34+ hematopoietic stem cell enumeration by flow cytometry. AB - In the present study, we compared three single platform methods for CD34+ hematopoietic stem cell (HSC) enumeration by flow cytometry. For this purpose, we analyzed the performance characteristics and results obtained from different HSC sources. Interlaboratory coefficients of variation (CV) for precision/reproducibility analysis varied from 4.0% to 6.7% / 6.7% to 9.2% for the low and 3.2% to 4.1% / 4.3% to 6.7%, respectively, for the high stem cell control. Correlation between methods ranged from 0.92% to 0.99%; Wilcoxon test showed no significant differences (p > 0.05); Bland-Altman analysis confirmed good agreement between assays (mean bias ranging from -0.48 to 6.91). Our results demonstrate very good intralaboratory correlation and agreement between methods, confirm the major impact of single platform strategy for accurate and reproducible HSC enumeration and suggest that high interlaboratory variability could be influenced by incorrect performance of validated methods. PMID- 22239041 TI - Ulcer care hit by red tape burden. PMID- 22239042 TI - "How can two years of effective pay cuts be described as fair?". PMID- 22239043 TI - "'Tis the season to take a stand against the war on nursing". PMID- 22239044 TI - "At Christmas, making a stand against routine can be enough". PMID- 22239045 TI - A tool to identify falling care quality. AB - Issues raised in the Mid Staffordshire Foundation Trust inquiry led staff at NHS South West to develop a tool that could predict falling standards, so preventive action could be taken before failings in care occurred. This article describes how the Quality, Effectiveness and Safety Trigger Tool (QuESTT) was developed and implemented in practice. PMID- 22239046 TI - Little voice: giving young patients a say. AB - BACKGROUND: Patient experience is widely measured in healthcare settings, but few tools exist that gather feedback directly from young patients. AIM: To develop a paediatric questionnaire to gain meaningful feedback from young hospital outpatients. METHOD: Two paper questionnaires were designed and tested--one for parents and one for young people. These were piloted in 2009 with 1,200 recent outpatients and their parents/carers from Sheffield Children's Foundation Trust. Rollout to 14 acute NHS trusts in England achieved an average response rate of 33%. RESULTS: The main problems for young outpatients related to waiting, pre appointment information and communication. Questionnaire validation showed that both surveys were accessible and a reliable measure of patient experience. CONCLUSIONS: It is important to give children and young people a say in their healthcare via tested methods that are appropriate to their needs and abilities. Results can help hospital outpatient departments to identify the main issues and problems experienced by their young patients. PMID- 22239047 TI - Developing evidence-based practice among students. AB - In response to government initiatives and the rise in patient empowerment, nurses are increasingly being challenged to deliver high-quality care supported by evidence-based practice. This can be a challenge for nurse educators providing the foundation for pre-registration student nurses. Evidence-based practice within nursing is achieved by developing and supporting patient-centred approaches to care using the most current evidence. This facilitates the development of a questioning approach incorporating the four principles of healthcare ethics--beneficence, non-maleficence, autonomy and justice. PMID- 22239048 TI - Money matters. PMID- 22239049 TI - [Effect of topical steroid on oral and nasal nitric oxide production in patients with allergic rhinitis]. AB - OBJECTIVE: To evaluate the effects of nasal mometasone furoate on oral and nasal nitric oxide (NO) production in patients with allergic rhinitis. METHOD: Twenty seven patients with moderate to severe symptoms of persistent allergic rhinitis were treated with mometasone furoate nasal spray (200 microg/d. qd) for 2 weeks. Nasal and oral exhaled nitric oxide concentrations, symptoms of rhinitis and quality of life were investigated before and after the treatment. RESULT: There was a significant improvement in nasal exhaled nitric oxide concentrations, symptoms of rhinitis and quality of life, but not in oral exhaled nitric oxide concentrations. Subjective improvements in symptoms and quality of life did not correlate significantly with objective measurements. CONCLUSION: Our study provides subjective and objective evidence on the efficacy of intranasal mometasone furoate in improving nasal symptoms and quality of life, as well as reducing nasal inflammation. PMID- 22239050 TI - [Clinical study of chronic invasive sinusitis caused by dematiaceous fungi]. AB - OBJECTIVE: To discuss the clinical presentation, diagnostic criterion and treatment principle of chronic invasive sinusitis caused by dematiaceous fungi. METHOD: One patient was diagnosed as chronic invasive sinusitis based on history, headache, especially eye symptoms without fever, sinus CT and MRI, endoscopic and cytological findings in the nasal cavity. Surgical debridement was performed, and the patient was administered with systemic anti-fungi treatment. RESULT: Alternaria was identified on culture. The patient was proved of tissue invasion histopathologically through biopsy. The patient survived after treatment without recurrence. CONCLUSION: Extensive and aggressive surgical debridement, prompt and adequate dosage of intravenous antifungal therapy , together with controlling of the underlying disease, all contribute to a complete resolution of the disease. PMID- 22239051 TI - [Expression of BRMS1 gene protein in nasal and paranasal sinus carcinomas]. AB - OBJECTIVE: To investigate the role and clinical significance of the expression of BRMS1 gene in development and progression of nasal and paranasal sinus carcinomas. METHOD: The expression of BRMS1 protein was detected by immunohistochemistry method in the 53 nasal and paranasal sinus carcinomas and 24 nasal polyp tissues and 10 normal mucosa. The expression of BRMS1 was analyzed in nasal and paranasal sinus carcinomas with different clinicopathological parameters. RESULT: The expression of BRMS1 in normal tissues (90.0%) and nasal polyp tissues (79.2%) was statistically significantly higher than that in nasal and paranasal sinus carcinomas (39.6%) (P < 0.01). There was a positive correlation between BRMS1 expression and TNM staging and lymph node metastasis; but not associated with pathological grade. CONCLUSION: The loss of BRMS1 expression may be involved in the development and progression of nasal and paranasal sinus carcinomas. PMID- 22239052 TI - [Clinical observation of mucoregulatory agents' application after chronic rhinosinusitis surgery]. AB - OBJECTIVE: To explore the effect of mucoregulatory agents during endoscopic sinus surgery. METHOD: Ninety-seven cases with chronic rhinosinusitis were randomly divided into three groups, with 31 cases in B group treated by ambroxol, 33 cases in C group treated by eucalyptol-limonene-pinene enteric soft capsule and 33 cases in control group (A group). The follow-up visit lasted for 6 months for three groups. Then, the therapeutic effects were evaluated and compared among these three groups. RESULT: By the end of 6 months after treatment,the effective rate was 90.3% and 97.0% for cases in the B and C groups respectively, and only 75.8% in A group. The difference between A and C was statistically significant (P < 0.05). CONCLUSION: Eucalyptol-limonene-pinene enteric soft capsule,as a multicomponent mucoregulatory agent, can obviously improve the secretion of mucosa and epithelial recovery, thus accelerate healing of the disease. It can also improve the success rate of functional endoscope sinus surgery, and may play a promising role in clinical application. PMID- 22239053 TI - [Etiology and treatment of delayed epistaxis after endoscopic surgery]. AB - OBJECTIVE: To evaluate the etiology and management of delayed epistaxis after endoscopic surgery. METHOD: To retrospectively analyze the clinical data of 11 cases for epistaxis after nasal endoscopic surgery. To compare their precipitating factors, their surgical approach, time and site of bleeding and management in order to find the intrinsic rules. RESULT: The precipitating factors, bleeding sites and treatments varied among patients. CONCLUSION: Delayed epistaxis after endoscopic surgery can not be neglected. There may be some precipitating factors. The surgical approach may be related to the bleeding site. It is better to treat the epistaxis using the endoscope to explore the bleeding site and to give corresponding intervention. PMID- 22239054 TI - [Modified-coblation assisted UPPP in treatment of severe obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To explore a new way to modify the UPPP and to assess the operative efficacy of modified-coblation assisted UPPP (M-CAUP) on patients with severe obstructive sleep apnea-hypopnea syndrome (OSAHS). METHOD: A retrospective analysis was made on surgical therapeutic effect of M-CAUP performed in our hospital. INCLUSION CRITERIA: 87 adult inpatients with severe OSAHS were involved in the study whose preoperative AHI were beyond 30/h and LSaO2 were under or equal to 85%. All those had the primary level obstruction within the retropalatal region as determined by PSG and airway pressure fluctuation monitoring (ApneaGraph 200, MRA-Medical Ltd, Gloucestershire UK) . The surgical approach of M-CAUP: (1) bilateral tonsillectomy by using Arthrocare EVac 70 T&A Wand. (2) dissection of velum palatinum space by using Arthrocare EVac 70 T&A Wand, ablation of fat tissue to removed it from the space, avoiding injure levator palatini muscle and tensor palatini muscle and preserving musculus uvula, maintaining the normal structure of oropharynx. (3) ablation of channel of soft palate by using Arthrocare EVac 55 T&A Wand to reduce the volume of soft palate moderately. (4) plasty: suturing the tonsilar fossa to close the space, interrupted suture two sides of palatine arch and uvula. All patients were followed up for six to eighteen months postoperatively and received PSG. RESULT: After M-CAUP, the pharyngeal cavity was enlarged while the basic structure of oropharynx was maintained and no nasopharyngeal refluxing occurred. The subjective symptoms were also improved evidently after operation. After operation, the AHI and Epworth sleepiness scale (ESS) decreased while LSaO2 increased. The reduction of AHI and ESS had statistical significance (P < 0.01), and the rise of LSaO2 also had statistical significance (P < 0.01). The total effective ratio of the operation was 89.7%. CONCLUSION: Despite of various treatment, the operative efficacy of conventional UPPP was almost not ideal on severe OSAHS due to complex pathogeny. It was proved that M-CAUP was an effective surgical treatment of severe OSAHS with less blood loss. The operation was minimally invasive and maintained the normal functions of palatopharynx in principle. It could be applied in clinical practice. PMID- 22239055 TI - [The misdiagnosis and erroneous treatment for airway foreign body in children]. AB - OBJECTIVE: To analyze the reasons and hazards of the misdiagnosis and erroneous treatment for airway foreign body in children, and explore the effective measures. METHOD: To analyze 452 cases of airway foreign body with the history of misdiagnosis in children. RESULT: The medical history and objective signs could be helpful to the diagnosis of airway foreign body. X ray examination is nessesary and useful, meanwhile, CT and multiple plane reconstruction provide another choice for the diagnosis. CONCLUSION: Doctors should recognize the hazards of delayed diagnosis of airway foreign body and avoid the misdiagnosis and erroneous treatment. Suitable time of intervention and surgical approach could decrease the complications and elevate healing rate. PMID- 22239056 TI - [OSAHS patient gas up-take cross-sectional area nasopharynx sound reflection examination and significance]. AB - OBJECTIVE: To explore a simple and accurate method for localization of upper airway obstruction in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and provide instructions for surgical treatment. METHOD: Fifty OSAHS patients confirmed by PSG underwent acoustic rhinometric and pharyngometric assessment by Eccovision. The parameters were recorded, including nasal minimal cross-sectional area (NMCA), distance of MCA from the nostril (DCAN), minimum cross-sectional area at the nasal valve(MCA), nasal resistance (NR) and nasal volume from 0 to 6 cm from the nostril (NCV), as well as pharyngeal cross sectional area (CSA) and volume from 4.8 to 15.0 cm. The sensitivity and specificity of acoustic rhinometry and pharyngometry on localization of airway obstruction was determined by a comprehensive imaging and endoscopic study. RESULT: In 50 cases with severe OSAHS, NMCA, DCAN, MCA, NCV, NR were (0.61 +/- 0.35) cm2, (2.06 +/- 0.12) cm, (0.87 +/- 0.12) cm2, (9.24 +/- 2.31)cm3 and (0.51 +/- 0.32)kPa/(L x min), respectively. Pharyngeal CSA and volume were statistically significantly lower than that in control group (P < 0.01). The value of DCAN was (2.06 +/- 0.12) cm, (9.50 +/- 4.08) cm, (13.10 +/- 2.52) cm in type I II, III patient, respectively. Compared with the control group, the difference was statistically significant. CONCLUSION: Acoustic rhinometry and pharyngometry is a simple and safe method in localization of airway obstruction in patients with OSAHS. PMID- 22239057 TI - [Inhibitory effect of silencing hTERT gene on growth of human squamous cell carcinoma xenograft in nude mice]. AB - OBJECTIVE: This study is to explore the inhibitory effect of silencing hTERT gene by short-hairpin RNA on growth of nasopharyngeal carcinoma xenograft in nude mice with RNAi technique. METHOD: Construction and expression of hTERT cDNA sequence according to the specific hTERT mRNA, including fluorescein eukaryotic expression vector, packaged into a lentivirus. qPCR and Western blot analyzed hTER.T mRNA and protein levels in transfected cells. Proliferation rate of transfected cells was determined by MTT assay in vitro. Cell growth cycle was detected by flow cytometry. The invasiveness of each group was compared using in vitro cell invasion assay. RESULT: RT-PCR and Western blot analysis showed that, hTERT siRNA significantly reduced hTERT mRNA and protein levels, especially hTERT siRNA1. siRNA treatment inhibited tumor cell proliferation, and cell migration and invasiveness were significantly lower. Tumor cell growth rate was significantly different between control group and siRNA group (P < 0.01) while tumor cell growth rate in empty virus group(NC group) and control group was not significantly different (P > 0.05). CONCLUSION: Lentivirus containing specific sequences of hTERT gene could significantly inhibit the growth of nasopharyngeal carcinoma cells line. hTERT siRNA expression vector can effectively inhibit NPC cell proliferation, migration and invasion, which may provide a novel molecular targets for gene therapy of nasopharyngeal carcinoma. PMID- 22239058 TI - [A preliminary study on the regulation mechanism of p38MAPK on MUC5AC in allergic rhinitis]. AB - OBJECTIVE: To detect the effect of p38 mitogen activated protein kinase (p38MAPK) and cyclooxygenase-2 (COX-2) on the expression of mucin5AC (MUC5AC) in human nasal mucosa induced by histamine in vitro, and to investigate the pathogenesis of mucus hypersecretion in allergic rhinitis (AR). METHOD: Western blot was performed to detect the protein expressions of p38MAPK, COX-2 and MUC5AC in nasal mucosa induced by histamine or blocked by selective inhibitors of p38MAPK and COX 2 of different concentration gradient. RESULT: Weak expressions of p38MAPK. COX-2 and MUC5AC were detected in normal nasal mucosa in vitro. The protein expressions of p38MAPK. COX-2 and MUC5AC increased in nasal mucosa induced by histamine in a dose-dependent manner. The histamine induced protein expressions of COX-2 and MUC5AC were dose-dependently attenuated by selective inhibitor of COX-2, namely NS-398. No apparent influence of NS-398 on the expression of p38MAPK was observed. The histamine induced protein expressions of p38MAPK, C()X-2 and MUCbAC dose-dependently decreased after nasal mucosa was treated by selective inhibitor of p38MAPK, namely SB203580. And no significant change of MUC5AC protein expression induced by NS-398 or SB203580 was observed. CONCLUSION: Our findings indicated that the histamine-induced increased expression of MUC5AC by activated p38MAPK/COX-2 may be a possible pathogenesis of mucus hypersecretion in AR. PMID- 22239059 TI - Adiposity and risk of proliferative diseases of the breast prior to the diagnosis of invasive breast cancer: results from a pilot study. PMID- 22239060 TI - Peripherally fused porphyrins via the Scholl reaction: synthesis, self-assembly, and mesomorphism. AB - Oxidative coupling of activated aryl groups attached to beta-positions of the porphyrin ring provides convenient access to derivatives containing peripherally fused phenanthrene and benzo[g]chrysene units. Tetra(benzochryseno)porphyrin, reported here for the first time, contains a nonplanar, sterically locked pi system and shows very intense electronic absorptions in the Q range of the electronic spectrum. Tetraphenanthroporphyrins show a tendency to aggregate in solution. In one case, a discrete dimer is formed, whose structure was investigated spectroscopically and theoretically. Derivatives bearing long alkyl chains are mesomorphic and exhibit columnar phases (tetraphenanthroporphyrins) and a monoclinic 3D phase (tetrabenzochrysenoporphyrin). The symmetry of column packing in the columnar phases is dependent on the number of alkyl chains per molecule. X-ray diffraction measurements show that, in spite of their nonplanarity, the aromatic cores in the mesophases are tightly stacked within the column. The corresponding stacking patterns were derived from the structure of the dimer, on the basis of geometrical analysis and molecular modeling. PMID- 22239061 TI - Volatile organic compounds in headspace over electrical components at 75 to 200 degrees C - part 1. identification of constituents and emission rates. AB - The identity and emission rates of volatile organic compounds (VOCs) in headspace vapors over electronic components were determined at temperatures from 75 to 200 degrees C using gas chromatography/mass spectrometry. The emission of VOCs may provide a basis to detect the onset of the overheating of electronic components in confined atmospheres near electronic bays on airplanes and submarines before smoldering or ignition. VOCs found in headspace vapors over components, including resistors, capacitors, diodes, transistors, and insulation from wires of a transformer, were composed of simple mixtures of substances with 6 to 10 carbon number from chemical families including ketones, aldehydes, substituted benzenes, alcohols, and phenols. Composition of the vapors was characteristic but not exclusive of a particular electrical component, except for phenols and methylstyrene, which were found only in a single component. Emission rates were expressed as nanogram of chemical per gram of component per minute, and increased from a low of 0.001 ng/g-min for nonanal from transformer wire at 100 degrees C to a maximum of 2.5 ng/g-min at 150 degrees C for isophorone from a resistor. Patterns of persistence with repeated sampling of headspace for components at 200 degrees C over 5 hr suggested that VOCs arose from impurities in plastics rather than from thermal decomposition of the polymer. PMID- 22239062 TI - Nucleotide diversity and selection signature in the domesticated silkworm, Bombyx mori, and wild silkworm, Bombyx mandarina. AB - To investigate the patterns of nucleotide diversity in domesticated silkworm, Bombyx mori L. (Lepidoptera: Bombycidae) and its wild relative, Chinese wild silkworm, Bombyx mandarina Moore, we sequenced nine nuclear genes. Neutrality test and coalescent simulation for these genes were performed to look at bottleneck intensity and selection signature; linkage disequilibrium (LD) within and between loci was employed to investigate allele association. As a result, B. mori lost 33-49% of nucleotide diversity relative to wild silkworm, which is similar to the loss levels found in major cultivated crops. Diversity of B. mori is significantly lower than that of B. mandarina measured as pi(total) (0.01166 vs. 0.1741) or theta(W)(0.01124 vs. 0.02206). Bottleneck intensity of domesticated silkworm is 1.5 (in terms of k = N(b) /d, N(b) -bottleneck population size; d-bottleneck duration) with different durations. Gene DefA showed signature of artificial selection by all analysis methods and might experience strong artificial selection in B. mori during domestication. For nine loci, both curves of LD decay rapidly within 200 bp and drop slowly when distance is > 200 bp, although that of B. mori decays slower than B. mandarina at loci investigated. However, LD could not be estimated at DefA in B. mori and at ER in both silkworms. Elevated LD observed in B. mori may be indicator of selection and demographic events. PMID- 22239063 TI - The density-dependency of dark- and low-background radiation effects on water and water solution properties. AB - The effects of dark -(Ev=0 lux) and low-background radiation (BGR), where R<1MURongen/h, on physicochemical properties (specific electrical conductivity, heat fusion, hydrogen peroxide (H2O2), and oxygen contents) of distilled water (DW) and physiological solution (PS) at 4 degrees C and 18 degrees C were studied. The incubation of DW and PS samples in dark and in low BGR (under dark) medium at 4 degrees C and 18 degrees C brings to changes of their physicochemical properties compared with DW and PS samples incubated in light and normal BGR condition (Ev=500-550 lux and R=17 MURoentgen/h). The observed changes of DW and PS properties depended on their initial temperature, density and ionic composition. It is suggested that water molecules dissociation and ions hydration are sensitive to illumination and BGR. Therefore, the cell-bathing medium can be considered as a messenger through which direct and non direct (by modulating of others factors-induced effects) influences of illumination and BGR on cell metabolism are realized. PMID- 22239064 TI - Mechanistic investigations of the ZnCl2-mediated tandem Mukaiyama aldol lactonization: evidence for asynchronous, concerted transition states and discovery of 2-oxopyridyl ketene acetal variants. AB - The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted beta-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl(2)-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl(2) and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated beta-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to beta lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system. PMID- 22239065 TI - Sensitization of ionizing radiation-induced apoptosis by ursolic acid. AB - Radiation therapy has been widely used for treating human cancers. However, cancer cells develop radioresistant phenotypes that decrease the efficacy of radiotherapy. Ionizing radiation (IR) induces the production of reactive oxygen species, which play an important role in apoptotic cell death. Therefore, radiation therapy combined with a sensitizer, which modulates cellular redox status, has the potential to enhance therapeutic efficacy in a variety of human cancers. Here, we investigated the radiosensitizing effects of ursolic acid (UA), a pentacyclic triterpenoid found in rosemary and holy basil. IR-induced apoptosis in cancer cell lines such as DU145, CT26 and B16F10 was significantly enhanced by UA, as reflected by DNA fragmentation, cellular redox status, mitochondrial dysfunction and modulation of apoptotic marker proteins. Additionally, UA combined with IR was also effective for inhibiting tumorigenesis in B16F10 melanoma cells implanted into mice. Taken together, these results suggest that applying UA together with IR may be an effective combination modality for treating cancer. PMID- 22239067 TI - Potentially inappropriate medication use in Indian elderly: comparison of Beers' criteria and Screening Tool of Older Persons' potentially inappropriate Prescriptions. AB - AIM: To compare Beers' criteria (BC) and Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) for prevalence, specificity, sensitivity and predictors for potentially inappropriate medication (PIM) use. METHODS: Patients aged >= 60 years from medicine wards of a tertiary care hospital were included. Comparisons between BC and STOPP were made using Pearson's chi(2) -test for categorical variables and Mann-Whitney U-test for continuous variables. Specificity and sensitivity were assessed by using 2 * 2 contingency table. Bivariate analysis and subsequent multivariate logistic regression was used to identify the predictors of PIM use. RESULTS: In the 540 patients included, prevalence of PIM use as per BC and STOPP was 24.6% and 13.3%, respectively. Sensitivity and specificity of BC in detecting PIM was 0.65 and 0.53, respectively. Considering the diagnoses/conditions, sensitivity and specificity of BC was 0.12 and 0.48, respectively, whereas independent of diagnoses/conditions, corresponding values were 0.75 and 0.54. PIM as per BC and STOPP accounted for 11 and 6 adverse drug reactions (ADR), respectively. Medications not listed in BC or STOPP were more likely to be associated with ADR. Multiple diseases (>= 4) and use of more drugs during hospital stay (10-14) predicted PIM use as per BC, whereas age (60-74 years) predicted PIM use as per STOPP. CONCLUSION: Overall, BC is useful in the detection of PIM use independent of diagnoses/conditions, whereas STOPP is useful in detection of PIM use considering the diagnoses/conditions. There is a need for consensus on using the tool for detection of PIM use in Indian elderly. PMID- 22239068 TI - Toward a stable alpha-cycloalkyl amino acid with a photoswitchable cationic side chain. AB - The N-alkylated indanylidenepyrroline (NAIP) Schiff base 3 is an unnatural alpha amino acid precursor potentially useful for the preparation of semisynthetic peptides and proteins incorporating charged side chains whose structure can be modulated via Z/E photoisomerization. Here we report that the heteroallylic protons of 3 led to partial loss of ethanol accompanied by formation of the novel heterocyclic system 4 during attempted deprotection. We also show that the same protons catalyze the thermal isomerization of 3, making the light-driven conformational control concept ineffective for times longer than a few hours. These problems are not present in the previously unreported compound 5 where the acidic methyl group is replaced by an H atom. Therefore, 5, rather than 3, constitutes a promising prototype for the design of building blocks capable to modulate the electrostatic potential of a protein in specific locations via light irradiation. PMID- 22239069 TI - Responses to risk: public submissions on Australian alcohol guidelines for low risk drinking. AB - INTRODUCTION AND AIMS: In 2007 the National Health and Medical Research Council issued the draft of the revised Australian alcohol guidelines. The document presented guidelines explicitly in terms of risk. This paper seeks to explore the public response to this document by analysing the submissions received during the 60 day period for public feedback. METHODS: One-hundred and three submissions were reviewed. Considerations of what interests were reflected in submissions and how interest groups responded to the framing of risk were examined. RESULTS: Submissions were received from individuals and organisations. Analysis revealed a range of views and rhetoric. Temperance interests wanted the guidelines' thresholds to be lower; the industry critiqued the evidence base as flawed and also argued that the public was unlikely to listen to low-risk drinking messages; submissions from public health groups and government wanted a greater rationale for the guidelines and were also concerned with the dropping of a second differentiation of a higher-risk level; personal testimonies supported the risk assessments based on personal experiences; and those working in clinical service provision expressed concern about the reception of the guidelines among client groups. DISCUSSION AND CONCLUSIONS: The diversity of views expressed seems to have had little effect in the revision of the guidelines. Disseminating the low risk drinking guidelines message poses many challenges. PMID- 22239070 TI - Outcomes after escalation of infliximab therapy in ambulatory patients with moderately active ulcerative colitis. AB - BACKGROUND: Infliximab (IFX) therapy escalation during maintenance treatment occurs frequently in clinical practice in patients with ulcerative colitis (UC). Outcomes for these patients have not been described. AIM: To describe the prevalence of, and outcomes after, IFX escalation during maintenance therapy in patients with moderate-severe UC. METHODS: Retrospective observational study of clinical outcomes in ambulatory patients with moderate-severe UC treated with maintenance IFX. RESULTS: Fifty-six ambulatory patients received IFX for moderate severe UC; fifty (89%) responded and proceeded to maintenance therapy. Mean duration of maintenance therapy was 14 months, with mean follow-up of 38 months. Twenty-seven patients (54%) required IFX therapy escalation after a mean of six maintenance infusions. Clinical remission was noted in 36% of the entire cohort (18/50) at 12 months; 19% in the escalation group and 56% in the non-escalation group. Patients who required IFX escalation were less likely to be in clinical remission at 12 months (OR 0.2, 95% CI 0.1-0.6, P = 0.01) when compared with those who did not. During the follow-up period, 27% of patients required a colectomy, and the mean time to colectomy was 17 months. Patients in the escalation group required a colectomy in 33% of cases, compared with 21% of non escalation patients. CONCLUSIONS: A significant proportion of ambulatory patients with UC treated with maintenance infliximab required therapy escalation over time. This was associated with lower remission, and higher colectomy, rates. PMID- 22239071 TI - Advanced exergoenvironmental analysis of a near-zero emission power plant with chemical looping combustion. AB - Carbon capture and storage (CCS) from power plants can be used to mitigate CO(2) emissions from the combustion of fossil fuels. However, CCS technologies are energy intensive, decreasing the operating efficiency of a plant and increasing its costs. Recently developed advanced exergy-based analyses can uncover the potential for improvement of complex energy conversion systems, as well as qualify and quantify plant component interactions. In this paper, an advanced exergoenvironmental analysis is used for the first time as means to evaluate an oxy-fuel power plant with CO(2) capture. The environmental impacts of each component are split into avoidable/unavoidable and endogenous/exogenous parts. In an effort to minimize the environmental impact of the plant operation, we focus on the avoidable part of the impact (which is also split into endogenous and exogenous parts) and we seek ways to decrease it. The results of the advanced exergoenvironmental analysis show that the majority of the environmental impact related to the exergy destruction of individual components is unavoidable and endogenous. Thus, the improvement potential is rather limited, and the interactions of the components are of lower importance. The environmental impact of construction of the components is found to be significantly lower than that associated with their operation; therefore, our suggestions for improvement focus on measures concerning the reduction of exergy destruction and pollutant formation. PMID- 22239073 TI - Theoretical studies of the excited doublet states of SF and SCl and singlet states of SF2, SFCl, and SCl2. AB - In previous work, we reported that the lowest-lying excited states of SF, SCl, SF(2), SFCl, and SCl(2) have recoupled pair bonds. In this study, we examine the analogous low-spin states--the (2)Sigma(-) and (2)Delta states of SF and SCl and the excited singlet states of SF(2), SCl(2), and SFCl--which also possess recoupled pair bonds. In contrast to the excited states treated previously, the states studied in the present work have the same spin multiplicities as their respective ground states and are thus potentially observable via electronic excitation. Of particular interest are the minima on the (1)A" potential energy surface of SFCl corresponding to bond-stretch isomers analogous to those found on the (3)A" surface. In addition, we discovered that the first two excited states ((1)A") accessible via vertical excitations from the ground state of SFCl have the electronic structure of the bond-stretch isomers. Thus, electronic excitation spectroscopic studies of SFCl could reveal a signature of the bond-stretch isomers. We will also present limited data on the lowest singlet Rydberg states of the triatomic species. Calculations were performed at the MRCI+Q/aug-cc pV(Q+d,5+d)Z levels of theory. PMID- 22239072 TI - Multinode acoustic focusing for parallel flow cytometry. AB - Flow cytometry can simultaneously measure and analyze multiple properties of single cells or particles with high sensitivity and precision. Yet, conventional flow cytometers have fundamental limitations with regards to analyzing particles larger than about 70 MUm, analyzing at flow rates greater than a few hundred microliters per minute, and providing analysis rates greater than 50,000 per second. To overcome these limits, we have developed multinode acoustic focusing flow cells that can position particles (as small as a red blood cell and as large as 107 MUm in diameter) into as many as 37 parallel flow streams. We demonstrate the potential of such flow cells for the development of high throughput, parallel flow cytometers by precision focusing of flow cytometry alignment microspheres, red blood cells, and the analysis of a CD4+ cellular immunophenotyping assay. This approach will have significant impact toward the creation of high throughput flow cytometers for rare cell detection applications (e.g., circulating tumor cells), applications requiring large particle analysis, and high volume flow cytometry. PMID- 22239074 TI - Tinea capitis favosa in a 73-year-old immunocompetent Tunisian woman. PMID- 22239075 TI - Special issue: SBiRM: invited papers from MPI Research summit/symposium: Current trends in developmental and reproductive toxicology --August 21-23, 2011. Preface. PMID- 22239076 TI - Economic benefits of using adaptive predictive models of reproductive toxicity in the context of a tiered testing program. AB - A predictive model of reproductive toxicity, as observed in rat multigeneration reproductive (MGR) studies, was previously developed using high throughput screening (HTS) data from 36 in vitro assays mapped to 8 genes or gene-sets from Phase I of USEPA ToxCast research program, the proof-of-concept phase in which 309 toxicologically well characterized chemicals were testing in over 500 HTS assays. The model predicted the effects on male and female reproductive function with a balanced accuracy of 80%. In a theoretical examination of the potential impact of the model, two case studies were derived representing different tiered testing scenarios to: 1) screen-out chemicals with low predicted probability of effect; and 2) screen-in chemicals with a high probability of causing adverse reproductive effects. We define 'testing cost efficiency' as the total cost divided by the number of positive chemicals expected in the definitive guideline toxicity study. This would approach $2.11 M under the current practice. Under case study 1, 22% of the chemicals were screened-out due to low predicted probability of adverse reproductive effect and a misclassification rate of 12%, yielding a test cost efficiency of $1.87 M. Under case study 2, 13% of chemicals were screened-in yielding a testing cost efficiency of $1.13 M per test-positive chemical. Applying the model would also double the total number of positives identified. It should be noted that the intention of the case studies is not to provide a definitive mechanism for screening-in or screening-out chemicals or account for the indirect costs of misclassification. The case studies demonstrate the customizability of the model as a tool in chemical testing decision-making. The predictive model of reproductive toxicity will continue to evolve as new assays become available to fill recognized biological gaps and will be combined with other predictive models, particularly models of developmental toxicity, to form an initial tier to an overarching integrated testing strategy. PMID- 22239078 TI - A critical evaluation of developmental and reproductive toxicology in nonhuman primates. AB - The nonhuman primates (NHPs) are used in many areas of biomedical research where their similarities to humans make them exclusively valuable animal models. The use of NHPs in pre-clinical testing is expected to increase due to the increase in the development of biological compounds for therapeutic uses. The regulatory agencies around the world including Food and Drug Administration (FDA) generally requires developmental and reproductive toxicity (DART) testing of all new drugs to be used by women of childbearing age or men of reproductive potential. NHPs are most frequently used for DART testing when commonly used rodents and/or rabbits are not pharmacologically relevant species. Animal studies are unique in that assessment of reproduction and development as DART studies are not performed in controlled clinical trials; therefore, pre-clinical safety assessment forms the basis for risk assessment for marketed drug products. This paper provides a critical evaluation of developmental and reproductive toxicity studies in NHPs. The manuscript will focus on species selection, limitation of International Conference for Harmonization stages (A-F) using NHPs as a test system, study designs, logistical/technical challenges, and strength, and limitations. It will also pinpoint confounding factors inherent to the test system that may complicate the interpretation of the NHP DART data. PMID- 22239077 TI - Alternative models in developmental toxicology. AB - In light of various pressures, toxicologists have been searching for alternative methods for safety testing of chemicals. According to a recent policy in the European Union (Regulation, Evaluation Authorisation and Restriction of Chemicals, REACH), it has been estimated that over the next twelve to fifteen years, approximately 30,000 chemicals may need to be tested for safety, and under current guidelines such testing would require the use of approximately 7.2 million laboratory animals [ Hofer et al. 2004 ]. It has also been estimated that over 80% of all animals used for safety testing under REACH legislation would be used for examining reproductive and developmental toxicity [Hofer et al., 2004]. In addition to REACH initiatives, it has been estimated that out of 5,000 to 10,000 new drug entities that a pharmaceutical company may start with, only one is finally approved by the Food and Drug Administration at a cost of over one billion dollars [ Garg et al. 2011 ]. A large portion of this cost is due to animal testing. Therefore, both the pharmaceutical and chemical industries are interested in using alternative models and in vitro tests for safety testing. This review will examine the current state of three alternative models - whole embryo culture (WEC), the mouse embryonic stem cell test (mEST), and zebrafish. Each of these alternatives will be reviewed, and advantages and disadvantages of each model will be discussed. These models were chosen because they are the models most commonly used and would appear to have the greatest potential for future applications in developmental toxicity screening and testing. PMID- 22239080 TI - Spermatozoa as biomarkers for the assessment of human male infertility and genotoxicity. AB - Establishing specific biomarkers for the assessment of human male fertility status is an important goal to ensure the fitness of the male contribution so as to support the birth of a healthy child. Spermatozoa are considered an optimal surrogate tissue for the evaluation of spermatogenic function. Unlike the cells of the testis, spermatozoa do not require invasive procedures to procure a sample. A broad range of sperm biomarkers and tests have been described as useful for the assessment of the sperm function. However, these approaches appear limited considering the current state of the art of molecular diagnostics that could be developed for this purpose. In this review, we outline the suite of sperm biomarkers that are currently in use to assess human male fertility status. Their use as indicators of genotoxic exposure will be discussed. PMID- 22239079 TI - Toxic stress prioritizes and imbalances stem cell differentiation: implications for new biomarkers and in vitro toxicology tests. AB - This hypothesis and review introduces rules of stem cell stress responses that provide biomarkers and alternative testing that replaces or reduces gestational tests using whole animals. These rules for the stress responses of cultured stem cells validate the organismal strategy of the stress response and show that it emulates what must happen if the conceptus implants during a response to stress in vivo. Specifically there is a profound threshold during a stress dose response where stem cell accumulation is significantly reduced. Below this threshold stress enzymes manage the stress response by converting anabolic to catabolic processes and by suppressing apoptosis, without affecting differentiation. However above this threshold the stem cell survival response converts to an organismal survival response where stress enzymes switch to new substrates and mediate loss of potency factors, gain of early essential differentiated lineages, and suppression of later essential lineages. Stressed stem cells 'compensate' for lower accumulation rates by differentiating a higher fraction of cells, and the organismal survival response further enhances adaptation by prioritizing the differentiation of early essential lineages. Thus compensatory and prioritized differentiation and the sets of markers produced are part of a response of cultured embryos and stem cells that emulate what must happen during implantation of a stressed gestation. Knowledge of these markers and use of stressed stem cell assays in culture should replace or reduce the number of animals needed for developmental toxicity and should produce biomarkers for stressed development in vitro and in vivo. PMID- 22239081 TI - Testicular histopathology in juvenile rat toxicity studies. AB - Histopathologic interpretation of juvenile toxicity studies is necessarily complicated by the dynamic developmental processes underway within the test subjects. In addition to potentially marked differences in compound metabolism, juvenile animals have vulnerable temporally defined proliferating cell populations compared to their adult counterparts. Pathologists require an understanding of developmental processes and conditions underway during exposure to the compound(s) in a juvenile toxicity study in order to interpret the terminal histopathology accurately. Postnatal testicular development in rats affords an example of how developmental considerations are essential to understanding toxic effects. This review provides an overview of testicular histology and pre- and postnatal testicular development, examples of juvenile rat testicular toxicity from the literature, and considerations for designing juvenile studies for safety assessment of pharmaceutical compounds. PMID- 22239083 TI - REACH and reproductive and developmental toxicology: still questions. AB - Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) is a new chemicals regulation law in the European Union (EU). The law is supplemented by tens of thousands of pages of guidance documents, and the implementation of REACH is still a work in progress. Requirements for chemical testing are based on the annual volume of a chemical or 'substance' that is produced or imported into the EU. These requirements include reproductive and developmental toxicity testing in experimental animals for an annual volume of 10 metric tonnes or more. However, under REACH, the testing in vertebrate animals may not be performed without permission, and the law encourages the use of alternative methods of filling data gaps on the toxicological properties of chemicals. These alternatives might include in vitro and structure-activity relationship studies, but the REACH technical guidance indicates that these kinds of studies are not adequate to replace reproductive and developmental toxicity testing in whole animals. The most practical opportunity for the avoidance of whole animal testing may be 'read-across,' a process in which gaps are filled using data from related compounds. A method called 'weight of evidence' under REACH may also be used to avoid whole animal reproductive and developmental toxicity testing based on existing data in regulation and non-regulation studies and based on factors such as chemical structure and anticipated exposure. It is also possible that thresholds of toxicological concerns will be accepted under REACH as a method to avoid vertebrate animal testing. PMID- 22239082 TI - 4-vinylcyclohexene diepoxide: a model chemical for ovotoxicity. AB - The occupational chemical 4-vinylcyclohexene diepoxide (VCD) has been shown to cause selective destruction of ovarian small pre-antral (primordial and primary) follicles in rats and mice by accelerating the natural, apoptotic process of atresia. Chemicals that destroy primordial follicles are of concern to women because exposure can result in premature ovarian failure (early menopause). Initial studies using in vivo exposure of rats determined that VCD specifically targets primordial and primary (small pre-antral) follicles and that repeated dosing is required. Through a method of isolation of ovarian small follicles, biochemical and molecular studies determined that intracellular pro-apoptotic pathways are activated following VCD dosing in rats. Subsequently an in vitro system using cultured whole neonatal rat ovaries was developed to provide more mechanistic information. That approach was used to demonstrate that the cell survival c-kit/kit ligand signaling pathway is the direct target for VCD-induced ovotoxicity. Specifically, VCD directly interacts with the oocyte-associated c kit receptor to inhibit its autophosphorylation, and thereby impair oocyte viability. The cellular and molecular approach developed to determine these findings is described in this article. PMID- 22239088 TI - Effects of carbon dioxide (CO2) laser perforation as skin pretreatment to improve sugar infusion process of frozen blueberries. AB - Sugar infusion is a widely used osmotic treatment for fruit preservation, but the process is inherently slow and the waxy skins of some fruits hinder mass transfer during the process. This work examined the utility of perforation by a carbon dioxide (CO(2)) laser as a novel skin treatment to improve the infusion process. In 2 experiments, individually quick frozen (IQF) blueberries were subjected to varying degrees of laser perforation (3 levels of perforation density * 3 levels of perforation depth), and then infused stepwise with high fructose corn syrup (HFCS) to a final degrees Brix of 70 using varying solution concentration increment (5, 10, 20, and 30 degrees Brix/d). At each concentration, increasing perforation density and depth promoted solute migration into the fruit with increased fruit weight (P < 0.05; up to 24.15%, 37.23%, 52.89%, 65.34% wt. increase at 5, 10, 20, and 30 degrees Brix/d compared to the controls). Laser treated blueberries maintained the original shape without excessive shrinkage and texture hardening due to enhanced solute incorporation, while the controls and mechanically treated samples were ruptured and wrinkled at the end of the process. Increasing solution concentrations shortened the process duration but decreased final fruit weight due to greater osmotic gradients. However, negative effects of using higher solution concentrations on final fruit weight were significantly alleviated with moderate-to-high doses of laser perforation (P < 0.001). Overall, the results demonstrate that laser perforation can be a viable skin pretreatment technique, offering marked improvement on final process yield, process efficiency, and product quality. PRACTICAL APPLICATION: CO(2) laser perforation as a novel skin pretreatment for sugar infusion of individually quick frozen (IQF) blueberries is presented. The technique markedly improves the product yield and quality. Although further investigation is needed, the method may potentially be used for other waxy skin fruits such as cranberries and cherries. PMID- 22239089 TI - Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression. AB - Ngb (neuroglobin) has been identified as a novel endogenous neuroprotectant. However, little is known about the regulatory mechanisms of Ngb expression, especially under conditions of hypoxia. In the present study, we located the core proximal promoter of the mouse Ngb gene to a 554 bp segment, which harbours putative conserved NF-kappaB (nuclear factor kappaB)- and Egr1 (early growth response factor 1) -binding sites. Overexpression and knockdown of transcription factors p65, p50, Egr1 or Sp1 (specificity protein 1) increased and decreased Ngb expression respectively. Experimental assessments with transfections of mutational Ngb gene promoter constructs, as well as EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) assays, demonstrated that NF-kappaB family members (p65, p50 and cRel), Egr1 and Sp1 bound in vitro and in vivo to the proximal promoter region of the Ngb gene. Moreover, a kappaB3 site was found as a pivotal cis-element responsible for hypoxia-induced Ngb promoter activity. NF-kappaB (p65) and Sp1 were also responsible for hypoxia-induced up-regulation of Ngb expression. Although there are no conserved HREs (hypoxia-response elements) in the promoter of the mouse Ngb gene, the results of the present study suggest that HIF-1alpha (hypoxia inducible factor-1alpha) is also involved in hypoxia-induced Ngb up-regulation. In conclusion, we have identified that NF-kappaB, Egr1 and Sp1 played important roles in the regulation of basal Ngb expression via specific interactions with the mouse Ngb promoter. NF-kappaB, Sp1 and HIF-1alpha contributed to the up regulation of mouse Ngb gene expression under hypoxic conditions. PMID- 22239090 TI - Structural and energetic effects in the molecular recognition of protonated peptidomimetic bases by 18-crown-6. AB - Absolute 18-crown-6 (18C6) affinities of nine protonated peptidomimetic bases are determined using guided ion beam tandem mass spectrometry techniques. The bases (B) included in this work are mimics for the n-terminal amino group and the side chains of the basic amino acids, i.e., the favorable sites for binding of 18C6 to peptides and proteins. Isopropylamine is chosen as a mimic for the n-terminal amino group, imidazole and 4-methylimidazole are chosen as mimics for the side chain of histidine (His), 1-methylguanidine is chosen as a mimic for the side chain of arginine (Arg), and several primary amines including methylamine, ethylamine, n-propylamine, n-butylamine, and 1,5-diamino pentane as mimics for the side chain of lysine (Lys). Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the peptidomimetic bases, as well as the proton bound complexes comprised of these species, (B)H(+)(18C6). The measured 18C6 binding affinities of the Lys side chain mimics are larger than the measured binding affinities of the mimics for Arg and His. These results suggest that the Lys side chains should be the preferred binding sites for 18C6 complexation to peptides and proteins. Present results also suggest that competition between Arg or His and Lys for 18C6 is not significant. The mimic for the n-terminal amino group exhibits a measured binding affinity for 18C6 that is similar to or greater than that of the Lys side chain mimics. However, theory suggests that binding to n terminal amino group mimic is weaker than that to all of the Lys mimics. These results suggest that the n-terminal amino group may compete with the Lys side chains for 18C6 complexation. PMID- 22239092 TI - Hermann Oppenheim's observations about music in aphasia. AB - Hermann Oppenheim was influential in many areas of neurology, but his ideas about music are relatively unknown. In 1888, he published a paper that outlined how the assessment of music skills in patients with aphasia could lead to a better understanding of aphasia and language. Oppenheim conducted the first comprehensive music assessment as part of a neurologic examination and presented the first case series of music in aphasia. His paper was widely cited and had significant influence over the next 30 years. Although largely unrecognized as such, Oppenheim was an important historical figure in the study of music and neurology. PMID- 22239091 TI - Caveolae optimize tissue factor-Factor VIIa inhibitory activity of cell-surface associated tissue factor pathway inhibitor. AB - TFPI (tissue factor pathway inhibitor) is an anticoagulant protein that prevents intravascular coagulation through inhibition of fXa (Factor Xa) and the TF (tissue factor)-fVIIa (Factor VIIa) complex. Localization of TFPI within caveolae enhances its anticoagulant activity. To define further how caveolae contribute to TFPI anticoagulant activity, CHO (Chinese-hamster ovary) cells were co transfected with TF and membrane-associated TFPI targeted to either caveolae [TFPI-GPI (TFPI-glycosylphosphatidylinositol anchor chimaera)] or to bulk plasma membrane [TFPI-TM (TFPI-transmembrane anchor chimaera)]. Stable clones had equal expression of surface TF and TFPI. TX-114 cellular lysis confirmed localization of TFPI-GPI to detergent-insoluble membrane fractions, whereas TFPI-TM localized to the aqueous phase. TFPI-GPI and TFPI-TM were equally effective direct inhibitors of fXa in amidolytic assays. However, TFPI-GPI was a significantly better inhibitor of TF-fVIIa than TFPI-TM, as measured in both amidolytic and plasma-clotting assays. Disrupting caveolae by removing membrane cholesterol from EA.hy926 cells, which make TFPIalpha, CHO cells transfected with TFPIbeta and HUVECs (human umbilical vein endothelial cells) did not affect their fXa inhibition, but significantly decreased their inhibition of TF-fVIIa. These studies confirm and quantify the enhanced anticoagulant activity of TFPI localized within caveolae, demonstrate that caveolae enhance the inhibitory activity of both TFPI isoforms and define the effect of caveolae as specifically enhancing the anti-TF activity of TFPI. PMID- 22239093 TI - Gasperini's syndrome: its neuroanatomical basis now and then. AB - Crossed brainstem syndromes consist of ipsilateral impairment of cranial nerves III-XII and contralateral impairment of the pyramidal and sensory tracts. Gasperini's syndrome, described in 1912 by the Italian internist Ubaldo Gasperini, is one of them. It results from a lesion of the caudal pontine tegmentum and is most frequently defined as ipsilateral impairment of cranial nerves V, VI, VII, and VIII and contralateral sensory loss. Since no autopsy was performed to confirm Gasperini's clinical observations, we analyzed all elements of his syndrome from a current perspective as well as in the light of the anatomical knowledge available to him. This resulted in a historical survey of the development of neuroanatomy over the last 300 years. PMID- 22239094 TI - A curiosity in the history of sciences: the words "megrim" and "migraine". AB - Vertigo has been described by medical doctors since Antiquity, but the condition is not limited to human medicine. It is also interesting to note that vertigo related disorders were long only mentioned in the descriptions of migraine: however, in the Corpus Hippocraticum, a pain with vertigo (odune kai skotodinie) was not considered as hemicrania; in Aretaeus medical text, scotoma was clearly another disease than heterocranie; although there could be metastases between them (pain could be followed by vertigo, as Boerhaave translated from Greek to Latin); Caelius Aurelianus, Ibn Zuhr of Seville, Isma'il Jurjani considered vertigo as a separate entity from "migraine" as well. One had to wait until 1831 for "ophthalmic migraine" (Piorry) to take systematically this disorder into account (to more or less causally relate it to migraine), and 1988 for the International Headache Society to acknowledge vertigo as a symptom of aura in "basilar migraine," which was given the better name of basilar-type migraine in 2004. From this point of view, veterinary medicine presents a particular interest because, for centuries, diseases mainly affecting horses - called in French "migraine," "mal de tete" (headache), "douleur de tete" (head pain), or in English "megrim(s)," "head-ach," "pain," and for which it is not self-evident that they are in any way related with the conditions that bear these names in humans - have been connected with vestibular impairments. Whatever is the relationship between the human and animal pathologies and, although it is impossible to interpret animal signs (abnormal behavior) with human symptoms (complaints), some impressive descriptions, written by Anglo-Saxon authors for the most part, seem to have played a significant role in the history of migraine. The purpose is to examine how a word in its English veterinary medical sense could have influenced French medical descriptions. PMID- 22239095 TI - Neurognostics question. PMID- 22239097 TI - NeurHistAlert 15. PMID- 22239098 TI - "Matthew effect" in neurosciences. PMID- 22239099 TI - Neurognostics answer. PMID- 22239100 TI - Effect of sweet wormwood Artemisia annua crude leaf extracts on some biological and physiological characteristics of the lesser mulberry pyralid, Glyphodes pyloalis. AB - The lesser mulberry pyralid, Glyphodes pyloalis Walker (Lepidoptera: Pyralidae) is a monophagous and dangerous pest of mulberry that has been recently observed in Guilan province, northern Iran. In this study, the crude methanol extract of sweet wormwood Artemisia annua L. (Asterales: Asteracaea) was investigated on toxicity, biological and physiological characteristics of this pest under controlled conditions (24 +/- 1 degrees C, 75 +/- 5% RH, and 16:8 L:D photoperiod). The effect of acute toxicity and sublethal doses on physiological characteristics was performed by topical application. The LC50 and LC20 values on fourth instar larvae were calculated as 0.33 and 0.22 gram leaf equivalent/ mL, respectively. The larval duration of fifth instar larvae in LC50 treatment was prolonged (5.8 +/- 0.52 days) compared with the control group (4.26 +/- 0.29 days). However larval duration was reduced in the LC20 treatment. The female adult longevity in the LC50 dose was the least (4.53 +/- 0.3 days), while longevity among controls was the highest (9.2 +/- 0.29 days). The mean fecundity of adults after larval treatment with LC50 was recorded as 105.6 +/- 16.84 eggs/female, while the control was 392.74 +/- 22.52 eggs/female. The percent hatchability was reduced in all treatments compared with the control. The effect of extract in 0.107, 0.053, 0.026 and 0.013 gle/mL on biochemical characteristics of this pest was also studied. The activity of alpha-amylase and protease 48 hours post-treatment was significantly reduced compared with the control. Similarly lipase, esterase, and glutathione S-transferase activity were significantly affected by A. annua extract. PMID- 22239101 TI - Change in fibrosis score as a predictor of mortality among HIV-infected patients with viral hepatitis. AB - Noninvasive markers of liver fibrosis, measured at baseline, have been shown to predict liver-related mortality. It remains unknown if a change in the value of the scores over time predicts mortality in patients with HIV and viral hepatitis. In this retrospective study, survival in HIV/hepatitis B virus (HBV; n = 67), HIV/hepatitis C virus (HCV; n = 43), and HIV/HBV/HCV (n = 41) patients was examined using Kaplan-Meier life table analysis. Aspartate aminotransferase (AST) to-platelet ratio index (APRI) and FIB-4 scores, two noninvasive markers of liver fibrosis, were calculated at baseline and at last available clinical follow-up to determine the change in fibrosis score. Factors associated with mortality were assessed by Cox proportional hazards, including the change in the noninvasive marker score between the two time points. All-cause mortality was determined by Social Security Death Index and chart review. Sixty-seven were coinfected with HIV/HBV, 43 with HIV/HCV, and 41 were triply infected (HIV/HBV/HCV). Kaplan-Meier analysis showed similar survival for the three groups at 7 years of follow-up (p = 0.10). However, median length of follow-up was lower in HIV/HCV (60.5; range 0 102) compared to HIV/HBV (75.7; 12.3-126.5) and HIV/HBV/HCV (80.0; 2.7-123) months, respectively, p = 0.02. Baseline fibrosis score (p = 0.002), an increase in the value for noninvasive measurements for fibrosis (p < 0.001), and the presence of HIV/HCV coinfection (p = 0.041) were each associated with higher risk for mortality. Baseline fibrosis score (p = 0.03) and an increase in FIB-4 score (p = 0.05) were independent predictors of all-cause mortality, but liver-related mortality was not evaluated. In this study, baseline fibrosis score was predictive of 7-year all-cause mortality. Further studies are needed in a prospective cohort to evaluate the predictive value of monitoring changes in fibrosis scores over time to predict mortality in patients with viral hepatitis. PMID- 22239102 TI - Mutations defective in ribonucleotide reductase activity interfere with pollen plastid DNA degradation mediated by DPD1 exonuclease. AB - Organellar DNAs in mitochondria and plastids are present in multiple copies and make up a substantial proportion of total cellular DNA despite their limited genetic capacity. We recently demonstrated that organellar DNA degradation occurs during pollen maturation, mediated by the Mg(2+) -dependent organelle exonuclease DPD1. To further understand organellar DNA degradation, we characterized a distinct mutant (dpd2). In contrast to the dpd1 mutant, which retains both plastid and mitochondrial DNAs, dpd2 showed specific accumulation of plastid DNAs. Multiple abnormalities in vegetative and reproductive tissues of dpd2 were also detected. DPD2 encodes the large subunit of ribonucleotide reductase, an enzyme that functions at the rate-limiting step of de novo nucleotide biosynthesis. We demonstrated that the defects in ribonucleotide reductase indirectly compromise the activity of DPD1 nuclease in plastids, thus supporting a different regulation of organellar DNA degradation in pollen. Several lines of evidence provided here reinforce our previous conclusion that the DPD1 exonuclease plays a central role in organellar DNA degradation, functioning in DNA salvage rather than maternal inheritance during pollen development. PMID- 22239103 TI - DNA-PKcs interacts with Aire and regulates the expression of toll-like receptors in RAW264.7 cells. AB - The autoimmune regulator (Aire) is a key mediator of the central tolerance for peripheral tissue self-antigen (PTAs) and is involved in the transcriptional control of many antigens in thymic medullary epithelial cells (mTECs). However, the function of Aire in peripheral lymphoid tissues and haematopoietic cells, particularly in monocytes and macrophages, remains poorly understood. We previously found that the expression of Toll-like receptor (TLR) 1, TLR3 and TLR8 was notably upregulated in pEGFPC1/Aire stably transfected RAW264.7 (GFP Aire/RAW) cells, while the expressions of other TLRs were not significantly changed. The mechanism by which Aire affects TLR1, TLR3 and TLR8 expression is not clear. Interactions with other proteins, such as DNA-dependent protein kinase (DNA-PK), are crucial for regulating the transcriptional activity of Aire. In this study, we found that Aire and DNA-PK catalytic subunit (DNA-PKcs) were co located in the nucleus of GFP-Aire/RAW cells, and they interact with each other. Small interfering RNA knock-down of DNA-PKcs in these cells decreased the expression of TLR1, TLR3 and TLR8, but no change was observed in pEGFPC1 stably transfected RAW264.7 (GFP/RAW) cells. We did not observe any change in the expressions of other TLRs after DNA-PKcs knock-down in GFP-Aire/RAW or GFP/RAW cells. A similar observation has been made in pEGFPC1/Aire or pEGFPC1 transiently transfected primary peritoneal macrophages. Using a luciferase activity assay, we found the that the transcriptional activity of TLR1, TLR3 and TLR8 promoters was also decreased after knock-down of DNA-PKcs in GFP-Aire/RAW cells. In conclusion, our results suggest that DNA-PKcs may interact with Aire to promote the expression of TLRs in RAW264.7 cells. PMID- 22239104 TI - Nanoparticle filtration performance of NIOSH-certified particulate air-purifying filtering facepiece respirators: evaluation by light scattering photometric and particle number-based test methods. AB - National Institute for Occupational Safety and Health (NIOSH) certification test methods employ charge neutralized NaCl or dioctyl phthalate (DOP) aerosols to measure filter penetration levels of air-purifying particulate respirators photometrically using a TSI 8130 automated filter tester at 85 L/min. A previous study in our laboratory found that widely different filter penetration levels were measured for nanoparticles depending on whether a particle number (count) based detector or a photometric detector was used. The purpose of this study was to better understand the influence of key test parameters, including filter media type, challenge aerosol size range, and detector system. Initial penetration levels for 17 models of NIOSH-approved N-, R-, and P-series filtering facepiece respirators were measured using the TSI 8130 photometric method and compared with the particle number-based penetration (obtained using two ultrafine condensation particle counters) for the same challenge aerosols generated by the TSI 8130. In general, the penetration obtained by the photometric method was less than the penetration obtained with the number-based method. Filter penetration was also measured for ambient room aerosols. Penetration measured by the TSI 8130 photometric method was lower than the number-based ambient aerosol penetration values. Number-based monodisperse NaCl aerosol penetration measurements showed that the most penetrating particle size was in the 50 nm range for all respirator models tested, with the exception of one model at ~200 nm size. Respirator models containing electrostatic filter media also showed lower penetration values with the TSI 8130 photometric method than the number-based penetration obtained for the most penetrating monodisperse particles. Results suggest that to provide a more challenging respirator filter test method than what is currently used for respirators containing electrostatic media, the test method should utilize a sufficient number of particles <100 nm and a count (particle number)-based detector. PMID- 22239105 TI - Renal function, efficacy and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study. AB - This multicenter, open-label, phase III study assessed renal function, safety, and efficacy in stable adult liver transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients received tacrolimus BID for 6weeks before conversion to tacrolimus QD (1:1 [mg:mg] total daily dose basis) for 12weeks. Primary endpoint: change in steady state creatinine clearance (CrCl) between treatment phases. Of 112 patients enrolled, 98 were converted to QD dosing (full analysis set [FAS]). Mean (SD) tacrolimus dose was 3.7 (1.7) mg/day during BID and at conversion, and 3.9 (1.8) mg/day at Week 12. 74.5% of patients required no dose adjustment on conversion (FAS). Mean tacrolimus whole blood trough levels were at the lower end of the recommended range during tacrolimus BID and QD; the difference between mean steady-state trough levels was statistically significant (7.5ng/ml vs. 6.5ng/ml; P<0.0001). Following conversion, mean tacrolimus trough levels were reduced by 15% (about 1ng/ml) without any cases of acute rejection, remained stable during the remainder of the study, and were more consistent, showing reduced between- and within-patient variability in trough levels. Renal function remained stable, demonstrating noninferiority of tacrolimus QD versus BID (relative difference in mean calculated CrCl -0.1% [+/-6.3%]). Patient and graft survival were 100%. Adverse events incidence was low during both treatment phases. PMID- 22239106 TI - Protective role of D-saccharic acid-1,4-lactone in alloxan induced oxidative stress in the spleen tissue of diabetic rats is mediated by suppressing mitochondria dependent apoptotic pathway. AB - The present study investigated the role of D-saccharic acid 1,4-lactone (DSL) in the spleen tissue of alloxan (ALX) induced diabetic rats. Diabetes was induced in rats by injecting ALX (at a dose of 120 mg/kg body weight) intraperitoneally in sterile normal saline. Elevated levels of blood glucose, glycosylated Hb and TNFalpha decreased levels of plasma insulin and disturbed intra-cellular antioxidant machineries were detected in ALX exposed animals. Oral administration of DSL at a dose of 80 mg/kg body weight, however, restored these alterations in diabetic rats. Studies on the mechanism of ALX-induced diabetes showed that hyperglycemia caused disruption of mitochondrial membrane potential in the spleen, released cytochrome C in the cytosol, activated caspase 3 and ultimately led to apoptotic cell death. Results suggest that DSL possesses the ability of protecting the spleen tissue from ALX-induced hyperglycemia and thus could act as an anti-diabetic agent in lessening diabetes associated spleen dysfunction. PMID- 22239107 TI - Ecological implications of behavioural syndromes. AB - Interspecific trait variation has long served as a conceptual foundation for our understanding of ecological patterns and dynamics. In particular, ecologists recognise the important role that animal behaviour plays in shaping ecological processes. An emerging area of interest in animal behaviour, the study of behavioural syndromes (animal personalities) considers how limited behavioural plasticity, as well as behavioural correlations affects an individual's fitness in diverse ecological contexts. In this article we explore how insights from the concept and study of behavioural syndromes provide fresh understanding of major issues in population ecology. We identify several general mechanisms for how population ecology phenomena can be influenced by a species or population's average behavioural type, by within-species variation in behavioural type, or by behavioural correlations across time or across ecological contexts. We note, in particular, the importance of behavioural type-dependent dispersal in spatial ecology. We then review recent literature and provide new syntheses for how these general mechanisms produce novel insights on five major issues in population ecology: (1) limits to species' distribution and abundance; (2) species interactions; (3) population dynamics; (4) relative responses to human-induced rapid environmental change; and (5) ecological invasions. PMID- 22239109 TI - Human neural stem cells in chronic spinal cord injury. AB - Translational research is inherently challenged to bridge the gap between preclinical research discoveries and clinical applications and discovering how to embed new knowledge into meaningful treatment concepts and eventually apply this in patients. The same is unquestionably true in spinal cord injury where specific challenges in the translation from bench to bed need to be considered. PMID- 22239108 TI - Minimal essential length of Clostridium botulinum C3 peptides to enhance neuronal regenerative growth and connectivity in a non-enzymatic mode. AB - C3 ADP-ribosyltransferase is a valuable tool to study Rho-dependent cellular processes. In the current study we investigated the impact of enzyme-deficient peptides derived from Clostridium botulinum C3 transferase in the context of neuronal process elongation and branching, synaptic connectivity, and putative beneficial effects on functional outcome following traumatic injury to the CNS. By screening a range of peptidic fragments, we identified three short peptides from C3bot that promoted axon and dendrite outgrowth in cultivated hippocampal neurons. Furthermore, one of these fragments, a 26-amino acid peptide covering the residues 156-181 enhanced synaptic connectivity in primary hippocampal culture. This peptide was also effective to foster axon outgrowth and re innervation in organotypical brain slice culture. To evaluate the potential of the 26mer to foster repair mechanisms after CNS injury we applied this peptide to mice subjected to spinal cord injury by either compression impact or hemisection. A single local administration at the site of the lesion improved locomotor recovery. In addition, histological analysis revealed an increased serotonergic input to lumbar motoneurons in treated compared with control mice. Pull-down assays showed that lesion-induced up-regulation of RhoA activity within the spinal cord was largely blocked by C3bot peptides despite the lack of enzymatic activity. PMID- 22239110 TI - Treating the obese dialysis patient: challenges and paradoxes. AB - Obesity is a major epidemic in the general population and has added unique challenges to renal replacement therapy as choice of access, dialysis adequacy, and preparation for kidney transplantation may all be affected. There are few clinical studies on managing obese patients with end-stage renal disease (ESRD) and no accepted strategies for the variety of problems encountered in this population. Attempts at weight loss are generally advisable to prevent obesity related surgical complications and improve patient and graft survival after kidney transplantation. This article reviews the unique aspects of managing obese patients with ESRD. PMID- 22239111 TI - On the lifetime of evaporating sessile droplets. AB - The evaporation of sessile droplets with a constant base radius (pinning mode) and a constant contact angle (depinning mode) has been experimentally observed. Here we analyzed the effect of substrate hydrophobicity on the lifetimes of evaporating droplets for the two modes. Theoretical predictions were obtained and compared with available experimental results. The theoretical analysis and experimental results show that linear methods of extrapolating limited experimental data for a transient droplet contact angle and base radius overpredict the droplet lifetime. Likewise, the linear extrapolation of limited experimental data for transient droplet volume underpredicts the droplet lifetime. Correct methods of extrapolating limited experimental data for transient droplet parameters are described, discussed, and validated. The new methods removed inconsistencies in the previous theory and experimental analysis. Master equations and master curves for the droplet lifetime for the two evaporation modes are obtained and experimentally confirmed. PMID- 22239112 TI - Psammomatous colloid carcinoma of the breast with micropapillary pattern. PMID- 22239113 TI - Mechanistic insights into the BINOL-derived phosphoric acid-catalyzed asymmetric allylboration of aldehydes. AB - BINOL-derived phosphoric acids catalyze the asymmetric allylboration of aldehydes. DFT and QM/MM hybrid calculations showed that the reaction proceeds via a transition state involving both a hydrogen-bonding interaction from the catalyst hydroxyl group to the pseudoaxial oxygen of the cyclic boronate and a stabilizing interaction from the phosphoryl oxygen of the catalyst to the formyl hydrogen of the aldehyde. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This mechanistic pathway is consistent with the experimentally observed enantioselectivity except in one case. We have used our model's predictions to guide our own experimental work. The conflict is resolved in favor of our calculations. PMID- 22239114 TI - Hierarchically structured free-standing hydrogels with liquid crystalline domains and magnetic nanoparticles as dual physical cross-linkers. AB - Here we report a modular strategy for preparing physically cross-linked and mechanically robust free-standing hydrogels comprising unique thermotropic liquid crystalline (LC) domains and magnetic nanoparticles both of which serve as the physical cross-linkers resulting in hydrogels that can be used as magnetically responsive soft actuators. A series of amphiphilic LC pentablock copolymers of poly(acrylic acid) (PAA), poly(5-cholesteryloxypentyl methacrylate) (PC5MA), and poly(ethylene oxide) (PEO) blocks in the sequence of PAA-PC5MA-PEO-PC5MA-PAA were prepared using reversible addition-fragmentation chain transfer polymerization. These pentablock copolymers served as macromolecular ligands to template Fe(3)O(4) magnetic nanoparticles (MNPs), which were directly anchored to the polymer chains through the coordination bonds with the carboxyl groups of PAA blocks. The resulting polymer/MNP nanocomposites comprised a complicated hierarchical structure in which polymer-coated MNP clusters were dispersed in a microsegregated pentablock copolymer matrix that further contained LC ordering. Upon swelling, the hierarchical structure was disrupted and converted to a network structure, in which MNP clusters were anchored to the polymer chains and LC domains stayed intact to connect solvated PEO and PAA blocks, leading to a free-standing LC magnetic hydrogel (LC ferrogel). By varying the PAA weight fraction (f(AA)) in the pentablock copolymers, the swelling degrees (Q) of the resulting LC ferrogels were tailored. Rheological experiments showed that these physically cross-linked free-standing LC ferrogels exhibit good mechanical strength with storage moduli G' of around 10(4)-10(5) Pa, similar to that of natural tissues. Furthermore, application of a magnetic field induced bending actuation of the LC ferrogels. Therefore, these physically cross-linked and mechanically robust LC ferrogels can be used as soft actuators and artificial muscles. Moreover, this design strategy is a versatile platform for incorporation of different types of nanoparticles (metallic, inorganic, biological, etc.) into multifunctional amphiphilic block copolymers, resulting in unique free-standing hybrid hydrogels of good mechanical strength and integrity with tailored properties and end applications. PMID- 22239115 TI - Synthesis of 7-oxo-dihydrospiro[indazole-5,4'-piperidine] acetyl-CoA carboxylase inhibitors. AB - Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4 formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2 substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors. PMID- 22239116 TI - Projecting water withdrawal and supply for future decades in the U.S. under climate change scenarios. AB - The sustainability of water resources in future decades is likely to be affected by increases in water demand due to population growth, increases in power generation, and climate change. This study presents water withdrawal projections in the United States (U.S.) in 2050 as a result of projected population increases and power generation at the county level as well as the availability of local renewable water supplies. The growth scenario assumes the per capita water use rate for municipal withdrawals to remain at 2005 levels and the water use rates for new thermoelectric plants at levels in modern closed-loop cooling systems. In projecting renewable water supply in future years, median projected monthly precipitation and temperature by sixteen climate models were used to derive available precipitation in 2050 (averaged over 2040-2059). Withdrawals and available precipitation were compared to identify regions that use a large fraction of their renewable local water supply. A water supply sustainability risk index that takes into account additional attributes such as susceptibility to drought, growth in water withdrawal, increased need for storage, and groundwater use was developed to evaluate areas at greater risk. Based on the ranking by the index, high risk areas can be assessed in more mechanistic detail in future work. PMID- 22239117 TI - Rational design of single-composition ABC collagen heterotrimers. AB - Design of heterotrimeric ABC collagen triple helices is challenging due to the large number of competing species that may be formed. Given the required one amino acid stagger between adjacent peptide strands in this fold, a ternary mixture of peptides can form as many as 27 triple helices with unique composition or register. Previously we have demonstrated that electrostatic interactions can be used to bias the helix population toward a desired target. However, homotrimeric assemblies have always remained the most thermally stable species in solution and therefore comprised a significant component of the peptide mixture. In this work we incorporate complementary modifications to this triple-helical design strategy to destabilize an undesirable competing state while compensating for this destabilization in the desired ABC composition. The result of these modifications is a new ABC triple-helical system with high thermal stability and control over composition, as observed by NMR. An additional set of modifications, which exchanges aspartate for glutamate, results in an overall lowering of stability of the ABC triple helix yet shows further improvement in the system's specificity. This rationally designed system helps to elucidate the rules governing the self-assembly of synthetic collagen triple helices and sheds light on the biological mechanisms of collagen assembly. PMID- 22239118 TI - Vibrational spectra of linear oligomers of carbonic acid: a quantum chemical study. AB - Gas phase quantum chemical calculations of linear, hydrogen bonded oligomers of carbonic acid have been carried out to examine the feasibility for such species to be the building blocks of crystalline carbonic acid. Infrared and Raman vibrational spectra have been calculated and are compared against experimentally known spectra for two polymorphs of carbonic acid. The calculated anharmonic frequencies of the linear oligomer agree well with the experimental data for the centrosymmetric beta-carbonic acid, rather than with that for the alpha polymorph. These calculations strongly suggest that beta-carbonic acid should consist of one-dimensional hydrogen bonded carbonic acid molecules in the anti anti conformation. PMID- 22239120 TI - Oligovalent amyloid-binding agents reduce SEVI-mediated enhancement of HIV-1 infection. AB - This paper evaluates the use of oligovalent amyloid-binding molecules as potential agents that can reduce the enhancement of human immunodeficiency virus 1 (HIV-1) infection in cells by semen-derived enhancer of virus infection (SEVI) fibrils. These naturally occurring amyloid fibrils found in semen have been implicated as mediators that can facilitate the attachment and internalization of HIV-1 virions to immune cells. Molecules that are capable of reducing the role of SEVI in HIV-1 infection may, therefore, represent a novel strategy to reduce the rate of sexual transmission of HIV-1 in humans. Here, we evaluated a set of synthetic, oligovalent derivatives of benzothiazole aniline (BTA, a known amyloid binding molecule) for their capability to bind cooperatively to aggregated amyloid peptides and to neutralize the effects of SEVI in HIV-1 infection. We demonstrate that these BTA derivatives exhibit a general trend of increased binding to aggregated amyloids as a function of increasing valence number of the oligomer. Importantly, we find that oligomers of BTA show improved capability to reduce SEVI-mediated infection of HIV-1 in cells compared to a BTA monomer, with the pentamer exhibiting a 65-fold improvement in efficacy compared to a previously reported monomeric BTA derivative. These results, thus, support the use of amyloid-targeting molecules as potential supplements for microbicides to curb the spread of HIV-1 through sexual contact. PMID- 22239121 TI - SERS-fluorescence joint spectral encoding using organic-metal-QD hybrid nanoparticles with a huge encoding capacity for high-throughput biodetection: putting theory into practice. AB - A new concept of optical encoding approach, surface enhanced Raman scattering (SERS)-fluorescence joint spectral encoding method (SFJSE), was demonstrated by using organic-metal-quantum dot (QD) hybrid nanoparticles (OMQ NPs) with a nanolayered structure. This method has two distinct characteristics, which make it more feasible to achieve enormous codes in practice, compared with a sole fluorescence- or SERS-based encoding protocol. One of the two characteristics is to use the joint SERS and fluorescence spectra as the encoding elements instead of an individual optical signal, resulting in a broadened optical spectrum range for efficient encoding. The other is to assemble SERS reporters and fluorescent agents onto different layers of OMQ NPs, leading to an easier fabrication protocol when a large number of agents need to be involved into encoding carriers. By conjugating different antibodies to OMQ NPs with varied codes, the potential application of such an encoding system in high-throughput detection has been investigated by multiplex sandwich immunoassays. The high specificity and sensitivity of the assays suggest that the SFJSE method could be developed as a powerful encoding tool for high-throughput bioanalysis with the use of OMQ NPs. PMID- 22239123 TI - Cardiac troponin T levels and exercise stress testing in patients with suspected coronary artery disease: the Akershus Cardiac Examination (ACE) 1 study. AB - Whether reversible ischaemia in patients referred for exercise stress testing and MPI (myocardial perfusion imaging) is associated with changes in circulating cTn (cardiac troponin) levels is controversial. We measured cTnT with a sensitive assay before, immediately after peak exercise and 1.5 and 4.5 h after exercise stress testing in 198 patients referred for MPI. In total, 19 patients were classified as having reversible myocardial ischaemia. cTnT levels were significantly higher in patients with reversible myocardial ischaemia on MPI at baseline, at peak exercise and after 1.5 h, but not at 4.5 h post-exercise. In patients with reversible ischaemia on MPI, cTnT levels did not change significantly after exercise stress testing [11.1 (5.2-14.9) ng/l at baseline compared with 10.5 (7.2-16.3) ng/l at 4.5 h post-exercise, P=0.27; values are medians (interquartile range)]. Conversely, cTnT levels increased significantly during testing in patients without reversible myocardial ischaemia [5.4 (3.0-9.0) ng/l at baseline compared with 7.5 (4.6-12.4) ng/l, P<0.001]. In conclusion, baseline cTnT levels are higher in patients with MPI evidence of reversible myocardial ischaemia than those without reversible ischaemia. However, although cTnT levels increase during exercise stress testing in patients without evidence of reversible ischaemia, this response appears to be blunted in patients with evidence of reversible ischaemia. Mechanisms other than reversible myocardial ischaemia may play a role for acute exercise-induced increases in circulating cTnT levels. PMID- 22239124 TI - Utilization of prehospital dispatch protocols to identify low-acuity patients. AB - OBJECTIVES: To describe the experience of a U.S. emergency medical services (EMS) agency utilizing a dispatch algorithm to identify low-acuity patients and determine whether secondary telephone triage by a nurse was associated with subsequent hospital admission among those patients. METHODS: This was a retrospective study of all patients meeting the low-acuity Omega classification by the Medical Priority Dispatch System (MPDS) in a large urban EMS system, conducted in two phases. Patients were excluded from the study if a refusal for transport was obtained, the call was received from a third-party caller, the MPDS system was not used, the patient was being referred from a skilled nursing facility, school, or university nursing office or physician's office, or if the call was referred to the Carolina Poison Center. Patients were enrolled over two phases using two different versions of the MPDS protocol, and in phase 2 patients were offered the option of speaking with an advice-line nurse. The outcome of interest was emergency department disposition, classified as hospital admission or discharge home. Admission to an intensive care unit (ICU) bed was also collected as a subcategory of hospital admission. RESULTS: Of the 1,862 patients in phase 1, 69.3% were discharged home from the emergency department, whereas in phase 2, 73.0% of the 1,078 patients were discharged home. Individuals were most frequently admitted to the hospital across both phases if they had a dispatch determinant of pregnancy, psychiatric/behavioral, fall, sick person. Hospital admission was also associated with receiving an EMS or emergency department procedure. There were 530 patients in phase 2 who underwent secondary triage by an advice-line nurse. Among this cohort of patients, 134 (25.3%) required subsequent hospital admission, with a further three (2.2%) requiring an ICU admission. CONCLUSIONS: This study identified a method for classifying patients during the dispatch period as low-acuity while attempting to ensure that those individuals received the medical care that they needed. PMID- 22239125 TI - The effects of immunosuppressants on vascular function, systemic oxidative stress and inflammation in rats. AB - Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8-week old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus-treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial-dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial-independent relaxation was impaired in tacrolimus treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function. PMID- 22239126 TI - Long-term persistence of BCG Pasteur in lungs of C57BL/6 mice following intranasal infection. AB - Different Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine substrains may vary in their efficacy. Here, we describe differences in disease progression and pathology in the lungs of female C57BL/6 mice infected intranasally with BCG Russia or BCG Pasteur and followed for 17 months. The lungs were investigated for bacillary load, histopathology and expression of cytosolic and secreted proteins by immunohistochemistry. BCG Russia was cleared from the lungs by 8 months. BCG Pasteur reached a low-level persistence at 8 months and remained at this level until the end of the experiment. BCG Pasteur induced greater pathology than BCG Russia, and there were more macrophage and lymphocyte infiltrates in animals infected with BCG Pasteur (P < 0.05). Bacterial growth correlated with cellular infiltration. All selected mycobacterial proteins were found to be expressed in the lesions by both BCG strains, and there were only minor variations between the strains. Furthermore, we identified isolated cells containing a high mycobacterial protein load in the normal-looking lung parenchyma. The infected cells in the healthy areas of the lung may represent the ability of mycobacteria to evade immune activation and thereby persist in the host. Clearance of BCG Russia indicates that a more effective and sterilizing immune response is established by this strain. On the other hand, the ability of BCG Pasteur to persist could be important for long-term protection against challenge with Mycobacterium tuberculosis. PMID- 22239127 TI - Exposure assessment and modeling of quartz in Swedish iron foundries for a nested case-control study on lung cancer. AB - Exposure assessment of quartz in Swedish iron foundries was performed based on historical and current measurement data. To evaluate the exposure-response relationship between quartz exposure and lung cancer, we modeled quartz exposure from our database of measurements using determinants job title, time period, and company. Based on these modeled exposure data, we conducted a nested case-control evaluation. In our database, the overall individual, daily time-weighted average (TWA) quartz concentrations of current and historical data varied between 0.0018 and 4.9 mg/m(3), averaging 0.083 mg/m(3). Job titles with mean TWAs for the whole study period exceeding the European Union recommended occupational exposure limit of 0.05 mg/m(3) were fettlers (0.087 mg/m(3)), furnace and ladle repair (0.42 mg/m(3)), and maintenance (0.054 mg/m(3)) workers. The mixed model analysis demonstrated significant determinants on the job level for furnace and ladle repair (beta = 4.06; 95% confidence interval [CI] 2.78-5.93). For all jobs, significantly higher exposure levels occurred only during the first time period, 1968-1979 (beta = 2.08; 95% CI 1.75-2.47), and a decreasing but not significant trend was noted for the three following 10-year time periods up to 2006 (beta = 1.0, 0.96 and 1, respectively). Two iron foundries had significantly higher quartz concentration levels than the others (beta = 1.31; 95% CI 1.00-1.71 and beta = 1.63; 95% CI 1.00-2.65, respectively). The individual cumulative quartz exposure measures were categorized in low, medium, and high exposure (0.5-<1, 1 1.9 and >= 2 mg/m(3)*years, respectively). In the nested case-control analysis, we found the highest odds ratios of lung cancer (OR 1.17; 95% CI 0.53-2.55) for the medium exposure group. No dose-response trend or significantly increased risk was determined for our high exposed group (>=2 mg/m(3)), representing 40 years of exposure at >0.05 mg/m(3) of quartz. To conclude, certain foundry workers are still exposed to high levels of quartz, but an increased risk of lung cancer caused by quartz exposure in these Swedish iron foundries could not be confirmed at our exposure levels. PMID- 22239128 TI - Chemical composition and larvicidal activities of the Himalayan cedar, Cedrus deodara essential oil and its fractions against the diamondback moth, Plutella xylostella. AB - Plants and plant-derived materials play an extremely important role in pest management programs. Essential oil from wood chips of Himalayan Cedar, Cedrus deodara (Roxburgh) Don (Pinales: Pinaceae), was obtained by hydrodistillation and fractionated to pentane and acetonitrile from which himachalenes and atlantones enriched fractions were isolated. A total of forty compounds were identified from these fractions using GC and GC-MS analyses. Essential oils and fractions were evaluated for insecticidal activities against second instars of the diamondback moth, Plutella xylostella L. (Lepidoptera: Yponomeutidae), using a leaf dip method. All samples showed promising larvicidal activity against larvae of P. xylostella. The pentane fraction was the most toxic with a LC50 value of 287 ug/ml. The himachalenes enriched fraction was more toxic (LC50 = 362 ug/ml) than the atlantones enriched fraction (LC50 = 365 ug/ml). LC50 of crude oil was 425 ug/ml and acetonitrile fraction was LC50 = 815 ug/ml. The major constituents, himachalenes and atlantones, likely accounted for the insecticidal action. Present bioassay results revealed the potential for essential oil and different constituents of C. deodara as botanical larvicides for their use in pest management. PMID- 22239130 TI - Cross-cultural analysis of cognitive attributions of smoking in thai and South Korean adolescents. AB - BACKGROUND: Understanding the cognitive attributions of smoking has the potential to advance youth smoking prevention efforts; however, research on this subject is limited in Asian countries. We attempted to determine the degree to which cognitive attributions of smoking differ among adolescents in 2 Asian countries, Thailand and South Korea. METHODS: We surveyed 10th- to 12th-grade students in Chiang Mai, Thailand (N = 2516) and Seoul, South Korea (N = 1166). Logistic regression determined association of attributions and current smoking and differences in attributions between Thai and South Korean students. RESULTS: Items with the highest agreement among South Koreans were "helps me to deal with stress" and "helps relax" and among Thai were "feel like I am making my own decisions" and "keeps from being bored." Significant predictors of current smoking were different between samples. Only 1 cognitive attribution predicted current smoking in both samples ("helps me to deal with stress"). CONCLUSION: The pattern of relevant cognitive attributions of smoking for the 2 samples was distinct, suggesting that cross-cultural differences merit consideration when designing prevention and cessation programs. Health education should strive to dispel the use of smoking as a coping strategy for dealing with stressful situations and distressful feelings and teach adolescents alternative healthy strategies for dealing with stress. PMID- 22239131 TI - School engagement among aboriginal students in northern Canada: perspectives from activity settings theory. AB - BACKGROUND: Educational disengagement is a public health concern among Aboriginal populations in many countries. It has been investigated previously in a variety of ways, with the conventional focus being on the children themselves. Activity settings are events and places, theorized in terms of their symbols, roles, time frame, funds, people, and physical location. According to the theory, particular behaviors and experiences are shaped by different configurations among these elements. This study explored how activity settings theory might provide new insight on school engagement. METHODS: Ethnographic study was undertaken at a grades primary to 12 school in a remote First Nations community in Canada's Northwest Territories. We collected data through interviews, focus groups, archival material, and field notes from 7 months of participant observation. An activity settings model acted as template for data collection and interpretation. RESULTS: Different aspects of the school's physical layout, routines, procedures, transport systems, mix of people, and rules were able to be systemically assessed and classified as either creating or eroding engagement. CONCLUSION: This study applies an activity setting analysis to school engagement, thereby allowing researchers to investigate the dynamic and nested nature of context or environmental influences on engagement. It provides grounded observations that invite direct opportunities for action on dimensions that teachers and practitioners might not otherwise "see." PMID- 22239132 TI - Sexual initiation, parent practices, and acculturation in Hispanic seventh graders. AB - BACKGROUND: Hispanic youths have high rates of sexually transmitted infections and pregnancies, yet little research has targeted multiple protective/risk factors for early sexual initiation in this group. This study examined two main factors--parenting practices and acculturation--on early sexual initiation among Hispanic middle school students in Texas. METHODS: Using data from Hispanic seventh graders (N = 655) in 15 urban middle schools in southeast Texas, we examined the association between parental monitoring/parent-child communication about sexual health and sexual initiation. RESULTS: After controlling for age, gender, parent/guardian education, family structure, acculturation level, and intervention status, the likelihood of ever having sex decreased 50% for every 1 point increase in the parental monitoring score (AOR = 0.50;95%CI = 0.34,0.75). No association was found between ever having sex and parent-child communication scores (AOR = 1.29;95%CI = 0.76,2.18). Furthermore, parental monitoring differed significantly between acculturation levels, 1-way analysis of variance F(2,652) = 5.07, p < 0.007. This finding was unrelated to the parental monitoring-initiation association in the multivariable model. CONCLUSION: Parental monitoring may delay sexual initiation among Hispanic middle school students. Parental monitoring differs by acculturation levels, warranting further investigation. These findings can inform school-based, parent-involved interventions designed to delay sexual initiation among Hispanic youth. PMID- 22239134 TI - The effect of nutrient-based standards on competitive foods in 3 schools: potential savings in kilocalories and grams of fat. AB - BACKGROUND: The study investigated how nutrient standards affected the number of kilocalories and grams of fat and saturated fat in competitive foods offered and sold in 3 high schools. METHODS: The study is a quasi-experimental design with 3 schools serving as the units of assignment and analysis. The effect of the nutrient standards was measured by the change in kilocalories and grams of fat and saturated fat in offerings and purchases of competitive foods pre- and postimplementation of the standards. A paired sample t-test was used to compare kilocalories and grams of fat and saturated fat pre- and postimplementation of nutrition standards. RESULTS: After the implementation of the nutrition standards, students in 3 high schools purchased significantly smaller numbers of kilocalories and grams of fat and saturated fat, during the postpolicy school year of 2007-2008 than during the prepolicy school year of 2004-2005. CONCLUSION: Using nutrient standards to guide the selection of competitive foods offered in school cafeterias may positively affect intake of kilocalories, total grams of fat, and total saturated fat of those foods. The quantitative assessment is novel and demonstrates the reduction in kilocalories and fat in both the competitive food offerings and purchases as a result of nutrient standards. PMID- 22239135 TI - Challenges to collaboration in school mental health and strategies for overcoming them. AB - BACKGROUND: This article reviews challenges to collaboration in school mental health (SMH) and presents practical strategies for overcoming them. METHODS: The importance of collaboration to the success of SMH programs is reviewed, with a particular focus on collaboration between school- and community-employed professionals. Challenges to effective collaboration between school- and community-employed professionals in SMH are considered. Strategies for overcoming challenges to effective collaboration are presented. RESULTS: Marginalization of the SMH agenda, limited interdisciplinary teamwork, restricted coordination mechanisms, confidentiality concerns, and resource and funding issues are key challenges to collaboration. Strategies targeted toward each of these challenges may help improve the effectiveness of SMH programs and ultimately student outcomes. CONCLUSIONS: Collaboration between school- and community-employed professionals is critical to the success of SMH programs. Despite its promise, the success of SMH programs can be jeopardized by ineffective collaboration between school- and community-employed professionals. Strategies to overcome marginalization, promote authentic interdisciplinary teamwork, build effective coordination mechanisms, protect student and family confidentiality, and promote policy change and resource enhancements should be addressed in SMH improvement planning. PMID- 22239136 TI - Construct validation of the Nurse Cultural Competence Scale: a hierarchy of abilities. AB - AIM: The aim of this study was to describe the development of a Nurse Cultural Competence Scale using Mokken scaling. BACKGROUND: The psychometrics of the present cultural competence assessment tools has been questioned. The levels of competence measured by existing tools are not capable of indicating individual differences. DESIGN: This study employed a cross-sectional design. A convenience sample of 172 on-the-job nursing students in a college of technology in Taiwan was recruited. METHODS: Based on previous literature, the Nurse Cultural Competence Scale comprising 41 items was developed to measure the concept of cultural awareness, cultural knowledge, cultural sensitivity and cultural skill. Mokken scaling analysis was conducted to investigate the unidimensionality and hierarchical nature of the scale. RESULTS: From the 41 items entered into the Mokken scaling procedure, 20 form a strong Mokken scale. The 20 items form a reliable and statistically significant scale which is negatively skewed. The ordering of the items from lowest to highest difficulty shows a hierarchy. RELEVANCE TO CLINICAL PRACTICE: Nursing managers and educators may use this scale to assess the levels of cultural competence of their members or students and then provide the education according to individual needs. PMID- 22239137 TI - Fatal crashes of 16- to 17-year-old drivers involving alcohol, nighttime driving, and passengers. AB - OBJECTIVE: The objective of this study was to provide a contemporary analysis of the alcohol-impaired driving problem among 16- to 17-year-olds and to consider the potential role of night and passenger restrictions in dealing with the alcohol problem by determining how many of the alcohol-related crashes take place at night or with passengers. METHODS: The data were derived from the Fatality Analysis Reporting System for 16- to 17-year-old passenger vehicle drivers in fatal crashes during 2005-2009. RESULTS: During the 5-year period, 15 percent of the 8664 16- to 17-year-old drivers in fatal crashes had positive blood alcohol concentrations, most of which were 0.08 percent or greater. Drivers in alcohol related crashes were more likely than those in non-alcohol-related crashes to be male, unbelted, in single vehicles, and speeding, and their crashes were more likely to occur on Saturday or Sunday, at night, and when passengers were present. Of the alcohol-related crashes, 88 percent took place at night or with passengers present or both, as did 67 percent of the non-alcohol-related crashes. CONCLUSIONS: Stronger night and passenger restrictions with increased compliance and greater application of alcohol-specific policies would likely be effective in reducing the alcohol-related and non-alcohol-related crashes of 16- to 17-year olds. Increasing the licensing age beyond age 16 would supplement the effectiveness of these actions. PMID- 22239133 TI - Effect of nutrition changes on foods selected by students in a middle school based diabetes prevention intervention program: the HEALTHY experience. AB - BACKGROUND: The HEALTHY primary prevention trial developed an integrated multicomponent intervention program to moderate risk factors for type 2 diabetes in middle schools. The nutrition component aimed to improve the quality of foods and beverages served to students. Changes in the School Breakfast Program (SBP), National School Lunch Program (NSLP), and a la carte venues are compared to the experience of control schools. METHODS: The intervention was implemented in 21 middle schools from winter 2007 through spring 2009 (following a cohort of students from sixth through eighth grades); 21 schools acted as observed controls. The nutrition component targeted school food service environmental change. Data identifying foods and nutrients served (selected by students for consumption) were collected over a 20-day period at baseline and end of study. Analysis compared end of study values for intervention versus control schools. RESULTS: Intervention schools more successfully limited dessert and snack food portion size in NSLP and a la carte and lowered fat content of foods served. Servings of high-fiber grain-based foods and/or legumes were improved in SBP but not NSLP. Intervention and control schools eliminated >1% fat milk and added sugar beverages in SBP, but intervention schools were more successful in NSLP and a la carte. CONCLUSION: The HEALTHY program demonstrated significant changes in the nutritional quality of foods and beverages served in the SBP, NSLP, and a la carte venues, as part of an effort to decrease childhood obesity and support beneficial effects in some secondary HEALTHY study outcomes. PMID- 22239138 TI - Nonprogression through graduated driver licensing: characteristics, traffic offending, and reasons for nonprogression. AB - OBJECTIVES: In a graduated driver license environment, (1) compare nonprogressors with progressors in terms of prelearner license sociodemographic and behavioral factors, (2) determine whether nonprogressors were more likely to have had a traffic offense than progressors, and (3) determine why nonprogressors chose not to progress. METHODS: Our study population was that of the New Zealand Drivers Study (NZDS), a prospective cohort study of newly licensed drivers designed to explore the relationship between a comprehensive range of driving and traffic safety related factors and subsequent traffic crashes and convictions among newly licensed drivers. Nonprogressors, those who had not progressed from a learner to a restricted license 2 years after being eligible to do so, were compared with progressors in terms of their sociodemographic, behavioral characteristics, and traffic offense outcomes. RESULTS: Nonprogressors represented 38 percent of the cohort and had different sociodemographic and behavioral profiles than progressors. A delay in progression was associated with reduced risk of being a traffic offender. The primary reasons reported for nonprogression were too lazy or busy or limited access to the means to drive. CONCLUSION: Before restricting how long a novice driver can hold a learner license, as has been suggested by the Ministry of Transport, consideration should be given to the potential increased risk of offending once unsupervised driving is permitted. PMID- 22239139 TI - Attitudes toward red light camera enforcement in cities with camera programs. AB - OBJECTIVE: To obtain information on attitudes and experiences related to red light camera enforcement in cities with camera programs and in Houston, Texas, where cameras were removed after voters rejected the program in November 2010. METHODS: Telephone surveys were conducted with 3111 drivers in 14 large cities (population greater than 200,000) with long-standing red light camera programs and 300 drivers in Houston, using random samples of landline and cell phone numbers in each city. For analyses combining responses from the 14 cities, cases were weighted to reflect each city's share of the total population for the 14 cities. RESULTS: Among drivers in the 14 cities with red light camera programs, two thirds favor the use of cameras for red light enforcement and 42 percent strongly favor it. The chief reasons for opposing cameras were the perceptions that cameras make mistakes and that the motivation for installing them is revenue, not safety. Forty-one percent of drivers favor using cameras to enforce right-turn-on-red violations. Nearly 9 in 10 drivers were aware of the camera enforcement programs in their cities, and 59 percent of these drivers believed that the cameras have made intersections safer. Almost half know someone who received a red light camera citation, and 17 percent had received at least one ticket themselves. When compared with drivers in the 14 cities with camera programs, the percentage of drivers in Houston who strongly favored enforcement was about the same (45%), but strong opposition was higher in Houston than in the other cities (28 versus 18%). CONCLUSIONS: Most drivers in cities with long standing red light camera programs support cameras and believe that the cameras have improved safety, but communities could do a better job of educating the public about the dangers of right-turn-on-red violations and the need for enforcement. Given that camera opponents frequently said cameras make mistakes, it appears that communities also could do a better job of explaining the safeguards that ensure that citations are issued only to drivers who clearly run red lights. PMID- 22239140 TI - Alcohol-impaired driving: average quantity consumed and frequency of drinking do matter. AB - OBJECTIVE: The objective of this article is to estimate and validate a logistic model of alcohol-impaired driving using previously ignored alcohol consumption behaviors, other risky behaviors, and demographic characteristics as independent variables. METHODS: The determinants of impaired driving are estimated using the US Centers for Disease Control and Prevention's (CDC) Behavioral Risk Factor Surveillance System (BRFSS) surveys. Variables used in a logistic model to explain alcohol-impaired driving are not only standard sociodemographic variables and bingeing but also frequency of drinking and average quantity consumed, as well as other risky behaviors. We use interactions to understand how being female and being young affect impaired driving. Having estimated our model using the 1997 survey, we validated our model using the BRFSS data for 1999. RESULTS: Drinking 9 or more times in the past month doubled the odds of impaired driving. The greater average consumption of alcohol per session, the greater the odds of driving impaired, especially for persons in the highest quartile of alcohol consumed. Bingeing has the greatest effect on impaired driving. Seat belt use is the one risky behavior found to be related to such driving. Sociodemographic effects are consistent with earlier research. Being young (18-30) interacts with two of the alcohol consumption variables and being a woman interacts with always wearing a seat belt. Our model was robust in the validation analysis. CONCLUSIONS: All 3 dimensions of drinking behavior are important determinants of alcohol-impaired driving, including frequency and average quantity consumed. Including these factors in regressions improves the estimates of the effects of all variables. PMID- 22239141 TI - The need for drugged driving per se laws: a commentary. AB - OBJECTIVE: Triggered by the new federal commitment announced by the Office of National Drug Control Policy (ONCDP) to encourage states to enact drugged driving per se laws, this article reviews the reasons to establish such laws and the issues that may arise when trying to enforce them. METHODS: A review of the state of drunk driving per se laws and their implications for drugged driving is presented, with a review of impaired driving enforcement procedures and drug testing technology. RESULTS: Currently, enforcement of drugged driving laws is an adjunct to the enforcement of laws regarding alcohol impairment. Drivers are apprehended when showing signs of alcohol intoxication and only in the relatively few cases where the blood alcohol concentration of the arrested driver does not account for the observed behavior is the possibility of drug impairment pursued. In most states, the term impaired driving covers both alcohol and drug impairment; thus, driver conviction records may not distinguish between the two different sources of impairment. As a result, enforcement statistics do not reflect the prevalence of drugged driving. CONCLUSIONS: Based on the analysis presented, this article recommends a number of steps that can be taken to evaluate current drugged driving enforcement procedures and to move toward the enactment of drug per se laws. PMID- 22239142 TI - Analysis of alcohol and drugs in oral fluid from truck drivers in Norway. AB - OBJECTIVE: To examine alcohol and drug use among truck drivers compared to car or van drivers in Norway by analyzing samples of oral fluid. METHODS: Drivers were selected for a voluntary and anonymous study using a stratified multistage cluster sampling procedure. Drivers of trucks were recruited at two control stations for heavy vehicles in southeastern Norway in collaboration with the Norwegian Roads Administration, and drivers of cars and vans were recruited in a roadside survey in collaboration with the mobile police service. Samples of oral fluid were taken by using the Statsure Saliva Sampler (Statsure Diagnostic Systems, Framingham, MA), and the drivers' gender, age, and nationality were recorded. Samples of oral fluid were analyzed for alcohol or drugs, in total 28 psychoactive substances. RESULTS: About 97 percent of the truck drivers and 94 percent of the car or van drivers agreed to participate in the study. Of the 882 studied truck drivers studied, 1.4 percent were female and 29.1 percent were Norwegian; of the 5305 car or van drivers, 27.6 percent were female and 90.9 percent were Norwegian. Alcohol or drugs were found in 1.9 and 6.6 percent of the samples from truck drivers and car/van drivers, respectively. The adjusted odds ratio (OR) for the detection of a psychoactive substance in a sample from a truck driver compared to car or van driver was 0.29; the 95 percent confidence interval (95% CI) was 0.17 to 0.53. The adjusted OR for the detection of an illegal drug was 0.42 (95% CI: 0.18-0.82), the adjusted OR for the detection of a psychoactive medicinal drug was 0.29 (95% CI: 0.13-0.68), and the adjusted OR for the detection of alcohol was 0.13 (95% CI: 0.02-1.10). CONCLUSIONS: The proportion of oral fluid samples containing psychoactive substances was lower for truck drivers than for car or van drivers. PMID- 22239143 TI - Preventing road injuries in children by applying feedback devices. AB - OBJECTIVE: The objective of this article is to determine how to prevent road injuries in schoolchildren by reducing the prevalence of speeding. METHODS: On a busy road in the neighborhood of a preschool and two secondary schools in Oberhaching (greater Munich, Germany), a board was mounted next to the road (visible to the drivers as well as the pedestrians). The board consisted of a picture of a smiling child. Underneath the picture, an LED display read "Thank you!" in green blinking letters when the speed limit was adhered to and "Slowly!" in red blinking letters when speeding was detected. The main outcome assessment was the number of drivers adhering to the speed limit in the experimental condition (i.e., facing the device) compared to the number in the control condition (on the same road within the same time period but traveling in the opposite direction; i.e., drivers not facing the device). RESULTS: In the control condition 27.6 percent (230) of drivers adhered to the speed limit compared to 41.1 percent (427) of drivers in the experimental condition, chi(2) = 36.1, P < .0001. Only 12 drivers exceeded the speed limit by more than 20 km per hour in the experimental condition, whereas 34 drivers did so in the control condition, chi(2) = 9.6, P < .01. DISCUSSION: The display is associated with a significantly lower percentage of speeding drivers but does not seem to be sufficient, because the majority of drivers still did not observe the speed limit in the presence of the display. Additional factors on how speed reduction can be achieved will be discussed in the light of future applications and possible modifications of the device. PMID- 22239144 TI - Front-to-rear crashes involving two vehicles with severe driver injury. AB - PURPOSE: This study investigates the risk for severe-to-fatal injury (Maximum Abbreviated Injury Scale [MAIS] 4+F) to drivers in two-vehicle crashes involving front impacts into the rear of another vehicle. METHODS: 1995-2009 National Automotive Sampling System-Crashworthiness Data System (NASS-CDS) was analyzed for driver injuries in front-to-rear crashes without rear occupants in either vehicle. The study involved 13+-year-old front outboard occupants in model year (MY) 1995+ light vehicles. Injury severity was subdivided into MAIS 0+6 and MAIS 4+F to assess the risk of severe-to-fatal injury (MAIS 4+F/MAIS 0+6). Injury risks were determined using weighted data for the drivers by impact type. Standard errors were calculated in SAS to determine +/-95 percent confidence intervals. An in-depth analysis was made of individual cases with severely injured drivers in the front and rear impacts. RESULTS: There were 215,163 drivers in the 15 years of NASS-CDS with known injuries in front-to-rear two vehicle collisions; 624 were severely injured (MAIS 4+F) in the rear impacts and 124 in the front impacts. The risk for severe-to-fatal driver injury was 0.290 +/ 0.241 percent in rear impacts and 0.058 +/- 0.057 percent in front impacts. The difference was not statistically significant (P > .05). There were 13 unweighted cases with MAIS 4+F driver injury in rear impacts. Most (77%) involved intrusion in the vicinity of the driver's seating area with the seat supported upright or deformed forward. There were 5 unweighted cases with severely injured drivers in frontal impacts. Three (60%) involved intrusion due to offset frontal loading. There was only one crash where both drivers were severely injured. CONCLUSIONS: In front-to-rear crashes with two vehicles, typically one driver was severely injured, not both. The risk of severe injury was not significantly different for drivers in the front or rear impacts. The risk was higher in rear impacts due to intrusion into the driver's seating area that supported or pushed the driver's seat forward. The risk for drivers in frontal crashes was also often related to intrusion due to offset loading and occupant compartment deformation. PMID- 22239145 TI - Epidemiologic study of road traffic injuries by road user type characteristics and road environment in Iran: a community-based approach. AB - OBJECTIVE: Crash injuries in traffic accidents are affected by a variety of factors. In this study we analyzed road user type information based on different contributing factors. METHOD: Data from all of the road traffic victims on a road extending from the east of the city of Tehran to Mazandaran province were included prospectively over a one-year period (May 2008 to May 2009). Data collected included the crash time, patient's age and sex, road user category, helmet or seat belt use, anatomical site of injury, Injury Severity Score (ISS), and mortality. Prevalence and cross-tabulations were included in the analysis. RESULTS: There were 433 patients, of whom 345 were hospitalized and 33 died either before or after arriving at the hospital. Sixty-nine percent of injured patients were vehicle occupants. Mean and median of ISS were higher for pedestrians, who accounted for 49 percent of the deaths. Head injury was the most common injury and injury to upper and lower extremities was the most common cause of admission. A significant difference in lower extremity injuries between vehicle occupants and nonoccupants was found. Sex and age group did not have a significant effect on mortality. Mortality was significantly higher in pedestrians (P < .001) when data were analyzed based on road user type. CONCLUSION: Because pedestrians are the most vulnerable road users, stricter legislation and law enforcement should be used to protect them. Greater protection can also be reached by holding effective public awareness campaigns on how to use different roads safely. On the other hand, because rear seat passengers are at the same risk for road traffic injuries as front seat passengers, employment of newer laws and preventive measures targeting this group of occupants can prevent many road traffic injuries (RTIs). PMID- 22239146 TI - Influence of belt pretensioning on dummy responses in 40 km/h rear-impact sled tests. AB - OBJECTIVE: This study compares dummy kinematics and biomechanical responses with and without belt pretensioning in matched rear sled tests. METHODS: Two rear impact sled tests were run at 40 km/h (25 mph) rear delta V with a lap-shoulder belted Hybrid III 50th percentile male dummy on Ford F-150 driver seats. One test was with the standard lap-shoulder belts and the other with a buckle pretensioner activated at 20 ms. The head, chest, and pelvis were instrumented with triaxial accelerometers. The upper and lower neck, thoracic spine, and lumbar spine had transducers measuring triaxial loads and moments. Lap and shoulder belt loads were measured. High-speed video recorded different views of the dummy motion. Dummy kinematics and biomechanical responses were compared to study the influence of belt pretensioning. RESULTS: The dummy kinematics and biomechanical responses were essentially similar with and without belt pretensioning in the rear-impact sled tests. There were higher belt loads with pretensioning, but they did not result in different dummy lumbar loads or pelvic, chest, and head accelerations. In a rear impact, the dummy moves rearward away from the belts that wrap around the chest and pelvis. The occupant loads the seat, which yields rearward restraining dummy motion. Though pretensioning caused a transient increase in belt load, it was of short duration and there was no sustained effect on occupant dynamics until late in rebound. CONCLUSIONS: The matched tests showed no difference in occupant restraint with and without buckle pretensioning in 40 km/h (25 mph) rear-impact sled tests. Belt pretensioning did not influence occupant responses in these rear impacts because the seat supported the occupant. PMID- 22239147 TI - Accuracy of a damage-based reconstruction method in NHTSA side crash tests. AB - OBJECTIVE: Delta-V (DeltaV), the magnitude of the velocity change experienced by a vehicle during a crash, is widely used as a predictor of injury risk. The National Automotive Sampling System/Crashworthiness Data System (NASS-CDS) uses the WinSMASH computer code to reconstruct DeltaV based on postcrash vehicle deformation. WinSMASH, a direct descendant of CRASH3, first uses vehicle damage to estimate absorbed energy and then applies momentum conservation to estimate DeltaV. This study aims to determine the accuracy of WinSMASH DeltaV reconstructions for NHTSA side crash tests. METHODS: This study is based upon 168 dynamic side impact tests conducted by the National Highway Traffic Safety Administration (NHTSA). For each crash test the actual DeltaV for the struck vehicle was first determined from test instrumentation. WinSMASH was then used to reconstruct the struck vehicle DeltaV for each test. WinSMASH-reconstructed DeltaVs were compared to measured DeltaVs for each test to assess reconstruction accuracy. RESULTS: WinSMASH predicts DeltaV at maximum crush, before restitution occurs. WinSMASH predictions of struck vehicle DeltaV at maximum crush were 20 percent high on average when using vehicle specific stiffnesses, with a great deal of inter-case variability in the error. When compared to the total struck vehicle DeltaV at separation (including restitution), WinSMASH overpredicted DeltaV by 11 percent. WinSMASH overpredicted the amount of energy absorbed in collisions by 40 percent, which is consistent with overprediction of DeltaV. When forced to reconstruct tests using the amount of absorbed energy calculated from the test data, error in WinSMASH DeltaV effectively disappeared. DISCUSSION: When reconstructing NHTSA side crash tests, WinSMASH overpredicts maximum crush DeltaV by about 20 percent on average. The primary factors determining the amount of DeltaV overprediction appear to be overprediction of absorbed energy and the assumption of zero restitution. WinSMASH vehicle side stiffness parameters are calculated based on artificially high energies; this may explain the overprediction of absorbed energy. WinSMASH's assumption of zero restitution partially masks the effect of energy overprediction. When given accurate reconstruction inputs and energy estimates, WinSMASH is capable of accurately reconstructing maximum crush DeltaV in NHTSA side crash tests but cannot compensate for restitution. PMID- 22239148 TI - Evaluation of the biofidelity of the HIII and MIL-Lx lower leg surrogates under axial impact loading. AB - OBJECTIVE: Lower leg injury risk is commonly assessed using an anthropomorphic test device (ATD). The current standard leg (the HIII) has been shown to have low biofidelity due to its geometry and material properties. A new surrogate (the MIL Lx) was developed to address these issues, specifically for anti-vehicular mine blast scenarios but with potential applications to high-force crashes in the automotive industry. Before it is adopted for use, the MIL-Lx must be evaluated under impact loading to ensure that it represents the natural lower leg response. METHODS: Axial impact loads were applied to both the HIII and the MIL-Lx at impact velocities of 2 to 7 m/s using a pneumatic impacting device. Testing was also conducted with the foot removed from both surrogates to enable comparison with previous tests of isolated cadaveric tibias at noninjurious and injurious (i.e., fracture) levels. To evaluate the effect of a boot on load attenuation, the HIII was impacted with and without a hiking boot. RESULTS: Forces in the MIL Lx were between 25 and 100 percent of those in the HIII (depending on impact conditions). The use of a boot reduced the peak force by approximately 65 percent at the highest impact velocities. The MIL-Lx fit the data from noninjurious cadaveric tibia tests with R(2) = 0.83. CONCLUSIONS: The MIL-Lx is a new surrogate that represents the response of the natural tibia under axial impact loading better than the HIII. The inclusion of a boot has a significant effect on loads in the leg and may influence injury assessment results. The MIL-Lx will be a useful tool for predicting lower leg injury risk over a wide range of impact velocities. PMID- 22239149 TI - Bull bars and vulnerable road users. AB - OBJECTIVES: Pedestrian injuries are a leading cause of the global death and injury burden, accounting for 65 percent of the 1.2 million annual road deaths. The purpose of this brief literature review is to examine whether bull bars, a rigid aftermarket accessory fitted to the front end of passenger vehicles, increase the risk of severe and fatal injuries to vulnerable road users in the event of a collision. METHODS: Applicable peer-reviewed research, review papers, and grey literature were identified from a search of MEDLINE; the Transportation Research Board (TRB) database composed of Transportation Research Information Services (TRIS) and International Transport Research Documentation (TRID) databases; the Cochrane Database of Systematic Reviews; and Google Scholar. The following search terms were used: "bull bars" OR "nudge bars" OR "sahara bars" AND "pedestrians" OR "vulnerable road users" for 1948 to March 1, 2011. A secondary set of search terms was also included "bull bars" OR "nudge bars" OR "sahara bars" OR "vehicle frontal protective systems" AND "pedestrians" OR "vulnerable road users" for 1948 to March 1, 2011. RESULTS: Neither the MEDLINE search nor the Cochrane Review search returned any relevant literature. The TRID search returned 19 research articles, 9 of which were included. Searches using Google Scholar returned 110 items, of which 21 were included in the present review after excluding patents and citations. Seven of the articles from TRID were also found in the Google Scholar search, resulting in 23 unique articles being included in this review. The studies used included 12 real-world studies, 3 computer modeling studies, and 8 laboratory testing studies. Very few studies examined the road safety of pedal-cyclists and motorcyclists; therefore, we focused solely on studies examining pedestrian safety. CONCLUSIONS: The literature reviewed in this study indicates that vehicles fitted with bull bars, particularly those without deformable padding, concentrate crash forces over a smaller area of vulnerable road users during collisions compared to vehicles not fitted with a bull bar. Rigid bull bars, such as those made from steel or aluminum, stiffen the front end of vehicles and interfere with the vital shock absorption systems designed in vehicle fronts. These devices therefore significantly alter the collision dynamics of vehicles, resulting in an increased risk of pedestrian injury and mortality in crashes. This literature review shows that bull bars do indeed increase the severity of injuries to vulnerable road users in the event of a collision and highlights the need for current traffic safety policies to reflect the safety concerns surrounding the use of bull bars. PMID- 22239150 TI - The timing of dialysis and kidney transplantation in type 1 diabetes. AB - Despite significant improvements in the treatment of diabetic nephropathy over the last 20 years, patients with type 1 diabetes are at high risk of developing end-stage renal disease (ESRD) and high mortality once ESRD develops. The timing of dialysis initiation has occurred earlier over the years, but a recent study has led to a re-evaluation of that approach. People with type 1 diabetes treated with pre-dialysis (pre-emptive) transplantation have a lower death rate than people with type 1 diabetes treated with dialysis. Living donor kidney transplantation is possible before starting dialysis and is associated with better kidney and patient outcomes as compared to transplantation while on dialysis. Multiple barriers remain that prevent people with type 1 diabetes from enjoying the reduced risk of death afforded by a pre-emptive kidney transplant, including lack of knowledge by primary care physicians, endocrinologists and nephrologists, late referral for transplantation, patient and family misconceptions about timing of transplantation and who can be a donor. New data on both the optimal time to initiate dialysis or to pursue transplantation will be reviewed. PMID- 22239151 TI - Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients. AB - AIM: FOXP3 gene is known to be important for regulatory T cell development and function, and is associated with the rejection of human kidney transplants. The present study was therefore conducted to determine the effect of FOXP3 polymorphisms on allograft rejection in renal transplant recipients. METHODS: A total of 166 adult patients were categorized into either a Rejection group (65 patients) or a No rejection group (101 patients). Rs3761547, rs3761548 and rs2232365 variant alleles in the FOXP3 gene were genotyped using a TaqMan probe technique, and their relationships with rejection were investigated. RESULTS: There was no significant difference in the genotype frequencies of rs3761547 and rs2232365 variants between patients with and without rejection history (P > 0.05). Binary logistic regression analysis showed that the rs3761548 AA genotype carriers were associated with about a fourfold greater risk for rejection compared with CC genotype (5 years post-transplant: odds ratio 3.95, 95% confidence interval 1.27-12.29, P = 0.018). Kaplan-Meier analysis revealed a lower mean time to the first rejection in rs3761548 AA compared with CC genotype patients (Log rank = 4.303, P = 0.038). Multivariate Cox regression analysis indicated that rs3761548 AA genotype carriers have up to about a twofold (hazard ratio 2.37, 95% confidence interval 1.17-4.80, P = 0.017) higher risk for rejection than CC carriers. CONCLUSION: Our study suggests an association between FOXP3 rs3761548 polymorphisms and allograft rejection in renal transplantation. This association should be further proven in large prospective studies because of the small sample size and confounding factors in this retrospective study. PMID- 22239152 TI - Dihydrophenanthridine: a new and easily regenerable NAD(P)H model for biomimetic asymmetric hydrogenation. AB - A new and easily regenerable NAD(P)H model 9,10-dihydrophenanthridine (DHPD) has been designed for biomimetic asymmetric hydrogenation of imines and aromatic compounds. This reaction features the use of hydrogen gas as terminal reductant for the regeneration of the DHPD under the mild condition. Therefore, the substrate scope is not limited in benzoxazinones; the biomimetic asymmetric hydrogenation of benzoxazines, quinoxalines, and quinolines also gives excellent activities and enantioselectivities. Meanwhile, an unexpected reversal of enantioselectivity was observed between the reactions promoted by the different NAD(P)H models, which is ascribed to the different hydride transfer pathway. PMID- 22239154 TI - Noncentrosymmetric inorganic open-framework chalcohalides with strong middle IR SHG and red emission: Ba3AGa5Se10Cl2 (A = Cs, Rb, K). AB - Novel SHG effective inorganic open-framework chalcohalides, Ba(3)AGa(5)Se(10)Cl(2) (A = Cs, Rb and K), have been synthesized by high temperature solid state reactions. These compounds crystallize in the tetragonal space group I 4 (No.82) with a = b = 8.7348(6) - 8.6341(7) A, c = 15.697(3) - 15.644(2) A, V = 1197.6(3) - 1166.2(2) A(3) on going from Cs to K. The polar framework of (3)(infinity)[Ga(5)Se(10)](5-) is constructed by nonpolar GaSe(4)(5- )tetrahedron (T1) and polar supertetrahedral cluster Ga(4)Se(10)(8-) (T2) in a zinc-blende topological structure with Ba/A cations and Cl anions residing in the tunnels. Remarkably, Ba(3)CsGa(5)Se(10)Cl(2) exhibits the strongest intensity at 2.05 MUm (about 100 times that of the benchmark AgGaS(2) in the particle size of 30-46 MUm) among chalcogenides, halides, and chalcohalides. Furthermore, these compounds are also the first open-framework compounds with red photoluminescent emissions. The Vienna ab initio theoretical studies analyze electronic structures and linear and nonlinear optical properties. PMID- 22239155 TI - DNA computation: a photochemically controlled AND gate. AB - DNA computation is an emerging field that enables the assembly of complex circuits based on defined DNA logic gates. DNA-based logic gates have previously been operated through purely chemical means, controlling logic operations through DNA strands or other biomolecules. Although gates can operate through this manner, it limits temporal and spatial control of DNA-based logic operations. A photochemically controlled AND gate was developed through the incorporation of caged thymidine nucleotides into a DNA-based logic gate. By using light as the logic inputs, both spatial control and temporal control were achieved. In addition, design rules for light-regulated DNA logic gates were derived. A step response, which can be found in a controller, was demonstrated. Photochemical inputs close the gap between DNA computation and silicon-based electrical circuitry, since light waves can be directly converted into electrical output signals and vice versa. This connection is important for the further development of an interface between DNA logic gates and electronic devices, enabling the connection of biological systems with electrical circuits. PMID- 22239156 TI - IL28B rs12979860 polymorphism does not influence outcomes of hepatitis B virus infection. AB - rs12979860 in interleukin 28B (IL28B) gene is associated with response to interferon-alpha therapy and natural viral clearance in hepatitis C. The role of this polymorphism is less known in hepatitis B virus (HBV) infection. We evaluated whether rs12979860 was associated with outcomes of HBV infection. There were 651 individuals with persistent infection (387 with liver cirrhosis, 264 without cirrhosis) and 226 healthy individuals who recovered from HBV infection. The genotypic distributions were compared between different phenotypes pertaining to disease progression and HBV markers. The polymorphism had no association with clearance of hepatitis B surface antigen and hepatitis B e antigen, HBV-DNA level, apparent hepatitis onset and liver cirrhosis (P > 0.05). These results suggest that rs12979860 does not have such a strong effect in hepatitis B compared to hepatitis C. PMID- 22239159 TI - High resolution millimeter-wave spectroscopy of cyclopropylphosphine-borane. AB - The microwave spectrum of cyclopropylphosphine-borane, C(3)H(5)PH(2)-BH(3), has been investigated in the frequency range 150-195 GHz. The spectral assignment was supported by high level ab initio calculations. Two stable conformations have been predicted: the most stable antiperiplanar form and synclinal form that is higher in energy by 7.3 kJ/mol. In the observed spectra, only the most stable antiperiplanar (ap) form has been assigned. The analysis of the rotational spectra in the lowest excited vibrational states of the ap conformer has enabled determination of the potential function for the C-P torsional mode in the vicinity of equilibrium position. The barrier to internal rotation of the BH(3) top has been determined to be 9.616(15) kJ/mol and agrees well with quantum chemical calculations. PMID- 22239161 TI - In vitro and in vivo antitumor activity of a methanol extract of Dregea volubilis leaves with its antioxidant effect. AB - CONTEXT: In India, Dregea volubilis (L.f.) Benth. ex Hook.f. (Asclepediaceae), a large twining shrub with a woody vine, is used to treat tumors traditionally. OBJECTIVE: This study evaluated the in vitro and in vivo antitumor activity of the methanol extract of Dregea volubilis leaves (MEDV) and elucidated its possible mechanism of action. MATERIALS AND METHODS: In vitro antitumor activity of MEDV was evaluated against Ehrlich ascites carcinoma (EAC) cell-line. In vivo antitumor and antioxidant activity of MEDV at three dose levels (50, 100, and 200 mg/kg) were determined against EAC tumor-bearing mice. After 24 h of EAC inoculation, the extract was administered for 9 consecutive days. After the administration of the last dose on the 9th day followed by 18 h fasting, mice from all groups were sacrificed to determine antitumor activity and hematological profiles along with liver related biochemical parameters like lipid peroxidation, antioxidant enzymatic activity, etc. RESULTS: For in vitro antitumor activity, IC(50) value of MEDV for EAC tumor cells was 85.51 +/- 4.07 ug/ml. The MEDV showed a decrease in tumor volume, packed cell volume and viable cell count and an increase in the non-viable cell count of the EAC tumor-bearing mice (p < 0.001). Hematological profile reverted near to normal level in extract treated mice. MEDV decreased the hepatic lipid peroxidation level and enhanced superoxide dismutase and catalase level in tumor-bearing mice (p < 0.001). DISCUSSION AND CONCLUSION: MEDV exhibited in vitro and in vivo antitumor activity in EAC tumor bearing mice mediated through augmenting antioxidant defense system. PMID- 22239162 TI - A molecular mechanism for modulating plasma Zn speciation by fatty acids. AB - Albumin transports both fatty acids and zinc in plasma. Competitive binding studied by isothermal titration calorimetry revealed that physiologically relevant levels of fatty acids modulate the Zn-binding capacity of albumin, with far-reaching implications for biological zinc speciation. The molecular mechanism for this effect is likely due to a large conformational change elicited by fatty acid binding to a high-affinity interdomain site that disrupts at least one Zn site. Albumin may be a molecular device to "translate" certain aspects of the organismal energy state into global zinc signals. PMID- 22239163 TI - Prolonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation. AB - One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation. Prolonged CI was associated with anticipation of proteinuria onset and graft function deterioration (ischemia: 90d; no ischemia: 150d), more severe tubular atrophy, interstitial fibrosis, and glomerulosclerosis, and increased mortality rate (180d survival, ischemia: 0%; no ischemia: 67%). In ischemic allografts, T and B cells were detected very early and were organized in inflammatory clusters. Higher expression of BAFF-R and TACI within the ischemic allografts indicates that B cells are mature and activated. As a consequence of B cell activity, anti-donor antibodies, glomerular C4d and IgG deposition, important features of chronic humoral rejection, appeared earlier in ischemic than in non-ischemic allograft recipients. Thus, prolonged CI time plays a main role in CAI development by triggering acceleration of cellular and humoral reactions of chronic rejection. Limiting CI time should be considered as a main target in kidney transplantation. PMID- 22239164 TI - Two novel techniques to screen Abies seedlings for resistance to the balsam woolly adelgid, Adelges piceae. AB - Since its introduction into the Southern Appalachians in the 1950s, the balsam woolly adelgid, Adelges piceae Ratzeburg (Hemiptera: Adelgidae), has devastated native populations of Fraser fir, Abies fraseri (Pursh) Poir. (Pinales: Pinaceae), and has become a major pest in Christmas tree plantations requiring expensive chemical treatments. Adelges piceae-resistant Fraser fir trees would lessen costs for the Christmas tree industry and assist in the restoration of native stands. Resistance screening is an important step in this process. Here, four studies directed toward the development of time- and cost-efficient techniques for screening are reported. In the first study, three methods to artificially infest seedlings of different ages were evaluated in a shade-covered greenhouse. Two-year-old seedlings had much lower infestation levels than 7 year old seedlings. Placing infested bark at the base of the seedling was less effective than tying infested bark to the seedling or suspending infested bolts above the seedling. Although the two latter techniques resulted in similar densities on the seedlings, they each have positive and negative considerations. Attaching bark to uninfested trees is effective, but very time consuming. The suspended bolt method mimics natural infestation and is more economical than attaching bark, but care must be taken to ensure an even distribution of crawlers falling onto the seedlings. The second study focused on the density and distribution of crawlers falling from suspended bolts onto paper gridded into 7.6 * 7.6 cm cells. Crawler density in a 30 cm band under and to each side of the suspended bolt ranged from 400 to over 3000 crawlers per cell (1 to 55 crawlers per cm2). In the third study, excised branches from 4 year-old A. fraseri and A. vetchii seedlings were artificially infested with A. piceae to determine whether this technique may be useful for early resistance screening. The excised A. fraseri branches supported complete adelgid development (crawler to egg-laying adult), and very little adelgid development occurred on A. vetchii branches. The fourth study compared infestation levels and gouting response on excised versus intact branches of 4 year-old A. fraseri seedlings from three different seed sources, and excised branches from 4 year-old and 25 year-old trees. There were no differences in infestation levels between excised versus intact branches nor in very young versus mature trees; gouting response was observed only on intact branches. PMID- 22239165 TI - Differences in clinical reasoning among nurses working in highly specialised paediatric care. AB - AIMS AND OBJECTIVES: The aim of the study was to examine differences in clinical reasoning among novice, experienced and specialist paediatric nurses. BACKGROUND: Highly specialised paediatric care requires specific knowledge and ongoing skill performance of the nurses employed. There is a lack of research in how paediatric nurses manage the daily care problems they encounter and how they acquire the skills required to give patients the best possible care. More knowledge is needed about how paediatric nurses with different experience and education reason and communicate about paediatric patient situations. DESIGN: The study was based on six recorded group discussions of a fictitious, but realistic paediatric case. Three categories of nurses: novices (n = 7), experienced (n = 7) and specialists (n = 7) from a paediatric hospital participated. A qualitative content analysis approach was chosen to examine differences in clinical reasoning. RESULTS: Several themes were uncovered: child's social situation, child abuse and the child's illness, qualitative differences emerged in how the nurses discussed the case. Three approaches were identified: a task-oriented approach (novices and experienced), an action-oriented approach (novices and experienced) and hypothesis-oriented approach (specialists) while discussing the case. CONCLUSION: When comparing nurses in three competence groups, it was established that the groups with extensive experience and specialist education reasoned differently than the other groups. Between the novice and experienced groups, no obvious differences were found. Thus, the importance of experience alone for the development of competence is still an open question. Experience combined with further education appears important for developing professional competence in paediatric care. RELEVANCE TO CLINICAL PRACTICE: Nurses' reasoning in clinical paediatric care is related to experience and training. PMID- 22239166 TI - Designed for deconstruction--poplar trees altered in cell wall lignification improve the efficacy of bioethanol production. AB - * There is a pressing global need to reduce the increasing societal reliance on petroleum and to develop a bio-based economy. At the forefront is the need to establish a sustainable, renewable, alternative energy sector. This includes liquid transportation fuel derived from lignocellulosic plant materials. However, one of the current limiting factors restricting the effective and efficient conversion of lignocellulosic residues is the recalcitrance of the substrate to enzymatic conversion. * In an attempt to assess the impact of cell wall lignin on recalcitrance, we subjected poplar trees engineered with altered lignin content and composition to two potential industrial pretreatment regimes, and evaluated the overall efficacy of the bioconversion to ethanol process. * It was apparent that total lignin content has a greater impact than monomer ratio (syringyl : guaiacyl) on both pretreatments. More importantly, low lignin plants showed as much as a 15% improvement in the efficiency of conversion, with near complete hydrolysis of the cellulosic polymer. * Using genomic tools to breed or select for modifications in key cell wall chemical and/or ultrastructural traits can have a profound effect on bioenergy processing. These techniques may therefore offer means to overcome the current obstacles that underpin the recalcitrance of lignocellulosic substrates to bioconversion. PMID- 22239167 TI - Multitemplates for the hierarchical synthesis of diverse inorganic materials. AB - Described here is a new and highly general strategy for multiple-template (multitemplate) patterning. This process is significant because it allows us to create various unusual shapes such as solid spheres, yolk-shell spheres, flowerlike particles, and structured nanocomponents. Alcoholysis of the metal organic precursors with mixtures of glycerol and various amounts of ethanol followed by calcination yields oxides. The glycerol plays the dual role of hierarchically assembling the metal-organic composites and stabilizing the structures during the subsequent conversions. Furthermore, we demonstrate for the first time that these metal-organic composites can be converted into oxides, nitrides, and highly graphitized carbon nanostructures. We show that these yolk shell structures display superior photocatalytic activity and electrochemical properties. PMID- 22239168 TI - Prospects for tertiary structure prediction of RNA based on secondary structure information. AB - We developed a method, called RNA Assembler using Secondary Structure Information Effectively (RASSIE), for predicting RNA tertiary structures using known secondary structure information. We attempted a fragment assembly-based method that uses a secondary structure-based fragment library. For several typical target structures such as stem-loops, bulge-loops, and 2-way junctions, our method provided numerous good quality candidate structures in less computational time than previously proposed methods. By using a high-resolution potential energy function, we were able to select good predicted structures from candidate structures. This method of efficient conformational search and detailed structure evaluation using high-resolution potential is potentially useful for the tertiary structure prediction of RNA. PMID- 22239169 TI - Nonintercalating nanosubstrates create asymmetry between bilayer leaflets. AB - The physical properties of lipid bilayers can be remodeled by a variety of environmental factors. Here we investigate using molecular dynamics simulations the specific effects of nanoscopic substrates or external contact points on lipid membranes. We expose palmitoyl-oleoyl phosphatidylcholine bilayers unilaterally and separately to various model nanosized substrates differing in surface hydroxyl densities. We find that a surface hydroxyl density as low as 10% is sufficient to keep the bilayer juxtaposed to the substrate. The bilayer interacts with the substrate indirectly through multiple layers of water molecules; however, despite such buffered interaction, the bilayers exhibit certain properties different from unsupported bilayers. The substrates modify transverse lipid fluctuations, charge density profiles, and lipid diffusion rates, although differently in the two leaflets, which creates an asymmetry between bilayer leaflets. Other properties that include lipid cross-sectional areas, component volumes, and order parameters are minimally affected. The extent of asymmetry that we observe between bilayer leaflets is well beyond what has been reported for bilayers adsorbed on infinite solid supports. This is perhaps because the bilayers are much closer to our nanosized finite supports than to infinite solid supports, resulting in a stronger support-bilayer electrostatic coupling. The exposure of membranes to nanoscopic contact points, therefore, cannot be considered as a simple linear interpolation between unsupported membranes and membranes supported on infinite supports. In the biological context, this suggests that the exposure of membranes to nonintercalating proteins, such as those belonging to the cytoskeleton, should not always be considered as passive nonconsequential interactions. PMID- 22239170 TI - Demand for and utilization of dental services according to household income in the adult population in Norway. AB - OBJECTIVES: The aim of this study was to describe the effect of income on demand and utilization of dental services according to household income in the adult population. METHODS: The data were collected using a questionnaire, which was sent to a random sample of Norwegians aged 20 years or older living at home, 1861 persons in total. Demand was measured according to whether the person had been to the dentist during the last year. Utilization was measured as expenditure for dental treatment for those who had been to the dentist during the last year. The independent variables were the respondents' household income, age, gender, education, dental status and the mean fee for a dental consultation in the municipality. In the first stage, we carried out a logistic regression analysis of the log odds of having demanded dental services during the last year. In the second stage, we carried out a multiple regression analysis of expenditure for dental treatment for those who had been to the dentist during the last year. RESULTS: Altogether, 80% of the respondents had been to the dentist during the last year. Demand during the last year varied most according to dental status. There was little difference between men and women. The results of the logistic regression showed that the probability of having been to the dentist was 0.82 for those with a household income of ?25 000 and 0.85 for those with a household income of ?100 000. Mean expenditure for dental treatment was ?355. There was no statistically significant relationship between household income and expenditure for dental treatment. CONCLUSIONS: Differences in demand for dental services according to household income are small, and there are no differences in utilization according to income. The findings are interesting, because in a population in which people have to pay almost all the costs for dental treatment themselves, one would expect the income differences in demand and utilization to be greater. PMID- 22239171 TI - Prediction of remarkable ambipolar charge-transport characteristics in organic mixed-stack charge-transfer crystals. AB - We have used density functional theory calculations and mixed quantum/classical dynamics simulations to study the electronic structure and charge-transport properties of three representative mixed-stack charge-transfer crystals, DBTTF TCNQ, DMQtT-F(4)TCNQ, and STB-F(4)TCNQ. The compounds are characterized by very small effective masses and modest electron-phonon couplings for both holes and electrons. The hole and electron transport characteristics are found to be very similar along the stacking directions; for example, in the DMQtT-F(4)TCNQ crystal, the hole and electron effective masses are as small as 0.20 and 0.26 m(0), respectively. This similarity arises from the fact that the electronic couplings of both hole and electron are controlled by the same superexchange mechanism. Remarkable ambipolar charge-transport properties are predicted for all three crystals. Our calculations thus provide strong indications that mixed-stack donor-acceptor materials represent a class of systems with high potential in organic electronics. PMID- 22239172 TI - Diclavatol and tetronic acids from Penicillium griseoroseum. AB - In our continuous studies on the chemistry of the endophytic fungus Penicillium griseoroseum, an endophyte isolated from fruits of Coffea arabica, we isolated clavatol, a dimethylated tetraketide, and its dimer which appears to be a novel natural compound. The studies also resulted in the identification of two known tetronic acids, viridicatic acid and terrestric acid, found in ethyl acetate and n-butanol extracts. Spectroscopic studies using 1-D and 2-D NMR and MS/MS analysis were performed to determine the structures of these compounds, first reported by this Penicillium. Two other tetronic acids congeners were identified through HPLC/MS/MS studies, based on fragmentation pattern of ions produced from ionised tetronic acids, and UV light absorptions. PMID- 22239173 TI - Uveodermatologic lymphoma in two young related Portuguese water dogs. AB - PURPOSE: Canine lymphoma (CL) is one of the most common forms of spontaneous canine neoplasia. Improved understanding of the genetic and environmental factors associated with CL may provide benefits for the study of non-Hodgkin's and Hodgkin's lymphoma in humans. Uveodermatologic lymphoma is reported in a single household of Portuguese water dog, and the etiology is discussed. METHODS: A 1 year-old female intact Portuguese water dog was referred to the Ophthalmology Service of the Veterinary Teaching Hospital of the Autonomous University of Barcelona because of acute blepharospasm of the right eye in association with a multinodular dermatosis. Physical and ophthalmological examination and a complete diagnostic work-up, including skin and ocular histopathology and immunohistochemistry, were performed. Three months prior, in Galicia (Spain), 1200 km away from Barcelona, a male dog of the same litter showed very similar oculodermatological clinical signs and skin histopathology, and immunohistochemistry were obtained. RESULTS: The clinical diagnoses were anterior exudative uveitis, iridal masses, and secondary glaucoma. Histopathology and immunohistochemistry revealed a nonepitheliotropic lymphoma rich in B cell in dog 1 and rich in T cell in dog 2. CONCLUSION: It is proposed that an underlying genetic predisposition could have played a role in the development of lymphoma in these two young related dogs. PMID- 22239174 TI - A crosstalk between bone and gonads. AB - The sex steroid hormones testosterone and estrogen are essential determinants not only of reproductive functions but also for bone growth and the maintenance of skeletal integrity. The importance of this latter form of regulation is best exemplified by the fact that gonadal failure triggers bone loss in both genders and causes osteoporosis in postmenauposal women. Traditionally, bone physiology is studied with the view that the skeleton is simply a recipient of hormonal inputs. However, a richer picture of bone physiology has recently emerged, and it is now clear that the skeleton is an endocrine organ itself. This is particularly relevant to the interplay between bone and gonads because genetics and biochemical evidence have established that bone, via the osteoblast-derived hormone osteocalcin, promotes testosterone biosynthesis. This review will present the mechanism of action of osteocalcin and will discuss the implications of this novel regulation. PMID- 22239175 TI - Attitudes toward genetic diagnosis and prenatal diagnosis of X-linked Alport syndrome in China. AB - AIM: Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant AS (XLAS) is the predominant inheritance form caused by mutations in COL4A5 gene. Attitudes toward genetic diagnosis and prenatal diagnosis for Chinese AS families were investigated. Attitudes toward genetic diagnosis and prenatal diagnosis in Chinese XLAS families were evaluated in the current study. METHODS: A total of 160 XLAS patients and their 126 healthy family members in China were interviewed. After providing background knowledge counselling and education on AS, their attitudes toward genetic diagnosis and prenatal diagnosis were evaluated by multiple-choice questionnaire. RESULTS: Majority of the respondents cared mostly about the prognosis and treatment effects of AS (89.9% vs 81.1%) since they considered that the worst outcome of XALS was renal insufficiency (92.3%). Of all the interviewees, 99.3% were interested in genetic research for the discovery of better treatments and more appropriate diagnostic tools (positive attitudes) (89.5% vs 73.2%). About 80% of the participants would accept prenatal testing and subsequent termination of pregnancy in cases of affected foetuses (boys: 86.8% and girls: 74.6%, respectively). CONCLUSION: Most Chinese XLAS families show positive attitudes and desire new discoveries in treatment and diagnosis. About 80% of respondents would approve prenatal testing with a desire for selective termination of pregnancy rather than predicting the health of a future child. PMID- 22239177 TI - Investigation of the factor structure of spirituality and religiosity in Iranian Shiite university students. AB - One of the important challenges facing psychologists of religion pertains to the definition of religiosity and spirituality. One way of understanding the connection between these two concepts is to suppose that one of them is a subset of the other. Another useful and sensitive way, however, is to view spirituality and religiosity as overlapping constructs, sharing some characteristics but also retaining nonshared features. Empirical studies examining the factor structure of spirituality and religiosity are scant and almost all of them come from Western culture. These factor analytic studies generally confirm that religiosity and spirituality can best be described in terms of two distinct yet correlated factors. To date, no study has investigated the relationship between these two constructs in Islamic cultures. To redress this imbalance, confirmatory factor analysis was used to examine the factor structure of religiosity and spirituality in two Iranian Shiite samples using an extensive set of scales (including Santa Clara Strength of Religious Faith, Spiritual Involvement and Beliefs Scale - Revised, Spiritual Meaning Scale, and Spiritual Transcendence Scale). Two hypothetical models were tested: a model that viewed spirituality and religiosity as correlated but separate constructs and a model that combined the indicators of religiosity and spirituality into a single construct. In keeping with the results obtained in Western cultures, results of confirmatory factor analyses, conducted in Study 1 (N=225) and Study 2 (N=288), revealed that a two-factor model fitted the data better than a single-factor model. Implications of the results are discussed, as are study limitations and directions for further research. PMID- 22239178 TI - Novel targeted therapies in head and neck cancer. AB - INTRODUCTION: Molecularly targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. AREAS COVERED: Targeted agents for HNSCC expected to improve the effectiveness of current therapy including HER family, Src-family kinase, cell cycle, MET, AKT, HDAC, PARP, COX inhibitors and antiangiogenesis. EXPERT OPINION: Epidermal growth factor receptor inhibitors are established in HNSCC and the need now is to find biomarkers for sensitivity to better select patients. Moreover, other pathway inhibitors hold significant promise and are being tested in clinical trials. Angiogenesis inhibition is likely to yield only modest efficacy alone but may augment existing standards. Lastly, one clinical arena where targeted therapies may find secure purchase is in the adjuvant or prevention setting where minimal or preneoplastic disease can be affected by inhibition of a single or few targets. PMID- 22239179 TI - Testing the effectiveness of community-based dengue vector control interventions using semiparametric mixed models. AB - OBJECTIVE: To evaluate the results obtained though intersectoral coordination and community empowerment in one study carried out during 6 years in Playa Municipality, Cuba. METHODS: A longitudinal assessment comparing one intervention and one control area was conducted. The intervention encompasses two main stages separated by two dengue outbreaks. The first stage, focused on strengthening intersectoral coordination, was initiated in January 2000. In August 2003, a complementary strategy, focused on community empowerment and was initiated in half of the intervention area. In the control area, routine dengue control activities continued without additional input. We used entomologic surveillance data from January 1999 to December 2005 to assess the effectiveness. We computed the Breteau index (BI) per health area and the 95% confidence interval for the difference between the BIs at each time point. A semiparametric mixed model to capture the evolution in time of Aedes aegypti larval densities was fitted. RESULTS: The BI in the control area showed the lowest value before starting the intervention. This was reversed 1 year after launching intersectoral activities for dengue control in the intervention area. In spite of spraying actions in all areas, the differences in BI between intervention and control areas remain significant until December 2002. Although for the next 2 years no differences were observed, they become significant again in December 2004, which corresponds with the implementation of the complementary community-based vector control strategy in the intervention area. CONCLUSIONS: The model fitted identified monotonous trends over time and reversal trends at particular moments. The confidence bands indicate sections with significant differences between areas. Our data increase the evidence that the intersectoral coordination and community empowerment strategy for A. aegypti control is effective. PMID- 22239182 TI - Recurrent ischemic colitis in a young female with the prothrombin G20210A mutation. PMID- 22239180 TI - Prevalence of Coxiella burnetii antibodies among febrile patients in Croatia, 2008-2010. AB - Despite the widespread distribution of Q fever, the prevalence in humans is not accurately known, because many infected people seroconvert without symptoms or with a mild febrile disease. The aim of this study was to determine the seroprevalence of Q fever in different regions of Croatia. During a 2-year period (2008-2010), serum samples from 552 febrile patients with prolonged cough aged 1 88 were tested for the presence of Coxiella burnetii antibodies by using indirect immunofluorescent assay. Sera from 27.5% patients showed IgG antibodies. Serological evidence of C. burnetii infection was found in patients from all parts of Croatia. Seroprevalence rates significantly differed among regions from 21.5% to 41.2% (p=0.001). Men were more often seropositive (31.6%) than women (22.2%; p=0.016). According to age, a progressive increase in the IgG seropositivity rates was observed as ranging from 6.7% in children less than 10 years of age to 39.2% in patients aged 40-49 (p=0.001). Above the age of 50, the IgG seroprevalence remained stable. Patients from rural areas were more often seropositive than patients from urban areas (40.8% vs. 19%), p<0.001). Acute Q fever was confirmed in 5.8% of patients. Cases occurred throughout the year. A majority of cases were reported during summer months. PMID- 22239185 TI - Pitfalls in the preoperative diagnosis of bilateral cerebellar infarction. PMID- 22239184 TI - Danazol induces prolonged survival of fully allogeneic cardiac grafts and maintains the generation of regulatory CD4(+) cells in mice. AB - Danazol, a derivative of testosterone, is useful for treatment of endometriosis as well as pretreatment for in vitro fertilization and embryo transfer, although its mechanisms of action are unclear. The aim of this study was to investigate the effect of danazol on alloimmune responses in murine heart transplantation. CBA male mice (H2(k) ) underwent transplantation of C57BL/6 male (H2(b) ) hearts and received a single dose of danazol (0.4, 1.2 or 4mg/kg/day) by intraperitoneal injection on the day of transplantation and for 6days thereafter. An adoptive transfer study was performed to determine whether regulatory cells were generated. The median survival time (MST) of allografts in danazol-treated (1.2 and 4mg/kg/day) mice was 28 and 63days, respectively, compared with 7days in untreated mice. Moreover, secondary CBA recipients given whole splenocytes or CD4(+) cells from primary danazol-treated (4mg/kg/day) CBA recipients 30days after transplantation had prolonged allograft survival (MSTs, 29 and 60days, respectively). Cell proliferation, interleukin (IL)-2 and interferon-gamma were suppressed in danazol-treated mice, whereas IL-4 and IL-10 were up-regulated. Moreover, danazol directly suppressed allo-proliferation in a mixed leukocyte culture. Flow cytometry showed an increased CD4(+) CD25(+) Foxp3(+) cell population in splenocytes from danazol-treated mice. Danazol prolongs cardiac allograft survival and generates regulatory CD4(+) cells. PMID- 22239186 TI - Wedding ambient aerosol sampling inlet for an intermediate flow rate (4 cfm) sampler. PMID- 22239187 TI - Abastumani forest aerosol experiment (1979): comparison to other nonurban halocarbons and nitrous oxide measurements. PMID- 22239188 TI - Ambient concentrations of hydrocarbons from conifers in atmospheric gases and aerosol particles measured in Soviet Georgia. PMID- 22239189 TI - Factors affecting the accuracy of quantitative measurement of priority pollutants using GCMS. PMID- 22239190 TI - Evidence of an additive effect for ozone plumes from small cities. PMID- 22239192 TI - Application of Van Krevelen's graphical-statistical method for the study of aquatic humic material. PMID- 22239191 TI - Resazurin reduction method for activated sludge process control. PMID- 22239193 TI - Design and performance of miniature cyclones for respirable aerosol sampling. PMID- 22239194 TI - High-level radioactive waste from fusion reactors. PMID- 22239195 TI - Chemical analysis of acid precipitation: pH and acidity determinations. PMID- 22239196 TI - Surface enrichment of trace elements in electric steel furnace dust. PMID- 22239197 TI - Practical method for determination of total cyanide in metal-containing waste waters. PMID- 22239198 TI - Comment on "Distribution of selected gaseous organic mutagens and suspect carcinogens in ambient air". PMID- 22239199 TI - Reply to comment on "Distributions of selected gaseous organic mutagens and suspect carcinogens in ambient air". PMID- 22239201 TI - Enhanced stability of Cu-BTC MOF via perfluorohexane plasma-enhanced chemical vapor deposition. AB - Metal organic frameworks (MOFs) are a leading class of porous materials for a wide variety of applications, but many of them have been shown to be unstable toward water. Cu-BTC (1,3,5 benzenetricarboxylic acid, BTC) was treated with a plasma-enhanced chemical vapor deposition (PECVD) of perfluorohexane creating a hydrophobic form of Cu-BTC. It was found that the treated Cu-BTC could withstand high humidity and even submersion in water much better than unperturbed Cu-BTC. Through Monte Carlo simulations it was found that perfluorohexane sites itself in such a way within Cu-BTC as to prevent the formation of water clusters, hence preventing the decomposition of Cu-BTC by water. This PECVD of perfluorohexane could be exploited to widen the scope of practical applications of Cu-BTC and other MOFs. PMID- 22239204 TI - Provisioning mass by females of the maritime earwig, Anisolabis maritima, is not adjusted based on the number of young. AB - The amount of parental provisioning is thought to reflect the need of offspring. This hypothesis was tested in the case of provisioning food mass to young with controlled clutch size using the maritime earwig, Anisolabis maritima Bonelli (Dermaptera: Anisolabididae). The female provisioned a constant mass of food to the young irrespective of the number of nymphs and the distance of food carrying. In addition, the survival rate of young did not change with adjusted clutch size. This study showed that A. maritima females appear to provide food mass to their nymphs independent of their number. PMID- 22239205 TI - The impact of nurse short message services and telephone follow-ups on diabetic adherence: which one is more effective? AB - AIM: To compare the effectiveness of two methods of follow-up: short message service and telephone follow-up on type 2 diabetes adherence for three months. BACKGROUND: Using telemedicine approaches may preserve appropriate blood glucose levels and may improve adherence to diabetes control recommendations in diabetic patients. DESIGN: A quasi-experimental, two-group, pretest and post-test design was used in this study to evaluate the effectiveness of nurse's follow-up via cellular phones and telephones. METHODS: The sample consisted of 77 patients with type 2 diabetes that randomly were assigned to two groups: telephone follow-up (n = 39) and short message service (n = 38). Telephone interventions were applied by a researcher for three months; twice a week for the first month and every week for the second and third month. For three successive months, the short message service group that received messages about adherence to therapeutic regimen was examined. The data gathering instrument included data sheets - to record glycosylated haemoglobin - and the questionnaire related to adherence therapeutic regimen. Data gathering was carried out at the beginning of the study and after three and six months. The data were analysed using descriptive and inferential statistic methods with SPSS version 11.5. RESULTS: Results showed that both interventions had significant mean changes in glycosylated haemoglobin. For the telephone group (p < 0.001), a mean change of -0.93 and for the short message service group (p < 0.001), a mean change of -1.01. There was no significant difference in diet adherence (p = 0.000), physical exercise (p = 0.000) and medication taking (p = 0.000) adherence in either groups. CONCLUSION: Intervention using short message services of cellular phones and nurse-led telephone follow-up improved HbA1c levels and adherence to diabetes therapeutic regimen for three months in type 2 diabetic patients. RELEVANCE TO CLINICAL PRACTICE: Both of follow-up intervention uses in this study can decrease HbA1c levels and escalate adherence to diabetes control recommendations in people with type 2 diabetes for three months. PMID- 22239203 TI - Bacterial iron-sulfur regulatory proteins as biological sensor-switches. AB - SIGNIFICANCE: In recent years, bacterial iron-sulfur cluster proteins that function as regulators of gene transcription have emerged as a major new group. In all cases, the cluster acts as a sensor of the environment and enables the organism to adapt to the prevailing conditions. This can range from mounting a response to oxidative or nitrosative stress to switching between anaerobic and aerobic respiratory pathways. The sensitivity of these ancient cofactors to small molecule reactive oxygen and nitrogen species, in particular, makes them ideally suited to function as sensors. RECENT ADVANCES: An important challenge is to obtain mechanistic and structural information about how these regulators function and, in particular, how the chemistry occurring at the cluster drives the subsequent regulatory response. For several regulators, including FNR, SoxR, NsrR, IscR, and Wbl proteins, major advances in understanding have been gained recently and these are reviewed here. CRITICAL ISSUES: A common theme emerging from these studies is that the sensitivity and specificity of the cluster of each regulatory protein must be exquisitely controlled by the protein environment of the cluster. FUTURE DIRECTIONS: A major future challenge is to determine, for a range of regulators, the key factors for achieving control of sensitivity/specificity. Such information will lead, eventually, to a system understanding of stress response, which often involves more than one regulator. PMID- 22239207 TI - Red blood cell alloimmunization in sickle cell anemia: more questions than answers? PMID- 22239208 TI - Predicting the quality of transplantable cord blood collections through prefreeze and postthaw Apgar scoring. PMID- 22239209 TI - The scientific method at work: xenotropic murine leukemia virus-related virus is neither a cause of chronic fatigue syndrome nor a threat to the blood supply. PMID- 22239210 TI - Transfusion medicine history illustrated. Both expressions of blood donors. PMID- 22239214 TI - Maternal ABO isohemagglutinins in infant circulation. PMID- 22239212 TI - Development and application of a high-throughput microneutralization assay: lack of xenotropic murine leukemia virus-related virus and/or murine leukemia virus detection in blood donors. AB - BACKGROUND: Xenotropic murine leukemia virus (MLV)-related virus (XMRV) and other related MLVs have been described with chronic fatigue syndrome and certain types of prostate cancer. In addition, prevalence rates as high as 7% have been reported in blood donors, raising the risk of transfusion-related transmission. Several laboratories have utilized microneutralization assays as a surrogate marker for detection of anti-MLV serologic responses--with up to 25% of prostate cancer patients reported to harbor neutralizing antibody responses. STUDY DESIGN AND METHODS: We developed a high-throughput microneutralization assay for research studies on blood donors using retroviral vectors pseudotyped with XMRV specific envelopes. Infection with these pseudotypes was neutralized by sera from both macaques and mice challenged with XMRV, but not preimmune serum. A total of 354 plasma samples from blood donors in the Reno/Tahoe area were screened for neutralization. RESULTS: A total of 6.5% of donor samples gave moderate neutralization of XMRV, but not control pseudotypes. However, further testing by Western blot revealed no evidence of antibodies against MLVs in any of these samples. Furthermore, no evidence of infectious virus or viral nucleic acid was observed. CONCLUSION: A microneutralization assay was developed for detection of XMRV and can be applied in a high-throughput format for large-scale studies. Although a proportion of blood donors demonstrated the ability to block XMRV envelope-mediated infection, we found no evidence that this inhibition was mediated by specific antibodies elicited by exposure to XMRV or MLV. It is likely that this moderate neutralization is mediated through another, nonspecific mechanism. PMID- 22239216 TI - The season for new beginnings. PMID- 22239215 TI - Recommendations for transfusion in ABO-incompatible hematopoietic stem cell transplantation. PMID- 22239220 TI - Entropic and electrostatic effects on the folding free energy of a surface attached biomolecule: an experimental and theoretical study. AB - Surface-tethered biomolecules play key roles in many biological processes and biotechnologies. However, while the physical consequences of such surface attachment have seen significant theoretical study, to date this issue has seen relatively little experimental investigation. In response we present here a quantitative experimental and theoretical study of the extent to which attachment to a charged-but otherwise apparently inert-surface alters the folding free energy of a simple biomolecule. Specifically, we have measured the folding free energy of a DNA stem loop both in solution and when site-specifically attached to a negatively charged, hydroxylalkane-coated gold surface. We find that whereas surface attachment is destabilizing at low ionic strength, it becomes stabilizing at ionic strengths above ~130 mM. This behavior presumably reflects two competing mechanisms: excluded volume effects, which stabilize the folded conformation by reducing the entropy of the unfolded state, and electrostatics, which, at lower ionic strengths, destabilizes the more compact folded state via repulsion from the negatively charged surface. To test this hypothesis, we have employed existing theories of the electrostatics of surface-bound polyelectrolytes and the entropy of surface-bound polymers to model both effects. Despite lacking any fitted parameters, these theoretical models quantitatively fit our experimental results, suggesting that, for this system, current knowledge of both surface electrostatics and excluded volume effects is reasonably complete and accurate. PMID- 22239222 TI - Delta-lactam derivative from thermophilic soil fungus exhibits in vitro anti allergic activity. AB - From cultures of thermophilic soil fungus Humicola grisea var thermoidea, a delta lactam derivative (3-(2-(4-hydroxyphenyl)-2-oxoethyl)-5,6-dihydropyridin-2(1H) one) that displayed anti-allergic activity was isolated, which was predicted by in silico computational chemistry approaches. The in vitro anti-allergic activity was investigated by beta-hexosaminidase release assay in rat basophilic leukaemia RBL-2H3 cells. The delta-lactam derivative exhibited similar anti-allergic activity (IC(50) = 18.7 +/- 6.7 uM) in comparison with ketotifen fumarate (IC(50) = 15.0 +/- 1.3 uM) and stronger anti-allergic activity than azelastine (IC(50) = 32.0 uM). Also, the MTT cytotoxicity assay with RBL-2H3 cells showed that delta lactam does not display cytotoxicity at concentrations lower than 50 uM. This study suggests that the delta-lactam derivative has the potential to be used as a lead compound in the development of anti-allergic drugs for clinical use in humans. PMID- 22239223 TI - 4D Brachytherapy, a novel real-time prostate brachytherapy technique using stranded and loose seeds. AB - What's known on the subject? and What does the study add? There are a number of techniques used successfully to perform brachytherapy, including 2-stage procedures and realtime techniques using loose seeds. This study demonstrates a one-stage realtime brachytherapy technique using stranded seeds with improved time efficiency and clinical outcome: 4D Brachytherapy. This paper reviews the development of a new one-stage prostate brachytherapy technique (4D Brachytherapy) using a combination of stranded and loose seeds. This novel technique utilizes a nomogram constructed from over 1000 procedures to calculate the seed requirement in advance of the implant. This allows stranded seeds to be pre-ordered and loaded prior to the procedure rather than per-operatively, resulting in a more efficient use of operating room time. The use of both stranded and loose seeds may reduce the risk of migration from peripherally placed seeds via the venous plexus, whilst maintaining the flexibility to optimize the dose within the prostate and especially at the apex of the gland. Prospectively collected data show significantly improved dosimetry: median D(90) 143 and 153 Gy (P < 0.005) and median V(100) 88% and 93% (P < 0.005) for the Seattle technique and 4D Brachytherapy implant technique, respectively. Also there was a reduced short-term urinary morbidity as assessed by the change in International Prostate Symptom Score (IPSS) at 3 months and 1 year compared with the Seattle technique. Mean (sd) change in IPSS from baseline at 1 year was 2.73 (5.92) and 0.97 (5.10) for the Seattle and 4D Brachytherapy series, respectively (P < 0.049). PMID- 22239221 TI - Rational approaches to improving selectivity in drug design. PMID- 22239224 TI - Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer. AB - What's known on the subject? and What does the study add? Whole gland brachytherapy has been used to successfully treat prostate cancer but the protocol for focal therapy has not previously been established. The consensus findings provide guidance on patient selection for focal brachytherapy as well as recommendations for conducting therapy and patient follow-up. Low dose rate prostate brachytherapy is an effective treatment for localized prostate cancer. Recently, it has been considered for use in a focused manner whereby treatment is targeted only to areas of prostate cancer. The objective of focal brachytherapy is to provide effective cancer control for low-risk disease but with reduced genitourinary and rectal side-effects in a cost-effective way. We report on the outputs of a consensus meeting of international experts in brachytherapy and focal therapy convened to consider the feasibility and potential development of focal brachytherapy. A number of factors were considered for focal brachytherapy including optimal patient selection, disease characterization and localization, treatment protocols and outcome measures. The consensus meeting also addressed the design of a clinical trial that would assess the oncological outcomes and side-effect profiles resulting from focal brachytherapy. PMID- 22239225 TI - Brachytherapy for the treatment of recurrent prostate cancer after radiotherapy or radical prostatectomy. AB - What's known on the subject? and What does the study add? The curative treatment of prostate cancer includes surgery, external beam radiation or interstitial radiation. However, a high percentage of patients may develop recurrent disease, which is often localised. The possibilities of treatment in these cases, including surgery or adjuvant radiotherapy, are not well defined. Brachytherapy is a well established first-line treatment option. We review and update the use of brachytherapy in the treatment of recurrences post-radiotherapy, brachytherapy or radical prostatectomy as an alternative to surgery and radiotherapy, with a focus on functional and oncological outcomes. Salvage therapeutic options following radical prostatectomy or radiotherapy for patients with local relapse of prostate cancer include radical prostatectomy, radiotherapy, brachytherapy or cryotherapy. Salvage radical prostatectomy following radiotherapy failure is associated with a 5-year PSA relapse-free rate of 30-40%. Biochemical relapse free survival rates after salvage radiotherapy following radical prostatectomy failure range from 10% to 77% after a follow-up of 22-60 months. A number of studies have evaluated salvage brachytherapy for radiotherapy failure and 5-year biochemical disease-free survival (bDFS) rate results reported are of the order of 20-87%; one study reported a 10-year bDFS rate of 54%. Fewer studies in small numbers of patients and with shorter follow-up have been conducted on brachytherapy for radical prostatectomy failure and bDFS rates reported include 25.8% at a median of 29 months to 70% at a median of 20 months. The side-effects were as expected for brachytherapy. A newer initiative conducted in Spain in a larger series of 42 patients with failure following radical prostatectomy involves brachytherapy with RAPID StrandTM(125) I seeds and real-time placement. The 5-year bDFS rate was 88.6% and cancer-specific survival was 97%; complication rates were low. Optimization of salvage brachytherapy is under way and involves accurate placement of seeds, dose optimization and optimal patient selection. PMID- 22239227 TI - Contemporary practice, however, bears little resemblance to those fi rst treated cases. Foreword. PMID- 22239226 TI - Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. AB - What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer. PMID- 22239228 TI - Zeolite synthesis in fluoride media: structure direction toward ITW by small methylimidazolium cations. AB - Pure silica ITW zeolite can be synthesized using 1,2,3-trimethylimidazolium and 1,3-dimethylimidazolium cations and fluoride anions as structure-directing agents (SDAs). Similarly to the previously reported 1,3,4-trimethylimidazolium, the dimethyl cation can also produce the zeolite TON, but this higher framework density phase finally transforms in situ into ITW. The structures of the as-made and calcined phases prepared with the new cations show a unit cell doubling along z, and the refined structures are reported. Periodic Density Functional Theory calculations provide the energies of the six SDA-ITW and SDA-TON zeolites, and their relative stabilities fully agree with the experimental observations. Structure-direction in this system is discussed from experimental and theoretical results that give strong support to the idea that strained silica frameworks are made possible in fluoride media by decreasing the covalent character of the Si-O bond. This decreased covalency is enhanced with the 1,2,3-trimethyl isomer, which is shown to be the strongest SDA for ITW and, at the same time, is the more hydrophilic of the three SDAs tested. Our observations with the three SDAs agree with the so-called Villaescusa's rule, i.e., the low framework density phase is favored at higher concentrations, but at the same time question the supersaturation hypothesis that has been proposed to explain this rule, since here the low-density phase is the most stable one. PMID- 22239229 TI - Emerging topics in epigenetics: ants, brains, and noncoding RNAs. AB - One of the greatest wonders in biology is the high degree of molecular organization and complexity achieved by multicellular life forms, which are typically composed by hundreds of cell types, each with a unique identity and function and all sharing the same genome. Long-term maintenance of these distinct cell identities requires epigenetic signals, molecular signatures that regulate gene expression and can be inherited during cell division. Some epigenetic signals also appear to have an intimate connection with brain function, with important implications for neuroscience and medicine. To better understand these phenomena, new technologies must be developed and nonconventional model organisms should be studied. For example, the genomes of eusocial insects, such as ants and honeybees, specify drastically different morphologies (polyphenism) and behaviors (polyethism) that yield adult individuals belonging to different castes, which carry out separate functions inside the colony. These sharp epigenetic differences present unique opportunities for the experimental dissection of molecular pathways that may be conserved in other organisms, including humans. PMID- 22239231 TI - The role of self-esteem in the misinformation effect. AB - Previous research using the Gudjonnson suggestibility scale has suggested a role for self-esteem in suggestibility, with participants low in self-esteem being more suggestible than participants high in self-esteem. Four experiments are presented examining the role of self-esteem in the misinformation effect and whether enhanced suggestibility effects in participants low in self-esteem reflect genuine memory impairment. In Experiments 1 and 4 participants completed a standard recognition test. In Experiment 2 participants completed the modified recognition test. In Experiment 3 participants completed a free recall test. In Experiments 1 and 4 participants low in self-esteem demonstrated greater misinformation effects than participants high in self-esteem. In Experiment 3 a 3 day retention interval was employed with the modified test and no differences were found between the two groups on the reporting of the new item. The findings suggest that participants low in self-esteem are particularly sensitive to demand characteristics and post-event suggestion but do not suffer from genuine memory impairment. PMID- 22239232 TI - Synthesis, alignment, and magnetic properties of monodisperse nickel nanocubes. AB - This Communication describes the synthesis of highly monodispersed 12 nm nickel nanocubes. The cubic shape was achieved by using trioctylphosphine and hexadecylamine surfactants under a reducing hydrogen atmosphere to favor thermodynamic growth and the stabilization of {100} facets. Varying the metal precursor to trioctylphosphine ratio was found to alter the nanoparticle size and shape from 5 nm spherical nanoparticles to 12 nm nanocubes. High-resolution transmission electron microscopy showed that the nanocubes are protected from further oxidation by a 1 nm NiO shell. Synchrotron-based X-ray diffraction techniques showed the nickel nanocubes order into [100] aligned arrays. Magnetic studies showed the nickel nanocubes have over 4 times enhancement in magnetic saturation compared to spherical superparamagnetic nickel nanoparticles. PMID- 22239233 TI - Replication-independent expression of anti-apoptosis marker genes in human peripheral blood mononuclear cells infected with the wild-type HIV-1 and reverse transcriptase variants. AB - Clinical trials with highly-active antiretroviral therapy (HAART) have shown that a substantial number of patients continue to show a decrease in viral load and/or increase or stable CD4(+) T-cell numbers even in the presence of multidrug resistant (MDR) viruses. We compared replication capacity (RC) and expression of anti-apoptosis marker genes (AAMGs) in human peripheral blood mononuclear (PBM) cells infected with NL4-3 (wild-type; WT) and mutant viruses. Replication kinetics assays showed a significant decrease in RC of all mutant viruses in comparison to the WT virus. The viruses containing patient-derived MDR RT without the K65R mutation (PSD5.2) replicated efficiently in comparison to the viruses with MDR RT containing the K65R mutation (PSD5.1), or the single mutations K65R and M184V. Compared with WT, a significant decrease in RCs of viruses: K65R (RC=0.39+/-0.02; p<=0.0001), M184V (RC=0.72+/-0.04; p<=0.0001), PSD5.1 (RC=0.32+/ 0.04; p<=0.0001), and PSD5.2 (RC=0.90+/-0.04; p=0.002) was observed on day 10. RT PCR-based apoptosis array was performed on total cellular RNA. Recombinant virus PSD5.2 showed a 1.5- to 6-fold upregulation in 8 AAMGs (AKT1, BAG3, BCL2A1, BFAR, BIRC2, BNIP1, BNIP3, and CFLAR) on day 1 and day 7 post-infection with respect to WT virus. PSD5.1 showed upregulation of only one gene (BAG1) on day 1 (1.75-fold) and day 7 (1.97-fold). Point mutant K65R showed a 1.5- to 4-fold upregulation of six AAMGs on day 7. Viruses with the M184V mutation showed upregulation of only one gene (BAG1). These observations indicate that the upregulation of specific AAMGs may not be dependent on the RCs of HIV-I variants, and that the possible interaction among mutated RT residues and viral and/or host proteins may induce CD4(+) T-cell-protective anti-apoptosis proteins. PMID- 22239234 TI - Associations between demographic variables and multiple measles-specific innate and cell-mediated immune responses after measles vaccination. AB - Measles remains a public health concern due to a lack of vaccine use and vaccine failure. A better understanding of the factors that influence variations in immune responses, including innate/inflammatory and adaptive cellular immune responses, following measles-mumps-rubella (MMR) vaccination could increase our knowledge of measles vaccine-induced immunity and potentially lead to better vaccines. Measles-specific innate/inflammatory and adaptive cell-mediated immune (CMI) responses were characterized using enzyme-linked immunosorbent assays to quantify the levels of secreted IL-2, IL-6, IL-10, IFN-alpha, IFN-gamma, IFN lambda1, and TNF-alpha in PBMC cultures following in vitro stimulation with measles virus (MV) in a cohort of 764 school-aged children. IFN-gamma ELISPOT assays were performed to ascertain the number of measles-specific IFN-gamma secreting cells. Cytokine responses were then tested for associations with self declared demographic data, including gender, race, and ethnicity. Females secreted significantly more TNF-alpha, IL-6, and IFN-alpha (p<0.001, p<0.002, p<0.04, respectively) compared to males. Caucasians secreted significantly more IFN-lambda1, IL-10, IL-2, TNF-alpha, IL-6, and IFN-alpha (p<0.001, p<0.001, p<0.001, p<0.003, p<0.01, and p<0.02, respectively) compared to the other racial groups combined. Additionally, Caucasians had a greater number of IFN-gamma secreting cells compared to other racial groups (p<0.001). Ethnicity was not significantly correlated with variations in measles-specific CMI measures. Our data suggest that innate/inflammatory and CMI cytokine responses to measles vaccine vary significantly by gender and race. These data further advance our understanding regarding inter-individual and subgroup variations in immune responses to measles vaccination. PMID- 22239236 TI - New approaches for the control of influenza. PMID- 22239235 TI - Double-stranded RNA-induced activation of activating protein-1 promoter is differentially regulated by the non-structural protein 1 of avian influenza A viruses. AB - Non-structural protein 1 (NS1) of influenza A viruses is a multifunctional protein that antagonizes the host immune response by interfering with several host signaling pathways. Based on putative amino acid sequences, NS1 proteins are categorized into two gene pools, allele A and allele B. Here we identified that allele A NS1 proteins of H6N8 and H4N6 are able to inhibit double-stranded RNA (dsRNA)-induced activating protein-1 (AP-1) promoter in cultured cell lines (human A549 and mink lung cells). Allele B NS1 proteins from corresponding subtypes of influenza A viruses are weak in this inhibition, despite significant levels of expression of each NS1 protein in human A549 cells. Furthermore, the capability to inhibit AP-1 promoter was mapped in the effector domain, since RNA binding domain alone lost its ability to inhibit this promoter activation. Chimeric forms of NS1 protein, composed of either RNA binding domain of allele A or B and effector domain of allele A or B, showed comparable inhibition to that of their wild-type NS1 proteins, or to the effector domain of corresponding NS1 proteins. Both alleles A and B NS1 proteins of H6N8 and H4N6 were expressed to significant levels, and were localized predominantly in the nucleus of human A549 cells. These results underscore the importance of the effector domain in inhibiting AP-1 promoter activation, and the biological function of the effector domain in stabilizing the RNA binding domain. Further, we revealed the versatile nature of NS1 in inhibiting the AP-1 transcription factor, in a manner dependent on allele type. Comprehensive studies, focusing on the molecular mechanisms behind this differential inhibition, may facilitate exploration of the zoonotic and pathogenic potential of influenza A viruses. PMID- 22239237 TI - Bisphenol A, an endocrine-disrupting chemical, and brain development. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in various industries and the field of dentistry. The consequent increase in BPA exposure among humans has led us to some concerns regarding the potential deleterious effects on reproduction and brain development. The emphasis of this review is on the effects of prenatal and lactational exposure to low doses of BPA on brain development in mice. We demonstrated that prenatal exposure to BPA affected fetal murine neocortical development by accelerating neuronal differentiation/migration during the early embryonic stage, which was associated with up- and down regulation of the genes critical for brain development, including the basic helix loop-helix transcription factors. In the adult mice brains, both abnormal neocortical architecture and abnormal corticothalamic projections persisted in the group exposed to the BPA. Functionally, BPA exposure disturbed murine behavior, accompanied with a disrupted neurotransmitter system, including monoamines, in the postnatal development period and in adult mice. We also demonstrated that epigenetic alterations in promoter-associated CpG islands might underlie some of the effects on brain development after exposure to BPA. PMID- 22239239 TI - Sequence variations in equine candidate genes For XX and XY inherited disorders of sexual development. AB - Inherited disorders of sexual development (DSD) cause sterility and infertility in horses. Mutations causing such disorders have been identified in other mammals, but there is little information on the molecular causes in horses. While the equine genome sequence has made it possible to identify candidate genes, additional tools are needed to routinely screen them for causative mutations. In this study, we designed a screening panel of polymerase chain reaction primer pairs for 15 equine genes. These are the candidate genes for testicular or ovotesticular XX DSD and XY DSD, the latter of which includes gonadal dysgenesis, androgen insensitivity syndrome (AIS), persistent Mullerian duct syndrome and isolated cryptorchidism. Six horses with testicular or ovotesticular XX DSD and controls were screened. In addition, candidate genes for androgen insensitivity syndrome, persistent Mullerian duct syndrome and isolated cryptorchidism were screened in normal horses. While no sequence variants were uniquely associated with XX DSD, the 38 sequence variants identified can serve as intragenic markers in genome-wide association studies or linkage studies to hasten mutation identification in equine XX DSD and XY DSD. PMID- 22239243 TI - Tin oxide dependence of the CO2 reduction efficiency on tin electrodes and enhanced activity for tin/tin oxide thin-film catalysts. AB - The importance of tin oxide (SnO(x)) to the efficiency of CO(2) reduction on Sn was evaluated by comparing the activity of Sn electrodes that had been subjected to different pre-electrolysis treatments. In aqueous NaHCO(3) solution saturated with CO(2), a Sn electrode with a native SnO(x) layer exhibited potential dependent CO(2) reduction activity consistent with previously reported activity. In contrast, an electrode etched to expose fresh Sn(0) surface exhibited higher overall current densities but almost exclusive H(2) evolution over the entire 0.5 V range of potentials examined. Subsequently, a thin-film catalyst was prepared by simultaneous electrodeposition of Sn(0) and SnO(x) on a Ti electrode. This catalyst exhibited up to 8-fold higher partial current density and 4-fold higher faradaic efficiency for CO(2) reduction than a Sn electrode with a native SnO(x) layer. Our results implicate the participation of SnO(x) in the CO(2) reduction pathway on Sn electrodes and suggest that metal/metal oxide composite materials are promising catalysts for sustainable fuel synthesis. PMID- 22239244 TI - Social systems: demographic and genetic issues. PMID- 22239245 TI - Retractions. Antioxidants and Redox Signaling (ARS). AB - Due to the recent findings of an investigation led by the U.S. Office of Research Integrity, and as a direct result of the falsification and manipulation of data in the articles listed below, Antioxidants and Redox Signaling (ARS) is officially retracting the following published papers, authored by Dipak K. Das. 1. Malik G, Gorbounov N, Das S, Gurusamy N, Otani H, Maulik N, Goswami S, Das DK. Ischemic preconditioning triggers nuclear translocation of thioredoxin and its interaction with Ref-1 potentiating a survival signal through the PI-3-kinase-Akt pathway. Antioxid Redox Signal 8:2101-2109, 2006. 2. Muinck ED, Nagy N, Tirziu D, Murakami M, Gurusamy N, Goswami SK, Ghatpande S, Engelman RM, Simons M, Das DK. Protection against myocardial ischemia-reperfusion injury by the angiogenic Masterswitch protein PR 39 gene therapy: the roles of HIF1alpha stabilization and FGFR1 signaling. Antioxid Redox Signal 9:437-445, 2007. These actions reinforce the high standards to which ARS is committed. PMID- 22239246 TI - A qualitative and quantitative analysis of von Willebrand factor contained in a very high-purity plasma-derived FVIII concentrate. AB - BACKGROUND AND OBJECTIVES: We studied the structural and functional properties of von Willebrand factor (VWF) molecules present in a very high-purity plasma derived factor VIII concentrate (VHP pdFVIII - Factane(r) ) because several observations suggest that the presence of VWF in factor VIII (FVIII) preparations may decrease their immunogenicity. MATERIALS AND METHODS: Ten marketed batches of VHP pdFVIII (Factane(r) ) with levels of VWF ranging from 15 to 39 IU/100 IU FVIII were analysed. The VWF multimeric pattern was studied by agarose gel electrophoresis. The binding of VWF to FVIII was studied by gel filtration and ELISA. The binding of VWF to GPIb was analysed by ELISA. RESULTS: The results showed that high-molecular-weight multimers of VWF were present in VHP pdFVIII (Factane(r) ). VWF subunits maintain a triplet structure similar to that of normal plasma. Regardless of the VWF content, all FVIII molecules of each batch were co-eluted with VWF, and no free FVIII was detectable. By immunoassays, VWF was found to be able to bind to FVIII and platelet GPIb in a similar manner to that of VWF in normal plasma. CONCLUSIONS: In all the VHP pdFVIII (Factane(r) ) batches studied, regardless of the level of VWF, the structure and capacity of VWF binding to FVIII and to platelet GPIb were fully preserved. PMID- 22239247 TI - Apple and sugar feeding in adult codling moths, Cydia pomonella: effects on longevity, fecundity, and egg fertility. AB - Attraction of adult codling moths, Cydia pomonella (L.) (Lepidoptera: Tortricidae), to sweet baits has been well documented. However, beneficial effects of sugar feeding on moth fitness have not been demonstrated. Longevity, fecundity, and egg fertility were examined for female/male pairs of moths maintained with the following food regimens: water, sucrose water, honey water, apple juice, apple flesh, or starved, i.e., no food or water provided. Longevity and total fecundity were enhanced in all treatments relative to the starved treatment moths. Sucrose water, honey water, and apple juice treatments yielded the highest longevity, but total fecundity was highest for moths maintained on honey water or apple juice. Total egg fertility did not differ among treatments. However, egg fertility declined more gradually over the female lifespan for the three aqueous solution diets of sucrose water, honey water, and apple juice. Similarly, fecundity per day declined more gradually over time for honey water and apple juice treatments. Performance of moths maintained with apple flesh was generally intermediate between that of moths with water and the three aqueous solution treatments. This suggests that moths benefit from feeding on ripe apple flesh, although apple may be more difficult to ingest or its nutrients less concentrated compared to aqueous solutions. The results presented here may explain attraction of adult moths to sweet baits as well as to odors from ripe fruit, which may be a natural source of food in the fall. PMID- 22239248 TI - Comparison of speech intelligibility, articulation and oromyofunctional behaviour in subjects with single-tooth implants, fixed implant prosthetics or conventional removable prostheses. AB - The purpose of this controlled study was to determine the impact of a single tooth implant, fixed implant prosthesis and completely removable dental prosthesis on intelligibility, articulation and oromyofunctional behaviour. Additionally, the self-perceived overall satisfaction of the dental replacements and the effect on speech was questioned. Objective (acoustic analysis) as well as subjective assessment techniques (perceptual evaluation) were used. The satisfaction of single-tooth implant group was very high (100%) followed by a satisfaction of 87% for the fixed implant prosthesis group and 68% for the removable prosthesis group. The results of the phonetic analyses revealed a normal intelligibility and oromyofunctional behaviour in the three groups of dental replacements. Only one type of articulation disorders was observed in the single-tooth implant group, followed by three types of disorders in the removable prosthesis group and six types of disorders in the fixed implant prosthesis group. In this last group, not only 87% of the subjects showed distortions of one or more consonants but also most consonants of the Dutch language were disturbed in comparison with the single-tooth implant and removable prosthesis users. Special attention must be paid to the fricative /s/ because in more than 50% of all groups, this sound is disturbed. PMID- 22239249 TI - An implantable biofuel cell for a live insect. AB - A biofuel cell incorporating a bienzymatic trehalase|glucose oxidase trehalose anode and a bilirubin oxidase dioxygen cathode using Os complexes grafted to a polymeric backbone as electron relays was designed and constructed. The specific power densities of the biofuel cell implanted in a female Blaberus discoidalis through incisions into its abdomen yielded maximum values of ca. 55 MUW/cm(2) at 0.2 V that decreased by only ca. 5% after ca. 2.5 h of operation. PMID- 22239251 TI - Evidence of coexistence of change of caged dynamics at T(g) and the dynamic transition at T(d) in solvated proteins. AB - Mossbauer spectroscopy and neutron scattering measurements on proteins embedded in solvents including water and aqueous mixtures have emphasized the observation of the distinctive temperature dependence of the atomic mean square displacements, , commonly referred to as the dynamic transition at some temperature T(d). At low temperatures, increases slowly, but it assumes stronger temperature dependence after crossing T(d), which depends on the time/frequency resolution of the spectrometer. Various authors have made connection of the dynamics of solvated proteins, including the dynamic transition to that of glass-forming substances. Notwithstanding, no connection is made to the similar change of temperature dependence of obtained by quasielastic neutron scattering when crossing the glass transition temperature T(g), generally observed in inorganic, organic, and polymeric glass-formers. Evidences are presented here to show that such a change of the temperature dependence of from neutron scattering at T(g) is present in hydrated or solvated proteins, as well as in the solvent used, unsurprisingly since the latter is just another organic glass-former. If unaware of the existence of such a crossover of at T(g), and if present, it can be mistaken as the dynamic transition at T(d) with the ill consequences of underestimating T(d) by the lower value T(g) and confusing the identification of the origin of the dynamic transition. The obtained by neutron scattering at not so low temperatures has contributions from the dissipation of molecules while caged by the anharmonic intermolecular potential at times before dissolution of cages by the onset of the Johari Goldstein beta-relaxation or of the merged alpha-beta relaxation. The universal change of at T(g) of glass-formers, independent of the spectrometer resolution, had been rationalized by sensitivity to change in volume and entropy of the dissipation of the caged molecules and its contribution to . The same rationalization applies to hydrated and solvated proteins for the observed change of at T(g). PMID- 22239250 TI - Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency. AB - A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5 diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3 isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats. PMID- 22239252 TI - Fluorophore targeting to cellular proteins via enzyme-mediated azide ligation and strain-promoted cycloaddition. AB - Methods for targeting of small molecules to cellular proteins can allow imaging with fluorophores that are smaller, brighter, and more photostable than fluorescent proteins. Previously, we reported targeting of the blue fluorophore coumarin to cellular proteins fused to a 13-amino acid recognition sequence (LAP), catalyzed by a mutant of the Escherichia coli enzyme lipoic acid ligase (LplA). Here, we extend LplA-based labeling to green- and red-emitting fluorophores by employing a two-step targeting scheme. First, we found that the W37I mutant of LplA catalyzes site-specific ligation of 10-azidodecanoic acid to LAP in cells, in nearly quantitative yield after 30 min. Second, we evaluated a panel of five different cyclooctyne structures and found that fluorophore conjugates to aza-dibenzocyclooctyne (ADIBO) gave the highest and most specific derivatization of azide-conjugated LAP in cells. However, for targeting of hydrophobic fluorophores such as ATTO 647N, the hydrophobicity of ADIBO was detrimental, and superior targeting was achieved by conjugation to the less hydrophobic monofluorinated cyclooctyne (MOFO). Our optimized two-step enzymatic/chemical labeling scheme was used to tag and image a variety of LAP fusion proteins in multiple mammalian cell lines with diverse fluorophores including fluorescein, rhodamine, Alexa Fluor 568, ATTO 647N, and ATTO 655. PMID- 22239253 TI - Overexpression of miR156 in switchgrass (Panicum virgatum L.) results in various morphological alterations and leads to improved biomass production. AB - Switchgrass (Panicum virgatum L.) has been developed into a dedicated herbaceous bioenergy crop. Biomass yield is a major target trait for genetic improvement of switchgrass. microRNAs have emerged as a prominent class of gene regulatory factors that has the potential to improve complex traits such as biomass yield. A miR156b precursor was overexpressed in switchgrass. The effects of miR156 overexpression on SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) genes were revealed by microarray and quantitative RT-PCR analyses. Morphological alterations, biomass yield, saccharification efficiency and forage digestibility of the transgenic plants were characterized. miR156 controls apical dominance and floral transition in switchgrass by suppressing its target SPL genes. Relatively low levels of miR156 overexpression were sufficient to increase biomass yield while producing plants with normal flowering time. Moderate levels of miR156 led to improved biomass but the plants were non-flowering. These two groups of plants produced 58%-101% more biomass yield compared with the control. However, high miR156 levels resulted in severely stunted growth. The degree of morphological alterations of the transgenic switchgrass depends on miR156 level. Compared with floral transition, a lower miR156 level is required to disrupt apical dominance. The improvement in biomass yield was mainly because of the increase in tiller number. Targeted overexpression of miR156 also improved solubilized sugar yield and forage digestibility, and offered an effective approach for transgene containment. PMID- 22239254 TI - Field tests of Poly(I:C) immunization with nervous necrosis virus (NNV) in sevenband grouper, Epinephelus septemfasciatus (Thunberg). AB - It was recently reported that Poly(I:C) immunization with live nervous necrosis virus (NNV) confers protection in sevenband grouper, Epinephelus septemfasciatus (Thunberg), from NNV infection. In the present study, we conducted field tests with sevenband grouper for the evaluation of Poly(I:C) immunization efficacy. In the first experiment, sevenband grouper were immunized with NNV followed by Poly(I:C) administration 7 weeks before natural occurrence of viral nervous necrosis (VNN). Survival rate of the naive fish was 71.0%, whereas that of the immunized fish was 99.8%. In the second experiment, sevenband grouper were immunized 10 months before VNN occurrence and survival rate of the non-treated and vaccinated fish was 79.5% and 97.5%, respectively. In the third experiment, we administered Poly(I:C) to sevenband grouper at 20 days after natural occurrence of VNN. The survival rate of the non-treated fish was 9.8%, whereas that of fish administered Poly(I:C) was 93.7%. Based on these results, it was concluded that Poly(I:C) immunization conferred protection in fish against NNV infection in field tests and the protection lasted more than 10 months. Furthermore, even after occurrence of VNN, fish mortality could be reduced by Poly(I:C) administration and there was an unexpected curative effect on VNN affected fish. PMID- 22239255 TI - Spatial anxiety relates to spatial abilities as a function of working memory in children. AB - Spatial ability is a strong predictor of students' pursuit of higher education in science and mathematics. However, very little is known about the affective factors that influence individual differences in spatial ability, particularly at a young age. We examine the role of spatial anxiety in young children's performance on a mental rotation task. We show that even at a young age, children report experiencing feelings of nervousness at the prospect of engaging in spatial activities. Moreover, we show that these feelings are associated with reduced mental rotation ability among students with high but not low working memory (WM). Interestingly, this WM * spatial anxiety interaction was only found among girls. We discuss these patterns of results in terms of the problem-solving strategies that boys versus girls use in solving mental rotation problems. PMID- 22239261 TI - Seven billion people today, many more tomorrow--how we got here and what we expect and wish. PMID- 22239262 TI - Venous and pulmonary thromboembolism and combined hormonal contraceptives. Systematic review and meta-analysis. AB - OBJECTIVE: A systematic review of studies published between January 1995 and April 2010 aimed at determining the effect of combined hormonal contraceptives (CHCs), administered orally, transdermally or vaginally, on the risk of venous thromboembolism (VTE). RESULTS: Of the 625 potentially eligible references reviewed, 25 studies meeting the inclusion and exclusion criteria were entered in the meta-analysis. The pooled relative risks of VTE associated with the various CHCs, depending on their progestogen, were: gestodene vs. levonorgestrel 1.33 (95% confidence interval [CI]: 1.08-1.63); desogestrel vs. levonorgestrel 1.93 (95% CI: 1.31-2.83); and drospirenone vs. levonorgestrel 1.67 (95% CI: 1.10 2.55). The pooled adjusted odds ratio for norgestimate vs. levonorgestrel was 1.11 (95% CI: 0.84-1.46) and that for cyproterone acetate vs. levonorgestrel 1.65 (95% CI: 1.30-2.11). CONCLUSIONS: The safest CHCs in terms of VTE are those containing levonorgestrel or norgestimate. The risk of VTE associated with desogestrel-, drospirenone- or cyproterone acetate-containing CHCs is greater than that associated with CHCs containing levonorgestrel. The increased risk of VTE found for CHCs with gestodene compared to CHCs with levonorgestrel seems smaller than in previous analyses. There were no differences in VTE risk between oral and transdermal CHCs containing norgestimate or norelgestromin, respectively. PMID- 22239263 TI - Age-disparate relationships and implications for STI transmission among young adults in Cape Town, South Africa. AB - OBJECTIVES: To estimate the prevalence of age-disparate (AD) relationships among young black and coloured adults in Cape Town (South Africa) and determine socio demographic predictors and individual and relationship characteristics of women in these relationships. METHODS: A secondary analysis of the Cape Area Panel Study (N = 1960) data was conducted. Descriptive statistics were used to quantify the age-mixing pattern and logistic regression was used to identify significant socio-demographic and behavioural correlates of AD relationships. RESULTS: Prevalence of AD relationships was high in both black (36%) and coloured (28%) women. The average age difference between male respondents and their partners increased with age. Young, black women who spent fewer nights under the same roof in one week, had a deceased parent, and were not currently attending classes were more likely to be in an AD relationship. Reports of sexually-transmitted infection (STI) symptoms in the last month and unprotected sex were more common among women in AD relationships. CONCLUSIONS: AD relationships are common among young women in Cape Town. Home and family stability is preventative of young women engaging in AD relationships. Therefore, holistic, societal interventions may reduce AD relationships, which are a risk factor for STIs. PMID- 22239264 TI - The CHOICE study: effect of counselling on the selection of combined hormonal contraceptive methods in 11 countries. AB - OBJECTIVES: To encourage healthcare professionals to counsel women seeking combined hormonal contraceptives (CHCs) about alternative CHCs and to study the influence of counselling on women's selection of CHCs. METHODS: Women (15-40 years old) in 11 countries who consulted HCPs about CHCs were counselled about the pill, transdermal patch, and vaginal ring. Both the HCPs and the women completed questionnaires. RESULTS: Of women who were counselled (n = 18,787), 47% selected another CHC method than originally planned. One in four who intended to use the pill chose another method (16% chose the patch; 65% chose the ring). In total, patch use increased from 5% -8% (difference = 3.7% [97.5% CI: 3.3-4.2]; p < 0.0001). Ring use nearly quadrupled from 8% -30% (difference = 21.7% [97.5% CI: 21.0-22.5]; p < 0.0001). Nearly all women who were undecided prior to counselling selected a method after counselling. Selection of the pill increased most in Russia (+ 11%) and Sweden (+ 5%); patch selection was greatest in Russia (+ 7%) and Israel (+ 6%); ring use increased most in Ukraine and in the Czech Republic and Slovakia (+ 36%). CONCLUSIONS: Counselling increases use of alternative CHCs, such as the patch and the ring. Considerable differences between countries were noted. PMID- 22239265 TI - Benign hereditary chorea 2: pathological findings in an autopsy case. AB - Two Japanese families with benign hereditary chorea (BHC) 2 have recently been reported. BHC 2 is characterized by adult-onset non-progressive chorea, and by genetic abnormality in the locus of chromosome 8q21.3-q23.3. This differs from the genetic abnormality previously reported in BHC. Here we report the first autopsied case of a member of one of two known families with BHC 2. A normally developed woman recognized choreiform movements of her bilateral upper extremities beginning approximately at age 40. The movements had slowly spread to her trunk and lower extremities by approximately age 60. Generalized muscular hypotonia was also observed. The symptoms persisted until her death at the age 83, but had not worsened. Neuropathological examination revealed mild to moderate neuronal loss and astrocytosis in the striatum and decreased volume of cerebral white matter with astrocytosis bilaterally. Additionally, sparse but widely distributed neurofibrillary tangles and argyrophilic threads as well as scattered tufted astrocytes immunoreactive for 4-repeat isoform of tau were observed in the cerebrum, brainstem and cerebellum, showing 4-repeat tauopathy similar to that of progressive supranuclear palsy (PSP). Unique neuronal cytoplasmic inclusions were observed in the oculomotor nuclei; however, any specific immunoreactivities (e.g. ubiquitin and p62) were not detected, suggesting the presence of previously undescribed protein intracellular inclusions. Clinicopathologically, chorea accompanied with generalized muscular hypotonia seemed to be associated with mild degeneration of the striatum and cerebral white matter. The significance of PSP like changes in the pathogenesis of BHC 2 remains to be elucidated. PMID- 22239269 TI - Insight into the common mechanism of the chromophore formation in the red fluorescent proteins: the elusive blue intermediate revealed. AB - Understanding the chromophore maturation process in fluorescent proteins is important for the design of proteins with improved properties. Here, we present the results of electronic structure calculations identifying the nature of a blue intermediate, a key species in the process of the red chromophore formation in DsRed, TagRFP, fluorescent timers, and PAmCherry. The chromophore of the blue intermediate has a structure in which the pi-system of the imidazole ring is extended by the acylimine bond, which can be represented by the model N-[(5 hydroxy-1H-imidazole-2yl)methylidene]acetamide (HIMA) compound. Ab initio and QM/MM calculations of the isolated model and protein-bound (mTagBFP) chromophores identify the anionic form of HIMA as the only structure that has absorption that is consistent with the experiment and is stable in the protein binding pocket. The anion and zwitterion are the only protonation forms of HIMA whose absorption (421 and 414 nm, or 2.95 and 3.00 eV) matches the experimental spectrum of the blue form in DsRed (the absorption maximum is 408 nm or 3.04 eV) and mTagBFP (400 nm or 3.10 eV). The QM/MM optimization of the protein-bound anionic form results in a structure that is close to the X-ray one, whereas the zwitterionic chromophore is unstable in the protein binding pocket and undergoes prompt proton transfer. The computed excitation energy of the protein-bound anionic form of the mTagBFP-like chromophore (3.04 eV) agrees with the experimental absorption spectrum of the protein. The DsRed-like chromophore formation in red fluorescent proteins is revisited on the basis of ab initio results and verified by directed mutagenesis revealing a key role of the amino acid residue 70, which is the second after the chromophore tripeptide, in the formation process. PMID- 22239270 TI - Vitamin C enhances the in vitro development of porcine pre-implantation embryos by reducing oxidative stress. AB - Vitamin C (Vc) is a natural compound supplemented to culture media to guarantee the appropriate reactive oxygen species (ROS) level, as well as protect cells from oxidative damage and apoptosis. The current study was conducted to determine the effects of Vc (0, 2.5, 5, 10, 20 and 40 MUg/ml) on the ROS production, developmental ability and quality of in vitro produced porcine parthenotes. The results show that: (i) the ROS levels in the embryos significantly decrease in the Vc-treated groups compared with the control (p < 0.05), (ii) the rates of blastocyst formation and total cell numbers in each blastocyst are significantly higher in the Vc-treated groups than in the control (p < 0.05); the optimum concentration of Vc is 20 MUg/ml, (iii) the relative expression of Bcl-xL significantly increases and that of Bax is downregulated after Vc treatment. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling analysis indicates that the ratio of apoptotic cells in the blastocyst is also significantly lower in Vc-treated groups (p < 0.05) and (iv) Vc treatment can also increase the expression of the Nanog gene in porcine embryos, with a fivefold increase in 20 MUg/ml Vc treatment compared with the control (p < 0.05). Therefore, Vc improves the development of porcine embryos by reducing the ROS levels. Vc addition in PZM-3 medium can decrease the number of apoptotic cells and increase the cell numbers in blastocysts to produce high-quality porcine embryos in vitro. PMID- 22239272 TI - Quantum mechanical/molecular mechanical study on the mechanism of the enzymatic Baeyer-Villiger reaction. AB - We report a combined quantum mechanical/molecular mechanical (QM/MM) study on the mechanism of the enzymatic Baeyer-Villiger reaction catalyzed by cyclohexanone monooxygenase (CHMO). In QM/MM geometry optimizations and reaction path calculations, density functional theory (B3LYP/TZVP) is used to describe the QM region consisting of the substrate (cyclohexanone), the isoalloxazine ring of C4a peroxyflavin, the side chain of Arg-329, and the nicotinamide ring and the adjacent ribose of NADP(+), while the remainder of the enzyme is represented by the CHARMM force field. QM/MM molecular dynamics simulations and free energy calculations at the semiempirical OM3/CHARMM level employ the same QM/MM partitioning. According to the QM/MM calculations, the enzyme-reactant complex contains an anionic deprotonated C4a-peroxyflavin that is stabilized by strong hydrogen bonds with the Arg-329 residue and the NADP(+) cofactor. The CHMO catalyzed reaction proceeds via a Criegee intermediate having pronounced anionic character. The initial addition reaction has to overcome an energy barrier of about 9 kcal/mol. The formed Criegee intermediate occupies a shallow minimum on the QM/MM potential energy surface and can undergo fragmentation to the lactone product by surmounting a second energy barrier of about 7 kcal/mol. The transition state for the latter migration step is the highest point on the QM/MM energy profile. Gas-phase reoptimizations of the QM region lead to higher barriers and confirm the crucial role of the Arg-329 residue and the NADP(+) cofactor for the catalytic efficiency of CHMO. QM/MM calculations for the CHMO catalyzed oxidation of 4-methylcyclohexanone reproduce and rationalize the experimentally observed (S)-enantioselectivity for this substrate, which is governed by the conformational preferences of the corresponding Criegee intermediate and the subsequent transition state for the migration step. PMID- 22239274 TI - Arachnoiditis ossificans of the cauda equina. AB - A case of post-traumatic arachnoiditis ossificans of the cauda equina is reported. The lesion is a rare pathological entity usually confined to the thoracic and high lumbar regions that can cause progressive spinal cord and cauda equine compression. The pathophysiology and therapeutic strategy of this rare entity are still controversial. PMID- 22239271 TI - The product of tadZ, a new member of the parA/minD superfamily, localizes to a pole in Aggregatibacter actinomycetemcomitans. AB - Aggregatibacter actinomycetemcomitans establishes a tenacious biofilm that is important for periodontal disease. The tad locus encodes the components for the secretion and biogenesis of Flp pili, which are necessary for the biofilm to form. TadZ is required, but its function has been elusive. We show that tadZ genes belong to the parA/minD superfamily of genes and that TadZ from A. actinomycetemcomitans (AaTadZ) forms a polar focus in the cell independent of any other tad locus protein. Mutations indicate that regions in AaTadZ are required for polar localization and biofilm formation. We show that AaTadZ dimerizes and that all TadZ proteins are predicted to have a Walker-like A box. However, they all lack the conserved lysine at position 6 (K6) present in the canonical Walker like A box. When the alanine residue (A6) in the atypical Walker-like A box of AaTadZ was converted to lysine, the mutant protein remained able to dimerize and localize, but it was unable to allow the formation of a biofilm. Another essential biofilm protein, the ATPase (AaTadA), also localizes to a pole. However, its correct localization depends on the presence of AaTadZ. We suggest that the TadZ proteins mediate polar localization of the Tad secretion apparatus. PMID- 22239275 TI - Minimally invasive microsurgical resection of primary, intradural spinal tumours using a tubular retraction system. AB - STUDY DESIGN: This is a retrospective review of prospectively collected data. BACKGROUND: Primary, intradural spinal tumours have traditionally been microsurgically resected following macrosurgical laminectomy or laminoplasty. We hypothesize that approach-related morbidity can be reduced with less-invasive approaches; we have therefore implemented a minimally invasive approach, with the assistance of a tubular retraction system, for microsurgical resection of primary intradural spinal tumours. METHODS: From January 2007 to December 2009, 54 patients underwent surgery for a spinal intradural tumour. Of these, nine patients who underwent minimally invasive posterior unilateral transmuscular surgery using a tubular retraction system were included in this study. Resection grade and surgery-related complications were retrospectively reviewed. RESULTS: All tumours were totally resected (verified by postoperative magnetic resonance imaging). There were no post-operative complications. Eight of the nine patients were mobilized on the day of surgery or on post-operative day 1. One patient was mobilized on post-operative day 2. CONCLUSIONS: Selected primary, intradural spinal tumours can be safely and successfully resected using a minimally invasive posterior unilateral transmuscular approach with the assistance of a tubular retraction system. PMID- 22239278 TI - Positron emission tomography in seizure disorders. AB - Positron emission tomography (PET) has been widely used in the study of seizure disorders. As a research tool, PET has been used to determine the pathophysiology of different seizures disorders, prognostic and diagnostic information, and the response to various interventions. PET imaging has also been used clinically to help with the detection of seizure foci. With the continued development of a large array of radiopharmaceuticals that can evaluate all of the components of different neurotransmitter systems as well as cerebral blood flow and metabolism, PET imaging will continue to play a key role in research and clinical applications for seizure disorders. PMID- 22239279 TI - Boom and bust: housing equity withdrawal and consumption decisions and their impacts on household wealth. AB - The authors examine whether the surge in housing refinance and equity withdrawal generated by the housing boom disproportionately affected older households in terms of decisions on whether to refinance, whether to withdraw equity, and how much to withdraw, and how in turn these decisions affected their household wealth. Using the Federal Reserve's Survey of Consumer Finances, the authors found the highest rates of refinancing and cashing out equity among older (although not necessarily the oldest) households. The authors also found that appreciation in house value, being a baby boomer, and having higher household income were the factors that most increased the probability of refinancing and withdrawing equity. Amounts cashed out were higher among older than among younger households. Ordinary least squares (OLS) estimates showed that amounts withdrawn were increased by price appreciation, financial assets, and income, along with being a "pre-boomer" or "early boomer." Older cohorts displayed larger wealth effects than younger ones, but their withdrawn equity was a smaller percentage of total net worth. A relatively small percentage of respondents' dollars was used for consumption, and most dollars were used for home improvement, other investment, or debt repayment. However, massive equity withdrawal and the subsequent collapse of housing prices have caused housing leverage to soar, putting some homeowners "underwater" and jeopardizing others' retirement preparedness. The ensuing housing finance crisis raises numerous policy issues, from reform of mortgage underwriting, securitization, servicing, and foreclosure procedures, to potential limitations on borrowing against unrealized housing equity gains, to enhanced government transfers for distressed older homeowners, to local and state revenue policy changes. PMID- 22239280 TI - Are baby boomers who care for their older parents planning for their own future long-term care needs? AB - A rapidly expanding number of baby boomers provide care to aging parents. This study examines associations between caregiver status and outcomes related to awareness and anticipation of future long-term care (LTC) needs using 2007 Connecticut Long-Term Care Needs Assessment survey data. Baby boomers who were adult child caregivers (n = 353) versus baby boomers who were not (n = 1242) were more likely to anticipate some future LTC needs and to have considered certain financing strategies. Although baby boomer adult child caregivers more readily anticipate some future LTC needs, they are not taking specific actions. It is important to address the need for public education directed toward those who are currently (or have recently completed) caring for aging parents. PMID- 22239281 TI - Health insurance for all long-term care workers: estimated costs and coverage impacts in Minnesota and recommendations for States. AB - A major barrier to building a strong workforce to meet the growing need for long care is lack of affordable health benefits. This study projects impacts of funding health coverage for all long-term care workers in Minnesota. Under the most cost effective model plan design, enrollment in employer-sponsored coverage would increase 73% to 100% for individual coverage and 26% to 42% for family coverage. Total monthly costs would be $698/worker in the commercial market or $634/worker through a new dedicated risk pool. Based on our findings and past research, the authors present recommendations for structuring and implementing a long-term care worker health insurance initiative. PMID- 22239282 TI - The importance of job training to job satisfaction of older workers. AB - If job training has positive impacts on worker satisfaction, then job training can have desirable consequences for an organization that result both directly through its effects on productivity and indirectly through its effects on job satisfaction. Furthermore, the aging of the workforce implies that older workers will become increasingly important to firms and to the economy. This study, therefore, seeks to examine the relationship between job training and job satisfaction, focusing in particular on U.S. workers born in 1964 or earlier. The results of ordered logit regression analysis indicate that availability and quality of training received directly affect job satisfaction. PMID- 22239283 TI - The long-term care insurance law in Israel: present and future. AB - Aging in place is a core component of the policy on aging in Israel. This was well expressed in the Long-Term Care Insurance law enacted in 1986 and implemented in 1988. Under the law, disabled persons can receive in-kind home- and community-based services to enable frail older adults to age in place and to complement or supplement the care provided primarily by family caregivers who are legally responsible for caregiving of their elderly family members. This article presents the main principles of the law and reviews the amendments that this law has undergone during the past 22 years. Finally, some core issues and dilemmas are discussed. PMID- 22239285 TI - Establishing dual electrogenerated chemiluminescence and multicolor electrochromism in functional ionic transition-metal complexes. AB - A combination of electrochromism and electroluminescence in functional materials could lead to single-layer dual electrochromic/electroluminescent (EC/EL) display devices, capable of simultaneous operation in emissive and reflective modes. Whereas such next generation displays could provide optimal visibility in any ambient lighting situation, materials available that exhibit such characteristics in the active layer are limited due to the required intrinsic multifunctionality (i.e., redox activity, electroluminescence, electrochromism, and ion conductivity) and to date can only be achieved via the rational design of ionic transition-metal complexes. Reported herein is the synthesis and characterization of a new family of acrylate-containing ruthenium (tris)bipyridine-based coordination complexes with multifunctional characteristics. Potential use of the presented compounds in EC/EL devices is established, as they are applied as cross linked electrochromic films and electrochemiluminescent layers in light-emitting electrochemical cell devices. Electrochromic switching of the polymeric networks between yellow, orange, green, brown and transmissive states is demonstrated, and electrochemiluminescent devices based on the complexes synthesized show red orange to deep red emission with lambda(max) ranging from 680 to 722 nm and luminance up to 135 cd/m(2). Additionally, a dual EC/EL device prototype is presented where light emission and multicolor electrochromism occur from the same pixel comprised of a single active layer, demonstrating a true combination of these properties in ionic transition-metal complexes. PMID- 22239286 TI - Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free energy studies. AB - In the present work, the binding of inhibitor TMC114 (darunavir) to wild-type (WT), single (I50V) as well as double (I50L/A71V) mutant HIV-proteases (HIV-pr) was investigated with all-atom molecular dynamics (MD) simulations as well as molecular mechanic-Poisson-Boltzmann surface area (MM-PBSA) calculation. For both the apo and complexed HIV-pr, many intriguing effects due to double mutant, I50L/A71V, are observed. For example, the flap-flap distance and the distance from the active site to the flap residues in the apo I50L/A71V-HIV-pr are smaller than those of WT- and I50V-HIV-pr, probably making the active site smaller in volume and closer movement of flaps. For the complexed HIV-pr with TMC114, the double mutant I50L/A71V shows a less curling of the flap tips and less flexibility than WT and the single mutant I50V. As for the other previous studies, the present results also show that the single mutant I50V decreases the binding affinity of I50V-HIV-pr to TMC, resulting in a drug resistance; whereas the double mutant I50L/A71V increases the binding affinity, and as a result of the stronger binding, the I50L/A71V may be well adapted by the TMC114. The energy decomposition analysis suggests that the increase of the binding for the double mutant I50L/A71V-HIV-pr can be mainly attributed to the increase in electrostatic energy by -5.52 kacl/mol and van der Waals by -0.42 kcal/mol, which are canceled out in part by the increase of polar solvation energy of 1.99 kcal/mol. The I50L/A71V mutant directly increases the binding affinity by approximately -0.88 (Ile50 to Leu50) and -0.90 (Ile50' to Leu50') kcal/mol, accounting 45% for the total gain of the binding affinity. Besides the direct effects from the residues Leu50 and Leu50', the residue Gly49' increases the binding affinity of I50L/A71V HIV-pr to the inhibitor by -0.74 kcal/mol, to which the electrostatic interaction of Leu50's backbone contributes by -1.23 kcal/mol. Another two residues Ile84 and Ile47' also increase the binding affinity by -0.22 and -0.29 kcal/mol, respectively, which can be mainly attributed to van der Waals terms (DeltaT(vdw) = -0.21 and -0.39 kcal/mol). PMID- 22239287 TI - Role of MDR1 C3435T and GABRG2 C588T gene polymorphisms in seizure occurrence and MDR1 effect on anti-epileptic drug (phenytoin) absorption. AB - AIMS: To assess the role of MDR1 and gamma-aminobutyric acid receptor-gamma 2 sub unit (GABRG2) gene polymorphism in seizure susceptibility in generalized seizure (GS) and febrile seizure (FS) patients and to evaluate MDR1 C3435T gene polymorphism's role in absorption of the anti-epileptic drug, phenytoin (PHT) in a cohort of patients. METHODS: One hundred twenty-seven cases of seizure (86 GS and 41 FS) patients were analyzed for MDR1 C3435T and GABRG2 C588T gene polymorphisms using restriction fragment length polymorphism-polymerase chain reaction. Serum PHT levels were analyzed. RESULTS: The T allele of MDR1 C3435T and GABRG2 C588T gene polymorphism was higher in GS in the Indian population compared with controls. From the data in GS, CT and TT genotype carriers of the MDR1 gene and TT genotype carriers of the GABRG2 gene had more recurrent seizures compared with others. MDR1 T allele carriers in the seizure reoccurrence (SR) group of GS and FS were high compared with the well-controlled seizure group (with no seizures after treatment). TT genotype carriers in SR group were high in FS (with regard to MDR1 gene polymorphism) and GS (with regard to GABRG2 gene polymorphism) compared with a well-controlled seizure group. MDR1 C3435T gene polymorphism affects serum PHT levels (p<0.015). Association of dose PHT ratio and genotype groups of MDR1 C3435T gene polymorphism showed a significant association (p<0.05). MDR1*CC genotype was more common in cases with low serum PHT levels.In addition, it is evident that CT and TT genotype carriers have a high percentage of SR with elevated serum PHT levels. CONCLUSIONS: Our results show that the MDR1 3435T and GABRG2 588T alleles play a role in seizure occurrence. Moreover, the MDR1 3435T allele also affects PHT absorption. We suggest MDR1 C3435T and GABRG2 C588T genotyping would be of value in order to lower the risk of concentration-dependent drug toxicity and for better patient management. PMID- 22239288 TI - Association study of apolipoprotein L-I Lys166Glu and Ile244Met gene variants with obesity in Chinese subjects. AB - AIMS: ApoL-I is a newly found component of high-density lipoprotein, and has a potential role in lipid metabolism. This study was mainly to examine the possible association of the ApoL-I gene polymorphism with obesity and plasma lipid levels in the Chinese population. METHODS: Three hundred nineteen Han Chinese (109 obese and 210 nonobese control subjects) in Chengdu area were studied using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The Lys and Glu allele frequencies of the apoL-I gene at the Lys166Glu site in obese and nonobese control groups were 0.830, 0.170 and 0.814, 0.186, respectively. The Ile and Met allele frequencies of the gene at Ile244Met site in the obese and the control groups were 0.844, 0.156 and 0.831, 0.169, respectively. The 166Glu and 244Met allele frequencies of the two polymorphisms in obese subjects were not different from those in the controls, respectively (p>0.05). In the nonobese group, subjects with genotype Lys/Lys at the Lys166Glu site or Ile/Ile at the Ile244Met site had a higher serum mean concentration of triglyceride (TG) as compared with those of corresponding Glu or Met allele carriers (p<0.05). In addition, serum apoC-III and apoE levels were affected by genotypes of Lys166Glu and Ile224Met polymorphisms, respectively, in the control group (all p<0.05). CONCLUSION: The current study, for the first time, provides evidence that Lys166Glu and Ile244Met polymorphisms in apoL-I gene are associated with TG, apoC III, and apoE levels in nonobese Chinese. However, these polymorphisms are not associated with obesity in the population. PMID- 22239289 TI - Pharmacogenetics of clopidogrel: comparison between a standard and a rapid genetic testing. AB - AIMS: CYP2C19 variant alleles are independent predictors of clopidogrel response variability and occurrence of major adverse cardiovascular events in high-risk vascular patients on clopidogrel therapy. Increasing evidence suggests a combination of platelet function testing with CYP2C19 genetic testing may be more effective in identifying high-risk individuals for alternative antiplatelet therapeutic strategies. A crucial point in evaluating the use of these polymorphisms in clinical practice, besides test accuracy, is the cost of the genetic test and rapid availability of the results. One hundred acute coronary syndrome patients were genotyped for CYP2C19*2,*3,*4,*5, and *17 polymorphisms with two platforms: Verigene((r)) and the TaqMan((r)) system. RESULTS: Genotyping results obtained by the classical TaqMan approach and the rapid Verigene approach showed a 100% concordance for all the five polymorphisms investigated. The Verigene system had shorter turnaround time with respect to TaqMan. The cost of reagents for TaqMan genotyping was lower than that for the Verigene system, but the effective manual staff involvement and the relative cost resulted in higher cost for TaqMan than for Verigene. CONCLUSIONS: The Verigene system demonstrated good performance in terms of turnaround time and cost for the evaluation of the clopidogrel poor metabolizer status, giving genetic information in suitable time (206 min) for a therapeutic strategy decision. PMID- 22239290 TI - Candidacy for kidney transplantation of older adults. AB - OBJECTIVES: To develop a prediction model for kidney transplantation (KT) outcomes specific to older adults with end-stage renal disease (ESRD) and to use this model to estimate the number of excellent older KT candidates who lack access to KT. DESIGN: Secondary analysis of data collected by the United Network for Organ Sharing and U.S. Renal Disease System. SETTING: Retrospective analysis of national registry data. PARTICIPANTS: Model development: Medicare-primary older recipients (aged >= 65) of a first KT between 1999 and 2006 (N = 6,988). Model application: incident Medicare-primary older adults with ESRD between 1999 and 2006 without an absolute or relative contraindication to transplantation (N = 128,850). MEASUREMENTS: Comorbid conditions were extracted from U.S. Renal Disease System Form 2728 data and Medicare claims. RESULTS: The prediction model used 19 variables to estimate post-KT outcome and showed good calibration (Hosmer Lemeshow P = .44) and better prediction than previous population-average models (P < .001). Application of the model to the population with incident ESRD identified 11,756 excellent older transplant candidates (defined as >87% predicted 3-year post-KT survival, corresponding to the top 20% of transplanted older adults used in model development), of whom 76.3% (n = 8,966) lacked access. It was estimated that 11% of these candidates would have identified a suitable live donor had they been referred for KT. CONCLUSION: A risk-prediction model specific to older adults can identify excellent KT candidates. Appropriate referral could result in significantly greater rates of KT in older adults. PMID- 22239291 TI - Comparison of safety and efficacy of insulin glargine and neutral protamine hagedorn insulin in older adults with type 2 diabetes mellitus: results from a pooled analysis. AB - OBJECTIVES: To compare the safety and efficacy of adding insulin glargine or neutral protamine Hagedorn (NPH) insulin to existing oral antidiabetic drug (OAD) regimens in adults with type 2 diabetes mellitus. DESIGN: Pooled analysis of data from five randomized controlled trials with similar designs. SETTING: Three hundred forty-two centers in more than 30 countries worldwide. PARTICIPANTS: Randomly selected individuals aged <= 80 with a body mass index <= 40 kg/m(2) and a glycosylated hemoglobin (HbA1c) level of 7.5% to 12.0%. MEASUREMENTS: Fixed and random-effects models were used to compare outcomes after 24 or 28 weeks of treatment (insulin glargine, n = 1,441; NPH insulin, n = 1,254) according to age (>=65, n = 604 vs < 65, n = 2,091) and age based on treatment (e.g., >=65 receiving insulin glargine vs NPH insulin). Outcomes included change in HbA1c, fasting blood glucose (FBG), insulin dose, and hypoglycemia incidence and event rates. RESULTS: At end point, participants aged 65 and older receiving insulin glargine had greater reductions in HbA1c and FBG than those receiving similar doses of NPH insulin. In contrast, for participants younger than 65, there were no statistically significant differences in reductions in HbA1c or FBG between insulin glargine and NPH insulin. Daytime hypoglycemia rates were similar in all groups, although the rates of nocturnal symptomatic and severe hypoglycemia were lower with insulin glargine than NPH insulin. CONCLUSION: Addition of insulin glargine to oral antidiabetic drugs in older adults with poor glycemic control may have modestly better glycemic benefits than adding NPH insulin, with low risk of hypoglycemia. PMID- 22239292 TI - Should care managers for older adults be located in primary care? A randomized controlled trial. AB - OBJECTIVES: To determine the effect of a primary care-based care management initiative on residential care placement and death in a population of frail older adults referred for needs assessment in New Zealand. DESIGN: Randomized controlled trial with follow-up at 3, 6, 12, 18, and 24 months for residential care placement and mortality. SETTING: Fifty-five family physician practices in New Zealand that established a care management initiative for older adults assessed as being at high risk of residential care placement in 2004 to 2006. PARTICIPANTS: Three hundred fifty-one individuals (243 female, 108 male) aged 65 and older (mean 81) who were assessed as being at risk of permanent residential care placement. INTERVENTIONS: The care management program (Coordinator of Services for Elderly) consisted of a nominated health professional care manager geographically aligned to family physicians housed with the family physician or located nearby. MEASUREMENTS: Rates of permanent residential care placement and mortality. RESULTS: The risk of permanent residential care placement or death was 0.36 for usual care (control group) and 0.26 for the care management initiative, a 10.2% absolute risk reduction, with the majority of the risk reduction seen in residential care placement (control group 0.25, intervention group 0.16). CONCLUSION: A family physician-aligned community care management approach reduces frail older adults' risk of mortality and permanent residential care placement. PMID- 22239293 TI - A call for guidance in the use of left ventricular assist devices in older adults. AB - Left ventricular assist devices (LVADs) are approved as "destination therapy" (permanent use without plans for transplantation) in individuals with advanced heart failure who are not candidates for a cardiac transplant; as such, these devices are increasingly being used in older adults. Although LVADs have been shown to increase quality of life and survival, the associated treatment burdens and complications deserve careful consideration. The current study illustrates myriad clinical challenges that can arise during long-term mechanical support using an older adult case history. Current data on LVAD use in older adults is reviewed, and a discussion of relevant points to consider before LVAD implantation in older adults, including advance care planning, assessment of gait and cognition, and the potential for substantial caregiver burden, is undertaken. PMID- 22239294 TI - Age and access to kidney transplantation. PMID- 22239296 TI - Creutzfeldt-Jakob disease: an under-recognized cause of dementia. PMID- 22239297 TI - Paradoxical multiple embolism in an old woman. PMID- 22239295 TI - Destination unknown: the ventricular assist device and the advance of technology. PMID- 22239299 TI - An unusual case of cholecystitis and liver abscesses in an older adult. PMID- 22239298 TI - A case of physical and mental adverse drug reactions associated with levetiracetam in post-stroke epilepsy. PMID- 22239300 TI - Achalasia in a nonagenarian presenting with recurring aspiration pneumonia. PMID- 22239301 TI - Adult-onset Still's disease in an 83-year-old. PMID- 22239302 TI - Break a sweat in the diagnosis and management of a flesh-colored nodule. PMID- 22239303 TI - An unusual case of poststroke hallucinations. PMID- 22239304 TI - Effect of enrollment in the Program of All-inclusive Care for the Elderly on end of-life care. PMID- 22239305 TI - Comparative analysis of state driving laws on crash rates of older drivers in all 50 US states. PMID- 22239306 TI - Fever of unknown origin in an older chinese population. PMID- 22239307 TI - Validation of the frail scale in a cohort of older Australian women. PMID- 22239308 TI - Association between late-life body mass index, waist circumference, and dementia: Kahrizak Elderly Study. PMID- 22239309 TI - Modifiable risk factors in midlife and the age of onset of diabetes mellitus: a 34-year follow-up study. PMID- 22239310 TI - Assessment of cognition, physical performance, and gait in the context of mild cognitive impairment and dementia. PMID- 22239311 TI - Treating older adults with advanced non-small cell lung cancer: a community cancer center experience. PMID- 22239313 TI - Obesity: is it a major risk for developing aspirin resistance in older adults? PMID- 22239312 TI - Prognosis of severe nosocomial sepsis in 33 older adults not eligible for intensive care units. PMID- 22239314 TI - Polypharmacy is an independent risk factor for oropharyngeal isolation of gram negative bacilli in older persons. PMID- 22239315 TI - Visual function in the 'oldest-old' 1 year after comprehensive vision rehabilitation. PMID- 22239317 TI - Predictors of functional recovery in older hospitalized adults. PMID- 22239316 TI - Constipation and metaiodobenzylguanidine myocardial scintigraphy abnormality. PMID- 22239318 TI - Validity of proxy-reported weight for older adults. PMID- 22239319 TI - Oestradiol is a protective factor for non-alcoholic fatty liver disease in healthy men. AB - Visceral fat is a risk factor for non-alcoholic fatty liver disease (NAFLD). A reduction in sex hormones is associated with increased abdominal fat. Thus, we investigated whether reduced testosterone (T) or oestradiol (E2) levels in men are associated with NAFLD and central obesity. The study involved a survey of 1,882 men between 20 and 60 years of age. We detected hepatic fat infiltration by ultrasound. Early morning serum was analyzed for total testosterone (TT), E2, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Free testosterone (FT) was calculated using the Vermeulen method. In the studied population, the prevalence of NAFLD, FSH, LH and SHBG increased with age, TT and FT declined with age, and E2 remained stable. However, in the NAFLD group, TT remained stable, FT and E2 declined, and hepatic fat infiltration increased (P < 0.001 for both). Using multivariate analysis, a correlation was found between E2 and NAFLD, with an odds ratio of 0.954 (95% confidence interval: 0.946-0.967). E2 is one of the protective factors against NAFLD in healthy men. T has no significant correlation with NAFLD. Further investigation would be required to assess the clinical consequences of reduced E2 in men with NAFLD, particularly for men whose TT remained stable. PMID- 22239320 TI - Quantitative chemical proteomics approach to identify post-translational modification-mediated protein-protein interactions. AB - Post-translational modifications (PTMs) (e.g., acetylation, methylation, and phosphorylation) play crucial roles in regulating the diverse protein-protein interactions involved in essentially every cellular process. While significant progress has been made to detect PTMs, profiling protein-protein interactions mediated by these PTMs remains a challenge. Here, we report a method that combines a photo-cross-linking strategy with stable isotope labeling in cell culture (SILAC)-based quantitative mass spectrometry to identify PTM-dependent protein-protein interactions. To develop and apply this approach, we focused on trimethylated lysine-4 at the histone H3 N-terminus (H3K4Me(3)), a PTM linked to actively transcribed gene promoters. Our approach identified proteins previously known to recognize this modification and MORC3 as a new protein that binds H3M4Me(3). This study indicates that our cross-linking-assisted and SILAC-based protein identification (CLASPI) approach can be used to profile protein-protein interactions mediated by PTMs, such as lysine methylation. PMID- 22239324 TI - Shedding new light on tribalism in health care. PMID- 22239323 TI - Do you really want to be a doctor? The highs and lows of identity development. PMID- 22239325 TI - Medical school and on-line learning: does optional attendance create absentee doctors? PMID- 22239326 TI - On aphorisms and the maintenance of biomedicine. PMID- 22239327 TI - Realising the potential value of feedback. PMID- 22239328 TI - Group processes in medical education: learning from social identity theory. AB - CONTEXT: The clinical workplace in which doctors learn involves many social groups, including representatives of different professions, clinical specialties and workplace teams. This paper suggests that medical education research does not currently take full account of the effects of group membership, and describes a theoretical approach from social psychology, the social identity approach, which allows those effects to be explored. METHODS: The social identity approach has a long history in social psychology and provides an integrated account of group processes, from the adoption of group identity through a process of self categorisation, to the biases and conflicts between groups. This paper outlines key elements of this theoretical approach and illustrates their relevance to medical education. RESULTS: The relevance of the social identity approach is illustrated with reference to a number of areas of medical education. The paper shows how research questions in medical education may be usefully reframed in terms of social identity in ways that allow a deeper exploration of the psychological processes involved. Professional identity and professionalism may be viewed in terms of self-categorisation rather than simply attainment; the salience of different identities may be considered as influences on teamwork and interprofessional learning, and issues in communication and assessment may be considered in terms of intergroup biases. CONCLUSIONS: Social identity theory provides a powerful framework with which to consider many areas of medical education. It allows disparate influences on, and consequences of, group membership to be considered as part of an integrated system, and allows assumptions, such as about the nature of professional identity and interprofessional tensions, to be made explicit in the design of research studies. This power to question assumptions and develop deeper and more meaningful research questions may be increasingly relevant as the nature and role of the medical profession change. PMID- 22239329 TI - Maximising medicine through aphorisms. AB - CONTEXT: Aphorisms are succinct sayings that offer advice. They have permanently coloured medical culture and inhabit it in the same way as uncertainty; they are acknowledged, but rarely explored. Little has been written analytically or critically about the meanings and purposes of aphorisms in contemporary medical education, especially as a processional activity that maintains tradition, but both adds to and reframes it. DISCUSSION: We note multiple purposes for medical aphorisms, including roles as heuristics (rules of thumb) for practice, and in the identity construction of the clinician within a community beset by professional uncertainty and accountability. We suggest that aphorisms should be cared for not simply as historical curiosities, but as renewable ways of creating an 'art of memory' in medical education, stimulating recognition and recall as aesthetic rhetorical devices. In this spirit, we encourage the development of aphorisms appropriate for 21st century medicine in a process that should include the involvement of patients in building a proxy public literacy to inform collaboration in clinical encounters. CONCLUSIONS: We propose a novel framework for aphorisms, emphasising strategies to enhance or maximise clinical judgement and professional behaviour, affirm identities, and educate the public via the media. PMID- 22239330 TI - Comparison of UMAT scores and GPA in prediction of performance in medical school: a national study. AB - CONTEXT: Medical schools continue to seek robust ways to select students with the greatest aptitude for medical education, training and practice. Tests of general cognition are used in combination with markers of prior academic achievement and other tools, although their predictive validity is unknown. This study compared the predictive validity of the Undergraduate Medicine and Health Sciences Admission Test (UMAT), the admission grade point average (GPA), and a combination of both, on outcomes in all years of two medical programmes. METHODS: Subjects were students (n = 1346) selected since 2003 using UMAT scores and attending either of New Zealand's two medical schools. Regression models incorporated demographic data, UMAT scores, admission GPA and performance on routine assessments. RESULTS: Despite the different weightings of UMAT used in selection at the two institutions and minor variations in student demographics and programmes, results across institutions were similar. The net predictive power of admission GPA was highest for outcomes in Years 2 and 5 of the 6-year programme, accounting for 17-35% of the variance; UMAT score accounted for < 10%. The highest predictive power of the UMAT score was 9.9% for a Year 5 written examination. Combining UMAT score with admission GPA improved predictive power slightly across all outcomes. Neither UMAT score nor admission GPA predicted outcomes in the final trainee intern year well, although grading bands for this year were broad and numbers smaller. CONCLUSIONS: The ability of the general cognitive test UMAT to predict outcomes in major assessments within medical programmes is relatively minor in comparison with that of the admission GPA, but the UMAT score adds a small amount of predictive power when it is used in combination with the GPA. However, UMAT scores may predict outcomes not studied here, which underscores the need for further validation studies in a range of settings. PMID- 22239331 TI - Does self-reported clinical experience predict performance in medical school and internship? AB - CONTEXT: Medical school admissions committees attempt to select the most qualified applicants. In addition to traditional performance measures, committees often look favourably upon applicants who report previous clinical experience. OBJECTIVES: This study aimed to determine if self-reported clinical experience is a valid indicator of future performance in medical school and internship. METHODS: We collected data for seven year groups (1993-1999; n = 1112) and operationalised trainee performance in terms of five outcomes: cumulative medical school grade point average (GPA); US Medical Licensing Examination (USMLE) Step 1 and 2 scores, and scores on a validated programme director's evaluation measuring intern expertise and professionalism. We then conducted a series of analyses of covariance to compare outcomes in applicants who self-reported previous clinical experience with outcomes in those who did not. In these analyses, the independent variable was self-reported clinical experience (yes/no), the covariate was undergraduate GPA, and the dependent variables were the five performance outcomes. RESULTS: In four of five analyses, we found no differences in the performance of the two groups (clinical experience versus no clinical experience). However, on the cumulative medical school GPA outcome, applicants who reported previous clinical experience had statistically significantly lower cumulative GPAs upon graduation than those who did not report such experience (F(1,940) = 9.35, p = 0.002, partial eta(2) = 0.01 [small effect size]). CONCLUSIONS: Our results suggest that applicants who self-report previous clinical experience may not be better candidates. In fact, on some measures of performance, these applicants may actually perform worse than those who report no clinical experience. PMID- 22239332 TI - A longitudinal integrated placement and medical students' intentions to practise rurally. AB - CONTEXT: Integrated longitudinal rural placements are designed to promote favourable student attitudes towards and facilitate return to rural practice upon graduation. We explored the impact of an integrated placement on medical students' attitudes towards rural practice. METHODS: Data were available from interviews with 10 medical students, 15 clinical supervisors and teachers, three community health staff, and focus groups made up of medical students. Socio cognitive career theory gave insight into the personal, contextual and experiential factors, as well as the career barriers, that influence students' rural practice intentions. Framework analysis was used to develop a thematic framework illustrating the key findings. RESULTS: The longitudinal placement enabled students to achieve personal goals, and enhanced self-efficacy beliefs and orientation towards the complex personal and professional demands of rural practice. The informal curriculum, including multifaceted interactions with patients and their families, clinical teachers and other health care staff, was a vital experiential component. Students assimilated these rich experiences into their practice and evolving notions of professional identity as rural practitioners. Some students had little intention of practising rurally, partly as a result of contextual barriers such as geographic isolation, family and relationship needs, restricted postgraduate training opportunities and limited opportunities for specialist practice. CONCLUSIONS: The richness of the informal curriculum in a longitudinal rural placement powerfully influenced students' intentions to practise rurally. It provided an important context for learning and evolving notions of professionalism and rural professional identity. This richness could be reinforced by developing formal curricula using educational activities based around service-led and interprofessional learning. To overcome the contextual barriers, the rural workforce development model needs to focus on socialising medical students into rural and remote medicine. More generic issues include student selection, further expansion of structured vocational training pathways that vertically integrate with longitudinal rural placements and the maintenance of rurally focused support throughout postgraduate training. PMID- 22239333 TI - Learning from clinical work: the roles of learning cues and credibility judgements. AB - CONTEXT: How learners interpret their clinical experiences to create meaningful learning has not been well studied. We explored experiences considered by doctors to be influential in their learning in order to better understand this process. METHODS: Using a grounded theory approach, we interviewed 22 academic doctors who had been in practice for <= 5 years. Participants were asked to reflect on experiences they considered to have been influential during their training. Constant comparative analysis for emerging themes was conducted iteratively with data collection. RESULTS: A model of clinical learning emerged in which the clinical work itself is central. As they observe and participate in clinical work, learners can attend to a variety of sources of information that facilitate the interpretation of the experience and the construction of knowledge from it. These 'learning cues' include feedback, role models, clinical outcomes, patient or family responses, and comparisons with peers. The integration of a cue depends on the learner's judgement of its credibility. Certain cues, such as clinical outcomes or feedback from patients, are seen as innately credible, whereas other cues, particularly feedback from supervisors, are subjected to critical judgement. CONCLUSIONS: Learners make complex judgements regarding the credibility of information about clinical performance. Credibility judgements influence the learning that arises from the clinical experience. Further understanding of how such judgements are made could guide educators in providing credible information to learners. PMID- 22239334 TI - Faculty staff perceptions of feedback to residents after direct observation of clinical skills. AB - CONTEXT: Performance-based workplace assessments are increasingly important in clinical training. Given the inaccuracy of self-assessment, the provision of external feedback to residents about their clinical skills is necessary for the development of expertise. However, little is known about the processes used by faculty members in giving feedback to residents after observing them with patients. This study explores the factors that underpin faculty members' decisions regarding the feedback they give to residents after directly observing them with patients and the factors that influence how feedback is delivered. METHODS: In 2009, 44 general internal medicine faculty staff responsible for out patient resident teaching from 16 internal medicine residency programmes watched four videotaped scenarios and two live scenarios of standardised residents (SRs) with standardised patients and rated the SRs using the mini-clinical evaluation exercise (mini-CEX) format. Faculty staff also provided feedback to the SRs after the live encounters. After each encounter, faculty staff were individually interviewed using a semi-structured interview. Interviews were videotaped, transcribed and analysed using grounded theory methods. RESULTS: Two broad themes were identified in faculty members' descriptions of the feedback process: variability in feedback techniques, and the factors that influence how faculty staff think and feel about delivering feedback. Multiple approaches to feedback delivery were observed. Faculty members' tensions in balancing positive and negative feedback, their own perceived self-efficacy, their perceptions of the resident's insight, receptivity, skill and potential, the faculty member-resident relationship and contextual factors impacted the feedback process. CONCLUSIONS: The provision of feedback by faculty staff to residents after observing resident patient interactions is a complex and dynamic process and is influenced by many factors. Understanding these cognitive and affective factors may provide insight into potential new approaches to faculty development to improve faculty staff's feedback skills and the effectiveness of their feedback. PMID- 22239335 TI - What is so difficult about managing clinical reasoning difficulties? AB - CONTEXT: Clinical reasoning is the cornerstone of medical competence. Difficulties in this area are often identified late in clinical training. Studies point to challenges faced by clinical educators in their dual roles as clinicians and educators. Little is known about the common, yet complex, issue of how they manage clinical reasoning difficulties. We therefore sought to: (i) describe the current state of affairs in various clinical teaching settings, and (ii) explore the factors that determine the behaviour of clinical educators in this respect. METHODS: Four focus groups were conducted with 26 clinical educators in general practice, internal medicine and emergency medicine in Belgium and Switzerland. Two researchers analysed the transcripts of the focus group discussions using Fishbein's integrative model of behaviour prediction in a theory-driven, immersion-crystallisation process. Experienced faculty members validated the findings. RESULTS: Across diverse settings, the process of identifying and remediating clinical reasoning difficulties was unstructured. Consistent with Fishbein's model, clinical educators' underlying beliefs determined their behaviour. They believed in the apprenticeship model of learning in the clinical environment, in which their educational role was limited to role-modelling and in which residents were responsible for assimilating skills. They were sceptical about the potential impact of remediation. A few more knowledgeable supervisors had a stronger sense of their educational role, but did not implement systematic procedures to manage clinical reasoning difficulties. Environmental constraints were symptomatic of a collective paradigm of residency as an apprenticeship, in which the focus is on clinical duties, rather than as an educational programme. CONCLUSIONS: In order to improve the current state of affairs in the management of clinical reasoning difficulties, a collective paradigm shift is required to alter the perception of residency as an apprenticeship to one of residency as a structured educational programme. Faculty development programmes should be designed in an integrated way so that they not only develop clinical educators' skills, but also modify their beliefs. PMID- 22239336 TI - Patient selection for bedside teaching: inclusion and exclusion criteria used by teachers. AB - CONTEXT: Bedside teaching encounters on hospital wards offer medical students opportunities to learn key medical and interpersonal skills. Although many aspects of bedside teaching have been studied, not much is known about the selection process used by medical teachers to find patients for these encounters. Patient selection could have a substantial impact on medical students' clinical experiences. Therefore, we studied the ways in which medical teachers select patients for bedside teaching and tried to determine the factors that affect patient selection. METHODS: Using a qualitative research approach, we interviewed 15 teachers from three departments within the Medical Faculty at Hamburg University on how they choose patients for bedside teaching encounters. We extracted selection criteria from the transcripts of the audio-recorded interviews and identified other factors that influenced selection. RESULTS: One main category and two minor categories of factors relevant to patient selection were identified: educational; bio-psycho-social, and structural. Medical teachers look primarily for patients who have diseases that fit their conceptions of the learning objectives of the lessons in question. The two minor categories influence their choice of patients in different ways. By finding a balance between these categories, they decide which patients are eligible for participation. As a result of these selection criteria, some patients are more likely to become involved in clinical teaching, whereas others may be omitted. CONCLUSIONS: Patient selection for bedside teaching is based on several criteria. Non-representative patient selection may narrow the learning experiences of medical students. Curriculum planners need to be aware that specific aspects of medical care may be neglected as a result of the exclusion of some patients. Teacher training and additional teaching formats should be provided to ensure that these are covered. PMID- 22239337 TI - Could simulation help operation room conflict management? PMID- 22239338 TI - Mind wandering has an impact in electronic teaching?cases. PMID- 22239339 TI - Pharmacokinetics and relative bioavailability of praziquantel in healthy water buffalo after oral and intramuscular administration. PMID- 22239341 TI - Dynamics and mechanism of DNA repair in a biomimetic system: flavin-thymine dimer adduct. AB - To mimic photolyase for efficient repair of UV-damaged DNA, numerous biomimetic systems have been synthesized, but all show low repair efficiency. The molecular mechanism of this low-efficiency process is still poorly understood. Here we report our direct mapping of the repair processes of a flavin-thymine dimer adduct with femtosecond resolution. We followed the entire dynamic evolution and observed direct electron transfer (ET) from the excited flavin to the thymine dimer in 79 ps. We further observed two competitive pathways, productive dimer ring splitting within 435 ps and futile back-ET in 95 ps. Our observations reveal that the underlying mechanism for the low repair quantum yield of flavin-thymine dimer adducts is the short-lived excited flavin moiety and the fast dynamics of futile back-ET without repair. PMID- 22239343 TI - Influence of dry soil on the ability of Formosan subterranean termites, Coptotermes formosanus, to locate food sources. AB - The effect of barriers of dry soil on the ability of Formosan subterranean termites, Coptotermes formosanus Shiraki (Isoptera: Rhinotermitidae), to construct tunnels and find food was evaluated. Termite movement and wood consumption in a three-chambered apparatus were compared between treatments with dry soil in the center container and treatments where the soil in the center container was moist. When a wood block was located in the release container, termites fed significantly more on that block, regardless of treatment or soil type. In the treatment with dry clay, none of the termites tunneled through the dry clay barrier to reach the distal container. When termites had to tunnel through a barrier of dry sand, topsoil, or clay to reach the sole wood block, there was no effect on wood consumption for the sand treatment, but there was significantly less feeding on wood in the treatments with dry topsoil or clay. When foraging arenas had a section of dry sand in the center, the dry sand significantly reduced tunneling in the distal section after 3 days, but not after 10 days. There was a highly significant effect on the ability of termites to colonize food located in dry sand. Only one feeding station located in dry sand was colonized by termites, compared with 11 feeding stations located in moist sand. PMID- 22239342 TI - Fatal subarachnoid hemorrhage caused by Aspergillus arteritis without angiographic abnormalities. AB - No source of bleeding is detected by angiogram in 15-20% of patients with nonaneurysmal subarachnoid hemorrhage (SAH). This negative angiographic finding might suggest a benign prognosis. We describe a case of fatal SAH caused by Aspergillus arteritis without formation of fusiform dilatation or aneurysms. A 76 year-old man with a 2-month history of progressive visual loss due to pachymeningitis around the optic nerves suffered from SAH in the bilateral sylvian fissures. Repetitive serum galactomannan assay and angiography showed no abnormality. Post mortem examination revealed marked proliferation of Aspergillus in the granulomas of the frontal base dura mater. In addition, major trunks and several branches of the bilateral middle cerebral arteries were invaded by Aspergillus hyphae, which destroyed the walls in the absence of dilatation and aneurysms. Invasive aspergillosis of the CNS often forms a mycotic aneurysm. However, four autopsy cases of nonaneurysmal SAH due to invasive aspergillosis have been reported. The present case is the second autopsy case of Aspergillus arteritis without angiographic abnormality, resulting in fatal SAH. Aggressive and continuous antifungal therapy is absolutely necessary in suspected cases of invasive aspergillosis of the CNS, even if angiography is negative and therapeutic markers of aspergillosis are normal. PMID- 22239344 TI - Nanomechanical recognition of N-methylammonium salts. AB - Turning molecular recognition into an effective mechanical response is critical for many applications ranging from molecular motors and responsive materials to sensors. Herein, we demonstrate how the energy of the molecular recognition between a supramolecular host and small alkylammonium salts can be harnessed to perform a nanomechanical task in a univocal way. Nanomechanical Si microcantilevers (MCs) functionalized by a film of tetra-phosphonate cavitands were employed to screen as guests the compounds of the butylammonium chloride series 1-4, which comprises a range of low molecular weight (LMW) molecules (molecular mass < 150 Da) that differ from each other by one or a few N-methyl groups (molecular mass 15 Da). The cavitand surface recognition of each individual guest drove a specific MC bending (from a few to several tens of nanometer), disclosing a direct, label-free, and real-time mean to sort them. The complexation preferences of tetraphosphonate cavitands toward ammonium chloride guests 1-4 were independently assessed by isothermal titration calorimetry. Both direct and displacement binding experiments concurred to define the following binding order in the alkylammonium series: 2 > 3 ~ 1 ? 4. This trend is consistent with the number of interactions established by each guest with the host. The complementary ITC experiments showed that the host-guest complexation affinity in solution is transferred to the MC bending. These findings were benchmarked by implementing cavitand-functionalized MCs to discriminate sarcosine from glycine in water. PMID- 22239345 TI - Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells. AB - Cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses is thought to play an essential role in certain forms of motor learning. Like hippocampal LTD, cerebellar LTD is mediated by the endocytosis of AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors at postsynaptic sites. However, similar sets of kinases and phosphatases have opposite regulatory effects on hippocampal and cerebellar LTD, although the mechanisms responsible for this difference remain largely unclear. Activity dependent dephosphorylation of stargazin (an AMPA receptor auxiliary protein) by calcineurin regulates hippocampal LTD, but whether and how stargazin is involved in cerebellar LTD is unknown. In this study, we showed that stargazin is highly phosphorylated at basal states and is dephosphorylated by the application of high KCl plus glutamate (K-glu) or of a metabotropic glutamate receptor agonist, (S) 3,5-dihydroxyphenylglycine (DHPG), both of which chemically induced LTD in cerebellar slices. This chemically induced dephosphorylation of stargazin was specifically blocked by a calcineurin inhibitor. Indeed, inclusion of the calcineurin auto-inhibitory peptide in the patch pipette solution completely inhibited the LTD induced by the conjunctive stimulation of PFs and Purkinje cells. Furthermore, in Purkinje cells expressing stargazin-9D, in which all nine serine residues are mutated to aspartate, neither conjunctive stimulus nor DHPG treatment induced LTD. Finally, immunohistochemical analyses revealed that neither K-glu nor DHPG induced the endocytosis of AMPA receptors in Purkinje cells expressing stargazin-9D. Together, these results indicate that hippocampal and cerebellar LTD share a common pathway, namely dephosphorylation of stargazin by calcineurin. PMID- 22239346 TI - Where the rubber meets the road. PMID- 22239348 TI - Defining productivity. PMID- 22239349 TI - 'Best practices'. PMID- 22239350 TI - Ten questions with... Ken Olbrish. PMID- 22239351 TI - Ask George. PMID- 22239352 TI - Achieving interoperability: what's happening out there? PMID- 22239353 TI - Infusion management: one journey in clinical innovation. PMID- 22239354 TI - Vendors and customers: five keys to a productive relationship. PMID- 22239355 TI - Managing multiple recalls in a fast-paced environment. PMID- 22239356 TI - Challenges in maintaining hemodialysis equipment. PMID- 22239357 TI - Leveraging network connectivity for quality assurance of clinical display monitors. AB - The VA Midwest Health Care Network, VISN 23, is one of 21 veteran integrated health service networks (VISN) under the Department of Veterans Affairs. There are approximately 300,000 imaging studies generated per year and currently more than 14,000 picture archiving and communication system (PACS) users in VISN 23. Biomedical Engineering Services within VISN 23 coordinates the provision of medical technology support. One emerging technology leverages network connectivity as a method of calibrating and continuously monitoring clinical display monitors in support of PACS. Utilizing a continuous calibration monitoring system, clinical displays can be identified as out of Digital Imaging and Communications in Medicine (DICOM) compliance through a centralized server. The technical group can receive immediate notification via e-mail and respond proactively. Previously, this problem could go unnoticed until the next scheduled preventive maintenance was performed. This system utilizes simple network management protocols (SNMP) and simple mail transfer protocols (SMTP) across a wide area network for real-time alerts from a centralized location. This central server supports and monitors approximately 320 clinical displays deployed across five states. Over the past three years of implementation in VISN 23, the remote calibration and monitoring capability has allowed for more efficient support of clinical displays and has enhanced patient safety by ensuring a consistent display of images on these clinical displays. PMID- 22239358 TI - Staffing models: how to do it right. PMID- 22239359 TI - The case for: a new name for the field. PMID- 22239360 TI - The case against: a new name for the field. PMID- 22239361 TI - Hospital executive tells CE how to demonstrate value. PMID- 22239362 TI - Certification process keeps wireless devices operating smoothly. PMID- 22239363 TI - The cost of regulating healthcare technology. PMID- 22239364 TI - CO-oximeters. PMID- 22239365 TI - Integrating patient data: safety concerns limit functionality. PMID- 22239366 TI - The value of certification. PMID- 22239367 TI - EKG signals, blanket warmers, and fluid warmers. PMID- 22239369 TI - Using technology to meet increased workload demands. PMID- 22239374 TI - The impact of parental incarceration on children and families. Introduction. PMID- 22239373 TI - Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore. AB - Depolarization of an individual mitochondrion or small clusters of mitochondria within cells has been achieved using a photoactivatable probe. The probe is targeted to the matrix of the mitochondrion by an alkyltriphenylphosphonium lipophilic cation and releases the protonophore 2,4-dinitrophenol locally in predetermined regions in response to directed irradiation with UV light via a local photolysis system. This also provides a proof of principle for the general temporally and spatially controlled release of bioactive molecules, pharmacophores, or toxins to mitochondria with tissue, cell, or mitochondrion specificity. PMID- 22239375 TI - Mentoring children of prisoners: program evaluation. AB - This program evaluation explores Seton Youth Shelters, Mentoring Children's Prisoners (MCP) Program. The following questions were research: (a) Where are the children residing, (b) Are mentoring services effective, (c) How are the children faring emotionally and psychologically, and (d) How often and what form of communication do they use. The findings reveal that youth participating in MCP have an increased interest in school, better relationships with their family, and find speaking to someone about everyday issues or problems helpful. Family members report a positive change in the youth attitude, increase interest in school, completion of homework, and greater interest in their well-being. PMID- 22239376 TI - Children of incarcerated parents: how a mentoring program can make a difference. AB - In spite of the rapid increase in the U.S. prison population, with subsequent increase of parent-prisoners, there are few requirements that social systems serving children take note of a parent's incarceration. Thus the special needs of children of incarcerated parents are almost invisible. Given the multiple risks that these children experience, it is critical to recognize community programs that can help bridge the difficulties children face during their parents' incarceration. This article reports the outcome of a mentoring program specifically targeted to these children. The results show that although mentoring cannot address all of the issues facing these children, it can produce positive outcomes that may mitigate some of the risks associated with being a child of an incarcerated parent. PMID- 22239377 TI - Learning from the ground up: responding to children affected by parental incarceration. AB - Beginning in the fall of 2007, Illinois' Division of Mental Health began piloting an early intervention program targeting children of incarcerated parents. The pilot program was situated within a community-based agency on the Westside of Chicago with a high number of currently and formerly incarcerated community members. This article describes the program theory upon which the pilot program was based, the perceived benefits from the perspective of participants and the service provider agency, lessons learned, and recommendations for making incarceration-sensitive interventions a routine part of children's mental health services. PMID- 22239378 TI - Mapping the critical service needs of adolescent children of prisoners. AB - This study explores the service needs of adolescent children of prisoners by collecting information directly from the youth. The conceptual and empirical literature focused on children of prisoners generally attempts to describe or understand the effects of parental incarceration on prisoners' offspring but frequently fails to include data gathered directly from youth or include their voices in the litany of suggested programs and services. This study employed concept mapping technology to investigate the service needs of 14 adolescent children of prisoners living in an urban city in the Midwest. The findings revealed perceptions of unmet physical, emotional, psychological, and social needs divided into six thematic clusters. The findings also suggest that a single service focus such as mentoring or tutoring may fail to meet the multiple and varied needs that these youth identified, especially those related to basic care such as food and clothing. Participants were asked to rate the themes on importance, and data suggest a high level of consistency between young women and young men. Strength-based solutions were then identified from the data to meet the needs of these youth. PMID- 22239379 TI - Mothers in prison: maintaining connections with children. AB - The significant increase in the number of incarcerated women ensures that many children must live without their mothers for some period of time. Women in prison were interviewed about their efforts to maintain relationships with their children. Mail and telephone contacts were more frequent than actual visits. Almost one half of mothers had never received a visit from their children. This article identifies challenges to the development and maintenance of contact between incarcerated mothers and their children. Recommendations are made for correctional agencies to enhance opportunities for incarcerated mothers to foster positive connections with their children. PMID- 22239380 TI - A qualitative study of incarcerated mothers' perceptions of the impact of separation on their children. AB - Many incarcerated women are mothers, and their children exhibit various responses to the separation that incarceration commands. This exploratory qualitative study examines incarcerated women's perceptions of the consequences of their illegal activity, confinement, and separation from their children on their offspring. The results indicate that although mothers are concerned about their children, they are typically unable to recognize the negative consequences of their actions on their children and their relationship with their children until beginning intensive treatment. Effective treatment must focus on the woman's personal issues along with their parenting abilities and skills to repair these relationships and promote healthy family functioning. PMID- 22239381 TI - Parental incarceration and kinship care: caregiver experiences, child well-being, and permanency intentions. AB - The number of children who reside with a relative because of parental incarceration has increased over the past two decades. Although these children are at risk for negative outcomes, some protective factors, such as a strong and nurturing caregiver experience, buffer the effect of parental incarceration. This study examined the experiences of 72 caregivers and 127 children to learn whether caregivers' stress and strain, readiness and capacity, perceptions of child well being, and unmet service needs are associated with permanency intentions. The study found strong inclinations against adoption, high intentions toward guardianship, and strong associations between these permanency choices and caregivers' experiences and their reports of unmet service needs and makes recommendations for policy, practice, and research advocacy. PMID- 22239382 TI - Does subsequent criminal justice involvement predict foster care and termination of parental rights for children born to incarcerated women? AB - This longitudinal study of 83 incarcerated women, who gave birth during incarceration and retained their parental rights through brief sentences, examines the intersection between subsequent criminal justice involvement postrelease and child welfare outcomes. Ten years of multiple state-level administrative data sets are used to determine if arrest or conviction predict foster care and/or termination of parental rights. Findings indicate that only felony arrest is a significant predictor of foster care involvement. Additionally, 69% of mothers retained legal custody, despite subsequent criminal involvement for many, suggesting supportive parenting programs and resources need to be available to these women throughout and after incarceration. PMID- 22239383 TI - Parental involvement with the criminal justice system and the effects on their children: a collaborative model for researching vulnerable families. AB - Despite the existing body of research examining the effects of imprisonment on incarcerated adults, as of yet, there is no solid empirical evidence for understanding the effects of parental involvement with the criminal justice system involvement (CJSI) on children and families. Accordingly, Columbia University-New York State's Child Psychiatric Epidemiology Group (CPEG), supported by a strong collaboration with The Bronx Defenders, a holistic public defender providing free legal representation, is conducting a longitudinal study examining the effects of parental involvement with the criminal justice system on this population. The study aims to understand, over time, the impact of parental CJSI on their children's mental health, including the effects of the collateral legal damage of CJSI (such as eviction and deportation), substance use, the development of risky behaviors leading to the child's potential involvement with the criminal justice system, as well as protective factors and identification of potential intervention points, which has the ability to inform public policy. PMID- 22239384 TI - Incarcerated fathers and parenting: importance of the relationship with their children. AB - This study examined the relationships of incarcerated fathers (n = 185) with their children while in a maximum security prison. Despite the attention to parental incarceration and at-risk children, the child welfare and corrections literature has focused mostly on imprisoned mothers and children. Demographic, sentence, child-related, and program participation factors were investigated for their influence on father-child relationships. Multiple regression analyses indicated race and sentence contributed to the father's positive perceptions of contacts with their children. Most important, many, though serving lengthy sentences, valued and perceived a positive father-child relationship. Results are discussed in light of implications for future research and social policy. PMID- 22239385 TI - African American fathers and incarceration: paternal involvement and child outcomes. AB - Despite only accounting for 6% of the general population, African American males represent nearly 50% of the prison population. To investigate the impact of mass incarceration on African American families, data from the Fragile Families and Child Well-Being study were analyzed. Specifically, the purpose of this study was to examine the impact of previous incarceration on African American fathers' instrumental and affective involvement with their children, and the extent to which their previous incarceration influences their children's behavior. Results revealed that 51% of the fathers in the sample had been incarcerated by their child's fifth birthday. The results also revealed that these fathers fared worse economically and were less involved with their children. Moreover, the children of previously incarcerated fathers had significantly worse behavioral problems than the children of fathers who had never been incarcerated. PMID- 22239386 TI - Positron emission tomography in psychiatric disorders. AB - Positron emission tomography (PET) has been widely used in the study of psychiatric disorders. It has been used most extensively in research to determine pathophysiology as well as prognostic and diagnostic information, and response to various interventions in different psychiatric disorders. PET imaging has also been used in the clinical setting, although primarily to help differentiate or diagnose specific disorders. With the continued development of a large array of radiopharmaceuticals that can evaluate all of the components of different neurotransmitter systems (such as serotonin and dopamine), PET imaging will continue to play a key role in research and clinical applications for psychiatric disorders. PMID- 22239387 TI - Genetic and nutritional effects on male traits and reproductive performance in Tribolium flour beetles. AB - In Tribolium flour beetles and other organisms, individuals migrate between heterogeneous environments where they often encounter markedly different nutritional conditions. Under these circumstances, theory suggests that genotype by-environment interactions (GEI) may be important in facilitating adaptation to new environments and maintaining genetic variation for male traits subject to directional selection. Here, we used a nested half-sib breeding design with Tribolium castaneum to partition the separate and joint effects of male genotype and nutritional environment on phenotypic variation in a comprehensive suite of life-history traits, reproductive performance measures across three sequential sexual selection episodes, and fitness. When male genotypes were tested across three nutritional environments, considerable phenotypic plasticity was found for male mating and insemination success, longevity and traits related to larval development. Our results also revealed significant additive genetic variation for male mating rate, sperm offence ability (P(2)), longevity and total fitness and for several traits reflecting both larval and adult resource use. In addition, we found evidence supporting GEI for sperm defence ability (P(1)), adult longevity and larval development; thus, no single male genotype outperforms others in every nutritional environment. These results provide insight into the potential roles of phenotypic plasticity and GEI in facilitating Tribolium adaptation to new environments in ecological and evolutionary time. PMID- 22239388 TI - Relationship proximity to victims of witnessed community violence: associations with adolescent internalizing and externalizing behaviors. AB - Witnessing community violence has been linked with several adverse outcomes for adolescents, including emotional and behavioral problems. Among youth who have witnessed community violence, proximity to the victim of community violence is one factor that may determine, in part, the nature of adolescents' responses to community violence exposure. The present study examines whether relationship proximity to the victim of community violence is associated with internalizing and externalizing behaviors among a sample of urban and predominantly African American adolescents (N = 501) who have witnessed community violence. In 10th grade, participants reported whether they had witnessed 10 community violence events during the past year, and, if so, whether the victim of the violence was a family member, close friend, acquaintance, or stranger. Witnessed community violence against a family member or close friend was associated with depressive symptoms, and witnessed community violence against known individuals was associated with anxiety symptoms. Witnessing community violence against familiar persons and strangers was linked with aggressive behavior. Gender differences in these associations and implications for assessment and intervention with community violence-exposed youth are discussed. PMID- 22239389 TI - Predictors of parental monitoring among families with a runaway adolescent. AB - Extensive research shows that parental monitoring is a critical factor in child adjustment. Using parent and adolescent reports, this study sought to examine predictors of parental monitoring among an understudied, high-risk sample of runaway adolescents. Parent-reported depressive symptoms, couple (romantic) relationship satisfaction, and adolescent-reported bonding with parents were used as predictors of both child- and parent-reported monitoring. Findings indicated that, among parents, the couple relationship was the primary predictor of monitoring, whereas among adolescents, the parent-child relationship was the primary predictor. Maternal depressive symptoms were unrelated to monitoring. These findings suggest the utility of considering monitoring as an interpersonal phenomenon rather than primarily a parent- or child-driven phenomenon. PMID- 22239390 TI - Risk for arrest: the role of social bonds in protecting foster youth making the transition to adulthood. AB - This study examines a sample of foster youth at the onset of the transition to adulthood and explores how social bonds are related to the risk of arrest during adulthood. Drawing from official arrest records, event history models are used to examine the time to arrest. Because individuals may be at risk for different types of crime, competing risk regression models are used to distinguish among arrests for drug-related, nonviolent, or violent crimes. Between the ages of 17 18 and 24, 46% of former foster youth experience an arrest. Arrests were evenly distributed across drug, nonviolent, and violent crimes columns. Although findings fail to support the significance of social bonds to interpersonal domains, bonds to employment and education are associated with a lower risk for arrest. Child welfare policy and practice implications for building connections and protections around foster youth are discussed. PMID- 22239391 TI - Mental illness, violence risk, and race in juvenile detention: implications for disproportionate minority contact. AB - Disproportionate minority contact (DMC) is a pervasive problem throughout the juvenile justice system. This article explored whether mental illness may be an explanatory factor in DMC. Data such as measures of violence risk and symptoms of mental illness were taken from intake interviews with 482 detained youth in Connecticut. Results indicated that racial minorities in detention have significantly lower violence risk than Caucasians but are disproportionately represented among detention populations relative to their proportions in the general population. In addition, DMC in these data was not explained by mental illness, seriousness of charges, violence risk, age, or gender. We suggest that mandated efforts to reduce DMC will need to address more than improving behavior or reducing symptoms of mental illness among detained minority youth. Instead, efforts should be focused on reducing the racial disparity evident in decisions made within the juvenile justice system. PMID- 22239392 TI - Predictors and responses to the growth in physical violence during adolescence: a comparison of students in Washington State and Victoria, Australia. AB - This study investigates patterns in violence over 3 time points in early- to mid adolescence in 2 statewide representative samples of youth, one in Washington State, USA, and the other in Victoria, Australia. Comparable data collection methods in both states were used to cross-nationally compare patterns of violence, risk factors, and responses to violence (school suspensions and arrests) in 2 policy contexts. Risk factors include early use of alcohol, binge drinking, involvement with antisocial peers, family conflict, poor family management, sensation seeking, and bully victimization. These are modeled as correlates of initial violence and predictors of change in violence over a 3-year period, from ages 12-15, for participating youth. Results suggest that patterns and predictors of violence are mostly similar in the 2 states. Initial levels of violence (age 13) and change over time in violence were associated in both states with more youth school suspensions and more police arrests in Grade 9. Some cross national differences were also shown. For example, correlations of violence with gender and violence with binge drinking were stronger in Victoria, whereas correlations of violence with early use of alcohol and with antisocial peer involvement were stronger in Washington State. Antisocial peer involvement and family conflict were significant predictors of a gradual increase in violence from Grades 7-9 for youth in Victoria only. Implications are discussed with attention to prevention and intervention efforts. PMID- 22239393 TI - Measuring school-related subjective well-being in adolescents. AB - The tripartite model of subjective well-being (SWB) incorporates 3 components: frequent positive emotions, infrequent negative emotions, and an overall positive evaluation of life circumstances (Diener, Suh, Lucas, & Smith, 1999). In light of the large amount of time that youth spend in school, this study investigated a tripartite model of school-related SWB among adolescents, based on 3 measures of SWB appropriate for adolescents. The measures included a measure of school satisfaction (SS) and measures of positive and negative emotions experienced specifically during school hours. Confirmatory factor analysis was conducted to analyze the factorial validity of 3- and 4-factor models of school-related SWB in a sample of 921 adolescents. Results indicated that a 4-factor model comprised of positive emotions, negative emotions, fear-related negative emotions, and SS best described the structure of school-related SWB in the current sample. Results also revealed a comparable factor structure for male and female students. The study points to the possible benefits of a contextualized approach to SWB that takes into account the specific environments in which adolescents live. PMID- 22239394 TI - Subjective well-being in school environments: promoting positive youth development through evidence-based assessment and intervention. AB - Research on subjective well-being indicates that it is associated with academic success and positive school functioning. Despite a wealth of empirical research demonstrating the benefits of interventions aimed at increasing middle and high school students' well-being, few educational institutions have adopted evidence based curricula that address this construct as a means of promoting future academic and social achievement. In addition, numerous studies have begun to identify several factors that contribute to well-being and thus have helped children and adolescents to be successful in both academic and social domains. These critical factors include personal goal setting, structured mentoring or life coaching, increasing gratitude, problem solving, and interpersonal skills. The present article provides a broad discussion of relevant research findings on these factors and advocates for the adoption of curricula that incorporate these components in order to ensure that best practices are utilized in the school environment and for positive youth development. Lastly, a theoretical proposal for empirically based assessment and interventions that encompass key components associated with increased child and adolescent well-being is provided. PMID- 22239395 TI - Perceptions of teachers' support, safety, and absence from school because of fear among victims, bullies, and bully-victims. AB - This study examines the distribution of the types of involvement in school violence (bullies, victims, bully-victims, and students not involved in violence) among the general population of Israeli school students. The prevalence of these different types of involvement was also examined according to gender, age or school level (junior high vs. high school), and ethnicity (Jewish vs. Arab). Further, the study examines the relationships between type of involvement in school violence and students' perceptions of teachers' support, safety, and absence from school because of fear. Data were obtained from a nationally representative, stratified sample of 13,262 students in grades 7-11 who responded to a self-report questionnaire on victimization by, and perpetration of, school violence and on perceptions of school climate. Data revealed that 3.6% of all students were victims of bullying (18.5% of those involved in violence). The proportion of bully-victims among male students was 6.4% (21.9% of all involved) compared with 1.1% (11.2% of all involved) among females. Bully-victims reported the lowest levels of teacher support and feelings of security and missed school because of fear significantly more often. The results point to the uniqueness of the bully-victim group. This group presents multiple challenges for school staff with these students needing special attention. PMID- 22239396 TI - Restraint and seclusion use in U.S. school settings: recommendations from allied treatment disciplines. AB - Restraint and seclusion (R&S) are high risk, emergency procedures that are used in response to perceived violent, dangerous situations. They have been employed for years in a variety of settings that serve children, such as psychiatric hospitals and residential treatment facilities, but are now being recognized as used in the public schools. The field of education has begun to examine these practices in response to national scrutiny and a Congressional investigation. The fields of mental health and child welfare were similarly scrutinized 10 years ago following national media attention and have advanced R&S practice through the adoption of a prevention framework and core strategies to prevent and reduce use. A review of the evolution of the national R&S movement, the adverse effects of these procedures, and a comprehensive approach to prevent their use with specific core strategies such as leadership, workforce development, and youth and family involvement in order to facilitate organizational culture and practice change are discussed. Proposed guidelines for R&S use in schools and systemic recommendations to promote R&S practice alignment between the child-serving service sectors are also offered. PMID- 22239397 TI - Seclusion and restraint practices in residential treatment facilities for children and youth. AB - Policymakers, advocates, and families remain concerned about the use of seclusion and restraint in residential treatment facilities for children and youth. This study used data from 2 national surveys to examine the extent to which residential treatment facilities consistently implement certain practices following incidents of seclusion or restraint. The study found that 76% of facilities reported having secluded or restrained youth in the previous year; 34% of these facilities reported that, following such incidents, they always debrief the youth, family, and staff; notify the attending physician; and record the incident in the treatment plan. Accredited facilities and those that conduct a trauma assessment upon admission were more than twice as likely as others to consistently implement these practices. States and providers should continue to monitor seclusion and restraint practices and identify opportunities for quality improvement. PMID- 22239398 TI - Can policy reform reduce seclusion and restraint of schoolchildren? PMID- 22239399 TI - 'I hold on to my teddy bear really tight': children's experiences when they are home alone. PMID- 22239400 TI - Education deformed: no child left behind and the race to the top. 'This almost reads like our business plans'. PMID- 22239401 TI - Advocacy: critical component in a comprehensive mental health system. AB - Although rights protection and best interest perspectives are frequently viewed as diametric opposites, mental health advocacy is an important strategy in pursuit of both civil rights and therapeutic goals for people with mental illness. Independent, client-centered advocacy supports the attainment of consumer-identified goals for recovery, equality, and social inclusion and mitigates the negative consequences of stigma and discrimination. Advocacy strives to return decision-making authority to consumers and thus to empower them to play a more central role in their own care, treatment, rehabilitation, and life choices. PMID- 22239402 TI - Using latent growth curve modeling to examine changes in mental health outcomes for children enrolled in a system of care. AB - MeckCARES, a system of care (SOC) in Mecklenburg County, North Carolina, is designed to serve youth with severe emotional disturbances and their families. This study employed latent growth curve (LGC) modeling to examine (a) the degree to which youth improved on indicators of adjustment over the course of the first year of enrollment in MeckCARES, and (b) the services or demographic variables associated with individual differences in the rate of change over time. Participant caregivers (N = 121) reported on 3 major indicators of youth adjustment at baseline, 6-month follow-up, and 12-month follow-up. Primary analyses indicated that there was a modest yet significant improvement in all 3 outcome measures over the first year of enrollment in MeckCARES. Additional analyses revealed that caregiver reports of receiving case management at any point in the first year were associated with improvement in behavioral and emotional strengths as well as a reduction in psychological and behavioral symptoms. No significant differences in rate of change were observed based on caregiver-reported receipt of individual or family therapy nor any demographic variables. These findings suggest that MeckCARES may be particularly effective when youth are receiving case management services. Additional implications for practice are discussed. PMID- 22239403 TI - Educational outcomes in a system of care for children with emotional disturbance. AB - In North Carolina, only 69% of high school students graduate in 4 years; however, recent data suggest that only 42% of students with mental and emotional disabilities graduate. MeckCARES, a system of care (SOC) in Mecklenburg County, North Carolina, is designed to serve youth with severe emotional disturbances and their families. The SOC philosophy is a prominent family-focused approach intended to provide comprehensive, coordinated networks of services, tailored to the needs of the child and family, while emphasizing the strengthening of natural community supports. In addition to other mental health objectives, a particular goal of MeckCARES is to address specific school-based needs of system-identified youth to improve educational outcomes and reduce the risk of dropping out. This study sought to assess empirically the impact that enrollment in MeckCARES has on graduation precursors; namely, grades, suspensions, and absences. This study found that, on average, enrollment in MeckCARES is not associated with positive changes in educational variables. Implications of these findings are discussed, as are future directions. For example, additional research is needed with more sensitive measurement and data collection procedures (i.e., access to graduation rates and Medicaid information) to adequately assess the impact of enrollment in MeckCARES on educational outcomes. PMID- 22239404 TI - The effects of caregiver social connections on caregiver, child, and family well being. AB - This study examines the degree to which caregiver social connectedness influences the effects of strain associated with caring for a child with severe emotional disturbance (SED) on caregiver well-being. We propose a model describing the relationships among the variables of interest and investigate elements of this model. Caregiver strain and social connections were significantly associated with caregiver well-being. Although, no significant interaction effects of caregiver strain and social connections were detected, study findings suggest that caregiver well-being can affect child progress and adjustment. Implications for child- and family-serving systems are considered. PMID- 22239405 TI - The moderating effect of adherence-promoting interventions with clients on evidence-based practices for children and adolescents with mental health problems. AB - Poor adherence of children and adolescents to evidence-based psychosocial interventions remains a fundamental impediment to treatment effectiveness. To maintain client adherence, researchers and clinicians have employed a number of adherence-promoting strategies, from telephone calls and letters to providing transportation costs and child care to motivational enhancement therapies. However, the influence of adherence promoters on intervention outcomes has not been reported. This study examined the moderating effect of adherence-promoting strategies in a survey and meta-analysis of randomized clinical trials of cognitive behavioral treatments, interpersonal therapy, and psycho-education for children and adolescents with mental health problems (k = 33). Results indicated the type and intensity of adherence promoters' moderated study effect sizes according to client characteristics (age, gender, diagnosis). Preliminary findings suggest that males had higher effect sizes when more intensive adherence promoting efforts were employed. Adherence-promoting efforts were associated with lower effect sizes for youths who were diagnosed with externalizing disorders. Results of this study suggest directions for future research to clarify clinical guidelines to maximize retention in evidence-based psychotherapy. PMID- 22239406 TI - Prenatal diagnosis of hemoglobinopathies by pyrosequencing: a more sensitive and rapid approach to fetal genotyping. AB - Prenatal diagnosis of the hemoglobinopathies by fetal DNA analysis is currently performed in most countries, either by DNA sequencing, restriction enzyme polymerase chain reaction (RE-PCR) or the amplification refractory mutation system (ARMS). These methods are time consuming and prolong the turnaround time for diagnosis. We here describe a method utilizing pyrosequencing for the prenatal diagnosis of 12 common nondeletional alpha- and beta-globin gene mutations in the UK population. In particular, it replaced the diagnosis of sickle cell disease by RE-PCR and for the diagnosis of beta-thalassemia (beta thal) by Sanger DNA sequencing. We have genotyped 148 chorionic villi and 29 uncultured amniotic fluid DNA samples by pyrosequencing and found 100% concordance with the fetal diagnosis result obtained by ARMS-PCR or DNA sequencing. Pyrosequencing was more robust, revealing an 83% decrease in diagnostic failures using uncultured amniocyte DNA samples, and also quantitative, revealing one case of allelic imbalance due to maternal DNA contamination. Overall, we found pyrosequencing to be simpler, more robust, quicker, and less expensive than conventional sequencing and RE-PCR, making it a good choice for rapid and cost-effective prenatal diagnosis of thalassemia and sickle cell disease. PMID- 22239407 TI - Differences between protein dynamics of hemoglobin upon dissociation of oxygen and carbon monoxide. AB - Protein dynamics of human adult hemoglobin (HbA) upon ligand photolysis of oxygen (O(2)) and carbon monoxide (CO) was investigated using time-resolved resonance Raman (TR(3)) spectroscopy. The TR(3) spectra of the both photoproducts at 1-ns delay differed from that of the equilibrium deligated form (deoxy form) in the frequencies of the iron-histidine stretching [nu(Fe-His)] and methine wagging (gamma(7)) modes, and the band intensity of pyrrole stretching and substituent bending (nu(8)) modes. Spectral changes of the O(2) photoproduct in the submicrosecond region were faster than those of the CO photoproduct, indicating that the structural dynamics following the photodissociation is ligand dependent for HbA. In contrast, no ligand dependence of the dynamics was observed for myoglobin, which has a structure similar to that of the subunit of HbA. The structural dynamics and relevance to the functionality of HbA also are discussed. PMID- 22239409 TI - Isothermal crystallization of short polymer chains induced by the oriented slab and the stretched bundle of polymer: a molecular dynamics simulation. AB - Information on the interfacial interaction is vital in understanding the crystallization of short polymer chains around oriented nuclei. However, this interaction is difficult to observe at the atomic level. Molecular dynamics simulations are performed to investigate the structural formation of polymer chains induced by the highly oriented slab or the stretched bundle of polymer chains. The results show that the surface-induced crystallization of polymer chains is greatly influenced by the foreign surface on the crystal structure and the morphology of the polymers, hence providing molecular-level support for previous experimental observations [Lotz et al. Macromolecules 1993, 26, 5915 and Yan et al. Macromolecules 2009, 42, 9321]. The order parameter S and the configurations show that the ability of the polypropylene (PP) slab to induce the polyethylene (PE) melt crystallization is weaker than that of the PE slab and that the short PE chains display multiple orientations on the PP slab. In addition, the crystallization rate was found to be dependent on the lattice matching between the free chains and the substrates on the contact lattice planes. PMID- 22239408 TI - Toll-like receptor (TLR)-7 and -8 modulatory activities of dimeric imidazoquinolines. AB - Toll-like receptors (TLRs) are pattern recognition receptors that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but are structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines are of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result in TLR7-antagonistic compounds which may be of value in addressing innate immune activation-driven immune exhaustion observed in HIV. We describe the syntheses and evaluation of TLR7 and TLR8 modulatory activities of dimeric constructs of imidazoquinoline linked at the C2, C4, C8, and N(1)-aryl positions. Dimers linked at the C4, C8, and N(1)-aryl positions were agonistic at TLR7; only the N(1)-aryl dimer with a 12-carbon linker was dual TLR7/8 agonistic. Dimers linked at C2 position showed antagonistic activities at TLR7 and TLR8; the C2 dimer with a propylene spacer was maximally antagonistic at both TLR7 and TLR8. PMID- 22239410 TI - HOXB7 expression is a prognostic factor for oral squamous cell carcinoma. PMID- 22239411 TI - Growth-dependent chemical and mechanical properties of cuticular membranes from leaves of Sonneratia alba. AB - Chemical and mechanical properties of the leaf cuticular membranes (CMs) of a mangrove, Sonneratia alba J. Smith, were analysed at various leaf development stages to evaluate their tolerance to environmental stress. Our analyses demonstrate that the CMs from leaves of S. alba at different growth stages are generally rich in wax (21.5-25.7%) and cutin (52.4-63.4%) which rapidly accumulate at the early stages of leaf growth, while cutan (4.3-10.3%) and polysaccharide (2.3-7.7%) continuously accumulate throughout growth. Immature CMs are physically weak and highly viscoelastic. However, CMs become strengthened and stiffened during leaf expansion and maturation (by factors of about 1.5 and 2.4, respectively) while their flexibility decreases (68-83% decrease). Finally, the CMs lose their strength at the senescent stage (30-43% decreasement). Correlation analysis between chemical composition and mechanical properties revealed that the cutin matrix is mainly responsible for the high viscoelastic properties of CMs, while wax, cutan and polysaccharide contributed to their elasticity. Wax also affected the strength of the CMs, whereas cutan and polysaccharide showed rigidizing effect. Rapid accumulation of wax and cutin in the CMs after bud burst followed by the mechanical supports of cutan and polysaccharide in an isolateral manner contributed to the remarkable environmental tolerance of S. alba. PMID- 22239413 TI - A complex of methylthioadenosine/S-adenosylhomocysteine nucleosidase, transition state analogue, and nucleophilic water identified by mass spectrometry. AB - An enzyme-stabilized nucleophilic water molecule has been implicated at the transition state of Escherichia coli methylthioadenosine nucleosidase (EcMTAN) by transition state analysis and crystallography. We analyzed the EcMTAN mass in complex with a femtomolar transition state analogue to determine whether the inhibitor and nucleophilic water could be detected in the gas phase. EcMTAN inhibitor and EcMTAN-inhibitor-nucleophilic water complexes were identified by high-resolution mass spectrometry under nondenaturing conditions. The enzyme inhibitor-water complex is sufficiently stable to exist in the gas phase. PMID- 22239414 TI - Laparoscopic skills training using inexpensive box trainers: which exercises to choose when constructing a validated training course. PMID- 22239415 TI - Prevalence and risk factors for third- and fourth-degree perineal lacerations during vaginal delivery: a multi-country study. AB - OBJECTIVE: To investigate the prevalence and risk factors of third- and fourth degree perineal lacerations in 24, mainly developing, countries. DESIGN: Analysis using cross-sectional data from the WHO Global Survey on Maternal and Perinatal Health. SETTING: Seven African, nine Asian and eight Latin American countries. POPULATION: Women at admission to hospital for delivery in 373 facilities between 2004 and 2008. METHODS: We estimated the country-wise prevalence of third- and fourth-degree perineal lacerations, and conducted region-wise multivariate logistic regression analyses to identify its risk factors. MAIN OUTCOME MEASURES: Prevalence and risk factors of third- and fourth-degree perineal lacerations. RESULTS: A total of 214,599 women who underwent vaginal delivery were analysed. The prevalence of third- and fourth-degree perineal lacerations ranged widely across countries [from 0.1% (China, Cambodia, India) to 15.0% (Philippines)] and facilities (from null to 76.3%). After the deletion of facilities reporting no third- or fourth-degree perineal lacerations, and also highly outlying facilities, the range in prevalence was 0.1% (Uganda) to 1.4% (Japan). Forceps assisted delivery, nulliparity and high birthweight were significant risk factors in all three regions. Vacuum-assisted delivery was also a significant risk factor in Africa and Asia. CONCLUSIONS: Misdiagnosis of third- and fourth-degree perineal lacerations in developing countries may be common. Correct recognition and diagnosis may lead to timely treatment and fewer sequelae. Risk factors of third- and fourth-degree perineal lacerations in developing countries were similar to those previously reported from developed countries. PMID- 22239416 TI - Development of de novo prolapse in untreated vaginal compartments after prolapse repair with and without mesh: a secondary analysis of a randomised controlled trial. AB - OBJECTIVE: To compare the de novo prolapse rate in the untreated vaginal compartments following conventional vaginal prolapse repair and tension-free vaginal mesh repair. DESIGN: Secondary analysis of a randomised controlled trial. SETTING: Thirteen centres in the Netherlands. POPULATION: Women with recurrent pelvic organ prolapse stage II or higher. METHODS: Random assignment to either conventional vaginal native tissue repair or vaginal mesh insertion. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: de novo pelvic organ prolapse stage II or higher in the untreated vaginal compartments at 12 months after surgery. SECONDARY OUTCOMES: de novo pelvic organ prolapse at and beyond the hymen, de novo prolapse beyond the hymen and prolapse domain scores of the Urogenital Distress Inventory. RESULTS: At 12 months ten of 59 women (17%) in the conventional group versus 29 of 62 women (47%) in the mesh group were diagnosed with a de novo pelvic organ prolapse stage II or higher in the untreated compartment (P < 0.001, odds ratio 4.3, 95% confidence interval 1.9-10.0). Additional apical support to a mesh augmented anterior repair significantly reduced the de novo prolapse rate. Women with a de novo prolapse in the mesh-treated group demonstrated significantly higher mean bother scores on the domain genital prolapse of the Urogenital Distress Inventory score (13.1 +/- 24.2) compared with those without de novo prolapse (2.9 +/- 13.9) (P = 0.03). CONCLUSION: Mesh-augmented prolapse repair in only one vaginal compartment is associated with a higher de novo prolapse rate in the untreated compartments compared with conventional vaginal native tissue repair in women with recurrent pelvic organ prolapse. PMID- 22239417 TI - Outcomes following hysterectomy or endometrial ablation for heavy menstrual bleeding: retrospective analysis of hospital episode statistics in Scotland. PMID- 22239420 TI - Level of birth care and operative delivery rates. PMID- 22239421 TI - Shift work and adverse pregnancy outcomes: comments on a recent meta-analysis. PMID- 22239423 TI - Is first-trimester crown-rump length associated with birthweight? PMID- 22239424 TI - Beyond the numbers: reporting potentially avoidable perinatal deaths. PMID- 22239429 TI - Pericytes as a new target for pathological processes in CADASIL. AB - CADASIL is a generalized angiopathy caused by mutations in NOTCH 3 gene leading to degeneration and loss of vascular smooth muscle cells (VSMC) in small arteries and arterioles. Since the receptor protein encoded by NOTCH 3 gene is expressed not only on VSMC but also on pericytes, pericytes and capillary vessels can be damaged by CADASIL. To check this hypothesis we examined microvessels in autopsy brains and skin-muscle biopsies of CADASIL patients. We found degeneration and loss of pericytes in capillary vessels. Pericytes were shrunken and their cytoplasm contained numerous vacuoles, big vesicular structures and complexes of enlarged pathological mitochondria. Degenerative changes were also observed within endothelial-pericytic connections, especially within peg-and-socket junctions. Nearby pericyte cell membranes or inside infoldings, deposits of granular osmiophilic material (GOM) were usually seen. In the affected capillaries endothelial cells revealed features of degeneration, selective death or swelling, leading to narrowing or occlusion of the capillary lumen. Our findings indicate that in CADASIL not only VSMC but also pericytes are severely damaged. Pericyte involvement in CADASIL can result in increased permeability of capillary vessels and disturbances in cerebral microcirculation, leading to white matter injury. Since in capillaries pericytes regulate vessel contractility, their degeneration can also cause defective vasomotor reactivity, the phenomenon observed very early in CADASIL, before development of histopathological changes in vessel walls. PMID- 22239430 TI - Phenolic composition and antioxidant effect of aqueous extract of Arisaema cum Bile, the Oriental Herb Medicine, in human fibroblast cells. AB - Phenolic composition and antioxidant activities of the aqueous extract of Arisaema cum Bile, which is widely used as a folk medicine in Korea, were determined. Phenolic composition profile revealed that the aqueous extract is rich in sinapic acid (13.14 mg/100 g extract), catechin (9.88 mg/100 g extract), neohesperidin (7.38 mg/100 g extract), and chlorogenic acid (3.64 mg/100 g extract). The aqueous extract effectively scavenged toward 2,2-diphenyl-1 picrylhydrazyl (90.63%), hydrogen peroxide (98.13%), and hydroxyl radical (59.62%) at 2.0 mg/mL, and also showed high reducing power. In cytotoxic evaluation, the aqueous extract exhibited no significant cytotoxicity in human fibroblast, and it also exhibited appreciable suppression of intracellular reactive oxygen species and inhibition of lipid peroxidation. In addition, the aqueous extract upregulated the level of glutathione in a dose-dependent manner. Taken together, the aqueous extract of Arisaema cum Bile could be considered as a potential natural source that may be useful for curing diseases arising from oxidative deterioration. PMID- 22239431 TI - Improving radioresponse through modification of the tumor immunological microenvironment. AB - Radioresponse is influenced by factors apart from the targeted cancer cells; in fact, endothelial cells and infiltrating immune cells within the tumor microenvironment (TME) are the two main components affecting the outcome of radiotherapy. The benefits of fractionated radiotherapy are attenuated through the upregulation of hypoxia inducible factor-1 alpha and vascular endothelial growth factor. The therapeutic effect of antiangiogenic agents is counteracted by the mobilization of endogenous proangiogenic cells to the TME. This study highlights the importance of radiation timing within a vascular normalization window and discusses the importance of immune cells that comprise the microenvironment. A balance between favorable tumor-infiltrating immune cells, including cytotoxic T cells, natural killer cells, and dendritic cells, and the unfavorable cells, such as tumor-associated macrophages and regulatory T cells, determines the final tumor-control probability. The reciprocal complementation between combinations of radiotherapy and immunotherapy strategies through modulation of the tumor immunological microenvironment may yield promising results in the future. PMID- 22239432 TI - Predictors of long-term outcome from intraperitoneal radioimmunotherapy for ovarian cancer. AB - Data was analyzed from 92 patients > 5 years after intraperitoneal (IP) radionuclide therapy (RIT) with (90)Y- or (177)Lu-CC49 to determine prognostic factors. Patients had CC49 antibody-reactive ovarian cancer confined to the abdominal cavity after primary debulking and chemotherapy. The first 27 patients received IP (177)Lu-CC49 alone; the remainder received Interferon (IFN), to increase the expression of the tumor-associated glycoprotein-72 (TAG-72) antigen, +/- IP paclitaxel (25-100 mg/m(2)) 2 days before RIT. Factors assessed by univariate (and some multivariate) analysis included age, race, body size, interval between initial diagnosis and RIT, interval between 2nd look surgery and RIT, (90)Y versus (177)Lu, MBq dose, paclitaxel dose, grade of tumor, extent of initial surgery, size of disease deposits prior to RIT, intensity of TAG reactivity, the addition of unlabeled antibody, and the development of human anti mouse antibody and/or serum sickness after murine antibody. A statistically significant improvement in progression-free survival (p <= 0.05) was noted for less bulky disease and younger age. Administration of paclitaxel plus IFN, an immune response, and use of (90)Y showed a favorable nonsignificant trend. Dose escalation of radionuclide did not change risk of progression; thus, this therapy may have therapeutic efficacy at modest dose levels. PMID- 22239433 TI - Targeting the PI3K signaling pathway in cancer therapy. AB - INTRODUCTION: The PI3K signaling pathway is involved in the regulation of cancer cell growth, motility, survival and metabolism. The pathway is frequently active in many different types of cancer-e.g., breast, bladder, prostate, thyroid, ovarian and NSCLC. Targetable genetic aberrations in this pathway give us many opportunities for development of targeted therapies for different types of cancer. AREAS COVERED: The genetic alterations in the PI3K/mammalian target of rapamycin (mTOR)/Akt pathway, as well as the drugs that target this pathway, either alone, in combination with other targeted agents or in chemotherapy. Targeted inhibitors of the PI3K pathway currently being tested in clinical trials in different types of human cancer. EXPERT OPINION: Small-molecule inhibitors targeting the PI3K/Akt/mTOR pathway show some success with these agents in current clinical trials. For further improvement in response, molecular correlates that can be used for patient selection, need to be determined. A more efficient and effective way to screen for patients to determine which patients are most likely to benefit from PI3K pathway inhibitors is also needed. PMID- 22239434 TI - Targeting the VEGF signaling pathway in cancer therapy. AB - INTRODUCTION: Angiogenesis was first proposed as a possible target for the treatment of human cancer several decades ago. During recent years, the discovery of VEGF as the main mediator of tumor angiogenesis enabled the specific and successful inhibition of angiogenesis in several experimental and clinical studies. AREAS COVERED: This review discusses recent data regarding the molecular mechanisms of VEGF signaling in cancer development, the response of various types of human cancer to anti-VEGF treatment, reasons for a failure of therapy and possible biomarkers for the prediction of therapeutic response. The literature discussed is based on a systematic analysis using PubMed and MEDLINE databases for articles presented in 2000 - 2011. EXPERT OPINION: Although anti-VEGF therapy has improved the treatment of several types of cancer during recent years, several questions still remain unanswered. For instance, in some patients, cancer develops resistance to anti-VEGF therapeutics following initially successful therapy, whereas others never show a response. Therefore, a more detailed knowledge of the molecular mechanisms involved in VEGF signaling and predictive biomarkers for a response to anti-VEGF therapy are among the most important challenges for VEGF research today. PMID- 22239436 TI - Targeting embryonic signaling pathways in cancer therapy. AB - INTRODUCTION: The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. AREAS COVERED: This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. EXPERT OPINION: CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established. PMID- 22239437 TI - Targeting the Fas/FasL signaling pathway in cancer therapy. AB - INTRODUCTION: The Fas/FasL system plays a significant role in tumorigenesis. Research has shown that its impairment in cancer cells may lead to apoptosis resistance and contribute to tumor progression. Thus, the development of effective therapies targeting the Fas/FasL system may play an important role in the fight against cancer. AREAS COVERED: In this review the recent literature on targeting the Fas/FasL system for therapeutic exploitation at different levels is reviewed. Promising pre-clinical approaches and various exceptions are highlighted. The potential of combined therapies is also explored, whereby tumor sensitivity to Fas-mediated apoptosis is restored, before an effective targeted therapy is employed. EXPERT OPINION: The success of the Fas/FasL system targeting for therapeutics will require a better understanding of the alterations conferring resistance, in order to use the most appropriate sensitizing chemotherapeutic or radiotherapeutic agents in combination with effective targeted therapies. PMID- 22239435 TI - Targeting the p53 signaling pathway in cancer therapy - the promises, challenges and perils. AB - INTRODUCTION: Research over the past three decades has identified p53 as a multi functional transcription factor. p53 influences myriad, highly diverse cellular processes, and represents one of the most important and extensively studied tumor suppressors. Activated by various stresses, p53 blocks cancer progression by provoking transient or permanent growth arrest, by enabling DNA repair, or by advancing cellular death programs. This anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated drug development efforts to (re-) activate p53 in established tumors. AREAS COVERED: The complexities of p53 signaling in cancer are summarized, including current strategies and challenges to restore p53's tumor suppressive function in established tumors, to inactivate p53 inhibitors, and to restore wild type function of p53 mutant proteins. EXPERT OPINION: p53 represents an attractive target for the development of anti-cancer therapies. Whether p53 is 'druggable', however, remains an area of active research and discussion, as p53 has pro-survival functions and chronic p53 activation accelerates aging, which may compromise the long-term homeostasis of an organism. The complex biology and dual functions of p53 in cancer prevention and age related cellular responses pose significant challenges to the development of p53 targeting cancer therapies. PMID- 22239439 TI - Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. AB - INTRODUCTION: The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types. AREAS COVERED: Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors. EXPERT OPINION: Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy. PMID- 22239438 TI - Targeting the EGFR signaling pathway in cancer therapy. AB - INTRODUCTION: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. AREAS COVERED: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also presented in this review. EXPERT OPINION: EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, a further understanding of the system is required to develop an effective anticancer regimen. A combination therapy that comprises an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy. PMID- 22239441 TI - Targeting the signaling pathways in cancer therapy. PMID- 22239440 TI - Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. AB - INTRODUCTION: The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials. AREAS COVERED: The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials. EXPERT OPINION: Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies. PMID- 22239442 TI - Large-scale domain conformational change is coupled to the activation of the Co-C bond in the B12-dependent enzyme ornithine 4,5-aminomutase: a computational study. AB - We present here an energetic and atomistic description of how D-ornithine 4,5 aminomutase (OAM), an adenosylcobalamin (AdoCbl; coenzyme B(12))-dependent isomerase, employs a large-scale protein domain conformational change to orchestrate the homolytic rupture of the Co-C bond. Our results suggest that in going from the open form (catalytically inactive) to the closed form (catalytically active), the Rossmann domain of OAM effectively approaches the active site as a rigid body. It undergoes a combination of a ~52 degrees rotation and a ~14 A translation to bring AdoCbl-initially positioned ~25 A away into the active-site cavity. This process is coupled to repositioning of the Ado moiety of AdoCbl from the eastern conformation to the northern conformation. Combined quantum mechanics and molecular mechanics calculations further indicate that in the open form, the protein environment does not impact significantly on the Co-C bond homolytic rupture, rendering it unusually stable, and thus catalytically inactive. Upon formation of the closed form, the Co-C bond is activated through the synergy of steric and electrostatic effects arising from tighter interactions with the surrounding enzyme. The more pronounced effect of the protein in the closed form gives rise to an elongated Co-C bond (by 0.03 A), puckering of the ribose and increased "strain" energy on the Ado group and to a lesser extent the corrin ring. Our computational studies reveal novel strategies employed by AdoCbl-dependent enzymes in the control of radical catalysis. PMID- 22239445 TI - The Global Fund and the re-configuration and re-emergence of 'civil society': widening or closing the democratic deficit? AB - The past decade has witnessed a tremendous growth in the scale and policy influence of civil society in global health governance. The AIDS 'industry' in particular opens up spaces for active mobilisation and participation of non-state actors, which further crystallise with an ever-increasing dominance of global health initiatives. While country evaluations of global initiatives call for a greater participation of 'civil society', the evidence base examining the organisation, nature and operation of 'civil society' and its claims to legitimacy is very thin. Drawing on the case of one of the most visible players in the global response to HIV epidemic, the Global Fund to Fight AIDS, Tuberculosis and Malaria, this article seeks to highlight the complex micropolitics of its interactions with civil society. It examines the nature of civil society actors involved in the Fund projects and the processes through which they gain credibility. We argue that the imposition of global structures and principles facilitates a reconfiguration of actors around newer forms of expertise and power centres. In this context, the notion of 'civil society' underplays differences and power dynamics between various institutions and conceals the agency of outsiders under the guise of autonomy of the state and people. PMID- 22239446 TI - The nanostructured origin of deformation twinning. AB - We have revealed the fundamental embryonic structure of deformation twins using in situ mechanical testing of magnesium single crystals in a transmission electron microscope. This structure consists of an array of twin-related laths on the scale of several nanometers. A computational model demonstrates that this structure should be a generic feature at the incipient stage of deformation twinning when there are correlated nucleation events. Our results shed light on the origin of twinning-induced plasticity and transformation toughening, critical to the development of advanced structural alloys with high strength, ductility, and toughness. PMID- 22239447 TI - Foreword to the special issue: fifteen years of lesbian scholarship: advances in methods and topics. PMID- 22239448 TI - Lesbians in empirical psychological research: a new perspective for the twenty first century? AB - Lesbians have been consistently ignored in empirical psychological research. The current research extends Lee and Crawford's ( 2007 ) comprehensive review, which used both quantitative and qualitative approaches to analyze the amount and kind of research on lesbians. Quantitative measures from 1975-2009 showed that the increase found in Lee and Crawford in 2001 has leveled off and the neglect of lesbians remains pronounced. Using cluster analysis of data derived from content analysis of abstracts published from 2003-2009, we identified six topic groups: Others' Attitudes, Sexual Orientation, Intimate Relationships, Coping and Coming Out, Lesbians' Problems, and Life in Heterosexual Society. In particular, transformative research was scarce and scattered across the identified clusters. Results are discussed in terms of what they reveal about the social construction of lesbianism in psychological research. PMID- 22239449 TI - Considering lesbian identity from a social-psychological perspective: two different models of "being a lesbian". AB - One long-standing project within lesbian studies has been to develop a satisfactory working definition of "lesbian." This article proposes two new models of a definition using principles of social psychology. Each model (a) utilizes the premise that gender lacks a categorical essence and (b) separates behavioral adherence to cultural stereotypes of femininity and masculinity from one's gender self-categorization. From these premises, I generate and critique two internally coherent models of lesbian identity that are inclusive (to different degrees) of various gender identities. For each model, the potential inclusion of trans men, trans women, genderqueers, and lesbian-identified cisgender men is evaluated. The explanatory power of these models is twofold. One, the models can serve as theoretical perspectives for scholars who study the intersection of gender and sexual identity. Two, the models can also characterize the everyday experience of people who have tacit working definitions of lesbian identity. PMID- 22239450 TI - Still stressful after all these years: a review of lesbians' and bisexual women's minority stress. AB - This article reviews the conceptualization of, and empirical literature on, lesbians' and bisexual women's sexual minority stress. In much of the early research, the experiences of sexual minority women and men were considered together (or women's experiences were inferred from men's), obscuring important differences. There is empirical and theoretical justification to consider the experiences of women and men separately and to develop and evaluate comprehensive models of sexual minority stress for women. Existing conceptualizations of sexual minority stress that include assessment of discrimination, victimization, harassment, concealment, internalized homonegativity may be applied, and perhaps adapted, to facilitate understanding of the unique stressors associated with women's sexual minority status. Future research must include mediators of the relationship between stressors and outcomes such as individual (e.g., coping and resilience) and group (e.g., social support, identification with a sexual minority community) resources. It is also essential to understand what factors may buffer the deleterious effects of these stressors. PMID- 22239451 TI - Lesbian mothers and their children: the third wave. AB - Research regarding lesbian mothers and their children has gone through a transformation in the last forty years. The first wave of research examined lesbians who had become parents while in heterosexual relationships. The second wave examined women who became parents within the context of lesbian relationships. Both of these waves focused on family functioning and child outcome, using heterosexual-headed families as comparison groups. The third wave of research, which is now underway, is focusing on the unique challenges faced by these families, and how lesbian mothers are creating and raising their families on their own terms. This article explores the research as it has evolved over the years and the direction in which it is headed. PMID- 22239452 TI - Clandestine existences and secret research: eliminating official discrimination in the Canadian military and going public in academia. AB - The 1990s was a notable decade for lesbians and gays in the Canadian military. Two important changes were the 1992 elimination of the official policy permitting discrimination against homosexual service members, and the 1996 introduction of benefits to same-sex partners. These changes radically influenced the psychological day-to-day reality of lesbian and gay military members. Yet, given the military culture, lesbian and gay members only began to come out in significant numbers at the turn of the century. This article presents an overview of our experience with researching the history of lesbians and gays in the Canadian military during the late 1990s and early years of the new century. It reveals the early clandestine nature of our research, and recounts some of the trials, tribulations, resistance, and successes we encountered when dealing with ethics boards and funding sources. It also describes our relationship with the media and how the military actively took steps to stall our efforts. We draw parallels between our experiences as researchers, and those of the lesbian service-members we were interviewing. PMID- 22239453 TI - Out lesbians in nursing: what would Florence say? AB - Research and education on lesbian health has increased substantially in quantity and quality in the past 40 years, but little of this work has been produced by nursing scholars. We began our academic nursing careers as out lesbian faculty at the same college of nursing in the late 1980s, where we collaborated on the earliest studies of attitudes about lesbians in the nursing profession. Our paths diverged in the early 1990s, but we shared similar experiences in nursing education that highlight the structural and attitudinal barriers within nursing that have inhibited lesbian health studies. The deeply imbedded lesbian phobia within nursing has historic roots that plague contemporary research, education, and practice. In this article, we discuss the inclusion of lesbian health in nursing, share some of our personal stories about the obstacles we encountered, and end with suggestions for changing this stifling climate for future generations of lesbian health scholars. PMID- 22239454 TI - My New Zealand lesbian studies through time and times. AB - In this article Alison J. Laurie reflects on her political activism and how it informs her academic scholarship and research interests relating to lesbian studies in New Zealand. She concludes that her desire for social change and commitment to lesbian community development inspired her early activism and has continued to inform her activism as well as her academic research and writing. She discusses her involvement in lesbian and gay organizations and campaigns, in New Zealand, Scandinavia, the United States and the United Kingdom, and the ideas that have informed and influenced her work. She pioneered the first lesbian studies courses in New Zealand, initially through community education, and from 1990 for university credit, and considers the contribution these courses can make. Finally, she reflects on several of her articles, book chapters and books considering how her work has developed during the past 50 years. PMID- 22239455 TI - Butch bottom-femme top? An exploration of lesbian stereotypes. AB - Lesbian gender labels (i.e., butch, soft butch, butch/femme, femme, and high femme) have set the stage for assumptions about lesbian attractions to sexual behaviors. This study explored the intersection of lesbian gender labels and attraction to sexual behaviors in 214 lesbian-identified women. Participants ranged in age from 18 to 69 with 48% being women of color. Contrary to stereotypes about sexual behavior in the lesbian community, very few differences emerged in regard to lesbian gender label. Overall, results do not support stereotypes about lesbian gender labels and suggest that behaviors in the lesbian community are fluid across labels. PMID- 22239456 TI - Karma eaters: the politics of food and fat in women's land communities in the United States. AB - Why is thinness so important among women who have largely rejected mainstream definitions of femininity? The idea of health has great cultural power and has come to symbolize not simply bodily but also spiritual, social, and moral well being. These ideas permeate U.S. culture, and in women's land communities, the virtue of hunger and the morality of health take on differently inflected but no less potent meanings. Ironically, in a context where women reject many gender restrictions--restrictions increasingly, as Sandra Bartky notes, focused on the female body-the importance of the thin (and thus properly feminine) body persists through the symbolism of health and virtue. PMID- 22239457 TI - Scavenger receptor class B type I: a multifunctional receptor. AB - The scavenger receptor class B type I (SR-B1) plays an important role in meditating the uptake of HDL-derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues. In addition to being ubiquitous, SR-B1 is a high density lipoprotein (HDL) receptor in many tissues, though the mechanism by which SR-B1 does this is unclear. Other than its role as an HDL receptor, SR-B1 is also involved in pathogen recognition; its expression can be modulated by lipopolysaccharide and oxidative stress; and it plays a significant role in the uptake of lipid soluble vitamins, such as vitamin E and carotenoids. In this short review, we have summarized the biological aspects to which SR-B1 has been thus far associated. PMID- 22239458 TI - A behavior-genetic study of the legacy of early caregiving experiences: academic skills, social competence, and externalizing behavior in kindergarten. AB - A critique of research examining whether early experiences with primary caregivers are reflected in adaptation is that relevant longitudinal studies have generally not employed genetically informed research designs capable of unconfounding shared genes and environments. Using the twin subsample (N = 485 pairs) of the Early Childhood Longitudinal Study-Birth Cohort, the current study provides evidence that early parental support (derived from observations at 24 months and around age 4, in prekindergarten) is associated with academic skills (r = .32), social competence (r = .15), and externalizing behavior (r = -.11) in kindergarten. Crucially, the shared environment accounted for virtually all of the correlation between parenting and academic skills, roughly half of the association between parenting and social competence, and approximately one fourth of the correlation between parenting and externalizing behavior. PMID- 22239459 TI - Synthesis and alignment of discrete polydiacetylene-peptide nanostructures. AB - Oligopeptides bearing internal diacetylene units are shown to self-assemble in water into one-dimensional nanostructures and aligned macroscopic hydrogels. The diacetylene units can be photopolymerized into polydiacetylenes that run coincident to the nanostructure and noodle long axes, and the resulting nanostructures show evidence for ambipolar charge transport. This self-assembly, alignment and polymerization technique provides a rapid way to produce globally aligned collections of conjugated polymer chains. PMID- 22239461 TI - Molecular thermodynamic analysis for assessing the relationship between reentrant swelling behavior and ternary liquid-liquid equilibrium for poly(N isopropylacrylamide) nanometer-sized gel particles in a water-tetrahydrofuran cosolvent system. AB - The influence of phase separation on swelling behavior was investigated based on the thermodynamic framework of reswelling phenomena. The cloud-point for a ternary system of water(1)-tetrahydrofuran (THF)(2)-poly(N isopropylacrylamide)(3) was examined by thermo-optical analysis (TOA). Nanometer sized N-isopropylacrylamide (NIPA) gel particles were prepared by precipitation polymerization, and their swelling behaviors were determined using photon correlation spectroscopy (PCS). NIPA gel particles underwent reswelling when the ratio of water to THF was varied. First, the modified double lattice model (MDL) was employed to determine ternary interaction energy parameters for the liquid liquid equilibrium (LLE) of linear poly-NIPA in a water-THF cosolvent system. The reentrant swelling equilibria of the NIPA gel in the water-THF system were then calculated using the interaction energy parameters. PMID- 22239462 TI - Hyperhemolysis syndrome complicating pregnancy in homozygous deltabeta thalassemia. AB - Hyperhemolysis syndrome in patients with sickle cell disease who are given compatible blood has been well described in the literature but a similar condition complicating pregnancy in beta-thalassemia (beta-thal) has not been reported. Pregnancy itself or continuation of blood transfusions can further exacerbate the condition which may become life-threatening. The exact mechanism of hyperhemolysis is not well understood. A bystander hemolysis mechanism has been proposed. Treatment with steroids, immunoglobulins and cyclosporin can be life saving. PMID- 22239460 TI - Population differentiation and restricted gene flow in Spanish crossbills: not isolation-by-distance but isolation-by-ecology. AB - Divergent selection stemming from environmental variation may induce local adaptation and ecological speciation whereas gene flow might have a homogenizing effect. Gene flow among populations using different environments can be reduced by geographical distance (isolation-by-distance) or by divergent selection stemming from resource use (isolation-by-ecology). We tested for and encountered phenotypic and genetic divergence among Spanish crossbills utilizing different species of co-occurring pine trees as their food resource. Morphological, vocal and mtDNA divergence were not correlated with geographical distance, but they were correlated with differences in resource use. Resource diversity has now been found to repeatedly predict crossbill diversity. However, when resource use is not 100% differentiated, additional characters (morphological, vocal, genetic) must be used to uncover and validate hidden population structure. In general, this confirms that ecology drives adaptive divergence and limits neutral gene flow as the first steps towards ecological speciation, unprevented by a high potential for gene flow. PMID- 22239463 TI - Competing carboxylases: circadian and metabolic regulation of Rubisco in C3 and CAM Mesembryanthemum crystallinum L. AB - The temporal co-ordination of ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco) and phosphoenolpyruvate carboxylase (PEPc) activities by Mesembryanthemum crystallinum L. in C(3) and crassulacean acid metabolism (CAM) modes was investigated under conventional light-dark (LD) and continuous light (LL) conditions. When C(3) , net CO(2) assimilation rate increased during each subjective night under LL with maximum carboxylation unrelated to Rubisco activation state. The CAM circadian rhythm of CO(2) uptake was more pronounced, with CO(2) assimilation rate maximal towards the end of each subjective night. In vivo and in vitro techniques were integrated to map carboxylase enzyme regulation to the framework provided by CAM LL gas exchange activity. Rubisco was activated in vitro throughout each subjective dark period and consistently deactivated at each subjective dawn, similar to that observed at true dawn in constitutive CAM species. Instantaneous carbon isotope discrimination showed in vivo carboxylase co-dominance during the CAM subjective night, initially by Rubisco and latterly C(4) (PEPc), despite both enzymes seemingly activated in vitro. The circadian rhythm in titratable acidity accumulation was progressively damped over successive subjective nights, but maintenance of PEPc carboxylation capacity ensures that CAM plants do not become progressively more 'C(3) -like' with time under LL. PMID- 22239465 TI - Design and characterization of optimized adenosine A2A/A1 receptor antagonists for the treatment of Parkinson's disease. AB - The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation. PMID- 22239467 TI - Photocontrollable peroxynitrite generator based on N-methyl-N-nitrosoaminophenol for cellular application. AB - We designed and synthesized a photocontrollable peroxynitrite (ONOO(-)) generator, P-NAP, which has N-methyl-N-nitrosoaminophenol structure with four methyl groups introduced onto the benzene ring to block reaction of the photodecomposition product with ONOO(-) and to lower the semiquinoneimine's redox potential. The semiquinoneimine intermediate generated by photoinduced release of nitric oxide (NO) reduces dissolved molecular oxygen to generate superoxide radical anion (O(2)(*-)), which reacts with NO to afford ONOO(-) under diffusion control (k = 6.7 * 10(9) M(-1) s(-1)). NO release from P-NAP under UV-A (330-380 nm) irradiation was confirmed by ESR spin trapping. Tyrosine nitration, characteristic of ONOO(-), was demonstrated by HPLC analysis of a photoirradiated aqueous solution of P-NAP and N-acetyl-l-tyrosine ethyl ester. ONOO(-) formation was confirmed with a ONOO(-)-specific fluorogenic probe, HKGreen-3, and compared with that from 3-(4-morpholinyl)sydnonimine hydrochloride (SIN-1), which is the most widely used ONOO(-) generator at present. The photoreaction of P-NAP was influenced by superoxide dismutase, indicating that generation of O(2)(*-) occurs before ONOO(-) formation. The quantum yield for formation of duroquinone, the main P-NAP photodecomposition product, was measured as 0.86 +/- 0.07 at 334 nm with a potassium ferrioxalate actinometer. Generation of ONOO(-) from P-NAP in HCT-116 cells upon photoirradiation was successfully imaged with HKGreen-3A. This is the first example of a photocontrollable ONOO(-) donor applicable to cultured cells. PMID- 22239468 TI - Transplanted bone marrow stromal cells protect neurovascular units and ameliorate brain damage in stroke-prone spontaneously hypertensive rats. AB - This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar Kyoto rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic medicine to prevent microvascular and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke. PMID- 22239469 TI - The impact of new cancer drugs in real practice oncology: a monoinstitutional experience. AB - Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (e.g. value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. We have analyzed a total of 856 cancer patients were registered in the onco-AIFA for various drugs. The results have shown that 38.1% of patients have received only few drug administrations and their treatment was stopped within 4 or 12 weeks (depending on the type of the drug schedule). We have examined the reasons, why their treatment was immediately suspended. PMID- 22239470 TI - Development of optimal kids insulin dosing system formulas for young children with type 1 diabetes mellitus. AB - OBJECTIVE: This study was designed to develop predictive formulas for precise insulin dosing in young children with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS: Consecutive 1-year data from a group of 14 young patients (eight girls, six boys) 3.9 +/- 0.8 years old with diabetes duration of 2.0 +/- 0.8 years, transitioned from multiple daily injections (MDI) to continuous subcutaneous insulin infusion (CSII), were analyzed to identify parameters governing optimal insulin dosing. Body mass index (BMI), total daily dose (TDD), total basal dose, insulin-to-carbohydrate ratio (ICR), correction factor (CF), and mean amplitude of glycemic excursion (MAGE) by continuous glucose monitoring and hemoglobin A(1c) (HbA(1c)) level were evaluated at baseline and every 3 months. The slopes of CF versus 1/TDD, bolus versus TDD, ICR versus 1/TDD, and CF versus ICR were determined. RESULTS: Kids Insulin Dosing System (KIDS) slope constants at follow up were associated with MAGE compared with baseline (P<0.0001) without significant changes in BMI (16.6 +/- 1.5 vs. 16.7 +/- 1.4 kg/m(2)) and HbA(1c) values (8.0 +/- 0.50% vs. 7.8 +/- 0.40%). The relationship between CF and TDD changed significantly during CSII compared with baseline MDI (P<0.0001), whereas the coefficients for ICR and TDD relationship remained relatively unchanged. The KIDS formulas estimated TDD=0.74*body weight, total basal dose=0.28*TDD, CF=2,800/TDD, and ICR=13.5*body weight/TDD. CONCLUSIONS: The interrelationships among ICR, CF, TBD, and TDD remained stable on CSII and were accompanied by decreased glycemic excursions. The KIDS formulas may yield consistent and easy estimates of insulin dosing factors in very young patients with T1DM. PMID- 22239472 TI - Peptide-mediated nanoengineering of inorganic particle surfaces: a general route toward surface functionalization via peptide adhesion domains. AB - The peptide-mediated functionalization of inorganic particle surfaces is demonstrated on gadolinium oxide (GdO) particles, revealing specific means to functionalize nano- or microparticles. Phage display screening is exploited to select 12mer peptides, which exhibit sequence-specific adhesion onto surfaces of GdO particles. These peptide adhesion domains are exploited to effectively decorate GdO particles with fluorescently labeled poly(ethylene oxide) (PEO), proving to result in a stable surface modification as shown by significant reduction of protein adsorption by 80%, compared to nonfunctionalized particles. Peptide adhesion and stability of the noncovalent coating are investigated by adsorption/elution experiments and Langmuir isotherms. Fluorescence microscopy, contact angle, and energy dispersive X-ray (EDX) measurements confirmed the sequence specificity of the interactions by comparing adhesion sequences with scrambled peptide sequences. Noncovalent, but specific modification of inorganic particle surfaces represents a generic strategy to modulate functionality and function of nano- or microparticle surfaces. PMID- 22239474 TI - Socio-economic resources and first-union formation in Finland, cohorts born 1969 81. AB - Social scientists generally agree that better individual economic prospects enhance the probability of marriage for men, whereas there are conflicting views with regard to women. Moreover, it is argued that cohabitation does not require as strong an economic foundation as marriage. The aim of this study, which was based on Finnish register data, was to find out how the socio-economic resources of young adults affect first-union formation, and whether the effects vary by sex or union type. The results show that high education, labour-force participation, and high income seem to promote union formation. The findings are similar for women and men, which is plausible given the comparatively gender-egalitarian societal context. Similar factors encourage entry into both union types, although the union-promoting effects of university-level education and stable employment are stronger in the marriage models, suggesting that long-term prospects are more important when marriage is contemplated. PMID- 22239475 TI - On the evolution of the sexually transmitted bacteria Haemophilus ducreyi and Klebsiella granulomatis. AB - Haemophilus ducreyi and Klebsiella (Calymmatobacterium) granulomatis are sexually transmitted bacteria that cause characteristic, persisting ulceration on external genitals called chancroid and granuloma inguinale, respectively. Those ulcers are endemic in developing countries or exist, as does granuloma inguinale, only in some geographic "hot spots."H. ducreyi is placed in the genus Haemophilus (family Pasteurellacae); however, this phylogenetic position is not obvious. The multiple ways in which the bacterium may be adapted to its econiche through specialized nutrient acquisitions; defenses against the immune system; and virulence factors that increase attachment, fitness, and persistence within genital tissue are discussed below. The analysis of K. granulomatis phylogeny demonstrated a high degree of identity with other Klebsiella species, and the name K. granulomatis comb. nov. was proposed. Because of the difficulty in growing this bacterium on artificial media, its characteristics have not been sufficiently defined. More studies are needed to understand bacterial genetics related to the pathogenesis and evolution of K. granulomatis. PMID- 22239476 TI - Remote stereocontrol in [3,3]-sigmatropic rearrangements: application to the total synthesis of the immunosuppressant mycestericin G. AB - The Ireland-Claisen [3,3]-sigmatropic rearrangement has been used to access biologically important beta,beta'-dihydroxy alpha-amino acids. The rearrangement reported is highly stereoselective and offers excellent levels of remote stereocontrol. This strategy has been used to synthesize the natural immunosuppressant mycestericin G and ent-mycestericin G, allowing for a revision of absolute configuration of this natural product. PMID- 22239477 TI - Crafting a national agenda for nursing education research. PMID- 22239478 TI - Moving beyond the exit examination. PMID- 22239479 TI - Role preparation for advanced practice nursing: practicing consultation and collaboration skills. PMID- 22239480 TI - Systematic study of compositional and synthetic control of vacancy and magnetic ordering in oxygen-deficient perovskites Ca2Fe(2-x)Mn(x)O(5+y)and CaSrFe(2 x)Mn(x)O(5+y) (x = 1/2, 2/3, and 1; y = 0-1/2). AB - Ten compounds belonging to the series of oxygen-deficient perovskite oxides Ca(2)Fe(2-x)Mn(x)O(5) and CaSrFe(2-x)Mn(x)O(5+y), where x = 1/2, 2/3, and 1 and y ~ 0-0.5, were synthesized and investigated with respect to the ordering of oxygen vacancies on both local and long-range length scales and the effect on crystal structure and magnetic properties. For the set with y ~ 0 the oxygen vacancies always order in the long-range sense to form the brownmillerite structure containing alternating layers of octahedrally and tetrahedrally coordinated cations. However, there is a change in symmetry from Pnma to Icmm upon substitution of Sr for one Ca for all x, indicating local T(d) chain (vacancy) disorder. In the special case of CaSrFeMnO(5) the neutron diffraction peaks broaden, indicating only short-range structural order on a length scale of ~160 A. This reveals a systematic progression from Ca(2)FeMnO(5) (Pnma, well-ordered tetrahedral chains) to CaSrFeMnO(5) (Icmm, disordered tetrahedral chains, overall short-range order) to Sr(2)FeMnO(5) (Pm3m, destruction of tetrahedral chains in a long-range sense). Systematic changes occur in the magnetic properties as well. While long-range antiferromagnetic order is preserved, the magnetic transition temperature, T(c), decreases for the same x when Sr substitutes for one Ca. A review of the changes in T(c) for the series Ca(2)Fe(2-x)M(x)O(5), taking into account the tetrahedral/octahedral site preferences for the various M(3+) ions, leads to a partial understanding of the origin of magnetic order in these materials in terms of a layered antiferromagnetic model. While in all cases the preferred magnetic moment direction is (010) at low temperatures, there is a cross over for x = 0.5 to (100) with increasing temperature for both the Ca(2)Fe(2-x)Mn(x)O(5) and the CaSrFe(2-x)Mn(x)O(5) series. For the y > 0 phases, while a brownmillerite ordering of oxygen vacancies is preserved for the Ca(2) phases, a disordered Pm3m cubic perovskite structure is always found when Sr is substituted for one Ca. Long-range magnetic order is also lost, giving way to spin glass or cluster-glass-like behavior below ~50 K. For the x = 0.5 phase, neutron pair distribution function (NPDF) studies show a local structure related to brownmillerite ordering of oxygen vacancies. Neutron diffraction data at 3.8 K show a broad magnetic feature, incommensurate with any multiple of the chemical lattice, and with a correlation length (magnetic domain) of 6.7(4) A. PMID- 22239481 TI - Screening for common nondeletional alpha-thalassemias in Chinese newborns by determination of Hb Bart's using the Sebia Capillarys 2 electrophoresis system. AB - The interaction of the nondeletional alpha-thalassemia (alpha-thal) mutations with the Southeast Asian double alpha-globin gene deletion results in nondeletional Hb H (beta4) disease. Hb Constant Spring (Hb CS, alpha142, TAA>CAA at alpha2) and Hb Quong Sze [Hb QS, alpha125, CTG>CCG (alpha2)] are the most common nondeletional alpha-thalassemias in the Chinese population. These alpha globin structural variants are unstable and undetectable by routine hemoglobin (Hb) electrophoresis. The amount of Hb Bart's (gamma4) in the cord blood of newborns correlates with the number of alpha-globin genes that are deleted. We determined the quantity of Hb Bart's in cord blood at birth with the Sebia CapillaryS electrophoresis system. Using Hb Bart's levels at 0.1-2.5% as a cut off range for nondeletional alpha-thal diagnosis, we detected 154 individuals in 6,525 newborns. Of the 154 samples, 12 were found to be Hb CS carriers, 10 Hb QS carriers, and one Hb Westmead [alpha122, CAC>CAG (alpha2)] carrier. We present the first report of the prevalence of Hb QS in our population. PMID- 22239482 TI - Computed and experimental chemical shift parameters for rigid and flexible YAF peptides in the solid state. AB - DFT methods were employed to compute the (13)C NMR chemical shift tensor (CST) parameters for crystals of YAF peptides (Tyr-Ala-Phe) with different stereochemistry for the Ala residue. Tyr-D-Ala-Phe 1 crystallizes in the C2 space group while Tyr-L-Ala-Phe crystallizes in either the P2(1)2(1)2 space group (2a) or the P6(5) space group (2b). PISEMA MAS measurements for samples with a natural abundance of (1)H and (13)C nuclei and (2)H QUADECHO experiments for samples with deuterium labeled aromatic rings were used to analyze the geometry and time scale of the molecular motion. At ambient temperature, the tyrosine ring of sample 1 is rigid and the phenylalanine ring undergoes a pi-jump, both rings in sample 2a are static, and both rings in sample 2b undergo a fast regime exchange. The theoretical values of the CST were obtained for isolated molecules (IM) and clusters employing the ONIOM approach. The experimental (13)C delta(ii) parameters for all of the samples were measured via a 2D PASS sequence. Significant scatter of the computed versus the experimental (13)C CST parameters was observed for 1 and 2b, while the observed correlation was very good for 2a. In this report, we show that the quality of the (13)C sigma(ii)/(13)C delta(ii) correlations, when properly interpreted, can be a source of important information about local molecular motions. PMID- 22239483 TI - Enhancing attachment organization among maltreated children: results of a randomized clinical trial. AB - Young children who have experienced early adversity are at risk for developing disorganized attachments. The efficacy of Attachment and Biobehavioral Catch-up (ABC), an intervention targeting nurturing care among parents identified as being at risk for neglecting their young children, was evaluated through a randomized clinical trial. Attachment quality was assessed in the Strange Situation for 120 children between 11.7 and 31.9 months of age (M = 19.1, SD = 5.5). Children in the ABC intervention showed significantly lower rates of disorganized attachment (32%) and higher rates of secure attachment (52%) relative to the control intervention (57% and 33%, respectively). These results support the efficacy of the ABC intervention in enhancing attachment quality among parents at high risk for maltreatment. PMID- 22239484 TI - Deep-UV surface-enhanced resonance Raman scattering of adenine on aluminum nanoparticle arrays. AB - We report the ultrasensitive detection of adenine using deep-UV surface-enhanced resonance Raman scattering on aluminum nanostructures. Well-defined Al nanoparticle arrays fabricated over large areas using extreme-UV interference lithography exhibited sharp and tunable plasmon resonances in the UV and deep-UV wavelength ranges. Theoretical modeling based on the finite-difference time domain method was used to understand the near-field and far-field optical properties of the nanoparticle arrays. Raman measurements were performed on adenine molecules coated uniformly on the Al nanoparticle arrays at a laser excitation wavelength of 257.2 nm. With this technique, less than 10 amol of label-free adenine molecules could be detected reproducibly in real time. Zeptomole (~30,000 molecules) detection sensitivity was readily achieved proving that deep-UV surface-enhanced resonance Raman scattering is an extremely sensitive tool for the detection of biomolecules. PMID- 22239486 TI - Size and asymmetry: are there costs to winning the royalty race? AB - Body size and morphology are key fitness-determining traits that can vary genotypically. They are likely to be important in social insect queens, which mate in swarms and found colonies independently, but genetic influences on queen morphology have been little investigated. Here, we show that the body size and morphology of queens are influenced by their genotype in the leaf-cutting ant Acromyrmex echinatior, a species in which certain lineages (patrilines) bias their development towards reproductive queens rather than sterile workers. We found no relationship between the queen-worker skew of patrilines and the size or morphology of queens, but there was a significant relationship with fluctuating asymmetry, which was greater in more queen-biased patrilines. Our results suggest that queen-biased patrilines do not incur a fitness cost in terms of body size, but may face more subtle costs in developmental stability. Such costs may constrain the evolution of royal cheating in social insects. PMID- 22239485 TI - A synthetic chalcone as a potent inducer of glutathione biosynthesis. AB - Chalcones continue to attract considerable interest due to their anti inflammatory and antiangiogenic properties. We recently reported the ability of 2',5'-dihydroxychalcone (2',5'-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure-activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4',6'-dimethoxy 2'-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements. PMID- 22239488 TI - Unique origin of colors of armchair carbon nanotubes. AB - The colors of suspended metallic colloidal particles are determined by their size dependent plasma resonance, while those of semiconducting colloidal particles are determined by their size-dependent band gap. Here, we present a novel case for armchair carbon nanotubes, suspended in aqueous medium, for which the color depends on their size-dependent excitonic resonance, even though the individual particles are metallic. We observe distinct colors of a series of armchair enriched nanotube suspensions, highlighting the unique coloration mechanism of these one-dimensional metals. PMID- 22239490 TI - Cribriform neuroepithelial tumor in the third ventricle: a case report and literature review. AB - Cribriform neuroepithelial tumor (CRINET) is a very rare and recently described entity of INI1-deficient intraventricular neuroepithelial tumor of primitive non rhabdoid cells with distinct cribriform formation and has a relatively favorable prognosis. A 14-month-old boy had presented with gait imbalance and was crawling for the last 2 weeks. MRI revealed a large, complex solid and cystic mass with dimensions of 55 * 55 * 50 mm in the vicinity of the third ventricle. Histopathologically, the tumor was composed of relatively small undifferentiated neuroepithelial cells arranged in a cribriform pattern and intervening solid sheets with true rosettes. Immunohistochemically, the tumor cells showed complete loss of nuclear INI1 expression and distinct expression of epithelial membrane antigen (EMA) along the luminal borders of the tubules or glands. The typical rhabdoid feature of tumor cells was absent. Ultrastructurally, the tumor cells were neuroepithelial cells that contained short linear rough endoplasmic reticula and distinct intercellular junctions. Here, we describe a new case of CRINET and also discuss its clinicopathological, immunohistochemical, and ultrastructural features. PMID- 22239491 TI - Inhibition of c-Jun N-terminal kinase and nuclear factor kappa B pathways mediates fisetin-exerted anti-inflammatory activity in lipopolysccharide-treated RAW264.7 cells. AB - Although fisetin, a natural flavonoid, was known to inhibit proliferation, carcinogenesis and inflammation, the underlying anti-inflammatory mechanism of fistein still remains unclear. Thus, in the present study, the anti-inflammatory mechanism of fisetin was investigated in association with mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB) pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 mouse macrophages. We found that fisetin significantly reduced the nitrate oxide (NO) production and also inhibited the expression of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) at protein and mRNA levels in LPS-stimulated cells. Consistently, fisetin significantly reduced the LPS stimulated secretion of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha). Furthermore, fisetin suppressed the activation of nuclear factor kappa B (NF-kappaB) and the phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal regulated kinase (ERK) and p38 MAPK in LPS-treated RAW264.7 cells. Overall, our findings demonstrate that fisetin exerted anti-inflammatory activity via inactivation of JNK and NF-kappaB in LPS-stimulated macrophage cells. PMID- 22239492 TI - Cardiovascular aspect of Beta-thalassaemia. AB - Beta-thalassaemia major is a genetic blood disorder caused by the reduced synthesis of beta globin chain. The consequences of the resulting chronic anaemia are also common and include growth retardation, bone marrow expansion, extramedular hematopoiesis, splenomegaly, increased intestinal iron absorption, susceptibility to infections, and hypercoagulability. Transfusional iron overload can affect heart function by directly damaging tissue through iron deposition or via iron-mediated effects at other sites. Cardiac dysfunction is common in patients with thalassaemia and is the leading cause of mortality. The main cardiac abnormalities reported in patients with thalassaemia major (TM) and iron overload are left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valvulopathies, arrhythmias and pericarditis. These cardiac abnormalities are a consequence of the general co-morbid conditions in thalassaemia but are closely related to concomitant endocrine deficiencies, hypercoagulability state and inflammatory milieu. Iron's toxicity within cells arises from its capacity to catalyse the production of reactive oxygen species that cause lipid peroxidation and organelle damage, which lead ultimately to cell death and fibrosis. With the introduction of new technologies such as cardiac magnetic resonance T2* , the early detection of cardiac iron overload and associated cardiac dysfunction is now possible, allowing time for reversal through iron chelation therapy. PMID- 22239493 TI - Experience with multiplex ARMS (MARMS)-PCR for the detection of common beta thalassemia mutations in India. AB - Beta (beta) Thalassemia is a common globin gene disorder in India. Although about 65 different mutations are known in the multiethnic populations of India, the group of 9 'core mutations', i.e. IVSI,5 (G > C){HBB:c.925G > C}, 619 base pair deletion(bp del){NG_000007.3:g.71609_72227del619}, FS8/9 (G){HBB:c.27_28insG}, IVSI,1 (G > T) {HBB:c.92G > T}, FS41/42 (-CTTT){HBB:c.124_127del-CTTT}, C15 (G > A){HBB:c.47G > A}, FS16 (-C){HBB:c.51delC}, C30 (G > C){HBB:c.93G > C} and C5 ( CT){HBB:c17_18delCT} cover about 96% of mutations in the carriers. We attempted a multiplex PCR to detect these mutations using ARMS method and strategized it in high risk groups of western India. The system was found reliable, cost effective, fast and most applicable for mutation screening of beta Thalassemia in Indian populations. PMID- 22239494 TI - Editorial of a special issue. Current status of therapeutics and preventive measures for patients with thalassaemia and sickle cell disease. PMID- 22239495 TI - An activity-based near-infrared glucuronide trapping probe for imaging beta glucuronidase expression in deep tissues. AB - beta-glucuronidase is an attractive reporter and prodrug-converting enzyme. The development of near-IR (NIR) probes for imaging of beta-glucuronidase activity would be ideal to allow estimation of reporter expression and for personalized glucuronide prodrug cancer therapy in preclinical studies. However, NIR glucuronide probes are not yet available. In this work, we developed two fluorescent probes for detection of beta-glucuronidase activity, one for the NIR range (containing IR-820 dye) and the other for the visible range [containing fluorescein isothiocyanate (FITC)], by utilizing a difluoromethylphenol glucuronide moiety (TrapG) to trap the fluorochromes in the vicinity of the active enzyme. beta-glucuronidase-mediated hydrolysis of the glucuronyl bond of TrapG generates a highly reactive alkylating group that facilitates the attachment of the fluorochrome to nucleophilic moieties located near beta glucuronidase-expressing sites. FITC-TrapG was selectively trapped on purified beta-glucuronidase or beta-glucuronidase-expressing CT26 cells (CT26/mbetaG) but not on bovine serum albumin or non-beta-glucuronidase-expressing CT26 cells used as controls. beta-glucuronidase-activated FITC-TrapG did not interfere with beta glucuronidase activity and could label bystander proteins near beta glucuronidase. Both FITC-TrapG and NIR-TrapG specifically imaged subcutaneous CT26/mbetaG tumors, but only NIR-TrapG could image CT26/mbetaG tumors transplanted deep in the liver. Thus NIR-TrapG may provide a valuable tool for visualizing beta-glucuronidase activity in vivo. PMID- 22239496 TI - Purification and characterization of polyphenol oxidase from rape flower. AB - The purification and partial enzymology characteristics of polyphenol oxidase (PPO) from rape flower were studied. After preliminary treatments, the crude enzyme solution was in turn purified with ammonium sulfate, dialysis, and Sephadex G-75 gel chromatography. The optimal conditions and stability of PPO were examined at different pH values and temperatures. Subsequently, PPO was also characterized by substrate (catechol) concentrations, inhibitors, kinetic parameters, and molecular weight. Results showed that the optimal pH for PPO activity was 5.5 in the presence of catechol and that PPO was relatively stable at pH 3.5-5.5. PPO was moderately stable at temperatures from 60 to 70 degrees C, whereas it was easily denatured at 80-90 degrees C. Ethylenediaminetetraacetic acid, sodium chloride, and calcium chloride had little inhibitive effects on PPO, whereas citric acid, sodium sulfite, and ascorbic acid had strongly inhibitive effects. The Michaelis-Menten constant (K(m)) and maximal reaction velocity (V(max)) of PPO were 0.767 mol/L and 0.519 Ab/min/mL of the crude PPO solution, respectively. PPO was finally purified to homogeneity with a purification factor of 4.41-fold and a recovery of 12.41%. Its molecular weight was 60.4 kDa, indicating that the PPO is a dimer. The data obtained in this research may help to prevent the enzymatic browning of rape flower during its storage and processing. PMID- 22239497 TI - Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C. AB - Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient. PMID- 22239498 TI - Impact of erythropoietin on sustained virological response to peginterferon and ribavirin therapy for HCV infection: a systematic review and meta-analysis. AB - Anaemia is a common complication of antiviral therapy for chronic hepatitis C virus (HCV) infection that necessitates dose reductions or therapy discontinuation. Administration of erythropoietin (EPO) is an alternative to ribavirin (RBV) dose reduction, but its advantage in terms of sustained virological response (SVR) has not been determined yet. In a systematic way, randomized studies were identified that evaluated the effect of EPO administration vs RBV dose reduction on virological response in patients who developed anaemia during anti-HCV therapy. The random-effects model was employed to run meta-analysis. SVR was set as the end point of interest. Data were abstracted from four studies containing 257 patients who developed anaemia during therapy. One hundred and twenty six subjects underwent RBV dose reduction. Patients who received EPO in response to haemoglobin drop had a significantly higher probability of achieving SVR compared with those who underwent RBV dose reduction because of anaemia (relative risk = 1.83 95% CI; 1.41-2.37). No heterogeneity was observed across study results (I(2) = 0). Publication bias assessment was nonsignificant. Our meta-analysis indicates that administration of EPO in patients who develop anaemia during anti-HCV therapy can considerably enhance SVR. Moreover, no adverse event of EPO administration was reported among included subjects. PMID- 22239499 TI - Characterization of nonrapid virologic response patients infected with HCV genotype 1 who may relapse after standard therapy with peginterferon plus ribavirin. AB - Approximately 50% of patients with hepatitis C virus (HCV) genotype 1 treated with peginterferon alfa-2a/ribavirin discontinue treatment early or experience a suboptimal response despite 48 weeks of therapy. The objective of this analysis was to develop a model to identify nonrapid virologic response (non-RVR) patients who may be candidates for intensified therapy that would increase treatment response. The retrospective analysis included non-RVR patients from four trials of 48-week peginterferon alfa-2a/ribavirin treatment. Patients were grouped into those who cleared virus between weeks 5 and 12 (complete early virologic responders, cEVR) or between weeks 13 and 24 (slow responders). A model was developed to predict relapse at the end of follow-up (week 72). An optimal model was evaluated and compared with current practice by using receiver operating characteristic curves, sensitivity and specificity. In total, 539 non-RVR patients were eligible for analysis of which 72% experienced cEVR and 28% were slow responders. Variables associated with relapse included age, ethnicity, baseline HCV RNA and interval of time to HCV RNA undetectable. The optimal model was most accurate at predicting patients at risk for relapse. The practice of considering treatment intensification (e.g. extending treatment duration) in all slow responders was less accurate but likely most practical. A week 4 HCV <2-log reduction was the earliest but least accurate marker. We developed a model that could identify non-RVR patients at high risk for relapse after 48 weeks of peginterferon alfa-2a plus ribavirin and who may benefit from intensified therapy to reduce this risk of relapse. PMID- 22239500 TI - Intravenous drug use: not a barrier to achieving a sustained virological response in HCV infection. AB - Hepatitis C virus (HCV) is commonly transmitted by intravenous drug use (IDU) but drug users are under represented in many treatment cohorts, this is because of the assumption of lowered treatment success. We assessed HCV treatment outcomes in active intravenous drug users and patients on opiate substitution therapy. The Tayside HCV treatment database was retrospectively analysed for consecutively treated patients based on risk factor for acquisition of HCV. Primary end point was sustained virological response (SVR). Two hundred and ninety-one consecutively treated patients were assessed. The overall SVR rate was 55.3%. The SVR rates by risk factor were; Non-IDU 61.4%, Ex-IDU 54.8% and Active IDU 47.1% (P = n/s). In the groups G1 patients SVR was; Non-IDU 52.7%, Ex-IDU 30.7% and active IDU 35.4% (P = n/s). In the non-G1 patients: non-IDU 65.1%, Ex-IDU 76.7% and active IDU 53.5%. Ex-IDU had a significantly better SVR than active IDU, other differences were not significant. Our results demonstrate that SVR rates in the active drug users and those on opiate substitution therapy can be achieved which are comparable with non-IDU infected individuals. Intravenous drug use in those engaged with treatment services should not be seen as a barrier to treatment of HCV. PMID- 22239501 TI - Mutations selected in the hepatitis C virus NS3 protease domain during sequential treatment with boceprevir with and without pegylated interferon alfa-2b. AB - Treatment with hepatitis C virus (HCV)-NS3-protease inhibitors lead to the selection of resistant variants. Viral kinetics and resistance profiles in patients who are re-treated with the same protease inhibitor are unknown. Viral kinetics and NS3-resistance mutations obtained by clonal sequencing of the NS3 protease were analyzed in nine HCV-genotype-1-infected nonresponder patients who were sequentially treated with boceprevir (400 mg t.i.d.) for 1 week, peginterferon-alfa-2b for 2 weeks and combination of the two for 2 weeks in varying order. In addition to predominant wild-type isolates, previously described boceprevir-resistant mutations (V36, T54, R155, A156, V170) were observed. Furthermore, two resistant mutations (Q41, F43) were detected for the first time in vivo. In three patients, mutations selected after initial treatment with boceprevir were re-selected during subsequent boceprevir exposure. However, mutational patterns after the first and second exposure to boceprevir were different in five patients. In one patient, a viral variant (V55A) known to reduce susceptibility to boceprevir was the predominant variant observed at baseline and throughout treatment and was associated with a shallow viral decline. Different resistance mutations were selected during treatment with boceprevir +/- peginterferon. Sequential short-term dosing of boceprevir was not associated with accumulation of resistant variants but pre-existing variants may impair virologic response. PMID- 22239502 TI - CCL5 mRNA is a marker for early fibrosis in chronic hepatitis C and is regulated by interferon-alpha therapy and toll-like receptor 3 signalling. AB - Mechanisms causing liver fibrosis during chronic hepatitis C virus infection (cHCV) are not sufficiently understood. This study was aimed to identify biomarkers for early fibrosis (EF) and to investigate their potential role in cHCV-related fibrogenesis. To this end, peripheral whole blood (PB) samples from 36 patients with cHCV recruited from two independent cohorts were subjected to microarray analysis 12 h before initiation of peginterferon-alpha (Peg-IFN-alpha) and ribavirin therapy. Liver biopsies were evaluated using the Batts-Ludwig staging (BL-S) classification system for fibrosis. We showed that gene expression profiles (N = 8) distinguished between EF (BL-S: 0,1) and late fibrosis (LF; BL S: 2,3,4) with 88.9% accuracy. Fibrosis-related functional annotations for chemokine-'C-C-motif'' ligand 5 (CCL5) provided foundation for focused investigation, and qRT-PCR confirmed that CCL5 mRNA levels (PB) reliably discriminate EF from LF (accuracy: 86.7%). Positive correlations (P < 0.05) with CCL5 mRNA levels and EF discovered gene expression profiles (PB) reflecting stable expression of IFN-alpha receptor 1, negative regulation of the MyD88 dependent toll-like receptor (TLR) pathway and decreased expression of TLR3 in vivo. Remarkably, Peg-IFN-alpha suppressed CCL5 mRNA levels (PB) in EF in vivo. These findings along with results from parallel in vitro investigation into the effect of IFN-alpha or poly I:C (TLR3-agonist) on CCL5 gene expression in hepatic stellate cells (HSC) attest to the multi-site involvement of these pathways in regulating fibrogenesis. In conclusion, we identified novel, reliable biomarkers for EF and exposed functional properties of the molecular network regulating CCL5 biosynthesis in peripheral or hepatic cell types with key roles in cHCV-related liver and/or immune pathogenesis. PMID- 22239503 TI - Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion. AB - Earlier studies addressing the hepatitis B virus (HBV) DNA cut-off level for inactive chronic HBV infection largely involved patients with normal alanine aminotransferase (ALT) for only 1-2 years and based on a single time HBV DNA assay. This study was conducted to address this issue using serial HBV DNA assays in patients with persistently normal ALT (PNALT) over 10 years following spontaneous hepatitis B e antigen (HBeAg) seroconversion. Serial serum specimens (mean 9 samples per patient) of 62 patients with PNALT and no disease progression over 10 years (median 18.1 years) after spontaneous HBeAg seroconversion were assayed for HBV DNA. Excluding assays within 1 year after HBeAg seroconversion, 21% and 82.3% of the patients with PNALT had HBV DNA levels persistently lower than 4 log(10) and 5 log(10) copies/mL, respectively, and only 8% had a level >= 5 log(10) copies/mL in at least two assays. Of the 27 patients with PNALT defined by ALT <30 U/L for male and <19 U/L for female, only 33% had serum HBV DNA level persistently <4 log(10) copies/mL. There was no significant difference in the serial HBV DNA changes among patients with different gender, HBV genotype or age at HBeAg seroconversion. Liver biopsy in nine patients invariably showed minimal necroinflammation and one showed Ishak fibrosis score 4. These results suggest that 5 log(10) copies/mL (20,000 IU/mL) is a more appropriate cut-off HBV DNA level for inactive chronic HBV infection in the setting of PNALT. PMID- 22239504 TI - Characterizing hepatitis B stigma in Chinese immigrants. AB - Health-related stigma is a cause of stress, alienation and discrimination that can serve as a barrier to prevention and care for infectious diseases such as HIV. Hepatitis B virus (HBV)-related stigma is common in Asian immigrants, but has not been formally evaluated. The aim of this study was to develop and validate the first HBV stigma instrument and to begin to evaluate HBV stigma in Chinese immigrants. The HBV stigma instrument was developed based on constructs from validated HIV stigma scales and organized into five domains. A written survey was compiled to include demographic data, HBV knowledge questions and stigma items. The survey was pilot tested in English and Chinese and then finalized. Data were obtained from 201 patients seen in an urban Chinatown Internal Medicine practice. The stigma items showed a high degree of reliability when assessed in aggregate (alpha = 0.85) as well as within individual domains. Stigma was greatest in the Fear of Contagion domain. Knowledge questions showed a corresponding deficit in understanding of modes of HBV transmission. An inverse relationship between stigma scores and familiarity with HBV provided evidence of construct validity. In multivariable analysis, having a family member with HBV and higher HBV knowledge subset scores were associated with lower degrees of stigma. In conclusion, the hepatitis B stigma instrument showed reliability and construct validity. The relationship identified between familiarity and knowledge regarding HBV with lower stigma scores provides the basis for the development of interventions to reduce HBV stigma. PMID- 22239505 TI - Preactivation of the interferon signalling in liver is correlated with nonresponse to interferon alpha therapy in patients chronically infected with hepatitis B virus. AB - Interferon alpha (IFN-alpha) therapy is widely used to treat patients with chronic hepatitis B (CHB) but the sustained response rate is low, and the molecular mechanisms for the ineffectiveness of IFN-alpha treatments are not known. We screened differentially expressed genes between responders (Rs) and nonresponders (NRs) in patients with CHB treated with IFN-alpha to explore the molecular basis for treatment failure. Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy. Gene expression levels were compared between seven patients who did not respond to therapy (NR) and six who did respond (R). Gene ontology category and KEGG pathway were analysed for differentially expressed genes, and the selected differentially expressed genes were confirmed using real-time polymerase chain reaction. We identified 3592 genes whose expression levels differed significantly between all Rs and NRs (P < 0.05); many of these genes are IFN-stimulated genes (ISGs) and immune-related genes. The ISGs were more highly expressed, while immune-related genes were inhibited in NRs before IFN-alpha treatment. Two ISGs (CEB1 and USP18) that are linked in an IFN inhibitory pathway are highly expressed in NRs, and a potential antiviral gene ISG20 was inhibited in NRs, suggesting a possible rationale for treatment nonresponse. Patients who do or do not respond to IFN have different liver gene expression profiles before IFN-alpha treatment. Preactivation of the IFN signalling pathway leading to the increased expression of inhibitory ISGs and inhibition of immune response in the pretreatment livers was associated with treatment failure. PMID- 22239506 TI - Prospective study of risk factors for hepatitis C virus acquisition by Caucasian, Hispanic, and Asian American patients. AB - Commonly known risk factors for infection with hepatitis C virus (HCV) include blood transfusion, injection drug use, intranasal cocaine use, and body tattoos. We hypothesized that Asian Americans infected with HCV may not identify with these established risk factors present in Caucasians and Hispanics, and our aim was to conduct a survey of risk factors in HCV-infected patients in these ethnic groups. In this prospective study, 494 patients infected with HCV completed a detailed risk assessment questionnaire at a liver centre in Northern California from 2001 to 2008. Among subjects participating in this study, 55% identified themselves as Caucasian, 20% as Hispanic, and 25% as Asian. Asian Americans were older, less likely to smoke or consume alcohol, and have a family history of cancer compared with Caucasians and Hispanics. The laboratory profiles were similar, and genotype 1 was the most common infection in all groups (74-75%). The great majority of Caucasians (94%) and Hispanics (86%) identified with commonly known risk factors, which was in contrast to 67% of Asians (P < 0.0001). The most common risk factors in Asians were blood transfusions (50%) and acupuncture (50%). Furthermore, 74% of Caucasians and 66% of Hispanics identified more than one major risk factor, while only 20% of Asians reported having more than one risk factor (P < 0.0001). Survey for established risk factors for acquisition of HCV may be more appropriate for risk assessment of Caucasians and Hispanics, but not for Asian Americans. These findings may guide the development of HCV screening in our increasingly diverse population. PMID- 22239507 TI - The tumour necrosis factor-alpha-238A allele increases the risk of chronic HBV infection in European populations. AB - Tumour necrosis factor-alpha (TNF-alpha) plays a pivotal role in viral clearance and host immune response to hepatitis B virus (HBV) infection, of which the production capacity in individuals is demonstrated to be influenced by a single nucleotide polymorphism within the promoter region of TNF-alpha genes. However, there have been conflicting results reported in previous studies on TNF-alpha-238 and TNF-alpha-863 gene promoter polymorphisms in chronic HBV infection. To derive a more precise estimation of their relationship, we searched Pubmed (January, 1966-August, 2010) and China Biological Medicine Database (January, 1978-August, 2010) and carried out a meta-analysis involving nineteen studies that included 5245 chronic HBV infection cases and 3181 controls describing G238A genotypes, and eleven studies totalling 3576 cases and 2044 controls describing C863A genotypes. The overall meta-analysis did not suggest significant associations of TNF-alpha-238 and TNF-alpha-863 gene promoter polymorphisms with chronic HBV infection. However, in subgroup analysis by ethnicity, it indicated that TNF alpha-238A allele carriers (GA + AA) in European populations had an increased risk of developing chronic HBV infection (OR = 2.22, 95% CI: 1.07-4.58, P = 0.032; OR = 4.46, 95% CI: 1.75-11.38, P = 0.002, respectively), when compared with spontaneous recovered and healthy populations, respectively. However, no significant associations were found in Asian populations in all genetic models. So, we draw the conclusion that the TNF-alpha-238A allele may increase the risk of chronic HBV infection in European populations. PMID- 22239508 TI - Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection. AB - BACKGROUND: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. METHODS: In a phase 1b study in Japan, 10 treatment-naive patients infected with hepatitis C virus genotype 1b with high viral load (>5 log(10) IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. RESULTS: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log(10) decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala(156) -substituted variants occurred in eight patients, and only one patient showed end-of-treatment response. The selected variants reverted to the wild-type during the 24-week follow-up period. CONCLUSION: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct-acting antiviral agents. PMID- 22239509 TI - Peginterferon alfa-2b plus weight-based ribavirin for 24 weeks in patients with chronic hepatitis C virus genotype 1 with low viral load who achieve rapid viral response. AB - In chronic hepatitis C (CHC), treatment duration may be individualized according to time to first undetectable hepatitis C virus (HCV) RNA, with patients who attain undetectable HCV RNA early in treatment being candidates for shorter regimens. The aim of this study was to determine the relapse rate in patients with CHC genotype (G) 1 infection and low baseline viral load who achieved undetectable HCV RNA by week 4 [rapid virologic response (RVR)] when treated for 24 weeks. This was an open-label, multicentre, noninterventional study. Adult patients with G1 CHC infection and baseline viral load <600,000 IU/mL who attained RVR were treated with peginterferon alfa-2b (1.5 MUg/kg/week) plus ribavirin (800-1200 mg/day) for 24 weeks, then followed for a further 24 weeks. The primary endpoint was relapse rate, defined as the proportion of patients with undetectable HCV RNA at treatment week 24 and detectable HCV RNA at week 24 follow-up. The secondary efficacy endpoint was sustained virologic response (SVR). Overall, 170 patients were included in the efficacy-evaluable population. The relapse rate was 9.7% (16/165, 95% confidence interval: 0.06-0.15), and SVR was attained by 149 of 170 patients (87.6%). Virologic outcomes were consistent regardless of age, gender, body weight and genotype. Seven patients reported treatment-emergent serious adverse events (AEs), and four patients discontinued treatment because of an AE. This study further demonstrates that peginterferon alfa-2b plus weight-based ribavirin for 24 weeks is an effective treatment strategy for treatment-naive patients with G1 CHC and low viral load who attain RVR. PMID- 22239510 TI - Serum PAI-1 is a novel predictor for response to pegylated interferon-alpha-2b plus ribavirin therapy in chronic hepatitis C virus infection. AB - Obesity and insulin resistance have been reported as negative predictors for sustained virological response (SVR) in hepatitis C virus (HCV) genotype 1 infected patients treated with pegylated interferon-alpha plus ribavirin. They are also known to affect serum levels of several cytokines including adipocytokines. But the association between these cytokines and treatment outcome has not been fully elucidated. We examined pretreatment serum levels of 14 cytokines among 190 patients who were treated with pegylated interferon-alpha-2b plus ribavirin for chronic HCV-1b infection with high viral load (>= 5 log IU/mL) and analyzed their contribution to treatment response. Plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor, and 11 clinical factors showed significant association with SVR in univariate logistic regression analysis. Four significant factors in multivariate analysis; serum PAI-1 (odds ratio [OR] = 15.42), body mass index (OR = 4.56), rs8099917 (OR = 4.95) and fibrosis stage (OR = 5.18) were identified as independent predictors. We constructed a simple and minimally invasive prediction score for SVR based on the presence of these factors except for fibrosis stage. The accuracy of this score was 73%, and was confirmed using an independent validation cohort consisting of 31 patients (68%). The strongest correlation was between PAI-1 level and platelet count (r = 0.38, P = 1.8 * 10(-7)), and PAI-1 level was inversely correlated with fibrosis stage. Serum PAI-1 is a novel predictor for the response to combination therapy against chronic HCV-1b infection and may be associated with liver fibrosis. PMID- 22239511 TI - Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to treat patients with genotype 1 chronic hepatitis C. AB - The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV) for difficult-to-treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG-IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20 100% of the planned dose (SVR rates 87.5-100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG-IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period. PMID- 22239512 TI - Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry. AB - We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) >= 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage. PMID- 22239513 TI - Hepatic expression of MxA and OAS1 in an ex vivo liver slice assay independently predicts treatment outcomes in chronic hepatitis C. AB - Antiviral effect of interferon is mediated by the expression of interferon stimulated genes (ISGs). However, because of the difficulty in obtaining paired liver biopsies before and after interferon treatment, the key ISGs expressed in human hepatocytes and responsible for interferon-based antiviral activities in chronic hepatitis C remain illusive. Prior to a standard course of peginterferon plus ribavirin therapy, 104 patients underwent a liver biopsy. A small piece of the liver biopsy sample from each patient was submitted for ex vivo tissue culture in the presence or absence of interferon. Hepatic expression of 8 ISGs was detected by RT-PCR. The ISG expression patterns and clinicopathological variables were correlated with subsequent treatment outcomes. Multivariate logistic regression analysis showed that hepatic MxA expression (P = 0.008) and leucocyte count (P = 0.040) independently predicted the end of therapeutic virological response, while hepatic OAS1 expression (P = 0.003), genotype 1 (P = 0.002), HCV-RNA level (P = 0.007), AST/ALT ratio (P = 0.004) and leucocyte count (P = 0.034) independently predicted the sustained virological response. Immunohistochemistry analysis showed that interferon-induced OAS1 expression localized to the hepatocytes. In conclusion, hepatic MxA and OAS1 expression predicted, respectively, the end of therapeutic and sustained virological responses in interferon-based treatment of chronic hepatitis C. PMID- 22239514 TI - Examining hepatitis C virus testing practices in primary care clinics. AB - Prior studies found that hepatitis C virus (HCV) risk assessment and testing in primary care clinics were suboptimal. We aimed to determine the actual HCV testing rate among patients with HCV risk factors and to identify variables predictive of testing. In order to do so, we performed a prospective cohort study among patients seen in four urban primary care clinics. At the initial visit, patients were given a questionnaire that listed HCV risk factors and they were instructed to check 'yes' or 'no' if they did or did not have a risk factor, respectively. Patients then handed this questionnaire to their physician during their initial visit. Among those who acknowledged having a HCV risk factor via the questionnaire, we determined the subsequent HCV testing rate and calculated adjusted odds ratios (aOR) with 95% confidence intervals (CI) to identify variables predictive of testing. Of the 578 individuals who acknowledged having a HCV risk factor via the questionnaire, only 8% (46/578) were tested for HCV within 2 months of their initial visit. Among those tested, 11% (5/46) had a positive HCV antibody test result. The only variable predictive of HCV testing after adjusting for confounders was having a specific HCV risk factor identified and documented in the chart by physicians [16% (26/159) vs 5% (20/419); aOR 4.5, 95% CI 2.1-9.5]. In summary, 92% of patients with a HCV risk factor were not tested for HCV in the primary care setting, and efforts to improve such rates are clearly warranted. PMID- 22239515 TI - Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus. AB - Hepatic iron overload has been described in chronic hepatitis C as a cofactor affecting fibrosis progression. Data in patients with chronic hepatitis B infection are scarce. We investigated hepatic iron deposits and serum iron indices in 205 consecutive patients with hepatitis B and compensated liver disease. Mean age of the patients was 42.4 +/- 12.4 years and 72.5% were males. Coinfection with hepatitis delta virus (HDV) was present in 8.8%. At least one of the serum iron indices was elevated in 41.5% of cases. Hepatic iron deposits were detected in 35.1% of patients, most of them being minimal (grade I) (59.7%) or mild (grade II) (27.8%). Variables significantly associated with hepatic iron deposits were male gender (P = 0.001), serum ferritin (P = 0.008), gammaGT (P = 0.05) and alkaline phosphatase (P = 0.05) levels. By multivariate analysis hepatic iron deposits correlated with serum ferritin [odds ratio (OR) 1.2, 95% confidence interval (CI) 1.05-1.4, P = 0.002]. Presence of mild-moderate (grades II and III) hepatic iron deposits could be excluded with high negative predictive value (90%) when serum ferritin was within normal values. A significant correlation between coinfection with HDV and hepatic iron deposits was also found (OR 4.23, 95% CI 1.52-11.82, P = 0.003). When compared to monoinfected cases, HDV positive patients had more elevated gammaGT (P = 0.03), more advanced fibrosis and more severe iron deposits (P < 0.0001). In conclusion, in well-compensated chronic hepatitis B infection, hepatic iron deposits and elevation of serum iron indices are common, especially in male gender and in patients coinfected with HDV. As HBV/HDV liver disease is generally more rapidly progressive than that caused by HBV monoinfection, we speculate that iron overload may be one of the factors contributing to the severity of liver disease. PMID- 22239516 TI - Immunohistochemistry for the diagnosis of hepatitis E virus infection. AB - Hepatitis E virus (HEV) is an emerging pathogen and the most common cause of acute viral hepatitis all over the world. We describe here an immunohistochemical method for the detection of HEV antigens (pORF2 and pORF3) in formalin-fixed, paraffin-embedded liver tissues using monoclonal antibodies raised against two of the virus proteins (pORF2 and pORF3). We analysed their specificity and sensitivity in comparison with serology and nucleic acid detection in cases of acute liver failure (ALF). We used this test on 30 liver biopsies collected post mortem from the patients of ALF caused by HEV infection. These cases were selected on the basis of positive results for enzyme immunoassay (IgM anti-HEV). Of the 30 cases taken from the archives of the Department of Pathology, the antibodies successfully stained all. However, only 25 serum samples (83.3%) of these were positive for HEV RNA. Fifteen controls used (Five noninfected liver tissues, five HBV- and five hepatitis C virus-infected liver tissues) were all negative. The immunohistochemical assay described here may prove a valuable tool for the detection of HEV infection in biopsy, autopsy and explant liver tissues and can serve as a link along with other available tests to delineate the extent of HEV-associated problem worldwide. PMID- 22239517 TI - Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. AB - In infants born to hepatitis B surface antigen (HBsAg)-positive mothers, failure after passive-active immunization still occurs. The role of maternal hepatitis B DNA level and other risk factors in this setting remains unclear. This study retrospectively evaluated virologic and other risk factors associated with immunoprophylaxis failure in infants born to HBsAg-positive mothers. Between January 2007 and March 2010, we reviewed the clinical and virologic tests in 869 mother-infant pairs. All infants received the identical passive-active immunization schedule after birth. The failure infants (HBsAg positive at 7-12 months of age) were compared to infants who were HBsAg negative when tested during this time period. Among 869 infants, 27 (3.1%) infants were immunoprophylaxis failures and the other 842 (96.9%) infants remained HBsAg negative. When mothers' pre-delivery HBV DNA levels were stratified to <6, 6 6.99, 7-7.99 and >= 8 log(10) copies/mL, the corresponding rates of immunoprophylaxis failure were 0%, 3.2% (3/95), 6.7% (19/282) and 7.6% (5/66), respectively (P < 0.001 for the trend). All failure infants were born to hepatitis B e antigen (HBeAg)-positive mothers. Multivariate logistic regression analysis identified maternal HBV DNA levels [odds ratio (OR) = 1.88, 95% confidence interval (CI): 1.07-3.30] and detectable HBV DNA in the cord blood (OR = 39.67, 95% CI: 14.22-110.64) as independent risk factors for immunoprophylaxis failure. All failure infants were born to HBeAg-positive mothers with HBV DNA levels >= 6 log(10) copies/mL. The presence of HBV DNA in cord blood predicted failure to passive-active immunization. PMID- 22239518 TI - Transient elastography for predicting clinical outcomes in patients with chronic liver disease. AB - There is increasing interest in developing noninvasive means to evaluate liver fibrosis in patients with chronic liver disease to determine disease severity, prognosis and optimal treatment. Transient elastography (TE) has previously been demonstrated to predict the presence or absence of advanced fibrosis. The current study was conducted to determine whether TE can identify patients with chronic liver disease at risk of clinical decompensation. A total of 667 patients underwent TE and were followed for a median of 861 days and 57 patients achieved the primary outcome, a composite of clinical endpoints including death, ascites, encephalopathy, increased Child Score >= 2, variceal bleed, hepatocellular carcinoma or listing for transplant. Overall, TE had an area under the receiver operating characteristic curve of 0.87 for predicting clinical outcome. Using a cut-off of 10.5 kPa, TE has a sensitivity, specificity, positive predictive value and negative predictive value (NPV) of 94.7%, 63.0%, 19.3% and 99.2%, respectively. A predictive model for clinical events was developed using generalized cross-validation for clinical endpoints considering TE, liver biopsy results and multiple other predictors. Individually, TE performed better than biopsy, or any other variable, for predicting clinical outcome [Harrell's C Statistic 0.86 for TE, 0.78 for stage]. Patients with a TE score of >12.5 kPa were found to have a relative hazard for clinical event of 18.99 compared with patients with TE score <10.5. A combined variable model including TE, aspartate aminotransferase/alanine aminotransferase ratio and model for end-stage liver disease (MELD) yielded the highest predictive accuracy with Harrell's C value of 0.93. In the subset of patients with cirrhosis, TE was not found to be independently associated with clinical outcomes in univariate or multivariate analysis although it retained a high sensitivity and NPV of 97.5% and 92.3%, respectively, at a kPa cut-off of 10.5. TE can successfully identify patients with chronic liver disease who are at low risk of clinical decompensation over a time period of 2 years. PMID- 22239519 TI - Predictors of outcome in children with acute viral hepatitis and coagulopathy. AB - The presence of coagulopathy in acute viral hepatitis (AVH) in children raises issues about prognosis and need for liver transplantation. We evaluated factors predicting outcome in such patients and determined the applicability of the paediatric acute liver failure study group (PALFSG) definition of acute liver failure (ALF) of coagulopathy alone in comparison with coagulopathy and encephalopathy. Children with AVH (clinical features, raised transaminases and positive viral serology) with uncorrectable coagulopathy [prothrombin time (PT) > 15 s] with or without hepatic encephalopathy (HE) were enrolled. Comparative analysis was based on (i) outcome: survivors/nonsurvivors and (ii) ALF criteria: group A coagulopathy (PT > 15 s) and encephalopathy and group B coagulopathy (PT > 20 s). We studied 130 children (86 boys, mean age 7.5 +/- 4.5 years): 86 recovered and 44 died. Single virus infection was present in 96 (74%), hepatitis A being the commonest (n-69). On multiple stepwise logistic regression analysis, age <3.5 years, serum bilirubin >= 16.7 mg/dL, PT >= 40.5 s and clinical signs of cerebral oedema were independent predictors of mortality. Mortality increased from 0% with single to 100% with four risk factors. Ninety-seven cases met the PALFSG criteria: group A-79 and group B-18. Group A subjects had higher mortality (55.6%vs 0%) and poorer liver functions (bilirubin 18.1 +/- 8.9 vs 13.8 +/- 6.9 mg/dL, PT 63.9 +/- 35.1 vs 27.2 +/- 5.2 s) than group B. PT deteriorated significantly with the appearance and progression of HE. One-third of children with AVH with coagulopathy die without transplantation. Age <3.5 years, bilirubin >= 16.7 mg/dL, PT >= 40.5 s and signs of cerebral oedema are predictors of poor outcome. Children with encephalopathy and coagulopathy have a poorer outcome than those with coagulopathy alone. PMID- 22239520 TI - The association of HIV viral load with indirect markers of liver injury. AB - This study assessed the association of HIV RNA with indirect markers of liver injury including FIB-4 index, liver enzymes and platelet counts in a high-risk Hispanic population. The data were derived from a prospective study that included 138 HIV/hepatitis C (HCV)-coinfected and 68 HIV-infected participants without hepatitis C or B co-infection (mono-infected). In unadjusted analyses, detectable HIV viral load (vs undetectable, <400 copies/mL) was associated with a 40% greater odds (OR 1.4, 95% CI: 1.1-1.9, P = 0.016) of FIB-4 > 1.45 in the HIV/HCV coinfected group and 70% greater odds of FIB-4 > 1.45 (OR 1.7, 95% CI: 1.0-2.8; P = 0.046) in the HIV-mono-infected group. In multivariable analyses, a 1 log(10) increase in HIV RNA was associated with a median increase in FIB-4 of 12% in the HIV/HCV-coinfected group and 11% in the HIV-mono-infected group (P < 0.0001). Among the HIV/HCV-coinfected group, the elevating effect of HIV RNA on FIB-4 was strongest at low CD4 counts (P = 0.0037). Among the HIV-mono-infected group, the association between HIV RNA and FIB-4 was independent of CD4 cell counts. HIV RNA was associated with alterations in both liver enzymes and platelet counts. HIV antiretroviral therapy was not associated with any measure of liver injury examined. This study suggests that HIV may have direct, injurious effects on the liver and that HIV viral load should be considered when these indirect markers are used to assess liver function. PMID- 22239521 TI - Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. AB - Acoustic Radiation Force Impulse (ARFI) imaging is a novel ultrasound-based elastography method that is integrated in a conventional ultrasound machine enabling the exact localization of measurement site. It might present an alternative method to transient elastography for the noninvasive assessment of liver fibrosis. At present, studies with small patient population have shown promising results. A systematic review and meta-analysis of pooled patient data were performed to evaluate the overall performance of ARFI for the staging of liver fibrosis. Literature databases were searched up to 10/2010. The authors of the original publication were contacted, and the original patient data were requested. A meta-analysis was performed using a random effect meta-analytic method for diagnostic tests. In addition, available data comparing ARFI with FibroScan with the DeLong test were evaluated. Literature search yielded nine full-paper publications evaluating ARFI while using liver biopsy as reference method. Original patient data were available from eight studies including 518 patients. The mean diagnostic accuracy of ARFI expressed as areas under ROC curves (AUROC) was 0.87 for the diagnosis of significant fibrosis (F >= 2), 0.91 for the diagnosis of severe fibrosis (F >= 3), and 0.93 for the diagnosis of cirrhosis. ARFI can be performed with good diagnostic accuracy for the noninvasive staging of liver fibrosis. PMID- 22239522 TI - Ischaemic colitis during interferon treatment for chronic hepatitis C: report of two cases and literature review. AB - Ischaemic colitis is known to be a severe emergency complication of interferon (IFN) therapy. However, as ischaemic colitis is an infrequent complication of IFN therapy, limited information is available regarding the safety of resuming IFN therapy after resolution of ischaemic colitis and subsequent recurrence. Here, we report two cases of ischaemic colitis during IFN therapy for chronic hepatitis C. Ischaemic colitis was fully healed within 1 week after its onset and IFN withdrawal, and IFN therapy was resumed following patients' wishes to do so. Ischaemic colitis did not recur after the resumption of IFN therapy, and sustained virological response was achieved in both patients. In this report, we also summarize the findings of 11 cases of IFN-associated ischaemic colitis (nine previously published cases plus our two cases) and review the clinical characteristics of ischaemic colitis during IFN therapy in patients with chronic hepatitis C. PMID- 22239523 TI - Hepatitis B virus suppresses the functional interaction between natural killer cells and plasmacytoid dendritic cells. AB - Natural killer cells (NK) are one of the key players in the eradication and control of viral infections. Infections with the hepatitis B virus (HBV) may lead to persistence in a subgroup of patients, and impaired NK cell functions have been observed in these patients. Crosstalk with other immune cells has been shown to modulate the function of NK cells. We studied the functional crosstalk between NK cells and plasmacytoid dendritic cell (pDC) and its modulation by HBV. Healthy human peripheral blood-derived NK cells and pDC were purified and cocultured in the presence or absence of HepG2.2.15-derived HBV under various in vitro conditions. The functionality of NK cells was assessed by evaluation of activation markers, cytokine production and cytotoxicity of carboxyfluorescein succinimidyl ester-labelled K562 target cells by flow cytometry or immunoassays. Additionally, the crosstalk was examined using NK and pDC from patients with chronic HBV. The activation of NK cells in cocultures with pDC, as demonstrated by CD69, CD25 and HLA-DR, was not affected by the presence of HBV. Similarly, when cocultured with pDC, the cytotoxic potential of NK cells was not influenced by HBV. However, HBV significantly inhibited pDC-induced IFN-gamma production by NK cells both in the presence and in the absence of CpG. As HBV did not affect cytokine-induced IFN-gamma production by NK cells cultured alone, the suppressive effect of HBV on NK cell function was mediated via interference with pDC-NK cell interaction. In contrast to other viruses, HBV does not activate pDC-NK cell interaction but inhibits pDC-induced NK cell function. In parallel with NK cells of patients with chronic HBV, which show diminished cytokine production with normal cytotoxicity, HBV specifically suppressed pDC-induced IFN-gamma production by NK cells without affecting their cytolytic ability. These data demonstrate that HBV modulates pDC-NK cell crosstalk, which may contribute to HBV persistence. PMID- 22239524 TI - Comparison of the hepatitis B virus core, surface and polymerase gene substitution rates in chronically infected patients. AB - For phylogenetic comparison of hepatitis B virus (HBV) isolates, often a region of the HBV surface gene is analysed. Because the surface gene completely overlaps the polymerase gene, its evolution is constrained, and it may not be the best choice for genetic comparison of HBV isolates. Analysing serial sample pairs of 33 chronically HBV-infected, untreated patients, with a cumulative follow-up of 184 years, the synonymous and nonsynonymous substitution rates of a part of the overlapping HBV surface and polymerase genes were compared to those of a nonoverlapping part of the HBV core gene. The substitution rate of the HBV core gene was higher (8.15 * 10(-4) vs 4.57 * 10(-4) substitutions/site/year) than that of the surface gene. The difference was mainly due to a significantly lower synonymous substitution rate in the surface gene, with dN/dS ratios of 0.412 in the core gene and 0.986 in the surface gene. Contrary to the core gene, the number of substitutions in the surface gene was higher in low viraemic hosts, who control HBV infection by suppressing replication. The number of substitutions in the core gene correlated more strongly with the duration of follow-up. The overlapping HBV surface and polymerase genes experience strong negative selection, which limits the number of substitutions. Because the HBV core gene reflects the duration of infection more accurately, it is more suitable for the analysis of short-term viral evolution and of hepatitis B transmission chains. PMID- 22239525 TI - Pretreatment HBeAg level and an early decrease in HBeAg level predict virologic response to entecavir treatment for HBeAg-positive chronic hepatitis B. AB - There are few reports on hepatitis B e antigen (HBeAg) titres during nucleos(t)ide analogues treatment. We investigated the changes in HBeAg levels in patients treated with entecavir and the usefulness of HBeAg quantification for predicting antiviral response. Ninety-five consecutive HBeAg-positive patients treated with entecavir for more than 48 weeks were enrolled. Serum levels of hepatitis B surface antigen (HBsAg), HBeAg and HBV DNA were assessed at 4-week intervals to week 24 and thereafter at 12-week intervals. Virologic response (Y1VR) was defined as an undetectable HBV DNA level at week 48 of therapy. During 48 weeks, HBeAg and HBV DNA level decreased significantly in a biphasic manner and HBsAg level tended to decease. Fifty-three patients (55.8%) attained Y1VR. Pretreatment HBeAg levels were significantly lower in the Y1VR group than in no Y1VR group. At week 4 and 12 of therapy, 25% and 41.4% of patients showed a decrease of HBeAg levels with >0.5 log(10) and >1.0 log(10) from baseline, respectively. These patients achieved more Y1VR than those with less decrease of HBeAg levels (97.7%vs 22.2% and 86.2%vs 29.3%, respectively). HBeAg level at week 12 had higher predictive values for Y1VR than HBV DNA level. Multivariate analysis revealed that a pretreatment HBeAg level of <360 PEIU/mL and the reduction in HBeAg level >1.0 log(10) at week 12 were associated with Y1VR. These results suggest that pretreatment HBeAg level and an early decrease in HBeAg level are useful measurements for predicting one-year virologic response during entecavir treatment. PMID- 22239526 TI - Impact of hepatitis B virus infection on metabolic profiles and modifying factors. AB - The metabolic syndrome may cause disease progression in patients with chronic hepatitis B (CHB). However, the interactions between hepatitis B virus (HBV) infection and metabolic factors remain unknown. We investigated the association of HBV infection with metabolic profiles in HBV-infected and noninfected subjects. In addition, the impacts of serum HBV DNA level on metabolic profiles were studied. Initially, a case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 322 patients with chronic HBV infection, and the control group consisted of 870 matched subjects without HBV infection. Fasting blood glucose, lipid profiles and adiponectin levels were compared. The results were then confirmed in a second retrospective cohort study in 122 CHB patients with serum HBV DNA levels and HOMA-IR index values. In the case-control analysis, the HBV group had significantly higher serum adiponectin, but lower triglyceride (TG) and high-density lipoprotein cholesterol (HDL) levels than the control group. These relationships already existed in subjects younger than 45 years of age and were modified by serum alanine aminotransferase (ALT) levels. In the retrospective cohort, serum HBV DNA levels were negatively proportional to TG levels, but not to other metabolic parameters. Moreover, this relationship was significant only in subjects with higher ALT levels. Compared with healthy adults, patients with chronic HBV infection have significantly higher serum adiponectin, but lower TG and HDL levels. These relationships are modified by ALT levels and already exist in middle-age patients with chronic HBV infection, implying HBV may interact with host metabolism. PMID- 22239527 TI - Serum microRNA-122 levels in different groups of patients with chronic hepatitis B virus infection. AB - miR-122 is a liver-specific microRNA, which also circulates in the blood. The levels of miR-122 in serum and plasma correlate with hepatic necroinflammation in patients with hepatitis B virus (HBV) infection. Here, we investigated whether miR-122 levels correlate with surrogate markers for viral replication and translation. Furthermore, we examined whether miR-122 levels differ in the different groups of HBV-infected patients and whether miR-122 levels may be useful to identify patients with higher or lower risk for liver disease progression. Therefore, RNA was extracted from sera of therapy-naive patients with HBV infection (n = 89) and from healthy volunteers (n = 19). The concentration of miR-122 was assessed by quantitative real-time reverse transcription PCR. HBs antigen and HBV DNA levels were quantified as surrogate parameters for HBV replication and translation. Liver biopsies were examined according to the histological activity index and the degree of fibrosis was assessed. We found that the miR-122 serum concentration correlated with the level of ALT, HBV DNA and HBs antigen (r = 0.259, P < 0.05; r = 0.225, P < 0.05; r = 0.508, P < 0.001, respectively). The miR-122 serum levels discriminated the different patient groups infected with HBV from healthy subjects (P < 0.001), and inactive carrier patients with high (>3500 IU/mL) or low (<3500 IU/mL) levels of HBs antigen could be differentiated by the miR-122 serum concentration (P < 0.05). As serum miR-122 levels strongly correlated with HBs antigen, it might be an indicator for viral translation. Furthermore, serum miR-122 levels discriminated HBV carrier patients with high or low risk for disease progression and may, thus, be an additional marker for risk stratification. PMID- 22239528 TI - Tumour necrosis factor-alpha-857T allele reduces the risk of hepatitis B virus infection in an Asian population. AB - Tumour necrosis factor-alpha (TNF-alpha) plays a pivotal role in hepatitis B virus (HBV) clearance and host immune response determining the chronicity of HBV infection. However, studies of the association between TNF-alpha-857 polymorphism and chronic HBV infection have reported conflicting results. So a meta-analysis was carried out to draw a more precise conclusion. Pubmed (January, 1966-March, 2011) and the China Biological Medicine Database (January, 1978-March, 2011) were searched using the keywords TNF-alpha gene polymorphism in combination with HBV infection without language restriction. Fourteen studies including 4929 chronic HBV infection cases and 2702 controls describing the C857T genotype were included in the meta-analysis. All fourteen studies focussed on an Asian population. The overall meta-analysis suggested that TNF-alpha-857T allele reduced the risk of chronic HBV infection in the Asian population (OR = 0.82, 95% CI: 0.71-0.95, P = 0.008) when compared with a spontaneously recovered population. In the sensitivity analyses of the groups obeying Hardy-Weinberg equilibrium (HWE), without the largest study population and without the smallest study population, a similar association was revealed (OR = 0.81, 95% CI: 0.68-0.98, P = 0.043; OR = 0.77, 95% CI: 0.68-0.87, P = 0.0001; OR = 0.81, 95% CI: 0.70-0.95, P = 0.009, respectively). However, when compared with a healthy population, no significant association was found in the Asian population in all groups. So, we draw the conclusion that the TNF-alpha-857T allele reduces the risk of chronic HBV infection in this Asian population. PMID- 22239529 TI - Inhibition of IkappaB kinase by thalidomide increases hepatitis C virus RNA replication. AB - Hepatic fibrosis is an integral element in the progression of chronic liver disease. Elevated hepatic interleukin (IL)-8 is an important contributor to fibrosis in patients chronically infected with the hepatitis C virus (HCV). Thalidomide has been used to reduce liver inflammation and fibrosis in HCV infected patients, but its impact on HCV replication remains unclear. This study examined the effect of thalidomide on HCV replication in vitro. Results revealed that while thalidomide reduced IL-8 and nuclear factor kappa B (NF-kappaB) activity by 95% and 46% in Huh-7 cells, increasing concentrations of thalidomide correlated with a linear rise in HCV replication (17-fold at 200 MUm). The NF kappaB inhibitors, wedelolactone and NF-kappaB activation inhibitor-1, which mimic the actions of thalidomide by preventing phosphorylation and activation of IkappaB kinase (IKK) and hence block NF-kappaB activity, increased HCV RNA by 18- and 19-fold, respectively. During in vitro HCV replication in Huh-7 cells, we observed a 30% increase in IKKalpha protein and 55% decrease in NF kappaB(p65)/RelA protein relative to cellular beta-actin. Ectopic expression of IKKalpha to enhance the inactive form of IKK in cells undergoing virus replication led to a 13-fold increase in HCV RNA. Conversely, enhanced expression of NF-kappaB(p65)/RelA in infected cells resulted in a 17-fold reduction in HCV RNA. In conclusion, HCV RNA replication was significantly augmented by the inhibition of IKK activation and subsequent NF-kappaB signalling, whereas a restoration of NF-kappaB activity by the addition of NF-kappaB/RelA markedly reduced HCV replication. This study lends added importance to the role of the NF kappaB signalling pathway in controlling HCV replication. PMID- 22239530 TI - Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity. AB - Phytochemicals exert antiviral activity and may play a potential therapeutic role in hepatitis C virus (HCV) infection. In this work, we aimed to isolate NS3 inhibitors from traditional Indian medicinal plants that were found, in our earlier study, to inhibit HCV NS3 protease activity and to evaluate their potential to inhibit HCV replication. A potent inhibitory effect of NS3 catalytic activity was obtained with Embelia ribes plant extracts. Quercetin, a ubiquitous plant flavonoid, was identified as the active substance in the fractioned extract. It was found to inhibit NS3 activity in a specific dose-dependent manner in an in vitro catalysis assay. Quercetin inhibited HCV RNA replication as analysed in the subgenomic HCV RNA replicon system. It also inhibited HCV infectious virus production in the HCV infectious cell culture system (HCVcc), as analysed by the focus-forming unit reduction assay and HCV RNA real-time PCR. The inhibitory effect of quercetin was also obtained when using a model system in which NS3 engineered substrates were introduced in NS3-expressing cells, providing evidence that inhibition in vivo could be directed to the NS3 and do not involve other HCV proteins. Our work demonstrates that quercetin has a direct inhibitory effect on the HCV NS3 protease. These results point to the potential of quercetin as a natural nontoxic anti-HCV agent reducing viral production by inhibiting both NS3 and heat shock proteins essential for HCV replication. PMID- 22239531 TI - Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation. AB - Patients with chronic hepatitis C infection may exhibit neuropsychological symptoms and cognitive impairment. Post-mortem studies of hepatitis C virus HCV quasispecies and replicative intermediates indicate that the brain might act as a separate compartment for viral replication and microglia may be the locus for infection and subsequent neuroinflammatory activity. We sought to use two independent in vivo imaging techniques to determine evidence of neuroinflammation in patients with histologically mild chronic hepatitis C. Using positron emission tomography (PET) with a ligand for microglial/brain macrophage activation, (11)C (R)-PK11195 (PK11195) and cerebral proton magnetic resonance spectroscopy, we determined whether there was evidence of neuroinflammation in a pilot study of 11 patients with biopsy-proven mild chronic hepatitis C, compared to healthy volunteers. Patients were characterized by cognitive testing and the fatigue impact scale to assess for CNS impairment. PK11195 binding potential was significantly increased in the caudate nucleus of patients, compared to normal controls (P = 0.03). The caudate and thalamic binding potential were more significantly increased in six patients with genotype 1 infection (P = 0.007) and positively correlated with viraemia (r = 0.77, P = 0.005). Basal ganglia myo inositol/creatine and choline/creatine ratios were also significantly elevated in patients with chronic hepatitis C compared to normal controls (P = 0.0004 and P = 0.01, respectively). Using PET, we demonstrated evidence of microglial activation, which positively correlated with HCV viraemia and altered cerebral metabolism in the brains of patients with mild hepatitis C. This provides further in vivo evidence for a neurotropic role for HCV. PMID- 22239532 TI - Longitudinal changes of the laboratory data of chronic hepatitis C patients with sustained virological response on long-term follow-up. AB - There is no study that follows up longitudinal changes in laboratory data of patients with C-viral chronic liver disease (C-CLD) who achieved sustained virological esponse (SVR) with interferon treatment in a long-term study. We investigated the laboratory data in a long-term retrospective cohort study of 581 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005. 467 were treated with interferon and 207 of these patients achieved SVR with follow-up periods of 8.36 +/- 5.13 years. Alanine aminotransferase (ALT) levels, albumin levels, platelet counts, and the aspartate aminotransferase (AST) to-platelet ratio index (APRI) values were serially examined during the follow-up period. None of the 207 patients with SVR exhibited hepatitis C virus (HCV) RNA positivity more than 6 months after the end of IFN treatment. Platelet counts and albumin levels increased only in those with eradication of HCV. APRI values decreased more in patients with SVR than in those with nonsustained virological responses (non-SVR). Patients who achieved SVR and had fibrosis stage 0-1 and 2-4 at enrolment had platelet counts that longitudinally increased by 2.81 +/- 3.95 and 5.49 +/- 4.53 * 10(3) /MUL during the 10-year follow-up period, respectively. Albumin levels continuously increased during the first 2 years by 0.15 +/- 0.31 and 0.33 +/- 0.37 in fibrosis stage 0-1 and 2-4, respectively and then plateaued. ALT levels decreased rapidly one year after the start of treatment by 110.3 +/- 140.0 and 100.5 +/- 123.4 in fibrosis 0-1 and 2-4, respectively. HCV RNA negativity persisted in all patients with SVR, and laboratory data including APRI longitudinally improved during the long-term follow-up period. PMID- 22239534 TI - Evolution of Chlamydia trachomatis. AB - We know surprisingly little about the evolutionary origins of Chlamydia trachomatis. It causes both ocular (trachoma) and sexually transmitted infections in humans, it is an obligate intracellular pathogen, and there are only a few "isolates" that have been well characterized. From the first few genomes analyzed, it seems that the C. trachomatis genome is highly conserved. The genomes possess high synteny and, in some cases, the sequence variation between genomes is as little as 20 SNPs. Recent indications from partial genome analyses suggest that recombination is the mechanism for generating diversity. There is no accurate molecular clock by which to measure the evolution of C. trachomatis. The origins of both sexually transmitted and ocular C. trachomatis are unclear, but it seems likely that they evolved with humans and shared a common ancestor with environmental chlamydiae some 700 million years ago. Subsequently, evolution within mammalian cells has been accompanied by radical reduction in the C. trachomatis genome. PMID- 22239535 TI - Screening of free radical scavengers from Erigeron breviscapus using on-line HPLC ABTS/DPPH based assay and mass spectrometer detection. AB - Erigeron breviscapus is a well-known traditional Chinese herbal medicine. In this study, on-line HPLC-ABTS/DPPH assay coupled with MS detection were applied to screen and identify the free radical scavengers in 70% methanol extracts of E. breviscapus. Using on-line HPLC-ABTS-MS and HPLC-DPPH-MS assay, 13 radical scavengers (including 4-O-caffeoylquinic acid (4-CQA) (1), 9-caffeoyl-2,7-anhydro 2-octulosonic acid (9-COA) (2), 3-caffeoyl-2,7-anhydro-3-deoxy-2 octulopyranosonic acid (3-CDOA) (3), erigeside I (4), quercetin-3-O-glucuronide (5), eriodictyol-7-O-glucuronide (6), scutellarin (7), 1,4-di-O-caffeoylquinic acid (1,4-di-CQA) (8), 3,5-di-CQA (9), 1-malonyl-3,5-di-CQA (10), erigoster B (11), 4,5-di-CQA (12) and 4,9-di-CDOA (13)) and 9 radical scavengers (including 1, 4, 7, 8, 9, 10, 11, 12 and 13) were discovered, respectively. Furthermore, the anti-oxidative activities of 4 compounds, including 7, 9, 11 and 12 were evaluated. Reverse anti-oxidative activity order of scutellarin and 3,5-di-CQA was observed in on-line HPLC-ABTS assay and on-line HPLC-DPPH assay. To validate their anti-oxidative activities, the off-line ABTS and DPPH assays were performed. Given sufficient reaction time, 3,5-di-CQA showed higher activity than scutellarin, which was consistent with the order obtained in on-line HPLC-ABTS assay. These results revealed that on-line HPLC-ABTS assay is a more sensitive method for screening and determining free radical scavengers, especially more suitable for those compounds with slower reaction kinetics. PMID- 22239537 TI - Assessment of new biocompatible poly(N-(morpholino)ethyl methacrylate)-based copolymers by transfection of immortalized keratinocytes. AB - Skin carcinomas are among the most commonly diagnosed tumors in the world. In this study, we investigated the transfection of immortalized keratinocytes, used as an in vitro model for skin carcinoma, using the antisense technology and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA)-based copolymers. In order to improve the transfection efficiency of the classic PDMAEMA polymers, copolymers were synthesized including a poly(N-morpholino)ethylmethacrylate) (PMEMA) moiety for an improved proton-sponge effect, intended to favour the release of the oligonucleotide from the acidic endosome. These copolymers were synthesized either statistically (with alternating PDMAEMA and PMEMA fragments) or in blocks (one PDMAEMA block followed by one PMEMA block). MTT assays were performed using the PDMAEMA-PMEMA copolymers and revealed no significant cytotoxicity of these polymers at an N/P ratio of 7.3. Using fluorescent oligonucleotides and analyzing transfection efficiency by flow cytometry, we noticed no significant differences between the two kinds of copolymers. However copolymers with a higher DMAEMA content and a higher Mn were also those displaying the highest vectorization efficiency. Confocal microscopy showed that these copolymers induced a fine granular distribution of the transfected antisense oligonucleotides inside the cells. We also assessed the functionality of the transfected antisense oligonucleotide by transfecting immortalized GFP expressing keratinocytes with a GFP antisense oligonucleotide using these copolymers. A significant silencing was achieved with a PDMAEMA-PMEMA in block copolymer (Mn=41,000, 89 % PDMAEMA). Together, these results suggest that PDMAEMA-PMEMA copolymers combining low toxicity, vectorization and proton sponge properties, can be efficiently used to transfect immortalized keratinocytes and so open new perspectives in the therapy of skin carcinomas as well as of other skin diseases of genetic or immunological origin. PMID- 22239538 TI - Strong Kleinman-forbidden second harmonic generation in chiral sulfide: La4InSbS9. AB - A new chiral sulfide family, Ln(4)InSbS(9) (Ln = La, Pr, Nd), with its own structure type in space group P4(1)2(1)2 or its enantiomorph P4(3)2(1)2 has been synthesized by solid-state reaction. Remarkably, the La member shows the strongest Kleinman-forbidden second harmonic generation to date, with an intensity 1.5 times that of commercial AgGaS(2) at a laser wavelength of 2.05 MUm, and exhibits type-I phase-matchable behavior. Density functional theory calculations and ab initio molecular dynamics simulations suggest that lattice vibrations may be responsible for the origin and magnitude of the strong SHG effect. PMID- 22239540 TI - Synthesis of a dicarba analogue of human beta-defensin-1 using a combined ring closing metathesis--native chemical ligation strategy. AB - We herein describe the first synthesis of the native antimicrobial protein HBD-1 making use of an orthogonal thiol protection strategy and a novel dicarba analogue thereof. The robust hydrocarbon linkage was installed by replacement of one disulfide bond using on-resin ring closing metathesis. The unprecedented 59 membered C-terminal cysteine macrocyclic fragment thus formed then engages in native chemical ligation allowing convergent access to this unique synthetic protein analogue. PMID- 22239539 TI - The role of notch 1 activation in cardiosphere derived cell differentiation. AB - Cardiosphere derived cells (CDC) are present in the human heart and include heterogeneous cell populations of cardiac progenitor cells, multipotent progenitors that play critical roles in the physiological and pathological turnover of heart tissue. Little is known about the molecular pathways that control the differentiation of CDC. In this study, we examined the role of Notch 1/J kappa-recombining binding protein (RBPJ) signaling, a critical cell-fate decision pathway, in CDC differentiation. We isolated CDC from mouse cardiospheres and analyzed the differentiation of transduced cells expressing the Notch1 intracellular domain (N1-ICD), the active form of Notch1, using a terminal differentiation marker polymerase chain reaction (PCR) array. We found that Notch1 primarily supported the differentiation of CDC into smooth muscle cells (SMC), as demonstrated by the upreguation of key SMC proteins, including smooth muscle myosin heavy chain (Myh11) and SM22alpha (Tagln), in N1-ICD expressing CDC. Conversely, genetic ablation of RBPJ in CDC diminished the expression of SMC differentiation markers, confirming that SMC differentiation CDC is dependent on RBPJ. Finally, in vivo experiments demonstrate enhanced numbers of smooth muscle actin-expressing implanted cells after an injection of N1-ICD-expressing CDC into ischemic myocardium (44+/-8/high power field (hpf) vs. 11+/-4/high power field (hpf), n=7 sections, P<0.05). Taken together, these results provide strong evidence that Notch1 promotes SMC differentiation of CDC through an RBPJ dependent signaling pathway in vitro, which may have important implications for progenitor cell-mediated angiogenesis. PMID- 22239541 TI - A walk across campus on a windy day: barriers to prostate cancer testing. PMID- 22239542 TI - Heavier alkaline earth catalysts for the intermolecular hydroamination of vinylarenes, dienes, and alkynes. AB - The heavier group 2 complexes [M{N(SiMe(3))(2)}(2)](2)(1, M = Ca; 2, M = Sr) and [M{CH(SiMe(3))(2)}(2)(THF)(2)] (3, M = Ca; 4, M = Sr) are shown to be effective precatalysts for the intermolecular hydroamination of vinyl arenes and dienes under mild conditions. Initial studies revealed that the amide precatalysts, 1 and 2, while compromised in terms of absolute activity by a tendency toward transaminative behavior, offer greater stability toward polymerization/oligomerization side reactions. In every case the strontium species, 2 and 4, were found to outperform their calcium congeners. Reactions of piperidine with para-substituted styrenes are indicative of rate-determining alkene insertion in the catalytic cycle while the ease of addition of secondary cyclic amines was found to be dependent on ring size and reasoned to be a consequence of varying amine nucleophilicity. Hydroamination of conjugated dienes yielded isomeric products via eta(3)-allyl intermediates and their relative distributions were explained through stereoelectronic considerations. The ability to carry out the hydroamination of internal alkynes was found to be dramatically dependent upon the identity of the alkyne substituents while reactions employing terminal alkynes resulted in the precipitation of insoluble and unreactive group 2 acetylides. The rate law for styrene hydroamination with piperidine catalyzed by [Sr{N(SiMe(3))(2)}(2)](2) was deduced to be first order in [amine] and [alkene] and second order in [catalyst], while large kinetic isotope effects and group 2 element-dependent DeltaS(++) values implicated the formation of an amine assisted rate-determining alkene insertion transition state in which there is a considerable entropic advantage associated with use of the larger strontium center. PMID- 22239543 TI - The influence of speaker reliability on first versus second label learning. AB - Children's confidence in their own knowledge may influence their willingness to learn novel information from others. Twenty-four-month-old children's (N = 160) willingness to learn novel labels for either familiar or novel objects from an adult speaker was tested in 1 of 5 conditions: accurate, inaccurate, knowledgeable, ignorant, or uninformative. Children were willing to learn a second label for an object from a reliable informant in the accurate, knowledgeable, and uninformative conditions; children were less willing to apply a novel label to a familiar object if the speaker previously was inaccurate or had expressed ignorance. However, when the objects were novel, children were willing to learn the label regardless of the speaker's knowledge level. PMID- 22239544 TI - Effect of ethylene glycol and its derivatives on the aggregation behavior of an ionic liquid 1-butyl-3-methyl imidazolium octylsulfate in aqueous medium. AB - The effect of ethylene glycol (EG) and its derivatives, ethylene glycol monomethyl ether (EGMME), or ethylene glycol dimethyl ether (EGDME), on the aggregation behavior of a surfactant-like ionic liquid (IL), 1-butyl-3-methyl imidazolium octylsulfate, [C(4)mim][C(8)OSO(3)], in aqueous solutions is investigated using conductivity, surface tension, fluorescence, (1)H NMR, and dynamic light scattering (DLS) measurements. Thermodynamic parameters such as Gibbs free energy (DeltaG(m) degrees ), standard enthalpy (DeltaH(m) degrees ), and standard entropy (DeltaS(m) degrees ) of aggregation are determined from the temperature dependence of conductivity. The interfacial properties of IL at the air/water interface in various mixed solvents are evaluated from surface tension measurements. Information about the local microenvironment and size of the aggregates is obtained from steady-state fluorescence using pyrene as a polarity probe and DLS measurements, respectively. (1)H NMR data has been employed to get detailed insight into the effect of organic additives on the IL aggregate structure and aggregation number. It has been observed that the addition of organic additives to water decreases the spontaneity of aggregation of IL. PMID- 22239545 TI - Ligand-based design of a potent and selective inhibitor of cytochrome P450 2C19. AB - A series of omeprazole-based analogues was synthesized and assessed for inhibitory activity against CYP2C19. The data was used to build a CYP2C19 inhibition pharmacophore model for the series. The model was employed to design additional analogues with inhibitory potency against CYP2C19. Upon identifying inhibitors of CYP2C19, ligand-based design shifted to attenuating the rapid clearance observed for many of the inhibitors. While most analogues underwent metabolism on their aliphatic side chain, metabolite identification indicated that for analogues such as compound 30 which contain a heterocycle adjacent to the sulfur moiety, metabolism primarily occurred on the benzimidazole moiety. Compound 30 exhibited improved metabolic stability (Cl(int) = 12.4 mL/min/nmol) and was selective in regard to inhibition of CYP2C19-catalyzed (S)-mephenytoin hydroxylation in human liver microsomes. Finally, representative compounds were docked into a homology model of CYP2C19 in an effort to understand the enzyme ligand interactions that may lead to favorable inhibition or metabolism properties. PMID- 22239546 TI - Outcome after renal transplantation in 26 dogs. AB - OBJECTIVES: To evaluate clinical outcome in dogs after renal transplantation and determine predictors of outcome. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 26) that had renal allograft transplantation. METHODS: Medical records (1994-2006) of 26 consecutive cases of dogs that had kidney transplantation were reviewed. History, signalment, pre- and postoperative clinicopathologic and monitoring variables, postoperative complications, immunosuppressive therapy, and survival were recorded. RESULTS: Median survival was 24 days (range, 0.5 to 4014 days) with a probability of survival to 15 days of 50% and the 100-day survival probability was 36%. Cause of death was attributed to thromboembolic disease in 8 dogs, infection in 6 dogs, and rejection in 1 dog. The only factor significantly associated with an increased likelihood of death was increasing age at time of surgery (P = .024). CONCLUSIONS: Canine renal transplantation in clinical patients is associated with a high morbidity and mortality and increasing recipient age has a negative association with outcome. Thromboembolic complications are a major cause of death in the immediate postoperative period and effective anticoagulation protocols may greatly improve survival in the future. PMID- 22239547 TI - Photocurrent and electronic activities of oriented-His-tagged photosynthetic light-harvesting/reaction center core complexes assembled onto a gold electrode. AB - A polyhistidine (His) tag was fused to the C- or N-terminus of the light harvesting (LH1)-alpha chain of the photosynthetic antenna core complex (LH1-RC) from Rhodobacter sphaeroides to allow immobilization of the complex on a solid substrate with defined orientation. His-tagged LH1-RCs were adsorbed onto a gold electrode modified with Ni-NTA. The LH1-RC with the C-terminal His-tag (C-His LH1 RC) on the modified electrode produced a photovoltaic response upon illumination. Electron transfer is unidirectional within the RC and starts when the bacteriochlorophyll a dimer in the RC is activated by light absorbed by LH1. The LH1-RC with the N-terminal His-tag (N-His LH1-RC) produced very little or no photocurrent upon illumination at any wavelength. The conductivity of the His tagged LH1-RC was measured with point-contact current imaging atomic force microscopy, indicating that 60% of the C-His LH1-RC are correctly oriented (N-His 63%). The oriented C-His LH1-RC or N-His LH1-RC showed semiconductive behavior, that is, had the opposite orientation. These results indicate that the His-tag successfully controlled the orientation of the RC on the solid substrate, and that the RC produced photocurrent depending upon the orientation on the electrode. PMID- 22239548 TI - Comparative metabolomics reveals biogenesis of ascarosides, a modular library of small-molecule signals in C. elegans. AB - In the model organism Caenorhabditis elegans, a family of endogenous small molecules, the ascarosides function as key regulators of developmental timing and behavior that act upstream of conserved signaling pathways. The ascarosides are based on the dideoxysugar ascarylose, which is linked to fatty-acid-like side chains of varying lengths derived from peroxisomal beta-oxidation. Despite the importance of ascarosides for many aspects of C. elegans biology, knowledge of their structures, biosynthesis, and homeostasis remains incomplete. We used an MS/MS-based screen to profile ascarosides in C. elegans wild-type and mutant metabolomes, which revealed a much greater structural diversity of ascaroside derivatives than previously reported. Comparison of the metabolomes from wild type and a series of peroxisomal beta-oxidation mutants showed that the enoyl CoA hydratase MAOC-1 serves an important role in ascaroside biosynthesis and clarified the functions of two other enzymes, ACOX-1 and DHS-28. We show that, following peroxisomal beta-oxidation, the ascarosides are selectively derivatized with moieties of varied biogenetic origin and that such modifications can dramatically affect biological activity, producing signaling molecules active at low femtomolar concentrations. Based on these results, the ascarosides appear as a modular library of small-molecule signals, integrating building blocks from three major metabolic pathways: carbohydrate metabolism, peroxisomal beta oxidation of fatty acids, and amino acid catabolism. Our screen further demonstrates that ascaroside biosynthesis is directly affected by nutritional status and that excretion of the final products is highly selective. PMID- 22239550 TI - Parasites as mediators of heterozygosity-fitness correlations in the Great Tit (Parus major). AB - Positive correlations between heterozygosity and fitness traits are frequently observed, and it has been hypothesized, but rarely tested experimentally, that parasites play a key role in mediating the heterozygosity-fitness association. We evaluated this hypothesis in a wild great tit (Parus major) population by testing the prediction that the heterozygosity-fitness association would appear in broods experimentally infested with a common ectoparasite, but not in parasite-free broods. We simultaneously assessed the effects of parental and offspring heterozygosity on nestling growth and found that body mass of nestlings close to independence, which is a strong predictor of post-fledging survival, increased significantly with nestling levels of heterozygosity in experimentally infested nests, but not in parasite-free nests. Heterozygosity level of the fathers also showed a significant positive correlation with offspring body mass under an experimental parasite load, whereas there was no correlation with the mothers' level of heterozygosity. Thus, our results indicate a key role for parasites as mediators of the heterozygosity-fitness correlations. PMID- 22239551 TI - Correlates for nocturia: a review of epidemiological studies. AB - Traditionally, nocturia was considered to be one of the symptoms of prostatism. However, this symptom has unusual characteristics compared with other lower urinary tract symptoms; for example, there is only a mild benefit for nocturia from treatment for benign prostatic hyperplasia. In the past decade, nocturia has been investigated as a separate symptom in epidemiological studies. These types of studies have shown various correlates for nocturia other than benign prostatic hyperplasia, as well as the prevalence of this symptom. These correlates include age, race/ethnicity, medical problems (such as hypertension, diabetes and stroke) psychological aspects, tasting habits, quality of life and even mortality. The cause-and-effect associations are not always obvious between nocturia and its correlates. In the present article, the author attempts to comprehensively review the correlates for nocturia shown by epidemiological studies. PMID- 22239552 TI - Anti-cellular and immunomodulatory potential of aqueous extract of Rhodiola imbricata rhizome. AB - In the present study, we have evaluated the anti-cellular and immunomodulatory potential of aqueous extract of Rhodiola imbricata rhizome (RAE). Rhodiola extract inhibited the proliferation of human T cell lymphoma cell line EL-4 and erythroleukemic cell line HL-60. Furthermore, treatment of human peripheral blood mononuclear cells (hPBMCs) with lipopolysaccharide (LPS) and RAE suppressed regulated upon activation, normal T cell expressed and secreted (RANTES) production. However, number of TNF-alpha spots was increased in RAE treated hPBMCs. The reverse transcriptase polymerase chain reaction (RT-PCR) analysis of RAE treated rat splenocytes confirmed the up regulation of TLR-4 mRNA expression. Therefore, the present study concludes that RAE has potent immune boosting activity which might be useful in immunocompromised individuals. PMID- 22239553 TI - Confined water dissociation in microporous defective silicates: mechanism, dipole distribution, and impact on substrate properties. AB - Interest in microporous materials has risen in recent years, as they offer a confined environment that is optimal to enhance chemical reactions. Calcium silicate hydrate (C-S-H) gel, the main component of cement, presents a layered structure with sub-nanometer-size disordered pores filled with water and cations. The size of the pores and the hydrophilicity of the environment make C-S-H gel an excellent system to study the possibility of confined water reactions. To investigate it, we have performed molecular dynamics simulations using the ReaxFF force field. The results show that water does dissociate to form hydroxyl groups. We have analyzed the water dissociation mechanism, as well as the changes in the structure and water affinity of the C-S-H matrix and water polarization, comparing the results with the behavior of water in a defective zeolite. Finally, we establish a relationship between water dissociation in C-S-H gel and the increase of hardness due to a transformation from a two- to a three-dimensional structure. PMID- 22239556 TI - Effects of curcumin and related compounds on processes involving alpha hydroxyethyl radicals. AB - Effects of curcumin and related compounds on product formation in radiolysis of aerated and deaerated ethanol were studied. Ab initio calculations of enthalpy values relating to O-H bond dissociation and H-atom addition to > C = O bonds of the compounds under study have been performed. The obtained data allowed the conclusion that the presence of a 7-carbon chain containing conjugated > C = C < and > C = O bonds in the structures of curcumin and its analogues makes these compounds capable of inhibiting the reactions involving alpha-hydroxyl-containing carbon-centered radicals. This finding broadens the existing views concerning radical-regulating properties of curcuminoids, and it should be taken into account when practical use of these compounds is envisaged. PMID- 22239554 TI - Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. AB - OBJECTIVES: The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to the loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG > 10 mmol L(-1) ), it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam. METHODS: The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored high-density lipoprotein (HDL) binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls. RESULTS: In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL (n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8). In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype. CONCLUSIONS: The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n = 3), APOC2 (n = 1) and APOA5 (n = 2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies. PMID- 22239558 TI - G-quadruplex-forming oligonucleotide conjugated to magnetic nanoparticles: synthesis, characterization, and enzymatic stability assays. AB - In the present work, we report the conjugation of superparamagnetic nanoparticles to a fluorescently labeled oligodeoxyribonucleotide (ODN) able to fold into stable unimolecular guanine quadruple helix under proper ion conditions by means of its thrombin-binding aptamer (TBA) sequence. The novel modified ODN, which contained a fluorescent dU(Py) unit at 3'-end and a 12-amino-dodecyl spacer (C(12)-NH(2)) at 5' terminus, was characterized by ESI-MS and optical spectroscopy (UV, CD, fluorescence), and analyzed by RP-HPLC chromatography and electrophoresis. From CD and fluorescence experiments, we verified that dU(Py) and C(12)-NH(2) incorporation does not interfere with the conformational stability of the G-quadruplex. Subsequently, the conjugation of the pyrene labeled ODN with the magnetite particles was performed, and the ODN-conjugated nanoparticles were studied through optical spectroscopy (UV, CD, fluorescence) and by enzymatic and chemical assays. We found that the nanoparticles enhanced the stability of the TBA ODN to enzymatic degradation. Finally, we evaluated the amount of the TBA-conjugated nanoparticles immobilized on a magnetic separator in view of the potential use of the nanosystem for the magnetic capture of thrombin from complex mixtures. PMID- 22239555 TI - Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. AB - The strict human pathogen Neisseria gonorrhoeae has caused gonorrhea for thousands of years, and currently gonorrhea is the second most prevalent bacterial sexually transmitted infection worldwide. Given the ancient nature of N. gonorrhoeae and its unique obligate relationship with humankind over the millennia, its remarkable ability to adapt to the host immune system and cause repeated infections, and its propensity to develop resistance to all clinically useful antibiotics, the gonococcus is an ideal pathogen on which to study the evolution of bacterial pathogenesis, including antimicrobial resistance, over the long term and within the host during infection. Recently, the first gonococcus displaying high-level resistance to ceftriaxone, identified in Japan, was characterized in detail. Ceftriaxone is the last remaining option for empirical first-line treatment, and N. gonorrhoeae now seems to be evolving into a true "superbug." In the near future, gonorrhea may become untreatable in certain circumstances. Herein, the history of antibiotics used for treatment of gonorrhea, the evolution of resistance emergence in N. gonorrhoeae, the linkage between resistance and biological fitness of N. gonorrhoeae, lessons learned, and future perspectives are reviewed and discussed. PMID- 22239560 TI - Chloride coordination by oligoureas: from mononuclear crescents to dinuclear foldamers. AB - A series of acyclic oligourea receptors which closely resemble the scaffolds and coordination behavior of oligopyridines have been synthesized. Assembly of the receptors with chloride ions afforded mononuclear anion complexes or dinuclear foldamers depending on the number of the urea groups. PMID- 22239559 TI - A pilot evaluation of older adolescents' sexual reference displays on Facebook. AB - Many older adolescents display sexual references on their social networking site profiles; this study investigated whether these references were associated with self-reported sexual intention, sexual experience, or risky sexual behavior. Public Facebook profiles of undergraduate freshmen were identified within 1 large U.S. university Facebook network. Profile owners who displayed sexual references (Displayers) and did not display references (Non-Displayers) were invited to complete surveys. Surveys measured sexual intention, using the Postponing Sexual Intercourse (PSI) scale, and sexual experiences. A higher PSI score was inversely related to intention to initiate sexual intercourse. Of the 118 profiles that met inclusion criteria, 85 profile owners completed surveys. Profile owners were mostly female (56.5%) and Caucasian (67.1%). The mean PSI score for Displayers was 6.5 +/- 1.6, and the mean PSI score for Non-Displayers was 10.2 +/- 0.6 (p = .02). There were no differences between Displayers and Non-Displayers regarding lifetime prevalence of sexual behavior, number of sexual partners, or frequency of condom use. Display of sexual references on college freshmen's Facebook profiles was positively associated with reporting intention to initiate sexual intercourse. Facebook profiles may present an innovative cultural venue to identify adolescents who are considering sexual activity and may benefit from targeted educational messages. PMID- 22239561 TI - Field-effect transistors based on thermally treated electron beam-induced carbonaceous patterns. AB - Electron beam-induced carbonaceous deposition (EBICD) derived from residual hydrocarbons in the vacuum chamber has many fascinating properties. It is known to be chemically complex but robust, structurally amorphous, and electrically insulating. The present study is an attempt to gain more insight into its chemical and electrical nature based on detailed measurements such as Raman, XPS, TEM, and electrical. Interestingly, EBIC patterns are found to be blue fluorescent when excited with UV radiation, a property which owes much to sp(2) carbon clusters amidst sp(3) matrix. Temperature-dependent Raman and electrical measurements have confirmed the graphitization of the EBICD through the decomposition of functional groups above 300 degrees C. Finally, graphitized EBIC patterns have been employed as active p-type channel material in the field effect transistors to obtain mobilities in the range of 0.2-4 cm(2)/V s. PMID- 22239563 TI - Editorial. PMID- 22239562 TI - Simultaneous determination of chloramphenicol and florfenicol in liquid milk, milk powder and bovine muscle by LC-MS/MS. AB - A validated method based on European and Brazilian legislation is reported. It is applicable to the simultaneous determination of chloramphenicol (CAP) and florfenicol (FF) by LC-MS/MS in liquid milk, milk powder and bovine muscle. The chromatographic analysis is completed in 6 min and the extraction procedure is very simple, involving only one step liquid-extraction with ethyl acetate. Where it proved necessary to include clean-up, an efficient and rapid step using C18 dispersive solid was added. Initially, a complete validation was performed with liquid milk matrix; later the scope was extended to the other matrices through extending the inter-day precision (within laboratory reproducibility) RSD values. An internal standard (d(5)-CAP) was employed for quantitative purposes. The method was shown to have good accuracy and precision for determining CAP residues at the level of 0.3-0.6 g kg(-1) and FF residues at the level of 5-15 ug kg(-1). PMID- 22239564 TI - The vulnerability to schizophrenia mainstream research paradigms and phenomenological directions. AB - Early psychopathological attempts to characterize the vulnerability to schizophrenia were based on the phenomenological method. From the beginning, phenomenologically-oriented psychopathologists have searched the basic vulnerability underlying schizophrenic phenomena in two main domains: depersonalization and derealisation/desocialization. Schizophrenic persons undergo a special kind of depersonalisation: the living body becomes a functioning body, a thing-like mechanism in which feelings, perceptions, and actions take place as if they happened in an outer space. They also endure a special kind of derealisation/de-socialization: the interpersonal scene becomes like a theatre stage, pervaded with a sense of unreality, on which the main actor is unaware of the plot, out of touch with the role he is acting and unable to make sense of the objects he encounters and of what the other people are doing. Many years later, the mainstream research paradigms employed to investigate the vulnerability concept in schizophrenic psychosis have included genetic studies, birth cohort studies, psychosis proneness, and clinical high risk. We will review these studies and conclude with an outline of future research directions focusing on three main features of the psychopathology of early schizophrenia: anomalies of the pre-reflexive self and of the social self (intersubjectivity), and existential re-orientation. PMID- 22239565 TI - The ultra high risk approach to define psychosis risk. AB - Although prodromal symptoms of psychosis have long been recognized, the clinical management of psychotic disorders conventionally begins at the first episode of frank psychosis, and, until recently, the period immediately preceding the first episode received relatively little attention. Over the last fifteen years, there has been increasing academic and clinical interest in people presenting with potentially prodromal symptoms. This clinical syndrome has been termed an "At Risk Mental State", and operationalised criteria, the "Ultra High Risk (UHR)", or "Clinical High Risk" criteria, have been developed to identify the syndrome. We will review here the mainstreams of the UHR paradigms focusing on the conceptual basis, potentials and limitations in current psychiatric research. PMID- 22239566 TI - Basic symptoms and the prediction of first-episode psychosis. AB - Recent focus on early detection and intervention in psychosis has renewed interest in subtle psychopathology beyond positive and negative symptoms. Such self-experienced sub-clinical disturbances are described in detail by the basic symptom concept. This review will give an introduction into the concept of basic symptoms and describe the development of the current instruments for their assessment, the Schizophrenia Proneness Instrument, Adult (SPI-A) and Child and Youth version (SPI-CY), as well as of the two at-risk criteria: the at-risk criterion Cognitive-Perceptive Basic Symptoms (COPER) and the high-risk criterion Cognitive Disturbances (COGDIS). Further, an overview of prospective studies using both or either basic symptom criteria and transition rates related to these will be given, and the potential benefit of combining ultra-high risk criteria, particularly attenuated psychotic symptoms, and basic symptom criteria will be discussed. Finally, their prevalence in psychosis patients, i.e. the sensitivity, as well as in general population samples will be described. It is concluded that both COPER and COGDIS are able to identify subjects at a high risk of developing psychosis. Further, they appear to be sufficiently frequent prior to onset of the first psychotic episode as well as sufficiently rare in persons of general population to be considered as valuable for an early detection of psychosis. PMID- 22239567 TI - Rationale and first results of developing at-risk (prodromal) criteria for bipolar disorder. AB - Bipolar affective disorder (BD) is a severe, recurrent and disabling disorder with devastating consequences for individuals, families and society. Although these hazards and costs provide a compelling rationale for development of early detection and early intervention strategies in BD, the development of at-risk criteria for first episode mania is still in an early stage of development. In this paper we review the literature with respect to the clinical, neuroantomical and neuropsychological data, which support this goal. We also describe our recently developed bipolar at-risk criteria (BAR). This criteria comprises the peak age range of the first onset of bipolar disorder, genetic risk, presenting with sub-threshold mania, cyclothymic features or depressive symptoms. An initial pilot evaluation of the BAR criteria in 22 subjects indicated conversion rates to proxies of first-episode mania of 23% within 265 days on average, and high specificity and sensitivity of the criteria. If prospective studies confirm the validity of the BAR criteria, then the criteria would have the potential to open up new avenues of research for indicated prevention in BD and might therefore offer opportunities to ameliorate the severity of, or even prevent BD. PMID- 22239568 TI - Can we detect psychotic-like experiences in the general population? AB - The continuum model of psychosis posits that psychotic symptoms are distributed throughout the population, with diagnosable clinical disorder existing at a certain point along this continuum. The total continuum is made up mainly of non clinical cases with clinical cases of psychosis representing only a small proportion of the total extended psychosis phenotype. This paper is a narrative review of studies of psychotic experiences in the general population. The evidence indicates reasonably high prevalence rates of psychotic experiences in the general population, substantially higher than the prevalence of psychotic disorders, and that they are associated with increased risk of future onset of diagnosable disorder, particularly when the experiences are persistent. Psychotic experiences in the general population share an extensive range of risk factors with schizophrenia and therefore provide a useful phenotype in which to study the aetiology of clinical psychosis. Some types of psychotic experiences, such as paranoid ideas, bizarre thinking and perceptual abnormalities, may indicate a greater level of risk for psychotic disorder than other psychotic experiences, such as magical thinking. There is a need for research that further explores the interplay between psychotic experiences and other risk factors (including psychological, environmental, neurocognitive and genetic factors) in the evolution of psychotic disorder, the types of psychotic experiences that are most associated with risk for clinical disorder, the specificity of risk associated with psychotic experiences, and the possible adaptive advantages of these experiences. PMID- 22239569 TI - Reliability and validity of the Comprehensive Assessment of the At Risk Mental State, Italian version (CAARMS-I). AB - The Comprehensive Assessment of the At Risk Mental State (CAARMS) is a semi structured interview designed to assess attenuated psychotic symptoms in people at ultra high risk of developing psychosis (UHR). It is widely used worldwide but no studies have ever assessed its psychometric properties in the Italian population. Here we tested the reliability and validity of the Italian version of the CAARMS (CAARMS-I). Psychometric properties (inter-rater reliability, internal coherence, construct validity, concurrent validity and predictive validity) were assessed in an Italian sample of ARMS subjects, first-episode subjects and matched controls. We found that the CAARMS-I demonstrates adequate validity and reliability and appears to be helpful in the diagnosis of the ARMS and prediction of psychosis transition. PMID- 22239570 TI - Abnormal bodily experiences may be a marker of early schizophrenia? AB - The purpose of this study is to answer the following question: What are the typical features of abnormal bodily experiences (ABEs) in persons affected by acute first-episode schizophrenia? Our overall objective is to contribute to enhance early diagnosis of schizophrenia, and providing supplementary diagnostic criteria especially for ultra-high risk patients. In a group of 39 patients with first-episode schizophrenia selected from a sample of 393 psychotic patients, 30 (76.9 %) reported ABEs. By means of a phenomenologically-based qualitative method of inquiry, we recognized four subtypes of ABEs whose main characteristics are dynamization of bodily boundaries and construction, morbid objectivization/devitalization, dysmorphic experiences and pain-like experiences. These four typologies of ABEs are documented through the patients' first-person self-descriptions, and then operationally defined. Two main properties emerge as tentative eidetic (defining) cores of ABEs in early schizophrenia: dynamization of bodily boundaries and construction, and morbid objectivization/devitalization. Sharpening the diagnostic sensibility for typically schizophrenic ABEs can help improve differential diagnosis between schizophrenia and other disorders entailing other types of anomalies of lived corporeality. Also, studying possible transitions from schizophrenic cenesthopathies to bodily delusions in persons with schizophrenia may refine the concept of bizarre delusions by improving its validity. Furthermore, our knowledge about the pathogenesis of schizophrenia may profit from an in-depth assessment of ABEs and their relationship with an abnormal sense of selfhood, especially in early schizophrenia. PMID- 22239571 TI - Neurocognition in the psychosis risk syndrome: a quantitative and qualitative review. AB - Cognitive dysfunction is a hallmark feature of schizophrenia and is evident across all phases of the illness. While prior meta-analyses have elucidated the level and pattern of cognitive deficits in the premorbid and post-onset periods of psychosis, no meta-analyses of studies of the putative prodromal period have been published. Our primary aim is to provide a meta-analysis of neurocognitive findings from 14 studies of psychosis risk syndrome (PRS) individuals published through February 2011, and compare the resulting profile with that synthesized by meta-analyses from other periods of the disorder. Meta-analysis of 1215 PRS individuals with a mean age of 19.2 (+/- 3.3) and 851 healthy control subjects yielded small-to-medium impairments across nine of 10 neurocognitive domains (Cohen's d = -0.26 to -0.67). Seven studies reported on PRS individuals who later developed psychosis (n = 175) and their baseline performance level generally yielded moderate-to-large ESs (d = -0.35 to -0.84). Mild cognitive deficits are reliably and broadly present in PRS individuals, falling at a level that is intermediate between healthy individuals and those diagnosed with schizophrenia, and at a level that is comparable to those at familial ("genetic") risk and with premorbid data. Moreover, baseline neurocognition in PRS individuals who converted to psychosis showed more severe deficits than non-converters in nearly all domains. However, considerable heterogeneity of ESs across studies in many domains underscores variability in phenotypic expression and/or measurement sensitivity, and a critical need for improved reporting of sample characteristics to support moderator variable analyses. PMID- 22239572 TI - Neuroimaging and resilience factors--staging of the at-risk mental state? AB - Over the past decade, vulnerability- and psychosis-associated structural and functional brain abnormalities in a population at high clinical risk to develop psychosis were intensively studied. We reviewed the results from studies comparing at-risk mental state (ARMS) individuals with and without subsequent transition to psychosis. Additionally, we introduced a new concept of splitting ARMS population according to the duration of the psychosis risk syndrome and their probability to develop psychosis. Studying the ARMS individuals still vulnerable to psychosis but with lower risk to transit can disclose the possible protective-resilience factors or characteristics. Resilience, understood as ability to recover from change, can be thus applied in the early intervention for high clinical risk for psychosis individuals. PMID- 22239573 TI - The relationship of developmental changes in white matter to the onset of psychosis. AB - Schizophrenia is a disorder with a pronounced developmental component. Accordingly, there is a growing interest in characterizing developmental changes in the period leading up to disease onset, in an effort to develop effective preventative interventions. One of the ongoing neurodevelopmental changes known to occur in the late adolescent period that often overlaps with the prodromal phase and time of onset is white matter development and myelination. In this critical review, a disruption in the normal trajectory of white matter development could potentially play an important role in the onset of psychosis. We seek to summarize the existing state of research on white matter development in prodromal subjects, with a particular focus on diffusion tensor imaging (DTI) measures. First, we describe the physiological basis of developmental white matter changes and myelination. Next, we characterize the pattern of white matter changes associated with typical development across adolescence as measured with DTI. Then, we discuss white matter changes observed in adult patients with schizophrenia and in individuals seen in genetic and clinical high risk states. Finally, we discuss the implications of these findings for future research directions and for potential therapeutic interventions. PMID- 22239574 TI - Relationship between gyrification and functional connectivity of the prefrontal cortex in subjects at high genetic risk of schizophrenia. AB - Measures of cortical folding ('gyrification') and connectivity are both reported to be disrupted in schizophrenia. There are also reports that increases in prefrontal gyrification may be predictive of subsequent illness in individuals at familial risk of the disorder. Such measures therefore have important potential clinical relevance. The nature of the relationship between cortical morphology and underlying connectivity is however unclear. In the current study we sought to explore the relationship between measures of gyrification and functional connectivity in a cohort of individuals at high genetic risk for the disorder. The theoretical background is based on the hypothesis that increased gyrification index (GI) in the prefrontal cortex may reflect increased short range regional connectivity. The cohort comprised 68 young unaffected relatives of schizophrenia patients and 21 healthy controls. Cortical folding was assessed using an automated Gyrification Index method (A-GI). Participants performed the Hayling sentence completion paradigm in the scanner and measures of functional connectivity were assessed using a correlation based approach. In the high risk subjects significant positive associations were found between prefrontal GI and prefrontal lateral-medial connectivity, while a negative correlation was found between prefrontal GI and prefrontal-thalamic connectivity. These associations indicate that measures describing morphological features of the brain surface relate to measures of underlying functional connectivity in the high risk subjects. Correlations in high risk people were more pronounced than in control subjects. We suggest our previous finding of increased prefrontal gyrification may therefore relate to increased local short range prefrontal connectivity and reduced long range connectivity. PMID- 22239575 TI - Episodic memory dysfunction in individuals at high-risk of psychosis: a systematic review of neuropsychological and neurofunctional studies. AB - Cognitive impairment is one of the key features of schizophrenia, with the largest effect sizes identified for verbal learning and memory, however little is known about its features in the time that precedes psychosis onset. Here we review a total of thirty-two studies that examined memory and learning in populations at clinical and genetic high-risk for psychosis. These studies can be divided into three different categories based on their design. Some were cross sectional and examined neuropsychological differences between high-risk individuals and healthy controls. A second type of studies included a clinical follow-up that permitted dividing participants based on their outcome to examine abnormalities specific of subsequent transition to psychosis as well as the inclusion of cognitive data in regression models for psychosis prediction. A third type of studies had a longitudinal design with measures repeated at two or more time points in order to examine the course of cognitive functions over time. We also reviewed all neurofunctional studies investigating subjects at risk for psychosis and focused on brain alterations associated with the above neuropsychological impairments. Results of cross-sectional studies revealed impairments in verbal learning and memory as well as executive function/working memory, attention and processing speed; in most of these studies, performance of individuals at clinical or genetic high-risk was intermediate between that of healthy controls and first episode patients. Neurofunctional investigations revealed altered brain functioning in the neural circuits underlying memory and learning processes. Results are less consistent in terms of clearly identifying cognitive differences and their progression over time between individuals subsequently developing psychosis and those remaining non-psychotic. However, studies that included cognitive variables in regression models or prediction algorithms suggest that some areas of cognition, particularly verbal memory, can increase the accuracy obtained in the identification of individuals developing psychosis beyond that based purely on psychopathological measures, suggesting that the inclusion of neurocognitive tests of domains for which there is evidence of prediction potential could be useful in a stepwise assessment of risk. PMID- 22239577 TI - Glutamate and psychosis risk. AB - Increasing evidence suggests that abnormalities in glutamatergic transmission may be associated with psychosis risk. Genetic polymorphisms associated with schizophrenia converge on NMDA receptor signalling pathways, and transgenic animal models and human neuroimaging studies have shown the functional impact of these risk alleles. Animal models have also shown that environmental risk factors, such as stress, cannabis use and maternal infection can result in glutamatergic dysfunction, and in vivo magnetic resonance spectroscopy (MRS) studies have detected glutamatergic abnormalities in individuals at clinical or genetic risk of psychosis. Glutamatergic dysfunction may impact on dopaminergic transmission, and ultimately lead to the emergence of psychosis. In this review, the evidence that genetic and environmental risk factors for psychosis impact on glutamatergic transmission is discussed. If glutamatergic abnormalities are present early in the disorder, this suggests that glutamatergic therapies may be useful in psychosis prevention. PMID- 22239576 TI - From the prodrome to chronic schizophrenia: the neurobiology underlying psychotic symptoms and cognitive impairments. AB - Schizophrenia is a chronic psychotic disorder that remains a considerable cause of global disease burden. Cognitive impairments are common and contribute significantly to the morbidity of the disorder. Over the last two decades or so molecular imaging studies have refined understanding of the pathophysiology underlying the development of psychosis and cognitive impairments. Firstly they have consistently implicated presynaptic dopaminergic dysfunction in the disorder, finding that dopamine synthesis capacity, dopamine release and baseline dopamine levels are increased in the illness. Secondly recent findings show that dopamine synthesis capacity is elevated in those that go on to develop psychosis in the following year, but not in those that do not, and appears to increase further with the development of psychosis. Thirdly evidence links greater dopamine synthesis capacity to poorer cognitive performance and altered frontal cortical function measured using functional imaging during cognitive tasks. Finally they have provided data on the nature of other neurofunctional alterations in the disorder, in particular in the serotonergic system and neuroinflammation. We review these findings and discuss their implications for understanding the neurobiology of psychosis and cognitive impairments in schizophrenia. PMID- 22239578 TI - Neurophysiological alterations in the prepsychotic phases. AB - Electroencephalography and Magnetoencephalography have provided valuable information about the brain functioning in psychosis. In the last few years, authors have demonstrated that there are neurophysiological alterations already in the prodromal period, before the development of psychosis. This makes them promising tools for predicting a future transition to psychosis. In this paper we review the latest studies using event-related potentials (ERP) in subjects clinically at high-risk of developing psychosis. We particularly focus in the P300, Mismatch-Negativity (MMN) and P50 paradigms, discussing the main findings, but also the limitations and challenges in electrophysiological studies in this population. PMID- 22239579 TI - Brain structural abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis of controlled magnetic resonance imaging studies. AB - A number of structural brain imaging studies and meta-analytic reviews have shown that multiple subtle brain abnormalities are consistently found in schizophrenia and bipolar disorder. Several studies suggest that schizophrenia and affective psychoses share a largely common pattern of brain abnormalities. Aim of the present study was to compare, by means of a meta-analytic approach, brain structural abnormalities, as detected by Magnetic Resonance Imaging (MRI), found at the onset of schizophrenia and bipolar disorder in order to address the question of the specificity of brain abnormalities across diagnostic groups. Forty-five studies were identified as suitable for analysis. In both schizophrenic and bipolar patients significant overall effect sizes were demonstrated for intracranial, whole brain, total grey and white matter volume reduction as well as for an increase of lateral ventricular volume at disease onset. Thus, the available literature data strongly indicate that some brain abnormalities are already present in first-episode schizophrenia or bipolar disorder and that there is a significant overlap of brain abnormalities in affective and non-affective psychotic disorders at the onset of the disease. However, whole grey matter volume deficits and lateral ventricular enlargement appear to be more prominent in first-episode schizophrenia whereas white matter volume reduction seems more prominent in bipolar disorder. The common vs specific trajectories of brain pathomorphology in schizophrenia and bipolar disorder are discussed. PMID- 22239580 TI - Cingulate volume abnormalities in emerging psychosis. AB - BACKGROUND: Neuroanatomical abnormalities, including cingulate cortex volume abnormalities, are a common feature in psychosis. However, the extent to which these are related to a vulnerability to psychosis, as opposed to the disorder per se, is less certain. AIM UND HYPOTHESES: The aim of the present study is to compare cingulate gray matter volumes in different stages of psychosis. We reviewed previous studies of subjects in a prodromal stage of psychosis and tested cingulate volume changes during the transition to psychosis. METHODS: A cross-sectional MRI study of manually traced cingulate gray-matter volumes in 37 individuals with an at risk mental state (ARMS) for psychosis, 23 individuals with a first-episode psychosis (FEP), and 22 healthy controls (HC) was performed using a 1.5 T MRI-scanner. 16 of 37 ARMS individuals (43 %) developed psychosis during follow up (ARMS-T), whereas 21 did not (ARMS-NT). The mean duration of follow up in ARMS was 25.1 months. 8 cingulate subregions were analysed in a region-of-interest analysis. RESULTS: Compared to HC, subjects with an ARMS had significantly reduced left caudal anterior cingulate cortex volume (p < 0.027). This finding was also evident at a trend level (p: 0.069) in FEP patients. Within ARMS, the ARMS-T group showed a significantly reduced whole right cingulate cortex (p: 0.036), right subgenual cingulate cortex (p: 0.036) and right posterior cingulate cortex (p: 0.012) compared to ARMS-NT. DISCUSSION: These results suggest that the at risk mental state is associated with cingulate volume reductions, in particular in the left caudal anterior cingulate cortex (CACC). These abnormalities do not only seem to occur with transition to psychosis, but may be a correlate of an increased vulnerability to psychosis. PMID- 22239581 TI - Biochemical markers of impending psychosis. AB - Recent years have witnessed numerous attempts at identifying the biological correlates of impending psychosis. Biochemical markers may theoretically provide a powerful approach to identify at-risk individuals, potentially leading to more effective intervention strategies to treat them. Hopefully, future developments in the field of research biochemistry in patients with at risk mental states or prodromal symptoms will make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different biochemical markers which have been recently demonstrated to be altered in the biological fluids of patients with impending psychosis. We will also examine the practical issues that seem to be limiting the effective integration of biomarkers into clinical development. PMID- 22239582 TI - Genetic vulnerability to psychosis and cortical function: epistatic effects between DAAO and G72. AB - Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p < 0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder. PMID- 22239583 TI - Immigration, social environment and onset of psychotic disorders. AB - The recent decade has been characterized by a resurging interest for socio environmental determinants of psychotic disorders, largely as a result of findings from studies of migration and psychotic disorders. This contribution reviews recent meta-analytic findings which confirm higher incidence rates of schizophrenia and related disorders among first- and second-generation immigrants than in non-immigrant populations, as well as substantial risk variation according to both ethnic minority groups and host society contexts. The relevance of social contexts in the onset of psychosis is also suggested by incidence variation according to the neighbourhood level ethnic density. While limited, an emerging literature suggests potential variations in psychotic-like experiences and at-risk mental states according to ethnic minority status. We then discuss the meaning of findings from migrant studies, as well as integrative models that attempt to account for ethnic variations in the incidence of psychosis and psychotic-like phenomena. In conclusion, there remain numerous gaps in our understanding of the relation between migration, ethnicity, social contexts and the onset of psychosis and we propose future research avenues to address these. In particular, there is a need for multilevel approaches integrating disciplines and methodologies across the psychosis continuum. PMID- 22239584 TI - Stress and the prodromal phase of psychosis. AB - Stress plays a role in most conceptualizations of the etiology of psychotic disorders. This is based on extensive research showing an association between the incidence of psychosis and psychosocial stress exposure (e.g., stressful life events and trauma) both in childhood and the weeks preceding a psychotic episode. There is also evidence of increased sensitivity to stressful events and dysregulation of biological stress systems. To better understand the relation of stress with the initial emergence of psychosis, research has increasingly focused on the psychosis prodrome, the period of functional decline that precedes clinical illness. Preliminary results suggest that increased incidence of early childhood trauma, heightened sensitivity to psychosocial stress, and dysregulation of biological stress response systems are present in the prodrome and associated with the onset and severity of psychosis. The current paper reviews this research and discusses the possible mechanisms responsible for these associations. This discussion includes the possible effect of stress on the hypothalamic-pituitary-adrenal [HPA] axis and hippocampus, and the role adolescent developmental changes may play in mediating this effect. Further longitudinal research combining clinical and biological measures of stress with techniques designed to assess developmental change in neural structure and function, cellular mechanisms, and genetic and epigenetic factors are critical for elucidating the role stress plays in the pathophysiology of psychotic illness. PMID- 22239585 TI - Cognitive remediation in the early course of schizophrenia: a critical review. AB - BACKGROUND: The aim of cognitive remediation is to target the cognitive impairments of patients with psychosis, including attentional deficits, memory problems, and limitations in planning and problem solving. It is hoped that by addressing these deficits, patients will be more able to take advantage of other interventions and will be more able to function in social and other domains. Many results in controlled trials of cognitive remediation in adult patients affected by schizophrenia have demonstrated its effectiveness on different cognitive domains and on patient's functioning. Some researchers speculate that deficits in cognition are more amenable to remediation during earlier phases of illness than when chronicity has developed. For these reasons cognitive rehabilitation should be a key component of early intervention programs, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease, and its possible application in the prodromal phase of the disease. PURPOSE OF REVIEW: The aim of this paper is to review the available literature on cognitive remediation in the prodromal phase and in the early course of schizophrenia. This review summarizes especially findings of cognitive changes induced in the early course or in the prodromal phases of schizophrenia by different remediation methods. Controlled studies of cognitive training are discussed in more detail. CONCLUSION: Few studies on the effects of cognitive training programs have been conducted in first episode or in early schizophrenia and only one study has been conducted in the prodromal phase of the disease. Although preliminary positive results have been achieved, more empirical research is needed to confirm the efficacy of cognitive remediation in the early course of schizophrenia, and future studies should address the issue of the usefulness of cognitive remediation in the prodromes of psychosis. PMID- 22239586 TI - Cannabis abuse and vulnerability to psychosis: targeting preventive services. AB - Cannabis is the most widely used illicit substance in the world and due to the high levels of use observed among young people with psychosis, most research has focused on the causal relationship between cannabis use and mental health problems. Despite a large interest in developing intervention models to target this group, there are as yet no established and effective methods of prevention and intervention focusing on cannabis use. In this paper we present the available evidence for the effectiveness of substance use treatments in patients with co morbid severe mental illness, as well as exploring the prevention and early intervention initiatives for substance use in the general population. PMID- 22239587 TI - Pharmacological prevention and treatment in clinical at-risk states for psychosis. AB - Over the last couple of decades, the treatment of psychoses has much advanced; yet, despite all progress, the individual and societal burden associated with psychosis and particularly schizophrenia has largely remained unchanged. Therefore, much hope is currently placed on indicated prevention as a mean to fight these burdens before they set in. Though the number of studies investigating pharmacological interventions is still limited, encouraging results have been reported from the pioneering trials, despite several methodological limitations. Furthermore, it has become clear that persons characterized by the at-risk criteria are already ill and do not only need preventive intervention, but also treatment. In consequence, outcome criteria have to be broadened to cover the current needs of the patients. As is indicated by a recent study successfully using Omega-3 fatty acids for both purposes, it may be promising to develop and investigate interventions especially for the at-risk state, independent of their effectiveness in manifest disease states. Treatment studies may become promoted by the proposed introduction of a new disorder category into DSM-V. Future prevention studies, however, need to solve the challenge of changing immediate transition rates, demanding for new risk enrichment strategies as a prerequisite for feasible trial designs. PMID- 22239588 TI - Cognitive behavioral therapy in prodromal psychosis. AB - There is a strong impetus in the psychosis research field to develop interventions that aim to prevent the onset of psychotic disorders. Over the past 15 years there has been a tremendous development in the work aimed at understanding the pre-psychotic period. More recently there has been a focus on developing and testing treatments both pharmacological and psychological that could potentially prevent or delay the onset of psychosis. One of the psychological treatments that has received the most attention is cognitive behavioral therapy (CBT). Relatively few trials have been completed and this paper reviews the existing trials. Implications of these trials for the treatment of this early phase as well as for designing future studies are discussed. PMID- 22239589 TI - Psychoeducation in subjects at elevated risk for psychosis--a critical review. AB - Pychoeducation is a useful and required intervention in subjects with elevated risk state of psychosis. Psychoeducation is, however, an under-investigated area in the field of early identification and prevention. Psychoeducation with this particular patient group needs to adapt to several unique features, e.g. the diagnostic uncertainty ("say it only in subjunctive") and problems of stigmatization. More research regarding the subjective psychoeducational needs of individuals at elevated risk for psychosis as well as more explicit provision and evaluation of psychoeducation in the elevated-risk state is strongly desirable. PMID- 22239590 TI - Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study. AB - OBJECTIVES: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. METHODS: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy ((1)H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and (1)H-MRS percentage change scores between scans were compared using repeated measures ANOVA and correlated with behavioural change scores. RESULTS: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects was seen for any brain metabolites as measured with (1)H MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. CONCLUSIONS: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder. PMID- 22239591 TI - Polyunsaturated fatty acids in emerging psychosis. AB - The role of polyunsaturated fatty acids and their metabolites for the cause and treatment of psychotic disorders are widely discussed. The efficacy as an augmenting agent in chronic schizophrenia seems to be small or not present, however epidemiological data, as well as some recent controlled studies in emerging psychosis point towards possible preventive effects of long-chain polyunsaturated fatty acids in early and very early stages of psychotic disorders and some potential secondary or tertiary beneficial long-term effects in later, more chronic stages, in particular for metabolic or extra-pyramidal side effects. In this comprehensive review, we describe the physiology and metabolism of polyunsaturated fatty acids, phospholipases, epidemiological evidence and the effect of these fatty acids on the brain and neurodevelopment. Furthermore, we examine the available evidence in indicated prevention in emerging psychosis, monotherapy, add-on therapy and tolerability. The neuroprotective potential of n 3 LC-PUFAs for indicated prevention, i.e. delaying transition to psychosis in high-risk populations needs to be further explored. PMID- 22239592 TI - Economic impact of early detection and early intervention of psychosis. AB - BACKGROUND: Whilst there is a growing body of evidence relating to the effectiveness of early detection and early intervention services there have been relatively few studies which have provided information on whether they are cost effective. AIM: The aim of this paper is to review the cost-effectiveness evidence for early detection and early intervention in psychosis. METHODS: Full economic evaluations, cost studies, and studies which do not report costs but do provide important resource use information were included in the review. RESULTS: All cost effectiveness analysis to date suggest that it is possible to offer help early in the development of psychosis in a cost effective manner. CONCLUSIONS: The potential longer term economic benefits of early detection and early intervention are required. PMID- 22239593 TI - Philosophical issues in the prodromal phase of psychosis. AB - In this paper we try to examine some of the philosophical issues that arise from the clinical and scientific study of the prodromal phase of psychotic illness. These issues can be broadly grouped in to ethical concerns and those relating to the philosophy of psychology and science. Specifically, we discuss the notion of the prodrome as a discrete disorder as opposed to being a segment of the continuum of psychosis, and whether we can define psychopathology purely via the use of neuroscientific variables and concepts. We argue that many psychopathological terms have definitions that rely on normative notions that themselves may not be able to be reduced to terms in cognitive neuroscience and hence a purely neuroscientific conception of psychopathology and of the prodromal phase of psychosis may be unachievable. Ethical concerns arise around the treatment of 'false positives', that is, those who may clinically look to be at risk but do not develop psychosis, and the reification of a subtle research category into a DSM-5 diagnosis. More subtle issues lie in the clinical encounter where one has to balance communicating risk about developing psychosis with attempts to normalize experiences and decrease anxiety. We conclude by noting that studying the brain solely will not enable us to comprehensively understand prodromal phase of psychosis: a close attention to continua and normativity is also required and that several important clinical and ethical issues arise in both indentifying and intervening in this high risk group, and that these are now cast sharply in to focus with the inclusion of the risk syndrome in the draft DSM 5. PMID- 22239594 TI - Ethical implications for clinical practice and future research in "at risk" individuals. AB - The last 15 years have witnessed a shift in schizophrenia research with increasing interest in earlier stages of illness with the hope of early intervention and ultimately prevention of psychotic illness. Large-scale longitudinal studies have identified clinical and biological risk factors associated with increased risk of psychotic conversion, which together with symptomatic and demographic risk factors may improve the power of prediction algorithms for psychotic transition. Despite these advances, 45-70% of at risk subjects in most samples do not convert to frank psychosis, but continue to function well below their age matched counterparts. The issue is of utmost importance in light of the upcoming DSM-V and the possible inclusion of the attenuated psychotic symptoms syndrome (APSS) diagnosis, with clinical and ethical implications. Clinical considerations include feasibility of reliably diagnosing the at risk state in non-academic medical centers, variable psychotic conversion rates, a non-uniform definition of conversion and extensive debate about treatment for individuals with an ill-defined outcome. On the ethical side, diagnosing APSS could lead to unnecessary prescribing of antipsychotics with long term deleterious consequences, slow research by providing a false sense of comfort in the diagnosis, and have psychosocial implications for those who receive a diagnosis. Thus it may be prudent to engage at risk populations early and to use broad-spectrum treatments with low risk benefit ratios to relieve functional impairments, while simultaneously studying all subsets of the at risk population. PMID- 22239595 TI - An unconventional role of ligand in continuously tuning of metal-metal interfacial strain. AB - We show that embedding of a surface ligand can dramatically affect the metal metal interfacial energy, making it possible to create nanostructures in defiance of traditional wisdom. Despite matching Au-Ag lattices, Au-Ag hybrid NPs can be continuously tuned from concentric core-shell, eccentric core-shell, acorn, to dimer structures. This method can be extended to tune even Au-Au and Ag-Ag interfaces. PMID- 22239596 TI - Naproxen glycine conjugate-synthesis, pharmaceutical preformulation and pharmacodynamic evaluation. AB - The project was aimed at synthesizing and characterizing amino acid conjugate of naproxen (categorically stated as Type II A prodrug) that is expected to enhance solubility without affecting permeability and is capable of delivering naproxen (NAP) to colon without significant reversion of prodrug in gastrointestinal conditions. Thus, naproxen-glycine conjugate (NAP-GLY) was prepared by conventional coupling method and the prodrug was characterized by FTIR, FTNMR, FAB mass and elemental analysis. The conjugate was then subjected to selected pharmaceutical preformulation studies like pH-solubility analysis, intrinsic dissolution rate and pH partition studies. These studies established 1.24 folds higher solubility of the (NAP-GLY) over NAP in phosphate buffer pH 7.4 without compromising its partitioning ability. The amino acid conjugate demonstrated superior intrinsic dissolution capabilities (30.9% enhancement) than NAP and in vitro reversion studies suggested its potential of safe transit to colon where the moiety is capable of reverting to 78.52% NAP after 72 hrs of the experiment. In vivo evaluation of NAP-GLY in experimentally induced colitis established its efficacy an anti-inflammatory prodrug moiety (ulcer index = 6.73 with respect to 42.5 for control) that was supported by histological studies. In addition to its ability to control colonic ulcers NAP-GLY demonstrated insignificant (P >0.05) gastric ulcerogenic potential. Conclusively, the conjugate when suitably formulated can be considered as therapeutically efficacious drug delivery system with fewer pharmaceutical limitations. PMID- 22239597 TI - Total synthesis of (-)-fusarisetin A and reassignment of the absolute configuration of its natural counterpart. AB - The first total synthesis of (-)-fusarisetin A, the enantiomer of naturally occurring acinar morphogenesis inhibitor (+)-fusarisetin A, was accomplished in 13 steps, leading to the reassignment of the absolute configuration of the natural product. The synthesis featured a Lewis acid-promoted intramolecular Diels-Alder reaction, a Pd-catalyzed O->C allylic rearrangement, a chemoselective Wacker oxidation, and a Dieckmann condensation/hemiketalization cascade. PMID- 22239598 TI - Structure revision of plakotenin based on computational investigation of transition states and spectroscopic properties. AB - We show that the previously [Tetrahedron Lett.1992, 33, 2579] proposed structure of natural plakotenin must be revised. Recently, the total synthesis of plakotenin was achieved via an intramolecular Diels-Alder reaction from a (E,E,Z,E)-tetraene as linear precursor. Using density functional theory, the computation of the four possible transition states for this reaction shows that the previously proposed structure could only have been formed via an energetically high-lying transition state, which is very unlikely. Instead, we suggest that the structure of plakotenin corresponds to the product formed via the lowest transition state. A comparison of experimental and theoretical optical rotation, circular dichroism, and two-dimensional nuclear Overhauser enhancement spectra conclusively proves that the structure of plakotenin is the one that is suggested by the transition state computations. Moreover, the simulation of the nuclear Overhauser enhancement spectra suggests that it is most likely that the misassignment of the (1)H chemical shifts of two methyl groups has led to the wrong structure prediction in the 1992 work. The previously proposed structure of iso-plakotenin remains unaffected by our structure revision, but the structures of homo- and nor-plakotenin must also be revised. The present work shows how the total synthesis of a natural product, together with the theoretical determination of the barrier heights of the reactions involved, can be of great help to assign its structure. It appears that intramolecular Diels-Alder reactions can be modeled accurately by today's first-principles methods of quantum chemistry. PMID- 22239599 TI - CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non-immune hydrops fetalis. PMID- 22239600 TI - In situ observation of multiple phase transitions in low-melting ionic liquid [BMIM][BF4] under high pressure up to 30 GPa. AB - In situ characterization of phase transitions and direct microscopic observations of a low-melting ionic liquid, 1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIM][BF(4)]), has been performed in detail by Raman spectroscopy. Compression of [BMIM][BF(4)] was measured under hydrostatic pressure up to ~30.0 GPa at room temperature by using a high-pressure diamond anvil cell. With pressure increasing, the characteristic bands of [BMIM][BF(4)] displayed nonmonotonic pressure-induced frequency shifts, and it is found to undergo four successive phase transitions at around 2.25, 6.10, 14.00, and 21.26 GPa. Especially, above a pressure of 21.26 GPa, luminescence of the sample occurs, which is connected with the most significant phase transition at around this pressure. It was indicated that the structure change under high pressure might be associated with a conformational change in the butyl chain. Upon releasing pressure, the spectrum was not recovered under a pressure up to 1.16 GPa, thereby indicating that this high-pressure phase remains stable over a large pressure range between 30 and 1.16 GPa in low-melting ionic liquid [BMIM][BF(4)]. Although the sample was kept under the normal pressure for 24 h, the spectrum was recovered, and it showed that the phase transition of [BMIM][BF(4)] was reversible. In other words, such a low-melting ionic liquid [BMIM][BF(4)] remains stable even after being treated under so a high pressure of up to 30 GPa. PMID- 22239601 TI - Isolation, structure elucidation, and biological evaluation of 16,23 epoxycucurbitacin constituents from Eleaocarpus chinensis. AB - Eight new 16,23-epoxycucurbitacin derivatives, designated as elaeocarpucins A-H (1-8), and five known cucurbitacins (9-13) were isolated from the chloroform soluble partitions of separate methanol extracts of the fruits and stem bark of Elaeocarpus chinensis collected in Vietnam. Isolation work was facilitated using a LC/MS dereplication procedure, and bioassay-guided fractionation was monitored using HT-29 human cancer cells. The structures of compounds 1-8 were determined on the basis of spectroscopic data interpretation, with the absolute configurations of isomers 1 and 2 established by the Mosher ester method. Compounds 1-13 were evaluated in vitro against the HT-29 cell line and using a mitochondrial transmembrane potential assay. Elaeocarpucin C (3), produced by partial synthesis from 16alpha,23alpha-epoxy-3beta,20beta-dihydroxy 10alphaH,23betaH-cucurbit-5,24-dien-11-one (13), was found to be inactive when evaluated in an in vivo hollow fiber assay using three different cancer cell types (dose range 0.5-10 mg/kg/day, i.p.). PMID- 22239602 TI - The quadriceps angle: reliability and accuracy in a fox (Vulpes vulpes) pelvic limb model. AB - OBJECTIVES: To evaluate the effect of measurement technique and limb positioning on quadriceps (Q) angle measurement, intra- and interobserver reliability, potential sources of error, and the effect of Q angle variation. STUDY DESIGN: Cadaveric radiographic study and computer modeling. ANIMALS: Pelvic limbs from red foxes (Vulpes vulpes). METHODS: Q angles were measured on hip dysplasia (HD) and whole limb (WL) view radiographs of each limb between the acetabular rim, mid point (Q1: patellar center, Q2: femoral trochlea), and tibial tuberosity. Errors of 0.5-2.0 mm at measurement landmarks alone and in combination were modeled to identify the effect on Q angle. The effect of measured Q angles on the medial force exerted on the patella (F(MEDIAL)) was calculated. RESULTS: The HD position yielded significantly (P < .001) more medial Q angles than the WL position. No significant difference was observed between Q1 and Q2, but Bland-Altman plots indicated they were not equivalent. Intra- and interobserver agreement was substantial. Q2 errors were inherently greater than Q1: the mid-point and tibial tuberosity are the most important sources of Q angle variability. Increasing Q angles significantly increased the exerted F(MEDIAL) (P < .0001, gradient 1.7%). CONCLUSIONS: Measurements are reliable, but Q2 is more prone to error than Q1, and the 2 measurement techniques are not interchangeable. Positional errors must be kept below 1.3 mm (Q1) or 0.8 mm (Q2). PMID- 22239603 TI - A linear-hyperbranched supramolecular amphiphile and its self-assembly into vesicles with great ductility. AB - A linear-hyperbranched supramolecular amphiphile was synthesized through the noncovalent coupling of adamantane-functionalized long alkyl chain (AD-C(n), n = 12, 18, 30) and hyperbranched polyglycerol grafted from beta-cyclodextrin (CD-g HPG) by the specific AD/CD host-guest interactions. The obtained supramolecular C(n)-b-HPGs self-assembled into unilamellar vesicles with great ductility that could be disassembled readily under a competitive host of beta-CD. PMID- 22239604 TI - High-mobility field-effect transistors from large-area solution-grown aligned C60 single crystals. AB - Field-effect transistors based on single crystals of organic semiconductors have the highest reported charge carrier mobility among organic materials, demonstrating great potential of organic semiconductors for electronic applications. However, single-crystal devices are difficult to fabricate. One of the biggest challenges is to prepare dense arrays of single crystals over large area substrates with controlled alignment. Here, we describe a solution processing method to grow large arrays of aligned C(60) single crystals. Our well aligned C(60) single-crystal needles and ribbons show electron mobility as high as 11 cm(2)V(-1)s(-1) (average mobility: 5.2 +/- 2.1 cm(2)V(-1)s(-1) from needles; 3.0 +/- 0.87 cm(2)V(-1)s(-1) from ribbons). This observed mobility is ~8 fold higher than the maximum reported mobility for solution-grown n-channel organic materials (1.5 cm(2)V(-1)s(-1)) and is ~2-fold higher than the highest mobility of any n-channel organic material (~6 cm(2)V(-1)s(-1)). Furthermore, our deposition method is scalable to a 100 mm wafer substrate, with around 50% of the wafer surface covered by aligned crystals. Hence, our method facilitates the fabrication of large amounts of high-quality semiconductor crystals for fundamental studies, and with substantial improvement on the surface coverage of crystals, this method might be suitable for large-area applications based on single crystals of organic semiconductors. PMID- 22239605 TI - Temperature-sensitive swelling of poly(N-isopropylacrylamide) brushes with low molecular weight and grafting density. AB - Temperature-sensitive poly(N-isopropylacrylamide) (PNIPAAm) brushes with different molecular weights M(n) and grafting densities sigma were prepared by the "grafting-to" method. Changes in their physicochemical properties according to temperature were investigated with the help of in situ spectroscopic ellipsometry and in situ attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. Brush criteria indicate a transition between a brush conformation below the lower critical solution temperature (LCST) and an intermediate to mushroom conformation above the LCST. By in situ ellipsometry distinct changes in the brush layer parameters (wet thickness, refractive index, buffer content) were observed. A broadening of the temperature region with maximum deswelling occurred with decreasing grafting density. The brush layer properties were independent of the grafting density below the LCST, but showed a virtually monotonic behavior above the LCST. The midtemperature theta(half) of the deswelling process increased with increasing grafting density. Thus grafting density-dependent design parameters for such functional films were presented. For the first time, ATR-FTIR spectroscopy was used to monitor segment density and hydrogen bonding changes of these very thin PNIPAAm brushes as a function of temperature based on significant variations of the methyl stretching, Amide I, as well as Amide II bands with respect to intensity and wavenumber position. No dependence on M(n) and sigma in the wavenumber shift of these bands above the LCST was found. The temperature profile of these band intensities and thus segment density was found to be rather step-like, exceeding temperatures around the LCST, while the respective profile of their wavenumber positions suggested continuous structural and hydration processes. Remaining buffer amounts and residual intermolecular segment/water interaction in the collapsed brushes above the LCST could be confirmed by both in situ methods. PMID- 22239606 TI - Origin and population history of a recent colonizer, the yellow warbler in Galapagos and Cocos Islands. AB - The faunas associated with oceanic islands provide exceptional examples with which to examine the dispersal abilities of different taxa and test the relative contribution of selective and neutral processes in evolution. We examine the patterns of recent differentiation and the relative roles of gene flow and selection in genetic and morphological variation in the yellow warbler (Dendroica petechia aureola) from the Galapagos and Cocos Islands. Our analyses suggest aureola diverged from Central American lineages colonizing the Galapagos and Cocos Islands recently, likely less than 300 000 years ago. Within the Galapagos, patterns of genetic variation in microsatellite and mitochondrial markers suggest early stages of diversification. No intra-island patterns of morphological variation were found, even across steep ecological gradients, suggesting that either (i) high levels of gene flow may be homogenizing the effects of selection, (ii) populations may not have had enough time to accumulate the differences in morphological traits, or (iii) yellow warblers show lower levels of 'evolvability' than some other Galapagos species. By examining genetic data and morphological variation, our results provide new insight into the microevolutionary processes driving the patterns of variation. PMID- 22239607 TI - A novel membrane-bound toxin for cell division, CptA (YgfX), inhibits polymerization of cytoskeleton proteins, FtsZ and MreB, in Escherichia coli. AB - Nearly all free-living bacteria carry toxin-antitoxin (TA) systems on their genomes, through which cell growth and death are regulated. Toxins target a variety of essential cellular functions, including DNA replication, translation, and cell division. Here, we identified a novel toxin, YgfX, on the Escherichia coli genome. The toxin, consisting of 135 residues, is composed of the N-terminal membrane domain, which encompasses two transmembrane segments, and the C-terminal cytoplasmic domain. Upon YgfX expression, the cells were initially elongated and then the middle portion of the cells became inflated to form a lemon shape. YgfX was found to interact with MreB and FtsZ, two essential cytoskeletal proteins in E. coli. The cytoplasmic domain [YgfX(C)] was found to be responsible for the YgfX toxicity, as purified YgfX(C) was found to block the polymerization of FtsZ and MreB in vitro. YgfY, located immediately upstream of YgfX, was shown to be the cognate antitoxin; notably, YgfX is the first membrane-associating toxin in bacterial TA systems. We propose to rename the toxin and the antitoxin as CptA and CptB (for Cytoskeleton Polymerization inhibiting Toxin), respectively. PMID- 22239608 TI - The effects of systemic isotretinoin and antibiotic therapy on the microbial floras in patients with acne vulgaris. AB - BACKGROUND: Although there are several studies about the alteration in skin flora, limited number of reports about changes in the microbial contents and their resistance profile of other body sites in patients treated with isotretinoin for acne vulgaris. OBJECTIVES: The aim of this study was to investigate the effects of systemic isotretinoin and antibiotic therapy on the microbial floras of oropharynx, nose and feces in acne patients. METHODS: Treatment groups of isotretinoin and antibiotics consisting of 20 and 15 patients, respectively were included. Microbiological culture samples were taken at baseline and once a month during 4-6 months of treatment period. RESULTS: Difference in microbial flora throughout the treatment period was detected at least among one of all culture samples of 15 (75%) and 5 (33%) patients in isotretinoin and antibiotic groups. There was statistically significant difference between two groups in means of alteration of the microbial flora (P = 0.013). The difference was definitely observed among nasal cultures (65%) in isotretinoin group and fecal cultures (20%) in the other. Staphylococcus aureus colonization was prominent in the microbial floras of nose and oropharynx and 2 of 14 nasal isolates were detected to be methicilline resistant while Escherichia coli with extended spectrum beta lactamase activity was detected in fecal floras of patients in isotretinoin group. CONCLUSIONS: Systemic isotretinoin and antibiotic treatments in acne patients precisely caused variations in the microbial floras of several sites of the body, while isotretinoin was commonly more responsible than antibiotics. Knowing that alterations in the microbial colonization of the flora regions may preceede infectious disease and bacterial resistance, treatment options and follow-up procedures in acne vulgaris should be carefully determined to reduce the risk of destruction of the microbial flora. PMID- 22239609 TI - Advance directive discussions: lost in translation or lost opportunities? AB - BACKGROUND: Previous studies have shown that minority populations have low rates of documented advance directives and express preferences for more life-prolonging interventions at the end of life. We sought to determine the impact of Latino ethnicity on patients' self-report of having an advance directive discussion and having a completed advance directive in the medical record at an index hospitalization for serious medical illness. METHODS: This was a prospective observational cohort study of 458 adults admitted to the general medical services of a safety net hospital, an academic medical center, and a Veterans' Affairs (VA) hospital. Patients were asked if they had discussed advance directives, and we reviewed medical records for documented advance directives. RESULTS: Overall, 45% of patients reported having had a discussion about advance directives (29% of Latinos compared with 54% of Caucasians, p=0.0002) and 24% of patients had a completed advance directive in their medical record (25% Latinos and 26% of Caucasians, p=not significant [ns]). Using logistic regression modeling and adjusting for socioeconomic status (SES), education level, and language spoken, Latinos (odds ratio [OR] 0.42, confidence interval [CI] 0.24-0.75) were less likely to report having advance directive discussions compared with Caucasians (referent). However, modeling of a completed advance directive in the medical record showed no significant difference between Latinos (OR 1.44, CI 0.73-2.85) and Caucasians (referent). CONCLUSIONS: The unexpected discrepancy we found highlights the need for more effective communication in advance care planning that includes education that is culturally sensitive and accessible to persons with low health literacy. PMID- 22239610 TI - Pristine graphite oxide. AB - Graphite oxide (GO) is a lamellar substance with an ambiguous structure due to material complexity. Recently published GO-related studies employ only one out of several existing models to interpret the experimental data. Because the models are different, this leads to confusion in understanding the nature of the observed phenomena. Lessening the structural ambiguity would lead to further developments in functionalization and use of GO. Here, we show that the structure and properties of GO depend significantly on the quenching and purification procedures, rather than, as is commonly thought, on the type of graphite used or oxidation protocol. We introduce a new purification protocol that produces a product that we refer to as pristine GO (pGO) in contrast to the commonly known material that we will refer to as conventional GO (cGO). We explain the differences between pGO and cGO by transformations caused by reaction with water. We produce ultraviolet-visible spectroscopic, Fourier transform infrared spectroscopic, solid-state nuclear magnetic resonance spectroscopic, thermogravimetric, and scanning electron microscopic analytical evidence for the structure of pGO. This work provides a new explanation for the acidity of GO solutions and allows us to add critical details to existing GO models. PMID- 22239611 TI - Study of the synergistic effects of salinity, pH, and temperature on the surface active properties of biosurfactants produced by Lactobacillus pentosus. AB - Many studies have investigated the effects of pH, temperature, and salinity on the surface-active properties of various surfactants, although in most cases the variables have been studied separately, without considering the effects of any interactions between them. In the present study, a Box-Behnken factorial design was applied to study the effects of pH, temperature, and salinity on the surface active properties of a biosurfactant produced by Lactobacillus pentosus. The data obtained enabled development of a second-order model describing the interrelationships between operational and experimental variables, by equations including linear, interaction, and quadratic terms. The variable that had the greatest effect on the surface-active properties of the biosurfactant was pH. Moreover, at pH 3-5.5, decreases in salinity and temperature acted synergistically, reducing the surface tension of the biosurfactant; at pH 8, the same effect was observed with increasing salinity and temperature. PMID- 22239613 TI - Thyroid dysfunction in obese pre-pubertal children: oxidative stress as a potential pathogenetic mechanism. AB - Although a relationship between obesity and hyperthyrotropinemia has been hypothesized in obese children, the underlying pathogenesis is not completely known. In the current cross-sectional study, we evaluated the thyroid function in a group of 80 obese pre-pubertal children compared to 41 healthy normal weight peers, exploring the possible association between hyperthyrotropinemia and oxidative stress. In all children, thyrotropin (TSH), free T4 (fT4), free T3 (fT3) and anti-thyroid antibodies were evaluated. Homeostatic model assessment of insulin resistance (HOMA-IR) level was evaluated as index of insulin resistance. We measured the endogenous secretory receptor for advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) and the urinary prostaglandin F2alpha (PGF 2alpha) as markers of oxidative stress. We found that TSH levels were significantly higher in obese children than controls. TSH significantly correlated with body mass index-standard deviation score (BMI-SDS), HOMA-IR, PGF 2alpha, esRAGE and sRAGE. The multiple linear regression showed that in obese children HOMA-IR, PGF-2alpha, esRAGE and sRAGE were significantly related to TSH, independently of BMI-SDS, age and gender. In obese children, hyperthyrotropinemia could be detected already in pre-pubertal age. The increased oxidative stress might represent one of the key regulators of TSH levels, early in life. PMID- 22239615 TI - Determination and confirmation of chloramphenicol in honey, fish and prawns by liquid chromatography-tandem mass spectrometry with minimum sample preparation: validation according to 2002/657/EC Directive. AB - A reliable, simple and sensitive liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) confirmation method has been developed for chloramphenicol (CAP) determination in honey, fish and prawns. For honey, samples were extracted with ethyl acetate, an aliquot was evaporated to dryness and re-dissolved in mobile phase. For fish and prawns, tissues were extracted with acetonitrile and chloroform. The organic layer was evaporated to dryness and the residue was re-constituted with water: acetonitrile (90:10). LC separation was achieved on a C18 column with gradient elution using a mobile phase of acetonitrile and water. Analysis was carried out on a triple-quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via electrospray interface operated in negative ionisation mode, with deuterated chloramphenicol d(5) (d(5)-CAP) as internal standard. Method validation was performed according to the criteria of Commission Decision 2002/657/EC. Four identification points were obtained for CAP with one precursor ion and two product ions. The limit of detection (LOD) was 0.02 ug kg(-1). Linear calibration curves were obtained over concentration ranges of 0.1-1.0 ug kg(-1) in tissues. Mean recoveries ranged from 85.5% to 115.6%, with the corresponding intra- and inter-day variation ranging from 1.0% to 22.5%, depending on matrix type and level of concentration. The decision limit (CCalpha) and detection capability (CCbeta) of the method were obtained for all matrices: 0.04 and 0.06 ug kg(-1), respectively, for prawns and fish and 0.05 and 0.09 ug kg(-1) for honey. PMID- 22239616 TI - Fluorescent peptide-PNA chimeras for imaging monoamine oxidase A mRNA in neuronal cells. AB - Monoamine oxidases (MAO) catalyze the oxidative deamination of many biogenic amines and are integral proteins found in the mitochondrial outer membrane. Changes in MAO-A levels are associated with depression, trait aggression, and addiction. Here we report the synthesis, characterization, and in vitro evaluation of novel fluorescent peptide-peptide nucleic acid (PNA) chimeras for MAOA mRNA imaging in live neuronal cells. The probes were designed to include MAOA-specific PNA dodecamers, separated by an N-terminal spacer to a MU-opioid receptor targeting peptide (DAMGO), with a spacer and a fluorophore on the C terminus. The probe was successfully delivered into human SH-SY5Y neuroblastoma cells through MU-opioid receptor-mediated endocytosis. The K(d) by flow cytometry was 11.6 +/- 0.8 nM. Uptake studies by fluorescence microscopy showed ~5-fold higher signal in human SH-SY5Y neuroblastoma cells than in negative control CHO K1 cells that lack MU-opioid receptors. Moreover, a peptide-mismatch control sequence showed no significant uptake in SH-SY5Y cells. Such mRNA imaging agents with near-infrared fluorophores might enable real time imaging and quantitation of neuronal mRNAs in live animal models. PMID- 22239617 TI - The first {Dy4} single-molecule magnet with a toroidal magnetic moment in the ground state. AB - A toroidal magnetic moment in the absence of a conventional total magnetic moment was first observed in a novel tetranuclear dysprosium cluster with nonmagnetic ground state. The toroidal state is quite robust with respect to variations of the exchange parameters. PMID- 22239614 TI - Helminth-host immunological interactions: prevention and control of immune mediated diseases. AB - Exposure to commensal and pathogenic organisms strongly influences our immune system. Exposure to helminths was frequent before humans constructed their current highly hygienic environment. Today, in highly industrialized countries, contact between humans and helminths is rare. Congruent with the decline in helminth infections is an increase in the prevalence of autoimmune and inflammatory disease. It is possible that exclusion of helminths from the environment has permitted the emergence of immune-mediated disease. We review the protective effects of helminths on expression of inflammatory bowel disease, multiple sclerosis, and animal models of these and other inflammatory diseases. We also review the immune pathways altered by helminths that may afford protection from these illnesses. Helminth exposure tends to inhibit IFN-gamma and IL-17 production, promote IL-4, IL-10, and TGF-beta release, induce CD4(+) T cell Foxp3 expression, and generate regulatory macrophages, dendritic cells, and B cells. Helminths enable protective pathways that may vary by specific species and disease model. Helminths or their products likely have therapeutic potential to control or prevent immune-mediated illness. PMID- 22239618 TI - Hybrid compounds: from simple combinations to nanomachines. AB - The combination of two different and independently acting compounds into one covalently linked hybrid compound can convey synergy from the effects of both independently acting moieties to the new composite compound, leading to a pharmacological potency greater than the sum of each individual moiety's potencies. Here, we review a variety of such hybrid compounds, which can consist of various functional parts, molecular recognition or subcellular targeting moieties, or combinations thereof, acting either simultaneously or sequentially. Such moieties within a hybrid compound can consist of a variety of substance classes, including small organic molecules, polypeptides or nucleic acids identified either via rational molecular design or selection from libraries. Precedent for hybrid compounds comes from naturally occurring proteins and small molecules, such as botulinum toxin and bleomycin, which are secreted by micro organisms. We review the high degree of suitability of hybrid compounds for the treatment of multifactorial diseases by simultaneously hitting several targets along an identified disease pathway. Examples are hybrid compounds against Alzheimer's disease, against the cancer-relevant phosphoinisitide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and epidermal growth factor signaling cascade, or in antimalarial therapy via simultaneous hitting of different mechanisms of hemozoin formation. Molecular recognition by peptides or aptamers (recognition-specific RNA or peptide sequences) can be combined with the transport of small molecule beta-sheet breakers or toxins, or targeting to ubiquitin-dependent proteolysis. The vision of molecular nanomachines is currently realized in sequentially acting modular nanotransporters, consisting of four modules including a target, a membrane and nuclear translocation sequence, as well as a drug attachment domain. Through the rational combination of existing drugs and the synergy of their effects, a rapid amplification of their potency may be achieved, greatly accelerating drug development. A further enhancement of simultaneous multitarget action is enabled through the design of multifunctional hybrid drugs with sequential effects that make these hybrid molecules resemble intelligent nanomachines. PMID- 22239619 TI - Polyphosphonium polymers for siRNA delivery: an efficient and nontoxic alternative to polyammonium carriers. AB - A water-soluble polyphosphonium polymer was synthesized and directly compared with its ammonium analog in terms of siRNA delivery. The triethylphosphonium polymer shows transfection efficiency up to 65% with 100% cell viability, whereas the best result obtained for the ammonium analog reaches only 25% transfection with 85% cell viability. Moreover, the nature of the alkyl substituents on the phosphonium cations is shown to have an important influence on the transfection efficiency and toxicity of the polyplexes. The present results show that the use of positively charged phosphonium groups is a worthy choice to achieve a good balance between toxicity and transfection efficiency in gene delivery systems. PMID- 22239620 TI - An empirical exploration of the relations between the health components of the International Classification of Functioning, Disability and Health (ICF). AB - PURPOSE: The aim of this study was to investigate the relations between the ICF components from a subjective perspective. METHOD: Data on health condition and perceived functioning were collected among 2941 individuals with at least one chronic disease or disorder. Path analysis was used with perceived level of participation as the final denominator. Three models were tested: one with the number of chronic diseases and disorders as an indicator of health condition, one with perceived health as indicator of health condition, and one with perceived health as part of the personal factors. RESULTS: Although all models showed a good fit, the model with the best fit was that with perceived health as an indicator of health condition. CONCLUSIONS: From a patient's perspective, components of the ICF scheme appear to be associated with each other, with perceived health being the best indicator of the health condition. PMID- 22239622 TI - Editorial: current topics on the epidemiology, pathogenesis, and treatment of diabetes mellitus and its complications. PMID- 22239621 TI - Structural basis for matrix metalloproteinase 1-catalyzed collagenolysis. AB - The proteolysis of collagen triple-helical structure (collagenolysis) is a poorly understood yet critical physiological process. Presently, matrix metalloproteinase 1 (MMP-1) and collagen triple-helical peptide models have been utilized to characterize the events and calculate the energetics of collagenolysis via NMR spectroscopic analysis of 12 enzyme-substrate complexes. The triple-helix is bound initially by the MMP-1 hemopexin-like (HPX) domain via a four amino acid stretch (analogous to type I collagen residues 782-785). The triple-helix is then presented to the MMP-1 catalytic (CAT) domain in a distinct orientation. The HPX and CAT domains are rotated with respect to one another compared with the X-ray "closed" conformation of MMP-1. Back-rotation of the CAT and HPX domains to the X-ray closed conformation releases one chain out of the triple-helix, and this chain is properly positioned in the CAT domain active site for subsequent hydrolysis. The aforementioned steps provide a detailed, experimentally derived, and energetically favorable collagenolytic mechanism, as well as significant insight into the roles of distinct domains in extracellular protease function. PMID- 22239623 TI - Aliskiren in patients with diabetes: a systematic review. AB - OBJECTIVE: Diabetic patients are at risk of macro- and micro-vascular complications, including diabetic nephropathy, and have difficulties in achieving blood pressure (BP) goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin aldosterone system. We aimed to systematically address the relevant evidence on the effects of aliskiren in diabetic individuals. METHODS: We considered randomized controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was recorded independently by 2 investigators. We were limited to trials published in English. RESULTS: PubMed search retrieved 16 items. After excluding 12, we ended with 4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg and median follow up was 2 months. Aliskiren was compared against angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most frequent indication for aliskiren therapy was diabetes plus hypertension and albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in diabetics, either as monotherapy (compared with placebo), or in addition to ACE inhibitors/ARB (compared with monotherapy), without any major safety considerations. CONCLUSIONS: There are promising results on the effect of aliskiren in diabetic patients, but the available evidence is limited so far. This is a poorly investigated field with few RCTs and new studies focusing on "hard" outcomes are needed. PMID- 22239624 TI - Genetic risk factors for type 2 diabetes: insights from the emerging genomic evidence. AB - Type-2 diabetes is a complex disease modified by a number of environmental and genetic factors that contribute at varying degrees to the final phenotype and possibly interact with each other. Deciphering the genetic background of the disease serves multiple goals ranging from expanding our knowledge on the disease pathogenesis and identifying future targets for drug development to successfully personalizing clinical disease prediction and prognosis. In the present review, we aimed to systematically appraise the current evidence from genome-wide association studies (GWAS) on type- 2 diabetes, identify the gene targets that have been assessed to-date, and discuss issues that stem from the rapid growth of this literature. Our search identified more than 60 recently identified loci implicated with type-2 diabetes and related traits assessed in populations of European and Asian ancestry. A considerable number of the proposed genes seem to be related to beta-cell development and function, but there are several genes identified as "diabetes-genes" whose underlying pathway linked to diabetes remains poorly understood. Despite the increasing numbers of identified genetic markers, a large proportion of the observed type-2 diabetes heritability remains unexplained; larger GWAS on enhanced genotyping platforms, refined ascertainment of the characteristics of the populations under study and additional information from whole-genome sequencing will contribute to a more comprehensive view of the genetic architecture of the disease. This information is also anticipated to improve the predictive ability of multiple-loci genetic risk scores that will eventually be able to identify disease susceptibility over and above the traditional non-genetic risk factors. PMID- 22239625 TI - Non-alcoholic fatty liver disease in type 2 diabetes: pathogenesis and treatment options. AB - Non-alcoholic fatty liver disease (NAFLD) is a common disorder and its prevalence is expected to increase due to the rising incidence of type 2 diabetes mellitus (T2DM) and obesity. NAFLD is associated with increased mortality rates and cardiovascular disease is the leading cause of death in these patients. The pathogenesis of NAFLD is not completely elucidated but insulin resistance and oxidative stress appear to play a major role. NAFLD is more prevalent and more severe in patients with T2DM. A multitude of pharmacological agents have been evaluated in NAFLD but most studies were small, short-term and yielded unsatisfactory results in terms of efficacy. Patients with T2DM and NAFLD appear to be even less responsive to the evaluated agents. Thus, the optimal management strategy for NAFLD remains unclear. On the other hand, preliminary data suggest that lifestyle intervention can reduce the incidence of NAFLD in overweight or obese patients with T2DM. Accordingly, prevention of obesity and T2DM is of paramount importance for the reduction of the prevalence of NAFLD and of its associated cardiovascular and liver-related complications. PMID- 22239626 TI - Pros and cons of aggressive blood pressure lowering in patients with type 2 diabetes. AB - The goal of treating hypertension in patients with diabetes is reduction of macrovascular and microvascular complications. Most current guidelines recommend more aggressive treatment goals with blood pressure (BP) targets of < 130/80 mmHg. Retrospective data analyses suggest an association between a lower BP and slower declines in chronic kidney disease (CKD) as well as greater cardiovascular (CV) risk reduction in patients with type 2 diabetes. Such recommendations, however, are not supported by appropriately powered prospective outcome trials. Indeed, several important questions regarding aggressive lowering of BP levels are still unanswered. Major limitations of most existing clinical trials of BP lowering in diabetes is the failure to either target or achieve mean systolic BP values below 130 mmHg. Data from more recent randomized trials that evaluated different levels of BP do not support a BP below 130/80 mmHg as providing further CV risk reduction and compared to levels below 140/90 mmHg. One consistent benefit of a lower BP level, however, is on reduction of cerebrovascular events. There is reasonable evidence that a lower BP level does further slow progression of advanced proteinuric kidney disease such that a BP goal < 130/80 mmHg is defensible. This review examines the data for and against aggressive BP lowering in patients with diabetes. PMID- 22239627 TI - Recent developments on coronary microvasculopathy after heart transplantation: a new target in the therapy of cardiac allograft vasculopathy. AB - Heart transplantation (HTx) is the treatment of choice for patients with refractory end-stage heart diseases. Although the procedure is considered effective in extending and improving quality of life, the onset of cardiac allograft vasculopathy (CAV) continues to limit the long-term success of HTx. Emerging data indicate that the endothelium plays a significant role in the onset, progression and complication of this multifactorial disease, with both immunologic and nonimmunologic risk factors contributing to its development. Improving our understanding of the integral role of the coronary microcirculation in CAV is of crucial clinical interest since it could provide further insights into the related pathophysiological mechanisms and possible new strategies for CAV prevention and therapy. Assessment of coronary microvasculopathy has been shown to be of predictive value after HTx. Predominant allograft microvascular dysfunction is detectable in 15-20% of patients after HTx. Very recently, stenotic microvasculopathy (detected in biopsy samples) has been characterized as a prognostic factor for long-term survival after HTx. The ability to detect and distinguish changes in epicardial and microvascular function may aid in identifying modifiable factors that lead to CAV. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), may have a beneficial effect on coronary microcirculation after HTx, although there is still a need to confirm the impact of vasodilators in improving the prognosis of HTx patients. We review the role of coronary microvasculopathy in HTx, its prevention and new potential pharmacological interventions. PMID- 22239628 TI - Editorial: the evolution of cell therapy towards enhancing vascular regeneration in the clinic. PMID- 22239629 TI - Insulin- and growth factor-resistance impairs vascular regeneration in diabetes mellitus. AB - Diabetes and pre-diabetes are major contributors to cardiovascular mortality and morbidity. Insulin resistance is a key pathophysiological determinant of the metabolic and vascular abnormalities noted in these disorders. Ineffective vascular repair is likely to be an important contributor to the development of endothelial dysfunction, and subsequently atherosclerosis, in patients with diabetes. Beyond the systemic effects of the insulin resistant phenotype, including factors such as dysglycaemia and inflammation, cellular insulin resistance is emerging as an important factor in diabetic vascular disease. Disordered signal transduction via the PI3-kinase/Akt and MAP-kinase cascades is a hallmark of cellular insulin resistance, and such changes have been linked with both endothelial dysfunction and impaired angiogenesis. In this review we highlight the importance of insulin resistance to vascular repair and regeneration, discuss important cross-talk between the intracellular signalling of insulin and key pro-angiogenic molecules, and link these concepts to common patterns of vascular disease. PMID- 22239630 TI - Cell-based therapy to promote angiogenesis in the brain following ischemic damage. AB - Cell-based therapies are a novel approach for regeneration of microvasculature. We have shown that administration of CD34-positive cells, the rich cell fraction of endothelial progenitor cells, after stroke induces angiogenesis that results in enhanced endogenous neurogenesis and functional recovery in a murine model. Moreover, injury-induced neurogenesis occurs in the human brain following a stroke during the acute to sub-acute period. Based on these observations, clinical trials of cell therapies that aim to regenerate micro-circulation in the brain following a stroke are ongoing worldwide. This review summarizes the current basic research findings about the link between angiogenesis and neurogenesis in the post-stroke brain and introduces the ongoing clinical trials of cell-based therapies for patients that have suffered a stroke. PMID- 22239631 TI - Genetically modified endothelial progenitor cells in the therapy of cardiovascular disease and pulmonary hypertension. AB - Since their initial discovery, endothelial progenitor cells (EPCs) have held tremendous promise for cell therapy for a variety of cardiovascular diseases including pulmonary hypertension. The clinical experience to date suggests that circulating or bone marrow mononuclear cells and EPCs can induce neovascularization, and enhance cardiac repair after myocardial function, as well as improvements in the hemodynamic and functional status of patients with idiopathic pulmonary arterial hypertension. Although these results are promising, the overall magnitude of the clinical benefits seen in these trials appear to be rather modest. Indeed, strong experimental evidence points towards a reduction in mobilization and impairment in function of EPCs in preclinical models and patients with cardiac disease or with cardiovascular risk factors such as advanced age, type I and II diabetes, hypercholesterolemia, coronary artery disease, as well as other conditions such as pulmonary hypertension. Genetic engineering of EPCs ex vivo, prior to transplantation, is a promising cell enhancement strategy for restoring the angiogenic potential of autologous, patient-derived cells. This review provides an update of the experimental studies that have used gene-modified EPC therapy to treat ischemic cardiovascular disease and pulmonary hypertension. PMID- 22239632 TI - Regenerative therapies for improving myocardial perfusion in patients with cardiovascular disease: failure to meet expectations but optimism for the future. AB - Cardiovascular disease continues to be a major cause of death in the Western world and has been extending into areas previously seemingly immune to its effects. Catheter-based interventions and coronary artery bypass surgery have markedly improved cardiovascular health, but a number of patients with coronary artery disease cannot undergo repeated interventions or they receive an incomplete revascularization with standard revascularization methods, which has been associated with a poor clinical outcome. Despite early demonstration of improvement in myocardial perfusion and function with growth factor, gene therapy or cellular therapies, clinical studies have found little if any real benefit. The discordance between positive pre-clinical studies and essentially negative clinical trials may in part be explained by a number of factors including abnormal vascular signaling, oxidative stress, a hostile local myocardial environment and technical issues related to the administration of these therapies. Patients with end-stage coronary disease are vastly different from the young, healthy animals that are generally used for pre-clinical testing. The presence of diabetes, hypercholesterolemia, and other conditions associated with endothelial dysfunction and coronary disease and altered vascular signaling can significantly limit the effectiveness of growth factors on the development of collateral vessels. This paper summarizes the results of regenerative therapies for the treatment of coronary disease and discusses the reasons why growth factor protein, gene therapies and cellular therapies have not been overall successful to date. PMID- 22239633 TI - Strategies for enhancing progenitor cell mobilization and function in diabetes. AB - Bone marrow (BM) holds a pool of stem and progenitor cells whose role is not limited to hematopoiesis. Indeed, growing evidences showed that BM-derived progenitors could contribute to various extents to cardiovascular homeostasis. Notably, diabetic patients experience an intrinsic defect of the progenitor pool, whereas some recent works point directly to an intrinsic defect of the BM, resulting in defective mobilization and impaired functions of progenitors. These defects could have important pathophysiological roles in the development of diabetic complications. An integrated approach, which enhances mobilization of progenitors and improves their functions, could represent a novel method to improve cardiovascular repair by endogenous progenitors. Furthermore, potential clinical trials of cell therapy would gain benefit from stratagems that enhance the number and functions of progenitors prior to transplantation. In this review we discuss the strategies to stimulate the mobilization of progenitors in diabetes and the protocols to improve their functions. PMID- 22239634 TI - Clinically relevant extracellular-matrix scaffolds for cell transplantation and vascular repair. AB - Due to the very limited ability of cardiac tissue to self-regenerate, the replacement of damaged cardiomyocytes and the repair of damaged extracellular matrix (ECM) are highly sought-after therapeutic strategies. Cell transplantation in ECM scaffolds has been shown to improve retention, phenotype, and function in vascular and muscle repair. In addition to cellular patches that involve the use of biomaterial scaffolds in combination with cells, acellular patches may have a role in intrinsically recruiting cells to damaged areas. This review focuses on the clinically relevant ECM scaffolds, their interactions with cells to stimulate functions such as adhesion, migration, proliferation, and differentiation, and their intrinsic role in ECM remodeling leading to vascular and possibly myocardial repair. PMID- 22239635 TI - Biofunctional materials for directing vascular development. AB - Engineered tissue constructs are inherently limited by their lack of microvascularization. Evidence suggests that combining a scaffold material with cells and their cell-secreted signals instigates tubule formation, and various strategies can be employed to tailor the vascular response. This review focuses on rationally designed materials capable of supporting functional neovessel formation and stabilization. Biomaterial scaffolds and their use as growth factor delivery systems are discussed, as well as other functional enhancement strategies to direct cellular responses for effective formation of a mature vascular network. PMID- 22239636 TI - Using extracellular matrix-derived peptides to alter the microenvironment for myocardial repair. AB - Myocardial repair remains a major challenge for both cellular and tissue engineering approaches. Several studies have been conducted looking at utilizing extracellular matrix-based therapies to promote repair after a myocardial infarction. In this review, strategies for treating myocardial infarctions using extracellular matrix-derived peptides are discussed. Using an ischemia/reperfusion myocardial infarction rodent model, we showed that extracellular-matrix-derived peptides were able to induce angiogenesis and alter the negative remodeling seen after a myocardial infarction. This therapy opens up a potentially new non-invasive strategy for repairing damaged cardiac tissue. PMID- 22239637 TI - Tissue engineering a small diameter vessel substitute: engineering constructs with select biomaterials and cells. AB - Cardiovascular disease (CVD) is a leading cause of death and hospitalization worldwide. The need for small caliber vessels ( < 6mm) to treat CVD patients has grown; however the availability of autologous vessels in cardiac and peripheral bypass candidates is limited. The search for an alternative vessel source is widespread with both natural and synthetic tissue engineered materials being investigated as scaffolds. Despite decades of exhaustive studies with decellularized extracellular matrices (ECM) and synthetic graft materials, the field remains in search of a commercially viable biomaterial construct substitute. While the previous materials have been assessed by evaluating their compatibility with fibroblasts, smooth muscle cells and endothelial cells, current materials are being conceived based on their interactions with stem cells, progenitor cells and monocytes, as the latter may hold the key to repair and regeneration. The graft's ability to recruit and maintain these cells has become a major research focus. The successful tissue engineering of a small caliber vessel graft requires the use of optimal material chemistry and biological function to promote cell recruitment into the graft while maintaining each functional phenotype during vessel tissue maturation. The discussion of these significant research challenges constitutes the focus of this review. PMID- 22239639 TI - Introducing the Methods Corner. PMID- 22239638 TI - Imaging stem cell therapy for the treatment of peripheral arterial disease. AB - Arteriosclerotic cardiovascular diseases are among the leading causes of morbidity and mortality worldwide. Therapeutic angiogenesis aims to treat ischemic myocardial and peripheral tissues by delivery of recombinant proteins, genes, or cells to promote neoangiogenesis. Concerns regarding the safety, side effects, and efficacy of protein and gene transfer studies have led to the development of cell-based therapies as alternative approaches to induce vascular regeneration and to improve function of damaged tissue. Cell-based therapies may be improved by the application of imaging technologies that allow investigators to track the location, engraftment, and survival of the administered cell population. The past decade of investigations has produced promising clinical data regarding cell therapy, but design of trials and evaluation of treatments stand to be improved by emerging insight from imaging studies. Here, we provide an overview of pre-clinical and clinical experience using cell-based therapies to promote vascular regeneration in the treatment of peripheral arterial disease. We also review four major imaging modalities and underscore the importance of in vivo analysis of cell fate for a full understanding of functional outcomes. PMID- 22239642 TI - pH-, sugar-, and temperature-sensitive electrochemical switch amplified by enzymatic reaction and controlled by logic gates based on semi-interpenetrating polymer networks. AB - Phenylboronic acid (PBA) moieties are grafted onto the backbone of poly(acrylic acid) (PAA), forming the PAA-PBA polyelectrolyte. The semi-interpenetrating polymer network (semi-IPN) films composed of PAA-PBA and poly(N,N diethylacrylamide) (PDEA) were then synthesized on electrode surface with entrapped horseradish peroxidase (HRP), designated as PDEA-(PAA-PBA)-HRP. The films demonstrated reversible pH-, fructose-, and thermo-responsive on-off behavior toward electroactive probe K(3)Fe(CN)(6) in its cyclic voltammetric (CV) response. This multiswitchable CV behavior of the system could be further employed to control and modulate the electrochemical reduction of H(2)O(2) catalyzed by HRP immobilized in the films with K(3)Fe(CN)(6) as the mediator in solution. The responsive mechanism of the system was also explored and discussed. The pH-sensitive property was attributed to the electrostatic interaction between the PAA component of the films and the probe at different pH; the thermo responsive behavior originated from the structure change of PDEA hydrogel component of the films with temperature; the fructose-sensitive property was ascribed to the structure change of the films induced by the complexation between the PBA constituent and the sugar. This smart system could be used as a 3-input logic network composed of enabled OR (EnOR) gates in chemical or biomolecular computing by combining the multiresponsive property of the films and the amplification effect of bioelectrocatalysis and demonstrated the potential perspective for fabricating novel multiswitchable electrochemical biosensors and bioelectronic devices. PMID- 22239643 TI - Complete mitochondrial genome of compactin-producing fungus Penicillium solitum and comparative analysis of Trichocomaceae mitochondrial genomes. AB - We determined the complete mitochondrial genome sequence of the compactin producing fungus Penicillium solitum strain 20-01. The 28 601-base pair circular mapping DNA molecule encodes a characteristic set of mitochondrial proteins and RNA genes and is intron-free. All 46 protein- and RNA-encoding genes are located on one strand and apparently transcribed in one direction. Comparative analysis of this mtDNA and previously sequenced but unannotated mitochondrial genomes of several medically and industrially important species of the Aspergillus/Penicillium group revealed their extensive similarity in terms of size, gene content and sequence, which is also reflected in the almost perfect conservation of mitochondrial gene order in Penicillium and Aspergillus. Phylogenetic analysis based on concatenated mitochondrial protein sequences confirmed the monophyletic origin of Eurotiomycetes. PMID- 22239644 TI - Understanding the degradation pathway of the pesticide, chlorpyrifos by noble metal nanoparticles. AB - Application of nanoparticles (NPs) in environmental remediation such as water purification requires a detailed understanding of the mechanistic aspects of the interaction between the species involved. Here, an attempt was made to understand the chemistry of noble metal nanoparticle-pesticide interaction, as these nanosystems are being used extensively for water purification. Our model pesticide, chlorpyrifos (CP), belonging to the organophosphorothioate group, is shown to decompose to 3,5,6-trichloro-2-pyridinol (TCP) and diethyl thiophosphate at room temperature over Ag and Au NPs, in supported and unsupported forms. The degradation products were characterized by absorption spectroscopy and electrospray ionization mass spectrometry (ESI MS). These were further confirmed by ESI tandem mass spectrometry. The interaction of CP with NP surfaces was investigated using transmission electron microscopy, energy dispersive analysis of X-rays, Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). XPS reveals no change in the oxidation state of silver after the degradation of CP. It is proposed that the degradation of CP proceeds through the formation of AgNP S surface complex, which is confirmed by Raman spectroscopy. In this complex, the P-O bond cleaves to yield a stable aromatic species, TCP. The rate of degradation of CP increases with increase of temperature and pH. Complete degradation of 10 mL of 2 ppm CP solution is achieved in 3 h using 100 mg of supported Ag@citrate NPs on neutral alumina at room temperature at a loading of ~0.5 wt %. The effect of alumina and monolayer protection of NPs on the degradation of CP is also investigated. The rate of degradation of CP by Ag NPs is greater than that of Au NPs. The results have implications to the application of noble metal NPs for drinking water purification, as pesticide contamination is prevalent in many parts of the world. Study shows that supported Ag and Au NPs may be employed in sustainable environmental remediation, as they can be used at room temperature in aqueous solutions without the use of additional stimulus such as UV light. PMID- 22239645 TI - Increasing and stabilizing beta-sheet structure of maize zein causes improvement in its rheological properties. AB - Wheat gluten proteins are considered to have the unique ability to form viscoelastic matrices that are essential for breadmaking. This study shows that maize seed storage protein (zein), if properly treated, can be made to function similarly to gluten at the protein secondary structure level with concomitant improved viscoelasticity. Here, we propose the concept of a small amount of coprotein (high molecular weight glutenin or casein) acting to stabilize a build up of beta-sheet structure in a zein-based dough, thus creating a viscoelastic matrix that is retained over time. This discovery is relevant to the need for gluten replacement viscoelastic proteins for wheat intolerant individuals and as well opens possibilities of creating wheatlike cereal varieties that could more cheaply substitute for wheat imports in developing countries. PMID- 22239646 TI - Ultrafast observation of a solvent dependent spin state equilibrium in CpCo(CO). AB - We report the observation of a solvent-dependent spin state equilibrium in the 16 electron photoproduct CpCo(CO). Time-resolved infrared spectroscopy has been used to observe the concurrent formation of two distinct solvated monocarbonyl photoproducts, both of which arise from the same triplet CpCo(CO) precursor. Experiments in different solvent environments, combined with electronic structure theory calculations, allow us to assign the two solvated photoproducts to singlet and triplet CpCo(CO)(solvent) complexes. These results add to our previous picture of triplet reactivity for 16-electron organometallic photoproducts, in which triplets were not believed to interact strongly with solvent molecules. In the case of this photoproduct, it appears that spin crossover does not present a significant barrier to reactivity, and relative thermodynamic stabilities determine the spin state of the CpCo(CO) photoproduct in solution on the picosecond time scale. While the existence of transition metal complexes with two thermally accessible spin states is well-known, this is, to our knowledge, the first observation of a transient photoproduct that exhibits an equilibrium between two stable spin states, and also the first observed case in which a solvent has been able to coordinate as a token ligand to two spin states of the same photoproduct. PMID- 22239647 TI - Inorganically functionalized PbS-CdS colloidal nanocrystals: integration into amorphous chalcogenide glass and luminescent properties. AB - Inorganic semiconductor nanocrystals (NCs) with bright, stable, and wavelength tunable luminescence are very promising emitters for various photonic and optoelectronic applications. Recently developed strategies for inorganic surface capping of colloidal NCs using metal chalcogenide complexes have opened new perspectives for their applications. Here we report an all-inorganic surface functionalization of highly luminescent IR-emitting PbS-CdS NCs and studies of their luminescence properties. We show that inorganic capping allows simple low temperature encapsulation of inorganic NCs into a solution-cast IR-transparent amorphous As(2)S(3) matrix. The resulting all-inorganic thin films feature stable IR luminescence in the telecommunication wavelength region. The high optical dielectric constant of As(2)S(3) also helps reduce the dielectric screening of the radiating field inside the quantum dot, enabling fast radiative recombination in PbS-CdS NCs. PMID- 22239648 TI - Biodegradable sleeves for metal implants to prevent implant-associated infection: an experimental in vivo study in sheep. AB - OBJECTIVE: To evaluate biocompatibility of biodegradable sleeves containing antimicrobial agents, designed for local drug delivery to prevent implant-related infection. STUDY DESIGN: Synthetic polyester sleeves (a copolymer of glycolide, caprolactone, trimethylene carbonate, lactide) were cast as thin films. The antimicrobial agents incorporated in the sleeves included gentamicin sulfate, triclosan, or a combination of these drugs. ANIMALS: Adult sheep (n = 15). METHODS: Two limited contact dynamic compression plates (LC-DCP) with or without sleeves were implanted on tibiae (bilateral) of 15 sheep. Sleeves were placed over the plates before implantation. Beneath half of the plates, 5-mm drill hole defects were made in the near cortex. Samples were harvested 4 weeks later for histology and microradiography. RESULTS: Macroscopically, no irritation of bone or adjacent tissue was seen. Small remnants of sleeves were visible on histology, and positively correlated with the presence of macrophages and foreign body cells. Thick sections showed no difference between the test samples and controls in terms of fibrous capsule formation, periosteal remodeling, and defect remodeling. Inflammatory cells, macrophages, and foreign body cells were more prominent in sections with sleeves, but were not statistically significantly different from controls. Cell numbers were within normal physiologic limits normally seen as cellular response to foreign bodies consisting of polymers. CONCLUSION: The normal healing response indicated that the biodegradable sleeves demonstrate tissue biocompatibility. PMID- 22239649 TI - Regulation of mature T cell responses by the Wnt signaling pathway. AB - The canonical Wnt signaling pathway is evolutionarily conserved and plays key roles during development of many organ systems. This pathway utilizes TCF/LEF transcription factors, beta-catenin coactivator, and TLE/GRG corepressors to achieve balanced regulation of its downstream gene expression. It is well established that several Wnt ligands and their effector proteins are crucial for normal T cell development. Recent studies have also revealed critical requirements for TCF-1 in generation and persistence of functional memory CD8(+) T cells, and in promoting Th2-differentiation and suppressing Th17 differentiation of activated CD4(+) T cells. Activation of beta-catenin facilitated CD8(+) memory T cell formation, with enhanced protective capacity and extended survival of CD4(+) CD25(+) regulatory T cells. Upregulation of Wnt ligands was observed in Drosophila in response to Toll signaling as well as in mammalian dendritic cells and macrophages upon microbial stimulation. These new findings suggest that modulating the activity of Wnt pathway may be a powerful approach to enhance protective immunity and treat autoimmune diseases. PMID- 22239650 TI - Reaction mechanism of naphthyl radicals with molecular oxygen. 1. Theoretical study of the potential energy surface. AB - Potential energy surfaces (PESs) of the reactions of 1- and 2-naphthyl radicals with molecular oxygen have been investigated at the G3(MP2,CC)//B3LYP/6-311G** level of theory. Both reactions are shown to be initiated by barrierless addition of O(2) to the respective radical sites of C(10)H(7). The end-on O(2) addition leading to 1- and 2-naphthylperoxy radicals exothermic by 45-46 kcal/mol is found to be more preferable thermodynamically than the side-on addition. At the subsequent reaction step, the chemically activated 1- and 2-C(10)H(7)OO adducts can eliminate an oxygen atom leading to the formation of 1- and 2-naphthoxy radical products, respectively, which in turn can undergo unimolecular decomposition producing indenyl radical + CO via the barriers of 57.8 and 48.3 kcal/mol and with total reaction endothermicities of 14.5 and 10.2 kcal/mol, respectively. Alternatively, the initial reaction adducts can feature an oxygen atom insertion into the attacked C(6) ring leading to bicyclic intermediates a10 and a10' (from 1-naphthyl + O(2)) or b10 and b10' (from 2-naphthyl + O(2)) composed from two fused six-member C(6) and seven-member C(6)O rings. Next, a10 and a10' are predicted to decompose to C(9)H(7) (indenyl) + CO(2), 1,2 C(10)H(6)O(2) (1,2-naphthoquinone) + H, and 1-C(9)H(7)O (1-benzopyranyl) + CO, whereas b10 and b10' would dissociate to C(9)H(7) (indenyl) + CO(2), 2-C(9)H(7)O (2-benzopyranyl) + CO, and 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H. On the basis of this, the 1-naphthyl + O(2) reaction is concluded to form the following products (with the overall reaction energies given in parentheses): 1-naphthoxy + O (-15.5 kcal/mol), indenyl + CO(2) (-123.9 kcal/mol), 1-benzopyranyl + CO (-97.2 kcal/mol), and 1,2-naphthoquinone + H (-63.5 kcal/mol). The 2-naphthyl + O(2) reaction is predicted to produce 2-naphthoxy + O (-10.9 kcal/mol), indenyl + CO(2) (-123.7 kcal/mol), 2-benzopyranyl + CO (-90.7 kcal/mol), and 1,2 naphthoquinone + H (-63.2 kcal/mol). Simplified kinetic calculations using transition-state theory computed rate constants at the high-pressure limit indicate that the C(10)H(7)O + O product channels are favored at high temperatures, while the irreversible oxygen atom insertion first leading to the a10 and a10' or b10 and b10' intermediates and then to their various decomposition products is preferable at lower temperatures. Among the decomposition products, indenyl + CO(2) are always most favorable at lower temperatures, but the others, 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H (from a10 and b10'), 1-C(9)H(7)O (1-benzopyranyl) + CO (from a10'), and 2-C(10)H(7)O (2 benzopyranyl) + O (from b10 and minor from b10'), may notably contribute or even become major products at higher temperatures. PMID- 22239651 TI - India's dam dilemma: an eco-friendly remedy. PMID- 22239652 TI - Template-assisted and self-activating clicked peptide as a synthetic mimic of the SH2 domain. AB - A new synthetic strategy for obtaining artificial receptors that selectively regulate and/or control specific protein/protein interactions was developed based on the template-assisted and the self-activating click reaction applied to a combinatorial library. Synthetic mimics of the Grb2-SH2 domain, examined as a model case, selectively bound to a target signaling protein to induce cytotoxicity and inhibit tumor growth in vivo. PMID- 22239653 TI - Quality of life measures for food allergy. AB - Food allergy has become an emerging health problem in Western societies. Although food allergy is characterized by a relatively low mortality and an almost continual absence of physical symptoms, food allergic patients are continually confronted with the possibility of potentially severe reactions and the necessity of dietary vigilance. Health-related quality of life (HRQL) may be the only meaningful outcome measure available for food allergy measuring this continuous burden. HRQL may be measured with generic or disease-specific instruments. Generic instruments may be relatively unresponsive to differences or changes in health status, whereas disease-specific instruments are generally more sensitive for relatively subtle problems related to a particular illness. Recently, a number of disease-specific questionnaires have become available to measure the HRQL of food allergic patients. An important area for further research is the interpretation of the outcome of HRQL measures. In this respect, the minimal clinically important difference (MCID) is of special interest. In combination with the numbers needed to treat (NNT), this may give an ultimate insight into the clinical relevance of an intervention. Since there is still no cure for food allergy, the only available treatment is strict avoidance of the culprit food and provision of emergency treatment. The double-blind placebo-controlled food challenge (DBPCFC) is considered to be the gold standard for diagnosing food allergy. A number of studies have investigated the perceptions of parents whose children underwent a DBPCFC. In contrast to the parental perception, there is much currently still unknown about the effects of undergoing a DBPCFC in the perceptions of patients. In addition to the research on MCID and NNT of food allergy HRQL questionnaires, further research should focus on deriving quality adjusted life years (QALYs) from food allergy HRQL questionnaires and the application of food allergy HRQL questionnaires at the individual patient level in clinical practice. PMID- 22239654 TI - Specific material recognition by small peptides mediated by the interfacial solvent structure. AB - We present evidence that specific material recognition by small peptides is governed by local solvent density variations at solid/liquid interfaces, sensed by the side-chain residues with atomic-scale precision. In particular, we unveil the origin of the selectivity of the binding motif RKLPDA for Ti over Si using a combination of metadynamics and steered molecular dynamics simulations, obtaining adsorption free energies and adhesion forces in quantitative agreement with corresponding experiments. For an accurate description, we employ realistic models of the natively oxidized surfaces which go beyond the commonly used perfect crystal surfaces. These results have profound implications for nanotechnology and materials science applications, offering a previously missing structure-function relationship for the rational design of materials-selective peptide sequences. PMID- 22239658 TI - Hydrogen bonded arrays: the power of multiple hydrogen bonds. AB - Hydrogen bond interactions in small covalent model compounds (i.e., deprotonated polyhydroxy alcohols) were measured by negative ion photoelectron spectroscopy. The experimentally determined vertical and adiabatic electron detachment energies for (HOCH(2)CH(2))(2)CHO(-)(2a), (HOCH(2)CH(2))(3)CO(-) (3a), and (HOCH(2)CH(2)CH(OH)CH(2))(3)CO(-) (4a)reveal that hydrogen-bonded networks can provide enormous stabilizations and that a single charge center not only can be stabilized by up to three hydrogen bonds but also can increase the interaction energy between noncharged OH groups by 5.8 kcal mol(-1) or more per hydrogen bond. This can lead to pK(a) values that are very different from those in water and can provide some of the impetus for catalytic processes. PMID- 22239657 TI - Getting in touch with the clathrin terminal domain. AB - The N-terminal domain (TD) of the clathrin heavy chain is folded into a seven bladed beta-propeller that projects inward from the polyhedral outer clathrin coat. As the most membrane-proximal portion of assembled clathrin, the TD is a major protein-protein interaction node. Contact with the TD beta-propeller occurs through short peptide sequences typically located within intrinsically disordered segments of coat components that usually are elements of the membrane-apposed, inner 'adaptor' coat layer. A huge variation in TD-binding motifs is known and now four spatially discrete interaction surfaces upon the beta-propeller have been delineated. An important operational feature of the TD interaction sites in vivo is functional redundancy. The recent discovery that 'pitstop' chemical inhibitors apparently occupy only one of the four TD interaction surfaces, but potently block clathrin-mediated endocytosis, warrants careful consideration of the underlying molecular basis for this inhibition. PMID- 22239655 TI - Chemical and biological consequences of oxidatively damaged guanine in DNA. AB - Of the four native nucleosides, 2'-deoxyguanosine (dGuo) is most easily oxidized. Two lesions derived from dGuo are 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy)?dGuo. Furthermore, while steady-state levels of 8-oxodGuo can be detected in genomic DNA, it is also known that 8-oxodGuo is more easily oxidized than dGuo. Thus, 8-oxodGuo is susceptible to further oxidation to form several hyperoxidized dGuo products. This review addresses the structural impact, the mutagenic and genotoxic potential, and biological implications of oxidatively damaged DNA, in particular 8-oxodGuo, Fapy?dGuo, and the hyperoxidized dGuo products. PMID- 22239660 TI - Activity of mannose-binding lectin in centenarians. AB - We analyzed MBL2 gene variants in two cohorts of centenarians, octo-nonagenarians and nonagenarians, and in the general population, one from Sardinia Island (Italy), recruited in the frame of the AKea study, and another from Campania (southern Italy), to search for haplotypes related to longevity. We also assessed in vitro the effect of mannose-binding lectin (MBL) on various human cells at different stage of senescence. The frequency of high and null activity haplotypes was significantly lower, and the frequency of intermediate activity haplotype significantly higher in centenarians and in subjects between 80 and 99 years from both the cohorts as compared each to the general population from the same geographic area. Furthermore, serum MBL concentration (also after normalization to serum albumin) was significantly lower in centenarians and in octo- and nonagenarians as compared to the general population, suggesting that intermediate MBL haplotype/activity may be protective. We also demonstrated that in vitro MBL protein bound to senescent IMR90 fibroblasts thereby causing cell lysis, but not to other types of cycle-arrested cells not in senescence. This implicates a novel role of MBL in the clearance of senescent cells. PMID- 22239659 TI - Semi-automated identification of N-Glycopeptides by hydrophilic interaction chromatography, nano-reverse-phase LC-MS/MS, and glycan database search. AB - Glycoproteins fulfill many indispensable biological functions, and changes in protein glycosylation have been observed in various diseases. Improved analytical methods are needed to allow a complete characterization of this complex and common post-translational modification. In this study, we present a workflow for the analysis of the microheterogeneity of N-glycoproteins that couples hydrophilic interaction and nanoreverse-phase C18 chromatography to tandem QTOF mass spectrometric analysis. A glycan database search program, GlycoPeptideSearch, was developed to match N-glycopeptide MS/MS spectra with the glycopeptides comprised of a glycan drawn from the GlycomeDB glycan structure database and a peptide from a user-specified set of potentially glycosylated peptides. Application of the workflow to human haptoglobin and hemopexin, two microheterogeneous N-glycoproteins, identified a total of 57 distinct site specific glycoforms in the case of haptoglobin and 14 site-specific glycoforms of hemopexin. Using glycan oxonium ions and peptide-characteristic glycopeptide fragment ions and by collapsing topologically redundant glycans, the search software was able to make unique N-glycopeptide assignments for 51% of assigned spectra, with the remaining assignments primarily representing isobaric topological rearrangements. The optimized workflow, coupled with GlycoPeptideSearch, is expected to make high-throughput semiautomated glycopeptide identification feasible for a wide range of users. PMID- 22239661 TI - Building a bridge to somewhere better: linking health care research and health policy. PMID- 22239662 TI - From research to health policy impact. PMID- 22239663 TI - A distal pocket Leu residue inhibits the binding of O2 and NO at the distal heme site of cytochrome c'. AB - Cytochromes c' are pentacoordinate heme proteins with sterically hindered distal sites that bind NO and CO but do not form stable complexes with O(2). Removal of distal pocket steric hindrance via a Leu->Ala mutation yields favorable O(2) binding (K(d) ~49 nM) without apparent H-bond stabilization of the Fe-O(2) moiety, as well as an extremely high distal heme-NO affinity (K(d) ~70 fM). The native Leu residue inhibits distal coordination of diatomic ligands by decreasing k(on) as well as increasing k(off). The connection between distal steric constraints, k(off) values, and distal to proximal heme-NO conversion is discussed. PMID- 22239664 TI - The diheme cytochrome c peroxidase from Shewanella oneidensis requires reductive activation. AB - We report the characterization of the diheme cytochrome c peroxidase (CcP) from Shewanella oneidensis (So) using UV-visible absorbance, electron paramagnetic resonance spectroscopy, and Michaelis-Menten kinetics. While sequence alignment with other bacterial diheme cytochrome c peroxidases suggests that So CcP may be active in the as-isolated state, we find that So CcP requires reductive activation for full activity, similar to the case for the canonical Pseudomonas type of bacterial CcP enzyme. Peroxide turnover initiated with oxidized So CcP shows a distinct lag phase, which we interpret as reductive activation in situ. A simple kinetic model is sufficient to recapitulate the lag-phase behavior of the progress curves and separate the contributions of reductive activation and peroxide turnover. The rates of catalysis and activation differ between MBP fusion and tag-free So CcP and also depend on the identity of the electron donor. Combined with Michaelis-Menten analysis, these data suggest that So CcP can accommodate electron donor binding in several possible orientations and that the presence of the MBP tag affects the availability of certain binding sites. To further investigate the structural basis of reductive activation in So CcP, we introduced mutations into two different regions of the protein that have been suggested to be important for reductive activation in homologous bacterial CcPs. Mutations in a flexible loop region neighboring the low-potential heme significantly increased the activation rate, confirming the importance of flexible loop regions of the protein in converting the inactive, as-isolated enzyme into the activated form. PMID- 22239665 TI - The impact of humorous media on attitudes toward persons with disabilities. AB - PURPOSE: To examine the relationship between disability-related humor and attitudes toward persons with disabilities in business students (i.e. "future employers"). METHOD: Students watched one of two films designed to reduce negative attitudes toward persons with disabilities (one humorous in tone and the other serious in tone) or no film at all, and completed a measure of attitudes toward persons with disabilities. RESULTS: Results indicated that, after controlling for previous contact with persons with disabilities, age, and gender, students who watched the humorous film reported significantly more positive attitudes toward persons with disabilities. CONCLUSIONS: Disability humor may be an effective means of positively influencing attitudes toward persons with disabilities in future employers. [ IMPLICATIONS FOR REHABILITATION: * The acceptance and integration of persons with disabilities into society continues to be limited by negative attitudes.* Previous research has shown that employers with positive attitudes toward persons with disabilities maybe more likely to hire a person with a disability than employers with negative attitudes.* In this study, students who watched a humorous film reported significantly more positive attitudes toward persons with disabilities than students who watched a serious film or no film at all.* Consequently, it may be beneficial to embed disability humor into job-placement strategies in order to improve attitudes and positively influence hiring decisions.] PMID- 22239667 TI - Is autologous stem cell transplantation for transformed follicular lymphoma still justifiable? PMID- 22239666 TI - Elevated levels of the norspermidine synthesis enzyme NspC enhance Vibrio cholerae biofilm formation without affecting intracellular norspermidine concentrations. AB - Biofilm formation in Vibrio cholerae is in part regulated by norspermidine, a polyamine synthesized by the enzyme carboxynorspermidine decarboxylase (NspC). The absence of norspermidine in the cell leads to a marked reduction in V. cholerae biofilm formation by an unknown mechanism. In this work, we show that overexpression of nspC results in large increases in biofilm formation and vps gene expression as well as a significant decrease in motility. Interestingly, increased NspC levels do not lead to increased concentrations of norspermidine in the cell. Our results show that NspC levels inversely regulate biofilm and motility and implicate the presence of an effective feedback mechanism maintaining norspermidine homeostasis in V. cholerae. Moreover, we provide evidence that NspC and the norspermidine sensor protein, NspS, provide independent and distinct inputs into the biofilm regulatory network. PMID- 22239668 TI - Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition. AB - The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses. PMID- 22239669 TI - Waldenstrom macroglobulinemia: a Surveillance, Epidemiology, and End Results database review from 1988 to 2005. PMID- 22239670 TI - Allogeneic transplant for myeloma in the era of new drugs: have the outcomes improved? PMID- 22239671 TI - The main organizational changes in dermatological practice in the Lombardy Region, Italy, from 2001 to 2009. AB - BACKGROUND: Changes in financing health care delivery, including the adoption of diagnosis-related groups (DRG), has deeply influenced dermatological practice across Europe. OBJECTIVE: To define the current status of dermatological care in the Lombardy Region, Italy, and compare the status of 2009 to that of 2001. METHODS: Data were analysed from the annual reports of the Healthcare General Department of the Lombardy Region; legislative and administrative data were taken into consideration. RESULTS: Beds for inpatients in Dermatologic Wards decreased from 251.7 (2001) to 49.07 (2009). In 2009, a large proportion of inpatients with skin diseases were admitted to non-dermatological departments. Beds for day hospital activities increased from 55.9 (2001) to 61.0 (2009), and the proportion of admissions for surgical purposes progressively increased. In addition, the complexity and quality of surgical procedures increased, in view of the need to justify a day-hospital admission. The total number of services for outpatients increased from 1,090,052 (2001) to 1,503,692 (2009); in addition, the weighted numbers (an indicator of complexity) increased from 2,117,000 (2001) to 3,644,032 (2009). The number of dermatologists with unlimited contracts decreased, and the number of low paid scholarship recipients and external consultants increased. Three of six medical faculties currently do not have a university department of Dermatology. CONCLUSION: Over the last decade, the number of patients hospitalized in Dermatological Departments has declined; moreover, patients hospitalized with dermatological disorders have been increasingly admitted to wards with a non-dermatologist attending physician. PMID- 22239672 TI - Metallic double shell hollow nanocages: the challenges of their synthetic techniques. AB - Hollow metallic nanoparticles have been attracting the attention of many researchers in the past five years due to their new properties and potential applications. The unique structure of the hollow nanoparticles; presence of two surfaces (internal and external), and the presence of both cavities and pores in the wall surfaces of these nanoparticles are responsible for their unique properties and applications. Here the galvanic replacement technique is used to prepare nanocages made of gold, platinum, and palladium. In addition, hollow double shell nanoparticles are made of two metal shells like Au-Pt, Pt-Au, Au-Pd, Pd-Au, Pd-Pt, and Pt-Pd. Silver nanocubes are used as templates during the synthesis of hollow nanoparticles with single metal shell or double shell nanocages. Most of the problems that could affect the synthesis of solid Silver nanocubes used as template as well as the double shell nanocages and their possible solutions are discussed in a detail. The sizes and shapes of the single shell and double-shell nanocages were characterized by a regular and high resolution TEM. A SEM mapping technique is also used to image the surface atoms for the double shell hollow nanoparticles in order to determine the thickness of the two metal shells. In addition, optical studies are used to monitor the effect of the dielectric properties of the other metals on the plasmonic properties of the gold nanoshell in these mixed nanoparticles. PMID- 22239674 TI - Change in tea polyphenol and purine alkaloid composition during solid-state fungal fermentation of postfermented tea. AB - The aim of this study was to evaluate tea polyphenol and purine alkaloid contents of pu-erh tea (Camellia assamica) in a fermentation solid system with Aspergillus niger and Aspergillus fumigatu. In addition, the objective was to find the major intermediate product during fermentation by HPLC-MS(n) analysis. The results showed the change of catechin, ester-catechins and gallic acid by quantitative analysis. In the early stages, the contents of ester-catechins were lightly increased. Then, ester-catechins were gradually degraded to produce catechins and gallic acid. Furthermore, a major metabolic intermediate compound of catechins was observed and elucidated by HPLC-DAD-MS(n) analysis. This study provided a reliable dynamic data description and metabolic pathway of tea polyphenols for postfermented pu-erh tea. PMID- 22239673 TI - Under-prescribing and non-adherence to medications after coronary bypass surgery in older adults: strategies to improve adherence. AB - The focus for this clinical review is under-prescribing and non-adherence to medication guidelines in older adults after coronary artery bypass grafting (CABG) surgery. Non-adherence occurs in all age groups, but older adults have a unique set of challenges including difficulty hearing, comprehending, and remembering instructions; acquiring and managing multiple medications; and tolerating drug-drug and drug-disease interactions. Still, non-adherence leads to increased morbidity, mortality, and costs to the healthcare system. Factors contributing to non-adherence include failure to initiate therapy before hospital discharge; poor education about the importance of each medication by hospital staff; poor education about medication side effects; polypharmacy; multiple daily dosing; excessive cost; and the physician's lack of knowledge of clinical indicators for use of medications. To improve adherence, healthcare systems must ensure that (i) all patients are prescribed the appropriate medications at discharge; (ii) patients fill and take these medications post-operatively; and (iii) patients continue long-term use of these medications. Interventions must target central administrative policies within healthcare institutions, the difficulties facing providers, as well as the concerns of patients. Corrective efforts need to be started early during the hospitalization and involve practitioners who can follow patients after the date on which surgical care is no longer needed. A solid, ongoing relationship between patients and their primary care physicians and cardiologists is essential. This review summarizes the post operative medication guidelines for CABG surgery, describes barriers that limit the adherence to these guidelines, and suggests possible avenues to improve medication adherence in older cardiac surgery patients. PMID- 22239676 TI - Induction of thermotropic bicontinuous cubic phases in liquid-crystalline ammonium and phosphonium salts. AB - Two series of wedge-shaped onium salts, one ammonium and the other phosphonium, having 3,4,5-tris(alkyloxy)benzyl moieties, exhibit thermotropic bicontinuous "gyroid" cubic (Cub(bi)) and hexagonal columnar liquid-crystalline (LC) phases by nanosegregation between ionophilic and ionophobic parts. The alkyl chain lengths on the cationic moieties, anion species, and alkyl chain lengths on the benzyl moieties have crucial effects on their thermotropic phase behavior. For example, triethyl-[3,4,5-tris(dodecyloxy)benzyl]ammonium hexafluorophosphate forms the thermotropic Ia3d Cub(bi) LC phase, whereas an analogous compound with trifluoromethanesulfonate anion shows no LC properties. Synchrotron small-angle diffraction intensities from the Ia3d Cub(bi) LC materials provide electron density maps in the bulk state. The resulting maps show convincingly that the Ia3d Cub(bi) structure is composed of three-dimensionally interconnected ion nanochannel networks surrounded by aliphatic domains. A novel differential mapping technique has been applied successfully. The map of triethyl-[3,4,5 tris(decyloxy)benzyl]ammonium tetrafluoroborate has been subtracted from that of the analogous ammonium salt with hexafluorophosphate anion in the Ia3d Cub(bi) phases. The differential map shows that the counteranions are located in the core of the three-dimensionally interconnected nanochannel networks. Changing from trimethyl- via triethyl- to tripropylammonium cation changes the phase from columnar to Cub(bi) to no mesophase, respectively. This sensitivity to the widened shape for the narrow end of the molecule is explained successfully by the previously proposed semiquantitative geometric model based on the radial distribution of volume in wedge-shaped molecules. The LC onium salts dissolve lithium tetrafluoroborate without losing the Ia3d Cub(bi) LC phase. The Cub(bi) LC materials exhibit efficient ion-transporting behavior as a result of their 3D interconnected ion nanochannel networks. The Ia3d Cub(bi) LC material formed by triethyl-[3,4,5-tris(decyloxy)benzyl]phosphonium tetrafluoroborate shows ionic conductivities higher than the analogous Ia3d Cub(bi) material based on ammonium salts. The present study indicates great potential of Cub(bi) LC nanostructures consisting of ionic molecules for development of transportation nanochannel materials. PMID- 22239675 TI - Cis-selective ring-opening metathesis polymerization with ruthenium catalysts. AB - Cis-selective ring-opening metathesis polymerization of several monocyclic alkenes as well as norbornene and oxanorbornene-type monomers using a C-H activated, ruthenium-based metathesis catalyst is reported. The cis content of the isolated polymers depended heavily on the monomer structure and temperature. A cis content as high as 96% could be obtained by lowering the temperature of the polymerization. PMID- 22239677 TI - Alteration of forest structure modifies the distribution of scale insect, Stigmacoccus garmilleri, in Mexican tropical montane cloud forests. AB - Stigmacoccus garmilleri Foldi (Hemiptera: Margarodidae) is an ecologically important honeydew-producing scale insect associated with oak trees (Quercus spp.) in highland forests of Veracruz, Mexico. The honeydew exudates of S. garmilleri serve as a significant nutrient source to many species of birds, insects, and sooty molds. Oak trees found in the forest interior, forest edge, and those scattered in pasture areas support scale insect colonies, though the pattern of insect infestations on trees within these varying landscape types has not been elucidated. This study aims to describe the distribution of scale insect infestation and any distinctions in honeydew production based on tree location. Scale insect density, honeydew volume, and sugar concentration were surveyed throughout a continuous landscape that included both patches of forest and scattered pasture trees. In addition, the anal filament through which the honeydew drop is secreted was also measured and was experimentally removed to test and measure regrowth. Scale insect densities on tree trunks were greatest on pasture trees, while intermediate densities were found on trees at the forest edge, and low densities on interior forest trees, suggesting that trees in disturbed areas are more susceptible to scale insect infestation. Trees with small diameters at breast height had significantly higher insect densities than trees with medium to large diameters. Trunk aspect (North, South, East, and West) was not a significant determinant of scale insect density. In forested areas higher densities of scale insects were found at three meters height in comparison to lower heights. Sugar concentrations and drop volumes of honeydew in forest and pasture areas were not significantly different. However, scale-insect anal tubes/filaments were significantly longer in pasture than they were in forests. Sugar concentrations of honeydew appeared to be positively correlated with temperature and negatively correlated with relative humidity. Experiments indicated that anal filaments could grow approximately 4 mm every 24 hours, and average tube growth was significantly faster in pasture than in forest, suggesting that there may be a physiological effect on the insect due to landscape disturbance. The results obtained in this study describe the increases in scale insect infestation of trees with forest disturbance. The effect of these increased scale insect densities on the host tree physiology is still to be resolved. PMID- 22239678 TI - Titration of nonstabilized diazoalkane solutions by fluorine NMR. AB - A new protocol for titrating nonstabilized diazoalkane solutions by quantitative (19)F NMR is reported. An excess of 2-fluorobenzoic acid dissolved in CDCl(3) is treated with the diazoalkane solution at a low temperature, immediately forming the corresponding 2-fluorobenzoate ester upon warming. A significant difference in the (19)F chemical shift between the ester and acid is seen, allowing facile and accurate integration to determine titer. The procedure is safe, rapid, and indicates the active diazoalkane concentration with high precision. PMID- 22239679 TI - Mechanism insights of ethane C-H bond activations by bare [Fe(III)?O]+: explicit electronic structure analysis. AB - Alkane C-H bond activation by various catalysts and enzymes has attracted considerable attention recently, but many issues are still unanswered. The conversion of ethane to ethanol and ethene by bare [Fe(III)?O](+) has been explored using density functional theory and coupled-cluster method comprehensively. Two possible reaction mechanisms are available for the entire reaction, the direct H-abstraction mechanism and the concerted mechanism. First, in the direct H-abstraction mechanism, a direct H-abstraction is encountered in the initial step, going through a collinear transition state C...H...O-Fe and then leading to the generation of an intermediate Fe-OH bound to the alkyl radical weakly. The final product of the direct H-abstraction mechanism is ethanol, which is produced by the hydroxyl group back transfer to the carbon radical. Second, in the concerted reaction mechanism, the H-abstraction process is characterized via overcoming four/five-centered transition states (6/4)TSH_c5 or (4)TSH_c4. The second step of the concerted mechanism can lead to either product ethanol or ethene. Moreover, the major product ethene can be obtained through two different pathways, the one-step pathway and the stepwise pathway. It is the first report that the former pathway starting from (6/4)IM_c to the product can be better described as a proton-coupled electron transfer (PCET). It plays an important role in the product ethene generation according to the CCSD(T) results. The spin-orbital coupling (SOC) calculations demonstrate that the title reaction should proceed via a two-state reactivity (TSR) pattern and that the spin-forbidden transition could slightly lower the rate-determining energy barrier height. This thorough theoretical study, especially the explicit electronic structure analysis, may provide important clues for understanding and studying the C-H bond activation promoted by iron-based artificial catalysts. PMID- 22239680 TI - Modeling population dynamics, landscape structure, and management decisions for controlling the spread of invasive plants. AB - Invasive plants cause substantial economic and environmental damage throughout the world. However, eradication of most invasive species is impossible and, in some cases, undesirable. An alternative is to slow the spread of an invasive species, which can delay impacts or reduce their extent. We identify three main areas where models are used extensively in the study of plant spread and its management: (i) identifying the key drivers of spread to better target management, (ii) determining the role spatial structure of landscapes plays in plant invasions, and (iii) integrating management structures and limitations to guide the implementation of control measures. We show how these three components have been approached in the ecological literature as well as their potential for improving management practices. Particularly, we argue that scientists can help managers of invasive species by providing information about plant invasion on which managers can base their decisions (i and ii) and by modeling the decision process through optimization and agent-based models (iii). Finally, we show how these approaches can be articulated for integrative studies. PMID- 22239681 TI - Femoral angular correction and lengthening in a large-breed puppy using a dynamic unilateral external fixator. AB - OBJECTIVE: To report treatment of a large-breed puppy with combined distal femoral valgus and length deficit caused by partial distal physeal closure. STUDY DESIGN: Clinical report. ANIMALS: Bernese Mountain Dog (4.5-month-old male). METHODS: The puppy was admitted for evaluation of a progressive severe left pelvic limb lameness (grade 3/4) of 6-week duration. Distal femoral valgus and severe length deficit deformity were treated by acute angular correction using a closing wedge ostectomy and progressive rapid-rate callus distraction using a dynamic, telescoping unilateral External Skeletal Fixator (ESF) designed for people. After acute angular correction and a 3-day latency period, a mean linear distraction rate of 3 mm/day was maintained for 3 weeks. The dynamic ESF (dESF) was removed at 4 weeks, after a 1-week consolidation phase. RESULTS: The dESF was stable and functional during distraction and bone healing. Distal femoral valgus conformation improved 50 degrees (from 41 degrees to 91 degrees ) and femoral length increased 42 mm at dESF removal (from 158 mm to 200 mm; 27%). After cessation of bone growth, no valgus and minimal (6%) length deficit were detected. At 4, 5, 6, 12, and 24 months after surgery, the dog was walking, trotting, and galloping normally. CONCLUSION: Acute angular correction and progressive rapid-rate callus distraction using a unilateral dESF allowed satisfactory treatment of combined distal femoral valgus and length deficit in a large-breed puppy. PMID- 22239682 TI - Pharmacogenomics of breast cancer targeted therapy: focus on recent patents. AB - Adjuvant endocrine therapy as well as other forms of targeted therapy such as HER2 inhibitors and antiangiogenic agents reduce the risk of recurrence and improve survival among women with hormone receptor positive breast cancer. However, a significant percentage of women who receive targeted therapy as adjuvant or metastatic treatment do not benefit from this therapy, while a number of women who initially respond will eventually develop disease progression and relapse while on therapy. The observed variability in treatment response to targeted breast cancer treatment could be partly explained by pharmacogenomics. This paper reviews evidence on the role of pharmacogenomics of breast targeted therapy focusing on the clinical relevance of genetic variation. In particular, this article reviews the role of pharmacogenomics of tamoxifen, aromatase inhibitors, HER-2 inhibitors and anti-angiogenic agents. In addition, recent patents in the field are presented that provide promising steps in the field of personalized treatment of breast cancer, although future studies are needed for determining the clinical benefit of the proposed inventions. Finally, we present a testable hypothesis to aide the search for biologically meaningful genetic variation Specifically, we suggest the publication of negative results in the field of pharmacogenomics and pharmacoproteomics, will benefit future research in the field. PMID- 22239683 TI - MicroRNA patents in demyelinating diseases: a new diagnostic and therapeutic perspective. AB - MicroRNAs (miRNAs, miRs) are a class of non-coding single-stranded RNAs, which can negatively regulate gene expression at posttranscriptional levels by miRNA mRNA interaction. It has been demonstrated that miRNAs play important roles in a variety of biological process, including cell proliferation, differentiation, apoptosis, and tumorigenesis. Recent studies have shown crucial roles of specific miRNAs in controlling oligodendrocyte (OL) differentiation and myelination. Dysregulation of miRNAs is a vital event in the pathogenesis of demyelinating diseases. Furthermore, new patents of miRNAs also provide new strategies for gene therapy and miR-drug development for demyelinating diseases, especially multiple sclerosis. In this review, we briefly introduce the roles of miRNAs in OL differentiation and in the pathogenesis of demyelinating diseases, with emphasis on the implication of miRNAs patents in disease diagnostic and therapeutic perspective and its related technologies and challenges in clinical application. PMID- 22239684 TI - Analysis of opportunities and challenges in patenting of Bacillus thuringiensis insecticidal crystal protein genes. AB - Bacillus thuringiensis (Bt) is the most widely used microbial control agent. The broad spectrum of susceptible hosts, production on artificial media and ease of application has caused the widespread use of this bacterium against several pests in agriculture, forest and vectors of human diseases. B.thuringiensis toxins are highly species specific which provide economic, environmental benefits, potential for future control and spread of the technology worldwide. This makes the B. thuringiensis crystal proteins an interesting tool for the implementation in integrated pest management programs. It has gained importance over the last 100 years for its biocontrol properties which is used in this review as a case study and analysis of the patents granted on B. thuringiensis was carried out. This study categorizes a number of patents related to B.thuringiensis insecticidal crystal proteins, application of B.thuringiensis insecticidal crystal proteins and the development of patentable technologies. The analyses were done using various criteria like patenting trends over the years, assignees playing a major role, comparison of the technology used in different patents and the patenting activity across the insect orders. Patent documents related to bacterium B.thuringiensis contain a trove of technical and commercial information and thus, patent analysis is considered as a useful tool for R management and techno economical development. Patent analysis also helps identifying and evaluating new and alternate technologies, keeping abreast with latest technologies for business interests, finding solutions to technical problems and ideas for new innovative trends. PMID- 22239685 TI - Insight into p95HER2 in breast cancer: molecular mechanisms and targeted therapies. AB - Breast cancer afflicts more than 1.3 million people worldwide and is the main cause of cancer-related deaths among women. Many efforts are underway to develop new therapeutic and biomarker strategies for the management of this disease. Hormone receptors and human epidermal growth factor receptor 2 (HER2) are currently the most important molecular tools in this regard. Moreover, targeted therapies including trastuzumab in particular are the primary treatment in both the adjuvant and recurrent settings. However, many studies reported that selected patients may present with resistance to trastuzumab due to the presence of p95HER2 fragments. To address this challenge, drugs such as lapatinib and others described in recent patents promise alternative therapeutic options. We discuss the most recent patents related to HER2 and p95HER2 fragments for breast cancer treatment. PMID- 22239686 TI - Interplay between size, composition, and phase transition of nanocrystalline Cr(3+)-doped BaTiO3 as a path to multiferroism in perovskite-type oxides. AB - Multiferroics, materials that exhibit coupling between spontaneous magnetic and electric dipole ordering, have significant potential for high-density memory storage and the design of complex multistate memory elements. In this work, we have demonstrated the solvent-controlled synthesis of Cr(3+)-doped BaTiO(3) nanocrystals and investigated the effects of size and doping concentration on their structure and phase transformation using X-ray diffraction and Raman spectroscopy. The magnetic properties of these nanocrystals were studied by magnetic susceptibility, magnetic circular dichroism (MCD), and X-ray magnetic circular dichroism (XMCD) measurements. We observed that a decrease in nanocrystal size and an increase in doping concentration favor the stabilization of the paraelectric cubic phase, although the ferroelectric tetragonal phase is partly retained even in ca. 7 nm nanocrystals having the doping concentration of ca. 5%. The chromium(III) doping was determined to be a dominant factor for destabilization of the tetragonal phase. A combination of magnetic and magneto optical measurements revealed that nanocrystalline films prepared from as synthesized paramagnetic Cr(3+)-doped BaTiO(3) nanocrystals exhibit robust ferromagnetic ordering (up to ca. 2 MU(B)/Cr(3+)), similarly to magnetically doped transparent conducting oxides. The observed ferromagnetism increases with decreasing constituent nanocrystal size because of an enhancement in the interfacial defect concentration with increasing surface-to-volume ratio. Element specific XMCD spectra measured by scanning transmission X-ray microscopy (STXM) confirmed with high spatial resolution that magnetic ordering arises from Cr(3+) dopant exchange interactions. The results of this work suggest an approach to the design and preparation of multiferroic perovskite materials that retain the ferroelectric phase and exhibit long-range magnetic ordering by using doped colloidal nanocrystals with optimized composition and size as functional building blocks. PMID- 22239687 TI - Epigenetic regulation of myofibroblast differentiation and extracellular matrix production in nasal polyp-derived fibroblasts. AB - BACKGROUND: Nasal polyposis is a multi-factorial disease associated with chronic inflammatory condition of the paranasal sinuses. Myofibroblast differentiation and extracellular matrix (ECM) accumulation are involved in the pathogenesis of nasal polyposis. OBJECTIVE: The aim of this study was to study the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on transforming growth factor (TGF)-beta1-induced myofibroblast differentiation and ECM accumulation in nasal polyp-derived fibroblasts (NPDFs). METHODS: Nasal polyp derived fibroblasts were isolated from nasal polyps of patients who have chronic rhinosinusitis with nasal polyp. TSA was treated in TGF-beta1-induced NPDFs. Expression levels of HDAC2, alpha-smooth muscle actin (SMA), TGF-beta1, collagen type I, acetylated Histone H3, acetylated Histone H4, phosphorylated Smad2/3 and Smad7 were determined by RT-PCR, western blot and/or immunofluorescent staining. The total collagen amount production was analysed by Sircol soluble collagen assay and contractile activity was measured by collagen gel contraction assay. HDAC2 inhibition by TSA or HDAC2 silencing was established by RT-PCR and western blot. The epigenetic effect on alpha-SMA gene inactivation was examined by chromatin immunoprecipitation assay. Proliferation was determined by Ki67 positive cell staining and cytotoxicity was assessed by 3-(4,5- dimethylthiazol 2yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. RESULTS: The expression levels of HDAC2, alpha-SMA and TGF-beta1 were increased in nasal polyp tissues compared to normal inferior turbinate tissues. TSA and HDAC2 silencing inhibited expression levels alpha-SMA, collagen and HDAC2. TSA induced hyperacetylation of histone and suppressed opening of alpha-SMA gene promoter in TGF-beta1-induced NPDFs. TSA inhibited TGF-beta1-induced Smad 2/3 and rescued TGF-beta1-suppressed Smad7 signalling pathway. Finally, TSA blocked proliferation in TGF-beta1-induced NPDFs and has no cytotoxic effect in NPDFs. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that HDAC inhibition is associated with myofibroblast differentiation and extracelluar matrix accumulation in nasal polyposis. TSA may be useful as an inhibitor of nasal polyp growth, and thus has potential to be used as a novel treatment option for nasal polyposis. PMID- 22239688 TI - Engineering biosensors with extended, narrowed, or arbitrarily edited dynamic range. AB - Biomolecular recognition has long been an important theme in artificial sensing technologies. A current limitation of protein- and nucleic acid-based recognition, however, is that the useful dynamic range of single-site binding typically spans an 81-fold change in target concentration, an effect that limits the utility of biosensors in applications calling for either great sensitivity (a steeper relationship between target concentration and output signal) or the quantification of more wide-ranging concentrations. In response, we have adapted strategies employed by nature to modulate the input-output response of its biorecognition systems to rationally edit the useful dynamic range of an artificial biosensor. By engineering a structure-switching mechanism to tune the affinity of a receptor molecule, we first generated a set of receptor variants displaying similar specificities but different target affinities. Using combinations of these receptor variants (signaling and nonsignaling), we then rationally extended (to 900000-fold), narrowed (to 5-fold), and edited (three state) the normally 81-fold dynamic range of a representative biosensor. We believe that these strategies may be widely applicable to technologies reliant on biorecognition. PMID- 22239689 TI - 2,4,8-trihydroxybicyclo [3.2.1]octan-3-one scavenges free radicals and protects against xenobiotic-induced cytotoxicity. AB - Currently, there is a great deal of interest in the study of natural compounds with free-radical-scavenging activity because of their potential role in maintaining human health and preventing diseases. In this paper, we report the antioxidant and cytoprotective properties of 2,4,8-trihydroxybicyclo [3.2.1]octan 3-one (TBO) isolated from the aqueous extract of Decalepis hamiltonii roots. Our results show that TBO is a potent scavenger of superoxide (O(2).-), hydroxyl (.OH), nitric oxide (.NO) and lipid peroxide (LOO.) - physiologically relevant free radicals with IC(50) values in nmolar (42-281) range. TBO also exhibited concentration-dependent secondary antioxidant activities such as reducing power, metal-chelating activity and inhibition of protein carbonylation. Further, TBO at nmolar concentration prevented CuSO(4)-induced human LDL oxidation. Apart from the in vitro free-radical-scavenging activity, TBO demonstrated cytoprotective activity in primary hepatocytes and Ehrlich ascites tumour (EAT) cells against oxidative-stress-inducing xenobiotics. The mechanism of cytoprotective action involved maintaining the intracellular glutathione (GSH), scavenging of reactive oxygen species (ROS) and inhibiting lipid peroxidation (LPO). Based on the results, it is suggested that TBO is a novel bioactive molecule with implications in both prevention and amelioration of diseases involving oxidative stress as well as in the general well-being. PMID- 22239690 TI - The aerobic oxidation of a Pd(II) dimethyl complex leads to selective ethane elimination from a Pd(III) intermediate. AB - Oxidation of the Pd(II) complex (N4)Pd(II)Me(2) (N4 = N,N'-di-tert-butyl-2,11 diaza[3.3](2,6)pyridinophane) with O(2) or ROOH (R = H, tert-butyl, cumyl) produces the Pd(III) species [(N4)Pd(III)Me(2)](+), followed by selective formation of ethane and the monomethyl complex (N4)Pd(II)Me(OH). Cyclic voltammetry studies and use of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap suggest an inner-sphere mechanism for (N4)Pd(II)Me(2) oxidation by O(2) to generate a Pd(III)-superoxide intermediate. In addition, reaction of (N4)Pd(II)Me(2) with cumene hydroperoxide involves a heterolytic O-O bond cleavage, implying a two-electron oxidation of the Pd(II) precursor and formation of a transient Pd(IV) intermediate. Mechanistic studies of the C-C bond formation steps and crossover experiments are consistent with a nonradical mechanism that involves methyl group transfer and transient formation of a Pd(IV) species. Moreover, the (N4)Pd(II)Me(OH) complex formed upon ethane elimination reacts with weakly acidic C-H bonds of acetone and terminal alkynes, leading to formation of a new Pd(II)-C bond. Overall, this study represents the first example of C-C bond formation upon aerobic oxidation of a Pd(II) dimethyl complex, with implications in the development of Pd catalysts for aerobic oxidative coupling of C-H bonds. PMID- 22239691 TI - The effects of training in time-limited dynamic psychotherapy: changes in therapeutic outcome. AB - The present study explored the effects on therapeutic outcomes of training therapists in brief manualized therapy. As part of the Vanderbilt II project, each of 16 therapists (8 psychiatrists and 8 clinical psychologists) treated 2 moderately disturbed adult patients using his or her customary short-term treatment methods; they then received a year of training in a manualized form of brief dynamic therapy, Time-Limited Dynamic Psychotherapy (TLDP); finally, they administered TLDP to 2 additional patients. It was hypothesized that training would result in improved outcomes generally and that differentially greater improvement would be seen in patients commonly considered less suitable for brief dynamic therapy. Outcome data obtained at termination failed to support either hypothesis. Measurements of interpersonal dependency obtained at a one-year follow-up were consistent with the first hypothesis, but the follow-up data were inconsistent with the second. A systematic review of the 32 posttraining cases suggested that the majority of the therapists had not achieved basic competence at TLDP. Die hier beschriebene Studie untersucht die Wirkungen eines Trainings in manualisierter Kurzzeitherapie auf das Therapierergebnis. Als Teil des Vanderbilt II Projektes behandelten jeweils 16 Therapeuten (8 Psychiater und 8 klinische Psychologen) zwei mittelgradig beeinrachtigte erwachsene Patienten mit den ihnen vertrauten Kurzzeitbehandlungsmethoden. Danach wurden sie uber ein Jahr in einer manualisierten Form psychodynamischer Kurzzeittherapie ausgebildet und wandten diese Therapie auf zwei weitere Patienten an. Es wurde angenommen, dass die Ausbildung in besseren Ergebnisdaten, die bei Ende der Therapie erhoben wurden, konnten diese Hypothese nicht bestatigen. Mabetae fur die interpersonale Abhangigkeit zu einem Einjahreskatamnesezeitpunkt waren mit der ersten Hypothese konform, aber inkonsistent mit der zweiten. Eine systematische Untersuchung der 32 nach der Ausbildung behandelten Falle legt nahe, dass die Mehrzahl der Therapeuten keine grundlegende Kompetenz in zeitlich limitierter dynamischer Psychotherapie erworben hatte. Cette eude explore les effets sur les resultats therapeutiques de la formation des therapeutes dans une therapie breve, manualissee. Dans le cadre du projet Vanderbilt II, chacun des 16 therapeutes (8 psychiatrs et 8 psychologues cliniciens) a traite deux patients adultes moderement perturbes, chacun par sa methode habituelle de therapie breve; ensuite ils ont recu une formation d'une annee dans une methode manualisee de therapie breve, la Psychotherapie Dynamique Limitee dans le Temps (TLDP); pour finir, ils ont applique la TLDP a de meilleurs resultats en general, et qu'une amelioration comparativement plus importante sera observee chez des patients habituellement consideres comme moins adaptes a une therapie dynamique bre. Les resultats obtenus a la terminaison n'ont pu confirmer aucune de ces hypotheses. Des mesures de la dependance interpersonnelle une annee apres etaient consistantes avec la premiere hypothese, mais les donnees catamnestiques etaient inconsistantes avec la deuxieme. Une revue systematique des 32 cas apres formation a suggere que la majorite des therapeutes n'avait pas acquis une competence de base en TLDP. Este estudio exploro la efectividad del entrenamiento de terapeutas en una terapia breve manualizada. Como parte del proyecto Vanderbilt II, dieciseis terapeutas (ocho psiquiatras y ocho psicologos clinicos) trataron dos pacientes adultos mooderadamente perturbados con sus metodos habituales de tratamiento a corto plazo. Estos terapeutas recibieron luego un ano de entrenamiento en terapia dinamica breve manualizada que se Ilamo Psicoterapia Dinamica de Tiempo limitado (TLDP). Finalmente, administraron esta TLDP a dos pacientes mas. La hipotesis fue que el entrenamiento ilevaria, en general, a resultados mejores y que habria mayor mejoramiento en pacientes menos aptos para una terapia dinamica breve. Los resultados a la terminacion no apoyaron ninguna de las dos hipotesis. Las mediciones de dependencia interpersonal al ano de seguimiento resultaron consistentes con la primera hipotesis, mientras que los resultados de seguimiento fueron inconsistentes con la segunda. Una revision sistematica de los treinta y dos casos luego del entrenamiento sugiere que la mayoria de los terapeutas no habia l. PMID- 22239692 TI - The influence of interpersonal problems and symptom severity on the duration and outcome of short-term psychodynamic psychotherapy. AB - This naturalistic outcome study investigated validity aspects of the Inventory of Interpersonal Problems (IIP [Horowitz, Straubeta, & Kordy, 1995]). The sample consisted of 180 patients who received short-term psychodynamic psychotherapy for an average number of 7.8 sessions and an average duration of 3.4 months. Small changes in pre-post-measures imply that the IIP is not to be recommended as an instrument for outcome evaluation in short-term psychotherapy, due to the traitlike character of its items. However, we showed by path analyses that a higher score on the affiliative dimension of the interpersonal circumplex goes along with a better treatment outcome. The influence of the dominance dimension is gender specific: male patients (who generally showed more dismissive and introverted behavior in this sample) received, if dismissive and introverted, a longer introductory therapy, whereafter they - in cases of high symptom load - were often referred to long-term treatment. Dominant male patients and, in general, female patients with high symptom scores, were referred faster, after only a few sessions. Results are discussed under aspects of adaptive therapist behavior. PMID- 22239693 TI - Self-image and perception of mother and father in psychotic and borderline patients. AB - Psychotic and borderline patients rated their self-image and their perception of their mother and father using the Structural Analysis of Social Behavior model (SASB). The borderline patients had more negative images of themselves and their parents, especially their fathers, than did the psychotic patients and the normal subjects, while the psychotic patients' ratings did not differ much from those of the normal subjects. The self-image was related to the images of both parents for borderline patients and normal subjects, while for the psychotic patients only the image of the mother was important for the self-image. In addition, the psychotic patients did not differentiate between the poles of control and autonomy in the introjected self-image. It was concluded that borderline patients are characterized by negative attachment, while psychotic patients are characterized by poor separation from the mother and poor differentiation between autonomy and control. The paper also discusses how this may influence the patients' relations to others. Psychotische und Borderline Patienten beurteilten ihr Selbstbild und ihre Wahrnehmung von Mutter und Vater mit Hilfe der strukturalen Analyse sozialen Verhaltens (SASB). Die Borderline Patienten hattten negativere Selbstbilder und Elternbilder (speziell Vaterbilder) als die psychotischen Patienten und gesunde Personen. Die Beurteilungen der psychotischen Patienten unterschieden sich dagegen nicht besonders von jenen Gesunder. Das Selbstbild stand in Beziehung zu beiden Elternbildern bei den Borderline Patienten und den Gesunden, wahrend bei den psychotischen Patienten nur das Mutterbild fur das Selbstbild bedeutsam war. Aubetaerdem konnte bei den psychotischen Patienten nicht zwischen den Polen der Kontrolle und Autonomie bzgl. der introjizierten Selbstbilder differenziert werden. Aus den Ergebnissen wird gefolgert, dass Borderline Patienten durch eine negative Bindung charackterisiert sind, psychotische Patienten dagegen durch eine mangelnde Separation von ihren Muttern und eine geringe Differenzierung zwischen Autonomie und Kontrolle. Es wird aubetaerdem diskutiert, wie die Ergebnisse auf die realen Beziehungen der Patienten zu anderen Menschen Einflus nehmen konnten. Des patients psychotiques et Borderline ont evalue leur image d'eux-memes et leur perception de leur mere et pere a l'aide du modele de l'Analyse Structural du Comportement Social (SASB. Les patients Borderline avaient des imagess plus negatives d'eux-memes et de leurs parents, surtout de leur pere, que les patients psychotiques et les sujets normaux, alors que les patients psychotiques se jugeaient a peine differemment des sujets normaux. L'image de soi etait en relation avec les images des deux parents pour les patients Borderline et pour les sujets normaux, alors que pour les patients psychotiques, seulement l'image de la mere jouait un role pour leur image. En plus, les patients psychotiques ne differenciaient pas entre les poles de controle et d'autonomie dans l'image de soi introjectee. Nous en avons conclu que les patients Borderline se caracterisent par un attachement negatif, et les patients psychotiques par une faible separation de la mere ainsi qu'une differenciation modeste entre autonomie et controle. L'influence de ceci sur les relations des patients avec les autrs est discutee dans cet article. Pacientes limitrofes y psicoticos evaluaron su autoimagen y la percepcion que tenian de sus padres usando el modelo de Analisis estructural del comportamiento social (SASB). Los pacientes limitrofes registraron imagenes mas negativas de si mismos y de sus progenitores, especialmente de su padre, que los pacientes psicoticos y los normales, mientras que las evaluaciones de los pacientes psicoticos no difirieron mucho de las de los sujetos normales. La autoimagen tuvo relacion con la imagen de ambos progenitores tanto en el caso de los pacientes limitrofes como de los sujetos normales, mientras que para los pacientes psicoticos no diferenciaron entre control y autonomia en la autoimagen introyectada. Se concluyo que los pacientes limitrofes se caracterizan por un apego negativo, mientras que los pacientes psicoticos muestran una pobre separacion de su madre y tambien pobre discriminacion entre autonomia y control. El trabajo tambien discute como esto puede influire sobre la relacion de los pacientes con los demas. PMID- 22239694 TI - Motivation to seek psychotherapy in patients with recurrent depressive disorder. AB - Fifty-five hospital-treated patients with the ICD-10 diagnosis of recurrent depressive episode(s) were classified according to the Newcastle Depressive Diagnostic Scale as having either psychogenic (n = 25) or endogenous (n = 30) depression and interviewed using the Composite International Diagnostic Interview and the Questionnaire for Assessment of Motivation to Seek Psychotherapy. The two groups were found to differ significantly from one another in two Motivation to Seek Psychotherapy subscales ("layman's etiology" and "general expectations from therapy"). The motivation to seek psychotherapy was greater in patients with psychogenic depression than in patients with endogenous depression. Nonetheless, psychotherapy is indispensable in treating endogenous depression, especially for patients under situational stress or at risk of suicide. PMID- 22239695 TI - A new approach to the study of therapeutic work in the transference. AB - This article proposes a new method for evaluating the effects of therapist and patient work in the transference. Work in the transference is often difficult for the patient, and may show a characteristic pattern of lag between a transference interpretation and its therapeutic effect. To account for this lag, we assessed patient responses to interpretations over the course of entire sessions. The narratives patients told about others, or Relationship Episodes (REs), were used as units of study. In a sample of three consecutive sessions taken from each of three psychodynamic cases, we identified several instances when transference work appeared to have an initial inhibitory effect, but facilitated progress over the course of the entire session. We recommend that to examine the effects of interpretations future studies use longer, more clinically meaningful segments of patient speech than have been used in the past. Dieser Beitrag propagiert eine neue Methode zur Evaluierung der Effekte von Ubertragungsarbeit durch Therapeut und Patient. Arbeit in der Ubertragung ist fur den Patienten oftmals schwierig und zeigt haufig eine charakteristisches Muster von zeitlichen Verzogerungen bzgl. Ubertragungsdeutungen und deren therapeutischen Effekten. Um diese zeitliche Verzogerung zu erklaren, untersuchten wir die Reaktionen von Patienten auf derartige Deutungen im Verlauf ganzer Sitzungen. Narrative, in denen die Patienten uber andere berichteten, also Beziehungsepisoden, dienten in dieser Studie als Einheit. In einter Stichprobe dreier aufeinanderfolgender Sitzugnen, die sich auf drei Falle bezogen, identifizierten wir verschiedene Umstande, unter denen Ubertragungsarbeit anfanglich einen hemmenden Affekt zu haben schien, letztlich aber den Gesamtverlauf der Sitzung gunstig beeinflussten. Wir empfehlen, in Zukunft die Effekte von Ubertragungsdeutungen auf der Basis langerer, klinische sinnvoller Segmente von Patientenaubetaerungen zu untersuchen als dies in der Vergangenheit der Fall war. Cet article propose une nouvelle methode pour evaluer les effets du travail sur le transfert entre therapeute et patient. Ce travail est souvent difficile pour le patient, et il peut y avoir un pattern caracteristique de delai entre une interpretation de transfert et son effet therapeutique. Pour expliquer ce delai, nous avons evalue les reponses des patients a des interpretatios au cours de seances entieres. C'est les narrations des patients sur d'autres, ou Episodes Relationnels (ERs), qui ont constitue les unites de base de cette etude. Dans un echantillon de 3 seances consecutives venant de 3 cas psychodynamiques, nous avons identifie plusieurs moments ou le traail sur le transfert semblait avoir un effet inhibitoire initial, mais favorisait le progres en regardant la seance entiere. Nous recommandons pour de futures etudes sur l'effet des interpretations de prendre des segments plus longs et cliniquement significatifs du recit du patient que ceux utilises dans le passe. Este articulo propone un nuevo metodo para evaluar los efectos del trabajo de terapeuta y paciente en la transferencia. El trabajo en la transferencia es, con frecuencia, dificil para el paciente y puede mostrar un lapso caracteristico entre una interpretacion transferencial y sus efectos terapeuticos. Para explicar este lapso, hemos evaluado las respuestas del paciente a las interpretaciones a lo largo de sesiones enteras. Como unidad de estudio se usaron las narrativas de los pacientes acerca de otros, o sea, los episodios relacionales (REs). En una muestra de tres sesiones consecutivas tomadas de tres casos psicodinamicos, identificamos varioss casos en los que la trasferencia parecia tener un efecto inicial inhibitorio, aunque se vio que a lo largo de la sesion facilitaba el progreso. Recomendamos que, para examinar los efectos de las interpretaciones, los futuros estudios usen segmentos mas largos y clinicamente mas significativos del habia del paciente que los que se usaron en el pasado. PMID- 22239696 TI - The dynamic assessment interview (DAI), interpersonal process measured by structural analysis of social behavior (SASB) and therapeutic outcome. AB - In this study we investigated the interrelationships between the Dynamic Assessment Interview (DAI), the interpersonal process of the assessment interview analyzed with Structural analysis of Social Behavior (SASB), and treatment outcome. The DAI is a semistructured interview and rating procedure designed to evaluate patient suitability for psychodynamic psychotherapy based on the patient's immediate interaction with the assessment interviewer. In the selected sample (n = 20) the DAI ratings showed no significant correlations with the SASB coded interpersonal process of the assessment interview nor with treatment outcome. The SASB-coded interpersonal process in the assessment interview correlated significantly with interpersonal process early in therapy and was able to predict treatment outcome. It is concluded that the abstract ''inner'' patient characteristics assumed to be of major prognostic importance for psychodynamic psychotherapy might be of limited validity, whereas the patient offered interpersonal process is worth further consideration as a predictor of treatment outcome. Finally, the relatively stressful structure of the DAI interview might have facilitated the prediction of treatment outcome from the interpersonal process in the assessment interview. PMID- 22239697 TI - An exploratory study of agreement between therapists' goals and patients' problems revealed by the rorschach. AB - This study describes and classifies goals as formulated by psychodynamically oriented psychotherapists, and examines the agreement between the therapists' goals and the patients' problems revealed by the Rorschach. One hundred thirty treatment plans were rated with regard to content, and five of the goal categories were compared to corresponding Rorschach clusters. Personality differences were examined between patients with low agreement between the therapists' goals and patients' problems and those with relatively high agreement. Patients with low agreement were characterized by a high degree of problem complexity and psychopathology, especially in thinking. They also showed signs of psychological defenses that might have obstructed the communication of their psychological problems to the therapists. The results suggest that the Rorschach may provide information about aspects of patients' psychological functioning which they are not able to communicate or which are not paid attention to by the therapists. PMID- 22239698 TI - Short- and long-term effects of medication and psychotherapy in the brief treatment of depression: further analyses of data from the NIMH TDCRP. AB - Prior analyses of data from the NIMH sponsored Treatment for Depression Collaborative Research Program (TDCRP; e.g., Elkin, 1994) indicated greater reduction of symptoms at midtreatment (eighth week) with Imipramine (IMI-CM) than with Cognitive-behavioral therapy (CBT) and Interpersonal therapy (IPT), but no significant differences in symptom reduction among these three active treatments at termination. Current analyses of previously unanalyzed data from ratings by therapists, clinical evaluators, and patients at termination and at 18-month follow-up also indicated no significant differences among these treatments in symptom reduction or ratings of current clinical condition. But significant treatment differences emerged at the 18-month follow-up in patients' ratings of the effects of treatment on their life adjustment. Patients in IPT reported greater satisfaction with treatment, and patients in both IPT and CBT reported significantly greater effects of treatment on their capacity to establish and maintain interpersonal relationships and to recognize and understand sources of their depression than did patients in IMI-CM or placebo. PMID- 22239700 TI - Enhanced separation and characterization of deamidated peptides with RP-ERLIC based multidimensional chromatography coupled with tandem mass spectrometry. AB - Deamidation of asparaginyl residues in proteins produces a mixture of asparaginyl, n-aspartyl, and isoaspartyl residues, which affects the proteins' structure, function, and stability. Thus, it is important to identify and quantify the products to evaluate the effects in biological systems. It is still a challenging task to distinguish between the n-Asp and isoAsp deamidation products in a proteome-wide analysis because of their similar physicochemical properties. The quantification of the isomeric deamidated peptides is also rather difficult because of their coelution/poor separation in reverse-phase liquid chromatography (RPLC). We here propose a RP-ERLIC-MS/MS approach for separating and quantifying on a proteome-wide scale the three products related to deamidation of the same peptide. The key to the method is the use of RPLC in the first dimensional separation and ERLIC (electrostatic repulsion-hydrophilic interaction chromatography) in the second, with direct online coupling to tandem MS. The coelution of the three deamidation-related peptides in RPLC is then an asset, as they are collected in the same fraction. They are then separated and identified in the second dimension with ERLIC, which separates peptides on the basis of both pI and GRAVY values. The coelution of the three products in RPLC and their efficient separation in ERLIC were validated using synthetic peptides, and the performance of ERLIC-MS/MS was tested using peptide mixtures from two proteins. Applying this sequence to rat liver tissue, we identified 302 unique N deamidated peptides, of which 20 were identified via all three deamidation related products and 70 of which were identified via two of them. PMID- 22239701 TI - Development and validation of a prognostic index for 2-year mortality in Chinese older residents living in nursing homes. AB - AIM: There is no mortality prediction index for Chinese nursing home older residents. The objective of this study was to derive and validate a 2-year mortality prognostic index for them. METHODS: We carried out a prospective cohort study on 1120 older residents from 12 nursing homes of Hong Kong. We obtained potential predictors of mortality and carried out updated functional assessment. Each risk factor associated independently with 2-year mortality in a derivation cohort was assigned a score based on the odds ratio, and risk scores were calculated for each participant by adding the points of risk factors present. Similar analysis was carried out on the validation cohort. RESULTS: Independent predictors of mortality included: aged 86-90 years (3 points); aged >= 91 years (4 points); Charlson comorbidity index >= 4 (6 points); Barthel Index 5-60 (5 points); Barthel Index 0 (10 points); number of hospitalizations in the preceding year (Adbefore) 1 (4 points); Adbefore 2 (5 points) and Adbefore >= 3 (6 points). In the derivation cohort, 2-year mortality was 10.8% in the low-risk group (<= 4 points) and 59.9% in the high-risk group (>= 14 points). In the validation cohort, 2-year mortality was 11.8% in the low-risk group and 60.4% in the high risk group. The receiver-operator characteristic curve area was 0.761 for the derivation cohort and 0.742 for the validation cohort. CONCLUSIONS: Our prognostic index had satisfactory discrimination and calibration in an independent sample of Chinese nursing home older residents. It can be used to identify older residents with a high risk for poor outcomes, who need a different level of care. PMID- 22239702 TI - Sternal kyphoplasty for metastatic lung cancer: image-guided palliative care, utilizing fluoroscopy and sonography. AB - Skeletal metastases can cause severe pain and functional impairment, secondary to direct invasion or osteolysis. Direct palliation of these metastases can reduce the burden of pain. Surgical excision or radiotherapy has been used to target these tumors. In precarious locations, such as the sternum, surgery may lead to significant morbidity. Radiotherapy requires multiple visits, which may be difficult for the severely disabled. Minimally invasive, image-guided procedures are gaining wider acceptance in treating these lesions. Kyphoplasty has been used for vertebral column metastases. Osteoplasty of a metastasis to a flat, non weight-bearing bone is rarely reported. The author reports the successful palliation of a sternal metastasis with kyphoplasty. Ultrasound imaging was used with fluoroscopy. Reproducibility, by other providers, is imperative with any emerging technique; this will facilitate wider patient access and device innovation. Hopefully, future multicenter trials will validate the efficacy and safety of this technique. PMID- 22239703 TI - Dermatological emergencies: a comparative study of activity in 2000 and 2010. AB - BACKGROUND AND OBJECTIVE: Studies of dermatological emergencies (DE) are few. We evaluated the activity in our DE unit in a 1-month retrospective study and compared the results with a similar study performed in the same department in 2000. METHODS: We reviewed the charts of all outpatients seen in the DE unit in January 2010, collecting data on age, sex, place of residence, referral mode, day and hour of consultation, true emergency or non-emergency, diagnosis and follow up. RESULTS: In January 2010, we serviced 605 patients (58% males, mean age 40 +/ 21 years), 21% more than in 2000; 43.5% were seen during off-duty hours vs. 49% in 2000 (P = 0.066), 49% were considered true emergencies vs. 43% in 2000 (P = 0.046), and 14% were referred by a physician vs. 23% in 2000 (P = 0.0001). In total, 35.2% of cases were infectious dermatoses in 2010 vs. 29% in 2000 (P = 0.026). Other diagnoses were eczema, urticaria and drug-related eruptions. Follow up was suggested to 53.3% of the patients. CONCLUSIONS: Our DE unit satisfies a genuine need. Its activity increased over 10 years, most likely because of the decrease in the number of dermatologists in France. Although our results are close to those reported in the literature, comparison with previously published studies is difficult because of the heterogeneity of the definition of DE. PMID- 22239704 TI - Effect of nutrient supplementation of crude or detoxified concentrated distilled grape marc hemicellulosic hydrolysates on the xylitol production by Debaryomyces hansenii. AB - Biosynthesis of xylitol using the yeast Debaryomyces hansenii NRRL Y-7426 was carried out using distilled grape marc (DGM) hemicellulosic hydrolysates directly concentrated by vacuum evaporation or after detoxification with activated charcoal. The effect of nutrient supplementation with vinasses, corn steep liquor (CSL) or commercial nutrients was explored. Using crude concentrated hemicellulosic hydrolysates, the maximum xylitol concentration, 11.3 g/L, was achieved after 172 hr (Q ( xylitol ) = 0.066 g/L-hr; Y ( xylitol ) (/SC) = 0.21 g/g); meanwhile, using detoxified concentrated hydrolysates, the concentration increased up to 19.7 g/L after 72 hr (Q ( xylitol ) = 0.274 g/L-hr; Y ( xylitol ) (/SC) = 0.38 g/g). On the other hand, using crude or detoxified hydrolysates, the xylose-to-xylitol bioconversion was strongly affected by the addition of nutrients, suggesting that these hydrolysates present essential nutrients favouring the growth of D. hansenii. PMID- 22239706 TI - Decoloring hemoglobin as a feedstock for second-generation bioplastics. AB - The color of red blood cell concentrate (RBCC) limits its application in human food, but there is potential to use it for second-generation bioplastics. Several methods have been developed to remove color from RBCC, but they are expensive or may produce difficult-to-remove toxic residues. Hydrogen peroxide treatment is a cheaper alternative. The effects of RBCC concentration, pH, and reaction temperature were the most important factors influencing the decolorizing process. They were investigated with the aim of developing a method that could be scaled to commercial level for producing a bioplastic feedstock. Initial trials showed pH was an important factor for decolorization and foaming. At pH 15 there was a 96% reduction in solution color and 8.4% solids were lost due to foaming. There was a 76% reduction in solution color at pH 2 and only 2.6% solids were lost due to foaming. The optimal reaction conditions were to centrifuge 9% w/w, pH 2 aqueous RBCC solution to remove aggregates. The solution was reacted at 30 degrees C with 7.5 g of 30% (w/w) hydrogen peroxide. These conditions achieved a 93% reduction in solution color after 3 hr and the molecular weight of the decolored protein was not significantly reduced. PMID- 22239705 TI - Improvement of 1,3-dihydroxyacetone production from Gluconobacter oxydans by ion beam implantation. AB - Improvement of dihydroxyacetone (DHA) production by mutagenesis of ion beam implantation and medium optimization using response-surface methodology (RSM) were investigated in this work. More than 1000 mutant strains were selected through a mutagenesis method using N(+) ions implantation with a dose of 60 * (2.6 * 10(13)) ions/cm(2) and energy of 10 keV. Several high-yield mutant strains were showed the potent application for DHA production and the genetically stable mutant strain G. oxydans ZJB09113 was selected for optimization of cultivation condition by RSM. The optimal medium for DHA fermentation is composed (in g/L) of yeast extract 4.88, CaCO(3) 2.00, and glycerol 52.86 mL/L (initial pH 4.89). The maximal DHA concentration of 40.0 g/L was achieved after 24 hr of shaken flask fermentation at 30 degrees C with 150 rpm, and 196.3% increase in DHA production in comparison with unoptimized conditions. PMID- 22239707 TI - Enhancement of ethanol production by simultaneous saccharification and fermentation (SSF) of rice straw using ethoxylated span 20. AB - In this work, four nonionic surfactants based on sorbitan monolaurate (Span 20) were synthesized by introducing ethylene oxide gas (n = 20, 40, 60, 80 ethylene oxide units) into Span 20 to give four new surfactants with different hydrophilic lipophilic balance (HLB), namely, E(20), E(40), E(60), and E(80). The structures of the prepared nonionic surfactants were elucidated using Fourier-transform infrared (FT-IR) and (1)H-nuclear magnetic resonance (NMR) spectroscopy. The surface-tension measurements were recorded. The effects of the prepared nonionic surfactants on the simultaneous saccharification and fermentation (SSF) of microwave/alkali-pretreated rice straw to produce ethanol were investigated. From the obtained data, it was found that the addition of the nonionic surfactants at 2.5 g/L had a positive effect on SSF. The maximum ethanol yield (76 and 55%) was obtained after 72 hr for rice straw using Kluyveromyces marxianus and Saccharomyces cerevisiae, respectively. Also, it was found that the ethanol yield increases with increasing HLB of the prepared nonionic surfactants by increasing ethylene oxide units. The adsorption of nonionic surfactants on lignocelluloses is proposed to be due to hydrophobic and hydrogen bonding interactions between nonionic surfactants and the lignin part in the lignocelulose. It can be concluded that additions of surface-active compounds, such as nonionic surfactants, increase enzymatic conversion of rice straw for bioethanol purposes. PMID- 22239708 TI - PURIFICATION and characterization of ddt-dehydrohalogenase from Pseudomonas putida T5. AB - DDT-dehydrohalogenase is involved in the catalytic degradation of p,p'-DDT by eliminating either HCl or Cl(-) to form DDD/DDE. Isolation, purification and characterization of DDT-dehydrohalogenase from a bacterial source is reported in this manuscript. Ten bacterial cultures belonging to DDT degrading microbial consortium were screened for the DDT-dehydrohalogenase activity. Among these, the clarified cell homogenate of Pseudomonas putida T5 showed higher DDT dehydrohalogenase activity and enzyme was purified to apparent homogeneity with 73% overall recovery. The relative molecular mass of the enzyme estimated by the SDS PAGE method was ~32 kDa. Native PAGE revealed the presence of a single band. The purity of the enzyme was confirmed by HPLC and capillary electrophoresis. The enzyme was stable for 4-5 h at pH 7.0 at the temperature optima of 37 degrees C. The K( m ) and V( max ), values for DDT-dehydrohalogenase were 3.7 uM and 6.8 uM min(-1), respectively. The enzyme was a glycoprotein with mannose forming the backbone. AIG-formed the N-terminus chain. Serine and tryptophan appeared to be involved at the active site. The enzyme appeared to be a metalloprotein containing Zn, Mg, and Ca ions. Monovalent and divalent cations (1 mM) inhibited the enzyme strongly. The primary sequence of HPLC purified enzyme was deduced by LC-MS-MALDI-ESI. PMID- 22239710 TI - An effective method of RNA isolation from Fallopia multiflora tuberous roots. AB - To isolate high-quality total RNA from Fallopia multiflora tuberous roots is difficult because of the presence of high levels of carbohydrates, phenolics, and other secondary metabolites. Since several procedures specialized for RNA isolation from polysaccharides and phenols rich tissues have resulted in poor yields, in this study, we developed a modified protocol that was derived from the traditional CTAB method. The protocol was able to produce high-quality and intact RNA from the tuberous roots of F. multiflora. The yield of total RNA was more than 0.15 mg/g fresh weight, with an A260/A280 ratio of 1.9-2.0. The obtained RNA was of sufficient quality and suitable for downstream application such as reverse transcription polymerase chain reaction (RT-PCR), Northern hybridization, and cDNA library construction. The protocol may also have wider applicability for total RNA isolation from other plant species with tuberous roots. PMID- 22239709 TI - Non-reducing alkaline solubilization and rapid on-column refolding of recombinant prion protein. AB - Mature prion protein (PrP) is a 208-residue polypeptide that contains a single disulfide bond. We report an alternative method to purify recombinant mouse PrP produced in Escherichia coli. Bacterial inclusion bodies were solubilized in a buffer containing 2 M urea at pH 12.5. The solubilized protein was rapidly purified on a nickel affinity column without a chaotrope gradient, followed by ion-exchange chromatography. The yield and purity of PrP produced by this alternative approach was similar to that obtained using a conventional solubilization and on-column refolding protocol. Recombinant PrP produced using the non-reducing purification protocol is properly folded, as determined by circular dichroism, and a competent substrate for amyloid fibril formation, as determined by Thoflavin-T dye binding assays. In summary, this report describes a rapid method for producing properly folded recombinant PrP without reducing agents or a chaotrope gradient. PMID- 22239711 TI - Biocatalytic activity of recombinant human beta-mannosidase immobilized onto magnetic nanoparticles for bioprocess. AB - Recombinant human beta-mannosidase (rhMANB) is an important glycosidase enzyme that degrades mannose-linked glycoproteins and mannan polysaccharides. rhMANB was purified and covalently immobilized onto magnetic nanoparticles. The immobilization of the enzyme was confirmed by Fourier-transform infrared spectroscopy (FTIR) and magnetic nanoparticles linked immunosorbent assay (MagLISA). Antibodies against rhMANB were raised, purified and characterized for MagLISA. The binding of rhMANB onto magnetic nanoparticles was found to be 65%. The V( max ) and K( m ) of immobilized rhMANB was observed 3.0-fold higher and 2.024-fold lower, respectively, as compared to unbound rhMANB. The stability and activity of immobilized enzyme was observed at different pH, temperature, and after storage at 4 degrees C. Metal chelators (oxalic acid, citric acid, and ascorbic acid) did not affect the enzyme activity of immobilized enzyme, whereas ethylenediamine tetraacetic acid reduced the activity. The results obtained from thin-layer chromatography indicate that immobilized rhMANB is more efficient than the unbound form to hydrolyze mannobiose, mannotriose, mannotetraose, mannopentose, galactoglucomannan, and locust bean gum. Magnetic nanoparticles suspended gel-permeation chromatography showed that 29% locust bean gum hydrolyzed efficiently during flow in the column. The immobilization of rhMANB will be a good process for gelling and saccharification of mannan polymers at industrial scale. PMID- 22239712 TI - Synergic effects of imidazolium ionic liquids on P123 mixed micelles for inducing micro/mesoporous materials. AB - A series of micro/mesoporous silica composites were synthesized with P123 and imidazolium ILs ([C(n)mim]X) as the co-templates. [C(n)mim]X showed notable synergic interaction with P123. By changing the alkyl chain length n in methylimidazolium, ring-like micropores were observed in the wall of the mesoporous materials when n = 4. While increasing n to 10, micropores and mesopores were found in different separated regions. Various anions of Cl(-), Br( ), and BF(4)(-) of ILs have little effect on the aggregation behavior of P123/C4X mixed micelles. The strong hydrogen bonding effect of BF(4)(-) has resulted in the ordered mesoporous channels with numerous micropores in the wall at a low temperature of 313 K. Hydrophobic C4PF(6) can only be solubilized in the core of P123 micelles, which resulted in the swelling of P123/C4PF(6) mixed aggregates and the ordered hexagonal porous silica materials at 313 K. The fundamental understanding of the synergic interaction and formation mechanisms of various porous silica materials can provide a general convenient way toward a rational design and synthesis of the micro/mesoporous composites. PMID- 22239713 TI - Genetic diversity and variance of Stentor coeruleus (Ciliophora: Heterotrichea) inferred from inter-simple sequence repeat (ISSR) fingerprinting. AB - We used inter-simple sequence repeat fingerprinting to analyze the genetic structure of 16 populations of Stentor coeruleus from three lakes and three ponds in China. Using 14 polymorphic primers, a total of 99 discernible DNA fragments were detected, among which 76 (76.77%) were polymorphic, indicating median genetic diversity in these populations. Further, both Nei's gene diversity (h) and Shannon's information index (I) between the different populations revealed a median genetic diversity. At the same time, gene flow was interpreted to be low. The main factors responsible for the median level of diversity and low gene flow within populations are probably due to a low frequency of sexual recombinations. Analysis of molecular variance showed that there was high genetic differentiation among the five water bodies. Both cluster analysis and a nonmetric multidimensional scaling analysis suggested that genotypes isolated from the same locations displayed a higher genetic similarity than those from different ones, separating populations into subgroups according to their geographical locations. However, there is a weak positive correlation between the genetic distance and geographical distance. PMID- 22239714 TI - Are proton pump inhibitors safe during pregnancy and lactation? Evidence to date. AB - Symptoms of gastro-oesophageal reflux disease (GORD or GERD) are estimated to occur in 30-50% of pregnancies, with the incidence approaching 80% in some populations. As with many other conditions in pregnancy, medical therapy with pharmaceutical agents is a concern, as the potential teratogenicity of medications is not well known. Although prevalence numbers are high, many patients have mild and infrequent symptoms, which often respond to lifestyle and dietary modifications. The exact mechanism and pathogenesis of GERD associated with pregnancy is likely multifactorial. Treatment strategies for patients not responding to conservative therapies include a step-up approach initially starting with antacids and alginates, and progressing to histamine H(2) receptor antagonists followed by proton pump inhibitor (PPI) therapy if indicated by symptoms. Although PPI therapy is the most effective treatment available for GERD, the data related to the safety for use during pregnancy and postpartum breastfeeding are mostly obtained from cohort analysis. Given the significant adverse impact of GERD on quality of life and functionality, the use of this class of medications should not be overly restricted based solely on the pregnancy. Based on the studies presented, exposure to PPI therapy during pregnancy seems to predispose the fetus to minimal risk and, overall, these medications should be discussed with the primary physician if symptomatically necessary in the pregnant patient. This evidence-based review will address the management and safety of PPI therapy during pregnancy and lactation, and briefly review the pathogenesis, clinical presentation and diagnosis of GERD in this population. PMID- 22239715 TI - N@C60-porphyrin: a dyad of two radical centers. AB - Dyads of endohedral nitrogen fullerene and porphyrin have been synthesized. In the two-radical-center dyad, the copper(II) tetraphenylporphyrin suppressed the electron spin resonance (ESR) signal of N@C(60) through intramolecular dipolar coupling with a strength of 27.0 MHz. Demetalation of the metalloporphyrin moiety of the dyad, which effectively turned the two-radical-center dyad into a single radical-center dyad, recovered 82% of the ESR signal of N@C(60). Such mechanism of switching a spin state on and off could find use in molecular spintronics applications. PMID- 22239716 TI - Identification of pinnatoxins and discovery of their fatty acid ester metabolites in mussels ( Mytilus edulis ) from eastern Canada. AB - Pinnatoxins are a group of fast-acting cyclic imine toxins previously identified in shellfish from Asia, the southern Pacific, and northern Europe. In this work pinnatoxins were detected in mussels from locations across the eastern coast of Canada. Pinnatoxin G (6) was the major structural variant present, sometimes at levels >80 MUg/kg, whereas much lower levels of pinnatoxin A (1) were detected in some samples. Increased concentrations were observed following base hydrolysis of extracts, leading to the discovery by LC-MS of a range of fatty acid esters of 6. Information on the structures of these acylated derivatives was provided through a series of mass spectrometric experiments, supported by partial synthesis, and it is proposed that the compounds are 28-O-acyl esters of 6. Although acyl esters of a range of other phycotoxins are known to form as metabolites in shellfish, this is the first report of their existence for this particular toxin class. The occurrence of pinnatoxins in North American shellfish further highlights the international distribution of these toxins. PMID- 22239717 TI - Novaluron causes reduced egg hatch after treating adult codling moths, Cydia pomenella: support for transovarial transfer. AB - The codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), is a primary pest of apples throughout the United States. Reliance on broad spectrum organophosphates has been declining with the slated cancellation and has shifted towards narrow spectrum insecticides. Novaluron, a chitin synthesis inhibitor, has primarily been used for its ovicidal and larvacidal activities. However, recent studies have demonstrated a transovarial effect after exposure to adults. The effects of novaluron were studied to determine if reduced egg hatch occurs after exposure of different sexes to this compound. Effects of this compound through horizontal transfer were also compared with a topical application to C. pomonella eggs. Results from independent exposure of different sexes to novaluron were different than the control for all three exposure types; male only, female only, and both treated. The horizontal transfer experiment yielded no significant difference while the topical application of novaluron on eggs showed significantly lower egg hatch. Although novaluron has no direct toxicity to adults, the results of this study demonstrate that the delayed lethal activity of this compound reduces hatching of eggs laid by treated adults. Along with the direct ovicidal and larvicidal properties of novaluron, the delayed lethal activity provides an important contribution to the overall control seen in the field. PMID- 22239718 TI - Ionization levels of doped copper indium sulfide chalcopyrites. AB - The electronic structure of modified chalcopyrite CuInS(2) has been analyzed from first principles within the density functional theory. The host chalcopyrite has been modified by introducing atomic impurities M at substitutional sites in the lattice host with M = C, Si, Ge, Sn, Ti, V, Cr, Fe, Co, Ni, Rh, and Ir. Both substitutions M for In and M for Cu have been analyzed. The gap and ionization energies are obtained as a function of the M-S displacements. It is interesting for both spintronic and optoelectronic applications because it can provide significant information with respect to the pressure effect and the nonradiative recombination. PMID- 22239719 TI - Development and function of interleukin 17-producing gammadelta T cells. AB - Interleukin (IL) 17 is a phylogenetically ancient cytokine that has been adopted by the adaptive immune system, and the investigation of adaptive T helper (Th) 17 cells has substantially contributed to our understanding of the molecular requirements for the induction, regulation, and function of IL-17. However, IL-17 is in fact produced by a large variety of innate immune cells and exerts its most significant biological functions at the interface of the organism with its environment, such as, for example, at epithelial surfaces, where gammadelta T cells are a prominent source of IL-17. In this review, we will give an overview on the concepts of commitment of gammadelta T cells to effector phenotypes, focusing on IL-17-producing gammadelta T cells (gammadeltaT17 cells). The role of gammadeltaT17 cells in animal models of autoimmunity will be discussed as well as the prerequisites for the development of human gammadeltaT17 cells and their potential importance for human disease conditions. PMID- 22239720 TI - Taxonomic and functional composition of the algal benthos exhibits similar successional trends in response to nutrient supply and current velocity. AB - In an effort to identify the causes and patterns of temporal change in periphytic communities, we examined biomass accumulation, taxonomic and functional composition, rate of species turnover, and pairwise species correlations in response to variability in current velocity and nutrient supply in artificial stream flumes. Divergent patterns in community growth and succession were observed between nutrient treatments and, to a lesser extent, between flow treatments best described by shifts in taxonomic and functional composition. Specifically, understory low profile species, tolerant to low resource supply, became dominant under low nutrients, while overstory high profile and motile species with higher nutrient demands dominated the high nutrient treatments. Increased resource supply or current velocity did not influence the species turnover rate, measured by a time-lag analysis. Interspecific interactions, especially competition, did not appear to be driving community dynamics, as the number of positive and negative pairwise species correlations ranged between low and extremely low, respectively. The overwhelming majority of correlations were not significant, indicating that species within the biofilm matrix were not perceptibly influencing one another. Thus, temporal trends in taxonomic and functional composition were largely environmentally driven, signifying that coexistence in biofilms is defined by the same mechanism along the hierarchy from species to functional groups. PMID- 22239721 TI - Air sampling in the breathing zone of neonatal foals for prediction of subclinical Rhodococcus equi infection. AB - REASONS FOR PERFORMING THE STUDY: Disease caused by Rhodococcus equi is a significant burden to the horse breeding industry worldwide. Early detection of rhodococcal pneumonia, albeit important to minimise treatment costs, is difficult because of the insidious nature of the disease and the lack of definitive diagnostic tests. OBJECTIVES: To investigate air sampling from the breathing zone of neonatal foals as a predictor of subsequent rhodococcal pneumonia. METHODS: Air samples were collected from the breathing zone of 53 neonatal foals (age <=10 days) and again at the time of routine ultrasonographic screening for R. equi pneumonia (age 1-2 months). RESULTS: Pneumonia was diagnosed ultrasonographically in 23% of foals. Virulent R. equi was detected in air from the breathing zone of 19% of neonatal foals and 45% of foals at age 1-2 months. There was no association between virulent R. equi in the breathing zone of foals and the subsequent ultrasonographic diagnosis of rhodococcal pneumonia. The median concentration of virulent R. equi in the breathing zone of both neonates (0 [range 0-4] colony-forming units [cfu]/250 l) and older foals (0 [range 0-3] cfu/250 l) was not significantly different from that in background air samples (0 [range 0-6] cfu/250 l). There was no difference in the concentration of virulent R. equi in the breathing zone of older foals that were diagnosed with rhodococcal pneumonia or clinically normal foals. CONCLUSION: Detection of virulent R. equi in air from the breathing zone was not a positive predictor of rhodococcal pneumonia in foals up to age <=2 months. POTENTIAL RELEVANCE: Selective culture of air samples from the breathing zone of young foals is not better at diagnosing rhodococcal pneumonia than early ultrasonographic screening. However, culture of air samples from the breathing zone of older foals remains a useful herd-based epidemiological tool. PMID- 22239722 TI - Membrane assembly driven by a biomimetic coupling reaction. AB - One of the major goals of synthetic biology is the development of non-natural cellular systems. In this work, we describe a catalytic biomimetic coupling reaction capable of driving the de novo self-assembly of phospholipid membranes. Our system features a coppercatalyzed azide-alkyne cycloaddition that results in the formation of a triazole-containing phospholipid analogue. Concomitant assembly of membranes occurs spontaneously, not requiring preexisting membranes to house catalysts or precursors. The substitution of efficient synthetic reactions for key biochemical processes may offer a general route toward synthetic biological systems. PMID- 22239723 TI - The relationship of pain and cognitive impairment with social vulnerability--an analysis of the Canadian Study of Health and Aging. AB - OBJECTIVE: The objective of this study was to delineate the relationship between noncancer pain and cognitive impairment with social vulnerability. DESIGN: The study was designed as a cross-sectional analysis of the Canadian Study of Health and Aging, 1996 wave. SETTING: Community-dwelling older adults in Canada. SUBJECTS: 3,776 study participants. OUTCOME MEASURES: Pain was categorized as no or very mild pain vs moderate or severe pain. Cognitive impairment was dichotomized from the Modified Mini-Mental State Examination (0-100) to no (>77) or impairment (77 or <). Social vulnerability (outcome) was operationalized as the accumulation of 39 possible self-report variables related to social circumstance, scores range from 0 to 1, where higher scores indicate greater vulnerability. Additional covariates included demographics, depressed mood, comorbidity, and functional impairment. Bivariate and multivariate relationships between pain and cognitive impairment with social vulnerability were assessed using t-tests and linear regression, respectively. RESULTS: Of 5,703 respondents, 1,927 were missing a component of the social vulnerability index and of these nine were missing a pain response, leaving 3,767 (66.1%) of the original sample. A total of 2,435 (64.6%) reported no/mild pain and 3,435 (91.2%) were cognitively intact. The mean (standard deviation) social vulnerability index was 9.97 (3.62) with scores ranging from 1.12 to 26.85. Moderate or severe pain 0.44 (95% confidence interval [CI] 0.21, 0.66, P < 0.01) and cognitive impairment 0.49 (95% CI 0.13, 0.86, P < 0.01) were independently associated with social vulnerability, but the interaction term was not statistically significant, 0.40 (95% CI 0.32,1.14, P = 0.27). CONCLUSION: Pain and cognitive impairment are independently associated with social vulnerability. Improvements in pain management might mitigate social vulnerability in a growing number of older adults with either or both conditions. PMID- 22239724 TI - Experimental and computational evidence for an inversion in guest capacity in high-generation triazine dendrimer hosts. AB - The synthesis, characterization, and host-guest chemistry of high-generation triazine dendrimers are described. With pyrene and camptothecin as guests, experiments revealed that the guest capacity of odd-generation triazine dendrimers increased until generation 7 but decreased at generation 9. Molecular dynamics simulations conducted in explicit solvent showed a useful fingerprint for this behavior in radial distribution functions of water molecules penetrating the interior of the dendrimers. A linear relationship between the guest capacity of dendrimers measured experimentally and the number of water molecules within the interior determined computationally was observed. PMID- 22239725 TI - Annatto extract and beta-carotene enhances antioxidant status and regulate gene expression in neutrophils of diabetic rats. AB - Annatto (Bixa orellana L.) contains a mixture of orange-yellowish pigments due to the presence of various carotenoids that have antioxidant effect. The immune system is especially vulnerable to oxidative damage because many immune cells, such as neutrophils, produce reactive oxygen and nitrogen species (ROS and RNS) as part of the body's defence mechanisms to destroy invading pathogens. It is well known that the function of neutrophils is altered in diabetes; one of the major functional changes in neutrophils in diabetes is the increased generation of extracellular superoxide via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system. The purpose of this study is to evaluate the production of ROS and nitric oxide (NO) as well as the expression of NADPH oxidase subunits, inducible nitric oxide (iNOS), superoxide dismutase (SOD) and catalase (CAT) in neutrophils from diabetic rats treated with annatto extract and beta-carotene. Forty-eight female Fisher rats were distributed into six groups according to the treatment received. All animals were sacrificed 7 days after treatment, and the neutrophils were isolated using two gradients of different densities. The ROS and NO were quantified by a chemiluminescence and spectrophotometric assays, respectively. Analyses of gene expression were performed using quantitative real time polymerase chain reaction (qRT-PCR). The results show that treatment with annatto extract and beta-carotene was able to decrease ROS production and the mRNA levels of p22(phox) and p47(phox) and increase the mRNA levels of SOD and CAT in neutrophils from diabetic rats. These data suggest that annatto extract and beta-carotene exerts antioxidant effect via inhibition of expression of the NADPH oxidase subunits and increase expression/activity of antioxidant enzymes. PMID- 22239726 TI - Anencephaly does not cause structural alterations in the fetal penis. AB - INTRODUCTION: Anencephaly is the most severe neural tube defect in human fetuses. There is an increasing need for tissue replacement in chronic diseases and reconstructive surgeries. Fetal tissues have been used as a substitute for native organs. AIM: The aim of this article was to compare the structure and morphology of the corpora cavernosa (CC) and spongiosum (SP) of penises from anencephalic and normal human fetuses. MAIN OUTCOME MEASURES: The main outcome measures of this study were the proposition of a new model for biological studies and tissue transplantation. METHODS: We studied 11 penises from normal human fetuses, aged 14-23 weeks postconception (WPC), and five penises from anencephalic fetuses, aged 18-22 WPC. The organs were removed and processed by routine histological and immunolabeling techniques. Analysis of connective tissue (Cot), smooth muscle (SMC), and elastic fiber (EF) were performed in sections. Data were expressed as area density (Ad) using digital processing and software. Means were statistically compared using the unpaired t-test and linear regression was performed. Statistical significance was considered if P<0.05. RESULTS: The intracavernosal septum was present in all samples. We did not observe differences in the Ad of Cot and SMC in the penises of anencephalic fetuses when compared with normal ones. The simple linear regression suggested that during human development, there is a gradual increase in Cot (R(2)=+0.45) and a decrease of SMC (R(2)=-0.62) in the CC in both groups studied. Elastin was observed only in fetuses from 20th WPC. CONCLUSIONS: There was no difference in the structure of the CC and corpus SP of anencephalic fetuses compared with normal ones. Elastin was documented from 20th WPC, which suggests the maintenance of erectile function. Histochemistry and immunolabeling suggested that penile shaft development is maintained and unaltered in anencephalic fetuses. Further studies should be performed to analyze anencephalic fetuses as a potential tissue-donating group and a model for biological studies. PMID- 22239728 TI - Influence of the preparation route on the supramolecular organization of lipids in a vesicular system. AB - A confocal fluorescence microscopy-based assay was used for studying the influence of the preparation route on the supramolecular organization of lipids in a vesicular system. In this work, vesicles composed of cholesterol and CTAB (1/1 mol %) or cholesterol and DOPC (2/8 mol %) and incorporating two membrane dyes were prepared by either a compressed fluid (CF)-based method (DELOS-susp) or a conventional film hydration procedure. They were subsequently immobilized and imaged individually using a confocal fluorescence microscope. Two integrated fluorescence intensities, I(dye1) and I(dye2), were assigned to each tracked vesicle, and their ratio, I(dye1)/I(dye2), was used for quantifying the degree of membrane inhomogeneity between individual vesicles within each sample. A distribution of I(dye1)/I(dye2) values was obtained for all the studied vesicular systems, indicating intrasample heterogeneity. The degree of inhomogeneity (DI) was similar for Chol/DOPC vesicles prepared by both procedures. In contrast, DI was more than double for the hydration method compared to the CF-based method in the case of Chol/CTAB vesicles, which can suffer from lipid demixing during film formation. These findings reveal a more homogeneous vesicle formation path by CFs, which warranted good homogeneity of the vesicular system, independently of the lipid mixture used. PMID- 22239727 TI - Design and characterization of 1D nanotubes and 2D periodic arrays self-assembled from DNA multi-helix bundles. AB - Among the key goals of structural DNA nanotechnology are to build highly ordered structures self-assembled from individual DNA motifs in 1D, 2D, and finally 3D. All three of these goals have been achieved with a variety of motifs. Here, we report the design and characterization of 1D nanotubes and 2D arrays assembled from three novel DNA motifs, the 6-helix bundle (6HB), the 6-helix bundle flanked by two helices in the same plane (6HB+2), and the 6-helix bundle flanked by three helices in a trigonal arrangement (6HB+3). Long DNA nanotubes have been assembled from all three motifs. Such nanotubes are likely to have applications in structural DNA nanotechnology, so it is important to characterize their physical properties. Prominent among these are their rigidities, described by their persistence lengths, which we report here. We find large persistence lengths in all species, around 1-5 MUm. The magnitudes of the persistence lengths are clearly related to the designs of the linkages between the unit motifs. Both the 6HB+2 and the 6HB+3 motifs have been successfully used to produce well-ordered 2D periodic arrays via sticky-ended cohesion. PMID- 22239729 TI - Survival period after tube feeding in bedridden older patients. AB - AIM: We prospectively studied survival periods after tube feeding. METHODS: Participants were 163 bedridden older patients suffering from dysphagia. RESULTS: A wide range of survival periods after tube feeding were observed within half a year without tube feeding after being bedridden. After this initial period, survival periods after tube feeding were limited to approximately half a year. Survival periods after tube feeding were positively proportional to the length of time patients were free from pneumonia after tube feeding. After tube feeding, patients died from pneumonia within half a year, and the frequency of pneumonia was 3.1 +/- 2.7 times (mean +/- SD) before death. CONCLUSION: Survival periods after tube feeding for less than 1 year were primarily determined by being bedridden for more than half a year without tube feeding and once pneumonia occurred; patients who were tube fed did not survive for more than half a year. PMID- 22239730 TI - Plasma metabonomics as a novel diagnostic approach for major depressive disorder. AB - Major depressive disorder (MDD) is a socially detrimental psychiatric disorder, contributing to increased healthcare expenditures and suicide rates. However, no empirical laboratory-based tests are available to support the diagnosis of MDD. In this study, a NMR-based plasma metabonomic method for the diagnosis of MDD was tested. Proton nuclear magnetic resonance ((1)H NMR) spectra of plasma sampled from first-episode drug-naive depressed patients (n = 58) and healthy controls (n = 42) were recorded and analyzed by orthogonal partial least-squares discriminant analysis (OPLS-DA). The OPLS-DA score plots of the spectra demonstrated that the depressed patient group was significantly distinguishable from the healthy control group. Moreover, the method accurately diagnosed blinded samples (n = 26) in an independent replication cohort with a sensitivity and specificity of 92.8% and 83.3%, respectively. Taken together, NMR-based plasma metabonomics may offer an accurate empirical laboratory-based method applicable to the diagnosis of MDD. PMID- 22239731 TI - Couples' reasons for adherence to, or discontinuation of, PDE type 5 inhibitors for men with erectile dysfunction at 12 to 24-month follow-up after a 6-month free trial. AB - INTRODUCTION: The history of treatments for erectile dysfunction (ED) has involved a repeated pattern of uptake, followed by abandonment of the various therapies in the medium term. Even effective and simple to use medications are not necessarily continued; discontinuation rates range between 15% and 60%. Despite the association between partner sexual function and men's use of PDE5, no previous studies have reported any contact with partners of men taking PDE5 for their ED. This study involved both partners in couples followed up at least 1 year after treatment of ED. AIM: The study sought clarification of factors influencing adherence to, or discontinuation of, oral ED medications from couples. We hypothesized that many factors contribute to decision making about ED medication use at >12 months. MAIN OUTCOME MEASURES: The main outcome measures of this article were interviews and International Index of Erectile Function erectile function domain. METHODS: A total of 155 interviews were conducted seeking details of frequency of usage and preference for the drugs available; reasons for that choice, or for discontinuation of use, were also sought. RESULTS: Of men interviewed, 71% were using PDE5 at 18 months. Most men interviewed were using the oral medications either 1-2x/week or 1-2x/month. Forty four percent of men who had decreased their use of the medications reported less need for them. Thirty-four men said the main reason they were using less medication was cost. "Partner issues" from the men's perspective were seldom reported in this study. However, for a number of women, "partner issues" meant a range of problems from separation to alcohol abuse, lack of communication, and lack of confidence, or fear of failure. CONCLUSIONS: This is the first study to ask couples why they decided to continue or stop using PDE5 when followed up. Female partners provided a different perspective on "partner issues" often cited as reasons for discontinuing PDE5 use. It was also clear that discontinuation did not mean couples were no longer sexually active. PMID- 22239732 TI - Toward a digital gene response: RNA G-quadruplexes with fewer quartets fold with higher cooperativity. AB - Changes in RNA conformation can alter gene expression. The guanine quadruplex sequence (GQS) is an RNA motif that folds in the presence of K(+) ions. Changes in the conformation of this motif could be especially important in regulating gene expression in plants because intracellular K(+) concentrations often increase during drought stress. Little is known about the folding thermodynamics of RNA GQS. We show here that RNA GQS with tracts containing three G's [e.g., (GGGxx)(4)] have a modest dependence on the K(+) concentration, folding with no or even negative cooperativity (Hill coefficients <=1), and are associated with populated folding intermediates. In contrast, GQS with tracts containing just two G's [e.g., (GGxx)(4)] have a steep dependence on the K(+) concentration and fold with positive cooperativity (Hill coefficients of 1.7-2.7) without significantly populating intermediate states. We postulate that in plants, the more stable G3 sequences are largely folded even under unstressed conditions, while the less stable G2 sequences fold only at the higher K(+) concentrations associated with cellular stress, wherein they respond sharply to changing K(+) concentrations. Given the binary nature of their folding, G2 sequences may find application in computation with DNA and in engineering of genetic circuits. PMID- 22239733 TI - Antimicrobial activity of human eosinophil granule proteins: involvement in host defence against pathogens. AB - Eosinophils have been associated with the pathophysiology of various allergic diseases and asthma. Eosinophils secrete a number of granule proteins that have been identified as effector molecules responsible for many of the actions of eosinophils. The four major eosinophil granule proteins, major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN) and eosinophil peroxidase have been shown to be involved in a number of eosinophil associated functions. EDN possesses antiviral activity against single stranded RNA viruses like respiratory syncytial virus, Hepatitis and HIV, whereas ECP and MBP have antibacterial and antiparasitic properties. This review summarizes the studies on antipathogenic activities of eosinophil granule proteins against bacteria, viruses, protozoans and helminths. PMID- 22239735 TI - Use of DNA barcodes to identify invasive armyworm Spodoptera species in Florida. AB - A critical component for sustaining adequate food production is the protection of local agriculture from invasive pest insects. Essential to this goal is the ability to accurately distinguish foreign from closely related domestic species, a process that has traditionally required identification using diagnostic morphological "keys" that can be both subtle and labor-intensive. This is the case for the Lepidopteran group of insects represented by Spodoptera, a genus of Noctuidae "armyworm" moths that includes several important agricultural pests. Two of the most destructive species, Spodoptera littoralis (Boisduval) (Lepidoptera: Noctuidae) and S. litura (F.) are not yet established in North America. To facilitate the monitoring for these pests, the feasibility of using DNA barcoding methodology for distinguishing between domestic and foreign Spodoptera species was tested. A DNA barcoding database was derived for a subset of Spodoptera species native to Florida, with an emphasis on those attracted to pheromone blends developed for S. litura or S. littoralis. These were then compared to the barcode sequences of S. litura collected from Taiwan and S. littoralis from Portugal. Consistent discrimination of the different species was obtained with phenetic relationships produced that were generally in agreement with phylogenetic studies using morphological characteristics. The data presented here indicate that DNA barcoding has the potential to be an efficient and accurate supplement to morphological methods for the identification of invasive Spodoptera pests in North America. PMID- 22239734 TI - Hamstring strain injuries: factors that lead to injury and re-injury. AB - Hamstring strain injuries (HSIs) are common in a number of sports and incidence rates have not declined in recent times. Additionally, the high rate of recurrent injuries suggests that our current understanding of HSI and re-injury risk is incomplete. Whilst the multifactoral nature of HSIs is agreed upon by many, often individual risk factors and/or causes of injury are examined in isolation. This review aims to bring together the causes, risk factors and interventions associated with HSIs to better understand why HSIs are so prevalent. Running is often identified as the primary activity type for HSIs and given the high eccentric forces and moderate muscle strain placed on the hamstrings during running these factors are considered to be part of the aetiology of HSIs. However, the exact causes of HSIs remain unknown and whilst eccentric contraction and muscle strain purportedly play a role, accumulated muscle damage and/or a single injurious event may also contribute. Potentially, all of these factors interact to varying degrees depending on the injurious activity type (i.e. running, kicking). Furthermore, anatomical factors, such as the biarticular organization, the dual innervations of biceps femoris (BF), fibre type distribution, muscle architecture and the degree of anterior pelvic tilt, have all been implicated. Each of these variables impact upon HSI risk via a number of different mechanisms that include increasing hamstring muscle strain and altering the susceptibility of the hamstrings to muscle damage. Reported risk factors for HSIs include age, previous injury, ethnicity, strength imbalances, flexibility and fatigue. Of these, little is known, definitively, about why previous injury increases the risk of future HSIs. Nevertheless, interventions put in place to reduce the incidence of HSIs by addressing modifiable risk factors have focused primarily on increasing eccentric strength, correcting strength imbalances and improving flexibility. The response to these intervention programmes has been mixed with varied levels of success reported. A conceptual framework is presented suggesting that neuromuscular inhibition following HSIs may impede the rehabilitation process and subsequently lead to maladaptation of hamstring muscle structure and function, including preferentially eccentric weakness, atrophy of the previously injured muscles and alterations in the angle of peak knee flexor torque. This remains an area for future research and practitioners need to remain aware of the multifactoral nature of HSIs if injury rates are to decline. PMID- 22239736 TI - Patterning nanoparticles in a three-dimensional matrix using an electric-field assisted gel transferring technique. AB - In this paper, we describe an electric-field-assisted gel transferring technique for patterning on two- and three-dimensional media. The transfer process starts with the preparation of a block of agarose gel doped with charged nanoparticles or molecules on top of a screen mask with desired patterns. This gel/mask construct is then brought into contact with the appropriate receiving medium, such as a polymer membrane or a piece of flat hydrogel. An electric field is applied to transfer the doped charged nanoparticles or molecules into the receiving medium with a pattern defined by the screen mask. This printing method is rapid and convenient, the results are reproducible, and the process can be done without using expensive micro/nanofabrication facilities. The capability to pattern structures such as arrays of nanoparticles into three-dimensional hydrogels may find applications for positioning cell signaling molecules to control cell growth and migration. PMID- 22239737 TI - An integrative variant analysis suite for whole exome next-generation sequencing data. AB - BACKGROUND: Whole exome capture sequencing allows researchers to cost-effectively sequence the coding regions of the genome. Although the exome capture sequencing methods have become routine and well established, there is currently a lack of tools specialized for variant calling in this type of data. RESULTS: Using statistical models trained on validated whole-exome capture sequencing data, the Atlas2 Suite is an integrative variant analysis pipeline optimized for variant discovery on all three of the widely used next generation sequencing platforms (SOLiD, Illumina, and Roche 454). The suite employs logistic regression models in conjunction with user-adjustable cutoffs to accurately separate true SNPs and INDELs from sequencing and mapping errors with high sensitivity (96.7%). CONCLUSION: We have implemented the Atlas2 Suite and applied it to 92 whole exome samples from the 1000 Genomes Project. The Atlas2 Suite is available for download at http://sourceforge.net/projects/atlas2/. In addition to a command line version, the suite has been integrated into the Genboree Workbench, allowing biomedical scientists with minimal informatics expertise to remotely call, view, and further analyze variants through a simple web interface. The existing genomic databases displayed via the Genboree browser also streamline the process from variant discovery to functional genomics analysis, resulting in an off-the-shelf toolkit for the broader community. PMID- 22239738 TI - An in vivo canine study to assess granulomatous responses in the MedStream Programmable Infusion System (TM) and the SynchroMed II Infusion System(r). AB - OBJECTIVE: A rare, but consistently reported complication of intrathecal (IT) delivery of opioids via programmable implantable infusion pumps is aseptic granuloma formation around the tip of the IT catheter. In the current study, the incidence and severity of IT granuloma formation was assessed for the MedStream Programmable Infusion and SynchroMed II Infusion pumps when delivering saline, baclofen, or morphine at varying concentrations and daily doses. DESIGN: Randomized study with six groups: 1) MedStream with 0.9% saline; 2) SynchroMed II with 0.9% saline; 3) MedStream with morphine sulfate; 4) SynchroMed II with morphine sulfate; 5) MedStream with baclofen; or 6) SynchroMed II with baclofen. The groups receiving morphine received either low or high concentrations (6 or 12.5 mg/mL) delivered in rates resulting in low to high (1.25-12 mg/day) daily doses. Animals receiving baclofen began at low dose/low concentration and underwent stepwise increases in concentration and dose to a maximum of 2 mg/mL/day. Animals receiving saline received a constant flow rate through either a silicone or a polyurethane IT catheter. SETTING: The study was set as in vivo laboratory experiment. SUBJECTS: 52 (21-32 kg) canines. INTERVENTIONS: Delivering IT saline, baclofen, or morphine through SynchroMed II and MedStream Programmable Infusion pumps. OUTCOME MEASURES: The incidence and severity of IT catheter tip granuloma formation was assessed with paraffin-embedded spinal cord sections by a pathologist without knowledge of treatment and compared between drug type, drug concentration, daily dose, and pump type. RESULTS: Granuloma formation occurred only in animals receiving morphine, with zero incidence in baclofen or saline infusion, regardless of catheter type. Granuloma incidence increased with increasing morphine concentration or daily dose (one [12.5%] low dose/low concentration, 3 [37.5%] low dose/high concentrations, 4 [50%] high dose/low concentration, and 7 [100%] high dose/high concentration). A granulomatous response to morphine was observed in 10 (63%) animals with SynchroMed II pumps and 5 (33%) animals with MedStream pumps, P = 0.156. CONCLUSIONS: In this in vivo canine model of IT drug delivery, catheter tip granuloma formation was associated with higher concentrations and daily doses of morphine infusion while none were seen with baclofen or saline, and was not associated with catheter type. For both pumps, granulomas were only produced in the presence of morphine infusion. These results suggest that the MedStream Programmable Infusion System has a granuloma safety profile at least equivalent to that of the SynchroMed II pump. PMID- 22239739 TI - Chemoenzymatic synthesis of uridine diphosphate-GlcNAc and uridine diphosphate GalNAc analogs for the preparation of unnatural glycosaminoglycans. AB - Eight N-acetylglucosamine-1-phosphate and N-acetylgalactosamine-1-phosphate analogs have been synthesized chemically and were tested for their recognition by the GlmU uridyltransferase enzyme. Among these, only substrates that have an amide linkage to the C-2 nitrogen were transferred by GlmU to afford their corresponding uridine diphosphate(UDP)-sugar nucleotides. Resin-immobilized GlmU showed comparable activity to nonimmobilized GlmU and provides a more facile final step in the synthesis of an unnatural UDP-donor. The synthesized unnatural UDP-donors were tested for their activity as substrates for glycosyltransferases in the preparation of unnatural glycosaminoglycans in vitro. A subset of these analogs was useful as donors, increasing the synthetic repertoire for these medically important polysaccharides. PMID- 22239740 TI - Propene poisoning on three typical Fe-zeolites for SCR of NOchi with NH3: from mechanism study to coating modified architecture. AB - Application of Fe-zeolites for urea-SCR of NO(x) in diesel engine is limited by catalyst deactivation with hydrocarbons (HCs). In this work, a series of Fe zeolite catalysts (Fe-MOR, Fe-ZSM-5, and Fe-BEA) was prepared by ion exchange method, and their catalytic activity with or without propene for selective catalytic reduction of NO(x) with ammonia (NH(3)-SCR) was investigated. Results showed that these Fe-zeolites were relatively active without propene in the test temperature range (150-550 degrees C); however, all of the catalytic activity was suppressed in the presence of propene. Fe-MOR kept relatively higher activity with almost 80% NO(x) conversion even after propene coking at 350 degrees C, and 38% for Fe-BEA and 24% for Fe-ZSM-5 at 350 degrees C, respectively. It was found that the pore structures of Fe-zeolite catalysts were one of the main factors for coke formation. As compared to ZSM-5 and HBEA, MOR zeolite has a one-dimensional structure for propene diffusion, relatively lower acidity, and is not susceptible to deactivation. Nitrogenated organic compounds (e.g., isocyanate) were observed on the Fe-zeolite catalyst surface. The site blockage was mainly on Fe(3+) sites, on which NO was activated and oxidized. Furthermore, a novel fully formulated Fe BEA monolith catalyst coating modified with MOR was designed and tested, the deactivation due to propene poisoning was clearly reduced, and the NO(x) conversion reached 90% after 700 ppm C(3)H(6) exposure at 500 degrees C. PMID- 22239741 TI - Validation of self-reported erythema: comparison of self-reports, researcher assessment and objective measurements in sun worshippers and skiers. AB - BACKGROUND: Most epidemiological data of sunburn related to skin cancer have come from self-reporting in diaries and questionnaires. We thought it important to validate the reliability of such data. OBJECTIVE: To validate the quality of self reported erythema by sun worshippers and skiers, and to validate the ability to determine erythema visually compared with objectively measured erythema. METHODS: The skin in a group of sun worshippers in Tenerife and of skiers in Austria was closely monitored over a week. The participants used a diary to record any erythema assessed on different skin sites and underwent a twice daily skin examination by researchers who assessed erythema on the same sites. Lastly, the erythema assessment was validated by objective measurements. RESULTS: We found that the participants' agreed with researchers' assessment of erythema in only 57 61% of cases, and that the researchers detected up to 28% more of the objectively measured erythema than the participants did. We also found that, even for the trained eye (researchers), it was difficult to detect an increase in erythema as only 71-91% of those cases with an increase >15 in measured erythema percentage were detected in the evening. Possibly, detection was impeded by a simultaneous increase in pigmentation. CONCLUSION: Self-assessment of erythema from diaries is unreliable. Erythema is considerably underestimated and possibly neglected. Even for the trained eye, it can be difficult to detect erythema. PMID- 22239742 TI - Comparing gender awareness in Dutch and Swedish first-year medical students- results from a questionaire. AB - BACKGROUND: To ascertain good and appropriate healthcare for both women and men implementation of gender perspectives in medical education is needed. For a successful implementation, knowledge about students' attitudes and beliefs about men, women, and gender is crucial. The aim of this study was to compare attitudes to gender and gender stereotyping among Dutch and Swedish male and female medical students. METHODS: In this cross-sectional study, we measured the attitudes and assumptions about gender among 1096 first year medical students (616 Dutch and 480 Swedish) with the validated Nijmegen Gender Awareness in Medicine Scale (N GAMS). The response rate was 94% in the Netherlands and 93% in Sweden. Univariate analysis of variance (ANOVA) was used to compare the scores between Dutch and Swedish male and female students. Linear regressions were used to analyze the importance of the background variables. RESULTS: There were significant differences in attitudes to gender between Dutch and Swedish students. The Swedish students expressed less stereotypical thinking about patients and doctors and the Dutch were more sensitive to gender differences. The students' sex mattered for gender stereotyping, with male students in both countries agreeing more with stereotypical statements. Students' age, father's birth country and mother's education level had some impact on the outcome. CONCLUSIONS: There are differences between cultures as well as between men and women in gender awareness that need to be considered when implementing gender in medical education.This study suggests that to arouse the students' interest in gender issues and make them aware of the significance of gender in medical work, the examples used in discussions need to be relevant and challenging in the context of the specific country. Due to different levels of knowledge and different attitudes within the student population it is important to create a climate for dialogue where students feel permitted to disclose their ideas and attitudes in order to become aware of what these are as well as their possible consequences on interaction and decision-making in medical work. PMID- 22239743 TI - Time to treatment for patients receiving BCS in a public and a private university hospital in Atlanta. AB - Delays in treatment for breast cancer can lead to poorer patient outcome. We analyzed time to treatment among female patients receiving breast-conserving surgery in two different hospital settings, public versus private. Retrospective chart review revealed 270 patients diagnosed during 2004-2008. Three consecutive time intervals were defined (Initial abnormal imaging [I] to core biopsy [II] to surgery /pathology staging [III] to oncology evaluation for adjuvant treatment). Multivariate analyses investigated hospital type and demographic factors. Overall median treatment time was 83 days, Interval II accounting for the longest (43 days). Only 55% of patients received the entire spectrum of care within 90 days; for each consecutive 30-day interval, percentages varied dramatically: 80.7%, 31.1%, and 68.9%.Public hospital patients experienced longer overall time to treatment than private patients (94 versus 77 days, p < 0.001); these differences persisted throughout the intervals. Longer wait times were experienced by African Americans versus Caucasians (89 versus 64 days, p = 0.003), unmarried versus married patients (93 versus 70 days, p < 0.001), and Medicaid-insured patients, p < 0.001. In multivariate analyses, hospital type, race, marital status, and insurance predicted timely treatment within one or more intervals. For patients undergoing breast-conserving therapy, time to treatment differs between private and public settings. However, barriers to timely treatment arise from both system based issues and patient socio-demographic factors. Studies are needed to evaluate and intervene on this intricate connection. PMID- 22239744 TI - Predictors of unintended pregnancy in Kersa, eastern Ethiopia, 2010. AB - BACKGROUND: In Ethiopia, little is known about pregnancy among rural women. Proper maternal health care depends on clear understanding of the reproductive health situation. The objective of this study was to identify predictors of unintended pregnancy in rural eastern Ethiopia. METHODOLOGY: This study was part of pregnancy surveillance at Kersa Demographic Surveillance and Health Research Center, East Ethiopia. Pregnant women were assessed whether their current pregnancy was intended or not. Data were collected by lay interviewers using uniform questionnaire. Odds Ratio, with 95% confidence interval using multiple and multinomial logistic regression were calculated to detect level of significance. RESULTS: Unintended pregnancy was reported by 27.9% (578/2072) of the study subjects. Out of which, 440 were mistimed and 138 were not wanted. Unintended pregnancy was associated with family wealth status (OR 1.47; 95% CI 1.14, 1.90), high parity (7 +) (OR 5.18; 95% CI 3.31, 8.12), and a longer estimated time to walk to the nearest health care facility (OR 2.24; 95% CI: 1.49, 3.39).In the multinomial regression, women from poor family reported that their pregnancy was mistimed (OR 1.69; 95% CI 1.27, 2.25). The longer estimated time (80 + minutes) to walk to the nearest health care facility influenced the occurrence of mistimed pregnancy (OR 2.58; 95% CI: 1.65, 4.02). High parity (7+) showed a strong association to mistimed and unwanted pregnancies (OR 3.11; 95% CI 1.87, 5.12) and (OR 14.34; 95% CI 5.72, 35.98), respectively. CONCLUSIONS: The economy of the family, parity, and walking distance to the nearest health care institution are strong predictors of unintended pregnancy. In order to reduce the high rate of unintended pregnancy Efforts to reach rural women with family planning services should be strengthened. PMID- 22239745 TI - Associations of instrumental activities of daily living and handgrip strength with oral self-care among home-dwelling elderly 75+. AB - OBJECTIVE: To study the associations of instrumental activities of daily living (IADL) and the handgrip strength with oral self-care among dentate home-dwelling elderly people in Finland. MATERIALS AND METHODS: The study analysed data for 168 dentate participants (mean age 80.6 years) in the population-based Geriatric Multidisciplinary Strategy for Good Care of the Elderly (GeMS) study. Each participant received a clinical oral examination and structured interview in 2004 2005. Functional status was assessed using the IADL scale and handgrip strength was measured using handheld dynamometry. RESULTS: Study participants with high IADL (scores 7-8) had odds ratios (ORs) for brushing their teeth at least twice a day of 2.7 [95% confidence intervals (CI) 1.1-6.8], for using toothpaste at least twice a day of 2.0 (CI 0.8-5.2) and for having good oral hygiene of 2.8 (CI 1.0 8.3) when compared with participants with low IADL (scores <=6). Participants in the upper tertiles of the handgrip strength had ORs for brushing the teeth at least twice a day of 0.9 (CI 0.4-1.9), for using the toothpaste at least twice a day of 0.9 (CI 0.4-1.8) and for good oral hygiene of 1.1 (CI 0.5-2.4) in comparison with the study subjects in the lowest tertile of handgrip strength. CONCLUSION: The results of this study suggest that the functional status, measured by means of the IADL scale, but not handgrip strength, is an important determinant of oral self-care among the home-dwelling elderly. PMID- 22239746 TI - Infrared spectroscopy of Si(CO)n+ complexes: evidence for asymmetric coordination. AB - Si(CO)(n)(+) and Si(CO)(n)(+)Ar complexes are produced via laser vaporization with a pulsed nozzle source and cooled in a supersonic beam. The ions are mass selected in a reflectron time-of-flight mass spectrometer and studied with infrared laser photodissociation spectroscopy near the free molecular CO vibration (2143 cm(-1)). Si(CO)(n)(+) complexes larger than n = 2 fragment by the loss of CO, whereas Si(CO)(n)(+)Ar complexes fragment by the loss of argon. All clusters have resonances near the free molecular CO stretch that provide distinctive patterns from which information on their structure and bonding can be obtained. The number of infrared-active bands, their frequency positions, and relative intensities indicate that larger species consist of an asymmetrically coordinated Si(CO)(2)(+) core with additional CO ligands attached via van der Waals interactions. Density functional theory computations are carried out in support of the experimental spectra. PMID- 22239747 TI - Time to take stock: a meta-analysis and systematic review of analgesic treatment disparities for pain in the United States. AB - BACKGROUND: The recent Institute of Medicine Report assessing the state of pain care in the United States acknowledged the lack of consistent data to describe the nature and magnitude of unrelieved pain and identify subpopulations with disproportionate burdens. OBJECTIVES: We synthesized 20 years of cumulative evidence on racial/ethnic disparities in analgesic treatment for pain in the United States. Evidence was examined for the 1) magnitude of association between race/ethnicity and analgesic treatment; 2) subgroups at an increased risk; and 3) the effect of moderators (pain type, setting, study quality, and data collection period) on this association. METHODS: United States studies with at least one explicit aim or analysis comparing analgesic treatment for pain between Whites and a minority group were included (SciVerse Scopus database, 1989-2011). RESULTS: Blacks/African Americans experienced both a higher number and magnitude of disparities than any other group in the analyses. Opioid treatment disparities were ameliorated for Hispanics/Latinos for "traumatic/surgical" pain (P = 0.293) but remained for "non-traumatic/nonsurgical" pain (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.64-0.77, P = 0.000). For Blacks/African Americans, opioid prescription disparities were present for both types of pain and were starker for "non-traumatic/nonsurgical" pain (OR = 0.66, 95% CI = 0.59-0.75, P = 0.000). In subanalyses, opioid treatment disparities for Blacks/African Americans remained consistent across pain types, settings, study quality, and data collection periods. CONCLUSION: Our study quantifies the magnitude of analgesic treatment disparities in subgroups of minorities. The size of the difference was sufficiently large to raise not only normative but quality and safety concerns. The treatment gap does not appear to be closing with time or existing policy initiatives. A concerted strategy is needed to reduce pain care disparities within the larger quality of care initiatives. PMID- 22239748 TI - Single-molecule dynamics of lysozyme processing distinguishes linear and cross linked peptidoglycan substrates. AB - The dynamic processivity of individual T4 lysozyme molecules was monitored in the presence of either linear or cross-linked peptidoglycan substrates. Single molecule monitoring was accomplished using a novel electronic technique in which lysozyme molecules were tethered to single-walled carbon nanotube field-effect transistors through pyrene linker molecules. The substrate-driven hinge-bending motions of lysozyme induced dynamic electronic signals in the underlying transistor, allowing long-term monitoring of the same molecule without the limitations of optical quenching or bleaching. For both substrates, lysozyme exhibited processive low turnover rates of 20-50 s(-1) and rapid (200-400 s(-1)) nonproductive motions. The latter nonproductive binding events occupied 43% of the enzyme's time in the presence of the cross-linked peptidoglycan but only 7% with the linear substrate. Furthermore, lysozyme catalyzed the hydrolysis of glycosidic bonds to the end of the linear substrate but appeared to sidestep the peptide cross-links to zigzag through the wild-type substrate. PMID- 22239749 TI - Preventing chronic disease in women of reproductive age: opportunities for health promotion and preventive services. PMID- 22239750 TI - An ecological model using promotores de salud to prevent cardiovascular disease on the US-Mexico border: the HEART project. AB - BACKGROUND: To address cardiovascular disease risk factors among Hispanics, a community model of prevention requires a comprehensive approach to community engagement. The objectives of our intervention were to reduce cardiovascular disease risk factors in Hispanics living in 2 low-income areas of El Paso, Texas, and to engage the community in a physical activity and nutrition intervention. METHODS: Drawing on lessons learned in phase 1 (years 2005-2008) of the HEART Project, we used an iterative, community-based process to develop an intervention based on an ecological framework. New community partners were introduced and community health workers delivered several elements of the intervention, including the curriculum entitled "Mi Corazon, Mi Comunidad" ("MiCMiC" [My Heart, My Community]). We received feedback from the project's Community Health Academy and Leadership Council throughout the development process and established a policy agenda that promotes integration of community health workers into the local and state workforce. OUTCOME: Collaboration with 2 new community partners, the YWCA and the Department of Parks and Recreation, were instrumental in the process of community-based participatory research. We enrolled 113 participants in the first cohort; 78% were female, and the mean age was 41 years. More than 50% reported having no health insurance coverage. Seventy-two (60%) participants attended 1 or more promotora-led Su Corazon, Su Vida sessions, and 74 (62%) participants attended 1 or more of the 15 exercise classes. INTERPRETATION: HEART phase 2 includes a multilevel ecological model to address cardiovascular disease risk among Hispanics. Future similarly targeted initiatives can benefit from an ecological approach that also embraces the promotora model. PMID- 22239751 TI - Intervention mapping as a guide for the development of a diabetes peer support intervention in rural Alabama. AB - INTRODUCTION: Peer support is a promising strategy for the reduction of diabetes related health disparities; however, few studies describe the development of such strategies in enough detail to allow for replication. The objective of this article is to describe the development of a 1-year peer support intervention to improve diabetes self-management among African American adults with diabetes in Alabama's Black Belt. METHODS: We used principles of intervention mapping, including literature review, interviews with key informants, and a discussion group with community health workers, to guide intervention development. Qualitative data were combined with behavioral constructs and principles of diabetes self-management to create a peer support intervention to be delivered by trained peer advisors. Feedback from a 1-month pilot was used to modify the training and intervention. RESULTS: The resulting intervention includes a 2-day training for peer advisors, who were each paired with 3 to 6 clients. A one-on one in-person needs assessment begins an intensive intervention phase conducted via telephone for 8 to 12 weeks, followed by a maintenance phase of at least once monthly contacts for the remainder of the intervention period. A peer support network and process measures collected monthly throughout the study supplement formal data collection points at baseline, 6 months, and 12 months. DISCUSSION: Intervention mapping provided a useful framework for the development of culturally relevant diabetes peer support intervention for African Americans living in Alabama's Black Belt. The process described could be implemented by others in public health to develop or adapt programs suitable for their particular community or context. PMID- 22239752 TI - A decade of sustaining best practices for tobacco control: Indiana's story. AB - The Indiana Tobacco Prevention and Cessation Agency (ITPC) was created in 2000 to address high tobacco use rates. This independent state agency, using Centers for Disease Control and Prevention (CDC) Best Practices for Comprehensive Tobacco Control Programs, administered a comprehensive program that supported community health coalitions and evidence-based public policy changes. From 2000 to 2011, ITPC operated in difficult budgetary and political environments and with less than 20% of the funding recommended by CDC. ITPC and its partners enabled social and cultural changes, reduced cigarette use rates, and increased the number of community smoke-free environments. Public health leaders in Indiana agreed that the independent agency model was effective in reducing the costs associated with tobacco-use-related disease and death. Despite broad public support for ITPC and its work, on April 29, 2011, the Indiana legislature passed a controversial budget bill that abolished the ITPC executive board and transferred its budget and function to the Indiana State Department of Health (ISDH). Although the tobacco control program is not insulated from political interference, the ISDH commissioner has created a new Tobacco Prevention and Cessation Commission, whose members report directly to him, with commitment to continue the programmatic focus of the former ITPC. Restoring full funding to the tobacco control program is necessary if Indiana's goal of decreasing the health care and business costs of tobacco use-related diseases are to be achieved. PMID- 22239753 TI - Price and healthfulness of snacks in 32 YMCA after-school programs in 4 US metropolitan areas, 2006-2008. AB - INTRODUCTION: A common perception is that healthful foods are more expensive than less healthful foods. We assessed the cost of beverages and foods served at YMCA after-school programs, determined whether healthful snacks were more expensive, and identified inexpensive, healthful options. METHODS: We collected daily snack menus from 32 YMCAs nationwide from 2006 to 2008 and derived prices of beverages and foods from the US Department of Agriculture price database. Multiple linear regression was used to assess associations of healthful snacks and of beverage and food groups with price (n = 1,294 snack-days). We identified repeatedly served healthful snacks consistent with Child and Adult Care Food Program guidelines and reimbursement rate ($0.74/snack). RESULTS: On average, healthful snacks were approximately 50% more expensive than less healthful snacks ($0.26/snack; SE, 0.08; P = .003). Compared to water, 100% juice significantly increased average snack price, after controlling for other variables in the model. Similarly, compared to refined grains with trans fats, refined grains without trans fat significantly increased snack price, as did fruit and canned or frozen vegetables. Fresh vegetables (mostly carrots or celery) or whole grains did not alter price. Twenty-two repeatedly served snacks met nutrition guidelines and the reimbursement rate. CONCLUSION: In this sample of after-school programs, healthful snacks were typically more expensive than less healthful options; however, we identified many healthful snacks served at or below the price of less healthful options. Substituting tap water for 100% juice yielded price savings that could be used toward purchasing more healthful foods (eg, an apple). Our findings have practical implications for selecting snacks that meet health and reimbursement guidelines. PMID- 22239754 TI - Dietary calcium and risk for prostate cancer: a case-control study among US veterans. AB - OBJECTIVE: The objective of this study was to examine the association between calcium intake and prostate cancer risk. We hypothesized that calcium intake would be positively associated with lower risk for prostate cancer. METHODS: We used data from a case-control study conducted among veterans between 2007 and 2010 at the Durham Veterans Affairs Medical Center. The study consisted of 108 biopsy-positive prostate cancer cases, 161 biopsy-negative controls, and 237 healthy controls. We also determined whether these associations differed for blacks and whites or for low-grade (Gleason score <7) and high-grade prostate cancer (Gleason score >=7). We administered the Harvard food frequency questionnaire to assess diet and estimate calcium intake. We used logistic regression models to obtain odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Intake of calcium from food was inversely related to risk for prostate cancer among all races in a comparison of cases and biopsy-negative controls (P = .05) and cases and healthy controls (P = .02). Total calcium was associated with lower prostate cancer risk among black men but not among white men in analyses of healthy controls. The highest tertile of calcium from food was associated with lower risk for high-grade prostate cancer in a comparison of high-grade cases and biopsy-negative controls (OR, 0.37; 95% CI, 0.15-0.90) and high-grade cases and healthy controls (OR, 0.38; 95% CI, 0.17-0.86). CONCLUSION: Calcium from food is associated with lower risk for prostate cancer, particularly among black men, and lower risk for high-grade prostate cancer among all men. PMID- 22239755 TI - Diagnosis and treatment of vaginal intraepithelial neoplasia. AB - OBJECTIVE: To audit our experience of the diagnosis and treatment of vaginal intraepithelial neoplasia (VAIN) in Kandang Kerbau Women's Hospital, Singapore. METHODS: The clinical records of the patients diagnosed as having VAIN at our institution in the calendar year 2009 were periodically reviewed until March 2011. RESULTS: There were 21 cases of VAIN. The mean follow-up duration was 18.2 months. The lesion grades were VAIN 1 in 9 patients (42.9%), VAIN 2 in 9 patients (42.9%), and VAIN 3 in 3 patients (14.3%). The mean patient age was 39.1 years. Sixteen patients (76.2%) were referred to our institution because of abnormal results to cytology tests and 4 patients (21.9%) were referred because of vaginal warts. The remaining patient was diagnosed from a surgical specimen. The diagnosis involved a cytology test, a colposcopic examination, an acetowhite test, a Schiller test, and a colposcopy-directed biopsy. The treatments varied and included watchful waiting but carbon dioxide laser vaporization was used the most frequently. CONCLUSION: After 6 months of follow-up 18 patients were considered cured, for an overall cure rate of 85.7%. Two patients wanted no treatment and disease remained persistent in 1 patient despite laser vaporization and intravaginal applications of imiquimod cream. PMID- 22239756 TI - Ovarian pregnancy in a patient with a levonorgestrel intrauterine system in situ. PMID- 22239758 TI - Can achievement goal theory provide a useful motivational perspective for explaining psychosocial attributes of medical students? AB - BACKGROUND: Psychosocial competence and frustration tolerance are important characteristics of skilled medical professionals. In the present study we explored the usefulness of applying a comprehensive motivational theory (Goal orientations), for this purpose. According to goal orientation theory, learning motivation is defined as the general goals students pursue during learning (either mastery goals - gaining new knowledge; or performance goals - gaining a positive evaluation of competence or avoiding negative evaluation). Perceived psychosocial abilities are a desirable outcome, and low frustration tolerance (LFT), is a negative feature of student behavior. The hypothesis was that the mastery goal would be positively associated with psychosocial abilities while performance goals would be positively associated with LFT. METHODS: 143 first year medical students completed at the end of an annual doctor-patient communication course a structured questionnaire that included measures of learning goal orientations (assessed by Pattern of Adaptive Learning Scale - PALS), psychosocial abilities (assessed by Psychological Medicine Inventory- student version -PMI-S) and Low Frustration Tolerance (LFT). RESULTS: All study variables were found reliable (Cronbach's alpha ranged from .66 to .90) and normally distributed. Hierarchical multiple regression analysis revealed significant associations supporting the hypotheses. The mastery goal orientation was positively associated with perceived psychosocial abilities (PMI-S) (beta = .16, p < .05) and negatively associated with low frustration tolerance (beta = .22, p < .05) while performance goal orientation was significantly associated with low frustration tolerance (beta = .36, p < .001). CONCLUSIONS: The results suggest that the goal orientations theory may be a useful theoretical framework for understanding and facilitating learning motivation among medical students. Limitations and suggestions for practice within medical education context are discussed. PMID- 22239757 TI - Lim homeobox genes in the Ctenophore Mnemiopsis leidyi: the evolution of neural cell type specification. AB - BACKGROUND: Nervous systems are thought to be important to the evolutionary success and diversification of metazoans, yet little is known about the origin of simple nervous systems at the base of the animal tree. Recent data suggest that ctenophores, a group of macroscopic pelagic marine invertebrates, are the most ancient group of animals that possess a definitive nervous system consisting of a distributed nerve net and an apical statocyst. This study reports on details of the evolution of the neural cell type specifying transcription factor family of LIM homeobox containing genes (Lhx), which have highly conserved functions in neural specification in bilaterian animals. RESULTS: Using next generation sequencing, the first draft of the genome of the ctenophore Mnemiopsis leidyi has been generated. The Lhx genes in all animals are represented by seven subfamilies (Lhx1/5, Lhx3/4, Lmx, Islet, Lhx2/9, Lhx6/8, and LMO) of which four were found to be represented in the ctenophore lineage (Lhx1/5, Lhx3/4, Lmx, and Islet). Interestingly, the ctenophore Lhx gene complement is more similar to the sponge complement (sponges do not possess neurons) than to either the cnidarian bilaterian or placozoan Lhx complements. Using whole mount in situ hybridization, the Lhx gene expression patterns were examined and found to be expressed around the blastopore and in cells that give rise to the apical organ and putative neural sensory cells. CONCLUSION: This research gives us a first look at neural cell type specification in the ctenophore M. leidyi. Within M. leidyi, Lhx genes are expressed in overlapping domains within proposed neural cellular and sensory cell territories. These data suggest that Lhx genes likely played a conserved role in the patterning of sensory cells in the ancestor of sponges and ctenophores, and may provide a link to the expression of Lhx orthologs in sponge larval photoreceptive cells. Lhx genes were later co-opted into patterning more diversified complements of neural and non-neural cell types in later evolving animals. PMID- 22239759 TI - Self-assembly of biofunctional polymer on graphene nanoribbons. AB - Graphene's adhesive properties owing to inherent van der Waals interactions become increasingly relevant in the nanoscale regime. Polymer self-assembly via graphene-mediated noncovalent interactions offers a powerful tool for the creation of anisotropic nanopatterned systems. Here, we report the supramolecular self-assembly of biofunctional-modified poly(2-methoxystyrene) on graphene nanoribbons prepared by unzipping multiwalled carbon nanotubes. This approach promotes the glycol-modified polymer to self-assemble into structured nanopatterns with preserved bioactivity. The self-assembly is attributed to enhanced van der Waals interactions and the associated charge transfer from polymer to graphene. These findings demonstrate that the assembly yields a prospective route to novel nanomaterial systems. PMID- 22239760 TI - Presentation battles. PMID- 22239761 TI - Galectin fingerprinting detects differences in expression profiles between bovine endometrium and placentomes as well as early and late gestational stages. AB - The concept of a network within the family of adhesion/growth regulatory galectins implies distinct spatio-temporal expression profiles. To test this assumption immunohistochemically for bovine placenta, placentomal (P) and interplacentomal tissues (IP) were collected at a slaughterhouse from the three stages of pregnancy (early gestation = day 30-130; mid gestation = day 130-220; late gestation = day 220-275). The specimens were snap-frozen or fixed in Bouin's solution, then embedded in paraffin. Gene expression for galectins-1, -3, -4 and 9 in P and IP of late gestational stages was monitored by RT-PCR. Galectin-type specific antibodies were used for immunohistochemical localization. In IP, galectin-1 was present in stroma cells and early gestational trophoblast giant cells (TGC), whereas galectin-3 was confined to uterine epithelial cells. In contrast, both galectins were found in epithelia of P tissue. Uterine epithelial cells and blood vessel walls were positive for galectin-4, while galectin-9 was detected predominantly in uterine epithelial cells and late gestational TGC. Our study thus reveals individual profiles among the galectins tested, an indication for specific functions exerted by each protein in the bovine endometrium and placenta. PMID- 22239762 TI - Investigation of confined placental mosaicism by CGH in IVF and ICSI pregnancies. AB - BACKGROUND: Assisted reproductive technologies include in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). It has been shown that embryos derived from ART have higher rates of aneuploidy. Although the majority of ART pregnancies are genetically normal, it is suspected that aneuploid embryos may persist as mosaics and lead to confined placental mosaicism (CPM). Due to the greater risks of sperm aneuploidy in infertile men, CPM may be more prevalent in ICSI than IVF pregnancies. In this report, we investigated the prevalence of CPM in IVF and ICSI pregnancies using comparative genomic hybridization and flow cytometry. METHODS: The placenta and umbilical cord blood were collected after birth. To determine the presence of CPM, karyotypes of umbilical cord blood were compared to the results of placental analyses. For each placenta, multiple villous sites were investigated for DNA gains/losses and polyploidy using comparative genomic hybridization and flow cytometry. Detected abnormalities were further confirmed by fluorescent in-situ hybridization (FISH). RESULTS: In total, 134 IVF/ICSI cases were investigated. CPM was detected in five of these cases (5/134) giving an overall rate of 3.73%. CPM was detected in one IVF case (1/31; 3.23%) and four ICSI cases (4/103; 3.88%). The prevalence of CPM in IVF and ICSI pregnancies was not statistically different from each other. CPM was not observed in 13 ICSI and 6 IVF cases that were determined to be small for gestational age (SGA). CONCLUSIONS: The prevalence of CPM in ICSI pregnancies is not greater than IVF pregnancies. In addition, the overall prevalence of CPM in ART pregnancies (IVF and ICSI) is similar to that of the general population. CPM was not observed in the limited cases that were affected by small for gestational age. Our results suggest that ART pregnancies are not at a greater risk for CPM. PMID- 22239763 TI - Stochastic simulation of chemically reacting systems using multi-core processors. AB - In recent years, computer simulations have become increasingly useful when trying to understand the complex dynamics of biochemical networks, particularly in stochastic systems. In such situations stochastic simulation is vital in gaining an understanding of the inherent stochasticity present, as these models are rarely analytically tractable. However, a stochastic approach can be computationally prohibitive for many models. A number of approximations have been proposed that aim to speed up stochastic simulations. However, the majority of these approaches are fundamentally serial in terms of central processing unit (CPU) usage. In this paper, we propose a novel simulation algorithm that utilises the potential of multi-core machines. This algorithm partitions the model into smaller sub-models. These sub-models are then simulated, in parallel, on separate CPUs. We demonstrate that this method is accurate and can speed-up the simulation by a factor proportional to the number of processors available. PMID- 22239764 TI - Extended hydrodynamic approach to quantum-classical nonequilibrium evolution. II. Application to nonpolar solvation. AB - The mixed quantum-classical formulation derived in our companion paper [D. Bousquet, K. H. Hughes, D. Micha, and I. Burghardt, J. Chem. Phys. 134, 064116 (2011)], which is based upon a hydrodynamic representation of the classical sector, is applied to nonequilibrium nonpolar solvation dynamics as exemplified by the solvation of the electronically excited NO molecule in a rare gas environment. Derived from a partition of the Hamiltonian into a primary (quantum) part and a secondary (classical) part the hydrodynamic equations are formulated for multi-quantum states and result in explicit equations of motion for populations and coherences. The hierarchy of hydrodynamic equations is truncated by the following approximate closure schemes: Gauss-Hermite closure, dynamical density functional theory approximation, and a generalized Maxwellian closure. A comparison of the dynamics using these three closure methods showed that the suitability of a particular closure scheme was dependent on the initial conditions and the nonequilibrium character of the dynamics. PMID- 22239765 TI - Basis set dependence of higher-order correlation effects in pi-type interactions. AB - The basis set dependence of higher-order correlation effects on pi-type interaction energies was examined by scanning the potential energy surfaces of five dimer systems. The dimers of acetylene (H-C=C-H), diacetylene (H-C=C-C=C-H), cyanogen (N=C-C=N), diphosphorous (P=P), and 1,4-diphosphabutadiyne (P=C-C=P) were studied in three different configurations: cross, parallel-displaced, and t shaped. More than 800 potential energy curves (PECs) were generated by computing the interaction energies for all 15 dimer configurations over a range of intermolecular distances with the MP2, coupled-cluster single double (CCSD), and coupled-cluster single double triple (CCSD(T)) methods in conjunction with 21 basis sets ranging from a small 6-31G*(0.25) split-valence basis set to a large aug-cc-pVQZ correlation consistent basis set. Standard extrapolation techniques were also used to construct MP2, CCSD, and CCSD(T) complete basis set (CBS) limit PECs as well as CBS limit higher-order correlation corrections based on the differences between CCSD(T) and MP2 interaction energies, denoted delta(MP2)(CCSD(T)), and the corresponding differences between CCSD(T) and CCSD interactions energies, denoted delta(CCSD)(CCSD(T)). Double-zeta basis sets struggled to reproduce the former but provided quite reasonable descriptions of the latter as long as diffuse functions were included. The aug-cc-pVDZ basis deviated from the delta(CCSD)(CCSD(T)) CBS limit by only 0.06 kcal mol(-1) on average and never by more than 0.24 kcal mol(-1), whereas the corresponding deviations were approximately twice that for the delta(MP2)(CCSD(T)) term. While triple-zeta basis sets typically improved results, only aug-cc-pVTZ provided appreciable improvement over utilizing the aug-cc-pVDZ basis set to compute delta(CCSD)(CCSD(T)). Counterpoise (CP) corrections were also applied to all double- and triple-zeta basis sets, but they rarely yielded a better description of these higher-order correlation effects. CP corrections only consistently improved results when the aug-cc-pVDZ basis set was used to compute delta(MP2)(CCSD(T)), yielding mean and maximum absolute deviations from the CBS values of 0.10 and 0.39 kcal mol(-1), respectively, for all five dimer systems. PMID- 22239766 TI - Long-range correlation energies from frequency-dependent weighted exchange-hole dipole polarisabilities. AB - Long-range correlation energies are calculated using an approximation of the single-particle density-density response function of the system that leads to an expression requiring only occupied orbitals and eigenvalues. Dipole-dipole polarisabilities and isotropic leading-order dispersion coefficients obtained from this approximation are shown to be in a reasonable agreement with corresponding values from the experiment or dipole oscillator strength distributions. The localised polarisabilities were used to calculate a long-range correlation correction to a hybrid-generalised gradient approximation functional using a proper damping function at short ranges. It was found that the hybrid density-functional theory+dispersion method obtained in this way has a comparable accuracy than high-level ab initio wave function methods at a much lower computational cost. This has been analysed for a number of systems from the GMTKN30 database including subsets for noncovalently bound complexes, relative energies for sugar conformers and reaction energies and barrier heights of pericyclic reactions of some medium sized organic molecules. PMID- 22239767 TI - The divide-expand-consolidate family of coupled cluster methods: numerical illustrations using second order Moller-Plesset perturbation theory. AB - Previously, we have introduced the linear scaling coupled cluster (CC) divide expand-consolidate (DEC) method, using an occupied space partitioning of the standard correlation energy. In this article, we show that the correlation energy may alternatively be expressed using a virtual space partitioning, and that the Lagrangian correlation energy may be partitioned using elements from both the occupied and virtual partitioning schemes. The partitionings of the correlation energy leads to atomic site and pair interaction energies which are term-wise invariant with respect to an orthogonal transformation among the occupied or the virtual orbitals. Evaluating the atomic site and pair interaction energies using local orbitals leads to a linear scaling algorithm and a distinction between Coulomb hole and dispersion energy contributions to the correlation energy. Further, a detailed error analysis is performed illustrating the error control imposed on all components of the energy by the chosen energy threshold. This error control is ultimately used to show how to reduce the computational cost for evaluating dispersion energy contributions in DEC. PMID- 22239768 TI - Constrained adiabatic trajectory method: a global integrator for explicitly time dependent Hamiltonians. AB - The constrained adiabatic trajectory method (CATM) is reexamined as an integrator for the Schrodinger equation. An initial discussion places the CATM in the context of the different integrators used in the literature for time-independent or explicitly time-dependent Hamiltonians. The emphasis is put on adiabatic processes and within this adiabatic framework the interdependence between the CATM, the wave operator, the Floquet, and the (t, t') theories is presented in detail. Two points are then more particularly analyzed and illustrated by a numerical calculation describing the H(2)(+) ion submitted to a laser pulse. The first point is the ability of the CATM to dilate the Hamiltonian spectrum and thus to make the perturbative treatment of the equations defining the wave function possible, possibly by using a Krylov subspace approach as a complement. The second point is the ability of the CATM to handle extremely complex time dependencies, such as those which appear when interaction representations are used to integrate the system. PMID- 22239769 TI - Stockholder projector analysis: a Hilbert-space partitioning of the molecular one electron density matrix with orthogonal projectors. AB - A previously introduced partitioning of the molecular one-electron density matrix over atoms and bonds [D. Vanfleteren et al., J. Chem. Phys. 133, 231103 (2010)] is investigated in detail. Orthogonal projection operators are used to define atomic subspaces, as in Natural Population Analysis. The orthogonal projection operators are constructed with a recursive scheme. These operators are chemically relevant and obey a stockholder principle, familiar from the Hirshfeld-I partitioning of the electron density. The stockholder principle is extended to density matrices, where the orthogonal projectors are considered to be atomic fractions of the summed contributions. All calculations are performed as matrix manipulations in one-electron Hilbert space. Mathematical proofs and numerical evidence concerning this recursive scheme are provided in the present paper. The advantages associated with the use of these stockholder projection operators are examined with respect to covalent bond orders, bond polarization, and transferability. PMID- 22239770 TI - A simple scheme for magnetic balance in four-component relativistic Kohn-Sham calculations of nuclear magnetic resonance shielding constants in a Gaussian basis. AB - We report the implementation of nuclear magnetic resonance (NMR) shielding tensors within the four-component relativistic Kohn-Sham density functional theory including non-collinear spin magnetization and employing London atomic orbitals to ensure gauge origin independent results, together with a new and efficient scheme for assuring correct balance between the large and small components of a molecular four-component spinor in the presence of an external magnetic field (simple magnetic balance). To test our formalism we have carried out calculations of NMR shielding tensors for the HX series (X = F, Cl, Br, I, At), the Xe atom, and the Xe dimer. The advantage of simple magnetic balance scheme combined with the use of London atomic orbitals is the fast convergence of results (when compared with restricted kinetic balance) and elimination of linear dependencies in the basis set (when compared to unrestricted kinetic balance). The effect of including spin magnetization in the description of NMR shielding tensor has been found important for hydrogen atoms in heavy HX molecules, causing an increase of isotropic values of 10%, but negligible for heavy atoms. PMID- 22239771 TI - Linear dependence and energy conservation in Gaussian wavepacket basis sets. AB - We propose a method for dealing with the problem of linear dependence in quantum dynamics simulations employing over-complete Gaussian wavepacket (GWP) basis sets. In particular, by periodically projecting out redundant basis functions using the matching pursuit algorithm whilst simultaneously introducing GWPs which avoid linear dependence with the current basis set, we find that numerical conditioning of the equations-of-motion can be readily controlled. In applications to particle tunnelling in one- and two-dimensional potentials, this method allows us to reproduce the exact quantum-mechanical results with fewer GWP basis functions than similar calculations with non-adaptive basis sets, a result which we trace back to the improved energy conservation of our adaptive approach. PMID- 22239772 TI - Considerations on describing non-singlet spin states in variational second order density matrix methods. AB - Despite the importance of non-singlet molecules in chemistry, most variational second order density matrix calculations have focused on singlet states. Ensuring that a second order density matrix is derivable from a proper N-electron spin state is a difficult problem because the second order density matrix only describes one- and two-particle interactions. In pursuit of a consistent description of spin in second order density matrix theory, we propose and evaluate two main approaches: we consider constraints derived from a pure spin state and from an ensemble of spin states. This paper makes a comparative assessment of the different approaches by applying them to potential energy surfaces for different spin states of the oxygen and carbon dimer. We observe two major shortcomings of the applied spin constraints: they are not size consistent and they do not reproduce the degeneracy of the different states in a spin multiplet. First of all, the spin constraints are less strong when applied to a dissociated molecule than when they are applied to the dissociation products separately. Although they impose correct spin expectation values on the dissociated molecule, the dissociation products do not have correct spin expectation values. Secondly, both under "pure spin state conditions" and under "ensemble spin state" conditions is the energy a convex function of the spin projection. Potential energy surfaces for different spin projections of the same spin state may give a completely different picture of the molecule's bonding. The maximal spin projection always gives the most strongly constrained energy, but is also significantly more expensive to compute than a spin-averaged ensemble. In the dissociation limit, both the problem of nondegeneracy of equivalent spin projections, size-inconsistency and unphysical dissociation can be corrected by means of subspace energy constraints. PMID- 22239773 TI - Importance of the correlation contribution for local hybrid functionals: range separation and self-interaction corrections. AB - Local hybrid functionals with their position-dependent exact-exchange admixture are a conceptually simple and promising extension of the concept of a hybrid functional. Local hybrids based on a simple mixing of the local spin density approximation (LSDA) with exact exchange have been shown to be successful for thermochemistry, reaction barriers, and a range of other properties. So far, the combination of this generation of local hybrids with an LSDA correlation functional has been found to give the most favorable results for atomization energies, for a range of local mixing functions (LMFs) governing the exact exchange admixture. Here, we show that the choice of correlation functional to be used with local hybrid exchange crucially influences the parameterization also of the exchange part as well as the overall performance. A novel ansatz for the correlation part of local hybrids is suggested based on (i) range-separation of LSDA correlation into short-range (SR) and long-range (LR) parts, and (ii) partial or full elimination of the one-electron self-correlation from the SR part. It is shown that such modified correlation functionals allow overall larger exact exchange admixture in thermochemically competitive local hybrids than before. This results in improvements for reaction barriers and for other properties crucially influenced by self-interaction errors, as demonstrated by a number of examples. Based on the range-separation approach, a fresh view on the breakdown of the correlation energy into dynamical and non-dynamical parts is suggested. PMID- 22239774 TI - A density matrix renormalization group method study of optical properties of porphines and metalloporphines. AB - The symmetrized density matrix renormalization group method is used to study linear and nonlinear optical properties of free base porphine and metalloporphine. Long-range interacting model, namely, Pariser-Parr-Pople model is employed to capture the quantum many-body effect in these systems. The nonlinear optical coefficients are computed within the correction vector method. The computed singlet and triplet low-lying excited state energies and their charge densities are in excellent agreement with experimental as well as many other theoretical results. The rearrangement of the charge density at carbon and nitrogen sites, on excitation, is discussed. From our bond order calculation, we conclude that porphine is well described by the 18-annulenic structure in the ground state and the molecule expands upon excitation. We have modeled the regular metalloporphine by taking an effective electric field due to the metal ion and computed the excitation spectrum. Metalloporphines have D(4h) symmetry and hence have more degenerate excited states. The ground state of metalloporphines shows 20-annulenic structure, as the charge on the metal ion increases. The linear polarizability seems to increase with the charge initially and then saturates. The same trend is observed in third order polarizability coefficients. PMID- 22239775 TI - Beam broadening of polar molecules and clusters in deflection experiments. AB - A beam of rotating dipolar particles (molecules or clusters) will broaden when passed through an electric or magnetic field gradient region. This broadening, which is a common experimental observable, can be expressed in terms of the variance of the distribution of the resulting polarization orientation (the direction cosine). Here, the broadening for symmetric-top and linear rotors is discussed. These two types of rotors have qualitatively different low-field orientation distribution functions, but behave similarly in a strong field. While analytical expressions for the polarization variance can be derived from first order perturbation theory, for experimental guidance it is important to identify the applicability and limitations of these expressions, and the general dependence of the broadening on the experimental parameters. For this purpose, the analytical results are compared with the full diagonalization of the rotational Stark-effect matrices. Conveniently for experimental estimations, it is found that for symmetric tops, the dependence of the broadening parameter on the rotational constant, the axial ratio, and the field strength remains similar to the analytical expression even outside of the perturbative regime. Also, it is observed that the shape envelope, the centroid, and the width of the orientation distribution function for a symmetric top are quite insensitive to the value of its rotational constant (except at low rotational temperatures). PMID- 22239776 TI - S...X halogen bonds and H...X hydrogen bonds in H2CS-XY (XY = FF, ClF, ClCl, BrF, BrCl, and BrBr) complexes: cooperativity and solvent effect. AB - Using ab initio calculations, we have studied the structures, properties, and nature of halogen bonds in H(2)CS-XY (XY = FF, ClF, ClCl, BrF, BrCl, and BrBr) complexes. The results show that the ring-shaped complexes are formed by a halogen bond (S...X) and a secondary hydrogen bond (H...X). We also analyzed the H(2)CS-ClF-ClF and FCl-H(2)CS-ClF complexes to investigate the cooperative and diminutive halogen bonding. The cooperative effect of halogen bonding is found in the former, while the diminutive effect is present in the latter. We finally considered the solvent effect on the halogen bond in H(2)CS-BrCl complex and found that the solvent has a prominent enhancing effect on it. The complexes have also been analyzed with natural bond orbital, atoms in molecules, and symmetry adapted perturbation theory method. PMID- 22239777 TI - Dynamic (hyper)polarizabilities of the sulphur dioxide molecule: coupled cluster calculations including vibrational corrections. AB - In this work we report results for dynamical (hyper)polarizabilities of the sulphur dioxide molecule with inclusion of vibrational corrections. The electronic contributions were computed analytically at the single and double coupled cluster level through response theories for the frequencies 0, 0.0239, 0.0428, 0.0656, 0.0720, and 0.0886 hartree. Contributions of the connected triple excitations to the dynamic electronic properties were also estimated through the multiplicative correction scheme. Vibrational corrections were calculated by means of the perturbation theoretical method. The results obtained show that the zero point vibrational correction is very small for all properties studied while the pure vibrational correction is relevant for the dc-Pockels effect, intensity dependent refractive index, and dc-Kerr effect. For these nonlinear optical processes, the pure vibrational corrections represent approximately 75%, 13%, and 6% of the corresponding electronic contributions for the higher frequencies quoted. The results presented for the polarizability are in good agreement with experimental values available in the literature. For the hyperpolarizabilities we have not obtained experimental results with precision sufficient for comparison. PMID- 22239778 TI - Isotope effect in normal-to-local transition of acetylene bending modes. AB - The normal-to-local transition for the bending modes of acetylene is considered a prelude to its isomerization to vinylidene. Here, such a transition in fully deuterated acetylene is investigated using a full-dimensional quantum model. It is found that the local benders emerge at much lower energies and bending quantum numbers than in the hydrogen isotopomer HCCH. This is accompanied by a transition to a second kind of bending mode called counter-rotator, again at lower energies and quantum numbers than in HCCH. These transitions are also investigated using bifurcation analysis of two empirical spectroscopic fitting Hamiltonians for pure bending modes, which helps to understand the origin of the transitions semiclassically as branchings or bifurcations out of the trans- and cis-normal bend modes when the latter become dynamically unstable. The results of the quantum model and the empirical bifurcation analysis are in very good agreement. PMID- 22239779 TI - Hydrogen bonds in the nucleobase-gold complexes: photoelectron spectroscopy and density functional calculations. AB - The nucleobase-gold complexes were studied with anion photoelectron spectroscopy and density functional calculations. The vertical detachment energies of uracil Au(-), thymine-Au(-), cytosine-Au(-), adenine-Au(-), and guanine-Au(-) were estimated to be 3.37 +/- 0.08 eV, 3.40 +/- 0.08 eV, 3.23 +/- 0.08 eV, 3.28 +/- 0.08 eV, and 3.43 +/- 0.08 eV, respectively, based on their photoelectron spectra. The combination of photoelectron spectroscopy experiments and density functional calculations reveals the presence of two or more isomers for these nucleobase-gold complexes. The major isomers detected in the experiments probably are formed by Au anion with the canonical tautomers of the nucleobases. The gold anion essentially interacts with the nucleobases through N-H...Au hydrogen bonds. PMID- 22239780 TI - Structure, energetics, and reactions of alkali tetramers. AB - Electronic structure calculations have been carried out for all possible alkali tetramers that can be formed from X(2) + X(2) -> X(2)X(2), X(2) + Y(2) -> X(2)Y(2), and XY + XY -> X(2)Y(2) alkali dimer association reactions. Vibrationally stable rhombic (D(2h)) and planar (C(s)) structures are found for all possible tetramers formed from the alkali metals, Li to Cs. All tetramer formation reactions (from ground state singlet homonuclear or heteronuclear dimers) are found to be exothermic with binding energies ranging from 6282 cm(-1) for Li(2)Li(2) to 1985 cm(-1) for Cs(2)Cs(2). Extensive calculations, carried out at long-range for several reactant pairs, indicate that there are barrier-less pathways for the formation of tetramers from dimer association reactions. At low temperatures, direct formation of tetramers is unlikely, owing to the large exothermicity associated with these association reactions, but atom exchange reactions (X(2) + Y(2) <-> XY + XY) are possible for some species. PMID- 22239781 TI - Photodissociation pathways and lifetimes of protonated peptides and their dimers. AB - Photodissociation lifetimes and fragment channels of gas-phase, protonated YA(n) (n = 1,2) peptides and their dimers were measured with 266 nm photons. The protonated monomers were found to have a fast dissociation channel with an exponential lifetime of ~200 ns while the protonated dimers show an additional slow dissociation component with a lifetime of ~2 MUs. Laser power dependence measurements enabled us to ascribe the fast channel in the monomer and the slow channel in the dimer to a one-photon process, whereas the fast dimer channel is from a two-photon process. The slow (1 photon) dissociation channel in the dimer was found to result in cleavage of the H-bonds after energy transfer through these H-bonds. In general, the dissociation of these protonated peptides is non prompt and the decay time was found to increase with the size of the peptides. Quantum RRKM calculations of the microcanonical rate constants also confirmed a statistical nature of the photodissociation processes in the dipeptide monomers and dimers. The classical RRKM expression gives a rate constant as an analytical function of the number of active vibrational modes in the system, estimated separately on the basis of the equipartition theorem. It demonstrates encouraging results in predicting fragmentation lifetimes of protonated peptides. Finally, we present the first experimental evidence for a photo-induced conversion of tyrosine-containing peptides into monocyclic aromatic hydrocarbon along with a formamide molecule both found in space. PMID- 22239782 TI - Core-to-Rydberg band shift and broadening of hydrogen bonded ammonia clusters studied with nitrogen K-edge excitation spectroscopy. AB - Nitrogen 1s (N 1s) core-to-Rydberg excitation spectra of hydrogen-bonded clusters of ammonia (AM) have been studied in the small cluster regime of beam conditions with time-of-flight (TOF) fragment-mass spectroscopy. By monitoring partial-ion yield spectra of cluster-origin products, "cluster" specific excitation spectra could be recorded. Comparison of the "cluster" band with "monomer" band revealed that the first resonance bands of clusters corresponding to N 1s -> 3sa(1)/3pe of AM monomer are considerably broadened. The changes of the experimental core-to Rydberg transitions DeltaFWHM (N 1s -> 3sa(1)/3pe) = ~0.20/~0.50 eV compare well with the x ray absorption spectra of the clusters generated by using density functional theory (DFT) calculation. The broadening of the core-to-Rydberg bands in small clusters is interpreted as being primarily due to the splitting of non equivalent core-hole N 1s states caused by both electrostatic core-hole and hydrogen-bonding (H(3)N...H-NH(2)) interactions upon dimerization. Under Cs dimer configuration, core-electron binding energy of H-N (H-donor) is significantly decreased by the intermolecular core-hole interaction and causes notable redshifts of core-excitation energies, whereas that of lone-pair nitrogen (H acceptor) is slightly increased and results in appreciable blueshifts in the core excitation bands. The result of the hydrogen-bonding interaction strongly appears in the n-sigma* orbital correlation, destabilizing H-N donor Rydberg states in the direction opposite to the core-hole interaction, when excited N atom with H-N donor configuration strongly possesses the Rydberg component of anti-bonding sigma* (N-H) character. Contributions of other cyclic H-bonded clusters (AM)(n) with n >= 3 to the spectral changes of the N 1s -> 3sa(1)/3pe bands are also examined. PMID- 22239783 TI - Influence of solute-solvent coordination on the orientational relaxation of ion assemblies in polar solvents. AB - We have investigated the rotational dynamics of lithium thiocyanate (LiNCS) dissolved in various polar solvents with time and polarization resolved vibrational spectroscopy. LiNCS forms multiple distinct ionic structures in solution that can be distinguished with the CN stretch vibrational frequency of the different ionic assemblies. By varying the solvent and the LiNCS concentration, the number and type of ionic structures present in solution can be controlled. Control of the ionic structure provides control over the volume, shape, and dipole moment of the solute, critical parameters for hydrodynamic and dielectric continuum models of friction. The use of solutes with sizes comparable to or smaller than the solvent molecules also helps amplify the sensitivity of the measurement to the short-ranged solute-solvent interaction. The measured orientational relaxation dynamics show many clear and distinct deviations from simple hydrodynamic behavior. All ionic structures in all solvents exhibit multi exponential relaxation dynamics that do not scale with the solute volume. For Lewis base solvents such as benzonitrile, dimethyl carbonate, and ethyl acetate, the observed dynamics strongly show the effect of solute-solvent complex formation. For the weak Lewis base solvent nitromethane, we see no evidence for solute-solvent complex formation, but still see strong deviation from the predictions of simple hydrodynamic theory. PMID- 22239784 TI - Theoretical study of the aqueous solvation of HgCl2: Monte Carlo simulations using second-order Moller-Plesset-derived flexible polarizable interaction potentials. AB - A study of the solvation of HgCl(2) including ab initio aggregates of up to 24 water molecules and the results of extensive Monte Carlo simulations for the liquid phase using MP2-derived interaction potentials is presented. The interaction potentials are flexible, polarizable, and include non-additive effects. We conclude that a cluster description of the solvation mechanism is limited when compared to the condensed phase. The molecular image derived from the MC simulations is peculiar. It resembles that of a hydrophobic solute, which explains the rather easy passage of this neutral molecule through the cell membrane; however, it also shows an intermittent binding of one, two, or three water molecules to HgCl(2) in the fashion of a hydrophilic solute. PMID- 22239785 TI - Clusters dissolution of Yb3+ in codoped SiO2-Al2O3-P2O5 glass fiber and its relevance to photodarkening. AB - Using a combination of pulse electron paramagnetic resonance and photoluminescence spectroscopy, we demonstrate the major role of phosphorous rather than aluminium in the rare-earth dissolution process, an essential advance in telecommunication and solid laser fields. Our results also provide new insight into the micro-structural origin of the photodarkening process occurring in Yb doped fiber. PMID- 22239786 TI - Clusters in a mixture of an "amphiphilic" ionic liquid and a nonionic liquid: theoretical study. AB - A Flory-Huggins type lattice approach is used to describe theoretically a heterogeneous mixture composed of an ionic liquid (IL) and a nonionic liquid (nIL). It is analyzed, how the behavior of the system depends on the difference in the affinities of the cations and the anions to the neutral molecules (i.e., on the "amphiphilicity" of the IL with respect to the nIL). It is proved that if the difference in the affinities is not large, two macrophases coexist in the mixture; if the difference exceeds a certain threshold value, the mixture becomes microheterogeneous: depending on its composition, it can turn either into ion clusters dispersed over the phase having low concentration of ions, or into clusters of neutral molecules dispersed over the phase having high concentration of ions. If the system is not close to the critical point, the ion clusters can be only small: the maximal ratio of their diameter to an ion diameter is of the order of ten; however, the clusters of nonionic molecules can be large, if the difference in the affinities has a certain value. It is predicted also that cavities can nucleate inside an IL, and clusters of ions can appear in a saturated vapor of an IL. PMID- 22239787 TI - Solute rotation in polar liquids: microscopic basis for the Stokes-Einstein-Debye model. AB - Here, we develop a framework for a molecular level understanding of the celebrated Stokes-Einstein-Debye (SED) formula. In particular, we explore reasons behind the surprising success of the SED model in describing dipolar solute rotation in complex polar media. Relative importance of solvent viscosity and solute-solvent dipolar interaction is quantified via a self-consistent treatment for the total friction on a rotating solute where the hydrodynamic contribution is modified by the friction arising from the longer ranged solute-solvent dipolar interaction. Although the solute-solvent dipolar coupling is obtained via the Mori-Zwanzig formalism, the inclusion of solvent structure via the wave vector dependent viscosity in the hydrodynamic contribution incorporates solvent molecularity in the present theory. This approach satisfactorily describes the experimental rotation times measured using a dipolar solute, coumarin 153 (C153), in protic and aprotic polar liquids, and more importantly, provides microscopic explanation for insignificant contribution of electrical interactions on solute rotation, in contrast to the substantial role played by the translational dielectric friction in the context of ionic mobility. It is also discussed on how the present theory can be suitably extended to study the rotation of a realistic solute in media other than dipolar solvents. PMID- 22239788 TI - Monte Carlo study of four dimensional binary hard hypersphere mixtures. AB - A multithreaded Monte Carlo code was used to study the properties of binary mixtures of hard hyperspheres in four dimensions. The ratios of the diameters of the hyperspheres examined were 0.4, 0.5, 0.6, and 0.8. Many total densities of the binary mixtures were investigated. The pair correlation functions and the equations of state were determined and compared with other simulation results and theoretical predictions. At lower diameter ratios the pair correlation functions of the mixture agree with the pair correlation function of a one component fluid at an appropriately scaled density. The theoretical results for the equation of state compare well to the Monte Carlo calculations for all but the highest densities studied. PMID- 22239789 TI - Structure and electronic properties of a benzene-water solution. AB - Electronic properties of benzene in water were investigated by a sequential quantum mechanical/molecular dynamics approach. Emphasis was placed on the analysis of the structure, polarization effects, and ionization spectrum. By adopting a polarizable model for both benzene and water the structure of the benzene-water solution is in good agreement with data from first principles molecular dynamics. Further, strong evidence that water molecules acquire enhanced orientational order near the benzene molecule is found. Upon hydration, the quadrupole moment of benzene is not significantly changed in comparison with the gas-phase value. We are also reporting results for the dynamic polarizability of benzene in water. Our results indicate that the low energy behaviour of the dynamic polarizability of gas-phase and hydrated benzene is quite similar. Outer valence Green's function calculations for benzene in liquid water show a splitting of the gas-phase energy levels associated with the 1e(1g)(pi), 2e(2g), and 2e(1u) orbitals upon hydration. Lifting of the orbitals degeneracy and redshift of the outer valence bands is related to symmetry breaking of the benzene structure in solution and polarization effects from the surrounding water molecules. PMID- 22239790 TI - Rotational dynamics of solvated carbon dioxide studied by infrared, Raman, and time-resolved infrared spectroscopies and a molecular dynamics simulation. AB - Rotational dynamics of solvated carbon dioxide (CO(2)) has been studied. The infrared absorption band of the antisymmetric stretch mode in acetonitrile is found to show a non-Lorentzian band shape, suggesting a non-exponential decay of the vibrational and/or rotational correlation functions. A combined method of a molecular dynamics (MD) simulation and a quantum chemical calculation well reproduces the observed band shape. The analysis suggests that the band broadening is almost purely rotational, while the contribution from the vibrational dephasing is negligibly small. The non-exponential rotational correlation decay can be explained by a simple rotor model simulation, which can treat large angle rotations of a relatively small molecule. A polarized Raman study of the symmetric stretch mode in acetonitrile gives a rotational bandwidth consistent with that obtained from the infrared analysis. A sub-picosecond time resolved infrared absorption anisotropy measurement of the antisymmetric stretch mode in ethanol also gives a decay rate that is consistent with the observed rotational bandwidths. PMID- 22239791 TI - Mediation of resonance energy transfer by a third molecule. AB - The influence of a third molecule on the rate of resonance energy transfer is studied using diagrammatic perturbation theory within the framework of molecular quantum electrodynamics. Two distinct mechanisms are identified. One corresponds to direct transfer between donor and acceptor while the other involves relay of energy by the third species. Fermi Golden rule transition rates valid for all separation distances beyond wave function overlap are evaluated for these two processes as well as for the interference term between direct and indirect exchange, thereby extending previous work which was limited to the near-zone only. Short- and long-range limits are also obtained in each case. It is found that in the near-zone the indirect rate contribution exhibits inverse sixth power dependence on relative distances of emitter and absorber relative to the third body, in contrast to its far-zone counterpart, which exhibits inverse square behavior. The interference term, however, displays inverse cubic dependence on all three distance vectors at short-range and inverse behavior in the far-zone. Interestingly, for a collinear arrangement of the three molecules in the near zone, the interference term is negative, reducing the overall rate of energy transfer. The results obtained are interpreted in terms of microscopic and macroscopic pictures of transfer occurring within a surrounding medium. PMID- 22239792 TI - Nuclear magnetic resonance investigation of dynamics in poly(ethylene oxide) based lithium polyether-ester-sulfonate ionomers. AB - Nuclear magnetic resonance spectroscopy has been utilized to investigate the dynamics of poly(ethylene oxide)-based lithium sulfonate ionomer samples that have low glass transition temperatures. (1)H and (7)Li spin-lattice relaxation times (T(1)) of the bulk polymer and lithium ions, respectively, were measured and analyzed in samples with a range of ion contents. The temperature dependence of T(1) values along with the presence of minima in T(1) as a function of temperature enabled correlation times and activation energies to be obtained for both the segmental motion of the polymer backbone and the hopping motion of lithium cations. Similar activation energies for motion of both the polymer and lithium ions in the samples with lower ion content indicate that the polymer segmental motion and lithium ion hopping motion are correlated in these samples, even though lithium hopping is about ten times slower than the segmental motion. A divergent trend is observed for correlation times and activation energies of the highest ion content sample with 100% lithium sulfonation due to the presence of ionic aggregation. Details of the polymer and cation dynamics on the nanosecond timescale are discussed and complement the findings of X-ray scattering and quasi-elastic neutron scattering experiments. PMID- 22239793 TI - Free energy profiles for penetration of methane and water molecules into spherical sodium dodecyl sulfate micelles obtained using the thermodynamic integration method combined with molecular dynamics calculations. AB - The free energy profiles, DeltaG(r), for penetration of methane and water molecules into sodium dodecyl sulfate (SDS) micelles have been calculated as a function of distance r from the SDS micelle to the methane and water molecules, using the thermodynamic integration method combined with molecular dynamics calculations. The calculations showed that methane is about 6-12 kJ mol(-1) more stable in the SDS micelle than in the water phase, and no DeltaG(r) barrier is observed in the vicinity of the sulfate ions of the SDS micelle, implying that methane is easily drawn into the SDS micelle. Based on analysis of the contributions from hydrophobic groups, sulfate ions, sodium ions, and solvent water to DeltaG(r), it is clear that methane in the SDS micelle is about 25 kJ mol(-1) more stable than it is in the water phase because of the contribution from the solvent water itself. This can be understood by the hydrophobic effect. In contrast, methane is destabilized by 5-15 kJ mol(-1) by the contribution from the hydrophobic groups of the SDS micelle because of the repulsive interactions between the methane and the crowded hydrophobic groups of the SDS. The large stabilizing effect of the solvent water is higher than the repulsion by the hydrophobic groups, driving methane to become solubilized into the SDS micelle. A good correlation was found between the distribution of cavities and the distribution of methane molecules in the micelle. The methane may move about in the SDS micelle by diffusing between cavities. In contrast, with respect to the water, DeltaG(r) has a large positive value of 24-35 kJ mol(-1), so water is not stabilized in the micelle. Analysis showed that the contributions change in complex ways as a function of r and cancel each other out. Reference calculations of the mean forces on a penetrating water molecule into a dodecane droplet clearly showed the same free energy behavior. The common feature is that water is less stable in the hydrophobic core than in the water phase because of the energetic disadvantage of breaking hydrogen bonds formed in the water phase. The difference between the behaviors of the SDS micelles and the dodecane droplets is found just at the interface; this is caused by the strong surface dipole moment formed by sulfate ions and sodium ions in the SDS micelles. PMID- 22239794 TI - Incorporating C2 into C60 films. AB - The material formed by depositing C(2)(-) anions onto/into thin C(60) films (on graphite) at room temperature has been studied by means of thermal desorption mass spectroscopy, ultraviolet photoionization spectroscopy, atomic force microscopy (AFM), and surface enhanced Raman spectroscopy. As-prepared, C(2)/C(60) films manifest thermal desorption behaviour which differs significantly from pure C(60) films. Whereas the latter can be fully sublimed, we observe decomposition of C(2)/C(60) films to a high-temperature-stable material while predominantly C(60), C(62), and C(64) are desorbed in parallel. Deposition of C(2)(-) also leads to significantly modified electronic and vibrational properties. Based on DFT model calculations of the Raman spectra, we suggest that as-prepared C(2)/C(60) films contain appreciable amounts of polymeric networks comprising -C(2)-C(60)-C(2)-C(60)- chains. Detection of sublimed C(62) and C(64) upon heating implies that thermal decomposition of C(2)/C(60) films involves addition/uptake of C(2) units into individual fullerene cages. Correspondingly, annealing films up to various intermediate temperatures results in significant modifications to valence-band UP spectra as well as to surface topographies as imaged by AFM. The novel carbonaceous material obtained by heating to T > 950 K has a finite density of states at the Fermi level in contrast to as-prepared C(2)/C(60). It comprises fused fullerene cages. PMID- 22239795 TI - Theory of nitrogen doping of carbon nanoribbons: edge effects. AB - Nitrogen doping of a carbon nanoribbon is profoundly affected by its one dimensional character, symmetry, and interaction with edge states. Using state-of the-art ab initio calculations, including hybrid exact-exchange density functional theory, we find that, for N-doped zigzag ribbons, the electronic properties are strongly dependent upon sublattice effects due to the non equivalence of the two sublattices. For armchair ribbons, N-doping effects are different depending upon the ribbon family: for families 2 and 0, the N-induced levels are in the conduction band, while for family 1 the N levels are in the gap. In zigzag nanoribbons, nitrogen close to the edge is a deep center, while in armchair nanoribbons its behavior is close to an effective-mass-like donor with the ionization energy dependent on the value of the band gap. In chiral nanoribbons, we find strong dependence of the impurity level and formation energy upon the edge position of the dopant, while such site-specificity is not manifested in the magnitude of the magnetization. PMID- 22239796 TI - Identification of the atomic scale structures of the gold-thiol interfaces of molecular nanowires by inelastic tunneling spectroscopy. AB - We examine theoretically the effects of the bonding geometries at the gold-thiol interfaces on the inelastic tunneling spectra of propanedithiolate (PDT) molecules bridging gold electrodes and show that inelastic tunneling spectroscopy combined with theory can be used to determine these bonding geometries experimentally. With the help of density functional theory, we calculate the relaxed geometries and vibrational modes of extended molecules each consisting of one or two PDT molecules connecting two gold nanoclusters. We formulate a perturbative theory of inelastic tunneling through molecules bridging metal contacts in terms of elastic transmission amplitudes, and use this theory to calculate the inelastic tunneling spectra of the gold-PDT-gold extended molecules. We consider PDT molecules with both trans and gauche conformations bound to the gold clusters at top, bridge, and hollow bonding sites. Comparing our results with the experimental data of Hihath et al. [Nano Lett. 8, 1673 (2008)], we identify the most frequently realized conformation in the experiment as that of trans molecules top-site bonded to both electrodes. We find the switching from the 42 meV vibrational mode to the 46 meV mode observed in the experiment to be due to the transition of trans molecules from mixed top-bridge to pure top-site bonding geometries. Our results also indicate that gauche molecular conformations and hollow site bonding did not contribute significantly to the experimental inelastic tunneling spectra. For pairs of PDT molecules connecting the gold electrodes in parallel we find total elastic conductances close to twice those of single molecules bridging the contacts with similar bonding conformations and small splittings of the vibrational mode energies for the modes that are the most sensitive to the molecule-electrode bonding geometries. PMID- 22239797 TI - Structure factors in granular experiments with homogeneous fluidization. AB - Velocity and density structure factors are measured over a hydrodynamic range of scales in a horizontal quasi-2D fluidized granular experiment, with packing fractions phi ? [10%, 40%]. The fluidization is realized by vertically vibrating a rough plate, on top of which particles perform a Brownian-like horizontal motion in addition to inelastic collisions. On one hand, the density structure factor is equal to that of elastic hard spheres, except in the limit of large length-scales, as it occurs in the presence of an effective interaction. On the other hand, the velocity field shows a more complex structure which is a genuine expression of a non-equilibrium steady state and which can be compared to a recent fluctuating hydrodynamic theory with non-equilibrium noise. The temporal decay of velocity modes autocorrelations is compatible with linear hydrodynamic equations with rates dictated by viscous momentum diffusion, corrected by a typical interaction time with the thermostat. Equal-time velocity structure factors display a peculiar shape with a plateau at large length-scales and another one at small scales, marking two different temperatures: the "bath" temperature T(b), depending on shaking parameters, and the "granular" temperature T(g) < T(b), which is affected by collisions. The two ranges of scales are separated by a correlation length which grows with phi, after proper rescaling with the mean free path. PMID- 22239798 TI - Self-metalation of 2H-tetraphenylporphyrin on Cu(111): an x-ray spectroscopy study. AB - The bonding and the temperature-driven metalation of 2H-tetraphenylporphyrin (2H TPP) on the Cu(111) surface under ultrahigh vacuum conditions were investigated by a combination of x-ray photoelectron spectroscopy (XPS) and near-edge x-ray absorption fine structure (NEXAFS) spectroscopy with density functional theory calculations. Thin films were prepared by organic molecular beam epitaxy and subsequent annealing. Our systematic study provides an understanding of the changes of the spectroscopic signature during adsorption and metalation. Specifically, we achieved a detailed peak assignment of the 2H-TPP multilayer data of the C1s and the N1s region. After annealing to 420 K both XPS and NEXAFS show the signatures of a metalloporphyrin, which indicates self-metalation at the porphyrin-substrate interface, resulting in Cu-TPP. Furthermore, for 2H-TPP monolayer samples we show how the strong influence of the copper surface is reflected in the spectroscopic signatures. Adsorption results in a strongly deformed macrocycle and a quenching of the first NEXAFS resonance in the nitrogen edge suggesting electron transfer into the LUMO. For Cu-TPP the spectroscopic data indicate a reduced interaction of first-layer molecules with the substrate as demonstrated by the relaxed macrocycle geometry. PMID- 22239799 TI - An immersed boundary method for Brownian dynamics simulation of polymers in complex geometries: application to DNA flowing through a nanoslit with embedded nanopits. AB - This work presents an immersed boundary method that allows fast Brownian dynamics simulation of solutions of polymer chains and other Brownian objects in complex geometries with fluctuating hydrodynamics. The approach is based on the general geometry Ewald-like method, which solves the Stokes equation with distributed regularized point forces in O(N) or O(NlogN) operations, where N is the number of point forces in the system. Time-integration is performed using a midpoint algorithm and Chebyshev polynomial approximation proposed by Fixman. This approach is applied to the dynamics of a genomic DNA molecule driven by flow through a nanofluidic slit with an array of nanopits on one wall of the slit. The dynamics of the DNA molecule was studied as a function of the Peclet number and chain length (the base case being lambda-DNA). The transport characteristics of the hopping dynamics in this device differ at low and high Peclet number, and for long DNA, relative to the pit size, the dynamics is governed by the segments residing in the pit. By comparing with results that neglect them, hydrodynamic interactions are shown to play an important quantitative role in the hopping dynamics. PMID- 22239800 TI - Multi-scale modeling of diffusion-controlled reactions in polymers: renormalisation of reactivity parameters. AB - The quantitative description of polymeric systems requires hierarchical modeling schemes, which bridge the gap between the atomic scale, relevant to chemical or biomolecular reactions, and the macromolecular scale, where the longest relaxation modes occur. Here, we use the formalism for diffusion-controlled reactions in polymers developed by Wilemski, Fixman, and Doi to discuss the renormalisation of the reactivity parameters in polymer models with varying spatial resolution. In particular, we show that the adjustments are independent of chain length. As a consequence, it is possible to match reactions times between descriptions with different resolution for relatively short reference chains and to use the coarse-grained model to make quantitative predictions for longer chains. We illustrate our results by a detailed discussion of the classical problem of chain cyclization in the Rouse model, which offers the simplest example of a multi-scale descriptions, if we consider differently discretized Rouse models for the same physical system. Moreover, we are able to explore different combinations of compact and non-compact diffusion in the local and large-scale dynamics by varying the embedding dimension. PMID- 22239801 TI - Solid effect dynamic nuclear polarization and polarization pathways. AB - Using dynamic nuclear polarization (DNP)/nuclear magnetic resonance instrumentation that utilizes a microwave cavity and a balanced rf circuit, we observe a solid effect DNP enhancement of 94 at 5 T and 80 K using trityl radical as the polarizing agent. Because the buildup rate of the solid effect increases with microwave field strength, we obtain a sensitivity gain of 128. The data suggest that higher microwave field strengths would lead to further improvements in sensitivity. In addition, the observation of microwave field dependent enhancements permits us to draw conclusions about the path that polarization takes during the DNP process. By measuring the time constant for the polarization buildup and enhancement as a function of the microwave field strength, we are able to compare models of polarization transfer, and show that the major contribution to the bulk polarization arises via direct transfer from electrons, rather than transferring first to nearby nuclei and then transferring to bulk nuclei in a slow diffusion step. In addition, the model predicts that nuclei near the electron receive polarization that can relax, decrease the electron polarization, and attenuate the DNP enhancement. The magnitude of this effect depends on the number of near nuclei participating in the polarization transfer, hence the size of the diffusion barrier, their T(1), and the transfer rate. Approaches to optimizing the DNP enhancement are discussed. PMID- 22239802 TI - Effect of glycerol and dimethyl sulfoxide on the phase behavior of lysozyme: theory and experiments. AB - Salt, glycerol, and dimethyl sulfoxide (DMSO) are used to modify the properties of protein solutions. We experimentally determined the effect of these additives on the phase behavior of lysozyme solutions. Upon the addition of glycerol and DMSO, the fluid-solid transition and the gas-liquid coexistence curve (binodal) shift to lower temperatures and the gap between them increases. The experimentally observed trends are consistent with our theoretical predictions based on the thermodynamic perturbation theory and the Derjaguin-Landau-Verwey Overbeek model for the lysozyme-lysozyme pair interactions. The values of the parameters describing the interactions, namely the refractive indices, dielectric constants, Hamaker constant and cut-off length, are extracted from literature or are experimentally determined by independent experiments, including static light scattering, to determine the second virial coefficient. We observe that both, glycerol and DMSO, render the potential more repulsive, while sodium chloride reduces the repulsion. PMID- 22239803 TI - Structure and dynamics of nano-sized raft-like domains on the plasma membrane. AB - Cell membranes are constitutively composed of thousands of different lipidic species, whose specific organization leads to functional heterogeneities. In particular, sphingolipids, cholesterol and some proteins associate among them to form stable nanoscale domains involved in recognition, signaling, membrane trafficking, etc. Atomic-detail information in the nanometer/second scale is still elusive to experimental techniques. In this context, molecular simulations on membrane systems have provided useful insights contributing to bridge this gap. Here we present the results of a series of simulations of biomembranes representing non-raft and raft-like nano-sized domains in order to analyze the particular structural and dynamical properties of these domains. Our results indicate that the smallest (5 nm) raft domains are able to preserve their distinctive structural and dynamical features, such as an increased thickness, higher ordering, lower lateral diffusion, and specific lipid-ion interactions. The insertion of a transmembrane protein helix into non-raft, extended raft-like, and raft-like nanodomain environments result in markedly different protein orientations, highlighting the interplay between the lipid-lipid and lipid protein interactions. PMID- 22239806 TI - Efficient creation of cellular micropatterns with long-term stability and their geometric effects on cell behavior. AB - Cellular micropatterning with bio-adhesive and nonadhesive areas has attracted increasing interest for the precise design of cell-to-surface attachment in cell biology studies, tissue engineering, cell-based biosensors, biological assays, and drug development and screening. In this paper we describe a simple and efficient method to create a two-dimensional stable cellular microenvironment, which is based on (1) forming a protein-resistant oligo(ethylene glycol) methyl ether methacrylate polymer layer on the substrates via surface-initiated atom transfer radical polymerization; (2) placing a defined photomask on the substrate and exposing the substrate to ultraviolet light; and (3) immersing the patterned surface in a fibronectin solution to form cell-adhesive protein patterns in a cell-resistant background. The resulting surfaces are tailored into cell-adhesive and cell-resistant regions. Three different types of cells (NIH-3T3, PC12, bone marrow-derived mesenchymal stem cells) are seeded on such patterned surfaces to form cellular patterns. The geometric effects on cell behavior are investigated. The long-term stability is tested by NIH-3T3 fibroblasts and mesenchymal stem cells and excellent retention of cellular patterns is observed. The strategy illustrated here offers an efficient way to create a stable, patterned cellular microenvironment, and could be employed in tissue engineering to study the effect of micropatterns on the proliferation and differentiation of cells, and in particular mesenchymal stem cells. PMID- 22239807 TI - Proteopolymersomes: in vitro production of a membrane protein in polymersome membranes. AB - Polymersomes are stable self-assembled architectures which mimic cell membranes. For characterization, membrane proteins can be incorporated into such bio-mimetic membranes by reconstitution methods, leading to so-called proteopolymersomes. In this work, we demonstrate the direct incorporation of a membrane protein into polymersome membranes by a cell-free expression system. Firstly, we demonstrate pore formation in the preformed polymersome membrane using alpha-hemolysin. Secondly, we use claudin-2, a protein involved in cell-cell interactions, to demonstrate the in vitro expression of a membrane protein into these polymersomes. Surface plasmon resonance (Biacore) binding studies with the claudin-2 proteopolymersomes and claudin-2 specific antibodies are performed to show the presence of the in vitro expressed protein in polymersome membranes. PMID- 22239808 TI - Fibroblast adhesion on unidirectional polymeric nanofilms. AB - Nanotextured polymeric surfaces with inclined rods reveal highly anisotropic properties concerning wetting and adhesion. In this work, we report on the interaction of fibroblast cells with these highly anisotropic materials. The authors quantified removal of adherent cells from such surfaces by a laminar flow. The critical shear force needed for cell removal from the surface depends on the inclination direction. Based on electron microscopy cross sections we deduce that interactions of cellular filopodia extending into the nanotextured surface are causing the direction depending removal. PMID- 22239809 TI - Interactions of nanobubbles with bovine serum albumin and papain films on gold surfaces. AB - Nanobubbles formed on monocrystalline gold/water interface by means of the ethanol-to-water solvent exchange were exposed to the solutions of either bovine serum albumin or papain proteins. Both proteins do not change the position of nanobubbles in water, as observed by in situ tapping mode atomic force microscopy imaging before and after the introduction of the protein. The aqueous environment was subsequently replaced by ethanol. While all nanobubbles were found to dissolve in ethanol in the presence of bovine serum albumin, most of them survived when papain was employed. The protective ability of papain was ascribed to its resistance towards the protein denaturation in aqueous solutions of ethanol. The authors employed in situ atomic force nanolithography to investigate the nanomorphology of the papain/nanobubble assemblies in ethanol. PMID- 22239810 TI - In vitro observation of dynamic ordering processes in the extracellular matrix of living, adherent cells. AB - Collecting information at the interface between living cells and artificial substrates is exceedingly difficult. The extracellular matrix (ECM) mediates all cell-substrate interactions, and its ordered, fibrillar constituents are organized with nanometer precision. The proceedings at this interface are highly dynamic and delicate. In order to understand factors governing biocompatibility or its counterpart antifouling, it is necessary to probe this interface without disrupting labels or fixation and with sufficient temporal resolution. Here the authors combine nonlinear optical spectroscopy (sum-frequency-generation) and microscopy (second-harmonic-generation), fluorescence microscopy, and quartz crystal microgravimetry with dissipation monitoring in a strategy to elucidate molecular ordering processes in the ECM of living cells. Artificially (fibronectin and collagen I) and naturally ordered ECM fibrils (zebrafish, Danio rerio) were subjected to nonlinear optical analysis and were found to be clearly distinguishable from the background signals of diffusive proteins in the ECM. The initial steps of fibril deposition and ordering were observed in vitro as early as 1 h after cell seeding. The ability to follow the first steps of cell substrate interactions in spite of the low amount of material present at this interface is expected to prove useful for the assessment of biomedical and environmental interfaces. PMID- 22239811 TI - Mixed poly (ethylene glycol) and oligo (ethylene glycol) layers on gold as nonfouling surfaces created by backfilling. AB - Backfilling a self-assembled monolayer (SAM) of long poly (ethylene glycol) (PEG) with short PEG is a well-known strategy to improve its potential to resist fouling. Here it is shown, using x-ray photoelectron spectroscopy, contact angle, and atomic force microscopy, that backfilling PEG thiol with oligo (ethylene glycol) (OEG) terminated alkane thiol molecules results in underbrush formation. The authors also confirm the absence of phase separated arrangement, which is commonly observed with backfilling experiments involving SAMs of short chain alkane thiol with long chain alkane thiol. Furthermore, it was found that OEG addition caused less PEG desorption when compared to alkane thiol. The ability of surface to resist fouling was tested through serum adsorption and bacterial adhesion studies. The authors demonstrate that the mixed monolayer with PEG and OEG is better than PEG at resisting protein adsorption and bacterial adhesion, and conclude that backfilling PEG with OEG resulting in the underbrush formation enhances the ability of PEG to resist fouling. PMID- 22239812 TI - Optimizing interfacial features to regulate neural progenitor cells using polyelectrolyte multilayers and brain derived neurotrophic factor. AB - The development of biomaterials with controllable interfacial features which have the capability to instruct cellular behavior are required to produce functional scaffolds for the treatment of spinal cord injury (SCI). Here, poly-E caprolactone surfaces were biofunctionalized via layer-by-layer (LbL) deposition. The polyelectrolytes employed in this LbL technique were heparin and poly-L lysine (PLL), the latter being chosen to improve cell adhesion and the subsequent cellular function of in vitrocultured neural progenitor cells. Material characterization results confirmed the deposition of well structured multilayers. Cell culture studies revealed significant differences in the cellular response to these adhesive/nonadhesive (PLL/heparin) polyelectrolyte multilayer (PEM)surfaces, with neurite outgrowth being significantly promoted on the PLL terminating layers. In addition, brain derived neurotrophic factor (BDNF) was adsorbed onto the LbL surfaces. This combined chemical and biological effect was then characterized in terms of neurite length along with the full length/truncated isoform 1 tyrosine kinase receptor (TrkB-FL/TrkB-T1) and growth associated protein-43 mRNA levels. Here, the authors report the differential effect of adsorbed and soluble BDNF of different concentrations. Adsorbed BDNF promoted neurite outgrowth and led to elevated, sustained TrkB mRNA levels. These findings highlight the potential of PEM biofunctionalized surfaces with integrated chemical and neurotrophin supportive cues to overcome SCI inhibitory environments and to promote regeneration. PMID- 22239814 TI - Immobilization of mycotoxins on modified nanodiamond substrates. AB - The effectiveness of modified nanodiamonds (NDs) for the adsorption of mycotoxins, aflatoxin B1 (AfB1) and ochratoxin A (OTA), are investigated in this paper. Binding and release mechanisms of the mycotoxins were addressed using an assortment of NDs modified by different surface treatments, including carboxylation, hydrogenation and hydroxylation, followed by isolating NDs of different sizes. Results indicate that AfB1 adsorption on NDs is directly related to aggregate size, whereas OTA adsorption is primarily centered upon electrostatic interactions that depend on the types of surface functional groups on the ND. Findings show that modified NDs with small aggregation sizes (~40 nm) have greater adsorption capacities for AfB1 than yeast cells walls and untreated NDs from various vendors, but comparable to activated charcoal. In OTA studies, positively charged NDs outperformed clay minerals, which are well-known and efficient sorbents for mycotoxins. Furthermore, ND adsorption capacities can be preserved in a wide range of pH. PMID- 22239813 TI - Co-culture of osteocytes and neurons on a unique patterned surface. AB - Neural and skeletal communication is essential for the maintenance of bone mass and transmission of pain, yet the mechanism(s) of signal transduction between these tissues is unknown. The authors established a novel system to co-culture murine long bone osteocyte-like cells (MLO-Y4) and primary murine dorsal root ganglia (DRG) neurons. Assessment of morphology and maturation marker expression on perlecan domain IV peptide (PlnDIV) and collagen type-1 (Col1) demonstrated that PlnDIV was an optimal matrix for MLO-Y4 culture. A novel matrix-specificity competition assay was developed to expose these cells to several extracellular matrix proteins such as PlnDIV, Col1, and laminin (Ln). The competition assay showed that approximately 70% of MLO-Y4 cells preferred either PlnDIV or Col1 to Ln. To co-culture MLO-Y4 and DRG, we developed patterned surfaces using micro contact printing to create 40 MUm * 1 cm alternating stripes of PlnDIV and Ln or PlnDIV and Col1. Co-culture on PlnDIV/Ln surfaces demonstrated that these matrix molecules provided unique cues for each cell type, with MLO-Y4 preferentially attaching to the PlnDIV lanes and DRG neurons to the Ln lanes. Approximately 80% of DRG were localized to Ln. Cellular processes from MLO-Y4 were closely associated with axonal extensions of DRG neurons. Approximately 57% of neuronal processes were in close proximity to nearby MLO-Y4 cells at the PlnDIV-Ln interface. The surfaces in this new assay provided a unique model system with which to study the communication between osteocyte-like cells and neurons in an in vitro environment. PMID- 22239815 TI - Letter from the editor. PMID- 22239816 TI - Review of immobilized antimicrobial agents and methods for testing. AB - Antimicrobial surfaces for food and medical applications have historically involved antimicrobial coatings that elute biocides for effective kill in solution or at surfaces. However, recent efforts have focused on immobilized antimicrobial agents in order to avoid toxicity and the compatibility and reservoir limitations common to elutable agents. This review critically examines the assorted antimicrobial agents reported to have been immobilized, with an emphasis on the interpretation of antimicrobial testing as it pertains to discriminating between eluting and immobilized agents. Immobilization techniques and modes of antimicrobial action are also discussed. PMID- 22239818 TI - Evaluation of endothelial function with brachial artery ultrasound in men with or without erectile dysfunction and classified as intermediate risk according to the Framingham Score. AB - INTRODUCTION: Flow-mediated vasodilation (FMD) of the brachial artery is a noninvasive tool used for endothelial function evaluation. There is increasing evidence that endothelial dysfunction is a common etiological factor for erectile dysfunction (ED) and cardiovascular events. AIM: To evaluate endothelial function with a high-resolution ultrasound device, to assess FMD in men diagnosed with ED and without clinical evidence of significant atherosclerotic disease, classified as "intermediate risk" according to the Framingham risk score (FRS). METHODS: This is a case-control study that included 52 consecutive men. In all men with ED evaluated by a score less than 22 on International Index of Erectile Function-5 questionnaire (IIEF-5), clinical parameters such as blood pressure, waist circumference, hip circumference, body mass index, lipid profile, fasting glucose, and serum total testosterone were obtained. These parameters were compared with those men without diagnosis of ED (IIEF-5 score>=22) (age-matched, also classified as "intermediate risk" according to the FRS). All underwent brachial artery ultrasound for assessment of FMD, as a noninvasive method to evaluate endothelial function. Statistical analysis was performed considering a P<0.05. MAIN OUTCOME MEASURES: Endothelium-dependent FMD was evaluated in the right brachial artery with a high-resolution ultrasound machine following reactive hyperemia. RESULTS: Thirty-four men were included in the ED group, and 18 were included in the group without ED. The mean ages were 59.61+/-9.87 and 56.18+/-10.93, respectively (P=0.27). Clinical and laboratory evaluations were similar between men with and without ED (P>0.05) except for waist circumference that was greater in patients with ED (mean=100.85 cm vs. 96.05; P<0.05). The percentage of FMD was higher in men without ED when compared with those with ED (mean FMD 11.33+/-6.08% vs. 4.24+/-7.06%, respectively; P=0.001). CONCLUSIONS: Men without established atherosclerotic disease presenting with ED demonstrated a worse endothelial function. PMID- 22239817 TI - Ectopic expression of cyclase associated protein CAP restores the streaming and aggregation defects of adenylyl cyclase a deficient Dictyostelium discoideum cells. AB - BACKGROUND: Cell adhesion, an integral part of D. discoideum development, is important for morphogenesis and regulated gene expression in the multicellular context and is required to trigger cell-differentiation. G-protein linked adenylyl cyclase pathways are crucially involved and a mutant lacking the aggregation specific adenylyl cyclase ACA does not undergo multicellular development. RESULTS: Here, we have investigated the role of cyclase-associated protein (CAP), an important regulator of cell polarity and F-actin/G-actin ratio in the aca- mutant. We show that ectopic expression of GFP-CAP improves cell polarization, streaming and aggregation in aca- cells, but it fails to completely restore development. Our studies indicate a requirement of CAP in the ACA dependent signal transduction for progression of the development of unicellular amoebae into multicellular structures. The reduced expression of the cell adhesion molecule DdCAD1 together with csA is responsible for the defects in aca- cells to initiate multicellular development. Early development was restored by the expression of GFP-CAP that enhanced the DdCAD1 transcript levels and to a lesser extent the csA mRNA levels. CONCLUSIONS: Collectively, our data shows a novel role of CAP in regulating cell adhesion mechanisms during development that might be envisioned to unravel the functions of mammalian CAP during animal embryogenesis. PMID- 22239819 TI - Rotational Resonance in milli-tesla fields detected by Field Cycling NMR. AB - Rotational Resonance (R(2)) between different spin Zeeman levels in samples of adamantane C(10)H(16) (homonuclear R(2)) and a mixture of C(10)H(16) and C(10)D(16) (both homonuclear and heteronuclear R(2)) has been studied. A Field Cycling NMR instrument was used to match the external field frequency nu(0) to a fixed frequency of sample rotation nu(r) at nu(r) = 40, 50 or 60 kHz. Rotational Resonance is observed at rational frequency ratios of nu(0)/nu(r), such as 12, 23, 32 and 1. The method may prove to become a useful tool for the determination of spin-spin distances in condensed matter. PMID- 22239821 TI - Meta-analysis: coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. AB - BACKGROUND: Coeliac disease has been associated with an increased risk of mortality and malignancy. However, the strength of this association is conflicting among different studies. AIM: To perform a systematic review and quantitative meta-analysis to determine the risk of all-cause mortality, any malignancy and lymphoid malignancy in coeliac disease patients. METHODS: Four electronic databases (Medline, PubMed, Embase and Current Contents Connect) were searched to 4 January 2012, with no language restrictions. From 8698 citations identified, a total of 17 studies met our inclusion criteria. RESULTS: The all cause mortality meta-analysis showed an increased risk for all-cause mortality in coeliac patients [odds ratio (OR) 1.24; 95% confidence interval (CI) 1.19-1.30]. A subgroup analysis showed that patients identified by positive serology alone were also at an increased risk of all-cause mortality (OR 1.16; 95% CI 1.02 1.31). The non-Hodgkin lymphoma (NHL) meta-analysis showed an increased risk for NHL in coeliac patients (OR 2.61; 95% CI 2.04-3.33). A subgroup analysis showed that patients identified by positive serology alone were also at an increased risk of NHL (OR 2.55; 95% CI 1.02-6.36). The T-cell non-Hodgkin lymphoma (TNHL) meta-analysis showed an increased risk of TNHL (OR 15.84; 95% CI 7.85-31.94). The any malignancy meta-analysis showed no increased risk (OR 1.07; 95% CI 0.89 1.29). CONCLUSIONS: Patients with coeliac disease are at an increased risk of mortality and non-Hodgkin lymphoma, particularly T-cell non-Hodgkin lymphoma; they do not have an increased risk of any malignancy overall. Serologically defined patients with coeliac disease have an elevated risk of mortality and non Hodgkin lymphoma. PMID- 22239820 TI - New insights regarding HCV-NS5A structure/function and indication of genotypic differences. AB - BACKGROUND: HCV is prevalent throughout the world. It is a major cause of chronic liver disease. There is no effective vaccine and the most common therapy, based on Peginterferon, has a success rate of ~50%. The mechanisms underlying viral resistance have not been elucidated but it has been suggested that both host and virus contribute to therapy outcome. Non-structural 5A (NS5A) protein, a critical virus component, is involved in cellular and viral processes. METHODS: The present study analyzed structural and functional features of 345 sequences of HCV NS5A genotypes 1 or 3, using in silico tools. RESULTS: There was residue type composition and secondary structure differences between the genotypes. In addition, second structural variance were statistical different for each response group in genotype 3. A motif search indicated conserved glycosylation, phosphorylation and myristoylation sites that could be important in structural stabilization and function. Furthermore, a highly conserved integrin ligation site was identified, and could be linked to nuclear forms of NS5A. ProtFun indicated NS5A to have diverse enzymatic and nonenzymatic activities, participating in a great range of cell functions, with statistical difference between genotypes. CONCLUSION: This study presents new insights into the HCV NS5A. It is the first study that using bioinformatics tools, suggests differences between genotypes and response to therapy that can be related to NS5A protein features. Therefore, it emphasizes the importance of using bioinformatics tools in viral studies. Data acquired herein will aid in clarifying the structure/function of this protein and in the development of antiviral agents. PMID- 22239822 TI - A network flow approach to predict drug targets from microarray data, disease genes and interactome network - case study on prostate cancer. AB - BACKGROUND: Systematic approach for drug discovery is an emerging discipline in systems biology research area. It aims at integrating interaction data and experimental data to elucidate diseases and also raises new issues in drug discovery for cancer treatment. However, drug target discovery is still at a trial-and-error experimental stage and it is a challenging task to develop a prediction model that can systematically detect possible drug targets to deal with complex diseases. METHODS: We integrate gene expression, disease genes and interaction networks to identify the effective drug targets which have a strong influence on disease genes using network flow approach. In the experiments, we adopt the microarray dataset containing 62 prostate cancer samples and 41 normal samples, 108 known prostate cancer genes and 322 approved drug targets treated in human extracted from DrugBank database to be candidate proteins as our test data. Using our method, we prioritize the candidate proteins and validate them to the known prostate cancer drug targets. RESULTS: We successfully identify potential drug targets which are strongly related to the well known drugs for prostate cancer treatment and also discover more potential drug targets which raise the attention to biologists at present. We denote that it is hard to discover drug targets based only on differential expression changes due to the fact that those genes used to be drug targets may not always have significant expression changes. Comparing to previous methods that depend on the network topology attributes, they turn out that the genes having potential as drug targets are weakly correlated to critical points in a network. In comparison with previous methods, our results have highest mean average precision and also rank the position of the truly drug targets higher. It thereby verifies the effectiveness of our method. CONCLUSIONS: Our method does not know the real ideal routes in the disease network but it tries to find the feasible flow to give a strong influence to the disease genes through possible paths. We successfully formulate the identification of drug target prediction as a maximum flow problem on biological networks and discover potential drug targets in an accurate manner. PMID- 22239823 TI - Hyperglycemia raises the threshold of levosimendan- but not milrinone-induced postconditioning in rat hearts. AB - BACKGROUND: The authors examined whether milrinone and levosimendan could exert cardiac postconditioning effects in rats under normoglycemia and hyperglycemia, and whether the effects could be mediated by mitochondrial permeability transition pore (mPTP). METHODS: Wistar rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received milrinone or levosimendan just before reperfusion under normoglycemic or hyperglycemic conditions with or without atractyloside, an mPTP opener. RESULTS: Under normoglycemia, both 30 MUg/kg milrinone (29 +/- 12%) and 10 MUg/kg levosimendan (33 +/- 13%) reduced infarct size compared with that in the control (58 +/- 7%). Under hyperglycemia, milrinone (34 +/- 13%) reduced infarct size at the same dose as under normoglycemia. In contrast, neither 10 nor 30 MUg/kg levosimendan protected hyperglycemic hearts, and only 100 MUg/kg levosimendan (32 +/- 9%) reduced infarct size compared with that in the hyperglycemic control (58 +/- 13%). All of these cardioprotective effects under normoglycemia and hyperglycemia are abolished by atractyloside. CONCLUSION: Milrinone and levosimendan exert postconditioning effects via inhibition of mPTP opening. Hyperglycemia raises the threshold of levosimendan-induced postconditioning, while milrinone-induced postconditioning is not influenced by hyperglycemia. PMID- 22239824 TI - Biomolecule surface patterning may enhance membrane association. AB - Under dehydration conditions, amphipathic late embryogenesis abundant proteins fold spontaneously from a random conformation into alpha-helical structures, and this transition is promoted by the presence of membranes. To gain insight into the thermodynamics of membrane association, we model the resulting alpha-helical structures as infinite rigid cylinders patterned with hydrophobic and hydrophilic stripes oriented parallel to their axis. Statistical thermodynamic calculations using single chain mean field theory show that the relative thickness of the stripes controls the free energy of interaction of the alpha-helices with a phospholipid bilayer, as does the bilayer structure and the depth of the equilibrium penetration of the cylinders into the bilayer. The results may suggest the optimal thickness of the stripes to mimic the association of such protein with membranes. PMID- 22239825 TI - Characterization of hypoactive sexual desire disorder (HSDD) in men. AB - INTRODUCTION: Little is known about Hypoactive Sexual Desire Disorder (HSDD) in men. AIM: To provide the first comprehensive characterization of men diagnosed with HSDD (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]) using established patient-reported outcomes (PROs) and new PROs developed in line with U.S. Food and Drug Administration (U.S. FDA) guidance. METHODS: This 4-week non-treatment study recruited men (N=200) with or without symptoms of low sexual desire and related distress. Men with erectile dysfunction, serum testosterone <300 ng/dL, or depression were excluded. Men completed assessments of sexual desire and sex-related distress and underwent structured clinical interviews for the diagnosis of HSDD. MAIN OUTCOME MEASURES: Primary endpoints were scores on the Sexual Desire Inventory (SDI), Male Desire Scale (MDS), Sexual Concerns Inventory-Male (SCI-M), and Sexual Desire Relationship Distress Scale (SDRDS) on day 28, and University of California, Los Angeles (UCLA) Psychosexual Diary on days 21-27. Scores are presented as median (interquartile range). RESULTS: There were no clinically relevant differences in age, serum testosterone, depressive symptomatology, erectile function, concomitant illness, or medication use between men with HSDD (N=109) and men without HSDD (N=91). However, clinically meaningful differences between men with and without HSDD were observed in sexual desire according to SDI score (40.0 [21.0] vs. 65.0 [25.0]) and MDS sexual desire domain score (18.0 [8.0] vs. 31.0 [13.0]), in sex-related distress according to SCI-M score (22.0 [12.0] vs. 6.0 [12.0]) and SDRDS score (36.0 [17.0] vs. 10.0 [16.0]), and in UCLA Psychosexual Diary sexual activity domain score (2.6 [2.7] vs. 4.9 [3.9]) (P<0.0001, for all). CONCLUSIONS: Based on a brief structured interview, diagnosis according to DSM-IV TR criteria for HSDD identified a population of men comparable with men without HSDD in age, serum testosterone, concomitant illness and medication use but distinct in their experience of sexual desire and distress associated with low desire. These controlled data characterize HSDD in men as a distinct sexual dysfunction. PMID- 22239826 TI - Rapid gene-based SNP and haplotype marker development in non-model eukaryotes using 3'UTR sequencing. AB - BACKGROUND: Sweet cherry (Prunus avium L.), a non-model crop with narrow genetic diversity, is an important member of sub-family Amygdoloideae within Rosaceae. Compared to other important members like peach and apple, sweet cherry lacks in genetic and genomic information, impeding understanding of important biological processes and development of efficient breeding approaches. Availability of single nucleotide polymorphism (SNP)-based molecular markers can greatly benefit breeding efforts in such non-model species. RNA-seq approaches employing second generation sequencing platforms offer a unique avenue to rapidly identify gene based SNPs. Additionally, haplotype markers can be rapidly generated from transcript-based SNPs since they have been found to be extremely utile in identification of genetic variants related to health, disease and response to environment as highlighted by the human HapMap project. RESULTS: RNA-seq was performed on two sweet cherry cultivars, Bing and Rainier using a 3' untranslated region (UTR) sequencing method yielding 43,396 assembled contigs. In order to test our approach of rapid identification of SNPs without any reference genome information, over 25% (10,100) of the contigs were screened for the SNPs. A total of 207 contigs from this set were identified to contain high quality SNPs. A set of 223 primer pairs were designed to amplify SNP containing regions from these contigs and high resolution melting (HRM) analysis was performed with eight important parental sweet cherry cultivars. Six of the parent cultivars were distantly related to Bing and Rainier, the cultivars used for initial SNP discovery. Further, HRM analysis was also performed on 13 seedlings derived from a cross between two of the parents. Our analysis resulted in the identification of 84 (38.7%) primer sets that demonstrated variation among the tested germplasm. Reassembly of the raw 3'UTR sequences using upgraded transcriptome assembly software yielded 34,620 contigs containing 2243 putative SNPs in 887 contigs after stringent filtering. Contigs with multiple SNPs were visually parsed to identify 685 putative haplotypes at 335 loci in 301 contigs. CONCLUSIONS: This approach, which leverages the advantages of RNA-seq approaches, enabled rapid generation of gene-linked SNP and haplotype markers. The general approach presented in this study can be easily applied to other non-model eukaryotes irrespective of the ploidy level to identify gene-linked polymorphisms that are expected to facilitate efficient Gene Assisted Breeding (GAB), genotyping and population genetics studies. The identified SNP haplotypes reveal some of the allelic differences in the two sweet cherry cultivars analyzed. The identification of these SNP and haplotype markers is expected to significantly improve the genomic resources for sweet cherry and facilitate efficient GAB in this non-model crop. PMID- 22239827 TI - An unusual case of subclinical diffuse glucagonoma coexisting with two nodules in the pancreas: characteristic features on computed tomography. AB - A lesion was discovered in the tail of the pancreas by ultrasonography performed during a health checkup for a 59-year-old Japanese man. Abdominal contrast enhanced computed tomography (CE-CT) revealed strong enhancement in a 4-cm tumor in the pancreatic tail and in a 1-cm tumor in the pancreatic body. Serum glucagon levels were elevated to 54,405 pg/mL and a preoperative diagnosis of glucagonoma was made. The pancreatic tail and spleen were resected en bloc, along with a protruding tumor in the pancreatic body. However, histopathological evaluation revealed diffuse glucagonoma throughout the pancreas. When we retrospectively reviewed abdominal CE-CT after the operation, the entire pancreas was seen to be enlarged and diffusely enhanced by strong spots. Immunohistochemical examination using anti-CD31 demonstrated rich microvessels in two solid glucagonomas as well as microglucagonoma throughout the entire pancreas, indicating hypervascularity. Enlarged pancreas and diffuse enhancement of the pancreas by strong spots may be characteristic features of diffuse glucagonoma on abdominal CE-CT. PMID- 22239828 TI - Splenic artery aneurysm. PMID- 22239830 TI - Bonding and impedance matching of acoustic transducers using silver epoxy. AB - Silver epoxy was selected to bond transducer plates on glass substrates. The properties and thickness of the bonding medium affect the electrical input impedance of the transducer. Thus, the thickness of the silver epoxy bonding layer was used as a design parameter to optimize the structure for the transducer input impedance to match the 50 Omega output impedance of most radio frequency (RF) generators. Simulation and experimental results show that nearly perfect matching is achieved without using any matching circuit. At the matching condition, the transducer operates at a frequency band a little bit below the half-wavelength resonant frequency of the piezoelectric plate. In experiments, lead titanate (PT) piezoelectric plates were employed. Both full-size, 11.5 mm * 2 mm * 0.4 mm, and half-size, 5.75 mm * 2 mm * 0.4 mm, can be well matched using optimal silver epoxy thickness. The transducer assemblies demonstrate high efficiency. The conversion loss from electrical power to acoustic power in soda lime glass is 4.3 dB. This loss is low considering the fact that the transducers operate at off-resonance by 12%. With proper choice of silver epoxy thickness, the transducer can be matched at the fundamental, the 3rd and 5th harmonic frequencies. This leads to the possible realization of triple-band transducers. Reliability was assessed with thermal cycling test according to Telcordia GR-468 Core recommendation. Of the 30 transducer assemblies tested, none broke until 2900 cycles and 27 have sustained beyond 4050 cycles. PMID- 22239829 TI - The soluble amino-terminal region of HVEM mediates efficient herpes simplex virus type 1 infection of gD receptor-negative cells. AB - BACKGROUND: Previous studies from our own and other labs reported the surprising finding that the soluble V domain of the herpes simplex virus type 1 (HSV-1) entry receptor nectin-1 can both block HSV infection of receptor-bearing cells and mediate infection of receptor-deficient cells. Here we show that this property is not unique to nectin-1. We generated a pair of truncated, soluble forms of the other major HSV-1 entry receptor, herpes virus entry mediator (HVEM or HveA), and examined its effects on HSV-1 infection of receptor-deficient cells. RESULTS: In cultures of CHO-K1 cells, sHveA102 comprising the two amino terminal cysteine-rich pseudorepeats (CRPs) of HVEM enabled infection of greater than 80% of the cells at an MOI of 3, while sHveA162 comprising the complete ectodomain failed to mediate infection. Both sHveA102 and sHveA162 blocked infection of CHO-K1 cells stably expressing HVEM in a dose-dependent manner, indicating that both were capable of binding to viral gD. We found that sHveA102 mediated infection involves pH-independent endocytosis whereas HSV infection of HVEM-expressing CHO-K1 cells is known to be pH-dependent. CONCLUSIONS: Our results suggest that the C-terminal portion of the soluble HVEM ectodomain inhibits gD activation and that this effect is neutralized in the full-length form of HVEM in normal infection. PMID- 22239831 TI - Meta-analysis: diagnostic medical radiation exposure in inflammatory bowel disease. AB - BACKGROUND: Diagnostic imaging plays a pivotal role in the diagnosis and management of inflammatory bowel disease (IBD); however, increasing use has led to concerns about the malignant potential of ionising radiation. Several studies have demonstrated that diagnostic imaging can result in exposure to potentially harmful levels of ionising radiation in IBD patients. AIM: To determine the pooled prevalence of increased exposure and pooled odds ratio of risk factors associated with exposure to potentially harmful levels of diagnostic medical radiation. METHODS: We searched Medline, EMBASE, CINHAL and reference lists of identified articles, without language restrictions in October 2011. RESULTS: Six studies with 1704 participants provided data on the proportion of patients receiving potentially harmful levels of radiation defined as >=50 milli-sieverts (mSv)-equivalent to 5 CT abdomen scans. The pooled prevalence was 8.8% (95% CI 4.4-16.8) for IBD patients and 11.1% (95% CI 5.7-20.5%) and 2% (95% CI 0.8-4.9%) for Crohn's disease and ulcerative colitis patients respectively. Five studies involving 2627 participants provided data for risk factors. IBD-related surgery and corticosteroid use were significant with pooled adjusted odds ratio of 5.4 (95% CI 2.6-11.2) and 2.4 (95% CI 1.7-3.4) respectively. CONCLUSIONS: About 1 in 10 patients may be exposed to potentially harmful levels of diagnostic medical radiation. Corticosteroid use and IBD related surgery increased this risk. Strategies to reduce radiation exposure while assessing disease activity need to be considered. PMID- 22239832 TI - The value of the cerebrospinal fluid tap test for predicting shunt effectiveness in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: The cerebrospinal fluid (CSF) tap test (TT) has been regarded as an important test for the prediction of shunt effectiveness in patients with suspected idiopathic normal pressure hydrocephalus (iNPH). Although its specificity and sensitivity are reportedly high, there remains some disagreement over this point. Herein, the TT as a test for predicting shunt effectiveness was investigated in our multicenter prospective study named SINPHONI and strategies to increase its predictability were examined. METHODS: One hundred suspected iNPH patients with the following entry criteria were enrolled in the study: (1) 60 to 85 years old, (2) one or more of the NPH triad signs, (3) ventriculomegaly (Evans index > 0.3), (4) high convexity tightness in coronal-section MRI, and (5) no antecedent disorders. Changes in NPH triad symptoms were assessed using the iNPH grading scale and other measures before and after removal of 30 ml lumbar CSF. A positive response to TT was pre-defined by specific improvements on the grading and other scales. A ventriculoperitoneal shunt was performed with a programmable valve. The sensitivity and specificity of the TT was calculated with a contingency table. A decision tree analysis was performed to increase the predictability of the TT. RESULTS: Among 100 patients, 80 were shunt responders. A statistically-significant variable between shunt responders and non-responders was CSF pressure. The changes in single variables in the iNPH grading scale after TT showed high specificity with low sensitivity. In contrast, change of the total score in the iNPH grading scale showed a relatively high sensitivity of 71.3% with specificity of 65%. A decision tree analysis revealed that using the iNPH grading scale total score and pre-shunt CSF pressure >= 15 cmH20, sensitivity increased to 82.5%, without a decrease in specificity. CONCLUSIONS: The sensitivity and specificity of the TT for predicting shunt responsiveness were optimum when improvement on any iNPH grading scale was combined with CSF pressure >= 15 cmH20. To increase the sensitivity of the TT, further effort is necessary. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, with the number NCT00221091. PMID- 22239833 TI - Extracellular overexpression of recombinant Thermobifida fusca cutinase by alpha hemolysin secretion system in E. coli BL21(DE3). AB - BACKGROUND: Extracellular expression of proteins has an absolute advantage in a large-scale industrial production. In our previous study, Thermobifida fusca cutinase, an enzyme mainly utilized in textile industry, was expressed via type II secretory system in Escherichia coli BL21(DE3), and it was found that parts of the expressed protein was accumulated in the periplasmic space. Due to the fact that alpha-hemolysin secretion system can export target proteins directly from cytoplasm across both cell membrane of E. coli to the culture medium, thus in the present study we investigated the expression of cutinase using this alpha hemolysin secretion system. RESULTS: T. fusca cutinase was fused with the specific signal peptide of alpha-hemolysin scretion system and expressed in E. coli BL21(DE3). In addition, HlyB and HlyD, strain-specific translocation components of alpha-hemolysin secretion system, were coexpressed to facilitate the enzyme expression. The cultivation of this engineered cell showed that cutinase activity in the culture medium reached 334 U/ml, which is 2.5 times that from type II secretion pathway under the same culture condition. The recombinant cutinase was further purified. Biochemical characterization of purified enzyme, which had an alpha-hemolysin secretion pathway signal peptide attached, had substrate specificity, pH and temperature profile, as well as application capability in bioscouring similar to that of wild-type cutinase. CONCLUSIONS: In the present study, T. fusca cutinase was successfully secreted to the culture media by alpha-hemolysin secretion system. This is the first report of cutinase being efficiently secreted by this pathway. Due to the limited cases of successful expression of industrial enzyme by E. coli alpha-hemolysin secretion system, our study further explored the utilization of this pathway in industrial enzymes. PMID- 22239834 TI - Binding-induced DNA assembly and its application to yoctomole detection of proteins. AB - We describe the binding-induced DNA assembly principle and strategy that enable ultrasensitive detection of molecular targets and potential construction of unique nanostructures/nanoreactors. Two DNA motifs that are conjugated to specific affinity ligands assemble preferentially only when a specific target triggers a binding event. The binding-induced assembly of the DNA motifs results in the formation of a highly stable closed-loop structure, raising the melting temperature (T(m)) of the hybrid by >30 degrees C and enabling effective differentiation of the target-specific assembly from the background. The ability to detect as few as a hundred molecules (yoctomole) of streptavidin, platelet derived growth factor, and prostate specific antigen represents an improvement of detection limits by 10(3)-10(5)-fold over traditional immunoassays. The assay is performed in a single tube, eliminating separation, immobilization, and washing steps of conventional assays. By incorporating unique signaling and structural features into the DNA motifs, we envision diverse applications in biosensing and nanotechnology. PMID- 22239835 TI - Rural origin plus a rural clinical school placement is a significant predictor of medical students' intentions to practice rurally: a multi-university study. AB - INTRODUCTION: Health workforce shortages are a major problem in rural areas. Australian medical schools have implemented a number of rural education and training interventions aimed at increasing medical graduates' willingness to work in rural areas. These initiatives include recruiting students from rural backgrounds, delivering training in rural areas, and providing all students with some rural exposure during their medical training. However there is little evidence regarding the impact of rural exposure versus rural origin on workforce outcomes. The aim of this study is to identify and assess factors affecting preference for future rural practice among medical students participating in the Australian Rural Clinical Schools (RCS) Program. METHODS: Questionnaires were distributed to 166 medical students who had completed their RCS term in 2006; 125 (75%) responded. Medical students were asked about their preferred location and specialty for future practice, their beliefs about rural work and life, and the impact of the RCS experience on their future rural training and practice preferences. RESULTS: Almost half the students (47%; n=58) self-reported a 'rural background'. Significantly, students from rural backgrounds were 10 times more likely to prefer to work in rural areas when compared with other students (p<0.001). For those preferring general practice, 80% (n=24) wished to do so rurally. Eighty-five per cent (n=105) of students agreed that their RCS experience increased their interest in rural training and practice with 62% (n=75) of students indicating a preference for rural internship/basic training after their RCS experience. A substantial percentage (86%; n=108) agreed they would consider rural practice after their RCS experience. CONCLUSIONS: This baseline study provides significant evidence to support rural medical recruitment and retention through education and training, with important insights into the factors affecting preference for future rural practice. By far the most significant predictor of rural practice intention is recruitment of students with a rural background who also undertake an RCS placement. This research also demonstrates significant demand for post-graduate rural training places, including specialty places, as RCS graduates become junior doctors and vocational trainees. PMID- 22239836 TI - Cervicofacial nontuberculous mycobacterial lymphadenitis in children. AB - INTRODUCTION: Nontuberculous mycobacteria are ubiquitous organisms readily isolated from natural waters, drinking water systems and soil. They form a continuous challenge to the human immune system which becomes apparent in patients with impaired immunity. However, most infections occur in seemingly healthy children. The clinical presentation consists of a unilateral, non-tender, persistent, cervical lymphadenopathy without systemic illness. Fistula formation may occur. MATERIAL AND METHODS: Patients were included if one or more of the following were positive; 1) mycobacterial culture, 2) acid-fast microscopy, 3) polymerase chain reaction and/or 4) granulomatous inflammation. RESULTS: On the basis of operative management, two distinct groups were established. Group 1 had an excision of all pathological tissue performed and Group 2 was treated with incision and drainage. There was a difference between the two groups in regard to the risk of developing a postoperative fistula. In Group 1, 50% developed a fistula compared with 91% in Group 2 (p = 0.06). CONCLUSION: Surgical treatment is generally advocated as the treatment of choice. Antibiotic treatment is associated with adverse effects and avoidance of surgery does not justify the inferior results related to antibiotics. A watch-and-wait strategy or antibiotic therapy may be considered when surgical excision carries a high risk of facial nerve injury. Although the lymph nodes may persist for months, spontaneous regression may occur and the children remain systemically well. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 22239837 TI - Policies and practices in the health-related reception of quota refugees in Denmark. AB - INTRODUCTION: Quota refugees coming to Denmark are mandated refugee status offshore and approximately 500 quota refugees are resettled annually. Upon arrival to Denmark, quota refugees are received directly in the municipalities and municipal caseworkers therefore have the practical responsibility for their health-related reception. The aim of this study was to investigate the health related reception of quota refugees in Denmark by focusing on the presence of municipal policies and practices, and to test for possible associations with these policies and practices. MATERIAL AND METHODS: The study was based on a survey of all Danish municipalities that had received quota refugees after 1 January 2007. A questionnaire was designed on the background of preliminary research. A total of 49 of the 58 includable respondents returned the questionnaire, which yielded a response rate of 84%. RESULTS: We found that 49% of the municipalities had no policies for health-related reception of quota refugees and 69% had no specific policies regarding general practitioners' general health assessment of quota refugees upon their arrival. Disparities between the municipalities were also found regarding their health-related practices. The presence of health-related policies and certain health-related practices were found to be associated with the number of quota refugees received and the size of municipality. CONCLUSION: Due to the lack of policies and the large responsibility of case workers who are not health professionals, there is a risk that the health needs of this particularly vulnerable group may not be met satisfactorily. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 22239838 TI - Decision to resuscitate or not in patients with chronic diseases. AB - INTRODUCTION: Do-not-resuscitate (DNR) decisions are frequently made without informing the patients. We attempt to determine whether patients and physicians wish to discuss the DNR decision, who they think, should be the final decision maker and whether they agree on the indication for cardiopulmonary resuscitation (CPR) in case of cardiac arrest. MATERIAL AND METHODS: We carried out a questionnaire survey among 112 haemodialysis patients and 17 physicians at department of nephrology, Herlev Hospital. The patients were interviewed orally, the physicians responded to written questionnaires. RESULTS: The majority of patients (86%) and physicians (88%) answered, that patients ought to be involved in the DNR decision. However they both wanted to be the final decision maker. Most patients (69%) desired CPR in case of cardiac arrest. Physicians would attempt to resuscitate 88% of the patients. In 30% of the cases, the patient and the physician disagreed on whether or not to attempt resuscitation. CONCLUSION: Both patients and physicians think they ought to make the final DNR decision. In practice, patients are often not involved. Since the patient and the physician disagree regarding the indication for CPR in one third of the cases, we must assume that many patients are resuscitated against their wishes. National guidelines are required. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 22239839 TI - Low incidence of non-alcoholic steatohepatitis in a Danish liver unit. AB - INTRODUCTION: Non-alcoholic fatty liver disease encompasses a spectrum of histological lesions ranging from steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. Simple steatosis is generally benign, while NASH can progress to severe liver disease. The aim of the present study was to quantify the number of patients with NASH and assess the prognosis associated with the condition in a large Danish referral centre for liver disease. MATERIAL AND METHODS: Through the pathology archives at Hvidovre Hospital, 348 patients with steatohepatitis diagnosed during the 1976-1987-period were identified. Data were systematically collected by review of available medical records. These data were supplemented by data from the Danish National Hospital Registry and the Registry of Causes of Death. RESULTS: A total of 100 patients referred from other hospitals were excluded as their records were missing and 236 patients were excluded, mainly due to a history of alcohol abuse; this left 14 patients to constitute the study population. At the end of the follow-up period which had a median duration of 16.7 years, ten of the patients had died: four of cardiovascular disease, four of extra-hepatic neoplasm and two of unknown causes. There were no liver-related deaths and only one patient developed cirrhosis. CONCLUSION: In a specialised referral centre, only few patients were diagnosed with NASH 25-30 years ago and those who were identified had a low risk of progression to cirrhosis and premature death. FUNDING: The local research council and the foundation for the study of liver diseases at Hvidovre Hospital provided funding for this study. TRIAL REGISTRATION: not relevant. PMID- 22239840 TI - No clinical advantages of coblation tonsillectomy compared with traditional tonsillectomy. AB - INTRODUCTION: Tonsillectomy may be performed by several methods. It is continuously being discussed which method is preferable with regard to postoperative haemorrhage, pain, activity and nutrition. MATERIAL AND METHODS: The present study is a prospective non-randomized study of tonsillectomy. It included 198 patients aged 14-40 years who either underwent coblation tonsillectomy or traditional "cold" tonsillectomy after random allocation to different surgeons. A total of 51 patients underwent coblation tonsillectomy and 147 patients underwent traditional tonsillectomy. We tested the hypothesis that there is no difference in postoperative pain experience between the two surgical techniques. The patients were followed for nine days postoperatively. They filled in a questionnaire on postoperative pain score, activity level and food intake. RESULTS: We found no statistically significant difference in pain perception between the two groups and there was no difference in their levels of activity. The intraoperative haemorrhage was significantly reduced in the coblation tonsillectomy group, but there was no difference in postoperative haemorrhage between the two groups. CONCLUSION: The overall results of this study suggest that neither coblation tonsillectomy nor traditional tonsillectomy enjoys an advantage over the other in patients aged 14-40 years. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 22239841 TI - Simple scoring of the Clock-Drawing test for dementia screening. AB - INTRODUCTION: This study assessed five scoring methods of the Clock-Drawing test (CDT). MATERIAL AND METHODS: A total of 72 out-patients and 29 healthy controls were assessed three times. At Visit 1, diagnostic procedure and assessments were performed with the Clinical Global Impressions (CGI) and Global Deterioration Scale (GDS), and the CDT and the Mini Mental State Examination (MMSE) were done blinded by a nurse. At Visit 2, CDT and MMSE were repeated, and at Visit 3 the CDT, CGI and the GDS were repeated. The CDTs were then rated by physicians and nurses using five different methods of scoring. Receiver-operating characteristics curve analyses were used to assess the CDT's suitability as a screening tool. Correlations between the five CDTs, other scales and predictive values were calculated. The extent to which three-word recall could improve the predictive values was analysed. RESULTS: Correlations between the CDTs and the other scales were good. The predictive values were almost identical (positive values: 93-97%; negative values: 70-74%). Three-word recall improved the values. Rates of dementia in general practice and corresponding predictive values were estimated which resulted in markedly lower positive values around 60% for a rate of dementia of 20%, and 40% for a rate of dementia of 10%. CONCLUSION: As predictive values were nearly identical, the shortest scoring manual (0 to 1) seems preferable. FUNDING: The study was partly funded by Novartis Pharma A/S. TRIAL REGISTRATION: Scientific Ethical Committee, 2003-2-17. PMID- 22239842 TI - Good long-term survival after paediatric heart transplantation. AB - INTRODUCTION: The brain-death criterion was introduced in Denmark in 1990. The first Danish paediatric heart transplantation (HTx) was performed at Copenhagen University Hospital, Rigshospitalet, in Copenhagen in 1991. We describe our experiences during the first 20 years with paediatric HTx. MATERIAL AND METHODS: This was a retrospective study of 37 paediatric patients (<18 years) who were listed for HTx from 1991 to 2011. RESULTS: A total of 26 of the 37 children listed underwent HTx, nine due to congenital heart disease (CHD) and 17 due to cardiomyopathy (CM). Ten patients died while being on the waiting list. One patient was withdrawn from the list due to spontaneous improvement. A total of 21 patients remain alive. Survival was 92% after five years and 82% after ten years. We had two early (CHD) and three late (CM) deaths. Complications were few, but significant. Early acute rejection occurred in seven patients, whereas one patient with repeated late episodes of acute rejection died from graft failure 5.5 years after HTx. We found a time-related progressive deterioration in renal function. Two patients underwent renal Tx, two others died while being on dialysis. Cardiac allograft vasculopathy occurred in three patients, two of whom died. The third remains alive today, 19 years after HTx. CONCLUSION: Our paediatric HTx results are comparable with those of larger international centres and consistent with true long-term survival. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 22239844 TI - Pain following hysterectomy: epidemiological and clinical aspects. AB - It is well known that different surgical procedures like amputation, thoracotomy, inguinal herniotomy, and mastectomy are associated with a risk of developing chronic postsurgical pain. Hysterectomy is the most frequent gynecological procedure with an annual frequency of 5000 hysterectomies for a benign indication in Denmark, but is has not previously been documented in detail to what extent this procedure leads to chronic pain. The aim of this PhD thesis was therefore to describe the epidemiology, type of pain, risk factors, and predictive factors associated with chronic pain after hysterectomy for a benign indication. The thesis includes four papers, of which one is based on a questionnaire study, two are based on a prospective clinical study, and one is a review of chronic pain after hysterectomy. The questionnaire paper included 1135 women one year after hysterectomy. A postal questionnaire about pain before and after hysterectomy was combined with data from the Danish Hysterectomy Database. Chronic postoperative pain was described by 32%, and the identified risk factors were preoperative pelvic pain, previous cesarean section, other pain problems and pain as an indication for hysterectomy. Spinal anesthesia was associated with a decreased risk of having pain after one year. The type of surgery (i.e. abdominal or vaginal hysterectomy) did not influence chronic pain. The prospective paper included 90 women referred for a hysterectomy on benign indication. The tests were performed before, on day 1, and 4 months after surgery and included questionnaires about pain, coping, and quality of life together with quantitative sensory testing of pain thresholds. Seventeen percent had pain after 4 months, and the risk factors were preoperative pain problems elsewhere and a high intensity of acute postoperative pain. Type of surgery was not a risk factor. Preoperative brush-evoked allodynia, pinprick hyperalgesia, and vaginal pain threshold were associated with a high intensity of acute postoperative pain, and preoperative brush-evoked allodynia was also associated with pelvic pain after 4 months. This PhD thesis shows that chronic postoperative pain is present after hysterectomy in 17-32% of women. The identified main risk factors are described above. The findings indicate that it is not the nerve injury itself, but more likely the underlying individual susceptibility to pain that is important for the development of chronic pain after hysterectomy. PMID- 22239845 TI - Improved DNA hybridization parameters by Twisted Intercalating Nucleic Acid (TINA). AB - This thesis establishes oligonucleotide design rules and applications of a novel group of DNA stabilizing molecules collectively called Twisted Intercalating Nucleic Acid - TINA. Three peer-reviewed publications form the basis for the thesis. One publication describes an improved and rapid method for determination of DNA melting points and two publications describe the effects of positioning TINA molecules in parallel triplex helix and antiparallel duplex helix forming DNA structures. The third publication establishes that TINA molecules containing oligonucleotides improve an antiparallel duplex hybridization based capture assay's analytical sensitivity compared to conventionel DNA oligonucleotides. Clinical microbiology is traditionally based on pathogenic microorganisms' culture and serological tests. The introduction of DNA target amplification methods like PCR has improved the analytical sensitivity and total turn around time involved in clinical diagnostics of infections. Due to the relatively weak hybridization between the two strands of double stranded DNA, a number of nucleic acid stabilizing molecules have been developed to improve the sensitivity of DNA based diagnostics through superior binding properties. A short introduction is given to Watson-Crick and Hoogsteen based DNA binding and the derived DNA structures. A number of other nucleic acid stabilizing molecules are described. The stabilizing effect of TINA molecules on different DNA structures is discussed and considered in relation to other nucleic acid stabilizing molecules and in relation to future use of TINA containing oligonucleotides in clinical diagnostics and therapy. In conclusion, design of TINA modified oligonucleotides for antiparallel duplex helixes and parallel triplex helixes follows simple purpose dependent rules. TINA molecules are well suited for improving multiplex PCR assays and can be used as part of novel technologies. Future research should test whether combinations of TINA molecules and other nucleic acid stabilizing molecules can increase analytical sensitivity whilst maintaining nucleobase mismatch discrimination in triplex helix based diagnostic assays. PMID- 22239846 TI - Combining vitamin A and vaccines: convenience or conflict? AB - The present thesis is based on 11 papers from 1995-2010. The studies have mainly taken place at the Bandim Health Project in Guinea-Bissau, West Africa, but a reanalysis of a randomised trial from Ghana is also included. My research has explored the consequences of combining high-dose vitamin A supplementation and childhood vaccines. Vitamin A deficiency is associated with increased mortality. To protect against the consequences of vitamin A deficiency the World Health Organization recommends that high-dose vitamin A supplements be given together with routine vaccines to children between 6 months and 5 years of age in more than 100 low-income countries. The recommendation is based on logistical considerations. The consequences of combining vitamin A and vaccines were not investigated in randomised trials prior to the implementation of this policy - it was assumed that the interventions were independent. My first project aimed to study the effect on the immune response to measles of providing vitamin A together with measles vaccine. We found that the two interventions were not independent. Vitamin A enhanced the antibody response to measles vaccine given at 9 months of age significantly, especially in boys. The effects were sustained over time; the children who had received vitamin A with their measles vaccine were more protected against measles at 6-8 years of age. Though vitamin A supplementation had a beneficial effect on the immune response to measles vaccine, it intrigued me that the effect of vitamin A supplementation on overall mortality was not always beneficial. While vitamin A was beneficial when given after 6 months of age, and two studies had shown a beneficial effect when given at birth, all studies testing the effect between 1-5 months of age had found no effect. These time windows are dominated by three different childhood vaccines: BCG vaccine given at birth, diphtheria-tetanus-pertussis (DTP) vaccine given between 1-5 months of age, and measles vaccine given at 9 months of age. These vaccines have been shown to have strong effects on mortality from infectious diseases in general, so-called non-specific effects. The live BCG and measles vaccine protects against more mortality than can be ascribed to the prevention of tuberculosis and measles, respectively. The inactivated DTP vaccine worryingly has been associated with increased mortality from other infectious diseases. Both positive and negative effects are strongest for girls. I proposed the hypothesis that vitamin A amplifies not only the specific vaccine effects, as we saw for measles vaccine, but also the non-specific effects of vaccines on mortality from other infectious diseases. According to my hypothesis, vitamin A would enhance the non-specific beneficial effects on mortality of BCG and measles vaccine, but also the negative effects of DTP vaccine. Hence, the hypothesis offered an explanation for the mortality-age pattern after vitamin A supplementation. Since it was formulated, I have aimed to test this hypothesis. Since it is associated with ethical problems to randomise children above 6 months of age to vitamin A supplementation, and to randomise children in general to recommended vaccines, we have had to be pragmatic when designing the trials. Hence, our studies have taken many different forms. We conducted an observational study during a vitamin A campaign in which missing vaccines were also provided, and a randomised trial testing the effect of two different doses of vitamin A during another campaign; we tested the effect of providing vitamin A with BCG at birth in two randomised trials, and we reanalysed data from one of the original randomised trials of vitamin A supplementation from the perspective of vaccination status. In all studies the main outcome was mortality. The results document that vitamin A supplements do more than protect against vitamin A deficiency. They support the hypothesis that vitamin A supplements interact with vaccines with important consequences for mortality. First, a smaller dose of vitamin A was more beneficial than a larger dose for girls. Second, the effect of vitamin A given with DTP vaccine was significantly different from the effect of vitamin A given with measles vaccine, and children, who received vitamin A with DTP vaccine, had higher mortality than children, who had received vitamin A alone, or who did not receive anything. Third, vitamin A given with BCG at birth interacted negatively with subsequent DTP vaccines in girls. Fourth, the effect of vitamin A to older children in Ghana depended on vaccination status, being beneficial in boys, but harmful in girls who received DTP vaccine during follow up. The results also show that boys and girls respond differently to vitamin A and vaccines. It is a common assumption within public health in low-income countries that interventions can be combined without producing unexpected consequences. The work presented in this thesis confronts this assumption; the results show that vitamin A and vaccines should be seen not only as specific interventions with specific and independent effects, but as immuno-modulators, which can interact with important consequences for overall mortality. Combining interventions can be convenient and lead to synergistic health benefits, but we documented several examples, where it also leads to unexpectedly increased mortality. Thus, to optimise the child health intervention policy in low-income countries a shift in paradigm is needed. Health interventions should no longer be seen as merely specific and independent, and the policy should probably not be the same for boys and girls. Though more complex, it is necessary to evaluate all health interventions in terms of their effect on overall mortality - and their potential interactions with other health interventions and potential sex differential effects should always be investigated. Only in this way can we assure that the children in the poorest countries get the best possible treatment and avoid using large amounts of money and resources on interventions which may, in worst case, kill them. PMID- 22239847 TI - Treatment of ascites and spontaneous bacterial peritonitis - part I. AB - National guidelines for treatment of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hyponatremia have been approved by the Danish Society of Gastroenterology and Hepatology. Ascites develops in approximately 60% of patients with cirrhosis during a 10 year period and is frequently associated with complications that determine the course of the disease and the prognosis. These evidence-based guidelines are divided in two parts and consider definitions, pathophysiology, diagnostic aspects, treatment, and prophylaxis. PMID- 22239848 TI - Treatment of the hepatorenal syndrome and hyponatremia in cirrhosis - part II. AB - National guidelines for treatment of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hyponatremia have been approved by the Danish Society of Gastroenterology and Hepatology. Ascites develops in approximately 60% of patients with cirrhosis during a 10 year period and is frequently associated with complications that determine the course of the disease and the prognosis. These evidence-based guidelines are divided in two parts and consider definitions, pathophysiology, diagnostic aspects, treatment, and prophylaxis. PMID- 22239849 TI - Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include alpha5 or alpha6 subunits and that mediate synaptosomal neurotransmitter release. AB - Desensitization is a complex property of nicotinic acetylcholine receptors (nAChR). Several subtypes of nAChR have high sensitivity to nicotine and mediate effects of nicotine at concentrations found in blood of tobacco smokers. Desensitization of some of these receptor subtypes has been studied in model systems, however, other subtypes have been difficult to express heterologously in native forms. In addition, model systems may not have the same accessory molecules and post-translational modifications found in native populations. We have used wild-type and subunit null mutant mice to study desensitization properties of the high sensitivity alpha4beta2-nAChRs including those that have alpha5 subunits at both GABAergic and dopaminergic nerve terminals. In addition, we have studied the desensitization of one subtype of alpha6beta2-nAChRs at dopaminergic terminals using alpha4 subunit null mutant mice. Exposure to low nicotine concentrations, leads to rapid, but partial desensitization of activity mediated by these receptors. alpha4beta2-nAChRs including alpha5 subunits show faster rates of recovery from desensitization than alpha4beta2-nAChRs without alpha5. Inclusion of the alpha5 subunit significantly shifts the concentration response for desensitization to higher values, indicating that receptors with alpha5 subunits are less desensitized by a 10-min exposure to low concentrations of nicotine. Receptors with alpha6 subunits appear to desensitize to a lesser degree than those with alpha4 subunits, indicating that alpha6beta2-nAChRs are somewhat resistant to desensitization by nicotine. These results highlight the importance of studying various receptor subtypes in native systems and how they may differentially respond to nicotine and to nicotinic drugs. PMID- 22239850 TI - Penile arterial waveform analyzing system for early identification of young adults with high risk of erectile dysfunction. AB - INTRODUCTION: High prevalence of erectile dysfunction in young adults has raised much concern regarding early identification of risk factors for timely intervention. AIM: This study aimed at identifying young males at risk through a novel penile arterial waveform analyzing system. METHODS: Between July 2009 and December 2010, 30 young adult volunteers of age 18 to 29 without known history of vascular diseases or erectile dysfunction were recruited. MAIN OUTCOME MEASURES: Basic demographic and anthropometric characteristics (i.e., age, body weight, body height, body mass index, waist circumference) were recorded. Blood samples were obtained for determining levels of testosterone, glycosylated hemoglobin, triglyceride, fasting sugar, low- and high-density lipoproteins (HDL). Data obtained from visual sexual stimulation (VSS) RigiScan and the penile arterial waveform amplitude (PAWA) ratios were compared in terms of their correlations with anthropometric and serum biochemical parameters using Pearson's correlation analysis. RESULTS: PAWA ratios were found to correlate with Rigidity (tip and base) (r = 0.425, P = 0.019 and r = 0.664, P < 0.001, respectively). Significant associations of PAWA ratios were noted not only with serum testosterone level but also with risk factors for metabolic and cardiovascular diseases including total triglyceride, HDL, age, waist circumference, body mass index, and diastolic blood pressure. However, VSS RigiScan failed in identifying significant correlations with HDL, age, and diastolic blood pressure. CONCLUSIONS: Not only could the penile waveform analyzing system assess penile endothelial function in young adults, but the results also showed significant associations with their serum testosterone levels and metabolic parameters. The findings suggest that PAWA ratio may serve as an indicator for early identification and treatment of young adults at risk of erectile dysfunction. PMID- 22239851 TI - Effect of modeled reduced gravity conditions on bacterial morphology and physiology. AB - BACKGROUND: Bacterial phenotypes result from responses to environmental conditions under which these organisms grow; reduced gravity has been demonstrated in many studies as an environmental condition that profoundly influences microorganisms. In this study, we focused on low-shear stress, modeled reduced gravity (MRG) conditions and examined, for Escherichia coli and Staphlyococcus aureus, a suite of bacterial responses (including total protein concentrations, biovolume, membrane potential and membrane integrity) in rich and dilute media and at exponential and stationary phases for growth. The parameters selected have not been studied in E. coli and S. aureus under MRG conditions and provide critical information about bacterial viability and potential for population growth. RESULTS: With the exception of S. aureus in dilute Luria Bertani (LB) broth, specific growth rates (based on optical density) of the bacteria were not significantly different between normal gravity (NG) and MRG conditions. However, significantly higher bacterial yields were observed for both bacteria under MRG than NG, irrespective of the medium with the exception of E. coli grown in LB. Also, enumeration of cells after staining with 4',6-diamidino-2 phenylindole showed that significantly higher numbers were achieved under MRG conditions during stationary phase for E. coli and S. aureus grown in M9 and dilute LB, respectively. In addition, with the exception of smaller S. aureus volume under MRG conditions at exponential phase in dilute LB, biovolume and protein concentrations per cell did not significantly differ between MRG and NG treatments. Both E. coli and S. aureus had higher average membrane potential and integrity under MRG than NG conditions; however, these responses varied with growth medium and growth phase. CONCLUSIONS: Overall, our data provides novel information about E. coli and S. aureus membrane potential and integrity and suggest that bacteria are physiologically more active and a larger percentage are viable under MRG as compared to NG conditions. In addition, these results demonstrate that bacterial physiological responses to MRG conditions vary with growth medium and growth phase demonstrating that nutrient resources are a modulator of response. PMID- 22239853 TI - Systematic review: the treatment of noncardiac chest pain with antidepressants. AB - BACKGROUND: Noncardiac chest pain (NCCP) is a common condition, affecting approximately 25% of the general population. The cause of NCCP can be classified as gastro-oesophageal reflux disease (GERD)-related NCCP, where antireflux therapy is the main treatment modality or alternatively as non-GERD-related NCCP, where pain modulators, including antidepressants, are utilised. AIM: To provide a systematic review evaluating the evidence for the use of antidepressants in the treatment of non-GERD-related NCCP. METHODS: A computerised literature and manual search was conducted to identify relevant randomised, placebo-controlled studies, published in any language for the evaluation of the effectiveness of antidepressant as a therapeutic intervention for NCCP. RESULTS: Six randomised placebo-controlled trials of antidepressant treatment for NCCP were identified. The medications included were selective serotonin reuptake inhibitors [paroxetine (n = 2), sertraline (n = 1)], tricyclic antidepressant [impramine (n = 1)], serotonin-norepinephrine reuptake inhibitor [venlafaxine (n = 1)] and a triazolopyridine [trazodone (n = 1)]. The percentage reduction in chest pain was statistically significant with venlafaxine (50% vs. 10%; P < 0.001), sertraline (63% vs. 15%; P = 0.02) and imipramine (52% vs. 1%; P = 0.03). The improvement in chest pain symptoms was independent of improvement in depression scores. Clinical global improvement also significantly improved in patients on venlafaxine, sertraline, paroxetine and trazodone. The percentage of patients in treatment groups reporting adverse effects were relatively high compared with those in placebo groups, although majority were statistically insignificant or significance was not reported. Nonetheless, adverse events were the reported reason for discontinuation of trials in 53% of patients from the antidepressant groups compared with 29% from the placebo group. CONCLUSIONS: There is modest evidence for the benefit of antidepressants in reducing NCCP and improving patients' general health. However, there is significant heterogeneity amongst the studies with several study limitations to warrant more rigorous trials and to assess the usefulness of low-dose antidepressants in non-GERD NCCP. PMID- 22239852 TI - Global gene expression changes in human embryonic lung fibroblasts induced by organic extracts from respirable air particles. AB - BACKGROUND: Recently, we used cell-free assays to demonstrate the toxic effects of complex mixtures of organic extracts from urban air particles (PM2.5) collected in four localities of the Czech Republic (Ostrava-Bartovice, Ostrava Poruba, Karvina and Trebon) which differed in the extent and sources of air pollution. To obtain further insight into the biological mechanisms of action of the extractable organic matter (EOM) from ambient air particles, human embryonic lung fibroblasts (HEL12469) were treated with the same four EOMs to assess changes in the genome-wide expression profiles compared to DMSO treated controls. METHOD: For this purpose, HEL cells were incubated with subtoxic EOM concentrations of 10, 30, and 60 MUg EOM/ml for 24 hours and global gene expression changes were analyzed using human whole genome microarrays (Illumina). The expression of selected genes was verified by quantitative real-time PCR. RESULTS: Dose-dependent increases in the number of significantly deregulated transcripts as well as dose-response relationships in the levels of individual transcripts were observed. The transcriptomic data did not differ substantially between the localities, suggesting that the air pollution originating mainly from various sources may have similar biological effects. This was further confirmed by the analysis of deregulated pathways and by identification of the most contributing gene modulations. The number of significantly deregulated KEGG pathways, as identified by Goeman's global test, varied, depending on the locality, between 12 to 29. The Metabolism of xenobiotics by cytochrome P450 exhibited the strongest upregulation in all 4 localities and CYP1B1 had a major contribution to the upregulation of this pathway. Other important deregulated pathways in all 4 localities were ABC transporters (involved in the translocation of exogenous and endogenous metabolites across membranes and DNA repair), the Wnt and TGF-beta signaling pathways (associated particularly with tumor promotion and progression), Steroid hormone biosynthesis (involved in the endocrine-disrupting activity of chemicals), and Glycerolipid metabolism (pathways involving the lipids with a glycerol backbone including lipid signaling molecules). CONCLUSION: The microarray data suggested a prominent role of activation of aryl hydrocarbon receptor-dependent gene expression. PMID- 22239854 TI - Solid-state NMR spectroscopy reveals anomer specific transport of galactose in the milk yeast Kluyveromyces lactis. AB - Genetic evidence indicates that only the beta-anomer of galactose is transported to Kluyveromyces lactis cells by galactose/glucose transporter Hgt1p, and that aldose-1-epimerase encoded by GAL10 is a prerequisite for growth on galactose. Minor aldose-1-epimerases other than Gal10p also exist in K. lactis. Using a mutant defective in both aldose-1-epimerases, we show by solid-state nuclear magnetic resonance spectroscopy that only beta-anomer is transported in the cell and stays without or with a slow rate of conversion to alpha-anomer. Signals due to intracellular beta-galactose appeared at two positions, both of which were shifted towards higher magnetic fields than that of beta-galactose in aqueous solution, suggesting that incorporated galactose binds to cellular components, probably proteins. PMID- 22239855 TI - Changes in malaria morbidity and mortality in Mpumalanga Province, South Africa (2001-2009): a retrospective study. AB - BACKGROUND: Malaria remains a serious epidemic threat in Mpumalanga Province. In order to appropriately target interventions to achieve substantial reduction in the burden of malaria and ultimately eliminate the disease, there is a need to track progress of malaria control efforts by assessing the time trends and evaluating the impact of current control interventions. This study aimed to assess the changes in the burden of malaria in Mpumalanga Province during the past eight malaria seasons (2001/02 to 2008/09) and whether indoor residual spraying (IRS) and climate variability had an effect on these changes. METHODS: This is a descriptive retrospective study based on the analysis of secondary malaria surveillance data (cases and deaths) in Mpumalanga Province. Data were extracted from the Integrated Malaria Information System. Time series model (Autoregressive Integrated Moving Average) was used to assess the association between climate and malaria. RESULTS: Within the study period, a total of 35,191 cases and 164 deaths due to malaria were notified in Mpumalanga Province. There was a significant decrease in the incidence of malaria from 385 in 2001/02 to 50 cases per 100,000 population in 2008/09 (P < 0.005). The incidence and case fatality (CFR) rates for the study period were 134 cases per 100,000 and 0.54%, respectively. Mortality due to malaria was lower in infants and children (CFR < 0.5%) and higher in those >65 years, with the mean CFR of 2.1% as compared to the national target of 0.5%. A distinct seasonal transmission pattern was found to be significantly related to changes in rainfall patterns (P = 0.007). A notable decline in malaria case notification was observed following apparent scale-up of IRS coverage from 2006/07 to 2008/09 malaria seasons. CONCLUSIONS: Mpumalanga Province has achieved the goal of reducing malaria morbidity and mortality by over 70%, partly as a result of scale-up of IRS intervention in combination with other control strategies. These results highlight the need to continue with IRS together with other control strategies until interruption in local malaria transmission is completely achieved. However, the goal to eliminate malaria as a public health problem requires efforts to be directed towards the control of imported malaria cases; development of strategies to interrupt local transmission; and maintaining high quality surveillance and reporting system. PMID- 22239856 TI - Biorefinery process for protein extraction from oriental mustard (Brassica juncea (L.) Czern.) using ethanol stillage. AB - Large volumes of treated process water are required for protein extraction. Evaporation of this water contributes greatly to the energy consumed in enriching protein products. Thin stillage remaining from ethanol production is available in large volumes and may be suitable for extracting protein rich materials. In this work protein was extracted from ground defatted oriental mustard (Brassica juncea (L.) Czern.) meal using thin stillage. Protein extraction efficiency was studied at pHs between 7.6 and 10.4 and salt concentrations between 3.4 * 10-2 and 1.2 M. The optimum extraction efficiency was pH 10.0 and 1.0 M NaCl. Napin and cruciferin were the most prevalent proteins in the isolate. The isolate exhibited high in vitro digestibility (74.9 +/- 0.80%) and lysine content (5.2 +/- 0.2 g/100 g of protein). No differences in the efficiency of extraction, SDS-PAGE profile, digestibility, lysine availability, or amino acid composition were observed between protein extracted with thin stillage and that extracted with NaCl solution. The use of thin stillage, in lieu of water, for protein extraction would decrease the energy requirements and waste disposal costs of the protein isolation and biofuel production processes. PMID- 22239857 TI - Outdoor adventure for young people with a mental illness. AB - AIM: The study aims to evaluate the efficacy of an Outdoor Adventure Group (OAG) for young people with a mental illness. It was hypothesized that participating in OAG would result in an increase in self-esteem, sense of mastery and social connectedness, compared with those who attended other Psychosocial Recovery Group Program groups based at Orygen Youth Health. In addition, those in the OAG would show an improved performance of personal goals. METHODS: Twenty-one youths (aged 15 to 25) participated in the OAG and 12 participated in other Psychosocial Recovery Group Program groups and served as the comparison group. Pre- and post evaluation measures included (i) Rosenberg Self Esteem Scale; (ii) Mastery Scale; (iii) Social Connectedness Scale; and (iv) personal goals for attending the OAG, rated 1-10 on current performance. The groups were based at Orygen Youth Health, Melbourne, Australia and run over an 8 to 10-week period. RESULTS: Participants of the OAG experienced an improvement in self-esteem (P = 0.001) and mastery (P = 0.001); these changes were not observed in the controls. There were a total of 80 personal goals for the OAG, with an average of 3.81 per person, and performance significantly improved in 66 (82.5%) goals. There were 10 categories of goals; the most common goals were related to self-improvement and social skills development. CONCLUSIONS: Increased self-esteem and mastery, and achievement of personal goals gained through the OAG, may facilitate, or be a precursor to, a young person's psychosocial recovery. PMID- 22239858 TI - Evaluation of hepatic and thyroid responses in male Sprague Dawley rats for up to eighty-four days following seven days of dietary exposure to potassium perfluorooctanesulfonate. AB - In a prior 28-day dietary study in rats with 20 and 100 ppm K+ PFOS, activation of PPARalpha and CAR/PXR were concluded to be etiological factors in K+ PFOS induced hepatomegaly and hepatic tumorigenesis. The objective of this study was to evaluate persistence/resolution of K+ PFOS-induced, liver-related effects in male Sprague Dawley rats following a 7-day dietary exposure to K+ PFOS at 20 or 100 ppm. Groups of 10 rats per treatment were observed on recovery Day(s) 1, 28, 56, and 84 following treatment. Changes consistent with hepatic PPARalpha and CAR/PXR activation noted on recovery Day 1 included: increased liver weight; decreased plasma cholesterol, alanine aminotransferase, and triglycerides; decreased liver DNA concentration and increased hepatocellular cytosolic CYP450 concentration; increased liver activity of acyl CoA oxidase, CYP4A, CYP2B, and CYP3A; increased liver proliferative index and decreased liver apoptotic index; decreased hepatocellular glycogen-induced vacuoles; increased centrilobular hepatocellular hypertrophy. Most effects resolved to control levels during recovery. Effects on plasma cholesterol, hepatocellular cytosolic CYP450 concentrations, liver apoptotic index, CYP3A, and centrilobular hepatocellular hypertrophy persisted through the end of the recovery period. Thyroid parameters (histology, apoptosis, and proliferation) were unaffected at all time points. Mean serum PFOS concentrations on recovery Day 1 were 39 and 140 MUg/mL (20 ppm and 100 ppm K+ PFOS, respectively), decreasing to 4 and 26 MUg/mL by recovery Day 84. Thus, hepatic effects in male rats resulting from K+ PFOS-induced activation of PPARalpha and CAR/PXR resolved slowly or were still present after 84-days following a 7-day dietary treatment, consistent with the slow elimination rate of PFOS. PMID- 22239859 TI - Copper-induced immunotoxicity involves cell cycle arrest and cell death in the spleen and thymus. AB - Copper is an essential trace element for human physiological processes. To evaluate the potential adverse health impact/immunotoxicological effects of this metal in situ due to over exposure, Swiss albino mice were treated (via intraperitoneal injections) with copper (II) chloride (copper chloride) at doses of 0, 5, or 7.5 mg copper chloride/kg body weight (b.w.) twice a week for 4 wk; these values were derived from LD50 studies using copper chloride doses that ranged from 0 to 40 mg/kg BW (2*/wk, for 4 wk). Copper treated mice evidenced immunotoxicity as indicated by dose-related decreases and increases, respectively, in thymic and splenic weights. Histomorphological changes evidenced in these organs were thymic atrophy, white pulp shrinkage in the spleen, and apoptosis of splenocytes and thymocytes; these observations were confirmed by microscopic analyses. Cell count analyses indicated that the proliferative functions of the splenocytes and thymocytes were also altered because of the copper exposures. Among both cell types from the copper treated hosts, flow cytometric analyses revealed a dose related increase in the percentages of cells in the Sub-G0/G1 state, indicative of apoptosis which was further confirmed by Annexin V binding assay. In addition, the copper treatments altered the expression of selected cell death related genes such as EndoG and Bax in a dose related manner. Immunohistochemical analyses revealed that there was also increased ubiquitin expression in both the cell types. In conclusion, these studies show that sublethal exposure to copper (as copper chloride) induces toxicity in the thymus and spleen, and increased Sub G0/G1 population among splenocytes and thymocytes that is mediated, in part, by the EndoG-Bax-ubiquitin pathway. This latter damage to these cells that reside in critical immune system organs are likely to be important contributing factors underlying the immunosuppression that has been documented by other investigators following acute high dose/chronic low-medium dose exposures to copper agents. PMID- 22239860 TI - Visual laterality in dolphins: importance of the familiarity of stimuli. AB - BACKGROUND: Many studies of cerebral asymmetries in different species lead, on the one hand, to a better understanding of the functions of each cerebral hemisphere and, on the other hand, to develop an evolutionary history of hemispheric laterality. Our animal model is particularly interesting because of its original evolutionary path, i.e. return to aquatic life after a terrestrial phase. The rare reports concerning visual laterality of marine mammals investigated mainly discrimination processes. As dolphins are migrant species they are confronted to a changing environment. Being able to categorize new versus familiar objects would allow dolphins a rapid adaptation to novel environments. Visual laterality could be a prerequisite to this adaptability. To date, no study, to our knowledge, has analyzed the environmental factors that could influence their visual laterality. RESULTS: We investigated visual laterality expressed spontaneously at the water surface by a group of five common bottlenose dolphins (Tursiops truncatus) in response to various stimuli. The stimuli presented ranged from very familiar objects (known and manipulated previously) to familiar objects (known but never manipulated) to unfamiliar objects (unknown, never seen previously). At the group level, dolphins used their left eye to observe very familiar objects and their right eye to observe unfamiliar objects. However, eyes are used indifferently to observe familiar objects with intermediate valence. CONCLUSION: Our results suggest different visual cerebral processes based either on the global shape of well-known objects or on local details of unknown objects. Moreover, the manipulation of an object appears necessary for these dolphins to construct a global representation of an object enabling its immediate categorization for subsequent use. Our experimental results pointed out some cognitive capacities of dolphins which might be crucial for their wild life given their fission-fusion social system and migratory behaviour. PMID- 22239861 TI - A novel study on amyloid beta peptide 40, 42 and 40/42 ratio in Saudi autistics. AB - OBJECTIVES: We examined whether plasma concentrations of amyloid beta (Abeta) as protein derivatives play a central role in the etiology of autistic features. DESIGN AND METHODS: Concentrations of human Abeta (1-42), Abeta (1-40), and Abeta (40/42) in the plasma of 52 autistic children (aged 3-16 years) and 36 age matched control subjects were determined by using the ELISA technique and were compared. RESULTS: Compared to control subjects, autistic children exhibited significantly lower concentrations of both Abeta (1-40) and Abeta (1-42) and lower Abeta (40/42) concentration ratio. Receiver operating characteristics curve (ROC) analysis showed that these measurements of Abeta peptides showed high specificity and sensitivity in distinguishing autistic children from control subjects. CONCLUSIONS: Lower concentrations of Abeta (1-42) and Abeta (1-40) were attributed to loss of Abeta equilibrium between the brain and blood, an imbalance that may lead to failure to draw Abeta from the brain and/or impairment of beta- and gamma- secretase's concentration or kinetics as enzymes involving in Abeta production. PMID- 22239862 TI - Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the DAISY study. AB - INTRODUCTION: Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. AIM: To assess the efficacy and tolerability of flibanserin, a postsynaptic 5-HT1A agonist/5-HT2A antagonist, in the treatment of premenopausal women with HSDD. METHODS: North American premenopausal women with HSDD (mean age 35 years) were randomized to 24 weeks' treatment with flibanserin 25 mg twice daily (N=396), 50 mg twice daily (N=392), 100 mg once daily at bedtime (N=395), or placebo (N=398). MAIN OUTCOME MEASURES: Co-primary endpoints were changed from baseline to study end in number of satisfying sexual events (SSE) and sexual desire score, measured daily using an eDiary. Secondary endpoints included change in Female Sexual Distress Scale-Revised (FSDS-R) total score and Item 13 score (distress due to low sexual desire), Female Sexual Function Index (FSFI) total and desire domain scores, and Patient's Global Impression of Improvement. RESULTS: Flibanserin 100 mg once daily was associated with an increase in SSE (P<0.01 vs. placebo) but the 25 mg and 50 mg twice daily doses were not. No group showed a significant increase in eDiary desire score vs. placebo. All flibanserin regimens improved FSDS-R total, FSDS-R Item 13, FSFI total, and FSFI desire domain scores vs. placebo (P<0.05, for all). More women receiving flibanserin 50 mg twice daily and 100 mg once daily considered their HSDD to have improved than women receiving placebo (44.1% and 47.0% vs. 30.3%, respectively) (P<0.000, 1 vs. placebo). The most frequently reported adverse events in women receiving flibanserin were somnolence (11.8%), dizziness (10.5%), and fatigue (10.3%). CONCLUSION: In premenopausal women with HSDD, flibanserin 100 mg once daily was well tolerated and associated with statistically significant improvements in SSE, sexual desire (FSFI desire domain score but not eDiary desire score), sexual function, and decrease in sexual distress vs. placebo. PMID- 22239863 TI - White matter myelin loss in the brains of aged dogs. AB - The significance of cerebral white matter (WM) demyelination in the cognitive decline of elderly humans is disputed. Cognitive decline also occurs in aged dogs, although the age-related changes that occur in the canine cerebral WM are yet to be studied, particularly with regard to their relevance to the WM alterations of elderly humans. The present study revealed age-dependent myelin loss in the frontal lobe WM of canine brains. The accumulation of ceroid lipofuscin-laden phagocytes was observed in the perivascular spaces of the WM and was correlated with the decrease in myelination. Also, myelin basic protein was detected in some of the vacuoles of these phagocytes. In the WM, beta-amyloid (Abeta) was deposited focally in capillary walls, and colocalized with apolipoprotein E (Apo E). Note that the dog is homozygous for Apo E4, which genotype is related to capillary CAA in humans. These findings indicate that WM demyelination occurs in aged dogs as well as in aged humans, hence WM alterations may account for age-related behavioral changes of the dog. In conclusion, dogs are useful for chronological studies of age-related WM changes. PMID- 22239864 TI - U.S. census unit population exposures to ambient air pollutants. AB - BACKGROUND: Progress has been made recently in estimating ambient PM(2.5) (particulate matter with aerodynamic diameter < 2.5 MUm) and ozone concentrations using various data sources and advanced modeling techniques, which resulted in gridded surfaces. However, epidemiologic and health impact studies often require population exposures to ambient air pollutants to be presented at an appropriate census geographic unit (CGU), where health data are usually available to maintain confidentiality of individual health data. We aim to generate estimates of population exposures to ambient PM(2.5) and ozone for U.S. CGUs. METHODS: We converted 2001-2006 gridded data, generated by the U.S. Environmental Protection Agency (EPA) for CDC's (Centers for Disease Control and Prevention) Environmental Public Health Tracking Network (EPHTN), to census block group (BG) based on spatial proximities between BG and its four nearest grids. We used a bottom-up (fine to coarse) strategy to generate population exposure estimates for larger CGUs by aggregating BG estimates weighted by population distribution. RESULTS: The BG daily estimates were comparable to monitoring data. On average, the estimates deviated by 2 MUg/m(3) (for PM(2.5)) and 3 ppb (for ozone) from their corresponding observed values. Population exposures to ambient PM(2.5) and ozone varied greatly across the U.S. In 2006, estimates for daily potential population exposure to ambient PM(2.5) in west coast states, the northwest and a few areas in the east and estimates for daily potential population exposure to ambient ozone in most of California and a few areas in the east/southeast exceeded the National Ambient Air Quality Standards (NAAQS) for at least 7 days. CONCLUSIONS: These estimates may be useful in assessing health impacts through linkage studies and in communicating with the public and policy makers for potential intervention. PMID- 22239865 TI - Repeat CT assessed CTV variation and PTV margins for short- and long-course pre operative RT of rectal cancer. AB - PURPOSE: To quantify the inter-fraction shape variation of the CTV in rectal cancer patients treated with 5 * 5 (SCRT) and 25 * 2 Gy (LCRT) and derive PTV margins. METHODS AND MATERIALS: Thirty-three SCRT with daily repeat CT scans and 30 LCRT patients with daily scans during the first week followed by weekly scans were included. The CTV was delineated on all scans and local shape variation was calculated with respect to the planning CT. Margin estimation was done using the local shape variation to assure 95% minimum dose for at least 90% of patients. RESULTS: Using 482 CT scans, systematic and random CTV shape variation was heterogeneous, ranging from 0.2 cm close to bony structures up to 1.0 cm SD at the upper-anterior CTV region. A significant reduction in rectal volume during LCRT resulted in an average 0.5 cm posterior shift of the upper-anterior CTV. Required margins ranged from 0.7 cm close to bony structures up to 3.1 and 2.3 cm in the upper-anterior region for SCRT and LCRT, respectively. CONCLUSIONS: Heterogeneous shape variation demands anisotropic PTV margins. Required margins were substantially larger in the anterior direction compared to current clinical margins. These larger margins were, however, based on strict delineated CTVs, resulting in smaller PTVs compared to current practice. PMID- 22239866 TI - Control chart analysis of data from a multicenter monitor unit verification study. AB - BACKGROUND AND PURPOSE: This study aims to investigate the process of monitor unit verification using control charts. Control charts is a key tool within statistical process control (SPC), through which process characteristics can be visualized, usually chronologically with statistically determined limits. MATERIAL AND METHODS: Our group has developed a monitor unit verification software that has been adopted at several Swedish institutions for pre-treatment verification of radiotherapy treatments. Deviations between point dose calculations using the treatment planning systems and using the independent monitor unit verification software from 9219 treatment plans and five different institutions were included in this multicenter study. The process of monitor unit verification was divided into subprocesses. Each subprocess was analyzed using probability plots and control charts. RESULTS: Differences in control chart parameters for the investigated subprocesses were found between different treatment sites and different institutions, as well as between different treatment techniques. 19 of 37 subprocesses met the clinical specification (+/- 5%), i.e. process capability index was equal to or above one. CONCLUSIONS: Control charts were found to be a useful tool for continuous analysis of data from the monitor unit verification software for patient specific quality control, as well as for comparisons between different institutions and treatment sites. The derived control chart limits were in agreement with AAPM TG114 guidelines on action levels. PMID- 22239867 TI - Endocrine disrupters: potential risk factors affecting sexual function in both men and women. PMID- 22239868 TI - Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: a population-based study. AB - OBJECTIVE: Although some studies have suggested that uric acid is a risk factor for mortality, this relationship is still uncertain in people with type 2 diabetes. METHODS: The study base was the population-based cohort of 1540 diabetic subjects (median age 68.9 years) of the Casale Monferrato Study. The role of serum uric acid on 15-years all-cause, cardiovascular and non cardiovascular mortality was assessed by multivariate Cox proportional hazards modeling. RESULTS: Baseline levels of serum uric acid were negatively correlated with HbA1c, were higher in men and in the elderly and were independently associated with components of the metabolic syndrome. Out of 14,179 person-years, 1000 deaths (514 due to cardiovascular diseases) were observed. Compared to the lower quartile of uric acid, HRs (95% CI) in the upper quartile were 1.47 (1.22 1.76) for all-cause mortality; 1.40 (1.09-1.80) for cardiovascular mortality and 1.50 (1.15-1.96) for non-cardiovascular mortality. In multiple adjusted models, however, HRs were 1.30 (1.06-1.60) for all-cause mortality, 1.13 (0.85-1.50) for cardiovascular mortality and 1.50 (1.11-2.02) for non-cardiovascular mortality (men 1.87, 1.19-2.95; women 1.20, 0.80-1.80); the latter appeared to be due to neoplastic diseases (HR in all combined quartiles vs. lower quartile: both sexes 1.59, 1.05-2.40; men 1.54, 0.83-2.84, women 1.68, 0.95-2.92). CONCLUSIONS: In diabetic people, uric acid is associated with components of the metabolic syndrome but it may not be accounted as an independent risk factor for cardiovascular mortality. The increased all-cause mortality risk with higher levels of uric acid might be due to increased neoplastic mortality and deserves future studies. PMID- 22239870 TI - Techniques in assessing fatigue in neuromuscular diseases. AB - Fatigue is common in neuromuscular disease and it may affect quality of life; however, it has not been adequately studied. We can approach fatigue in neuromuscular diseases systematically. Questionnaires are used to assess subjective or experienced fatigue, and with the wide availability of the Internet, many patients can fill out questionnaires through Web-based surveys. Researchers can use force-generation protocols to evaluate physical fatigability and attention protocols to evaluate mental fatigability. Using these techniques to further understand the mechanisms of subjective and physiologic fatigue will help physicians to develop more effective treatments for fatigue and improve patients' quality of life. PMID- 22239869 TI - Use of skeletal muscle MRI in diagnosis and monitoring disease progression in Duchenne muscular dystrophy. AB - Studies have shown promise in using various approaches of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy to evaluate skeletal muscle involvement in Duchenne muscular dystrophy. However, these studies have mainly been performed using a cross-sectional design, and the correlation of these MRI changes with disease progression and disease severity has not been fully elucidated. Overall, skeletal muscle MRI is a powerful and sensitive technique in the evaluation of muscle disease, and its use as a biomarker for disease progression or therapeutic response in clinical trials deserves further study. PMID- 22239871 TI - The utility of electromyography and mechanomyography for assessing neuromuscular function: a noninvasive approach. AB - This article introduces the utility of electromyography (EMG) and mechanomyography (MMG) for the assessment of neuromuscular function, and discusses the interpretation of the EMG and MMG signals for various exercise perturbations. The results of these studies suggest that the use of EMG and MMG to determine muscle fatigue is robust. Future studies with clinical populations are needed, however, to determine the optimal use of EMG and/or MMG for assessing muscle function in rehabilitative settings. PMID- 22239872 TI - Novel concepts integrated in neuromuscular assessments for surgical restoration of arm and hand function in tetraplegia. AB - Surgical restoration of key functions of the upper extremity has tremendous potential to increase autonomy, mobility, and self-esteem by resuming critical abilities in patients with tetraplegia. New strategies of surgical reconstruction and postoperative rehabilitation of upper extremity function in tetraplegic patients have been developed, based on basic science and clinical studies. In contrast to traditional hand reconstruction with separate flexors and extensors phases, combining 7 individual procedures provides key pinch and finger flexion together with passive opening of hand in one stage. Further research should aim at combining traditional algorithms with new approaches, such as immediate postoperative activation, combined procedures and nerve transfers. PMID- 22239873 TI - The effects of active and passive stretching on muscle length. AB - Active stretch is necessary for regulating muscle fiber length (ie, the number of series sarcomeres). Elevated cytoplasmic calcium is the proposed component of contractile activity required to activate signaling pathways for sarcomere number regulation. Passive stretch reduces muscle tissue stiffness, most likely by signaling connective tissue remodeling via fibroblasts. Passive stretch may induce sarcomere addition if the muscle fibers are lengthened sufficiently to raise cytoplasmic calcium through stretch-activated calcium channels. The magnitude of stretch in vivo is limited by the physiologic range of movement and stretch pain tolerance. The greatest effect of stretching muscle fibers is expected when the lengthening exceeds the optimum fiber length (Lo). PMID- 22239874 TI - Hypohomocysteinemia: a potentially treatable cause of peripheral neuropathology? AB - Perturbations of homocysteine metabolism are associated with increased risk for cardiovascular disease, stroke, dementia, and depression, among other major diseases. To assess the relationship between hypohomocysteinemia (HH) and idiopathic peripheral neuropathy (IPN), a retrospective review of 37,442 patients from a tertiary medical clinic was performed. Of patients with HH, 5.9% had IPN versus 0.6% of patients without IPN. Overall, 41% of patients with HH had IPN. These observations indicate that although HH is uncommon in the general population, there is a striking relationship between HH and the incidence of IPN. This article discusses the clinical ramifications of these findings. PMID- 22239875 TI - Regional and whole-body dual-energy X-ray absorptiometry to guide treatment and monitor disease progression in neuromuscular disease. AB - Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials. PMID- 22239876 TI - Establishing clinical end points of respiratory function in large animals for clinical translation. AB - Respiratory dysfunction due progressive weakness of the respiratory muscles, particularly the diaphragm, is a major cause of death in the neuromuscular disease (NMD) X-linked myotubular myopathy (XLMTM). Methods of respiratory assessment in patients are often difficult, especially in those who are mechanically ventilated. The naturally occuring XLMTM dog model exhibits a phenotype similar to that in patients and can be used to determine quantitative descriptions of dysfunction as clinical endpoints for treatment and the development of new therapies. In experiments using respiratory impedance plethysmography (RIP), XLMTM dogs challenged with the respiratory stimulant doxapram displayed significant changes indicative of diaphragmatic weakness. PMID- 22239877 TI - New opportunities and novel paradigms to support neuromuscular research. AB - This article provides an overview of the structure and function of the National Skeletal Muscle Research Center (NSMRC) at the University of California, San Diego, which is one of the 7 research centers of the Medical Rehabilitation Research Infrastructure Network, created to facilitate access for physicians to experts, technology, and resources from scientific fields related to medical rehabilitation. The 4 cores of the NSMRC are described as a resource for rehabilitation medicine practitioners to use for clinically relevant muscle research. PMID- 22239878 TI - Skeletal muscle edema in muscular dystrophy: clinical and diagnostic implications. AB - Muscle degeneration in muscular dystrophies often includes a period of edema before fatty replacement of muscle tissue. Magnetic resonance imaging (MRI) has been used successfully to characterize muscle and fat patterns in several types of muscular dystrophies. Recent MRI techniques enable characterization of edema in tissues. This article reviews the advantages of using MRI assessment of edema and fat in muscle tissue to evaluate disease progression, and discusses inflammation and sarcolemma compromise as sources of edema in muscular dystrophy. Lastly, refining current techniques and adapting other MRI capabilities may enhance detection and assessment of edema for better evaluation of disease progression and treatment outcomes. PMID- 22239879 TI - Cardiac MRI in muscular dystrophy: an overview and future directions. AB - Cardiac complications are a common feature of many muscular dystrophies. Although many modalities (eg, ultrasound) provide exceptional efficacy for early diagnosis, repeated monitoring, and therapeutic management, MRI has become the gold standard for anatomic and functional characterization. An increasing number of studies, especially in the dystrophinopathies, use strain imaging to evaluate function. This article summarizes these studies and attempts to integrate an understanding of other relevant cardiac features (eg, fibrosis) into interpreting this work. Finally, a general roadmap forward is provided as these tools are increasingly used for treatment assessment and tactical patient management in the future. PMID- 22239880 TI - Neuromuscular ultrasonography: quantifying muscle and nerve measurements. AB - Neuromuscular ultrasonography can be used both descriptively and quantitatively in the evaluation of patients with neuromuscular disorders. This article reviews the quantitative use of this technology, particularly measurements of the size and echogenicity of nerve and muscle, as a tool for assessing the severity, progression, and response of these tissues to therapeutic interventions. Neuromuscular ultrasonography has several features, including portability and noninvasiveness, that make it an attractive research tool for advancing the diagnosis and treatment of neuromuscular disorders. PMID- 22239882 TI - Exercise testing in metabolic myopathies. AB - Metabolic myopathies are a group of genetic disorders specifically affecting glucose/glycogen, lipid, and mitochondrial metabolism. The main metabolic myopathies that are evaluated in this article are the mitochondrial myopathies, fatty acid oxidation defects, and glycogen storage disease. This article focuses on the usefulness of exercise in the evaluation of genetic metabolic myopathies. PMID- 22239884 TI - Aging of human muscle: understanding sarcopenia at the single muscle cell level. AB - The loss of muscle mass with age, also known as sarcopenia, is a major scientific and public health problem. Muscle atrophy is associated with the loss of functional capacity and poor health outcomes in elderly men and women. A detailed understanding of this problem in humans can be enhanced by the use of experiments with single muscle fibers. It is likely that both muscle atrophy and a decrease in muscle-fiber quality contribute to muscle dysfunction among the elderly. A better understanding of sarcopenia at the single-fiber level may lead to the design of more effective rehabilitative interventions. PMID- 22239881 TI - The paradox of muscle hypertrophy in muscular dystrophy. AB - Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy. PMID- 22239885 TI - Advancing neuromuscular medicine through integration, translation, and collaboration. PMID- 22239883 TI - Nutrition strategies to improve physical capabilities in Duchenne muscular dystrophy. AB - There is no current cure for Duchenne muscular dystrophy (DMD), and palliative and prophylactic interventions to improve the quality of life of patients remain limited, with the exception of corticosteroids. This article describes 2 potential nutritional interventions for the treatment of DMD, green tea extract (GTE) and the branched-chain amino acid leucine, and their positive effects on physical activity. Both GTE and leucine are suitable for human consumption, are easily tolerated with no side effects, and, with appropriate preclinical data, could be brought forward to clinical trials rapidly. PMID- 22239887 TI - Post-systolic shortening: a functional window into ischemic memory? PMID- 22239886 TI - Assessment of myocardial ischemic memory using speckle tracking echocardiography. AB - OBJECTIVES: The aim of this study was to evaluate which regional myocardial parameters derived from speckle tracking echocardiography could demonstrate myocardial ischemic memory in a brief ischemia-reperfusion dog model. BACKGROUND: Myocardial ischemic memory imaging, denoting the visualization of abnormalities provoked by ischemia and sustained even after restoration of perfusion, can convey important clinical information. We previously reported that post-systolic shortening (PSS) remains in the risk area after recovery from brief ischemia. However, it is still unclear whether abnormalities in other regional deformation parameters persist after relief from brief ischemia. METHODS: Echocardiographic data were chronologically acquired from 11 dogs during 2 min of coronary occlusion followed by reperfusion. Regional systolic and diastolic deformation parameters, including parameters related to PSS, were measured from radial and circumferential strain and from strain rate analyzed in the risk and normal areas. Strain imaging diastolic index (SI-DI), which had been proposed as a parameter for assessing ischemic memory, was also calculated. RESULTS: Peak systolic strain, end-systolic strain, and peak systolic strain rate decreased in the risk area during occlusion but recovered to the baseline level immediately after reperfusion. Strain rate during early diastole decreased during occlusion; however, the decrease did not persist after reperfusion. Post-systolic strain index (PSI) and time-to-peak strain index, which are parameters of PSS, increased during occlusion. These increases persisted until 10 to 20 min after reperfusion (circumferential PSI: 0.02 +/- 0.04 [baseline] vs. 0.08 +/- 0.04 [20 min], p < 0.05). SI-DI did not show a significant change during occlusion because of a large variation. CONCLUSIONS: Although abnormalities of PSS-related parameters alone persisted after recovery from 2-min occlusion, abnormalities of other deformation parameters, such as strain rate during early diastole, did not. These data suggest that assessment of PSS by speckle tracking echocardiography is useful for detecting myocardial ischemic memory. PMID- 22239889 TI - CMR imaging for diastolic hemodynamic assessment fantasy or reality? PMID- 22239888 TI - Simultaneous right and left heart real-time, free-breathing CMR flow quantification identifies constrictive physiology. AB - OBJECTIVES: The purpose of this study was to evaluate the ability of a novel cardiac magnetic resonance (CMR) real-time phase contrast (RT-PC) flow measurement technique to reveal the discordant respirophasic changes in mitral and tricuspid valve in flow indicative of the abnormal hemodynamics seen in constrictive pericarditis (CP). BACKGROUND: Definitive diagnosis of CP requires identification of constrictive hemodynamics with or without pericardial thickening. CMR to date has primarily provided morphological assessment of the pericardium. METHODS: Sixteen patients (age 57 +/- 13 years) undergoing CMR to assess known or suspected CP and 10 controls underwent RT-PC that acquired simultaneous mitral valve and tricuspid valve inflow velocities over 10 s of unrestricted breathing. The diagnosis of CP was confirmed via clinical history, diagnostic imaging, cardiac catheterization, intraoperative findings, and histopathology. RESULTS: Ten patients had CP, all with increased pericardial thickness (6.2 +/- 1.0 mm). RT-PC imaging demonstrated discordant respirophasic changes in atrioventricular valve inflow velocities in all CP patients, with mean +/- SD mitral valve and tricuspid valve inflow velocity variation of 46 +/- 20% and 60 +/- 15%, respectively, compared with 16 +/- 8% and 24 +/- 11% in patients without CP (p < 0.004 vs. patients with CP for both) and 17 +/- 5% and 31 +/- 13% in controls (p < 0.001 vs. patients with CP for both). There was no difference in atrioventricular valve inflow velocity variation between patients without CP compared with controls (p > 0.3 for both). Respiratory variation exceeding 25% across the mitral valve yielded a sensitivity of 100%, a specificity of 100%, and an area under the receiver-operating characteristic curve of 1.0 to detect CP physiology. Using a cutoff of 45%, variation of transtricuspid valve velocity had a sensitivity of 90%, a specificity of 88%, and an area under the receiver operating characteristic curve of 0.98. CONCLUSIONS: Accentuated and discordant respirophasic changes in mitral valve and tricuspid valve inflow velocities characteristic of CP can be identified noninvasively with RT-PC CMR. When incorporated into existing CMR protocols for imaging pericardial morphology, RT PC CMR provides important hemodynamic evidence with which to make a definite diagnosis of CP. PMID- 22239890 TI - Assessment of the accuracy and reproducibility of RV volume measurements by CMR in congenital heart disease. AB - OBJECTIVES: The purpose of this study was to determine whether right ventricular (RV) volumes are more accurately and reproducibly measured by cardiac magnetic resonance (CMR) in an axial orientation or in a short-axis orientation in patients with congenital heart disease (CHD). BACKGROUND: There is little agreement on the most suitable imaging plane for RV volumetric analysis in the setting of abnormal RV physiology. METHODS: Measurements of RV volumes from datasets acquired in axial and short-axis orientations were made in 50 patients with CHD. RV stroke volumes (SV) calculated using these 2 methods were compared with forward flow measured in the pulmonary trunk by phase contrast (PC) imaging. Repeated volume measurements were made to assess intraobserver and interobserver reliability. Bland-Altman plots and Lin's concordance correlation coefficient (CCC) were used for all analyses of agreement. RESULTS: Analysis of all subjects revealed a statistically significant difference in interobserver reliability of RV end-systolic volume (ESV) measurements that favored the axial method (p = 0.047). The magnitude of measurement differences between observers in this case was small (-2.8 ml/m(2); 95% confidence interval: -5.6 to 0.0). There was no difference between the 2 contouring methods in terms of intraobserver reliability in measurements of RV end-diastolic volume (EDV), ESV, ejection fraction, or SV (p > 0.05 in all cases). In subjects with RV EDV >= 150 ml/m(2), RV SV measured using axial contours yielded better agreement with forward flow measured in the pulmonary trunk (CCC = 0.63) than did measurements made using short-axis contours (CCC = 0.56; p = 0.007). CONCLUSIONS: Trends favoring the axial orientation in terms of reproducibility were not clinically significant. In subjects with RV EDV >= 150 ml/m(2), the axial orientation yields RV volume measurements that agree more closely with flow measured in the pulmonary trunk than does the short-axis orientation. PMID- 22239891 TI - Correlation between arterial FDG uptake and biomarkers in peripheral artery disease. AB - OBJECTIVES: A prospective, multicenter (18)fluorine-fluorodeoxyglucose ((18)F FDG) positron emission tomography (PET)/computed tomography (CT) imaging study was performed to estimate the correlations among arterial FDG uptake and atherosclerotic plaque biomarkers in patients with peripheral artery disease. BACKGROUND: Inflammation within atherosclerotic plaques is associated with instability of the plaque and future cardiovascular events. Previous studies have shown that (18)F-FDG-PET/CT is able to quantify inflammation within carotid artery atherosclerotic plaques, but no studies to date have investigated this correlation in peripheral arteries with immunohistochemical confirmation. METHODS: Thirty patients across 5 study sites underwent (18)F-FDG-PET/CT imaging before SilverHawk atherectomy (FoxHollow Technologies, Redwood City, California) for symptomatic common or superficial femoral arterial disease. Vascular FDG uptake (expressed as target-to-background ratio) was measured in the carotid arteries and aorta and femoral arteries, including the region of atherectomy. Immunohistochemistry was performed on the excised atherosclerotic plaque extracts, and cluster of differentiation 68 (CD68) level as a measure of macrophage content was determined. Correlations between target-to-background ratio of excised lesions, as well as entire arterial regions, and CD68 levels were determined. Imaging was performed during the 2 weeks before surgery in all cases. RESULTS: Twenty-one patients had adequate-quality (18)F-FDG-PET/CT peripheral artery images, and 34 plaque specimens were obtained. No significant correlation between lesion target-to-background ratio and CD68 level was observed. CONCLUSIONS: There were no significant correlations between CD68 level (as a measure of macrophage content) and FDG uptake in the peripheral arteries in this multicenter study. Differences in lesion extraction technique, lesion size, the degree of inflammation, and imaging coregistration techniques may have been responsible for the failure to observe the strong correlations with vascular FDG uptake observed in previous studies of the carotid artery and in several animal models of atherosclerosis. PMID- 22239893 TI - Tracking cell therapy: bioluminescence lighting the way. PMID- 22239892 TI - Molecular imaging of bone marrow mononuclear cell survival and homing in murine peripheral artery disease. AB - OBJECTIVES: This study aims to provide insight into cellular kinetics using molecular imaging after different transplantation methods of bone marrow-derived mononuclear cells (MNCs) in a mouse model of peripheral artery disease (PAD). BACKGROUND: MNC therapy is a promising treatment for PAD. Although clinical translation has already been established, there is a lack of knowledge about cell behavior after transplantation and about the mechanism whereby MNC therapy might ameliorate complaints of PAD. METHODS: MNCs were isolated from F6 transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Male FVB and C57Bl6 mice (n = 50) underwent femoral artery ligation and were randomized into 4 groups receiving the following: 1) single intramuscular (IM) injection of 2 * 10(6) MNCs; 2) 4 weekly IM injections of 5 * 10(5) MNCs; 3) 2 * 10(6) MNCs intravenously; and 4) phosphate-buffered saline as control. Cells were characterized by flow cytometry and in vitro bioluminescence imaging (BLI). Cell survival, proliferation, and migration were monitored by in vivo BLI, which was validated by ex vivo BLI, post-mortem immunohistochemistry, and flow cytometry. Paw perfusion and neovascularization was measured with laser Doppler perfusion imaging (LDPI) and histology, respectively. RESULTS: In vivo BLI revealed near-complete donor cell death 4 weeks after IM transplantation. After intravenous transplantation, BLI revealed that cells migrated to the injured area in the limb, as well as to the liver, spleen, and bone marrow. Ex vivo BLI showed presence of MNCs in the scar tissue and adductor muscle. However, no significant effects on neovascularization were observed, as monitored by LDPI and histology. CONCLUSIONS: This is one of the first studies to assess kinetics of transplanted MNCs in PAD using in vivo molecular imaging. MNC survival is short-lived, MNCs do not preferentially home to injured areas, and MNCs do not significantly stimulate perfusion in this particular model. PMID- 22239894 TI - Imaging of receptors for advanced glycation end products in experimental myocardial ischemia and reperfusion injury. AB - OBJECTIVES: The aim of this study was to image expression of receptor for advanced glycation end products (RAGE) in a mouse model of myocardial reperfusion injury. BACKGROUND: RAGE and its ligands are implicated in the pathogenesis of ischemia/reperfusion injury and infarction. We hypothesized that RAGE-directed quantitative imaging of myocardial uptake of technetium-99m ((99m)Tc)-anti-RAGE F(ab')(2) in a mouse model of myocardial ischemic injury can detect RAGE expression and show quantitative differences between early (18 to 20 h) and later times (48 h) after reperfusion. METHODS: Twenty-five wild-type (WT) mice underwent left anterior descending coronary artery occlusion for 30 min. Mice were injected with 19.98 +/- 1.78 MBq of (99m)Tc anti-RAGE F(ab')(2) at 2 time points after reperfusion (at 18 to 20 h [n = 8] and at 48 h [n = 12]) and 5 h later with 6.14 +/- 2.0 MBq of thallium-201 ((201)Tl). Five WT mice were injected with nonspecific F(ab')(2) and (201)Tl 18 to 20 h after reperfusion. Six WT mice underwent sham operation without coronary intervention. After injection with (201)Tl, all mice immediately underwent dual isotope single-photon emission computed tomography/computed tomography. At completion of imaging, hearts were counted and sectioned. RESULTS: The uptake of (99m)Tc-anti-RAGE F(ab')(2) in the ischemic zone from the scans as mean percentage injected dose was significantly greater at 18 to 20 h (5.7 +/- 2.1 * 10(-3)%) as compared with at 48 h (1.4 +/- 1.1 * 10(-3)%; p < 0.001) after reperfusion. Disease and antibody controls showed no focal uptake in the infarct. Gamma well counting of the myocardium supported the quantitative scan data. By immunohistochemical staining there was greater caspase-3 and RAGE staining at 18 to 20 h versus at 48 h (p = 0.04 and p = 0.01, respectively). On dual immunofluorescence, RAGE colocalized mainly with injured cardiomyocytes undergoing apoptosis. CONCLUSIONS: RAGE expression in myocardial ischemic injury can be imaged in vivo using a novel (99m)Tc-anti-RAGE F(ab')(2). RAGE plays a role in several cardiovascular diseases and is a potential target for clinical imaging. PMID- 22239895 TI - Visualizing the RAGE molecular: imaging after MI provides insight into a complex receptor. PMID- 22239896 TI - Ex vivo assessment of vascular response to coronary stents by optical frequency domain imaging. AB - OBJECTIVES: This study sought to examine the capability of optical frequency domain imaging (OFDI) to characterize various morphological and histological responses to stents implanted in human coronary arteries. BACKGROUND: A precise assessment of vascular responses to stents may help stratify the risk of future adverse events in patients who have been treated with coronary stents. METHODS: Fourteen human stented coronary segments with implant duration >= 1 month from 10 hearts acquired at autopsy were interrogated ex vivo by OFDI and intravascular ultrasound (IVUS). Comparison with histology was assessed in 134 pairs of images where the endpoints were to investigate: 1) accuracy of morphological measurements; 2) detection of uncovered struts; and 3) characterization of neointima. RESULTS: Although both OFDI and IVUS provided a good correlation of neointimal area with histology, the correlation of minimum neointimal thickness was inferior in IVUS (R(2) = 0.39) as compared with OFDI (R(2) = 0.67). Similarly, IVUS showed a weak correlation of the ratio of uncovered to total stent struts per section (RUTSS) (R(2) = 0.24), whereas OFDI maintained superiority (R(2) = 0.66). In a more detailed analysis by OFDI, identification of individual uncovered struts demonstrated a sensitivity of 77.9% and specificity of 96.4%. Other important morphological features such as fibrin accumulation, excessive inflammation (hypersensitivity), and in-stent atherosclerosis were characterized by OFDI; however, the similarly dark appearance of these tissues did not allow for direct visual discrimination. The quantitative analysis of OFDI signal reflections from various in-stent tissues demonstrated distinct features of organized thrombus and accumulation of foamy macrophages. CONCLUSIONS: The results of the present study reinforce the potential of OFDI to detect vascular responses that may be important for the understanding of long-term stent performance, and indicate the capability of this technology to serve as a diagnostic indicator of clinical success. PMID- 22239897 TI - On OCT and finding the uncovered tracks... PMID- 22239898 TI - Noninvasive LV pressure estimation using subharmonic emissions from microbubbles. AB - To develop a new noninvasive approach to quantify left ventricular (LV) pressures using subharmonic emissions from microbubbles, an ultrasound scanner was used in pulse inversion grayscale mode; unprocessed radiofrequency data were obtained with pulsed wave Doppler from the aorta and/or LV during Sonazoid infusion. Subharmonic data (in dB) were extracted and processed. Calibration factor (mm Hg/dB) from the aortic pressure was used to estimate LV pressures. Errors ranged from 0.19 to 2.50 mm Hg when estimating pressures using the aortic calibration factor, and were higher (0.64 to 8.98 mm Hg) using a mean aortic calibration factor. Subharmonic emissions from ultrasound contrast agents have the potential to noninvasively monitor LV pressures. PMID- 22239899 TI - Imaging for planning of cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is a novel therapy for patients with refractory heart failure (HF). Large clinical trials evaluating CRT have demonstrated significant improvements in cardiac survival, decreases in recurrent HF hospitalization, and improvements in indexes of quality of life. Although numerous mechanisms are involved in CRT's therapeutic effects, correction of both interventricular and intraventricular mechanical dyssynchrony has been postulated as the key mechanism. To date, most large randomized controlled trials evaluating CRT have identified dyssynchronous patients on the basis of prolongation of the QRS complex from the baseline electrocardiogram. Concerns have been raised regarding the use of this measure for patient selection, stemming from a significant 30% to 40% nonresponse rate to CRT. Because of the cost and invasive nature of CRT, optimal patient selection for this therapy has become a priority for HF specialists and electrophysiologists. Cardiac imaging modalities have attempted to fulfill this need to improve patient selection by identifying mechanical dyssynchrony. Although early echocardiographic studies reported promising results, more recent larger scale studies have curtailed this enthusiasm, with a lack of established selection criteria for CRT in the current practice guidelines. This review summarizes the evidence to date and the potential role of imaging modalities in the selection and care of patients with HF referred for CRT. PMID- 22239900 TI - Coronary artery calcium scanning should be used for primary prevention: pros and cons. PMID- 22239901 TI - CMR with late gadolinium enhancement in genotype positive-phenotype negative hypertrophic cardiomyopathy. PMID- 22239902 TI - Variations in coronary lumen dimensions measured in vivo. PMID- 22239903 TI - Atrial function in patients undergoing CRT. PMID- 22239905 TI - Ischemic episode and hanging on to a painful memory... PMID- 22239906 TI - Exploration of polyelectrolytes as draw solutes in forward osmosis processes. AB - The development of the forward osmosis (FO) process has been constrained by the slow development of appropriate draw solutions. Two significant concerns related to draw solutions are the draw solute leakage and intensive energy requirement in recycling draw solutes after the FO process. FO would be much attractive if there is no draw solute leakage and the recycle of draw solutes is easy and economic. In this study, polyelectrolytes of a series of polyacrylic acid sodium salts (PAA Na), were explored as draw solutes in the FO process. The characteristics of high solubility in water and flexibility in structural configuration ensure the suitability of PAA-Na as draw solutes and their relative ease in recycle through pressure-driven membrane processes. The high water flux with insignificant salt leakage in the FO process and the high salt rejection in recycle processes reveal the superiority of PAA-Na to conventional ionic salts, such as NaCl, when comparing their FO performance via the same membranes. The repeatable performance of PAA-Na after recycle indicates the absence of any aggregation problems. The overall performance demonstrates that polyelectrolytes of PAA-Na series are promising as draw solutes, and the new concept of using polyelectrolytes as draw solutes in FO processes is applicable. PMID- 22239907 TI - COPD exacerbations in general practice: variability in oral prednisolone courses. AB - BACKGROUND: The use of oral corticosteroids as treatment of COPD exacerbations in primary care is well established and evidence-based. However, the most appropriate dosage regimen has not been determined and remains controversial. Corticosteroid therapy is associated with a number of undesirable side effects, including hyperglycaemias, so differences in prescribing might be relevant. This study examines the differences between GPs in dosage and duration of prednisolone treatment in patients with a COPD exacerbation. It also investigates the number of general practitioners (GPs) who adjust their treatment according to the presence of diabetic co-morbidity. METHODS: Cross-sectional study among 219 GPs and 25 GPs in training, located in the Northern part of the Netherlands. RESULTS: The response rate was 69%. Nearly every GP prescribed a continuous dose of prednisolone 30 mg per day. Among GPs there were substantial differences in treatment duration. GPs prescribed courses of five, seven, ten, or fourteen days. A course of seven days was most common. The duration of treatment depended on exacerbation and disease severity. A course of five days was especially prescribed in case of a less severe exacerbation. In a more severe exacerbation duration of seven to fourteen days was more common. Hardly any GP adjusted treatment to the presence of diabetic co-morbidity. CONCLUSION: Under normal conditions GPs prescribe prednisolone quite uniformly, within the range of the current Dutch guidelines. There is insufficient guidance regarding how to adjust corticosteroid treatment to exacerbation severity, disease severity and the presence of diabetic co-morbidity. Under these circumstances, there is a substantial variation in treatment duration. PMID- 22239908 TI - Synthesis and characterization of gold-chitosan nanocomposite and application of resultant nanocomposite in sensors. AB - Chitosan gold nanocomposite (CGNC) was synthesized in a single step process and the pH dependent properties of the composite were investigated. The structure of the polymer was pH dependent and gelation of the polymer observed at pH 4-5. Transmission electron microscopy (TEM) analysis showed that the distribution of gold nanoparticles within unit area varied with the gelation of the polymer, without affecting the size of the nanoparticles. The resulting CGNC system was explored for its use as a sensor for the detection of lead. It was found that lead could be detected at a concentration of 1 MUM by absorption spectroscopy. The CGNC was electrodeposited on a gold electrode and the deposited film was used for the detection of lead using cyclic voltammetry. Lead could be detected with a detection limit of 10 MUM. The fabrication reproducibility for four sensor electrodes showed a relative standard deviation (RSD) of 2.09% for the determination of 1 mM lead nitrate. The developed sensor system showed high reproducibility, stability and satisfactory selectivity. PMID- 22239909 TI - Efficacy assessment of acid mine drainage treatment with coal mining waste using Allium cepa L. as a bioindicator. AB - The aim of this study was to evaluate the efficacy of the treatment of acid mine drainage (AMD) with calcinated coal mining waste using Allium cepa L. as a bioindicator. The pH values and the concentrations of aluminum, iron, manganese, zinc, copper, lead and sulfate were determined before and after the treatment of the AMD with calcinated coal mining waste. Allium cepa L. was exposed to untreated and treated AMD, as well as to mineral water as a negative control (NC). At the end of the exposure period, the inhibition of root growth was measured and the mean effective concentration (EC(50)) was determined. Oxidative stress biomarkers such as lipid peroxidation (TBARS), protein carbonyls (PC), catalase activity (CAT) and reduced glutathione levels (GSH) in the fleshy leaves of the bulb, as well as the DNA damage index (ID) in meristematic cells, were evaluated. The results indicated that the AMD treatment with calcinated coal mining waste resulted in an increase in the pH and an expressive removal of aluminum, iron, manganese and zinc. A high sub-chronic toxicity was observed when Allium cepa L. was exposed to the untreated AMD. However, after the treatment no toxicity was detected. Levels of TBARS and PC, CAT activity and the DNA damage index were significantly increased (P<0.05) in Allium cepa L. exposed to untreated AMD when compared to treated AMD and also to negative controls. No significant alteration in the GSH content was observed. In conclusion, the use of calcinated coal mining waste associated with toxicological tests on Allium cepa L. represents an alternative system for the treatment and biomonitoring of these types of environmental contaminants. PMID- 22239910 TI - Outbreaks of human monkeypox after cessation of smallpox vaccination. AB - The recent observation of a surge in human monkeypox in the Democratic Republic of the Congo (DRC) prompts the question of whether cessation of smallpox vaccination is driving the phenomenon, and if so, why is re-emergence not universal throughout the historic geographic range of the virus? Research addressing the virus's mechanisms for immune evasion and induction, as well as that directed at elucidating the genes involved in pathogenesis in different viral lineages (West African vs Congo Basin), provide insights to help explain why emergence appears to be geographically limited. Novel vaccines offer one solution to curtail the spread of this disease. PMID- 22239911 TI - A GO intervention program for enhancing elementary school children's cognitive functions and control abilities of emotion and behavior: study protocol for a randomized controlled trial. AB - BACKGROUND: Executive function is critical for children's healthy development. We propose an intervention program to enhance children's executive function using the game, GO. Many neuroimaging studies have revealed that playing GO is related to executive function. In addition, previous studies also revealed that executive function can be enhanced by training. We will perform a randomized controlled trial to investigate the effectiveness of a GO intervention group and a control group without intervention. METHODS/DESIGN: 35 elementary school children aged 8 to 10 were recruited from Edogawa elementary school in Tokyo, Japan. They will be randomized into two groups; either the 5-week GO intervention group or no intervention control group. We will ask the participants of the intervention group to join the GO course which will be held once every week for five weeks (total: six times). In the GO course, the children will be taught GO by the GO masters of the Nihon Ki-in and enjoy it for an hour. Besides the course, the participants will perform GO problems about twenty minutes a day, three times a week during the intervention period. We will use the Stroop task, the digit span, the Raven's colored progressive matrices, the Span-board task, and the Behavioral inhibition/behavioral activation scale for the outcome measures. Outcomes will be measured at a baseline (Assessment 1) and 5 weeks after the intervention program started (Assessment 2). The intervention group will be compared with the control group using one-way analyses of covariance with the difference between Assessment 1 and Assessment 2 measures as dependent variables and pretest scores as covariates. DISCUSSION: To our knowledge, this study will be the first RCT to investigate the efficacy of a GO intervention program for elementary school children. If this intervention is effective, we will be able to take the next steps in making an educational program to enhance children's executive function and other cognitive abilities using GO. In addition, we further will investigate the transfer effects of the GO intervention program through executive function. We also will investigate neuroplasticity with the GO intervention using neuroimaging. PMID- 22239912 TI - Intrinsic and extrinsic discoloration of dimethacrylate and silorane based composites. AB - OBJECTIVE: The purpose of this study was to evaluate the intrinsic and extrinsic color change of dimethacrylate and silorane-based composites. MATERIALS AND METHODS: Five contemporary composites were included within the study (Filtek LS Low Shrink Posterior Restorative [SIL], Filtek SupremeXT [SPR], Filtek Z250 [Z25], Filtek P60 [P60], and Admira [ADM]). Twenty-five specimens (8-mm diameter, 1.5-mm thickness) were prepared for each composite. After baseline color measurements were taken, specimens were immersed in 4 staining solutions (red wine, coffee, cola, and tea) or distilled water (n=5). After a 24-h and 1-month immersion, the color values of each specimen were remeasured and the color change values (DeltaE(ab)(*)) were calculated. Statistical analyses were evaluated by one-way ANOVA and Tukey HSD test. RESULTS: Amongst the solutions, red wine had the highest DeltaE(ab)(*) value in all the composite restoratives. After the final measurement, ADM exhibited the lowest discoloration, whereas SPR exhibited the highest color change. Additionally, the color change for SIL after 1 month in distilled water was higher than the clinically accepted cut-off of 3.3. This change was correlated with an increasing L value according to the multiple regression analysis. CONCLUSION: All of the restorative materials used in this study were susceptible to staining by commonly consumed beverages drinks, especially red wine and coffee; however, in water, only SIL became whiter with time. PMID- 22239913 TI - Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation. AB - BACKGROUND: Although cigarette smoking is the principal cause of lung carcinogenesis, chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, has been identified as an independent risk factor for lung cancer. Bacterial colonization, particularly with non-typeable Haemophilus influenzae (NTHi), has been implicated as a cause of airway inflammation in COPD besides cigarette smoke. Accordingly, we hypothesized that lung cancer promotion may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure. RESULTS: Herein, we investigated the effects of bacterial induced COPD-like inflammation and tobacco carcinogen-enhanced tumorigenesis/inflammation in the retinoic acid inducible G protein coupled receptor knock out mouse model (Gprc5a-/- mouse) characterized by late-onset, low multiplicity tumor formation. Three-month-old Gprc5a-/- mice received 4 intraperitoneal injections of the tobacco-specific carcinogen, NNK, followed by weekly exposure to aerosolized NTHi lysate for 6 months. The numbers of inflammatory cells in the lungs and levels of several inflammatory mediators were increased in Gprc5a-/- mice treated with NTHi alone, and even more so in mice pretreated with NNK followed by NTHi. The incidence of spontaneous lung lesions in the Gprc5a-/- mice was low, but NTHi exposure led to enhanced development of hyperplastic lesions. Gprc5a-/- mice exposed to NNK alone developed multiple lung tumors, while NTHi exposure increased the number of hyperplastic foci 6-fold and the tumor multiplicity 2-fold. This was associated with increased microvessel density and HIF-1alpha expression. CONCLUSION: We conclude that chronic extrinsic lung inflammation induced by bacteria alone or in combination with NNK enhances lung tumorigenesis in Gprc5a-/- mice. PMID- 22239916 TI - Deep brain stimulation in Parkinson's disease: opening up the race towards better technology. PMID- 22239915 TI - Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial. AB - BACKGROUND: The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. METHODS: This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18-80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. FINDINGS: Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4.27 h vs 1.77 h, difference 2.51 [95% CI 0.87-4.16]; p=0.003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24.8 vs 40.8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. INTERPRETATION: Constant current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage controlled stimulation. FUNDING: St Jude Medical Neuromodulation Division. PMID- 22239914 TI - Chloride intracellular channels modulate acute ethanol behaviors in Drosophila, Caenorhabditis elegans and mice. AB - Identifying genes that influence behavioral responses to alcohol is critical for understanding the molecular basis of alcoholism and ultimately developing therapeutic interventions for the disease. Using an integrated approach that combined the power of the Drosophila, Caenorhabditis elegans and mouse model systems with bioinformatics analyses, we established a novel, conserved role for chloride intracellular channels (CLICs) in alcohol-related behavior. CLIC proteins might have several biochemical functions including intracellular chloride channel activity, modulation of transforming growth factor (TGF)-beta signaling, and regulation of ryanodine receptors and A-kinase anchoring proteins. We initially identified vertebrate Clic4 as a candidate ethanol-responsive gene via bioinformatic analysis of data from published microarray studies of mouse and human ethanol-related genes. We confirmed that Clic4 expression was increased by ethanol treatment in mouse prefrontal cortex and also uncovered a correlation between basal expression of Clic4 in prefrontal cortex and the locomotor activating and sedating properties of ethanol across the BXD mouse genetic reference panel. Furthermore, we found that disruption of the sole Clic Drosophila orthologue significantly blunted sensitivity to alcohol in flies, that mutations in two C. elegans Clic orthologues, exc-4 and exl-1, altered behavioral responses to acute ethanol in worms and that viral-mediated overexpression of Clic4 in mouse brain decreased the sedating properties of ethanol. Together, our studies demonstrate key roles for Clic genes in behavioral responses to acute alcohol in Drosophila, C. elegans and mice. PMID- 22239917 TI - Finite element model predictions of intracranial hemorrhage from non-impact, rapid head rotations in the piglet. AB - Clinicians are charged with the significant task of distinguishing between accidental and inflicted head trauma. Oftentimes this distinction is straightforward, but many times probabilities of injuries from accidental scenarios are unknown making the differential diagnosis difficult. For example, it is unknown whether intracranial hemorrhage (IH) can occur at a location other than a focal contact site following a low height fall. To create a foundation for predicting regional IH in infants, we sought to identify the biomechanical response and injury threshold best able to predict IH in 3-5 day old piglets. First, finite element (FE) model simulations of in situ animal studies were performed to ascertain the optimal representation of the pia-arachnoid complex, cerebrospinal fluid and cortical vasculature (PCC) for predicting brain strain and brain/skull displacement. Second, rapid head rotations resulting in various degrees of IH were simulated (n=24) to determine the biomechanical predictor and injury threshold most closely correlated with IH. FE models representing the PCC with either spring connectors or solid elements between the brain and skull resulted in peak brain strain and brain/skull displacement similar to measured values in situ. However, when predicting IH, the spring connector representation of the PCC had the best predictive capability for IH with a sensitivity of 80% and a specificity of 85% when >= 1% of all spring connectors had at least a peak strain of 0.31 mm/mm. These findings and reported methodology will be used in the development of a human infant FE model to simulate real-world falls and identify injury thresholds for predicting IH in infants. PMID- 22239919 TI - Stigma, abortion, and disclosure--findings from a qualitative study. AB - INTRODUCTION: This study qualitatively explores perceptions of women who have experienced abortion care. It explores women's journey through abortion from confirmation of pregnancy to post-abortion. AIM: The study seeks to understand the implications of these perceptions for policy and practice. MAIN OUTCOME MEASURES: A qualitative study involving in-depth semi-structured interviews with 17 women, aged between 22 and 57 years, who had undergone legal induced abortion in the UK when they were 16 years or older. Participants were not recruited under the age of 16 because of the ethical and legal complexities of interviewing minors. Additionally, 16 years was deemed to be the most appropriate age as this is the legal age of consent in the UK. METHODS: Participants were recruited from 12 community contraception and sexual health clinics in two NHS trusts, one in England and one in Wales. Participant recruitment was set at a minimum of 12 and participants were recruited on a "first come first served basis" (i.e., the first 12 who contacted the researcher). The number of participants was raised to seventeen as this was the number deemed to be the most suitable for data saturation in this particular qualitative research. RESULTS: Women in this study understood abortion as highly taboo and a potentially personally stigmatizing event. These perceptions continued to affect disclosure to others, long after the abortion, and affected women's perceptions of the response of others, including society in general, significant others, and health professionals. CONCLUSIONS: Women's experiences of abortion may be influenced by perceived negative social attitudes. Health professionals and abortion service providers might combat the perceived isolation of women undergoing abortion by attending not only to clinical/technical aspects of the procedure but also to women's psychological/emotional sensitivities surrounding the event. PMID- 22239918 TI - Maternal obesity in the rat programs male offspring exploratory, learning and motivation behavior: prevention by dietary intervention pre-gestation or in gestation. AB - We studied the effects of maternal high fat diet (HFD, 25% calories from fat administered before and during pregnancy and lactation) and dietary intervention (switching dams from HFD to control diet) at different periconceptional periods on male offspring anxiety related behavior, exploration, learning, and motivation. From weaning at postnatal day (PND) 21, female subjects produced to be the mothers in the study received either control diet (CTR - 5% calories from fat), HFD through pregnancy and lactation (MO), HFD during PNDs 21-90 followed by CTR diet (pre-gestation (PG) intervention) or HFD from PND 21 to 120 followed by CTR diet (gestation and lactation (G) intervention) and bred at PND 120. At 19 days of gestation maternal serum corticosterone was increased in MO and the PG and G dams showed partial recovery with intermediate levels. In offspring, no effects were found in the elevated plus maze test. In the open field test, MO and G offspring showed increase zone entries, displaying less thigmotaxis; PG offspring showed partial recuperation of this behavior. During initial operant conditioning MO, PG and G offspring displayed decreased approach behavior with subsequent learning impairment during the acquisition of FR-1 and FR-5 operant conditioning for sucrose reinforcement. Motivation during the progressive ratio test increased in MO offspring; PG and G intervention recuperated this behavior. We conclude that dietary intervention can reverse negative effects of maternal HFD and offspring outcomes are potentially due to elevated maternal corticosterone. PMID- 22239920 TI - Cu(I)-catalyzed synthesis of imidazo[1,2-a]pyridines from aminopyridines and nitroolefins using air as the oxidant. AB - A copper-catalyzed method for the synthesis of imidazo[1,2-a]pyridines with aminopyridines and nitroolefins using air as oxidation agent in a one-pot procedure has been developed. In this process, the reaction appears to be very general and suitable for construction of a variety of imidazo[1,2-a]pyridines. PMID- 22239921 TI - Finite element analysis of the effect of loading curve shape on brain injury predictors. AB - Prediction of traumatic and mild traumatic brain injury is an important factor in managing their prevention. Currently, the prediction of these injuries is limited to peak linear and angular acceleration loading curves derived from laboratory reconstructions. However it remains unclear as to what aspect of these loading curves contributes to brain tissue damage. This research uses the University College Dublin Brain Trauma Model (UCDBTM) to analyse three distinct loading curve shapes meant to represent different helmet loading scenarios. The loading curves were applied independently in each axis of linear and angular acceleration and their effect on currently used predictors of TBI and mTBI was examined. Loading curve shape A had a late time to peak, B an early time to peak and C had a consistent plateau. The areas under the curve for all three loading curve shapes were identical. The results indicate that loading curve A produced consistently higher maximum principal strains and Von Mises stress than the other two loading curve types. Loading curve C consistently produced the lowest values of maximum principal strain and Von Mises stress, with loading curve B being lowest in only 2 cases. The areas of peak Von Mises stress and Principal strain also varied depending on loading curve shape and acceleration input. PMID- 22239922 TI - Fatigue research in 2011: from the bench to practice. AB - Over the last 20 years, academic, industry and community stakeholders have been meeting at a biennial scientific conference to discuss fatigue-related research and policy in the transportation, resources and health sectors. During this period, the research conducted around the world has progressed substantially: we now better understand the basic processes of sleep and circadian physiology that underpin performance; we better understand that fatigue risk management in the absence of any discussion about sleep is fruitless at worst and inadequate at best; and we are improving the capacity of models and other technologies to assist us to predict, monitor, identify, minimise and mitigate fatigue-related risk. At the same time however, the relationship between performance on simple cognitive tasks in laboratory settings and performance on complex tasks required to operate efficiently and safely in the workplace, remains a stumbling block. This special issue brings together fifteen papers that cover the range of areas in the field of fatigue research and challenges us as researchers, regulators, industry representatives and community members to continue the work of managing the risk of fatigue. PMID- 22239923 TI - A model of shiftworker sleep/wake behaviour. AB - Software-based biomathematical models of alertness provide a means to estimate fatigue-related risk in advance of a schedule being worked. Obtaining a good estimate of employees' sleep/wake behaviour during non-work periods is critical in obtaining accurate estimates of alertness. This is because estimates of alertness are generated based on estimated sleep and wake times, not rest and work times per se. The purpose of the current analysis was to evaluate the predictive validity of a novel version of a previously published sleep predictor model. This model was originally designed to predict sleep probability for aviation pilots in connection with long-haul flight operations. It has since been modified to predict sleep periods for industrial shiftwork rosters in non transmeridian environments. The algorithm uses two procedures to predict sleep timing and duration: (1) estimate the total amount of sleep likely to be obtained in a given rest period; and then (2) estimate the timing and duration of sleep periods within that rest period. The sleep periods predicted in the second procedure are generated such that their combined sum is a priori equivalent to the total amount of sleep predicted in the first procedure. The model was parameterized and validated based on a sample of 225 train drivers who collected work/rest and sleep/wake data for two weeks during normal commercial operations. Agreement between observed and predicted sleep periods was robust (percent agreement=85%) and compared favourably with agreement levels between sleep behaviours exhibited by the same individual on distinct occasions but where shift sequences were repeated. These results are discussed within the context of ongoing efforts to develop individualized biomathematical models of alertness. PMID- 22239925 TI - Predicting pilot's sleep during layovers using their own behaviour or data from colleagues: implications for biomathematical models. AB - Biomathematical models are used in industry to estimate how much sleep people are likely to get on different work patterns, and how efficient and safe people are likely to be at work. Since there is evidence to suggest that individuals respond differently to sleep loss, there has been a recent focus on trying to account for individual differences. One possible approach could use past behaviour to predict future responses to similar working conditions. This study investigated the predictive value of sleep timing and duration data for a particular individual on a break between shifts relative to data from their colleagues. Sleep diaries and wrist actigraphy were collected from 306 international long-haul pilots for at least 2-weeks. Fifty layovers, equivalent in origin and destination, length and timing, were completed twice by individual pilots. Matched layovers done by other pilots (n=2311) were also identified. Layover periods were analysed for minute-by minute correspondence of sleep or wake (yes/no), and total sleep time (TST). Using an individual's own data improved concordance by approximately 5% relative to using a large sample of different pilots, and by 10% relative to using a random sample of 50 different pilots. Using an individual's own TST to predict their TST on an equivalent layover yielded an r value of 0.83, compared to r=0.78 when data from a colleague was used, and r=0.73 using different pilots in a random sample of equivalent size. The mean difference in TST using pilots' own data was <20 min, compared to <40 min using data from colleagues. However, the confidence limits on these differences were large (up to 8h). Results suggest that for international pilots on specific layover patterns, knowing the past behaviour of an individual may only represent a modest improvement over knowing the length and timing of a colleague's sleep, when it comes to predicting their sleep behaviour. PMID- 22239924 TI - Systematic individual differences in sleep homeostatic and circadian rhythm contributions to neurobehavioral impairment during sleep deprivation. AB - Individual differences in vulnerability to neurobehavioral performance impairment during sleep deprivation are considerable and represent a neurobiological trait. Genetic polymorphisms reported to be predictors have suggested the involvement of the homeostatic and circadian processes of sleep regulation in determining this trait. We applied mathematical and statistical modeling of these two processes to psychomotor vigilance performance and sleep physiological data from a laboratory study of repeated exposure to 36 h of total sleep deprivation in 9 healthy young adults. This served to quantify the respective contributions of individual differences in the two processes to the magnitudes of participants' individual vulnerabilities to sleep deprivation. For the homeostatic process, the standard deviation for individual differences was found to be about 60% as expressed relative to its group-average contribution to neurobehavioral performance impairment. The same was found for the circadian process. Across the span of the total sleep deprivation period, the group-average effect of the homeostatic process was twice as big as that of the circadian process. In absolute terms, therefore, the impact of the individual differences in the homeostatic process was twice as large as the impact of the individual differences in the circadian process in this study. These modeling results indicated that individualized applications of mathematical models predicting performance on the basis of a homeostatic and a circadian process should account for individual differences in both processes. PMID- 22239926 TI - Duty periods with early start times restrict the amount of sleep obtained by short-haul airline pilots. AB - Most of the research related to human fatigue in the aviation industry has focussed on long-haul pilots, but short-haul pilots also experience elevated levels of fatigue. The aim of this study was to examine the impact of early start times on the amount of sleep obtained prior to duty and on fatigue levels at the start of duty. Seventy short-haul pilots collected data regarding their duty schedule and sleep/wake behaviour for at least two weeks. Data were collected using self-report duty/sleep diaries and wrist activity monitors. Mixed-effects regression analyses were used to examine the effects of duty start time (04:00 10:00 h) on (i) the total amount of sleep obtained in the 12h prior to the start of duty and (ii) self-rated fatigue level at the start of duty. Both analyses indicated significant main effects of duty start time. In particular, the amount of sleep obtained in the 12h prior to duty was lowest for duty periods that commenced between 04:00 and 05:00 h (i.e. 5.4h), and greatest for duty periods that commenced between 09:00 and 10:00 h (i.e. 6.6h). These data indicate that approximately 15 min of sleep is lost for every hour that the start of duty is advanced prior to 09:00 h. In addition, self-rated fatigue at the start of duty was highest for duty periods that commenced between 04:00 and 05:00 h, and lowest for duty periods that commenced between 09:00 and 10:00 h. Airlines should implement a fatigue risk management system (FRMS) for short-haul pilots required to work early-morning shifts. One component of the FRMS should be focussed on the production of 'fatigue-friendly' rosters. A second component of the FRMS should be focussed on training pilots to optimise sleep opportunities, to identify circumstances where the likelihood of fatigue is elevated, and to manage the risks associated with fatigue-related impairment. PMID- 22239927 TI - Sleep and sleepiness during an ultra long-range flight operation between the Middle East and United States. AB - This study provides a practical example of fatigue risk management in aviation. The sleep and sleepiness of 44 pilots (11 trips * 4 pilot crew) working an ultra long-range (ULR; flight time >16 h) round-trip operation between Doha and Houston was assessed. Sleep was assessed using activity monitors and self-reported sleep diaries. Mean Karolinska Sleepiness Scores (KSS) for climb and descent did not exceed 5 ("neither alert nor sleepy"). Mean daily sleep duration was maintained above 6.3h throughout the operation. During in-flight rest periods, 98% of pilots obtained sleep and sleepiness was subsequently reduced. On layover (49.5h) crew were advised to sleep on Doha or Universal Co-ordinated Time (UTC), but 64% slept during the local (social) night time. Pilots originating from regions with a siesta culture were more likely to nap and made particularly effective use of their daytime in-flight rest periods. The results indicate that the operation is well designed from a fatigue management perspective. PMID- 22239928 TI - Beyond working time: factors affecting sleep behaviour in rail safety workers. AB - There are many factors that may affect the sleep behaviour and subsequent fatigue risk of shift workers. In the Australian rail industry the emphasis is primarily on the impact of working time on sleep. The extent to which factors other than working time might affect the sleep behaviour of employees in the large and diverse Australian rail industry is largely unknown. The present study used sleep, work and fatigue diaries completed for two weeks, in conjunction with actigraphy, to understand the contribution of demographic and health factors to sleep behaviour in 40 rail safety workers. Both shift type and having dependents were significant predictors of sleep duration (P<.05). Sleep duration was greatest prior to night shifts, followed by afternoon shifts and morning shifts. Participants with dependents got significantly less sleep than participants without dependents. Both timing of sleep and smoking were significant predictors of sleep quality (P<.05). Day sleeps were associated with lower subjective sleep quality than night sleeps and smokers reported poorer sleep quality than non smokers. These findings indicate that factors other than working time have the potential to influence both the sleep duration and subjective sleep quality of rail safety workers. PMID- 22239929 TI - At home and away: measuring the sleep of Australian truck drivers. AB - The causes of fatigue in truck drivers related to work hours have been studied extensively and are reasonably well understood. However, much less is known about how rest opportunities can be structured to optimise recovery from fatigue. The nature of the road transport industry often requires that rest be taken in various locations. New investigation in this area, focusing on sleep obtained in truck cabs and other non-home environments is critically important to complement existing understanding. This study examined sleep at home and in truck cabs, in truck drivers who were actively working during the time of the study. Thirty seven male drivers aged between 24 and 63 years (age: 48.7 +/- 9.0 years; mean +/ SD) wore activity monitors (also known as 'sleep watches') and completed work and sleep diaries for a period of 21 days, recording their subjective fatigue levels before, during and after work shifts, and before and after sleep periods. They also self-rated their sleep quality and noted the number of times they woke during sleep periods. Analyses focused on home versus in-truck sleep periods. The subjective data suggested that a greater quantity (P<.001) and quality (P<.05) of sleep was obtained at home than in the truck, and that sleeping at home more effectively reduced fatigue levels (P<.001). The objective data showed trends towards longer sleep length at home, but other variables, including total sleep per 24h and sleep quality, showed no significant differences. This study demonstrates that measuring sleep quantity and quality in operational road transport environments is feasible. The findings caution against over-reliance on laboratory and simulator studies since there are critical aspects of the operating environment that cannot be validly studied in artificially controlled settings. This study is unique in its direct examination of sleep quantity and quality in truck drivers sleeping at home and away from home. PMID- 22239930 TI - Research and guidelines for implementing Fatigue Risk Management Systems for the French regional airlines. AB - This paper describes research that aims to provide the overall scientific basis for implementation of a Fatigue Risk Management System (FRMS) for French regional airlines. The current research has evaluated the use of different tools and indicators that would be relevant candidates for integration into the FRMS. For the Fatigue Risk Management component, results show that biomathematical models of fatigue are useful tools to help an airline to prevent fatigue related to roster design and for the management of aircrew planning. The Fatigue Safety assurance includes two monitoring processes that have been evaluated during this research: systematic monitoring and focused monitoring. Systematic monitoring consists of the analysis of existing safety indicators such as Air Safety Reports (ASR) and Flight Data Monitoring (FDM). Results show a significant relationship between the hours of work and the frequency of ASR. Results for the FDM analysis show that some events are significantly related to the fatigue risk associated with the hours of works. Focused monitoring includes a website survey and specific in-flight observations and data collection. Sleep and fatigue measurements have been collected from 115 aircrews over 12-day periods (including rest periods). Before morning duties, results show a significant sleep reduction of up to 40% of the aircrews' usual sleep needs leading to a clear increase of fatigue during flights. From these results, specific guidelines are developed to help the airlines to implement the FRMS and for the airworthiness to oversight the implementation of the FRMS process. PMID- 22239931 TI - Fatigue-related crashes involving express buses in Malaysia: will the proposed policy of banning the early-hour operation reduce fatigue-related crashes and benefit overall road safety? AB - Fatigue-related crashes have long been the topic of discussion and study worldwide. The relationship between fatigue-related crashes and time of day is well documented. In Malaysia, the possibility of banning express buses from operating during the early-hours of the morning has emerged as an important consideration for passenger safety. This paper highlights the findings of an impact assessment study. The study was conducted to determine all possible impacts prior to the government making any decision on the proposed banning. This study is an example of a simple and inexpensive approach that may influence future policy-making process. The impact assessment comprised two major steps. The first step involved profiling existing operation scenarios, gathering information on crashes involving public express buses and stakeholders' views. The second step involved a qualitative impact assessment analysis using all information gathered during the profiling stage to describe the possible impacts. Based on the assessment, the move to ban early-hour operations could possibly result in further negative impacts on the overall road safety agenda. These negative impacts may occur if the fundamental issues, such as driving and working hours, and the need for rest and sleep facilities for drivers, are not addressed. In addition, a safer and more accessible public transportation system as an alternative for those who choose to travel at night would be required. The proposed banning of early-hour operations is also not a feasible solution for sustainability of express bus operations in Malaysia, especially for those operating long journeys. The paper concludes by highlighting the need to design a more holistic approach for preventing fatigue-related crashes involving express buses in Malaysia. PMID- 22239932 TI - The influence of circadian time and sleep dose on subjective fatigue ratings. AB - Subjective ratings of fatigue are increasingly being used as part of a suite of tools to assess fatigue-related risk on the road and in the workplace. There is some debate however, as to whether individuals can accurately gauge their own fatigue states, particularly under conditions of sleep restriction. It is also unclear which references are used by individuals to assess fatigue - for example prior sleep, time of day, workload, or previous ratings. The current study used a sophisticated laboratory protocol to examine the independent contributions of sleep, circadian phase and sleep debt to fatigue ratings. Importantly, participants had no knowledge of time of day, how much sleep they were getting, or how long they were awake. Twenty-eight healthy, young males participated in one of two conditions of a 28 h forced desynchrony protocol - severe sleep restriction (4.7h sleep and 23.3h wake) or moderate sleep restriction (7h sleep and 21 h wake). Fatigue ratings were provided prior to and following each sleep period using the Samn-Perelli fatigue scale. Repeated measures ANOVAs were used to analyse the effects of circadian phase, sleep dose and study day. Results demonstrated an effect of circadian phase on both pre-sleep and post-sleep fatigue ratings. The significant effect of study day is interpreted as an effect of circadian time, as opposed to accumulating sleep debt. An effect of sleep dose was only seen in post-sleep fatigue ratings. The findings suggest that post-sleep fatigue ratings may be sensitive to prior sleep and may be useful as an indicator of fatigue-related risk, particularly when triangulated with information about recent total sleep time. PMID- 22239933 TI - Simulated driving under the influence of extended wake, time of day and sleep restriction. AB - Around a fifth of all road accidents can be attributed to fatigued drivers. Previous studies indicate that driving performance is influenced by time of day and decreases with sustained wakefulness. However, these influences occur naturally in unison, confounding their effects. Typically, when people drive at a poor time of day and with extended wake, their sleep is also restricted. Hence, the aim of the current study was to determine the independent effects of prior wake and time of day on driving performance under conditions of sleep restriction. The driving performance of fourteen male participants (21.8 +/- 3.8 years, mean +/- SD) was assessed during a 10 min simulated driving task with speed/lane mean, variability and violations (speeding and crashes) measured. Participants were tested at 2.5h intervals after waking, across 7 * 28 h days with a sleep:wake ratio of 1:5. By forced desynchrony each driving session occurred at 9 doses of prior wake and within 6 divisions of the circadian cycle based on core body temperature. A mixed models ANOVA revealed significant main effects of circadian phase, prior wake and sleep debt on lane violations. In addition, three significant two-way interactions (circadian phase * prior wake, prior wake * sleep debt, sleep debt * circadian phase) and one three-way interaction (circadian * prior wake * sleep debt) were identified. The presence of the large interaction effects shows that the influence of each factor is largely dependent on the magnitude of the other factors. For example, the presence of the time of day influence on driving performance is dependent on the length of prior wake or the presence of sleep debt. The findings suggest that people are able to undertake a low-difficulty simulated drive safely, at least for a short period, during their circadian nadir provided that they have had sufficient sleep and have not been awake too long. PMID- 22239934 TI - The effect of sleep restriction on snacking behaviour during a week of simulated shiftwork. AB - Due to irregular working hours shiftworkers experience circadian disruption and sleep restriction. There is some evidence to indicate that these factors adversely affect health through changes in snacking behaviour. The aim of this study was to investigate the impact of sleep restriction, prior wake and circadian phase on snacking behaviour during a week of simulated shiftwork. Twenty-four healthy males (age: 22.0 +/- 3.6 years, mean +/- SD) lived in a sleep laboratory for 12 consecutive days. Participants were assigned to one of two schedules: a moderate sleep restriction condition (n=10) equivalent to a 6-h sleep opportunity per 24h or a severe sleep restriction condition (n=14) equivalent to a 4-h sleep opportunity per 24h. In both conditions, sleep/wake episodes occurred 4h later each day to simulate a rotating shiftwork pattern. While living in the laboratory, participants were served three meals and were provided with either five (moderate sleep restriction condition) or six (severe sleep restriction condition) snack opportunities daily. Snack choice was recorded at each opportunity and assigned to a category (sweet, savoury or healthy) based on the content of the snack. Data were analysed using a Generalised Estimating Equations approach. Analyses show a significant effect of sleep restriction condition on overall and sweet snack consumption. The odds of consuming a snack were significantly greater in the severe sleep restriction condition (P<0.05) compared to the moderate sleep restriction condition. In particular, the odds of choosing a sweet snack were significantly increased in the severe sleep restriction condition (P<0.05). Shiftworkers who are severely sleep restricted may be at risk of obesity and related health disorders due to elevated snack consumption and unhealthy snack choice. To further understand the impact of sleep restriction on snacking behaviour, future studies should examine physiological, psychological and environmental motivators. PMID- 22239935 TI - Fatigue biomarker index: an objective salivary measure of fatigue level. AB - Fatigue changed the composition of the small-molecular weight (sMW) proteome of saliva during a 10h session of moderate (70% of maximum ventilatory threshold) physical exertion. Saliva samples were collected from nine recreationally trained cyclists participating in a cross-over study designed to simulate prolonged manual labor, a military operation or wildfire-suppression work. During each hour of the study, participants performed an exercise program that included upper and lower body exercises separated by short periods of recovery. Over the course of the study, fatigue level increased as suggested by a significant increase in the participants' relative perceived exertion. The composition of the sMW proteome was investigated using reversed-phase liquid chromatography with mass spectrometric detection. Isotopes of acetic anhydride were used for mass-specific labeling of samples and subsequent identification of ions with significant changes in intensity. Cluster analysis was used to identify a pair of peptides with concentrations that changed in opposite directions with fatigue level, i.e. concentration of one peptide increased while concentration of the other decreased. The sequences of the two peptides were determined by high-resolution mass spectrometry. The ratio of the ion intensities of these two peptides, referred to as the fatigue biomarker index, was calculated for subjects throughout the study. The FBI values from the start of the study likely arose from a different distribution than the FBI values measured at the end of the study (Mann-Whitney test, P<.05). While this study is restricted to a small population of recreationally trained cyclists performing exercise under controlled conditions, it holds promise for the development of an objective salivary measurement of fatigue that is applicable to a much broader population performing in uncontrolled environments. PMID- 22239936 TI - Can a simple balance task be used to assess fitness for duty? AB - Human fatigue, caused by sleep loss, extended wakefulness, and/or circadian misalignment, is a major cause of workplace errors, incidents and accidents. In some industries, employees are required to undertake fitness for duty testing at the start of a shift to identify instances where their fatigue risk is elevated, so that minimisation and/or mitigation strategies can be implemented. Postural balance has been proposed as a fitness for duty test for fatigue, but it is largely untested. Therefore, the purpose of this study was to examine the impact of sleep loss, extended wakefulness and circadian phase on postural balance. Fourteen male participants spent 10 consecutive days in a sleep laboratory, including three adaptation days and eight simulated shiftwork days. To simulate a quickly rotating roster, shiftwork days were scheduled to begin 4h later each day, and consisted of a 23.3-h wake episode and a 4.7-h sleep opportunity. Every 2.5h during wake, balance was measured while standing as still as possible on a force platform with eyes open for one minute, and eyes closed for one minute. Subjective sleepiness was assessed using the Karolinska Sleepiness Scale. Core body temperature, continuously recorded with rectal thermistors, was used to determine circadian phase. For measures of postural balance and subjective sleepiness, data were analysed using three separate repeated measures ANOVA with two within-subjects factors: circadian phase (six phases) and prior wake (nine levels). For subjective sleepiness, there was a significant effect of prior wake and circadian phase. In particular, sleepiness increased as prior wake increased, and was higher during biological night-time than biological daytime. For the eyes open balance task, there was no effect of prior wake or circadian phase. For the eyes closed balance task, there was a significant effect of circadian phase such that balance was poorer during the biological night-time than biological daytime, but there was no effect of prior wake. These results indicate that postural balance may be a viable tool for assessing fatigue associated with time of day, but may not be useful for assessing fatigue associated with extended hours of wake. PMID- 22239937 TI - Restricted sleep and negative affective states in commercial pilots during short haul operations. AB - This study aims to investigate (1) the relationship between restricted sleep and Heightened Emotional Activity (HEA) during normal flight operations, and (2) whether sleep patterns influence the strength of the HEA as a response to threats. Accident investigation reports continue to highlight the relationship between restricted sleep and poor safety outcomes. However, to date we have a limited understanding of how sleep and HEA interact. A total of 302 sectors of normal airline flight operations were observed by trained observers, and instances of heightened emotional activity were recorded. During the cruise phase of each of these sectors, crew members were asked to calculate the amount of sleep they had obtained in previous 24 and 48 h. In the 302 sectors of normal flight operations, 535 instances of HEA were observed. Descriptive analyses of instances of HEA and sleep in the prior 24 and 48 h showed a significant relationship between the occurrence of HEA and recent sleep. The relationship between restricted sleep and HEA suggests that there may well be further implications with respect to operational safety. PMID- 22239938 TI - ADIPOQ gene polymorphisms and susceptibility to polycystic ovary syndrome: a HuGE survey and meta-analysis. AB - Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders. The aim of this study was to investigate possible associations between 45T/G and 276G/T variants of the ADIPOQ gene and susceptibility to PCOS. A meta analysis of 11 published case-control studies on the 45T/G variant of the ADIPOQ gene (involving a total of 1176 patients with PCOS and 1759 controls) and eight published case-control studies on the 276G/T variant of the ADIPOQ gene (involving a total of 895 patients with PCOS and 1024 controls) was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. The comparison of G vs. T in ADIPOQ 45T/G showed significant differential susceptibility to PCOS (OR=1.397, 95% CI 1.156-1.689). A significant association was also found between PCOS susceptibility and the comparison of G vs. T in ADIPOQ 276G/T (OR 0.812, 95% CI 0.704-0.937). However, protective effects were found in both sites under the co-dominant model for Caucasians. Further studies are warranted to assess these associations in greater detail, especially in Asian populations. PMID- 22239939 TI - L-arginine pathway in neonates with meconium-stained amniotic fluid. AB - OBJECTIVE: To study the arginase, nitric oxide synthase and nitric oxide pathways associated with passage of meconium. STUDY DESIGN: Cord blood samples were collected from 20 newborns with meconium-stained amniotic fluid (MSAF) and from 23 newborns with clear amniotic fluid. Cord blood pH, arginase, nitric oxide synthase and nitric oxide levels were compared between the groups. RESULT: The differences between the arginase and nitric oxide measurements of the newborns with MSAF and those with clear amniotic fluid were significant. In the MSAF group arginase levels were significantly lower (p=0.007) and nitric oxide levels were significantly higher (p=0.032) than the clear amniotic fluid group. CONCLUSION: Hypoxia may be involved in the pathogenesis of meconium passage due to decreased arginase and increased nitric oxide levels. PMID- 22239940 TI - Gene expression patterns of the 11beta-hydroxysteroid dehydrogenase 2 enzyme in human placenta from intrauterine growth restriction: the role of impaired feto maternal glucocorticoid metabolism. AB - OBJECTIVE: To assess 11-beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. STUDY DESIGN: We compared 11-beta-HSD2 gene expression in placental samples from all IUGR pregnancies treated in our clinic between January 1, 2010 and January 1, 2011 vs. 140 normal pregnancy samples from the same study period. Clinical characteristics were also assessed and compared between the IUGR and normal pregnancy groups. RESULTS: Mean gestational weight gain in the IUGR group was significantly lower than in the control group. Similarly, change in body mass index (BMI) was lower. Impending intrauterine fetal asphyxia was significantly more common in the IUGR group. The 11beta-HSD2 gene was underexpressed compared to controls, but this underexpression was only observed after the 33rd gestational week. Within the IUGR group, in cases of impending intrauterine fetal asphyxia the 11beta-HSD2 gene was underexpressed compared to both impending asphyxia in non-IUGR cases, or IUGR without impending asphyxia. CONCLUSION: Low gestational weight gain appears to predict IUGR. The 11beta-HSD2 gene in IUGR is underexpressed and may result in an impaired placental barrier, decreasing protection against maternal glucocorticoids, which are thought to be prominent in fetal programming. Maternal glucocorticoid exposure resulting from an impaired placental barrier may increase the risk for cardiovascular and metobolic disorders later in adult life. In IUGR, before the 33rd gestational week, the expression of the 11beta-HSD2 gene remains physiological. The underexpression of this gene after the 33rd week in impending intrauterine fetal asphyxia in IUGR points to an increased sensitivity to hypoxia when impending asphyxia is present in the late phase of IUGR pregnancies. PMID- 22239942 TI - Two dyad-free Shaker-type K+ channel blockers from scorpion venom. AB - Most of scorpion toxins affecting voltage-gated K+ channels (KTxs) contain a functional dyad composed of a lysine and an aromatic amino acid separated by a suitable distance. By means of two-electrode voltage clamp technique, we describe functional characterization of two Mesobuthus martensii KTxs (BmP02 and BmP03) without the dyad. These two toxins differ by only one single residue at site 16 (K16N) but they display differential affinities on insect and mammalian Shaker type K+ channels expressed in Xenopus oocytes. At 1 MUM concentration, BmP02 and BmP03 inhibited currents of rK(v)1.1, rK(v)1.2, rK(v)1.3, and Shaker IR, but lacked detectable activity on rK(v)1.4. The half-inhibitory concentrations (IC50) of BmP02 for rK(v)1.1, rK(v)1.2, rK(v)1.3 and Shaker IR channels are 1.95 MUM, 4.40 MUM, 7 nM and 20.44 MUM, respectively. For BmP03, the corresponding IC50 values for these channels are 5.48 MUM, 530 nM, 85.4 nM, and 4.64 MUM, respectively. Affinity variation (more than 10-fold) between BmP02 and BmP03 on rK(v)1.3 indicates functional importance of a cationic side chain at site 16. A pH-dependent experiment and a double mutant cycle analysis suggest that the residue K16 resides on the channel-facing surface of the toxin and within 5 A of rK(v)1.3 position 401. These two toxins block rK(v)1.3 in a weak voltage dependent manner and both slightly shift the current activation curve to positive potentials. Our work is thus crucial to further understanding structure-function relationship of KTxs without a functional dyad. PMID- 22239941 TI - A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians. AB - BACKGROUND: There is reason to expect strong genetic influences on the risk of developing active pulmonary tuberculosis (TB) among latently infected individuals. Many of the genome wide linkage and association studies (GWAS) to date have been conducted on African populations. In order to identify additional targets in genetically dissimilar populations, and to enhance our understanding of this disease, we performed a multi-stage GWAS in a Southeast Asian cohort from Indonesia. METHODS: In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian samples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In stage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals from the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB association in an independent Caucasian cohort (n = 3,760) from Russia. RESULTS: Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal significance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1, DYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4. CONCLUSIONS: Mechanisms of immune defense suggested by some of the identified genes exhibit biological plausibility and may suggest novel pathways involved in the host containment of infection with TB. PMID- 22239943 TI - Determination of hypoxia and dietary copper mediated sub-lethal toxicity in carp, Cyprinus carpio, at different levels of biological organisation. AB - Hypoxic events frequently occur in the aquatic environment in association with micro pollutants, including heavy metals. Only a few studies are however available on the uptake and biological responses of heavy metals under hypoxic conditions. To elucidate the phenomenon, mirror carp Cyprinus carpio L. (16.13 16.22 g) were exposed chronically to dietary copper (Cu; 250 and 500 mg kg dry wt.(-1)) for 30 d under normoxic (8.25 mg O(2) L(-1)) and hypoxic (~3 mg O(2) L( 1)) conditions and adopting an integrated approach, sub-lethal biomarker responses were determined at different levels of biological organisation. Level of oxidative DNA damage (as determined by modified Comet assay) showed strong significant difference following exposure to dietary Cu level under normoxic (1.6 fold) as well as under hypoxic condition at both Cu levels (2.1 and 2.5-folds respectively). Significant difference was also observed for haematological parameters (i.e. increased red and white blood cells, haematocrit value and haemoglobin concentration). Quantitative histology revealed alterations in tissues (i.e. liver and gills) for hypoxic and all dietary Cu treatment groups under both normoxic and hypoxic conditions suggesting a compensatory response to these organs (p<0.05). The order of Cu accumulation in tissues (as determined by ICP-OES) was liver>intestine>kidney>gill. Interestingly, SGR under both normoxic and hypoxic conditions reduced with elevating Cu levels (p=0.019). Overall, the results provide evidence for enhanced toxicological responses in fish following exposure to Cu either alone or in combination with hypoxic condition and lends support to the evolving viewpoint that many water quality guidelines should be revisited in terms of new ecotoxicological criteria. PMID- 22239944 TI - Propiconazole inhibits the sterol 14alpha-demethylase in Glomus irregulare like in phytopathogenic fungi. AB - The increasing concentrations impact (0.02, 0.2 and 2 mg L(-1)) of a Sterol Biosynthesis Inhibitor (SBI) fungicide, propiconazole, was evaluated on development and sterol metabolism of two non-target organisms: mycorrhizal or non mycorrhizal transformed chicory roots and the arbuscular mycorrhizal fungus (AMF) Glomus irregulare using monoxenic cultures. In this work, we provide the first evidence of a direct impact of propiconazole on the AMF by disturbing its sterol metabolism. A significant decrease in end-products sterols contents (24 methylcholesterol and in 24-ethylcholesterol) was observed concomitantly to a 24 methylenedihydrolanosterol accumulation indicating the inhibition of a key enzyme in sterol biosynthesis pathway, the sterol 14alpha-demethylase like in phytopathogenic fungi. A decrease in end-product sterol contents in propiconazole treated roots was also observed suggesting a slowing down of the sterol metabolism in plant. Taken together, our findings suggest that the inhibition of the both AM symbiotic partners development by propiconazole results from their sterol metabolism alterations. PMID- 22239945 TI - Estrone direct photolysis: by-product identification using LC-Q-TOF. AB - The identification of degradation products generated upon photolysis of estrone (E1), a natural estrogenic hormone, under simulated UV irradiation conditions was addressed by the use of LC-Q-TOF mass spectrometry. The structures of the main degradation products were elucidated, demonstrating how the use of model molecules 5,6,7,8-tetrahydro-2-naphtol (THN), 2-methylcyclopentanone (MCP), labeled molecule estrone D(4) (E1-D(4)), the investigation of the fragmentation pathways of the parent E1, the concurrent use of CID and exact mass measurements permit the characterization of structural modifications induced by photodegradation processes. In the present study, we identified nine major by products of which seven photoproducts correspond to E1H(+) modified in positions other than the C-2, C-4 and C-16 of E1. Most of them showed one to three additional hydroxylations preferentially located on the aromatic ring of the parent E1, which confirms that these products may present environmental risk. Applications to real water samples have been conducted to extend the validity of the present study to environmental samples. PMID- 22239946 TI - Expression of genes associated with the antigen presentation and processing pathway are consistently regulated in early Mycobacterium avium subsp. paratuberculosis infection. AB - The primary objective of this study was to evaluate early gene expression profiles associated with paratuberculosis in cattle exposed to known infectious doses of Mycobacterium avium sub-species paratuberculosis (MAP). A Johne's disease experimental infection field trial was conducted on a mixed population of Holstein and Holstein Red cattle. Blood samples from four MAP exposed and four unexposed cattle, selected based on IFNgamma expressions were taken at 9, 13 and 21 weeks and RNA processed to Affymetrix GeneChipTM Bovine Genome arrays. Ontological analysis revealed consistent differences in gene expression between MAP exposed and control animals. A stark variation was observed in expression of a number of genes along antigen presentation pathways, suggesting that MAP exposure potentially results in the host immune response switching to a CD8(+) biased antigen presentation profile. This requires further in-depth analysis since it exposes a hitherto unconfirmed association between MAP exposure and in vivo MHC gene modulation. PMID- 22239947 TI - Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis. AB - OBJECTIVE: To analyze the levels of interleukin-33 (IL-33) in the serum of patients with rheumatoid arthritis (RA) and investigated its possible pathophysiological importance. METHODS: The concentrations of IL-33 and matrix metalloproteinase (MMP)-3 were measured by enzyme-linked immunosorbent assay (ELISA) in the serum of 121 patients with RA and 47 controls. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anticyclic citrullinated peptide (anti-CCP) were measured by standard laboratory techniques. Interstitial lung disease (ILD) was identified on high-resolution computed tomography. Disease activity in RA was scored with the Disease Activity Score 28 based on C-reactive protein levels (DAS28-CRP). The bone erosion of RA patients was evaluated by modified Sharp Score (MSS). RESULTS: Serum levels of IL 33 and MMP-3 were significantly higher in RA patients than in healthy controls. Significant higher levels of IL-33 were found in CCP-positive group and in patients with ILD. There was positive correlation between the levels of IL-33 and RF. Moreover, there was also positive correlation between IL-33 and MMP-3, MSS. CONCLUSION: These data support the hypothesis that IL-33 may be involved in RA pathogenesis and it may partly contribute to the bone erosion in RA patients. PMID- 22239948 TI - Methodologic issues in the measurement of interleukin-16 in clinical blood samples using immunoassays. AB - Quantitation of interleukin-16 (IL-16) in clinical blood samples has strongly increased, since IL-16 appears to be involved in the pathogenesis of several inflammatory diseases. IL-16 is synthesized in the cell cytoplasm as precursor protein (pro-IL-16), which can be processed by caspase-3 into N-terminal (N-IL 16) and C-terminal (C-IL-16) fragments. C-IL-16 is described to be subsequently secreted. Using commercially available IL-16 ELISA, a pro-IL-16 ELISA and immunoprecipitation analysis, we investigated, whether type and handling of blood samples influence IL-16 quantitation and whether existing IL-16 ELISA are specific for C-IL-16. We observed that cell-rich plasma samples reflect falsely elevated IL-16 concentrations due to cell contaminations. Interestingly, not C-IL 16, but pro-IL-16 represents the major IL-16 form in cell-rich plasma samples. Notably, commercially IL-16 ELISA could not distinguish between C-IL-16 and pro IL-16. Thus, cell-rich plasma samples should not be used for IL-16 measurements and new methods are necessary for quantitation of C-IL-16 and pro-IL-16 uniquely. PMID- 22239949 TI - Local knowledge and socio-economic determinants of traditional medicines' utilization in livestock health management in Southwest Nigeria. AB - Smallholder livestock farmers in Nigeria utilize traditional medicines derived from medicinal plants (PMs) for the maintenance of their animals' health. This study was designed to determine the PMs used in the study area and their level of utilization by livestock farmers, compare the level of utilization of PMs across the three states surveyed and identify the socio-economic factors influencing farmer's utilization of PMs. Thirty-five PMs were identified. Farmers had considerable knowledge about the identified PMs but about 80.0% of them used the PMs to poor/moderate extent. There were statistical differences in the utilization level of PMs among the three states. Six socio-economic variables were found to be statistically significant in influencing PMs' utilization. Farmer's age, household size, distance to the nearest veterinary hospital/clinic and extent of travels, had positive effects while negative effects were exhibited by farm income and number of heads of livestock. It was concluded that there was considerable knowledge about PMs and that utilization of PMs varied between the three states. It was recommended that local knowledge of PMs be preserved in the study area through screening and documentation. PMID- 22239950 TI - Roles of long, non-coding RNA in chromosome-wide transcription regulation: lessons from two dosage compensation systems. AB - A large part of higher eukaryotic genomes is transcribed into RNAs lacking any significant open reading frame. This "non-coding part" has been shown to actively contribute to regulating gene expression, but the mechanisms are largely unknown. Particularly instructive examples are provided by the dosage compensation systems, which assure that the single X chromosome in male cells and the two X chromosomes in female cells give rise to similar amounts of gene product. Although this is achieved by very different strategies in mammals and fruit flies, long, non-coding RNAs (lncRNAs) are involved in both cases. Here we summarize recent progress towards unraveling the mechanisms, by which the Xist and roX RNAs mediate the selective association of regulators with individual target chromosomes, to initiate dosage compensation in mammals and fruit flies, respectively. PMID- 22239951 TI - Deciphering the effects of gene deletion on yeast longevity using network and machine learning approaches. AB - Longevity is one of the most basic and one of the most essential properties of all living organisms. Identification of genes that regulate longevity would increase understanding of the mechanisms of aging, so as to help facilitate anti aging intervention and extend the life span. In this study, based on the network features and the biochemical/physicochemical features of the deletion network and deletion genes, as well as their functional features, a two-layer model was developed for predicting the deletion effects on yeast longevity. The first stage of our prediction approach was to identify whether the deletion of one gene would change the life span of yeast; if it did, the second stage of our procedure would automatically proceed to predict whether the deletion of one gene would increase or decrease the life span. It was observed by analyzing the predicted results that the functional features (such as mitochondrial function and chromatin silencing), the network features (such as the edge density and edge weight density of the deletion network), and the local centrality of deletion gene, would have important impact for predicting the deletion effects on longevity. It is anticipated that our model may become a useful tool for studying longevity from the angle of genes and networks. Moreover, it has not escaped our notice that, after some modification, the current model can also be used to study many other phenotype prediction problems from the angle of systems biology. PMID- 22239953 TI - Combination therapy with InsB9-23 peptide immunization and CTLA4-IgG does not reverse diabetes in NOD mice. PMID- 22239952 TI - Effect of acute administration of Pistacia lentiscus L. essential oil on rat cerebral cortex following transient bilateral common carotid artery occlusion. AB - BACKGROUND: Ischemia/reperfusion leads to inflammation and oxidative stress which damages membrane highly polyunsaturated fatty acids (HPUFAs) and eventually induces neuronal death. This study evaluates the effect of the administration of Pistacia lentiscus L. essential oil (E.O.), a mixture of terpenes and sesquiterpenes, on modifications of fatty acid profile and endocannabinoid (eCB) congener concentrations induced by transient bilateral common carotid artery occlusion (BCCAO) in the rat frontal cortex and plasma. METHODS: Adult Wistar rats underwent BCCAO for 20 min followed by 30 min reperfusion (BCCAO/R). 6 hours before surgery, rats, randomly assigned to four groups, were gavaged either with E.O. (200 mg/0.45 ml of sunflower oil as vehicle) or with the vehicle alone. RESULTS: BCCAO/R triggered in frontal cortex a decrease of docosahexaenoic acid (DHA), the membrane highly polyunsaturated fatty acid most susceptible to oxidation. Pre-treatment with E.O. prevented this change and led further to decreased levels of the enzyme cyclooxygenase-2 (COX-2), as assessed by Western Blot. In plasma, only after BCCAO/R, E.O. administration increased both the ratio of DHA-to-its precursor, eicosapentaenoic acid (EPA), and levels of palmytoylethanolamide (PEA) and oleoylethanolamide (OEA). CONCLUSIONS: Acute treatment with E.O. before BCCAO/R elicits changes both in the frontal cortex, where the BCCAO/R-induced decrease of DHA is apparently prevented and COX-2 expression decreases, and in plasma, where PEA and OEA levels and DHA biosynthesis increase. It is suggested that the increase of PEA and OEA plasma levels may induce DHA biosynthesis via peroxisome proliferator-activated receptor (PPAR) alpha activation, protecting brain tissue from ischemia/reperfusion injury. PMID- 22239954 TI - Phenotype and function of dendritic cells of patients with systemic lupus erythematosus. AB - Dendritic cells (DC) regulate the activation and differentiation of T cells. They are activated by signals of inflammation and tissue damage, and thus could play a role in the amplification and perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE). Here we analyzed the phenotype of circulating DC from patients with SLE and studied their differentiation from monocytes. Peripheral blood DC exhibited increased levels of activation in patients with SLE. Although their in vitro differentiation process occurred normally, their responses to activation stimuli (LPS, TNF-alpha plus PGE(2), anti-CD40) were abnormal when compared to DC differentiated from healthy monocytes. When incubated in the presence of IL-10, DC from patients with SLE were able to induce tolerance to allogeneic antigens in a normal manner. Our results suggest that DC from patients with SLE are abnormal, in part due to the effect of abundant pro inflammatory signals, but also because of intrinsic cellular defects that alter their responses to activation stimuli. PMID- 22239955 TI - An event-level analysis of adding exogenous lubricant to condoms in a sample of men who have vaginal sex with women. AB - INTRODUCTION: Little is known about the characteristics of sexual events during which individuals choose to use lubricant with condoms. AIMS: The aims of this article were to evaluate the determinants of adding lubricant to condoms during baseline and at the event level, to assess the event-level variables' influence on adding lubricants to condoms, and to assess the event-level influence of using condoms with lubricant on event-level condom attitudes. METHODS: A total of 1,874 men completed a 30-day Internet-based prospective daily diary study of sexual behavior and condom use. MAIN OUTCOME MEASURES: Baseline data included demographic variables and information about condom education. Daily diary data included reports of penile-vaginal sex regarding intercourse duration, intercourse intensity, intoxication level, condom application method, partner contraceptive method, and partner and relationship characteristics. RESULTS: Lubricant was added to 24.3% of the study-provided condoms and 26.2% of the condoms selected by study participants. Those with more education and those who were married were more likely to add lubrication to condoms. Adding lubricant to condoms, a female partner putting the condom on with her hands and using contraception, and the event occurring with a wife (vs. girlfriend) was significantly associated with longer intercourse. Event-level lubricant and condom use significantly predicted lower willingness to buy the condom it was used with, as well as to recommend the condom. Adding exogenous lubricant was not related to the participants' confidence in condoms as a method to prevent pregnancy and sexually transmitted infections. CONCLUSIONS: The event-level nature of this study provided for a more comprehensive assessment of the situational factors that are associated with applying lubricant to condoms. Findings from this study suggest that men are adding lubricant to condoms for reasons other than to increase condom efficacy. PMID- 22239956 TI - Using an ensemble system to improve concept extraction from clinical records. AB - Recognition of medical concepts is a basic step in information extraction from clinical records. We wished to improve on the performance of a variety of concept recognition systems by combining their individual results. We selected two dictionary-based systems and five statistical-based systems that were trained to annotate medical problems, tests, and treatments in clinical records. Manually annotated clinical records for training and testing were made available through the 2010 i2b2/VA (Informatics for Integrating Biology and the Bedside) challenge. Results of individual systems were combined by a simple voting scheme. The statistical systems were trained on a set of 349 records. Performance (precision, recall, F-score) was assessed on a test set of 477 records, using varying voting thresholds. The combined annotation system achieved a best F-score of 82.2% (recall 81.2%, precision 83.3%) on the test set, a score that ranks third among 22 participants in the i2b2/VA concept annotation task. The ensemble system had better precision and recall than any of the individual systems, yielding an F score that is 4.6% point higher than the best single system. Changing the voting threshold offered a simple way to obtain a system with high precision (and moderate recall) or one with high recall (and moderate precision). The ensemble based approach is straightforward and allows the balancing of precision versus recall of the combined system. The ensemble system is freely available and can easily be extended, integrated in other systems, and retrained. PMID- 22239957 TI - Corynebacterium diphtheriae 67-72p hemagglutinin, characterized as the protein DIP0733, contributes to invasion and induction of apoptosis in HEp-2 cells. AB - Although Corynebacterium diphtheriae has been classically described as an exclusively extracellular pathogen, there is growing evidence that it may be internalized by epithelial cells. The aim of the present report was to investigate the nature and involvement of the surface-exposed non-fimbrial 67-72 kDa proteins (67-72p), previously characterized as adhesin/hemagglutinin, in C. diphtheriae internalization by HEp-2 cells. Transmission electron microscopy and bacterial internalization inhibition assays indicated the role of 67-72p as invasin for strains of varied sources. Cytoskeletal changes with accumulation of polymerized actin in HEp-2 cells beneath adherent 67-72p-adsorbed microspheres were observed by the Fluorescent actin staining test. Trypan blue staining method and Methylthiazole tetrazolium reduction assay showed a significant decrease in viability of HEp-2 cells treated with 67-72p. Morphological changes in HEp-2 cells observed after treatment with 67-72p included vacuolization, nuclear fragmentation and the formation of apoptotic bodies. Flow cytometry revealed an apoptotic volume decrease in HEp-2 cells treated with 67-72p. Moreover, a double staining assay using Propidium Iodide/Annexin V gave information about the numbers of vital vs. early apoptotic cells and late apoptotic or secondary necrotic cells. The comparative analysis of MALDI-TOF MS experiments with the probes provided for 67-72p CDC-E8392 with an in silico proteome deduced from the complete genome sequence of C. diphtheriae identified with significant scores 67 72p as the protein DIP0733. In conclusion, DIP0733 (67-72p) may be directly implicated in bacterial invasion and apoptosis of epithelial cells in the early stages of diphtheria and C. diphtheriae invasive infection. PMID- 22239958 TI - Incidence and survival of oesophageal and gastric cancer in England between 1998 and 2007, a population-based study. AB - BACKGROUND: Major changes in the incidence of oesophageal and gastric cancers have been reported internationally. This study describes recent trends in incidence and survival of subgroups of oesophageal and gastric cancer in England between 1998 and 2007 and considers the implications for cancer services and policy. METHODS: Data on 133,804 English patients diagnosed with oesophageal and gastric cancer between 1998 and 2007 were extracted from the National Cancer Data Repository. Using information on anatomical site and tumour morphology, data were divided into six groups; upper and middle oesophagus, lower oesophagus, oesophagus with an unspecified anatomical site, cardia, non-cardia stomach, and stomach with an unspecified anatomical site. Age-standardised incidence rates (per 100,000 European standard population) were calculated for each group by year of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan-Meier method. RESULTS: The majority of oesophageal cancers were in the lower third of the oesophagus (58%). Stomach with an unspecified anatomical site was the largest gastric cancer group (53%). The incidence of lower oesophageal cancer increased between 1998 and 2002 and remained stable thereafter. The incidence of cancer of the cardia, non-cardia stomach, and stomach with an unspecified anatomical site declined over the 10 year period. Both lower oesophageal and cardia cancers had a much higher incidence in males compared with females (M:F 4:1). The incidence was also higher in the most deprived quintiles for all six cancer groups. Survival was poor in all sub-groups with 1 year survival ranging from 14.8-40.8% and 5 year survival ranging from 3.7-15.6%. CONCLUSIONS: An increased focus on prevention and early diagnosis, especially in deprived areas and in males, is required to improve outcomes for these cancers. Improved recording of tumour site, stage and morphology and the evaluation of focused early diagnosis programmes are also needed. The poor long-term survival reinforces the need for early detection and multidisciplinary care. PMID- 22239959 TI - A predictive model identifies patients most likely to have inadequate bowel preparation for colonoscopy. AB - BACKGROUND & AIMS: An inadequate level of bowel preparation can affect the efficacy and safety of colonoscopy. Although some factors have been associated with outcome, there is no strategy to identify patients at high risk for inadequate preparation. We searched for factors associated with an inadequate level of preparation and tested the validity of a predictive clinical rule based on these factors. METHODS: We performed a prospective study of 2811 consecutive patients who underwent colonoscopy examinations at 18 medical centers; clinical and demographic data were collected before the colonoscopy. Bowel preparation was classified as adequate or inadequate; 925 patients (33%) were found to have inadequate preparation. Multivariate analysis was used to identify factors associated with inadequate preparation, which were expressed as odds ratio (OR) and used to build a predictive model. RESULTS: Factors associated with inadequate bowel preparation included being overweight (OR, 1.5), male sex (OR, 1.2), a high body mass index (OR, 1.1), older age (OR, 1.01), previous colorectal surgery (OR, 1.6), cirrhosis (OR, 5), Parkinson disease (OR, 3.2), diabetes (OR, 1.8), and positive results in a fecal occult test (OR, 0.6). These factors predicted which patients would have inadequate cleansing with 60% sensitivity, 59% specificity, 41% positive predictive value, and 76% negative predictive value; they had an under the receiver operating characteristic curve value of 0.63. Assuming 100% efficacy of a hypothetical regimen to address patients predicted to be at risk of inadequate preparation, the rate would decrease from 33% to 13%. CONCLUSIONS: We identified factors associated with inadequate bowel preparation for colonoscopy and used these to build an accurate predictive model. PMID- 22239960 TI - A molecular simulation study of the effects of stationary phase and solute chain length in reversed-phase liquid chromatography. AB - The effects of stationary phase and solute chain length are probed by carrying out Monte Carlo simulations of dimethyl triacontyl (C30), dimethyl octadecyl (C18), dimethyl octyl (C8), and trimethyl (C1) silane grafted, and bare silica stationary phases in contact with a water/methanol mobile phase and by examining the retention of solutes from 1 to 14 carbons in length. Fairly small differences in structure are observed when comparing the C30, C18, C8 systems and the retention mechanism of nonpolar alkane solutes shows contribution from both partitioning and adsorption on all three of these stationary phases. Unlike in the other systems, the mobile phase solvent is highly structured at its interface with the C1 and bare silica phases, the former being enriched in methanol and the latter in water. Alkane solutes are unretained at the bare silica surface while alcohol solutes are only slightly enriched at the silica surface due to hydrogen bonding with surface silanols and surface bound solvent. With regard to solute size, it appears that the retention mechanism is not affected by the chain length of the solute. PMID- 22239961 TI - Determination of pharmaceutically related compounds by suppressed ion chromatography: II. Interactions of analytes with the suppressor. AB - For the hyphenation of ion chromatography to nebulising detectors or mass spectrometry, suppression of the non-volatile ionic eluent to water is a required step. However, suppression of weakly acidic or weakly basic organic analytes can potentially lead to losses of analytes during suppression resulting from precipitation, hydrophobic adsorption onto the suppressor, or permeation of the analyte through the suppressor membranes. This study investigates the interactions between the suppressor and weak organic acid analytes, including pharmaceutically related compounds, for eluents containing organic solvent. Correlations were observed between analyte recovery rates after electrolytic suppression and the eluent composition, the suppression conditions, and the physico-chemical properties of the analytes. These results suggest that hydrophobic adsorption interactions occur in the electrolytic suppressor and that these interactions are ameliorated by the addition to the eluent of high levels of organic solvents, especially acetonitrile. Use of eluents containing 80% acetonitrile resulted in very low losses of analyte during suppression. Recovery experiments conducted in various compartments of the electrolytic suppressor showed that some analytes permeated through the suppressor membrane into the regenerant chambers, but this could be prevented by adding organic solvent to the regenerant solution. It was also noted that analyte losses increased with ageing of the electrolytic suppressors. Chemical suppression avoids some of the analyte losses observed with an electrolytic suppressor, but when used under the correct conditions, electrolytic suppressors gave close to equivalent performance to chemical suppressors. PMID- 22239962 TI - Shape effects on reflexive spatial attention are driven by the dorsal stream. AB - In a modified reflexive spatial attention paradigm, when the cue and the target are at the same spatial location, processing of the target is faster when the cue and the target have different shapes compared to same (shape effect). Recent physiological findings suggest distinct population level encoding of shape in ventral versus dorsal cortical visual streams in monkeys. In human observers, we tested whether the effect of shape on reflexive spatial attention could be attributed to ventral and/or dorsal stream encoding of shape. In the modified reflexive spatial attention paradigm, we varied the shapes of the cue and target. Based on data from monkey physiology (Lehky & Sereno, 2007), we selected four pairs of cue and target shapes. In some pairs, cue and target were similarly encoded (similar encoding distance) by a population of cells in the lateral intraparietal cortex, a dorsal stream area, but more dissimilarly encoded (having a greater encoding distance) by a population of cells in the anterior inferotemporal cortex (AIT), a ventral stream area. In other pairs, cue and target were similarly encoded in AIT and had greater dissimilarity in LIP encoding. We found that pairs of cue and target with greater dissimilarity in LIP encoding produced larger and more consistent shape effects up to a cue to target onset asynchrony (CTOA) of 450 ms. The shape effects for cue and target pairs with greater dissimilarity in AIT encoding were smaller and inconsistent, suggesting that shape effects in reflexive spatial attention are largely driven by the dorsal stream. PMID- 22239964 TI - Mass spectrometric quantification of glycogen to assess primary substrate accumulation in the Pompe mouse. AB - Glycogen storage in the alpha-glucosidase knockout((6neo/6neo)) mouse recapitulates the biochemical defect that occurs in the human condition; as such, this mouse serves as a model for the inherited metabolic deficiency of lysosomal acid alpha-glucosidase known as Pompe disease. Although this model has been widely used for the assessment of therapies, the time course of glycogen accumulation that occurs as untreated Pompe mice age has not been reported. To address this, we developed a quantitative method involving amyloglucosidase digestion of glycogen and quantification of the resulting free glucose by liquid chromatography/electrospray ionization-tandem mass spectrometry. The method was sensitive enough to measure as little as 0.1 MUg of glycogen in tissue extracts with intra- and interassay coefficients of variation of less than 12%. Quantification of glycogen in tissues from Pompe mice from birth to 26 weeks of age showed that, in addition to the accumulation of glycogen in the heart and skeletal muscle, glycogen also progressively accumulated in the brain, diaphragm, and skin. Glycogen storage was also evident at birth in these tissues. This method may be particularly useful for longitudinal assessment of glycogen reduction in response to experimental therapies being trialed in this model. PMID- 22239963 TI - Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain. AB - We describe here a gas chromatography-tandem mass spectrometry (GC/MS/MS) method for the sensitive and concurrent determination of extracellular tryptophan and the kynurenine pathway metabolites kynurenine, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) in rat brain. This metabolic cascade is increasingly linked to the pathophysiology of several neurological and psychiatric diseases. Methodological refinements, including optimization of MS conditions and the addition of deuterated standards, resulted in assay linearity to the low nanomolar range. Measured in samples obtained by striatal microdialysis in vivo, basal levels of tryptophan, kynurenine, and QUIN were 415, 89, and 8 nM, respectively, but 3-HK levels were below the limit of detection (<2 nM). Systemic injection of kynurenine (100 mg/kg, i.p.) did not affect extracellular tryptophan but produced detectable levels of extracellular 3-HK (peak after 2-3 h: ~50 nM) and raised extracellular QUIN levels (peak after 2h: ~105 nM). The effect of this treatment on QUIN, but not on 3-HK, was potentiated in the N-methyl-D-aspartate (NMDA)-lesioned striatum. Our results indicate that the novel methodology, which allowed the measurement of extracellular kynurenine and 3-HK in the brain in vivo, will facilitate studies of brain kynurenines and of the interplay between peripheral and central kynurenine pathway functions under physiological and pathological conditions. PMID- 22239965 TI - Transfer of PBDEs and chlorinated POPs from mother to pup during lactation in harp seals Phoca groenlandica. AB - Seven mother-pup pairs of harp seal (Phoca groenlandica) were sampled during the lactation season near Magdalen Islands, QC, Canada. The blubber and serum of pups and mothers as well as the milk of mothers were analyzed for polybrominated diphenyl ethers and several chlorinated persistent organic pollutants (POPs) to evaluate their transfer prior to weaning. Principal component analysis demonstrated significant variations in contaminant distribution patterns between seal tissues of mothers and pups. The selectivity in the transfer of POPs between mothers and pups appeared mainly driven by their log K(ow) (octanol/water partition coefficient). The most selective transfer step for the POPs examined occurred between the blubber and the serum of the mother. A novel approach to examine temporal changes of POP concentrations in tissues of seals which take into account the contamination of mothers was developed. A general decrease of POP concentrations in pup tissues throughout lactation may suggest a growth dilution. A concomitant rise of POP concentrations was observed in maternal blubber and serum and in milk as lactation progresses. The intensive offloading of contaminants via lactation constitutes a major but selective excretory route for reproductive female seals and also a significant route of exposure for suckling pup seals. PMID- 22239966 TI - The impact of future climate on historic interiors. AB - The socio-economic significance of climate change is widely recognised. However, its potential to affect our cultural heritage has not been discussed in detail (i.e. not explicit in IPCC 4) even though the cultural impacts of future outdoor climate have been the focus of some European Commission projects (e.g. NOAH'S ARK) and World Heritage Centre reports. Recently there have been a few projects that have examined the changing environmental threats to tangible heritage indoors (e.g. Preparing Historic Collections for Climate Change and Climate for Culture). Here we predict future indoor temperature and humidity, and damage arising from changes to climate in historic rooms in Southern England with little climate control, using simple building simulations coupled with high resolution (~5 km) climate predictions. The calculations suggest an increase in indoor temperature over the next century that is slightly less than that outdoors. Annual relative humidity shows little change, but the seasonal cycles suggest drier summers and slightly damper winters indoors. Damage from mould growth and pests is likely to increase in the future, while humidity driven dimensional change to materials (e.g. wood) should decrease somewhat. The results allow collection managers to prepare for the impact of long-term climate change, putting strategic measures in place to prevent increased damage, and thus preserve our heritage for future generations. PMID- 22239967 TI - [Pathological gambling in adolescence]. AB - Today's juveniles are the first generation to be raised in an environment where gambling is very accessible and socially acceptable. The recent legalization of Internet gambling has increased this accessibility. With 28,8 millions of gamblers in France in 2010, many believe that gambling is an innocent leisure activity. The first results of the national survey on the prevalence of gambling practices conducted in France show that in 2010, 1.3% of the population had a gambling problem. Also, despite the prohibition of gambling to minors, the mean age of onset of gambling behavior in the world is 11.5 years. Gambling (even non problematic) in adolescence is associated with poor school performance, criminal behavior and family conflict. Recreational gambling shares with pathological gambling high rates of psychiatric comorbidities in adults, and risk behaviors among adolescents. Similarly, international studies show prevalence of problem gambling 2 to 4 times higher among adolescents than among adult, 3.5% to 8% of adolescents between 12 and 17 are pathological gamblers. The validity of the screening instruments and the frequency of spontaneous recovery in adulthood are discussed to explain the high prevalence in adolescence. This article proposes a focus on the practice of gambling in adolescence and its characteristics when the practice becomes pathological. We discuss the epidemiological, diagnostic, etiologic and therapeutic aspects of this problem. Three major types of risk factors implicated in gambling problems are identified: some of them are related to the subject (individual factors), others are related to the object of the addiction, here the gambling activity by itself (structural factors) like Internet with the recent legalization of gambling online, and the last are related to environment (contextual or situational factors). Thus, the development and maintenance of pathological gambling in youth seems to be conditioned by the interaction of a person and a gambling activity, in a particular context. This conceptual model is based on the well-known theory of Olivenstein on toxicomania, which was proposed in the seventies. In France, very few is known about problem gambling in this age and its implications in terms of treatment, prevention and research. There is little in the way of specific treatments for adolescent pathological gamblers so we briefly reviewed possibilities and limits. We discuss the importance to develop prevention, in particular to delay the initiation, and the necessity of research to develop screening instruments and news studies to have a better knowledge of this population. PMID- 22239969 TI - [Shaken baby syndrome: what's new in the diagnosis of shaking, the mechanism, and judicial matters]. PMID- 22239970 TI - [Coping with an unnamed birth. A study of parents of children born with disorders of sexual development]. PMID- 22239972 TI - Effect of visual displays and locations on laparoscopic surgical training task. AB - The number of minimally invasive surgical (MIS) procedures has substantially increased since its introduction due to health and recovery benefits for patients. However, there are potential performance issues in MIS for surgeons due to perceptual processing demands associated with supporting technologies. Monitor location has been identified as a major factor influencing performance in these types of procedures. This study examined the effect of multiple monitors on performance during a laparoscopic surgical training task (peg transfer among instruments). Twenty-four novice subjects were exposed to different monitor conditions including a default position, a biomechanically compatible position, and a position collocated with the operating surface as well as the combination of the latter two. Subjective rankings and cognitive workload were also assessed. Results revealed a significant effect of monitor position on task time when compared to subjects' baseline training task time using the default monitor setup. Collocating the monitor with the operating surface was shown to be superior in terms of task time. There were no significant differences among monitor positions in terms of perceived workload. The results of this study provide an applicable guide for the design of MIS setups in the operating room to promote surgeon performance. PMID- 22239973 TI - Equine poisoning by coffee husk (Coffea arabica L.). AB - BACKGROUND: In Brazil, coffee (Coffea arabica) husks are reused in several ways due to their abundance, including as stall bedding. However, field veterinarians have reported that horses become intoxicated after ingesting the coffee husks that are used as bedding. The objective of this study was to evaluate whether coffee husk consumption causes intoxication in horses. RESULTS: Six horses fed coast cross hay ad libitum were given access to coffee husks and excitability, restlessness, involuntary muscle tremors, chewing movements and constant tremors of the lips and tongue, excessive sweating and increased respiration and heart rates were the most evident clinical signs. Caffeine levels were measured in the plasma and urine of these horses on two occasions: immediately before the coffee husks were made available to the animals (T0) and at the time of the clinical presentation of intoxication, 56 h after the animals started to consume the husks (T56). The concentrations of caffeine in the plasma (p < 0.001) and urine (p < 0.001) of these animals were significantly greater at T56 than at T0. CONCLUSIONS: It was concluded that consumption of coffee husks was toxic to horses due to the high levels of caffeine present in their composition. Therefore, coffee husks pose a risk when used as bedding or as feed for horses. PMID- 22239974 TI - Respiratory control when measuring respiratory sinus arrhythmia during a talking task. AB - The current study explored the effects of talking on respiratory sinus arrhythmia (RSA) during a semi-structured emotional interview (Adult Attachment Interview) using 76 female undergraduates. The effectiveness of 2 different methodological approaches (i.e. talking baseline or transfer function) was explored as respiratory control during talking tasks. RSA was collected during resting baseline, talking baseline, and interview conditions. Subjective reports of distress were higher in the interview than in the other 2 conditions. Mean RSA levels were significantly lower in the 2 talking tasks than in the resting baseline. After applying a transfer function for respiratory control, there were no significant differences between the 3 conditions. Moderator analyses yielded lower RSA values in the talking baseline and interview conditions for participants who reported greater distress during the interview. It was concluded that respiratory controls are likely necessary when using RSA in talking paradigms and that both approaches appeared to be adequate. PMID- 22239976 TI - New insights into cancer-related proteins provided by the yeast model. AB - Cancer is a devastating disease with a profound impact on society. In recent years, yeast has provided a valuable contribution with respect to uncovering the molecular mechanisms underlying this disease, allowing the identification of new targets and novel therapeutic opportunities. Indeed, several attributes make yeast an ideal model system for the study of human diseases. It combines a high level of conservation between its cellular processes and those of mammalian cells, with advantages such as a short generation time, ease of genetic manipulation and a wealth of experimental tools for genome- and proteome-wide analyses. Additionally, the heterologous expression of disease-causing proteins in yeast has been successfully used to gain an understanding of the functions of these proteins and also to provide clues about the mechanisms of disease progression. Yeast research performed in recent years has demonstrated the tremendous potential of this model system, especially with the validation of findings obtained with yeast in more physiologically relevant models. The present review covers the major aspects of the most recent developments in the yeast research area with respect to cancer. It summarizes our current knowledge on yeast as a cellular model for investigating the molecular mechanisms of action of the major cancer-related proteins that, even without yeast orthologues, still recapitulate in yeast some of the key aspects of this cellular pathology. Moreover, the most recent contributions of yeast genetics and high-throughput screening technologies that aim to identify some of the potential causes underpinning this disorder, as well as discover new therapeutic agents, are discussed. PMID- 22239975 TI - LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Gialpha dependent PI-3kinase signalling. AB - COPD is a disease of innate immunity and bacterial infections are a dominant cause of exacerbations in the later stages resulting in poor health and high mortality. The pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) is sensed by immune cells through activation of the toll-like receptor 4 (TLR4). This leads to the activation of NADPH oxidase (NOX) and NF-kappaB which together drive COPD inflammation. In this study we show in human PBMCs that LPS stimulated proinflammatory cytokine release (CXCL8 and IL6) was inhibited by approximately 50% by the broad specificity phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Our results also demonstrate that activation of PI3K following LPS stimulation is mediated by a NOX4 dependent mechanism releasing endogenous H2O2, as the NOX4 inhibitor apocynin blocked LPS induced AKT phosphorylation. Moreover, LPS-induced PI3K activation was inhibited by the anti oxidant N-acetylcysteine in a concentration dependent manner (IC50 ~100 MUM). In addition, our data demonstrated that inhibition of small G proteins, by pre treatment with pertussis toxin, inhibited LPS-induced AKT phosphorylation. Furthermore, the G-protein inhibitors pertussis toxin and mastoparan both inhibited LPS-induced CXCL8 and IL-6 release by approximately 50%. Together, these data indicate there is a mechanism in human PBMCs where TLR4 activation by LPS leads to ROS generation through NOX4 and activation of the PI3K pathway. This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines. PMID- 22239977 TI - A population-based study on the association between gastric ulcers and erectile dysfunction in Taiwan. AB - INTRODUCTION: While erectile dysfunction (ED) and cardiovascular disease have long been known to share endothelial dysfunction as a common contributory underlying mechanism, little research has been conducted taking endothelial dysfunction as common ground to investigate the potential association between ED and gastric ulcers (GUs). AIM: This population-based case-control study aimed to investigate the association of ED with GU. METHODS: This study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. The study group comprised 6,906 patients who visited ambulatory care centers or were hospitalized with a diagnosis of ED. The comparison group was 20,718 randomly selected enrollees. Conditional logistic regression was used to examine associations between ED and prior GU. MAIN OUTCOME MEASURE: The prevalence and risk between cases and controls were calculated of having been previously diagnosed with GU. RESULTS: Of the sampled subjects, 3,861 (14%) were diagnosed before the index date, 1,358 (19.7%) were cases, and 2,503 (12.1%) were controls (P<0.001). After adjusting for hypertension, diabetes, hyperlipidemia, renal disease, coronary heart disease, obesity, alcohol abuse/alcohol dependence syndrome, and socioeconomic status (SES), conditional logistic regression analysis revealed that cases were more likely to have been diagnosed with GU than controls (odds ratio [OR]=1.65, 95% confidence interval [CI]=1.53-1.77). Stratification by age revealed that the youngest group (18-29) of ED patients had the most increased likelihood of having been previously diagnosed with GU when compared with matched controls (OR=4.12, 95% CI=2.41-7.03). The likelihood decreased with age, with the oldest group of ED patients having the least increased likelihood of prior GU when compared with matched controls (OR=1.44, 95%CI=1.23-1.68). CONCLUSION: Our findings suggest a positive association between prior GU and a subsequent diagnosis with ED. PMID- 22239978 TI - Panax notoginseng and its components decreased hypertension via stimulation of endothelial-dependent vessel dilatation. AB - Ginsenoside Rb1 and Rg1 are major components of Panax notoginseng (P.N.), an herb with known clinical efficacy in hypertension and myocardial ischemia in Eastern countries. This investigation is to elicit the mechanism of these components in hypertension via their effect on vascular reaction. To assess the ability of P.N. in hypertension, P.N. extracts were injected in spontaneously hypertensive rats (SHR) via the vena caudalis; Low dosages of P.N. extracts significantly lowered blood pressure in SHR. Examination with Rb1 and Rg1 revealed significant vasodilatation using mouse coronary arteries in a dose-dependent manner. Rb1- and Rg1-induced vasodilatation was blocked by pre-incubation with eNOS and PI3K inhibitors. Coronaries of eNOS-/- mice showed attenuated vasodilatation with Rb1 and Rg1. In addition, both Rb1 and Rg1 induce nitric oxide (NO) generation through increasing the phosphorylation of eNOS, activating Na+-independent l arginine transport, and stimulating cationic amino acid transport (CAT)-1 mRNA expression in cultured endothelial cells. CONCLUSION: Ginsenoside Rb1 and Rg1 increased endothelial-dependent vessel dilatation through the activation of NO by modulating the PI3K/Akt/eNOS pathway and l-arginine transport in endothelial cells. These findings may have important implications for understanding the mechanisms of clinical efficacy of the herb P.N. when used in the regulation of blood pressure. PMID- 22239979 TI - Inhibitory effects of pectenotoxins from marine algae on the polymerization of various actin isoforms. AB - Pectenotoxins (PTXs) are marine toxins produced by dinoflagellates and which accumulate in shellfish. There are at least 14 different analogs of PTX with slight variations in structure leading to different chemical properties and consequently different toxicities. Since preliminary studies have shown that the parent compound PTX1 targets actin, we investigated the effects of two analogs, PTX2 and PTX2 seco acid, on the polymerization and depolymerization of skeletal muscle actin, smooth muscle actin, cardiac muscle actin, and non-muscle actin. Optimized actin assays using fluorescently labeled skeletal muscle actin and SDS PAGE were jointly used to determine the relative amounts of filamentous and globular actin formed during polymerization and depolymerization experiments. Our findings suggest that PTX2 causes a dose-dependent decrease in both the rate and yield of skeletal muscle actin polymerization (IC50 values of 44 and 177 nM; respectively), with no significant effects on depolymerization. Moreover, the inhibitory effects of PTX2 are conserved towards other actin isoforms (i.e., smooth muscle, cardiac muscle, and non-muscle), as the inhibitory effects on actin polymerization were also observed with similar IC50 values (range: 19-94 nM). No inhibitory effects on polymerization were observed for PTX2 seco acid, suggesting an intact lactone ring is necessary for bioactivity. PMID- 22239980 TI - Resting heart rate as a predictor of metabolic dysfunctions in obese children and adolescents. AB - BACKGROUND: Recent studies have identified that a higher resting heart rate (RHR) is associated with elevated blood pressure, independent of body fatness, age and ethnicity. However, it is still unclear whether RHR can also be applied as a screening for other risk factors, such as hyperglycemia and dyslipidemia. Thus, the purpose of the presented study was to analyze the association between RHR, lipid profile and fasting glucose in obese children and adolescents. METHODS: The sample was composed of 180 obese children and adolescents, aged between 7-16 years. Whole-body and segmental body composition were estimated by Dual-energy X ray absorptiometry. Resting heart rate (RHR) was measured by heart rate monitors. The fasting blood samples were analyzed for serum triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose, using the colorimetric method. RESULTS: Fasting glucose, TC, triglycerides, HDL-C, LDL-C and RHR were similar in both genders. The group of obese subjects with a higher RHR presented, at a lower age, higher triglycerides and TC. There was a significant relationship between RHR, triglycerides and TC. In the multivariate model, triglycerides and TC maintained a significant relationship with RHR independent of age, gender, general and trunk adiposity. The ROC curve indicated that RHR has a high potential for screening elevated total cholesterol and triglycerides as well as dyslipidemia. CONCLUSION: Elevated RHR has the potential to identify subjects at an increased risk of atherosclerosis development. PMID- 22239983 TI - Cationic polyvinylamine binding to anionic microgels yields kinetically controlled structures. AB - Polyvinylamine (PVAm) binding (absorption and adsorption) to carboxylated microgels gave colloidally stable, cationic microgels that can be centrifuged, washed, freeze dried, and redispersed in water with no loss in colloidal stability. Because both PVAm and the carboxylated microgels are pH sensitive, changes in microgel swelling and electrophoretic mobility in response to pH change can be positive or negative depending upon pH and the PVAm content of the microgels. For a given PVAm molecular weight, the steady-state saturated mass fraction of bound PVAm in the microgels varied by a factor of four in our experiments. We proposed that the PVAm content at saturation was controlled by the relative rates of the initial attachment of PVAm chains versus the rate of attached chain spreading on and into the microgel structure. This explanation was further supported by a series of quartz crystal microbalance measurements. Finally, PVAm binding to two types of PNIPAM microgels shows general features recently reported for other polyelectrolyte types. Specifically: (1) for surface localized anionic charges on the microgels, the mass fraction of bound PVAm increased with PVAm molecular weight and vice versa; (2) in virtually all conditions, the quantity of adsorbed cationic ammonium groups was much greater than the carboxylate content of the microgel; and (3) sodium chloride additions lowered the mass fraction of bound PVAm. PMID- 22239981 TI - Two replication regions in the pJM1 virulence plasmid of the marine pathogen Vibrio anguillarum. AB - Vibrio anguillarum is a fish pathogen that causes vibriosis, a serious hemorrhagic septicemia, in wild and cultured fish. Many serotype O1 strains of this bacterium harbor the 65kb plasmid pJM1 carrying the majority of genes encoding the siderophore anguibactin iron transport system that is one of the most important virulence factors of this bacterium. We previously identified a replication region of the pJM1 plasmid named ori1. In this work we determined that ori1 can replicate in Escherichia coli and that the chromosome-encoded proteins DnaB, DnaC and DnaG are essential for its replication whereas PolI, IHF and DnaA are not required. The copy number of the pJM1 plasmid is 1-2, albeit cloned smaller fragments of the ori1 region replicate with higher copy numbers in V. anguillarum while in E. coli we did not observe an obvious difference of the copy numbers of these constructs which were all high. Furthermore, we were able to delete the ori1 region from the pJM1 plasmid and identified a second replication region in pJM1 that we named ori2. This second replication region is located on ORF25 that is within the trans-acting factor (TAFr) region, and showed that it can only replicate in V. anguillarum. PMID- 22239984 TI - Morphological determination of face-centered-cubic metallic nanoparticles by X ray diffraction. AB - X-ray diffraction studies of face-centered-cubic metallic nanoparticles with different morphologies are discussed based on the experimental data and the calculation of the Debye equation with the truncated and perfect strain models. At least four basic morphologies frequently observed in face-centered-cubic metallic nanoparticles, namely sphere, cube, decahedron, and icosahedron, can be clearly distinguished from their characteristic integrated intensity ratios of the first two X-ray diffraction peaks, that is, (200) to (111). PMID- 22239982 TI - Two independent replicons can support replication of the anthrax toxin-encoding plasmid pXO1 of Bacillus anthracis. AB - The large pXO1 plasmid (181.6kb) of Bacillus anthracis encodes the anthrax toxin proteins. Previous studies have shown that two separate regions of pXO1 can support replication of pXO1 miniplasmids when introduced into plasmid-less strains of this organism. No information is currently available on the ability of the above two replicons, termed RepX and ORFs 14/16 replicons, to support replication of the full-length pXO1 plasmid. We generated mutants of the full length pXO1 plasmid in which either the RepX or the ORFs 14/16 replicon was inactivated by TargeTron insertional mutagenesis. Plasmid pXO1 derivatives containing only the RepX or the ORFs 14/16 replicon were able to replicate when introduced into a plasmid-less B. anthracis strain. Plasmid copy number analysis showed that the ORFs 14/16 replicon is more efficient than the RepX replicon. Our studies demonstrate that both the RepX and ORFs 14/16 replicons can independently support the replication of the full-length pXO1 plasmid. PMID- 22239985 TI - Measurement and analysis of forces in bubble and droplet systems using AFM. AB - The use of atomic force microscopy to measure and understand the interactions between deformable colloids - particularly bubbles and drops - has grown to prominence over the last decade. Insight into surface and structural forces, hydrodynamic drainage and coalescence events has been obtained, aiding in the understanding of emulsions, foams and other soft matter systems. This article provides information on experimental techniques and considerations unique to performing such measurements. The theoretical modelling frameworks which have proven crucial to quantitative analysis are presented briefly, along with a summary of the most significant results from drop and bubble AFM measurements. The advantages and limitations of such measurements are noted in the context of other experimental force measurement techniques. PMID- 22239986 TI - Structural characterisation of alkyl amine-capped zinc sulphide nanoparticles. AB - Nanoparticles capped with amine ligands with different steric properties, dodecylamine and oleylamine, respectively, are investigated in the solid state as well as in solution. A combined X-ray diffraction, small angle X-ray scattering and electron microscopy investigation showed that the nanoparticles exhibit the sphalerite modification of ZnS as crystal phase with a diameter of 3-5 nm. A close packing of the monocrystalline nanoparticles in the solid state is observed. However, in the dodecylamine sample, besides spherical particles, a fraction of the nanoparticles is elongated. The nanoparticles are readily resoluble in apolar solvents like hexane. Dynamic light scattering (DLS) and SAXS investigations of the solutions reveal that the nanoparticles are dissolved as singular particles. In the case of oleylamine-capped ZnS, a defined core-shell structure with a ZnS core with a diameter of 4 nm and an organic shell with a thickness of approximately 2 nm have been found. Dodecylamine-capped nanoparticles slightly tend to form agglomerates with a diameter of approximately 40 nm. PMID- 22239987 TI - Malate-aspartate shuttle and exogenous NADH/cytochrome c electron transport pathway as two independent cytosolic reducing equivalent transfer systems. AB - In mammalian cells aerobic oxidation of glucose requires reducing equivalents produced in glycolytic phase to be channelled into the phosphorylating respiratory chain for the reduction of molecular oxygen. Data never presented before show that the oxidation rate of exogenous NADH supported by the malate aspartate shuttle system (reconstituted in vitro with isolated liver mitochondria) is comparable to the rate obtained on activation of the cytosolic NADH/cytochrome c electron transport pathway. The activities of these two reducing equivalent transport systems are independent of each other and additive. NADH oxidation induced by the malate-aspartate shuttle is inhibited by aminooxyacetate and by rotenone and/or antimycin A, two inhibitors of the respiratory chain, while the NADH/cytochrome c system remains insensitive to all of them. The two systems may simultaneously or mutually operate in the transfer of reducing equivalents from the cytosol to inside the mitochondria. In previous reports we suggested that the NADH/cytochrome c system is expected to be functioning in apoptotic cells characterized by the presence of cytochrome c in the cytosol. As additional new finding the activity of reconstituted shuttle system is linked to the amount of alpha-ketoglutarate generated inside the mitochondria by glutamate dehydrogenase rather than by aspartate aminotransferase. PMID- 22239988 TI - Urinary excretion of 8-oxo-7,8-dihydroguanine as biomarker of oxidative damage to DNA. AB - Oxidatively damaged DNA may be important in carcinogenesis. 8-Oxo-7,8 dihydroguanine (8-oxoGua) is an abundant and mutagenic lesion excised by oxoguanine DNA glycosylase 1 (OGG1) and measurable in urine or plasma by chromatographic methods with electrochemical or mass spectrometric detectors, reflecting the rate of damage in steady state. A common genetic OGG1 variant may affect the activity and was associated with increased levels of oxidized purines in leukocytes without apparent effect on 8-oxoGua excretion or major change in cancer risk. 8-OxoGua excretion has been associated with exposure to air pollution, toxic metals, tobacco smoke and low plasma antioxidant levels, whereas fruit and vegetable intake or dietary interventions showed no association. In rodent studies some types of feed may be source of 8-oxoGua in collected urine. Of cancer therapies, cisplatin increased 8-oxoGua excretion, whereas radiotherapy only showed such effects in experimental animals. Case-control studies found high excretion of 8-oxoGua in relation to cancer, dementia and celiac disease but not hemochromatosis, although associations could be a consequence rather than reflecting causality of disease. One prospective study found increased risk of developing lung cancer among non-smokers associated with high excretion of 8 oxoGua. Urinary excretion of 8-oxoGua is a promising biomarker of oxidatively damaged DNA. PMID- 22239990 TI - [Assessment of a software application tool for managing nursing care processes in the period 2005-2010]. AB - OBJECTIVES: To identify problems and critical points in the software application. METHOD: Assessment of the implementation of the software tool "Azahar" used to manage nursing care processes. The monitored population consisted of nurses who were users of the tool, at the Hospital and those who benefited from it in Primary Care. Each group was selected randomly and the number was determined by data saturation. A qualitative approach was employed using in-depth interviews and group discussion as data collection techniques. RESULTS: The nurses considered that the most beneficial and useful application of the tool was the initial assessment and the continuity of care release forms, as well as the recording of all data on the nursing process to ensure quality. The disadvantages and weaknesses identified were associated with the continuous variability in their daily care. The nurses related an increase in workload with the impossibility of entering the records into the computer, making paper records, thus duplicating the recording process. Likewise, they consider that the operating system of the software should be improved in terms of simplicity and functionality. CONCLUSION: The simplicity of the tool and the adjustment of workloads would favour its use and as a result, continuity of care. PMID- 22239991 TI - Extent of cancer of less than 50% in any prostate needle biopsy core: how many millimeters are there? PMID- 22239989 TI - Ubiquitination, intracellular trafficking, and degradation of connexins. AB - Gap junction channels provide a conduit for communication between neighboring cells. The function of gap junction channels is regulated by posttranslational modifications of connexins, the proteins that comprise these channels. Ubiquitination of connexins has increasingly been viewed as one mechanism by which cells regulate the level of connexins present in cells, as well as the corresponding intercellular communication. Here we review the current knowledge of connexin ubiquitination and the effects this may have on gap junctional communication. PMID- 22239992 TI - Interleukin-10 promoter microsatellite polymorphisms influence the immune response to heparin and the risk of heparin-induced thrombocytopenia. AB - INTRODUCTION: Heparin-induced thrombocytopenia (HIT) results from an atypical immune response with synthesis of IgG antibodies (Abs) to platelet factor 4/heparin complexes (PF4/H), and probably involves both B and T cells. We investigated whether 3 single nucleotide polymorphisms (SNPs), rs1800896 ( 1082G/A), rs1800871 (-819C/T) and rs1800872 (-592C/A) and the polymorphic CA repeat microsatellites IL10R [5325CA(11_15)] and IL10G [8134CA(14_29)] are associated with the synthesis of Abs to PF4/heparin and HIT. MATERIALS AND METHODS: Eighty-two patients with definite HIT and two control groups were studied. The first control group (Ab(neg)) consisted of 85 patients without Abs to PF4/heparin after cardiopulmonary bypass (CPB). The second control group (Ab(pos)) consisted of 84 patients who had developed significant levels of PF4 specific antibodies after CPB, but without HIT. RESULTS: Allele frequencies of the 3 SNPs were similar in HIT patients and controls. Fourteen alleles in IL10G (G16 to G29) and 3 alleles in IL10R (R13 to R15) were defined. The short G20 allele of IL10G was more frequent in Ab(neg) patients (8.2%) than in Ab(pos) (2.9%) and HIT patients (3%). It thereby appeared to protect against developing Abs to PF4/heparin (OR 0.29; 95% CI [0.12-0.70], p=0.006). Combined haplotypes cH1/cH8 comprising the short G20 + R13 alleles were less frequent in HIT (OR 0.33; 95% CI [0.11-0.97], p=0.036), and levels of Abs to PF4 in Ab(pos) patients were lower in cH1/cH8 subjects (p=0.019). CONCLUSION: These results suggest that IL10 promoter microsatellite polymorphisms might influence the immune response against PF4/heparin and the risk of HIT. PMID- 22239993 TI - Plasma derivatives: new products and new approaches. AB - The infusion of plasma-derived or recombinant factors to treat bleeding disorders such as hemophilia A and B is a success story in the management of a chronic disease. The effectiveness of this approach is however limited by challenges with adverse effects of treatment. The most notable of these are the development of inhibitory antibodies that target the protein therapeutic. The current standard of care for management of hemophiliacs is prophylactic treatment that includes frequent infusions of a Factor VIII product. Failure to comply with the prophylactic regimen is a major hurdle in the management of these patients. We discuss here more recent findings that argue for a pharmacogenetic approach to understanding (and eventually circumventing) immunogenicity. We also review strategies used to bioengineer coagulation factors to extend the half-lives of coagulation proteins. The rapid progress in the last few years to bioengineer coagulation factors in different ways to attain this goal is described. Finally, novel technologies and potential products are emerging that utilize synthetic molecules in lieu of replacement proteins obviating the limitations associated with replacement therapies. PMID- 22239995 TI - Editorial. Good quality science reporting. PMID- 22239994 TI - A need for careful evaluation of endotoxin contents in acellular pertussis-based combination vaccines. AB - Two batches each of diphtheria-tetanus-acellular pertussis vaccine (DTaP) and that combined with inactivated polio vaccine purchased from foreign markets were tested by mouse body weight decreasing (BWD) toxicity test and Limulus amaebocyte lysate (LAL) test. Three out of the four imported vaccine batches showed the levels of BWD toxicity even comparable to that of DT-whole cell pertussis vaccine. BWD toxicity test is based on endotoxin dose-dependent weight loss of mice and has been used for controlling endotoxin in DTaP. Although of the strong BWD toxicity of the imported vaccines, there was no marked difference in LAL test results between the imported vaccines and Japanese DTaP. However, one imported DTaP batch showed very strong interference with LAL activity of spiked lipopolysaccharide (LPS). The batch interfered not only with LAL activity but also with pyrogenicity and prostaglandin E(2) induction activity. However, the pyrogenicity of the spiked LPS could be recovered from the precipitated fraction of the batch by treating with phosphate buffer to suggest the possibility of recovering in vivo toxicity. As an adequate in vitro test method could not be identified for controlling the safety of the interfering batch, an appropriate in vivo test would be required for testing such vaccines. PMID- 22239996 TI - Segmentation of nerve fibers using multi-level gradient watershed and fuzzy systems. AB - OBJECTIVE: This paper presents an algorithm based on multi-level watershed segmentation combined with three fuzzy systems to segment a large number of myelinated nerve fibers in microscope images. The method can estimate various geometrical parameters of myelinated nerve fibers in peripheral nerves. It is expected to be a promising tool for the quantitative assessment of myelinated nerve fibers in related research. MATERIALS AND METHODS: A novel multi-level watershed scheme iteratively detects pre-candidate nerve fibers. At each immersion level, watershed segmentation extracts the initial axon locations and obtains meaningful myelinated nerve fiber features. Thereafter, according to a priori characteristics of the myelinated nerve fibers, fuzzy rules reject unlikely pre-candidates and collect a set of candidates. Initial candidate boundaries are then refined by a fuzzy active contour model, which flexibly deforms contours according to the observed features of each nerve fiber. A final scan with a different set of fuzzy rules based on the a priori properties of the myelinated nerve fibers removes false detections. A particle swarm optimization method is employed to efficiently train the large number of parameters in the proposed fuzzy systems. RESULTS: The proposed method can automatically segment the transverse cross-sections of nerve fibers obtained from optical microscope images. Although the microscope image is usually noisy with weak or variable levels of contrast, the proposed system can handle images with a large number of myelinated nerve fibers and achieve a high fiber detection ratio. As compared to manual segmentation by experts, the proposed system achieved an average accuracy of 91% across different data sets. CONCLUSION: We developed an image segmentation system that automatically handles myelinated nerve fibers in microscope images. Experimental results showed the efficacy of this system and its superiority to other nerve fiber segmentation approaches. Moreover, the proposed method can be extended to other applications of automatic segmentation of microscopic images. PMID- 22239997 TI - The social production of substance abuse and HIV/HCV risk: an exploratory study of opioid-using immigrants from the former Soviet Union living in New York City. AB - BACKGROUND: Several former Soviet countries have witnessed the rapid emergence of major epidemics of injection drug use (IDU) and associated HIV/HCV, suggesting that immigrants from the former Soviet Union (FSU) may be at heightened risk for similar problems. This exploratory study examines substance use patterns among the understudied population of opioid-using FSU immigrants in the U.S., as well as social contextual factors that may increase these immigrants' susceptibility to opioid abuse and HIV/HCV infection. METHODS: In-depth interviews were conducted with 10 FSU immigrants living in New York City who initiated opioid use in adolescence or young adulthood, and with 6 drug treatment providers working with this population. Informed by a grounded theory approach, interview transcripts were inductively coded and analyzed to identify key themes. RESULTS: The "trauma" of the immigration/acculturation experience was emphasized by participants as playing a critical role in motivating opioid use. Interview data suggest that substance use patterns formed in the high-risk environment of the FSU may persist as behavioral norms within New York City FSU immigrant communities - including a predilection for heroin use among youth, a high prevalence of injection, and a tolerance for syringe sharing within substance using peer networks. Multiple levels of social context may reproduce FSU immigrants' vulnerability to substance abuse and disease such as: peer-based interactional contexts in which participants typically used opioids; community workplace settings in which some participants were introduced to and obtained opioids; and cultural norms, with roots in Soviet-era social policies, stigmatizing substance abuse which may contribute to immigrants' reluctance to seek disease prevention and drug treatment services. CONCLUSION: Several behavioral and contextual factors appear to increase FSU immigrants' risk for opioid abuse, IDU and infectious disease. Further research on opioid-using FSU immigrants is warranted and may help prevent increases in HIV/HCV prevalence from occurring within these communities. PMID- 22239998 TI - Single-field sterile-scrub, preparation, and dwell for laparoscopic hysterectomy. AB - Type VII laparoscopic hysterectomy is classified as a "clean-contaminated" procedure because the surgery involves contact with both the abdominal and vaginal fields. Because the vulva has traditionally been perceived as a separate but contaminated field, operating room guidelines have evolved to require that surgeons gloved and gowned at the abdominal field either avoid contact with the urethral catheter, the uterine manipulator, and the introitus or change their gloves and even re-gown after any contact with those fields. In the belief that the perception of the vaginal field as contaminated stems from inadequate preoperative preparation instructions, we have developed a rigorous abdomino perineo-vaginal field preparation technique to improve surgical efficiency and prevent surgical site infections. This thorough scrub, preparation, and dwell technique enables the entire abdomino-perineo-vaginal field to be safely treated as a single sterile field while maintaining a low rate of surgical site infection, and should be further investigated in randomized studies. PMID- 22239999 TI - Influences of the G2350A polymorphism in the ACE gene on cardiac structure and function of ball game players. AB - BACKGROUND: Except for the I/D polymorphism in the angiotensin I-converting enzyme (ACE) gene, there were few reports about the relationship between other genetic polymorphisms in this gene and the changes in cardiac structure and function of athletes. Thus, we investigated whether the G2350A polymorphism in the ACE gene is associated with the changes in cardiac structure and function of ball game players. Total 85 healthy ball game players were recruited in this study, and they were composed of 35 controls and 50 ball game players, respectively. Cardiac structure and function were measured by 2-D echocardiography, and the G2350A polymorphism in the ACE gene analyzed by the SNaPshot method. RESULTS: There were significant differences in left ventricular mass index (LVmassI) value among each sporting discipline studied. Especially in the athletes of basketball disciplines, indicated the highest LVmassI value than those of other sporting disciplines studied (p < 0.05). However, there were no significant association between any echocardiographic data and the G2350A polymorphism in the ACE gene in the both controls and ball game players. CONCLUSIONS: Our data suggests that the G2350A polymorphism in the ACE gene may not significantly contribute to the changes in cardiac structure and function of ball game players, although sporting disciplines of ball game players may influence the changes in LVmassI value of these athletes. Further studies using a larger sample size and other genetic markers in the ACE gene will be needed. PMID- 22240000 TI - Overexpression of extracellular superoxide dismutase has a protective role against hyperoxia-induced brain injury in neonatal mice. AB - There is increasing evidence that hyperoxia, particularly at the time of birth, may result in neurological injury, in particular to the susceptible vasculature of these tissues. This study was aimed at determining whether overexpression of extracellular superoxide dismutase (EC-SOD) is protective against brain injury induced by hyperoxia. Transgenic (TG) mice (with an extra copy of the human extracellular superoxide dismutase gene) and wild-type (WT) neonate mice were exposed to hyperoxia (95% of F(i) o(2) ) for 7 days after birth versus the control group in room air. Brain positron emission tomography (PET) scanning with fludeoxyglucose (FDG) isotope uptake was performed after exposure. To assess apoptosis induced by hyperoxia exposure, caspase 3 ELISA and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed. Quantitative western blot for the following inflammatory markers was performed: glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, macrophage-inhibiting factor, and phospho-AMP-activated protein kinase. PET scanning with FDG isotope uptake showed significantly higher uptake in the WT hyperoxia neonate brain group (0.14 +/- 0.03) than in both the TG group (0.09 +/- 0.01) and the control group (0.08 +/- 0.02) (P< 0.05). Histopathological investigation showed more apoptosis and dead neurons in hippocampus and cerebellum brain sections of WT neonate mice after exposure to hyperoxia than in TG mice; this finding was also confirmed by TUNEL staining. The caspase 3 assay confirmed the finding of more apoptosis in WT hyperoxia neonates (0.814 +/- 0.112) than in the TG hyperoxic group (0.579 +/- 0.144) (P < 0.05); this finding was also confirmed by TUNEL staining. Quantitative western blotting for the inflammatory and metabolic markers showed significantly higher expression in the WT group than in the TG and control groups. Thus, overexpression of EC-SOD in the neonate brain offers significant protection against hyperoxia-induced brain damage. PMID- 22240001 TI - A study of possible associations between single nucleotide polymorphisms in the serotonin receptor 1A, 1B, and 2C genes and self-reported ejaculation latency time. AB - INTRODUCTION: Previous research has indicated that serotonergic genes may influence ejaculatory function. Attempts to investigate effects of polymorphisms in serotonergic genes have been carried out, but so far, no study has conducted exploratory genotype analyses regarding the serotonin receptor 1A, 1B, and 2C subtypes, which have been hypothesized to mediate the inhibitory effects of serotonin on ejaculation in rodents. AIM: The aim of the present study was to investigate effects of a total of six single nucleotide polymorphisms (SNPs) located in genes encoding serotonin receptor subtypes 1A, 1B, and 2C on self reported ejaculation latency time. METHODS: A retrospective self-report measure of ejaculation latency time was used to investigate ejaculatory function in a population-based sample of 1,399 male twins. DNA was collected using self administered saliva sampling. MAIN OUTCOME MEASURE: Calculations of allelic effects were conducted using the Generalized Estimating Equations module of PASW 18.0, which appropriately controls for between-subjects dependence. RESULTS: Out of six investigated polymorphisms, two SNPs (both serotonin receptor 5-HT(1B) linked) had a significant main effect on ejaculation latency time. Of these, one (rs11568817) remained significant after Bonferroni correction for multiple testing, indicating that individuals homozygous for the G allele had significantly shorter ejaculation latencies. CONCLUSIONS: The results of this study support the hypothesis that serotonergic genes play a role in ejaculatory function in the general population. Replication of the results of the present study is warranted. PMID- 22240002 TI - Are marginalized women being left behind? A population-based study of institutional deliveries in Karnataka, India. AB - BACKGROUND: While India has made significant progress in reducing maternal mortality, attaining further declines will require increased skilled birth attendance and institutional delivery among marginalized and difficult to reach populations. METHODS: A population-based survey was carried out among 16 randomly selected rural villages in rural Mysore District in Karnataka, India between August and September 2008. All households in selected villages were enumerated and women with children 6 years of age or younger underwent an interviewer administered questionnaire on antenatal care and institutional delivery. RESULTS: Institutional deliveries in rural areas of Mysore District increased from 51% to 70% between 2002 and 2008. While increasing numbers of women were accessing antenatal care and delivering in hospitals, large disparities were found in uptake of these services among different castes. Mothers belonging to general castes were almost twice as likely to have an institutional birth as compared to scheduled castes and tribes. Mothers belonging to other backward caste or general castes had 1.8 times higher odds (95% CI: 1.21, 2.89) of having an institutional delivery as compared to scheduled castes and tribes. In multivariable analysis, which adjusted for inter- and intra-village variance, Below Poverty Line status, caste, and receiving antenatal care were all associated with institutional delivery. CONCLUSION: The results of the study suggest that while the Indian Government has made significant progress in increasing antenatal care and institutional deliveries among rural populations, further success in lowering maternal mortality will likely hinge on the success of NRHM programs focused on serving marginalized groups. Health interventions which target SC/ST may also have to address both perceived and actual stigma and discrimination, in addition to providing needed services. Strategies for overcoming these barriers may include sensitization of healthcare workers, targeted health education and outreach, and culturally appropriate community-level interventions. Addressing the needs of these communities will be critical to achieving Millennium Development Goal Five by 2015. PMID- 22240003 TI - Developmental and insecticide-resistant insights from the de novo assembled transcriptome of the diamondback moth, Plutella xylostella. AB - We present here the de novo assembly and annotation of the transcriptome of Plutella xylostella (diamondback moth (DBM)), a widespread destructive pest of cruciferous plants, using short reads generated by Illumina sequencing from different developmental stages and insecticide-resistant strains. A total of 171,262 non-redundant sequences, denoted as unigenes, were obtained. They represented approximately 100-fold of all DBM mRNA and EST sequences in GenBank thus far. We identified 38,255 unigenes highly similar to the known functional protein-coding genes, most of which were annotated using gene ontology (GO) and orthologous groups of proteins (COG). Global profiling of differentially expressed unigenes revealed enriched GOs and biological pathways that were related to specific developmental stages and insecticide resistance. We also evaluated the resistance-related single nucleotide polymorphism (SNP) using this high-throughput genotyping method. The newly developed transcriptome will facilitate researches on the DBM developmental biology and insecticide resistance evolution, and ultimately provide better pest management systems. PMID- 22240004 TI - Identification of differentially expressed genes in cucumber (Cucumis sativus L.) root under waterlogging stress by digital gene expression profile. AB - High-throughput tag-sequencing (Tag-seq) analysis based on the Solexa Genome Analyzer platform was applied to analyze the gene expression profiling of cucumber plant at 5 time points over a 24h period of waterlogging treatment. Approximately 5.8 million total clean sequence tags per library were obtained with 143013 distinct clean tag sequences. Approximately 23.69%-29.61% of the distinct clean tags were mapped unambiguously to the unigene database, and 53.78% 60.66% of the distinct clean tags were mapped to the cucumber genome database. Analysis of the differentially expressed genes revealed that most of the genes were down-regulated in the waterlogging stages, and the differentially expressed genes mainly linked to carbon metabolism, photosynthesis, reactive oxygen species generation/scavenging, and hormone synthesis/signaling. Finally, quantitative real-time polymerase chain reaction using nine genes independently verified the tag-mapped results. This present study reveals the comprehensive mechanisms of waterlogging-responsive transcription in cucumber. PMID- 22240006 TI - Obese patients overestimate physicians' attitudes of respect. AB - OBJECTIVE: To evaluate whether obese patients overestimate or underestimate the level of respect that their physicians hold toward them. METHODS: We performed a cross-sectional analysis of data from questionnaires and audio-recordings of visits between primary care physicians and their patients. Using multilevel logistic regression, we evaluated the association between patient BMI and accurate estimation of physician respect. Physician respectfulness was also rated independently by assessing the visit audiotapes. RESULTS: Thirty-nine primary care physicians and 199 of their patients were included in the analysis. The mean patient BMI was 32.8 kg/m2 (SD 8.2). For each 5 kg/m2 increase in BMI, the odds of overestimating physician respect significantly increased [OR 1.32, 95% CI 1.04 1.68, p=0.02]. Few patients underestimated physician respect. There were no differences in ratings of physician respectfulness by independent evaluators of the audiotapes. CONCLUSION: We consider our results preliminary. Patients were significantly more likely to overestimate physician respect as BMI increased, which was not accounted for by increased respectful treatment by the physician. PRACTICE IMPLICATIONS: Among patients who overestimate physician respect, the authenticity of the patient-physician relationship should be questioned. PMID- 22240005 TI - Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos. AB - Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt's Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt's Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure. PMID- 22240007 TI - Factors that influence parents' experiences with results disclosure after newborn screening identifies genetic carrier status for cystic fibrosis or sickle cell hemoglobinopathy. AB - OBJECTIVE: Newborn screening (NBS) identifies genetic carriers for sickle cell hemoglobinopathy and cystic fibrosis. We aimed to identify factors during initial NBS carrier results disclosure by primary care providers (PCPs) that influenced parents' experiences and reactions. METHODS: Open-ended responses from telephone interviews with 270 parents of carriers were analyzed using mixed-methods. Conventional content analysis identified influential factors; chi-square tests analyzed relationships between factors and parent-reported reactions. RESULTS: Parents reported positive (35%) or negative (31%) reactions to results disclosure. Parents' experiences were influenced by specific factors: content messages (72%), PCP traits (47%), and aspects of the setting (30%). Including at least one of five specific content messages was associated (p<0.05) with positive parental reactions; omitting at least one of four specific content messages was associated (p<0.05) with negative parental reactions. Parents reported positive reactions when PCPs avoided jargon or were perceived as calm. Parents reported negative reactions to jargon usage and results disclosure by voicemail. CONCLUSION: Parents identified aspects of PCP communication which influenced their reactions and results disclosure experiences. PRACTICE IMPLICATIONS: Our findings suggest ways PCPs may improve communication of carrier results. PCPs should provide specific content messages and consider how their actions, characteristics, and setting can influence parental reactions. PMID- 22240008 TI - Influence of stearyl and trifluoromethylquinoline modifications of the cell penetrating peptide TP10 on its interaction with a lipid membrane. AB - The PepFect family of cell-penetrating peptides (CPPs) was designed to improve the delivery of nucleic acids across plasma membranes. We present here a comparative study of two members of the family, PepFect3 (PF3) and PepFect6 (PF6), together with their parental CPP transportan-10 (TP10), and their interactions with lipid membranes. We show that the addition of a stearyl moiety to TP10 increases the amphipathicity of these molecules and their ability to insert into a lipid monolayer composed of zwitterionic phospholipids. The addition of negatively charged phospholipids into the monolayer results in decreased binding and insertion of the stearylated peptides, indicating modification in the balance of hydrophobic versus electrostatic interactions of peptides with lipid bilayer, thus revealing some clues for the selective interaction of these CPPs with different lipids. The trifluoromethylquinoline moieties, in PF6 make no significant contribution to membrane binding and insertion. TP10 actively introduces pores into the bilayers of large and giant unilamellar vesicles, while PF3 and PF6 do so only at higher concentrations. This is consistent with the lower toxicity of PF3 and PF6 observed in previous studies. PMID- 22240009 TI - The transmembrane domain of caveolin-1 exhibits a helix-break-helix structure. AB - Caveolin is an integral membrane protein that is found in high abundance in caveolae. Both the N- and C- termini lie on the same side of the membrane, and the transmembrane domain has been postulated to form an unusual intra-membrane horseshoe configuration. To probe the structure of the transmembrane domain, we have prepared a construct of caveolin-1 that encompasses residues 96-136 (the entire intact transmembrane domain). Caveolin-1(96-136) was over-expressed and isotopically labeled in E. coli, purified to homogeneity, and incorporated into lyso-myristoylphosphatidylglycerol micelles. Circular dichroism and NMR spectroscopy reveal that the transmembrane domain of caveolin-1 is primarily alpha-helical (57-65%). Furthermore, chemical shift indexing reveals that the transmembrane domain has a helix-break-helix structure which could be critical for the formation of the intra-membrane horseshoe conformation predicted for caveolin-1. The break in the helix spans residues 108 to 110, and alanine scanning mutagenesis was carried out to probe the structural significance of these residues. Our results indicate that mutation of glycine 108 to alanine does not disrupt the structure, but mutation of isoleucine 109 and proline 110 to alanine dramatically alters the helix-break-helix structure. To explore the structural determinants further, additional mutagenesis was performed. Glycine 108 can be substituted with other small side chain amino acids (i.e. alanine), leucine 109 can be substituted with other beta-branched amino acids (i.e. valine), and proline 110 cannot be substituted without disrupting the helix-break helix structure. PMID- 22240010 TI - VDAC structure, selectivity, and dynamics. AB - VDAC channels exist in the mitochondrial outer membrane of all eukaryotic organisms. Of the different isoforms present in one organism, it seems that one of these is the canonical VDAC whose properties and 3D structure are highly conserved. The fundamental role of these channels is to control the flux of metabolites between the cytosol and mitochondrial spaces. Based on many functional studies, the fundamental structure of the pore wall consists of one alpha helix and 13 beta strands tilted at a 46 degrees angle. This results in a pore with an estimated internal diameter of 2.5nm. This structure has not yet been resolved. The published 3D structure consists of 19 beta strands and is different from the functional structure that forms voltage-gated channels. The selectivity of the channel is exquisite, being able to select for ATP over molecules of the same size and charge. Voltage gating involves two separate gating processes. The mechanism involves the translocation of a positively charged portion of the wall of the channel to the membrane surface resulting in a reduction in pore diameter and volume and an inversion in ion selectivity. This mechanism is consistent with experiments probing changes in selectivity, voltage gating, kinetics and energetics. Other published mechanisms are in conflict with experimental results. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism. PMID- 22240011 TI - Characteristics of electrocardiographic repolarization in acute myocardial infarction complicated by ventricular fibrillation. AB - BACKGROUND AND PURPOSE: Some de- and re-polarization patterns can reflect an increased risk of ventricular tachyarrhythmias. We studied whether some electrocardiographic (ECG) patterns are able to predict the development of ventricular fibrillation (VF) during acute myocardial infarction (MI). METHODS: We compared the patterns of ST-T segment of 78 patients who developed VF during acute MI (patient with VF) vs 170 comparable patients with acute MI but with no VF complications. RESULTS: Of the VF group, 47 developed out-of-hospital VF and 31 developed VF after their admission to the hospital. A steep downsloping ST segment toward a negative T wave with or without a short, flat, or rising portion at the initial portion was observed in 69.2% of the 78 patients: 61.3% in patients with pre-VF and 74.5% in patients with post-VF, vs 9.4% of patients who did not develop VF (P < .0001). In 90.6% of the latter, a typical upward-concave or convex "ischemic" pattern of the ST segment was observed. Thus, the characteristic ST-T patterns were highly associated with VF with a specificity greater than 90%. CONCLUSIONS: A steep downsloping ST segment may characterize the ECGs of patients who develop VF during acute MI. PMID- 22240013 TI - Functioning within a relationship: mother-infant synchrony and infant sleep. AB - The aim of this study was to investigate the coupling of the biological system of infant sleep and the social system of mother-infant synchrony. Before birth and shortly after birth the systems appear to be connected, but it is unclear whether this remains the case over time. This study therefore examined whether infant sleep measured at 6 weeks and 5 months could predict mother-infant gaze synchrony after a social challenge at 5 months (N=84). Infant sleep was measured in terms of sleep bout duration, which normally increases during this period. Gaze was defined in terms of looking at each other's head simultaneously, known as gaze synchrony, or looking elsewhere. Results showed that infant sleep could predict the temporal dynamics of the mother-infant interaction in terms of flexibility of gaze pattern shifts. The larger the increase in sleep bout duration over age, the more flexible the interaction appeared to be. Maternal Age, type of feeding and change of feeding appeared to function as confounding variables in this relation. Infant sleep could not predict percentage of synchrony (central tendency measure) or the average sequence length of gaze patterns (temporal dynamic measure). PMID- 22240012 TI - hsp65 PCR-restriction analysis (PRA) with capillary electrophoresis for species identification and differentiation of Mycobacterium kansasii and Mycobacterium chelonae-Mycobacterium abscessus group. AB - OBJECTIVES: The aim of the present study was to identify and differentiate Mycobacterium kansasii and Mycobacterium chelonae-Mycobacterium abscessus group strains isolated from clinical and environmental sources in different countries. METHODS: PCR-restriction analysis of the hsp65 gene (PRA) with automated capillary electrophoresis was applied to the isolates previously identified by conventional biochemical testing and the molecular INNO-LiPA MYCOBACTERIA assay. RESULTS: PRA performed very well in comparison with the two other methods (96.4% concordance). Among 27 M. kansasii isolates, this method detected five genetic types, of which type 1 represented the most common clinical isolate, as it is worldwide. PRA differentiated 29 M. chelonae-M. abscessus group isolates into Mycobacterium immunogenum type 2 (n=13), M. chelonae (n=12), and M. abscessus types 1 (n=1) and 2 (n=1). M. immunogenum was the most frequent (69%) isolate from humans, but only one of 11 cases was clinically significant. M. chelonae was the most commonly (83%) recovered from water. PRA also identified two isolates with hsp65 alleles representing previously unreported patterns. CONCLUSIONS: PRA based on automated capillary electrophoresis is a rapid, simple, and reliable method for the identification and differentiation of both clinically relevant and environmental isolates of M. kansasii and M. chelonae-M. abscessus group. PMID- 22240014 TI - Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes. AB - Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of immunomodulatory and supporting hematopoiesis. Nevertheless, it is unclear whether the characteristics of MSCs are altered in diseased states. In this study, we obtained and expanded MSCs from bone marrow of patients with myelodysplastic syndromes (MDS). Our results showed that MSCs derived from MDS (MDS-MSCs) were similar to normal adult bone marrow derived MSCs in morphology, growth property, surface epitopes, and differentiation ability in vitro. In addition, MDS-MSCs had normal karyotype and ultrastructure. However, MDS-MSCs appeared to be impaired in immunomodulatory and supporting hematopoiesis function. Although, MDS-MSCs could express hematopoietic cytokines and support hematopoiesis in long term culture, Real time quantitative polymerase chain reaction showed that the expression of hematopoietic cytokines in MDS-MSCs was much lower than that of normal adult derived MSCs. Moreover, MDS MSCs showed reduced hematopoiesis support function, as compared to their normal counterparts. Lastly, the capacity of MDS-MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. These results indicate that MDS-MSCs have impaired immunomodulatory and hematopoiesis support functions, suggesting their critical role in the pathogenesis of MDS. PMID- 22240016 TI - The PSS-SR as a screening tool for PTSD in first-episode psychosis patients. AB - AIM: We examined the validity of the PTSD Symptom Scale - Self-Report (PSS-SR) as a screening instrument for post-traumatic stress disorder (PTSD) in patients recovering from first-episode psychosis. METHODS: Sixty-one patients from the Early Psychosis Intervention Programme in Singapore completed the PSS-SR questionnaire. The Clinician-Administered PTSD Scale was administered by a blinded interviewer as the 'gold standard' to identify patients with PTSD. The sensitivity, specificity and receiver operating characteristic curve were used to determine the screening performance of the PSS-SR. RESULTS: The score representing the optimal cut-off point for the PSS-SR was 14, with a sensitivity and specificity of 0.83 and 0.71, respectively. The area under the curve was determined to be 0.82 (95% CI: 0.70-0.95). CONCLUSION: These data suggest that the PSS-SR can be a useful screening instrument for PTSD in patients recovering from their first psychotic episode. PMID- 22240017 TI - Galectin-3 immunohistochemistry in the vomeronasal organ of the domestic pig, Sus scrofa. AB - The immunohistochemical localization of galectin-3, a beta-galactoside-binding protein, was studied in the vomeronasal organ (VNO) of fetal, 1-day-old, and 6 month-old pigs. In all age groups, the porcine VNO consisted of vomeronasal sensory epithelium (VSE) located medially and non-sensory vomeronasal respiratory epithelium (VRE) located laterally. In the pig, the VNO epithelium increased in height with postnatal development from fetus to adult. In the VSE of all stages examined, galectin-3 immunostaining was seen in the supporting cells and free border, but not in receptor or basal cells. Galectin-3 immunostaining was seen in all layers of the VRE, and the intensity increased with postnatal development. In the lamina propria, galectin-3 was detected in some ductal epithelial cells and the vomeronasal nerve sheath, but not in the acini of the Jacobson glands in all age groups. In view of these observations, we postulate that galectin-3 plays a role in cell survival and cell adhesion in both the VSE and VRE of porcine VNO in all age groups. PMID- 22240018 TI - Open wedge high tibial osteotomy: cause of patellar descent. AB - This was a retrospective review of the nine open wedge high tibial osteotomy (HTO) done in a regional hospital in Hong Kong from 2006 to 2008. The mechanical hip-knee-ankle angle improved from average 169.5 degrees (164 degrees -175 degrees ) to average 183.9 degrees (179 degrees -187 degrees ). Patellar descent was noted in all patients postoperatively, with Blackburne-Peel (BP) index significantly changing from 0.78 (0.64-0.93) to 0.59 (0.38-0.78) (p < 0.05). This change was strongly correlated with the size of anterior bone graft (r = -0.766; p = 0.016). The patellar tendon length as measured by Insall-Salvati index was not changed (pre-operative: 1.02 (0.88-1.25), final: 1.09 (0.8-1.22) (p = 0.683)), inferring that scarring contracture of patellar tendon was not related to patellar descent. PMID- 22240019 TI - Implementing conventional logic unconventionally: photochromic molecular populations as registers and logic gates. AB - In this paper we detail experimental methods to implement registers, logic gates and logic circuits using populations of photochromic molecules exposed to sequences of light pulses. Photochromic molecules are molecules with two or more stable states that can be switched reversibly between states by illuminating with appropriate wavelengths of radiation. Registers are implemented by using the concentration of molecules in each state in a given sample to represent an integer value. The register's value can then be read using the intensity of a fluorescence signal from the sample. Logic gates have been implemented using a register with inputs in the form of light pulses to implement 1-input/1-output and 2-input/1-output logic gates. A proof of concept logic circuit is also demonstrated; coupled with the software workflow describe the transition from a circuit design to the corresponding sequence of light pulses. PMID- 22240020 TI - Characterization of the ptr5+ gene involved in nuclear mRNA export in fission yeast. AB - To analyze the mechanisms of mRNA export from the nucleus to the cytoplasm, we have isolated eleven mutants, ptr [poly(A)(+) RNA transport] 1 to 11, which accumulate poly(A)(+) RNA in the nucleus at a nonpermissive temperature in Schizosaccharomyces pombe. Of those, the ptr5-1 mutant shows dots- or a ring-like accumulation of poly(A)(+) RNA at the nuclear periphery after shifting to the nonpermissive temperature. We cloned the ptr5(+) gene and found that it encodes a component of the nuclear pore complex (NPC), nucleoporin 85 (Nup85). The ptr5-1 mutant shows no defects in protein transport, suggesting the specific involvement of Ptr5p/Nup85p in nuclear mRNA export in S. pombe. We identified Seh1p, a nucleoporin interacting with Nup85p, an mRNA-binding protein Mlo3p, and Sac3p, a component of the TREX-2 complex involved in coupling of nuclear mRNA export with transcription, as multi-copy suppressors for the ptr5-1 mutation. In addition, we found that the ptr5-1 mutation is synthetically lethal with a mutation of the mRNA export factor Rae1p, and that the double mutant exaggerates defective nuclear mRNA export, suggesting that Ptr5p/Nup85p is involved in nuclear mRNA export through Rae1p. Interestingly, the ptr5-1 mutation also showed synthetic effects with several prp pre-mRNA splicing mutations, suggesting a functional linkage between the NPCs and the splicing apparatus in the yeast nucleus. PMID- 22240021 TI - Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-kappaB pathway. AB - Accumulating evidence suggests that adipose tissue is the main source of pro inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration of SVS for 1month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-alpha, IL6, IL10, IL1beta, KC, MIP 1alpha, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-kappaB) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-kappaB pathway. PMID- 22240022 TI - Differential effects of substrate-analogue inhibitors on nitric oxide synthase dimerization. AB - Nitric oxide synthase (NOS) isoforms are hemoenzymes that are only active as homodimers. We have examined the effect of the substrate-analogue inhibitors, N(G)-monomethyl-L-arginine (L-NMA), N(G)-nitro-L-arginine (L-NNA), N(G)-nitro-L arginine methyl ester (L-NAME), N(5)-(1-iminoethyl)-L-ornithine (L-NIO), and N(6) (1-iminoethyl)-L-lysine (L-NIL), the guanidine-containing inhibitor aminoguanidine (AG), and the amidine moiety-containing iNOS-specific inhibitor 1400W, on the formation of NOS dimer. Of these inhibitors, L-NMA effectively not only inhibited iNOS dimerization, but also destabilized its dimeric form in RAW264.7 cells stimulated with lipopolysaccharide plus interferon-gamma, but not eNOS dimerization in endothelial cells. Importantly, this inhibition was highly correlated with NO production. These inhibitory effects were significantly reversed by addition of L-arginine. However, L-NNA, L-NAME, and AG in part or significantly increased dimerization of iNOS and eNOS in intact cells, and the other inhibitors assessed did not alter dimerization of iNOS and eNOS. These data taken together suggest that substituted groups of an arginine guanidino moiety play an important role in NOS dimerization as well as its catalytic activity. Our results indicate that l-NMA can inhibit iNOS-dependent NO production by preventing iNOS dimerization and destabilizing its dimeric form. PMID- 22240024 TI - Reduced expression of Kruppel-like factor 17 is related to tumor growth and poor prognosis in lung adenocarcinoma. AB - Kruppel-like factor 17 (KLF17), a new member of the Kruppel-like factors (KLFs), has been reported to be a negative regulator of epithelial-mesenchymal transition (EMT) and metastasis in breast cancer. However, the biological role and clinical significance of KLF17 in lung adenocarcinoma has been less clear. In the present study, we showed that KLF17 expression was decreased in lung adenocarcinoma. Reduced expression of KLF17 was correlated significantly with a short survival time in patients with lung adenocarcinoma (P<0.0001). Moreover, KLF17 expression was an independent prognostic indicator for patients with lung adenocarcinoma. KLF17 expression level was correlated with the tumor stage (P=0.016) and tumor size (P=0.001) in lung adenocarcinoma. Overexpression of KLF17 inhibited cell growth in A549 and PC-9 cell lines. In conclusion, it is possible that KLF17 inhibits tumor growth in lung adenocarcinoma. The reduced expression of KLF17 is a valuable prognostic indicator for patients with lung adenocarcinoma, and KLF17 could be a novel target for treatment of lung adenocarcinoma. PMID- 22240023 TI - Nicotine-mediated induction of E-selectin in aortic endothelial cells requires Src kinase and E2F1 transcriptional activity. AB - Smoking is highly correlated with enhanced likelihood of atherosclerosis by inducing endothelial dysfunction. In endothelial cells, various cell-adhesion molecules including E-selectin, are shown to be upregulated upon exposure to nicotine, the addictive component of tobacco smoke; however, the molecular mechanisms underlying this induction are poorly understood. Here we demonstrate that nicotine-induced E-selectin transcription in human aortic endothelial cells (HAECs) could be significantly blocked by alpha7-nAChR subunit inhibitor, alpha BT, Src-kinase inhibitor, PP2, or siRNAs against Src or beta-Arrestin-1 (beta Arr1). Further, chromatin immunoprecipitations show that E-selectin is an E2F1 responsive gene and nicotine stimulation results in increased recruitment of E2F1 on E-selectin promoter. Inhibiting E2F1 activity using RRD-251, a disruptor of the Rb-Raf-1 kinase interaction, could significantly inhibit the nicotine-induced recruitment of E2F1 to the E-selectin promoter as well as E-selectin expression. Interestingly, stimulation of HAECs with nicotine results in increased adhesion of U937 monocytic cells to HAECs and could be inhibited by pre-treatment with RRD 251. Similarly, depletion of E2F1 or Src using RNAi blocked the increased adhesion of monocytes to nicotine-stimulated HAECs. These results suggest that nicotine-stimulated adhesion of monocytes to endothelial cells is dependent on the activation of alpha7-nAChRs, beta-Arr1 and cSrc regulated increase in E2F1 mediated transcription of E-selectin gene. Therefore, agents such as RRD-251 that can target activity of E2F1 may have potential therapeutic benefit against cigarette smoke induced atherosclerosis. PMID- 22240025 TI - Structural evolution and tissue-specific expression of tetrapod-specific second isoform of secretory pathway Ca2+-ATPase. AB - Secretory pathway Ca-ATPases are less characterized mammalian calcium pumps than plasma membrane Ca-ATPases and sarco-endoplasmic reticulum Ca-ATPases. Here we report analysis of molecular evolution, alternative splicing, tissue-specific expression and subcellular localization of the second isoform of the secretory pathway Ca-ATPase (SPCA2), the product of the ATP2C2 gene. The primary structure of SPCA2 from rat duodenum deduced from full-length transcript contains 944 amino acid residues, and exhibits 65% sequence identity with known SPCA1. The rat SPCA2 sequence is also highly homologous to putative human protein KIAA0703, however, the latter seems to have an aberrant N-terminus originating from intron 2. The tissue-specificity of SPCA2 expression is different from ubiquitous SPCA1. Rat SPCA2 transcripts were detected predominantly in gastrointestinal tract, lung, trachea, lactating mammary gland, skin and preputial gland. In the newborn pig, the expression profile is very similar with one remarkable exception: porcine bulbourethral gland gave the strongest signal. Upon overexpression in cultured cells, SPCA2 shows an intracellular distribution with remarkable enrichment in Golgi. However, in vivo SPCA2 may be localized in compartments that differ among various tissues: it is intracellular in epidermis, but enriched in plasma membranes of the intestinal epithelium. Analysis of SPCA2 sequences from various vertebrate species argue that ATP2C2 gene radiated from ATP2C1 (encoding SPCA1) during adaptation of tetrapod ancestors to terrestrial habitats. PMID- 22240026 TI - Extracellular signal-regulated kinase (ERK) dictates osteogenic and/or chondrogenic lineage commitment of mesenchymal stem cells under dynamic compression. AB - Elucidating the intracellular signaling cascades which lead to differentiation programs can be a daunting but necessary task. Even more so when the nature of the differentiating stimuli can elicit different biochemical responses yet achieve the same functional outcome. In the field of cartilage and bone regeneration the importance of the extracellular signal-regulated kinase (ERK) pathway has been a controversial issue as of late. Whether differentiation results from a soluble chemical induction or a microenvironmental cue on the cells seems to have a determining effect on the role that this pathway plays in ultimate cell fate. Here we explore the role of the ERK1/2 pathway on the mechanical induction of chondrogenesis of bone marrow mesenchymal stem cells (MSC). The cells were encapsulated in fibrin gel scaffolds and subjected to a dynamic mechanical compression stimulus previously demonstrated to induce chondrogenic differentiation of the cells with and without the addition of PD98059, a selective inhibitor for the ERK1/2 pathway. Samples were then analyzed by RT-PCR and histochemical staining for markers of both chondrogenic and osteogenic differentiation. Our results show that dynamic compression induces the chondrogenic differentiation of the cells and that inhibition of the ERK1/2 pathway completely abolishes this chondrogenic response. On the other hand, inhibition of ERK1/2 under dynamic compression augments the osteogenic response of the cells and significantly increases their expression of alkaline phosphatase (ALP), collagen type I (COLI) and osteocalcin (OCN) (P<0.05). These results were confirmed by the histochemical staining where dynamically compressed samples show staining for sulfated glycosaminoglycans (sGAG) while the inhibited and compressed samples show no sGAG but present positive staining for microcalcifications. These results would suggest that the activation of ERK1/2 can determine the ultimate cell fate between the chondrogenic and osteogenic programs in cells stimulated under dynamic unconfined mechanical compression. PMID- 22240027 TI - Selective accumulation and growth inhibition of hybrid liposomes to human hepatocellular carcinoma cells in relation to fluidity of plasma membranes. AB - Hybrid liposomes (HLs), composed of l-alpha-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) dodecyl ether, have selectively inhibited the growth of human hepatocellular carcinoma (HCC) cells without affecting normal hepatocytes to trigger apoptosis via caspase-3 activation. Furthermore, HLs distinguished between the HCC and normal cells which had higher and lower membrane fluidities respectively, then fused and accumulated preferentially into the membranes of HCC cells. It is noteworthy that the anti-cancer activity of HLs correlated well with the fluidity of cell membranes for HCC and other cancer cells. These results suggest that HLs could target cancer cell-membranes in relation to their lipid fluidity that provide the possibility of novel nanotherapy for intractable cancer. PMID- 22240028 TI - Protein profiles in human ovarian cancer cell lines correspond to their metabolic activity and to metabolic profiles of respective tumor xenografts. AB - Many solid tumors show a large variability in glycolytic activity and lactate accumulation, which has been correlated with different metastatic spread, radioresistance and patient survival. To investigate potential differences in protein profiles underlying these metabolic variances, the highly glycolytic human ovarian cancer cell line OC316 was investigated and compared with the less glycolytic line IGROV-1. Extracellular acidification and oxygen consumption were analyzed with an extracellular flux analyzer. Glycolysis-associated proteins, including specific membrane transporters, were quantified through in-cell western analyses. Metabolic properties of corresponding tumor xenografts were assessed via induced metabolic bioluminescence imaging. Extracellular flux analyses revealed elevated bioenergetics of OC316 cells. Hexokinase II, pyruvate kinase, pyruvate dehydrogenase E1 beta subunit and pyruvate dehydrogenase kinase 1, as well as the glucose transporter 1 and the monocarboxylate transporter 4, were overexpressed in these cells compared with IGROV-1. When generating tumor xenografts in SCID mice, cells maintained their glycolytic behavior, i.e. OC316 showed higher lactate concentrations than IGROV-1 tumors. In summary, a congruency between protein profiles and metabolic properties has been demonstrated in the human ovarian cancer lines investigated. Also, a perpetuation of glycolytic characteristics during the transition from in vitro to the in vivo situation has been documented. This model system could be useful for systematic studies on therapeutic intervention by manipulation of tumor glycolysis and associated pathways. PMID- 22240030 TI - The current status of S-100B as a biomarker in melanoma. AB - Melanoma is the most malignant type of all skin cancer types. It causes over 75% of all skin cancer related mortality. In the Netherlands, the total number of new diagnosed melanoma patients is expected to increase from 2400 patients in 2000 to 4800 patients in 2015. After surgical treatment, 20-28% of melanoma patients present with loco-regional recurrence, 26-60% with regional recurrences, and 15 50% with distant metastases. Early detection of lymph node (micro) metastases by means of a sentinel lymph node biopsy (SLNB) is therefore of crucial importance since early lymph node dissection decrease treatment morbidity and improve overall survival. However when patients present with palpable nodes, given the heterogeneity in survival, the suspicion rises that numerous patients have a form of subclinical dissemination, which can remain undetected by current modern imaging methods. Biomarkers could illuminate on this matter, although there is very little understanding of their biological significance. It can be expected that the strongest biological markers are surrogates of key biological events. The protein S-100B seems to be the best analyzed biomarker in melanoma. It has the potential to identify high-risk stage III melanoma patients who may benefit from adjuvant systematic treatment. In the stratification of new adjuvant therapeutic trials in patients with loco-regional recurrences, we therefore recommend the use of S-100B in the stratification. Since an effective (adjuvant) therapy for loco-regional metastatic and disseminated melanoma is recently introduced, the use of S-100B seems to alter dramatically in the near future. PMID- 22240029 TI - HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy. AB - BACKGROUND: HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy. METHODS: In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry). RESULTS: HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02 0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel. CONCLUSIONS: This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000506998. PMID- 22240031 TI - Awareness and acceptability of human papillomavirus vaccine: an application of the instrumental variables bivariate probit model. AB - BACKGROUND: Although lower uptake rates of the human papillomavirus (HPV) vaccine among socioeconomically disadvantaged populations have been documented, less is known about the relationships between awareness and acceptability, and other factors affecting HPV vaccine uptake.The current study aimed to estimate the potential effectiveness of increased HPV vaccine awareness on the acceptability of HPV vaccination in a nationally representative sample of women, using a methodology that controlled for potential non-random selection. METHODS: This study used a population-based sample from the 2007 Health Information National Trends Survey, a cross-sectional study of the US population aged 18 years or older, and focused on the subsample of 742 women who have any female children under the age of 18 years in the household. An instrumental variables bivariate probit model was used to jointly estimate HPV vaccine awareness and acceptability. RESULTS: The proportion of HPV vaccine acceptability among the previously aware and non-aware groups was 58% and 47%, respectively. Results from the instrumental variables bivariate probit model showed that the estimated marginal effect of awareness on acceptability was 46 percentage points, an effect that was even greater than observed. CONCLUSIONS: Among populations who are not currently aware of the HPV vaccine, the potential impact of raising awareness on acceptability of HPV vaccination is substantial. This finding provides additional support to strengthening public health programs that increase awareness and policy efforts that address barriers to HPV vaccination. PMID- 22240032 TI - Having and being an other-sex crush during early adolescence. AB - This study examined other-sex crush experiences (both having and being perceived as an other-sex crush) among 544 young adolescents (mean age=12.74 years). Results indicated that 56% had at least one current other-sex crush, with little overlap between crushes, friends, and boyfriends/girlfriends. Significant associations between other-sex crush scores (scores reflecting the number of crush nominations received) and physical attractiveness, relational aggression, physical aggression, and popularity, as reported by same-sex and other-sex peers, were found. In addition, crush scores were (a) associated with same-sex likeability for boys (but not girls) and (b) uniquely related to peer nominations of popularity and physical attractiveness, as reported by other-sex peers. Neither having nor being perceived as an other-sex crush was uniquely related to loneliness. Taken together, the findings suggest that other-sex crushes are normative experiences during early adolescence that warrant further research attention. PMID- 22240034 TI - Characterization of Gordonia sp. strain CC-NAPH129-6 capable of naphthalene degradation. AB - A naphthalene-degrading isolate able to utilize naphthalene as a sole carbon source was identified as Gordonia sp. CC-NAPH129-6. Here a detail characterization of the naphthalene catabolic genes present in this strain was conducted. In nar region four structural genes (narAa, narAb, narB, narC), two regulatory genes (narR1, narR2), a rubredoxin encoding gene (rub1) and a gene (orf7) with unknown function were obtained. When compared with most of the members within naphthalene-degrading Rhodococcus, these naphthalene catabolic genes in strain CC-NAPH129-6 were organized into an operon-like gene cluster and present in the same order. This naphthalene gene cluster located in a 97-kb small plasmid of strain CC-NAPH129-6, as can be seen from the PFGE and Southern blot hybridization data. Besides, a partial transposase sequence containing an IS element structure with 12-nt inverted repeat at both ends was found, which was flanked by direct repeats downstream the narC gene in strain CC-NAPH129-6. This novel transposase gene sequence was unlike to the transposase sequence found between narR2 and rub1 genes in Rhodococcus opacus R7. The comparative analyses of the naphthalene catabolic genes, 16S rRNA and gyrB gene present in strain CC NAPH129-6 and naphthalene-degrading Rhodococcus species imply that the naphthalene catabolic genes in strain CC-NAPH129-6 might be horizontally transferred from Rhodococcus members. This is the first report demonstrating that naphthalene catabolic genes organized into an operon-like gene cluster in the genus Gordonia, and this might provide evidence of the importance of this actinobacterial lineage in the bioremediation of oil-contaminated soils. PMID- 22240035 TI - Distinct roles in folding, CD81 receptor binding and viral entry for conserved histidine residues of hepatitis C virus glycoprotein E1 and E2. AB - The protonation of histidine in acidic environments underpins its role in regulating the function of pH-sensitive proteins. For pH-sensitive viral fusion proteins, histidine protonation in the endosome leads to the activation of their membrane fusion function. The HCV (hepatitis C virus) glycoprotein E1-E2 heterodimer mediates membrane fusion within the endosome, but the roles of conserved histidine residues in the formation of a functional heterodimer and in sensing pH changes is unknown. We examined the functional roles of conserved histidine residues located within E1 and E2. The E1 mutations, H222A/R, H298R and H352A, disrupted E1-E2 heterodimerization and reduced virus entry. A total of five out of six histidine residues located within the E2 RBD (receptor-binding domain) were important for the E2 fold, and their substitution with arginine or alanine caused aberrant heterodimerization and/or CD81 binding. Distinct roles in E1-E2 heterodimerization and in virus entry were identified for His691 and His693 respectively within the membrane-proximal stem region. Viral entry and cell-cell fusion at neutral and low pH values were enhanced with H445R, indicating that the protonation state of His445 is a key regulator of HCV fusion. However, H445R did not overcome the block to virus entry induced by bafilomycin A1, indicating a requirement for an endosomal activation trigger in addition to acidic pH. PMID- 22240036 TI - The effects of fibromyalgia syndrome on female sexuality: a controlled study. AB - INTRODUCTION: Fibromyalgia may have negative effects on sexual function in women. AIMS: To evaluate the sexuality of women with fibromyalgia and healthy control subjects, and to investigate the relation between sexuality and clinical parameters of fibromyalgia. MAIN OUTCOME MEASURES: Female Sexual Function Index (FSFI), Tender Points Count (TPC), Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire (FIQ), and Visual Analog Scale (VAS). METHODS: Clinical evaluation and surveys were done with 126 women with fibromyalgia and 132 healthy women. RESULTS: Patients with fibromyalgia had higher BDI scores and lower frequency of sexual intercourse than control subjects. The mean FSFI scores (total and all domains) were significantly lower in patients with fibromyalgia than control subjects. Mean FSFI scores (total and most domains) were significantly lower in patients with fibromyalgia who had BDI score>=17 than those who had BDI score<17. In women with fibromyalgia, a significant negative correlation was noted between total FSFI score, and both FIQ and BDI scores. CONCLUSIONS: Fibromyalgia has negative effects on female sexual function that are aggravated by depression. PMID- 22240037 TI - Evaluation of electrospray ionization mass spectrometry as a tool for characterization of small soluble protein aggregates. AB - Protein aggregation continues to attract significant interest in many areas of biology and medicine not only due to its pivotal role in the etiology of conformational diseases (such as Parkinson's and Alzheimer's) but also due to its importance in the biopharmaceutical sector, where aggregation of protein therapeutics exerts a deleterious effect on their efficacy and safety. Despite the tremendous success of electrospray ionization mass spectrometry (ESI MS) in a large number of studies of noncovalent protein interactions, application of this technique to study aggregation processes has been very limited so far, and lower resolution techniques, such as size exclusion chromatography (SEC) and analytical ultracentrifugation, remain the default tools in characterizing small soluble protein aggregates. In this work we used heat-stressed human antithrombin III (AT), a 58 kDa glycoprotein, to compare SEC and ESI MS as a means to probe composition of the complex mixture of soluble oligomeric species generated by heat-induced aggregation. SEC allows several oligomeric species to be observed and collected, followed by their identification with ESI MS. The same oligomeric species can be also directly observed in the ESI MS of the unfractionated sample of the heat-stressed AT. The abundance distribution of these small soluble aggregates in ESI MS and SEC cannot be compared directly, since the ESI signal is linked to the molar concentration of the analyte in solution, whereas the UV absorption detection in SEC reports weight concentration. However, once the appropriate corrections are made, the abundance of the small aggregates derived from ESI MS becomes remarkably close to that calculated based on SEC data, suggesting that ESI MS may be directly applied for semiquantitative characterization of soluble protein aggregates. PMID- 22240039 TI - Community health and advocacy training in pediatrics: using asset-based community development for sustainability. PMID- 22240038 TI - Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages. AB - Opioids have been shown to affect both innate and adaptive immunity. We previously showed that morphine affects the macrophage production of pro inflammatory cytokines after LPS in a NFkB dependent manner. Toll like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkB activation. TLR4 is considered the Lipopolysaccaride (LPS) receptor. The data here presented show that, in murine macrophages, morphine impacts on the immune function acting on the early step of pathogen recognition. Morphine, when added to RAW 264.7 cells and when injected into mice (s.c. 20mg/kg) is in fact able to decrease TLR4 both at mRNA and protein level in RAW cells and peritoneal macrophages. In the same cells, the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation. The effect of the two drugs is moreover lost in case of co-administration. Experiments with MOR KO mice and with DAMGO (MOR specific agonist) confirm that the effect of morphine on TLR4 mRNA in peritoneal macrophages is due to the MOR activation. Moreover the effect on TLR4 is blocked by PTX thus indicating the involvement of a G(i) protein after MOR binding. This work unveils a clear link between MOR activation and TLR4, suggesting a new possible mechanism at the basis of the peripheral immunosuppressive effect of opioids. PMID- 22240033 TI - Corticosteroid therapy in patients with primary viral pneumonia due to pandemic (H1N1) 2009 influenza. AB - OBJECTIVE: During the first pandemic, some patients with pandemic (H1N1) 2009 influenza were treated with corticosteroids. The objective of this study was to assess the effect on survival of corticosteroid therapy in patients with pandemic (H1N1) 2009 influenza. METHODS: Prospective, observational, multicenter study performed in 148 ICU. Data were recorded in the GTEI/SEMICYUC registry. Adult patients with pandemic (H1N1) 2009 influenza confirmed by rt-PCR were included in the analysis. Database records specified corticosteroid type and reason for corticosteroid treatment. RESULTS: 372 patients with the diagnosis of primary viral pneumonia and completed outcomes treated in an ICU were included in the database. Mechanical ventilation was used in 70.2% of the patients. 136 (36.6%) patients received corticosteroids after a diagnosis of primary viral pneumonia. Obesity (35.6% vs 47.8% p = 0.021) and asthma (7.6% vs 15.4% p = 0.018), were more frequent in the group treated with corticosteroids. A Cox regression analysis adjusted for severity and potential confounding factors found that the use of corticosteroid therapy was not significantly associated with mortality (HR = 1.06, 95% CI 0.626-1.801; p = 0.825). CONCLUSIONS: Corticosteroid therapy in a selected group of patients with primary viral pneumonia due to pandemic (H1N1) 2009 influenza does not improve survival. PMID- 22240046 TI - Risk factors for medication-induced diabetes mellitus. PMID- 22240056 TI - A descriptive study of 'non-cases' and referral rates to an early intervention for psychosis service. AB - AIM: Despite there being approximately 200 early intervention services for psychosis worldwide, little is known about the referral rates to these services, the diagnoses and needs of individuals found not to have a first episode of psychosis (FEP). Firstly, we aimed to describe the diagnoses for individuals who were found not to have a FEP (non-cases) following an assessment using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV (SCID). We then aimed to examine the referral rates of cases and non cases to an early intervention service. METHODS: All individuals referred to the early intervention service underwent a clinical assessment using the SCID. RESULTS: In a 4-year period, there were 632 referrals to the early intervention service for psychosis, and of these, 53% (n = 338) were found to have a FEP, 5% (n = 34) were found to have an at-risk mental state for psychosis and 41% (n = 260) were found to be 'non-cases'. This represents a ratio of 1.9:1 of referrals to cases, or approximately 2:1. Of the non-cases, 27% (n = 62) satisfied criteria for a mood disorder, with major depressive disorder the commonest diagnosis. A further 18% (n = 42) of non-cases satisfied criteria for an anxiety disorder and nearly half of these were diagnosed with social phobia. The ratio of referrals to cases was not consistent over time and rose from 1.3:1 in the first year to 2:1 in the fourth year. CONCLUSION: A large proportion of individuals referred to an early intervention for psychosis service were found not to have psychotic disorder, however they still have significant needs regarding their mental health. PMID- 22240057 TI - Influence of compost addition on lead and arsenic bioavailability in reclaimed orchard soil assessed using Porcellio scaber bioaccumulation test. AB - Long-term application of lead arsenate in orchards has led to a significant accumulation of Pb and As in the topsoil. Reclamation of old orchards for agricultural purposes entails the exposure of humans to Pb and As, which can be reduced by adequate remediation actions. In this study, we assessed the remediation efficiency of compost addition, commonly used as a sustainable agricultural practice, in decreasing the human exposure Pb and As by direct ingestion. The remediation was evaluated based on Pb and As bioavailability, assessed by means of a selective non-exhaustive chemical extraction (modified Morgan extraction, MME), with a physiologically based extraction test (PBET) for the assessment of Pb and As bioavailability in ingested soils and with a novel in vivo bioaccumulation test with isopods (Porcellio scaber). All the tests showed that compost addition consistently reduced Pb, but increased As potential bioavailability. The bioaccumulation test with P. scaber was sensitive to changes in Pb and As bioavailability in test soils. However, the results indicate that the bioavailability of As could be under- or overestimated using solely chemical extraction tests. Indirect assessment of trace metal bioavailability with bioaccumulation in isopods can be used as complementary source of data to the existing in vitro chemical extraction test approach for the estimation of human exposure to trace elements in polluted and remediated soil. This is the first report on the use of As accumulation in P. scaber as a tool for the assessment of As bioavailability in contaminated orchard soil. PMID- 22240058 TI - Quantification of Fusarium graminearum and Fusarium culmorum by real-time PCR system and zearalenone assessment in maize. AB - Zearalenone (ZEA) is a mycotoxin produced by some species of Fusarium, especially by Fusarium graminearum and F. culmorum. ZEA induces hyperoestrogenic responses in mammals and can result in reproductive disorders in farm animals. In the present study, a real-time PCR (qPCR) assay has been successfully developed for the detection and quantification of Fusarium graminearum based on primers targeting the gene PKS13 involved in ZEA biosynthesis. A standard curve was developed by plotting the logarithm of known concentrations of F. graminearum DNA against the cycle threshold (Ct) value. The developed real time PCR system was also used to analyze the occurrence of zearalenone producing F. graminearum strains on maize. In this context, DNA extractions were performed from thirty-two maize samples, and subjected to real time PCR. Maize samples also were analyzed for zearalenone content by HPLC. F. graminearum DNA content (pg DNA/ mg of maize) was then plotted against ZEA content (ppb) in maize samples. The regression curve showed a positive and good correlation (R2=0.760) allowing for the estimation of the potential risk from ZEA contamination. Consequently, this work offers a quick alternative to conventional methods of ZEA quantification and mycological detection and quantification of F. graminearum in maize. PMID- 22240059 TI - Acid and alcohol tolerance of Escherichia coli O157:H7 in pulque, a typical Mexican beverage. AB - Pulque is a traditional Mexican fermented alcoholic beverage produced from the nectar of maguey agave plants. No data exist on the behavior of Escherichia coli O157:H7 in agave nectar and pulque. An initial trial was done of the behavior of E. coli O157:H7 during fermentation of nectar from a single producer, a nectar mixture from different producers and "seed" pulque. A second trial simulating artisanal pulque production was done by contaminating fresh nectar with a cocktail of three E. coli O157:H7 strains, storing at 16 degrees and 22 degrees C for 14 h, adding seed pulque and fermenting until pulque was formed. A third trial used pulque from the second trial stored at 22 degrees C as seed to ferment fresh nectar at 22 degrees C for 48 h (fermentation cycle). This procedure was repeated for an additional two fermentation cycles. During incubation at 16 degrees or 22 degrees C in the first trial, the E. coli O157:H7 strains multiplied in both the single producer nectar and nectar mixture, reaching maximum concentration at 12h. E. coli O157:H7 cell concentration then decreased slowly, although it survived at least 72 h in both fermented nectars. E. coli O157:H7 did not multiply in the seed pulque but did survive at least 72 h. In the second trial, the numbers of E. coli O157:H7 increased approximately 1.5 log CFU/ml at 22 degrees C and 1.2 log CFU/ml at 16 degrees C after 14 h. After seed pulque was added, E. coli O157:H7 concentration decreased to approximately 2 log CFU/ml, and then remained constant until pulque was produced. In the third trial, the E. coli O157:H7 cells multiplied and survived during at least three nectar fermentation cycles. The results suggest that E. coli O157:H7 can develop acid and alcohol tolerance in pulque, and constitutes a public health risk for pulque consumers. PMID- 22240060 TI - Microbial biodiversity, quality and shelf life of microfiltered and pasteurized extended shelf life (ESL) milk from Germany, Austria and Switzerland. AB - Information on factors limiting the shelf life of extended shelf life (ESL) milk produced by microfiltration and subsequent pasteurization is very limited. In this study, three different batches of ESL milk were analyzed at different stages of the production process and during storage at 4 degrees C, 8 degrees C and 10 degrees C in order to evaluate the changes in bacterial cell counts, microbial diversity and enzymatic quality. Additionally, detailed biodiversity analyses of 250 retail ESL milk packages produced by five manufacturers in Germany, Austria and Switzerland were performed at the end of shelf life. It was observed that microfiltration decreased the microbial loads by 5-6 log10 units to lower than 1 CFU/mL. However, bacterial counts at the end of shelf life were extremely variable and ranged between <1 and 8 log10 CFU/mL. 8% of all samples showed spoilage indicated by cell counts higher than 6 log10 CFU/mL. The main spoilage groups of bacteria were Gram-negative post-process recontaminants (Acinetobacter, Chryseobacterium, Psychrobacter, Sphingomonas) and the spore formers Paenibacillus and Bacillus cereus, while other spore formers and Microbacterium spp. did not reach spoilage levels. Paenibacillus spp. and B. cereus apparently influenced enzymatic spoilage, as indicated by increased free fatty acid production, pH 4.6 soluble peptide fractions and off-flavors. In some cases, enzymatic spoilage was observed although microbial counts were well below 6 log10 CFU/mL. Thirteen B. cereus isolates were characterized for their toxin profiles and psychrotolerance. Hbl, nhe, and cytK toxin genes were detected in ten, thirteen, and four isolates, respectively, whereas the ces gene was always absent. Interestingly, only three of the thirteen isolates could be allocated to psychrotolerant genotypes, as indicated by the major cold shock cspA gene signature. Generally, large discrepancies in microbial loads and biodiversity were observed at the end of shelf life, even among packages of the same production batch. We suggest that such unexpected differences may be due to very low cell counts after ESL treatment, causing stochastic variations of initial species distributions in individual packages. This would result in the development of significantly different bacterial populations during cold storage, including the occasional development of high numbers of pathogenic species such as B. cereus or Acinetobacter. PMID- 22240061 TI - Bacteriocin formation by dominant aerobic sporeformers isolated from traditional maari. AB - The antimicrobial activity of 8 Bacillus spp. and 2 Lysinibacillus spp. representing the predominant aerobic sporeformers during traditional maari fermentations, a traditional fermented baobab seeds product from Burkina Faso, was investigated. The antimicrobial activity was assessed against a total of 31 indicator organisms representing various Gram-negative and positive pathogens. The screening showed that 3 Bacillus subtilis strains (B3, B122 and B222) in particular had antimicrobial activity against some Gram-positive organisms and were selected for further studies. It was found that the antimicrobial substances produced were heat stable, in-sensitive to catalase, sensitive to protease and trypsin but resistant to the proteolytic action of papain and proteinase K and equally active at pH values ranging from 3 to 11. Bacteriocin secretion started in late exponential growth phase and maximum activity was detected during the stationary growth phase. The production of bacteriocin by B. subtilis B3, B122 and B222 was dependent on the aeration conditions. Maximum production of bacteriocin was observed under reduced aeration. Specific primers were used to screen isolates B3, B122 and B222 for genes involved in the synthesis of the bacteriocins subtilosin A, subtilin, sublancin and ericin. Amplicons of the expected sizes were detected for iywB, sboA, sboX, albA and spaS involved in the biosynthesis of subtilosin and subtilin, respectively. The translated nucleotide sequences had 100% identity to the YiwB, SboX and SboA amino acid sequences of the subtilosin A producing B. subtilis subsp. subtilis strain 168. Interestingly there was a 3 amino acid deletion at the N-terminal part of AlbA in B3, B122 and B222 that probably alters the activity of this enzyme. Analysis of the spaS gene sequences of B3, B122 and B222, encoding a subtilin precursor peptide, showed that the translated nucleotide sequence had 98% identity with the corresponding SpaS amino acid sequence of subtilin producing B. subtilis subsp. spizizenii strain ATCC6633. PMID- 22240062 TI - Drugs in the brain--cellular imaging with receptor microscopic autoradiography. AB - For cell and tissue localization of drugs, receptor microscopic autoradiography is reviewed, including its development history, multiple testing, extensive applications and significant discoveries. This sensitive high-resolution imaging method is based on the use of radiolabeled compounds (esp. tagged with (3)H or (125)I), preservation through freezing of in vivo localization of tissue constituents, cutting thin frozen sections, and close contact with the recording nuclear emulsion. After extensive testing of the utility of this method, the distribution of radiolabeled compounds has been identified and characterized for estradiol, progestagens, adrenal steroids, thyroid hormone, ecdysteroids, vitamin D, retinoic acid, metabolic indicators glucose and 2-deoxyglucose, as well as extracellular space indicators. Target cells and associated tissues have been characterized with special stains, fluorescing compounds, or combined autoradiography-immunocytochemistry with antibodies to dopamine-beta-hydroxylase, GABA, enkephalin, specific receptor proteins, or other cellular products. Blood brain barrier and brain entries via capillary endothelium, ependyma, or circumventricular recess organs have been visualized for (3)H-dexamethasone, (210)Pb lead, and (3)H-1,25(OH)(2) vitamin D(3). With this histopharmacologic approach, cellular details and tissue integrative overviews can be assessed in the same preparation. As a result, information has been gained that would have been difficult or impossible otherwise. Maps of brain drug distribution have been developed and relevant target circuits have been recognized. Examples include the stria terminalis that links septal-amygdaloid-thalamic-hypothalamic structures and telencephalic limbic system components which extend as the periventricular autonomic-neuroendocrine ABC (Allocortex-Brainstem-Circuitry) system into the mid and hindbrain. Discoveries with radiolabeled substances challenged existing paradigms, engendering new concepts and providing seminal incentives for further research toward understanding drug actions. Most notable are discoveries made during the 1980s with vitamin D in the brain together with over 50 target tissues that challenged the century-old doctrine of vitamin D's main role as 'the calcitropic hormone', when the new data made it apparent that the main biological function of this multifunctional sunshine hormone rather is maintenance of life and adapting vital functions to the solar environment. In the brain, vitamin D, in close relation to sex and adrenal steroids, participates in the regulation of the secretion of neuro-endocrines, such as, serotonin, dopamine, nerve growth factor, acetyl choline, with importance in prophylaxis and therapy of neuro psychiatric disorders. Histochemical imaging with high cellular-subcellular resolution is necessary for obtaining detailed information, as this review indicates. New spectrometric methods, like MALDI-MSI, are unlikely to furnish the same information as receptor microautoradiography does, but can provide important correlative molecular information. PMID- 22240063 TI - Morphological aspects of interactions between microparticles and mammalian cells: intestinal uptake and onward movement. AB - Uptake of ingested microparticles into small intestinal tissues and on to secondary organs has moved from being an anecdotal phenomenon to a recognised and quantifiable process, which is relevant to risk assessment of accidental exposure, treatment of multi-organ dysfunction syndrome and therapeutic uses of encapsulated drug or vaccine delivery. This review puts in context with the literature the findings of a morphological study of microparticle uptake, using two approaches. The first is a rat in vivo in situ model, appropriate to a study rooted in the exposure of human populations to microparticles. Latex microspheres 2 MUm in diameter are the principal particle type used, although others are also investigated. Most data are based on microscopy, but analysis of macerated bulk tissue is also useful. Uptake occurs at early time points after a single dose and is shown to take place almost entirely at villous rather than Peyer's patch sites: however, multiple feeding and therefore a longer time-span produces a higher proportion of particles associated with Peyer's patches, albeit for very small total uptake at those later time points. Uptake is less affected by species, fasting and immunological competence than by age and reproductive status. The second approach uses in vitro methods to confirm the role of intercellular junctions in particle uptake. Particle-associated tight junction opening, in a Caco-2 monolayer, is reflected in changes in transepithelial resistance and particle uptake across the epithelial monolayer: Tight junction opening and particle uptake are both increased further by external irradiation, ethanol and sub-epithelial macrophages, but reduced by exposure to ice. An M cell model has looser tight junctions than Caco-2 cells, but a similar level of particle uptake. These results, along with the changes seen in junctional proteins after particle addition, confirm the role of tight junctions in uptake but suggest that adhering junctions are also important. PMID- 22240064 TI - Analysis of LIN28A in early human ovary development and as a candidate gene for primary ovarian insufficiency. AB - Lin28 proteins are emerging as important regulators of microRNAs in endocrine systems. Lin28a regulates primordial germ cell development and puberty timing in mice, whereas the related protein LIN28B is associated with age at menarche in genome-wide association studies in humans. Here, we studied expression of LIN28A and LIN28B in early human gonad development. LIN28A increased in the developing ovary between 6 and 9weeks post conception, but not in the developing testis. Immunohistochemistry demonstrated LIN28A in peripheral germ cells. LIN28B was expressed at lower levels in both tissues and did not increase with time. As disruption of Lin28a affects germ cell development in mice, LIN28A was considered a candidate gene for primary ovarian insufficiency (POI) in humans. However, no significant changes were found in 50 women studied. These findings show LIN28A is strongly expressed in germ cells during early human ovary development, but disruption of LIN28A is not a common cause of POI. PMID- 22240065 TI - A comparative profile of the microRNA transcriptome in immature and mature porcine testes using Solexa deep sequencing. AB - MicroRNAs (miRNAs) are small noncoding regulatory RNAs that play key roles in many diverse biological processes such as spermatogenesis. However, no study has been performed on the miRNA transcriptome of developing porcine testes. Here, we employed Solexa deep sequencing technology to extend the repertoire of porcine testis miRNAs and extensively compare the expression patterns of sexually immature and mature porcine testes. Solexa sequencing of two small RNA libraries derived from immature (30 days) and mature (180 days) pig testis samples yielded over 25 million high-quality reads. Overall, the two developmental stages had significantly different small RNA compositions. A custom data analysis pipeline identified 398 known and/or homologous conserved porcine miRNAs, 15 novel pig specific miRNAs and 56 novel candidate miRNAs. We further observed multiple mature miRNA variants and identified a new bidirectional transcribed miRNA locus, ssc-mir-181a. A total of 122 miRNAs were differentially expressed in the immature and mature testes, and 10 were validated using quantitative RT-PCR. Furthermore, GO and KEGG pathway analyses of the predicted miRNA targets further illustrate the likely roles for these differentially expressed miRNAs in spermatogenesis. This study is the first comparative profile of the miRNA transcriptome in immature and mature porcine testes using a deep sequencing approach, and it provides a useful resource for future studies on the role of miRNAs in spermatogenesis and male infertility treatment. PMID- 22240066 TI - Implementation and monitoring of a quality management system based on the standard UNE-EN-ISO 15189 in a urine culture unit. AB - OBJECTIVES: To evaluate the implementation of a quality management system based on ISO-15189 in a urine culture unit. DESIGN AND METHODS: The effectiveness of improvement actions was measured by quality indicators. RESULTS: The errors in the pre-analytical phase and the rate of contaminated urine decreased significantly. The traceability, response time and external quality control were fulfilled. CONCLUSIONS: The implementation of ISO-15189 was effective in improving the management of a urine culture unit. PMID- 22240067 TI - Low density lipoprotein S-homocysteinylation is increased in acute myocardial infarction patients. AB - OBJECTIVES: We have investigated on the levels of homocysteine linked to LDL in acute myocardial infarction patients. DESIGN AND METHODS: We used capillary electrophoresis to measure LDL-bound thiols in 16 AMI individuals and 32 healthy volunteers. RESULTS: We found a significant increase of apo-B homocysteine and cysteine levels in LDL fraction of AMI subjects. CONCLUSIONS: Our findings suggest that also LDL S-homocysteinylation may be considered among the markers for the CVD risk evaluation. PMID- 22240068 TI - Is blood ammonia influenced by kidney function? A prospective study. AB - BACKGROUND: We have investigated whether blood ammonia is increased with worsening CKD. METHODS: Fifty eight subjects with a range of CKD were recruited for analysis of plasma ammonia and other electrolytes. RESULTS: The concentrations of plasma ammonia were all within the normal reference range and there was no correlation between ammonia and CKD without any effect of dialysis. CONCLUSIONS: Blood ammonia is not elevated in or related to the severity of chronic kidney disease. PMID- 22240069 TI - [Multicystic lung revealing a Sjogren's syndrome]. AB - The Sjogren's syndrome is a chronic inflammatory autoimmune disease that affects primarily the exocrine glands, but can affect other organs particularly the lungs. Cystic lung disease is very significant but exceptionally recounted in the literature. We report the case of a patient, 54 years old, whose disease was discovered incidentally after a routine chest radiograph. The diagnosis of cystic lung revealing a primary Sjogren's syndrome was held before a group of radio clinical, immunological and histological arguments. Through our observation, the diagnosis of Sjogren's syndrome should be included in the list of diagnoses to raise in a multicystic lung. PMID- 22240070 TI - [Nicardipine induced hypoxia: role of hypoxic pulmonary vasoconstriction]. AB - Nicardipine is a commonly used anti-hypertensive drug for acute situations. We report the case of a 55-year-old man with hypoxemic pneumonia, who presented a worsening of his hypoxia secondary to the injection of this calcium channel inhibitor (CCI). This side effect was probably caused by inhibition of hypoxic pulmonary vasoconstriction. Effects of CCI on pulmonary vessels are well-known. They don't induce clinically relevant hypoxemia in patients without acute pulmonary pathology. This case report shows that nicardipine can severely worsen haematosis of patients with acute hypoxia. CCI should probably not be used in such patients. PMID- 22240071 TI - Impact of proximal cytoplasmic droplets on quality traits and in-vitro embryo production efficiency of cryopreserved bull spermatozoa. AB - BACKGROUND: Proximal cytoplasmic droplets (PCDs), a remnant of germ cell cytoplasm, are common non-specific morphological defects in bovine semen. This study evaluated the effect of higher percentages of PCDs on the quality of frozen thawed bovine semen, embryo production and early embryo development. METHODS: Three ejaculates from each of five (group 1: PCD <= 1%, control) and eight adult Bos indicus bulls (group 2: PCD >= 24%) were analysed. Semen samples were examined for: post-thaw motility, vigour of movement, concentration, sperm morphology, slow thermoresistance test (STT), membrane integrity, acrosome status, mitochondrial function using fluorescent probes association (FITC-PSA, PI and JC-1) and sperm chromatin integrity using acridine orange assay. Two bulls from group 2, with 28.5% and 48.5% PCD, respectively, and three bulls from the control group, each with 0% PCD, were selected for IVF (in vitro fertilisation). RESULTS: Semen analyses revealed a significant correlation (P < 0.01) between increased rates of PCD and sperm quality traits. Nevertheless, no differences were observed in sperm motility and vigour either before or after the STT or in the percentage of intact acrosomes (analysed by differential interference contrast microscopy (DIC) after STT), but membrane integrity, acrosome status (evaluated with FITC-PSA staining method after thawing) and mitochondrial function were reduced, when compared with group 1 (P < 0.05). The higher incidence of PCD was positively correlated to chromatin damage, especially after three hours of incubation at 37 degrees C. IVF showed similar results for bull C2 (group 1, control) and bull P2 (group 2, group with higher PCDs). CONCLUSION: Higher PCD levels influenced spermatozoa quality traits. IVF and embryo development data showed that cleavage, blastocyst formation and blastocyst hatching may have been influenced by the interaction of morphology traits and individual bull effects. PMID- 22240072 TI - Pulmonary endarterectomy normalizes interventricular dyssynchrony and right ventricular systolic wall stress. AB - BACKGROUND: Interventricular mechanical dyssynchrony is a characteristic of pulmonary hypertension. We studied the role of right ventricular (RV) wall stress in the recovery of interventricular dyssynchrony, after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In 13 consecutive patients with CTEPH, before and 6 months after pulmonary endarterectomy, cardiovascular magnetic resonance myocardial tagging was applied. For the left ventricular (LV) and RV free walls, the time to peak (Tpeak) of circumferential shortening (strain) was calculated. Pulmonary Artery Pressure (PAP) was measured by right heart catheterization within 48 hours of PEA. Then the RV free wall systolic wall stress was calculated by the Laplace law. RESULTS: After PEA, the left to right free wall delay (L-R delay) in Tpeak strain decreased from 97 +/- 49 ms to -4 +/- 51 ms (P < 0.001), which was not different from normal reference values of -35 +/- 10 ms (P = 0.18). The RV wall stress decreased significantly from 15.2 +/- 6.4 kPa to 5.7 +/- 3.4 kPa (P < 0.001), which was not different from normal reference values of 5.3 +/- 1.39 kPa (P = 0.78). The reduction of L-R delay in Tpeak was more strongly associated with the reduction in RV wall stress (r = 0.69,P = 0.007) than with the reduction in systolic PAP (r = 0.53, P = 0.07). The reduction of L-R delay in Tpeak was not associated with estimates of the reduction in RV radius (r = 0.37,P = 0.21) or increase in RV systolic wall thickness (r = 0.19,P = 0.53). CONCLUSION: After PEA for CTEPH, the RV and LV peak strains are resynchronized. The reduction in systolic RV wall stress plays a key role in this resynchronization. PMID- 22240073 TI - Any difference? Use of a CAM provider among cancer patients, coronary heart disease (CHD) patients and individuals with no cancer/CHD. AB - BACKGROUND: Although use of complementary and alternative medicine (CAM) among cancer patients has been described previously, prevalence of use has not commonly been compared to other disease groups in a true population sample where CAM use or cancer is not the main focus. The aims of the present study are to (1) examine how CAM use in cancer patients differs from people with a previous CHD diagnosis and people with no cancer or CHD diagnosis in an unselected general population and (2), investigate the use of a CAM provider among individuals with a previous cancer diagnosis. METHODS: A total of 8040 men and women aged 29 to 87 in the city of Tromso, Norway filled in a questionnaire developed specifically for the Tromso V study with questions on life style and health issues. Visits to a CAM provider within the last 12 months and information on cancer, heart attack and angina pectoris (heart cramp) were among the questions. 1449 respondents were excluded from the analyses. RESULTS: Among the 6591 analysed respondents 331 had a prior cancer diagnosis, of whom 7.9% reported to have seen a CAM provider within the last 12 months. This did not differ significantly from neither the CHD group (6.4%, p = 0.402) nor the no cancer/CHD group (9.5%, p = 0.325). CONCLUSION: According to this study, the proportion of cancer patients seeing a CAM provider was not statistically significantly different from patients with CHD or individuals without cancer or CHD. PMID- 22240074 TI - Specific expression of human interferon-gamma controls hepatitis B virus replication in vitro in secreting hepatitis B surface antigen hepatocytes. AB - Interferon-gamma (IFN-gamma) has been reported to have antiviral activity against Hepatitis B virus (HBV) and to suppress HBV replication noncytolytically in vivo. Since systemic administration of IFN-gamma may cause severe adverse effects, studies of the effects of liver-specific IFN-gamma expression from adenoviral vectors in vivo have been investigated. In this study, a novel strategy has been described that drives specific expression of human IFN-gamma in HBsAg-secreting hepatocytes. A bicistronic expression vector has been developed, pcDNA3.1-HBV antisense S gene-HCV core protein gene-HCV internal ribosome entry sites (IRES) IFN-gamma (pcDNA-SCIgamma), by inserting four DNA fragments into pcDNA3.1. Tight modulation of HCV IRES-dependent translation by the HCV core protein was achieved using an antisense RNA technique with a bicistronic expression vector. HepG2 cells and HepG2.2.15 cells stably expressing HBV were transduced with pcDNA SCIgamma to test the responsiveness of IFN-gamma to HBsAg expression. Gene transfer resulted in a low background and a 30-fold induction of IFN-gamma expression from pcDNA-SCIgamma in a cell-specific fashion. Hepatocyte-specific IFN-gamma expression controlled effectively HBV replication in HBsAg-secreting HepG2.2.15 cells without cell toxicity. PMID- 22240076 TI - Found and missed: failing to recognize a search target despite moving it. AB - We present results from five search experiments using a novel 'unpacking' paradigm in which participants use a mouse to sort through random heaps of distractors to locate the target. We report that during this task participants often fail to recognize the target despite moving it, and despite having looked at the item. Additionally, the missed target item appears to have been processed as evidenced by post-error slowing of individual moves within a trial. The rate of this 'unpacking error' was minimally affected by set size and dual task manipulations, but was strongly influenced by perceptual difficulty and perceptual load. We suggest that the error occurs because of a dissociation between perception for action and perception for identification, providing further evidence that these processes may operate relatively independently even in naturalistic contexts, and even in settings like search where they should be expected to act in close coordination. PMID- 22240075 TI - Antigen-capture ELISA for the detection of Rift Valley fever virus nucleoprotein using new monoclonal antibodies. AB - Monoclonal antibodies (MAbs) raised against the nucleoprotein (NP) of Rift Valley fever virus (RVFV) were developed, and an antigen-capture enzyme-linked immunosorbent assay (Ag-capture ELISA) system was developed for the detection of RVFV NP. The assay detected RVFV antigen from culture supernatants containing as little as 7.8-31.3 pfu per 100 MUl. Reactivity with various truncated NPs indicated that MAb C10-54 bound only to the full-length NP, probably due to recognition of a conformational epitope, whereas MAbs G2-36 and D5-59 bound to a linear epitope ranging from amino acid residues 195-201 in the C-terminal region. Based on the alignments of the amino acid sequence of RVFV NP, the epitope regions of MAbs G2-36 and D5-59 were completely conserved among all RVFV strains. These results suggest that the MAbs are applicable to the Ag-capture ELISA for the diagnosis of RVFV infections. PMID- 22240077 TI - Growth variations in OF1 mice following chronic exposure of parental and filial generations to a 15 MUT, 50 Hz magnetic field. AB - The growth of a first filial generation (F1) of OF1 mice was studied following chronic exposure of their mothers and themselves to a magnetic field of 15 MUT (rms) and 50 Hz. The parental generation (F0) remained for 98 days in this field, after that time they were mated, went through pregnancy, birth, lactation, and the weaning of their offspring in this field. The latter remained exposed to this field until reaching adulthood (220 days). Control animals were treated in the same way but were exposed only to the Earth's magnetic field. The growth data for the offspring were analyzed using a generalization of Koop's equation. Using this model, four phases were identified: lactation growth acceleration, post-weaning growth acceleration, growth stabilization, and a stationary phase. Exposure to the artificial magnetic field was associated with a marked increase in maximum growth rate in the exposed animals during the post-weaning growth acceleration phase, and with a reduction in mass gain in the F1 mice (especially in males) during the third of these phases. In addition, the growth stabilization phase was more extended in exposed females and shorter in exposed males than in the control animals. Furthermore, statistically significant differences were seen between the mean body masses of exposed and control F1 males from 49-123 days. Exposure to the artificial magnetic field might have been associated with the stimulated growth rate seen over the noticeably shortened second and third growth phases (leaving these animals lighter by the stationary phase compared to controls) and a possible acceleration of aging. Both processes could be responsible for the stationary phase being reached at an earlier age, especially in males. PMID- 22240078 TI - Synergistic activity of coriander oil and conventional antibiotics against Acinetobacter baumannii. AB - In this study we investigated the existence of synergistic antibacterial effect between coriander (Coriandrum sativum L.) essential oil and six different antibacterial drugs (cefoperazone, chloramphenicol, ciprofloxacin, gentamicin, tetracycline and piperacillin). The antibacterial activity of coriander oil was assessed using microdilution susceptibility testing and synergistic interaction by checkerboard assays. The association of coriander essential oil with chloramphenicol, ciprofloxacin, gentamicin and tetracycline against Acinetobacter baumannii showed in vitro effectiveness, which is an indicator of a possible synergistic interaction against two reference strains of A. baumannii (LMG 1025 and LMG 1041) (FIC index from 0.047 to 0.375). However, when tested the involvement between coriander essential oil and piperacillin or cefoperazone, the isobolograms and FIC index showed an additive interaction. The in vitro interaction could improve the antimicrobial effectiveness of ciprofloxacin, gentamicin and tetracycline and may contribute to resensitize A. baumannii to the action of chloramphenicol. PMID- 22240079 TI - Bioassay-guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root. AB - Fissistigma cavaleriei (Levl) Rehd (Annonaceae) is used as a folklore medicine for treatment of inflammation, arthritis, and tuberculosis by Miao people in China. In the present study, the antiangiogenic activity of F. cavaleriei was investigated. The chorioallantoic membrane of the fertilized hen's egg (CAM assay) was used to determine antiangiogenic activity of the plant extract. Compound (1), a compound with antiangiogenic activity, was isolated by bioassay guided fractionation from F. cavaleriei for the first time. The structure of compound (1) was elucidated on the basis of spectroscopic methods. Colorimetric COX (ovine) inhibitor screening assay was used to determine its inhibitory effect on COX-1 and COX-2. MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines. As a result, compound (1) showed a selectively inhibiting effect on COX-2 and could inhibit the growth of tumor cells in vitro. The antitumor activity of compound (1) was further confirmed by the observation that compound (1) administration significantly inhibited the growth of S-180 cells in mice. Moreover, compound (1) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S-180 cells while combined with doxorubicin. In conclusion, compound (1) is a multi-target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment. PMID- 22240080 TI - 3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo. AB - pAp (3'-5' phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity. PMID- 22240081 TI - Regional inequalities in the use of contraception in Spain: a multilevel approach. AB - The aim of the present study was to describe the influence of individual and regional socioeconomic factors on the use of contraception among women in Spain in 2006. A cross-sectional study was carried out among women aged 15-49 years (n=5141). The prevalence of contraception use was analyzed as a function of individual and regional characteristics using weighted multilevel logistic regression models. The use of contraception in more deprived regions was lower during first sexual intercourse but higher during the four weeks prior to the interview. Inequalities in the use of contraception were observed among women in Spain after accounting for both individual and regional characteristics. PMID- 22240082 TI - Genetic variability of Echinococcus granulosus sensu stricto in Europe inferred by mitochondrial DNA sequences. AB - The genetic diversity of Echinococcus granulosus sensu stricto (s.s.) metacestodes from four European countries was evaluated by the DNA sequence analysis of the cytochrome c oxidase subunit 1 (cox1) mitochondrial gene. Of the 312 organisms investigated, 132 were from Bulgaria, 35 from Hungary, 89 from Italy and 56 from Romania. Considerable intraspecific variation was observed in the mitochondrial cox1 sequences: 24 haplotypes were detected in the Eastern European population and seven in the Italian population. The Eastern European population parsimony network displayed a star-like features consisting of the most common haplotype EG1 (G1 genotype) and the three major haplotypes: EG2, EG3 and EG4. The EG1 was also the major haplotype in the Italian population network, though with a higher prevalence (73%) compared to the Eastern European network. The percentage of the population constituted by the G1 genotype was used as an indirect index to evaluate the genetic diversity within E. granulosus s.s. populations of Eurasia. A clinal correlation between the percentage of the G1 genotype and the geographical regions of Eurasia was observed: the G1 genotype is highly represented in the Mediterranean Basin; it decreases in Eastern Europe and South-West Asia and increases in China. This clinal correlation could reflect the spreading of livestock domestication from Southern-Western Asia during the Neolithic period, beginning around 12,000 BC. PMID- 22240083 TI - Longitudinal invariance of posttraumatic stress disorder symptoms in adolescent earthquake survivors. AB - The present study examined the invariance of four models of posttraumatic stress disorder symptoms (PTSD) across time through an analysis of symptom ratings from the PTSD Checklist-Civilian version. Participants included 403 junior middle school students recruited from Sichuan, China at 5 and 11 months after the 2008 Sichuan earthquake. Confirmatory factor analysis using measurement and structural invariance testing found that four tested models were non-invariant (i.e., different) over time on PTSD's variable intercepts (indicating symptom severity) and residual error variances, but were invariant on PTSD's factor loadings and structural parameters. The two 4-factor intercorrelated models and the newly proposed 5-factor model were superior to the model defined in DSM-IV; however, the best fitting model was the newest proposed 5-factor model. These findings extend our understanding of PTSD's factor structure that the factor structure may be quite stable over time. PMID- 22240084 TI - Effectiveness of quetiapine plus lamotrigine maintenance therapy in challenging bipolar disorder patients. AB - OBJECTIVE: Assess quetiapine plus lamotrigine (QTP+LTG) combination maintenance therapy effectiveness in challenging bipolar disorder (BD). METHOD: Outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form were naturalistically prescribed QTP+LTG. RESULTS: Fifty-four outpatients with challenging BD, taking in addition to QTP+LTG, a mean+/-SD of 2.1+/-1.6 (in 63.0% at least 2) other psychotropic and 2.3+/-1.9 non-psychotropic prescription medications, had QTP+LTG maintenance trials. Median(mean+/-SD) QTP+LTG duration was 401(730+/-756) days. Final QTP and LTG doses were 87.5(188+/ 211) and 300(287+/-108) mg/day, respectively. Half (27/54) of patients discontinued QTP (in 19), LTG (in 6), or QTP+LTG (in 2), after 294(415+/-414) days - due to side-effects in 10, inefficacy in seven, non-adherence in five, and other reasons in five. 42.6%(23/54) had additional pharmacotherapy intervention for emergent mood symptoms, after 175(261+/-237) days, with at least one psychotropic added (in 16/54) or substantively (by >=50%) increased (in 7/54). 55.6%(30/54) had recurrent mood episodes, after 126(187+/-158) days, most often depressive (in 35.2%), although 64.8%(35/54) were euthymic at final visit taking QTP+LTG. Sedation increased significantly during treatment among those with side effect discontinuations, and 19.2%(10/52, all having QTP added to LTG) had clinically significant (>=7%) weight gain. LIMITATIONS: No placebo comparison group. Small sample of predominantly female Caucasian insured outpatients taking complex concurrent medication regimens. CONCLUSION: Additional studies are warranted to confirm our preliminary observation that QTP+LTG maintenance may be effective in patients with challenging BD. PMID- 22240085 TI - Clinical relevance of comorbidity in anxiety disorders: a report from the Netherlands Study of Depression and Anxiety (NESDA). AB - BACKGROUND: To study the clinical relevance of type of comorbidity and number of comorbid disorders in anxiety disorders. Four groups were compared according to sociodemographic-, vulnerability- and clinical factors: single anxiety disorder, anxiety-anxiety comorbidity, anxiety-depressive comorbidity and "double" comorbidity (i.e. anxiety and depressive comorbidity). METHODS: Data were obtained from the Netherlands Study of Anxiety and Depression (NESDA). A sample of 1004 participants with a current anxiety disorder was evaluated. RESULTS: As compared with single anxiety, anxiety-anxiety comorbidity was associated with higher severity, greater chronicity and more treatment. Anxiety-anxiety comorbidity was associated with an earlier age of onset and a more chronic course compared with anxiety-depressive comorbidity, while anxiety-depressive comorbidity was associated with more severe symptoms and more impaired functioning than anxiety-anxiety comorbidity. "Double" comorbidity was associated with higher severity, greater chronicity, more treatment and increased disability. Sociodemographic and vulnerability factors were comparable among the four groups. Limitations A prospective design would be more appropriate to study the outcome. In this study no distinction was made between whether depression or anxiety disorder preceded the current anxiety disorder. CONCLUSIONS: It is clinical relevant to diagnose and treat comorbidity among anxiety disorders as it is associated with higher severity and more chronicity. Whereas anxiety-anxiety comorbidity has an earlier age of onset and a more chronic course, anxiety depressive comorbidity leads to more treatment and impaired functioning. "Double" comorbidity leads to even more severity, chronicity and impairment functioning compared with both anxiety-anxiety and anxiety-depressive comorbidity. PMID- 22240086 TI - Better to give than to take? Interactive social decision-making in severe major depressive disorder. AB - BACKGROUND: Although recent studies focusing on major depressive disorder (MDD) suggest altered social decision-making, studies using the Ultimatum Game (UG) in patients with severe, clinical MDD do not exist. Moreover, all aforementioned studies so far focused on responder behavior and thus fairness considerations; to this date, no one investigated social interactive behavior which involves proposer behavior possibly requiring second-order mentalizing as well. METHODS: Thirty-nine MDD patients and 22 healthy controls played a modified UG, both in the roles of responder and proposer against the same partner. RESULTS: MDD patients accepted both fair and unfair offers as many times as the healthy controls in their role as responder. Importantly, however, in the role of proposer MDD patients offered significantly more than the control group did. LIMITATIONS: Most patients were treated with psychotropic medication. CONCLUSIONS: Responder behavior demonstrates that MDD patients are capable of making social decisions on fairness considerations in the same way as healthy controls do. The observed proposer behavior, however, could indicate that MDD patients are more focused on avoiding rejection. These findings provide unique evidence that social decision-making--as studied in a realistic context--is disturbed in MDD. PMID- 22240087 TI - A prospective examination of the association between the centrality of a loss and post-loss psychopathology. AB - BACKGROUND: Research has shown that the extent to which a negative event has become central to one's everyday inferences, life-story, and identity is associated with the severity of psychopathology experienced following this event. The current study aimed to extend this prior research by examining the prospective linkage between the centrality of a loss-event and post-loss psychopathology. METHODS: To this end, 176 individuals, bereaved within the past year, completed the Centrality of Event Scale (CES) with their loss as the anchor event, together with measures of Prolonged Grief Disorder (PGD), depression, and bereavement-related Posttraumatic Stress-Disorder (PTSD) and complementary questionnaires. One hundred participants again completed symptom-measures one year later. RESULTS: Findings showed that (a) the centrality of a loss was associated with concurrent symptom-levels of PGD, depression, and PTSD; (b) the centrality of a loss predicted PGD-severity, depression-severity, and PTSD severity one year later, after controlling for baseline symptom-levels; (c) these cross-sectional and prospective linkages remained significant when controlling for relevant demographic and loss-related variables, as well as for indices of neuroticism, attachment anxiety, attachment avoidance and persistent closeness to the lost person. LIMITATIONS: Limitations include the under-representation of men and the reliance on self-report measures. CONCLUSIONS: The current findings provide evidence that the centrality of a negative event is a prospective predictor of post-event psychopathology. PMID- 22240088 TI - The Female Genital Self-Image Scale (FGSIS): validation among a sample of female college students. AB - INTRODUCTION: Gynecological exams continue to be underused among young women, possibly due to a woman's genital self-image. AIMS: The purpose of this study was to (i) examine college women's genital image using the Female Genital Self-Image Scale (FGSIS); (ii) assess the reliability, validity, and factor structure of data collected on the FGSIS; and (iii) examine the relationship between FGSIS scores and gynecological exam behaviors. METHOD: Data were collected in November/December 2010 from 450 undergraduate women. MAIN OUTCOME MEASURES: Descriptive statistics were utilized to analyze demographic variables. A comprehensive psychometric assessment of the FGSIS included: (i) a reliability assessment of internal consistency; (ii) conducting a confirmatory factor analysis (CFA) to identify factor structure; and (iii) structural equation modeling and predictive discriminant analysis to asses the predictive qualities of the FGSIS on gynecological exam behavior. RESULTS: CFA analyses yielded a two factor FGSIS structure: X(2) (12, N=450)=49.77; P<0.001, Root Mean Square Error of Approximation=0.08, Comparative Fit Index=0.98, Normed Fit Index=0.97. Reliability assessments indicated very good internal consistency for the scale (alpha=0.89), as well as for factor one (alpha=0.86) and factor two (alpha=0.82). Women who engaged in at least one gynecological exam during the past 24 months had a significantly more positive genital self-image than those who had not (t (449)=-2.501; P=0.01). CONCLUSIONS: Data collected using the FGSIS were found to be valid and reliable in this sample, further supporting the utility of the scale and aiding in the understanding of college women's genital image using an underlying two-factor approach. This has important implications for the development of sexual health and women's health programs and discussions. Specifically, a two-factor FGSIS can aid medical and health professionals in better understanding relationships between genital image and gynecological exam behavior. PMID- 22240089 TI - Clinically relevant microfluidic magnetophoretic isolation of rare-cell populations for diagnostic and therapeutic monitoring applications. AB - Cells of biomedical interest are, despite their functional significance, often present in very small numbers. Therefore the analysis and isolation of previously inaccessible rare cells, such as peripheral hematopoietic stem cells, endothelial progenitor cells, or circulating tumor cells, require efficient, sensitive, and specific procedures that do not compromise the viability of the cells. The current study builds on previous work on a rationally designed microfluidic magnetophoretic cell separation platform capable of throughputs of 240 MUL min( 1). Proof-of-concept was first conducted using MCF-7 (1-1000 total cells) as the target rare cell spiked into high concentrations of Raji B-lymphocyte nontarget cells (~10(6) total cells). These experiments lead to the establishment of a magnet-based separation for the isolation of 50 MCF-7 cells directly from whole blood. Results show an efficiency of collection greater than 85%, with a purity of over 90%. Next, resident endothelial progenitor cells and hematopoietic stem cells are directly isolated from whole human blood in a rapid and efficient fashion (>96%). Both cell populations could be simultaneously isolated and, via immunofluorescent staining, individually identified and enumerated. Overall, the presented device illustrates a viable separation platform for high purity, efficient, and rapid collection of rare cell populations directly from whole blood samples. PMID- 22240090 TI - The effects of different endocrine disruptors defining compound-specific alterations of gene expression profiles in the developing testis. AB - Environmental contaminants considered endocrine disruptors have been shown to affect testis development and function but the mechanisms of action are not clear. We now have analyzed the effects on the transcriptome in testes of mice exposed to mono-(2-ethylhexyl)-phthalate (9.2; 46.3 or 92.7 mg/kg/d), zearalenone (1.3; 3.9 or 6.6 mg/kg/d), lindane (16.6; 32.2 or 64.4 mg/kg/d), bisphenol-A (0.16; 16 or 64 mg/kg/d) or 17beta-estradiol (0.006; 0.012 or 0.048 mg/kg/d). The compounds were orally administered in the drinking water during distinct developmental periods: (A) mothers were exposed only during the two weeks before mating; (B) the exposure was continued during pregnancy until birth or (C) exposure was continued for a further four weeks after birth. Testes were studied at four weeks of age. Mono-(2-ethylhexyl)-phthalate and zearalenone, both produced specific alterations of gene signatures. Interestingly, this was irrespective of the concentration of the toxicant or the developmental period during which exposure occurred. PMID- 22240091 TI - Development of key messages for adolescents on providing basic mental health first aid to peers: a Delphi consensus study. AB - AIM: Most young people fail to receive professional treatment for mental disorders; however, they do indicate a preference for sharing problems with peers. This article describes key messages about knowledge and actions to form the basis of a basic mental health first aid (MHFA) course for adolescents to increase recognition of and help seeking for mental health problems by teaching the best knowledge and helping actions a young person can undertake to support a peer with a mental health problem. METHODS: The Delphi method was used to achieve consensus among Australian and Canadian youth mental health experts regarding the importance of statements that describe helping actions a young person can take, and information they should have, to support a friend with a mental health problem. There were two expert panels, one consisting of 36 youth mental health consumer advocates and the other of 97 Youth MHFA instructors. Panellists rated each statement according to how appropriate it would be as a basic mental health first aid message for both a junior adolescent (12-15 years) and a senior adolescent (16-18 years). RESULTS: Out of 98 statements, 78 were endorsed as key basic MHFA messages for junior adolescents and 81 were endorsed for senior adolescents. CONCLUSION: The study has identified key messages for adolescents on how they can help a peer. These messages will form the basis of the curriculum for an MHFA course for adolescents, which will aim to facilitate early recognition of and help seeking for mental health problems in adolescents. PMID- 22240092 TI - Induction of durable responses by oral etoposide monochemotherapy in patients with metastatic Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is an aggressive, rare tumour of the skin. For advanced cases with distant organ metastases several different regimens of chemotherapeutics have been described. Disease specific 5-year survival rates for these patients are approximately 11%. In this case series we report our experience with orally administered etoposide (100 mg at days 1 to 10 in a 31 day cycle) in 4 patients. We treated two male and two female patients with a median age of 68.5 years. In our four treated patients the disease control rate (complete remission, partial remission, stable disease) was 100%. Three out of four patients reached complete remission. Promisingly, two of our patients had long lasting, durable responses which, until now, have lasted for 16 and 36 months, respectively. The mean follow up time after start of therapy was 14.25 months (range 1-36 months). Etoposide treatment was generally well tolerated, the most common side effect was neutropenia, in one case CTC grade 3. In conclusion, orally administered etoposide in metastatic Merkel cell carcinoma was highly effective and well tolerated. PMID- 22240093 TI - Symmetry and reproducibility of the components of dynamic stability in young adults at different walking velocities on the treadmill. AB - In the literature, analysis of dynamic gait stability using the extrapolated center of mass concept is often an objective that assumes reproducible and symmetrical data. Here, we examined the validity of this assumption by analyzing subjects walking at different velocities. Eleven healthy young subjects walked on a treadmill at six different velocities (1.0-2.0m.s(-1)). Dynamic stability at touchdown of the left and right foot (10 gait trials for each body side) was investigated by using the margin of stability, determined as the difference between base of support and extrapolated center of mass. Dynamic stability parameters showed no significant differences (P>0.05) between gait trials, with a root mean square difference in margin of stability of less than 1.62cm. Correlation coefficients between trials were above 0.70 for all parameters, demonstrating that two gait trials are sufficient to obtain reproducible data. In more than 90% of the cases, the absolute symmetry index was below 8% with no relevant functional differences between body sides. We concluded that analyzing two gait trials for one body side is sufficient to determine representative characteristics of the components of dynamic stability in healthy young adults while walking on the treadmill at a wide range of velocities. PMID- 22240094 TI - Nested hierarchy, small worlds, brain complexity, and emergence: Comment on "Neuroontology, neurobiological naturalism, and consciousness: a challenge to scientific reduction and a solution" by Todd E. Feinberg. PMID- 22240095 TI - Alternative folding pathways of the major porin OprF of Pseudomonas aeruginosa. AB - OprF is the major porin of Pseudomonas aeruginosa and allows very slow, nonspecific, diffusion of solutes. The low permeability of this porin channel is a major factor that enhances other types of resistance mechanisms and often creates strong multidrug resistance in this nosocomial pathogen. We have previously shown that the low permeability is caused by the folding of OprF into two conformers: a majority, two-domain closed-channel conformer containing the N terminal transmembrane beta-barrel and the C-terminal periplasmic, globular domain; and a minority, one-domain open-channel conformer comprising < 5% of the protein population. Our analysis of the bifurcate folding pathway using site directed mutagenesis showed that slowing down the folding of the two-domain conformer increases the fraction of the open, one-domain conformer. Use of outer membrane protein assembly machinery mutants showed that the absence of the Skp chaperone led to an increased proportion of open conformers. As many environmental pathogens causing nosocomial infections appear to have outer membrane protein (OmpA)/OprF homologs as the major porin, efforts to understand the low permeability of these 'slow porins' are important in our fight against these organisms. PMID- 22240096 TI - Obesity and disease activity in juvenile idiopathic arthritis. AB - BACKGROUND: Children with physical disabilities may have an increased risk for obesity and obesity might be a risk factor for inflammatory arthritis. The aims of this study were: to determine the prevalence of obesity in children and adolescents with juvenile idiopathic arthritis (JIA), and to examine the association between obesity and disease activity in this population. FINDINGS: A cross-sectional analysis of all patients with JIA attending a pediatric rheumatology clinic, between October 2009 and September 2010, was performed. A linear regression model was used to explore the association between obesity and disease activity in patients with JIA. A total of 154 subjects were included in the analysis; median age was 10.6 years, 61% were female, and 88% were white. Obesity was found in 18%, 12% were overweight, and 3% were underweight. There was no association between obesity and JADAS-27 (Juvenile Arthritis Disease Activity Score 27), physician's assessment of disease activity, parent's assessment of child's well-being, erythrocyte sedimentation rate, number of active joints, or C reactive protein (p-value range 0.10 to 0.95). CONCLUSIONS: Although 18% of patients with JIA were obese, we did not find an association between obesity and disease activity. As obesity confers an additional health risk in children with arthritis, addressing this co-morbidity should be a health priority in patients with JIA. Future studies are necessary to further explore potential associations between obesity, development of JIA, and disease activity. PMID- 22240097 TI - The functional role of the Meis/Prep-binding elements in Pax6 locus during pancreas and eye development. AB - Pax6 is an essential transcription factor for lens, lacrimal gland and pancreas development. Previous transgenic analyses have identified several Pax6 regulatory elements, but their functional significance and binding factors remain largely unknown. In this study, we generated two genomic truncations to delete three elements that were previously shown to bind to the Meis/Prep family homeoproteins. One 3.1 kb deletion (Pax6(?DP/?DP)) removed two putative pancreatic enhancers and a previously identified ectodermal enhancer, while a 450 bp sub-deletion (Pax6(?PE/?PE)) eliminated only the promoter-proximal pancreatic enhancer. Immunohistochemistry and quantitative RT-PCR showed that the Pax6(?PE/?PE) pancreata had a significant decrease in Pax6, glucagon, and insulin expression, while no further reductions were observed in the Pax6(?DP/?DP) mice, indicating that only the 450 bp region is required for pancreatic development. In contrast, Pax6(?DP/?DP), but not Pax6(?PE/?PE) mice, developed stunted lacrimal gland and lens hypoplasia which was significantly more severe than that reported when only the ectodermal enhancer was deleted. This result suggested that the ectodermal enhancer must cooperate with its neighboring sequences to regulate the Pax6 ectodermal expression. Finally, we generated conditional knockouts of Prep1 in the lens and pancreas, but surprisingly, did not observe any developmental defects. Together, these results provide functional evidence for the independent and synergistic roles of the Pax6 upstream enhancers, and they suggest the potential redundancy of Meis/Prep protein in Pax6 regulation. PMID- 22240098 TI - Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death. AB - Bone morphogenetic proteins (BMPs) are secreted signals that regulate apical ectodermal ridge (AER) functions and interdigital programmed cell death (PCD) of developing limb. However the identities of the intracellular mediators of these signals are unknown. To investigate the role of Smad proteins in BMP-regulated AER functions in limb development, we inactivated Smad1 and Smad5 selectively in AER and ventral ectoderm of developing limb, using Smad1 or/and Smad5 floxed alleles and an En1(Cre/+) knock-in allele. Single inactivation of either Smad1 or Smad5 did not result in limb abnormalities. However, the Smad1/Smad5 double mutants exhibited syndactyly due to a reduction in interdigital PCD and an increase in interdigital cell proliferation. Cell tracing experiments in the Smad1/Smad5 double mutants showed that ventral ectoderm became thicker and the descendents of ventral En1(Cre/+) expressing ectodermal cells were located at dorsal interdigital regions. At the molecular level, Fgf8 expression was prolonged in the interdigital ectoderm of embryonic day (E) 13 Smad1/Smad5 double mutants, suggesting that the ectopic Fgf8 expression may serve as a survival signal for interdigital epithelial and mesenchymal cells. Our result suggests that Smad1 and Smad5 are required and function redundantly as intracellular mediators for BMP signaling in the AER and ventral ectoderm. Smad1/Smad5 signaling in the AER and ventral ectoderm regulates interdigital tissue regression of developing limb. Our mutants with defects in interdigital PCD could also serve as a valuable model for investigation of PCD regulation machinery. PMID- 22240099 TI - [Transcatheter aortic valve implantation: results of a new therapeutic option for high surgical risk aortic stenosis]. AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement in patients with severe aortic stenosis (AS) and unacceptably high surgical risk. METHODS: We present our first two years' experience with TAVI. A total of 76 AS patients were evaluated for TAVI and 23 of them underwent a TAVI procedure. These patients had a mean EuroSCORE of 22.4% and a mean age of 81.5 years, and were prospectively followed for a mean of 12.9 +/- 11 months. RESULTS: The percutaneous aortic valve was successfully implanted in 100% of the patients. Mortality at 30 days was 4%. The most common complications were access site-related bleeding and transfusion (22%), followed by new permanent pacemaker implantation (9%). After a mean follow-up of 12.9 months, survival was 87%. In a maximum follow-up of 30 months there were no cases of prosthesis dysfunction or cardiovascular death. CONCLUSIONS: Two years after the introduction of a TAVI program in our center, the procedure has established itself as a safe and effective alternative for patients with severe AS and unacceptably high surgical risk. PMID- 22240100 TI - Effects of L-carnosine on splenic sympathetic nerve activity and tumor proliferation. AB - l-Carnosine (beta-alanyl-l-histidine), a dipeptide of the amino acids beta alanine and histidine, is found in mammalian tissues including those in the central nervous system and in skeletal muscles. In the present study, we examined the effects of intraduodenal (ID) injection of l-carnosine on splenic sympathetic nerve activity (splenic-SNA) in urethane-anesthetized rats and found that ID injection of 3.3mg/kg of body weight of l-carnosine significantly suppressed splenic-SNA. Since it has been suggested that splenic-SNA reduction increases natural killer (NK) activity of splenic cells, which in turn elevates tumor immunity, we then investigated the effect of l-carnosine on the proliferation of human colon cancer cells transplanted into athymic nude mice. The findings of this study revealed that 1mg/mL of l-carnosine solution given as the only drinking water inhibited tumor proliferation. These results suggest that l carnosine suppresses splenic-SNA and inhibits cancer cell proliferation, probably by elevating NK activity. PMID- 22240101 TI - Using a cognitive endophenotype to identify risk genes for depression. AB - We theorized the cognitive vulnerability factor featured in hopelessness theory [2] to be a novel endophenotype for depression. We investigated two possible genetic contributors to individual differences in cognitive vulnerability (and, in turn, depression): the BDNF gene and the COMT gene. Results showed that individuals (n=95) with the BDNF Val(66) genotype had significantly greater levels of cognitive vulnerability than individuals with a BDNF Met(66) genotype. In addition, among individuals with high levels of cognitive vulnerability, those with the Val(66) genotype were significantly more likely than participants with a Met(66) genotype to experience increases in depressive symptoms when faced with increased stress. The COMT gene was not associated with cognitive vulnerability or risk for depression. Results support the use of the cognitive vulnerability factor featured in hopelessness theory as an endophenotype associated with depression as well as the role of the BDNF gene in a cognitive subtype of depression. PMID- 22240102 TI - Lateral hypothalamic area mediated the aggravated effect of microinjection of Baclofen into cerebellar fastigial nucleus on stress gastric mucosal damage in rats. AB - Cerebellum, primarily believed as a subcortical somatic motor center, is increasingly considered to be implicated in visceral activities. However, little is known about its regulation on gastrointestinal organs. In this research, we investigated the aggravated effect of microinjection of gamma-aminobutyric acid receptor subtype B (GABA(B)R) agonist, Baclofen into cerebellar fastigial nucleus (FN) on stress gastric mucosal damage (SGMD) and its possible regulatory mechanism. The gastric mucosal damage index was chosen to indicate the severity of gastric mucosal injure. Immunohistochemistry and transferase-mediated dUTP biotin nick-endlabeling (TUNEL) methods were used to detect the variations of lateral hypothalamic area (LHA) and gastric mucosa. It had been demonstrated that FN participates in regulation of SGMD via its GABA(B)R and GABA neural pathway, which passes through the decussation of superior cerebellar peduncle and projects to the GABA receptors in LHA. Meanwhile, celiac sympathetic nerve involves in this process via mediating neural discharge, which results in the decrease of gastric mucosal blood flow. Additionally, apoptosis, proliferation and oxidation in gastric mucosa, and gastric acid contribute in the mechanism. It could be expected that these results might suggest insights to the cerebellar and hypothalamic function, and the treatment of gastrointestinal diseases. PMID- 22240103 TI - Intraneural dexamethasone applied simultaneously to rat sciatic nerve constriction delays the development of hyperalgesia and allodynia. AB - Although neuroimmune interactions associated with the development of pain sensitization in models of neuropathic pain have been widely studied, there are some aspects that require further investigation. Thus, we aimed to evaluate whether the local intraneural or perineural injections of dexamethasone, an efficacious anti-inflammatory and immunosuppressant drug, delays the development of both thermal hyperalgesia and mechanical allodynia in an experimental model of neuropathic pain in rats. Hargreaves and electronic von Frey tests were applied. The chronic constriction injury (CCI) of right sciatic nerve was performed. Single intraneural dexamethasone administration at the moment of constriction delayed the development of sensitization for thermal hyperalgesia and mechanical allodynia. However, perineural administration of dexamethasone, at the highest dose, did not delay experimental pain development. These results show that inflammation/immune response at the site of nerve lesion is an essential trigger for the pathological changes that lead to both hyperalgesia and allodynia. In conclusion, this approach opens new opportunities to study cellular and molecular neuroimmune interactions associated with the development of pain derived from peripheral neuropathies. PMID- 22240104 TI - Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils. AB - Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus. PMID- 22240105 TI - Association of HADHA expression with the risk of breast cancer: targeted subset analysis and meta-analysis of microarray data. AB - BACKGROUND: The role of n-3 fatty acids in prevention of breast cancer is well recognized, but the underlying molecular mechanisms are still unclear. In view of the growing need for early detection of breast cancer, Graham et al. (2010) studied the microarray gene expression in histologically normal epithelium of subjects with or without breast cancer. We conducted a secondary analysis of this dataset with a focus on the genes (n = 47) involved in fat and lipid metabolism. We used stepwise multivariate logistic regression analyses, volcano plots and false discovery rates for association analyses. We also conducted meta-analyses of other microarray studies using random effects models for three outcomes--risk of breast cancer (380 breast cancer patients and 240 normal subjects), risk of metastasis (430 metastatic compared to 1104 non-metastatic breast cancers) and risk of recurrence (484 recurring versus 890 non-recurring breast cancers). RESULTS: The HADHA gene [hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit] was significantly under-expressed in breast cancer; more so in those with estrogen receptor-negative status. Our meta-analysis showed an 18.4%-26% reduction in HADHA expression in breast cancer. Also, there was an inconclusive but consistent under-expression of HADHA in subjects with metastatic and recurring breast cancers. CONCLUSIONS: Involvement of mitochondria and the mitochondrial trifunctional protein (encoded by HADHA gene) in breast carcinogenesis is known. Our results lend additional support to the possibility of this involvement. Further, our results suggest that targeted subset analysis of large genome-based datasets can provide interesting association signals. PMID- 22240106 TI - Pulmonary tumor thrombotic microangiopathy with cor pulmonale due to desmoplastic small round cell tumor. AB - A 12-year-old boy presented acutely after an episode of syncope with perioral cyanosis. He died 19 hours after admission due to cor pulmonale as a complication of metastatic desmoplastic small round cell tumor in the lungs with associated tumor thrombotic microangiopathy. PMID- 22240109 TI - An evidence-based catheter bundle alters central venous catheter strategy in newborn infants. AB - OBJECTIVE: To assess whether introduction of an evidence-based percutaneously inserted central catheter (PICC) care bundle reduced the risk of central line associated bloodstream infection (CLABSI), thus altering the comparative risk of CLABSI in infants. STUDY DESIGN: This retrospective cohort study included all infants for whom an umbilical venous catheter (UVC) was placed as part of routine care between Jan 1, 2006, and Dec 31, 2009, a period during which standardized PICC insertion and care bundles were introduced. Duration of UVC use was divided in <= 7 days and >7 days. RESULTS: Infants in the <= 7 days UVC group had 1.0 CLABSI/1000 catheter days, and infants in the >7 days UVC group had 4.0 CLABSI/1000 catheter days (P < .001). Controlling for birth weight, gestational age, and antibiotic use, the >7 days UVC group had a greater risk of CLABSI (OR, 5.48) than the <= 7 days UVC group. CLABSI rate increased more rapidly in UVC than PICC with increasing duration of catheter rose. CONCLUSIONS: Replacement of a UVC with a PICC when central venous access is needed after 7 days of age may reduce CLABSI. PMID- 22240107 TI - beta-cell dysfunction in adolescents and adults with newly diagnosed type 2 diabetes mellitus. AB - OBJECTIVE: To compare beta-cell function in adolescents and adults with newly diagnosed type 2 diabetes (T2DM). STUDY DESIGN: Thirty-nine adolescents with T2DM, 38 age- and weight-matched control subjects, and 19 adults with T2DM were studied. The adolescent subjects with diabetes were divided on the basis of whether they needed insulin to control their initial hyperglycemia. The primary outcome variable was the disposition index, computed from the acute insulin response to glucose corrected for insulin sensitivity (1/Homeostatic model assessment of insulin resistance). RESULTS: The disposition index was significantly reduced in all 3 diabetic groups (control n=3360, adolescents with T2DM without insulin n=630, adolescents with T2DM with insulin n=120, adults with T2DM n=200; P<.001), and the adolescents with more severe hyperglycemia at diagnosis had lower disposition index than those with a more modest presentation (P<.05). CONCLUSION: At the time of diagnosis, adolescents with T2DM have significant beta-cell dysfunction, comparable with adults newly diagnosed with T2DM. Thus, severe beta-cell impairment can develop within the first two decades of life and is likely to play a central role in the pathogenesis of T2DM in adolescents. PMID- 22240108 TI - Implementation of clinical practice guidelines for pediatric weight management. AB - OBJECTIVE: To evaluate the effect of computer-assisted decision tools that standardize pediatric weight management in a large, integrated health care system for the diagnosis and management of child and adolescent obesity. STUDY DESIGN: This was a large scale implementation study to document the impact of the Kaiser Permanente Southern California Pediatric Weight Management Initiative. An average of 739, 816 outpatient visits per year in children and adolescents from 2007 to 2010 were analyzed. Height, weight, evidence of exercise and nutrition counseling, and diagnoses of overweight and obesity were extracted from electronic medical records. RESULTS: Before the initiative, 66% of all children and adolescents had height and weight measured. This increased to 94% in 2010 after 3 years of the initiative (P < .001). In children and adolescents who were overweight or obese, diagnosis of overweight or obesity increased significantly from 12% in 2007 to 61% in 2010 (P < .001), and documented counseling rates for exercise and nutrition increased significantly from 1% in 2007 to 50% in 2010 (P < .001). CONCLUSIONS: Computer-assisted decision tools to standardize pediatric weight management with concurrent education of pediatricians can substantially improve the identification, diagnosis, and counseling for overweight or obese children and adolescents. PMID- 22240110 TI - Rapid and progressive pulmonary fibrosis in 2 families with DNA repair deficiencies of undetermined etiology. AB - Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family. PMID- 22240112 TI - Gastrointestinal bleeding in infantile hemangioma: a complication of segmental, rather than multifocal, infantile hemangiomas. AB - OBJECTIVE: To highlight an association of facial segmental hemangiomas with gastrointestinal bleeding in infants with infantile hemangiomas. STUDY DESIGN: We conducted a multicenter retrospective case series study. RESULTS: Ten female patients met study inclusion criteria; 8 were Caucasian, 9 had a facial segmental hemangioma, and 9 cases met the diagnostic criteria for definitive posterior fossa malformations, hemangioma, arterial lesions, cardiac anomalies/coarctation of the aorta and eye abnormalities syndrome with abnormalities of the aorta and cerebral arteriopathy. Severe gastrointestinal bleeding requiring blood transfusion occurred in 9 cases, with age at presentation of gastrointestinal bleeding ranging from 8 days to 6 months. When detected, the location of the hemangioma in the small intestine was in the distribution of the superior mesenteric artery. More than one agent was required to control the gastrointestinal bleeding, including oral or intravenous steroids, vincristine, oral propranolol, interferon, and resection of the small intestine. All cases needed ongoing support care with red blood cell transfusions. CONCLUSIONS: Gastrointestinal bleeding is a rare complication of true infantile hemangioma. The segmental pattern of the cutaneous hemangioma associated with gastrointestinal bleeding should suggest a segmental infantile hemangioma of the lower gastrointestinal tract. PMID- 22240111 TI - Executive summary of the workshop "Nutritional Challenges in the High Risk Infant". PMID- 22240113 TI - The use of complementary and alternative medicine among people living with diabetes in Sydney. AB - BACKGROUND: Complementary and alternative medicine (CAM) is common in patients with chronic disease such as diabetes mellitus. The primary objective of the study was to determine the overall prevalence and type of CAM use in individuals with diabetes mellitus (DM) in Western Sydney and to compare the prevalence and factors associated with CAM use with the literature. METHODS: A multicenter cross sectional study was undertaken using a self-completed questionnaire distributed to patients with DM attending a public hospital and specialist endocrinology clinics in the region. The type of DM and pattern of CAM utilisation were analyzed. RESULTS: Sixty nine people responded to the questionnaire: age range of 18-75 years during a twelve week collection period. Overall, 32 respondents with diabetes were using some form of CAM, resulting in a utilisation rate of 46.3%. Twenty of the 32 CAM users used CAM specifically to treat their diabetes accounting for 28.9% of the respondent sample population. Multivitamins (40%), cinnamon, Co-enzyme q10 and prayer were the most frequently used CAM modalities. There was no significant difference between males and females, age range, income or diabetes complications between CAM and non-CAM users. (p values each > 0.05) The factor most significantly associated with CAM usage was being born overseas (p = 0.044). CONCLUSIONS: Almost half the respondents (46.3%) used CAM: 28% used CAM specifically to treat their diabetes. Individuals born overseas were significantly more likely to use CAM than those born in Australia. Other factors such as age, gender, wealth and duration of living with diabetes were not associated with higher rate of CAM usage. PMID- 22240115 TI - Prediction of the mode of interaction between monoterpenes and the nitroreductase from Enterobacter cloacae by docking simulation. AB - Monoterpenes from the essential oils of several plants have been shown to enhance the bactericidal activities of nitrofurantoin and furazolidone against the bacteria of Enterobacteriaceae family. In this study, computer-aided molecular modeling and docking techniques have been employed to simulate the theoretical mode of interaction between monoterpenes and Enterobacter cloacae nitroreductase. Enhancement of nitro drug potency in the presence of monoterpenes may be the result of modulation of nitroreductase activity. Binding nitroreductase with monoterpenes may decrease the efficient conversion of toxic reactive intermediates to final products lacking bactericidal activity. PMID- 22240114 TI - Characterization and differential expression of a ferritin protein from Fasciola hepatica. AB - Ferritins are proteins that play a central role in maintaining intracellular iron balance. A cDNA clone of Fasciola hepatica (687 bp long) encoding a putative 228 amino acid polypeptide (FhFtn-1) homologous with ferritins of vertebrates and invertebrates was identified. FhFtn-1 contains a conserved motif of the ferroxidase center typical of vertebrate ferritins. Phylogenetic tree analysis showed that FhFtn-1 clusters with two ferritins of Paragonimus westermani, which suggests a common ancestry for the ferritins of these two trematodes. Recombinant FhFtn-1 protein expressed and purified from an Escherichia coli system showed iron-uptake ability. Moreover, FhFtn-1 showed strong reactivity with sera from rabbits infected with F. hepatica for 2-12 weeks, which suggests that this protein could be a potential antigen for immunodiagnosis of fascioliasis. qPCR analysis demonstrated that FhFtn-1-mRNA is expressed at significantly higher levels in adults and unembryonated eggs than in juveniles or miracidia. These results represent the first characterization of a ferritin protein from the liver fluke F. hepatica. PMID- 22240116 TI - Antihypertensives in people with gout or asymptomatic hyperuricaemia. PMID- 22240118 TI - NHS Commissioning Board needs targets for integrated care to become a reality, conference hears. PMID- 22240117 TI - Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. AB - OBJECTIVE: To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension. DESIGN: Nested case-control study. SETTING: UK general practice database, 2000-7. PARTICIPANTS: All incident cases of gout (n = 24,768) among adults aged 20-79 and a random sample of 50,000 matched controls. MAIN OUTCOME MEASURE: Relative risk of incident gout associated with use of antihypertensive drugs. RESULTS: After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n = 29,138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for beta blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend). CONCLUSIONS: Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, beta blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout. PMID- 22240119 TI - Novel structural arrangement of nematode cystathionine beta-synthases: characterization of Caenorhabditis elegans CBS-1. AB - CBSs (cystathionine beta-synthases) are eukaryotic PLP (pyridoxal 5 *-phosphate) dependent proteins that maintain cellular homocysteine homoeostasis and produce cystathionine and hydrogen sulfide. In the present study, we describe a novel structural arrangement of the CBS enzyme encoded by the cbs-1 gene of the nematode Caenorhabditis elegans. The CBS-1 protein contains a unique tandem repeat of two evolutionarily conserved catalytic regions in a single polypeptide chain. These repeats include a catalytically active C-terminal module containing a PLP-binding site and a less conserved N-terminal module that is unable to bind the PLP cofactor and cannot catalyse CBS reactions, as demonstrated by analysis of truncated variants and active-site mutant proteins. In contrast with other metazoan enzymes, CBS-1 lacks the haem and regulatory Bateman domain essential for activation by AdoMet (S-adenosylmethionine) and only forms monomers. We determined the tissue and subcellular distribution of CBS-1 and showed that cbs-1 knockdown by RNA interference leads to delayed development and to an approximately 10-fold elevation of homocysteine concentrations in nematode extracts. The present study provides the first insight into the metabolism of sulfur amino acids and hydrogen sulfide in C. elegans and shows that nematode CBSs possess a structural feature that is unique among CBS proteins. PMID- 22240121 TI - Role of ITAM signaling module in signal integration. AB - Diverse cell types use a small number of evolutionarily conserved signaling modules to integrate external cues and elicit distinct functions. A question thus arises as to how does a receptor, which contains a single signaling module, produce distinct outcomes to diverse signals, particularly if such module is shared amongst a family of receptors? Emerging data suggest that many immunoreceptors, all of which use a conserved ITAM-module for their signaling, can couple with members of additional classes of membrane receptors to deliver unique signal(s) to the cell. We discuss the possible biological purposes and mechanisms behind these interactions at the plasma membrane. We offer a conceptual framework to understand information processing within the immune system and discuss the new biology of old receptors involving their structural and functional collaborations that evolved to deliver unique signal(s) to the cell using a limited set of conserved signaling modules. PMID- 22240120 TI - Transcriptional mechanisms that regulate T helper 1 cell differentiation. AB - Recent research has made great strides in uncovering the mechanisms by which the T helper 1 (Th1) cell gene expression program is established. In particular, studies examining the transcription factors T-bet, STAT1, and STAT4 have elucidated their roles in regulating Th1 signature genes, including Ifng, and have started to address their contributions to the epigenetic states in Th1 cells. Additionally, new findings have provided information about how the co expression of T helper cell lineage-defining transcription factors impacts the phenotype of the cell. In this review, we will briefly highlight the research from the last few years examining the epigenetic states in T helper cells and the mechanisms by which they are established. We will then discuss how this new information contributes to our understanding of the flexibility of T helper cell genetic programs. PMID- 22240122 TI - Differential effects of LY294002 and wortmannin on inducible nitric oxide synthase expression in glomerular mesangial cells. AB - Nitric oxide (NO) that is produced by inducible nitric oxide synthase (iNOS) is associated with the pathophysiology of glomerulonephritis. Numerous studies have focused on the regulation of NO production by iNOS to reduce NO-mediated cytotoxicity. In the present study, we demonstrated the differential effects of two phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, on lipopolysaccharide- (LPS) and interferon (IFN)-gamma-induced NO production in a glomerular mesangial cell line, MES-13 cells. At dosages without affecting cell viability of MES-13 cells, 5MUM LY294002 showed a more-significant inhibitory effect on LPS/IFN-gamma-induced NO production, and iNOS protein and gene expressions than did 1MUM wortmannin. Akt phosphorylation in MES-13 cells declined upon the addition of wortmannin, but not upon treatment with LY294002. Suppression of PI3K expression by small interfering (si)RNA exhibited no effect on LPS/IFN-gamma-stimulated NO production or iNOS protein expression in MES-13 cells. Neither LY294002 nor wortmannin reduced IFN-gamma-induced STAT-1alpha phosphorylation. LY294002 exhibited a more-significant inhibitory effect on NF kappaB luciferase activities than wortmannin in LPS/IFN-gamma-stimulated MES-13 cells. Moreover, LY294002, but not wortmannin, accelerated iNOS protein degradation and reduced the iNOS dimer/monomer ratio in MES-13 cells. Although both LY294002 and wortmannin are known as PI3K inhibitors, their differential effects on iNOS expression in MES-13 cells indicate that the effects of LY294002 on inhibiting NF-kappaB activation and accelerating iNOS protein degradation are through a mechanism independent of PI3K. PMID- 22240124 TI - Hypothermia therapy: neurological and cardiac benefits. AB - Due to its protective effect on the brain and the myocardium, hypothermia therapy (HT) has been extensively studied in cardiac arrest patients with coma as well as in patients presenting with acute myocardial infarction (MI). In the setting of cardiac arrest, randomized studies have shown that HT decreases mortality and improves neurological outcomes. Subsequent guidelines have therefore recommended cooling (32 degrees C to 34 degrees C) for 12 to 24 h in unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest due to ventricular fibrillation. Observational studies have also confirmed the feasibility of this therapy in clinical practice and support its early application in patients with nonventricular fibrillation cardiac arrest and in post-resuscitation circulatory shock. In patients with acute MI, available clinical evidence does not yet support HT as the standard of care, because no study to date has shown a clear net benefit in such a cohort. After a brief review of the mechanisms of action for HT, we provide a review of the clinical evidence, cooling techniques, and potential adverse effects associated with HT in the setting of post-cardiac arrest patient and acute MI. PMID- 22240123 TI - Two mucosal-parenteral schedules to coadminister a multiantigenic formulation against HIV-1 in Balb/c mice. AB - Previous studies showed that simultaneous immunization through the nasal (IN) and subcutaneous (SC) route of a multiantigenic formulation induced a Th1 anti-HIV humoral and cellular immune responses. The formulation was comprised of a recombinant protein of HIV-1 (named CR3; Cellular Response number 3) and the surface and nucleocapsid antigens of hepatitis B virus. This study asks whether four times simultaneous administration through the IN and SC routes (SC+IN) of the multiantigenic formulation induces a similar systemic and mucosal immune responses than two sequential IN priming and two SC boosting (2IN&2SC) inoculations in mice. To answer this question, we tested the same total dose of each antigen per animal in both schedules of inoculation. We found that SC+IN and 2IN&2SC coadministration induced comparable levels of CR3(HIV)-specific IFN-gamma secreting cells and CD8+ cells proliferation in the systemic compartment of animals. Consistent with these findings, a similar Th1 profile considering anti CR3 IgG1:IGg2a ratio was observed. Additionally, the level of IgG antibodies and the frequency of seroconverting animals in vagina were not different. However, in the case of IgA antibodies the same parameters were significantly higher in the SC+IN group. We also found important level of HBsAg-specific antibodies in serum and vaginal washes. PMID- 22240125 TI - Transapical aortic valve implantation: incidence and predictors of paravalvular leakage and transvalvular regurgitation in a series of 358 patients. AB - OBJECTIVES: The aim of this study was to evaluate the results when the surgical concept of not accepting intraprocedural paravalvular leakage was applied for transcatheter aortic valve implantation (TAVI). BACKGROUND: The surgical strategy of conventional aortic valve replacement does not accept paraprosthetic leakage and requires immediate action to eliminate it. However, paravalvular leakage is the major concern after TAVI. METHODS: A total of 358 patients underwent transapical TAVI with balloon-expandable prostheses. The modified procedural strategy consisted of precise positioning of the prosthesis using a modified TAVI technique and immediate additional intraprocedural treatment to eliminate relevant paravalvular leakage. RESULTS: Balloon redilation of the transcatheter valve was performed in 18 patients (5%), and additional second valves were implanted in 13 (4%). At the end of the procedure, 186 patients (52%) had no paravalvular or transvalvular regurgitation. In the remaining 172 patients, paravalvular leakage was observed in 113 (32%), transvalvular leakage in 47 (13%), and both in 12 (3%). Leakage was trace in 88 patients (25%), mild in 82 (23%), and moderate in 2 (0.6%). Multivariate analysis identified male sex, New York Heart Association functional class IV, and no previous aortic valve replacement as predictors of post-procedural leakage. Cumulative survival was not dependent on post-procedural regurgitation rate. Overall mortality was 5 +/- 1% at 30 days, 14 +/- 2% at 6 months, 17 +/- 2% at 1 year, and 33 +/- 4% at 2 years. CONCLUSIONS: The modified procedural strategy of transapical TAVI with a balloon expandable prosthesis was associated with a low incidence of relevant prosthetic regurgitation. PMID- 22240126 TI - Pulmonary pressures and death in heart failure: a community study. AB - OBJECTIVES: The purpose of this study was to determine among community patients with heart failure (HF) whether pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography was associated with death and improved risk prediction over established factors, using the integrated discrimination improvement and net reclassification improvement. BACKGROUND: Although several studies have focused on idiopathic pulmonary arterial hypertension, less is known about pulmonary hypertension among patients with HF, particularly about its prognostic value in the community. METHODS: Between 2003 and 2010, Olmsted County residents with HF prospectively underwent assessment of ejection fraction, diastolic function, and PASP by Doppler echocardiography. RESULTS: PASP was recorded in 1,049 of 1,153 patients (mean age 76 +/- 13; 51% women). Median PASP was 48 mm Hg (25th to 75th percentile: 37.0 to 58.0). There were 489 deaths after a follow-up of 2.7 +/- 1.9 years. There was a strong positive graded association between PASP and mortality. Increasing PASP was associated with an increased risk of death (hazard ratio [HR]: 1.45, 95% confidence interval [CI]: 1.13 to 1.85 for tertile 2; HR: 2.07, 95% CI: 1.62 to 2.64 for tertile 3 vs. tertile 1), independently of age, sex, comorbidities, ejection fraction, and diastolic function. Adding PASP to models including these clinical characteristics resulted in an increase in the c-statistic from 0.704 to 0.742 (p = 0.007), an integrated discrimination improvement gain of 4.2% (p < 0.001), and a net reclassification improvement of 14.1% (p = 0.002), indicating that PASP improved prediction of death over traditional prognostic factors. All results were similar for cardiovascular death. CONCLUSIONS: Among community patients with HF, PASP strongly predicts death and provides incremental and clinically relevant prognostic information independently of known predictors of outcomes. PMID- 22240127 TI - Pulmonary hypertension: the great leveler. PMID- 22240128 TI - Clinical outcome in asymptomatic severe aortic stenosis: insights from the new proposed aortic stenosis grading classification. AB - OBJECTIVES: This study examined the clinical course of patients with asymptomatic severe aortic stenosis (AS) according to the new proposed aortic valve stenosis grading classification. BACKGROUND: The management of patients with asymptomatic severe AS remains controversial. Moreover, under the same denomination of severe AS, several entities might be identified according to transvalvular flow rates and pressure gradients, resulting in 4 flow-gradient patterns. METHODS: Transthoracic echocardiography and measurement of B-type natriuretic peptide level from venous blood sample were performed in 150 consecutive patients with asymptomatic severe AS and normal exercise test. Patients were classified in 4 groups, depending on left ventricular flow state (normal flow [NF] vs. low flow [LF]: 35 ml/m(2)) and pressure gradient levels (low gradient [LG] vs. high gradient [HG]: 40 mm Hg). RESULTS: Patients with NF/LG had significantly lower B type natriuretic peptide than those with LF/HG and LF/LG. The mean follow-up was 27 +/- 12 months. At 2 years, cardiac event-free survival was 83 +/- 6%, 44 +/- 6%, 30 +/- 12%, and 27 +/- 13% in NF/LG, NF/HG, LF/HG, and LF/LG groups, respectively (p < 0.0001). On multivariable analysis, LF/LG (hazard ratio [HR]: 5.26, 95% confidence interval [CI]: 2.04 to 14.3, p = 0.045) and LF/HG (HR: 2.38, 95% CI: 1.02 to 5.55, p = 0.001) were identified as strong independent determinants of poor prognosis as compared with NF/HG. By limiting the multivariable analysis to patients with LF, LF/LG was an independent predictor of markedly reduced cardiac event-free survival when compared with LF/HG (HR: 5.4, 95% CI: 1.03 to 28.6, p = 0.046). CONCLUSIONS: The use of the new proposed AS grading classification integrating valve area and flow-gradient patterns allows a better characterization of the clinical outcome of patients with asymptomatic severe AS. PMID- 22240129 TI - Varying hemodynamics and differences in prognosis in patients with asymptomatic severe aortic stenosis and preserved ejection fraction: a call to review cutoffs and concepts. PMID- 22240130 TI - Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. AB - OBJECTIVES: This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. BACKGROUND: Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. METHODS: In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. RESULTS: All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. CONCLUSIONS: Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department. PMID- 22240131 TI - Intramyocardial injection of platelet gel promotes endogenous repair and augments cardiac function in rats with myocardial infarction. AB - OBJECTIVES: This study sought to explore the therapeutic potential of platelet gel for the treatment of myocardial infarction. BACKGROUND: Cardiac dysfunction after acute myocardial infarction is a major cause of heart failure. Current therapy relies on prompt reperfusion and blockage of secondary maladaptive pathways by small molecules. Platelet gels are biomaterials rich in cytokines and growth factors, which can be manufactured in an autologous manner and are effective in various models of wound healing. However, the potential utility of platelet gel in cardiac regeneration has yet to be tested. METHODS: Platelet gel was derived from syngeneic rats and its morphology, biocompatibility, secretion of beneficial factors, and in vivo degradation profile were characterized. RESULTS: After delivery into infarcted rat hearts, the gel was efficiently infiltrated by cardiomyocytes and endothelial cells. Gel-treated hearts exhibited enhanced tissue protection, greater recruitment of endogenous regeneration, higher capillary density, and less compensatory myocyte hypertrophy. The cardiac function of control-injected animals deteriorated over the 6-week time course, while that of platelet gel-injected animals did not. In addition, the gel did not exacerbate inflammation in the heart. CONCLUSIONS: Intramyocardial injection of autologous platelet gel ameliorated cardiac dysfunction after myocardial infarction. The striking functional benefits, the simplicity of manufacturing, and the potentially autologous nature of this biomaterial provide impetus for further translation. PMID- 22240133 TI - Dipeptidyl peptidase-4 inhibitor: another player for cardiovascular protection. PMID- 22240132 TI - A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E deficient mice. AB - OBJECTIVES: The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS). BACKGROUND: The new class of anti-type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon like peptide (GLP)-1. METHODS: Endothelial function was examined by acetylcholine induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease. RESULTS: DFS significantly improved endothelial dysfunction (89.9 +/- 3.9% vs. 79.2 +/- 4.3% relaxation at 10(-4) mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001). CONCLUSIONS: A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium. PMID- 22240134 TI - Reversible circumflex coronary artery occlusion during percutaneous transvenous mitral annuloplasty with the Viacor system. PMID- 22240135 TI - Cardiac transplantation in arrhythmogenic right ventricular dysplasia/cardiomyopathy. PMID- 22240136 TI - Training methodology for transseptal catheterization should incorporate difficult anatomic conditions and the use of intracardiac echocardiographic imaging. PMID- 22240137 TI - Exercise training as treatment of depression in heart failure. PMID- 22240139 TI - Potential pitfalls of meta-analyses of observational studies in cardiovascular research. PMID- 22240140 TI - Giant left anterior descending artery aneurysm: the value of cardiac magnetic resonance imaging. PMID- 22240141 TI - Processing of facial expressions of emotions by adults with Down syndrome and moderate intellectual disability. AB - The processing of facial expressions of emotions by 23 adults with Down syndrome and moderate intellectual disability was compared with that of adults with intellectual disability of other etiologies (24 matched in cognitive level and 26 with mild intellectual disability). Each participant performed 4 tasks of the Florida Affect Battery and an original task in which they had to match facial expressions after observing the complete face or one of its halves. Adults with Down syndrome did not show any specific difficulties in recognizing facial expressions in spite of showing a poorer discrimination between facial expressions and tended to take more notice of the lower half of the face. PMID- 22240142 TI - Persons with multiple disabilities exercise adaptive response schemes with the help of technology-based programs: three single-case studies. AB - The present three single-case studies assessed the effectiveness of technology based programs to help three persons with multiple disabilities exercise adaptive response schemes independently. The response schemes included (a) left and right head movements for a man who kept his head increasingly static on his wheelchair's headrest (Study I), (b) left- and right-arm movements for a woman who tended to hold both arms/hands tight against her body (Study II), and (c) touching object cues on a computer screen for a girl who rarely used her residual vision for orienting/guiding her hand responses. The technology involved microswitches/sensors to detect the response schemes and a computer/control system to record their occurrences and activate preferred stimuli contingent on them. Results showed large increases in the response schemes targeted for each of the three participants during the intervention phases of the studies. The importance of using technology-based programs as tools for enabling persons with profound and multiple disabilities to practice relevant responses independently was discussed. PMID- 22240143 TI - Naming speed as a clinical marker in predicting basic calculation skills in children with specific language impairment. AB - The present study investigated the role of naming speed in predicting the basic calculation skills (i.e., addition and subtraction) of kindergartners with Specific Language Impairment (SLI), when compared to a group of Normal Language Achieving (NLA) children. Fifty-three kindergartners with SLI and 107 kindergartners with NLA were tested on cognitive, linguistic and basic calculation skills. The results showed that phonological awareness, grammatical ability, general intelligence and working memory accounted for the variation in the basic calculation skills of both groups. However, an additional effect of naming speed on both addition and subtraction was found for the group of children with SLI, suggesting that naming speed may act as a clinical marker in identifying those children who are likely to develop problems in basic calculation skills. PMID- 22240144 TI - Colour as an environmental cue when learning a route in a virtual environment: typical and atypical development. AB - Typically developing (TD) 6-year-olds and 9-year-olds, and older children and adults with Williams syndrome (WS) navigated through brick-wall mazes in a virtual environment. Participants were shown a route through three mazes, each with 6 turns. In each maze the floor of each path section was a different colour such that colour acted as an environmental cue. The colours employed were either easy to verbalise (focal colours) or difficult to verbalise (non-focal colours). We investigated whether participants would verbally code the colour information in the focal colour condition only, and whether this facilitated route-learning. All groups could learn the routes; the WS group required more learning trials to learn the route and achieved lower memory scores than both of the TD groups. Despite this, all groups showed the same pattern of results. There was no effect of condition on the ability to learn the maze. However, when asked which colours featured in each route, higher memory scores were achieved for the focal colour (verbalisable) than the non-focal colour (non-verbalisable) condition. This suggests that, in both young children and individuals with WS, once a route has been learnt, the nature of the environmental cues within it can impact an individual's representation of that route. PMID- 22240145 TI - Advanced glycation endproducts in horses with insulin-induced laminitis. AB - Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of cancer, inflammatory conditions and diabetic complications. An interaction of AGEs with their receptor (RAGE) results in increased release of pro-inflammatory cytokines and reactive oxygen species (ROS), causing damage to susceptible tissues. Laminitis, a debilitating foot condition of horses, occurs in association with endocrine dysfunction and the potential involvement of AGE and RAGE in the pathogenesis of the disease has not been previously investigated. Glucose transport in lamellar tissue is thought to be largely insulin-independent (GLUT-1), which may make the lamellae susceptible to protein glycosylation and oxidative stress during periods of increased glucose metabolism. Archived lamellar tissue from horses with insulin-induced laminitis (n=4), normal control horses (n=4) and horses in the developmental stages (6h, 12h and 24h) of the disease (n=12) was assessed for AGE accumulation and the presence of oxidative protein damage and cellular lipid peroxidation. The equine-specific RAGE gene was identified in lamellar tissue, sequenced and is now available on GenBank. Lamellar glucose transporter (GLUT-1 and GLUT-4) gene expression was assessed quantitatively with qRT-PCR in laminitic and control horses and horses in the mid developmental time-point (24 h) of the disease. Significant AGE accumulation had occurred by the onset of insulin-induced laminitis (48 h) but not at earlier time points, or in control horses. Evidence of oxidative stress was not found in any group. The equine-specific RAGE gene was not expressed differently in treated and control animals, nor was the insulin-dependent glucose transporter GLUT-4. However, the glucose transporter GLUT-1 was increased in lamellar tissue in the developmental stages of insulin-induced laminitis compared to control horses and the insulin-independent nature of the lamellae may facilitate AGE formation. However, due to the lack of AGE accumulation during disease development and a failure to detect an increase in ROS or upregulation of RAGE, it appears unlikely that oxidative stress and protein glycosylation play a central role in the pathogenesis of acute, insulin-induced laminitis. PMID- 22240146 TI - DNA-capped mesoporous silica nanoparticles as an ion-responsive release system to determine the presence of mercury in aqueous solutions. AB - We have developed DNA-functionalized silica nanoparticles for the rapid, sensitive, and selective detection of mercuric ion (Hg(2+)) in aqueous solution. Two DNA strands were designed to cap the pore of dye-trapped silica nanoparticles. In the presence of ppb level Hg(2+), the two DNA strands are dehybridized to uncap the pore, releasing the dye cargo with detectable enhancements of fluorescence signal. This method enables rapid (less than 20 min) and sensitive (limit of detection, LOD, 4 ppb) detection, and it was also able to discriminate Hg(2+) from twelve other environmentally relevant metal ions. The superior properties of the as-designed DNA-functionalized silica nanoparticles can be attributed to the large loading capacity and highly ordered pore structure of mesoporous silica nanoparticles, as well as the selective binding of thymine rich DNA with Hg(2+) . Our design serves as a new prototype for metal-ion sensing systems, and it also has promising potential for detection of various targets in stimulus-release systems. PMID- 22240147 TI - Self-castration by a transsexual woman: financial and psychological costs: a case report. AB - INTRODUCTION: The out-of-pocket cost for an elective orchiectomy, which is often not covered by health insurance, is a significant barrier to male-to-female transsexuals ready to proceed with their physical transition. This and other barriers (lack of access to a surgeon willing to perform the operation, waiting times, and underlying psychological and psychiatric conditions) lead a subset of transsexual women to attempt self-castration. Little information has been published on the financial costs and implications of self-castration to both patients and health care systems. AIM: We compare the financial and psychological costs of elective surgical orchiectomy vs. self-castration in the case of a transsexual woman in her 40s. METHODS: We interviewed the patient and her providers and obtained financial information from local reimbursement and billing specialists. RESULTS: After experiencing minor hemorrhage following the self castration, our patient presented to the emergency department and underwent a bilateral inguinal exploration, ligation and removal of bilateral spermatic cords, and complicated scrotal exploration, debridement, and closure. She was admitted to the psychiatric service for a hospital stay of three days. The total bill was U.S. $14,923, which would compare with U.S. $4,000 for an elective outpatient orchiectomy in the patient's geographical area. CONCLUSIONS: From a financial standpoint, an elective orchiectomy could have cost the health care system significantly less than a hospital admission with its associated additional costs. From a patient safety standpoint, elective orchiectomy is preferable to self-castration which carries significant risks such as hemorrhage, disfigurement, infection, urinary fistulae, and nerve damage. Healthcare providers of transsexual women should carefully explore patient attitudes toward self-castration and work toward improving access to elective orchiectomy to reduce the number of self-castrations and costs to the overall health care system. Further research on the financial implications of self-castration from different health care systems and from a series of patients is needed. PMID- 22240148 TI - Hereditary diffuse gastric cancer: the always-forgotten Meckel's diverticulum. PMID- 22240149 TI - Mindfulness, functioning and catastrophizing after multidisciplinary pain management for chronic low back pain. AB - We examined mindfulness in people with chronic low back pain who were attending a multidisciplinary pain management programme. Participants completed questionnaires at baseline (n=116) and after a 3-month cognitive-behaviourally informed multidisciplinary intervention (n=87). Self-reported mindfulness was measured before and after the intervention, and relationships were explored between mindfulness, disability, affect and pain catastrophizing. Mindfulness increased following participation in the intervention, and greater mindfulness was predictive of lower levels of disability, anxiety, depression and catastrophizing, even when pain severity was controlled. Mediator analyses suggested that the relationship between mindfulness and disability was mediated by catastrophizing. It is possible that cognitive-behavioural interventions and processes can affect both catastrophizing and mindfulness. PMID- 22240150 TI - Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf /SKN-1 and p53/CEP-1. AB - The nucleolus has recently emerged as a major coordinator of cellular stress responses by regulating the tumor suppressor p53. However, it is not known if the nucleolus regulates the cap 'n' collar (CnC) transcription factors SKN-1 and Nrf2, which activate conserved antioxidant and detoxification responses in C. elegans and mammals, respectively. A screen for negative regulators of detoxification genes in C. elegans identified the conserved WD40 repeat containing protein WDR-46. This protein is highly conserved with yeast UTP7, which functions in 18S rRNA processing and assembly of the 40S small ribosomal subunit. WDR-46 is expressed in the nucleoli of multiple tissues in C. elegans and is required for rRNA processing. Mutation or silencing of WDR-46 activates the single C. elegans CnC homologue SKN-1 and increases expression of its target genes. Depletion of wdr-46 reduces lifespan and stress resistance and SKN-1 partially compensates. Lastly, the C. elegans p53 homologue CEP-1 is partially required for activation of gst-4 when wdr-46 or other ribosome processing genes are silenced but not when translation initiation genes are silenced suggesting that disruptions to nucleolar function can activate SKN-1 by a mechanism that involves p53/cep-1 and is independent of protein translation. PMID- 22240151 TI - Effects of antioxidant gene therapy on retinal neurons and oxidative stress in a model of retinal ischemia/reperfusion. AB - Retinal ischemia/reperfusion (I/R) results in neuronal death and generation of reactive oxygen species. The aim of this study was to investigate the neuroprotective effect of manganese superoxide dismutase (SOD2) on retinal ganglion cells (RGCs) in an I/R-induced retinal injury model. One eye of each Wistar rat was pretreated with recombinant adeno-associated virus containing the SOD2 gene (AAV-SOD2) or recombinant AAV containing the GFP gene (AAV-GFP) by intravitreal injection 21 days before initiation of I/R injury. Retinal I/R injury was induced by elevating intraocular pressure for 1h, and reperfusion was established immediately afterward. The number of RGCs and the inner plexiform layer (IPL) thickness were measured by Fluorogold retrograde labeling and hematoxylin and eosin staining at 6 h, 24 h, 72 h, and 5 days after injury. Superoxide anion, the number of RGCs, IPL thickness, malondialdehyde (MDA) level, 8-hydroxy-2-deoxyguanosine (8-OHdG) level, MnSOD (manganese superoxide dismutase) activity, and nitrotyrosine level were measured by fluorescence staining, immunohistochemistry, and enzyme-linked immunosorbent analysis at 5 days after I/R injury. Severe RGC loss, reduced IPL thickness, reduced MnSOD activity, and increased superoxide ion, MDA, 8-OHdG, and nitrotyrosine production were observed after I/R injury. Administration of AAV-SOD2 significantly reduced the levels of superoxide ion, MDA, 8-OHdG, and nitrotyrosine and prevented the damage to RGCs and IPL. Delivery of the antioxidant gene inhibited I/R-induced RGC and IPL damage by reducing oxidative stress and nitrative stress, suggesting that MnSOD may be relevant for the neuroprotection of the inner retina from I/R-related diseases. PMID- 22240152 TI - Structurally related (-)-epicatechin metabolites in humans: assessment using de novo chemically synthesized authentic standards. AB - Accumulating data suggest that diets rich in flavanols and procyanidins are beneficial for human health. In this context, there has been a great interest in elucidating the systemic levels and metabolic profiles at which these compounds occur in humans. Although recent progress has been made, there still exist considerable differences and various disagreements with regard to the mammalian metabolites of these compounds, which in turn are largely a consequence of the lack of availability of authentic standards that would allow for the directed development and validation of expedient analytical methodologies. In this study, we developed a method for the analysis of structurally related flavanol metabolites using a wide range of authentic standards. Applying this method in the context of a human dietary intervention study using comprehensively characterized and standardized flavanol- and procyanidin-containing cocoa, we were able to identify the structurally related (-)-epicatechin metabolites (SREM) postprandially extant in the systemic circulation of humans. Our results demonstrate that (-)-epicatechin-3'-beta-D-glucuronide, (-)-epicatechin-3' sulfate, and a 3'-O-methyl-(-)-epicatechin-5/7-sulfate are the predominant SREM in humans and further confirm the relevance of the stereochemical configuration in the context of flavanol metabolism. In addition, we also identified plausible causes for the previously reported discrepancies regarding flavanol metabolism, consisting, to a significant extent, of interlaboratory differences in sample preparation (enzymatic treatment and sample conditioning for HPLC analysis) and detection systems. Thus, these findings may also aid in the establishment of consensus on this topic. PMID- 22240153 TI - Trimer hydroxylated quinone derived from apocynin targets cysteine residues of p47phox preventing the activation of human vascular NADPH oxidase. AB - Enzymatically derived oligophenols from apocynin can be effective inhibitors of human vascular NADPH oxidase (Nox). An isolated trimer hydroxylated quinone (IIIHyQ) has been shown to inhibit endothelial NADPH oxidase with an IC(50) ~30 nM. In vitro studies demonstrated that IIIHyQ is capable of disrupting the interaction between p47(phox) and p22(phox), thereby blocking the activation of the Nox2 isoform. Herein, we report the role of key cysteine residues in p47(phox) as targets for the IIIHyQ. Incubation of p47(phox) with IIIHyQ results in a decrease of ~80% of the protein free cysteine residues; similar results were observed using 1,2- and 1,4-naphthoquinones, whereas apocynin was unreactive. Mutants of p47(phox), in which each Cys was individually replaced by Ala (at residues 111, 196, and 378) or Gly (at residue 98), were generated to evaluate their individual importance in IIIHyQ-mediated inhibition of p47(phox) interaction with p22(phox). Specific Michael addition on Cys196, within the N-SH3 domain, by the IIIHyQ is critical for disrupting the p47(phox)-p22(phox) interaction. When a C196A mutation was tested, the IIIHyQ was unable to disrupt the p47(phox)-p22(phox) interaction. However, the IIIHyQ was effective at disrupting this interaction with the other mutants, displaying IC(50) values (4.9, 21.0, and 2.3MUM for the C111A, C378A, and C98G mutants, respectively) comparable to that of wild-type p47(phox). PMID- 22240154 TI - Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-beta1-dependent mechanism. AB - Fibrotic remodelling of lung parenchymal and airway compartments is the major contributor to life-threatening organ dysfunction in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD). Since transforming growth factor-beta1 (TGF-beta1) is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage (BAL) from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition (EMT) via the augmentation of TGF beta1. We show that in response to 400MUM hydrogen peroxide (H(2)O(2)) A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells (PBECs) undergo EMT displaying morphology changes, decreased expression of epithelial markers (E-cadherin and ZO-1), increased expression of mesenchymal markers (vimentin and alpha-smooth muscle actin) as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of TGF-beta1. Inhibition of TGF-beta1 signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone (PBN) and superoxide dismutase 3 (SOD3) prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, TGF-beta1 and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease. PMID- 22240155 TI - Subcytotoxic mercury chloride inhibits gap junction intercellular communication by a redox- and phosphorylation-mediated mechanism. AB - Gap junctions play a central role in coordinating intercellular signal transduction pathways to control tissue homeostasis. Deregulation of gap junctional intercellular communication is a common phenotype of cancer cells and supports its involvement in the carcinogenesis process. Many carcinogens, like environmental heavy-metal chemical pollutants, are known to activate various signal transduction mechanisms and modulate GJIC. They act as tumor promoters on preexisting "initiated" cells, rather than as genotoxic initiators, albeit their mode of action is often unknown. In this study we investigated the effect of Hg(II) (HgCl(2)) on GJIC in cultured human keratinocytes. It is shown that subcytotoxic concentrations of HgCl(2) as low as 10 nM cause inhibition of the GJIC, assessed by dye transfer assay, despite enhanced expression of connexins. In addition, HgCl(2)-treated keratinocytes exhibited a decrease of free thiols and accumulation of mitochondria-derived reactive oxygen species, albeit no effect on the respiratory chain activity was observed. Treatment of HgCl(2) exposed keratinocytes with the PKC inhibitor calphostin C and with all-trans retinoic acid resulted in rescue of the mitochondrial ROS overproduction and full recovery of the GJIC. Similar results were obtained with the PKA activator db cAMP. Overall, the presented results support a cross-talk between the altered intracellular redox tone and PKA- and PKC-mediated signaling in HgCl(2) challenged keratinocytes. These events, although not cytotoxic, lead to inhibition of GJIC and possibly to carcinogenic priming. PMID- 22240156 TI - Group cognitive behavioural therapy for first episode psychosis: who's referred, who attends and who completes it? AB - AIM: Most national guidelines recommend psychological therapy for people with first-episode psychosis (FEP) but interventions proven effective in randomized control trials (RCTs) conducted in research settings do not always translate effectively to real-world clinical environments. In a limited health system, it is important to understand the system and patient barriers to participation in effective treatment. We sought to determine what patient characteristics influenced clinicians' decision to refer or not to refer to group cognitive behavioural therapy for FEP and what characteristics were associated with those referred attending/not attending and adhering/not adhering to the programme. METHODS: Between 2006 and 2008, all cases of confirmed FEP from a defined geographical region were examined using the Structured Clinical Interview for DSM IV-TR Axis I Disorders for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses, the Scale for Assessment of Positive Symptoms, Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia and Birchwood Insight Scale. Duration of untreated psychosis was established using the Beiser Scale. RESULTS: Of the 124 (77 males, 47 females) people in the final sample, 88 (72%) were referred for cognitive behavioural therapy (CBT), 52 (59%) attended and 12 (23%) did not complete CBT. Those with higher levels of insight into the need for treatment (U = 740.00, z = -2.63, P = 0.008) and higher levels of positive symptoms (t (120) = -3.064, P = 0.003) were more likely to be referred to CBT. Those with higher educational attainment (chi(2) = 9.48, P = 0.03) and fewer negative symptoms, particularly in relation to global attention (t (85) = 2.32, P = 0.03), were more likely to attend and complete CBT. CONCLUSION: Within an early intervention service for FEP, it appears that individuals with less education, more negative symptoms and less insight experienced significant barriers to successfully completing group CBT. More information for referring clinicians about the benefits of CBT for FEP could help increase referral rates. Assertive outreach for people at risk of disengaging or non-adherence should also be considered. PMID- 22240157 TI - Association of left ventricular diastolic dysfunction with elevated NT-proBNP in type 2 diabetes mellitus patients with preserved ejection fraction: the supplemantary role of tissue doppler imaging parameters and NT-proBNP levels. AB - BACKGROUND: Early diagnosis of cardiovascular disease in diabetic patients may be important to introduce treatment early. Echocardiography is a method used to show the ventricular functions. A ventricular hormone, BNP is used to identify the changes in the ventricular function in early period. NT-proBNP which is a more stable compound with a longer half-life is used in measurement of BNP. METHODS: Left ventricular diastolic dysfunction (LVDD) was detected and NT-proBNP levels were measured in forty-four asymptomatic patients with ages of 30-70 and type 2 DM and control group consisted of 40 healthy individuals from the same age group. RESULTS: NT-proBNP levels were found as 566.7 +/- 738.5 pg/ml in the diabetics with LVDD detected, 166.3 +/- 137.1 pg/ml in the diabetics without LVDD and 134.5 +/- 77.2 pg/ml in the control group. Levels of NT-proBNP were significantly higher in the group with left ventricular diastolic dysfunction (p<0.05). However, when the levels of NT-proBNP in the diabetic patients without LVDD were compared with the controls, the difference was not significant (p>0.05). NT proBNP levels were found significantly higher in LVDD group compared to the controls without a difference between the ejection fractions (p<0.05). CONCLUSION: High levels of NT-proBNP was correlated tissue Doppler echocardiography findings in type 2 DM patients with preserved ejection fraction. PMID- 22240158 TI - Intentional binding and the sense of agency: a review. AB - It is nearly 10 years since Patrick Haggard and colleagues first reported the 'intentional binding' effect (Haggard, Clark, & Kalogeras, 2002). The intentional binding effect refers to the subjective compression of the temporal interval between a voluntary action and its external sensory consequence. Since the first report, considerable interest has been generated and a fascinating array of studies has accumulated. Much of the interest in intentional binding comes from the promise to shed light on human agency. In this review we survey studies on intentional binding, focusing, in particular, on the link between intentional binding and the sense of agency (the experience of controlling action to influence events in the environment). We suggest that, whilst it is yet to be fully explicated, the link between intentional binding and the sense of agency is compelling. We conclude by considering outstanding questions and future directions for research on intentional binding. PMID- 22240161 TI - Late onset of livedo reticularis induced by amantadine treatment concomitant with erythrocytosis. PMID- 22240162 TI - Outer membrane protein A and OprF: versatile roles in Gram-negative bacterial infections. AB - Outer membrane protein A (OmpA) is an abundant protein of Escherichia coli and other enterobacteria and has a multitude of functions. Although the structural features and porin function of OmpA have been well studied, its role in the pathogenesis of various bacterial infections has emerged only during the last decade. The four extracellular loops of OmpA interact with a variety of host tissues for adhesion to and invasion of the cell and for evasion of host-defense mechanisms when inside the cell. This review describes how various regions present in the extracellular loops of OmpA contribute to the pathogenesis of neonatal meningitis induced by E. coli K1 and to many other functions. In addition, the function of OmpA-like proteins, such as OprF of Pseudomonas aeruginosa, is discussed. PMID- 22240164 TI - Churg-Strauss syndrome: case series. AB - Churg-Strauss syndrome (CSS) is a systemic necrotizing vasculitis of the small and medium vessels, associated with extravascular eosinophilic granulomas, peripheral eosinophilia and asthma. This is a rare syndrome of unknown etiology, affecting both genders and all age groups. CSS patients usually respond well to steroid treatment, although relapses are common after it ends. Timely diagnosis and treatment generally lead to a good prognosis with a 90% survival rate at one year. A brief review of CSS is presented, with particular attention to diagnosis, therapy and recent developments in this area. The authors then report and discuss the clinical, laboratory and imaging characteristics of four patients admitted to an Internal Medicine Department with this diagnosis. The treatment, response and follow-up of the cases are also described. PMID- 22240163 TI - NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration. AB - BACKGROUND: Activation of microglia causes the production of proinflammatory factors and upregulation of NADPH oxidase (NOX) that form reactive oxygen species (ROS) that lead to neurodegeneration. Previously, we reported that 10 daily doses of ethanol treatment induced innate immune genes in brain. In the present study, we investigate the effects of chronic ethanol on activation of NOX and release of ROS, and their contribution to ethanol neurotoxicity. METHODS: Male C57BL/6 and NF-kappaB enhanced GFP mice were treated intragastrically with water or ethanol (5 g/kg, i.g., 25% ethanol w/v) daily for 10 days. The effects of chronic ethanol on cell death markers (activated caspase-3 and Fluoro-Jade B), microglial morphology, NOX, ROS and NF-kappaB were examined using real-time PCR, immunohistochemistry and hydroethidine histochemistry. Also, Fluoro-Jade B staining and NOX gp91phox immunohistochemistry were performed in the orbitofrontal cortex (OFC) of human postmortem alcoholic brain and human moderate drinking control brain. RESULTS: Ethanol treatment of C57BL/6 mice showed increased markers of neuronal death: activated caspase-3 and Fluoro-Jade B positive staining with Neu-N (a neuronal marker) labeling in cortex and dentate gyrus. The OFC of human post-mortem alcoholic brain also showed significantly more Fluoro-Jade B positive cells colocalized with Neu-N, a neuronal marker, compared to the OFC of human moderate drinking control brain, suggesting increased neuronal death in the OFC of human alcoholic brain. Iba1 and GFAP immunohistochemistry showed activated morphology of microglia and astrocytes in ethanol-treated mouse brain. Ethanol treatment increased NF-kappaB transcription and increased NOX gp91phox at 24 hr after the last ethanol treatment that remained elevated at 1 week. The OFC of human postmortem alcoholic brain also had significant increases in the number of gp91phox + immunoreactive (IR) cells that are colocalized with neuronal, microglial and astrocyte markers. In mouse brain ethanol increased gp91phox expression coincided with increased production of O2- and O2- - derived oxidants. Diphenyleneiodonium (DPI), a NOX inhibitor, reduced markers of neurodegeneration, ROS and microglial activation. CONCLUSIONS: Ethanol activation of microglia and astrocytes, induction of NOX and production of ROS contribute to chronic ethanol-induced neurotoxicity. NOX-ROS and NF-kappaB signaling pathways play important roles in chronic ethanol-induced neuroinflammation and neurodegeneration. PMID- 22240165 TI - Fused in sarcoma (FUS) interacts with the cytolinker protein plectin: implications for FUS subcellular localization and function. AB - Fused in sarcoma (FUS) is a multifunctional protein involved in transcriptional control, pre-mRNA processing, RNA transport and translation. The domain structure of FUS reflects its functions in gene regulation and its ability to interact with other proteins, RNA and DNA. By use of a recombinant fragment of FUS in pull-down experiments followed by mass spectrometry analysis we have identified a novel interaction between the FUS N-terminal and the cytolinker plectin. An in situ proximity ligation assay confirmed that FUS-plectin interactions take place in the cytoplasm of cells. Furthermore, plectin deficient cells showed an altered subcellular localization of FUS and a deregulated expression of mRNAs bound to FUS. Our results show that plectin is important for normal FUS localization and function. Mutations involving FUS are causative factors in sarcomas and leukemias and also hereditary forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Plectin deficiency causes epidermolysis bullosa, a disease involving the skin and neuromuscular system. The novel FUS-plectin interaction offers new perspectives for understanding the role of FUS and plectin mutations in the pathogenesis of these diseases. PMID- 22240166 TI - Role of Epac and protein kinase A in thyrotropin-induced gene expression in primary thyrocytes. AB - cAMP pathway activation by thyrotropin (TSH) induces differentiation and gene expression in thyrocytes. We investigated which partners of the cAMP cascade regulate gene expression modulations: protein kinase A and/or the exchange proteins directly activated by cAMP (Epac). Human primary cultured thyrocytes were analysed by microarrays after treatment with the adenylate cyclase activator forskolin, the protein kinase A (PKA) activator 6-MB-cAMP and the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP (007) alone or combined with 6-MB-cAMP. Profiles were compared to those of TSH. Cultures treated with the adenylate cyclase- or the PKA activator alone or the latter combined with 007 had profiles similar to those induced by TSH. mRNA profiles of 007-treated cultures were highly distinct from TSH-treated cells, suggesting that TSH-modulated gene expressions are mainly modulated by cAMP and PKA and not through Epac in cultured human thyroid cells. To investigate whether the Epac-Rap-RapGAP pathway could play a potential role in thyroid tumorigenesis, the mRNA expressions of its constituent proteins were investigated in two malignant thyroid tumor types. Modulations of this pathway suggest an increased Rap pathway activity in these cancers independent from cAMP activation. PMID- 22240167 TI - Glycoproteomic identification of galectin-3 and -8 ligands in bronchoalveolar lavage of mild asthmatics and healthy subjects. AB - BACKGROUND: Galectins, a family of small carbohydrate binding proteins, have been implicated in regulation of inflammatory reactions, including asthma and fibrosis in the lungs. Galectins are found in cells of the airways and in airway secretions, but their glycoprotein ligands there have only been studied to a very limited extent. METHODS: Bronchoalveolar lavage (BAL) fluid from mild asthmatics and healthy volunteers were fractionated by affinity chromatography on the immobilized galectins. Total (10-30 MUg) and galectin bound (~1-10 MUg) protein fractions were identified, quantified and compared using shot-gun proteomics and spectral counts. RESULTS: About 175 proteins were identified in unfractionated BAL-fluid, and about 100 bound galectin-3 and 60 bound galectin-8. These included plasma glycoproteins, and typical airway proteins such as SP-A2, PIGR and SP-B. The concentration of galectin-binding proteins was 100-300 times higher than the concentration of galectins in BAL. CONCLUSION: The low relative concentration of galectins in BAL makes it likely that functional interactions with glycoproteins occur at sites rich in galectin, such as cells of the airways, rather than the extracellular fluid itself. The profile of galectin bound proteins differed between samples from asthma patients and healthy subjects and correlated with the presence of fibroblasts or eosinophils. This included appearance of a specific galectin-8-binding glycoform of haptoglobin, previously shown to be increased in serum in other inflammatory conditions. GENERAL SIGNIFICANCE: It is technically feasible to identify galectin-binding glycoproteins in low concentration patient samples such as BAL-fluid, to generate biomedically interesting results. This article is part of a Special Issue entitled Glycoproteomics. PMID- 22240168 TI - Molecular and structural basis for N-glycan-dependent determination of glycoprotein fates in cells. AB - BACKGROUND: N-linked oligosaccharides operate as tags for protein quality control, consigning glycoproteins to different fates, i.e. folding in the endoplasmic reticulum (ER), vesicular transport between the ER and the Golgi complex, and ER-associated degradation of glycoproteins, by interacting with a panel of intracellular lectins in the early secretory pathway. SCOPE OF REVIEW: This review summarizes the current state of knowledge regarding the molecular and structural basis for glycoprotein-fate determination in cells that is achieved through the actions of the intracellular lectins and its partner proteins. MAJOR CONCLUSIONS: Cumulative frontal affinity chromatography (FAC) data demonstrated that the intracellular lectins exhibit distinct sugar-binding specificity profiles. The glycotopes recognized by these lectins as fate determinants are embedded in the triantennary structures of the high-mannose-type oligosaccharides and are exposed upon trimming of the outer glucose and mannose residues during the N-glycan processing pathway. Furthermore, recently emerged 3D structural data offer mechanistic insights into functional interplay between an intracellular lectin and its binding partner in the early secretory pathway. GENERAL SIGNIFICANCE: Structural biology approaches in conjunction with FAC methods provide atomic pictures of the mechanisms behind the glycoprotein-fate determination in cells. This article is a part of a Special issue entitled: Glycoproteomics. PMID- 22240169 TI - Coherence of evidence from systematic reviews as a basis for evidence strength - a case study in support of an epistemological proposition. AB - BACKGROUND: This article aims to offer, on the basis of Coherence theory, the epistemological proposition that mutually supportive evidence from multiple systematic reviews may successfully refute radical, philosophical scepticism. METHODS: A case study including seven systematic reviews is presented with the objective of refuting radical philosophical scepticism towards the belief that glass-ionomer cements (GIC) are beneficial in tooth caries therapy. The case study illustrates how principles of logical and empirical coherence may be applied as evidence in support of specific beliefs in healthcare. RESULTS: The results show that radical scepticism may epistemologically be refuted on the basis of logical and empirical coherence. For success, several systematic reviews covering interconnected beliefs are needed. In praxis, these systematic reviews would also need to be of high quality and its conclusions based on reviewed high quality trials. CONCLUSIONS: A refutation of radical philosophical scepticism to clinical evidence may be achieved, if and only if such evidence is based on the logical and empirical coherence of multiple systematic review results. Practical application also requires focus on the quality of the systematic reviews and reviewed trials. PMID- 22240170 TI - A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. AB - BACKGROUND: Patients ingesting ethylene glycol, isopropanol, methanol, and propylene glycol ('toxic alcohols') often present with non-specific signs and symptoms. Definitive diagnosis of toxic alcohols has traditionally been by gas chromatography (GC), a technique not commonly performed on-site in hospital clinical laboratories. The objectives of this retrospective study were: 1) to assess the diagnostic accuracy of the osmolal gap in screening for toxic alcohol ingestion and 2) to determine the common reasons other than toxic alcohol ingestion for elevated osmolal gaps. METHODS: Electronic medical records from an academic tertiary care medical center were searched to identify all patients in the time period from January 1, 1996 to September 1, 2010 who had serum/plasma ethanol, glucose, sodium, blood urea nitrogen, and osmolality measured simultaneously, and also all patients who had GC analysis for toxic alcohols. Detailed chart review was performed on all patients with osmolal gap of 9 or greater. RESULTS: In the study period, 20,669 patients had determination of serum/plasma ethanol and osmolal gap upon presentation to the hospitals. There were 341 patients with an osmolal gap greater than 14 (including correction for estimated contribution of ethanol) on initial presentation to the medical center. Seventy-seven patients tested positive by GC for one or more toxic alcohols; all had elevated anion gap or osmolal gap or both. Other than toxic alcohols, the most common causes for an elevated osmolal gap were recent heavy ethanol consumption with suspected alcoholic ketoacidosis, renal failure, shock, and recent administration of mannitol. Only 9 patients with osmolal gap greater than 50 and no patients with osmolal gap greater than 100 were found to be negative for toxic alcohols. CONCLUSIONS: Our study concurs with other investigations that show that osmolal gap can be a useful diagnostic test in conjunction with clinical history and physical examination. PMID- 22240171 TI - Valproic acid improves the tolerance for the stress in learned helplessness rats. AB - In this study, we investigated whether previously stressed rats with learned helplessness (LH) paradigm could recover from depressive-like behavior four weeks after the exposure, and also whether chronic treatment with valproic acid (VPA) could prevent behavioral despair due to the second stress on days 54 in these animals. Four weeks after induction of LH, we confirmed behavioral remission in the previously stressed rats. Two-way analysis of variance (ANOVA) performed with two factors, pretreatment (LH or Control) and drug (VPA or Saline), revealed a significant main effect of the drug on immobility time in forced swimming test. Post hoc test showed a shorter immobility time in the LH+VPA group than in the LH+Saline group. Immunohistochemical study of synapsin I showed a significant effect of drug by pretreatment interaction on immunoreactivity of synapsin I in the hippocampus: its expression levels in the regions were higher in the LH+VPA group than in the LH+Saline group. These results suggest that VPA could prevent the reappearance of stress-induced depressive-like behaviors in the rats recovering from prior stress, and that the drug-induced presynaptic changes in the expression of synapsin I in the hippocampus of LH animals might be related to improved tolerance toward the stress. PMID- 22240172 TI - Risk factors of surgical evacuation following second-trimester medical termination of pregnancy. AB - BACKGROUND: Second-trimester medical termination of pregnancy (TOP) is associated with a higher risk of surgical evacuation than earlier medical TOP. Little is known about risk factors of surgical evacuation. Therefore, we assessed these risk factors among women undergoing second-trimester medical TOP. STUDY DESIGN: Data on 227 women were derived from a prospective randomized trial comparing 1- and 2-day mifepristone-misoprostol intervals in second-trimester medical TOP between 2008 and 2010. RESULTS: The rate of surgical evacuation was 30.8%. The risk of surgical evacuation was increased by a history of curettage [odds ratio (OR) 4.4; 95% confidence interval (CI) 1.7-11.7], fetal indications for TOP (OR 6.1; 95% CI 1.1-34.4), age above 24 years (OR 2.4; 95% CI 1.1-5.3) and a 2-day interval (OR 2.2; 95% CI 1.1-4.1). CONCLUSIONS: History of curettage, fetal indication, increasing age and 2-day interval between mifepristone and misoprostol increase the risk of surgical evacuation in cases of second-trimester medical TOP. These findings are important when optimizing clinical service in second-trimester TOP. PMID- 22240174 TI - Ethnic differences in factors associated with the use of contraception among 20- to 44-year-old women in Estonia and St. Petersburg, Russia. AB - BACKGROUND: The aim of this study was to explore factors associated with contraception among 20- to 44-year-old women in different ethnic groups in two Eastern European countries. STUDY DESIGN: Data on sexually experienced women in need of contraception taken from population-based cross-sectional surveys, conducted in Estonia (n=1680) and in St. Petersburg (n=798), were analyzed. Factors associated with contraception nonuse or the use of unreliable contraceptive methods were explored using multivariate logistic regression analysis. RESULTS: The age-standardized prevalence rate of contraception nonuse or the use of unreliable contraceptive methods was high (27.3% among Estonian speaking women in Estonia, 39.9% and 42.5% among Russian-speaking women in Estonia and in St. Petersburg, respectively). Age, economic subsistence, high risk sexual behavior and smoking did not correlate with contraception nonuse or the use of unreliable contraceptive methods among Russian-speaking women in Estonia and in St. Petersburg; this was in contrast to Estonian-speaking women in Estonia. Previous childbirth and abortion reduced the risk of contraception nonuse or the use of unreliable contraceptive methods among Estonian-speaking women in Estonia (adjusted odds ratio, 0.50; 95% confidence interval [CI], 0.31 0.81) but elevated the risk among Russian-speaking women in St. Petersburg (1.99; 1.17-3.40). Abortion, not previous childbirth, was associated with an increased risk among Russian-speaking women in Estonia (2.94; 1.25-6.95). CONCLUSIONS: The importance of different risk factors associated with contraceptive use varies between different ethnic groups. Cross-national comparisons are essential for the design of public health policies that decrease the burden of sexual ill health. PMID- 22240175 TI - Contraception and abortion coverage: What do primary care physicians think? AB - BACKGROUND: Insurance coverage for family planning services has been a highly controversial element of the US health care reform debate. Whether primary care providers (PCPs) support public and private health insurance coverage for family planning services is unknown. STUDY DESIGN: PCPs in three states were surveyed regarding their opinions on health plan coverage and tax dollar use for contraception and abortion services. RESULTS: Almost all PCPs supported health plan coverage for contraception (96%) and use of tax dollars to cover contraception for low-income women (94%). A smaller majority supported health plan coverage for abortions (61%) and use of tax dollars to cover abortions for low-income women (63%). In adjusted models, support of health plan coverage for abortions was associated with female gender and internal medicine specialty, and support of using tax dollars for abortions for low-income women was associated with older age and internal medicine specialty. CONCLUSION: The majority of PCPs support health insurance coverage of contraception and abortion, as well as tax dollar subsidization of contraception and abortion services for low-income women. PMID- 22240176 TI - Pelvic surgery and hospitalization among Chilean women after nonsurgical sterilization with quinacrine pellets between 1977 and 1989. AB - BACKGROUND: Concern about quinacrine lingers because of its carcinogenic effects in rats. We describe results of long-term follow-up of women who underwent quinacrine pellet sterilization in Chile between 1977 and 1989 (N=1492). METHODS: We interviewed the women or relatives in five rounds of data collection between 1991-1993 and 2006-2007, and reviewed hospital records. Median follow-up was 18.5 years; total person-time was 23,894 woman-years. This analysis focuses on pelvic and abdominal surgeries and conditions. We used survival analysis to estimate the 15-year cumulative probability of hysterectomy, other pelvic surgical procedures and relevant adverse events. RESULTS: Uterine fibroids were by far the most common gynecologic condition, reported by 11% of the cohort. Surgical procedures were recorded for 15% of the cohort; hysterectomy was the most frequent procedure (10%), followed by salpingectomy (2%). The 15-year probability of any pelvic or abdominal procedure was 14.7 per 100 women (95% confidence interval 12.4-16.9). The probability of hysterectomy was 9.3 per 100 women (95% confidence interval 7.4-11.1). Number of quinacrine insertions had little impact on the probabilities. CONCLUSION: During long-term follow-up of women who received quinacrine pellets for nonsurgical sterilization, the incidence of noncancer adverse outcomes was not unusually high, and no alarming patterns emerged. PMID- 22240178 TI - Normalization of blood loss in women with heavy menstrual bleeding treated with an oral contraceptive containing estradiol valerate/dienogest. AB - BACKGROUND: The study was conducted to assess the efficacy of estradiol valerate/dienogest (E2V/DNG) administered using an estrogen step-down and progestogen step-up approach in a 28-day regimen in the treatment of heavy menstrual bleeding (HMB) using clinical end points allowing E2V/DNG to be compared with other available medical therapies. STUDY DESIGN: This was a pooled analysis of data from two identically designed randomized, placebo-controlled, multiple center studies conducted in Europe, Australia and North America that assessed the effectiveness of E2V/DNG in reducing menstrual blood loss (MBL) in women with HMB. Women aged >= 18 years with objectively confirmed HMB were randomized to E2V/DNG (n=220) or placebo (n=135) for seven treatment cycles. Outcomes analyzed included absolute reduction in MBL from baseline, proportion of women successfully treated (defined as MBL below 80 mL and >= 50% reduction in MBL), proportion with MBL below 80 mL and proportion with >= 50% reduction in MBL from baseline. RESULTS: At study end, 63.6% and 11.9% of patients were successfully treated with E2V/DNG and placebo, respectively, with 68.2% and 15.6% of women with MBL below 80 mL, and 70.0% and 17.0% with MBL reduction >= 50% (all p<.001). CONCLUSION: E2V/DNG is highly effective for the treatment of HMB and is associated with a high rate of treatment success. PMID- 22240179 TI - Lack of insurance and parity influence choice between long-acting reversible contraception and sterilization in women postpregnancy. AB - BACKGROUND: Disparities in postpregnancy contraception utilization exist, with low-income women disproportionately undergoing sterilization. We assessed the impact of increased intrauterine device (IUD) availability on rates of female sterilization. STUDY DESIGN: Hospital billing records were used to identify women with an IUD placement or sterilization within 1 year of a pregnancy at a university hospital between Oct 2005 and Jun 2007. Demographic data were compared between women receiving either an IUD or sterilization. RESULTS: There were 365 sterilizations and 223 IUD placements during the study period. IUD placements doubled over the study period from 6% to 12% of all deliveries, while sterilizations remained stable at 11% (p<.001). Demographic variables were examined for women with either public or private insurance who had financial access to both sterilization (n=253) and IUD (n=223). Women receiving sterilization were slightly older (mean age 31 years versus 30 years, p=.03), of higher parity (median three versus two, p<.01), more likely to have had cesarean delivery (69% versus 31%, p<.001) and more likely to have public insurance (77% versus 23%, p<.001) than women who received IUD. Approximately 45% of women delivering in Oregon in 2007 were publicly insured (2010 Maternal and Child Health Update: States Make Progress Towards Improving Systems of Care. National Governor's Association, Table 6. Available at http://www.nga.org/files/live/sites/NGA/files/pdf/MCHUPDATE2010.PDF, accessed Nov 2011). After adjusting for age, parity and type of delivery, women choosing sterilization were more likely to have public insurance than women choosing IUD (odds ratio 8.4, 95% confidence interval 4.7-14.9, p<.0001). CONCLUSIONS: Women choosing sterilization are more likely to have public insurance than women choosing IUD and may represent a continued trend toward nonreversible contraception among women of lower socioeconomic status despite available long acting reversible methods. PMID- 22240180 TI - Music as an auxiliary analgesic during first trimester surgical abortion: a randomized controlled trial. AB - BACKGROUND: Music has served as an auxiliary analgesic in perioperative settings. This study evaluates the impact of intraoperative music added to routine pain control measures during first trimester surgical abortion. STUDY DESIGN: We analyzed data from 101 women randomized to undergo abortion with routine pain control measures only (ibuprofen and paracervical block) or with the addition of intraoperative music via headphones. The primary outcome was the change in preoperative and postoperative pain scores on a 100-mm visual analog scale. Secondary outcomes included change in anxiety and vital signs, and satisfaction. RESULTS: Baseline characteristics were similar between groups. The magnitude of increase in pain scores was greater in the intervention than in the control group (+51.0 mm versus +39.3 mm, p=.045). Overall pain control was rated as good or very good by 70% of the intervention and 75% of the control group (p=.65). CONCLUSIONS: Intraoperative music added to routine pain control measures increases pain reported during abortion. PMID- 22240181 TI - Emerging roles of RETINOBLASTOMA-RELATED proteins in evolution and plant development. AB - RETINOBLASTOMA-RELATED (RBR) proteins are plant homologs of the human tumor suppressor pRB. Similar to their animal counterparts they have roles in cell cycle regulation and differentiation. We discuss recent findings of the evolution of RBR functions ranging from a molecular ruler and metabolic integrator in algae to a coordinator of differentiation in gametophytes. Genetic analysis and manipulation of protein levels during gametophytic and post-embryonic plant development are now providing new insights into the function of RBR in stem cell maintenance, cell specification and differentiation. We briefly explain interactions of RBR with chromatin-modifying complexes that appear to be a central underlying molecular mechanism during developmental transitions. PMID- 22240182 TI - Cost-cutting capital investment proposals in chronic pain management. PMID- 22240183 TI - Tracheal pouch and Murphy eye. PMID- 22240184 TI - Glutamate-induced cell death in HT22 mouse hippocampal cells is attenuated by paxilline, a BK channel inhibitor. AB - In the present study, we show that the large conductance calcium-activated potassium channel (BK(Ca) channel) inhibitor paxilline protects neuronal cells against glutamate-induced cell death. In our studies, we used HT22 mouse hippocampal cells as an experimental model and observed that the effect of paxilline was dose-dependent. We also found that other inhibitors of BK(Ca) channels, iberiotoxin and charybdotoxin, were not cytoprotective. Paxillinol, which is a structural analog of paxilline but does not inhibit BK(Ca) channel, also protected HT22 cells against glutamate-induced toxicity. These data suggest that the observed cytoprotection was not related to BK(Ca) channel inhibition by paxilline. In addition, paxilline neither restored glutathione levels nor reduced the amount of reactive oxygen species upon glutamate treatment. Our results suggest that paxilline protects neuronal HT22 cells against glutamate-induced cell death independently of BK(Ca) channel activity and oxidative stress induced by glutamate treatment. PMID- 22240185 TI - Nephrotoxic effects from chronic toxic cyanobacterial blooms in fishes with different trophic levels in a large Chinese lake. AB - Physiological and biochemical responses in kidneys of fishes with different trophic levels to toxic cyanobacterial blooms were studied. We sampled four fishes: the phytoplanktivorous Hypophthalmichthys molitrix and Aristichthys nobilis, the omnivorous Carassius auratus, and the carnivorous Culter ilishaeformis. Alterations of the antioxidant (GSH) and the major antioxidant enzymes (CAT, SOD, GPx, GST) were monitored monthly. Catalase and glutathione S transferase were significantly higher during blooms than before and after blooms. All fishes showed ultrastructural alterations during blooms, which mainly are inosculation of foot processes in epithelial cell of glomeruli and mitochondria swelling in the proximal tubules. The results suggested that kidney impairment from chronic exposure of toxic cyanobacterial blooms might be the first step, and then followed by hepatic failure. Compared with livers in terms of physiological status, the weaker antioxidant ability of kidney made it more susceptible to chronic MCs exposure, besides its effective accumulation of MC metabolites. PMID- 22240186 TI - Enhanced effects by mixtures of three estrogenic compounds at environmentally relevant levels on development of Chinese rare minnow (Gobiocypris rarus). AB - The combined effects of 17beta-estradiol, diethylstilbestrol and nonylphenol at environmentally relevant levels were studied on development of Chinese rare minnow. No effects on hatchability of embryos, survival of larvae, body length and body weight were found in the fish exposed to the single chemicals and their mixtures. But significant vitellogenin induction and testis somatical index reduction were observed in adult males exposed to the mixtures. Meanwhile, the sex ratio of adult fish skewed to female was found in the fish exposed to high concentration of the mixture. These results revealed not only that the co exposure of xenoestrogens can enhance the adverse effects on the development of fish, but that the adverse effects were induced by co-exposure of xenoestrogens below the threshold of similar detectable effects for single xenoestrogen. The observations in the present study highlight the potential ecological hazard posed by the coexistence of xenobiotics in the realistic aquatic environment. PMID- 22240187 TI - Direct contact test for estimating the ecotoxicity of aerosol samples. AB - Atmospheric particulate matter with aerodynamic diameter less than 10 MUm (PM10) and 2.5 MUm (PM2.5) is now identified as one of the most dangerous pollutants on human health by the EU new directive on air quality (2008/50/CE). Although these primary pollutants are monitored in cities, little information is available on their ecotoxicity. In this paper a 'whole-aerosol' testing protocol is suggested based on the kinetic version of the Vibrio fischeri bioluminescence inhibition test. PMID- 22240188 TI - Trace metal imbalance associated with oxidative stress and inflammatory status in anti-hepatitis C virus antibody positive subjects. AB - Toxic and essential trace metals, oxidative stress, and inflammatory status were evaluated in anti-hepatitis C virus (HCV) antibody-positive subjects. Blood biochemical parameters were determined in anti-HCV antibody-positive (n=17) and negative controls (n=46). Compared with controls, anti-HCV antibody-positive individuals had significantly lower concentrations of plasma zinc (Zn); higher copper (Cu), iron (Fe), lead (Pb), cadmium (Cd), and aluminum (Al); and lower activities of erythrocyte antioxidant enzymes glutathione peroxidase and catalase, and elevated superoxide dismutase. Significantly increased lipid peroxidation malondialdehyde (MDA), and inflammatory markers such as alanine aminotransferase (ALT), high sensitivity C-reactive protein (hs-CRP), ferritin, and Cu/Zn ratios, as well as decreased albumin and high density lipoprotein (HDL) concentrations were observed. We have found significant interactions between toxic (e.g., Pb, Cd, and Al) and essential metals (e.g., Zn, Cu, Fe), which correlated with MDA. In conclusion, anti-HCV antibody-positive subjects had abnormal distributions of trace metals that may aggravate oxidative stress and inflammation, and exacerbate hepatic damage. PMID- 22240189 TI - Erectile function outcome after bilateral nerve sparing radical prostatectomy: which patients may be left untreated? AB - INTRODUCTION: Several studies have shown that erectile function (EF) recovery in patients undergoing bilateral nerve sparing radical prostatectomy (BNSRP) improves significantly when phosphodiesterase type 5 inhibitors (PDE5) are administered following surgery. AIM: The aim of this article was to identify patients who may recover EF after retropubic BNSRP (BNSRRP) without PDE5. METHODS: We included 293 patients treated with BNSRRP at a single center. Postoperative EF recovery was defined as an EF domain score of the International Index of Erectile Function (IIEF) >=22. No patient received any treatment for postoperative erectile dysfunction (ED). Kaplan-Meier curves assessed time to EF recovery according to patient age, preoperative EF, and Charlson comorbidity index (CCI). Univariable and multivariable Cox regression models tested the association between predictors and EF recovery. Finally, the rate of EF recovery of untreated patients after BNSRP was compared with a subset of patients with similar preoperative characteristics but receiving PDE5. MAIN OUTCOME MEASURE: The main outcome measure of this article was the IIEF-EF domain score. RESULTS: Overall, 105/293 (35.8%) reached an IIEF-EF >=22 after a mean follow-up of 26.8 months. At multivariable analyses, age, preoperative IIEF-EF, and CCI achieved independent predictor status (all P<=0.04). Patients <55 years had a 72.4% EF recovery rate compared with 30% of patients >70 years (P<0.001). Similarly, preoperatively fully potent patients (IIEF-EF >=26) had a 56.6% chance of recovering EF after surgery compared with 18% of patients with severe ED before surgery (P<0.001). The rate of EF recovery in untreated patients <55 years and with a pre-op IIEF-EF >=22 was higher but did not differ significantly from comparable patients receiving PDE5 (P=0.11). CONCLUSIONS: Overall, the rate of EF postoperative recovery in patients left untreated after surgery is modest (35.8%). Although younger patients with a good preoperative EF may experience good EF recovery rates even without any treatment, use of PDE5 after surgery further improved their functional outcomes. Therefore, a therapy for ED should be offered to all patients treated with BNSRP. PMID- 22240190 TI - Localization of tumor necrosis factor in the canine testis, epididymis and spermatozoa. AB - Tumor necrosis factor (TNF), formerly known as Tumor necrosis factor alpha is now regarded as a natural component of the mammalian seminal plasma (SP). Although not completely clarified, its functions in the SP have been associated with paradoxal roles, such as sperm survival in the female genital tract, while at high levels negatively affect sperm survival and fertility potential. Recently, it has been discovered that canine inseminated spermatozoa display a strong immunoreaction for TNF when lining the female endometrium. As a continuation of this finding, the present work aimed at documenting TNF localization in the canine testes and epididymis and in freshly ejaculated spermatozoa (SPZ) through immunohisto- or cytochemistry. Immunoreaction for TNF was found in all samples used. In the dog testis, TNF immunoexpression was limited to the seminiferous tubules, where late round spermatids (SPD) showed weak intensity of immunostaining, while elongating and elongated SPD evidenced moderate and the residual bodies a strong intensity. In the epididymis, a gradual progressive increase of TNF immunolabelling was found throughout the epididymal regions, ranging from a weak intensity at the caput epididymis to a moderate intensity at the cauda. TNF immunolabelling was found in mature SPZ during the epididymal transit and also in freshly ejaculated SPZ, which showed a strong midpiece immunolabelling. Data presented here provide important information on expression of TNF in spermatozoa, which is acquired by the SPZ during their formation at the testis. It further provides the basis for subsequent studies on the physiological importance of cytokines in sperm function. PMID- 22240191 TI - Ecoinformatics: supporting ecology as a data-intensive science. AB - Ecology is evolving rapidly and increasingly changing into a more open, accountable, interdisciplinary, collaborative and data-intensive science. Discovering, integrating and analyzing massive amounts of heterogeneous data are central to ecology as researchers address complex questions at scales from the gene to the biosphere. Ecoinformatics offers tools and approaches for managing ecological data and transforming the data into information and knowledge. Here, we review the state-of-the-art and recent advances in ecoinformatics that can benefit ecologists and environmental scientists as they tackle increasingly challenging questions that require voluminous amounts of data across disciplines and scales of space and time. We also highlight the challenges and opportunities that remain. PMID- 22240192 TI - Examples of electrostatic electron optics: the Farrand and Elektros microscopes and electron mirrors. AB - The role of Gertrude Rempfer in the design of the Farrand and Elektros microscopes is evoked. The study of electron mirror optics, aberration correction using mirrors and the development of microscopes employing electron mirrors are recapitulated, accompanied by a full bibliography, of earlier publications in particular. PMID- 22240193 TI - [Clinical phenotypes associated with selective IgA deficiency: a review of 330 cases and a proposed follow-up protocol]. AB - Selective IgA deficiency is the most common Primary Immune Deficiency. Only a small proportion of these patients present during childhood, but this proportion increases over the years, and may be associated with an IgG subclass deficiency with increased susceptibility to respiratory and digestive tract infections. During childhood, IgA deficient patients may also refer to symptoms related to allergic and autoimmune diseases or tumours. AIMS: To describe the relationship of selective IgA deficiency with infections, allergic diseases, autoimmune disorders and tumours. To investigate the presence of other immune disorders associated with selective IgA deficiency. To suggest a follow-up protocol for these patients. METHODS: Retrospective study of paediatric patients (<18 years) being followed-up in the Clinical Immunology Department between 1992 and 2007, as well as laboratory records with IgA values below 50mg/L. Clinical records were reviewed (frequency and intensity of diseases associated with selective IgA deficiency) along with immunology tests performed. RESULTS: A total of 330 paediatric patients were identified with a selective IgA deficiency: 39 (11.8%) suffered from recurrent ear infections (2 developed secondary deafness), 58 (17.5%) from recurrent upper respiratory tract infections, and 20 patients (6%) from recurrent pneumonia, 6 of whom developed secondary bronchiectasis and 2 underwent a lobectomy. A relationship with atopic disease was found in 62 (18.78%) of patients. Regarding digestive disorders, chronic diarrhoea was found in 21 (6.5%), coeliac disease in 22 (6.6%), and persistently high plasma transaminases in 3. Autoimmune manifestations were found in 38 (11.5%), juvenile chronic arthritis, type 1 diabetes, vitiligo, cytopenia, and Crohn's disease, amongst others). Tumours were identified in 5 (1.5%). An IgG sub-class deficiency was found in 5 patients (4%), and 6 patients had a confirmed deficiency in antibody production. CONCLUSIONS: In our cohort, 56.6% of patients with IgA deficiency showed other comorbidities which were, in decreasing frequency: recurrent infections (respiratory and ear infections), allergic diseases, autoimmunity and tumours. Some patients will develop a more severe humoral defect (IgG subclass deficiency with or without antibody deficiency). PMID- 22240194 TI - [Presence of family members while performing invasive procedures. A prospective study]. AB - INTRODUCTION: Family members of child patients have traditionally not been allowed to be present during invasive procedures. OBJECTIVES: To evaluate the level of satisfaction of family members, healthcare professionals, and the patients themselves, when family members are present during invasive procedures carried out in the pediatric emergency department. MATERIALS AND METHODS: A prospective observational study was carried out, which included a questionnaire containing demographic information, the details of the procedure, and the level of satisfaction of the patient, their family members, and the healthcare professionals present. RESULTS: Data was obtained from 75 procedures. In 5 of these, family members chose not to be present during the procedure. The most frequent procedures were lumbar punctures (44%), laceration repairs (22,7%) and venopunctures (17,3%). All (100%) the children who were asked wanted their family members to be present. 90% of family members and 57% of healthcare professionals were of the opinion that the presence of family members facilitated the procedure. Furthermore, 90% of family members and 76% of healthcare professionals thought that family presence was beneficial to the patient. 95% of family members and 71% of healthcare professionals thought that the option to be present during invasive procedures should be given to family members. 73% of healthcare professionals were satisfied with the presence of family members. On a scale of one to ten, overall satisfaction of family members was 9.5. CONCLUSIONS: In our experience, family presence during invasive procedures is possible, and we have found this to be beneficial to the child. We also found that both family members and healthcare professionals were accepting and also satisfied with this new practice policy. PMID- 22240196 TI - Social functioning in early psychosis: are all the domains predicted by the same variables? AB - AIM: The study aims to determine the predictive value of negative symptoms, depression, short-term verbal learning and gender on three areas of social functioning--social life, vocational functioning and independent living skills- in a sample of 88 individuals with early psychosis. METHODS: Participants were recruited from early psychosis intervention programmes and community mental health clinics in British Columbia, Canada, and completed the following measures: client's assessment of strengths, interests, and goals, brief psychiatric rating scale, Beck depression inventory and California verbal learning task. RESULTS: Multiple linear regressions revealed that: more negative symptoms and higher depression predicted a less active social life; more negative symptoms and poorer short-term verbal learning ability predicted lower vocational functioning; and more negative symptoms and male gender predicted lower independent living skills. CONCLUSION: Results suggest that negative symptoms are predictive of all three areas of functioning but that specific variables add significant unique variance to individual areas of social functioning. Although a global social functioning score can be considered useful, greater precision can be gained by the use of domain-specific measures. PMID- 22240197 TI - The expression of TLR pathway molecules in peripheral blood mononuclear cells and their relationship with tumor invasion and cytokine secretion in laryngeal carcinoma. AB - PURPOSE: The aim of this study was to analyze of TLRs mRNA expression in peripheral blood mononuclear cells as potential biomarkers of neoplastic lesions progress and to evaluate their role in the possible mechanisms responsible for the secretion of cytokines in laryngeal cancer. MATERIAL/METHODS: The analysis of TLR2, TLR4, TRAF6, IRAK1 expression in isolated PBMCs by the reverse transcription PCR (RT-PCR) analysis as well as IL-6, IL-8 and TNF-alpha levels in supernatants of peripheral blood mononuclear cells from 55 patients with carcinoma of the larynx was performed by ELISA. The invasiveness of carcinoma was evaluated according to tumor front grading, TFG. RESULTS: We noted that tumors with a well-defined borderline were characterized by significantly higher values of the average expression of TRAF6. Our research also confirmed that more aggressive carcinomas according to TFG, with a more dispersed type of invasion were characterized by significantly lower values of the average expression of IRAK1. Moreover, we observed that tumors with the invasion of cartilage were characterized by significantly lower values of the average expression of TLR4. In addition, the relationships of TLR2 with IL-6 and TNF-alpha level were highlighted. Significant interconnections were also found between the TLR4 and IL 8, TNF-alpha, IL-6 secretion after stimulation. The relationships of TRAF6 with IL-8 production after stimulation were noted. CONCLUSIONS: Our findings confirmed the implication of the TLRs pathway molecules in proinflammatory cytokine secretions and their importance as encouraging potential indicators for assessment of the degree of aggressive tumor phenotype. PMID- 22240198 TI - Fission and proliferation of peroxisomes. AB - Peroxisomes are remarkably dynamic, multifunctional organelles, which react to physiological changes in their cellular environment and adopt their morphology, number, enzyme content and metabolic functions accordingly. At the organelle level, the key molecular machinery controlling peroxisomal membrane elongation and remodeling as well as membrane fission is becoming increasingly established and defined. Key players in peroxisome division are conserved in animals, plants and fungi, and key fission components are shared with mitochondria. However, the physiological stimuli and corresponding signal transduction pathways regulating and modulating peroxisome maintenance and proliferation are, despite a few exceptions, largely unexplored. There is emerging evidence that peroxisomal dynamics and proper regulation of peroxisome number and morphology are crucial for the physiology of the cell, as well as for the pathology of the organism. Here, we discuss several key aspects of peroxisomal fission and proliferation and highlight their association with certain diseases. We address signaling and transcriptional events resulting in peroxisome proliferation, and focus on novel findings concerning the key division components and their interplay. Finally, we present an updated model of peroxisomal growth and division. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease. PMID- 22240199 TI - SYBR Green-based real-time PCR targeting kinetoplast DNA can be used to discriminate between the main etiologic agents of Brazilian cutaneous and visceral leishmaniases. AB - BACKGROUND: Leishmaniases control has been hampered by the unavailability of rapid detection methods and the lack of suitable therapeutic and prophylactic measures. Accurate diagnosis, which can distinguish between Leishmania isolates, is essential for conducting appropriate prognosis, therapy and epidemiology. Molecular methods are currently being employed to detect Leishmania infection and categorize the parasites up to genus, complex or species level. Real-time PCR offers several advantages over traditional PCR, including faster processing time, higher sensitivity and decreased contamination risk. RESULTS: A SYBR Green real time PCR targeting the conserved region of kinetoplast DNA minicircles was able to differentiate between Leishmania subgenera. A panel of reference strains representing subgenera Leishmania and Viannia was evaluated by the derivative dissociation curve analyses of the amplified fragment. Distinct values for the average melting temperature were observed, being 78.95 degrees C +/- 0.01 and 77.36 degrees C +/- 0.02 for Leishmania and Viannia, respectively (p < 0.05). Using the Neighbor-Joining method and Kimura 2-parameters, the alignment of 12 sequences from the amplified conserved minicircles segment grouped together L. (V.) braziliensis and L. (V.) shawii with a bootstrap value of 100%; while for L. (L.) infantum and L. (L.) amazonensis, two groups were formed with bootstrap values of 100% and 62%, respectively. The lower dissociation temperature observed for the subgenus Viannia amplicons could be due to a lower proportion of guanine/cytosine sites (43.6%) when compared to species from subgenus Leishmania (average of 48.4%). The method was validated with 30 clinical specimens from visceral or cutaneous leishmaniases patients living in Brazil and also with DNA samples from naturally infected Lutzomyia spp. captured in two Brazilian localities. CONCLUSIONS: For all tested samples, a characteristic amplicon melting profile was evidenced for each Leishmania subgenus, corroborating the data from reference strains. Therefore, the analysis of thermal dissociation curves targeting the conserved kinetoplast DNA minicircles region is able to provide a rapid and reliable method to identify the main etiologic agents of cutaneous and visceral leishmaniases in endemic regions of Brazil. PMID- 22240200 TI - TET2, a tumor suppressor in hematological disorders. AB - The TET family of proteins has been described a few years ago. Only recently, their roles in DNA modification, through the oxidation of methyl-cytosine, and in normal and malignant development, through the description of TET2 as a tumor suppressor have been documented. The conjunction of these findings has prompted large efforts to understand the biology of these novel entities. Here, we summarize the recent results implicating TET2 in hematological malignancies suggesting that further studies are required to fully understand the role of DNA methylation alterations during transformation. PMID- 22240202 TI - Recognition of different DNA sequences by a DNA-binding protein alters protein dynamics differentially. AB - lambda-Repressor-operator sites interaction, particularly O(R)1 and O(R)2, is a key component of the lambda-genetic switch. FRET from the dansyl bound to the C terminal domain of the protein, to the intercalated EtBr in the operator DNA indicates that the structure of the protein is more compact in the O(R)2 complex than in the O(R)1 complex. Fluorescence anisotropy reveals enhanced flexibility of the C-terminal domain of the repressor at fast timescales after complex formation with O(R)1. In contrast, O(R)2 bound repressor shows no significant enhancement of protein dynamics at these timescales. These differences are shown to be important for correct protein-protein interactions. Altered protein dynamics upon specific DNA sequence recognition may play important roles in assembly of regulatory proteins at the correct positions. PMID- 22240203 TI - A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel((r))) insertion. AB - INTRODUCTION: Implantable testosterone pellets were approved by the Food and Drug Administration in 1972 for the treatment of testosterone deficiency syndrome (TDS). Clinical use of this testosterone delivery modality has been limited until its recent reintroduction (Testopel((r)) , Slate Pharmaceuticals, Durham, NC, USA). Six academic institutions collaborated and combined their databases to more fully characterize serum testosterone levels after the pellet implantations. AIMS: To assess the time-dependent serum testosterone levels after subcutaneous testosterone pellets in clinical practice for the treatment of TDS. METHODS: Data were retrospectively pooled and analyzed from data in six academic institutions. Variables included patient age, total testosterone concentrations before and after implantation, the number of testosterone pellets implanted, and the time from implantation to measurement of serum testosterone concentrations. Three hundred eighty men undergoing 702 insertions were included for analysis using JMP (version 4.0.4; SAS Institute, Cary, NC, USA). MAIN OUTCOME MEASURES: Main outcome measures were postimplantation total testosterone levels and investigator reported adverse events. Testosterone levels as a function of the number of pellets implanted and time from implantation were assessed. RESULTS: Implantation of six to >=10 testosterone pellets (450 to >=750 mg) increased total testosterone into the therapeutic range at 1 month postimplantation and sustained therapeutic levels (>300) for 4-6 months. Higher pellet numbers (10-12 pellets) were associated with higher, more consistent, and longer maintenance of testosterone levels within the therapeutic range. Four extrusions and three hematomas were reported early in our experience; other investigator-reported adverse events were generally mild to moderate in nature and transient in duration. No subjects required analgesics. CONCLUSIONS: Testosterone pellets (Testopel((r)) , Slate Pharmaceuticals) provide sustained levels of testosterone for at least 4 months and up to 6 months in men with TDS. Implantation of >=8 pellets achieved optimal results with respect to peak mean testosterone level and duration of effect. Testosterone pellets were generally well tolerated. PMID- 22240201 TI - Interrogating genomic and epigenomic data to understand prostate cancer. AB - Major breakthroughs at the beginning of this century in high-throughput technologies have profoundly transformed biological research. Significant knowledge has been gained regarding our biological system and its disease such as malignant transformation. In this review, we summarize leading discoveries in prostate cancer research derived from the use of high-throughput approaches powered by microarrays and massively parallel next-generation sequencing (NGS). These include the seminal discovery of chromosomal translocations such as TMPRSS2 ERG gene fusions as well as the identification of critical oncogenes exemplified by the polycomb group protein EZH2. We then demonstrate the power of interrogating genomic and epigenomic data in understanding the plethora of mechanisms of transcriptional regulation. As an example, we review how androgen receptor (AR) binding events are mediated at multiple levels through protein-DNA interaction, histone and DNA modifications, as well as high-order chromatin structural changes. PMID- 22240204 TI - Phosphorus and nitrogen effects on microbial euendolithic communities and their bioerosion rates. AB - Cages and fertilizers were used at Glover's Atoll, Belize to test the relative importance of nitrogen (N) and phosphorus (P) to microbial euendolithic communities (bacteria, algae and fungi) and their bioerosion rates of Strombus gigas shells after 56-days of exposure. By the end of the experiment, the abundance of green algae was higher than cyanobacteria and fungi in N and N+P treatments, although green algae did not increase proportionally with increasing N concentrations, suggesting that green algae were co-limited by P and N. In contrast, cyanobacteria abundance increased with increasing P concentration, suggesting that cyanobacteria were P-limited. Fungi were not significantly affected by the addition of nutrients. Microbioerosion rates in the N and N+P treatments were 2-times greater than rates in the P treatment and 15-times greater than the control treatment. Results demonstrate that increased nutrient concentrations on coral reefs may increase microbioerosion rates, and variations in nutrient ratios can modify microborers community composition. PMID- 22240205 TI - Tumor necrosis factor-alpha-mediated threonine 435 phosphorylation of p65 nuclear factor-kappaB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus. AB - BACKGROUND: Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-alpha in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE. METHODS: SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-alpha and NF-kappaB subunits. RESULTS: Following SE, most activated microglia showed strong TNF-alpha immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-alpha by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC. CONCLUSION: These findings suggest that impairments of endothelial cell functions via TNF-alpha-mediated p65-Thr 485 NF-kappaB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss. PMID- 22240206 TI - Mobile Medical Education (MoMEd) - how mobile information resources contribute to learning for undergraduate clinical students - a mixed methods study. AB - BACKGROUND: Mobile technology is increasingly being used by clinicians to access up-to-date information for patient care. These offer learning opportunities in the clinical setting for medical students but the underlying pedagogic theories are not clear. A conceptual framework is needed to understand these further. Our initial questions were how the medical students used the technology, how it enabled them to learn and what theoretical underpinning supported the learning. METHODS: 387 medical students were provided with a personal digital assistant (PDA) loaded with medical resources for the duration of their clinical studies. Outcomes were assessed by a mixed-methods triangulation approach using qualitative and quantitative analysis of surveys, focus groups and usage tracking data. RESULTS: Learning occurred in context with timely access to key facts and through consolidation of knowledge via repetition. The PDA was an important addition to the learning ecology rather than a replacement. Contextual factors impacted on use both positively and negatively. Barriers included concerns of interrupting the clinical interaction and of negative responses from teachers and patients. Students preferred a future involving smartphone platforms. CONCLUSIONS: This is the first study to describe the learning ecology and pedagogic basis behind the use of mobile learning technologies in a large cohort of undergraduate medical students in the clinical environment. We have developed a model for mobile learning in the clinical setting that shows how different theories contribute to its use taking into account positive and negative contextual factors.The lessons from this study are transferable internationally, to other health care professions and to the development of similar initiatives with newer technology such as smartphones or tablet computers. PMID- 22240207 TI - Ras oncogenes in oral cancer: the past 20 years. AB - Oral squamous cell carcinoma (OSCC) of head and neck is associated with high morbidity and mortality in both Western and Asian countries. Several risk factors for the development of oral cancer are very well established, including tobacco chewing, betel quid, smoking, alcohol drinking and human papilloma virus (HPV) infection. Apart from these risk factors, many genetic factors such as oncogenes, tumor suppressor genes and regulatory genes are identified to involve in oral carcinogenesis with these risk factors dependent and independent manner. Ras is one of the most frequently genetically deregulated oncogene in oral cancer. In this review, we analyze the past 22years of literature on genetic alterations such as mutations and amplifications of the isoforms of the ras oncogene in oral cancer. Further, we addressed the isoform-specific role of the ras in oral carcinogenesis. We also discussed how targeting the Akt and MEK, downstream effectors of the PI3K/Akt and MAPK pathways, respectively, would probably pave the possible molecular therapeutic target for the ras driven tumorigenesis in oral cancer. Analysis of these ras isoforms may critically enlighten specific role of a particular ras isoform in oral carcinogenesis, enhance prognosis and pave the way for isoform-specific molecular targeted therapy in OSCC. PMID- 22240209 TI - Management of dredge material in the Republic of Ireland - A review. AB - As an island nation the Republic of Ireland's ports and harbours are key to the economic wellbeing of the country as they are the primary transport link to the United Kingdom, mainland Europe and beyond. This paper examines the main aspects of the Irish dredging industry with comparison to international practice and standards, including the source of the dredge material and volumes generated annually, the dredging plant employed and the management processes currently practised. Relevant European and Irish legislation governing dredging, disposal at sea and waste licensing are presented. The potential impacts of disposal at sea are discussed with the implications for the Irish dredging industry of recently introduced European Directives assessed. Beneficial use rates for dredge material and the techniques implemented in Ireland are examined and compared with international practice. Recent notable beneficial use projects for dredge material and proposed innovative dredge material management techniques for specific dredging projects in Ireland are presented. Proposals to encourage greater beneficial use of dredge material and minimise disposal at sea for Ireland are presented including the introduction of environmental credits, tax breaks and a grant system for pilot schemes. An alternative disposal at sea charge fee structure is also recommended to encourage alternative dredge material management practices. Ireland's management of contaminated sediment is also presented with recent projects described highlighting the current practice of primarily exporting contaminated sediment to mainland Europe. Alternative methods of treatment of contaminated sediment are assessed in an Irish context. Future issues and challenges facing the Irish dredging industry are assessed and a critical analysis of the current approaches to dredge material management is presented. PMID- 22240210 TI - Patient preferences for characteristics differentiating ovarian stimulation treatments. AB - BACKGROUND: Little is known concerning patient preferences for IVF treatments. The objective of this study was to elicit patient preferences for characteristics differentiating ovarian stimulation treatments. METHODS: Women undergoing IVF were recruited from six clinics in Sweden between May 2010 and December 2010. Included patients completed a study questionnaire consisting of one contingent valuation (CV) question (with six different bids) and 16 conjoint analysis (CA) questions formulated as discrete choices between two hypothetical ovarian stimulation treatments (defined in terms of manufacturing method, method of administration, time required for administration, dose variability and hypothetical price). Patient preferences were derived using multinomial logit modelling. RESULTS: The final study population consisted of 294 women (mean age of 35). Respondents were willing to pay ?360 [95% confidence interval (CI): ?340 ?390] to receive FSH derived from DNA technology instead of highly purified extract from urine from post-menopausal women, ?300 (95% CI: ?280-?320) to administer the FSH using a prefilled injection pen instead of a conventional syringe, ?30 (95% CI: ?20-?40) per saved minute required for administration and ?530 (95% CI: ?500-?570) to reduce the dose variability from 10-20% to 1-2% (P< 0.001 for all estimates). The result from the CV was similar to the CA. CONCLUSIONS: Women undergoing IVF place significant value on characteristics differentiating ovarian stimulation treatments. Product-specific aspects should be taken into account by decision-makers when discriminating between commercial gonadotrophins in clinical practice to align health-care decision-making with patient preferences and potentially improve the effectiveness of IVF interventions through enhanced patient satisfaction and treatment compliance. Preferences for treatment characteristics should also be considered in evaluations of ovarian stimulation products to capture their true value from a patient perspective. PMID- 22240208 TI - Bone mechanotransduction may require augmentation in order to strengthen the senescent skeleton. AB - Physical exercise is thought to hold promise as a non-invasive countermeasure against skeletal fragility arising from post-menopausal and age-related osteoporosis. Importantly, mechanical loading and exercise are capable of increasing bone size via periosteal expansion, which by far, is the most effective means of strengthening the structure of a given bone. The focus of this review was to therefore explore whether exercise has the potential to increase periosteal modeling and bone size in the senescent skeleton. A survey of exercise trials in humans suggests that exercise interventions that enhance periosteal modeling in the young skeleton fail to do the same in the elderly skeleton. Underlying this ineffectiveness, in vitro studies indicate that aging lowers basal levels of cell function and degrades bone mechanotransduction at a variety of levels from altered second messenger signaling to gene expression driving proliferation and/or differentiation. Given these age-related alterations, the ultimate efficacy of an exercise intervention may depend upon concurrent supplementation that directly address deficits in signaling and/or cell function. In this context, in vivo animal models of mechanical loading that simulate the muted periosteal adaptation in the elderly hold potential to examine the efficacy of countermeasures. Preliminary in vivo experiments suggest that pharmacologically counteracting age-related deficits in cellular function can restore exercise induced periosteal modeling in the senescent skeleton to levels observed in young animals. If the safety and efficacy of this strategy were to be confirmed for human use, it would enable the utilization of exercise as a viable countermeasure against skeletal fragility at senescence. PMID- 22240212 TI - [Second-line treatment of metastatic non-small cell lung carcinoma: What are the options today? What are the perspectives for tomorrow?]. PMID- 22240213 TI - [Improving compliance to CPAP in sleep apnea syndrome: from coaching to telemedicine]. PMID- 22240214 TI - [Surgery for empyema: still a burning issue!]. PMID- 22240215 TI - [Incidence of sarcoidosis in Guadeloupe. A 13-year retrospective study: 1997 2009]. AB - INTRODUCTION: Sarcoidosis is a systemic granulomatosis of unknown origin with a high incidence in the Afro-American population. There is no epidemiologic data regarding Afro-Caribbean population. The aim of our study was to evaluate the incidence and epidemiologic data of the disease, on the island of Guadeloupe, (French West Indies; 402 500 inhabitants, 90% Afro-Caribbean people) during the 13-years period between 1/01/1997 and 31/12/2009. METHOD: We performed a retrospective study including exclusively patients with a diagnosis of sarcoidosis confirmed by histological examination of the involved tissues. RESULTS: One hundred and thirteen patients were enrolled in the study. One hundred and eleven patients (98%) were black Caribbean of African European descent. Eighteen patients (16%) were more than 65 years old. The crude annual incidence over the study period was 2.9 cases per 100,000 inhabitants (IC 95%: [2,4-3,4]). The main localization of the disease was the chest (89%). Radiographic stages were distributed as following: I (31%), II (39%), III (15%), IV (2%). CONCLUSION: Our study showed a low incidence rate of sarcoidosis on the island of Guadeloupe over the study period with a high rate of old patients. PMID- 22240216 TI - [Pemetrexed salvage chemotherapy for NSCLC: implementation study]. AB - BACKGROUND: Registration trials demonstrated the activity of pemetrexed in non small cell lung carcinoma (NSCLC) either in combination with first-line agents or in monotherapy for salvage treatment. The aim of our implementation study was to verify, in an unselected population, the results obtained with pemetrexed salvage chemotherapy in clinical practice. PATIENTS AND METHODS: The charts of all patients diagnosed with NSCLC, receiving pemetrexed for progressive disease after at least one previous course of chemotherapy, were retrospectively reviewed in two academic institutions. Response was assessed according to WHO and toxicity using the CTCAE and WHO criteria. RESULTS: Between November 2004 and September 2009, 84 patients were given pemetrexed as second, third or greater than third line therapy (n=18/14/52). Intent-to-treat response rate was 11.9% (95% CI, 5% 18.8%). Median progression-free survival was 2.2 months and median survival time was 6.4 months. The most frequent grade 3-5 toxicity was neutropenia (23.9%). CONCLUSION: Salvage chemotherapy with pemetrexed for progressing NSCLC confirmed, in an unselected population, who had been extensively treated previously, the level of activity observed in registration trials although a significant toxicity was noted. PMID- 22240217 TI - [Screening contacts for latent tuberculosis infection (LTBI) using an interferon test in Paris in 2009]. AB - There are two reasons for screening contacts: one is to identify cases of secondary tuberculosis disease (TB) and the other is to identify new cases of latent tuberculosis infection (LTBI). The tuberculin skin test (TST) and the interferon-gamma-release assay (IGRA) have their limitations when used for the detection of LTBI. They neither allow a definite diagnosis of LTBI nor provide information as to the date of onset. The present study was observational, multi centre (four centers) and retrospective. Six hundred and one contacts were included. The results of the QFT test showed 88 positive (15 %). Among the 144 index cases, all presented with pulmonary disease and 89 cases were sputum positive. In our series, 101 contacts belonged to the family circle. The four factors that had a significant positive impact on the result of the QFT test were: increasing age, the region of birth of the contact (high incidence areas), both of which may indicate old infection, while contact within the family and sputum positivity of the index case probably indicate recent infection. Only sputum positivity influenced the decision to treat the LTBI. We propose a tool aimed at facilitating the decision making process in QFT positive cases. Estimation of the duration of LTBI should help the physician to decide on the need for preventative treatment as well as a search for factors that increase the risk of progression to TB disease. PMID- 22240218 TI - [Education of patients with sleep apnea syndrome: Feasibility of a phone coaching procedure. Phone-coaching and SAS]. AB - INTRODUCTION: The most commonly used treatment for obstructive sleep apnea syndrome (OSA) is the application of continuous positive airway pressure (CPAP) during sleep. However compliance with this treatment is frequently below 70%. METHODS: The main aim of this study was to evaluate the feasibility of an educational intervention (EI) delivered in phone calls made to OSA patients (n=66) treated with CPAP by a home care provider (SADIR). The educational intervention consisted of five sessions of telephone based counseling intervention by appropriately trained staff delivered on day 3, 10, 30, 60 and 90 after initiation of treatment. Secondary objectives were to compare, using a case control design, CPAP compliance of OSA patients (n=133) with or without EI. RESULTS: Ninety-eight percent of patients accepted the intervention to participate in the study. Fifty-seven patients (86%) received the full intervention program and 44 patients (66%) strictly respected the pre-defined timings per protocol. A higher adherence to CPAP at six months was observed in the EI group compared to patient without EI (94% versus 81%) (P<0.05). CPAP compliance at three months was 54minutes higher in the EI group compared to the control group (4h39+/-2h17 and 3h45+/-2h45 respectively) but this difference was not statistically significant. CONCLUSION: An educational intervention dispensed by phone is applicable and would have an impact on CPAP compliance. Its efficacy on long-term compliance has to be confirmed in a larger group using a randomized procedure. PMID- 22240219 TI - [Early results of pleural decortication for empyema: an African series of 51 cases]. AB - OBJECTIVE: To evaluate the short term outcome of patients who underwent pleuro pulmonary decortication. METHOD: This is a retrospective study of 174 patients treated for thoracic empyema in Point G Hospital, Bamako/Mali, between 2004 and 2007. Perioperative data of 51 patients who underwent pleuro-pulmonary decortication had been recorded. RESULTS: Of the 174 patients treated, 51 (29.3%) underwent pleuro-pulmonary decortication. 84.5% were male and 70.6% were less than 45 years old. A recent history of tuberculosis was found in 59%. Among the four patients selected for a thoracoscopic procedure, only two were treated successfully. A conventional postero-lateral thoracotomy was used in the remaining 49 patients. The lung expansion, estimated intraoperatively, was complete in 43 cases and incomplete in eight cases. Among these eight patients with incomplete lung expansion, four developed a secondary empyema and required a thoracoplasty. The postoperative mortality was 6% (three patients). CONCLUSION: In our hospital, one third of patients with thoracic empyema required a pleuro pulmonary decortication. Incomplete lung expansion is a potential risk factor of postoperative infection necessitating re-operation or more extensive surgical procedures. PMID- 22240220 TI - [Management of wheezing disorders in infants participating in the PARIS birth cohort]. AB - BACKGROUND: While wheezing disorders are common in preschool children, their management is not well defined. The aim of this study was to assess the use of medical health care resources due to wheezing disorders in infants aged 18 months followed up in the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort. METHODS: Data on wheezing disorders, medical visits and medication on account of respiratory disorders during the previous 12 months were collected with a standardized questionnaire, administered by a paediatrician, during the health check offered to every child aged 18 months included in the PARIS birth cohort. RESULTS: The prevalence of wheezing disorders during the past 12 months amounted to 560/1974 (28.4%). Among wheezers, 493 (89.3%) required a medical visit because of difficult breathing; 61 (11.0%) went to the emergency room, 35 (6.4%) were admitted to the hospital and 375 (67.2%) received an inhaled anti asthmatic medication. Recourse to chest physiotherapy was reported in 472 of them (85.1%). CONCLUSION: This study confirms the high use of healthcare resources because of wheezing disorders in infants and suggests a higher use of anti asthmatic medications in France compared to other European countries. PMID- 22240221 TI - [Home telemonitoring of CPAP: a feasibility study]. AB - BACKGROUND: The most commonly used treatment for the sleep apnoea syndrome (SAS) is the application of constant positive airway pressure (CPAP) during sleep. Compliance is an essential element in the efficiency of CPAP. This is dependent on the quality of the management of care and on the education of the patients. With the emergence of telemedicine, telemonitoring of CPAP has been developed in France. METHODS: This study will be observational and multicentered. The main aim is to evaluate the feasibility of CPAP telemonitoring in SAS patients (n=90). During the installation of the equipment, the patients will be instructed how to connect the CPAP Secure Digital card to a data transmitting box every week for two months. The actual number and frequency of remote-monitoring box connections will be recorded. The data transmission will be made to the study coordinator, the home care provider SADIR, by the way of a telemedicine platform, located in France. EXPECTED RESULTS: This study will allow measurement of the adherence of the patients to their CPAP treatment by telemonitoring using this new tool of data transmission and the impact of this on CPAP compliance. PMID- 22240222 TI - [Drug-induced pneumonitis due to sirolimus: an interaction with atorvastatin?]. AB - INTRODUCTION: Sirolimus is an immunosupressant used in renal transplantation because of its lack of nephrotoxicity. We report four cases of pneumonitis due to sirolimus, possibly revealing an interaction with atorvastatin. CASE REPORT: Four patients (previously on long-term treatment with atorvastatin) presented with respiratory symptoms between 3 and 56 months after starting treatment with sirolimus following renal transplantation. Thoracic CT scans showed bilateral areas of peripheral alveolar consolidation. Bronchial lavage showed a lymphocytic alveolitis. Open-lung biopsy showed organizing pneumonia associated with diffuse alveolar damage and caseating granulomata. We attributed the pneumonitis to sirolimus on account of clinical and radiological resolution within 1 to 6 months of stopping treatment. We raise the possibility of an association between sirolimus and atorvastatin by competition for their hepatic degradation pathway via cytochrome P450 3A4. CONCLUSION: Sirolimus causes drug-induced pneumonitis that is predominantly an organizing pneumonia. Atorvastatin may encourage its development by competition with sirolimus in the liver. PMID- 22240223 TI - [Schwannoma of the vagus nerve: diagnostic strategy and therapeutic approach]. AB - INTRODUCTION: Scwhannomas are uncommon neurogenic tumors of the mediastinum. Most of them are located in the posterior mediastinum usually in the paralateral gutters. We report the case of an uncommon localisation of such a tumour appended to the right vagus nerve in the middle mediastinum. CASE REPORT: The patient was 50 years old and complained of thoracic pain, shortness of breath and dysphagia. CT scanning of thorax and abdomen revealed a heterogeneous mass in the middle mediastinum, which was not visible on plain radiography. Further investigation included transoesophageal ultrasound and PET scan. The diagnosis was confirmed by histopathology after mini video-assisted thoracotomy. The schwannoma was entirely removed without any post-surgical complications. CONCLUSION: We report a novel case of schwannoma arising from the vagus nerve and review the diagnostic strategies. PET scanning has poor sensitivity and specificity and does not therefore contribute to confirm the diagnosis which depends on exploring the mediastimun surgically. PMID- 22240224 TI - [Respiratory failure due to acid maltase deficiency]. AB - Acid maltase deficiency (AMD) is a metabolic myopathy which may be revealed at adulthood by respiratory muscle weakness, resulting in reduced vital capacity, alveolar hypoventilation and sleep apnoea. We observed two men, 39 and 42 years old respectively, suffering from asthenia and exertional dyspnoea for several months. After a stay in the intensive care unit, as a result of respiratory failure associated with pneumonia, these patients were referred to the respiratory medicine unit on account of persistent hypercapnia during the day and a fall in oxygen saturation at night. The investigations revealed proximal muscle weakness, a reduced vital capacity, alveolar hypoventilation (PaCO2: 67 and 49 mmHg), reduced maximum static inspiratory and expiratory pressures, carbon dioxide hyporesponsiveness and sleep apnoea on overnight polysomnography. Electromyography showed a myopathic pattern. Muscle biopsy confirmed the diagnosis of AMD. Non-invasive ventilation overnight partially corrected the clinical symptoms and the resting hypercapnia in both patients. The adulthood form of AMD is a rare disease that should be considered in a large number of clinical situations, particularly in unexplained respiratory failure. Our observations suggest that non invasive ventilation together with enzyme supplementation (Myozyme(r)) is effective in correcting alveolar hypoventilation. PMID- 22240225 TI - [Pulmonary aspergillosis complicating atypical mycobacterial infection in two patients suffering from chronic obstructive pulmonary disease]. AB - INTRODUCTION: Atypical mycobacteria and Aspergillus are opportunistic organisms responsible for severe pulmonary diseases whose development is encouraged by the presence of chronic obstructive pulmonary disease (COPD) and related immunosuppression. CASE REPORTS: We report the cases of two patients, both alcoholics with emphysematous COPD, who developed chronic pulmonary aspergillosis following atypical mycobacterial infection. Patient 1 developed chronic necrotising aspergillosis several months after the diagnosis of infection with Mycobacterium avium. Patient 2 developed an aspergilloma several weeks after the diagnosis of infection with Mycobacterium xenopi. The association of these two pathologies presents diagnostic and therapeutic problems that are discussed. CONCLUSION: The development of Aspergillus pulmonary disease may complicate atypical mycobacterial infections and explain a poor response to treatment. Our two case reports suggest that a systematic search should be made for pulmonary aspergillosis during the follow-up of patients with atypical mycobacterial infection. PMID- 22240226 TI - [Bronchiolo-alveolar carcinoma and lung transplantation]. AB - INTRODUCTION: Bronchiolo-alveolar carcinoma is a controversial indication for lung transplantation because of the risk of recurrence. We report three cases and propose some risk factors for recurrence. CASE REPORTS: Our study concerns three patients transplanted at the Louis-Pradel Hospital between 1991 and 2010. The first patient relapsed 86 months after transplantation, benefited from surgical treatment, then died of renal failure. A second patient died of infection, without recurrence, 72 months after transplantation. The third had an early recurrence at 7 months and died 27 months after transplantation. The risk factors for recurrence appear to be: clinically "aggressive" presentation and histological stromal pulmonary invasion by the carcinoma. CONCLUSION: Diffuse bronchiolo-alveolar carcinoma is a possible indication of lung transplantation. The risk of recurrence imposes some requirements: a precise histological diagnosis and a slow clinical course. PMID- 22240227 TI - [Pleural effusion in hereditary haemorrhagic telangiectasia: hemothorax or empyema?]. AB - INTRODUCTION: In hereditary hemorrhagic telangiectasia the pulmonary arteriovenous malformations frequently lead to complications. In a case of pleural effusion in a patient with known pulmonary arterio-venous malformations, the first diagnosis to consider is a hemothorax even though alternatives such as empyema are possible. CASE REPORT: We report the case of a 35-year-old woman with a known diagnosis of hereditary hemorrhagic telangiectasia with bilateral arteriovenous malformations, who was admitted to the emergency department with subacute dyspnoea and left thoracic pain. The clinical examination suggested a hemothorax. Pulmonary angiography was performed and showed an arteriovenous malformation in the left lower lobe. Embolisation was undertaken and at the same time a chest tube was inserted. Pus was evacuated leading to the final diagnosis of pleural empyema. Progress was good despite an episode acute respiratory distress due to a pulmonary embolism. CONCLUSION: Pleural empyema is rarely described in the context of hereditary hemorrhagic telangiectasia with pulmonary arteriovenous malformations. In the case of pleural effusion this diagnosis should be considered even though hemothorax is more common. PMID- 22240228 TI - [Unsuspected danger of a medicinal preparation]. AB - INTRODUCTION: Inhaled foreign bodies are commonly reported in childhood but less so among adults. We report the case of a patient who inhaled a medicinal preparation containing meprobamate and quinine sulfate. The consequence of this was caustic damage to the airways. CASE REPORT: A 64-year-old woman came to the emergency room because of dyspnea, oropharyngeal pain and sialorrhea. She reported that she had inhaled a capsule containing meprobamate and quinine sulfate the previous day. Flexible bronchoscopy showed evidence of caustic damage to the larynx and lower airways. The patient was treated by fasting, corticoids and intravenous broad-spectrum antibiotics. All the lesions recovered and she was discharged from the hospital 15 days after the event. CONCLUSIONS: Inhalation of drugs mostly leads to airway obstruction. Risk of harm is influenced by neurological status, the motility of the digestive system and the properties of the drug. To the best of our knowledge, this is the first time that caustic airway disease has been described following inhalation of a medicinal preparation containing meprobamate and quinine. It highlights the need to be familiar with the chemical properties of medications when prescribing them to patients who are at risk of aspiration. PMID- 22240229 TI - [Anaphylaxis due to chicken meat]. AB - Acute anaphylaxis due to chicken meat is very rare; only a few cases have been reported in the literature. We report the case of a 13-year-old girl, with a past history of allergic urticaria due to eggs, who presented immediately after ingestion of lightly grilled chicken meat with facial edema, dysphonia, acute dyspnoea and a feeling of suffocation. A few months later, the patient developed asthma in the vicinity of poultry and after contact with chicken feathers. PMID- 22240230 TI - Investigation of novel rapidly synergistic cloud point extraction pattern for bismuth in water and geological samples coupling with flame atomic absorption spectrometry determination. AB - Rapidly synergistic cloud point extraction (RS-CPE) greatly simplified and accelerated the procedure of traditional cloud point extraction (CPE). In order to expand the application of RS-CPE, this work was carried out after the establishment of the improved extraction technique. The new established extraction method was firstly applied for bismuth extraction and determination coupled with flame atomic absorption spectrometry (FAAS) in this work. The improved RS-CPE was accomplished in the room temperature in 1 min. Non-ionic surfactant Triton X-100 (TX-100) was used as extractant. Octanol worked as cloud point revulsant and synergic reagent. TX-100 has a relatively high cloud point temperature (CPT), which limited its application in CPE. In this work, TX-100 accomplished the RS-CPE procedure in room temperature successfully. The factors influencing RS-CPE, such as concentrations of reagents, pH, conditions of phase separation, effect of environmental temperatures, salt effect and instrumental conditions, were studied systematically. Under the optimal conditions, the limit of detection (LOD) for bismuth was 4.0 MUg L(-1), with sensitivity enhancement factor (EF) of 43. The proposed method greatly improved the sensitivity of FAAS for the determination of bismuth and was applied to the determination of trace bismuth in real and certified samples with satisfactory analytical results. The proposed method was rapid, simple, and sensitive. PMID- 22240231 TI - The FTIR studies of gels and thin films of Al2O3-TiO2 and Al2O3-TiO2-SiO2 systems. AB - In this work, samples in form of bulk ones and thin films were obtained using the sol-gel method. The bulk samples were heated at different temperatures (500 degrees C, 850 degrees C and 1100 degrees C) corresponding to the annealing process of coatings, deposited on different substrates by dipping and pulling out samples from the proper sol with the stable speed. Thin films of both Al2O3-TiO2 and Al2O3-TiO2-SiO2 systems were deposited on carbon, steel and titanium substrates in two different ways: as single layers obtained from Al2O3 sol, TiO2 sol and Al2O3 sol or deposited as mixed coatings from Al2O3-TiO2 sol as well as Al2O3-TiO2-SiO2 one. All bulk samples were studied by the FTIR spectroscopy and the X-ray diffractometry while thin films were also investigated by the electron microscopy. In the IR spectra of Al2O3-TiO2 samples, as well as gels and coatings, bands due to the vibrations of AlO bonds of the octahedrally and tetrahedrally coordinated aluminum were observed. The IR spectra of samples of Al2O3-TiO2-SiO2 system differ from that of Al2O3-TiO2 ones in presence of bands assigned to the SiO bond vibrations and in positions of bands due to AlO bond vibrations. In all spectra of bulk samples and coatings, the positions of TiO bond vibrations were ascribed basing on the IR spectra of the pure anatase and rutile. PMID- 22240232 TI - Discrimination of raw and processed Dipsacus asperoides by near infrared spectroscopy combined with least squares-support vector machine and random forests. AB - Most herbal medicines could be processed to fulfill the different requirements of therapy. The purpose of this study was to discriminate between raw and processed Dipsacus asperoides, a common traditional Chinese medicine, based on their near infrared (NIR) spectra. Least squares-support vector machine (LS-SVM) and random forests (RF) were employed for full-spectrum classification. Three types of kernels, including linear kernel, polynomial kernel and radial basis function kernel (RBF), were checked for optimization of LS-SVM model. For comparison, a linear discriminant analysis (LDA) model was performed for classification, and the successive projections algorithm (SPA) was executed prior to building an LDA model to choose an appropriate subset of wavelengths. The three methods were applied to a dataset containing 40 raw herbs and 40 corresponding processed herbs. We ran 50 runs of 10-fold cross validation to evaluate the model's efficiency. The performance of the LS-SVM with RBF kernel (RBF LS-SVM) was better than the other two kernels. The RF, RBF LS-SVM and SPA-LDA successfully classified all test samples. The mean error rates for the 50 runs of 10-fold cross validation were 1.35% for RBF LS-SVM, 2.87% for RF, and 2.50% for SPA-LDA. The best classification results were obtained by using LS-SVM with RBF kernel, while RF was fast in the training and making predictions. PMID- 22240233 TI - N-(4-nitrobenzoyl)-N'-(1,5-dimethyl-3-oxo-2-phenyl-1H-3(2H)-pyrazolyl)-thiourea hydrate: synthesis, spectroscopic characterization, X-ray structure and DFT studies. AB - The title molecule (C19H17N5O4S.H2O) was synthesized and characterized by IR-NMR spectroscopy, MS and single-crystal X-ray diffraction. The molecular geometry, vibrational frequencies and gauge-independent atomic orbital (GIAO) 1H and 13C NMR chemical shift values of the compound in the ground state have been calculated by using the density functional theory (DFT) method with 6-31G(d) basis set, and compared with the experimental data. All the assignments of the theoretical frequencies were performed by potential energy distributions using VEDA 4 program. The calculated results show that the optimized geometries can well reproduce the crystal structural parameters, and the theoretical vibrational frequencies and 1H and 13C NMR chemical shift values show good agreement with experimental data. To determine conformational flexibility, the molecular energy profile of the title compound was obtained with respect to the selected torsion angle, which was varied from -180 degrees to +180 degrees in steps of 10 degrees . Besides, molecular electrostatic potential (MEP), frontier molecular orbitals (FMO) analysis and thermodynamic properties of the compound were investigated by theoretical calculations. PMID- 22240234 TI - SSRIs and persistent pulmonary hypertension of the newborn. PMID- 22240235 TI - Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. AB - OBJECTIVE: To assess whether maternal use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary hypertension in the newborn, and whether such an effect might differ between specific SSRIs. DESIGN: Population based cohort study using data from the national health registers. SETTING: Denmark, Finland, Iceland, Norway, and Sweden, 1996-2007. PARTICIPANTS: More than 1.6 million infants born after gestational week 33. MAIN OUTCOME MEASURES: Risks of persistent pulmonary hypertension of the newborn associated with early and late exposure to SSRIs during pregnancy and adjusted for important maternal and pregnancy characteristics. Comparisons were made between infants exposed and not exposed to SSRIs. RESULTS: Around 30 000 women had used SSRIs during pregnancy and 11 014 had been dispensed an SSRI later than gestational week 20. Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11 014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% confidence interval 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: adjusted odds ratio 1.4 (95% confidence interval 1.0 to 2.0). CONCLUSIONS: The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold. The increased risk seems to be a class effect. PMID- 22240236 TI - Is the female G-spot truly a distinct anatomic entity? AB - INTRODUCTION: The existence of an anatomically distinct female G-spot is controversial. Reports in the public media would lead one to believe the G-spot is a well-characterized entity capable of providing extreme sexual stimulation, yet this is far from the truth. AIM: The aim of this article was to provide an overview of the evidence both supporting and refuting the existence of an anatomically distinct female G-spot. METHODS: PubMed search for articles published between 1950 and 2011 using key words "G-spot," "Grafenberg spot," "vaginal innervation," "female orgasm," "female erogenous zone," and "female ejaculation." Clinical trials, meeting abstracts, case reports, and review articles that were written in English and published in a peer-reviewed journal were selected for analysis. MAIN OUTCOME MEASURE: The main outcome measure of this article was to assess any valid objective data in the literature that scientifically evaluates the existence of an anatomically distinct G-spot. RESULTS: The literature cites dozens of trials that have attempted to confirm the existence of a G-spot using surveys, pathologic specimens, various imaging modalities, and biochemical markers. The surveys found that a majority of women believe a G-spot actually exists, although not all of the women who believed in it were able to locate it. Attempts to characterize vaginal innervation have shown some differences in nerve distribution across the vagina, although the findings have not proven to be universally reproducible. Furthermore, radiographic studies have been unable to demonstrate a unique entity, other than the clitoris, whose direct stimulation leads to vaginal orgasm. CONCLUSIONS: Objective measures have failed to provide strong and consistent evidence for the existence of an anatomical site that could be related to the famed G-spot. However, reliable reports and anecdotal testimonials of the existence of a highly sensitive area in the distal anterior vaginal wall raise the question of whether enough investigative modalities have been implemented in the search of the G spot. PMID- 22240237 TI - Exceptional lexical skills but executive language deficits in school starters and young adults with Turners syndrome: implications for X chromosome effects on brain function. AB - TS school starters had enhanced receptive and expressive language on standardised assessment (CELF-P) and enhanced rhyme judgements, spoonerisms, and lexical decision, indicating enhanced phonological skills and word representations. There was marginal but consistent advantage across lexico-semantic tasks. On executive tasks, speeded naming of numbers was impaired but not pictures. Young TS adults had enhanced naming and receptive vocabulary, indicating enhanced semantic skills. There were consistent deficits in executive language: phonemic oral fluency, rhyme fluency, speeded naming of pictures, numbers and colours; sentence completion requiring supression of prepotent responses. Haploinsufficiency of X chromosome drives mechanisms that affect the anatomical and neurochemical development of the brain, resulting in enhanced temporal lobe aspects of language. These strengths co-exist with impaired development of frontal lobe executive language systems. This means not only that these elements of language can decouple in development but that their very independence is driven by mechanisms linked to the X-chromosome. PMID- 22240238 TI - Control of Giardia infections with ronidazole and intensive hygiene management in a dog kennel. AB - Infections with the intestinal protozoan parasite Giardia in dogs and cats are common. Clinical signs vary from asymptomatic to small bowel diarrhea and associated discomfort. The control of infections in dogs is frequently a frustrating issue for animal owners and veterinarians. Drugs with antiprotozoal activity such as fenbendazole and metronidazole are recommended, however, they do not show 100% efficacy and superinfections occur regularly. Ronidazole is currently the drug of choice for the treatment of Tritrichomonas foetus in cats and there is now limited information available about its efficacy against Giardia spp. In the kennel investigated, dogs regularly showed loose feces and the presence of Giardia (assemblage C, renamed as G. canis) cysts. An elimination strategy of this parasite involving strict hygiene management and disinfection of the enclosures with 4-chlorine-M-cresol, oral treatment with ronidazole (30 50mg/kg BW bid for 7 days) and two shampooings (containing chlorhexidine) at the beginning and the end of the treatments was implemented for a group of 6 dogs. As a control another group of 7 dogs was transferred to the disinfected enclosures and shampooed, but left untreated. Dog feces were tested for the presence of Giardia cysts (SAF concentration technique) or Giardia antigen with a commercial ELISA (NOVITEC((r))) and a quick immunochromatography-based test (SensPERT((r))) before and between 5 and 40 days after the last treatment. All ronidazole-treated dogs were negative for Giardia cysts and antigen up to 26 days after the last treatment, while between 1 and 5 of the control animals tested positive in each of the test series. At this point, also dogs of the control group were again moved into clean enclosures, shampooed twice and treated with ronidazole. Five, 12 and 19 days after the last treatment, the dogs in the control group tested negative for Giardia cysts and antigen. However, all animals had again positive results at later time points in at least one of the three applied diagnostic techniques within 33-61 days after treatment. Furthermore, all dogs had episodes of diarrhea (for 1-4 days) within 14-31 days after treatment and unformed feces during the whole experiment. The positive effect of ronidazole against Giardia infections in dogs could be confirmed in this study. In particular, the combination of ronidazole treatment combined with the disinfection of the environment and shampooing of the dogs was highly effective in reducing Giardia cyst excretion and may therefore constitute an alternative control strategy for canine giardiosis. PMID- 22240239 TI - [Daily interruption of sedation: always a quality indicator?]. AB - The Spanish Society of Critical Care Medicine (SEMICYUC) has recently published an updated version of Quality Indicators in Critical Care. Daily sedative interruption is included among them. As this practice is controversial, research studies are revised and guidelines for its implementation are proposed. PMID- 22240240 TI - GluN3 subunit-containing NMDA receptors: not just one-trick ponies. AB - The two GluN3 subunits were the last NMDA receptor subunits to be cloned some 15 years ago. Strikingly, despite the steadily growing interest in their function, their physiological role remains elusive. The original billing as dominant negative modulators of classical NMDA receptors composed of GluN1 and GluN2 subunits has given way to proposals of much more complex functions, including roles in synaptogenesis and synaptic plasticity. In addition, GluN3 subunits in the absence of GluN2 surprisingly assemble with GluN1 into excitatory glycine receptors. This review provides an overview of the unique spatial and temporal expression patterns of the GluN3 subunits, discusses proposed functions and physiological roles for receptors comprising these subunits, and briefly summarizes their putative involvement in several neural diseases. PMID- 22240241 TI - Molecular pathogenesis of granulosa cell tumors of the ovary. AB - Granulosa cell tumors of the ovary (GCT) comprise a distinct subset of ovarian cancers that account for approximately 5% of all ovarian malignancies. They are thought to arise from normal proliferating granulosa cells of the late preovulatory follicle and exhibit many morphological and biochemical features of these cells. GCT are distinct from other ovarian carcinomas in their hormonal activity; their ability to secrete estrogen, inhibin, and Mullerian inhibiting substance accounts for some of the clinical manifestations of the disease and also provides useful tumor markers for disease surveillance. Although considered to be of low malignant potential, GCT are commonly associated with slow, indolent disease progression, and frequent yet long delays to tumor recurrence are characteristic of this disease. Unlike the more intensely investigated epithelial ovarian tumors, relatively little is known about the molecular and genetic changes that give rise to GCT. To date, many investigations have centered around pathways known to be involved in normal granulosa cell proliferation, including those activated by FSH receptor stimulation. Most recently, the finding that approximately 97% of adult GCT harbor a somatic missense mutation in the FOXL2 gene (c.402C->G; p.C134W) represents an exciting advancement in the field of GCT research. The high frequency with which the mutation occurs in adult GCT, along with its absence from juvenile GCT and other human malignancies is suggestive of an oncogenic or gain-of-function mutation and, indeed, that the mutation is pathognomonic for adult GCT. In this review, we explore the implications of this finding and the most recent work characterizing molecular pathways of potential pathogenetic significance in GCT. PMID- 22240243 TI - Childhood obesity in developing countries: epidemiology, determinants, and prevention. AB - Rapidly changing dietary practices and a sedentary lifestyle have led to increasing prevalence of childhood obesity (5-19 yr) in developing countries recently: 41.8% in Mexico, 22.1% in Brazil, 22.0% in India, and 19.3% in Argentina. Moreover, secular trends indicate increasing prevalence rates in these countries: 4.1 to 13.9% in Brazil during 1974-1997, 12.2 to 15.6% in Thailand during 1991-1993, and 9.8 to 11.7% in India during 2006-2009. Important determinants of childhood obesity include high socioeconomic status, residence in metropolitan cities, female gender, unawareness and false beliefs about nutrition, marketing by transnational food companies, increasing academic stress, and poor facilities for physical activity. Childhood obesity has been associated with type 2 diabetes mellitus, the early-onset metabolic syndrome, subclinical inflammation, dyslipidemia, coronary artery diseases, and adulthood obesity. Therapeutic lifestyle changes and maintenance of regular physical activity through parental initiative and social support interventions are the most important strategies in managing childhood obesity. Also, high-risk screening and effective health educational programs are urgently needed in developing countries. PMID- 22240245 TI - The reinnervation pattern of wounds and scars after treatment with transforming growth factor beta isoforms. AB - BACKGROUND: Wounds deprived of innervation fail to heal normally, and hypertrophic scars may be abnormally innervated. Manipulation of wounds alters the subsequent degree of scarring, and isoforms of transforming growth factor beta (TGFbeta) are well established in this role, whilst TGFbeta3 is undergoing clinical trials as an antiscarring agent for clinical use. It is unclear if treated wounds show changes in their innervation patterns as they mature into scars. METHODS: Mice underwent 1cm(2) full thickness skin excisions which were treated with TGFbeta1 or TGFbeta3. Wounds were harvested between 5 and 84 days (n=6 at each time point). Sections underwent histological scar assessment and immunohistochemical staining for protein gene product 9.5 (PGP9.5), a pan neuronal marker, and the sensory neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP). RESULTS: There was no difference in the reinnervation pattern between the peripheral and central parts of the wounds. Wounds treated with TGFbeta3 healed with dermal collagen organised more like normal skin, whereas TGFbeta1 treated wounds had abnormally orientated collagen within the scar compared to control treated wounds. Nerve fibre growth into the wounds followed a similar pattern in control and treated wounds, with only one significant difference during the healing process- at 42 days, the density of nerve fibres immunostained with PGP9.5 within the scar was greater than in control wounds. By 84 days, the density of PGP9.5, CGRP and SP immunopositive fibres were similar in control wounds and those treated with TGFbeta isoforms. CONCLUSIONS: Changes in reinnervation patterns of wounds treated with TGFbeta isoforms were only slightly different from those of control wounds, and by 84 days, the patterns were similar. PMID- 22240246 TI - Securing fingertip dressings: the new 'cinch pink' technique. PMID- 22240247 TI - Proximal-type epithelioid sarcoma: case report of an unusual presentation. AB - Epithelioid sarcoma, first described by Enzinger in 1970, classically presents in young adults and usually arises in the distal extremities. The proximal-type variant, first described in 1997 as a rare aggressive form of sarcoma, usually arises more proximally. It carries a higher mortality rate than classical limb epithelioid sarcoma and is often resistant to multimodal treatment. We report the case of a 27-year old male who had a delayed diagnosis of proximal-type epithelioid sarcoma of the forearm. This was originally thought to be a necrotising soft tissue infection and was unfortunately metastatic at the time of eventual diagnosis. The clinical and histopathological features of this challenging tumour are discussed and the relevant literature is reviewed. PMID- 22240248 TI - Blood puncture as a nondestructive sampling tool to obtain DNA in frogs: comparison of protocols and survival analysis. AB - In molecular biology studies of Anura, nondestructive methods to obtain genetic material are needed as alternatives to toe clipping. This work evaluates a nondestructive method for sampling DNA from blood puncture, comparing the performance of three different extraction protocols (Qiagen Kit, Salting-out and Chelex). We collected 134 individuals of Eleutherodactylus johnstonei, extracting blood via puncture of the medial vein using commercial-grade glucometer lancets. We extracted 100-1880 ng DNA, finding no differences between the extraction protocols. We compared the quality of the resulting DNA through amplification and sequencing of the 16S mitochondrial gene. Amplification was successful for the three extraction protocols, although Chelex showed better performance, making it the most recommendable protocol for extraction of DNA from blood. The resulting sequences corresponded to those registered in the GenBank for this species. Additionally, we found no significant differences in survival or weight change between the individuals that were manipulated and a control group (mean survival 66.7% treated, 62.9% untreated). Data reveal that blood samples obtained by puncture are a convenient alternative to other tissues (phalange, buccal swab, liver) that have traditionally been used as DNA sources for anurans. The technique is applicable to small and large species, covering most anuran diversity, provides enough DNA for many genetic applications and produces no noticeable effect on the survival or performance, given that it does not affect the motor parts or the dexterity of the animals. PMID- 22240249 TI - Cancer immunotherapy: are we there yet? PMID- 22240242 TI - Emerging role of mast cells and macrophages in cardiovascular and metabolic diseases. AB - Mast cells are essential in allergic immune responses. Recent discoveries have revealed their direct participation in cardiovascular diseases and metabolic disorders. Although more sophisticated mechanisms are still unknown, data from animal studies suggest that mast cells act similarly to macrophages and other inflammatory cells and contribute to human diseases through cell-cell interactions and the release of proinflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. Reduced cardiovascular complications and improved metabolic symptoms in animals receiving over-the-counter antiallergy medications that stabilize mast cells open another era of mast cell biology and bring new hope to human patients suffering from these conditions. PMID- 22240250 TI - Atropine-sensitive hippocampal theta oscillations are mediated by Cav2.3 R-type Ca2+ channels. AB - Hippocampal theta oscillations are key elements in numerous behavioral and cognitive processes. Based on the dualistic theory of theta oscillations, one can differentiate between atropine-sensitive and atropine-insensitive theta subtypes. Urethane-induced atropine-sensitive theta oscillations are driven by muscarinic signal transduction pathways through G protein q/11 alpha subunit (Galpha(q/11)), phospholipase beta( 1/4) (PLCbeta( 1/4), inositol trisphosphate (InsP3), diacylglycerole (DAG), and protein kinase C (PKC). Recent findings illustrate that Ca(v)2.3 Ca2+ channels are important targets of muscarinic signaling in the hippocampus mediating plateau potential generation, epileptiform burst activity, and complex rhythm generation in the septohippocampal network. To investigate the physiological implications of Ca(v)2.3 Ca2+ channels in hippocampal theta oscillations we performed radiotelemetric intrahippocampal (cornu ammonis (CA1)) recordings in urethane (800 mg/kg, i.p.) and atropine (50 mg/kg, i.p.) treated Ca(v)2.3+/+ and Ca(v)2.3-/- mice followed by wavelet analysis of EEG data. Our results demonstrate that Ca(v)2.3 ablation, unlike PLCbeta1 deletion, does not result in complete abolishment of urethane-induced theta oscillations and that both mean and total theta duration is not significantly inhibited by subsequent atropine treatment, indicating that Ca(v)2.3 Ca2+ channels are important mediators of atropine-sensitive theta. Although theta frequency remained unchanged between both genotypes, the temporal characteristics of theta distribution, that is, theta architecture were significantly affected by the loss of Ca(v)2.3 Ca2+ channels. Our data suggest, for the first time, that Ca(v)2.3 voltage-gated Ca2+ channels (VGCC) are an important factor in septohippocampal synchronization associated with theta oscillation. PMID- 22240252 TI - Sex-specific changes in gene expression and behavior induced by chronic Toxoplasma infection in mice. AB - There is growing evidence that Toxoplasma gondii modifies the behavior of its intermediate hosts. We investigated the molecular basis of these infection induced behavioral changes, followed by five related behavioral tests to assess the extent of biological relevance. Gene expression signatures were generated in the frontal cortex of male and female mice during the latent stage of infection. We found marked sex-dependent expression differences in mice. In female mice, Toxoplasma infection altered the expression of genes involved in the development of the forebrain, neurogenesis, and sensory and motor coordination (i.e. downregulation of fatty acid-binding protein 7 and eyes absent homolog 1, upregulation of semaphorin 7A). In male mice, infection led mainly to modulation of genes associated with olfactory function (i.e. downregulation of a number of olfactory receptors and dopamine receptor D4, upregulation of slit homolog 1). Although infection appears to affect the olfactory function in male mice, it is the female but not male mice that exhibited attraction to cat odor. In contrast, infected male mice showed a deficit in social transmission of food preference. In contrast to males, infected females displayed locomotor hyperactivity in open field. General olfaction and sensorimotor gating were normal in both male and female infection. Our results indicate that the sex of the host plays a major role in determining variable brain and behavior changes following Toxoplasma infection. These observations are consistent with heterogeneity of neuropsychiatric outcomes of the infection in humans. PMID- 22240251 TI - Reduced expression of the MU opioid receptor in some, but not all, brain regions in mice with OPRM1 A112G. AB - OPRM1 A118G is a common single nucleotide polymorphism (SNP) in the coding region of the human mu opioid receptor (MOPR) gene OPRM1. This SNP is associated with higher morphine doses required for postoperative analgesia as well as a variety of drug addiction phenotypes. A mouse model possessing the equivalent substitution (A112G) in the Oprm1 gene was generated to facilitate mechanistic studies. Mice homozygous for the G112 allele (G/G) displayed lower antinociception to morphine compared with those homozygous for A112 allele (A/A), similar to humans, suggesting that the mice are a good model to further characterize underlying factors contributing to phenotypes associated with this SNP. Here, we compared [3H]DAMGO binding to the MOPR in the brains of A/A and G/G mice using quantitative in vitro autoradiography. A/A mice exhibited higher [3H]DAMGO binding than G/G in the cingulate, motor, and insular cortices, nucleus accumbens core and shell, hypothalamus, thalamus, amygdala, periaqueductal gray, superficial gray of superior colliculus, and ventral tegmental area. No genotype differences were observed in somatosensory cortex, caudate putamen, and hippocampus. When males and females were examined separately, A/A mice showed higher [3H]DAMGO binding than G/G mice in more brain regions in males than in females. Radioligand binding using brain membranes also showed higher [3H]DAMGO binding in the cortex and thalamus in A/A mice than G/G mice but no genotype differences in the caudate putamen or hippocampus. Thus, the A112G SNP is associated with reduced MOPR expression in some, but not all, brain regions, and appears to have some sex differences. The elevated MOPR expression in periaqueductal gray and thalamus in A/A mice are consistent with their higher antinociceptive responses to morphine. The higher MOPR levels in nucleus accumbens and/or ventral tegmental area of A/A mice is consistent with the higher morphine-induced hyperactivity and locomotor sensitization observed in these mice. Thus, these results provide some insights into the observed decreased clinical opioid potency in humans with the A118G SNP. PMID- 22240253 TI - Association of erectile dysfunction with atopic dermatitis: a population-based case-control study. AB - INTRODUCTION: Some studies have highlighted the high prevalence of erectile dysfunction (ED) in patients with dermatological diseases such as psoriasis, chronic hand eczema, and systemic sclerosis. However, to date, there is still no study that has explored the relationship between ED and atopic dermatitis (AD). AIM: Using a population-based data set, this case-control study aimed to examine the association of ED with prior AD by comparing the risk of prior AD between patients with ED and matched controls in Taiwan. METHODS: This study used administrative claims data from the Taiwan National Health Insurance program. We identified 3,997 patients with newly diagnosed ED as cases and randomly selected 19,985 subjects without a history of ED as controls. Conditional logistic regression was used to calculate the odds ratio (OR) and corresponding 95% confidence interval (CI) for previously diagnosed AD between cases and controls. MAIN OUTCOME MEASURE: The prevalence and risk of having been previously diagnosed with AD between cases and controls were calculated. RESULTS: Of the 23,982 sampled subjects, 1,758 (7.3%) had been previously diagnosed with AD; it was found among 425 (10.6%) cases and among 1,333 (6.7%) controls (P<0.001). Conditional logistic regression analysis demonstrated that cases were more likely to have prior AD than controls (OR=1.60, 95% CI=1.42-1.80, P<0.001) after adjusting for monthly income, geographic location, urbanization level, hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, and alcohol abuse/alcohol dependence syndrome. CONCLUSIONS: There was an association between ED and prior AD. We suggest that clinicians should be more attentive to sexual complaints from patients with AD. PMID- 22240254 TI - A psychometric appraisal of the DREEM. AB - BACKGROUND: The quality of the Educational environment is a key determinant of a student centred curriculum. Evaluation of the educational environment is an important component of programme appraisal. In order to conduct such evaluation use of a comprehensive, valid and reliable instrument is essential. One of most widely used contemporary tools for evaluation of the learning environment is the Dundee Ready Education Environment Measure (DREEM). Apart from the initial psychometric evaluation of the DREEM, few published studies report its psychometric properties in detail. The aim of this study was to examine the psychometric quality of the DREEM measure in the context of medical education in Ireland and to explore the construct validity of the device. METHODS: 239 final year medical students were asked to complete the DREEM inventory. Anonymised responses were entered into a database. Data analysis was performed using PASW 18 and confirmatory factor analysis performed. RESULTS: Whilst the total DREEM score had an acceptable level of internal consistency (alpha 0.89), subscale analysis shows that two subscales had sub-optimal internal consistency. Multiple group confirmatory factor analysis (using Fleming's indices) shows an overall fit of 0.76, representing a weak but acceptable level of fit. 17 of the 50 items manifest fit indices less than 0.70. We sought the best fitting oblique solution to the 5-subscale structure, which showed large correlations, suggesting that the independence of the separate scales is open to question. CONCLUSIONS: There has perhaps been an inadequate focus on establishing and maintaining the psychometric credentials of the DREEM. The present study highlights two concerns. Firstly, the internal consistency of the 5 scales is quite variable and, in our sample, appears rather low. Secondly, the construct validity is not well supported. We suggest that users of the DREEM will provide basic psychometric appraisal of the device in future published reports. PMID- 22240244 TI - Sex differences and sex steroids in lung health and disease. AB - Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span. PMID- 22240255 TI - Knockdown of menin affects pre-mRNA processing and promoter fidelity at the interferon-gamma inducible IRF1 gene. AB - BACKGROUND: The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. As an activator, MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-gamma signaling. RESULTS: RNAi-mediated knockdown of MEN1 alters the H3K4 dimethylation and H3 acetylation profiles, and the localization of histone deacetylase 3, at IRF1. While MEN1 knockdown does not impact the rate of transcription, IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells. The processed mRNA and translated protein product are concomitantly reduced, and the antiviral state is attenuated. Additionally, the transcription start site at the IRF1 promoter is disrupted in the MEN1-depleted cells. The H3K4 demethylase, lysine specific demethylase 1, is also associated with IRF1, and its inhibition alters H3K4 methylation and disrupts the transcription start site as well. CONCLUSIONS: Taken together, the data indicate that MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing. PMID- 22240256 TI - Relationships of PBMC microRNA expression, plasma viral load, and CD4+ T-cell count in HIV-1-infected elite suppressors and viremic patients. AB - BACKGROUND: HIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy. The mechanisms of suppression are incompletely understood. Modulation of HIV-1 replication by miRNAs has been reported, but the role of small RNAs in ES is unknown. Using samples from a well-characterized ES cohort, untreated viremic patients, and uninfected controls, we explored the PBMC miRNA profile and probed the relationships of miRNA expression, CD4+ T-cell counts, and viral load. RESULTS: miRNA profiles, obtained using multiple acquisition, data processing, and analysis methods, distinguished ES and uninfected controls from viremic HIV-1 infected patients. For several miRNAs, however, ES and viremic patients shared similar expression patterns. Differentially expressed miRNAs included those with reported roles in HIV-1 latency (miR-29 family members, miRs -125b and -150). Others, such as miR-31 and miR-31*, had no previously reported connection with HIV-1 infection but were found here to differ significantly with uncontrolled HIV 1 replication. Correlations of miRNA expression with CD4+ T-cell count and viral load were found, and we observed that ES with low CD4+ T-cell counts had miRNA profiles more closely related to viremic patients than controls. However, expression patterns indicate that miRNA variability cannot be explained solely by CD4+ T-cell variation. CONCLUSIONS: The intimate involvement of miRNAs in disease processes is underscored by connections of miRNA expression with the HIV disease clinical parameters of CD4 count and plasma viral load. However, miRNA profile changes are not explained completely by these variables. Significant declines of miRs-125b and -150, among others, in both ES and viremic patients indicate the persistence of host miRNA responses or ongoing effects of infection despite viral suppression by ES. We found no negative correlations with viral load in viremic patients, not even those that have been reported to silence HIV-1 in vitro, suggesting that the effects of these miRNAs are exerted in a focused, cell-type specific manner. Finally, the observation that some ES with low CD4 counts were consistently related to viremic patients suggests that miRNAs may serve as biomarkers for risk of disease progression even in the presence of viral suppression. PMID- 22240258 TI - Role of engineered nanocarriers for axon regeneration and guidance: current status and future trends. AB - There are approximately 1.5 million people who experience traumatic injuries to the brain and 265,000 who experience traumatic injuries to the spinal cord each year in the United States. Currently, there are few effective treatments for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. Smart, remotely tunable, multifunctional micro- and nanocarriers hold promise for delivering treatments to the CNS and targeting specific neurons to enhance axon regeneration and synaptogenesis. Furthermore, assessing the efficacy of treatments could be enhanced by biocompatible nanovectors designed for imaging in vivo. Recent developments in nanoengineering offer promising alternatives for designing biocompatible micro- and nanovectors, including magnetic nanostructures, carbon nanotubes, and quantum dot-based systems for controlled release of therapeutic and diagnostic agents to targeted CNS cells. This review highlights recent achievements in the development of smart nanostructures to overcome the existing challenges for treating CNS injuries. PMID- 22240260 TI - To our dear friend, Dick Rothman. PMID- 22240261 TI - About the 53rd meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO). PMID- 22240259 TI - MiR-200a is involved in rat epididymal development by targeting beta-catenin mRNA. AB - The expression of 350 microRNAs (miRNAs) in epididymis of rat from postnatal development to adult (from postnatal days 7-70) was profiled with home-made miRNA microarray. Among them, 48 miRNAs changed significantly, in which the expression of miR-200a increased obviously with time, in a good agreement with that obtained from northern blot analysis. The real-time quantitative-polymerase chain reaction result indicated that temporal expression of rat beta-catenin was exactly inversed to that of miR-200a during rat epididymal development, implying that miR 200a might also target beta-catenin mRNA in rat epididymis as reported by Saydam et al. in humans. The bioinformatic analysis indicated that 3' untranslated region of rat beta-catenin mRNA did contain a putative binding site for miR-200a. Meanwhile, it was found that the sequence of this binding site was different from that of human beta-catenin mRNA with a deletion of two adjacent nucleotides (U and C). But the results of luciferase targeting assay in HEK 293T cells and the overexpression of miR-200a in rat NRK cells demonstrated that miR-200a did target rat beta-catenin mRNA and cause the suppression of its expression. All these results show that miR-200a should be involved in rat epididymal development by targeting beta-catenin mRNA of rat and suppressing its expression. PMID- 22240262 TI - Post-translational oxidative modification of beta2-glycoprotein I and its role in the pathophysiology of the antiphospholipid syndrome. AB - Vascular thrombosis and/or recurrent miscarriages are the main characteristics defining Antiphospholipid Syndrome (APS). Currently there is no well-defined clinical features and/or laboratory tests that predicts the risk of adverse prognostic outcomes in APS. In this short review, we report the importance of posttranslational modification of beta2 glycoprotein I, the major autoantigen in the APS beta2 glycoprotein I that may, in part, explain possible mechanisms for the generation of auto antibodies to beta2 glycoprotein I. A specific ELISA measuring the level of oxidised beta2 glycoprotein I could be used as a potential new laboratory test - along with other laboratory tests - to more accurately predict the risk of having a clinical event in patients with APS. PMID- 22240263 TI - Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study. AB - OBJECTIVE: The objective was to examine the effects of colestimide on blood glucose, visceral fat, adipocytokines, and bile acid conjugate fractions in Japanese patients. METHODS: This study was an open-label, randomized, case control, crossover study of colestimide 3 g/day in 40 Japanese patients with type 2 diabetes mellitus (T2D) and hypercholesterolemia. Patients were assigned to the colestimide group in which pravastatin and colestimide were administered orally and to the statin group in which pravastatin alone was administered orally. The principal outcome measures were serum lipid levels, fasting plasma glucose level in the early morning, hemoglobin A1c (HbA(1c)), visceral fat area (VFA), and serum 1,5-anhydroglucitol (1,5-AG) level. RESULTS: Serum low-density lipoprotein cholesterol levels significantly decreased from 113+/-38 mg/dl at baseline to 90+/-20 mg/dl (P=.009) at week 12 of colestimide administration. HbA(1c) significantly decreased from 7.4%+/-0.9% at baseline to 6.9%+/-0.9% (P=.001) at week 12 of colestimide administration. Serum 1,5-AG levels increased from 9.4+/ 10.1 MUg/ml to 12.4+/-9.5 MUg/ml (P=.05) at week 12 of colestimide administration. The statin group showed no significant changes in lipids and 1,5 AG. However, DeltaVFA was inversely correlated with Deltacholic acid, and multivariate analysis revealed that DeltaVFA was a significant explanatory variable. CONCLUSIONS: Colestimide holds promise not only for the treatment of hypercholesterolemia but also for the possible improvement of T2D and visceral fat obesity. PMID- 22240265 TI - Risk and protective factors associated with gang affiliation among high-risk youth: a public health approach. AB - BACKGROUND: Gang violence accounted for 20% of homicides in large cities from 2002 to 2006. Preventing gang affiliation (ie, youth who either desire or have gang membership) might reduce subsequent gang activity. Previous research has focused on identifying risk factors for gang affiliation; however, little information is available on protective factors. AIM: To identify risk and protective factors to provide more direction for gang violence prevention strategies. METHODS: The author analysed cross-sectional survey data from 4131 youths in grades 7, 9, 11 and 12. Data were collected in 2004 from students in a high-risk, urban public school district. Regression analyses were conducted to assess the association between gang affiliation and alcohol and drug use, delinquency, depressed mood, suicidal ideation, peer victimisation, parental monitoring and positive reinforcement, adult, family and peer support, coping skills, and school connectedness. Analyses were controlled for sex, race/ethnicity and age. RESULTS: An estimated 7% of youths were gang affiliated. Adjusting for all factors, gang affiliation was positively associated with engaging in any delinquent behaviours (prevalence OR: 2.07; 95% CI 1.18 to 3.64), frequent alcohol use (OR: 2.62; 95% CI 1.85 to 3.72) and frequent drug use (OR: 1.95; 95% CI 1.15 to 3.29). Gang affiliation was negatively associated with moderate levels of parental monitoring (OR: 0.67; 95% CI 0.54 to 0.85) and coping skills (OR: 0.54; 95% CI 0.42 to 0.71). CONCLUSIONS: The findings suggest the potential benefit of increasing parental monitoring and coping skills and reducing delinquency, alcohol use and drug use to prevent gang affiliation. PMID- 22240264 TI - Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia. AB - AIM: The aim was to evaluate the therapeutic effectiveness of granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood mononuclear cells (PBMNCs) in critical limb ischemia (CLI) of type 2 diabetic patients. METHOD: Forty diabetic patients with CLI were enrolled and randomized to treatment and control groups. In the treatment group, the patients received subcutaneous injections of recombinant human G-CSF (30 MU/day) for 5 days to mobilize stem cells. PBMNCs were collected and transplanted by multiple intramuscular injections of 1 ml in 1 1.5-cm depth into ischemic limbs. RESULTS: At the end of 12 weeks of follow-up, the baseline and end point results in transplant group were as follows: Fontaine score improved from 3.8+/-03 to 3+/-0.5 (P=.0001), ankle brachial pressure index increased from 0.68+/-0.24 to 0.87+/-024 (P=.001), transcutaneous oxygen increased from 33+/-14 mmHg to 44+/-10 mmHg (P=.0001), and 6-min walking distance improved from 280+/-82 m to 338+/-98 m (P=.0001). Pain score decreased from 8.2+/ 1.3 to 5.63+/-1.6 (P=.001), and the number of patients with limb ulcers was reduced from 9/20 (45%) to 3/20 (15%) (P=.031). In the control group, Fontaine score, 6-min walking distance, and pain score were improved; ankle brachial pressure index and transcutaneous oxygen pressure were not improved. The number of patients with limb ulcers did not change in the control group. There are improvement in amputation rates, collateral vessel development, and number of limb ulcers healed. CONCLUSIONS: These results indicate that the autologous transplantation of G-CSF that mobilized PBMNCs in CLI diabetic patients is safe and effective in patient compliant reduction and improved perfusion. PMID- 22240266 TI - Single-layer CVD-grown graphene decorated with metal nanoparticles as a promising biosensing platform. AB - A new approach to the development of a single-layer graphene sensor decorated with metal nanoparticles is presented. Chemical vapor deposition is used to grow single layer graphene on copper. Decoration of the single-layer graphene is achieved by electroless deposition of Au nanoparticles using the copper substrate as a source of electrons. Transfer of the decorated single-layer graphene on glassy carbon electrodes offers a sensitive platform for biosensor development. As a proof of concept, 10 units of glucose oxidase were deposited on the surface in a Nafion matrix to stabilize the enzyme as well as to prevent interference from ascorbic acid and uric acid. Amperometric linear response calibration in the MUmoll(-1) is obtained. The presented methodology enables highly sensitive platforms for biosensor development, providing a scalable roll-to-roll production with a much more reproducible scheme when compared to the graphene biosensors reported previously based on drop-cast of multi-layer graphene suspensions. PMID- 22240267 TI - Maternal health needs and interest in screening for depression and health behaviors during pediatric visits. AB - INTRODUCTION: Our aims were to assess postpartum health care barriers; health status (including depression and health behaviors); missed opportunities to discuss maternal health at health visits; acceptability of maternal screening in pediatric settings; and association of these variables with income level and race/ethnicity. METHOD: A mail survey was used with names randomly drawn from birth files and balanced for race/ethnicity and income level. RESULTS: The adjusted response rate was 27.6%, with 41% reporting one or more health care barrier(s), 22% screening positive for depression, and 30% screening positive for alcohol abuse. Women of lower income were eight times more likely than those of higher income to have health care barriers (adjusted odds ratio = 8.15; 95% confidence interval: 3.60, 18.44). Missed discussions of postpartum depression or behavioral health during pediatric or other health care visits ranged from 26% to 79%. Acceptability of discussing topics, including depression, smoking, and alcohol use at pediatric care visits generally exceeded 85%. DISCUSSION: Postpartum women experienced income-associated barriers to health care and generally had favorable views about maternal screening in pediatric settings. PMID- 22240268 TI - [Pleural effusion secondary to pancreaticopleural fistula following acute pancreatitis]. AB - Pancreaticopleural fistula is a rare complication of acute or chronic pancreatitis, requiring medical (somatostatin), endoscopic or surgical treatment, with medical treatment being the first option. We describe the case of a 64-year old man who showed complete disruption of Wirsung's duct that was diagnosed through ultrasound endoscopy and was complicated by the development of a subphrenic collection, diaphragm perforation and subsequent empyema. Medical therapy was attempted without success, and anatomical restoration of the duct was achieved after endoscopic treatment. The patient also required surgery to evacuate the pleural collection. PMID- 22240269 TI - Glycosylations and truncations of functional cereal phytases expressed and secreted by Pichia pastoris documented by mass spectrometry. AB - Cereal purple acid phosphatase-type phytases, PAPhy, play an essential role in making phosphate accessible to mammalian digestion and reducing the environmental impact of manure. Studying the potential of PAPhy requires easy access to the enzymes. For that purpose wheat and barley isophytases have been expressed in Pichia pastoris from constructs encoding the alpha-mating factor at the N-termini and a His6 tag before the stop codon in all constructs. A protein chemical study of a C-terminally truncated recombinant wheat phytase, r-TaPAPhy_b2, was carried out to clarifying the posttranslational processing of proteins secreted from P. pastoris. Extensive mass spectrometric sequencing of tryptic, chymotryptic and AspN derived peptides of both the native and endoH deglycosylated forms showed: (i) All mating factor derived sequence had been removed and further unspecific proteolysis left highly heterogeneous N-terminal variant forms of r-TaPAPhy; (ii) The His6 tag had been retained or slightly truncated; (iii) All seven potential N glycan sites were glycosylated except for two sites which were partially glycosylated by ca. 90% and 30%; (iv) Among the nine cysteine residues of this phytase, the most N-terminal residue is free, whereas the remaining eight appear to be disulfide bonded. It is noteworthy that already the first step in ESI-MS/MS sequencing had fragmented the hyper glycosylated peptides into free Z, Y and X mass spectrometric glycan fragments attached to the peptide. PMID- 22240271 TI - Failure evaluation after a 6-year retention period: a comparison between glass fiber-reinforced (GFR) and multistranded bonded retainers. AB - OBJECTIVES: The aim of this study was to compare bond failure and breakage rates of two types of bonded lingual orthodontic retainers (GFR and .0175" multistranded stainless steel wire [MST]) after a 6-year retention period. SUBJECTS AND METHODS: Eighty-five young adults were randomly divided into two groups: 40 subjects received 48 GFR retainers (14 maxillary and 34 mandibular retainers), and 45 subjects received 50 MST retainers (18 maxillary and 32 mandibular retainers). A Fisher's exact test was performed in order to identify significant differences in the percentage of detachment and breakage of the retainers between the groups. RESULTS: The maxillary detachment rates were 21.42% for the GFR group and 22.22% for the MST group; the mandibular detachment rates were 11.76% for the GFR group and 15.62% for the MST group. The maxillary breakage rates were 7.14% for the GFR group and 16.66% for the MST group; the mandibular breakage rates were 8.82% for the GFR group and 15.62% for the MST group. The differences were not statistically significant. CONCLUSION: GFR and multistranded stainless steel retainers showed similar results in terms of bond failure and breakage after 6 years of retention. The use of GFR retainers as a retention strategy should not be discouraged and could be considered a viable esthetic alternative to stainless steel wire retainers. PMID- 22240272 TI - The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men. AB - INTRODUCTION: Sexual dysfunction is common in patients with major depressive disorder (MDD). Antidepressant medications especially the selective serotonin reuptake inhibitors (SSRIs) may improve depressive symptoms but further decrease sexual function. Gepirone extended release (gepirone-ER) differs from the SSRIs in only affecting the 5-HT(1A) receptor and has demonstrated efficacy in treatment of depression and sexual dysfunction in depressed women. This report describes the effect of gepirone-ER on sexual function in depressed men. AIM: The aims of this article were to study the effects of gepirone-ER on sexual function in men with MDD and to determine if positive effects are independent of antidepressant or anxiolytic activity. MAIN OUTCOME MEASURES: The main outcome measures of this article were Hamilton depression rating scale (HAMD-17), and changes in sexual functioning questionnaire (CSFQ). METHODS: In an 8-week study, gepirone-ER, placebo, or fluoxetine were administered in a double-blind fashion to 181 depressed men. The CSFQ results were used to determine quality of sexual function. To test for an antidepressant or anxiolytic effect, a 50% reduction in HAMD-17 score separated antidepressant responders from nonresponders, and item 12 of the HAMD scale (psychic anxiety) scores of 0 or 1 separated anxiolytic responders from nonresponders. RESULTS: Gepirone-ER treatment improved total sexual function compared with placebo measured by the CSFQ at weeks 4 (P=0.012) and 8 (P=0.046). At 4 weeks, almost every CSFQ domain is improved. The orgasm domain was especially improved, 67% by week 4. Gepirone-ER antidepressant and anxiolytic nonresponders showed significant improvement in sexual function. Fluoxetine treatment did not produce improvement. In fact, fluoxetine-treated subjects had lower scores on the total CSFQ, less than placebo, and significantly less than gepirone-ER. CONCLUSION: Gepirone-ER improves sexual dysfunction in depressed men. All domains of sexual function improved. Gepirone-ER has a pro sexual effect independent of antidepressant or anxiolytic activity. PMID- 22240274 TI - Apelin supports primary rat retinal Muller cells under chemical hypoxia and glucose deprivation. AB - Muller cells support the integrity of the blood-retinal barrier, whereas their dysfunction under pathological conditions may contribute to retinal edema formation. The apelin peptide, as the endogenous ligand of G protein-coupled receptor APJ, participates in numbers of physiological and pathological processes. Recent studies highlight its emerging role against ischemic injury. Our study aimed to investigate the potential neuroprotection of apelin for primary rat retinal Muller cells under hypoxia or glucose-deprivation (GD) by cell viability, migration and apoptosis, as well as apelin/APJ immunofluorescence labeling and mRNA expression. The results showed that exogenous apelin significantly stimulated Muller cells viability and migration under normal, hypoxic and glucose-free condition, also prevented apoptosis. Apelin immunoreactivities represented weak and diffuse staining in the cytoplasm, along with restricted nuclear APJ expression. They both appeared stronger immunoreactivities after 12h hypoxia. Under hypoxic stress, apelin mRNA expression began to increase at 6h (9.97 folds, p<0.01), and APJ mRNA also up regulated (2h 6.50 folds, p<0.05; 4h 2.25 folds, p<0.05; 6h 14 folds, p<0.01), whereas they both down-regulated during 4-12h GD. Our results suggested that apelin induced the tolerance of Muller cells to hypoxia and GD. Its administration might be a promising protection for blood-retinal barrier to ischemia. PMID- 22240276 TI - Scientific misconduct is worryingly prevalent in the UK, shows BMJ survey. PMID- 22240275 TI - Donor identification and consent for deceased organ donation: summary of NICE guidance. PMID- 22240277 TI - Differential regulation of gonadotropin receptors by bone morphogenetic proteins in the zebrafish ovary. AB - Follicle-stimulating hormone receptor (fshr) and luteinizing hormone/choriogonadotropin receptor (lhcgr) exhibit differential temporal expression patterns during zebrafish folliculogenesis with fshr being dominant during vitellogenic growth and lhcgr increasing its expression dramatically before maturation. The dynamic and distinct expression patterns of fshr and lhcgr suggest that they are under tight regulatory control. However, the underlying mechanisms for the differential expression of the two receptors remain unknown. We have recently demonstrated that members of bone morphogenetic protein (BMP) family are largely expressed in the oocyte, while their receptors are exclusively localized on the follicle cells, suggesting a potential paracrine signaling from the oocyte to the follicle cells by BMPs. In this study, we investigated the effects of zebrafish BMP2b (zfBmp2b) and BMP4 (zfBmp4) on the expression of fshr and lhcgr using a novel co-culture approach. The recombinant zfBmp2b or zfBmp4 producing CHO cells were co-cultured with the zebrafish follicle cells followed by real-time qPCR analysis of fshr and lhcgr expression. Our results showed that zfBmp2b and zfBmp4 both down-regulated fshr, while up-regulated lhcgr expression at 24 h of co-culturing. This finding, together with the high expression level of BMP receptors in the follicle cells prior to oocyte maturation, strongly suggests a potential role for BMPs in the differential expression of fshr and lhcgr, especially in the full-grown follicles before maturation. As BMPs are largely expressed in the oocyte, this also implies an important role for the oocyte in orchestrating the differentiation and function of the follicle cells. PMID- 22240273 TI - Cytoarchitecture and cortical connections of the anterior cingulate and adjacent somatomotor fields in the rhesus monkey. AB - The cytoarchitecture and cortical connections of the anterior cingulate, medial and dorsal premotor, and precentral region are investigated using the Nissl and NeuN staining methods and the fluorescent retrograde tract tracing technique. There is a gradual stepwise laminar change in the cytoarchitectonic organization from the proisocortical anterior cingulate region, through the lower and upper banks of the cingulate sulcus, to the dorsolateral isocortical premotor and precentral motor regions of the frontal lobe. These changes are characterized by a gradational emphasis on the lower stratum layers (V and VI) in the proisocortical cingulate region to the upper stratum layers (II and III) in the premotor and precentral motor region. This is accompanied by a progressive widening of layers III and VI, a poorly delineated border between layers III and V and a sequential increase in the size of layer V neurons culminating in the presence of giant Betz cells in the precentral motor region. The overall patterns of corticocortical connections paralleled the sequential changes in cytoarchitectonic organization. The proisocortical areas have connections with cingulate motor, supplementary motor, premotor and precentral motor areas on the one hand and have widespread connections with the frontal, parietal, temporal and multimodal association cortex and limbic regions on the other. The dorsal premotor areas have connections with the proisocortical areas including cingulate motor areas and supplementary motor area on the one hand, and premotor and precentral motor cortex on the other. Additionally, this region has significant connections with posterior parietal cortex and limited connections with prefrontal, limbic and multimodal regions. The precentral motor cortex also has connections with the proisocortical areas and premotor areas. Its other connections are limited to the somatosensory regions of the parietal lobe. Since the isocortical motor areas on the dorsal convexity mediate voluntary motor function, their close connectional relationship with the cingulate areas form a pivotal limbic-motor interface that could provide critical sources of cognitive, emotional and motivational influence on complex motor function. PMID- 22240279 TI - Resin-composite cytotoxicity varies with shade and irradiance. AB - OBJECTIVES: The study was aimed at investigating the cytotoxicity of different composites as a function of composite shade and the light curing unit (LCU) employed. METHODS: Non-polymerized and polymerized samples of the composites Grandio((r)) (VOCO, Cuxhaven), Solitaire((r)) (Heraeus Kulzer, Hanau) and Filtek Z 250((r)) (3M/Espe, Seefeld) in two markedly differing shades (A2, C2) were prepared. Polymerization was performed with two LCUs: Heliolux II (Ivoclar/Vivadent, Ellwangen) and Swiss Master Light (EMS, Nyon, Switzerland). To obtain composite extracts, the samples were immersed in cell culture medium (DMEM -Dulbecco's Modified Eagle Medium), which was replaced daily up to the 7th day of the experiment, and then on the 14th, 21st and 28th day. After incubation of human gingival fibroblasts (HGF) with the extracts obtained, cytotoxicity was determined using the MTT test. RESULTS: With the non-polymerized samples, essentially no influence of the composite shades investigated on HGF viability was detected, with the exception of the Solitaire material, where a higher cytotoxicity of the shade C2 in the non-polymerized state was found at the end of the observation period. After polymerization of the different composites, the cytotoxic reaction observed for the extracts of shade C2 was stronger than that observed for A2. After polymerization with the Heliolux II (HLX) LCU, the extracts of composites Grandio and Solitaire C2 were significantly more toxic than those of the A2 shade (p<0.01). Polymerization with the Swiss Master Light (SML) reduces this cytotoxic effect. The extracts of the Grandio composite showed the least cytotoxic effect throughout the observation period, irrespective of the LCU used. For the extracts of the Z250 specimens, the cytotoxicity observed was generally higher. SIGNIFICANCE: The results show that the shade of the composite has an influence on its cytotoxicity and that this cytotoxicity is also influenced by the light curing unit used. It was observed that composites of the darker shade (C2) had a higher cytotoxicity, which varied with the LCU employed. PMID- 22240278 TI - Tissue engineering: from research to dental clinics. AB - Tissue engineering is an interdisciplinary field that combines the principles of engineering, material and biological sciences toward the development of therapeutic strategies and biological substitutes that restore, maintain, replace or improve biological functions. The association of biomaterials, stem cells, growth and differentiation factors has yielded the development of new treatment opportunities in most of the biomedical areas, including Dentistry. The objective of this paper is to present the principles underlying tissue engineering and the current scenario, the challenges and the perspectives of this area in Dentistry. SIGNIFICANCE: The growth of tissue engineering as a research field has provided a novel set of therapeutic strategies for biomedical applications. Indeed, tissue engineering may lead to new strategies for the clinical management of patients with dental and craniofacial needs in the future. PMID- 22240280 TI - Scutular tinea of the scrotum by Candida guilliermondii. PMID- 22240281 TI - Effect of acupuncture on perception threshold: a randomised controlled trial. AB - OBJECTIVE: To determine the current perception thresholds (CPTs) for arm and mental foramen areas to enable a quantitative evaluation of the effectiveness of acupuncture treatment. METHODS: Ninety-eight volunteers enrolled as participants and were randomly assigned to one of three groups: an acupuncture group (34 subjects); a sham acupuncture group (32 subjects) and a waiting group (32 subjects). CPTs for the arm and mental foramen areas were determined before and after acupuncture at LI4 Hegu of the left hand. A Neurometer CPT was used to evaluate the perception threshold at the homolateral mental foramen and arm. For further exploration, thresholds of homolateral and contralateral mental foramina were determined before and after acupuncture in a subgroup of 13 participants in the acupuncture group. RESULTS: Acupuncture at LI4 increased the perception thresholds of the left mental foramen in the acupuncture group significantly (p<0.01). The increases were significantly greater than in the control group for all frequencies, and significantly greater than sham acupuncture for 250 Hz and 5 Hz. In the subgroup, only the CPTs at 5 Hz increased significantly for the contralateral mental foramen. CONCLUSIONS: Acupuncture at LI4 increases the perception threshold in the mandibular area, but not in the arm. This finding is probably related to the analgesic effect of acupuncture. PMID- 22240282 TI - Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. AB - BACKGROUND: The phase III Sorafenib Asia-Pacific (AP) trial-conducted in China, Taiwan and South Korea - confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib. METHODS: In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1-2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety. FINDINGS: Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32-0.87 and 0.31-0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups. INTERPRETATION: The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status. PMID- 22240283 TI - First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study. AB - BACKGROUND: Conatumumab is a fully human monoclonal agonist antibody that binds to death receptor 5 and induces apoptosis in sensitive cells. This study evaluated the safety and efficacy of doxorubicin +/- conatumumab as first-line systemic therapy for metastatic or locally advanced/unresectable soft-tissue sarcoma. METHODS: In Phase I, six patients received doxorubicin (75 mg/m2) with conatumumab (15 mg/kg) every 3 weeks. In Phase II, patients were randomised (2:1) to receive doxorubicin with either double-blind conatumumab 15 mg/kg (conatumumab doxorubicin; n=86) or placebo (placebo-doxorubicin; n=42). Patients who progressed on placebo-doxorubicin could receive open-label conatumumab monotherapy post-chemotherapy (n=21). FINDINGS: The expected histopathologic subtypes (e.g. leiomyosarcoma, liposarcoma, others) were represented in this trial. No unexpected adverse events were noted in either Phase I or II. Median progression-free survival in Phase II was 5.6 and 6.4 months in the conatumumab doxorubicin and placebo-doxorubicin arms, respectively (stratified HR: 1.00; p=0.973), with more early progressions noted in the first 3.5 months in the conatumumab-doxorubicin arm. Median overall survival was not reached after 8.6 months median follow-up in either arm. Common adverse events were nausea (conatumumab-doxorubicin: 66%; placebo-doxorubicin: 80%), alopecia (55%; 63%), fatigue (60%; 38%) and neutropenia (32%; 50%). Post-chemotherapy results were not notably improved by conatumumab dosing. INTERPRETATION: Addition of conatumumab to doxorubicin appeared to be safe but did not improve disease control in a heterogeneous unselected group of patients with soft tissue sarcomas. The results of this trial are very useful for estimating the outcomes of first-line therapy of sarcoma patients treated with standard doxorubicin. PMID- 22240284 TI - Electroporation adopting trains of biphasic pulses enhances in vitro and in vivo the cytotoxic effect of doxorubicin on multidrug resistant colon adenocarcinoma cells (LoVo). AB - Few articles in the literature have focused on electroporation as a strategy to reverse multidrug resistance (MDR) of tumour cells and they are mostly limited to the improved efficacy of bleomycin. We tested the application of trains of biphasic pulses to cell suspensions and to murine xenografts as a strategy to increase the uptake of doxorubicin (DOX) and to enhance its cytotoxicity against chemoresistant cells. The human colon adenocarcinoma cell line LoVo DX, expressing MDR phenotype with high levels of P-glycoprotein (P-gp), has been used. The in vitro and in vivo studies gave the following results: (i) the application of the electric pulses to the cell suspension, immediately before DOX administration, induced a significant increase of drug retention; (ii) confocal microscopy observations showed a remarkable increase of intranuclear accumulation of DOX induced by electroporation; (iii) cell survival assay revealed a decrease of cell viability in the cultures treated with the combination of electroporation and doxorubicin; (iv) scanning electron microscopy observations revealed consistent morphological changes after the combined exposure to electroporation and doxorubicin; (v) in implanted mice the combined treatment induced an evident slowdown on the tumour growth when compared to treatment with DOX alone; (vi) histopathological analysis evidenced tumour destruction and its replacement by scar tissue in the tumours treated with the combination of doxorubicin and electroporation. PMID- 22240286 TI - Psychological profiles in patients with recurrent aphthous ulcers. AB - The aim of this study was to investigate the psychological profiles of patients with recurrent aphthous ulcers (RAUs). 50 patients (27 men and 23 women, mean age 31.44+/-9.95 years) with diagnosed RAUs participated in this study. 50 controls who matched the patients in age and gender were also recruited. The participants' personality and psychological profiles were assessed using the Hospital Anxiety and Depression Scale (HAD) and the Neuroticism-Extraversion-Openness Five Factor Inventory (NEO-FFI). Data analysis showed that females had higher HAD anxiety scores than males in both patients and controls. Patients' age, intensity of pain and number, position, duration, and frequency of ulcers had no relation to HAD and NEO-FFI scores. Patients reported higher levels of anxiety in comparison to controls, but both reported comparable depression scores. Patients' NEO-FFI scores were not different from those reported by controls and the psychological profiles of patients and controls were similar. In conclusion; stressful situations and conditions (i.e. anxiety) rather than personality profiles and stable psychological traits were related to the occurrence of recurrent aphthous ulcers. PMID- 22240288 TI - [Ischemic stroke as the first manifestation of Wegener's granulomatosis]. AB - The most characteristic clinical manifestations of Wegener's granulomatosis are upper and lower respiratory tract and renal involvement. The central nervous system manifestations are uncommon and occur usually late in the course of the disease. We report a 48-year-old man who presented with an ischemic stroke as the first manifestation of Wegener's granulomatosis. Wegener's granulomatosis should be considered in the differential diagnosis of ischemic stroke even in the absence of extraneurological involvement. PMID- 22240287 TI - Determination of trigeminocardiac reflex during rhinoplasty. AB - In most rhinoplasty procedures, osteotomies are usually required. The osteotomy areas are innervated by sensory branches of the trigeminal nerve. The trigeminocardiac reflex (TCR) is clinically defined as the sudden onset of parasympathetic activity during stimulation of the trigeminal nerve. When an osteotomy is performed or external pressure is applied over the nasal bone, the infraorbital nerve may send signals via this nerve. The aim of this prospective study is to determine the blood pressure changes and occurrence of TCR during rhinoplasty. one hundred and eight patients were enrolled into the study. Lidocaine and adrenaline combination (LAC) was injected only into the left lateral osteotomy sites. All patients underwent median, right-side, then left side lateral osteotomies and nasal pyramid infracture. The haemodynamic changes were recorded. A 10% or more decrease in the heart rate from baseline was considered a TCR. TCR was detected in nine patients following lateral osteotomies and nasal pyramid infracture procedures (8.3%). The authors determined that LAC injection prior to osteotomy did not prevent TCR. Manipulation at or near the infraorbital nerve during rhinoplasty may cause TCR, even if local anaesthetic infiltration is used. PMID- 22240290 TI - [Validation of a clinical prediction rule for the diagnosis of deep vein thrombosis of the lower limbs in primary care]. AB - PURPOSE: Patients with suspected deep vein thrombosis (DVT) are often managed on an outpatient basis. The aim of the study was to validate a clinical prediction rule specifically for use in primary care to help physicians in their decision to start anticoagulant therapy while awaiting ultrasound examination. PATIENTS AND METHODS: Between September 2007 and October 2008, 194 general practitioners prospectively included patients with clinically suspected DVT without clinically suspected pulmonary embolism. All patients underwent a standardized clinical assessment in order to collect items included in the clinical prediction rule (personal history of venous thromboembolism +1, immobilization in previous month+1, estrogen contraceptive+2, active malignancy+3, swelling of the calf+1, the presence of an alternative diagnosis more likely than that of DVT-3. DVT unlikely if score<2, likely if score>=2). RESULTS: Among the 164 included patients, 56 (34%) had DVT of them 28 (17%) had a proximal DVT. Proportions of confirmed DVT were 29% in the unlikely group and 43% in the likely group against 26% and 63% respectively in the derivation study. CONCLUSIONS: This clinical prediction rule might not fulfill the required conditions to be considered as a usable help in the ambulatory management of DVT. Variations of the cut-off value could enhance its performance. PMID- 22240289 TI - [A chronic recurring sharp pain]. PMID- 22240291 TI - Murine cardiac images obtained with focusing pinhole SPECT are barely influenced by extra-cardiac activity. AB - Ultra-high-resolution SPECT images can be obtained with focused multipinhole collimators. Here we investigate the influence of unwanted high tracer uptake outside the scan volume on reconstructed tracer distributions inside the scan volume, for (99m)Tc-tetrofosmin myocardial perfusion scanning in mice. Simulated projections of a digital mouse phantom (MOBY) in a focusing multipinhole SPECT system (U-SPECT-II, MILabs, The Netherlands) were generated. With this system differently sized user-defined scan volumes can be selected, by translating the animal in 3D through the focusing collimators. Scan volume selections were set to (i) a minimal volume containing just the heart, acquired without translating the animal during scanning, (ii) a slightly larger scan volume as is typically applied for the heart, requiring only small XYZ translations during scanning, (iii) same as (ii), but extended further transaxially, and (iv) same as (ii), but extended transaxially to cover the full thorax width (gold standard). Despite an overall negative bias that is significant for the minimal scan volume, all selected volumes resulted in visually similar images. Quantitative differences in the reconstructed myocardium between gold standard and the results from the smaller scan volume selections were small; the 17 standardized myocardial segments of a bull's eye plot, normalized to the myocardial mean of the gold standard, deviated on average 6.0%, 2.5% and 1.9% for respectively the minimal, the typical and the extended scan volume, while maximum absolute deviations were respectively 18.6%, 9.0% and 5.2%. Averaged over ten low-count noisy simulations, the mean absolute deviations were respectively 7.9%, 3.2% and 1.9%. In low-count noisy simulations, the mean and maximum absolute deviations for the minimal scan volume could be reduced to respectively 4.2% and 12.5% by performing a short survey scan of the exterior activity and focusing the remaining scan time at the organ of interest. We conclude that reconstructed tracer distribution in the myocardium can be influenced by activity in surrounding organs when a too narrow scan volume is used. With slightly larger scan volumes this problem is adequately suppressed. This approach produced a smaller mean deviation and may be more effective than employing a narrow scan volume with an additional survey scan. PMID- 22240292 TI - Characterization of vaginal lactobacilli in women after kidney transplantation. AB - Limited number of publications described vaginal microflora after kidney transplantation. Our PubMed search revealed only 18 publications including words "vaginal bacteria & kidney transplant" in the period of 1978-2011. The aim of this study was to characterize lactobacilli isolated from vaginal swabs of women after kidney transplantation, compared with healthy women. Eighteen renal transplant recipients (mean age 36.1) and 20 healthy women (mean age 36.0) were evaluated. Lactobacilli were cultured on MRS and Columbia blood agars. Biochemical identification with API 50 CHL (bioMerieux, Marcy L'Etoile, France) and multiplex PCR according to Song et al. was performed. Lactobacilli were tested for production of H(2)O(2). Minimal inhibitory concentrations (MICs) of selected antimicrobial agents were determined with E-tests (bioMerieux, Marcy L'Etoile, France) and interpreted with CLSI and EUCAST criteria. No bacterial vaginosis was found among studied women. Two strains of group I were identified as Lactobacillus delbrueckii; 18 strains as Lactobacillus gasseri and 15 strains as Lactobacillus crispatus. Only 3 strains from group II were not identified by species-specific mPCR. Group IV was represented with 2 unidentified strains. Vaginal lactobacilli isolated from healthy women represented more homogenous group compared with heterogenous renal transplant recipients. Biochemical identification of lactobacilli by API 50 CHL kits was concordant with mPCR results only in 7 cases (17.5%), all 7 strains were identified as L. crispatus. Majority (93%) of lactobacilli were H(2)O(2) producers. All isolated lactobacilli (100%) demonstrated high resistance to metronidazole (MIC > 256 MUg/ml). Only 2 strains resistant to vancomycin (MICs: 32 and 256 MUg/ml respectively), in the study and control group, and one to moxifloxacin (MIC = 32 MUg/ml), were found. Resistance to metronidazole and vancomycin was concordant in CLSI and EUCAST (2010) criteria. Although significant differences between lactobacilli isolated from vaginas of kidney transplant and healthy women were not demonstrated, we demonstrated strains resistant to metronidazole, vancomycin and moxifloxacin in groups of examined women. Our study was performed on a small group of kidney transplant recipients and further more detailed molecular studies on a larger group of patients are required to confirm our results. PMID- 22240293 TI - Design of novel FN3 domains with high stability by a consensus sequence approach. AB - The use of consensus design to produce stable proteins has been applied to numerous structures and classes of proteins. Here, we describe the engineering of novel FN3 domains from two different proteins, namely human fibronectin and human tenascin-C, as potential alternative scaffold biotherapeutics. The resulting FN3 domains were found to be robustly expressed in Escherichia coli, soluble and highly stable, with melting temperatures of 89 and 78 degrees C, respectively. X ray crystallography was used to confirm that the consensus approach led to a structure consistent with the FN3 design despite having only low-sequence identity to natural FN3 domains. The ability of the Tenascin consensus domain to withstand mutations in the loop regions connecting the beta-strands was investigated using alanine scanning mutagenesis demonstrating the potential for randomization in these regions. Finally, rational design was used to produce point mutations that significantly increase the stability of one of the consensus domains. Together our data suggest that consensus FN3 domains have potential utility as alternative scaffold therapeutics. PMID- 22240294 TI - Determination of SGK1 mRNA in non-small cell lung cancer samples underlines high expression in squamous cell carcinomas. AB - BACKGROUND: Lung cancer represents the most frequent cause of death for cancer. In non-small cell lung cancer (NSCLC), which accounts for the vast majority of this disease, only early detection and treatment, when possible, may significantly affect patient's prognosis. An important role in NSCLC malignancy is attributed to the signal transduction pathways involving PI3Kinase, with consequent activation of the AKT family factors. The serum and glucocorticoid kinase (SGK) factors, which share high structural and functional homologies with the AKT factors, are a family of ubiquitously expressed serine/threonine kinases under the control of cellular stress and hormones. SGK1 is the most represented SGK member. METHODS: By means of immunohistochemistry and quantitative real-time PCR, we determined SGK1 protein and mRNA expression in a cohort of 66 formalin fixed, paraffin-embedded NSCLC surgical samples. All samples belonged to patients with a well-documented clinical history. RESULTS: mRNA expression was significantly higher in squamous cell carcinomas, and correlated with several clinical prognostic indicators, being elevated in high-grade tumors and in tumors with bigger size and worse clinical stage. No correlation was found between SGK1 protein expression and these clinical parameters. CONCLUSIONS: This explorative analysis of SGK1 expression in NSCLC samples highlights the potential role of this factor in NSCLC patients' prognosis. Moreover, the higher expression in the squamous cell carcinoma subtype opens new therapeutic possibilities in this NSCLC subtype by designing specific kinase inhibitors. PMID- 22240295 TI - Sleeping respiratory rates in apparently healthy adult dogs. AB - Respiratory rate monitoring of cardiac patients is recommended by many cardiologists. However, little objective data exist about respiratory rates in apparently healthy dogs when collected in the home environment. We measured sleeping respiratory rates (SRR) in apparently healthy dogs and compared sleeping and resting respiratory rates (RRR) with a cross-sectional prospective study. Participants collected 12-14 one-minute SRR over a period ranging from 1 week to 2 months on 114 privately owned adult dogs. Selected participants simultaneously collected RRR. Mean within-dog average SRR (SRR(mean)) was 13breaths per minute (breaths/min). No dog had SRR(mean) >23 breaths/min; three dogs had instantaneous SRR measurements >30 breaths/min. Dogs had higher RRR(mean) (19 breaths/min) than SRR(mean) (15 breaths/min) (P<0.05). Canine SRR(mean) was unaffected by age, bodyweight or geographic location. Data acquisition was considered relatively simple by most participants. This study shows that apparently healthy adult dogs generally have SRR(mean) <30 breaths/min and rarely exceed this rate at any time. PMID- 22240296 TI - Application of subproteomics in the characterization of Gram-positive bacteria. AB - Gram-positive bacteria cause a series of diseases in human, animals and plants. There has been increasing interest in efforts to investigate pathogenesis of bacteria using multiple "omic" strategies including proteomics. Proteins in different cell fractions of bacteria may play different vital roles in various physiological processes, such as adhesion, invasion, internalization, sensing, respiration, oxidative stress protection and pathogenicity. Subproteomics specifically focuses on the pre-fractionated cellular proteins and thus may be able to characterize more low-abundance molecules that are usually overlooked by the traditional whole-cell proteomics, providing comprehensive information for further investigations. This review intends to outline the current progress, challenges and future development of subproteomics in the characterization of Gram-positive bacteria. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22240297 TI - Changes in hepatic protein expression in spontaneously hypertensive rats suggest early stages of non-alcoholic fatty liver disease. AB - Hypertension is a systemic disorder affecting numerous physiological processes throughout the body. As non-alcoholic fatty liver disorder (NAFLD) is a common comorbidity of hypertension in humans, we hypothesized that molecular hepatic physiology would be altered in a model of genetic hypertension. Despite the broad use of the spontaneously hypertensive rat (SHR) model, little is known regarding how hypertension influences hepatic function under basal conditions. In order to determine whether hypertension induces changes in the hepatic protein expression suggestive of early stages of NAFLD, we compared the whole tissue proteome of livers from SHR and Wistar Kyoto (WKY) 16 week old rats using 2DGE and MALDI-TOF MS. Fifteen proteins were identified that display different levels of expression between the SHR and WKY livers: 50% of proteins have mitochondrial or anti oxidant functions while 20% are involved in lipid metabolism. Quininoid dihydropterin reductase, sulfite oxidase, and glutathione-S-transferase mu 1 were all identified as either undergoing a difference in post-translation modification or a difference in protein abundance in SHR compared to WKY livers. As oxidative stress is a well described component of both NAFLD and hypertension in SHR, the identification of novel changes in protein expression provides possible mechanisms connecting these two pathologies in humans. PMID- 22240299 TI - [Impact of different methods of estimating renal function on determining eligibility for cisplatin (CDDP)-based chemotherapy in patients with invasive urothelial carcinoma]. AB - Assessment of renal function is important to determine the appropriate dose for cisplatin (CDDP)-based chemotherapy. Many previous CDDP-based chemotherapy trials for bladder cancer have required a creatinine-clearance (Ccr) ?60 ml/min for entry. However, there is little evidence on renal function assessed by estimated glomerular filtration rate (eGFR) using the 4-variable Modification of Diet in Renal Disease Study Equation (MDRD), which has recently been introduced, to determine the eligibility for CDDP-based chemotherapy. To evaluate the proportion of patients with invasive urothelial carcinoma(UC) who would be ineligible ("unfit") to receive CDDP-based chemotherapy based on eGFR criteria (eGFR <60 ml/min/1.73 m2), and to determine the side effects of chemotherapy in these "unfit" patients, we conducted a retrospective clinical study. Our study population consisted of 61 consecutive patients who underwent 100% dose CDDP based chemotherapy for invasive UC with 24 h-Ccr?50 ml/min between June 2001 and July 2009. We assessed renal function using 3 equations (eGFR, Ccr according to Cockcroft-Gault formula (C-G Ccr), and Ccr examined by 24-hour urine collection (24 h-Ccr)) as well. Mean values of eGFR, C-G Ccr, and 24 h-Ccr were 58.6, 68.9, and 82.8 ml/min, respectively (P< 0.001). In total, 29/61(48%) patients were ineligible ("unfit") to receive chemotherapy based on eGFR criteria. However, there was no difference in the frequency of side effects between eGFR ?60 ml/min/ 1.73 m2 and eGFR <60 ml/min/1.73 m2 groups. Our observations suggest that 24 h Ccr?50 ml/min would be a reasonable cutoff for CDDP-based chemotherapy even when eGFR <60 ml/min/1.73 m2. PMID- 22240300 TI - [Investigation of pharmacokinetics of crushed imidafenacin 0.1-mg tablet after single oral administration in healthy men]. AB - The crushing of tablets and opening of capsules should not be performed without proper care, as these actions may adversely affect the pharmaceutical release mechanisms. However, various clinical circumstances occasionally necessitate these actions. The long-term stability of the commercial formulation of imidafenacin was confirmed after crushing of tablets. For the safe administration of crushed imidafenacin tablets, we examined the pharmacokinetics of crushed imidafenacin 0. 1-mg tablet after single oral administration in healthy men. Plasma concentrations were measured in 6 male volunteers (age, 33.3 +/- 10.6 years) orally administered crushed imidafenacin under fasting conditions. Imidafenacin was rapidly absorbed and plasma concentrations peaked (Cmax) at 414 +/- 108 pg/ml after 1.5 h (Tmax ; median), after which the drug was rapidly eliminated with a half-life (t1/2) of 2.8 +/- 0. 3 h. Area under the plasma concentration-time curve (AUC0-10) was 1,680 +/- 334 pg?h/ml. There were no significant differences in Cmax, Tmax and t1/2 between the crushed and tablet medications. Thus, crushing has almost no influence on the pharmacokinetics of imidafenacin. Consequently, this study was made available as information for patients requiring crushed anticholinergic agents. PMID- 22240301 TI - [Renal metastasis from prostatic adenocarcinoma : a case report]. AB - We report a case of renal metastases from prostate cancer to show that the possibility of tumor metastasis, although rare, should be considered in the differential diagnosis of renal mass. A 67-year-old man was found to have a renal mass on computed tomographic scan incidentally. He had had total androgen blockage (bicalutamide + leuprolerin) and chemotherapy (docetaxel hydrate ) for treatment of prostate cancer discovered 33 months ago. On the basis of the clinical features and radiologic results, the patient was thought to have a second malignant tumor, and we performed left nephrectomy. The pathological finding of this case was renal metastasis from prostatic adenocarcinoma. He died 18 months postnephrectomy. PMID- 22240298 TI - Nature and nurture in Foxp3(+) regulatory T cell development, stability, and function. AB - Foxp3(+) regulatory T lymphocytes (Treg) are critical homeostatic regulators of immune and inflammatory responses. Their absence leads to fulminant multiorgan autoimmunity. This review explores recent studies that have altered our emerging view of the development, stability, and plasticity of these cells. Treg appear not to be a single entity, but a family of immunomodulatory cell types with shared capabilities. On a first level, Treg may alternatively form in response to developmental cues in the thymus as a distinct lineage of CD4(+) T cells or adaptively, in response to environmental cues received by mature conventional CD4(+) T lymphocytes. These 2 populations bear distinct specificity, stability, and genetic profiles and are differentially used in immune responses. Secondarily, in a manner analogous to the generation of T helper (Th)-1, Th2, and other T cell subsets, Treg may further specialize, adapting to the needs of their immunologic surroundings. Treg therefore comprise developmentally distinct, functionally overlapping cell populations that are uniquely designed to preserve immunologic homeostasis. They combine an impressive degree of both stability and adaptability. PMID- 22240302 TI - [A case of giant renal angiomyolipoma treated by partial nephrectomy]. AB - A 38-year-old woman visited our hospital complaining of decreased appetite and sensation of pressure on her abdomen. Computed tomographic scan revealed right giant renal angiomyolipoma. Partial nephrectomy was performed. The resected specimen weighed 970 grams. The histological diagnosis was consistent with angiomyolipoma. Partial nephrectomy was performed because the connection between the tumor and the kidney was in a small range and the tumor was detached easily from the surrounding tissue. PMID- 22240303 TI - [A case of small cell carcinoma of the renal pelvis]. AB - A 77-year-old man visited our hospital with a chief complaint of asymptomatic gross hematuria. He was diagnosed with right renal pelvic tumor (7 cm) involving right renal hilar and inter-aortocaval lymph node metastases by radiological evaluation, and cytologic examination of urine indicated small cell carcinoma. After neoadjuvant chemotherapy with gemcitabine and cisplatin, right nephroureterctomy with bladder cuff, and right renal hilar and inter-aortocaval lymph node dissection was performed. Histological examination of the specimen revealed a small cell carcinoma of the renal pelvis (ypT3N2). After the operation, adjuvant chemotherapy with etopside and carboplatin was administered in combination with radiation therapy. At 5 months after the operation, there has been no evidence of recurrence. To our knowledge, this is the 38th report of a small cell carcinoma originating from the kidney in the literature. PMID- 22240304 TI - [Nested variant of urothelial carcinoma of bladder : a case report]. AB - A 58-year-old man visited our hospital with gross hematuria. Cystoscopy revealed a papillary tumor around the left ureteral orifice. Transurethral resection of bladder tumor (TUR-Bt) was performed and histopathological findings revealed a nested variant of urothelial carcinoma. Computed tomography (CT) revealed no involvement of other organs. Laparoscopic radical cystectomy and orthotopic neobladder substitution (Studer methods) were performed. The histopathological stage was pT3aN0M0. Adjuvant chemotherapy (gemcitabine + cisplatin) was performed. The patient is currently free from disease at five months after the surgery. PMID- 22240305 TI - [A case of a foreign body (sheath dilator) in the urethra and bladder]. AB - An 84-year-old man presented with the chief complaints of fever and disturbance of consciousness at another hospital. A sheath dilator had been inserted into the urethra instead of an indwelling catheter at the hospital. Since he had previously been treated for myelodysplastic syndrome in our Department of Internal Medicine, he was transferred to our hospital. He presented at our Department with the chief complaints of urinary difficulty and lower abdominal fullness. Kidney-ureter-bladder x-ray and computed tomography revealed the sheath dilator in the uretha and bladder. First, we performed a percutaneous cystostomy under local anesthesia. Second, we utilized optical forceps and successfully removed the sheath dilator transurethrally under intravenous anesthesia. PMID- 22240306 TI - [Prostatic metastasis of renal cell carcinoma]. AB - A 71-year-old man underwent a radical nephrectomy for right renal cell carcinoma in April, 2005. Pathological findings revealed clear cell carcinoma, G3>G2, pT3a. Three years later, he underwent a craniotomy for tumor resection of solitary brain metastasis. In October, 2008, he came to our hospital because of urinary retention. Benign prostate hypertrophy was diagnosed by ultrasonography and digital rectal examination. Serum prostate specific antigen level was 2.55 ng/dl. While he was treated with oral alpha 1-blocker initially, a urethral catheter was inserted in December, 2009. Because of frequent obstruction of the catheter by hematuria, transureathral prostectomy was performed. Pathological findings revealed prostatic metastasis of renal cell carcinoma. Metastasis of renal cell carcinoma to the prostate is rare, and only 7 cases including the present case have been reported. PMID- 22240307 TI - Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity. AB - Emerging evidence indicates that certain behavioral traits, such as anxiety, are associated with the development of depression-like behaviors after exposure to chronic stress. However, single traits do not explain the wide variability in vulnerability to stress observed in outbred populations. We hypothesized that a combination of behavioral traits might provide a better characterization of an individual's vulnerability to prolonged stress. Here, we sought to determine whether the characterization of relevant behavioral traits in rats could aid in identifying individuals with different vulnerabilities to developing stress induced depression-like behavioral alterations. We also investigated whether behavioral traits would be related to the development of alterations in the hypothalamic-pituitary-adrenal axis and in brain activity - as measured through phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)--in response to an acute stressor following either sub-chronic (2 weeks) or chronic (4 weeks) unpredictable stress (CUS). Sprague-Dawley rats were characterized using a battery of behavioral tasks, and three principal traits were identified: anxiety, exploration and activity. When combined, the first two traits were found to explain the variability in the stress responses. Our findings confirm the increased risk of animals with high anxiety developing certain depression-like behaviors (e.g., increased floating time in the forced swim test) when progressively exposed to stress. In contrast, the behavioral profile based on combined low anxiety and low exploration was resistant to alterations related to social behaviors, while the high anxiety and low exploration profile displayed a particularly vulnerable pattern of physiological and neurobiological responses after sub-chronic stress exposure. Our findings indicate important differences in animals' vulnerability and/or resilience to the effects of repeated stress, particularly during initial or intermediate levels of stress exposure, and they highlight that the behavioral inhibition profile of an animal provides a particular susceptibility to responding in a deleterious manner to stress. PMID- 22240308 TI - Finding differentially expressed genes in high dimensional data: Rank based test statistic via a distance measure. AB - We present a rank-based test statistic for the identification of differentially expressed genes using a distance measure. The proposed test statistic is highly robust against extreme values and does not assume the distribution of parent population. Simulation studies show that the proposed test is more powerful than some of the commonly used methods, such as paired t-test, Wilcoxon signed rank test, and significance analysis of microarray (SAM) under certain non-normal distributions. The asymptotic distribution of the test statistic, and the p-value function are discussed. The application of proposed method is shown using a real life data set. PMID- 22240309 TI - Award-winning articles and posters from the World Federation of Chiropractic's 11th Biennial Congress 2011. AB - This editorial reviews the scientific sessions and announces the 4 award-winning scientific articles from the World Federation of Chiropractic 11th Biennial Congress held in Rio de Janeiro from April 6, to 9, 2011, that are published in this issue of the Journal of Manipulative and Physiological Therapeutics. PMID- 22240310 TI - Cryopreserved Plasmodium vivax and cord blood reticulocytes can be used for invasion and short term culture. AB - The establishment of a Plasmodium vivaxin vitro culture system is critical for the development of new vaccine, drugs and diagnostic tests. Although short-term cultures have been successfully set up, their reproducibility in laboratories without direct access to P. vivax-infected patients has been limited by the need for fresh parasite isolates. We explored the possibility of using parasite isolates and reticulocytes, both cryopreserved, to perform invasion and initiate short-term culture. Invasion results obtained with both cryopreserved isolates and reticulocytes were similar to those obtained with fresh samples. This method should be easily replicated in laboratories outside endemic areas and will substantially contribute to the development of a continuous P. vivax culture. In addition, this model could be used for testing vaccine candidates as well as for studying invasion-specific molecular mechanisms. PMID- 22240311 TI - High resolution array in the clinical approach to chromosomal phenotypes. AB - Array genomic hybridization (AGH) has recently been implemented as a diagnostic tool for the detection of submicroscopic copy number variants (CNVs) in patients with developmental disorders. However, there is no consensus regarding the choice of the platform, the minimal resolution needed and systematic interpretation of CNVs. We report our experience in the clinical diagnostic use of high resolution AGH up to 100 kb on 131 patients with chromosomal phenotypes but previously normal karyotype. We evaluated the usefulness in our clinics and laboratories by the detection rate of causal CNVs and CNVs of unknown clinical significance and to what extent their interpretation would challenge the systematic use of high resolution arrays in clinical application. Prioritizing phenotype-genotype correlation in our interpretation strategy to criteria previously described, we identified 33 (25.2%) potentially pathogenic aberrations. 16 aberrations were confirmed pathogenic (16.4% syndromic, 8.5% non-syndromic patients); 9 were new and individual aberrations, 3 of them were pathogenic although inherited and one is as small as approx 200 kb. 13 of 16 further CNVs of unknown significance were classified likely benign, for 3 the significance remained unclear. High resolution array allows the detection of up to 12.2% of pathogenic aberrations in a diagnostic clinical setting. Although the majority of aberrations are larger, the detection of small causal aberrations may be relevant for family counseling. The number of remaining unclear CNVs is limited. Careful phenotype-genotype correlations of the individual CNVs and clinical features are challenging but remain a hallmark for CNV interpretation. PMID- 22240312 TI - Evolutionary analysis of prokaryotic heat-shock transcription regulatory protein sigma32. AB - Heat-stress to any living cell is known to trigger a universal defense response, called heat-shock response, with rapid induction of tens of different heat-shock proteins. Bacterial heat-shock genes are transcribed by the sigma(32)-bound RNA polymerase instead of the normal sigma(70)-bound RNA polymerase. In this study, the diversity in sequence, variation in secondary structure and function amongst the different functional regions of the proteobacterial sigma(32) family of proteins, and their phylogenetic relationships have been analyzed. Bacterial sigma(32) proteins can be subdivided into different functional regions which are referred to as regions 2, 3, and 4. There is a great deal of sequence conservation among the functional regions of proteobacterial sigma(32) family of proteins though some mutations are also present in these regions. Region 2 is the most conserved one, while region 4 has comparatively more variable sequences. In the present work, we tried to explore the effects of mutations in these regions. Our study suggests that the sequence diversities due to natural mutations in the different regions of proteobacterial sigma(32) family lead to different functions. So far, this study is the first bioinformatic approach towards the understanding of the mechanistic details of sigma(32) family of proteins using the protein sequence information only. This study therefore may help in elucidating the hitherto unknown molecular mechanism of the functionalities of sigma(32)family of proteins. PMID- 22240313 TI - MCPH1/BRIT1 represses transcription of the human telomerase reverse transcriptase gene. AB - MCPH1, a repressor of human telomerase reverse transcriptase (hTERT) function, is implicated in cellular immortalization. But little is known about how MCPH1 represses telomerase activity. In this study, to determine the mechanism by which MCPH1 regulates hTERT gene expression, we examined the role of MCPH1 in regulating the hTERT promoter in vitro. Co-transfection of the hTERT promoter with MCPH1 in Hela cells could inhibit the hTERT promoter activity. The EMSA assay demonstrated that MCPH1 could bind to the proximal hTERT promoter. Overexpression of MCPH1 could repress telomerase activity, and the repression was abolished by knocking down the MCPH1 expression using siRNA in U2OS cells. We propose that MCPH1 functions as a transcriptional repressor of hTERT in vitro. Since the activation of telomerase, widely observed in human tumor cell lines, is a critical step in tumorigenesis, our findings provide new insights into delineating the tumor-suppressing function of MCPH1 through its down-regulation of hTERT/telomerase expression. PMID- 22240314 TI - Association of genetic variants of fibrinolytic system with stroke and stroke subtypes. AB - Genetic variants of tPA (PLAT) and PAI-1 genes have been suggested to be the risk factors for stroke. In the present case-control study we investigated the association of -7351C/T polymorphism (rs2020918) and I/D polymorphism of tPA gene and Insertion/deletion polymorphism (4G/5G) of PAI-1 gene with genetic predisposition to ischemic stroke. 516 stroke patients and 513, sex and age matched healthy controls were involved in the study. We did not find a significant association of tPA -7351C/T polymorphism and PAI-1 4G/5G polymorphism with stroke. However, in case of I/D polymorphism significant difference was observed in the genotypic distribution and allelic frequency between the stroke patients and healthy controls. DD genotype and D allele associated significantly with stroke (p=0.002 and <0.001 respectively). We also found significant association of I/D polymorphism with intracranial large artery atherosclerosis and stroke of undetermined etiology. Exploring the association between gene-gene interaction (26 combinations including the three variants) and stroke, we found that individuals with CC+4G4G+DD, CC+5G5G+ID, CT+4G5G+ID, CT+5G5G+II, CT+5G5G+ID and TT+4G5G+II had a significantly higher risk of stroke. The results of this study suggest that -7351C/T polymorphism of tPA and 4G/5G polymorphism of PAI-1 are not associated with stroke, while as DD genotype and D allele of tPA gene are important risk factors for ischemic stroke. Further we found that the subjects with different tPA and PAI genotype combinations displayed a significantly high risk for overall ischemic stroke suggesting that gene-gene interaction involving more variants may change the susceptibility of particular subjects to the disease. PMID- 22240315 TI - Molecular cloning, tissue expression and protein structure prediction of the porcine 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) gene. AB - 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) is the rate-limiting enzyme for cholesterol synthesis. Its activity is regulated via a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Here, we cloned a full-length transcript of porcine HMGR by RT-PCR and RACE. The porcine HMGR cDNA (2864 bp,GenBank accession no. DQ432054) contains a 2658 bp open reading frame and shares 91% identify with those of human and cattle, and 85%, 85% and 84% identify with the HMGR coding sequences of Norway rat, golden hamster, and house mouse, respectively. The deduced porcine HMGR protein consists of 885 amino acids with a calculated molecular mass of 97.15 kDa(GenBank accession no. ABD96089). The amino acid sequence similarities correspond to 95%, 95%, 92%, 92% and 92% when compared with human, cattle, Norway rat, golden hamster and house mouse sequences, respectively. The structure and function of HMGR deduced protein product were predicted by bioinformatic approaches. HMGR-specific transcripts were found in 15 different tissues from pig by RT-PCR and Real-time PCR. The relative expression level of HMGR was high in liver, heart, kidney, bladder and subcutaneous fat, medium in lung, uterus and large intestine, and low in cerebrum, spleen, spinal cord, stomach, ovary, longissimus muscle, and small intestine. The SNPs analysis of HMGR showed that there were five SNPS and three of them are synonymous mutations and the other two are missense mutations. Taken together, our data may lay a ground for further investigation of HMGR's functions and regulatory mechanisms in swine. PMID- 22240316 TI - Methane production on thickened, pre-fermented manure. AB - Over 9 million dairy cows generate an estimated 226 billion kg of wet manure annually in the US. The purpose of this study was to demonstrate the viability of a novel two-stage anaerobic digestion (AD) process for producing methane-rich biogas on pre-fermented dairy manure. In summary, it was observed that AD of thickened pre-fermented manure can generate comparable biogas quantities to AD using raw manure, with enhanced methane content. Despite receiving a lower quality (i.e., partially biodegraded) substrate, biogas stoichiometry and overall process stability in the two-stage system was also comparable to AD receiving raw manure. Finally, the two-stage AD was more enriched with the acetoclastic methanogen Methanosarcinaceae (Msc; compared to AD of raw manure) and biogas production appeared closely linked with the Msc fraction. In fact, the enhanced enrichment of Msc likely contributed to the successful and stable operations. PMID- 22240317 TI - Vaccination with WT-1 (Wilms' tumor gene-1) peptide and BCG-CWS in melanoma. PMID- 22240318 TI - The band 12 issue of norbornane: a study of higher shake-up states. AB - In line with a recent study of the electronic structure of the cage compound norbornane (J. Chem. Phys. 121 (2004), 10525; J. Phys. Chem. A 109 (2005), 4267), symmetry adapted cluster expansion configuration interaction (SAC-CI) general R calculations have been performed and compared with results obtained by the third order algebraic diagrammatic construction scheme [ADC(3)]. Comparison has been made with previously performed electron momentum spectroscopy (EMS) and ultraviolet photo-electron measurements. The region around ~25 eV (band 12), characterized by an elaborated band in the EMS spectrum which is missing in previous Green's function and ADC calculations, is investigated. This study is completed with outer-valence Green's function (OVGF) and SAC-CI/SD-R calculations, and results are obtained by employing (single and double) ionization extended second order ADC [ADC(2)-x]. Since ADC(3) only includes 2h-1p shake-up states, while SAC-CI general-R also includes higher order states, the agreement between both methods assures that the higher order shake-up states do not play an important role in the ionization spectrum of norbornane. While the band-12 issue of norbornane is therefore still open for further discussion, a tentative description in terms of ultrafast nuclear dynamical effects and autoionization processes has become more plausible. PMID- 22240319 TI - The Neurospora crassa OS MAPK pathway-activated transcription factor ASL-1 contributes to circadian rhythms in pathway responsive clock-controlled genes. AB - The OS-pathway mitogen-activated protein kinase (MAPK) cascade of Neurospora crassa is responsible for adaptation to osmotic stress. Activation of the MAPK, OS-2, leads to the transcriptional induction of many genes involved in the osmotic stress response. We previously demonstrated that there is a circadian rhythm in the phosphorylation of OS-2 under constant non-stress inducing conditions. Additionally, several osmotic stress-induced genes are known to be regulated by the circadian clock. Therefore, we investigated if rhythms in activation of OS-2 lead to circadian rhythms in other known stress responsive targets. Here we identify three more osmotic stress induced genes as rhythmic: cat-1, gcy-1, and gcy-3. These genes encode a catalase and two predicted glycerol dehydrogenases thought to be involved in the production of glycerol. Rhythms in these genes depend upon the oscillator component FRQ. To investigate how the circadian signal is propagated to these stress induced genes, we examined the role of the OS-responsive transcription factor, ASL-1, in mediating circadian gene expression. We find that while the asl-1 transcript is induced by several stresses including an osmotic shock, asl-1 mRNA accumulation is not rhythmic. However, we show that ASL-1 is required for generating normal circadian rhythms of some OS-pathway responsive transcripts (bli-3, ccg-1, cat-1, gcy-1 and gcy-3) in the absence of an osmotic stress. These data are consistent with the possibility that post-transcriptional regulation of ASL-1 by the rhythmically activated OS-2 MAPK could play a role in generating rhythms in downstream targets. PMID- 22240322 TI - Transgenic expression of ZBP1 in neurons suppresses cocaine-associated conditioning. AB - To directly address whether regulating mRNA localization can influence animal behavior, we created transgenic mice that conditionally express Zipcode Binding Protein 1 (ZBP1) in a subset of neurons in the brain. ZBP1 is an RNA-binding protein that regulates the localization, as well as translation and stability of target mRNAs in the cytoplasm. We took advantage of the absence of ZBP1 expression in the mature brain to examine the effect of expressing ZBP1 on animal behavior. We constructed a transgene conditionally expressing a GFP-ZBP1 fusion protein in a subset of forebrain neurons and compared cocaine-cued place conditioning in these mice versus noninduced littermates. Transgenic ZBP1 expression resulted in impaired place conditioning relative to nonexpressing littermates, and acutely repressing expression of the transgene restored normal cocaine conditioning. To gain insight into the molecular changes that accounted for this change in behavior, we identified mRNAs that specifically immunoprecipitated with transgenic ZBP1 protein from the brains of these mice. These data suggest that RNA-binding proteins can be used as a tool to identify the post-transcriptional regulation of gene expression in the establishment and function of neural circuits involved in addiction behaviors. PMID- 22240324 TI - What a nostril knows: olfactory nerve-evoked AMPA responses increase while NMDA responses decrease at 24-h post-training for lateralized odor preference memory in neonate rat. AB - Increased AMPA signaling is proposed to mediate long-term memory. Rat neonates acquire odor preferences in a single olfactory bulb if one nostril is occluded at training. Memory testing here confirmed that only trained bulbs support increased odor preference at 24 h. Olfactory nerve field potentials were tested at 24 h in slices from trained and untrained bulbs. A larger AMPA component and a smaller NMDA component characterized responses in the bulb receiving odor preference training. Field potential changes were not seen in a bulbar region separate from the lateral odor-encoding area. These results support models in which memory is mediated by increased olfactory nerve-mitral cell AMPA signaling, and memory stability is promoted by decreased NMDA-mediated signaling. PMID- 22240323 TI - Single prolonged stress disrupts retention of extinguished fear in rats. AB - Clinical research has linked post-traumatic stress disorder (PTSD) with deficits in fear extinction. However, it is not clear whether these deficits result from stress-related changes in the acquisition or retention of extinction or in the regulation of extinction memories by context, for example. In this study, we used the single prolonged stress (SPS) animal model of PTSD and fear conditioning procedures to examine the effects of prior traumatic stress on the acquisition, retention, and context-specificity of extinction. SPS administered one week prior to fear conditioning had no effect on the acquisition of fear conditioning or extinction but disrupted the retention of extinction memories for both contextual and cued fear. This SPS effect required a post-stress incubation period to manifest. The results demonstrate that SPS disrupts extinction retention, leading to enhanced fear renewal; further research is needed to identify the neurobiological processes through which SPS induces these effects. PMID- 22240325 TI - Drinking motives and alcoholic beverage preferences among Italian adolescents. AB - Although drinking motives have been largely studied, research taking into account the Mediterranean drinking culture and focusing on motives specifically associated to adolescents' developmental tasks is lacking. For these reasons the study investigates drinking motives in a group of Italian adolescents and their relationships with drunkenness and high levels of alcohol consumption (wine, beer, spirits and alcopops). A self-report questionnaire on drinking motives and amount of alcohol use was administered to 784 adolescents, boys (46%) and girls, ages 15-19. Using confirmatory factor analysis and stepwise logistic regressions, we found that: 1) motives for drinking were coping, conformity, self-affirmation and experimentation-transgression; 2) coping motives were positively related to the high consumption of all alcoholic beverages and to drunkenness; 3) conformity motives were negatively related to high beer consumption and drunkenness, while experimentation-transgression motives were positively related to high alcopops consumption. Implications for prevention are discussed. PMID- 22240326 TI - EEG-LORETA endophenotypes of the common idiopathic generalized epilepsy syndromes. AB - OBJECTIVE: We tested the hypothesis that the cortical areas with abnormal local EEG synchronization are dissimilar in the three common idiopathic generalized epilepsy (IGE) phenotypes: IGE patients with absence seizures (ABS), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures exclusively (EGTCS). PATIENTS AND METHODS: Groups of unmedicated ABS, JME and EGTCS patients were investigated. Waking EEG background activity (without any epileptiform potentials) was analyzed by a source localization method, LORETA (Low Resolution Electromagnetic Tomography). Each patient group was compared to a separate, age-matched group of healthy control persons. Voxel-based, normalized broad-band (delta, theta, alpha, and beta) and very narrow band (VNB, 1Hz bandwidth, from 1 to 25Hz) LORETA activity (=current source density, A/m(2)) were computed for each person. Group comparison included subtraction (average patient data minus average control data) and group statistics (multiple t-tests, where Bonferroni-corrected p<0.05 values were accepted as statistically significant). RESULTS: Statistically not significant main findings were: overall increased delta and theta broad band activity in the ABS and JME groups; decrease of alpha and beta activity in the EGTCS group. Statistically significant main findings were as follows. JME group: bilaterally increased theta activity in posterior (temporal, parietal, and occipital) cortical areas; bilaterally increased activity in the medial and basal prefrontal area in the 8Hz VNB; bilaterally decreased activity in the precuneus, posterior cingulate and superior parietal lobule in the 11Hz and 21-22Hz VNBs. ABS group: bilaterally increased theta activity emerged in the basal prefrontal and medial temporal limbic areas. Decreased activity was found at 19-21Hz in the right postcentral gyrus and parts of the right superior and medial temporal gyri. EGTCS group: decreased activity was found in the frontal cortex and the postcentral gyrus at 10-11Hz, increased activity in the right parahippocampal gyrus at 16-18Hz. DISCUSSION: Increased theta activity in the posterior parts of the cortex is the endophenotype for JME. Increased theta activity in the fronto-temporal limbic areas is the endophenotype for ABS. Statistically not significant findings might indicate diffuse biochemical abnormality of the cortex in JME and ABS. SIGNIFICANCE: EEG-LORETA endophenotypes may correspond to the selective propensity to generate absence and myoclonic seizures in the ABS and JME syndromes. PMID- 22240327 TI - CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy. AB - The ketogenic diet (KD) is a non-pharmacological treatment of medically refractory epilepsy in children. Its mechanisms of action are still unclear but monoamine neurotransmitters have been proposed to be involved. Norepinephrine, dopamine, and serotonin are known to modulate seizure susceptibility in many animal models. We examined whether the concentrations of norepinephrine, dopamine, and serotonin metabolites were affected by the KD in children with pharmacoresistant epilepsy. The metabolites of norepinephrine, HMPG, of dopamine, HVA, and of serotonin, 5-HIAA, were analyzed in cerebrospinal fluid (CSF) before and 3 months after starting the KD. Twenty-six children (mean age 5.9 years) participated. Twenty-one children had generalized epilepsy and five partial. CSF was sampled by lumbar puncture. Seizure frequency before and during the diet was determined. Highly significant changes were found for HVA (p=0.0002) and 5-HIAA (p=0.004), which were both decreased during the KD compared to before diet. The levels of HMPG were unchanged. However, no differences were found between response groups. Valproate medication affected the levels of HMPG during diet with decreased levels in children on valproate and increased in those not on valproate (p=0.04). Our study indicates that the KD significantly alters the levels of metabolites of dopamine and serotonin but with a stable ratio HVA/5 HIAA in the CSF of children with refractory epilepsy, which finding may be of importance for the mechanism of action. PMID- 22240328 TI - [Botulinum toxin A: analgesic treatment for temporomandibular joint disorders]. AB - INTRODUCTION: Pain, along with clicking, sub-luxation, and blocking, is one of the main symptoms for patients presenting with temporomandibular joint disorders. We assessed the effectiveness of botulinum toxin A (BOTOX((r)), Allergan) as analgesic treatment for temporomandibular joint disorders. PATIENTS AND METHOD: Twenty-six patients with chronic pain linked to temporomandibular joint disorders were prospectively assessed. Botulinum toxin A was injected in masseter and temporalis muscles. Follow-up parameters, at one and three months, were: measuring mouth opening and diduction, muscle tenderness and pain using a visual analogue scale. RESULTS: There was a significant (P<0.0001) decrease of pain, an increased mouth opening, and diduction at three months. Seventy percent of the patients felt less muscle tenderness. The patient felt his psychological state had improved and so did his family. DISCUSSION: Botulinum toxin A significantly decreases pain and improves movements of patients presenting with temporomandibular joint disorders. The effects are prolonged three months after the injection. PMID- 22240329 TI - [Conservative surgery for a mandibular condyle osteochondroma]. AB - INTRODUCTION: Osteochondroma is a rare benign bone tumor of the mandibular condyle (90 cases reported). The symptoms are similar to those of temporomandibular joint disorders: painful temporomandibular joint, joint sounds, and modification of dental occlusion. CASE REPORT: A 37-year-old female patient consulted for a wide left laterodeviation of the mandible. CT scan revealed a 27 mm long bony growth on the condyle. The condyle neck was osteotomized, then the tumor and condyle head were split, the condyle was then remodeled and osteosynthesized on the condyle neck. The functional and esthetic results were satisfactory at 12 months without any recurrence or relapse. DISCUSSION: The authors present a novel conservative technique, slightly different from those reported in the literature. There are several therapeutic alternatives. They can be classified in three groups: invasive, non-invasive, and conservative techniques. Nevertheless, osteochondroma is a benign tumor and its management should be as little invasive as possible. PMID- 22240330 TI - Surveillance imaging modality does not affect detection rate of asymptomatic secondary interventions following EVAR. AB - OBJECTIVES: Literature reports that surveillance imaging following endovascular aortic aneurysm repair (EVAR) gives rise to asymptomatic secondary interventions (SI) in 1.4-9% of cases. This retrospective study aimed to evaluate whether the modality of surveillance imaging influences the detection rate of asymptomatic SI. MATERIALS AND METHODS: Two EVAR surveillance protocols were compared at the same vascular centre. Protocol I, performed from January 2003 to December 2006, consisted of colour duplex ultrasound scan (CDU) plus CT angiography (CTA) 1 month after procedure and every 6 months thereafter. Protocol II, performed from January 2007 to June 2010, consisted of CDU plus CTA 1 month after operation and CDU plus plain abdominal films (XR) every 6 months thereafter. In the second protocol, CTA was carried out only during follow-up in specific conditions. The term 'asymptomatic SI' was used when the necessity for SI was detected by imaging alone on an elective basis, prior to development of any symptoms. RESULTS: Enrolment included 376 and 341 consecutive patients with a mean follow-up of 1148 days (range 1-3204 days) and 942 days (range1-1512 days) in Protocols I and II, respectively (p < 0.001). Freedom rates from aneurysmal rupture, freedom from SI and detection rate for asymptomatic SI at 3 years were 98.3% and 98.7% (p = 0.456), 82% and 83.5%(p = 0.876) and 8.8% (n = 33/376) and 8.5%(n = 25/341) (p = 0.49) in Protocols I and II, respectively. Estimated comparison of the costs, radiation exposure and contrast used at 3 years in Protocol I versus Protocol II showed that Protocol II allowed for a three-, four- and six fold reduction in overall costs, radiation exposure and contrast used, respectively (p < 0.0001). CONCLUSIONS: The detection rate of asymptomatic SI following EVAR is not affected by the type of surveillance imaging. A surveillance schedule based primarily on CDU and XR appears to be justified. PMID- 22240331 TI - Analysis of stroke after TEVAR involving the aortic arch. AB - OBJECTIVE: To analyse the incidence of stroke after thoracic endovascular aortic repair (TEVAR) for aortic arch disease. METHODS: In the last decade, 393 patients received TEVAR at our Institution; in 143 cases the aortic arch was involved (32 zones '0', 35 zones '1' and 76 zone '2'). The left subclavian artery (LSA) was revascularised selectively in 75 cases; the proximal LSA was ligated or occluded with a plug in 55 cases before endograft (EG) deployment. RESULTS: Initial clinical success, perioperative mortality, spinal cord ischaemia and stroke in TEVAR patients with or without arch involvement were, respectively, 86.7% vs. 94.4%, 4.2% vs. 2.4%, 2.1% vs. 3.6% and 2.8% vs. 1.2%. The stroke rate was 9.4% (P < 0.02) in 'zone 0', 0% in 'zone 1' and 1.3% in 'zone 2' with scans showing severe atheroma and/or thrombus in all cases. Stroke was observed in patients with 2.6% or without 2.9% LSA revascularisation; however, it was never observed in patients in whom the LSA was occluded before EG deployment and in 4.5% of patients in whom it was patent at the time of EG deployment. CONCLUSIONS: Stroke after TEVAR is not infrequent especially when the arch is involved. Careful patient selection together with a strategy to reduce embolisation such as occlusion of supra-aortic trunks before EG deployment may play a beneficial role. PMID- 22240332 TI - Comment on 'Insulin-like growth factor 1--a novel biomarker of abdominal aortic aneurysm'. PMID- 22240333 TI - Carotid revascularization to prevent stroke. PMID- 22240334 TI - The use of transcutaneous oximetry to predict healing complications of lower limb amputations: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the validity of transcutaneous oximetry (TcPO(2)) as a predictor of lower limb amputation healing complications. DESIGN: A systematic review and meta-analysis. METHODS: We searched five major medical databases, relevant review articles and reference lists and included all studies that evaluated TcPO(2) for its ability to predict lower limb amputation healing failure. We selected eligible articles and conducted data abstraction independently and in duplicate. RESULTS: Thirty-one studies, enrolling 1824 patients with 1960 amputations, met our inclusion criteria. Only one study reported undertaking a multivariable analysis, which demonstrated that a TcPO(2) level below 20 mmHg was an independent predictor of re-amputation occurrence (adjusted odds ratio (OR) 3.08, 95% confidence interval (CI) 1.19-7.98). Fourteen prospective cohort studies reported data that allowed for the calculation of an unadjusted relative risk of lower limb amputation healing complications leading to amputation revision associated with a TcPO(2) level below cut-offs of 10 mmHg (1.80; 95% CI 1.19-2.72), 20 mmHg (1.75; 95% CI 1.27-2.40) 30 mmHg (1.41; 95% CI 1.22-1.62) and 40 mmHg (1.24; 95% CI 1.13-1.39). CONCLUSIONS: This review suggests that TcPO(2) predicts healing complications of lower limb amputations. A value of less than 40 mmHg results in a 24% increased risk of healing complication compared to over 40 mmHg and the risk further increases as the TcPO(2) decreases. There is, however, insufficient evidence to judge whether this tool adds important information beyond clinical data or to suggest an optimal threshold value. There is a need for a large, sufficiently powered study that adjusts for appropriate clinical variables. PMID- 22240335 TI - Long-term results of iliac aneurysm repair with iliac branched endograft: a 5 year experience on 100 consecutive cases. AB - BACKGROUND: Iliac branch device (IBD) technique has been introduced as an appealing and effective solution to avoid complications occurring during repair of aorto-iliac aneurysm with extensive iliac involvement. Nevertheless, no large series with long-term follow-up of IBD are available. The aim of this study was to analyse safety and long-term efficacy of IBD in a consecutive series of patients. METHODS: Between 2006 and 2011, 100 consecutive patients were enrolled in a prospective database on IBD. Indications included unilateral or bilateral common iliac artery aneurysms combined or not with abdominal aneurysms. Patients were routinely followed up with computed tomography. Data were reported according to the Kaplan-Meier method. RESULTS: There were 96 males, mean age 74.1 years. Preoperative median common iliac aneurysm diameter was 40 mm (interquartile range (IQR): 35-44 mm). Sixty-seven patients had abdominal aortic aneurysm >35 mm (IQR: 40-57 mm) associated with iliac aneurysm. Eleven patients presented hypogastric aneurysm. Twelve patients underwent isolated iliac repair with IBD and 88 patients received associated endovascular aortic repair. Periprocedural technical success rate was 95%, with no mortality. Two patients experienced external iliac occlusion in the first month. At a median follow-up of 21 months (range 1-60) aneurysm growth >3 mm was detected in four iliac (4%) arteries. Iliac endoleak (one type III and two distal type I) developed in three patients and buttock claudication in four patients. Estimated patency rate of internal iliac branch was 91.4% at 1 and 5 years. Freedom from any reintervention rate was 90% at 1 year and 81.4% at 5 years. No late ruptures occurred. CONCLUSIONS: Long-term results show that IBD use can ensure persistent iliac aneurysm exclusion at 5 years, with low risk of reintervention. This technique can be considered as a first endovascular option in patients with extensive iliac aneurysm disease and favourable anatomy. PMID- 22240337 TI - When is supervised exercise therapy considered useful in peripheral arterial occlusive disease? A nationwide survey among vascular surgeons. AB - OBJECTIVES: Although international guidelines state that supervised exercise therapy (SET) should be offered to all patients with intermittent claudication (IC), SET appears to be underutilised in clinical practice. The aim of this study was to document current opinions of Dutch vascular surgeons on SET as treatment option for peripheral arterial occlusive disease (PAOD). MATERIALS AND METHODS: Vascular surgeons and fellows in vascular surgery were asked to complete a 24 question survey either at the 2011 Annual Meeting of the Dutch Society for Vascular Surgery or online. RESULTS: Ninety-one participants, including 83 vascular surgeons (51% of all Dutch vascular surgeons), completed the survey. The respondents would refer 75.4% of newly diagnosed patients with IC for SET. SET was considered less useful in patients with IC and major (cardiopulmonary) co morbidity or a significant iliac artery stenosis. In critical limb ischaemia, the combination of SET and angioplasty was considered useful in 71.9%. Respondents regarded patient satisfaction (63.3%) and improvement in pain-free or maximal walking ability (26.6%) as clinically most relevant goals of SET. Most (84.4%) agreed that SET should also include lifestyle management. CONCLUSION: Although the vast majority of Dutch vascular surgeons consider SET as an important treatment option for PAOD, SET should receive more emphasis in clinical practice since arguments not to refer for SET are outdated. Furthermore, vascular surgeons agree that lifestyle management should be integrated in SET. PMID- 22240336 TI - Validation of a new duplex derived haemodynamic effectiveness score, the saphenous treatment score, in quantifying varicose vein treatments. AB - OBJECTIVES: To evaluate a duplex-derived score for varicose vein treatments using numerical values of haemodynamic effectiveness. DESIGN: The saphenous treatment score (STS) was developed prospectively to compare the effect of endovenous treatments on reflux within saphenous segments. PATIENTS: Sixty-six patients were randomised to endovenous laser ablation (EVLA) or ultrasound-guided foam sclerotherapy (UGFS) to the great saphenous vein (GSV). METHODS: Assessments included the Aberdeen varicose vein severity score (AVVSS), the venous clinical severity score (VCSS), the venous filling index (VFI) and the STS. RESULTS: A mean STS of 5.70 decreased to 3.30, P < .0005, post-treatment. The median (IQR) AVVSS, VCSS and VFI (ml/sec) decreased from 21.52(15.48) to 18.86(11.27), P = .14, from 6(4) to 3(4), P < .0005 and from 7.1(6.9) to 1.9(.9) P < .0005, respectively. In 15 patients requiring additional UGFS the mean STS values decreased from 5.8 to 4.13 and then to 2.6 P < .0005, respectively. The individual above and below knee mean treatment differences in STS on 38 EVLA and 28 UGFS patients were 1.92 and .87 (EVLA) compared to 1.57 and .29 (UGFS) P = .001, respectively. CONCLUSIONS: The STS has been shown to grade the haemodynamic effects of different treatments as well as ongoing treatments on the GSV. PMID- 22240338 TI - Midterm outcomes and risk stratification after endovascular therapy for patients with critical limb ischaemia due to isolated below-the-knee lesions. AB - OBJECTIVES: To assess and risk stratify midterm clinical outcomes after endovascular therapy (EVT) by angioplasty only of patients with critical limb ischaemia (CLI) due to isolated below-the-knee (BTK) lesions. DESIGN: Retrospective multicenter study. MATERIALS AND METHODS: Between March 2004 and October 2010, 465 limbs (Rutherford 5 and 6: 79%) from 406 patients were studied. Overall survival, limb salvage, and re-intervention were examined out to 3 years by the Kaplan-Meier method and the log-rank test. Their independent predictors and risk stratification were analysed. RESULTS: Patient age was 71 +/- 11 yrs, with 69% diabetics and 60% on dialysis. Mean follow-up was 18 +/- 15 months. Overall survival was 76 +/- 2 and 57 +/- 4% at 1 and 3, years, respectively. Survival predictors were body mass index <18, non-ambulatory status and ejection fraction <45%. Two-year limb salvage rate was 80 +/- 2%. Factors associated with major amputation were ulcers (Rutherford 6), diabetes mellitus, C-reactive protein>5 mg/dL, and age < 60 years. Two-year freedom from re-intervention was 66 +/- 3%; age and below-the-ankle runoff number after angioplasty was negatively associated with re-intervention. CONCLUSIONS: Despite relatively high mortality and re-intervention rates, limb salvage rate was acceptable after EVT for CLI patients with isolated BTK lesions. Risk stratification allows occurrence estimation for each end point. PMID- 22240340 TI - Protective immune response against Toxoplasma gondii elicited by a recombinant DNA vaccine with a novel genetic adjuvant. AB - Previous immunological studies from our laboratory have demonstrated the potential role of Toxoplasma gondii antigens SAG1 and GRA2 as vaccine candidates. To further evaluate the vaccine's effects, a series of recombinant DNA vaccines pVAX1-SAG1, pVAX1-GRA2 and pVAX1-SAG1-GRA2, termed pSAG1, pGRA2 and pSAG1-GRA2, respectively, were constructed. A plasmid pVAX1-S/PreS2, termed pSPreS2 encoding hepatitis B virus (HBV) surface antigen (HBsAg) S and PreS2 as a novel genetic adjuvant, was also constructed. The expression abilities of those DNA plasmids were examined in HFF cells by Western blotting. Then BALB/c mice were intramuscularly immunized with DNA plasmids and followed by challenging with the highly virulent T. gondii RH strain. The results demonstrated that the recombinant DNA vaccine pSAG1-GRA2 was capable of eliciting high levels of antibodies, a Th1 type of immune response with significant production of IFN gamma and low levels of IL-4 or IL-10 in BALB/c mice, and partial protection against the acute phase of toxoplasmosis as compared to pSAG1, pGRA2 and controls. In addition, the adjuvant pSPreS2 formulated with DNA vaccine induced a Th1 type of immune response and therefore might be a novel genetic adjuvant to DNA vaccine for further investigation. PMID- 22240339 TI - The mitochondrial K(ATP) channel--fact or fiction? AB - The mitochondrial ATP-dependent K(+) channel (mitoK(ATP)) is widely considered by many to play a central role in cardioprotection by ischemic and pharmacological preconditioning and by ischemic postconditioning. Nevertheless, several laboratories have questioned the existence of mitoK(ATP). This article summarizes the evidence for and against and addresses two key questions: How strong is the evidence for the presence of a K(ATP) channel in mitochondria? Are the pharmacological agents used to modulate mitoK(ATP) activity sufficiently specific to allow the role of these channels in cardioprotection to be established? PMID- 22240341 TI - Impact of vaccine protection against multiple HPV types on the cost-effectiveness of cervical screening. AB - Cross-protection against non-HPV16/18 types and the emergence of broad spectrum vaccines protecting against multiple HPV types will influence the cost effectiveness of future screening. To assess this influence we used an individual based simulation model describing the relation between 14 HPV types and cervical disease, allowing the occurrence of multiple type infections. Screening scenarios for vaccinated women were evaluated, firstly for HPV16/18 vaccination with partial cross-protection against HPV 31, 33, 45 and 58 and secondly, for broad spectrum vaccination against 5-13 HPV types. The vaccine-induced incidence reduction of type-specific infection was varied from 0 to 95% in the cross protection setting and set at 100% in the setting of broad spectrum vaccines. Scenarios of either cytology or HPV DNA screening were considered under varying lifetime number of screening rounds. At a cost-effectiveness threshold of ?20,000/QALY, four times HPV DNA screening between 30 and 60 years was the selected scenario in addition to HPV16/18 vaccination, whether or not cross protection was conferred (?6707 and ?9994/QALY, respectively). In the absence of cross-protection, a fifth screening round might be considered (ICER ?22,967/QALY). In addition to broad spectrum vaccination, one screen during lifetime was cost-effective up to an 11-valent vaccine. If the vaccine-induced type-specific incidence reduction was lowered to 99%, one screen during lifetime was cost-effective even in addition to 13-valent vaccination. In conclusion, in a cohort of HPV16/18 vaccinated women, four rounds of HPV DNA screening is cost effective. One screen during lifetime remains cost-effective in addition to broad spectrum vaccination offering protection against many high-risk HPV types. PMID- 22240342 TI - Oral administration of allergen extracts from mugwort pollen desensitizes specific allergen-induced allergy in mice. AB - Clinically, sublingual immunotherapy (SLIT) using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. We hypothesized that oral administration of a high-dose of allergen extracts imitates SLIT, which may prevent IgE-related responses in allergic diseases. In the present study, we investigated the effects of oral administration of allergen extracts from mugwort pollen (MP) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in an allergic mouse model. After administration of MPdrop containing Art v 1 and Art v 4 extracts derived from MP specifically in MP-sensitized mice, the effects of MPdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, and serum IgE and IgG levels were investigated. The results indicated that MPdrop not only prevented the AHR in response to methacholine in a dose-dependent manner but also significantly reduced the total serum and allergen-specific IgE levels. All of the maximal effects were achieved at a dose of 100MUg/(kgd) and were comparable to the effects of dexamethasone at a dose of 0.5mg/(kgd). Furthermore, oral administration of MPdrop dose-dependently elevated allergen-specific serum IgG2a levels, reduced total and allergen-specific IgE levels and normalized the imbalance between the Th1 cytokine IL-12 and Th2 cytokines IL-4 and IL-5. Finally, oral administration of MPdrop significantly reduced goblet cell hyperplasia and eosinophilia in the MP-sensitized allergic mouse model. These data suggest that MPdrop effectively improves specific allergen-induced inflammation and AHR in MP-sensitized and -challenged mice and provides the rationale for clinical use of MPdrop in the specific allergen-induced asthma. PMID- 22240343 TI - Heparanase DNA vaccine delivered by electroporation induces humoral immunity and cytoimmunity in animal models. AB - Electroporation (EP)-assisted DNA vaccination has been proven effective as an approach to the treatment of cancer. Although heparanase (HPA) is a potential target for patients with advanced tumor diseases, the efficacy of immunotherapeutic strategies targeting HPA has never been evaluated. In this study, humoral immunity was elicited using genetic vaccinations between C57BL/6J mice and Macaca fascicularis. The immunized serum neutralized HPA activity and attenuated the invasion of B16 cells in vitro. In addition, T lymphocytes from the splenic cells of the immunized mice induced HPA-specific cytotoxic lymphocytes (CTLs), which verified cytoimmunity. Prophylactic vaccination significantly suppressed tumor growth and metastasis in vivo and prolonged the survival rate in tumor-bearing murine models. In addition, RT-PCR and Western blot analyses of the primary tumors indicated less proliferation and angiogenesis and more apoptosis in the HPA-immunization immunotherapy groups. Simultaneously, the levels of IL-2, IL-4, and IFN-gamma were not significantly greater in the HPA immunized group than in PBS controls. Thus, we conclude that the combination of an anti-HPA antibody and a CTL response in HPA-immunization gene therapy is enough to attenuate tumor growth and metastasis. This is the first time that a DNA vaccine targeting HPA immunization assisted by EP has induced humoral immunity and cytoimmunity in vivo. This provides a basis for the continued development of DNA vaccines targeting HPA and the use of such vaccines in clinical settings. PMID- 22240344 TI - CD205 antigen targeting combined with dendritic cell recruitment factors and antigen-linked CD40L activation primes and expands significant antigen-specific antibody and CD4(+) T cell responses following DNA vaccination of outbred animals. AB - Dendritic cell antigen targeting primes robust immune responses in mouse models. Optimizing this immunization strategy in the actual hosts that require protection will advance development of efficacious contemporary vaccines. In a proof-of concept study, we tested the immunogenicity of a single, low dose of a novel multi-component DNA construct expressing a CD205-targeted antigen fused to a CD40L minimal functional domain for linked DC activation. The DNA construct was formulated with DNA-encoded Flt3L and GM-CSF for DC recruitment and the formulation was evaluated in MHC class II-matched calves. Immunization of the calves with the CD205 antigen-targeting construct mixed with the cytokine constructs induced significant IFN-gamma-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and antibody responses detectable within one week post immunization. CD205 antigen-targeting significantly expanded IFN-gamma-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and IgG antibody responses three weeks post-immunization. Nineteen weeks post-priming, the IFN-gamma-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and the IgG titers were waning, but they remained significant. Following boosting at nineteen weeks post immunization, the immune responses primed by the CD205-targeted antigen underwent rapid recall and the mean response tripled within one week post-boost. Comparative analysis of the immune responses observed one week post-priming versus the responses detected one week post-boost revealed that the average number of the IFN-gamma-secreting CD4(+) T-cells observed in the calves immunized with the CD205 antigen targeting construct increased five-fold, the mean CD4(+) T cell proliferation increased three-fold, whereas the mean IgG antibody titer increased two hundred-fold. These promising outcomes support testing the protective efficacy of CD205-targeted antigens in the calf model. PMID- 22240345 TI - CIGB-247: a VEGF-based therapeutic vaccine that reduces experimental and spontaneous lung metastasis of C57Bl/6 and BALB/c mouse tumors. AB - CIGB-247 is a novel cancer therapeutic vaccine that uses a mutated form of human VEGF as antigen. Being metastatic disease the most dramatic factor of tumor biology affecting patient survival and cure, preclinical evaluation of the impact of CIGB-247 vaccination on experimental metastasis mouse models is highly relevant, and constitutes the focus of this work. CIGB-247 was administered in a weekly schedule known to effectively reduce primary tumor growth. The vaccine was tested in experimental and spontaneous metastasis models of colon (CT26), lung (3LL-D122) and breast (F3II) carcinomas growing in C57Bl/6 or BALB/c mice. Primary tumor growth parameters, metastatic counts, and/or animal survival were recorded. Histology and specific humoral and cellular responses to the vaccine were evaluated. As compared to control groups, CIGB-247 vaccination significantly reduced the number and size of metastatic tumor foci in lungs after intravenous inoculation of CT26 and 3LL-D122 tumor cells. Spontaneous lung dissemination from 3LL-D122 and F3II breast tumor cells implanted in the footpad, or subcutaneously, was also reduced by immunization with CIGB-247. The vaccine elicited in both mouse strains antibodies specific for human and murine VEGF that effectively blocked the interaction of VEGF with VEGF receptor 2. Differing from other experimental reports that describe the use of VEGF for active tumor immunotherapy, CIGB-247 elicited a specific cellular response, measured both by a DTH increment and the induction of spleen cells cytotoxic to syngeneic tumor cells producing murine VEGF. In summary our results reinforce the potential of CIGB-247 vaccination to reduce both tumor growth and the number and size of tumor metastasis in lungs, the latter both after direct inoculations of cells in the blood stream, or as part of primary tumor progression in immunocompetent mice. PMID- 22240346 TI - Differential effects of intravenous anesthetics on hepatosplanchnic microcirculation in rats: sidestream dark-field imaging study. AB - This study aimed to investigate the effects of intravenous anesthetics on hepatosplanchnic microcirculation in laparotomized mechanically ventilated rats using Sidestream Dark-field (SDF) imaging. Thirty male Wistar rats were divided into 5 groups (n = 6 each). All rats were initially anesthetized with 60 mg/kg pentobarbital (i.p.) for instrumentation. This was followed by either ketamine, propofol, thiopental, midazolam or saline+fentanyl (iv bolus over 5 min and then maintenance over 90 min). SDF imaging of the liver and distal ileum microcirculation was performed at the baseline and at t = 5, 35, 65 and 95 min. In propofol group there was increase of functional sinusoidal density (FSD) following induction (+25%, P < 0.05) and maintenance at t = 95 min (+10.3%, P < 0.05), in ketamine and midazolam group decrease of FSD was observed after induction (-20.4%, P < 0.05; -10.1%, P < 0.05) and during maintenance at t = 65 min (-11.6%, P < 0.05; -11.4%, P < 0.05) when compared to baseline. Following induction with propofol functional capillary density (FCD) of ileal longitudinal muscle layer increased (+10.6%, P < 0.05) and returned to baseline values during maintenance. Ketamine and midazolam decreased FCD of longitudinal layer after induction (-24.6%, P < 0.05; -21.1%, P < 0.05) and remained decreased during maintenance at t = 95 min (-10.8%, P < 0.05; -15.5%, P < 0.05). In thiopental and control group, changes in microcirculatory parameters were not significant throughout the study. In conclusion, intravenous anesthetics affect the hepatosplanchnic microcirculation differentially, propofol has shown protective effect on the liver and intestinal microcirculation. PMID- 22240347 TI - Erythrocyte deformability evaluated by laser diffractometry in polycythemia vera. AB - We evaluated the erythrocyte deformability in a group of subjects with polycythemia vera (PV) using a Rheodyn-SSD Laser Diffractometer, at the shear stresses of 6, 12, 30 and 60 Pa. Our data showed a significant decrease of red cell deformability, expressed as elongation index (EI), in PV subjects compared with normal controls. These results suggest that the hyperviscosity syndrome accompanying this myeloproliferative disease may be considered a mixed form, resulting from the association of a polycythemic condition with a sclerocythemic disorder. PMID- 22240348 TI - Protein oxidation in mild essential hypertension. PMID- 22240349 TI - The determination of tissue perfusion and collateralization in peripheral arterial disease with indocyanine green fluorescence angiography. AB - PURPOSE: Indocyanine green (ICG) fluorescence angiography is used to evaluate tissue perfusion in many different medical fields. This study aims to evaluate the value of ICG angiography in the determination of tissue perfusion in the PAD lower extremities. MATERIAL AND METHODS: In a prospective clinical study, ICG angiography was used to evaluate tissue perfusion and collateralization in 30 PAD patients. The perfusion index and maximum fluorescence intensity (MPI) were calculated as arterial perfusion parameters. RESULTS: Significant differences in the perfusion index were found for the different PAD stages (p < 0.001). Poor collateralization was associated with a significantly lower perfusion index than good collateralization (p = 0.003). A ROC analysis for the perfusion index showed a positive likelihood ratio of 6.00 and a negative likelihood ratio of 0.00 with an area under the curve of 0.949 to discriminate critical and non-critical PAD. CONCLUSION: ICG angiography is a promising diagnostic tool to quantify tissue perfusion and demonstrate critical limb ischemia and collateralization in lower extremities affected by PAD. PMID- 22240351 TI - Ischaemic postconditioning reduces serum and tubular TNF-alpha expression in ischaemic-reperfused kidney in healthy rats. AB - OBJECTIVE: We studied the protective effects of postconditioning (PS) in healthy and hypercholesterolemic rats after renal ischaemia-reperfusion (IR) injury. We aimed to examine cytokine expression and apoptosis in tissue damage after revascularisation (TNF-alpha levels in serum and tissue). METHODS: Male Wistar rats (n = 32) were divided into four groups. The animals of normal feed groups (NF) were fed with normal rat chow and the cholesterol feed groups (CF) were fed with 1.5% cholesterol containing diet for 8 weeks. Anaesthetized rats underwent a 45-min cross-clamping in both kidney pedicles. Ischaemia was followed by 120-min reperfusion with or without PS protocol (group PS vs. IR). Postconditioning was induced by four intermittent periods of ischaemia-reperfusion of 15-s duration each. Serum cholesterol, triglyceride, urea and creatinine levels were determined. Proinflammation was characterized by the measurement of serum TNF alpha. Tissue injury in kidney was determined by formaline-fixed, paraffin embedded tissue sections. Tissue TNF-alpha levels were determined by immunohistochemistry. RESULTS: Significant elevation was observed in serum TNF alpha level after IR injury in normal feed groups, which was reduced by PS. In CF group neither the elevation nor the postconditioning induced reduction were as significant as in the NF groups. In normal feed group PS caused a significant reduction in tissue TNF-alpha level which was significantly higher in CF. CONCLUSIONS: Ischaemic postconditioning proved to be an effective defense against IR in NF groups, but it was ineffective in CF groups in kidney tissue. PMID- 22240352 TI - Relationships between insulin sensitivity measured with the oral minimal model and blood rheology. AB - In studies using the intravenous glucose tolerance test with minimal model analysis we reported that low insulin sensitivity (SI) is associated with increased erythrocyte aggregability and plasma viscosity, that appeared to be markers of insulin resistance. Recently, development of modelling has made available a new approach of insulin sensitivity from oral glucose tolerance test data (oral minimal model). We aimed at determining in 111 subjects (51 men, 62 women, age 11-77 yr), insulin sensitivity with this approach together with blood viscosity parameters. With this approach the Myrenne indexes of red cell aggregation were negatively correlated to SI (M; r = -0.456; p = 0.0007; M1; r = 0.397; p = 0.004) while plasma viscosity was not. Correlations with fasting insulin levels (Ib) were weaker (M; r = 0.2711; p = 0.05; M1; r = 0.373; p = 0.007). Accordingly, a stepwise regression analysis selects M as the best correlate of SI and M1 as the best correlate of Ib. With this approach plasma viscosity does not exhibit any clear relationship with SI. This study supports the concept that RBC hyperaggregability is the prominent hemorheologic symptom of insulin resistance. PMID- 22240353 TI - Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. AB - Several beneficial effects of resveratrol (RES), a natural antioxidant present in red wine have already been described. The aim of our study was to investigate if RES had a clinically measurable cardioprotective effect in patients after myocardial infarction. In this double-blind, placebo controlled trial 40 post infarction Caucasian patients were randomized into two groups. One group received 10 mg RES capsule daily for 3 months. Systolic and diastolic left ventricular function, flow-mediated vasodilation (FMD), several laboratory and hemorheological parameters were measured before and after the treatment. Left ventricular ejection fraction showed an increasing tendency (ns) by RES treatment. However, left ventricular diastolic function was improved significantly (p < 0.01) by RES. A significant improvement in endothelial function measured by FMD was also observed (p < 0.05). Low-density lipoprotein (LDL) level significantly decreased (p < 0.05) in the RES treated group. Red blood cell deformability decreased and platelet aggregation increased significantly in the placebo group (p < 0.05), while resveratrol treatment has prevented these unfavourable changes. Concerning other measured parameters no significant changes were observed neither in placebo nor in RES group. Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD). PMID- 22240354 TI - Minimal model-derived insulin sensitivity, insulin secretion and glucose tolerance: relationships with blood rheology. AB - Insulin resistance is associated with a mild hyperviscosity syndrome, which is more closely related to insulin resistance than to the clinical scoring of the metabolic syndrome. In studies using the intravenous glucose tolerance test with minimal model analysis we reported that low insulin sensitivity (SI) is associated with increased erythrocyte aggregability (EA). Actually, this issue is confusing because insulin resistance is often associated with compensatory hyperinsulinemia (insulin being a hormone with reported hemorheologic effects) and that a decline in insulin secretion has marked metabolic effects that modify blood rheology. From the intravenous glucose tolerance test (IVGTT) the minimal model allows the calculation of SI, insulin response, and an overall glucose tolerance parameter termed "disposition index" (DI) that measures whether insulin response is adequate or not for the level of insulin sensitivity. In this study we assessed SI, insulin response, and DI during an IVGTT in 335 subjects of both genders (age 8-77 yr; BMI 14-67 kg/m2). SI was only correlated (negatively) with EA (Myrenne M r = -0.285; p = 0.0001; M1 r = -0.240 p = 0.003). Fasting insulin was also correlated (positively) with EA (Myrenne M r = 0.233, 0.00880; M1 r = 0.320 p = 0.0003; SEFAM TA r = -0.342 p = 0.04; SEFAM S60 r = 0.419 p = 0.01) and SEFAM RBC disaggregation thresholds (gammaS = r = 0.372 p = 0.025; gammaD = r = 0.504 p = 0.002). Fasting DI (SI * fasting insulin) is negatively correlated to M (r = -0.274; p = 0.002) and M1 (r = -0.225; p = 0.01) but also positively to whole blood viscosity (r = 0.168; p = 0.01) and hematocrit (r = 0.142; p = 0.05). Stimulatory DI (SI * insulin peak) fails to be correlated with any parameter of EA but is negatively correlated to whole blood viscosity (r = -0.150; p = 0.02) and plasma viscosity (r = -0.163; p = 0.01). This study confirms that red cell aggregability is associated with insulin resistance and hyperinsulinemia, but plasma viscosity seems to be more related to overall glucose tolerance than to either SI or insulinemia. PMID- 22240355 TI - Rheological blood behaviour is not related to gender in morbidly obese subjects. PMID- 22240356 TI - Association between red blood cell distribution width and the risk of future cardiovascular events. AB - In patients with acute myocardial infarction (AMI), high red blood cell distribution width (RDW) seems to predict further cardiovascular events, although the mechanism and its possible relation with anaemia and inflammation remains uncertain. We determined in 119 AMI patients before hospital discharge RDW, along with haemoglobin, haematimetric indices and inflammatory parameters (fibrinogen, C-reactive protein, plasma viscosity, neutrophil count). In the follow-up period (21 +/- 11 months), 30 patients (25%) developed a recurrent cardiovascular event. In the lineal regression analysis, MCH and neutrophil count were independent determinants for RDW (beta coefficient = -0.544 p < 0.001; beta coefficient: 0.279 p = 0.001, respectively). The logistic regression analysis showed that RDW >14% increases the risk of future events by 6 times; OR 6.19 IC 95% (2.1-18.5); even after adjusting for anaemia, mean corpuscular haemoglobin (MCH) <27 pg/L, fibrinogen >400 mg/dL and neutrophil count >5.7 (103/MUL). Our results confirm that RDW, an available and inexpensive measurement reported in routine blood cell counts, seems to be an independent predictor for recurrent cardiovascular events in AMI patients. As we found no association of RDW with either anaemia or inflammatory parameters, the mechanism responsible for increased RDW deserves further research. PMID- 22240357 TI - Erythrocyte deformability dependence on band 3 protein in an in-vitro model of hyperfibrinogenemia. AB - Recent evidence has shown that plasma fibrinogen, a major cardiovascular risk factor, interacts with the erythrocyte membrane and acts to influence blood flow via erythrocyte nitric oxide (NO) modulation. In the present in-vitro study, whole blood samples were harvested from healthy subjects and aliquots were incubated in the absence (control aliquots) and presence of fibrinogen at different degrees of band 3 phosphorylation, and the erythrocyte deformability was determined. The present study shows that in the presence of higher fibrinogen concentrations, similar to those found in inflammatory conditions, erythrocyte deformability is increased only when band 3 is dephosphorylated by the presence of syk inhibitor and at low shear stress. On the contrary, no changes were verified in the presence of fibrinogen when band 3 is allowed to be phosphorylated by inhibiting the phosphotyrosine phosphatase enzyme activity with calpeptin. We also observed that the presence of fibrinogen at higher concentration does not induce changes in erythrocyte deformability in the absence of modulators of the band 3 phosphorylation degree. However, the mechanisms by which fibrinogen signalling modulates erythrocyte function remain to be clarified and are currently under study. PMID- 22240358 TI - Hemorheological consequences of hind limb ischemia-reperfusion differs in normal and gonadectomized male and female rats. AB - It is known that hemorheological parameters show gender differences that might be altered by gonadectomy (GoE). Since micro-rheological parameters (erythrocyte deformability and aggregation) sensitively change during and after ischemia reperfusion (I/R), the question arises whether the hemorheological effects of I/R may show gender differences and further changes might be expected when GoE and I/R are additive. Sprague-Dawley rats were divided into six groups: Control males and females, I/R males and females with 1-hour hind limb ischemia, GoE + I//R males and females when 3 months after bilateral gonadectomy the I/R was induced. Before and just after ischemia, and on the 1st-3rd-5th-7th postoperative days blood samples were taken (lateral tail vein, 0.3-0.5 mL) for analyzing hematological parameters, erythrocyte's deformability (slit-flow ektacytometer) and aggregation (light-transmission aggregometer). Leukocyte and platelet counts raised markedly in gonadectomized animals during the investigated days. Hemorheological changes of I/R showed gender differences: significant impairment of erythrocyte deformability was found on the 1st-3rd postoperative days, expressed mostly in females. In gonadectomized females the postischemic deformability values were impaired. Erythrocyte aggregation index significantly raised by the 1st postoperative day, dominantly in males. It is suggested that gonadectomy may act as an additional rheological 'risk factor' related to blood micro-rheological parameters in ischemia-reperfusion. PMID- 22240359 TI - The importance of rheological parameters in the therapy of the dry form of age related macular degeneration with rheohaemapheresis. AB - To date, rheological treatment is the only chance to control the advanced dry form of age-related macular degeneration and arrest its progression to legal blindness. Rheohaemapheresis can change the main rheological parameters, blood and plasma viscosity, as well as change erythrocyte aggregability, improve erythrocyte flexibility and lead to substantial improvement when other methods of therapy fail. In this study, we describe changes in the levels of rheological efficacy indicators after rheohaemapheresis and their clinical significance in the dry form of age-related macular degeneration (AMD). Seventy-two patients with AMD were randomised; 34 controls, and 38 patients were treated with rheohaemapheresis (separator Cobe Spectra + Evaflux filter). After the procedures, alpha2-macroglobulin levels decreased by approximately 58%, fibrinogen by approximately 65%, IgM by approximately 67%, LDL cholesterol by approximately 71%, apolipoprotein B by approximately 65%, and lipoprotein (a) by approximately 42%. These decreases correspond with a decrease in blood and plasma viscosity (14/12%), clinical improvement (arrest of disease progression, even visual improvement in some cases), and heretofore-unreported improvement (even reattachment) of drusen retinal pigment epithelium detachment. Our modification of rheohaemapheresis is safe (5.4% of patients experienced clinically insignificant side effects). PMID- 22240360 TI - Arterio-venous gradients of endothelial progenitor cells reveal a complex kinetics in human limb ischemia. AB - Ischemic recruitment of endothelial progenitor cells (EPCs) in involved in compensatory angiogenic in animal models, but this still needs to be substantiated in humans. We enrolled 12 patients, who underwent surgical correction of abdominal aortic aneurysm without atherosclerosis of leg arteries (n = 4) or lower limb atherosclerosis obliterans (AO; n = 8). We measured VEGF, SDF-1, lactate and CD34+ KDR+ EPCs in the arterial and venous circulation of lower limbs. We found that, irrespectively of AO stage and lactate production, there was no consistent arterio-venous gradient of EPC, VEGF and SDF-1. Notably, in 4/8 patients, EPCs were more abundant in the vein than in the artery. EPC gradient was directly correlated with VEGF gradient and inversely correlated with SDF-1 gradient. In conclusion, we failed to show any consistent gradient of EPCs across ischemic limbs in relation to severity of atherosclerosis obliterans, but we speculatively suggest that a bidirectional traffic of EPCs in and out the ischemic tissue might be regulated by VEGF and SDF-1. PMID- 22240361 TI - Following-up hemorheological consequences of gonadectomy in male and female rats. AB - Growing number of clinical and experimental data reflect to the gender differences of hemorheological parameters. However, little is known about the potential hemorheological effect of gonadectomy and consequent changes in sex hormone concentration. Adult, same-aged male and female rats were involved in the study. In control male and female group no surgical intervention was performed. In gonadectomized (GoE) male and female groups bilateral orchidectomy or ovariectomy were completed. Body weight measurement and blood sampling were carried out in the 1st, 2nd and 3rd postoperative months. The GoE females had significant bodyweight augmentation and their plasma estrogen concentration decreased by 40-45% by the 1st postoperative month, while in males the testosterone level was not detectable after gonadectomy. Leukocyte and platelet counts moderately increased in GoE males. Elongation index values of erythrocytes slightly decreased in both genders after gonadectomy, showing converging values. Erythrocyte aggregation index values of GoE females significantly raised by the 2nd month. It can be concluded that gonadectomy in rats resulted in alteration (dominantly impairment) of blood microrheological parameters, by different manner in males and females. Supposedly decrease in estrogen can cause more expressed hemorheological changes than the cessation of testosterone. PMID- 22240362 TI - Protective effects of 3,4-dihydroxyphenyl lactic acid on lipopolysaccharide induced cerebral microcirculatory disturbance in mice. AB - This study intended to examine the effect of 3,4-dihydroxyphenyl lactic acid (DLA), a major ingredient of Salvia miltiorrhiza, on lipopolysaccahride (LPS) induced mouse cerebral cortical microcirculatory disturbance. Velocity of red blood cells in, and albumin leakage from venules, and the numbers of leukocytes rolling on, and adherent to the venular wall were determined by an up-right microscope after LPS (5 mg/kg/h) infusion with or without administration of DLA (5 mg/kg/h). Expression of adhesion molecules CD11b/CD18 and L-selectin on neutrophils, plasma concentration of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were evaluated by flow cytometry. Concentration of TNF-alpha in supernatants of LPS-stimulated mononuclear cells was evaluated in vitro by flow cytometry as well. LPS exposure significantly increased the number of rolling and adherent leukocytes as well as albumin leakage, and decreased the velocity of red blood cells in venules. In addition, LPS stimulation apparently increased the expression of CD11b/CD18 on neutrophils, the concentration of plasma TNF-alpha, and the production of TNF-alpha from mononuclear cells. Treatment with DLA significantly ameliorated LPS-induced insults in mice, including cerebral microcirculatory disturbance, the expression of CD11b/CD18 on neutrophils, and the increased concentration of plasma TNF-alpha and the production of TNF-alpha from mononuclear cells. PMID- 22240363 TI - Study of erythrocyte aggregation at pulsatile flow conditions with backscattering analysis. AB - In vivo red blood cell aggregation will vary under pulsatile flow but few studies have been reported due to various difficulties in generating physiological flow conditions and detecting RBC aggregation. The present study developed a microfluidic system that generates cyclic pulsatile flow through a microchannel. Backscattered light signals from human blood were recorded over time and analyzed for RBC aggregation in pulsatile flow. Four different blood samples (control, normal RBCs in PBS, hardened RBCs in autologous plasma, and hardened RBCs in PBS) were examined. In a cyclic pulsatile flow condition, light intensity-time curve for the control and hardened RBCs in plasma exhibited apparent critical shear stresses that were similar to the respective values measured at a single pulse flow condition. During entire cycles of pulsatile flow, the measured critical shear stress remained nearly constant. We conclude that the critical shear stress can be observed in cyclic pulsatile flow and would be an important index to represent in-vivo pulsatile blood flow rheology. PMID- 22240364 TI - Whole blood viscosity and erythrocyte deformability are related to endothelium dependent vasodilation and coronary risk in the elderly. The prospective investigation of the vasculature in Uppsala seniors (PIVUS) study. AB - It has previously been shown that a high hemoglobin value, a major determinant of whole blood viscosity (WBV), predicts cardiovascular events. One putative mechanism might be an impaired endothelial function. Erythrocyte deformability is another rheologic feature of the erythrocyte being of importance for the flow properties of the blood, especially in the capillaries. The present study evaluates the relationships between blood viscosity, erythrocyte deformability assessed as erythrocyte fluidity (EF), coronary risk and endothelial vasodilatory function. In the population-based PIVUS study (1016 subjects aged 70); endothelium-dependent vasodilation (EDV) was evaluated by the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). WBV, plasma viscosity (PV) and EF were measured in a random sample of 573 subjects. WBV and PV were positively and EF negatively related to Framingham risk score. EDV was inversely related to both whole blood and plasma viscosity. FMD was not related to any rheologic variable. In multiple regression analyses WBV and EF were significantly related to EDV independently of gender, hypertension, smoking, hypercholesterolemia, obesity and diabetes. Acetylcholine-induced vasodilation in the forearm, but not FMD, was negatively related to whole blood viscosity and positively related to EF independently of traditional risk factors in elderly subjects, indicating a pathophysiological link between impaired hemorheology and coronary risk. PMID- 22240365 TI - Lack of association between systolic blood pressure and blood viscosity in normotensive healthy subjects. AB - OBJECTIVE: A direct relationship between blood pressure and viscosity has frequently been reported, although clear data are not available. To better understand the relationship between these two variables, we evaluated blood viscosity and blood pressure in a group of healthy subjects without cardiovascular risk factors. METHODS: Healthy subjects were selected from participants in a campaign of prevention of cardiovascular disease (n = 103). They underwent blood sampling for measurement of plasma and blood viscosity, haematocrit, blood lipids and glucose. The quantity and distribution of body fat was assessed by body mass index and waist/hip ratio, respectively. RESULTS: Systolic blood pressure (SBP) correlated significantly with age (r = 0.222) and waist/hip ratio (r = 0.374). Diastolic blood pressure (DBP) correlated significantly with waist/hip ratio (r = 0.216), haematocrit (r = 0.333) and blood viscosity (r = 0.258). Multiple linear regression analyses demonstrated that the only variable significantly associated with SBP was age, while haematocrit was the only variable significantly associated with DBP. Blood viscosity was closely related to waist/hip ratio. CONCLUSION: These findings show that SBP, in healthy subjects, is not influenced by haematocrit and blood viscosity. In contrast, DBP is related to the values of haematocrit. Among classical cardiovascular risk factors, waist/hip ratio is closely related to blood viscosity. PMID- 22240366 TI - Effects of vasoactive substances on the neurovascular structures and microcirculation in the developing callus 10 and 15 days after bone injury. AB - The developing callus requires sufficient oxygen and substrate supply. Despite the importance of these processes, we have limited understanding of regulation of the callus microcirculation. We aimed to assess the role of vasoactive substances in the microcirculation of the callus in a gap osteotomy model in the rabbit detected by laser-Doppler flowmetry. The reactions were elicited with locally applied vasoactive substances: epinephrine (E), calcitonine-gene related protein (CGRP), substance P (SP), sodium nitroprusside (SNP) and Ebrantil (Ebr) on the 10th and 15th postoperative days. Changes of the circulatory parameters were compared to changes in the ipsilateral femoral bone marrow. Perfusion pressure, maximal change of the blood flow and 50% recovery time (50RT) of the flow reactions and peripheral micro vascular resistance (MVR) was calculated. Systemic blood pressure (BP) was measured directly with an arterial catheter. Reactive neurovascular structures, sensitive to neuropeptides and vasoactive substances, appear at a very early stage of callus formation. On the 10th postoperative day, 2/3 of the blood flow velocity of the intact tibia has already returned, and the values are higher on the 15th postoperative day than those of the intact tibia. The basal blood flow velocities (prior to administration of any substance) are significantly higher on the 15th postoperative day than on the 10th. PMID- 22240367 TI - "Studying the cutaneous microcirculatory response during upper-limb exercise in healthy, older, sedentary people". AB - This study investigated changes incurred in cutaneous skin blood flux (SKBF) in the superficial veins of the lower limb by upper limb exercise training in the form of arm-cranking in 14 healthy participants over the age of 50 years. Changes in cutaneous microvascular function of the lower leg were assessed using laser Doppler Flowmetry (LDF) during a 30-minute exercise session undertaken over 4 exercise periods. Both SKBF and Time to reach Peak Perfusion (Tmax) were improved significantly during the 2nd (e.g. 121 (+/- 107.2) vs 280 (+/- 269.1) and 171 (+/ 34.4) vs. 247 (+/- 38.3) respectively) when compared to the first exercise period, while values approaching initial levels in the following stages. The results indicate that the thermoregulatory and vasodilation mechanisms observed during exercise in middle-aged and older healthy people are different to the one appearing in younger age groups, suggesting a more extensive effect of the age related structural changes than it was previously thought. PMID- 22240368 TI - Rheological alterations and thrombotic events in patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Nevertheless, how hemorheological alterations contribute to thrombotic risk remains a question of debate. We aimed to determine the rheological profile in 105 patients with SLE (24 with a thrombotic event) and 105 healthy controls. We determined blood viscosity and erythrocyte aggregation along with plasma lipids and fibrinogen. Although SLE patients showed lower blood viscosity at 230 s(-1) at a native hematocrit when compared with controls (p < 0.001), differences disappeared after adjusting the hematocrit to 45% (p = 0.095). When comparing SLE patients with and without thrombotic events, no differences in any rheological parameter were found (p > 0.05), except in fibrinogen which was higher in patients with thrombosis (p = 0.013). No differences in the rheological parameters were observed when venous and arterial thrombotic events were compared, although a tendency for higher fibrinogen was observed in patients with venous thrombosis (p = 0.053). Only hematocrit, fibrinogen and triglycerides were independent predictors of native blood viscosity in the multivariate regression analysis, even after adjusting for continuous variables and for tobacco and hypertension: beta coefficient: 0.727 p < 0.001; beta coefficient: 0.152 p = 0.003 and beta coefficient: 0.133 p = 0.015, respectively. The logistic regression analysis revealed that neither increased native blood viscosity (BVn > 4.33) nor increased erythrocyte aggregation (EA1 > 7.85) increased thrombotic risk: OR 0.636, CI 0.313-3.12, p = 0.578 and OR 2.01, CI 0.77-5.20, p = 0.152, respectively. However, hyperfibrinogenemia (Fbg > 342 mg/dL) increased thrombotic risk by around three times: OR 3.44 CI 1.32-8.96, p = 0.011. Our results suggest that the role of blood viscosity and erythrocyte aggregation in thrombotic risk in SLE patients fails to demonstrate any association. PMID- 22240369 TI - Concerning the importance of changes in hemorheological parameters caused by acid base and blood gas alterations in experimental surgical models. AB - Acid-base equilibrium and pH of blood have important clinical consequences in numerous diseases and pathophysiological conditions. The micro-rheological parameters of blood, such as red blood cell deformability and red blood cell aggregation are influenced by several metabolic factors, and provide information regarding inflammatory, septic and tissue or organ ischemia-reperfusion processes. Despite the anticipated logical relation of the blood acid-base condition, blood gas parameters and pH to red blood cell deformability and aggregation, controversial data can be found in the literature. Furthermore, related to ischemia-reperfusion hemorheological studies little is known about this issue. In this paper we aimed to thought-provokingly overview some aspect of acid-base changes, blood pH and hemorheological parameters, discussing certain results from ischemia-reperfusion experimental surgical models (local versus systemic changes), laboratory technical and experimental design protocols related to in vitro and in vivo studies. PMID- 22240370 TI - Elevated hematocrit in nonalcoholic fatty liver disease: a potential cause for the increased risk of cardiovascular disease? AB - BACKGROUND AND AIM: Hematocrit is an important hemorheological parameter. Both hematocrit and nonalcoholic fatty liver disease (NAFLD) are strongly correlated with cardiovascular disease. However, there is no study to explore the direct relationship of hematocrit with NAFLD. METHODS: Hematocrit levels were analyzed from 1,821 Chinese Han adults, and questionnaire and physical examination were administered to know and suspect the relationship with NAFLD. RESULTS: NAFLD morbidity was positively correlated with hematocrit levels in both male and female. Multivariate-adjusted odds ratio illustrated that, compared with the lowest quartile of hematocrit, the highest quartile subjects had a 185% and 386% increased risk for developing NAFLD in male and female, respectively. Further receiver operating characteristic analysis showed that the optimal cutoff value of hematocrit for detecting NAFLD was 42.75 in male and 37.55 in female. Unhealthy lifestyles had similar effects on NAFLD and hematocrit. CONCLUSIONS: The prevalence of NAFLD is positively associated with hematocrit levels. Though the cause-effect relationship between NAFLD and hematocrit still needs further investigation to clarify, the elevated hematocrit in NAFLD patients may be of significance to link NAFLD and cardiovascular disease. PMID- 22240371 TI - Blood viscosity and hemodynamics during exercise. AB - We tested the effects of submaximal exercise on blood viscosity (eta(b)), nitric oxide production (NO) and hemodynamics. Relationships between the exercise induced changes that occurred in these parameters were investigated. Nine subjects performed exercise for 15 min at 105% of the first ventilatory threshold. Mean arterial pressure (MAP) and cardiac output (Qc) were measured, allowing the determination of systemic vascular resistance (SVR). Blood was sampled at rest and at the end of exercise. The eta(b) was determined at high shear rate and was used to calculate systemic vascular hindrance (VH). NO production was estimated by measuring plasma concentrations of NO stable end products (NOx). Qc, MAP, eta(b) and NOx, increased with exercise, whereas SVR and VH decreased. The changes between rest and exercise were calculated and tested for correlations. We observed: 1) a positive correlation between the increase in eta(b) and the increase in NOx; 2) a negative correlation between the increase in NOx and the decrease in VH; 3) a negative correlation between the increase in eta(b) and the decrease in SVR. Although the increase in Qc and blood flow during exercise probably promoted NO production due to shear dependent stimulation of the endothelium, the present results also support that the rise in eta(b) during exercise may be necessary for NO production and adequate vasodilation. PMID- 22240372 TI - Microvascular abnormalities in the bulbar conjunctiva of contact lens users. AB - Soft contact lenses are commonly used to improve vision acuity or in cosmetic enhancement. We hypothesize that contact lens use can cause inadvertent damage to either the conjunctival microcirculation via direct vasoocclusion when the lens physically interacts with or damages the underlying vessels, or to the bulbar conjunctiva itself when the lens rests unevenly on the surface of the bulbar conjunctiva. Computer-assisted intravital microscopy was utilized to document (via video recording) and objectively quantify (via image analysis) real-time microvascular abnormalities resulting from changes and vessel remodeling in the conjunctival microcirculation in long-term (>2 yrs) contact lens users (n = 102), with non-users serving as control subjects (n = 29). A severity index (SI)- computed as the arithmetic sum of the abnormalities found in the conjunctival microcirculation in each contact lens user--was established for objective comparison with control subjects and critical interpretation. Contact lens user SI was significantly higher than control SI (user = 6.21 +/- 1.26; control = 2.31 +/- 1.49; p < 0.05), indicative of severe vasculopathy arising from contact lens use. The users also had significantly wider conjunctival vessel diameter (user = 71.25 +/- 12.09 MUm; control = 52.20 +/- 5.10 MUm; p < 0.05). Additional abnormalities, including damaged vessels, hemosiderin deposits (from damaged vessels or injury to the surface of the bulbar conjunctiva), vessel sludging, intermittent blood flow, and vessel tortuosity were commonly found in or adjacent to locations where the contact lens physically rested on the underlying conjunctival vessels. These results strongly suggest that microvascular abnormalities and remodeling changes occurred as a result of the inadvertent physical interaction of the lenses with either the underlying conjunctival vessels or the surface of the bulbar conjunctiva in contact lens users. PMID- 22240373 TI - Videocapillaroscopy study of post traumatic lower limb loss of tissue treated with and without acellular dermal substitute. AB - A 46 years old male with a post traumatic loss of tissue localized on the anterior surface of the right thigh and knee due to a road accident, was treated with different surgical reconstructive techniques. Combined use of autologous skin graft and acellular dermal substitute Integra(r) allowed the satisfactory recovery of the patient who was discharged after 82 days from the trauma. To analyse the characteristics and the quality of the healing tissues we performed a videocapillaroscopy study to assess the microcirculatory pattern of the autologous skin grafted on the dermal substitute in comparison with the autologous skin grafted on granulation tissue. The videocapillaroscopy was performed in the zone skin grafted directly on granulation tissue, Zone 1 (Z1); on the region of the lesion in the knee, treated with dermal substitute and autologous skin graft, Zone 2 (Z2), and on the undamaged controlateral knee skin. Zone 3 (Z3). The results showed that the capillary density was similar between Z2 and Z3, while in Z1, the zone skin grafted on the granulation tissue without Integra(r) the capillary density was significatively reduced. These preliminary observations within the clinical data may be an useful contribute to better understand the tissue healing process. PMID- 22240374 TI - Protein carbonyl groups in trained subjects. AB - The purpose of this research was to evaluate the plasma protein carbonyl groups (PC) in 81 trained subjects (TS) who practiced regular, non professional physical activity. They were divided into three groups according to the type of sport they practiced (endurance, mixed or power). On fasting venous blood we examined the PC groups employing an enzyme-linked immunosorbent assay (ELISA) kit, in which 2,4 dinitrophenyl-hydrazine reacts with the PC forming a stable hydrazone product. In the whole group of TS a significant decrease in PC was present, in comparison with sedentary controls (SC). Dividing TS into groups, we observed a decreased PC concentration in those practicing endurance and mixed sports, but not in those practicing power sports. There was no difference between men and women for PC either in SC or in TS; male TS had a PC concentration significantly lower than male SC. Our data show that body proteins are more protected against oxidative stress in subjects who practice endurance and mixed sports. These results give further support to the promotion of regular physical activity including aerobic exercise. PMID- 22240375 TI - Subcutaneous adipose tissue blood flow and vasomotion in morbidly obese patients: long term effect of gastric bypass surgery. AB - Since recent findings suggest a relationship between reduction in adipose tissue blood flow (ATBF) and metabolic or vascular complications in obese patients (Ob pts), increase in ATBF may be considered as a further goal in the treatment of obesity, besides fat mass reduction. Therefore, this preliminary study aimed at assess subcutaneous ATBF and vasomotion in morbidly obese patients and whether sustained weight loss induced by Roux-en-Y gastric bypass (RYGB) affects the same parameters. Using laser-Doppler flowmetry (LDF) and spectral Fourier analysis, subcutaneous ATBF was measured and subcutaneous ATBF oscillations (ATBF-O) were analyzed - within three frequency intervals related to vasomotion - in 16 Ob-pts, before and about one year after RYGB, and in 10 lean, healthy control subjects (CS). Before RYGB, Ob-Pts showed an important reduction in subcutaneous ATBF compared to CS (4.8 +/- 2.7 PU vs 79.9 +/- 34.5 PU, respectively; p < 0.0001), as well as higher normalized power spectral density (N-PSD) values of subcutaneous ATBF-O, - related to vasomotion. One year after RYGB, sustained weight loss in Ob pts was associated with a slight but significant increase in subcutaneous ATBF (10.0 +/- 6.6 PU, p < 0.05) and with almost complete normalization in N-PSD values of ATBF-O, related to vasomotion, compared to before RYGB. The slight subcutaneous ATBF increase, we observed in Ob-pts after sustained weight loss, moves toward a desirable goal. This finding suggests verifying whether an even more sustained weight loss in Ob-pts could determine a greater increase in subcutaneous ATBF and/or, more importantly, it could also determine a significant increase in visceral ATBF. PMID- 22240376 TI - The effects of long term aerobic exercise on the hemorheology in rats fed with high-fat diet. AB - Hypercholesterolemia is one of the cardiovascular risk factors sensitive to preventive and control interventions. Here we created a hypercholesterolemia model to investigate the effect of the long term aerobic exercise (swimming) on the hemorheology of rats fed with high-fat diet. We found that the rats fed with high-fat diet developed hypercholesterolmia and hepatic steatosis and their hemorheological and coagulative properties were all impaired as compared to those of the rats fed with standard diet. But after exercise, the total cholesterol and triglyceride in the plasma were significantly decreased and the severity of hepatic steatosis were reduced. Exercise greatly improved the erythrocytes' hemorheological properties, including deformability, electrophoretic mobility and osmotic fragility. Exercise also markedly lowered the activated partial thromboplastin time (APTT) but had moderate effects on other coagulative parameters. The high oxidative stress level, as indicated by plasma MDA concentration, in rats with high-fat diet was significantly attenuated to the normal level after exercise. The present study suggests that long term aerobic exercise could remarkably improve the abnormal hemorheological property and the oxidative stress in rats with hypercholesterolemia. PMID- 22240377 TI - Preliminary findings in the heart rate variability and haemorheology response to varied frequency and duration of walking in women 65-74 yr with type 2 diabetes. AB - Heart rate variability (HRV) and haemorheology adaptations to 12 wk of varied dose treadmill walking were investigated in women aged 65-74 yr with type 2 diabetes. Subjects were randomly allocated into two groups where exercise frequency and session duration were manipulated (Group 1: 2 * 60 min.wk(-1) or Group 2: 4 * 30 min.wk(-1)), but intensity and accumulated weekly duration of exercise were consistent between groups (100% gas-exchange threshold; 120 min.wk( 1)). Twelve weeks of exercise training significantly improved peak oxygen uptake, time to exhaustion, and gas-exchange threshold (p < 0.05), independent of exercise group. Exercise training did not significantly change glycaemic control or body mass. Red blood cell (RBC) aggregation and RBC deformability significantly decreased (p < 0.05) for both groups. No change in HRV was observed for Group 1, whereas several key indicators of HRV were significantly improved in Group 2 (p < 0.05). The present study was the first to report decreased RBC aggregation following an exercise-only intervention and that exercise training improved RBC aggregation without a concomitant improvement in glycaemic control. The accumulated weekly exercise duration may be the most important training component for the prescription of exercise in older women with type 2 diabetes. PMID- 22240378 TI - Effects of cigarette smoking on morphology and aggregation of erythrocytes. AB - Erythrocyte deformability and aggregation are important parameters related to blood flow in cardiovascular system. These are generally determined by various techniques. The present work is an attempt to implement a computerized procedure based on microscopic images of erythrocytes, obtained from cigarette smokers, to calculate these and related parameters. The subjects who have been smoking for more than ten years (Group 2) are selected and the calculated parameters are compared with that of non-smoking subjects (Group 1). The shape parameters area, perimeter and form factor of erythrocytes show significant change in Group 2 compared to that of Group 1. The erythrocyte aggregation, as measured by area occupied by aggregates, shows significant reduction in smokers, attributed to enhanced cell-cell interaction in Group 2. The ratio of crenated to normal erythrocytes increases immediately after smoking but reverts back to initial level after a gap of more than one hour, which is attributed to the change in metabolic activity of erythrocytes. PMID- 22240379 TI - Cell-specific regulation of acetylcholinesterase expression under inflammatory conditions. AB - Acetylcholine (ACh) has been shown to exert an anti-inflammatory function by down modulating the expression of pro-inflammatory cytokines. Its availability can be regulated at different levels, namely at its synthesis and degradation steps. Accordingly, the expression of acetylcholinesterase (AChE), the enzyme responsible for ACh hydrolysis, has been observed to be modulated in inflammation. To further address the mechanisms underlying this effect, we aimed here at characterizing AChE expression in distinct cellular types pivotal to the inflammatory response. This study was performed in the human acute leukaemia monocytyc cell line, THP-1, in human monocyte-derived primary macrophages and in human umbilical cord vein endothelial cells (HUVEC). In order to subject these cells to inflammatory conditions, THP-1 and macrophage were treated with lipopolysaccharide (LPS) from E.coli and HUVEC were stimulated with the tumour necrosis factor alpha (TNF-alpha). Our results showed that although AChE expression was generally up-regulated at the mRNA level under inflammatory conditions, distinct AChE protein expression profiles were surprisingly observed among the distinct cellular types studied. Altogether, these results argue for the existence of cell specific mechanisms that regulate the expression of acetylcholinesterase in inflammation. PMID- 22240380 TI - Erythrocyte as a biological sensor. AB - The erythrocytes ability of sensing the local oxygen gradient through the hemoglobin conformation, along with changes in nitric oxide mobilization and vasomotor repercussions at the microcirculation, were reviewed in detail in this article. Different approachs trying to explain the erythrocyte death were additionally documented. Also, the influence of several types of molecules (vasoactive, oxidant/reductor) on the erythrocyte roles as sensor of (i) oxygen tissue needs, (ii) blood viscosity and myogenic environment, (iii) and inflammatory conditions were mentioned in order to highlight its physiologycal function and substitute the erroneous idea of the erythrocyte being simply a hemoglobin sac content. PMID- 22240381 TI - The effects of exercise in water at 4 degrees C and 25 degrees C on the rheological properties of blood and the composition of fatty acids in the erythrocyte membranes of laboratory rats. AB - The aim of this study was to assess the influence of a single session of maximal exercise performed in water (4 degrees C or 25 degrees C) on blood rheological properties and the composition of fatty acids in the erythrocyte membranes of laboratory rats. This study will permit better understanding of the reactions occurring in the organism during rapid cooling in cold water, especially in regards to the hemorheological and biochemical parameters of blood. When compared to the control group, exercise performed in water at 4 degrees C led to an increase in the elongation index (EI, from 0.30 Pa to 4.24 Pa) with no concurrent changes in erythrocyte aggregation, blood plasma viscosity, and fatty acid composition (saturated, unsaturated, saturated/unsaturated, monounsaturated, polyunsaturated polyunsaturated-n3, polyunsaturated-n6 fatty acids) of the erythrocyte membrane. In rats swimming in water at 25 degrees C, we observed an increase in EI at shear stress from 0.30 Pa to 2.19 Pa, along with a decrease in the half-time of total aggregation when compared to the control group. These changes in erythrocyte rheological properties can be treated as a protective reaction to thermal stress resulting in their improved deformability. PMID- 22240382 TI - Abnormal flow adhesion of sickle red blood cells to human placental trophoblast extracellular matrix. AB - Pregnancy in sickle cell disease (SCD) has been associated with increased complications such as vaso-occlusive crises, severe anemia and foetal loss. It has been proposed that the sickling of red blood cells (RBCs) inside the placenta circulation could participate to these complications. The present study investigated the adhesion of sickle RBCs on human trophoblast-derived cell and its extracellular matrix. Results demonstrated 1) similar adhesion of sickle RBCs and healthy RBCs to trophoblast but 2) a greater adhesion of sickle RBCs to the extracellular matrix of trophoblasts as compared with healthy RBCs. This greater adhesion could partly involve the Lu/BCAM glycoproteins and could participate to the complications reported in SCD pregnant women. PMID- 22240383 TI - Attenuating effect of post-treatment with QiShen YiQi Pills on myocardial fibrosis in rat cardiac hypertrophy. AB - QiShen YiQi Pills((r)) (QSYQ) is a compound Chinese medicine used for treatment of cardiovascular diseases. However, the potential of QSYQ to inhibit cardiac fibrosis in left ventricle hypertrophy is not explored to date. We investigated the effects of post-treatment with QSYQ on rat myocardial fibrosis in left ventricle hypertrophy induced by pressure over-load through ascending aortic stenosis. QSYQ was administrated 4 weeks after the surgery, at a dose of 0.8 g/kg/day over the next 4 weeks, while echocardiography was performed 4 and 8 weeks, respectively, after the surgery. Eight weeks after the surgery, myocardial blood flow was determined by Laser-Doppler Perfusion Imager and the ratio of heart weight to body weight (HW/BW) was estimated, in concurrent evaluation of myocardial histology and ultrastructure, as well as collagen content by sirius red staining, and immunohistochemistry staining for CD68 and transforming growth factor beta 1. Post-treatment with QSYQ significantly alleviated left ventricular posterior wall end diastolic thickness and the HW/BW, increased left ventricle ejection fraction and left ventricle fractional shortening. QSYQ also decreased myocardial fibrosis size. The expression of CD68 and transforming growth factor beta 1 were obviously suppressed after QSYQ treatment. The results suggest that post-treatment with QSYQ attenuates pressure over-load-induced cardiac hypertrophy and myocardial fibrosis through interfering in inflammatory process. PMID- 22240384 TI - Moderate endurance exercise is not a risk for rhabdomyolysis or renal failure in sickle cell trait carriers. AB - This study tested the hypothesis that trained sickle cell trait (SCT) carriers are not subjected to greater risk of rhabdomyolysis or renal failure in response to moderate submaximal exercise than subjects with normal hemoglobin (CONT). Blood markers in 11 trained SCT carriers and 12 control counterparts were measured before and after 40 min of exercise at 55% of peak power output (Ppeak) conducted in thermoneutral environment. Body weights decreased with exercise in the same proportion in the two groups (from 65.1 +/- 7.0 kg to 64.1 +/- 7.0 kg and from 70.2 +/- 6.6 to 68.6 +/- 6.6 kg at the end of exercise in SCT and CONT, respectively). Heart rate and rectal temperature increased in the two groups in response to exercise, but the groups remained closely matched. Serum urea, CRP, CK and LDH were similar in the two groups and remained unchanged in response to exercise. Creatinine, Na(+), K(+), Cl(-) and myoglobin concentrations increased above baseline in response to exercise, with changes of the same magnitude in the two groups. In summary, the results of the present study suggest that moderate submaximal exercise is not unsafe from a biochemical point of view for sportsmen carrying SCT. PMID- 22240385 TI - Investigation of critical shear stress with simultaneous measurement of electrical impedance, capacitance and light backscattering. AB - Recent electrical investigation of hemorheology provided useful information on the kinetics of red blood cell (RBC) aggregation. However, because of the inconsistent results in the electrical measurements, we need to understand the electrical characteristics of RBC aggregation at various flow conditions. In the present study, AC electrical-capacitance (EC) and -impedance (EI) and light backscattering (LB) were simultaneously measured for transient shear-decreasing blood flow in a microchannel. EI, EC and LB signals of RBCs in plasma show similar time-varying curves, both yielding either a peak or a minimal point in the optimal frequency range (10~500 kHz). Critical shear stress (CSS) determined from EC showed the nearly same results as that determined from LB, with yielding hematocrits-independence and dextran-concentration dependence. However, the high concentration of fibrinogen caused electrical saturation, which resulted in different results of CSS determined from between LB and EC. These results suggest that electrical properties of RBC suspensions should be further examined to replace the optical method of measurement of RBC aggregation. PMID- 22240386 TI - Epigenetic regulation of adipogenesis by histone methylation. AB - Histone methylation is implicated in both gene activation and repression, depending on the specific lysine residue that gets methylated. Recent years have witnessed an explosive expansion of the list of remarkably site-specific histone methyltransferases and demethylases, which greatly facilitates the study on the biological functions of histone methylation in gene expression and cell differentiation in mammalian cells. Adipogenesis represents an excellent model system to understand transcriptional and epigenetic regulation of gene expression and cell differentiation. While transcriptional regulation of adipogenesis has been extensively studied, the roles of epigenetic mechanisms in particular histone methylation in regulation of adipogenesis have just begun to be understood. This review will summarize the recent progress on epigenetic regulation of adipogenesis by histone methylation, with a focus on histone H3K4 and H3K27. The available evidence suggests that site-specific histone methylations play critical roles in adipogenesis and control the expression of both positive and negative master regulators of adipogenesis. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22240387 TI - Ubiquitin and assembly of export competent mRNP. AB - The production of mature and export competent mRNP (mRNA ribonucleoprotein) complexes depends on a series of highly coordinated processing reactions. RNA polymerase II (RNAPII) plays a central role in this process by mediating the sequential recruitment of mRNA maturation and export factors to transcribing genes, thereby establishing a strong functional link between transcription and export through nuclear pore complexes (NPC). Growing evidence indicates that post translational modifications participate in the dynamic association of processing and export factors with mRNAs ensuring that the transitions and rearrangements undergone by the mRNP occur at the right time and place. This review mainly focuses on the role of ubiquitin conjugation in controlling mRNP assembly and quality control from transcription down to export through the NPC. It emphasizes the central role of ubiquitylation in organizing the chronology of events along this highly dynamic pathway. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. PMID- 22240388 TI - Divergent KSHV/HHV-8 subtype D strains in New Caledonia and Solomon Islands, Melanesia. AB - BACKGROUND: KSHV/HHV-8 is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and most multicentric Castleman's disease cases. KSHV exhibits a high genetic variability comprising five genotypes (A-E). Few data are yet available concerning the situation of KSHV, its genetic variability and the associated diseases in Melanesia. OBJECTIVES: We performed a study on 626 natives Melanesians from New Caledonia and Vanikoro Island to evaluate KSHV seroprevalence and characterize molecularly the viral strains. STUDY DESIGN: Plasma from 343 males and 283 females (age range: 15-86 years, mean age: 60) were tested for KSHV latent antibodies by an immunofluorescence assay (IFA) using BC-3 cells. DNAs extracted from peripheral blood buffy-coat of KSHV seropositive individuals were amplified to obtain a 737-bp fragment of the ORF-K1 gene. Phylogenetic analyses were then performed. RESULTS: Among 626 samples, 148 were IFA positive (dilution>=1:80). The overall seroprevalence was 23.6% (25.2% in New Caledonia, 17.5% in Vanikoro). Fifteen (8 men and 7 women, mean age 69 years) out of 148 DNA samples were found PCR positive. All ORF-K1 sequences belonged to KSHV genotype D. A geographic clustering according to the island of origin of KSHV infected persons was clearly observed with sequences from New Caledonia clustering with most Vanuatu strains. CONCLUSIONS: New Caledonia and Vanikoro are endemic for KSHV with a high diversity of genotype D variants. These strains were probably introduced into New Caledonia during multiple waves of migrations of Melanesian and Polynesian individuals that have colonized this archipelago. PMID- 22240389 TI - Development of fast dissolving oral film containing dexamethasone as an antiemetic medication: clinical usefulness. AB - We developed a fast dissolving oral film containing 4 mg dexamethasone and examined the clinical effect of the film as the antiemetic by a randomized controlled crossover study in breast cancer patients receiving a combination chemotherapy with anthracycline and cyclophosphamide, a highly emetogenic chemotherapy. The film was prepared as reported previously using microcrystalline cellulose, polyethylene glycol, hypromellose, polysorbate 80 and 5% low substituted hydroxypropylcellulose as base materials. The uniformity of the film was shown by the relative standard deviation of 2.7% and acceptance value of 5.9% by the Japanese Pharmacopoeia. Patients were administered with 8 mg dexamethasone as oral film or tablet on days 2-4 after chemotherapy in addition to the standard antiemetic medication. The rates of complete protection from vomiting during acute and delayed phases were not different between film-treated group and tablet treated group. The time course of the complete protection from nausea or vomiting during 0-120 h was also similar between the two groups. Patient's impressions on the oral acceptability in respect of the taste and ease in taking were significantly better for film than for tablet. Therefore, the present fast dissolving oral film containing dexamethasone seems to be potentially useful as an antiemetic agent in patients receiving highly emetogenic chemotherapy. PMID- 22240390 TI - Preparation and characterization of paclitaxel-loaded DSPE-PEG-liquid crystalline nanoparticles (LCNPs) for improved bioavailability. AB - Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as a new drug nanocarrier system for improving bioavailability for both hydrophilic and hydrophobic drugs. In this study, self-assembled LCNPs based on soy phosphatidyl choline and glycerol dioleate, which was known possessing low toxicity and negligible hemolysis, were prepared using poly(ethylene glycol) grafted 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE-PEG) as the dispersing agent. Paclitaxel (PTX) was used as a model hydrophobic drug. The particle size of the optimized DSPE-PEG-LCNPs and PTX-loaded DSPE-PEG-LCNPs were around 70nm. Crossed polarized light microscopy was used to characterize the phase behavior of liquid crystalline (LC) matrices, which showed a fan-like birefringent texture in dark background indicating the coexistence of reversed cubic and hexagonal phase in the optimized LC matrix. Transmission electron microscopy and cryo-field emission scanning electron microscopy revealed its internal water channel and "twig-like" surface morphology. PTX-loaded DSPE-PEG LCNPs exhibited a biphasic drug sustained release pattern with a relatively fast release at the initial stage and a sustained release afterwards. PTX-loaded DSPE PEG-LCNPs presented higher AUC (410.942+/-72.522MUg/Lh) when compared with commercial product Taxol (212.670+/-41.396MUg/Lh). These results indicated that DSPE-PEG-LCNPs might serve as a potential sustained release system for poorly water-soluble agents. PMID- 22240391 TI - Multiple sclerosis in the context of TNF blockade and inflammatory bowel disease. PMID- 22240392 TI - Who cares for empathy? PMID- 22240393 TI - Incidence of human papillomavirus infection in male sexual partners of women diagnosed with CIN II-III. AB - INTRODUCTION: Human papillomavirus (HPV) infection is a very common sexually transmitted disease which has been strongly related to cervical cancer and cervical intraepithelial neoplasia (CIN), penile cancer and intraepithelial and infiltrating anal squamous cell carcinoma. OBJECTIVES: To describe the HPV status of male sexual partners of women diagnosed with CIN II/III and to evaluate the practical usefulness of the HPV detection in urine as a reliable marker of genital high-risk HPV infection in men. METHODS: Ninety-one heterosexual male partners (mean age 32.7) were included in the study. A panel of epidemiological data was recorded. Peniscopy was performed at the first visit and after 6 months. Urine samples and anal and penile scrapings were obtained and Hybrid Capture II test for high-risk HPV was performed. Physical examination disclosed clinically or peniscopic lesions in only 5.4% patients. HPV was isolated in 12.9% and 6.2% of penile and anal scrapings respectively whereas HPV detection was positive in 28% of urine samples. Overall, 41% of the evaluated patients presented at least one finding diagnostic of HPV infection. CONCLUSION: HPV detection in male partners of women with CIN is a frequent event, and urine HPV detection by Hybrid Capture test is a sensitive method for its detection. The determination of HPV in urine samples seems to be a simple method to investigate the subrogated genital HPV infection in men. PMID- 22240395 TI - Computer assisted dental rehabilitation in free flaps reconstructed jaws: one year follow-up of a prospective clinical study. AB - Continuity defects in bone after resection of the jaw may cause problems, and osseo-myocutaneous free flaps are the gold standard for their reconstruction. Implant-supported prosthetic rehabilitation is reliable with these microvascular options, although it is still a serious challenge. The aim of this prospective clinical study was to describe the advantages of implants restored according to a computer-assisted surgical protocol. A group of 10 consecutive patients (both sexes) had already been treated and followed up for at least 1 year after prosthetic loading. The NobelGuide protocol had to be modified to adapt the technique for these patients who had had reconstructions. A total of 56 fixtures were installed and, when possible, immediately loaded (overall survival of implants 95%). Every patient was given correct provisional prosthetic rehabilitation, which was most satisfactory as far as chewing, social functioning, and overall quality of life were concerned. Three-dimensional computed tomographic (CT) examination showed a mean (SD) marginal bone loss of 1.06 (0.5)mm. We used a modified technique of computer-assisted implant surgery in jaws that had been reconstructed with free flaps; from these preliminary findings this approach seems valid when it comes to function, improving prosthetic restoration, and aesthetics. PMID- 22240394 TI - Usefulness of combined in vivo skin comet assay and in vivo skin micronucleus test. AB - We have already found that the in vivo skin comet assay is useful for the evaluation of primary DNA damage induced by genotoxic chemicals in epidermal skin cells. The aim of the present study was to evaluate the sensitivity and specificity of the combined in vivo skin comet assay and in vivo skin micronucleus (MN) test using the same animal to explore the usefulness of the new test method. The combined alkaline comet assay and MN test was carried out with three chemicals: 4-nitroquinoline-1-oxide (4NQO), N-methyl-N'-nitro-N nitrosoguanidine (MNNG) and benzo[a]pyrene (B[a]P). In the first experiment, we compared DNA- and chromosome-damaging effects of 3 [72, 24 and 3 hours (h) before sacrifice] and 4 applications (72, 48, 24 and 3h before sacrifice) of 4NQO, which induces dermal irritancy. The animals were euthanized and their skin was sampled for the combination test. As a result, the 4-application method was able to detect both DNA- and chromosome-damaging potential with a lower concentration; therefore, in the second experiment, MNNG and B[a]P were topically applied four times, respectively. The animals were euthanized, and then their skins were sampled for combination tests. In the alkaline comet assay, significant differences in the percent of DNA (%DNA) in the tail were observed in epidermal skin cells treated with MNNG and B[a]P. In the MN test, an increased frequency of MN cells (%MN) cells was observed by treatment with MNNG; however, there were no significant increases. In contrast, significant differences in %MN were observed by treatment with B[a]P. From these results, we conclude that the combined in vivo skin comet assay and in vivo MN test was useful because it can detect different genotoxicity with the same sampling time and reduce the number of animals used. PMID- 22240396 TI - A "star" retractor in head and neck surgery. PMID- 22240398 TI - A novel mutation in the LMNA gene causes congenital muscular dystrophy with dropped head and brain involvement. AB - We describe a 22-month-old girl with axial muscle and diaphragmatic weakness as well as motor developmental delay without mental retardation. The striking clinical feature was a dropped head, although she could walk unaided. T2/FLAIR brain MRI revealed a focal abnormality with high signal intensity in the white matter including U-fibers. A muscle biopsy showed active necrotic and regenerative processes. These distinct clinical findings prompted a mutational analysis of the lamin A (LMNA) gene, and we identified a novel heterozygous mutation in LMNA (c.1330_1338dup9). This is the first report of an Asian patient with LMNA-related congenital muscular dystrophy (L-CMD) and a dropped head. PMID- 22240397 TI - Type IV fimbrial subunit protein ApfA contributes to protection against porcine pleuropneumonia. AB - Porcine pleuropneumonia caused by Actinobacillus pleuropneumoniae accounts for serious economic losses in the pig farming industry worldwide. We examined here the immunogenicity and protective efficacy of the recombinant type IV fimbrial subunit protein ApfA as a single antigen vaccine against pleuropneumonia, or as a component of a multi-antigen preparation comprising five other recombinant antigens derived from key virulence factors of A. pleuropneumoniae (ApxIA, ApxIIA, ApxIIIA, ApxIVA and TbpB). Immunization of pigs with recombinant ApfA alone induced high levels of specific serum antibodies and provided partial protection against challenge with the heterologous A. pleuropneumoniae serotype 9 strain. This protection was higher than that engendered by vaccination with rApxIVA or rTbpB alone and similar to that observed after immunization with the tri-antigen combination of rApxIA, rApxIIA and rApxIIIA. In addition, rApfA improved the vaccination potential of the penta-antigen mixture of rApxIA, rApxIIA, rApxIIIA, rApxIVA and rTbpB proteins, where the hexa-antigen vaccine containing rApfA conferred a high level of protection on pigs against the disease. Moreover, when rApfA was used for vaccination alone or in combination with other antigens, such immunization reduced the number of pigs colonized with the challenge strain. These results indicate that ApfA could be a valuable component of an efficient subunit vaccine for the prevention of porcine pleuropneumonia. PMID- 22240399 TI - No NDM-1 carriage in healthy persons from Mumbai: reassuring for now. PMID- 22240400 TI - Panton-Valentine leucocidin gene carriage among Staphylococcus aureus strains recovered from skin and soft tissue infections in Turkey. AB - OBJECTIVES: Regardless of methicillin resistance, Panton-Valentine leucocidin (PVL)-positive Staphylococcus aureus isolates are associated with various types of infections and outbreaks. Limited data exist about the PVL content of S. aureus strains in Turkey. In this multicentre study, we aimed to assess the PVL positivity and antimicrobial susceptibilities of S. aureus isolates recovered from skin and soft tissue samples of both community and nosocomial origin in the study period, 2007-08. METHODS: Two hundred and forty-two [92 community-acquired (CA) and 150 hospital-acquired (HA)] isolates were included in the study. Analysis of mecA and PVL was carried out using PCR. All isolates underwent susceptibility testing according to the CLSI. RESULTS: Out of 242 isolates, 77 were mecA positive. PVL was not found among methicillin-resistant S. aureus (MRSA) isolates, but 8 (5.3%) HA methicillin-susceptible S. aureus (MSSA) and 14 (15.2%) CA-MSSA, mostly isolated from furuncles (71.4%), were positive for PVL. Among PVL-positive strains, the penicillin resistance rate was 90.9%. Low resistance rates, <10%, were detected for erythromycin, fusidic acid and co trimoxazole. PVL-positive strains showed higher rates of susceptibility to erythromycin, gentamicin and rifampicin than negative isolates. CONCLUSIONS: Based on the findings of this study, infection related to PVL-carrying CA-MRSA is not at an alarmingly high level, but population-based surveillance studies should be done to determine the real status. PMID- 22240401 TI - Reduction of fluoroquinolone use is associated with a decrease in methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Pseudomonas aeruginosa isolation rates: a 10 year study. AB - OBJECTIVES: High rates of methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Pseudomonas aeruginosa may be related, in part, to the overuse of fluoroquinolones. The objective was to analyse and correlate long-term surveillance data on MRSA and fluoroquinolone-resistant P. aeruginosa rates and antibiotic consumption after implementation of an institution-wide programme to reduce fluoroquinolone use. METHODS: An interrupted time series/quasi experimental study of monthly fluoroquinolone use and MRSA and fluoroquinolone resistant P. aeruginosa isolation rates was carried out in a tertiary hospital during three periods: pre-intervention (January 2000-August 2005), intervention (September 2005-March 2006), and post-intervention (March 2006-March 2010). The effect of the intervention on the consumption of fluoroquinolones and bacterial resistance was assessed using segmented regression analyses. RESULTS: Mean monthly fluoroquinolone consumption dropped by 29.1 defined daily doses per 1000 patient-days (DDD/1000 PD) (95% CI 13.1-45.9; P = 0.0005) from a mean of 148.2 to 119.1 DDD/1000 PD during the intervention period. A sustained and significant decrease in fluoroquinolone consumption of -0.95 DDD/1000 PD/month was also observed during the post-intervention period (P = 0.0002). During the post intervention period the rate of fluoroquinolone-resistant P. aeruginosa continuously decreased, from a mean of 42% to 26%, with a constant relative change rate of -13%/year (95% CI -19 to -5, P = 0.001). A decrease in the MRSA rate was observed during the intervention period, from a mean resistance rate of 27% to 21% (P < 0.0001). CONCLUSIONS: We showed the sustained impact of a fluoroquinolone control programme on the reduction of fluoroquinolone use with a significant decrease in fluoroquinolone-resistant P. aeruginosa and MRSA rates over 4 years. PMID- 22240402 TI - Prophylactic efficacy of single dose pulmonary administration of amphotericin B inhalation powder in a guinea pig model of invasive pulmonary aspergillosis. AB - OBJECTIVES: Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. METHODS: Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. RESULTS: Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. CONCLUSIONS: Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation. PMID- 22240403 TI - The impact of detectives' manner of questioning on rape victims' disclosure. AB - Research has documented that few reported rapes are prosecuted by the legal system. The purpose of this study is to explain how the interactions between victims and detectives can strengthen or weaken the investigation itself. Twenty rape victims were interviewed to examine how law enforcement detectives' manner of questioning affects rape victims' level of disclosure. Using qualitative methodology, the results show that the detectives' manner of questioning can play a role in victims' disclosure. Detectives using a gentle manner of questioning with victims can help produce stronger victim statements and thus build stronger cases for prosecution. PMID- 22240404 TI - Qualitative study of an operations research project to engage abused women, health providers, and communities in responding to gender-based violence in Vietnam. AB - This article describes an action research project designed to engage women, health providers, and communities to respond to gender-based violence (GBV) in Vietnam. Based on results from in-depth interviews and group discussions, it considers the extent to which the project approaches were empowering for abused women. The results underscore the problems entailed in introducing systematic screening for gender-based violence into government health facilities in the low resource setting of Vietnam, the importance of combining ideational change and rights components with support for abused women, and the difficulty of engaging male perpetrators. PMID- 22240405 TI - Effect of population-based screening on breast cancer mortality. PMID- 22240406 TI - Oral azithromycin for treatment of yaws. PMID- 22240407 TI - Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial. AB - BACKGROUND: Yaws--an endemic treponematosis and, as such, a neglected tropical disease--is re-emerging in children in rural, tropical areas. Oral azithromycin is effective for syphilis. We assessed the efficacy of azithromycin compared with intramuscular long-acting penicillin to treat patients with yaws. METHODS: We did an open-label, non-inferiority, randomised trial at Lihir Medical Centre, Papua New Guinea, between Sept 1, 2010, and Feb 1, 2011. Children aged 6 months to 15 years with a serologically confirmed diagnosis of yaws were randomly allocated, by a computer-generated randomisation sequence, to receive either one 30 mg/kg oral dose of azithromycin or an intramuscular injection of 50,000 units per kg benzathine benzylpenicillin. Investigators were masked to group assignment. The primary endpoint was treatment efficacy, with cure rate defined serologically as a decrease in rapid plasma reagin titre of at least two dilutions by 6 months after treatment, and, in participants with primary ulcers, also by epithelialisation of lesions within 2 weeks. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10%. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01382004. FINDINGS: We allocated 124 patients to the azithromycin group and 126 to the benzathine benzylpenicillin group. In the per-protocol analysis, after 6 months of follow-up, 106 (96%) of 110 patients in the azithromycin group were cured, compared with 105 (93%) of 113 in the benzathine benzylpenicillin group (treatment difference -3.4%; 95% CI -9.3 to 2.4), thus meeting prespecified criteria for non-inferiority. The number of drug related adverse events (all mild or moderate) was similar in both treatment groups (ten [8%] in the azithromycin group vs eight [7%] in the benzathine benzylpenicillin group). INTERPRETATION: A single oral dose of azithromycin is non-inferior to benzathine benzylpenicillin and avoids the need for injection equipment and medically trained personnel. A change to the simpler azithromycin treatment regimen could enable yaws elimination through mass drug administration programmes. FUNDING: International SOS and Newcrest Mining. PMID- 22240408 TI - Elimination of cholera transmission in Haiti and the Dominican Republic. PMID- 22240410 TI - Pulmonary hypertension in early life. PMID- 22240409 TI - Clinical features of paediatric pulmonary hypertension: a registry study. AB - BACKGROUND: Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension. METHODS: Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients' physicians according to the individual's health-care needs. FINDINGS: 362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure >=25 mm Hg, pulmonary capillary wedge pressure <=12 mm Hg, and pulmonary vascular resistance index >=3 WU/m(-2)). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3-12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent with preserved right heart function. INTERPRETATION: TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies. FUNDING: Actelion Pharmaceuticals. PMID- 22240411 TI - Efficacy and mechanism of action of arachidonic acid in the treatment of hamsters infected with Schistosoma mansoni or Schistosoma haematobium. AB - We have recently shown that in vitro and in vivo exposure of Schistosoma mansoni and Schistosoma haematobium to 5-10mM arachidonic acid (ARA) induces parasite surface membrane disintegration and eventual attrition. Here we report on the optimum ARA dose and post-infection treatment time for maximum schistosome demise in hamsters. A series of four experiments for each schistosome species indicated that oral administration of ARA after patency led to a highly significant (P<0.02 to <0.001) reduction in worm burden accompanied by a significant (P<0.05) decrease in worm egg load. ARA-mediated attrition in vivo appeared to be associated with high titres of serum antibodies to tegumental antigens. In support, serum antibodies from patently infected and ARA-treated hamsters readily bound to the surface membrane of ARA-exposed adult worms, as judged by indirect membrane immunofluorescence. More importantly, addition of serum antibodies and peripheral blood mononuclear cells significantly enhanced ARA-mediated adult worm attrition in vitro. These data together show that the schistosomicidal effect of ARA in laboratory animals is enhanced by immune effectors and is highly efficacious and entirely safe. PMID- 22240412 TI - Orthostatic hypotension (OH) and mortality in relation to age, blood pressure and frailty. AB - Systolic hypertension and OH, as with many other deficits, accumulate with age. This deficit accumulation results in frailty: enhanced vulnerability to adverse outcomes. This study evaluated OH in relation to age, frailty, systolic hypertension, and mortality. In the population-based Canadian Study of Health and Aging second clinical examination, complete data were available on 1347 people, mean age=83.3 (SD=6.4)years. A frailty index (FI) was calculated from a 52-item Comprehensive Geriatric Assessment (CGA), yielding an FI-CGA from 0 (no deficits) to 1.0 (52 deficits). The mean change in blood pressure from lying to standing was 7.3+/-15.6 mmHg (range +94 to -60). In total, 239 people (17.7%) had OH (change >20 mmHg systolic or >10 mmHg diastolic). Mean systolic blood pressure was higher (155.8+/-23.3 mmHg) in people with OH than in those without (141.4+/ 23 mmHg), as was the FI-CGA (0.18 vs. 0.16). OH increased with frailty and systolic hypertension, but not age. Unadjusted, OH was associated with an increased risk of death (relative risk=1.21, 95% confidence interval 1.19-1.23). Adjusted for frailty, this result was not significant. OH may be a marker of the system dysregulation seen in frailty, but as a state variable is a less powerful marker of vulnerability than is the FI-CGA. PMID- 22240413 TI - Dietary acrylamide exposure of the French population: results of the second French Total Diet Study. AB - Acrylamide is a heat-induced carcinogen compound that is found in some foods consequently to cooking or other thermal processes. In the second French Total Diet Study (TDS), acrylamide was analysed in 192 food samples collected in mainland France to be representative of the population diet and prepared "as consumed". Highest mean concentrations were found in potato chips/crisps (954 MUg/kg), French fries and other fried potatoes (724 MUg/kg), and salted biscuits other than potato chips (697 MUg/kg). Exposure of general adult and child populations was assessed by combining analytical results with national consumption data. Mean acrylamide exposure was assessed to be 0.43+/-0.33 MUg/kg of body weight (bw) per day for adults and 0.69+/-0.58 MUg/kg bw/day for children. Although the exposure assessed is lower than in previous evaluations, the calculated margins of exposure, based on benchmark dose limits defined for carcinogenic effects, remain very low especially for young children (below 100 at the 95th percentile of exposure), indicating a health concern. It is therefore advisable to continue efforts in order to reduce dietary exposure to acrylamide. PMID- 22240414 TI - Lethal effect of dehydroleucodine (DhL) on amphibian Bufo arenarum embryos. AB - The dehydroleucodine is a sesquiterpene lactone isolated from Artemisia douglasiana Besser which is used in popular medicine. Toxicity tests using embryos of amphibian have been widely used in order to predict toxic effects of different compounds. However, to our knowledge, there are not studies focussed on the toxic effects of dehydroleucodine on Bufo arenarum, which is an anuran widely distributed in South America. The effect of dehydroleucodine on the survival of embryos was evaluated in an acute test during the early life stage of B. arenarum embryos. Lethality and the degree of adverse effects were dehydroleucodine dose dependent. Overall, amphibian early life stages appeared to be more susceptible to the embryotoxicity associated with exposure to dehydroleucodine, especially at concentration greater that 3mM. This increased susceptibility may result from the relatively high rate of cellular differentiation and morphogenesis that occurs at this early stage of development. PMID- 22240415 TI - Assessment of dietary cadmium exposure in Sweden and population health concern including scenario analysis. AB - The median dietary cadmium exposure for adults in Sweden is around 1 MUg/kg/week and the upper 95th and 99th percentiles are 1.6-1.8 and 1.9-2.2 MUg/kg/week, respectively. Potatoes and wheat flour were the most important food categories, contributing with 40-50% to the exposure. Differences in dietary patterns between high and low exposed individuals were observed; for high exposed individuals, seafood and spinach contributed with an exposure similar to that low exposed individuals received from potatoes and wheat flour. Consequences of differences in methodology used for exposure assessment are discussed. The median exposure is a factor 2 lower compared to that estimated by the European Food Safety Authority (EFSA). It is also a factor 1.4 lower compared to that of the assessment used for development of the EFSA tolerable weekly intake (TWI). The potential importance of this latter fact was addressed by adjusting the present assessment to that used for TWI derivation. While the percentage of the population exceeding the TWI was <1% for the present data, it was around 3% for adjusted data, which is more in line with observations at the level of urinary cadmium. Scenario analysis was also performed to addresses the consequence of increasing/decreasing cadmium occurrence levels. PMID- 22240416 TI - Route-dependent effects of cadmium/cadmium and magnesium acute treatment on parameters of oxidative stress in rat liver. AB - The study was designed to evaluate and compare the effects of single oral (or) and intraperitoneal (i.p.) cadmium (Cd) administration on parameters of oxidative stress in liver of rats. Furthermore, investigation on protective effects of magnesium (Mg) or and i.p. pretreatment on the same parameters was performed. Wistar rats were administrated oral dose of Cd (30 mg Cd/kg b.w.)/Cd+Mg (30 mg Cd/kg b.w., 50 mg Mg/kg b.w.) or i.p. dose of Cd (1.5 mg Cd/kg b.w.)/Cd+Mg (1.5 mg Cd/kg b.w., 3 mg Mg/kg b.w.) and sacrificed after 24 h. In liver homogenates superoxide anion, malondialdehyde, non-protein sulfhydryl groups, total sulfhydryl groups content, and superoxide dismutase activity were determined. Cadmium intoxication caused the increase of superoxide anion and malondialdehyde levels and had negative effect on investigated parameters of antioxidant defense system, except on total sulfhydryl groups. The negative effect was more emphasized after i.p. Cd administration. Oral Mg pretreatment induced more pronounced positive effect than Mg given intraperitoneally that can be attributed, at least partly, to Cd and Mg interactions on the level of GIT. On the basis of the obtained results it can be concluded that both Cd and Cd+Mg effects on parameters of oxidative stress in rats liver are route-dependent. PMID- 22240418 TI - Muscle artifacts in multichannel EEG: characteristics and reduction. AB - OBJECTIVE: To study the characteristics of unintentional muscle activities in clinical EEG, and to develop a high-throughput method to reduce them for better revealing drug or biological effects on EEG. METHODS: Two clinical EEG datasets are involved. Pure muscle signals are extracted from EEG using Independent Component Analysis (ICA) for studying their characteristics. A high-throughput method called ICA-SR is introduced based on a new feature named Spectral Ratio (SR). RESULTS: The spectral and temporal characteristics of the muscle artifacts are illustrated using representative muscle signals. The spatial characteristics are presented at both the group- and the subject-level, and are consistent under three different electrode reference methodologies. Objectively compared with an existing method, ICA-SR is shown to reduce more artifacts, while introduce less distortion to EEG. Its effectiveness is further demonstrated in real clinical EEG with the help of a CO(2)-inhalation EEG recording session. CONCLUSION: The characteristics of unintentional muscle activities align with the reported characteristics of controlled muscle activities. Artifact spatial characteristics can be EEG equipment dependent. The ICA-SR method can effectively and efficiently process clinical EEG. SIGNIFICANCE: Armed with advanced signal processing algorithms, this study expands our knowledge of muscle activities in EEG from muscle-controlled experiments to general clinical trials. The ICA-SR method provides an urgently needed solution with validated performance for efficiently processing large volumes of clinical EEG. PMID- 22240417 TI - Muscle and skin sympathetic activities in Ross syndrome. AB - OBJECTIVES: Ross syndrome (RS) is a rare degenerative disorder characterized by tonic pupil, areflexia and anhydrosis. The underlying lesion affects postganglionic skin sympathetic nerve fibers whereas the postganglionic muscle sympathetic branch is thought to be spared. Microneurography explores both skin and muscle peripheral sympathetic branches and it does not usually detect peripheral sympathetic outflow in either branch in chronic autonomic failure syndromes. The aim of this study was to record sympathetic activity by microneurography for the first time in RS patients to confirm the selective involvement of skin sympathetic nerve activity (SSNA) with spared muscle sympathetic nerve activity (MSNA). METHODS: We studied seven patients (49 +/- 14 years, four males) with a typical clinical picture and skin biopsy findings. Patients underwent cardiovascular reflexes and microneurography from the peroneal nerve (anhydrotic skin) to record MSNA, SSNA and the corresponding organ effector responses (skin sympathetic response-SSR and skin vasomotor response-SVR) in the same innervation field. The absence of sympathetic bursts was established after exploring at least three different corresponding nerve fascicles. Twenty age matched healthy subjects served as controls. RESULTS: RS patients complained of diffuse anhydrosis and they showed tonic pupil and areflexia. Cardiovascular reflexes were normal. All patients displayed absent SSNA, SSR and SVR whereas MSNA was always recorded showing normal characteristics. CONCLUSION: Microneurographic study of sympathetic activity from affected skin confirmed the selective involvement of skin sympathetic activity with spared muscle sympathetic activity and it may represent the neurophysiological hallmark of the disease. SIGNIFICANCE: Microneurography together with clinical and skin biopsy findings may contribute to RS diagnosis. Our data also suggest that autonomic damage in RS does not involve cardiovascular activity. PMID- 22240419 TI - JIDC approaches its fifth birthday. PMID- 22240420 TI - Tuberculosis: novel approaches to an old disease. PMID- 22240421 TI - Nodal tuberculosis revisited: a review. AB - Lymphadenitis is the most common extrapulmonary manifestation of tuberculosis. Tuberculous lymphadenitis is considered to be the local manifestation of the systemic disease, whereas lymphadenitis due to nontuberculous mycobacteria is truly a localized disease. A high index of suspicion is needed for the diagnosis of tuberculous lymphadenitis which is known to mimic a number of pathological conditions. Over the last two to three decades, fine needle aspiration cytology (FNAC) has emerged as a simple out-patient diagnostic procedure for the evaluation of tuberculous lymphadenitis and has replaced lymph node biopsy for histopathology. A number of molecular methods have also been introduced in diagnostics which have greatly improved the diagnostic accuracy. This article provides a review of epidemiology, clinical manifestations, and pathogenesis and emphasizes current trends in pathologic diagnosis of nodal tuberculosis. PMID- 22240422 TI - Assessment of knowledge and practice of private practitioners regarding tuberculosis control in Ethiopia. AB - INTRODUCTION: Ethiopia has a growing private health sector. In recent years, the directly observed treatment short course (DOTS) strategy was initiated in selected private health facilities in the country. The objective of the present study was to assess knowledge and practice of private practitioners in tuberculosis (TB) control in Amhara Region, Ethiopia. METHODOLOGY: An institution based cross-sectional study was conducted among 112 private practitioners selected from all private health facilities in the region. The study was conducted between May and August 2008 and data was collected using a semi structured questionnaire. Group differences were analyzed using the chi-square test. RESULTS: Fifty-nine (52.7%) of the private practitioners suspected TB in patients with three weeks' duration of cough. Only 37 (33.0%) of the private practitioners were able to precisely list the correct treatment regimens for all categories as recommended in the National Tuberculosis and Leprosy Control Program guidelines. The correct frequency of TB treatment monitoring was provided by 44 (50%) of the respondents. Overall 44 (39.3%) of the private practitioners did not have satisfactory knowledge about the directly observed treatment short course (DOTS) strategy. Those who attended DOTS training during the two years prior to the survey were more likely to have satisfactory knowledge compared to those who did not receive training (OR 4.45, 95% CI: 1.33, 14.87, p < 0.02). CONCLUSION: A significant proportion of private practitioners did not have satisfactory knowledge and practice about DOTS. The provision of regular DOTS refresher courses improves TB management for patients in the region. PMID- 22240423 TI - Diagnostic defaulters: an overlooked aspect in the Indian Revised National Tuberculosis Control Program. AB - INTRODUCTION: The Revised National Tuberculosis Control Program (RNTCP) aims to achieve detection of 70% of new smear-positive patients in a community and to cure 85% of such patients. Though an elaborate recording and reporting system is in place to monitor the success of the program, no record of patients who do not complete the diagnostic process is currently maintained. The present study, performed in a tertiary care hospital, attempted to estimate the proportion of this group of patients, who were labeled "diagnostic defaulters. METHODOLOGY: This prospective observational study was conducted over one year on consecutive patients presenting with cough of more than two weeks' duration. A total of two sputum samples were obtained from each patient, including a spot sample and a morning sample collected on the following day. Zeihl-Neelsen staining, reporting and external quality assessment of smear-microscopy was done per RNTCP guidelines. RESULTS: Of the 2,349 patients recruited, 175 defaulted on the second day. The positivity rates for the spot and morning samples were 18.3% and 18.9%, respectively (p > 0.001). Of the 175 defaulters, 31 were found to be smear positive, thereby implying that the proportion of diagnostic defaulters was 17.7%. All 21 diagnostic defaulters contacted by telephone were found to be unaware of their smear-positive status. CONCLUSION: The high proportion of diagnostic defaulters, the majority of whom were unaware of their sputum-positive status, emphasizes the need to recognize the importance of this group of patients to better control tuberculosis. PMID- 22240424 TI - Pulmonary disease caused by Mycobacterium simiae in Iran's national referral center for tuberculosis. AB - INTRODUCTION: Several species of non-tuberculosis mycobacteria (NTM) can affect humans and can cause either symptomatic or asymptomatic infection. This study aimed to determine the clinical and radiological manifestation, as well as the treatment, of M. simiae in patients in Masih Daneshvari Hospital, a TB referral hospital in Iran. METHODOLOGY: This retrospective study involved all patients presenting to our referral center from 2002 to 2009, with confirmation of M. simiae pulmonary infection. For all patients, sputum smear and culture for identification was performed, as was drug susceptibility testing. Additionally, PCR identification methods for NTM, and high-resolution CT scan were conducted. All patients were treated according to American Thoracic Society recommendations. RESULTS: In total, 26 cases of M. simiae were identified in our center. The mean age of the patients was 58.23 +/- 16.9years. Only one patient was HIV positive, and all but one were Iranian. The most frequent symptom was coughing (92.3%), and 100% of the patients had nodular lesions. In addition, bronchiectasis and cavitation were present in 84.6% and 88.5% respectively. All the patients were resistant to every first-line drug. Two patients failed the treatment, and twenty four were cured, after which no recurrence of the disease was observed. CONCLUSION: M. simiae may present with clinical and radiological manifestations consistent with tuberculosis, and be resistant to anti-TB agents. A more efficient treatment for NTMs such as M. simiae is needed, to shorten the period of treatment and proved fewer adverse effects than current therapies. PMID- 22240425 TI - Multidrug-resistant tuberculosis in Rawalpindi, Pakistan. AB - INTRODUCTION: Multidrug-resistant (MDR) tuberculosis (TB) strains are resistant to isoniazid and rifampicin. Clinical characteristics, drug susceptibility patterns, and outcomes of MDR-TB patients treated at Holy Family Hospital, Rawalpindi, Pakistan, were studied from January 2007 to April 2010. METHODOLOGY: Thirty diagnosed patients (60% male and 40% female) of MDR pulmonary TB were included. Each patient was treated according to WHO guidelines and followed for two years. Clinical characteristics (age, gender, literate or illiterate educational status, employment status, and income), drug susceptibility testing (DST) reports, and outcome (cured, treatment failure, default, and died) of each patient was noted. RESULTS: Mean patient age was 36.2 +/- 15.4 years. In total, 60% patients were illiterate, 60% employed, 60% had income < Rs 5000 (42 Euro per month), 73.3% lived in an overcrowded residence, 60% were smokers, and 83.3% had taken anti-tuberculosis therapy previously. DST of MDR-TB strains for ethambutol, pyrazinamide, and streptomycin showed high resistance ( > 60%). Except for ofloxacin and ciprofloxacin, < 20% resistance was noted in second-line anti tuberculosis agents. Overall, 10% of patients were cured, 40% died, 20% had treatment failure, and 30% patients defaulted. CONCLUSION: Pulmonary MDR-TB in Rawalpindi, Pakistan, is common in young males, poverty related circumstances, and has poor outcome. DST shows high resistance to first- line anti-tuberculosis agents and quinolones. PMID- 22240426 TI - Resistance patterns of Mycobacterium tuberculosis isolates from pulmonary tuberculosis patients in Nairobi. AB - INTRODUCTION: In Kenya, which ranks thirteenth of 27 high tuberculosis burden countries, diagnosis is based on Ziehl-Neelsen staining alone and patients are treated without information on sensitivity patterns. This study aimed to determine resistance patterns of Mycobacterium tuberculosis isolated from pulmonary samples. METHODOLOGY: Pulmonary tuberculosis patients in Nairobi were randomly sampled after informed consent and recruited into the study using a structured questionnaire. Specimens were cultured in liquid and solid media, and drug susceptibility tests were performed for first-line drugs including (isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide). RESULTS: Eighty six (30%) of 286 isolates were resistant to at least one of five antibiotics tested. Thirty-seven (30.2%) isolates were resistant to isoniazid; 15 (11.6%) to streptomycin; 13 (4.5%) to ethambutol; four (1.4%) to rifampin ; and 30 (10.4%) to pyrazinamide. Double resistance was seen as follows: four (1.4%) isolates were resistant to both isoniazid and pyrazinamide; four (1.4%) to streptomycin and isoniazid; and one (0.3%) to rifampin and streptomycin. Two isolates (0.7%) were multidrug resistant, and one was triple resistant with an additional resistance to ethambutol. Results also showed 88.7% of patients were below the age of 40 years, while 26.3% were HIV positive. The majority of the patients (66.5%) were unemployed or self-employed in small businesses, with 79.4% earning less than 100 USD per month. CONCLUSION: The high resistance observed in isoniazid, which is a first-line drug, could result in an increase in multidrug resistance unless control programs are strengthened. Poverty should be addressed to reduce infection rates. PMID- 22240427 TI - Evaluation of conventional molecular diagnosis of Mycobacterium tuberculosis in clinical specimens from Morocco. AB - INTRODUCTION: Tuberculosis is a major public health threat, annually affecting new individuals worldwide, especially those in developing countries. Rapid detection of the agent and effective treatment are two important factors in controlling this disease. METHODOLOGY: The present study aimed to evaluate polymerase chain reaction (PCR) as a rapid and direct molecular method for the diagnosis of Mycobacterium tuberculosis (MTB) in 70 clinical specimens (62 sputum samples, six cerebrospinal fluids, and two biopsies) using heat shock protein (hsp65) as the gene target. Automated sequencing of the same gene was used for the identification of MTB to the species level. RESULTS: The sensitivity of PCR was 81.13%, with specificity of 88.24%; the positive and negative predictive values were 95.56% and 60%, respectively. CONCLUSION: Based on these results, the hsp65 gene sequence can be used to differentiate the members of MTB complex from non-tuberculosis mycobacteria (NTM). PMID- 22240428 TI - Improved detection of Mycobacterium tuberculosis using two independent PCR targets in a tertiary care centre in South India. AB - INTRODUCTION: Tuberculosis (TB) causes significant morbidity and mortality worldwide as one of the leading infectious diseases. In India, more than 1.8 million new cases occur every year. Rapid and accurate diagnosis of TB would improve patient care and limit its transmission. This study aimed to evaluate a dual target polymerase chain reaction (PCR) diagnostic assay to detect Mycobacterium tuberculosis from pulmonary and extra-pulmonary samples at a tertiary care centre in South India. METHODOLOGY: Samples were collected from patients with a low index of suspicion of TB. Acid-fast smears were performed by Auramine O fluorescent microscopy and PCR was performed by using two site specific primer pairs targeting IS6110 by nested PCR and TRC4 by conventional PCR. Amplified products for IS6110 and/or TRC4 were indicative of M. tuberculosis. RESULTS: Among 114 (19 pulmonary and 95 extra-pulmonary) samples tested by PCR assay, 12 (11%) were positive for both IS6110 and TRC4, of which 11 (10%) were non-respiratory and one was (1%) respiratory in origin. PCR for TRC4 alone was positive for eight (7%) non-respiratory and two (2%) respiratory samples, while IS6110 alone tested positive for six (5%) non-respiratory samples and one (1%) respiratory sample. Of a total of 29 PCR positive samples, 17 (15 %) were acid-fast smear positive. CONCLUSION: Although the target site of IS6110 is specific for M. tuberculosis, some strains from South India may lack this region. Therefore, the use of an additional target site (TRC4) is required for improved detection of M. tuberculosis. PMID- 22240429 TI - Comparison of PCR with standard culture of fine needle aspiration samples in the diagnosis of tuberculosis lymphadenitis. AB - INTRODUCTION: Lymphadenopathy is the commonest form of extrapulmonary tuberculosis (TB) Clinical diagnosis of TB in lymph nodes requires aspiration of the material and isolation of mycobacteria. Bacterial culture is the gold standard for detection of tubercle bacilli, but it is time-consuming and requires specialized safety procedures and a BSL3 laboratory. However, PCR is a rapid method which requires small volumes of samples and can also be performed on killed bacilli to ensure safety. This project was designed to compare direct fine needle aspirate (FNA) PCR with culture in the diagnosis of tuberculosis lymphadenitis. METHODOLOGY: Direct examination of samples with EZN staining, culture, cytology and PCR was performed on previously collected FNA from the patients with suspected tuberculosis lymphadenitis. RESULTS: In total, 38% of the samples were positive for TB by culture, 11.8% by EZN staining, 23.4% by PCR, and 59.8% by cytology. Cytology had the highest sensitivity (81%) and EZN stain the least (22.9%). The specificity of EZN stain was the highest (92.4%) while cytology was the lowest (50%). In this study, out of 50 culture-positive samples, 21 (42%) were positive by PCR while 8 (10.8%) out of 74 culture-negative samples were positive by PCR. CONCLUSIONS: Although PCR is a sensitive diagnostic method, its sensitivity was shown to be low in this study. Therefore, we recommend that further studies should be conducted on fresh aspirate samples to investigate for possible PCR inhibitors which may limit the sensitivity of PCR diagnosis. PMID- 22240430 TI - Mycobacterium tuberculosis complex detected by modified fluorescent in situ hybridization in lymph nodes of clinical samples. AB - INTRODUCTION: Lymph node tuberculosis (TB) is the leading cause of extrapulmonary tuberculosis and is the most frequently identified type in Aguascalientes, Mexico. Conventional diagnosis has serious limitations for rapid detection of extrapulmonary tuberculosis in clinical samples. Here PCR and modified FISH have been tested as complementary diagnosis methods for extrapulmonary tuberculosis. METHODOLOGY: The specific insertion sequence IS6110 for Mycobacterium tuberculosis complex was used to perform PCR and build DNA and PNA FISH probes (20bp). PCR and modified DNA and PNA FISH assays were performed to evaluate 41 lymph node paraffin-embedded tissue samples, in comparison with the histopathology diagnosis, which was considered the gold standard (22 positive and 19 negative). RESULTS: In comparison with histopathology diagnosis PCR showed 62.5 % sensitivity and 77.8 % specificity (chi(2) = 4.583 p < 0.05). Modified DNA FISH showed 71.4% sensitivity and 84.6% specificity (chi(2) = 11.21 p < 0.05). PNA FISH showed 66.7% sensitivity and 60.0% specificity (chi(2) = 2.93 p > 0.05). Ziehl Neelsen stain was positive in only four cases of 22 lymph node samples positive to histopathology. In contrast, PCR and modified DNA FISH were positive in 20 cases of the same group. The negative cases were coincident in all tests. CONCLUSIONS: PCR and DNA FISH showed a significant increase in the number of cases detected and also showed higher sensitivity and specificity compared with data reported by traditional methodology. In developing countries, these techniques could help to complement the early diagnosis and timely treatment of extrapulmonary tuberculosis. PMID- 22240431 TI - Utility of an interferon-gamma release assay as a potential diagnostic aid for active pulmonary tuberculosis. AB - INTRODUCTION: Sensitivity, specificity, early confirmation and obtaining an optimal specimen are challenging problems in active tuberculosis (TB) diagnosis. Interferon-gamma release assay (IGRA) is a good indicator for latent TB but can it be useful as a diagnostic tool for active TB? This study was designed to address these challenges and assess the potential of IGRA as a diagnostic indicator of active pulmonary TB by comparing it with other MT diagnostic conventional methods and molecular methods. METHODOLOGY: The study was conducted on 91 patients with suspicion of pulmonary active TB. QuantiFERON-TB-Gold In Tube, a commercial IFN-gamma assay, was compared with Ziehl Neelsen (ZN) smear, Lowenstein Jensen's (LJ) egg-based culture, and real-time polymerase chain reaction. The final clinical diagnosis was the standard comparator of the study. RESULTS: Active pulmonary TB was confirmed in 48/91 (52.7%) patients. Sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) were 72.9%, 100%, 100%, 76.78% for ZN smear, 77.1%, 97.67%, 97.36%, 79.24% for LJ culture, 89.9%, 67.4%, 75.4%, 85.3% for IGRA, and 66.6%, 95.3%, 94.1%, 71.9% for real-time PCR, respectively. CONCLUSION: Albeit confounding in the case of latent TB infected patients presenting with non-TB pulmonary disease, IGRA was more sensitive than the other conventional and molecular methods, so it may improve diagnostic accuracy when used in combination with other standard methods. High NPV of IGRA for the diagnosis of active TB proposed an additional role of this test to exclude the infection with active TB. PMID- 22240432 TI - The MCP-1 (CCL2) -2518 GG genotype is associated with protection against pulmonary tuberculosis in Moroccan patients. AB - INTRODUCTION: Both monocyte chemoattractant protein-1 (MCP-1), also designated officially as chemokine (C-C motif) ligand 2 (CCL2), and interleukin-12 p40 (IL 12 p40) molecules, encoded by polymorphic genes, are central components of the immune response to infection by Mycobacterium tuberculosis (Mtb). Their genetic diversity has previously been associated with the outcome of tuberculosis (TB) infection. We investigated whether the MCP-1 -2518 A/G and the IL-12B (p40) +1188 A/C polymorphisms influence susceptibility to or resistance against pulmonary tuberculosis (PTB) in a Moroccan population group. METHODOLOGY: Genomic DNA from 337 patients along with 204 healthy controls were genotyped for the above mentioned genetic variations using polymerase chain reaction-based restriction fragment length polymorphism assay. RESULTS: We found a higher prevalence of homozygous MCP-1 -2518 G allele in healthy individuals than in patients (pc = 0.04; odds ratio = 0.35; 95% confidence interval = 0.13 - 0.86), suggesting a potential protective effect, whereas analysis of IL-12B +1188 variation failed to reveal any such association. CONCLUSION: Our results are in agreement with recent findings in Ghanaian patients, complying with the known genetic admixture of the Moroccan population. PMID- 22240433 TI - Investigation of the levels of oxidative stress parameters in HIV and HIV-TB co infected patients. AB - INTRODUCTION: Among opportunistic pathogens associated with acquired immunodeficiency syndrome (AIDS), Mycobacterium tuberculosis is distinguished by its relative virulence and potential for person-to-person transmission. Oxidative stress is associated with TB infection with a high level in patients with HIV-TB co-infection. However, the comparative level of oxidative stress in HIV patients on highly active anti-retroviral therapy (HAART) and naive (untreated) HIV patients is not clear. METHODOLOGY: This study is aimed to determine the level of oxidative stress and haematological parameters in HIV patients (naive), HIV patients undergoing HAART, and HIV-TB co-infected patients. In total, 100 consenting subjects were recruited from the AIDS Prevention Iniative in Nigeria (APIN) Clinic. For controls, normal male healthy volunteers were recruited from the blood donor clinic and females from the APIN clinic staff members, both of the Lagos University Teaching Hospital. Measurements of antioxidant enzyme activity and lipid peroxidation were performed according to standard procedures. Haematological parameters were determined using a fully automated hematology analyzer. RESULTS: Red blood cells significantly decreased (P <= 0.001) in all patients when compared with control subjects. The lipid peroxidation (MDA) was significantly high (P <= 0.05) in naive patients when compared to HIV patients on HAART. The decrease in the levels of GSH in both naive and HIV-TB co-infected patients (P <= 0.001) and HIV patients on HAART (P < 0.05) were significant when compared to control patients. CONCLUSION: There is lower antioxidant level and higher MDA in naive and HIV-TB co-infected patients as compared to HIV patients on HAART and the seronegative patients. PMID- 22240434 TI - Primary tubercular psoas abscess: a rare presentation. AB - Primary tubercular psoas abscess is a rare clinical entity and has seldom been reported in an otherwise healthy person. Here we report an interesting case of primary tubercular psoas abscess in an immunocompetent male with no other traceable source. PMID- 22240435 TI - Clinical and radiological deterioration due to Mycobacterium szulgai in an asthmatic patient. AB - We report the case of a 23-year-old asthmatic woman who had clinical and radiological deterioration due to Mycobacterium szulgai infection and good response to anti-mycobacterial treatment without any structural abnormalities in previous lung imaging studies. M. szulgai may be considered a pathogen able to cause deterioration of respiratory health even in patients with previously normal lungs. PMID- 22240436 TI - Isolated tuberculous epididymo-orchitis: an unusual presentation of tuberculosis. AB - Isolated epididymo-orchitis is an unusual presentation of tuberculosis. A case of bilateral epididymitis and right-sided orchitis with scrotal involvement in a 38 year-old male patient is presented. Strong clinical suspicion of tuberculous etiology was confirmed by appropriate investigations of epididymal biopsy. The patient improved clinically with antitubercular therapy. PMID- 22240437 TI - Preliminary remarks on assembly whole genome sequencing of MDR M. tuberculosis isolated in Vietnam. PMID- 22240438 TI - Morphological modification by Tubercle bacilli: no time for denial. PMID- 22240439 TI - Performance of QuantiFERON TB in a student population at low risk of tuberculosis. PMID- 22240440 TI - Extrarenal effects of aldosterone. AB - PURPOSE OF REVIEW: The renal distal tubule has been considered for a long time as the main cellular target of aldosterone, where the hormone enhances sodium reabsorption and potassium secretion. However, other cell types in nonepithelial tissues, such as the heart, the vessels, adipose tissue, and macrophages, are now also recognized as targets for aldosterone. The functions that aldosterone exerts in these nonclassical target tissues are still a matter of debate. This review will highlight the recent findings on the extrarenal effects of aldosterone. RECENT FINDINGS: Numerous studies showed that aldosterone exerts profibrotic and proinflammatory effects, but one or more cofactors such as salt, angiotensin II, and oxidative stress are required. Moreover, inflammation and macrophage infiltration are a prerequisite to aldosterone-induced cardiac fibrosis. This underlines a key role for aldosterone and the mineralocorticoid receptor in macrophages. Inflammatory effects of aldosterone in vascular smooth muscle cells involve trafficking to lipid rafts/caveolae through receptor tyrosine kinases. Finally, a growing body of evidence indicates a prominent role of aldosterone/mineralocorticoid receptor in the metabolic syndrome, in insulin resistance, and in adipocyte biology. SUMMARY: The idiom from Socrates, 'the more we learn, the less we know', can be applied to aldosterone with its different facets and its pleiotropic effects. There is clear evidence for rapid nongenomic effects of aldosterone, mineralocorticoid receptor-dependent and mineralocorticoid receptor-independent signaling, in the heart, the vessels, and other nonepithelial tissues, leading to inflammation, fibrosis, and progression of cardiovascular diseases including hypertension and metabolic syndrome. PMID- 22240441 TI - Novel antimicrobial-resistant bacteria among patients requiring chronic hemodialysis. AB - PURPOSE OF REVIEW: Antimicrobial-resistant bacteria (ARB) including resistant strains of Staphylococcus aureus, enterococci, and Gram-negative bacteria have the potential to cause serious infections among patients requiring chronic hemodialysis (CHD). The purpose of this article is to review novel ARB, which have emerged in this patient population, their mechanisms of transmission, and preventive efforts aimed at limiting their dissemination. RECENT FINDINGS: New strains of ARB, including community-acquired methicillin-resistant S. aureus, S. aureus strains with reduced susceptibility to vancomycin, vancomycin-resistant S. aureus and multidrug-resistant Gram-negative bacteria (MDRGN), are emerging among the CHD population. Extended-spectrum beta-lactamase Gram-negative bacteria (ESBLGN) are among the most common MDRGN strains. These ESBLGN are resistant to the great majority of antimicrobials. The carbapenems remain the only optimal antimicrobial choice to treat ESBLGN infections. Intrafacility spread of ARB in dialysis units occurs between patients through contaminated hands and clothes of healthcare workers (HCWs), as well as contaminated inanimate surfaces. Spread of ARB to family members of both patients and HCWs has also been documented. SUMMARY: Colonization and infection with ARB continues to present a significant threat to patients receiving CHD. Interventions to reduce the spread of ARB should include infection control measures and judicious use of antimicrobials. PMID- 22240442 TI - The interaction between prorenin, renin and the (pro)renin receptor: time to rethink the role in hypertension. AB - PURPOSE OF REVIEW: Elevated prorenin levels are seen in diabetics with microvascular disease. The discovery of a receptor capable of binding renin and prorenin [(P)RR] and triggering an intracellular signal in the laboratory setting raised the expectation that prorenin might be directly responsible for these vascular disorders. However, there has been substantial disagreement concerning the signaling properties of renin and prorenin and it has been impossible to inactivate the (P)RR gene in mouse to define its function. RECENT FINDINGS: Mouse and rat models in which prorenin is highly overexpressed do not demonstrate the glomerulosclerosis typically seen in severe diabetic nephropathy, but do exhibit an increase in blood pressure that is angiotensin II-dependent. (P)RR has been shown to colocalize with other subunits of the vacuolar ATPase in the kidney and heart and to be necessary for Wnt signaling in a renin-independent manner. Although whole-body inactivation of the (P)RR gene is lethal, tissue-specific inactivation results in severe disorders associated with massive cell death. SUMMARY: These results do not support a role of direct prorenin or renin signaling through (P)RR in vascular disorders. Rather, they suggest that the main role of (P)RR is as a subunit of the vacuolarATPase complex. Whether or not (P)RR is responsible for the ability of prorenin to generate angiotensin II in tissues has not been resolved. PMID- 22240443 TI - New insights into hypertension-associated erectile dysfunction. AB - PURPOSE OF REVIEW: Erectile dysfunction is recognized as a quality-of-life disorder that needs to be treated. Currently, it is estimated to affect as many as 30 million American men. Thirty percent of hypertensive patients complain of erectile dysfunction. The understanding of common mechanisms involved in the cause of erectile dysfunction associated with hypertension, and the investigation of antihypertensive drugs that impact erectile dysfunction, will provide important tools toward identifying new therapeutic targets that will improve the quality of life for patients in these conditions. RECENT FINDINGS: Hypertension and erectile dysfunction are closely intertwined diseases, which have endothelial dysfunction as a common base. During hypertension and/or erectile dysfunction, disturbance of endothelium-derived factors can lead to an increase in vascular smooth muscle (VSM) contraction. Hypertension can lead to erectile dysfunction as a consequence of high blood pressure (BP) or due to antihypertensive treatment. However, growing evidence suggests erectile dysfunction is an early sign for hypertension. Also, some phosphodiesterase-5 inhibitors used to treat erectile dysfunction can improve BP, but the link between these conditions has not been totally understood. SUMMARY: This review will discuss the interplay between hypertension and erectile dysfunction, exploring newest insights regarding hypertension-associated erectile dysfunction, as well as the effect of antihypertensive drugs in erectile dysfunction patients. PMID- 22240444 TI - Membranous nephropathy: the start of a paradigm shift. AB - PURPOSE OF REVIEW: Primary membranous nephropathy is a common glomerular disease characterized by sub-epithelial immune deposits that has become the prototype of an autoimmune glomerular disease. The purpose of this review is to highlight recent advances regarding the pathogenesis of membranous nephropathy as well as potential new therapies. RECENT FINDINGS: The discovery of two major podocyte antigens, neutral endopeptidase (NEP), involved in rare cases of neonatal membranous nephropathy, and the M-type phospholipase A2 receptor 1 (PLA2R1), the first antigen discovered in adults, have been major 'breakthroughs' in our understanding of the pathogenesis of human membranous nephropathy. Anti-PLA2R antibodies appear to predict activity of the disease as well as response to therapy. Pediatric and adult cases of membranous nephropathy occurring in the presence of circulating cationic bovine serum album (BSA) and anti-BSA antibodies have also been described, raising the possibility that food antigens may be involved in the development of membranous nephropathy. Moreover, the results of genetic susceptibility have become available. Exciting progress has also been made in the treatment of this disease including therapy with adrenocorticotropic hormone and rituximab. SUMMARY: Understanding disease pathogenesis is crucial in guiding patient evaluation and designing appropriate therapy. Recent discoveries have helped to elucidate the pathophysiology of membranous nephropathy and may facilitate a more patient-specific treatment approach in these patients. PMID- 22240445 TI - Novel tyrosine kinase signaling pathways: implications in vascular remodeling. AB - PURPOSE OF REVIEW: This review summarizes the recent advances in molecular mechanisms by which five classes of receptor tyrosine kinases (RTKs) contribute to vascular remodeling. RECENT FINDINGS: Recent findings have expanded our knowledge regarding RTK regulation. In particular, G-protein-coupled receptors, mineralocorticoid receptors, mechanical and oxidative stresses transactivate RTKs. These receptors are highly interactive with many downstream targets (including tyrosine kinases and other RTKs) and function as key regulatory nodes in a dynamic signaling network. Interactions between vascular and nonvascular (immune and neuronal) cells are controlled by RTKs in vascular remodeling. Inhibition of RTKs could be an advantageous therapeutic strategy for vascular disorders. SUMMARY: RTK-dependent signaling is important for regulation of key functions during vascular remodeling. However, current challenges are related to integration of the data on multiple RTKs in vascular pathology. PMID- 22240446 TI - Vertebral fracture assessment in asymptomatic men and its impact on management. AB - INTRODUCTION: Recognition of vertebral fractures (VFs) change the patient's diagnostic classification, estimation of fracture risk, and threshold for pharmacological intervention. Vertebral fracture assessment (VFA) enables the detection of VFs in the same session as bone mineral density (BMD) testing. OBJECTIVE: To study prevalence and risk factors of VFs using VFA in asymptomatic men and measure its impact on patients' management. METHODS: We enrolled 791 men aged between 45 and 89 (mean age, weight and BMI of 62.4+/-8.6) (45 to 89) years, 74.9+/-12.7 (40 to 163) and 26.3+/-4.0 (16.6 to 43.8) kg/m(2), respectively. Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative (SQ) approach and morphometry. RESULTS: VFs were identified in 318 (40.3%): 206 (26.0%) had grade 1 and 112 (14.2%) had grade 2 or 3. As would be expected, the prevalence of VFA-detected fractures globally increased significantly with age and as BMI and BMD declined. A fracture was identified on VFA in 85 (32.4%) of men with normal BMD (6.9% had grade 2/3 VFs) and in 144 (35.8%) with osteopenia (11.7% had grade 2/3 VFs). Stepwise regression analysis showed that presence of VFs was independently related to the osteoporotic status (OR=4.761, 95%CI [2.956-7.668]; p<0.0001) and current smoking (OR=1.717, 95%CI [1.268-2.323]; p=0.002). CONCLUSION: Our results support the recommendation to enlarge the indications of VFA to all the men referred for DXA measurement. PMID- 22240447 TI - Next-generation sequencing for simultaneous determination of human papillomavirus load, subtype, and associated genomic copy number changes in tumors. AB - Human papillomavirus (HPV) infection in cases of squamous cell carcinoma of the oropharynx is a powerful predictive and prognostic biomarker. We describe how the use of next-generation sequencing can provide a novel method for the detection of HPV in DNA isolated from formalin-fixed paraffin-embedded tissues. Using this methodology in a cohort of 44 head and neck tumors, we identified the samples that contained HPV sequences, the viral subtype involved, and a direct readout of viral load. Specificity of HPV detection by sequencing compared to traditional detection methods using either PCR or p16 immunohistochemistry was 100%. Sensitivity was 50% when either compared to PCR [confidence interval (CI) = 29% to 71%] or 75% when compared to p16 (CI = 47% to 91%). In addition, we demonstrate the ability of next-generation sequencing to detect other HPV subtypes that would not have been detected by traditional methods, and we demonstrated the ability to apply this method to any tumor and any virus in a panel of eight human cancer cell lines. This methodology also provides a tumor genomic copy number karyogram, and in the samples analyzed here, a lower level of chromosome instability was detected in HPV-positive tumors compared to HPV negative tumors, as observed in previous studies. Thus, the use of next generation sequencing for the detection of HPV provides a multiplicity of data with clinical significance in a single test. PMID- 22240449 TI - Long-term association of economic inequality and mortality in adult Costa Ricans. AB - Despite the large number of studies, mostly in developed economies, there is limited consensus on the health effects of inequality. Recently a related literature has examined the relationship between relative deprivation and health as a mechanism to explain the economic inequality and health relationship. This study evaluates the relationship between mortality and economic inequality, as measured by area-level Gini coefficients, as well as the relationship between mortality and relative deprivation, in the context of a middle-income country, Costa Rica. We followed a nationally representative prospective cohort of approximately 16,000 individuals aged 30 and over who were randomly selected from the 1984 census. These individuals were then linked to the Costa Rican National Death Registry until Dec. 31, 2007. Hazard models were used to estimate the relative risk of mortality for all-cause and cardiovascular disease mortality for two indicators: canton-level income inequality and relative deprivation based on asset ownership. Results indicate that there was an unexpectedly negative association between canton income inequality and mortality, but the relationship is not robust to the inclusion of canton fixed-effects. In contrast, we find a positive association between relative deprivation and mortality, which is robust to the inclusion of canton fixed-effects. Taken together, these results suggest that deprivation relative to those higher in a hierarchy is more detrimental to health than the overall dispersion of the hierarchy itself, within the Costa Rican context. PMID- 22240450 TI - Determinants, self-management strategies and interventions for hope in people with mental disorders: systematic search and narrative review. AB - Developing a recovery focus in mental health services is a policy goal internationally, and hope is a central component of recovery. Yet determinants of hope of people with mental disorders are not well known, nor are strategies and interventions that increase hope. This study aims to systematically summarise the available evidence to fill four relevant knowledge gaps: (1) hope scales used in psychiatric research, (2) determinants of hope, (2) hope-fostering self management strategies, and (3) interventions to increase hope for people with mental disorders. We conducted a systematic literature search in April 2011 and a narrative synthesis of publications including qualitative and quantitative studies. Results for the first time provide a comprehensive overview of existing evidence and identify important scientific knowledge gaps: (1) Hope scales used do slightly vary in focus but are overall comparable. (2) Most published research used cross-sectional designs resulting in a high number of potential determinants of hope. No studies prospectively investigated the influence of these determinants. (3) Hope fostering self-management strategies of people with mental disorders were described in qualitative studies only with experimental studies completely missing. (4) While some recovery oriented interventions were shown to increase hope as a secondary outcome, there are no successful interventions specifically aimed at increasing hope. This review provides the basis for both practical and research recommendations: The five most promising candidate interventions to improve hope in people with mental disorders are (i) collaborative strategies for illness management, (ii) fostering relationships, (iii) peer support, (iv) helping clients to assume control and to formulate and pursue realistic goals, and (v) specific interventions to support multiple positive factors such as self-esteem, self-efficacy, spirituality and well-being. These may serve to directly improve care and to develop theory-based models and testable interventions to improve hope in mental health as well as in allied fields. PMID- 22240448 TI - Impact of collection and storage of lung tumor tissue on whole genome expression profiling. AB - Gene expression profiling could assist in revealing biomarkers of lung cancer prognosis and progression. The handling of biological samples may strongly influence global gene expression, a fact that has not been addressed in many studies. We sought to investigate the changes in gene expression that may occur as a result of sample processing time and conditions. Using Illumina Human WG-6 arrays, we quantified gene expression in lung carcinoma samples from six patients obtained at chest opening before and immediately after lung resection with storage in RNAlater [T1a((CO)) and T1b((LR))], after receipt of the sample for histopathology, placed in RNAlater [T2a((HP))]; snap frozen [T2b((HP.SF))]; or snap frozen and stored for 1 week [T2c((HP.SFA))], as well as formalin-fixed, paraffin-embedded (FFPE) block samples. Sampling immediately after resection closely represented the tissue obtained in situ, with only 1% of genes differing more than twofold [T1a((CO)) versus T1b((LR))]. Delaying tissue harvest for an average of 30 minutes from the operating theater had a significant impact on gene expression, with approximately 25% of genes differing between T1a((CO)) and T2a((HP)). Many genes previously identified as lung cancer biomarkers were altered during this period. Examination of FFPE specimens showed minimal correlation with fresh samples. This study shows that tissue collection immediately after lung resection with conservation in RNAlater is an optimal strategy for gene expression profiling. PMID- 22240451 TI - Social stratification and adolescent overweight in the United States: how income and educational resources matter across families and schools. AB - The current study examines how poverty and education in both the family and school contexts influence adolescent weight. Prior research has produced an incomplete and often counterintuitive picture. We develop a framework to better understand how income and education operate alone and in conjunction with each other across families and schools. We test it by analyzing data from Wave 1 of the U.S.-based National Longitudinal Study of Adolescent Health (N = 16,133 in 132 schools) collected in 1994-1995. Using hierarchical logistic regression models and parallel indicators of family- and school-level poverty and educational resources, we find that at the family-level, parent's education, but not poverty status, is associated with adolescent overweight. At the school level, the concentration of poverty within a school, but not the average level of parent's education, is associated with adolescent overweight. Further, increases in school poverty diminish the effectiveness of adolescents' own parents' education for protecting against the risks of overweight. The findings make a significant contribution by moving beyond the investigation of a single socioeconomic resource or social context. The findings push us to more fully consider when, where, and why money and education matter independently and jointly across health-related contexts. PMID- 22240452 TI - Effect of non-steroidal anti-inflammatory drugs on the histology of basal cell carcinomas. AB - BACKGROUND: Aggressive histology is not rare in BCC. Large studies from referral centers report incidences of aggressive histology BCC ranging from 2.5- 44%. These aggressive BCC are characterized by subclinical extension, invasive behavior, local recurrence and challenging treatment. OBJECTIVES: To examine the association between non-steroidal anti-inflammatory drug (NSAID) use and the different histological subtypes of basal cell carcinoma (BCC). METHODS: The design was a nested case-control study. The two population-based cohorts were of patients with a primary BCC diagnosis during January and May 2010 (n=136) and NSAID use in the 15 years prior to baseline. All the lesions were excised and analyzed to determinate the histological subtype of BCC as aggressive or non aggressive. Odds ratios (ORs) and 95% confidence intervals (CIs), using conditional logistic regression, were calculated with the SPSS software to estimate the association of aggressive histological subtypes of BCC and use of NSAID. We controlled the potential confounding factors. RESULTS: The rate of non aggressive BCC associated with exposure to NSAID was increased (OD: 0.34; 95% CI: 0.14-0.84) after adjusting for covariants. LIMITATIONS: our sample is small. We collected data regarding use of NSAID over a wide time ranges, so that we are unable to propose when the potential benefits of NSAID on the histology of BCC would happen. CONCLUSION: According to our data, NSAID exposure is associated with a decreased risk of aggressive BCC. PMID- 22240453 TI - Quantification of damage at different stages of cryopreservation of endangered North American bison (Bison bison) semen and the effects of extender and freeze rate on post-thaw sperm quality. AB - Semen cryopreservation is an important technique for the banking of animal germplasm from endangered species and exploitation of genetically superior sires through artificial insemination. Being a member of bovidae family, bison semen has poor freezing ability as compared to dairy and beef bulls' semen. This study was designed to quantify the damage to bison sperm at different stages of cryopreservation, and to determine the effects of extender (commercial Triladyl((r)) vs. custom made tris-citric acid [TCA]) and freeze rate (-10, -25 and -40 degrees C/min) on post-thaw quality of bison semen. Semen was collected from five bison bulls (three woods and two plains) via electroejaculation. In Experiment 1, semen was diluted in Triladyl(r) extender and frozen with freeze rate -10 degrees C/min. Sperm motility characteristics were recorded in fresh, diluted, cooled (4 degrees C) and freeze-thawed semen using computer-assisted sperm analyzer (CASA). In Experiment 2, semen was diluted in Triladyl(r) or TCA extender, and frozen with three different freeze rates, i.e. -10, -25 or -40 degrees C/min. Thawing was performed at 37 degrees C for 60s. Post-thaw sperm motility characteristics were assessed using CASA, and sperm structural characteristics (plasma membrane, mitochondrial membrane potential and acrosomes) were evaluated using flow cytometer, at 0 and 3h while incubating semen at 37 degrees C. In Experiment 1, total and progressive motilities did not differ among pre-freeze stages of cryopreservation (P>0.05). However, sperm total and progressive motilities declined (P<0.001) in freeze-thawed semen by 35% and 42%, respectively, compared to after cooling (pre-freeze) semen. In Experiment 2, Triladyl(r), as compared to TCA, yielded greater (P<0.05) post-thaw sperm total motility (41% compared to 36%) and progressive motility (34% compared to 29%) at 0h, respectively. The percent change in post-thaw sperm total and progressive motilities, VAP, VCL, VSL, IPM-high DeltaPsim and IPM-IACR during 3h incubation at 37 degrees C, was less (P<0.05) in TCA than in Triladyl(r). There was an effect of freeze rate on post-thaw sperm average path velocity at 0h, and total motility, progressive motility, VCL, IPM and IPM-IACR at 3h were the greatest (P<0.05) when bison semen was frozen at -40 degrees C/min. Likewise, the percent change in post-thaw sperm total and progressive motilities, during 3h incubation at 37 degrees C, was less (P<0.05) in bison semen frozen at -40 degrees C/min. All post-thaw bison sperm characteristics decreased (P<0.05) from 0h to 3h, during incubation at 37 degrees C. In conclusion, the maximum damage to bison sperm occurred during freeze-thaw processes. Post-thaw total and progressive motilities of bison sperm were greater in Triladyl(r) at 0h whereas sperm survival was greater in TCA extender during 3h post-thaw incubation. Bison sperm had greater survival (P<0.05) when frozen at -40 degrees C/min freeze rate. PMID- 22240455 TI - ESCRT-III polymers in membrane neck constriction. AB - The endosomal sorting complex required for transport (ESCRT)-III machinery contributes to membrane deformation and scission in cytokinesis, intraluminal vesicle formation, autophagy and virus budding. Recombinant ESCRT-III subunits polymerize in vitro into filaments, tubes, sheets or rings, and ESCRT-III dependent filaments have been observed in cells at virus bud necks and at the cytokinetic abscission site. These observations have inspired speculation about how ESCRT-III could mediate constriction and fission of membrane necks. Based on the polymer structures observed in vitro and in vivo, we discuss models for ESCRT III function and outline how emerging technologies could be used to test these models. PMID- 22240454 TI - Engineered myocardial tissues constructed in vivo using cardiomyocyte-like cells derived from bone marrow mesenchymal stem cells in rats. AB - BACKGROUND: To explore the feasibility of constructing engineered myocardial tissues (EMTs) in vivo, using polylactic acid -co-glycolic acid (PLGA) for scaffold and cardiomyocyte-like cells derived from bone marrow mesenchymal stem cells (BMMSCs) for seeded cells. METHODS: BMMSCs were isolated from femur and tibia of Sprague-Dawley (SD) rats by density-gradient centrifugation. The third passage cells were treated with 10 MUmol/L 5-azacytidine (5-aza) and 0.1 MUmol/L angiotensin II (Ang II) for 24 h, followed by culturing in complete medium for 3 weeks to differentiated into cardiomyocyte-like cells. The cardiomyocyte-like cells were seeded into PLGA scaffolds to form the grafts. The grafts were cultured in the incubator for three days and then implanted into the peritoneal cavity of SD rats. Four weeks later, routine hematoxylin-eosin (HE) staining, immunohistochemical staining for myocardium-specific cardiac troponin I (cTnI), scanning electron microscopy and transmission electron microscopy were used to analyze the morphology and microconstruction of the EMTs in host rats. RESULTS: HE staining showed that the cardiomyocyte-like cells distributed equally in the PLGA scaffold, and the nuclei arranged in the spindle shape. Immunohistochemical staining revealed that majority of engrafted cells in the PLGA -Cardiomyocyte like cells group were positive for cTnI. Scanning electron microscopy showed that the inoculated cells well attached to PLGA and grew in 3 dimensions in construct. Transmission electron microscopy showed that the EMTs contained well arranged myofilaments paralleled to the longitudinal cell axis, the cells were rich in endoplasmic reticulum and mitochondria, while desmosomes, gap junction and Z line like substances were also can be observed as well within the engrafted cells. CONCLUSION: We have developed an in vivo method to construct engineered myocardial tissue. The in vivo microenvironment helped engrafted cells/tissue survive and share similarities with the native heart tissue. PMID- 22240457 TI - Modifications modulate anticodon loop dynamics and codon recognition of E. coli tRNA(Arg1,2). AB - Three of six arginine codons are read by two tRNA(Arg) isoacceptors in Escherichia coli. The anticodon stem and loop of these isoacceptors (ASL(Arg1,2)) differs only in that the position 32 cytidine of tRNA(Arg1) is posttranscriptionally modified to 2-thiocytidine (s(2)C(32)). The tRNA(Arg1,2) are also modified at positions 34 (inosine, I(34)) and 37 (2-methyladenosine, m(2)A(37)). To investigate the roles of modifications in the structure and function, we analyzed six ASL(Arg1,2) constructs differing in their array of modifications by spectroscopy and codon binding assays. Thermal denaturation and circular dichroism spectroscopy indicated that modifications contribute thermodynamic and base stacking properties, resulting in more order but less stability. NMR-derived structures of the ASL(Arg1,2) showed that the solution structures of the ASLs were nearly identical. Surprisingly, none possessed the U turn conformation required for effective codon binding on the ribosome. Yet, all ASL(Arg1,2) constructs efficiently bound the cognate CGU codon. Three ASLs with I(34) were able to decode CGC, whereas only the singly modified ASL(Arg1,2)(ICG) with I(34) was able to decode CGA. The dissociation constants for all codon bindings were physiologically relevant (0.4-1.4 MUM). However, with the introduction of s(2)C(32) or m(2)A(37) to ASL(Arg1,2)(ICG), the maximum amount of ASL bound to CGU and CGC was significantly reduced. These results suggest that, by allowing loop flexibility, the modifications modulate the conformation of the ASL(Arg1,2), which takes one structure free in solution and two others when bound to the cognate arginyl-tRNA synthetase or to codons on the ribosome where modifications reduce or restrict binding to specific codons. PMID- 22240456 TI - The antibiotic thermorubin inhibits protein synthesis by binding to inter-subunit bridge B2a of the ribosome. AB - Thermorubin is a small-molecule inhibitor of bacterial protein synthesis, but relatively little is known about the molecular mechanism by which it blocks translation. The structure of the complex between thermorubin and the 70S ribosome from Thermus thermophilus reported here shows that thermorubin interacts with the ribosome in a way that is distinct from any other known class of ribosome inhibitor. Though it is structurally similar to tetracycline, it binds to the ribosome at an entirely different location-the interface between the small and large subunits that is formed by inter-subunit bridge B2a. This region of the ribosome is known to play a role in the initiation of translation, and thus, the binding site we observe is consistent with evidence suggesting that thermorubin inhibits the initiation stage of protein synthesis. The binding of thermorubin induces a rearrangement of two bases on helix 69 of the 23S rRNA, and presumably, this rearrangement blocks the binding of an A-site tRNA, thereby inhibiting peptide bond formation. Due in part to its low solubility in aqueous media, thermorubin has not been used clinically, although it is a potent antibacterial agent with low toxicity (Therapeutic Index>200). The interactions between thermorubin and the ribosome, as well as its adjacency to the observed binding sites of three other antibiotic classes, may enable the design of novel derivatives that share thermorubin's mode of action but possess improved pharmacodynamic properties. PMID- 22240458 TI - Activation of apoptotic pathways in the absence of cell death in an inner-ear immortomouse cell line. AB - Aminoglycoside antibiotics and cisplatin (CDDP) are the major ototoxins of clinical medicine due to their capacity to cause significant and permanent hearing loss by targeting the mammalian sensory cells. Understanding the pathogenesis of damage is the first step in designing effective prevention of drug-induced hearing loss. In-vitro systems greatly enhance the efficiency of biochemical and molecular investigations through ease of access and manipulation. HEI-OC1, an inner ear cell line derived from the immortomouse, expresses markers for auditory sensory cells and, therefore, is a potential tool to study the ototoxic mechanisms of drugs like aminoglycoside antibiotics and CDDP. HEI-OC1 cells (and also HeLa cells) efficiently take up fluorescently tagged gentamicin and respond to drug treatment with changes in cell death and survival signaling pathways. Within hours, the c-Jun N-terminal kinase pathway and the transcription factor AP-1 were activated and at later times, the "executioner caspase", caspase 3. These responses were robust and elicited by both gentamicin and kanamycin. However, despite the initiation of apoptotic pathways and transient changes in nuclear morphology, cell death was not observed following aminoglycoside treatment, while administration of CDDP led to significant cell death as determined by flow cytometric measurements; beta-galactosidase analysis ruled out senescence in gentamicin-treated cells. The ability to withstand treatment with aminoglycosides but not with CDDP suggests that this cell line might be helpful in providing some insight into the differential actions of the two ototoxic drugs. PMID- 22240459 TI - Spatial release from masking in a free-field source identification task by gray treefrogs. AB - Humans and other animals often communicate acoustically in noisy social groups, in which the background noise generated by other individuals can mask signals of interest. When listening to speech in the presence of speech-like noise, humans experience a release from auditory masking when target and masker are spatially separated. We investigated spatial release from masking (SRM) in a free-field call recognition task in Cope's gray treefrog (Hyla chrysoscelis). In this species, reproduction requires that females successfully detect, recognize, and localize a conspecific male in the noisy social environment of a breeding chorus. Using no-choice phonotaxis assays, we measured females' signal recognition thresholds in response to a target signal (an advertisement call) in the presence and absence of chorus-shaped noise. Females experienced about 3 dB of masking release, compared with a co-localized condition, when the masker was displaced 90 degrees in azimuth from the target. The magnitude of masking release was independent of the spectral composition of the target (carriers of 1.3 kHz, 2.6 kHz, or both). Our results indicate that frogs experience a modest degree of spatial unmasking when performing a call recognition task in the free-field, and suggest that variation in signal spectral content has small effects on both source identification and spatial unmasking. We discuss these results in the context of spatial unmasking in vertebrates and call recognition in frogs. PMID- 22240461 TI - The cost-effectiveness of cotrimoxazole in people with advanced HIV infection initiating antiretroviral therapy in sub-Saharan Africa. AB - BACKGROUND: In sub-Saharan Africa, high mortality rates have been reported among patients with advanced HIV infection initiating antiretroviral therapy (ART). We evaluated the cost-effectiveness of expanding access to cotrimoxazole (CTX) for persons with HIV in averting mortality during the first 6 months of ART. We also evaluated possible cost savings related to prevention of specific opportunistic infections (OIs). METHODS: We developed a decision-analytic model to estimate the incremental cost, deaths averted, and incremental cost-effectiveness ratio. The model compared 2 scenarios for providing CTX and evaluated potential benefits of increased CTX coverage in reducing deaths and cases of OI. The base case scenario represents an estimated current level of CTX coverage among adults initiating ART in low-income countries (65%). The comparator is 97% coverage (excluding only those with contraindications to CTX). We conducted sensitivity analyses on all parameters in the model. RESULTS: Full coverage reduced deaths from 94 to 72 per 1000 patients, averting 22 deaths during the first 6 months of ART compared with the base case. The incremental cost of moving from base case to full coverage was estimated at $3.29 per person on ART and $146.91 per death averted over 6 months. Additional benefits from averted OI cases would likely be realized as well as savings from averted OI treatment costs. CONCLUSIONS: Our findings suggest that expanding CTX coverage is a cost-effective approach to reducing mortality among patients who present with advanced HIV and initiate ART. The expansion of coverage may also yield benefits for OIs. PMID- 22240460 TI - Trends in reasons for hospitalization in a multisite United States cohort of persons living with HIV, 2001-2008. AB - INTRODUCTION: Hospitalization rates for comorbid conditions among persons living with HIV in the current highly active antiretroviral therapy era are unknown. METHODS: Hospitalization data from 2001 to 2008 were obtained on 11,645 adults receiving longitudinal HIV care at 4 geographically diverse US HIV clinics within the HIV Research Network. Modified clinical classification software from the Agency for Healthcare Research and Quality assigned primary ICD-9 codes into diagnostic categories. Analysis was performed with repeated measures negative binomial regression. RESULTS: During 2001 to 2008, the rate of AIDS-defining illness (ADI) hospitalizations declined from 6.7 to 2.7 per 100 person-years, incidence rate ratio per year, 0.89 (0.87, 0.91). Among the other diagnostic categories with average rates >2 per 100 person-years, cardiovascular hospitalizations increased over time [1.07 (1.03, 1.11)], whereas non-AIDS defining infection [0.98 (0.96, 1.00)], psychiatric [0.96 (0.93, 1.00)], and gastrointestinal/liver [0.96 (0.92, 1.00)] were slightly decreasing or stable. Although less frequent overall, renal and pulmonary admissions also increased over time in univariate and multivariate analyses. Of all diagnostic categories, ADI admissions had the longest mean length of stay, 10.5 days. DISCUSSION: ADI hospitalizations have continued to decline in recent years but are still relatively frequent and potentially costly given long lengths of stay. Increases or stability in the rates of chronic end-organ disease admissions imply a need for broader medical knowledge among individual clinicians and/or teams who care for persons living with HIV and a need for long-term access to medications for these conditions. PMID- 22240462 TI - Higher SLPI expression, lower immune activation, and increased frequency of immune cells in a cohort of Colombian HIV-1 controllers. AB - BACKGROUND: There are 2 new phenotypes of HIV-1-positive individuals who exhibit a spontaneous and sustained control of viral replication at least for 1 year without antiretroviral therapy (elite controllers <50 copies/mL and viremic controllers <2000 copies/mL). Mechanisms related to this spontaneous control of viral replication are poorly understood. METHODS: The study included HIV-1 controllers (patients with at least 1 year of HIV-1 diagnosis, highly active antiretroviral therapy naive, and with viral loads less than 2000 copies/mL) and HIV-1 progressors without antiretroviral therapy (viral load >2500 copies/mL, and CD4 T-cell count >250 cells/MUL at the time of sampling). The expression of soluble factors, leukocyte protease inhibitor (SLPI) and human alpha-defensins-1 (HAD-1), was measured by real-time polymerase chain reaction from neutrophil cultures with or without HIV stimulation; the frequency and phenotype of innate and adaptive immune cells were determined by flow cytometry, and frequency of human leukocyte antigen alleles was determined by polymerase chain reaction sequence-specific oligonucleotide typing. RESULTS: As expected, HIV-1 controllers had higher CD4 T-cell counts and lower viral load when compared with HIV-1 progressor individuals; in addition, they exhibited lower expression of activation markers, higher frequency of myeloid dendritic cell, lower percentage of regulatory T cells and natural killer cells, and higher expression of SLPI. CONCLUSIONS: All together, these findings suggest that the control of the immune activation status and the production of antiviral proteins by innate immune cells could be associated to the mechanisms involved in the control of HIV-1 replication and better preservation of the CD4 T-cell count. PMID- 22240463 TI - HIV controllers are distinguished by chemokine expression profile and HIV specific T-cell proliferative potential. AB - BACKGROUND: HIV controllers demonstrate a natural ability to control HIV replication in the absence of antiretroviral therapy. We performed a comprehensive evaluation of inflammation and T-cell activation in a demographically unique cohort of HIV controllers and noncontrollers. METHODS: Plasma concentrations of 22 cytokines and chemokines were evaluated using a multiplex bead array approach. Multicolor flow cytometry was used to measure baseline levels of T-cell activation and regulatory T cells (Tregs) and HIV specific T-cell cytokine (interferon gamma, interleukin 2) and proliferation responses. RESULTS: HIV controllers were characterized by elevated macrophage inflammatory protein 1alpha and low levels of interferon gamma-induced protein 10, monocyte chemotactic protein 1, and Transforming growth factor beta. Activated (CD38(+) HLA DR(+)) CD4(+) and CD8(+) T cells were reduced in HIV controllers relative to noncontrollers. HIV controllers and noncontrollers had comparable proportions of Tregs within the CD4(+) T-cell compartment, but absolute Treg counts were depleted in noncontrollers. Absolute Treg counts correlated inversely with T-cell activation. Proliferative CD4(+) and CD8(+) T cell responses directed against HIV gag epitopes were found most frequently among HIV controllers with the lowest viral loads (elite controllers) and were rarely detected among noncontrollers, supporting a relationship between HIV-specific T cell proliferation and viral control. CONCLUSIONS: Collectively, these data suggest a model in which HIV controllers maintain low levels of viral replication through robust HIV-specific T-cell responses in an environment of low inflammation and reduced availability of activated target cells. PMID- 22240465 TI - Cost-effectiveness of tuberculosis diagnostic strategies to reduce early mortality among persons with advanced HIV infection initiating antiretroviral therapy. AB - BACKGROUND: In sub-Saharan Africa, patients with advanced HIV experience high mortality during the first few months of antiretroviral therapy (ART), largely attributable to tuberculosis (TB). We evaluated the cost-effectiveness of TB diagnostic strategies to reduce this early mortality. METHODS: We developed a decision analytic model to estimate the incremental cost, deaths averted, and cost-effectiveness of 3 TB diagnostic algorithms. The model base case represents current practice (symptoms screening, sputum smear, and chest radiography) in many resource-limited countries in sub-Saharan Africa. We compared the current practice with World Health Organization (WHO)-recommended practice with culture and WHO-recommended practice with the Xpert mycobacterium tuberculosis and resistance to rifampicin test and considered relevant medical costs from a health system perspective using the timeframe of the first 6 months of ART. We conducted univariate and probabilistic sensitivity analyses on all parameters in the model. RESULTS: When considering TB diagnosis and treatment and ART costs, the cost per patient was $850 for current practice, $809 for the algorithm with Xpert test, and $879 for the algorithm with culture. Our results showed that both WHO recommended algorithms avert more deaths among TB cases than does the current practice. The algorithm with Xpert test was least costly at reducing early mortality compared with the current practice. Sensitivity analyses indicated that cost-effectiveness findings were stable. CONCLUSIONS: Our analysis showed that culture or Xpert were cost-effective at reducing early mortality during the first 6 months of ART compared with the current practice. Thus, our findings provide support for ongoing efforts to expand TB diagnostic capacity. PMID- 22240464 TI - Long-term antiretroviral treatment outcomes in seven countries in the Caribbean. AB - OBJECTIVES: To report long-term HIV treatment outcomes in 7 Caribbean countries. DESIGN: Observational cohort study. METHODS: We report outcomes for all antiretroviral therapy (ART) naive adult patients enrolled on ART from program inception until study closing for cohorts in Barbados, the Dominican Republic, Haiti, Jamaica, Martinique, Trinidad, and Puerto Rico. Incidence and predictors of mortality were analyzed by time-to-event approaches. RESULTS: A total of 8203 patients were on ART from 1998 to 2008. Median follow-up time was 31 months (interquartile range: 14-50 months). The overall mortality was 13%: 6% in Martinique, 8% in Jamaica, 11% in Trinidad, 13% in Haiti, 15% in the Dominican Republic, 15% in Barbados, and 24% in Puerto Rico. Mortality was associated with male gender [hazard ratio (HR), 1.58; 95% confidence interval (CI): 1.33 to 1.87], body weight (HR, 0.85 per 10 pounds; 95% CI: 0.82 to 0.89), hemoglobin (HR, 0.84 per g/dL; 95% CI: 0.80 to 0.88), CD4 cell count (0.90 per 50 CD4 cells; 95% CI: 0.86 to 0.93), concurrent tuberculosis (HR, 1.58; 95% CI: 1.25 to 2.01) and age (HR, 1.19 per 10 years; 95% CI: 1.11 to 1.28). After controlling for these variables, mortality in Martinique, Jamaica, Trinidad, and Haiti was not significantly different. A total of 75% of patients remained alive and in care at the end of the study period. CONCLUSIONS: Long-term mortality rates vary widely across the Caribbean countries. Much of the difference can be explained by disease severity at ART initiation, nutritional status, and concurrent tuberculosis. Earlier ART initiation will be critical to improve the outcomes. PMID- 22240466 TI - Annual cycle of hypoxia off the Changjiang (Yangtze River) Estuary. AB - The annual cycle of hypoxia off the Changjiang Estuary, China, was assessed from data acquired during nine cruises in 2006-2007. Hypoxia began to develop in late spring and early summer, reached its maximum in August, weakened in the autumn and finally disappeared in the winter. Hypoxia first developed south-east of the Changjiang Estuary in June, appeared in the east and north-east in July, and spread both south and north of the Changjiang Estuary in August. By September, it had started to recede in the north-east, and had dissipated in the southern part of the studied area by winter. The geographical displacement of the hypoxic zone was controlled by both seasonal changes in regional water column stratification and variations of the northward extension of the Taiwan Warm Current toward the Changjiang Estuary. PMID- 22240467 TI - Medial cervical tumefaction in adults: what diagnosis? Thyroglossal duct cyst. PMID- 22240468 TI - Differential effects of ADORA2A gene variations in pre-attentive visual sensory memory subprocesses. AB - The ADORA2A gene encodes the adenosine A(2A) receptor that is highly expressed in the striatum where it plays a role in modulating glutamatergic and dopaminergic transmission. Glutamatergic signaling has been suggested to play a pivotal role in cognitive functions related to the pre-attentive processing of external stimuli. Yet, the precise molecular mechanism of these processes is poorly understood. Therefore, we aimed to investigate whether ADORA2A gene variation has modulating effects on visual pre-attentive sensory memory processing. Studying two polymorphisms, rs5751876 and rs2298383, in 199 healthy control subjects who performed a partial-report paradigm, we find that ADORA2A variation is associated with differences in the efficiency of pre-attentive sensory memory sub-processes. We show that especially the initial visual availability of stimulus information is rendered more efficiently in the homozygous rare genotype groups. Processes related to the transfer of information into working memory and the duration of visual sensory (iconic) memory are compromised in the homozygous rare genotype groups. Our results show a differential genotype-dependent modulation of pre attentive sensory memory sub-processes. Hence, we assume that this modulation may be due to differential effects of increased adenosine A(2A) receptor signaling on glutamatergic transmission and striatal medium spiny neuron (MSN) interaction. PMID- 22240469 TI - Genetic rediscovery of an 'extinct' Galapagos giant tortoise species. PMID- 22240470 TI - Polarization vision: Drosophila enters the arena. AB - Two new studies introduce the power of Drosophila genetics to polarization vision, revealing distinct photoreceptor inputs to polarotactic behaviour mediated by dorsal and ventral eye regions. PMID- 22240471 TI - Wound healing: calcium flashes illuminate early events. AB - What are the earliest signals produced at a wound edge that mobilise epithelial cells to heal the wound? Live analysis of wound healing in the worm Caenorhabditis elegans shows that calcium may be the key early trigger. PMID- 22240472 TI - Thermoregulation: an orphan receptor finds its way in the cold. AB - The hypometabolic state of torpor is a widely utilized and well-orchestrated response to food shortage. A new study shows that the melatonin-related orphan receptor GPR50 plays an important function in metabolic regulation for entry into torpor. PMID- 22240473 TI - Visual cognition: rats compare shapes among the crowd. AB - Rats can discriminate simple shapes visually, even if they are moved around, made smaller, or partially covered up; the strategy they use may help shed light on human brain mechanisms for discriminating complex features, such as faces. PMID- 22240474 TI - Human microbiome: a genetic bazaar for microbes? AB - A recent study suggests that lateral gene transfer has been particularly intense among human-associated microbes. What can this tell us about our relationship with our internal microbial world? PMID- 22240475 TI - Binocular vision: the eyes add and subtract. AB - Our two eyes' views of the outside world are slightly different, providing the basis for stereopsis. A new study has found evidence that the human visual system has separately adaptable channels for adding and subtracting the neural signals from the two eyes, supporting an unconventional view of the initial stages of stereopsis. PMID- 22240476 TI - Brain organization: wiring economy works for the large and small. AB - The highest-resolution test to date of the wire minimization hypothesis has found that this principle works well for brain regions with a volume just over 400 MUm(3). What is the wire minimization hypothesis, and why should anyone care about it? PMID- 22240477 TI - Neurogenesis: premature mitotic entry lets cleavage planes take off! AB - Mutations in the gene microcephalin/MCPH1 result in the neurodevelopmental disease microcephaly. A recent report provides evidence that MCPH1 controls neuroprogenitor entry into mitosis via the Chk1-Cdc25b centrosome maturation pathway. PMID- 22240478 TI - Mechanisms of autophagosome biogenesis. AB - Autophagy is a unique membrane trafficking process whereby newly formed membranes, termed phagophores, engulf parts of the cytoplasm leading to the production of double-membraned autophagosomes that get delivered to lysosomes for degradation. This catabolic pathway has been linked to numerous physiological and pathological conditions, such as development, programmed cell death, cancer, pathogen infection, neurodegenerative disorders, and myopathies. In this review, we will focus on recent studies in yeast and mammalian systems that have provided insights into two critical areas of autophagosome biogenesis - the source of the autophagosomal membranes, and the mechanisms regulating the fusion of the edges of the double-membraned phagophores to form autophagosomes. PMID- 22240479 TI - Sperm storage. PMID- 22240480 TI - Strand-specific miR-28-5p and miR-28-3p have distinct effects in colorectal cancer cells. AB - BACKGROUND & AIMS: MicroRNAs (miRNAs) can promote or inhibit tumor growth and are therefore being developed as targets for cancer therapies. They are diverse not only in the messenger RNAs (mRNA) they target, but in their production; the same hairpin RNA structure can generate mature products from each strand, termed 5p and 3p, that can bind different mRNAs. We analyzed the expression, functions, and mechanisms of miR-28-5p and miR-28-3p in colorectal cancer (CRC) cells. METHODS: We measured levels of miR-28-5p and miR-28-3p expression in 108 CRC and 49 normal colorectal samples (47 paired) by reverse transcription, quantitative real-time polymerase chain reaction. The roles of miR-28 in CRC development were studied using cultured HCT116, RKO, and SW480 cells and tumor xenograft analyses in immunodeficient mice; their mRNA targets were also investigated. RESULTS: miR-28 5p and miR-28-3p were down-regulated in CRC samples compared with normal colon samples. Overexpression of miRNAs in CRC cells had different effects and the miRNAs interacted with different mRNAs: miR-28-5p altered expression of CCND1 and HOXB3, whereas miR-28-3p bound NM23-H1. Overexpression of miR-28-5p reduced CRC cell proliferation, migration, and invasion in vitro, whereas miR-28-3p increased CRC cell migration and invasion in vitro. CRC cells overexpressing miR-28 developed tumors more slowly in mice compared with control cells, but miR-28 promoted tumor metastasis in mice. CONCLUSION: miR-28-5p and miR-28-3p are transcribed from the same RNA hairpin and are down-regulated in CRC cells. Overexpression of each has different effects on CRC cell proliferation and migration. Such information has a direct application for the design of miRNA gene therapy trials. PMID- 22240481 TI - Diverse functional properties of Wilson disease ATP7B variants. AB - BACKGROUND & AIMS: Wilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. METHODS: We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells. Protein function was analyzed by measuring catalytic activity and copper ((64)Cu) transport into vesicles. We studied intracellular localization of variants of ATP7B that had measurable transport activities and were tagged with green fluorescent protein in mammalian cells using confocal laser scanning microscopy. RESULTS: Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor intermediate formation or had partial losses of activity. In mammalian cells, transport-competent variants differed in stability and subcellular localization. CONCLUSIONS: Variants in ATP7B associated with Wilson disease disrupt the protein's transport activity, result in its mislocalization, and reduce its stability. Single assays are insufficient to accurately predict the effects of ATP7B variants the function of its product and development of Wilson disease. These findings will contribute to our understanding of genotype-phenotype correlation and mechanisms of disease pathogenesis. PMID- 22240482 TI - RACK1 suppresses gastric tumorigenesis by stabilizing the beta-catenin destruction complex. AB - BACKGROUND & AIMS: Dysregulation of Wnt signaling has been involved in gastric tumorigenesis by mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1, GNB2L1) is involved in development of different tumor types, but its expression and function have not been investigated in gastric tumors. METHODS: We analyzed expression of RACK1 in gastric tumor samples and their matched normal tissues from 116 patients using immunohistochemistry. Effects of knockdown with small interfering RNAs or overexpression of RACK1 in gastric cancer cell lines were evaluated in cell growth and tumor xenograft. RACK1 signaling pathways were investigated in cells and zebrafish embryos using immunoblot, immunoprecipitation, microinjection, and in situ hybridization assays. RESULTS: Expression of RACK1 was reduced in gastric tumor samples and correlated with depth of tumor infiltration and poor differentiation. Knockdown of RACK1 in gastric cancer cells accelerated their anchorage-independent proliferation in soft agar, whereas overexpression of RACK1 reduced their tumorigenicity in nude mice. RACK1 formed a complex with glycogen synthase kinase Gsk3beta and Axin to promote the interaction between Gsk3beta and beta-catenin and thereby stabilized the beta-catenin destruction complex. On stimulation of Wnt3a, RACK1 repressed Wnt signaling by inhibiting recruitment of Axin by Dishevelled 2 (Dvl2). Moreover, there was an inverse correlation between expression of RACK1 and localization of beta-catenin to the cytoplasm/nucleus in human gastric tumor samples. CONCLUSIONS: RACK1 negatively regulates Wnt signaling pathway by stabilizing the beta-catenin destruction complex and act as a tumor suppressor in gastric cancer cells. PMID- 22240483 TI - Estrogen receptor alpha represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4alpha. AB - BACKGROUND & AIMS: Women with hepatitis B virus (HBV) infection usually have lower viral loads than men, reducing their risk of liver cancer. There are 2 androgen-responsive elements in the HBV enhancer I that contribute to higher viral titers in men. We investigated whether and how estrogen signaling affects progression of HBV infection. METHODS: Ovariectomy and estrogen supplementation were used to evaluate the effect of estrogen on HBV titers in transgenic mice with replicating HBV in hepatocytes. The effect of estrogen signaling on transcription of HBV genes, and the mechanisms of regulation, were studied in HepG2 cells. RESULTS: HBV titers increased in female mice after ovariectomy and decreased in male mice supplemented with estrogen. Hepatic expression of estrogen receptor (ER)-alpha was increased by estrogen exposure. In HepG2 cells, up regulation of ER-alpha reduced HBV transcription, which required a specific region within enhancer I. Direct DNA binding of ER-alpha and histone deacetylase activity were not required for ER-alpha-mediated repression of HBV genes. Overexpression of hepatocyte nuclear factor (HNF)-4alpha, which binds to this region, overcame the repressive effect of ER-alpha. ER-alpha did not repress transcription of an HBV replicon with a mutant HNF-4alpha binding site within enhancer I. Coimmunoprecipitation assays showed an interaction between ER-alpha and HNF-4alpha; this interaction prevented HNF-4alpha binding to enhancer I and activation of HBV transcription. CONCLUSIONS: Estrogen can repress transcription of HBV genes by up-regulating ER-alpha, which interacts with and alters binding of HNF-4alpha to the HBV enhancer I. These findings might account for the lower viral load and reduced incidence of liver cancer in HBV-infected women than men. PMID- 22240484 TI - Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. AB - BACKGROUND & AIMS: The pathogenesis of liver fibrosis involves activation of hepatic stellate cells, which is associated with depletion of intracellular lipid droplets. When hepatocytes undergo autophagy, intracellular lipids are degraded in lysosomes. We investigated whether autophagy also promotes loss of lipids in hepatic stellate cells to provide energy for their activation and extended these findings to other fibrogenic cells. METHODS: We analyzed hepatic stellate cells from C57BL/6 wild-type, Atg7(F/F), and Atg7(F/F)-GFAP-Cre mice, as well as the mouse stellate cell line JS1. Fibrosis was induced in mice using CCl(4) or thioacetamide (TAA); liver tissues and stellate cells were analyzed. Autophagy was blocked in fibrogenic cells from liver and other tissues using small interfering RNAs against Atg5 or Atg7 and chemical antagonists. Human pulmonary fibroblasts were isolated from samples of lung tissue from patients with idiopathic pulmonary fibrosis or from healthy donors. RESULTS: In mice, induction of liver injury with CCl(4) or TAA increased levels of autophagy. We also observed features of autophagy in activated stellate cells within injured human liver tissue. Loss of autophagic function in cultured mouse stellate cells and in mice following injury reduced fibrogenesis and matrix accumulation; this effect was partially overcome by providing oleic acid as an energy substrate. Autophagy also regulated expression of fibrogenic genes in embryonic, lung, and renal fibroblasts. CONCLUSIONS: Autophagy of activated stellate cells is required for hepatic fibrogenesis in mice. Selective reduction of autophagic activity in fibrogenic cells in liver and other tissues might be used to treat patients with fibrotic diseases. PMID- 22240485 TI - A collaborative public health approach to clubfoot intervention in 10 low-income and middle-income countries: 2-year outcomes and lessons learnt. AB - Untreated clubfoot has been acknowledged as a public health problem in low-income countries. In 2007-2009, a 10-country initiative was implemented by a collaboration of nongovernmental organizations and Ministries of Health to establish and strengthen national programmes for management of clubfoot using the Ponseti technique. Independent evaluation used quantitative data on programme outcomes and qualitative data from service providers and users. Overall, 110 clubfoot clinics were established, 634 practitioners were trained and 7705 children were enrolled for treatment. The public health model of establishing services for clubfoot on a national level was found to be successful in the majority of countries included. PMID- 22240486 TI - The origin and diversity of the HIV-1 pandemic. AB - This review examines the enormous progress that has been made in the past decade in understanding the origin of HIV, HIV genetic variability, and the impact of global HIV diversity on the pandemic. Multiple zoonotic transmissions of simian immunodeficiency virus (SIV) have resulted in different HIV lineages in humans. In addition, the high mutation and recombination rates during viral replication result in a great genetic variability of HIV within individuals, as well as within populations, upon which evolutionary selection pressures act. The global HIV pandemic is examined in the context of HIV evolution, and the global diversity of HIV subtypes and recombinants is discussed in detail. Finally, the impact of HIV diversity on pathogenesis, transmission, diagnosis, treatment, the immune response, and vaccine development is reviewed. PMID- 22240487 TI - When can we choose to forget? An ERP study into item-method directed forgetting of emotional words. AB - Emotionally arousing information is treated in a specialised manner across a number of different processing stages, and memory for affective events is often found to be heightened by virtue of this. However, in some cases, emotional experiences might be the very ones that we would like to forget. Here, two item method directed forgetting studies are presented which investigate people's ability to intentionally forget affective words when stimuli and memory instructions are presented simultaneously. In the first experiment an interaction between task instruction and emotional content was evident in a diminished directed forgetting effect for emotional words, suggesting that they may be relatively resistant to deliberate forgetting. The interaction between instruction and emotion appeared both in free recall of words and in a yes-no recognition task. In the second study, an ERP procedure was utilised to investigate whether emotion modulates the effects of instruction during the initial encoding of stimuli. Recognition data again showed a clear interaction between instruction and emotion, with a reduced directed forgetting effect for emotional words. The ERP data demonstrated evidence for individual effects of both emotion and instruction during encoding; however, despite this, no evidence for an interaction between these factors was evident in the ERP data. As such, we conclude that even when study items are presented simultaneously with their associated memory instructions, neither does emotion prevent differential processing of directed forgetting instruction, nor does memory instruction prevent differential processing of emotion during early encoding. Implications are discussed in relation to the directed forgetting literature and more broadly with respect to circumstances under which emotion and cognitive processing work in parallel or in competition with each other. PMID- 22240489 TI - Bioaccumulation, oxidative stress and HSP70 expression in Cyprinus carpio L. exposed to microcystin-LR under laboratory conditions. AB - Microcystin-LR (MC-LR) produced by cyanobacteria are potent specific hepatotoxins. So far the pathogenesis of environmental MC-LR toxicity to aquatic organisms has not been fully elucidated. In the present study the accumulation of MC-LR was investigated in various organs/tissues of Cyprinus carpio L. (C. carpio) following exposure to MC-LR for 14 d at environmentally relevant concentrations (0.1 to 10 MUg L(-1)). Results showed that the presence of MC-LR enhanced toxin accumulation in all investigated organs and the highest accumulation was found in the liver of fish exposed to 5.0 MUg L(-1) of MC-LR. An EPR analysis indicated .OH intensity in liver was significantly induced at 0.1 MUg L(-1) of MC-LR and then restored when the MC-LR concentration was greater than 0.1 MUg L(-1). After 14-day exposure, MC-LR (1.0-10.0 MUg L(-1) of MC-LR) caused a pronounced promotion of glutathione S-transferase (GST) activity and a depletion of reduced glutathione (GSH) content in fish liver, which indicated that GSH was involved in detoxification of MC-LR and the conjugation reaction of MC-LR and GSH occurred. A mild oxidative damage was evidenced by the accumulation of malondialdehyde (MDA) level at 5.0 MUg L(-1) of MC-LR exposure, but which was restored when the MC-LR concentration was increased to 10.0 MUg L(-1). The responses of antioxidant enzymes and the induction of HSP70 expression might contribute to MC-LR tolerance of C. carpio. However, the protein phosphatase (PP) activities were strikingly inhibited in all treated groups. Thus, the overall toxicity of environmental MC-LR on C. carpio seems to be initiated in the liver via both the ROS pathway and the PP inhibition pathway, and the latter might be more important when ambient MC-LR concentration is greater than 0.1 MUg L(-1). More importantly, these results can help to support the evaluation on the potential effects of MC-LR under common environmental concentrations. PMID- 22240490 TI - Multiple epidermal cysts in hemodialysis patients. PMID- 22240491 TI - Contraception in obese older women. AB - Obesity is increasing in most western countries and rises significantly with age. Obese women are as sexually active as women of normal weight, and new sexual relationships in the older reproductive years are becoming more commonplace and still require effective contraception. Continuation of pregnancy in a woman over 40 carries health risks which are exacerbated by the presence of obesity. A high proportion of pregnancies in women over 40 are unplanned and end in therapeutic abortion. The prevalence of obesity and the high rates of contraceptive use amongst older women mean that any increase in associated risk is likely to be of public health concern. There are very few data on the specific risks of contraceptive use in obese older women. As fertility declines with age, all methods become increasingly effective. No single method is contraindicated by age alone but particular caution is required where the use of estrogen containing preparations is considered as the risks associated with estrogen are all also independently associated with increasing age and body mass index. Non-estrogen containing methods are available, whether hormonal, barrier or surgical, which are effective, acceptable and safer in the obese older woman. Some methods of contraception may indeed have particular non-contraceptive benefits for this population. PMID- 22240492 TI - A patient with angina at night: core curriculum chapters 3 (non-invasive imaging) and 9 (chronic ischaemic heart disease). PMID- 22240493 TI - Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. AB - AIMS: Recent studies have demonstrated that erythrocytes are a potential component in atheromatous lesions and thrombus formation in patients with ST elevation myocardial infarction (STEMI). The purpose of this study was to determine the associations of red blood cell (RBC) component of coronary thrombi with oxidative stress and myocardial reperfusion. METHODS AND RESULTS: Aspirated thrombi from 178 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, RBCs, fibrin, macrophages, and neutrophils [myeloperoxidase (MPO)]. The thrombi were divided into tertiles according to the percentage of glycophorin-A-positive area: low (glycophorin-A-positive area <33%; n = 60), intermediate (<54 to 33%; n = 59), and high group (>=54%; n = 59). We also measured plasma MPO levels on admission. In the thrombi, the number of MPO-positive cells in the high-RBC group was significantly greater than that in the low-RBC group (high, 927 +/- 385; intermediate, 765 +/- 406; low, 279 +/- 220 cells/mm(2); P< 0.0001). Plasma MPO levels were significantly higher in the high-RBC group than that in the low-RBC group [low 43.1 (25.0-71.6); intermediate 71.0 (32.9-111.2); high 74.3 (31.1 126.4)ng/mL; P< 0.005]. Distal embolization occurred more frequently in the high RBC group (P= 0.0009). Moreover, the signs of impaired myocardial reperfusion, as indicated by incomplete ST-segment resolution (STR) and lower myocardial blush grades (MBG), and progression of left ventricular remodelling at 6 months were frequently observed in the high-RBC group (high vs. low: STR, P= 0.056; MBG, P< 0.01; remodelling, P< 0.01). CONCLUSION: The present study demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in STEMI patients. PMID- 22240494 TI - Transcatheter aortic valve implantation: 3-year outcomes of self-expanding CoreValve prosthesis. AB - AIMS: The paucity of evidences about the long-term durability of currently available transcatheter prostheses is one of the main issues of transcatheter aortic valve implantation (TAVI). We sought to assess 3-year clinical and echocardiographic outcomes of patients undergoing TAVI with the third generation CoreValve prosthesis (Medtronic Incorporation, MN, USA). METHODS AND RESULTS: From the Italian CoreValve registry, 181 who underwent TAVI from June 2007 to August 2008 and eligible for 3-year follow-up were analysed. All outcomes were defined according to the Valve Academic Research Consortium. All-cause mortality at 1, 2, and 3 years was 23.6, 30.3, and 34.8%, respectively. Cardiovascular death at 1, 2, and 3 years was 11.2, 12.1, and 13.5%, respectively. The actuarial survival free from a composite of death, major stroke, myocardial infarction, and life-threatening bleeding was 69.6% at 1 year, 63.5% at 2 years, and 59.7% at 3 years. Patients with renal insufficiency had a higher mortality at 3-year follow up (49.0 vs. 29.2%, P = 0.007); moreover, patients experiencing post-procedural major or life-threatening bleeding had a higher rate of mortality already seen at 30 days (21.6 vs. 2.8%; P < 0.001) and this result was sustained at 3-year follow up (62.2 vs. 27.7%; P < 0.001). Mean pressure gradients decreased from 52.2 +/- 18.1 mmHg (pre-TAVI) to 10.3 +/- 3.1 mmHg (1-year post-TAVI) (P < 0.001); aortic valve area increased from 0.6 +/- 0.2 cm(2) (pre-TAVI) to 1.8 +/- 0.4 cm(2) (1 year post-TAVI); these results remained stable over the 3 years of follow-up. Paravalvular leak was observed in the majority of patients. There were no cases of progression to moderate or severe regurgitation. No cases of structural valve deterioration were observed. CONCLUSION: This multicentre study demonstrates that TAVI with the 18-Fr CoreValve ReValving System is associated with sustained clinical and functional cardiovascular benefits in high-risk patients with symptomatic aortic stenosis up to 3-year follow-up. Non-cardiac causes accounted for the majority of deaths at follow-up. PMID- 22240495 TI - Prognostic impact of a chronic total occlusion in a non-infarct-related artery in patients with ST-segment elevation myocardial infarction: 3-year results from the HORIZONS-AMI trial. AB - AIMS: We sought to investigate the impact of multivessel disease (MVD) with and without a chronic total occlusion (CTO) in a non-infarct-related artery (IRA) on mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: In the HORIZONS-AMI trial, of 3283 patients undergoing primary PCI, 1524 patients (46.4%) had single-vessel disease (SVD), 1477 (45.0%) had MVD without a CTO, and 283 (8.6%) had MVD with a CTO in a non-IRA. Compared with SVD patients and MVD patients without a CTO, patients with a non-IRA CTO were significantly less likely to achieve post-procedural TIMI 3 flow (P = 0.0003), more often had absent myocardial blush (P = 0.0002), and less frequently achieved complete ST-segment resolution (P = 0.0001). By multivariable analysis, MVD with CTO in a non-IRA was an independent predictor of both 0- to 30-day mortality [hazard ratio (HR) 2.88, 95% confidence interval (CI) 1.41-5.88, P = 0.004] and 30-day to 3-year mortality (HR 1.98, 95% CI 1.19-3.29, P= 0.009), while MVD without a CTO was a significant predictor for 0- to 30-day mortality (HR 2.20, 95% CI 1.00-3.06, P = 0.049) but not late mortality. CONCLUSION: In patients with STEMI undergoing primary PCI in the HORIZONS-AMI trial, MVD with or without a CTO in a non-IRA was an independent predictor of early mortality. The presence of a CTO in a non-IRA was also an independent predictor of increased late mortality to 3 years. PMID- 22240496 TI - A 53-year-old man with recent onset shortness of breath and electrocardiographic changes. PMID- 22240497 TI - Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study. AB - AIMS: Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive. METHODS AND RESULTS: Twenty-three patients with coronary artery disease (CAD) completed this randomized, double blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 +/- 2.6 to 7.0 +/- 3.1 (P < 0.0001), while no change was observed with placebo (5.4 +/- 2.4 to 4.7 +/- 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 +/- 0.09 to 0.66 +/- 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo. CONCLUSION: This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress. PMID- 22240498 TI - Risk of acute kidney injury in patients who undergo coronary angiography and cardiac surgery in close succession. AB - AIMS: Cardiac surgery and coronary angiography are both associated with risk of acute kidney injury (AKI). We hypothesized that the risk of post-operative AKI increases when coronary angiogram and cardiac surgery are performed in close succession, without sufficient time for recovery from the adverse effects of intravenous contrast. METHODS AND RESULTS: We included 2133 consecutive patients who underwent cardiac surgery at the Minneapolis Veterans Administration Medical Center from 2004 to 2010. Acute kidney injury was defined by the AKI network and the risk, injury, failure, loss, end-stage (RIFLE) criteria. Patients were 66 +/- 10 years old. Mean pre-operative creatinine and estimated glomerular filtration rate were 1.1 +/- 0.4 mg/dL and 75 +/- 22 mL/min/1.73 m(2), respectively. Cardiac surgery was performed 14 days (range 0-235) after coronary angiography. Acute kidney injury occurred in 680 (32%) patients per AKI network, 390 (18%) patients per RIFLE risk, and 111 (5%) patients per RIFLE injury criteria. Age, body mass index, diabetes mellitus, New York Heart Association class III/IV, cardiopulmonary bypass time, and impaired pre-operative renal function were independent predictors of AKI. However, time between coronary angiogram and cardiac surgery was not a predictor (P = 0.41). AKI occurred in 35% of 433 patients operated within 3 days of coronary angiogram vs. 31% of 1700 patients operated after 3 days (P = 0.17). Results were the same in patients with impaired pre-operative renal function and those with contrast-induced nephropathy. CONCLUSION: Risk of AKI after cardiac surgery is not influenced by the time between coronary angiogram and cardiac surgery. These results do not support the notion of delaying cardiac surgery for the sole purpose of renal recovery after coronary angiogram. PMID- 22240499 TI - Why all the struggle about CK-MB and PCI? PMID- 22240501 TI - Primary aortic sarcoma with multiple metastatic sites. PMID- 22240500 TI - Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study. AB - AIMS: Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP +/-) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. METHODS AND RESULTS: Murine: the DSP (+/-) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S(1)-S(2) protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation-repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P = 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. CONCLUSION: Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction-repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification. PMID- 22240502 TI - Inhibition of p38 pathway leads to OA-like changes in a rat animal model. AB - OBJECTIVES: The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is involved in a variety of inflammatory responses, including cytokine generation, cell differentiation proliferation and apoptosis. Here, we examined the effects of systemic p38 MAPK inhibition on cartilage cells and OA disease progression by both in vitro and in vivo approaches. METHODS: p38 kinase activity was evaluated in normal and OA cartilage cells by measuring the amount of phosphorylated protein. To examine the function of p38 signalling pathway in vitro, normal chondrocytes were isolated and differentiated in the presence or absence of p38 inhibitor SB203580 and analysed for chondrogenic phenotype. Effect of systemic p38 MAPK inhibition in normal and OA (induced by menisectomy) rats were analysed by treating animals with vehicle alone [dimethylsulphoxide (DMSO)] or p38 inhibitor (SB203580). Damage to the femur and tibial plateau was evaluated by modified Mankin score, histology and immunohistochemistry. RESULTS: Our in vitro studies have revealed that a down-regulation of chondrogenic and an increase of hypertrophic gene expression occurs in the normal chondrocytes when p38 is neutralized by a pharmacological inhibitor. We further observed that the basal levels of p38 phosphorylation were decreased in OA chondrocytes compared with normal chondrocytes. These findings together indicate the importance of this pathway in the regulation of cartilage physiology and its relevance to OA pathogenesis. At the in vivo level, systematic administration of a specific p38 MAPK inhibitor, SB203580, continuously for more than a month led to a significant loss of proteoglycan, aggrecan and cartilage thickness. On the other hand, SB203580-treated normal rats showed a significant increase in Terminal dUTP nick end-labelling (TUNEL)-positive cells, cartilage hypertrophy markers such as Type 10 collagen, Runt-related transcription factor and MMP-13 and substantially induced OA-like phenotypic changes in the normal rats. In addition, menisectomy induced OA rat models that were treated with p38 inhibitor showed aggravation of cartilage damage. CONCLUSIONS: In summary, this study has provided evidence that the component of the p38 MAPK pathway is important to maintain cartilage health, and its inhibition can lead to severe cartilage degenerative changes. The observations in this study highlight the possibility of using activators of the p38 pathway as an alternative approach in the treatment of OA. PMID- 22240503 TI - Tubulointerstitial nephritis, uveitis, hearing loss and vestibular failure: TINU atypical Cogan's overlap syndrome. PMID- 22240504 TI - Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies. AB - OBJECTIVE: To investigate comprehensively the relationships between Behcet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses. METHODS: Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I(2) and Q-statistics, and modelled using meta-regression. RESULTS: Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical characteristics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant. CONCLUSION: The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement. PMID- 22240505 TI - Metabolomics of human cerebrospinal fluid identifies signatures of malignant glioma. AB - Cerebrospinal fluid is routinely collected for the diagnosis and monitoring of patients with neurological malignancies. However, little is known as to how its constituents may change in a patient when presented with a malignant glioma. Here, we used a targeted mass-spectrometry based metabolomics platform using selected reaction monitoring with positive/negative switching and profiled the relative levels of over 124 polar metabolites present in patient cerebrospinal fluid. We analyzed the metabolic profiles from 10 patients presenting malignant gliomas and seven control patients that did not present malignancy to test whether a small sample size could provide statistically significant signatures. We carried out multiple unbiased forms of classification using a series of unsupervised techniques and identified metabolic signatures that distinguish malignant glioma patients from the control patients. One subtype identified contained metabolites enriched in citric acid cycle components. Newly diagnosed patients segregated into a different subtype and exhibited low levels of metabolites involved in tryptophan metabolism, which may indicate the absence of an inflammatory signature. Together our results provide the first global assessment of the polar metabolic composition in cerebrospinal fluid that accompanies malignancy, and demonstrate that data obtained from high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of biomarkers and classification of neurological diseases. PMID- 22240507 TI - Review of a fluid resuscitation protocol: "fluid creep" is not due to nursing error. AB - Recent reviews of burn resuscitation have included the suggestion that "fluid creep" may be influenced by practitioner error. Our center uses a nursing-driven resuscitation protocol that permits titration of fluid based on hourly urine output, including the addition of colloid when patients fail to respond appropriately. The purpose of this study was to examine protocol compliance. We reviewed 140 patients (26 children) with burns of >=20% TBSA who received protocol-directed resuscitation from 2005 to 2010. We compared each patient's actual hourly fluid infusion with that predicted by the protocol. Sixty-seven patients (48%) completed resuscitation using crystalloid alone, whereas 73 patients required colloid supplementation. Groups did not differ in age, gender, weight, or time from injury to admission. Patients requiring colloid had larger median total burns (33.0 vs 23.5% TBSA) and full-thickness burns (15.5 vs 4.5% TBSA) and more inhalation injuries (60.3 vs 28.4%; P < .001) than those who resuscitated with crystalloid alone. Because we included basic maintenance fluids in their regimen, patients had median predicted requirements of 5.4 ml/kg/%TBSA. Crystalloid-only patients required fluid volumes close to Parkland predictions (4.7 ml/kg/%TBSA), whereas patients who received colloid required more fluid than the predicted volume (7.5 ml/kg/%TBSA). However, the hourly difference between the predicted and received fluids was a median of only 1.0% (interquartile range: -6.1 to 11.1%) and did not differ between groups. Pediatric patients had greater calculated differences than adults. Crystalloid patients exhibited higher urine outputs than colloid patients until colloid was started, suggesting that early over-resuscitation did not contribute to fluid creep. Adherence to our protocol for burn shock resuscitation was excellent overall. Fluid creep exhibited by more seriously injured patients was not due to nurses' failure to follow the protocol. This review has illuminated some opportunities for practice improvement, possibly using a computerized decision support system. PMID- 22240508 TI - Correlation of internal jugular vein/common carotid artery ratio to central venous pressure: a pilot study in pediatric burn patients. AB - The purpose of this pilot study was to identify the relationship between the ratio of the diameter/cross-sectional area of the internal jugular vein (IJV) and carotid artery and the central venous pressure (CVP). After obtaining approval from our Institutional Review Board, ultrasound images were repeatedly obtained from participants on consecutive days when a thoracic central line was in place. The CVP was then measured in standardized fashion, using our bedside monitors. A blinded observer measured the diameter of the common carotid artery and IJV, for comparison. Similarly, digital images were analyzed to compare an estimate of the cross-sectional areas of the same vessels. Six patients met enrollment criteria, and one patient was excluded after enrollment before any measurements being made. The remaining five patients had a mean age of 7 years (range: 9 months to 15 years) and mean burn size of 64% (SD, +/-15), and no patients had inhalation injuries. All patients in this study were mechanically ventilated. Measurements were made from one patient while spontaneously breathing. One patient reading occurred while on vasopressor support (levophed at 2 MUg/kg/hr). CVP values ranged from 1 to 25 mm Hg. Comparison of the ratio of the IJV/common carotid artery cross-sectional area with CVP revealed that a ratio of 2 or greater was associated with a CVP of at least 8 mm Hg (P < .001). These preliminary results suggest that if the cross-sectional area of the vein is at least twice that of the artery, then the CVP seems to be >=8 mm Hg. PMID- 22240506 TI - Integrated proteomic, transcriptomic, and biological network analysis of breast carcinoma reveals molecular features of tumorigenesis and clinical relapse. AB - Gene and protein expression changes observed with tumorigenesis are often interpreted independently of each other and out of context of biological networks. To address these limitations, this study examined several approaches to integrate transcriptomic and proteomic data with known protein-protein and signaling interactions in estrogen receptor positive (ER+) breast cancer tumors. An approach that built networks from differentially expressed proteins and identified among them networks enriched in differentially expressed genes yielded the greatest success. This method identified a set of genes and proteins linking pathways of cellular stress response, cancer metabolism, and tumor microenvironment. The proposed network underscores several biologically intriguing events not previously studied in the context of ER+ breast cancer, including the overexpression of p38 mitogen-activated protein kinase and the overexpression of poly(ADP-ribose) polymerase 1. A gene-based expression signature biomarker built from this network was significantly predictive of clinical relapse in multiple independent cohorts of ER+ breast cancer patients, even after correcting for standard clinicopathological variables. The results of this study demonstrate the utility and power of an integrated quantitative proteomic, transcriptomic, and network analysis approach to discover robust and clinically meaningful molecular changes in tumors. PMID- 22240509 TI - Early withdrawal of life support in severe burn injury. AB - Despite many advances in modern burn care, deaths still occur in the burn intensive care unit. For patients with severe burns, providers may advocate to withdraw life support early during hospitalization when the extent of injury makes survival highly unlikely or when the patient's condition deteriorates during resuscitation. Our regional burn center has implemented a stepwise withdrawal protocol since 2001 in an effort to standardize symptoms palliation at the end of life. In this study, the authors evaluated the frequency of early withdrawal and the protocol impact on end-of-life processes of care in burn patients who died within 72 hours of hospitalization. A 13-year review of all burn patients aged >=18 years admitted to our burn center to identify all patients who died within 72 hours of hospitalization was performed. Patients were dichotomized to the periods before (1995 to mid-2001) and after implementation of standardized withdrawal protocol (mid-2001 to 2007). Descriptive analyses were performed to compare end-of-life care processes between the two periods. A total of 4374 adult patients with acute burns were admitted during the 13-year study period, of which 252 (6%) died during hospitalization. Of the patients who died within 72 hours, 106 (84%) had withdrawal of life support compared with 20 (16%) who died with ongoing life support. Higher mean TBSA distinguished patients who died by withdrawal (61 vs 48%, P = .06). Since mid-2001, all 61 patients who had life support withdrawn were by protocol. Implementation of the protocol has led to more frequent use of opioid infusion (98 vs 87%, P = .07) and benzodiazepine infusion (95 vs 49%, P < .01), without hastening time to death (median 5.0 vs 5.5 hours, P = .70). The large majority of early burn deaths at our regional center occur via withdrawal of life support. Implementation of a protocolized withdrawal has resulted in more consistent provision of analgesia and sedation without hastening death. Burn centers should consider using a protocol for withdrawal of life support to improve consistency in end-of-life symptoms palliation. PMID- 22240510 TI - Silk protein fibroin from Antheraea mylitta for cardiac tissue engineering. AB - The human heart cannot regenerate after an injury. Lost cardiomyocytes are replaced by scar tissue resulting in reduced cardiac function causing high morbidity and mortality. One possible solution to this problem is cardiac tissue engineering. Here, we have investigated the suitability of non-mulberry silk protein fibroin from Indian tropical tasar Antheraea mylitta as a scaffold for engineering a cardiac patch in vitro. We have tested cell adhesion, cellular metabolic activity, response to extracellular stimuli, cell-to-cell communication and contractility of 3-days postnatal rat cardiomyocytes on silk fibroin. Our data demonstrate that A. mylitta silk fibroin exhibits similar properties as fibronectin, a component of the natural matrix for cardiomyocytes. Comparison to mulberry Bombyx mori silk protein fibroin shows that A. mylitta silk fibroin is superior probably due to its RGD domains. 3D scaffolds can efficiently be loaded with cardiomyocytes resulting in contractile patches. In conclusion, our findings demonstrate that A. mylitta silk fibroin 3D scaffolds are suitable for the engineering of cardiac patches. PMID- 22240512 TI - In vitro and in vivo safety of aqueous extracts of Graptopetalum paraguayense E. Walther. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Graptopetalum paraguayense E. Walther, a widely consumed vegetable in Taiwan, has many biological effects and has been used in folk medicine to alleviate hepatic disorders, exert diuretic effects, and relieve pain and infections. However, little data exist regarding its safety. MATERIALS AND METHODS: Two genotoxicity assays were performed: chromosomal aberration of Chinese hamster ovary (CHO-K1 cells) (in vitro) and micronucleus assay in mice (in vivo). Acute oral toxicity and 28-day repeated feeding toxicity tests were performed by oral gavage in Sprague-Dawley (SD) rats. RESULTS: GWE did not increase micronucleus ratios in vivo, and by chromosome aberration assay, GWE was safe up to 1.2mg/ml with regard to clastogenicity. Chromatid breakage was observed at high concentrations (2.5 and 5.0mg/ml) of GWE. GWE had no acute lethal effect at the maximum dose (5g/kg bw) in rats. In the 28-day study, there were no adverse effects on body weight, feed consumption, hematology, blood biochemical parameters, organ weight, or pathology. CONCLUSION: The acute toxicity study showed that the LD(50) of GWE was greater than the tested dose (up to 1g/kg bw) in SD rats. In the subacute toxicity study, the no observed adverse effect level (NOAEL) of GWE in rats was 1g/kg bw. The in vivo study of mammalian erythrocyte micronuclei confirmed the Ames test results, demonstrating that GWE has no mutagenicity. High doses of GWE require further examination due to its clastogenic potential. PMID- 22240513 TI - NHS cuts and women's rights. PMID- 22240511 TI - Phosphorescent nanoparticles for quantitative measurements of oxygen profiles in vitro and in vivo. AB - We present the development and characterization of nanoparticles loaded with a custom phosphor; we exploit these nanoparticles to perform quantitative measurements of the concentration of oxygen within three-dimensional (3-D) tissue cultures in vitro and blood vessels in vivo. We synthesized a customized ruthenium (Ru)-phosphor and incorporated it into polymeric nanoparticles via self assembly. We demonstrate that the encapsulated phosphor is non-toxic with and without illumination. We evaluated two distinct modes of employing the phosphorescent nanoparticles for the measurement of concentrations of oxygen: 1) in vitro, in a 3-D microfluidic tumor model via ratiometric measurements of intensity with an oxygen-insensitive fluorophore as a reference, and 2) in vivo, in mouse vasculature using measurements of phosphorescence lifetime. With both methods, we demonstrated micrometer-scale resolution and absolute calibration to the dissolved oxygen concentration. Based on the ease and customizability of the synthesis of the nanoparticles and the flexibility of their application, these oxygen-sensing polymeric nanoparticles will find a natural home in a range of biological applications, benefiting studies of physiological as well as pathological processes in which oxygen availability and concentration play a critical role. PMID- 22240514 TI - Older people and standards of health and social care. PMID- 22240515 TI - An exploration of palliative care provision in Scottish care homes. AB - This paper suggests that there is an imbalance between the ideal and the actual palliative care provision for some older people living and dying in care homes in Scotland. Successive studies demonstrate that care home residents are increasingly frail and disabled. Many experience challenging physical and psychosocial symptoms which could benefit from a palliative approach to alleviate suffering and promote comfort. However, palliative needs for people with non malignant conditions, such as dementia, can be complex, and not easily identified or managed. A range of challenging factors currently impact palliative care provision for care home residents in Scotland including: the insufficiency of robust NHS healthcare support, the skill mix of the care home workforce, and the promotion of palliative tools as the primary means of improving the quality of palliative care in non-specialist settings. Issues highlighted in this paper give cause for concern on a number of levels, particularly as the demand for palliative care in care homes is likely to increase in the near future. Therefore, sustained collaborative effort from leaders in the health, social and care home sectors is recommended if practical solutions are to be found for this vulnerable population. PMID- 22240516 TI - Addressing the problems of long-term urethral catheterization: part 2. AB - This is the second of a two-part article and addresses the problems encountered throughout the life of a catheter from those relating to its insertion, through the time when it is in situ, to those associated with its removal. Catheters can cause discomfort and reasons for this are discussed including latex allergy, atrophic changes in women, blockage or bypass. The draft National Institute for Health and Clinical Excellence infection control guidance is discussed with reference to catheter maintenance solutions. Sexuality can be an unvoiced concern to patients with catheters in situ and clinicians are encouraged to discuss such issues with the patient, where relevant. Issues including catheter expulsion, bladder spasm and difficulties in catheter removal, including the non-deflating balloon and cuffing are addressed. The article concludes that although every patient is an individual with a unique set of problems, learning how to address one series of difficulties will help when dealing with subsequent challenges. PMID- 22240517 TI - Patient Group Directions: a safe and effective practice? AB - Patient Group Directions (PGDs) have been used in clinical practice for a decade. They enable non-medical practitioners to supply medicines to patients, in certain legally defined circumstances, without a doctor's prescription and in accordance with a pre-defined protocol. The authors aimed to review the existing literature in order to identify and evaluate the evidence regarding the quality, safety and acceptability of PGDs within care systems and their impact on health outcomes. Searches of relevant databases were conducted, articles screened against eligibility criteria and relevant data extracted. A number of key issues emerged from the data including quality and safety of practice, acceptability to patients and practitioners, access to treatment and implications for professional roles and responsibilities. There were no data related to health outcomes. The review concludes that while PGDs may be an acceptable way to deliver care, their impact on patient outcomes and health status has been poorly studied. PMID- 22240518 TI - Return on investment: workload, complexity and value of the CNS. AB - The rheumatology nurse specialist (RNS) has become an integral and vital part of the multidisciplinary team and is valued by patients. Yet, a number of challenges regularly face all clinical nurse specialists (CNS) in the UK. The perception that CNS are an expensive and poorly defined nursing resource results in regular threats to their sustainability, particularly that of the RNS. This study examined return on investment of the RNS. METHOD: An interrelational Structured Query Language (SQL) database collected data on the day-to-day activities of the RNS based on previous models of CNS and RNS work, and qualitative narrative data were then subjected to data mining. RESULTS: The RNS represented an excellent return on investment, in terms of income generation activity, patient safety and efficiency. These outcomes were achieved using key principles of proactive case management using vigilance, rescue work and brokering. The mean average per whole time equivalent (WTE) RNS per annum represents L 175,168 in terms of income/savings to an employing NHS Trust. This figure is likely to be an underestimation, as calculations on reduction in bed days in hospital have not been included. PMID- 22240519 TI - Research ethics application: a guide for the novice researcher. AB - The aim of this paper is to assist the novice researcher in the research ethics application process. The novice researcher in this context refers to any researcher negotiating a research ethics application for the first time. This may be a student or a more experienced registered nurse engaged in research activity. The paper applies ethical principles to the varied elements of a research ethics application form to explain the theoretical basis of the application criteria. The impetus for this paper arose following an internal audit of the decisions made by the research ethics committee of the nursing department at the Institute of Technology in Tralee, Ireland. The audit revealed the common reasons why full approval was not granted following initial review. This information prompted the development of a paper which would assist novice researchers in avoiding common errors and omissions in the research ethics application process. Despite the specific requirements of individual research ethics committees in different jurisdictions, the fundamental elements of research ethics approval remain unchanged. While the paper has local origins, its relevance holds a wider appeal. The paper takes a structured approach using the three ethical principles of respect for persons, beneficence, and justice, as outlined by the Belmont Report (1979) to provide a framework for discussion. Despite the advent of other frequently used frameworks for research ethics, the principles of the Belmont report remain constant as guidance for good practice in the research ethics context. PMID- 22240520 TI - Higher education reform: conflict of interest or enhanced experience? AB - The path that nurse education in the UK has taken since it moved into the higher education (HE) system in the early 1990s has been directly influenced, not only by Department of Health policy, but also by changes to the way in which HE is structured and managed. The White Paper Higher Education: Students at the Heart of the System (Department for Business Innovation and Skills, 2011a) outlined the coalition Government's plans to encourage better standards of teaching in HE and greater responsiveness to student experience. The reforms promote competition and contestability between HE institutions to attract students and recommend removing barriers for new providers to enter the market. The decision to introduce a strong business model for HE has a number of implications for nurse education, both in the way that it is delivered and how student nurses are positioned among their peers. There is a potential conflict of interest between the student as a source of income for the HE institution and the student nurse as a member of a professional organization dedicated to ensuring the safety of the public. The decision to make it easier for alternative providers to obtain degree awarding powers could also encourage providers to take greater ownership of healthcare qualifications in the future. PMID- 22240521 TI - Health visitors and community nurses: the future of children's services. PMID- 22240522 TI - Can nurses help to promote earlier diagnosis of bowel cancer? PMID- 22240523 TI - How to make the most of your nursing placement. PMID- 22240524 TI - Using anonymized NHS data without consent: a step too far? AB - On 5 December 2011, the Government announced that NHS data will be made more widely available to researchers (BBC News, 2011). David Cameron suggested that 'everyone was to be a research patient' (BBC News, 2011) with anonymized NHS patient data being opened up to researchers in the private sector as well as the NHS. The proposals envisaged that all such data is opened up to researchers unless patients opt out. This article explores the relationship between patient privacy, confidentiality and the public interest, and asks whether anonymization is simply enough or whether we need a broader debate as to what constitutes disclosure in the public interest and its boundaries. PMID- 22240525 TI - Levels of patient harm in primary care. PMID- 22240526 TI - Professional development: from staff nurse to nurse consultant. Part 3: making time. PMID- 22240527 TI - Pensions: lessons from the past. PMID- 22240528 TI - Portal-systemic collaterals and hepatic encephalopathy. PMID- 22240529 TI - Portosystemic collaterals are not prerequisites for the development of hepatic encephalopathy in cirrhotic rats. AB - BACKGROUND: Liver functions and portosystemic collaterals influence the development and severity of hepatic encephalopathy (HE) in cirrhosis. However, it has not been examined which factor has a greater influence or if shunts can be used to determine the presence and severity of HE. The expression of tumor necrosis factor-alpha (TNF-alpha) is increased in cirrhosis, and its role in HE deserves further evaluation. METHODS: Portal hypertension was induced by portal vein ligation (PVL; a model of high-degree portosystemic shunting without significant liver damage) and liver cirrhosis was induced by bile duct ligation (BDL; a model of low-degree shunting with liver cirrhosis) in male Spraque-Dawley rats. Sham-operated rats were used as controls. Motor activity counts, hemodynamic parameters, plasma levels, liver biochemistry parameters, TNF-alpha, and a flow-pressure curve study of portosystemic collaterals (where a higher slope indicates fewer portosystemic collaterals) were performed on Day 7 after PVL and Week 5 after BDL. RESULTS: Portal pressure was significantly higher in the PVL and BDL groups than in controls. The liver biochemistry parameters, TNF alpha, and motor activities were not significantly different between the PVL and PVL-control groups. In the BDL group, TNF-alpha, AST, and total bilirubin levels were significantly higher and the motor activity counts were lower than in the BDL-control group. Moreover, in the BDL rats, TNF-alpha (p=0.037, R=-0.490), AST (p=0.007, R=-0.595) and total bilirubin (P=0.001, R=-0.692) levels, but not the slopes of the flow-pressure curves, were significantly and negatively correlated with the motor activity counts. CONCLUSION: The presence of a high degree of portosystemic shunting without significant liver damage may not be adequate for the development of HE. PMID- 22240530 TI - Frequency and risk factors associated with atherosclerotic plaques in patients with a zero coronary artery calcium score. AB - BACKGROUND: Analysis of the coronary artery calcium levels usually provides important information that can be used in patient prognosis and stratification of treatment when coronary artery disease is suspected. However, plaques, with or without significant stenosis, have been reported in patients without coronary artery calcium. The aim of this study was to determine the frequency and risk factors of the development of coronary artery plaques in individuals with a zero calcium score. METHODS: Analysis of coronary artery calcium levels and coronary computed tomography angiography (CTA) were performed using 64-slice computed tomography (CT). The demographic data, clinical risk factors, and imaging features of 519 consecutive patients (54 +/- 10 years, male:female ratio of 56:44) were retrospectively analyzed. The presence of plaques and the degree of the resulting stenosis were recorded. Descriptive, univariate, and multivariate analyses were carried out to identify the frequency and risk factors associated with the presence of coronary artery plaques. RESULTS: Among 66 patients, 82 coronary arteries were found to have plaques, and six coronary arteries showed significant stenosis. Univariate analysis showed that an age greater than 55 years, male gender, a body mass index (BMI) of more than 27, hypertension, and diabetes mellitus are significant factors associated with the development of coronary artery plaques. Multivariate logistic regression analysis showed that an age over 55 years (p = 0.012, OR = 2.13, 95% C.I. = 1.18-3.84) and BMI greater than 27 (p = 0.026, OR = 2.01, 95% C.I. = 1.09-3.72) are independent factors associated with the presence of plaques in patients with a zero calcium score. CONCLUSION: The results of this study show that plaques are present in a significant proportion of individuals with a zero coronary artery calcium score. In addition, advanced age and obesity are risk factors associated with the development of plaques. PMID- 22240531 TI - Clinical outcomes and prognostic factors of Ewing sarcoma: a clinical analysis of 12 patients in Taiwan. AB - BACKGROUND: Ewing sarcoma is extremely rare in people from East and Southeast Asia. METHODS: The records of 12 patients diagnosed with primary Ewing sarcoma and treated at our institution from 1997 to 2009 were retrospectively reviewed. RESULTS: There were seven male and five female patients and their mean age at diagnosis was 22 years (range, 12-48 years). Two patients (16.7%) had distant metastasis at diagnosis. The primary tumor sites were the trunk in seven patients (58.3%) and the extremities in five patients (41.7%). Eleven patients received neoadjuvant chemotherapy followed by wide excision surgery, and then adjuvant chemotherapy. One patient received only chemotherapy without surgical intervention due to poor cardiac and pulmonary function. At a mean follow-up of 33 months, the 2-year overall survival rate (OS) was 45.5%. Distant metastasis was the only statistically significant prognostic factor of OS in our study. The 2-year OS rates of patients with lung metastasis and without lung metastasis were 0% and 42.9%, respectively (p = 0.021). The t(11;22)(q24:q12) translocation was present in all patients in our series. CONCLUSION: We confirmed that distant metastases is highly predictive of a poor outcome, and that the t(11;22)(q24:q12) translocation was present in all patients in our series. PMID- 22240532 TI - Predictive indications of operation and mortality following renal trauma. AB - BACKGROUND: This study is a review of our experiences related to managing patients with renal injuries and identifying the predictive indicators of surgery and mortality. METHODS: A retrospective review study was performed in our university hospital. Patients with renal injuries were enrolled. Data comparisons were performed between four patient groups (operation vs. nonoperation groups and mortality vs. survival groups, respectively). RESULTS: Seventy-three patients were enrolled in this study, 55 of whom (75.34%) were male. Nine patients (12.33%) were severely injured (Injury severity score (ISS) >= 16), and nine (12.33%) had high renal injury scores (Renal injury scale (RIS) >= 4). Seven patients (9.59%) had received operations, and four (5.48%) died of hemorrhagic shock and multiple organ failure. After performing multivariate analysis, patients who received operations had significantly higher ISS (>=16) and RIS (>=4) scores compared with patients who did not undergo operations. ISS >= 16 and Glasgow coma scale (GCS) < 8 were significantly correlated with mortality. CONCLUSION: In conclusion, ISS >= 16 and RIS >= 4 are predictive factors for necessitating an operation, and higher injury severity (ISS >= 16) and lower consciousness level (GCS < 8) scores are significantly associated with mortality after renal trauma. PMID- 22240533 TI - Prevalence of maternal group B streptococcus colonization and vertical transmission in low-risk women in a single institute. AB - BACKGROUND: Intrapartum administration of antibiotics lowers the risk of neonatal group B streptococcus (GBS) infection based on recommended guidelines (a risk based approach and a culture-based screening approach). However, many pregnant women do not undergo culture-based screening, nor treatment with prophylactic antibiotics after a GBS risk-based approach. Therefore, the value of GBS detection in asymptomatic low-risk pregnant women is controversial. METHODS: A cohort study of 354 asymptomatic pregnant women at more than 37 weeks' gestation who were planning to undergo vaginal delivery, and 118 neonates (107 paired samples of both mother and newborn), was conducted to evaluate the GBS colonization rate of these pregnant women and the subsequent vertical transmission rate, using a culture method. RESULTS: The positive rate for GBS culture was 6.2% (22/354). Among 107 paired samples, six maternal samples and one neonatal sample were positive for GBS culture, with an estimated vertical transmission rate of 16.7% (1/6). CONCLUSION: Although the positive rate of GBS culture was lower in asymptomatic low-risk pregnant women, the possibility of vertical transmission might be high. This finding is worthy of further investigation. PMID- 22240534 TI - Differences between children and adults with otitis media with effusion treated with CO(2) laser myringotomy. AB - BACKGROUND: The safety and advantages of CO(2) laser myringotomy for otitis media with effusion (OME) are well described. The goal of such treatment is to avoid unnecessary ventilation tube insertion. Comparisons between different age groups treated with this modality are lacking, and prognostic factors for treatment outcomes are not available. METHODS: We conducted a retrospective cohort study that included 130 children (160 ears) and 96 adults (108 ears) with OME persisting after conservative antibiotic treatment. In eligible patients, we performed laser myringotomy in the affected ear. Follow-up was scheduled every week for 1 month and then every month for 6 months. Results for 233 ears were available for analysis; 24 ears were excluded (19 due to cancer, four due to a cleft palate, and one due to Down syndrome) and 10 patients (11 ears) were lost during follow-up. A logistic regression model was used for analysis, with success of therapy as the binary outcome. RESULTS: Adult patients had more unilateral lesions (p < 0.001) and serous fluid effusions (p < 0.001) than did the pediatric patients. However, there was no significant difference in the cure rate (children: 58.1%; adults: 64.7%) and positive culture rate (children: 15.1%; adults: 14.3%) between patient groups. Three factors were found to be associated with a poor prognosis: multiple occurrences in children (p < 0.001), mucoid effusion (p = 0.04), and a history of ventilation tube use in adults (p < 0.001). No other variables predicted treatment outcome. CONCLUSION: Our findings suggest that CO(2) laser myringotomy is a useful treatment modality for OME in children and adults, except for children with multiple occurrences and in adults with mucoid effusions and a history of ventilation tube use. PMID- 22240535 TI - A predictive model of the association between gene polymorphism and the risk of noise-induced hearing loss caused by gunfire noise. AB - BACKGROUND: Noise-induced hearing loss (NIHL) is one of the common diseases in otology. In general, we assume that most people who are exposed to loud noise constantly, e.g., soldiers, will suffer from hearing loss. Hearing loss is related to the gene polymorphisms, with the Wolfram syndrome type 1 gene (T2500C), interleukin-4 receptor alpha chain (Q576R) and chloride channel-Kb (T481S) polymorphisms being most related to NIHL. METHODS: We analyzed the association between the polymorphisms and the risk of NIHL in 119 subjects who were exposed to the same loud gunfire. In the current study, 39 persons with hearing loss and 80 with normal hearing were recruited from military officers and soldiers that were exposed to gunfire. RESULTS: The results showed that the genetic variation of Wolfram syndrome type 1 gene was a more crucial factor than other genes in causing hearing loss. There was a significant difference (p=0.027) in WFS1 (T2500C) polymorphism between NIHL subjects and controls. CONCLUSION: In this study, we found that although loud noise could usually result in hearing damage, the clinical characteristics of hearing loss were irrelevant to gunfire noise. The gene polymorphisms provide predictors for us to evaluate the risk of NIHL prior to gunshot training. PMID- 22240536 TI - Bladder outlet obstruction due to labial agglutination. AB - Here, we report the case of a 63-year-old female patient who presented with emptying symptoms and was subsequently diagnosed with delayed labial agglutination. The adhered labia minora were divided by blunt dissection, and a topical estrogen ointment was applied after surgery. The patient's voiding symptoms were completely resolved and no recurrence of labial agglutination was noted 3 months after surgery. Labial agglutination is rare but often manifests with nonspecific emptying symptoms. Nevertheless, it can be easily diagnosed on physical examination and successfully treated by surgical intervention and the application of a local estrogen ointment. We present this rare case in order to emphasize the importance of physical examination. PMID- 22240537 TI - Dural sinus malformation with arteriovenous fistulae in a newborn: positive outcome following endovascular management. AB - Dural sinus malformation (DSM) is an extremely rare and congenital cerebrovascular malformation that is associated with dural arteriovenous fistula and a large dural lake, which may mimic the clinical malformations of an infantile dural arteriovenous shunt or the vein of Galen. Early diagnosis and treatment of DSM is crucial in order to avoid irreversible brain injuries or heart failure. Here, we report an unusual case of extensive DSM that showed good clinical and angiographic results after endovascular embolization. PMID- 22240538 TI - High times for low-frequency stimulation as endocannabinoids engage in hippocampal long-term depression. PMID- 22240539 TI - Mathematical coupling and the true role of baseline severity in acute mania trials. PMID- 22240540 TI - Immunogenicity of an inactivated monovalent 2009 influenza A (H1N1) vaccine in patients who have cancer. AB - BACKGROUND: The immune response of patients who have cancer, who may be receiving immunosuppressive therapy, is generally considered to be decreased. This study aimed to evaluate the immune response of cancer patients to the 2009 influenza A (H1N1) vaccine. PATIENTS AND METHODS: We conducted a prospective single site study comparing the immune response after H1N1 vaccination of healthy controls (group A), patients who had solid tumors and were taking myelosuppressive chemotherapy (group B), patients who had solid tumors and were taking nonmyelosuppressive or no treatment (group C), and patients who had hematologic malignancies (group D). RESULTS: At 2-6 weeks after vaccination, seroconversion was observed in 80.0% of group A (95% confidence interval [CI], 65.0%-89.7%), 72.2% of group B (95% CI, 55.9%-84.3%), 87.0% of group C (95% CI, 72.2%-94.7%), and 75.0% of group D (95% CI, 52.8%-89.2%) (p = NS). The geometric mean titer ratio, that is, geometric mean factor increase in antibody titer after vaccination, was 12.6 (95% CI, 7.9-19.9), 12.7 (95% CI, 7.3-22.1), 23.0 (95% CI, 13.9-38.2), and 12.1 (95% CI, 5.3-27.9) (p = NS), and the seroprotection rates were 95.5% (95% CI, 84.0%-99.6%), 79.0% (95% CI, 63.4%-89.2%), 90.5% (95% CI, 77.4%-96.8%), and 90.0% (95% CI, 71%-98.7%) in the corresponding groups (p = NS). Immune responses were robust regardless of malignancy, or time intervals between the use of myelosuppressive or immunosuppressive medications and vaccination. No participants developed clinical H1N1 infection. CONCLUSION: Cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls. PMID- 22240542 TI - Vaccination of oncology patients: an effective tool and an opportunity not to be missed. PMID- 22240544 TI - Acute effect of whole-body vibration on power, one-repetition maximum, and muscle activation in power lifters. AB - The purpose of this study was to investigate the acute effect of whole-body vibration with a frequency of 50 Hz (WBV(50Hz)) on peak power in squat jump (SJ), 1 repetition maximum (1RM) in parallel squat, and electromyography (EMG) activity and compare them with no-vibration conditions in power lifters. Twelve national level male power lifters (age 24 +/- 5 years, body mass 110 +/- 24 kg, height 179 +/- 7 cm) tested peak power in SJ and 1RM in parallel squat while they were randomly exposed to WBV(50Hz) or to no vibration. These tests were performed in a Smith Machine. Peak power output was higher while performed with a WBV(50Hz) compared with the no-WBV condition (p < 0.05). This increase in power output was accompanied by higher EMG starting values and EMG peak values of the investigated thigh muscles during WBV(50Hz) (p < 0.05). There was no difference between adding WBV(50Hz) and no-vibration conditions in 1RM parallel squat. In conclusion, the results of this study suggest that the application of WBV(50Hz) acutely increases peak power output during SJ in well strength trained individuals such as power lifters. This increase in power was accompanied by an increased EMG activity in the quadriceps muscles. However, in 1RM parallel squat, there was no difference between WBV50Hz and no-vibration conditions. Therefore, adding WBV(50Hz) has no acute additive effect on 1RM parallel squat in power lifters and, based on the present findings, may thus not be recommended in the training to improve 1RM in power lifters. However, WBV(50Hz) seems to have an acute additive effect on peak power output and may be used in well strength trained individuals for whom a high power output is important for performance. PMID- 22240545 TI - Neuromuscular fatigue induced by a 90-minute soccer game modeling. AB - This study aimed to quantify neuromuscular fatigue induced by a soccer game. Eight amateur soccer players (age 20.4 +/- 1.3 years, mass 70.4 +/- 6.9 kg, and height 174.9 +/- 5.2 cm) reproduced a 90-minute soccer game modeling composed of two 45-minute periods separated by a 15-minute rest. Torque of quadriceps and hamstring muscle groups associated with electromyography, sprint speed, and vertical jump height was assessed before, at halftime, and immediately after the modeling. Most physical qualities decreased throughout the game with greater decays at match end than at halftime. Contrarily to quadriceps muscles, hamstring torque impairments were not accompanied by electromyographic activity reductions. Squat jump height was reduced at halftime and game end without any change for countermovement jumps. The sprint speed decrease was associated with stride frequency impairments without any change in amplitude and contact time. We concluded on torque production capacity and specific performance impairments during and after soccer games. Neuromuscular fatigue appeared primarily centrally mediated as attested by the reduced quadriceps muscle activity. PMID- 22240546 TI - Physiological correlates of multiple-sprint ability and performance in international-standard squash players. AB - From measures on a battery of fitness tests in elite-standard squash players on different tiers of a national performance program, we examined the relationships among test scores and player rank, and fitness factors important for squash specific multiple-sprint ability. Thirty-one (20 men, 11 women) squash players from the England Squash performance program participated: n = 12 senior; n = 7 transition; n = 12 talented athlete scholarship scheme (TASS) players. In 1 test session and in a fixed order, the players completed a battery of tests to assess countermovement jump height, reactive strength, change-of-direction speed, and multiple-sprint ability on squash-specific tests and endurance fitness. Two-way analysis of variance compared senior, transition, and TASS players by sex on all measures except jump height where only senior and transition players were compared. Effect size (ES) was calculated for all comparisons. Pearson's correlation examined relationships among test scores and multiple-sprint ability. Spearman's rho investigated relationships among test scores and players' rank in men and women separately. Regardless of sex, seniors outperformed TASS players on all except the endurance test (p < 0.05, ES at least 1.1). Seniors had better multiple-sprint ability than did transition players (p < 0.01, ES = 1.2). Transition outperformed TASS players on the reactive-strength test (p < 0.05, ES = 1.0). Men outperformed women in all tests at all performance program tiers (p < 0.05, ES at least 0.5). In men, rank was related to multiple-sprint ability, fastest-multiple-sprint-test repetition, and change-of-direction speed (rho = 0.78, 0.86, 0.59, respectively). In women, rank was related to fastest multiple sprint-test repetition (rho = 0.65). In men and women, multiple-sprint ability was related to change-of-direction speed (r = 0.9 and 0.84) and fastest-multiple sprint-test repetition (r = 0.96 for both) and to reactive strength in men (r = 0.71). The results confirm that high-intensity variable-direction exercise capabilities are important for success in elite squash. PMID- 22240547 TI - A comparison of the effects of 6 weeks of traditional resistance training, plyometric training, and complex training on measures of strength and anthropometrics. AB - Complex training (CT; alternating between heavy and lighter load resistance exercises with similar movement patterns within an exercise session) is a form of training that may potentially bring about a state of postactivation potentiation, resulting in increased dynamic power (Pmax) and rate of force development during the lighter load exercise. Such a method may be more effective than either modality, independently for developing strength. The purpose of this research was to compare the effects of resistance training (RT), plyometric training (PT), and CT on lower body strength and anthropometrics. Thirty recreationally trained college-aged men were trained using 1 of 3 methods: resistance, plyometric, or complex twice weekly for 6 weeks. The participants were tested pre, mid, and post to assess back squat strength, Romanian dead lift (RDL) strength, standing calf raise (SCR) strength, quadriceps girth, triceps surae girth, body mass, and body fat percentage. Diet was not controlled during this study. Statistical measures revealed a significant increase for squat strength (p = 0.000), RDL strength (p = 0.000), and SCR strength (p = 0.000) for all groups pre to post, with no differences between groups. There was also a main effect for time for girth measures of the quadriceps muscle group (p = 0.001), the triceps surae muscle group (p = 0.001), and body mass (p = 0.001; post hoc revealed no significant difference). There were main effects for time and group * time interactions for fat-free mass % (RT: p = 0.031; PT: p = 0.000). The results suggest that CT mirrors benefits seen with traditional RT or PT. Moreover, CT revealed no decrement in strength and anthropometric values and appears to be a viable training modality. PMID- 22240548 TI - The construct and longitudinal validity of the basketball exercise simulation test. AB - The purpose of this study was to assess the validity of the recently developed Basketball Exercise Simulation Test (BEST). Ten semiprofessional (age, 22.7 +/- 6.1 years; height, 189.6 +/- 9.5 cm; weight, 86.5 +/- 18.7 kg; % body fat, 14.7 +/- 3.5%) and 10 recreational (age, 26.6 +/- 4.0 years; height, 185.9 +/- 7.9 cm; weight, 92.6 +/- 8.4 kg; % body fat, 23.8 +/- 6.3%) male basketball players volunteered for the study. The participants completed a Yo-Yo Intermittent Recovery Test (Yo-Yo IRT) and BEST trial midway through the playing season. Eight participants (semiprofessional, n = 4; recreational, n = 4) completed an additional Yo-Yo IRT and BEST trial at the end of the playing season. Performance measures from the BEST included sprint decrement (%), mean sprint and circuit time (seconds), and total distance covered (m). Construct validity was calculated using Student's unpaired t-tests to identify the differences in Yo-Yo IRT and BEST performances between playing levels. Longitudinal validity was determined based on the relationship between changes (%) in Yo-Yo IRT1 and BEST performances across the season. Semiprofessional players performed significantly (p < 0.01) better in the Yo-Yo IRT (1,283 +/- 62 vs. 636 +/- 297 m) and BEST (mean sprint time: 1.45 +/- 0.01 vs. 1.65 +/- 0.03 seconds; mean circuit time: 18.98 +/- 1.79 vs. 22.72 +/- 2.01 seconds; sprint decrement: 8.54 +/- 0.15 vs. 15.38 +/- 0.27%) compared with recreational players. For the group as a whole, a strong relationship was evident between the changes in BEST sprint decrement and changes in Yo-Yo IRT performance (R = -0.815, p = 0.014) across the season. In conclusion, the BEST displayed both discriminative and longitudinal validities and provides a novel match-specific fitness test for basketball players. PMID- 22240541 TI - Neoplasms associated with germline and somatic NF1 gene mutations. AB - INTRODUCTION: Neurofibromatosis 1 is a tumor predisposition genetic syndrome with autosomal dominant inheritance and virtually 100% penetrance by the age of 5 years. NF1 results from a loss-of-function mutation in the NF1 gene, resulting in decreased levels of neurofibromin in the cell. Neurofibromin is a negative regulator of various intracellular signaling pathways involved in the cellular proliferation. Although the loss of heterozygosity in the NF1 gene may predispose NF1 patients to certain malignancies, additional genetic alterations are a prerequisite for their development. The precise nature of these additional genetic alterations is not well defined, and genetic testing of all malignancies in NF1 patients becomes an essential component of future research in this subset of patients. In addition to germline NF1 mutations, alteration of the somatic NF1 gene is associated with sporadic malignancies such as adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic astrocytoma. MATERIALS AND METHODS: A comprehensive English and non-English language search for all articles pertinent to malignancies associated with NF1 was conducted using PubMed, a search engine provided by the U.S. National Library of Medicine and the National Institutes of Health. Key words searched included the following: "malignancies associated with NF1", "tumors associated with NF1", and "NF1 and malignancies". A comprehensive analysis in terms age and mode of presentation, investigation and therapeutic modalities, and outcome of the published data was performed and compared with similar information on the sporadic cases. RESULTS: Malignancies in NF1 patients typically occur at an earlier age and, with an exception of optic pathway gliomas, certain types of malignancies carry a poor prognosis compared with their sporadic counterparts. Malignancies are the leading cause of death in NF1 patients, resulting in a 10- to 15-year decreased life expectancy compared with the general population. CONCLUSIONS: The lack of well-defined screening tests for early detection and the nonspecific clinical presentation contributes to a poorer outcome in malignancies associated with NF1. Small study group size, mixed patient population, and a lack of uniformity in reporting research results make comparison of treatment outcome for this group difficult. An International Consensus Meeting to address and recommend best practices for screening, diagnosis, management, and follow-up of malignancies associated with NF1 is needed. PMID- 22240549 TI - Insulin sensitivity after maximal and endurance resistance training. AB - The purpose of the study was to compare the effects of maximal resistance training (MRT) vs. endurance resistance training (ERT) on improvements in insulin levels and glucose tolerance in overweight individuals at risk of developing type 2 diabetes. Eighteen participants with baseline values suggesting impaired glucose tolerance were randomly assigned to 1 of 2 groups. Group 1 engaged in supervised MRT (Bernstein inverted pyramid system: 5 * 3-4, 60-85% 1 repetition maximum [1RM]), 3 d.wk(-1) over 4 months, whereas members of group 2 acted as controls. Later, group 2 engaged in supervised ERT (3 * 12-15, 45-65% 1RM), 3 d.wk(-1) over a 4 month period with the 2 prebaselines as controls. Both interventions consisted of 8 exercises that included the entire body. Glucose (fasting and 2-hour test), insulin and C-peptide measures were assessed from pre to post in both groups. The MRT led to reduced blood levels of 2-hour glucose (p = 0.044) and fasting C-peptide (p = 0.023) and decreased insulin resistance (p = 0.040). The ERT caused a significant reduction in the blood levels of insulin (p = 0.023) and concomitant positive effects on % insulin sensitivity (p = 0.054) and beta-cell function (p = 0.020). The findings indicate that both MRT and ERT lead to decreased insulin resistance in people with a risk of developing type 2 diabetes; MRT led to a greater increase in glucose uptake capacity (in muscles), whereas ERT led to greater insulin sensitivity, supporting the recommendation of both MRT and ERT as primary intervention approaches for individuals at a risk of developing type 2 diabetes. PMID- 22240550 TI - The effects of plyometric training on sprint performance: a meta-analysis. AB - The purpose of this meta-analysis was to attempt to gain a clear picture of the magnitude of sprint performance improvements expected after chronic plyometric training (PT) and to identify specific factors that influence the treatment effects. Studies employing a PT intervention and containing data necessary to calculate effect size (ES) were included in the analysis. A total of 26 studies with a total of 56 ES met the inclusion criterion. Analysis of ES demonstrated that the strategies that seem to maximize the probability of obtaining significantly (p < 0.05) greater improvement in sprint performance included training volume for <10 weeks; a minimum of 15 sessions; and high-intensity programs with >80 combined jumps per session. To optimize sprint enhancement, the combination of different types of plyometrics and the use of training programs that incorporate greater horizontal acceleration (i.e., sprint-specific plyometric exercises, jumps with horizontal displacement) would be recommended, rather than using only one form of jump training (p < 0.05). No extra benefits were found to be gained from doing plyometrics with added weight. The loading parameters identified in this analysis should be considered by the professional sprinters and specialized trainers with regard to the most appropriate dose response trends PT to optimized sprint performance gains. PMID- 22240551 TI - Positional relationships between various sprint and jump abilities in elite American football players. AB - The purpose of this study was to investigate positional relationships between sprint and jump abilities and body mass in elite college American football players (n = 1,136). Data from the annual National Football League combine over the years 2005-2009 were examined. The measures included for examination were the 9.1-, 18.3-, 36.6-, and flying 18.3-m sprints and the vertical and horizontal jumps. Pearson's correlation coefficients (r) were calculated to determine the relationships between the tests, and coefficients of determination (r2) were used to determine common variance. With the exception of the relationship between the 9.1-m and the flying 18.3-m sprints, the relationships between all sprints are very strong. Vertical jump ability is more strongly associated with maximum speed, as compared with acceleration. Horizontal jump ability is similarly associated with maximum speed and acceleration. The 9.1-, 18.3-, and flying 18.3 m sprints and the jump tests would appear to measure independent skills. Stationary start sprints up to 36.6 m appear to be heavily influenced by acceleration and may thus measure similar characteristics. The flying 18.3-m sprint is recommended as a measure of maximum speed. Body mass was most strongly associated with performance in the lineman group. When body mass was controlled for, correlations weakened across all the groups. The role of body mass remains unclear. Regardless of sport, the present research supports the notion that the relationships between various sprint and jump abilities warrant positional consideration. Coaches and practitioners will be able to use the findings of this research to better test and monitor athletes requiring different skills. PMID- 22240552 TI - The influence of blood lactate sample site on exercise prescription. AB - The aims of this study were first to determine the level of agreement between the fingertip and earlobe for the measurement of blood lactate, and second, to examine whether these sample sites may be used interchangeably when distinguishing lactate parameters routinely used in the physiological assessment and exercise prescription. Twenty healthy men performed an incremental cycle ergometry step test. Capillary blood samples were taken simultaneously at the end of each increment from the earlobe and the fingertip to determine blood lactate concentration. The power output and the heart rate at different lactate parameters (LT, LT1, 2, and 4 mMol.L(-1)) were calculated from the lactate values. The average bias in blood lactate concentration measured from the fingertip and the earlobe was 9.2% with 95% of measures differing by between 24.9 and 58.7%. There were no significant differences between sample sites (p = 0.201); however, there was a strong positive relationship (R2 = 0.9455). At the different lactate parameters, there were no differences in determining the heart rate (except at 4 mMol.L(-1) [p = 0.028], equating to 2 b.min(-1)) and power output between sample sites. In conclusion, this high level of agreement and negligible differences in prescribing exercise using power output and heart rate from commonly used lactate parameters, determined from the earlobe and the fingertip indicate that these sample sites could be used interchangeably for physiological assessment during cycle ergometry. PMID- 22240553 TI - Positive effect of lower body compression garments on subsequent 40-kM cycling time trial performance. AB - This study aimed to investigate the effect of wearing graduated compression garments during recovery on subsequent 40-km time trial performance. In a randomized single-blind crossover experiment, 14 trained multisport male athletes (mean +/- SD: age 33.8 +/- 6.8 years, 40-km time 66:11 +/- 2:10 minutes:seconds) were given a graduated full-leg-length compressive garment (76% Meryl Elastane, 24% Lycra) or a similar-looking noncompressive placebo garment (92% Polyester, 8% Spandex) to wear continuously for 24 hours after performing an initial 40-km time trial in their normal cycling attire. After the 24-hour recovery period, the compression (or placebo) garments were removed, and a second 40-km time trial was then completed to gauge the effect of each garment on subsequent performance. One week later, the groups were reversed and testing procedures repeated. The participant's hydration status, nutritional intake, and training were similar before each set of trials. Performance time in the second time trial was substantially improved with compression compared with placebo garments (1.2 +/- 0.4%, mean +/- 90% confidence interval). This improvement resulted in a substantially higher average power output after wearing the compression garment compared with that after wearing the placebo garment (3.3 +/- 1.1%). Differences in oxygen cost and rating of perceived exertion between groups were trivial or unclear. The wearing of graduated compressive garments during recovery is likely to be worthwhile and unlikely to be harmful for well-trained endurance athletes. PMID- 22240554 TI - Two-stage treatment of a secondary aortoesophageal fistula after thoracic endovascular aneurysm repair. AB - Secondary aortoesophageal fistula is a relatively rare but very often lethal complication that may develop after thoracic endovascular aneurysm repair (TEVAR). The clinical syndrome is well explained by the Chiari triad: midthoracic pain and/or dysphagia, and sentinel minor hematemesis followed by massive hematemesis. The incidence of this serious complication has increased with the growing number of patients undergoing TEVAR. This case report describes a patient who was seen in the emergency department at this hospital because of fever, sepsis and thoracic pain radiating to the back and unresponsive to drug therapy, diagnosed with a secondary aortoesophageal fistula and subsequently treated with a two stage surgical procedure. PMID- 22240555 TI - Treatment of a splenic artery aneurysm with concomitant malignancy. PMID- 22240557 TI - Secretory phospholipase A2 group IID Is involved in progesterone-induced acrosomal exocytosis of human spermatozoa. AB - Phospholipase A2 (PLA(2)) plays a major role during acrosomal exocytosis (AE) in mammalian spermatozoa, but the identity of PLA(2) subtypes present in spermatozoa remains elusive. This study explored whether secretory PLA(2) Group IID (sPLA(2)-IID) isoform is present in human spermatozoa and whether it is involved in AE. Localization and expression of sPLA(2)-IID in human spermatozoa were explored by immunofluorescence staining and Western blot analysis. Occurrence of AE was evaluated by triple staining, and arachidonic acid (AA) levels were quantified by gas chromatography-mass spectrometry. Sperm motion parameters and hyperactivation were analyzed by computer-assisted sperm analysis. sPLA(2)-IID was localized in the postacrosomal region of the head and the midpiece of tail in human sperm. A 16-kd protein band was detected by Western blotting in sperm extracts. Progesterone-induced AE was significantly inhibited in a concentration-dependent manner using a sPLA(2)-IID neutralizing antibody. The increase in AA levels seen during progesterone-stimulated exocytosis was significantly abrogated by the antibody. The sPLA(2)-IID antibody significantly inhibited hyperactivation, sperm curvilinear velocity, and amplitude of lateral head displacement, but it did not affect the proportion of motile sperm. In conclusion, sPLA(2)-IID is present at the head and midpiece in the human sperm, and activation of such sPLA(2)-IID seems to be involved in AE. Therefore, sPLA(2)-IID isoform plays a functional role during the AE in human sperm. PMID- 22240558 TI - Optimization of a filter-lysis protocol to purify rat testicular homogenates for automated spermatid counting. AB - Quantifying testicular homogenization-resistant spermatid heads (HRSH) is a powerful indicator of spermatogenesis. These counts have traditionally been performed manually using a hemocytometer, but this method can be time consuming and biased. We aimed to develop a protocol to reduce debris for the application of automated counting, which would allow for efficient and unbiased quantification of rat HRSH. We developed a filter-lysis protocol that effectively removes debris from rat testicular homogenates. After filtering and lysing the homogenates, we found no statistical differences between manual (classic and filter-lysis) and automated (filter-lysis) counts using 1-way analysis of variance with Bonferroni's multiple comparison test. In addition, Pearson's correlation coefficients were calculated to compare the counting methods, and there was a strong correlation between the classic manual counts and the filter-lysis manual (r = 0.85, P = .002) and the filter-lysis automated (r = 0.89, P = .0005) counts. We also tested the utility of the automated method in a low-dose exposure model known to decrease HRSH. Adult Fischer 344 rats exposed to 0.33% 2,5-hexanedione in the drinking water for 12 weeks demonstrated decreased body (P = .02) and testes (P = .002) weights. In addition, there was a significant reduction in the number of HRSH per testis (P = .002) when compared to controls. A filterlysis protocol was optimized to purify rat testicular homogenates for automated HRSH counts. Automated counting systems yield unbiased data and can be applied to detect changes in the testis after low-dose toxicant exposure. PMID- 22240559 TI - The comparison of the aging male symptoms (AMS) scale and androgen deficiency in the aging male (ADAM) questionnaire to detect androgen deficiency in middle-aged men. AB - The prevalence of androgen deficiency in men increases with aging. Two common instruments, the Aging Male Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire, are often used to screen for androgen deficiency in clinical practice. The aim of this study is to compare the capability of the AMS scale and the ADAM questionnaire to detect androgen deficiency in middle-aged Taiwanese men. In April 2008, a free health screening was conducted by Kaohsiung Medical University Hospital. All participants completed a health questionnaire and had blood samples drawn between 8:00 am and noon. Serum total testosterone (TT), albumin, and sex hormone-binding globulin levels were measured. The level of free testosterone (FT) was calculated. Clinical symptoms associated with androgen deficiency were screened by using the AMS scale and ADAM questionnaire. Androgen deficiency was defined as TT < 300 ng/dL or both TT < 300 ng/dL and FT< 5 ng/dL. In total, 339 men were included in the final analysis, with the mean age of 54.6 +/- 4.9 years (range, 47-65 years). Androgen deficiency was found in 75 men (22.1%) based on the criteria of TT < 300 ng/dL, and in 54 men (15.9%) based on the criteria of TT < 300 ng/dL and FT < 5 ng/dL. When detecting participants with both TT < 300 ng/dL and FT < 5 ng/dL, the sensitivity and specificity of the AMS scale were 57.4% and 48.1%, compared with 66.7% and 25.6% for the ADAM questionnaire. In a sample of middle aged Taiwanese men, neither the AMS scale nor the ADAM questionnaire had sufficient sensitivity and specificity to detect androgen deficiency. In addition to using those 2 screening instruments, a thorough physical and biochemical workup should still be conducted in patients at risk or suspected of androgen deficiency. PMID- 22240560 TI - "Andrology"--The New Journal of the American Society of Andrology and the European Academy of Andrology. PMID- 22240561 TI - HIPAA and its effect on informatics. PMID- 22240562 TI - Omaha system partnership for knowledge discovery and healthcare quality: nursing terminology in action. PMID- 22240564 TI - Effects of online support group format (moderated vs peer-led) on depressive symptoms and extent of participation in women with breast cancer. AB - The purposes of this study were to evaluate the effects of different formats of online group support (moderated vs peer-led) on depressive symptoms and extent of participation in women with breast cancer. A randomized longitudinal design was used to address the study aims. The setting was a secure password-protected Web page. Fifty women with breast cancer, at least 21 years old, who had Internet access participated. Subjects were randomly assigned to moderated or peer-led groups, given a password, and instructed to complete the study questionnaires at baseline and again at 6, 12, and 16 weeks. The independent variables were types of online support (moderated or peer-led), and the dependent variables were depressive symptoms and extent of participation. There were no significant differences in depressive symptoms by group or by extent of group participation. Moderated groups read and posted significantly more messages than did peer-led groups. This study adds to the research base on different group formats for online support and the extent of participation and nonparticipation (lurking) in online groups. It provides a springboard for additional studies that include ethnic minorities, people with different types of cancer, and men. PMID- 22240566 TI - Impact of surgeon volume on patient safety in laparoscopic gynecologic surgery. AB - OBJECTIVE: To determine the impact of surgeon volume on patient outcomes in gynecologic laparoscopic surgery. METHODS: We reviewed all patients who underwent a laparoscopic procedure between January 2000 and December 2008. Surgeons were divided into 3 groups based on surgical volume. The mean number of surgeries per year was calculated for each surgeon. Means were categorized into 3 groups. The low-, medium-, and high-volume surgeon groups were compared with respect to level of surgical complexity and intraoperative and postoperative complications. RESULTS: The study included 829 surgeries. Low-volume surgeons (n=5) performed 5 (31.3%) low-complexity, 10 (62.5%) intermediate-complexity, and 1 (6.3%) high complexity procedures. Medium-volume surgeons (n=6) performed 26 (11.1%) low complexity, 203 (86.8%) intermediate-complexity, and 5 (2.1%) high-complexity procedures. High-volume surgeons (n=5) performed 47 (8.1%) low-complexity, 439 (75.8%) intermediate-complexity, and 93 (16.1%) high-complexity procedures. The distribution of surgical complexity was significantly different between the 3 groups of surgeons defined by volume (P<0.001). Conversion rates were higher for low-volume surgeons when compared to high-volume surgeons (18.8% vs. 5.2%; P=0.04). Similarly, overall complication rates (<30 days) were higher for low volume surgeons compared to high-volume surgeons (31.3% vs. 17%, P=0.003). Mean length of hospital stay was longer for low-volume (2.4 days) than for medium volume (1.3 days) and high-volume surgeons (1.6 days) (P=0.003). CONCLUSION: High and medium-volume gynecologic laparoscopists performed a greater proportion of intermediate- and high-complexity procedures than did low-volume surgeons. High volume surgeons have a lower rate of conversions, overall postoperative complications, and shorter mean length of hospital stay when compared to low volume surgeons. PMID- 22240567 TI - Terminology management for implantable cardiac electronic device lead macro dislodgement. PMID- 22240575 TI - Specific bilateral ear infiltration as an early manifestation of chronic lymphocytic leukaemia. PMID- 22240577 TI - Tudor-SN and ADAR1 are components of cytoplasmic stress granules. AB - Hyperediting by adenosine deaminases that acts on RNA (ADARs) may result in numerous Adenosine-to-Inosine (A-to-I) substitutions within long dsRNA. However, while countless RNAs may undergo hyperediting, the role for inosine-containing hyperedited dsRNA (IU-dsRNA) in cells is poorly understood. We have previously shown that IU-dsRNA binds specifically to various components of cytoplasmic stress granules, as well as to other proteins such as Tudor Staphylococcal Nuclease (Tudor-SN). Tudor-SN has been implicated in diverse roles in mammalian cells, including transcription, splicing, RNAi, and degradation. Moreover, we have shown that Tudor-SN interacts directly with stress granule proteins. Here we show that Tudor-SN localizes to cytoplasmic stress granules in HeLa cells undergoing arsenite-induced oxidative stress, or following transfection with long dsRNA (poly[IC]), which initiates an interferon cascade. We additionally demonstrate a novel interaction between Tudor-SN and ADAR1. Finally, we show that ADAR1 is also localized to stress granules in HeLa cells following various stresses. PMID- 22240579 TI - Proprioception and functional deficits of partial meniscectomized knees. AB - BACKGROUND: The partial meniscectomy leads to proprioceptive knee deficits in a short period after the arthroscopic procedure; however, to our knowledge, a limited number of studies have investigated the long-term outcomes of partial meniscectomy on the knee joint proprioception. AIM: The aim of the present study was to assess the proprioception and muscle function of the partial meniscectomized knee through balance and functional tests 1-2 years posterior to arthroscopic surgery. DESIGN: This was an observational study. SETTING: Partially meniscectomized persons after 1-2 years. POPULATION: Twenty-six male patients who had an arthroscopic partial meniscectomy at the age between 20-40. METHODS: All patients performed balance (Biodex Stability System and balance boards) and functional (triple jump) tests. On the balance system the deviations from the horizontal plane were recorded, on the balance boards their performance was timed, and on the functional test triple jump their performance was recorded in meters. RESULTS: One-way Anova was used to determine significant differences between the healthy and injured limb. The level of statistical significance was set at p<0.05. The results revealed significant differences (p<0.05) between the healthy and injured limb at all balance and functional tests performed. CONCLUSION: The present study demonstrated that 1-2 years after partial meniscectomy, patients had reduced proprioception and knee muscular ability in the operated leg compared to the non-operated leg. Clinical rehabilitation impact. Proprioception and knee muscular ability deficits significantly affect objective knee function, indicating the importance not only of the restoring muscle function but also of the proprioception ability in partial meniscectomy patients. PMID- 22240581 TI - Tailoring metal-organic framework catalysts by click chemistry. AB - We successively introduce new catalytic centers through click reaction into MOFs and modify their environment by addition of lipophilic groups. The resulting bifunctionalized MOF provides an optimized balance between basicity and lipophilicity and shows outstanding performance for the transesterification reaction. PMID- 22240582 TI - High-contrast en bloc staining of neuronal tissue for field emission scanning electron microscopy. AB - Conventional heavy metal poststaining methods on thin sections lend contrast but often cause contamination. To avoid this problem, we tested several en bloc staining techniques to contrast tissue in serial sections mounted on solid substrates for examination by field emission scanning electron microscopy (FESEM). Because FESEM section imaging requires that specimens have higher contrast and greater electrical conductivity than transmission electron microscopy (TEM) samples, our technique uses osmium impregnation (OTO) to make the samples conductive while heavily staining membranes for segmentation studies. Combining this step with other classic heavy metal en bloc stains, including uranyl acetate (UA), lead aspartate, copper sulfate and lead citrate, produced clean, highly contrasted TEM and scanning electron microscopy (SEM) samples of insect, fish and mammalian nervous systems. This protocol takes 7-15 d to prepare resin-embedded tissue, cut sections and produce serial section images. PMID- 22240583 TI - A multispectral optical illumination system with precise spatiotemporal control for the manipulation of optogenetic reagents. AB - Optogenetics is an excellent tool for noninvasive activation and silencing of neurons and muscles. Although they have been widely adopted, illumination techniques for optogenetic tools remain limited and relatively nonstandardized. We present a protocol for constructing an illumination system capable of dynamic multispectral optical targeting of micrometer-sized structures in both stationary and moving objects. The initial steps of the protocol describe how to modify an off-the-shelf video projector by insertion of optical filters and modification of projector optics. Subsequent steps involve altering the microscope's epifluorescence optical train as well as alignment and characterization of the system. When fully assembled, the illumination system is capable of dynamically projecting multispectral patterns with a resolution better than 10 MUm at medium magnifications. Compared with other custom-assembled systems and commercially available products, this protocol allows a researcher to assemble the illumination system for a fraction of the cost and can be completed within a few days. PMID- 22240584 TI - Intravital multiphoton imaging of immune responses in the mouse ear skin. AB - Multiphoton (MP) microscopy enables the direct in vivo visualization, with high spatial and temporal resolution, of fluorescently tagged immune cells, extracellular matrix and vasculature in tissues. This approach, therefore, represents a powerful alternative to traditional methods of assessing immune cell function in the skin, which are mainly based on flow cytometry and histology. Here we provide a step-by-step protocol describing experimental procedures for intravital MP imaging of the mouse ear skin, which can be easily adapted to address many specific skin-related biological questions. We demonstrate the use of this procedure by characterizing the response of neutrophils during cutaneous inflammation, which can be used to perform in-depth analysis of neutrophil behavior in the context of the skin microanatomy, including the epidermis, dermis and blood vessels. Such experiments are typically completed within 1 d, but as the procedures are minimally invasive, it is possible to perform longitudinal studies through repeated imaging. PMID- 22240585 TI - Isolation and characterization of mouse and human esophageal epithelial cells in 3D organotypic culture. AB - This protocol describes the isolation and characterization of mouse and human esophageal epithelial cells and the application of 3D organotypic culture (OTC), a form of tissue engineering. This model system permits the interrogation of mechanisms underlying epithelial-stromal interactions. We provide guidelines for isolating and cultivating several sources of epithelial cells and fibroblasts, as well as genetic manipulation of these cell types, as a prelude to their integration into OTC. The protocol includes a number of important applications, including histology, immunohistochemistry/immunofluorescence, genetic modification of epithelial cells and fibroblasts with retroviral and lentiviral vectors for overexpression of genes or RNA interference strategies, confocal imaging, laser capture microdissection, RNA microarrays of individual cellular compartments and protein-based assays. The OTC (3D) culture protocol takes 15 d to perform. PMID- 22240586 TI - Croatian medical students see academic dishonesty as an acceptable behaviour: a cross-sectional multicampus study. AB - AIM: To provide insights into the students' attitude towards academic integrity and their perspective of academic honesty at Croatian medical schools. METHODS: A cross-sectional study using an anonymous questionnaire containing 29 questions on frequency of cheating, perceived seriousness of cheating, perceptions on integrity atmosphere, cheating behaviour of peers and on willingness to report misconduct. Participants were third-year (preclinical) and fifth-year (clinical) students from all four Croatian Schools of Medicine. Outcome measures were descriptive statistical correlates and differences in students' self-reported educational dishonesty, perceptions of cheating behaviour and medical school integrity atmosphere. RESULTS: Of the 1074 students enrolled in the third and fifth year, 662 (62%) completed the questionnaire. A large proportion of the students (97%) admitted using some method of cheating and 78% admitted engaging in at least one form of misconduct. About 50% had a lenient attitude towards six acts of academic dishonesty. Only 2% reported another student for cheating. Risk factors for cheating were strongly correlated with students' perceptions of peer cheating behaviour, peer approval of cheating, low perception of seriousness of cheating and inappropriate severity level of exams and teaching materials. CONCLUSIONS: Cheating is prevalent in Croatian medical schools and academic dishonesty is seen as acceptable behaviour among numerous future Croatian doctors. PMID- 22240587 TI - Older peoples' attitudes towards euthanasia and an end-of-life pill in The Netherlands: 2001-2009. AB - INTRODUCTION: With an ageing population, end-of-life care is increasing in importance. The present work investigated characteristics and time trends of older peoples' attitudes towards euthanasia and an end-of-life pill. METHODS: Three samples aged 64 years or older from the Longitudinal Ageing Study Amsterdam (N=1284 (2001), N=1303 (2005) and N=1245 (2008)) were studied. Respondents were asked whether they could imagine requesting their physician to end their life (euthanasia), or imagine asking for a pill to end their life if they became tired of living in the absence of a severe disease (end-of-life pill). Using logistic multivariable techniques, changes of attitudes over time and their association with demographic and health characteristics were assessed. RESULTS: The proportion of respondents with a positive attitude somewhat increased over time, but significantly only among the 64-74 age group. For euthanasia, these percentages were 58% (2001), 64% (2005) and 70% (2008) (OR of most recent versus earliest period (95% CI): 1.30 (1.17 to 1.44)). For an end-of-life pill, these percentages were 31% (2001), 33% (2005) and 45% (2008) (OR (95% CI): 1.37 (1.23 to 1.52)). For the end-of-life pill, interaction between the most recent time period and age group was significant. CONCLUSIONS: An increasing proportion of older people reported that they could imagine desiring euthanasia or an end-of life pill. This may imply an increased interest in deciding about your own life and stresses the importance to take older peoples' wishes seriously. PMID- 22240588 TI - Autophagy can promote but is not required for epithelial cell extrusion in the amnioserosa of the Drosophila embryo. AB - During Drosophila embryogenesis the majority of the extra-embryonic epithelium known as the amnioserosa (AS) undergoes programmed cell death (PCD) following the completion of the morphogenetic process of dorsal closure. Approximately ten percent of AS cells, however, are eliminated during dorsal closure by extrusion from the epithelium. Using biosensors that report autophagy and caspase activity in vivo, we demonstrate that AS cell extrusion occurs in the context of elevated autophagy and caspase activation. Furthermore, we evaluate AS extrusion rates, autophagy, and caspase activation in embryos in which caspase activity or autophagy are altered by genetic manipulation. This includes using the GAL4/UAS system to drive expression of p35, reaper, dINR (ACT) and Atg1 in the AS; we also analyze embryos lacking both maternal and zygotic expression of Atg1. Based on our results we suggest that autophagy can promote, but is not required for, epithelial extrusion and caspase activation in the amnioserosa. PMID- 22240589 TI - Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress. AB - Autophagy regulates cell survival and cell death upon various cellular stresses, yet the molecular signaling events involved are not well defined. Here, we established the function of a proteolytic Cyclin E fragment (p18-CycE) in DNA damage-induced autophagy, apoptosis, and senescence. p18-CycE was identified in hematopoietic cells undergoing DNA damage-induced apoptosis. In epithelial cells exposed to DNA damage, chronic but not transient expression of p18-CycE leads to higher turnover of LC3 I/II and increased emergence of autophagosomes and autolysosomes. Levels of p18-CycE, which was generated by proteolytic cleavage of endogenous Cyclin E, were greatly increased by chloroquine and correlated with LC 3II conversion. Preventing p18-CycE genesis blocked conversion of LC3 I to LC3 II. Upon DNA damage, cytoplasmic ataxia-telangiectasia-mutated (ATM) was phosphorylated in p18-CycE-expressing cells resulting in sustained activation of the adenosine-mono-phosphate-dependent kinase (AMPK). These lead to sustained activation of mammalian autophagy-initiating kinase ULK1, which was abrogated upon inhibiting ATM and AMPK phosphorylation. Moreover, p18-CycE was degraded via autophagy followed by induction of senescence. Both autophagy and senescence were prevented by inhibiting autophagy, which leads to increased apoptosis in p18-CycE expressing cells by stabilizing p18-CycE expression. Senescence was further associated with cytoplasmic co-localization and degradation of p18-CycE and Ku70. In brief, chronic p18-CycE expression-induced autophagy leads to clearance of p18 CycE following DNA damage and induction of senescence. Autophagy inhibition stabilized the cytoplasmic p18-CycE-Ku70 complex leading to apoptosis. Thus, our findings define how chronic apoptotic stress and DNA damage initiate autophagy and regulate cell survival through senescence and/or apoptosis. PMID- 22240590 TI - Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. AB - Neuroepithelial cells undergoing differentiation efficiently remodel their cytoskeleton and shape in an energy-consuming process. The capacity of autophagy to recycle cellular components and provide energy could fulfill these requirements, thus supporting differentiation. However, little is known regarding the role of basal autophagy in neural differentiation. Here we report an increase in the expression of the autophagy genes Atg7, Becn1, Ambra1 and LC3 in vivo in the mouse embryonic olfactory bulb (OB) during the initial period of neuronal differentiation at E15.5, along with a parallel increase in neuronal markers. In addition, we observed an increase in LC3 lipidation and autophagic flux during neuronal differentiation in cultured OB-derived stem/progenitor cells. Pharmacological inhibition of autophagy with 3-MA or wortmannin markedly decreased neurogenesis. These observations were supported by similar findings in two autophagy-deficient genetic models. In Ambra1 loss-of-function homozygous mice (gt/gt) the expression of several neural markers was decreased in the OB at E13.5 in vivo. In vitro, Ambra1 haploinsufficient cells developed as small neurospheres with an impaired capacity for neuronal generation. The addition of methylpyruvate during stem/progenitor cell differentiation in culture largely reversed the inhibition of neurogenesis induced by either 3-MA or Ambra1 haploinsufficiency, suggesting that neural stem/progenitor cells activate autophagy to fulfill their high energy demands. Further supporting the role of autophagy for neuronal differentiation Atg5-null OB cells differentiating in culture displayed decreased TuJ1 levels and lower number of cells with neurites. These results reveal new roles for autophagy-related molecules Atg5 and Ambra1 during early neuronal differentiation of stem/progenitor cells. PMID- 22240591 TI - Atg4 recycles inappropriately lipidated Atg8 to promote autophagosome biogenesis. AB - Atg8 is a ubiquitin-like protein required for autophagy in the budding yeast Saccharomyces cerevisiae. A ubiquitin-like system mediates the conjugation of the C terminus of Atg8 to the lipid phosphatidylethanolamine (PE), and this conjugate (Atg8-PE) plays a crucial role in autophagosome formation at the phagophore assembly site/pre-autophagosomal structure (PAS). The cysteine protease Atg4 processes the C terminus of newly synthesized Atg8 and also delipidates Atg8 to release the protein from membranes. While the former is a prerequisite for lipidation of Atg8, the significance of the latter in autophagy has remained unclear. Here, we show that autophagosome formation is significantly retarded in cells deficient for Atg4-mediated delipidation of Atg8. We find that Atg8-PE accumulates on various organelle membranes including the vacuole, the endosome and the ER in these cells, which depletes unlipidated Atg8 and thereby attenuates its localization to the PAS. Our results suggest that the Atg8-PE that accumulates on organelle membranes is erroneously produced by lipidation system components independently of the normal autophagic process. It is also suggested that delipidation of Atg8 by Atg4 on different organelle membranes promotes autophagosome formation. Considered together with other results, we propose that Atg4 acts to compensate for the intrinsic defect in the lipidation system; it recycles Atg8-PE generated on inappropriate membranes to maintain a reservoir of unlipidated Atg8 that is required for autophagosome formation at the PAS. PMID- 22240593 TI - Safety and tolerability of once-daily controlled-release carvedilol 10-80 mg in Japanese patients with chronic heart failure. AB - BACKGROUND: The aim of the present study was to assess the safety and tolerability of the controlled-release (CR) formulation of the beta-blocker carvedilol in Japanese patients with chronic heart failure (HF). METHODS AND RESULTS: In this multicenter, randomized, open-label, phase I/II dose-escalation study, 41 patients receiving standard therapy for chronic HF were randomized in a ratio of 1:1 to carvedilol CR or immediate-release (IR) carvedilol. The primary objective was to evaluate the tolerability and safety of escalating doses of carvedilol CR (10-40 mg/day), with a reference arm of 5-20 mg/day of carvedilol IR. In addition, the tolerability and safety of titration to a carvedilol CR dose up to 80 mg/day were examined, as were plasma concentrations of carvedilol and changes in vital signs. The proportions of patients who completed 40-mg/day carvedilol CR and 20-mg/day carvedilol IR were 42% (8/19) and 50% (11/22), respectively. In the CR group, 7/19 (37%) attained a dose of 80 mg. During the primary evaluation period, 7/19 (37%) and 4/22 (18%) patients experienced drug related adverse events in the CR and IR groups, respectively, the characteristics of which were similar between groups. CONCLUSIONS: No new safety issues emerged in Japanese chronic HF patients treated with carvedilol CR in contrast to those known in carvedilol IR. PMID- 22240594 TI - Left ventricular mechanical dyssynchrony impairs exercise capacity in patients with coronary artery disease with preserved left ventricular systolic function and a QRS duration <= 120 ms. AB - BACKGROUND: Left ventricular (LV) mechanical dyssynchrony can lead to impairment of LV function and is associated with adverse clinical outcomes in coronary artery disease (CAD) patients. The impact of LV dyssynchrony on exercise capacity (EC) in patients with CAD was investigated. METHODS AND RESULTS: An echocardiographic examination with tissue Doppler imaging and exercise treadmill testing in 151 CAD patients with normal LV ejection fraction was performed. LV intra- and inter-ventricular dyssynchrony were defined by the standard deviation of time interval between LV 6 basal segments (Ts-SD), and the time interval from the right ventricular (RV) free wall to LV lateral wall (Ts-RV) respectively, and EC was measured as metabolic equivalents (METs) on the treadmill. Patients with impaired EC (defined by a METs <= 8, which is the mean MET of the study population) were older (71 +/- 7 vs. 62 +/- 2 years, P<0.01), however, there were no differences in gender and clinical status such as prevalence of prior myocardial infarction (MI), regional wall motion abnormality (RWMA), and coronary revascularization between patients with (n=90) or without (n=61) impaired EC. Univariate analysis showed that age, body mass index, LV systolic and diastolic volume, mitral inflow A velocity, and Ts-SD were all significantly associated with METs (all P<0.05). However, multivariate regression analysis revealed that old age (odd ratio [OR]: 1.136, 95% confidence interval [CI]: 1.080-1.196, P<0.001), and Ts-SD (OR: 1.026, 95%CI: 1.003-1.049, P=0.027) only were independent predictors for impaired EC. CONCLUSIONS: In patients with CAD, LV systolic dyssynchrony predicts impaired EC independently of history of previous MI or RWMA. PMID- 22240595 TI - Tissue Doppler imaging dyssynchrony parameter derived from the myocardial active wall motion improves prediction of responders for cardiac resynchronization therapy. AB - BACKGROUND: The aim of this study was to propose modified tissue Doppler imaging (TDI) parameters derived from the first active wall motion and to assess them for the better prediction of cardiac resynchronization therapy (CRT) responders in comparison with to original TDI parameters. METHODS AND RESULTS: In 61 patients with CRT, time from QRS onset to peak velocities by TDI (Ts), which were derived from active wall motion identified by longitudinal strain rate (LSR) value, were assessed. Time from QRS onset to the negative peak of LSR (TLSR) was also assessed. Modified standard deviation of Ts in 12 left ventricular (LV) segments (Ts-SD), that of TLSR (TLSR-SD), differences of Ts between septum and lateral wall (Ts-SL), and that of TLSR (TLSR-SL) were calculated. Original Ts-SD and Ts SL were calculated by previously described methods. Responders were defined as patients with LV end-systolic volume reduction (>15%) at 6 months after CRT: 35 patients (57%) were identified as CRT responders. Area under the receiver operating characteristics curve (AUC) of modified Ts-SD (0.87) was significantly higher than that of Ts-SD (0.65), Ts-SL (0.62), and TLSR-SL (0.69). AUC of modified Ts-SL was significantly higher than those of Ts-SD, and Ts-SL. AUC of TLSR-SD (0.82) also was significantly higher than that of Ts-SD. CONCLUSIONS: Modified TDI dyssynchrony parameters derived from the first active wall motion improve the ability to predict responders to CRT. PMID- 22240596 TI - Hemodialysis-induced P-wave signal-averaged electrocardiogram alterations are indicative of vulnerability to atrial arrhythmias. AB - BACKGROUND: Atrial fibrillation (AF) is the most common supraventricular arrhythmia, often occurring during hemodialysis (HD). Prolongation of the total filtered P-wave duration (PWD) and reduction of the root mean square voltages for the last 20 ms of the P wave (RMS20) on a P-wave signal-averaged electrocardiogram (P-SAECG) are predictors of AF. We investigated whether HD induces alterations of P-SAECG, and determined the influential factors. METHODS AND RESULTS: Thirty-three end-stage kidney disease patients (66.7 +/- 12.6 years, 23 males) undergoing maintenance HD were enrolled in this study. Digital ambulatory P-SAECG monitoring and laboratory examination of serum proteins and ions were carried out before, during, and after the HD sessions. Data were analyzed by multiple regression analysis. PWD was significantly prolonged, and RMS20 significantly reduced, during HD. These values recovered after completion of HD. Multiple regression analysis showed that prolongation of PWD significantly correlated with HD duration and the rate of removal of body fluid. On the other hand, RMS20 significantly correlated with HD duration and blood urea nitrogen variation. CONCLUSIONS: HD resulted in prolongation of PWD and reduction of RMS20, indicating the vulnerability of HD patients to AF. These P-SAECG changes correlated with HD duration and the rate of removal of the body fluid. These findings underline the importance of the control of dialysis variables in the prevention of atrial arrhythmias following HD. PMID- 22240597 TI - Effects of voglibose and nateglinide on glycemic status and coronary atherosclerosis in early-stage diabetic patients. AB - BACKGROUND: Postprandial hyperglycemia and hyperinsulinemia have been considered as important determinants for the development of atherosclerosis. However, it remains to be elucidated whether correction of the postprandial glycemic status prevents atherosclerotic changes. METHODS AND RESULTS: The DIANA (DIAbetes and diffuse coronary NArrowing) study is a prospective randomized open-label multicenter trial. The 302 patients with coronary artery disease (CAD), impaired glucose tolerance/diabetes mellitus (DM) pattern according to 75-g oral glucose tolerance test and HbA(1c) <6.9% were randomly assigned to life-style intervention (n=101), voglibose (0.9 mg/day, n=100) or nateglinide treatment (180 mg/day, n=101). We compared 1-year coronary atherosclerotic changes evaluated by quantitative coronary arteriography. Although voglibose significantly increased the number of patients with normal glucose tolerance at 1 year, there were no significant differences in coronary atherosclerotic changes at 1 year. However, overall, less atheroma progression was observed in patients in whom glycemic status was improved at 1 year (%change in total lesion length: 3.5% vs. 26.2%, P<0.01, %change in averaged lesion length: 0.7% vs. 18.6%, P=0.02). CONCLUSIONS: Although coronary atherosclerotic changes were similar for voglibose and nateglinide, an improvement in glycemic status at 1 year was associated with less atheroma progression regardless of the treatment. Our findings underscore the management of glycemic abnormality to prevent coronary atherosclerotic changes in Japanese early-stage DM patients with CAD. PMID- 22240600 TI - Contemporary medical management of systolic heart failure. AB - Pharmacological therapy of systolic left ventricular dysfunction has evolved over the past 3 decades. Current therapy is focused primarily on the regulation of the renin-angiotensin-aldosterone axis and sympathetic nervous system. Additional targets of pharmacotherapy include vasoconstriction, impaired nitric oxide metabolism, inflammation and improving myocardial function. As therapies in chronic systolic heart failure have evolved beyond diuretics and digoxin, so too has mortality improved. Future directions in the management of heart failure include cell-based and genetic therapy, and further refinement of current therapy through genetics. PMID- 22240601 TI - Hemodynamic classifications of acute heart failure and their clinical application: - an update -. AB - Acute heart failure (AHF) is classically defined by signs and symptoms related to elevated ventricular filling pressures. Regardless of precipitant, underlying etiology or ejection fraction, the vast majority of hospital admissions are the result of worsening chronic HF. For the acutely decompensated patient, 4 hemodynamic profiles, stratified by degree of congestion ("dry" or "wet") and adequacy of perfusion ("warm" or "cold") predict prognosis and guide therapy. Relief of congestion is the primary goal of AHF management. Loop diuretics remain the mainstay of AHF treatment, but new modalities such as veno-venous ultrafiltration are promising. For patients with evidence of hypoperfusion, vasoactive agents may be needed to facilitate diuresis. The decision to use vasodilators or inotropes is complex and the need for invasive hemodynamic monitoring is often determined by the individual patient's characteristics. Routine use of inotropes should be discouraged; however when used, the short-term hemodynamic benefits conferred by these agents must be balanced against their tendency to increase adverse events. Although these strategies are effective in alleviating symptoms in most patients, management dilemmas arise from cardiorenal interactions and limitations in effective novel therapies. Epidemiological studies continue to emphasize that AHF portends a poor prognosis. Further studies are needed to improve our understanding and outcomes in this growing patient population. PMID- 22240598 TI - Percutaneous coronary intervention with drug-eluting stent implantation vs. coronary artery bypass grafting for multivessel coronary artery disease in metabolic syndrome patients with acute myocardial infarction. AB - BACKGROUND: Coronary artery bypass grafting (CABG) has been the treatment of choice for management of multivessel coronary artery disease, but percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is increasingly being preferred. The aim of the present study was to compare outcomes of PCI with DES implantation (PCI-DES) and CABG for treating multivessel disease in metabolic syndrome patients with acute myocardial infarction (AMI). METHODS AND RESULTS: A total of 1,839 consecutive metabolic syndrome patients with AMI who underwent PCI DES (n=1,715) and CABG (n=124) for treatment of multivessel disease were selected from Korea Acute Myocardial Infarction Registry from November 2005 through December 2006. Primary endpoint was 12-month all-cause mortality. The mortality rate at 12 months was significantly lower in the PCI-DES group (4.8% vs. 12.2% in CABG, P=0.014) on univariate analysis. According to a Cox model, 12-month mortality was similar between the 2 groups (P=0.603), which remained the same despite propensity score adjustment (P=0.485). Rate of repeat revascularization was significantly higher in the PCI-DES group compared to the CABG group (P<0.001). At 12 months, major adverse cardiovascular and cerebrovascular event (MACCE)-free survival was higher in ST-elevation MI (STEMI) patients in the CABG group. CONCLUSIONS: PCI-DES had an equivalent 12-month mortality risk to CABG for the treatment of multivessel disease in metabolic syndrome patients with AMI. CABG is more favorable for STEMI patients in terms of MACCE. PMID- 22240602 TI - Options to overcome clopidogrel response variability. AB - Oral antiplatelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopdiogrel, the most important of which is the wide response variability of platelet inhibition. The response to clopidogrel is affected by various clinical variables, genetic variations involved in its activation, and drug-drug interactions. Therefore, clinicians are faced with challenges in situations where high inhibition of platelets is necessary and in cases where the response to clopidogrel may be suboptimal. There are various ways of overcoming the response variability and this review will focus on the practical methods available. Namely, the data and evidence regarding increasing the dose of clopidogrel, adding cilostazol to standard dual antiplatelet therapy, and switching to more recently developed agents will be covered. PMID- 22240603 TI - Percutaneous transluminal pulmonary angioplasty for distal-type chronic thromboembolic pulmonary hypertension. PMID- 22240604 TI - Guidelines for risks and prevention of sudden cardiac death (JCS 2010): - digest version -. PMID- 22240606 TI - Critical role of CD4(+)CD25(+) regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia. AB - Autoimmune response suppression by regulatory T cells (Tregs) helps to maintain peripheral immune tolerance, and defects in this mechanism are thought to play a role in the pathogenesis of various autoimmune diseases. In patients with immune thrombocytopenia, naturally occurring CD4(+)CD25(+) Tregs are both functionally impaired and reduced in number. This study was undertaken to investigate Tregs' role in preventing immune thrombocytopenia in mice. Treg-deficient mice were prepared by inoculation of Treg-depleted CD4(+)CD25(-) T cells isolated from BALB/c mice into syngeneic nude mice intravenously. Platelet count, proportion of reticulated platelets, platelet-associated IgG, platelet-associated anti-platelet antibodies, and IgG anti-platelet antibody production in splenocyte cultures were examined by flow cytometry. Of 69 Treg-deficient mice, 25 (36%) spontaneously developed thrombocytopenia that lasted at least 5 weeks. The platelet-associated IgG level and proportion of reticulated platelets were elevated in the thrombocytopenic mice. Platelet eluates and splenocyte culture supernatants prepared from thrombocytopenic mice, but not from nonthrombocytopenic mice, contained IgG antibodies capable of binding to intact platelets. Simultaneous transfer of Tregs completely prevented the onset of thrombocytopenia, but Treg transfer after the onset of thrombocytopenia had no apparent effect. Treatment with IgG anti-cytotoxic T lymphocyte-associated antigen 4 antibody canceled this Treg-governed suppressive effect. In summary, these results indicate that Tregs play a critical role in preventing murine autoantibody-mediated thrombocytopenia by engaging cytotoxic T lymphocyte-associated antigen 4. PMID- 22240607 TI - Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through beta-catenin signaling. AB - Sonic hedgehog (Shh) signaling plays an important role in many human cancers and cancer stem cells. Here we investigate the activity and functional role of Shh signaling in chronic myeloid leukemia (CML) and leukemia progenitor cells. Differential activation of Shh signaling was found in about 50% CML chronic phase samples, about 70% of CML accelerated phase samples, and >80% CML blast crisis phase samples. Deregulated activation of Shh signaling was observed in CD34(+) and c-kit(+) leukemia progenitor cells. Stimulation of Shh signaling with exogenous Shh peptide induced expansion of CD34(+) and c-kit(+) progenitor cells (p < 0.05), inversely, blocking the pathway with signal inhibitor induced cell apoptosis (p < 0.05). Low level of Shh protein was observed in CML bone marrow stromal cells, and CD34(+) progenitor cells are less sensitive to exogenous Shh peptide and more sensitive to cyclopamine than CD34(-) cells (p < 0.05), implying cell-autonomous activation of Shh signaling play a predominant role in progenitor cells. Coactivation of Shh and beta-catenin signaling was found in CD34(+) and c kit(+) progenitor cells. Administration of Shh-neutralizing antibody or Wnt3a neutralizing antibody in c-kit(+) progenitor cells induced cell apoptosis; however, Wnt3a peptide could salvage cell apoptosis, while Shh peptide failed to revert anti-Wnt3a-induced cell apoptosis. C-MYC, GLI1, BCL-2, and P21 were also found to be downstream targets of Shh signaling, mediating apoptosis or G(2)/M cell cycle arrest of progenitor cells. Our results demonstrate that autoactivated Shh signaling provides survival and proliferative cues in CML progenitor cells through downstream beta-catenin signaling, suggesting a novel therapeutic approach in CML. PMID- 22240608 TI - alpha-Tocopherol succinate- and AMD3100-mobilized progenitors mitigate radiation induced gastrointestinal injury in mice. AB - The goal of this study was to elucidate the role of alpha-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating the ionizing-radiation induced gastrointestinal syndrome in mice. We demonstrate the efficacy of a bridging therapy that will allow the lymphohematopoietic system of severely immunocompromised victims exposed to ionizing radiation to recover from high doses of radiation. CD2F1 mice were irradiated with a high dose of radiation causing gastrointestinal syndrome (11 Gy, cobalt-60 gamma-radiation) and then transfused intravenously (retro-orbital sinus) with whole blood or peripheral blood mononuclear cells (PBMC) from TS- and AMD3100-injected mice 2, 24, or 48 hours post irradiation and monitored for 30-day survival. Jejunum sections were analyzed for tissue area, surviving crypts, villi, mitotic figures, and basal lamina enterocytes. Our results demonstrate that infusion of whole blood or PBMC from TS- and AMD3100-injected mice significantly improved survival of mice receiving a high dose of radiation. Histopathology and immunostaining of jejunum from irradiated and TS- and AMD3100-mobilized PBMC-transfused mice reveal significant protection of gastrointestinal tissue from radiation injury. We demonstrate that TS and AMD3100 mobilize progenitors into peripheral circulation and that the infusion of mobilized progenitor-containing blood or PBMC acts as a bridging therapy for immune-system recovery in mice exposed to high, potentially fatal, doses of ionizing radiation. PMID- 22240609 TI - ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34(+) CD38(-) population to imatinib. AB - Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients. PMID- 22240610 TI - Complete neurological recovery after systemic air embolism during endoscopic retrograde cholangiopancreatography. AB - Systemic air embolisms are a rare but often a fatal complication of endoscopic retrograde cholangiopancreatography (ERCP). Only few cases have been reported in scientific studies. This paper concerns a case of a systemic air embolism that occurred during endoscopic sphincterotomy for gallstone removal in a 79-year-old woman and discusses possible mechanisms. The basic vital and neurologic signs of the woman deteriorated abruptly towards the end of the procedure. It was believed to be an air embolism and an urgent transthoracic echocardiography was ordered which confirmed the etiological diagnosis. Supportive measures were initiated: she was administered 100% oxygen, she was placed head down, left lateral position and fluid resuscitation was started to increase venous pressure. We considered hyperbaric oxygen therapy for neurological injury but, despite the severe initial presentation, she had a complete clinical recovery with only conservative treatment. Present experience stresses the importance of the awareness of this uncommon complication: a close vigilance of the anesthetists during ERCP is critical to ensure early diagnosis and a timely intervention. PMID- 22240611 TI - Immunonutrition in the surgical patient. AB - Both malnutrition and the physical injury related to trauma and surgery increase the expression of T-helper 2 (Th2) lymphocytes which cause impaired cell mediated immunity. Activation of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system with the release of cortisol and catecholamines drive the development of Th2 cells. Th2 cytokines result in the accumulation of arginase-1 expressing myeloid-derived suppressor cells in lymphoid tissue. The myeloid derived suppressor cells cause an arginine deficient state resulting in impaired lymphocyte function. Prostaglandin-E2 released following trauma plays a synergetic role with cortisol and catecholamines in driving these pathways. There is now increasing evidence that immunomodulating enteral formulas supplemented with arginine and omega-3 fatty acids can reverse many of the immune mediated changes and decrease the number of adverse outcomes after major surgery and trauma. These immunomodulating enteral formulas should be strongly considered in surgical patients undergoing major surgery and following severe trauma. PMID- 22240612 TI - Recent vitamin D and sepsis. PMID- 22240613 TI - What would you do if you do not have a pediatric self-inflating bag? PMID- 22240614 TI - Neuromuscular patients as candidates for non invasive ventilation during the weaning process. PMID- 22240615 TI - Effect of three different doses of ketamine prior to general anaesthesia on postoperative pain following Caesarean delivery: a prospective randomized study. AB - BACKGROUND: Ketamine is an analgesic suitable for the induction of anesthesia during Caesarean delivery. This double blind, randomized trial examined the effect of intravenous ketamine used before the induction of general anesthesia on morphine consumption, immediate and long term postoperative pain after Cesarean delivery. METHODS: One hundred and forty term pregnant women undergoing elective Cesarean delivery were randomized into four groups (N.=35 each), placebo (0.9% normal saline), ketamine 0.25, 0.5, or 1 mg kg(-1) intravenously. In all patients 2-2.5 mg kg(-1) propofol was used for the induction of anesthesia, 0.6 mg kg(-1) rocuronium to facilitate the tracheal intubation and 50% oxygen in N2O and sevoflurane (end-tidal concentration of 1.2-1.3 %) for the maintenance of anesthesia. Postoperative analgesia was provided with intravenous morphine chloride patient-controlled analgesia (PCA) and rescue analgesia with intramuscular diclofenac sodium in the postoperative period. Apgar scores of the neonates and hemodynamic variables of the mothers were recorded during anaesthesia. Groups were compared regarding the cumulative morphine consumption and pain scores assessed with a numerical rating (0-10) scale at 2, 6, 12, 18, 24, and 48 h postoperatively. Postoperative side effects were recorded. Patients were evaluated for persistent postoperative pain at 2 weeks, 1 and 6 months, and 1 year. RESULTS: The cumulative morphine consumption at 48 hours after the surgery was the primary outcome of the study. There was no significant difference in terms of acute pain at 2 (P=0.3), 6 (P=0.7), 12 (P=0.4), 18 (P=0.4), 24 (P=0.8), and 48 (P=0.5) hours postoperatively. Cumulative morphine consumption obtained at 2 (P=0.9), 6 (P=0.5), 12 (P=0.4), 18 (P=0.4), 24 (P=0.1), and 48 (P=0.2) hours was also similar among the groups. Prolonged postoperative pain evaluated 2 weeks (P=0.3), 1 month (P=0.7), 6 months (P=0.1) and 1 year (P=0.3) after the operation was also similar among the groups. There was no significant difference in side effects among the groups during the postoperative 48 hours. Apgar scores at 1 min (P=0.5) and 5 mins (P=0.5) were similar among the groups. Maternal intraoperative hemodynamic parameters were similar among the groups. CONCLUSION: There was no difference regarding early and late postoperative pain and morphine consumption with ketamine at doses of 0.25, 0.5, and 1 mg kg(-1) in women undergoing Caesarean delivery under general anaesthesia, compared with the control group. PMID- 22240616 TI - Sedation in the intensive care unit. AB - Analgesics and sedatives are commonly prescribed in the ICU environment for patient comfort, however, recent studies have shown that these medications can themselves lead to adverse patient outcomes. Interventions that facilitate a total dose reduction in analgesic and sedative medications e.g. the use of nurse controlled protocol guided sedation, the combination of spontaneous awakening and breathing trials, and the use of short acting medications, are associated with improved outcomes such as decreased time of mechanical ventilation and ICU length of stay. This purpose of this review is to provide an overview of the pharmacology of commonly prescribed analgesics and sedatives, and to discuss the evidence regarding best prescribing practices of these medications, to facilitate early liberation from mechanical ventilation and to promote animation in critically ill patients. PMID- 22240617 TI - Ultrasound identification of nerve cords in the infraclavicular fossa: a clinical study. AB - BACKGROUND: This study aimed to analyze nerve trunk anatomy in the infraclavicular fossa and to correlate these data with the most common anthropometric parameters. METHODS: A Mylab 30 Gold (Esaote) and the linear transducer LA523 (7.5 MHz frequency) were used. The probe was oriented according to a parasagittal plane, parallel to the lateral chest wall and immediately medial to the coracoid process underneath the clavicle. Measurements included the distance between the artery and the cutaneous surface (mm) and the apical corner of the ultrasound image (mm), the number of identified nervous cords and their position related to the axillary artery, and the position and number of axillary veins. Sex, age, height, weight, body mass index (BMI), biceps girth, and breast size were recorded. Statistical analysis included calculation of linear Pearson correlation coefficient and Student's t test. RESULTS: Two hundred and two consecutive patients were enrolled. The position of the three cords was highly variable around the artery. In a small but significant percentage of patients (8.9%), the medial and the lateral cords were located together at the top of the artery. The visibility of the trunks and the distance between the upper part of the artery and the apical corner of the ultrasound image correlated with anthropometric characteristics. The vein position with respect to the artery and nerves was markedly variable. CONCLUSION: Sono-anatomic study of the infraclavicular region adds important data that is useful when conducting nerve blocks to improve safety and likelihood of success. PMID- 22240618 TI - Use of pulse pressure variation to estimate changes in preload during experimental acute normovolemic hemodilution. AB - BACKGROUND: Acute normovolemic hemodilution (ANH) is an alternative to blood transfusion in surgeries involving blood loss. This experimental study was designed to evaluate whether pulse pressure variation (PPV) would be an adequate tool for monitoring changes in preload during ANH, as assessed by transesophageal echocardiography. METHODS: Twenty-one anesthetized and mechanically ventilated pigs were randomized into three groups: CTL (control), HES (hemodilution with 6% hydroxyethyl starch at a 1:1 ratio) or NS (hemodilution with saline 0.9% at a 3:1 ratio). Hemodilution was performed in animals of groups NS and HES in two stages, with target hematocrits 22% and 15%, achieved at 30-minute intervals. After two hours, 50% of the blood volume withdrawn was transfused and animals were monitored for another hour. Statistical analysis was based on ANOVA for repeated measures followed by multiple comparison test (P<0.05). Pearson's correlations were performed between changes in left ventricular end-diastolic volume (LVEDV) and PPV, central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP). RESULTS: Group NS received a significantly greater amount of fluids during ANH (NS, 900 +/- 168 mL vs. HES, 200 +/- 50 mL, P<0.05) and presented greater urine output (NS, 2643 +/- 1097 mL vs. HES, 641 +/- 338 mL, P<0.001). Significant decreases in LVEDV were observed in group NS from completion of ANH until transfusion. In group HES, only increases in LVEDV were observed, at the end of ANH and at transfusion. Such changes in LVEDV (?LVEDV) were better reflected by changes in PPV (?PPV, R=-0.62) than changes in CVP (?CVP, R=0.32) or in PAOP (?PAOP, R=0.42, respectively). CONCLUSION: Changes in preload during ANH were detected by changes in PPV. ?PPV was superior to ?PAOP and ?CVP to this end. PMID- 22240619 TI - Usefulness of an anesthetic conserving device (AnaConDaTM) in sevoflurane anesthesia. AB - BACKGROUND: The anesthetic conserving device (AnaConDaTM) is a disposable vaporizer that can save consumption of inhalational anesthetic used in low sevoflurane concentration. This study was performed to investigate whether AnaConDa when used at high sevoflurane concentration (1.5% to 2.0%) could save sevoflurane consumption and hasten emergence from anesthesia without any adverse effects. METHODS: Thirty patients for ear surgery were equally divided into AnaConDa and control groups. Anesthesia was induced with intravenous anesthetics. After intubation sevoflurane inhalation started by infusion at 25 mL/h in the AnaConDa group and by inhalation of 2.0% (conventional vaporizer setting) in the control group. During anesthesia, end-tidal sevoflurane concentration was kept between 1.5 and 2.0% in both groups. The time to first detection of end-tidal sevoflurane, the time to sevoflurane concentration reached 1.5%, sevoflurane consumption, and emergence time were compared between the two groups. Adverse effects were checked. RESULTS: Sevoflurane consumption was smaller, time to first detection of end-tidal sevoflurane was longer, time to sevoflurane concentration reached 1.5% was longer, emergence time was shorter, and decrease of end-tidal sevoflurane concentration after stop of administration was faster in the AnaConDa group significantly. Clear Water accumulation with no smell in the filter was observed in 12 of 15 patients in the AnaConDa group. CONCLUSION: In general anesthesia with sevoflurane 1.5% to 2.0%, AnaConDa could save sevoflurane consumption and fasten emergence from anesthesia compared to conventional vaporizer, while water accumulation in the filter should be cautioned. PMID- 22240620 TI - The optimal effect site concentration of remifentanil in combination with intravenous midazolam and topical lidocaine for awake fibreoptic nasotracheal intubation in patients undergoing cervical spine surgery. AB - BACKGROUND: Remifentanil has been suggested as a suitable agent for conscious sedation during fibreoptic intubation. We evaluated the optimal effect site concentration (Ce) of remifentanil target-controlled infusion (TCI) for awake nasotracheal fibreoptic intubation in patients undergoing elective cervical spine surgery. METHODS: Nineteen ASA I-II patients were enrolled. Patients were premedicated with midazolam (<70 kg 1.5 mg; >70 kg 2.0 mg) intravenously. The EC(50) and EC(95) of remifentanil Ce for smooth intubation were determined using Dixon's up-and-down method and isotonic regression. Smooth intubation was considered to have failed when patients exhibited sustained and repetitive coughing with head lift during the procedure. Intubation time, number of attempts, adverse events, and hemodynamic variables were also recorded. Patients were asked to recall the procedure and grade satisfaction at postoperative 24 h. RESULTS: The EC(50) of remifentanil Ce for smooth intubation was 2.33+/-0.38 ng.mL-1 as calculated by Dixon's method. The estimated EC(95) of remifentanil Ce was 3.38 (95% confidence interval 2.90-3.46) ng.mL-1. Median intubation time (min) was longer in failed smooth intubation than in smooth intubation (8.0 vs. 6.1, P=0.048). Eleven patients (58%) recalled the procedure and 16 patients (84%) rated their satisfaction score as good or excellent. CONCLUSION: The estimated EC(95) of remifentanil Ce for smooth nasotracheal fibreoptic intubation with conscious sedation was 3.38 (95% CI 2.90-3.46) ng.mL-1 when used in combination with midazolam and topical lidocaine. Remifentanil TCI may provide a tolerable experience of awake fibreoptic intubation despite the high incidence of recall. PMID- 22240621 TI - Influence of continuous renal replacement therapy on cardiac output measurement using thermodilution techniques. AB - BACKGROUND: Acute renal failure (ARF) ranks among the most frequent complications in critically ill patients and continuous renal replacement therapy (CRRT) is a typical treatment regimen in intensive care patients. Contributing factors to ARF, such as septic shock and hemodynamic instability require extended hemodynamic monitoring, and the simultaneous use of CRRT and cardiac output measurement is common. In view of this, a systematic analysis of the interaction between CRRT and cardiac output measurements by thermodilution is warranted. Cardiac output (CO) is commonly measured with thermodilution-based methods in critically ill patients. The methods are accurate but the measurements are affected by inconstant indicator volumes or changes in blood temperature. Because continuous renal replacement therapy (CRRT) may alter blood volume and temperature, we investigated its effect on thermodilution-based CO measurement. METHODS: Thirty-two intensive care patients with both CRRT and CO monitoring were studied. Hemodynamic parameters were first measured in quintuple with bolus injections of cold saline during CRRT. Further five measurements were performed after CRRT had been shut off, and a final five measurements were performed after it had been restarted. Fifty measurement series were performed in patients with a pulmonary artery catheter and 25 in patients using a transpulmonary thermodilution method (PiCCO(r)). RESULTS: The first measurements in each series after switching CRRT off or on deviated most markedly from the average. When these measurements were excluded, the averaged CO values with and without CRRT differed significantly but by <7% (P<0.05). CONCLUSION: Substantial measurement error was only observed immediately after CRRT was switched off or on. Subsequent CO measurements did not depend on the CRRT status. Interrupting CRRT before measuring CO is not generally recommended, however, if interrupted, it is crucial to wait for blood temperature to reach a steady state before initiating the first measurements. PMID- 22240622 TI - Impact of the European Paediatric Life Support course on knowledge of resuscitation guidelines among Austrian emergency care providers. AB - BACKGROUND: Even though anaesthetists do not resuscitate children on a daily basis, they need to perform paediatric life support regularly due to their different duties. As the knowledge of international guidelines varies widely, highly standardized European Paediatric Life Support (EPLS) courses have been introduced to improve standards of care. This national survey among Austrian anaesthetists and EPLS course participants evaluated the impact of this course at the end of the guideline period 2005-2010. METHODS: After approval by the institutional review board an online survey about paediatric resuscitation guidelines was sent to EPLS course participants of the guideline period 2005 (EPLS group) and members of the Austrian Society of Anaesthesia, Resuscitation and Intensive Care (OGARI) two weeks before publication of the resuscitations guidelines 2010. Respondents without an EPLS course were assigned to the non-EPLS group. RESULTS: Of 333 respondents 247 finished the survey. One hundred eighty five persons were assigned to EPLS group and 62 to the non-EPLS group. Members of the EPLS group performed significantly better than the non-EPLS group (76 +/- 19% correct answers EPLS group vs. 63 +/- 18% correct answers non-EPLS group, p<0.0001). Furthermore, the EPLS group performed better than anesthetists with regular resuscitation training and or resuscitation experience but without an EPLS course. CONCLUSION: The attendance of an EPLS course within the guideline period 2005 significantly increased the theoretical knowledge of paediatric resuscitation guidelines. PMID- 22240623 TI - Successful treatment of a folliculotropic mycosis fungoides with bexarotene and PUVA. PMID- 22240624 TI - Multiple sclerosis: a chronic infective cerebrospinal venulitis? AB - The aetiology proposed for the development of chronic cerebrospinal venous insufficiency (CCSVI) associated with multiple sclerosis (MS) has been the presence of congenital truncular venous malformations. However, this hypothesis is not consistent with the epidemiology or geographical incidence of MS and is not consistent with many of the ultrasonographic or radiographical findings of the venous disturbances found in MS patients. However, the probability of a venous aetiology of MS remains strong based on evidence accumulated from the time the disorder was first described. The method used in this review was to search PubMed for all past medical publications related to vascular, venous, haematological, epidemiological, biochemical, and genetic investigations and treatments of MS. Epidemiological and geographical findings of prevalence of MS indicate the involvement of an infective agent. This review of the venous pathology associated with MS describes a hypothesis that the pathogenesis of the venous disease could be initiated by a respiratory infective agent such as Chlamydophila pneumonia, which causes a specific chronic persistent venulitis affecting the cerebrospinal venous system. Secondary spread of the agent would initially be via the lymphatic system to specifically involve the azygos, internal jugular and vertebral veins. The hypothesis proposes mechanisms by which an infective venous vasculitis could result in the specific neural damage, metabolic, immunological and vascular effects observed in MS. The hypothesis described is consistent with many of the known facts of MS pathogenesis and therefore provides a framework for further research into a venous aetiology for the disease. If MS does result from a chronic infective venulitis rather than a syndrome involving congenital truncular venous malformations, then additional therapies to the currently used angioplasties will be required to optimize results. PMID- 22240626 TI - Mucosal immunology: Multifunctional gut IgA+ plasma cells. PMID- 22240627 TI - Black humour in health care: a laughing matter? PMID- 22240628 TI - Genetics and its relevance to palliative nursing practice. PMID- 22240625 TI - Early immune events in the induction of allergic contact dermatitis. AB - The skin is a barrier site that is exposed to a wide variety of potential pathogens. As in other organs, pathogens that invade the skin are recognized by pattern-recognition receptors (PRRs). Recently, it has been recognized that PRRs are also engaged by chemical contact allergens and, in susceptible individuals, this elicits an inappropriate immune response that results in allergic contact dermatitis. In this Review, we focus on how contact allergens promote inflammation by activating the innate immune system. We also examine how innate immune cells in the skin, including mast cells and dendritic cells, cooperate with each other and with T cells and keratinocytes to initiate and drive early responses to contact allergens. PMID- 22240629 TI - The Liverpool Care Pathway provides clarity and focus; communication, care, and compassion come from you. PMID- 22240630 TI - Improving practice using action research: resolving the problem of kinking with non-metal cannulae. AB - In one UK hospice, inpatient unit records showed that over 8 years 12 needlestick injuries related to continuous subcutaneous infusion of medication occurred. Following a change-over to Teflon cannulae no further incidents were reported. However, when the more sensitive and accurate McKinley T34 syringe drivers were introduced in 2007 a new problem of recurrent occlusion alarm sounding manifested. Investigation revealed that the Teflon cannulae were often kinking, delaying medication delivery and necessitating re-siting of the cannula. The action research approach was used to find an alternative device to improve practice and ensure that both staff and patients were safeguarded. This paper explains how that process was followed until a satisfactory alternative was sourced and evidenced, including an account of the problems that were experienced along the way. PMID- 22240631 TI - Evaluating the impact of nurse independent prescribing in a weekend clinical nurse specialist service. AB - Nurse independent prescribing (NIP) is having a significant positive impact on patient care, yet little is written about NIP initiatives in the out-of-hours (OOH) period, which is a critical time for those with palliative care needs who wish to remain at home. This paper evaluates the impact of an NIP initiative in one weekend clinical nurse specialist (CNS) service in the UK. A 6-month audit of prescribing activity data is presented along with the results of a survey of local GPs. The paper concludes that NIP offers an effective way for the CNS working in the OOH period to offer timely and appropriate symptom control in a single, seamless consultation. Discussion surrounds the factors that affect the success of NIP initiatives and practical recommendations for other providers developing such a service. PMID- 22240632 TI - Identifying, documenting, and reviewing preferred place of death: an audit of one UK hospice. AB - BACKGROUND: Current UK health-care policy suggests that good end-of-life care includes choosing a place for death. This paper examines the extent to which patients' preferred place of death (PPD) is identified, documented, and reviewed in one UK hospice. METHOD: A total of 150 case notes were audited using a data capture form. Case notes of patients who died in January 2008 (n=50), January 2009 (n=50), and January 2010 (n=50) were accessed during September-November 2010. The data are presented using descriptive statistics. RESULTS: PPD was documented in 28 cases (18.6%), conversations about end-of-life preferences were documented in 16 cases (10.6%), and preferences were reviewed in 6 cases (4%). Of the 28 patients whose preferences were documented, 25 (89.2%) died in their stated place of choice. CONCLUSIONS: Rates of PPD identification, documentation, and review were low at this hospice. This raises further research questions about how and why end-of-life choices are being made. PMID- 22240633 TI - Visiting all hours: a focus group study on staff's views of open visiting in a hospice. AB - St Columba's Hospice, Edinburgh, is a busy specialist palliative care unit with 30 inpatient beds. A previous publication reported the first strand of a qualitative exploratory study evaluating the impact of open visiting on patients at the hospice. This paper reports on the second strand, which sought to elicit the views of the hospice staff through focus group interviews. The main themes identified were valuing the family and friends as visitors, involving the family as part of the care team, patient powerlessness over visiting, shared rooms and their impact on visitors and patients, and the staff role as advocates or gatekeepers. Several strategies for developing a flexible and 'patient controlled' visiting policy were identified, including quiet times without visitors, restriction of visitor numbers in shared rooms, and encouraging breaks from visiting. Since the study was completed, the hospice's visiting policy has been modified to ensure that it is patient-centred and meets the needs of patients and families. PMID- 22240634 TI - Caring for children and families in the community: experiences of Irish palliative care clinical nurse specialists. AB - An increasing number of children require care at home owing to life-limiting illness. In addition, there is growing recognition of the specific care needs of such children and their families, and it is anticipated that recent developments in children's palliative care will result in more people accessing these services. In the Republic of Ireland (ROI), community palliative care clinical nurse specialists (CNSs), who are not registered children's nurses, contribute significantly to the support of these children and families. This study aimed to obtain a picture of the current nursing service that would help to determine whether the needs of these patients are being met. Seven community palliative care CNSs from across one health region in the ROI participated in a focus group. Four key themes emerged: gaining access to the child and family, role complexities, pressures of caring, and support strategies. Provision of community children's palliative care by the CNS is complex. The participants demonstrated their commitment to consult, coordinate, negotiate, and ultimately deliver the care required by children and families, but against a background of issues relating to accessing the patient and family, the complexity of the CNS role, and the pressures that such work incurs. PMID- 22240635 TI - Politics and palliative care: Italy. PMID- 22240636 TI - Pomegranate seed oil in women with menopausal symptoms: a prospective randomized, placebo-controlled, double-blinded trial. AB - OBJECTIVE: The aim of this study was to investigate the potential effects of pomegranate seed oil (PGS) on menopausal symptoms. METHODS: The prospective randomized, placebo-controlled, double-blinded trial was completed by 81 postmenopausal women, who received two daily doses of either 30 mg PGS containing 127 MUg of steroidal phytoestrogens per dose or a placebo for 12 weeks. The participants reported their number of hot flashes and completed the Menopause Rating Scale II at baseline and at weeks 4, 8, 12, and 24. At baseline and after 12 weeks, hormonal status was determined. RESULTS: After 12 weeks of treatment, PGS reduced the number of hot flashes per day by 4.3 (38.7%), whereas placebo reduced it by 2.5 (25.6%). Both groups were significant compared with baseline, but the treated group was not significant compared with the placebo group (P = 0.17). After 24 weeks, the treated group showed a mean of 7.1 (interquartile range, 4.0) hot flashes per day compared with the placebo group with a mean of 8.8 (interquartile range, 5.0; P = 0.02). Although the overall sum score of the Menopause Rating Scale II parameters at week 12 decreased in the treated group from 16.0 to 9.0 at week 12 and in the placebo group from 18.0 to 14.5 (P = 0.08), the sum score of the vegetative somatic symptoms subgroup decreased strongly versus placebo (P < 0.03), attributable mainly to an improvement in sleeping disorders. PGS did not affect the hormone status, and no adverse effects were reported. CONCLUSIONS: In postmenopausal women, PGS does not significantly reduce hot flashes within a 12-week observation period, but further studies are needed to investigate the long-term effect. PMID- 22240637 TI - Glucosamine-induced insulin resistance in ovariectomized rats is relevant to decreasing the expression of glucose transport protein subtype 4 in the skeletal muscle and in increasing the size of pancreatic islets. AB - OBJECTIVE: Glucosamine (GlcN) is a popular nutritional supplement used to treat osteoarthritis in postmenopausal women. Postmenopausal women are at higher risk of type 2 diabetes mellitus and metabolic syndrome because of ovarian hormone deficiency. We used ovariectomized (OVX) rats as the model to investigate whether GlcN would induce insulin resistance (IR) in OVX rats and the underlying mechanisms. METHODS: The rats were divided into four groups: (1) sham-operated group (SHAM), (2) SHAM with GlcN treatment (SHAM + GlcN), (3) OVX group, (4) OVX with GlcN treatment (OVX + GlcN). Intraperitoneal (IP) GlcN was given at 12 weeks after the surgical procedure for 2 weeks. The IP glucose tolerance test (IPGTT) was performed to measure plasma glucose and insulin and to calculate the clinical homeostasis model assessment-IR (HOMA-IR) and glucose-insulin index. Western blot analysis for the detection of glucose transport protein subtype 4 expression in the skeletal muscle and histopathological examination of the changes in pancreatic islets were also performed. RESULTS: Fasting plasma glucose increased in the OVX + GlcN group, and fasting plasma insulin and HOMA-IR were elevated more significantly in this group. In addition, plasma glucose, plasma insulin, HOMA-IR, and glucose-insulin index were significantly elevated only in the OVX with GlcN group after IP glucose injection, implying that IR was induced by GlcN only in female rats without the protection of ovarian hormone. In addition, we found that treatment with GlcN decreased the expression of glucose transport protein subtype 4 in the skeletal muscle and induced pancreatic islet hyperplasia only in OVX rats. CONCLUSIONS: The results demonstrate that female rats do not develop IR upon GlcN treatment except after ovariectomy. Those who take GlcN after menopause or bilateral oophorectomy should watch their blood glucose level closely, especially after meals. PMID- 22240638 TI - Relationship between bone turnover biomarkers, mandibular bone mineral density, and systemic skeletal bone mineral density in premenopausal and postmenopausal Indian women. AB - OBJECTIVE: Postmenopausal osteoporosis is one of the most common metabolic bone disorders. Osteoporosis is reported to cause bone loss in the alveolar processes of maxilla and mandible, which provide bony framework for tooth anchorage. However, the association between systemic osteoporosis and oral health remains controversial. Available evidence suggests that Indian women have lower peak bone mass than their Western/other Asian counterparts. The present study evaluated the relationship between mandibular bone mineral density (mBMD), systemic skeletal BMD, and bone metabolism in premenopausal and postmenopausal Indian women. METHODS: One hundred twenty-four premenopausal and 247 postmenopausal healthy women were included in the study. The BMD of the body of mandible, radius ultradistal, total hip, femur neck, and lateral spine were measured using dual energy x-ray absorptiometry. Serum and urine biomarkers were determined using commercial kits. RESULTS: Univariate regression analysis followed by stepwise multivariate regression analysis to obtain the best fit model demonstrated the BMD of radius ultradistal, serum inorganic phosphorus, estradiol, and sex hormone binding globulin as significant predictors of mBMD in premenopausal women. The BMD of femur neck, serum ionized calcium, bone-specific alkaline phosphatase, osteocalcin, and urine total pyridinoline were significantly associated with mBMD in postmenopausal women. The significant association between mBMD and number of teeth present was observed in the whole group of premenopausal and postmenopausal women. CONCLUSIONS: Varied predictors of mBMD were observed in premenopausal and postmenopausal women. The results suggest that the screening for these biomarkers and serum ionized calcium should be useful (1) to assess the status of mBMD particularly in women requiring surgical dental intervention that include bone manipulation and (2) for early detection and management of women with the risk of developing osteoporosis. PMID- 22240639 TI - Pushing the envelope: living donor pancreas transplantation. AB - PURPOSE OF REVIEW: More than 160 living donor segmental pancreas/islet transplants have been done since the first in 1977, more than three-quarters at one institution. We review this three-decade experience to project future application. Initially, living donor pancreas transplants were done because the results with deceased donors were poor. As the results with deceased donors improved, the incentive to do living donor transplants declined but never disappeared. A living donor simultaneous pancreas-kidney transplant in a uremic diabetic can correct diabetes and pre-empt dialysis with one operation, obviating the high mortality rate of waiting for a deceased donor. Solitary pancreas transplant candidates with preformed human leukocyte antigen antibodies but a negative cross match to a living donor volunteer also benefit. RECENT FINDINGS: The technical failure rate of living donor pancreas transplants was high in the initial cases (>1/3), nearly double that for deceased donors, but has since declined to nearly zero. Living donor segmental pancreatectomy has little surgical morbidity (currently done laparoscopically) with only a small risk for diabetes by strict selection criteria. living donor and deceased donor graft survival rates are equivalent. Islet allografts have been done from three living donors, the last one successfully, showing the potential for further application. SUMMARY: The incentives for living donor transplants are to eliminate long-wait times for a deceased donor organ and to improve outcomes. With both the incentive is high, but either by itself is sufficient. As the number of pancreas transplant candidates increase, so will wait times for a deceased donor organ. For this reason, living donor pancreas/islet transplant volume will likely increase in the years to come. PMID- 22240640 TI - Current world literature. PMID- 22240643 TI - Correction. PMID- 22240644 TI - Correction. PMID- 22240645 TI - Correction. PMID- 22240646 TI - Accuracy of LightCycler(R) SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review protocol. AB - Background There is growing interest in the potential utility of molecular diagnostics in improving the detection of life-threatening infection (sepsis). LightCycler(r) SeptiFast is a multipathogen probe-based real-time PCR system targeting DNA sequences of bacteria and fungi present in blood samples within a few hours. We report here the protocol of the first systematic review of published clinical diagnostic accuracy studies of this technology when compared with blood culture in the setting of suspected sepsis. Methods/design Data sources: the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA), the NHS Economic Evaluation Database (NHSEED), The Cochrane Library, MEDLINE, EMBASE, ISI Web of Science, BIOSIS Previews, MEDION and the Aggressive Research Intelligence Facility Database (ARIF). STUDY SELECTION: diagnostic accuracy studies that compare the real-time PCR technology with standard culture results performed on a patient's blood sample during the management of sepsis. DATA EXTRACTION: three reviewers, working independently, will determine the level of evidence, methodological quality and a standard data set relating to demographics and diagnostic accuracy metrics for each study. Statistical analysis/data synthesis: heterogeneity of studies will be investigated using a coupled forest plot of sensitivity and specificity and a scatter plot in Receiver Operator Characteristic (ROC) space. Bivariate model method will be used to estimate summary sensitivity and specificity. The authors will investigate reporting biases using funnel plots based on effective sample size and regression tests of asymmetry. Subgroup analyses are planned for adults, children and infection setting (hospital vs community) if sufficient data are uncovered. Dissemination Recommendations will be made to the Department of Health (as part of an open access HTA report) as to whether the real-time PCR technology has sufficient clinical diagnostic accuracy potential to move forward to efficacy testing during the provision of routine clinical care. Registration PROSPERO-NIHR Prospective Register of Systematic Reviews (CRD42011001289). PMID- 22240647 TI - The longitudinal prevalence of MRSA in care home residents and the effectiveness of improving infection prevention knowledge and practice on colonisation using a stepped wedge study design. AB - Objectives To determine the prevalence and health outcomes of meticillin resistant Staphylococcus aureus (MRSA) colonisation in elderly care home residents. To measure the effectiveness of improving infection prevention knowledge and practice on MRSA prevalence. Setting Care homes for elderly residents in Leeds, UK. Participants Residents able to give informed consent. Design A controlled intervention study, using a stepped wedge design, comprising 65 homes divided into three groups. Baseline MRSA prevalence was determined by screening the nares of residents (n=2492). An intervention based upon staff education and training on hand hygiene was delivered at three different times according to group number. Scores for three assessment methods, an audit of hand hygiene facilities, staff hand hygiene observations and an educational questionnaire, were collected before and after the intervention. After each group of homes received the intervention, all participants were screened for MRSA nasal colonisation. In total, four surveys took place between November 2006 and February 2009. Results MRSA prevalence was 20%, 19%, 22% and 21% in each survey, respectively. There was a significant improvement in scores for all three assessment methods post-intervention (p<=0.001). The intervention was associated with a small but significant increase in MRSA prevalence (p=0.023). MRSA colonisation was associated with previous and subsequent MRSA infection but was not significantly associated with subsequent hospitalisation or mortality. Conclusions The intervention did not result in a decrease in the prevalence of MRSA colonisation in care home residents. Additional measures will be required to reduce endemic MRSA colonisation in care homes. PMID- 22240648 TI - Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau. AB - Objective Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%. Previous studies indicate that the effect of VAS may vary with vaccination status. The authors evaluated the effect of VAS provided in campaigns on child survival overall and by sex and vaccination status at the time of supplementation. Design Observational cohort study. Setting and participants The study was conducted in the urban study area of the Bandim Health Project in Guinea-Bissau. The authors documented participation or non-participation in two national vitamin A campaigns in December 2007 and July 2008 for children between 6 and 35 months of age. Vaccination status was ascertained by inspection of vaccination cards. All children were followed prospectively. Outcome measures Mortality rates for supplemented and non-supplemented children were compared in Cox models providing mortality rate ratios (MRRs). Results The authors obtained information from 93% of 5567 children in 2007 and 90% of 5799 children in 2008. The VAS coverage was 58% in 2007 and 68% in 2008. Mortality in the supplemented group was 1.5% (44 deaths/2873 person-years) and 1.6% (20 deaths/1260 person years) in the non-supplemented group (adjusted MRR=0.78 (0.46; 1.34)). The effect was similar in boys and girls. Vaccination cards were seen for 86% in 2007 and 84% in 2008. The effect of VAS in children who had measles vaccine as their last vaccine (2814 children, adjusted MRR=0.34 (0.14; 0.85)) differed from the effect in children who had diphtheria-tetanus-pertussis vaccine as their last vaccine (3680 children, adjusted MRR=1.29 (0.52; 3.22), p=0.04 for interaction). Conclusion The effect of VAS differed by most recent vaccination, being beneficial after measles vaccine but not after diphtheria-tetanus-pertussis vaccine. PMID- 22240649 TI - Acupuncture in practice: mapping the providers, the patients and the settings in a national cross-sectional survey. AB - Background There is relatively limited knowledge about the practitioners who provide acupuncture treatment within the UK, what conditions patients consult for and the treatment provided. Objectives To characterise the conditions treated and by whom, to examine characteristics of the treatment and to explore trends over time. Method A cross-sectional survey of the UK acupuncture practitioners was conducted; 800 practitioners were selected by computer-generated randomisation sequences from the four major UK-based professional associations. Data collected on the practitioners included demographic details, association membership, statutorily regulated status, practice setting, style of acupuncture, diagnostic methods and needle response sought. Practitioners recorded details of their 10 most recent patients, including demographic details, primary reason for consulting and lifestyle advice provided. Results 330 practitioners responded comprising doctors (29%) physiotherapists (29%), nurses (15%) and independent acupuncturists (27%): 62% were women with median age of 48 years. The majority (68%) practiced in independent settings and 42% practiced within the National Health Service. Patients most commonly consulted for low back, neck, shoulder and knee pain, as well as headaches and migraine. Treatment for infertility by independent acupuncturists was found to have increased fivefold in 10 years. Conclusion Acupuncture provides a substantial contribution to the healthcare of the UK, with an estimated 4 million sessions provided annually. The primary complaints for which patients consult reflect the growing evidence base on acupuncture for these conditions. These data provide a basis for decision-making regarding policy and practice. PMID- 22240650 TI - Eosinophils in the oesophageal mucosa: clinical, pathological and epidemiological relevance in children: a cohort study. AB - Objectives Eosinophilic oesophagitis (EO) shows eosinophilic infiltration of the mucosa and can present with symptoms indistinguishable from gastrooesophageal reflux disease (GORD). The authors describe the clinical, endoscopic and histopathological features of all cases of histological EO presenting during 2007 2008 with a 2-year follow-up. The incidence of paediatric EO and the features of a subgroup with features of both GORD and EO ('overlap' syndrome (OS)) are described. Design Biopsies with an average of 15 eosinophils/high-power field (HPF) were reviewed in the cohort. OS was suggested when there was coexistence of clinical and histological features of EO and GORD (abnormal pH study), which improved with proton pump inhibitors. Setting Tertiary care. Participants All cases with >=15 eosinophils/HPF entered the study. Primary outcome measures Patients with EO had an average of 15 eosinophils/HPF. Secondary outcome measures Other histological features of EO included microabscesses, dilated intercellular spaces, basal cell hyperplasia, papillary elongation, etc. Results 24 cases of EO were identified, 13 men and 11 women. The incidence of paediatric oesophageal eosinophilia in the region was 9/100 000 children. 11 of the 24 patients (46%) presented with some form of allergy, six with poor feeding/food aversion, five with dysphagia and four with vomiting. After follow-up, 56.5% were confirmed to have EO, 30.5% responded to treatment for GORD and were categorised as OS, 9% developed eosinophilic gastroenteritis and 4% did not have further upper gastrointestinal symptoms. Conclusions Accurate diagnosis of EO, especially the differentiation from GORD, requires appropriate clinicopathological correlation. A significant proportion of patients with eosinophilia in the mucosa also have GORD (OS). These patients improve after treating the underlying GORD. The study was registered as a Service Evaluation with the Trust (number SE74). PMID- 22240651 TI - Exposure to bisphosphonates and risk of cancer: a protocol for nested case control studies using the QResearch primary care database. AB - Introduction Bisphosphonates are becoming a common treatment for osteoporosis particularly after discovery of the association between hormone replacement therapy and increased risk of breast cancer. As osteoporosis develops with age, treatment is a long-term intervention. Randomised control trials typically have limited follow-up times, which restricts investigation of the effects of the drugs on risk of primary cancers. A few observational studies have demonstrated a reduced risk of breast cancer and possibly of endometrial cancer in bisphosphonate users. Two epidemiological studies have studied the effect of the drugs on oesophageal cancer but did not reach any definite conclusions. So far, no effects on colorectal and stomach cancer have been shown. This study will investigate the association of bisphosphonates with risks of the 10 most common primary cancers. Methods and analysis A series of nested case-control studies will be based on the general population using records from 660 UK general practices within the QResearch Database. Cases will be patients with primary cancers diagnosed between 1996 and 2011. Each case will be matched by age, sex, practice and calendar year to five controls, who are alive and registered with the practice at the time of diagnosis of the case. Exposure to bisphosphonates will be defined as at least one prescription during the study period. For the most common cancers with substantial numbers of observations, the effect of the duration of the treatment and different types of bisphosphonates will be studied. Conditional logistic regression will be applied to produce ORs adjusted for smoking status, socioeconomic status, ethnicity, cancer-specific co-morbidities and use of other medications. PMID- 22240652 TI - Addressing geographical variation in the progression of non-communicable diseases in Peru: the CRONICAS cohort study protocol. AB - Background The rise in non-communicable diseases in developing countries has gained increased attention. Given that around 80% of deaths related to non communicable diseases occur in low- and middle-income countries, there is a need for local knowledge to address such problems. Longitudinal studies can provide valuable information about disease burden of non-communicable diseases in Latin America to inform both public health and clinical settings. Methods The CRONICAS cohort is a longitudinal study performed in three Peruvian settings that differ by degree of urbanisation, level of outdoor and indoor pollution and altitude. The author sought to enrol an age- and sex-stratified random sample of 1000 participants at each site. Study procedures include questionnaires on socio demographics and well-known risk factors for cardiopulmonary disease, blood draw, anthropometry and body composition, blood pressure and spirometry before and after bronchodilators. All participants will be visited at baseline, at 20 and 40 months. A random sample of 100 households at each site will be assessed for 24 h particulate matter concentration. Primary outcomes include prevalence of risk factors for cardiopulmonary diseases, changes in blood pressure and blood glucose over time and decline in lung function. Discussion There is an urgent need to characterise the prevalence and burden of non-communicable diseases in low- and middle-income countries. Peru is a middle-income country currently undergoing a rapid epidemiological transition. This longitudinal study will provide valuable information on cardiopulmonary outcomes in three different settings and will provide a platform to address potential interventions that are locally relevant or applicable to other similar settings in Latin America. PMID- 22240653 TI - The effect of MELatOnin on Depression, anxietY, cognitive function and sleep disturbances in patients with breast cancer. The MELODY trial: protocol for a randomised, placebo-controlled, double-blinded trial. AB - Introduction Breast cancer represents about one-third of all cancer diagnoses and accounts for about 15% of cancer deaths in women. Many of these patients experience depression, anxiety, sleep disturbances and cognitive dysfunction. This may adversely affect quality of life and also contribute to morbidity and mortality. Melatonin is a regulatory circadian hormone having, among others, a hypnotic and an antidepressive effect. It has very low toxicity and very few adverse effects compared with the more commonly used antidepressants and hypnotics. Methods and analysis The objective of this double-blind, randomised, placebo-controlled trial is to investigate whether treatment with oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore, the authors will examine whether a specific clock-gene, PER3, is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction. The MELODY trial is a prospective double-blinded, randomised, placebo-controlled trial in which the authors intend to include 260 patients. The primary outcome is depressive symptoms measured by the Major Depression Inventory. The secondary outcomes are anxiety measured by a Visual Analogue Scale, total sleep time, sleep efficiency, sleep latency and periods awake measured by actigraphy and changes in cognitive function measured by a neuropsychological test battery. Tertiary outcomes are fatigue, pain, well-being and sleep quality/quantity measured by Visual Analogue Scale and sleep diary and sleepiness measured by the Karolinska Sleepiness Scale. The PER3 genotype is also to be determined in blood samples. PMID- 22240655 TI - Bilateral Bartholin's gland hematic cysts after cesarean delivery: an uncommon entity. PMID- 22240656 TI - Kinetics of oxidation of nitrosodisulfonate anion radical with a metallo superoxide. AB - The metal bound superoxide in MU-superoxo-bis[pentaamminecobalt(III)](5+) (1) oxidizes the nitrosodisulfonate anion radical (NDS(2-)) by two electrons. Oxidized NDS(2-) quickly decomposes to SO(4)(2-) and NO. 1 is itself reduced to the corresponding hydroperoxo complex which also decomposes fast to Co(ii), NH(4)(+) ions and oxygen. 1.5 moles of volatile products formed per mole of 1 mixed with excess NDS(2-). In the absence of superoxide in a bridged complex, e.g. the MU-amido-bis[pentaamminecobalt(III)](5+) complex fails to oxidize the nitroxyl radicals, NDS(2-), TEMPO and 4-oxo TEMPO. With excess NDS(2-) over 1, the reaction is first-order with respect to [1], [NDS(2-)] and inverse first order in [H(+)]. The activation entropy, DeltaS(?), is largely negative, increased ionic strength decreased the rate and a Bronsted plot is fairly linear with a negative slope. Oxidant MU-superoxo bis[(ethylenediamine)(diethylenetriamine)cobalt(III)](5+) has ligands sterically more crowded though more basic than ammonia in 1. It oxidizes NDS(2-) much more slowly. No solvent kinetic isotope effect (k(H(2)O/D(2)O)~ 1) could be seen; a spin-adduct formation by the conjugate base of 1 followed by electron transfer is postulated. PMID- 22240654 TI - Cancer risk with folic acid supplements: a systematic review and meta-analysis. AB - Objective To explore if there is an increased cancer risk associated with folic acid supplements given orally. Design Systematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer incidence and/or cancer mortality. Studies on folic acid fortification of foods were not included. Data sources Cochrane Library, Medline, Embase and Centre of Reviews and Dissemination, clinical trial registries and hand-searching of key journals. Results From 4104 potential references, 19 studies contributed data to our meta-analyses, including 12 randomised controlled trials (RCTs). Meta analysis of the 10 RCTs reporting overall cancer incidence (N=38 233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI 1.00 to 1.14) compared to controls. Overall cancer incidence was not reported in the seven observational studies. Meta-analyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI 1.03 to 1.49) for the men receiving folic acid compared to controls. No significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type. Total cancer mortality was reported in six RCTs, and a meta-analysis of these did not show any significant difference in cancer mortality in folic acid supplemented groups compared to controls (RR 1.09, 95% CI 0.90 to 1.30). None of the observational studies addressed mortality. Conclusions A meta-analysis of 10 RCTs showed a borderline significant increase in frequency of overall cancer in the folic acid group compared to controls. Overall cancer incidence was not reported in the seven observational studies. Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk. PMID- 22240663 TI - Autophagy provides nutrients for nonassimilating fungal structures and is necessary for plant colonization but not for infection in the necrotrophic plant pathogen Fusarium graminearum. AB - The role of autophagy in necrotrophic fungal physiology and infection biology is poorly understood. We have studied autophagy in the necrotrophic plant pathogen Fusarium graminearum in relation to development of nonassimilating structures and infection. We identified an ATG8 homolog F. graminearum ATG8 whose first 116 amino acids before the predicted ATG4 cleavage site are 100% identical to Podospora anserina ATG8. We generated a DeltaFgatg8 mutant by gene replacement and showed that this cannot form autophagic compartments. The strain forms no perithecia, has reduced conidia production and the aerial mycelium collapses after a few days in culture. The collapsing aerial mycelium contains lipid droplets indicative of nitrogen starvation and/or an inability to use storage lipids. The capacity to use carbon/energy stored in lipid droplets after a shift from carbon rich conditions to carbon starvation is severely inhibited in the DeltaFgatg8 strain demonstrating autophagy-dependent lipid utilization, lipophagy, in fungi. Radial growth rate of the DeltaFgatg8 strain is reduced compared with the wild type and the mutant does not grow over inert plastic surfaces in contrast to the wild type. The ability to infect barley and wheat is normal but the mutant is unable to spread from spikelet to spikelet in wheat. Complementation by inserting the F. graminearum atg8 gene into a region adjacent to the actin gene in DeltaFgatg8 fully restores the WT phenotype. The results showed that autophagy plays a pivotal role for supplying nutrients to nonassimilating structures necessary for growth and is important for plant colonization. This also indicates that autophagy is a central mechanism for fungal adaptation to nonoptimal C/N ratios. PMID- 22240664 TI - Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer. AB - Recent studies have suggested that dysregulation of autophagy plays a pivotal role in tumorigenesis. Here, we determined the prognostic value of autophagy related protein Beclin 1 in gastric cancer. A total of 153 primary gastric cancer patients were subjected to analysis of Beclin 1 expression and survival prognosis. Among them, 68 patients were assigned randomly and used as a training set to generate a cutoff score for Beclin 1 expression by receive operating characteristic (ROC) curve analysis. The ROC-generated cutoff score was subjected to analyze the association of Beclin 1 with clinical characteristics and patient outcome. In a testing set (n = 85) and overall patients (n = 153), both univariate and multivariate analysis found that low expression of Beclin 1 predicted adverse overall survival and progression-free survival for gastric cancer patients. Furthermore, in each stage of gastric cancer patients, Beclin 1 expression was a prognostic indicator in patients with stage II, III and IV. Importantly, a reverse relationship between Beclin 1 and Bcl-xL expression was demonstrated. In patients of elevated Bcl-xL expression, a subset with lower Beclin 1 expression displayed an inferior overall survival and progression-free survival than those with higher Beclin 1 expression. Thus, our data demonstrated that low expression of Beclin 1, associated with high Bcl-xL, played as an independent biomarker, contributing to a more aggressive cancer cell phenotype and poor prognosis for gastric tumor. PMID- 22240666 TI - Another fine mess. PMID- 22240665 TI - Lipopolysaccharide represses the expression of ATP-binding cassette transporter G1 and scavenger receptor class B, type I in murine macrophages. AB - OBJECTIVE AND DESIGN: To investigate the regulation of cholesterol transporters, including ATP-binding cassette transporter A1 (ABCA1), ABCG1 and scavenger receptor class B, type I (SR-BI), by inflammatory stimuli in macrophages. MATERIALS AND TREATMENTS: RAW 264.7 macrophages and mouse peritoneal macrophages were treated with inflammatory stimuli with or without rosiglitazone, a peroxisome proliferator activated receptor gamma (PPARgamma) agonist, or T0901317, a liver X receptor (LXR) agonist. METHODS: Real-time PCR and Western blotting for cholesterol transporters as well as cellular cholesterol efflux to high-density lipoprotein 2 (HDL(2)) were determined. RESULTS: In RAW 264.7 macrophages, lipopolysaccharide (LPS) significantly reduced ABCG1 and PPARgamma as well as cholesterol efflux to HDL(2). Rosiglitazone and T0901317 induced ABCA1 and ABCG1 several-fold, but LPS reduced only ABCG1. ABCG1 and SR-BI proteins, but not ABCA1, were decreased by LPS. In mouse peritoneal macrophages, LPS, tumor necrosis factor alpha and interleukin-1beta decreased ABCG1, SR-BI, LXRalpha and PPARgamma mRNA. The agonists increased ABC transporter expression but LPS reduced mRNA of T0901317-induced ABCA1 as well as basal and agonists-induced ABCG1. SR-BI protein was increased by rosiglitazone but LPS decreased the levels. CONCLUSION: The data suggest that inflammatory insults repress ABCG1 and SR-BI expression partly dependent on PPARgamma with a minimal effect on ABCA1 expression. PMID- 22240667 TI - Unfairness for mouth cancer patients. PMID- 22240668 TI - Sugar-coated dentistry. PMID- 22240669 TI - Subperiosteal implants. PMID- 22240670 TI - Disappointingly little evidence. PMID- 22240671 TI - Further NHS amazement. PMID- 22240672 TI - Not so hard to swallow. PMID- 22240685 TI - Contemporary dental practice in the UK: demographic details and practising arrangements in 2008. AB - OBJECTIVES: To determine, by postal questionnaire, the demographic profile and practising details of general dental practitioners in the UK in 2008. METHODS: A piloted 89 question postal questionnaire was distributed in 2007/2008 to 1,000 dentists, with effective addresses in the UK, whose names and addresses were obtained by random selection from the General Dental Council (GDC) register. RESULTS: Six hundred and ninety-one questionnaires were returned, of which 662 were useable - an acceptable 66% useable response rate. Of the respondents, 69% were male and 59% were practice principals. Fifty-three percent of the respondents' practices were in town or city centres with a wide geographic distribution. Single-handed practitioners accounted for 17% of respondents, with the mean number of dentists per practice being 3.6 (median 3.0). Typically, respondents' practices provided a mean of 26 patient care sessions per week, with each dentist treating on average 15 patients per session - 16 minutes per patient on average including surgery turnaround time, assuming 4 hour sessions. Hygienists typically treated seven patients per session - 34 minutes per patient on average including surgery turnaround time, assuming 4 hour sessions. Respondents stated that 57% of patients were treated under the NHS arrangements, with 28% being private, 7% independent and 7% insurance-based. Responses indicated that 73% of the respondents used a computerised patient management system, 67% had an internet connection and 60% used email, principally for correspondence, ordering materials and other uses such as referrals and research. Forty-five percent of respondents owned an intra-oral camera, with 45% of those using it routinely. Regarding new concepts, the use of nickel-titanium endodontic files (61%), digital imaging (28%) and zirconia all-ceramic bridgework (27%) were the most frequently cited innovations currently used by the respondents. Regarding the most notable changes in findings when compared with a related study conducted in 2000, these were connected to the method of payment with the proportion of NHS patients dropping to 57% compared with 86%; the volume of postgraduate education undertaken by dentists, with a 50% increase in the proportion of respondents having attended five or more courses each year (63% compared with 40% in 2000); and the use of zirconia all-ceramic bridgework (27% of respondents). CONCLUSIONS: The findings of the present study are considered to indicate increasing commercialism of dentistry in the UK, with evidence of many practitioners adopting new technologies, underpinned by substantial participation in postgraduate education. PMID- 22240686 TI - Current concepts on the management of tooth wear: part 1. Assessment, treatment planning and strategies for the prevention and the passive management of tooth wear. AB - The aim of this series of four articles on tooth wear management is to provide the reader with the necessary information in order to be able to successfully manage cases of tooth wear, regardless of the cause, severity and location of the wear pattern seen. The content will largely focus on contemporary clinical techniques, illustrated where possible by case examples. Emphasis will be placed on 'additive adhesive techniques' utilising fixed prosthodontic protocols; however, cases of tooth wear amongst partially dentate patients involving the use of removable prostheses will also be described. The importance of patient consent and contingency planning will also be discussed. Paper 1 will describe the assessment of the wear patient, including the rationale for the planning of dental care. Also discussed will be the administration of preventative and passive management strategies for cases displaying tooth wear. PMID- 22240691 TI - Summary of: Specialists' management decisions and attitudes towards mucositis and peri-implantitis. PMID- 22240692 TI - Summary of: the Kushida Index as a screening tool for obstructive sleep apnoea hypopnoea syndrome. PMID- 22240693 TI - A guide to entry into specialist training. AB - Dental graduates have a number of career pathways to choose from, one of which is to train as a specialist. It is sometimes difficult to obtain good advice on entering the specialist training process. This paper, aimed at recent dental graduates, gives an overview of what is required of applicants who wish to obtain a specialty registrar (StR) position in one of the 13 dental specialties recognised by the General Dental Council. The potential financial implications of specialist training are outlined, along with information on dental foundation training, MFDS and MJDF examinations and postgraduate degrees. The importance of gaining experience in clinical governance and research is outlined. Advice regarding the application process and interview technique is also included. It is the authors' intention that, having read this paper, recent dental graduates will have increased knowledge of the various career paths that lead to specialisation and those interested in specialising will have improved knowledge of how to begin their journey. PMID- 22240694 TI - Updated guidance on medical emergencies and resuscitation in the dental practice. AB - This article outlines the updated guidance relating to the management of medical emergencies in the dental practice. The incidence of medical emergencies in the dental practice is discussed. The key recommendations from the Resuscitation Council UK on the treatment of medical emergencies in the dental practice are listed, with specific reference to oxygen therapy, medications and automated external defibrillators. An overview to the professional responsibilities of dental practitioners and dental care professionals is provided. PMID- 22240713 TI - Specialists' management decisions and attitudes towards mucositis and peri implantitis. AB - BACKGROUND: Pathology of the peri-implant tissues, namely peri-implant mucositis and peri-implantitis are conditions that are often encountered and can threaten the long term survival of the implants. AIM: This study aimed to compare the attitudes of registered specialists in periodontology in Australia and the UK towards aetiology, prevalence, diagnosis and management of mucositis and peri implantitis. METHODS: A validated questionnaire was used and the sample consisted of UK and Australian specialists. RESULTS: There were differences in the demographics of specialists in the two countries, with the Australian specialists being significantly younger. Most specialists in both countries identified the prevalence of peri-implant pathology between 0-25%. Although there was agreement as to the role of plaque in the aetiopathogenesis of the diseases, UK specialists were more likely to include adverse loading and smoking as etiological factors. There were significant differences in the management of the disease between the groups, including the use of mouth rinses, local and systemic antibiotics. Australians were more likely to use systemic antibiotics than in the UK. CONCLUSIONS: The results suggested that differences in professional demographics, educational resources and market factors, and the absence of consensus treatment standards can significantly affect the treatment modalities patients finally receive. PMID- 22240714 TI - The Kushida Index as a screening tool for obstructive sleep apnoea-hypopnoea syndrome. AB - OBJECTIVES: To test the validity of the Kushida Index for screening for sleep apnoea in a West of Scotland adult population. METHODS: Specific intra-oral measurements and respiratory polysomnography were carried out on 71 patients in this prospective study. The intra-oral measurements were applied to the Kushida formula to obtain a value for the Kushida Index. This value was compared to the diagnosis obtained using polysomnography in the conventional manner. RESULTS: The sensitivity of the Kushida Index in this present study was 68% (95% CI 50-81) and the specificity was 71% (95% CI 52-84). The positive predictive value was 71% and the negative predictive value was 67%. The Mallampati score, Epworth sleepiness score and enlargement of the tongue, soft palate or tonsils were not statistically significantly related to a diagnosis of sleep apnoea (p >0.05). CONCLUSION: With the limited sensitivity and specificity of the Kushida Index demonstrated in this study, this test cannot be recommended as a screening tool for sleep apnoea in a West of Scotland population. PMID- 22240715 TI - Verbal episodic memory in 426 multiple sclerosis patients: impairment in encoding, retrieval or both? AB - Episodic memory is frequently impaired in multiple sclerosis (MS) patients but the exact nature of the disorder is controversial. It was initially thought to be due to a retrieval deficit but some studies have demonstrated an encoding deficit, which could be linked to a slowing of information processing speed or to a deficit in elaboration of strategies. The main objective of this study is to assess the prevalence and the nature of verbal episodic memory (VEM) impairment in MS patients. We retrieved memory performances of 426 patients [314 F-112 M; mean age: 46.1 years; median Expanded Disability Status Scale (EDSS) score: 3.1] from a neuropsychological data base. VEM was assessed using the 16 words RL-RI 16 test. 66% MS patients present at least one recall impaired in VEM (37.2% from 2 to 5 recall). 14.2% MS patients present an impairment in encoding phase. We observed that 5% of patients presented recognition difficulties. Correlations were observed between VEM performances and EDSS, and disease duration but no group effect (ANOVA) is observed between form of MS and VEM performances. These results confirm the high prevalence of VEM impairment in MS patients. Deficits affect mainly information retrieval in early stage MS patients and are then linked to encoding as disability increases. Storage disorders are infrequent, so cognitive rehabilitation with mental imaging could be effective in MS patients. PMID- 22240716 TI - Nocistatin and nociceptin modulate c-Fos expression in the mice thalamus. AB - Nocistatin and nociceptin/orphanin FQ (N/OFQ) are two neuropeptides which may have opposite effects in several biological functions but their neuro-anatomical sites of interaction are not fully clear. We investigated interaction between the effect of intracerebroventricular (i.c.v.) injection of nocistatin and N/OFQ, on c-Fos expression in the mouse thalamus, using c-Fos immunohistochemistry. We found that co-injection of nocistatin with N/OFQ significantly modulates c-Fos expression in the thalamus. The present study strongly suggests that "Nocistatin Nociceptin" interaction system in the thalamus may be the promising neuromodulatory sites in the investigation of unlocking their possible therapeutic circuit in nociception, memory and anxiety. PMID- 22240717 TI - A chemometrics approach for simultaneous determination of cyanazine and propazine based on a carbon paste electrode modified by a molecularly imprinted polymer. AB - In a completely rational and designed approach, simultaneous determination of cyanazine and propazine in environmental and food samples was performed using a molecularly imprinted polymer modified carbon paste electrode (MIP-CPE) and partial least squares. The MIP-CPE designed is based on the theoretical studies functioned as a selective recognition element and pre-concentrator agent for cyanazine and propazine. Fractional factorial and central composite designs were performed to recognize, and subsequently optimize, the variables affecting the cathodic stripping voltammetric currents for the analytes. The important variables were identified to be accumulation potential with optimum values of 0.45 and -0.44 V and pH with optimum values of 2.40 and 2.34 for cyanazine and propazine, respectively. Exploration of the overall optimum conditions for simultaneous determination of cyanazine and propazine resulted in accumulation potential of -0.44 V and pH of 2.4. Dynamic linear ranges of 0.05-9.00 MUmol L( 1) and 0.01-1.00 MUmol L(-1) and detection limits of 0.010 and 0.001 MUmol L(-1) were obtained for cyanazine and propazine, respectively. The results of the application of the proposed method on the simultaneous determination of cyanazine and propazine in foodstuffs and environmental samples were satisfactory. PMID- 22240719 TI - SRD5A3-CDG: a patient with a novel mutation. AB - Congenital disorders of glycosylation (CDG) are genetic diseases with an extremely broad spectrum of clinical presentations due to defective glycosylation of glycoproteins and glycolipids. Some 45 CDG types have been reported since the first clinical description in 1980. Protein glycosylation disorders are defects in protein N- and/or O-glycosylation. Dolichol phosphate is the carrier of the N glycan during their assembly first at the outside and subsequently at the inside of the endoplasmic reticulum (ER) membrane, and hence is a key molecule in protein glycosylation. Recently, defects have been identified in the last three steps of the dolichol phosphate biosynthesis: dolicholkinase deficiency (DK1 CDG), steroid 5alpha-reductase type 3 deficiency (SRD5A3-CDG), and dehydrodolichyl diphosphate synthase deficiency (DHDDS-CDG). We report on a patient with SRD5A3-CDG carrying a novel (homozygous) mutation. The diagnostic features of this novel inborn error of glycosylation are psychomotor retardation, nystagmus, visual impairment due to variable eye malformations, cerebellar abnormalities/ataxia, and often ichthyosiform skin lesions. PMID- 22240720 TI - Ghrelin levels increase after pictures showing food. AB - The neuropeptide ghrelin is a major signal for food intake in various species including humans. After exogenous ghrelin administration, food intake and body weight increase in rodents. In normal human subjects, ghrelin administration increases self-rated appetite and calorie intake and prompts the imagination of favorite meals. It is unclear so far whether ghrelin levels are affected by external cues such as sight of food. We investigated the influence of pictures showing food compared to neutral pictures on ghrelin levels in young normal male subjects (n = 8). The study consisted of two consecutive sessions with a one-week interval. During each session, blood for later analysis of plasma concentrations of ghrelin was collected between 08:15 and 13:00 every 15 min (between 10:30 and 11:30 every 10 min). Breakfast and lunch was provided at 08:30 and 12:00, respectively. Fifty pictures were presented from 10:30 to 10:45 showing neutral images during the first session and food contents during the second session. As expected, ghrelin levels increased before each meal independent of the picture contents. In addition, ghrelin levels during the 30-min interval following the presentation of pictures with food increased significantly compared to the 30-min interval before this presentation (area under the curve (AUC): 188 % vs. 158 %, P < 0.05). The difference in the increases between the two picture conditions was also significant (P < 0.05). Our findings suggest that sight of food elevates ghrelin levels in healthy volunteers. PMID- 22240722 TI - The size of large adipose cells is a predictor of insulin resistance in first degree relatives of type 2 diabetic patients. AB - Early studies reported that the size of adipose cells correlates with insulin resistance. However, a recent study comparing moderately obese, sensitive and resistant subjects, with comparable BMI (~30), did not detect any significant difference in the size of the large cells, but rather a smaller proportion of large cells in the resistant subjects, suggesting impaired adipogenesis. We hypothesize that a decreased proportion, rather than the size, of large adipose cells is also associated with insulin resistance in first-degree relatives of type 2 diabetic patients. Thirty-five leaner (BMI 18-34) subjects who were relatively healthy were recruited. Insulin sensitivity was measured by the euglycemic, hyperinsulinemic clamp. Needle biopsies of abdominal subcutaneous fat were assayed for adipose cell size by fitting the cell size distribution with two exponentials and a Gaussian function. The fraction of large cells was defined as the area of the Gaussian peak and the size of the large cells was defined as its center (c(p)). Glucose infusion rate (GIR) and c(p) were negatively correlated, but insulin sensitivity and the proportion of large cells were not correlated. BMI and c(p) were also strongly correlated, but a relationship of modest correlation between the cell size and insulin resistance was still significant after correcting for BMI. In contrast to moderately obese subjects, in the first degree relatives of type 2 diabetic patients both BMI and the size of the large adipose cells predict the degree of insulin resistance; no correlation is found between the proportion of large adipose cells and insulin resistance. PMID- 22240721 TI - Common variants in the CD36 gene are associated with oral fat perception, fat preferences, and obesity in African Americans. AB - Animal studies show that CD36, a fatty acid translocase, is involved in fat detection and preference, but these findings have not been reported in humans. The objective of this study was to determine whether human genetic variation in 5 common CD36 polymorphisms is associated with oral fat perception of Italian salad dressings, self-reported acceptance of high-fat foods and obesity in African American adults (n = 317). Ratings of perceived oiliness, fat content, and creaminess were assessed on a 170-mm visual analogue scale (VAS) in response to salad dressings that were 5%, 35%, and 55% fat-by-weight content. Acceptance of added fats and oils and high-fat foods was self-reported and anthropometric measures were taken in the laboratory. DNA was isolated from saliva and genotyped at 5 CD36 polymorphisms. Three polymorphisms, rs1761667, rs3840546, and rs1527483 were associated with the outcomes. Participants with the A/A genotype at rs1761667 reported greater perceived creaminess, regardless of the fat concentration of the salad dressings (P < 0.01) and higher mean acceptance of added fats and oils (P = 0.02) compared to those with other genotypes at this site. Individuals who had C/T or T/T genotypes at rs1527483 also perceived greater fat content in the salad dressings, independent of fat concentration (P = 0.03). BMI and waist circumference were higher in participants who were homozygous for a deletion (D/D) at rs3840546, compared to I/D or D/D individuals (P < 0.001), but only 2 D/D individuals were tested, so this finding needs replication. This is the first study to demonstrate an association between common variants in CD36 and fat ingestive behaviors in humans. PMID- 22240723 TI - Postmenopausal sex hormones in relation to body fat distribution. AB - Being overweight or obese increases the risk of postmenopausal breast cancer. A potential reason may be the frequently observed positive association of BMI with endogenous sex hormones and its negative association with sex hormone-binding globulin (SHBG). The purpose of this study was to investigate whether a woman's body fat distribution shows a BMI-independent association with these breast cancer-related biomarkers. Performing cross-sectional analyses among 1,180 postmenopausal women, we assessed whether associations of surrogates for an abdominal (waist circumference; waist-to-hip ratio, WHR) and gluteofemoral (hip circumference) fat distribution with estrone, total and free estradiol, androstenedione, total and free testosterone, and SHBG changed after adjustment for, or stratification by, BMI. All anthropometric measures were positively associated with estrogens and free testosterone, and negatively with SHBG. After adjustment for BMI, associations of free estradiol, free testosterone, and SHBG with both waist circumference and WHR remained significant, but all initially significant associations with hip circumference were abolished. In stratified analyses, waist circumference and WHR correlated with free estradiol, free testosterone, and SHBG in women with a BMI < 30 kg/m(2) but not in women with a BMI >= 30 kg/m(2). The latter suggests that in obese women, a possibly unique effect of abdominal fat on these biomarkers may be masked by the already large amount of overall body fat. On the whole, our results indicate that waist circumference and WHR, but not hip circumference, are associated with SHBG and SHBG-related sex hormones (free estradiol and free testosterone) independently of BMI. PMID- 22240724 TI - Assessing screening policies for childhood obesity. AB - To address growing concerns over childhood obesity, the United States Preventive Services Task Force (USPSTF) recently recommended that children undergo obesity screening beginning at age 6. An Expert Committee recommends starting at age 2. Analysis is needed to assess these recommendations and investigate whether there are better alternatives. We model the age- and sex-specific population-wide distribution of BMI through age 18 using National Longitudinal Survey of Youth (NLSY) data. The impact of treatment on BMI is estimated using the targeted systematic review performed to aid the USPSTF. The prevalence of hypertension and diabetes at age 40 are estimated from the Panel Study of Income Dynamics (PSID). We fix the screening interval at 2 years, and derive the age- and sex-dependent BMI thresholds that minimize adult disease prevalence, subject to referring a specified percentage of children for treatment yearly. We compare this optimal biennial policy to biennial versions of the USPSTF and Expert Committee recommendations. Compared to the USPSTF recommendation, the optimal policy reduces adult disease prevalence by 3% in relative terms (the absolute reductions are <1%) at the same treatment referral rate, or achieves the same disease prevalence at a 28% reduction in treatment referral rate. If compared to the Expert Committee recommendation, the reductions change to 6 and 40%, respectively. The optimal policy treats mostly 16-year olds and few children under age 14. Our results suggest that adult disease is minimized by focusing childhood obesity screening and treatment on older adolescents. PMID- 22240725 TI - The effects of reality television on weight bias: an examination of The Biggest Loser. AB - Weight-loss reality shows, a popular form of television programming, portray obese individuals and their struggles to lose weight. While the media is believed to reinforce obesity stereotypes and contribute to weight stigma, it is not yet known whether weight-loss reality shows have any effect on weight bias. The goal of this investigation was to examine how exposure to 40-min of The Biggest Loser impacted participants' levels of weight bias. Fifty-nine participants (majority of whom were white females) were randomly assigned to either an experimental (one episode of The Biggest Loser) or control (one episode of a nature reality show) condition. Levels of weight bias were measured by the Implicit Associations Test (IAT), the Obese Person Trait Survey (OPTS), and the Anti-fat Attitudes scale (AFA) at baseline and following the episode viewing (1 week later). Participants in The Biggest Loser condition had significantly higher levels of dislike of overweight individuals and more strongly believed that weight is controllable after the exposure. No significant condition effects were found for implicit bias or traits associated with obese persons. Exploratory analyses examining moderation of the condition effect by BMI and intention to lose weight indicated that participants who had lower BMIs and were not trying to lose weight had significantly higher levels of dislike of overweight individuals following exposure to The Biggest Loser compared to similar participants in the control condition. These results indicate that anti-fat attitudes increase after brief exposure to weight-loss reality television. PMID- 22240727 TI - 24-h core temperature in obese and lean men and women. AB - Maintenance of core temperature is a major component of 24-h energy expenditure, and its dysregulation could contribute to the pathophysiology of obesity. The relationship among temperature, sex, and BMI, however, has not been fully elucidated in humans. This study investigated core temperature in obese and lean individuals at rest, during 20-min exercise, during sleep, and after food consumption. Twelve lean (18.5-24.9 kg/m(2)) and twelve obese (30.0-39.9 kg/m(2)) healthy participants, ages 25-40 years old, were admitted overnight in a clinical research unit. Females were measured in the follicular menstrual phase. Core temperature was measured every minute for 24 h using the CorTemp system, a pill sized sensor that measures core temperature while in the gastrointestinal tract and delivers the measurement via a radio signal to an external recorder. Core temperature did not differ significantly between the obese and lean individuals at rest, postmeals, during exercise, or during sleep (P > 0.5), but core temperature averaged over the entire study was significantly higher (0.1-0.2 degrees C) in the obese (P = 0.023). Each individual's temperature varied considerably during the study, but at all times, and across the entire study, women were ~0.4 degrees C warmer than men (P < 0.0001). These data indicate that obesity is not associated with a lower core temperature but that women have a higher core temperature than men at rest, during sleep, during exercise, and after meals. PMID- 22240726 TI - Dual-energy X-ray performs as well as clinical computed tomography for the measurement of visceral fat. AB - Visceral adipose tissue (VAT) is associated with adverse health effects including cardiovascular disease and type 2 diabetes. We developed a dual-energy X-ray absorptiometry (DXA) measurement of visceral adipose tissue (DXA-VAT) as a low cost and low radiation alternative to computed tomography (CT). DXA-VAT was compared to VAT assessed using CT by an expert reader (E-VAT). In addition, the same CT slice was also read by a clinical radiographer (C-VAT) and a best-fit anthropomorphic and demographic VAT model (A-VAT) was developed. Whole body DXA, CT at L4-L5, and anthropometry were measured on 272 black and white South African women (age 29 +/- 8 years, BMI 28 +/- 7 kg/m(2), waist circumference (WC) 89 +/- 16 cm). Approximately one-half of the dataset (n = 141) was randomly selected and used as a training set for the development of DXA-VAT and A-VAT, which were then used to estimate VAT on the remaining 131 women in a blinded fashion. DXA-VAT (r = 0.93, standard error of the estimate (SEE) = 16 cm(2)) and C-VAT (r = 0.93, SEE = 16 cm(2)) were strongly correlated to E-VAT. These correlations with E-VAT were significantly stronger (P < 0.001) than the correlations of individual anthropometry measurements and the A-VAT model (WC + age, r = 0.79, SEE = 27 cm(2)). The inclusion of anthropometric and demographic measurements did not substantially improve the correlation between DXA-VAT and E-VAT. DXA-VAT performed as well as a clinical read of VAT from a CT scan and better than anthropomorphic and demographic models. PMID- 22240728 TI - Identification of a preassembled TRH receptor-G(q/11) protein complex in HEK293 cells. AB - Protein-protein interactions define specificity in signal transduction and these interactions are central to transmembrane signaling by G-protein-coupled receptors (GPCRs). It is not quite clear, however, whether GPCRs and the regulatory trimeric G-proteins behave as freely and independently diffusible molecules in the plasma membrane or whether they form some preassociated complexes. Here we used clear-native polyacrylamide gel electrophoresis (CN-PAGE) to investigate the presumed coupling between thyrotropin-releasing hormone (TRH) receptor and its cognate G(q/11) protein in HEK293 cells expressing high levels of these proteins. Under different solubilization conditions, the TRH receptor (TRH-R) was identified to form a putative pentameric complex composed of TRH-R homodimer and G(q/11) protein. The presumed association of TRH-R with G(q/11)alpha or Gbeta proteins in plasma membranes was verified by RNAi experiments. After 10- or 30-min hormone treatment, TRH-R signaling complexes gradually dissociated with a concomitant release of receptor homodimers. These observations support the model in which GPCRs can be coupled to trimeric G proteins in preassembled signaling complexes, which might be dynamically regulated upon receptor activation. The precoupling of receptors with their cognate G-proteins can contribute to faster G-protein activation and subsequent signal transfer into the cell interior. PMID- 22240730 TI - Birdsong neurolinguistics: songbird context-free grammar claim is premature. AB - There are remarkable behavioral, neural, and genetic similarities between song learning in songbirds and speech acquisition in human infants. Previously, we have argued that this parallel cannot be extended to the level of sentence syntax. Although birdsong can indeed have a complex structure, it lacks the combinatorial complexity of human language syntax. Recently, this conclusion has been challenged by a report purporting to show that songbirds can learn so-called context-free syntactic rules and then use them to discriminate particular syllable patterns. Here, we demonstrate that the design of this study is inadequate to draw such a conclusion, and offer alternative explanations for the experimental results that do not require the acquisition and use of context-free grammar rules or a grammar of any kind, only the simpler hypothesis of acoustic similarity matching. We conclude that the evolution of vocal learning involves both neural homologies and behavioral convergence, and that human language reflects a unique cognitive capacity. PMID- 22240731 TI - Diffusion modeling of interference in vibrotactile working memory. AB - The nature of interference in working memory has been a subject of discussion for decades. It has previously been argued that irrelevant stimuli can interfere with working memory by being encoded into memory. Previous findings have suggested that irrelevant sensory activity can interfere with the storage of information in tactile working memory. More recently, it has been suggested that this type of interference may operate through the overwriting of stored information by interfering sensory stimuli, even when participants are instructed to ignore such stimuli. Such a mechanism of interference is consistent with previous theoretical proposals. In the present study, we use a computational diffusion model to demonstrate that previous empirical findings are best explained by the encoding of irrelevant sensory information and subsequent interference. PMID- 22240735 TI - Interrogation of electrocatalytic water oxidation mediated by a cobalt complex. AB - Examination of the aqueous electrochemistry of a Co(II) complex bearing a pentadentate ligand suggests that the catalytic current corresponding to water oxidation is molecular in origin, and does not emanate exclusively from Co-oxide phases formed in situ. PMID- 22240732 TI - Cotransplantation of ex vivo expanded and unexpanded cord blood units in immunodeficient mice using insulin growth factor binding protein-2-augmented mesenchymal cell cocultures. AB - Ex vivo expansion of cord blood (CB) hematopoietic stem cells and cotransplantation of 2 CB units (CBUs) could enhance the applicability of CB transplantation in adult patients. We report an immunodeficient mouse model for cotransplantation of ex vivo expanded and unexpanded human CB, showing enhanced CB engraftment and provide proof of concept for this transplantation strategy as a means of overcoming the limiting cell numbers in each CBU. CBUs were expanded in serum-free medium supplemented with stem cell factor, Flt-3 ligand, thrombopoietin, and insulin growth factor binding protein-2 together with mesenchymal stromal cell coculture. Unexpanded and expanded CB cells were cotransplanted by tail vein injection into 45 sublethally irradiated nonobese diabetic SCID-IL2gamma(-/-) (NSG) mice. Submandibular bleeding was performed monthly, and mice were sacrificed 4 months after transplantation to analyze for human hematopoietic engraftment. Expansion of non-CD34(+) selected CB cells yielded 40-fold expansion of CD34(+) cells and 3.1-fold expansion of hematopoietic stem cells based on limiting dilution analysis of NSG engraftment. Mice receiving expanded grafts exhibited 4.30% human cell repopulation, compared with 0.92% in mice receiving only unexpanded grafts at equivalent starting cell doses, even though the unexpanded graft predominated in long-term hematopoiesis (P = .07). Ex vivo expanded grafts with lower initiating cell doses also showed equivalent engraftment to unexpanded grafts with higher cell dose (8.0% versus 7.9%; P = .93). In conclusion, ex vivo expansion resulted in enhanced CB engraftment despite eventual rejection by the unexpanded CBU. PMID- 22240733 TI - Prophylactic and preemptive therapy with dasatinib after hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. PMID- 22240736 TI - In vitro inhibitory properties of ferrocene-substituted chalcones and aurones on bacterial and human cell cultures. AB - Two series of ten chalcones and ten aurones, where ferrocene replaces the C ring and with diverse substituents on the A ring were synthesized. The compounds were tested against two antibiotic-sensitive bacterial strains, E. coli ATCC 25922 and S. aureus ATCC 25923, and two antibiotic-resistant strains, S. aureus SA-1199B and S. epidermidis IPF896. The unsubstituted compound and those with methoxy substitution showed an inhibitory effect on all bacterial strains at minimum inhibitory concentrations ranging between 2 and 32 mg L(-1). For four of these compounds, the effect was bactericidal, as opposed to bacteriostatic. The corresponding organic aurones did not show growth inhibition, underscoring the role of the ferrocene group. The methoxy-substituted aurones and the unsubstituted aurone also showed low micromolar (IC(50)) activity against MRC-5 non-tumoral lung cells and MDA-MB-231 breast cancer cells, suggesting non specific toxicity. PMID- 22240737 TI - Evidencing cost efficiencies in specialist palliative care. AB - In this difficult economic climate there is an increasing need in health care not only to measure improvements in quality of care but also to evidence cost efficiencies in services. Although specialist palliative care (SPC) has historically been viewed as synonymous with provision of quality care for patients, this seems unlikely to be viewed in the future as an inherent guarantee of optimum efficiency. It looks as though the SPC fraternity is going to have to quantify its value for money. PMID- 22240738 TI - The Royal College of Nursing guidance on responding to a request to hasten death. AB - In July 2009, when the Royal College of Nursing (RCN) Council in the UK moved to a neutral position on assisted suicide, it also determined that guidance for its members was needed. In October 2011 this guidance was finally published (RCN, 2011). Here the context, scope, and content of this publication are considered. PMID- 22240739 TI - Dementia deaths in hospice: a retrospective case note audit. AB - Dementia is now recognized as a progressive terminal illness and it is established that people with dementia have significant palliative care needs as they approach the end of life. However, population prevalence studies suggest that very few people with dementia access hospice services in the UK. The literature further suggests that hospice staff may be inadequately prepared to care for people with dementia. A retrospective internal case note audit covering a 3-month period of referrals was undertaken in one hospice in the south of England as part of work to establish staff education requirements arising from patient make-up. Only patients over the age of 65 were included. Of the 288 case notes audited, 9% of the patients had either been diagnosed with dementia or suffered with dementia as a comorbidity. The results of the audit suggest that the number of people with dementia referred to hospice services may have increased in the last decade. This is in keeping with expectations and future predictions resulting from increased disease surveillance and an increasingly ageing population. PMID- 22240740 TI - Challenges that specialist palliative care nurses encounter when caring for patients with advanced dementia. AB - Specialist palliative care (SPC) has expanded recently in Ireland to incorporate diseases other than cancer, including dementia. Two care areas that pose specific challenges for SPC nurses when caring for people with advanced dementia are pain and nutrition/hydration. Assessment and management of pain for a patient who has advanced dementia differs greatly from that for a typical palliative care patient. Similarly, nutrition and hydration pose extraordinary ethical and practical dilemmas not encountered when caring for a patient without dementia. This paper reports a literature review which revealed that although evidence based information related to each of these areas is available, it tends to be written from the perspective of health professionals with an interest in dementia rather than from the perspective of the SPC nurse. SPC nurses require evidence based palliative care research to guide their practice, but such research appears to be limited for patients with advanced dementia. Knowledge from specialists in both dementia care and palliative care needs to be combined if we are to provide these patients with the best possible end-of-life care. Further research is required and evidenced-based guidelines need to be formulated. PMID- 22240741 TI - Experiences of nurses practising home-based palliative care in a rural South African setting. AB - BACKGROUND: Home-based care is necessary in rural South Africa owing to the impact of the HIV/AIDS epidemic, inaccessible health-care institutions, and overcrowding in hospitals. Palliative care has been introduced as part of home based care and there is a call for research to inform practice, training, and support of caregivers. This exploratory paper reports on four nurses' experiences of providing home-based palliative care (HBPC) in rural KwaZulu-Natal. METHODOLOGY: The study employed the qualitative method of photo-elicitation, which was used as a launching point for individual one-to-one interviews with the participants. FINDINGS: HBPC increases access to care and provides a means of humanizing care and supporting patients in familiar community structures. It also enables nurses to practise independently and facilitates practise of traditional customs and use of traditional medicines. Challenges include patients' understanding of palliative care and nurses being placed at risk. CONCLUSION: The study uncovered several benefits to HBPC for patients and nurses, but also highlighted various challenges in its implementation. Further research is needed before any recommendations for practice, training, and support can be made. PMID- 22240742 TI - Use of dependency and prioritization tools by clinical nurse specialists in palliative care: an exploratory study. AB - AIMS: The principal aim was to assess the utility of three needs assessment/dependency tools for use in community-based palliative care services. Specific objectives were to assess a sample of patients receiving specialist palliative care community nursing using these tools, to assess the predictive ability of each tool, and to explore the utility of prioritizing and measuring patient dependency from a clinical nurse specialist (CNS) perspective. METHOD: In phase 1, 22 community-based CNSs completed the Vale prioritization tool for all patients visited during a 3-month period (n=162). They also completed either the Graves and Payne (2007) or the Birch et al (1997) dependency tool after each visit. In phase 2 a focus group (n=8) and two one-to-one interviews with CNS participants explored the perceived utility of all three tools. RESULTS: The Vale prioritization tool appeared to be the most useful for prioritizing patient need and managing workload. Statistical analysis highlighted minimal differences between the two dependency tools, neither of which predicted length of visit. Three themes were identified from phase 2: difficulties with routine administration, points of divergence between the two dependency tools, and workload concerns. CONCLUSION: While the Vale prioritization tool emerged as the most useful, the findings raise questions about the overall utility and practical application of these kinds of tools with community-based palliative care patients. Further research is needed to identify/develop, adapt, and evaluate appropriate, setting-specific dependency tools for use with this population. PMID- 22240743 TI - ICDs and patients in palliative care: the clinical experience turned into clinical policy. AB - As the global population grows and ages, an increasing number of patients are being referred to specialist palliative care services with multiple comorbidities. A parallel increase in interventional cardiology technology, techniques, and availability means that an increasing minority of these patients are having an implantable cardioverter defibrillator device (ICD) in place. It is essential that issues relating to these devices are discussed early in patients' planning for end-of-life care, as the discharging of a device in a patient who has chosen not to be resuscitated will be contrary to their wishes. These issues are explored here by presenting two case studies with vastly different outcomes that were experienced at a hospice in Australia. Examination of these case studies by the hospice staff culminated in the development of a policy for the home-based palliative care team and the hospice inpatient unit for deactivation of ICDs according to patients' and caregivers' wishes at a variety of stages of their palliative care journey. Elements of this policy are also presented here as guidance for others looking to implement similar processes. PMID- 22240744 TI - Emotional safety in the workplace: one hospice's response for effective support. AB - Emotional support is important for health professionals working in the demanding area of hospice/palliative care. While physical safety practices and effective human resource support are generally available to staff, one New Zealand hospice has taken this a step further by developing an emotional safety policy that incorporates personal, professional, and organizational measures designed to protect and promote staff members' emotional safety and to minimize stress and fatigue. The aim of this paper is to provide the background and rationale for this work, to introduce a case study around best practice, and to describe the development of the emotional safety policy, which provides effective support for all staff working at the hospice. PMID- 22240746 TI - Politics and palliative care: the Netherlands. AB - Dion Smyth's review of the internet for palliative nursing. PMID- 22240747 TI - Resistin level in coronary artery disease and heart failure: the central role of kidney function. AB - OBJECTIVES: The aim of this study was to evaluate resistin levels in patients with coronary artery disease (CAD) with or without chronic heart failure, in order to define its independent predictor. METHODS: One hundred and seven outpatients with CAD were enrolled in the study and divided into three groups: CAD without left-ventricular systolic dysfunction (group 1); CAD with left ventricular dysfunction without heart failure symptoms (group 2); CAD with overt heart failure (group 3). Plasma resistin was determined by ELISA. RESULTS: Resistin progressively increased from group 1 (10.7+/-5.0 ng/ml) to groups 2 (11.8+/-5.8 ng/ml) and 3 (17.0+/-6.8 ng/ml), with the difference reaching statistical significance in group 3 versus groups 1 and 2 (P=0.001). A multivariable model of analysis demonstrated that the best predictor of plasma resistin level was the estimated glomerular filtration rate (P<0.001), indicating that reduction of kidney function was the main cause of the adipokine increase observed in patients with CAD and overt heart failure. CONCLUSIONS: Our data confirm the rise of resistin plasma levels previously described in patients affected by chronic heart failure; however, in our study, this relationship seemed to be mediated mainly by the level of kidney function, and only partially by the severity of ventricular dysfunction. PMID- 22240748 TI - Echocardiography-guided versus fluoroscopy-guided temporary pacing in the emergency setting: an observational study. AB - BACKGROUND: The insertion of a temporary pacemaker can be a lifesaving procedure in the emergency setting. OBJECTIVES: This is an observational monocentric study comparing echocardiography-guided temporary pacemaker via the right internal jugular vein to standard fluoroscopy-guided temporary pacemaker via the femoral vein; the procedure was tested for noninferiority. METHODS: Patients needing urgent pacing were consecutively enrolled. Primary efficacy endpoints were time to pacing and need for catheter replacement. Primary safety endpoint was a composite outcome of overall complications. RESULTS: One hundred and six patients (77 +/- 10 years) were enrolled: 53 underwent echocardiographic-guided and 53 fluoroscopy-guided temporary pacemaker. Baseline characteristics of the two groups of treatment were similar. Time to pacing was shorter in the echocardiography-guided than in the fluoroscopy-guided group (439 +/- 179 vs. 716 +/- 235 s; P<0.0001; power 100%). During the pacing (54 +/- 35 h), there was a higher incidence of pacemaker malfunction in the fluoroscopy-guided group [15 vs. 3 patients; odds ratio (OR) 6.5, confidence interval (CI) 95% 1.9-29.7, P<0.001; power 5.7%] and there was a significantly lower incidence of complications in the echocardiography-guided temporary pacemaker group (6 vs. 22 patients; OR 0.18, CI 95% 0.06-0.49, P<0.001; echocardiography-guided temporary pacemaker events rate 0.1929 vs. fluoroscopy-guided temporary pacemaker events rate 1.398 per 100 person-hours paced, P<0.0001). In the standard group there was one death attributable to a temporary pacemaker complication (sepsis). CONCLUSION: Echocardiography-guided temporary pacemaker is a well-tolerated procedure that could allow reliable insertion of a temporary pacemaker; therefore, it is a well tolerated option in an emergency setting and in hospitals where fluoroscopy is not available. PMID- 22240749 TI - Adherence junction proteins in angiogenesis: modulation by aspirin and salicylic acid. AB - BACKGROUND: The development of neovasculature correlates with plaque instability and rupture as well as tumor growth and aggressiveness. In recent years, aspirin has emerged as a powerful modality in prophylaxis of cardiovascular events, which may be linked to its inhibitory effects on angiogenesis. METHODS AND RESULTS: We studied the role of endothelial adherens junctions in angiogenesis and the modulation of adherens junctions by acetylsalicylic acid (ASA) and salicylic acid as mechanisms of the angiostatic potential of these agents. Exposure of human umbilical cord endothelial cells (HUVECs) to vascular endothelial growth factor (VEGF) significantly enhanced tube formation. The disruption of adherens junctions as well as phosphorylation and cytoplasmic translocation of VE-cadherin and p120 catenin were early consequences of VEGF addition to the medium bathing the HUVECs. Pretreatment with ASA and salicylic acid prevented changes in adherence junction proteins and inhibited VEGF-induced tube formation by HUVECs in a dose-dependent manner. CONCLUSION: Angiogenesis is associated with significant alterations in adherens junctions. Both ASA and salicylic acid reduce angiogenesis by modulating adherens junctions. PMID- 22240750 TI - Effect of adenosine intracoronary bolus on myonecrosis occurrence in elective PCI (RACE trial). PMID- 22240751 TI - Alteration of baroreflex sensitivity in the elderly: the relationship with metabolic syndrome components. PMID- 22240752 TI - Effects of early reperfusion on creatine kinase release in patients with acute myocardial infarction: implications for reperfusion injury. PMID- 22240753 TI - Atrial fibrillation management in Asia: from the Asian expert forum on atrial fibrillation. AB - Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with increased morbidity and mortality. AF has a slightly lower incidence and prevalence in Asian populations than in Western populations, but the associated relative risk of stroke and mortality is similar. Patients with AF in Asia have similar disease profiles and CHADS2 score distributions compared to those in the West, with the exception of a slightly higher prevalence of valvular heart diseases in Asia. Acute ventricular rate control should be the initial consideration in patients with AF and rapid ventricular rate. Anti-arrhythmic drugs have only a modest long-term effect on maintenance of sinus rhythm, and clinical trials in both the West and the East show that chronic rhythm control is not superior to chronic rate control in terms of cardiovascular outcomes, most likely because the benefit of anti-arrhythmic drugs in these trials was often offset by proarrhythmic effects. ECG-driven trials for AF should be replaced by outcome-driven ones. ATHENA is the largest outcome trial to confirm the superiority of a new anti-arrhythmic drug in improving cardiovascular outcomes. The choice of anti-arrhythmic drugs for AF should be based on both safety and efficacy in improving cardiovascular outcomes. For long-term rate control, a lenient strategy with a ventricular rate of less than 110bpm may be adequate, but more strict rate control may be required if patients continue to complain of symptoms. Catheter ablation should be reserved for patients who remain symptomatic despite optimal medical therapy. PMID- 22240755 TI - S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuated tumor necrosis factor-alpha-induced inflammatory signaling and dysfunction in endothelial cells. PMID- 22240754 TI - The prevalence of aortic calcification in Japanese compared to white and Japanese American middle-aged men is confounded by the amount of cigarette smoking. AB - BACKGROUND: The prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men. METHODS: We conducted a population-based study of 903 randomly-selected men aged 40-49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, US, and 292 Japanese men in Hawaii, US (2002-2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) >0 and >= 100. RESULTS: Japanese (35.8%) had significantly less AoCaS>0 compared to both white (68.8%, p<0.001) and Japanese-American (62.3%, p<0.001) but similar AoCaS >= 100 (19.4%, 18.3%, 22.6%, respectively, p=0.392). The pack years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r=0.26), white (r=0.39), and Japanese-American (r=0.45). CONCLUSIONS: The prevalence of AC defined both >0 and >= 100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors. PMID- 22240756 TI - Association of novel biomarkers with future cardiovascular events is influenced by ethnicity: results from a multi-ethnic cohort. AB - BACKGROUND: We sought to define the influence of ethnicity on associations between novel biomarkers and cardiovascular disease (CVD) events among Multi Ethnic Study of Atherosclerosis (MESA) study participants, a community based population of asymptomatic US adults. METHODS: Baseline (log transformed) levels of biomarkers namely C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), D-dimer, plasmin-antiplasmin complex (PAP) and factor VIII were used to predict the cumulative incidence of all CVD events in an ethnicity stratified study cohort from Cox-proportional hazard analysis where models were adjusted for relevant confounders. RESULTS: Ethnic cohorts included 2362 Caucasians, 1601 African Americans, 1353 Hispanics, and 751 Chinese. At mean 4.6 years of follow up, 286 CVD events were identified with cumulative incidence of 11.3% in Caucasians, 9.8% in African Americans, 11.3% in Hispanics and 6.9% in Chinese. Biomarker risk association with CVD events incidence was significantly influenced by ethnicity with positive association (HR, 95% CI, p value) being shown for: CRP among Caucasians only (1.23, 1.04-1.47, <0.01) IL-6 among African Americans only (1.69, 1.15-2.48, <0.01) and fibrinogen among Caucasians (3.05, 1.21-7.69, 0.02), African Americans (3.51, 1.09-11.2, 0.03) and Hispanics (4.16, 1.23-14.1, 0.02) only. None of the biomarkers were able to predict CVD in Chinese. Association between above biomarkers and CVD was bi-directional: cases with CVD events had higher mean levels of biomarkers; cases in higher quartiles of biomarkers had increased cumulative incidence of CVD events. CONCLUSION: Study results from a vast, ethnically diverse, asymptomatic US adult population suggest that biomarker association with incident CVD events is significantly influenced by ethnicity. PMID- 22240757 TI - Quantitative comparison of clopidogrel 600 mg, prasugrel and ticagrelor, against clopidogrel 300 mg on major adverse cardiovascular events and bleeding in coronary stenting: synthesis of CURRENT-OASIS-7, TRITON-TIMI-38 and PLATO. AB - The convention of loading with clopidogrel 300 mg before coronary intervention may be due for change, but to what? Newer antiplatelet agents may offer better outcomes, at some financial cost. Disappointingly for decision-making clinicians, head-to-head comparisons for the newer alternatives are not available. We systematically review and compare the three alternative strategies: clopidogrel 600 mg, prasugrel and ticagrelor. A total of 14 studies have compared these strategies with the long-standing convention of 300 mg. Throughout this analysis, we consistently report incremental costs and consequences using clopidogrel 300 mg as the reference strategy. Risk ratios for major adverse cardiovascular events at 30 days were 0.74 (95% confidence interval 0.66-0.82, p=0.002) for clopidogrel 600 mg, 0.78 (0.69-0.89; p<0.001) for prasugrel and 0.88 (0.77-1.00; p=0.045) for ticagrelor. All-cause mortality risk ratios were 0.87 (0.74-1.03) with clopidogrel 600 mg, 0.95 (0.78-1.16) with prasugrel and 0.78 (0.69-0.89) with ticagrelor. TIMI major bleeding has risk ratio 0.92 (0.74-1.16; p=0.85) with clopidogrel 600 mg, 1.32 (1.03-1.16; p=0.03) with prasugrel and 1.25 (1.03-1.53; p=0.03) with ticagrelor. Incremental cost for the first year was L0.32 (US$0.50, ?0.40) with clopidogrel 600 mg, L608 (US$977, ?709) with prasugrel and L665 (US$1068, ?775) with ticagrelor. All three strategies have shown a similar reduction in MACE at 30 days by comparison to clopidogrel 300 mg. All three strategies offer progressive benefit, most marked with Ticagrelor. Whether this is worth both the risk of non-compliance with twice-a-day dosing in real-life patients lacking the same motivation as their trial-volunteer counterparts, and the 2000-fold difference in incremental cost, is the remaining matter for debate. PMID- 22240758 TI - Undiagnosed sleep apnoea syndrome in patients with acute myocardial infarction: potential importance of the STOP-BANG screening tool for clinical practice. PMID- 22240759 TI - Hypertensive crisis: comparison between diabetics and non-diabetics--response to comment. PMID- 22240760 TI - Differential effects of trimetazidine on vascular smooth muscle cell and endothelial cell in response to carotid artery balloon injury in diabetic rats. AB - BACKGROUND: Treatment with trimetazidine (TMZ), 1-[2,3,4-trimethoxybenzyl] piperazine, dihydrochloride, improves cardiac function and ameliorates endothelial dysfunction. However, its potential efficacy against restenosis after balloon injury has not been addressed. We investigated the effect of TMZ on reducing the occurrence of restenosis in the carotid artery in response to balloon injury and explored potential mechanisms for the effects. MATERIAL AND METHODS: Streptozotocin (40 mg/kg)-injected Sprague-Dawley rats and Otsuka Long Evans Tokushima Fatty rats were used for type 1 and type 2 diabetes models, respectively. Both types of rats were divided into three groups: control and TMZ treatment 10 and 20mg/kg per day (n=10 per group). TMZ or normal saline was given orally from 2 weeks before to 2 weeks after carotid injury. RESULTS: Four weeks of TMZ treatment resulted in a significant and dose-dependent reduction in the intima-media ratio in diabetic rats. This effect was accompanied by decreased proliferation of vascular smooth muscle cells (VSMCs) and accelerated re endothelialization after carotid balloon injury. In vitro study with VSMCs decreased proliferation and migration, while human umbilical vein endothelial cells (HUVECs) increased proliferation and decreased apoptosis after TMZ treatment. Antioxidative effects of TMZ were observed in both VSMCs and HUVECs. CONCLUSIONS: Reduction of restenosis by TMZ treatment involved changes in antioxidative and anti-inflammatory properties, which are cell-specific effects on either survival or apoptosis. The specific actions and physiological effects of TMZ may contribute to better understanding of the pathogenesis of atherosclerosis, which is a major complication of diabetes mellitus. PMID- 22240761 TI - HMGB1: a potential therapeutic target for myocardial ischemia and reperfusion injury. PMID- 22240762 TI - Acquired von Willebrand disease in Jarvik 2000 recipients: a single center experience. PMID- 22240763 TI - Basilar artery occlusion after acute myocardial infarction. PMID- 22240764 TI - Stress-induced cardiomyopathy in a patient with chronic spinal cord transection at the level of C5: endocrinologically mediated catecholamine toxicity. PMID- 22240765 TI - Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis. AB - INTRODUCTION: There is conflicting evidence about the impact of gender on outcomes after coronary artery bypass grafting (CABG). METHODS: We performed a multivariate logistic regression and propensity score matched analyses in 13,115 patients (75% men) who underwent CABG between January 1, 1995 and December 31, 2009. The primary outcome was in-hospital mortality. Secondary outcomes included post-operative respiratory failure, stroke, myocardial infarction, sternal and leg wound infections, atrial fibrillation (AF), renal failure, need for postoperative intra-aortic balloon pump (IABP) support, and length of hospital stay. RESULTS: A higher proportion of women (184; 5.6%) suffered in-hospital death compared to men (264; 2.7%), p<0.0001. After propensity score matching (n=3600 total, 1800 in each group), female gender was an independent predictor of mortality after isolated CABG (odds ratio [OR]=1.84; 95% confidence interval [CI] 1.22-2.78). Women also experienced a higher incidence of postoperative complications including stroke (3.8% vs. 2.3%, OR 1.37; 95% CI 1.08-1.73) and leg wound infection (3.4% vs. 1.7%, OR 1.75; 95% CI 1.36-2.54) on multivariate regression analyses. However, these differences were not significant after propensity score matching. We also observed a lower risk of post-operative AF (21.2% vs. 22.1%, OR 0.78; 95% CI 0.70-0.86) in women that remained significant after propensity matching (O.R. 0.76; 95% C.I. 0.65-0.90). Length of hospital stay was longer in women compared with men (11.9 +/- 9.0 vs. 10.4 +/- 9.2 days, p<0.0001). CONCLUSIONS: Female gender is an independent predictor of increased mortality and a lower incidence of post-operative AF after isolated CABG. PMID- 22240766 TI - Updates on new oral anticoagulants and percutaneous devices for stroke prevention in patients with non-valvular atrial fibrillation. PMID- 22240767 TI - Do surgical procedures affect EuroSCOREs' performance? The role of tricuspid valve surgery. PMID- 22240768 TI - Percutaneous coronary intervention with or without on-site coronary artery bypass surgery: a systematic review and meta-analysis. AB - BACKGROUND: Current American Heart Association guidelines recommend against the performance of elective or primary percutaneous coronary intervention (PCI) without on-site surgical backup (i.e. a class III and IIb recommendation respectively). Despite this, numerous centers have already implemented PCI programs with no on-site surgery backup (NSOS). METHODS: To evaluate the necessity for on-site surgical backup (SOS) when performing PCI we performed a systematic review and meta-analysis. English-language articles published from 1966 through December 2010 were retrieved using keyword searches of Medline and Scopus, supplemented by letters to authors and reviews of all bibliographies. Article inclusion and data extraction was performed by two independent reviewers. We identified 18 articles published between 1992 and 2009 which contained reported events on 1,150,200 patients. RESULTS: The combined odds ratio calculated using a random effects model for death with NSOS was 0.93 (95% CI, 0.80-1.09). In studies with data reported for primary PCI and elective PCI the OR for death was 0.91 (95% CI, 0.84-1.00) and 1.04 (95% CI, 0.67-1.63). A lack of effect of SOS was maintained when analysis was performed by study type or by either primary or elective PCI. No differences in rates of emergency coronary artery bypass grafting, post procedural myocardial infarction, target vessel revascularization, or cerebrovascular accidents were observed between SOS and NSOS centers. CONCLUSION: Both primary and elective PCI can safely be performed at NSOS centers without an increase in mortality or PCI related complications. AHA/ACC guidelines should reflect the lack of benefit conferred by on-site surgical backup. In establishing PCI programs, adequate operator/center volumes, patient selection, and geographic/population considerations should take precedence rather than the availability of on-site surgical backup during PCI. PMID- 22240769 TI - Left ventricular filling patterns and its relation to left ventricular untwist in patients with type 1 diabetes and normal ejection fraction. AB - BACKGROUND: We evaluated young patients with type 1 diabetes (T1DM) who had normal left ventricular (LV) ejection fraction and used speckle tracking echocardiography to assess changes in LV untwisting. We used cardiac magnetic resonance imaging (MRI) to assess the LV filling patterns in these subjects. METHODS: We recruited 33 T1DM patients and 32 age-matched healthy controls (HC) into the study. Study participants underwent echocardiography, cardiac MRI and metabolic exercise testing. RESULTS: The early peak LV untwisting rate (E) was similar in T1DM and HC (-11.9 +/- 4.6 0/cm/s vs -11.3 +/- 4.7 0/cm/s, P=0.29) but the late peak LV untwisting rate (A) was significantly increased in T1DM (-6.2 +/ 3 0/cm/s vs -4.9 +/- 3.9 0/cm/s, P<0.05). The time to early peak untwisting rate was not different (50.9 +/- 9.6% vs 48.4 +/- 7.3%, P=0.12) but the time to late peak untwisting rate was significantly delayed in T1DM patients (80.4 +/- 12.5% vs 72.7 +/- 14.6%, P<0.05). The LV filling patterns demonstrated a significantly increased left atrial (LA) contribution to LV filling in T1DM. On linear regression peak late filling rate (r=0.60, P<0.000), trans-mitral A wave (r=0.25, P<0.05) and A' (r=0.30, P<0.01) were predictors of LA contribution to LV filling. CONCLUSION: We demonstrate for the first time using speckle tracking that LV untwisting rate E is preserved and untwisting rate A is increased and delayed in young patients with uncomplicated T1DM. The LA contribution to LV filling is increased in these patients and is directly related to increases in other indices of LA function like peak late filling rate, trans-mitral A wave and A'. PMID- 22240770 TI - Assessment of aortic root dimensions in patients with suspected Marfan syndrome: intraindividual comparison of contrast-enhanced and non-contrast magnetic resonance angiography with echocardiography. AB - PURPOSE: Our purpose was to evaluate intraindividually the performance of contrast-enhanced magnetic resonance angiography (MRA) and non-contrast MRA for aortic root diameter measurements and to compare the results with routinely performed echocardiography in patients with suspected Marfan syndrome. METHODS AND MATERIALS: Aortic roots were examined prospectively in 51 consecutive patients with suspected Marfan syndrome by using contrast-enhanced MRA and non contrast MRA at 1.5 T. Two readers independently measured aortic root diameters at the annulus, sinuses of Valsalva and sinutubular junction in both data sets and compared results with echocardiographic data. Intraclass correlation coefficient, Pearson correlation coefficient, Bland-Altman, and two-sided t-test were used to assess agreement between observers and methods. RESULTS: 38 (74.5%) of the 51 patients (25 female, 26 male; mean age 37.1 +/- 13.7 years) had Marfan syndrome. Both, contrast-enhanced MRA and non-contrast MRA measurements of the sinuses of Valsalva revealed a strong correlation with echocardiography (r=0.850 and r=0.893, respectively). Intraclass correlation was markedly better for non enhanced MRA (r=0.904) when compared to contrast-enhanced MRA (r=0.690). Image quality (p<0.001) as well as interobserver agreement (p<0.0042) of measurements of the sinuses of Valsalva was significantly better for non-enhanced MRA than for contrast-enhanced MRA. CONCLUSION: Non-contrast MRA was more reliable and more valid than contrast-enhanced MRA for assessment of aortic root dimensions in patients with suspected Marfan syndrome. Therefore contrast agents can be omitted for establishing the diagnosis of aortic involvement in Marfan syndrome. PMID- 22240771 TI - The paralympic winter athlete. PMID- 22240772 TI - Clinicopathologic profile of hypopigmented mycosis fungoides in India. AB - BACKGROUND: Hypopigmented mycosis fungoides (HMF) is an under recognized disease in India, which is often mistaken for Hansen disease or vitiligo, resulting in delayed diagnosis and treatment. AIM: To describe the clinical, histopathologic and immunohistochemical features of HMF in Indian patients. MATERIALS AND METHODS: All cases presenting as hypopigmented lesions that were signed out as MF between 2001 and 2009 (15 cases) were included. Clinical data and histopathology slides were reviewed. Immunostains for CD4, CD8, and CD1a were done, where tissue was available. RESULTS: The age ranged from 14 to 38 years with a male preponderance. The commonest presentation was multiple hypopigmented patches on limbs and trunk with the duration of the lesions varying from 4 months to 14 years. All cases showed a psoriasiform/lichenoid epidermal pattern, disproportionate epidermotropism, basilar tagging of lymphocytes, monomorphous lymphocytes, haloed lymphocytes, and wiry dermal collagen. Other important findings were infiltration of hair follicles, larger epidermal lymphocytes, atypia of dermal lymphocytes, and stuffed dermal papillae. Dermal edema was absent in all cases. Immunohistochemistry done on 10 cases showed a CD8 phenotype in 6 cases and CD4 phenotype in the remaining 4 cases. CONCLUSIONS: Histopathology supplemented by immunohistochemistry is reliable in making a diagnosis of HMF. It is important to be aware of this uncommon, yet significant disease. PMID- 22240773 TI - Coexistence of patch stage mycosis fungoides and interstitial granuloma annulare in the same patient: a pitfall in the clinicopathologic diagnosis of mycosis fungoides. AB - Several clinical and histopathologic variants of mycosis fungoides (MF) have been well described, including the often elusive interstitial MF. Differentiation from other inflammatory disorders, such as interstitial granuloma annulare (GA) and inflammatory morphea, may be extremely difficult. We report a case of MF and GA coexisting in a 54-year-old woman who initially presented to clinic in 2000 with slightly scaly patches on the trunk and extremities, histopathologically diagnostic of MF. A second biopsy taken a few months later revealed an interstitial infiltrate that was initially interpreted as interstitial MF. Over the following 10 years, additional biopsies revealed features of conventional MF. In 2009, a new biopsy showed unequivocal features of interstitial GA. Reevaluation of the original biopsy, diagnostic of "interstitial MF," revealed that this, too, could be better classified as interstitial GA than interstitial MF. Our case illustrates that MF and interstitial GA may coexist simultaneously, thus representing a pitfall in the histopathologic diagnosis of MF. Given the similarities in clinicopathologic presentation, dermatologists and dermatopathologists should be cautious not to inadvertently misinterpret GA as interstitial MF. PMID- 22240774 TI - Mammary Paget disease in Darier disease: beware the wolf in sheep's clothing. AB - This case describes new onset mammary Paget disease arising in the background of Darier disease. Clinically and histologically, lesions of Darier disease can mask the lesions of mammary Paget disease. A high index of suspicion is necessary to diagnose Paget disease in a patient with Darier disease, for a potentially fatal disease could easily be missed. PMID- 22240775 TI - A case of congenital spindle cell xanthogranuloma. PMID- 22240776 TI - Cutaneous ciliated cyst on the finger: a cutaneous mullerian cyst. AB - As previously recognized by various authors, "cutaneous ciliated cyst" is a confusing term. Typically, the term refers to rare cystic lesions, commonly found on the lower limbs of women in their reproductive years. To date, 40 cases diagnosed as "cutaneous ciliated cyst" have been reported in the literature. Histologically, the cysts are composed of a simple layer of ciliated columnar cells along with nonciliated columnar cells, cuboidal cells, and round "peg-like" cells, resembling fallopian tube epithelium. This histology has been described in cysts found in males and females and in locations other than the lower limbs. Controversy has thus arisen over the etiology of these lesions, with some believing that the cysts arise from heterotopic Mullerian rests and others advocating for ciliated metaplasia of eccrine glands. We herein describe the first case of cutaneous ciliated cyst of Mullerian origin occurring on the dorsal thumb of a 16-year-old female. A review of literature shows that 2 groups of cysts are covered under the umbrella term "cutaneous ciliated cysts." We thus propose the abandonment of the confusing term "cutaneous ciliated cyst" and the adoption of "cutaneous Mullerian cysts" for estrogen receptor/progesterone receptor-positive lesions resembling simple fallopian tube epithelium and "Cutaneous ciliated eccrine cyst" for estrogen receptor/progesterone receptor negative lesions usually occurring in males, which are immunohistochemically compatible with an eccrine origin. PMID- 22240777 TI - A phase I trial of adeno-associated virus serotype 1-gamma-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. AB - gamma-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the gamma-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27 years; range 16-38 years) with del525T homozygous mutation of the gamma-sarcoglycan gene and no gamma-sarcoglycan immunostaining on muscle biopsy were divided into three equal groups to receive three escalating doses of an adeno-associated virus serotype 1 vector expressing the human gamma-sarcoglycan gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3 * 10(9) viral genomes in 100 ul, the second group received a single injection of 1.5 * 10(10) viral genomes in 100 ul, and the third group received three simultaneous 100-ul injections at the same site, delivering a total dose of 4.5 * 10(10) viral genomes. No serious adverse effects occurred during 6 months of follow-up. All nine patients became adeno-associated virus serotype 1 seropositive and one developed a cytotoxic response to the adeno-associated virus serotype 1 capsid. Thirty days later, immunohistochemical analysis of injected muscle biopsy specimens showed gamma-sarcoglycan expression in all three patients who received the highest dose (4.7-10.5% positively stained fibres), while real time polymerase chain reaction detected gamma-sarcoglycan messenger RNA. In one patient, gamma-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of gamma sarcoglycan expression (<1% positively stained fibres) were also detectable. Expression of gamma-sarcoglycan protein can be induced in patients with limb girdle muscular dystrophy type 2C by adeno-associated virus serotype 1 gene transfer, with no serious adverse effects. PMID- 22240778 TI - Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2. AB - BACKGROUND: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2 overexpressing advanced breast cancer pretreated with trastuzumab. METHODS: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated. RESULTS: Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1. CONCLUSION: The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance. PMID- 22240779 TI - The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells. AB - BACKGROUND: Resistance to chemotherapeutic agents has been associated with a failure of cancer cells to induce apoptosis. Strategies to restore apoptosis have led to the development of BH3 mimetics, which inhibit anti-apoptotic Bcl-2 family members. We examined the sensitivity of three oesophageal cancer cell lines to 5 fluorouracil (5-FU) alone and in combination with the BH3 mimetic HA14-1. METHODS: Clonogenic assays, morphology, markers of autophagy and apoptosis were used to assess the involved death mechanisms. RESULTS: In response to 5-FU treatment, OE21 cells induce apoptosis, KYSE450 and KYSE70 cells are more resistant and induce autophagy accompanied by type II cell death. Autophagy induction results in ineffective treatment as substantial numbers of cells survive and re-populate. HA14-1 did not improve 5-FU treatment or reduce colony re-growth in the apoptosis deficient KYSE70 cells. However, the sensitivity of OE21 (apoptotic) and KYSE450 cells (apoptosis deficient/type II cell death) was significantly improved. In OE21 cells, treatment with 5-FU and HA14-1 resulted in augmentation of apoptosis. In KYSE450 cells, the reduction in recovering colonies following combination treatment was due to the enhancement of type II cell death. CONCLUSION: The efficacy of HA14-1 is cell line dependent and is not reliant on apoptosis induction. PMID- 22240780 TI - Population-based cancer incidence in Sikkim, India: report on ethnic variation. AB - BACKGROUND: A Population-Based Cancer Registry (PBCR) was set up in Sikkim (a state in the North Eastern India) in 2003. We examined incidence rates by ethnic groups from 2003-2008. METHODS: Age-adjusted incidence rates (AARs) per 100,000 person-years were calculated by direct method using the world standard population, and analysed by ethnic group (Bhutia, Rai and other). RESULT: There were a total of 1148 male and 1063 female cases of cancer between 2003 and 2008 on the Sikkim PBCR. The overall AARs were 89.4 and 99.4 per 100,000 person-years in males and females, respectively. Incidence rates were highest amongst the Bhutia group (AAR=172.4 and 147.4 per 100,000 person-years in males and females, respectively), and the largest difference in rates were observed for stomach cancers with AARs being 12.6 and 4.7 times higher in the Bhutia group compared with other ethnic groups in males and females, respectively. CONCLUSION: These observations call for further epidemiological investigations and the introduction of screening programmes. PMID- 22240781 TI - Relationship of increased aurora kinase A gene copy number, prognosis and response to chemotherapy in patients with metastatic colorectal cancer. AB - BACKGROUND: Increased Aurora kinase A gene copy number (AURKA-CN) has been reported in metastatic colorectal cancer (mCRC), with unknown relationship to clinical outcome. We correlated increased AURKA-CN in mCRC tumours with KRAS mutation status, overall and progression-free survival (OS, PFS). METHODS: Sixty one mCRC tumours were analysed for AURKA-CN using q-PCR, and KRAS mutation status by direct sequencing. Expression of AURKA protein was analysed by immunohistochemistry. Cox-proportional hazard method, Kaplan-Meier curves and log rank statistics were used to estimate and compare the hazard ratios and median survival between the groups. RESULTS: In all, 68% of tumour exhibited high AURKA CN, and 29% had a KRAS mutation, without correlation between the two. Patients with high AURKA-CN tumours had longer median OS (48.6 vs 18.8 months, P=0.01), with stronger trend among KRAS wild-type tumours (median OS not reached vs 18.8 months, P=0.003). Progression-free survival was longer on first-line or second line chemotherapy among patients with KRAS wild-type and high vs low AURKA-CN (first: 17.6 vs 5.13 months, P=0.04; second: 10.4 vs 5.1 months, P=0.01). AURKA CN level did not affect outcomes among patients with KRAS mutant tumours. CONCLUSION: Increased AURKA-CN is common in mCRC tumours and is associated with longer OS and longer PFS during chemotherapy, particularly in KRAS wild-type tumours. PMID- 22240782 TI - Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). AB - BACKGROUND: The FAST is a 2 * 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G based doublet does not improve treatment outcome. PMID- 22240783 TI - Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I/II trial of the AGO study group. AB - INTRODUCTION: Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin. METHODS: This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m(-2) plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib. RESULTS: Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients. CONCLUSION: Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option. PMID- 22240784 TI - The relationship between tumour necrosis, tumour proliferation, local and systemic inflammation, microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma. AB - BACKGROUND: There is increasing evidence that the local and systemic inflammatory responses are associated with survival in oesophageal cancer. The aim of this study was to examine the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation and microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma. METHODS: The interrelationship between tumour necrosis, tumour proliferation, local inflammatory response (Klintrup-Makinen criteria, intra tumoural CD8+ lymphocyte and macrophage infiltration), systemic inflammatory response (modified Glasgow Prognostic score (mGPS)), and microvessel density was examined in 121 patients undergoing potentially curative resection for oesophageal adenocarcinoma (including type I and II tumours of the gastro oesophageal junction). RESULTS: Tumour necrosis was not significantly associated with any tumour measure other than the degree of differentiation. On multivariate analysis, only age (HR 1.93, 95% CI 1.23-3.04, P=0.004), mGPS (HR 2.91, 95% CI 1.51-5.62, P=0.001), positive to total lymph node ratio (HR 2.38, 95% CI 1.60 3.52, P<0.001) and macrophage infiltration (HR 1.49, 95% CI 1.02-2.18, P=0.041) were independently associated with cancer-specific survival in oesophageal adenocarcinoma. Intra-tumoural macrophages were associated with tumour proliferation (P<0.001) and CD8+ lymphocytes infiltration (P<0.01). CONCLUSION: The results of this study suggest that tumour necrosis does not link local and systemic inflammatory responses and is not significantly associated with survival. In contrast, tumour macrophage infiltration appears to have a central role in the proliferative activity and the coordination of the inflammatory cell infiltrate and is independently associated with poorer survival in patients with oesophageal adenocarcinoma. PMID- 22240785 TI - Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinomas are highly lethal tumours of the intrahepatic or extrahepatic biliary tract. The aetiology is largely unknown, and the potential roles of gallstones and gall bladder removal (cholecystectomy) need to be addressed in a large study with a long follow-up. METHODS: A population-based nationwide Swedish cohort study was carried out, in which patients hospitalised for gallstone diagnosis with or without gallbladder removal (cholecystectomy) between 1965 and 2008 were identified in the Swedish Patient Registry. The cohort was followed up for cancer in the Swedish Cancer Registry. The observed numbers of intra- and extrahepatic cholangiocarcinomas that developed after one year of follow-up were compared with the expected numbers, calculated from the corresponding background population, and the relative risks were estimated by standardised incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: Among the 192,960 non-cholecystectomised individuals with gallstones, there was a more than two-fold overall increased risk of both intra- and extra- hepatic cholangiocarcinomas, which remained stable over the follow-up period (SIR 2.77, 95% CI 2.17-3.49, and SIR 2.58, 95% CI 2.21-3.00, respectively). In the cholecystectomy cohort, including 345,251 people and 4,854,969 person-years, 325 incident cholangiocarcinomas were identified, of which 98 (30%) were intrahepatic and 227 (70%) were extrahepatic. Initially (1-4 years after surgery), the risk was increased for both intrahepatic cholangiocarcinoma (SIR 1.80, 95% CI 1.19 2.62) and extrahepatic cholangiocarcinoma (SIR 2.29, 95% CI 1.83-2.82), but no increase remained after 10 years of follow-up or more (SIR 1.10, 95% CI 0.79 1.48, and SIR 0.87, 95% CI 0.70-1.07, respectively). INTERPRETATION: Gallstones seem to increase the risk of both intra- and extrahepatic cholangiocarcinoma. However, this risk seems to decline to the level of the background population with time after cholecystectomy. PMID- 22240786 TI - Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. AB - BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective. PMID- 22240787 TI - Risk profiles of prostate cancers identified from UK primary care using national referral guidelines. AB - OBJECTIVE: Prostate cancer in the United Kingdom is mainly diagnosed from primary care referrals based on national guidelines published by the Department of Health. Here we investigated the characteristics of cancers detected through the use of these guidelines. METHODS: A prospective two-centre study was established to assess men referred from the primary care based on the UK national guidelines. RESULTS: The overall cancer detection rate was 43% (169 out of 397) with 15% (26 out of 169) of all cancers metastatic at presentation. Amongst 50-69-year-old men these rates were 34% (68 out of 200) and 15% (10 out of 68). Only 21% (25 out of 123) of men with local cancers had low-risk disease. In comparison to a historical cohort from 2001 (n=137) we found no overall differences in rates of metastatic disease, locally advanced tumours, or risk categories. Amongst 50-69 year-old men with local disease, however, we observed an increase in detection of low-risk cancers in a contemporary cohort (P=0.04). This was primarily because of the increased detection of low-stage organ-confined tumours in this group (P=0.02). CONCLUSION: Use of the UK prostate cancer guidelines detects a high proportion of clinically significant cancers. Use of the guidelines does not seem to have led to an overall change in the clinical characteristics of presenting cancers. There may, however, be a specific benefit in detecting more low-risk disease in younger men. PMID- 22240788 TI - Changes in circulating microRNA levels associated with prostate cancer. AB - BACKGROUND: The aim of this study was to investigate the hypothesis that changes in circulating microRNAs (miRs) represent potentially useful biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer. METHODS: Real time polymerase chain reaction analysis of 742 miRs was performed using plasma derived circulating microvesicles of 78 prostate cancer patients and 28 normal control individuals to identify differentially quantified miRs. RESULTS: A total of 12 miRs were differentially quantified in prostate cancer patients compared with controls, including 9 in patients without metastases. In all, 11 miRs were present in significantly greater amounts in prostate cancer patients with metastases compared with those without metastases. The association of miR-141 and miR-375 with metastatic prostate cancer was confirmed using serum-derived exosomes and microvesicles in a separate cohort of patients with recurrent or non recurrent disease following radical prostatectomy. An analysis of five selected miRs in urine samples found that miR-107 and miR-574-3p were quantified at significantly higher concentrations in the urine of men with prostate cancer compared with controls. CONCLUSION: These observations suggest that changes in miR concentration in prostate cancer patients may be identified by analysing various body fluids. Moreover, circulating miRs may be used to diagnose and stage prostate cancer. PMID- 22240789 TI - FGFR2 gene amplification and clinicopathological features in gastric cancer. AB - BACKGROUND: Frequency of FGFR2 amplification, its clinicopathological features, and the results of high-throughput screening assays in a large cohort of gastric clinical samples remain largely unclear. METHODS: Drug sensitivity to a fibroblast growth factor receptor (FGFR) inhibitor was evaluated in vitro. The gene amplification of the FGFRs in formalin-fixed, paraffin-embedded (FFPE) gastric cancer tissues was determined by a real-time PCR-based copy number assay and fluorescence in situ hybridisation (FISH). RESULTS: FGFR2 amplification confers hypersensitivity to FGFR inhibitor in gastric cancer cell lines. The copy number assay revealed that 4.1% (11 out of 267) of the gastric cancers harboured FGFR2 amplification. No amplification of the three other family members (FGFR1, 3 and 4) was detected. A FISH analysis was performed on 7 cases among 11 FGFR2 amplified cases and showed that 6 of these 7 cases were highly amplified, while the remaining 1 had a relatively low grade of amplification. Although the difference was not significant, patients with FGFR2 amplification tended to exhibit a shorter overall survival period. CONCLUSION: FGFR2 amplification was observed in 4.1% of gastric cancers and our established PCR-based copy number assay could be a powerful tool for detecting FGFR2 amplification using FFPE samples. Our results strongly encourage the development of FGFR-targeted therapy for gastric cancers with FGFR2 amplification. PMID- 22240790 TI - Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. AB - BACKGROUND: Whether red and processed meat consumption is a risk factor for pancreatic cancer remains unclear. We conducted a meta-analysis to summarise the evidence from prospective studies of red and processed meat consumption and pancreatic cancer risk. METHODS: Relevant studies were identified by searching PubMed and EMBASE databases through November 2011. Study-specific results were pooled using a random-effects model. RESULTS: Eleven prospective studies, with 6643 pancreatic cancer cases, were included in the meta-analysis. An increase in red meat consumption of 120 g per day was associated with an overall relative risk (RR) of 1.13 (95% confidence interval (CI)=0.93-1.39; P(heterogeneity)<0.001). Red meat consumption was positively associated with pancreatic cancer risk in men (RR=1.29; 95% CI=1.08-1.53; P(heterogeneity)=0.28; five studies), but not in women (RR=0.93; 95% CI=0.74-1.16; P(heterogeneity)=0.21; six studies). The RR of pancreatic cancer for a 50 g per day increase in processed meat consumption was 1.19 (95% CI=1.04-1.36; P(heterogeneity)=0.46). CONCLUSION: Findings from this meta-analysis indicate that processed meat consumption is positively associated with pancreatic cancer risk. Red meat consumption was associated with an increased risk of pancreatic cancer in men. Further prospective studies are needed to confirm these findings. PMID- 22240791 TI - Serum biomarker panels for the diagnosis of gastric adenocarcinoma. AB - BACKGROUND: Currently, serum biomarkers, which are sufficiently sensitive and specific for early detection and risk classification of gastric adenocarcinoma do not exist. Therefore, this study identified a panel of serum biomarkers for the diagnosis of gastric adenocarcinoma. METHODS: A 29-plex array platform with 29 biomarkers, consisting of 11 proteins discovered through proteomics and 18 previously known to be cancer-associated, was constructed. A test/training set consisting of 120 gastric adenocarcinoma and 120 control samples were examined. After 13 proteins were selected as candidate biomarkers, multivariate classification analyses were used to identify algorithms for diagnostic biomarker combinations. These algorithms were independently validated using a set of 95 gastric adenocarcinoma and 51 control samples. RESULTS: Epidermal growth factor receptor (EGFR), pro-apolipoprotein A1 (proApoA1), apolipoprotein A1, transthyretin (TTR), regulated upon activation, normally T-expressed and presumably secreted (RANTES), D-dimer, vitronectin (VN), interleukin-6, alpha-2 macroglobulin, C-reactive protein and plasminogen activator inhibitor-1 were selected as classifiers in the two algorithms. These algorithms differentiated between the majority of gastric adenocarcinoma and control serum samples in the training/test set with high accuracy (>88%). These algorithms also accurately classified in the validation set (>85%). CONCLUSION: Two panels of combinatorial biomarkers, including EGFR, TTR, RANTES, and VN, are developed, which are less invasive method for the diagnosis of gastric adenocarcinoma. They could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy. PMID- 22240793 TI - Features of childhood cancer in primary care: a population-based nested case control study. AB - BACKGROUND: This study investigated the risk of cancer in children with alert symptoms identified in current UK guidance, or with increased consultation frequency in primary care. METHODS: A population-based, nested case-control study used data from the General Practice Research Database. In all, 1267 children age 0-14 years diagnosed with childhood cancer were matched to 15,318 controls. Likelihood ratios and positive predictive values (PPVs) were calculated to assess risk. RESULTS: Alert symptoms recorded in the 12 and 3 months before diagnosis were present in 33.7% and 27.0% of cases vs 5.4% and 1.4% of controls, respectively. The PPV of having cancer for any alert symptom in the 3 months before diagnosis was 0.55 per 1000 children. Cases consulted more frequently particularly in the 3 months before diagnosis (86% cases vs 41% controls). Of these, 36% of cases and 9% of controls had consulted 4 times or more. The PPV for cancer in a child consulting 4 times or more in 3 months was 0.13 per 1000 children. CONCLUSION: Alert symptoms and frequent consultations are associated with childhood cancer. However, individual symptoms and consultation patterns have very low PPVs for cancer in primary care (e.g., of 10,000 children with a recorded alert symptom, approximately 6 would be diagnosed with cancer within 3 months). PMID- 22240792 TI - Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). AB - BACKGROUND: To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC). METHODS: Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1) every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg( 1) every 3 weeks (Arm-B). RESULTS: Three hundred thirty-three patients (Arm A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm. CONCLUSION: The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC. PMID- 22240794 TI - Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma. AB - BACKGROUND: In a randomized phase III trial of sunitinib vs interferon-alfa (IFN alpha) in metastatic renal cell carcinoma (mRCC), better baseline quality of life (QoL) was predictive of longer survival. Using this dataset, we have developed a novel prognostic tool that establishes a relationship between baseline QoL scores and median survival time. METHODS: Baseline QoL was assessed using the FACT Kidney Symptom Index-15 item (FKSI-15), its disease-related symptoms (FKSI-DRS) subscale, and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. Weibull models estimated median progression-free survival (mPFS) and overall survival (mOS) as a function of baseline QoL. RESULTS: Longer PFS and OS were associated with higher baseline FKSI-15, FKSI-DRS, and FACT-G scores (P<0.05), and baseline FKSI-15 score was the best predictor of survival. For example, for a baseline FKSI-15 score of 60, the predicted mPFS was 67.9 weeks, and predicted mOS was 240.6 weeks. The magnitude of benefit was greater with sunitinib vs IFN alpha for a given baseline QoL score. CONCLUSION: This novel tool indicates that baseline FKSI-15 scores were linked to mPFS and mOS in a clear and interpretable way. The results support evaluation of patient-reported QoL symptoms at baseline as a prognostic indicator of survival in clinical research and practice. PMID- 22240796 TI - Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients. AB - BACKGROUND: This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2. METHODS: The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks. RESULTS: In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d. CONCLUSION: The toxicity profile and PK properties of oral TAK-285 warrant further evaluation. PMID- 22240795 TI - The DNA damage response in viral-induced cellular transformation. AB - The DNA damage response (DDR) has emerged as a critical tumour suppressor pathway responding to cellular DNA replicative stress downstream of aberrant oncogene over-expression. Recent studies have now implicated the DDR as a sensor of oncogenic virus infection. In this review, we discuss the mechanisms by which tumour viruses activate and also suppress the host DDR. The mechanism of tumour virus induction of the DDR is intrinsically linked to the need for these viruses to promote an S-phase environment to replicate their nucleic acid during infection. However, inappropriate expression of viral oncoproteins can also activate the DDR through various mechanisms including replicative stress, direct interaction with DDR components and induction of reactive oxygen species. Given the growth-suppressive consequences of activating the DDR, tumour viruses have also evolved mechanisms to attenuate these pathways. Aberrant expression of viral oncoproteins may therefore promote tumourigenesis through increased somatic mutation and aneuploidy due to DDR inactivation. This review will focus on the interplay between oncogenic viruses and the DDR with respect to cellular checkpoint control and transformation. PMID- 22240797 TI - Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection. AB - BACKGROUND: Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer among HIV-infected persons, in addition to smoking. METHODS: A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer Registries (1985-2010), and were individually matched to 337 controls by centre, gender, HIV transmission category, age and calendar period. Odds ratios (ORs) were estimated by conditional logistic regression. RESULTS: Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its strong association with lung cancer (OR for current vs never=14.4, 95% confidence interval (95% CI): 3.36-62.1). No significant associations were observed between CD4+ cell count and lung cancer, neither when measured within 1 year (OR for <200 vs >=500=1.21, 95% CI: 0.49-2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not significantly associated with lung cancer (OR for ever vs never=0.67, 95% CI: 0.29-1.52), and nor was a history of AIDS with (OR=0.49, 95% CI: 0.19-1.28) or without (OR=0.53, 95% CI: 0.24-1.18) pulmonary involvement. CONCLUSION: Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary disease, but seems to be attributable to heavy smoking. PMID- 22240798 TI - Loss of PTEN is associated with elevated EGFR and HER2 expression and worse prognosis in salivary gland cancer. AB - BACKGROUND: Activity of the tumour-suppressor gene PTEN is reduced in different types of cancer and implicates non-responsiveness to targeted therapy. This study evaluates the gene and protein status of PTEN in salivary gland carcinomas. METHODS: A total of 287 carcinomas of the major and minor salivary glands were investigated for phosphatase and tensin homologue located on chromosome 10 (PTEN) deletion and loss of PTEN expression using fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC), respectively. Results were correlated to clinicopathological parameters, long-term survival, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (IHC and FISH) status of the tumours. RESULTS: Hemizygous deletions of PTEN were found in 35 out of 232 (15.1%) carcinomas, while homozygous deletions were observed in 17 out of 232 (7.3%) tumours. Phosphatase and tensin homologue located on chromosome 10 deletion was common in certain histological subtypes and especially homozygous deletion was associated with high-grade malignancy, lymph node metastases and unfavourable long-term prognosis (P<0.001). Loss of PTEN expression was present in 59 out of 273 (21.6%) carcinomas and was significantly correlated to genomic PTEN deletion, high-grade malignancy (P<0.001), increased tumour size (P=0.036), lymph node metastases (P=0.007) and worse disease-specific survival (P=0.002). Genomic PTEN deletion, in particular homogenous deletion (P<0.001) predominantly occurred in tumours with increased gene copy number of EGFR (60.0%) and/or amplification of HER2 (63.6%). Loss of PTEN expression was frequently found in tumours overexpressing EGFR (28.6%) and/or HER2 (52.6%). CONCLUSION: PTEN function is reduced in different types of salivary gland cancer indicating unfavourable prognosis. Its association with EGFR and HER2 signalling might affect targeted therapy. PMID- 22240800 TI - CA-125 can be part of the tumour evaluation criteria in ovarian cancer trials: experience of the GCIG CALYPSO trial. AB - BACKGROUND: CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression. METHODS: In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression. RESULTS: In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment. CONCLUSION: CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment. PMID- 22240799 TI - Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer. AB - BACKGROUND: There are still no effective treatments for superficial bladder cancer (SBC)/non-muscle invasive bladder cancer. Following treatment, 20% of patients still develop metastatic disease. Superficial bladder cancer is often multifocal, has high recurrences after surgical resection and recurs after intravesical live Bacillus Calmette-Guerin. Oncovex(GALV/CD), an oncolytic herpes simplex virus-1, has shown enhanced local tumour control by combining oncolysis with the expression of a highly potent pro-drug activating gene and the fusogenic glycoprotein. METHODS: In vitro fusion/prodrug/apoptotic cell-based assays. In vivo orthotopic bladder tumour model, visualised by computed microtomography. RESULTS: Treatment of seven human bladder carcinoma cell lines with the virus resulted in tumour cell killing through oncolysis, pro-drug activation and glycoprotein fusion. Oncovex(GALV/CD) and mitomycin C showed a synergistic effect, whereas the co-administration with cisplatin or gemcitabine showed an antagonistic effect in vitro. Transitional cell cancer (TCC) cells follow an apoptotic cell death pathway after infection with Oncovex(GALV/CD) with or without 5-FC. In vivo results showed that intravesical treatment with Oncovex(GALV/CD) + prodrug (5-FC) reduced the average tumour volume by over 95% compared with controls. DISCUSSION: Our in vitro and in vivo results indicate that Oncovex(GALV/CD) can improve local tumour control within the bladder, and potentially alter its natural history. PMID- 22240809 TI - FOXO1 increases CCL20 to promote NF-kappaB-dependent lymphocyte chemotaxis. AB - Hepatic insulin resistance (IR) is associated with liver inflammatory diseases, but molecular mechanisms for the association remained elusive. IR is known to increase activity of forkhead box-containing protein O subfamily-1 (FOXO1), a transcription factor that was recently shown to enhance proinflammatory cytokine production in macrophages and adipocytes. Here we report that overexpression of constitutively active FOXO1 markedly increased chemokine ligand 20 (CCL20) expression and secretion in HepG2 hepatoma cells treated with TNF-alpha. The opposite was seen when endogenous FOXO1 was silenced. FOXO1 did not bind CCL20 promoter directly; instead, it potentiated CCL20 transcription through increasing the binding of p65/p50 heterodimer to a functional nuclear factor-kappaB site in the human CCL20 promoter. The conditional medium from TNF-alpha-treated HepG2 cells stimulated migration of human peripheral blood mononuclear cells. This stimulation was significantly enhanced when FOXO1 was overexpressed, and attenuated when FOXO1 was silenced. CCL20 antibody partly blocked the synergistic effect of FOXO1 and TNF-alpha on peripheral blood mononuclear cells migration. Additionally, TNF-alpha antagonizes the insulin/Akt signal transduction, thus leading to activation of FOXO1, which is capable of mediating a transcriptional activation role in response to TNF-alpha on CCL20 gene expression in HepG2 cells and promotes lymphocyte chemotaxis. Furthermore, we found that FOXO1 and CCL20 were coordinately up-regulated in the insulin resistant and inflammatory cell infiltrated liver of db/db mice, an animal model that displayed hepatic and systemic low-grade inflammation. In conclusion, our data suggest that FOXO1 links IR to lymphocyte chemotaxis in the insulin-resistant hepatocytes and livers by amplifying nuclear factor-kappaB-dependent hepatic CCL20 production. PMID- 22240810 TI - Deletion of CaMKK2 from the liver lowers blood glucose and improves whole-body glucose tolerance in the mouse. AB - Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca(2+)/CaM-dependent protein kinase family that is expressed abundantly in brain. Previous work has revealed that CaMKK2 knockout (CaMKK2 KO) mice eat less due to a central nervous system -signaling defect and are protected from diet-induced obesity, glucose intolerance, and insulin resistance. However, here we show that pair feeding of wild-type mice to match food consumption of CAMKK2 mice slows weight gain but fails to protect from diet-induced glucose intolerance, suggesting that other alterations in CaMKK2 KO mice are responsible for their improved glucose metabolism. CaMKK2 is shown to be expressed in liver and acute, specific reduction of the kinase in the liver of high-fat diet-fed CaMKK2(floxed) mice results in lowered blood glucose and improved glucose tolerance. Primary hepatocytes isolated from CaMKK2 KO mice produce less glucose and have decreased mRNA encoding peroxisome proliferator-activated receptor gamma coactivator 1 alpha and the gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, and these mRNA fail to respond specifically to the stimulatory effect of catecholamine in a cell-autonomous manner. The mechanism responsible for suppressed gene induction in CaMKK2 KO hepatocytes may involve diminished phosphorylation of histone deacetylase 5, an event necessary in some contexts for derepression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha promoter. Hepatocytes from CaMKK2 KO mice also show increased rates of de novo lipogenesis and fat oxidation. The changes in fat metabolism observed correlate with steatotic liver and altered acyl carnitine metabolomic profiles in CaMKK2 KO mice. Collectively, these results are consistent with suppressed catecholamine-induced induction of gluconeogenic gene expression in CaMKK2 KO mice that leads to improved whole-body glucose homeostasis despite the presence of increased hepatic fat content. PMID- 22240812 TI - Lateral supraorbital approach applied to tuberculum sellae meningiomas: experience with 52 consecutive patients. AB - BACKGROUND: Various surgical approaches for the removal of tuberculum sellae meningiomas (TSMs) have previously been described. OBJECTIVE: To assess the reliability and safety of the lateral supraorbital (LSO) approach to remove TSMs. METHODS: We identified all TSM patients operated on at the Department of Neurosurgery at Helsinki University Central Hospital, Finland, by the senior author (J.H.) using the LSO approach between September 1997 and August 2010. We retrospectively analyzed the clinical data, radiological findings, surgical treatment, histology, and outcome of patients and discuss the operative technique. RESULTS: Apparent complete tumor removal was achieved in 45 patients (87%). Of 42 patients, preexisting visual deficit improved in 22, remained the same in 13, and worsened in 7, and de novo visual deficit occurred in 1 patient. At 3 months post-discharge, 47 patients (90%) had a good recovery, 4 (8%) were moderately disabled, and 1 (2%) died 40 days after surgery of unexplained cardiac arrest. Seven patients (13%) had minimal residual tumors, 2 of which required reoperation. During the median follow-up of 59 months (range, 1-133 months), tumor recurred in 1 of the patients who had undergone a second operation. CONCLUSION: TSMs of all sizes can be removed via the LSO approach with minimal morbidity and mortality. Low-power or no coagulation is recommended near the optic nerves and the optic chiasm to preserve their vascular support from the internal carotid artery perforators. Our results are comparable to those obtained using more extensive and time-consuming approaches. We recommend the LSO approach to remove TSMs. PMID- 22240811 TI - PPAR-gamma activation restores pancreatic islet SERCA2 levels and prevents beta cell dysfunction under conditions of hyperglycemic and cytokine stress. AB - The maintenance of intracellular Ca(2+) homeostasis in the pancreatic beta-cell is closely regulated by activity of the sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) pump. Our data demonstrate a loss of beta-cell SERCA2b expression in several models of type 2 diabetes including islets from db/db mice and cadaveric diabetic human islets. Treatment of 832/13 rat INS-1-derived cells with 25 mm glucose and the proinflammatory cytokine IL-1beta led to a similar loss of SERCA2b expression, which was prevented by treatment with the peroxisome proliferator-activated receptor (PPAR)-gamma agonist, pioglitazone. Pioglitazone was able to also protect against hyperglycemia and cytokine-induced elevations in cytosolic Ca(2+) levels, insulin-secretory defects, and cell death. To determine whether PPAR-gamma was a direct transcriptional regulator of the SERCA2 gene, luciferase assays were performed and showed that a -259 bp region is sufficient to confer PPAR-gamma transactivation; EMSA and chromatin immunoprecipitation experiments confirmed that PPAR-gamma directly binds a PPAR response element in this proximal region. We next sought to characterize the mechanisms by which SERCA2b was down-regulated. INS-1 cells were exposed to high glucose and IL-1beta in time course experiments. Within 2 h of exposure, activation of cyclin dependent kinase 5 (CDK5) was observed and correlated with increased serine-273 phosphorylation of PPAR-gamma and loss of SERCA2 protein expression, findings that were prevented by pioglitazone and roscovitine, a pharmacological inhibitor of CDK5. We conclude that pioglitazone modulates SERCA2b expression through direct transcriptional regulation of the gene and indirectly through prevention of CDK5-induced phosphorylation of PPAR-gamma. PMID- 22240813 TI - [Errors about legionnaire disease in hospitals]. PMID- 22240814 TI - [Faith and morals in aid work]. PMID- 22240816 TI - [Pop the Champagne]. PMID- 22240817 TI - [The Supreme Court's verdict is correct]. PMID- 22240818 TI - [Stroke--a multidisciplinary approach]. PMID- 22240819 TI - [Independent research environments are!]. PMID- 22240820 TI - [Psychotherapy supervision in specialist training]. PMID- 22240822 TI - Poor follow-up after screening for tuberculosis. PMID- 22240823 TI - [Tuberculosis among asylum seeking persons in state admission centers]. PMID- 22240824 TI - Symptom assessment in palliative medicine. PMID- 22240825 TI - Life expectancy and cause of death in men examined at medical check-ups in 1964. AB - BACKGROUND: The purpose of the study was to determine the associations between blood pressure, body mass index and smoking habits, recorded at routine health check-ups with the occupational health officer, and life expectancy and cause specific mortality through several decades. MATERIAL AND METHODS: Participants in the Linseed Oil Study were followed from 1967 through 2005 with respect to total and cause-specific mortality in the Cause of Death Registry. The population studied consisted of 15,934 men who were born between 1905 and 1914 and were in work in 1967. The analyses used various multivariate regression methods. RESULTS: A total of 15,535 participants (97.5%) had died, and the average age at death was 76.6 years (SD 9.1). Blood pressure, body mass index and cigarette smoking were related to the age of death and mortality due to cardiovascular disease, lung cancer and respiratory system diseases. High systolic blood pressure (>= 160 mm) was associated with a life-expectancy shortening of 5 years, 15 cigarettes daily with 3.5 years and a confirmed elevated sedimentation rate with a 3.3 year shortening of life expectancy. The excess mortality persisted throughout the follow-up period. The association with blood pressure gradually lessened, while the association with smoking and body mass index did not change over time. The association with smoking was weaker than in most early studies. INTERPRETATION: The results of routine health check-ups in the occupational health service can predict lost years of life through several decades. PMID- 22240826 TI - Attitudes to seeking medical assistance--variations depending on social background? AB - BACKGROUND: Increasing socio-economic inequalities in health, within a country as well as internationally, give rise to a timely question: Are there any systematic differences between people from differing social backgrounds with regard to their attitude to seeking professional medical assistance when experiencing physical problems of varying kinds? MATERIAL AND METHOD: The data material is taken from the Norwegian part of the cross-sectional survey "European Social Survey" (2004 2005). The analyses are based on data from personal interviews with 741 men and 694 women aged 25-75. The correlation between education level and attitude to seeking medical assistance in the case of four minor hypothetical symptoms was analysed using logistic regression. RESULTS: The proportion responding that they would have sought medical attention decreased with increasing level of education. In the unadjusted analyses, the education-related differences were statistically significant for all symptom scenarios for both genders. In the adjusted analyses, this pattern was observed only among women: women with the lowest level of education chose to see a doctor more often than women with the highest level of education (OR varied from 1.62 (95% CI 1.02-2.56) for a severe headache to 2.24 (95% CI 1.40-3.58) for a sore throat). INTERPRETATION: The findings indicate that attitudes to seeking medical assistance - in the sense of how people believe they ought to think and act, and what they believe to be perceived as socially acceptable in given situations - vary systematically with level of education. PMID- 22240827 TI - How does kidney transplantation affect the relationship between donor and recipient? AB - BACKGROUND: There is now a widespread use of kidneys from living donors in Norway. This results in reduced mortality and disease among recipients compared with the use of kidneys from deceased donors. However, there are numerous ethical issues connected with the use of organs from living donors. This article aims to examine how the relationship between recipients and known, living donors is affected by transplantation. MATERIAL AND METHODS: The article is based on a systematic literature search in MedLine. RESULTS: There is little research concerning the direct impact on the relationship between donor and recipient. Most donors report having an improved, or equally good relationship with recipients after transplantation. However, one study shows that when recipients receive a kidney from a parent during adolescence, conflicts frequently arise. The material also shows that good relationships have a tendency to improve, while poor or imbalanced relationships more often deteriorate following transplantation. INTERPRETATION: It is very important to survey the relationship between a recipient and a potential donor before transplantation to avoid relational conflicts. PMID- 22240828 TI - [Dravet syndrome as a cause of epilepsy and learning disability]. AB - BACKGROUND: Dravet syndrome is a severe, genetic epileptic encephalopathy with seizures starting during the first year of life. We present a review of the genetic and clinical picture along with treatment aspects. MATERIAL AND METHODS: This review is based on a non-systematic literature search in PubMed until April 2011 and the personal experiences of the authors. RESULTS: Dravet syndrome should be suspected in children with febrile hemiconvulsions or tonic-clonic seizures in the first year of life. Non-febrile seizures also occur, and other seizure types gradually appear, e.g. myoclonic jerks, atypical absences or focal seizures. In adulthood the clinical picture is less characteristic. The clinical diagnosis is supported by genetic testing; 70-80% of the patients have mutations in the sodium channel subunit gene SCN1A. Seizure control is difficult to achieve, but valproate, benzodiazepines and stiripentol may cause improvement, whereas sodium channel blockers, such as lamotrigine and carbamazepine may aggravate the tendency towards seizures. INTERPRETATION: Dravet syndrome appears to be an under recognised condition among both children and adults with severe epilepsy and learning disability. Clinical information from the first years of life is essential in making the diagnosis. A correct diagnosis at an early age is essential for appropriate treatment and genetic counselling. PMID- 22240829 TI - Young woman with lasting back pain. PMID- 22240830 TI - [A man in his 50's with fever, reduced consciousness and rigidity]. PMID- 22240831 TI - The devil is in the details. PMID- 22240832 TI - [Sick from sickness, substance abuse or medicine]. PMID- 22240833 TI - Self-help groups for substance addiction. PMID- 22240834 TI - [100 years with vitamins]. PMID- 22240835 TI - [Do we take tuberculosis seriously?]. PMID- 22240836 TI - The prognosis for pancreatic cancer patients--better than feared. PMID- 22240837 TI - [What is the duration of pregnancy?]. PMID- 22240838 TI - Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake. AB - Cyclosporin A (CsA) causes a number of clinically relevant drug-drug interactions (DDIs) by inhibiting OATP1B1 and OATP1B3. In the present study, long-lasting inhibitory effects of CsA on these transporters were examined in comparison to tacrolimus (TCR). OATP1B1- and OATP1B3-expressing HEK293T cells, OATP1B1 expressing MDCK II cells, and human hepatocytes were preincubated with CsA or TCR, and uptake studies were carried out in their presence or absence. Western blot or immunohistochemical studies were done in OATP1B1-expressing HEK293T cells. The pretreatment of OATP1B1- and OATP1B3-expressing cells with 0.5-10 uM CsA, but not TCR, resulted in a reduction in their activity, even after washing out CsA from the incubation media. Preincubating the cells with CsA significantly enhanced its inhibitory effects on OATP1B1 and OATP1B3 by coincubation at 0.1-1 uM. Preincubation with 1 uM CsA caused a reduction in OATP1B1 activity for at least 18 h after its removal. The expression of OATP1B1 was not affected by incubation with CsA and no obvious change in its intracellular localization was observed. The long-lasting inhibition by CsA was also observed in human hepatocytes. Thus, CsA has a long-lasting inhibitory effect on OATP1B1 and OATP1B3. It may attribute to the clinically relevant DDIs between OATP substrates and CsA. PMID- 22240839 TI - Impact of concomitant antacid administration on gabapentin plasma exposure and oral bioavailability in healthy adult subjects. AB - The aim of this open-label, randomized, and 3-period crossover study was to evaluate the influences of concomitant antacid administration on the plasma disposition, intestinal absorption, and urinary excretion of gabapentin in humans. Gabapentin (200 mg) was orally administered alone, with 1 g magnesium oxide (MgO), or with 20 mg omeprazole to 13 healthy adult subjects. Oral bioavailability (BA) of gabapentin was estimated by 24-h urine collection. The C(max), T(max) and AUC(0-infinity) of gabapentin + MgO were significantly lower than that of gabapentin alone (by 33%, 36% and 43%, respectively) and gabapentin + omeprazole (by 29%, 46% and 40%, respectively). In contrast, no significant differences were observed in the plasma disposition parameters of gabapentin between the treatments with and without omeprazole. The gabapentin BA in the MgO treatment was significantly lower, by 32% and 39%, compared to the gabapentin alone and with omeprazole treatment, respectively. There was no significant difference in the gabapentin BA between the gabapentin alone and with omeprazole treatment. Concomitant MgO and omeprazole did not affect the renal clearance of gabapentin. In conclusion, concomitant MgO decreased the gabapentin exposure through the reduction of intestinal absorption extent and rate. This reduction may be independent of the suppression of gastrointestinal acidification caused by antacids. PMID- 22240840 TI - The effects of N-glycosylation on the glucuronidation of zidovudine and morphine by UGT2B7 expressed in HEK293 cells. AB - UDP-glucuronosyltransferases (UGTs) are glycoproteins in endoplasmic reticulum membranes. UGT2B7 is an important UGT isoenzyme expressed in human liver and glucuronidates various endogenous and exogenous substances. Although this enzyme has three potential N-glycosylation sites (asparagine at positions 67, 68 and 315), no information is available on the actual glycosylated sites and the effects of N-glycosylation on its enzymatic functions. We thus constructed HEK293 cells expressing wild-type UGT2B7 and five mutants (N67Q, N68Q, N315Q, N68Q/N315Q and N67Q/N68Q/N315Q) in which an asparagine at one or more potential N glycosylation sites was substituted with a glutamine. An immunoblot analysis of whole cell lysate (S9) fractions with or without treatment with an endoglycosidase revealed that UGT2B7 was N-glycosylated at Asn-68 and Asn-315 but not Asn-67. Kinetic analysis employing the S9 fractions as enzyme sources and zidovudine (AZT) and morphine as typical substrates demonstrated that the abolition of N-glycosylation decreased the affinity for AZT but increased that for morphine without affecting reaction velocities, while it decreased the affinity for UDPGA as a cofactor regardless of the substrate used. These results suggest that N-glycosylation differentially affects the glucuronidation of AZT and morphine by human UGT2B7. PMID- 22240841 TI - Genetic variations of the MCT4 (SLC16A3) gene in the Chinese and Indian populations of Singapore. AB - MCT4 (SLC16A3) is the third member of the monocarboxylate transporter (MCT) family and is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study aimed to identify genetic variations of the SLC16A3 gene that may be present in the ethnic Chinese (n = 95) and Indian (n = 96) groups of the Singaporean population. The genetic variations in the promoter, coding region and exon-intron junctions of the SLC16A3 gene encoding the MCT4 transporter were screened by DNA sequencing. A total of 46 genetic variants were detected in the SLC16A3 gene, of which 33 are novel. Of these variants, 22 are located in the promoter regions, 2 in the 5' untranslated region (UTR), 10 in the coding exons (5 nonsynonymous and 5 synonymous variations), 6 in 3'UTR and 6 in the intron. Of the 5 nonsynonymous variants, only 44C>T (Ala15Val) was predicted by PolyPhen and SIFT as having a potentially damaging effect on protein function, whereas 55G>A (Gly19Ser), 574G>A (Val192Met) and 916G>A (Gly306Ser) had conflicting results between the SIFT and PolyPhen algorithms. Finally, 641C>T (Ser214Phe) was predicted to be a tolerated variant. PMID- 22240842 TI - Pharmacokinetics and pharmacodynamics of KR-66223, a novel DPP-4 inhibitor. AB - KR-66223 is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. We studied the pharmacokinetic and pharmacodynamic characteristics of KR-66223 in rats, monkeys, and dogs to predict PK/PD profiles in humans. KR-66223 exhibited a moderate volume of distribution (0.3-1.8 L/kg), moderate systemic clearance (1-1.76 L/h/kg), long half-life (>3 h), and low oral bioavailability (below 2.5% in all tested species). The EC(50)s for DPP-4 inhibition as calculated by the E(max) model was below 4.25 ng/mL across all species, confirming KR-66223 as a potent DPP-4 inhibitor. In vitro plasma protein binding suggested that it was available (69 89%), correlating with its volume of distribution in animals. Using allometric scaling and the E(max) model, human systemic clearance, volume of the central compartment, volume of the peripheral compartment, and EC50 for DPP-4 inhibition were predicted to be 0.31 L/h/kg, 0.1 L/kg, 2.4 L/kg, and 3 ng/mL, respectively. These results can serve as a valuable foundation for future clinical trials. PMID- 22240844 TI - Leadership and social enterprise in tissue viability. PMID- 22240843 TI - Physicochemical and pharmacokinetic characterization of amorphous solid dispersion of tranilast with enhanced solubility in gastric fluid and improved oral bioavailability. AB - In the present study, amorphous solid dispersion (ASD) formulations of tranilast (TL) with 8 hydrophilic polymers were prepared by a solvent evaporation method with the aim of improving dissolution behavior in gastric fluid and thereby enhancing oral bioavailability. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, drug polymer interaction, and stability. Of all TL formulations, ASD formulation with Eudragit EPO exhibited the highest improvement in dissolution behavior with a 3,000-fold increase in the first-order dissolution rate under acidic conditions (pH 1.2). Spectroscopic studies using infrared and near-infrared analyses revealed the drug-polymer interaction in the Eudragit EPO-based ASD formulation. On the basis of dissolution, crystallinity, and stability data, the maximum allowable drug load in the Eudragit EPO-based ASD formulation was deduced to be ca. 50%. Pharmacokinetic profiling of orally dosed TL formulations in rats was also carried out using UPLC/ESI-MS. After oral administration of the Eudragit EPO based ASD formulation in rats, enhanced TL exposure was observed with an increase of oral bioavailability by 19-fold, and the variation of AUC was ca. 4 times lower than that with crystalline TL. With these data, the ASD approach could be a viable formulation strategy for enhancing the wettability and oral bioavailability of TL, resulting in improved therapeutic potential of TL for the treatment of inflammatory diseases. PMID- 22240845 TI - Use of ultrasound in assessment of necrotic tissue in pressure ulcers with adjacent undermining. AB - OBJECTIVE: To reveal the specific ultrasonic imaging findings of non-visible necrotic tissue in pressure ulcers (PUs) with undermining and describe the images objectively. The predictive validity of the specific images of the undermined necrotic tissue was also determined. METHOD: Using digital ultrasonography (12 MHz linear transducer, MyLab25; Hitachi Medical Corporation), we imaged PUs with undermining every 2 weeks. PUs were also monitored by DESIGN-R, a PU assessment tool, at the same time. RESULTS: Ten patients had 11 PUs with undermining and all ulcers were located in the sacral region. The necrotic tissue showed high echogenicity with no layers, unclear borders and an uneven gray level (cloud-like image). Granulation tissue appeared as a low echoic image which had no layers, was of coarse resolution and an even gray level. There were significant differences between the pixel uniformity of the necrotic tissue (84.0) and granulation tissue (53.9) compared with uninjured tissue (65.5; p=0.000 and 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of cloud-like image were 87.5%, 91.7%, 77.8% and 95.6%, respectively. CONCLUSION: The results suggest that cloud-like image is the most useful diagnostic indicator for non-visible necrotic tissue in PUs with undermining and is the best prognostic indicator for PU healing. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare. There were no external sources of funding for this study. PMID- 22240846 TI - The experience of patients with complex wounds and the use of NPWT in a home-care setting. AB - OBJECTIVE: To explore the experience of patients living with complex wounds and the impact of undergoing negative pressure wound therapy (NPWT) as part of their treatment. METHOD: Qualitative data were collected from eight patients, using semi-structured interviews. A purposive, stratified sampling approach was used to identify participants with a range of wound types, as well as age and gender. Participants were recruited from one primary care trust and were interviewed, following 10 days of treatment with NPWT. The matrix-based 'Framework' approach, from the National Centre for Social Research, was used to structure the analysis. RESULTS: Of the eight participants recruited, five were female and three male, with an age range of 46-77 years. Five overarching categories, with their constituent themes, were identified from the data. The first, developing a wound through crisis, has three themes: a failing body, missed diagnosis and failed professional intervention. The second category, decreased control, has four related themes: poor communication; failed wound healing; poor discharge planning and failure to recover. The third category, increased control, has four themes: understanding what is happening; symptom control; positive professional relationships and returning to health. The fourth category, using NPWT, has two themes: information and understanding of NPWT and expectations and experience of NPWT. The final category sets out participant recommendations about the device and has two themes: device issues and improving professional practice. CONCLUSION: This study investigated the experience of patients undergoing NPWT for complex wounds in the home setting and reveals a number of the psychosocial effects of using this therapy in this environment. Participants saw NPWT as an active intervention, associated with improved wound healing and symptom control. The participant experience described in this study, and the recommendations they make, provide a valuable resource to inform service improvement programmes and wound research. DECLARATION OF INTEREST: This study was supported by a research grant from Smith & Nephew Ltd. PMID- 22240847 TI - Manuka honey as an effective treatment for chronic pilonidal sinus wounds. AB - OBJECTIVE: A retrospective study to investigate the effectiveness of topical manuka honey in the treatment of chronic or recurrent pilonidal sinus disease (PSD), assessing the ability of this simple dressing technique to achieve complete wound healing, the time taken to achieve healing and the recurrence rate. METHOD: All patients who received manuka honey dressing therapy following surgical intervention for chronic or recurrent PSD were identified over a 4-year period. In a retrospective review of case notes, data were collected on patient sex, age, nature of surgical procedures performed, time to achieve complete wound healing, and recurrences after completion of honey therapy. RESULTS: Seventeen patients were eligible for inclusion in the study. Mean time to commence honey therapy post-surgery was 93 days (5-517 days; median 33 days); 15 patients achieved complete wound healing, in a mean time of 65 days (14-264 days; median 49 days). Honey was discontinued in one patient due to an adverse event, and two patients experienced recurrence several months after completing honey therapy. CONCLUSION: Manuka honey dressing therapy provides an effective topical treatment for chronic/recurrent PSD. Further research is necessary to determine the optimum dressing protocol. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare. There were no external sources of funding for this study. PMID- 22240848 TI - A cohort study on the efficacy of a polyhexanide-containing biocellulose dressing in the treatment of biofilms in wounds. AB - OBJECTIVE: This cohort study evaluated the clinical efficacy of a polyhexanide containing biocellulose dressing, Suprasorb X+PHMB (Lohmann & Rauscher GmbH), for the eradication of biofilms in non-healing wounds. Polyhexanide (PHMB) has been shown to have microbicidal activity when applied to chronic wounds and burns. METHOD: Twenty-eight patients, aged over 18 years, who presented at an outpatient wound clinic with non-healing locally infected and/or critically colonised wounds of various aetiologies that showed clinical signs of biofilm were included in the study. Sixteen patients (nine females), with a mean age of 60.9+/-21.6 years, were included in the analysis. The patients were prospectively followed for a maximum of 24 weeks or until healing for analysis of safety and efficacy endpoints. Evolution of wound size was conducted with tracings and standardised digital photographs as well as for determining healing rates. RESULTS: At 24 weeks,12 wounds (75%) had healed (complete epithelialisation with no drainage). Of those wounds that had not closed, the mean wound area had reduced by 61% at week 24. Ten patients (63%) had a good reduction of the biofilm, five (32%) scored moderate and one (6%) had no reduction noted at week 24. The mean percentage of granulation tissue had increased significantly (p<0.04) when comparing day 0 (38%) with week 24 (77%). Yellow tissue present in the wound bed decreased (p<0.01): 62% (day 0) versus 23% (week 24). All patients reported reduced pain after dressing change. CONCLUSION: The results suggest that continuous application of PHMB, using a biocellulose wound dressing, reduced biofilm in the stagnating wounds treated, thus promoting healing. The treatment was comfortable, safe and reduced wound pain at dressing change. The PHMB containing biocellulose dressing seems to be suitable for lightly to moderately exuding wounds. DECLARATION OF INTEREST: This study was supported by a scientific grant from Lohmann & Rauscher. PMID- 22240849 TI - Chronic plantar ulcer secondary to congenital indifference to pain. AB - Congenital indifference to pain (CIP) is a rare condition characterised by painless injuries beginning in early life, with normal sensory exam findings. Young people with inexplicable, painless chronic wounds may present to the plastic surgeon for surgical management. Given the young age of onset and high likelihood of postoperative failure, alternative options for closure of non healing wounds should be considered. We present the case of a 17-year-old boy with congenital indifference to pain and successful management of his longstanding plantar ulcer. PMID- 22240850 TI - Silver and nanoparticles of silver in wound dressings: a review of efficacy and safety. AB - Wound infections present a significant clinical challenge, impacting on patient morbidity and mortality, with significant economic implications. Silver impregnated wound dressings have the potential to reduce both wound bioburden and healing time. The silver ion Ag+ is the active antimicrobial entity; it can interfere with thiol (-SH) groups and provoke the generation of reactive oxygen species (ROS), a major contributor to its antibacterial efficacy. Recently, silver nanoparticles have gained considerable interest in wound bioburden reduction and in anti-inflammation, as they can release Ag+ ions at a greater rate than bulk silver, by virtue of their large surface area. If released from dressings, they also have the potential to cross biological compartments. This review aims to consolidate recent findings as to the efficacy and safety of different formulations of silver used as an antiseptic agent in dressings, summarising the features of silver nanomaterials, with particular attention to the dose-dependencies for biological effects, highlighting the need for information on their uptake and potential biological effects. PMID- 22240852 TI - Adapting to change: focus on new policy. PMID- 22240851 TI - Iizaka et al. (2011) critique. PMID- 22240853 TI - Epidemiology of hospitalization for acute bronchiolitis in children: differences between RSV and non-RSV bronchiolitis. AB - We study the clinical, management and outcome differences between respiratory syncytial virus (RSV) positive and negative bronchiolitis. A retrospective review of the medical records of children <= 2 years of age with acute bronchiolitis between January 1995 and December 2006 was done. There were 2,384 patients hospitalized for acute bronchiolitis, and 1,495 (62.7%) were RSV infections. Overall, hospitalization rate was 55/1,000 admissions. Mortality occurred in 0.08% of cases. Bronchiolitis due to RSV was more frequent from November to March (97%). RSV bronchiolitis had longer hospital stays (6 vs. 5 days, P<0.0001), higher risk of intensive care unit (ICU) admission (OR 2.7; 95%CI 1.87-3.9) and more oxygen use (OR 2.2; 95%CI 1.8-2.6). Infants < 2 months had longer median hospital stay (6 vs. 5 days, P <0.0001) and higher risk of ICU admission (OR 3.4; 95%CI 2.5-4.6). Prematures of < 32 gestational weeks, congenital heart disease, and atelectasis/condensation were the main risk factors for ICU admission in both RSV and non-RSV bronchiolitis. The introduction of palivizumab in prematures diminished hospitalization for RSV bronchiolitis, oxygen need, length of hospital stay and mechanical ventilation. In conclusion, this study supports that RSV bronchiolitis seems to be a more severe disease than that caused by other viruses. PMID- 22240854 TI - Restriction modification (RM) tests associated to additional molecular markers for screening prevalent MRSA clones in Brazil. AB - In this study, we associated the restriction modification (RM) tests to the polymerase chain reaction (PCR) detection of molecular markers (SCCmec III, seh, agr II-SCCmec IV, and lukSF) for revealing the main methicillin-resistant Staphylococcus aureus (MRSA) clones circulating in Brazil. This simple and rapid approach allowed a precise classification of the MRSA analyzed when compared with pulsed-field gel electrophoresis (PFGE) data. PMID- 22240855 TI - Tinea capitis due to Microsporum vanbreuseghemii: report of two cases. AB - Two cases of dermatophytosis caused by Microsporum vanbreuseghemii are reported. A 7-year-old boy and his brother were examined for tinea capitis. Hair samples and skin scrapings were collected from each patient to microscopy and culture. Direct microscopic examination of the hairs using lactophenol revealed an ectothrix invasion. Cultures inoculated with portions of clinical material yielded M. vanbreuseghemii after 2 weeks. The identification of the fungi were based on colony morphology on mycobiotic agar, microscopic characteristic on slide cultures, biochemical reactions and hair perforation tests. PMID- 22240857 TI - Metal immobilization and phosphorus leaching after stabilization of pyrite ash contaminated soil by phosphate amendments. AB - In this study we would like to show the importance of a holistic approach to evaluation of chemical stabilization using phosphate amendments. An extensive evaluation of metal stabilization in contaminated soil and an evaluation of the leaching of phosphorus induced after treatment were performed. The soil was highly contaminated with Cu (2894 mg kg(-1)), Zn (3884 mg kg(-1)), As (247 mg kg( 1)), Cd (12.6 mg kg(-1)) and Pb (3154 mg kg(-1)). To immobilize the metals, mixtures of soil with phosphate (from H(3)PO(4) and hydroxyapatite (HA) with varying ratios) were prepared with a constant Pb : P molar ratio of 1: 10. The acetic acid extractable concentration of Pb in the mixture with the highest amount of added phosphoric acid (n(H(3)PO(4)) : n(HA) = 3 : 1) was reduced to 1.9% (0.62 mg L(-1)) of the extractable Pb concentration in the untreated soil, but the content of water extractable phosphorus in the samples increased from 0.04 mg L(-1) in the untreated soil sample up to 14.3 mg L(-1) in the same n(H(3)PO(4)) : n(HA) = 3 : 1 mixture. The high increase in arsenic mobility was also observed after phosphate addition. The PBET test showed phosphate induced reduction in Pb bioavailability. In attempting to stabilize Pb in the soil with the minimum treatment-induced leaching of phosphorus, it was found that a mixture of soil with phosphate addition in the molar ratio of H(3)PO(4) : HA of 0.75 : 1 showed the most promising results, with an acetic acid extractable Pb concentration of 1.35 mg L(-1) and a water extractable phosphorus concentration of 1.76 mg L(-1). The time-dependent leaching characteristics of metals and phosphorus for this mixture were evaluated by a column experiment, where irrigation of the soil mixture with the average annual amount of precipitation in Slovenia (1000 mm) was simulated. The phosphorus concentration in the leachates decreased from 2.60 mg L(-1) at the beginning of irrigation to 1.00 mg L(-1) at the end. PMID- 22240858 TI - Low-dose glucocorticoid therapy complements the pituitary-adrenocortical system and reduces anxiety and insomnia in myasthenia gravis patients. AB - Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors of the skeletal muscles. Depending on the disease burden, MG patients may experience chronic dysregulation of both the hormonal stress axis and the immune system, consequently, aggravating the disease itself but also leading to secondary psychopathological abnormalities. A long term clinical course requires long-term glucocorticoid (GC) therapy, which may change the psychological state by affecting the pituitary-adrenocortical system in MG patients. In this study, we investigated the function of the pituitary adrenocortical system in MG patients who were treated with prednisolone (PSL) and evaluated their quality of life by using the Medical Outcomes Study 36-item Short Form Health Survey and the 28-item general health questionnaire (GHQ-28). ACTH and cortisol levels in the plasma of patients who were treated with PSL (PSL[+] group, n = 18) were lower than those in the plasma of patients who were treated without PSL (PSL[-] group, n = 29; P < 0.05 and P < 0.01, respectively). In the PSL(+) group, we confirmed that cortisol levels negatively correlated with daily PSL dosages (P < 0.05). The anxiety and depression scores from the GHQ-28 in the PSL(+) group were lower than those in the PSL(-) group (P < 0.05, respectively). There was no significant correlation between cortisol levels and corticotropin levels in plasma of the PSL(-) group. However, we confirmed that corticotropin levels positively correlated with cortisol levels in plasma (P < 0.01) and negatively correlated with anxiety/insomnia scores from the GHQ-28 (P < 0.05) in the PSL(+) group. In conclusion, low-dose GC treatment complemented the pituitary adrenocortical system and improved the psychological state in MG patients. PMID- 22240859 TI - Gabapentin as add-on treatment for somatoform disorder: a case report. AB - Somatoform disorder is a relatively common and severe disorder for which pharmacotherapy has been minimally studied. We report a case of 30-year-old woman with treatment-resistant somatoform disorder that was successfully treated with add-on treatment of gabapentin. Our result showed that gabapentin 1800 mg/day could be tried in case of treatment-resistant somatoform disorder as an add-on strategy. However, controlled trials are needed to investigate the effectiveness of gabapentin in the management of this condition. PMID- 22240860 TI - Paroxetine-associated hypereosinophilia may clinically resemble a panic attack. AB - Hypereosinophilia is asymptomatic but can induce organ damage, which may cause neurological system abnormalities. We recently encountered a 29-year-old woman with depressive episodes who had eosinophilia as well as hyperventilation attacks, tremor, insomnia, and arthralgia of extremities after receiving paroxetine treatment. In parallel with the decrease in paroxetine dose, eosinophil count decreased and the related symptoms improved. Because it is sometimes difficult to distinguish between psychiatric symptoms such as panic attack and eosinophilia-related symptoms, frequent hematologic examination is required for patients treated with paroxetine. PMID- 22240861 TI - Dose-dependent impulse control disorders in piribedil overdose. AB - We describe a 73-year-old female patient with Parkinson disease who developed impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) owing to piribedil overdose. She was initially put on piribedil 150 mg; and owing to disease progression, levodopa was added 4 years later. Three years later, piribedil was raised to 200 mg; but presumably owing to a misunderstanding, she took 400 mg/d, which was well tolerated and produced an improvement in her parkinsonian symptoms.However, over the next few weeks, she started shopping compulsively, buying unnecessary clothes and food. In addition, she visited her dog's veterinarian several times a day with nonsense queries. She began to have financial problems and family disruption. During an examination, mild dyskinesia was evident.We diagnosed ICDs and most likely dopamine dysregulation syndrome DDS. Piribedil doses were decreased to 200 mg/d and levodopa increased up to 750 mg/d, with a clear improvement in compulsive behavior without worsening of the dyskinesia.Our case shows that even in cases in which regular doses of dopamine agonists are harmless, dose increments can induce these unwanted effects. PMID- 22240862 TI - A further case of nicotine sensitivity in multiple system atrophy. AB - We describe a 64-year-old patient affected by multiple system atrophy (MSA) whose symptoms of cerebellar ataxia were temporarily markedly worsened by smoking a cigarette. Interestingly, a similar phenomenon was reported in the original description of MSA by Graham and Oppenheimer in 1969, although never again since then. Cholinergic involvement is present in MSA, as shown by recent pathological and functional neuroimaging studies. Further studies are warranted to investigate the prevalence of nicotine sensitivity in MSA and shed light on its neurochemical substrate. PMID- 22240863 TI - Dextromethorphan/quinidine for chorea: an open-label assessment. PMID- 22240865 TI - Agranulocytosis induced by proton pump inhibitors. AB - We report the first published case of agranulocytosis induced by omeprazole and its recurrence with esomeprazole, the S-isomer form of omeprazole. Interestingly, we found an homozygotous mutation of CYP2C19*17, responsible for the metabolism of proton pump inhibitors. PMID- 22240866 TI - Analysis of intersegmental trough and proximal latency of smooth muscle contraction using high-resolution esophageal manometry. AB - BACKGROUND AND AIMS: Intersegmental troughs (ISTs) between striated and smooth muscle contraction segments on high-resolution manometry (HRM) have been linked to hypomotility disorders. We investigated the relationship between ISTs, latency of initiation of smooth muscle contraction, and motor patterns in symptomatic patients and normal controls. METHODS: HRM Clouse plots were analyzed in 199 participants (47.2+/-1.2 y, 112F/87M), categorized into 110 participants with gastroesophageal reflux disease (GERD), 74 symptomatic participants without GERD, and 15 healthy controls. IST length was measured in centimeters and percentage esophageal length, designated extended when >=20% esophageal length on >30% swallows. Proximal latency was measured as the time interval between onset of skeletal and smooth muscle contraction segments, and designated prolonged when >=4s in >=50% of swallows. RESULTS: ISTs of any length were noted in 74.6% swallows and in 92.5% of participants, with a similar frequency across the 3 groups. ISTs and proximal latency were both longer in the GERD group, especially when Barrett esophagus was present, compared with non-GERD patients or controls (P<=0.03 across groups); extended IST and prolonged proximal latency followed similar trends. On multivariate logistic regression, extended IST predicted GERD [odds ratio (OR), 2.30; 95% confidence intervals (CI) 1.18-4.47], as did lower esophageal sphincter pressure <5 mm Hg (OR, 3.79-3.96; 95% CI 1.77-8.49), after controlling for age and sex; prolonged proximal latency predicted both GERD (OR, 2.03; 95% CI 1.01-4.12) and Barrett esophagus (OR 1.91, 95% CI 1.24-2.94). CONCLUSIONS: Measurement of IST and proximal latency add value to HRM analysis, and may be markers of esophageal hypomotility. PMID- 22240867 TI - Suzuki reactions of extended scope: the '9-MeO-9-BBN variant' as a complementary format for cross-coupling. AB - While the Suzuki coupling has gained paramount importance, the basic set-up of the reaction has remained essentially unchanged for decades. It consists of the palladium-catalyzed coupling of organoboron reagents with aryl- or alkenyl halides, -sulfonates or related electrophiles in the presence of a base. One of the few alternative formats for this transformation is the '9-MeO-9-BBN variant', which is distinguished by not requiring an added base as a promoter. Rather, polar organometallic reagents R-M (R = Me, alkyl, aryl, heteroaryl, alkenyl, alkynyl etc.) are first intercepted with 9-MeO-9-BBN to give the corresponding borinate complexes, which then pass the R-group onto an organopalladium complex generated in situ as the electrophilic partner. This procedure allowed the structural reach of the Suzuki coupling to be extended, and served in a host of advanced applications, most notably for elaborate sp-sp(2) and sp(3)-sp(2) coupling processes. PMID- 22240878 TI - From synthetic to biogenic Mg-containing calcites: a comparative study using FTIR microspectroscopy. AB - The formation mechanism of the thermodynamically unstable calcite phase, very high Mg calcite, in biological organisms such as sea urchin or corallina algae has been an enigma for a very long time. In contrast to conventional methods such as KBr pellet Fourier Transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD), FTIR microspectroscopy (FTIRM) provides additional information about a local disorder such as an amorphous phase or the occlusion of Mg ions in the calcite lattice. In this work, we characterise for the first time systematically synthetic and biogenic Mg-containing calcium carbonate samples (especially sea urchin teeth--SUT) in detail by using two FTIRM instruments and compare these samples with KBr pellet FTIR measurements. Furthermore, we present spectra from geogenic calcite and dolomite minerals, recorded with both FTIRM systems, as well as KBr pellet FTIR spectra as references. We analyse the spectra by applying multi-peak curve fitting on the in-plane-bending (nu(4)) and out-of plane (nu(2)) bands. Based on the obtained results we attribute the two singlet bands at ~860-865 cm(-1) and ~695-704 cm(-1) observed in the SUT FTIRM spectra to the existence of amorphous calcium carbonate (ACC), and report for the first time the existence of ACC at the mature end of SUT. In the other three studied biominerals, however, we did not find any ACC. Also, based on the FTIRM results, we observe that not only nu(4), but also nu(2) shifts to higher wavenumbers if more calcium ions are replaced by magnesium ions in the calcite lattices. PMID- 22240879 TI - The calculation of baseline serum creatinine overestimates the diagnosis of acute kidney injury in patients undergoing cardiac surgery. AB - INTRODUCTION AND OBJECTIVES: The current definition and classification of acute kidney injury is based on consensus criteria (RIFLE and AKIN systems). Creatinine is the most commonly used of the recommended parameters (creatinine, glomerular filtration rate and diuresis). If the baseline value is not known, it can be calculated based on the simplified MDRD equation, assuming a filtration rate of 75 ml/min/1.73 m2 for the calculation. The aim of this study was to evaluate the diagnostic impact of using estimated baseline creatinine compared to the actual value measured in patients undergoing cardiac surgery. METHODS: Analysis of patients undergoing major cardiac surgery, who were prospectively included in a database. The maximum RIFLE stage reached was calculated for each patient using the measured and estimated baseline creatinine levels. The impact on the diagnosis was analysed using intraclass correlation coefficients, concordance analysis and Bland-Altman plots. RESULTS: The incidence of postoperative acute kidney injury in 2103 cases between 2002 and 2007 was 29.1%, according to estimated creatinine (14.3% with the measure). This represents an overestimation of 104%, with an intraclass correlation of 0.12. By excluding patients with known chronic kidney disease (glomerular filtration rate [<60 ml/min/1.73 m2), both the overestimation (2.4%) and the correlation (0.57) improved. CONCLUSIONS: The calculation of baseline creatinine using the MDRD equation overestimates the incidence of acute kidney injury after cardiac surgery, and is an inadequate method for detection when the baseline value is unknown. PMID- 22240881 TI - Making clinically informed R&D a reality. AB - Many exciting new initiatives are described in this month's international organisations' update (see pages 600-604). One that caught my eye is the first EPUAP focus meeting on 'Technological Innovations in Pressure Ulcer Diagnosis, Prevention and Treatment', which takes place in Tel Aviv, Israel, on 16-17 April 2012. In case you're wondering how relevant a focus group on technological innovation is to you, especially in this current climate of cuts and cost savings, then please note this is an opportunity for clinicians to influence, in part, the scientific agenda of both researchers and industry. PMID- 22240880 TI - Echocardiographic impact of hydration status in dialysis patients. AB - INTRODUCTION: Cardiovascular disease is the main cause of death in Chronic Kidney Disease patients. Left ventricular hypertrophy is the most common manifestation and it is linked to arterial hypertension and overhydration. The goal of this paper is to stratify dialyzed patients according to hydration status and to make an evaluation about the possible echocardiography alterations of the different groups. METHODS: A transversal study was carried out with 117 patients: 65 were on hemodialysis and 52 on peritoneal dialysis. We performed the following tests: multifrequency bioimpedance with the BCM-Body Composition Freesenius' Monitor system, transthoracic echocardiography, and blood tests. If ECW/TBW (extracellular water vs total body water) normalization ratio for age and gender was > 2.5% SD, the patient was considered overhydrated. RESULTS: HD patients are significantly overhydrated before HD (67.1%) compared to DP patients (46.1%), and almost half of the overhydrated population presents arterial hypertension. However, after an HD session, a better control of the hydration status is reached (26.1%). DP patients frequently present high arterial pressure and/or are under antihypertensive treatment (DP 76.9% vs HD 49.2%). Left ventricular hypertrophy is much more common in HD overhydrated patients, eccentric LVH being more prevalent. Overhydrated patients present significantly high values of LAVI, ILVM, OH/ECW. CONCLUSIONS: Bioimpedance technique allows for the detection of a large number of overhydrated patients. Echocardiographic alterations in dialyzed patients show a high correlation between the hydration stage by ECW/TBW normalized ratio for age and gender and the LAVI and ILVM. PMID- 22240882 TI - Efficacy of a total occlusive ionic silver-containing dressing combination in decreasing risk of surgical site infection: an RCT. AB - OBJECTIVE: To perform a comparative assessment of the efficacy of total occlusive ionic silver-containing dressing (TOISD) combination vs no dressing after colorectal surgery. METHOD: The surgical sites from both groups were swabbed and sent for culture and sensitivity upon wound closure (superficial incisional skin surface) in the operating theatre, as a baseline for bacterial colonisation. The patients' surgical wounds in the study group were dressed with TOISD combination and the patient's surgical wounds in the control group received the conventional method of no dressing. A second swab was taken from the superficial incisional skin surface for culture and sensitivity investigation between the fifth to seventh postoperative day for comparison of the bacterial colonisation in the two groups. RESULTS: One-hundred and sixty-six patients were recruited. Six patients dropped out before the fifth postoperative day, leaving 79 patients in the control group and 81 patients in the study group. Microbial swab cultures revealed significant differences between the two groups (p<0.001, mean=1.43+/ 0.63) in bacterial colonisation. The odds ratio (OR) of patients with wounds in the control group was 4.1 (95%CI is 1.884, 8.964) more likely to be contaminated with bacteria compared with wounds covered with occlusive ionic silver-containing dressing. CONCLUSION: TOISD was found to be effective in reducing bacterial colonisation on the surgical site compared with no dressing. However, it properties were unable to be put into use if there were the surgical sites were not infested with bacterial. Although TOISD might not be necessarily on surgical incisional site not infested with bacteria for the initial post-operation days, it is helpful in preventing further transcription and division for opportunistic bacteria, thus might reduce the risk of superficial incisional SSI. The use of TOSID though statistically insignificant compared to no dressing, could also be possible in reducing the risk and exaceration of deep incisional SSI. PMID- 22240883 TI - In vitro interaction of chronic wound bacteria in biofilms. AB - OBJECTIVE: To use in vitro biofilm models of wound bacterial isolates and compare the biofilms produced for different combinations of wound bacterial species. METHOD: In vitro biofilms, generated by Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus oralis and Micrococcus luteus in microtitre plates and a constant depth film fermentor (CDFF), were studied. The tested isolates all originated from chronic venous leg ulcers. Biofilms of individual and dual combinations of these species were generated in microtitre plate wells at 37 degrees C for 24-96 hours and also in the CDFF for 7 days. The extent of biofilm formation from these systems was then measured using crystal violet staining and/or total viable counts. RESULTS: All the chronic wound bacteria formed biofilms (both individually and in mixed culture) in these models. In mixed species microtitre plate biofilms, both P. aeruginosa and S. aureus appeared to antagonise biofilm formation by S. oralis and M. luteus, with P. aeruginosa completely inhibiting the growth of these organisms. Similar effects were evident in the CDFF model, when all four bacterial species were added simultaneously, with M. luteus being 'out-competed' by the other organisms present and occurring at numbers at the limits of detection; however, there was an apparent increase in the numbers of S. oralis compared with its single culture equivalent. CONCLUSION: The study highlighted differences in biofilm formation ability for the tested species in both closed and open model systems. Using dual species biofilms, distinct species antagonism was observed with apparent antagonism of pathogenic species over 'commensal' ones. Such a finding provides insight into possible bacterial interactions during development of 'non-healing' wound biofilms. PMID- 22240884 TI - A comparison of the antimicrobial efficacy of two silver-containing wound dressings on burn wound isolates. AB - OBJECTIVE: To evaluate and compare the efficacy of a silver alginate (SA) dressing and a silver carboxymethyl cellulose (SCMC) dressing on burn isolates grown within the quasi/non-biofilm state and the biofilm phenotypic states. METHOD: Antimicrobial activity was tested using 46 burn wound isolates with a corrected zone of inhibition (CZOI) assay on agar (quasi/non-biofilm) and poloxamer (biofilm). RESULTS: All Gram-negative and positive isolates evaluated were found to be sensitive to both silver containing wound dressings, although superior antimicrobial activity was observed for a select number of specific bacteria when grown in the quasi/non-biofilm phenotypic state, for the SCMC dressing. However, the majority of isolates demonstrated reduced sensitivity to silver when grown as a biofilm, compared with growth in the quasi/non-biofilm phenotypic state. Both dressings demonstrated equivalent antimicrobial activity on Gram-negative isolates grown in the biofilm phenotypic state. For the Gram positive isolates growing in the biofilm phenotypic state, there appeared to be greater sensitivity to the SA dressing compared with the SCMC dressing, although this result was not statistically significant. CONCLUSION: This study demonstrated the antimicrobial effectiveness of an SA and SCMC dressing in inhibiting the growth of burn isolates residing in both the quasi/non-biofilm and biofilm phenotypic states. It also suggests the SA dressing could be more effective on Gram-positive isolates grown in the biofilm phenotypic state, compared with SCMC dressing. PMID- 22240885 TI - Ecthyma gangrenosum in a premature low-birth-weight newborn. AB - Ecthyma gangrenosum is a well-recognised cutaneous infection in critically ill and immunocompromised patients. It is commonly associated with Pseudomonas aeruginosa septicaemia. Classic lesions of ecthyma gangrenosum comprise deep ulcers with ecchymotic, gangrenous centres, bright red areolae and typical raised, purplish, indurated, rolled-out edges. We report ecthyma gangrenosum in a premature low-birth-weight neonate, delivered at home to a third gravida mother with history of chorioamnionitis. He was admitted to a private hospital on third day of life, with a diagnosis of early-onset neonatal sepsis and received multiple antibiotics over next 22 days. The infant was referred to the paediatrics emergency department of Sir Sunderlal Hospital, Banaras Hindu University in a condition of shock, pneumonitis and generalised sepsis. Two gangrenous ulcers with gray-black eschar were present, one over the neck and another over the back. He was diagnosed as a case of neonatal sepsis with ecthyma gangrenosum. Blood culture revealed growth of Pseudomonas aeruginosa, sensitive only to imipenem. The infant died the day following admission. PMID- 22240886 TI - An RCT on the effects of topical CGP on surgical wound appearance and residual scarring in bilateral total-knee arthroplasty patients. AB - OBJECTIVE: To test the hypothesis that topically applied calcium glycerophosphate (CGP) would improve the appearance of the wound following bilateral knee replacement. METHOD: Healthy patients, aged 45-75 years, scheduled for bilateral total-knee replacement surgery were recruited into the study. One knee was randomly assigned to the treatment group, while the contralateral knee was designated the control (standard care). Subjects were instructed to apply a preparation of 10% CGP in an aqueous lotion to the treated knee once daily for 42 days, starting at the third postoperative day. Functional sealing and cosmetic appearance of the incision were evaluated by two surgeons by direct examination of the patient and then by two experienced assessors from photographs. The investigators qualitatively scored the intensity and extent of erythema along the incision and over the entire knee, the appearance of visible oedema along the incision and over the knee, and the overall clinical impression of wound healing. All four assessors were blinded to the subjects' allocation and the latter two assessors to the initial investigators' assessments. Subjects were also followed up for an additional 46 weeks, giving a total study duration of 12 months. RESULTS: Twenty patients completed the study. Statistical analysis showed that both the area and intensity of erythema along the incision were significantly reduced in the treated vs untreated knee over the entire study period. The analysis further showed that treatment significantly reduced oedema, both along the incision and across the entire knee. The differences were most marked at the seventh postoperative day and diminished with time. No adverse effects were observed for any patient, in either treated or untreated knees. CONCLUSION: These data demonstrate that postoperative application of 10% CGP could improve the appearance of the wound following total knee arthroplasty. PMID- 22240888 TI - Initial report of KSCC0803: feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japanese patients. AB - BACKGROUND: A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in Japanese patients. METHODS: We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m(2)/day) was given orally on days 1-14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint. RESULTS: Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 [66.0%; 95% confidence interval (CI), 55.7-75.3%] and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8-79.5%). Adverse events which led to treatment discontinuation included hand-foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%. CONCLUSIONS: This collaborative multi facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients. PMID- 22240889 TI - Role of prophylactic ipsilateral central compartment lymph node dissection in papillary thyroid microcarcinoma. AB - Central compartment lymph node (CCLN) management in patients without clinical or radiologic evidence of CCLN metastasis is debatable. The aim of the present study was to evaluate outcomes of surgery for papillary thyroid microcarcinoma (PTMC) with prophylactic ipsilateral CCLN dissection (PI-CCND) in a large cohort of patients treated at one single institution in a 5-year follow-up. Between January 2000 and December 2005, 2192 patients with papillary thyroid carcinoma underwent thyroid surgery. Inclusion criteria were patients with PTMC, absence of clinical or radiologic evidence of CCLN metastasis, and a follow-up for a period >=60 months. Data from 842 patients were retrieved in the current retrospective cohort study. PI-CCND was routinely performed in addition to thyroid surgery in all cases. Ipsilateral CCLN metastasis was found in 218 patients (25.9%). Postoperative complications included 76 cases of transient hypoparathyroidism (9%), 11 cases of permanent hypoparathyroidism (2.6%), four cases of vocal cord palsy (0.5%), and one case of bleeding (0.1%). Univariate analysis and multivariate logistic regression analysis revealed that CCLN metastasis was statistically significantly correlated with tumor size and extracapsular invasion. Recurrence has been observed to date in 19 patients (2.26%). No CCLN site recurrence occured in patients who underwent PI-CCND. This study demonstrates the technical feasibility and safety of PI- CCND, which is a better way to determine lymph node status for a more accurate staging of disease and risk stratification. PI-CCND should be considered even if clinical or radiological exams are negative for CCLN metastasis. PMID- 22240890 TI - Growth of an aggressive tumor during pregnancy in an acromegalic patient. AB - Pregnancy in acromegalic patients is a rare event, but is usually uneventful, with stable GH and IGF-I levels and no tumor enlargement. Medical treatment can usually be withdrawn without problems and although no major adverse event has been reported, the suspension of drug treatments is generally recommended. No case report exists in the literature regarding evolution of a somatotropinoma with invasiveness markers throughout pregnancy. We report a case of an acromegalic patient who was submitted to surgery and treated with octreotide LAR maintaining a stable residual tumor and an IGF-I close to the normal levels. Her tumor presented with a high Ki-67 (11.6%) and a low aryl hydrocarbon receptor interacting protein (AIP) expression. When she became pregnant, octreotide LAR was withdrawn, and despite remaining asymptomatic during pregnancy, tumor growth occurred with compression of surrounding structures. In conclusion, pregnancy in acromegalic patients has usually a favorable prognosis with no tumor growth. However, in the presence of high Ki-67 labeling index and low AIP expression, tumor enlargement may occur and somatostatin analogue treatment throughout the pregnancy should be considered. PMID- 22240891 TI - Variants of endothelial nitric oxide synthase gene are associated with components of metabolic syndrome in an Arab population. AB - Genetics plays a crucial role in the development of metabolic syndrome (MetS). Here we examined the association between endothelial nitric oxide synthase (eNOS) gene polymorphisms and MetS in a Saudi Arabian cohort to extend the understanding of the genetic basis of MetS in diverse ethnic populations. Anthropometric, clinical and biochemical parameters as well as genotyping for 894G>T, -786T>C variants of eNOS gene by PCR-RFLP and 4a/b by direct PCR were performed in 886 Saudi Arabians (477 MetS and 409 Non-MetS). The genotype distribution (TT, p=0.001; TC, p=0.001; TC+CC, p=0.001) and allele (T, p=0.007; C, p=0.007) frequency of the -786T>C SNP were significantly different between Non-MetS and MetS subjects which remained significant after Bonferroni correction. Moreover: 1) the GT and GT+TT genotypes of the 894G>T SNP were associated with elevated blood pressure (p=0.017, and p=0.022, respectively); 2) the ab variant of 4a/b polymorphism was associated with decreased HDL levels (p= 0.044); and 3) the TC+CC genotype and C allele of the -786T>C SNP were associated with increased fasting glucose levels (p=0.039, and p=0.028, respectively). Also, G-a-C was identified as the risk haplotype for MetS susceptibility (p=0.034). The results suggest a significant association of 894G>T, 4a/b and -786T>C polymorphisms with MetS and its components is present in an Arab population. A genetic predisposition to develop abnormal metabolic phenotypes, consistent with an increased prevalence of metabolic phenotypes can be detected in this ethnic group. PMID- 22240892 TI - Immunocytochemical localization of kisspeptin neurons in the rat forebrain with special reference to sexual dimorphism and interaction with GnRH neurons. AB - Kisspeptin/metastin has been implicated as a critical regulator in luteinizing hormone (LH) secretion and the reproductive system mediating the effect of estrogen on GnRH neurons. In the present study we examined the sex differences in the effects of estrogen on Kiss1/kisspeptin expression in the forebrain by using gonadectomized rats to assess the interaction of kisspeptin and GnRH neurons. Kiss1/kisspeptin cell bodies were abundant in the rostral periventricular area of the third ventricle (RV3P) and the arcuate nucleus (ARC). A few cell bodies were also observed in other portions of the forebrain, i.e. the bed nucleus of the stria terminalis (BST), the paraventricular hypothalamic nucleus (PaAP), the ventromedial hypothalamic nucleus (VMH), and the medial amygdaloid nucleus (MeA). Kisspeptin-immunoreactive fibers were found mainly in the median eminence (ME), the ARC, and the RV3P, but were scarce in the preoptic area (POA), where GnRH neurons are localized. We also found that estrogen triggers expression of the Kiss1 gene and peptide within all the regions except the ARC, and that the effects in the RV3P, BST, PaAP, and VMH are greater in estrogen treated ovariectomized female rat. It is noteworthy that kisspeptin and GnRH neurons were densely associated in the ME but were rarely in contact in the POA. Thus, our results suggest that kisspeptin-positive neurons, except for the ones in the ARC, are related not only to estrogen-positive feedback, but also sex dimorphism, and that kisspeptin regulates GnRH release in the ME rather than the POA. PMID- 22240893 TI - Distinct structural and optical regimes in natural silk spinning. AB - This study investigates the relationship between birefringence and mechanical properties in the dragline silk of the gold orb weaving spider Nephila edulis. Using a custom birefringence-tensile testing device, we probed the orientation and water-induced swelling of fibers spun at variety of drawing rates ranging from 0.003 to 400 mm s(-1). Our results indicate that based upon drawing rate, silk fibers fall into three distinct regimes each with characteristic orientation and swelling properties. Further investigation using in situ tensile testing reveals interactions between a fiber's drawing speed, mechanical properties, and orientation that support previous model predictions. We propose that simultaneous birefringence-tensile testing provides a unique and readily accessible insight into the structural behavior of this interesting and important biomaterial. PMID- 22240894 TI - Alternative splicing of Bim and Erk-mediated Bim(EL) phosphorylation are dispensable for hematopoietic homeostasis in vivo. AB - The pro-apoptotic BH3-only protein Bim has a major role in hematopoietic homeostasis, particularly in the lymphocyte compartment, where it strongly affects immune function. The three major Bim isoforms (Bim(EL), Bim(L) and Bim(S)) are generated by alternative splicing. Bim(EL), the most abundant isoform, contains a unique sequence that has been reported to be the target of phosphorylation by several MAP kinases. In particular, Erk1/2 has been shown to interact with Bim(EL) through the DEF2 domain of Bim(EL) and specifically phosphorylate this isoform, thereby targeting it for ubiquitination and proteasomal degradation. To examine the physiological importance of this mechanism of regulation and of the alternative splicing of Bim, we have generated several Bim knock-in mouse strains and analyzed their hematopoietic system. Although mutation in the DEF2 domain reduces Bim(EL) degradation in some circumstances, this mutation did not significantly increase Bim's pro-apoptotic activity in vivo nor impact on the homeostasis of the hematopoietic system. We also show that Bim(EL) and Bim(L) are interchangeable, and that Bim(S) is dispensable for the function of Bim. Hence, we conclude that physiological regulation of Bim relies on mechanisms independent of its alternative splicing or the Erk-dependent phosphorylation of Bim(EL). PMID- 22240895 TI - The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo. AB - The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-me-/- mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-me-/- erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-me-/- erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-me-/- erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. PMID- 22240896 TI - Somatic gonad sheath cells and Eph receptor signaling promote germ-cell death in C. elegans. AB - Programmed cell death eliminates unwanted cells during normal development and physiological homeostasis. While cell interactions can influence apoptosis as they do other types of cell fate, outside of the adaptive immune system little is known about the intercellular cues that actively promote cell death in healthy cells. We used the Caenorhabditis elegans germline as a model to investigate the extrinsic regulators of physiological apoptosis. Using genetic and cell biological methods, we show that somatic gonad sheath cells, which also act as phagocytes of dying germ cells, promote death in the C. elegans germline through VAB-1/Eph receptor signaling. We report that the germline apoptosis function of VAB-1 impacts specific cell death pathways, and may act in parallel to extracellular signal-regulated kinase MAPK signaling. This work defines a non autonomous, pro-apoptotic signaling for efficient physiological cell death, and highlights the dynamic nature of intercellular communication between dying cells and the phagocytes that remove them. PMID- 22240897 TI - Regulation in the targeting of TRAIL receptor 1 to cell surface via GODZ for TRAIL sensitivity in tumor cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), promote the selective clearing of various malignancies by inducing apoptosis, holding the promise as a potent therapeutic agent for anticancer. Though DR4 and DR5 have high sequence similarity, differential regulation of both receptors in human tumor cells remains largely unexplored. Here, we repot that golgi-specific Asp-His-His-Cys (DHHC) zinc finger protein (GODZ) regulates TRAIL/DR4-mediated apoptosis. Using the SOS protein recruitment-yeast two-hybrid screening, we isolated GODZ that interacted with the death domain of DR4. GODZ binds to DR4, but not to DR5, through the DHHC and the C-terminal transmembrane domain. Expression level of GODZ affects apoptosis of tumor cells triggered by TRAIL, but not that induced by TNF-alpha/cycloheximide (CHX) or DNA-damaging drugs. In parallel, GODZ functions to localize DR4 to the plasma membrane (PM) via DHHC motif. Also, introduction of mutation into the cysteine-rich motif of DR4 results in its mistargeting and attenuates TRAIL- or GODZ-mediated apoptosis. Interestingly, GODZ expression is highly downregulated in Hep-3B tumor cells, which show resistance to TRAIL. However, reconstitution of GODZ expression enhances the targeting of DR4 to cell surface and sensitizes Hep-3B cells to TRAIL. Taken together, these data establish that GODZ is a novel DR4-selective regulator responsible for targeting of DR4 to the PM, and thereby for TRAIL-induced apoptosis. PMID- 22240898 TI - ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease. AB - Aberrant chromatin remodeling is involved in the pathogenesis of Huntington's disease (HD) but the mechanism is not known. Herein, we report that mutant huntingtin (mtHtt) induces the transcription of alpha thalassemia/mental retardation X linked (ATRX), an ATPase/helicase and SWI/SNF-like chromatin remodeling protein via Cdx-2 activation. ATRX expression was elevated in both a cell line model and transgenic model of HD, and Cdx-2 occupancy of the ATRX promoter was increased in HD. Induction of ATRX expanded the size of promyelocytic leukemia nuclear body (PML-NB) and increased trimethylation of H3K9 (H3K9me3) and condensation of pericentromeric heterochromatin, while knockdown of ATRX decreased PML-NB and H3K9me3 levels. Knockdown of ATRX/dXNP improved the hatch rate of fly embryos expressing mtHtt (Q127). ATRX/dXNP overexpression exacerbated eye degeneration of eye-specific mtHtt (Q127) expressing flies. Our findings suggest that transcriptional alteration of ATRX by mtHtt is involved in pericentromeric heterochromatin condensation and contributes to the pathogenesis of HD. PMID- 22240899 TI - The 5th International p63/p73 Workshop: much more than just tumour suppression. PMID- 22240900 TI - Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis. AB - Amino-acid starvation leads to an inhibition of cellular proliferation and the induction of programmed cell death (PCD) in the Drosophila ovary. Disruption of insulin signaling has been shown to inhibit the progression of oogenesis, but it is unclear whether this phenotype mimics starvation. Here, we investigate whether the insulin-mediated phosphoinositide kinase-3 pathway regulates PCD in mid oogenesis. We reasoned that under well-fed conditions, disruption of positive components of the insulin signaling pathway within the germline would mimic starvation and produce degenerating egg chambers. Surprisingly, mutants did not mimic starvation but instead produced many abnormal egg chambers in which the somatic follicle cells disappeared and the germline persisted. These abnormal egg chambers did not show an induction of caspases and lysosomes like that observed in wild-type (WT) degenerating egg chambers. Egg chambers from insulin signaling mutants were resistant to starvation-induced PCD, indicating that a complete block in insulin-signaling prevents the proper response to starvation. However, target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. These results suggest that inhibition of the insulin signaling pathway is not sufficient to regulate starvation-induced PCD in mid oogenesis. Furthermore, starvation-induced PCD is regulated by Tor signaling converging with the canonical insulin signaling pathway. PMID- 22240901 TI - TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis. AB - Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane. PMID- 22240902 TI - Dopamine affects the change of pain-related electrical activity induced by morphine dependence. AB - Morphine is among the most effective analgesics. However, many evidences suggest that, besides the well-know analgesic activity, repeated opioids treatment can induce some side effects such as dependence, hyperalgesia and tolerance. The mechanism of noxious information transmission in the central nervous system after dependence is not clear. An important neurotransmitter, dopamine (DA) participates not only in the process of opioid dependence but also in pain modulation in the central nervous system. In the present study we observed changes of electrical activities of pain-excitation neurons (PENs) and pain inhibition neurons (PINs) in the caudate nucleus (Cd) following the development of morphine dependence. We also observed the role of DA on these changes. Our results revealed that both the latency of PEN discharges and the inhibitory duration of PIN discharges decreased, and the net increased values of PEN and PIN discharges increased in the Cd of morphine dependent rats. Those demonstrated that electrical activities of both PENs and PINs increased in morphine dependent rats. DA inhibited the electrical activities of PENs and enhanced those of PINs in morphine dependent rats. PMID- 22240903 TI - The prevalence and outcome of effusive constrictive pericarditis: a systematic review of the literature. AB - There is sparse information on the epidemiology of effusive constrictive pericarditis (ECP). The objective of this article was to review and summarise the literature on the prevalence and outcome of ECP, and identify gaps for further research. The prevalence of ECP ranged from 2.4 to 14.8%, with a weighted average of 4.5% [95% confidence interval (CI) 2.2-7.5%]. Sixty-five per cent (95% CI: 43 82%) of patients required pericardiectomy regardless of the aetiology. The combined death rate across the studies was 22% (95(CI: 4-50%). The prevalence of ECP is low in non-tuberculous pericarditis, while pericardiectomy rates are high and mortality is variable. In this review, of 10 patients identified with tuberculous ECP, only one presumed case had a definite diagnosis of ECP. Appropriate studies are needed to determine the epidemiology of ECP in tuberculous pericarditis, which is one of the leading causes of pericardial disease in the world. PMID- 22240904 TI - Locally enhanced concentration and detection of oligonucleotides in a plug-based microfluidic device. AB - We propose a novel technique that allows oligonucleotides with specific end modification within a plug in a plug-based microfluidic device to undergo a locally enhanced concentration at the rear of the plug as the plug moves downstream. DNA was enriched and detected in situ upon exploiting a combined effect underlain by an entropic force induced through fluid shear (i.e. a hydrodynamic-repellent effect) and the interfacial adsorption (aqueous/oil interface) attributed to affinity. Flow fields within a plug were visualized quantitatively using micro-particle image velocimetry (micro-PIV); the distribution of the fluid shear strain rate explains how the hydrodynamic repellent effect engenders a dumbbell-like region with an increased concentration of DNA. The concentration of FAM (6-carboxy-fluorescein)-labeled DNA (FC-DNA) and of TAMRA (tetramethyl-6-carboxyrhodamine)-labeled DNA (TC-DNA), respectively, and the hybridization of probe DNA (modified with FAM) with target DNA (modified with TAMRA) were investigated in devices; a confocal fluorescence microscope (CFM) was utilized to monitor the processes and to resolve the corresponding 2D patterns and 3D reconstruction of the DNA distribution in a plug. TC-DNA, but not FC-DNA, concentrating within a plug was affected by the combined effect so as to achieve a concentration factor (C(r)) twice that of FC-DNA because of the lipophilicity of TAMRA. Using fluorescence resonance-energy transfer (FRET), we characterized the hybridization of the DNA in a plug; the detection limit of a system, improved by virtue of the proposed technique (the locally enhanced concentration), for DNA detection was estimated to be 20-50 nM. This technique enables DNA to concentrate locally in a nL-pL free-solution plug, the locally enhanced concentration to profit the hybridization efficiency and the detection of DNA, prospectively serving as a versatile means to accomplish a rapid DNA detection in a small volume for a Lab-on-a-Chip (LOC) system. PMID- 22240905 TI - Reduced Pd density of states in Pd/SAM/Au junctions: the role of adsorbed hydrogen atoms. AB - Experiments have shown that a Pd monolayer deposited electrochemically on a Au supported self-assembled monolayer (SAM) of 4-mercaptopyridine (Mpy) exhibits a strongly reduced Pd local density of states (LDOS) at the Fermi energy (E(f)). Understanding the origin of this modified electronic structure is crucial for the use of the sandwich design as a platform for future nanoelectronics. Here we suggest that hydrogen adsorption might be the origin of the modified electronic properties. We performed periodic density functional theory calculation to explore the influence of hydrogen adsorption on the geometric and electronic structure of a Pd/Mpy/Au(111) complex. Dissociative adsorption of H(2) on a Pd monolayer on top of a Mpy SAM is a strongly exothermic process leading to atomic hydrogen atoms preferentially located at the hollow sites. Due to the formation of a strong Pd-H bond the Pd-SAM interaction realized via one-fold N-Pd bonds is substantially weakened. Upon hydrogen adsorption, the Pd LDOS becomes significantly modified exhibiting a drastic reduction of the density of states at E(f). The calculated spectra are in a good agreement with the experiment for a hydrogen coverage corresponding to two monolayers which is still thermodynamically allowed. PMID- 22240906 TI - Fasting and post-challenge glucose as quantitative cardiovascular risk factors: a meta-analysis. AB - AIM: The post-challenge glucose (PCG) level has been suggested to be superior to the fasting blood glucose (FG) level for predicting the risk of future cardiovascular disease (CVD); however, the extent of its superiority has not been consistently shown among previous cohort studies. Therefore, we conducted a meta analysis to summarize the quantitative association of FG and PCG with CVD risk and compared the strengths of the two associations. METHOD: Electronic literature searches using MEDLINE and EMBASE with an additional manual search were conducted for prospective observational studies of the association of FG and PCG with CVD risk. Studies were included if they were prospective studies in which the relative risk (RR) of CVD per 1 standard deviation increase in both FG and PCG could be estimated. Pooled relative risks for the incremental increase were calculated as RR(FG) and RR(PCG) using a bivariate random-effects model. RESULT: Data were obtained from 14 eligible studies that included 70,889 participants and 2,927 cases. The pooled RR(FG) and RR(PCG) (95% confidence interval) were, respectively, 1.15 (1.06 to 1.26) and 1.24 (1.12 to 1.36); the difference was significant (P =0.001). The association of PCG with CVD risk was stronger in studies that targeted participants with a baseline mean FG < 100 mg/dl (P < 0.001) or mean age >= 55 years (P =0.004). CONCLUSIONS: Overall, the association of PCG with CVD risk was stronger than that of FG by approximately 50% on a log scale. Measuring PCG is especially important in populations with relatively low FG levels or in the elderly, although it is often burdensome in routine clinical practice. PMID- 22240908 TI - Homocysteine is related to aortic mineralization in patients with ischemic heart disease. AB - Homocysteine is implicated as an early atherosclerotic promoter, which enhances the smooth muscle cell proliferation and produces free radicals that induce cellular damage. These factors must have a role in the progression of atherosclerosis that subsequently leads to vascular mineralization. AIM: Identify a correlation between the plasma concentration of total homocysteine and the amount of minerals that accumulate in the aorta of patients with atherosclerosis. METHODS: We performed a cross-sectional study in 13 patients with three-vessel coronary artery disease, undergoing coronary artery bypass surgery. Aortic and mammary artery specimens were analyzed using a scanning electron microscope with an energy dispersive X-ray spectrometer. The homocysteine was determined using an immunonephelometry method. RESULTS: The amount of minerals in the aorta was greater (300 +/- 181.6 particles per 500 um2 than that in the mammary artery (64 +/- 45 particles per 500 um2 (p < 0.01). The average tHcy was 9.5 +/- 2.3 umol/L. The Spearman's rank correlation coefficient was positive between tHcy, and aortic iron (p < 0.05). CONCLUSIONS: Our study demonstrates that the aorta is dramatically affected by mineralization compared to the mammary artery. In addition, a direct correlation was identified between the levels of tHcy and the iron particles in the aortic wall. PMID- 22240909 TI - Geometric analysis and blood flow simulation of basilar artery. AB - AIM: The aim of this study was to find a region of low wall shear stress (WSS) in a basilar artery using 3-dimensional (3D) geometric analysis and blood flow simulation. METHODS: A 61-year-old patient who underwent follow-up time-of-flight magnetic resonance angiography (TOF-MRA) of the brain was recruited as the subject of the present study. In the basilar artery, the angle of the directional vector was calculated for the region of low WSS. The subject's 3D arterial geometry and blood flow velocity from a transcranial Doppler examination were used for a blood flow simulation study. The regions of low WSS identified by both geometric analysis and blood flow simulation were compared, and these methods were repeated for the basilar arteries of various geometries from other patients. RESULTS: Two distinct arterial angulations along the basilar artery were identified: lateral and anterior angulations on the anteroposterior and lateral TOF-MR views, respectively. A low WSS region was observed in the distal portion along the inner curvatures of both angulations in the basilar artery. The directional vectors of the region of low WSS calculated by geometric analysis and blood flow simulation were very similar (correlation coefficient= 0.996, p < 0.001). Follow-up MRA confirmed the progression of plaque in the region of low WSS. CONCLUSION: Detailed geometric analysis and blood flow simulation of the basilar artery identified lateral and anterior angulations which determined the low WSS region in the distal portion along the inner curvatures of the angulations. PMID- 22240910 TI - Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits. AB - AIM: Existing evidence suggests that endothelial lipase (EL) plays an important role in high-densitylipoprotein (HDL) metabolism. Because rabbits are a useful animal model for the study of human lipid metabolism and atherosclerosis, we characterized rabbit EL (rEL) expression and investigated its relationship with plasma HDL levels in normal and hyperlipidemic rabbits. METHODS: We cloned the rEL cDNA and analyzed the EL tissue expression using Northern blotting, real-time RT-PCR, Western blotting, and in situ hybridization. We evaluated the effects of rEL antisense on plasma HDL levels. RESULTS: We found that rEL mRNA was highly expressed in cholesterol synthesis-related organs, including the liver, testis, and adrenal along with its expression in the lung, kidney, bone marrow, and small intestine. Interestingly, Watanabe heritable hyperlipidemic (WHHL) rabbits, a model of human familial hypercholesterolemia, had lower plasma levels of HDLs than normal rabbits. The plasma HDL levels in WHHL rabbits were inversely associated with high levels of plasma rEL proteins and hepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides into rabbits resulted in the elevation of plasma large HDLs. Furthermore, we demonstrated that rEL mRNA was expressed by both endothelial cells and macrophages in the lesions of aortic atherosclerosis of WHHL rabbits. CONCLUSIONS: rEL is expressed in multiple tissues and may have many physiological and pathophysiological functions, such as in the regulation of cholesterol metabolism and atherosclerosis. Our results suggest that EL is an important regulator of plasma HDL levels in rabbits. PMID- 22240911 TI - Background to discuss guidelines for control of plasma HDL-cholesterol in Japan. AB - A decrease in high density lipoprotein-cholesterol (HDL-C) is a strong risk factor for atherosclerotic disorders in Japan, probably more important than an increase in low density lipoprotein-cholesterol (LDL-C). While there are rational grounds for the argument that elevation of HDL-C leads to decreased risk, there has as yet been no direct evidence of such an effect. If elevation of HDL-C decreases the risk, this effect is expected throughout the normal range of HDL-C or perhaps even higher than that. Simulation based on epidemiological data indicated that it may eventually reduce the incidence of ischemic heart disease by 60-70% in Japan. In the risk management guideline, "low" HDL-C is presently defined as 40 mg/dL or below. While there is no evidence that strongly urges a change in this definition, the results of epidemiological studies support "The higher the HDL-C level, the lower the risk,"even in the "normal range". Elevation of the HDL-C level may reduce the risk, probably at least up to 70 mg/dL; however, there are no supportive data for this effect still being obtained over 80 mg/dL. Patients with homozygous CETP deficiency should be followed-up while controlling other risk factors, so as not to dismiss the possibility of a risk increase with an extremely elevated HDL-C level. PMID- 22240914 TI - Influence of ethanol extract of Ginkgo biloba leaves on the isolated rat heart work and mitochondria functions. AB - In this study, we attempted to elucidate whether the effects of ethanol extract of Ginkgo biloba leaves (GBE) observed previously on isolated rat heart mitochondria may be realized in situ (in case of isolated heart perfused under normal conditions and under ischemia-reperfusion). We found that GBE at low concentrations (0.01, 0.05, and 0.1 MUL/mL) does not affect the heart rate and parameters of electrocardiogram (ECG) but produces a small increase in the coronary flow. Higher concentration of GBE (0.2 and 0.3 MUL/mL) diminished the heart rate, decreased the coronary flow, and tended to enhance the parameters of ECG. The contractility of isolated rat heart and mitochondrial nicotinamide adenine dinucleotide reduced form fluorescence decreased in a GBE concentration dependent manner. Mitochondria isolated from hearts pre-perfused with GBE (0.05 MUL/mL) for 20 minutes before nonflow global ischemia-reperfusion (45 min/15 min) showed higher respiratory rates with pyruvate + malate in state 2 and state 3, higher respiratory control index, and diminished H2O2 generation compared with untreated group. Higher GBE concentration, 0.4 MUL/mL, had no effect on H2O2 generation and did not prevent the ischemia-reperfusion-induced decrease of pyruvate + malate oxidation in state 3 but even enhanced it. However, in the case of nonischemic perfusions, this GBE concentration had no significant effect on these parameters of respiratory functions of isolated heart mitochondria. PMID- 22240915 TI - Levosimendan attenuates hypoxia-induced pulmonary hypertension in a porcine model. AB - BACKGROUND: Levosimendan was hypothesized to attenuate hypoxic pulmonary vasoconstriction (HPV). METHODS: Fourteen anaesthetized pigs (30.9 +/- 1.0 kg) were studied in normoxia (FiO2~0.21) and hypoxia (FiO2~0.10), before and 10-90 minutes after infusion of placebo (n = 7) or levosimendan (n = 7). RESULTS: Compared with normoxia, hypoxia baseline at FiO2~0.10 (n = 14) increased pulmonary vascular resistance (PVR) by 1.9 +/- 0.4 Wood Units (WU) (P < 0.001), mean pulmonary artery pressure (MPAP) by 14.3 +/- 0.9 mm Hg (P < 0.001), mean right atrial pressure (MRAP) by 2.1 +/- 0.4 mm Hg (P < 0.001), pulmonary capillary wedge pressure (PCWP) by 1.5 +/- 0.3 mm Hg (P < 0.001), cardiac output (CO) by 1.3 +/- 0.2 L/minute (P < 0.001) and heart rate (HR) by 19.9 +/- 5.5 beats.per minute (P < 0.001). Systemic vascular resistance (SVR) decreased by 7.2 +/- 1.0 WU (P < 0.001), MAP and stroke volume (SV) remained unaltered (P = ns). Compared with hypoxia baseline, levosimendan decreased MPAP and PVR (P < 0.05), by approximately 9% and 19%, respectively, plateauing between 10 and 90 minutes. SV increased (P < 0.05) by approximately 22%, plateauing after 60 minutes. MRAP, PCWP, HR, CO, MAP, SVR, and blood-O2 consumption remained unaltered (P = ns). Compared with hypoxia baseline, with placebo, MPAP remained stable (P = ns), PVR increased (P < 0.05) and CO decreased (P < 0.05) by approximately 20% and 11% after 60-90 and 30-90 minutes, respectively. SV decreased (P < 0.05) by approximately 8%, plateauing after 60-90 minutes. PCWP and MRAP decreased (P < 0.05) by approximately 12%, plateauing after 10-60 and 10-90 minutes, respectively. MPAP, HR, MAP, SVR, and blood-O2 consumption remained unchanged (P = ns), except at 60 minutes where MAP decreased (P < 0.05) by approximately 4%. CONCLUSIONS: Levosimendan attenuated HPV and the cardiodepressive effect of sustained hypoxia. PMID- 22240916 TI - Ginsenoside-Rb1 and tetramethylpyrazine phosphate act synergistically to prevent dilated cardiomyopathy in cTnTR141W transgenic mice. AB - Ginsenoside-Rb1 (Rb1) is known to be partially associated with the inhibition of heparin-binding epidermal growth factor-like growth factor (HB-EGF). Tetramethylpyrazine phosphate (TMPP) inhibits the activation of the calcium/calmodulin/calmodulin-dependent protein kinase (Ca2+/CaM/CaMKII) pathway. The alpha-myosin heavy chain cTnT(R141W) transgenic mouse was previously reported as a model for dilated cardiomyopathy (DCM), and it was used to test the effects of combinations of Rb1 and TMPP in reversing the progression of DCM and the potential mechanism. Survival, echocardiography, histologic features assessed the effectiveness of Rb1 and TMPP treatments. Western blot and reverse transcription polymerase chain reactions were used to determine expression levels of certain genes. This study clearly demonstrated that treatment with a combination of Rb1 and TMPP could inhibit the expression of HB-EGF, calmodulin1 (Calm1), and calcium/calmodulin-dependent protein kinase II beta (Camk2b). Rb1 alone mainly reduced the expression of HB-EGF, and TMPP alone mainly reduced the expression of Calm1 and Camk2b. Treatment with Rb1 and TMPP had synergistic effects on the amelioration of chamber dilation, contractile dysfunction, interstitial fibrosis, and ultrastructural degeneration in cTnT(R141W) mice when compared with the results of treatment with Rb1 or TMPP alone, and those were probably due to the inhibition of both HB-EGF and the Ca2+/CaM/CaMKII pathway. PMID- 22240913 TI - Induced pluripotent stem cells as a disease modeling and drug screening platform. AB - Induced pluripotent stem cells (iPSCs) hold great hopes for therapeutic application in various diseases. Although ongoing research is dedicated to achieving clinical translation of iPSCs, further understanding of the mechanisms that underlie complex pathogenic conditions is required. Compared with other classical models for studying diseases, iPSCs provide considerable advantages. A newly emerging application of iPSCs is in vitro disease modeling, which can significantly improve the never-ending search for new pharmacological cures. Here, we will discuss current efforts to create iPSC-dependent patient-specific disease models. Furthermore, we will review the use of iPSCs for development and testing of new therapeutic agents and the implications for high-throughput drug screening. PMID- 22240918 TI - Looking through the eyes of the patient. PMID- 22240917 TI - SM-368229, a novel promising mineralocorticoid receptor antagonist, shows antihypertensive efficacy with minimal effect on serum potassium level in rats. AB - The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist with partial agonistic activity, and spironolactone (SPI) on systolic blood pressure (SBP) and serum potassium in spontaneously hypertensive rats. SM-368229 given for 2 weeks prevented the increase in SBP without serum potassium elevation, but the treatment with SPI prevented SBP increase with serum potassium elevation. To elucidate the contribution of partial agonistic activity of SM-368229 for MR in the mitigation of serum potassium elevation, we studied the relationships between sodium balance decrease, as an index of antimineralocorticoid action, and serum potassium elevation in adrenalectomized and/or potassium-loaded rats, using SM-368229 and its derivatives (DSR-11861 and DSR-14397) showing different partial agonist activities for MR (12%, 0%, and 36%, respectively). DSR-11861 and SPI reversed sodium balance and increased serum potassium. SM-368229 also reversed sodium balance but did not show apparent serum potassium increase. Although DSR-14397 did not show serum potassium increase, its antimineralocorticoid action was very weak. These findings indicate that serum potassium elevation is negatively related to partial agonistic activities for MR, and SM-368229 shows antihypertensive efficacy with minimal effect on serum potassium level, probably due to its partial agonistic property. PMID- 22240919 TI - Quality of life for cancer patients: From diagnosis to treatment and beyond. PMID- 22240920 TI - Multi-source evaluation of interpersonal and communication skills of family medicine residents. AB - There is a lack of information on the use of multi-source evaluation to assess trainees' interpersonal and communication skills in Oriental settings. This study is conducted to assess the reliability and applicability of assessing the interpersonal and communication skills of family medicine residents by patients, peer residents, nurses, and teaching staffs and to compare the ratings with the objective structured clinical examination (OSCE). Our results revealed instruments used by staffs, peers, nurses, and self-evaluation have good internal consistency reliability (alpha > 0.90), except for the behavioral checklist (alpha = 0.57). Staffs', peers', and nurses' evaluations were highly correlated with one another (r = 0.722 for staff- and peer-rating, r = 0.734 for staff- and nurse-rating, r = 0.634 for peer- and nurse-rating). However, residents' self rating and patients-rating were not correlated to ratings by any other raters. OSCE evaluation was correlated to peer-rating (r = 0.533) and staff-rating (r = 0.642), but not correlated to self- or patient-rating. The generalizability study revealed the major sources of variance came from the types of rater and the interaction of residents and types of rater. This study found self-rating and patient-rating were not consistent with other sources of rating on residents' interpersonal and communication skills. Whether variations among different types of rater in a multi-source evaluation should be regarded as measurement errors or complementary information is worth further study. PMID- 22240921 TI - Treatment with targeted vesicular stomatitis virus generates therapeutic multifunctional anti-tumor memory CD4 T cells. AB - A generally applicable, easy-to-use method of focusing a patient's immune system to eradicate or prevent cancer has been elusive. We are attempting to develop a targeted virus to accomplish these aims. We previously created a recombinant replicating vesicular stomatitis virus (VSV) that preferentially infected Her2/neu expressing breast cancer cells and showed therapeutic efficacy in an implanted Balb/c mouse tumor model. The current work shows that this therapy generated therapeutic anti-tumor CD4 T cells against multiple tumor antigens. CD4 T cells transferred directly from cured donor mice could eradicate established tumors in host mice. T cells were transferred directly from donor mice and were not stimulated ex vivo. Both tumors that expressed Her2/neu and those that did not were cured by transferred T cells. Analysis of cytokines secreted by anti tumor memory CD4 T cells displayed a multifunctional pattern with high levels of interferon-gamma, interleukin (IL)-4 and IL-17. Anti-tumor memory CD4 T cells traveled to the mesenteric lymph nodes and were activated there. Treatment with targeted recombinant replicating VSV is a potent immune adjuvant that generates therapeutic, multifunctional anti-tumor memory CD4 T cells that recognize multiple tumor antigens. Immunity elicited by viral therapy is independent of host major histocompatibility complex or knowledge of tumor antigens. Virus induced tumor immunity could have great benefit in the prevention and treatment of tumor metastases. PMID- 22240922 TI - Penetrating keratoplasty in congenital hereditary endothelial dystrophy. AB - PURPOSE: To compare the results of penetrating keratoplasty (PK) in a series of congenital hereditary endothelial dystrophy (CHED) patients operated at amblyogenic years and at later ages. METHODS: Records of 65 eyes of 35 CHED patients who underwent PK were reviewed retrospectively. Visual results and graft clarity rates were compared between patients operated after (group 1) and before (group 2) 12 years of age. Results were also compared between eyes with and without nystagmus. RESULTS: Group 1 consisted of 47 eyes (24 patients), whereas group 2 consisted of 18 eyes (11 patients). Thirteen patients (54%) in group 1 and 10 patients (91%) in group 2 had nystagmus. Mean ages at surgery were 26.4 and 7.6 years in group 1 and group 2, respectively. Mean follow-up period was 101.0 months in group 1 and 59.7 months in group 2. Group 1 cases had better graft clarity rates than group 2 cases (P = 0.023). Postoperative best-corrected visual acuities (BCVAs) were 20/80 or better in 39 eyes of group 1 (83%) and in 5 eyes of group 2 (28%). Visual outcomes were found significantly better in group 1 cases (P < 0.001). In group 1, 76% of eyes with nystagmus and 91% of eyes without nystagmus had BCVAs of 20/80 or better. In group 1, both preoperative and postoperative BCVAs were found significantly better in eyes without nystagmus (P < 0.001 and P = 0.002, respectively). CONCLUSIONS: Delayed keratoplasty seems to offer better graft outcomes and visual prognosis to CHED patients, even in the presence of nystagmus. PMID- 22240923 TI - "In situ" corneal and contact lens thickness changes with high-resolution optical coherence tomography. AB - PURPOSE: To show the use of high-resolution spectral-domain optical coherence tomography (HR-SOCT) for the in situ evaluation of epithelial, stromal, and contact lens (CL) thickness changes under closed-eye conditions without lens removal. METHODS: Eight young healthy patients wore a thick soft CL for 90 minutes under closed-eye conditions, and measures of epithelial and stromal corneal thickness were obtained at regular intervals using a HR-SOCT (Copernicus HR; Optopol Tech. SA, Zawiercie, Poland). RESULTS: Minimal changes in epithelial thickness were detected with a transient statistically significant increase in epithelial thickness in the fellow control eye 30 minutes after insertion (P = 0.028). A significant and progressive increase in stromal thickness up to 8% after 90 minutes of lens wear was observed at a constant rate of 2.5% every 30 minutes, being statistically significant in all observations (P < 0.001). Fellow control eyes also showed a significant increase in stromal thickness at a much lower rate of 0.5% every 30 minutes. Lens thickness decreased significantly by 2% after 90 minutes of lens wear under closed-eye conditions (P < 0.001). Individual analysis showed that all eyes displayed stromal swelling, whereas only half of them showed epithelial swelling. CONCLUSIONS: Increase in stromal thickness and a slight decrease in lens thickness were observed in response to a hypoxic stimulus under closed-eye conditions. HR-SOCT is a powerful tool to investigate in vivo the physiological interactions between cornea and CLs. PMID- 22240924 TI - BINOCULAR RIVALRY AND NEURAL DYNAMICS. AB - The Gestalt psychologists were fascinated with dynamics evident in visual perception, and they theorized that these dynamics were attributable to ever changing electrical potentials within topographically organized brain fields. Dynamic field theory, as it was called, was subsequently discredited on grounds that the brain does not comprise a unitary electrical field but, instead, a richly interconnected network of discrete computing elements. Still, this modern conceptualization of brain function faces the challenge of explaining the fact that perception is dynamic in space and in time. To pursue the question of visual perception and cortical dynamics, we have focused on spatio-temporal transitions in dominance during binocular rivalry. We have developed techniques for initiating and measuring these transitions psychophysically and for measuring their neural concomitants using functional magnetic resonance imaging (fMRI). Our findings disclose the existence of waves of cortical activity that travel across the retinotopic maps that define primary and secondary visual areas within occipital cortex, in correspondence with the subjective perception of spreading waves of dominance during binocular rivalry. This paper reviews the results from those studies. PMID- 22240926 TI - Literary lightning (in a bottle). PMID- 22240925 TI - Drug and alcohol use by homicide victims in Trinidad and Tobago, 2001-2007. AB - This paper examines toxicology results from homicide victims in Trinidad and Tobago to explore patterns in pre-mortem drug and alcohol use. Toxicology test results were obtained for 1,780 homicide victims. Toxicology data from the coroner's office were linked with police data on homicide incidents to examine patterns in drug use and homicide. Trinidad and Tobago homicide victims tested positive for cannabis at a significantly higher rate (32%) than the average rate among other drug toxicology studies. Victims tested positive for alcohol (29%), cocaine (7%), and opioids (1.5%) at rates that were either comparable with or lower than those of homicide victims examined in other studies. The proportion of victims testing positive for cannabis grew significantly from 2001 to 2007; the proportions for alcohol and other drugs were fairly stable over time. Toxicology results also varied by homicide motive, weapon type, and the demographic characteristics of the victim. Toxicology data are a useful source for understanding patterns in drug use and homicide. Though such data have limitations, when combined with other types of data, they can often provide unique insights about a community's drug and violence problems. PMID- 22240927 TI - Optimum microcurrent stimulation intensity for galvanotaxis in human fibroblasts. AB - OBJECTIVE: In this study, we develop methods to measure galvanotaxis of fibroblasts and determined the optimum conditions of electrical stimulation. METHOD: An inverted 35mm dish containing cell suspensions (3*105 primary human skin fibroblasts, DMEM, and 10% FBS) was placed on the centre of a 100mm dish. The 35mm dish was removed 24 hours later, and culture medium was added to the 100mm dish. Fibroblasts were randomised (double-blind) into three groups, where electrical stimulation was given at varying intensities: 0UA (control), 50UA, and 100UA. Electrical stimulation (frequency=0.3Hz) was conducted, for a duration of 4 hours, with platinum electrodes in a CO2 incubator. We took pictures immediately before and 20 hours after stimulation. We calculated the migration ratio to the negative pole by dividing the area of attached fibroblasts after stimulation with that before stimulation. RESULTS: The migration ratio to the negative pole was significantly higher in the 100UA group than in the control group (p<0.05). The ratios were 0.902+/-0.292 in the control group, 1.128+/-0.253 in the 50UA group, and 1.24+/-0.300 in the 100UA group. CONCLUSION: This study observed the change in cell proliferation during the initial 24-hour period after plating and was thus able to quantitatively evaluate the migration. The results suggest that a low-intensity direct current promotes migration to the negative pole of human dermal fibroblasts, which is charged with positive electricity. Several clinical reports using the methods in this study showed the microcurrent efficacy for pressure ulcer healing. Electrical stimulation based on our in vitro experiment might be important for the development of physical therapy for pressure ulcers. PMID- 22240929 TI - An open label non-comparative case series on the efficacy of an enzyme alginogel. AB - OBJECTIVE: To evaluate the efficacy of an enzyme alginogel in outpatients with chronic or acute wounds left to heal by secondary intention. METHOD: This evaluation was a single-centre, single-arm, case series involving 23 patients with wounds of diverse aetiologies treated with the enzyme alginogel (Flaminal; Flen Pharma). The product was applied in accordance with the manufacturer's instructions and wounds were covered with secondary dressings. Treatment was based on a scheduled protocol and patients were assessed at days 14, 30 and 60. RESULTS: Median baseline dimensions for the wounds were surface area 2.6cm2 and volume 2.8cm3. Median wound duration before application of the enzyme alginogel was 292 days, with 16 chronic wounds (78%). Three wounds were clinically infected at baseline; two were negative by day 14 and the third by day 30. After 2 months, wound surface area and volume had decreased, as could be expected. Two adverse events were reported: an allergic reaction in the skin surrounding the wound and transient maceration. CONCLUSION: The enzyme alginogel facilitated healing in chronic and acute wounds of diverse aetiologies. Additional research is warranted to confirm the clinical utility of the dressings in the management of chronic or acute wounds left to heal by secondary intention. PMID- 22240928 TI - Comparison of PHMB-containing dressing and silver dressings in patients with critically colonised or locally infected wounds. AB - OBJECTIVE: This study compares treatment with a polihexanide-containing biocellulose wound dressing (BWD+PHMB) versus the best local standard of silver dressings (Ag) in painful, critically colonised (wounds-at-risk) or locally infected wounds. METHOD: Patients with wounds of various aetiologies, a baseline VAS pain score >4 and a semi-quantitative bacterial load of ++ or higher were randomly allocated to receive treatment with either BWD+PHMB or Ag. Patients with systemic infections and/or using systemic antibiotics were excluded. The primary endpoint, patient-reported pain (VAS total pain, including the sub-scores pain at night, during the day, before, and 15min after dressing changes), was compared between treatment groups and scored on days 0, 1, 3, 7, 14, 21 and 28. Secondary outcomes of bacterial load, wound bed and periwound skin condition, quality of life and dressing handling were assessed at the same visits. RESULTS: Thirty eight patients (BWD+PHMB, n=21 [24 wounds]; Ag, n=17 [18 wounds]) were included in the analyses. Baseline variables showed no significant differences. Wound pain was reduced significantly in both groups, with a better pain reduction noted for BWD+ PHMB (p<0.001) before dressing changes. Compared with Ag, in the BWD+PHMB group critical colonisation and local wound infection had been reduced significantly faster and better (p<0.001) over the 28-day study period. Improved quality of life, good tolerability and no adverse events were demonstrated for both groups. CONCLUSION: Both BWD+PHMB and AG were effective in reducing pain and bacterial burden. However, that BWD+PHMB was significantly faster and better in removing the critical bacterial load, makes this dressing an attractive therapeutic option to treat critically colonised and locally-infected wounds. PMID- 22240930 TI - Clinimetrics of tristimulus colourimeters in scar assessment: a review of evidence. AB - OBJECTIVE: To review the evidence regarding the use of tristimulus colourimeters (TC) in scar assessment. METHOD: A literature search was performed using Ovid and the Cochrane database with the search terms 'scar assessment', 'clinimetrics', 'tristimulus colourimeter', 'microcolour', 'chromameter' and 'colour spectrometer'. RESULTS: Wound colour is usually assessed with a visual analogue scale, such as VSS or POSAS. Research on objectifying the assessment by using an assessment tool has so far been encouraging, but has failed to show a benefit over the visual analogue scales in terms of validity, accuracy and reproducibility. Studies vary in methodological quality. CONCLUSION: Research on TC clinimetrics has shown moderate to high concurrent validity, reliability and reproducibility of these products in terms of assessing vascularity, but less correlation in terms of pigmentation, when compared with the visual scoring systems. The evidence for using TC is based on a relatively small number of studies, and more research is needed before widespread implementation of TC for assessing scar maturation is recommended. PMID- 22240931 TI - Cryoglobulinaemic leg ulcers associated with transient ischaemic attack. AB - This study report an 87-year-old male patient with multiple, superficial non healing leg ulcers and transient ischaemic attack. Testing for serum cryoglobulins returned positive and for serum immunofixation electrophoresis displayed increased monoclonal IgG-kappa. Histological examination revealed epidermis ulceration, accumulations of neutrophils with nuclear dust or debris (leukocytoclasia) and PAS positive homogen eosinophilic fibrin deposition in the vessel wall. Leucocytoclastic vasculitis was diagnosed pathologically. Direct immunofluorescence testing was performed for confirmation of the diagnosis of cutaneous vasculitis, with intravascular deposition of IgA, IgG, IgM and C3 in the walls of vessels of papillary and reticular dermis. There was no underlying disease and the patient was diagnosed with cryoglobulinaemia type I. Leg ulcers responded successfully to treatment with high dose steroids and anticoagulant agents and healed within 2 months. PMID- 22240932 TI - Mood disorders in patients with acute and chronic wounds: a health professional perspective. AB - OBJECTIVE: This exploratory study surveys a group of practitioners to discover their perspectives on the prevalence of stress, anxiety and mood disorders among their patients with acute and chronic wounds. METHOD: A questionnaire survey was sent to an convenience sample of 81 health professionals. The questionnaire included items about the health professionals' perceptions of the prevalence of mood disorders among their patients, and their perceptions of potential contributory factors and treatments. RESULTS: Thirty-nine health professionals (48%), including tissue viability nurses, nurses and podiatrists, responded to the survey. The majority of respondents believed that 50-75% of their patients with chronic wound were suffering from mood problems related to their condition. Despite this, most practitioners believed that few of their patients were actually receiving treatment for these mood- related problems. One quarter of patients with acute wounds were considered to have related problems with mood. Practitioners believed anxiety and feeling helpless were the most common mood problems among their patients, while chronic pain/discomfort of the wound and inability to complete everyday tasks were potential contributory factors to these problems. CONCLUSION: The findings suggest that the health professionals who responded to the survey were aware of behavioural signs of stress, anxiety and mood problems in their patients with chronic wounds. Furthermore, the majority of practitioners did not feel that their patients were receiving help or treatment for these problems. It is therefore suggested that increased awareness of the behavioural signs of stress, anxiety and mood problems among patients with wounds could help to improve the patient's experience of wound care, as acknowledgement of mood problems could lead to the most appropriate form of treatment or help for individual patients. PMID- 22240933 TI - Erratum to: Psychometric evaluation of the Cystic Fibrosis Questionnaire-Revised in a national, US sample. AB - PURPOSE: The psychometric properties of a health-related quality of life (HRQOL) instrument, the Cystic Fibrosis Questionnaire-Revised (CFQ-R), were evaluated in a national, US sample of patients with cystic fibrosis (CF). This is the first psychometric evaluation of the revised version of this instrument. METHODS: The Epidemiologic Study of CF is a national, US multicenter longitudinal cohort study containing CFQ-R and health outcomes data. Developmentally appropriate versions of the CFQ-R were available from 7,330 patients aged 6-70 years and a proxy version from 2,728 parents of school-age children. The CFQ-R was completed during a "stable" or "sick" visit before recording health outcomes such as weight, lung function, and pulmonary exacerbations. RESULTS: There were few floor and ceiling effects and strong internal consistency (Cronbach alpha >=0.70) for most scales. The CFQ-R consistently discriminated between patients seen for sick-versus-well visits, and among stages of disease severity based on lung function. As predicted, women with CF reported worse HRQOL than men on scales not related to body image and weight. Strong parent-child agreement was found on scales measuring observable behaviors (respiratory symptoms). Convergence between CFQ-R scales and health outcomes provided evidence of construct validity. CONCLUSIONS: The CFQ-R demonstrated robust psychometric properties and consistent associations with health outcomes in a large national, US sample. Normative data are available to aid in interpretation. PMID- 22240934 TI - Focal physiologic fluorodeoxyglucose activity in the gastrointestinal tract is located within the colonic lumen. AB - AIM: Physiologic activity of 18F-fluorodeoxyglucose (FDG) in the intestinal tract occurs frequently in patients undergoing PET/computed tomography (CT) imaging, appearing most often in the colon. The purpose of this study is to determine the localization of the FDG within the colon. We hypothesize that intestinal FDG activity is intraluminal. METHODS: In a prospective Institutional Review Board approved and Health Insurance Portability and Accountability Act-compliant study, patients with physiologic colonic FDG activity on PET/CT scans were enrolled to undergo repeat imaging 2 h after stimulation of colonic motility with a high-fat meal. RESULTS: We identified 13 patients who had focal FDG activity in their colon during a routine clinical PET/CT scan. After administration of a high-fat meal, 10 patients (77%) demonstrated antegrade movement of FDG along the colon, consistent with luminal clearance. CONCLUSION: Our results suggest that normal physiologic FDG activity within the large intestine, seen on PET/CT scans, is intraluminal. PMID- 22240935 TI - Low-dose thallium-201 protocol with a cadmium-zinc-telluride cardiac camera. AB - OBJECTIVES: Thallium-201 is efficient for myocardial perfusion imaging, but leads to relatively high radiation exposure in patients. The purpose of this study was to compare the efficiency of low-dose thallium-201 imaging with cadmium-zinc telluride (CZT) cameras with regular-dose thallium-201 imaging with conventional cameras. METHODS: We prospectively studied 137 consecutive patients referred for stress myocardial perfusion imaging who had previously had a myocardial single photon emission computed tomography with thallium-201. We injected at stress a low dose of thallium-201 (1.1 MBq/kg, 28 uCi/kg), performed a 5-7 min scan with a CZT camera (GE DNM 530c), and assessed redistribution imaging when the initial images were abnormal. We compared the CZT scan with the conventional dual-head tomographic camera scan taken previously with a regular dose of thallium-201. RESULTS: The average delay between both scans was 22 months. The stress dose was 88 +/- 16 (2.38 +/- 0.43 mCi) versus 125 +/- 13 MBq (3.38 +/- 0.34 mCi; a 30% reduction). The time for camera acquisition was 6 versus 13 min (a 54% reduction). The myocardial counts were increased two-fold with CZT (mean: 446 Kcounts). The quality of CZT images was better in 69% of the cases. There were 59 artifacts with conventional cameras and 29 artifacts with CZT (P<0.01). The diagnostic agreement was calculated in patients without clinical or angiographic changes between both scans (115 patients) and was high (97%). The effective dose at stress was less than 12 mSv. High myocardial counting allowed for further decrease in the injected activity, leading to an effective dose as low as 8 mSv. CONCLUSION: With reduced activities of thallium-201 and low effective doses, the CZT camera provides reliable, high-quality imaging. PMID- 22240936 TI - Choroidal observations in Vogt-Koyanagi-Harada disease using high-penetration optical coherence tomography. AB - BACKGROUND: The aim of this work was to investigate the choroidal morphologic changes of Vogt-Koyanagi-Harada (VKH) disease in vivo using high-penetration optical coherence tomography (HP-OCT) with a long-wavelength light source (1,060 nm). METHODS: Fourteen patients with VKH disease were included in this study: 12 eyes of six patients with treatment-naive acute VKH in the first 6-12 months after diagnosis and 16 eyes of eight patients in the convalescent phase with a sunset glow fundus appearance. A prototype HP-OCT instrument was used to observe the deep choroid and sclera. The choroidal thickness was measured for more than 6 months in eyes with acute disease. The choroidal thickness in patients with a sunset glow fundus appearance for 2-9 years after the onset was also examined. RESULTS: In 12 eyes with acute VKH disease, the baseline choroidal thickness was significantly (p < 0.0001) greater than in controls. After treatment, the choroidal thickness decreased over time. However, the choroidal thickness increased markedly again in four eyes with recurrent disease. The mean thickness at 12 months was significantly less than the normal value (p < 0.0001). In 16 eyes with a sunset glow fundus appearance, the choroidal thickness was significantly (p < 0.0001) thinner compared to the controls. CONCLUSIONS: Significant choroidal thickness changes underlie VKH disease, which progress over time. Objective measurement of the choroidal thickness using HP-OCT may be useful for longitudinal evaluation of VKH activity. PMID- 22240937 TI - A survey of stakeholder knowledge, experience, and opinions of advance directives for mental health in Virginia. AB - An innovative Virginia health care law enables competent adults with serious mental illness to plan for treatment during incapacitating crises using an integrated advance directive with no legal distinction between psychiatric or other causes of decisional incapacity. This article reports results of a survey of 460 individuals in five stakeholder groups during the initial period of the law's implementation. All respondents held favorable views of advance directives for mental health care. Identified barriers to completing and using advance directives varied by group. We conclude that relevant stakeholders support implementation of advance directives for mental health, but level of baseline knowledge and perception of barriers vary. A multi-pronged approach will be needed to achieve successful implementation of advance directives for mental health. PMID- 22240938 TI - Developing and maintaining partnerships as the foundation of implementation and implementation science: reflections over a half century. PMID- 22240940 TI - Micronuclei formation induced by X-ray irradiation does not always result from DNA double-strand breaks. AB - X-ray induced formation of micronuclei is generally thought to result from DNA double-strand breaks (DSBs). However, DNA DSBs inhibit the cell cycle progression that is required for micronucleus formation. In order to reconcile this apparent discrepancy, we investigated whether DNA DSBs induced during the G1 phase could lead to micronucleus formation. We irradiated human embryonic (HE17) cells that had been treated with a radical scavenger, either DMSO or ascorbic acid (AsA), and determined the level of suppression of DNA DSBs or micronuclei. When DNA DSBs were evaluated using 53BP1 foci, treatment with 5 mM AsA did not inhibit the numbers of foci at various intervals after X-ray irradiation; however, treatment with 5 mM or 256 mM DMSO did have a significant inhibitory effect. By contrast, an assay of micronucleus numbers showed that treatment with 5 mM or 256 mM DMSO before X-ray irradiation resulted in almost no inhibition of micronucleus formation, but treatment with 5 mM AsA did have a significant inhibitory effect. These results clearly showed that AsA could suppress micronucleus formation, although it was not effective for suppression of DNA DSBs. Therefore, we conclude that DNA DSBs induced in the G1 phase do not directly lead to micronucleus formation. PMID- 22240939 TI - Interstitial brachytherapy using virtual planning and Doppler transrectal ultrasonography guidance for internal iliac lymph node metastasis. AB - To expand the indications for high-dose-rate interstitial brachytherapy (HDR ISBT) for deep-seated pelvic tumors, we investigated the usefulness of Doppler transrectal ultrasonography (TRUS) guidance and virtual planning. The patient was a 36-year-old female. She had right internal iliac lymph node oligometastasis of vaginal cancer 12 months after radical radiotherapy. The tumor could not be found by gray-scale TRUS and physical examination. Virtual planning was performed using computed tomography with template and vaginal cylinder insertion. We uploaded the images to our treatment planning software and reconstructed the contours of the clinical target volume (CTV) and right internal iliac vessel. Virtual needle applicators were plotted using the template holes for virtual planning. At the time of implantation, Doppler TRUS was used to prevent vessel injury by needle applicators. Applicators were implanted in accordance with virtual planning and Doppler TRUS could detect the right iliac vessel. The percentage of CTV covered by the prescribed dose was 99.8%. The minimum dose received by the maximally irradiated 0.1-cc volume for the right internal iliac vessel was 95% prescribed dose. Complete response was achieved, however, radiological findings showed marginal recurrence at 15 months after HDR-ISBT. Post-radiation neuropathy occurred as a late complication four months after treatment; however, the pain was well controlled by medication. We consider that virtual planning and Doppler TRUS are effective methods in cases where it is difficult to detect the tumor by physical examination and gray-scale TRUS, thereby expanding the indications for ISBT. PMID- 22240941 TI - Single-arc volumetric modulated arc therapy planning for left breast cancer and regional nodes. AB - We have successfully created a single arc volumetric modulated arc therapy (VMAT) plan for treating post-surgical left breast/chest wall and regional nodes using Elekta multileaf collimator (MLC). Dose volume histograms (DVHs) were compared between the VMAT plans and conventional tangential beam plans using a field-in field technique, leading to significant DVH advantages in the VMAT plans. The difference between Elekta VMAT and Varian RapidArc due to different MLC designs was discussed in terms of the number of arcs required to cover a large target, highlighting a single arc capability of Elekta VMAT for a large target volume which may be less sensitive to unexpected organ motion during dose delivery. PMID- 22240942 TI - Daily CT measurement of needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy for postoperative recurrent uterine cancer. AB - We investigated daily needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy (HDR-ISBT) for postoperative recurrent uterine cancer. Eight patients with postoperative recurrent uterine cancer received HDR-ISBT with or without external beam radiotherapy using our unique ambulatory technique. To analyze displacement, we obtained daily computed tomography (CT) images for 122 flexible needle applicators at 21, 45, 69, and 93 hours after implantation. Displacement was defined as the length between the center of gravity of titanium markers and the needle applicator tips along the daily CT axis. For cases in which displacement was not corrected, we also calculated the dose that covered 90% of the clinical target volume (D90(CTV)) using a dose-volume histogram (DVH). Median caudal needle applicator displacement at 21, 45, 69, and 93 hours was 3, 2, 4, and 5 mm, respectively. More than 15 mm displacement was observed for 2% (2 of 122) and 17% (10 of 60) of needle applicators at 21 and 93 hours, respectively. Cases in which dwell positions were not changed to correct the treatment plan, 2 of 8 patients showed more than 10% reduction in D90(CTV) values compared with the initial treatment plan. Correction of dwell positions of the treatment source improves treatment DVH for multifractionated HDR-ISBT. PMID- 22240943 TI - Proton magnetic resonance imaging with para-hydrogen induced polarization. AB - A major challenge in imaging is the detection of small amounts of molecules of interest. In the case of magnetic resonance imaging (MRI) their signals are typically concealed by the large background signal of e.g. the body. This problem can be tackled by hyperpolarization which increases the NMR signals up to several orders of magnitude. However, this strategy is limited for (1)H, the most widely used nucleus in NMR and MRI, because the enormous number of protons in the body screens the small amount of hyperpolarized ones. Here, we describe a method giving rise to high (1)H MRI contrast for hyperpolarized molecules against a large background signal. The contrast is based on the J-coupling induced rephasing of the NMR signal of molecules hyperpolarized via PHIP and it can easily be implemented in common pulse sequences. We discuss several scenarios with different or equal dephasing times T(2)* for the hyperpolarized and thermally polarized compounds and verify our approach by experiments. This method may open up unprecedented opportunities to use the standard MRI nucleus (1)H for e.g. metabolic imaging in the future. PMID- 22240944 TI - Editors note. PMID- 22240945 TI - Gender and assistance: historical and conceptual considerations regarding assistance practices and policies. AB - The article offers some theoretical and historical reflections on the concept of gender as it relates to the notion of assistance. Explores the political dimensions of both concepts and problematizes the dichotomy between the gender marked realms of the political and the pre-political, a dichotomy that has greatly influenced modern political theory and thought. It examines the modern state's care practices and the transformations in assistance which occurred within the charitable and assistance organizations that took shape in parallel and in consonance with this state action. PMID- 22240946 TI - From the agricultural colony to the hospital-colony: configurations for psychiatric care in Brazil in the first half of the twentieth century. AB - The meanings given to the institutional model of the colonies in psychiatric care in Brazil are assessed, duly considering their different configurations in the context of public health policies in the first half of the twentieth century. The central thread of this analysis is the case of the Colonia Juliano Moreira, an institution founded in 1924 in Rio de Janeiro. It seeks to show the meaning attributed to the concept of agricultural colony and its importance in shaping the Colonia Juliano Moreira, in order to understand how the ideological precept of agricultural colony was translated into the concept of hospital-colony from the 1940s onwards, when this institution experienced a steady process of marked expansion of its physical structure and its therapeutic resources. PMID- 22240947 TI - [Notes on hospital architecture in Brazil: between the traditional and the modern]. AB - The relationship between the history of health assistance and architecture is not always obvious. The article points to some challenges in investigating this relation, which is most readily visible in the construction of medical facilities, especially hospitals and sanitariums. In Brazil, this fledgling field has begun drawing the attention of researchers from the applied human and social sciences, especially in more recent decades. PMID- 22240948 TI - [Men of the sugarcane fields and their hospitals: the architecture of health under the Estado Novo]. AB - The article explores the emergence of an architectural heritage in the realm of healthcare assistance for workers in the sugarcane agroindustry in Brazil following enactment of the law known as the Estatuto da Lavoura Canavieira (1941), under the auspices of the Instituto do Acucar e do Alcool and as part of Estado Novo policies (1937-1945). The institute proposed solutions based on surveys conducted at sugarcane mills in cane-producing states and on the medical and hospital system adopted by the institute's enlightened bureaucracy in the 1940s, which took the U.S. system as its model. Special focus is given to the central hospitals in Pernambuco and especially in Alagoas, which opposed institute guidelines. PMID- 22240949 TI - The health education of folk midwives: the Servico Especial de Saude Publica and mother-child assistance (1940-1960). AB - The article addresses an endeavor by Servico Especial de Saude Publica (Sesp) to train folk midwives who worked in rural communities and to exercise control over these women's activities. The task was entrusted to the agency's prenatal and child hygiene programs, established between the 1940s and 1960s. The agency believed this training and control initiative would be of major importance in helping ensure the success of its project to establish local sanitary services offering mother-child assistance. The goal of working directly with the folk midwives was not only to force them to employ strict hygiene standards when delivering and caring for newborns but especially to use their influence and prestige within these communities to convince the general population to adopt good health practices. PMID- 22240950 TI - [Without pain you will bring forth children: medical power, gender, and politics in new forms of assisted childbirth in Argentina (1960-1980)]. AB - The methods known as painless childbirth, childbirth without fear, psychoprophylaxis, and birth without violence were popularized in the 1960s and 1980s. The article examines discussions about these methods and reactions to them in Argentina and analyzes the resistance and support encountered in the local medical field when they were first tried out, along with the role played by women. It investigates the meanings of many of these ideas within the period's context of social mobilization, institutional instability, military coups, violence, censorship, and repression but also of major transformations in gender roles and relations. Lastly, it reflects on how demands for respected pregnancy and childbirth fit in with policies on sexuality and reproduction and with the feminist movement. PMID- 22240951 TI - [Mothers, children, and the policies of Chile's Servicio Nacional de Salud (1952 1964)]. AB - This description and exploration of the early years of Servicio Nacional de Salud, founded in 1952, analyzes the agency's progress and challenges, as well as the role of the Programa de Salud Materno-Infantil. The latter program lent continuity to a variety of sanitary protection policies for mothers and children dating to the 1920s, while also improving and expanding on existing policies and devising new ones within the framework of social medicine. The program recorded successes but also encountered limitations, which derived not only from agency specific problems but also from the social and economic ills afflicting the country as a whole. PMID- 22240952 TI - Maternity protection for working women in Argentina: legal and administrative aspects in the first half of the twentieth century. AB - This article discusses the construction of social policies aimed at working women as mothers in Argentina. Thus, we examine the legal corpus, the scope of legislation, and the criticisms of its implementation coming from civil society and from medical, legal and political circles. We focus on the debate about the creation of the Caja de Maternidad (1934) and the shifts in the discussions regarding welfare policy for working women during Peron's first term in office. The methodology is based on a qualitative analysis of parliamentary debates, proposals for legislative reform and reactions in the press. PMID- 22240954 TI - [Scientific charity: Moncorvo Filho and the Instituto de Protecao e Assistencia a Infancia of Rio de Janeiro (1899-1930)]. AB - The article follows the trajectory of Doctor Arthur Moncorvo Filho and the Instituto de Protecao e Assistencia a Infancia, an organization that he founded in Rio de Janeiro in 1899. It examines them within the context of the construction of Brazil's institutional network in the field of children's health assistance in the first half of the twentieth century, a process that combined philanthropic activities, scientific practices, and public investments. This philanthropic physician played a model role, as he conjoined assistance activities with the application of innovative medical techniques and proposed or called for public policies that targeted motherhood and children. PMID- 22240953 TI - [Poverty and assistance in Rio de Janeiro under the First Republic]. AB - In the 1910s, some of Rio de Janeiro's most renowned intellectuals and philanthropists, known as the reformers, launched proposals for offering assistance to the poor, drawn in part from the debate then underway in Europe about alternative ways of fighting poverty. This analysis explores how these reformers received ideas proposed or implemented in Europe and how they adapted them to Brazilian reality, advocating measures intended to ameliorate problems related to Brazil's socalled social question. PMID- 22240955 TI - [Healthcare professions: a critical analysis of care]. AB - The article focuses on the activities of nurses and physical therapists within Brazil's Unified Health System (Sistema Unico de Saude), especially the Family Health Program. With the appearance of new professions and redefinitions in the practices of traditional healthcare professions, the subsequent multi professional, interdisciplinary type of work has presented challenges when it comes to training new generations of healthcare providers, all part of an endeavor to humanize care and provide universalist, integrated, high-quality services. Collective health has contributed to this effort by networking with other fields of knowledge and human sciences. Healthcare fields have also sometimes tended to disregard any type of exchange with the human sciences, preferring to limit interactions to biomedical fields. PMID- 22240956 TI - [Biographies as a possible path in the construction of a professional identity in the field of nursing]. AB - The article analyzes the role of biographies in constructing a professional identity in the field of nursing and their use as a teaching tool in the history of the field at both undergraduate and graduate nursing courses. It surveys some biographies of women who contributed to the development of the field and who left a legacy that has inspired its providers. The conclusion is that biographies can play a role in nursing education, contributing to the construction of a professional identity by conveying the field's values. PMID- 22240957 TI - [Philanthropy, government, and the fight against leprosy (1920-1945)]. AB - The 1920s creation of Sociedades de Assistencia aos Lazaros e Defesa Contra a Lepra under Brazil's First Republic (1889-1930) represented a milestone in relations between assistance organizations and the government. Although these organizations were at first autonomous decision-makers, their guidelines changed after they established closer relations with the government, which enacted reforms in policies to fight leprosy following the 1930 creation of the Ministry of Education and Public Health, especially during the long tenure of Minister Gustavo Capanema (1934-1945). PMID- 22240958 TI - [Training and providing assistance: images of Curitiba's Senai school in the 1940s and 1950s]. AB - A branch of the Servico Nacional de Aprendizagem Industrial (Senai) was set up in Parana in 1943 to train industrial labor. Images and written records held by the Parana State Federation of Industries depict aspects of technical training at the Senai school in Curitiba, both from an institutional perspective and from the students', through their discourse. A comparison of these images and discourses serves to highlight the vicissitudes of this private institution's vocational training project, which received government support for the instruction of industrial workers, especially apprentices. PMID- 22240959 TI - [Pro Matre: an archive and sources on the history of motherhood in Rio de Janeiro]. AB - Inaugurated in February 1919 to provide assistance to mothers and children from underprivileged social groups, the nearly century-old Maternidade Pro Matre maternity hospital was an initiative of physician and philanthropist Fernando Magalhaes and of feminist Stella de Carvalho Guerra Duval, with the support of society women from Rio de Janeiro. Its creation was part of a mother-child assistance movement that historiography now calls the 'maternalist project,' which was based on the notion of the cultural inseparability of mother and child. The sources available at Pro Matre's institutional archive open up research possibilities in the field of mother-child assistance in Rio de Janeiro and, by extension, Brazil. PMID- 22240960 TI - [French lines in Recife architecture: Pedro II Hospital]. AB - Pedro II Hospital was inaugurated in Recife in 1861 and for several decades was the leading center of its kind in the state of Pernambuco and in Northeast Brazil. Its construction followed French design, as developed by physician Jacques-Rene Tenon, that is, the so-called pavilion style that was the norm in Pernambuco and in Brazil for many years. After being nearly abandoned in 1982, the hospital was reformed shortly thereafter and reopened its doors to offer a variety of services, thanks to negotiations between the Instituto de Medicina Integral Professor Fernando Figueira and the Archdiocese of Olinda and Recife. PMID- 22240961 TI - [State, civil society, and health policies in Europe (nineteenth and twentieth centuries)]. PMID- 22240962 TI - [The promotion of women in social space as an effect of the regulation of motherhood and childhood]. PMID- 22240963 TI - [Reconstructing motherhood: pediatric and obstetric discourse in women's magazines in the 1920s]. PMID- 22240964 TI - [From the dream of social ascent to the life of a laborer: shop clerks in Rio de Janeiro at the turn of the nineteenth to twentieth centuries]. PMID- 22240965 TI - Sentinel lymph node biopsy in patients with breast cancer using superparamagnetic iron oxide and a magnetometer. AB - BACKGROUND: Some hospitals lack facilities for radioisotopes in sentinel node biopsy. A novel method is used with a superparamagnetic tracer and a magnetometer instead of a radioisotope. METHODS: Thirty patients were included in the study after obtaining IRB approval. Superparamagnetic iron oxide and patent blue dye were injected in the subareolar breast tissue. Following a few minutes of massage to promote migration of the iron tracer and blue dye throughout the lymphatic vessels, the axillary lymph nodes were detected transdermally using a handheld magnetometer and followed by standard axillary dissection in all patients. RESULTS: Of 30 patients evaluated, sentinel lymph nodes were identified in 90% (27/30) using both blue dye and magnetic tracer. Sentinel lymph nodes were identified using the magnetic method in 23/30 (77%) and blue dye in 24/30 (80%). There was one false-negative sentinel node, resulting in an overall sensitivity of 6/7 (86%). CONCLUSIONS: This is the first study to use a magnetic tracer to identify sentinel lymph nodes in patients with breast cancer. This new technique may alter the role of radioisotopes with further refinement and experience. PMID- 22240966 TI - Ternary resin-bound Dynamic Combinatorial Chemistry. AB - The ability to carry out simultaneous orthogonal exchange chemistries has opened new opportunities for increasing the numerical and structural diversity accessible to Dynamic Combinatorial Chemistry. We present proof-of-concept experiments demonstrating this concept is transferrable to resin-bound DCC, facilitating the generation and analysis of libraries with greater structural diversity. PMID- 22240967 TI - Design and construction of coordination polymers based on 2,2'-dinitro-4,4' biphenyldicarboxylate and semi-rigid N-donor ligands: diverse structures and magnetic properties. AB - Eight 2D and 3D coordination polymers, [Mn(NBPDC)(1,4-bimb)](n) (1), [Zn(NBPDC)(1,4-bimb)](n) (2), [Cd(NBPDC)(1,4-bimb)](n) (3), [Mn(2)(NBPDC)(2)(1,3 bimb)(H(2)O)](n) (4), {Zn(NBPDC)(1,3-bimb)}(n) (5), [Cd(2)(NBPDC)(2)(1,3 bimb)(2)(H(2)O)](n) (6), [Mn(NBPDC)(4,4'-bimbp)](n) (7), and [Cd(2)(NBPDC)(2)(4,4'-bimbp)(2)](n) (8), (NBPDC = 2,2'-dinitro-4,4' biphenyldicarboxyl acid, 1,4-bimb = 1,4-bis(imidazol-1-ylmethyl) benzene, 1,3 bimb = 1,3-bis(imidazol-1-ylmethyl) benzene, and 4,4'-bimbp = 4,4'-(bis(imidazol l-ylmethylene)) biphenyl), have been prepared and structurally characterized. In these coordination polymers, NBPDC and three N-donor ligands link different metal ions and SBUs to construct diverse architectures. Compounds 1 and 3 are isomorphic, showing a two-fold interpenetrating pcu topology. Compound 2 presents a 2D (4, 4) net. Compound 4 is a hex framework built by the linkage of ligands with infinite rod-shaped SBUs. Compound 5 presents a unprecedented eight-fold interpenetrating sra topology. Compound 6 exhibits a unique 2D {6(3)}{6(5).8} topology with four-fold interpenetrating structure. Compound 7 presents a 3D hex topology, and compound 8 shows a (4, 4) net. The magnetic properties of compounds 1, 4, and 7 have been characterized. Compound 1 displays interesting spin-canting antiferromagnetism and metamagnetism simultaneously. Compound 7 exhibits spin canting antiferromagnetism. PMID- 22240968 TI - Retrievable vena cava filters: a clinical review. AB - Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (PE), is a major cause of morbidity and mortality. Parenteral anticoagulant treatment with full-dose unfractioned heparin, low-molecular-weight heparin, or fondaparinux, followed by oral treatment with the vitamin K antagonists, is recommended for the majority of patients. However, in the presence of contraindications to anticoagulant treatment, bleeding complications during antithrombotic treatment, or VTE recurrences despite optimal anticoagulation, interruption of the inferior vena cava with a filter is a potential option aimed to prevent life-threatening PE. Currently, the vast majority of filters implanted worldwide are of the permanent type, but their use is associated with a number of long term complications. Non-permanent filters represent an important alternative, and in particular retrievable filters are an attractive option because they may be either left in place permanently or safely retrieved after a quite long period when they become unnecessary. In this review, we summarize the currently available literature regarding retrievable vena cava filters and we discuss current evidences on their efficacy and safety. Moreover, the appropriate indications for their use in daily clinical practice are reviewed. PMID- 22240969 TI - Frequent long-distance flyer's undesirable mileage: an organized giant thrombus stuck in PFO. PMID- 22240971 TI - Inside an unquiet mind. Music and science join forces to explore mental ill health. PMID- 22240970 TI - Regulation of TOR by small GTPases. AB - TOR is a conserved serine/threonine kinase that responds to nutrients, growth factors, the bioenergetic status of the cell and cellular stress to control growth, metabolism and ageing. A diverse group of small GTPases including Rheb, Rag, Rac1, RalA and Ryh1 play a variety of roles in the regulation of TOR. For example, while Rheb binds to and activates TOR directly, Rag and Rac1 regulate its localization and RalA activates it indirectly through the production of phosphatidic acid. Here, we review recent findings on the regulation of TOR by small GTPases. PMID- 22240972 TI - Neutrophils--the unexpected helpers of B-cell activation. PMID- 22240973 TI - Research and practice coming together. The advent of personalized medicine is bringing clinical research and practice closer together. PMID- 22240974 TI - The anglerfish deception. The light of proposed reform in the regulation of GM crops hides underlying problems in EU science and governance. PMID- 22240975 TI - Emerging journals. The benefits of and challenges for publishing scientific journals in and by emerging countries. PMID- 22240976 TI - Parathyroidectomy for the attainment of NKF-K/DOQITM and KDIGO recommended values for bone and mineral metabolism in dialysis patients with uncontrollable secondary hyperparathyroidism. AB - PURPOSE: The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQITM) 2003 and Kidney Disease: Improving Global Outcomes (KDIGO) 2009 have established guidelines for the treatement of secondary hyperparathyroidism. This study evaluated the impact of parathyroidectomy to achieve recommended values for parathyroid hormone, calcium, phosphorus and CaxPO(4) product in dialysis patients with severe secondary hyperparathyroidism that is resistant to medical treatment. METHODS: This study included 43 consecutive patients who underwent parathyroidectomy for a severe form of secondary hyperparathyroidism (SHPT) that is unresponsive to medical treatment. The serum iPTH, calcium and phosphorus levels were measured prior to surgery, every morning after surgery for 5 days and on the first, sixth and eighth postoperative months. RESULTS: Following parathyroidectomy, a significant decline in iPTH values was observed in all patients; however, after the 8-month study period, only one of these patients achieved a serum iPTH concentration within the K/DOQI recommended target range. Unlike iPTH, targeting for calcium, phosphorus and CaxPO(4) at the last follow-up were 55.8%, 60.5% and 93%, respectively. These values indicated a significant improvement in comparison to preoperative percentages. In regards to the KDIGO recommended guidelines, the iPTH levels did not significantly change at the end of our study compared to preoperative values; however, calcium levels significantly declined and phosphorus levels significantly improved compared to preoperative values. CONCLUSIONS: Although the majority of patients fail to reach recommended iPTH values, parathyroidectomy remains a valuable tool to attain these NKF-K/DOQI recommendations for serum calcium, phosphorus and CaxPO(4) in dialysis patients with secondary hyperparathyroidism resistant to medical therapy. Parathyroidectomy was shown to be an inadequate intervention for achieving KDIGO recommendations. PMID- 22240977 TI - Prenatal carbofuran exposure inhibits hippocampal neurogenesis and causes learning and memory deficits in offspring. AB - Neurogenesis is a process of generation of new neurons in the hippocampus and associated with learning and memory. Carbofuran, a carbamate pesticide, elicits several neurochemical, neurophysiological, and neurobehavioral deficits. We evaluated whether chronic prenatal oral exposure of carbofuran during gestational days 7-21 alters postnatal hippocampal neurogenesis at postnatal day 21. We found carbofuran treatment significantly decreased bromodeoxyuridine (BrdU) positive cell proliferation and long-term survival in the hippocampus only but not in the cerebellum. We observed a reduced number of transcription factor SOX-2 and glial fibrillary acidic protein (GFAP) colabeled cells, decreased nestin messenger RNA (mRNA) expression, and decreased histone-H3 phosphorylation following carbofuran treatment, suggesting a decreased pool of neural progenitor cells (NPC). Colocalization of BrdU with doublecortin (DCX), neuronal nuclei (NeuN), and GFAP suggested decreased neuronal differentiation and increased glial differentiation by carbofuran. The number of DCX(+) and NeuN(+) neurons, NeuN protein levels, and fibers length of DCX(+) neurons were decreased by carbofuran. Carbofuran caused a significant downregulation of mRNA expression of the neurogenic genes/transcription factors such as neuregulin, neurogenin, and neuroD1 and upregulation of the gliogenic gene Stat3. Carbofuran exposure led to increased BrdU/caspase 3 colabeled cells, an increased number of degenerative neurons and profound deficits in learning and memory processes. The number and size of primary neurospheres derived from the hippocampus of carbofuran-treated rats were decreased. These results suggest that early gestational carbofuran exposure diminishes neurogenesis, reduces the NPC pool, produces neurodegeneration in the hippocampus, and causes cognitive impairments in rat offspring. PMID- 22240978 TI - Cadmium associated with inhaled cadmium oxide nanoparticles impacts fetal and neonatal development and growth. AB - One industrially important metal oxide nanoparticle (NP) is cadmium oxide (CdO). A study was performed using timed-pregnant CD-1 mice to determine if Cd associated with inhaled CdO NP could reach the placenta and adversely affect the developing fetus and/or neonate. Pregnant mice were exposed by inhalation either every other day to 100 MUg of freshly generated CdO/m(3) (exposure 1) or daily to 230 MUg CdO/m(3) (exposure 2). In each exposure, mice were exposed to CdO NP or carrier gas (control) for 2.5 h from 4.5 days post coitus (dpc) through 16.5 dpc. At 17.5 dpc, fetuses and placentas from both exposures 1 and 2 were collected, measured, and weighed. A subgroup from the second exposure was allowed to give birth, and neonates were weighed daily until weaning. Cadmium in the uterus and placenta, as well as in other maternal organs, was elevated in NP-treated mice, but was undetectable in fetuses at 17.5 dpc. Daily inhalation of 230 MUg CdO NP/m(3) decreased the incidence of pregnancy (i.e., no evidence of implantation) by 23%, delayed maternal weight gain, altered placental weight, and decreased fetal length, as well as delayed neonatal growth. This study demonstrates that inhalation of CdO NP during pregnancy adversely affects reproductive fecundity and alters fetal and postnatal growth of the developing offspring. PMID- 22240979 TI - Proinflammatory adhesion molecules facilitate polychlorinated biphenyl-mediated enhancement of brain metastasis formation. AB - Polychlorinated biphenyls (PCBs) are environmental toxicants that cause vascular inflammation and facilitate the development of brain metastases. The crucial event in metastasis formation is adhesion of blood-borne tumor cells to the vascular endothelium, followed by their transcapillary migration. The aim of the present study was to examine the mechanisms of PCB118-induced brain metastasis formation at the blood-brain barrier level with the focus on tumor cell adhesion to the brain endothelium. PCB118 was administered orally to wild-type or intercellular cell adhesion molecule-1 (ICAM-1)-deficient mice, followed by an injection of Lewis lung carcinoma cells into the carotid artery. Treatment with PCB118 resulted in enhanced development of brain metastases. Injection of tumor cells induced overexpression of ICAM-1 and vascular endothelial cell adhesion molecule-1 (VCAM-1) in brain endothelium that was further potentiated in mice exposed to PCB118. PCB118 did not affect the number of adhered and extravasated tumor cells in ICAM-1-deficient mice. Additional in vitro studies indicated that VCAM-1-neutralizing antibody protected against PCB118-induced adhesion of tumor cells to cultured brain endothelial cells. These results indicate that exposure to selected PCB congeners, such as PCB118, induces adhesion and transcapillary migration of tumor cells. This process is facilitated by proinflammatory adhesion molecules and results in potentiation of brain metastasis formation. PMID- 22240981 TI - Intracellular Pb2+ content monitoring using a protein-based Pb2+ indicator. AB - Lead ion (Pb(2+)) is one of the most hazardous heavy metals to almost all life forms. The components of store-operated Ca(2+) entry as a molecular gateway have been previously found to participate in the cytotoxic entry of Pb(2+). However, the safe levels of intracellular Pb(2+) hiding in blood Pb(2+) levels are still not determined with full certainty. The present study aimed to construct protein based Pb(2+) indicators to help establish a reliable setting for the content monitoring of intracellular Pb(2+). A series of Pb(2+) indicators based on fluorescence resonance energy transfer, Met-leads, were developed. The Pb(2+) binding protein PbrR (from Cupriavidus metallidurans CH34) was applied between the fluorescent protein pair ECFP(DeltaC11) and cp173Venus. The spectral patterns and sensing ranges of all Met-leads were characterized in vitro. Among these constructs, Met-lead 1.59 had relatively high ion selectivity and broad dynamic range (3.3-5.7). Consequently, this Met-lead was adopted in the cellular Pb(2+) biosensing. The intracellular Pb(2+) content in human embryonic kidney cells was successfully monitored using Met-lead 1.59 under both short- and long-term treatments. The existence of intracellular Pb(2+) can be significantly sensed using Met-lead 1.59 after 3 h 0.5MUM (10 MUg/dl) exposure, which is 200 times more improved than previous live-cell indicators. In summary, a new Pb(2+) indicator, Met-lead 1.59, was successfully developed for advanced research on Pb(2+) toxicology. PMID- 22240980 TI - Effects of silver nanoparticles on primary mixed neural cell cultures: uptake, oxidative stress and acute calcium responses. AB - In the body, nanoparticles can be systemically distributed and then may affect secondary target organs, such as the central nervous system (CNS). Putative adverse effects on the CNS are rarely investigated to date. Here, we used a mixed primary cell model consisting mainly of neurons and astrocytes and a minor proportion of oligodendrocytes to analyze the effects of well-characterized 20 and 40 nm silver nanoparticles (SNP). Similar gold nanoparticles served as control and proved inert for all endpoints tested. SNP induced a strong size dependent cytotoxicity. Additionally, in the low concentration range (up to 10 MUg/ml of SNP), the further differentiated cultures were more sensitive to SNP treatment. For detailed studies, we used low/medium dose concentrations (up to 20 MUg/ml) and found strong oxidative stress responses. Reactive oxygen species (ROS) were detected along with the formation of protein carbonyls and the induction of heme oxygenase-1. We observed an acute calcium response, which clearly preceded oxidative stress responses. ROS formation was reduced by antioxidants, whereas the calcium response could not be alleviated by antioxidants. Finally, we looked into the responses of neurons and astrocytes separately. Astrocytes were much more vulnerable to SNP treatment compared with neurons. Consistently, SNP were mainly taken up by astrocytes and not by neurons. Immunofluorescence studies of mixed cell cultures indicated stronger effects on astrocyte morphology. Altogether, we can demonstrate strong effects of SNP associated with calcium dysregulation and ROS formation in primary neural cells, which were detectable already at moderate dosages. PMID- 22240982 TI - Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles. AB - The toxicology of nanoparticles (NPs) is an area of intense investigation that would be greatly aided by improved understanding of the relationship between NP structure and inflammogenicity. To evaluate how their physicochemical parameters influence toxicity, we assembled a panel of 15 metal/metal oxide NPs and attempted to relate various physicochemical parameters, including zeta potential (zetaP) and solubility, to lung inflammogenicity. The acute pulmonary inflammogenicity of the 15 NPs showed a significant correlation with one of two structural parameters-zetaP under acid conditions for low-solubility NPs and solubility to toxic species for high-solubility NPs. zetaP is the electrical potential created between the surface of a particle, with its associated ions, and the medium it exists in and provides information concerning the particle surface charge. We suggest that inside the phagolysosome under acid conditions, a high positive zetaP may allow NPs to damage the integrity of the phagolysosomal membrane leading to inflammation. In the case of high-solubility NPs, inflammogenicity depends on the ions that are produced during dissolution of NP inside the acidic phagolysosomes; if the ions are toxic, then phagolysosomes will be destabilized and cause inflammation. These two parameters may have utility in preliminary assessment of the potential lung inflammation hazard of the large number of NPs that require testing. PMID- 22240983 TI - Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain. AB - The highly toxic organophosphorus compound VX [O-ethyl S-[2 (diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day * 5 days/week * 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure. PMID- 22240984 TI - Identification and pathway mapping of furan target proteins reveal mitochondrial energy production and redox regulation as critical targets of furan toxicity. AB - Furan, a heat-generated food contaminant, is hepatotoxic and carcinogenic in rodents. Furan is oxidized by cytochrome P450 2E1 to cis-2-butene-1,4-dial, a chemically reactive alpha,beta-unsaturated dialdehyde, which has been identified as the key toxic metabolite of furan based on its ability to interact with tissue nucleophiles. In addition to genotoxicity, sustained cytotoxicity mediated through covalent binding of cis-2-butene-1,4-dial to critical target proteins is thought to play a key role in furan carcinogenicity. To identify putative protein targets of reactive furan metabolites, male F344/N rats (n = 5 per dose) were administered a single dose of [3,4-(14)C]-furan (20 mCi/mmol) at doses associated with hepatotoxicity following long-term exposure (0.1 and 2 mg/kg body weight [bw]). Liver proteins were separated by two-dimensional gel electrophoresis and protein spots carrying radiolabel were located by fluorography. In total, 83 discrete protein spots containing (14)C were consistently detected in livers of animals given [3,4-(14)C]-furan at 2.0 mg/kg bw, accounting for 4-5% of the proteome covered by our analyses. Protein spots were excised and digested in gel with trypsin for identification by protein mass spectrometry. Protein database search and subsequent pathway mapping identified 61 proteins localized predominantly in the cytosol and mitochondria, including structural proteins, mitochondrial enzymes involved in glucose metabolism, mitochondrial beta oxidation, and adenosine triphosphate synthesis, and proteins that participate in the maintenance of redox homeostasis and protein folding. Collectively, our data suggest that functional loss of several individual proteins and interference with pathways, most notably mitochondrial energy production, redox regulation, and protein folding, may combine to disrupt cell homeostasis and cause hepatocyte cell death. PMID- 22240985 TI - Trapped neutrophil syndrome in a Border Collie dog: clinical, clinico-pathologic, and molecular findings. AB - Trapped neutrophil syndrome (TNS) is an autosomal recessive inherited neutropenia known in Border Collies since the 1990's. Recently, the causative mutation has been identified in the canine VPS13B gene and a DNA-based diagnosis has now become available. The present paper describes clinical and clinico-pathologic findings in a Border Collie with TNS that was molecularly diagnosed for the first time in Japan. In a 10-week-old male Border Collie with microgenesis and symptoms related to recurrent infections, a hematological examination revealed severe leukopenia due to neutropenia, suggesting the dog to be affected by inherited neutropenic immunodeficiency. Direct DNA sequencing demonstrated that the dog was homozygous for the causative mutation of TNS and both its parents were heterozygous carriers. In addition, a simple and rapid polymerase chain reaction based length polymorphism analysis coupled with microchip electrophoresis was developed for the genotyping of TNS. This assay could discriminate clearly all genotypes, suggesting that it was suitable for both individual diagnosis and large-scale surveys for prevention. PMID- 22240986 TI - Complex apocrine carcinoma with dominant myoepithelial proliferation in a dog. AB - A rare case of complex apocrine carcinoma displaying dominant myoepithelial proliferation developed in the right leg subcutis of a 10-year-old male dog. The major cell population consisted of diffusely proliferating p63-expressing neoplastic cells that were largely myoepithelial in origin co-expressing alpha smooth muscle actin. A small portion of the cell population consisted of concomitant basal epithelial cells lacking alpha-smooth muscle actin expression. The minor population consisted of p63-negative apocrine gland cells that expressed cytokeratin 8. The myoepithelial cell population showed a rather stronger proliferation activity than did the apocrine epithelial population. Thus, this tumor might have been derived from basal epithelial cells characterized by more predominant myoepithelial differentiation than luminal apocrine epithelial differentiation. PMID- 22240987 TI - Plasma adrenomedullin concentration in dogs with myxomatous mitral valvular disease. AB - Adrenomedullin (AM), a peptide identified to have vasodilating and natriuretic effects, is involved in the regulation of the cardiovascular system. To evaluate plasma AM concentration in dogs with myxomatous mitral valvular disease (MMVD), and to investigate the associations between the concentrations of plasma AM and natriuretic peptides and the echocardiographic data, we evaluated plasma AM concentrations in 31 healthy control dogs and 57 dogs with MMVD. Plasma AM concentrations in dogs with MMVD were higher than that in the control subjects. The plasma AM concentration increased in conjunction with the severity of heart failure according to the International Small Animal Cardiac Health Council (ISACHC). The AM concentrations were 25.1 +/- 5.0 fmol/ml (ISACHC class Ia), 29.9 +/- 11.0 fmol/ml (ISACHC class Ib), 43.4 +/- 19.8 fmol/ml (ISACHC class II) and 73.5 +/- 21.7 fmol/ml (ISACHC class III) and 7.5 +/- 5.1 fmol/ml (control group), respectively. The receiver operating characteristic curve indicated an area of 0.93 (95% CI, 0.8801-0.9889; <0.0001), a cutoff value of 30.5 fmol/ml, a sensitivity of 87.1%, and a specificity of 82.5% for the determination of congestive heart failure. Plasma AM concentrations correlated with atrial natriuretic peptide concentrations, LA/Ao ratio, and left ventricular diameter. In conclusion, AM may be a potential diagnostic marker for canine MMVD and possibly plays a pathophysiological role in collaboration with the other neurohumoral factors such as natriuretic peptides. PMID- 22240988 TI - Pro-apoptotic effects of tepoxalin, a cyclooxygenase/lipoxygenase dual inhibitor, on canine synovial fibroblasts. AB - Canine osteoarthritis occurs frequently and causes secondary synovitis. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is one of the major therapeutic options for pain management of joint diseases. Tepoxalin has an unique property as an NSAIDs that suppresses both cyclooxygenase and lipoxygenase. The purpose of this study was to evaluate antiproliferative effects of tepoxalin on cultured canine synovial cells. Cytotoxic effects of tepoxalin, carprofen, meloxicam and AA-861 on cultured canine synoviocytes were evaluated by MTT colorimetric assay. Apoptosis was detected by morphological observations with Giemsa or annexin V/Hoechst 33342 staining and by the inhibition of caspase-3 activity with N-Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO). Cytotoxic effects of tepoxalin were evident in comparison with the effects of carprofen or meloxicam. The same tendency of cytotoxicity was observed when 5-lipoxygenase was inhibited by AA-861. The morphological findings and contradictory effects of Ac-DEVD-CHO with regard to the cytotoxicity proved the proapoptotic effects of tepoxalin. In conclusion, tepoxalin might control osteoarthritic synovitis by inducing apoptosis in proliferating synoviocytes, while most NSAIDs that selectively inhibit cyclooxygenase-2 most likely would not suppress synovial proliferation. PMID- 22240989 TI - Long-term follow-up of Jewish women with a BRCA1 and BRCA2 mutation who underwent population genetic screening. AB - There are two mutations in BRCA1 and one in BRCA2, which are present in up to 2.5% of Jewish women. Population genetic testing for Jewish women has been proposed; however, it is unclear how this would impact the uptake of cancer prevention options and psychosocial functioning in women with a positive result. Two thousand and eighty unselected Jewish women were tested for the Jewish BRCA mutations, and 1.1% were positive. Cancer-related distress was measured before testing, and at 1 and 2 years post-testing. Information on uptake of cancer risk reduction options was collected at 2 years. Breast and ovarian cancer risks were estimated using BRCAPRO. Within 2 years of receiving a positive result, 11.1% of women had prophylactic mastectomy, and 89.5% had a prophylactic oophorectomy. The mean breast cancer risk was estimated to be 37.2% at time of testing, compared to 20.9% at 2 years post-testing. The mean ovarian cancer risk was estimated to be 24.5% at time of testing, compared to 7.5% at 2 years following testing. Distress decreased between 1 and 2 years for women with prophylactic mastectomy and oophorectomy (P = 0.02), and for women with prophylactic oophorectomy only (P = 0.04) but not for those with neither surgery. The majority of Jewish women with a BRCA mutation identified through a population screening elected prophylactic oophorectomy, but a few had a prophylactic mastectomy. Uptake of either surgery resulted in decreased distress. Provision of population BRCA testing resulted in reduced risks of breast and ovarian cancers in women with a mutation. PMID- 22240990 TI - Structure, reactivity, photoactivity and stability of Ti-O based materials: a theoretical comparison. AB - Ti-O based materials have attracted great attention recently for their potential applications in clean energy generation and environment remediation. To screen Ti O based materials for specific applications, the atomic-level understanding of the subtle discrepancy of their properties is of paramount importance. In this regard, the density functional theory computations have been performed to systematically compare the physicochemical properties of three selected Ti-O based materials: anatase titanium dioxides, sodium trititanates and sodium hexatitanates. Due to their structure discrepancy, sodium trititanates show the highest chemical reactivity. However, titanium dioxides are found to be the most photoactive materials. The reactivity and photoactivity of sodium hexatitanates fall between those of titanium dioxide and sodium trititanates. In the meantime, our energetic analysis also confirms that the thermal stabilities of Ti-O based materials are strongly dependent on the acid-base conditions. Titanium dioxides are preferred under acidic conditions, while titanates are more stable in basic solutions. PMID- 22240994 TI - Synthesis of the phosphino-fullerene PPh2(o-C6H4)(CH2NMeCH)C60 and its function as an eta1-P or eta3-P,C2 ligand. AB - Following the method of Prato et al., reaction of C(60), N-methylglycine and o (diphenylphosphino)benzaldehyde affords PPh(2)(o-C(6)H(4))(CH(2)NMeCH)C(60) (1) in moderate yield. Compound 1 reacts with W(CO)(4)(NCMe)(2) to produce W(CO)(4)(eta(3)-PPh(2)(o-C(6)H(4))(CH(2)NMeCH)C(60)) (2), through coordination of the phosphine group and one 6 : 6-ring junction of fullerene. Reaction of 1 and Os(3)(CO)(11)(NCMe) affords Os(3)(CO)(11)(PPh(2)(o-C(6)H(4))(CH(2)NMeCH)C(60)) (3), which undergoes a cluster fragmentation reaction in refluxing toluene to produce Os(CO)(3)(eta(3)-PPh(2)(o-C(6)H(4))(CH(2)NMeCH)C(60)) (4). Thermal reaction of 1 and Os(3)(CO)(12) affords 3 and 4. On the other hand, reaction of 1 and Ru(3)(CO)(12) yields only the mononuclear complex Ru(CO)(3)(eta(3)-PPh(2)(o C(6)H(4))(CH(2)NMeCH)C(60)) (5). The structures of 1-3 and 5 were determined by an X-ray diffraction study. PMID- 22240996 TI - Application of principal component and discriminant analyses to morpho-structural indices of indigenous and exotic chickens raised under intensive management system. AB - The objectives of this study were to investigate the relationships between body weight and morpho-structural indices to predict body weight from their orthogonal body shape characters using principal component analysis and to morphologically classify the chicken genotypes using multivariate discriminant analysis. Data used were from 273 randomly selected 12-weeks-old indigenous chickens of normal feathered (NF), frizzle-feathered (FF), naked-neck (NN) and Anak Titan (AT) genotypes. Phenotypic correlation among body weight and most biometric traits ranged from 0.227-0.876, -0.7-0.901, 0.034-0.968 and -0.207-0.849 for NF, NN and AT chickens, respectively. Factor analysis with varimax rotation of interrelated traits revealed three principal components which accounted for 83.1%, 74.4%, 78.8% and 76.5% of the total variance in NF, FF, NN and AT chickens in the order listed. Breast girth, keel length, thigh length, shank length and wing length were found to be the most discriminating variables to separate the chicken genotypes. The longest distance (72.54) occurred between AT and NF genotypes while the shortest distance (4.27) was recorded for FF and NN genotypes. Classification results showed that 85.2% of AT genotype was correctly classified into their source population. However, 22.7% of NF was misclassified as NN, while 33.3% of NN was misclassified as NF chickens. These results suggest that there is high rate of gene flow between these two indigenous chicken genotypes. Information obtained from this study may be considered useful in breed improvement programmes for selection, characterization, conservation and better management of Nigerian indigenous chickens. PMID- 22240997 TI - Elastic stockings versus inelastic bandages for ulcer healing: a fair comparison? PMID- 22240998 TI - So there is a difference, but how big is it? Measuring the effect size for binary outcomes. PMID- 22240999 TI - Reply to letter to the editor by R. Bush. Phlebology 2011;26:131-2. PMID- 22241000 TI - Post-operative deep sternal wound infections: making an early microbiological diagnosis. AB - OBJECTIVES: Early microbiological diagnosis of deep sternal wound infections (DSWI) could improve outcomes by allowing targeted antibiotic treatment. This study aims to analyse the utility of superficial sternal wound swabs and blood cultures. METHODS: From January 2005 to June 2011, 70 patients were prospectively identified with DSWI. Microbiological data were obtained retrospectively to study the correlation between superficial sternal swabs, blood cultures and the final culture results from deep sternal tissue. Colonization with multi-resistant organisms (MROs) was also analysed for its significance in the microbiological aetiology of DSWI. Patient characteristics were obtained to analyse predictors of infection caused by specific groups of organisms. RESULTS: Superficial swabs predicted the pathogen 75% of the time (n = 43). Specific to Staphylococcus aureus (n = 27), the positive predictive value of a superficial sternal swab was found to approach 100%. Colonization with MRO is 100% predictive of the pathogen in DSWI. The absence of gram-negative organisms from superficial swabs or blood cultures (n = 48) has a negative predictive value of 98%. The inclusion of blood cultures predicted the pathogen 82% of the time across all types of bacterial infections. Patient characteristics did not appear to predispose to infections caused by specific groups of organisms. CONCLUSIONS: Superficial swabs and blood cultures appear to be useful in establishing the microbiological aetiology of DSWI. Routing testing and reporting of these samples could enable early and targeted antimicrobial therapy in DSWI to improve outcomes. PMID- 22241001 TI - Established markers of renal and hepatic failure are not appropriate to predict mortality in the acute stage before extracorporeal life support implantation. AB - OBJECTIVES: End-organ function, especially of the kidney and liver, actual inflammation and acid-base balance affect the outcome in extracorporeal life support (ECLS) patients. However, the often unexpected necessity of ECLS implies that information on patients is scarce. Even established global scores are not always useful in the rapid decision process for ECLS. Therefore, we evaluated laboratory parameters for kidney or liver function and for inflammation and acid base balance with regard to outcome. METHODS: The retrospective analysis includes 69 consecutive adult patients with veno-arterial ECLS. Laboratory markers for function of kidney (creatinine, urea) and liver (total bilirubin in plasma, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase) as well as for inflammation (C-reactive protein, leucocyte counts) and acid-base balance (pH, lactate) were acquired within 24 h before ECLS implantation. RESULTS: A total of 38 patients (55%) could be weaned or bridged. Bridged patients were switched to ventricular assist devices, n=10, or total artificial hearts, n=2, and one patient underwent heart transplantation. Overall, 26 ECLS patients (38%) survived for >4 weeks. Thirty-one patients (45%) died on ECLS. About three out of four patients presented with impaired renal or hepatic performance, approximately two-thirds with signs of increased inflammatory state, and more than a half with deranged acid-base balance. Neither signs of hepatic or renal failure nor of inflammation or impaired acid-base balance allowed a prediction of survival in these patients. The outcome did also not depend on indication for ECLS implantation. However, there was a significant correlation between the patients' age and mortality (P=0.006). CONCLUSIONS: Our data indicate that renal and hepatic insufficiency, increased inflammatory state and deranged acid-base balance as determined by pre-operative laboratory data are not associated with poor outcome of ECLS. Further, survival is not related to indications for ECLS. In a number of patients, ECLS allows for successful bridging to other treatment options. PMID- 22241002 TI - Aortic valve calcium scoring is a predictor of significant paravalvular aortic insufficiency in transapical-aortic valve implantation. AB - OBJECTIVE: Transapical-aortic valve implantation (TA-AVI) has evolved as routine for selected high-risk patients. However, paravalvular leaks >1+ remain an unsolved issue using current generations of transcatheter valve devices. The purpose of this study was to investigate the impact of native aortic valve calcification on paravalvular leaks and outcomes using the Edwards SAPIENTM prosthesis. METHODS: One hundred and twenty consecutive patients (out of 307 TA AVIs) with preoperative computed tomography aged 82.6 +/- 6.2 years, 75.0% female were included. Implanted prosthetic valve sizes were 23 mm (n = 31) and 26 mm (n = 89), respectively. Mean logistic European System for Cardiac Operative Risk Evaluation-Score was 30.1 +/- 15.5% and mean Society of Thoracic Surgeons-Score was 12.8 +/- 7.9%. Electrocardiographic (ECG)-gated cardiac computed tomography allowed to quantify the amount of calcification of aortic valve leaflets using a scoring analogous to the Agatston calcium scoring of coronary arteries [Aortic Valve Calcium Scoring (AVCS)]. Paravalvular leaks were assessed intraoperatively by echocardiography and root angiography. RESULTS: All valves were implanted successfully. The mean AVCS in patients without paravalvular leaks (n = 66) was 2704 +/- 1510; with mild paravalvular leaks (n = 31) was 3804 +/- 2739 (P = 0.05); and with moderate paravalvular leaks (n = 4) was 7387 +/- 1044 (P = 0.002). There was a significant association between the AVCS and paravalvular leaks [odds ratio (OR; per AVCS of 1000), 11.38; 95% confidence interval (CI) 2.33-55.53; P = 0.001)] and a trend towards a higher incidence of new pacemaker implantation (OR 1.27; 95% CI 0.85-1.89; P = 0.26). No association was found to 30-day mortality, major cardiac events and stroke rate (OR 1.05; 95% CI 0.84 1.32; P = 0.68; OR 0.92; 95% CI 0.68-1.25; P = 0.57 and OR 0.90; 95% CI 0.41 1.96; P = 0.79, respectively). Overall 30-day mortality was 14.2%. CONCLUSION: Severe native valve calcifications are predictive for postoperative relevant paravalvular leak. AVCS prior to TA-AVI might serve as an additional tool to reconsider the TAVI indication to reduce the risk of paravalvular leaks especially in so-called operable patients. PMID- 22241003 TI - Surgical strategy for tubercular abscess in the chest wall: experience of 120 cases. AB - OBJECTIVES: We aim to optimize surgical strategy to decrease relapse of tubercular abscess in the chest wall (TACW). METHODS: The records of 120 patients who underwent surgical treatment for TACW from May 2005 to March 2011 were retrospectively reviewed. We conducted the following surgical treatment as '6C + A' by abbreviating the first alphabet of each step: (i) careful exploration of the abscess; (ii) complete resection; (iii) cavity washing using sodium bicarbonate solution; (iv) coverage using muscle flap; (v) continuous suction and drainage; (vi) compression dressing and (vii) anti-tuberculosis medication. RESULTS: One hundred and thirteen cases were discharged for rehabilitation with the first stage wound healing (113/120). Four cases postoperatively suffered from subcutaneous fistula which was healed after dressing changes for 1-2 months. Three patients with an abscess relapse underwent the second operation 2 months after the first operation. Follow-ups ranged from 2 months to 6 years and demonstrated no recurrence. CONCLUSIONS: We deem the surgical procedures '6C + A' effective to obviate relapse of TACW. PMID- 22241004 TI - Initial experience with polytetrafluoroethylene leaflet extensions for aortic valve repair. AB - OBJECTIVES: The purpose of this study is to evaluate our initial experience with aortic valve repair using polytetraflouroethylene (PTFE) leaflet extensions in congenital valvular disease. METHODS: From October 2008 through February 2011, 13 patients underwent aortic valvuloplasty by PTFE leaflet extensions. All valves were repaired in a tri-leaflet configuration using PTFE leaflet extensions. The median age at operation was 14 years (1.8-19.7 years) and the median weight was 58 kg (9.5-86 kg). Previous interventions included balloon valvuloplasty in two patients, aortic valvuloplasty in one and coarctation repair in one patient. Eight (73%) patients had combined aortic stenosis and insufficiency, three (23%) had isolated insufficiency and two (15%) had stenosis only. In 10 (77%) patients, a bicuspid aortic valve was present. RESULTS: The follow-up ranged from 2 to 30 months (mean follow-up 14.8 +/- 9 months). At the latest echocardiography follow up, six patients had none or trace aortic insufficiency, six patients had a mild aortic insufficiency and one patient had a mild-to-moderate insufficiency. The mean aortic insufficiency degree decreased from 1.8 +/- 1.2 preoperatively to 0.8 +/- 0.6 at the follow-up (P < 0.01). The mean gradient across the aortic valve decreased from 56 +/- 40 mmHg preoperatively to 12 +/- 13 mmHg at the follow-up (P < 0.0008). All patients are alive. There were no reoperations. The median hospital stay was 9 days (4-21 days). CONCLUSIONS: The use of PTFE leaflet extensions is an effective technique for aortic valve reconstruction in congenital valvular disease. Long-term follow-up is necessary to assess the durability of this type of repair. PMID- 22241005 TI - Contemporary outcomes of conventional aortic valve replacement in 638 octogenarians: insights from an Italian Regional Cardiac Surgery Registry (RERIC). AB - OBJECTIVES: Few data exist on contemporary outcomes after conventional aortic valve replacement (AVR) in the elderly. Accordingly, we evaluated contemporary outcomes and identified predictors of reduced survival in a large series of octogenarians undergoing AVR. METHODS: The Regione Emilia Romagna Cardiac Surgery registry (RERIC) database (n = 2 6938) was queried for clinical features, hospital and mid-term outcomes of octogenarians undergoing AVR between 2003 and 2009. Predictors of hospital and mid-term mortality were identified. RESULTS: The study population consisted of 638 patients. NYHA class III-IV, congestive heart failure, cerebrovascular disease, extra-cardiac arteriopathy, mostly exacerbated patients' clinical profile. Mean log-EuroSCORE was 13.0%. Overall hospital mortality and stroke rates were 4.5% and 1.3%, respectively. Other post-operative complications included renal failure (4.9%), intubation time >48 h (3.4%), complete atrio-ventricular block (4.4%). NYHA III-IV (OR = 2.7; CI 95%:1.2-6.7) and CCS III-IV (OR = 3.1; CI 95%:1.1-9.4) emerged as independent predictors of hospital mortality on multivariate analysis. At 6 years, octogenarians' survival rate was similar to the expected survival of the age- and sex-matched regional population. CCS III-IV (HR = 2.1; CI 95%:1.2-4), preoperative creatinine > 2.1 (HR = 2.8; CI 95%:1.4-5.9), extra-cardiac arteriopathy (HR = 1.5; CI 95%:1.1-2.1) and peripheral neurological dysfunction (HR = 3.8; CI 95%:1.4-10.4) emerged as independent risk factors for decreased 6 years' survival. CONCLUSIONS: This study, showing that contemporary outcomes after AVR are excellent, may help to improve treatment decision-making in elderly patients with aortic valve disease. PMID- 22241006 TI - Spontaneous pneumothorax in a patient with buffalo chest. PMID- 22241007 TI - Total arterial off-pump surgery provides excellent outcomes and does not compromise complete revascularization. AB - OBJECTIVES: The combination of aortic 'no-touch' off-pump surgery (OPCAB) and total arterial revascularization (TAR) can reduce peri-procedural morbidity and yields excellent long-term outcomes albeit at a reported risk of incomplete revascularization. The feasibility of OPCAB-TAR with specific regards to the complete revascularization (CR) in patients with multi-vessel disease was evaluated. METHODS: From 2003 to 2010, 712 patients underwent TAR including 526 patients who had OPCAB-TAR and 186 patients who received on-pump TAR [(ONCAB grafting (ONCABG)-TAR)]. Of these, 52% (n = 272; OPCAB) vs. 83% (n = 155; ONCABG) had triple-vessel disease (TVD). To balance patient characteristics, a non parsimonious, propensity score (PS) model was applied. Endpoints evaluated were mortality, stroke, major adverse cardiac and cerebrovascular events (MACCE). To evaluate CR, an 'Index of CR' (ICOR) was calculated, defined as the number of distal anastomoses divided by the number of the diseased coronary vessels. CR was assumed when the following requirements were fulfilled: the number of distal anastomoses was equal to or higher than that of diseased vessels (ICOR >= 1), and all affected coronary territories (left anterior descending, circumflex artery and/or right coronary artery) were grafted. RESULTS: Mortality was comparable between groups, whereas OPCAB patients suffered from significantly decreased rates of MACCE [3.0 vs. 7.0%; propensity-adjusted odd ratio (PAOR) = 0.24; confidence interval (CI) 95% 0.08-0.66; P = 0.006] including a clear trend towards reduced stroke and myocardial infarction. In the subgroup with TVD, OPCAB patients presented with significantly reduced rates for MACCE (1.8 vs. 5.8%; PAOR = 0.07; CI 95% 0.01-0.65; P = 0.02), including a significantly lower rate for stroke. For all-comers, the number of diseased vessels was lower after OPCAB (2.36 +/- 0.73 vs. 2.87 +/- 0.39; P < 0.001) and consequently, these patients received an overall lower number of distal anastomoses (2.42 +/- 1.15 vs. 3.06 +/ 0.98; P < 0.001). Although the ICOR was slightly lower (1.04 +/- 0.37 vs. 1.07 +/- 0.37; P = 0.02), CR was achieved more frequently in OPCAB patients (82.1 vs. 73.1%; P = 0.01). In the subgroup with TVD, the number of distal anastomoses (2.99 +/- 1.14 vs. 3.10 +/- 0.98; P = 0.19) and the ICOR (1.00 +/- 0.38 vs. 1.03 +/- 0.33; P = 0.19) was comparable between groups. The frequency of CR was slightly higher (75 vs. 67.7%; P = 0.11), and the proportion of complete in situ grafting was significantly higher after OPCAB (37.1 vs. 23.9%; P = 0.005). CONCLUSIONS: Aortic 'no-touch' OPCAB-TAR leads to a significant reduction of MACCE. It does not compromise CR in patients with TVD and thus can be safely applied to these patients. PMID- 22241008 TI - Validated scoring system for risk assessment in major thoracic surgery: how surgery boils down to risk and benefit! PMID- 22241009 TI - Transfusion of blood during cardiac surgery is associated with higher long-term mortality in low-risk patients. AB - OBJECTIVE: Numerous reports have emphasized the need for reduction in transfusions of allogeneic red blood cells (RBC) due to increased morbidity and mortality. Nevertheless, transfusion rates are still high in several cardiac surgery institutions. Reports on long-term survival after cardiac surgery and RBC transfusion are few. METHODS: Data from the Western Denmark Heart Registry (WDHR) were used to identify all (25,117) adult cardiac surgery performed in four centres during 1999-2010. Patients with multiple entries (1049), re-do cardiac surgery (985), special/complex procedures (2329), dying within 30 days (668) and not eligible for follow-up (85) were excluded leaving a cohort of 20,001. Registration in the WDHR is mandatory. WDHR and the unique Danish Civil Registration System with continuous sequential updates of the Danish population ensure that all patients and outcomes are accounted for. RESULTS: Kaplan-Meier survival plot for low-risk patients (EuroSCORE 0-4), undergoing simple cardiac surgery showed a significantly lower estimated survival after >4500 days (0.637 vs. 0.745) when receiving perioperative RBC transfusion (P<0.0001). The difference was less evident in patients with EuroSCORE 5-9 (0.373 vs. 0.4436, P<0.0001), while high-risk patients showed no difference. Adjusted risk ratio, after RBC transfusion, containing among others age, sex, EuroSCORE and diabetes, was 1.83 (95% CI (confidence interval) 1.67-2.01). The survival rate was independent of up till six units of RBC. CONCLUSION: Long-term follow-up of low risk patients undergoing simple cardiac surgery demonstrates a more than 10% higher mortality when receiving perioperative RBC transfusion. Even transfusion of 1-2 units seems to carry a risk of that magnitude. PMID- 22241010 TI - Twinned single-lung transplantation: a privileged model for the study of recipient-dependent factors of outcome. AB - OBJECTIVES: Lung transplantation is the only life-saving treatment for end-stage respiratory disease. The outcome will depend on the graft quality, surgical conditions and recipient factors. Twinned single-lung transplantation defines as two different recipients treated with lung grafts from the same donor. Recipient dependent factors of the outcome can be studied more accurately as the graft quality is supposed equal for both recipients. METHODS: We reviewed all single lung transplantations performed in France between 1998 and 2008 in the French registry run by the 'Agence de Biomedecine'. Criteria for donor lung quality and twinned recipient data were recorded in a database. The whole medical history and the transplantation outcome were reviewed for each patient and compared with its twin recipient. We compared twins on the basis of their opposed characteristics and on the basis of the opposed endpoint outcome. Endpoints were primary graft dysfunction (PGD) grade III, and mortality at 1, 3 and 12 months. RESULTS: A total of 387 single-lung transplantations were performed in 10 French centres; 180 were twinned recipients from 90 donors. Statistical analysis revealed a significantly different outcome for PGD only. PGD was significantly higher (P < 0.05) in fibrosis recipients compared with emphysema twins. In 28 pairs (31%), the outcome was discordant for PGD, and fibrosis was significantly more often involved compared with emphysema (P = 0.04). Sixty-two pairs had a similar outcome: two pairs showed PGD in both recipients while 60 pairs were free of PGD. CONCLUSIONS: We conclude that recipient's disease is a major determinant of the outcome. Fibrosis is associated with an increased risk for PGD. PMID- 22241011 TI - A comparison of intrascleral bleb height by anterior segment OCT using three different implants in deep sclerectomy. AB - PURPOSE: To compare intrascleral blebs characteristics after deep sclerectomy (DS) with three intrascleral implants using the Visante anterior segment optical coherence tomography. METHODS: This is a cross-sectional study including 60 eyes of 51 patients that underwent DS with Sk-Gel, Esnoper, and Aquaflow implant. Intraocular pressure (IOP) measurement, slit-lamp examination, and Visante scans were performed the same day in all the patients. Visante scans were done through the intrascleral bleb at 45 degrees , 90 degrees , and 135 degrees and the bleb height was measured. RESULTS: Sk-Gel was used in 19 eyes (31.66%), Esnoper in 22 eyes (36.66%), and Aquaflow in 19 eyes (31.66%). The median time lapsed from the surgery was 15.50 months 25th and 75th percentiles (p(25) 8.25; p(75) 20). The median IOP was 13 mm Hg (p(25) 10; p(75) 15), with no significant differences among implants (P = 0.232). Overall, the correlation between the scleral bleb height and the IOP was statistically significant at 45 degrees (r=-0.359; P = 0.004), 90 degrees (r = -0.410; P = 0.001), and 135 degrees (r = -0.417; P = 0.001). However, Sk-Gel did not show any statistically significant correlation between the scleral height and IOP whereas the other two groups (Esnoper and Aquaflow) showed a significant correlation. There were no differences in the bleb height among implants. CONCLUSION: There was a moderate inverse correlation between the scleral bleb height and the IOP measurement after DS with Esnoper and Aquaflow implants. There were no differences in bleb height among the three implants. PMID- 22241012 TI - Retinal detachment associated with optic disc colobomas and morning glory syndrome. AB - We report the diagnosis and treatment of patients with retinal detachment and/or retinoschisis associated with optic nerve coloboma or morning glory syndrome. A retrospective review of patients with optic nerve coloboma or morning glory syndrome with associated retinal detachment or retinoschisis was conducted. For five patients (six eyes), we report the clinical findings, spectral domain optical coherence tomography (OCT) imaging, intraoperative findings, and treatment outcomes. OCT scans demonstrate a bilaminar structure of maculopathy, consisting of inner schisis-like changes and outer layer retinal detachment. In most cases, a retinal break was demonstrated within the optic disc defect with three-dimensional OCT imaging. Glial tissue was sometimes observed within the anomalous defect. Vitrectomy and resection of the tractional tissue in these cases produced good anatomical and visual outcomes. Retinal detachment spontaneously resolved in cases where traction was not present. Traction may contribute to the pathogenesis of retinal detachment associated with colobomatous optic disc anomalies, either directly or by creating a secondary retinal break. OCT imaging assists with understanding the contributing factors to retinal detachment in individual cases of colobomatous optic disc anomalies and can thereby assist with determining the most effective approach to management. PMID- 22241014 TI - New approaches for the treatment of diabetic macular oedema: recommendations by an expert panel. AB - The current standard therapy for patients with diabetic macular oedema (DME)- focal/grid laser photocoagulation--usually does not improve impaired vision, and many patients lose vision despite laser therapy. Recent approval of ranibizumab by the European Medicines Agency to treat visual impairment due to DME fulfils the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients. We reviewed 1- and 2-year clinical trial findings for ranibizumab used as treatment for DME to formulate evidence-based treatment recommendations in the context of this new therapy. DME with or without visual impairment should be considered for treatment when it fulfils the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria for clinically significant oedema. For DME with centre involvement and associated vision loss due to DME, monthly ranibizumab monotherapy with treatment interruption and re-initiation based on VA stability is recommended. Laser therapy based on ETDRS guidelines is recommended for other forms of clinically significant DME without centre involvement or when no vision loss has occurred, despite centre involvement. Because these recommendations are based on randomised controlled trials of 1-2 years duration, guidance may need updating as long-term ranibizumab data become available and as additional therapeutic agents are assessed in clinical trials. PMID- 22241015 TI - Idiopathic macular hole in a child. PMID- 22241016 TI - Combined OCT and colour fundus photography in virtual clinic assessments of wet AMD patients. PMID- 22241017 TI - Visual outcome in Japanese patients with Acanthamoeba keratitis. AB - PURPOSE: To identify prognostic factors affecting visual outcome in Acanthamoeba keratitis (AK) treated with topical chlorhexidine gluconate (CHG). METHODS: A total of 35 eyes in 34 patients with AK were treated with 0.02% topical CHG. Patients were divided into two groups according to the final visual outcome: Group 1, final visual acuity (VA) of 20/25 or greater (22 eyes); Group 2, less than 20/25 (13 eyes). We compared these groups and evaluated the effectiveness of topical CHG compared with outcomes in previous reports. RESULTS: Ring infiltrate was observed more often in Group 2 (4.5% vs 61.5%, OR 33.6, 95% confidence interval (CI) 3.4-333.9, P<0.01). The duration between onset and diagnosis of AK was significantly longer (24.9 days vs 48.4 days, OR 1.03, 95% CI 1.00-1.06, P = 0.04) and VA at initial examination (log MAR) significantly lower (0.47 vs 1.59, OR 25.5, 95% CI 3.4-186.7, P<0.01) in Group 2 (visual outcome <20/25). Multivariate analysis revealed that only VA at initial examination was independently associated with worse visual outcome (adjusted OR 24.5, 95% CI 1.9 312.6, P=0.01). Seventeen (85.0%) of the 20 eyes diagnosed within 1 month and 24 (82.8%) of 29 eyes diagnosed within 2 months achieved a VA of 20/40 or greater. CONCLUSION: VA at initial examination was the most predictive factors for final visual outcome in AK. Topical CHG was comparably effective to other treatments, including polyhexamethyl biguanide and propamidine isethionate. PMID- 22241018 TI - Discoid lupus erythematosus of the periorbita: clinical dilemmas, diagnostic delays. AB - PURPOSE: Untreated periocular discoid lupus erythematosus (DLE), though very rare, may lead to significant morbidity with lid deformities, trichiasis, and symblepharon formation. We present the largest reported cohort of patients with biopsy-proven DLE solely affecting the periorbital region. METHODS: Observational case series of patients managed over a 7-year period (2004-10). RESULTS: Seven patients (one male) presented to the Adnexal Service at Moorfields Eye Hospital at a median age of 47 years (range 23-71 years); median interval from symptom onset to biopsy-proven diagnosis was 38 months (range 6-86 months). Changes in peripheral skin were present in 1 patient (occurring after the initial eyelid presentation) and the presenting periocular features were dissimilar across the group, these included: chronic blepharo-conjunctivitis, madarosis, atypical chalazia, depigmentation of the eyelid margin, or marked, persistent periocular oedema with dacryoadenitis.Two cases settled spontaneously, but five required systemic hydroxychloroquine or intralesional corticosteroid injections. CONCLUSION: Periorbital DLE is rare and very varied in its presentation, the protean manifestations often resulting in significant diagnostic delay. All patients with unusual periocular skin disease and those with a refractory inflammatory dermopathy, should undergo biopsy of involved tissue(s), thus leading to earlier diagnosis and prevention of permanent cicatricial periocular changes. PMID- 22241019 TI - Assessing Graves' ophthalmopathy-specific quality of life in Korean patients. AB - AIM: To investigate the clinical significance of Grave's ophthalmopathy-specific quality of life (GO-QOL) in Korean patients. METHODS: A cross-sectional study was conducted at the Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea, on 98 consecutive Grave's ophthalmopathy (GO) patients. The GO-QOL survey provided by Terwee and colleagues and suggested by the European group on Graves' orbitopathy (EUGOGO) was translated into Korean language and distributed to study participants. Clinical severity was judged by scores of the modified NOSPECS classification, and inflammatory activity was measured by a seven-point scale of clinical activity score (CAS). RESULTS: The mean GO-QOL scores were 73.7 (standard deviation (SD), 26) for visual functioning, 61.9 (SD 26) for appearance, and 67.8 for total quality of life (QOL; SD 22). The worse QOL scores for each part were significantly associated with the higher modified NOSPECS score and CAS after adjusting for confounders such as age and sex (P<0.05, respectively). In particular, decreased QOL scores for visual function were significantly correlated with a higher grade of extraocular muscle involvement (P<0.05). Lower QOL scores for appearance were associated with more severe soft-tissue involvement and proptosis (P<0.05, respectively). CONCLUSIONS: GO-QOL suggested by EUGOGO showed correlation with objective clinical parameters. GO-QOL can be a simple and effective tool in the evaluation of the clinical and psychological illness of GO patients. PMID- 22241020 TI - Surgical and visual outcome following 20-gauge vitrectomy in proliferative diabetic retinopathy over a 10-year period, evidence for change in practice. AB - INTRODUCTION: The study reports 10-year anatomical and visual outcome in patients who underwent pars plana vitrectomy (PPV) for complications due to proliferative diabetic retinopathy (PDR). METHODS: Retrospective analysis of patients undergoing 20 G PPV from January 1999 to May 2010 for tractional retinal detachment (TRD) and non-clearing vitreous hemorrhage (NCVH) secondary to PDR recorded prospectively on an electronic patient record. The primary aim was to study anatomical success and eyes with visual acuity (VA) of <= 0.3 logMAR at last follow-up. RESULTS: There were 346 eyes of 249 patients with mean age of 55.63 years and follow-up of 1.44 years. In all, 95.3% of eyes had a flat retina at final follow-up. Overall 136/346 (39.4%) eyes had final VA of logMAR <= 0.3 (Snellen 6/12) and 129 (37.3%) had logMAR >= 1.0 (Snellen 6/60). In all, 50/181 (27.6%) eyes with TRD and 84/165 (50.9%) with NCVH achieved final VA of <= 0.3 logMAR (Snellen 6/12). A total of 218 (63.1%) showed >= 0.3 logMAR improvement from baseline to last follow-up. Both preoperative VA and final postoperative (post-op) VA (P<0.001) improved significantly with each year from 1999 to 2010. The commonest peroperative complication was iatrogenic retinal tear formation (28.4%). This was a risk factor for the development of post-op retinal detachment, odds ratio: 3.90 (95% confidence interval: 1.91-7.97, P = 0.0002). Silicone oil was used in 5.2% of patients at the primary procedure. In all, 9.2% required removal of non clearing post vitrectomy hemorrhage. CONCLUSIONS: Outcomes from vitreoretinal surgery for complications of diabetic retinopathy have improved. In addition, the visual outcome after diabetic vitrectomy steadily improved over the 10-year period, which may in part be due to the move to operate on patients with better vision. PMID- 22241021 TI - Retrobulbar hemodynamic parameters in open-angle and angle-closure glaucoma patients. AB - PURPOSE: The purpose of this study is to compare the retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery (CRA), and posterior ciliary arteries (PCA), in open-angle glaucoma (OAG) and angle-closure glaucoma (ACG) patients. PATIENTS AND METHODS: A total of 52 eyes from 52 patients with OAG and 25 eyes from 25 ACG patients who met the inclusion/exclusion criteria were included in this cross-sectional study. Peak systolic velocity, end-diastolic velocity, and Pourcelot resistivity index (RI) were assessed in the OA, CRA, and PCA. Intraocular pressure (IOP) was measured both with the Goldmann applanation tonometer (GAT) and with the Dynamic Contour tonometer (DCT) three times, respectively. Ocular pulse amplitude was measured using DCT. RESULTS: The RI was significantly higher in both the ophthalmic and short PCA in the OAG patients as compared with that in those ACG patients, P=0.003 and 0.048, respectively. There was no correlation between the IOP measured with GAT and the retrobulbar hemodynamic parameters in either OAG or ACG. CONCLUSIONS: There was an increased resistance to blood flow in the OA of OAG as compared with ACG patients. Additionally, the degree of circulatory disturbance was not related to either the IOP or the visual-field damage. PMID- 22241022 TI - Viral causes of unexplained anterior uveitis in Thailand. AB - AIMS: To assess the possible role of virus infection in patients with unexplained anterior uveitis (AU). METHODS: Intraocular fluid and plasma samples of 30 HIV negative AU patients who were unresponsive or poorly responsive to topical steroid therapy were analyzed for nucleic acid of cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV) by real-time polymerase chain reaction (PCR) and for intraocular antibodies against these viruses by Goldmann-Witmer coefficient (GWC) analysis. Of these 30 cases, 21 were tested for rubella virus by GWC analysis, 16 of which also had PCR assessment of aqueous for rubella virus. RESULTS: Viral uveitis determined by either real-time PCR and/or GWC was documented in 20 out of 30 patients (67%). Of 30 paired samples tested by both methods for HSV, CMV, and VZV, 15 showed positive results (CMV (10), HSV (4), and VZV (1)). Real-time PCR was positive in 8/15 (53%), whereas GWC was positive in 10/15 (67%). Out of 10 CMV-positive patients, four had endotheliitis, two had Posner-Schlossman syndrome, and one Fuchs heterochromic uveitis syndrome (FHUS). Five out of 21 (24%) samples tested by GWC for Rubella virus were positive, three of which exhibited clinical features of FHUS. CONCLUSIONS: Our results indicate that CMV is a major cause of AU in Thailand and show that FHUS can be caused by both CMV and Rubella virus. PMID- 22241024 TI - The impact of education on caregiver burden on two inpatient oncology units. AB - Providing standardized education can alleviate the burden felt by the caregiver and improve health outcomes for both the patient and caregiver. Four disease groups were included in this study that represent a significantly longer hospital stay than other cancers: acute myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, or those undergoing blood marrow transplant. The complexity of care is significantly higher, necessitating greater caregiver burden following hospitalization. Eligible patients and their caregivers received post hospitalization care education through an Oncology CarePartner Program addressing the patient's physical and emotional needs. The impact of the CarePartners program on caregiver burden was evaluated by the Oberst Caregiving Burden Scale (OCBS) and Bakas Caregiving Outcomes Scale (BCOS) on two oncology units (medical/oncology (n = 17) and blood marrow transplant (n = 21)) at three times: within 5 days of admission (T1), patient discharge from the hospital (T2), and 30 days post-discharge (T3). There were significant increases seen from T1-T2 (median = 4, p = 0.0007) and T1-T3 (median = 5.5, p = 0.003) in the BCOS. No significant changes in OCBS (time or difficulty) were seen. Standardized patient education helped improve caregivers' overall well-being but lacked in impacting the time spent and difficulty with caregiving tasks. Educational changes to address these specific areas or evaluation by different scales are both worth further investigation. PMID- 22241025 TI - The impact factor for the Brazilian Journal of Pulmonology is arriving. PMID- 22241026 TI - Asthma control and quality of life in patients with moderate or severe asthma. AB - OBJECTIVE: To evaluate the association between degree of asthma control and health-related quality of life in patients with moderate or severe asthma. METHODS: This was a descriptive observational study involving 59 outpatients with moderate or severe asthma under treatment at the Asthma Outpatient Clinic of the Federal University of Ceara Walter Cantidio University Hospital, in the city of Fortaleza, Brazil. The patients were evaluated regarding sociodemographic and clinical characteristics, as well as spirometric parameters. The asthma control status was assessed using the asthma control test (ACT), and quality of life was assessed using the Saint George's Respiratory Questionnaire (SGRQ). RESULTS: The mean age of the patients was 55.0 +/- 12.4 years, and 76.3% were female. The ACT score showed statistically significant negative correlations with all SGRQ scores: total (r = -0.72); symptoms (r = -0.78); activity (r = -0.67); and impact (r = -0.68). Multiple regression analysis showed that the most robust predictive variables for SGRQ total score were ACT score (coefficient = -3.18; 95% CI: -4.14 to -2.23) and duration of disease (coefficient = -0.29; 95% CI: -0.54 to -0.03). The ACT score also explained the linear variation of the SGRQ domains: symptoms (coefficient = -3.41; 95% CI: -4.45 to -2.37); activity (coefficient = -3.07; 95% CI: -4.57 to -1.57); and impact (coefficient = -2.68; 95% CI: -3.71 to -1.65). CONCLUSIONS: The degree of asthma control appears to have a significant impact on health-related quality of life. PMID- 22241027 TI - Analysis of physiological variables during acute hypoxia and maximal stress test in adolescents clinically diagnosed with mild intermittent or mild persistent asthma. AB - OBJECTIVE: To analyze adolescents clinically diagnosed with asthma, in terms of the physiological changes occurring during acute hypoxia and during a maximal stress test. METHODS: This was a descriptive, cross-sectional study involving 48 adolescents (12-14 years of age) who were divided into three groups: mild intermittent asthma (MIA, n = 12); mild persistent asthma (MPA, n = 12); and control (n = 24). All subjects were induced to acute hypoxia and were submitted to maximal stress testing. Anthropometric data were collected, and functional variables were assessed before and after the maximal stress test. During acute hypoxia, the time to a decrease in SpO2 and the time to recovery of SpO2 (at rest) were determined. RESULTS: No significant differences were found among the groups regarding the anthropometric variables or regarding the ventilatory variables during the stress test. Significant differences were found in oxygen half-saturation pressure of hemoglobin prior to the test and in PaO2 prior to the test between the MPA and control groups (p = 0.0279 and p = 0.0116, respectively), as was in the oxygen extraction tension prior to the test between the MIA and MPA groups (p = 0.0419). There were no significant differences in terms of the SpO2 times under any of the conditions studied. Oxygen consumption and respiratory efficiency were similar among the groups. The use of a bronchodilator provided no significant benefit during the hypoxia test. No correlations were found between the hypoxia test results and the physiological variables. CONCLUSIONS: Our findings suggest that adolescents with mild persistent asthma have a greater capacity to adapt to hypoxia than do those with other types of asthma. PMID- 22241028 TI - Use of inhaler devices and asthma control in severe asthma patients at a referral center in the city of Salvador, Brazil. AB - OBJECTIVE: To evaluate the use of inhaler devices by patients with severe asthma treated via the Programa para o Controle da Asma e Rinite Alergica na Bahia(ProAR, Bahia State Asthma and Allergic Rhinitis Control Program), recording the frequency of their errors in performing key steps and the relationship between such errors and the lack of asthma control. METHODS: A cross-sectional study involving 467 patients enrolled in the ProAR in the city of Salvador, Brazil. The devices evaluated were metered dose inhalers (MDIs), with or without a spacer, and dry powder inhalers (DPIs; Pulvinal(r) or Aerolizer(r)). For the assessment of the inhalation technique, a checklist was used; the patients were asked to demonstrate the technique so that an interviewer could observe all of the steps performed. For the assessment of asthma control, we used the 6-item asthma control questionnaire. RESULTS: Most of the patients showed appropriate inhalation techniques when using the devices. When using an MDI, few patients made mistakes in the key step of "coordinating activation and inhalation" (5.2% and 9.1% with and without the use of a spacer, respectively). During Pulvinal(r) use, 39% of the patients did not inhale quickly and deeply, compared with only 5.8% during Aerolizer(r) use. Of the patients that made use of Aerolizer(r) alone, 71.3% appropriately performed all of the essential steps, and their asthma was controlled. CONCLUSIONS: Most of the patients in this sample, all of whom had been submitted to periodic checks of their inhalation technique (as part of the program), used the devices appropriately. Proper inhalation technique is associated with asthma symptom control. PMID- 22241029 TI - Ethyl 2-cyanoacrylate tissue adhesive in partial lobectomy in rats. AB - OBJECTIVE: To determine the efficacy of ethyl 2-cyanoacrylate adhesive in repairing the lung parenchyma after partial lobectomy in rats, in terms of hemostasis/aerostasis, scarring, and surgical time. METHODS: The study involved 30 Wistar rats, randomly divided into five groups (one control group and four study groups). In the study groups, the lung parenchyma was repaired with either cyanoacrylate adhesive or surgical suture following resection of a small or large fragment (25% or 50%, respectively) of the left caudal lung lobe. RESULTS: Surgical time and hemostasis time were shorter in the two groups treated with the adhesive than in the two submitted to suture. There were no significant differences among the groups regarding specific lung compliance. Adherences and inflammatory reactions were more severe in the groups submitted to suture. CONCLUSIONS: In this study, the use of cyanoacrylate adhesive helped reduce the surgical time and the intensity of inflammatory reactions, as well as preserving lung compliance. Cyanoacrylate adhesives should be considered an option for lung parenchyma repair, decreasing the risk of complications after partial lobectomy in humans. PMID- 22241030 TI - Functional performance on the six-minute walk test in patients with cystic fibrosis. AB - OBJECTIVE: To compare patients with cystic fibrosis and healthy individuals in terms of their functional performance on the six-minute walk test (6MWT). METHODS: A prospective, cross-sectional study involving healthy individuals and patients with cystic fibrosis treated at a referral university hospital in the city of Campinas, Brazil. The 6MWT was administered in accordance with the American Thoracic Society guidelines, and it was repeated after a 30-min rest period. For all of the participants, RR, HR, SpO2, and Borg scale scores were obtained. For the cystic fibrosis patients, nutritional status and spirometric values were determined. Patients with pulmonary exacerbation were excluded. Spearman's correlation coefficient and repeated measures ANOVA were used. RESULTS: The cystic fibrosis group comprised 55 patients, and the control group comprised 185 healthy individuals. The mean ages were 12.2 +/- 4.3 and 11.3 +/- 4.3 years, respectively. The six-minute walk distance (6MWD) was significantly shorter in the cystic fibrosis group than in the control group for both tests (547.2 +/- 80.6 m vs. 610.3 +/- 53.4 m for the first and 552.2 +/- 82.1 m vs. 616.2 +/- 58.0 m for the second; p < 0.0001 for both). The 6MWD correlated with age, weight, and height only in the cystic fibrosis group. During the tests, SpO2 remained stable, whereas HR and RR increased. CONCLUSIONS: In our sample, functional performance on the 6MWT was poorer among the cystic fibrosis patients than among the healthy controls in the same age bracket, and we found immediate repetition of the test to be unadvisable. PMID- 22241031 TI - Bronchodilator effect on maximal breath-hold time in patients with obstructive lung disease. AB - OBJECTIVE: To identify the role of bronchodilators in the maximal breath-hold time in patients with obstructive lung disease (OLD). METHODS: We conducted a case-control study including patients with OLD and a control group. Spirometric tests were performed prior to and after the use of a bronchodilator, as were breath-hold tests, using an electronic microprocessor and a pneumotachograph as a flow transducer. Respiratory flow curves were displayed in real time on a portable computer. The maximal breath-hold times at end-inspiratory volume and at end-expiratory volume (BHTmaxV EI and BHTmaxV EE, respectively) were determined from the acquired signal. RESULTS: A total of 35 patients with OLD and 16 controls were included. Prior to the use of a bronchodilator, the BHTmaxV EI was significantly lower in the OLD group than in the control group (22.27 +/- 11.81 s vs. 31.45 +/- 15.73 s; p = 0.025), although there was no significant difference between the two groups in terms of the post-bronchodilator values (24.94 +/- 12.89 s vs. 31.67 +/- 17.53 s). In contrast, BHTmaxV EE values were significantly lower in the OLD group than in the control group, in the pre- and post bronchodilator tests (16.88 +/- 6.58 s vs. 22.09 +/- 7.95 s; p = 0.017; and 21.22 +/- 9.37 s vs. 28.53 +/- 12.46 s; p = 0.024, respectively). CONCLUSIONS: Our results provide additional evidence of the clinical usefulness of the breath-hold test in the assessment of pulmonary function and add to the existing knowledge regarding the role of the bronchodilator in this test. PMID- 22241032 TI - Spirometry with bronchodilator test: effect that the use of large-volume spacers with antistatic treatment has on test response. AB - OBJECTIVE: To evaluate whether the use of inhaled albuterol via a metered-dose inhaler with a large-volume spacer with antistatic treatment modifies the bronchodilator test results when compared with the usual technique (no spacer). METHODS: A prospective study involving 24 patients, 18-45 years of age, clinically suspected of having asthma, and under treatment at the Outpatient Pulmonary Clinic of the Federal University of Minas Gerais Hospital das Clinicas, located in the city of Belo Horizonte, Brazil. All of the patients underwent two bronchodilator tests: one with and one without the use of a large-volume spacer. RESULTS: There was no significant difference in the variation of FEV1 prior to and after bronchodilator use between the two techniques (mean DeltaFEV1 = 0.01 L; 95% CI: -0.05 to 0.06; p = 0.824). No statistically significant difference was found between the two techniques regarding the qualitative results on the bronchodilator test (p = 1.00). There was concordance between the techniques in terms of the bronchodilator test results (kappa coefficient = 0.909; p < 0.005). CONCLUSIONS: According to the results of this study, the use of large-volume spacers does not significantly modify bronchodilator test results. PMID- 22241033 TI - Effect of seasonality on the occurrence of respiratory symptoms in a Brazilian city with a tropical climate. AB - OBJECTIVE: To evaluate the effect that seasonality has on the occurrence of respiratory symptoms in a Brazilian city with a tropical climate. METHODS: This was a cross-sectional study, in which data related to subjects who sought outpatient treatment at a primary health care clinic in the city of Goiania, Brazil, were correlated with daily meteorological data. Over a one-year period, all the patients who met the inclusion criteria were interviewed on 44 distinct, randomly selected days (11 days per season). We used ANOVA in order to compare the means of the dependent variables by season. Correlations were drawn between each dependent variable and each meteorological variable. The effects of the meteorological variables were analyzed with an AutoRegressive Moving Average with eXogenous input (ARMAX) model. RESULTS: Of the 3,354 participants, 494 (14.6%) had respiratory symptoms. Although temperature variation alone had no effect on the number of individuals with respiratory symptoms, the low levels of humidity during winter resulted in a statistically significant difference among the seasons (p < 0.01). The mean minimum relative humidity on the three days prior to the interviews correlated negatively with the number of subjects with respiratory symptoms (p = 0.04). An ARMAX model including the same variable showed a statistically significant coefficient (p < 0.0001). CONCLUSIONS: In this sample, the number of subjects with respiratory symptoms increased significantly when the relative humidity dropped, and this increase could be predicted using meteorological data. PMID- 22241034 TI - Clinical, radiological, and laboratory characteristics in pulmonary tuberculosis patients: comparative study of HIV-positive and HIV-negative inpatients at a referral hospital. AB - OBJECTIVE: To compare clinical, radiological, and laboratory characteristics of individuals with pulmonary tuberculosis co-infected or not with HIV. METHODS: A cross-sectional study, in which signs and symptoms were assessed by anamnesis and physical examination in patients hospitalized with pulmonary tuberculosis. The results of sputum smear microscopy and culture for Mycobacterium tuberculosis, as well as hemoglobin levels and CD4+ T-cell counts, were obtained from medical records, and chest X-ray reports were consulted. RESULTS: We included 50 pulmonary tuberculosis patients, who were divided into two groups (HIV-positive and HIV-negative; n = 25 per group). The mean age of the participants was 38.4 +/ 10.5 years; 46 (92%) were males; and 27 (54%) were White. Expectoration was presented by 21 (84%) and 13 (52%) of the patients in the HIV-negative and HIV positive groups, respectively (p = 0.016). Radiological findings of cavitation were present in 10 (43%) and 2 (10%) of the patients in the HIV-negative and HIV positive groups, respectively (p = 0.016), whereas an interstitial pattern was observed in 18 (78%) and 8 (40%), respectively (p = 0.012). The mean hemoglobin level was 11.1 +/- 2.9 g/dL and 9.3 +/- 2.2 g/dL in the HIV-negative and HIV positive groups, respectively (p = 0.015). CONCLUSIONS: In our sample of tuberculosis patients, expectoration was less prevalent, hemoglobin levels were lower, and cavitation was less common, as was an interstitial pattern, among those co-infected with HIV than among those without HIV co-infection. PMID- 22241035 TI - Pulmonary tuberculosis treatment regimen recommended by the Brazilian National Ministry of Health: predictors of treatment noncompliance in the city of Porto Alegre, Brazil. AB - OBJECTIVE: To determine the predictors of noncompliance with the pulmonary tuberculosis treatment regimen recommended by the Brazilian National Ministry of Health, in previously treatment-naive patients with active tuberculosis treated in the city of Porto Alegre, Brazil. METHODS: This was a case-control study involving six referral primary health care clinics for tuberculosis in Porto Alegre. We reviewed the medical charts of all previously treatment-naive patients with active pulmonary tuberculosis who were noncompliant with the treatment between 2004 and 2006. Those were paired with other patients having similar characteristics and having been cured. We conducted univariate and multivariate analyses. RESULTS: Of the 2,098 patients included, 218 (10.4%) became noncompliant with the treatment. In the multivariate analysis, the factors most strongly associated with treatment noncompliance were being an alcoholic (with or without concomitant use of illicit drugs), being HIV-infected, not residing with family members, and having a low level of education. In the univariate analysis, treatment noncompliance was also significantly associated with being younger and with being non-White. Gender was not significantly associated with treatment noncompliance; nor was the occurrence of adverse effects of the drugs included in the regimen. CONCLUSIONS: In the population studied, being an alcoholic, being HIV-infected, and not residing with family members were the major predictors of noncompliance with treatment for pulmonary tuberculosis among previously treatment-naive patients. PMID- 22241036 TI - Outcomes of tuberculosis treatment among inpatients and outpatients in the city of Sao Paulo, Brazil. AB - OBJECTIVE: To compare inpatient and outpatient treatment of tuberculosis, in terms of outcomes, in the city of Sao Paulo, Brazil, as well to determine which variables are most frequently associated with hospitalization. METHODS: A prospective, longitudinal study carried out between January and December of 2007, at two large hospitals and at outpatient clinics, in two regions of the city of Sao Paulo. For inpatients, data were collected with a structured questionnaire. Additional data were obtained from the Sao Paulo State Department of Health Tuberculosis Database. RESULTS: Of the 474 patients included in the study, 166 were inpatients, and 308 were outpatients. The multivariate analysis showed that hospitalization for tuberculosis was associated with hospital/emergency room diagnosis of tuberculosis (OR = 55.42), with HIV co-infection (OR = 18.57), with retreatment (OR = 18.51), and with having previously sought treatment at another health care facility (OR = 12.32). For the inpatient and outpatient groups, the overall cure rates were 41.6% and 78.3%, respectively, compared with 30.4% and 58.5% for those who were co-infected with HIV, whereas the overall mortality rates were 29.5% and 2.6%, respectively, compared with 45.7% and 9.8% for those who were co-infected with HIV. CONCLUSIONS: Among inpatients, tuberculosis appears to be more severe and more difficult to diagnose, resulting in lower cure rates and higher mortality rates, than among outpatients. In addition, tuberculosis patients co-infected with HIV have less favorable outcomes. PMID- 22241037 TI - Ex vivo experimental model: split lung block technique. AB - Since they were first established, ex vivo models of lung reconditioning have been evaluated extensively. When rejected donor lungs are used, the great variability among the cases can hinder the progress of such studies. In order to avoid this problem, we developed a technique that consists of separating the lung block into right and left blocks and subsequently reconnecting those two blocks. This technique allows us to have one study lung and one control lung. PMID- 22241038 TI - Minimally invasive bronchoscopic resection of benign tumors of the bronchi. AB - OBJECTIVE: Primary benign tumors of the trachea and main bronchi are uncommon. Interventional bronchoscopy allows the diagnosis and the treatment of some of these lesions. METHODS: We reviewed four cases endoscopically treated at our institution. RESULTS: Two patients had hamartoma, and two patients had endobronchial lipoma. In all of the cases, the interventional technique for the resection was the use of a polypectomy snare and electrocautery. The only complication reported was one episode of bronchospasm. CONCLUSIONS: Minimally invasive bronchoscopic resection is a safe, effective method for treating selected benign tumors of the main airway and has a low complication rate. PMID- 22241039 TI - Evaluation of articles on pulmonology published in Brazilian journals other than the Brazilian Journal of Pulmonology. AB - In Brazil, research on pulmonology has become increasingly more visible in recent years. In addition to the Brazilian Journal of Pulmonology, other journals have contributed to that by publishing relevant articles in this area. The objective of this article was to briefly report the most relevant studies on pulmonology that were published in other important Brazilian journals between 2009 and 2010. Altogether, there were 56 articles related to the various subareas that compose the field of respiratory diseases. PMID- 22241040 TI - Treatment of antineutrophil cytoplasmic antibody-associated vasculitis: update. AB - In its various forms, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by a systemic inflammation of the small and medium-sized arteries (especially in the upper and lower respiratory tracts, as well as in the kidneys). The forms of AAV comprise Wegener's granulomatosis (now called granulomatosis with polyangiitis), microscopic polyangiitis, renal AAV, and Churg-Strauss syndrome. In this paper, we discuss the phases of AAV treatment, including the induction phase (with cyclophosphamide or rituximab) and the maintenance phase (with azathioprine, methotrexate, or rituximab). We also discuss how to handle patients who are refractory to cyclophosphamide. PMID- 22241041 TI - 18F-fluorodeoxyglucose positron emission tomography as a noninvasive method for the diagnosis of primary pulmonary artery sarcoma. AB - Pulmonary artery sarcomas are rare, difficult-to-diagnose tumors that frequently mimic chronic pulmonary thromboembolism. We report the cases of two female patients with clinical signs of dyspnea and lung masses associated with pulmonary artery filling defects on chest CT angiography. We performed 18F fluorodeoxyglucose positron emission tomography, which revealed increased radiotracer uptake in those lesions. Pulmonary artery sarcoma was subsequently confirmed by anatomopathological examination. We emphasize the importance of this type of tomography as a noninvasive method for the diagnosis of these tumors. PMID- 22241042 TI - Acute pulmonary schistosomiasis: HRCT findings and clinical presentation. PMID- 22241043 TI - International participation in collaborative studies published in pulmonology journals: where does the Brazilian Journal of Pulmonology rank? PMID- 22241044 TI - A novel position for postural relief of dyspnea. PMID- 22241045 TI - The effect of iron availability on transcription of the Neisseria meningitidis fHbp gene varies among clonal complexes. AB - Factor H binding protein (fHbp) is a major antigenic component of novel vaccines designed to protect against meningococcal disease. Prediction of the potential coverage of these vaccines is difficult, as fHbp is antigenically variable and levels of expression differ among isolates. Transcriptional regulation of the fHbp gene is poorly understood, although evidence suggests that oxygen availability is involved. In this study iron accessibility was found to affect fHbp transcription. However, regulation differed among meningococcal clonal complexes (ccs). For the majority of isolates, increased iron concentrations upregulated transcription. This effect was enhanced by the presence of a 181 bp insertion element upstream of fHbp, associated with isolates belonging to cc4 and cc5. Conversely, meningococci belonging to cc32 showed iron-repressed control of fHbp, as regulation was dominated by cotranscription with the iron-repressed upstream gene cbbA. These results highlight the complexity of fHbp regulation and demonstrate that control of transcription can vary among genetic lineages. PMID- 22241046 TI - Cereulide produced by Bacillus cereus increases the fitness of the producer organism in low-potassium environments. AB - Cereulide, produced by certain Bacillus cereus strains, is a lipophilic cyclic peptide of 1152 Da that binds K(+) ions with high specificity and affinity. It is toxic to humans, but its role for the producer organism is not known. We report here that cereulide operates for B. cereus to scavenge potassium when the environment is growth limiting for this ion. Cereulide-producing B. cereus showed higher maximal growth rates (u(max)) than cereulide non-producing B. cereus in K(+)-deficient medium (K(+) concentration ~1 mM). The cereulide-producing strains grew faster in K(+)-deficient than in K(+)-rich medium with or without added cereulide. Cereulide non-producing B. cereus neither increased u(max) in K(+) deficient medium compared with K(+)-rich medium, nor benefited from added cereulide. Cereulide-producing strains outcompeted GFP-labelled Bacillus thuringiensis in potassium-deficient (K(+) concentration ~1 mM) but not in potassium-rich (K(+) concentration ~30 mM) medium. Exposure to 2 uM cereulide in potassium-free medium lacking an energy source caused, within seconds, a major efflux of cellular K(+) from B. cereus not producing cereulide as well as from Bacillus subtilis. Cereulide depleted the cereulide non-producing B. cereus and B. subtilis cells of a major part of their K(+) stores, but did not affect cereulide-producing B. cereus strains. Externally added 6-10 uM cereulide triggered the generation of biofilms and pellicles by B. cereus. The results indicate that both endogenous and externally accessible cereulide supports the fitness of cereulide-producing B. cereus in environments where the potassium concentration is low. PMID- 22241047 TI - Multilocus sequence phylogenetic analysis of Avibacterium. AB - This study examined 49 field isolates of the genus Avibacterium, with the 49 being allocated to 36 epidemiologically unrelated groups and one isolate from each group being examined in detail. In addition, six type and reference strains were investigated. Phylogenetic analysis of partially sequenced recN, rpoB, infB, pgi and sodA genes confirmed the existence of the species Avibacterium paragallinarum, while a species complex encompassing Avibacterium volantium, Avibacterium avium, Avibacterium gallinarum, Avibacterium endocarditis and Avibacterium sp. A could not be resolved. All isolates shared at least one identical sequence in one gene, indicating low diversity or horizontal gene transfer (HGT) between isolates. Such HGT between isolates of defined species and unclassified isolates combined with high sequence similarity can be explained as the result of an ongoing speciation process. The alternative explanation is that Av. volantium, Av. avium and Avibacterium sp. A were misclassified originally. Except for Av. paragallinarum, identification of species of Avibacterium seems problematic, even by DNA sequencing, as shown in the present investigation. The results indicate that Avibacterium probably contains only two or three species. Until the taxonomic revision is completed we recommend that isolates that do not fit with named species by genotype and phenotype be designated Avibacterium sp. PMID- 22241048 TI - NhaP1 is a K+(Na+)/H+ antiporter required for growth and internal pH homeostasis of Vibrio cholerae at low extracellular pH. AB - Vibrio cholerae has adapted to a wide range of salinity, pH and osmotic conditions, enabling it to survive passage through the host and persist in the environment. Among the many proteins responsible for bacterial survival under these diverse conditions, we have identified Vc-NhaP1 as a K(+)(Na(+))/H(+) antiporter essential for V. cholerae growth at low environmental pH. Deletion of the V. cholerae nhaP1 gene caused growth inhibition when external potassium was either limited (100 mM and below) or in excess (400 mM and above). This growth defect was most apparent at mid-exponential phase, after 4-6 h of culture. Using a pH-sensitive GFP, cytosolic pH was shown to be dependent on K(+) in acidic external conditions in a Vc-NhaP1-dependent manner. When functionally expressed in an antiporterless Escherichia coli strain and assayed in everted membrane vesicles, Vc-NhaP1 operated as an electroneutral alkali cation/proton antiporter, exchanging K(+) or Na(+) ions for H(+) within a broad pH range (7.25-9.0). These data establish the putative V. cholerae NhaP1 protein as a functional K(+)(Na(+))/H(+) antiporter of the CPA1 family that is required for bacterial pH homeostasis and growth in an acidic environment. PMID- 22241050 TI - Deletion of the murein hydrolase CbpD reduces transformation efficiency in Streptococcus thermophilus. AB - Recently it has been shown that Streptococcus thermophilus is competent for natural genetic transformation. This property is widespread among streptococci and may include all members of the genus. Upon entering the competent state, streptococci start transcribing a number of competence-specific genes whose products are required for binding, uptake and processing of transforming DNA. In addition to the core competence genes, competent streptococci express a number of accessory genes that are dispensable for transformation in the laboratory, but presumably play an important role under natural conditions. In Streptococcus pneumoniae, one of these accessory genes encodes a competence-specific murein hydrolase termed CbpD. Experimental evidence indicates that pneumococcal CbpD is part of a predatory mechanism that lyses noncompetent sister cells or members of closely related species in order to release homologous DNA that can be taken up by the competent attacker cells. Competent S. thermophilus LMG18311 cells produce a CbpD-like protein, Stu0039, which might have the same or a similar function. In the present study we have characterized this protein and shown that it is a murein hydrolase with a novel type of cell surface-binding domain. Furthermore, we show that Stu0039 is rapidly inactivated by H(2)O(2) produced during aerobic growth of S. thermophilus. We propose that this inactivation mechanism has evolved for self-protection purposes to prevent extensive autolysis in a competent population. Interestingly, in contrast to pneumococcal CbpD, which does not affect the transformation properties of the producer strain, deletion of Stu0039 reduces the transformability of S. thermophilus. PMID- 22241049 TI - Analysis of hydrogenase 1 levels reveals an intimate link between carbon and hydrogen metabolism in Escherichia coli K-12. AB - Two of the three [NiFe]-hydrogenases (Hyd) of Escherichia coli have a hydrogen uptake function in anaerobic metabolism. While Hyd-2 is maximally synthesized when the bacterium grows by fumarate respiration, Hyd-1 synthesis shows a correlation with fermentation of sugar substrates. In an attempt to advance our knowledge on the physiological function of Hyd-1 during fermentative growth, we examined Hyd-1 activity and levels in various derivatives of E. coli K-12 MC4100 with specific defects in sugar utilization. MC4100 lacks a functional fructose phosphotransferase system (PTS) and therefore grows more slowly under anaerobic conditions in rich medium in the presence of d-fructose compared with d-glucose. Growth in the presence of fructose resulted in an approximately 10-fold increase in Hyd-1 levels in comparison with growth under the same conditions with glucose. This increase in the amount of Hyd-1 was not due to regulation at the transcriptional level. Reintroduction of a functional fruBKA-encoded fructose PTS into MC4100 restored growth on d-fructose and reduced Hyd-1 levels to those observed after growth on d-glucose. Reducing the rate of glucose uptake by introducing a mutation in the gene encoding the cAMP receptor protein, or consumption through glycolysis, by introducing a mutation in phosphoglucose isomerase, increased Hyd-1 levels during growth on glucose. These results suggest that the ability to oxidize hydrogen by Hyd-1 shows a strong correlation with the rate of carbon flow through glycolysis and provides a direct link between hydrogen, carbon and energy metabolism. PMID- 22241051 TI - Effect of development on [Ca2+]i transients to ATP in petrosal ganglion neurons: a pharmacological approach using optical recording. AB - ATP, acting through P2X(2)/P2X(3) receptor-channel complexes, plays an important role in carotid body chemoexcitation in response to natural stimuli in the rat. Since the channels are permeable to calcium, P2X activation by ATP should induce changes in intracellular calcium ([Ca(2+)](i)). Here, we describe a novel ex vivo approach using fluorescence [Ca(2+)](i) imaging that allows screening of retrogradely labeled chemoafferent neurons in the petrosal ganglion of the rat. ATP-induced [Ca(2+)](i) responses were characterized at postnatal days (P) 5-8 and P19-25. While all labeled cells showed a brisk increase in [Ca(2+)](i) in response to depolarization by high KCl (60 mM), only a subpopulation exhibited [Ca(2+)](i) responses to ATP. ATP (250-1,000 MUM) elicited one of three temporal response patterns: fast (R1), slow (R2), and intermediate (R3). At P5-8, R2 predominated and its magnitude was attenuated 44% by the P2X(1) antagonist, NF449 (10 MUM), and 95% by the P2X(1)/P2X(3)/P2X(2/3) antagonist, TNP-ATP (10 MUM). At P19-25, R1 and R3 predominated and their magnitudes were attenuated 15% by NF449, 66% by TNP-ATP, and 100% by suramin (100 MUM), a nonspecific P2 purinergic receptor antagonist. P2X(1) and P2X(2) protein levels in the petrosal ganglion decreased with development, while P2X(3) protein levels did not change significantly. We conclude that the profile of ATP-induced P2X-mediated [Ca(2+)](i) responses changes in the postnatal period, corresponding with changes in receptor isoform expression. We speculate that these changes may participate in the postnatal maturation of chemosensitivity. PMID- 22241052 TI - Recurrent laryngeal nerve activity exhibits a 5-HT-mediated long-term facilitation and enhanced response to hypoxia following acute intermittent hypoxia in rat. AB - A progressive and sustained increase in inspiratory-related motor output ("long term facilitation") and an augmented ventilatory response to hypoxia occur following acute intermittent hypoxia (AIH). To date, acute plasticity in respiratory motor outputs active in the postinspiratory and expiratory phases has not been studied. The recurrent laryngeal nerve (RLN) innervates laryngeal abductor muscles that widen the glottic aperture during inspiration. Other efferent fibers in the RLN innervate adductor muscles that partially narrow the glottic aperture during postinspiration. The aim of this study was to investigate whether or not AIH elicits a serotonin-mediated long-term facilitation of laryngeal abductor muscles, and if recruitment of adductor muscle activity occurs following AIH. Urethane anesthetized, paralyzed, unilaterally vagotomized, and artificially ventilated adult male Sprague-Dawley rats were subjected to 10 exposures of hypoxia (10% O(2) in N(2), 45 s, separated by 5 min, n = 7). At 60 min post-AIH, phrenic nerve activity and inspiratory RLN activity were elevated (39 +/- 11 and 23 +/- 6% above baseline, respectively). These responses were abolished by pretreatment with the serotonin-receptor antagonist, methysergide (n = 4). No increase occurred in time control animals (n = 7). Animals that did not exhibit postinspiratory RLN activity at baseline did not show recruitment of this activity post-AIH (n = 6). A repeat hypoxia 60 min after AIH produced a significantly greater peak response in both phrenic and RLN activity, accompanied by a prolonged recovery time that was also prevented by pretreatment with methysergide. We conclude that AIH induces neural plasticity in laryngeal motoneurons, via serotonin-mediated mechanisms similar to that observed in phrenic motoneurons: the so-called "Q-pathway". We also provide evidence that the augmented responsiveness to repeat hypoxia following AIH also involves a serotonergic mechanism. PMID- 22241053 TI - Running perturbations reveal general strategies for step frequency selection. AB - Recent research has suggested that energy minimization in human walking involves both a fast preprogrammed process and a slow optimization process. Here, we studied human running to test whether these two processes represent control mechanisms specific to walking or a more general strategy for minimizing energetic cost in human locomotion. To accomplish this, we used free response experiments to enforce step frequency with a metronome at values above and below preferred step frequency and then determined the response times for the return to preferred steady-state step frequency when the auditory constraint was suddenly removed. In forced response experiments, we applied rapid changes in treadmill speed and examined response times for the processes involved in the consequent adjustments to step frequency. We then compared the dynamics of step frequency adjustments resulting from the two different perturbations to each other and to previous results found in walking. Despite the distinct perturbations applied in the two experiments, both responses were dominated by a fast process with a response time of 1.47 +/- 0.05 s with fine-tuning provided by a slow process with a response time of 34.33 +/- 0.50 s. The dynamics of the processes underlying step frequency adjustments in running match those found previously in walking, both in magnitude and relative importance. Our results suggest that the underlying mechanisms are fundamental strategies for minimizing energetic cost in human locomotion. PMID- 22241054 TI - Handling objects in old age: forces and moments acting on the object. AB - We measured the external moments and digit-tip force directions acting on a freely moveable object while it was grasped and manipulated by old (OA) and young (YA) adults. Participants performed a grasp and lift task and a precision orientation (key-slot) task with a precision (thumb-finger) grip. During the grasp-lift task the OA group misaligned their thumb and finger contacts and produced greater grip force, greater external moments on the object around its roll axis, and oriented force vectors differently compared with the YA group. During the key-slot task, the OA group was more variable in digit-tip force directions and performed the key-slot task more slowly. With practice the OA group aligned their digits, reduced their grip force, and minimized external moments on the object, clearly demonstrating that the nervous system monitored and actively manipulated one or more variables related to object tilt. This was true even for the grip-lift task, a task for which no instructions regarding object orientation were given and which could tolerate modest amounts of object tilt without interfering with task goals. Although the OA group performed the key slot task faster with experience, they remained slower than the YA group. We conclude that with old age comes a reduced ability to control the forces and moments applied to objects during precision grasp and manipulation. This may contribute to the ubiquitous slowing and deteriorating manual dexterity in healthy aging. PMID- 22241055 TI - Long-term use of high-heeled shoes alters the neuromechanics of human walking. AB - Human movement requires an ongoing, finely tuned interaction between muscular and tendinous tissues, so changes in the properties of either tissue could have important functional consequences. One condition that alters the functional demands placed on lower limb muscle-tendon units is the use of high-heeled shoes (HH), which force the foot into a plantarflexed position. Long-term HH use has been found to shorten medial gastrocnemius muscle fascicles and increase Achilles tendon stiffness, but the consequences of these changes for locomotor muscle tendon function are unknown. This study examined the effects of habitual HH use on the neuromechanical behavior of triceps surae muscles during walking. The study population consisted of 9 habitual high heel wearers who had worn shoes with a minimum heel height of 5 cm at least 40 h/wk for a minimum of 2 yr, and 10 control participants who habitually wore heels for less than 10 h/wk. Participants walked at a self-selected speed over level ground while ground reaction forces, ankle and knee joint kinematics, lower limb muscle activity, and gastrocnemius fascicle length data were acquired. In long-term HH wearers, walking in HH resulted in substantial increases in muscle fascicle strains and muscle activation during the stance phase compared with barefoot walking. The results suggest that long-term high heel use may compromise muscle efficiency in walking and are consistent with reports that HH wearers often experience discomfort and muscle fatigue. Long-term HH use may also increase the risk of strain injuries. PMID- 22241056 TI - Erythropoietin administration acutely stimulates resting energy expenditure in healthy young men. AB - Treatment with recombinant human erythropoietin (rHuEpo) improves insulin sensitivity in patients with end-stage renal disease, and animal studies indicate that Epo increases fat oxidation. However, the metabolic effects of rHuEpo have never been experimentally studied in healthy humans. The aim was to investigate the effects of an acute rHuEpo bolus on substrate metabolism and insulin sensitivity in healthy young men. Ten healthy young men were studied in a single blinded, randomized crossover design with a 2-wk washout period receiving 400 IU/kg rHuEpo or placebo. Substrate metabolism was evaluated by indirect calorimetry and tracer infusions, and insulin sensitivity by a hyperinsulinemic euglycemic clamp; and PCR and Western blotting measured protein expression and content, respectively. Resting energy expenditure (REE) increased significantly after rHuEpo [basal: 1,863.3 +/- 67.2 (kcal/day) (placebo) vs. 2,041.6 +/- 81.2 (rHuEpo), P < 0.001; clamp: 1,903.9 +/- 68.3 (placebo) vs. 2,015.7 +/- 114.4 (rHuEpo), P = 0.03], but the increase could not be explained by changes in mRNA levels of uncoupling protein 2 or 3. Fat oxidation in the basal state tended to be higher after rHuEpo but could not be explained by changes in mRNA levels of CPT1 and PPARalpha or AMPK and ACC protein phosphorylation. Insulin-stimulated glucose disposal, glucose metabolism, and whole body and forearm protein metabolism did not change significantly in response to rHuEpo. In conclusion, a single injection of rHuEpo acutely increases REE in healthy human subjects. This calorigenic effect is not accompanied by distinct alterations in the pattern of substrate metabolism or insulin sensitivity. PMID- 22241058 TI - Sweat rate prediction equations for outdoor exercise with transient solar radiation. AB - We investigated the validity of employing a fuzzy piecewise prediction equation (PW) [Gonzalez et al. J Appl Physiol 107: 379-388, 2009] defined by sweat rate (m(sw), g.m(-2).h(-1)) = 147 + 1.527.(E(req)) - 0.87.(E(max)), which integrates evaporation required (E(req)) and the maximum evaporative capacity of the environment (E(max)). Heat exchange and physiological responses were determined throughout the trials. Environmental conditions were ambient temperature (T(a)) = 16-26 degrees C, relative humidity (RH) = 51-55%, and wind speed (V) = 0.5-1.5 m/s. Volunteers wore military fatigues [clothing evaporative potential (i(m)/clo) = 0.33] and carried loads (15-31 kg) while marching 14-37 km over variable terrains either at night (N = 77, trials 1-5) or night with increasing daylight (N = 33, trials 6 and 7). PW was modified (Pw,sol) for transient solar radiation (R(sol), W) determined from measured solar loads and verified in trials 6 and 7. PW provided a valid m(sw) prediction during night trials (1-5) matching previous laboratory values and verified by bootstrap correlation (r(bs) of 0.81, SE +/- 0.014, SEE = +/- 69.2 g.m(-2).h(-1)). For trials 6 and 7, E(req) and E(max) components included R(sol) applying a modified equation Pw,sol, in which m(sw) = 147 + 1.527.(E(req,sol)) - 0.87.(E(max)). Linear prediction of m(sw) = 0.72.Pw,sol + 135 (N = 33) was validated (R(2) = 0.92; SEE = +/-33.8 g.m(-2).h( 1)) with PW beta-coefficients unaltered during field marches between 16 degrees C and 26 degrees C T(a) for m(sw) <= 700 g.m(-2).h(-1). PW was additionally derived for cool laboratory/night conditions (T(a) < 20 degrees C) in which E(req) is low but E(max) is high, as: PW,cool (g.m(-2).h(-1)) = 350 + 1.527.E(req) - 0.87.E(max). These sweat prediction equations allow valid tools for civilian, sports, and military medicine communities to predict water needs during a variety of heat stress/exercise conditions. PMID- 22241057 TI - Variation in the uncoupling protein 2 and 3 genes and human performance. AB - Uncoupling proteins 2 and 3 (UCP2 and UCP3) may negatively regulate mitochondrial ATP synthesis and, through this, influence human physical performance. However, human data relating to both these issues remain sparse. Examining the association of common variants in the UCP3/2 locus with performance phenotypes offers one means of investigation. The efficiency of skeletal muscle contraction, delta efficiency (DE), was assessed by cycle ergometry in 85 young, healthy, sedentary adults both before and after a period of endurance training. Of these, 58 were successfully genotyped for the UCP3-55C>T (rs1800849) and 61 for the UCP2-866G>A (rs659366) variant. At baseline, UCP genotype was unrelated to any physical characteristic, including DE. However, the UCP2-866G>A variant was independently and strongly associated with the DE response to physical training, with UCP2-866A allele carriers exhibiting a greater increase in DE with training (absolute change in DE of -0.2 +/- 3.6% vs. 1.7 +/- 2.8% vs. 2.3 +/- 3.7% for GG vs. GA vs. AA, respectively; P = 0.02 for A allele carriers vs. GG homozygotes). In multivariate analysis, there was a significant interaction between UCP2-866G>A and UCP3-55C>T genotypes in determining changes in DE (adjusted R(2) = 0.137; P value for interaction = 0.003), which was independent of the effect of either single polymorphism or baseline characteristics. In conclusion, common genetic variation at the UCP3/2 gene locus is associated with training-related improvements in DE, an index of skeletal muscle performance. Such effects may be mediated through differences in the coupling of mitochondrial energy transduction in human skeletal muscle, but further mechanistic studies are required to delineate this potential role. PMID- 22241059 TI - High-intensity training improves airway responsiveness in inactive nonasthmatic children: evidence from a randomized controlled trial. AB - PURPOSE: the relationship between physical activity and airway health in children is not well understood. The purpose of this study was to determine whether 8 wk of high-intensity exercise training would improve airway responsiveness in prepubescent, nonasthmatic, inactive children. METHODS: 16 healthy, prepubescent children were randomized [training group (TrG) n = 8, control group (ConG) n = 8]. Prior to and following 8 wk of training (or no training), children completed pulmonary function tests (PFTs): forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), forced expiratory flow at 25-75% of vital capacity (FEF(25 75)), and exhaled nitric oxide (FENO). Children completed an incremental cycle Vo(2max) test, eucapnic voluntary hyperventilation (EVH), anthropometric tests, and blood tests to determine fasting blood glucose, total cholesterol, HDL, LDL, and triglycerides. Body fat percentage was determined using dual-energy X-ray absorptiometry pretraining and bioelectrical impedance pre- and posttraining. RESULTS: there were no differences (P > 0.05) in anthropometric measures or PFTs between TrG and ConG at baseline. In the TrG, there was a significant increase in Vo(2max) (~24%) and a decrease in total cholesterol (~13%) and LDL cholesterol (~35%) following training. There were improvements (P < 0.05) in DeltaFEV(1) both postexercise (pre: -7.60 +/- 2.10%, post: -1.10 +/- 1.80%) and post-EVH (pre: 6.71 +/- 2.21%, post: -1.41 +/- 1.58%) with training. The DeltaFEF(25-75) pre post exercise also improved with training (pre: -16.10 +/- 2.10%, post: -6.80 +/- 1.80%; P < 0.05). Lower baseline body fat percentages were associated with greater improvements in pre-post exercise DeltaFEV(1) following training (r = 0.80, P < 0.05). CONCLUSION: these results suggest that in nonasthmatic prepubescent children, inactivity negatively impacts airway responsiveness, which can be improved with high-intensity training. Excess adiposity, however, may constrain these improvements. PMID- 22241060 TI - Multilevel model estimation of age-dependent individual-specific trajectories for left ventricular echocardiographic indexes in an asymptomatic elderly cohort. AB - Few studies have been performed on the individual-specific trajectory of left ventricular aging as assessed by echocardiography in an asymptomatic elderly cohort. In the present study, a representative cohort of elderly men, who were long-term asymptomatic for cardiovascular issues, were selected from an ongoing observational aging study. Annual echocardiographic data were used to establish an age-dependent hierarchical model. Based on two-level linear regression results, four echocardiographic indexes [left ventricular mass (LVmass; -1.872 g/yr), posterior ventricular wall thickness (-0.048 mm/yr), fraction shortening (0.097/yr), and transmitral peak A velocity (-0.006 m.s(-1).yr(-1))] changed significantly with increasing age and were age- and subject-dependent. The most characterized results of the study were the significant, age-related, within individual variances in echocardiographic results, which were observed using the likelihood ratio test at an occasion-dependent level. Of these, fluctuated amplitudes of two systolic variables [i.e., LVmass (con/age = -0.012 +/- 0.004; P = 0.0007) and fraction shortening (con/age = -0.001 +/- 0.004; P = 0.05)] were significantly attenuated with increasing age within individuals. On the other hand, the age-related variability of four diastolic Doppler variables [i.e., peak A velocity (con/age = 0.003 +/- 0.002; P = 0.0009), peak E velocity (con/age = 0.004 +/- 0.003; P = 0.01), E/A ratio (con/age = 0.007 +/- 0.003; P = 0.0002), and deceleration time of E wave (con/age = 0.025 +/- 0.007; P < 0.0001)] significantly increased with increasing age within individuals. The age-related individual variability of left ventricular indexes observed in this continuous asymptomatic cohort may reflect the mechanism of preclinical, individualized heart aging. In conclusion, successfully fitted multilevel models were applied as a valuable tool to determine the mechanism of individual cardiac aging in the elderly. PMID- 22241061 TI - A threshold lung volume for optimal mechanical effects on upper airway airflow dynamics: studies in an anesthetized rabbit model. AB - Increasing lung volume improves upper airway airflow dynamics via passive mechanisms such as reducing upper airway extraluminal tissue pressures (ETP) and increasing longitudinal tension via tracheal displacement. We hypothesized a threshold lung volume for optimal mechanical effects on upper airway airflow dynamics. Seven supine, anesthetized, spontaneously breathing New Zealand White rabbits were studied. Extrathoracic pressure was altered, and lung volume change, airflow, pharyngeal pressure, ETP laterally (ETPlat) and anteriorly (ETPant), tracheal displacement, and sternohyoid muscle activity (EMG%max) monitored. Airflow dynamics were quantified via peak inspiratory airflow, flow limitation upper airway resistance, and conductance. Every 10-ml lung volume increase resulted in caudal tracheal displacement of 2.1 +/- 0.4 mm (mean +/- SE), decreased ETPlat by 0.7 +/- 0.3 cmH(2)O, increased peak inspiratory airflow of 22.8 +/- 2.6% baseline (all P < 0.02), and no significant change in ETPant or EMG%max. Flow limitation was present in most rabbits at baseline, and abolished 15.7 +/- 10.5 ml above baseline. Every 10-ml lung volume decrease resulted in cranial tracheal displacement of 2.6 +/- 0.4 mm, increased ETPant by 0.9 +/- 0.2 cmH(2)O, ETPlat was unchanged, increased EMG%max of 11.1 +/- 0.3%, and a reduction in peak inspiratory airflow of 10.8 +/- 1.0%baseline (all P < 0.01). Lung volume, resistance, and conductance relationships were described by exponential functions. In conclusion, increasing lung volume displaced the trachea caudally, reduced ETP, abolished flow limitation, but had little effect on resistance or conductance, whereas decreasing lung volume resulted in cranial tracheal displacement, increased ETP and increased resistance, and reduced conductance, and flow limitation persisted despite increased muscle activity. We conclude that there is a threshold for lung volume influences on upper airway airflow dynamics. PMID- 22241063 TI - Communication skills training for emergency medicine residents. AB - OBJECTIVE: To determine the effects of a communication skills training program on emergency medicine residents and patient satisfaction. MATERIALS AND METHODS: Twenty emergency medicine residents attended a 6-week psychoeducation program that was intended to improve their communication skills. The first three sessions of the psychoeducation program consisted of theoretical education on empathy and communication. Other sessions covered awareness, active communication, and empathic skills on a cognitive behavioral basis using discussion, role play, and homework within an interactive group. The effects of the program were assessed using a communication skills scale, empathy scale, and patient satisfaction survey and were reflected by the reduction in the number of undesirable events between doctors and patients in the emergency department. RESULTS: The mean communication skills score increased from 178.7+/-19 to 189.2+/-16 after training (P<0.02). Empathy score also increased from 29.5+/-9 to 30.7+/-8, but this difference was not statistically significant (P=0.1). The patient satisfaction survey of 576 patients demonstrated increased scores on confidence in the doctor (88.2+/-14.6-93.6+/-10.3; P<0.01); the doctor's respect, kindness, and thoughtfulness (90.3+/-10.8-94.1+/-16.5; P<0.01); individualized attention (86.7+/-9.4-93.9+/-11.1; P<0.01); devotion of adequate time to listening (88.6+/ 12.3-90.8+/-14.1; P=0.04); and counseling and information delivery (90.1+/-11.3 92.2+/-11.7; P=0.02). The number of undesirable events between doctors and patients decreased 75% from 12 to three. CONCLUSION: Participation in a communication skills training program was associated with improved communication skills of emergency medicine residents, increased patient satisfaction, and decreased complaints. PMID- 22241062 TI - Effects of corticosteroid treatment on airway inflammation, mechanics, and hyperpolarized 3He magnetic resonance imaging in an allergic mouse model. AB - The purpose of this study was to assess the effects of corticosteroid therapy on a murine model of allergic asthma using hyperpolarized (3)He magnetic resonance imaging (MRI) and respiratory mechanics measurements before, during, and after methacholine (MCh) challenge. Three groups of mice were prepared, consisting of ovalbumin sensitized/ovalbumin challenged (Ova/Ova, n = 5), Ova/Ova challenged but treated with the corticosteroid dexamethasone (Ova/Ova+Dex, n = 3), and ovalbumin-sensitized/saline-challenged (Ova/PBS, n = 4) control animals. All mice underwent baseline 3D (3)He MRI, then received a MCh challenge while 10 2D (3)He MR images were acquired for 2 min, followed by post-MCh 3D (3)He MRI. Identically treated groups underwent respiratory mechanics evaluation (n = 4/group) and inflammatory cell counts (n = 4/group). Ova/Ova animals exhibited predominantly large whole lobar defects at baseline, with significantly higher ventilation defect percentage (VDP = 19 +/- 4%) than Ova/PBS (+2 +/- 1%, P = 0.01) animals. Such baseline defects were suppressed by dexamethasone (0%, P = 0.009). In the Ova/Ova group, MCh challenge increased VDP on both 2D (+30 +/- 8%) and 3D MRI scans (+14 +/- 2%). MCh-induced VDP changes were diminished in Ova/Ova+Dex animals on both 2D (+21 +/- 9%, P = 0.63) and 3D scans (+7 +/- 2%, P = 0.11) and also in Ova/PBS animals on 2D (+6 +/- 3%, P = 0.07) and 3D (+4 +/- 1%, P = 0.01) scans. Because MCh challenge caused near complete cessation of ventilation in four of five Ova/Ova animals, even as large airways remained patent, this implies that small airway (<188 MUm) obstruction predominates in this model. This corresponds with respiratory mechanics observations that MCh challenge significantly increases elastance and tissue damping but only modestly affects Newtonian airway resistance. PMID- 22241065 TI - Upregulation of heart PFK-2/FBPase-2 isozyme in skeletal muscle after persistent contraction. AB - Fructose-2,6-bisphosphate (Fru-2,6-P(2)) is the most potent allosteric activator of liver 6-phosphofructo-1-kinase enzyme, which is crucial for glycolysis. It is present in skeletal muscle but its importance is controversial as a regulator of muscle glycolysis. This study aims to determine the role of Fru-2,6-P(2) in the control of muscle glycolysis during contraction. Muscle contraction was produced by chronic low-frequency stimulation of rabbit tibialis anterior for 24 h, followed by a rest period of 48 h. To determine muscle glycolysis adaptation, we applied a short functional electrostimulation test using the same system of low frequency stimulation for 1, 3, and 10 s. The variation in concentration of lactate and pyruvate was used to calculate the flux along the glycolysis pathway and the Fru-1,6-P(2)/Fru-6-P ratio permitted to analyze the 6-phosphofructo-1 kinase activation. Fru-2,6-P(2) levels increased over the 24 h of stimulation and remained elevated after the rest period, this being the only metabolite that kept the changes produced by chronic low-frequency stimulation during the rest. During the short functional electrostimulation test, the glycolytic pathway in stimulated and rested muscle was more active than in control muscle, which coincided with higher kinase activity of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2/FBPase-2) enzyme. Furthermore, we found a decrease in muscle, liver, and ubiquitous PFK-2/FBPase-2 isoform expression and an increase in heart isoform expression. For the first time, we demonstrate that a persistent increase in Fru-2,6-P(2) produced by a change in PFK-2/FBPase-2 isoform expression may play an important role in the regulation of muscle glycolysis during the first moments of exercise. PMID- 22241066 TI - Mild traumatic brain injury in UK military personnel returning from Afghanistan and Iraq: cohort and cross-sectional analyses. AB - OBJECTIVES: : To assess (a) the prevalence of mild traumatic brain injury (mTBI) in UK military personnel deployed to Iraq and/or Afghanistan, (b) the risk factors associated with mTBI, and (c) the association between mTBI and subsequent postconcussion symptoms (PCS). PARTICIPANTS: : A total of 4620 personnel deployed to Iraq and/or Afghanistan who completed a questionnaire between 2007 and 2009, of whom 2333 were also studied in 2005, participated in the study. MAIN OUTCOME MEASURES: : Mild traumatic brain injury during deployment, as identified using a modified version of the Brief Traumatic Brain Injury Screen questionnaire; symptoms associated with PCS in the month before questionnaire completion. RESULTS: : The prevalence of mTBI was 4.4%, and the prevalence in those with a combat role was 9.5%. Having an mTBI was associated with current symptoms of posttraumatic stress disorder (adjusted odds ratio (AOR), 5.2; 95% confidence interval [CI], 2.3-11.4), alcohol misuse (AOR, 2.3; 95% CI, 1.4-3.7), and multiple physical symptoms (AOR, 2.6; 95% CI, 1.3-5.2). Only 3 of 9 symptoms remained associated with mTBI after adjustment. Psychological distress and alcohol misuse recorded before deployment were associated with subsequent mTBI. CONCLUSIONS: : The prevalence of mTBI in UK military is lower than that in the US military. Symptoms of current posttraumatic stress disorder and alcohol misuse are associated with mTBI. Symptoms of mental disorder predated occurrence of mTBI. The majority PCS were not associated with mTBI. PMID- 22241067 TI - Peculiarity of methoxy group-substituted phenylhydrazones in Fischer indole synthesis. AB - We found that the Fischer indole synthesis of ethyl pyruvate 2 methoxyphenylhydrazone (5) with HCl/EtOH gave an abnormal product, ethyl 6 chloroindole-2-carboxylate (7), as the main product, with a smaller amount of ethyl 7-methoxyindole-2-carboxylate (6) as the normal product. This abnormal reaction was the result of a cyclization on the side with the substituent (methoxy group) of a benzene ring on phenylhydrazone, which was not previously observed. In this initial investigation, we focused on 1) the application of the above-mentioned abnormal Fischer indole synthesis, 2) the details of this reaction of phenylhydrazone with other kinds of substituents, 3) the mechanism of the first step of the Fischer indole synthesis, 4) the abnormal reaction in methoxydiphenylhydrazones, and 5) a synthetic device to avoid an abnormal reaction. The results of these studies are summarized herein. PMID- 22241069 TI - Al3+ induced planarization, conformational arrest and metallochromic shift in a pyrimidine dione dye: insight from integrated hybrid quantum-classical calculations. AB - In order to explore the possibilities of simulating metallochromism by modern molecular modeling, we apply a sequential hybrid quantum-classical approach to a prototype metallochromic system-the Al(3+) ion and pyrimidinedione (PY) dye complex. The complex shows several structural features with relevance for the metallochromism: the PY dye exhibits conformers with dynamical transitions between twisted structures, which are inhibited by the addition of the metal ion leading to planarization and a conformational arrest: the Al(3+) ion behaves like a structure-modifier for both intra and intermolecular degrees of freedom and with respect to the intermolecular solvation shell structure. The sequential approach that we have employed uses DFT/MM molecular dynamics for structure modeling and TDDFT/PCM for property modeling. The computed metallochromic shift between PY and the Al(PY)(3+) complex in DMSO solvent is obtained in excellent agreement with experiment. The results infer optimism for future use of such modeling techniques to design metallochromic indicators. PMID- 22241068 TI - Pharmacological chaperone therapy for Fabry disease. AB - Fabry disease is an inherited lysosomal storage disorder caused by deficient alpha-galactosidase A activity. Many missense mutations in Fabry disease often cause misfolded gene products, which leads to their retention in the endoplasmic reticulum by the quality control system; they are then removed by endoplasmic reticulum-associated degradation. We discovered that a potent alpha-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells. The oral administration of 1-deoxygalactonojirimycin to transgenic mice expressing human mutant alpha-galactosidase A resulted in significant increases in alpha-galactosidase A activity in various organs, with concomitant reductions in globotriaosylceramide, which contributes to the pathology of Fabry disease. Seventy-eight missense mutations were found to be responsive to 1 deoxygalactonojirimycin. These data indicate that many patients with Fabry disease could potentially benefit from pharmacological chaperone therapy. PMID- 22241070 TI - MicroRNA profiling in K-562 cells under imatinib treatment: influence of miR-212 and miR-328 on ABCG2 expression. AB - BACKGROUND: Despite the enormous success of imatinib in chronic myeloid leukemia (CML), therapy resistance has emerged in a significant proportion of patients, partly because of the overexpression of ABC efflux transporters. METHODS: Using an array comprising 667 miRNAs, we investigated whether the expression of microRNAs (miRNAs) is altered in CML K-562 cells becoming resistant to increasing concentrations of imatinib. ABCB1 and ABCG2 mRNA (quantitative real-time PCR) and protein expression (western blot) were quantified under short-term and 4 months' imatinib treatment. Interaction of miR-212 and miR-328 with ABCG2 was investigated by transfection experiments and reporter gene assays using respective miRNA precursors or miRNA inhibitors. RESULTS: Although ABCB1 protein was not expressed, ABCG2 protein was 7.2-fold elevated after long-term treatment with 0.3 umol/l imatinib and decreased gradually at higher concentrations. miRNAs miR-212 and miR-328 were identified to correlate inversely with ABCG2 expression under these conditions. Short-term treatment also induced ABCG2 protein concentration dependently and caused a downregulation of miR-212, but not of miR 328 at all tested concentrations (P=0.050). Reporter gene assays confirmed miR 212 to target the 3'-UTR region of ABCG2. In contrast, transfection of anti-miR 212 revealed an upregulation of ABCG2 protein expression, whereas the effect of anti-miR-328 was weak. CONCLUSION: Our study suggests an association of imatinib treatment, miRNA downregulation and ABCG2 overexpression, possibly contributing to the mechanisms involved in imatinib distribution and response in CML therapy. PMID- 22241071 TI - Family factors in the development, treatment, and prevention of childhood anxiety disorders. AB - It is now widely accepted that anxiety disorders run in families, and current etiological models have proposed both genetic and environmental pathways to anxiety development. In this paper, the familial role in the development, treatment, and prevention of anxiety disorders in children is reviewed. We focus on three anxiety disorders in youth, namely, generalized, separation, and social anxiety as they often co-occur both at the symptom and disorder level and respond to similar treatments. We begin by presenting an overview of a broad range of family factors associated with anxiety disorders. Findings from these studies have informed intervention and prevention strategies that are discussed next. Throughout the paper we shed light on the challenges that plague this research and look toward the future by proposing directions for much needed study and discussing factors that may improve clinical practice and outcomes for affected youth and their families. PMID- 22241072 TI - Unique neurological manifestations of dengue virus in pediatric population: a case series. AB - Dengue infection is endemic in developing countries posing a major public health problem. Clinical manifestations form a broad spectrum and include uncomplicated dengue fever, dengue hemorrhagic fever and dengue shock syndrome. We report three confirmed cases of dengue infection in pediatric population with central nervous system involvement with certain unreported manifestations resulting in diagnostic dilemma. Increasing evidence of neurotropism by dengue virus emphasizes that clinician be aware of such association and consider dengue infection in cases of febrile encephalitis and myelitis in endemic areas. Early diagnosis and appropriate supportive cars can reverse this potentially fatal disease. PMID- 22241073 TI - Spontaneous and serial rupture of both Achilles tendons associated with secondary hyperparathyroidism in a patient receiving long-term hemodialysis. AB - The spontaneous and serial rupture of the bilateral Achilles tendons without history of significant trauma is an uncommon complication in long-term hemodialysis (HD) patients. The majority of these patients have additional predisposing factors, such as previous use of fluoroquinolone antibiotics or corticosteroids. In general, this condition is associated with a coexisting systemic disease, including chronic kidney disease (CKD), secondary hyperparathyroidism, systemic lupus erythematosus (SLE), and diabetes mellitus (DM). Here, we report a 46-year-old man who had been undergoing regular HD for 11 years. He developed a spontaneous and consecutive rupture of both Achilles tendons. Based on previous reports of tendon ruptures in uremic patients and on the patient's lack of corticosteroid or fluoroquinolone use, we believe that secondary hyperparathyroidism was the predisposing factor in this patient. The mechanism seems to be related to a high parathyroid hormone (PTH) level, which results in osteolytic bone resorption at the tendon insertion site. Treatment and prevention of such tendon ruptures include early surgical repair and control of secondary hyperparathyroidism, by use of vitamin D analogs, and total parathyroidectomy, with or without autotransplantation of a parathyroid gland. PMID- 22241074 TI - Product formation in the Prato reaction on Sc3N@D(5h)-C80: preference for [5,6] bonds, and not pyracylenic bonds. AB - We report here reaction energies and NMR data for the N-tritylpyrrolidino mono adducts of Sc(3)N@D(5h)-C(80). The pyracylene adduct that was previously suggested to be important for the Prato reaction is ruled out both from energetic and NMR points of view. PMID- 22241075 TI - Subclinical cobalamin deficiency. AB - PURPOSE OF REVIEW: This review focuses on recent developments and controversies in the diagnosis, consequences, and management of subclinical cobalamin deficiency (SCCD), which affects many elderly persons. RECENT FINDINGS: Diagnosis of SCCD depends exclusively on biochemical tests whose individual limitations suggest that combinations of tests are needed, especially in epidemiologic research. The causes of SCCD are unknown in more than 60% of cases, which limits prognostic predictions and identification of health consequences. After years of varying, often inconclusive associations, new clinical trials suggest that homocysteine reduction by high doses of folic acid, cobalamin, and pyridoxine may reduce progression of structural brain changes and cognitive impairment, especially in predisposed individuals. The causative or contributory roles, if any, of SCCD itself in cognitive dysfunction require direct study. If the findings are confirmed, high-dose supplementation with three vitamins will probably be more effective than fortification of the diet. SUMMARY: The story of SCCD, which is severalfold times more common in the elderly than clinical cobalamin deficiency but also differs from it in arising only infrequently from severe malabsorption and thus being less likely to progress, continues to evolve. Preventive benefits need to be confirmed and expanded, and will require fuller understanding of SCCD pathophysiology, natural history, and health consequences. PMID- 22241076 TI - Innate immunity in the small intestine. AB - PURPOSE OF REVIEW: This article reviews the most recent publications on innate immunity in the small intestine. We will go over the innate immune receptors that act as sensors of microbial presence or cell injury, Paneth cells as the main epithelial cell type that secrete antimicrobial peptides, and mucosal production of immunoglobulin A (IgA). In addition, we will give an update on examples of imbalance of the innate immune response resulting in clinical disease with the most relevant example being Crohn's disease. RECENT FINDINGS: Toll-like receptors (TLRs) are involved in B-cell homing to the intestine, rejection of small intestinal allografts, and recruitment of mast cells. The TLR adaptor Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-beta is necessary to activate innate immunity after Yersinia enterocolitica infection. Moreover, MyD88 is required to keep the intestinal microbiota under control and physically separated from the epithelium, and RegIIIgamma is responsible for the bacterial segregation from the lining epithelial cells. In Crohn's disease, ATG16L1 T300A variant promotes a proinflammatory response; and miR-196 downregulates a protective immunity-related GTPase family M protein (IRGM) polymorphism leading to impaired clearance of adherent Escherichia coli in the intestine. SUMMARY: The intestine is continuously exposed to dietary and microbial antigens. The host has to maintain intestinal homeostasis to keep the commensal and pathogenic bacteria under control. Some of the mechanisms to do so are by expression of innate immune receptors, production of antimicrobial peptides, secretion of IgA, or autophagy of intracellular bacteria. Unfortunately, in some cases the innate immune response fails to protect the host and chronic inflammation, transplant rejection, or other disorders may occur. PMID- 22241083 TI - A fluorescent amino acid probe to monitor efficiency of peptide conjugation to glass surfaces for high density microarrays. AB - Using a fluorescent NBD amino acid, new protease substrates were developed that are attractive because of the excellent chemical stability and long wavelength of excitation (480 nm) of the NBD fluorophore. The fluorescent peptides are synthesized by Fmoc solid-phase peptide synthesis. An example peptide was efficiently immobilized onto a microarray surface using click chemistry, and its proteolysis was monitored by fluorescence imaging. Excellent site specificity was achieved for the protease. Fluorescent peptides are also used to monitor the conjugation efficiency onto a surface using a standard microarray scanner. PMID- 22241077 TI - Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors. AB - PURPOSE OF REVIEW: To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance. RECENT FINDINGS: Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogs in short bowel syndrome and Crohn's disease. This review highlights the evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn's disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that suppressor of cytokine signaling protein induction by GH or GLP2 in normal or inflamed intestine may limit IGF1 induced growth, but protect against risk of dysplasia or fibrosis, is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. SUMMARY: IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed. PMID- 22241085 TI - PRAS40 is a functionally critical target for EWS repression in Ewing sarcoma. AB - Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3' untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease. PMID- 22241084 TI - LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFalpha expression and receptor tyrosine kinase signaling. AB - Smac mimetics block inhibitor of apoptosis proteins to trigger TNFalpha-dependent apoptosis in cancer cells. However, only a small subset of cancer cells seem to be sensitive to Smac mimetics and even sensitive cells can develop resistance. Herein, we elucidated mechanisms underlying the intrinsic and acquired resistance of cancer cells to Smac mimetics. In vitro and in vivo investigations revealed that the expression of the cell surface protein LRIG1, a negative regulator of receptor tyrosine kinases (RTK), is downregulated in resistant derivatives of breast cancer cells sensitive to Smac mimetics. RNA interference-mediated downregulation of LRIG1 markedly attenuated the growth inhibitory activity of the Smac mimetic SM-164 in drug-sensitive breast and ovarian cancer cells. Furthermore, LRIG1 downregulation attenuated TNFalpha gene expression induced by Smac mimetics and increased the activity of multiple RTKs, including c-Met and Ron. The multitargeted tyrosine kinase inhibitors Crizotinib and GSK1363089 greatly enhanced the anticancer activity of SM-164 in all resistant cell derivatives, with the combination of SM-164 and GSK1363089 also completely inhibiting the outgrowth of resistant tumors in vivo. Together, our findings show that both upregulation of RTK signaling and attenuated TNFalpha expression caused by LRIG1 downregulation confers resistance to Smac mimetics, with implications for a rational combination strategy. PMID- 22241086 TI - B effector cells activated by a chimeric protein consisting of IL-2 and the ectodomain of TGF-beta receptor II induce potent antitumor immunity. AB - We have previously shown that interleukin (IL)-2 receptor-expressing lymphoid cells stimulated with a chimeric protein linking IL-2 to the ectodomain of TGF beta receptor II (also known as FIST) become resistant to TGF-beta-mediated suppression and produce significant amounts of proinflammatory cytokines. In this study, we have characterized the antigen presentation properties of FIST stimulated B cells (hereafter inducible B effector cells, iBEC). FIST converts naive splenic B cells to B effector cells characterized by potent antigen presentation properties and production of TNFalpha and IFNgamma. iBECs display hyperphosphorylation of STAT3 and STAT5 downstream of the IL-2 receptor and upregulation of T-bet expression. iBECs maintain B-cell identity based on the expression of PAX5 and CD19 and overexpress Smad7, which confers resistance to TGF-beta-mediated suppression of B-cell activation. iBEC antitumor immunity was determined by a mouse model of lymphoma-expressing ovalbumin (E.G7-OVA) as a specific tumor antigen. OVA-pulsed iBECs function as antigen-presenting cells (APC) in vitro by inducing the activation of OVA-specific CD4(+) and CD8(+) T cells, respectively, and in vivo by conferring complete protective immunity against E.G7-OVA tumor challenge. In addition, OVA-pulsed iBECs promote tumor regression in immunocompetent C57Bl/6 mice bearing E.G7-OVA tumors. In conclusion, iBECs represent an entirely novel B cell-derived APC for immune therapy of cancer. PMID- 22241087 TI - Detection of circulating tumor cells and tumor stem cells in patients with breast cancer by using flow cytometry: a valuable tool for diagnosis and prognosis evaluation. AB - Circulating tumor stem cells (CTSC), a subpopulation of circulating tumor cells (CTC), may lead to recurrent diseases. The aim of this study was to detect CTC (CD45(-)EpCAM(+)) and CTSC (CD45(-)EpCAM(+)CD44(+)CD24(-)) of breast cancer (BC) patients, as well as to explore their clinical relevance. CTC and CTSC in peripheral blood (PB) of 45 female BC patients were detected by using flow cytometry (FCM). SKBR-3 cells were mixed with MNC of four healthy volunteers at different ratios in order to evaluate the sensitivity of FCM. Real-time quantitative polymerase chain reaction (QRT-PCR) was conducted and compared with FCM. The expression of EPCAM between CTC < 50 and CTC >= 50 groups (19.98 +/- 23.93 versus 29.46 +/- 29.27 * 10(-5)), and the expression of CD44 between CTSC negative and positive groups (0.85 +/- 0.91 versus 0.81 +/- 0.75) were statistically the same. FCM had higher specificity than QRT-PCR. Statistical differences were obtained between CTC < 50 and CTC >= 50 groups among different TNM stages, histology stages, estrogen receptor (ER) status and progesterone receptor (PR) status (P < 0.05). Statistical differences between CTSC negative and positive groups within different TNM stages and regional lymph node metastasis (RLNM) status (P < 0.05) were also obtained. Moreover, the percentage of CTC on CD45 negative cells (CD45(-)C) among different clinical pathology was statistically different, P = 0.000. Additionally, the percentage of CTSC on CD45( )C with TNM stage was rising (0: 0.00 +/- 0.000/00, I: 0.03 +/- 0.050/00, II: 0.06 +/- 0.140/00, III: 0.10 +/- 0.090/00, IV: 0.29 +/- 0.350/00, P = 0.034). Statistical difference in the percentage of CTSC on CD45(-)C among different RLNM status (P = 0.001) was also obtained. FCM to detect CTC and CTSC may be used to diagnose disease at early stage, to guide clinical therapy or to predict prognosis. PMID- 22241088 TI - Autozygome maps dispensable DNA and reveals potential selective bias against nullizygosity. AB - PURPOSE: Copy number variants are an important source of human genome diversity. The widespread distribution of hemizygous copy number variants in the DNA of healthy humans suggests that haploinsufficiency is largely tolerated. However, little is known about the extent to which corresponding nullizygosity (two-copy deletion) is similarly tolerated. METHODS: We analyzed a cohort of first cousin unions to enrich for shared parental hemizygous events and tested their Mendelian inheritance in offspring. RESULTS: Analysis of autozygous DNA blocks (autozygome) in the offspring not only proved an efficient method of mapping "dispensable" DNA but also revealed potential selective bias against the occurrence of nullizygous changes. This bias was not restricted to genic copy number variants and was not accounted for by a high rate of miscarriages. CONCLUSIONS: The autozygome is an efficient way to map dispensable segments of DNA and may reveal selective bias against nullizygosity in healthy individuals. PMID- 22241089 TI - Barriers to integrating personalized medicine into clinical practice: a best worst scaling choice experiment. AB - PURPOSE: As advances in genomics make genome sequencing more affordable, the availability of new genome-based diagnostic and therapeutic strategies (i.e., personalized medicine) will increase. This wave will hit front-line physicians who may be faced with a plethora of patients' expectations of integrating genomic data into clinical care. The objective of this study was to elicit the preferences of physicians about regarding applying personalized medicine in their clinical practice as these strategies become available. METHODS: Using a best worst scaling (BWS) choice experiment, we estimated the relative importance of attributes that influence physicians' decision for using personalized medicine. Six attributes were included in the BWS: type of genetic tests, training for genetic testing, clinical guidelines, professional fee, privacy protection laws, and cost of genetic tests. A total of 197 physicians in British Columbia completed the experiment. Using latent class analysis (LCA), we explored the physicians' heterogeneities in preferences. RESULTS: "Type of genetic tests" had the largest importance, suggesting that the physicians' decision was highly influenced by the availability of genetic tests for patients' predisposition to diseases and/or drug response. "Training" and "guidelines" were the attributes with the next highest importance. LCA identified two classes of physicians. Relative to class 2, class 1 had a larger weight for the "type of genetic tests," but smaller weights for "professional fee" and "cost of tests." CONCLUSION: We measured relative importance of factors that affect the decision of physicians to incorporate personalized medicine in their practice. These results can be used to design the policies for supporting physicians and facilitating the use of personalized medicine in the future. PMID- 22241090 TI - Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". AB - Biotinidase recycles the vitamin biotin. Biotinidase deficiency is an autosomal recessively inherited neurocutaneous disorder. The symptoms of the disorder can be successfully treated or prevented by administering pharmacological doses of biotin. The biotinidase gene (BTD) has been cloned and sequenced; its genomic organization has been determined and more than 150 mutations have been identified. The disorder meets the major criteria for newborn screening and is being universally adopted in the United States and in many countries around the world. Newborn screening will limit our understanding about the natural history of the disorder. Regardless, the disorder is an ideal example of an inherited metabolic disorder that if untreated can result in major disabilities, but if identified early can be readily treated by the oral administration of a vitamin. PMID- 22241091 TI - "What does it mean?": uncertainties in understanding results of chromosomal microarray testing. AB - PURPOSE: The increased sensitivity of chromosomal microarray (CMA) technology as compared with traditional cytogenetic analysis allows for improved detection of genomic alterations. However, there is potential for uncertainty in the interpretation of test results in some cases. This paper explores how families understand and make meaning of CMA test results, and identifies the needs of families undergoing CMA testing. METHODS: We conducted semistructured interviews with parents of 25 pediatric outpatients with CMA test results indicating either a pathogenic alteration or a variant of unknown significance (VUS). Interviews were analyzed qualitatively. RESULTS: Three domains of understanding were identified: comprehension of results, interpretations of scientific uncertainty, and personal meaning for the child and family. Incomplete comprehension of test results and scientific uncertainty were prominent themes for families receiving results in both the VUS and pathogenic categories. Receiving results from non geneticists and by telephone, long waits to see a geneticist, and misleading Internet searches all contributed to misunderstandings. CONCLUSION: Differentiating domains of understanding allows for the identification of uncertainties that can be reduced or managed in order to improve understanding of CMA results. Using this framework, we suggest interventions to promote clarity and address the informational needs of families undergoing CMA testing. PMID- 22241092 TI - NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation. AB - PURPOSE: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder. METHODS: Custom high resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed. RESULTS: Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms-such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication-as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsufficiency due to heterozygous loss-of function mutations; such mutations may result in a more severe CdLS phenotype. CONCLUSION: Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies. PMID- 22241093 TI - Prioritization of future genetics education for general practitioners: a Delphi study. AB - PURPOSE: General practitioners (GPs) are increasingly expected to deliver genetics services in daily patient care. Education in primary care genetics is considered suboptimal and in urgent need of revision and innovation. The aim of this study was to prioritize topics for genetics education for general practice. METHODS: A Delphi consensus procedure consisting of three rounds was conducted. A purposively selected heterogeneous panel (n = 18) of experts, comprising six practicing GPs who were also engaged in research, five GP trainers, four clinical genetics professionals, and three representatives of patient organizations, participated. Educational needs regarding genetics in general practice in terms of knowledge, skills, and attitudes were rated and ranked in a top-10 list. RESULTS: The entire panel completed all three rounds. Kendall's coefficient of concordance indicated significant agreement regarding the top 10 genetic education needs (P < 0.001). "Recognizing signals that are potentially indicative of a hereditary component of a disease" was rated highest, followed by "Evaluating indications for referral to a clinical genetics centre" and "Knowledge of the possibilities and limitations of genetic tests." CONCLUSIONS: The priorities resulting from this study can inform the development of educational modules, including input for case-based education, to improve GP performance in genetic patient care. PMID- 22241094 TI - IRB perspectives on the return of individual results from genomic research. AB - PURPOSE: Return of individual research results from genomic studies is a hotly debated ethical issue in genomic research. However, the perspective of key stakeholders-institutional review board (IRB) professionals-has been missing from this dialogue. This study explores the positions and experiences of IRB members and staff regarding this issue. METHODS: In-depth interviews with 31 IRB professionals at six sites across the United States. RESULTS: IRB professionals agreed that research results should be returned to research participants when results are medically actionable but only if the participants want to know the results. Many respondents expected researchers to address the issue of return of results (ROR) in the IRB application and informed-consent document. Many respondents were not comfortable with their expertise in genomics research and only a few described actual experiences in addressing ROR. Although participants agreed that guidelines would be helpful, most were reticent to develop them in isolation. Even where IRB guidance exists (e.g., Clinical Laboratory Improvement Act (CLIA) lab certification required for return), in practice, the guidance has been overruled to allow ROR (e.g., no CLIA lab performs the assay). CONCLUSION: An IRB-researcher partnership is needed to help inform responsible and feasible institutional approaches to returning research results. PMID- 22241095 TI - Enhancing geneticists' perspectives of the public through community engagement. AB - PURPOSE: Given the rapid pace of genetic and genomic research and technology development, public engagement on scientific issues may be mutually beneficial to the research community and the general public. The public may benefit from a greater understanding of concepts and new applications, and researchers can build awareness of public knowledge, perceptions, and potential concerns about genomic research and applications. METHODS: We developed and piloted a public engagement program called Genome Diner to facilitate dialog between genetic/genomic researchers (n = 40) and middle school students (n = 76) and their parents (n = 83) from the local community. Program impact was assessed through pre- and post Diner surveys for each group. RESULTS: After participation in Genome Diner, researchers' views were positively affected regarding the (adult) public's level of understanding of genetic concepts, beliefs about relevance of research, and the importance of researcher-community interaction. CONCLUSION: Through an interactive discussion with students and parents, researchers gained valuable insight into public perspectives about genome research. The engagement format of the Genome Diner program presents a novel method of fostering trust and relationships between the two groups and to inform both the public and the researchers, whose work may depend on public opinion and participation. PMID- 22241096 TI - Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience. AB - PURPOSE: To evaluate the growth, development, and medical histories of children with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening. METHODS: Chart review of patients diagnosed with short-chain acyl-CoA dehydrogenase or isobutyryl-CoA dehydrogenase deficiency at our center. RESULTS: There were 16 children with short-chain acyl-CoA dehydrogenase deficiency, including 10 with two pathogenic mutations, and 8 with isobutyryl-CoA dehydrogenase deficiency. All but one patient has had normal growth and development, and that patient also had the 22q deletion syndrome. CONCLUSION: Our data and previous reports suggest that the majority of individuals with short-chain acyl-CoA dehydrogenase or isobutyryl-CoA dehydrogenase deficiencies have normal growth and development. PMID- 22241097 TI - NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype. AB - PURPOSE: Neurofibromatosis, type 1 (NF1) is an autosomal dominant disorder caused by mutations of the neurofibromin 1 (NF1) gene at 17q11.2. Approximately 5% of individuals with NF1 have a 1.4-Mb heterozygous 17q11.2 deletion encompassing NF1, formed through nonallelic homologous recombination (NAHR) between the low copy repeats that flank this region. NF1 microdeletion syndrome is more severe than NF1 caused by gene mutations, with individuals exhibiting facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. Although NAHR can also cause reciprocal microduplications, reciprocal NF1 duplications have been previously reported in just one multigenerational family and a second unrelated proband. METHODS: We analyzed the clinical features in seven individuals with NF1 microduplications, identified among 48,817 probands tested in our laboratory by array-based comparative genomic hybridization. RESULTS: The only clinical features present in more than one individual were variable DD/ID, facial dysmorphisms, and seizures. No neurofibromas were present. Three sets of parents were tested: one duplication was apparently de novo, one inherited from an affected mother, and one inherited from a clinically normal father. CONCLUSION: This is the first report comparing the phenotypes of nonrelated individuals with NF1 microduplications. This comparison will allow for further definition of this emerging microduplication syndrome. PMID- 22241098 TI - Genes and plays: bringing ELSI issues to life. AB - Ethical complexities surround the promise of genomic technology and the power of genetic information as they alter conceptions of identity and dynamics within personal and professional relationships. Creative approaches such as dramatic vignettes offer a unique analytical stage for imagining the bioethical past and future. Dramatic narratives can bring to life images of differing perspectives and values when experiencing innovations in medicine. Although the scientific landscape shifts, concerns expressed in theatre from 50 years ago parallel many contemporary ELSI (ethical, legal, and social implications) issues, highlighting the ongoing struggle to appreciate the impact of emerging genetic technologies on relationships. To illuminate these enduring concerns, we explore how perceptions and relationships have influenced-and been influenced by-genetics as portrayed through dramatic vignettes. We build on the legacy of using case vignettes as a clinical teaching modality, and believe similar value exists within the research ethics domain. The selection of dialogue discussed encompasses abbreviated excerpts from two existing and one original vignette that we staged at the ELSI 2011 Congress and various academic and health institutions. PMID- 22241099 TI - The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository. AB - PURPOSE: Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned. METHODS: We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs. RESULTS: Parents hoped to receive IRRs that would help them better understand their children's condition(s). They understood that this outcome was unlikely, but hoped that their children's participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive. CONCLUSIONS: It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children's IRRs in order to effectively communicate the implications to parents during the consenting process. PMID- 22241100 TI - Molecular genetic testing for fragile X syndrome: laboratory performance on the College of American Pathologists proficiency surveys (2001-2009). AB - PURPOSE: The College of American Pathologists offers biannual proficiency testing for molecular analysis of fragile X syndrome. The purpose of this study was to analyze laboratory performance on the fragile X proficiency surveys from 2001 to 2009. METHODS: Individual laboratory responses were analyzed for accuracy of genotype determination (normal, gray zone, premutation, or full mutation) and size analysis of the FMR1 trinucleotide repeat region. The analytical sensitivity and specificity of testing for fragile X were calculated, and laboratory performance for trinucleotide repeat sizing was evaluated. RESULTS: Overall, laboratories demonstrated analytical sensitivity of 99% and 96% for detection of full mutations associated with fragile X syndrome in males and females, respectively; analytical sensitivity of 98% for detection of premutations; and analytical specificity of 99.9%. Size measurements of the CGG repeat region were acceptable from most laboratories, with an increase in the range of reported sizes observed for larger repeat expansions. CONCLUSIONS: Molecular genetic testing for fragile X syndrome demonstrated excellent sensitivity and specificity by laboratories participating in the College of American Pathologists (CAP) surveys. Allele sizing demonstrated good performance overall with improved accuracy over the study period. Participation in proficiency testing can aid laboratories in assessing individual performance and need for calibration of assays. PMID- 22241101 TI - A pre-visit website with question prompt sheet for counselees facilitates communication in the first consultation for breast cancer genetic counseling: findings from a randomized controlled trial. AB - PURPOSE: The initial breast cancer genetic counseling visit is mainly educational, with large amounts of relatively standard information and little counselee participation. Counselors might provide more counselee-specific information if counselees would participate more. A pre-visit website providing computer-tailored information and a question prompt sheet (QPS) might help counselees to pursue a more active role. METHODS: Counselees were randomized to receive usual care (UC) or UC plus the pre-visit website. The QPS questions were sent to the counselor before the visit. All counselees completed a baseline questionnaire, and visits were videotaped. RESULTS: Intervention-group counselees (n = 102) did not ask more questions than UC-group counselees (n = 90). However, counselees in the intervention group more often shared their agenda (B = 10.37; confidence interval (CI) 2.68-18.06; P = 0.01), directed the communication (B = 0.41; CI 0.28-0.53; P = 0.01), and paraphrased the counselors' words (B = 5.18; CI 0.43-9.92; P = 0.03). Counselors introduced and answered the QPS questions. As a result, they provided more information about the topics of these questions, and the information provided was more specific to whether there was an indication for DNA testing. CONCLUSION: A pre-visit website with QPS helped counselees to communicate more assertively. As a result, the information provided was more counselee specific, without affecting the visit duration. PMID- 22241102 TI - Genetics researchers' and IRB professionals' attitudes toward genetic research review: a comparative analysis. AB - PURPOSE: Genetic research involving human participants can pose challenging questions related to ethical and regulatory standards for research oversight. However, few empirical studies describe how genetic researchers and institutional review board (IRB) professionals conceptualize ethical issues in genetic research or where common ground might exist. METHODS: Parallel online surveys collected information from human genetic researchers (n = 351) and IRB professionals (n = 208) regarding their views about human participant oversight for genetic protocols. RESULTS: A range of opinions were observed within groups on most issues. In both groups, a minority thought it likely that people would be harmed by participation in genetic research or identified from coded genetic data. A majority of both groups agreed that reconsent should be required for four of the six scenarios presented. Statistically significant differences were observed between groups on some issues, with more genetic researcher respondents trusting the confidentiality of coded data, fewer expecting harms from reidentification, and fewer considering reconsent necessary in certain scenarios. CONCLUSION: The range of views observed within and between IRB and genetic researcher groups highlights the complexity and unsettled nature of many ethical issues in genome research. Our findings also identify areas where researcher and IRB views diverge and areas of common ground. PMID- 22241103 TI - Navigating a research partnership between academia and industry to assess the impact of personalized genetic testing. AB - PURPOSE: To describe the process of structuring a partnership between academic researchers and two personalized genetic testing companies that would manage conflicts of interest while allowing researchers to study the impact of this nascent industry. METHODS: We developed a transparent process of ongoing communication about the interests of all research partners to address challenges in establishing study goals, survey development, data collection, analysis, and manuscript preparation. Using the existing literature on conflicts of interest and our experience, we created a checklist for academic and industry researchers seeking to structure research partnerships. RESULTS: Our checklist includes questions about the risk to research participants, sponsorship of the study, control of data analysis, freedom to publish results, the impact of the research on industry customers, openness to input from all partners, sharing results before publication, and publication of industry-specific data. Transparency is critical to building trust between partners. Involving all partners in the research development enhanced the quality of our research and provided an opportunity to manage conflicts early in the research process. CONCLUSION: Navigating relationships between academia and industry is complex and requires strategies that are transparent and responsive to the concerns of all. Employing a checklist of questions prior to beginning a research partnership may help to manage conflicts of interest. PMID- 22241105 TI - BRCA1/2 carriers: their childbearing plans and theoretical intentions about having preimplantation genetic diagnosis and prenatal diagnosis. AB - PURPOSE: To assess the impact of BRCA1/2 test results on carriers' reproductive decision-making and the factors determining their theoretical intentions about preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND). METHODS: Unaffected BRCA1/2 mutation carriers of childbearing age (N = 605; 449 women; 151 men) were included at least 1 year after the disclosure of their test results in a cross-sectional survey nested in a national cohort. Multivariate adjustment was performed on the data obtained in self-administered questionnaires. RESULTS: Response rate was 81.0%. Overall, 32.5% and 50% said that they would undergo PGD/PND, respectively, at a theoretical next pregnancy, whereas only 12.1% found termination of pregnancy (TOP) acceptable. Theoretical intentions toward PGD did not depend on gender/age, but were higher among those with no future childbearing plans (adjusted odds ratio (AOR) 95% confidence interval (CI): 3.5 (1.9-6.4)) and those having fewer relatives with cancer (AOR 1.5 95% CI (1.0-2.3)). Greater TOP acceptability was observed among males and those with lower educational levels; 85.4% of respondents agreed that information about PGD/PND should be systematically delivered with the test results. CONCLUSIONS: The closer to reproductive decision-making BRCA1/2 carriers are, i.e., when they are more likely to be making future reproductive plans, the less frequently they intend to have PGD. Carriers' theoretical intentions toward PND are discussed further. PMID- 22241104 TI - Argininosuccinate lyase deficiency. AB - The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of argininosuccinic acid to arginine and fumarate. ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with hyperammonemia within the first few days after birth or as a late-onset form with episodic hyperammonemia and/or long-term complications that include liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen-scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation (OLT) is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy. PMID- 22241106 TI - Familial clustering of schizophrenia, bipolar disorder, and major depressive disorder. AB - PURPOSE: To investigate familial clustering of schizophrenia, bipolar disorder, and major depressive disorder. METHODS: Combining data from a psychiatric case registry and Statistics Netherlands provided information on 4,673 affected probands and 18,692 matched population controls. RESULTS: Probands with schizophrenia had relative risks (RRs) for having a sibling with schizophrenia of 3.77 (95% confidence interval (CI): 2.60-5.46) and with bipolar disorder of 1.79 (95% CI: 0.64-4.96) as compared with a reference proband. Probands affected with bipolar disorder have an RR of 6.51 (95% CI: 2.60-16.29) for having a sibling with bipolar disorder and of 1.71 (95% CI: 0.71-4.14) for having a sibling with schizophrenia as compared with a reference proband. Probands affected with major depressive disorder also have increased risk for having a sibling with schizophrenia (RR: 2.04, 95% CI: 1.54-2.72) as compared with a reference proband, which was similar to the risk for having a sibling with major depressive disorder (RR: 1.91, 95% CI: 1.63-2.24) or bipolar disorder (RR: 2.06, 95% CI: 1.18-3.60). CONCLUSION: Our findings suggest, as previous studies have, that risk across schizophrenia and bipolar disorder is considerably lower (twofold) than within diagnostic entities, whereas for major depressive disorder risk is similar within and across diagnostic entities. PMID- 22241107 TI - Critical polyelectrolyte adsorption under confinement: planar slit, cylindrical pore, and spherical cavity. AB - We explore the properties of adsorption of flexible polyelectrolyte chains in confined spaces between the oppositely charged surfaces in three basic geometries. A method of approximate uniformly valid solutions for the Green function equation for the eigenfunctions of polymer density distributions is developed to rationalize the critical adsorption conditions. The same approach was implemented in our recent study for the "inverse" problem of polyelectrolyte adsorption onto a planar surface, and on the outer surface of rod-like and spherical obstacles. For the three adsorption geometries investigated, the theory yields simple scaling relations for the minimal surface charge density that triggers the chain adsorption, as a function of the Debye screening length and surface curvature. The encapsulation of polyelectrolytes is governed by interplay of the electrostatic attraction energy toward the adsorbing surface and entropic repulsion of the chain squeezed into a thin slit or small cavities. Under the conditions of surface-mediated confinement, substantially larger polymer linear charge densities are required to adsorb a polyelectrolyte inside a charged spherical cavity, relative to a cylindrical pore and to a planar slit (at the same interfacial surface charge density). Possible biological implications are discussed briefly in the end. PMID- 22241108 TI - Dengue vaccines: closer but not there yet. PMID- 22241109 TI - Reduction in morbidity and mortality from childhood diarrhoeal disease after species A rotavirus vaccine introduction in Latin America - a review. AB - Countries in Latin America were among the first to implement routine vaccination against species A rotavirus (RVA). We evaluate data from Latin America on reductions in gastroenteritis and RVA disease burden following the introduction of RVA vaccine. Published literature was reviewed to identify case-control studies of vaccine effectiveness and population-based studies examining longitudinal trends of diarrhoeal disease reduction after RVA vaccine introduction in Latin American countries. RVA vaccine effectiveness and impact on gastroenteritis mortality and hospitalization rates and RVA hospitalization rates are described. Among middle-income Latin American countries with published data (Mexico, Brazil, El Salvador and Panama), RVA vaccine contributed to a gastroenteritis-associated mortality reduction of 22-41%, a gastroenteritis associated hospitalization reduction of 17-51% and a RVA hospitalization reduction of 59-81% among children younger than five years of age. In Brazil and El Salvador, case-control studies demonstrated that a full RVA vaccination schedule was 76-85% effective against RVA hospitalization; a lower effectiveness of 46% was seen in Nicaragua, the only low-income country with available data. A growing body of literature offers convincing evidence of "real world" vaccine program successes in Latin American settings, which may be expanded as more countries in the region include RVA vaccine in their immunization programs. PMID- 22241110 TI - Chikungunya virus outbreak in Kerala, India, 2007: a seroprevalence study. AB - India was affected by a major outbreak of chikungunya fever caused by Chikungunya virus (CHIKV) during 2006-2007. Kerala was the worst affected state during 2007 with a contribution of 55.8% suspected cases in the country. However, except for clinically reported case records, no systematic information is available on infection status of CHIKV in the region. Hence, we carried out a post-epidemic survey to estimate seroprevalence status [immunoglobulin G (IgG)] in the community using commercially available indirect immunofluorescence test. This methodology had been reported to be highly specific and sensitive for CHIKV infection. The study area selected was the worst affected mid-highlands region of Kerala which harbour vast area of rubber plantations. The study evidenced 68% of the population to be seropositive for CHIKV IgG. Males were found more affected than females (chi2 = 9.86; p = 0.002). Among males, prevalence was significantly higher in the age classes 21-30 (chi2 = 5.46; p = 0.019) and 31-40 (chi2 = 5.84; p = 0.016) years. This may be due to high occupational risk of the male population engaged in plantation activities exposed to infective bites of Aedes albopictus. The current study provides an insight into the magnitude of CHIKV outbreak in Kerala. PMID- 22241111 TI - Ectoparasitic insects (Diptera: Streblidae and Siphonaptera: Ischnopsyllidae) of bats from Iquitos and surrounding areas (Loreto, Peru). AB - Based on specimens collected from bats of different families, we add new species and extend the known ecological distribution and host associations of insect ectoparasites of bats in Peru. New information is provided for the distribution of 26 species of parasites (25 Diptera and 1 Siphonaptera: Ischnopsyllidae). Four species (Neotrichobius ectophyllae, Strebla galindoi, Strebla paramirabilis and Myodopsylla wolffsohni wolffsohni) are new for Peru and 16 represent new records for the department of Loreto. Also, we found 17 new host-ectoparasite relationships. Of note, we found remarkable new association between Neotrichobius delicatus and bat species from the families Molossidae and Noctilionidae and a novel association between Paradyschiria parvula and a species of Vespertilionidae. Host-ectoparasite specificity was recorded with 14 species as monoxenous, three oligoxenous, seven pleioxenous and two polyxenous. PMID- 22241112 TI - Spotted fever group Rickettsia infecting ticks (Acari: Ixodidae) in the state of Santa Catarina, Brazil. AB - During 2006-2008, a total of 260 adult ticks were collected from domestic and wild animals in different regions of the state of Santa Catarina (SC), Brazil, including areas where human cases of Brazilian spotted fever have been reported. Collected ticks belonging to nine species (Amblyomma aureolatum, Amblyomma cajennense, Amblyomma dubitatum, Amblyomma longirostre, Amblyomma ovale, Amblyomma tigrinum, Dermacentor nitens, Rhipicephalus microplus and Rhipicephalus sanguineus) were tested by polymerase chain reaction (PCR) for rickettsial infection. Overall, eight (3.1%) ticks were found to be infected with Rickettsia species. After sequencing the PCR products, we determined that the sequences generated from three A. aureolatum, one A. ovale and one R. sanguineus from the municipality of Blumenau, one A. ovale from the municipality of Aguas Mornas and one A. ovale from the municipality of Urussanga were identical to the corresponding partial rickettsial ompA gene sequence of Rickettsia parkeri strain Atlantic rainforest. The sequence generated from one A. longirostre from Blumenau was 100% identical to the corresponding partial rickettsial ompA gene sequence of Rickettsia amblyommii strain AL. Because R. parkeri strain Atlantic rainforest was recently shown to have caused two cases of human spotted fever in other states of Brazil, the role of this rickettsial agent as a possible etiological agent of spotted fever in SC is discussed. PMID- 22241113 TI - Human polyomaviruses JC and BK in the urine of Brazilian children and adolescents vertically infected by HIV. AB - The aim of this study was to characterize the urinary excretion of the BK (BKV) and JC (JCV) human polyomaviruses in a cohort of human immunodeficiency virus (HIV)-infected children and adolescents. One hundred and fifty-six patients were enrolled: Group I included 116 HIV-infected children and adolescents [median age = 11.4 years (y); range 1-22 y]; Group II included 40 non-HIV-infected healthy controls (median age = 11.37 y; range 7-16 y). Single urine samples from both groups were screened for the presence of JCV and BKV DNA by polymerase chain reaction at enrolment. The overall rate of JCV and BKV urinary excretion was found to be 24.4% and 40.4%, respectively (n = 156). Group I had urinary excretion of JCV and BKV in 27.6% and 54.3% of subjects, respectively. In contrast, Group II showed positive results for JCV in 17.5% of subjects and for BKV in 12.5% of subjects (p Pearson JCV = 0.20; p Pearson BKV < 0.0001). In Group I, there was no association between JCV/BKV shedding and age, gender or CD4 values. Patients with an HIV viral load < 50 copies/mL had a lower excretion of BKV (p < 0.001) and a trend of lower JCV excretion (p = 0.07). One patient in Group I (1/116, 0.9%) showed clinical and radiological features consistent with progressive multifocal leukoencephalopathy, suggesting that children with HIV/polyomavirus coinfection should be kept under surveillance. PMID- 22241114 TI - Immunodetection of Helicobacter sp. and the associated expression of ABO blood group antigens in the gastric mucosa of captive and free-living New World primates in the Amazon region. AB - The histo-blood group ABH antigens were first described in humans. These antigens are only present on erythrocytes from great apes and humans, while in more primitive animals they are found in tissues and body fluids. The ABH antigens are mainly distributed in tissues exposed to the external environment and potentially serve as ligands for pathogens or inhibitors of tissue connections. The objective of this paper was two-fold: (i) to determine the presence of Helicobacter sp. in the gastric mucosa of 16 captive and 24 free-living New World monkeys and (ii) to evaluate the presence of histopathological alterations related to bacterial infection and the associated expression of ABH antigens in the tissue. Stomach tissues from 13 species of monkey were assessed using haematoxylin-eosin and modified Gram staining (Hucker) methods. An immunohistochemical analysis of the tissue revealed the presence of infectious bacteria that were characteristic of the genus Helicobacter sp. The results demonstrate that various species of monkey might be naturally infected with the Helicobacter sp. and that there is an increased susceptibility to infection. This study serves as a comparative analysis of infection between human and non-human primates and indicates the presence of a new species of Helicobacter. PMID- 22241115 TI - Genetic diversity of noroviruses in Brazil. AB - Norovirus (NoV) infections are a major cause of acute gastroenteritis outbreaks around the world. In Brazil, the surveillance system for acute diarrhoea does not include the diagnosis of NoV, precluding the ability to assess its impact on public health. The present study assessed the circulation of NoV genotypes in different Brazilian states by partial nucleotide sequencing analysis of the genomic region coding for the major capsid viral protein. NoV genogroup II genotype 4 (GII.4) was the prevalent (78%) followed by GII.6, GII.7, GII.12, GII.16 and GII.17, demonstrating the great diversity of NoV genotypes circulating in Brazil. Thus, this paper highlights the importance of a virological surveillance system to detect and characterize emerging strains of NoV and their spreading potential. PMID- 22241116 TI - Biological, biochemical and molecular features of Trypanosoma cruzi strains isolated from patients infected through oral transmission during a 2005 outbreak in the state of Santa Catarina, Brazil: its correspondence with the new T. cruzi Taxonomy Consensus (2009). AB - We examined strains of Trypanosoma cruzi isolated from patients with acute Chagas disease that had been acquired by oral transmission in the state of Santa Catarina, Brazil (2005) and two isolates that had been obtained from a marsupial (Didelphis aurita) and a vector (Triatoma tibiamaculata). These strains were characterised through their biological behaviour and isoenzymic profiles and genotyped according to the new Taxonomy Consensus (2009) based on the discrete typing unities, that is, T. cruzi genotypes I-VI. All strains exhibited the biological behaviour of biodeme type II. In six isolates, late peaks of parasitaemia, beyond the 20th day, suggested a double infection with biodemes II + III. Isoenzymes revealed Z2 or mixed Z1 and Z2 profiles. Genotyping was performed using three polymorphic genes (cytochrome oxidase II, spliced leader intergenic region and 24Salpha rRNA) and the restriction fragment length polymorphism of the kDNA minicircles. Based on these markers, all but four isolates were characterised as T. cruzi II genotypes. Four mixed populations were identified: SC90, SC93 and SC97 (T. cruzi I + T. cruzi II) and SC95 (T. cruzi I + T. cruzi VI). Comparison of the results obtained by different methods was essential for the correct identification of the mixed populations and major lineages involved indicating that characterisation by different methods can provide new insights into the relationship between phenotypic and genotypic aspects of parasite behaviour. PMID- 22241117 TI - Search for a platelet-activating factor receptor in the Trypanosoma cruzi proteome: a potential target for Chagas disease chemotherapy. AB - Chagas disease (CD) causes the highest burden of parasitic diseases in the Western Hemisphere and is therefore a priority for drug research and development. Platelet-activating factor (PAF) causes the CD parasite Trypanosoma cruzi to differentiate, which suggests that the parasite may express PAF receptors. Here, we explored the T. cruzi proteome for PAF receptor-like proteins. From a total of 23,000 protein sequences, we identified 29 hypothetical proteins that are predicted to have seven transmembrane domains (TMDs), which is the main characteristic of the G protein-coupled receptors (GPCRs), including the PAF receptor. The TMDs of these sequences were independently aligned with domains from 25 animal PAF receptors and the sequences were analysed for conserved residues. The conservation score mean values for the TMDs of the hypothetical proteins ranged from 31.7-44.1%, which suggests that if the putative T. cruzi PAF receptor is among the sequences identified, the TMDs are not highly conserved. These results suggest that T. cruzi contains several GPCR-like proteins and that one of these GPCRs may be a PAF receptor. Future studies may further validate the PAF receptor as a target for CD chemotherapy. PMID- 22241118 TI - Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients. AB - Mutations located in the 109-amino acid fragment of NS5B are typically associated with resistance to interferon (IFN) and ribavirin (RIB) and to new antiviral drugs. The prevalence of these mutations was examined in 69 drug-naive individuals with hepatitis C virus (HCV) infections in Rio de Janeiro, Brazil. Mutations related to non-response to IFN/RIB were observed in all subtypes studied (1a, 1b, 2b, 3a and 4). The most common mutation was Q309R, present in all subtypes, except subtype 2b with frequency above 20%. D244N was detected only in subtype 3a and A333E was detected only in subtype 2b. We did not detect the S282T, S326G or T329I mutations in any of the samples analysed. Of note, the C316N mutation, previously related to a new non-nucleoside compound (HCV796 and AG-021541), was observed in only eight of 33 (24%) samples from subtype 1b. Site 316 was under positive selection in this HCV variant. Our data highlight the presence of previously described resistance mutations in HCV genotypes from drug naive patients. PMID- 22241119 TI - Seroconversion for West Nile and St. Louis encephalitis viruses among sentinel horses in Colombia. AB - We prospectively sampled flavivirus-naive horses in northern Colombia to detect West Nile virus (WNV) and St. Louis encephalitis virus (SLEV) seroconversion events, which would indicate the current circulation of these viruses. Overall, 331 (34.1%) of the 971 horses screened were positive for past infection with flaviviruses upon initial sampling in July 2006. During the 12-month study from July 2006-June 2007, 33 WNV seroconversions and 14 SLEV seroconversions were detected, most of which occurred in the department of Bolivar. The seroconversion rates of horses in Bolivar for the period of March-June 2007 reached 12.4% for WNV and 6.7% for SLEV. These results comprise the first serologic evidence of SLEV circulation in Colombia. None of the horses sampled developed symptoms of encephalitis within three years of initial sampling. Using seroconversions in sentinel horses, we demonstrated an active circulation of WNV and SLEV in northern Colombia, particularly in the department of Bolivar. The absence of WNV attributed equine or human disease in Colombia and elsewhere in the Caribbean Basin remains a topic of debate and speculation. PMID- 22241120 TI - Characterisation of virulence genes in methicillin susceptible and resistant Staphylococcus aureus isolates from a paediatric population in a university hospital of Medellin, Colombia. AB - Virulence and antibiotic resistance are significant determinants of the types of infections caused by Staphylococcus aureus and paediatric groups remain among the most commonly affected populations. The goal of this study was to characterise virulence genes of methicillin-susceptible S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) strains isolated from a paediatric population of a Colombian University Hospital during 2009. Sixty MSSA and MRSA isolates were obtained from paediatric patients between zero-14 years. We identified the genes encoding virulence factors, which included Panton-Valentine leucocidine (PVL), staphylococcal enterotoxins A-E, exfoliative toxins A and B and toxic shock syndrome toxin 1. Typing of the staphylococcal chromosome cassette mec (SCCmec) was performed in MRSA strains. The virulence genes were more diverse and frequent in MSSA than in MRSA isolates (83% vs. 73%). MRSA strains harboured SCCmec types IVc (60%), I (30%), IVa (7%) and V (3%). SCCmec type IVc isolates frequently carried the PVL encoding genes and harboured virulence determinants resembling susceptible strains while SCCmec type I isolates were often negative. PVL was not exclusive to skin and soft tissue infections. As previously suggested, these differences in the distribution of virulence factor genes may be due to the fitness cost associated with methicillin resistance. PMID- 22241121 TI - High-density lipoprotein prevents SAA-induced production of TNF-alpha in THP-1 monocytic cells and peripheral blood mononuclear cells. AB - In this study, we evaluated whether human serum and lipoproteins, especially high density lipoprotein (HDL), affected serum amyloid A (SAA)-induced cytokine release. We verified the effects of SAA on THP-1 cells in serum-free medium compared to medium containing human serum or lipoprotein-deficient serum. SAA induced tumour necrosis factor-alpha (TNF-alpha) production was higher in the medium containing lipoprotein-deficient serum than in the medium containing normal human serum. The addition of HDL inhibited the SAA-induced TNF-alpha release in a dose-dependent manner. This inhibitory effect was specific for HDL and was not affected by low-density lipoprotein or very low-density lipoprotein. In human peripheral blood mononuclear cells, the inhibitory effect of HDL on TNF alpha production induced by SAA was less pronounced. However, this effect was significant when HDL was added to lipoprotein-deficient medium. In addition, a similar inhibitory effect was observed for interleukin-1 beta release. These findings confirm the important role of HDL and support our previous hypothesis that HDL inhibits the effects of SAA during SAA transport in the bloodstream. Moreover, the HDL-induced reduction in the proinflammatory activity of SAA emphasizes the involvement of SAA in diseases, such as atherosclerosis, that are characterized by low levels of HDL. PMID- 22241122 TI - Comparison of the insecticide susceptibilities of laboratory strains of Aedes aegypti and Aedes albopictus. AB - A susceptible strain of Aedes albopictus derived from the Gainesville strain (Florida, USA) was established in our laboratory. The larvicidal efficacies of the neurotoxic insecticides temephos, permethrin and the pure cis and trans permethrin isomers and the microbial insecticide Bacillus thuringiensis israelensis (Bti) against Ae. albopictus were estimated and compared to a susceptible strain of Aedes aegypti. The larvicidal effect of insect growth regulator pyriproxyfen was also evaluated in both mosquito strains. The median lethal concentration/median emergency inhibition values for Ae. aegypti and Ae. albopictus, respectively, were: temephos, 3.058 and 6.632 ppb, permethrin, 3.143 and 4.933 ppb, cis-permethrin, 4.457 and 10.068 ppb, trans-permethrin, 1.510 and 3.883 ppb, Bti, 0.655 and 0.880 ppb and pyriproxyfen, 0.00774 and 0.01642 ppb. Ae. albopictus was more tolerant than Ae. aegypti to all six larvicides evaluated. The order of susceptibility for Ae. aegypti was pyriproxyfen > Bti > trans-permethrin > temephos > permethrin > cis-permethrin and for Ae. albopictus was pyriproxyfen > Bti > trans-permethrin > permethrin > temephos > cis permethrin. Because both species can be found together in common urban, suburban and rural breeding sites, the results of this work provide baseline data on the susceptibility of Ae. albopictus to insecticides commonly used for controlling Ae. aegypti in the field. PMID- 22241123 TI - Laboratory and field evaluation of the effects of the neonicotinoid imidacloprid on the oviposition response of Aedes (Stegomyia) aegypti Linnaeus (Diptera: Culicidae). AB - In this paper, we assessed the suitability of using the neonicotinoid imidacloprid with standard ovitraps by evaluating the ovicidal properties of imidacloprid and its influence on the oviposition response of gravid females of Aedes (Stegomyia) aegypti Linnaeus (Diptera: Culicidae). First, we calculated the imidacloprid lethal dose 99 (LD(99)) by exposing third instar larvae of the target species to different concentrations of the insecticide. Next, Ae. aegypti eggs were exposed to the imidacloprid LD(99) for 24 h and hatching inhibition was recorded. Finally, we investigated any potential repellent effect of the imidacloprid solution on the oviposition response of gravid Aedes females in field and laboratory conditions. The LD(99) obtained from larvae tests proved to be sufficient to keep any exposed eggs from hatching. No repellent effect was observed; females laid as many eggs in imidacloprid-treated ovitraps as in traps containing either clean water or temephos-treated water in both field and laboratory conditions. Our results indicate that imidacloprid is a suitable insecticide for treating ovitraps against Ae. aegypti. PMID- 22241124 TI - The genetic diversity and phenotypic characterisation of Streptococcus agalactiae isolates from Rio de Janeiro, Brazil. AB - Streptococcus agalactiae isolates are more common among pregnant women, neonates and nonpregnant adults with underlying diseases compared to other demographic groups. In this study, we evaluate the genetic and phenotypic diversity in S. agalactiae strains from Rio de Janeiro (RJ) that were isolated from asymptomatic carriers. We analysed these S. agalactiae strains using pulsed-field gel electrophoresis (PFGE), serotyping and antimicrobial susceptibility testing, as well as by determining the macrolide resistance phenotype, and detecting the presence of the ermA/B, mefA/E and lnuB genes. The serotypes Ia, II, III and V were the most prevalent serotypes observed. The 60 strains analysed were susceptible to penicillin, vancomycin and levofloxacin. Resistance to clindamycin, chloramphenicol, erythromycin, rifampin and tetracycline was observed. Among the erythromycin and/or clindamycin resistant strains, the ermA, ermB and mefA/E genes were detected and the constitutive macrolides, lincosamides and streptogramin B-type resistance was the most prevalent phenotype observed. The lnuB gene was not detected in any of the strains studied. We found 56 PFGE electrophoretic profiles and only 22 of them were allocated in polymorphism patterns. This work presents data on the genetic diversity and prevalent capsular serotypes among RJ isolates. Approximately 85% of these strains came from pregnant women; therefore, these data may be helpful in developing future prophylaxis and treatment strategies for neonatal syndromes in RJ. PMID- 22241125 TI - Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients. AB - A high prevalence of occult hepatitis B (OHB) genotype H infections has been observed in the native Mexican Nahua population. In addition, a low incidence of hepatitis B virus (HBV)-associated hepatocellular carcinoma has been described in Mexico. The immune response to infection among OHB-infected patients has been poorly evaluated in vivo. Therefore, we assessed the expression profiles of 23 cytokines in OHB genotype H-infected Nahua patients. A total of 41 sera samples from natives of the Nahua community were retrospectively analysed. Based on their HBV antibody profiles, patients were stratified into two groups: OHB patients (n = 21) and patients that had recovered from HBV infection (n = 20). Herein, we report distinctive cytokines profiles in OHB-infected individuals. Compared to healthy controls (n = 20) and patients who resolved HBV infection, OHB-infected patients displayed an increase in interleukin (IL)-2 secretion in addition to a characteristic inflammation profile (decrease in IL-8 and tumour necrosis factor alpha levels and increased levels of tumour growth factor-beta). IL-15 and interferon-gamma levels were reduced in OHB-infected individuals when compared to those patients who resolved HBV infection. In contrast, OHB patients showed an increase in monocyte chemoattractant protein (MCP)-1 and MCP-2 compared to healthy controls and patients who resolved HBV infection. These findings suggest that cytokine expression can influence the severity of OHB disease and could lead to new investigation into the treatment of liver and other infectious diseases. PMID- 22241126 TI - Trypanosoma cruzi trypomastigotes induce cytoskeleton modifications during HeLa cell invasion. AB - It has been recently shown that Trypanosoma cruzi trypomastigotes subvert a constitutive membrane repair mechanism to invade HeLa cells. Using a membrane extraction protocol and high-resolution microscopy, the HeLa cytoskeleton and T. cruzi parasites were imaged during the invasion process after 15 min and 45 min. Parasites were initially found under cells and were later observed in the cytoplasm. At later stages, parasite-driven protrusions with parallel filaments were observed, with trypomastigotes at their tips. We conclude that T. cruzi trypomastigotes induce deformations of the cortical actin cytoskeleton shortly after invasion, leading to the formation of pseudopod-like structures. PMID- 22241127 TI - Molecular evidence for a single taxon, Anopheles nuneztovari s.l., from two endemic malaria regions in Colombia. AB - To elucidate the Anopheles nuneztovari s.l. taxonomic status at a microgeographic level in four malaria endemic localities from Antioquia and Cordoba, Colombia, fragments of the cytochrome oxidase subunit I (COI) and the white gene were used. The COI analysis showed low genetic differentiation with fixation index (F(ST)) levels between -0.02-0.137 and Nm values between 3-infinity, indicating the presence of high gene flow among An. nuneztovari s.l. populations from the four localities. The COI network showed a single most common haplotype, type 1 (n = 55), present in all localities, as the likely ancestral haplotype. Analysis of the white gene showed that An. nuneztovari s.l. populations from both departments grouped with haplotypes 19 and 20, which are part of lineage 3 reported previously. The results of the present study suggest that An. nuneztovari s.l. is a single taxon in the area of the present study. PMID- 22241128 TI - Anthropogenic influence on the distribution, abundance and diversity of sandfly species (Diptera: Phlebotominae: Psychodidae), vectors of cutaneous leishmaniasis in Panama. AB - In Panama, species of the genus Lutzomyia are vectors of American cutaneous leishmaniasis (ACL). There is no recent ecological information that may be used to develop tools for the control of this disease. Thus, the goal of this study was to determine the composition, distribution and diversity of Lutzomyia species that serve as vectors of ACL. Sandfly sampling was conducted in forests, fragmented forests and rural environments, in locations with records of ACL. Lutzomyia gomezi, Lutzomyia panamensis and Lutzomyia trapidoi were the most widely distributed and prevalent species. Analysis of each sampling point showed that the species abundance and diversity were greatest at points located in the fragmented forest landscape. However, when the samples were grouped according to the landscape characteristics of the locations, there was a greater diversity of species in the rural environment locations. The Kruskal Wallis analysis of species abundance found that Lu. gomezi and Lu. trapidoi were associated with fragmented environments, while Lu. panamensis, Lutzomyia olmeca bicolor and Lutzomyia ylephiletor were associated with forested environments. Therefore, we suggest that human activity influences the distribution, composition and diversity of the vector species responsible for leishmaniasis in Panama. PMID- 22241129 TI - Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs. AB - The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs) have shown anti leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (SigmaFICs) and the overall mean SigmaFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean SigmaFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean SigmaFIC and the isobologram graphic analysis. PMID- 22241130 TI - Distribution of phlebotomine fauna (Diptera: Psychodidae) across an urban-rural gradient in an area of endemic visceral leishmaniasis in northern Brazil. AB - The number of visceral leishmaniasis (VL) cases has increased over the past 10 years in Brazil, especially in the North and Northeast regions of the country. The aim of this study was to evaluate the urbanisation of VL vectors in Barcarena, Para, an area in northern Brazil where VL is endemic. Sandflies were captured using Centers for Disease Control (CDC) light traps along an urban-rural gradient. The CDC traps were installed inside hen houses at a height of 150 cm. A total of 5,089 sandflies were collected and 11 species were identified. The predominant species was Lutzomyia longipalpis (rate of 95.15%), which suggests its participation in the transmission of VL. A total of 1,451 Lu. longipalpis females were dissected and no Leishmania infections were detected. Most of the sandflies were captured at the border of a forest (88.25%) and no flies were captured in the urban area, which suggests that transmission is still restricted to rural sites. However, the fact that a specimen was collected in an intermediate area indicates that urbanisation is a real possibility and that vector monitoring is important. PMID- 22241131 TI - Cotrimoxazole enhances the in vitro susceptibility of Coccidioides posadasii to antifungals. AB - The aim of the present study was to evaluate the effect of cotrimoxazole on the in vitro susceptibility of Coccidioides posadasii strains to antifungals. A total of 18 strains of C. posadasii isolated in Brazil were evaluated in this study. The assays were performed in accordance with the Clinical and Laboratory Standards Institute guidelines and the combinations were tested using the checkerboard method. The minimum inhibitory concentrations were reduced by 11, 2.4, 4.3 and 3.5 times for amphotericin B, itraconazole, fluconazole and voriconazole, respectively. Moreover, it was seen that cotrimoxazole itself inhibited C. posadasii strains in vitro. The impairment of folic acid synthesis may be a potential antifungal target for C. posadasii. PMID- 22241132 TI - Report of Lutzomyia longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae: Phlebotominae) in a cutaneous-leishmaniasis-endemic area of Panama. AB - Lutzomyia longipalpis is the primary vector of the parasite responsible for visceral leishmaniasis in the Americas. In the present study, Lu. longipalpis was found in a domiciliary area in Limon, a district in Capira, a region in which cutaneous leishmaniasis is endemic in Panama. Previously, this species has been found in a humid forest in this same region. Finding Lu. longipalpis in domiciliary areas indicates that this species may be adapting to new habitats and that it may play a role in the transmission of leishmaniasis in Panama. PMID- 22241133 TI - Vaxcine(TM): an oil-based adjuvant for influenza vaccines. AB - Vaccination is the method of choice for the prevention of influenza infection. However, the quantity of the antigen available, especially in the case of pandemics, often fails to meet the global demand. However, improved adjuvants can overcome this problem. Preliminary results obtained in this study revealed that one year after a single subcutaneous immunisation with influenza A H3N2 virus in an oil-based carrier, Vaxcine(TM), outbreed mice produced a high immunoglobulin G response that lasted for up to one year and exhibited less variation in titre compared with the response of the control group treated with alum. The haemagglutination-inhibition titres induced by Vaxcine(TM) were also higher than those generated by alum. These data indicate that Vaxcine(TM) is a good adjuvant candidate for seasonal influenza vaccines. PMID- 22241134 TI - The activity of a metronidazole analogue and its beta-cyclodextrin complex against Trypanosoma cruzi. AB - In this study we prepared an inclusion complex between an iodide analogue of metronidazole (MTZ-I) and cyclodextrin (CD) to develop a safer and more effective method of treating Trypanosoma cruzi infections. According to our results, MTZ-I and MTZ-I:beta-CD were 10 times more active than MTZ, demonstrating that the presence of an iodine atom on the side chain increased the trypanocidal activity while maintaining its cytotoxicity. The selective index shows that MTZ-I was 10 times more active against T. cruzi than it was against mammalian cells. The modification of MTZ side chains provides a promising avenue for the development of new drugs. PMID- 22241136 TI - Home measurement of blood pressure and cardiovascular disease: systematic review and meta-analysis of prospective studies. AB - OBJECTIVE: Examine the relationship between home blood pressure (BP) and risk for all-cause mortality, cardiovascular mortality and cardiovascular events. METHODS: We conducted a systematic review and meta-analysis of prospective studies of home BP. Primary outcomes were all-cause mortality, cardiovascular mortality and cardiovascular events. We extracted hazard ratios and 95% confidence intervals (CIs) which were pooled with a random-effects model. Heterogeneity was assessed using the I statistic. RESULTS: We identified eight studies with 17 698 participants. Follow-up was 3.2-10.9 years. For all-cause mortality (n = 747) the hazard ratio for home BP was 1.14 (95% CI 1.01-1.29) per 10 mmHg increase in systolic BP compared to 1.07 (0.91-1.26) for office BP. For cardiovascular mortality (n = 193) the hazard ratio for home BP was 1.29 (1.02-1.64) per 10 mmHg increase in systolic BP compared to 1.15 (0.91-1.46) for office BP. For cardiovascular events (n = 699) the hazard ratio for home BP was 1.14 (1.09-1.20) per 10 mmHg increase in systolic BP compared to 1.10 (1.06-1.15) for office BP. In three studies which adjusted for office and home BP the hazard ratio was 1.20 (1.11-1.30) per 10 mmHg increase in systolic BP for home BP adjusted for office BP compared to 0.99 (0.93-1.07) per 10 mmHg increase in systolic BP for office BP adjusted for home BP. Diastolic results were similar. CONCLUSIONS: Home BP remained a significant predictor of cardiovascular mortality and cardiovascular events after adjusting for office BP suggesting it is an important prognostic variable over and above that of office BP. PMID- 22241135 TI - Recovery from water stress affects grape leaf petiole transcriptome. AB - Fast and efficient recovery from water stress is a key determinant of plant adaptation to changing meteorological conditions modulating transpiration, i.e. air temperature and humidity. We analysed transcriptomic responses during rehydration after water stress in grapevine leaf petioles, where embolism formation and repair commonly take place, and where metabolic changes related to embolism recovery are expected to be particularly important. We compared gene expression of recovering plants with irrigated controls, upon high and low transpiration conditions, using cDNA microarrays. In parallel, we assessed the daily dynamics of water relations, embolism formation and repair, and leaf abscisic acid concentration. In recovering plants, the most affected gene categories were secondary metabolism, including genes linked to flavonoid biosynthesis; sugar metabolism and transport, and several aquaporin genes. The physiological dynamics of recovery were lower and the number of differentially expressed probes was much lower upon low transpiration than found in actively transpiring grapevines, suggesting the existence of a more intense metabolic reorganization upon high transpiration conditions and of a signal eliciting these responses. In plants recovering under high transpiration, abscisic acid concentrations significantly increased, and, in parallel, transcripts linked to abscisic acid metabolism and signalling (ABA-8'-hydroxylase, serine-threonine kinases, RD22 proteins) were upregulated; a trend that was not observed upon low transpiration. Our results show that recovery from water stress elicits complex transcriptomic responses in grapevine. The increase observed in abscisic acid cellular levels could represent a signal triggering the activation of responses to rehydration after stress. PMID- 22241137 TI - Postsystolic strain index is associated with delayed diastolic lengthening and diastolic dysfunction of the left ventricle in untreated hypertension. AB - OBJECTIVE: Postsystolic shortening is associated with hypertensive heart disease, and the degree of postsystolic shortening can be measured by postsystolic strain index (PSI) of the left ventricle (LV) derived from speckle tracking echocardiography. We studied the association between PSI with delayed diastolic lengthening and diastolic dysfunction in hypertension. METHODS: This study recruited 46 patients (mean age 56 +/- 13 years, 24 men) with untreated hypertension, and 26 normal individuals (mean age 55 +/- 11 years, 9 men) as controls. Hypertension patients were further divided into two groups based on the presence of diastolic dysfunction. PSI was calculated as [(postsystolic peak longitudinal strain - end-systolic strain)/end-systolic strain] * 100%. Timing of left-ventricular diastolic lengthening was determined by measurements of time to onset of early diastolic mitral annulus lengthening by tissue Doppler imaging. RESULTS: Total PSI was significantly higher in patients with diastolic dysfunction (252 +/- 257 vs. 98 +/- 72%, P = 0.002). After multivariate analysis, PSI was independently associated with diastolic dysfunction in hypertension [every 10% increment of PSI, odds ratio (OR) 1.13, 95% confidence interval (CI) 1.01-1.27, P = 0.036]. PSI was independently correlated with serum procollagen type I carboxyterminal propeptide (beta = 0.382, P = 0.028) after multivariable analysis, and time delay from onset of early mitral inflow to onset of early diastolic medial (beta = 0.405, P = 0.004) or lateral (beta = 0.582, P < 0.001) annulus lengthening. CONCLUSIONS: Increased PSI was associated with increased procollagen type I carboxyterminal propeptide and diastolic dysfunction in hypertension. Postsystolic shortening was associated with delayed diastolic lengthening which contributed to diastolic dysfunction in hypertension. PMID- 22241138 TI - Can ambulatory blood pressure measurements substitute assessment of subclinical cardiovascular damage? AB - OBJECTIVE: We have previously demonstrated that markers of subclinical organ damage (SOD) improve cardiovascular risk prediction in healthy individuals. We wanted to investigate whether this additive effect of SOD was due to inaccurate blood pressure (BP) measurement or whether ambulatory BP (AMBP) added further to risk prediction. METHODS: In a population cohort of 1385 Danish individuals free of cardiovascular disease and diabetes, we recorded traditional risk factors, AMBP and pulse wave velocity (PWV), urine albumin/creatinine ratio (UACR), left ventricular mass index (LVMI) and carotid atherosclerotic plaques at baseline. A composite cardiovascular endpoint (CEP) consisting of cardiovascular death and nonfatal myocardial infarction and stroke was recorded in national registries. RESULTS: During a median follow-up of 12.8 years, a total of 119 CEPs occurred. In categorical analysis, presence of SOD as well as masked hypertension increased sensitivity of Systemic Coronary Risk Estimation from 73.9 to 89.1% (P < 0.001) and reduced specificity from 60.1 to 41.8% (P < 0.001). In continuous analysis, logUACR [hazard ratio = 1.20 (95% confidence interval [CI] 1.05-1.38), P = 0.009], atherosclerotic plaques [hazard ratio = 1.82 (95% CI 1.21-2.74), P = 0.004] and 24-h SBP [hazard ratio = 1.34 (95% CI 1.12-1.60), P = 0.002] but not logPWV or LVMI predicted CEP in a model with adjustments for age, sex, conventional BP, total cholesterol and smoking. Compared with a risk model using only traditional risk factors, adding PWV, UACR, plaques, LVMI and 24-h SBP increased C-index significantly from 0.76 to 0.79% and produced a net reclassification improvement of 23.3% (P = 0.001). CONCLUSION: UACR and plaques predicted cardiovascular events independently of AMBP and improved risk prediction. PMID- 22241139 TI - Renal artery diameter, renal function and resistant hypertension in patients with low-to-moderate renal artery stenosis. AB - BACKGROUND: Atherosclerotic renovascular disease is associated with resistant hypertension and chronic kidney disease, although the causal relationship is discussed. To date, the role of renal artery diameter on these pathological conditions was not clearly studied. We aimed to identify the association of reference diameter and minimal luminal renal artery diameter with glomerular filtration rate (GFR) and resistant hypertension in a high cardiovascular risk population. METHODS: In this cross-sectional, single-center study, we enrolled 734 patients who underwent a renal angiography immediately after a coronary angiography indicated for a diagnosis of ischemic heart disease. RESULTS: Mean age was 64 +/- 10 years (men 72%). GFR was 79 +/- 22 ml/min per 1.73 m(2). Five hundred and eighteen patients had no luminal narrowing and 216 patients had low to-moderate luminal narrowing (10-70%, mean 36%). A positive significant association between reference diameter and GFR was detected in patients without luminal narrowing [beta 2.2 ml/min per 1.73 m(2) for 1 mm increase, 95% confidence interval (CI) 0.3-4.0, P < 0.05] and in those with low-to-moderate luminal narrowing (beta 7.7 ml/min per 1.73 m(2) for 1 mm increase, 95% CI 4.2 11.1, P < 0.001). The lowest quartile of reference diameter (<5.2 mm) was associated with GFR less than 60 ml/min per 1.73 m(2) [odds ratio (OR) 3.18, 95% CI 1.61-6.29, P < 0.001]. Patients with resistant hypertension had low minimal diameter and reference diameter. Reference diameter less than 5.2 mm was associated with an increased risk of resistant hypertension (OR 2.63, 95% CI 1.02 6.77, P < 0.05). CONCLUSIONS: Small renal arteries, defined by a low reference diameter or minimal luminal diameter, are independently associated with low GFR and resistant hypertension, independent of the degree of stenosis and major confounders. PMID- 22241140 TI - Sex difference of the prevalence and risk factors associated with prehypertension among urban Chinese adults from 33 communities of China: the CHPSNE study. AB - BACKGROUND: As a new category of blood pressure (BP) classification according to the Seventh Report of The Joint National Committee, prehypertension has aroused people's great concern in recent years due to its associations with increased incidence of cardiovascular disease. However, there is little information about the epidemiology of prehypertension in urban China. The aim of this study is to estimate the prevalence of prehypertension and to identify its risk factors among urban Chinese men and women. METHODS: A cross-sectional survey in a representative sample of 25 196 Chinese adults aged 18-74 years was conducted in three cities of northeast of China during 2009 and 2010. Body weight, height, waist circumference, and BP were measured by trained observers. RESULTS: Overall, the prevalence of prehypertension was 56.9%, men 71.1% and women 44.6%, respectively. Multivariate analysis revealed that higher education or a higher family income were risk factors of prehypertension among men, but shown as protective factors among women. Among men, high odds ratios (ORs) of prehypertension were found in overweight [OR 2.31; 95% confidence interval (CI) 2.02-2.71] and obese (OR 7.92, 95% CI 4.36-14.42) adults (defined as body mass index), whereas abdominal obesity (OR 2.94, 95% CI 2.48-3.57) (defined as waist circumference) was the main determinant for prehypertension status in women. CONCLUSION: Our results indicate that hypertension is highly prevalent in urban China and there is a sex difference in the relationships between risk factors and prehypertension. PMID- 22241141 TI - Orthostatic blood pressure response, carotid intima-media thickness, and plasma fibrinogen in older nondiabetic adults. AB - OBJECTIVE: Although recent studies have indicated that both orthostatic hypotension and orthostatic hypertension (OHTN) independently predict cardiovascular events, the underlying mechanisms are still debatable. METHODS: A total of 700 nondiabetic adults (43% men, age 64 years) were examined by orthostatic blood pressure (BP) test, carotid artery ultrasonography, and biochemical tests including plasma fibrinogen and lipid profile. Multivariate adjusted logistic regression was applied to assess association of intima-media thickness (IMT) and P-fibrinogen with orthostatic hypotension and OHTN. In addition, distribution of IMT and P-fibrinogen across quintiles of orthostatic systolic BP (SBP) response was analyzed. RESULTS: Orthostatic hypotension and OHTN were found in 40 (5.7%) and 45 (6.4%) study participants, respectively. Both IMT [odds ratio (OR), 95% confidence interval (CI) per one-SD increment: 1.27, 1.01-1.60; P = 0.04] and P-fibrinogen (OR 1.44, 1.07-1.93; P = 0.02) were associated with orthostatic hypotension in a crude model. After adjustment relationship between orthostatic hypotension and IMT was slightly attenuated (OR 1.26, 0.96-1.65; P = 0.09) but was substantially unchanged in regard to P fibrinogen (OR 1.45, 1.06-1.99; P = 0.02). In contrast, OHTN showed no association with either IMT or P-fibrinogen (adjusted OR 1.09, 0.78-1.52; P = 0.61, and 0.97, 0.70-1.34; P = 0.84, respectively). Distribution of IMT across quintiles of orthostatic SBP response was U-shaped, whereas that of fibrinogen was more linear but none of borderline quintiles (with pronounced hypertensive or hypotensive response) significantly differed from the middle quintiles in a fully adjusted model. CONCLUSION: In older nondiabetic adults only orthostatic hypotension seems to independently correlate with increased carotid atherosclerosis and systemic inflammation. PMID- 22241142 TI - Ambulatory arterial stiffness index does not accurately assess arterial stiffness. AB - INTRODUCTION: The ambulatory arterial stiffness index (AASI), derived from ambulatory blood pressure monitoring (ABPM) recordings, has been proposed as a surrogate marker of arterial stiffness. However, there is controversy to what extent it reflects stiffness or is affected by other parameters. Using a previously validated one-dimensional computer model of the arterial circulation, the relative importance of the different determinants of the AASI was explored. METHODS: Arterial distensibility (inverse of stiffness), peripheral resistance, heart rate, maximal cardiac elastance and venous filling pressure were varied from 80 to 120% of their initial value in steps of 10% to generate 3125 BP values, mimicking the daily fluctuations in one theoretical patient. From this dataset, we assessed the confidence with which AASI can be derived in this patient, as well as the influence of different individual parameters on AASI. To assess the ability of AASI to detect large changes in arterial stiffness, two additional patients were simulated with a distensibility of 50 and 25% of the default distensibility, respectively. RESULTS: The distribution of AASI values, obtained from 10 000 ABPM simulations (each using 72 BP values randomly selected among 3125) was normal [AASI = 0.43 +/- 0.04 (SD)]. An increase in heart rate, distensibility or resistance from 80 to 120% of its default value caused the AASI to decrease by 37, 21 or 9%, respectively. Whereas there was no overlap in the distensibility ranges for the three theoretical patients, the amount of overlap between the AASI distributions was substantial. CONCLUSION: The confounding effects of vascular resistance and heart rate seriously limit the use of AASI as a marker of stiffness. PMID- 22241143 TI - Requirements for professional office blood pressure monitors. AB - For more than half a century measurement of blood pressure in the doctor's office using a mercury sphygmomanometer and the auscultatory method has been the cornerstone for hypertension management. However, due to the environmental and service issues mercury devices will not be available in the near future. As the mercury sphygmomanometer is being progressively eliminated from clinical use, it is being replaced by a variety of devices, which may not have been validated. This change in the practice of measurement may have an unpredictable impact on the threshold levels used for the diagnosis of hypertension and may also influence the management of hypertension. This expert document provides (i) information on the current availability of technologies and devices with potential for professional use (oscillometric, hybrid, aneroid and mercury devices) and the advantages and limitations of each one of them, and (ii) guidance on the requirements and selection of mercury-free blood pressure monitors for professional use. With the increasing use of automated oscillometric devices it is likely that the auscultatory technique will soon become redundant. However, consideration will be given to some of the technical aspects of the oscillometric technique and to the educational aspects of auscultation that may make it premature to abandon the technique altogether. PMID- 22241144 TI - Peripheral chemoreflex activation contributes to sympathetic baroreflex impairment in chronic heart failure. AB - BACKGROUND: Chemoreflex-mediated sympathetic activation contributes to both initiation and progression of chronic heart failure (CHF). METHOD: To study the direct role of increased peripheral chemosensitivity in reducing sympathetic baroreflex function in CHF patients, we compared sympathetic baroreflex function, assessed by the slope of the relationship between muscle sympathetic nerve activity (MSNA) and DBP, in CHF patients with augmented (n = 18) and normal (n = 20) peripheral chemosensitivity. Using a double-blind, randomized, vehicle controlled study, we examined the effect of chemoreflex deactivation (by breathing 100% oxygen for 15 min) on sympathetic baroreflex function in CHF patients with elevated and with normal chemosensitivity. RESULTS: Baseline MSNA was elevated (60.6 +/- 3.2 vs. 48.9 +/- 3.7 bursts/min, P < 0.05) and sympathetic baroreflex function impaired (3.06 +/- 0.55 vs. 5.51 +/- 0.69 % bursts/mmHg, P < 0.05) in CHF patients with augmented peripheral chemosensitivity compared with controls. Administration of 100% oxygen led to a significant decrease in MSNA (from 60.5 +/- 3.2 to 52.6 +/- 3.2 bursts/min, P < 0.001) and increase in sympathetic baroreflex (from 2.95 +/- 0.56 to 6.18 +/- 0.77, P < 0.001) in CHF patients with enhanced chemoreflex sensitivity. In contrast, neither room air nor 100% oxygen changed MSNA, hemodynamics or sympathetic baroreflex function in CHF patients with normal chemosensitivity. CONCLUSION: We report for the first time that increased peripheral chemoreflex sensitivity directly decreases sympathetic baroreflex function in CHF patients. This interaction contributes to sympathetic overactivity and blunted sympathetic baroreflex function of CHF patients and may explain how chemoreceptors contribute to the bad prognosis of CHF patients. PMID- 22241145 TI - Evaluation of 2 self-report measures of physical activity with accelerometry in young adults. AB - BACKGROUND: The purpose of this paper is to evaluate self-reported physical activity of young adults using 1-week and 1-year recall measures with an accelerometer as the criterion measure. METHODS: Participants were a subsample (N = 121, 24 +/- 1.7 yrs) from a large longitudinal cohort study. Participants completed a detailed 1-year physical activity recall, wore an accelerometer for 1 week and then completed a brief 1-week physical activity recall when they returned the accelerometer. RESULTS: Mean values for moderate-to-vigorous physical activity (MVPA) from the 3 instruments were 3.2, 2.2, and 13.7 hours/wk for the accelerometer, 1-week recall, and 1-year recall, respectively (all different from each other, P < .001). Spearman correlations for moderate, vigorous, and MVPA between the accelerometer and the 1-week recall (0.30, 0.50, and 0.40, respectively) and the 1-year recall (0.31, 0.42, and 0.44, respectively) demonstrated adequate validity. CONCLUSIONS: Both recall instruments may be used for ranking physical activity at the group level. At the individual level, the 1-week recall performed much better in terms of absolute value of physical activity. The 1-year recall overestimated total physical activity but additional research is needed to fully test its validity. PMID- 22241149 TI - A new strategy for chiral recognition of amino acids. AB - A new strategy is established for detecting chiral amino acids based on the electron transfer from hemoglobin Fe(II) to Cu(II) in copper complexes of the amino acids. The sensor shows a highly selective recognition of arginine enantiomers. PMID- 22241150 TI - Ubiquitous Brms1 expression is critical for mammary carcinoma metastasis suppression via promotion of apoptosis. AB - Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells are able to spread to distant sites and proliferate to become secondary lesions. Effective treatment of metastatic disease has been limited; therefore, an increased molecular understanding to identify biomarkers and therapeutic targets is needed. Breast cancer metastasis suppressor 1 (BRMS1) suppresses development of pulmonary metastases when expressed in a variety of cancer types, including metastatic mammary carcinoma. Little is known of Brms1 function throughout the initiation and progression of mammary carcinoma. The goal of this study was to investigate mechanisms of Brms1-mediated metastasis suppression in transgenic mice that express Brms1 using polyoma middle T oncogene induced models. Brms1 expression did not significantly alter growth of the primary tumors. When expressed ubiquitously using a beta-actin promoter, Brms1 suppressed pulmonary metastasis and promoted apoptosis of tumor cells located in the lungs but not in the mammary glands. Surprisingly, selective expression of Brms1 in the mammary gland using the MMTV promoter did not significantly block metastasis nor did it promote apoptosis in the mammary glands or lung, despite MMTV-induced expression within the lungs. These results strongly suggest that cell type-specific over-expression of Brms1 is important for Brms1-mediated metastasis suppression. PMID- 22241151 TI - Elevated incidence of sleep apnoea in acromegaly-correlation to disease activity. AB - PURPOSE: An elevated prevalence of sleep apnoea (SA) in patients with acromegaly has been suggested. METHODS: We performed polysomnographies in 52 patients with acromegaly (25 m, 27 f, age 51 years, range 19-82 years). Patients were defined having SA if they had more than five apnoeas or hypopnoeas per hour (respiratory disturbance index = RDI). The type of SA was divided into obstructive (OSA), central (CSA) or mixed (OSA+CSA). Seventeen patients had newly diagnosed disease, and 18 patients were treated with somatostatin analogues. RESULTS: Twenty-three patients had controlled disease activity (mean GH levels <1 MUg/l during a 3-h profile and normalised IGF-1 levels). Twelve had active acromegaly despite medical treatment. Thirty patients (58%) had SA. Twenty-five of those had OSA, three had CSA, and two had mixed. Of the patients with active disease, 66% had SA, compared to 48% in the cured group. Significantly more patients with hypertension (n = 18) than without hypertension (n = 12, p = 0.041) had SA. Basal glucose was not significantly different between patients with (100 mg/dl, range 75-207 mg/dl) and without SA (92 mg/dl, range 74-120 mg/dl), but HbA1c was significantly higher in patients with SA (5.9% (4.9-9.0%) vs. 5.4% (4.3-6.1%), p = 0.001). A positive correlation between RDI and BMI (p = 0.04), RDI and age (p = 0.013) and RDI and disease activity (p = 0.014) was seen. No major correlation could be found between RDI and the duration of disease activity nor between RDI and GH levels. CONCLUSION: RDI correlates positively with disease activity but not with the duration of the disease. The parameters of the metabolic syndrome are positively associated to the degree of SA in acromegalic patients. PMID- 22241152 TI - [Prognosis of 75 patients with juvenile myelomonocytic leukemia: prospective study by MDS committee in the Japanese Society of Pediatric Hematology]. AB - Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic/myeloproliferative disorder of young children. Because the disease is rare and the diagnosis is difficult, a prospective registration of patients suspected of having JMML with a pathological central review have been conducted by the MDS Committee of the Japanese Society of Pediatric Hematology. Between 1999 and 2006, 75 children with JMML were enrolled and diagnosed through this system. Median age at diagnosis was 20 months (1~85 months). Cytogenetic abnormalities were detected in 21 patients, including 11 with monosomy 7. The 5-year overall survival (OS) was 60%. Regarding the treatment, 61 of the 75 patients received stem cell transplantation (SCT). Conditioning regimen varied widely, and the source of grafts was bone marrow for 43 patients, peripheral blood for 5, and cord blood for 13. The 5-year OS after SCT was 61%. Notably, patients who received cord blood transplantation had inferior survival than those who received grafts from other sources (38 vs. 68%; P=0.03). Given better recognition of the disease, a multi-center protocol study on SCT, JMML11, is now being planned by the Japanese Pediatric Leukemia/Lymphoma Study Group. PMID- 22241153 TI - [Lung injury associated with bortezomib therapy in Japan]. AB - Bortezomib (Velcade((r))), a proteasome inhibitor, was launched for the treatment of relapsed or refractory multiple myeloma in Japan in December 2006. Prior to approval in Japan, high incidence (15.2%) and mortality (6.5%) of bortezomib therapy-related lung disorders were reported with private import treatment. Therefore the Velcade Lung Disorder Panel (the Panel) was established and the cases have been reviewed. A total of 3,556 patients, including 823 post-marketing surveillance (PMS) patients, have received bortezomib since April 25, 2009. The incidence of lung disorders associated with bortezomib therapy was 2.33% (3.77% in case of PMS). The panel reviewed the detailed information of 70 cases and classified the CT and X-ray images as follows: (1)Interstitial pneumonia; diffuse alveolar damage pattern, hypersensitivity pneumonia pattern and others (2)Vascular hyperpermiability; (non-cardiogenic) pulmonary edema pattern and capillary leak syndrome-like pattern (3)Hypoxia. These post-marketing data showed that the incidence of lung disorders in Japan was lower than expected based on private import data. PMID- 22241154 TI - [Acute monoblastic leukemia following granular lymphocyte proliferative disorder]. AB - Granular lymphocyte proliferative disorder (GLPD) is often concomitant with a malignant tumor. We report a patient who developed acute monoblastic leukemia (AMoL) following GLPD. An 82-year-old Japanese man was admitted to our hospital for anemia in December 2006. The patient was diagnosed as having GLPD. In May 2007, the lymphadenopathy developed and the blasts in peripheral blood started to increase. The monoclonal rearrangement of T-cell receptor genes was not detected on Southern blot analysis. Surface marker analysis revealed that the blasts were positive for CD13 and CD64. The level of lysozyme in serum and urine were increased. Based on these findings, he was diagnosed with AMoL. The immunohistochemistry of the bone marrow clot specimen in the diagnosis of GLPD revealed the concomitant presence of a few small clusters of CD34+ cells. This finding suggests that the granular lymphocytes responded to the early stage of AMoL. We should monitor carefully the development of acute myeloid leukemia in newly diagnosed GLPD patients. PMID- 22241155 TI - [Sustained complete remission of intravascular large B-cell lymphoma with recurrent CNS involvement by autologous peripheral blood stem cell transplantation preconditioned with TBC regimen]. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal large B-cell lymphoma characterized by the growth of lymphoma cells only within the lumina of small vessels in various organs. IVLBCL is an intractable hematological disease, in particular, the high incidence of central nervous system (CNS) involvement is one of the causes of the poor prognosis of IVLBCL. Autologous stem cell transplantation (ASCT) is an effective therapeutic option for refractory or high-risk aggressive lymphoma. However, it is unknown whether ASCT is an effective treatment for CNS involvement of aggressive lymphoma including IVLBCL. We show a case of a 39-year-old woman with recurrent CNS involvement of IVLBCL receiving autologous peripheral blood stem cell transplantation (auto-PBSCT) preconditioned with high-dose thiotepa, busulfan, cyclophosphamide (TBC regimen). Culture-negative febrile neutropenia developed requiring antimicrobial therapy, but nonhematological adverse effects including stomatitis and neurotoxicity, with grade >= 3, were not observed. The patient achieved and has maintained complete remission (CR) for 24 months after TBC/auto PBSCT and has survived for around 30 months from the diagnosis of the CNS recurrence. The clinical course of this case suggests that auto-PBSCT preconditioned with TBC could be one of the therapeutic options for the treatment of CNS involvement of IVLBCL. PMID- 22241156 TI - [Bilateral renal infiltration of acute lymphoblastic leukemia cells at relapse after allogeneic stem cell transplantation]. AB - A 44-year-old male patient was diagnosed with acute lymphoblastic leukemia (CD10+, CD19+, CD20 weak) and underwent unrelated bone marrow transplantation (uBMT) with a conditioning regimen of cyclophosphamide plus total body irradiation during first complete remission (CR). Twenty months post-uBMT, the serum creatinine level (Cre) increased gradually, up to >= 1.5 mg/dl at 23 months. Since the increase in Cre was observed continuously, imaging examinations were performed and showed significant bilateral enlargement of the kidneys. Renal biopsy showed diffuse invasion of TdT, CD10 and CD19 positive lymphoid cells in the tubulo-interstitial region. Since leukemia cells were observed in the bone marrow, it was diagnosed as relapse in the bone marrow and kidney. Following reinduction chemotherapy, both kidneys returned to normal size. The patient entered into a second CR, but relapse occurred 6 months thereafter. The patient underwent uBMT again with a reduced-intensity conditioning regimen and CR has been maintained up to 5 months post-second uBMT. Although it is considered rare for relapse to occur with diffuse enlargement of both kidneys, as shown in this case, it is important to confirm the state of the kidney by performing blood tests and image diagnosis during the early phase, when renal dysfunction of an uncertain cause occurs after transplantation. PMID- 22241157 TI - [Systemic amyloidosis associated with IgD-lambda multiple myeloma]. AB - We describe here a case of systemic amyloidosis associated with IgD multiple myeloma. A 59-year-old man was admitted to our hospital in April 2009, because of macroglossia and swelling in both wrists and fingers. He had difficulty moving his limbs and was aware of peripheral neuropathy. Skin biopsy revealed extensive deposition of amyloidosis, which was positive by Congo red staining. Laboratory findings were as follows: serum electrophoresis revealed IgD lambda monoclonal protein, and Bence-Jones protein was detected. Monoclonal IgD protein had a concentration of 727 mg/dl, and a bone marrow aspiration revealed 49.6% of plasma cells. These findings led to a diagnosis of IgD multiple myeloma with systemic amyloidosis. The patient was treated with MP (melphalan and methylprednisolone), high-dose dexamethasone and VAD therapy (vincristine, adriamycin and dexamethasone), but systemic amyloidosis progressed, and his general condition deteriorated. Coexistence of IgD multiple myeloma and systemic amyloidosis is rare, and accumulation of case reports is needed to gain a better understanding of this condition. PMID- 22241158 TI - [Acute myeloid leukemia with t(16;21)(q24;q22) in a child]. AB - The t(16;21)(q24;q22), a rare chromosomal translocation observed mostly in therapy-related acute myelogenous leukemia (AML), produces a RUNX1-CBFA2T3 fusion gene. Here we report a de novo AML case of 1-year-old girl with t(16;21)(q24;q22). In this case, we demonstrated the RUNX1-CBFA2T3 fusion gene and established quantitative RT-PCR for detecting minimal residual disease. PMID- 22241159 TI - [Cardiogenic shock due to takotsubo cardiomyopathy during induction therapy for acute myeloid leukemia]. AB - A 61-year-old man admitted for pancytopenia was diagnosed with acute myeloid leukemia. On day 26 of induction therapy, the patient suddenly developed cardiogenic shock. The ultrasound cardiogram showed imaging features typical of takotsubo cardiomyopathy. Cardiogenic shock caused by takotsubo cardiomyopathy is rare in patients with hematological malignancies but is a severe complication during chemotherapy. PMID- 22241160 TI - Influence of hydrogen bonding on excitonic coupling and hierarchal structure of a light-harvesting porphyrin aggregate. AB - Helical porphyrin nanotubes of tetrakis(4-sulfonatophenyl)porphyrin (TSPP) were examined in DCl/D(2)O solution using resonance Raman and resonance light scattering spectroscopy to probe the influence of hydrogen bonding on the excitonic states. Atomic force microscopy reveals similar morphology for aggregates deposited from DCl/D(2)O and from HCl/H(2)O solution. Deuteration results in subtle changes to the aggregate absorption spectrum but large changes in the relative intensities of Raman modes in the J-band excited resonance Raman spectra, revealing relatively more reorganization along lower-frequency vibrational modes in the protiated aggregate. Depolarization ratio dispersion and changes in the relative Raman intensities for excitation wavelengths spanning the J-band demonstrate interference from overlapping excitonic transitions. Distinctly different Raman excitation profiles for the protiated and deuterated aggregates reveal that isotopic substitution influences the excitonic structure of the J-band. The deuterated aggregate exhibits a nearly two-fold increase in intensity of resonance light scattering as a result of an increase in the coherence number, attributed to decreased exciton-phonon scattering. We propose that strongly coupled cyclic N-mers, roughly independent of isotopic substitution, largely decide the optical absorption spectrum, while water mediated hydrogen bonding influences the further coherent coupling among them when they are assembled into nanotubes. The results show that, similar to natural light-harvesting complexes such as chlorosomes, hydrogen bonding can have a critical influence on exciton dynamics. PMID- 22241161 TI - One-pot synthesis of conducting graphene-polymer composites and their strain sensing application. AB - In situ reduction of graphite oxide in polymer powder has been implemented using focused solar electromagnetic radiation. The simultaneous reduction of graphite oxide, melting of the polymer and embedding of reduced graphite oxide nanoflakes in polymer offer a new way of synthesizing conducting graphene/polymer composites. An electromechanical application of the present reduced graphite oxide-PVDF nanocomposite has been proposed with a gauge factor of 12.1. PMID- 22241162 TI - HIV treatment as prevention: [corrected] next steps. PMID- 22241164 TI - P50 suppression and its neural generators in antipsychotic-naive first-episode schizophrenia before and after 6 months of quetiapine treatment. AB - BACKGROUND: Numerous studies have demonstrated sensory gating deficits in schizophrenia. However, only a few longitudinal studies report on the effects of antipsychotic treatment on sensory gating deficits and their results are inconsistent. In the present study, P50 suppression and its neural generators were investigated in antipsychotic-naive first-episode patients with schizophrenia before and after 6 months of treatment with quetiapine. METHODS: Thirty-four antipsychotic-naive first-episode schizophrenia patients and age and gender matched healthy controls were tested in an auditory sensory gating paradigm at baseline and after 6 months. During this period, the patients were treated with quetiapine, while controls received no treatment. Sixteen patients completed the study. RESULTS: Patients showed significant reduced P50 suppression compared with controls at baseline but not at follow-up. Furthermore, a significant positive correlation between baseline P50 suppression and dose of quetiapine at follow-up was found. P50 suppression in patients receiving above median dosages of quetiapine increased significantly from baseline to follow-up. At baseline, a frontocentral source was significantly more active in patients than in controls at the time of the testing stimulus. CONCLUSIONS: The present findings suggest that P50 suppression deficits are already present at an early stage of schizophrenia. Furthermore, particularly those patients with more severe gating deficits appeared to need higher dosages of quetiapine, although their clinical symptoms did not seem to indicate this. Quetiapine treatment significantly improved these gating deficits. Furthermore, a frontocentral source in the brain appeared to be involved in the deficient P50 gating of the patients. PMID- 22241163 TI - Double-negative T cells during HIV/SIV infections: potential pinch hitters in the T-cell lineup. AB - PURPOSE OF REVIEW: This review summarizes the role of CD3+CD4-CD8- double negative T cells, which have both regulatory and helper T-cell functions and may have the potential to compensate for the reduced levels of CD4 T cells during SIV/HIV infection. RECENT FINDINGS: Double-negative T cells have been characterized in several human diseases and in murine models of autoimmunity and transplantation, where they exhibit both immunoregulatory and helper T-cell-like function. During the natural nonpathogenic SIV infection of African nonhuman primates, the lack of clinical disease progression is associated with the presence of double-negative T cells that maintain helper T-cell functions while remaining refractory to viral infection. Moreover, DN T cells may compensate for very low levels of CD4+ T cells observed in a cohort of SIV-infected sooty mangabeys that have remained free of clinical AIDS for over 10 years. These studies identify a potential for double-negative T cells to provide critical helper function during HIV infection. SUMMARY: Double-negative T cells with some CD4+ T-cell functions are associated with a nonpathogenic outcome during SIV infection and represent a potential immune therapeutic target in HIV-infected patients. PMID- 22241165 TI - Increased intrinsic brain activity in the striatum reflects symptom dimensions in schizophrenia. AB - Striatal dysfunction is thought to be a fundamental element in schizophrenia. Striatal dopamine dysfunction impacts on reward processing and learning and is present even at rest. Here, we addressed the question whether and how spontaneous neuronal activity in the striatum is altered in schizophrenia. We therefore assessed intrinsic striatal activity and its relation with disorder states and symptom dimensions in patients with schizophrenia. We performed resting-state functional (rs-fMRI) and structural magnetic resonance imaging as well as psychometric assessment in 21 schizophrenic patients during psychosis. On average 9 months later, we acquired follow-up data during psychotic remission and with comparable levels of antipsychotic medication. Twenty-one age- and sex-matched healthy controls were included in the study. Independent component analysis of fMRI data yielded spatial maps and time-courses of coherent ongoing blood-oxygen level-dependent signal fluctuations, which were used for group comparisons and correlation analyses with scores of the positive and negative syndrome scale. During psychosis, coherent intrinsic activity of the striatum was increased in the dorsal part and correlated with positive symptoms such as delusion and hallucination. In psychotic remission of the same patients, activity of the ventral striatum was increased and correlated with negative symptoms such as emotional withdrawal and blunted affect. Results were controlled for volumetric and medication effects. These data provide first evidence that in schizophrenia intrinsic activity is changed in the striatum and corresponds to disorder states and symptom dimensions. PMID- 22241166 TI - Regulation of beta-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin. AB - AIMS: Clinical markers of cardiac autonomic function, such as heart rate and response to exercise, are important predictors of cardiovascular risk. Tetrahydrobiopterin (BH4) is a required cofactor for enzymes with roles in cardiac autonomic function, including tyrosine hydroxylase and nitric oxide synthase. Synthesis of BH4 is regulated by GTP cyclohydrolase I (GTPCH), encoded by GCH1. Recent clinical studies report associations between GCH1 variants and increased heart rate, but the mechanistic importance of GCH1 and BH4 in autonomic function remains unclear. We investigate the effect of BH4 deficiency on the autonomic regulation of heart rate in the hph-1 mouse model of BH4 deficiency. METHODS AND RESULTS: In the hph-1 mouse, reduced cardiac GCH1 expression, GTPCH enzymatic activity, and BH4 were associated with increased resting heart rate; blood pressure was not different. Exercise training decreased resting heart rate, but hph-1 mice retained a relative tachycardia. Vagal nerve stimulation in vitro induced bradycardia equally in hph-1 and wild-type mice both before and after exercise training. Direct atrial responses to carbamylcholine were equal. In contrast, propranolol treatment normalized the resting tachycardia in vivo. Stellate ganglion stimulation and isoproterenol but not forskolin application in vitro induced a greater tachycardic response in hph-1 mice. beta1-adrenoceptor protein was increased as was the cAMP response to isoproterenol stimulation. CONCLUSION: Reduced GCH1 expression and BH4 deficiency cause tachycardia through enhanced beta-adrenergic sensitivity, with no effect on vagal function. GCH1 expression and BH4 are novel determinants of cardiac autonomic regulation that may have important roles in cardiovascular pathophysiology. PMID- 22241167 TI - Is expertise in pediatric surgery necessary to perform laparoscopic splenectomy in children? An experience from a department of general surgery. AB - Splenectomy is frequently required in children for various hematologic pathologic findings. Because of progress in minimally invasive techniques, laparoscopic splenectomy (LS) has become feasible. The objective of this report is to present a monocentric experience and to evaluate the efficacy of and complications observed after laparoscopic splenic procedures in a department of general surgery. 57 consecutive LSs have been performed in a pediatric population between January 2000 and October 2010. There were 33 females and 24 males with a median age of 12 years (range 4-17). Indications were: hereditary spherocytosis 38 cases, idiopathic thrombocytopenic purpura 10, sickle cell disease (SCD) 6, thrombocytopenic thrombotic purpura 2 and non-hodgkin lymphoma 1 case. Patients were operated on using right semilateral position, employing Atlas Ligasure vessel sealing system in 49 cases (86%) and Harmonic Scalpel + EndoGIA in 8. In 24 patients (42.1%), a cholecystectomy was associated. Two patients required conversion to open splenectomy (3.5%). In three cases, a minilaparotomy was performed for spleen removal (5.2%). Accessory spleens were identified in three patients (5.2%). Complications (8.8%) included bleeding (two), abdominal collection (one) and pleural effusion (two). There was no mortality. Average operative time was 128 min (range 80-220). Average length of stay was 3 days (range 2-7). Mean blood loss was 80 ml (range 30-500) with a transfusion rate of 1.7% (one patient). Laparoscopic spleen surgery is safe, reliable and effective in the pediatric population with hematologic disorders and is associated with minimal morbidity, zero mortality, and a short length of stay. Ligasure vessel sealing system shortened operative time and blood loss. On the basis of the results, we consider laparoscopic approach the gold standard for the treatment of these patients even in a department of general surgery. PMID- 22241169 TI - Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies. AB - Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) 2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours. PMID- 22241168 TI - Chylothorax complicating thoracic surgery: conservative or early surgical management? AB - Postoperative chylothorax is a rare complication in thoracic surgery. There is considerable controversy concerning the management of chylothorax with some physicians favoring conservative treatment while others favor a surgical one. Considering the current surgical experience with VATS and by reviewing the problems and outcome of conservative management, the guidelines regarding timing of surgery in patients with chylous leak need to be revised. PMID- 22241171 TI - Cell-penetrating properties of the transactivator of transcription and polyarginine (R9) peptides, their conjugative effect on nanoparticles and the prospect of conjugation with arsenic trioxide. AB - Cell-penetrating peptides (CPPs) are short chains of amino acids with the distinct ability to cross cell plasma membranes. They are usually between seven and 30 residues in length. The mechanism of action is still a highly debated subject among researchers; it seems that a commonality between all CPPs is the presence of positively charged residues within the amino acid chain. Polyarginine and the transactivator of transcription peptide are two widely used CPPs. One distinct application of these CPPs is the ability to further enhance the therapeutic properties of a range of different agents. One group of agents of particular importance are nanoparticles (NPs). Most NPs have no mechanism for cellular uptake. Hence, by conjugating CPPs to NPs, the amount of NPs taken up by cells can be increased, and therefore, the therapeutic benefits can be maximized. Some examples of this will be explored further in this review. In addition to CPPs, the concept of conjugation with the anticancer drug arsenic trioxide is reviewed and the prospect of transactivator of transcription-conjugated arsenic trioxide albumin microspheres is also discussed. Recent locked nucleic acid technology to stabilize nucleotides (RNA or DNA) aptamer complexes able to target cancer cells more specifically and selectively to kill tumour cells and spare normal body cells. NPs tagged with modified locked nucleic acid-aptamers have the potential to kill cancer cells more specifically and effectively while sparing normal cells. PMID- 22241170 TI - Ampelopsin sodium exhibits antitumor effects against bladder carcinoma in orthotopic xenograft models. AB - The aim of this study was to establish xenograft models of tumor in mice bladder and evaluate the antitumor efficacy of ampelopsin sodium (Amp-Na). A total of 2*10 human bladder carcinoma EJ cells and murine sarcoma 180 cells were instilled into the bladder of BALB/c nu/nu mice and Swiss mice after preconditioning to establish the tumor model. Mice bearing orthotopic tumors were treated with Amp Na by intravenous, intraperitoneal, or intravesical instillation. In addition, the pharmacokinetics property of Amp-Na was investigated in normal BALB/c mice. Our results showed that Amp-Na was excreted mainly through the urine, where it existed at a high concentration. Amp-Na significantly inhibited the proliferation of EJ and sarcoma 180 cells both in vivo and in vitro and this can be at least partially attributed to the cell cycle arrest induced by Amp-Na. This study suggests that the use of Amp-Na is an attractive chemotherapeutic modality for bladder cancer patients. PMID- 22241172 TI - The combination of docetaxel, cisplatin, and 5-fluorouracil in advanced gastric cancer: a single-institution experience. AB - The addition of docetaxel to cisplatin and 5-fluorouracil was shown to confer a survival benefit in patients with advanced gastric cancer (one; AGC), although with increased toxicity. We hereby report our experience with the use of docetaxel, cisplatin, and 5-fluorouracil (DCF). Data on all consecutive patients who received first-line treatment with DCF at our institute were analyzed retrospectively. Twenty-three patients were included. The median age was 63 years. Patients received an average of 10 cycles (range, 1-24). All experienced grade >=3 toxicity, requiring hospitalization in 35%. There was one toxic death. The median progression-free and overall survival rates were 10.0 and 12.8 months, respectively; the 2-year and 3-year survival rates were 22 and 17%, respectively. The DCF regimen is indeed associated with substantial toxicity, although manageable. Nevertheless, the observed benefit was remarkable compared with any previous report on chemotherapy in AGC, and should therefore represent a valid treatment option in AGC and a platform for future combinations. PMID- 22241173 TI - Invited review nonmulberry silk biopolymers. AB - The silk produced by silkworms are biopolymers and can be classified into two types--mulberry and nonmulberry. Mulberry silk of silkworm Bombyx mori has been extensively explored and used for century old textiles and sutures. But for the last few decades it is being extensively exploited for biomedical applications. However, the transformation of nonmulberry silk from being a textile commodity to biomaterials is relatively new. Within a very short period of time, the combination of load bearing capability and tensile strength of nonmulberry silk has been equally envisioned for bone, cartilage, adipose, and other tissue regeneration. Adding to its advantage is its diverse morphology, including macro to nano architectures with controllable degradation and biocompatibility yields novel natural material systems in vitro. Its follow on applications involve sustained release of model compounds and anticancer drugs. Its 3D cancer models provide compatible microenvironment systems for better understanding of the cancer progression mechanism and screening of anticancer compounds. Diversely designed nonmulberry matrices thus provide an array of new cutting age technologies, which is unattainable with the current synthetic materials that lack biodegradability and biocompatibility. Scientific exploration of nonmulberry silk in tissue engineering, regenerative medicine, and biotechnological applications promises advancement of sericulture industries in India and China, largest nonmulberry silk producers of the world. This review discusses the prospective biomedical applications of nonmulberry silk proteins as natural biomaterials. PMID- 22241174 TI - A novel lentivirus for quantitative assessment of gene knockdown in stem cell differentiation. AB - Loss of gene function is a valuable tool for screening genes in cellular processes including stem cell differentiation differentiation. However, the criteria for evaluating gene knockdown are usually based on end-point analysis and real-time, dynamic information is lacking. To overcome these limitations, we engineered a shRNA encoding LentiViral Dual Promoter vector (shLVDP) that enabled real-time monitoring of mesenchymal stem (MSC) differentiation and simultaneous gene knockdown. In this vector, the activity of the alpha-smooth muscle actin (alphaSMA) promoter was measured by the expression of a destabilized green fluorescent protein, and was used as an indicator of myogenic differentiation; constitutive expression of discosoma red fluorescent protein was used to measure transduction efficiency and to normalize alphaSMA promoter activity; and shRNA was encoded by a doxycycline (Dox)-regulatable H1 promoter. Importantly, the normalized promoter activity was independent of lentivirus titer allowing quantitative assessment of gene knockdown. Using this vector, we evaluated 11 genes in the TGF-beta1 or Rho signaling pathway on SMC maturation and on MSC differentiation along the myogenic lineage. As expected, knockdown of genes such as Smad2/3 or RhoA inhibited myogenic differentiation, while knocking down the myogenic differentiation inhibitor, Klf4, increased alphaSMA promoter activity significantly. Notably, some genes for example, Smad7 or KLF4 showed differential regulation of myogenic differentiation in MSC from different anatomic locations such as bone marrow and hair follicles. Finally, Dox-regulatable shRNA expression enabled temporal control of gene knockdown and provided dynamic information on the effect of different genes on myogenic phenotype. Our data suggests that shLVDP may be ideal for development of lentiviral microarrays to decipher gene regulatory networks of complex biological processes such as stem cell differentiation or reprogramming. PMID- 22241175 TI - Engineered human Tmpk fused with truncated cell-surface markers: versatile cell fate control safety cassettes. AB - Cell-fate control gene therapy (CFCGT)-based strategies can augment existing gene therapy and cell transplantation approaches by providing a safety element in the event of deleterious outcomes. Previously, we described a novel enzyme/prodrug combination for CFCGT. Here, we present results employing novel lentiviral constructs harboring sequences for truncated surface molecules (CD19 or low affinity nerve growth factor receptor) directly fused to that CFCGT cDNA (TmpkF105Y). This confers an enforced one-to-one correlation between cell marking and eradication functions. In-vitro analysis demonstrated the full functionality of the fusion product. Next, low-dose 3'-azido-3'-deoxythymidine (AZT) administration to non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice injected with transduced clonal K562 cells suppressed tumor growth; furthermore, one integrated vector on average was sufficient to mediate cytotoxicity. Further, in a murine xenogeneic leukemia-lymphoma model we also demonstrated in-vivo control over transduced Raji cells. Finally, in a proof-of principle study to examine the utility of this cassette in combination with a therapeutic cDNA, we integrated this novel CFCGT fusion construct into a lentivector designed for treatment of Fabry disease. Transduction with this vector restored enzyme activity in Fabry cells and retained AZT sensitivity. In addition, human Fabry patient CD34(+) cells showed high transduction efficiencies and retained normal colony-generating capacity when compared with the non transduced controls. These collective results demonstrated that this novel and broadly applicable fusion system may enhance general safety in gene- and cell based therapies. PMID- 22241176 TI - A simple detection system for adenovirus receptor expression using a telomerase specific replication-competent adenovirus. AB - Adenovirus serotype 5 (Ad5) is frequently used as an effective vector for induction of therapeutic transgenes in cancer gene therapy or of tumor cell lysis in oncolytic virotherapy. Ad5 can infect target cells through binding with the coxsackie and adenovirus receptor (CAR). Thus, the infectious ability of Ad5 based vectors depends on the CAR expression level in target cells. There are conventional methods to evaluate the CAR expression level in human target cells, including flow cytometry, western blotting and immunohistochemistry. Here, we show a simple system for detection and assessment of functional CAR expression in human tumor cells, using the green fluorescent protein (GFP)-expressing telomerase-specific replication-competent adenovirus OBP-401. OBP-401 infection induced detectable GFP expression in CAR-expressing tumor cells, but not in CAR negative tumor cells, nor in CAR-positive normal fibroblasts, 24 h after infection. OBP-401-mediated GFP expression was significantly associated with CAR expression in tumor cells. OBP-401 infection detected tumor cells with low CAR expression more efficiently than conventional methods. OBP-401 also distinguished CAR-positive tumor tissues from CAR-negative tumor and normal tissues in biopsy samples. These results suggest that GFP-expressing telomerase-specific replication-competent adenovirus is a very potent diagnostic tool for assessment of functional CAR expression in tumor cells for Ad5-based antitumor therapy. PMID- 22241177 TI - Development of the Nanobody display technology to target lentiviral vectors to antigen-presenting cells. AB - Lentiviral vectors (LVs) provide unique opportunities for the development of immunotherapeutic strategies, as they transduce a variety of cells in situ, including antigen-presenting cells (APCs). Engineering LVs to specifically transduce APCs is required to promote their translation towards the clinic. We report on the Nanobody (Nb) display technology to target LVs to dendritic cells (DCs) and macrophages. This innovative approach exploits the budding mechanism of LVs to incorporate an APC-specific Nb and a binding-defective, fusion-competent form of VSV.G in the viral envelope. In addition to production of high titer LVs, we demonstrated selective, Nb-dependent transduction of mouse DCs and macrophages both in vitro and in situ. Moreover, this strategy was translated to a human model in which selective transduction of in vitro generated or lymph node (LN) derived DCs and macrophages, was demonstrated. In conclusion, the Nb display technology is an attractive approach to generate LVs targeted to specific cell types. PMID- 22241178 TI - AAV-based neonatal gene therapy for hemophilia A: long-term correction and avoidance of immune responses in mice. AB - Hemophilia A gene therapy has been hampered by immune responses to vector associated antigens and by neutralizing antibodies or inhibitors against the factor VIII (FVIII) protein; these 'inhibitors' more commonly affect hemophilia A patients than those with hemophilia B. A gene replacement strategy beginning in the neonatal period may avoid the development of these immune responses and lead to prolonged expression with correction of phenotype, thereby avoiding long-term consequences. A serotype rh10 adeno-associated virus (AAV) was developed splitting the FVIII coding sequence into heavy and light chains with the chicken beta-actin promoter/CMV enhancer for dual recombinant adeno-associated viral vector delivery. Virions of each FVIII chain were co-injected intravenously into mice on the second day of life. Mice express sustained levels of FVIII antigen >=5% up to 22 months of life without development of antibodies against FVIII. Phenotypic correction was manifest in all AAV-FVIII-treated mice as demonstrated by functional assay and reduction in bleeding time. This study demonstrates the use of AAV in a gene replacement strategy in neonatal mice that establishes both long-term phenotypic correction of hemophilia A and lack of antibody development against FVIII in this disease model where AAV is administered shortly after birth. These studies support the consideration of gene replacement therapy for diseases that are diagnosed in utero or in the early neonatal period. PMID- 22241179 TI - LIM domain protein-3 (LMP3) cooperates with BMP7 to promote tissue regeneration by ligament progenitor cells. AB - Gene transfer of key regulators of osteogenesis for mesenchymal stem cells represents a promising strategy to regenerate bone. It has been reported that LMP3, a transcription variant of LIM domain mineralization protein (LMP) lacking LIM domains, can induce osteogenesis in vitro and in vivo. As little is known about the effects of LMP3 gene therapy on periodontal ligament (PDL) cell osteogenic differentiation, this study sought to explore whether gene delivery of LMP3 can promote PDL cell mineralization and bone formation. Our results showed that adenoviral mediated gene transfer of LMP3 (AdLMP3) significantly upregulated ALP (Alkaline Phosphatase), BSP (Bone Sialoprotein) and BMP2 gene expression and increased in vitro matrix mineralization in human PDL. Although AdLMP3 gene delivery to PDL cells did not induce ectopic bone formation in vivo, we found that AdLMP3 augments new bone formation, which co-delivered with AdBMP7 gene transfer. Our study provides the evidence that there is a synergistic effect between LMP3 and BMP-7 in vivo, suggesting that LMP3 delivery may be used to augment BMP-mediated osteogenesis. LMP3 and BMP-7 combinatory gene therapy may also have specific applications for oral and periodontal regenerative medicine. PMID- 22241180 TI - LYVE-1 upregulation and lymphatic invasion correlate with adverse prognostic factors and lymph node metastasis in neuroblastoma. AB - Neuroblastoma (NB) accounts for 15% of all childhood cancer deaths. The majority of patients have widespread lymphatic and/or haematogenous metastases at diagnosis, but lymphangiogenesis has not been well documented. Sixty-seven NBs were immunostained for the lymphatic endothelial marker, LYVE-1, and the lymphatic density (LD) and lymphatic invasion (LI), were counted in LYVE-1 expressing lymphatics. LYVE-1-stained lymphatic vessels and LI were present in 26/67 (39%) and 14/67 (21%) of the NBs, respectively. Central LD (CLD) and LI were higher in NBs from stage 4 (p = 0.012, p = 0.004, respectively), high-risk group (p = 0.030, p = 0.002), NBs with high mitosis karyorrhexis index (MKI) (p = 0.011, p = 0.005), unfavourable histology group (p = 0.040, p = 0.017) and distant lymph node metastasis (LNM) (p < 0.001 for each). Marginal LD (MLD) was higher in patients with LNM (p < 0.001). CLD and MLD correlated with LI (p < 0.001 each). Total LYVE-1 protein levels, quantified by a sensitive enzyme-linked immunosorbent assay (n = 55), were also higher in NBs from patients with stage 4 disease (p = 0.046), high-risk group (p = 0.028), MYCN-amplified NBs (p = 0.034) and LNM (p = 0.038). Kaplan-Meier analysis showed that the presence of CLD was associated with both worse OS at 5 years (77% [95% CI: 62-87%] versus 60% [95% CI: 32-80%], p = 0.062) and EFS (74% [95% CI: 58-85%] versus 43% [95% CI: 15 69%], p = 0.070) and LI with OS (71% [95% CI: 57-81%] versus 56% [95% CI: 26 78%], p = 0.055). Significant upregulation of LYVE-1 and the presence of LI in patients with stage 4 and high-risk disease, MYCN-amplification and LNM suggests that LYVE-1 may have value as predictors of outcome. PMID- 22241182 TI - Journal networking in nursing: a challenge to be shared. PMID- 22241181 TI - A multi-centre pathologist survey on pathological processing and regression grading of colorectal cancer resection specimens treated by neoadjuvant chemoradiation. AB - To ascertain the approach and degree of consensus of pathologists in the handling and regression grading of colorectal cancer resection specimens treated with neoadjuvant chemoradiation, a ten-part questionnaire was circulated to 18 gastrointestinal pathologists in eight countries. The questions were specific and addressed pertinent issues related to colorectal cancer with neoadjuvant chemoradiation. There is a lack of consensus on how to handle the specimen, number of sections taken, correlation with pre- and post-operative radiological imaging, and especially, regression grading schema employed. Consensus in the form of guidelines is required so that the pathological assessment of these specimens will provide clinically relevant information for patient management, irrespective of location. PMID- 22241183 TI - [The meanings that postpartum women assign to gestational hypertension and premature birth]. AB - The objective of this study was to understand the meanings that postpartum women assign to gestational hypertension that resulted in premature birth. Participants were 70 women, with a mean age of 28 years, 85.7% of whom delivered between the 32nd and 36th gestational week. A questionnaire with subjective questions was applied to identify the meanings of gestational hypertension and premature delivery for postpartum women. Results were analyzed based on the Theory of Social Representations. We observed the construction of a negative social representation, with death as the central nucleus and negative aspects as the peripheral nuclei. The latter derive from the risks the mother and fetus were exposed to during pregnancy and later in the postpartum period with the hospitalization of the child in the neonatal intensive care unit. PMID- 22241184 TI - [Normative prenatal evaluation at a philanthropic maternity hospital in Sao Paulo]. AB - This cross-sectional study counted with the participation of 301 pregnant women seen in 2009 at a philanthropic maternity hospital in the city of Sao Paulo (a prenatal support program named Pre-Natal do Amparo Maternal - PN-AM). The objectives of this study were to evaluate the prenatal care according to the initial gestational age, the number of appointments that were held, the continuity of the assistance, and relate the appropriateness with the socio demographic, obstetric and local variables of the initial prenatal care. The analysis criteria used was initiating prenatal care before 120 days of gestation and attending at least six appointments. The relationship between the variables was analyzed using the Chi-Square Test. Results showed that 41.5% of the pregnant women initiated prenatal care at another health care service and transferred spontaneously to the PN-AM; 74.1% initiated the prenatal care early and 80.4% attended at least six appointments; 63.1% met both criteria simultaneously. Appropriate prenatal care showed a statistically significant difference for mother's age, steady partner, employment, place of residence, having a companion during the appointment and place where prenatal care was initiated. PMID- 22241185 TI - [Transferring mothers from a free-standing birth center to a reference hospital]. AB - The objective of this descriptive study was to characterize the transfers of mothers from the Sapopemba Birth Center to reference hospitals in Sao Paulo, from September 1998 to July 2008. The studied population was 229 cases of mother transfers. Data were obtained from medical records and record books of the transferred women. Descriptive analysis was performed. The transfer rate was 5.8% (5.5% in the intrapartum period and 0.3% in the postpartum period). Most women who were transferred to the hospital were nulliparous (78.6%). The most common reason for intrapartum transfers was fetal or pelvis abnormalities (22.6%), and abnormal placental detachment (50%) for women in the postpartum period. Some conditions such as nulliparity, cervical dilation at admission, rupture of the membranes and gestational age over 40 weeks were highlighted as important variables for studying the risk factors for mothers being transferred. PMID- 22241186 TI - [Sound pressure levels in the neonatal intensive care unit]. AB - The objectives of the study were to assess sound pressure level (SPL) in two rooms of a Neonatal Intensive Care Unit (NICU) and to identify their sources. This quantitative-descriptive study was conducted in two rooms of a NICU of a University Hospital in Sao Paulo, Brazil. Three dosimeters were used to register SPL (total of 261 hours). A 48-hour register of noise sources was obtained. The results showed high SPL in both rooms. The greatest mean Leq were 71.0 dBA (room A) and 68.0 dBA (room B). Main noise sources in both units were: NICU hallway noise, traffic and conversation among professionals. The results indicate that SPLs in NICU rooms are higher than the levels recommended by regulatory agencies. A guideline was developed and an educational program was implemented as a means to reduce sound pressure levels. PMID- 22241187 TI - [The development of sexuality in children in a risk situation]. AB - The objective of this study was to depict and analyze the development of sexuality in children in a risk situation. Forty-two children, of ages between 6 and 12 years, were interviewed in pairs, using techniques to facilitate communication. The qualitative, descriptive-exploratory method was used, according to Thematic Content Analysis. The lack of guidance and information, the inadequate references and sources of knowledge and the violation of their rights characterize the course of sexuality in these children. Away from fairy tales, they discovered the dichotomy between love and sex, which was associated to violent events. PMID- 22241188 TI - [Communication process: a group activities tool in the family health strategy]. AB - The objective of the present study was to analyze the communication process tools triggered in group activities in the Family Health strategy. Data collection was performed using semi-structured interviews recorded with 51 nurses and through non-participating, non-systematic public observation in natural situations of 19 group activities analyzed according to content qualitative approach. Based on the reports of the professionals, two categories emerged: dialogue-action and dialogue-interaction, which evinced that the communication process is an instrumental means of group activities in the Family Health strategy. The former by the predominant use of verbal language as a means for developing operational procedures specific to each professional in relation to monitoring the health of the client, and the latter as an instrument in which, according to the nurses, there is a simultaneous use of verbal and nonverbal communication. PMID- 22241189 TI - [Attitudes of nurses towards families: validation of the scale Families' Importance in Nursing Care--Nurses Attitudes]. AB - The attitudes of nurses towards families determine the care process. With this study, we aimed to obtain an instrument that would allow us to learn about this variable. Hence, our purpose was to perform the cross-cultural adaptation and evaluate the psychometric features of the Portuguese version of the instrument Families' Importance in Nursing Care - Nurses Attitudes (FINC-NA), which aims to evaluate the attitudes of nurses towards the importance of involving the patient's family in the nursing care. The method recommended by the literature was followed. The sample consisted of 136 nurses working in primary health care. The results obtained in the reliability tests showed good internal consistency (Cronbach's Alpha=0.87). The psychometric study permits us to state that the Portuguese version of the FINC-NA, which in Portuguese is referred to as A importancia das familias nos cuidados de enfermagem - atitudes dos enfermeiros (IFCE-AE), is a reliable and valid tool. PMID- 22241190 TI - [Mucositis in head and neck cancer patients undergoing radiochemotherapy]. AB - The objective of present study was to classify oral mucositis according to the Common Toxicity Criterion (CTC) international parameters in head and neck tumor patients simultaneously treated with radio and chemotherapy, and characterize a patient profile in our area, observing the individuals' habits, tumor characteristics, treatment protocol and acute reaction intensity. Fifty patients undergoing simultaneous 66 to 70 Gy megavoltage radiotherapy and cisplatin/carboplatin chemotherapy were evaluated in this study. Weekly evaluations of the degree of mucositis were perfoemed according to CTC, a four degree ordinal scale; 36% of all patients and 100% of those with diabetes discontinued treatment due to mucositis, showing that this pathology contributes to the severity of mucositis. PMID- 22241191 TI - [Friends and neighbors: an active social network for adult and elderly hypertensive individuals]. AB - The family network is fundamental in people's lives, but when it is inefficient, friends play an essential role in providing physical and mental support. The objective of this study was to understand how the network represented by the friends and neighbors of hypertensive adult and elderly individual works. This qualitative study was performed with 20 individuals with ages between 50 and 80 years, living in Maringa - Parana. Results showed that the time of residence affects the attachment between the hypertensive individual and his/her neighbors and pointed at the resources and locations they used to contact friends. Friendships are an important source of support, and this attachment may in fact be stronger than kinship ties. We reinforce the need for health care professionals to value friendship networks, as it serves as a strategy for a more effective health care, with contemplates the subject as a whole. PMID- 22241192 TI - The role of the New Trauma and Injury Severity Score (NTRISS) for survival prediction. AB - The objective of this study was to verify if replacing the Injury Severity Score (ISS) by the New Injury Severity Score (NISS) in the original Trauma and Injury Severity Score (TRISS) form would improve the survival rate estimation. This retrospective study was performed in a level I trauma center during one year. ROC curve was used to identify the best indicator (TRISS or NTRISS) for survival probability prediction. Participants were 533 victims, with a mean age of 38+/-16 years. There was predominance of motor vehicle accidents (61.9%). External injuries were more frequent (63.0%), followed by head/neck injuries (55.5%). Survival rate was 76.9%. There is predominance of ISS scores ranging from 9-15 (40.0%), and NISS scores ranging from 16-24 (25.5%). Survival probability equal to or greater than 75.0% was obtained for 83.4% of the victims according to TRISS, and for 78.4% according to NTRISS. The new version (NTRISS) is better than TRISS for survival prediction in trauma patients. PMID- 22241193 TI - [An epidemiological survey on motorcycle accident victims assisted at a reference trauma center of Sergipe]. AB - The trauma caused by motorcycle accidents affects a large number of victims and is a serious public health problem in Brazil. This documental study was performed with a quantitative approach with the objective to raise epidemiological data from 554 motorcycle accident victims assisted in September and October 2006 in a referral center for trauma of Sergipe. The result analysis shows a predominance of men (82.7%) with mean age of 27.78 years, who were admitted during the night shift (45.9%), Sunday (27.3%), whose injuries were abrasions (n=169) on the head, face and neck. The victims stayed in the hospital for up to 12 hours (76%) and were discharged. Of the registered cases, 14.6% were suspected of having consumed alcohol and 19.3% were not wearing a helmet during the accident. PMID- 22241194 TI - [Quality of life of adults with spinal cord injury: a study using the WHOQOL bref]. AB - The objective of this study was to evaluate the quality of life (QOL) of adults with spinal cord injury and to identify the domains that may influence QOL. Data was collected using the WHOQOL-bref and a questionnaire with sociodemographic variables. Participants were 47 subjects, with a mean age of 42.95 years, 91.5% males and 8.5% females. The domains obtained the following scores: physical (58.59), psychological (63.82), social (68.79), and environmental (55.20). Through multiple linear regression, it was verified the correlation between domain scores and the perception of QOL: physical (p <0.187), psychological (p <0.399), social (p <0.000), and environmental (p <0.008). In conclusion, most participants (55.3%) are unsatisfied with their QOL, and the social and environmental domains showed a higher correlation with QOL. PMID- 22241195 TI - [Pressure ulcers in surgery patients: incidence and associated factors]. AB - Pressure ulcers are an important perioperatory care quality indicator This is a longitudinal case series study, performed with the following objectives: to estimate the incidence of pressure ulcers in patients submitted to medium and large surgeries; rate them according to the stage and location; verify the association with the variables: gender, age, body mass index (BMI), co morbidities, surgical position, duration of surgery, anesthesia type and use of positioning devices, with presence or absence of pressure ulcers. Data collection took place in 2007 in Sao Paulo, with 199 patients, 20.6% of which presented pressure ulcers, and most (98.6%) in stages I and II, and the main location was the trunk (35.1%). The variables: position, surgery time, general anesthesia, and device use had a statistically significant association. In conclusion, there is a high incidence of pressure ulcers among surgical patients, requiring actions aimed at reducing this type of injury. PMID- 22241196 TI - [Nurses' knowledge about Nursing Care Systematization: from theory to practice]. AB - The objective of this study is to analyze the knowledge that nurses from a large hospital in Recife, Pernambuco, have about Nursing Care Systematization (NCS). This is a descriptive, exploratory, quantitative study. The study population consisted of 107 clinical nurses, with a sample of 73 (68%). Data collection was performed in June 2008, using a semi-structured questionnaire that was filled out by the subjects. We found that 50 (69%) nurses had no knowledge about NCS, especially about nursing diagnoses. We identified the absence of forms in most hospitalization units. The nurses gave several justifications for their not working with NCS, including work overload and the scarcity of forms. We concluded that there is a need for more incentives by the institution and through policies, so as to permit nurses a greater autonomy in their practice. PMID- 22241197 TI - [Helping relationship skills in nurses: the validation of a measurement instrument]. AB - Considering the importance of assessing nurses' helping relationship skills, it was necessary to use reliable and context-adapted instruments. Thus, the objective of this study was to assess the psychometric properties of the Helping Relationship Skills Inventory (Inventario de Competencias Relacionais de Ajuda, ICRA), by conducting reliability and validity studies to increase the level of confidence or accuracy of the data obtained using this instrument. This quantitative study was conducted on a sample of 690 nurses who worked in six hospitals and eight health centres in Portugal. The results indicate a multidimensional structure of helping relationship skills, divided into four different dimensions (generic, empathetic, communication and contact skills) with a positive correlation between them. Cronbach's alpha for each dimension was higher than .79, showing a good internal consistency of the items within each factor. PMID- 22241198 TI - [The integrality of care and communicative actions in the cross-discipline practice in intensive care]. AB - Cross-disciplinary work in health is an important element to deliver comprehensive health care actions. The present study analyzed cross-disciplinary actions in intensive care according to Habermas. This case study was performed using a qualitative approach. The empiric material capture was collected by observing the setting and using semi-structured interviews with health workers. The information was analyzed using the meaning interpretation technique. The analysis revealed two thematic lines: individual instrumental care in view of the clinical inconstancy, and the collective care fragmented by functions. This result weakens the worker/worker and the worker/patient interactions and compromises the association between health actions. As it does not favor communicative actions, it becomes fragile and the strategic/instrumental action is evinced. PMID- 22241199 TI - [Technology in intensive care and its effects on nurses' actions]. AB - The objective of this study was to identify the social representations that nurses have about technology applied to intensive care, and relate them to their ways of acting while caring for patients. This qualitative study was performed using social representations as the theoretical-methodological framework. Interviews were performed with 24 nurses, in addition to systematic analysis and thematic content analysis. The results were organized into three categories about the lack of technological knowledge, approach strategies, mastering that knowledge and using it. The knowledge necessary to handle the technology, and the time of experience using that technology guide the nurses' social representations implying on their care attitudes. In conclusion, the staffing policy for an intensive care setting should consider the nurses' experiences and specialized education. PMID- 22241200 TI - [Group process: reflections of a nursing team]. AB - The objective of this qualitative, exploratory-descriptive study was to analyze the group process of a nursing team at Hospital de Clinicas de Porto Alegre (HCPA), under the light of Pichon-Riviere's Operative Group Theory. Data collection took place in 2008, using a semi-structured questionnaire and focal group. The group work concept is one of the four categories that resulted from the study, and is the object of approach in the present article. It was found that the knowledge about the group process must be shared, disseminated and discussed since the undergraduate studies and developed across the professional career. As the team learns and is able to identify the main indicators of the group process, it becomes possible to improve operatively, considering not only the outcomes but mainly the course covered until achieving the goal, aiming at group learning. PMID- 22241201 TI - [The NAS system: Nursing Activities Score in mobile technology]. AB - The objective of this study was to present the computerized structure that enables the use of the Nursing Activities Score (NAS) in mobile technology. It is a project for the development of technology production based on software engineering, founded on the theory of systems development life cycle. The NAS system was built in two modules: the search module, which is accessed using a personal computer (PC), and Data Collection module, which is accessed through a mobile device (Smartphone). The NAS system was constructed to allow other forms, in addition to the NAS tool, to be included in the future. Thus, it is understood that the development of the NAS will bring nurses closer to mobile technology and facilitate their accessibility to the data of the instrument relating to patients, thus assisting in decision-making and in staffing to provide nursing care. PMID- 22241202 TI - [Social representations of caring and treating: the look of patients and professionals]. AB - The objective of this study was to learn about the central nucleus of the social representations of caring and treating for patients and nurses. This qualitative study was founded on the theoretical-methodological framework of the structural approach of social representations. Participants were 90 subjects, who answered a questionnaire using the free association technique. Data analysis was performed using Evoc software. Results show that the social representations that patients and professionals have of the concepts of caring express an ethical, sensitive, solidary, affective and committed relationship with a loving human life. However, the representations of treating point at different meanings and different expectations. In conclusion, the difference between these representations is rather concerning and deserves special attention. Such discrepancy denounces that the service that the professionals have delivered does not meat the demand and desires of patients. PMID- 22241203 TI - [Stress, coping and health conditions of hospital nurses]. AB - The objective of this quantitative study was to identify stressing factors, level of stress in nurses, overall health conditions, and coping strategies used by nurses in the working environment. Data collection was performed using three instruments: a survey for daily activities, an inventory of coping strategies, and an inventory for overall health conditions. The population of this study was composed by 143 nurses, most of them with a low level of stress (55.25%) and with a regular health condition (50.35%). Regarding coping forms, problem solving was the factor of highest average. In conclusion, educational actions must be encouraged with an aim to offer tools for professionals to develop coping strategies in their everyday activities, thus minimizing the effect of stress on their health conditions and at work. PMID- 22241204 TI - [The efficacy of three hand asepsis techniques using chlorhexidine gluconate (CHG 2%)]. AB - The scrubbing of hands and forearms using antiseptic agents has been the standard pre-operative procedure to prevent surgical site infection. With the introduction of antiseptic agents, the need to use brushes for pre-operative disinfection has been questioned and it has been recommended that the procedure be abandoned due to the injuries it may cause to the skin. With the purpose to provide the foundations for the efficacy of pre-operative asepsis without using brushes or sponges, the objective of this study was to evaluate three methods of pre operative asepsis using an antimicrobial agent containing chlorhexidine gluconate - CHG 2%; hand-scrubbing with brush (HSB), hand-scrubbing with sponge (HSS), and hand-rubbing with the antiseptic agent (HRA) only. A comparative crossover study was carried with 29 healthcare providers. Antimicrobial efficacy was measured using the glove-juice method before and after each tested method. Statistical analyses showed there were no significant differences regarding the number of colony-forming units when comparing HRA, HSB, and HSS techniques (p=0.148), which theoretically disregards the need to continue using brushes or sponges for hand asepsis. PMID- 22241205 TI - [Acute myeloid leukemia versus professional occupation: the profile of workers treated at the Recife Hematology Hospital]. AB - The objective of this study was to learn the profile of workers in the economically active age group admitted from 1997 to 2007 to a hematology hospital, diagnosed with acute myeloid leukemia (AML); check which professions have the highest prevalence among the assisted workers who died; and identify the occupational risks compatible with the appearance of AML in the prevalent professions. This is a quantitative, exploratory study. Most profiles were characterized as originally from the agreste and the metropolitan region of the state of Pernambuco, male, white, and with incomplete primary education. The most common occupations were related to agriculture and domestic work, both of which involve the use of chemical substances that, according to literature, are possible factors involved in triggering the pathology. PMID- 22241206 TI - [Professional satisfaction of nurses working with home care]. AB - The objective of this study was to learn the level of satisfaction that nurses have about their work. Participants were 34 nurses, who answered the Professional Satisfaction Index (PSI), translated and validated for the Portuguese language and adapted to home care. The following six components were analyzed: Interaction, Autonomy, Remuneration, Professional Status, Organizational Norms, and Working Requirements. The PSI found in the study was 13.19. This was a low value, considering the possible variation from 0.9 to 37.1, though it was greater than the satisfaction indexes found in other nurse studies. PMID- 22241207 TI - [Medical device reprocessing: a regulatory model proposal for Brazilian hospitals]. AB - Medical device reprocessing is extremely important and complex, thus requiring both the operational skills for its implementation and the technical qualification of the professionals involved in the activity. The typical issues of medical device reprocessing involve technical, economical and regulatory aspects when involving either the so-called reusable articles or those considered as for a single use. The objective of the present study is to propose a new regulatory model for medical device reprocessing in Brazil that would, on the one hand, satisfy the requirements for quality and safety, as recommended in the literature and, on the other hand, prove to be operational under the conditions prevailing in Brazilian hospitals. The elaboration of the present normative proposal was based on the Consensus Conference technique among specialists in the area. Guided by the contribution of these specialists, a proposal is put forth of a regulatory model for reprocessing medical products, so as to address some previously identified gaps in the normative body currently used in Brazil. PMID- 22241208 TI - [The dissertations produced in the Graduate and Master's in Nursing Program at Universidade Federal do Parana]. AB - This descriptive, retrospective documental study was performed with the objective to analyze the dissertations produced in the Graduate and Master's in Nursing Program at Universidade Federal do Parana, considering the adjustment of its lines of research. To do this, a critical reading was performed of the abstracts and thematic analysis was used to look at the dissertations and their inclusion in the lines of research, as well as the methods, approaches, subjects, location and research techniques used. A total 64 abstracts were analyzed from dissertations that were available online. Of the analyzed productions most make a qualitative focus and use interviews. It was found that the dissertations are in line with the lines of research proposed in the Master's Degree in Program and their analysis can contribute to re-dimensioning pathways, research lines and studies that the program has developed. PMID- 22241209 TI - [Panorama of nursing distance education in Brazil]. AB - The development of distance education is associated with the popularization and democratization of the accessibility to information and communication technologies. Nursing has been using this modality of education in both undergraduate and graduate courses, which has provided knowledge about other technologies, an easier accessibility, flexibility of time and space, and reduced costs. The objective of this study is map the national higher education distance nursing courses. This exploratory, descriptive study was developed by visiting governmental, non-governmental and institutional websites. Two undergraduate and nine graduate courses in nursing were found, which is considered to be a low number, considering that distance education is an appropriate pedagogical tool that permits to prepare a large number of nurses who are geographically dispersed and who do not have access to the conventional educational processes. PMID- 22241210 TI - [The supply and use of psychotropic drugs in Psychosocial Care Centers in Southern Brazil]. AB - The description of the supply and use of psychotropic drugs at the Centers for Psychosocial Care (CAPS) is relevant for the effectiveness of assistance from mental health services. The objective was to describe the use and supply of these drugs in CAPS types I and II, in Southern Brazil. This is a cross-sectional study, in which surveys were conducted, in May and June 2006, on the structural aspects of the referred service using charts of 1162 users, and self-applied questionnaires answered by 30 engineers working at CAPS where these users were being monitored. Users were identified as mostly female, adult, middle-aged, low economic status, mainly with a diagnosis of major depression and using antidepressants. It was also found that there might be a lack of distribution and supply of psychotropic drugs in the public health system (SUS) network, which affects the drug therapy of this specialized mental health service, given the socioeconomic conditions of the users. PMID- 22241211 TI - [Systematic review and meta-analysis of the predictive value of C-reactive protein in postoperative infections]. AB - This systematic review on C-reactive protein (CRP) was performed with the purpose to identify its predictive value in the prognosis/diagnosis of infection in surgical patients. The sources used in the search were: COCHRANE, EMBASE, LILACS, MEDLINE and OVID, and bibliographic references of the located studies. All studies found increased CRP levels after surgery in cases of postoperative infection (PO), in eight studies a CRP peak between the second and third PO was reported as normal aspect of the CRP curve, reducing in patients without postoperative complications and increasing in patients with complications. The meta-analysis revealed an average of 85% (sensitivity), 86% (specificity), the area under the SROC curve was 0.9060, and the Odds Ratio was 23.56. Along with other clinical interventions, CRP is considerably valuable in the prognosis/diagnosis of postoperative infections. PMID- 22241212 TI - [Nursing interventions for stroke patients: an integrative literature review]. AB - The objective of this study was to analyze the knowledge on nursing interventions for hospitalized stroke patients. An integrative literature review was performed by accessing five online databases, in September 2009. The descriptors used in the search were nursing care and stoke, in Portuguese, English and Spanish. A total 223 articles were found, and 12 were selected. It was found in the articles that there was a greater number of clinical nursing interventions, followed by educational, managerial and research interventions. Clinical interventions are more related to the biological aspects of patients. As to the educational interventions, the articles point at the fundamental role of nurses, as well as that of relatives and caregivers. The main managerial intervention was the coordination of health care. As for research interventions, only one was identified and described as the development and improvement of health care practice through clinical evidence. PMID- 22241213 TI - [Mental health in primary health care: practices of the family health team]. AB - The inclusion of mental health care actions in the context of the Brazilian Public Health System (SUS; Sistema Unico de Saude) contributes to the consolidation of the Brazilian Psychiatric reform and demands redirecting the practices of family health teams with users with mental health needs. The objective of this study is to identify and analyze the scientific production and actions developed by family health team professionals in mental health care. Systematic analysis originated the following themes: home visits to mentally ill patients and their relatives; attachment and welcoming; referrals; therapeutic workshops. In conclusion, the mental health actions developed in primary care are not performed consistently and depend on the professional or on the political decision of the administrator, which shows that professionals should use new practices to develop comprehensive care, and, therefore, there is a need to invest in improving the qualification of the professionals. PMID- 22241214 TI - [Systematic review of theories: a tool to evaluate and analyze selected studies]. AB - The objective of this study is to report on the experience of constructing and using an instrument to collect and analyze theoretical-methodological references of studies, in systematic literature reviews. The goal is for researchers to have available an instrument that is appropriate for evaluating the studies that present their theoretical foundations, and for health professionals to have access to the theoretical explanations for study results and their applications in the practice of health care. The dissociation of theory from practice may lead to a lack of motivation at the work site and practices of repeating procedures without any awareness of the underlying concepts that base the interpretation of a health-disease phenomenon. Therefore we call on researchers to conduct reviews on the theoretical foundations of certain health-disease phenomena and we propose questions related to the inclusion criteria, critical appreciation and data extraction to be addressed in instruments. PMID- 22241215 TI - Value of diffusion-weighted imaging for the discrimination of pancreatic lesions: a meta-analysis. AB - OBJECTIVE: We aimed to explore the role of diffusion-weighted imaging (DWI) in the discrimination of pancreatic lesions through meta-analysis. METHODS: The MEDLINE, EMBASE, Cancerlit, and Cochrane Library databases, from January 2001 to August 2011, were searched for studies evaluating the diagnostic performance of DWI in the discrimination of pancreatic lesions. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves. RESULTS: A total of 11 studies with 586 patients, who fulfilled all of the inclusion criteria, were considered for the analysis. No publication bias was found. The pooled sensitivity of DWI was 0.86 [95% (confidence interval (CI), 0.78, 0.91] and the pooled specificity was 0.91 (95% CI, 0.81, 0.96). Overall, LR+ was 9.8 (95% CI, 4.1, 23.3) and LR- was 0.15 (95% CI, 0.09, 0.26). The area under the curve of the summary receiver operating characteristic was 0.94 (95% CI, 0.91-0.96). In subgroup analysis, prospectively designed studies had the highest pooled sensitivity (0.87, 95% CI 0.75, 0.94) and specificity (0.96, 95% CI 0.91, 0.99) (P<0.05). Study sensitivity was not correlated with the prevalence of pancreatic lesions (R=0.1076, P=0.3247). CONCLUSION: A limited number of small studies suggest that DWI is a potentially technically feasible measure to differentiate malignant from benign pancreatic lesions. However, it is still controversial and is limited in that it can only distinguish certain lesions. High-quality prospective studies on DWI for the discrimination of pancreatic lesions still need to be conducted. PMID- 22241216 TI - Antifibrotic and antioxidant effects of N-acetylcysteine in an experimental cholestatic model. AB - OBJECTIVES: Several studies have suggested that oxidative stress may play an important role in the pathogenesis of hepatic injury during cholestasis in rats and humans. The aim of this study was to evaluate the ability of N-acetylcysteine (NAC) to prevent the damage induced by bile duct ligation (BDL) for 28 days in male Wistar rats. METHODS: NAC was administered daily (300 mg/kg, orally) for 28 days. Alanine aminotransferase was quantified in the serum; lipid peroxidation, glutathione, and catalase activity were measured in the liver. Fibrosis was assessed by measuring the liver hydroxyproline content; transforming growth factor-beta (TGF-beta), interleukin (IL)-6, and IL-10 were determined in the liver by a western blot and quantified densitometrically. RESULTS: The induction of cholestatic damage by BDL was associated with an increase in alanine aminotransferase. Oxidative stress was also evaluated; lipid peroxidation increased, whereas the liver glutathione content and catalase activity decreased by BDL. NAC treatment prevented these alterations. Hydroxyproline was increased by chronic BDL, but NAC preserved the normal hydroxyproline levels. Cytokines TGF beta, IL-6, and IL-10 increased after 28 days of BDL. NAC was effectively significant in preventing TGF-beta and IL-6 expression and further augmented the IL-10 expression. CONCLUSION: Our data indicate that in the development to cholestatic liver damage, oxidative stress plays an important role and this in turn leads to fibrosis. This study shows that the beneficial effects of NAC are because of its antioxidant and immunomodulatory properties. PMID- 22241217 TI - Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma. AB - Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblastomas. We found AJAP1 expression absent or reduced in 86% and 100% of primary glioblastoma tumors and cell lines, respectively, and the loss of expression correlates with AJAP1 methylation. Restoration of AJAP1 gene expression by transfection or demethylation agents results in decreased tumor cell migration in glioblastoma cell lines. This work shows the significant loss of expression of AJAP1 in glioblastoma and provides evidence of its role in the highly migratory characteristic of these tumors. PMID- 22241218 TI - Phosphoinositide 3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt's lymphoma cells to BH3 mimetics. AB - Burkitt's lymphoma (BL), driven by translocation and overexpression of the c-MYC gene, is an aggressive, highly proliferative lymphoma, and novel therapeutic strategies are required to overcome drug resistance following conventional treatments. The importance of the prosurvival BCL-2 family member BCL-X(L) in BL cell survival suggests that antagonistic BH3-mimetic compounds may have therapeutic potential. Here, we show that treatment of BL cell lines with ABT-737 induces caspase-3/7 activation and apoptosis with varying potency. Using selective inhibitors, we identify phosphoinositide 3-kinase (PI3K) as a proproliferative/survival pathway in BL cells and investigate the potential of combined pharmacologic inhibition of both the BCL-2 family and PI3K signaling pathway. PI3K/AKT inhibition and ABT-737 treatment induced synergistic caspase activation, augmented BL cell apoptosis, and rendered chemoresistant cells sensitive. Targeting mTORC1/2 with PP242 was also effective, either as a monotherapy or, more generally, in combination with ABT-737. The combined use of a dual specificity PI3K/mTOR inhibitor (PI 103) with ABT-737 proved highly efficacious. PI 103 treatment of BL cells was associated with an increase in BIM/MCL-1 expression ratios and loss of c-MYC expression. Furthermore, blocking c MYC function using the inhibitor 10058-F4 also induced apoptosis synergistically with ABT-737, suggesting that maintenance of expression of BCL-2 family members and/or c-MYC by the PI3K/AKT/mTOR pathway could contribute to BL cell survival and resistance to ABT-737. The combined use of BH3 mimetics and selective mTORC1/2 inhibitors may therefore be a useful novel therapeutic approach for the treatment of B-cell malignancy, including chemoresistant lymphomas. PMID- 22241221 TI - Violence in the emergency department. PMID- 22241220 TI - The activation of MEK/ERK signaling pathway by bone morphogenetic protein 4 to increase hepatocellular carcinoma cell proliferation and migration. AB - Hepatocellular carcinoma (HCC) is one of the most common visceral malignancies worldwide, with a very high incidence and poor prognosis. Bone morphogenesis protein 4 (BMP4), which belongs to the TGF-beta superfamily of proteins, is a multifunctional cytokine, which exerts its biologic effects through SMAD- and non SMAD-dependent pathways, and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. Here, we first show that BMP4 and its receptor, BMPR1A, are overexpressed in a majority of primary HCCs and that it promotes the growth and migration of HCC cell lines in vitro. We also establish that BMP4 can induce HCC cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression. Our study indicates that the induction of HCC cell proliferation is independent of the SMAD signaling pathway, as Smad4 knockdown of HCC cell lines still leads to the upregulation of CDK1 and cyclin B1 expression after BMP4 treatment. Using mitogen-activated protein/extracellular signal-regulated kinase (MEK) selective inhibitors, the induction of CDK1, cyclin B1 mRNA and protein were shown to be dependent on the activation of MEK/extracellular signal-regulated kinase (ERK) signaling. In vivo xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than the control groups. Our findings show that the upregulation of BMP4 and BMPR1A in HCC promotes the proliferation and metastasis of HCC cells and that CDK1 and cyclin B1 are important SMAD-independent molecular targets in BMP4 signaling pathways, during the HCC tumorigenesis. It is proposed that BMP4 signaling pathways may have potential as new therapeutic targets in HCC treatment. PMID- 22241222 TI - A new way of looking at the face? PMID- 22241219 TI - Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype. AB - Prostate cancer metastases and hematopoietic stem cells (HSC) frequently home to the bone marrow, where they compete to occupy the same HSC niche. We have also shown that under conditions of hematopoietic stress, HSCs secrete the bone morphogenetic proteins (BMP)-2 and BMP-6 that drives osteoblastic differentiation from mesenchymal precursors. As it is not known, we examined whether metastatic prostate cancer cells can alter regulation of normal bone formation by HSCs and hematopoietic progenitor cells (HPC). HSC/HPCs isolated from mice bearing nonmetastatic and metastatic tumor cells were isolated and their ability to influence osteoblastic and osteoclastic differentiation was evaluated. When the animals were inoculated with the LNCaP C4-2B cell line, which produces mixed osteoblastic and osteolytic lesions in bone, HPCs, but not HSCs, were able to induced stromal cells to differentiate down an osteoblastic phenotype. Part of the mechanism responsible for this activity was the production of BMP-2. On the other hand, when the animals were implanted with PC3 cells that exhibits predominantly osteolytic lesions in bone, HSCs derived from these animals were capable of directly differentiating into tartrate-resistant acid phosphatase positive osteoclasts through an interleukin-6-mediated pathway. These studies for the first time identify HSC/HPCs as novel targets for future therapy involved in the bone abnormalities of prostate cancer. PMID- 22241223 TI - The eye in virology. AB - This article outlines the ocular complications of viral infection. The emphasis is on the most common viruses encountered by the physician, and their clinical features and treatment are discussed while demonstrating the variation and often significant sequelae of ocular viral infection. PMID- 22241224 TI - The eye and phacomatoses. AB - This article reviews the ocular and neuro-opthalmic manifestations of phacomatoses, while emphasizing important differential diagnoses that exist based on their clinical features. Variations in the definition of phacomatoses do exist, but conditions not meeting the classical definition are also presented. PMID- 22241225 TI - The eye in rheumatology. AB - Rheumatic conditions affect a wide variety of tissues, including the eye, and can cause significant visual loss. Early diagnosis coupled with appropriate management, using immunosuppression where necessary, can significantly improve the outcome. This article reviews the most common manifestations seen in clinical practice. PMID- 22241226 TI - The eye in renal disease. AB - This article summarizes the ocular pathology that can be seen in conjunction with renal disease. Both the eye and the kidney can be the target of systemic disease processes, but the eye can also be affected as a consequence of either renal disease or its treatment. PMID- 22241227 TI - The eye in haematological disease. AB - The eye allows living functioning blood vessels to be observed and is thus ideal for the study of haematological disease. Disorders of the blood have significant ocular manifestations and pose a real threat to vision, making knowledge of the subject essential to ophthalmologists, haematologists, oncologists and general physicians. PMID- 22241228 TI - Allocation of kidney transplants in the UK. AB - Live and donation after cardiac death has increased markedly recently. The allocation system for donation after brain death reserves the least mismatched organs for young people. Live donors most often donate to relatives but a scheme tries to 'exchange' live donor kidneys when direct transplantation is not possible. PMID- 22241229 TI - Surgery: a stressful business. AB - Over the years the surgical stress response and the efforts to modify it have been the subject of a great deal of research. Most recently this has led to the development of 'enhanced recovery' programmes which are revolutionizing perioperative patient care across the UK. PMID- 22241230 TI - Opportunities for learning in the surgical workplace and how they can be exploited: a practical guide. AB - Training times and the working week have been shortened but the amount needed to be learned remains the same. This article demonstrates how trainees in surgery can incorporate learning opportunities into their normal working day. PMID- 22241231 TI - Joseph Bell: surgeon and master of 'spot diagnosis'. PMID- 22241232 TI - Surgical emphysema of the neck following arthroscopic shoulder surgery. PMID- 22241233 TI - Hip pain in an elderly man: beware the obturator hernia. PMID- 22241234 TI - Orbital involvement in multiple myeloma. PMID- 22241235 TI - Review your pensions ahead of April 2012 changes. PMID- 22241238 TI - How to run an acute medical take. PMID- 22241237 TI - The obstetric spinal: why sit when you can lie? PMID- 22241239 TI - The fluttering patient: an approach to the patient with palpitations. PMID- 22241240 TI - Clinical coding. PMID- 22241241 TI - The bisferiens pulse. PMID- 22241242 TI - Computer programs for modeling mammalian cell batch and fed-batch cultures using logistic equations. AB - A MATLAB((r)) toolbox was developed for applying the logistic modeling approach to mammalian cell batch and fed-batch cultures. The programs in the toolbox encompass sensitivity analyses and simulations of the logistic equations in addition to cell specific rate estimation. The toolbox was first used to generate time courses of the sensitivity equations for characterizing the relationship between the logistic variable and the model parameters. Subsequently, the toolbox was used to describe CHO cell data from batch and fed-batch mammalian cell cultures. Cell density, product, glucose, lactate, glutamine, and ammonia data were analyzed for the batch culture while fed-batch analysis included cell density and product concentration. In all instances, experimental data were well described by the logistic equations and the resulting specific rate profiles were representative of the underlying cell physiology. The 6-variable batch culture data set was also used to compare the logistic specific rates with those from polynomial fitting and discrete derivative methods. The polynomial specific rates grossly misrepresented cell behavior in the initial and final stages of culture while those based on discrete derivatives had high variability due to computational artifacts. The utility of logistic specific rates to guide process development activities was demonstrated using specific protein productivity versus growth rate trajectories for the 3 cultures examined in this study. Overall, the computer programs developed in this study enable rapid and robust analysis of data from mammalian cell batch and fed-batch cultures which can help process development and metabolic flux estimation. PMID- 22241243 TI - Correlation between the band gap, elastic modulus, Raman shift and melting point of CdS, ZnS, and CdSe semiconductors and their size dependency. AB - With structural miniaturization down to the nanoscale, the detectable quantities of solid materials no longer remain constant but become tunable. For the II-VI semiconductors example, the band gap expands, the elastic modulus increases, the melting point drops, and the Raman optical phonons experience red shift associated with creation of low frequency Raman acoustic modes that undergo blue shift with decreasing the dimensional scale. In order to understand the common origin of the size dependency of these seemingly irrelevant properties, we formulated these quantities for CdS, ZnS, and CdSe semiconductors from the perspectives of bond order-length-strength correlation and the local bond averaging approach. Consistency between the theory predictions and the measured size dependence of these quantities clarified that the undercoordination-induced local strain and quantum entrapment and the varied fraction of undercoordinated atoms of the entire solid correlate these quantities and dominate their size effect. PMID- 22241244 TI - Revisiting the March 11, 2011 earthquake and tsunami: resilience and restoration. PMID- 22241245 TI - A study of the atmospherically important reactions of dimethylsulfide (DMS) with I2 and ICl using infrared matrix isolation spectroscopy and electronic structure calculations. AB - The reactions of dimethylsulfide (DMS) with molecular iodine (I(2)) and iodine monochloride (ICl) have been studied by infrared matrix isolation spectroscopy by co-condensation of the reagents in an inert gas matrix. Molecular adducts of DMS + I(2) and DMS + ICl have also been prepared using standard synthetic methods. The vapour above each of these adducts trapped in an inert gas matrix gave the same infrared spectrum as that recorded for the corresponding co-condensation reaction. In each case, the infrared spectrum has been interpreted in terms of a van der Waals adduct, DMS : I(2) and DMS : ICl, with the aid of infrared spectra computed for their minimum energy structures at the MP2 level. Computed relative energies of minima and transition states on the potential energy surfaces of these reactions were used to understand why they do not proceed further than the reactant complexes DMS : I(2) and DMS : ICl. The main findings of this research are compared with results obtained earlier for the DMS + Cl(2) and DMS + Br(2) reactions, and the atmospheric implications of the conclusions are also considered. PMID- 22241246 TI - Preoperative short-course radiotherapy with delayed surgery in primary rectal cancer. AB - BACKGROUND: Short-course radiotherapy (SRT) with immediate surgery and long course chemoradiotherapy (CRT) are currently the standard preoperative treatment options for rectal cancer. SRT with surgery delayed for 4-8 weeks (SRT-delay) is an option described for patients with locally advanced tumours who are not fit for CRT. This study examined early toxicity, response to radiotherapy (RT) and short-term outcomes of SRT-delay. METHODS: Patients in the Stockholm region diagnosed with rectal cancer between January 2002 and December 2008, who received SRT (25 Gy over 5-7 days) and had surgery with resection of the primary tumour more than 4 weeks after the start of RT, were identified from a prospective register. Additional data were obtained by retrospective review of clinical records. RESULTS: A total of 112 patients had SRT and delayed surgery. The reasons given for SRT included primary unresectable disease and co-morbidities. Severe RT-induced toxicity was noted in six patients (5.4 per cent). Signs of tumour regression were seen on magnetic resonance imaging in 74 per cent of patients reassessed after RT. Pathological stage (44.9 versus 60.7 per cent stage 0-II; P < 0.001), tumour category (11.9 versus 29.4 per cent T0-T2; P < 0.001) and node category (45.8 versus 63.6 per cent N0; P = 0.014) were significantly lower than those at initial assessment. Nine patients (8.0 per cent) had a complete pathological response. CONCLUSION: The SRT-delay schedule was a feasible alternative with low toxicity. The study indicated a downstaging effect of SRT if surgery was delayed. PMID- 22241247 TI - Rare genomic deletions and duplications and their role in neurodevelopmental disorders. AB - Copy number variations (CNVs) are deletions and duplications of DNA sequences that vary in length from a few base pairs to several million. While these structural variations are often benign, they can disrupt vital biological functions and result in disease. CNVs have been identified as causal in a number of neurodevelopmental disorders (NDs), including but not limited to, autism, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. Here, we examine CNV research into these disorders, and discuss relevant methodological considerations. By identifying specific rare deletions and duplications, we may be better able to determine the etiology of neurodevelopmental disorders and identify appropriate treatments. PMID- 22241249 TI - Lead concentration increase in the hepatic and gill soluble fractions of European chub (Squalius cephalus)-an indicator of increased Pb exposure from the river water. AB - PURPOSE: To examine if chronic exposure of feral fish to elevated Pb concentrations in the river water (up to 1 MUg L(-1)), which are still lower than European recommendations for dissolved Pb in surface waters (7.2 MUg L(-1); EPCEU (Official J L 348:84, 2008)), would result in Pb accumulation in selected fish tissues. METHODS: Lead concentrations were determined by use of HR ICP-MS in the gill and hepatic soluble fractions of European chub (Squalius cephalus) caught in the Sutla River (Croatia-Slovenia). RESULTS: At the site with increased dissolved Pb in the river water, soluble gill Pb levels (17.3 MUg L(-1)) were approximately 20 times higher compared to uncontaminated sites (0.85 MUg L(-1)), whereas the ratio between contaminated (18.1 MUg L(-1)) and uncontaminated sites (1.17 MUg L( 1)) was lower for liver (15.5). Physiological variability of basal Pb concentrations in soluble gill and hepatic fractions associated to fish size, condition, sex, or age was not observed, excluding the possibility that Pb increase in chub tissues at contaminated site could be the consequence of studied biotic parameters. However, in both tissues of Pb-exposed specimens, females accumulated somewhat more Pb than males, making female chubs potentially more susceptible to possible toxic effects. CONCLUSIONS: The fact that Pb increase in gill and hepatic soluble fractions of the European chub was not caused by biotic factors and was spatially restricted to one site with increased dissolved Pb concentration in the river water points to the applicability of this parameter as early indicator of Pb exposure in monitoring of natural waters. PMID- 22241248 TI - Gene * environment interaction models in psychiatric genetics. AB - Gene-environment (G * E) interaction research is an emerging area in psychiatry, with the number of G * E studies growing rapidly in the past two decades. This article aims to give a comprehensive introduction to the field, with an emphasis on central theoretical and practical problems that are worth considering before conducting a G * E interaction study. On the theoretical side, we discuss two fundamental, but controversial questions about (1) the validity of statistical models for biological interaction and (2) the utility of G * E research for psychiatric genetics. On the practical side, we focus on study characteristics that potentially influence the outcome of G * E interaction studies and discuss strengths and pitfalls of different study designs, including recent approaches like Genome-Environment Wide Interaction Studies (GEWIS). Finally, we discuss recent developments in G * E interaction research on the most heavily investigated example in psychiatric genetics, the interaction between a serotonin transporter gene promoter variant (5-HTTLPR) and stress on depression. PMID- 22241250 TI - Use of statin medications and risk of esophageal adenocarcinoma in persons with Barrett's esophagus. AB - BACKGROUND: Persons with Barrett's esophagus experience increased incidence of esophageal adenocarcinoma and may benefit from use of preventives. Studies suggest that statin medications may have chemopreventive properties; we therefore assessed the association between statin use and progression to esophageal adenocarcinoma. METHODS: In a prospective cohort of 411 persons with Barrett's, Cox regression was used to calculate HRs for nonsteroidal anti-inflammatory drug (NSAID) and statin use accounting for variation in use during follow-up and adjusting for age, sex, and smoking. RESULTS: The HRs for statin use among all participants were 0.59 [95% confidence interval (CI), 0.26-1.33] and 0.68 (95% CI, 0.30-1.54) before and after further adjustment for NSAID use, respectively. Among persons with high-grade dysplasia, the HRs for statin use were 0.31 (95% CI, 0.11-0.86) and 0.41 (95% CI, 0.13-1.26) before and after adding NSAIDs to the model, respectively. CONCLUSIONS: While the reduced risk of esophageal adenocarcinoma observed among statin users may be explained by chance, the point estimates are similar in magnitude to those previously reported for NSAID use in this cohort and are unlikely to be confounded by known risk factors. IMPACT: Further study in larger cohorts and meta-analyses of the potential for statins to reduce risk of esophageal adenocarcinoma is warranted. PMID- 22241252 TI - [Stress, anxiety and depression in magistrates from Lima, Peru]. AB - OBJECTIVE: To measure the general and work related stress, depression and anxiety in Magistrates (Judges and District Attorneys) of Lima Judicial District. MATERIAL AND METHODS: We carried out a transversal and descriptive study. A population of 1137 magistrates from the Lima Jurisdictional District of the Judicial System, was randomly sampled by a strata representing every agency of the Judicial System. The final sample included 287 magistrates: 138 District Attorneys and 149 Judges. After informed consent, a questionnaire composed by four previously validated instruments was applied to measure general and work related stress, anxiety and depression. RESULTS: General stress was present in 18.5 % of the participants; work related stress 33.7 %; anxiety 12.5 %, and depression 15 %. All three conditions were present in 6.6 % of the participants and at least one in 25.9 %. General stress was associated to depression (OR: 4.9; IC95 % 1.6-15.1) and anxiety (OR: 8.5; IC95 % 2.5-28.6) by logistic regression. CONCLUSION: Lima Judicial District's Magistrates present a triad composed by high levels of labor stress, anxiety and depression. A quarter of the participants present at least one of those conditions. In that perspective, it is recommended that intervention and preventive programs address stress, anxiety and depression simultaneously, given their strong association. PMID- 22241253 TI - [Genetic polymorphism of apolipoprotein E in a Peruvian population]. AB - OBJECTIVES: To determine the allelic and genotypic frequencies of the APOE gene in a sample of a population group in Peru. MATERIALS AND METHODS: Cross-sectional analytic study in 189 apparently healthy volunteers, workers of the Instituto Nacional de Ciencias Neurologicas in Lima, Peru, divided into 5 groups by birth department and two generations ancestry. Genomic DNA was amplified using PCR RFLP. The resulting fragments were detected by 12 % polyacrylamide gel electrophoresis. RESULTS: The epsilon3 allele is the most frequent in all the groups (93.9 %), with low epsilon4 (5 %) and epsilon2 (1.1 %) allele frequencies. The analysis of heterozygosity (H) for each group displays intermediate diversity between 10 and 20%. Population genetic diversity (Ht) and diversity within populations (Hs) are 14.43 % and 14.31% respectively, suggesting genetic proximity between the studied groups for the ApoE polymorphism. CONCLUSIONS: Allele frequencies of the ApoE gene found show that allele epsilon3 has one of the highest frequencies and epsilon4 allele one of the lowest compared to other population groups in the world, with possible implications in the risk of neurological, cardiovascular and other diseases in our country. PMID- 22241251 TI - [Ethics, bioethics and medicine]. PMID- 22241254 TI - [Clinical and polysomnographyc differences between obese and non obese patients with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVES: To describe the clinical and polysomnographyc differences between obese and non- obese patients with obstructive sleep apnea-hypopnea (OSAH) syndrome. MATERIALS AND METHODS: A physical examination, the Epworth Sleepiness Scale (ESS) and a polysomnography were performed to all included patients. Obesity was defined as a body mass index (BMI) of >= 30 kg/m(2). RESULTS: 408 patients with OSAH were analyzed, out of these, 119 (47 %) were obese. OSAH was mild in 101 (25 %), moderate in 91 (22 %) and severe in 216 (53 %). There were no age, sex and EES score differences between obese and non-obese patients. Cervical perimeter and sleepiness prevalence according to the ESS were significant higher in obese population. Obese patients had higher comorbidity related to dyslipidemia, high blood pressure and coronary disease. With respect to the polysomnographyc variables, the indexes of respiratory events and the levels of oxygen saturation were worse in obese patients. There were no differences in the other variables. The regression analysis showed association between obesity and OSAH severity. CONCLUSIONS: OSAH is a clinical condition not limited to obese population, although this group has a higher comorbidity and OSAH severity. PMID- 22241255 TI - [Enteroviral central nervous system infections in children treated at a hospital in Lima, Peru]. AB - OBJECTIVES: To determine the frequency and clinical features of central nervous system infections caused by enterovirus in children treated at the Hospital Nacional Cayetano Heredia in Lima, Peru. MATERIALS AND METHODS: A prospective, descriptive study was performed from April 2008 to March 2010. Patients aged 1 month - 14 years with clinical diagnosis of encephalitis or aseptic meningitis were included. We investigated the presence of enterovirus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and varicella-zoster virus (VZV) by polymerase chain reaction (PCR). RESULTS: 97 patients were included, out of which 69 % had acute encephalitis and 31 % acute meningitis. Enteroviruses were identified in 52,6% of all acute non-bacterial central nervous system infections; corresponding to 83,3 % of meningitis and 38,8 % of encephalitis. There were no cases of infection due to HSV-1, HSV-2 or VZV. Enterovirus infections reached 82,9 % in the warm months (November-January) and 28,6 % in the colder months (May July). CONCLUSIONS: Enteroviruses are the principal etiologic agents in acute aseptic meningitis and encephalitis in pediatric patients in Lima, Peru. Enteroviruses have a seasonal epidemiological pattern with a clear increase in the number of cases during the summer months. It is useful to have this rapid diagnostic method available as an aid in the management of acute central nervous system infections. PMID- 22241256 TI - [Children hospitalized with influenza pneumonia AH1N1/2009 pandemic in the INSN]. AB - OBJECTIVE: To determine the clinical and demographic characteristics of pneumonia with influenza virus AH1N1/2009 pandemic at the National Institute of Child. METHODS: Retrospective case series in children hospitalized for influenza pneumonia pandemic AH1N1/2009 in a pediatric hospital. Reviewed the medical records between the months of June to September 2009. All cases had virological confirmation, we describe the clinical characteristics and conditions of severity. RESULTS: A total of 74 children of pneumonia with influenza virus AH1N1/2009 pandemic (NVIp), of those 50 were community acquire pneumonia viral (NACv) and 24 pneumonia nosocomial viral (NNv), 16 required mechanical ventilation. 12 died, all had preexisting factors. NN cases showed statistical association with mortality. The most frequent factors were malnutrition, respiratory infections, congenital heart disease and neurological deficits In NACv cases the children under 6 years accounted for 72% (36/50). The median disease duration was 5 days. The most frequent symptoms were fever, cough, runny nose. Received oseltamivir 82%. The chest radiograph 48% of cases showed patchy infiltrates and 44% interstitial infiltrate on chest radiograph. Protein c reactive (CRP) more than 10mg / L was significantly associated with respiratory failure (p <0.05). CONCLUSIONS: Cases of NN found who had more mortality, even those who had the highest PCR and those with preexisting condition. PMID- 22241257 TI - [To inadequate indication of blood transfusion in a reference hospital in Lima, Peru]. AB - OBJECTIVES: To determine frequency and clinical criteria associated to the inadequate indication of blood products. MATERIALS AND METHODS: A cross-sectional study was performed between June and October 2002. Clinical charts and the laboratory tests from patients receiving blood transfusions were examined. A blood transfusion guideline was elaborated based on published consensus, and used to determine whether the indications for blood products transfusion was adequate or inadequate. RESULTS: A total of 311 blood transfusions were evaluated. The global prevalence of inappropriate indication was of 33.8 %. Red blood cells (RBC) were used inappropriately in 25 %, fresh frozen plasma (FFP) in 59 %, platelets in 13 % and cryoprecipitate in 88 %. From surgery related transfusions half of the indications were inadequate. In internal medicine, ICU and emergency related transfusions, approximately one third of the indications were inadequate. The FFP is the worst used blood product. CONCLUSIONS: We found a high frequency of inadequate blood transfusion. The identification of the specific clinical criteria used in inadequate indications transfusions will help in designing a better educational strategy towards a more rational use of the blood products. PMID- 22241258 TI - [Registry of patients with stroke stated in a public hospital of Peru, 2000 2009]. AB - We performed a descriptive study taking on account the characteristics of the registries of the patients hospitalized at the Hospital Nacional Cayetano Heredia between the years 2000 and 2009 with stroke as hospitalization diagnosis. 2225 records were obtained from patients older than 18, with stroke. According to ICD 10, 1071 had diagnosis of ischemic stroke, 554 were hemorrhagic, 183 were subarachnoid hemorrhage, 49 were ischemic plus hemorrhagic, 10 were transient ischemic attack (TIA) and in 358 we were unable to specify the type of stroke. 352 deaths were recorded (19.6 %), most of them during the first 3 days. The male / female ratio was 1.09, the mean age 64.1 +/- 17.2 years and the median length of hospital stay was 9 days. The most common associated conditions were high blood pressure, atrial fibrillation and type 2 diabetes mellitus. The mortality found is the highest reported in our country, constant in all age groups and higher in women. PMID- 22241259 TI - [Effect of sacha inchi oil (plukenetia volubilis l) on the lipid profile of patients with hyperlipoproteinemia]. AB - We performed a pilot, experimental, open study in order to know the effect, effective dosage and secondary effects of sacha inchi's (Plukenetia Huallabamba) [corrected] oil on the lipid profiles of patients with hypercholesterolemia. We included 24 patients of ages 35 to 75, to whom we measured total cholesterol (TC), HDL, triglycerides (Tg), glucose (G), non-esterified fatty acids (NEFA) and insulin (I) levels in blood, then we randomized them to receive sacha inchi oil orally 5 ml or 10 ml of a suspension of sacha inchi oil (2gr/5ml) for four months. The oil intake produced a decrease in the mean values of TC, and NEFA, and a rise in HDL in both subgroups. The subgroup receiving 10 ml was associated to an increase in the insulin levels. Sacha inchi oil appears to have beneficial effects on the lipid profile of patients with dyslipidemia, but their efficacy and security should be evaluated in randomized clinical trials. PMID- 22241260 TI - [Nontraumatic spinal cord injury: etiology, demography and clinics]. AB - We performed a retrospective and descriptive cross-sectional; study in 210 hospitalized patients with spinal cord injury at the National Institute of Rehabilitation (INR), Callao, Peru from 2000-2006. The goal was to describe etiology, and clinical and socio-demographic characteristics of non traumatic spinal cord injuries (LMNT). We found a prevalence of 27 % for LMNT, average age at onset of 32.0 years, male gender 50.5 %, and secondary education completed in 41.9 %, poverty 90.5 %. The infectious etiology (viral and bacterial) was predominant in 37.6 %, with 11.9 infected with HTLVI. Although the INR is a reference center, the findings can't be generalized because it isn't a representative sample of the Peruvian population, further studies are necessary to propose strategies for prevention and control, considering the high cost of integral rehabilitation treatment in these patients. PMID- 22241261 TI - [Dog bite accidents in a children hospital at Lima, Peru. Retrospective study from 1995 - 2009]. AB - From 1995 to 2009, 206 cases of dog bites were recorded among hospitalized patients at the Children National Health of, Lima-Peru. The median of age was 4 years, and for hospitalization time was 3 days. Most patients were males (61.7 %). The bites occurred in the house of a third person (39.3 %), on the street (33.5 %), or in the victim's house (27.2 %). A 66.5 % of the bites were provoked and 88.8 % were from animals known to the victim. The dog breed was recognized in 34 % (52.9 % were mongrel dogs). Multiple lesions were identified in 79.1 %, and the most frequently bitten areas were head and neck (79.1 %). Complications were reported in 20.4 % and aesthetic sequelae in 94.7 %. PMID- 22241262 TI - [Use of medication in elderly people don't institutionalized]. AB - Misuse of drugs in the elderly is a rampant public health problem. We conducted a cross-sectional study using a self-administered survey to assess drug use and inadedequate prescription among noninstotunilazed elderly patients in the city of La Plata, Argentina in 2009. The total number of respondents was 215. The average number of drugs used per person was 3.19 +/- 2.02, polypharmacy was present in 24.1 % of subjects. Potentially inappropriate medications (MPI) were given in 25.5 %, 31.9 % and 30.0 % of the patients, according to Beers criteria, Priscus list, and STOPP criteria, respectively. This research found that potentially inappropriate prescribing is common and there is a growing need for a list of potentially inappropriate medications, as appropriate to each situation, that considers situations where treatment is suboptimal. PMID- 22241263 TI - [Molecular mechanisms of antibiotic resistance in Escherichia coli- associated diarrhea]. AB - Antibiotic resistance is an emerging problem worldwide present in many bacteria, specially in Escherichia coli, which has high percentages of resistance to ampicilline, thrimethoprim-sulfamethoxazole, tetracycline, chloramphenicol and nalidixic acid, which implies important complications in antibiotic treatment when required. The increasing antibiotic resistance is due to the acquisition of different molecular mechanisms of resistance through point chromosomal mutations and /or horizontal transfer of genetic material between related or different species facilitated by some genetic elements such as integrons. This review discusses the effects of the most common molecular mechanisms of antibiotic resistance in E. coli: enzymatic inactivation, changes in the target site and permeability disturbances. Getting to know the mechanisms of resistance which are involved, as the World Health Organization recommends, will allow us to improve the surveillance of the antibiotic resistance, the control policies and the antibiotic utilization at a national level. PMID- 22241264 TI - [Challenges of bioethics in twenty-first century medicine]. AB - In order to propose possible challenges of bioethics in the twenty-first century medicine, it is necessary to consider that there were some past challenges (at the origin of this new discipline called bioethics), that the challenges have been modified with scientific, biomedical and humanistic breakthroughs, considering at the same time that challenges that may arise in the future will be, in different ways, a result of this historical evolution. The major challenges would be in the future: the unsolved problems of justice, equity and poverty; the challenges posed by the introduction of new technologies with the nanomedicine paradigm; and finally, the challenges driven by breakthroughs in neurosciences with the neuroethics paradigm. PMID- 22241265 TI - [Ethics and investigation]. AB - The authors make a critical evaluation of the ethical aspects of research based on their experience as university teachers and members of Ethics Committees. They invite to the discussion on topics that they consider polemic. They begin by mentioning the regulatory role of the International and Local Ethical Norms and of the Ethics Committees. They comment on the position of South American bioethicists regarding the so-called ethical "double standard" and on the liberalization of the use of the placebo. They criticize the damage that the system of patents causes on low- resources patients, as well as the lack of interest in the development of new medications to treat neglected diseases or those diseases which are only prevalent in poor countries, and the excessive length of the Informed Consents. They finish giving their opinion about the distribution of the clinical trials among the researchers, the problems that affect the Ethics Committees and some contents of the Regulation of Clinical Trials of the National Institute of Health. PMID- 22241266 TI - [Ethics and medicine: the experience of the Peruvian Medical Association]. AB - This article shows the work of the Peruvian Medical Association with respect to ethical disciplinary procedures, but also shows how, beyond the ethical control, the Order has promoted through a set of actions, a technically competent health care that respects the dignity and fundamental human rights. Part of these actions are the establishment of the Patient's Day, the emphasis in improving the quality and safety in the care of the users of the health services, the initiative to prevent and treat adverse events, the regulation and improvement of the physicians training both in pre as in post-graduate levels, and the demand for the establishment of an optimal health system and policies that will realize the right to health in the context of the principles of bioethics. PMID- 22241267 TI - [Progress and challenges of clinical trials registration in Latin America and the Caribbean's]. AB - Clinical trial registries are one of the main sources of information concerning health research interventions that have been or are being carried out throughout the world. The World Health Organization (WHO) established a minimum data set to be recorded (20 items), which was agreed upon internationally with the stakeholders, and established a network of primary and associated records. In addition to the register ClinicalTrial.Gov (of the United States of America), there are currently two primary registries in the Americas (from Brazil and Cuba) that meet WHO requirements and provide data to WHO's International Clinical Trials Registry Platform (ICTRP). Furthermore, there are important advances in the region related to the regulations, development and implementation of national registries and to the support of the ethics committees and editors to this initiative. PMID- 22241269 TI - [Agents by dimorphic fungi and Cryptococcus neoformans infections]. PMID- 22241270 TI - [The human papillomavirus vaccine: some precisions]. PMID- 22241271 TI - [Excellence research in altitude: fifty years after the foundation of the Instituto de Investigaciones de la altura of the Universidad Peruana Cayetano Heredia]. PMID- 22241272 TI - [Contribution of the societies of medical students to scientific publications in Scielo-Peru, 2009-2010]. PMID- 22241273 TI - [Is there a space for research during the medical residency in Peru?]. PMID- 22241274 TI - [Migration of Peruvan physicians to Spain, 2005-2009]. PMID- 22241275 TI - [Paralitic poliomyelitis caused by the oral Sabin vaccine: time for a vaccine change?]. PMID- 22241276 TI - [Under reporting of depressive disorders]. PMID- 22241277 TI - [The need for evaluating the peruvian clinical guidelines for treatment of mental disorders]. PMID- 22241278 TI - Comments on the AZFc markers used for screening of Yq microdeletions. PMID- 22241279 TI - Spontaneous inter-conversion of insulin fibril chirality. AB - Amyloid fibrils are associated with many neurodegenerative diseases and are considered to be the energetically most favorable form of proteins. Here we report that a small pH change initiates spontaneous transformation of insulin fibrils from one polymorph to another. As a result, fibril supramolecular chirality overturns both accompanying morphological and structural changes. PMID- 22241280 TI - Systematic review and meta-analysis of the effect of North American working hours restrictions on mortality and morbidity in surgical patients. AB - BACKGROUND: Short duty hours, imposed by the Accreditation Council of Graduate Medical Education (ACGME) regulations, have been claimed to be associated with loss of continuity of care among surgical patients, leading to a potentially increased risk of adverse surgical outcomes. This systematic review and meta analysis assessed the strength of associations between duty hour restrictions and morbidity and mortality of various surgical procedures. METHODS: MEDLINE, Embase, BIOSIS Previews((r)), the Education Resources Information Center and the Cochrane Central Register of Controlled Trials (January 2000 to September 2009) were searched, and reports screened to identify comparative studies of mortality and morbidity before and after the introduction of ACGME regulation periods. Random effects (RE) and quality-effects (QE) meta-analyses were performed to determine the risk of morbidity or death associated with long duty hours compared with shorter duty hours. Results are presented as odds ratio (OR) with 95 per cent confidence interval. RESULTS: A total of 19 data sets (10 articles), including 730,648 subjects in the mortality studies and 64,346 in the morbidity studies, were analysed. Long duty hours were associated with a non-significantly increased risk of death compared with shorter duty hours (OR 1.28, 0.94 to 1.73). There was no difference in morbidity between the two groups (OR 1.03, 0.67 to 1.57). Mortality associations were generally stronger for general surgery, more recent studies and higher-quality studies. Heterogeneity was evident among the studies included. CONCLUSION: The reduction in working hours has not affected patient care negatively in terms of demonstrable differences in morbidity and mortality. However, it cannot be distinguished whether this effect is actually due to a non detrimental effect of the reduction in working hours or whether any such detriment is offset by continually improving patient care and increased surgical supervision. PMID- 22241281 TI - No negative symptoms in healthy volunteers after single doses of amisulpride, aripiprazole, and haloperidol: a double-blind placebo-controlled trial. AB - Noncompliance and poor outcome in patients with schizophrenia are closely related to the negative symptoms secondary to antipsychotics. No controlled study has evaluated whether amisulpride and aripiprazole induce negative symptoms. The aim of this study was to assess the effects of single doses of amisulpride, aripiprazole, haloperidol, and risperidone in healthy volunteers. Seventy-eight young volunteers took part in this double-blind, randomized, placebo-controlled, parallel study of four antipsychotics: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, and 2 mg risperidone. Assessments of negative symptoms were done 4 h after administration using both subjective rating scales (Neuroleptic Induced Deficit Syndrome Scale and Subjective Deficit Syndrome Scale) and an objective rating scale (Scale for the Assessment of Negative Symptoms). Risperidone only produced significant increases on the avolition score of the Neuroleptic Induced Deficit Syndrome Scale and blunted affect and alogia scores of the Scale for the Assessment of Negative Symptoms compared with placebo. The effect on blunted affect persisted after controlling for mental sedation. Amisulpride, aripiprazole, and haloperidol did not induce negative symptoms. Aripiprazole and risperidone induced mild extrapyramidal symptoms. The most common adverse events were somnolence and cognitive slowing. These data indicate that a single risperidone dose induces negative symptoms in normal volunteers, whereas amisulpride, aripiprazole, and haloperidol do not. These characteristics of antipsychotics should be considered when choosing optimal drugs for patients with psychosis. PMID- 22241282 TI - Simulating and evaluating the local behavior of small pedestrian groups. AB - Recent advancements in local methods have significantly improved the collision avoidance behavior of virtual characters. However, existing methods fail to take into account that in real life pedestrians tend to walk in small groups, consisting mainly of pairs or triples of individuals. We present a novel approach to simulate the walking behavior of such small groups. Our model describes how group members interact with each other, with other groups and individuals. We highlight the potential of our method through a wide range of test-case scenarios. We evaluate the results from our simulations using a number of quantitative quality metrics, and also provide visual and numerical comparisons with video footages of real crowds. PMID- 22241283 TI - Automated construction of low-resolution, texture-mapped, class-optimal meshes. AB - In this paper, we present a framework for the groupwise processing of a set of meshes in dense correspondence. Such sets arise when modeling 3D shape variation or tracking surface motion over time. We extend a number of mesh processing tools to operate in a groupwise manner. Specifically, we present a geodesic-based surface flattening and spectral clustering algorithm which estimates a single class-optimal flattening. We also show how to modify an iterative edge collapse algorithm to perform groupwise simplification while retaining the correspondence of the data. Finally, we show how to compute class-optimal texture coordinates for the simplified meshes. We present alternative algorithms for topologically symmetric data which yield a symmetric flattening and low-resolution mesh topology. We present flattening, simplification, and texture mapping results on three different data sets and show that our approach allows the construction of low-resolution 3D morphable models. PMID- 22241284 TI - Constraint fluids. AB - We present a fluid simulation method based on Smoothed Particle Hydrodynamics (SPH) in which incompressibility and boundary conditions are enforced using holonomic kinematic constraints on the density. This formulation enables systematic multiphysics integration in which interactions are modeled via similar constraints between the fluid pseudoparticles and impenetrable surfaces of other bodies. These conditions embody Archimede's principle for solids and thus buoyancy results as a direct consequence. We use a variational time stepping scheme suitable for general constrained multibody systems we call SPOOK. Each step requires the solution of only one Mixed Linear Complementarity Problem (MLCP) with very few inequalities, corresponding to solid boundary conditions. We solve this MLCP with a fast iterative method. Overall stability is vastly improved in comparison to the unconstrained version of SPH, and this allows much larger time steps, and an increase in overall performance by two orders of magnitude. Proof of concept is given for computer graphics applications and interactive simulations. PMID- 22241285 TI - Pb3+ radiation defects in Ca9Pb(PO4)6(OH)2 hydroxyapatite nanoparticles studied by high-field (W-band) EPR and ENDOR. AB - W-band pulsed EPR and ENDOR investigations of X-ray irradiated nanoparticles of synthetic hydroxyapatite Ca(9)Pb(PO(4))(6)(OH)(2) are performed. It is shown that in the investigated species lead ions probably replace the Ca(1) position in the hydroxyapatite structure. PMID- 22241286 TI - The effects of maternal diabetes on expression of insulin-like growth factor-1 and insulin receptors in male developing rat hippocampus. AB - Diabetes during pregnancy causes neurodevelopmental and neurocognitive abnormalities in offspring. Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. We examined the effects of maternal diabetes on insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (InsR) expression in the developing rat hippocampus. Female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was killed at P0, P7, and P14. We found a significant bilateral upregulation of both IGF-1R and InsR transcripts in the hippocampus of pups born to diabetic mothers at P0, as compared to controls. However, at the same time point, the results of western blot analysis revealed only a slight change in their protein levels. At P7, there was a marked bilateral reduction in mRNA expression and protein levels of IGF-1R, although not of InsR in the diabetic group. We also found a downregulation in IGF1-R transcripts, especially in left hippocampus of the diabetic group at P14. Moreover, at the same time point, InsR expression was significantly decreased in both hippocampi of diabetic newborns. When compared with controls, we did not find any difference in hippocampal IGF-1R or InsR mRNA and protein levels in the insulin-treated group. The present study revealed that diabetes during pregnancy strongly influences the regulation of both IGF-1R and InsR in the right/left developing hippocampi. Furthermore, the rigid control of maternal glycaemia by insulin administration normalized these effects. PMID- 22241287 TI - Minimally invasive versus open esophagectomy for cancer: more questions than answers. PMID- 22241288 TI - Minimally invasive esophagectomy: short-term outcomes appear comparable to open esophagectomy. PMID- 22241289 TI - Surgical stress response and postoperative immune function after laparoscopy or open surgery with fast track or standard perioperative care: a randomized trial. AB - OBJECTIVE: To evaluate the effect of laparoscopic or open colectomy with fast track or standard perioperative care on patient's immune status and stress response after surgery. METHODS: Patients with nonmetastasized colon cancer were randomized to laparoscopic or open colectomy with fast track or standard care. Blood samples were taken preoperatively (baseline), and 1, 2, 24, and 72 hours after surgery. Systemic HLA-DR expression, C-reactive protein, interleukin-6, growth hormone, prolactin, and cortisol were analyzed. RESULTS: Nineteen patients were randomized for laparoscopy and fast track care (LFT), 23 for laparoscopy and standard care (LS), 17 for open surgery and fast track care (OFT), and 20 for open surgery and standard care (OS). Patient characteristics were comparable. Mean HLA-DR was 74.8 in the LFT group, 67.1 in the LS group, 52.8 in the OFT group, and 40.7 in the OS group. Repeated-measures 2-way analysis of variance (ANOVA) showed this can be attributed to type of surgery and not aftercare (P = 0.002). Interleukin-6 levels were highest in the OS group. Repeated-measures 2 way ANOVA showed this can be attributed to type of surgery and not aftercare (P = 0.001). C-reactive protein levels were highest in the OS group. Following repeated-measures 2-way ANOVA, this can be attributed to type of surgery and not aftercare (P = 0.022). Growth hormone was lowest in the LFT group. Following repeated-measures 2-way ANOVA, this can be attributed to type of aftercare and not to type of surgery (P = 0.033). No differences between the groups were seen regarding prolactin or cortisol. No differences in (infectious) complication rates were observed between the groups. CONCLUSIONS: This randomized trial showed that immune function of HLA-DR in patients undergoing laparoscopic surgery with fast track care remains highest. This can be attributed to type of surgery and not aftercare. These results may indicate a reason for the accelerated recovery of patients treated laparoscopically within a fast track program as described in the LAparoscopy and/or FAst track multimodal management versus standard care (LAFA-Trial) (www.trialregister.nl, protocol NTR222). PMID- 22241290 TI - Hyperthermic pelvic perfusion with tumor necrosis factor-alpha for locally advanced cancers: encouraging results of a phase II study. AB - PURPOSE: To assess the efficacy of isolated pelvic perfusion (IPP) with tumor necrosis factor (TNF)-alpha and melphalan in patients with locally advanced cancers in the pelvic and groin area requiring mutilating surgery. METHODS: A total of 27 patients were enrolled (carcinoma, n = 17; sarcoma/melanoma, n = 4; and endocrine tumor, n = 6). They were candidates for exarticulation (n = 3) or exenteration (n = 11) or were judged unresectable (n = 13). In installing IPP, tourniquets were positioned around both thighs, and an inflated pressure suit was placed at a subthoracic position. Tumor necrosis factor-alpha (300 MUg) was injected in the perfusate, followed 5 minutes later by melphalan at 1.5 mg/kg. After 30 minutes, the remaining drugs were washed out. Leakage was assessed with technetium Tc 99m radiolabeled human serum albumin, and a pharmacokinetic study was performed. Efficacy was based on the complete response rate observed on magnetic resonance imaging. RESULTS: Pelvic/systemic ratios of melphalan/TNF/technetium Tc 99m were 14.2/7/3.6. Responses on magnetic resonance imaging were as follows: 30% complete, 30% partial, 19% no change, and 15% progression. Two patients were not evaluable because they did not receive the treatment. Pre-IPP/post-IPP median percentage of necrosis on magnetic resonance imaging was 10%/70%. Median follow-up was 43 months. Median overall survival was 17 months. Twelve-month survival rate, disease-free survival, and local and metastatic recurrence rates were 67%, 30%, 57%, and 26%, respectively. CONCLUSIONS: Isolated pelvic perfusion with TNF-alpha compares favorably with historical data, as it was observed in limb perfusion and could provide a chance to translate its successful combination with chemotherapy into treatment of locally advanced pelvic cancers. PMID- 22241291 TI - Liver regeneration after portal vein embolization using absorbable and permanent embolization materials in a rabbit model. AB - OBJECTIVE: To compare the safety and hypertrophy response after portal vein embolization (PVE) using 2 absorbable and 3 permanent embolization materials. BACKGROUND: Portal vein embolization is used to increase future remnant liver volume preoperatively. Application of temporary, absorbable embolization materials could be advantageous in some situations, provided sufficient hypertrophy is achieved from the nonembolized lobe. METHODS: Six groups of rabbits (n = 5) underwent PVE of 80% of the total liver volume using saline (sham), gelatin sponge, fibrin glue, polyvinyl alcohol particles with coils, n butyl cyanoacrylate, or polidocanol. The rabbits were killed after 7 days. Portography, computed tomographic volumetry, Doppler ultrasonography, laboratory liver function and damage parameters (nonembolized) liver-to-body weight ratio, immunohistochemistry, and cytokine and growth factor tissue levels were assessed to examine the differences in the liver regeneration response. RESULTS: Polidocanol was discontinued because of toxic reactions in 3 rabbits. Gelatin sponge was the only material that was absorbed after 7 days and resulted in less hypertrophy of the nonembolized lobe than the other 3 materials. There were no significant differences in hypertrophy response between the other 3 embolization groups. Volumetric data obtained from computed tomography were supported by liver to-body weight ratio and the amount of proliferating hepatocytes. The volume gain of the nonembolized lobe was proportional to the volume loss of the embolized liver lobes. The number of Kupffer cells in the embolized liver lobe was significantly higher in the fibrin glue, polyvinyl alcohol particles with coils, and n-butyl cyanoacrylate groups than in the sham and gelatin sponge groups. However, the levels of interleukin-6, tumor necrosis factor-alpha, hepatocyte growth factor, and transforming growth factor-beta1 were significantly lower. CONCLUSIONS: Temporary occlusion using gelatin sponge for PVE resulted in significantly less hypertrophy response than the use of permanent embolization materials. Except for polidocanol, none of the embolization materials exhibited evident hepatotoxicity. PMID- 22241292 TI - Osteopontin regulates epithelial mesenchymal transition-associated growth of hepatocellular cancer in a mouse xenograft model. AB - OBJECTIVE: To determine the efficacy of osteopontin (OPN) targeting in hepatocellular cancer (HCC). SUMMARY/BACKGROUND: OPN is associated with HCC growth and metastasis and represents a unique therapeutic target. METHODS: OPN and epithelial-mesenchymal transition (EMT) markers, alpha-smooth muscle actin (SMA), vimentin, and tenascin-c, were measured in archived human HCC tissues from metastatic (n = 4) and nonmetastatic (n = 4) settings. Additional studies utilized human Sk-Hep-1 (high OPN expression) and Hep3b (low OPN expression) HCC cells. An RNA aptamer (APT) that avidly binds (Kd = 18 nM; t1/2 = 7 hours) and ablates OPN binding was developed. Adhesion, migration/invasion, and EMT markers were determined with APT or a mutant control aptamer (Mu-APT). RFP-Luc-Sk-Hep-1 were implanted into NOD-scid mice livers and followed by using bioluminescence imaging. After verification of tumor growth, at week 3, APT (0.5 mg/kg; n = 4) or Mu-APT (0.5 mg/kg; n = 4) was injected q48h. When mice were killed at week 8, tumor cells were reisolated and assayed for EMT markers. RESULTS: OPN and EMT markers were significantly increased in the metastatic cohort. APT inhibited Sk Hep-1 adhesion and migration/invasion by 5- and 4-fold, respectively. APT significantly decreased EMT protein markers, SMA, vimentin, and tenascin-c. In contrast, APT did not alter Hep3B adhesion, or migration/invasion. EMT markers were slightly decreased. In the in vivo model, at weeks 6 to 8, APT inhibited HCC growth by more than 10-fold. SMA, vimentin, and tenascin-c mRNAs were decreased by 60%, 40%, and 49%, respectively, in RFP-positive Sk-Hep-1 recovered by fluorescence-activated cell sorting (P < 0.04 vs Mu-APT for all). CONCLUSIONS: APT targeting of OPN significantly decreases EMT and tumor growth of HCC. PMID- 22241294 TI - Field-effect transistors fabricated from diluted magnetic semiconductor colloidal nanowires. AB - Field-effect transistors (FETs) fabricated from undoped and Co(2+)-doped CdSe colloidal nanowires show typical n-channel transistor behaviour with gate effect. Exposed to microscope light, a 10 times current enhancement is observed in the doped nanowire-based devices due to the significant modification of the electronic structure of CdSe nanowires induced by Co(2+)-doping, which is revealed by theoretical calculations from spin-polarized plane-wave density functional theory. PMID- 22241293 TI - Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response. AB - OBJECTIVE: We determined whether postburn hyperglycemia and insulin resistance are associated with endoplasmic reticulum (ER) stress/unfolded protein response (UPR) activation leading to impaired insulin receptor signaling. BACKGROUND: Inflammation and cellular stress, hallmarks of severely burned and critically ill patients, have been causally linked to insulin resistance in type 2 diabetes via induction of ER stress and the UPR. METHODS: Twenty severely burned pediatric patients were compared with 36 nonburned children. Clinical markers, protein, and GeneChip analysis were used to identify transcriptional changes in ER stress and UPR and insulin resistance-related signaling cascades in peripheral blood leukocytes, fat, and muscle at admission and up to 466 days postburn. RESULTS: Burn-induced inflammatory and stress responses are accompanied by profound insulin resistance and hyperglycemia. Genomic and protein analysis revealed that burn injury was associated with alterations in the signaling pathways that affect insulin resistance, ER/sarcoplasmic reticulum stress, inflammation, and cell growth/apoptosis up to 466 days postburn. CONCLUSION: Burn-induced insulin resistance is associated with persistent ER/sarcoplasmic reticulum stress/UPR and subsequent suppressed insulin receptor signaling over a prolonged period of time. PMID- 22241296 TI - Preparing for the MRCS examination: a simple guide. PMID- 22241295 TI - Mechanical Signals As a Non-Invasive Means to Influence Mesenchymal Stem Cell Fate, Promoting Bone and Suppressing the Fat Phenotype. AB - Pluripotent mesenchymal stem cells (MSCs) are considered ideal therapeutic targets in regenerative medicine, as they hold the capacity to differentiate into higher order connective tissues. The potential to harness MSCs for disease treatment and acceleration of repair will ultimately depend on an improved understanding of how physical and/or chemical signals regulate their activity, and the ability of exogenous stimuli to enhance MSC proliferation and define MSC fate. Recent appreciation that bone marrow osteoprogenitors are inversely proportional to adipocyte precursors suggests that their shared progenitor, the MSC, will commit to one lineage at the cost of the other. This interrelationship may contribute to the phenotype of sedentary subjects who have more fat and less bone, while conversely, to the outcome of exercise being less fat and more bone. Mechanical biasing of MSC lineage selection suggests that physical signals may influence the quantity of both fat and bone through developmental, as well as metabolic or adaptive pathways. Considered with the recent finding that low magnitude mechanical signals (LMMS) suppress the development of subcutaneous and visceral fat without elevating energy expenditure, this indicates that MSCs are ideally positioned as mechanosensitive elements central to musculoskeletal adaptation, but that the signals needn't be large to be influential. The biasing of MSC differentiation by mechanical signals represents a unique means by which adiposity can be inhibited while simultaneously promoting a better skeleton, and may provide the basis for a safe, non-invasive, non-pharmacologic strategy to prevent both obesity and osteoporosis, yet uniquely - without targeting the resident fat or bone cell. PMID- 22241297 TI - Wrist joint aspiration. PMID- 22241298 TI - Presenting in the orthopaedic trauma meeting. PMID- 22241300 TI - [Experimental study on the functional regulation of naringin in human periodontal ligament cells]. AB - PURPOSE: To detect the effect of naringin on human periodontal ligament cells' (hPDLCs) proliferation,bone formation and OPG mRNA expression. METHODS: hPDLCs were primarily cultured and identified in vitro through enzyme digestion combined tissue culture method. With 3-(4, 5-Dimethylthiazol-2- yl)-2, 5 diphenyltetrazolium bromide (MTT) method, enzyme linked immunosorbent assay and RT-PCR, the hPDLCs' proliferation, alkaline phosphatase (ALP) activity, expression of collagen protein-I and OPG mRNA were observed after treatment with different concentrations (100,10,1.0,0.1,0.01mg/L) of naringin at different times. SPSS16.0 software package was used for statistical analysis. RESULTS: Primary cultured hPDLCs had good shape; Significant promotion of proliferation,ALP activity and collagen protein-I expression of hPDLCs with naringin was found at the dose of 1.0 mg/L; and 1.0mg/L naringin regulated the expression of OPG mRNA in time-dependent manner. CONCLUSION: Naringin might significantly promote the proliferation of hPDLCs and conversion into the osteoblast. PMID- 22241301 TI - [Effect of different heat treatment on the bonding strength of porcelain and Co Cr alloy]. AB - PURPOSE: To investigate and compare the effect of different heat treatment on the metal- ceramic bonding strength and the interfacial microstructure of the Co-Cr alloy. METHODS: Thirty specimens were made according to ISO 9693,and then divided into 3 groups (n=10) through the measurements .Group A(degassed 60s):degassed and then maintained 60s in 980 degrees centigrade Group B(degassed 60s and preoxidation 60s): degassed and maintained 60s in 980 degrees centigrade, then were maintained continuously for 60s in 980 degrees centigrade after re gassed,Group C(degassed 120s): degassed and maintained 120s in 980 degrees centigrade. The bonding strengths of the three groups were evaluated through three point bending test. Six specimens divided into 3 group were made in the same method to observe the metal-ceramic interface through scanning electronic microscope(SEM) and energy dispersive spectrum(EDS).The bonding strength data were analyzed using ANOVA and Bonferroni's test by SPSS13.0 software package. RESULTS: The mean value of bonding strength was (39.03+/-2.70)MPa for group A, (34.43+/-2.36)MPa for group B, (31.65+/-1.49)MPa for group C, respectively. There were significant difference between every two groups (P<0.05). SEM demonstrated that the width of interfacial transition layer was 12.3-16.4MUm in group A, 15.2 21.8MUm in group B and 26.3-32.2MUm in group C. CONCLUSIONS: Higher metal-ceramic bonding strength for Co-Cr alloy will be formed under the situation of degassed,and maintained 60s in 980 degrees centigrade ; while extending degassed time, prolonging the heat maintained time and preoxidation after degassing will reduce metal-ceramic bonding strength. PMID- 22241302 TI - [Effect of beryllium on chemical elements of cell membrane and H2O2 production of Streptococcus oralis]. AB - PURPOSE: To evaluate the effect of beryllium (Be(2+)) on chemical elements of cell membrane and H2O2 production of Streptococcus oralis (S.oralis), thus to explore the microbiologic mechanisms of periodontal diseases which may occur after prosthodontic treatment. METHODS: S.oralis was put into artificial saliva with different Be(2+) concentration (5mg/L, 10mg/L, 20mg/L and 40mg/L) and anaerobic cultured for 24 hours. The amount of chemical elements in the membrane of S.oralis were tested with X-ray energy dispersive spectroscopy, and the H(2)O(2) produced by S.oralis was detected with ABTS-HRP. The data were analyzed with one-way ANOVA using SPSS 11.0 software package. RESULTS: The amount of calcium in the cell membrane of beryllium treated S. oralis decreased, while the amount of phosphorus increased. Natrium increased with the increase of Be(2+) in the culture, but changed contrarily when S. oralis was treated with 20mg/L Be(2+). H(2)O(2) produced by S. oralis reduced when the concentration of Be(2+) was at 40mg/L(P<0.05). CONCLUSIONS: Beryllium affects the amount of chemical elements in cell membrane and H(2)O(2) production of S. oralis, which may result in a disturbance in the microecologic balance of subgingival microbes after proshodontic treatments and eventually contribute to periodontal diseases. PMID- 22241303 TI - [Study on the microleakage between the composite resin and cavity wall after Er,Cr:YSGG laser preparation]. AB - PURPOSE: To evaluate microleakage between the composite resin and cavity wall after Er,Cr:YSGG laser preparation. METHODS: Class V cavities were prepared in 30 sound extracted human premolars. The teeth were randomly divided into 3 groups (n=10).Group 1 was treated with Er,Cr:YSGG+37% phosphoric acid, group 2 was treated with Er,Cr:YSGG+FL-BOND and group 3 was treated with Er,Cr:YSGG+17% EDTA.Then the specimens were subjected to thermocycling and staining. The marginal microleakage was assessed by dye penetration method and scanning electronic microscope(SEM). The data was analyzed with SPSS11.0 software package. RESULTS: In occlusal margins,microleakage in group 2 was significantly lower than that in the other two laser groups(P<0.05).No significant difference was found between group 1 and 3 by dye penetration method.The space between the restorations and tooth structure revealed that there was significant difference between group 2 and 3(P<0.05).No significant difference was found between the other two laser groups by SEM. In gingival margins, microleakage test and the space between the restorations and tooth structure revealed that there was no significant difference among the three laser groups.There was significant difference in microleakage between the occlusal and gingival margins only in group 2(P<0.05). CONCLUSIONS: It is concluded that self-etch adhesive system was effective in reducing microleakage of the occlusal margins between the composite resin and the cavity wall after Er,Cr:YSGG laser preparation.There was no significant difference in microleakage after using a total etch adhesive system and EDTA. PMID- 22241304 TI - [Research on periodontal changes on the compression side during rapid tooth movement into newly distracted bone]. AB - PURPOSE: To investigate periodontal remodeling mechanism on the compression side during early tooth movement into newly distracted bone. METHODS: Ten male Beagle dogs were selected. Distraction osteogenesis was performed on randomized side as experimental group, while the fourth premolars were extracted on the other side as control group. Then the third premolars were distalized with 30g orthodontic force instantly after the cessation of distraction or extraction. The distance of the tooth movement was measured with a sliding caliper every week. Each distance was measured 3 times and the mean value was recorded. The measurement data were analysed with paired t test by SPSS 18.0 software package. Beagle dogs were killed in the first, second, fourth week after tooth movement. Slices were obtained for HE staining and TRAP staining to observe the periodontal tissue on the compression side. RESULTS: The average moving velocity of the teeth in the distracted bone was (1.055+/-0.054)mm per week, which was significantly faster than that in the control group(P<0.05).There was no apparent lag period in the experimental group. In addition, there was no hyalinization observed on the compression side of the periodontal tissue in the experimental group, while the amount and area of distribution of the TRAP-positive cells on the compression side was significantly larger and strongly expressed. CONCLUSIONS: The moving velocity of the teeth in the newly distracted bone was significantly faster, and no apparent lag period, which may be related to no hyalinization and more early appeared, vigorous and wide-distributed osteoclasts on the compression side of the periodontal tissue. PMID- 22241305 TI - [A study on the stability of miniscrew on different loading time as orthodontic anchorage]. AB - PURPOSE: To evaluate the stability of the miniscrew on different loading time as orthodontic anchorage. METHODS: 2 healthy adult male Beagle dogs were used in this study. 48 mini-implants were implanted into the maxilla and mandible of the dogs. The miniscrews were divided into 8 different groups,1 group was loaded 0g as control group and the others were loaded 200g forces as experimental groups. 200g forces were loaded on the corresponding mini-implant anchorages immediately after implantation and at the time of 1w,2w,3w,4w,5w and 6w after implantation. The dogs were sacrificed at 12w after implantation. Histological progresses of implant-bone interfaces was examined with light microscope. Blue deposition and contact ratio were calculated and analyzed using SPSS13.0 software package. RESULTS: Fibrous and osseous-integration was noted in the interface, there was no significant difference in bone deposition ratio and bone contact ratio. CONCLUSION: Different force loading time does not affect the stability of the mini-implant anchorage. PMID- 22241306 TI - [Effects of TiSi coating on corrosion resistance of dental Co-Cr alloy]. AB - PURPOSE: To investigate the effect of titanium-silicon(TiSi) coating on corrosion resistance of dental CoCr alloy. METHODS: The commonly used CoCr alloy was cast into 10mm*10mm*3mm specimen in size. Then the specimen was coated with TiSi on the surface by sol-gel method. The specimens were immersed in artificial saliva. Weight loss method was used to analyze corrosion rate. Element analysis using Auger Electron Spectroscopy (AES) was performed to compare the content of element before and after coating of TiSi in artificial saliva. SAS8.0 software package was used for statistical analysis. RESULTS: By weight lost method, before and after coating TiSi, the corrosive rate was 0.163 g.m(-2).h(-1) and 0.138 g.m( 2).h(-1) respectively. With AES, in Co-Cr alloy not coating TiSi, atomic concentration (g.m(-2)) of Ni, Co, Cr and Si was 7.728582657,0.008801153,0.306195965 and 0.194851978,respectively. After coating Ti-Si,the content of Ni, Co, Cr and Si and 4.745189808,0.004718889, 0.153195362 and 0.778406136, respectively. The release rate of the Ni,Co,cr were decreased after coating. CONCLUSION: TiSi coating can improve corrosion resistance of CoCr alloy. PMID- 22241307 TI - [Effects of lipopolysaccharides from various Porphyromonas on the expression of CD14 and TLRs in mouse osteoblast]. AB - PURPOSE: To observe the effect of lipopolysaccharides(LPS) extracted from Porphyromonas endodontalis(P.e) and Porphyromonas gingivals(P.g) on the expression of CD14 and TLRs in osteoblast. METHODS: MC3T3-E1 cells were stimulated with 10MUg/mL P.e-LPS and P.g-LPS. The change of CD14,TLR2 and TLR4 mRNA was observed at different time point (0,1,3,6,12,24h) using RT-PCR,and the expression of CD14,TLR2 and TLR4 protein was measured by flow cytometry at 24 hour. Statistical analysis was performed using one-way ANOVA and Dunnett t test with SPSS11.0 software package. RESULTS: MC3T3-E1 cells were stimulated with 10MUg/mL P.e-LPS for 1h,the expression of CD14 and TLR4 mRNA increased significantly. There was no increase of TLR2 mRNA with stimulation of P.e-LPS. The CD14,TLR2 and TLR4 mRNA expression increased significantly after stimulation with 10MUg/mL P.g-LPS. Flow cytometry showed that CD14 and TLR4 protein increased significantly after stimulation with 10MUg/mL P.e-LPS. CD14,TLR2 and TLR4 protein increased significantly after treatment with 10MUg/mL P.g-LPS. CONCLUSIONS: CD14,TLR4 receptors are involved in P.e-LPS effect and CD14,TLR2 and TLR4 receptors are involved in P.g-LPS effect in mouse osteoblast. PMID- 22241308 TI - [The effect of MAB225 on radiosensitivity of salivary gland adenoid cystic carcinoma]. AB - PURPOSE: To observe the effect of epidermal growth factor receptor's monoclonal antibody(MAB225) on radiosensitivity of salivary gland adenoid cystic carcinoma cell. METHODS: Bi-fluorescence stain ,MTT test and fluorescence flow cytometry(FCM) were used to observe the apoptosis rate and radiosensitizing effect for MAB225 on ACC-2 cell.SPSS11.0 software package was used for data analysis. RESULTS: Through bi-fluorescence stain, MTT test and fluorescence flow cytometry(FCM),it was found that MAB225 combined with radiation treatment produced a 3-fold induction of apoptosis rate, whereas exposure to radiation alone induced apoptosis only 1 fold, compared to the control group. CONCLUSION: MAB225 enhanced radiosensitivity and decreased survival rates of ACC-2 cell in vitro after radiation. PMID- 22241309 TI - [Analysis of the effect of relieving dental crowding by using a newly designed low frictional force single-wing bracket on typodont model]. AB - PURPOSE: To compare the effect of relieving dental crowding by using a newly designed low frictional force single-wing bracket and conventional MBT brackets on typodont model. METHODS: Two replicated typodont models were made with a same crowded upper arch. The two different types of bracket were bound separately on two typodont models. Clinical course was simulated with warm bath. The typodont models' crowded upper arch was aligned with 0.014 NiTi. The data were analyzed for t test using SPSS12.0 software package. RESULTS: In the MBT bracket group, the degree of the dental crowding reduced 2.58mm, compared with 5.49mm in the newly designed group.Significant difference between self-ligating brackets and conventional design was found between the two groups(P<0.05). CONCLUSIONS: It is indicated that the newly designed low frictional force single-wing-bracket relieves dental crowding faster than the conventional MBT bracket on typodont model. PMID- 22241310 TI - [A preliminary study on speech therapy for marginal velopharyngeal insufficiency]. AB - PURPOSE: To investigate the feature and therapy of patients with marginal velopharyngeal insufficiency(MVPI). METHODS: Fifteen patients(10 males,5 females, age ranging form 8 to 25 years, mean age of 17.6 years) with MVPI were selected. All the patients received behavior therapy and speech therapy. Chinese speech intelligibility test and blow test were carried out before and after the therapy. RESULTS: All cases achieved satisfactory results through 12 to 20 weeks of speech therapy. The results of speech intelligibility test and blow test after therapy were better than those before therapy. CONCLUSIONS: For patients with MVPI, a satisfactory result and pronunciation improvement could be obtained through a series of behavior therapy and a good velopharyngeal closure. PMID- 22241311 TI - [Myoepithelial carcinoma of salivary glands: a clinical analysis of 13 cases]. AB - PURPOSE: This study retrospectively analyzed the clinical data of 13 patients with myoepithelial carcinoma of salivary glands for improving the accuracy of diagnosis and treatment outcome. METHODS: Thirteen cases with myoepithelial carcinoma of the salivary glands in Xiangya Hospital from January 1992 to September 2010 were reviewed, including the clinical biological behavior, diagnosis,treatment and prognosis. RESULTS: Thirteen patients included 6 men and 7 women, aged from 14 to 71 years (median 40 years).The tumor occurred predominantly in the parotid gland (53.8%).Among the 13 cases,7 were clinically misdiagnosed as benign tumors and 2 were misdiagnosed pathologically. All cases underwent operation. Two cases received surgery plus adjuvant chemotherapy; five cases underwent surgery plus adjuvant radiotherapy. 4(30.8%) had cervical lymph node metastasis and 2 cases(15.4%) developed distant metastasis. Follow-up time ranged from 3 months to 6 years. Six cases died of local recurrence or distal metastasis. CONCLUSIONS: Myoepithelial carcinoma of the salivary glands is a rare tumor. The diagnosis is depended on histology and immunohistochemistry. The tumor has a high rate of distant metastasis and high rate of lymph node metastasis in T3 to T4 cases. Radical surgery is the treatment of choice. Elective neck dissection should be considered in T3 to T4 cN0 cases. The effect of chemotherapy and radiotherapy needs to be investigated. PMID- 22241312 TI - [Study on the expression and potential effect of PD-L1mRNA and PD-L2mRNA in oral lichen planus]. AB - PURPOSE: To study the expression of PD-L1 and PD-L2mRNA in oral lichen planus(OLP) patients' peripheral blood and focal mucosa, and the different expression of target molecules in gene level in different clinical and pathological OLP groups. METHODS: The expression of PD-L1 and PD-L2 mRNA in OLP patients, which included 35 reticular and 25 atrophic-erosive OLP patients, 38 cases without dysplasia and 22 cases with dysplasia, was examined by real-time PCR. Peripheral blood and mucosa from 10 volunteers were used as control. All the results were analysed with Wilcoxon test by SAS.6.12 software package. RESULTS: The expression of PD-L2mRAN, but not PD-L1, was significantly higher in oral mucosa of OLP patients (P<0.01), while decreased in OLP patients' peripheral blood (P=0.0415). The gene expression of PD-L2 differed between different clinical types, and had highly significant correlation between the OLP patients' focal mucosa and peripheral blood(r=0.6976, P<0.0001). CONCLUSIONS: PD-L2 may have some potential effect on the pathogenesis of OLP at systemic and local level. PMID- 22241313 TI - [Clinical evaluation of lingual fixed retainer combined with Hawley retainer and vacuum-formed retainer]. AB - PURPOSE: To evaluate the clinical efficacy of vacuum-formed retainers (VFRs) and lingual fixed retainers combined with Hawley retainers (combined retainers, CRs). METHODS: Forty five patients immediately after orthodontic treatment were randomly allocated to either VFRs (n=25) or CRs (n=20) groups. Overbite, overjet and calculus index scores (CIS) were recorded at pretreatment (T0), debonding (T1), 6 months (T2) and 12 months (T3) after maintenance. The tooth rotation, intercanine and intermolar width, and Little's index of irregularity were recorded on the study models of lower arches. The difference between the two groups was analyzed with SAS 6.12 software package. RESULTS: No significant difference was noted during retention time in VFRs(P>0.05). Likewise, there was no significant difference between VFRs and CRs, except that the change of CIS in CRs was significantly larger than those in VFRs(P<0.05). The incidence of breakage of vacuum-formed retainers was 24<, which was comparable with that of lingual fixed retainers (20<). CONCLUSIONS: Both vacuum-formed retainers and lingual fixed retainers combined with Hawley retainers have good retention during the first 12-month retention period. Considering patients' compliance and retention efficacy, lingual fixed retainer with Hawley retainer at night is a better choice for retention. PMID- 22241314 TI - [Therapeutic effect of staged treatment for huge mandibular cystic lesions]. AB - PURPOSE: To investigate the therapeutic effect of staged treatment for huge mandibular cystic lesions. METHODS: The study enrolled 18 cases of huge cystic lesions whose extent in X-ray film exceeded 5 cm from 2005 to 2009 in our hospital, 6 of them presented mal-aligned dentition. Decompression was first given under local anesthesia to make the entire extent gradually reduced to half of its primary extent, then the cysts were enucleated secondarily combined with simultaneous Bio-oss insertion under general anesthesia, followed by X-ray examination monthly to observe the density of bone, and normal orthodontic treatment was given to 6 cases with malocclusion. RESULTS: The lesions reduced to around half of the primary extent in 4 to 6 months after decompression,the density of bone substitute became almost similar to adjacent bone 6 to 12 months after secondary operation, no case had recurrence within 2 to 3 years. 6 cases with malocclusion were corrected after 2 to 3 years of orthodontic therapy. CONCLUSIONS: The staged treatment can retain the whole mandible and teeth at the same time of enucleation of the cyst, and achieve excellent aesthetic result combined with orthodontic therapy. PMID- 22241315 TI - [The accuracy of linear measurements of jaw implant regions obtained by multi slice spiral CT and dental software]. AB - PURPOSE: To evaluate the measurement accuracy by multi-slice spiral CT(MSCT) and dental software as a tool for preoperative design before tooth implantations. METHODS: Twenty volunteers with marker template underwent MSCT. The diameter of the front teeth crowns in the bucco-lingual direction were measured by MSCT using a standard dental software package. Postoperatively, the same distances were clinically measured using a sliding caliper. The consistency between the two measurements was analyzed by paired t test using SPSS17.0 software package. RESULTS: The difference of measurements was -0.04-0.21mm. There was no significant difference between the CT and the manual measurement of the crown diameter in the bucco-lingual direction(P>0.05). CONCLUSIONS: The results demonstrate that MSCT and marker template promises to be a valuable method for the measurement of jaw implant regions. PMID- 22241316 TI - [The application of desocclusol and manual mechanical method in endodontic retreatment]. AB - PURPOSE: To investigate the clinical method to remove a gutta-percha and root canal sealers. METHODS: 168 root canals which had been filled with gutta-percha were selected,all root canals needed endodontic retreatment.The root canal fillings were removed and the root canal was re-prepared with the method of desocclusol and manual mechanical method. Then the root canal was filled again with lateral condensation technique. RESULTS: With manual mechanical method and desocclusol,all original root canal fillings were removed completely. The combined method could effectively prevent the formation of step,root canal-side wear,broken equipment or other complications during the course of retreatment.The success rate of retreatment was 89.3%. CONCLUSIONS: Combined manual mechanical method with desocclusol could improve the success rate of recanalization of the root canal and saved time and effort. It is a method which could reduce the intensity and improve the efficiency of dentists, and worthy of wide clinical application. PMID- 22241317 TI - [Efficacy of a dentifrice containing 5% potassium nitrate on dental hypersensitivity]. AB - PURPOSE: To evaluate the efficacy of a dentifrice containing 5% potassium nitrate (test) on dental hypersensitivity compared with the fluoride dentifrice (control) over a 4-week period. METHODS: The study design was a randomized ,double-blinded ,controlled clinical trial. 63 subjects were randomly divided into 2 groups, with 31 were given a 5% potassium nitrate dentifrice (experimental group) and the other 32 given a fluoride dentifrice (control group). Both groups were instructed to brush their teeth twice a day. An air blast stimulus was used to measure the degree of pain using a VAS scale. The data were analysed by the nonparametric Mann-Whitney U test and Wilcoxon-test with SPSS13.0 software package. RESULTS: The VAS (baseline=68.29+/-8.263, 4-week=31.71+/-6.378) was significantly reduced over the 4 weeks period in the experimental group (P<0.05). After 4 weeks, VAS in the experimental group was significantly lower than that in the control group(P<0.05). CONCLUSION: The study demonstrates that the dentifrice containing 5% potassium nitrate effectively reduces dental hypersensitivity. PMID- 22241318 TI - [Presurgical nasoalveolar molding in infants with cleft lip and palate: analysis of 29 cases]. AB - PURPOSE: The objective of this study was to treat the cleft lip and alveolus, nasal deformity with presurgical nasoalveolar molding (PNAM), to elucidate the problems and treatment methods, which may be helpful for the use of PNAM in clinic. METHODS: Twenty nine infants with cleft lip and palate (CLP) were treated with PNAM in our center. There were 19 unilateral and 10 bilateral CLP patients. The initial visit time was 3 to 150 days after birth. Treatment time ranged from 2.5 to 3 months. The appliance was modified at 2-week interval. RESULTS: According to the evaluation standards, 17 infants were treated successfully with the closure of cleft lip and alveolar processes, reposition of the deformed nasal cartilages, and increased length of columella. The lip and nasal deformities of 9 infants were corrected partly, which were helpful for surgery. There were 3 infants giving up PNAM. CONCLUSIONS: There were five important facts for the successful treatment, including initial visit time, impression of the intraoral cleft defect, modification of the plate and the nasal stent, and use of nasal splints. Orthodontics and plastic surgeons should have the same views for PNAM in infants, which will advance the treatment level for cleft lip and palate. PMID- 22241319 TI - [Cone beam computed tomographic analysis of cortical bone thickness of upper molar region for miniscrew]. AB - PURPOSE: To quantitatively evaluate the cortical bone thickness at upper molar miniscrew sites. METHODS: Sixty Angle's Class II division I patients were involved in this study(30 males and 30 females), measurements of cortical bone thickness were done with cone beam computer tomography(CBCT) scanning. The contact point of upper second premolar and upper first molar was chosen for center of coordinate. Totally 20 layers of cortical bone were measured every 1 mm. Paired t test was performed with SPSS 15.0 for Windows to evaluate the differences between both sides, and one-way ANOVA was performed to compare the changes in different layers. RESULTS: The cortical bone thickness had no significant difference between left and right side. Below the 7th layer, cortical bone could not be seen or very thin (less than 0.5mm). Above the 10th to 12th layers, thickness of cortical bone was more than 1.5mm. The average cortical bone thickness was 2.12+/-0.72mm in male, and 1.86+/-0.83mm in female (above 7th layer). In the cortical area above the 6th layer, 13 layers of cortical bone thickness were significantly different(P<0.05) and only 2 layers had no significant difference(P>0.05). CONCLUSIONS: In this area, the cortical bone thickness is gradually increased from occlusal to gingival directions; and the cotical bone is thicker in male than in female at the same level. PMID- 22241320 TI - [Pleomorphic adenoma of parotid gland: MR imaging findings]. AB - PURPOSE: To evaluate the diagnostic value of MR imaging and conventional contrast -enhanced MR imaging appearance in pleomorphic adenoma (PA) of the parotid gland. METHODS: We retrospectively reviewed pre- and post-contrast MR images of pleomorphic adenoma with pathologic correlation in 17 cases (6 men and 11 women; median age, 50 years; range, 27-70 years) collected between 2005 and 2011 from our pathologic and radiologic database. RESULTS: All of the tumors showed well defined margins, and 12 patients with lobulations. The tumors in 16 patients had capsules. The average maximal diameter was 2.6cm (ranged from 1.0 to 6.3cm). Cystic changes were seen in 6 cases and calcification in 2 cases. On T1-weighted images (T1WI), all tumors showed homogeneously SI equal or lower to normal muscle. On fat-suppressed T2-weighted images (T2WI), all of them showed marked higher SI. On gadolinium-enhanced T1WI, all tumors demonstrated marked enhancement. The tumor showed homogenous enhancement in 4 cases and inhomogeneous in the remaining 13 cases. The enhancement pattern showed low wash-in. CONCLUSIONS: PA of the parotid gland tends to be an isolated and well-defined mass with lobulations, capsules and cystic and/or calcification changes on MR imaging. PA of the parotid gland had characteristics in delayed enhancement patterns. PMID- 22241321 TI - [Study of chin morphology in Angle Class II division 2 malocclusion after non extraction orthodontic treatment]. AB - PURPOSE: To investigate the effect of non-extraction orthodontic treatment on the changes of chin morphology in Angle Class II division 2 malocclusion patients without tooth extractions. METHODS: A total of 20 patients with Class II division 2 malocclusion were treated with MBT straight wire appliance. Cephalometrics analysis was performed before and after treatment. The chin morphology, the position of the incisors and the profile before and after orthodontic treatment were included in the analysis. The data was analysed statistically with PASW statistics18. RESULTS: With the correction of the lingually inclined maxillary incisors, the mandibular plane moved anteroinferiorly and the anterior lower facial height increased.The chin moved forward, with introcession, the depth of the mentolabial sulcus and the chin projection decreased. Upper lip-E line and lower lip-E line became normal or close to normal. All cases showed a better improvement of the profile after treatment(P<0.05). CONCLUSIONS: In Class II division 2 malocclusion patients, after the lingually inclined maxillary incisors were corrected,the chin position could be orthodontically changed and soft tissue profile will be more esthetical. PMID- 22241322 TI - [National examinations for dentist in Japan and implications]. AB - Questions such as the law that was accorded by National Board Examinations for Dentist in Japan, the qualification of the examinee, the organization of the committee, the implementation of the exam, testing items development and the eligibility criteria were introduced in details in this article. The evolution of the number of qualified candidates and the issues for development needed to be explored were proposed. PMID- 22241323 TI - Practical limitations of cone-beam computed tomography in 3D cephalometry. AB - 3D cone beam computed tomography (CBCT) images offer a unique and new appreciation of the anatomical structures and underlying anomalies not possible with conventional radiographs. However, in almost all aspects of CBCT imaging, from utilization to application, inherent limitations and pitfalls exist. Importantly, these inherent limitations and pitfalls have practical implications which need to be addressed before the potential of this technology can be fully realized. The purpose of this review was to explore the current limitations and pitfalls associated with CBCT imaging to allow for better and more accurate understanding of the possibilities this imaging modality could offer, particularly pertaining to 3D cephalometry. PMID- 22241324 TI - The potential role of progesterone during pregnancy as an induction of infantile hemangioma. AB - Infantile hemangioma(IH) is one of the most common benign tumors in infants characterized by occurrence within a few weeks after birth, rapid growth during the first year and spontaneous involution over a period of several years.Despite the high incidence rate of 5%-10% in infants of mixed European descent, detailed pathogenesis of IH remains elusive. Recent studies have indicated multipotential stem cells derived from hemangioma tissue(HemSCs) could recapitulate human infantile hemangioma in immunodeficient mice. Considering the effect of progesterone on regulation of cytokines and growth factors in endometrium as well as the inhibition of immune response, using progesterone during pregnancy might help the HemSCs escape from the immune response and reside in the tissue of embryo by the aid of increased MMPs and decreased TIMPs,then proliferation was stimulated by increased growth factors like VEGF and bFGF.Thus,IH is potentially produced. PMID- 22241326 TI - Current world literature. PMID- 22241325 TI - Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma. AB - BACKGROUND: Epidemiological studies have linked obesity with many cancers. The insulin-like growth factor (IGF) 1 axis may be an important mediator in obesity associated cancer. This study examined the relationship between IGF-1 and its receptor (IGF-1R) in oesophageal adenocarcinoma, a cancer strongly linked to obesity. METHODS: Patients with oesophageal adenocarcinoma considered suitable for attempted curative treatment were studied. Visceral adiposity was defined by waist circumference or visceral fat area. Free and total IGF-1 in serum were measured by enzyme-linked immunosorbent assay. Quantitative polymerase chain resection was used to determine mRNA expression of IGF-1 and IGF-1R in resected tumour samples. IGF-1R expression in tissue microarrays (TMAs) was quantified by immunohistochemistry. RESULTS: A total of 220 patients were studied. Total and free IGF-1 levels were significantly increased in the serum of viscerally obese patients. Gene expression analysis revealed a significant association between obesity status and both IGF-1R (P = 0.021) and IGF-1 (P = 0.031) in tumours. TMA analysis demonstrated that IGF-1R expression in resected tumours was significantly higher in viscerally obese patients than in those of normal weight (P = 0.023). Disease-specific survival was longer in patients with negative IGF 1R expression than in those with IGF-1R-positive tumours (median 60.0 versus 23.4 months; P = 0.027). CONCLUSION: This study highlighted the association of the IGF axis with visceral obesity, and a potential impact on the biology of oesophageal adenocarcinoma through its receptor. Targeting the IGF axis may have a rationale in future studies. PMID- 22241327 TI - Converging on critical dietary components: are specific fruits and vegetables key? PMID- 22241328 TI - Protein turnover regulated by cholesterol. PMID- 22241329 TI - Epigenetic memory, MBD2 and the endothelium. PMID- 22241330 TI - Diabetes: coronary heart disease equivalent? PMID- 22241332 TI - The primary cilium as a dual sensor of mechanochemical signals in chondrocytes. AB - The primary cilium is an immotile, solitary, and microtubule-based structure that projects from cell surfaces into the extracellular environment. The primary cilium functions as a dual sensor, as mechanosensors and chemosensors. The primary cilia coordinate several essential cell signaling pathways that are mainly involved in cell division and differentiation. A primary cilium malfunction can result in several human diseases. Mechanical loading is sense by mechanosensitive cells in nearly all tissues and organs. With this sensation, the mechanical signal is further transduced into biochemical signals involving pathways such as Akt, PKA, FAK, ERK, and MAPK. In this review, we focus on the fundamental functional and structural features of primary cilia in chondrocytes and chondrogenic cells. PMID- 22241334 TI - The tension between educational equivalency and equipoise in medical education research. PMID- 22241335 TI - How do medical students view the work life of primary care and specialty physicians? AB - BACKGROUND AND OBJECTIVES: Student perceptions of day-to-day physician work life, and relationships between these perceptions and specialty choices, have not been quantitatively explored. The study's purposes were to measure student perceptions of primary care and specialist physician work life, including administrative burden, time pressures, autonomy, and relationships with patients, to determine whether senior students' perceptions vary from junior students' perceptions and to determine whether students with primary care career plans view primary care work life differently than their peers. METHODS: A cross-sectional anonymous survey was offered to all students at three allopathic US medical schools between 2006 and 2008. RESULTS: Of 1,533 eligible students, 983 submitted usable surveys (response rate 64.1%). Students viewed the day-to-day work life of all physicians negatively but viewed primary care physician work life more negatively. Senior students viewed specialist work life more positively and primary care work life more negatively than junior students. Students planning primary care and specialist careers had similar views of primary care and specialist work life. CONCLUSIONS: Students have negative views of the work life of all physicians, especially primary care physicians. Students planning careers in primary care share this negative view of their future work life, suggesting that their career choices are not based on different work life perceptions. PMID- 22241333 TI - Organogenesis and functional genomics of the endocrine pancreas. AB - Functional genomics, the analysis of the wealth of data produced by genome-wide analyses of gene expression, protein-protein, and protein-DNA interactions, has revolutionized biomedical research. Our ability to determine global gene expression profiles, transcription factor-binding sites, and histone modification maps using microarray-based technologies and next-generation sequencing applications has greatly enhanced our understanding of gene regulatory networks and the molecular wiring diagrams of cells and tissues. The organogenesis of the endocrine pancreas involves numerous signaling events within the endoderm-derived pancreatic epithelium and the surrounding mesenchyme, as well as complex transcription factor networks. Detailed understanding of the differentiation process from foregut endoderm to mature endocrine cells has enabled the rational design of in vitro differentiation protocols that coax embryonic stem cells into beta-like cells that might enable cell replacement therapy for diabetes in the future. In this review, we summarize the research studies that have utilized genomic tools to elucidate endocrine pancreatic organogenesis. PMID- 22241336 TI - Epistemology and uncertainty: a follow-up study with third-year medical students. AB - BACKGROUND AND OBJECTIVES: Prior research results indicate a relationship between medical epistemology (ie, how a physician organizes and prioritizes the biological and psychosocial data of a patient presentation) and stress reactions to uncertainty among primary care physicians. However, little is known about when this relationship forms. The purpose of this study was to begin answering this question by exploring the relationship between medical epistemology and stress reactions to uncertainty among a group of 89 third-year medical students from the class of 2010 of a three-campus state medical school located in the southwestern US. METHODS: Data from Likert-type measures of medical epistemology and stress reactions to uncertainty were extracted from course evaluation information that was collected at the start (T1) and end (T2) of a continuity clinic experience that spanned most of the students' third year. Using these data, the authors conducted a simple bivariate regression analysis to identify the relationship between medical epistemology and stress reactions to uncertainty (Model 1), and a multivariate regression analysis to test for the independent effect of medical epistemology on stress reactions to uncertainty while controlling for gender and specialty interest (Model 2). These two regression models were calculated for both the T1 and T2 data sets. RESULTS: The two regression models at T1 indicated no significant relationships between medical epistemology and stress reactions to uncertainty; however, the two regression models at T2 indicated that a biopsychosocial epistemology is associated with less stress reactions to uncertainty, and a biomedical epistemology is associated with more stress reactions to uncertainty. CONCLUSIONS: The third year is an opportune time for medical educators to help shape and develop students' medical epistemology and stress reactions to uncertainty. PMID- 22241337 TI - Are students less likely to report pertinent negatives in post-encounter notes? AB - BACKGROUND AND OBJECTIVES: In completing post-encounter notes (PENs), students are believed to under-report about 30% of the important information obtained in the medical history. The resulting incomplete clinical notes can contribute to adverse patient care and medicolegal outcomes. We hypothesized that pertinent negative items would be more likely to be under-reported than positive items. We compared reporting rates for pertinent positive and negative items on two cases in a clinical skills assessment (CSA) taken by all 55 third-year students. Based on standardized patient (SP) checklists, students obtained 87% of both positive and negative items. Scoring of PENs found significant differences in the reporting rates for positive (75%) and negative (52%) items. These results were consistent for each case. Students appear to be able to elicit pertinent negative information from patients but, although these items may be crucial in the medical history, they are significantly more likely than positive items to be omitted from the clinical note. PMID- 22241338 TI - If you build it, will they come? A qualitative evaluation of the use of video based decision aids in primary care. AB - BACKGROUND AND OBJECTIVES: Given the growing presence of Patient-centered Medical Home practices and the need for patient participation, it is concerning that tools to improve patient participation are not widely used in primary care. Despite demonstrated effect on decision quality and patient satisfaction, decision aids (DAs) are not broadly utilized. We conducted focus groups to examine the use of DAs and uncovered barriers to greater DA utilization in primary care. METHODS: The University of California, San Diego family medicine clinics use an integrated process to prescribe DA videos. We conducted provider and patient focus groups to explore use of DAs in three clinics. Using a qualitative phenomenological design, we analyzed thematic content using immersion techniques. RESULTS: Focus group discussions identified six categories: patient benefits, physician benefits, process improvements needed, reasons DAs are prescribed, barriers to watching DAs, and the role of the DA. These categories encompassed 21 themes. Four themes were salient for improving DA utilization: follow-up process needs improvement, prescribing process needs improvement, patients were unclear regarding each DA's purpose, and patient benefits. CONCLUSIONS: While previous studies have described expected barriers to hypothetical DA distribution, our analysis reveals barriers reported by physicians, staff, and patients based on actual experience in practice. Decision aids can improve patient participation in health decisions. However, physicians and patients have to recognize a need for these tools before they will be adopted in practice. PMID- 22241339 TI - The annual program review of effectiveness: a process improvement approach. AB - BACKGROUND AND OBJECTIVES: All residencies and fellowships are required by the Accreditation Council for Graduate Medical Education (ACGME) and local institutional policy to conduct an annual program review of educational effectiveness. However, a number of family medicine residencies were cited for having an inadequate annual review or for failing to document the review in 2008. The ACGME and university offices of graduate medical education provide program directors some guidance on conducting and documenting annual program reviews, but few articles describe a detailed process for such a review. In this article, the authors describe the systematic process their program uses to conduct and document an annual program review and argue that the annual program review is an excellent way of modeling quality improvement to residents and showing residents and faculty that their input helps improve the residency and the residents' educational experiences. The article also describes metrics included in the process and tells how resident and faculty participation is integrated in the review. Specific outcomes of the process are also described. The authors believe that other residency programs and fellowship programs can adapt this process to conduct annual reviews that improve educational and clinical outcomes. PMID- 22241340 TI - Why do some eligible families forego public insurance for their children? A qualitative analysis. AB - BACKGROUND AND OBJECTIVES: Central to health insurance reform discussions was the recurring question: why are eligible children not enrolled in public insurance programs? We interviewed families with children eligible for public insurance to (1) learn how they view available services and (2) understand their experiences accessing care. METHODS: Semi-structured, in-depth interviews with 24 parents of children eligible for public coverage but not continuously enrolled were conducted. We used a standard iterative process to identify themes, followed by immersion/crystallization techniques to reflect on the findings. RESULTS: Respondents identified four barriers: (1) confusion about insurance eligibility and enrollment, (2) difficulties obtaining public coverage and/or services, (3) limited provider availability, and (4) non-covered services and/or coverage gaps. Regardless of whether families had overcome these barriers, all had experienced stigma associated with needing and using public assistance. There was not just one point in the process where families felt stigmatized. It was, rather, a continual process of stigmatization. We present a theoretical framework that outlines how families continually experience stigma when navigating complex systems to obtain care: when they qualify for public assistance, apply for assistance, accept the assistance, and use the public benefit. This framework is accompanied by four illustrative archetypes. CONCLUSIONS: This study provides further insight into why some families forego available public services. It suggests the need for a multi-pronged approach to improving access to health care for vulnerable children, which may require going beyond incremental changes within the current system. PMID- 22241341 TI - Incoming resident experience and comfort with procedures designated as "basic". AB - BACKGROUND: Recent consensus guidelines have recommended uniformity in procedural training in family medicine residency programs. The consensus documentation suggestions are based on expectations of procedural training prior to residency. Few studies have evaluated the perceived baseline level of procedural competency prior to residency training. METHODS: Twenty incoming PGY-1 residents completed a "procedural experience survey," asking respondents to identify their prior experience and current comfort levels with 19 "basic" procedures. RESULTS: For seven procedures, no prior experience was the most common response. For 15 of the 19 procedures, at least one respondent reported no prior experience. The residents' self-reported comfort levels varied widely for each procedure. CONCLUSIONS: The survey results showed that experience and comfort with procedures often performed in family medicine varies widely among incoming residents. This raises the question of whether documentation of resident competence in these procedures should be recommended as a baseline and monitored throughout residency training. PMID- 22241342 TI - For Jose. PMID- 22241343 TI - Fairness to students top priority. PMID- 22241344 TI - We can get there from here: strategic plans and family medicine. PMID- 22241345 TI - [Robotic surgery for cancer treatment]. AB - Surgical operation is still one of the important options for treatment of many types of cancer. In the present-day treatment of cancer, patients' quality of life is focused on and surgeons need to provide minimally invasive surgery without decreasing the curability of disease. Endoscopic surgery contributed to the prevalence of minimally -invasive surgery. However it has also raised a problem regarding differences in surgical techniques among individual surgeons. Robot-assisted surgery provides some resolutions with 3D vision and increases the freedom of forceps manipulation. Furthermore, 3D visual magnification, scaling function, and the filtering function of surgical robots may make it possible for surgeons to perform microsurgery more delicate than open surgery. Here, we report the present status and the future of the representative surgical robot, and the da Vinci surgical system. PMID- 22241346 TI - [Present and future state of cancer screening for esophageal cancer and gastric cancer]. AB - Recently, endoscopic examinations have played a major role in the diagnosis and treatment in the field of gastroenterology. It is considered that endoscopy would be an important examination for cancer screening of the esophagus and the stomach. However, endoscopic services for cancer screening are in short supply. Furthermore, we have to take the complications and poor economic benefits of endoscopy in to consideration when we apply it as a practical cancer screening system. Thus, an effective primary screening system must be provided for the endoscopic screening of cancer of the esophagus and the stomach. People with a defect in aldehyde dehydrogenase-2(ALDH2)should be distinguished by their facial flushing in drinking and for their high risks of esophageal cancer. In cases with gastric cancer screening by endoscopy, an x-ray study is expected to be a primary screening because of its efficacy. It already has been recommended for population based screening in Japanese guidelines for gastric cancer screening. In cases with opportunistic screening of gastric cancer, patients should be allowed to choose from several studies such as the x-ray study, direct endoscopy, and the so called high risk screening of gastric cancer for estimating risks and planning of screening for gastric cancer. PMID- 22241347 TI - [What is needed for colorectal cancer screening in Japan]. AB - There have been accumulated evidence with colorectal cancer(CRC)screening programs using the fecal occult blood test (FOBT). However, the purpose of CRC mortality reduction has not been attained as are the same with the other cancer screening programs in Japan. Thus the present issue with the CRC screening program is how we could reach the goal. Organized screening(OS), which is the strategy for reducing cancer mortality through screening, should be constructed in Japan for the purpose. Scientific evidence to reduce mortality is the prerequisite of OS. In addition, the second step required is to establish a quality assurance system or the management of the screening program, which can maximize the benefit and minimize the harms from screening. Finally, establishing a call-recall system enabling high participation rate is important. The above change may need an implementation of institutional reform on cancer screening in Japan. PMID- 22241348 TI - [Screening for lung cancer: present and future]. AB - A certified method for lung cancer screening in Japan is the combination of chest X-ray and sputum cytology. The chest Xray examination is intended primarily for the detection of peripheral-type lung cancer. Interpretation of the films should be performed by two different physicians, and the films of screenees suspected to have abnormal shadow should be compared to the same screenee's films from previous screening visits. Sputum cytology is conducted for heavy smokers, and is useful for early detection of central lung cancer. The efficacy of this lung cancer screening method has been shown in several case control studies. There are some problems to solve i. e., a low rate of attendance and inadequate quality control. Low-dose thoracic CT screening is performed with an exposure within a single breath hold, and its interpretation can be conducted with films, CRT, or a LCD monitor. Even when taken at low doses, the radiation exposure dose is large compared to a chest X-ray, being about 3-10 times greater than the absorbed dose and 20-40 times greater than the effective dose. Since the radiation dose in a usual clinical condition is much higher, the clinical condition is not recommended for screening. Concerning the efficacy of low-dose CT screening for heavy-smokers, a positive result was reported in June 2011, and further detailed analyses are required. There are still some problems to solve i. e., the management of undiagnosed shadows, harm caused by the screening, quality control, and efficacy in non-smokers. PMID- 22241349 TI - [Cervical cancer screening]. AB - There is abundant evidence that cervical cancer screening with conventional cytology(CC)has reduced mortality from cervical cancer. Based on the evidence, CC has been implemented as a modality of the population-based screening for the last several decades in Japan. Several issues are currently faced during screening. For instance, very low coverage is one of the greatest unsolved problems. At the same time, a reliable system is required to monitor specimen adequacy and to calculate detection rates of not only invasive cancer, but also cervical intraepithelial neoplasia(CIN), for the quality control and evaluation of screening efficacy. Recently, two new modalities may be applicable for cervical cancer screening. One is liquid-based cytology(LBC)and the other is the HPV test. LBC and CC did not differ significantly in terms of sensitivity and specificity for detection of CIN2+or CIN3+. HPV tests are superior to CC in sensitivity but are inferior in specificity for detection of CIN2+or CIN3+. Because there is a possibility reducing mortality from and incidence of invasive cervical cancer, implementation of these modalities to Japan should be taken into consideration. Prior to this, however, it is necessary to organize a system to compare performance indicators reflecting the effectiveness of the new modalities to those of CC in a population-based screening. Also, these results must be disclosed for a steady perspective on the cervical cancer screening in Japan. PMID- 22241350 TI - [Breast cancer]. AB - In Japan, the incidence rate of breast cancer is increasing every year so as to become the most common cancer among Japanese women. One of every 16 women is anticipated to eventually suffer from breast cancer. However, unlike the incidence rate, the mortality rate of breast cancer is low, and the 5-year survival rate is about 80%. Mammography screening has been shown to be effective, but the screening rate is still low(20-30%), compared to screening rates for other organs. To increase the screening rate, the Japanese government has introduced free breast cancer screening. To make the system for breast cancer screening more efficient, we should determine the risk factors for Japanese women, and conduct such screening at public expense. PMID- 22241351 TI - [Screening for prostate cancer: an up date]. AB - Recently, large prospective randomized controlled trials such as the European Randomized Study of Screening for Prostate Cancer(ERSPC), the subsequent Goteborg study, and the alternative analysis of the Prostate, Lung, Colorectal, and Ovarian (PLCO)Cancer Screening Trial conducted in the USA, demonstrated very important evidence contributing to screening for prostate cancer. In the Goteborg study, the median mortality reduction in the screening group during 14 years of follow-up was 44%, according to an intention-to-screen analysis. Introducing PSA based screening could lead to evident mortality reduction and the prevention of metastatic disease progression, which may decrease QOL. Furthermore, establishing an optimal screening system that includes more accurate detection methods, minimally invasive treatment and active surveillance strategy(which minimizes over detection, overtreatment, and loss of QOL due to treatment), would improve the clinical validity of PSA screening. It is very important to conduct PSA-based screening according to well-balanced guidelines published by the Japanese Urological Association. PMID- 22241352 TI - [Pemetrexed as second-line treatment and beyond for elderly patients with advanced non-small-cell lung cancer]. AB - BACKGROUND: In Japan, the standard first-line therapy for elderly patients with advanced non-small lung cancer(NSCLC)is docetaxel(DOC)monotherapy. However, there is very limited information about second-line and beyond chemotherapy regimens for elderly patients with advanced NSCLC. Pemetrexed(PEM)monotherapy has been recognized as a standard regimen for advanced NSCLC in second-line settings, just as DOC monotherapy has been. PURPOSE: The objective of this study was to examine the efficacy and safety of PEM as second-line therapy and beyond for elderly patients. METHODS: The records of previously -treated elderly patients with advanced NSCLC, who had been treated with PEM as second-line therapy and beyond between July 2009 and December 2010, were retrospectively reviewed. RESULTS: median age: 73 years old(range 70-79 years old); gender: male/female, 11/8; PS 0 1/>=2, 19/0; clinical stage: III B/IV/postoperative recurrence, 4/10/5; pathology: adeno/LCNEC/other, 17/1/1 patient. The objective response-rate and disease control-rate were 15. 8% and 57. 9%, respectively. Median progression free survival time was 3. 2 months. There were no treatment-related deaths, and most of the toxicities of the treatment regimen were mild and acceptable. CONCLUSION: PEM monotherapy exhibits activity in previously treated elderly NSCLC patients and has an acceptably low toxicity. Further study is warranted to confirm our results. PMID- 22241353 TI - [Initial report of strontium-89 chloride treatment for painful osseous metastases at Sakai Municipal Hospital]. AB - Strontium-89 chloride has been available at our hospital for painful osseous metastases since October 2008. Of the 17 patients(22 treatments)seen until September 2010, response to initial treatment of 13 patients was analyzed. These included cancers of the lung(5 patients, 6 treatments), breast(4 patients), thyroid(2 patients, 5 treatments), liver, 1, and prostate, 1. Other treatments patients received within 1 month of Sr-89 injection were; chemotherapy, 5 patients; radiotherapy, 3 patients; and bisphosphonate, 9 patients. The treatment effects were assessed 1 month after injection, and for 11 of the 13 patients, pain-relief was obtained in a mild and gradual manner. Transient flare was frequently observed, some of which made assessment of pain-relief in 6 patients difficult. We recognized that the bone marrow function before treatment was well above the 'Optimal Treatment Manual Japan ' criteria. After treatment, bone marrow functions kept above the value of grade 2(CTCAE), and even in 5 patients with recent or concomitant chemotherapy, it remained above grade 3 of the CTCAE criteria. These results led us to the conclusion that the indication and inclusion criteria for strontium-89 chloride treatment should be patients with an earlier bone metastasis burden that is currently manifested, without too much attention to bone marrow function criteria. PMID- 22241354 TI - [Antiemetic effect of aprepitant in cancer patients receiving Cisplatin regimen]. AB - The efficacy and safety of aprepitant(APR)were examined in cancer patients who received chemotherapy including cisplatin(CDDP)at a dose of >= 50mg/m2.APR was administered concomitantly with conventional antiemetic therapy to 20 patients(APR group)in a prospective study performed from May to July 2010. In addition, a retrospective study based on medical records of 20 patients(conventional therapy group)from February to April 2010 was performed.These patients received antiemetic therapy with a serotonin receptor antagonist and dexamethasone. Significantly more patients did not vomit in the 5 day study period(days 1-5).Also, severity of vomiting was significantly improved over the 5-day period and in the late phase(days 2-5)in the APR group, compared to the conventional therapy group. Loss of appetite was significantly improved over the 5-day period and the acute(day 1)and late phases, leading to increased food intake during the 5-day period and late phase. There were no adverse events with suspected involvement of APR, and the tolerability was favorable. These results suggest that APR is useful for nausea, vomiting, and appetite loss caused by CDDP, which is a highly emetic drug, and that such guideline-based antiemetic therapy might improve the quality of life of patients. PMID- 22241355 TI - [Provision of information by pharmacists regarding the effective timing of co administration of first-generation serotonin receptor antagonists and dexamethasone for chemotherapy-induced nausea and vomiting in patients receiving Doxorubicin and cyclophosphamide chemotherapy for breast cancer]. AB - The combination of doxorubicin and cyclophosphamide is a standard chemotherapy regimen for breast cancer. Nausea and vomiting are two common adverse effects that may lead to a significant deterioration in the patient's quality of life. We report on the provision of information by pharmacists regarding the effective timing of the co-administration of first-generation serotonin receptor antagonists and dexamethasone for nausea and vomiting in patients receiving doxorubicin and cyclophosphamide (AC) chemotherapy for breast cancer. A total of 51 patients were enrolled in this study between January 2009 and December 2009. Vomiting was grade 0 in 34(67%)patients, grade 1 in 13(25%)patients, grade 2 in 3(6%)patients, and grade 3 in 1(2%)patient. Nausea was grade 0 in 17(33%)patients, grade 1 in 13(25%)patients, grade 2 in 13(25%) patients, and grade 3 in 15(29%)patients. The relative risk factors of vomiting were as follows: age, 1. 27; tumor size, 11. 05; node status, 1. 86; and chemotherapy, 0. 409. Only tumor size showed a significant difference(p=0. 006). The results of this study of 34 patients suggest that aprepitant may not be necessary for preventing AC chemotherapy. They showed that the provision of information by pharmacists regarding the effective timing of the co-administration of first generation serotonin receptor-antagonists and dexamethasone is effective in patients who cannot take aprepitant. PMID- 22241356 TI - [Impact on opioid precipitation of opioid-starting titration path]. AB - To investigate the effect clinical path of cancer pain treatments for opioid naive patients has on physician practice, a prepost quasi-experimental study was performed. The primary outcome measure was the percentage of patients who received 'recommended pain treatments' during the study periods. We determined the treatment to be the treatment of choice, if the physician 1) ordered a rescue dose, 2) prescribed a laxative, and 3) prescribed antiemetics when starting opioids. The secondary outcome measure was the number of newly consulted patients for our palliative care team. The end-points were measured before and after disseminating the clinical path. The rate of patients receiving recommended pain treatments significantly increased after disseminating the clinical path(p=0.03): 17%(33/18)to 61%(19/31). Patients who received a rescue order, laxative, or antiemetic when starting opioids were: 44% vs. 68%, 77% vs. 90%, and 66% vs. 77%, respectively. The number of patients newly consulting the palliative care team was increased(21 cases to 42 cases/4 month). In conclusion, the clinical path of cancer pain treatments is useful for improving the physician's practice when starting opioids for cancer pain, and might contribute to enhancing palliative care team availability. PMID- 22241357 TI - [Nutritional assessment using MUST(Malnutrition Universal Screening Tool) in outpatient chemotherapy]. AB - OBJECTIVE: We set out to see if nutritional assessment(management)using MUST could be useful for patients undergoing outpatient chemotherapy. METHODS: The study sample consisted of 197 patients undergoing outpatient chemotherapy between June 2010 and November 2010. The results of MUST, serum albumin levels, and nutritional intervention were investigated. RESULTS: High- and medium-risk patients requiring nutritional therapy was comprised of 17/78 breast cancer(21. 8%), 16/63 hematologic malignancy(25. 4%), and 26/56 colonic cancer(46. 4%)patients.Moreover, the serum albumin level in high- and medium-risk patients was likely to decrease compared to low-risk patients, suggesting the usefulness of MUST. DISCUSSION AND CONCLUSION: It is important to assess nutritional status focusedon simplicity, objectivity, andspeedin outpatient chemotherapy. Assessment of patients' nutritional status and cancer treatment compliance are expected to be improved using MUST. PMID- 22241358 TI - [Anti-RANKL antibody for treatment of patients with bone metastasis from breast cancer]. AB - Breast cancer is known to be associated with a high incidence of bone metastases. Recent advances in treatment for breast cancer have improved patient prognosis, including those with bone metastasis, highlighting the importance of treating bone metastasis to reduce incidence of skeletal complications and to improve patients' QOL. Currently, bisphosphonates(BP), which are recommended by domestic and international clinical practice guidelines, are commonly used for the treatment of bone metastasis. However, the outcomes of BP therapy leave room for improvement in regard to their efficacy, safety, and convenience. Prior studies have indicated that RANK ligand(RANKL), a cytokine mainly expressed in osteoblasts and bone marrow stromal cells, plays an important role in bone resorption by osteoclasts, which are key mediators in the formation and progression of bone metastasis. Denosumab is a fully human monoclonal anti-RANKL antibody which suppresses differentiation, activation, and survival of osteoclasts by inhibiting the binding of RANKL to its receptor, RANK. In a phase III clinical trial, denosumab significantly decreased the time-to-first and time to-first-and-subsequent skeletal related events(SRE), compared with zoledronic acid in advanced breast cancer patients with bone metastases. Further more, denosumab was more effective than zoledronic acid in preventing the progression of bone pain and maintaining patients QOL. In the future, treatment of bone metastases for breast cancer patients is expected to evolve further with the introduction of denosumab, which is conveniently administered by subcutaneous injection. PMID- 22241359 TI - [Evaluation of the S-1 granule forms in gastric cancer patients who received treatment with S-1 capsule-questionnaire survey about drug dosage forms]. AB - The S-1(tegafur/gimeracil/oteracil potassium)granule was developed to meet the needs of patients with cancer. Although the choice of the patients was thought to spread by the addition of the new agent type, the recognition of the S-1 granule is still low and you should adapt yourself to what kind of patients or are unknown. Therefore, we conducted a questionnaire survey of patients with gastric cancer undergoing treatment with S-1 capsules to investigate the adaptation and taste of the patients. As a result, although it was the investigation by the patients during S-1 capsule remedy, it was replied when 21. 3%(13/61 case)'had good granule,'and all cases raised it by the reason of there'not being the sense of incongruity of the throat at taking.'Also, about the global assessment of granule, the proportion of patient who replied'very good'or'good'were 31. 1% and 47%, in all cases and in the cases that felt the sense of incongruity of the throat during S-1 capsule remedy, respectively. Therefore, in the patients treated with the S-1 capsule, there were thought to be the patients who expected treatment with a granule. By the results of this survey, it was found that it is necessary to perform a medical teaching including dosage form to contribute to the adherence improvement of the patients. PMID- 22241360 TI - [A case of bone marrow carcinomatosis from breast cancer treated with weekly Paclitaxel]. AB - We report a case of bone marrow carcinomatosis originating from breast cancer that was treated with weekly paclitaxel (PTX). A 42-year-old female patient underwent mastectomy with axillary lymph node dissection for breast cancer in 2001. Multiple bone metastases were diagnosed in 2008, but she remained stable with chemotherapy and hormonal therapy for about two years. In 2010, thrombocytopenia occurred, and she was diagnosed with bone marrow carcinomatosis after bone marrow biopsy. She was treated with weekly PTX(80 mg/m2), and recovered successfully after treatment. About one year has elapsed since initiation of therapy, and there has been no recurrence. Bone marrow carcinomatosis originating from breast cancer is very rare, and is regarded as a disease with a poor prognosis. However, weekly PTX could be a valid treatment for prolonging survival of bone marrow carcinomatosis originating from breast cancer. PMID- 22241361 TI - [A case of docetaxel-induced acute lung injury refractory to treatment]. AB - A 59-year-old man was diagnosed with squamous cell cancer of the upper lobe of the left lung 11 months before his current admission. The clinical stage was T2N3M1(Stage IV). We started chemotherapy(carboplatin/gemcitabine), which was administered for 7 courses and discontinued 5 months before admission, but he subsequently showed a local relapse. Therefore, we restarted second-line chemotherapy(docetaxel)on admission. Only a single dose of docetaxel was administered, but the patient was diagnosed with respiratory failure 18 days afterwards. The chest roentgenogram and computed tomography showed ground-glass opacities. Bronchoalveolar lavage and blood test data showed no evidence of infection. We diagnosed the patient with acute lung injury induced by docetaxel. The patient was admitted to the intensive care unit, and therapy with steroids and sivelestat was initiated. In addition, artificial respiration, direct hemoperfusion with a polymyxin B-immobilized fiber column, etc., were performed. However, this intensive care regimen was unsuccessful, and the patient died 31 days after docetaxel administration. Docetaxel is generally used in the treatment of non-small-cell lung cancer. However, the present case showed that its use might lead to fatal drug-induced lung injury. PMID- 22241362 TI - [A case of recurrent esophageal cancer with lymph node and lung metastases, successfully treated with systemic chemotherapy and radiofrequency-ablation]. AB - We report a case of recurrent esophageal cancer with lymph node and lung metastases, successfully treated with systemic chemotherapy and radiofrequency ablation(RFA). A 45-year-old man was diagnosed with thoracic esophageal cancer.Radical esophagectomy with three-field lymphadenectomy was performed.After 6 months, mediastinal lymph node recurrence occurred.Although the size of the recurrent mediastinal lymph nodes were reduced after 10 courses of systemic chemotherapy, two new lung metastatic nodules appeared in the right segments 8 and 9.CT -guided percutaneous RFA was successfully achieved for the 2 lesions.However, 6 months after the RFA, a local recurrence at the RFA site of segment 9 occurred, and an additional RFA was performed for this tumor.Five years and four months after the first operation, the tumor marker level remained within a normal range, and the patient is doing very well without any signs of recurrence. RFA appears to be an effective and minimally invasive technique for controlling local recurrence of esophageal cancer when combined with systemic chemotherapy. PMID- 22241363 TI - [A case of endocrine cell carcinoma of the esophagus successfully treated by chemoradiotherapy]. AB - The patient was a 74-year-old man who suffered from epigastric abdominal pain. He visited our hospital in April 2008. An esophageal endocrine cell carcinoma was pointed out by gastrointestinal endoscopy, and he was diagnosed as esophageal endoscopic cell carcinoma with mediastinum lymph node by CT scan(Stage IVa: cT3N4M0). Concurrent chemoradiotherapy using CDDP+EP was started. After two courses, the primary tumor was markedly reduced, and endoscopy showed only a scar. We diagnosed the patient as being in complete remission. However, CT showed a liver metastasis relapse in June 2009, and we started AMR as second-line chemotherapy. His general condition went into a decline, however, He died on October 2, 2009. PMID- 22241364 TI - [A case of advanced gastric cancer with multiple bone metastases and distant lymph node metastases successfully treated by S-1/CDDP combination chemotherapy]. AB - We describe a 46-year-old man who presented with the chief complaint of lower back pain. The patient was diagnosed with advanced gastric cancer accompanied by multiple bone metastases, with compression fractures in the thoracolumbar vertebrae as well as distant lymph node metastases. He was administered eight courses of S-1/CDDP combination chemotherapy. Treatment results were as follows: primary lesion, non-CR/non-PD; lymph node metastases, CR; and bone metastases, non-CR/non-PD. As only the primary lesion showed a tendency toward progression after completion of eight courses, distal gastrectomy with D1 dissection was performed. Histopathological test results were ypT1b(SM1)and ypN1(2/22). The histological grade following treatment was grade 2 for both the primary lesion and the lymph nodes Following subsequent treatment with S-1 monotherapy and zoledronic acid, the disease did not progress, and at one year and four months since diagnosis and six months since surgery, CR and non-CR/non-PD have been maintained for the lymph node metastases and bone metastases, respectively. PMID- 22241365 TI - [A case of advanced gastric cancer with peritoneal dissemination successfully treated with S-1 and intraperitoneal docetaxel administration]. AB - A 76-year-old man was admitted to our hospital for the treatment of remnant gastric cancer. Laparotomy revealed massive lymph node metastasis, direct invasion of the transverse colon, and peritoneal dissemination. Partial resection of remnant stomach with transverse colon and intraperitoneal infuser port implantation were performed. After surgery, he underwent chemotherapy with docetaxel(DOC)administered intraperitoneally, and S-1. CT scan showed no tumors, and the patient was judged to be a complete response(CR)without serious adverse events. We switched DOC to intravenous injection because of port damage, and grade 3 adverse events appeared frequently until the chemotherapy was stopped. It has been 30 months since we stopped the chemotherapy, and the patient is still alive with no evidence of tumor recurrence 48 months after surgery. PMID- 22241366 TI - [Improved QOL in a case of remnant gastric cancer with common bile duct obstruction treated with weekly paclitaxel therapy and cholecystojejunostomy]. AB - We report a patient with unresectable remnant gastric cancer with common bile duct stricture, whose quality of life(QOL) was improved by switching to cholecystojejunostomy from percutaneous transhepatic gallbladder drainage(PTGBD). He was a 69-year-old man who underwent distal gastrectomy(Billroth I reconstruction)3 years previously, and he vomited many times due to cancer at the anastomosis. It could not be resected because of its involvement with the hepatoduodenal ligament, and therefore, gastrojejunostomy was performed. Four days later, abdominal pain occurred and gallbladder swelling was observed, resulting from common bile duct obstruction. PTGBD relieved the pain, and four courses of S-1/cisplatin (CDDP)treatment were performed. The bile duct stenosis was still so severe that the chemotherapy regimen was changed to weekly paclitaxel(PTX). The bile amount of PTGBD decreased after its four courses and the tube, which was a great burden for the patient, was removed. Because abdominal pain recurred in 2 weeks, the tube needed to be reinserted. An endoscopic stent was not inserted successfully. We performed cholecystojejunostomy and he was finally free from the PTGBD tube. The spread of cancer to the cystic duct was controlled by continuing the PTX for more than 20 courses. Thus, this case highlights PTX's contribution toward improving the patient's QOL. PMID- 22241367 TI - [A case of bile duct cancer with positive surgical margin obtaining long-term survival after S-1 monotherapy]. AB - We report a case of bile duct cancer with a positive surgical margin obtaining long-term survival after S-1 monotherapy. A 79-year-old male with fever and liver dysfunction was admitted to our hospital. After a series of examinations he was diagnosed as hilar cholangiocarcinoma, which was treated with bile duct resection and biliary reconstruction for adhesion and pulmonary dysfunction of tuberculosis. Histopathological findings revealed that both surgical margins of the bile duct were positive. After operation, the patient received S-1 oral monotherapy(100mg/day for 28 days, followed by 14 days of rest)for 3 years. The patient has been alive for 5 years without recurrence. PMID- 22241368 TI - [A case of adenosquamous carcinoma of lower extrahepatic bile duct]. AB - We report a 83-year-old female with bile duct cancer who underwent subtotal stomach preserving pancreatoduodenectomy. Pathologically, her tumor was diagnosed as adenosquamous carcinoma of the lower extrahepatic bile duct with final stage IVb[pT3pN3M(-)].The prognosis of patients with adenosquamous carcinoma of the bile duct is very poor, and the reason is thought to be its tendency to invade the pancreas.Although she was an aged patient, we performed adjuvant chemotherapy using gemcitabine.No recurrence has occurred until this day, 30 months after the operation.This is thought to be an effect of the adjuvant chemotherapy, considering its poor prognosis. PMID- 22241369 TI - [A case of curatively resected locally advanced cancer of the pancreatic body treated by distal pancreatectomy with en bloc celiac axis resection after neoadjuvant chemotherapy]. AB - A 68-year-old man with locally advanced pancreatic body cancer invading the celiac axis(CA, including common hepatic artery)and in contact with the superior mesenteric artery(SMA)underwent 2 courses of neoadjuvant chemotherapy(NAC); gemcitabine hydrochloride(GEM 1,000 mg/m / / 2, on day 1 and 15)and S 1(100mg/m2day, 2-weeks of continuous administration followed by 1-week rest). The tumor volume and the contact area to SMA were greatly diminished. All tumor markers were reduced. He underwent R0 resection by distal pancreatectomy with en bloc celiac axis resection(DP-CAR). After the surgery, he could continue adjuvant chemotherapy; (GEM 1,000 mg/m2)only twice because of malnutrition. Nine months later CT revealed local recurrence and multiple lung metastases. The patient died 371 days after surgery. Appropriate NAC can contribute to R0 resection in locally advanced pancreatic cancer. PMID- 22241370 TI - [A case of recurrent rectal cancer with idiopathic thrombocytopenic purpura showing rapid progression, suggesting disseminated intravascular coagulopathy]. AB - A 64-year-old female with idiopathic thrombocytopenic purpura(ITP)was admitted to our hospital under the diagnosis of rectal cancer. Intersphincteric resection and splenectomy were performed after high-dose gamma globulin therapy. Thirteen months after the surgery, she suffered from a local recurrence and groin and pelvic lymph node metastases. Radiotherapy was planned before curative resection. During radiation, she complained of severe back pain and high fever with severe thrombocytopenia, and was admitted to our hospital. The examinations revealed disseminated intravascular coagulopathy(DIC), probably induced by multiple bone and hepatic metastases. Although anti-DIC therapy and chemotherapy with FOLFIRI were performed, thrombocytopenia did not improve, and she died of cancer progression about 2 months after admission. We report a case ofDIC induced by cancer progression with ITP. Since thrombocytopenia may be induced by either DIC or ITP, selecting a treatment for such a patient is difficult. We report the present case in detail and discuss findings from the literature. PMID- 22241371 TI - [Low-dose mirtazapine improved nausea and appetite loss during S-1 therapy]. AB - This paper presents a man in his 80's with pancreatic cancer(cStage IV). He suffered from nausea duringS -1 therapy, and therefore, prochlorperazine maleate at a daily dose of 15 mgwas administered. However, refractory nausea was diagnosed because it did not improve, and mirtazapine at a daily dose of 7. 5 mgbefore bedtime was started. Nausea was improved in the next morning, and the patient ate almost all of his breakfast. After that, no nausea appeared, and his food intake was robust. Mirtazapine is a new antidepressant called noradrenergic and specific serotonergic antidepressant(NaSSA)and blocks 5-HT3 receptors to improve nausea. Mirtazapine is usually started at a daily dose of 15 mg, but this dose induces somnolence. Therefore, mirtazapine was administered at a low daily dose of 7. 5 mgin the present case. No somnolence or disturbance of daily life was seen, and administration was safely continued. We conclude that low-dose mirtazapine is one effective option for refractory nausea duringS -1 therapy. PMID- 22241372 TI - Selective, direct activation of high-conductance, calcium-activated potassium channels causes smooth muscle relaxation. AB - High-conductance calcium-activated potassium (Maxi-K) channels are present in smooth muscle where they regulate tone. Activation of Maxi-K channels causes smooth muscle hyperpolarization and shortening of action-potential duration, which would limit calcium entry through voltage-dependent calcium channels leading to relaxation. Although Maxi-K channels appear to indirectly mediate the relaxant effects of a number of agents, activators that bind directly to the channel with appropriate potency and pharmacological properties useful for proof of-concept studies are not available. Most agents identified to date display significant polypharmacy that severely compromises interpretation of experimental data. In the present study, a high-throughput, functional, cell-based assay for identifying Maxi-K channel agonists was established and used to screen a large sample collection (>1.6 million compounds). On the basis of potency and selectivity, a family of tetrahydroquinolines was further characterized. Medicinal chemistry efforts afforded identification of compound X, from which its two enantiomers, Y and Z, were resolved. In in vitro assays, Z is more potent than Y as a channel activator. The same profile is observed in tissues where the ability of either agent to relax precontracted smooth muscles, via a potassium channel-dependent mechanism, is demonstrated. These data, taken together, suggest that direct activation of Maxi-K channels represents a mechanism to be explored for the potential treatment of a number of diseases associated with smooth muscle hyperexcitability. PMID- 22241373 TI - Clinical factors correlated with the success rate of miniscrews in orthodontic treatment. AB - Miniscrews offer a reliable alternative for anchorage during orthodontic treatment, particularly for non-cooperative patients or periodontal patients with alveolar bone loss. The study aims at assessing the correlation of various clinical indicators with the success or failure of miniscrews used for anchorage during orthodontic treatment. Thirty-four consecutive patients with a cumulative total of 82 miniscrews implanted participated in the study. Generalized Estimating Equations were used to assess the correlation of various factors with success rates. The miniscrew was considered the unit of analysis clustered within site and within patient. The overall success rate of miniscrews was 90.2%. For every additional miniscrew used in a patient's oral cavity, the success rate was reduced by 67%. Retromandibular triangle and palatal placement and in movable mucosa resulted in lower success rate. The miniscrew length and diameter were found to correlate with success rates. Orthodontic force applied on miniscrews for uprighting purposes showed a lower success rate than that used for retraction. This study revealed that miniscrews present high success rates. The number of miniscrews used per patient, the miniscrew site placement, the soft tissue type of placement, the miniscrew length and diameter as well as the orthodontic force applied on the miniscrew showed significant correlation with success rates. PMID- 22241374 TI - Carcinoma ex pleomorphic adenoma of the sublingual gland: a case report. AB - We report a case of carcinoma ex pleomorphic adenoma of a sublingual gland in a 70-year-old man. Under a clinical diagnosis of benign salivary gland tumor, excision of the mass with the sublingual salivary gland in an en bloc fashion via an intraoral approach was performed. Histopathologically, there was a rupture of the fibrous capsule and diffuse cell-rich sheets composed of myoepithelial cells with round nuclei were also seen. Immunohistochemically, the cells that composed of cell rich sheets were positive to smooth muscle actin. Final diagnosis of myoepithelial carcinoma ex pleomorphic adenoma was made. PMID- 22241375 TI - The occlusal plane in the facial context: inter-operator repeatability of a new three-dimensional method. AB - The repeatability of a non-invasive digital protocol proposed to evaluate the three-dimensional (3D) position of the occlusal plane in the face is assessed. Dental virtual models and soft tissue facial morphology of 20 adult subjects were digitally integrated using a 3D stereophotogrammetric imaging system. The digital 3D coordinates of facial and dental landmarks were obtained by two different operators. Camper's (facial) and occlusal (dental) planes were individuated, and their 3D relationships were measured. The repeatability of the protocol was investigated and showed no significant differences in repeated digitizations. The angle between occlusal and Camper's planes was smaller than 2 degrees in the frontal and horizontal projections. In the sagittal projection, the angle was observed to be, on average, 4.9 degrees . The determined occlusal plane pitch, roll and yaw values show good agreement with previously published data obtained by different protocols. The current non-invasive method was repeatable, without inter-operator differences and can facilitate assessment of healthy subjects. PMID- 22241376 TI - Spontaneous brain activity in mild cognitive impairment revealed by amplitude of low-frequency fluctuation analysis: a resting-state fMRI study. AB - Spontaneous low-frequency fluctuations (LFF) in the blood-oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal have been shown to reflect cerebral spontaneous neural activity. The objective of this study was to explore brain functional changes in patients with mild cognitive impairment (MCI) by measuring the amplitude of the BOLD signals. Eighteen amnestic MCI patients and 20 healthy elderly individuals underwent the fMRI scan. The amplitude of LFF (ALFF) was calculated using REST software. MCI patients showed decreased ALFF in the right hippocampus and parahippocampal cortex, left lateral temporal cortex and right ventral medial prefrontal cortex and increased ALFF in the left temporal-parietal joint (TPJ) and inferior parietal lobule. The ALFF value in the right hippocampus and parahippocampal cortex was positively correlated with the scores of Mini-Mental State Exam. Reduced medial temporal lobe activity may implicate the underlying memory impairment mechanisms in MCI. Increased TPJ and inferior parietal lobule activity may indicate the compensatory mechanism in MCI patients. These findings suggest that ALFF analysis could provide a useful tool in the fMRI study of MCI. PMID- 22241377 TI - Clinical trials of antiarrhythmic therapies and optimizing health care resource deployment: the need for a paradigm shift. PMID- 22241378 TI - Detection of microhemorrhage in posterior reversible encephalopathy syndrome using susceptibility-weighted imaging. AB - BACKGROUND AND PURPOSE: PRES-related vasogenic edema is potentially reversible while hemorrhage occurs in only 15.2%-17.3% of patients. However, the true incidence of hemorrhage could be higher when SWI is considered. Thus, we set out to determine the incidence of MH, SAH, and IPH in PRES by using SWI and to particularly evaluate whether such MHs are reversible. MATERIALS AND METHODS: Thirty-one patients with PRES and SWI were included, 17 having follow-up SWI. Two neuroradiologists reviewed SWI, FLAIR, DWI, and CE-T1WI. The presence and number of MHs (<5 mm) on SWI, SAH, and IPH (>5 mm) were recorded at presentation and follow-up. We evaluated associations between the presence of MH on SWI and DWI lesions, SAH, IPH, contrast enhancement, and MR imaging severity. RESULTS: Hemorrhage was present in 20/31 patients (64.5%), with MHs on SWI in 18/31 (58.1%) at presentation and in 11/17 (64.7%) at follow-up. SAH was present in 3/31 on SWI and 4/31 on FLAIR, while 2/31 had IPH. At follow-up, no patients had acquired new MHs; 2/5 MHs in 1 patient resolved. Four patients with available SWI before PRES developed MHs after PRES onset. No association was found between the presence of MHs on SWI and DWI, SAH, IPH, enhancement, and MR imaging severity (all P > .05). CONCLUSIONS: SWI showed a higher rate of MH than previously described, underscoring the potential of SWI in evaluating PRES. Such MHs typically persist and may develop after PRES onset. However, the clinical relevance of MHs in PRES is yet to be determined. We propose that MHs in PRES relate to endothelial cell dysfunction. PMID- 22241379 TI - TICI: if you are not confused, then you are not paying attention. PMID- 22241380 TI - White matter alteration of the cingulum in Parkinson disease with and without dementia: evaluation by diffusion tensor tract-specific analysis. AB - BACKGROUND AND PURPOSE: In PD, the neurodegenerative process begins in the brain stem and extends to the limbic system and finally into the cerebral cortex. We used diffusion tensor tractography to investigate the FA of the cingulate fiber tracts in patients with PD with and without dementia. MATERIALS AND METHODS: Fifteen patients with PD, 15 patients with PDD, and 15 age-matched healthy controls underwent diffusion tensor imaging with a 3T MR imager. Diffusion tensor tractography images of the anterior and posterior cingulate fiber tracts were generated. Mean diffusivity and FA were measured along the tractography of the anterior and posterior cingulate fiber tracts. One-way ANOVA with the Scheffe post hoc test was used to compare results among the groups. RESULTS: FA was significantly lower in patients with PDD than in healthy controls in both the anterior and the posterior cingulate fiber tracts (P = .003, P = .015) and significantly lower in patients with PD than in healthy controls (P = .003) in the anterior cingulate fiber tract. There were no significant mean diffusivity differences among the groups. MMSE and FA values of the anterior cingulate fiber tracts in patients with PDD were significantly correlated (r = 0.633, P < .05). CONCLUSIONS: The reduced FA in patients with PD and PDD might reflect neuropathologic changes such as Lewy body pathology in the cingulate fibers. This abnormality might contribute to the dementing process in PD. PMID- 22241381 TI - Diagnosis of recanalization of the intracranial artery has poor inter-rater reliability. AB - BACKGROUND AND PURPOSE: Recanalization is the important outcome measure for acute stroke therapy. Several methods of recanalization assessment are used in clinical practice, but few studies have addressed their reliability. We, therefore, sought to assess interobserver reliability of the diagnosis of intracranial artery recanalization following intervention by using TIMI criteria. MATERIALS AND METHODS: The digital angiography scans of all patients with acute ischemic stroke during 2009 undergoing DSA and endovascular procedures at Ostrava University Hospital were assessed in the study. Images were retrospectively evaluated for intracranial artery recanalization on the TIMI scale by 2 experienced neuroradiologists who were blinded to clinical findings and to each other. RESULTS: The angiography scans of 43 patients (16 females; age, 70.5 +/- 14 years; median baseline NIHSS score, 15 [IQR, 11-18]) were retrospectively evaluated in our study. At 3 months, 27% of patients had mRS scores <= 2 and mortality was 18%. Two radiologists diagnosed TIMI grades as follows: TIMI 0, 16%, and 16%; TIMI 1, 21%, and 8%; TIMI 2a, 32% and 29%; TIMI 2b, 13% and 16%; TIMI 3, 18, and 31%. Interobserver agreement for recanalization was weighted kappa = 0.4 (95% CI, 0.2-0.6). CONCLUSIONS: The diagnosis of recanalization after interventional procedures was found to have poor interobserver agreement between 2 experienced neuroradiologists. TIMI criteria, therefore, do not permit reliable comparison of the efficacy of recanalization therapy among different studies. PMID- 22241382 TI - Endovascular therapy of 500 small asymptomatic unruptured intracranial aneurysms. AB - BACKGROUND AND PURPOSE: Although the natural course of UIAs remains unclear, the risk of aneurysmal SAH due to small (<10 mm) asymptomatic UIAs is low. Endovascular therapy for UIAs has increased because of device development and the need for less invasive treatment. We report the results, safety, and efficacy of endovascular therapy of small asymptomatic UIAs. MATERIALS AND METHODS: A total of 457 patients with 500 small asymptomatic UIAs (maximum diameter < 10 mm) underwent endosaccular coil embolization at Juntendo University Hospital and affiliated hospitals. We retrospectively evaluated the technical feasibility, immediate and short-to-midterm follow-up anatomic results, procedure-related complications, and clinical outcomes. RESULTS: Endosaccular coil embolization was completed in 481 aneurysms (96.2%) and attempted in 19 (3.8%). Completed aneurysms were treated with the simple (39.5%), balloon-assisted (51.4%), and double-catheter (9.1%) techniques. Immediate angiographic outcomes were CO for 309 (64.2%) aneurysms, RN for 72 (15.0%), and RA for 100 (20.8%). Procedure related complications occurred in 38 aneurysms (7.6%): 19 ischemic, 11 hemorrhagic, and 8 others. Permanent morbidity and mortality were 0.8% and 0.2%, respectively. Anatomic outcome of 427 aneurysms followed up for >6 months with conventional catheter or MR angiographies showed recanalization in 72 (16.9%) aneurysms, necessitating retreatment in 9.9% (mean, 31.4 months). No patients had aneurysmal SAH during the clinical follow-up period (mean, 34.7 months). CONCLUSIONS: In this series, endovascular therapy of small asymptomatic UIAs was highly feasible with low morbidity and mortality rates. PMID- 22241383 TI - Clinical correlation of a new MR imaging method for assessing lumbar foraminal stenosis. AB - BACKGROUND AND PURPOSE: Recently, Lee et al reported a new grading system for the lumbar spinal foraminal stenosis. They considered the type of stenosis, the amount of fat obliteration, and the presence of nerve root compression. Our aim was to evaluate whether a new MR imaging grading system correlated with symptoms and neurologic signs and could replace the previous grading system. MATERIALS AND METHODS: We examined 91 patients (M/F = 49:42; mean age, 50 years) who visited our institution and underwent MR imaging of the L-spine and were evaluated by 2 musculoskeletal radiologists. The presence and grade of lumbar foraminal stenosis at the maximal narrowing point was assessed according to the new grading system suggested by Lee et al (Lee system) and the Wildermuth grading system (Wildermuth system). Results were correlated with clinical manifestations and neurologic physical examination. Statistical analysis was performed by using kappa statistics, categoric regression analysis, and nonparametric correlation analysis (Spearman correlation). RESULTS: Interobserver agreement in the grading of foraminal stenosis between the 2 readers was substantially correlated (kappa of Lee system = 0.767, kappa of Wildermuth system = 0.734). The Rs for reader 1 and reader 2 between the Lee system and the Wildermuth system were 0.880 and 0.885, between Lee system and PNM were 0.715 and 0.604, and between the Wildermuth system and PNM were 0.800 and 0.680. For patients younger than 50 years of age, the R between the Lee and Wildermuth systems was higher than that for patients 50 years or older, but the Rs between the grading system and PNM were lower in the younger group than in the older group. The Rs of the Wildermuth system with PNM were higher in the older group than in the younger group; the differences between the Rs of the Lee system with PNM and the Wildermuth system with PNM were higher in the older group (0.016 [young] versus 0.130 [old] and 0.008 versus 0.107). CONCLUSIONS: Interobserver agreement of the Lee system was slightly higher than the Wildermuth system and substantially correlated. Both systems are good for evaluation of lumbar spinal foraminal stenosis, but the Lee system showed slightly better interobserver agreement and good clinical correlation in the younger group of patients. PMID- 22241384 TI - Up and down the stairs with dr. Shapiro. PMID- 22241385 TI - Safety of protected carotid artery stenting in patients with severe carotid artery stenosis and carotid intraplaque hemorrhage. AB - BACKGROUND AND PURPOSE: Carotid IPH can be detected with MR imaging. The aim of this study was to determine the safety of CAS using an emboli protection device in patients with severe carotid artery stenosis and MR imaging-depicted carotid IPH. MATERIALS AND METHODS: We retrospectively reviewed a prospective data base that included 91 consecutive patients with severe carotid stenosis and high-risk features who were treated with CAS by using an emboli protection device. Seventy eight of the included patients underwent prestenting 3D TOF MRA. IPH was defined as the presence of high signal intensity within the carotid plaque, greater than 150% of the signal intensity of the adjacent neck muscle on TOF source images. The primary outcome measure was the combined incidence of stroke, MI, and death within 30 days of CAS. Associations between IPH and the primary outcome were investigated. RESULTS: IPH was detected on TOF MRA in 30 patients. Symptomatic patients were more common in the IPH group than in the non-IPH group (66.7% vs 41.7%; P = .032). Overall, 30-day stroke, MI, or death rates were 6.6%. There was no significant difference in the primary outcome between the IPH and non-IPH groups (10% and 6.25%, respectively; hazard ratio for IPH, 1.151; 95% CI, 0.035 to 37.500; P = .937). A logistic regression showed there was no independent variable associated with the primary outcome. CONCLUSIONS: The results of this study indicate that protected CAS seems to be safe in patients with severe carotid stenosis and IPH. PMID- 22241386 TI - Age-related complications following endovascular treatment of unruptured intracranial aneurysms. AB - BACKGROUND AND PURPOSE: The factors that led us to do the research for this paper was a desire to see if elderly patients did as well as non-elderly patients during endovascular intracranial aneurysm treatment. By doing this research, we could better stratify the most appropriate treatment for each patient with an aneurysm. The purpose of this study was to determine whether the incidence of procedural complications was greater in the elderly, defined as patients older than 65 years of age, compared with nonelderly patients undergoing elective endovascular treatment for intracranial aneurysms. MATERIALS AND METHODS: A retrospective review was performed in patients undergoing elective endovascular treatment of intracranial aneurysms between 2000 and 2010 at 1 institution. "Minor complications" were defined as those resulting in minimal or no loss of function that resolved before dismissal; "major complications" were complications that resulted in loss of function or complications that required a subsequent invasive therapy. Major complications were further stratified into those with and without neurologic disability, defined as an mRS score of >3. T tests and chi(2) analyses were used to compare groups. RESULTS: Three hundred fifty-five patients underwent 394 endovascular procedures treating 75 aneurysm recurrences and 319 untreated aneurysms. One hundred eight (30%) were elderly. There was no significant difference in the rate of complications in the elderly compared with the nonelderly (33% versus 26%, respectively; P = .18). Major complications were significantly more prevalent in the elderly than in the nonelderly (17% versus 7.4%, respectively, P = .004). Major complications with neurologic disability were also significantly more prevalent in the elderly compared with the nonelderly (8.2% versus 1.8%, respectively, P = .004). CONCLUSIONS: Major functional complications were markedly more common in the elderly compared with the nonelderly. PMID- 22241387 TI - Magnetization transfer imaging in premanifest and manifest Huntington disease. AB - BACKGROUND AND PURPOSE: MTI has the potential to detect abnormalities in normal appearing white and gray matter on conventional MR imaging. Early detection methods and disease progression markers are needed in HD research. Therefore, we investigated MTI parameters and their clinical correlates in premanifest and manifest HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 78 participants (28 controls, 25 PMGC, 25 MHD) were included. Brain segmentation of cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed using FSL's automated tools FAST and FIRST. Individual MTR values were calculated from these regions and MTR histograms constructed. Regression analysis of MTR measures from all gene carriers with clinical measures was performed. RESULTS: MTR peak height was reduced in both cortical gray (P = .01) and white matter (P = .006) in manifest HD compared with controls. Mean MTR was also reduced in cortical gray matter (P = .01) and showed a trend in white matter (P = .052). Deep gray matter structures showed a uniform pattern of reduced MTR values (P < .05). No differences between premanifest gene carriers and controls were found. MTR values correlated with disease burden and motor and cognitive impairment. CONCLUSIONS: Throughout the brain, disturbances in MTI parameters are apparent in early HD and are homogeneous across white and gray matter. The correlation of MTI with clinical measures indicates the potential to act as a disease monitor in clinical trials. However, our study does not provide evidence for MTI as a marker in premanifest HD. PMID- 22241388 TI - Dual-energy CT in the evaluation of intracerebral hemorrhage of unknown origin: differentiation between tumor bleeding and pure hemorrhage. AB - BACKGROUND AND PURPOSE: Detection of underlying tumor in patients with unknown origin acute ICH may be difficult because acute hematoma may mask enhancement of tumor on postcontrast CT. We intended to investigate the clinical utility of DECT in differentiating tumor bleeding from pure ICH. MATERIALS AND METHODS: Using a dual-source CT scanner, we obtained TNC single-energy and postcontrast DECT scans for 56 patients with unknown-origin spontaneous ICH. From the 2 sets of postcontrast DECT images obtained with different tube energy, EA (equivalent to conventional postcontrast CT), VNC, color-coded iodine overlay, fusion images of iodine overlay and VNC images were produced. The diagnostic performances of fusion, EA, and combined EA and TNC images for detecting underlying tumors were compared. RESULTS: Of the 56 patients, 17 had primary or metastatic tumors (18 lesions) and 39 had nontumorous ICH. The sensitivities of fusion, EA, and combined EA and TNC images for detecting brain tumors were 94.4%, 61.1%, and 66.7%, respectively, and their specificities were 97.4%, 92.3%, and 89.7%, respectively. The areas under the ROC curves were 0.964, 0.786, and 0.842, respectively. Overall, the diagnostic performance of fusion images was significantly superior to EA (P = .006) and combined EA and TNC (P = .011) images. CONCLUSIONS: DECT may be useful in detecting underlying tumors in patients with unknown-origin ICH. PMID- 22241389 TI - White matter abnormalities are related to microstructural changes in preterm neonates at term-equivalent age: a diffusion tensor imaging and probabilistic tractography study. AB - BACKGROUND AND PURPOSE: Preterm infants have a high risk of brain injury and neurodevelopmental impairment, often associated with WMA on conventional MR imaging. DTI can provide insight into white matter microstructure. The aim of this study was to investigate the association between WMA on conventional MR imaging and DTI parameters in specific fibers in preterm neonates at term equivalent age. MATERIALS AND METHODS: Seventy preterm neonates (39 boys and 31 girls) were included in the study. WMA were classified as no, mild, moderate, or severe. Probabilistic tractography provided tract volumes, FA, MD, lambda(//), and lambda(?) in the CST, SLF, TRs, and corpus callosum. Data were compared by using MANOVA, and adjustment for multiple comparisons was performed. RESULTS: Important associations were found between WMA and microstructural changes. Compared with neonates with no WMA (n = 41), those with mild WMA (n = 27) had significantly increased lambda(?) and MD in the left ATR, the left sensory STR, the bilateral motor STR, and for lambda(?) also in the right CST; FA decreased significantly in the left sensory STR. Diminished tract volumes and altered diffusion indices were also observed in the 2 neonates with moderate WMA. CONCLUSIONS: Altered DTI indices in specific tracts, with lambda(?) as most prominent, are associated with mild WMA in preterm neonates at term-equivalent age. PMID- 22241390 TI - Visiting with Dr. Ralph Heinz. PMID- 22241391 TI - Acute effects of alcohol on the human brain: diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: DTI can provide information about brain ultrastructure by quantifying water diffusion. Our objective was to assess the value of DTI in detecting the acute effects of alcohol on healthy human brains. MATERIALS AND METHODS: Sixteen healthy volunteers were studied with conventional MR imaging and DTI before and 0.5, 1, 2, and 3 hours after the initiation of acute alcohol administration. Two DTI parameters, FA and ADC, were measured in the frontal lobe, internal capsule, external capsule, precentral gyrus, postcentral gyrus, thalamus, middle cerebellar peduncle, and brain stem. BrACs were measured at each time point after drinking to estimate BACs. RESULTS: No abnormalities were found by conventional MR imaging at any time point in all subjects. ADC values of the frontal lobe, thalamus, and middle cerebellar peduncle were significantly reduced, reaching a minimum value at 1 or 2 hours, and FA values of the frontal lobe were significantly increased, reaching a maximal value at 0.5 hour in both doses. BrAC (BAC) was significantly increased to reach a peak at 0.5 hour in both doses and decreased gradually. CONCLUSIONS: DTI can detect changes in brains after acute alcohol consumption that are not detectable by conventional MR imaging. The frontal lobe, thalamus, and middle cerebellar peduncle are more vulnerable to the effects of acute alcohol consumption. DTI is more effective than BrAC or BAC for the detection of alcohol-induced changes on the human brain. PMID- 22241392 TI - Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data. AB - SUMMARY: Increasing evidence suggests that patients with L2-HGA have a predisposition to cerebral neoplasms. This may be related to the pathologic accumulation of L2-HG because high amounts of 2-HG have been found in brain neoplasms that have IDH1 mutations. Our experience, on the basis of 11 previously unreported cases of L2-HGA, 3 of which developed cerebral neoplasms during the course of the disease, also supports an association between L2-HGA and cerebral neoplasms. We conducted a meta-analysis of published data, and we identified 295 patients (including our 11 patients) with L2-HGA. In 14 patients, the metabolic disorder was associated with cerebral neoplasms, suggesting an approximately 5% prevalence rate of CNS neoplasms in patients with L2-HGA; nonetheless, it may still be an underestimate. L2-HGA is an important disease "model" that provides further evidence to support the recently proposed pathogenetic role of 2-HG in the development of cerebral neoplasms. PMID- 22241393 TI - Intracranial dural arteriovenous fistulas: classification, imaging findings, and treatment. AB - Intracranial DAVFs are pathologic dural-based shunts and account for 10%-15% of all intracranial arteriovenous malformations. These malformations derive their arterial supply primarily from meningeal vessels, and the venous drainage is either via dural venous sinuses or through the cortical veins. DAVFs have a reported association with dural sinus thrombosis, venous hypertension, previous craniotomy, and trauma, though many lesions are idiopathic. The diagnosis is dependent on a high level of clinical suspicion and high-resolution imaging. Cross-sectional imaging techniques by using CT and MR imaging aid in the diagnosis, but conventional angiography remains the most accurate method for complete characterization and classification of DAVFs. The pattern of venous drainage observed on dynamic vascular imaging determines the type of DAVF and correlates with the severity of symptoms and the risk of hemorrhage. PMID- 22241394 TI - Correlation of apparent diffusion coefficient at 3T with prognostic parameters of retinoblastoma. AB - BACKGROUND AND PURPOSE: Pathologic prognostic parameters for retinoblastoma have been defined. Our purpose was to correlate ADC values at 3T with prognostic parameters of retinoblastoma. MATERIALS AND METHODS: This study included 72 children (30 boys and 42 girls, mean age 19 +/- 2.6 months) with retinoblastoma. Pretreatment diffusion-weighted MR imaging was performed on a 3T scanner with b factors of 0, 500, and 1000 seconds/mm(2). ADC values were calculated and pathologic specimens were analyzed. ADC values of the tumors were then correlated with prognostic parameters, including degree of histologic differentiation, tumor size, bilaterality, choroidal invasion, and optic nerve extension. RESULTS: The mean ADC value of retinoblastoma was 0.49 +/- 0.12 * 10(-3) mm(2)/s. The ADC values of well- and moderately differentiated tumors were significantly different (P = .007) from poorly and undifferentiated retinoblastoma. There was also a significant difference in the ADC value among small, medium, and large tumors (P = .015), as well as between unilateral and bilateral retinoblastoma (P = .001), and this was independent of the degree of differentiation. The ADC value was also significantly lower (P = .003) when optic nerve invasion was present. There was no correlation of ADC value with growth pattern or choroidal invasion (P = .640 and 0.661, respectively). The ADC value of retinoblastoma was well correlated with the degree of differentiation of the tumor (r = 0.87, P = .007) and inversely correlated with the size of the tumor (r = -0.68, P = .015). CONCLUSIONS: ADC correlated with some of the accepted parameters of poor prognosis for retinoblastoma and may serve as a noninvasive prognostic parameter for assessment of newly diagnosed retinoblastoma. PMID- 22241395 TI - Parathyroid lesions: characterization with dual-phase arterial and venous enhanced CT of the neck. AB - This clinical report describes the enhancement characteristics of hypersecreting parathyroid lesions on dual-phase neck CT. We retrospectively analyzed the enhancement characteristics of 5 pathologically confirmed PTH-secreting lesions on dual-phase CT examinations. Attenuation values were measured for PTH-secreting lesions, vascular structures (CCA and IJV), and soft tissue structures (thyroid gland, jugulodigastric lymph node, and submandibular gland). From the attenuation values, "relative enhancement washout percentage" and "tissue-vascular ratio" were calculated and compared. All lesions decreased in attenuation from arterial to venous phase, while the mean attenuation values of other soft tissue structures increased. A high relative enhancement washout percentage was correlated with parathyroid lesions (P < .006). The tissue-CCA ratio and tissue IJV ratio for PTH-secreting lesions in the arterial phase were statistically significantly higher compared with soft tissue structures (P < .05). If these results are validated in future larger studies, noncontrast and delayed venous phases of 4D-CT could be eliminated to markedly reduce radiation exposure. PMID- 22241396 TI - Giemsa as a fluorescent dye for mineralizing bone-like nodules in vitro. AB - Giemsa was first used as a fluorescent dye for mineralized bone and cartilage in tissue sections. The aim of this study was to establish the use of Giemsa as a fluorescent dye for mineralizing bone-like nodules produced in cell cultures. Osteoblasts were grown under mineralizing conditions for 14 days, producing typical bone-like nodules. Upon staining with Giemsa stock solution for 1 min, the mineralizing nodules could be selectively visualized emitting intense green and red fluorescence when observed under blue and green illumination, respectively. The textural details of the nodules were clearly observed under fluorescence microscopy, allowing to identify regions with different degrees of mineralization. The mineralized nature of the nodules was confirmed using von Kossa's method, Alizarin Red S staining and x-ray mapping for Ca and P in a scanning electron microscope, showing a strong correlation between the mineralizing and the fluorescent nodules. The selective fluorescence was related to the mineral phase, being absent in decalcified samples. The use of Giemsa as a fluorescent dye for mineralizing bone-like nodules presents a simple alternative method to quickly analyze biomineralization assays in vitro under fluorescence microscopy, particularly in the biological evaluation of biomaterials. PMID- 22241397 TI - Cooperative effect of temperature and linker functionality on CO2 capture from industrial gas mixtures in metal-organic frameworks: a combined experimental and molecular simulation study. AB - In this work, the cooperative effect of temperature and linker functionality on CO(2) capture in metal-organic frameworks (MOFs) was investigated using experimental measurements in combination with molecular simulations. To do this, four MOFs with identical topology but different functional groups on the linkers and three important CO(2)-containing industrial gas mixtures were adopted. The interplay between linker functionality and temperature was analyzed in terms of CO(2) storage capacity, adsorption selectivity, working capacity of CO(2) in temperature swing adsorption (TSA) processes, as well as sorbent selection parameter (S(ssp)). The results show that the effect of linker functionality on CO(2) capture performance in the MOFs is strongly interconnected with temperature: up to moderate pressures, the lower the temperature, the larger the effect of the functional groups. Furthermore, the modification of a MOF by introducing more complex functional groups can not only improve the affinity of framework for CO(2), but also reduce the free volume, and thus may contribute negatively to CO(2) capture capability when the packing effect is obvious. Therefore, when we design a new MOF for a certain CO(2) capture process operated at a certain temperature, the MOF should be designed to have maximized affinity for CO(2) but with a negligible or small effect caused by the reduction of free volume at that temperature and the corresponding operating pressure. PMID- 22241398 TI - High-throughput preparation of complex multi-scale patterns from block copolymer/homopolymer blend films. AB - A simple, straightforward process for fabricating multi-scale micro- and nanostructured patterns from polystyrene-block-poly(2-vinylpyridine) (PS-b P2VP)/poly(methyl methacrylate) (PMMA) homopolymer in a preferential solvent for PS and PMMA is demonstrated. When the PS-b-P2VP/PMMA blend films were spin-coated onto a silicon wafer, PS-b-P2VP micellar arrays consisting of a PS corona and a P2VP core were formed, while the PMMA macrodomains were isolated, due to the macrophase separation caused by the incompatibility between block copolymer micelles and PMMA homopolymer during the spin-coating process. With an increase of PMMA composition, the size of PMMA macrodomains increased. Moreover, the P2VP blocks have a strong interaction with a native oxide of the surface of the silicon wafer, so that the P2VP wetting layer was first formed during spin coating, and PS nanoclusters were observed on the PMMA macrodomains beneath. Whereas when a silicon surface was modified with a PS brush layer, the PS nanoclusters underlying PMMA domains were not formed. The multi-scale patterns prepared from copolymer micelle/homopolymer blend films are used as templates for the fabrication of gold nanoparticle arrays by incorporating the gold precursor into the P2VP chains. The combination of nanostructures prepared from block copolymer micellar arrays and macrostructures induced by incompatibility between the copolymer and the homopolymer leads to the formation of complex, multi-scale surface patterns by a simple casting process. PMID- 22241399 TI - A biomechanical comparison of a locking plate, a nail, and a 95 degrees angled blade plate for fixation of subtrochanteric femoral fractures. AB - OBJECTIVE: To compare the biomechanical performance of a cephalomedullary nail (CMN), a proximal femoral locking plate, and a 95 degrees angled blade plate in a comminuted subtrochanteric fracture model. METHODS: A comminuted subtrochanteric femoral fracture model was created with a 2-cm gap below the lesser trochanter in 15 pairs of human cadaveric femora confirmed to be nonosteoporotic. The femora were randomized to treatment with one of the previously mentioned 3 devices. Each was tested under incrementally increasing cyclic load up to 90,000 cycles from 50% to 250% of body weight to simulate progressive weight bearing during 3 months of an average 700-N (approximately, 70 kg or 150 lb) person. Force, number of cycles, and total load sustained to reach 10 mm of displacement were compared. Failure modes were also noted. RESULTS: The CMN construct withstood significantly more cycles, failed at a significantly higher force, and withstood a significantly greater load than either of the plate constructs (P < 0.001). Varus collapse was significantly lower in the CMN construct (P < 0.0001). Modes of failure differed among implant-bone constructs with damage to the femoral head through implant cutout in 5 of 10 blade plate specimens and 2 of 10 CMN specimens, whereas no damage to the femoral head bone was observed in any of the locking plate constructs. CONCLUSIONS: The CMN construct was biomechanically superior to either the locking plate or 95 degrees blade plate constructs. The locking plate construct was biomechanically equivalent to the blade plate construct. PMID- 22241400 TI - The palliation of malignant pleural effusions. PMID- 22241401 TI - Screening for breast cancer: time for a rethink. PMID- 22241403 TI - Spinal metastasis. PMID- 22241404 TI - Biological therapy for rheumatoid arthritis: where are we now? AB - Since the introduction of targeted biological therapies, the implications of a new diagnosis of rheumatoid arthritis have changed dramatically. There are now several therapeutic options available for these patients and the target of treatment - remission - is now a realistic goal. PMID- 22241405 TI - Management of branch retinal vein occlusion. AB - This article addresses advances in the management of branch retinal vein occlusion - a common retinal vascular disorder in elderly patients which is a significant cause of ocular morbidity. New intravitreal therapies have improved the prognosis for patients, albeit with significant cost implications. PMID- 22241406 TI - Use of bevacizumab in the treatment of metastatic colorectal cancer. AB - The Cancer Drugs Fund may allow more patients in England access to clinically effective cancer therapies. In this article oncologists already familiar with the clinical evidence, and experienced in treating with bevacizumab, share practical recommendations on optimal first-line use of this treatment for metastatic colorectal cancer. PMID- 22241407 TI - Pathophysiology, management and complications of hypothermia. AB - Hypothermia, either accidental or therapeutic, is when the body's core temperature is less than 35.0 degrees C. This article examines the pathophysiology, clinical features and management of both intentional and unintentional hypothermia with a focus on the current literature regarding treatment protocols. PMID- 22241408 TI - The role of lumbar disc replacement in the surgical management of low back pain. AB - Spinal fusion has long been the standard surgical treatment for degenerative disorders of the spine, but clinical outcomes are often unpredictable. Lumbar disc replacement allows removal of the pain source while preserving motion. This article explores the role of lumbar disc replacement in the surgical management of low back pain. PMID- 22241409 TI - Clinical leadership: a role for students? AB - Since the publication of the 'To Err is Human' report, patient safety and quality improvement has been an increasingly important agenda in health care. This article explores the role that students can play in leading change in health-care systems. PMID- 22241410 TI - An unusual nasal polyp: skull base meningioma with extracranial extension into the nasal cavity. PMID- 22241411 TI - Meticillin-resistant Staphylococcus aureus liver abscess. PMID- 22241412 TI - Horner's syndrome: an incidental confounder. PMID- 22241413 TI - A rare visual side effect of urinary tract infection in a patient with a suprapubic catheter. PMID- 22241414 TI - Joseph Lister: father of modern surgery. PMID- 22241417 TI - Hopes, dreams and investments. PMID- 22241416 TI - Involvement of extracranial arteries in paradoxical embolism. PMID- 22241419 TI - Complex system, simple solutions. PMID- 22241420 TI - Your right to blow the whistle. AB - The NHS Constitution has now enshrined within it a number of pledges concerning whistle blowing. This comes as a result of a recent Department of Health (DH) public consultation concerning the Constitution and whistle blowing (DH, 2011). Changes to the Constitution will add an expectation that staff should raise concerns at the earliest opportunity. It also pledges that NHS organizations should support staff by ensuring their concerns are fully investigated and that there is someone independent, outside of their team, to speak to. It will aim to add clarity around the existing legal right for staff to raise concerns about safety, malpractice or other wrong doing without suffering any detriment. PMID- 22241421 TI - Abusing the privelege to care: shame on us (cont.). AB - Ian Peate, Editor in Chief of BJN, wrote the editorial 'Abusing the privelege: to care - shame on us' which was adapted and published on the BBC website There was an overwhelming response to Ian's piece and some more examples are shown here. PMID- 22241422 TI - The role of the nurse in mechanical ventilation. AB - Many patients admitted onto the intensive care unit (ICU) require airway maintenance and mechanical ventilator support (Cook et al, 2011). It is important that all qualified nurses working in critical care environments understand the indications for the use of mechanical ventilation, the modes of ventilation delivery, and the most common associated complications. Mechanical ventilators assist the movement of gases (air) into and out of a patient's lungs, while minimizing the effort of breathing (Scholz et al, 2011). Indicators for the use of mechanical ventilation include the maintenance of oxygenation, the management of type I reparatory failure, the removal of carbon dioxide, the management of type II respiratory failure, cardiorespiratory arrest and central nervous system depression (Oh et al, 2008). PMID- 22241423 TI - Oxygen saturation and secretion weight after endotracheal suctioning. AB - Endotracheal suctioning is a common aspect of nursing care to mechanically ventilated patients. The aim of this study was to investigate the effects of two suctioning techniques on oxygen saturation (SaO2) and the amount of drained secretions. A quasi-experimental study of 103 mechanically-ventilated patients was conducted from two tertiary hospitals in Greece. Two suctioning techniques were applied to each patient: with normal saline instillation and without. Normal saline instillation was associated with increased secretions' weight (p<0.001) and no significant differences in SaO2 values compared with no instillation. In examining each suctioning technique separately, the use of normal saline instillation was associated with a decrease in SaO2 levels 1 minute (p<0.001) and 15 minutes (p=0.002) after this procedure. In addition, suctioning without normal saline instillation was associated with a decrease in SaO2 1 minute (p<0.001) after the suction. In conclusion, normal saline instillation is related with a negative outcome on patient oxygenation for a prolonged period after the suction and causes the removal of a greater amount of secretions than the applied technique with no instillation. Comparing the two techniques, none is superior to the other resulting from the statistically insignificant comparative differences in SaO2 values. PMID- 22241424 TI - Simulation training for hyperacute stroke unit nurses. AB - National clinical guidelines have emphasized the need to identify acute stroke as a clinical priority for early assessment and treatment of patients on hyperacute stroke units. Nurses working on hyperacute stroke units require stroke specialist training and development of competencies in dealing with neurological emergencies and working in multidisciplinary teams. Educational theory suggests that experiential learning with colleagues in real-life settings may provide transferable results to the workplace with improved performance. Simulation training has been shown to deliver situational training without compromising patient safety and has been shown to improve both technical and non-technical skills (McGaghie et al, 2010). This article describes the role that simulation training may play for nurses working on hyperacute stroke units explaining the modalities available and the educational potential. The article also outlines the development of a pilot course involving directly relevant clinical scenarios for hyperacute stroke unit patient care and assesses the benefits of simulation training for hyperacute stroke unit nurses, in terms of clinical performance and non-clinical abilities including leadership and communication. PMID- 22241425 TI - Stoma care-related skin problems and solutions. PMID- 22241426 TI - Venous leg ulcers and the impact of compression bandaging. AB - Venous leg ulcers are a major health issue in terms of financial burden to the NHS, nurses' input, and physical, psychological and social impact to the patient. The best practice management of leg ulcers is the application of high compression, which is a complex task and requires substantial skill and knowledge. Healing and recurrence rates are poor in some cases and this adds to the physical and psychosocial impact, as well as the financial burden. Many of the sequelae of ulceration hinder patients' ability to tolerate treatment. Nurses must acknowledge the difficulties patients face and become skilled in holistic assessment, care planning and the delivery of patient-focused best practice. PMID- 22241427 TI - Psoriasis: a challenging multidisciplinary task. PMID- 22241428 TI - Physiological measures of assessing infant pain: a literature review. AB - Neonatal pain assessment is not standardized. Clinicians may use various parameters in the measurement of pain which can lead to different interpretations. Currently, there is no validated biological marker for assessing infant pain in any age group. However, in the non-verbal patient, the most feasible way to assess pain may be by evaluation of physiological parameters. The author conducted a systematic review of the literature using qualitative methods and seven research papers were selected for review, in which physiological measures were used in the assessment of neonatal pain. Heart rate was the most frequently used physiological pain measure in these studies. Oxygen saturation, blood pressure and respiratory rate lacked sensitivity and specificity and cannot be used independently. These measures may detect pain but cannot quantify it and are, therefore, not useful assessments of chronic pain. The multidimensional approach to pain assessment may be the most appropriate owing to the correlation between behavioural and physiological indicators of pain in the neonate. PMID- 22241429 TI - Is care planning still relevant in the 21st century? AB - As we progress into the second decade of the 21st century, the healthcare needs of an increasingly diverse population are changing. Children's nurses must respond to these challenges by creating clear and effective plans of care in collaboration with children and their families. Legally and professionally, children's nurses are required to accurately record plans of care given to individual patients to provide a legal document demonstrating that care has been delivered (Nursing and Midwifery Council (NMC), 2008). Within this article, an overview of the nursing process and its components will be discussed, considering how this process assists in organizing and prioritizing care delivery to the child or young person and family. In addition, the support offered by a framework such as the Roper, Logan and Tierney model of nursing , in systematically assessing, planning and documenting care to meet individuals' needs, must be reinforced and its application practiced. Subsequently, the use and contribution of such processes and frameworks to the organization and delivery of care will be examined within the context of a clinically-based scenario, which has helped to explore students' knowledge and skills in the second year of a 3-year undergraduate programme. The authors firmly believe that care planning skills are fundamental to safeguarding vulnerable children, their families and, indeed, the nursing profession in this current challenging socioeconomic environment. PMID- 22241430 TI - Professional development part 1: the importance of professional development. PMID- 22241431 TI - Long-term conditions: does the NHS support patients? AB - Professor Alan Glasper considers the results of the Department of Health study into the attitudes and behaviour of those living with a long-term condition. While the results are generally positive, work still needs to be done to both prevent long-term conditions from occurring in the first place and support those living with them. PMID- 22241432 TI - Ensuring safe health care and dealing appropriately with patient complaints. AB - John Tingle discusses two important publications. One is on patient safety from the National Patient Safety Agency and the other is on NHS complaints from the Health Service Ombudsman. PMID- 22241433 TI - Complaints management: get it right. PMID- 22241434 TI - Response to 'Mildly decreased glomerular filtration rate is associated with poor coronary collateral circulation in patients with coronary artery disease'. PMID- 22241435 TI - Evaluation of time, attendance of medical staff, and resources during radiotherapy for breast cancer patients. The DEGRO-QUIRO trial. AB - BACKGROUND AND PURPOSE: To conform to recommendations regarding the treatment of breast cancer, an estimation of costs and personnel to assure treatment is required. To date no recommendations based on real time measurements are available. The DEGRO (German Society of Radiation Oncology), therefore, initiated a prospective multicenter evaluation of core procedures of radiotherapy. In this analysis, the results regarding human resources and room occupation during the treatment of breast cancer are presented. PATIENTS AND METHODS: Three academic radiation oncology centers (Erlangen, Munster, Mannheim) prospectively documented their workflow and working time for all breast cancer patients from July-October 2008. Subsequently, a statistical analysis was performed. RESULTS: The longest working time of physicians was the definition of the target volume and organs at risk (mean 33 min). Furthermore, physicians needed much time for general tasks, which included conversations. Physicists needed the most time for treatment planning and authorization (64 min), whereas technicians were mostly needed in day-to-day radiotherapy treatment (15 min, 31 min including verification). Despite significant differences in specific steps between centers, overall working times and room occupation were comparable and representative. Special procedures (intraoperative radiotherapy/multicatheter brachytherapy) required considerable amounts of additional working time of physicians and physicists. CONCLUSION: In this prospective analysis, data of human resources and room occupation during treatment of breast cancer are presented for the first time. Each patient consumes about 12 h of human resources for treatment and 3.75 h for general tasks (physicians 4.7 h, physicists 1.8 h, and technicians 9.2 h). PMID- 22241439 TI - Understanding scarring: scarless fetal wound healing as a model. PMID- 22241440 TI - A new xenotransplantation model reveals tumor-initiating cells in cutaneous squamous cell carcinoma. AB - Two articles by Patel et al. in this issue demonstrate reproducible, high frequency xenografting of both primary human cutaneous squamous cell carcinoma (SCC) tissue and single-cell suspensions, as well as the existence of a small population of CD133(+) tumor-initiating cells that are capable of regenerating the hierarchical organization and histology of the original tumor through multiple xenograft passages. PMID- 22241441 TI - MEK'ing the most of p53 reactivation therapy in melanoma. AB - Melanoma is one of the few tumor types in which p53 is functionally repressed without extraneous mutations. With the number of kinase-based drug targets rapidly declining, p53 represents a relatively untapped resource for therapeutic intervention. Studies in other tumor types have demonstrated that reactivation of p53 is a viable strategy to initiate sustained tumor regression; combining p53 reactivation while inhibiting traditional genetic targets, such as mitogen activated protein kinase/extracellular signal-related kinase kinase (MEK), holds therapeutic promise. PMID- 22241442 TI - It's all about position: the basal layer of human epidermis is particularly susceptible to different types of sunlight-induced DNA damage. AB - In this issue, Tewari et al. show that although UVB most effectively causes cyclobutane pyrimidine dimers (CPDs) at the human epidermal surface, UVA-induced CPDs predominate in the basal layer. Previous studies found higher accumulation of UVA-induced 8-oxo-7,8-dihydro-2'-deoxyguanosine and mutations in the basal layer. Therefore, the epidermal basal layer is particularly sensitive to UVA induced genetic damage and the formation of mutations. PMID- 22241443 TI - Optical antenna for photofunctional molecular systems. AB - Optical antennas can enhance the efficiency of photon-molecule interactions. To design efficient antenna structures, it is essential to consider physicochemical aspects in addition to electromagnetic considerations. Specifically, chemical interactions between optical antennas and molecules have to be controlled to enhance the overall efficiency. For this purpose, sphere-plane nanostructures are suitable optical antennas for molecular-modified functional electrode systems when a well-defined electrode is utilized as a platform. PMID- 22241444 TI - [Organ procurement in Germany: a regional survey among students]. AB - BACKGROUND AND OBJECTIVE: In Germany the extent of organ donation is still low and not sufficent to duly address all patients on the waiting lists. It is likely that a lack of information and a consecutive uncertainty in the adult population relate to this imbalance. Virtually no data exist about teenagers' knowledge of the facts of organ donation. METHODS: 4000 questionnaires were distributed in secondary schools in the state capital city Mainz, Germany. The students were asked to respond to 12 questions. The survey was voluntary and performed in class, without the students using any information sources. RESULTS: Data from 1155 questionnaires were analysed. Overall 11.3 % of the teenagers carried an organ donor card. 48.9 % of the students had spoken about organ donation and brain death in their families. 37.0 % of the students declined organ donation. Of these, 72.4 % named a lack of education and informations as the primary reason for this statement. More non-German than German pupils declined organ donation (43.4 % vs. 36.2 %). CONCLUSIONS: More than half of the pupils between 14 years and 20 years of age support the concept of organ transplantation as therapeutic option. Nevertheless the proportion of organ card holders is small among these students. These regional results identify an information deficit in young people in Germany as one of the main causes for inadequate acceptance of organ donation. Therefore, information and structured education should be intensified in German schools as possible measure to increase the number of future organ donor card holders in Germany. PMID- 22241445 TI - [Jaundice and pancreatic mass: typical clinical presentation of a rare disease]. AB - HISTORY AND ADMISSION FINDINGS: An 81-year-old man presented with jaundice and a pancreatic tumor. 6 years ago transperitoneal nephrectomy had been performed because of a clear cell renal cancer (pT3b pN0 pM0). INVESTIGATIONS: Laboratory tests showed normocytic anemia and signs of cholestasis. Abdominal ultrasonography revealed a well-defined mass of the head of the pancreas with a diameter of about 4 cm, and a previously diagnosed adrenal mass which had slightly increased in size. Contrast-enhanced ultrasound demonstrated a hyperenhancing of the pancreatic mass, untypical for primary adenocarcinoma of the pancreas. Endoscopic ultrasound-guided fine-needle aspiration disclosed a metastasis of the previously resected renal cancer. TREATMENT AND COURSE: Bilary spincterotomy and stent insertion were performed. Because of proven pancreatic metastasis and suspected adrenal metastasis of renal cancer palliative treatment with multi-targeted receptor tyrosine kinase inhibitor sunitinib was initiated. CONCLUSION: Renal cell carcinomas are the most common primary tumors leading to pancreatic metastasis. In contrast to ductal adenocarcinoma pancreatic metastasis shows hyperenhancement when examined by using contrast-enhanced ultrasonography. Endoscopic ultrasound-guided fine-needle aspiration helps to confirm the suspected diagnosis. PMID- 22241446 TI - [Early benefit evaluation of drugs: procedure and bases for decision-making]. PMID- 22241447 TI - [65-year-old woman with progressive cortical hyperintensity]. PMID- 22241448 TI - [Adverse ocular drug reactions of systemic antimicrobial agents]. AB - Antimicrobial therapy can cause adverse ocular drug reactions. They are most often noticed by changes of the eyes' anterior segments or by pain and visual disturbances. It is important that physicians but also patients are watchful for the symptoms and know about their potential dangerous consequences because the chance for reversibility may depend on their early detection. During therapy with voriconazol about one third of patients complain of visual disturbances soon after the first doses but symptoms generally resolve after a short period of time without sequelae. Telithromycin may impair accommodation due to its anticholinergic activity. Neuropathies of the optic nerve may be caused by ethambutol, isoniazid, streptomycin, and linezolid. The first symptoms, such as disturbances in colour vision, typically occur with a latency of several weeks after start of therapy. This adverse effect may result in serious long term impairment of visual function. Toxic effects on the mitochondria in retinal ganglion cells are discussed as underlying mechanisms. Rifabutin and cidofovir may cause intraocular inflammatory reactions. In addition cidofovir may induce a pronounced reduction of the ocular pressure. Adverse drug reactions are often dose dependent and therefore influenced by impaired kidney or liver function, pharmacogenetics, or by drug-drug interactions. Potential serious drug induced ocular side effects require close cooperation with an ophthalmologist for evaluation of the individual risk benefit ratio, if possible, even before beginning of antimicrobial therapy. PMID- 22241449 TI - [Myiasis in an extensive wound]. PMID- 22241450 TI - [TSH radioreceptor assay]. PMID- 22241451 TI - Radiologic findings of urachal mucinous cystadenocarcinoma causing pseudomyxoma peritonei. AB - Urachal mucinous cystadenocarcinoma causing pseudomyxoma peritonei is very rare. We report a case of a 59-year-old man with urachal mucinous adenocarcinoma associated with pseudomyxoma peritonei, and our radiologic findings. Ultrasonography revealed a well delineated, large cystic tumor adjacent to the anterior wall of the abdomen. Computed tomography and magnetic resonance imaging revealed a tumor of which the left posterior wall was defective. A large amount of ascites was present in the peritoneal cavity. The ascites caused displacement of the intestinal structures toward the dorsal region. The tumor wall and septa in the ascites were well enhanced on contrast-enhanced images. Radiologically, pseudomyxoma peritonei due to rupture of urachal cystic tumor was considered. The pathologic diagnosis was mucinous adenocarcinoma and pseudomyxoma peritonei. PMID- 22241453 TI - A comprehensive transcriptome assembly of Pigeonpea (Cajanus cajan L.) using sanger and second-generation sequencing platforms. AB - A comprehensive transcriptome assembly for pigeonpea has been developed by analyzing 128.9 million short Illumina GA IIx single end reads, 2.19 million single end FLX/454 reads, and 18 353 Sanger expressed sequenced tags from more than 16 genotypes. The resultant transcriptome assembly, referred to as CcTA v2, comprised 21 434 transcript assembly contigs (TACs) with an N50 of 1510 bp, the largest one being ~8 kb. Of the 21 434 TACs, 16 622 (77.5%) could be mapped on to the soybean genome build 1.0.9 under fairly stringent alignment parameters. Based on knowledge of intron junctions, 10 009 primer pairs were designed from 5033 TACs for amplifying intron spanning regions (ISRs). By using in silico mapping of BAC-end-derived SSR loci of pigeonpea on the soybean genome as a reference, putative mapping positions at the chromosome level were predicted for 6284 ISR markers, covering all 11 pigeonpea chromosomes. A subset of 128 ISR markers were analyzed on a set of eight genotypes. While 116 markers were validated, 70 markers showed one to three alleles, with an average of 0.16 polymorphism information content (PIC) value. In summary, the CcTA v2 transcript assembly and ISR markers will serve as a useful resource to accelerate genetic research and breeding applications in pigeonpea. PMID- 22241452 TI - Survivorship care plans in research and practice. AB - The Institute of Medicine (IOM) recommends the use of survivorship care plans (SCPs) for all cancer survivors. Developing useful SCPs requires understanding what survivors and their providers need and how SCPs can be implemented in practice. Published studies investigating the perspectives of stakeholders (survivors, primary care providers, and oncology providers) were reviewed regarding the content and use of SCPs. All National Cancer Institute (NCI) designated cancer centers were surveyed concerning the extent to which SCPs for survivors of breast and colorectal cancers are in use, their concordance with the IOM's recommendation, and details about SCP delivery. Survivors and primary care providers typically lack the information the IOM suggested should be included in SCPs. Oncology providers view SCPs favorably but express concerns about the feasibility of their implementation. Fewer than one-half (43%) of NCI-designated cancer centers deliver SCPs to their breast or colorectal cancer survivors. Of those that do, none deliver SCPs that include all components recommended by the IOM. Survivors' and providers' opinions about the use of SCPs are favorable, but there are barriers to implementation. SCPs are not widely used in NCI-designated cancer centers. Variation in practice is substantial, and many components recommended by the IOM framework are rarely included. ? PMID- 22241454 TI - The interplay of catechol ligands with nanoparticulate iron oxides. AB - The unique properties exhibited by nanoscale materials, coupled with the multitude of chemical surface derivatisation possibilities, enable the rational design of multifunctional nanoscopic devices. Such functional devices offer exciting new opportunities in medical research and much effort is currently invested in the area of "nanomedicine", including: multimodal imaging diagnostic tools, platforms for drug delivery and vectorisation, polyvalent, multicomponent vaccines, and composite devices for "theranostics". Here we will review the surface derivatisation of nanoparticulate oxides of iron and iron@iron-oxide core shells. They are attractive candidates for MRI-active therapeutic platforms, being potentially less toxic than lanthanide-based materials, and amenable to functionalisation with ligands. However successful grafting of groups onto the surface of iron-based nanoparticles, thus adding functionality whilst preserving their inherent properties, is one of the most difficult challenges for creating truly useful nanodevices from them. Functionalised catechol-derived ligands have enjoyed success as agents for the masking of superparamagnetic iron-oxide particles, often so as to render them biocompatible with medium to long-term colloidal stability in the complex chemical environments of biological milieux. In this perspective, the opportunities and limitations of functionalising the surfaces of iron-oxide nanoparticles, using coatings containing a catechol derived anchor, are analysed and discussed, including recent advances using dopamine-terminated stabilising ligands. If light-driven ligand to metal charge transfer (LMCT) processes, and pH-dependent ligand desorption, leading to nanoparticle degradation under physiologically relevant conditions can be suppressed, colloidal stability of samples can be maintained and toxicity ascribed to degradation products avoided. Modulation of the redox behaviour of iron catecholate systems through the introduction of an electron-withdrawing substituent to the aromatic pi-system of the catechol is a promising approach towards achieving these goals. PMID- 22241455 TI - Boron oxynitride nanoclusters on tungsten trioxide as a metal-free cocatalyst for photocatalytic oxygen evolution from water splitting. AB - Here we show that B(2)O(3-x)N(x) nanoclusters can be formed on the surface of WO(3) particles by a combination of thermal oxidation of tungsten boride (WB) in air and the subsequent nitriding process in gaseous ammonia. The resultant nanoclusters are found to play an apparent role in improving the photocatalytic oxygen evolution of WO(3) by promoting the surface separation of photoexcited charge-carriers. PMID- 22241456 TI - A patient's way. PMID- 22241457 TI - The ethics of deactivating a pacemaker in a pacing-dependent patient: reflections on a case study. AB - The decision to deactivate a pacemaker in a pacing-dependent patient is troubling for some health professionals who may regard such interventions as hastening death and therefore ethically impermissible. This may be especially concerning in situations where a patient is unable to clearly state what their preferences may be and the decision--were it to be made--will almost certainly result in the patient's immediate death. In this discussion, we reflect on some of the ethical aspects that arise when JP, a 75-year-old woman who is pacing dependent, suffers a significant brain injury, and the family request that her pacemaker be deactivated. Taking into account the clinical reality of her situation, the united wishes and loving concern of her husband and family, and their substituted judgment regarding her likely preferences, we claim that the decision to deactivate her pacemaker was ethically sound. PMID- 22241458 TI - The phantom of death improving quality of life: you live until you die. AB - The purpose of this study was, using secondary analysis on data collected from previous empirical studies, to focus on improving the quality of life due to the new possibilities for living after a cancer diagnosis. No matter how long or short the life will be, quality of life in palliative care is about "living in the best way" until death. The data analysis identified 4 main themes; death as a main concern, reevaluating life, living a normal life with support, and living until death. The key message is that the patients are living until they die. Palliative care should facilitate and support the patients in their new life situation in order to sustain their quality of life. They are still alive--living until death. PMID- 22241459 TI - Death representation of caregivers in hospice. AB - In this study, we investigated caregiver's death representation in hospice. The results presented here are a further analysis of the data collected in our previous study, concerning the evaluation of the caregiver in hospice. The data analysis of 24 caregivers of patients hospitalized in Rimini Hospice (Italy) underlined that caregivers avoiding death representation of the patient admitted to hospice had fewer protective factors (52.3%) and more risk factors (47.7%) than caregivers nonavoiding (66.5% and 33.5%, respectively). Caregivers avoiding death representation, moreover, experienced a greater distress (58%) than those nonavoiding (42%). PMID- 22241460 TI - Should I stay or should I go: a study of hospice palliative care volunteer satisfaction and retention. AB - Forty-one hospice palliative care volunteers (from 6 community- and 3 hospital based programs) participated in informal group discussions regarding (1) what aspects of their work provide them with the most (and least) satisfaction; (2) why they continue to volunteer; and (3) why they might stop. In 5 of the 9 programs, volunteers said that feeling appreciated by the patients/families they support gave them great satisfaction. Boundary issues and/or role ambiguities were among the least satisfying aspects of their work, mentioned by volunteers in 4 programs. Volunteers in all 9 programs mentioned that they continue to volunteer because it makes a difference/helps others/meets a need in other people's lives. Among the reasons given for potentially stopping volunteering were a family crisis, burnout, old age, and other commitments. PMID- 22241461 TI - The principle of distributive justice. PMID- 22241462 TI - A functional variant of the collagen type III alpha1 gene modify risk of sporadic intracranial aneurysms. AB - Abnormalities in type III collagen in the arterial walls cause certain familial intracranial aneurysms (IAs); however, it remains unknown whether COL3A1 variants contribute to the risk of sporadic IAs. To study whether COL3A1 variants are associated with sporadic IAs, the association of COL3A1 variants with sporadic IAs was tested in 298 cases and 488 controls, replicated in an independent population of 192 cases and 1,690 controls, and further verified in 633 patients with intra-cerebral hemorrhage, 1,074 hypertensives, and 1,883 controls. We found that allele A of SNP rs1800255 conferred a 1.71-fold increased risk for IAs (adjusted odds ratio: OR = 1.71, 95% confidence interval: CI 1.19-2.45, P = 0.004) and results in an amino acid change of Ala698Thr, which led to a lower thermal stability of the peptide. These results were confirmed in the independent study. The associations were independent of the presence of hemorrhagic stroke and hypertension. These results support the view that the functional variant of COL3A1 is genetic risk factors for IAs in the Chinese population. PMID- 22241463 TI - Nicaraguan migration and the prevalence of adolescent childbearing in Costa Rica. AB - This study describes the dynamics of adolescent childbearing of Nicaraguan-born and Costa Rican-born adolescents in Costa Rica and examines the association between socio-demographic factors and adolescent childbearing in the country. We studied Nicaraguan-born and Costa Rican adolescents using the data of the 2000 Census. Multivariate logistic regression was used to analyze the association between country of origin and adolescent childbearing, while controlling for socio-demographic factors (age, education, union, urbanization and poverty). 26% of Nicaraguan-born migrants and 9.5% of Costa Ricans had given birth during adolescence. The migrants' increased odds of pregnancy decreased from 3.34 (CI 3.21, 3.48) to 1.88 (CI 1.79, 1.97) when controlling for socio-demographic factors. Age, low educational attainment, urban residence, poverty and union were all significant predictors of adolescent pregnancy. Nicaraguan-born status is associated with adolescent childbearing in Costa Rica. Further research is needed to understand what factors, other than socio-demographic indicators, contribute to the differing prevalence of adolescent childbearing in Costa Rica. PMID- 22241464 TI - Density functional study of S(N) 2 substitution reactions for CH(3) Cl + CX(1) X(2*-) (X(1) X(2) = HH, HF, HCl, HBr, HI, FF, ClCl, BrBr, and II). AB - A systematic investigation on the S(N) 2 displacement reactions of nine carbene radical anions toward the substrate CH(3) Cl has been theoretically carried out using the popular density functional theory functional BHandHLYP level with different basis sets 6-31+G (d, p)/relativistic effective core potential (RECP), 6-311++G (d, p)/RECP, and aug-cc-pVTZ/RECP. The studied models are CX(1) X(2*-) + CH(3) Cl -> X(2) X(1) CH(3) C(*) + Cl(-) , with CX(1) X(2*-) = CH(2) (*-) , CHF(* ) , CHCl(*-) , CHBr(*-) , CHI(*-) , CF(2) (*-) , CCl(2) (*-) , CBr(2) (*-) , and CI(2) (*-) . The main results are proposed as follows: (a) Based on natural bond orbital (NBO), proton affinity (PA), and ionization energy (IE) analysis, reactant CH(2) (*-) should be a strongest base among the anion-containing species (CX(1) X(2*-) ) and so more favorable nucleophile. (b) Regardless of frontside attacking pathway or backside one, the S(N) 2 reaction starts at an identical precomplex whose formation with no barrier. (c) The back-S(N) 2 pathway is much more preferred than the front-S(N) 2 one in terms of the energy gaps [DeltaE cent?(front)-DeltaE cent?(back)], steric demand, NBO population analysis. Thus, the back-S(N) 2 reaction was discussed in detail. On the one hand, based on the energy barriers (DeltaE cent? and DeltaE ovr?) analysis, we have strongly affirmed that the stabilization of back attacking transition states (b-TSs) presents increase in the order: b-TS-CI(2) < b-TS-CBr(2) < b-TS-CCl(2) < b-TS-CHI < b-TS-CHBr < b-TS-CHCl < b-TS-CF(2) < b-TS-CHF < b-TS-CH(2) . On the other hand, depended on discussions of the correlations of DeltaE ovr? with influence factors (PA, IE, bond order, and DeltaE def?), we have explored how and to what extent they affect the reactions. Moreover, we have predicted that the less size of substitution (alpha-atom) required for the gas-phase reaction with alpha nucleophile is related to the alpha-effect and estimated that the reaction with the stronger PA nucleophile, holding the lighter substituted atom, corresponds to the greater exothermicity given out from reactants to products. PMID- 22241466 TI - Controlled fabrication of flower-like nickel oxide hierarchical structures and their application in water treatment. AB - Flower-like NiO hierarchical structures with 2-5 MUm diameter assembled from nanosheet building blocks have been successfully fabricated via a wet-chemical method combined with thermodecomposition technology. The template-free method is facile and effective in preparing flower-like NiO superstructures in high yield. The intermediate product and final hierarchical structures are characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform IR (FTIR), and thermogravimetric analysis (TGA). The effects of growth temperature and reaction time on the morphologies of the as-prepared structures were investigated by SEM characterization and a possible mechanism for the formation of flower-like NiO is proposed. Based on the nitrogen adsorption and desorption measurements, the BET surface area of the as obtained sample is 55.7 m2/g and the pore-size distribution plot indicates a bimodal mesopore distribution, with pore sizes of ca. 2.6 nm and 7.4 nm, respectively. In comparison with sphere-like and rod-like structures, the flower like NiO hierarchical structures show an excellent ability to rapidly remove various pollutants when used as adsorbent and photocatalyst in waste-water treatment, which may be attributed to its unique hierarchical and porous surface structures. PMID- 22241465 TI - The effect of beta-carotene supplementation on the pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1-infected patients. AB - beta-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results from in vitro studies suggest that beta-carotene may inhibit or induce cytochrome P450 enzymes and transporters. The study objective was to investigate the effect of beta-carotene on the steady-state pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1 infected individuals. Twelve hour nelfinavir pharmacokinetic analysis was conducted at baseline and after 28 days of beta-carotene supplementation (25,000 IU twice daily). Nelfinavir and M8 concentrations were measured with validated assays. Non compartmental methods were used to calculate the pharmacokinetic parameters. Geometric mean ratios comparing day 28 to day 1 area under the plasma concentration-time curve (AUC(0-12 h)), maximum (C(max)) and minimum (C(min)) concentrations of nelfinavir and M8 are presented with 90% confidence intervals. Eleven subjects completed the study and were included in the analysis. There were no significant differences in nelfinavir AUC(0-12 h) and C(min) (-10%, +4%) after beta-carotene supplementation. The M8 C(min) was increased by 31% while the M8 AUC(0-12 h) and C(max) were unchanged. During the 28 day period, mean CD4+ % and CD4+:CD8+ ratio increased significantly (p < 0.01). beta-carotene supplementation increased serum carotene levels but did not cause any clinically significant difference in the nelfinavir and M8 exposure. PMID- 22241467 TI - Evaluation of the immunity activity of glycyrrhizin in AR mice. AB - In this study, we evaluated effect of glycyrrhizin on immunity function in allergic rhinitis (AR) mice. The AR mice model were induced by dripping ovalbumin in physiological saline (2 mg mL-1, 10 MUL) into the bilateral nasal cavities using a micropipette. After the AR model was induced, mice were randomly divided into six groups: the normal control, model, lycopene 20 mg kg-1 (as positive control drug) group, and glycyrrhizin 10, 20, 30 mg kg-1 groups. After the sensitization day 14, lycopene (20 mg/kg BW) and glycyrrhizin (10, 20 and 30 mg/kg BW) were given orally for 20 days once a day. Mice in the normal control and model groups were given saline orally once a day for 20 days. Results showed that glycyrrhizin treatment could dose-dependently significantly reduce blood immunoglobulin E (IgE), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), nitrous oxide (NO), tumor necrosis factor-alpha (TNF-alpha) levels and nitrous oxide synthase (NOS) activity and enhance blood immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), interleukin-2 (IL-2) and interleukin-12 (IL-12) levels in AR mice. Furthermore, glycyrrhizin treatment could dose-dependently significantly enhance acetylcholinesterase (AchE) activity and reduce substance P (SP) level in peripheral blood and nasal mucosa of AR mice. We conclude that glycyrrhizin can improve immunity function in AR mice, suggesting a potential drug for the prevention and therapy of AR. PMID- 22241468 TI - Reaction characteristics of andrographolide and its analogue AL-1 with GSH, as a simple chemical simulation of NF-kappaB inhibition. AB - 14-alpha-Lipoic acid-3,19-dihydroxyandrographolide (AL-1, 2) is an analogue of andrographolide (Andro, 1) coupled to alpha-lipoic acid (LA, 4). AL-1 was at least 10-fold more potent than the natural parent compound Andro in inhibiting nuclear factor (NF)-kappaB activation in RIN-m cells. In the present study, glutathione (GSH, 3) was used as a simple chemical model molecule of NF-kappaB with cysteine 62. The characteristics of the reaction between AL-1 or Andro and GSH were investigated to trace some possible elucidation for the inhibitive mechanism and stronger inhibition of AL-1 to NF-kappaB activation. The results showed that the main reaction products of AL-1 and Andro were identical, sulfhydryl adduct and amino adduct. AL-1 reacted much faster than Andro with GSH. The product yield of AL-1 was much higher than that of Andro. It was speculated that AL-1 might inhibit NF-kappaB by the same mechanism as Andro. And the faster reaction rate and higher yield may account for the stronger NF-kappaB inhibition of AL-1 when compared with Andro. PMID- 22241469 TI - Structural model of channelrhodopsin. AB - Channelrhodopsins (ChRs) are light-gated cation channels that mediate ion transport across membranes in microalgae (vectorial catalysis). ChRs are now widely used for the analysis of neural networks in tissues and living animals with light (optogenetics). For elucidation of functional mechanisms at the atomic level, as well as for further engineering and application, a detailed structure is urgently needed. In the absence of an experimental structure, here we develop a structural ChR model based on several molecular computational approaches, capitalizing on characteristic patterns in amino acid sequences of ChR1, ChR2, Volvox ChRs, Mesostigma ChR, and the recently identified ChR of the halophilic alga Dunaliella salina. In the present model, we identify remarkable structural motifs that may explain fundamental electrophysiological properties of ChR2, ChR1, and their mutants, and in a crucial validation of the model, we successfully reproduce the excitation energy predicted by absorption spectra. PMID- 22241470 TI - Regulation of transcription factor Twist expression by the DNA architectural protein high mobility group A2 during epithelial-to-mesenchymal transition. AB - Deciphering molecular mechanisms that control epithelial-to-mesenchymal transition (EMT) contributes to our understanding of how tumor cells become invasive and competent for intravasation. We have established that transforming growth factor beta activates Smad proteins, which induce expression of the embryonic factor high mobility group A2 (HMGA2), which causes mesenchymal transition. HMGA2 associates with Smad complexes and induces expression of an established regulator of EMT, the zinc finger transcription factor Snail. We now show that HMGA2 can also induce expression of a second regulator of EMT, the basic helix-loop-helix transcription factor Twist. Silencing of endogenous Twist demonstrated that this protein acts in a partially redundant manner together with Snail. Double silencing of Snail and Twist reverts mesenchymal HMGA2-expressing cells to a more epithelial phenotype when compared with single silencing of Snail or Twist. Furthermore, HMGA2 can directly associate with A:T-rich sequences and promote transcription from the Twist promoter. The new evidence proposes a model whereby HMGA2 directly induces multiple transcriptional regulators of the EMT program and, thus, is a potential biomarker for carcinomas displaying EMT during progression to more advanced stages of malignancy. PMID- 22241471 TI - Human protein arginine methyltransferase 7 (PRMT7) is a type III enzyme forming omega-NG-monomethylated arginine residues. AB - Full-length human protein arginine methyltransferase 7 (PRMT7) expressed as a fusion protein in Escherichia coli was initially found to generate only omega N(G)-monomethylated arginine residues in small peptides, suggesting that it is a type III enzyme. A later study, however, characterized fusion proteins of PRMT7 expressed in bacterial and mammalian cells as a type II/type I enzyme, capable of producing symmetrically dimethylated arginine (type II activity) as well as small amounts of asymmetric dimethylarginine (type I activity). We have sought to clarify the enzymatic activity of human PRMT7. We analyzed the in vitro methylation products of a glutathione S-transferase (GST)-PRMT7 fusion protein with robust activity using a variety of arginine-containing synthetic peptides and protein substrates, including a GST fusion with the N-terminal domain of fibrillarin (GST-GAR), myelin basic protein, and recombinant human histones H2A, H2B, H3, and H4. Regardless of the methylation reaction conditions (incubation time, reaction volume, and substrate concentration), we found that PRMT7 only produces omega-N(G)-monomethylarginine with these substrates. In control experiments, we showed that mammalian GST-PRMT1 and Myc-PRMT5 were, unlike PRMT7, able to dimethylate both peptide P-SmD3 and SmB/D3 to give the expected asymmetric and symmetric products, respectively. These experiments show that PRMT7 is indeed a type III human methyltransferase capable of forming only omega N(G)-monomethylarginine, not asymmetric omega-N(G),N(G)-dimethylarginine or symmetric omega-N(G),N(G')-dimethylarginine, under the conditions tested. PMID- 22241472 TI - Molecular identification of hydroxylysine kinase and of ammoniophospholyases acting on 5-phosphohydroxy-L-lysine and phosphoethanolamine. AB - The purpose of the present work was to identify the catalytic activity of AGXT2L1 and AGXT2L2, two closely related, putative pyridoxal-phosphate-dependent enzymes encoded by vertebrate genomes. The existence of bacterial homologues (40-50% identity with AGXT2L1 and AGXT2L2) forming bi- or tri-functional proteins with a putative kinase belonging to the family of aminoglycoside phosphotransferases suggested that AGXT2L1 and AGXT2L2 acted on phosphorylated and aminated compounds. Vertebrate genomes were found to encode a homologue (AGPHD1) of these putative bacterial kinases, which was therefore likely to phosphorylate an amino compound bearing a hydroxyl group. These and other considerations led us to hypothesize that AGPHD1 corresponded to 5-hydroxy-L-lysine kinase and that AGXT2L1 and AGXT2L2 catalyzed the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine and 5-phosphohydroxy-L-lysine. The three recombinant human proteins were produced and purified to homogeneity. AGPHD1 was indeed found to catalyze the GTP-dependent phosphorylation of 5-hydroxy-L-lysine. The phosphorylation product made by this enzyme was metabolized by AGXT2L2, which converted it to ammonia, inorganic phosphate, and 2-aminoadipate semialdehyde. AGXT2L1 catalyzed a similar reaction on phosphoethanolamine, converting it to ammonia, inorganic phosphate, and acetaldehyde. AGPHD1 and AGXT2L2 are likely to be the mutated enzymes in 5-hydroxylysinuria and 5-phosphohydroxylysinuria, respectively. The high level of expression of AGXT2L1 in human brain, as well as data in the literature linking AGXT2L1 to schizophrenia and bipolar disorders, suggest that these diseases may involve a perturbation of brain phosphoethanolamine metabolism. AGXT2L1 and AGXT2L2, the first ammoniophospholyases to be identified, belong to a family of aminotransferases acting on omega-amines. PMID- 22241473 TI - Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4alpha in adult mice. AB - Hepatocyte nuclear factor 4alpha (HNF4alpha) regulates genes involved in lipid and bile acid synthesis, gluconeogenesis, amino acid metabolism, and blood coagulation. In addition to its metabolic role, HNF4alpha is critical for hepatocyte differentiation, and loss of HNF4alpha is associated with hepatocellular carcinoma. The hepatocyte-specific Hnf4a knock-out mouse develops severe hepatomegaly and steatosis resulting in premature death, thereby limiting studies of the role of this transcription factor in the adult animal. In addition, gene compensation may complicate analysis of the phenotype of these mice. To overcome these issues, an acute Hnf4a knock-out mouse model was generated through use of the tamoxifen-inducible ErT2cre coupled to the serum albumin gene promoter. Microarray expression analysis revealed up-regulation of genes associated with proliferation and cell cycle control only in the acute liver-specific Hnf4alpha-null mouse. BrdU and ki67 staining confirmed extensive hepatocyte proliferation in this model. Proliferation was associated with induction of the hepatomitogen Bmp7 as well as reduced basal apoptotic activity. The p53/p63 apoptosis effector gene Perp was further identified as a direct HNF4alpha target gene. These data suggest that HNF4alpha maintains hepatocyte differentiation in the adult healthy liver, and its loss may directly contribute to hepatocellular carcinoma development, thus indicating this factor as a possible liver tumor suppressor gene. PMID- 22241474 TI - Molecular dynamics simulations of creatine kinase and adenine nucleotide translocase in mitochondrial membrane patch. AB - Interaction between mitochondrial creatine kinase (MtCK) and adenine nucleotide translocase (ANT) can play an important role in determining energy transfer pathways in the cell. Although the functional coupling between MtCK and ANT has been demonstrated, the precise mechanism of the coupling is not clear. To study the details of the coupling, we turned to molecular dynamics simulations. We introduce a new coarse-grained molecular dynamics model of a patch of the mitochondrial inner membrane containing a transmembrane ANT and an MtCK above the membrane. The membrane model consists of three major types of lipids (phosphatidylcholine, phosphatidylethanolamine, and cardiolipin) in a roughly 2:1:1 molar ratio. A thermodynamics-based coarse-grained force field, termed MARTINI, has been used together with the GROMACS molecular dynamics package for all simulated systems in this work. Several physical properties of the system are reproduced by the model and are in agreement with known data. This includes membrane thickness, dimension of the proteins, and diffusion constants. We have studied the binding of MtCK to the membrane and demonstrated the effect of cardiolipin on the stabilization of the binding. In addition, our simulations predict which part of the MtCK protein sequence interacts with the membrane. Taken together, the model has been verified by dynamical and structural data and can be used as the basis for further studies. PMID- 22241475 TI - Cell contact-dependent functional selectivity of beta2-adrenergic receptor ligands in stimulating cAMP accumulation and extracellular signal-regulated kinase phosphorylation. AB - Activation of beta(2)-adrenegic receptor (beta(2)-AR) leads to an increase in intracellular cAMP and activation of ERK. These two signals are activated by the interaction of the receptor with different transducer partners. We showed that the intrinsic activities of beta(2)-AR ligands for stimulating cAMP production and ERK phosphorylation responses in HEK-293 cells were not correlated. The lack of correlation resulted mainly from the discrepancy between the intrinsic activities of two groups of ligands for these two responses: The first group consisted of clenbuterol, cimaterol, procaterol, and terbutaline which acted as full agonists for cAMP production but displayed very weak effect on ERK phosphorylation. The second group comprised adrenaline and noradrenaline which displayed higher intrinsic activity for the ERK phosphorylation than for the cAMP response. Thus, both groups behaved as functionally selective ligands. The functional selectivity of the first group was observable only in adherent cells when confluence was approximately 100%. When cell-cell contact was minimized either by decreasing the density of the adherent cells or by bringing the cells into suspension, the first group of ligands gained the ability to stimulate ERK phosphorylation without a change in their effect on cAMP production. In contrast, selectivity of the second group was independent of the adherence state of the cells. Our results show that the inherent "bias" of ligands in coupling a G protein-coupled receptor to different transducers may not always be revealed as functional selectivity when there is a "cross-talk" between the signaling pathways activated by the same receptor. PMID- 22241476 TI - Functional identification of triterpene methyltransferases from Botryococcus braunii race B. AB - Botryococcus braunii race B is a colony-forming, green algae that accumulates triterpene oils in excess of 30% of its dry weight. The composition of the triterpene oils is dominated by dimethylated to tetramethylated forms of botryococcene and squalene. Although unusual mechanisms for the biosynthesis of botryococcene and squalene were recently described, the enzyme(s) responsible for decorating these triterpene scaffolds with methyl substituents were unknown. A transcriptome of B. braunii was screened computationally assuming that the triterpene methyltransferases (TMTs) might resemble the S-adenosyl methionine dependent enzymes described for methylating the side chain of sterols. Six sterol methyltransferase-like genes were isolated and functionally characterized. Three of these genes when co-expressed in yeast with complementary squalene synthase or botryococcene synthase expression cassettes resulted in the accumulation of mono- and dimethylated forms of both triterpene scaffolds. Surprisingly, TMT-1 and TMT 2 exhibited preference for squalene as the methyl acceptor substrate, whereas TMT 3 showed a striking preference for botryococcene as its methyl acceptor substrate. These in vivo preferences were confirmed with in vitro assays utilizing microsomal preparations from yeast overexpressing the respective genes, which encode for membrane-associated enzymes. Structural examination of the in vivo yeast generated mono- and dimethylated products by NMR identified terminal carbons, C-3 and C-22/C-20, as the atomic acceptor sites for the methyl additions to squalene and botryococcene, respectively. These sites are identical to those previously reported for the triterpenes extracted from the algae. The availability of closely related triterpene methyltransferases exhibiting distinct substrate selectivity and successive catalytic activities provides important tools for investigating the molecular mechanisms responsible for the specificities exhibited by these unique enzymes. PMID- 22241477 TI - Identification of a region that assists membrane insertion and translocation of the catalytic domain of Bordetella pertussis CyaA toxin. AB - The adenylate cyclase (CyaA) toxin, one of the virulence factors secreted by Bordetella pertussis, the pathogenic bacteria responsible for whooping cough, plays a critical role in the early stages of respiratory tract colonization by this bacterium. The CyaA toxin is able to invade eukaryotic cells by translocating its N-terminal catalytic domain directly across the plasma membrane of the target cells, where, activated by endogenous calmodulin, it produces supraphysiological levels of cAMP. How the catalytic domain is transferred from the hydrophilic extracellular medium into the hydrophobic environment of the membrane and then to the cell cytoplasm remains an unsolved question. In this report, we have characterized the membrane-interacting properties of the CyaA catalytic domain. We showed that a protein covering the catalytic domain (AC384, encompassing residues 1-384 of CyaA) displayed no membrane association propensity. However, a longer polypeptide (AC489), encompassing residues 1-489 of CyaA, exhibited the intrinsic property to bind to membranes and to induce lipid bilayer destabilization. We further showed that deletion of residues 375-485 within CyaA totally abrogated the toxin's ability to increase intracellular cAMP in target cells. These results indicate that, whereas the calmodulin dependent enzymatic domain is restricted to the amino-terminal residues 1-384 of CyaA, the membrane-interacting, translocation-competent domain extends up to residue 489. This thus suggests an important role of the region adjacent to the catalytic domain of CyaA in promoting its interaction with and its translocation across the plasma membrane of target cells. PMID- 22241478 TI - Interactions between beta-catenin and transforming growth factor-beta signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). AB - Interactions between transforming growth factor-beta (TGF-beta) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated beta-catenin-dependent and transforming growth factor-beta1 (TGF-beta1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the beta catenin/CBP (but not beta-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-beta1-mediated alpha-smooth muscle actin (alpha-SMA) and collagen induction in AEC. We now demonstrate that TGF-beta1 induces LEF/TCF TOPFLASH reporter activation and nuclear beta-catenin accumulation, while LiCl augments TGF-beta-induced alpha-SMA expression, further confirming co-operation between beta-catenin- and TGF-beta-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of beta-catenin and overexpression of ICAT abrogated effects of TGF-beta1 on alpha-SMA transcription/expression, indicating a requirement for beta-catenin in these Smad3-dependent effects. Following TGF-beta treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and beta-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of alpha-SMA via complex formation among Smad3, beta-catenin, and CBP. ICG-001 inhibited alpha-SMA expression/transcription in response to TGF-beta as well as alpha-SMA promoter occupancy by beta-catenin and CBP, demonstrating a previously unknown requisite TGF-beta1/beta-catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by beta-catenin/Smad3 co localization and CBP expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-beta. PMID- 22241479 TI - Functional transcriptional regulatory sequence (TRS) RNA binding and helix destabilizing determinants of murine hepatitis virus (MHV) nucleocapsid (N) protein. AB - Coronavirus (CoV) nucleocapsid (N) protein contains two structurally independent RNA binding domains. These are denoted N-terminal domain (NTD) and C-terminal domain and are joined by a charged linker region rich in serine and arginine residues (SR linker). In mouse hepatitis virus (MHV), the NTD binds the transcriptional regulatory sequence (TRS) RNA, a conserved hexanucleotide sequence required for subgenomic RNA synthesis. The NTD is also capable of disrupting a short RNA duplex. We show here that three residues on the beta3 (Arg 125 and Tyr-127) and beta5 (Tyr-190) strands play key roles in TRS RNA binding and helix destabilization with Ala substitutions of these residues lethal to the virus. NMR studies of the MHV NTD.TRS complex revealed that this region defines a major RNA binding interface in MHV with site-directed spin labeling studies consistent with a model in which the adenosine-rich 3'-region of TRS is anchored by Arg-125, Tyr-127, and Tyr-190 in a way that is critical for efficient subgenomic RNA synthesis in MHV. Characterization of CoV N NTDs from infectious bronchitis virus and from severe acute respiratory syndrome CoV revealed that, although detailed NTD-TRS determinants are distinct from those of MHV NTD, rapid helix destabilization activity of CoV N NTDs is most strongly correlated with CoV function and virus viability. PMID- 22241481 TI - Injectable hydrogel materials for spinal cord regeneration: a review. AB - Spinal cord injury (SCI) presents a complex regenerative problem due to the multiple facets of growth inhibition that occur following trauma to the cord parenchyma and stroma. Clinically, SCI is further complicated by the heterogeneity in the size, shape and extent of human injuries. Many of these injuries do not breach the dura mater and have continuous viable axons through the injury site that can later lead to some degree of functional recovery. In these cases, surgical manipulation of the spinal cord by implanting a preformed scaffold or drug delivery device may lead to further damage. Given these circumstances, in situ-forming scaffolds are an attractive approach for SCI regeneration. These synthetic and natural polymers undergo a rapid transformation from liquid to gel upon injection into the cord tissue, conforming to the individual lesion site and directly integrating with the host tissue. Injectable materials can be formulated to have mechanical properties that closely match the native spinal cord extracellular matrix, and this may enhance axonal ingrowth. Such materials can also be loaded with cellular and molecular therapeutics to modulate the wound environment and enhance regeneration. This review will focus on the current status of in situ-forming materials for spinal cord repair. The advantages of, and requirements for, such polymers will be presented, and examples of the behavior of such systems in vitro and in vivo will be presented. There are helpful lessons to be learned from the investigations of injectable hydrogels for the treatment of SCI that apply to the use of these biomaterials for the treatment of lesions in other central nervous system tissues and in organs comprising other tissue types. PMID- 22241480 TI - Retention of triplicated phytoene synthase (PSY) genes in Brassica napus L. and its diploid progenitors during the evolution of the Brassiceae. AB - The extent of genome redundancy exhibited by Brassica species provides a model to study the evolutionary fate of multi-copy genes and the effects of polyploidy in economically important crops. Phytoene synthase (PSY) catalyzes the first committed reaction of the carotenoid biosynthetic pathway, which has been shown to be rate-limiting in Brassica napus seeds. In Arabidopsis thaliana, a single PSY gene (AtPSY) regulates phytoene synthesis in all tissues. Considering that diploid Brassica genomes contain three Arabidopsis-like subgenomes, the objectives of the present work were to determine whether PSY gene families exist in B. napus (AACC) and its diploid progenitor species, Brassica rapa (AA) and Brassica oleracea (CC); to establish the level of retention of Brassica PSY genes; to map PSY gene family members in the A and C genomes and to compare Brassica PSY gene expression patterns. A total of 12 PSY homologues were identified, 6 in B. napus (BnaX.PSY.a-f) and 3 in B. rapa (BraA.PSY.a-c) and B. oleracea (BolC.PSY.a-c). Indeed, with six members, B. napus has the largest PSY gene family described to date. Sequence comparison between AtPSY and Brassica PSY genes revealed a highly conserved gene structure and identity percentages above 85% at the coding sequence (CDS) level. Altogether, our data indicate that PSY gene family expansion preceded the speciation of B. rapa and B. oleracea, dating back to the paralogous subgenome triplication event. In these three Brassica species, all PSY homologues are expressed, exhibiting overlapping redundancy and signs of subfunctionalization among photosynthetic and non-photosynthetic tissues. This evidence supports the hypothesis that functional divergence of PSY gene expression facilitates the accumulation of high levels of carotenoids in chromoplast-rich tissues. Thus, functional retention of triplicated Brassica PSY genes could be at least partially explained by the selective advantage provided by increased levels of gene product in floral organs. A better understanding of carotenogenesis in Brassica will aid in the future development of transgenic and conventional cultivars with carotenoid-enriched oil. PMID- 22241482 TI - Dramatically enhanced solid-state electrochemiluminescence of CdTe quantum dots composed with TiO2 nanoparticles. PMID- 22241483 TI - Do practicing clinicians agree with expert ratings of neonatal intensive care unit quality measures? AB - OBJECTIVE: To assess the level of agreement when selecting quality measures for inclusion in a composite index of neonatal intensive care quality (Baby-MONITOR) between two panels: one comprised of academic researchers (Delphi) and another comprised of academic and clinical neonatologists (clinician). STUDY DESIGN: In a modified Delphi process, a panel rated 28 quality measures. We assessed clinician agreement with the Delphi panel by surveying a sample of 48 neonatal intensive care practitioners. We asked the clinician group to indicate their level of agreement with the Delphi panel for each measure using a five-point scale (much too high, slightly too high, reasonable, slightly too low and much too low). In addition, we asked clinicians to select measures for inclusion in the Baby MONITOR based on a yes or no vote and a pre-specified two-thirds majority for inclusion. RESULT: In all, 23 (47.9%) of the clinicians responded to the survey. We found high levels of agreement between the Delphi and clinician panels, particularly across measures selected for the Baby-MONITOR. Clinicians selected the same nine measures for inclusion in the composite as the Delphi panel. For these nine measures, 74% of clinicians indicated that the Delphi panel rating was 'reasonable'. CONCLUSION: Practicing clinicians agree with an expert panel on the measures that should be included in the Baby-MONITOR, enhancing face validity. PMID- 22241484 TI - The heart of nursing: past, present and future. PMID- 22241485 TI - Healthy peristomal skin is essential. PMID- 22241486 TI - Vaginal thrush: treating and advising the patient. PMID- 22241488 TI - Lessons from history: asylum patients' Christmas experience. AB - This article outlines the asylum building programme of the mid-to-late nineteenth century and focuses on case studies of the two Hampshire asylums built during this period, the subject of the author's doctoral thesis. It demonstrates the plight of 'pauper lunatic' before asylum reform and contrasts this with the improved quality of life provided by the Hampshire County Lunatic Asylum and the Borough of Portsmouth Lunatic Asylum respectively. Asylum care during this period followed the moral treatment regime which became the Victorian blueprint for mental health, components of which are illustrated. Criticism of this regime is addressed briefly and arguments are made against anachronistic analysis. Comparison with contemporary in-patient care and treatment is made concluding with a call to reconsider some of the better aspects of earlier care delivery. The particular experience of patients in Hampshire asylums at Christmas is used to exemplify the points raised. PMID- 22241489 TI - Addressing the problems of long-term urethral catheterization: Part 1. AB - This is that first of a two-part article looking at the indications for long-term urethral catheterization and good practice, including the use of aseptic non touch technique used in insertion, and the choice of catheter length and Charriere size. The various routes that bacteria can take to the bladder are discussed, and the reduction in catheter-associated urinary tract infection (CAUTI) through the use of the closed drainage system is considered. It is essential that adequate information is kept relating to catheter care and catheter insertion; documentation, and what should be recorded in the casenotes is discussed. The article then examines the series of Department of Health initiatives aimed at reducing CAUTIs. Recent safety driving programmes related to the Quality, Innovation, Productivity and Prevention programme, Safety Express, quality indicators, nurse-sensitive outcome measures, high impact actions and Energise for Excellence in Care are more fully discussed. Case studies of areas displaying how their High Impact Actions have made marked improvements in catheter care and the reduction in CAUTI are reported. PMID- 22241490 TI - Anti-embolism stockings and proximal indentation. AB - The authors of this study noticed that the elastic garters of below knee anti embolism stockings (AES) were indenting the proximal calves of patients after application and feared this might be interrupting venous return. This was lower on one ward which had a rigorous standardized protocol for sizing and checking stockings. Hypotheses were that proximal indentation caused higher proximal than distal pressures (reverse gradients) and that by adopting the standardized protocol throughout the unit, proximal indentation could be reduced. Fifty-seven patients were recruited after total hip replacement (THR) or total knee replacement (TKR) in a regional orthopaedic centre. The authors implemented the standardized protocol for sizing stockings and measured the pressures under them. After implementation of the standardized protocol, proximal indentation fell from 53% to 19% (p<0.05), incorrectly sized stockings from 74% to 34% (p<0.05) and removal of stockings by patients from 32% to 0% (p<0.05). In total, 21% of patients had reverse gradients which occurred in 41% of legs with proximal indentation and 8% without. When reverse gradients or proximal indentation exist, AES may not be as effective and may be counterproductive. A standardized protocol of nursing practice is critical to optimizing AES after THR and TKR. More in-vivo research is needed on AES after hip and knee replacement. PMID- 22241491 TI - Constipation: symptoms, assessment and treatment. PMID- 22241492 TI - Myelodysplastic syndrome: 2011 and beyond. PMID- 22241493 TI - The management of sickness absence in the NHS. AB - Sickness absence continues to be an economic burden to the NHS. Managers are faced with employees' sickness episodes and may have some challenges in managing this issue. This article draws on sickness absence statistics to highlight the extent of the problem in the NHS in England. It focuses on some influencing factors and possible causes of sickness absence, and explores strategies that managers could adopt when managing sickness absence in their clinical environments. It concludes by highlighting the important role that managers play in the process of managing sickness rates. PMID- 22241494 TI - Cognitive behavioural therapy and its relevance to nursing. AB - Over the last 20 years, cognitive behavioural therapy (CBT) has gained considerable momentum in mental healthcare practice. Its extensive evidence base for the treatment of mental health problems is well documented with the National Institute for Health and Clinical Excellence (2007a; b), which has recommended CBT as a key treatment modality in its best practice guidelines. More recently, the use of CBT has widened to a diverse range of physical healthcare environments, including dentistry, occupational therapy, palliative care and physiotherapy (Chartered Society of Physiotherapists, 2004; Buchanan and Zakrzewska, 2008; Donaghy et al, 2008; Hesslop, 2009), with preliminary research highlighting its use in improving patient outcomes both in terms of reduction in morbidity and improved quality of life. In this article, the authors outline the principles and techniques of CBT, give examples of how this form of psychotherapy can be applied within nursing practice, and discuss the theoretical and practical underpinnings that align CBT and nursing. PMID- 22241495 TI - Welsh Government proposals: organ and tissue donation reforms. AB - In November 2011, the Welsh Government published a consultation document setting out proposals for legislation on organ and tissue donation. The scheme would introduce a notable change in the law from a consent-based 'opt-in' scheme for transplantation to an 'opt-out' one. This article explores the scope of the current law concerning organ transplantation. It considers the proposals for reform and some of the challenges which might arise in implementing the legislation. PMID- 22241496 TI - Issues in nursing documentation and record-keeping practice. AB - Record keeping is an essential part of nursing practice with clinical and legal significance. Good quality record keeping is linked with improvements in patient care, while poor standards of documentation are regarded as contributing to poor quality nursing care. The quality of nursing documentation has consistently been found to be failing to meet recommended standards. This article will provide an overview of the literature on record-keeping practice and examine what makes good quality record keeping and the factors that prevent nurses from achieving good documentation standards. This article will also look at ways that documentation standards can be improved and the impact that accountability has on the record keeping practices of nurses. PMID- 22241497 TI - The WHO Patient Safety Curriculum Guide. PMID- 22241498 TI - Professional development: from staff nurse to nurse consultant. Part 2: Experience and education. PMID- 22241499 TI - Reducing harm from severe cold weather: health implications. PMID- 22241500 TI - Simply put. PMID- 22241501 TI - The role of nitric oxide in the effects of cumin (Cuminum Cyminum L.) fruit essential oil on the acquisition of morphine-induced conditioned place preference in adult male mice. AB - OBJECTIVE: Nitric oxide is a neural messenger molecule in the central nervous system that is generated from L-arginine via the nitric oxide synthase (NOS) and is involved in many important oplold-induced effects. In Iranian ancient medicine, Cuminum cyminum L (green seed) has been used for the treatment of some diseases. In the present study, the effect of intraperitoneal (ip) administration of different doses of cumin fruit essential oil (FEO) on the acquisition of morphine-induced conditioned place preference (GPP) in L-arginine-treated mice was investigated. METHODS: A total of 213 adult male albino Wistar mice were used in these experiments. The CPP paradigm was carried out in 5 continuous days, pre conditioning, conditioning and post-conditioning. Animals were randomly assigned to one of the two groups for place conditioning. CPP was induced by subcutaneous (sc) injection of morphine (5 mg/kg) in 3 days conditioning schedule. On the test day, conditioning scores and locomotor activity were recorded by Ethovision software. RESULTS: Sole administration of different doses of cumin FEO (0.01%, 0.1%, 0.5%, 1% and 2%; lp) or L-arginine (50, 100 and 200 mg/kg; lp) during the CPP protocol could not induce CPP. Nonetheless, morphine-induced CPP was decreased by different doses of cumin FEO (0.01%-2%), whereas it was increased by L-arginine (50-200 mg/kg) when they were injected before morphine (5 rug/kg) during a 3-day conditioning phase (acquisition period). Additionally, cumin FEO could interestingly attenuate the raising effect of L-arginine on morphine induced CPP in a dose-dependent manner. CONCLUSIONS: It is suggested that some components of the Cuminum cyminum L. seed attenuate the excessive effect of L arginine on morphine-induced CPP through the NOS inhibitory mechanism. It seems that cumin FEO possibly acts as a NOS inhibitor. PMID- 22241502 TI - Effect of Huogu II Formula (II) with medicinal guide Radix Achyranthis Bidentatae on bone marrow stem cells directional homing to necrosis area after osteonecrosis of the femoral head in rabbit. AB - OBJECTIVE: To investigate the effect of Huogu II Formula (II) with medicinal guide Radix Achyranthis Bidentatae (Ach) on bone marrow stem cells (BMSCs) homing to necrosis area after osteonecrosis of the femoral head (ONFH) frozen by liquid nitrogen in rabbit as well as to explore the mechanism of prevention and treatment for ONFH. METHODS: The animal model of ONFH was established by liquid nitrogen frozen on the rabbit left hind leg. Forty-eight Japanese White rabbits were randomly assigned to sham-operated group, model group, Huogu II group, and Huogu II plus Ach group, with 12 rabbits in each. During the course of ONFH animal model establishment, all rabbits were subcutaneously injected with recombinant human granulocyte colony-stimulating factor [rhG-CSF, 30 MUg/(kg.day) for continuous 7 days]. Meanwhile, normal saline and decoction of the two formulae were administrated by gavage, respectively. White blood cells (WBC) were counted in peripheral blood before and after injection of rhG-CSF. Materials were drawn on the 2nd and 4th weeks after model built; bone glutamine protein (BGP) and bone morphogenetic protein 2 (BMP2) levels in serum were tested. Histopathologic changes were observed by hematoxylin and eosin (HE) staining. BMP2 mRNA levels were detected with in situ hybridization (ISH) staining. 5-Bromo 2'-deoxyuridine (BrdU) and stromal cell derived factor 1 (SDF-1) were measured by immunohistochemical assay in femoral head of the left hind leg. RESULTS: Compared with the shamoperated group, the ratio of empty lacuna, serum BGP, and SDF-1 level in the model group increased significantly, and BMP2 in both serum and femoral head decreased significantly. However, in comparison with the model group, the empty lacuna ratio of Huogu II group and Huogu II plus Ach group decreased obviously in addition to the levels of serum BGP and BMP2, and the expressions of BMP2 mRNA, BrdU, and SDF-1 increased significantly. Above changes were particularly obvious in Huogu II plus Ach group. BGP and SDF-1 on the 2nd week and empty lacuna rate and serum BMP2 level on the 4th week in Huogu II group significantly exceeded their counterparts. On the 2nd week, only in Huogu II plus Ach group that the BrdU counting rose significantly. On the 4th week, empty lacuna rate and serum BMP2 level in Huogu II plus Ach group exceeded those in Huogu II group distinctively. CONCLUSIONS: To a certain extent, the medicinal guide Ach improves the preventive and therapeutic effects of Huogu II Formula on experimental ONFH model. The possible mechanism of this is related to its promoting effect on directional homing of BMSCs to the necrosis area. PMID- 22241503 TI - Effect and mechanisms of Gong-tone music on the immunological function in rats with Liver (Gan)-qi depression and Spleen (Pi)-qi deficiency syndrome in rats. AB - OBJECTIVE: To investigate the effects and mechanisms of Gong-tone music on the immunological function in rats with the Chinese medicine syndrome of Liver (Gan) qi stagnation and Spleen (Pi)-qi deficiency (LSSD). METHODS: Twenty five male Wistar rats of SPF grade were randomly divided into 5 groups: normal group, model group, Xiaoyao Powder () group, Gong-tone group and combined group (the combination of Gong-tone and Xiaoyao Powder), with 5 rats in each group. The rat model for the Chinese medicine syndrome of LSSD was induced by chronic bandage and irregular diet. The course of treatment was 21 days. After the treatment, the levels of serum gastrin and IgG were detected by enzyme-linked immunoabsorbent assay (ELISA). Phagocytosis of macrophages was detected by the neutral red uptake assay and T cell proliferation was investigated by 3-(4,5-dimethylthiazolyl)-2,5 diphenyltetrazolium bromide (MTT) assay. RESULTS: The serum gastrin, macrophage phagocytosis, IgG level and proliferation ability of T cells in the model group were significantly decreased compared with those in the normal group (P <0.05). Compared with those in the model group, the serum levels of gastrin, macrophage phagocytosis, IgG level and proliferation ability of T cells in Gong-tone, Xiaoyao Powder, and combined groups were significantly increased (P <0.05). The combined group was superior to either Gong-tone group or Xiaoyao Powder group. CONCLUSION: Gong-tone music may upregulate the immunological function and play a role in adjuvant therapy in the Chinese syndrome of LSSD. PMID- 22241504 TI - The investigation of the correlation between metabolic syndrome and Chinese medicine constitution types in senior retired military personnel of the People's Liberation Army. AB - OBJECTIVE: To investigate the incidence of metabolic syndrome (MS) and the distribution of constitutional pattern in elderly retired personnel of the People's Liberation Army. METHODS: Adopting the method of cross-sectional field investigation, from June to December in 2008, the investigation questionnaires were completed by the aged over 60 and collected from 69 military retired residences in the 4 cities of Shanghai, Nanjing, Hangzhou and Qingdao. Other data, including demographic characteristics, physiological characteristics, life style and former medical history, were collected and analyzed. The statistical analysis for the database was drawn up by the software Epidata 3.0. RESULTS: A total of 4,502 people were included in this study, and 35.3% of them were diagnosed with MS. There was no obvious difference in mobility among ages (60 to 69, 70 to 79 and over 80, P>0.05). Referring to the MS patients in the 70s age group, both the phlegm-dampness and dampness-heat constitutional types were evidently higher than those in the 60s age group (P=0.019, P=0.008); while MS patients in 80s and older showed a significantly lower incidence of dampness-heat constitution than those in the 60s (P=0.00); and ql-deficiency constitution was obviously higher in the 80s age group than those in the other two groups (P=0.00). The top 3 constitutions in MS people were, respectively, phlegm dampness, dampness-heat and qi-deficiency constitution; while in non-MS people, the top 3 constitutions were gentleness, qi-deficiency and phlegm-dampness. When the patient's body mass index (BMI) was more than 25 kg/m(2), the rate of phlegm dampness and dampness-heat constitution significantly increased, while the rate of qi-deficiency constitution declined; the discrepancy was significant (P=0.00). CONCLUSIONS: The prevalence rate of MS in military senior people was 35.3%, which did not vary among the three age groups. Phlegm-dampness, dampness-heat and qi deficiency constitution were the three dominant constitutional types seen in the MS patients. The distribution of constitution formation was different in MS people and non-MS people. For different dimensions of BMI, the proportion of each kind of constitutions was varied. PMID- 22241505 TI - Cancer complementary and alternative medicine research at the US National Cancer Institute. AB - The United States National Cancer Institute (NCI) supports complementary and alternative medicine (CAM) research which includes different methods and practices (such as nutrition therapies) and other medical systems (such as Chinese medicine). In recent years, NCI has spent around $120 million each year on various CAM-related research projects on cancer prevention, treatment, symptom/side effect management and epidemiology. The categories of CAM research involved include nutritional therapeutics, pharmacological and biological treatments, mind-body interventions, manipulative and body based methods, alternative medical systems, exercise therapies, spiritual therapies and energy therapies on a range of types of cancer. The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) supports various intramural and extramural cancer CAM research projects. Examples of these cancer CAM projects are presented and discussed. In addition, OCCAM also supports international research projects. PMID- 22241506 TI - The influence of the total flavonoids of Hedysarum polybotry on the proliferation, cell cycle, and expressions of p21Ras and proliferating cell nuclear antigen gene in erythroleukemia cell line K562. AB - OBJECTIVE: To investigate the effect of total flavonoids of Hedysarum polybotry on the proliferation, cell cycle, and expressions of p21(Ras) and proliferating cell nuclear antigen (PCNA) gene in erythroleukemia cell line K562. METHODS: The effect of total flavonoids of Hedysarum polybotry on K562 cell line survival was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction assay. The time- and dose-dependent manner was also observed. The cell cycle and apoptosis were analyzed with flow cytometry (FCM). The immunocytochemistry method was applied to quantitatively analyze the effects of flavonoids of Hedysarum polybotry on changes p21(Ras) and PCNA gene expressions. RESULTS: Flavonoids of Hedysarum polybotry (20-100 MUg/mL) significantly inhibited the proliferation of K562 cells in a time- and dose-dependent manner. After K562 cells were cultured for 48 h, total flavonoids of Hedysarum polybotry had no significant effect on the apoptosis of K562 cells but showed significantly inhibition (P<0.01), indicating that total flavonoids of Hedysarum polybotry could induce K562 cells arrested at G(0)/G(1) and G(2)/M phases. Compared with the control group, p21(Ras) and PCNA gene expressions were decreased significantly in K562 cells treated with total flavonoids of Hedysarum polybotry (40 and 80 MUg/mL, respectively) for 48 h. CONCLUSION: The inhibitory effect on proliferation of K562 cells was observed in the groups treated with flavonoids of Hedysarum polybotry, which might be related to cells arresting. PMID- 22241507 TI - Amino acid-based formula as a rescue strategy in feeding very-low-birth-weight infants with intrauterine growth restriction. AB - BACKGROUND AND AIM: Very-low-birth-weight (VLBW) neonates may develop severe intolerance to standard preterm formula especially if they are associated with intrauterine growth restriction (IUGR). We tested the hypothesis that these infants may tolerate an elemental, amino acid-based formula as a rescue feeding strategy. METHODS: In a prospective, case-control pilot study, we enrolled VLBW IUGR infants enterally fed with standard preterm formula (SPF) at daily increments of 16 mL/kg. If gastric residuals accounted for >70% of milk feed in the previous 24 hours, then feedings were temporarily withheld and then resumed with amino acid formula (AAF) increased at the same speed. Cases on AAF were compared to controls on SPF and with cases themselves while on SPF. Primary outcome was the time to reach full enteral feedings. Secondary outcomes were time on parenteral nutrition, time on central venous catheter, and formula tolerability based on the amount of gastric residual volume. RESULTS: Sixty-four infants (22 cases) were enrolled. Although during the total duration of nutrition, cases had worse primary and secondary outcomes, when on AAF, cases were comparable to controls in time to full enteral feeding (14.4 vs 14 days), time on parenteral nutrition, and time on central venous catheter. Cases on AAF and controls had similar gastric residual volumes. At day 3 after AAF introduction, cases had a significantly reduced number (%) of gastric residual volume >5 mL/kg over total number of feedings (5.6 vs 1.5%; P < 0.05) and the mean gastric residual volume (2.7 vs 0.6 mL; P < 0.05) compared to themselves while on SPF. No difference was detected in weight at 21 and 28 days, in main serum parameters and outcome at discharge. Growth at 12 months of corrected age was also comparable. CONCLUSIONS: In our population of VLBW IUGR newborns with severe feeding intolerance, a short course on AAF was a safe and effective means of nutritional rescue. PMID- 22241508 TI - Steroid-responsive autoimmune sclerosing cholangitis with liver granulocytic epithelial lesions. PMID- 22241509 TI - Prevalence of celiac disease among first-degree relatives of patients with celiac disease. AB - OBJECTIVES: Celiac disease, an autoimmune enteropathy that affects the proximal small intestine, is characteristically seen in people who have a genetic susceptibility to gluten sensitivity. Celiac patients' first-degree relatives are more at risk of acquiring the disease. The objective of the present study was consequently to determine the prevalence of celiac disease in a group of first degree relatives of our patients with celiac disease. METHODS: First-degree relatives of 195 patients with celiac disease attending a gastroenterology unit underwent serologic screening. Antitissue transglutaminase (anti-tTG) immunoglobulin A (IgA) and total serum IgA tests were used for first-level screening. Duodenal biopsy was recommended to subjects showing positive results to anti-tTG IgA testing. Biopsy samples were obtained by endoscopy, and biopsy specimens were evaluated and classified according to Marsh classification. RESULTS: Positive anti-tTG IgA was found in 46 first-degree relatives (9.5%), whereas serum IgA levels were normal. Of 46 serology-positive relatives, 34 agreed to the endoscopy procedure. Histological changes characteristic of celiac disease were found in 23 subjects. The prevalence of celiac disease among the first-degree relatives was found to be at least 4.8%. Of 34 subjects that underwent biopsy, 11 were evaluated as Marsh 0, 5 as Marsh 1, 4 as Marsh 2, 12 as Marsh 3, and 2 as Marsh 4. Of the biopsy-positive subjects, 3 were mothers, 1 was a father, and 19 were siblings. CONCLUSIONS: The present study identified 23 undiagnosed cases of celiac disease among 484 first-degree relatives of 195 patients with celiac disease, confirming the high prevalence (4.8%) of the disease in this specific group. It is suggested that an extensive screening policy be mandatory for these subjects. PMID- 22241511 TI - Feasibility of using MR enterography for the assessment of terminal ileitis and inflammatory activity in children with Crohn disease. AB - BACKGROUND AND OBJECTIVE: Radiation exposure increases cancer risk in children with Crohn disease (CD). Magnetic resonance enterography (MRE) can image the gastrointestinal tract without exposure to radiation. The aim of the present study was to determine whether our MRE protocol could diagnose terminal ileitis and the degree of inflammatory activity in children with CD. METHODS: Retrospective review of patients 18 years of age or younger who underwent MRE for known or suspected CD from June 15, 2007 to April 1, 2010. MRE was performed with Volumen and water as oral contrast and gadolinium-based intravenous contrast. No antiperistaltic agent was used. Each MRE was compared with ileal biopsies obtained within 90 days. Severity of inflammation on MRE was scored and compared with the Pediatric Crohn Disease Activity Index (PCDAI). RESULTS: Seventy-two patients underwent 80 MREs during the study period. Forty-two of the 72 patients (58.3%) underwent colonoscopy within 90 days of MRE, and the terminal ileum was intubated in 33. Compared with histology, MRE had a sensitivity of 71.4% and a specificity of 100% for terminal ileitis. The positive and negative predictive values were 100% and 70%, respectively. PCDAI was calculated in 39 of the 72 patients (54.2%) and had a statistically significant positive correlation with MRE score of 0.37 (P = 0.020426). CONCLUSIONS: In children with known or suspected CD, our MRE protocol has a high specificity and positive predictive value for terminal ileitis. Severity of inflammation on MRE had a statistically significant positive correlation with PCDAI. PMID- 22241510 TI - Long-chain PUFA in granulocytes, mononuclear cells, and RBC in patients with cystic fibrosis: relation to liver disease. AB - BACKGROUND AND AIM: Patients with cystic fibrosis (CF) have low levels of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in plasma or red blood cells (RBC), as also seen in other chronic and acute liver diseases. The differences may be more pronounced in CF transmembrane conductance regulator protein (CFTR) regulated tissues such as granulocytes, monocytes, and lymphocytes. The aim of the present study was to investigate whether patients with CF-related liver disease have lower n-3 LCPUFA level than patients with CF without liver disease. METHODS: Twenty patients with known CF-related liver disease were matched with 20 CF patients without. Blood samples were analysed for liver biochemistry and haematology. Granulocytes, mononuclear cells, and RBC were separated by density gradient centrifugation, and fatty acid composition was measured by gas chromatography. Hepatic ultrasound was scored according to Williams et al. Hepatic transit time (HTT) was measured with the ultrasound contrast agent SonoVue. RESULTS: No significant differences were seen in either n-6 or n-3 LCPUFAs in any cell line when the 2 groups were compared. In a multiple regression analysis including HTT, age, Pseudomonas aeruginosa infection, diabetes mellitus, treatment with ursodeoxycholic acid, forced expiratory volume in 1 second (% of predicted value), and Williams' ultrasound scoring scale, only n-3 LCPUFA docosahexaenoic acid in mononuclear cell membranes was positively associated with HTT (P = 0.02). The arachidonic acid/docosahexaenoic acid ratio within the mononuclear cells was negatively associated with both HTT (P = 0.003) and Williams' ultrasound scoring scale (P = 0.03). For RBC-LCPUFAs, no significant associations were seen. CONCLUSIONS: These findings indicate that in patients with CF, the degree of liver disease was negatively associated with LCPUFA n-3 levels in CFTR-expressing white blood cells but unrelated to those levels in CFTR-negative RBC. PMID- 22241512 TI - FGIDs in children are associated with many nonpsychiatric comorbidities: the tip of an iceberg? AB - Functional gastrointestinal disorders (FGIDs) are common. The poor health-related quality of life in FGIDs is a combination of gastrointestinal symptoms and comorbid conditions. We determined by using the Ohio Dysautonomia questionnaire the medical comorbidities in 38 children with FGID. Almost all of the subjects had a comorbid disorder, with orthostatic symptoms in 89%, fainted >3*/lifetime in 17%, headaches with migrainous features in 40%, other types of chronic pain in 50%, and fatigue lasting >6 months in approximately 33%. These findings constitute a critical first step in changing the paradigm of our approach to FGID as a broader systemic disorder, not one limited to the gastrointestinal tract. PMID- 22241513 TI - Esomeprazole for the treatment of GERD in infants ages 1-11 months. AB - OBJECTIVES: Gastroesophageal reflux disease (GERD) is present in pediatric patients when reflux of gastric contents causes troublesome symptoms and/or complications. The present study evaluates the efficacy and safety of esomeprazole in infants ages 1 to 11 months with GERD. METHODS: In this multicenter randomized, double-blind, placebo-controlled, parallel-group, treatment-withdrawal study, infants received open-label, weight-adjusted doses of esomeprazole (2.5-10 mg) once daily for 2 weeks. Infants with symptom improvement were randomized to esomeprazole (weight-adjusted doses [2.5-10 mg]) or placebo for 4 weeks. The primary endpoint was time to discontinuation owing to symptom worsening based on global assessments by the parent/guardian and physician. Adverse events were recorded. RESULTS: Of the 98 patients enrolled, 81 (82.7%) experienced symptom improvement determined by physician global assessment (PGA) during open-label esomeprazole treatment; 80 entered the double-blind phase. During this phase, discontinuation rates owing to symptom worsening were 48.8% (20/41) for placebo-treated versus 38.5% (15/39) for esomeprazole-treated patients (hazard ratio 0.69; P = 0.28). Posthoc analysis of infants with symptomatic GERD (ie, no diagnostic procedure performed) revealed that time to discontinuation was significantly longer with esomeprazole than placebo (hazard ratio 0.24; P = 0.01); the complementary subgroup difference was not significant (hazard ratio 1.39; P = 0.48). Esomeprazole was well tolerated. CONCLUSIONS: The discontinuation rate owing to symptom worsening did not differ significantly between infants receiving esomeprazole versus those receiving placebo. Improved diagnostic criteria in this age group are needed to identify infants with GERD who may benefit from acid suppression therapy. PMID- 22241514 TI - Applications of luminescent inorganic and organometallic transition metal complexes as biomolecular and cellular probes. AB - The rich photophysical properties of luminescent inorganic and organometallic transition metal complexes, such as their intense, long-lived, and environment sensitive emission, render them excellent candidates for biological and cellular studies. In this Perspective, we review examples of biological probes derived from luminescent transition metal complexes with a d(6), d(8), or d(10) metal center. The design of luminescent covalent labels and noncovalent probes for protein molecules is discussed. Additionally, the recent applications of these complexes as cellular probes and bioimaging reagents are described. Emphasis is put on the structural features, photophysical behavior, biomolecular interactions, cellular uptake, and intracellular localization properties of luminescent transition metal complexes. PMID- 22241515 TI - Embryonic development of a whirligig beetle, Dineutus mellyi, with special reference to external morphology (insecta: Coleoptera, Gyrinidae). AB - The egg morphology and successive changes of developing embryos of the whirligig beetle, Dineutus mellyi (Adephaga: Gyrinidae) are described from observations based on light and scanning electron microscopy. The egg surface is characterized by minute conical projections covering the entire egg surface, a stalk-like micropylar projection at the anterior pole of the egg, and a longitudinal split line along which the chorion is cleaved during the middle embryonic stages. The germ band or embryo is formed on the ventral egg surface, and develops on the surface throughout the egg period; thus, the egg is a superficial type, as is the case in most coleopteran species. A pair of lateral tracheal gills (LTGs) of the first abdominal segment originates from appendage-like projections arising at the lateral side of pleuropodia, and the LTGs of the second to ninth abdominal segments are arranged in a row with that of the first segment. Therefore, LTGs are structures with serial homology. The paired dorsal tracheal gills (DTGs) of the ninth abdominal segment are formed on the regions just latero-dorsal to the LTGs of this segment. Regarding the pleuropodia as the structures being homologous with thoracic legs, neither the LTGs nor DTGs are homologous with thoracic legs, but originate in the more lateral region corresponding to the future pleura of the thoracic segments. The last (10th) abdominal segment in the larva is formed by the fusion of the embryonic 10th and 11th abdominal segments. Four terminal hooks at the end of the last abdominal segment originate from two pairs of swellings on the posterior end of the embryonic 11th abdominal segment. It is proposed that the terminal hooks possibly correspond to the claws of medially fused cerci of the embryonic 11th abdominal segment. PMID- 22241517 TI - [Chances of scientific and clinical cooperations in china]. PMID- 22241518 TI - [Recent update on tumour biology and treatment of Merkel Cell carcinoma]. AB - Merkel cell carcinoma (MCC) is a carcinoma arising from Merkel cells located in the basal layer of the epidermis. The skin of the head and neck is a common site for MCC, occurring generally in fair-skinned elderly patients. MCC is considered as the most lethal skin cancer. Radical surgical excision with pathological verification of complete removal of the tumour is the recommended treatment. Early MCC can be cured by surgery with or without postoperative radiation therapy, whereas advanced MCC is currently considered to be incurable. In the year 2008, a new polyoma virus was found in the tumour genome of the MCC tumours. MCPyV (Merkel cell polyoma virus) appears to be the first example of a human oncogenic polyoma virus. Specific mutations in the viral genome and its clonal integration to the tumour genome are strong evidence against MCPyV as being a passenger virus that secondarily infects MCC tumours. The purpose of this review article is to shed light on this rare skin cancer and introduce the latest advances in research on MCC. PMID- 22241519 TI - [Viability of autologous fat grafts harvested with the Coleman technique and the tissu trans system (shippert method): a comparative study]. AB - Various methods for harvesting and refining autologous fat grafts have been described. One of the standard procedures, the Coleman technique, is based on manual aspiration to reduce the negative presssure and the centrifugation of the grafts. The Shippert technique uses automatic liposuction with reduced negative pressure and abstains from centifugation in order not to reduce viability of the graft by exposing it to centrifugal forces. This study intends to compare the viability of fat grafts processed with the above-mentioned methods.Fat grafts were obtained in 9 patients by using both the Tissu Trans system (Shippert technique) and the Coleman technique. To evaluate the impact of centrifugation forces, the grafts harvested with the Coleman technique were treated with standard adjustment of the centrifuge and also with doubled g-force. Viability of fat grafts was analysed with the WST-8 test and with annexin V/PI assay FACS analysis.The viability of fat grafts processed by the Coleman technique was significantly higher compared to the Shippert technique on applying the WST-8 test. Applying the annexin V/PI analysis, the viability of fat grafts was almost equal with both techniques. Whereas the fat grafts processed with the Tissu Trans system are injected without condensation, the grafts refined with the Coleman technique were concentrated 3 times by centrifugation compared to the primary liposuctioned graft volumes.The Coleman technique allows the preparation of a fat graft containing more viable cells than the Shippert technique. This is in part due to the condensation of the graft by centrifugation using the Coleman technique. The factor of condensation of the grafts harvested and refined with the Coleman technique exceeds the factor of increased fat graft viability in comparison to the Shippert technique. The Tissu Trans system is more than twice as fast and easier to use with a preferential use for large volume grafts like in breast augmentation, whereas the Coleman technique produces a more condensed graft, favouring it for fat grafting to the face where less volume is needed. PMID- 22241520 TI - [Patients' decision for aesthetic surgery]. AB - INTRODUCTION: Aesthetic surgery is a service which entails a high degree of trust. Service evaluation prior to provision is difficult for the patient. This leads to the question of how to manage the service successfully while still focusing on the medical needs. The decision to undergo an operation is not influenced by the operation itself, but by preoperative events which induce the patient to have the operation done. According to "buying decisions" for products or in service management, the decision for an aesthetic operation is extensive; the patient is highly involved and actively searching for information using different directed sources of information. The real "buying decision" consists of 5 phases: problem recognition, gathering of information, alternative education, purchase decision, and post purchase behaviour. PATIENTS AND METHODS: A retrospective survey of 40 female patients who have already undergone an aesthetic operation assessed for problem recognition, which types of information were collected prior to the appointment with the surgeon, and why the patients have had the operation at our hospital. They were also asked how many alternative surgeons they had been seen before. RESULTS: Most of the patients had been thinking about undergoing an operation for several years. They mainly used the web for their research and were informed by other (non-aesthetic) physicians/general practitioners. Requested information was about the aesthetic results and possible problems and complications. Patients came based on web information and because of recommendations from other physicians. 60% of all interviewees did not see another surgeon and decided to have the operation because of positive patient-doctor communication and the surgeon's good reputation. Competence was considered to be the most important quality of the surgeon. However, the attribute was judged on subjective parameters. Environment, office rooms and staff were assessed as important but not very important. Costs of surgery were ranked second. DISCUSSION: Influence on patients' decision is only possible by high quality operation results, which in turn lead to good reputation with (non-aesthetic) physicians and patients. In contrast to print advertisements, the provision of information via the internet is of tremendous importance and must be both information and comprehensible. Not only the aesthetic result should be depicted, but also questions such as "when will I be fit after surgery", and possible problems and complications should be described honestly. Besides the described word-of-mouth recommendations web fora resemble a virtual extension of recommendation. Whether such web based fora will prevail as a significant source of information remains unclear. Board certification in plastic and aesthetic surgery ("Facharzt" qualification) was assessed as very important. Thus, this is relevant information which should be emphasized. Most important for the patients' decision, however, was patient-doctor communication. To develop a basis of trust, communication should be open and reliable. An adequate time span has to be planned for the first appointment with the patient. In addition to aesthetic results, risks and possible complications have to be discussed. An open and comprehensible conversation which does not sugar-coat the operation is assessed as very positive. Finally, based on this consultation the surgeon is suggestive of his surgical competence. This underlines that core competence in aesthetic surgery is a medical one. PMID- 22241521 TI - [Comparison of pedicle and free tissue transfers in the German DRG system]. AB - Diagnosis-Related Groups (DRGs) are a patient classification system grouping related types of patients to the resources they have consumed. In this analysis, we compared pedicle and free flaps in plastic and reconstructive surgery in the actual German DRG system. After grouping common flaps while systematically modifying the diagnosis, the operative procedure(s), and the receptor site, reimbursement and thresholds of length of stay were identified. The mean value of the average length of stay was higher in free flaps as compared to pedicle flaps (15 vs. 9 days) and the mean reimbursement in free flaps was almost twice as high as in pedicle flaps (8 936 ? vs. 4 582 ?). Regarding the diagnosis, third-grade open fractures in pedicle flaps and full-thickness burns in free flaps are in the vanguard of reimbursement. Higher DRG conformity is generally found with free flaps. Different possibilities in coding the procedures and the strong dependence on the underlying diagnosis lead to variations of remuneration and length of stay, which are not explainable and sometimes even seem paradoxical. Furthermore, mixed calculation creates DRGs that lose the ability to describe the real effort. PMID- 22241522 TI - Reaction of an alkyne with dinickel-diphenylsilyl complexes. An emissive disilane formed via the consecutive Si-C and Si-Si bond-making processes. AB - [{Ni(dmpe)}(2)(MU-SiHPh(2))(2)] (dmpe = 1,2-bis(dimethylphosphino)ethane) reacted with PhC=CPh to yield fluorescent 1,2-bis{(E)-1,2-diphenylethenyl}-1,1,2,2 tetraphenyldisilane via addition of the Si-H bond of the ligand to the alkyne and subsequent coupling of the tertiary silyl ligands forming the Si-Si bond. PMID- 22241523 TI - Donor-(pi-bridge)-azinium as D-pi-A+ one-dimensional and D-pi-A(+)-pi-D multidimensional V-shaped chromophores. AB - Heteroaromatic cations reacted with N-heteroarylacetylenes under Sonogashira conditions to allow easy access to potential single donor D-pi-A(+) and V-shaped D-pi-A(+)-pi-D chromophores, where the acceptor moiety A is the pi-deficient pyridinium cation and the donor moiety is represented by different pi-excessive N heterocycles. The beta hyperpolarizabilities were measured using hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including Density Functional Theory (DFT) and correlated Hartree-Fock-based methods (RCIS(D)). PMID- 22241524 TI - Selection of weighting factors for quantification of PET radioligand binding using simplified reference tissue models with noisy input functions. AB - Input function noise contributes to model-predicted values and should be accounted for during parameter estimation. This problem has been examined in the context of PET data analysis using a noisy image-derived arterial input function. Huesman and Mazoyer (1987 Phys. Med. Biol 32 1569-79) incorporated the effect of error in the measured input function into the objective function and observed a subsequent improvement in the accuracy of parameters estimated from a kinetic model of cardiac blood flow. Such a treatment has not been applied to the reference region models commonly used to analyze dynamic positron emission tomography data with receptor-ligand tracers. Here, we propose a strategy for selection of weighting factors that accounts for noise in the reference region input function and test the method on two common formulations of the simplified reference tissue model (SRTM). We present a simulation study which demonstrates that the proposed weighting approach improves the accuracy of estimated binding potential at high noise levels and when the reference tissue and target regions of interest are of comparable size. In the second simulation experiment, we show that using a small, homogeneous reference tissue with our weighting technique may have advantages over input functions derived from a larger (and thus less noisy), heterogeneous region with conventional weighting. A comparative analysis of clinical [(11)C]flumazenil data found a small but significant increase in estimated binding potential when using the proposed weighting method, consistent with the finding of reduced negative bias in our simulation study. The weighting strategy described here accounts for noise in the reference region input function and may improve the performance of the SRTM in applications where data are noisy and the reference region is relatively small. This technique may offer similar benefits to other models using reference region inputs, particularly those derived from the SRTM. PMID- 22241525 TI - Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer. AB - One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR 372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines. PMID- 22241528 TI - Epigenetics for ecotoxicologists. PMID- 22241526 TI - Undetectable role of oxidative DNA damage in cell cycle, cytotoxic and clastogenic effects of Cr(VI) in human lung cells with restored ascorbate levels. AB - Cultured human cells are invaluable biological models for mechanistic studies of genotoxic chemicals and drugs. Continuing replacement of animals in toxicity testing will further increase the importance of in vitro cell systems, which should accurately reproduce key in vivo characteristics of toxicants such as their profiles of metabolites and DNA lesions. In this work, we examined how a common severe deficiency of cultured cells in ascorbate (Asc) impacts the formation of oxidative DNA damage by hexavalent chromium (chromate). Cr(VI) is reductively activated inside the cells by both Asc and small thiols but with different rates and spectra of intermediates and DNA adducts. We found that Cr(VI) exposure of H460 human lung epithelial cells in standard culture (<0.01 mM cellular Asc) induced biologically significant amounts of oxidative DNA damage. Inhibition of oxidative damage repair in these cells by stable XRCC1 knockdown strongly enhanced cytotoxic effects of Cr(VI) and led to depletion of cells from G(1) and accumulation in S and G(2) phases. However, restoration of physiological levels of Asc (~ 1 mM) completely eliminated Cr(VI) hypersensitivity of XRCC1 knockdown. The induction of chromosomal breaks assayed by the micronucleus test in Asc-restored H460, primary human lung fibroblasts, and CHO cells was also unaffected by the XRCC1 status. Centromere-negative (clastogenic) micronuclei accounted for 80-90% of all Cr(VI)-induced micronuclei. Consistent with the micronuclei results, Asc-restored cells also showed no increase in the levels of poly(ADP-ribose), which is a biochemical marker of single-stranded breaks. Asc had no effect on cytotoxicity of O(6)-methylguanine, a lesion produced by direct DNA alkylation. Overall, our results indicate that the presence of physiological levels of Asc strongly suppresses pro-oxidant pathways in Cr(VI) metabolism and that the use of standard cell cultures creates a distorted profile of its genotoxic properties. PMID- 22241530 TI - Common patterns of violence experiences and depression and anxiety among adolescents. AB - PURPOSE: A considerable amount of research has examined violence experiences and psychopathology; however, few studies have examined how multiple settings and experiences of violence are associated with major depressive disorder (MDD) and generalized anxiety disorder (GAD). METHODS: The sample included 2,345 adolescents from a community-based sample in the US. The mean age was 14 years at the time that violence experiences in the home, school, and neighborhood were reported; psychiatric outcomes were assessed 2 years later using the Diagnostic Interview Schedule for Children. We applied latent class analysis to identify adolescents with common patterns of violence exposure and obtained adjusted prevalence ratios for the associations between violence classes and psychopathology. RESULTS: A four-class model was selected based on fit statistics and meaningfulness, and adolescents were categorized into four classes: low violence, home violence, neighborhood violence/traumatic news, and multiple settings of violence. Relative to adolescents in the low violence class, risk of MDD for adolescents in the home violence, neighborhood violence/traumatic news, and multiple settings classes was 1.62, 1.47, and 2.44 times higher, respectively (p values <0.05); risk for GAD was 1.61 and 2.87 times higher for adolescents in the neighborhood violence/traumatic news and multiple settings classes, respectively (p values <0.05). CONCLUSION: Exposure to a high level of violence within a single domain or multiple domains-poses significant risk for MDD and GAD, and risk increases with high exposure in multiple domains. Thus, pervasive exposure to violence is associated with the highest risk for the development of psychopathology. Based on these results, prevention and treatment efforts should target adolescents exposed to violence in multiple settings. PMID- 22241531 TI - Childhood problem behavior and parental divorce: evidence for gene-environment interaction. AB - OBJECTIVE: The importance of genetic and environmental influences on children's behavioral and emotional problems may vary as a function of environmental exposure. We previously reported that 12-year-olds with divorced parents showed more internalizing and externalizing problems than children with married parents, and that externalizing problems in girls precede and predict later parental divorce. The aim of the current study was to investigate as to whether genetic and environmental influences on internalizing and externalizing problems were different for children from divorced versus non-divorced families. METHODS: Maternal ratings on internalizing and externalizing problems were collected with the Child Behavior Checklist in 4,592 twin pairs at ages 3 and 12 years, of whom 367 pairs had experienced a parental divorce between these ages. Variance in internalizing and externalizing problems at ages 3 and 12 was analyzed with biometric models in which additive genetic and environmental effects were allowed to depend on parental divorce and sex. A difference in the contribution of genetic and environmental influences between divorced and non-divorced groups would constitute evidence for gene-environment interaction. RESULTS: For both pre and post-divorce internalizing and externalizing problems, the total variances were larger for children from divorced families, which was mainly due to higher environmental variances. As a consequence, heritabilities were lower for children from divorced families, and the relative contributions of environmental influences were higher. CONCLUSIONS: Environmental influences become more important in explaining variation in children's problem behaviors in the context of parental divorce. PMID- 22241532 TI - Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors. AB - Urokinase plasminogen activator (uPA) is an enzyme involved in cancer growth and metastasis. Therefore, the design of inhibitors of uPA is of high therapeutic value, and several chemical families have been explored, even if none has still emerged, emphasizing the need of a rationalized approach. This work represents a complete computational study of uPA complexed with five inhibitors, which present weak similarities. Molecular dynamics simulations in explicit solvent were conducted, and structural analyses, along with molecular mechanics (MM)/Poisson Boltzmann surface area free energies estimations, yield precious structure activity relationships of these inhibitors. Besides, we realized supplemental QM/MM computations that improved drastically the quality of our models providing original information on the hydrogen bonds and charge transfer effects, which are, most often, neglected in other studies. We suggest that these simulations and analyses could be reproduced for other systems involving protein/ligand molecular recognitions. PMID- 22241533 TI - Dual surface modification with PEG and corn trypsin inhibitor: effect of PEG:CTI ratio on protein resistance and anticoagulant properties. AB - The objective of this study was to investigate the bioactivity and protein resistant properties of dual functioning surfaces modified with PEG for protein resistance and corn trypsin inhibitor (CTI) for anticoagulant effect. Surfaces on gold substrate were prepared with varying ratios of free PEG to CTI-conjugated PEG. Two methods designated, respectively, "sequential" and "direct" were used. For sequential surfaces, PEG was first immobilized on gold and the surfaces were incubated with CTI at varying concentration. For direct surfaces, a PEG-CTI conjugate was synthesized and gold surfaces were modified using solutions of the conjugate of varying concentration. The CTI density on these surfaces was measured using radiolabeled CTI. Water contact angles were measured and the thickness of PEG-CTI layers was determined by ellipsometry. Fibrinogen adsorption from buffer and human plasma, and adsorption from binary solutions of fibrinogen and alpha-lactalbumin were investigated using radiolabeling methods. Bioactivity of the surfaces was evaluated via their effects on FXIIa inhibition and plasma clotting time. It was found that as the ratio of CTI-conjugated PEG to free PEG increased, bioactivity increased but protein resistance was relatively constant. It is concluded that on these surfaces conjugation of PEG to CTI does not greatly compromise the protein resistance of the PEG but results in improved interactions between the CTI and the "target" protein FXIIa. At the same CTI density, sequential surfaces were more effective in terms of inhibiting FXIIa and prolonging clotting time. PMID- 22241535 TI - The even-handed approach: strategies for the deployment of racemic chiral catalysts. AB - Asymmetric catalysis is predominantly associated with the use of enantiomerically pure chiral ligands and catalysts. Although racemic chiral catalysts have been employed quite extensively in polymerization, their utility in mainstream organic synthesis and catalyst development has arguably been rather overlooked. This Minireview collates various themes for the strategic application of racemic ligands and catalysts, ranging from the estimation of selectivity and determination of enantiomeric excess, through to control of regio- and stereochemical outcomes, and mechanistic studies. What emerges is a clear picture that, in isolation or in concert with enantiopure catalysts, the "even-handed" approach has much to offer. PMID- 22241534 TI - Fine-needle aspiration of a pharyngoesophageal diverticulum mimicking a calcified thyroid nodule on ultrasonography. PMID- 22241536 TI - [Ptosis update]. PMID- 22241537 TI - [Congenital ptosis]. AB - Simple congenital ptosis is the most common form, characterised by fatty dystrophy and fibrosis of the levator muscle, which leads to a restricted elevation in upgaze and a lid lag in downgaze. In the complicated form additional changes will be found: fibrosis of extraocular muscles, synkinesia or anomalies of the lids. Moreover, congenital ptosis is relatively often associated with refractive errors and/or disturbance of the binocular vision. Therefore a careful examination is necessary. Therapeutic management includes first prevention of amblyopia either by occlusion or by early surgical intervention. The choice of operation depends on the grade of ptosis, the actual levator function and the presence of lid anomalies as well. PMID- 22241538 TI - [Blepharophimosis ptosis epicanthus inversus syndrome (BPES) (corrected)]. AB - The blepharophimosis ptosis epicanthus inversus syndrome (BPES, also known as Waardenburg syndrome) was probably first reported by Ammon in 1841 and discribed more fully by Vignes in 1889. Its primary effects on the soft tissue of the midface are blepharophimosis, ptosis, epicanthus inversus and telecanthus. It starts with the epicanthic folds at about the age of 3-4 years, followed by the correction of the ptosis about 9-12 months later. Early surgery may be necessary for amblyopia. In 1995 the gene locus was identified as 3Q23. BPES is due to a mutation within a single gene, the FOXL2 gene. In female patients an early childhood ovarian insufficiency must be excluded. PMID- 22241539 TI - [Simple rules for orientation in transcutaneous ptosis surgery--a contribution to the surgical anatomy or: how not to get lost in the upper eyelid]. AB - Surgical preparation in the upper eyelid follows well defined anatomic structures. Nevertheless, even an experienced surgeon can loose orientation in the presence of fatty degeneration, oedema or bleeding. Some simple rules can help to stay oriented and identify the landmarks. The preaponeurotic fat has a distinct colour, structure and texture and is a landmark for the levator muscle lying underneath it. This defines a first simple rule: it is not preaponeurotic fat if it does not look like preaponeurotic fat. The orbital septum may weaken and allow orbital fat to prolapse, but it stays firmly attached at the upper orbital rim. A second simple rule therefore adresses its identification: if a structure does not move with inferior tension, it cannot be muscle or fat (it must be septum). Identifying the landmarks preaponeurotic fat, orbital septum and tarsus will facilitate anatomic correlation and surgical preparation. In summary: Rule No. 1--If it does not look like preaponeurotic fat, then it isn't. Rule No. 2--If it does not move with traction, it is neither muscle nor fat (but probably septum). Rule No. 3--If things get confusing, stop and consider rules 1 and 2. PMID- 22241540 TI - [Optimised frontal suspension for correction of complicated ptosis]. AB - Complicated ptosis can be corrected by frontal suspension with autologous fascia lata. Via an open approach, the fascia is implanted between the brow and the tarsal plate behind the septum. The oblique implantation between the tarsus and the brow preserves the flexibility of elevation, closure and blinking of the upper lid. Additionally, the skin crease is improved by this technique. PMID- 22241541 TI - [Transcanalicular microendoscopic laser DCR: technique and results]. AB - Transcanalicular microendoscopic diode laser DCR combined with 5-mm balloon dacryoplasty is an innovative procedure in lacrimal surgery. This procedure is minimally invasive and provides the possibility to fill the gap between the first step procedures (LDP, MDP) and external or internal DCR. PMID- 22241542 TI - [Venous and arterial occlusions of the retina]. PMID- 22241543 TI - Role of endogenous estrogen on the incidence of coronary heart disease in men. AB - Estrogens protect the vascular system in women, but its effect in men is unclear. We evaluated the impact of estrogen on the male cardiovascular system. Of 140 Chinese males, 55 (aged 61.2 +/- 3.5) were cases and 60 (aged 59.5 +/- 4.6) were controls. Compared with the control group, only serum estradiol ([E2]; P < .01) levels but not testosterone ([T]; P = .21) were significantly lower in the cases. Linear and multiple regression analysis showed that serum T was positively associated with triglycerides ([TG]; r = .439, P < .01) and d-dimer (r = .258, P < .05) but negatively associated with high-density lipoprotein cholesterol (HDL C) levels (r = -.267, P < .05) and C-reactive protein (CRP; r = -.214, P < .05). Estradiol was highly associated with TG (r = .783, P < .01) and HDL-C (r = .515, P < .01) but was negatively related with low-density lipoprotein cholesterol (LDL C; P < .05), total cholesterol/HDL-C (P < .05), CRP (P < .01), and d-dimer (P < .01). In conclusion, serum E2 and T levels affect coronary heart disease risk factors in males. PMID- 22241544 TI - Towards a more realistic biomechanical modelling of breast malignant tumours. AB - We develop a biomechanical model of an isolated stellate breast tumour under mammographic compression forces for a range of reported mechanical properties, both linear elastic and hyperelastic. We also introduce different volumes of increased density/stiffness around the tumour as well as a solid pressure effect. We show that each of these issues--well known to clinicians but ignored to date in models--has a non-negligible effect on stresses and strains/deformations. PMID- 22241547 TI - Bivalve esterases as biomarker: identification and characterization in European cockles (Cerastoderma edule). AB - This study characterized esterase activity in Cerastoderma edule tissues using different substrates and specific inhibitors and identified the tissue distribution of esterases in this species. Synthetic thiocholines and thioacetate esters and specific inhibitors (eserine, BW284C51 and iso-OMPA) were used to identify and quantify cholines and carboxyl esterases. The results demonstrated the presence of a non-specific propionyl thiocholine (PrSCh)-cleaving cholinesterase (ChE) and a large amount of carboxylesterases (CaE). For further studies using C. edule esterases as biomarkers, our results suggest that the adductor muscle, with PrSCh (5 mM) as substrate should be used to analyze ChE, and for CaE analyses, phenyl thioacetate should be used in digestive gland extracts (PSA, 5 mM). PMID- 22241545 TI - Rare germline mutations in PALB2 and breast cancer risk: a population-based study. AB - Germline mutations in the PALB2 gene are associated with an increased risk of developing breast cancer but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (P = 0.04). The first-degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of noncarrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3-fold increase in risk (95% CI: 1.8-13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 vs. 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk. PMID- 22241548 TI - Intelligent diagnosing of intellectual disabilities in offenders: food for thought. AB - Research on offenders with intellectual disabilities (IDs) in the criminal justice arena is on the rise, reflected by a growing number of relevant publications each year. However, there is a long recognized methodological problem that hampers the comparability of empirical studies and that raises doubts about the accuracy of prevalence rates, comorbidities, and various correlates and characteristics. In this paper we will argue that the crux of the problem can, on the one hand, be found in the plurality of assessment methods for intelligence and adaptive functioning, which are not all sufficiently reliable and valid. On the other hand, assessment of IQ in criminal justice and mental health-related areas appears to be informed more by practical aspects and needs rather than grounded in a solid theoretical model. Hence, we suggest that the Cattell-Horn-Carroll (CHC) model of intelligence has potential value in this regard, and deserves a closer look. Finally, we will discuss its incorporation into, and possible implications for, criminal justice practice and future study designs. PMID- 22241549 TI - A pi-pi 3D network of tetranuclear MU2/MU3-carbonato Dy(III) bis pyrazolylpyridine clusters showing single molecule magnetism features. AB - 2,6-Di(pyrazole-3-yl)pyridine, 3-bpp, forms a porous (4(9).6(6)) pi-pi mediated 3D network of trigonal pyramidal [Dy(III)(4)] carbonato-bridged complexes, with hexagonal channels comprising 54% of the unit cell volume, the material displaying slow magnetisation reversal. PMID- 22241552 TI - Enhanced fluorescence detection of metal ions using light-harvesting mesoporous organosilica. AB - Enhanced fluorescence detection of metal ions was realized in a system consisting of a fluorescent 2,2'-bipyridine (BPy) receptor and light-harvesting periodic mesoporous organosilica (PMO). The fluorescent BPy receptor with two silyl groups was synthesized and covalently attached to the pore walls of biphenyl (Bp) bridged PMO powder. The fluorescence intensity from the BPy receptor was significantly enhanced by the light-harvesting property of Bp-PMO, that is, the energy funneling into the BPy receptor from a large number of Bp groups in the PMO framework which absorbed UV light effectively. The enhanced emission of the BPy receptor was quenched upon the addition of a low concentration of Cu(2+) (0.15-1.2*10(-6) M), resulting in the sensitive detection of Cu(2+). Upon titration of Zn(2+) (0.3-6.0*10(-6) M), the fluorescence excitation spectrum was systematically changed with an isosbestic point at 375 nm through 1:1 complexation of BPy and Zn(2+) similar to that observed in BPy-based solutions, indicating almost complete preservation of the binding property of the BPy receptor despite covalent fixing on the solid surface. These results demonstrate that light-harvesting PMOs have great potential as supporting materials for enhanced fluorescence chemosensors. PMID- 22241553 TI - Recent performance improvements to the DFT and TDDFT in GAMESS. AB - The general atomic and molecular electronic structure system (GAMESS) is a quantum chemistry package used in the first-principles modeling of complex molecular systems using density functional theory (DFT) as well as a number of other post-Hartree-Fock methods. Both DFT and time-dependent DFT (TDDFT) are of particular interest to the materials modeling community. Millions of CPU hours per year are expended by GAMESS calculations on high-performance computing systems; any substantial reduction in the time-to-solution for these calculations represents a significant saving in CPU hours. As part of this work, three areas for improvement were identified: (1) the exchange-correlation (XC) integration grid, (2) profiling and optimization of the DFT code, and (3) TDDFT parallelization. We summarize the work performed in these task areas and present the resulting performance improvement. These software enhancements are available in 12JAN2009R3 or later versions of GAMESS. PMID- 22241551 TI - The neuroanatomy of genetic subtype differences in Prader-Willi syndrome. AB - Despite behavioral differences between genetic subtypes of Prader-Willi syndrome (PWS), no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of PWS [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)]. Fifteen individuals with PWS due to a typical deletion [(DEL) type I; n = 5, type II; n = 10], eight with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume (WMV) between groups, covarying for age, sex, and body mass index (BMI). Overall, compared to HWC, PWS individuals had lower gray matter volumes (GMV) that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower WMVs in the brain stem, cerebellum, medial temporal, and frontal cortex. Compared to UPD, the DEL subtypes had lower GMV primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and WMVs in the orbitofrontal and limbic cortices compared to HWC. These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes. PMID- 22241554 TI - Borane-mediated carbon dioxide reduction at ruthenium: formation of C1 and C2 compounds. PMID- 22241557 TI - Dietary fiber and protein: nutritional therapy in chronic kidney disease and beyond. AB - The health benefits of dietary fiber in the general population are increasingly recognized. Krishnamurthy et al. provide compelling evidence that chronic kidney disease (CKD) further augments these benefits. CKD, besides a microinflammatory state, is a state of increased proteolytic fermentation. Both these harmful conditions are exacerbated by dietary protein and reversed by dietary fiber. Future nutrition guidelines should consider recommending a higher consumption of dietary fiber or potassium-free alternatives such as prebiotics in CKD patients. PMID- 22241558 TI - Prehypertension and chronic kidney disease: the ox or the plow? AB - Nearly ten years ago, practice recommendations supported use of the clinical classification of 'prehypertension' for people with systolic blood pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg. This recommendation was based on observations that these ranges of blood pressure were associated with enhanced cardiovascular and cerebrovascular risks compared with blood pressure less than 120/80 mm Hg. Recent observations, including the report by Yano and colleagues, also suggest that prehypertension is an important risk factor for the development of chronic kidney disease. PMID- 22241550 TI - Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications. AB - Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: (i) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; (ii) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; (iii) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and (iv) 5'- and 3'-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases. PMID- 22241560 TI - Does urinary neutrophil gelatinase-associated lipocalin really solve the issue of discriminating prerenal from intrinsic acute kidney injury? PMID- 22241561 TI - Warfarin-related nephropathy. PMID- 22241563 TI - The therapeutic tradeoff between the adverse impacts of a lower GFR and long-term renal protection. PMID- 22241567 TI - Nephrology Crossword: Interventional nephrology--dialysis access and beyond! PMID- 22241566 TI - Perinephric extramedullary hematopoiesis. PMID- 22241568 TI - Demonstration of photoluminescence and metal-enhanced fluorescence of exfoliated MoS2. PMID- 22241569 TI - Assessing asthma control: symptom scores, GINA levels of asthma control, lung function, and exhaled nitric oxide. AB - BACKGROUND: The childhood asthma control test (C-ACT) is a validated symptom score for assessing asthma control in children. We used a slightly modified version (C-ACT(M) ) of the German C-ACT and compared our results with the literature, correlated the children's part of C-ACT (C-ACT(children) ) with a visual analogue scale (VAS(children) ), explored the agreement between C-ACT(M) and GINA levels of asthma control, as well as the relationship between C-ACT(M) and lung function and exhaled nitric oxide (FeNO). METHODS: We investigated 107 children with a diagnosis of asthma. The study protocol consisted of a clinical examination, assessment of asthma control according to GINA guidelines, administration of C-ACT(M) , VAS(children) , lung function, and FeNO. RESULTS: Of our patients 66% had, according to GINA, partly controlled-/uncontrolled asthma, 18% were uncontrolled according to C-ACT(M) . Children with partly controlled /uncontrolled asthma according to GINA had lower C-ACT(M) scores than did children with controlled asthma (16.1 +/- 3.6 SD vs. 25.4 +/- 1.8 SD; P < 0.000), and children with a C-ACT(M) score <= 19 had poorer lung function (mean FEV1% predicted 81.5 +/- 13.5 SD vs. 94.2 +/- 12.1 SD; P = 0.002). Spearman's rank correlation coefficients revealed significant correlations between all symptom scores. Multiple linear regression adjusted for age, gender, FEV1 and FeNO demonstrated a significant relationship between C-ACT(M) , VAS(children) , and FEV1 (P = 0.003, resp. <0.000), but no significant correlation between C-ACT(M) , VAS(children) , and FeNO. CONCLUSIONS: The German version of C-ACT(M) is valid and useful for monitoring children with asthma along with tests aimed to follow up lung function and airway inflammation. Concordance between C-ACT(M) and GINA is moderate, because asthma control assessed by C-ACT(M) allows more symptoms and lung function is not included in the scoring. PMID- 22241570 TI - Acid and non-acid reflux during physiotherapy in young children with cystic fibrosis. AB - BACKGROUND: Gastro-esophageal reflux (GOR) may contribute to lung disease in children with cystic fibrosis (CF). There is conflicting evidence regarding the effect of chest physiotherapy (CPT) in the head-down position on GOR. Furthermore, there is currently no evidence on the impact of physiotherapy on GOR as assessed by pH-multichannel intraluminal impedance (pH-MII). AIMS: (1) To characterize GOR in young children with CF. (2) To determine whether the head down position during physiotherapy exacerbates GOR. METHODS: Children were studied using pH-MII monitoring over 24-hr, during which they received two 20-min sessions of CPT. One session was performed in "modified" drainage positions with no head-down tilt and the alternate session in "gravity-assisted" drainage positions, which included 20 degrees head-down tilt. RESULTS: Twenty children with CF (8 males), median age 12 months (range 8-34) were recruited. A total of 1,374 reflux episodes were detected in all children, of which 869 (63%) were acid and 505 (37%) were non-acid. Seventy-two percent of the episodes migrated proximally. During CPT, there was no significant difference between total number of reflux episodes in the modified or gravity-assisted positions, median [inter quartile range (IQR)] 1 (0-2.5) compared to 1 (0.75-3) episode, respectively, P = 0.63. There was also no significant difference between the number of reflux episodes which migrated proximally, median (IQR) 1 (0-2) compared to 0 (0-2) episodes, respectively, P = 0.75. CONCLUSION: In young children with CF, GOR is primarily acidic and proximal migration is common. Physiotherapy in the head-down position does not appear to exacerbate GOR. The impact of GOR on lung disease remains to be elucidated. PMID- 22241571 TI - Lung function decline from adolescence to young adulthood in cystic fibrosis. AB - BACKGROUND: Despite improving survival in cystic fibrosis (CF) patients, there is a mortality peak in early adulthood. Defining risk factors that predict significant worsening of lung disease in young adulthood may identify opportunities to improve outcomes in adults. METHODS: We identified 4,680 patients in the Epidemiologic Study of Cystic Fibrosis 1994-2005 with data in both adolescence (age 14.0-17.4 years) and young adulthood (age 18.5-22.0 years) and analyzed 2,267 who had >=5 encounters and >=5 measurements of forced expiratory volume in 1 second (FEV(1) ) spanning >=1 year during both adolescence and young adulthood, and >=1 encounter with weight and height and >=1 FEV(1) measurement age 17.5-18.5 years. We compared the annualized rates of decline in FEV(1) during adolescence and young adulthood stratified by best FEV(1) around age 18. Logistic regression was used to identify risk factors associated with substantial decline (>20 points) in FEV(1) % predicted in young adulthood. RESULTS: Annual rate of decline was greater in young adulthood than in adolescence. Risk factors for substantial decline included slower rate of FEV(1) decline, greater FEV(1) variability, faster body mass index (BMI) decline, male sex, chronic inhaled antibiotics, Haemophilus influenzae detection, and absence of multidrug-resistant Pseudomonas aeruginosa in adolescence, and lower than expected FEV(1) and BMI around age 18. CONCLUSIONS: Decline in lung function accelerates in young adults with CF, especially in those with early stage lung disease. Adolescents at risk for substantial decline in lung function in young adulthood have higher FEV(1) and worse nutritional status, among other identifiable risk factors. PMID- 22241573 TI - An experimental investigation into the effect of periodic motion on proton dosimetry using polymer gel dosimeters and a programmable motion platform. AB - Organ motion in proton therapy affects treatment dose distribution during both double-scattering (DS) and uniform-scanning (US) deliveries. We investigated the dosimetric impact of target motion using three-dimensional polymer gel dosimeters and a programmable motion platform. A simple one-beam treatment plan with 16 cm range and 6 cm modulation was generated from the treatment planning system (TPS) in both the DS and US modes. One gel dosimeter was irradiated with a stationary DS beam. Two other gel dosimeters were irradiated with the DS and US beams while they moved in the same sinusoidal motion profile using a programmable motion platform. The dose distribution of the stationary DS delivery agreed with the TPS plan. Dosimetric comparisons between DS motion delivery and the MATLAB-based motion model showed insignificant differences. Dose-volume histograms of a cylindrical target volume inside the gel dosimeters showed target coverage degradation caused by motion. A three-dimensional gamma index calculation (3% and 3 mm) confirmed different dosimetric impacts from DS and US with the same target motion. This polymer-gel-dosimeter-based study confirmed the dosimetric impact of intrafraction target motion and its interplay with temporal delivery of different energy layers in US proton treatments. PMID- 22241572 TI - Infection control knowledge, attitudes, and practices among cystic fibrosis patients and their families. AB - BACKGROUND: In 2003, the Cystic Fibrosis (CF) Foundation in the United States published evidence-based infection control guidelines and distributed these to CF care centers. However, it is unclear how well the guidelines have been disseminated to patients and families, how well patients and families understand the principles of infection control, and what barriers they experience implementing the guidelines. METHODS: We assessed infection control knowledge, attitudes, and practices among CF patients and their families at 17 randomly selected CF centers. Anonymous surveys were completed by CF patients (>=16 years old) or their family members (patients <16 years old). To adjust for similarities of patients within each center, generalized estimating equations regression was used. RESULTS: From January 2007 to May 2009, 1,399 respondents completed surveys of whom 38% were patients and 62% were family members (overall mean age of patients = 14 years). Overall, 65% of respondents were aware of the CF infection control guidelines, but only 30% had discussed them more than once with their CF care team. More than one discussion was associated with increased knowledge of infection control, including routes of pathogen transmission; the importance of avoiding close contact with other CF patients; increased confidence in practicing infection control; and increased belief in the health benefits of infection control. CONCLUSIONS: This study revealed that many CF patients and families are aware of the infection control guidelines, but that few had discussed them more than once with their CF teams. These findings underscore the importance of engaging patients and their families in regular discussions about infection control that address questions and concerns including the potential impact of infection control on health and well-being. Further strategies are needed to overcome barriers to implementing these guidelines. PMID- 22241576 TI - [Cataract surgery and age-related macular degeneration]. PMID- 22241574 TI - Osteodystrophy in chronic liver diseases. AB - Osteoporosis and osteomalacia are, to date, among the most common metabolic diseases in the world. Lately, an association between metabolic bone diseases and chronic liver disease has been increasingly reported, inducing many authors to create a new nosographic entity known as 'hepatic osteodystrophy.' The importance of such a condition is further increased by the morbidity of these two diseases, which greatly reduce the quality of life because of frequent fractures, especially vertebral and femoral neck ones. For this reason, early identification of high-risk patients should be routinely performed by measuring bone mass density. The explanation for the association between bone diseases and chronic liver disease is still uncertain, and involves many factors: from hypogonadism to use of corticosteroid drugs, from genetic factors to interferon therapy. To date, few studies have been conducted, and all with a small number of patients to establish definitive conclusions about the possible treatment, but some evidence is beginning to emerge about the safety and efficacy of bisphosphonates. PMID- 22241575 TI - Association of High Sensitivity C-Reactive Protein Concentrations and Metabolic Syndrome among Thai Adults. AB - OBJECTIVE: To investigate the association of high sensitivity C-reactive protein (hsCRP) concentrations and metabolic syndrome among Thai adults. METHODS: This cross-sectional study is comprised of 467 Thai participants (209 men and 258 women) receiving annual health check-up. Spearman's rank correlation coefficients were used to assess associations of metabolic parameters (age, waist circumference, blood pressure, triglycerides, HDL-C, fasting plasma glucose, fasting insulin and uric acid) with hsCRP concentrations for men and women, respectively. Multivariable logistic regression procedures were used to estimate the risk (odds ratios [OR] and 95% confidence intervals [95% CI]) of metabolic syndrome according to low, moderate and high hsCRP concentrations (<1.0, 1.0-3.0 and >3.0 mg/l, respectively). RESULTS: Measures of adiposity and fasting insulin were positively and significantly correlated with hsCRP concentrations among women with and without metabolic syndrome. Similar associations were observed among men without metabolic syndrome. After controlling for confounders, moderately elevated hsCRP concentrations were associated with a 2.38-fold increased risk of metabolic syndrome (OR=2.38, 95% CI: 1.20-4.72) among men. Men with high hsCRP concentrations had a 5.45-fold increased risk of metabolic syndrome (OR=5.45, 95% CI: 2.24-13.27) when compared with those who had low hsCRP concentrations. The corresponding odds ratios for women with moderately elevated and high hsCRP concentrations were 4.92 (OR=4.92, 95% CI: 2.34-10.35) and 11.93 (OR=11.93, 95% CI: 5.54-25.72), respectively. CONCLUSIONS: These findings are consistent with the literature suggesting a role of hsCRP as a biomarker for metabolic syndrome. PMID- 22241577 TI - [Hereditary retinal dystrophies]. PMID- 22241578 TI - [Adverse drug reactions in ophthalmology - update 2011/12]. PMID- 22241580 TI - Development of a routine method for the simultaneous confirmation and determination of clenbuterol in urine by minimal labeling isotope pattern deconvolution and GC-EI-MS. AB - A novel and fast routine method for the simultaneous determination and confirmation of clenbuterol in bovine and human urine samples by gas chromatography electron ionization mass spectrometry (GC-EI-MS) has been developed. The method employs isotope dilution mass spectrometry (IDMS) and is based on a combination of minimal labeling (a single (13)C label in the molecule) and isotope pattern deconvolution (IPD). This new methodology does not require the construction of a methodological calibration graph, and was compared with the classical IDMS procedure employed in clenbuterol analysis based on the use of a deuterated compound as internal standard (d(9)-clenbuterol) and a calibration curve. The sample preparation consists of simple extraction with dichloromethane, which was dried and derivatized with chloro(chloromethyl)dimethylsilane, generating a cyclic dimethylsilamorpholine (DMS) derivative suitable for GC(EI)MS detection and identification. This compound produces five intense ions in the electron ionization source, which allow the presence of clenbuterol to be confirmed in just one analysis, as demanded by European Union directives. The accuracy of the method was studied by performing recovery experiments at different concentration levels (from 0.3 to 5 ng g(-1)) in 5 mL bovine urine samples using two labeled compounds: an in-house-synthesized (13)C(1)-clenbuterol and a commercially available d(9)-clenbuterol. The detection limit of the method in human urine was 0.050 ng g(-1) with a sample volume of 10 mL, and is thus suitable for antidoping control purposes. Finally, the (13)C(1)-clenbuterol standard was employed for the determination of clenbuterol in two reference materials, BCR-503 and BCR-504 (lyophilized bovine urine). The concentrations obtained were in agreement with the certified values, with a reproducibility of below 1% RSD. PMID- 22241581 TI - Mn-doped ZnSe d-dots-based alpha-methylacyl-CoA racemase probe for human prostate cancer cell imaging. AB - In this paper, we report the successful use of non-cadmium-based Mn-doped ZnSe d dots (Mn/ZnSe) as highly efficient and nontoxic optical probes for human prostate cancer cells imaging. Mn/ZnSe d-dots are directly prepared in aqueous solution. The alpha-methylacyl-CoA racemase (AMACR) is overexpressed in prostate cancers; the presence of antibodies specific for AMACR is more sensitive and specific than serum prostate specific antigen levels in distinguishing patients with prostate cancers. Mn/ZnSe d-dots were linked to anti-AMACR to form Mn/ZnSe d-dots-anti AMACR bioconjugates for the direct prostate cancer cell imaging. 3-(4,5 Dimethylthiazol-2-yl)-2 and 5-diphenyl tetrazolium bromide assay demonstrated that Mn/ZnSe d-dots exhibited favorable cytocompatibility to LNCaP cells with high concentration (1 mM) and long-time incubation (24 h). Furthermore, cellular imaging results demonstrated that Mn/ZnSe d-dots were remarkably efficacious for high-specificity cell imaging. The antibody-mediated delivery of the bioconjugates was further confirmed by the observation of no fluorescence signals in vitro targeting in nonprostate-cancer-based cell lines which are negative for AMACR. Mn/ZnSe d-dots as non-cadmium-based safe and efficient optical imaging nanoprobes could therefore be used for targeting imaging and treatment of cancers in the early stage. PMID- 22241583 TI - Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss. AB - Some cases of maternally inherited isolated deafness are caused by mtDNA mutations, frequently following an exposure to aminoglycosides. Two mitochondrial genes have been clearly described as being affected by mutations responsible for this pathology: the ribosomal RNA 12S gene and the transfer RNA serine (UCN) gene. A previous study identified several candidate novel mtDNA mutations, localized in a variety of mitochondrial genes, found in patients with no previous treatment with aminoglycosides. Five of these candidate mutations are characterized in the present study. These mutations are localized in subunit ND1 of complex I of the respiratory chain (m.3388C>A [p.MT-ND1:Leu28Met]), the tRNA for Isoleucine (m.4295A>G), subunit COII of complex IV (m.8078G>A [p.MT CO2:Val165Ile]), the tRNA of Serine 2 (AGU/C) (m.12236G>A), and Cytochrome B, subunit of complex III (m.15077G>A [p.MT-CYB:Glu111Lys]). Cybrid cell lines have been constructed for each of the studied mtDNA mutations and functional studies have been performed to assess the possible consequences of these mutations on mitochondrial bioenergetics. This study shows that a variety of mitochondrial genes, including protein-coding genes, can be responsible for nonsyndromic deafness, and that exposure to aminoglycosides is not required to develop the disease, giving new insights on the molecular bases of this pathology. PMID- 22241584 TI - Highlighting and trying to overcome a serious drawback with QSPR studies; data collection in different experimental conditions (mixed-QSPR). AB - The experimental conditions in quantitative structure-property relationship (QSPR) studies need to be the same for each dataset in case one wishes to relate the property, only to the structure. This major drawback limits QSPR studies due to two reasons: (1) Gathering of physicochemical data obtained under the same experimental condition is difficult. (2) The obtained model is just useful to predict the physicochemical properties under the specific experimental condition. In this article, we report an attempt to highlight the shortcoming of QSPR studies for a property that was measured under different experimental conditions. In addition, we reveal inadequacies that correlating the fluorescence properties and the descriptor of the solvent has. These defects are eventually removed by taking into account the solvent-solute interactions in descriptor calculations. Quantum chemical calculations (HF/6-31G*) were carried out to optimize geometry and calculate the structural descriptors. The genetic algorithm combined with multiple linear regression method was utilized to construct the linear QSPR models. Because of the better nonlinear relationship between the quantum yield of fluorescence and structural descriptors in comparison with those of a linear relationship, support vector machine was used to construct the nonlinear QSPR model. Result analyses demonstrated that the proposed models meet our goal. PMID- 22241585 TI - Elements of metabolic evolution. AB - Research into the origin of evolution is polarized between a genetics-first approach, with its focus on polymer replication, and a metabolism-first approach that takes aim at chemical reaction cycles. Taking the latter approach, we explored reductive carbon fixation in a volcanic hydrothermal setting, driven by the chemical potential of quenched volcanic fluids for converting volcanic C1 compounds into organic products by transition-metal catalysts. These catalysts are assumed to evolve by accepting ever-new organic products as ligands for enhancing their catalytic power, which in turn enhances the rates of synthetic pathways that give rise to ever-new organic products, with the overall effect of a self-expanding metabolism. We established HCN, CO, and CH(3)SH as carbon nutrients, CO and H(2) as reductants, and iron-group transition metals as catalysts. In one case, we employed the "cyano-system" [Ni(OH)(CN)] with [Ni(CN)(4)](2-) as the dominant nickel-cyano species. This reaction mainly produced alpha-amino acids and alpha-hydroxy acids as well as various intermediates and derivatives. An organo-metal-catalyzed mechanism is suggested that mainly builds carbon skeletons by repeated cyano insertions, with minor CO insertions in the presence of CO. The formation of elemental nickel (Ni(0)) points to an active reduced-nickel species. In another case, we employed the mercapto-carbonyl system [Co(2)(CO)(8)]/Ca(OH)(2)/CO for the double-carbonylation of mercaptans. In a "hybrid system", we combined benzyl mercaptan with the cyano system, in which [Ni(OH)(CN)] was the most productive for the double-carbon fixation reaction. Finally, we demonstrated that the addition of products of the cyano system (Gly, Ala) to the hybrid system increased productivity. These results demonstrate the chemical possibility of metabolic evolution through rate promotion of one synthetic reaction by the products of another. PMID- 22241586 TI - A thermally baffled device for highly stabilized convective PCR. AB - Rayleigh-Benard convective PCR is a simple and effective design for amplification of DNA. Convective PCR is, however, extremely sensitive to environmental temperature fluctuations, especially when using small- diameter test tubes. Therefore, this method is inherently unstable with limited applications. Here, we present a convective PCR device that has been modified by adding thermal baffles. With this thermally baffled device the influence from fluctuations in environmental temperature were significantly reduced, even in a wind tunnel (1 m/s). The thermally baffled PCR instrument described here has the potential to be used as a low-cost, point-of-care device for PCR-based molecular diagnostics in the field. PMID- 22241588 TI - The 1,1-carboboration of bis(alkynyl)phosphanes as a route to phosphole compounds. PMID- 22241587 TI - Eliminating the need for refractive index matching in optical CT scanners for radiotherapy dosimetry: I. Concept and simulations. AB - Optical computed tomography has now become a well-established method for making empirical measurements of 3D dose distributions in radiotherapy treatment verification. The requirement for effective refractive index matching as part of the scanning process has long been an inconvenience for users, limiting the speed of sample throughput. We propose a new method for reconstructing data that takes explicit account of the refracted path of the light rays and demonstrate theoretically the conditions under which there are sufficient data to create a good reconstruction. Examples of the performance of the algorithm are given. For smoothly varying data, reconstructed images of very high quality are obtained, with RMS deviation of under 1% from the original, provided that the irradiated region lies entirely within a critical radius. For the dosimeter material PRESAGE, this critical value is approximately 0.65 of the sample radius. Regions outside this are not reconstructed successfully, but we argue that there are many cases where this disadvantage is outweighed by the benefits of the technique. PMID- 22241589 TI - Ortho-functionalized perylenediimides for highly fluorescent water-soluble dyes. AB - Clearly visible: A water-soluble and highly fluorescent perylenediimide is synthesized via ruthenium-catalyzed alkylation with outstanding yields. For the first time, the possibility to use phosphonate derivatives in a Murai-type reaction is demonstrated. PMID- 22241590 TI - Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. AB - OPINION STATEMENT: Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease that may occur in recipients of solid organ transplants (SOT) and hematopoietic stem cell transplant. The risk of lymphoma is increased 20-120% compared with the general population with risk dependent in part on level of immune suppression. In addition, recent data have emerged, including HLA and cytokine gene polymorphisms, regarding genetic susceptibility to PTLD. Based on morphologic, immunophenotypic, and molecular criteria, PLTD are classified into 4 pathologic categories: early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma. Evaluation by expert hematopathology is critical in establishing the diagnosis. The aim of therapy for most patients is cure with the concurrent goal of preservation of allograft function. Given the pathologic and clinical heterogeneity of PTLD, treatment is often individualized. A mainstay of therapy remains reduction of immune suppression (RI) with the level of reduction being dependent on several factors (e.g., history of rejection, current dosing, and type of allograft). Outside of early lesions and/or low tumor burden, however, RI alone is associated with cure in a minority of subjects. We approach most newly-diagnosed polymorphic and monomorphic PTLDs similarly using frontline single-agent rituximab (4 weeks followed by abbreviated maintenance) in conjunction with RI. Frontline combination chemotherapy may be warranted for patients with high tumor burden in need of prompt response or following failure of RI and/or rituximab. Due to chemotherapy-related complications in PTLD, especially infectious, we advocate comprehensive supportive care measures. Surgery or radiation may be considered for select patients with early-stage disease. For PTLD subjects with primary CNS lymphoma, we utilize therapeutic paradigms similar to immunocompetent CNS lymphoma using high-dose methotrexate based therapy with concurrent rituximab therapy and sequential high-dose cytarabine. Finally, novel therapeutic strategies, especially adoptive immunotherapy, should continued to be explored. PMID- 22241591 TI - Evaluation of a method for projection-based tissue-activity estimation within small volumes of interest. AB - A new method of compensating for tissue-fraction and count-spillover effects, which require tissue segmentation only within a small volume surrounding the primary lesion of interest, was evaluated for SPECT imaging. Tissue-activity concentration estimates are obtained by fitting the measured projection data to a statistical model of the segmented tissue projections. Multiple realizations of two simulated human-torso phantoms, each containing 20 spherical 'tumours', 1.6 cm in diameter, with tumour-to-background ratios of 8:1 and 4:1, were simulated. Estimates of tumour- and background-activity concentration values for homogeneous as well as inhomogeneous tissue activities were compared to the standard uptake value (SUV) metrics on the basis of accuracy and precision. For perfectly registered, high-contrast, superficial lesions in a homogeneous background without scatter, the method yielded accurate (<0.4% bias) and precise (<6.1%) recovery of the simulated activity values, significantly outperforming the SUV metrics. Tissue inhomogeneities, greater tumour depth and lower contrast ratios degraded precision (up to 11.7%), but the estimates remained almost unbiased. The method was comparable in accuracy but more precise than a well-established matrix inversion approach, even when errors in tumour size and position were introduced to simulate moderate inaccuracies in segmentation and image registration. Photon scatter in the object did not significantly affect the accuracy or precision of the estimates. PMID- 22241592 TI - Prophylactic intravenous nimodipine treatment in skull base surgery: pharmacokinetic aspects. AB - BACKGROUND: Nimodipine is primarily used in subarachnoid hemorrhage (SAH). Clinical trials revealed also a beneficial effect of prophylactic nimodipine treatment on cranial nerve functions following vestibular schwannoma surgery. OBJECTIVE: The unknown pharmacokinetics of prophylactically administered nimodipine were investigated. METHODS: Samples were taken from 27 patients with skull base lesions. Prophylactic intravenous nimodipine infusion was started 5.8 25.8 h (mean 17.9 h) before surgery. Nimodipine concentrations were determined in serum (intra- and postoperatively), cerebrospinal fluid (CSF) (intraoperatively), and tissue samples. RESULTS: Wide interindividual differences were observed. Mean concentrations for nimodipine were 46.9 ng/ml (SD: 6.4; min. 4.1 and max. 92.7 ng/ml) in intraoperative serum, 73.2 ng/ml (SD: 16.7; min. 6.6 and max. 253 ng/ml) in postoperative serum and 8.3 ng/ml (SD: 1.5; min. 1.0 und max. 29.7 ng/ml) in intraoperative CSF. The correlation between intra- and postoperative serum (p=0.004, r=0.560) and between intra-operative serum and CSF concentration (p=0.003, r=0.567) were statistically significant. Furthermore the correlation between intraoperative serum concentration and concentrations collected from vestibular nerves was high (r=0.711), but not statistically significant (p=0.178). CONCLUSIONS: Interindividually, continously administered intravenous nimodipine produces considerably variable serum levels. Controls of nimodipine serum concentrations may be useful to optimize nimodipine medication in skull base surgery and in the management of SAH. The serum nimodipine level is a useful marker for CSF and intracranial nerve tissue concentrations of nimodipine. PMID- 22241595 TI - Reaction pathways from single-molecule trajectories. AB - Signal-pair histograms map transitions between different states of a single molecule and open new opportunities for the reconstruction of kinetic pathways. PMID- 22241593 TI - Recurrent giant cell glioblastoma with the neuroradiologic picture of multiple meningiomas. PMID- 22241596 TI - Fluoroscopic findings in pediatric eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EE) is an inflammatory disorder of the esophagus characterized by symptoms such as dysphagia, food sticking and heartburn. Several fluoroscopic findings have been described in EE, but the frequency of these findings is unknown. OBJECTIVE: To identify the frequency of imaging findings in pediatric-age patients with eosinophilic esophagitis. MATERIALS AND METHODS: A retrospective study was performed evaluating all upper GI and esophagram studies performed between 2000 and 2008 in patients up to age 21 with a pathological diagnosis of EE. In order to be included in the study, the upper GI or esophagram had to be performed either before EE was diagnosed or within 30 days of the diagnosis. Two pediatric radiologists evaluated each study for the presence or absence of multiple findings of EE. The radiology reports from the time of the study were then read to establish a concurrent diagnosis of esophageal dysmotility or gastroesophageal reflux. Finally, the hospital electronic medical record was evaluated to obtain demographic and pathology information. RESULTS: Of the 579 patients with biopsy-proven EE, 107 (18%) were included in the study and underwent a total of 112 upper GI or esophagram examinations. The most common finding on these examinations was a normal esophagus (58/112; 52%) followed by gastroesophageal reflux (21/112; 19%) and irregular contractions (17/112; 15%). Less frequent findings included strictures, dysmotility, mucosal irregularity, esophageal rings and filling defects. CONCLUSION: Fluoroscopic studies are not a sensitive method to diagnose EE because nearly half of the studies are normal. Findings that have been described in the setting of EE such as food impaction, a ringed esophagus, a small-caliber esophagus and esophageal stricture do not occur with a high enough frequency to reliably make a diagnosis. PMID- 22241597 TI - 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles: synthesis, anticancer activity, and inhibition of tubulin polymerization. AB - A new series of 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles (3 a-h) were synthesized by C-arylation of 2-arylimidazo[2,1-b]benzothiazoles using palladium acetate as catalyst, and the resulting compounds were evaluated for their anticancer activity. Compounds 3 a, 3 e, and 3 h exhibited good antiproliferative activity, with GI50 values in the range of 0.19-83.1 MUM. Compound 3 h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI50 value of 0.88 MUM. This compound also induced cell-cycle arrest in the G2/M phase and inhibited tubulin polymerization followed by activation of caspase-3 and apoptosis. A high-throughput tubulin polymerization assay showed that the level of inhibition for compound 3 h is similar to that of combretastatin A-4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3 a, 3 e, and 3 h to the colchicine binding pocket of tubulin. PMID- 22241599 TI - Magnetic anisotropy in a dysprosium/DOTA single-molecule magnet: beyond simple magneto-structural correlations. PMID- 22241600 TI - An extended cure model and model selection. AB - We propose a novel interpretation for a recently proposed Box-Cox transformation cure model, which leads to a natural extension of the cure model. Based on the extended model, we consider an important issue of model selection between the mixture cure model and the bounded cumulative hazard cure model via the likelihood ratio test, score test and Akaike's Information Criterion (AIC). Our empirical study shows that AIC is informative and both the score test and the likelihood ratio test have adequate power to differentiate between the mixture cure model and the bounded cumulative hazard cure model when the sample size is large. We apply the tests and AIC methods to leukemia and colon cancer data to examine the appropriateness of the cure models considered for them in the literature. PMID- 22241601 TI - Theoretical investigation on the transportation behavior of molecular wires with redox reaction. AB - A series of model molecules [sequential quinone (Q) or hydroquinone (HQ) rings connected by triple bonds] as molecular wires have been investigated by using density functional theory combined with nonequilibrium Green's function method. The results show that the system has two discrete conductance states: a low conductance state with Q form, and a high-conductance state with HQ form. The systematic investigations have suggested that more Q/HQ pairs in the system may improve the on/off ratio, though long molecule reduces the conductance of the molecular junction. The switch mechanism has been explained via molecular electronic structure as well as transmission spectra. PMID- 22241602 TI - Cardiac effects of granisetron in a prospective crossover randomized dose comparison trial. AB - PURPOSE: Cardiac side effects of granisetron have been studied mostly in adult patients that are using cardiotoxic chemotherapeutics. There is limited evidence in pediatric age group and no information in pediatric oncology patients with non cardiotoxic chemotherapeutics. METHODS: In this prospective, crossover randomized study, the cardiac side effects of granisetron are compared in pediatric oncology patients who had carboplatin based chemotherapy. They were randomized to receive either 10 or 40 MUg kg(-1) dose(-1) of granisetron before each cycle of chemotherapy. We drew blood for creatine phosphokinase (CPK), CPK-muscle band (MB) and Troponin-T before and 24 h after administering granisetron. Electrocardiography (ECG) tracings were taken at 0, 1, 2, 3, 6 and 24 h of granisetron. Twenty-four hours Holter ECG monitorisation was performed after each granisetron infusion. RESULTS: A total of 16 patients (median 8.7 years of age) were treated with weekly consecutive courses of carboplatin. There was bradycardia (p = 0.000) in patients that had granisetron at 40 MUg/kg and PR interval was shortened in patients that had granisetron at 10 MUg/kg dose (p = 0.021). At both doses of granisetron, QTc interval and dispersion were found to be similar. CPK, CK-MB and Troponin-T values were found to be normal before and 24 h after granisetron infusion. CONCLUSIONS: As the first study that has studied cardiac side effects of granisetron in patients that are not using cardiotoxic chemotherapeutics, we conclude that granisetron at 40 MUg kg(-1) dose(-1) causes bradycardia only. We have also demonstrated that granisetron does not cause any clinically cardiac side effects either at 10 or 40 MUg kg(-1) dose(-1). However, our results should be supported by prospective randomized studies with larger samples of patient groups. PMID- 22241603 TI - Tuning the physicochemical properties of diverse phenolic ionic liquids for equimolar CO2 capture by the substituent on the anion. AB - Phenolic ionic liquids for the efficient and reversible capture of CO(2) were designed and prepared from phosphonium hydroxide and substituted phenols. The electron-withdrawing or electron-donating ability, position, and number of the substituents on the anion of these ionic liquids were correlated with the physicochemical properties of the ionic liquids. The results show that the stability, viscosity, and CO(2)-capturing ability of these ionic liquids were significantly affected by the substituents. Furthermore, the relationship between the decomposition temperature, the CO(2)-absorption capacity, and the basicity of these ionic liquids was quantitatively correlated and further rationalized by theoretical calculation. Indeed, these ionic liquids showed good stability, high absorption capacity, and low absorption enthalpy for CO(2) capture. This method, which tunes the physicochemical properties by making use of substituent effects in the anion of the ionic liquid, is important for the design of highly efficient and reversible methods for CO(2)-capture. This CO(2) capture process using diverse phenolic ionic liquids is a promising potential method for CO(2) absorption with both high absorption capacity and good reversibility. PMID- 22241604 TI - Skin-derived fibroblasts for the treatment of refractory Achilles tendinosis: preliminary short-term results. AB - BACKGROUND: Chronic Achilles tendinosis is a common musculoskeletal disorder often refractory to conservative management. Our study aimed to assess the safety and efficacy of the use of autologous skin-derived collagen-producing cells in the treatment of refractory Achilles tendinosis. METHODS: We conducted a randomized, double-blind study on forty Achilles tendons in thirty-two patients (eight with bilateral involvement) who had a clinical and radiographic diagnosis of Achilles tendinosis. The patients ranged from twenty-two to sixty-seven years old and had a mean age of 45.2 years. The patients with unilateral involvement were randomized into the treatment group (twelve patients) and control group (twelve patients). The eight patients with bilateral involvement were individually randomized into treatment and control groups, with eight Achilles tendons in each group. Achilles tendons in the treatment group were injected under ultrasound guidance with laboratory-expanded, skin-derived fibroblasts suspended in autologous plasma. The control group received ultrasound-guided injection of a local anesthetic and physiotherapy. The Victorian Institute of Sport Assessment (VISA) questionnaire and visual analog scale (VAS) scores were used as the main outcome measures for both groups. RESULTS: Significant differences in the mean VISA and VAS scores were detected between the treatment and the control groups for the patients with unilateral involvement at six months (p < 0.001 for both). With use of the Mann-Whitney U Test, significant differences in the VISA score were observed at the second visit and at the three month and six-month visits (p = 0.02, p = 0.007, and p < 0.001 respectively). The VAS scores also showed significant differences at the second visit and at the six month evaluation (p = 0.014 and p < 0.001, respectively). The eight patients with bilateral involvement were analyzed separately; with the number of patients studied, no significant differences in the VISA or VAS scores were observed between the treatment group and the control group. CONCLUSIONS: These preliminary short-term results demonstrate that the injection of skin-derived fibroblasts for the treatment of Achilles tendinosis is safe. However, larger studies with a longer duration of follow-up are required to determine the long-term effectiveness before wider clinical application is considered. PMID- 22241605 TI - Platelet-rich plasma: the next big thing?: commentary on an article by Ujash Sheth, BHSc, et al.: "Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis". PMID- 22241606 TI - Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. AB - BACKGROUND: The recent emergence of autologous blood concentrates, such as platelet-rich plasma, as a treatment option for patients with orthopaedic injuries has led to an extensive debate about their clinical benefit. We conducted a systematic review and meta-analysis to determine the efficacy of autologous blood concentrates in decreasing pain and improving healing and function in patients with orthopaedic bone and soft-tissue injuries. METHODS: We searched MEDLINE and Embase for randomized controlled trials or prospective cohort studies that compared autologous blood concentrates with a control therapy in patients with an orthopaedic injury. We identified additional studies by searching through the bibliographies of eligible studies as well as the archives of orthopaedic conferences and meetings. RESULTS: Twenty-three randomized trials and ten prospective cohort studies were identified. There was a lack of consistency in outcome measures across all studies. In six randomized controlled trials (n = 358) and three prospective cohort studies (n = 88), the authors reported visual analog scale (VAS) scores when comparing platelet-rich plasma with a control therapy across injuries to the acromion, rotator cuff, lateral humeral epicondyle, anterior cruciate ligament, patella, tibia, and spine. The use of platelet-rich plasma provided no significant benefit up to (and including) twenty-four months across the randomized trials (standardized mean difference, 0.34; 95% confidence interval [CI], -0.75 to 0.06) or the prospective cohort studies (standardized mean difference, -0.20; 95% CI, -0.64 to 0.23). Both point estimates suggested a small trend favoring platelet-rich plasma, but the associated wide confidence intervals were consistent with nonsignificant effects. CONCLUSIONS: The current literature is complicated by a lack of standardization of study protocols, platelet-separation techniques, and outcome measures. As a result, there is uncertainty about the evidence to support the increasing clinical use of platelet-rich plasma and autologous blood concentrates as a treatment modality for orthopaedic bone and soft-tissue injuries. PMID- 22241607 TI - Shared written case formulations and weight change in outpatient therapy for anorexia nervosa: a naturalistic single case series. AB - The therapeutic effects of written shared case formulations are underexplored and have not been examined in anorexia nervosa. This study explored the relationship between (a) the delivery (b) the quality of a shared written case formulation and weight in outpatient psychological therapy for anorexia nervosa. A naturalistic single case series approach was used to examine the case notes of women who had attended a specialist eating disorders service over a 2-year period. The case notes of 15 adult women who had undergone outpatient psychological therapy for anorexia nervosa with a shared written case formulation component were reviewed. The impact of the quality of the case formulation on weekly weight was examined for 14 of the clients where the case formulation was available. The nature of the relationship between the delivery of the written shared case formulation and weight was examined for all 15 clients. There was some evidence to support an association between delivery of the shared written case formulation and weight changes (both weight gain [five out of 15 clients] and weight loss [three out of 15 clients]) in individual cases. Higher case formulation quality was related to cases where weight change did not occur. The delivery of case formulations can be associated with important therapeutic change (both beneficial and potentially harmful) in anorexia nervosa. Future research into the causal mechanisms associated with sharing formulations will face the challenge of adopting strategies that allow for an in-depth exploration of complex therapy variables whilst overcoming methodological challenges. PMID- 22241608 TI - Potential for promoting recurrent laryngeal nerve regeneration by remote delivery of viral gene therapy. AB - OBJECTIVES/HYPOTHESIS: The aims of this study were to demonstrate the ability to enhance nerve regeneration by remote delivery of a viral vector to the crushed recurrent laryngeal nerve (RLN), to demonstrate the usefulness of a crushed RLN model to test the efficacy of viral gene therapy, and to discuss future potential applications of this approach. STUDY DESIGN: Animal study. METHODS: Adult Sprague Dawley rats were assigned to two groups. In the experimental group, an adeno associated viral (AAV) vector carrying a zinc-finger transcription factor, which stimulates endogenous insulinlike growth factor I production (AAV2-TO-6876vp16), was injected into the crushed RLN. In the control group, an AAV vector carrying the gene for green fluorescent protein was injected into the crushed RLN. Unilateral RLN paralysis was confirmed endoscopically. At 1 week, laryngeal endoscopies were repeated and recorded. Larynges were cryosectioned in 15-MUm sections and processed for acetylcholine histochemistry (motor endplates) followed by neurofilament immunoperoxidase (nerve fibers). Percentage nerve endplate contact (PEC) was determined and compared. Vocal fold motion was evaluated by blinded reviewers using a visual analogue scale (VAS). RESULTS: The difference between PEC on the crushed and uncrushed sides was statistically less in the experimental group (0.54 +/- 0.18 vs. 0.30 +/- 0.26, P = .0006). The VAS score at 1 week was significantly better in the experimental group (P = .002). CONCLUSIONS: AAV2-TO-6876vp16 demonstrated a neurotrophic effect when injected into the crushed RLN. The RLN offers a conduit for viral gene therapy to the brainstem that could be useful for the treatment of RLN injury or bulbar motor neuron disease. PMID- 22241609 TI - Chondrogenic differentiation of induced pluripotent stem cells from osteoarthritic chondrocytes in alginate matrix. AB - Induced pluripotent stem cells (iPSCs) have the potential to revolutionise cell therapy; however, it remains unclear whether iPSCs can be generated from human osteoarthritic chondrocytes (OCs) and subsequently induced to differentiate into chondrocytes. In the present study, we investigated the differentiation potential of OCs into iPSCs using defined transcription factors and explored the possibility of using these OC-derived iPSCs for chondrogenesis. Our study demonstrates that iPSCs can be generated from OCs and that these iPSCs are indistinguishable from human embryonic stem cells (hESCs). To promote chondrogenic differentiation, we used lentivirus to transduce iPSCs seeded in alginate matrix with transforming growth factor-beta1 (TGF-beta1) and then in vitro co-cultured these iPSCs with chondrocytes. Gene expression analysis showed that this combinational strategy promotes the differentiation of the established iPSCs into chondrocytes in alginate matrix. Increased expression of cartilage related genes, including collagen II, aggrecan, and cartilage oligomeric matrix protein (COMP), and decreased gene expression of the degenerative cartilage marker, vascular endothelial growth factor (VEGF), were observed. The histological results revealed a dense sulphated extracellular matrix in the co culture of TGF-beta1-transfected iPSCs with chondrocytes in alginate matrix. Additionally, in vivo chondroinductive activity was also evaluated. Histological examination revealed that more new cartilage was formed in the co-culture of TGF beta1-transfected iPSCs with chondrocytes in alginate matrix. Taken together, our data indicate that iPSCs can be generated from OCs by defined factors and the combinational strategy results in significantly improved chondrogenesis of OC derived iPSCs. This work adds to our understanding of potential solutions to osteoarthritic cell replacement problem. PMID- 22241610 TI - Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche. AB - Mesenchymal stem cells (MSCs) within their native environment of the stem cell niche in bone receive biochemical stimuli from surrounding cells. These stimuli likely influence how MSCs differentiate to become bone precursors. The ability of MSCs to undergo osteogenic differentiation is well established in vitro;however, the role of the natural cues from bone's regulatory cells, osteocytes and osteoblasts in regulating the osteogenic differentiation of MSCs in vivo are unclear. In this study we delineate the role of biochemical signalling from osteocytes and osteoblasts, using conditioned media and co-culture experiments, to understand how they direct osteogenic differentiation of MSCs. Furthermore, the synergistic relationship between osteocytes and osteoblasts is examined by transwell co-culturing of MSCs with both simultaneously. Osteogenic differentiation of MSCs was quantified by monitoring alkaline phosphatase (ALP) activity, calcium deposition and cell number. Intracellular ALP was found to peak earlier and there was greater calcium deposition when MSCs were co-cultured with osteocytes rather than osteoblasts, suggesting that osteocytes are more influential than osteoblasts in stimulating osteogenesis in MSCs. Osteoblasts initially stimulated an increase in the number of MSCs, but ultimately regulated MSC differentiation down the same pathway. Our novel co-culture system confirmed a synergistic relationship between osteocytes and osteoblasts in producing biochemical signals to stimulate the osteogenic differentiation of MSCs. This study provides important insights into the mechanisms at work within the native stem cell niche to stimulate osteogenic differentiation and outlines a possible role for the use of co-culture or conditioned media methodologies for tissue engineering applications. PMID- 22241611 TI - Two new Kirschsteiniothelia species with Dendryphiopsis anamorphs cluster in Kirschsteiniotheliaceae fam. nov. AB - Two new Kirschsteiniothelia species are proposed in this study; both were collected on decaying wood from Chiang Mai and Chiang Rai provinces in northern Thailand. The taxa were isolated and the morphological characters are described and illustrated. ITS, LSU and SSU combined sequence analysis showed taxa of Kirschsteiniothelia separating into three lineages: (i) K. elaterascus grouped within Morosphaeriaceae (Pleosporales); (ii) K. maritima clustered with Mytilinidion spp. as a sister group in the Mytilinidiaceae clade; and (iii) the two new Kirschsteiniothelia species, which produce Dendryphiopsis anamorphs in culture, clustered with K. aethiops (the generic type) and the anamorph D. atra. The new family Kirschsteiniotheliaceae is introduced to accommodate taxa grouping with K. aethiops. K. elaterascus is transferred to Morosphaeria (Morosphaeriaceae) and a new genus Halokirschteiniothelia is introduced to accommodate K. maritima (Mytilinidiaceae). PMID- 22241613 TI - Rodaucea, a new genus of the Laboulbeniales. AB - The new genus Rodaucea is created for a new species of Laboulbeniales parasitic on carrion beetles from Ecuador. The new genus is characterized by the presence of two unequal secondary receptacles flanking cell II on opposite sides. The perithecia have the wall cells arranged in four tiers distinctly unequal in height and the antheridia are phialid-like structures borne terminally on branches of primary and secondary appendages. PMID- 22241612 TI - Penicillium solitum produces a polygalacturonase isozyme in decayed Anjou pear fruit capable of macerating host tissue in vitro. AB - A polygalacturonase (PG) isozyme was isolated from Penicillium solitum-decayed Anjou pear fruit and purified to homogeneity with a multistep process. Both gel filtration and cation exchange chromatography revealed a single PG activity peak, and analysis of the purified protein showed a single band with a molecular mass of 43 kDa, which is of fungal origin. The purified enzyme was active from pH 3.5 6, with an optimum at pH 4.5. PG activity was detectable 0-70 C with 50 C maximum. The purified isozyme was inhibited by the divalent cations Ca(2+), Mg(2+), Mn(2+) and Fe(2+) and analysis of enzymatic hydrolysis products revealed polygalacturonic acid monomers and oligomers. The purified enzyme has an isoelectric point of 5.3 and is not associated with a glycosylated protein. The PG isozyme macerated fruit tissue plugs in vitro and produced ~1.2-fold more soluble polyuronides from pear than from apple tissue, which further substantiates the role of PG in postharvest decay. Data from this study show for the first time that the purified PG produced in decayed Anjou pear by P. solitum, a weakly virulent fungus, is different from that PG produced by the same fungus in decayed apple. PMID- 22241614 TI - Use of drift substrates to characterize marine fungal communities from the west coast of Portugal. AB - This survey reports the occurrence, diversity and similarity of marine fungi associated with five categories of drift substrates (Arundo donax, Phragmites australis, Spartina maritima, "other stems" and driftwood) collected on four sandy beaches of the western coast of Portugal. "Other stems" and driftwood are composite samples with a variety of identified and unidentified pieces of non woody and woody substrates respectively. Fifty-six taxa were identified, including 38 Ascomycota and 18 anamorphic fungi. Twenty-six taxa were generalists; however several cases of "substrate recurrence" were identified. The very frequent fungi differed among the categories of studied substrates, with the exception of Corollospora maritima, very frequent on four categories. Except for S. maritima, P. australis and driftwood, cases of multiple fungal colonization were rare. S. maritima was the single substrate with five different marine fungi on one sample, as well as with the highest number of very frequent fungi, highest percentage of colonization and average number of fungi per sample. Driftwood presented the highest value of fungal richness (37 taxa) and A. donax the lowest (22 taxa). ANOSIM analysis of similarity showed that all substrates supported different fungal communities with the exception of the pair P. australis/"other stems". The effect of sample size on estimated fungal richness was tested, and the results let us conclude that, although most of the sporadic fungi (<1% occurrence) will be detected only in a very large number of samples, 60 samples of A. donax and "other stems" and 70 samples of all the other substrates may suffice to assess their respective representative marine mycota. PMID- 22241615 TI - Ten polymorphic microsatellite loci identified from a small insert genomic library for Peronospora tabacina. AB - Ten polymorphic microsatellite loci for the obligate biotrophic, oomycete pathogen of tobacco, Peronospora tabacina, were identified from a small insert genomic library enriched for GT motifs. Eighty-five percent of the 162 loci identified were composed of dinucleotide repeats, whereas only 4% and 11% were tri-and tetra-nucleotide repeats respectively. About 82% of all the microsatellites were perfect and within the library; only about 7% of the loci were duplicated. Primers were designed for 63 loci; 10 loci were polymorphic, 19 were monomorphic and 34 either failed to amplify or produced ambiguous/inconsistent results. The 10 polymorphic loci were characterized with 44 isolates of P. tabacina collected from tobacco plants growing in Europe, the Near East and North and South America. The number of alleles per locus was either three or four with a mean of 3.2, and the mean number of genotypes per locus was 3.6. Observed heterozygosity was 0.32-0.95, whereas expected heterozygosity was 0.44-0.69 for these loci. All loci except PT054 did not conform to the Hardy Weinberg distribution. Polymorphic information content (PIC) for the loci was 0.35-0.69 with a mean of 0.50. These microsatellite loci provide a set of markers sufficient to perform genetic diversity and population studies of P. tabacina, and possibly other species of Peronospora. PMID- 22241616 TI - Compression paddle tilt correction in full-field digital mammograms. AB - During the acquisition of a mammogram the breast is compressed between the compression paddle and the support table. When compression is applied, the upper plate is tilted which results in variation in breast thickness from the chest wall to the breast margin. Variation in breast thickness influences the grey level values of the image and hampers image analysis, such as volumetric breast density estimation. In this paper, we present and compare two methods that estimate and correct image tilt. The first method estimates tilt from fatty tissue regions. The second method is based on the entropy of the grey-level distribution of the image. Both methods use a classifier that distinguishes fatty areas from dense tissue based on texture features independent of tilt. The tilt correction methods are evaluated by assessing their accuracies in estimating artificial tilts that are added to images that are known to have only a small tilt. On average, both methods are able to estimate the artificial tilt. To the best of our knowledge, this is the first paper that presents and validates tilt correction methods on individual mammograms. PMID- 22241617 TI - Pyrazinamide: a frontline drug used for tuberculosis. Molecular mechanism of action resolved after 50 years? PMID- 22241618 TI - Free-energy landscapes of ion movement through a G-quadruplex DNA channel. PMID- 22241619 TI - Relationship of maternal knowledge of anemia with maternal and child anemia and health-related behaviors targeted at anemia among families in Indonesia. AB - Our specific aim was to characterize maternal knowledge of anemia and its relationship to maternal and child anemia and to behaviors related to anemia reduction. We examined the relationship between maternal knowledge of anemia and anemia in the mother and the youngest child, aged 6-59 months, in 7,913 families from urban slums and 37,874 families from rural areas of Indonesia. Knowledge of anemia was defined based upon the mother's ability to correctly name at least one symptom of anemia and at least one treatment or strategy for reducing anemia. Hemoglobin was measured in both the mother and the child. In urban and rural areas, respectively, 35.8 and 36.9% of mothers had knowledge of anemia, 28.7 and 25.1% of mothers were anemic (hemoglobin <12 g/dL), and 62.3 and 54.0% of children were anemic (hemoglobin <11 g/dL). Maternal knowledge of anemia was associated with child anemia in urban and rural areas, respectively (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.79, 1.02, P = 0.10; OR 0.93, 95% CI 0.87, 0.98, P = 0.01) in multivariate logistic regression models adjusting for potential confounders. There was no significant association between maternal knowledge of anemia and maternal anemia. Maternal knowledge of anemia was significantly associated with iron supplementation during pregnancy and child consumption of fortified milk. There was no association of maternal knowledge of anemia with child deworming. Maternal knowledge of anemia is associated with lower odds of anemia in children and with some health behaviors related to reducing anemia. PMID- 22241620 TI - Electronic structure and thermochemical properties of silicon-doped lithium clusters Li(n)Si0/+, n = 1-8: new insights on their stability. AB - A theoretical investigation on small silicon-doped lithium clusters Li(n)Si with n = 1-8, in both neutral and cationic states is performed using the high accuracy CCSD(T)/complete basis set (CBS) method. Location of the global minima is carried out using a stochastic search method and the growth pattern of the clusters emerges as follows: (i) the species Li(n)Si with n <= 6 are formed by directly binding one Li to a Si of the smaller cluster Li(n-1)Si, (ii) the structures tend to have an as high as possible symmetry and to maximize the coordination number of silicon. The first three-dimensional global minimum is found for Li(4)Si, and (iii) for Li(7)Si and Li(8)Si, the global minima are formed by capping Li atoms on triangular faces of Li(6)Si (O(h)). A maximum coordination number of silicon is found to be 6 for the global minima, and structures with higher coordination of silicon exist but are less stable. Heats of formation at 0 K (Delta(f)H(0)) and 298 K (Delta(f)H(298)), average binding energies (E(b)), adiabatic (AIE) and vertical (VIE) ionization energies, dissociation energies (D(e)), and second order difference in total energy (Delta(2)E) of the clusters in both neutral and cationic states are calculated from the CCSD(T)/CBS energies and used to evaluate the relative stability of clusters. The species Li(4)Si, Li(6)Si, and Li(5)Si(+) are the more stable systems with large HOMO-LUMO gaps, E(b), and Delta(2)E. Their enhanced stability can be rationalized using a modified phenomenological shell model, which includes the effects of additional factors such as geometrical symmetry and coordination number of the dopant. The new model is subsequently applied with consistency to other impure clusters Li(n)X with X = B, Al, C, Si, Ge, and Sn. PMID- 22241621 TI - Current hepatitis delta virus type 1 (HDV1) infections in central and eastern Turkey indicate a wide genetic diversity that is probably linked to different HDV1 origins. AB - Hepatitis delta virus (HDV) is a subviral pathogen of humans, a satellite of hepatitis B virus (HBV) that induces severe acute and chronic liver diseases. The genus Deltavirus consists of eight clades or genotypes, with HDV1 being ubiquitous and frequently characterized. In Turkey, HDV1 infection is highly endemic among HBsAg carriers, especially in the southeastern region. In this study, we analyzed 34 samples from patients who were chronically infected with HBV/HDV, originating from 22 cities of rural regions in the central and eastern parts of Turkey, in order to determine the levels of viral replication and genetic diversity. HDV RNA levels ranged between 3.02 and 8.75 Log copies/mL, and HBV DNA was detected in 25 samples (73.5%), with values ranging from 2.53 to 5.30 Log copies/mL. Analysis of nucleotides 900-1280 of HDV genomes (n = 34) and full length (n = 17) sequences indicated that all of the strains belonged to genotype HDV1. However, a high genetic diversity was observed among the isolates, with a mean full-length dissimilarity score of 13.05%. HDV sequences clustered with sequences from Western Europe (n = 11), Eastern Europe and Asia (n = 19) or Africa (n = 4). HDV1 isolates related to strains of African origin had a serine residue instead of an alanine at position 202 of the large delta protein. HBV preS1 sequences obtained for 34 isolates indicated an HBV/D genotype in all cases. Taken together, our results indicate that in Turkey, where HBV-HDV dual infection is highly endemic, both viruses have high levels of replication, and HDV strains exhibit wide genetic diversity, which might reflect ancient evolution and/or successive outbreaks. PMID- 22241622 TI - Avian reovirus triggers autophagy in primary chicken fibroblast cells and Vero cells to promote virus production. AB - Avian reovirus (ARV) is an important cause of disease in poultry. Although ARV is known to induce apoptosis in infected cells, the interaction between ARV and its target cells requires further elucidation. In this report, we show that the ARV isolate strain GX/2010/1 induces autophagy in both Vero and primary chicken embryonic fibroblast (CEF) cells based on the appearance of an increased number of double-membrane vesicles, the presence of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) dot formation, and the elevated production of LC3II. We further demonstrate that the class I phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway contributes to autophagic induction by ARV infection. Moreover, treatment of ARV-infected cells with the autophagy inducer rapamycin increased viral yields, while inhibition of the autophagosomal pathway using chloroquine led to a decrease in virus production. Altogether, our studies strongly suggest that autophagy may play a critical role in determining viral yield during ARV infection. PMID- 22241624 TI - Otologic complications of cotton swab use: one institution's experience. AB - OBJECTIVES/HYPOTHESIS: To evaluate the indications for observation versus surgery in the management of cotton swab-induced tympanic membrane perforations (TMP). STUDY DESIGN: Institutional review board-approved retrospective cohort study of 1,540 patients with a diagnosis of TMP from 2001 to 2010. Patients with a cotton swab injury were subdivided into two groups: observation and surgery. METHODS: Data collection included demographics, symptoms, surgery type, and pre- and postintervention audiometry. Successful outcomes were defined as healed TMP; resolution/improvement of vertigo, tinnitus, or facial nerve paralysis; and/or closure of the air-bone gap (ABG). RESULTS: Fifty-four of 1,540 patients presented with a cotton swab-induced TMP. Four of the 54 patients (7.4%) underwent delayed surgical repair with 100% success. Preoperatively, one patient had a facial nerve paralysis and two had vertigo with confirmed perilymphatic fistulae (PLF). Postoperatively, the facial nerve paralysis resolved, and one patient had mild vertigo. Fifty of 54 patients opted to forego surgery with 35 patients available for follow-up. Thirty-four (97%) of the 35 patients had spontaneous healing. The average time to perforation closure was 1.75 months. Twelve of 35 patients had no ABG after healing. CONCLUSIONS: Observation is an appropriate consideration for patients who have a TMP due to a cotton swab injury. Surgical intervention should be offered early when a PLF is suspected, or if facial paralysis, severe vertigo, and/or profound sensorineural hearing loss are present. As otolaryngologists, we should be reluctant to offer surgical intervention of an acute injury without significant symptoms as most patients will heal spontaneously within 2 months. PMID- 22241625 TI - Evaluation of the antiplasmodial and cytotoxicity potentials of husk fiber extracts from Cocos nucifera, a medicinal plant used in Nigeria to treat human malaria. AB - Nigeria is an African country where transmission of malaria occurs all year round and where most inhabitants use plants as remedies against parasitic diseases, including malaria. Some of such medicinal plants have their antimalarial efficacies already demonstrated experimentally, active compounds isolated and the mechanism of drug action suggested. Decoction of Cocos nucifera husk is used in the middle belt region of Nigeria as an antimalarial remedy. In our current studies, we tested extracts from husks of four varieties of C. nucifera, all collected in Brazil, where the plant fruit is popularly named 'coco'. The husks of coco mestico, amarelo, anao and gigante collected in the Northeast of Brazil were used to prepare extracts at the Chemistry Department, Federal University of Alagoas (UFAL), which were then tested for their antiplasmodial activities, cytotoxicities and hemolytic activities in vitro. Only the hexane extract of coco mestico was active against the blood forms of Plasmodium falciparum human malaria parasite maintained in continuous culture. Most extracts presented selectivity indices of <10, while hexane extract of coco mestico had a selectivity index of 35, meaning that the extract is not toxic. The isolation of the active compounds from coco mestico husks has not yet been done. PMID- 22241627 TI - Nine case series with phototoxic dermatitis related to Chenopodium album. AB - Chenopodium album L. ssp. album is a common plant species worldwide, especially in humid areas. Sun exposure after oral intake of the plant can lead to sunburn like rashes owing to its furocoumarin content. In this article, we reported nine patients who developed dermatitis with edema, erythema and necrosis on the face and dorsum of the hands. Each was exposed to sunlight after eating selemez (the vernacular name of C. album L. ssp. album). The plant samples analyzed by an expert botanist were described as C. album L. ssp. album belonging to Chenopodiacea family. PMID- 22241626 TI - Effects of morin-5'-sulfonic acid sodium salt (NaMSA) on cyclophosphamide-induced changes in oxido-redox state in rat liver and kidney. AB - Cyclophosphamide (CPX) is an anticancer drug with immunosuppressive properties. Its adverse effects are partly connected to the induction of oxidative stress. Some studies indicate that water-soluble derivative of morin-morin-5'-sulfonic acid sodium salt (NaMSA) exhibits strong antioxidant activity. The aim of present study was to evaluate the effect of NaMSA on CPX-induced changes in oxido-redox state in rat. Experiment was carried out on Wistar rats divided in three experimental groups (N = 12) receiving: 0.9% saline, CPX (15 mg/kg) or CPX (15 mg/kg) + NaMSA (100 mg/kg), respectively, and were given intragastrically for 10 days. Malondialdehyde (MDA) and glutathione (GSH) concentrations and superoxide dismutase (SOD) activity were determined in liver and kidneys. Catalase (CAT) activity was assessed only in liver. Treatment with CPX resulted in significant decrease in MDA level in both tissues, which was completely reversed by NaMSA treatment only in liver. In comparison to the control group significant decrease in SOD activity were observed in both tissues of CPX receiving group. In kidneys this parameter was fully restored by NaMSA administration. CPX evoked significant decrease in GSH concentration in kidneys, which was completely reversed by NaMSA treatment. No significant changes were seen in GSH levels and CAT activity between all groups in liver. Results of our study suggest that CPX may exert significant impact on oxido-redox state in both organs. NaMSA fully reversed the CPX-induced changes, especially MDA level in liver, SOD activity and GSH concentration in kidneys and it may be done by enhancement of activity/concentration of endogenous antioxidants. PMID- 22241628 TI - Amelioration of cisplatin-induced toxicity in mice by carotenoid meso-zeaxanthin. AB - Carotenoid meso-zeaxanthin ((3R, 3'S)-beta, beta-carotene-3,3'-diol [MZ]) was evaluated for its protective effect against cisplatin-induced nephrotoxicity in Swiss albino mice. Oral administration of MZ was started 5 days prior to cisplatin (16 mg/kg body weight, intraperitoneally as a single dose) injection. Animals in all groups were killed 72 h after cisplatin treatment. In serum, renal function markers like urea and creatinine, which were drastically elevated in cisplatin-treated control animals, were found to be decreased significantly by MZ pretreatment. Cisplatin-induced myelosuppression was also found to be significantly ameliorated by MZ as evident from the increase in white blood cell count, bone marrow cellularity and number of maturing monocytes in MZ-treated animals when compared with cisplatin alone-treated control animals. The levels of antioxidant enzymes-superoxide dismutase, catalase and glutathione peroxidase-as well as the glutathione level in the kidney were decreased after cisplatin treatment. But the levels were markedly increased by the carotenoid treatment in a dose-dependent manner. Addition of MZ was found to inhibit singlet oxygen produced by toluidine blue in vitro. Moreover, administration of MZ to the animals inhibited increased lipid peroxidation, conjugated dienes and hydroperoxides that are formed in the kidney by cisplatin administration. The results of histopathological analysis supported the protective potential of MZ against cisplatin-induced toxicity. PMID- 22241629 TI - Short-term exposure of 4-hydroxynonenal induces mitochondria-mediated apoptosis in PC12 cells. AB - 4-Hydroxynonenal (4-HNE) is one of the most reactive aldehydic by-products of lipid peroxidation. The role of 4-HNE in the etiology of various neurodegenerative disorders including cerebral ischemia/reperfusion, Alzheimer's disease, Parkinson's disease, etc. has been documented. We and others have reported that long-term toxic insults of 4-HNE triggers apoptotic signals and oxidative stress in various cells. However, the status of apoptosis following short-term exposure and underlying mechanisms has not been explored so far. We studied the apoptotic changes in PC12 cells receiving short-term exposure of 4 HNE. A significant dose-dependent induction in reactive oxygen species (ROS) and early response markers (c-Fos, c-Jun, and GAP-43) were observed in cells exposed to 4-HNE (10, 25, and 50 uM) for 1h. Following the exposure of PC12 cells to 4 HNE, the levels of protein and messenger RNA expressions of P(53), Bax, and caspase 3 were significantly upregulated, whereas the levels of Bcl(2) was downregulated. We could record the apoptotic signals and ROS generation in PC12 cells receiving 4-HNE exposure for such a short period of time. Induction in the expression and activity of caspase 3 has also indicated the mitochondrial mediation in the apoptosis induction. PMID- 22241630 TI - Altered expressions of MMP-2, MMP-9, and TIMP-2 in placentas from women exposed to lead. AB - Experimental studies have shown that prenatal exposure to lead (Pb) produces morphological changes related to extracellular matrix remodelling. To analyse whether the matrix metalloproteinases (MMPs), particularly MMP-2, MMP-9, and the tissue inhibitor of metalloproteinases-2 (TIMP-2), are associated with morphological alterations found in placentas, the expression of these enzymes was evaluated by immunohistochemical and image analyses in placentas of women with histories of environmental exposure to Pb. The median maternal concentration of Pb in blood was 4.68 ug/dL (x = 5.85 +/- 6.48 ug/dL). Significant differences related to the exposure to Pb were not detected in newborn or placenta weight. MMP-2, MMP-9, and TIMP-2 were expressed in the syncytiotrophoblast layer of placental villi. A significant increase in both MMP-2 and MMP-9 was observed in placentas of women with concentrations of Pb in blood >=4.68 ug/dL (p = 0.01 and 0.03 for MMP-2 and MMP-9, respectively) and decrease in TIMP-2 expression (p = 0.01) resulted in a significant increase in MMP-2/TIMP-2 ratio (p < 0.01). Increased expression of MMPs may be induced to aid in repairing placental tissue damaged by the exposure to Pb and that TIMP-2 decreases its expression to permit tissue repair. Increased expression of MMPs may be important to consider as a mechanism for generating placental abnormalities and in the induction of preterm delivery or abortion. PMID- 22241631 TI - On the mechanism of the palladium-catalyzed beta-arylation of ester enolates. AB - The palladium-catalyzed beta-arylation of ester enolates with aryl bromides was studied both experimentally and computationally. First, the effect of the ligand on the selectivity of the alpha/beta-arylation reactions of ortho- and meta fluorobromobenzene was described. Selective beta-arylation was observed for the reaction of o-fluorobromobenzene with a range of biarylphosphine ligands, whereas alpha-arylation was predominantly observed with m-fluorobromobenzene for all ligands except DavePhos, which gave an approximate 1:1 mixture of alpha-/beta arylated products. Next, the effect of the substitution pattern of the aryl bromide reactant was studied with DavePhos as the ligand. We showed that electronic factors played a major role in the alpha/beta-arylation selectivity, with electron-withdrawing substituents favoring beta-arylation. Kinetic and deuterium-labeling experiments suggested that the rate-limiting step of beta arylation with DavePhos as the ligand was the palladium-enolate-to-homoenolate isomerization, which occurs by a beta?H-elimination, olefin-rotation, and olefin insertion sequence. A dimeric oxidative-addition complex, which was shown to be catalytically competent, was isolated and structurally characterized. A common mechanism for alpha- and beta-arylation was described by DFT calculations. With DavePhos as the ligand, the pathway leading to beta-arylation was kinetically favored over the pathway leading to alpha-arylation, with the palladium-enolate to-homoenolate isomerization being the rate-limiting step of the beta-arylation pathway and the transition state for olefin insertion its highest point. The nature of the rate-limiting step changed with PCy(3) and PtBu(3) ligands, and with the latter, alpha-arylation became kinetically favored. The trend in selectivity observed experimentally with differently substituted aryl bromides agreed well with that observed from the calculations. The presence of electron withdrawing groups on these bromides mainly affected the alpha-arylation pathway by disfavoring C-C reductive elimination. The higher activity of the ligands of the biaryldialkylphosphine ligands compared to their corresponding trialkylphosphines could be attributed to stabilizing interactions between the biaryl backbone of the ligands and the metal center, thereby preventing deactivation of the beta-arylation pathway. PMID- 22241632 TI - Occupational exposure to particles and incidence of stroke. AB - OBJECTIVES: This paper aims to investigate the relation between occupational exposure to particles, particle size, and the incidence of ischemic and hemorrhagic stroke. METHODS: The cohort included all manual workers identified from the Swedish National Census in 1980, who were alive as of 1 January 1987. First time events of ischemic or hemorrhagic stroke during the period 1987-2005 were identified through linkage to the Hospital Discharge Register and the National Cause of Death Register. A job-exposure matrix for exposure to small (<1 um) and large (>1 um) particles was developed and applied. Hazard ratios (HR) were estimated by Cox regression with adjustment for age, socioeconomic group, and residential area. RESULTS: Increased HR of ischemic stroke were found among both women and men occupationally exposed to small as well as large particles for >=5 years. The risks were higher for workers exposed for >=5 years compared to "ever exposed" participants indicating a dose-response relationship, but no trend with exposure intensity was observed. A tentative association between particle exposure and hemorrhagic stroke was also found. CONCLUSIONS: Occupational exposure to small and large particles was associated with increased risks of ischemic stroke. Further studies are needed to explore the relationships between exposure to different types of particles and various doses and the occurrence of stroke among women as well as men. PMID- 22241633 TI - Neurological complications of hemodialysis: state of the art. AB - Neurological complications frequently affect chronic kidney disease patients. They are important causes of morbidity and mortality. We present a review of neurological complications affecting hemodialysis patients, focusing on classical and new aspects. Neurological complications can be classified as central or peripheral, but they also include other conditions such as muscle and autonomic disorders. Neurological complications in hemodialysis patients are often underdiagnosed and undertreated. Dialysis treatment can modify the clinical pattern and the course of neurological complications, but it may also directly induce some specific, dialysis-related complications. A strict collaboration between nephrologists, neurologists and other specialists can potentially improve prevention and management of these disorders and improve quality of life for hemodialysis patients. PMID- 22241634 TI - Body mass index has no effect on rate of progression of chronic kidney disease in subjects with type 2 diabetes mellitus. AB - BACKGROUND: The incidences of obesity and chronic kidney disease (CKD) are reaching epidemic levels. Recently obesity has been associated with the development of CKD. However, it is unclear whether obesity is a risk factor for the progression of CKD. This study investigated the effect of raised body mass index (BMI, calculated as kg/m2) on the rate of CKD progression in a group of patients with CKD and type 2 diabetes mellitus. METHODS: The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a large epidemiological study conducted in Manchester, UK. From the CRISIS database, we assessed the rate of progression of CKD in 229 adults who met the inclusion criteria. Baseline measurements such as BMI, estimated glomerular filtration rate (eGFR) and systolic and diastolic blood pressure were collected. eGFR measurements were obtained during follow-up to calculate the rate of eGFR change (DeltaeGFR). Linear regression analysis and independent sample t-test were used in data analysis. RESULTS: After a mean follow-up period of 31 months, linear regression analysis showed no relationship between DeltaeGFR and BMI. Furthermore, independent sample t-test comparing the obese (BMI =30) and nonobese (BMI <30) groups' DeltaeGFR showed no statistical significance (p=0.572). Similar results were observed after stratification according to CKD stages 3, 4 and 5. CONCLUSION: Raised BMI did not influence the rate of progression of chronic kidney disease in patients with type 2 diabetes mellitus. PMID- 22241635 TI - Establishing goals of volume management in critically ill patients with renal failure. AB - BACKGROUND: Volume management remains a challenging component of caring for the critically ill. Renal failure complicates fluid management. We sought to identify relationships between delta blood volume and physiology-based targets for both the adequacy of left ventricular filling (stroke volume index [SVI]) and preload dependency (stroke volume variability [SVV]) in patients undergoing dialysis in the intensive care unit. METHODS: Patients undergoing dialysis with an arterial line in place were eligible. Delta blood volume was measured during dialysis along with simultaneous SVI and SVV via an arterial pressure cardiac output monitor. Patients were dichotomized as "negative" fluid strategy if fluid was removed, or "positive" fluid strategy if fluid was added during renal replacement therapy. Delta blood volume's association with SVI and SVV was examined separately by fluid strategy group. RESULTS: A total of 26 patients (11 continuous and 15 intermittent dialysis) were investigated. Compared with that in patients with negative fluid strategy, SVV was significantly higher at baseline in patients with positive fluid strategy, while baseline SVI was significantly lower. Fluid removal was associated with significant increases to SVV in both strategy groups. Fluid removal was associated with significant decreases to SVI, and this effect was similar regardless of fluid strategy. CONCLUSION: Physiologic variables assessing cardiac performance (SVI) and preload responsiveness (SVV) provide simple yet meaningful targets when one is determining the best approach for volume management in critically ill patients undergoing dialysis. PMID- 22241636 TI - Risk factors associated with increased left ventricular mass index in chronic kidney disease patients evaluated using echocardiography. AB - BACKGROUND: It is still not clear which factors are associated with left ventricular mass index (LVMI) in chronic kidney disease (CKD) patients, based on the patient's physical and biochemical parameters at the time of echocardiography. The objective of the present study was to identify factors associated with LVMI in CKD patients (predialysis patients), using echocardiography. METHODS: Physical, biochemical and LVMI data evaluated by echocardiography were retrospectively analyzed in 930 CKD patients in Juntendo University Hospital, Tokyo, Japan. RESULTS: Levels of systolic blood pressure (SBP) and hemoglobin (Hb) were independent risk factors for increased LVMI in multivariate regression analysis. SBP was significantly correlated with LVMI (r=0.314, p<0.0001). The level of Hb was inversely correlated with LVMI (r= 0.372, p<0.0001). LVMI increased with decreasing renal function. SBP was significantly higher in patients with left ventricular hypertrophy (LVH) in CKD stages 2 and 5, and Hb was significantly lower in patients with LVH in stages 4 and 5 than in the group without LVH. CONCLUSIONS: It is important to treat hypertension and anemia to prevent LVH in CKD patients. These findings have some therapeutic implications for treatment strategies for predialysis patients. PMID- 22241637 TI - Podocalyxin-positive glomerular epithelial cells in urine correlate with a positive outcome in FSGS. AB - BACKGROUND: Parietal epithelial cells (PECs) and podocytes are the 2 epithelial cell types in the glomerulus. In contrast to podocytes, PECs have the ability to proliferate lifelong, and they can transdifferentiate into other cell types. We previously published that excretion of podocalyxin (PDX)-positive PECs in the urine correlates with disease activity in different glomerular diseases. METHODS: In this analysis we investigated whether excretion of PDX-positive cells in the urine might have a prognostic value for proteinuria development and kidney function in focal segmental glomerulosclerosis (FSGS). RESULTS: We found that patients diagnosed with FSGS and with significant excretion of PDX-positive cells in the urine had a negative change in serum creatinine in the follow-up analysis. In contrast to that, FSGS-patients without excretion of PDX-positive cells showed a positive change in serum creatinine. There was a significant negative correlation between PDX-positive cells in the urine and change in serum creatinine. Mean change in urine protein in FSGS patients with excretion of PDX positive cells in the urine did not differ significantly from patients with no cell excretion, but we could demonstrate a negative correlation between PDX positive cells and change in total urine protein. CONCLUSIONS: Our data suggest that FSGS patients excreting large amounts of PDX-positive cells in their urine have a better outcome regarding kidney function and proteinuria compared with patients without excretion of PDX-positive cells. These data imply that PDX positive cells have a positive effect on podocyte regeneration in FSGS patients. PMID- 22241638 TI - Depression in dialysis patients and its association with nutritional markers and quality of life. AB - BACKGROUND: Depression is the most widely prevalent psychiatric disorder in dialysis and can result in a lower quality of life (QoL) and probably a worse nutritional status. The aim of this study was to evaluate the associations among depression, QoL and nutritional status in hemodialysis. METHODS: This study included 104 patients on dialysis longer than 3 months, aged 18-65 years. Their nutritional status was assessed according to body mass index (BMI), serum albumin and phase angle; QoL was assessed using the SF-36 questionnaire, and their risk of depression was measured using the Beck Depression Inventory (BDI). Associations among depression, QoL and nutritional status were assessed using Fisher's exact test, and correlations between continuous variables were examined by Pearson's coefficient. RESULTS: Depression was detected in 65.3% of patients, and all of the dimensions of QoL were compromised, with the worst values observed for role-functioning physical (RP) and general health (GH). A negative correlation between the dimensions of QoL and BDI score was observed. Serum albumin was significantly correlated with general health (GH), and phase angle with physical functioning (PF). CONCLUSION: A high prevalence of depression was detected, as well as reduced mean scores for QoL. BDI score was significantly correlated with both physical and mental components of QoL. Phase angle was associated with physical functioning (PF) and physical component summary scales (PCS), whereas no nutritional marker was associated with the BDI score. The periodic monitoring of depression should be implemented in hemodialysis, in addition to monitoring QoL and nutritional status. A better understanding of these relationships could result in a better efficiency of dialysis treatment. PMID- 22241639 TI - Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. AB - BACKGROUND: Pentoxifylline (PTF) is a potential therapeutic agent in chronic kidney disease due to its antiinflammatory and antiproteinuric effects that may influence the progression of renal disease. SUBJECTS AND METHODS: We conducted a prospective randomized trial of 91 patients with estimated glomerular filtration rate (eGFR) <60 ml/min, calculated with 4-variable Modification of Diet in Renal Disease (MDRD-4) Study equation. Patients were randomly assigned to treatment with PTF 400 mg (twice a day) (n=46) or to continue their usual therapy (n=45). Clinical, biochemical and inflammatory parameters were measured at baseline, and at 6 and 12 months of treatment. The objective of the study was to analyze the effect of PTF treatment on inflammatory markers and secondarily the effect on renal disease progression. RESULTS: Baseline characteristics were similar in the 2 groups. High-sensitivity C-reactive protein (hs-CRP), serum fibrinogen and TNF alpha decreased significantly in patients treated with PTF in comparison with the control group at 12 months (p=0.002, p=0.001 and p=0.000, respectively). Median urinary albumin excretion did not decrease with PTF treatment. In the PTF group, there was no significant change in eGFR after 12 months (from 42.3 +/- 10.2 to 44.7 +/- 11.3 ml/min per 1.73 m(2)), whereas in the control group there was a worsening by the end of the study (from 40.1 +/- 12.4 to 35.7 +/- 13.4 ml/min per 1.73 m(2)) (p=0.000 between groups). CONCLUSIONS: PTF treatment decreases inflammatory markers in chronic kidney disease and stabilizes renal function. PMID- 22241640 TI - Do topical antibiotics reduce exit site infection rates and peritonitis episodes in peritoneal dialysis patients? The Pan Thames Renal Audit. AB - BACKGROUND AND OBJECTIVES: Peritonitis is the major cause of peritoneal dialysis (PD) technique failure. Prophylactic topical antibiotics have been reported to reduce peritoneal dialysis catheter exit site infections (ESI) and peritonitis rates. METHODS: We audited the effect of different exit site practices in the 12 Pan Thames and South East England PD centres, on ESIs and peritonitis between 2005 and 2008. RESULTS: PD patients used prophylactic mupirocin (n=1,270), gentamicin (n=502) and no prophylactic antibiotics (n=1,203); annualised ESI rates were reduced with mupirocin (median 0.18, interquartile range [IQR] 0.13 0.23, patient episodes per year, vs. median 0.32, IQR 0.24-0.69, for no antibiotic prophylaxis, p<0.01). Gentamicin treatment was not significantly lower (median 0.29, IQR 0.21-0.47). Staphylococcal ESIs accounted for 39.6% in the no antibiotic group and fell to 25.7% with mupirocin and 28.2% with gentamicin. Despite the reduction in ESIs, there was no significant reduction in peritonitis rates (no antibiotics: median 0.56, IQR 0.5-0.65; mupirocin: median 0.55, IQR 0.53-0.75; and gentamicin: median 0.47, IQR 0.32-0.65). In particular, mupirocin did not reduce Staphylococcus aureus peritonitis rates. CONCLUSIONS: Topical antibiotics have been reported to reduce both ESI and peritonitis rates in controlled trials, and although in this audit of routine clinical practice, topical mupirocin did reduce overall ESI rates and both mupirocin and gentamicin reduced S. aureus ESIs, neither reduced overall peritonitis rates. PMID- 22241641 TI - Reversal of diabetic nephropathy: lessons from pancreas transplantation. AB - Pancreas transplantation is the only therapeutic intervention able to achieve and maintain long-term euglycemia, without risks of hypoglycemia; this makes it possible to test the impact of normoglycemia in the different stages of diabetic nephropathy. Pancreas and islet transplantation in animal models prevent the development of diabetic nephropathy lesions and ameliorate or reverse established glomerular lesions. In type 1 diabetic patients, pancreas transplantation, performed simultaneously or after kidney transplantation, has been shown to prevent the recurrence of diabetic glomerulopathy lesions. The established lesions of diabetic nephropathy have been considered to be irreversible; pancreas transplantation alone allows us to test whether this is true. To this end, we studied renal structure before and 5 and 10 years after pancreas transplantation in 8 nonuremic type 1 diabetic patients. These patients, with a long diabetes duration, had established diabetic nephropathy lesions at the time of transplantation. We report that diabetic glomerulopathy lesions, unchanged at 5 years post pancreas transplantation, significantly improved after 10 years, with complete normalization of glomerular structure in most patients. Thus this study demonstrates that the lesions of diabetic nephropathy are reversed by long-term normoglycemia and that the human kidney has the potential in humans to obtain a substantial architectural remodeling of the glomerular and tubular structures toward healing. PMID- 22241642 TI - Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases. PMID- 22241643 TI - Prokaryotic diversity in sediments beneath two polar glaciers with contrasting organic carbon substrates. AB - Microbial ecosystems beneath glaciers and ice sheets are thought to play an active role in regional and global carbon cycling. Subglacial sediments are assumed to be largely anoxic, and thus various pathways of organic carbon metabolism may occur here. We examine the abundance and diversity of prokaryotes in sediment beneath two glaciers (Lower Wright Glacier in Antarctica and Russell Glacier in Greenland) with different glaciation histories and thus with different organic carbon substrates. The total microbial abundance in the Lower Wright Glacier sediment, originating from young lacustrine sediment, was an order of magnitude higher (~8 * 10(6) cells per gram of wet sediment) than in Russell Glacier sediment (~9 * 10(5) cells g(-1)) that is of Holocene-aged soil origin. 4% of the microbes from the Russell Glacier sediment and 0.04-0.35% from Lower Wright Glacier were culturable at 10 degrees C. The Lower Wright Glacier subglacial community was dominated by Proteobacteria, followed by Firmicutes. The Russell Glacier library was much less diverse and also dominated by Proteobacteria. Low numbers and diversity of both Euryarchaeota and Crenarchaeota were found in both sediments. The identified clones were related to bacteria with both aerobic and anaerobic metabolisms, indicating the presence of both oxic and anoxic conditions in the sediments. PMID- 22241644 TI - Physicochemical studies on glycation-induced structural changes in human IgG. AB - Glycation of biomolecules leads to the formation of advanced glycation end products (AGEs). Glycation of immunoglobulin G (IgG) has been implicated in autoimmune diseases such as rheumatoid arthritis (RA). In this study, human IgG was glycated with physiological concentration of glucose. The changes induced in IgG were analyzed by UV, fluorescence, circular dichroism, and Fourier transform infrared (FTIR) spectroscopy; thermal denaturation studies, native, and Sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis. The ketoamine moieties and carbonyl content were also quantitated in glycated IgG. We report structural perturbations, increased carbonyl content, and ketoamine moieties in the glycated IgG. This may interfere with the normal function of IgG and may contribute to initiation of arthritic complications. AGEs damaged IgG may be used as a biomarker for early detection of RA and the associated secondary complications. PMID- 22241645 TI - The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury. AB - The pathological consequences of traumatic head injury result largely from the opening of the mitochondrial permeability transition pore (mPTP). The mPTP opens due to a decrease in brain phosphorylation energy resulting in a further decrease in brain ATP production and a measurable increase in brain heat generation and temperature. The increase in brain temperature can be measured transcranially by near infrared spectroscopy which can be used to diagnose traumatic brain injury (TBI) and to monitor treatment. Effective therapy of TBI can be achieved by closure of the mPTP by administration of cyclosporine A or by oral administration of ketone body esters. While ketosis has previously been known to prevent damage from TBI, the availability of oral ketone esters presents the first practical modality of achieving therapeutic levels of ketone bodies. PMID- 22241647 TI - National trends in oropharyngeal cancer surgery and the effect of surgeon and hospital volume on short-term outcomes and cost of care. AB - OBJECTIVES/HYPOTHESIS: The past 2 decades have witnessed an increase in the use of chemoradiation in the treatment of oropharyngeal cancer. We sought to characterize contemporary patterns of oropharyngeal cancer surgical care and the effect of volume on surgical care and short-term outcomes. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Using the Nationwide Inpatient Sample database, temporal trends in oropharyngeal cancer surgical care were evaluated in 75,828 cases performed from 1993 through 2008, and relationships between volume and mortality, complications, length of stay, and costs were evaluated in 29,030 cases performed from 2003 through 2008 using regression analysis, adjusting for patient and provider characteristics. RESULTS: Oropharyngeal cancer surgery from 2001 through 2008 was associated with increased use of high-volume hospitals (odds ratio [OR], 2.2; P = .016); an increase in tonsil (OR, 1.4; P < .001) and tongue base (OR, 1.3; P = .001) tumors; an increase in patients aged 40 to 64 years (OR, 1.5; P < .001); a decrease in partial glossectomy (OR, 0.8; P < .001), pharyngectomy (OR, 0.8; P = .003), mandibulectomy (OR, 0.6; P < .001) and laryngectomy procedures (OR, 0.6; P < .001); and an increase in prior radiation (OR, 1.7; P = .026), advanced comorbidity (OR, 1.4; P = .007), and wound complications (OR, 1.5; P = .029), compared to 1993 through 2000. High-volume hospitals were significantly associated with pharyngectomy (OR, 2.6; P = .001), while high-volume surgeons were associated with flap reconstruction (OR, 1.6; P = .005) and prior radiation (OR, 2.6; P = .013). After controlling for all other variables, a statistically significant interaction was observed between high-volume surgeons and high-volume hospitals, with reduced hospital-related costs for surgery performed by high volume surgeons at high-volume hospitals. CONCLUSIONS: These data reflect changing trends in the epidemiology and primary management of oropharyngeal cancer, with meaningful differences in the type of surgical care provided by high volume providers. PMID- 22241648 TI - Detection of nickel in fish organs with a two-photon fluorescent probe. AB - Molecular imaging by two-photon microscopy (TPM) has become indispensable to the study of biology/medicine owing to its capability of imaging deep inside intact tissues. To make TPM a more-versatile tool, a large variety of two-photon probes are needed. Herein, we report a new two-photon fluorescent probe (ANi2) that can be excited by 750 nm femtosecond pulses and detect Ni(2+) ions in fresh fish organs at 90-175 MUm depth without interference from the pH value or from other biologically relevant species through the use of TPM. TPM images of fish organs labeled with ANi2 revealed that Ni(2+) ions accumulate in fish organs in the order: kidney > heart > gill >= liver. Moreover, a linear relationship was found between the two-photon-excited fluorescence (TPEF) and the inductively coupled plasma mass spectrometry intensities (ICP-MS), thereby allowing the quantitative measurement of Ni(2+) ions in live tissue. PMID- 22241650 TI - Treatment of infantile hemangiomas with the 595-nm pulsed dye laser using different pulse widths in an Asian population. AB - INTRODUCTION: The pulsed dye laser (PDL) using varying fluences and pulse durations have been used to treat hemangiomas. This study aims to examine the efficacy and safety of the 595-nm PDL for the treatment of infantile hemangiomas using short (1.5-3 milliseconds) versus long (10 milliseconds) pulse durations and high fluences. MATERIALS AND METHODS: This is a retrospective study of patients with hemangiomas (n = 23) treated with the 595-nm PDL from 2003 to 2007. The parameters used for the short pulse duration group (n = 15) were 7-mm spot size, fluence 10-13.5 J/cm(2) and dynamic cooling device (DCD) spray duration of 50 milliseconds and delay of 30 milliseconds. For the long pulse duration group (n = 8), parameters were 7-mm spot size, fluence 10.5-14.5 J/cm(2) and DCD spray duration of 40 milliseconds and delay of 20 milliseconds. RESULTS: The number of treatments required to achieve complete or near complete resolution of the hemangioma ranged from 3 to 14 for the short pulse duration group (mean: 8) and for the long pulse duration group, 4-14 treatments (mean: 9). For both groups, more treatments were needed to achieve clearance of mixed hemangiomas (n = 13) compared to superficial hemangiomas (n = 10) (on average, 4-5 treatments more). Erythema, edema, and purpura lasted for about a week in the short pulse duration group but only 2 days in the long pulse duration group. There was no ulceration or hypertrophic scarring noted in both groups. CONCLUSION: Both short and long pulse durations using moderately high fluences are equally effective in the treatment of infantile hemangiomas. Shorter pulse durations had a slightly higher incidence of side effects compared to longer pulse duration in our patients with darker phototypes. Hemangiomas are tumors with relatively large diameter blood vessels and this provides the basis for the use of longer pulse durations. PMID- 22241651 TI - In vitro and in vivo uncaging and bioluminescence imaging by using photocaged upconversion nanoparticles. PMID- 22241649 TI - Disease and genetic contributions toward local tissue volume disturbances in schizophrenia: a tensor-based morphometry study. AB - Structural brain deficits, especially frontotemporal volume reduction and ventricular enlargement, have been repeatedly reported in patients with schizophrenia. However, it remains unclear whether brain structural deformations may be attributable to disease-related or genetic factors. In this study, the structural magnetic resonance imaging data of 48 adult-onset schizophrenia patients, 65 first-degree nonpsychotic relatives of schizophrenia patients, 27 community comparison (CC) probands, and 73 CC relatives were examined using tensor-based morphometry (TBM) to isolate global and localized differences in tissue volume across the entire brain between groups. We found brain tissue contractions most prominently in frontal and temporal regions and expansions in the putamen/pallidum, and lateral and third ventricles in schizophrenia patients when compared with unrelated CC probands. Results were similar, though less prominent when patients were compared with their nonpsychotic relatives. Structural deformations observed in unaffected patient relatives compared to age similar CC relatives were suggestive of schizophrenia-related genetic liability and were pronounced in the putamen/pallidum and medial temporal regions. Schizophrenia and genetic liability effects for the putamen/pallidum were confirmed by regions-of-interest analysis. In conclusion, TBM findings complement reports of frontal, temporal, and ventricular dysmorphology in schizophrenia and further indicate that putamen/pallidum enlargements, originally linked mainly with medication exposure in early studies, also reflect a genetic predisposition for schizophrenia. Thus, brain deformation profiles revealed in this study may help to clarify the role of specific genetic or environmental risk factors toward altered brain morphology in schizophrenia. PMID- 22241653 TI - Emotional processing following recovery from anorexia nervosa. AB - OBJECTIVE: Evidence suggests that poor emotional processing perpetuates anorexia nervosa (AN); however, emotional processing following recovery and interactions between aspects of processing remain unknown. This study examined beliefs about emotions, emotional tolerance and avoidance and emotion suppression to preserve relationships in recovered AN patients. It also explored whether beliefs about emotion are related to emotional avoidance. DESIGN: A cross-sectional between groups design was employed. METHOD: Currently ill (n = 40), recovered AN patients (n = 24) and a sample of healthy controls (n = 48) completed measures of clinical and demographic background in addition to the Beliefs About Emotions, Distress Tolerance and Silencing the Self emotional processing questionnaires. RESULTS: Recovered and healthy control groups were comparable (except for higher externalised self-perception in recovered participants) and both had better emotional processing than current AN patients. Beliefs about emotions correlated with level of emotional avoidance. CONCLUSIONS: This study demonstrates functional levels of emotional processing following recovery from AN. It substantiates models proposing that maladaptive beliefs about emotions link to emotional avoidance and supports inclusion of these factors as treatment foci. PMID- 22241654 TI - Collection of clinical and epidemiological data for genetic linkage and association studies. AB - Modern gene-mapping can include linkage studies, which correlate the presence of disease to broad genomic regions in either small or large family units, and association studies, which can narrow the location of a disease-predisposing trait to a single gene using either case-control or family data. This unit provides an overview of key concepts and presents guidelines for collecting diagnostic, epidemiological, and genealogical data from potential study participants. The commentary discusses the use of publicly available data from online resources, methods for evaluating evidence of genetic versus environmental influences in a disease or disease-related endophenotype, and use of e-forms to capture data electronically. PMID- 22241655 TI - Identifying functional annotation for noncoding genomic sequences. AB - The recent success of genome-wide association studies has generated a trove of biologically significant variants implicated in human disease. However, many, if not most, of these variants fall in noncoding regions that have traditionally lacked much functional annotation. New data sets and tools allow for a more detailed assessment of potential importance of noncoding genetic variants. An overview of types of regulatory annotation that are currently available, and approaches to analyzing this data are provided with emphasis on usage of the UCSC genome browser. PMID- 22241656 TI - Determination of sialylated and neutral oligosaccharides in urine by mass spectrometry. AB - This protocol describes a method to allow for the detection of specific oligosaccharide fragments in urine by tandem mass spectrometry. The detection of fragments with specific masses indicates the presence of one of a number of diseases where the deficiency of lysosomal enzymes involved in the degradation of the glyco- moieties of glycoproteins is present in the patient. This method describes the derivatization of oligosaccharides present in urine with phenyl-1 methylpyrazolone, which renders them hydrophobic, thus allowing desalting with Combi cleanup columns prior to injection. This method allows the detection of storage of oligosaccharides, which may indicate the presence of one of the infantile Pompe disease, alpha-mannosidosis, Gm1-gangliosidosis, Sandhoff disease, sialidosis, galactosialidosis, I-cell disease, and aspartylglucosaminuria. PMID- 22241657 TI - Interpretation of genomic copy number variants using DECIPHER. AB - Many patients suffering from developmental disorders have submicroscopic deletions or duplications affecting the copy number of dosage-sensitive genes or disrupting normal gene expression. Many of these changes are novel or extremely rare, making clinical interpretation problematic and genotype/phenotype correlations difficult. Identification of patients sharing a genomic rearrangement and having phenotypes in common increases certainty in the diagnosis and allows characterization of new syndromes. The DECIPHER database is an online repository of genotype and phenotype data whose chief objective is to facilitate the association of genomic variation with phenotype to enable the clinical interpretation of copy number variation (CNV). This unit shows how DECIPHER can be used to (1) search for consented patients sharing a defined chromosomal location, (2) navigate regions of interest using in-house visualization tools and the Ensembl genome browser, (3) analyze affected genes and prioritize them according to their likelihood of haploinsufficiency, (4) upload patient aberrations and phenotypes, and (5) create printouts at different levels of detail. By following this protocol, clinicians and researchers alike will be able to learn how to characterize their patients' chromosomal imbalances using DECIPHER. PMID- 22241658 TI - Molecular diagnosis of hearing loss. AB - This unit discusses an approach to identifying a genetic etiology in an individual with nonsyndromic hearing loss. The unit begins with a discussion of the decision-making process that can be used to determine whether specific genes and/or a large gene panel should be used for molecular diagnosis of a patient presenting with nonsyndromic hearing loss. Next, two protocols are presented: (1) a full gene-sequencing assay to identify mutations in the GJB2 gene (encoding connexin 26), the most common cause of congenital hearing loss, and (2) an assay to detect the presence of the GJB6-D13S1830 deletion, a 342-kb deletion that causes hearing loss in homozygosity or in combination with a single GJB2 mutation. Finally, the unit ends with a strategy for determining the clinical significance of the test results, which can be challenging given the extensive genetic heterogeneity associated with hearing loss. PMID- 22241659 TI - Optimal wavelengths for vein-selective photothermolysis. AB - BACKGROUND AND OBJECTIVE: Oxyhemoglobin (HbO(2)) has been regarded as the primary target chromophore for selective photothermolysis of vascular malformations. In theory, venous lesions might be better treated with wavelengths preferentially absorbed by deoxyhemoglobin (Hb). STUDY DESIGN/MATERIALS AND METHODS: Wavelength dependent fluence thresholds for photocoagulation of whole human blood were determined in glass capillary samples with measured oxygen saturation levels. Pulsed dye lasers at 585, 590, 595, 600, 633 nm, a 694 nm ruby laser, a 755 nm alexandrite laser, and a 1,064 nm Nd:Yag laser were used, all with 1.5-3 milliseconds pulse width and similar exposure spot size. RESULTS: Selectivity (a lower fluence threshold) for venous blood was maximal at 694 nm, and significant at 595, 600, 633, and 755 nm. At 633 nm, a wavelength with strong relative absorption by metHb, selectivity for venous blood was much less than expected. The Nd:YAG laser at 1,064 nm showed significant selectivity for arterial blood. CONCLUSION: Preferential photocoagulation of venous blood is possible at wavelengths with a high Hb/HbO(2) absorption coefficient ratio. Laser-induced metHb may also affect wavelength-dependent selective photothermolysis. Venular malformations such as port wine stains could potentially be treated more selectively with ~630-780 nm sources. Nd:YAG laser pulses at 1,064 nm tend to affect arterial more than venous blood. PMID- 22241660 TI - Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis. AB - OBJECTIVES/HYPOTHESIS: A new concept of IgG4-related sclerosing sialadenitis characterized by high serum IgG4 levels and tissue infiltration of IgG4 expressing plasmacytes has recently been proposed. To determine appropriate serum levels of IgG4 for monitoring disease activity, a total of 36 serum samples and eight tissue samples from patients with IgG4-related sclerosing sialadenitis were studied. STUDY DESIGN: A retrospective clinical study at Yamagata University School of Medicine. METHODS: The patient group consisted of six males and four females with an average age of 60 years (range, 47-74 years). Serum levels of IgG4 and the density of IgG4-positive plasmacytes in affected tissues were studied. RESULTS: All patients had elevated serum IgG4 levels (>135 mg/dL), and IgG4-positive plasmacytes (IgG4+ plasma cells/IgG+ plasma cells >50%) were observed in the involved salivary glands. Six patients with IgG4-related sclerosing sialadenitis with high IgG4/IgG ratios and prominent infiltration of IgG4-positive plasmacytes in the involved salivary glands had systemic complications, including pancreatitis, retroperitoneal fibrosis, and/or inflammatory pseudotumor of the lung after swelling of the salivary glands. All six of these patients were successfully treated with systemic corticosteroids. CONCLUSIONS: In the six patients with systemic complications, treatment with systemic corticosteroids reduced the salivary gland enlargement and lowered serum IgG4 concentrations. These results suggest that IgG4 plays an important role in the pathogenesis of IgG4-related sclerosing sialadenitis, and that IgG4 levels and IgG4/IgG ratios may be used as additional indicators of disease activity and as biomarkers for potential life-threatening complications. PMID- 22241661 TI - Monodisperse REPO4 (RE = Yb, Gd, Y) hollow microspheres covered with nanothorns as affinity probes for selectively capturing and labeling phosphopeptides. AB - Rare-earth phosphate microspheres with unique structures were developed as affinity probes for the selective capture and tagging of phosphopeptides. Prickly REPO(4) (RE = Yb, Gd, Y) monodisperse microspheres, that have hollow structures, low densities, high specific surface areas, and large adsorptive capacities were prepared by an ion-exchange method. The elemental compositions and crystal structures of these affinity probes were confirmed by energy-dispersive spectroscopy (EDS), powder X-ray diffraction (XRD), and Fourier-transform infrared (FTIR) spectroscopy. The morphologies of these compounds were investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen-adsorption isotherms. The potential ability of these microspheres for selectively capturing and labeling target biological molecules was evaluated by using protein-digestion analysis and a real sample as well as by comparison with the widely used TiO(2) affinity microspheres. These results show that these porous rare-earth phosphate microspheres are highly promising probes for the rapid purification and recognition of phosphopeptides. PMID- 22241662 TI - The many faces of autonomy. AB - What does autonomy mean from a moral point of view? Throughout Western history, autonomy has had no less than four different meanings. The first is political: the capacity of old cities and modern states to give themselves their own laws. The second is metaphysical, and was introduced by Kant in the second half of the 18th century. In this meaning, autonomy is understood as an intrinsic characteristic of all rational beings. Opposed to this is the legal meaning, in which actions are called autonomous when performed with due information and competency and without coercion. This last meaning, the most frequently used in bioethics, is primarily legal instead of moral. Is there a proper moral meaning of the word autonomy? If so, this would be a fourth meaning. Acts can only be called moral when they are postconventional (using the terminology coined by Lawrence Kohlberg), inner-directed (as expressed by David Riesman), and responsible (according to Hannah Arendt). Such acts are autonomous in this new, fourth, and to my mind, the only one proper, moral meaning. The goal of ethics cannot be other than forming human beings capable of making autonomous and responsible decisions, and doing so because they think this is their duty and not because of any other nonmoral motivation, like comfort, convenience, or satisfaction. The goal of ethics is to promote postconventional and mature human beings. This was what Socrates tried to do with the young people of Athens. And it is also the objective of every course of ethics and of any process of training. PMID- 22241665 TI - Real-time guidance of thermal and ultrashort pulsed laser ablation in hard tissue using inline coherent imaging. AB - BACKGROUND AND OBJECTIVE: During tissue ablation, laser light can be delivered with high precision in the transverse dimensions but final incision depth can be difficult to control. We monitor incision depth as it progresses, providing feedback to ensure that material removal occurs within a localized target volume, reducing the possibility of undesirable damage to tissues below the incision. MATERIALS AND METHODS: Ex vivo cortical and cancellous bone was ablated using pulsed lasers with center wavelengths of 1,064 and 1,070 nm, while being imaged in real-time using inline coherent imaging (ICI) at rates of up to 300 kHz and axial resolution of ~6 um. With real-time feedback, laser exposure was terminated before perforating into natural inclusions of the cancellous bone and verified by brightfield microscopy of the crater cross-sections accessed via side-polishing. RESULTS: ICI provides direct information about incision penetration even in the presence of intense backscatter from the pulsed laser and plasma emissions. In this study, ICI is able to anticipate structures 176 +/- 8 um below the ablation front with signal intensity 9 +/- 2 dB above the noise floor. As a result, the operator is able to terminate exposure of the laser sparing a 50 um thick layer of bone between the bottom of the incision to a natural inclusion in the cancellous bone. Versatility of the ICI system was demonstrated over a wide range of light-tissue interactions from thermal regime to direct solid-plasma transition. CONCLUSIONS: ICI can be used as non-contact real-time feedback to monitor the depth of an incision created by laser ablation, especially in heterogeneous tissue where ablation rate is less predictable. Furthermore, ICI can image below the ablation front making it possible to stop laser exposure to limit unintentional damage to subsurface structures such as blood vessels or nervous tissue. PMID- 22241664 TI - Prognosis of lymphoma in patients following treatment with 6 mercaptopurine/azathioprine for inflammatory bowel disease. AB - BACKGROUND: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective for induction and maintenance therapy of Crohn's disease (CD) and ulcerative colitis (UC). There is an increased risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with 6-MP/AZA. Little, however, is known about the prognosis of IBD patients treated with 6-MP/AZA who develop lymphoma. METHODS: We conducted a retrospective review of 8780 records from three tertiary IBD centers and the records of 600 lymphoma patients from an academic Hematology and Oncology Center. The primary endpoint variable was survival of IBD patients with a lymphoma diagnosis treated or not treated with 6-MP/AZA. A secondary endpoint was the relative survival rate (by gender, race, and ethnicity) extrapolated from the Surveillance Epidemiology and End Results (SEER) database, computed for each subject. RESULTS: Fourteen IBD patients were diagnosed with lymphoma. Twelve had CD and two had UC. Seven patients had treatment with 6-MP/AZA and seven had not. Two patients who received 6-MP/AZA died (both 1 year after diagnosis) and two patients who had not received 6-MP/AZA died (one after 2 years, another 3 years after diagnosis), all from lymphoma. Survival at last follow-up was similar to expected survival based on extrapolated SEER data for both 6-MP/AZA treated and untreated patients. CONCLUSIONS: We found no differences of survival with lymphoma between IBD patients and expected survival for the general population. Also, the prognosis for those IBD patients treated with 6-MP/AZA was not worse than lymphoma patients not treated with 6-MP/AZA. Statistical analysis, however, was limited by the small sample size and heterogeneity of the patients studied. PMID- 22241666 TI - Discovery of a full-color-tunable fluorescent core framework through direct C-H (hetero)arylation of N-heterocycles. PMID- 22241668 TI - Risk of cancer in patients with inflammatory bowel disease and venous thromboembolism: a nationwide cohort study. AB - BACKGROUND: Venous thromboembolism (VTE) may be a harbinger of cancer. Inflammatory bowel disease (IBD) is known to increase the risk of VTE, but it is unclear whether VTE in IBD patients is also a marker for occult cancer. We assessed the risk of cancer after VTE in IBD patients. METHODS: We conducted a population-based cohort study by linking Danish medical registries during 1978 2008. We calculated standardized incidence ratios (SIRs) by comparing observed cancer incidence after VTE in IBD patients with that expected based on national cancer incidence in the Danish population. RESULTS: A total of 895 IBD patients with VTE were followed for a total of 5290 person-years. During the first year of follow-up, 28 (3.1%) patients were diagnosed with cancer, corresponding to an SIR of 3.2 (95% confidence interval [CI]: 2.2, 4.7). Patients with ulcerative colitis or Crohn's disease had similar relative risks (SIR = 3.1 [95% CI: 1.9, 4.9] and SIR = 3.5 [95% CI: 1.7, 6.3], respectively). In IBD patients <55 years the SIR was 5.7 (95% CI: 2.3, 11.8) and in patients >=55 years the SIR was 2.8 (95% CI: 1.8, 4.3). During the second and subsequent years of follow-up 61 cancers were diagnosed (SIR = 1.2 [95% CI: 0.92, 1.6]). CONCLUSIONS: In patients with IBD a VTE event is not only a consequence of their disease, but might also be a marker of occult cancer. We suggest that IBD patients with VTE should follow the same diagnostic work-up guidelines as non-IBD VTE patients. PMID- 22241669 TI - Measurement of quetiapine and four quetiapine metabolites in human plasma by LC MS/MS. AB - There is interest in monitoring plasma concentrations of N-desalkylquetiapine in relation to antidepressant effect. A simple LC-MS/MS method for quetiapine and four metabolites in human plasma (50 MUL) has been developed to measure concentrations of these compounds attained during therapy. Analytes and internal standard (quetiapine-d8) were extracted into butyl acetate-butanol (10:1, v/v) and a portion of the extract analysed by LC-MS/MS (100 * 2.1 mm i.d. Waters Spherisorb S5SCX; eluent: 50 mmol/L methanolic ammonium acetate, pH* 6.0; flow rate 0.5 mL/min; positive ion APCI-SRM, two transitions per analyte). Assay calibration (human plasma calibrators) was linear across the ranges studied (quetiapine and N-desalkylquetiapine 5-800, quetiapine sulfoxide 100-15,000, others 2-100 ug/L). Assay validation was as per FDA guidelines. Quetiapine sulfone was found to be unstable and to degrade to quetiapine sulfoxide. In 47 plasma samples from patients prescribed quetiapine (prescribed dose 200-950 mg/day), the (median, range) concentrations found (ug/L) were: quetiapine 83 (7 748), N-desalkylquetiapine, 127 (7-329), O-desalkylquetiapine 12 (2-37), 7 hydroxyquetiapine 3 (<1-48), and quetiapine sulfoxide 3,379 (343-21,704). The analyte concentrations found were comparable to those reported by others except that the concentrations of the sulfoxide were markedly higher. The reason for this discrepancy in unclear. PMID- 22241670 TI - Acquisition of 3He ventilation images, ADC, T2* and B1 maps in a single scan with compressed sensing. AB - In imaging of human lungs with hyperpolarised noble gases, measurements of apparent diffusion coefficient (ADC) and relaxation time provide valuable information for the assessment of lung microstructure. In this work, a sequence was developed for interleaved acquisition of ventilation images, ADC, T(2)* and flip angle maps in a single scan from the human lungs with a single dose of inhaled (3)He at 3 T. Spatially registered ventilation images with parametric maps were obtained. The total acquisition time was reduced by random undersampling of the k-space and reconstruction using compressed sensing (CS). The gain in speed was used for an increase in spatial resolution. Mean ADC values from the fully sampled and undersampled CS data exhibit no statistically significant difference in a given subject. The mean T(2)* values, however, were found to differ significantly, which is attributed to the combined effect of low signal-to-noise ratio (SNR) of the fully sampled data and the smoothing effect inherent in CS reconstruction. PMID- 22241673 TI - Huntington's disease: objective assessment of posture--a link between motor and functional deficits. AB - BACKGROUND: Postural deficits in Huntington's disease are linked to functional impairment. We investigated whether assessment of center-of-mass variability using posturography provides objective and quantitative measures that correlate to the severity of motor phenotype, functional measures, and genotype as assessed by a disease burden score (based on repeat length and age). In addition, we investigated whether withdrawing visual feedback facilitates the detection of postural deficits. METHODS: Using a force plate, the ability of symptomatic Huntington's disease patients (n = 34) and controls (n = 20) to stand as stably as possible was assessed in eyes-open and eyes-closed conditions. RESULTS: All posturographic measures (DISTANCE, VELOCITY, and SURFACE of centre-of-mass mobility) were increased in patients and correlated to (1) the UHDRS Total Motor Score, (2) the UHDRS Total Functional Capacity, (3) the UHDRS Functional Assessment Score, and (4) the disease burden score. Correlations to motor and functional measures were stronger when visual feedback was provided. CONCLUSIONS: Posturography may provide useful objective and quantitative measures of postural motor dysfunction in Huntington's disease. PMID- 22241671 TI - Effects of Alzheimer's disease transgenes on neurochemical expression in the mouse brain determined by 1H MRS in vitro. AB - Transgenic models of human disease can be used to understand pathology and to discover biomarkers of disease presence, progression and response to therapy. Here we report a study of longitudinal metabolic differences between TASTPM transgenic Alzheimer's disease (AD) mice and their wild type counterparts using (1)H magnetic resonance spectroscopy (MRS) to look for potential biomarkers for use in AD research and drug discovery. Chloroform methanol extractions were performed on the brains of mice aged between 3 and 18 months. (1)H MR spectra were recorded from the aqueous fractions. Absolute metabolite concentrations, determined from resonance integrals relative to an internal standard, were analysed by 2-way ANOVA (genotype x age). Significant effects of age alone were identified for creatine, glutamine and total choline-containing compounds. There was a marked increase in creatine in the oldest (15-18 mo) TASTPM mice. The increase in creatine was unexpected and may be caused by osmotic stress in older animals as plaque load increases. Care should be taken when using creatine as a reference metabolite during scans of these animals in vivo. A significant effect of genotype alone was identified for myo-inositol (MI), which was higher in TASTPM mice at all ages. Succinate, glycerophosphocholine and choline all showed significant effects of age and genotype. No significant effects were detected in N-acetylaspartate (NAA) levels. Increased MI could be a marker of gliosis or microglial activation in TASTPM mice, but the absence of an age dependence for MI levels means it may be a biomarker of disease, but not of disease progression. Decreased succinate is indicative of disrupted neuronal energy metabolism, an effect that has been seen in human AD. PMID- 22241674 TI - Barriers to enrollment in inflammatory bowel disease randomized controlled trials: an investigation of patient perspectives. AB - BACKGROUND: Despite a sizeable inflammatory bowel disease (IBD) population in the United States, large trials in IBD have difficulty recruiting patients. Reasons for low enrollment are uncertain. Our objective was to investigate specific barriers to enrollment in clinical trials by determining aspects of study design, disease state, demographics, and previous experiences with research that influence a patient's willingness to participate. METHODS: Patients with Crohn's disease (CD) and ulcerative colitis (UC) at the Massachusetts General Hospital Crohn's and Colitis Center were surveyed. RESULTS: Most participants (61%) had participated in some clinical research previously, although 50% of those were not interested in participating in a future study. Frequent doctor visits (69%), requirement of colonoscopy (55%), or sigmoidoscopy (49%), and blinding (46%) were the biggest deterrent study requirements. With each addition of one of these components, potential enrollment fell from 43.2% (86) to 14.6% (29) interested patients. Respondents were likely to participate in studies that were open label (60%), initially randomized then open label (57.6%), or saw the same doctor (52.5%). Among those disinclined to participate, strategies to boost enrollment included monetary compensation, an open-label component, or providing the same doctor at each visit. Men and patients who were currently flaring were more likely to participate. CONCLUSIONS: Elements of study design negatively and positively influence willingness to participate. Invasive procedures, randomization, and frequent visits negatively influenced willingness to participate and as each of these components are added, a significant additive percent of potential subjects are lost. Strategies to further identify barriers to enrollment within IBD study populations should be pursued. PMID- 22241675 TI - Retracted: Terbium-sensitized fluorescence method for the determination of dopamine in biological fluids and tablet formulation. PMID- 22241676 TI - The 'mangrove sign' for velamentous umbilical cord insertion. PMID- 22241677 TI - BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy. AB - BACKGROUND: Because prostate cancer exhibits a great variability in clinical outcome, biomarkers that can be used in daily practice are needed to better stratify patients into prognostic groups. Since steroid hormones play a central role in the development and progression of prostate cancer, we aimed to analyze in a matched nested case-control study the value of molecules involved in steroid signaling, to predict recurrence after radical prostatectomy, independently from standard prognostic tools. METHODS: Among 1,200 patients treated by radical prostatectomy with negative margins with at least 4 years follow-up, 121 prostate cancers with biochemical relapse were matched after pathological reassessment with 121 cancers with identical clinicopathological features but without relapse. Immunohistochemistry was performed on tissue microarrays, using antibodies directed against molecules involved in androgen and estrogen signaling, including hormone receptors, enzymes (such as the five alpha reductases 1,2 and 3, aromatase, alpha-keto reductase 1C3 and squalene epoxidase), the breast cancer antiestrogen resistance 1 (BCAR1), and the proliferation marker Ki67. RESULTS: The median follow-up for patients without recurrence was 7 years. Both cell proliferation and BCAR1 expression were significantly associated with biochemical relapse, in univariate and multivariate analysis. In subgroup analysis, the sole predictive marker in patients with well-differentiated prostate cancer was BCAR1 (P = 0.004), whereas only proliferation (P = 0.001) was significantly associated with relapse in less-differentiated prostate cancer patients. CONCLUSIONS: BCAR1 is an independent predictor of recurrence after radical prostatectomy for "low risk" prostate cancer. The use of this biomarker may enable more individualized treatment approaches. PMID- 22241678 TI - Assessment of depressive symptoms and functional outcomes in patients with major depressive disorder treated with duloxetine versus placebo: primary outcomes from two trials conducted under the same protocol. AB - OBJECTIVE: Return of functional ability is a central goal in the treatment of major depressive disorder. We conducted two trials with the same protocol that was designed to assess functioning after 8 Weeks of treatment with duloxetine. METHODS: The a priori primary outcome was improvement in the Hamilton Depression Rating Scale (HAMD) item 7 (work/activities). Secondary outcomes included improvement in depressive symptoms assessed by the HAMD Maier subscale, and improvement in functioning assessed by the Sheehan Disability Scale (SDS), and the Social Adaptation Self-evaluation Scale (SASS). Patients were randomly assigned to duloxetine 60 mg/day (Trial I, n = 257; Trial II, n = 261) or placebo (Trial I, n = 127; Trial II, n = 131). Changes from baseline were analyzed using a mixed-effects model repeated measures approach. RESULTS: At Week 8, duloxetine was superior to placebo in improving HAMD work/activities (p < 0.001) in Trial II, but not Trial I (p = 0.051), and Maier scores (p < 0.01) in both trials. At Week 12, duloxetine was superior to placebo on improving SASS scores in both trials, and the SDS in Trial II. CONCLUSION: Treatment with duloxetine was associated with significant improvement in depressive symptoms compared with placebo, but improvement in HAMD work/activities was inconsistent at 8 weeks. PMID- 22241679 TI - Comparison of medical costs among patients using adalimumab and infliximab: a retrospective study (COMPAIRS). AB - BACKGROUND: Anti-tumor necrosis factor (TNF) medications have similar efficacy in Crohn's disease (CD), but have not been compared in the real world. This study compared health costs and utilization for patients with CD newly initiating anti TNF therapy with adalimumab (ADA) or infliximab (IFX) by using insurance data. METHODS: CD patients initiating ADA or IFX therapy were identified from the MarketScan database. ADA and IFX groups were matched using a propensity score. The primary endpoint was direct costs of healthcare for the 6 months following initiation. The secondary endpoints compared healthcare utilization between groups. RESULTS: After propensity matching, characteristics were similar between the ADA (n = 623) and IFX (n = 623) groups. During the 6-month interval following anti-TNF initiation, healthcare costs were significantly lower for ADA compared with IFX. Total healthcare cost was $18,885 for ADA and $24,355 for IFX, a difference in cost of $5,470 (P < 0.0001). CD-related costs made up the majority of the costs: $16,454 for ADA and $22,316 for IFX (P < 0.0001). The largest difference in cost was seen in outpatient visits: $2,082 difference between the two groups (P < 0.0001). Both all-cause and CD-related hospitalization decreased for both ADA and IFX groups. Emergency room and hospitalization use in the 6 month follow-up period was not statistically different between groups, although numerically slightly higher in the IFX group. CONCLUSIONS: Patients with CD using ADA had lower healthcare costs than patients using IFX; this difference was partly driven by outpatient medical costs. PMID- 22241680 TI - Deep sequencing study of the MTHFR gene to identify variants associated with myelomeningocele. AB - INTRODUCTION: Neural tube defects (NTDs) are congenital anomalies caused by a combination of genetic and environmental influences. A defect below the head region resulting in protuberance of meninges and nervous tissue is termed myelomeningocele (MM). MM, the most common NTD compatible with survival, occurs in approximately 1 in 1000 births worldwide. Maternal preconceptional and periconceptional folate supplementation reduces the risk of NTDs by up to 70%. A key enzyme in folate metabolism is 5, 10-methylene-tetrahydrofolate reductase (MTHFR). OBJECTIVES: Sequence the 12 exons of the MTHFR gene among 96 subjects with MM to identify variants potentially contributing to the disease trait. METHODS: Exons were amplified by polymerase chain reaction, and the products were sequenced with the Sanger method to reveal sequence variants compared to MTHFR reference sequences. Association of variants was examined by Fisher's test. RESULTS: A novel variant c.171+3G>T was identified in intron 1 in one affected subject. The variant was not found in the subject's unaffected mother's DNA, and the unaffected father's DNA was unavailable. We found significant differences in allele frequencies for seven SNPs in MM subjects compared with ethnically matched reference populations reported in the single nucleotide polymorphism database. CONCLUSION: We identified a novel variant c.171+3G>T in the MTHFR gene that potentially affects splicing in an affected subject. In addition, we observed five SNPs (rs13306561, rs2274976, rs2066462, rs12121543, and rs1476413) in the MTHFR gene not previously shown to associate with MM. The current study provides additional evidence that multiple variations in the MTHFR gene are associated with MM. PMID- 22241681 TI - Multi-modal quantitative MRI investigation of brain tissue neurodegeneration in multiple sclerosis. AB - PURPOSE: To investigate the utility of multimodal quantitative MRI (qMRI) and atlas-based methods to identify characteristics of lesion-driven injury and neurodegeneration in relapsing remitting multiple sclerosis (RRMS). MATERIALS AND METHODS: This work is health insurance portability and accountability act compliant. High resolution T1-weighted, dual echo, and fluid-attenuated inversion recovery and diffusion tensor MRI images were prospectively acquired on 68 RRMS patients (range, 25-58 years) and 68 age-matched controls. The data were analyzed using standardized human brain atlas-based tissue segmentation procedures to obtain regional volumes and their corresponding T2 relaxation times and DTI maps. RESULTS: Group-averaged brain atlas-based qMRI maps of T2, fractional anisotropy and diffusivities are visually presented and compared between controls and RRMS. The analysis shows a widespread injury in RRMS. Atrophy of the corpus callosum (CC) was substantial in RRMS. The qMRI attributes of the neocortex in combination with the CC such as T2 and diffusivities were elevated and correlated with disability. CONCLUSION: Using a standardized multimodal qMRI acquisition and analyses that accounted for lesion distribution we demonstrate that cerebral pathology is widespread in RRMS. Our analysis of CC and neocortex qMRI metrics in relation to disability points to a neurodegenerative injury component that is independent from lesions. PMID- 22241683 TI - Medication attitudes and beliefs in patients with psychotic and affective disorders on maintenance treatment. AB - RATIONALE: Patient attitudes and beliefs regarding the cost-benefits of medications may influence treatment adherence. However, beliefs and attitudes about psychotropic medications have not been well studied across different clinical populations. OBJECTIVE: This study sought to compare medication attitudes, beliefs, and clinical characteristics in patients with psychotic disorders versus those with affective disorders. METHOD: Clinician-rated and self report measures were used to assess the drug attitudes, beliefs, and clinical features of outpatients with affective and psychotic disorders on stable medications. RESULTS: There were no significant differences in the overall medication attitudes and beliefs scores between the clinical groups. The affective group, however, were less likely to believe that medications would prevent hospitalisation (p < 0.05) and were less likely to use an aid as a reminder to take their medication (p < 0.05). Medication attitudes and beliefs were found to have significant correlation with reported side effects (p < 0.01) but not with educational level and duration or severity of illness. CONCLUSIONS: Patients with psychotic disorders did not show more negative attitudes or beliefs about medication than those with affective disorders. It would be clinically important that equal care is taken to assess perceived drug side effects, and attitudes and beliefs about medications across diagnostic groups. PMID- 22241682 TI - Effect of dual inhibition of apoptosis and autophagy in prostate cancer. AB - PURPOSE: Targeting multiple anti-apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as ABT-737. Given recent studies demonstrating that autophagy is a resistance mechanism to multiple therapeutic agents in the setting of apoptotic inhibition, we hypothesized that hydroxychloroquine (HCQ), an anti-malarial drug that inhibits autophagy, will increase cytotoxicity of ABT-737. EXPERIMENTAL DESIGN: Cytotoxicity of ABT-737 and HCQ was assessed in vitro in PC-3 and LNCaP cells, and in vivo in a xenograft mouse model. The role of autophagy as a resistance mechanism was assessed by siRNA knockdown of the essential autophagy gene beclin1. ROS was measured by flow cytometry, and mitophagy assessed by the mCherry-Parkin reporter. RESULTS: Induction of autophagy by ABT-737 was a mechanism of resistance in prostate cancer cell lines. Therapeutic inhibition of autophagy with HCQ increased cytotoxicity of ABT-737 both in vitro and in vivo. ABT-737 induced LC-3 and decreased p62 expression by immunoblot in cell lines and by immunohistochemistry in tumors in vivo. Assessment of ROS and mitochondria demonstrated that ROS production by ABT-737 and HCQ was a mechanism of cytotoxicity. CONCLUSIONS: We demonstrated that autophagy inhibition with HCQ enhances ABT-737 cytotoxicity in vitro and in vivo, that LC-3 and p62 represent assessable markers in human tissue for future clinical trials, and that ROS induction is a mechanism of cytotoxicity. These results support a new paradigm of dual targeting of apoptosis and autophagy in future clinical studies. PMID- 22241685 TI - Thermal simulations in the human head for high field MRI using parallel transmission. AB - PURPOSE: To investigate, via numerical simulations, the compliance of the specific absorption rate (SAR) versus temperature guidelines for the human head in magnetic resonance imaging procedures utilizing parallel transmission at high field. MATERIALS AND METHODS: A combination of finite element and finite difference time-domain methods was used to calculate the evolution of the temperature distribution in the human head for a large number of parallel transmission scenarios. The computations were performed on a new model containing 20 anatomical structures. RESULTS: Among all the radiofrequency field exposure schemes simulated, the recommended 39 degrees C maximum local temperature was never exceeded when the local 10-g average SAR threshold was reached. On the other hand, the maximum temperature barely complied with its guideline when the global SAR reached 3.2 W/kg. The maximal temperature in the eye could very well rise by more than 1 degrees C in both cases. CONCLUSION: Considering parallel transmission, the recommended values of local 10-g SAR may remain a relevant metric to ensure that the local temperature inside the human head never exceeds 39 degrees C, although it can lead to rises larger than 1 degrees C in the eye. Monitoring temperature instead of SAR can provide increased flexibility in pulse design for parallel transmission. PMID- 22241684 TI - Chitin microparticles for the control of intestinal inflammation. AB - BACKGROUND: Chitin is a polymer of N-acetylglucosamine with the ability to regulate innate and adaptive immune responses. However, the detailed mechanisms of chitin-mediated regulation of intestinal inflammation are only partially known. METHODS: In this study chitin microparticles (CMPs) or phosphate-buffered saline (PBS) were orally administered to acute and chronic colitis models every 3 days for 6 consecutive weeks beginning at weaning age. The effects of this treatment were evaluated by histology, cytokine production, coculture study, and enteric bacterial analysis in dextran sodium sulfate (DSS)-induced colitis or T cell receptor alpha (TCRalpha) knockout chronic colitis models. RESULTS: Histologically, chitin-treated mice showed significantly suppressed colitis as compared with PBS-treated mice in both animal models. The production of interferon-gamma (IFN-gamma) was upregulated in the mucosa of chitin-treated mice compared with control mice. The major source of IFN-gamma-producing cells was CD4+ T cells. In mouse dendritic cells (DCs) we found that CMPs were efficiently internalized and processed within 48 hours. Mesenteric lymph nodes (MLNs) CD4+ T cells isolated from chitin-treated mice produced a 7-fold higher amount of IFN gamma in the culture supernatant after being cocultured with DCs and chitin as compared with the control. Proliferation of carboxyfluorescein succinimidyl ester (CFSE)(low) CD4+ T cells in MLNs and enteric bacterial translocation rates were significantly reduced in chitin-treated mice when compared with the control. In addition, CMPs improved the imbalance of enteric bacterial compositions and significantly increased interleukin (IL)-10-producing cells in noninflamed colon, indicating the immunoregulatory effects of CMPs in intestinal mucosa. CONCLUSIONS: CMPs significantly suppress the development of inflammation by modulating cytokine balance and microbial environment in colon. PMID- 22241688 TI - Incorporating financial protection into decision rules for publicly financed healthcare treatments. AB - Almost all health systems seek to offer some form of publicly financed healthcare insurance, and governments must therefore choose the size of the benefit package and the types of treatments to cover. Conventionally, the usual approach of economists has been to recommend choices on the basis of cost effectiveness of treatments, using metrics such as the 'cost per quality adjusted life year'. However, this approach is based on the assumption of health maximization subject to a budget constraint and ignores the potential impact of any additional concern with protecting individuals from the financial consequences of a health shock. Furthermore, it does not take account of the possible availability of complementary privately funded health care. This paper develops a model in which risk-averse individuals care about health but also place a value on protection from the financial consequences of rare but costly events. The paper shows how conventional cost-effectiveness analysis can readily be augmented to take account of financial protection objectives. The results depend on whether or not there exists a market in complementary privately funded health care. They have important implications for the methodology adopted by health technology assessment agencies and for the broader design of publicly funded health systems. PMID- 22241687 TI - Nitrogen-doped carbon nanotube-based bilayer thin film as transparent counter electrode for dye-sensitized solar cells (DSSCs). AB - Carbon nanotubes (CNTs) have been widely considered as one of the promising candidates for replacing fluorine-doped tin oxide (FTO)/platinum (Pt) electrodes to reduce the fabrication cost of dye-sensitized solar cells (DSSCs). Here, we report that a bilayer transparent film containing N-doped CNTs (which are highly catalytic) and normal CNTs (which are highly conductive) as a counter electrode in DSSCs results in efficiencies up to 2.18%, yet still maintains a good transparency with a transmittance of approximately 57% at 550 nm. PMID- 22241686 TI - Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate. AB - This study examined the association between 49 markers in the Runt-related transcription factor 2 (RUNX2) gene and nonsyndromic cleft lip with/without cleft palate (CL/P) among 326 Chinese case-parent trios, while considering gene environment (GxE) interaction and parent-of-origin effects. Five single nucleotide polymorphisms (SNPs) showed significant evidence of linkage and association with CL/P and these results were replicated in an independent European sample of 825 case-parent trios. We also report compelling evidence for interaction between markers in RUNX2 and environmental tobacco smoke (ETS). Although most marginal SNP effects (i.e., ignoring maternal exposures) were not statistically significant, eight SNPs were significant when considering possible interaction with ETS when testing for gene (G) and GxE interaction simultaneously or when considering GxE alone. Independent samples from European populations showed consistent evidence of significant GxETS interaction at two SNPs (rs6904353 and rs7748231). Our results suggest genetic variation in RUNX2 may influence susceptibility to CL/P through interacting with ETS. PMID- 22241689 TI - Mixed effect Poisson log-linear models for clinical and epidemiological sleep hypnogram data. AB - Bayesian Poisson log-linear multilevel models scalable to epidemiological studies are proposed to investigate population variability in sleep state transition rates. Hierarchical random effects are used to account for pairings of subjects and repeated measures within those subjects, as comparing diseased with non diseased subjects while minimizing bias is of importance. Essentially, non parametric piecewise constant hazards are estimated and smoothed, allowing for time-varying covariates and segment of the night comparisons. The Bayesian Poisson regression is justified through a re-derivation of a classical algebraic likelihood equivalence of Poisson regression with a log(time) offset and survival regression assuming exponentially distributed survival times. Such re-derivation allows synthesis of two methods currently used to analyze sleep transition phenomena: stratified multi-state proportional hazards models and log-linear generalized estimating equations (GEE) models for transition counts. An example data set from the Sleep Heart Health Study is analyzed. Supplementary material includes the analyzed data set as well as the code for a reproducible analysis. PMID- 22241693 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: does the 'seatbelt sign' predict intra-abdominal injury after motor vehicle trauma in children? AB - A short cut review was carried out to establish whether the seat belt sign was a significant predictor of intra-abdominal injury in children involved in motor vehicle collisions. 51 papers were found using the reported searches, of which three presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that seatbelt sign appears to be associated with an increased risk of intra-abdominal injuries, especially gastrointestinal and pancreatic injuries. PMID- 22241690 TI - Deficiency of N-acetylgalactosamine in O-linked oligosaccharides of IgA is a novel biologic marker for Crohn's disease. AB - BACKGROUND: Ideal biomarkers are required to be developed for the diagnosis and prediction of the treatment of inflammatory bowel disease (IBD). We have reported that alteration of N-linked oligosaccharides of immunoglobulin (Ig) G is a novel diagnostic marker of IBD. Oligosaccharide alterations of IgA, however, have not been investigated in IBD patients. METHODS: N- and O-linked oligosaccharides of serum IgA purified from 32 patients with Crohn's disease (CD), 30 patients with ulcerative colitis (UC), and 30 healthy volunteers (HV) were analyzed with high performance liquid chromatography and mass spectrometry. Enzymes related to oligosaccharide attachment were investigated. RESULTS: N-linked oligosaccharides of IgA were not different between IBD and HV. In contrast, the number of N acetylgalactosamines per hinge glycopeptide (GalNAc/HP) in the O-linked oligosaccharides of IgA was significantly decreased in patients with CD compared with UC and HV. GalNAc/HP had high sensitivity and specificity for discriminating between CD and HV based on receiver operating characteristic analysis. Lower GalNAc/HP was associated with more severe disease activity of CD. Changes in GalNAc/HP levels in 6 weeks after treatment with infliximab were associated with the clinical activity of CD at 30 weeks. GalNAc transferase expression of naive B cells and extent of GalNAc attachment in IgA were significantly decreased by interleukin-21 in vitro. CONCLUSIONS: The number of GalNAc attached in the IgA O linked glycans of CD patients was significantly decreased, and strongly correlated with the clinical activity. Alterations of GalNAc attachment in IgA could be useful as a novel diagnostic and prognostic marker of CD. PMID- 22241694 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: should capnography be routinely used during procedural sedation in the Emergency Department? AB - A short cut review was carried out to establish whether capnography should be routinely used during procedural sedation in Emergency Departments. 206 papers were found using the reported searches, of which nine presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is that capnography may provide early warning of ventilatory changes that could result in hypoxia. PMID- 22241695 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: can pregabalin effectively diminish acute herpetic pain and reduce the incidence of post-herpetic neuralgia? AB - A short cut review was carried out to establish whether pregabalin can reduce acute herpetic pain and reduce post herpetic neuralgia. 48 papers were found using the reported searches, of which one presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. It is concluded that pregabalin does not seem to decrease the intensity of pain related to acute herpes zoster. Moreover, it does not decrease the incidence of post herpetic neuralgia. More research is needed on this topic to clarify this issue [corrected]. PMID- 22241697 TI - The biological function of the WD40 repeat-containing protein p55/Caf1 in Drosophila. AB - BACKGROUND: The p55 family WD40 repeat-containing histone chaperone proteins are components of several chromatin regulatory complexes (such as PRC2, NURF and CAF 1) and interact with histone H4, yet their functional relevance in vivo is unclear. RESULTS: Here we use Drosophila as a genetic model to dissect the function of p55/Caf1 during development. In agree with a recent report, we find that p55 is essential for Drosophila development and is required for cell proliferation and viability. However, our data further demonstrate that histone H3K27 di-/tri-methylation and PRC2-mediated gene silencing still occur normally when p55 is missing. p55 is also implicated in bridging chromatin regulatory complexes to the chromatin by binding to histone H4, but we find that a transgene of p55 whose binding pocket is disrupted could still functionally substitute the wild-type p55 for the survival. CONCLUSIONS: Our studies suggest that p55 is not crucial for PRC2-mediated gene silencing in vivo, and the vital function of p55 is probably not dependent on its interaction with histone H4. PMID- 22241698 TI - Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC. AB - Imatinib has been accepted as frontline treatment for patients with chronic myeloid leukaemia (CML), and patients generally receive doses ranging from 400 to 800 mg/day. Previous studies have demonstrated that maintaining imatinib plasma levels (IMPLs) >1000 ng/mL leads to improved responses and long-term outcomes. However, IMPLs vary among patients because of factors such as drug-drug interactions, adherence, toxicity and differential levels of expression of cellular efflux/influx proteins. In this study, IMPLs were analysed in 191 patients with CML and were compared with achievement of molecular and cytogenetic responses (CyR). IMPLs were also correlated with renal and hepatic dysfunction. Additionally, self-reported adherence was monitored. The median and mean IMPLs were 994 ng/mL and 1070 +/- 686 ng/mL, respectively, with 96 patients (50%) achieving plasma levels >1000 ng/mL. Self-reported patient compliance was 98%. Patients who achieved a complete CyR (CCyR) had significantly higher IMPLs (1078 +/- 545 ng/mL) than those without CyR (827 +/- 323 ng/mL, p = 0.045). When grouped together, patients who achieved a CCyR or partial CyR had significantly higher IMPLs than patients who achieved a minimal CyR or did not achieve a CyR (1066 ng/mL vs 814 ng/mL, p = 0.002). There was no significant difference observed in the IMPLs between patients who achieved molecular responses (n = 177) on treatment (major molecular response, 976 +/- 385 ng/mL versus complete molecular response, 1138 +/- 809 ng/mL, p = 0.387). Mean IMPLs were similar in patients with or without renal or hepatic impairment. Overall, this study confirmed previous reports that higher IMPLs correlate with clinical responses and demonstrated that imatinib exposure did not differ in patients with or without liver and/or renal dysfunction. The use of IMPL testing and patient diaries may be practical tools for the management of imatinib therapy in patients with CML. PMID- 22241699 TI - Integrated models of care in managing inflammatory bowel disease: a discussion. AB - The World Health Organization has recommended the integrated model of care as the current best practice of care, and, in recent years, it has been gaining popularity worldwide in various settings. However, there have been very few reports on applications of this model to the care of patients with gastrointestinal problems and no reports in the case of inflammatory bowel disease (IBD). However, several IBD centres worldwide have been using the model as part of their standard care. This discussion paper aims to bring together these units' shared experiences with a range of integrated models of care in order to identify common features and provide recommendations on aspirational care for IBD patients. PMID- 22241701 TI - Composite carbon nanotube/carbon electrodes for electrical double-layer super capacitors. PMID- 22241702 TI - Synthesis of 2'-deoxy-5-(methylselenyl)cytidine and Se-DNAs for structural and functional studies. PMID- 22241703 TI - Mitochondrial DNA 8993T>G mutation in a child with ornithine transcarbamylase deficiency and leigh syndrome: an unexpected association. AB - MC, female, is the third child of a nonconsanguineous Portuguese couple, born after an uneventful pregnancy and delivery. A positive family history of ornithine transcarbamylase deficiency, associated with the IVS8+1 G>A mutation in the ornithine transcarbamylase gene, prompted prenatal diagnosis with identification of the same mutation in the proband. During an episode of Klebsiella pneumoniae sepsis at 1.5 months of age, lactic acidosis and moderate hyperammonemia were noticed. After a short asymptomatic period, progressive neurologic symptoms, with normal ammonemia, persistent hyperlactacidemia, and typical lesions in brain computed tomography (CT) scan led to a diagnosis of Leigh syndrome. Mitochondrial respiratory chain complex V was reduced in the liver. The mtDNA 8993T>G mutation was identified in the liver, muscle, and blood (82%-87% heteroplasmy). She died at 6 months of age. This case represents a benign phenotype of ornithine transcarbamylase deficiency, associated with a severe mitochondrial respiratory chain disorder due to an mtDNA pathogenic mutation. PMID- 22241704 TI - Efficacy of constraint-induced therapy on functional performance and health related quality of life for children with cerebral palsy: a randomized controlled trial. AB - To better generalize training effects to the context of daily living, home-based constraint-induced therapy has been proposed. Therapeutic success of constraint induced therapy is limited as to whether the improvements in functional performance can be transferred to quality of life. This randomized controlled trial aimed to investigate the efficacy of home-based constraint-induced therapy on functional performance and health-related quality of life. Twenty-two children with spastic unilateral cerebral palsy (6-8 years, 10 boys) were randomly assigned to receive constraint-induced therapy or traditional rehabilitation. Home-based constraint-induced therapy had immediate and maintaining effects on motor efficacy and functional performance and induced greater gains in health related quality of life in the long run than in the short term. The home-based constraint-induced therapy protocol (relatively moderate intensity and shortened constraint time), which might balance the effectiveness and compliance of participants and caregivers, may be an effective alternative to conventional constraint-induced therapy. PMID- 22241705 TI - Changing child neurology training: evolution or revolution? AB - Child neurology training must change as our understanding of the diseases of the developing nervous system increases. A proposed child neurology training path leading to certification in child neurology would eliminate all but 3 months of adult neurology training; however gaining approval for a new Accreditation Council for Graduate Medical Education (ACGME) training program would be an arduous task. I review why this change would add significant administrative and financial burdens and how this change in training could negatively affect the education of child neurology residents. I believe that modifications of the current training requirements already underway could achieve the same aims with fewer losses. PMID- 22241706 TI - Vincristine-related neuropathy versus acute inflammatory demyelinating polyradiculoneuropathy in children with acute lymphoblastic leukemia. AB - The objective of this study was to evaluate whether electroneurography could help in differentiating between vincristine-induced neuropathy and acute inflammatory demyelinating polyradiculoneuropathy. We performed electroneurography in 7 children from September 2006 to March 2009 admitted to receive chemotherapy including vincristine for acute lymphoblastic leukemia, in whom severe acute limb weakness developed, suggesting vincristine-induced neuropathy. Three of 7 patients had electroneurography, suggesting acute inflammatory demyelinating polyradiculoneuropathy. They received intravenous immunoglobulins without discontinuing chemotherapy, and within 10 days their electroclinical conditions improved. Although electroneurography showed only absent F waves, preventing us from reaching a definitive neurophysiological diagnosis of acute inflammatory demyelinating polyradiculoneuropathy, children's presenting clinical manifestations, their disease course, and rapid and complete recovery after intravenous immunoglobulins argued strongly in its favor. A prompt, correct differential diagnosis of vincristine neuropathy and acute inflammatory demyelinating polyradiculoneuropathy in patients with acute lymphoblastic leukemia receiving vincristine is essential to improve disease outcome and prolong life expectancy. PMID- 22241708 TI - Dominantly inherited nonprogressive cerebellar hypoplasia identified in utero. AB - Cerebellar hypoplasia is the hallmark of a heterogeneous group of disorders that are caused by genetic and metabolic disorders. Prenatal identification of cerebellar hypoplasia and accurate prediction of outcome are challenging. Autosomal dominant nonprogressive cerebellar ataxia is a rare disorder that typically presents with early hypotonia and delayed motor milestones followed by the onset of mild ataxia and occasionally cognitive impairment. We present a case of a mother and her female fetus. Fetal sonography and magnetic resonance imaging (MRI) showed generalized cerebellar hypoplasia. The mother had mild learning difficulties and clinically showed minor features of cerebellar ataxia. Her MRI also demonstrated extreme cerebellar hypoplasia. The diagnosis of autosomal dominant nonprogressive cerebellar ataxia was suggested. This is the first report of prenatal diagnosis of autosomal dominant nonprogressive cerebellar ataxia. We recommend obtaining a family history, examining the parents, and when appropriate obtaining an MRI before counseling parents of a fetus with a brain malformation. PMID- 22241707 TI - Ophthalmoplegic "migraine" or recurrent ophthalmoplegic cranial neuropathy: new cases and a systematic review. AB - Ophthalmoplegic migraine is a poorly understood neurologic syndrome characterized by recurrent bouts of head pain and ophthalmoplegia. By reviewing cases presenting to our centers in whom the phenotype has been carefully dissected, and systematically reviewing all published cases of ophthalmoplegic migraine in the magnetic resonance imaging (MRI) era, this review sets out to clearly define the syndrome and discuss possible etiologies. We found that in up to one-third of patients, the headache was not migrainous or associated with migrainous symptoms. In three-quarters of the cases involving the third nerve, there was focal nerve thickening and contrast enhancement on MRI. Observational data suggest systemic corticosteroids may be beneficial acutely. The etiology remains unclear, but may involve recurrent bouts of demyelination of the oculomotor nerve. "Ophthalmoplegic migraine" is a misnomer in that it is probably not a variant of migraine but rather a recurrent cranial neuralgia. A more appropriate name might be "ophthalmoplegic cranial neuropathy." PMID- 22241709 TI - Friedreich-like ataxia as an initial manifestation of mitochondrial DNA 8344A>G mutation. AB - A previously healthy 10-year-old girl presented with subacute onset of ataxia and acute-onset cardiac and pulmonary failure. Magnetic resonance imaging (MRI) of the brain showed symmetric T2 fluid-attenuated inversion recovery hyperintensities in the dorsal pons, medulla, and inferior cerebellar peduncles; nerve conduction velocities and electromyography demonstrated a sensorimotor axonal neuropathy consistent with Friedreich ataxia. Within 12 months, the patient fully recovered and molecular testing of the frataxin gene was unremarkable. Two years later, the patient returned with acute neurologic decompensation and died one month later from progressive demyelination of the brainstem. Mitochondrial DNA sequencing revealed a mutation at 8344A>G in transfer RNA lysine with heteroplasmy at 98% consistent with a diagnosis of a primary mitochondrial disorder. PMID- 22241710 TI - Autonomic dysfunction in childhood Guillain-Barre syndrome. AB - This investigation correlated incidence and degree of autonomic dysfunction with the degree of motor impairment in children hospitalized with Guillain-Barre syndrome. Motor weakness varies, as does the effect on autonomic function including heart rate, vasomotor stability, sweating, continence, and blood pressure. After Institutional Review Board approval, hospitalized patients with Guillain-Barre syndrome <19 years were included for retrospective chart review. There were 26 patients (12 boys), with a mean age of 11.3 years (range, 6-17 years). The average hospital stay was 10.6 days. Twenty-four (92%) recovered by 2 to 6 months without functional disability. Bradycardia and sweating disturbances were not observed. Hypertension occurred in 18 of 26 (69%) and tachycardia in 20 of 26 (77%) patients. The proportion of children with hypertension and/or tachycardia increased, as did the motor disability grade (P < .043 and P < .018, respectively). Hypertension occurred 9 to 15 days from symptom onset and within 24 to 48 hours of maximum motor disability in 89%. Multiple autonomic disturbances compound the course of childhood Guillain-Barre syndrome. PMID- 22241711 TI - Human tail: nature's aberration. AB - Human tail refers to a congenital cutaneous appendix protruding from the lumbosacral region. It is usually associated with an underlying spina bifida occulta, a form of spinal dysraphism. A contiguous fibrolipoma can sometimes be seen extending from the subcutaneous portion of the tail into the inferior spinal cord, resulting in tethered cord syndrome. Management of such lesions includes complete neurologic examination and magnetic resonance imaging. Early diagnosis and microsurgical intervention can prevent development or progression of severe neurologic defects in later life. PMID- 22241712 TI - Patterns of cognitive and fine motor deficits in a case of Dandy-Walker continuum. AB - Cerebellar vermian hypoplasia in the context of Dandy-Walker complex is a relatively common disorder associated with a variety of cognitive and behavioral deficits in addition to impairment in motor control. Few studies, however, have examined the neuropsychological profiles of children with isolated hypoplasias of the cerebellum. Herein, we report a 6-year-old girl with Dandy-Walker continuum presenting with mild mental retardation and an inability to produce intelligible speech, despite adequate comprehension of single items and simple instructions. She was able to articulate vowels but not consonants, and fine motor function was deficient. Visual memory was intact for single items but not for multiple items, and visuospatial perception was impaired. An inability to form intelligible speech is not typically reported in cases of isolated vermian hypoplasia. The case extends our knowledge of the phenotypes associated with cerebellar hypoplasia and its relation to fine motor and articulatory control. PMID- 22241713 TI - Fetal alcohol spectrum disorders--implications for child neurology, part 2: diagnosis and management. AB - In part 1, we discussed the mechanism of alcohol exposure, dosimetry, and the teratogenic pathways of damage to the fetus. In part 2, we review the diagnosis of fetal alcohol spectrum disorders and the developmental implications of prenatal alcohol exposure. Fetal alcohol spectrum disorders are associated with increased rates of mental retardation, seizure disorders, brain malformations, and premature mortality. The risk of comorbid disorders is increased among this population, which enhances phenotype severity and complexity of management. Recurrence rates are high and younger siblings tend to be more severely affected. Detection of prenatal alcohol use warrants substance abuse intervention, which can avoid exposure in subsequent pregnancies. Fetal alcohol spectrum disorders are common developmental disorders with a phenotype that is influenced by both age and development and require long-term management. Child neurologists are essential in the diagnosis and management of fetal alcohol spectrum disorders. PMID- 22241714 TI - Urgent referrals for seizure evaluation to a tertiary care neurology center: a pilot study. AB - This study evaluates the outcome of urgent neurologic referrals. This was a retrospective review of all referrals to the Floating Hospital for Children in 1 month. The total number of patients referred to our center was 223. Amongst those, 108 were new patients and 195 were follow-up visits; 30 patients were deemed urgent, yet 6 of them did not present to their visit. Urgent and routinely scheduled patients were compared based on the need for further evaluation or medication initiation following their visit. The frequency of visit outcomes was statistically similar between urgently and nonurgently referred patients. We did observe though, that diagnostic testing and medication were initiated more frequently for the patients urgently referred for seizure compared with those routinely scheduled patients for seizure evaluation. For this reason, we suggest that pediatric neurologists preferentially should hold clinic space open for urgent referrals for patients with new-onset seizure. PMID- 22241715 TI - Isolated Histoplasma capsulatum meningoencephalitis in an immunocompetent child. AB - Histoplasmosis with central nervous system involvement typically arises in the immunocompromised patient with disseminated fungal disease. Rarely, neurologic histoplasmosis may arise as an isolated syndrome in immunocompetent individuals without evidence of general dissemination. The disease often is diagnostically challenging, and a high index of suspicion is required for diagnosis. We describe an immunocompetent 13-year-old girl with atypical symptoms and unusual radiologic findings due to laboratory-confirmed histoplasma meningoencephalitis. She responded well to antifungal therapy. PMID- 22241716 TI - Development of polymeric palladium-nanoparticle membrane-installed microflow devices and their application in hydrodehalogenation. AB - We have developed a variety of polymeric palladium-nanoparticle membrane installed microflow devices. Three types of polymers were convoluted with palladium salts under laminar flow conditions in a microflow reactor to form polymeric palladium membranes at the laminar flow interface. These membranes were reduced with aqueous sodium formate or heat to create microflow devices that contain polymeric palladium-nanoparticle membranes. These microflow devices achieved instantaneous hydrodehalogenation of aryl chlorides, bromides, iodides, and triflates by 10-1000 ppm within a residence time of 2-8 s at 50-90 degrees C by using safe, nonexplosive, aqueous sodium formate to quantitatively afford the corresponding hydrodehalogenated products. Polychlorinated biphenyl (10-1000 ppm) and polybrominated biphenyl (1000 ppm) were completely decomposed under similar conditions, yielding biphenyl as a fungicidal compound. PMID- 22241718 TI - Recognizing menopause in women with amenorrhea induced by cytotoxic chemotherapy for endocrine-responsive early breast cancer. AB - Cytotoxic anticancer treatment may induce amenorrhea or menopause to a variable extent. These side effects may not only impair or impede fertility but also cause sexual dysfunction, bone loss, and menopausal symptoms, with a strikingly negative effect on quality of life in many women. Aromatase inhibitors (AIs) are a recommended adjuvant endocrine treatment option in postmenopausal patients affected by early breast cancer (EBC) but are contraindicated in premenopausal women and in those with residual ovarian function. Women over 40 years of age with chemotherapy-induced amenorrhea (CIA) and routine hormonal levels consistent with menopause may receive an AI as adjuvant endocrine treatment. For these women, the tools available to identify menopause do not appear to be completely reliable. This review focused on the pathophysiology of ovarian toxicity induced by cytotoxic agents and on potentially useful methods to diagnose chemotherapy induced menopause in patients treated with adjuvant chemotherapy for endocrine responsive EBC. Moreover, practical approaches are proposed to distinguish true menopausal women, who would benefit from AIs, from those with transient or persistent CIA. PMID- 22241717 TI - Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. AB - Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected. PMID- 22241719 TI - The microRNA expression changes associated with malignancy and SDHB mutation in pheochromocytoma. AB - Currently, the diagnosis of malignant pheochromocytoma can only be made when there is clinical evidence of metastasis or extensive local invasion. Thus, there is a need for new diagnostic marker(s) to identify tumors with malignant potential. The purpose of this study was to identify microRNAs (miRNAs) that are differentially expressed between benign and malignant pheochromocytomas and assess their diagnostic accuracy. Toward this aim, we analyzed miRNA expression in benign and malignant pheochromocytoma tumor samples using whole genome microarray profiling. Microarray analysis identified eight miRNAs that were significantly differentially expressed between benign and malignant pheochromocytomas. We measured a subset of these miRNAs directly by RT-PCR and found that miR-483-5p, miR-183, and miR-101 had significantly higher expression in malignant tumors as compared to their benign counterparts. Area under the receiver operating curve (AUC) analysis indicated that miR-483-5p, miR-101, and miR-183 could be useful diagnostic markers for distinguishing malignant from benign pheochromocytomas. In addition, these miRNAs could be detected in pheochromocytoma patient serum. Overall our data suggest that misexpression of miR-483-5p, miR-101, and miR-183 is associated with malignant pheochromocytoma. PMID- 22241720 TI - The role of fibroblast growth factor receptor 4 overexpression and gene amplification as prognostic markers in pediatric and adult adrenocortical tumors. PMID- 22241721 TI - Applying new clinicopathological characteristics to prognostication in advanced thyroid carcinoma. AB - In the February 2011 issue of Endocrine-Related Cancer, Deandreis et al. reported that increased FDG uptake was prognostic in patients with metastatic thyroid cancer. Fludeoxyglucose-positron emission tomography (FDG-PET) is routinely used in the staging and follow-up of patients with cancer. This study gives further evidence for the role of FDG-PET scanning in metastatic thyroid cancer, especially to identify patients with aggressive disease requiring systemic therapy. PMID- 22241722 TI - Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation. AB - The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status of BRAF gene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown of SHH and GLI expression by miRNA constructs that target SHH or GLI mRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment. PMID- 22241723 TI - Bone laminarity in the avian forelimb skeleton and its relationship to flight mode: testing functional interpretations. AB - Wing bone histology in three species of birds was characterized in order to test hypotheses related to the relationship between skeletal microstructure and inferred wing loading during flight. Data on the degree of laminarity (the proportion of circular vascular canals) and the occurrence of secondary osteons were obtained from three species that utilize different primary flight modes: the Double-crested cormorant, a continuous flapper; the Brown pelican, a static soarer; and the Laysan albatross, a dynamic soarer. Laminarity indices were calculated for four quadrants for each of the three main wing elements. Ulnae and carpometacarpi were predicted to exhibit quadrant specific patterns of laminarity due to hypothesized differences in locally applied loads related to the attachment of flight feathers. However, few differences among the quadrants were identified. No significant differences were identified among the three elements, which is notable as different bones are likely experiencing different loading conditions. These results do not support the concept of bone functional adaptation in the primary structure of the wing elements. Significant differences in laminarity were found among the three primary flight modes. The dynamic soaring birds exhibited significantly lower laminarity than the flapping and static soaring birds. These results support the proposed hypothesis that laminarity is an adaptation for resisting torsional loading. This may be explained by overall wing shape: whereas dynamic soaring birds have long slender wings, flappers and static soaring birds have broader wings with a larger wing chord that would necessarily impart a higher torsional moment on the feather bearing bones. PMID- 22241724 TI - Surgical repair for abdominal aortic aneurysm concomitant with iliac arterial disease using InterGardTM Quadrifurcated. AB - InterGardTM Quadrifurcated [InterVascular S.A. (MAQUET Cardiovascular), La Ciotat, France], a knitted quadrifurcated prosthetic graft, is useful to simplify the procedures for patients with abdominal aortic aneurysm concomitant with iliac arterial disease. From March 2008 to April 2010, 59 patients underwent abdominal aortic aneurysm repair in our department. InterGardTM Quadrifurcated was used in 22 patients (37.3%). All patients were male with a mean age of 72.1 +/- 12.1 years (range from 45 to 90 years). Four were emergency cases. Nineteen patients had common iliac arterial lesions, and 19 patients had internal iliac arterial lesions. In addition to abdominal aortic aneurysm repair, reconstruction of bilateral internal iliac arteries was performed in 4 patients, reconstruction of unilateral internal iliac artery in 15 (right 6, left 9), and internal mesenteric artery in 13. There was one hospital death due to nonocclusive mesenteric infarction. There were two complications, which were intestinal perforation and intestinal obstruction. All of these three cases were emergency cases. Computed tomography scan 1 week after operation showed that all reconstructed grafts were patent. Although patients with abdominal aortic aneurysm concomitant with iliac arterial disease had many preoperative comorbidities, surgical results with InterGardTM Quadrifurcated were satisfactory. It is useful to simplify the procedures for these patients. PMID- 22241725 TI - Radiation dosimetry is a necessary ingredient for a perfectly mixed molecular radiotherapy cocktail. PMID- 22241726 TI - In situ formation of porous space maintainers in a composite tissue defect. AB - Reconstruction of composite defects involving bone and soft tissue presents a significant clinical challenge. In the craniofacial complex, reconstruction of the soft and hard tissues is critical for both functional and aesthetic outcomes. Constructs for space maintenance provide a template for soft tissue regeneration, priming the wound bed for a definitive repair of the bone tissue with greater success. However, materials used clinically for space maintenance are subject to poor soft tissue integration, which can result in wound dehiscence. Porous materials in space maintenance applications have been previously shown to support soft tissue integration and to allow for drug release from the implant to further prepare the wound bed for definitive repair. This study evaluated solid and low porosity (16.9% +/- 4.1%) polymethylmethacrylate space maintainers fabricated intraoperatively and implanted in a composite rabbit mandibular defect model for 12 weeks. The data analyses showed no difference in the solid and porous groups both histologically, evaluating the inflammatory response at the interface and within the pores of the implants, and grossly, observing the healing of the soft tissue defect over the implant. These results demonstrate the potential of porous polymethylmethacrylate implants formed in situ for space maintenance in the craniofacial complex, which may have implications in the potential delivery of therapeutic drugs to prime the wound site for a definitive bone repair. PMID- 22241727 TI - Melanoma and rheumatoid arthritis (brief report). AB - The aim of this study is to assess melanoma risk in rheumatoid arthritis (RA). A literature review was performed, retrieving observational studies over 1990-2010 that provided estimates of relative risk of melanoma associated with RA, compared to the general population. We generated standardized incidence ratio (SIR) estimates across all studies, first pooling the data and then performing a random effects model to generate the SIRs. We retrieved 713 citations; after reviewing the titles and abstracts, 124 were further reviewed, and of these, 11 met our inclusion criteria for analysis. Pooling the data, there were a total of 601 melanomas that were observed over 1,351,061 patient-years of follow-up, or 4.4 cases per 10,000 years. The expected number of melanomas over this interval was 596.2 for a pooled SIR of 1.01 [95% confidence interval (CI), 0.93, 1.09]. Excluding the two patient groups that were known to be exposed to biologics, the SIR estimate was unchanged (1.01; 95 CI, 0.93, 1.10). Our random-effects model similarly indicated an SIR for melanoma of 0.95 [95% credible interval (CrI), 0.86, 1.03] overall and 0.95 (95% CrI, 0.86, 1.04) excluding the two patient groups that were known to be exposed to biologics. These results do not highlight an important increased risk for melanoma in RA patients over-all, compared to the general population. It is not clear whether the risk is different for patients specifically exposed to biologic agents, although data are relatively few. Further study, especially of RA patients with a past history of melanoma, is warranted. PMID- 22241728 TI - The demonstration of the number, course, and the location of nutrient artery canals of the femur by multidetector computed tomography. AB - PURPOSE: The aim of this study was to evaluate the number, course, width and location of nutrient artery canals of the femur by using multidetector computed tomography (MDCT). METHODS: Sixty-six adult (35 right and 31 left) dry femurs were included in this study and scanned by MDCT. Nutrient artery canals were evaluated on the multi-planar reformatted and volume rendered images which were reproduced on the basis of axial images. RESULTS: The median value of nutrient artery canals was two (minimum 1 and maximum 6). We determined that there was a negative correlation between the number of nutrient canals and the canal diameters. The outer ostia of the nutrient artery canals were most frequently located at the middle third segment of femoral diaphysis (65%). While the vast majority of the canals were showing upward courses (95%), only a few canals were having transverse (3%) or downward (2%) courses. Most encountered location of outer ostia of the canals according to linea aspera was the medial lip of the linea aspera (44%). Various variations were demonstrated in the number, course, and location of nutrient artery canals using MDCT. CONCLUSIONS: In conclusion, the knowledge of the topographic features of the nutrient artery canals may be useful in various clinical implications such as bone grafting or radiologic evaluation for the fracture lines. PMID- 22241729 TI - Increased new bone formation with a surface magnesium-incorporated deproteinized porcine bone substitute in rabbit calvarial defects. AB - This study investigated the effects of magnesium ion (Mg) incorporation into the surface of deproteinized porcine cancellous bone in the bone healing of rabbit calvarial defects with the expectation of utilizing the integrin-ligand binding enhancement effect of Mg, and compared its bone healing capacity with that of untreated porcine cancellous bone and deproteinized bovine bone (Bio-Oss). Hydrothermal treatment was performed to produce Mg-incorporated porcine bone using an alkaline Mg-containing solution. The surface morphology and chemical composition of the samples were investigated using scanning electron microscopy, energy-dispersive X-ray spectrometry, and X-ray photoelectron spectroscopy. Defects 7 mm in diameter were created in the calvaria of 14 adult male New Zealand White rabbits and were filled with (1) untreated porcine bone (PB), (2) Bio-Oss, and (3) Mg-containing porcine bone (MG). The percentage of newly formed bone (NB%) was evaluated histomorphometrically at 2 and 4 weeks after implantation. Hydrothermal treatment resulted in a Mg-containing surface in porcine bone covered with nanostructures ~100 nm in size. The MG group supported better new bone formation compared with the other groups. Osteoconductive new bone formation was observed in the central defect area in the MG group at an early healing time-point. Histomorphometric analysis revealed significantly greater NB% in the MG group when compared with the untreated PB and Bio-Oss groups at 4 weeks (p < 0.05). The Mg-incorporated porcine bone with surface nanostructures achieved rapid new bone formation in the osseous defects of rabbit calvaria compared with untreated xenografts of porcine and bovine origin. PMID- 22241730 TI - beta-Amyloid peptide is internalized into chick retinal neurons and alters the distribution of myosin Vb. AB - The most common neurodegenerative disorder afflicting the aging human population is Alzheimer's disease (AD). A major hallmark of AD is dementia from a loss of neuronal function, attributed to the presence and accumulation of beta-amyloid (Abeta) peptide into senile plaques. Preceding senile plaque formation, abnormalities in axons can be observed as changes in morphologies and intracellular trafficking. Recently, it has been recognized that Abeta also accumulates within neurons and this intraneuronal Abeta accumulation has been reported to be critical in the disruption of synapses and cognitive function. Here, we report on the internalization of a fluorescently labeled Abeta peptide into cultured chick retinal neurons. The pattern of Abeta distribution during the time course of incubation is reminiscent of the endocytic pathway. Furthermore, the distribution of the internalized Abeta peptide converges with that of myosin Vb and both relocalize from the axon to cell body. These observations are consistent with the hypothesis that AD proceeds as a result of an imbalance between Abeta production and Abeta clearance, suggesting a role for myosin Vb in this process. PMID- 22241731 TI - Differential regulation of Knotted1-like genes during establishment of the shoot apical meristem in Norway spruce (Picea abies). AB - Establishment of the shoot apical meristem (SAM) in Arabidopsis embryos requires the KNOXI transcription factor SHOOT MERISTEMLESS. In Norway spruce (Picea abies), four KNOXI family members (HBK1, HBK2, HBK3 and HBK4) have been identified, but a corresponding role in SAM development has not been demonstrated. As a first step to differentiate between the functions of the four Norway spruce HBK genes, we have here analyzed their expression profiles during the process of somatic embryo development. This was made both under normal embryo development and under conditions of reduced SAM formation by treatment with the polar auxin transport inhibitor NPA. Concomitantly with the formation of an embryonic SAM, the HBK2 and HBK4 genes displayed a significant up-regulation that was delayed by NPA treatment. In contrast, HBK1 and HBK3 were up-regulated prior to SAM formation, and their temporal expression was not affected by NPA. Ectopic expression of the four HBK genes in transgenic Arabidopsis plants further supported similar functions of HBK2 and HBK4, distinct from those of HBK1 and HBK3. Together, the results suggest that HBK2 and HBK4 exert similar functions related to the SAM differentiation and somatic embryo development in Norway spruce, while HBK1 and HBK3 have more general functions during embryo development. PMID- 22241732 TI - Collagen-silica xerogel nanohybrid membrane for guided bone regeneration. AB - A collagen-silica xerogel hybrid membrane was fabricated by a sol-gel process for guided bone regeneration (GBR). The silica xerogel synthesized by the sol-gel method was distributed uniformly within the collagen matrix in the form of nanoparticles. The hybridization of the silica xerogel with collagen improved the biological properties of the membrane significantly. Preosteoblast cells were observed to adhere well and grow much more actively on the hybrid membrane than on the pure collagen membrane. In particular, the hybrid membrane containing 30% of the silica xerogel showed the highest level of osteoblast differentiation. Moreover, the GBR ability, as assessed by the in vivo animal test, was superior to that of the pure collagen membrane. These findings suggest that the collagen silica xerogel hybrid can be used as a GBR membrane. PMID- 22241733 TI - Nuclear features in endometrial cytology: comparison of endometrial glandular and stromal breakdown and endometrioid adenocarcinoma grade 1. AB - This study was to clarify the nuclear features of "condensed clusters of stromal cells (EGBD-stromal cells)" and "metaplastic clumps with irregular protrusions (EGBD-metaplastic cells)" which may be recognized in endometrial glandular and stromal breakdown (EGBD) cases in liquid-based cytologic (LBC) preparations of endometrial brushings. The material consists of cytologic smears of 20 cases of proliferative endometrium (PE), 20 cases of EGBD, and 20 cases of endometrioid adenocarcinoma grade 1 (G1) for which histopathological diagnosis was obtained by endometrial curettage. Nuclear findings were examined in PE cells, EGBD-stromal cells, EGBD-metaplastic cells, and G1 cells, respectively. It was examined about the following items: (1) Nuclear shape; (2) A long/minor axis ratio in cell nuclei; (3) An area of cell nuclei; (4) Overlapping nuclei; (5) The distribution pattern of nuclei within cell clusters. The following observations were made: (1) In PE cells, round-oval nuclei appeared to predominate, overlapping nuclei were not observed, and a slightly abnormal distribution pattern of nuclei was recorded; (2) In EGBD-stromal cells, reniform nuclei were characteristically observed, nuclei had small size and a generally elongated appearance, overlapping nuclei were recognized, and a remarkable abnormal distribution pattern of nuclei was found; (3) In EGBD-metaplastic cells, spindle nuclei were a characteristic feature, nuclei were larger in size and had a bipolar appearance, overlapping nuclei with moderately abnormal distribution pattern of nuclei were identified; (4) In G1 cells round-oval nuclei predominated, overlapping nuclei with moderately abnormal distribution pattern of nuclei were found. The study demonstrates that the analysis of selected nuclear findings appears to be very useful in the cytopathological assessment of endometrial lesions in LBC samples, especially for the discrimination of EGBD and G1. PMID- 22241734 TI - Cytotoxicity and cellular uptake of lysozyme-stabilized gold nanoparticles. AB - The particle size and surface properties of gold nanoparticles are critical factors for the interactions between nanoparticles and cells. To produce noncytotoxic gold nanoparticles, a straightforward method for the synthesis of gold nanoparticles designed involving the reduction and stabilization by a protein such as a lysozyme in conjunction with microwave irradiation. The cooperative combination of a lysozyme with a high affinity for metal ions and the microwave irradiation allowed to form biocompatible gold nanoparticles in an aqueous system. In addition, the cell toxicity and the cellular uptake pathways of the gold nanoparticles synthesized against mouse embryonic fibroblast NIH-3T3 cells were studied and found to be taken up by receptor-mediated endocytosis. In addition, the lysozyme-stabilized gold nanoparticles are accumulated in the cytoplasm as well as the nucleus without any significant cytotoxicity. PMID- 22241735 TI - A case of blastic plasmacytoid dendritic cell neoplasm: cytomorphological findings of the touch imprint specimen of lymph node. AB - The patient is a 75-year-old man with axillary lymphadenopathy presenting an indurated papule on his buttock. Touch imprint cytology of the biopsied axillary lymph node revealed the monotonous appearance of medium-sized tumor cells. The nuclei had a slightly irregular contour, finely dispersed chromatin, and a conspicuous nucleolus. Some tumor cells had intracytoplasmic microvacuoles. Immunohistochemistry of the imprint specimens showed that the tumor cells were positive for CD56 and CD123. Histological diagnosis of the lesion was blastic plasmacytoid dendritic cell neoplasm (BPDCN). Epstein-Barr virus-encoded RNAs were not detected in the tumor cells. Neither immunoglobulin heavy chain genes nor T- cell receptor genes was clonally rearranged. BPDCN should be strongly considered during the differential diagnosis of CD56-positive neoplasms of the skin. We demonstrated a possible contribution of the cytomorphological and immunohistochemical findings of the touch imprint specimens to the diagnosis of BPDCN. PMID- 22241736 TI - Effect of ouabain on myocardial ultrastructure and cytoskeleton during the development of ventricular hypertrophy. AB - The aim of this work is to study cytoskeletal impairment during the development of ouabain-induced ventricular hypertrophy. Male Sprague-Dawley rats were treated with either ouabain or saline. Systolic blood pressure (SBP) was recorded weekly. At the end of the 3rd and 6th week, the rats were killed and cardiac mass index were measured. Hematoxylin-eosin and Sirius red staining were carried out and cardiac ultrastructure were studied using transmission electron microscopy. The mRNA level of Profilin-1, Desmin, PCNA, TGF-beta(1) and ET-1 in the left ventricle were measured using real-time quantitative PCR while their protein levels were examined by Western blot or immunohistochemistry. After 3 weeks, there was no significant difference in the mean SBP, cardiac mass index, mRNA and protein expression of PCNA, TGF-beta(1) and ET-1 between the two groups. However, ouabain-treated rats showed disorganized cardiac cytoskeleton with abnormal expression of Profilin-1 and Desmin. After 6 weeks, the cardiac mass index remained the same in the two groups while PCNA, TGF-beta(1), and ET-1 have been upregulated in ouabain-treated rats. The cardiac cytoskeletal impairment was more severe in ouabain-treated rats with further changes of Profilin-1 and Desmin. Cytoskeletal abnormality is an ultra-early change during ouabain-induced ventricular hypertrophy, before the release of hypertrophic factors. Therapy for prevention of ouabain-induced hypertrophy should start at the early stage by preventing the cytoskeleton from disorganization. PMID- 22241737 TI - Comparative reproducibility of the noninvasive ultrasound methods for the assessment of vascular function. AB - The aim of this work was to assess the reproducibility of ultrasound parameters of vascular function, since these measurements are currently recommended by the guidelines for the evaluation of the cardiovascular risk. Twenty subjects (51 +/- 17 years, 11 men) had vascular ultrasound (Aloka Prosound alpha10) performed by two observers, at the level of the right common carotid artery for assessment of intima-media thickness (IMT), "wall tracking", and "wave-intensity analysis", and at the level of the right brachial artery for the assessment of flow-mediated dilation (FMD). Wave intensity is a hemodynamic index, evaluating ventriculo arterial interaction and can be measured in real time by a double-beam ultrasound technique through simultaneous recording of carotid arterial blood flow velocity and diameter. Carotido-femoral pulse wave velocity (PWV) was determined using the Complior method. Intra- and inter-observer reproducibility was assessed during a first session, when three consecutive acquisitions were made (first observer -> second observer -> first observer); repeatability was evaluated 1 week later (second observer). The most reproducible and repeatable parameters were PWV (intraobserver +/-3.3%, interobserver +/-2.6%, repeatability +/-5.6%) and IMT (+/ 3.7, +/-4.3, +/-4.9%, respectively). Intraobserver reproducibility for arterial stiffness and ventriculo-arterial coupling parameters was the highest for the beta index (+/-3.8%), and the lowest for the second systolic peak (+/-22.4%). Interobserver reproducibility and repeatability varied between very good for the wave speed (+/-5.5 and +/-4.3%), and unsatisfactory for the negative area (+/ 31.8 and +/-38.6%). FMD had good reproducibility (intraobserver +/-11.6%, interobserver +/-8%, repeatability +/-7%), whereas augmentation index had only satisfactory results (+/-17.8, +/-8.4, +/-23.8%, respectively). Only some parameters of vascular function have good reproducibility and repeatability, better or similar to other ultrasound methods and, therefore, these are ready to be used in routine clinical practice. PMID- 22241738 TI - Intrapancreatic accessory spleen: a case report and review of literature. AB - Intrapancreatic accessory spleen is not an uncommon entity and usually located in the tail of the pancreas. Most of them are asymptomatic and incidental findings on radiologic study or at autopsy. On imaging study, it appears to be a well defined, solitary, and hypervascular lesion; therefore, it may be confused with pancreatic neoplasms, such as neuroendocrine neoplasm, well-differentiated adenocarcinoma, solid pseudopapillary tumor, or metastatic tumor to the pancreas. As such, the diagnostic fine-needle aspiration biopsy of the lesion may be performed. Several case reports describing cytological features of the lesion have been published in recent years. Among them, the most commonly identified cytological findings are sheets of a heterogeneous population of lymphocytes and prominent traversing blood vessels. Herein, we report an unusual EUS-FNA case of intrapancreatic accessory spleen. In addition to above previously well-described cytological features, our case revealed many cells with fine granular chromatin and areas with pseudo rosette-like architecture, mimicking and engendering the differential diagnosis of pancreatic neuroendocrine tumors. Although cytological findings of our case are rare, they may extend our current knowledge and provide additional differential diagnostic information for this entity. PMID- 22241739 TI - Regulation of iron metabolism in Hamp (-/-) mice in response to iron-deficient diet. AB - BACKGROUND: Hepcidin, the liver-secreted iron regulatory peptide, maintains systemic iron homeostasis in response to several stimuli including dietary iron levels and body iron status. In addition, iron metabolism is controlled by several local regulatory mechanisms including IRP and Hif-2alpha activities independently of hepcidin. However, the roles of these mechanisms and their interaction particularly in hepcidin-deficient individuals are not yet fully understood. We, therefore, aimed to explore whether Hamp disruption affects iron homeostatic responses to dietary iron deficiency. METHODS: Hepcidin1 knockout (Hamp (-/-)) mice and heterozygous littermates were fed with control or iron deficient diet for 2 weeks. The expression of iron-related genes and proteins were determined by quantitative PCR and Western blot, respectively. RESULTS: Two week iron-deficient diet feeding in Hamp (-/-) mice did not alter serum iron but significantly reduced liver non-heme iron levels. This was also associated with increased ferroportin protein expression in the duodenum and spleen, whereas decreased expression was found in the liver. In addition, significant inductive effects of iron-deficient diet on Dcytb and DMT1 mRNA expression in the duodenum were noted with more pronounced effects in Hamp (-/-) mice compared with controls. CONCLUSIONS: Hamp (-/-) mice exhibited a more dramatic increase in the expression of iron transport machinery, which may be responsible for the unaltered serum iron levels upon iron-deficient diet feeding in these mice. Despite the lack of hepcidin, Hamp (-/-) mice can maintain a degree of iron homeostasis in response to altered dietary iron through several hepcidin independent mechanisms. PMID- 22241741 TI - Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. AB - Extrapulmonary tuberculosis (EPTB) accounts for more than 20% of tuberculosis (TB) cases. Xpert MTB/RIF (Xpert) (Cepheid, Sunnyvale, CA, USA) is a fully automated amplification system, for which excellent results in the diagnosis of pulmonary TB in highly endemic countries have been recently reported. We aimed to assess the performance of the Xpert system in diagnosing EPTB in a low incidence setting. We investigated with Xpert a large number of consecutive extrapulmonary clinical specimens (1,476, corresponding to 1,068 patients) including both paediatric (494) and adult samples. We found, in comparison with a reference standard consisting of combination of culture and clinical diagnosis of TB, an overall sensitivity and specificity of 81.3% and 99.8% for Xpert, while the sensitivity of microscopy was 48%. For biopsies, urines, pus and cerebrospinal fluids the sensitivity exceeded 85%, while it was slightly under 80% for gastric aspirates. It was, in contrast, lower than 50% for cavitary fluids. High sensitivity and specificity (86.9% and 99.7%, respectively) were also obtained for paediatric specimens. Although the role of culture remains central in the microbiological diagnosis of EPTB, the sensitivity of Xpert in rapidly diagnosing the disease makes it a much better choice compared to smear microscopy. The ability to rule out the disease still remains suboptimal. PMID- 22241743 TI - Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation. AB - Sarcoidosis is not only a multisystem, but also a multinational disease that is prevalent throughout the world, including Europe, the USA and Japan. Lung involvement in sarcoidosis is seemingly invariable, with up to 95% of patients manifesting some form of pulmonary disease during the course of their lifetime. The natural history of sarcoidosis in the lung is quite variable and spans the spectrum from spontaneous resolution to advanced fibrocystic disease in ~5% of cases. Advanced sarcoidosis will be the subject of this review with a special focus on pulmonary hypertension and lung transplantation as a last-resort treatment option for some patients with end-stage disease. PMID- 22241742 TI - The impact of ageing and sex on the association between sleepiness and sleep disordered breathing. AB - The aim of our study was to investigate age-related changes in sleepiness symptoms associated with sleep disordered breathing (SDB). Wisconsin Sleep Cohort participants were assessed using polysomnography, the Epworth Sleepiness Scale (ESS) and the multiple sleep latency test (MSLT). SDB was defined as an apnoea/hypopnoea index >=15 events.h(-1), and sleepiness as ESS >=10 and MSLT <=5 min. Odds ratios were calculated using generalised estimating equations associating sleepiness with SDB, and conditional logistic regression examining changes in longitudinal sleepiness status (ESS only). Models were a priori stratified by sex. ESS was measured in 1,281 participants and MSLT in 998 at multiple time-points (ESS n=3,695; MSLT n=1,846). Significant interactions were found between SDB and age in males, but not females. The odds ratios modelled for sleepiness in a 40-yr-old male with SDB were significant compared to a male without SDB (ESS 2.1 and MSLT 2.9); however, these associations were not significant at 60 yrs of age. The within-subject odds ratio for sleepiness was also significant at 40 yrs of age (OR 3.4), but not at 60 yrs of age. The age related reductions in the association between sleepiness and SDB may have clinical implications for the diagnosis and treatment of SDB in older people as sleepiness is often used as a therapeutic target. PMID- 22241745 TI - Predicting survival in newly diagnosed idiopathic pulmonary fibrosis: a 3-year prospective study. AB - The natural history of idiopathic pulmonary fibrosis (IPF) is not well defined and its clinical course is variable. We sought to investigate the survival and incidence of acute exacerbations (AEs) and their significant predictors in newly diagnosed patients. 70 patients newly diagnosed with IPF were prospectively followed for at least 3 yrs. Baseline evaluation included Medical Research Council dyspnoea score (MRCDS), 6-min walk test, pulmonary function tests, all of which were repeated at 6 months, and high-resolution computed tomography. A retrospective cohort of 68 patients was used for confirmation. Mean survival from the time of diagnosis was 30 months, with a 3-yr mortality of 46%. A Risk stratificatiOn ScorE (ROSE) based on MRCDS > 3, 6-min walking distance <= 72% predicted and composite physiologic index > 41 predicted 3-yr mortality with high specificity. 6-month progression of ROSE predicted rapid progression. 3-yr incidence of AE was 18.6%, mostly occurring in the first 18 months; risk factors for AE were concomitant emphysema and low diffusing coefficient of the lung for carbon monoxide. Results were confirmed in an independent cohort of patients. In newly diagnosed IPF, advanced disease at presentation, rapid progression and AEs are the determinants of 3-yr survival. The purpose of the multifactorial ROSE is to risk-stratify patients in order to predict survival and detect rapid disease progression. PMID- 22241744 TI - Differential switching to IgG and IgA in active smoking COPD patients and healthy controls. AB - Several studies have demonstrated the presence of B-cell follicles and autoantibodies in chronic obstructive pulmonary disease (COPD). It is unclear against which antigens this B-cell response is directed and whether it contributes to development or worsening of disease. We assessed different B-cell subsets in blood and lung tissue from COPD patients and controls, and compared differences in B-cell responsiveness to stimulation with lung-specific antigens. Active smoking induced an adaptive immune response with relatively high levels of (class-switched) memory B-cells in blood and immunoglobulin (Ig)G memory B-cells in the lung. COPD smokers showed more switching to IgG, whereas healthy smokers switched more to IgA. COPD patients had higher levels of memory B-cells in the lung and stimulation with lung-specific antigens induced higher numbers of anti decorin antibody-producing cells in COPD patients compared with healthy controls. Differential switching to IgG and IgA indicates that the adaptive immune response to smoke differs between COPD patients and healthy controls. A higher level of memory B-cells in the lungs of COPD patients may reflect an antigen-specific immune response, which could be directed against decorin, as suggested by the induction of anti-decorin antibody-producing cells in response to antigen specific stimulation in COPD patients. PMID- 22241746 TI - Interaction of matrix metalloproteinases with pulmonary pollutants. AB - An air pollutant consists of any atmospheric substance that may harm humans, animals, vegetation or material. Various air pollutants have been reported, differing in their physicochemical characteristics. They can be grouped into four categories: gaseous pollutants (e.g. ozone, sulfur dioxide, oxides of nitrogen, carbon monoxide and volatile organic compounds), persistent organic pollutants, heavy metals (e.g. cadmium, lead and mercury) and particulate matter (coarse, fine and ultrafine). These pollutants can reach the respiratory system, eliciting pulmonary and/or systemic effects. These effects include inflammation, tissue remodelling and carcinogenesis: all phenomena where matrix metalloproteases (MMPs) play critical roles, given their broad effects on matrix remodelling and modulation of inflammation and cell signalling. Moreover, since expression and activity of MMPs can be induced by such stimuli, the hypothesis has been raised that MMPs could be involved in the health effects of pollutants. Until now, the implication of MMPs in these effects has been studied only for some pollutants and for a restricted selection of MMPs (mainly MMP-1, -2, -9 and -12), while evidence for a link between MMP induction/activation and health effects remains scarce. A larger number of studies is, therefore, needed in order to better understand the implication of MMPs in health effects associated with air pollution. PMID- 22241748 TI - Radiotherapy and chemotherapy for elderly patients with stage I-II unresected lung cancer. AB - Radiotherapy (RT) is the standard therapy for unresected stage I-II nonsmall cell lung cancer (NSCLC). Using population-based data, we compared survival and toxicity among unresected elderly patients treated with combined chemoradiotherapy (CRT) or RT alone. Using the Surveillance, Epidemiology and End Results (SEER) registry (National Cancer Institute, Bethesda, MD, USA) we identified 3,006 cases of unresected stage I-II NSCLC. We used propensity score methods to compare survival and rates of toxicity of patients treated with RT versus CRT. Overall, 844 (28%) patients received CRT. Adjusted analyses showed that CRT was associated with improved survival (hazard ratio 0.85, 95% CI 0.78 0.94). Combination therapy was also associated with better survival among stage I patients treated with intermediate complexity RT (HR 0.80, 95% CI 0.70-0.90); however, no difference in survival was observed among patients treated with complex RT. In stage II patients, CRT was associated with improved survival regardless of the RT technique (HR 0.61-0.72). CRT was associated with increased odds of toxicity. Despite increased toxicity, CRT may improve survival of elderly unresected patients with stage II disease as well as stage I NSCLC treated with intermediate RT complexity. Randomised trials are needed to clarify the balance of benefits and risk of CRT in unresected patients. PMID- 22241747 TI - Caveolin-1 regulation of store-operated Ca(2+) influx in human airway smooth muscle. AB - Caveolae, plasma membrane invaginations with constitutive caveolin proteins, harbour proteins involved in intracellular calcium ([Ca(2+)](i)) regulation. In human airway smooth muscle (ASM), store-operated Ca(2+) entry (SOCE) is a key component of [Ca(2+)](i) regulation, and contributes to increased [Ca(2+)](i) in inflammation. SOCE involves proteins Orai1 and stromal interaction molecule (STIM)1. We investigated the link between caveolae, SOCE and inflammation in ASM. [Ca(2+)](i) was measured in human ASM cells using fura-2. Small interference RNA (siRNA) or overexpression vectors were used to alter expression of caveolin-1 (Cav-1), Orai1 or STIM1. Tumour necrosis factor (TNF)-alpha was used as a representative pro-inflammatory cytokine. TNF-alpha increased SOCE following sarcoplasmic reticulum Ca(2+) depletion, and increased whole-cell and caveolar Orai1 (but only intracellular STIM1). Cav-1 siRNA decreased caveolar and whole cell Orai1 (but not STIM1) expression, and blunted SOCE, even in the presence of TNF-alpha. STIM1 overexpression substantially enhanced SOCE: an effect only partially reversed by Cav-1 siRNA. In contrast, Orai1 siRNA substantially blunted SOCE even in the presence of TNF-alpha. Cav-1 overexpression significantly increased Orai1 expression and SOCE, especially in the presence of TNF-alpha. These results demonstrate that caveolar expression and regulation of proteins such as Orai1 are important for [Ca(2+)](i) regulation in human ASM cells and its modulation during inflammation. PMID- 22241749 TI - Primary squamous cell carcinoma of the endometrium: two cases and a review of the literature. AB - Primary squamous cell carcinoma of the endometrium (PSCCE) is a rare entity, with fewer than 100 cases reported in the literature. We report two cases of PSCCE and review the literature regarding associated markers and treatment outcomes. Many different markers have been tested for association with PSCCE, with mixed results. Thus, it is likely that several etiologic factors are responsible for the development of PSCCE. Further, due to the rarity of the condition, the optimal postoperative management of patients with PSCCE remains to be defined. PMID- 22241750 TI - Concomitantly elevated serum matrix metalloproteinases 3 and 9 can predict survival of synchronous squamous cell carcinoma of the upper aero-digestive tract. AB - Matrix metalloproteinases (MMPs) are elevated in patients with squamous cell carcinoma (SCC) over either the head and neck (HNSCC) or the esophagus (ESCC). Synchronous SCC with both HNSCC and ESCC predispose to worse survival. This study tested if serum MMP levels correlate with clinical features and predict survival for HNSCC, ESCC, and synchronous SCC. One hundred and thirty patients with SCCs in upper aero-digestive tract (70 ESCC, 20 HNSCC, and 40 synchronous SCC) and 74 healthy controls were assessed for serum MMP-3, -7, and -9 titers by enzyme linked immunosorbent assay. The titers were validated to their correlations to clinical features and survival rates of the different SCC groups. Patients with SCCs had significantly higher serum MMP-3, -7, and -9 titers than the controls (P < 0.001) but there was no difference among the three SCC groups. Based on the optimal MMP cut-off values by ROC curve, elevated MMP-3 and MMP-9, but not MMP-7, correlated with distant metastasis and poor survival (P < 0.05). Concomitantly elevated MMP-3 (>14 ng/mL) and MMP-9 (>329.3 ng/mL) independently correlated with poor two-year survival (P = 0.002, by log rank test). Cox regression confirmed that such concomitant elevation was superior to the tumor stage of either ESCC or HNSCC in predicting survival for synchronous SCC. Serum MMPs are elevated in SCC of the upper aero-digestive tract. Especially for synchronous SCC, concomitantly elevated MMP-3 and MMP-9 levels serve as better biomarkers to predict prognosis than TNM staging of ESCC or HNSCC. PMID- 22241751 TI - Retroperitoneal recurrence of a stage 1 renal cell carcinoma four years following core biopsy and fine needle aspiration: possible needle tract seeding. PMID- 22241753 TI - Nanoscale biocoordination polymers: novel materials from an old topic. AB - Nature bestows many gifts upon us, among which countless biomolecules have the ability to bridge metal ions and exert the important function in biology. By taking advantage of specific interactions between metal ions and biomolecules, this article highlights a novel concept for construction of nanoscale biocoordination polymers through replacement of synthetic organic molecules with natural biomolecules as building blocks. The most recent advances are summarized and future challenges are discussed. It can be anticipated that nanoscale biocoordination polymers will become a diverse and rapidly growing class of novel materials and potentially lead to a breakthrough in biological applications. PMID- 22241754 TI - Oxidative amidation of aromatic ethers catalyzed by rhodium acetate. PMID- 22241756 TI - Social determinants of health behaviours and social change. PMID- 22241757 TI - Multiple roles and all-cause mortality: the Japan Collaborative Cohort Study. AB - BACKGROUND: Two contrasting perspectives on the effects of multiple roles; the 'role overload hypothesis' and the 'role enhancement model', have been proposed to predict variations in health. The aim of this study was to evaluate the impact of multiple roles on all-cause mortality in Japan where gender roles are currently changing. METHODS: A total of 76,758 individuals from the Japan Collaborative Cohort Study were followed for an average of 15.7 years. Hazard ratios (HRs) with 95% confidence intervals were calculated from proportional hazard models to estimate the risk of all-cause mortality according to multiple roles (spouse, parent and worker, and combinations of these roles). RESULTS: After adjusting for potential confounding factors, the risks of all-cause mortality were elevated among men and women without a role. The number of roles was also associated with all-cause mortality risk, showing the highest risk values among those with no roles compared with those with triple roles (HR: 1.66 in men and 1.78 in women). The impact of the lack of a role was generally greater in men than in women and also in the middle-aged than in the elderly. CONCLUSION: A beneficial effect of multiple roles was suggested among Japanese. The fewer roles they had, the higher all-cause mortality risks were observed. The risk values of those with fewer roles were generally higher in men than in women and also in the middle-aged than in the elderly, partially explained by greater role overload in middle-aged women than other groups in Japan. PMID- 22241758 TI - Incidence and 30-day case fatality for acute myocardial infarction in England in 2010: national-linked database study. AB - BACKGROUND: There are limited national population-based epidemiological data on acute myocardial infarction (AMI) in England, making the current burden of disease, and clinical prognosis, difficult to quantify. The aim of this study was to provide national estimates of incidence and 30-day case fatality rate (CFR) for first and recurrent AMI in England. METHODS: Population-based study using person-linked routine hospital and mortality data on 79 896 individuals of any age, who were admitted to hospital for AMI or who died suddenly from AMI in 2010. RESULTS: Of 82 252 AMI events in 2010, 83% were first. Age-standardized incidence of first AMI per 100 000 population was 130 (95% CI 129-131) in men and 55.9 (95% CI 55.3-56.6) in women. Age-standardized 30-day overall CFRs including sudden AMI deaths for men and women, respectively, were 32.4% (95% CI 32.0-32.9) and 30.3% (95% CI 29.8-30.9) for first AMI and 29.7% (95% CI 28.7-30.7) and 26.7% (95% CI 25.5-27.9) for recurrent AMI. Age-standardized hospitalized 30-day CFR was 12.0% (95% CI 11.6-12.3) for men and 12.3% (95% CI 11.9-12.7) for women. CONCLUSIONS: While the majority of AMIs are not fatal, of those that are, two-thirds occur as sudden AMI deaths. About one in six of all AMIs are recurrent events. These findings reinforce the importance of primary and secondary prevention in reducing AMI morbidity and mortality. PMID- 22241760 TI - Periodic leg movement, nasal CPAP, and expiratory muscles. AB - BACKGROUND: Periodic leg movements (PLMs) may appear during nasal CPAP titration, persisting despite the elimination of hypopneas. METHODS: Systematic recordings of expiratory abdominal muscles on the right and left sides with surface electromyographic (EMG) electrodes lateral to navel, and close from the lateral side of abdomen, were added during nasal CPAP titration for treatment of obstructive sleep apnea (OSA). Positive airway pressure was titrated during nocturnal polysomnography, based on analysis of the flow curve derived from the CPAP equipment and EEG analysis, including persistence of phases A2 and A3 of the cyclic alternating pattern (CAP). The requirement was to eliminate American Association of Sleep Medicine (AASM)-defined hypopnea and also flow limitation and abnormal EEG patterns. When CPAP reached valid results, it was lowered at the time of awakening by 2 or 3 cm H(2)O, and titration was performed again. Data collected during a 7-month period on adults with a prior diagnosis of OSA who had received treatment with nasal CPAP regardless of age and sex were rendered anonymous and were retrospectively rescored by a blinded investigator. RESULTS: Eighty-one successively seen patients with PLMs during CPAP titration were investigated. Elimination of AASM-defined hypopnea was not sufficient to eliminate the PLMs observed during the titration; higher CPAP eliminated flow limitation and CAP phases A2 and A3 and persisting PLMs. PLMs were associated with simultaneous EMG bursts in expiratory abdominal muscles. CONCLUSIONS: The presence of PLMs during CPAP titration indicates the persistence of sleep disordered breathing. PLMs during CPAP titration are related to the presence of abdominal expiratory muscle activity. PMID- 22241761 TI - The effect of end-of-life discussions on perceived quality of care and health status among patients with COPD. AB - BACKGROUND: Despite strong preferences for discussions about end-of-life care, patients with COPD do not often have these discussions with their providers. Our objective was to determine whether patients who reported having end-of-life discussions also reported higher perceived markers of quality of care and health status. METHODS: A cross-sectional study of data collected at baseline for a trial to improve the occurrence and quality of end-of-life communication in patients with COPD was conducted. The primary exposure was self-reported acknowledgment of having discussions about end-of-life planning with their physicians. The primary outcome measures were patient-reported quality of care and satisfaction with care, which were dichotomized as best imaginable quality of care vs other ratings of quality and highest satisfaction vs other ratings of satisfaction. We adjusted for confounding factors, including patient and provider characteristics, using logistic regression clustered by provider. RESULTS: Three hundred seventy-six patients were enrolled, of whom 55 (14.6%) reported having end-of-life discussions. Individuals who reported having end-of-life discussions with their physicians were significantly more likely to rate their quality of care as the best imaginable (OR, 2.07; 95% CI, 1.05-4.09) and to be very satisfied with their medical care (OR, 1.98; 95% CI, 1.10-3.55). Discussions were more likely to have occurred among patients with worse health status as measured by St. George Respiratory Questionnaire total and impact scores. CONCLUSIONS: Patients who reported having end-of-life care discussions with their physicians had higher perceived quality of care and satisfaction with their physicians. Discussing end-of-life care with patients who have COPD may improve their perceived overall quality of and satisfaction with care. PMID- 22241763 TI - Prognostic significance of the extent of visceral pleural invasion in completely resected node-negative non-small cell lung cancer. AB - OBJECTIVE: Visceral pleural invasion (VPI) has been defined as invasion of the tumor beyond the elastic layer (PL1), including invasion to the visceral pleural surface (PL2). The aim of this study was to evaluate the prognostic factors and patterns of recurrence in resected node-negative non-small cell lung cancer (NSCLC) with VPI. METHODS: We retrospectively reviewed the clinicopathologic characteristics of 355 patients with resected node-negative NSCLC with VPI at Taipei Veterans General Hospital between 1990 and 2006. The prognostic value and patterns of recurrence were analyzed and compared between PL1 and PL2 groups. RESULTS: The median follow-up time was 54.2 months. The 5-year overall survival rate and probability of freedom from recurrence were 61.9% and 66.2%, respectively. The extent of VPI was PL1 in 300 patients (84.5%) and PL2 in 55 (15.5%). During follow-up, 107 patients (30.1%) developed recurrence. The patterns of recurrence included local recurrence only in 20 patients (18.7%), distant metastasis only in 59 (55.1%), and both local recurrence and distant metastasis in 28 (26.2%). Thirteen of the 107 patients (12.1%) with recurrence developed malignant pleural effusion. The percentage of malignant pleural effusion in the PL2 group was significantly higher than that in the PL1 group (P = .006). Patients with PL2 had significantly worse overall survival (P = .046) and lower probability of freedom from recurrence (P = .028) in multivariate analysis. CONCLUSIONS: PL2 was a significant prognostic factor for recurrence and worse overall survival in node-negative NSCLC with VPI. This information is important for further design of clinical trials for aggressive adjuvant therapy. PMID- 22241764 TI - The efficacy and safety of the novel long-acting beta2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. AB - BACKGROUND: Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting beta(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 MUg in patients with moderate to severe COPD. METHODS: Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 MUg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24 h weighted mean FEV(1) on days 1 and 28 and time to increases of >= 100 mL or >= 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. RESULTS: VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of >= 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-MUg doses vs placebo. All doses of VI were associated with a low incidence of treatment related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. CONCLUSIONS: VI 25 and 50 MUg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo. PMID- 22241762 TI - Upper airway lymphoid tissue size in children with sickle cell disease. AB - BACKGROUND: The prevalence of obstructive sleep apnea syndrome (OSAS) is higher in children with sickle cell disease (SCD) as compared with the general pediatric population. It has been speculated that overgrowth of the adenoid and tonsils is an important contributor. METHODS: The current study used MRI to evaluate such an association. We studied 36 subjects with SCD (aged 6.9 +/- 4.3 years) and 36 control subjects (aged 6.6 +/- 3.4 years). RESULTS: Compared with control subjects, children with SCD had a significantly smaller upper airway (2.8 +/- 1.2 cm(3) vs 3.7 +/- 1.6 cm(3), P < .01), and significantly larger adenoid (8.4 +/- 4.1 cm(3) vs 6.0 +/- 2.2 cm(3), P < .01), tonsils (7.0 +/- 4.3 cm(3) vs 5.1 +/- 1.9 cm(3), P < .01), retropharyngeal nodes (3.0 +/- 1.9 cm(3) vs 2.2 +/- 0.9 cm(3), P < .05), and deep cervical nodes (15.7 +/- 5.7 cm(3) vs 12.7 +/- 4.0 cm(3), P < .05). Polysomnography showed that 19.4% (seven of 36) of children with SCD had OSAS compared with 0% (zero of 20) of control subjects (P < .05) and that in children with SCD the apnea-hypopnea index correlated positively with upper airway lymphoid tissues size (r = 0.57, P < 001). In addition, children with SCD had lower arterial oxygen saturation nadir (84.3% +/- 12.3% vs 91.2% +/- 4.2%, P < .05), increased peak end-tidal CO(2) (53.4 +/- 8.5 mm Hg vs 42.3 +/- 5.3 mm Hg, P < .001), and increased arousals (13.7 +/- 4.7 events/h vs 10.8 +/- 3.8 events/h, P < .05). CONCLUSIONS: Children with SCD have reduced upper airway size due to overgrowth of the surrounding lymphoid tissues, which may explain their predisposition to OSAS. PMID- 22241765 TI - Not such a different world: providing contraception services in Lesotho. PMID- 22241766 TI - Ethnic differences in disease presentation of uterine cancer in New Zealand women. AB - OBJECTIVES: Little is known about the ethnic differences in disease presentation of uterine cancer in New Zealand women. The objectives of this study were two fold: (1) to estimate the incidence and mortality of uterine cancer among women in New Zealand and (2) to examine the association of ethnicity and socioeconomic status with tumour stage and grade, at presentation of uterine cancer. METHODS: Retrospective survey of cancer cases identified from the New Zealand Cancer Registry. The authors analysed all 3203 uterine cancer cases registered with the New Zealand Cancer Registry during the period 1 January 1997 to 31 December 2006. Ethnic groups were defined based on the self-identified ethnicity recorded on the cancer registry: Ma-ori, Pacific and non-Maori non-Pacific women. Socioeconomic status was categorised as quintiles of the New Zealand Deprivation Index 2006. The mortality to incidence ratio was used as a measure of prognosis. Logistic regression was used to estimate age, ethnic and deprivation adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Pacific and Maori women have higher incidence (32.4 and 17.7 per 100 000 women, respectively) and mortality rates of uterine cancer (12.1 and 7.4 per 100 000 women, respectively). Women in the most deprived areas are more likely to present with an advanced stage of uterine cancer (OR 1.64, 95% CI 1.09-2.48). Maori and Pacific women are less likely to present with well-differentiated tumours (OR 0.69, 95% CI 0.52-0.92 and OR 0.72, 95% CI 0.52-0.99, respectively). CONCLUSIONS: Maori and Pacific women, and those from lower socioeconomic areas, are more likely to present with advanced uterine cancer. PMID- 22241767 TI - G-quadruplex structure and stability illuminated by 2-aminopurine phasor plots. AB - The use of time-resolved fluorescence measurements in studies of telomeric G quadruplex folding and stability has been hampered by the complexity of fluorescence lifetime distributions in solution. The application of phasor diagrams to the analysis of time-resolved fluorescence measurements, collected from either frequency-domain or time-domain instrumentation, allows for rapid characterization of complex lifetime distributions. Phasor diagrams are model free graphical representations of transformed time-resolved fluorescence results. Simplification of complex fluorescent decays by phasor diagrams is demonstrated here using a 2-aminopurine substituted telomeric G-quadruplex sequence. The application of phasor diagrams to complex systems is discussed with comparisons to traditional non-linear regression model fitting. Phasor diagrams allow for the folding and stability of the telomeric G-quadruplex to be monitored in the presence of either sodium or potassium. Fluorescence lifetime measurements revealed multiple transitions upon folding of the telomeric G-quadruplex through the addition of potassium. Enzymatic digestion of the telomeric G-quadruplex structure, fluorescence quenching and Forster resonance energy transfer were also monitored through phasor diagrams. This work demonstrates the sensitivity of time resolved methods for monitoring changes to the telomeric G-quadruplex and outlines the phasor diagram approach for analysis of complex time-resolved results that can be extended to other G-quadruplex and nucleic acid systems. PMID- 22241768 TI - Sensitive and label-free biosensing of RNA with predicted secondary structures by a triplex affinity capture method. AB - A novel biosensing approach for the label-free detection of nucleic acid sequences of short and large lengths has been implemented, with special emphasis on targeting RNA sequences with secondary structures. The approach is based on selecting 8-aminoadenine-modified parallel-stranded DNA tail-clamps as affinity bioreceptors. These receptors have the ability of creating a stable triplex stranded helix at neutral pH upon hybridization with the nucleic acid target. A surface plasmon resonance biosensor has been used for the detection. With this strategy, we have detected short DNA sequences (32-mer) and purified RNA (103 mer) at the femtomol level in a few minutes in an easy and level-free way. This approach is particularly suitable for the detection of RNA molecules with predicted secondary structures, reaching a limit of detection of 50 fmol without any label or amplification steps. Our methodology has shown a marked enhancement for the detection (18% for short DNA and 54% for RNA), when compared with the conventional duplex approach, highlighting the large difficulty of the duplex approach to detect nucleic acid sequences, especially those exhibiting stable secondary structures. We believe that our strategy could be of great interest to the RNA field. PMID- 22241769 TI - Distal chromatin structure influences local nucleosome positions and gene expression. AB - The positions of nucleosomes across the genome influence several cellular processes, including gene transcription. However, our understanding of the factors dictating where nucleosomes are located and how this affects gene regulation is still limited. Here, we perform an extensive in vivo study to investigate the influence of the neighboring chromatin structure on local nucleosome positioning and gene expression. Using truncated versions of the Saccharomyces cerevisiae URA3 gene, we show that nucleosome positions in the URA3 promoter are at least partly determined by the local DNA sequence, with so-called 'anti-nucleosomal elements' like poly(dA:dT) tracts being key determinants of nucleosome positions. In addition, we show that changes in the nucleosome positions in the URA3 promoter strongly affect the promoter activity. Most interestingly, in addition to demonstrating the effect of the local DNA sequence, our study provides novel in vivo evidence that nucleosome positions are also affected by the position of neighboring nucleosomes. Nucleosome structure may therefore be an important selective force for conservation of gene order on a chromosome, because relocating a gene to another genomic position (where the positions of neighboring nucleosomes are different from the original locus) can have dramatic consequences for the gene's nucleosome structure and thus its expression. PMID- 22241770 TI - Structural and biochemical characterization of HP0315 from Helicobacter pylori as a VapD protein with an endoribonuclease activity. AB - VapD-like virulence-associated proteins have been found in many organisms, but little is known about this protein family including the 3D structure of these proteins. Recently, a relationship between the Cas2 family of ribonucleases associated with the CRISPR system of microbial immunity and VapD was suggested. Here, we show for the first time the structure of a member of the VapD family and present a relationship of VapD with Cas2 family and toxin-antitoxin (TA) systems. The crystal structure of HP0315 from Helicobacter pylori was solved at a resolution of 2.8 A. The structure of HP0315, which has a modified ferredoxin like fold, is very similar to that of the Cas2 family. Like Cas2 proteins, HP0315 shows endoribonuclease activity. HP0315-cleaved mRNA, mainly before A and G nucleotides preferentially, which means that HP0315 has purine-specific endoribonuclease activity. Mutagenesis studies of HP0315 revealed that D7, L13, S43 and D76 residues are important for RNase activity, in contrast, to the Cas2 family. HP0315 is arranged as an operon with HP0316, which was found to be an antitoxin-related protein. However, HP0315 is not a component of the TA system. Thus, HP0315 may be an evolutionary intermediate which does not belong to either the Cas2 family or TA system. PMID- 22241771 TI - New methods for finding common insertion sites and co-occurring common insertion sites in transposon- and virus-based genetic screens. AB - Insertional mutagenesis screens in mice are used to identify individual genes that drive tumor formation. In these screens, candidate cancer genes are identified if their genomic location is proximal to a common insertion site (CIS) defined by high rates of transposon or retroviral insertions in a given genomic window. In this article, we describe a new method for defining CISs based on a Poisson distribution, the Poisson Regression Insertion Model, and show that this new method is an improvement over previously described methods. We also describe a modification of the method that can identify pairs and higher orders of co occurring common insertion sites. We apply these methods to two data sets, one generated in a transposon-based screen for gastrointestinal tract cancer genes and another based on the set of retroviral insertions in the Retroviral Tagged Cancer Gene Database. We show that the new methods identify more relevant candidate genes and candidate gene pairs than found using previous methods. Identification of the biologically relevant set of mutations that occur in a single cell and cause tumor progression will aid in the rational design of single and combinatorial therapies in the upcoming age of personalized cancer therapy. PMID- 22241772 TI - SLiCE: a novel bacterial cell extract-based DNA cloning method. AB - We describe a novel cloning method termed SLiCE (Seamless Ligation Cloning Extract) that utilizes easy to generate bacterial cell extracts to assemble multiple DNA fragments into recombinant DNA molecules in a single in vitro recombination reaction. SLiCE overcomes the sequence limitations of traditional cloning methods, facilitates seamless cloning by recombining short end homologies (>=15 bp) with or without flanking heterologous sequences and provides an effective strategy for directional subcloning of DNA fragments from Bacteria Artificial Chromosomes (BACs) or other sources. SLiCE is highly cost effective as a number of standard laboratory bacterial strains can serve as sources for SLiCE extract. In addition, the cloning efficiencies and capabilities of these strains can be greatly improved by simple genetic modifications. As an example, we modified the DH10B Escherichia coli strain to express an optimized lambda prophage Red recombination system. This strain, termed PPY, facilitates SLiCE with very high efficiencies and demonstrates the versatility of the method. PMID- 22241773 TI - Conformational and thermodynamic properties modulate the nucleotide excision repair of 2-aminofluorene and 2-acetylaminofluorene dG adducts in the NarI sequence. AB - Nucleotide excision repair (NER) is a major repair pathway that recognizes and corrects various lesions in cellular DNA. We hypothesize that damage recognition is an initial step in NER that senses conformational anomalies in the DNA caused by lesions. We prepared three DNA duplexes containing the carcinogen adduct N-(2' deoxyguanosin-8-yl)-7-fluoro-2-acetylaminofluorene (FAAF) at G(1), G(2) or G(3) of NarI sequence (5'-CCG(1)G(2)CG(3)CC-3'). Our (19)F-NMR/ICD results showed that FAAF at G(1) and G(3) prefer syn S- and W-conformers, whereas anti B-conformer was predominant for G(2). We found that the repair of FAAF occurs in a conformation-specific manner, i.e. the highly S/W-conformeric G(3) and -G(1) duplexes incised more efficiently than the B-type G(2) duplex (G(3)~G(1)> G(2)). The melting and thermodynamic data indicate that the S- and W-conformers produce greater DNA distortion and thermodynamic destabilization. The N-deacetylated N (2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene (FAF) adducts in the same NarI sequence are repaired 2- to 3-fold less than FAAF: however, the incision efficiency was in order of G(2)~G(1)> G(3), a reverse trend of the FAAF case. We have envisioned the so-called N-acetyl factor as it could raise conformational barriers of FAAF versus FAF. The present results provide valuable conformational insight into the sequence-dependent UvrABC incisions of the bulky aminofluorene DNA adducts. PMID- 22241774 TI - Kinetics and mechanism of G-quadruplex formation and conformational switch in a G quadruplex of PS2.M induced by Pb2+. AB - DNA sequences with guanine repeats can form G-quartets that adopt G-quadruplex structures in the presence of specific metal ions. Using circular dichroism (CD) and ultraviolet-visible (UV-Vis) spectroscopy, we determined the spectral characteristics and the overall conformation of a G-quadruplex of PS2.M with an oligonucleotide sequence, d(GTG(3)TAG(3)CG(3)TTG(2)). UV-melting curves demonstrate that the Pb(2+)-induced G-quadruplex formed unimolecularly and the highest melting temperature (T(m)) is 72 degrees C. The analysis of the UV titration results reveals that the binding stoichiometry of Pb(2+) ions to PS2.M is two, suggesting that the Pb(2+) ions coordinate between adjacent G-quartets. Binding of ions to G-rich DNA is a complex multiple-pathway process, which is strongly affected by the type of the cations. Kinetic studies suggest that the Pb(2+)-induced folding of PS2.M to G-quadruplex probably proceeds through a three step pathway involving two intermediates. Structural transition occurs after adding Pb(NO(3))(2) to the Na(+)- or K(+)-induced G-quadruplexes, which may be attributed to the replacement of Na(+) or K(+) by Pb(2+) ions and the generation of a more compact Pb(2+)-PS2.M structure. Comparison of the relaxation times shows that the Na(+)->Pb(2+) exchange is more facile than the K(+)->Pb(2+) exchange process, and the mechanisms for these processes are proposed. PMID- 22241775 TI - Structural bias in T4 RNA ligase-mediated 3'-adapter ligation. AB - T4 RNA ligases are commonly used to attach adapters to RNAs, but large differences in ligation efficiency make detection and quantitation problematic. We developed a ligation selection strategy using random RNAs in combination with high-throughput sequencing to gain insight into the differences in efficiency of ligating pre-adenylated DNA adapters to RNA 3'-ends. After analyzing biases in RNA sequence, secondary structure and RNA-adapter cofold structure, we conclude that T4 RNA ligases do not show significant primary sequence preference in RNA substrates, but are biased against structural features within RNAs and adapters. Specifically, RNAs with less than three unstructured nucleotides at the 3'-end and RNAs that are predicted to cofold with an adapter in unfavorable structures are likely to be poorly ligated. The effect of RNA-adapter cofold structures on ligation is supported by experiments where the ligation efficiency of specific miRNAs was changed by designing adapters to alter cofold structure. In addition, we show that using adapters with randomized regions results in higher ligation efficiency and reduced ligation bias. We propose that using randomized adapters may improve RNA representation in experiments that include a 3'-adapter ligation step. PMID- 22241776 TI - Comprehensive literature review and statistical considerations for GWAS meta analysis. AB - Over the last decade, genome-wide association studies (GWAS) have become the standard tool for gene discovery in human disease research. While debate continues about how to get the most out of these studies and on occasion about how much value these studies really provide, it is clear that many of the strongest results have come from large-scale mega-consortia and/or meta-analyses that combine data from up to dozens of studies and tens of thousands of subjects. While such analyses are becoming more and more common, statistical methods have lagged somewhat behind. There are good meta-analysis methods available, but even when they are carefully and optimally applied there remain some unresolved statistical issues. This article systematically reviews the GWAS meta-analysis literature, highlighting methodology and software options and reviewing methods that have been used in real studies. We illustrate differences among methods using a case study. We also discuss some of the unresolved issues and potential future directions. PMID- 22241777 TI - Stoichiometry of MutS and MutL at unrepaired mismatches in vivo suggests a mechanism of repair. AB - Mismatch repair (MMR) is an evolutionarily conserved DNA repair system, which corrects mismatched bases arising during DNA replication. MutS recognizes and binds base pair mismatches, while the MutL protein interacts with MutS-mismatch complex and triggers MutH endonuclease activity at a distal-strand discrimination site on the DNA. The mechanism of communication between these two distal sites on the DNA is not known. We used functional fluorescent MMR proteins, MutS and MutL, in order to investigate the formation of the fluorescent MMR protein complexes on mismatches in real-time in growing Escherichia coli cells. We found that MutS and MutL proteins co-localize on unrepaired mismatches to form fluorescent foci. MutL foci were, on average, 2.7 times more intense than the MutS foci co-localized on individual mismatches. A steric block on the DNA provided by the MutHE56A mutant protein, which binds to but does not cut the DNA at the strand discrimination site, decreased MutL foci fluorescence 3-fold. This indicates that MutL accumulates from the mismatch site toward strand discrimination site along the DNA. Our results corroborate the hypothesis postulating that MutL accumulation assures the coordination of the MMR activities between the mismatch and the strand discrimination site. PMID- 22241778 TI - The structural basis for the oligomerization of the N-terminal domain of SATB1. AB - Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene expression regulator essential for T-cell development and breast cancer tumor growth and metastasis. The oligomerization of the N-terminal domain of SATB1 is critical for its biological function. We determined the crystal structure of the N-terminal domain of SATB1. Surprisingly, this domain resembles a ubiquitin domain instead of the previously proposed PDZ domain. Our results also reveal that SATB1 can form a tetramer through its N-terminal domain. The tetramerization of SATB1 plays an essential role in its binding to highly specialized DNA sequences. Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets. Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance. PMID- 22241779 TI - End-to-end attraction of duplex DNA. AB - Recent experiments [Nakata, M. et al., End-to-end stacking and liquid crystal condensation of 6 to 20 basepair DNA duplexes. Science 2007; 318:1276-1279] have demonstrated spontaneous end-to-end association of short duplex DNA fragments into long rod-like structures. By means of extensive all-atom molecular dynamic simulations, we characterized end-to-end interactions of duplex DNA, quantitatively describing the forces, free energy and kinetics of the end-to-end association process. We found short DNA duplexes to spontaneously aggregate end to-end when axially aligned in a small volume of monovalent electrolyte. It was observed that electrostatic repulsion of 5'-phosphoryl groups promoted the formation of aggregates in a conformation similar to the B-form DNA double helix. Application of an external force revealed that rupture of the end-to-end assembly occurs by the shearing of the terminal base pairs. The standard binding free energy and the kinetic rates of end-to-end association and dissociation processes were estimated using two complementary methods: umbrella sampling simulations of two DNA fragments and direct observation of the aggregation process in a system containing 458 DNA fragments. We found the end-to-end force to be short range, attractive, hydrophobic and only weakly dependent on the ion concentration. The relation between the stacking free energy and end-to-end attraction is discussed as well as possible roles of the end-to-end interaction in biological and nanotechnological systems. PMID- 22241780 TI - A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases. AB - Exome sequencing strategy is promising for finding novel mutations of human monogenic disorders. However, pinpointing the casual mutation in a small number of samples is still a big challenge. Here, we propose a three-level filtration and prioritization framework to identify the casual mutation(s) in exome sequencing studies. This efficient and comprehensive framework successfully narrowed down whole exome variants to very small numbers of candidate variants in the proof-of-concept examples. The proposed framework, implemented in a user friendly software package, named KGGSeq (http://statgenpro.psychiatry.hku.hk/kggseq), will play a very useful role in exome sequencing-based discovery of human Mendelian disease genes. PMID- 22241781 TI - The rotation-coupled sliding of EcoRV. AB - It has been proposed that certain type II restriction enzymes (REs), such as EcoRV, track the helical pitch of DNA as they diffuse along DNA, a so-called rotation-coupled sliding. As of yet, there is no direct experimental observation of this phenomenon, but mounting indirect evidence gained from single-molecule imaging of RE-DNA complexes support the hypothesis. We address this issue by conjugating fluorescent labels of varying size (organic dyes, proteins and quantum dots) to EcoRV, and by fusing it to the engineered Rop protein scRM6. Single-molecule imaging of these modified EcoRVs sliding along DNA provides us with their linear diffusion constant (D(1)), revealing a significant size dependency. To account for the dependence of D(1) on the size of the EcoRV label, we have developed four theoretical models describing different types of motion along DNA and find that our experimental results are best described by rotation coupled sliding of the protein. The similarity of EcoRV to other type II REs and DNA binding proteins suggests that this type of motion could be widely preserved in other biological contexts. PMID- 22241782 TI - Direct interaction of ligand-receptor pairs specifying stomatal patterning. AB - Valves on the plant epidermis called stomata develop according to positional cues, which likely involve putative ligands (EPIDERMAL PATTERNING FACTORS [EPFs]) and putative receptors (ERECTA family receptor kinases and TOO MANY MOUTHS [TMM]) in Arabidopsis. Here we report the direct, robust, and saturable binding of bioactive EPF peptides to the ERECTA family. In contrast, TMM exhibits negligible binding to EPF1 but binding to EPF2. The ERECTA family forms receptor homomers in vivo. On the other hand, TMM associates with the ERECTA family but not with itself. While ERECTA family receptor kinases exhibit complex redundancy, blocking ERECTA and ERECTA-LIKE1 (ERL1) signaling confers specific insensitivity to EPF2 and EPF1, respectively. Our results place the ERECTA family as the primary receptors for EPFs with TMM as a signal modulator and establish EPF2-ERECTA and EPF1-ERL1 as ligand-receptor pairs specifying two steps of stomatal development: initiation and spacing divisions. PMID- 22241784 TI - Vertical incision intraoral silicone chin augmentation. AB - OBJECTIVE: Solid silicone augmentation mentoplasty is a common procedure with consistent aesthetic results in properly selected patients. While many plastic surgeons employ the external approach, the intraoral method affords excellent aesthetic outcomes while avoiding an external scar. This is the largest series in the literature describing the midline intraoral incision approach with minimal disruption of soft tissues. STUDY DESIGN: Case series. SETTING: Academic medical center. SUBJECTS AND METHODS: One hundred twenty-five patients underwent chin augmentation with solid silicone implants between 2004 and 2010. Among these implants, 105 were placed transorally. Eighty-five patients were followed for at least 1 year. Demographic information, indications, patient satisfaction questionnaire results, and complications were recorded. RESULTS: All implants yielded satisfactory results with no displacement, infection, tissue reaction, lower lip incompetence, mental nerve injury, or intraoral implant contamination. Two cases of superficial mucosal irritation at the suture site were observed and resolved without consequence. Symmetry, projection, and overall balance of facial components were excellent. Although all patients were satisfied with the functional and aesthetic results, 20% stated they would like further augmentation. Patients were extremely satisfied with the lack of an external scar. CONCLUSIONS: Based on our series, the intraoral technique with a midline incision avoiding disruption of the mentalis muscle is recommended for its ease, simplicity, patient satisfaction, low complication rate, and circumvention of an external scar. The external approach should be considered in cases that require a very large implant. PMID- 22241783 TI - Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. AB - Protein lysine methylation is one of the most widespread post-translational modifications in the nuclei of eukaryotic cells. Methylated lysines on histones and nonhistone proteins promote the formation of protein complexes that control gene expression and DNA replication and repair. In the cytoplasm, however, the role of lysine methylation in protein complex formation is not well established. Here we report that the cytoplasmic protein chaperone Hsp90 is methylated by the lysine methyltransferase Smyd2 in various cell types. In muscle, Hsp90 methylation contributes to the formation of a protein complex containing Smyd2, Hsp90, and the sarcomeric protein titin. Deficiency in Smyd2 results in the loss of Hsp90 methylation, impaired titin stability, and altered muscle function. Collectively, our data reveal a cytoplasmic protein network that employs lysine methylation for the maintenance and function of skeletal muscle. PMID- 22241785 TI - Prevalence of positional plagiocephaly in teens born after the "Back to Sleep" campaign. AB - OBJECTIVES: To determine the prevalence of positional plagiocephaly and brachycephaly in teenagers born after the "Back to Sleep" campaign but before orthotic helmet treatment became widely available and to provide long-term outcomes data on those children with plagiocephaly who were not treated with remolding therapy. STUDY DESIGN: Cross-sectional analysis. SETTING: Local high schools in the Minneapolis-St Paul Metro area. SUBJECTS AND METHODS: Subjects were selected if they attended participating high schools and were born after the Back to Sleep campaign began. Skull measurements, including transcranial diameter, length, and width, were taken. Overall facial appearance was inspected for any apparent abnormal characteristics. Cranial vault asymmetry and cephalic index were calculated for each participant. Plagiocephaly was diagnosed if cranial vault asymmetry was >1 cm. Brachycephaly was diagnosed if the cephalic index was >0.90. RESULTS: There were 1045 participants, ranging from 12 to 17 years old, with an average age of 15.7 years. The prevalence of plagiocephaly was 1.1%. The prevalence of brachycephaly was 1.0%. The overall prevalence of a deformational cranial abnormality was 2.0%. Of those who met diagnostic criteria of plagiocephaly or brachycephaly, 38.1% were noted to have abnormal facial characteristics. CONCLUSIONS: The prevalence of plagiocephaly and brachycephaly in teenagers is significantly lower than the 20% to 48% prevalence found in infants in previous studies, suggesting most children will outgrow the condition without intervention. Additional studies are needed to determine which patients might benefit from treatment and which will likely have resolution without intervention, since treating all infants who meet criteria results in significant overtreatment. PMID- 22241786 TI - Prevalence of biofilms and their response to medical treatment in chronic rhinosinusitis without polyps. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of biofilms and the effects of medical treatment modalities in chronic rhinosinusitis (CRS) patients without nasal polyps. STUDY DESIGN: Randomized controlled trial. SETTINGS: Tertiary referral hospital. SUBJECTS AND METHODS: The authors randomly divided 32 adult patients with CRS without nasal polyps into 2 groups. In the first group (n = 16), oral clarithromycin was administered 500 mg/bid for 2 weeks and then 250 mg/d for the following 6 weeks. In the second group (n = 16), an 8 week course of 200-mcg/d topical mometasone furoate was added to the clarithromycin regimen, identical to the first group. The pre- and posttreatment nasal tissue samples were evaluated by scanning electron microscopy for biofilm prevalence and graded from 0 to 3 according to density and extension. RESULTS: Biofilms were detected in 24 of 32 patients (75%) before the treatment (grades 1 3). Biofilms were detected in 14 of 32 patients (43.8%) after the treatment (grades 1-2). When each group was evaluated independently, there was a significant improvement after the treatment in both groups I and II. When the biofilm grades of group I were compared to those of group II, there was no significant difference both in the pre- and posttreatment evaluation. CONCLUSION: The prevalence of biofilms in CRS without polyps was 75% in our study. Regression of biofilms to 43% was observed under medical treatment. Adding nasal steroids to macrolides gave no further benefit. PMID- 22241787 TI - Prophylactic perioperative antibiotic use in endoscopic sinus surgery: a systematic review and meta-analysis. AB - CONTEXT: Perioperative antibiotics are widely used to improve the outcomes of endoscopic sinus surgery. OBJECTIVE: The aim of this study was to summarize the evidence on the effect of perioperative antibiotic prophylaxis on outcomes of endoscopic sinus surgery. DATA SOURCES AND REVIEW METHODS: We searched electronic databases from inception through May 2011 for any relevant clinical trials or observational studies. Two reviewers working independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta analysis was used to pool the relative risks (RRs) and the standardized mean differences (SMDs) across trials. RESULTS: We found 4 eligible trials with varying quality, of which 3 were included in the quantitative analysis. Antibiotic prophylaxis was associated with a nonsignificant reduction in the incidence of infections (relative risk, 0.76; 95% confidence interval [CI], 0.64 to 1.09), symptoms scores (SMD, -0.04; 95% CI, -0.46 to 0.38), and endoscopic scores (SMD, -0.09; 95% CI, 0.30 to 0.13). The heterogeneity associated with the analysis was significant only for the outcome of change in symptoms score (I squared values, 0%, 70%, and 0% for the 3 outcomes, respectively). CONCLUSIONS: Trial data available to date are unable to demonstrate a statistically significant reduction in infection, symptom scores, or endoscopic scores to support the routine use of postoperative prophylactic antibiotics following endoscopic sinus surgery. Our analysis was limited by the number of published trials related to this topic. PMID- 22241788 TI - 2012 update on meaningful use of electronic health records: recommendations from the AAO-HNS Medical Informatics Committee. AB - In 2011, the US federal government implemented an oversight program to encourage the adoption and meaningful use of electronic health records (EHRs). Otolaryngologists may receive as much as $44,000 under Medicare or $63,750 under Medicaid as part of this law. To receive this full benefit, otolaryngologists must acquire a certified EHR and demonstrate stage 1 meaningful use requirements by the end of 2012. Furthermore, the Office of the National Coordinator for Health IT intends to advance meaningful use requirements to stage 2 (estimated to go in effect in 2014) and stage 3 requirements. This commentary discusses updated recommendations from the Academy of Otolaryngology-Head and Neck Surgery Medical Informatics Committee for implementing meaningful use of EHRs, receiving incentive payments, and preparing for potential stage 2 and stage 3 requirements. PMID- 22241789 TI - Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. AB - PURPOSE: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC). EXPERIMENTAL DESIGN: Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed. RESULTS: Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug. CONCLUSIONS: Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome. PMID- 22241790 TI - Copy number losses define subgroups of dedifferentiated liposarcoma with poor prognosis and genomic instability. AB - PURPOSE: Molecular events underlying progression of well-differentiated liposarcoma (WDLS) to dedifferentiated liposarcoma (DDLS) are poorly defined. This study sought to identify copy number alterations (CNA) associated with dedifferentiation of WDLS, with DDLS morphology, and with patient outcomes. EXPERIMENTAL DESIGN: Fifty-five WDLS and 52 DDLS were analyzed using Agilent 244K comparative genomic hybridization and Affymetrix U133A expression arrays. CNAs were identified by RAE analysis. Thirty-nine of the DDLS specimens were categorized morphologically by a single pathologist. RESULTS: Nine regions of CNA were identified as recurrent in DDLS but not WDLS; 79% of DDLS had at least one of these CNAs. Loss of the chromosome segment 11q23-24, the most common event, was observed only in DDLS that morphologically resembled the genomically complex sarcomas, undifferentiated pleomorphic sarcoma and myxofibrosarcoma. 11q23-24 loss was itself associated with increased genomic complexity in DDLS. Loss of 19q13, but not 11q23-24, was associated with poor prognosis. Median disease specific survival was shorter for patients with19q13 loss (27 months) than for patients with diploid 19q13 (>90 months; P < 0.0025), and 19q13 loss was associated with local recurrence (HR, 2.86; P = 0.013). Common copy number losses were associated with transcriptional downregulation of potential tumor suppressors and adipogenesis-related genes (e.g., EI24 and CEBPA). CONCLUSIONS: Dedifferentiation of WDLS is associated with recurrent CNAs in 79% of tumors. In DDLS, loss of 11q23-24 is associated with genomic complexity and distinct morphology whereas loss of 19q13 predicts poor prognosis. CNAs in liposarcoma improve risk stratification for patients and will help identify potential tumor suppressors driving liposarcoma progression. PMID- 22241791 TI - High-risk ovarian cancer based on 126-gene expression signature is uniquely characterized by downregulation of antigen presentation pathway. AB - PURPOSE: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. EXPERIMENTAL DESIGN: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. RESULTS: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 * 10(-20)). We validated its predictive ability with five other data sets using multivariate analysis (Tothill's data set, P = 1 * 10(-5); Bonome's data set, P = 0.0033; Dressman's data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response-related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. CONCLUSIONS: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. PMID- 22241793 TI - Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R). AB - BACKGROUND: Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent. METHODS: A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency. RESULTS: There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year. CONCLUSIONS: Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll R. PMID- 22241792 TI - Lenalidomide-induced immunomodulation in multiple myeloma: impact on vaccines and antitumor responses. AB - PURPOSE: To show that the immunomodulatory drug lenalidomide can be used in patients with relapsed multiple myeloma to augment vaccine responses. EXPERIMENTAL DESIGN: Early phase clinical trial of patients with multiple myeloma who received at least one prior therapy. Patients were treated with single-agent lenalidomide and randomized to receive two vaccinations with pneumococcal 7 valent conjugate vaccine (PCV) on different schedules. Cohort A received the first PCV vaccination prior to the initiation of lenalidomide and the second vaccination while on lenalidomide. Cohort B received both vaccinations while on lenalidomide. RESULTS: PCV-specific humoral and cellular responses were greater in cohort B than A and were more pronounced in the bone marrow than the blood, suggesting that maximal vaccine efficacy was achieved when both vaccines were administered concomitantly with lenalidomide. Patients with a clinical myeloma response showed evidence of a tumor-specific immune response with increases in myeloma-specific IFN-gamma(+) T cells and reductions in Th-17 cells. CONCLUSIONS: This is the first clinical evidence showing that lenalidomide augments vaccine responses and endogenous antitumor immunity in patients and as such may serve as an adjuvant for cancer and possibly infectious vaccines. PMID- 22241794 TI - Lymphoplasmacytic lymphoma causing light chain cast nephropathy. AB - Plasma cell dyscrasias are frequently associated with kidney disease through the production of monoclonal immunoglobulin but with a diverse set of pathologic renal patterns. While almost all patients with a renal biopsy showing a cast nephropathy have myeloma, kidney involvement associated with pathological immunoglobulin light chains and lymphoma is rare. To our knowledge, this is the first report of a cast nephropathy associated with lymphoplasmacytic lymphoma. We emphasize the relation between light chain deposition and renal dysfunction in this disease with production of light chains. A therapeutic approach that decreases light chain production appears to be warranted in these patients. PMID- 22241795 TI - Altered relative concentrations of high-energy phosphates in patients with uraemic cardiomyopathy measured by magnetic resonance spectroscopy. AB - BACKGROUND: Premature sudden cardiovascular death is the commonest cause of death in end-stage renal disease (ESRD) patients and is associated with uraemic cardiomyopathy [left ventricular hypertrophy (LVH), systolic dysfunction (LVSD) or LV dilation]. High-energy phosphates (HEP), quantified using phosphorus-31 magnetic resonance spectroscopy, are reduced in patients with diabetes, heart failure and uraemia. Phosphocreatine:beta adenosine triphosphate (PCr:ATP) ratio is an index of metabolic activity. We compared resting HEPs in ESRD patients and hypertensive patients (with and without LVH) who had normal renal function (LVH only or normal myocardia). We also assessed associations of HEP levels with abnormalities of uraemic cardiomyopathy. METHODS: Fifty-three ESRD and 30 hypertensive patients (18 with LVH, 12 with normal myocardia) underwent phosphorus magnetic resonance spectroscopy of their left ventricle. PCr:ATP ratios were calculated from (31)P-MR spectra obtained from long-axis views of the left ventricle. RESULTS: There were no significant differences in age, LV mass, chamber sizes and ejection fraction between patient groups. PCr:ATP was significantly lower in ESRD patients compared to hypertensive patients, irrespective of the presence or absence of LVH (P = 0.01). In the ESRD group, PCr:ATP was significantly lower in patients with LVSD (P = 0.05) and LV dilation (P = 0.01). LVH was not associated with significant difference in PCr:ATP. CONCLUSIONS: ESRD patients have lower HEP levels compared to hypertensive patients. Lower PCr:ATP ratio, indicating altered myocardial metabolic function in ESRD patients, is associated with features of uraemic cardiomyopathy. PMID- 22241796 TI - Protesters as "passionate economists": a dynamic dual pathway model of approach coping with collective disadvantage. AB - To explain the psychology behind individuals' motivation to participate in collective action against collective disadvantage (e.g., protest marches), the authors introduce a dynamic dual pathway model of approach coping that integrates many common explanations of collective action (i.e., group identity, unfairness, anger, social support, and efficacy). It conceptualizes collective action as the outcome of two distinct processes: emotion-focused and problem-focused approach coping. The former revolves around the experience of group-based anger (based in appraised external blame for unfair collective disadvantage). The latter revolves around beliefs in the group's efficacy (based in appraised instrumental coping potential for social change). The model is the first to make explicit the dynamic nature of collective action by explaining how undertaking collective action leads to the reappraisal of collective disadvantage, thus inspiring future collective action. The authors review empirical support for the model, discuss its theoretical and practical implications, and identify directions for future research and application. PMID- 22241798 TI - Heat-assisted electrodissolution of platinum in an ionic liquid. PMID- 22241797 TI - Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006. AB - Standard treatment for glioblastoma multiforme (GBM) changed in 2005 when addition of temozolomide (TMZ) to maximal surgical resection followed by radiation therapy (RT) was shown to prolong survival in a clinical trial. In this study, we assessed treatment patterns and survival of patients with GBM in community settings in the United States. Patients with newly diagnosed GBM who were aged >=20 years in 2006 (n = 1202) were identified as part of the National Cancer Institute 's Patterns of Care Studies. We assessed treatment patterns, and in the subset of patients who received total or partial surgical resection, we used multivariable regression analysis to assess patient, clinical, and health system factors associated with receipt of adjuvant chemotherapy and RT and survival through 2008. Approximately 65% of patients with GBM received total or partial surgical resection, and approximately 70% of these patients received adjuvant TMZ and RT. Receipt of adjuvant therapy was associated with patient age, marital status, health insurance, and tumor location. Median survival in all patients was 10 months (95% confidence interval [CI], 9-11 months). Receipt of adjuvant therapy following resection was associated with a lower risk of dying in adjusted analyses for patients who received TMZ and RT (hazard ratio [HR], 0.25; 95% CI, 0.18-0.35) and other adjuvant therapies (HR, 0.55; 95% CI, 0.37-0.81), compared with no adjuvant therapy. We observed rapid diffusion of a new standard of treatment, adjuvant and concurrent TMZ with RT, among adult patients with newly diagnosed GBM in the community setting following publication of a pivotal clinical trial. PMID- 22241799 TI - Probability of heterosexual HIV-1 transmission per coital act in sub-Saharan Africa. PMID- 22241808 TI - The salience of family worldview in mourning an elderly husband and father. AB - OBJECTIVE: The purpose of this study was to qualitatively explore family reaction to the death of the elderly husband and father in the family. METHODS: We qualitatively interviewed 34 families (a family included a widow and 2 adult biological children) approximately 6-15 months after the death. In private, one on-one in-depth interviews, we discussed how the death affected each family member as an individual and how each member perceived that the death altered the family as a unit. RESULTS: An individual's worldview, embedded in the smaller culture of the family and the larger culture of society, offers a template for appropriate grief reactions. DISCUSSION: Our article builds on the constructs of worldview, grief for the husband and father, and narrative at the juncture of self-evaluation, as family members reflected on where they stood in their own journey through life. PMID- 22241800 TI - Determinants of per-coital-act HIV-1 infectivity among African HIV-1 serodiscordant couples. AB - BACKGROUND: Knowledge of factors that affect per-act infectivity of human immunodeficiency virus type 1 (HIV-1) is important for designing HIV-1 prevention interventions and for the mathematical modeling of the spread of HIV-1. METHODS: We analyzed data from a prospective study of African HIV-1-serodiscordant couples. We assessed transmissions for linkage within the study partnership, based on HIV-1 sequencing. The primary exposure measure was the HIV-1 seropositive partners' reports of number of sex acts and condom use with their study partner. RESULTS: Of 3297 couples experiencing 86 linked HIV-1 transmissions, the unadjusted per-act risks of unprotected male-to-female (MTF) and female-to-male (FTM) transmission were 0.0019 (95% confidence interval [CI], .0010-.0037) and 0.0010 (95% CI, .00060-.0017), respectively. After adjusting for plasma HIV-1 RNA of the HIV-1-infected partner and herpes simplex virus type 2 serostatus and age of the HIV-1-uninfected partner, we calculated the relative risk (RR) for MTF versus FTM transmission to be 1.03 (P = .93). Each log(10) increase in plasma HIV-1 RNA increased the per-act risk of transmission by 2.9 fold (95% CI, 2.2-3.8). Self-reported condom use reduced the per-act risk by 78% (RR = 0.22 [95% CI, .11-.42]). CONCLUSIONS: Modifiable risk factors for HIV-1 transmission were plasma HIV-1 RNA level and condom use, and, in HIV-1-uninfected partners, herpes simplex virus 2 infection, genital ulcers, Trichomonas vaginalis, vaginitis or cervicitis, and male circumcision. PMID- 22241809 TI - Baby Boomers and the shifting political construction of old age. AB - Employing the political construct of "target" populations, we suggest that the Boomers in old age will constitute a conceptually distinct population from that represented by either their parents or grandparents. A fourfold typology organized along the dimensions posited by Schneider and Ingram (1993) yields categorizations of target populations as Dependent, Deviant, Advantaged, or Contender. Although these authors labeled the aged as Advantaged, categorizations of target populations can and do change over time. Using historical analysis, we explore, first, the transformation of the aged from Dependent to Advantaged and the more recent transformation to Contender status. This latest shift is reinforced by the perceived characteristics of the Boomer cohort itself now entering old age and by economic and political circumstances severely constraining policy agendas and options. We argue that the combination of weakened legitimacy in the face of pressing needs among many of the Boomer population may result in a fracturing of elders' longstanding singular political imagery. More affluent Boomers will continue to fight for their benefits as Contenders, whereas vulnerable Boomers may be relegated back to the Dependent categorization. PMID- 22241810 TI - Outcomes of a telehealth intervention for homebound older adults with heart or chronic respiratory failure: a randomized controlled trial. AB - PURPOSE: Telehealth care is emerging as a viable intervention model to treat complex chronic conditions, such as heart failure (HF) and chronic obstructive pulmonary disease (COPD), and to engage older adults in self-care disease management. DESIGN AND METHODS: We report on a randomized controlled trial examining the impact of a multifaceted telehealth intervention on health, mental health, and service utilization outcomes among homebound medically ill older adults diagnosed with HF or COPD. Random effects regression modeling was used, and we hypothesized that older adults in the telehealth intervention (n = 51) would receive significantly better quality of care resulting in improved scores in health-related quality of life, mental health, and satisfaction with care at 3 months follow-up as compared with controls (n = 51) and service utilization outcomes at 12 months follow-up. RESULTS: At follow-up, the telehealth intervention group reported greater increases in general health and social functioning, and improved in depression symptom scores as compared with usual care plus education group. The control group had significantly more visits to the emergency department than the telehealth group. There was an observed trend toward fewer hospital days for telehealth participants, but it did not reach significance at 12 months. IMPLICATIONS: Telehealth may be an efficient and effective method of systematically delivering integrated care in the home health sector. The use of telehealth technology may benefit homebound older adults who have difficulty accessing care due to disability, transportation, or isolation. PMID- 22241811 TI - Portraits of aging men in late medieval Italy. AB - PURPOSE: This essay examines the human experience of aging in the distant past by investigating a group of aging men during the 14th century in an Italian city, Bergamo, using notarial "documents of practice" from that community. Studying the aging process and its effects on the lives of people in the medieval era has three-fold significance: it broadens our understanding of aging as a human construct and a human experience, challenges an antihistorical theory of aging, and reinforces the importance of studying the specific experiences of aging individuals in both the past and the present. DESIGN OF THE STUDY: A qualitative study. Methods of analysis include nominative linkage and an investigation of the physical effects of aging on an individual, as seen in the documents of 1 long-lived notary. RESULTS: Aging clerics and notaries in Bergamo took on positions of increasing authority in the church and related institutions in the last decades of their lives. IMPLICATIONS: The documented activities of a group of affluent men in 14th-century Bergamo suggest that although there was little recorded discussion of "old age" as a life stage in that community, for these men, aging was a real social process with both positive and negative impacts on their lives. Giving a human face to these aging men of the distant past models an approach to the study of the aging process that has relevance for both historians and gerontologists alike. PMID- 22241812 TI - Reducing information avoidance through affirmation. AB - Although screening for medical problems can have health benefits, the potentially threatening nature of the results can lead people to avoid screening. In three studies, we examined whether affirming people's self-worth reduces their avoidance of medical-screening feedback. Participants completed an online risk calculator for a fictitious medical condition and then were offered a choice to receive or not receive their risk feedback. Our results showed that affirmation decreased participants' avoidance of risk feedback (Study 1) and eliminated the increased avoidance typically observed when risk feedback might obligate people to engage in undesired behavior (Study 2) and when feedback is about risk for an untreatable disease (Study 3). These findings suggest that affirmation may be an effective strategy for increasing rates of medical screening. PMID- 22241813 TI - Reactance versus rationalization: divergent responses to policies that constrain freedom. AB - How do people respond to government policies and work environments that place restrictions on their personal freedoms? The psychological literature offers two contradictory answers to this question. Here, we attempt to resolve this apparent discrepancy. Specifically, we identify the absoluteness of a restriction as one factor that determines how people respond to it. Across two studies, participants responded to absolute restrictions (i.e., restrictions that were sure to come into effect) with rationalization: They viewed the restrictions more favorably, and valued the restricted freedoms less, compared with control participants. Participants responded in the opposite way to identical restrictions that were described as nonabsolute (i.e., as having a small chance of not coming into effect): In this case, participants displayed reactance, viewing the restrictions less favorably, and valuing the restricted freedoms more, compared with control participants. We end by discussing future research directions. PMID- 22241814 TI - Electrophysiological examination of embodiment in vision and action. AB - A wealth of behavioral data has shown that the visual properties of objects automatically potentiate motor actions linked with them, but how deeply are these affordances embedded in visual processing? In the study reported here, we used electrophysiological measures to examine the time course of affordance resulting from the leftward or rightward orientation of the handles of common objects. Participants were asked to categorize those objects using a left- or right-handed motor response. Lateralized readiness potentials showed rapid motor preparation in the hand congruent with the affordance provided by the object only 100 to 200 ms after stimulus presentation and up to 400 ms before the actual response. Examination of event-related potentials also revealed an effect of handle orientation and response-hand congruency on the visual P1 and N1 components. Both of these results suggest that activity in the early sensory pathways is modulated by the action associations of objects and the intentions of the viewer. PMID- 22241815 TI - Saving the last for best: a positivity bias for end experiences. PMID- 22241816 TI - Relationship between CRP polymorphism and cardiovascular events in Chinese peritoneal dialysis patients. AB - BACKGROUND AND OBJECTIVES: The single-nucleotide polymorphism (SNP) -717A->G substitution, rs2794521, was found in the promoter of the C-reactive protein (CRP) gene. Functional studies showed that A allele promoter has higher transcriptional activity than the G allele. This study investigated the association between this SNP and the outcome of Chinese patients undergoing peritoneal dialysis (PD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study included 441 new PD patients (232 men; mean age +/- SD, 56.7+/-13.5 years). CRP genotyping was determined; patients were followed for 41.3+/-18.3 months for cardiovascular events. RESULTS: For the entire cohort, 5-year event-free survival rates did not differ between the AA and AG/GG groups (35.7% and 31.9%, respectively; P=0.64). However, there was significant interaction between plasma cholesterol levels and CRP genotype groups on event-free survival (P=0.04 for interaction). For patients with cholesterol levels of 200 mg/dl or greater, the 5 year event-free survival rate in the AG/GG group was significantly better than that in the AA group (54.7% versus 40.0%; P=0.04), whereas there was no difference in event-free survival between genotype groups for patients with cholesterol levels less than 200 mg/dl. CONCLUSIONS: CRP gene -717AG or GG genotypes is associated with cardiovascular benefit to Chinese PD patients with cholesterol levels of 200 mg/dl or greater. These findings suggest a complex interaction among cholesterol, CRP, and cardiovascular disease in PD patients. PMID- 22241817 TI - Localization of tubular adaptation to renal sodium loss in Gitelman syndrome. AB - BACKGROUND AND OBJECTIVES: Gitelman syndrome (GS) is a salt-wasting tubulopathy that results from the inactivation of the human thiazide-sensitive sodium chloride cotransporter located in the distal convoluted tubule. Tubular adaptation to renal sodium loss has been described and localized in the distal tubule in experimental models of GS but not in humans with GS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The tubular adaptation to renal sodium loss is described. Osmole-free water clearance and endogenous lithium clearance with furosemide infusion are used to compare 7 patients with genetically confirmed GS and 13 control participants. RESULTS: Neither endogenous lithium clearance nor osmole-free water clearance disclosed enhanced proximal fluid reabsorption in patients with GS. These patients displayed significantly lower osmole-free water clearance factored by inulin clearance (7.1 +/- 1.9 versus 10.1 +/- 2.2; P<0.01) and significantly lower fractional sodium reabsorption in the diluting nephron (73.2% +/- 7.1% versus 86.1% +/- 4.7%; P<0.005), consistent with the inactivation of the thiazide-sensitive sodium chloride cotransporter. The furosemide-induced reduction rate of fractional sodium reabsorption in the diluting segment was higher in patients with GS (75.6% +/- 6.1% versus 69.9% +/- 3.2%; P<0.039), suggesting that sodium reabsorption would be enhanced in the cortical part of the thick ascending limb of the loop of Henle in patients with GS. CONCLUSIONS: These findings suggest that tubular adaptation to renal sodium loss in GS would be devoted to the cortical part of the thick ascending limb of the loop of Henle in humans. PMID- 22241818 TI - Kidney dysfunction and cognitive decline in women. AB - BACKGROUND AND OBJECTIVES: ESRD is associated with substantial cognitive deficits but whether earlier kidney dysfunction predicts cognitive decline is less well defined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: More than 1700 women aged >=70 years in the Nurses' Health Study had plasma creatinine and urinary albumin/creatinine ratios (ACRs) measured in 2000, within 12 months of their initial cognitive testing. These participants had repeated assessments of cognition administered by phone every 2 years, including tests for general cognition, verbal memory, verbal fluency, and working memory for up to 6 years of follow-up. Mixed-effects regression analysis was applied to calculate mean differences in the rate of cognitive decline between women with an estimated GFR <60 ml/min per 1.73 m(2) or an ACR >=5 mg/g versus referent levels. RESULTS: The median age was 74 years at initial cognitive testing, 99% of women were Caucasian, median plasma creatinine was 0.8 mg/dl, and 25% had an ACR >=5 mg/g. The difference in cognitive decline with a baseline ACR >=5 mg/g versus an ACR <5 mg/g was equivalent to the difference observed with 2-7 years of aging; that is, a higher ACR was associated with 2-7 times faster decline in all four cognitive domains assessed (all P values <0.05) than that attributed to each 1 year of aging alone. No associations were observed between an eGFR <60 ml/min per 1.73 m(2) and cognitive decline. CONCLUSIONS: A baseline urinary ACR >=5 mg/g, a level not traditionally considered clinically significant, is independently associated with faster decline in cognitive function. PMID- 22241820 TI - Inflammatory cell markers as indicators of atherosclerotic renovascular disease. PMID- 22241821 TI - A hydrocarbon-soluble lithium hydride complex. PMID- 22241819 TI - Mortality in kidney disease patients treated with phosphate binders: a randomized study. AB - BACKGROUND AND OBJECTIVES: Dietary phosphorous overload and excessive calcium intake from calcium-containing phosphate binders promote coronary artery calcification (CAC) that may contribute to high mortality of dialysis patients. CAC has been found in patients in early stages of nondialysis-dependent CKD. In this population, no study has evaluated the potential role of phosphorus binders on mortality. This study aimed to evaluate all-cause mortality as the primary end point in nondialysis-dependent CKD patients randomized to different phosphate binders; secondary end points were dialysis inception and the composite end point of all-cause mortality and dialysis inception. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a randomized, multicenter, nonblinded pilot study. Consecutive outpatients (n=212; stage 3-4 CKD) were randomized to either sevelamer (n=107) or calcium carbonate (n=105). Phosphorus concentration was maintained between 2.7 and 4.6 mg/dl for patients with stage 3-4 CKD and between 3.5 and 5.5 mg/dl for patients with stage 5 CKD. The CAC score was assessed by computed tomography at study entry and after 6, 12, 18, and 24 months. All-cause mortality, dialysis inception, and the composite end point were recorded for up to 36 months. RESULTS: In patients randomized to sevelamer, all-cause mortality and the composite end point were lower; a nonsignificant trend was noted for dialysis inception. CONCLUSIONS: Sevelamer provided benefits in all-cause mortality and in the composite end point of death or dialysis inception but not advantages in dialysis inception. Larger studies are needed to confirm these results. PMID- 22241824 TI - High-pressure synthesis and characterization of the alkali diazenide Li2N2. PMID- 22241823 TI - Direct fluorescence monitoring of DNA base excision repair. PMID- 22241822 TI - Obesity and liver cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. AB - OBJECTIVE: With increased interest in non-alcoholic steatohepatitis, its common co-morbid condition, obesity, has recently attracted much attention as a risk factor for liver cancer. Recent studies also suggest that obesity may play a role in the development of liver cancer in alcoholic cirrhosis or viral hepatitis and in the general population. METHODS: We systematically reviewed epidemiologic studies on overweight/obesity and liver cancer among Japanese populations. Original data were obtained by searching the MEDLINE (PubMed) and Ichushi databases, complemented by manual searches. The evaluation was performed in terms of the magnitude of association in each study and the strength of evidence ('convincing', 'probable', 'possible' or 'insufficient'), together with biologic plausibility. RESULTS: Among nine cohort studies identified, five (four on patients with chronic liver disease and one on local residents) reported a weak to strong positive association, while four (one on patients with hepatitis B and three on local residents) found no association [summary relative risk for one unit increase in body mass index (kg/m(2)) 1.07, 95% confidence interval 1.03 1.10]. All three case-control studies identified (two on cirrhotic patients and one on atomic bomb survivors) reported a strong positive association (summary relative risk 1.31, 95% confidence interval 1.12-1.53). Overall, the summary relative risk was estimated at 1.13 (95% confidence interval 1.07-1.20), and overweight/obese individuals had a relative risk of 1.74 (95% confidence interval 1.33-2.28) compared with those who had normal/low weight. CONCLUSIONS: We conclude that overweight or obesity 'probably' increases the risk of primary liver cancer, to a moderate degree, among the Japanese population. PMID- 22241825 TI - The lipid-linked oligosaccharide donor specificities of Trypanosoma brucei oligosaccharyltransferases. AB - We recently presented a model for site-specific protein N-glycosylation in Trypanosoma brucei whereby the TbSTT3A oligosaccharyltransferase (OST) first selectively transfers biantennary Man(5)GlcNAc(2) from the lipid-linked oligosaccharide (LLO) donor Man(5)GlcNAc(2)-PP-Dol to N-glycosylation sequons in acidic to neutral peptide sequences and TbSTT3B selectively transfers triantennary Man(9)GlcNAc(2) to any remaining sequons. In this paper, we investigate the specificities of the two OSTs for their preferred LLO donors by glycotyping the variant surface glycoprotein (VSG) synthesized by bloodstream form T. brucei TbALG12 null mutants. The TbALG12 gene encodes the alpha1-6 mannosyltransferase that converts Man(7)GlcNAc(2)-PP-Dol to Man(8)GlcNAc(2)-PP Dol. The VSG synthesized by the TbALG12 null mutant in the presence and the absence of alpha-mannosidase inhibitors was characterized by electrospray mass spectrometry both intact and as pronase glycopetides. The results show that TbSTT3A is able to transfer Man(7)GlcNAc(2) as well as Man(5)GlcNAc(2) to its preferred acidic glycosylation site at Asn263 and that, in the absence of Man(9)GlcNAc(2)-PP-Dol, TbSTT3B transfers both Man(7)GlcNAc(2) and Man(5)GlcNAc(2) to the remaining site at Asn428, albeit with low efficiency. These data suggest that the preferences of TbSTT3A and TbSTT3B for their LLO donors are based on the c-branch of the Man(9)GlcNAc(2) oligosaccharide, such that the presence of the c-branch prevents recognition and/or transfer by TbSTT3A, whereas the presence of the c-branch enhances recognition and/or transfer by TbSTT3B. PMID- 22241826 TI - Structural characterization of Schistosoma mansoni adult worm glycosphingolipids reveals pronounced differences with those of cercariae. AB - Immune responses induced by glycans upon infection with Schistosoma mansoni may be mediated by either schistosomal glycoproteins or glycosphingolipids. In this study, we have elucidated the structural features of both carbohydrate moieties and respective ceramide units of complex glycosphingolipids from adult S. mansoni. Obtained data revealed a vast structural heterogeneity due to manifold combinations of different oligosaccharides and ceramide entities. Observed carbohydrate moieties included Lewis(X) (Le(X); Gal(beta1-4)[Fuc(alpha1 3)]GlcNAc) as well as, in part, multiply fucosylated LacdiNAc (LDN; GalNAc(beta1 4)GlcNAc) carbohydrate epitopes. Corresponding lipid portions comprised predominantly C18-sphingosine as well as C18- and C20-phytosphingosine derivatives. Intriguingly, glycosphingolipids carrying an Le(X) epitope contained predominantly C18-sphingosine, whereas LDN-based species exhibited mostly phytosphingosine derivatives, in addition to C18-sphingosine, indicating that the two classes of glycosphingolipids might be synthesized via different biosynthetic routes. Compared with literature data, adult worm glycosphingolipids with Le(X) epitopes revealed clear structural differences in comparison to corresponding cercarial species which have been shown to exhibit mainly sphinganine bases with 18-21 carbon atoms. Therefore, it may be hypothesized that the divergent structural features of the respective ceramide moieties are responsible for the published observation that only adult worm, but not cercarial glycosphingolipids are able to induce dendritic cell activation skewing the T-cell response toward a Th1 profile. PMID- 22241827 TI - Glycoproteomic characterization of recombinant mouse alpha-dystroglycan. AB - alpha-Dystroglycan (DG) is a key component of the dystrophin-glycoprotein complex. Aberrant glycosylation of the protein has been linked to various forms of congenital muscular dystrophy. Unusually alpha-DG has previously been demonstrated to be modified with both O-N-acetylgalactosamine and O-mannose initiated glycans. In the present study, Fc-tagged recombinant mouse alpha-DG was expressed and purified from human embryonic kidney 293T cells. alpha-DG glycopeptides were characterized by glycoproteomic strategies using both nano liquid chromatography matrix-assisted laser desorption ionization and electrospray tandem mass spectrometry. A total of 14 different peptide sequences and 38 glycopeptides were identified which displayed heterogeneous O glycosylation. These data provide new insights into the complex domain-specific O glycosylation of alpha-DG. PMID- 22241829 TI - Smoking desistance and personality change in emerging and young adulthood. AB - INTRODUCTION: We attempted to replicate and extend (Welch, P., & Poulton, R. [2009]. Personality influences on change in smoking behavior. Health Psychology, 28, 292-299. doi:10.1037/a0013471) findings regarding the relationship between smoking involvement and personality change. METHODS: Two time frames (18-25, 18 35) in a cohort of college students (N = 489 at baseline) followed for 17 years were used. Impulsivity, neuroticism, and 4 measures of smoking involvement were assessed at each time point. RESULTS: Individuals who desisted in smoking involvement tended to exhibit the largest decreases in neuroticism and impulsivity from ages 18 to 25. From ages 18 to 35, changes in smoking involvement were only significantly associated with changes in impulsivity. CONCLUSIONS: These findings add to the literature demonstrating decreasing neuroticism, and impulsivity correlates with decreased substance involvement during emerging adulthood. PMID- 22241828 TI - Evaluation of the brief questionnaire of smoking urges in Black light smokers. AB - INTRODUCTION: This study evaluated the factor structure of the Brief Questionnaire of Smoking Urges (QSU-Brief) within a sample of Black light smokers (1-10 cigarettes per day). METHODS: The QSU-Brief was administered to 540 (mean age = 46.5; 66.1% women) urban Black light smokers upon entering a smoking cessation clinical trial. An exploratory factor analysis (EFA) was conducted to evaluate the factor structure of this 10-item measure. RESULTS: An EFA indicated that as in other samples, the construct of craving in a Black sample is defined by 2 factors; 1 factor emphasizing the positive reinforcement of smoking and the other factor emphasizing the negative reinforcement properties of smoking. CONCLUSIONS: Findings largely replicate a 2-factor structure of craving seen in smokers from other racial/ethnic groups, demonstrating the clinical utility of the QSU-Brief in measuring craving in Black light smokers. PMID- 22241832 TI - Synergistic CD40 signaling on APCs and CD8 T cells drives efficient CD8 response and memory differentiation. AB - The role of CD4 help during CD8 response and memory differentiation has been clearly demonstrated in different experimental models. However, the exact mechanisms of CD4 help remain largely unknown and preclude replacement therapy to develop. Interestingly, studies have shown that administration of an agonist aCD40ab can substitute CD4 help in vitro and in vivo, whereas the targets of this antibody remain elusive. In this study, we address the exact role of CD40 expression on APCs and CD8 T cells using aCD40ab treatment in mice. We demonstrate that aCD40 antibodies have synergetic effects on APCs and CD8 T cells. Full efficiency of aCD40 treatment requires CD40 expression on both populations: if one of these cell populations is CD40-deficient, the CD8 T cell response is impaired. Most importantly, direct CD40 signaling on APCs and CD8 T cells affects CD8 T cell differentiation differently. In our model, CD40 expression on APCs plays an important but dispensable role on CD8 T cell expansion and effector functions during the early phase of the immune response. Conversely, CD40 on CD8 T cells is crucial and nonredundant for their progressive differentiation into memory cells. Altogether, these results highlight that CD40 CD40L-dependent and independent effects of CD4 help to drive a complete CD8 T cell differentiation. PMID- 22241831 TI - Varenicline blocks beta2*-nAChR-mediated response and activates beta4*-nAChR mediated responses in mice in vivo. AB - INTRODUCTION: The smoking cessation aid, varenicline, has higher affinity for the alpha4beta2-subtype of the nicotinic acetylcholine receptor (alpha4beta2*-nAChR) than for other subtypes of nAChRs by in vitro assays. The mechanism of action of acute varenicline was studied in vivo to determine (a) subtype activation associated with physiological effects and (b) dose relationship as an antagonist of nicotine. METHODS: Acute doses of saline, nicotine, and varenicline were given to mice, and locomotor depression and hypothermia were measured. Subunit null mutant mice as well as selective antagonists were used to study mode of action of varenicline as an agonist. Varenicline as an antagonist of nicotine was also investigated. RESULTS: Varenicline evokes locomotor depression and hypothermia at higher doses than necessary for nicotine. Null mutation of the alpha7- or beta2 nAChR subunit did not decrease the effectiveness of varenicline; however, null mutation of the beta4 subunit significantly decreased the magnitude of the varenicline effect. Effects of the highest dose studied were blocked by mecamylamine (general nAChR antagonist) and partially antagonized by hexamethonium (largely peripheral nAChR antagonist). No significant block was seen with ondansetron antagonist of 5-hydroxytryptamine 3 receptor. Using a dose of nicotine selective for beta2*-nAChR subtype effects with these tests, dose dependent antagonism by varenicline was seen. Effective inhibitory doses were determined and appear to be in a range consistent with binding affinity or desensitization of beta2*-nAChRs. CONCLUSIONS: Varenicline acts as a functional antagonist of beta2*-nAChRs, blocking certain effects of nicotine. At higher doses, varenicline is an agonist of beta4*-nAChRs producing physiological changes in mice. PMID- 22241830 TI - Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits. AB - INTRODUCTION: The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes. METHODS: The study sample was ascertained from the Finnish Twin Cohort study. Twin pairs born 1938-1957 and concordant for a history of cigarette smoking were recruited along with their family members (mainly siblings), as part of the Nicotine Addiction Genetics consortium. The study sample consisted of 1,428 individuals (59% males) from 735 families, with mean age 55.6 years. RESULTS: We detected multiple novel associations for ND. DSM-IV ND symptoms associated significantly with the proxy SNP Locus 1 (rs2036527, p = .000009) and Locus 2 (rs578776, p = .0001) and tolerance factor of the Nicotine Dependence Syndrome Scale (NDSS) showed suggestive association to rs11636753 (p = .0059), rs11634351 (p = .0069), and rs1948 (p = .0071) in CHRNB4. Furthermore, we report significant association with DSM-IV ND diagnosis (rs2036527, p = .0003) for the first time in a Caucasian population. Several SNPs indicated suggestive association for traits related to ages at smoking initiation. Also, rs11636753 in CHRNB4 showed suggestive association with regular drinking (p = .0029) and the comorbidity of depression and ND (p = .0034). CONCLUSIONS: We demonstrate novel associations of DSM-IV ND symptoms and the NDSS tolerance subscale. Our results confirm and extend association findings for other ND measures. We show pleiotropic effects of this gene cluster on multiple measures of ND and also regular drinking and the comorbidity of ND and depression. PMID- 22241834 TI - What determines the rate of excited-state intramolecular electron-transfer reaction of 4-(N,N'-dimethylamino)benzonitrile in room temperature ionic liquids? A study in [bmim][PF6]. AB - The kinetics of excited-state intramolecular electron-transfer reaction and dynamics of solvation of the intramolecular charge transfer (ICT) state of 4 (N,N'-dimethylamino)benzonitrile (DMABN) was studied in 1-butyl-3 methylimidazloium hexafluorophosphate, [bmim][PF(6)], by monitoring the dual fluorescence of the system. The picosecond time-resolved emission spectra (TRES) of DMABN exhibit decay of the locally excited (LE) emission intensity and shift of the ICT emission peak position with time, thus capturing the kinetics of evolution of the ICT state from the LE state and solvent relaxation of the ICT state. These results show that the LE->ICT transformation rate is determined not by the slow dynamics of solvation in ionic liquid, but is controlled mainly by the rate of structural reorganization of the molecule, which accompanies the electron-transfer process in this polar viscous medium. Even though both solvent reorganization around photo-excited DMABN and structural rearrangement of the molecule are dependent on the viscosity of the medium, it is the latter process that contributes to the viscosity dependence of the LE->ICT transformation. PMID- 22241833 TI - Sialoglycoproteins adsorbed by Pseudomonas aeruginosa facilitate their survival by impeding neutrophil extracellular trap through siglec-9. AB - PA is an opportunistic pathogen that is commonly associated with severe infection in immunocompromised hosts. Siglec-9 binds with Sias by cis interaction on the neutrophil surface, thereby reducing immunological activity. However, neutrophils bind with pathogens through trans interactions of siglec-9 with Sias. Neutrophils kill invading pathogens by NETs, along with extracellular phagocytosis. Here, we report the mode of the adsorption of Sias by PA from host serum, the interaction of PA(+Sias) with human neutrophils, and the resulting neutrophil immunological activity. The alpha2-3-linked sialoglycoproteins adsorbed by PA exhibited potent binding with the soluble siglec-9-Fc chimeras, CHO-siglec-9 and siglec-9 on neutrophils. The binding between PA(+Sias) and neutrophils was blocked by the synthetic sialoglycan Neu5Acalpha2-3Galbeta1-4GlcNAc, confirming the linkage specific, Sias-siglec-9 interaction. The PA(+Sias) and siglec-9 interaction on neutrophils reduced the level of ROS and the release of elastase, resulting in a reduction of NETs formation, demonstrating the role of the sialoglycoproteins adsorbed by PA in the weakening of neutrophil activity. The resistance of PA(+Sias) to NETs was made evident by the increased survival of PA(+Sias). Moreover, the decrease in PA(-Sias) survival demonstrated the involvement of NETs formation in the absence of the Sias-siglec-9 interaction. N-actylcysteine or sivelestat-pretreated neutrophils enhanced the survival of PA(-Sias). DNAse pretreated neutrophils did not exhibit any NETs formation, resulting in the enhanced escape of PA(-Sias). Taken together, one of the survival mechanisms of PA(+Sias) is the diminution of innate immunity via its adsorption of sialoglycoproteins by its engagement of the inhibitory molecule siglec-9. This is possibly a general mechanism for pathogens that cannot synthesize Sias to subvert immunity. PMID- 22241835 TI - Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. AB - Brown adipose tissue (BAT) is an energy-expending organ that produces heat. Expansion or activation of BAT prevents obesity and diabetes. Chronic cold exposure enhances thermogenesis in BAT through uncoupling protein 1 (UCP1) activation triggered via a beta-adrenergic pathway. Here, we report that the cold sensing transient receptor potential melastatin 8 (TRPM8) is functionally present in mouse BAT. Challenging brown adipocytes with menthol, a TRPM8 agonist, up regulates UCP1 expression and requires protein kinase A activation. Upon mimicking long-term cold exposure with chronic dietary menthol application, menthol significantly increased the core temperatures and locomotor activity in wild-type mice; these effects were absent in both TRPM8(-/-) and UCP1(-/-) mice. Dietary obesity and glucose abnormalities were also prevented by menthol treatment. Our results reveal a previously unrecognized role for TRPM8, suggesting that stimulation of this channel mediates BAT thermogenesis, which could constitute a promising way to treat obesity. PMID- 22241836 TI - Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression. AB - Covalent modifications of histones play an important role in chromatin architecture and dynamics. In particular, histone lysine methylation is important for transcriptional control during diverse biological processes. The nuclear protein Jmjd5 (also called Kdm8) is a histone lysine demethylase that contains a JmjC domain in the C-terminal region. In this study, we have generated Jmjd5 deficient mice (Jmjd5(Delta)(/)(Delta)) to investigate the in vivo function of Jmjd5. Jmjd5(Delta)(/)(Delta) embryos showed severe growth retardation, resulting in embryonic lethality at the mid-gestation stage. Mouse embryonic fibroblasts (MEFs) derived from Jmjd5 hypomorphic embryos (Jmjd5(neo/neo)) also showed the growth defect. Quantitative PCR analysis of various cell cycle regulators indicated that only Cdkn1a expression was upregulated in Jmjd5(neo/neo) MEFs and Jmjd5(Delta)(/)(Delta) embryos. A knockdown assay with Cdkn1a-specific small interfering RNAs revealed that the growth defect of Jmjd5(neo/neo) MEFs was significantly rescued. In addition, a genetic study using Jmjd5(Delta)(/)(Delta); Cdkn1a(Delta)(/)(Delta) double-knockout mice showed that the growth retardation of Jmjd5(Delta)(/)(Delta) embryos was partially rescued by Cdkn1a deficiency. Chromatin immunoprecipitation analysis showed that increased di-methylated lysine 36 of histone H3 (H3K36me2) and reduced recruitment of endogenous Jmjd5 were detected in the transcribed regions of Cdkn1a in Jmjd5(neo/neo) MEFs. Taken together, these results suggest that Jmjd5 physiologically moderates embryonic cell proliferation through the epigenetic control of Cdkn1a expression. PMID- 22241837 TI - Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis. AB - Rest (RE1-silencing transcription factor, also called Nrsf) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells in vitro by preventing precocious expression of neuronal genes. However, the function of Rest during neurogenesis in vivo remains to be elucidated because of the early embryonic lethal phenotype of conventional Rest knockout mice. In the present study, we have generated Rest conditional knockout mice, which allow the effect of genetic ablation of Rest during embryonic neurogenesis to be examined in vivo. We show that Rest plays a role in suppressing the expression of neuronal genes in cultured neuronal cells in vitro, as well as in non-neuronal cells outside of the central nervous system, but that it is dispensable for embryonic neurogenesis in vivo. Our findings highlight the significance of extrinsic signals for the proper intrinsic regulation of neuronal gene expression levels in the specification of cell fate during embryonic neurogenesis in vivo. PMID- 22241838 TI - Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression. AB - During neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers. PMID- 22241839 TI - Excitatory glutamate is essential for development and maintenance of the piloneural mechanoreceptor. AB - The piloneural collar in mammalian hairy skin comprises an intricate pattern of circumferential and longitudinal sensory afferents that innervate primary and secondary pelage hairs. The longitudinal afferents tightly associate with terminal Schwann cell processes to form encapsulated lanceolate nerve endings of rapidly adapting mechanoreceptors. The molecular basis for piloneural development, maintenance and function is poorly understood. Here, we show that Nefh-expressing glutamatergic neurons represent a major population of longitudinal and circumferential sensory afferents innervating the piloneural collar. Our findings using a VGLUT2 conditional-null mouse model indicate that glutamate is essential for innervation, patterning and differentiation of NMDAR(+) terminal Schwann cells during piloneural collar development. Similarly, treatment of adult mice with a selective NMDAR antagonist severely perturbed piloneural collar structure and reduced excitability of these mechanosensory neurons. Collectively, these results show that DRG-derived glutamate is essential for the proper development, maintenance and sensory function of the piloneural mechanoreceptor. PMID- 22241840 TI - A putative tyrosine phosphorylation site of the cell surface receptor Golden goal is involved in synaptic layer selection in the visual system. AB - Golden goal (Gogo) is a cell surface protein that is crucial for proper synaptic layer targeting of photoreceptors (R cells) in the Drosophila visual system. In collaboration with the seven-transmembrane cadherin Flamingo (Fmi), Gogo mediates both temporary and final layer targeting of R-cell axons through its cytoplasmic activity. However, it is not known how Gogo activity is regulated. Here, we show that a conserved Tyr-Tyr-Asp (YYD) tripeptide motif in the Gogo cytoplasmic domain is required for photoreceptor axon targeting. Deleting the YYD motif is sufficient to abolish Gogo function. We demonstrate that the YYD motif is a phosphorylation site and that mutations in the YYD tripeptide impair synaptic layer targeting. Gogo phosphorylation results in axon stopping at the temporary targeting layer, and dephosphorylation is crucial for final layer targeting in collaboration with Fmi. Therefore, both temporary and final layer targeting strongly depend on the Gogo phosphorylation status. Drosophila Insulin-like receptor (DInR) has been reported to regulate the wiring of photoreceptors. We show that insulin signaling is a positive regulator, directly or indirectly, of YYD motif phosphorylation. Our findings indicate a novel mechanism for the regulation of Gogo activity by insulin signaling-mediated phosphorylation. We propose the model that a constant phosphorylation signal is antagonized by a presumably temporal dephosphorylation signal, which creates a permissive signal that controls developmental timing in axon targeting. PMID- 22241841 TI - Novel Tfap2-mediated control of soxE expression facilitated the evolutionary emergence of the neural crest. AB - Gene duplication has been proposed to drive the evolution of novel morphologies. After gene duplication, it is unclear whether changes in the resulting paralogs' coding-regions, or in their cis-regulatory elements, contribute most significantly to the assembly of novel gene regulatory networks. The Transcription Factor Activator Protein 2 (Tfap2) was duplicated in the chordate lineage and is essential for development of the neural crest, a tissue that emerged with vertebrates. Using a tfap2-depleted zebrafish background, we test the ability of available gnathostome, agnathan, cephalochordate and insect tfap2 paralogs to drive neural crest development. With the exception of tfap2d (lamprey and zebrafish), all are able to do so. Together with expression analyses, these results indicate that sub-functionalization has occurred among Tfap2 paralogs, but that neo-functionalization of the Tfap2 protein did not drive the emergence of the neural crest. We investigate whether acquisition of novel target genes for Tfap2 might have done so. We show that in neural crest cells Tfap2 directly activates expression of sox10, which encodes a transcription factor essential for neural crest development. The appearance of this regulatory interaction is likely to have coincided with that of the neural crest, because AP2 and SoxE are not co expressed in amphioxus, and because neural crest enhancers are not detected proximal to amphioxus soxE. We find that sox10 has limited ability to restore the neural crest in Tfap2-deficient embryos. Together, these results show that mutations resulting in novel Tfap2-mediated regulation of sox10 and other targets contributed to the evolution of the neural crest. PMID- 22241842 TI - Geographical variation and incidence of inflammatory bowel disease among US women. AB - OBJECTIVE: Geographical variation in the incidence of Crohn's disease (CD) and ulcerative colitis (UC) according to the latitude of residence has been reported in Europe. However, there are no comparable data in the USA. The incidence of CD and UC in relation to latitude was assessed in a geographically diverse population of women enrolled in two large prospective studies in the USA. DESIGN: A prospective study was undertaken of women enrolled in the Nurses' Health Study I (NHS) in 1976 and in the NHS II in 1989. Information on state of residence at the time of birth, at age 15 years and age 30 years was collected in 1992 in NHS I and in 1993 in NHS II. Reported diagnoses of incident CD or UC to the end of 2003 were confirmed by medical record review. Cox proportional hazards models were used to calculate HRs and 95% CIs for risk of CD and UC. RESULTS: In both cohorts, among 175,912 women reporting their residence in 1992, 257 cases of CD and 313 cases of UC were documented over 3,428,376 person-years of follow-up. The incidence of CD and UC increased significantly with increasing latitude (p(trend)<0.01), with residence at age 30 years more strongly associated with risk. Compared with women residing in northern latitudes at age 30, the multivariate-adjusted HR for women residing in southern latitudes was 0.48 (95% CI 0.30 to 0.77) for CD and 0.62 (95% CI 0.42 to 0.90) for UC. The effect of latitude of residence on risk of CD and UC did not vary according to smoking history (p(interaction)=0.26 for CD and 0.99 for UC). CONCLUSION: In a population of US women, increasing latitude of residence was associated with a higher incidence of CD and UC. PMID- 22241843 TI - Cancer incidence among workers exposed to softwood dust in Lithuania. AB - OBJECTIVES: The aim of this study was to assess cancer incidence in a cohort of woodworkers exposed to softwood dust in a Lithuanian wooden joinery products factory. METHODS: The study population consisted of 1518 workers (1080 men and 438 women) employed in the factory for at least 1 year between 1947 and 1996 and living in Lithuania on 1 January 1978, when the follow-up for cancer incidence began. The follow-up period for cancer was 1978-2007. Cancer risk was assessed by standardised incidence ratios (SIR) with reference to the national population. RESULTS: Overall cancer incidence was not increased among woodworkers. However, the number of mouth and pharynx cancer cases among male woodworkers was significantly increased compared with expected numbers (SIR 2.19, 95% CI 1.17 to 3.74). A higher risk was found for cancer of the buccal cavity than for pharyngeal cancer (SIRs 2.83 and 1.45, respectively). The SIR for larynx cancer was also elevated (SIR 1.39, 95% CI 0.64 to 2.64) among men, while the number of lung cancer cases was higher than expected only among women (SIR 2.07, 95% CI 00.57 to 5.31). CONCLUSIONS: This results of this study support the hypothesis that exposure to softwood dust may increase the risk of oral and pharyngeal cancer. No support was found for an increased risk of other respiratory cancers among workers exposed to softwood dust. PMID- 22241844 TI - Cumulative years in occupation and the risk of hip or knee osteoarthritis in men and women: a register-based follow-up study. AB - OBJECTIVES: Occupational workload has been associated with an increased risk of osteoarthritis (OA), but only little research has been conducted among female workers. The objective of this study was to analyse if men and women in farming, construction or healthcare work have increased risk of developing OA of the hip or knee. METHODS: A follow-up study based on register data of the whole Danish working population in the period 1981 to 2006 followed up for hip or knee OA during 1996 to 2006. Cumulative years in occupation were calculated for assessment of dose-response relationship. Gender-specific analyses were carried out with Cox regression models using age as timescale and adjusting for calendar period, income, unemployment and previous knee injury, and done separately for hip and knee OA. RESULTS: Male floor layers and bricklayers and male and female healthcare assistants had the highest risks of knee OA, and farmers had the highest risk of hip OA. Male farmers had increased risk of hip OA already after 1 5 years in occupation (HR, 1.63) and a dose-response-related risk of hip OA (HR up to 4.22). Generally, the risk of OA increased with cumulative years in the occupation in both men and women. CONCLUSIONS: Occupations with heavy physical workload present a strong risk for hip and knee OA in both men and women, and the risks increase with cumulative years in occupation and noticeable hip OA among male farmers. PMID- 22241845 TI - Occupational class as the indicator of socioeconomic position. PMID- 22241846 TI - Analyses of cadmium and kidney function in lead workers should be adjusted for lead. PMID- 22241847 TI - Structures, energetics and reaction mechanisms of nitrous oxide on transition metal-doped and -undoped single-wall carbon nanotubes. AB - The catalytic activity of carbon nanotubes (CNTs) for the removal of greenhouse gases, like nitrous oxide (N(2)O), can be fine-tuned by metal doping. We modify the inert surfaces of CNTs with Sc, Ti and V transition metals in order to investigate their capability of converting N(2)O to N(2). The stable composite catalysts of Sc-, Ti- and V-doped (5,5)single-walled carbon nanotubes (SWCNTs), along with the unmodified one were investigated by periodic DFT calculations. Without metal doping, the N(2) O decomposition on the bare tube proceeds over a high energy barrier (54.3 kcal mol(-1)) which in the presence of active metals is reduced to 3.6, 8.0 and 10.2 kcal mol(-1) for V-, Ti- and Sc-doped (5,5)SWCNTs, respectively. The superior reactivity is a result of the facilitated electron transfer between the tube and N(2)O caused by the overlap between the d orbitals of the metal and the p orbitals of N(2)O. PMID- 22241848 TI - Instantaneous normal mode analysis of a series of model molten salts. AB - A combination of analytical theory and molecular dynamics simulation was previously used to investigate how the dynamics of a fused salt are affected by the distributions of mass and charge in its component ions. These studies are now extended by using instantaneous normal mode analysis to explore how changes in ionic structure affect translational and rotational dynamics at different frequencies. The results indicate that the details of the charge distribution are important in coupling translational and rotational motion in ionic liquids. The observations are broadly consistent with the predictions of the charge lever moment formalism, and provide insight on the nature of dynamics in fused salts. PMID- 22241849 TI - High-resolution scanning transmission electron microscopy (HRSTEM) techniques: high-resolution imaging and spectroscopy side by side. AB - This work presents an overview of high-resolution scanning transmission electron microscopy (HRSTEM) techniques and exemplifies the novel quantitative characterization possibilities that have emerged from recent advances in these methods. The synergistic combination of atomic resolution imaging and spectroscopy provided by HRSTEM is highlighted as a unique feature that can provide a comprehensive analytical description of material properties at the nanoscale. State-of-the-art high-angle annular dark field and annular bright field examples are depicted as well as the use of X-ray energy-dispersive spectroscopy and electron energy-loss spectroscopy for probing samples properties at the atomic scale. In addition, promising techniques such as cathodoluminescence, confocal HRSTEM, and diffraction mapping are introduced. The presented examples and results indicate that HRSTEM-related techniques are fundamental tools for comprehensive assessment of properties at the atomic scale. PMID- 22241850 TI - Influence of 2'-deoxy sugar moiety on excited-state protonation equilibrium of adenine and adenosine with acridine inside SDS micelles: a time-resolved study with quantum chemical calculations. AB - The protonation dynamics of the DNA base adenine (Ade) and its nucleoside 2' deoxyadenosine (d-Ade) are investigated by monitoring the deprotonation kinetics of an N-heterocyclic DNA intercalator, acridine (Acr), in the confined environment of sodium dodecyl sulfate (SDS) micelles. Protonation of acridine (AcrH(+)) occurs at the hydrophilic interface and this species remains in dynamic equilibrium with its deprotonated counterpart (Acr) inside the hydrophobic core of SDS micelles. Quenching of the fluorescence of AcrH(+)* at 478 nm is observed after addition of Ade and d-Ade with Stern-Volmer constant (K(SV)) 298 and 75 M( 1), respectively, with a concomitant increment in Acr* at 425 nm. Time-resolved fluorescence studies reveal quenching in the lifetime of AcrH(+)*. The relative amplitude of AcrH(+)* decreases from 0.97 to 0.51 and 0.97 to 0.89 with equimolar addition of Ade and d-Ade, respectively. These observations are explained by excited-state proton transfer (ESPT) from AcrH(+)* to the bases. The reduced K(SV) value and negligible change in the relative amplitudes of AcrH(+)* with d Ade infer that ESPT is hindered substantially by the presence of a 2'-deoxy sugar unit. Transient time-resolved absorption spectra of Acr reflect that Ade reduces the absorbance of (3)AcrH(+)*; however, d-Ade keeps it unaltered for more than a time delay of 2 MUs. The optimized geometries calculated by quantum chemical methods reflect deprotonation of AcrH(+)* with protonation at the N1 position of Ade, while it remains protonated with d-Ade. The hindered ESPT between AcrH(+)* and d-Ade singles out the significance of the 2'-deoxy sugar moiety in controlling the deprotonation kinetics. PMID- 22241851 TI - 'Many voices, one song': a model for an oral health programme as a first step in establishing a health promoting school. AB - Four health promoting (HP) schools were established in rural communities in Uganda by a joint Ugandan/Canadian university team. The model was based on a successful Canadian health promotion initiative designed to address poor oral health in Aboriginal children in rural and remote communities. Careful situation analysis, orientation of partner schools and collaborative development of educational materials and evaluation methodology preceded implementation. The intervention had three elements: inclusion of health topics by teachers in regular classroom activities; health education delivered by the university team to reinforce key educational concepts; and daily in-school tooth brushing to develop healthy practices. All children entering Grade 1 at four schools were recruited for 4 years; evaluation included year 1 pre-intervention and annual end of-year data collection of quantitative and qualitative measures. Principal findings at 4 years included: an increase from baseline in the original cohort (n = 600) in those brushing at least once daily (p < 0.05) and before bed (p < 0.05); improved oral health (less 'bad breath', pain and absences for emergency dental treatment); more comprehensive health knowledge. Other positive observations were change in the schools' health culture; children sharing new health knowledge and advocating for health practices learned; and evolution of health promotion activity to address other community-identified issues following success with the initial oral health component. University faculty and students learned from participation in programme delivery and community-based educational opportunities. School-based health promotion using this oral health model was readily accepted, implemented, sustained and evaluated; all communities took ownership, and all schools continue their programmes. Addressing oral health through HP schools is novel in Africa, and several lessons learned are of potential value for similar health promotion initiatives in sub-Saharan Africa. PMID- 22241852 TI - Videotaped interviews as a medium to enhance cross-cultural programme evaluation. AB - Evaluation is a required component of interventions. Written data are the predominant source. However, video recording is used in many applications to evaluate a range of encounters and practices. We report assessment of the role of videotaped interviews in programme evaluation. Interviews using a consistent script of open-ended questions were recorded during evaluation of an international child-health promotion programme in Uganda by individuals with basic training and equipment. Participants were a convenience sample of programme team members (six school teachers, and six Ugandan and 12 Canadian health-care trainees) who had completed the annual written evaluation questionnaire. Evaluators reviewed each participant's videotaped interview and questionnaire, content coded the responses against a criterion-based check list, documented how many times factual information was contributed on each question and compared the data. Videos were also assessed for strong positive or negative emotion. Videotaped interviews provided more comprehensive responses than written questionnaires, and were more accurate where mis-comprehension of question meaning occurred. The video interview, unlike the written questionnaire, allowed rephrasing for clarification. The video interview medium enhanced programme evaluation by providing more facts, greater insight into the effects of the interventions and clearer direction for future activity. Hence, video-recorded feedback has great potential value in applied research for comprehensive programme evaluation. PMID- 22241853 TI - The concept of scalability: increasing the scale and potential adoption of health promotion interventions into policy and practice. AB - Increased focus on prevention presents health promoters with new opportunities and challenges. In this context, the study of factors influencing policy-maker decisions to scale up health promotion interventions from small projects or controlled trials to wider state, national or international roll-out is increasingly important. This study aimed to: (i) examine the perspectives of senior researchers and policy-makers regarding concepts of 'scaling up' and 'scalability'; (ii) generate an agreed definition of 'scalability' and (iii) identify intervention and research design factors perceived to increase the potential for interventions to be implemented on a more widespread basis or 'scaled up'. A two-stage Delphi process with an expert panel of senior Australian public health intervention researchers (n = 7) and policy-makers (n = 7) and a review of relevant literature were conducted. Through this process 'scalability' was defined as: the ability of a health intervention shown to be efficacious on a small scale and or under controlled conditions to be expanded under real world conditions to reach a greater proportion of the eligible population, while retaining effectiveness. Results showed that in health promotion research insufficient attention is given to issues of effectiveness, reach and adoption; human, technical and organizational resources; costs; intervention delivery; contextual factors and appropriate evaluation approaches. If these issues were addressed in the funding, design and reporting of intervention research, it would advance the quality and usability of research for policy-makers and by doing so improve uptake and expansion of promising programs into practice. PMID- 22241854 TI - Unique author identifier; what are we waiting for? PMID- 22241855 TI - Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. AB - BACKGROUND: Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the 'molar tooth sign'), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical/molecular diagnosis and management challenging. CC2D2A mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of CC2D2A mutations in patients with JS have been incompletely reported. METHODS: Subjects with JS from 209 families were evaluated to identify mutations in CC2D2A. Clinical and imaging features in subjects with CC2D2A mutations were compared with those in subjects without CC2D2A mutations and reports in the literature. RESULTS: 10 novel CC2D2A mutations in 20 subjects were identified; a summary is provided of all published CC2D2A mutations. Subjects with CC2D2A-related JS were more likely to have ventriculomegaly (p<0.0001) and seizures (p=0.024) than subjects without CC2D2A mutations. No mutation-specific genotype-phenotype correlations could be identified, but the findings confirm the observation that mutations that cause CC2D2A-related JS are predicted to be less deleterious than mutations that cause CC2D2A-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C terminal region, identify these regions as important for the biological mechanisms underlying JS. CONCLUSIONS: CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A related JS should be monitored for hydrocephalus and seizures. PMID- 22241856 TI - Impaired adaptation of gastrointestinal motility following chronic stress in maternally separated rats. AB - Exposure to early life stress causes increased stress responsiveness and permanent changes in the central nervous system. We recently showed that delayed gastric emptying (GE) and accelerated colonic transit (CT) in response to acute restraint stress (ARS) were completely restored following chronic homotypic stress (CHS) in rats via upregulation of hypothalamic oxytocin (OXT) expression. However, it is unknown whether early life stress affects hypothalamic OXT circuits and gastrointestinal motor function. Neonatal rats were subjected to maternal separation (MS) for 180 min/day for 2 wk. Anxiety-like behaviors were evaluated by the elevated-plus-maze test. GE and CT were measured under nonstressed (NS), ARS, and CHS conditions. Expression of corticotropin-releasing factor (CRF) and OXT in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real time RT-PCR and immunohistochemistry. MS increased anxiety-like behaviors. ARS delayed GE and accelerated CT in control and MS rats. After CHS, delayed GE and accelerated CT were restored in control, but not MS, rats. CRF mRNA expression was significantly increased in response to ARS in control and MS rats. Increased CRF mRNA expression was still observed following CHS in MS, but not control, rats. In response to CHS, OXT mRNA expression was significantly increased in control, but not MS, rats. The number of OXT-immunoreactive cells was increased following CHS in the magnocellular part of the PVN in control, but not MS, rats. MS impairs the adaptation response of gastrointestinal motility following CHS. The mechanism of the impaired adaptation involves downregulation of OXT and upregulation of CRF in the hypothalamus in MS rats. PMID- 22241857 TI - RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter. AB - The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK- and PKC-selective inhibitors Y 27632 and Go 6850 (10(-8) to 10(-4) M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA/ROCK II, PKC alpha, MYPT1, CPI-17, and MLC(20) in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC(20), before and after Y 27632 and Go 6850. Data show higher levels of RhoA/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA/ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment. PMID- 22241858 TI - Intracellular cholesterol-binding proteins enhance HDL-mediated cholesterol uptake in cultured primary mouse hepatocytes. AB - A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4 yl)-amino]-23,24-bisnor-5-cholen-3beta-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in <1 min and initial rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD 95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2/SCP-x/L-FABP null mice and hepatocytes. Taken together, these results suggest that L-FABP, particularly in the absence of SCP 2, plays a significant role in HDL-mediated cholesterol uptake in cultured primary hepatocytes. PMID- 22241859 TI - Nicotine suppresses hyperexcitability of colonic sensory neurons and visceral hypersensivity in mouse model of colonic inflammation. AB - Recently, we reported that nicotine in vitro at a low 1-MUM concentration suppresses hyperexcitability of colonic dorsal root ganglia (DRG; L(1)-L(2)) neurons in the dextran sodium sulfate (DSS)-induced mouse model of acute colonic inflammation (1). Here we show that multiple action potential firing in colonic DRG neurons persisted at least for 3 wk post-DSS administration while the inflammatory signs were diminished. Similar to that in DSS-induced acute colitis, bath-applied nicotine (1 MUM) gradually reduced regenerative multiple-spike action potentials in colonic DRG neurons to a single action potential in 3 wk post-DSS neurons. Nicotine (1 MUM) shifted the activation curve for tetrodotoxin (TTX)-resistant sodium currents in inflamed colonic DRG neurons (voltage of half activation changed from -37 to -32 mV) but did not affect TTX-sensitive currents in control colonic DRG neurons. Further, subcutaneous nicotine administration (2 mg/kg b.i.d.) in DSS-treated C57Bl/J6 male mice resulted in suppression of hyperexcitability of colonic DRG (L(1)-L(2)) neurons and the number of abdominal constrictions in response to intraperitoneal injection of 0.6% acetic acid. Collectively, the data suggest that neuronal nicotinic acetylcholine receptor mediated suppression of hyperexcitability of colonic DRG neurons attenuates reduction of visceral hypersensitivity in DSS mouse model of colonic inflammation. PMID- 22241860 TI - Colonic microbiome is altered in alcoholism. AB - Several studies indicate the importance of colonic microbiota in metabolic and inflammatory disorders and importance of diet on microbiota composition. The effects of alcohol, one of the prominent components of diet, on colonic bacterial composition is largely unknown. Mounting evidence suggests that gut-derived bacterial endotoxins are cofactors for alcohol-induced tissue injury and organ failure like alcoholic liver disease (ALD) that only occur in a subset of alcoholics. We hypothesized that chronic alcohol consumption results in alterations of the gut microbiome in a subgroup of alcoholics, and this may be responsible for the observed inflammatory state and endotoxemia in alcoholics. Thus we interrogated the mucosa-associated colonic microbiome in 48 alcoholics with and without ALD as well as 18 healthy subjects. Colonic biopsy samples from subjects were analyzed for microbiota composition using length heterogeneity PCR fingerprinting and multitag pyrosequencing. A subgroup of alcoholics have an altered colonic microbiome (dysbiosis). The alcoholics with dysbiosis had lower median abundances of Bacteroidetes and higher ones of Proteobacteria. The observed alterations appear to correlate with high levels of serum endotoxin in a subset of the samples. Network topology analysis indicated that alcohol use is correlated with decreased connectivity of the microbial network, and this alteration is seen even after an extended period of sobriety. We show that the colonic mucosa-associated bacterial microbiome is altered in a subset of alcoholics. The altered microbiota composition is persistent and correlates with endotoxemia in a subgroup of alcoholics. PMID- 22241861 TI - Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier. AB - Intestinal epithelial barrier disruption is a feature of inflammatory bowel disease (IBD), but whether barrier disruption precedes or merely accompanies inflammation remains controversial. Tight junction (TJ) adhesion complexes control epithelial barrier integrity. Since some TJ proteins reside in cholesterol-enriched regions of the cell membrane termed lipid rafts, we sought to elucidate the relationship between rafts and intestinal epithelial barrier function. Lipid rafts were isolated from Caco-2 intestinal epithelial cells primed with the proinflammatory cytokine interferon-gamma (IFN-gamma) or treated with methyl-beta-cyclodextrin as a positive control for raft disruption. Rafts were also isolated from the ilea of mice in which colitis had been induced in conjunction with in vivo intestinal permeability measurements, and lastly from intestinal biopsies of ulcerative colitis (UC) patients with predominantly mild or quiescent disease. Raft distribution was analyzed by measuring activity of the raft-associated enzyme alkaline phosphatase and by performing Western blot analysis for flotillin-1. Epithelial barrier integrity was estimated by measuring transepithelial resistance in cytokine-treated cells or in vivo permeability to fluorescent dextran in colitic mice. Raft and nonraft fractions were analyzed by Western blotting for the TJ proteins occludin and zonula occludens-1 (ZO-1). Our results revealed that lipid rafts were disrupted in IFN-gamma-treated cells, in the ilea of mice with subclinical colitis, and in UC patients with quiescent inflammation. This was not associated with a clear pattern of occludin or ZO-1 relocalization from raft to nonraft fractions. Significantly, a time-course study in colitic mice revealed that disruption of lipid rafts preceded the onset of increased intestinal permeability. Our data suggest for the first time that lipid raft disruption occurs early in the inflammatory cascade in murine and human colitis and, we speculate, may contribute to subsequent disruption of epithelial barrier function. PMID- 22241862 TI - Clathrin mediates endocytosis of progastrin and activates MAPKs: role of cell surface annexin A2. AB - Cell-surface-associated annexin A2 (CS-ANXA2) is a nonconventional "receptor" for progastrin; expression levels of both are elevated in colon cancers, and downregulation of either reduces tumorigenic potential of cells. We recently reported internalization of progastrin in target cells. Here, mechanisms mediating internalization of progastrin were examined. Initially, we confirmed that cell-surface ANXA2 mediates binding and internalization of progastrin in intestinal cells. Progastrin, covalently linked to sepharose beads, failed to activate p38MAPK/ERKs, suggesting internalization of progastrin was required for eliciting biological effects; importantly annexin A2 expression and availability of CS-ANXA2 were required for internalization of progastrin. Clathrin expression and formation of clathrin-coated pits were critically required for endocytotic internalization of progastrin; in the absence of clathrin, progastrin failed to activate p38MAPK/ERKs. Downregulation of caveolin had no effect on binding or internalization of progastrin. We therefore demonstrate for the first time that progastrin binds CS-ANXA2 and is rapidly internalized via clathrin-mediated endocytotic pathway, resulting in activation of MAPKinases. Targeting clathrin mediated endocytosis of progastrin may thus inhibit previously reported co carcinogenic/tumorigenic effects of progastrin on intestinal cells. PMID- 22241864 TI - Abortion and the argument from potential: what we owe to the ones who might exist. AB - I challenge the idea that the argument from potential (AFP) represents a valid moral objection to abortion. I consider the form of AFP that was defended by Hare, which holds that abortion is against the interests of the potential person who is prevented from existing. My reply is that AFP, though not unsound by itself, does not apply to the issue of abortion. The reason is that AFP only works in the cases of so-called same number and same people choices, but it falsely presupposes that abortion is such a kind of choice. This refutation of AFP implies that (1) abortion is not only morally permissible but sometimes even morally mandatory and (2) abortion is morally permissible even when the potential person's life is foreseen to be worth living. PMID- 22241863 TI - Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation: role of Ca2+-dependent mitochondrial formation of reactive oxygen species. AB - Onset of the mitochondrial permeability transition (MPT) is the penultimate event leading to lethal cellular ischemia-reperfusion injury, but the mechanisms precipitating the MPT after reperfusion remain unclear. Here, we investigated the role of mitochondrial free Ca(2+) and reactive oxygen species (ROS) in pH- and MPT-dependent reperfusion injury to hepatocytes. Cultured rat hepatocytes were incubated in anoxic Krebs-Ringer-HEPES buffer at pH 6.2 for 4 h and then reoxygenated at pH 7.4 to simulate ischemia-reperfusion. Some cells were loaded with the Ca(2+) chelators, BAPTA/AM and 2-[(2-bis-[carboxymethyl]aono-5 methoxyphenyl)-methyl-6-methoxy-8-bis[carboxymethyl]aminoquinoline, either by a cold loading protocol for intramitochondrial loading or by warm incubation for cytosolic loading. Cell death was assessed by propidium iodide fluorometry and immunoblotting. Mitochondrial Ca(2+), inner membrane permeability, membrane potential, and ROS formation were monitored with Rhod-2, calcein, tetramethylrhodamine methylester, and dihydrodichlorofluorescein, respectively. Necrotic cell death increased after reoxygenation. Necrosis was blocked by 1 MUM cyclosporin A, an MPT inhibitor, and by reoxygenation at pH 6.2. Confocal imaging of Rhod-2, calcein, and dichlorofluorescein revealed that an increase of mitochondrial Ca(2+) and ROS preceded onset of the MPT after reoxygenation. Intramitochondrial Ca(2+) chelation, but not cytosolic Ca(2+) chelation, prevented ROS formation and subsequent necrotic and apoptotic cell death. Reoxygenation with the antioxidants, desferal or diphenylphenylenediamine, also suppressed MPT-mediated cell death. However, inhibition of cytosolic ROS by apocynin or diphenyleneiodonium chloride failed to prevent reoxygenation-induced cell death. In conclusion, Ca(2+)-dependent mitochondrial ROS formation is the molecular signal culminating in onset of the MPT after reoxygenation of anoxic hepatocytes, leading to cell death. PMID- 22241865 TI - How 'decent' is a decent minimum of health care? AB - This article tries to analyze the meaning of a decent minimum of health care, by confronting the idea of decent care with the concept of justice. Following the ideas of Margalith about a decent society, the article argues that a just minimum of care is not necessarily a decent minimum. The way this minimum is provided can still humiliate individuals, even if the end result is the best possible distribution of the goods as seen from the viewpoint of justice. This analysis is combined with an analysis from the perspective of solidarity, particularly of reflective solidarity, as a way to develop decent care, which is care that does not humiliate individuals and maintains their dignity. PMID- 22241866 TI - Epistemic humility and medical practice: translating epistemic categories into ethical obligations. AB - Physicians and other medical practitioners make untold numbers of judgments about patient care on a daily, weekly, and monthly basis. These judgments fall along a number of spectrums, from the mundane to the tragic, from the obvious to the challenging. Under the rubric of evidence-based medicine, these judgments will be informed by the robust conclusions of medical research. In the ideal circumstance, medical research makes the best decision obvious to the trained professional. Even when practice approximates this ideal, it does so unevenly. Judgments in medical practice are always accompanied by uncertainty, and this uncertainty is a fickle companion--constant in its presence but inconstant in its expression. This feature of medical judgments gives rise to the moral responsibility of medical practitioners to be epistemically humble. This requires the recognition and communication of the uncertainty that accompanies their judgment as well as a commitment to avoiding intuitive innovations. PMID- 22241867 TI - Comparison of bone mineral density in the jaws of patients with and without chronic periodontitis. AB - OBJECTIVES: Although several studies have addressed the relationship between systemic bone mineral status and the severity of periodontitis, there is little knowledge of the relationship between periodontal disease and locally detected bone mineral density. The aim of this study was to compare the mandibular bone mineral density of patients with chronic periodontitis with that of periodontally healthy subjects. METHODS: 48 systemically healthy subjects were included in the study and underwent a periodontal examination to determine their status. 24 subjects were periodontally healthy and the other 24 had moderate or severe chronic periodontitis. The mandibular bone mineral density of the subjects was determined by dual energy X-ray absorptiometry. The region of interest on the body of the mandible was independently determined on the dual energy absorptiometry radiographs, and a computer calculated the bone mineral density of these regions. RESULTS: The mandibular bone mineral density of the subjects with periodontitis was significantly lower than that of the periodontally healthy subjects (p < 0.01). There were significant negative correlations between the mandibular bone mineral density values and parameters related to the amount of periodontal destruction. CONCLUSIONS: Low bone mineral density in the jaw may be associated with chronic periodontitis. PMID- 22241868 TI - Unusual manifestation of a multiple myeloma in the hyoid bone. AB - The most common manifestation of plasma cell neoplasms is multiple myeloma. Solitary and localized tumours in the form of solitary plasmacytoma of the bone or extramedullary plasmacytoma are rare. In the late stages of multiple myeloma, bulky bone tumour infiltrates may be found which may be the primary clinical manifestation of the previously unknown malignancy. We report a case of a hyoid bone tumour with extramedullary plasma cell infiltrates in the oropharynx in multiple myeloma. PMID- 22241869 TI - Enlarged follicles and temporomandibular joint abnormalities in mucolipidosis Type III. AB - Mucolipidosis Type III, or pseudo-Hurler polydystrophy, is a rare genetic abnormality, the result of a mutation to one of two genes that encode the hexameric protein N-acetylglucosaminyl-1-phosphotransferase (Glc-NAc-PT). The abnormality results in the accumulation of unprocessed macromolecules in cell and tissue compartments throughout the body. In this case report, we describe the clinical and radiographic findings of a 15-year-old male with this disorder. He presented with bilateral ectopically developing mandibular molar teeth with enlarged follicles and multiple joint involvement, including the temporomandibular joints. The patient underwent surgical removal of the molar teeth and curettage of the associated follicles. The subsequent histopathological examination of the tissues revealed hyperplastic follicles suggestive of dentigerous cysts. This report presents the plain film and cone beam CT examinations of the patient. PMID- 22241870 TI - Effectiveness of the analysis of craniofacial morphology and pharyngeal airway morphology in the treatment of children with obstructive sleep apnoea syndrome. AB - OBJECTIVE: In general, no consensus has been reached regarding the diagnostic criteria for obstructive sleep apnoea syndrome (OSAS) in children and the criteria for selecting treatment are inconsistent. Therefore, the craniofacial and pharyngeal airway morphology of OSAS in children who had undergone drug therapy (non-op group) and OSAS in children who had undergone both drug therapy and surgical therapy (adenotonsillectomy) (op group) were compared. The purpose of this study was to examine the effectiveness of craniofacial morphology and pharyngeal airway morphology analysis in the treatment of children with OSAS. METHODS: The craniofacial and pharyngeal airway morphology of the control group, the non-op group and the op group were compared to examine the differences of each group. The comparison used Mann-Whitney's U test. RESULTS: A comparison between the non-op and the op groups showed significant differences in the facial axis, mandibular plane angle, ramus plane to the SN (porion and orbit) point, point Pog (pogonion) to the McNamara line, anteroposterior dysplasia indicator (APDI), D-AD1 [the distance between the posterior nasal spine (PNS) point and the nearest adenoid tissue, measured along the PNS-Ba (basion) point plane], D-AD2 (the distance between the PNS point and the nearest adenoid tissue, measured along a line from the PNS point perpendicular to the S (sella turcica)-Ba point plane), upper pharynx and soft palatal length. The op group showed significantly lower values of APDI than the non-op group, indicating that the op group showed a significant occlusion of class II, and that the mandibular bone was positioned posteriorly relative to the maxillary bone. CONCLUSIONS: The op group showed a significant posterior position and backward rotation of the mandibular bone, stenosis of the nasopharyngeal airway and an elongated soft palate compared with the non-op group, and it was speculated that there was a high probability of the necessity of surgical therapy (adenotonsillectomy) when a morphological factor played a major role as a cause of obstructive sleep apnoea. We recommend craniofacial morphology analysis and pharyngeal airway morphology analysis in the diagnosis and treatment planning of OSAS children. PMID- 22241871 TI - Congenital infiltrating lipomatosis of the face with exophytic temporomandibular joint ankylosis: a case report and review of the literature. AB - Congenital infiltrating lipomatosis of the face (CIL-F) is a rare lipomatous lesion with diffuse fatty infiltration of tissues and hyperplasia of underlying bone. We report clinical and CT findings in an unusual case of CIL-F presenting with progressive hemifacial asymmetry, manifesting as severely restricted mouth opening owing to exophytic temporomandibular joint ankylosis. The role of imaging in diagnosis is presented with a review of the literature. Differential diagnosis of CIL-F and its exclusion as a cause of hemifacial hyperplasia are also discussed. PMID- 22241872 TI - Changes of parotid and submandibular glands caused by radiotherapy--an ultrasound evaluation. AB - OBJECTIVE: Radiotherapy may alter the normal morphology of salivary glands located in the radiation field. These changes could be evaluated safely by sonography; however, there have been few studies in this regard. This study is aimed at evaluating the sonographic changes of the parotid and submandibular glands in patients undergoing radiotherapy for head and neck malignancies. METHODS: 20 patients (16 males and 4 females) with head and neck malignancies who had been referred for radiotherapy to the Qaem Hospital in Mashhad, Iran, entered the study. Length, height, depth, echotexture, echogenicity and margins of parotid and submandibular glands were evaluated in three stages (I, before radiotherapy; II, 2 weeks after radiotherapy; and III, 6-7 weeks after radiotherapy) using sonography. Peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index (RI) were also evaluated by Doppler sonography. RESULTS: Significant differences in length, height and depth (p = 0.000, p = 0.000, and p = 0.39, respectively) and also echotexture, echogenicity and gland margins (p = 0.000) were observed before and after radiotherapy. Doppler sonography results showed no significant differences regarding PSV, EDV and RI between sonographic stages. Echotexture and echogenicity were the only independent parameters that showed significant differences in sonographic stages I and II (p = 0.000). Length in stage I and II (p = 0.000) and echogenicity in stage III (p = 0.038) were the only parameters that showed significant differences between the two glands. CONCLUSION: Radiotherapy may change the echotexture, echogenicity and margins of the salivary glands from homogenic to heterogenic, hyperechoic to hypoechoic and regular to irregular, respectively, and may reduce their size. PMID- 22241873 TI - Gorham's disease: a report of a case with mandibular involvement in a 10-year follow-up study. AB - Gorham's disease, or vanishing bone disease, is a rare condition of unknown aetiology. Any bone of the body can be affected, although there is a predilection for the pelvis, humerus, axial skeleton and the mandible. The mandible is the most commonly involved bone in the maxillofacial region. 41 cases have been reported so far in the literature showing involvement of the mandible in Gorham's disease. This paper presents a rare case of Gorham's disease involving the mandible in a 38-year-old male with a 10-year follow-up. PMID- 22241875 TI - Texture analysis of CT images in the characterization of oral cancers involving buccal mucosa. AB - OBJECTIVE: The aim of this study was to investigate the usefulness of texture analysis in the characterization of oral cancers involving the buccal mucosa and to assess its effectiveness in differentiating between the various grades of the tumour. METHODS: Contrast enhanced CT examination was carried out in 21 patients with carcinoma of the buccal mucosa who had consented to retrospective analysis during a research study that was approved by the institutional review board. Two regions of interest (ROIs) were created, one at the site of the lesion and the other at the contralateral normal side. Texture analysis measures of fractal dimension (FD), lacunarity and grey level co-occurrence matrix (GLCM) were computed for each ROI. The numeric data from the two ROIs were compared and were correlated with the tumour grade as confirmed by biopsy. RESULTS: The difference between the mean FD and GLCM parameters of the lesion vs the normal ROI were statistically significant (p < 0.05); no significant difference was observed between the three grades of tumour for any of the parameters (p > 0.05). CONCLUSION: Texture analysis on CT images is a potential method in the characterization of oral cancers involving the buccal mucosa and deserves further investigation as a predictor of tumour aggression. PMID- 22241874 TI - Contrast-enhanced CT and MRI for detecting neck metastasis of oral cancer: comparison between analyses performed by oral and medical radiologists. AB - OBJECTIVES: The aim of the study was to verify the concordance of contrast enhanced CT (CECT) and MRI evaluation among four radiologists in detecting metastatic cervical lymph nodes of oral cancer patients. METHODS: Ten patients underwent clinical and imaging examinations (CECT and MRI). Four radiologists, two oral and maxillofacial radiologists (OMRs) and two medical radiologists (MRs), independently analysed the images twice. Cohen's kappa index and Wilcoxon signed-rank test were used to verify the concordance between all analyses. RESULTS: Regarding the interobserver agreement, the OMRs presented excellent kappa values for determining the regional lymph nodes (N-stage) in both CECT and MRI. The MRs presented moderate agreement for CECT evaluation at the first reading, but no concordance was found for the other analyses. When each imaging modality was analysed separately, kappa values were higher between all examiners. Greater variability was demonstrated between N-stage evaluation using different examinations. All radiologists were able to identify a greater number of metastatic lymph nodes in CECT than in MRI, except one MR, but no significant difference was found for all readers. The differences between the number of metastatic lymph nodes among all radiologists were not statistically significant. Moderate intraobserver agreement was observed for CECT and MRI evaluation, except for one MR. CONCLUSIONS: The differences found between the N-stage performed by OMRs and MRs support the necessity of a multidisciplinary approach in the imaging evaluation of metastatic nodes. Further studies are necessary to confirm which imaging modality should be employed when evaluating neck areas. PMID- 22241876 TI - Radiographic manifestations of the temporomandibular joint in a case of Proteus syndrome. AB - Proteus syndrome is a rare disorder with progressive asymmetrical and disproportionate overgrowth of various tissues of the body. The syndrome is characterized by a wide range of malformations, including craniofacial deformities. Extraoral examination revealed several of the classical craniofacial features of Proteus syndrome: pronounced hemifacial hypertrophy, macrodactyly and hyperostosis. Intraoral examination revealed a high arched palate and gingival hyperplasia. Other findings were unilateral enlargement of the tongue, alveolar growth and dilaceration of the roots of the teeth. There were severe degenerative changes and deformities in the left temporomandibular joint but the oversized condyle was asymptomatic; there was no pain, limitation and deviation at mouth opening. Treatment was not necessary owing to the asymptomatic situation but periodic follow-up with clinical and radiographic examination was considered. The aim of this article is to describe the radiographic manifestations of an asymptomatic condyle malformation and other craniofacial, oral and dental findings in a 33-year-old female patient with known Proteus syndrome. PMID- 22241877 TI - Bilateral bifid mandibular condyles diagnosed with three-dimensional reconstruction. AB - Bifid mandibular condyles (BMCs) are rare anomalies. The overwhelming majority of prior reports described their predominantly unilateral occurrence diagnosed by panoramic radiography. We present an even rarer case of bilateral BMC initially identified by panoramic radiography and confirmed with colour-enhanced three dimensional CT. These images substantiate the theory that the secondary condyles arise from the neck of the mandible (Lopez-Lopez et al. Bifid condyle: review of the literature of the last 10 years and report of two cases. Cianio 2010; 28: 136 140). PMID- 22241878 TI - Metal artefact reduction with cone beam CT: an in vitro study. AB - BACKGROUND: Metal in a patient's mouth has been shown to cause artefacts that can interfere with the diagnostic quality of cone beam CT. Recently, a manufacturer has made an algorithm and software available which reduces metal streak artefact (Picasso Master 3D(r) machine; Vatech, Hwaseong, Republic of Korea). OBJECTIVES: The purpose of this investigation was to determine whether or not the metal artefact reduction algorithm was effective and enhanced the contrast-to-noise ratio. METHODS: A phantom was constructed incorporating three metallic beads and three epoxy resin-based bone substitutes to simulate bone next to metal. The phantom was placed in the centre of the field of view and at the periphery. 10 data sets were acquired at 50-90 kVp. The images obtained were analysed using a public domain software ImageJ (NIH Image, Bethesda, MD). Profile lines were used to evaluate grey level changes and area histograms were used to evaluate contrast. The contrast-to-noise ratio was calculated. RESULTS: The metal artefact reduction option reduced grey value variation and increased the contrast-to-noise ratio. The grey value varied least when the phantom was in the middle of the volume and the metal artefact reduction was activated. The image quality improved as the peak kilovoltage increased. CONCLUSION: Better images of a phantom were obtained when the metal artefact reduction algorithm was used. PMID- 22241879 TI - Volumetric difference evaluation of registered three-dimensional pre-operative and post-operative CT dental data. AB - OBJECTIVE: The purpose of this study is to propose a complete methodology for automatically registering three-dimensional (3D) pre-operative and post-operative CT scan dental volumes as well as to provide a toolset for quantifying and evaluating their volumetric differences. METHODS: The proposed methodology was applied to cone beam CT (CBCT) data from 20 patients in order to assess the volume of augmented bone in the alveolar region. In each case, the pre-operative and post-operative data were registered using a 3D affine-based scheme. The performance of the 3D registration algorithm was evaluated by measuring the average distance between the edges of the registered sets. The differences between the registered sets were assessed through 3D subtraction radiography. The volume of the differences was finally evaluated by defining regions of interest in each slice of the subtracted 3D data and by combining all respective slices to model the desired volume of interest. The effectiveness of the algorithm was verified by applying it to several reference standard-shaped objects with known volumes. RESULTS: Satisfactory alignment was achieved as a low average offset of 1.483 +/- 1.558 mm was recorded between the edges of the registered sets. Moreover, the estimated volumes closely matched the volumes of the reference objects used for verification, as the recorded volume differences were less than 0.4 mm(3) in all cases. CONCLUSION: The proposed method allows for automatic registration of 3D CBCT data sets and the volumetric assessment of their differences in particular areas of interest. The proposed approach provides accurate volumetric measurements in three dimensions, requiring minimal user interaction. PMID- 22241881 TI - Septic thrombosis of the cavernous sinus secondary to a Streptococcus milleri oral infection. AB - Septic thrombosis of the cavernous sinus (STCS) is an uncommon and potentially lethal disease. Sphenoid and ethmoid sinusitis followed by facial cutaneous infections represents the most common aetiologies, with Staphylococcus aureus as the main responsible organism followed by the Streptococcus pneumoniae. Although all infectious foci of the head and neck area can potentially spread to the cavernous sinus, STCS from oral infection is an exceptionally rare occurrence. We report the unusual case of a patient who presented with an acute STCS secondary to a generalized Streptococcus milleri periodontitis. This case highlights the importance of systematically performing a detailed examination of the oral cavity in patients presenting with intracranial infections caused by uncommon pathogens such as the Streptococcus milleri group. PMID- 22241880 TI - Bilateral adenomatoid odontogenic tumour of the maxilla in a 2-year-old female- the report of a rare case and review of the literature. AB - Multifocal odontogenic lesions are uncommon and have only been observed in conditions associated with known genetic mutations. To the best of our knowledge, only two cases of multifocal adenomatoid odontogenic tumours (AOT) have previously been reported in the literature. In this study, we report the first case of a bilateral, separate AOT in the maxilla in the midline in a 2-year-old female. The patient presented with bilateral expansile masses in the maxilla on either side of the midline which had been present for 6 months. She was asymptomatic and had occasional difficulty in breathing. The tumour was diagnosed as AOT and was surgically enucleated along with the associated teeth. The patient recovered well and has been on recall for 5 years. The follow-up panoramic radiograph made a fortnight ago revealed evidence of three new radio-opaque lesions with an associated tooth in the region of the anterior mandible, the premolar region of the right maxilla and the molar region of the left maxilla. To acquire additional information about AOT, all reports regarding AOT cited in 'PubMed' from 1995 onward were reviewed and the incidence, clinical features, radiographic features and management of AOT are discussed in this study. PMID- 22241882 TI - Infraorbital ethmoid (Haller's) cells: a panoramic radiographic study. AB - OBJECTIVE: Haller's cells or infraorbital ethmoid cells refer to the ethmoidal pneumatization of the superior aspect of the maxillary sinus and floor of the orbit. The clinical importance of these entities initiated this study with an aim to determine the prevalence and characteristics of Haller's cells on panoramic radiographs. METHODS: The study group comprised 600 healthy adults of both genders with an age range of 18-60 years. One panoramic radiograph for each of the patients was made and interpreted for the presence of Haller's cells. The data collected were subjected to statistical analysis: frequencies/percentages, descriptive statistics, chi(2) test and cross-tabulation (contingency table analysis) to obtain the results. RESULTS: Haller's cells were noted in 96 patients, accounting for a prevalence of 16%. Of these patients, 77.1% were unilateral while 22.9% were bilateral. Among 96 cases, a total of 204 cells were found. The majority of the cells were round or ovoid in shape. The unilocular type of Haller's cells occurring unilaterally was statistically significant. CONCLUSION: This study has attempted to explore the characteristics of Haller's cells on panoramic radiographs. A description of Haller's cells on these radiographs may prove vital in enumerating the differential diagnosis for patients afflicted with intractable orofacial pain and reduce the risk of untoward intraoperative complications during endonasal procedures. PMID- 22241883 TI - MRI analysis of the relationship between bone changes in the temporomandibular joint and articular disc position in symptomatic patients. AB - OBJECTIVES: The aim of this study was to investigate bone changes in the condyle, articular eminence and glenoid fossa in relation to the position of the articular disc. METHODS: 148 temporomandibular joints (TMJs) of 74 symptomatic patients who underwent MRI were evaluated. The position of the disc was classified as either normal (N), disc displacement with reduction (DDwR), disc displacement without reduction (DDwoR) and posterior displacement (PD). Bone changes were investigated in the condyle and temporal components of the TMJ and classified as osteophytosis, sclerosis or erosion. RESULTS: There were no bone changes in the glenoid fossa of the temporal bone. Of the total number of TMJs studied, 94 (63.5%) were N, 34 (23%) presented DDwoR, 19 (12.8%) presented DDwR and 1 (0.7%) presented PD. The bone changes in the condyle and posterior aspect of the articular eminence were associated with the position of the disc. The bone changes in the anterior aspect of the articular eminence were not associated with the position of the disc. CONCLUSION: In cases of DDwoR, bone changes in the condyles were more common. The combination of erosion and osteophytosis in the condyle and the bone changes of the posterior aspect of the articular eminence were associated with disc position. PMID- 22241884 TI - Calcification of the external carotid arteries and their branches. AB - This patient had longstanding hypercalcaemia and hyperphosphataemia owing to chronic renal disease, then finally failure, inducing tertiary hyperparathyroidism. He also had long histories of diabetes mellitus type II, hypertension and hypercholesterolaemia. He then reported a painful expansile swelling of the anterior mandible which was diagnosed as a "brown tumour". Subsequent review of the CT data set by an oral and maxillofacial radiologist revealed two patterns of calcification of the carotid arteries. A pipestem pattern was observed bilaterally along almost the entire lengths of the external carotid artery, a muscular artery, and its branches whereas plaque-like calcification was observed in the common and internal carotid arteries (elastic arteries). The pipestem pattern, hitherto an unreported feature affecting the external carotid artery, may represent a metastatic calcified deposit owing to hypercalcaemia and hyperphosphataemia in the tunica media of muscular arteries, resulting in arteriosclerosis, which maintains a patent lumen. The plaque-like pattern is representative of lumen-occluding calcified atherosclerosis associated with the long histories of diabetes mellitus type II, hypertension and hypercholesterolaemia. As this patient did not have any symptoms and/or signs of myofacial pain, facial dysfunction or numbness, the calcification of his external carotid arteries and branches were considered as arteriosclerosis. The brown tumour responded to the parathyroidectomy and the renal transplant. PMID- 22241885 TI - Evaluation of mandibular bone mineral density using the dual-energy X-ray absorptiometry technique in edentulous subjects living in an endemic fluorosis region. AB - OBJECTIVES: Fluoride is one of the biological trace elements with a strong affinity for osseous, cartilaginous and dental tissue. The dental and skeletal effects of high fluoride intake have already been studied in the literature, but little is known about the effects of high fluoride intake on edentulous mandibles. The purpose of this study was to evaluate the effects of high fluoride intake on mandibular bone mineral density (BMD) measured by the dual-energy X-ray absorptiometry (DXA) technique in edentulous individuals with systemic fluorosis. METHODS: 32 people who were living in an endemic fluorosis area since birth and 31 people who were living in a non-endemic fluorosis area since birth (control group) participated in this study. Systemic fluorosis was diagnosed in the patients using the sialic acid (NANA)/glycosaminoglycan (GAG) ratio. The BMDs of the mandibles were determined by the DXA technique. RESULTS: The serum NANA/GAG ratios in the fluorosis group were significantly lower than those in the control group (p < 0.001). There was also a statistically significant difference in mandibular BMD measurements (p < 0.05) between the systemic fluorosis and control groups, as measured by the DXA technique. Mandibular body BMD measurements were higher in the fluorosis group (1.25 +/- 0.24 g cm(-2)) than in the control group (1.01 +/- 0.31 g cm(-2)). CONCLUSIONS: The results of the study showed that fluoride intake higher than the optimum level causes increased mandibular BMD in edentulous individuals. Further dose-related studies are needed to determine the effects of high fluoride intake on bony structures of the stomatognathic system. PMID- 22241887 TI - Seed biology in the 21st century: perspectives and new directions. PMID- 22241888 TI - Placental hypoxia and foetal development versus alcohol exposure in pregnancy. AB - AIMS: To examine the causes of variability in the effect of maternal drinking on the foetus, with particular reference to the pattern, frequency and duration of the period of drinking, differences in maternal, foetal and placental metabolism of ethanol/acetaldehyde, and genetic factors. METHODS: Narrative review of published studies of the pathogenesis of foetal alcohol syndrome (FAS) with emphasis in the development of the central nervous system. RESULTS: Animal models suggest that acetaldehyde, the primary hepatic oxidative metabolite of ethanol, reaches the foetus either by placental production or by placental transference, which in turn could affect foetal growth and development. The most likely hypothesis regarding the decrease of foetal growth is via hypoxia and increased oxidative/nitrative stress, which interfere with cellular processes that require oxygen in order to function adequately, such as placental transport. CONCLUSION: There seems to be an association between the teratogenic effect, hypoxia and oxidative stress, the molecular mechanism involved (e.g. apoptosis) and the range of effects. The review sums ups the evidence that could explain some of the abnormalities in the brain development that could be related to behavioural problems observed in individuals with FAS/foetal alcohol spectrum disorder. This suggests that alcohol consumption produces failures in the normal migration of radial cells, from which the rest of the brain cells would eventually develop. PMID- 22241889 TI - Denosumab for postmenopausal osteoporosis? AB - Osteoporosis is the most common clinical disorder of bone metabolism, and is characterised by low bone mass and deterioration of the microarchitecture of bone tissue that results in increased bone fragility and susceptibility to bone fracture. In the UK, it is estimated that osteoporosis affects over 3 million people and leads to 230,000 fractures per year. It occurs most commonly in postmenopausal women and prevalence increases markedly with age, from 2% in women at 50 years to more than 25% at 80 years of age. Denosumab (Prolia - Amgen) is a monoclonal antibody that decreases bone resorption. It has been licensed in the EU for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and also for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. Here, we review the role of denosumab in the management of postmenopausal osteoporosis. PMID- 22241890 TI - Herbal medicines for osteoarthritis. AB - Osteoarthritis is one of the leading causes of pain and disability. In the UK, up to 8.5 million people are affected by joint pain that may be attributed to the condition. Non-surgical treatment options include lifestyle measures (e.g. exercise); local therapy involving heat or cold; manual therapy; transcutaneous electrical nerve stimulation (TENS); topical capsaicin; simple analgesics; NSAIDs; opioids; and intra-articular corticosteroid injections. Studies have reported widespread use of complementary and alternative therapies such as herbal medicines by patients with arthritis. Here we review the efficacy and safety of herbal medicines for symptoms of osteoarthritis. PMID- 22241891 TI - Neutrophil serine proteases promote IL-1beta generation and injury in necrotizing crescentic glomerulonephritis. AB - The pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing crescentic GN (NCGN) is incompletely understood. Dipeptidyl peptidase I (DPPI) is a cysteine protease required for the activation of neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase, and proteinase 3, which are enzymes that modulate inflammation. We used a mouse model of anti-myeloperoxidase (MPO) antibody-induced NCGN to determine whether active NSPs contribute to its pathogenesis. MPO-deficient animals immunized with murine MPO, irradiated, and transplanted with wild-type bone marrow developed NCGN. In contrast, transplantation with bone marrow that lacked DPPI or lacked both neutrophil elastase and proteinase 3 protected mice from NCGN induced by anti-MPO antibody. The kidneys of mice reconstituted with DPPI-deficient bone marrow generated significantly less IL-1beta than did those of mice reconstituted with wild-type bone marrow; similarly, in vitro, DPPI-deficient monocytes produced significantly less IL-1beta in response to anti-MPO antibody than did wild-type monocytes. This reduction in IL-1beta was NSP dependent; exogenous addition of PR3 restored IL beta production in DPPI-deficient monocytes. Last, the IL-1 receptor antagonist anakinra protected animals against anti-MPO antibody-induced NCGN (16.7%+/-6.0% versus 2.4%+/-1.7% crescents), suggesting that IL-1beta is a critical inflammatory mediator in this model. These data suggest that the development of anti-MPO antibody-induced NCGN requires NSP-dependent IL-1beta generation and that these processes may provide therapeutic targets for ANCA-mediated diseases in humans. PMID- 22241892 TI - A look at transactivation of the EGF receptor by angiotensin II. PMID- 22241893 TI - Managing microvascular complications of diabetes with microRNAs. PMID- 22241894 TI - The crossroad of RAAS modulation, inflammation, and oxidative stress in dialysis patients: light at the end of the tunnel? PMID- 22241895 TI - ESAs in transplant anemia: one size does not "fit all". PMID- 22241896 TI - Racial disparities in Hodgkin's lymphoma: a comprehensive population-based analysis. AB - BACKGROUND: Racial disparity has been investigated in a number of cancers; however, there remains a comparative paucity of data in Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We examined time-, age-, and gender-specific incidence, disease characteristics, and survival across and within races for adolescent/adult HL (age 10-79 years) diagnosed during 1992-2007 in the SEER 13 registries. RESULTS: A total of 15 662 HL cases were identified [11,211 non Hispanic whites, 2067 Hispanics, 1662 blacks, and 722 Asian/Pacific Islanders (A/PI)]. Similar to whites, A/PIs had bimodal age-specific incidence, while blacks and Hispanics did not. Further, HL was significantly more common in Hispanics versus whites age>65 years (7.0/1*10(6) versus 4.5/1*10(6), respectively, P<0.01). By place of birth, US-born Hispanics and A/PIs age 20-39 years had higher incidence of HL versus their foreign-born counterparts (P<0.05), however, rates converged age>40 years. Interestingly, from 1992-1997 to 2003 2007, A/PI incidence rates increased >50% (P<0.001). Moreover, this increase was restricted to US-born A/PI. We also identified a number of disease-related differences based on race. Finally, 5-, 10-, and 15-year overall survival rates were inferior for blacks and Hispanics compared with whites (P<0.005 and P<0.001, respectively) and A/PI (P<0.018 and P<0.001, respectively). These differences persisted on multivariate analysis. CONCLUSION: Collectively, we identified multiple racial disparities, including survival, in adolescent/adult HL. PMID- 22241897 TI - Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. AB - PURPOSE: Anti-epidermal growth factor receptor (EGFR) agents [monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs)] are targeted therapies used in advanced cancers. Arterial and venous thromboembolic events (ATEs and VTEs excluding catheter-related events) were not investigated with these agents, and the risk of these events is still unknown. PATIENTS AND METHODS: We have carried out a meta-analysis in order to determine the incidence and the relative risk (RR) of VTEs and ATEs associated with these agents. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies. RESULTS: A total of 13 studies (7611 patients) was selected for this meta-analysis. The associated RRs of VTEs (11 studies comprising 7073 patients) and ATEs (5 studies consisting of 3030 patients) were 1.32 (95% CI 1.07-1.63; P equals 0.01) and 1.34 (95% CI 0.94-1.9; P equals 0.11) compared with control patients. The analysis of VTEs was also stratified by class of agents: MoAbs (RR 1.34; P equals 0.01) and oral TKIs (RR 1.16; P equals 0.65). CONCLUSION: Anti-EGFR agents are associated with a significant increase in the risk of VTEs. In particular, the risk is significant with cetuximab and panitumumab in settings where these drugs are currently approved. PMID- 22241898 TI - Association between the nuclear to cytoplasmic ratio of p27 and the efficacy of adjuvant polychemotherapy in early breast cancer. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic and predictive value of p27 expression in patients with early breast cancer. PATIENTS AND METHODS: Quantitative immunofluorescence assays for p27 were done on a tissue microarray that included 823 samples from patients randomized between anthracycline-based chemotherapy and no chemotherapy. Quantification of p27 was done using the AQUA(r) system (HistoRx, Inc., Branford, CT). Both p27 nuclear expression and the nuclear to cytoplasmic ratio were assessed. RESULTS: Nuclear p27 expression was not predictive for the efficacy of anthracycline-based chemotherapy [adjusted P=0.18 for disease-free survival (DFS)] nor prognostic [95% confidence interval (CI) 0.99-1.01, P=0.49]. However, p27 nuclear/cytoplasmic ratio was predictive for the efficacy of adjuvant chemotherapy (adjusted P=0.016 DFS). The adjusted hazard ratio (HR) for relapse associated with adjuvant chemotherapy was 0.56 (95% CI 0.37-0.84, P=0.005) and 1.06 (95% CI 0.76-1.47, P=0.74) for patients with high and low nuclear/cytoplasmic ratio, respectively. p27 N/C ratio was prognostic in patients treated with chemotherapy (HR for relapse or death for a 1 unit increase in p27 N/C ratio was 0.30, 95% CI 0.12-0.77) but not in the untreated arm (HR for relapse or death was 1.27, 95% CI 0.58-2.8). CONCLUSIONS: This study did not confirm the role of p27 nuclear expression as a prognostic parameter. However, the p27 nuclear/cytoplasmic ratio was predictive in patients treated with anthracycline-based chemotherapy. PMID- 22241899 TI - The prognostic and predictive value of serum CA19.9 in pancreatic cancer. AB - BACKGROUND: Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used. METHODS: We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC. RESULTS: By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P=0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels>90 U/ml did not benefit from adjuvant chemotherapy (P=0.7194) compared with those with a CA19.9 of <=90 U/ml (median 26.0 vs 16.7 months, P=0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P=0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%. CONCLUSIONS: Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation. PMID- 22241900 TI - The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register. AB - OBJECTIVES: To compare the risk of keratinoctye skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) in patients treated for rheumatoid arthritis (RA) compared with the general population, and to determine whether anti-tumour necrosis factor (TNF) therapy exacerbates this risk. METHODS: Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting. RESULTS: SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84). CONCLUSIONS: Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer. PMID- 22241901 TI - Changes in matrix protein biochemistry and the expression of mRNA encoding matrix proteins and metalloproteinases in posterior tibialis tendinopathy. AB - OBJECTIVES: Adult-acquired flat foot secondary to a dysfunctional posterior tibialis tendon (PTT) is often treated by surgical transfer of the flexor digitorum longus tendon (FDLT). In this study, the authors compared normal PTT, stage II dysfunctional PTT and replacement FDLT, aiming to define changes in collagen modification, glycosaminoglycan (GAG) and the expression of matrix and metalloproteinase mRNA. METHODS: Normal PTTs were obtained from patients with no history of tendon problems. Samples of dysfunctional PTT and replacement FDLT tissue were obtained from patients undergoing surgical reconstruction. Tissue samples were analysed for total collagen and GAG, pentosidine and collagen cross links. Total RNA was assayed for mRNA encoding matrix proteins and metalloproteinases, using real-time reverse transcription PCR. Differences between clinical groups were assessed using non-parametric statistics. RESULTS: Dysfunctional PTT contained higher levels of GAG and lower levels of pentosidine than normal PTT or FDLT. In contrast, collagen in FDLT contained fewer ketoimine and more aldimine cross-links than either normal or dysfunctional PTT. mRNA encoding types I and III collagens, aggrecan, biglycan, matrix metalloproteinase (MMP)-2, -13 and -23, and a disintegrin and metalloproteinase (ADAM)-12L each showed increased levels in dysfunctional PTT compared with either normal PTT or (except MMP-13) FDLT. In contrast, MMP-3 and ADAM with thrombospondin domain (ADAMTS)-5 mRNA were lower in both dysfunctional PTT and FDLT than in normal PTT, while ADAMTS-1 mRNA was lower in dysfunctional PTT than in FDLT. CONCLUSIONS: Stage II dysfunctional PTT shows biochemical and molecular changes consistent with a chronic remodelling of the extracellular matrix, rather than rupture, while the replacement FDLT resembles normal PTT in many, but not all, parameters. PMID- 22241904 TI - What I've learned from BMJ case reports: It's not just arthritis... PMID- 22241905 TI - How to use serum-specific IgE measurements in diagnosing and monitoring food allergy. PMID- 22241902 TI - Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis. AB - OBJECTIVES: To explore the relationship of serious infection risk with current and prior oral glucocorticoid (GC) therapy in elderly patients with rheumatoid arthritis (RA). METHODS: A case-control analysis matched 1947 serious infection cases to five controls, selected from 16207 RA patients aged >= 65 between 1985 2003 in Quebec, Canada. Adjusted odds ratios for infection associated with different GC patterns were estimated using conventional models and a weighted cumulative dose (WCD) model. RESULTS: The WCD model predicted risks better than conventional models. Current and recent GC doses had highest impact on current risk. Doses taken up to 2.5 years ago were also associated with increased risk, albeit to a lesser extent. A current user of 5mg prednisolone had a 30%, 46% or 100% increased risk of serious infection when used continuously for the last 3 months, 6 months or 3 years, respectively, compared to a non-user. The risk associated with 5mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month. Discontinuing a two-year course of 10mg prednisolone six months ago halved the risk compared to ongoing use. CONCLUSIONS: GC therapy is associated with infection risk in older patients with RA. The WCD model provided more accurate risk estimates than conventional models. Current and recent doses have greatest impact on infection risk, but the cumulative impact of doses taken in the last 2-3 years still affects risk. Knowing how risk depends on pattern of GC use will contribute to an improved benefit/harm assessment. PMID- 22241906 TI - What I've learned from clinical evidence: head scratchers. PMID- 22241908 TI - Clinical significance of blood pressure ratios in hypertensive crisis in children. AB - OBJECTIVES: Hypertensive crisis is categorised into hypertensive urgency and hypertensive emergency. The present work aimed to determine the effect of different gradings of blood pressure (BP) ratios in predicting the severity of paediatric hypertensive crisis. METHODS: This was a retrospective case series, based in the paediatric emergency departments of the Changhua Christian Hospital and the Tzu-Chi General Hospital, Taiwan. From 1995 to 2010, the correlation between the severity of hypertension (HTN) and the difference in elevated systolic BP and 99th percentile plus 5 mm Hg (dSBP), the difference in elevated diastolic BP and 99th percentile plus 5 mm Hg (dDBP), dSBP ratio (dSBP/99th percentile plus 5 mm Hg) and dDBP ratio were analysed. A total of 110 children with a first attack of hypertensive crisis were recruited. RESULTS: Patients with hypertensive crisis caused by essential HTN had lower dDBP ratios than the other causes (p=0.033), while those with an oncological aetiology had the highest dSBP and dDBP ratios among all the aetiologies. For clinical presentations, patients with nausea/vomiting and visual impairment presented with higher dSBP ratios than those without the symptoms (both p<0.05), but patients with altered consciousness had higher dSBP and dDBP ratios than those who had clear consciousness (p<0.05). Children with hypertensive urgency had lower dSBP and dDBP ratios than those with hypertensive emergency (both p<0.05). CONCLUSIONS: dDBP and dSBP ratios may serve as BP parameters in predicting the severity of paediatric hypertensive crisis. A dSBP ratio greater than 20% may indicate a critical point for severe hypertensive crisis in children. PMID- 22241909 TI - Proof-of-concept study of monitoring cancer drug therapy with cerenkov luminescence imaging. AB - Cerenkov luminescence imaging (CLI) has emerged as a less expensive, easier-to use, and higher-throughput alternative to other nuclear imaging modalities such as PET. It is expected that CLI will find many applications in biomedical research such as cancer detection, probe development, drug screening, and therapy monitoring. In this study, we explored the possibility of using CLI to monitor drug efficacy by comparisons against PET. To assess the performance of both modalities in therapy monitoring, 2 murine tumor models (large cell lung cancer cell line H460 and prostate cancer cell line PC3) were given bevacizumab versus vehicle treatments. Two common radiotracers, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and (18)F-FDG, were used to monitor bevacizumab treatment efficacy. METHODS: One group of mice (n = 6) was implanted with H460 xenografts bilaterally in the shoulder region, divided into treatment and control groups (n = 3 each), injected with (18)F-FLT, and imaged with PET immediately followed by CLI. The other group of mice (n = 6) was implanted with PC3 xenografts in the same locations, divided into treatment and control groups (n = 3 each), injected with (18)F-FDG, and imaged by the same modalities. Bevacizumab treatment was performed by 2 injections of 20 mg/kg at days 0 and 2. RESULTS: On (18)F-FLT scans, both CLI and PET revealed significantly decreased signals from H460 xenografts in treated mice from pretreatment to day 3. Moderately increased to unchanged signals were observed in untreated mice. On (18)F-FDG scans, both CLI and PET showed relatively unchanged signals from PC3 tumors in both treated and control groups. Quantifications of tumor signals of Cerenkov luminescence and PET images showed that the 2 modalities had excellent correlations (R(2) > 0.88 across all study groups). CONCLUSION: CLI and PET exhibit excellent correlations across different tumor xenografts and radiotracers. This is the first study, to our knowledge, demonstrating the use of CLI for monitoring cancer treatment. The findings warrant further exploration and optimization of CLI as an alternative to PET in preclinical therapeutic monitoring and drug screening. PMID- 22241910 TI - Validation of an automatic dose injection system for Ictal SPECT in epilepsy. AB - The purpose of our study was to evaluate the performance and clinical usefulness of an automated injector system (AIS) that administers an automated injection for ictal SPECT after calculating the volume of tracer to be injected over time. METHODS: To test the AIS, repeated injections were performed at different times after tracer preparation. The clinical study consisted of 56 patients with drug resistant, complex partial seizures. Tracer for ictal SPECT was injected using automated injection in 27 patients and manual injection (MI) in the remaining 29. Injection time (T(I)) was measured in seconds from seizure onset to the end of volume injection. The SISCOM (Subtraction Ictal Spect Co-registered to MRI) procedure was used to locate the epileptogenic seizure focus with SPECT. The definition of seizure focus was made by consensus of the epilepsy unit using conventional diagnostic methods. RESULTS: During the experimental phase, there were no system failures, and the error in injected doses when using automated injection was lower than with MI. During the clinical phase, T(I) using manual injection was 41 s with a range of 14-103 s, compared with an AIS average of 33 s with a range of 19-63 s (P < 0.05). Ictal SPECT and SISCOM successfully localized the seizure focus in 21 of the 27 patients (78%) by AIS and in 19 of the 29 patients (65%) by MI (P = 0.14). Furthermore, nursing staff found the AIS method more convenient than the MI method. CONCLUSION: An AIS can improve the quality of work of the nursing staff in the neurology ward and allow a finer adjustment of the injection dose. Early results using an AIS would indicate a reduction in injection time and improved SPECT accuracy. PMID- 22241911 TI - Large decreases in standardized uptake values after definitive radiation are associated with better survival of patients with locally advanced non-small cell lung cancer. AB - We evaluated potential associations between maximum standardized uptake value (SUV(max)) on (18)F-FDG PET before and after radiation therapy (RT) and survival outcomes for patients with locally advanced non-small cell lung cancer. METHODS: Patients with stage III non-small cell lung cancer (n = 49) who had undergone (18)F-FDG PET at the M.D. Anderson Cancer Center both before and up to 3.5 mo after undergoing radiochemotherapy were studied; exclusion criteria were patients with a history of thoracic surgery, RT, or other cancer or those who had received a total radiation dose less than 60 Gy. We assessed associations between overall survival (OS) or disease-free survival (DFS) and post-RT SUV(max) and the extent of decrease in SUV(max) in the primary tumor (PT) and regional lymph nodes (LNs). SUV(max) was assessed as a continuous variable by Cox proportional hazards regression analysis. RESULTS: Univariate and multivariate analyses showed that having a high post-RT SUV(max) (either PT or LNs) was associated with a higher risk of death (univariate analyses: hazard ratio [HR] for PT SUV(max), 1.27, P < 0.0001; HR for LN SUV(max), 1.32, P = 0.004) and disease recurrence (univariate analyses: HR for PT SUV(max), 1.16, P = 0.004; HR for LN SUV(max), 1.32, P = 0.001). Moreover, after definitive RT, the greater the decrease in SUV(max) in the lesion that had the highest SUV(max) at diagnosis, the longer the OS (HR, 0.06; P = 0.002), DFS (HR, 0.03; P = 0.001), local-regional control (HR, 0.04; P = 0.002), and distant metastasis-free survival (HR, 0.07; P = 0.028). CONCLUSION: The post-RT SUV(max) in both the PT and the LNs was a predictor of survival specifically, the higher the residual SUV(max) after RT, the poorer the OS and DFS; and the greater the decrease in SUV(max) in the lesion with the highest SUV(max) at diagnosis, the longer the OS and DFS. This information should help to identify patients who are at high risk of recurrence and for whom additional treatments can be designed accordingly. PMID- 22241912 TI - PET imaging of estrogen receptors as a diagnostic tool for breast cancer patients presenting with a clinical dilemma. AB - 16alpha-(18)F-fluoro-17beta-estradiol ((18)F-FES) is an estrogen receptor (ER) specific PET tracer with various potential interesting applications. The precise contribution of this technique in current clinical practice, however, has yet to be determined. Therefore, the aim of this study was to evaluate the value of (18)F-FES PET in breast cancer patients presenting with a clinical dilemma. METHODS: (18)F-FES PET examination could be requested by referring physicians for patients with a history of ER-positive breast cancer and the presence of a clinical dilemma despite complete standard work-up. All requests for (18)F-FES PET required a positive arbitration by a dedicated medical oncologist and nuclear medicine physician. The referring physician was asked to fill in validated questionnaires before, shortly after, and at more than 3 mo after (18)F-FES PET to determine indication, diagnostic value, and therapeutic consequences of (18)F FES PET. To further validate (18)F-FES PET findings, (18)F-FES PET lesions were quantified and compared with centrally reviewed conventional imaging. RESULTS: Thirty-three patients underwent (18)F-FES PET between December 2008 and October 2010. (18)F-FES PET was requested to evaluate equivocal lesions on conventional work-up (n = 21), ER status in metastatic patients (n = 10), and the origin of metastases (n = 2). (18)F-FES-positive lesions were observed in 22 patients. (18)F-FES PET was especially sensitive for bone metastases, detecting 341 bone lesions, compared with 246 by conventional imaging. The sensitivity for liver metastases was poor, and quantification of (18)F-FES uptake in liver lesions was hampered by high physiologic background. (18)F-FES uptake was highly variable between all metastases (range of standardized uptake value, 1.20-18.81), and 45% of the patients with a positive (18)F-FES PET finding had both (18)F-FES-positive and (18)F-FES-negative metastases. (18)F-FES PET improved diagnostic understanding in 88% of the patients and led to therapy change in 48% of the patients. CONCLUSION: With the exception of liver metastases, whole-body imaging of ER expression with (18)F-FES PET can be a valuable additional diagnostic tool when standard work-up is inconclusive. (18)F-FES PET supported therapy decisions by improving diagnostic understanding and providing information on ER status of tumor lesions. PMID- 22241913 TI - Radiation dosimetry and biodistribution of the TSPO ligand 11C-DPA-713 in humans. AB - Whole-body PET/CT was used to characterize the radiation dosimetry of (11)C-DPA 713, a specific PET ligand for the assessment of translocator protein. METHODS: Six healthy control subjects, 3 men and 3 women, underwent whole-body dynamic PET scans after bolus injection of (11)C-DPA-713. Subjects were scanned from head to mid thigh with 7 passes performed, with a total PET acquisition of approximately 100 min. Time-activity curves were generated in organs with visible tracer uptake, and tissue residence times were calculated. Whole-body dosimetry was calculated using OLINDA 1.1 software, assuming no voiding. RESULTS: The absorbed dose is highest in the lungs, spleen, kidney, and pancreas. The lungs were determined to be the dose-limiting organ, with an average absorbed dose of 2.01 * 10(-2) mSv/MBq (7.43 * 10(-2) rem/mCi). On the basis of exposure limits outlined in the U.S. Food and Drug Administration Code of Federal Regulations (21CFR361.1), the single-dose limit for (11)C-DPA-713 radiotracer injection is 2,487.6 MBq (67.3 mCi). CONCLUSION: (11)C-DPA-713 has an uptake pattern that is consistent with the biodistribution of translocator protein and yields a dose burden that is comparable to that of other (11)C-labeled PET tracers. PMID- 22241914 TI - Triple-negative breast cancer: early assessment with 18F-FDG PET/CT during neoadjuvant chemotherapy identifies patients who are unlikely to achieve a pathologic complete response and are at a high risk of early relapse. AB - Triple-negative breast cancer, an aggressive subtype, represents 15% of invasive breast tumors. This prospective study investigated whether early changes in (18)F FDG tumor uptake during neoadjuvant chemotherapy (NAC) can predict outcomes. METHODS: Twenty (M0) patients underwent (18)F-FDG PET/CT at baseline and after the second cycle. NAC was continued irrespective of PET results. RESULTS: At surgery, 6 patients had a pathologic complete response, whereas 14 had residual tumor. Four patients showed early relapse (in the 2 y after surgery). There were 11 metabolic responders and 9 nonresponders using a 42% decrease in maximum standardized uptake value as a cutoff. In nonresponding patients, the risk of residual tumor at surgery was 100% (vs. 45% in responders; P = 0.014), and the risk of early relapse was 44% (vs. 0%; P = 0.024). CONCLUSION: A less than 42% decrease in (18)F-FDG uptake at 2 cycles means residual tumor at the end of NAC and a high risk of early relapse. PMID- 22241915 TI - Frequently used healthcare services in urban slums of Dhaka and adjacent rural areas and their determinants. AB - BACKGROUND: To compare patterns of healthcare service user preference between urban slums in Dhaka and adjacent rural areas and to identify key determinants of those preferences. METHODS: The data were collected through baseline surveys conducted in 2008 and 2009. A total of 3207 subjects aged 10-90 years were systematically selected from 12 big slums in Dhaka and 3 rural villages outside Dhaka. RESULTS: Two frequently used healthcare sources utilized in 1 month preceding the baseline survey were pharmacies (slum, 42.6%; rural, 30.1%) and government hospitals/clinics (GVHC; slum, 13.5%; rural, 8.9%). According to the multilevel logistic regression analysis adjusted for age, sex and marital status, the likelihood of using pharmacies and GVHC were higher for those subjects who used non-hygienic toilets, who reported food deficiency at a family level, who expressed dissatisfaction about family income and who stated poor health status. Some more factors namely overweight, living in permanently structured house, smoking bidis and less frequency of watching TV were associated with higher likelihood of using GVHC. CONCLUSIONS: Pharmacy was the most dominant healthcare service in both areas. As persons running pharmacies often provide poor quality of healthcare services, they need continuous training and back-up supports to improve their quality of services and to strengthen the overall healthcare system in Bangladesh. PMID- 22241917 TI - Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. AB - OBJECTIVES: To estimate the incidence of clinically diagnosed congenital adrenal hyperplasia (CAH), clinical features and age at first presentation. To assess the potential benefit of newborn screening for CAH. DESIGN: Active surveillance through the British Paediatric Surveillance Unit of all children aged under 16 years with newly diagnosed CAH, undertaken prospectively between August 2007 and August 2009. Twelve laboratories testing for CAH reported new diagnoses between August 2007 and January 2009. Reporting clinicians completed clinical questionnaires. SETTING: England, Wales and Scotland. RESULTS: 144 children with CAH were reported, of whom 132 (92%) had 21-hydroxylase deficiency. Thirty-six (25%) children were Asian and 62 (43%; 95% CI 35% to 51%) were boys. Incidence of new diagnoses in children <= 16 years was 0.60 (95% CI 0.50 to 0.71) per 100,000. Eighty-six (59%; 36 boys) children were diagnosed in the first year of life (estimated birth prevalence 5.48 (95% CI 4.42 to 6.81) per 100,000), most (77; 89%) of whom presented in the first month of life. Virilised genitalia were found in three-quarters of girls. Twenty-seven newborns first presented with salt wasting crises, of whom 18 (67%; 16 boys) presented on or after 14 days of age. CONCLUSIONS: Approximately one child in every 18 000 born in Great Britain has CAH. Similar numbers of boys and girls present clinically in the first year of life, but boys present with more severe manifestations, such as salt-wasting crises. Around 70% of newborns who first present with salt-wasting crisis would be detected earlier through newborn screening. PMID- 22241916 TI - Dehydration in children with diabetic ketoacidosis: a prospective study. AB - OBJECTIVES: To investigate the association between the degree of patient dehydration on presentation with diabetic ketoacidosis (DKA) and clinical and laboratory parameters obtained on admission. DESIGN: Prospective descriptive study. SETTING: A tertiary care children's hospital. PATIENTS: Thirty-nine paediatric patients (1 month-16 years) presenting with 42 episodes of DKA. INTERVENTION: Clinical and biochemical variables were collected on admission. Dehydration was calculated by measuring acute changes in body weight during the period of illness. All patients were treated according to a previously established protocol. MAIN OUTCOME MEASURES: Magnitude of dehydration, defined as % loss of body weight (LBW), was determined by the difference in body weight obtained at presentation and at discharge. The relationship between the magnitude of dehydration and the clinical assessment and biochemical parameters was examined. RESULTS: The median (25th-75th centiles) magnitude of dehydration at presentation was 5.7% (3.8-8.3%) (mean +/- SD 6.8 +/- 5%). Neither the initial clinical assessment nor the comprehensive biochemical profile at admission correlated with the magnitude of dehydration. Despite considerable variation in the degree of dehydration and biochemical disequilibrium, all patients recovered from DKA within 24 h with a standardised therapeutic approach. Furthermore, the rapidity of patient recovery did not correlate with the magnitude of dehydration on presentation or the amount of fluid administered (median (25th-75th centiles) 48.8 ml/kg (38.5-60.3)) in the first 12 h. CONCLUSION: The magnitude of dehydration in DKA is not reflected by either clinical or biochemical parameters. These findings need confirmation in larger studies. PMID- 22241918 TI - Aetiology and epidemiology of fever in children presenting to the emergency department of a French paediatric tertiary care centre after international travel. AB - OBJECTIVE: As few data are available on the causes of fever in children returning from international travel, the authors studied children presenting to a French tertiary care centre with fever. METHODS: Children presenting to the emergency department of the Robert Debre Paediatric Hospital, Paris, France between July and December 2007 with fever that occurred within 3 months of a stay abroad were included in this retrospective study. RESULTS: The children (n=538) had most commonly visited North Africa (NA) (n=214), sub-Saharan Africa (SSA) (n=185) and Europe (n=67). Their median age was 2.8 years (IQR 1.4-5.8). The median time between their return to France and the onset of fever was 5 days (IQR 0-18). Cosmopolitan infections represented 85% of the established diagnoses (97.8% and 63.9% in the children returning from NA and SSA, respectively). Fever of unknown origin accounted for 19.3% of cases. Malaria was the leading tropical infection. Excluding malaria, diarrhoeal diseases were more frequent in the children returning from NA (38.5%) than in those returning from SSA (24.5%). Malaria was associated with stays in endemic countries that exceeded 30 days (OR 3.13, 95% CI 1.02 to 9.59). CONCLUSION: Cosmopolitan infections are the leading cause of fever in French children returning from tropical and subtropical areas. However, all febrile children who have returned from an endemic area should be tested for malaria. PMID- 22241919 TI - Slice, dice and eventually something will happen. PMID- 22241920 TI - Question 1. Do febrile convulsions cause CSF pleocytosis? PMID- 22241921 TI - Question 2. Does regular cleaning of stethoscopes result in a reduction in nosocomial infections? PMID- 22241922 TI - Question 3 Does a higher initial dose of adenosine improve cardioversion rates in supraventricular tachycardia? PMID- 22241923 TI - Combination therapy with low-dose transpupillary thermotherapy and intravitreal ranibizumab for neovascular age-related macular degeneration: a 24-month prospective randomised clinical study. AB - AIM: To compare the effect of combined low-dose transpupillary thermotherapy (TTT) and intravitreal ranibizumab with sham TTT and intravitreal ranibizumab in patients with neovascular age-related macular degeneration (AMD). METHODS: A 24 month, double-masked, randomised, active-controlled clinical trial. 100 patients with primary neovascular AMD were randomly assigned (1:1) to receive intravitreal ranibizumab and sham TTT or intravitreal ranibizumab and low-dose TTT. After an initial loading phase of ranibizumab patients were assigned to receive quarterly low-dose TTT (136 mW/mm) or sham TTT for 24 months. Retreatment with ranibizumab was allowed in both treatment groups using a variable dosing regimen. The primary endpoint was the number of intravitreal injections with ranibizumab. Secondary endpoints included change in best corrected visual acuity (BCVA), central retinal thickness (CRT) and lesion area. RESULTS: In the per protocol (PP) population (78 patients) the mean number of ranibizumab injections was 8.0 in the sham TTT group versus 6.3 in the TTT group (p<0.05). The mean number of injections between 0-12 months and 13-24 months was 4.8 versus 4.6 (p>0.05) and 3.2 versus 1.7 (p<0.01) in the sham TTT and TTT groups, respectively. There was no statistically significant difference in BCVA (+4.0 vs +0.9 ETDRS letters), CRT (-49.9% vs 36.4%) or lesion area (-0.3% vs -10.6%) between the treatment groups at the final examination. The results of the intent-to-treat population (92 patients) were similar to the PP population. CONCLUSIONS: Treatment with low-dose TTT significantly reduced the number or intravitreal injections of ranibizumab over 24 months. The results suggest that low-dose TTT can serve as an adjuvant in combination with intravitreal ranibizumab for neovascular AMD. CLINICAL TRIAL REGISTRATION NUMBER: The trial is registered at http://clinicaltrials.gov (no NCT00599222). PMID- 22241924 TI - Conjunctival and corneal ulcerations: keep a sharp eye on nicorandil. PMID- 22241925 TI - Extraocular muscle insertion positions and outcomes of strabismus surgery: correlation analysis and anatomical comparison of Western and Chinese populations. AB - BACKGROUND/AIMS: To compare the insertion locations of extraocular muscles between Taiwanese (Han Chinese) and Western populations and to determine whether anatomical differences warrant different surgical guidelines. METHODS: Insertion locations were compared between a Taiwanese population of subjects who had received surgical treatment for strabismus and a control group who had not. Insertion locations and surgical outcomes in the strabismus group were also compared with those reported in other countries. RESULTS: In Taiwanese subjects, extraocular muscle insertion locations were not significantly different between strabismus subjects and controls. However, the distances from the insertion location to the limbus of the inferior rectus, lateral rectus and superior rectus were significantly shorter in the Taiwanese subjects than in Western populations. CONCLUSION: Extraocular muscle insertion locations for the Taiwanese population in this study significantly differed from those reported in studies of Western populations. Therefore, surgical guidelines for performing lateral rectus recession to treat exotropia in Western populations may be inappropriate for Taiwanese and other Asian populations. PMID- 22241926 TI - Epidemiology, risk factors and management of paediatric diabetic retinopathy. AB - Diabetic retinopathy (DR), a common complication of both type 1 and type 2 diabetes, is rarely expressed at a level greater than background retinopathy during childhood and adolescence. Epidemiological studies in paediatric diabetic patients together with data from the Diabetes Control and Complications Trial have demonstrated the importance of glycaemic control in delaying or preventing the development of DR; thus, the incidence of DR has declined somewhat over the past two decades. Both prepubertal and postpubertal years with diabetes contribute to the overall probability of DR development. In addition to duration of disease and degree of glycaemic control, other risk factors for DR development include elevated blood pressure, lipid profiles, serum levels of advanced glycation endproducts, evidence for early stage atherosclerosis, increased calibre of retinal blood vessels and several genetic factors, such as enzymes involved in glucose and lipid metabolism. Annual screening is recommended, with mydriatic stereoscopic fundus photography being the most sensitive detection method. Both pathophysiology and treatment in paediatric populations are essentially the same as described for adult populations, with treatment usually not required until adulthood is reached. PMID- 22241927 TI - A clinical method to assess the effect of visual loss on the ability to perform activities of daily living. AB - BACKGROUND/AIMS: To develop a clinically applicable, performance-based measure of the ability to perform visually related activities. METHODS: 99 patients with glaucoma and 21 subjects with a normal ocular examination completed a nine-item performance-based test (the Assessment of Ability Related to Vision (AARV)), received a standard ophthalmic clinical examination and answered the questions on the National Eye Institute's Visual Functioning Questionnaire (NEI-VFQ-25). All combinations of two, three or four items of the full nine-item AARV test were analysed, and their scores were compared with the full AARV scores and with clinical measures. RESULTS: The correlation of four items (detecting motion, reading signs, finding objects and navigating an obstacle course) reduced test time from 60+/-5 min to 14+/-4 min and yielded results highly related to the nine item test, including maintaining the relationship with clinical measures and with the NEI-VFQ-25. CONCLUSION: A compressed AARV correlates highly with the full test, with a method of evaluating quality of life, and with clinical measures, yet takes on average 14 min to perform. As such, it may provide a clinically useful method of evaluating the worsening effects of illness and the benefits of treatments that affect visual loss on the ability to perform visually related activities. PMID- 22241928 TI - Use of mini-monoka stents for punctal/canalicular stenosis. AB - BACKGROUND: Proximal lacrimal system stenosis may cause debilitating epiphora and recurrent ocular infections. Mini-monoka stents are primarily used in the management of canalicular lacerations. Evidence regarding their use to treat punctal/canalicular stenosis is sparse. Compared with dacryocystorhinostomy, a punctocanaliculoplasty with mini-monoka stenting is quicker, less invasive with reduced postoperative complications/recovery time. AIMS: To assess the effectiveness of mini-monoka punctocanaliculoplasty for treatment of punctal/canalicular stenosis. METHODS: A retrospective case note analysis was performed on 77 consecutive patients (123 eyes). RESULTS: 73% of eyes had punctal stenosis, 72% had canalicular stenosis; 46% had a combination of the above. 20% had some degree of lid laxity and 29% had nasolacrimal duct stenosis. 101 eyes (82%) had significant improvement in symptoms and were discharged without further intervention. Excluding the patients with structural comorbidity the success rate improved to 88%. CONCLUSIONS: Mini-monoka punctocanaliculoplasty is an effective, safe, simple and relatively non-invasive treatment strategy for the management of epiphora secondary to punctal and/or canalicular stenosis. PMID- 22241929 TI - Relative impact of maternal depression and associated risk factors on offspring psychopathology. AB - BACKGROUND: In general, mothers with depression experience more environmental and family risk factors, and lead riskier lifestyles, than mothers who are not depressed. AIMS: To test whether the exposure of a child to risk factors associated with mental health adds to the prediction of child psychopathology beyond exposure to maternal depression. METHOD: In 7429 mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children in the UK, maternal depression was assessed when the children were aged 1.5 years; multiple risk factor exposures were examined between birth and 2 years of age; and DSM-IV based externalising and internalising diagnoses were evaluated when the children were 7.5 years of age. RESULTS: Children of clinically depressed mothers were exposed to more risk factors associated with maternal mental health. Maternal depression increased diagnoses of externalising and internalising disorders, but a substantial portion of these associations was explained by increased risk factor exposure (41% for externalising and 37% for internalising disorders). At the same time, these risk exposures significantly increased the odds of both externalising and internalising diagnoses, over and above the influence of maternal depression. CONCLUSIONS: Children of clinically depressed mothers are exposed to both maternal psychopathology and risks that are associated with maternal mental health. These results may explain why treating mothers with depression shows beneficial effects for children, but does not completely neutralise the increased risk of psychopathology and impairment. PMID- 22241930 TI - Treatment-resistant and insufficiently treated depression and all-cause mortality following myocardial infarction. AB - BACKGROUND: Depression is a known risk factor for mortality after an acute myocardial infarction. Patients with treatment-responsive depression may have a better prognosis than those with treatment-resistant depression. AIMS: We sought to determine whether mortality following acute myocardial infarction was associated with treatment-resistant depression. METHOD: Follow-up began after myocardial infarction and continued until death or censorship. Depression was counted as present if diagnosed any time during the study period. Treatment for depression was defined as receipt of 12 or more weeks of continuous antidepressant therapy at a therapeutic dose during follow-up. Treatment resistant depression was defined as use of two or more antidepressants plus augmentation therapy, receipt of electroconvulsive therapy or use of monoamine oxidase inhibitors. Mean duration of follow-up was 39 months. RESULTS: During follow-up of 4037 patients with major depressive disorder who had had a myocardial infarction, 6.9% of those with insufficiently treated depression, 2.4% of those with treated depression and 5.0% of those with treatment-resistant depression died. A multivariable survival model that adjusted for sociodemographics, anxiety disorders, beta-blocker use, mortality risk factors and health service utilisation indicated that compared with treated patients, insufficiently treated patients were 3.04 (95% CI 2.12-4.35) times more likely and patients with treatment-resistant depression were 1.71 (95% CI 1.05-2.79) times more likely to die. CONCLUSIONS: All-cause mortality following an acute myocardial infarction is greatest in patients with depression who are insufficiently treated and is a risk in patients with treatment-resistant depression. However, the risk of mortality associated with treatment-resistant depression is partly explained by comorbid disorders. Further studies are warranted to determine whether changes in depression independently predict all cause mortality. PMID- 22241931 TI - Intellectual disability and other neuropsychiatric outcomes in high-risk children of mothers with schizophrenia, bipolar disorder and unipolar major depression. AB - BACKGROUND: Recent evidence points to partially shared genetics of neuropsychiatric disorders. AIMS: We examined risk of intellectual disability and other neuropsychiatric outcomes in 3174 children of mothers with schizophrenia, bipolar disorder or unipolar major depression compared with 3129 children of unaffected mothers. METHOD: We used record linkage across Western Australian population-based registers. The contribution of obstetric factors to risk of intellectual disability was assessed. RESULTS: Children were at significantly increased risk of intellectual disability with odds ratios (ORs) of 3.2 (95% CI 1.8-5.7), 3.1 (95% CI 1.9-4.9) and 2.9 (95% CI 1.8-4.7) in the maternal schizophrenia, bipolar disorder and unipolar depression groups respectively. Multivariate analysis suggests familial and obstetric factors may contribute independently to the risk. Although summated labour/delivery complications (OR = 1.4, 95% CI 1.0-2.0) just failed to reach significance, neonatal encephalopathy (OR = 7.7, 95% CI 3.0-20.2) and fetal distress (OR = 1.8, 95% CI 1.1-2.7) were independent significant predictors. Rates of rare syndromes in children of mothers with mental disorder were well above population rates. Risk of pervasive developmental disorders, including autism, was significantly elevated for children of mothers with bipolar disorder. Risk of epilepsy was doubled for children of mothers with unipolar depression. CONCLUSIONS: Our findings provide epidemiological support for clustering of neuropsychiatric disorders. Further larger epidemiological studies are warranted. PMID- 22241932 TI - External devices (including orthotics) to control excessive foot pronation. PMID- 22241933 TI - A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance--Part 29. PMID- 22241934 TI - Life Events, Sibling Warmth, and Youths' Adjustment. AB - Sibling warmth has been identified as a protective factor from life events, but stressor-support match-mismatch and social domains perspectives suggest that sibling warmth may not efficiently protect youths from all types of life events. We tested whether sibling warmth moderated the association between each of family wide, youths' personal, and siblings' personal life events and both depressive symptoms and risk-taking behaviors. Participants were 187 youths aged 9-18 (M = 11.80 years old, SD = 2.05). Multiple regression models revealed that sibling warmth was a protective factor from depressive symptoms for family-wide events, but not for youths' personal and siblings' personal life events. Findings highlight the importance of contextualizing protective functions of sibling warmth by taking into account the domains of stressors and adjustment. PMID- 22241935 TI - Adsorption and desorption of CO on Ni decorated stepped Rh(553). AB - Vicinal surfaces are important in surface science, as they show interesting electronic structures and reactivities due to the steps. In this paper the adsorption and desorption of carbon monoxide on the stepped Rh(553) surface decorated with Ni is reported. With 0.1 to 0.3 monolayer Ni on Rh(553) one and two atoms broad Ni wires along the Rh steps are formed. The adsorption and desorption of carbon monoxide on these surfaces is investigated using thermal desorption spectroscopy (TDS) and reflection absorption infra red spectroscopy (RAIRS). TDS shows a marked change from just one broad TDS peak on pure Rh(553) to 4 distinct peaks with increasing Ni decoration. RAIRS shows that already at 0.1 monolayer Ni the CO adsorption states on bridge sites on the Rh step atoms are completely quenched. In addition it is shown that with Ni films up to 3 monolayer the on top adsorption sites for CO on Ni are preferred over the bridge and hollow adsorption sites in contrast to what is known from the Ni(111) surface. PMID- 22241936 TI - Evaluative Conditioning: The "How" Question. AB - Evaluative conditioning (EC) refers to attitude formation or change toward an object due to that object's mere co-occurrence with another valenced object or objects. This chapter focuses on the "how" question, that is, the question of what cognitive processes intervene between mere co-occurrence and attitude formation or change. Though EC has typically been thought of as occurring through a single, albeit contentious, mechanism, we begin by pointing out that both the heterogeneity of EC methodologies and the abundance of inconsistent results suggest that multiple processes with different characteristics can produce EC. We describe how the earliest posited process of EC, Pavlovian conditioning or signal learning, is a valid mechanism of EC that appears to have operated in some experiments but is unlikely to have operated in others and also cannot account for various EC findings. We describe other mechanisms of EC, when they can be expected to occur, and what characteristics they have. We particularly focus our attention on a process model of EC we have recently introduced, the implicit misattribution model. Finally, we describe the implications of a multi-process view of EC, which we argue can help resolve theoretical controversies and further the application of EC as a practical intervention for influencing attitudes in various domains. PMID- 22241937 TI - G proteins as regulators of ion channel function. AB - Virtually unknown just a decade ago, GTP-binding proteins (G proteins) have become a major focus of current research. This family of closely related proteins transduce extracellular signals (such as hormones, neurotransmitters and sensory stimuli) into effector responses (1,2). It is now evident that ion channel permeability is one such effector response. In fact, the striking increase in the frequency of reports that demonstrate G protein-regulated ion channel function suggests that channels whose permeability mechanism can be altered by a G protein mediated process may be more the rule than the exception. It is well-known that the cAMP-dependent modulation of ion channels is under the control of G proteins that regulate adenylate cyclase activity(3,4). However recent studies demonstrate that G proteins also transduce agonist-induced changes in channel activity that do not involve adenylate cyclase. It is on this aspect of G protein signal transduction that this review will focus. PMID- 22241938 TI - Characterization of the mechanical and thermal interface of copper films on carbon substrates modified by boron based interlayers. AB - The manipulation of mechanical and thermal interfaces is essential for the design of modern composites. Amongst these are copper carbon composites which can exhibit excellent heat conductivities if the Cu/C interface is affected by a suitable interlayer to minimize the Thermal Contact Resistance (TCR) and to maximize the adhesion strength between Cu and C.In this paper we report on the effect of boron based interlayers on wetting, mechanical adhesion and on the TCR of Cu coatings deposited on glassy carbon substrates by magnetron sputtering. The interlayers were 5 nm thick and consisted of pure B and B with additions of the carbide forming metals Mo, Ti and Cr in the range of 5 at.% relative to B. The interlayers were deposited by RF magnetron sputtering from either a pure B target or from a composite target. The interlayer composition was checked by Auger Electron Spectroscopy and found to be homogenous within the whole film.The system C-substrate/interlayer/Cu coating was characterized in as deposited samples and samples heat treated for 30 min at 800 degrees C under High Vacuum (HV), which mimics typical hot pressing parameters during composite formation. Material transport during heat treatment was investigated by Secondary Ion Mass Spectroscopy (SIMS). The de-wetting and hole formation in the Cu coating upon heat treatment were studied by Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). The adhesion of the Cu coating was evaluated by mechanical pull-off testing. The TCR was assessed by infrared photothermal radiometry (PTR). A correlation between the adhesion strength and the value of the TCR which was measured by PTR was determined for as deposited as well as for heat treated samples. PMID- 22241940 TI - Compliance with Xylitol and Sorbitol Chewing Gum Regimens in Clinical Trials. AB - OBJECTIVE: The purpose of this study was to investigate compliance of long-term xylitol and sorbitol chewing gum regimens in adult women participating in a double-blind randomized controlled clinical trial. DESIGN: The participants included 122 mothers (age range: 16-35 years) residing in the city of Bauru, Sao Paulo, Brazil. Compliance with the xylitol and sorbitol chewing gum regimens was assessed by weighing, with a precision balance, all used gums returned in zip lock bags during the study period of 33 months. The total number of returned bags in both chewing gum groups was computed and the differences between groups were determined by one-way ANOVA. Compliance was further categorized into excellent, good, fair or poor based on the distribution of the combined data for both groups by quartiles. These distributions for the xylitol and sorbitol groups were subjected to chi-square analysis. RESULTS: Compliance was always superior for the xylitol group in all categories. These distributions were, however, not significantly different in statistical terms. Average compliance in the xylitol chewing gum group was significantly higher when compared to the sorbitol chewing gum group (p=0.0481). CONCLUSIONS: The results suggest that compliance, and possibly acceptance in this population, was superior for xylitol chewing gum than for sorbitol chewing gum. PMID- 22241941 TI - Capacity fade in Sn-C nanopowder anodes due to fracture. AB - Sn based anodes allow for high initial capacities, which however cannot be retained due to the severe mechanical damage that occurs during Li-insertion and de-insertion. To better understand the fracture process during electrochemical cycling three different nanopowders comprised of Sn particles attached on artificial graphite, natural graphite or micro-carbon microbeads were examined. Although an initial capacity of 700 mAh g(-1) was obtained for all Sn-C nanopowders, a significant capacity fade took place with continuous electrochemical cycling. The microstructural changes in the electrodes corresponding to the changes in electrochemical behavior were studied by transmission and scanning electron microscopy. The fragmentation of Sn observed by microscopy correlates with the capacity fade, but this fragmentation and capacity fade can be controlled by controlling the initial microstructure. It was found that there is a dependence of the capacity fade on the Sn particle volume and surface area fraction of Sn on carbon. PMID- 22241939 TI - The Lymphocyte Potassium Channels Kv1.3 and KCa3.1 as Targets for Immunosuppression. AB - The voltage-gated Kv1.3 and the calcium-activated KCa3.1 potassium channel modulate many calcium-dependent cellular processes in immune cells, including T cell activation and proliferation, and have therefore been proposed as novel therapeutic targets for immunomodulation. Kv1.3 is highly expressed in CCR7(-) effector memory T cells and is emerging as a target for T-cell mediated diseases like multiple sclerosis, rheumatoid arthritis, type-1 diabetes mellitus, allergic contact dermatitis, and psoriasis. KCa3.1 in contrast is expressed in CCR7(+) naive and central memory T cells, as well as in mast cells, macrophages, dedifferentiated vascular smooth muscle cells, fibroblasts, vascular endothelium, and airway epithelium. Given this expression pattern, KCa3.1 is a potential therapeutic target for conditions ranging from inflammatory bowel disease, multiple sclerosis, arthritis, and asthma to cardiovascular diseases like atherosclerosis and post-angioplasty restenosis. Results from animal studies have been supportive of the therapeutic potential of both Kv1.3 and KCa3.1 blockers and have also not shown any toxicities associated with pharmacological Kv1.3 and KCa3.1 blockade. To date, two compounds targeting Kv1.3 are in preclinical development but, so far, no Kv1.3 blocker has advanced into clinical trials. KCa3.1 blockers, on the other hand, have been evaluated in clinical trials for sickle cell anemia and exercise-induced asthma, but have so far not shown efficacy. However, the trial results support KCa3.1 as a safe therapeutic target, and will hopefully help enable clinical trials for other medical conditions that might benefit from KCa3.1 blockade. PMID- 22241942 TI - Utilizing a high fundamental frequency quartz crystal resonator as a biosensor in a digital microfluidic platform. AB - We demonstrate the operation of a digital microfluidic lab-on-a-chip system utilizing Electro Wetting on Dielectrics (EWOD) as the actuation principle and a High Fundamental Frequency (HFF; 50 MHz) quartz crystal microbalance (QCM) resonator as a mass-sensitive sensor. In a first experiment we have tested the reversible formation of a phosphor-lipid monolayer of phospholipid vesicles out of an aqueous buffer suspension onto a bio-functionalized integrated QCM sensor. A binding of bio-molecules results in an altered mass load of the resonant sensor and a shift of the resonance frequency can be measured. In the second part of the experiment, the formation of a protein multilayer composed of the biomolecule streptavidin and biotinylated immunoglobulin G was monitored. Additionally, the macroscopic contact angle was optically measured in order to verify the bio specific binding and to test the implications onto the balance of the surface tensions. Using these sample applications, we were able to demonstrate and to verify the feasibility of integrating a mass-sensitive QCM sensor into a digital microfluidic chip. PMID- 22241943 TI - New antiangiogenics in non-small cell lung cancer treatment: VargatefTM (BIBF 1120) and beyond. AB - Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named "vascular disrupting agents," tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances. PMID- 22241944 TI - Critical appraisal of ticagrelor in the management of acute coronary syndrome. AB - Ticagrelor is a novel P2Y12 receptor antagonist which, like clopidogrel and prasugrel, functions by blocking adenosine diphosphate-mediated platelet aggregation. However, unlike the aforementioned agents, the binding of ticagrelor to this receptor is reversible. Ticagrelor is also believed to mediate some of its beneficial effects by augmenting the effects of adenosine, which is another unique pharmacologic property of this drug. In terms of antiplatelet effect, ticagrelor is more potent than clopidogrel and produces a faster and stronger inhibition of platelet aggregation. This may also be an advantage of ticagrelor over prasugrel, but this has not been adequately studied. Due to the reversible nature of the binding of ticagrelor to the platelet receptor, ticagrelor has a relatively fast offset of effect, with platelet aggregation approaching pretreatment levels about 3 days after discontinuation of therapy. This has advantages in patients requiring invasive procedures, but also makes medication adherence very important in order to be able to maintain an effective antiplatelet effect. Ticagrelor has been shown to be clinically superior to clopidogrel when given to patients with an acute coronary syndrome, resulting in significantly lower rates of myocardial infarction and vascular death. However, ticagrelor is indicated to be administered with aspirin, and the clinical benefits of ticagrelor may be less when daily dosages of aspirin exceed 100 mg. As expected, bleeding is the most common adverse effect with ticagrelor, although it occurs at rates comparable with those seen for clopidogrel with the exception of noncoronary artery bypass graft-related major bleeding and fatal intracranial bleeds, the latter of which occurs only rarely. Dyspnea is another common adverse effect with ticagrelor, although this is usually not severe and resolves with drug discontinuation. Unlike clopidogrel, there are no known pharmacogenomic concerns with ticagrelor, and emerging data suggest ticagrelor to be effective in patients resistant to clopidogrel, although more study is needed on this topic. While preliminary data suggest ticagrelor to be cost effective when compared with generic clopidogrel, the acquisition cost of ticagrelor is not insignificant and this will likely be an issue for many health care organizations. Currently, ticagrelor is well positioned to assume an active role in the treatment of coronary artery disease due to an impressive efficacy profile and reasonable safety. Its ultimate role in therapy will continue to evolve as studies on this drug continue eg, (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin, PEGASUS) and more information hopefully becomes available on its use in clopidogrel nonresponders and relative safety and efficacy compared with prasugrel. PMID- 22241945 TI - Emerging patient safety issues under health care reform: follow-on biologics and immunogenicity. AB - US health care reform includes an abbreviated pathway for follow-on biologics, also known as biosimilars, in an effort to speed up access to these complex therapeutics. However, a key patient safety challenge emerges from such an abbreviated pathway: immunogenicity reactions. Yet immunogenicity is notoriously difficult to predict, and even cooperative approaches in licensing between companies have resulted in patient safety concerns, injury, and death. Because approval pathways for follow-on forms do not involve cooperative disclosure of methods and manufacturing processes by innovator companies and follow-on manufacturers, the potential for expanded immunogenicity must be taken into account from a risk management and patient safety perspective. The US Institute of Safe Medication Practices (ISMP) has principles of medication safety that have been applied in the past to high-risk drugs. We propose adapting ISMP principles to follow-on biologic forms and creating systems approaches to warn, rapidly identify, and alert providers regarding this emerging patient safety risk. This type of system can be built upon and provide lessons learned as these new drug forms are developed and marketed more broadly. PMID- 22241946 TI - The effect of hyoscine butylbromide in shortening the first stage of labor: A double blind, randomized, controlled, clinical trial. AB - BACKGROUND AND OBJECTIVES: Hyoscine butylbromide (HBB) is widely used in labor rooms. There have been many studies on the use of HBB during labor with conflicting results, involving both primiparous and multiparous women. The aim of this trial was to study the efficacy of HBB for shortening the first stage of labor in primiparous women. METHODS: The study was a randomized, double blind, controlled trial. Ninety-seven primigravid term pregnant women in spontaneous labor received either hyoscine butylbromide or a placebo intramuscularly once the women entered the active phase of labor. The primary outcome measured was the duration of the first stage of labor. Secondary outcomes were the duration of the second and third stages of labor, blood loss at delivery, rate of cesarean section, and Apgar scores for the neonates. RESULTS: A total of 97 women yielded data for analysis. Of these, 45 women received the placebo and 52 received HBB. The mean duration of the first stage in the control group was 215 minutes, compared with 165 minutes in the study group, representing a decrease of 23.3% (P = 0.001). There were no significant changes in the duration of the second (P = 0.063) or third (P = 0.0418) stages of labor, and no significant differences in blood loss or Apgar scores. There was a slightly higher (but statistically insignificant) rate of instrumental delivery in the control group, but no difference in the Cesarean section rate. There was a 60% reduction in opioid analgesic use in the HBB group. CONCLUSION: HBB is effective in significantly reducing the duration of the first stage of labor, and is not associated with any apparent adverse maternal or neonatal outcomes. PMID- 22241947 TI - Update of a comparative analysis of cost minimization following the introduction of newly available intravenous iron therapies in hospital practice. AB - BACKGROUND: The clinical need to be able to administer high doses of intravenous iron conveniently as a rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. The maximum dose of ferric carboxymaltose is 1000 mg. The maximum dose of iron isomaltoside 1000 is based on 20 mg/kg body weight without a specified ceiling dose, thereby increasing the scope of being able to achieve total iron repletion with a single infusion. This ability to give high doses of iron is important in the context of managing iron deficiency anemia, which is associated with a number of clinical conditions where demands for iron are high. It is also an important component of the strategy as an alternative to blood transfusion. Affordability is a key issue for health services. Recent price changes affecting iron sucrose and ferric carboxymaltose, plus modifications to the manufacturers' prescribing information, have provoked this update. METHODS: This study is a comparative analysis of the costs of acquiring and administering the newly available intravenous iron formulations against standard treatments in the hospital setting. The costs include the medication, nursing costs, equipment, and patient transportation. Three dosage levels (600 mg, 1000 mg, and 1600 mg) are considered. RESULTS AND CONCLUSION: The traditional standard treatments, blood and iron sucrose, cost more than the alternative intravenous iron preparations across the dose spectrum and sensitivities. Low molecular weight iron dextran is the least expensive option at the 1600 mg dose level but has the caveat of a prolonged administration time and requirement for a test dose. At 600 mg and 1000 mg dose levels, both iron isomaltoside 1000 and ferric carboxymaltose are more economical than low molecular weight iron dextran. Iron isomaltoside 1000 is less expensive than ferric carboxymaltose at all dose levels. Newly available iron preparations appear to be clinically promising, cost effective, and practical alternatives to current standards of iron repletion. PMID- 22241948 TI - Critical review of cancer risk associated with angiotensin receptor blocker therapy. AB - The role of drugs in new cancer occurrence and cancer-related death is a major concern. Recently, a meta-analysis raised the possibility that angiotensin receptor blockers (ARBs) might have an adverse effect on patients. This generated a significant debate until the publication of two further meta-analyses, neither of which demonstrated an increased risk of new cancer occurrence or cancer related death with the use of ARBs in patients with hypertension, heart failure, and/or nephropathy. This illustrates that the results of meta-analyses should be interpreted cautiously and critically as bias, such as selection bias, might lead to erroneous conclusions. Overall, the bulk of evidence today indicates that ARBs are not associated with increased cancer risk. PMID- 22241950 TI - Office and ambulatory blood pressure control with a fixed-dose combination of candesartan and hydrochlorothiazide in previously uncontrolled hypertensive patients: results of CHILI CU Soon. AB - BACKGROUND: Fixed-dose combinations of candesartan 32 mg and hydrochlorothiazide (HCTZ) have been shown to be effective in clinical trials. Upon market entry we conducted a noninterventional study to document the safety and effectiveness of this fixed-dose combination in an unselected population in primary care and to compare blood pressure (BP) values obtained during office measurement (OBPM) with ambulatory blood pressure measurement (ABPM). METHODS: CHILI CU Soon was a prospective, noninterventional, noncontrolled, open-label, multicenter study with a follow-up of at least 10 weeks. High-risk patients aged >=18 years with previously uncontrolled hypertension were started on candesartan 32 mg in a fixed dose combination with either 12.5 mg or 25 mg HCTZ. OBPM and ABPM reduction and adverse events were documented. RESULTS: A total of 4131 patients (52.8% male) with a mean age of 63.0 +/- 11.0 years were included. BP was 162.1 +/- 14.8/94.7 +/- 9.2 mmHg during office visits at baseline. After 10 weeks of candesartan 32 mg/12.5 mg or 25 mg HCTZ, mean BP had lowered to 131.7 +/- 10.5/80.0 +/- 6.6 mmHg (P < 0.0001 for both comparisons). BP reduction was comparable irrespective of prior or concomitant medication. In patients for whom physicians regarded an ABPM to be necessary (because of suspected noncontrol over 24 hours), ABP at baseline was 158.2/93.7 mmHg during the day and 141.8/85.2 mmHg during the night. At the last visit, BP had significantly reduced to 133.6/80.0 mmHg and 121.0/72.3 mmHg, respectively, resulting in 20.8% being normotensive over 24 hours (<130/80 mmHg). The correlation between OBPM and ABPM was good (r = 0.589 for systolic BP and r = 0.389 for diastolic BP during the day). Of those who were normotensive upon OBPM, 35.1% had high ABPM during the day, 49.3% were nondippers, and 3.4% were inverted dippers. Forty-nine adverse events (1.19%) were reported, of which seven (0.17%) were regarded as serious. CONCLUSION: Candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ is safe and effective for further BP lowering irrespective of prior antihypertensive drug class not being able to control BP. PMID- 22241949 TI - Differential clinical profile of candesartan compared to other angiotensin receptor blockers. AB - The advantages of blood pressure (BP) control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1]) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8-32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article. PMID- 22241951 TI - The effect of chronic heart failure and type 2 diabetes on insulin-stimulated endothelial function is similar and additive. AB - AIM: Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes. METHODS: Twenty three patients with systolic heart failure and no history of diabetes, seven patients with both systolic heart failure and type 2 diabetes, 19 patients with type 2 diabetes, and ten healthy controls were included in the study. Endothelial function was studied by venous occlusion plethysmography. Insulin-stimulated endothelial function was assessed after intra-arterial infusion of insulin followed by co-infusion with serotonin in three different dosages. Forearm glucose uptake was measured during the insulin infusion. RESULTS: Patients with systolic heart failure had impaired insulin-stimulated endothelial function. The percentage increase in blood flow during co-infusion with insulin and serotonin dose response study was 24.74% +/- 6.16%, 23.50% +/- 8.32%, and 22.29% +/- 10.77% at the three doses respectively, compared to the healthy control group 45.96% +/- 11.56%, 67.40% +/- 18.11% and 84.57% +/- 25.73% (P = 0.01). Insulin-stimulated endothelial function was similar in heart failure patients and patients with type 2 diabetes, while it was further deteriorated in patients suffering from both heart failure and diabetes with a percentage increase in blood flow of 19.15% +/- 7.81%, -2.35% +/- 11.76%, and 5.82% +/- 17.70% at the three doses of serotonin, respectively. Forearm glucose uptake was impaired in patients with heart failure compared to healthy controls (P = 0.03) and tended to be further impaired by co existence of diabetes (P = 0.08). CONCLUSION: Systolic heart failure and type 2 diabetes result in similar vascular insulin resistance and reduced muscular insulin-stimulated glucose uptake. The effects of systolic heart failure and type 2 diabetes appear to be additive. PMID- 22241952 TI - Benefits of once-daily therapies in the treatment of hypertension. AB - In patients with hypertension, 24-hour blood pressure control is the major therapeutic goal. The number of daily doses is one characteristic of an antihypertensive agent that may affect the adequacy of 24-hour control. One measure of therapeutic coverage is the 24-hour trough-to-peak ratio, which determines the suitability of an agent for once-daily administration. The closer an agent is to a 100% trough-to-peak ratio, the more uniform the 24-hour coverage and therefore blood pressure control. High trough-to-peak ratio, long-acting antihypertensive medications lower blood pressure more gradually, which reduces the likelihood of adverse events attributable to abrupt drug action that occurs with shorter-acting agents. In hypertension, the natural diurnal variation of blood pressure may be altered, including elevated nighttime pressures. An optimal once-daily hypertension therapy would not only lower blood pressure but also normalize any blunted circadian variations in blood pressure. The benefits of once-daily agents with sustained therapeutic coverage may also be explained, in part, by increased patient adherence to simpler regimens as well as lower loss of blood pressure control during virtually inevitable intermittent noncompliance. Studies have demonstrated that once-daily antihypertensive agents have the highest adherence compared with twice-daily or multiple daily doses, including greater adherence to the prescribed timing of doses. PMID- 22241953 TI - Clinical utility of vandetanib in the treatment of patients with advanced medullary thyroid cancer. AB - Vandetanib (ZD6474) became the first systemic agent to be approved for the treatment of metastatic or locally advanced medullary thyroid cancer. It was a proof of principle, because it is an orally bioavailable medication that targets the growth factors felt to be important in the pathogenesis of this disease, ie, the rearranged during transfection proto-oncogene and vascular endothelial growth factor receptor. It was tested initially in two Phase II studies at doses of 100 mg and 300 mg daily. Although activity was seen at both doses, the higher dose was chosen for a randomized, placebo-controlled Phase II study. This trial, which accrued more than 300 patients, showed a statistically significant benefit for the group taking vandetanib compared with those taking placebo medication. Progression-free survival for the vandetanib arm has not been reached, compared with 19 months for the placebo arm. The main toxicity appears to be diarrhea, although some patients experienced significant side effects, including torsades de pointes and sudden cardiac death. Therefore, it is now necessary for practitioners to enroll in a Risk Evaluation Mitigation Strategy before being allowed to prescribe this medication, to reduce the risk of serious side effects occurring. PMID- 22241954 TI - Narrated lived experiences of self-care and health among rural-living older persons with a strong sense of coherence. AB - Sense of coherence (SOC), with its components comprehensibility, manageability, and meaningfulness, is a major factor in the ability to cope successfully with stressors and is closely related to health. Qualitative studies related to SOC are scarce, and in this phenomenological interview study, self-care is investigated in relation to SOC. The aim of this study was to describe the lived experiences of self-care and features that may influence health and self-care among older home-dwelling individuals living in rural areas and who have a strong SOC. Eleven persons with a mean age of 73.5 years and a SOC value in the range of 153-188, measured by Antonovsky's 29-item SOC scale, were interviewed. The interviews were recorded, transcribed verbatim, and analyzed with a phenomenological descriptive method. The findings showed that successful self care involves having, when needed, contact with the health care system, being conscious of a sound lifestyle, being physically and mentally active, being engaged, having social contacts with family and/or others, and being satisfied and positive and looking forward. Formal and informal caregivers should be conscious of the importance of motivating and supporting older individuals with respect to these dimensions of self-care. PMID- 22241955 TI - Expectant parents' experiences of parental education within the antenatal health service. AB - Being an expectant parent is a life changing event and it is something that most people will experience in their lifetime. Many people who are parents for the first time will participate in parenting education. Most of the previous studies associated with parenting education focus on subjects such as birth outcome and breastfeeding. The purpose of this study is to focus on the less investigated aspect of the parents' experience of participating in parenting education with Maternal Healthcare Services (MVC). A qualitative, phenomenological, hermeneutical method was selected to be used to analyze our findings and we used the statements of twenty participants to accumulate enough material to develop it into twelve sub-themes and five themes. The results of this study show that these expectant parents had few or no expectations of the parenting education that they were going to participate in. Generally speaking the parents seemed to be satisfied with the program. They described their reasons for participating as a chance to get together with other people in similar circumstances and to share information and they found a midwife to be a trustworthy professional person to confirm the information that was available to them from other sources. PMID- 22241957 TI - Expression of EGFRvIII in glioblastoma: prognostic significance revisited. AB - The epidermal growth factor receptor variant III (EGFRvIII) is associated with increased proliferation of glioma cells. However, the impact of EGFRvIII on survival of patients with glioblastoma (GBM) has not been definitively established. In the present study, we prospectively evaluated 73 patients with primary GBM treated with surgical resection and standard radio/chemotherapy. The EGFRvIII was assessed by reverse transcription-polymerase chain reaction (PCR), O(6)-methylguanine methyltransferase (MGMT) promoter methylation was assessed by methylation-specific PCR, and phosphatase and tension homolog (PTEN) expression was assessed by immunohistochemistry. In 14 patients of this series, who presented with tumor recurrence, EGFRvIII was determined by real-time PCR. Sensitivity to temozolomide (TMZ) was assessed in vitro on GBM neurosphere cell cultures with different patterns of EGFRvIII expression. Age 60 years or younger, preoperative Karnofsky Performance Status score of 70 or higher, recursive partitioning analysis score III and IV, methylated MGMT, and Ki67 index of 20% or less were significantly associated with longer overall survival (OS; P = .0069, P = .0035, P = .0007, P = .0437, and P = .0286, respectively). EGFRvIII identified patients with significantly longer OS (P = .0023) and the association of EGFRvIII/Ki67 of 20% or less, EGFRvIII/normal PTEN, EGFRvIII/methylated MGMT, and EGFRvIII/normal PTEN/methylated MGMT identified subgroups of GBM patients with better prognosis. In recurred GBMs, EGFRvIII expression was approximately two fold lower than in primary tumors. In vitro, the EGFRvIII-negative GBM neurosphere cells were more resistant to TMZ than the positive ones. In conclusion, in contrast with previous studies, we found that EGFRvIII is associated with prolonged survival of GBM patients treated with surgery and radio/chemotherapy. Depletion of EGFRvIII in recurrent GBMs as well as differential sensitivity to TMZ in vitro indicates that the EGFRvIII-negative cell fraction is involved in resistance to radio/chemotherapy and tumor repopulation. PMID- 22241958 TI - Cyclophilin B expression is associated with in vitro radioresistance and clinical outcome after radiotherapy. AB - The tools for predicting clinical outcome after radiotherapy are not yet optimal. To improve on this, we applied the COXEN informatics approach to in vitro radiation sensitivity data of transcriptionally profiled human cells and gene expression data from untreated head and neck squamous cell carcinoma (HNSCC) and bladder tumors to generate a multigene predictive model that is independent of histologic findings and reports on tumor radiosensitivity. The predictive ability of this 41-gene model was evaluated in patients with HNSCC and was found to stratify clinical outcome after radiotherapy. In contrast, this model was not useful in stratifying similar patients not treated with radiation. This led us to hypothesize that expression of some of the 41 genes contributes to tumor radioresistance and clinical recurrence. Hence, we evaluated the expression the 41 genes as a function of in vitro radioresistance in the NCI-60 cancer cell line panel and found cyclophilin B (PPIB), a peptidylprolyl isomerase and target of cyclosporine A (CsA), had the strongest direct correlation. Functional inhibition of PPIB by small interfering RNA depletion or CsA treatment leads to radiosensitization in cancer cells and reduced cellular DNA repair. Immunohistochemical evaluation of PPIB expression in patients with HNSCC was found to be associated with outcome after radiotherapy. This work demonstrates that a novel 41-gene expression model of radiation sensitivity developed in bladder cancer cell lines and human skin fibroblasts predicts clinical outcome after radiotherapy in head and neck cancer patients and identifies PPIB as a potential target for clinical radiosensitization. PMID- 22241959 TI - Identification of MET and SRC activation in melanoma cell lines showing primary resistance to PLX4032. AB - PLX4032/vemurafenib is a first-in-class small-molecule BRAF(V600E) inhibitor with clinical activity in patients with BRAF mutant melanoma. Nevertheless, drug resistance develops in treated patients, and strategies to overcome primary and acquired resistance are required. To explore the molecular mechanisms involved in primary resistance to PLX4032, we investigated its effects on cell proliferation and signaling in a panel of 27 genetically characterized patient-derived melanoma cell lines. Cell sensitivity to PLX4032 was dependent on BRAF(V600E) and independent from other gene alterations that commonly occur in melanoma such as PTEN loss, BRAF, and MITF gene amplification. Two cell lines lacking sensitivity to PLX4032 and harboring a different set of genetic alterations were studied as models of primary resistance. Treatment with the MEK inhibitor UO126 but not with PLX4032 inhibited cell growth and ERK activation. Resistance to PLX4032 was maintained after CRAF down-regulation by siRNA indicating alternative activation of MEK-ERK signaling. Genetic characterization by multiplex ligation-dependent probe amplification and analysis of phosphotyrosine signaling by MALDI-TOF mass spectrometry analysis revealed the activation of MET and SRC signaling, associated with the amplification of MET and of CTNNB1 and CCND1 genes, respectively. The combination of PLX4032 with drugs or siRNA targeting MET was effective in inhibiting cell growth and reducing cell invasion and migration in melanoma cells with MET amplification; similar effects were observed after targeting SRC in the other cell line, indicating a role for MET and SRC signaling in primary resistance to PLX4032. Our results support the development of classification of melanoma in molecular subtypes for more effective therapies. PMID- 22241960 TI - Neutralization of tumor necrosis factor bioactivity ameliorates urethane-induced pulmonary oncogenesis in mice. AB - Tumor necrosis factor (TNF) has been implicated in inflammation-associated tumor progression. Although multiple reports identified a role for TNF signaling in established cancers, few studies have assessed the impact of TNF blockade on early tumor formation promotion. We aimed at exploring the effects of TNF neutralization in a preclinical mouse model of lung carcinogenesis. For this, Balb/c mice (n = 42) received four weekly intraperitoneal urethane injections (1 g/kg) and twice-weekly intraperitoneal soluble TNF receptor (etanercept; 10 mg/kg) administered during tumor initiation/promotion, tumor progression, or continuously (months 1, 6, and 1-8 after urethane start, respectively). Lung oncogenesis was assessed after 8 months. In separate short-term studies, Balb/c mice (n = 21) received a single control or urethane injection followed by twice weekly intraperitoneal control or sTNFR:Fc injections. Lung inflammation was assessed after 1 week. We found that sTNFR:Fc treatment during tumor initiation/promotion resulted in a significant reduction of tumor number but not dimensions. However, sTNFR:Fc administered during tumor progression did not impact tumor multiplicity but significantly decreased tumor diameter. Continued sTNFR:Fc administration was effective in halting both respiratory tumor formation and progression in response to urethane. This favorable impact was associated with impaired cellular proliferation and new vessel formation in lung tumors. In addition, TNF neutralization altered the lung inflammatory response to urethane, evidenced by reductions in TNF and macrophage and increases in interferon gamma and interleukin 10 content of the air spaces. sTNFR:Fc treatment of RAW264.7 macrophages downregulated TNF and enhanced interferon gamma and interleukin 10 expression. In conclusion, TNF neutralization is effective against urethane induced lung oncogenesis in mice and could present a lung chemoprevention strategy worth testing clinically. PMID- 22241961 TI - Noninvasive imaging reveals inhibition of ovarian cancer by targeting CXCL12 CXCR4. AB - Patients with metastatic ovarian cancer continue to have a dismal prognosis, emphasizing the need for new strategies to identify and develop new molecular targets for therapy. Chemokine CXCL12 and its receptor CXCR4 are upregulated in metastatic ovarian cancer cells and the intraperitoneal tumor microenvironment. CXCL12-CXCR4 signaling promotes multiple steps in proliferation and dissemination of ovarian cancer cells, suggesting that targeted inhibition of this pathway will limit tumor progression. To investigate CXCL12-CXCR4 signaling in ovarian cancer and establish effects of inhibiting this pathway on tumor progression and survival, we designed a Gaussia luciferase complementation imaging reporter system to detect CXCL12 binding to CXCR4 in ovarian cancer cells. In cell-based assays, we established that the complementation imaging reporter could detect CXCL12 binding to CXCR4 and quantify specific inhibition of ligand-receptor interaction. We monitored CXCL12-CXCR4 binding and inhibition in a mouse xenograft model of metastatic human ovarian cancer by imaging Gaussia luciferase complementation and assessed tumor progression with firefly luciferase. Bioluminescence imaging studies in living mice showed that treatment with AMD3100, a clinically approved inhibitor of CXCL12-CXCR4, blocked ligand-receptor binding and reduced growth of ovarian cancer cells. Treatment with AMD3100 also modestly improved overall survival of mice with metastatic ovarian cancer. The Gaussia luciferase complementation imaging reporter system will facilitate further preclinical development and optimization of CXCL12-CXCR4 targeted compounds for treatment of ovarian cancer. Our research supports clinical translation of existing CXCR4 inhibitors for molecular therapy for ovarian cancer. PMID- 22241962 TI - Requirement of nuclear factor kappaB for Smac mimetic-mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. AB - Defects in apoptosis contribute to treatment resistance and poor outcome of pancreatic cancer, calling for novel therapeutic strategies. Here, we provide the first evidence that nuclear factor (NF) kappaB is required for Smac mimetic mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. The Smac mimetic BV6 cooperates with gemcitabine to reduce cell viability and to induce apoptosis. In addition, BV6 significantly enhances the cytotoxicity of several anticancer drugs against pancreatic carcinoma cells, including doxorubicin, cisplatin, and 5-fluorouracil. Molecular studies reveal that BV6 stimulates NF-kappaB activation, which is further increased in the presence of gemcitabine. Importantly, inhibition of NF-kappaB by overexpression of the dominant-negative IkappaBalpha superrepressor significantly decreases BV6- and gemcitabine-induced apoptosis, demonstrating that NF-kappaB exerts a proapoptotic function in this model of apoptosis. In support of this notion, inhibition of tumor necrosis factor alpha (TNFalpha) by the TNFalpha blocking antibody Enbrel reduces BV6- and gemcitabine-induced activation of caspase 8 and 3, loss of mitochondrial membrane potential, and apoptosis. By demonstrating that BV6 and gemcitabine trigger a NF-kappaB-dependent, TNFalpha-mediated loop to activate apoptosis signaling pathways and caspase-dependent apoptotic cell death, our findings have important implications for the development of Smac mimetic based combination protocols in the treatment of pancreatic cancer. PMID- 22241963 TI - Ras-related tumorigenesis is suppressed by BNIP3-mediated autophagy through inhibition of cell proliferation. AB - Autophagy plays diverse roles in Ras-related tumorigenesis. H-ras(val12) induces autophagy through multiple signaling pathways including Raf-1/ERK pathway, and various ERK downstream molecules of autophagy have been reported. In this study, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) is identified as a downstream transducer of the Ras/Raf/ERK signaling pathway to induce autophagy. BNIP3 was upregulated by H-ras(val12) at the transcriptional level to compete with Beclin 1 for binding with Bcl-2. H-ras(val12)-induced autophagy suppresses cell proliferation demonstrated both in vitro and in vivo by expression of ectopic BNIP3, Atg5, or interference RNA of BNIP3 (siBNIP3) and Atg5 (shAtg5) using mouse NIH3T3 and embryo fibroblast cells. H-ras(val12) induces different autophagic responses depending on the duration of Ras overexpression. After a short time (48 hours) of Ras overexpression, autophagy inhibits cell proliferation. In contrast, a longer time (2 weeks) of Ras overexpression, cell proliferation was enhanced by autophagy. Furthermore, overexpression of mutant Ras, BNIP3, and LC3-II was detected in bladder cancer T24 cells and the tumor parts of 75% of bladder cancer specimens indicating a positive correlation between autophagy and tumorigenesis. Taken together, our mouse model demonstrates a balance between BNIP3-mediated autophagy and H-ras(val12)-induced tumor formation and reveals that H-ras(val12) induces autophagy in a BNIP3-dependent manner, and the threshold of autophagy plays a decisive role in H-ras(val12) induced tumorigenesis. Our findings combined with others' reports suggest a new therapeutic strategy against Ras-related tumorigenesis by negative or positive regulation of autophagic activity, which is determined by the level of autophagy and tumor progression stages. PMID- 22241965 TI - Development of the use of conversational cues to assess reality status. AB - In this study we assessed children's ability to use information overheard in other people's conversations to judge the reality status of a novel entity. Three to 9-year-old children (N = 101) watched video clips in which two adults conversed casually about a novel being. Videos contained statements that either explicitly denied, explicitly affirmed, or implicitly acknowledged the entity's existence. Results indicated that children of all ages used statements of denial to discount the reality status of the novel entity, but that this ability improved with age. By age 5, children used implicit existence cues to judge a novel entity as being real. Not until age 9, however, did children begin to doubt the existence of entities whose reality status was explicitly affirmed in conversation. Overall, results indicate that the ability to use conversational cues to determine reality status is present in some children as early as age 3, but recognition of the nuanced language of belief continues to develop during the elementary-school years. PMID- 22241966 TI - Air monitoring: new advances in sampling and detection. AB - As the harmful effects of low-level exposure to hazardous organic air pollutants become more evident, there is constant pressure to improve the detection limits of indoor and ambient air monitoring methods, for example, by collecting larger air volumes and by optimising the sensitivity of the analytical detector. However, at the other end of the scale, rapid industrialisation in the developing world and growing pressure to reclaim derelict industrial land for house building is driving the need for air monitoring methods that can reliably accommodate very high-concentration samples in potentially aggressive matrices. This paper investigates the potential of a combination of two powerful gas chromatography based analytical enhancements-sample preconcentration/thermal desorption and time of-flight mass spectrometry-to improve quantitative and qualitative measurement of very-low-(ppt) level organic chemicals, even in the most complex air samples. It also describes new, practical monitoring options for addressing equally challenging high-concentration industrial samples. PMID- 22241967 TI - Protecting High Energy Barriers: A New Equation to Regulate Boost Energy in Accelerated Molecular Dynamics Simulations. AB - Molecular dynamics (MD) is one of the most common tools in computational chemistry. Recently, our group has employed accelerated molecular dynamics (aMD) to improve the conformational sampling over conventional molecular dynamics techniques. In the original aMD implementation, sampling is greatly improved by raising energy wells below a predefined energy level. Recently, our group presented an alternative aMD implementation where simulations are accelerated by lowering energy barriers of the potential energy surface. When coupled with thermodynamic integration simulations, this implementation showed very promising results. However, when applied to large systems, such as proteins, the simulation tends to be biased to high energy regions of the potential landscape. The reason for this behavior lies in the boost equation used since the highest energy barriers are dramatically more affected than the lower ones. To address this issue, in this work, we present a new boost equation that prevents oversampling of unfavorable high energy conformational states. The new boost potential provides not only better recovery of statistics throughout the simulation but also enhanced sampling of statistically relevant regions in explicit solvent MD simulations. PMID- 22241968 TI - Force Field Benchmark of Organic Liquids: Density, Enthalpy of Vaporization, Heat Capacities, Surface Tension, Isothermal Compressibility, Volumetric Expansion Coefficient, and Dielectric Constant. AB - The chemical composition of small organic molecules is often very similar to amino acid side chains or the bases in nucleic acids, and hence there is no a priori reason why a molecular mechanics force field could not describe both organic liquids and biomolecules with a single parameter set. Here, we devise a benchmark for force fields in order to test the ability of existing force fields to reproduce some key properties of organic liquids, namely, the density, enthalpy of vaporization, the surface tension, the heat capacity at constant volume and pressure, the isothermal compressibility, the volumetric expansion coefficient, and the static dielectric constant. Well over 1200 experimental measurements were used for comparison to the simulations of 146 organic liquids. Novel polynomial interpolations of the dielectric constant (32 molecules), heat capacity at constant pressure (three molecules), and the isothermal compressibility (53 molecules) as a function of the temperature have been made, based on experimental data, in order to be able to compare simulation results to them. To compute the heat capacities, we applied the two phase thermodynamics method (Lin et al. J. Chem. Phys.2003, 119, 11792), which allows one to compute thermodynamic properties on the basis of the density of states as derived from the velocity autocorrelation function. The method is implemented in a new utility within the GROMACS molecular simulation package, named g_dos, and a detailed expose of the underlying equations is presented. The purpose of this work is to establish the state of the art of two popular force fields, OPLS/AA (all-atom optimized potential for liquid simulation) and GAFF (generalized Amber force field), to find common bottlenecks, i.e., particularly difficult molecules, and to serve as a reference point for future force field development. To make for a fair playing field, all molecules were evaluated with the same parameter settings, such as thermostats and barostats, treatment of electrostatic interactions, and system size (1000 molecules). The densities and enthalpy of vaporization from an independent data set based on simulations using the CHARMM General Force Field (CGenFF) presented by Vanommeslaeghe et al. (J. Comput. Chem.2010, 31, 671) are included for comparison. We find that, overall, the OPLS/AA force field performs somewhat better than GAFF, but there are significant issues with reproduction of the surface tension and dielectric constants for both force fields. PMID- 22241964 TI - The interconnectedness of cancer cell signaling. AB - The elegance of fundamental and applied research activities have begun to reveal a myriad of spatial and temporal alterations in downstream signaling networks affected by cell surface receptor stimulation including G protein-coupled receptors and receptor tyrosine kinases. Interconnected biochemical pathways serve to integrate and distribute the signaling information throughout the cell by orchestration of complex biochemical circuits consisting of protein interactions and covalent modification processes. It is clear that scientific literature summarizing results from both fundamental and applied scientific research activities has served to provide a broad foundational biologic database that has been instrumental in advancing our continued understanding of underlying cancer biology. This article reflects on historical advances and the role of innovation in the competitive world of grant-sponsored research. PMID- 22241969 TI - Short conduction delays cause inhibition rather than excitation to favor synchrony in hybrid neuronal networks of the entorhinal cortex. AB - How stable synchrony in neuronal networks is sustained in the presence of conduction delays is an open question. The Dynamic Clamp was used to measure phase resetting curves (PRCs) for entorhinal cortical cells, and then to construct networks of two such neurons. PRCs were in general Type I (all advances or all delays) or weakly type II with a small region at early phases with the opposite type of resetting. We used previously developed theoretical methods based on PRCs under the assumption of pulsatile coupling to predict the delays that synchronize these hybrid circuits. For excitatory coupling, synchrony was predicted and observed only with no delay and for delays greater than half a network period that cause each neuron to receive an input late in its firing cycle and almost immediately fire an action potential. Synchronization for these long delays was surprisingly tight and robust to the noise and heterogeneity inherent in a biological system. In contrast to excitatory coupling, inhibitory coupling led to antiphase for no delay, very short delays and delays close to a network period, but to near-synchrony for a wide range of relatively short delays. PRC-based methods show that conduction delays can stabilize synchrony in several ways, including neutralizing a discontinuity introduced by strong inhibition, favoring synchrony in the case of noisy bistability, and avoiding an initial destabilizing region of a weakly type II PRC. PRCs can identify optimal conduction delays favoring synchronization at a given frequency, and also predict robustness to noise and heterogeneity. PMID- 22241970 TI - Multi-scale inference of interaction rules in animal groups using Bayesian model selection. AB - Inference of interaction rules of animals moving in groups usually relies on an analysis of large scale system behaviour. Models are tuned through repeated simulation until they match the observed behaviour. More recent work has used the fine scale motions of animals to validate and fit the rules of interaction of animals in groups. Here, we use a Bayesian methodology to compare a variety of models to the collective motion of glass prawns (Paratya australiensis). We show that these exhibit a stereotypical 'phase transition', whereby an increase in density leads to the onset of collective motion in one direction. We fit models to this data, which range from: a mean-field model where all prawns interact globally; to a spatial Markovian model where prawns are self-propelled particles influenced only by the current positions and directions of their neighbours; up to non-Markovian models where prawns have 'memory' of previous interactions, integrating their experiences over time when deciding to change behaviour. We show that the mean-field model fits the large scale behaviour of the system, but does not capture fine scale rules of interaction, which are primarily mediated by physical contact. Conversely, the Markovian self-propelled particle model captures the fine scale rules of interaction but fails to reproduce global dynamics. The most sophisticated model, the non-Markovian model, provides a good match to the data at both the fine scale and in terms of reproducing global dynamics. We conclude that prawns' movements are influenced by not just the current direction of nearby conspecifics, but also those encountered in the recent past. Given the simplicity of prawns as a study system our research suggests that self-propelled particle models of collective motion should, if they are to be realistic at multiple biological scales, include memory of previous interactions and other non-Markovian effects. PMID- 22241971 TI - Failure of adaptive self-organized criticality during epileptic seizure attacks. AB - Critical dynamics are assumed to be an attractive mode for normal brain functioning as information processing and computational capabilities are found to be optimal in the critical state. Recent experimental observations of neuronal activity patterns following power-law distributions, a hallmark of systems at a critical state, have led to the hypothesis that human brain dynamics could be poised at a phase transition between ordered and disordered activity. A so far unresolved question concerns the medical significance of critical brain activity and how it relates to pathological conditions. Using data from invasive electroencephalogram recordings from humans we show that during epileptic seizure attacks neuronal activity patterns deviate from the normally observed power-law distribution characterizing critical dynamics. The comparison of these observations to results from a computational model exhibiting self-organized criticality (SOC) based on adaptive networks allows further insights into the underlying dynamics. Together these results suggest that brain dynamics deviates from criticality during seizures caused by the failure of adaptive SOC. PMID- 22241973 TI - Landscape epidemiology and control of pathogens with cryptic and long-distance dispersal: sudden oak death in northern Californian forests. AB - Exotic pathogens and pests threaten ecosystem service, biodiversity, and crop security globally. If an invasive agent can disperse asymptomatically over long distances, multiple spatial and temporal scales interplay, making identification of effective strategies to regulate, monitor, and control disease extremely difficult. The management of outbreaks is also challenged by limited data on the actual area infested and the dynamics of spatial spread, due to financial, technological, or social constraints. We examine principles of landscape epidemiology important in designing policy to prevent or slow invasion by such organisms, and use Phytophthora ramorum, the cause of sudden oak death, to illustrate how shortfalls in their understanding can render management applications inappropriate. This pathogen has invaded forests in coastal California, USA, and an isolated but fast-growing epidemic focus in northern California (Humboldt County) has the potential for extensive spread. The risk of spread is enhanced by the pathogen's generalist nature and survival. Additionally, the extent of cryptic infection is unknown due to limited surveying resources and access to private land. Here, we use an epidemiological model for transmission in heterogeneous landscapes and Bayesian Markov-chain-Monte-Carlo inference to estimate dispersal and life-cycle parameters of P. ramorum and forecast the distribution of infection and speed of the epidemic front in Humboldt County. We assess the viability of management options for containing the pathogen's northern spread and local impacts. Implementing a stand-alone host free "barrier" had limited efficacy due to long-distance dispersal, but combining curative with preventive treatments ahead of the front reduced local damage and contained spread. While the large size of this focus makes effective control expensive, early synchronous treatment in newly-identified disease foci should be more cost-effective. We show how the successful management of forest ecosystems depends on estimating the spatial scales of invasion and treatment of pathogens and pests with cryptic long-distance dispersal. PMID- 22241972 TI - Dopamine, affordance and active inference. AB - The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. PMID- 22241974 TI - Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies. AB - Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/. PMID- 22241975 TI - A model of ant route navigation driven by scene familiarity. AB - In this paper we propose a model of visually guided route navigation in ants that captures the known properties of real behaviour whilst retaining mechanistic simplicity and thus biological plausibility. For an ant, the coupling of movement and viewing direction means that a familiar view specifies a familiar direction of movement. Since the views experienced along a habitual route will be more familiar, route navigation can be re-cast as a search for familiar views. This search can be performed with a simple scanning routine, a behaviour that ants have been observed to perform. We test this proposed route navigation strategy in simulation, by learning a series of routes through visually cluttered environments consisting of objects that are only distinguishable as silhouettes against the sky. In the first instance we determine view familiarity by exhaustive comparison with the set of views experienced during training. In further experiments we train an artificial neural network to perform familiarity discrimination using the training views. Our results indicate that, not only is the approach successful, but also that the routes that are learnt show many of the characteristics of the routes of desert ants. As such, we believe the model represents the only detailed and complete model of insect route guidance to date. What is more, the model provides a general demonstration that visually guided routes can be produced with parsimonious mechanisms that do not specify when or what to learn, nor separate routes into sequences of waypoints. PMID- 22241976 TI - A mathematical methodology for determining the temporal order of pathway alterations arising during gliomagenesis. AB - Human cancer is caused by the accumulation of genetic alterations in cells. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and thus represent promising targets for therapeutic intervention. We have previously described a computational approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to determine the temporal sequence of genetic alterations during tumorigenesis from cross-sectional genomic data of tumors at their fully transformed stage. Since alterations within a set of genes belonging to a particular signaling pathway may have similar or equivalent effects, we applied a pathway-based systems biology approach to the RESIC methodology. This method was used to determine whether alterations of specific pathways develop early or late during malignant transformation. When applied to primary glioblastoma (GBM) copy number data from The Cancer Genome Atlas (TCGA) project, RESIC identified a temporal order of pathway alterations consistent with the order of events in secondary GBMs. We then further subdivided the samples into the four main GBM subtypes and determined the relative contributions of each subtype to the overall results: we found that the overall ordering applied for the proneural subtype but differed for mesenchymal samples. The temporal sequence of events could not be identified for neural and classical subtypes, possibly due to a limited number of samples. Moreover, for samples of the proneural subtype, we detected two distinct temporal sequences of events: (i) RAS pathway activation was followed by TP53 inactivation and finally PI3K2 activation, and (ii) RAS activation preceded only AKT activation. This extension of the RESIC methodology provides an evolutionary mathematical approach to identify the temporal sequence of pathway changes driving tumorigenesis and may be useful in guiding the understanding of signaling rearrangements in cancer development. PMID- 22241977 TI - A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection. AB - We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naive patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naive and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents. PMID- 22241978 TI - Vaccinomics and personalized vaccinology: is science leading us toward a new path of directed vaccine development and discovery? AB - As is apparent in many fields of science and medicine, the new biology, and particularly new high-throughput genetic sequencing and transcriptomic and epigenetic technologies, are radically altering our understanding and views of science. In this article, we make the case that while mostly ignored thus far in the vaccine field, these changes will revolutionize vaccinology from development to manufacture to administration. Such advances will address a current major barrier in vaccinology-that of empiric vaccine discovery and development, and the subsequent low yield of viable vaccine candidates, particularly for hyper variable viruses. While our laboratory's data and thinking (and hence also for this paper) has been directed toward viruses and viral vaccines, generalization to other pathogens and disease entities (i.e., anti-cancer vaccines) may be appropriate. PMID- 22241979 TI - Eurasian-origin gene segments contribute to the transmissibility, aerosol release, and morphology of the 2009 pandemic H1N1 influenza virus. AB - The epidemiological success of pandemic and epidemic influenza A viruses relies on the ability to transmit efficiently from person-to-person via respiratory droplets. Respiratory droplet (RD) transmission of influenza viruses requires efficient replication and release of infectious influenza particles into the air. The 2009 pandemic H1N1 (pH1N1) virus originated by reassortment of a North American triple reassortant swine (TRS) virus with a Eurasian swine virus that contributed the neuraminidase (NA) and M gene segments. Both the TRS and Eurasian swine viruses caused sporadic infections in humans, but failed to spread from person-to-person, unlike the pH1N1 virus. We evaluated the pH1N1 and its precursor viruses in a ferret model to determine the contribution of different viral gene segments on the release of influenza virus particles into the air and on the transmissibility of the pH1N1 virus. We found that the Eurasian-origin gene segments contributed to efficient RD transmission of the pH1N1 virus likely by modulating the release of influenza viral RNA-containing particles into the air. All viruses replicated well in the upper respiratory tract of infected ferrets, suggesting that factors other than viral replication are important for the release of influenza virus particles and transmission. Our studies demonstrate that the release of influenza viral RNA-containing particles into the air correlates with increased NA activity. Additionally, the pleomorphic phenotype of the pH1N1 virus is dependent upon the Eurasian-origin gene segments, suggesting a link between transmission and virus morphology. We have demonstrated that the viruses are released into exhaled air to varying degrees and a constellation of genes influences the transmissibility of the pH1N1 virus. PMID- 22241980 TI - A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection. AB - Clinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb' that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb'-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematopoietic progenitor cells (HPCs) infected in vitro. pUL138 is encoded on polycistronic transcripts that also encode 3 additional proteins, pUL133, pUL135, and pUL136, collectively comprising the UL133-UL138 locus. This work represents the first characterization of these proteins and identifies a role for this locus in infection. Similar to pUL138, pUL133, pUL135, and pUL136 are integral membrane proteins that partially co-localized with pUL138 in the Golgi during productive infection in fibroblasts. As expected of ULb' sequences, the UL133-UL138 locus was dispensable for replication in cultured fibroblasts. In CD34+ HPCs, this locus suppressed viral replication in HPCs, an activity attributable to both pUL133 and pUL138. Strikingly, the UL133-UL138 locus was required for efficient replication in endothelial cells. The association of this locus with three context-dependent phenotypes suggests an exciting role for the UL133-UL138 locus in modulating the outcome of viral infection in different contexts of infection. Differential profiles of protein expression from the UL133-UL138 locus correlated with the cell-type dependent phenotypes associated with this locus. We extended our in vitro findings to analyze viral replication and dissemination in a NOD-scid IL2Rgamma(c) (null)-humanized mouse model. The UL133-UL138(NULL) virus exhibited an increased capacity for replication and/or dissemination following stem cell mobilization relative to the wild-type virus, suggesting an important role in viral persistence and spread in the host. As pUL133, pUL135, pUL136, and pUL138 are conserved in virus strains infecting higher order primates, but not lower order mammals, the functions encoded likely represent host-specific viral adaptations. PMID- 22241981 TI - Eight RGS and RGS-like proteins orchestrate growth, differentiation, and pathogenicity of Magnaporthe oryzae. AB - A previous study identified MoRgs1 as an RGS protein that negative regulates G protein signaling to control developmental processes such as conidiation and appressorium formation in Magnaporthe oryzae. Here, we characterized additional seven RGS and RGS-like proteins (MoRgs2 through MoRgs8). We found that MoRgs1 and MoRgs4 positively regulate surface hydrophobicity, conidiation, and mating. Indifference to MoRgs1, MoRgs4 has a role in regulating laccase and peroxidase activities. MoRgs1, MoRgs2, MoRgs3, MoRgs4, MoRgs6, and MoRgs7 are important for germ tube growth and appressorium formation. Interestingly, MoRgs7 and MoRgs8 exhibit a unique domain structure in which the RGS domain is linked to a seven transmembrane motif, a hallmark of G-protein coupled receptors (GPCRs). We have also shown that MoRgs1 regulates mating through negative regulation of Galpha MoMagB and is involved in the maintenance of cell wall integrity. While all proteins appear to be involved in the control of intracellular cAMP levels, only MoRgs1, MoRgs3, MoRgs4, and MoRgs7 are required for full virulence. Taking together, in addition to MoRgs1 functions as a prominent RGS protein in M. oryzae, MoRgs4 and other RGS and RGS-like proteins are also involved in a complex process governing asexual/sexual development, appressorium formation, and pathogenicity. PMID- 22241982 TI - Inflammasome-dependent pyroptosis and IL-18 protect against Burkholderia pseudomallei lung infection while IL-1beta is deleterious. AB - Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. The interaction of B. pseudomallei with the inflammasome and the role of pyroptosis, IL-1beta, and IL-18 during melioidosis have not been investigated in detail. Here we show that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1beta and IL-18 and are critical for inflammasome-mediated resistance to melioidosis. In vitro production of IL-1beta by macrophages or dendritic cells infected with B. pseudomallei was dependent on NLRC4 and NLRP3 while pyroptosis required only NLRC4. Mice deficient in the inflammasome components ASC, caspase 1, NLRC4, and NLRP3, were dramatically more susceptible to lung infection with B. pseudomallei than WT mice. The heightened susceptibility of Nlrp3-/- mice was due to decreased production of IL-18 and IL-1beta. In contrast, Nlrc4-/- mice produced IL-1beta and IL-18 in higher amount than WT mice and their high susceptibility was due to decreased pyroptosis and consequently higher bacterial burdens. Analyses of IL-18-deficient mice revealed that IL-18 is essential for survival primarily because of its ability to induce IFNgamma production. In contrast, studies using IL-1RI-deficient mice or WT mice treated with either IL 1beta or IL-1 receptor agonist revealed that IL-1beta has deleterious effects during melioidosis. The detrimental role of IL-1beta appeared to be due, in part, to excessive recruitment of neutrophils to the lung. Because neutrophils do not express NLRC4 and therefore fail to undergo pyroptosis, they may be permissive to B. pseudomallei intracellular growth. Administration of neutrophil-recruitment inhibitors IL-1ra or the CXCR2 neutrophil chemokine receptor antagonist antileukinate protected Nlrc4-/- mice from lethal doses of B. pseudomallei and decreased systemic dissemination of bacteria. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1beta. PMID- 22241983 TI - Inflammatory monocytes and neutrophils are licensed to kill during memory responses in vivo. AB - Immunological memory is a hallmark of B and T lymphocytes that have undergone a previous encounter with a given antigen. It is assumed that memory cells mediate better protection of the host upon re-infection because of improved effector functions such as antibody production, cytotoxic activity and cytokine secretion. In contrast to cells of the adaptive immune system, innate immune cells are believed to exhibit a comparable functional effector response each time the same pathogen is encountered. Here, using mice infected by the intracellular bacterium Listeria monocytogenes, we show that during a recall bacterial infection, the chemokine CCL3 secreted by memory CD8+ T cells drives drastic modifications of the functional properties of several populations of phagocytes. We found that inflammatory ly6C+ monocytes and neutrophils largely mediated memory CD8+ T cell bacteriocidal activity by producing increased levels of reactive oxygen species (ROS), augmenting the pH of their phagosomes and inducing antimicrobial autophagy. These events allowed an extremely rapid control of bacterial growth in vivo and accounted for protective immunity. Therefore, our results provide evidence that cytotoxic memory CD8+ T cells can license distinct antimicrobial effector mechanisms of innate cells to efficiently clear pathogens. PMID- 22241984 TI - Allelic variation on murine chromosome 11 modifies host inflammatory responses and resistance to Bacillus anthracis. AB - Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT), as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6) background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36-74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT. PMID- 22241985 TI - Identification and characterization of a novel non-structural protein of bluetongue virus. AB - Bluetongue virus (BTV) is the causative agent of a major disease of livestock (bluetongue). For over two decades, it has been widely accepted that the 10 segments of the dsRNA genome of BTV encode for 7 structural and 3 non-structural proteins. The non-structural proteins (NS1, NS2, NS3/NS3a) play different key roles during the viral replication cycle. In this study we show that BTV expresses a fourth non-structural protein (that we designated NS4) encoded by an open reading frame in segment 9 overlapping the open reading frame encoding VP6. NS4 is 77-79 amino acid residues in length and highly conserved among several BTV serotypes/strains. NS4 was expressed early post-infection and localized in the nucleoli of BTV infected cells. By reverse genetics, we showed that NS4 is dispensable for BTV replication in vitro, both in mammalian and insect cells, and does not affect viral virulence in murine models of bluetongue infection. Interestingly, NS4 conferred a replication advantage to BTV-8, but not to BTV-1, in cells in an interferon (IFN)-induced antiviral state. However, the BTV-1 NS4 conferred a replication advantage both to a BTV-8 reassortant containing the entire segment 9 of BTV-1 and to a BTV-8 mutant with the NS4 identical to the homologous BTV-1 protein. Collectively, this study suggests that NS4 plays an important role in virus-host interaction and is one of the mechanisms played, at least by BTV-8, to counteract the antiviral response of the host. In addition, the distinct nucleolar localization of NS4, being expressed by a virus that replicates exclusively in the cytoplasm, offers new avenues to investigate the multiple roles played by the nucleolus in the biology of the cell. PMID- 22241986 TI - Zebrafish: a see-through host and a fluorescent toolbox to probe host-pathogen interaction. PMID- 22241987 TI - Type 1 interferons and antiviral CD8 T-cell responses. PMID- 22241988 TI - Lymphoid tissue damage in HIV-1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. AB - Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naive CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naive T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naive T cell populations increases significantly, resulting in progressive depletion of both naive CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naive T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naive T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution. PMID- 22241989 TI - Legionella pneumophila secretes a mitochondrial carrier protein during infection. AB - The Mitochondrial Carrier Family (MCF) is a signature group of integral membrane proteins that transport metabolites across the mitochondrial inner membrane in eukaryotes. MCF proteins are characterized by six transmembrane segments that assemble to form a highly-selective channel for metabolite transport. We discovered a novel MCF member, termed Legionellanucleotide carrier Protein (LncP), encoded in the genome of Legionella pneumophila, the causative agent of Legionnaire's disease. LncP was secreted via the bacterial Dot/Icm type IV secretion system into macrophages and assembled in the mitochondrial inner membrane. In a yeast cellular system, LncP induced a dominant-negative phenotype that was rescued by deleting an endogenous ATP carrier. Substrate transport studies on purified LncP reconstituted in liposomes revealed that it catalyzes unidirectional transport and exchange of ATP transport across membranes, thereby supporting a role for LncP as an ATP transporter. A hidden Markov model revealed further MCF proteins in the intracellular pathogens, Legionella longbeachae and Neorickettsia sennetsu, thereby challenging the notion that MCF proteins exist exclusively in eukaryotic organisms. PMID- 22241990 TI - Slit2/Robo4 signaling modulates HIV-1 gp120-induced lymphatic hyperpermeability. AB - Dissemination of HIV in the host involves transit of the virus and virus-infected cells across the lymphatic endothelium. HIV may alter lymphatic endothelial permeability to foster dissemination, but the mechanism is largely unexplored. Using a primary human lymphatic endothelial cell model, we found that HIV-1 envelope protein gp120 induced lymphatic hyperpermeability by disturbing the normal function of Robo4, a novel regulator of endothelial permeability. HIV-1 gp120 induced fibronectin expression and integrin alpha5beta1 phosphorylation, which led to the complexing of these three proteins, and their subsequent interaction with Robo4 through its fibronectin type III repeats. Moreover, pretreatment with an active N-terminus fragment of Slit2, a Robo4 agonist, protected lymphatic endothelial cells from HIV-1 gp120-induced hyperpermeability by inhibiting c-Src kinase activation. Our results indicate that targeting Slit2/Robo4 signaling may protect the integrity of the lymphatic barrier and limit the dissemination of HIV in the host. PMID- 22241991 TI - Replication in cells of hematopoietic origin is necessary for Dengue virus dissemination. AB - Dengue virus (DENV) is a mosquito-borne pathogen for which no vaccine or specific therapeutic is available. Although it is well established that dendritic cells and macrophages are primary sites of DENV replication, it remains unclear whether non-hematopoietic cellular compartments serve as virus reservoirs. Here, we exploited hematopoietic-specific microRNA-142 (miR-142) to control virus tropism by inserting tandem target sites into the virus to restrict replication exclusively in this cell population. In vivo use of this virus restricted infection of CD11b+, CD11c+, and CD45+ cells, resulting in a loss of virus spread, regardless of the route of administration. Furthermore, sequencing of the targeted virus population that persisted at low levels, demonstrated total excision of the inserted miR-142 target sites. The complete conversion of the virus population under these selective conditions suggests that these immune cells are the predominant sources of virus amplification. Taken together, this work highlights the importance of hematopoietic cells for DENV replication and showcases an invaluable tool for the study of virus pathogenesis. PMID- 22241992 TI - Molecular determinants and dynamics of hepatitis C virus secretion. AB - The current model of hepatitis C virus (HCV) production involves the assembly of virions on or near the surface of lipid droplets, envelopment at the ER in association with components of VLDL synthesis, and egress via the secretory pathway. However, the cellular requirements for and a mechanistic understanding of HCV secretion are incomplete at best. We combined an RNA interference (RNAi) analysis of host factors for infectious HCV secretion with the development of live cell imaging of HCV core trafficking to gain a detailed understanding of HCV egress. RNAi studies identified multiple components of the secretory pathway, including ER to Golgi trafficking, lipid and protein kinases that regulate budding from the trans-Golgi network (TGN), VAMP1 vesicles and adaptor proteins, and the recycling endosome. Our results support a model wherein HCV is infectious upon envelopment at the ER and exits the cell via the secretory pathway. We next constructed infectious HCV with a tetracysteine (TC) tag insertion in core (TC core) to monitor the dynamics of HCV core trafficking in association with its cellular cofactors. In order to isolate core protein movements associated with infectious HCV secretion, only trafficking events that required the essential HCV assembly factor NS2 were quantified. TC-core traffics to the cell periphery along microtubules and this movement can be inhibited by nocodazole. Sub-populations of TC-core localize to the Golgi and co-traffic with components of the recycling endosome. Silencing of the recycling endosome component Rab11a results in the accumulation of HCV core at the Golgi. The majority of dynamic core traffics in association with apolipoprotein E (ApoE) and VAMP1 vesicles. This study identifies many new host cofactors of HCV egress, while presenting dynamic studies of HCV core trafficking in infected cells. PMID- 22241993 TI - The cysteine rich necrotrophic effector SnTox1 produced by Stagonospora nodorum triggers susceptibility of wheat lines harboring Snn1. AB - The wheat pathogen Stagonospora nodorum produces multiple necrotrophic effectors (also called host-selective toxins) that promote disease by interacting with corresponding host sensitivity gene products. SnTox1 was the first necrotrophic effector identified in S. nodorum, and was shown to induce necrosis on wheat lines carrying Snn1. Here, we report the molecular cloning and validation of SnTox1 as well as the preliminary characterization of the mechanism underlying the SnTox1-Snn1 interaction which leads to susceptibility. SnTox1 was identified using bioinformatics tools and verified by heterologous expression in Pichia pastoris. SnTox1 encodes a 117 amino acid protein with the first 17 amino acids predicted as a signal peptide, and strikingly, the mature protein contains 16 cysteine residues, a common feature for some avirulence effectors. The transformation of SnTox1 into an avirulent S. nodorum isolate was sufficient to make the strain pathogenic. Additionally, the deletion of SnTox1 in virulent isolates rendered the SnTox1 mutated strains avirulent on the Snn1 differential wheat line. SnTox1 was present in 85% of a global collection of S. nodorum isolates. We identified a total of 11 protein isoforms and found evidence for strong diversifying selection operating on SnTox1. The SnTox1-Snn1 interaction results in an oxidative burst, DNA laddering, and pathogenesis related (PR) gene expression, all hallmarks of a defense response. In the absence of light, the development of SnTox1-induced necrosis and disease symptoms were completely blocked. By comparing the infection processes of a GFP-tagged avirulent isolate and the same isolate transformed with SnTox1, we conclude that SnTox1 may play a critical role during fungal penetration. This research further demonstrates that necrotrophic fungal pathogens utilize small effector proteins to exploit plant resistance pathways for their colonization, which provides important insights into the molecular basis of the wheat-S. nodorum interaction, an emerging model for necrotrophic pathosystems. PMID- 22241994 TI - Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents. AB - HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1)--or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI 1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF 429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care. PMID- 22241995 TI - Production of virus-derived ping-pong-dependent piRNA-like small RNAs in the mosquito soma. AB - The natural maintenance cycles of many mosquito-borne pathogens require establishment of persistent non-lethal infections in the invertebrate host. The mechanism by which this occurs is not well understood, but we have previously shown that an antiviral response directed by small interfering RNAs (siRNAs) is important in modulating the pathogenesis of alphavirus infections in the mosquito. However, we report here that infection of mosquitoes with an alphavirus also triggers the production of another class of virus-derived small RNAs that exhibit many similarities to ping-pong-dependent piwi-interacting RNAs (piRNAs). However, unlike ping-pong-dependent piRNAs that have been described previously from repetitive elements or piRNA clusters, our work suggests production in the soma. We also present evidence that suggests virus-derived piRNA-like small RNAs are capable of modulating the pathogenesis of alphavirus infections in dicer-2 null mutant mosquito cell lines defective in viral siRNA production. Overall, our results suggest that a non-canonical piRNA pathway is present in the soma of vector mosquitoes and may be acting redundantly to the siRNA pathway to target alphavirus replication. PMID- 22241996 TI - (Homo)glutathione deficiency impairs root-knot nematode development in Medicago truncatula. AB - Root-knot nematodes (RKN) are obligatory plant parasitic worms that establish and maintain an intimate relationship with their host plants. During a compatible interaction, RKN induce the redifferentiation of root cells into multinucleate and hypertrophied giant cells essential for nematode growth and reproduction. These metabolically active feeding cells constitute the exclusive source of nutrients for the nematode. Detailed analysis of glutathione (GSH) and homoglutathione (hGSH) metabolism demonstrated the importance of these compounds for the success of nematode infection in Medicago truncatula. We reported quantification of GSH and hGSH and gene expression analysis showing that (h)GSH metabolism in neoformed gall organs differs from that in uninfected roots. Depletion of (h)GSH content impaired nematode egg mass formation and modified the sex ratio. In addition, gene expression and metabolomic analyses showed a substantial modification of starch and gamma-aminobutyrate metabolism and of malate and glucose content in (h)GSH-depleted galls. Interestingly, these modifications did not occur in (h)GSH-depleted roots. These various results suggest that (h)GSH have a key role in the regulation of giant cell metabolism. The discovery of these specific plant regulatory elements could lead to the development of new pest management strategies against nematodes. PMID- 22241997 TI - Insights into minor group rhinovirus uncoating: the X-ray structure of the HRV2 empty capsid. AB - Upon attachment to their respective receptor, human rhinoviruses (HRVs) are internalized into the host cell via different pathways but undergo similar structural changes. This ultimately results in the delivery of the viral RNA into the cytoplasm for replication. To improve our understanding of the conformational modifications associated with the release of the viral genome, we have determined the X-ray structure at 3.0 A resolution of the end-stage of HRV2 uncoating, the empty capsid. The structure shows important conformational changes in the capsid protomer. In particular, a hinge movement around the hydrophobic pocket of VP1 allows a coordinated shift of VP2 and VP3. This overall displacement forces a reorganization of the inter-protomer interfaces, resulting in a particle expansion and in the opening of new channels in the capsid core. These new breaches in the capsid, opening one at the base of the canyon and the second at the particle two-fold axes, might act as gates for the externalization of the VP1 N-terminus and the extrusion of the viral RNA, respectively. The structural comparison between native and empty HRV2 particles unveils a number of pH sensitive amino acid residues, conserved in rhinoviruses, which participate in the structural rearrangements involved in the uncoating process. PMID- 22241998 TI - Trypanosoma cruzi trans-sialidase in complex with a neutralizing antibody: structure/function studies towards the rational design of inhibitors. AB - Trans-sialidase (TS), a virulence factor from Trypanosoma cruzi, is an enzyme playing key roles in the biology of this protozoan parasite. Absent from the mammalian host, it constitutes a potential target for the development of novel chemotherapeutic drugs, an urgent need to combat Chagas' disease. TS is involved in host cell invasion and parasite survival in the bloodstream. However, TS is also actively shed by the parasite to the bloodstream, inducing systemic effects readily detected during the acute phase of the disease, in particular, hematological alterations and triggering of immune cells apoptosis, until specific neutralizing antibodies are elicited. These antibodies constitute the only known submicromolar inhibitor of TS's catalytic activity. We now report the identification and detailed characterization of a neutralizing mouse monoclonal antibody (mAb 13G9), recognizing T. cruzi TS with high specificity and subnanomolar affinity. This mAb displays undetectable association with the T. cruzi superfamily of TS-like proteins or yet with the TS-related enzymes from Trypanosoma brucei or Trypanosoma rangeli. In immunofluorescence assays, mAb 13G9 labeled 100% of the parasites from the infective trypomastigote stage. This mAb also reduces parasite invasion of cultured cells and strongly inhibits parasite surface sialylation. The crystal structure of the mAb 13G9 antigen-binding fragment in complex with the globular region of T. cruzi TS was determined, revealing detailed molecular insights of the inhibition mechanism. Not occluding the enzyme's catalytic site, the antibody performs a subtle action by inhibiting the movement of an assisting tyrosine (Y119), whose mobility is known to play a key role in the trans-glycosidase mechanism. As an example of enzymatic inhibition involving non-catalytic residues that occupy sites distal from the substrate-binding pocket, this first near atomic characterization of a high affinity inhibitory molecule for TS provides a rational framework for novel strategies in the design of chemotherapeutic compounds. PMID- 22241999 TI - Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver. AB - Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1 IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1 IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy. PMID- 22242000 TI - The Caenorhabditis elegans synthetic multivulva genes prevent ras pathway activation by tightly repressing global ectopic expression of lin-3 EGF. AB - The Caenorhabditis elegans class A and B synthetic multivulva (synMuv) genes redundantly antagonize an EGF/Ras pathway to prevent ectopic vulval induction. We identify a class A synMuv mutation in the promoter of the lin-3 EGF gene, establishing that lin-3 is the key biological target of the class A synMuv genes in vulval development and that the repressive activities of the class A and B synMuv pathways are integrated at the level of lin-3 expression. Using FISH with single mRNA molecule resolution, we find that lin-3 EGF expression is tightly restricted to only a few tissues in wild-type animals, including the germline. In synMuv double mutants, lin-3 EGF is ectopically expressed at low levels throughout the animal. Our findings reveal that the widespread ectopic expression of a growth factor mRNA at concentrations much lower than that in the normal domain of expression can abnormally activate the Ras pathway and alter cell fates. These results suggest hypotheses for the mechanistic basis of the functional redundancy between the tumor-suppressor-like class A and B synMuv genes: the class A synMuv genes either directly or indirectly specifically repress ectopic lin-3 expression; while the class B synMuv genes might function similarly, but alternatively might act to repress lin-3 as a consequence of their role in preventing cells from adopting a germline-like fate. Analogous genes in mammals might function as tumor suppressors by preventing broad ectopic expression of EGF-like ligands. PMID- 22242001 TI - Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus. AB - The Prader-Willi syndrome (PWS [MIM 17620]) and Angelman syndrome (AS [MIM 105830]) locus is controlled by a bipartite imprinting center (IC) consisting of the PWS-IC and the AS-IC. The most widely accepted model of IC function proposes that the PWS-IC activates gene expression from the paternal allele, while the AS IC acts to epigenetically inactivate the PWS-IC on the maternal allele, thus silencing the paternally expressed genes. Gene order and imprinting patterns at the PWS/AS locus are well conserved from human to mouse; however, a murine AS-IC has yet to be identified. We investigated a potential regulatory role for transcription from the Snrpn alternative upstream exons in silencing the maternal allele using a murine transgene containing Snrpn and three upstream exons. This transgene displayed appropriate imprinted expression and epigenetic marks, demonstrating the presence of a functional AS-IC. Transcription of the upstream exons from the endogenous locus correlates with imprint establishment in oocytes, and this upstream exon expression pattern was conserved on the transgene. A transgene bearing targeted deletions of each of the three upstream exons exhibited loss of imprinting upon maternal transmission. These results support a model in which transcription from the Snrpn upstream exons directs the maternal imprint at the PWS-IC. PMID- 22242002 TI - Substitutions in the amino-terminal tail of neurospora histone H3 have varied effects on DNA methylation. AB - Eukaryotic genomes are partitioned into active and inactive domains called euchromatin and heterochromatin, respectively. In Neurospora crassa, heterochromatin formation requires methylation of histone H3 at lysine 9 (H3K9) by the SET domain protein DIM-5. Heterochromatin protein 1 (HP1) reads this mark and directly recruits the DNA methyltransferase, DIM-2. An ectopic H3 gene carrying a substitution at K9 (hH3(K9L) or hH3(K9R)) causes global loss of DNA methylation in the presence of wild-type hH3 (hH3(WT)). We investigated whether other residues in the N-terminal tail of H3 are important for methylation of DNA and of H3K9. Mutations in the N-terminal tail of H3 were generated and tested for effects in vitro and in vivo, in the presence or absence of the wild-type allele. Substitutions at K4, K9, T11, G12, G13, K14, K27, S28, and K36 were lethal in the absence of a wild-type allele. In contrast, mutants bearing substitutions of R2, A7, R8, S10, A15, P16, R17, K18, and K23 were viable. The effect of substitutions on DNA methylation were variable; some were recessive and others caused a semi dominant loss of DNA methylation. Substitutions of R2, A7, R8, S10, T11, G12, G13, K14, and P16 caused partial or complete loss of DNA methylation in vivo. Only residues R8-G12 were required for DIM-5 activity in vitro. DIM-5 activity was inhibited by dimethylation of H3K4 and by phosphorylation of H3S10, but not by acetylation of H3K14. We conclude that the H3 tail acts as an integrating platform for signals that influence DNA methylation, in part through methylation of H3K9. PMID- 22242003 TI - Duox, Flotillin-2, and Src42A are required to activate or delimit the spread of the transcriptional response to epidermal wounds in Drosophila. AB - The epidermis is the largest organ of the body for most animals, and the first line of defense against invading pathogens. A breach in the epidermal cell layer triggers a variety of localized responses that in favorable circumstances result in the repair of the wound. Many cellular and genetic responses must be limited to epidermal cells that are close to wounds, but how this is regulated is still poorly understood. The order and hierarchy of epidermal wound signaling factors are also still obscure. The Drosophila embryonic epidermis provides an excellent system to study genes that regulate wound healing processes. We have developed a variety of fluorescent reporters that provide a visible readout of wound dependent transcriptional activation near epidermal wound sites. A large screen for mutants that alter the activity of these wound reporters has identified seven new genes required to activate or delimit wound-induced transcriptional responses to a narrow zone of cells surrounding wound sites. Among the genes required to delimit the spread of wound responses are Drosophila Flotillin-2 and Src42A, both of which are transcriptionally activated around wound sites. Flotillin-2 and constitutively active Src42A are also sufficient, when overexpressed at high levels, to inhibit wound-induced transcription in epidermal cells. One gene required to activate epidermal wound reporters encodes Dual oxidase, an enzyme that produces hydrogen peroxide. We also find that four biochemical treatments (a serine protease, a Src kinase inhibitor, methyl-beta-cyclodextrin, and hydrogen peroxide) are sufficient to globally activate epidermal wound response genes in Drosophila embryos. We explore the epistatic relationships among the factors that induce or delimit the spread of epidermal wound signals. Our results define new genetic functions that interact to instruct only a limited number of cells around puncture wounds to mount a transcriptional response, mediating local repair and regeneration. PMID- 22242004 TI - Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation. AB - Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations. PMID- 22242005 TI - MAPK/ERK signaling regulates insulin sensitivity to control glucose metabolism in Drosophila. AB - The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels. PMID- 22242006 TI - The RNA silencing enzyme RNA polymerase v is required for plant immunity. AB - RNA-directed DNA methylation (RdDM) is an epigenetic control mechanism driven by small interfering RNAs (siRNAs) that influence gene function. In plants, little is known of the involvement of the RdDM pathway in regulating traits related to immune responses. In a genetic screen designed to reveal factors regulating immunity in Arabidopsis thaliana, we identified NRPD2 as the OVEREXPRESSOR OF CATIONIC PEROXIDASE 1 (OCP1). NRPD2 encodes the second largest subunit of the plant-specific RNA Polymerases IV and V (Pol IV and Pol V), which are crucial for the RdDM pathway. The ocp1 and nrpd2 mutants showed increases in disease susceptibility when confronted with the necrotrophic fungal pathogens Botrytis cinerea and Plectosphaerella cucumerina. Studies were extended to other mutants affected in different steps of the RdDM pathway, such as nrpd1, nrpe1, ago4, drd1, rdr2, and drm1drm2 mutants. Our results indicate that all the mutants studied, with the exception of nrpd1, phenocopy the nrpd2 mutants; and they suggest that, while Pol V complex is required for plant immunity, Pol IV appears dispensable. Moreover, Pol V defective mutants, but not Pol IV mutants, show enhanced disease resistance towards the bacterial pathogen Pseudomonas syringae DC3000. Interestingly, salicylic acid (SA)-mediated defenses effective against PsDC3000 are enhanced in Pol V defective mutants, whereas jasmonic acid (JA) mediated defenses that protect against fungi are reduced. Chromatin immunoprecipitation analysis revealed that, through differential histone modifications, SA-related defense genes are poised for enhanced activation in Pol V defective mutants and provide clues for understanding the regulation of gene priming during defense. Our results highlight the importance of epigenetic control as an additional layer of complexity in the regulation of plant immunity and point towards multiple components of the RdDM pathway being involved in plant immunity based on genetic evidence, but whether this is a direct or indirect effect on disease-related genes is unclear. PMID- 22242007 TI - Interspecific sex in grass smuts and the genetic diversity of their pheromone receptor system. AB - The grass smuts comprise a speciose group of biotrophic plant parasites, so called Ustilaginaceae, which are specifically adapted to hosts of sweet grasses, the Poaceae family. Mating takes a central role in their life cycle, as it initiates parasitism by a morphological and physiological transition from saprobic yeast cells to pathogenic filaments. As in other fungi, sexual identity is determined by specific genomic regions encoding allelic variants of a pheromone-receptor (PR) system and heterodimerising transcription factors. Both operate in a biphasic mating process that starts with PR-triggered recognition, directed growth of conjugation hyphae, and plasmogamy of compatible mating partners. So far, studies on the PR system of grass smuts revealed diverse interspecific compatibility and mating type determination. However, many questions concerning the specificity and evolutionary origin of the PR system remain unanswered. Combining comparative genetics and biological approaches, we report on the specificity of the PR system and its genetic diversity in 10 species spanning about 100 million years of mating type evolution. We show that three highly syntenic PR alleles are prevalent among members of the Ustilaginaceae, favouring a triallelic determination as the plesiomorphic characteristic of this group. Furthermore, the analysis of PR loci revealed increased genetic diversity of single PR locus genes compared to genes of flanking regions. Performing interspecies sex tests, we detected a high potential for hybridisation that is directly linked to pheromone signalling as known from intraspecies sex. Although the PR system seems to be optimised for intraspecific compatibility, the observed functional plasticity of the PR system increases the potential for interspecific sex, which might allow the hybrid-based genesis of newly combined host specificities. PMID- 22242009 TI - Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals. AB - Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ~1.5%), drawn from ~78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5*10-28), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10-6) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme. PMID- 22242008 TI - A genetic screening strategy identifies novel regulators of the proteostasis network. AB - A hallmark of diseases of protein conformation and aging is the appearance of protein aggregates associated with cellular toxicity. We posit that the functional properties of the proteostasis network (PN) protect the proteome from misfolding and combat the proteotoxic events leading to cellular pathology. In this study, we have identified new components of the proteostasis network that can suppress aggregation and proteotoxicity, by performing RNA interference (RNAi) genetic screens for multiple unrelated conformationally challenged cytoplasmic proteins expressed in Caenorhabditis elegans. We identified 88 suppressors of polyglutamine (polyQ) aggregation, of which 63 modifiers also suppressed aggregation of mutant SOD1(G93A). Of these, only 23 gene-modifiers suppressed aggregation and restored animal motility, revealing that aggregation and toxicity can be genetically uncoupled. Nine of these modifiers were shown to be effective in restoring the folding and function of multiple endogenous temperature-sensitive (TS) mutant proteins, of which five improved folding in a HSF-1-dependent manner, by inducing cytoplasmic chaperones. This triage screening strategy also identified a novel set of PN regulatory components that, by altering metabolic and RNA processing functions, establish alternate cellular environments not generally dependent on stress response activation and that are broadly protective against misfolded and aggregation-prone proteins. PMID- 22242010 TI - The connection between space and thinking: an interview with Rafael Vinoly by Jane Gitschier. PMID- 22242011 TI - DNA methylation of the gonadal aromatase (cyp19a) promoter is involved in temperature-dependent sex ratio shifts in the European sea bass. AB - Sex ratio shifts in response to temperature are common in fish and reptiles. However, the mechanism linking temperature during early development and sex ratios has remained elusive. We show in the European sea bass (sb), a fish in which temperature effects on sex ratios are maximal before the gonads form, that juvenile males have double the DNA methylation levels of females in the promoter of gonadal aromatase (cyp19a), the enzyme that converts androgens into estrogens. Exposure to high temperature increased the cyp19a promoter methylation levels of females, indicating that induced-masculinization involves DNA methylation mediated control of aromatase gene expression, with an observed inverse relationship between methylation levels and expression. Although different CpGs within the sb cyp19a promoter exhibited different sensitivity to temperature, we show that the increased methylation of the sb cyp19a promoter, which occurs in the gonads but not in the brain, is not a generalized effect of temperature. Importantly, these effects were also observed in sexually undifferentiated fish and were not altered by estrogen treatment. Thus, methylation of the sb cyp19a promoter is the cause of the lower expression of cyp19a in temperature masculinized fish. In vitro, induced methylation of the sb cyp19a promoter suppressed the ability of SF-1 and Foxl2 to stimulate transcription. Finally, a CpG differentially methylated by temperature and adjacent to a Sox transcription factor binding site is conserved across species. Thus, DNA methylation of the aromatase promoter may be an essential component of the long-sought-after mechanism connecting environmental temperature and sex ratios in vertebrate species with temperature-dependent sex determination. PMID- 22242012 TI - Functional specialization of the plant miR396 regulatory network through distinct microRNA-target interactions. AB - MicroRNAs (miRNAs) are ~21 nt small RNAs that regulate gene expression in animals and plants. They can be grouped into families comprising different genes encoding similar or identical mature miRNAs. Several miRNA families are deeply conserved in plant lineages and regulate key aspects of plant development, hormone signaling, and stress response. The ancient miRNA miR396 regulates conserved targets belonging to the GROWTH-REGULATING FACTOR (GRF) family of transcription factors, which are known to control cell proliferation in Arabidopsis leaves. In this work, we characterized the regulation of an additional target for miR396, the transcription factor bHLH74, that is necessary for Arabidopsis normal development. bHLH74 homologs with a miR396 target site could only be detected in the sister families Brassicaceae and Cleomaceae. Still, bHLH74 repression by miR396 is required for margin and vein pattern formation of Arabidopsis leaves. MiR396 contributes to the spatio-temporal regulation of GRF and bHLH74 expression during leaf development. Furthermore, a survey of miR396 sequences in different species showed variations in the 5' portion of the miRNA, a region known to be important for miRNA activity. Analysis of different miR396 variants in Arabidopsis thaliana revealed that they have an enhanced activity toward GRF transcription factors. The interaction between the GRF target site and miR396 has a bulge between positions 7 and 8 of the miRNA. Our data indicate that such bulge modulates the strength of the miR396-mediated repression and that this modulation is essential to shape the precise spatio-temporal pattern of GRF2 expression. The results show that ancient miRNAs can regulate conserved targets with varied efficiency in different species, and we further propose that they could acquire new targets whose control might also be biologically relevant. PMID- 22242013 TI - Microenvironmental regulation by fibrillin-1. AB - Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin 1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFbeta signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS 10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFbeta signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes. PMID- 22242014 TI - Genome-wide assessment of AU-rich elements by the AREScore algorithm. AB - In mammalian cells, AU-rich elements (AREs) are well known regulatory sequences located in the 3' untranslated region (UTR) of many short-lived mRNAs. AREs cause mRNAs to be degraded rapidly and thereby suppress gene expression at the posttranscriptional level. Based on the number of AUUUA pentamers, their proximity, and surrounding AU-rich regions, we generated an algorithm termed AREScore that identifies AREs and provides a numerical assessment of their strength. By analyzing the AREScore distribution in the transcriptomes of 14 metazoan species, we provide evidence that AREs were selected for in several vertebrates and Drosophila melanogaster. We then measured mRNA expression levels genome-wide to address the importance of AREs in SL2 cells derived from D. melanogaster hemocytes. Tis11, a zinc finger RNA-binding protein homologous to mammalian tristetraprolin, was found to target ARE-containing reporter mRNAs for rapid degradation in SL2 cells. Drosophila mRNAs whose expression is elevated upon knock down of Tis11 were found to have higher AREScores. Moreover high AREScores correlate with reduced mRNA expression levels on a genome-wide scale. The precise measurement of degradation rates for 26 Drosophila mRNAs revealed that the AREScore is a very good predictor of short-lived mRNAs. Taken together, this study introduces AREScore as a simple tool to identify ARE-containing mRNAs and provides compelling evidence that AREs are widespread regulatory elements in Drosophila. PMID- 22242015 TI - Checkpoints in a yeast differentiation pathway coordinate signaling during hyperosmotic stress. AB - All eukaryotes have the ability to detect and respond to environmental and hormonal signals. In many cases these signals evoke cellular changes that are incompatible and must therefore be orchestrated by the responding cell. In the yeast Saccharomyces cerevisiae, hyperosmotic stress and mating pheromones initiate signaling cascades that each terminate with a MAP kinase, Hog1 and Fus3, respectively. Despite sharing components, these pathways are initiated by distinct inputs and produce distinct cellular behaviors. To understand how these responses are coordinated, we monitored the pheromone response during hyperosmotic conditions. We show that hyperosmotic stress limits pheromone signaling in at least three ways. First, stress delays the expression of pheromone-induced genes. Second, stress promotes the phosphorylation of a protein kinase, Rck2, and thereby inhibits pheromone-induced protein translation. Third, stress promotes the phosphorylation of a shared pathway component, Ste50, and thereby dampens pheromone-induced MAPK activation. Whereas all three mechanisms are dependent on an increase in osmolarity, only the phosphorylation events require Hog1. These findings reveal how an environmental stress signal is able to postpone responsiveness to a competing differentiation signal, by acting on multiple pathway components, in a coordinated manner. PMID- 22242016 TI - Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks. AB - Genome-wide dynamic changes in DNA methylation are indispensable for germline development and genomic imprinting in mammals. Here, we report single-base resolution DNA methylome and transcriptome maps of mouse germ cells, generated using whole-genome shotgun bisulfite sequencing and cDNA sequencing (mRNA-seq). Oocyte genomes showed a significant positive correlation between mRNA transcript levels and methylation of the transcribed region. Sperm genomes had nearly complete coverage of methylation, except in the CpG-rich regions, and showed a significant negative correlation between gene expression and promoter methylation. Thus, these methylome maps revealed that oocytes and sperms are widely different in the extent and distribution of DNA methylation. Furthermore, a comparison of oocyte and sperm methylomes identified more than 1,600 CpG islands differentially methylated in oocytes and sperm (germline differentially methylated regions, gDMRs), in addition to the known imprinting control regions (ICRs). About half of these differentially methylated DNA sequences appear to be at least partially resistant to the global DNA demethylation that occurs during preimplantation development. In the absence of Dnmt3L, neither methylation of most oocyte-methylated gDMRs nor intragenic methylation was observed. There was also genome-wide hypomethylation, and partial methylation at particular retrotransposons, while maintaining global gene expression, in oocytes. Along with the identification of the many Dnmt3L-dependent gDMRs at intragenic regions, the present results suggest that oocyte methylation can be divided into 2 types: Dnmt3L-dependent methylation, which is required for maternal methylation imprinting, and Dnmt3L-independent methylation, which might be essential for endogenous retroviral DNA silencing. The present data provide entirely new perspectives on the evaluation of epigenetic markers in germline cells. PMID- 22242017 TI - Poly(ADP-Ribose) polymerase 1 (PARP-1) regulates ribosomal biogenesis in Drosophila nucleoli. AB - Poly(ADP-ribose) polymerase 1 (PARP1), a nuclear protein, utilizes NAD to synthesize poly(AD-Pribose) (pADPr), resulting in both automodification and the modification of acceptor proteins. Substantial amounts of PARP1 and pADPr (up to 50%) are localized to the nucleolus, a subnuclear organelle known as a region for ribosome biogenesis and maturation. At present, the functional significance of PARP1 protein inside the nucleolus remains unclear. Using PARP1 mutants, we investigated the function of PARP1, pADPr, and PARP1-interacting proteins in the maintenance of nucleolus structure and functions. Our analysis shows that disruption of PARP1 enzymatic activity caused nucleolar disintegration and aberrant localization of nucleolar-specific proteins. Additionally, PARP1 mutants have increased accumulation of rRNA intermediates and a decrease in ribosome levels. Together, our data suggests that PARP1 enzymatic activity is required for targeting nucleolar proteins to the proximity of precursor rRNA; hence, PARP1 controls precursor rRNA processing, post-transcriptional modification, and pre ribosome assembly. Based on these findings, we propose a model that explains how PARP1 activity impacts nucleolar functions and, consequently, ribosomal biogenesis. PMID- 22242019 TI - Supplementation of vitamin C reduces blood glucose and improves glycosylated hemoglobin in type 2 diabetes mellitus: a randomized, double-blind study. AB - No study has ever examined the effect of vitamin C with metformin on fasting (FBS) and postmeal blood glucose (PMBG) as well as glycosylated hemoglobin (HbA1c) in the treatment of type 2 diabetes mellitus (DM). The goal was to examine the effect of oral vitamin C with metformin on FBS, PMBG, HbA1c, and plasma ascorbic acid level (PAA) with type 2 DM. Seventy patients with type 2 DM participated in a prospective, double-blind, placebo-controlled, 12-week study. The patients with type 2 DM were divided randomly into placebo and vitamin C group of 35 each. Both groups received the treatment for twelve weeks. Decreased PAA levels were found in patients with type 2 diabetes mellitus. This level was reversed significantly after treatment with vitamin C along with metformin compared to placebo with metformin. FBS, PMBG, and HbA1c levels showed significant improvement after 12 weeks of treatment with vitamin C. In conclusion, oral supplementation of vitamin C with metformin reverses ascorbic acid levels, reduces FBS, PMBG, and improves HbA1c. Hence, both the drugs in combination may be used in the treatment of type 2 DM to maintain good glycemic control. PMID- 22242018 TI - The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants. AB - Pink1 is a mitochondrial kinase involved in Parkinson's disease, and loss of Pink1 function affects mitochondrial morphology via a pathway involving Parkin and components of the mitochondrial remodeling machinery. Pink1 loss also affects the enzymatic activity of isolated Complex I of the electron transport chain (ETC); however, the primary defect in pink1 mutants is unclear. We tested the hypothesis that ETC deficiency is upstream of other pink1-associated phenotypes. We expressed Saccaromyces cerevisiae Ndi1p, an enzyme that bypasses ETC Complex I, or sea squirt Ciona intestinalis AOX, an enzyme that bypasses ETC Complex III and IV, in pink1 mutant Drosophila and find that expression of Ndi1p, but not of AOX, rescues pink1-associated defects. Likewise, loss of function of subunits that encode for Complex I-associated proteins displays many of the pink1 associated phenotypes, and these defects are rescued by Ndi1p expression. Conversely, expression of Ndi1p fails to rescue any of the parkin mutant phenotypes. Additionally, unlike pink1 mutants, fly parkin mutants do not show reduced enzymatic activity of Complex I, indicating that Ndi1p acts downstream or parallel to Pink1, but upstream or independent of Parkin. Furthermore, while increasing mitochondrial fission or decreasing mitochondrial fusion rescues mitochondrial morphological defects in pink1 mutants, these manipulations fail to significantly rescue the reduced enzymatic activity of Complex I, indicating that functional defects observed at the level of Complex I enzymatic activity in pink1 mutant mitochondria do not arise from morphological defects. Our data indicate a central role for Complex I dysfunction in pink1-associated defects, and our genetic analyses with heterologous ETC enzymes suggest that Ndi1p-dependent NADH dehydrogenase activity largely acts downstream of, or in parallel to, Pink1 but upstream of Parkin and mitochondrial remodeling. PMID- 22242020 TI - Postoperative complications after thoracic surgery in the morbidly obese patient. AB - Little has been recently published about specific postoperative complications following thoracic surgery in the morbidly obese patient. Greater numbers of patients who are obese, morbidly obese, or supermorbidly obese are undergoing surgical procedures. Postoperative complications after thoracic surgery in these patients that can lead to increased morbidity and mortality, prolonged hospital stay, and increased cost of care are considered. Complications include difficulties with mask ventilation and securing the airway, obstructive sleep apnea with risk of oversedation, pulmonary complications related to reduced total lung capacity, reduced functional residual capacity, and reduced vital capacity, risks of aspiration pneumonitis and ventilator-associated pneumonia, cardiomyopathies, and atrial fibrillation, inadequate diabetes management, positioning injuries, increased risk of venous thrombosis, and pulmonary embolism. The type of thoracic surgical procedure may also pose other problems to consider during the postoperative period. Obese patients undergoing thoracic surgery pose a challenge to those caring for them. Those working with these patients must understand how to recognize, prevent, and manage these postoperative complications. PMID- 22242021 TI - Molecular-targeted therapies for hematologic malignancies. PMID- 22242023 TI - Postcesarean thromboprophylaxis with two different regimens of bemiparin. AB - Objectives. To compare the effectiveness of postcesarean thromboprophylaxis with two different regimens of bemiparin. Material and Methods. The study included 646 women with cesarean delivery in our hospital within a 1-year period, randomly assigned to one of two groups for prophylaxis with 3500 IU bemiparin once daily for 5 days or 3500 IU bemiparin once daily for 10 days. Results. There was one case of pulmonary embolism (first day following cesarean). An additional risk factor was present in 98.52% of the women, most frequently emergency cesarean, anemia, or obesity. The only risk factors for thromboembolic disease significantly related to pulmonary thromboembolism were placental abruption and prematurity. There were no differences in thromboembolic events among the two thromboprophylaxis regimens. Conclusions. Cesarean-related thromboembolic events were reduced in our study population due to the thromboprophylactic measures taken. Thromboprophylaxis with 3500 IU bemiparin once daily for 5 days following cesarean was sufficient to avoid thromboembolic events. PMID- 22242022 TI - Reflux revisited: advancing the role of pepsin. AB - Gastroesophageal reflux disease is mediated principally by acid. Today, we recognise reflux reaches beyond the esophagus, where pepsin, not acid, causes damage. Extraesophageal reflux occurs both as liquid and probably aerosol, the latter with a further reach. Pepsin is stable up to pH 7 and regains activity after reacidification. The enzyme adheres to laryngeal cells, depletes its defences, and causes further damage internally after its endocytosis. Extraesophageal reflux can today be detected by recognising pharyngeal acidification using a miniaturised pH probe and by the identification of pepsin in saliva and in exhaled breath condensate by a rapid, sensitive, and specific immunoassay. Proton pump inhibitors do not help the majority with extraesophageal reflux but specifically formulated alginates, which sieve pepsin, give benefit. These new insights may lead to the development of novel drugs that dramatically reduce pepsinogen secretion, block the effects of adherent pepsin, and give corresponding clinical benefit."For now we see through a glass, darkly."-First epistle, Chapter 13, Corinthians. PMID- 22242024 TI - Polycystic diseases in visceral organs. AB - Primary cilia are nonmotile, microtubule-based, antenna-like organelles projecting from the apical surface of most mammalian cells. Elegant studies have established the importance of ciliary structure and function in signal transduction and the sensory roles of cilia in maintaining healthy cellular state. In particular, dysfunctional cilia have been implicated in a large number of diseases mainly characterized by the presence of fluid-filled cysts in various organs. Aside from polycystic kidney disease (PKD), however, the roles of cilia in polycystic liver disease (PLD), polycystic pancreas disease (PPD), and polycystic ovarian syndrome (PCOS) are still very vague. In addition, although gender and sex hormones are known to regulate cyst formation, their roles in regulating physiological functions of cilia need to be further explored. PMID- 22242025 TI - Infertility and adenomyosis. AB - Classically, the diagnosis of adenomyosis has only been possible on a hysterectomy specimen, usually in women in their late fourth and fifth decades, and, therefore, evaluating any relationship with infertility was simply not possible. As a consequence, to this day, no epidemiologic data exists linking adenomyosis to a state of subfertility. Today, new imaging techniques have enabled a noninvasive diagnosis at a much earlier time and a number of single case or small series reports have appeared showing that medical, surgical, or combined treatment can restore fertility in women with adenomyosis, an indirect proof of an association. At the functional level, several anomalies found in the so-called junctional zone, or inner myometrium, in adenomyosis patients have been shown to be associated with poor reproductive performance, mainly through perturbed uterine peristalsis. Additional evidence for an association comes from experimental data: in baboons, adenomyosis is associated with lifelong primary infertility, as well as to endometriosis. Finally, indirect proof comes from studies of the eutopic and ectopic endometrium in women with adenomyosis proving the existence of an altered endometrial function and receptivity. In conclusion, sufficient indirect proof exists linking adenomyosis to infertility to warrant systematic clinical studies. PMID- 22242026 TI - Adherence with drug therapy in pregnancy. AB - Available information suggests that nonadherence with medication is a common problem in pregnant women. Not taking prescribed drugs may have potentially negative consequences as patients may not achieve their therapeutic goal. In addition to the many factors that may influence medication-taking behaviour in the general population, unique challenges are encountered in pregnant women as both maternal health and fetal well-being must be considered. On the one hand, pregnant women may be motivated to keep their underlying disease under control, while, on the other hand, fear and anxiety regarding the potential harmful effects of their medication on their unborn child may result in poor adherence with needed medication. Providing evidence-based information, ideally preconceptually, regarding the effects of their medication during pregnancy may be important in avoiding misperceptions that lead to nonadherence. PMID- 22242027 TI - Acute management of cocaine-associated methaemoglobinaemia. AB - Methaemoglobinaemia is a potentially life-threatening complication of problem drug use. This is a case report of a 29-year-old man who presented himself cyanosed after a cocaine binge. It highlights the diagnosis and management of this condition from an acute medical perspective. PMID- 22242028 TI - Diverse presentation of secondary aortoenteric fistulae. AB - Secondary aortoenteric fistula, due to mechanical erosion or infection of a prosthetic graft, is a very rare cause of gastrointestinal bleeding and an uncommon complication of abdominal aortic aneurysm repair. A retrospective chart review conducted at our institution revealed 5 cases of secondary AEF occurring between 2006 and 2010. Presentations were diverse, including hematemesis, coffee ground emesis, and unexplained sepsis. Delay in diagnosis was common. In reporting these cases, we seek to highlight the diverse clinical spectrum and potentially misleading features of this condition. Clinicians must retain a high index of suspicion to avoid potentially catastrophic outcomes. PMID- 22242029 TI - Topical ophthalmic cyclosporine in the treatment of toxic epidermal necrolysis. AB - Aim. To describe a case of toxic epidermal necrolysis (TEN) with ocular involvement treated with topical ophthalmic cyclosporine. Case Presentation. A 20 year-old woman developed TEN following administration of carbamazepine that was prescribed for epilepsy. Ophthalmic examination revealed bilateral pseudomembranous conjunctivitis. She was hospitalized in the intensive care unit and treated with intravenous corticosteroid and immunoglobulin. Topical cyclosporine was used in combination with topical corticosteroids for ocular surface disease. Following two months of ocular treatment, she recovered without any severe ocular complication. Ocular examination at the four-month followup showed a 2 mm of symblepharon in the lower fornix as the sole pathologic finding. Conclusion. Topical ophthalmic cyclosporine may contribute to decrease the ophthalmic complications of TEN and should be considered in the acute stage of the disease. PMID- 22242030 TI - Necrotizing fasciitis in a pediatric patient caused by lancefield group g streptococcus: case report and brief review of the literature. AB - We report a case of necrotizing fasciitis with an accompanying toxic shock syndrome caused by Group G Streptococcus in a pediatric patient with a lymphatic malformation. Pediatricians need to be aware of the possibility of such infections, especially in those with vascular/lymphatic malformations, as early treatment is critical for survival. PMID- 22242031 TI - Primitive neuroectodermal tumor of the liver: a case report. AB - Primary liver sarcomas represent a rare group of neoplasias, with angiosarcoma being the most common histological type. Primitive neuroectodermal tumor (PNET) represents a high malignant neoplasia that usually affects the central nervous system and soft tissues. An 18-year-old male patient was admitted with clinical complains of pain in the right upper abdominal quadrant. The clinical evaluation revealed a solid mass in the right hepatic lobe. On the gross examination of the resected liver specimen, the right lobe of the liver was replaced by a yellow-red solid mass measuring 21 cm in its largest dimension. On the histopathology, a tumor composed of small round blue cells with little cytoplasm and round nuclei was identified. The lesion revealed positive immunoexpression for vimentin and CD99 and negative immunostaining for desmin, CD45, cytokeratin, and neuroblastoma protein, suggesting, then, the diagnosis of PNET. Although it is an unusual tumor, it should be considered in the differential diagnosis of liver masses, especially in young patients. PMID- 22242033 TI - Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus Host Disease-A Phase II Study. AB - The efficacy and the safety of the administration of multipotent mesenchymal stromal cells (MMSCs) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic hematopoietic cell transplantation (HSCT) were studied. This prospective clinical trial was based on the random patient allocation to the following two groups receiving (1) standard GVHD prophylaxis and (2) standard GVHD prophylaxis combined with MMSCs infusion. Bone marrow MMSCs from hematopoietic stem cell donors were cultured and administered to the recipients at doses of 0.9-1.3 * 10(6)/kg when the blood counts indicated recovery. aGVHD of stage II-IV developed in 38.9% and 5.3% of patients in group 1 and group 2, respectively, (P = 0.002). There were no differences in the graft rejection rates, chronic GVHD development, or infectious complications. Overall mortality was 16.7% for patients in group 1 and 5.3% for patients in group 2. The efficacy and the safety of MMSC administration for aGVHD prophylaxis were demonstrated in this study. PMID- 22242032 TI - Tissue engineering strategies in ligament regeneration. AB - Ligaments are dense fibrous connective tissues that connect bones to other bones and their injuries are frequently encountered in the clinic. The current clinical approaches in ligament repair and regeneration are limited to autografts, as the gold standard, and allografts. Both of these techniques have their own drawbacks that limit the success in clinical setting; therefore, new strategies are being developed in order to be able to solve the current problems of ligament grafting. Tissue engineering is a novel promising technique that aims to solve these problems, by producing viable artificial ligament substitutes in the laboratory conditions with the potential of transplantation to the patients with a high success rate. Direct cell and/or growth factor injection to the defect site is another current approach aiming to enhance the repair process of the native tissue. This review summarizes the current approaches in ligament tissue engineering strategies including the use of scaffolds, their modification techniques, as well as the use of bioreactors to achieve enhanced regeneration rates, while also discussing the advances in growth factor and cell therapy applications towards obtaining enhanced ligament regeneration. PMID- 22242034 TI - Relatively low prevalence of peripheral and placental Plasmodium infection at delivery in bangui, central african republic. AB - Introduction. The aim of this study was to estimate the prevalence of malaria among women giving birth in Bangui. Association between sociodemographic characteristics of those women and malaria, as well as prevention compliance (use of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTsp) and insecticide-treated bed nets (ITNs)), was analyzed. Methods. During September 2009, a survey was conducted on 328 women who gave birth at two main maternities of Bangui. Information was obtained by standardized questionnaire about sociodemographic criteria, IPTsp, other antimalarial treatment, and use of bet nets. Smears prepared from peripheral and placental blood were analysed for malaria parasites. Findings and Discussion. Positive results were found in 2.8% of thick peripheral blood smears and in 4.0% of placental slides. A proportion of 30.5% of the women had received at least two doses of IPTsp during the current pregnancy. Only a proportion of 42.4% of this study population had ITNs. Multigravid women were less likely to use IPTsp and ITNs. However, use of IPTsp was associated with personal income and secondary or university educational status. Hence, although this relatively prevalence was observed, more efforts are needed to implement IPTsp and ITNs, taking into account sociodemographic criteria. PMID- 22242036 TI - Characterization of outer membrane vesicles from Brucella melitensis and protection induced in mice. AB - The outer membrane vesicles (OMVs) from smooth B. melitensis 16 M and a derived rough mutant, VTRM1 strain, were purified and characterized with respect to protein content and induction of immune responses in mice. Proteomic analysis showed 29 proteins present in OMVs from B. melitensis 16 M; some of them are well known Brucella immunogens such as SOD, GroES, Omp31, Omp25, Omp19, bp26, and Omp16. OMVs from a rough VTRM1 induced significantly higher expression of IL-12, TNFalpha, and IFNgamma genes in bone marrow dendritic cells than OMVs from smooth strain 16 M. Relative to saline control group, mice immunized intramuscularly with rough and smooth OMVs were protected from challenge with virulent strain B. melitensis 16 M just as well as the group immunized with live strain B. melitensis Rev1 (P < 0.005). Additionally, the levels of serum IgG2a increased in mice vaccinated with OMVs from rough strain VTRM1 consistent with the induction of cell-mediated immunity. PMID- 22242037 TI - Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany: a retrospective model analysis. AB - BACKGROUND: Data on the economic impact of Lyme borreliosis (LB) on European health care systems is scarce. This project focused on the epidemiology and costs for laboratory testing in LB patients in Germany. MATERIALS AND METHODS: We performed a sentinel analysis of epidemiological and medicoeconomic data for 2007 and 2008. Data was provided by a German statutory health insurance (DAK) company covering approx. 6.04 million members. In addition, the quality of diagnostic testing for LB in Germany was studied. RESULTS: In 2007 and 2008, the incident diagnosis LB was coded on average for 15,742 out of 6.04 million insured members (0.26%). 20,986 EIAs and 12,558 immunoblots were ordered annually for these patients. For all insured members in the outpatient sector, a total of 174,820 EIAs and 52,280 immunoblots were reimbursed annually to health care providers (cost: 2,600,850?). For Germany, the overall expected cost is estimated at 51,215,105?. However, proficiency testing data questioned test quality and standardization of diagnostic assays used. CONCLUSION: Findings from this study suggest ongoing issues related to care for LB and may help to improve future LB disease management. PMID- 22242035 TI - More than just tumor destruction: immunomodulation by thermal ablation of cancer. AB - Over the past decades, thermoablative techniques for the therapy of localized tumors have gained importance in the treatment of patients not eligible for surgical resection. Anecdotal reports have described spontaneous distant tumor regression after thermal ablation, indicating a possible involvement of the immune system, hence an induction of antitumor immunity after thermoinduced therapy. In recent years, a growing body of evidence for modulation of both adaptive and innate immunity, as well as for the induction of danger signals through thermoablation, has emerged. Induced immune responses, however, are mostly weak and not sufficient for the complete eradication of established tumors or durable prevention of disease progression, and combination therapies with immunomodulating drugs are being evaluated with promising results. This article aims to summarize published findings on immune modulation through radiofrequency ablation, cryoablation, microwave ablation therapy, high-intensity focused ultrasound, and laser-induced thermotherapy. PMID- 22242038 TI - Unveiling the mechanisms for decreased glutathione in individuals with HIV infection. AB - We examined the causes for decreased glutathione (GSH) in individuals with HIV infection. We observed lower levels of intracellular GSH in macrophages from individuals with HIV compared to healthy subjects. Further, the GSH composition found in macrophages from HIV(+) subjects heavily favors oxidized glutathione (GSSG) which lacks antioxidant activity, over free GSH which is responsible for GSH's antioxidant activity. This decrease correlated with an increase in the growth of Mycobacterium tuberculosis (M. tb) in macrophages from HIV(+) individuals. In addition, we observed increased levels of free radicals, interleukin-1 (IL-1), interleukin-17 (IL-17) and transforming growth factor-beta (TGF-beta) in plasma samples derived from HIV(+) individuals compared to healthy subjects. We observed decreased expression of the genes coding for enzymes responsible for de novo synthesis of GSH in macrophages derived from HIV(+) subjects using quantitative PCR (qPCR). Our results indicate that overproduction of proinflammatory cytokines in HIV(+) individuals lead to increased production of free radicals. This combined with the decreased expression of GSH synthesis enzymes leads to a depletion of free GSH and may lead in part to the loss of immune function observed in HIV patients. PMID- 22242039 TI - HIV and malnutrition: effects on immune system. AB - HIV or human immunodeficiency virus infection has assumed worldwide proportions and importance in just a span of 25 years. Continuous research is being done in many parts of the world regarding its treatment and vaccine development, and a lot of money has flown into this. However, fully understanding the mechanisms of immune depletion has still not been possible. The focus has also been on improving the quality of life of people living with HIV/AIDS through education, counselling, and nutritional support. Malnutrition further reduces the capacity of the body to fight this infection by compromising various immune parameters. Knowledge of essential components of nutrition and incorporating them in the management goes a long way in improving quality of life and better survival in HIV-infected patients. PMID- 22242040 TI - Melastoma malabathricum (L.) Smith Ethnomedicinal Uses, Chemical Constituents, and Pharmacological Properties: A Review. AB - Melastoma malabathricum L. (Melastomataceae) is one of the 22 species found in the Southeast Asian region, including Malaysia. Considered as native to tropical and temperate Asia and the Pacific Islands, this commonly found small shrub has gained herbal status in the Malay folklore belief as well as the Indian, Chinese, and Indonesian folk medicines. Ethnopharmacologically, the leaves, shoots, barks, seeds, and roots of M. malabathricum have been used to treat diarrhoea, dysentery, hemorrhoids, cuts and wounds, toothache, and stomachache. Scientific findings also revealed the wide pharmacological actions of various parts of M. malabthricum, such as antinociceptive, anti-inflammatory, wound healing, antidiarrheal, cytotoxic, and antioxidant activities. Various types of phytochemical constituents have also been isolated and identifed from different parts of M. malabathricum. Thus, the aim of the present review is to present comprehensive information on ethnomedicinal uses, phytochemical constituents, and pharmacological activities of M. malabathricum. PMID- 22242041 TI - Remotely sensed image classification by complex network eigenvalue and connected degree. AB - It is a well-known problem of remotely sensed images classification due to its complexity. This paper proposes a remotely sensed image classification method based on weighted complex network clustering using the traditional K-means clustering algorithm. First, the degree of complex network and clustering coefficient of weighted feature are used to extract the features of the remote sensing image. Then, the integrated features of remote sensing image are combined to be used as the basis of classification. Finally, K-means algorithm is used to classify the remotely sensed images. The advantage of the proposed classification method lies in obtaining better clustering centers. The experimental results show that the proposed method gives an increase of 8% in accuracy compared with the traditional K-means algorithm and the Iterative Self-Organizing Data Analysis Technique (ISODATA) algorithm. PMID- 22242042 TI - Decoding key nodes in the metabolism of cancer cells: sugar & spice and all things nice. AB - In the past 5 years, a convergence of studies has resulted in a broad appreciation in the cancer research community that reprogramming of cellular metabolism may be more central to cancer than appreciated in the past 30 years. The re-emergence of cancer metabolism stems in part from discoveries that a number of common oncogenes and tumor suppressor genes more directly control cell metabolism than previously thought. In addition, a number of what would previously have been called "card-carrying" metabolic enzymes have been identified as human tumor suppressors or oncogenes, causally mutated in a variety of human cancers. This growing appreciation of the role of altered cell metabolism has led to further investigation into the rate-limiting proteins involved in different aspects of the unique metabolism of tumor cells. Targeting cancer metabolism with drugs requires a therapeutic window in which tumor cells, compared to normal tissues, have a greater dependence on specific metabolic enzymes. Themes that have emerged in the past decade of developing oncogene targeted cancer therapeutics suggest that tumors with distinct oncogenic lesions are likely to require drugs that target distinct metabolic pathways. Ultimately, the hope is that detailed knowledge of oncogene and tumor suppressor gene functions and their effects on metabolism will lead to drug combinations that will be far more effective in treating cancers. PMID- 22242043 TI - Fibroepithelial polyp in an anal fistulous track: a sign of chronic pathology. AB - Hypertrophied anal papillae and fibroepithelial polyps are benign acquired polypoid lesions of the anal canal. The development and protrusion of a fibroepithelial polyp in an anal fistulous track is described. This is a rare physical sign of chronic anal pathology. PMID- 22242044 TI - A potential relationship between diffuse musculoskeletal pain and hypogonadism. AB - Some men presenting with diffuse musculoskeletal pain have testosterone values below the normal range for their age. While scant evidence suggests that functional status in such men may improve with testosterone replacement therapy, there are currently no published studies evaluating a potential correlation between diffuse musculoskeletal pain and male hypogonadism. In a cohort of 45 hypogonadal men with diffuse musculoskeletal pain we found a negative correlation between the duration of pain in years and baseline total testosterone values. Although advancing age would theoretically predispose individuals to lower testosterone concentrations, age was not independently associated with baseline testosterone values, nor were any other variables we examined. At this time generalised screening of gonadal function for such men is not indicated. A prospective study would more clearly evaluate a potential relationship between diffuse musculoskeletal pain and testosterone values in men and might determine if testosterone replacement leads to any measurable improvement. PMID- 22242045 TI - A supratonsillar parapharyngeal cleft. PMID- 22242046 TI - An unusual case of dyspnoea in an elderly man. AB - Defective closure of the posterolateral pleuroperitoneal canal during embryogenesis gives rise to a congenital hernia (usually left sided) which was originally described by Bochdalek in 1948. It manifests primarily in children with respiratory symptoms and pulmonary hypoplasia. It is exceptionally rare for this defect to present in adulthood, with just over 50 symptomatic cases being described in the literature. Most adolescent and adult cases are diagnosed incidentally during imaging for upper gastrointestinal symptoms. It is unusual for adults to present with respiratory symptoms. We describe the case of a 71 year-old man who presented with features of left ventricular failure due to an exceptionally large, right sided Bochdalek hernia. This is the oldest clinical presentation of a right sided Bochdalek hernia, which uniquely included trans diaphragmatic herniation of the pancreas. PMID- 22242047 TI - Pulmonary artery sarcoma: a rare disease. AB - Pulmonary artery sarcomas (PAS) are rare and probably incurable tumours. The clinical manifestations are non-specific and very similar to that of patients with thromboembolic disease, resulting in delay of the correct diagnosis and proper treatment. We report the case of a 66-year-old woman with PAS diagnosed by computed tomography guided biopsy. Chemotherapy treatment was initiated but the patient died 11 months after diagnosis. PMID- 22242048 TI - Hypocalcaemic fit in an adolescent boy with undiagnosed rickets. AB - Rickets in early childhood has been well documented in the literature. We present the case of a teenage Somalian boy who had a generalised tonic-clonic fit (an unusual presentation of rickets in late childhood) and was diagnosed with vitamin D deficient rickets. PMID- 22242049 TI - A patient with multiple blisters in the skin and mucous membranes. AB - A case is presented of a patient who was referred to the rheumatology department with symptoms of systemic lupus erythematosus and bullous disease. A 55-year-old woman with 2 year history of blistering involving the hands and face, presented with new lesions on the thorax, feet, toes, inferior lip, and tongue accompanied by pruritus. The patient also had joint pain without inflammation of the knees, ankles, and hands. After the investigations the patient was diagnosed with a blistering disorder, specifically epidermolysis bullosa acquisita. The patient completely recovered following treatment with topical and oral corticosteroids, and colchicine. PMID- 22242050 TI - Bilateral adrenal masses: varying aetiologies. PMID- 22242051 TI - Splenic flexure volvulus. AB - We present the case of a woman in her 50s presenting with acute abdominal pain and absolute constipation. Subsequent investigations revealed large bowel obstruction which was shown on computed tomography scan to be secondary to a rare volvulus of the splenic flexure of her colon. The patient was taken for an urgent laparotomy with resection of 45 cm of large bowel and formation of a primary anastomosis. Though she initially made a good postoperative recovery, she unfortunately later developed complications as a result of her surgery requiring further laparotomies. She later died of multiple organ failure, 2 months following her admission. PMID- 22242052 TI - A female soccer player with recurrent haemoptysis and iron deficiency anaemia: idiopathic pulmonary haemosiderosis (IPH)-case report and literature review. AB - A 19-year-old woman presented with repeated episodes of haemoptysis and shortness of breath. Blood tests revealed iron deficiency anaemia and chest imaging studies showed bilateral lung opacities. In further laboratory tests and technical examination including bronchoalveolar lavage and transbronchial lung biopsy, pulmonary embolism, cardiac disease, and pulmonary vasculitis due to autoimmune disease were ruled out. Finally, a diagnosis of idiopathic pulmonary haemosiderosis (IPH) was made in January 2008. The patient was treated with prednisone, azathioprine, and oral iron supplementation. Subsequently, the patient's condition and haemoglobin value improved notably. In May 2009, the patient was in full disease remission including a normal blood count and normal iron parameters. IPH is a rare cause of diffuse alveolar haemorrhage of unknown origin. It occurs most frequently in children and adolescents and typically presents with recurrent haemoptysis due to alveolar bleeding. However, pulmonary signs and symptoms often are obscure in children. In these cases iron deficiency anaemia is the prominent clinical finding. The purpose of this case report is to increase awareness of IPH as a possible cause of recurrent haemoptysis and anaemia. PMID- 22242053 TI - Adult ileocolic intussusception secondary to ileocaecal valve polyp. AB - Intussusception is relatively common in children, but it is a rare cause of abdominal pain and intestinal obstruction in adults. The aetiology, clinical presentation and management of this condition differs in adults and children. Preoperative clinical diagnosis is usually difficult due to the non-specific and intermittent nature of the symptoms. Ultrasound and computed tomography can be helpful in establishing the diagnosis. We present a case of adult ileocolic intussusception with classical radiological signs and operative findings. In adults the diagnosis of intussusception should be considered in a case of intermittent abdominal pain, especially with clinical signs of intermittent bowel obstruction. PMID- 22242054 TI - Anti-TNFalpha antibody infliximab treatment for an infant with fistulising Crohn's disease. AB - A female infant presented at the age of 4 weeks with dyschezia and bloody streaking of stools which did not improve on elemental formula for proposed cow's milk protein allergy. At 6 months of age perianal ulceration appeared which evolved into multiple fistulas opening into the perineum. A diagnosis of infantile Crohn's disease was made after colonoscopy and histopathology examination and exclusion of other conditions. An 8 week trial of total parenteral nutrition, in addition to corticosteroids, salazopyrine, metronidazole, and azathioprine failed to arrest deterioration of the perianal fistulas. Treatment with the anti-TNFalpha antibody infliximab was started at 5 mg/kg/dose at 9 months of age. She was given three doses at 0, 2, and 6 weeks, respectively. This resulted in significant healing of her fistulas and cessation of fistula output. This improvement was sustained at the time of last follow-up 10 months after treatment. PMID- 22242055 TI - Pulmonary protection. AB - This report describes the case of a 23-year-old woman who presented with symptoms, signs and radiology suggesting pneumonia. Despite courses of antibiotics, her condition did not improve. Bronchoscopy was eventually performed which revealed a membranous object in her right upper lobe bronchus. The object was easily removed and discovered to be a condom. Retrospective questioning found that the women was currently working as an escort girl and often performed oral sex on male clients. The patient remembered coughing very violently during a recent session which is presumably when the condom was inhaled. She had not volunteered this information initially as she was sensitive about her occupation, and also because she had not been directly asked. This case illustrates the importance of taking a detailed occupational history from a patient presenting with respiratory symptoms as this may have led to a quicker diagnosis and spared the patient courses of antibiotics. PMID- 22242056 TI - Delayed presentation of a swallowed partial denture. AB - We report a unique case of a young patient who accidentally swallowed his partial denture and alarmingly only presented to our ear, nose and throat (ENT) department 4 weeks later despite several previous presentations to primary and secondary care. The partial denture was successfully removed under general anaesthetic using direct laryngoscopy following admission. He was discharged on a normal diet 6 days later after oesophageal perforation was excluded using a contrast swallow. PMID- 22242057 TI - Acute myocardial infarction with ST segment elevation in inferior and anterior leads: right ventricular infarction. AB - We describe the case of a patient who developed an acute myocardial infarction (MI) with ST segment elevations simultaneously in anterior and inferior leads during exercise testing. The patient became hypotensive and unconscious, and an anterior MI was suspected. After systemic thrombolytic therapy, blood pressure improved, and the electrocardiogram (ECG) showed no further ST deviations. Thirty minutes later, chest pain and ST segment elevations recurred. A second thrombolytic bolus was administered, after which the electrocardiographic signs of MI promptly resolved. Coronary angiography revealed two severe complex stenotic lesions in the right coronary artery and one in the left anterior descending coronary artery. Percutaneous coronary intervention and stent implantation were performed in both affected coronary vessels. Interpretation of the ECG indicated clear evidence of an acute inferior wall MI. In this particular case, ST segment elevations in V1-V4 were due to the right ventricular involvement. PMID- 22242058 TI - Unusual simultaneous multifocal rupture of oesophagus, stomach and diaphragm after blunt trauma. AB - An unusual case of simultaneous multifocal rupture of the oesophagus, stomach and diaphragm after blunt trauma is described. The characteristic computed tomography scans (with intraluminal contrast application) of the ruptured oesophagus are shown, and successful management is presented. PMID- 22242059 TI - Atypical presentation of focal nodular hyperplasia. AB - A 27-year-old man, previously healthy, had an enlarging liver mass incidentally noted at a health check-up 6 months earlier. There were no known risk factors for hepatocellular carcinoma. The hepatic tumour seen on magnetic resonance imaging had characteristics of high T2 and low T1 signals, early hyper-enhancement and mild delayed enhancement, which was atypical for focal nodular hyperplasia (FNH). An atypical hepatectomy was performed smoothly and the pathologic confirmation of FNH was finally made. He was discharged without complications. PMID- 22242060 TI - Catastrophic cerebral antiphospholipid syndrome presenting as cerebral infarction with haemorrhagic transformation after sudden withdrawal of warfarin in a patient with primary antiphospholipid syndrome. AB - Catastrophic antiphospholipid syndrome (APS) is caused by thrombotic vascular occlusions that affect both small and large vessels, producing ischaemia in the affected organs. The "catastrophic" variant of the antiphospholipid syndrome (cAPS) develops over a short period of time. Although patients with cAPS represent <1% of all patients with APS, they are usually life threatening with a 50% mortality rate. A strong association with concomitant infection is thought to act as the main trigger of microthromboses in cAPS. Several theories have been proposed to explain these physiopathological features. Some of them suggest the possibility of molecular mimicry between components of infectious microorganisms and natural anticoagulants, which might be involved in the production of cross reacting antiphospholipid antibodies. We present a case of catastrophic cerebral APS characterised by massive temporal lobe infarction and subsequent haemorrhagic transformation after sudden withdrawal of warfarin. PMID- 22242061 TI - Appendiceal diverticulosis. PMID- 22242062 TI - Post-traumatic dizziness. AB - Following an episode of syncope, a 42-year-old woman was referred to exclude a cardiac cause. This primary event was determined to be a straightforward case of vasovagal syncope, resulting in mild head trauma. Following this, the patient was left with symptoms of dizziness and a subjective "muzzy" sensation. Initially assumed to be a form of "post-concussive symptom", she was referred to a neurologist who employed neurovestibular manoeuvres to both determine the cause of these symptoms and satisfactorily resolve them. PMID- 22242063 TI - Abdominal abscess due to retained gallstones 5 years after laparoscopic cholecystectomy. AB - A 76-year-old female patient with diabetes presented with pyrexia and a recurrent painful right sided loin swelling. One year previously she had undergone radiological drainage of a large right sided loin abscess. At index presentation she was investigated both radiologically and endoscopically and a source for the abscess was not found. On this presentation, a computed tomography scan confirmed a large retroperitoneal abscess pointing through the lateral abdominal wall musculature. Surgical drainage was undertaken whereby the abscess was drained and several large gallstones extruded through the incision. The patient subsequently recuperated and the wound has healed successfully by second intention. Five years previously the patient had undergone an "uncomplicated" laparoscopic cholecystectomy. This case highlights the catastrophic late effects of dropped gallstones during laparoscopic cholecystectomy. PMID- 22242064 TI - Effect of Lactobacillus casei on Streptococcus bovis in faecal flora. AB - Bacteraemia caused by Streptococcus bovis is often associated with colorectal tumours. Also, experimental studies have been proposed that S bovis acts as a promoter of tumours. We report the case of a man with colon adenoma who had a high proportion of S bovis in his faecal flora. He was treated with a Lactobacillus casei preparation (BLP) and the effect on the faecal flora was examined. L casei reduced the proportion of S bovis (from 43% down to 9%), and the effect continued after the administration of BLP was stopped. Our data indicate that BLP can repress the excessive colonisation of S bovis. PMID- 22242065 TI - Altered mental state and the Whipple triad. AB - A 47-year-old man presented with episodes of altered mental state initially felt to be complex partial seizures, but which were in fact hypoglycaemic episodes. An insulinoma was confirmed and eventually localised. He underwent an abdominal computed tomography scan and intraoperative laparoscopy, but required selective venous sampling to localise the tumour. Fifteen months after his surgery there is no evidence of recurrence of his insulinoma. PMID- 22242066 TI - Use of suction to treat intramedullary spinal cysticercosis. PMID- 22242068 TI - Toxic megacolon from hypervirulent Clostridium difficile infection (ribotype 027) following elective total knee replacement: an emerging challenge in modern health care. AB - We present a rare case of community acquired (presenting in hospital on the day of admission or within 48 h of admission) Clostridium difficile infection (CDI) with the hypervirulent (ribotype 027) strain causing toxic megacolon in a patient, diagnosed on the third postoperative day following an elective total knee replacement. The patient did not have any of the commonly reported risk factors for CDI. The source of sepsis was initially presumed to be the operated prosthetic joint, and this caused a delay in the correct diagnosis and institution of appropriate antimicrobial treatment which may have contributed to a poorer outcome. This case highlights the risk of patients arriving from the community manifesting life threatening CDI in the hospital. PMID- 22242067 TI - Skin rash, headache and abnormal behaviour: unusual presentation of intracranial haemorrhage in dengue fever. AB - Dengue viral infections are one of the most important mosquito borne diseases in the world. The dengue virus is a single stranded RNA virus belonging to the Flaviviridae family. There are four serotypes (DEN 1-4) classified according to biological and immunological criteria. Patients may be asymptomatic or their condition may give rise to undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF), or dengue shock syndrome. Annually, 100 million cases of dengue fever and half a million cases of DHF occur worldwide and 2.5 billion people are at risk. At present, dengue is endemic in 112 countries. Early recognition and prompt initiation of appropriate treatment are vital if disease related morbidity and mortality are to be limited. We present an interesting case of dengue fever with headache, skin rash and abnormal behaviour who had a massive intracranial haemorrhage with fatal outcome. PMID- 22242069 TI - Leptospirosis diagnosed by molecular DNA detection on skin biopsy. AB - Leptospirosis is one of the most common anthropozoonoses in the world. Humans are accidental hosts who get infected through damaged skin or conjunctiva from environmental sources such as soil and water contaminated by urine or tissues from infected animals. We report the case of a young man for whom the diagnosis was obtained by polymerase chain reaction (PCR) detection from a skin biopsy. PMID- 22242070 TI - Do not resuscitate order in a patient with iatrogenic life threatening complications due to a bagatelle. AB - A patient with a history of metastatic bronchial carcinoma and end stage heart disease was admitted to hospital, after an accidental fall, because of epistaxis requiring nasal tamponade and blood transfusions. On day 2 the patient suffered from acute dyspnoea and finally respiratory and cardiac arrest. The patient was successfully resuscitated despite a do not resuscitate order (DNR order). A bolus aspiration of the nasal tamponade's gauze was discovered as the reason for the arrest. This case report underlines the ethical dilemma in patients with an otherwise undisputed DNR order when the arrest is: (1) easy to resolve but not easy to detect; (2) iatrogenic in nature; and (3) is occurring in an unmonitored area (for example, the ward) as compared with an arrest in a well monitored area (for example, the intensive care unit and operating room). PMID- 22242071 TI - Chemotherapy induced Hyponatraemia. AB - We present a case report of chemotherapy induced renal salt wasting syndrome (RSWS) that was initially diagnosed and managed as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), based on osmolality values as well as hydration status. The patient was receiving chemotherapy for metastatic testicular cancer. Progressive deterioration of electrolyte balance prompted the diagnosis of RSWS. This was confirmed by a high urinary sodium concentration, a simple but important investigation which is rarely requested in the initial investigation of hyponatraemia. Urine sodium concentration is high in RSWS but normal in SIADH. With chemotherapy playing such an important role in cancer management, the correct diagnosis of hyponatraemia in an oncology patient is vital in order to allow appropriate management. Although the distinctions between SIADH and RSWS can be very subtle, the management of these two distinct clinical situations is very different-namely, fluid restriction versus salt replacement. PMID- 22242072 TI - Metastatic breast disease: an all too common cause of back pain. AB - A 50-year-old multiparous woman presented with a 3 month history of back pain. She was initially treated for non-mechanical back pain by her primary care physician, but was subsequently discovered to have a right sided clinical breast cancer and palpable axillary lymphadenopathy. An oestrogen/progesterone receptor positive invasive ductal carcinoma with axillary metastatic disease was confirmed on breast clinic triple assessment. Magnetic resonance imaging of the spine revealed an L1 vertebral body metastatic fracture with cord compression and other axial and non-axial stable skeletal metastases. The patient underwent immediate orthopaedic spinal stabilisation with full resolution of her back pain, and began primary endocrine breast cancer therapy with outpatient spinal radiotherapy planned. PMID- 22242073 TI - Oesophageal food impaction in achalasia treated with Coca-Cola and nifedipine. AB - Achalasia is characterised by the loss of peristaltic movement in the distal oesophagus and failure of the lower oesophageal sphincter relaxation, which results in impaired oesophageal emptying. We report a case of a 92-year-old frail woman with a history of achalasia, who presented with acute oesophageal obstruction due to impaction of a large amount of food material. She was treated successfully with nifedipine, in combination with Coca-Cola (original product, not sugar free), so avoiding the risks associated with repeated endoscopic intubation and piecemeal removal of the oesophageal content. PMID- 22242074 TI - Intracameral injection of ranibizumab caused regression of iris neovascularisation and clearance of hyphaema in a non-diabetic patient with ischaemic remnant retinal flap in a silicone filled eye. AB - The use of 0.5 mg/0.05 ml of ranibizumab intracamerally, to induce regression of iris neovascularisation in a non-diabetic patient, is reported. A 55-year-old Malay man presented with left eye rubeosis and hyphaema secondary to ischaemic remnant retinal flap in his silicone filled pseudophakic eye. Regression of rubeosis and resolution of hyphaema was noted within 4 days of injection of intracameral ranibizumab, allowing repeat vitrectomy to be performed without much bleeding, thus facilitating removal of his intraocular lens and laser to remaining flap. One month postoperatively he remained comfortable with counting fingers vision similar to the pre-hyphaema period. PMID- 22242075 TI - Florid reactive lymphoid hyperplasia of terminal ileum. AB - Florid lymphoid hyperplasia in the terminal ileum can present to surgeons as an acute abdominal pain. Only few cases were reported in the literature. Our case illustrates that a rare case of florid lymphoid hyperplasia can present to surgeons as acute appendicitis. During the operation the gross appearance may mimic Crohn's disease. A limited resection is sufficient to clinch the diagnosis of florid lymphoid hyperplasia / Crohn's disease. In florid lymphoid hyperplasia limited resection may be curative. PMID- 22242076 TI - Wegener's granulomatosis in pregnancy: a case report and review of the medical literature. AB - A Caucasian woman in the third trimester of her sixth pregnancy was diagnosed with Wegener's granulomatosis (WG) following investigation for recurrent ear infections and a persistent dry cough. Chest radiograph showed granulomatous lesions and the c-ANCA (antineutrophil cytoplasmic antibody) was strongly positive. She required pulsed methylprednisolone and cyclophosphamide followed by oral prednisolone and azathioprine to control the disease process during and after pregnancy. Neither the disease nor aggressive treatment adversely affected the pregnancy and she delivered a healthy baby girl by elective induction at 37 weeks. A review of the literature on Wegener's granulomatosis in pregnancy is presented. PMID- 22242077 TI - Rapidly progressive bone destruction of the finger as first presentation of systemic metastases from lung cancer. AB - We report a case of a man with locally advanced lung adenocarcinoma and no evidence of metastatic disease presenting with rapid onset pain and swelling of his right second finger. Radiographically and clinically this was felt to be osteomyelitis and he was treated with intravenous antibiotics. He clinically worsened, and upon biopsy was found to have metastatic adenocarcinoma of the digit. He was treated with radiotherapy with some symptom improvement. He shortly thereafter developed diffuse skeletal metastases. PMID- 22242078 TI - A patient's informative mistake: niacin is very effective in correcting dyslipidaemia. AB - A 72-year-old man at high risk for cardiovascular disease, with a history of peripheral vascular disease and type 2 diabetes, presented with lipids above targets despite maximum daily treatment with atorvastatin 80 mg, fenofibrate supra 160 mg daily, and ezetimibe 10 mg. His low density lipoprotein cholesterol (LDL-C) was 2.6 mmol/l, total cholesterol: HDL ratio 5.6, and high density lipoprotein cholesterol (HDL-C) 0.9 mmol/l. Because his lipids were not within target, he was advised to start 2250 mg of niacin in three divided doses daily. For 5 months, he mistakenly took 2250 mg of niacin three times daily, a consumption of 6750 mg/day! The effects on his lipids were: HDL-C increased nearly 100% to 1.7 mmol/l, LDL-C decreased by 50% to 1.3 mmol/l, and cholesterol: HDL ratio decreased by over 50% to 2.1. His excessive intake dramatically demonstrates the positive effect of niacin on lipids. Fortunately he did not suffer adverse effects from taking more than the recommended limit of 3000 mg/day. PMID- 22242079 TI - Jack stone. PMID- 22242080 TI - Laparoscopic management of chylous ascites following laparoscopic donor nephrectomy. AB - Laparoscopic donor nephrectomy (LDN) is an established operation for organ procurement in living donor transplantation. Living donor renal transplantation is being performed more frequently and is associated with better graft function and survival. The minimal access approach for organ procurement from healthy individuals ensures early convalescence and improved patient participation. Here we describe a rare complication of LDN. Postoperative chylous ascites frequently occurs secondary to aortic surgery. Though previously described after LDN, its treatment remains contentious. Conventional strategies have adopted an expectant approach with medical management. These include parenteral feeding, bowel rest and somatostatin analogue usage. We report laparoscopic suture ligation as the principal management of postoperative chyle leak. We advocate surgical exploration in acute onset, high output chylous ascites. Pre-existing port site incisions were used for undertaking successful laparoscopic repair. This surgical approach enabled faster convalescence and reduced hospital stay-important considerations for our healthy living donor. PMID- 22242081 TI - Hypocalcaemia, long QT interval and atrial arrhythmias. AB - Calcium has diverse roles in neuromuscular mechanisms. Within the cardiovascular system, hypocalcaemia is known to both impair myocardial contractility and prolong the QT interval, predisposing to ventricular arrhythmias. We present a case of chronic hypocalcaemia with prolonged QT interval associated with an atrial arrhythmia. Recent studies of congenital long QT syndrome suggest there is also a predisposition to atrial arrhythmias. Our case raises the hypothesis that acquired causes of long QT cause similar repolarisation abnormalities that predispose to atrial arrhythmias. PMID- 22242082 TI - Results of a healthcare worker (HCW) survey on environmental awareness as an instrument for the preparation of an environmental report for the University Medicine Greifswald. AB - BACKGROUND: Environmental reporting is increasingly important for medical facilities. Currently, hospitals can determine the content of an environmental report as they see fit. OBJECTIVE: To examine the utility and scope of an employee survey as an instrument for the preparation of an environmental report at the University Hospital Greifswald. METHOD: For this purpose a questionnaire was developed with a focus on environmental behaviour and the significance attached to the protection of the environment. RESULTS: The employees of the University Medicine Greifswald attach an unexpectedly high significance to the protection of the environment. Based on this finding, this potential should be used to promote the optimal implementation of ecological-economic behaviour within the University Medicine. CONCLUSION: An employee survey is a useful instrument in the preparation of an environmental report. PMID- 22242083 TI - Comparison of the antioxidant potential in urine, saliva and skin. AB - AIM: Free radicals, oxidative stress and their possible consequences for health are becoming increasingly important in modern medicine. Reactive species influence the organism, potentially causing oxidative cell damage. They can be produced by exogenous sources, or be a product of a variety of not only physiological metabolic processes, such as immune response, but also pathological processes. The antioxidant protection system protects the organism from oxidative damage caused by reactions producing an excess of free radicals. The analysis of antioxidant potential (AOP) is therefore becoming increasingly important for the diagnosis of individual vitality. METHOD: The photochemoluminescence method was used to measure the AOP in urine and saliva, spectrometry was employed to measure the beta-carotene content of the skin. In addition, it was investigated whether the AOP(saliva) correlated with the AOPU(urine) (uric-acid independent AOP) as well as the beta-carotene content of the skin. RESULTS: The AOP was significantly higher in urine than in saliva, and both values were significantly positively correlated with each other. However, there was no significant correlation to the beta-carotene content of the skin. DISCUSSION: The components of the AOPU(urine) are accumulated over time (night), whereas AOP measurement in saliva is like a snapshot, which explains why AOPU(urine) was significantly higher than AOP(saliva), although the two parameters are correlated with each other. beta carotene is a fat-soluble antioxidant, whereas in our study, only water-soluble antioxidants were determined in the urine. This explains why there is no positive correlation between beta-carotene of the skin and AOP. CONCLUSION: For the characterization of the AOP in epidemiological studies, we recommend determining the AOPU(urine) and parallel to this, the beta-carotene content of the skin. PMID- 22242084 TI - Unusual infections: Femoral abscess due to Nocardia abscessus in a patient suffering from metastatic peripheral bronchial carcinoma and hygienic consequences. AB - During the course of a peripheral bronchial carcinoma with pulmonary and cerebral metastases a femoral abscess developed in a 49 year-old patient after radio- and chemotherapy. A bacterial strain, which was isolated four times from a deep wound of the left thigh was tentatively identified as a member of the genus Nocardia on the basis of selected phenotypic and chemotaxonomic characteristics. The isolate was confirmed to belong to Nocardia abscessus by 16S rRNA gene sequencing. This species had previously been described as the causative agent of soft tissue infections. Although rare, nocardia soft tissue infections as complication of systemic nocardiosis are typical air born infections of immuncompromised patients and need specific attention. Infection prevention can be realized by restriction of soil and aerosol (builder's dust) together with antibiotic intervention (oral administration of trimethoprim/sulfamethoxazole). PMID- 22242085 TI - Persistently elevated IgA antibodies to Mycoplasma pneumoniae in patients with internal carotid artery stenosis. AB - BACKGROUND: It has been suggested that Mycoplasma pneumoniae may play a role in the development of atherosclerosis, but to date this association is still a matter of debate due to conflicting findings. METHODS: We have investigated the levels of specific IgA antibodies to M. pneumoniae in 91 patients with internal carotid artery (ICA) stenosis using a commercial kit (SeroMPTM IgA; Savyon Diagnostics, Israel; cut-off value: 20 binding units; BU). All patients underwent surgery for ICA stenosis. From each patient, the first serum sample (S1) was taken before surgery, and the second after an interval of 6 month (S2). RESULTS: The S1 seroprevalence was 18.7% (17/91). Thirteen of the 17 patients with positive S1 levels also remained positive after six month, whereby no decrease of IgA level was seen (median S1 level: 34 BU, range: 22-65 BU; median S2 level: 37 BU, range: 22-58 BU). Specifically, six of the patients showed an increased level after 6 months, and six a decrease, with the level remaining constant in one patient. In contrast, only 3 of the 74 S1 negative patients became positive for anti-M. pneumoniae IgA between the taking of the first and the second serum specimen (p<0.01). None of the assessed demographic factors or risk factors for atherosclerosis was associated with IgA seropositivity, neither were the degree CAVK or the degree of stenosis. CONCLUSION: These findings cannot be explained throughout by the general seroprevalence, or by past respiratory tract infections with the pathogen, and therefore may suggest a role for M. pneumoniae in the development of atherosclerosis, since a chronic infection must be assumed. PMID- 22242086 TI - Clinical results of the application of a hemoglobin spray to promote healing of chronic wounds. AB - A new technological approach for supplying hypoxic chronic wounds with oxygen is a moist wound treatment with aqueous solutions containing tissue compatible oxygen binders. This facilitates diffusion of oxygen, necessary for the healing process, from the surroundings (room air through an open-porous wound padding) into the ulcerous tissue. A product that is still in development is a spray which contains hemoglobin obtained from domestic pigs. Clinical investigations (a clinical trial, treatment observations and single patient uses) are presented, which were performed to create clinical data regarding efficiency and safety of this product. All data have shown that the application of the hemoglobin spray promoted wound healing in all analyzed cases.Data from a clinical study in Mexico and subsequent therapy observations revealed that in 39 out of 42 patients (93%) the treated wounds were healed. 9 patients from a series of therapy observations in Monterrey (Mexico) showed similar observations. All treated wounds were closed. Single patient uses carried out in Witten (Germany; 6 wounds from 8 (75%)) and Prague (Czech Republic; 5 wounds from 5 (100%) were healed) further support these results: The application of hemoglobin spray can promote healing of chronic wounds. Within the framework of the clinical investigation, the treatment observations, and the individual healing experiments the hemoglobin spray was applied more than 2,000 times onto chronic wounds of 82 patients. In all cases, the spray was well tolerated and there were no adverse event that might have been an adverse reaction to the hemoglobin spray. PMID- 22242087 TI - Minimum inhibitory (MIC) and minimum microbicidal concentration (MMC) of polihexanide and triclosan against antibiotic sensitive and resistant Staphylococcus aureus and Escherichia coli strains. AB - BACKGROUND: An in-vitro study was conducted investigating the antimicrobial efficacy of polihexanide and triclosan against clinical isolates and reference laboratory strains of Staphylococcus aureus and Escherichia coli. METHODS: The minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC) were determined following DIN 58940-81 using a micro-dilution assay and a quantitative suspension test following EN 1040. Polihexanide was tested in polyethylene glycol 4000, triclosan in aqueous solutions. RESULTS: Against all tested strains the MIC of polihexanide ranged between 1-2 ug/mL. For triclosan the MICs varied depending on strains ranging between 0.5 ug/mL for the reference strains and 64 ug/mL for two clinical isolates. A logRF >5 without and logRF >3 with 0.2% albumin burden was achieved at 0.6 ug/mL triclosan. One exception was S. aureus strain H-5-24, where a triclosan concentration of 0.6 ug/mL required 1 minute without and 10 minutes with albumin burden to achieve the same logRFs. Polihexanide achieved a logRF >5 without and logRF >3 with albumin burden at a concentration of 0.6 ug/mL within 30 sec. The exception was the North-German epidemic MRSA strain, were an application time of 5 minutes was required. CONCLUSION: The clinical isolates of E. coli generally showed higher MICs against triclosan, both in the micro-dilution assay as well in the quantitative suspension test than comparable reference laboratory strains. For polihexanide and triclosan strain dependant susceptibility was shown. However, both antimicrobial compounds are effective when used in concentrations common in practice. PMID- 22242088 TI - Management of leg and pressure ulcer in hospitalized patients: direct costs are lower than expected. AB - BACKGROUND: In Germany, cost calculations on the financial burden of wound treatment are scarce. Studies for attributable costs in hospitalized patients estimate for pressure ulcer additional costs of ? 6,135.50 per patient, a calculation based on the assumption that pressure ulcers will lead to prolonged hospitalization averaging 2 months. The scant data available in this field prompted us to conduct a prospective economical study assessing the direct costs of treatment of chronic ulcers in hospitalized patients. STUDY DESIGN: The study was designed and conducted as an observational, prospective, multi-centre economical study over a period of 8 months in three community hospitals in Germany. PATIENTS: Direct treatment costs for leg ulcer (n=77) and pressure ulcer (n=35) were determined observing 67 patients (average age: 75+/-12 years). 109 treatments representing 111 in-ward admissions and 62 outpatient visits were observed. During a total of 3,331 hospitalized and 867 outpatient wound therapies, 4,198 wound dressing changes were documented. MAIN OUTCOME MEASURE: Costs of material were calculated on a per item base. Direct costs of care and treatment, including materials used, surgical interventions, and personnel costs were determined. RESULTS: An average of ? 1,342 per patient (? 48/d) was spent for treatment of leg ulcer (staff costs ? 581, consumables ? 458, surgical procedures ? 189, and diagnostic procedures ? 114). On average, each wound dressing change caused additional costs of ? 15. For pressure ulcer, ? 991 per patient (? 52/d) was spent on average (staff costs ? 313, consumables ? 618, and for surgical procedures ? 60). Each wound dressing change resulted in additional costs of ? 20 on average. CONCLUSION: When direct costs of chronic wounds are calculated on a prospective case-by-case basis for a treatment period over 3 months, these costs are lower than estimated to date. While reduction in prevalence of chronic wounds along with optimised patient care will result in substantial cost saving, this saving might be lower than expected. Our results, however, do not serve as basis for making any conclusions on cost-benefit analysis for both, the affected individual, as well as for the society. PMID- 22242089 TI - Practices of skin care among nurses in medical and surgical intensive care units: results of a self-administered questionnaire. AB - Dermatitis of hands is a problem among nurses. The aim of this prospective questionnaire based survey was to analyze practice and knowledge of skin care of medical and surgical nurses. 250 questionnaires were distributed. 49% of respondent stated that they perform skin care at least 1-2 times/day. After hand wash 15% of participants perform skin protection, after hand-disinfection only 2%. 40% give skin care products less than 3 minutes to be applied. It was shown that this knowledge is lacking in many individuals, leading to wrong behavior at work and insufficient use of skin protection and skin care products. PMID- 22242090 TI - Decontamination of room air and adjoining wall surfaces by nebulizing hydrogen peroxide. AB - AIM: In 2010, the ASP GLOSAIR(TM) 400 was introduced in Germany for nebulizing hydrogen peroxide (H(2)O(2)). Since there were no results of practical experience, the new method was to be checked under practical conditions for its effectiveness in decontaminating air in rooms, infested with mold after water damage and, at the same time, under experimentally controlled conditions, test surfaces, contaminated with Aspergillus brasiliensis. METHOD: After the nebulizer was used in two rooms with a massive mold infestation, the air colony count was determined (MAS-100((r)) Zinsser Analytik) and, at the same time, the mold infestation in samples of wall plaster.As part of this controlled study, test surfaces contaminated with Aspergillus brasiliensis were positioned vertically and horizontally in a test room. The effectiveness of the nebulization (5-6% H(2)O(2) for 2 hours) was tested on these surfaces according to EN 13697. RESULTS: In a massive mold infestation resulting from water damage (worst case), an approximately 9-fold decrease in the mold content and an approximately 13-fold decrease in the number of colony-forming units (sum of the bacteria + fungi) could be detected in the room air immediately after the nebulizing was finished. Even in samples of wall and joint plaster, the molds were reduced, although to a distinctly lesser extent. By indoor nebulization of 5-6% H(2)O(2), A. brasiliensis was reduced >4 log on vertical and horizontal surfaces. DISCUSSION: In rooms with a massive mold infestation, the ASP GLOSAIR(TM) 400 system is suitable for attaining a clear reduction in the fungal and bacterial room air load, lasting for a week. On vertical and horizontal surfaces, contaminated experimentally with A. brasiliensis, a reduction of >4 lg is achieved. As a load of 10(4) to 10(5) fungal spores is unlikely to occur on pre-cleaned surfaces, the GLOSAIR(TM) 400 can be considered a suitable complementary process for the substantial reduction of fungal contamination. PMID- 22242091 TI - Foot-operated door opener to eliminate the door handle as a source of contamination. AB - AIM: As door handles represent a transmission route for viruses and micro organisms, a door opening and closing mechanism should be developed without manual operation. METHOD: To solve the problem, a device for opening the door with the help of a foot pedal was built into the door leaf. RESULTS: The design enables mechanical opening of the door with a foot pedal without manual operation. Subsequently, the door closes with the help of a mechanical locking mechanism. DISCUSSION: The foot-operated door opener constitutes an additional option to the door handle. Together with the equipment of a soft closing mechanism, it is possible to prevent noise emanating from the door latch impinging on the door frame. Using this construction, the door handle as a transmission vector is eliminated. In addition, the transport of goods held with two hands simultaneously is facilitated. CONCLUSION: With a foot-operated door opener instead of the traditional manual door handle, it is possible to open doors with a foot pedal. This prevents contamination of door handles with pathogens. PMID- 22242092 TI - Refurbishment works in a hospital during normal operation. AB - BACKGROUND: Construction and renovation work in hospitals pose risks of fungal airborne infections for immunosuppressed patients. If possible, reconstruction work will be postponed to periods without patient treatment. However, in many situations urgent damage demands immediate refurbishment works before the transferring of patients to other wards or closure of wards is possible. Reported here are infection control related measures and implemented procedures after two incidents of water damage which occurred on a surgical ward and an intensive care unit at the University hospital of Essen. METHODS: Between January and April 2009 and between September and October 2009, respectively, concentration of air-borne particles and number of viable fungi were measured at two surgical wards and one ICU. Preventive Infection Control Measures included erection of protective walls and HEPA filtration of air from the renovation area. RESULTS: During the renovation work on the surgical ward concentrations of moulds and particles >=5 um were significantly higher on the left side of the renovation area than on the right side (p=0.036 and p<0.001). Concentrations of particles >=1 um and particles >=5 um on both sides of the renovation area were significantly increased when compared with the control ward on the same floor but not when compared with the control ward on the other floor. Particles of all size were significantly elevated on the ICU during the renovation work. Aspergillus fumigatus could neither be cultured of the air of cardiac surgery intensive care unit nor of the intermediate care unit (control ward). During renovation works there was no nosocomial mould infection of patients treated on the two wards. CONCLUSION: Provided that the renovation area is tightly insulated from the areas of patient care on a ward, closure does not seem to be necessary during renovation works because variation of airborne fungi is similar to that of outdoor or control air. However a multidisciplinary team should be established. This team should perform risk assessment and determine necessary protective measures before starting any construction, renovation or maintenance work in health care settings. PMID- 22242093 TI - Functional separation of septic and aseptic surgical procedures. AB - Current evidence does not favour constructional over functional separation of septic and aseptic surgical procedures in terms of overall hygiene maintenance and incidence of skin and soft tissue infections. In both laminar and turbulent flow air operating theatres, air is not a relevant source of pathogens if surface disinfection is carried out properly.Final cleaning after a septic procedure includes a thorough wipe-disinfection of all potentially contaminated near and distant surfaces, including maintaining the necessary and effective exposure time of the chosen surface disinfectant. Cleaning utensils and clothes of all team members must be disposed of before leaving the theatre, and a complete change of gowns is mandatory before re-entering the operating room area. Strict adherence to this code of behaviour will allow for efficient functional separation of clean and contaminated surgical procedures without compromising patient safety. PMID- 22242094 TI - Endowashers: an overlooked risk for possible post-endoscopic infections. AB - BACKGROUND: Prevention of post-endoscopy infections is an important objective to assure patient safety. Endowashers, or high throughput irrigation water pumps, are a frequently used device on endoscopes. Recommendations published by professional bodies and regulatory health agencies cover not only adequate reprocessing of fiber-endoscopes but also state accepted methods of regular microbial sampling. Although major instruments like endoscopes are covered by these recommendations, other devices used as optional add-ons for endoscopes are not included. OBJECTIVE: The aim of this prospective study was to investigate the potential for endowashers to act as a possible source of infection. METHOD: 24 endowashers were sampled. Sterile rinse-water was pumped through the endowasher and tested microbiologically according to standardised tests. Sampling was performed in 18 hospitals, including 2 university teaching hospitals, in northern Germany. If endowashers were contaminated, devices were reprocessed and re tested. RESULTS: Of 44 samples, 6 (14%) were contaminated with pathogens of up to >20,000 cfu/ml. Pseudomonas aeruginosa and other Gram-negative non-fermenters such as Stenotrophomonas spp. (18x) and Acinetobacter spp. (2x), followed by Staphylococcus aureus (1x), Enterobacter cloacae (1x), Candida albicans (1x), Serratia spp. (1x), Streptococcus spp. (1x) and others (2x). CONCLUSION: Endowashers can be a potential source of infection. Despite their common use, they are not routinely sampled microbiologically. Endowashers should be clearly mentioned in respective guidelines and routine quality control sampling of endowashers should be part of such recommendations. If endowashers are not monitored regularly, devices with single-use hoses should be used. PMID- 22242095 TI - Bacterial contamination of anesthesia machines' internal breathing-circuit systems. AB - BACKGROUND: Bacterial contamination of anesthesia breathing machines and their potential hazard for pulmonary infection and cross-infection among anesthetized patients has been an infection control issue since the 1950s. Disposable equipment and bacterial filters have been introduced to minimize this risk. However, the machines' internal breathing-circuit-system has been considered to be free of micro-organisms without providing adequate data supporting this view. The aim of the study was to investigate if any micro-organisms can be yielded from used internal machines' breathing-circuit-system. Based on such results objective reprocessing intervals could be defined. METHODS: The internal parts of 40 anesthesia machines' breathing-circuit-system were investigated. Chi-square test and logistic regression analysis were performed. An on-site process observation of the re-processing sequence was conducted. RESULTS: Bacterial growth was found in 17 of 40 machines (43%). No significant difference was ascertained between the contamination and the processing intervals. The most common contaminants retrieved were coagulase negative Staphylococci, aerobe spore forming bacteria and Micrococcus species. In one breathing-circuit-system, Escherichia coli, and in one further Staphylococcus aureus were yielded. CONCLUSION: Considering the availability of bacterial filters installed on the outlet of the breathing-circuit-systems, the type of bacteria retrieved and the on-site process observation, we conclude that the contamination found is best explained by a lack of adherence to hygienic measures during and after re processing of the internal breathing-circuit-system. These results support an extension of the re-processing interval of the anesthesia apparatus longer than the manufacturer's recommendation of one week. However, the importance of adherence to standard hygienic measures during re-processing needs to be emphasized. PMID- 22242096 TI - Microbiological safety and cost-effectiveness of weekly breathing circuit changes in combination with heat moisture exchange filters: a prospective longitudinal clinical survey. AB - AIM: To assess the safety and cost effectiveness of a usage for seven days of breathing circuit systems (BCSs) in combination with heat moisture exchanger filters (HMEF) in operation room anesthesia. METHOD: In a prospective longitudinal clinical study, the contamination on high-risk surfaces (HMEF together with inner and outer surface of BCS) was monitored over 1, 2, 5, and 7 days. RESULTS of endogenous respiratory patient flora and contamination flora of BCS, HMEF and bag were compared. Costs of prolonged use of BCS together with HMEF up to 7 days were calculated. RESULTS: Neither physiological respiratory flora nor colonizing pathogens of the oropharynx of the ventilated patients were transmitted through the filters at any time. None of the included patients developed a postoperative pneumonia. Using the BCS for 24 hours provides a cost savings of up to 40% versus single use. Extending the change interval from 24 hours to 48 hours saved over 50% compared to change after each patient, and an additional 19% compared to change after 24 hours. In combination with a HMEF BCS can be used up to 7 days without clinical risk on multiple patients in operation room settings. CONCLUSION: Expanding the usage of berating in combination with usage of moist exchange filters is feasible, microbiologically safe and cost effective, as 41% of material costs per ventilation may be saved. Further research is needed to confirm these results. PMID- 22242097 TI - Titanium-copper-nitride coated spacers for two-stage revision of infected total hip endoprostheses. AB - Within the first two years after total hip arthroplasty implant-associated infection has become the second most common reason for a revision surgery. Two stage implant exchange is frequently conducted using temporary spacers made of antibiotic-loaded cement in order to prevent a bacterial colonization on the spacer. Avoiding several disadvantages of cement spacers, a conventional hemi endoprosthesis was equipped with a copper-containing implant coating for inhibition of bacterial biofilms. In the present paper details of this novel treatment concept are presented including a case report. PMID- 22242098 TI - Two-stage revision of implant-associated infections after total hip and knee arthroplasty. AB - Septic loosening of total hip and knee endoprostheses gains an increasing proportion of revision arthroplasties. Operative revisions of infected endoprostheses are mentally and physically wearing for the patient, challenging for the surgeon and a significant economic burden for healthcare systems. In cases of early infection within the first three weeks after implantation a one stage revision with leaving the implant in place is widely accepted. The recommendations for the management of late infections vary by far. One-stage revisions as well as two-stage or multiple revision schedules have been reported to be successful in over 90% of all cases for certain patient collectives. But implant associated infection still remains a severe complication. Moreover, the management of late endoprosthetic infection requires specific logistics, sufficient and standardized treatment protocol, qualified manpower as well as an efficient quality management. With regard to the literature and experience of specialized orthopaedic surgeons from several university and regional hospitals we modified a commonly used treatment protocol for two-stage revision of infected total hip and knee endoprostheses. In addition to the achievement of maximum survival rate of the revision implants an optimisation of the functional outcome of the affected artificial joint is aimed for. PMID- 22242100 TI - MRSA distribution and epidemiological procedures evaluation at two hospitals in Northern Poland. AB - In the present study we have analyzed the impact of modified MRSA screening of carriers and patients on epidemiological situation of MRSA during 2008-2010, comparing two regional hospitals with similar bed numbers and similar ward profiles in Northern Poland. In 2008 the proportion of MRSA to all S. aureus isolates was 14.4% resp. 6.0%, in 2009 8.3% resp. 4.7% and in 2010 6.5% in both hospitals. Independent of the different prevention and intervention strategy in both hospitals the different MRSA incidence seems to be due to regional epidemic settings. PMID- 22242101 TI - One-day point prevalence of emerging bacterial pathogens in four secondary and five tertiary care German hospitals - results from a pilot study of the German Society for Hospital Hygiene (Deutsche Gesellschaft fur Krankenhaushygiene, DGKH). AB - OBJECTIVE: Data on the prevalence of emerging bacterial pathogens like extended spectrum-lactamase-building (ESBL) Gram negative organisms, multiresistant Pseudomonas and Acinetobacter species or toxin-building Clostridium difficile in German hospitals are sparse. To provide data for different regions in Germany, a one-day point prevalence study with five tertiary care hospitals and four secondary care hospitals was conducted on the 10(th) of February 2010. METHOD: For participating hospitals, the level of care (primary/secondary/tertiary), staffing with infection prevention personnel, availability of a MRSA-screening, microbiological support and the prevalence of five emerging bacterial pathogens in intensive care, surgical and medical wards was assessed by questionnaire. RESULTS: Overall, 3411 patients were included. In tertiary hospitals, the following prevalences were given: MRSA 1.8%, ESBL E. coli 0.45%, ESBL Klebsiella spp. 0.41%, multiresistant Pseudomonas 0.53%, multiresistant Acinetobacter species 0.15%, VRE 0.49% und Clostridium difficile 1.01%. In secondary hospitals, as prevalences resulted for MRSA 3.48%, ESBL E. coli 0.4%, ESBL Klebsiella spp. 0.4%, multiresistant Pseudomonas 0%, multiresistant Acinetobacter species 0%, VRE 0.13% und Clostridium difficile 1.34%. DISCUSSION: The prevalence of MRSA found is comparable to other prevalence studies published in the last years, but remarkably higher than reported by the German National Surveillance System (KISS). As no prevalence data for other pathogens as MRSA could be found, only data from the ITS-KISS are available for comparison. Again, the prevalences found in the present study are much higher than reported by the KISS. Whether this is by chance or indicates a systematic underreporting in the KISS remains unclear. CONCLUSION: The results from this one day point prevalence study show that prevalences of emerging bacterial pathogens differ markedly between regions, departments and hospitals. This can be explained by regional, methodical and other difference associated with the level of care provided by these hospitals. Still, the prevalences found fit well to other prevalence studies from the last years but are remarkably higher than to be expected by the KISS. As questionnaire based one-day prevalence studies have been shown to be inexpensive and feasible, such studies, using a fixed day and protocol, should be extendedly used in the future to collect representative data for Germany. By such initiatives, scientific societies as the DGKH can take part in collecting valuable epidemiological data of emerging bacterial pathogens. PMID- 22242102 TI - Uniform documentation of measures in cases of MRSA - an important step towards improving the quality of treatment. AB - The basis for the management and documentation of multiresistant organisms (MRO) in medical facilities in Germany are the Infection Protection Act (IPA) and the recommendations given by the Commission for Hospital Hygiene and Infection Prevention at the Robert Koch Institute (KRINKO).With the Infection Protection Amendment Act an accounting capability for the treatment of patients with MRO will be established in the outpatient care sector. At the same time an electronic documentation is required. In order to comply with the law demanding that the transfer of data concerning the carrier status of a patient should be done without any delays or errors and with minimal effort. Therefore, the documentation should be done according to standards across all sectors and institutions.The documentation of services by multiple providers is to plan with all stakeholders in order to meet the requirements for a proper and professional documentation.The sheet developed in the framework of the HICARE project allows documenting the decolonisation process across sector and service providers. Additionally, it is approved by the MDK MV for documenting the additional efforts to claim the OPS 8-987. PMID- 22242099 TI - Incidence and clinical implication of nosocomial infections associated with implantable biomaterials - catheters, ventilator-associated pneumonia, urinary tract infections. AB - Health care associated infections, the fourth leading cause of disease in industrialised countries, are a major health issue. One part of this condition is based on the increasing insertion and implantation of prosthetic medical devices, since presence of a foreign body significantly reduces the number of bacteria required to produce infection. The most significant hospital-acquired infections, based on frequency and potential severity, are those related to procedures e.g. surgical site infections and medical devices, including urinary tract infection in catheterized patients, pneumonia in patients intubated on a ventilator and bacteraemia related to intravascular catheter use. At least half of all cases of nosocomial infections are associated with medical devices.Modern medical and surgical practices have increasingly utilized implantable medical devices of various kinds. Such devices may be utilized only short-time or intermittently, for months, years or permanently. They improve the therapeutic outcome, save human lives and greatly enhance the quality of life of these patients. However, plastic devices are easily colonized with bacteria and fungi, able to be colonized by microorganisms at a rate of 0.5 cm per hour. A thick biofilm is formed within 24 hours on the entire surface of these plastic devices once inoculated even with a small initial number of bacteria.The aim of the present work is to review the current literature on causes, frequency and preventive measures against infections associated with intravascular devices, catheter related urinary tract infection, ventilator-associated infection, and infections of other implantable medical devices. Raising awareness for infection associated with implanted medical devices, teaching and training skills of staff, and establishment of surveillance systems monitoring device-related infection seem to be the principal strategies used to achieve reduction and prevention of such infections. The intelligent use of suitable antiseptics in combination with medical devices may further support reduction and prevention of such infections. In addition to reducing the adverse clinical outcomes related with these infections, such reduction may substantially decrease the economic burden caused by device-related infection for health care systems. PMID- 22242103 TI - HIC@RE ... and its relevance for a company like RIEMSER. AB - The increased incidence of infections caused by methicillin-resistant strains of Staphylococcus aureus (MRSA) burdens the healthcare systems with significant additional costs. Simple measures such as active MRSA screening can lead to a reduction of infectious events and massive savings. To establish an effective and comprehensive strategy for prevention and eradication of MRSA, the cooperation and networking of all stakeholders in the health care system is necessary. Pharmaceutical companies are part of the health care system; they therefore have a vital and ethical interest that care within the health system will be further optimized and thus continue to remain affordable. The targets of the HIC@RE project demonstrate the interests of the pharmaceutical and health-care research company RIEMSER Arzneimittel AG, so that a sufficient rationale is given for cooperation in this project. PMID- 22242104 TI - On the economic impact of a regional management of multidrug-resistant bacteria. AB - The increasing number of people who are colonized or infected with multidrug resistant bacteria imposes a high economic burden on society which includes the negative impact on health status as an intangible cost. An economic analysis leads to the conclusion that currently too little is done to prevent or control infections. The reasons include insufficient incentives for health care providers, a lack of reliable data on both the prevalence and the effects of infection, and a lack of coordination among the different branches of the health care sector. A regional management of multidrugresistant bacteria which does not focus on a single branch but rather on the health care sector overall can achieve a substantial reduction in the number of infected people and of the associated economic cost for society. PMID- 22242105 TI - Can the Hazard Assessment and Critical Control Points (HACCP) system be used to design process-based hygiene concepts? AB - Recently, the HACCP (Hazard Analysis and Critical Control Points) concept was proposed as possible way to implement process-based hygiene concepts in clinical practice, but the extent to which this food safety concept can be transferred into the health care setting is unclear. We therefore discuss possible ways for a translation of the principles of the HACCP for health care settings. While a direct implementation of food processing concepts into health care is not very likely to be feasible and will probably not readily yield the intended results, the underlying principles of process-orientation, in-process safety control and hazard analysis based counter measures are transferable to clinical settings. In model projects the proposed concepts should be implemented, monitored, and evaluated under real world conditions. PMID- 22242106 TI - The project HICARE: cross-sectoral action alliance against multi-resistant pathogens. AB - Multi-resistant pathogens are a serious problem on a considerable scale for the health sector. Patients with infections induced by multi-resistant bacteria cause enormous additional treatment costs of around 20,500 ? per insured. Due to the recently used billing and documentation system there is a significant shortage of information transparency. The guidelines for hospital hygiene and infection prevention published by the Robert Koch Institute (RKI) include a presumption provision, which means that subject to compliance with these guidelines the observance of the current state of medical science is suspected. In case of a derogation, a scientific justification is necessary, which is used e.g. in connection with liability questions. Within the framework of legal reforms in 2011, the legislator aspires a nationwide improvement of hygiene quality in medical institutions and information transparency. Many specific issues about the general reporting obligation of infections with multi-resistant pathogens or about the standardized exchange of infection documentations between medical institution and health authority remain unresolved.Regional, cross-sectoral networks create the base to tackle targeted measures collectively and may develop sustainable and tailored solutions for their region. With these considerations in mind, the project HICARE was founded in Mecklenburg-Vorpommern. The project pursues the aim to develop an intervention strategy against the spread of multi resistant pathogens. Health insurances make an important contribution to quality of medical treatment by participation. PMID- 22242107 TI - Epidemiology of multi-resistant organisms - challenges to a regional data management system. AB - The health care region Baltic Coast is within the framework of the joint project HICARE (Health, Innovative Care & Regional Economy) to be developed from January 2011 to December 2014 into a model region to combat the spread of multi-resistant organisms (MRO). The concept of the project area "IT & Epidemiology" will be introduced here. An IT system is to be developed and implemented consisting of two interconnected elements, a central data management and a web-based support system for information and decision. Particular challenges are the consolidation of data decentrally collected from numerous and heterogeneous data sources, compliance with the data privacy protection laws and the complex management of patients' informed consent. The information collected by the central data management will be the basis of epidemiological evaluations. Prevalence and incidence of MRO in patients and staff of medical facilities, single risk factors as well as risk profiles, the range and extent of treatments including their effectiveness and sustainability will be investigated. Furthermore, cost and cost utility analyses will be performed. PMID- 22242108 TI - Mastering old challenges with new alliances - how to breathe life in the amendments to the federal regulations for infection control in Germany. PMID- 22242109 TI - Tissue-Dependent Expression of Estrogen Receptor beta in 17beta-Estradiol Mediated Attenuation of Autoimmune CNS Inflammation. AB - Treatment strategies using therapeutic estrogen are being developed and tested for multiple sclerosis (MS). MS is an autoimmune inflammatory disease that attacks the central nervous system, damages myelin and produces neurode generative changes associated with periodic and chronic progression of functional neurological deficit. Experimental studies in chimeric bone marrow transplant mice treated with 17beta-estradiol (E2) have revealed that the estrogen receptor 1 (Esr-1, or -alpha) expressed exclusively within the non-hematopoietic tissue compartment is sufficient for mediating a beneficial neuroprotective therapeutic response in mice lacking Esr-1 expression on T lymphocytes or other bone marrow derived cells. Less is known regarding requirements for estrogen receptor-2 (Esr 2, or -beta) expression in E2-mediated therapy. Here, we tested and compared requirements for Esr-2 expression within distinct tissue compartments in bone marrow transplant mice. Our studies support a crucial role for Esr-1 in E2 treatment and demonstrate that Esr-2 expressed by non-bone marrow-derived cells plays a role in sustaining the neuroprotective response mediated through Esr-1. PMID- 22242110 TI - Are Private Schools Better Than Public Schools? Appraisal for Ireland by Methods for Observational Studies. AB - In observational studies the assignment of units to treatments is not under control. Consequently, the estimation and comparison of treatment effects based on the empirical distribution of the responses can be biased since the units exposed to the various treatments could differ in important unknown pretreatment characteristics, which are related to the response. An important example studied in this article is the question of whether private schools offer better quality of education than public schools. In order to address this question we use data collected in the year 2000 by OECD for the Programme for International Student Assessment (PISA). Focusing for illustration on scores in mathematics of 15-years old pupils in Ireland, we find that the raw average score of pupils in private schools is higher than of pupils in public schools. However, application of a newly proposed method for observational studies suggests that the less able pupils tend to enroll in public schools, such that their lower scores is not necessarily an indication of bad quality of the public schools. Indeed, when comparing the average score in the two types of schools after adjusting for the enrollment effects, we find quite surprisingly that public schools perform better on average. This outcome is supported by the methods of instrumental variables and latent variables, commonly used by econometricians for analyzing and evaluating social programs. PMID- 22242111 TI - Automated discovery of food webs from ecological data using logic-based machine learning. AB - Networks of trophic links (food webs) are used to describe and understand mechanistic routes for translocation of energy (biomass) between species. However, a relatively low proportion of ecosystems have been studied using food web approaches due to difficulties in making observations on large numbers of species. In this paper we demonstrate that Machine Learning of food webs, using a logic-based approach called A/ILP, can generate plausible and testable food webs from field sample data. Our example data come from a national-scale Vortis suction sampling of invertebrates from arable fields in Great Britain. We found that 45 invertebrate species or taxa, representing approximately 25% of the sample and about 74% of the invertebrate individuals included in the learning, were hypothesized to be linked. As might be expected, detritivore Collembola were consistently the most important prey. Generalist and omnivorous carabid beetles were hypothesized to be the dominant predators of the system. We were, however, surprised by the importance of carabid larvae suggested by the machine learning as predators of a wide variety of prey. High probability links were hypothesized for widespread, potentially destabilizing, intra-guild predation; predictions that could be experimentally tested. Many of the high probability links in the model have already been observed or suggested for this system, supporting our contention that A/ILP learning can produce plausible food webs from sample data, independent of our preconceptions about "who eats whom." Well-characterised links in the literature correspond with links ascribed with high probability through A/ILP. We believe that this very general Machine Learning approach has great power and could be used to extend and test our current theories of agricultural ecosystem dynamics and function. In particular, we believe it could be used to support the development of a wider theory of ecosystem responses to environmental change. PMID- 22242113 TI - Influence of statistical estimators of mutual information and data heterogeneity on the inference of gene regulatory networks. AB - The inference of gene regulatory networks from gene expression data is a difficult problem because the performance of the inference algorithms depends on a multitude of different factors. In this paper we study two of these. First, we investigate the influence of discrete mutual information (MI) estimators on the global and local network inference performance of the C3NET algorithm. More precisely, we study 4 different MI estimators (Empirical, Miller-Madow, Shrink and Schurmann-Grassberger) in combination with 3 discretization methods (equal frequency, equal width and global equal width discretization). We observe the best global and local inference performance of C3NET for the Miller-Madow estimator with an equal width discretization. Second, our numerical analysis can be considered as a systems approach because we simulate gene expression data from an underlying gene regulatory network, instead of making a distributional assumption to sample thereof. We demonstrate that despite the popularity of the latter approach, which is the traditional way of studying MI estimators, this is in fact not supported by simulated and biological expression data because of their heterogeneity. Hence, our study provides guidance for an efficient design of a simulation study in the context of network inference, supporting a systems approach. PMID- 22242112 TI - Protein phosphatase 2A interacts with the Na,K-ATPase and modulates its trafficking by inhibition of its association with arrestin. AB - BACKGROUND: The P-type ATPase family constitutes a collection of ion pumps that form phosphorylated intermediates during ion transport. One of the best known members of this family is the Na+,K+-ATPase. The catalytic subunit of the Na+,K+ ATPase includes several functional domains that determine its enzymatic and trafficking properties. METHODOLOGY/PRINCIPAL FINDINGS: Using the yeast two hybrid system we found that protein phosphatase 2A (PP2A) catalytic C-subunit is a specific Na+,K+-ATPase interacting protein. PP-2A C-subunit interacted with the Na+,K+-ATPase, but not with the homologous sequences of the H+,K+-ATPase. We confirmed that the Na+,K+-ATPase interacts with a complex of A- and C-subunits in native rat kidney. Arrestins and G-protein coupled receptor kinases (GRKs) are important regulators of G-protein coupled receptor (GPCR) signaling, and they also regulate Na+,K+-ATPase trafficking through direct association. PP2A inhibits association between the Na+,K+-ATPase and arrestin, and diminishes the effect of arrestin on Na+,K+-ATPase trafficking. GRK phosphorylates the Na+,K+-ATPase and PP2A can at least partially reverse this phosphorylation. CONCLUSIONS/SIGNIFICANCE: Taken together, these data demonstrate that the sodium pump belongs to a growing list of ion transport proteins that are regulated through direct interactions with the catalytic subunit of a protein phosphatase. PMID- 22242115 TI - Upper temperature limits of tropical marine ectotherms: global warming implications. AB - Animal physiology, ecology and evolution are affected by temperature and it is expected that community structure will be strongly influenced by global warming. This is particularly relevant in the tropics, where organisms are already living close to their upper temperature limits and hence are highly vulnerable to rising temperature. Here we present data on upper temperature limits of 34 tropical marine ectotherm species from seven phyla living in intertidal and subtidal habitats. Short term thermal tolerances and vertical distributions were correlated, i.e., upper shore animals have higher thermal tolerance than lower shore and subtidal animals; however, animals, despite their respective tidal height, were susceptible to the same temperature in the long term. When temperatures were raised by 1 degrees C hour(-1), the upper lethal temperature range of intertidal ectotherms was 41-52 degrees C, but this range was narrower and reduced to 37-41 degrees C in subtidal animals. The rate of temperature change, however, affected intertidal and subtidal animals differently. In chronic heating experiments when temperature was raised weekly or monthly instead of every hour, upper temperature limits of subtidal species decreased from 40 degrees C to 35.4 degrees C, while the decrease was more than 10 degrees C in high shore organisms. Hence in the long term, activity and survival of tropical marine organisms could be compromised just 2-3 degrees C above present seawater temperatures. Differences between animals from environments that experience different levels of temperature variability suggest that the physiological mechanisms underlying thermal sensitivity may vary at different rates of warming. PMID- 22242114 TI - The role of osteopontin (OPN/SPP1) haplotypes in the susceptibility to Crohn's disease. AB - BACKGROUND: Osteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2819 Caucasian individuals (n = 841 patients with Crohn's disease (CD), n = 473 patients with ulcerative colitis (UC), and n = 1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754 = p.Asp80Asp, rs1126616 = p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p = 0.0004, OR = 0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060 rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value = 2.07*10-8). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p = 3.66*10-5). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p = 4.18*10-2) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p = 4.18*10-2) but none of these associations remained significant after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion. PMID- 22242117 TI - Thermal adaptation and diversity in tropical ecosystems: evidence from cicadas (Hemiptera, Cicadidae). AB - The latitudinal gradient in species diversity is a central problem in ecology. Expeditions covering approximately 16 degrees 54' of longitude and 21 degrees 4' of latitude and eight Argentine phytogeographic regions provided thermal adaptation data for 64 species of cicadas. We test whether species diversity relates to the diversity of thermal environments within a habitat. There are general patterns of the thermal response values decreasing in cooler floristic provinces and decreasing maximum potential temperature within a habitat except in tropical forest ecosystems. Vertical stratification of the plant communities leads to stratification in species using specific layers of the habitat. There is a decrease in thermal tolerances in species from the understory communities in comparison to middle level or canopy fauna. The understory Herrera umbraphila Sanborn & Heath is the first diurnally active cicada identified as a thermoconforming species. The body temperature for activity in H. umbraphila is less than and significantly different from active body temperatures of all other studied species regardless of habitat affiliation. These data suggest that variability in thermal niches within the heterogeneous plant community of the tropical forest environments permits species diversification as species adapt their physiology to function more efficiently at temperatures different from their potential competitors. PMID- 22242116 TI - Time-course global expression profiles of Chlamydomonas reinhardtii during photo biological H2 production. AB - We used a microarray study in order to compare the time course expression profiles of two Chlamydomonas reinhardtii strains, namely the high H2 producing mutant stm6glc4 and its parental WT strain during H2 production induced by sulfur starvation. Major cellular reorganizations in photosynthetic apparatus, sulfur and carbon metabolism upon H2 production were confirmed as common to both strains. More importantly, our results pointed out factors which lead to the higher H2 production in the mutant including a higher starch accumulation in the aerobic phase and a lower competition between the H2ase pathway and alternative electron sinks within the H2 production phase. Key candidate genes of interest with differential expression pattern include LHCSR3, essential for efficient energy quenching (qE). The reduced LHCSR3 protein expression in mutant stm6glc4 could be closely related to the high-light sensitive phenotype. H2 measurements carried out with the LHCSR3 knock-out mutant npq4 however clearly demonstrated that a complete loss of this protein has almost no impact on H2 yields under moderate light conditions. The nuclear gene disrupted in the high H2 producing mutant stm6glc4 encodes for the mitochondrial transcription termination factor (mTERF) MOC1, whose expression strongly increases during -S-induced H2 production in WT strains. Studies under phototrophic high-light conditions demonstrated that the presence of functional MOC1 is a prerequisite for proper LHCSR3 expression. Furthermore knock-down of MOC1 in a WT strain was shown to improve the total H2 yield significantly suggesting that this strategy could be applied to further enhance H2 production in other strains already displaying a high H2 production capacity. By combining our array data with previously published metabolomics data we can now explain some of the phenotypic characteristics which lead to an elevated H2 production in stm6glc4. PMID- 22242118 TI - Nuclear, mitochondrial and plastid gene phylogenies of Dinophysis miles (Dinophyceae): evidence of variable types of chloroplasts. AB - The Dinophysis genus is an ecologically and evolutionarily important group of marine dinoflagellates, yet their molecular phylogenetic positions and ecological characteristics such as trophic modes remain poorly understood. Here, a population of Dinophysis miles var. indica was sampled from South China Sea in March 2010. Nuclear ribosomal RNA gene (rDNA) SSU, ITS1-5.8S-ITS2 and LSU, mitochondrial genes encoding cytochrome B (cob) and cytochrome C oxidase subunit I (cox1), and plastid rDNA SSU were PCR amplified and sequenced. Phylogenetic analyses based on cob, cox1, and the nuclear rRNA regions showed that D. miles was closely related to D. tripos and D. caudata while distinct from D. acuminata. Along with morphology the LSU and ITS1-5.8S-ITS2 molecular data confirmed that this population was D. miles var. indica. Furthermore, the result demonstrated that ITS1-5.8S-ITS2 fragment was the most effective region to distinguish D. miles from other Dinophysis species. Three distinct types of plastid rDNA sequences were detected, belonging to plastids of a cryptophyte, a haptophyte, and a cyanobacterium, respectively. This is the first documentation of three photosynthetic entities associated with a Dinophysis species. While the cyanobacterial sequence likely represented an ectosymbiont of the D. miles cells, the detection of the cryptophyte and haptophyte plastid sequences indicates that the natural assemblage of D. miles likely retain more than one type of plastids from its prey algae for temporary use in photosynthesis. The result, together with recent findings of plastid types in other Dinophysis species, suggests that more systematic research is required to understand the complex nutritional physiology of this genus of dinoflagellates. PMID- 22242119 TI - Genome analysis of cytochrome P450s and their expression profiles in insecticide resistant mosquitoes, Culex quinquefasciatus. AB - Here we report a study of the 204 P450 genes in the whole genome sequence of larvae and adult Culex quinquefasciatus mosquitoes. The expression profiles of the P450 genes were compared for susceptible (S-Lab) and resistant mosquito populations, two different field populations of mosquitoes (HAmCq and MAmCq), and field parental mosquitoes (HAmCq(G0) and MAmCq(G0)) and their permethrin selected offspring (HAmCq(G8) and MAmCq(G6)). While the majority of the P450 genes were expressed at a similar level between the field parental strains and their permethrin selected offspring, an up- or down-regulation feature in the P450 gene expression was observed following permethrin selection. Compared to their parental strains and the susceptible S-Lab strain, HAmCq(G8) and MAmCq(G6) were found to up-regulate 11 and 6% of total P450 genes in larvae and 7 and 4% in adults, respectively, while 5 and 11% were down-regulated in larvae and 4 and 2% in adults. Although the majority of these up- and down-regulated P450 genes appeared to be developmentally controlled, a few were either up- or down regulated in both the larvae and adult stages. Interestingly, a different gene set was found to be up- or down-regulated in the HAmCq(G8) and MAmCq(G6) mosquito populations in response to insecticide selection. Several genes were identified as being up- or down-regulated in either the larvae or adults for both HAmCq(G8) and MAmCq(G6); of these, CYP6AA7 and CYP4C52v1 were up-regulated and CYP6BY3 was down-regulated across the life stages and populations of mosquitoes, suggesting a link with the permethrin selection in these mosquitoes. Taken together, the findings from this study indicate that not only are multiple P450 genes involved in insecticide resistance but up- or down-regulation of P450 genes may also be co responsible for detoxification of insecticides, insecticide selection, and the homeostatic response of mosquitoes to changes in cellular environment. PMID- 22242120 TI - LTR retrotransposons in fungi. AB - Transposable elements with long terminal direct repeats (LTR TEs) are one of the best studied groups of mobile elements. They are ubiquitous elements present in almost all eukaryotic genomes. Their number and state of conservation can be a highlight of genome dynamics. We searched all published fungal genomes for LTR containing retrotransposons, including both complete, functional elements and remnant copies. We identified a total of over 66,000 elements, all of which belong to the Ty1/Copia or Ty3/Gypsy superfamilies. Most of the detected Gypsy elements represent Chromoviridae, i.e. they carry a chromodomain in the pol ORF. We analyzed our data from a genome-ecology perspective, looking at the abundance of various types of LTR TEs in individual genomes and at the highest-copy element from each genome. The TE content is very variable among the analyzed genomes. Some genomes are very scarce in LTR TEs (<50 elements), others demonstrate huge expansions (>8000 elements). The data shows that transposon expansions in fungi usually involve an increase both in the copy number of individual elements and in the number of element types. The majority of the highest-copy TEs from all genomes are Ty3/Gypsy transposons. Phylogenetic analysis of these elements suggests that TE expansions have appeared independently of each other, in distant genomes and at different taxonomical levels. We also analyzed the evolutionary relationships between protein domains encoded by the transposon pol ORF and we found that the protease is the fastest evolving domain whereas reverse transcriptase and RNase H evolve much slower and in correlation with each other. PMID- 22242122 TI - The promoter of the cereal VERNALIZATION1 gene is sufficient for transcriptional induction by prolonged cold. AB - The VERNALIZATION1 (VRN1) gene of temperate cereals is transcriptionally activated by prolonged cold during winter (vernalization) to promote flowering. To investigate the mechanisms controlling induction of VRN1 by prolonged cold, different regions of the VRN1 gene were fused to the GREEN FLUORESCENT PROTEIN (GFP) reporter and expression of the resulting gene constructs was assayed in transgenic barley (Hordeum vulgare). A 2 kb segment of the promoter of VRN1 was sufficient for GFP expression in the leaves and shoot apex of transgenic barley plants. Fluorescence increased at the shoot apex prior to inflorescence initiation and was subsequently maintained in the developing inflorescence. The promoter was also sufficient for low-temperature induction of GFP expression. A naturally occurring insertion in the proximal promoter, which is associated with elevated VRN1 expression and early flowering in some spring wheats, did not abolish induction of VRN1 transcription by prolonged cold, however. A translational fusion of the promoter and transcribed regions of VRN1 to GFP, VRN1::GFP, was localised to nuclei of cells at the shoot apex of transgenic barley plants. The distribution of VRN1::GFP at the shoot apex was similar to the expression pattern of the VRN1 promoter-GFP reporter gene. Fluorescence from the VRN1::GFP fusion protein increased in the developing leaves after prolonged cold treatment. These observations suggest that the promoter of VRN1 is targeted by mechanisms that trigger vernalization-induced flowering in economically important temperate cereal crops. PMID- 22242121 TI - Bidirectional coupling between astrocytes and neurons mediates learning and dynamic coordination in the brain: a multiple modeling approach. AB - In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a "learning signal" to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters. PMID- 22242123 TI - The E1B19K oncoprotein complexes with Beclin 1 to regulate autophagy in adenovirus-infected cells. AB - The mechanisms underlying adenovirus-mediated autophagy are currently unknown. Recently, members of the Bcl-2 protein family have been associated with autophagy. It was also reported that the Bcl-2 homology-3 (BH3) domain encompassed by both Beclin 1 and Bcl-2-like proteins is essential for their pro autophagy or anti-autophagy functions. Here, we report for the first time that E1B19K, the adenovirus BH3 domain protein, interacts with Beclin 1 to initiate autophagy. Using immunoprecipitation assays we showed that expression of E1B19K in the host cell disrupted the physical interactions between Beclin 1 and Bcl-2 proteins. The displacement of Bcl-2 was coincident with the recruitment of PI3KC3 to the Beclin 1/E1B19K complexes. As a result of the changes in the components of the Beclin 1 interactome, there was activation of PI3KC3, as showed by the identification of PI3K-mediated lipid phosphorylation, and subsequent formation of autophagosomes. Importantly, the BH3 functional domain of E1B19K protein was required for the heterodimerization with Beclin 1. We also showed that transfer of E1B19K was sufficient to trigger autophagy in cancer cells. Consistent with these data, mutant adenoviruses encompassing a deletion of the E1B19K gene produced a marked deficiency in the capability of the virus to induce autophagy as showed by examining the lipidation and cleavage of LC3-I as well as the subcellular localization of LC3-II, the decrease in the levels of p62, and the formation of autophagosomes. Our work offers new information on the mechanisms of action of the adenoviral E1B19K protein as partner of Beclin 1 and positive regulator of autophagy. PMID- 22242124 TI - Interleukin 15 levels in serum may predict a severe disease course in patients with early arthritis. AB - BACKGROUND: Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA). METHODOLOGY AND RESULTS: Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (beta Coefficient [95% confidence interval]: 0.12 [0.06-0.18]; p<0.001) or ACPA (0.34 [0.01-0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007). CONCLUSIONS: Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatment. PMID- 22242125 TI - Stress-induced C/EBP homology protein (CHOP) represses MyoD transcription to delay myoblast differentiation. AB - When mouse myoblasts or satellite cells differentiate in culture, the expression of myogenic regulatory factor, MyoD, is downregulated in a subset of cells that do not differentiate. The mechanism involved in the repression of MyoD expression remains largely unknown. Here we report that a stress-response pathway repressing MyoD transcription is transiently activated in mouse-derived C2C12 myoblasts growing under differentiation-promoting conditions. We show that phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2alpha) is followed by expression of C/EBP homology protein (CHOP) in some myoblasts. ShRNA driven knockdown of CHOP expression caused earlier and more robust differentiation, whereas its constitutive expression delayed differentiation relative to wild type myoblasts. Cells expressing CHOP did not express the myogenic regulatory factors MyoD and myogenin. These results indicated that CHOP directly repressed the transcription of the MyoD gene. In support of this view, CHOP associated with upstream regulatory region of the MyoD gene and its activity reduced histone acetylation at the enhancer region of MyoD. CHOP interacted with histone deacetylase 1 (HDAC1) in cells. This protein complex may reduce histone acetylation when bound to MyoD regulatory regions. Overall, our results suggest that the activation of a stress pathway in myoblasts transiently downregulate the myogenic program. PMID- 22242126 TI - Ablation of Mrds1/Ofcc1 induces hyper-gamma-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice. AB - Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as "the Japan Mouse Clinic". No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum gamma-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-gamma-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-gamma-glutamyl transpeptidasemia and schizophrenia. PMID- 22242127 TI - Role of conserved non-coding regulatory elements in LMW glutenin gene expression. AB - Transcriptional regulation of LMW glutenin genes were investigated in-silico, using publicly available gene sequences and expression data. Genes were grouped into different LMW glutenin types and their promoter profiles were determined using cis-acting regulatory elements databases and published results. The various cis-acting elements belong to some conserved non-coding regulatory regions (CREs) and might act in two different ways. There are elements, such as GCN4 motifs found in the long endosperm box that could serve as key factors in tissue specific expression. Some other elements, such as the AACA/TA motifs or the individual prolamin box variants, might modulate the level of expression. Based on the promoter sequences and expression characteristic LMW glutenin genes might be transcribed following two different mechanisms. Most of the s- and i-type genes show a continuously increasing expression pattern. The m-type genes, however, demonstrate normal distribution in their expression profiles. Differences observed in their expression could be related to the differences found in their promoter sequences. Polymorphisms in the number and combination of cis-acting elements in their promoter regions can be of crucial importance in the diverse levels of production of single LMW glutenin gene types. PMID- 22242129 TI - Inflammatory-induced hibernation in the fetus: priming of fetal sheep metabolism correlates with developmental brain injury. AB - Prenatal inflammation is considered an important factor contributing to preterm birth and neonatal mortality and morbidity. The impact of prenatal inflammation on fetal bioenergetic status and the correlation of specific metabolites to inflammatory-induced developmental brain injury are unknown. We used a global metabolomics approach to examine plasma metabolites differentially regulated by intrauterine inflammation. Preterm-equivalent sheep fetuses were randomized to i.v. bolus infusion of either saline-vehicle or LPS. Blood samples were collected at baseline 2 h, 6 h and daily up to 10 days for metabolite quantification. Animals were killed at 10 days after LPS injection, and brain injury was assessed by histopathology. We detected both acute and delayed effects of LPS on fetal metabolism, with a long-term down-regulation of fetal energy metabolism. Within the first 3 days after LPS, 121 metabolites were up-regulated or down-regulated. A transient phase (4-6 days), in which metabolite levels recovered to baseline, was followed by a second phase marked by an opposing down-regulation of energy metabolites, increased pO(2) and increased markers of inflammation and ADMA. The characteristics of the metabolite response to LPS in these two phases, defined as 2 h to 2 days and at 6-9 days, respectively, were strongly correlated with white and grey matter volumes at 10 days recovery. Based on these results we propose a novel concept of inflammatory-induced hibernation of the fetus. Inflammatory priming of fetal metabolism correlated with measures of brain injury, suggesting potential for future biomarker research and the identification of therapeutic targets. PMID- 22242128 TI - Identification of close relatives in the HUGO Pan-Asian SNP database. AB - The HUGO Pan-Asian SNP Consortium has recently released a genome-wide dataset, which consists of 1,719 DNA samples collected from 71 Asian populations. For studies of human population genetics such as genetic structure and migration history, this provided the most comprehensive large-scale survey of genetic variation to date in East and Southeast Asia. However, although considered in the analysis, close relatives were not clearly reported in the original paper. Here we performed a systematic analysis of genetic relationships among individuals from the Pan-Asian SNP (PASNP) database and identified 3 pairs of monozygotic twins or duplicate samples, 100 pairs of first-degree and 161 second-degree of relationships. Three standardized subsets with different levels of unrelated individuals were suggested here for future applications of the samples in most types of population-genetics studies (denoted by PASNP1716, PASNP1640 and PASNP1583 respectively) based on the relationships inferred in this study. In addition, we provided gender information for PASNP samples, which were not included in the original dataset, based on analysis of X chromosome data. PMID- 22242130 TI - Resveratrol inhibits protein translation in hepatic cells. AB - Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2alpha. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling. PMID- 22242131 TI - A spontaneous mutation in contactin 1 in the mouse. AB - Mutations in the gene encoding the immunoglobulin-superfamily member cell adhesion molecule contactin1 (CNTN1) cause lethal congenital myopathy in human patients and neurodevelopmental phenotypes in knockout mice. Whether the mutant mice provide an accurate model of the human disease is unclear; resolving this will require additional functional tests of the neuromuscular system and examination of Cntn1 mutations on different genetic backgrounds that may influence the phenotype. Toward these ends, we have analyzed a new, spontaneous mutation in the mouse Cntn1 gene that arose in a BALB/c genetic background. The overt phenotype is very similar to the knockout of Cntn1, with affected animals having reduced body weight, a failure to thrive, locomotor abnormalities, and a lifespan of 2-3 weeks. Mice homozygous for the new allele have CNTN1 protein undetectable by western blotting, suggesting that it is a null or very severe hypomorph. In an analysis of neuromuscular function, neuromuscular junctions had normal morphology, consistent with previous studies in knockout mice, and the muscles were able to generate appropriate force when normalized for their reduced size in late stage animals. Therefore, the Cntn1 mutant mice do not show evidence for a myopathy, but instead the phenotype is likely to be caused by dysfunction in the nervous system. Given the similarity of CNTN1 to other Ig-superfamily proteins such as DSCAMs, we also characterized the expression and localization of Cntn1 in the retinas of mutant mice for developmental defects. Despite widespread expression, no anomalies in retinal anatomy were detected histologically or using a battery of cell-type specific antibodies. We therefore conclude that the phenotype of the Cntn1 mice arises from dysfunction in the brain, spinal cord or peripheral nervous system, and is similar in either a BALB/c or B6;129;Black Swiss background, raising a possible discordance between the mouse and human phenotypes resulting from Cntn1 mutations. PMID- 22242132 TI - Effects of cord serum insulin, IGF-II, IGFBP-2, IL-6 and cortisol concentrations on human birth weight and length: pilot study. AB - BACKGROUND: The IGF system is recognised to be important for fetal growth. We previously described increased Insulin-like growth factor binding protein (IGFBP) 2 cord serum concentrations in intra-uterine growth retardation (IUGR) compared with appropriate for gestational age (AGA) newborns, and a positive relationship of IGFBP-2 with Interleukin (IL)-6. The role of cortisol in the fetus at birth is largely unknown, and interactions among peptides are their real effect on birth size is unknown. Furthermore, almost all studies have previously assayed peptides in serum several years after birth, and follow-up data from pregnancy are always lacking. This study aimed at establishing and clarifying the effect of cord serum insulin, IGF-II, IGFBP-2, cortisol and IL-6 concentrations on birth length and weight. METHODS: 23 IUGR and 37 AGA subjects were followed up from the beginning of pregnancy, and were of comparable gestational age. Insulin, IGF-II, IGFBP-2, cortisol and IL-6 concentrations were assayed in cord serum at birth, and a multiple regression model was designed and applied to assess which were the significant biochemical determinants of birth size. RESULTS: Insulin, cortisol, and IL-6, showed similar concentrations in IUGR and AGA as previously described, whereas IGF-II was lower, and IGFBP-2 increased in IUGR compared with AGA. IGF-II serum concentration was found to have a significant positive effect on both birth length (r:(:)0.546; p: 0.001) and weight (r:0.679; p: 0.0001). IGFBP-2 had a near significant negative effect on both birth weight (r:-0.342; p: 0.05) and length (r:-0.372; p:0.03). CONCLUSION: IGF-II cord serum concentration was shown to have a significant positive effect on both birth length and weight, whereas IGFBP-2 had a significant negative effect. Insulin, cortisol, and IL-6 cord serum concentrations had no significant effect on birth size. PMID- 22242133 TI - A photocytes-associated fatty acid-binding protein from the light organ of adult Taiwanese firefly, Luciola cerata. AB - BACKGROUND: Intracellular fatty acid-binding proteins (FABPs) are considered to be an important energy source supplier in lipid metabolism; however, they have never been reported in any bioluminescent tissue before. In this study, we determined the structural and functional characteristics of a novel FABP (lcFABP) from the light organ of adult Taiwanese firefly, Luciola cerata, and showed anatomical association of lcFABP with photocytes. PRINCIPAL FINDINGS: Our results demonstrated the primary structure of lcFABP deduced from the cDNA clone of light organ shares structural homologies with other insect and human FABPs. In vitro binding assay indicated the recombinant lcFABP binds saturated long chain fatty acids (C14-C18) more strongly than other fatty acids and firefly luciferin. In addition, tissue distribution screening assay using a rabbit antiserum specifically against the N-terminal sequence of lcFABP confirmed the light organ specific expression of lcFABP. In the light organ, the lcFABP constituted about 15% of total soluble proteins, and was detected in both cytosol and nucleus of photocytes. CONCLUSIONS: The specific localization of abundant lcFABP in the light organ suggests that sustained bioluminescent flashes in the light organ might be a high energy demanding process. In photocytes, lcFABP might play a key role in providing long chain fatty acids to peroxisomes for the luciferase catalyzed long chain acyl-CoA synthetic reaction. PMID- 22242134 TI - Knock-down of both eIF4E1 and eIF4E2 genes confers broad-spectrum resistance against potyviruses in tomato. AB - BACKGROUND: The eukaryotic translation initiation factor eIF4E plays a key role in plant-potyvirus interactions. eIF4E belongs to a small multigenic family and three genes, eIF4E1, eIF4E2 and eIF(iso)4E, have been identified in tomato. It has been demonstrated that eIF4E-mediated natural recessive resistances against potyviruses result from non-synonymous mutations in an eIF4E protein, which impair its direct interaction with the potyviral protein VPg. In tomato, the role of eIF4E proteins in potyvirus resistance is still unclear because natural or induced mutations in eIF4E1 confer only a narrow resistance spectrum against potyviruses. This contrasts with the broad spectrum resistance identified in the natural diversity of tomato. These results suggest that more than one eIF4E protein form is involved in the observed broad spectrum resistance. METHODOLOGY/PRINCIPAL FINDINGS: To gain insight into the respective contribution of each eIF4E protein in tomato-potyvirus interactions, two tomato lines silenced for both eIF4E1 and eIF4E2 (RNAi-4E) and two lines silenced for eIF(iso)4E (RNAi iso4E) were obtained and characterized. RNAi-4E lines are slightly impaired in their growth and fertility, whereas no obvious growth defects were observed in RNAi-iso4E lines. The F1 hybrid between RNAi-4E and RNAi-iso4E lines presented a pronounced semi-dwarf phenotype. Interestingly, the RNAi-4E lines silenced for both eIF4E1 and eIF4E2 showed broad spectrum resistance to potyviruses while the RNAi-iso4E lines were fully susceptible to potyviruses. Yeast two-hybrid interaction assays between the three eIF4E proteins and a set of viral VPgs identified two types of VPgs: those that interacted only with eIF4E1 and those that interacted with either eIF4E1 or with eIF4E2. CONCLUSION/SIGNIFICANCE: These experiments provide evidence for the involvement of both eIF4E1 and eIF4E2 in broad spectrum resistance of tomato against potyviruses and suggest a role for eIF4E2 in tomato-potyvirus interactions. PMID- 22242135 TI - Probing the SELEX process with next-generation sequencing. AB - BACKGROUND: SELEX is an iterative process in which highly diverse synthetic nucleic acid libraries are selected over many rounds to finally identify aptamers with desired properties. However, little is understood as how binders are enriched during the selection course. Next-generation sequencing offers the opportunity to open the black box and observe a large part of the population dynamics during the selection process. METHODOLOGY: We have performed a semi automated SELEX procedure on the model target streptavidin starting with a synthetic DNA oligonucleotide library and compared results obtained by the conventional analysis via cloning and Sanger sequencing with next-generation sequencing. In order to follow the population dynamics during the selection, pools from all selection rounds were barcoded and sequenced in parallel. CONCLUSIONS: High affinity aptamers can be readily identified simply by copy number enrichment in the first selection rounds. Based on our results, we suggest a new selection scheme that avoids a high number of iterative selection rounds while reducing time, PCR bias, and artifacts. PMID- 22242137 TI - Prognostic significance of vitamin D receptor polymorphisms in head and neck squamous cell carcinoma. AB - BACKGROUND: In patients with advanced non-small-cell lung cancer, vitamin D receptor (VDR) polymorphisms and haplotypes are reported to be associated with survival. We hypothesized that a similar association would be observed in patients with head and neck squamous-cell carcinoma (HNSCC). METHODS: In a post hoc analysis of our previous prospective cohort study, VDR polymorphisms including Cdx2 G/A (rs11568820), FokI C/T (rs10735810), BsmI A/G (rs1544410), ApaI G/T (rs7976091), and TaqI T/C (rs731236) were genotyped by sequencing in 204 consecutive patients with HNSCC who underwent tumor resection. Progression-free survival was compared between VDR polymorphisms using Kaplan-Meier survival curves with log-rank tests and Cox proportional hazard models adjusting for age, gender, smoking status, primary tumor sites, postoperative stages, existence of residual tumor, and postoperative treatment with chemotherapy or radiotherapy. RESULTS: During a median follow-up of 1,047 days, tumor progression and death occurred in 76 (37.3%) and 27 (13.2%) patients, respectively. The FokI T/T genotype was associated with poor progression-free survival: median survival for T/T was 265 days compared with 1,127 days for C/C or C/T (log-rank test: P = 0.0004; adjusted hazard ratio, 3.03; 95% confidence interval, 1.62 to 5.67; P = 0.001). In contrast, the other polymorphisms (Cdx2, BsmI, ApaI, TaqI) showed no significant association with progression-free survival. The A-T-G (Cdx2-FokI ApaI) haplotype demonstrated a significant association with a higher progression rate (P = 0.02). CONCLUSION: These results suggest that VDR polymorphisms and haplotypes may be associated with prognosis in patients with HNSCC, although the sample size is not large enough to draw definitive conclusions. PMID- 22242136 TI - Pseudomonas aeruginosa PilY1 binds integrin in an RGD- and calcium-dependent manner. AB - PilY1 is a type IV pilus (tfp)-associated protein from the opportunistic pathogen Pseudomonas aeruginosa that shares functional similarity with related proteins in infectious Neisseria and Kingella species. Previous data have shown that PilY1 acts as a calcium-dependent pilus biogenesis factor necessary for twitching motility with a specific calcium binding site located at amino acids 850-859 in the 1,163 residue protein. In addition to motility, PilY1 is also thought to play an important role in the adhesion of P. aeruginosa tfp to host epithelial cells. Here, we show that PilY1 contains an integrin binding arginine-glycine-aspartic acid (RGD) motif located at residues 619-621 in the PilY1 from the PAK strain of P. aeruginosa; this motif is conserved in the PilY1s from the other P. aeruginosa strains of known sequence. We demonstrate that purified PilY1 binds integrin in vitro in an RGD-dependent manner. Furthermore, we identify a second calcium binding site (amino acids 600-608) located ten residues upstream of the RGD. Eliminating calcium binding from this site using a D608A mutation abolished integrin binding; in contrast, a calcium binding mimic (D608K) preserved integrin binding. Finally, we show that the previously established PilY1 calcium binding site at 851-859 also impacts the protein's association with integrin. Taken together, these data indicate that PilY1 binds to integrin in an RGD- and calcium dependent manner in vitro. As such, P. aeruginosa may employ these interactions to mediate host epithelial cell binding in vivo. PMID- 22242138 TI - Controlling the spread of disease in schools. AB - Pandemic and seasonal infectious diseases such as influenza may have serious negative health and economic consequences. Certain non-pharmaceutical intervention strategies--including school closures--can be implemented rapidly as a first line of defense against spread. Such interventions attempt to reduce the effective number of contacts between individuals within a community; yet the efficacy of closing schools to reduce disease transmission is unclear, and closures certainly result in significant economic impacts for caregivers who must stay at home to care for their children. Using individual-based computer simulation models to trace contacts among schoolchildren within a stereotypical school setting, we show how alternative school-based disease interventions have great potential to be as effective as traditional school closures without the corresponding loss of workforce and economic impacts. PMID- 22242139 TI - Irreversible EGFR inhibitor EKB-569 targets low-LET gamma-radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. AB - EKB-569 (Pelitinib), an irreversible EGFR tyrosine kinase inhibitor has shown potential therapeutic efficiency in solid tumors. However, cell-killing potential in combination with radiotherapy and its underlying molecular orchestration remain to be explored. The objective of this study was to determine the effect of EKB-569 on ionizing radiation (IR)-associated NFkappaB-dependent cell death. SCC 4 and SCC-9 cells exposed to IR (2Gy) with and without EKB-569 treatment were analyzed for transactivation of 88 NFkappaB pathway molecules, NFkappaB DNA binding activity, translation of the NFkappaB downstream mediators, Birc1, 2 and 5, cell viability, metabolic activity and apoptosis. Selective targeting of IR induced NFkappaB by EKB-569 and its influence on cell-fate were assessed by overexpressing (p50/p65) and silencing (DeltaIkappaBalpha) NFkappaB. QPCR profiling after IR exposure revealed a significant induction of 74 NFkappaB signal transduction molecules. Of those, 72 were suppressed with EKB-569. EMSA revealed a dose dependent inhibition of NFkappaB by EKB-569. More importantly, EKB-569 inhibited IR-induced NFkappaB in a dose-dependent manner, and this inhibition was sustained up to at least 72 h. Immunoblotting revealed a significant suppression of IR-induced Birc1, 2 and 5 by EKB-569. We observed a dose-dependent inhibition of cell viability, metabolic activity and apoptosis with EKB-569. EKB-569 significantly enhanced IR-induced cell death and apoptosis. Blocking NFkappaB improved IR-induced cell death. Conversely, NFkappaB overexpression negates EKB-569 -induced cell-killing. Together, these pre clinical data suggest that EKB-569 is a radiosensitizer of squamous cell carcinoma and may mechanistically involve selective targeting of IR-induced NFkappaB-dependent survival signaling. Further pre-clinical in-vivo studies are warranted. PMID- 22242141 TI - The c4h, tat, hppr and hppd genes prompted engineering of rosmarinic acid biosynthetic pathway in Salvia miltiorrhiza hairy root cultures. AB - Rational engineering to produce biologically active plant compounds has been greatly impeded by our poor understanding of the regulatory and metabolic pathways underlying the biosynthesis of these compounds. Here we capitalized on our previously described gene-to-metabolite network in order to engineer rosmarinic acid (RA) biosynthesis pathway for the production of beneficial RA and lithospermic acid B (LAB) in Salvia miltiorrhiza hairy root cultures. Results showed their production was greatly elevated by (1) overexpression of single gene, including cinnamic acid 4-hydroxylase (c4h), tyrosine aminotransferase (tat), and 4-hydroxyphenylpyruvate reductase (hppr), (2) overexpression of both tat and hppr, and (3) suppression of 4-hydroxyphenylpyruvate dioxygenase (hppd). Co-expression of tat/hppr produced the most abundant RA (906 mg/liter) and LAB (992 mg/liter), which were 4.3 and 3.2-fold more than in their wild-type (wt) counterparts respectively. And the value of RA concentration was also higher than that reported before, that produced by means of nutrient medium optimization or elicitor treatment. It is the first report of boosting RA and LAB biosynthesis through genetic manipulation, providing an effective approach for their large scale commercial production by using hairy root culture systems as bioreactors. PMID- 22242140 TI - Analysis of biological features associated with meiotic recombination hot and cold spots in Saccharomyces cerevisiae. AB - Meiotic recombination is not distributed uniformly throughout the genome. There are regions of high and low recombination rates called hot and cold spots, respectively. The recombination rate parallels the frequency of DNA double-strand breaks (DSBs) that initiate meiotic recombination. The aim is to identify biological features associated with DSB frequency. We constructed vectors representing various chromatin and sequence-based features for 1179 DSB hot spots and 1028 DSB cold spots. Using a feature selection approach, we have identified five features that distinguish hot from cold spots in Saccharomyces cerevisiae with high accuracy, namely the histone marks H3K4me3, H3K14ac, H3K36me3, and H3K79me3; and GC content. Previous studies have associated H3K4me3, H3K36me3, and GC content with areas of mitotic recombination. H3K14ac and H3K79me3 are novel predictions and thus represent good candidates for further experimental study. We also show nucleosome occupancy maps produced using next generation sequencing exhibit a bias at DSB hot spots and this bias is strong enough to obscure biologically relevant information. A computational approach using feature selection can productively be used to identify promising biological associations. H3K14ac and H3K79me3 are novel predictions of chromatin marks associated with meiotic DSBs. Next generation sequencing can exhibit a bias that is strong enough to lead to incorrect conclusions. Care must be taken when interpreting high throughput sequencing data where systematic biases have been documented. PMID- 22242142 TI - Efficient maximum likelihood estimation of kinetic rate constants from macroscopic currents. AB - A new method is described that accurately estimates kinetic constants, conductance and number of ion channels from macroscopic currents. The method uses both the time course and the strength of correlations between different time points of macroscopic currents and utilizes the property of semiseparability of covariance matrix for computationally efficient estimation of current likelihood and its gradient. The number of calculation steps scales linearly with the number of channel states as opposed to the cubic dependence in a previously described method. Together with the likelihood gradient evaluation, which is almost independent of the number of model parameters, the new approach allows evaluation of kinetic models with very complex topologies. We demonstrate applicability of the method to analysis of synaptic currents by estimating accurately rate constants of a 7-state model used to simulate GABAergic macroscopic currents. PMID- 22242143 TI - Twist1 directly regulates genes that promote cell proliferation and migration in developing heart valves. AB - Twist1, a basic helix-loop-helix transcription factor, is expressed in mesenchymal precursor populations during embryogenesis and in metastatic cancer cells. In the developing heart, Twist1 is highly expressed in endocardial cushion (ECC) valve mesenchymal cells and is down regulated during valve differentiation and remodeling. Previous studies demonstrated that Twist1 promotes cell proliferation, migration, and expression of primitive extracellular matrix (ECM) molecules in ECC mesenchymal cells. Furthermore, Twist1 expression is induced in human pediatric and adult diseased heart valves. However, the Twist1 downstream target genes that mediate increased cell proliferation and migration during early heart valve development remain largely unknown. Candidate gene and global gene profiling approaches were used to identify transcriptional targets of Twist1 during heart valve development. Candidate target genes were analyzed for evolutionarily conserved regions (ECRs) containing E-box consensus sequences that are potential Twist1 binding sites. ECRs containing conserved E-box sequences were identified for Twist1 responsive genes Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a. Twist1 binding to these sequences in vivo was determined by chromatin immunoprecipitation (ChIP) assays, and binding was detected in ECCs but not late stage remodeling valves. In addition identified Twist1 target genes are highly expressed in ECCs and have reduced expression during heart valve remodeling in vivo, which is consistent with the expression pattern of Twist1. Together these analyses identify multiple new genes involved in cell proliferation and migration that are differentially expressed in the developing heart valves, are responsive to Twist1 transcriptional function, and contain Twist1-responsive regulatory sequences. PMID- 22242144 TI - Organizing effects of testosterone and economic behavior: not just risk taking. AB - Recent literature emphasizes the role that testosterone, as well as markers indicating early exposure to T and its organizing effect on the brain (such as the ratio of second to fourth finger, [Formula: see text]), have on performance in financial markets. These results may suggest that the main effect of T, either circulating or in fetal exposure, on economic behavior occurs through the increased willingness to take risks. However, these findings indicate that traders with a low digit ratio are not only more profitable, but more able to survive in the long run, thus the effect might consist of more than just lower risk aversion. In addition, recent literature suggests a positive correlation between abstract reasoning ability and higher willingness to take risks. To test the two hypotheses of testosterone on performance in financial activities (effect on risk attitude versus a complex effect involving risk attitude and reasoning ability), we gather data on the three variables in a sample of 188 ethnically homogeneous college students (Caucasians). We measure a [Formula: see text] digit ratio, abstract reasoning ability with the Raven Progressive Matrices task, and risk attitude with choice among lotteries. Low digit ratio in men is associated with higher risk taking and higher scores in abstract reasoning ability when a combined measure of risk aversion over different tasks is used. This explains both the higher performance and higher survival rate observed in traders, as well as the observed correlation between abstract reasoning ability and risk taking. We also analyze how much of the total effect of digit ratio on risk attitude is direct, and how much is mediated. Mediation analysis shows that a substantial part of the effect of T on attitude to risk is mediated by abstract reasoning ability. PMID- 22242145 TI - The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation. AB - Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade. PMID- 22242146 TI - Disrupted functional brain connectivity in partial epilepsy: a resting-state fMRI study. AB - Examining the spontaneous activity to understand the neural mechanism of brain disorder is a focus in recent resting-state fMRI. In the current study, to investigate the alteration of brain functional connectivity in partial epilepsy in a systematical way, two levels of analyses (functional connectivity analysis within resting state networks (RSNs) and functional network connectivity (FNC) analysis) were carried out on resting-state fMRI data acquired from the 30 participants including 14 healthy controls(HC) and 16 partial epilepsy patients. According to the etiology, all patients are subdivided into temporal lobe epilepsy group (TLE, included 7 patients) and mixed partial epilepsy group (MPE, 9 patients). Using group independent component analysis, eight RSNs were identified, and selected to evaluate functional connectivity and FNC between groups. Compared with the controls, decreased functional connectivity within all RSNs was found in both TLE and MPE. However, dissociating patterns were observed within the 8 RSNs between two patient groups, i.e, compared with TLE, we found decreased functional connectivity in 5 RSNs increased functional connectivity in 1 RSN, and no difference in the other 2 RSNs in MPE. Furthermore, the hierarchical disconnections of FNC was found in two patient groups, in which the intra-system connections were preserved for all three subsystems while the lost connections were confined to intersystem connections in patients with partial epilepsy. These findings may suggest that decreased resting state functional connectivity and disconnection of FNC are two remarkable characteristics of partial epilepsy. The selective impairment of FNC implicated that it is unsuitable to understand the partial epilepsy only from global or local perspective. We presumed that studying epilepsy in the multi-perspective based on RSNs may be a valuable means to assess the functional changes corresponding to specific RSN and may contribute to the understanding of the neuro pathophysiological mechanism of epilepsy. PMID- 22242147 TI - Shared pattern of endocranial shape asymmetries among great apes, anatomically modern humans, and fossil hominins. AB - Anatomical asymmetries of the human brain are a topic of major interest because of their link with handedness and cognitive functions. Their emergence and occurrence have been extensively explored in human fossil records to document the evolution of brain capacities and behaviour. We quantified for the first time antero-posterior endocranial shape asymmetries in large samples of great apes, modern humans and fossil hominins through analysis of "virtual" 3D models of skull and endocranial cavity and we statistically test for departures from symmetry. Once based on continuous variables, we show that the analysis of these brain asymmetries gives original results that build upon previous analysis based on discrete traits. In particular, it emerges that the degree of petalial asymmetries differs between great apes and hominins without modification of their pattern. We indeed demonstrate the presence of shape asymmetries in great apes, with a pattern similar to modern humans but with a lower variation and a lower degree of fluctuating asymmetry. More importantly, variations in the position of the frontal and occipital poles on the right and left hemispheres would be expected to show some degree of antisymmetry when population distribution is considered, but the observed pattern of variation among the samples is related to fluctuating asymmetry for most of the components of the petalias. Moreover, the presence of a common pattern of significant directional asymmetry for two components of the petalias in hominids implicates that the observed traits were probably inherited from the last common ancestor of extant African great apes and Homo sapiens.These results also have important implications for the possible relationships between endocranial shape asymmetries and functional capacities in hominins. It emphasizes the uncoupling between lateralized activities, some of them well probably distinctive to Homo, and large-scale cerebral lateralization itself, which is not unique to Homo. PMID- 22242148 TI - SRPX2 is a novel chondroitin sulfate proteoglycan that is overexpressed in gastrointestinal cancer. AB - SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly posttranslational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand-glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family. PMID- 22242149 TI - Ellagic acid derivatives from Rubus ulmifolius inhibit Staphylococcus aureus biofilm formation and improve response to antibiotics. AB - BACKGROUND: Biofilms contribute to the pathogenesis of many forms of Staphylococcus aureus infection. Treatment of these infections is complicated by intrinsic resistance to conventional antibiotics, thus creating an urgent need for strategies that can be used for the prevention and treatment of biofilm associated infections. METHODOLOGY/PRINCIPAL FINDINGS: This study demonstrates that a botanical natural product composition (220D-F2) rich in ellagic acid and its derivatives can limit S. aureus biofilm formation to a degree that can be correlated with increased antibiotic susceptibility. The source of this composition is Rubus ulmifolius Schott. (Rosaceae), a plant used in complementary and alternative medicine in southern Italy for the treatment of skin and soft tissue infections. All S. aureus clonal lineages tested exhibited a reduced capacity to form a biofilm at 220D-F2 concentrations ranging from 50-200 ug/mL, which were well below the concentrations required to limit bacterial growth (530 1040 ug/mL). This limitation was therapeutically relevant in that inclusion of 220D-F2 resulted in enhanced susceptibility to the functionally-distinct antibiotics daptomycin, clindamycin and oxacillin. Testing with kidney and liver cell lines also demonstrated a lack of host cell cytotoxicity at concentrations of 220D-F2 required to achieve these effects. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that extract 220D-F2 from the root of Rubus ulmifolius can be used to inhibit S. aureus biofilm formation to a degree that can be correlated with increased antibiotic susceptibility without toxic effects on normal mammalian cells. Hence, 220D-F2 is a strong candidate for development as a botanical drug for use in the prevention and treatment of S. aureus biofilm associated infections. PMID- 22242150 TI - CD44 expression in oro-pharyngeal carcinoma tissues and cell lines. AB - Expression of CD44, a transmembrane hyaluronan-binding glycoprotein, is variably considered to have prognostic significance for different cancers, including oral squamous cell carcinoma. Although unclear at present, tissue-specific expression of particular isoforms of CD44 might underlie the different outcomes in currently available studies. We mined public transcriptomics databases for gene expression data on CD44, and analyzed normal, immortalized and tumour-derived human cell lines for splice variants of CD44 at both the transcript and protein levels. Bioinformatics readouts, from a total of more than 15,000 analyses, implied an increased CD44 expression in head and neck cancer, including increased expression levels relative to many normal and tumor tissue types. Also, meta-analysis of over 260 cell lines and over 4,000 tissue specimens of diverse origins indicated lower CD44 expression levels in cell lines compared to tissue. With minor exceptions, reverse transcribed polymerase chain reaction identified expression of the four main isoforms of CD44 in normal oral keratinocytes, transformed lines termed DT and HaCaT, and a series of paired primary and metastasis-derived cell lines from oral or pharyngeal carcinomas termed HN4/HN12, HN22/HN8 and HN30/HN31. Immunocytochemistry, Western blotting and flow cytometric assessments all confirmed the isoform expression pattern at the protein level. Overall, bioinformatic processing of large numbers of global gene expression analyses demonstrated elevated CD44 expression in head and neck cancer relative to other cancer types, and that the application of standard cell culture protocols might decrease CD44 expression. Additionally, the results show that the many variant CD44 exons are not fundamentally deregulated in a diverse range of cultured normal and transformed keratinocyte lines. PMID- 22242151 TI - Real-time analysis of Drosophila post-embryonic haemocyte behaviour. AB - BACKGROUND: The larval stage of the model organism Drosophila is frequently used to study host-pathogen interactions. During embryogenesis the cellular arm of the immune response, consisting of macrophage-like cells known as plasmatocytes, is extremely motile and functions to phagocytise pathogens and apoptotic bodies, as well as produce extracellular matrix. The cellular branch of the larval (post embryonic) innate immune system consists of three cell types--plasmatocytes, crystal cells and lamellocytes--which are involved in the phagocytosis, encapsulation and melanisation of invading pathogens. Post-embryonic haemocyte motility is poorly understood thus further characterisation is required, for the purpose of standardisation. METHODOLOGY: In order to examine post-embryonic haemocyte cytoskeletal dynamics or migration, the most commonly used system is in vitro cell lines. The current study employs an ex vivo system (an adaptation of in vitro cell incubation using primary cells), in which primary larval or pre pupal haemocytes are isolated for short term analysis, in order to discover various aspects of their behaviour during events requiring cytoskeleton dynamics. SIGNIFICANCE: The ex vivo method allows for real-time analysis and manipulation of primary post-embryonic haemocytes. This technique was used to characterise, and potentially standardised, larval and pre-pupal haemocyte cytoskeleton dynamics, assayed on different extracellular matrices. Using this method it was determined that, while larval haemocytes are unable to migrate, haemocytes recovered from pre-pupae are capable of migration. PMID- 22242152 TI - Identification of fluorescent compounds with non-specific binding property via high throughput live cell microscopy. AB - INTRODUCTION: Compounds exhibiting low non-specific intracellular binding or non stickiness are concomitant with rapid clearing and in high demand for live-cell imaging assays because they allow for intracellular receptor localization with a high signal/noise ratio. The non-stickiness property is particularly important for imaging intracellular receptors due to the equilibria involved. METHOD: Three mammalian cell lines with diverse genetic backgrounds were used to screen a combinatorial fluorescence library via high throughput live cell microscopy for potential ligands with high in- and out-flux properties. The binding properties of ligands identified from the first screen were subsequently validated on plant root hair. A correlative analysis was then performed between each ligand and its corresponding physiochemical and structural properties. RESULTS: The non stickiness property of each ligand was quantified as a function of the temporal uptake and retention on a cell-by-cell basis. Our data shows that (i) mammalian systems can serve as a pre-screening tool for complex plant species that are not amenable to high-throughput imaging; (ii) retention and spatial localization of chemical compounds vary within and between each cell line; and (iii) the structural similarities of compounds can infer their non-specific binding properties. CONCLUSION: We have validated a protocol for identifying chemical compounds with non-specific binding properties that is testable across diverse species. Further analysis reveals an overlap between the non-stickiness property and the structural similarity of compounds. The net result is a more robust screening assay for identifying desirable ligands that can be used to monitor intracellular localization. Several new applications of the screening protocol and results are also presented. PMID- 22242154 TI - A federated design for a neurobiological simulation engine: the CBI federated software architecture. AB - Simulator interoperability and extensibility has become a growing requirement in computational biology. To address this, we have developed a federated software architecture. It is federated by its union of independent disparate systems under a single cohesive view, provides interoperability through its capability to communicate, execute programs, or transfer data among different independent applications, and supports extensibility by enabling simulator expansion or enhancement without the need for major changes to system infrastructure. Historically, simulator interoperability has relied on development of declarative markup languages such as the neuron modeling language NeuroML, while simulator extension typically occurred through modification of existing functionality. The software architecture we describe here allows for both these approaches. However, it is designed to support alternative paradigms of interoperability and extensibility through the provision of logical relationships and defined application programming interfaces. They allow any appropriately configured component or software application to be incorporated into a simulator. The architecture defines independent functional modules that run stand-alone. They are arranged in logical layers that naturally correspond to the occurrence of high-level data (biological concepts) versus low-level data (numerical values) and distinguish data from control functions. The modular nature of the architecture and its independence from a given technology facilitates communication about similar concepts and functions for both users and developers. It provides several advantages for multiple independent contributions to software development. Importantly, these include: (1) Reduction in complexity of individual simulator components when compared to the complexity of a complete simulator, (2) Documentation of individual components in terms of their inputs and outputs, (3) Easy removal or replacement of unnecessary or obsoleted components, (4) Stand-alone testing of components, and (5) Clear delineation of the development scope of new components. PMID- 22242153 TI - GW8510 increases insulin expression in pancreatic alpha cells through activation of p53 transcriptional activity. AB - BACKGROUND: Expression of insulin in terminally differentiated non-beta cell types in the pancreas could be important to treating type-1 diabetes. Previous findings led us to hypothesize involvement of kinase inhibition in induction of insulin expression in pancreatic alpha cells. METHODOLOGY/PRINCIPAL FINDINGS: Alpha (alphaTC1.6) cells and human islets were treated with GW8510 and other small-molecule inhibitors for up to 5 days. Alpha cells were assessed for gene- and protein-expression levels, cell-cycle status, promoter occupancy status by chromatin immunoprecipitation (ChIP), and p53-dependent transcriptional activity. GW8510, a putative CDK2 inhibitor, up-regulated insulin expression in mouse alpha cells and enhanced insulin secretion in dissociated human islets. Gene-expression profiling and gene-set enrichment analysis of GW8510-treated alpha cells suggested up-regulation of the p53 pathway. Accordingly, the compound increased p53 transcriptional activity and expression levels of p53 transcriptional targets. A predicted p53 response element in the promoter region of the mouse Ins2 gene was verified by chromatin immunoprecipitation (ChIP). Further, inhibition of Jun N-terminal kinase (JNK) and p38 kinase activities suppressed insulin induction by GW8510. CONCLUSIONS/SIGNIFICANCE: The induction of Ins2 by GW8510 occurred through p53 in a JNK- and p38-dependent manner. These results implicate p53 activity in modulation of Ins2 expression levels in pancreatic alpha cells, and point to a potential approach toward using small molecules to generate insulin in an alternative cell type. PMID- 22242155 TI - The effect of finasteride and dutasteride on the growth of WPE1-NA22 prostate cancer xenografts in nude mice. AB - BACKGROUND: 5alpha-reductase 1 (5alphaR1) and 5alpha-reductase 2 (5alphaR2) convert testosterone into the more potent androgen dihydrotestosterone. 5alphaR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5alphaR1 and decreased 5alphaR2 expression. Previously, finasteride (5alphaR2 inhibitor) treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5alphaR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5alphaR1 and 5alphaR2 inhibitor) treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation. METHODOLOGY/PRINCIPAL FINDINGS: Sixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet) diet groups. Pre- and post-groups began their treatment diets 1-2 weeks prior to or 3 weeks after subcutaneous injection of 1*105 WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study's conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgen-sensitive. CONCLUSION: The lack of response of WPE1-NA22 prostate cancer cells to androgen treatment may explain the inadequate tumor growth observed. Additional studies are needed to determine whether finasteride and dutasteride are effective in decreasing prostate cancer development/growth. PMID- 22242156 TI - Granger causality analysis of steady-state electroencephalographic signals during propofol-induced anaesthesia. AB - Changes in conscious level have been associated with changes in dynamical integration and segregation among distributed brain regions. Recent theoretical developments emphasize changes in directed functional (i.e., causal) connectivity as reflected in quantities such as 'integrated information' and 'causal density'. Here we develop and illustrate a rigorous methodology for assessing causal connectivity from electroencephalographic (EEG) signals using Granger causality (GC). Our method addresses the challenges of non-stationarity and bias by dividing data into short segments and applying permutation analysis. We apply the method to EEG data obtained from subjects undergoing propofol-induced anaesthesia, with signals source-localized to the anterior and posterior cingulate cortices. We found significant increases in bidirectional GC in most subjects during loss-of-consciousness, especially in the beta and gamma frequency ranges. Corroborating a previous analysis we also found increases in synchrony in these ranges; importantly, the Granger causality analysis showed higher inter subject consistency than the synchrony analysis. Finally, we validate our method using simulated data generated from a model for which GC values can be analytically derived. In summary, our findings advance the methodology of Granger causality analysis of EEG data and carry implications for integrated information and causal density theories of consciousness. PMID- 22242158 TI - Evolutionary determinants of genetic variation in susceptibility to infectious diseases in humans. AB - Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology. PMID- 22242157 TI - GABA expression and regulation by sensory experience in the developing visual system. AB - The developing retinotectal system of the Xenopus laevis tadpole is a model of choice for studying visual experience-dependent circuit maturation in the intact animal. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to play a critical role in the formation of sensory circuits in this preparation, however a comprehensive neuroanatomical study of GABAergic cell distribution in the developing tadpole has not been conducted. We report a detailed description of the spatial expression of GABA immunoreactivity in the Xenopus laevis tadpole brain at two key developmental stages: stage 40/42 around the onset of retinotectal innervation and stage 47 when the retinotectal circuit supports visually-guided behavior. During this period, GABAergic neurons within specific brain structures appeared to redistribute from clusters of neuronal somata to a sparser, more uniform distribution. Furthermore, we found that GABA levels were regulated by recent sensory experience. Both ELISA measurements of GABA concentration and quantitative analysis of GABA immunoreactivity in tissue sections from the optic tectum show that GABA increased in response to a 4 hr period of enhanced visual stimulation in stage 47 tadpoles. These observations reveal a remarkable degree of adaptability of GABAergic neurons in the developing brain, consistent with their key contributions to circuit development and function. PMID- 22242159 TI - Low CXCL13 expression, splenic lymphoid tissue atrophy and germinal center disruption in severe canine visceral leishmaniasis. AB - Visceral leishmaniasis is associated with atrophy and histological disorganization of splenic compartments. In this paper, we compared organized and disorganized splenic lymphoid tissue from dogs naturally infected with Leishmania infantum assessing the size of the white pulp compartments, the distribution of T, B and S100+ dendritic cells, using immunohistochemistry and morphometry and the expression of CCR7 and the cytokines, CXCL13, lymphotoxin (LT)-alpha, LT beta, CCL19, CCL21, TNF-alpha, IL-10, IFN-gamma and TGF-beta, using by real time RT-PCR. The lymphoid follicles and marginal zones were smaller (3.2 and 1.9 times, respectively; Mann-Whitney, P<0.02) in animals with disorganized splenic tissue in comparison to those with organized splenic lymphoid tissue. In spleens with disorganized lymphoid tissue, the numbers of T cells and S100+ dendritic cells were decreased in the follicles, and the numbers of B cells were reduced in both the follicles and marginal zones. CXCL13 mRNA expression was lower in animals with disorganized lymphoid tissue (0.5+/-0.4) compared to those with organized lymphoid tissue (2.7+/-2.9, both relative to 18S expression, P = 0.01). These changes in the spleen were associated with higher frequency of severe disease (7/12) in the animals with disorganized than in animals with organized (2/13, Chi-square, P = 0.01) splenic lymphoid tissue. The data presented herein suggest that natural infection with Leishmania infantum is associated with the impairment of follicular dendritic cells, CXCL13 expression, B cell migration and germinal center formation and associates these changes with severe clinical forms of visceral leishmaniasis. Furthermore the fact that this work uses dogs naturally infected with Leishmania infantum emphasizes the relevance of the data presented herein for the knowledge on the canine and human visceral leishmaniasis. PMID- 22242160 TI - HGF-induced PKCzeta activation increases functional CXCR4 expression in human breast cancer cells. AB - The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCzeta activity. After transfection with PKCzeta-siRNA, the phosphorylation of PKCzeta and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCzeta activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCzeta from cytosol to plasma membrane indicated that HGF was capable of activating PKCzeta, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCzeta, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCzeta. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCzeta-mediated pathway, while suppression of PKCzeta by RNA interference may abrogate cancer cell spreading. PMID- 22242161 TI - Isotropic 3D nuclear morphometry of normal, fibrocystic and malignant breast epithelial cells reveals new structural alterations. AB - BACKGROUND: Grading schemes for breast cancer diagnosis are predominantly based on pathologists' qualitative assessment of altered nuclear structure from 2D brightfield microscopy images. However, cells are three-dimensional (3D) objects with features that are inherently 3D and thus poorly characterized in 2D. Our goal is to quantitatively characterize nuclear structure in 3D, assess its variation with malignancy, and investigate whether such variation correlates with standard nuclear grading criteria. METHODOLOGY: We applied micro-optical computed tomographic imaging and automated 3D nuclear morphometry to quantify and compare morphological variations between human cell lines derived from normal, benign fibrocystic or malignant breast epithelium. To reproduce the appearance and contrast in clinical cytopathology images, we stained cells with hematoxylin and eosin and obtained 3D images of 150 individual stained cells of each cell type at sub-micron, isotropic resolution. Applying volumetric image analyses, we computed 42 3D morphological and textural descriptors of cellular and nuclear structure. PRINCIPAL FINDINGS: We observed four distinct nuclear shape categories, the predominant being a mushroom cap shape. Cell and nuclear volumes increased from normal to fibrocystic to metastatic type, but there was little difference in the volume ratio of nucleus to cytoplasm (N/C ratio) between the lines. Abnormal cell nuclei had more nucleoli, markedly higher density and clumpier chromatin organization compared to normal. Nuclei of non-tumorigenic, fibrocystic cells exhibited larger textural variations than metastatic cell nuclei. At p<0.0025 by ANOVA and Kruskal-Wallis tests, 90% of our computed descriptors statistically differentiated control from abnormal cell populations, but only 69% of these features statistically differentiated the fibrocystic from the metastatic cell populations. CONCLUSIONS: Our results provide a new perspective on nuclear structure variations associated with malignancy and point to the value of automated quantitative 3D nuclear morphometry as an objective tool to enable development of sensitive and specific nuclear grade classification in breast cancer diagnosis. PMID- 22242163 TI - A low-cost GPS GSM/GPRS telemetry system: performance in stationary field tests and preliminary data on wild otters (Lutra lutra). AB - BACKGROUND: Despite the increasing worldwide use of global positioning system (GPS) telemetry in wildlife research, it has never been tested on any freshwater diving animal or in the peculiar conditions of the riparian habitat, despite this latter being one of the most important habitat types for many animal taxa. Moreover, in most cases, the GPS devices used have been commercial and expensive, limiting their use in low-budget projects. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a low-cost, easily constructed GPS GSM/GPRS (Global System for Mobile Communications/General Packet Radio Service) and examined its performance in stationary tests, by assessing the influence of different habitat types, including the riparian, as well as water submersion and certain climatic and environmental variables on GPS fix-success rate and accuracy. We then tested the GPS on wild diving animals, applying it, for the first time, to an otter species (Lutra lutra). The rate of locations acquired during the stationary tests reached 63.2%, with an average location error of 8.94 m (SD = 8.55). GPS performance in riparian habitats was principally affected by water submersion and secondarily by GPS inclination and position within the riverbed. Temporal and spatial correlations of location estimates accounted for some variation in the data sets. GPS-tagged otters also provided accurate locations and an even higher GPS fix success rate (68.2%). CONCLUSIONS/SIGNIFICANCE: Our results suggest that GPS telemetry is reliably applicable to riparian and even diving freshwater animals. They also highlight the need, in GPS wildlife studies, for performing site specific pilot studies on GPS functioning as well as for taking into account eventual spatial and temporal correlation of location estimates. The limited price, small dimensions, and high performance of the device presented here make it a useful and cost-effective tool for studies on otters and other aquatic or terrestrial medium-to-large-sized animals. PMID- 22242162 TI - Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults. AB - BACKGROUND: DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques. METHODOLOGY/PRINCIPAL FINDINGS: We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response. CONCLUSIONS/SIGNIFICANCE: This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity. TRIAL REGISTRATION: Clinicaltrials.gov NCT00115960 NCT00111605. PMID- 22242164 TI - Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1). AB - 17beta-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17beta-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17beta-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17beta-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17beta-HSD1 inhibitors bearing a benzothiazole scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC50 values in the nanomolar range for the transformation of E1 to E2 by 17beta-HSD1, reasonable selectivity against 17beta-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17beta-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17beta-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17beta-HSD1 inhibitors for the development of potential therapeutics. PMID- 22242166 TI - Elevated aspartate and alanine aminotransferase levels and natural death among patients with methamphetamine dependence. AB - BACKGROUND: Methamphetamine is one of the fastest growing illicit drugs worldwide, causing multiple organ damage and excessive natural deaths. The authors aimed to identify potential laboratory indices and clinical characteristics associated with natural death through a two-phase study. METHODS: Methamphetamine-dependent patients (n = 1,254) admitted to a psychiatric center in Taiwan between 1990 and 2007 were linked with a national mortality database for causes of death. Forty-eight subjects died of natural causes, and were defined as the case subjects. A time-efficient sex- and age-matched nested case control study derived from the cohort was conducted first to explore the potential factors associated with natural death through a time-consuming standardized review of medical records. Then the identified potential factors were evaluated in the whole cohort to validate the findings. RESULTS: In phase I, several potential factors associated with natural death were identified, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), comorbid alcohol use disorder, and the prescription of antipsychotic drugs. In phase II, these factors were confirmed in the whole cohort using survival analysis. For the characteristics at the latest hospital admission, Cox proportional hazards models showed that the adjusted hazard ratios for natural death were 6.75 (p<0.001) in the group with markedly elevated AST (>80 U/L) and 2.66 (p<0.05) in the group with mildly elevated AST (40-80 U/L), with reference to the control group (<40 U/L). As for ALT, the adjusted hazard ratios were 5.41 (p<0.001), and 1.44 (p>0.05). Comorbid alcohol use disorder was associated with an increased risk of natural death, whereas administration of antipsychotic drugs was not associated with lowered risk. CONCLUSIONS: This study highlights the necessity of intensive follow-up for those with elevated AST and ALT levels and comorbid alcohol use disorder for preventing excessive natural deaths. PMID- 22242165 TI - Arcuate fasciculus abnormalities and their relationship with psychotic symptoms in schizophrenia. AB - Disruption of fronto-temporal connections involving the arcuate fasciculus (AF) may underlie language processing anomalies and psychotic features such as auditory hallucinations in schizophrenia. No study to date has specifically investigated abnormalities of white matter integrity at particular loci along the AF as well as its regional lateralization in schizophrenia. We examined white matter changes (fractional anisotropy (FA), axial diffusivity (AD), asymmetry indices) along the whole extent of the AF and their relationship with psychotic symptoms in 32 males with schizophrenia and 44 healthy males. Large deformation diffeomorphic metric mapping and Fiber Assignment Continuous Tracking were employed to characterize FA and AD along the geometric curve of the AF. Our results showed that patients with schizophrenia had lower FA in the frontal aspects of the left AF compared with healthy controls. Greater left FA and AD lateralization in the temporal segment of AF were associated with more severe positive psychotic symptoms such as delusions and hallucinations in patients with schizophrenia. Disruption of white matter integrity of the left frontal AF and accentuation of normal left greater than right asymmetry of FA/AD in the temporal AF further support the notion of aberrant fronto-temporal connectivity in schizophrenia. AF pathology can affect corollary discharge of neural signals from frontal speech/motor initiation areas to suppress activity of auditory cortex that may influence psychotic phenomena such as auditory hallucinations and facilitate elaboration of delusional content. PMID- 22242167 TI - AHR2 mutant reveals functional diversity of aryl hydrocarbon receptors in zebrafish. AB - The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2(hu3335)), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2(hu3335) zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2(hu3335) functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses. PMID- 22242168 TI - Pre-power-stroke cross-bridges contribute to force transients during imposed shortening in isolated muscle fibers. AB - When skeletal muscles are activated and mechanically shortened, the force that is produced by the muscle fibers decreases in two phases, marked by two changes in slope (P1 and P2) that happen at specific lengths (L1 and L2). We tested the hypothesis that these force transients are determined by the amount of myosin cross-bridges attached to actin and by changes in cross-bridge strain due to a changing fraction of cross-bridges in the pre-power-stroke state. Three separate experiments were performed, using skinned muscle fibers that were isolated and subsequently (i) activated at different Ca2+ concentrations (pCa2+ 4.5, 5.0, 5.5, 6.0) (n = 13), (ii) activated in the presence of blebbistatin (n = 16), and (iii) activated in the presence of blebbistatin at varying velocities (n = 5). In all experiments, a ramp shortening was imposed (amplitude 10%L0, velocity 1 L0*sarcomere length (SL)*s-1), from an initial SL of 2.5 um (except by the third group, in which velocities ranged from 0.125 to 2.0 L0*s-1). The values of P1, P2, L1, and L2 did not change with Ca2+ concentrations. Blebbistatin decreased P1, and it did not alter P2, L1, and L2. We developed a mathematical cross-bridge model comprising a load-dependent power-stroke transition and a pre-power-stroke cross-bridge state. The P1 and P2 critical points as well as the critical lengths L1 and L2 were explained qualitatively by the model, and the effects of blebbistatin inhibition on P1 were also predicted. Furthermore, the results of the model suggest that the mechanism by which blebbistatin inhibits force is by interfering with the closing of the myosin upper binding cleft, biasing cross bridges into a pre-power-stroke state. PMID- 22242169 TI - Superior analgesic effect of an active distraction versus pleasant unfamiliar sounds and music: the influence of emotion and cognitive style. AB - Listening to music has been found to reduce acute and chronic pain. The underlying mechanisms are poorly understood; however, emotion and cognitive mechanisms have been suggested to influence the analgesic effect of music. In this study we investigated the influence of familiarity, emotional and cognitive features, and cognitive style on music-induced analgesia. Forty-eight healthy participants were divided into three groups (empathizers, systemizers and balanced) and received acute pain induced by heat while listening to different sounds. Participants listened to unfamiliar Mozart music rated with high valence and low arousal, unfamiliar environmental sounds with similar valence and arousal as the music, an active distraction task (mental arithmetic) and a control, and rated the pain. Data showed that the active distraction led to significantly less pain than did the music or sounds. Both unfamiliar music and sounds reduced pain significantly when compared to the control condition; however, music was no more effective than sound to reduce pain. Furthermore, we found correlations between pain and emotion ratings. Finally, systemizers reported less pain during the mental arithmetic compared with the other two groups. These findings suggest that familiarity may be key in the influence of the cognitive and emotional mechanisms of music-induced analgesia, and that cognitive styles may influence pain perception. PMID- 22242171 TI - Testing in mice the hypothesis that melanin is protective in malaria infections. AB - Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria. PMID- 22242170 TI - Impedance responses reveal beta2-adrenergic receptor signaling pluridimensionality and allow classification of ligands with distinct signaling profiles. AB - The discovery that drugs targeting a single G protein-coupled receptor (GPCR) can differentially modulate distinct subsets of the receptor signaling repertoire has created a challenge for drug discovery at these important therapeutic targets. Here, we demonstrate that a single label-free assay based on cellular impedance provides a real-time integration of multiple signaling events engaged upon GPCR activation. Stimulation of the beta2-adrenergic receptor (beta2AR) in living cells with the prototypical agonist isoproterenol generated a complex, multi featured impedance response over time. Selective pharmacological inhibition of specific arms of the beta2AR signaling network revealed the differential contribution of G(s)-, G(i)- and Gbetagamma-dependent signaling events, including activation of the canonical cAMP and ERK1/2 pathways, to specific components of the impedance response. Further dissection revealed the essential role of intracellular Ca2+ in the impedance response and led to the discovery of a novel beta2AR-promoted Ca2+ mobilization event. Recognizing that impedance responses provide an integrative assessment of ligand activity, we screened a collection of beta-adrenergic ligands to determine if differences in the signaling repertoire engaged by compounds would lead to distinct impedance signatures. An unsupervised clustering analysis of the impedance responses revealed the existence of 5 distinct compound classes, revealing a richer signaling texture than previously recognized for this receptor. Taken together, these data indicate that the pluridimensionality of GPCR signaling can be captured using integrative approaches to provide a comprehensive readout of drug activity. PMID- 22242172 TI - Quantifying the dynamics of coupled networks of switches and oscillators. AB - Complex network dynamics have been analyzed with models of systems of coupled switches or systems of coupled oscillators. However, many complex systems are composed of components with diverse dynamics whose interactions drive the system's evolution. We, therefore, introduce a new modeling framework that describes the dynamics of networks composed of both oscillators and switches. Both oscillator synchronization and switch stability are preserved in these heterogeneous, coupled networks. Furthermore, this model recapitulates the qualitative dynamics for the yeast cell cycle consistent with the hypothesized dynamics resulting from decomposition of the regulatory network into dynamic motifs. Introducing feedback into the cell-cycle network induces qualitative dynamics analogous to limitless replicative potential that is a hallmark of cancer. As a result, the proposed model of switch and oscillator coupling provides the ability to incorporate mechanisms that underlie the synchronized stimulus response ubiquitous in biochemical systems. PMID- 22242173 TI - Recognizing intimate partner violence in primary care: Western Cape, South Africa. AB - INTRODUCTION: Interpersonal violence in South Africa is the second highest contributor to the burden of disease after HIV/AIDS and 62% is estimated to be from intimate partner violence (IPV). This study aimed to evaluate how women experiencing IPV present in primary care, how often IPV is recognized by health care practitioners and what other diagnoses are made. METHODS: At two urban and three rural community health centres, health practitioners were trained to screen all women for IPV over a period of up to 8 weeks. Medical records of 114 thus identified women were then examined and their reasons for encounter (RFE) and diagnoses over the previous 2-years were coded using the International Classification of Primary Care. Three focus group interviews were held with the practitioners and interviews with the facility managers to explore their experience of screening. RESULTS: IPV was previously recognized in 11 women (9.6%). Women presented with a variety of RFE that should raise the index of suspicion for IPV- headache, request for psychiatric medication, sleep disturbance, tiredness, assault, feeling anxious and depressed. Depression was the commonest diagnosis. Interviews identified key issues that prevented health practitioners from screening. CONCLUSION: This study demonstrated that recognition of women with IPV is very low in South African primary care and adds useful new information on how women present to ambulatory health services. These findings offer key cues that can be used to improve selective case finding for IPV in resource-poor settings. Universal screening was not supported by this study. PMID- 22242174 TI - High-throughput functional microRNAs profiling by recombinant AAV-based microRNA sensor arrays. AB - BACKGROUND: microRNAs (miRNAs) are small and non-coding RNAs which play critical roles in physiological and pathological processes. A number of methods have been established to detect and quantify miRNA expression. However, method for high throughput miRNA function detection is still lacking. PRINCIPAL FINDINGS: We describe an adeno-associated virus (AAV) vector-based microRNA (miRNA) sensor (Asensor) array for high-throughput functional miRNA profiling. Each Asensor contains a Gaussia luciferase (Gluc) and a firefly luciferase (Fluc) expression cassette to sense functional miRNA and to serve as an internal control respectively. Using this array, we acquired functional profiles of 115 miRNAs for 12 cell lines and found "functional miRNA signatures" for several specific cell lines. The activities of specific miRNAs including the let-7 family, miR-17-92 cluster, miR-221, and miR-222 in HEK 293 cells were compared with their expression levels determined by quantitative reverse transcriptase polymerase chain reaction (QRT-PCR). We also demonstrate two other practical applications of the array, including a comparison of the miRNA activity between HEK293 and HEK293T cells and the ability to monitor miRNA activity changes in K562 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). CONCLUSIONS/SIGNIFICANCE: Our approach has potential applications in the identification of cell types, the characterization of biological and pathological processes, and the evaluation of responses to interventions. PMID- 22242175 TI - Human PAPS synthase isoforms are dynamically regulated enzymes with access to nucleus and cytoplasm. AB - In higher eukaryotes, PAPS synthases are the only enzymes producing the essential sulphate-donor 3'-phospho-adenosine-5'-phosphosulphate (PAPS). Recently, PAPS synthases have been associated with several genetic diseases and retroviral infection. To improve our understanding of their pathobiological functions, we analysed the intracellular localisation of the two human PAPS synthases, PAPSS1 and PAPSS2. For both enzymes, we observed pronounced heterogeneity in their subcellular localisation. PAPSS1 was predominantly nuclear, whereas PAPSS2 localised mainly within the cytoplasm. Treatment with the nuclear export inhibitor leptomycin B had little effect on their localisation. However, a mutagenesis screen revealed an Arg-Arg motif at the kinase interface exhibiting export activity. Notably, both isoforms contain a conserved N-terminal basic Lys Lys-Xaa-Lys motif indispensable for their nuclear localisation. This nuclear localisation signal was more efficient in PAPSS1 than in PAPSS2. The activities of the identified localisation signals were confirmed by microinjection studies. Collectively, we describe unusual localisation signals of both PAPS synthase isoforms, mobile enzymes capable of executing their function in the cytoplasm as well as in the nucleus. PMID- 22242176 TI - Lower-order effects adjustment in quantitative traits model-based multifactor dimensionality reduction. AB - Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to account for important lower-order genetic effects. These may hamper the identification of genuine epistasis. If lower-order genetic effects contribute to the genetic variance of a trait, identified statistical interactions may simply be due to a signal boost of these effects. In this study, we restrict attention to quantitative traits and bi allelic SNPs as genetic markers. Moreover, our interaction study focuses on 2-way SNP-SNP interactions. Via simulations, we assess the performance of different corrective measures for lower-order genetic effects in Model-Based Multifactor Dimensionality Reduction epistasis detection, using additive and co-dominant coding schemes. Performance is evaluated in terms of power and familywise error rate. Our simulations indicate that empirical power estimates are reduced with correction of lower-order effects, likewise familywise error rates. Easy-to-use automatic SNP selection procedures, SNP selection based on "top" findings, or SNP selection based on p-value criterion for interesting main effects result in reduced power but also almost zero false positive rates. Always accounting for main effects in the SNP-SNP pair under investigation during Model-Based Multifactor Dimensionality Reduction analysis adequately controls false positive epistasis findings. This is particularly true when adopting a co-dominant corrective coding scheme. In conclusion, automatic search procedures to identify lower-order effects to correct for during epistasis screening should be avoided. The same is true for procedures that adjust for lower-order effects prior to Model-Based Multifactor Dimensionality Reduction and involve using residuals as the new trait. We advocate using "on-the-fly" lower-order effects adjusting when screening for SNP-SNP interactions using Model-Based Multifactor Dimensionality Reduction analysis. PMID- 22242177 TI - Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. AB - Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes. We developed a specific multi-gene survival model for the Proneural subtype in the TCGA (the Cancer Genome Atlas) discovery set which we have validated in the TCGA validation set. In addition, we have performed network analysis in the form of Bayesian Network discovery and Ingenuity Pathway Analysis to further dissect the underlying biology of this gene signature in the etiology of GBM. We theorize that the strong predictive value of the IFN/STAT1 gene signature in the Proneural subtype may be due to chemotherapy and/or radiation resistance induced through prolonged constitutive signaling of these genes during the course of the illness. The results of this study have implications both for better prediction models for survival outcome in GBM and for improved understanding of the underlying subtype specific molecular mechanisms for GBM tumor progression and treatment response. PMID- 22242178 TI - Circulating micro-RNAs as potential blood-based markers for early stage breast cancer detection. AB - INTRODUCTION: MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development. MiRNAs offer great potential as biomarkers for cancer detection due to their remarkable stability in blood and their characteristic expression in many different diseases. We investigated whether microarray-based miRNA profiling on whole blood could discriminate between early stage breast cancer patients and healthy controls. METHODS: We performed microarray-based miRNA profiling on whole blood of 48 early stage breast cancer patients at diagnosis along with 57 healthy individuals as controls. This was followed by a real-time semi-quantitative Polymerase Chain Reaction (RT-qPCR) validation in a separate cohort of 24 early stage breast cancer patients from a breast cancer screening unit and 24 age matched controls using two differentially expressed miRNAs (miR-202, miR-718). RESULTS: Using the significance level of p<0.05, we found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down regulated miRNAs in our microarray panel of 1100 miRNAs and miRNA star sequences could be detected. A set of 240 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 78.8%, and a sensitivity of 92.5%, as well as an accuracy of 85.6%. Two miRNAs were validated by RT-qPCR in an independent cohort. The relative fold changes of the RT-qPCR validation were in line with the microarray data for both miRNAs, and statistically significant differences in miRNA expression were found for miR-202. CONCLUSIONS: MiRNA profiling in whole blood has potential as a novel method for early stage breast cancer detection, but there are still challenges that need to be addressed to establish these new biomarkers in clinical use. PMID- 22242179 TI - RDR2 partially antagonizes the production of RDR6-dependent siRNA in sense transgene-mediated PTGS. AB - BACKGROUND: RNA-DEPENDENT RNA POLYMERASE6 (RDR6) and SUPPRESSOR of GENE SILENCING 3 (SGS3) are required for DNA methylation and post-transcriptional gene silencing (PTGS) mediated by 21-nt siRNAs produced by sense transgenes (S-PTGS). In contrast, RDR2, but not RDR6, is required for DNA methylation and TGS mediated by 24-nt siRNAs, and for cell-to-cell spreading of IR-PTGS mediated by 21-nt siRNAs produced by inverted repeat transgenes under the control of a phloem-specific promoter. PRINCIPAL FINDINGS: In this study, we examined the role of RDR2 and RDR6 in S-PTGS. Unlike RDR6, RDR2 is not required for DNA methylation of transgenes subjected to S-PTGS. RDR6 is essential for the production of siRNAs by transgenes subjected to S-PTGS, but RDR2 also contributes to the production of transgene siRNAs when RDR6 is present because rdr2 mutations reduce transgene siRNA accumulation. However, the siRNAs produced via RDR2 likely are counteractive in wildtype plants because impairement of RDR2 increases S-PTGS efficiency at a transgenic locus that triggers limited silencing, and accelerates S-PTGS at a transgenic locus that triggers efficient silencing. CONCLUSIONS/SIGNIFICANCE: These results suggest that RDR2 and RDR6 compete for RNA substrates produced by transgenes subjected to S-PTGS. RDR2 partially antagonizes RDR6 because RDR2 action likely results in the production of counteractive siRNA. As a result, S-PTGS efficiency is increased in rdr2 mutants. PMID- 22242180 TI - Conformational altered p53 as an early marker of oxidative stress in Alzheimer's disease. AB - In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named "unfolded p53", was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients. PMID- 22242181 TI - The homeobox gene Gsx2 regulates the self-renewal and differentiation of neural stem cells and the cell fate of postnatal progenitors. AB - The Genetic screened homeobox 2 (Gsx2) transcription factor is required for the development of olfactory bulb (OB) and striatal neurons, and for the regional specification of the embryonic telencephalon. Although Gsx2 is expressed abundantly by progenitor cells in the ventral telencephalon, its precise function in the generation of neurons from neural stem cells (NSCs) is not clear. Similarly, the role of Gsx2 in regulating the self-renewal and multipotentiality of NSCs has been little explored. Using retroviral vectors to express Gsx2, we have studied the effect of Gsx2 on the growth of NSCs isolated from the OB and ganglionic eminences (GE), as well as its influence on the proliferation and cell fate of progenitors in the postnatal mouse OB. Expression of Gsx2 reduces proliferation and the self-renewal capacity of NSCs, without significantly affecting cell death. Furthermore, Gsx2 overexpression decreases the differentiation of NSCs into neurons and glia, and it maintains the cells that do not differentiate as cycling progenitors. These effects were stronger in GESCs than in OBSCs, indicating that the actions of Gsx2 are cell-dependent. In vivo, Gsx2 produces a decrease in the number of Pax6+ cells and doublecortin+ neuroblasts, and an increase in Olig2+ cells. In summary, our findings show that Gsx2 inhibits the ability of NSCs to proliferate and self-renew, as well as the capacity of NSC-derived progenitors to differentiate, suggesting that this transcription factor regulates the quiescent and undifferentiated state of NSCs and progenitors. Furthermore, our data indicate that Gsx2 negatively regulates neurogenesis from postnatal progenitor cells. PMID- 22242182 TI - Dichotomy of tyrosine hydroxylase and dopamine regulation between somatodendritic and terminal field areas of nigrostriatal and mesoaccumbens pathways. AB - Measures of dopamine-regulating proteins in somatodendritic regions are often used only as static indicators of neuron viability, overlooking the possible impact of somatodendritic dopamine (DA) signaling on behavior and the potential autonomy of DA regulation between somatodendritic and terminal field compartments. DA reuptake capacity is less in somatodendritic regions, possibly placing a greater burden on de novo DA biosynthesis within this compartment to maintain DA signaling. Therefore, regulation of tyrosine hydroxylase (TH) activity may be particularly critical for somatodendritic DA signaling. Phosphorylation of TH at ser31 or ser40 can increase activity, but their impact on L-DOPA biosynthesis in vivo is unknown. Thus, determining their relationship with L-DOPA tissue content could reveal a mechanism by which DA signaling is normally maintained. In Brown-Norway Fischer 344 F1 hybrid rats, we quantified TH phosphorylation versus L-DOPA accumulation. After inhibition of aromatic acid decarboxylase, L-DOPA tissue content per recovered TH protein was greatest in NAc, matched by differences in ser31, but not ser40, phosphorylation. The L-DOPA per catecholamine and DA turnover ratios were significantly greater in SN and VTA, suggesting greater reliance on de novo DA biosynthesis therein. These compartmental differences reflected an overall autonomy of DA regulation, as seen by decreased DA content in SN and VTA, but not in striatum or NAc, following short-term DA biosynthesis inhibition from local infusion of the TH inhibitor alpha-methyl-p-tyrosine, as well as in the long-term process of aging. Such data suggest ser31 phosphorylation plays a significant role in regulating TH activity in vivo, particularly in somatodendritic regions, which may have a greater reliance on de novo DA biosynthesis. Thus, to the extent that somatodendritic DA release affects behavior, TH regulation in the midbrain may be critical for DA bioavailability to influence behavior. PMID- 22242183 TI - Retail price and point of sale display of tobacco in the UK: a descriptive study of small retailers. AB - BACKGROUND: Since the implementation of the 2002 Tobacco Advertising and Promotion Act, point-of-sale (PoS) tobacco displays are one of few remaining means of communication between the tobacco industry and customers in the UK. This study aimed to explore the characteristics of tobacco displays in a UK city, and particularly to assess the tobacco prices and promotional offers, types and pack sizes on display. METHODS: Digital pictures of PoS displays were taken in 117 small retail shops in Nottingham in mid 2010. Data were analysed using Windows Photo Gallery software and SPSS version 16. RESULTS: Just over half (52%) of cigarette packs on display were packs of 20, and 43% packs of 10. Cigarette prices differed substantially between brands, ranging from L4.19 to L6.85 for 20 packs, and from L2.12 to L3.59 for 10-packs. Forty four percent of cigarette packs and 40% of RYO (Roll-Your-Own) tobacco pouches, almost exclusively lower priced brands, were displayed with a pricemark, implying a promotional price offer. Eighty percent of 20-pack cigarette brand or brand variants on sale were priced below the EU-defined Most Popular Price Category (MPPC) for the UK in 2010; 45% were priced below the Weighted Average Price (WAP), which replaced the MPPC in 2011. CONCLUSION: PoS displays communicate value by displaying a high proportion of lower cost brands, and smaller and hence lower-cost packs, and by displaying price discounts on packs. The MPPC substantially overestimated the prices at which most 20-cigarette packs were available. Removal of PoS displays will prevent this means of price marketing but our study also suggests that minimum pricing of 20-pack cigarettes, prohibition of sale of cigarettes in packs less than 20, and plain packaging to prevent pricemarking are necessary if price is to be used effectively as a tobacco control measure. PMID- 22242184 TI - The function of anal fin egg-spots in the cichlid fish Astatotilapia burtoni. AB - Color and pigmentation patterns of animals are often targets of sexual selection because of their role in communication. Although conspicuous male traits are typically implicated with intersexual selection, there are examples where sex specific displays play a role in an intrasexual context, e.g. when they serve as signals for aggression level and/or status. Here, we focus on the function of a conspicuous male ornament in the most species-rich tribe of cichlid fishes, the haplochromines. A characteristic feature of these ca. 1500 species are so-called egg-spots in form of ovoid markings on the anal fins of males, which are made up of carotenoid based pigment cells. It has long been assumed that these yellow, orange or reddish egg-spots play an important role in the courtship and spawning behavior of these maternal mouth-brooding fishes by mimicking the eggs of a conspecific female. The exact function of egg-spots remains unknown, however, and there are several hypotheses about their mode of action. To uncover the function of this cichlid-specific male ornament, we used female mate choice experiments and a male aggression test in the haplochromine species Astatotilapia burtoni. We manipulated the number and arrangement of egg-spots on the anal fins of males, or removed them entirely, and tested (1) female preference with visual contact only using egg-traps, (2) female preference with free contact using paternity testing with microsatellites and (3) male aggression. We found that females did not prefer males with many egg-spots over males with fewer egg-spots and that females tended to prefer males without egg-spots over males with egg-spots. Importantly, males without egg-spots sired clutches with the same fertilization rate as males with egg-spots. In male aggression trials, however, males with fewer egg-spots received significantly more attacks, suggesting that egg-spots are an important signal in intrasexual communication. PMID- 22242185 TI - Trafficking-deficient G572R-hERG and E637K-hERG activate stress and clearance pathways in endoplasmic reticulum. AB - BACKGROUND: Long QT syndrome type 2 (LQT2) is the second most common type of all long QT syndromes. It is well-known that trafficking deficient mutant human ether a-go-go-related gene (hERG) proteins are often involved in LQT2. Cells respond to misfolded and trafficking-deficient proteins by eliciting the unfolded protein response (UPR) and Activating Transcription Factor (ATF6) has been identified as a key regulator of the mammalian UPR. In this study, we investigated the role of ER chaperone proteins (Calnexin and Calreticulin) in the processing of G572R-hERG and E637K-hERG mutant proteins. METHODS: pcDNA3-WT-hERG, pcDNA3-G572R-hERG and pcDNA3-E637K-hERG plasmids were transfected into U2OS and HEK293 cells. Confocal microscopy and western blotting were used to analyze subcellular localization and protein expression. Interaction between WT or mutant hERGs and Calnexin/Calreticulin was tested by coimmunoprecipitation. To assess the role of the ubiquitin proteasome pathway in the degradation of mutant hERG proteins, transfected HEK293 cells were treated with proteasome inhibitors and their effects on the steady state protein levels of WT and mutant hERGs were examined. CONCLUSION: Our results showed that levels of core-glycosylated immature forms of G572R-hERG and E637K-hERG in association with Calnexin and Calreticulin were higher than that in WT-hERG. Both mutant hERG proteins could activate the UPR by upregulating levels of active ATF6. Furthermore, proteasome inhibition increased the levels of core-glycosylated immature forms of WT and mutant hERGs. In addition, interaction between mutant hERGs and Calnexin/Calreticulin was stronger after proteasome inhibition, compared to WT-hERG. These results suggest that trafficking-deficient G572R-hERG and E637K-hERG mutant proteins can activate ER stress pathways and are targeted to the proteasome for degradation. Calnexin and Calreticulin play important roles in these processes. PMID- 22242186 TI - Type II heat-labile enterotoxins from 50 diverse Escherichia coli isolates belong almost exclusively to the LT-IIc family and may be prophage encoded. AB - Some enterotoxigenic Escherichia coli (ETEC) produce a type II heat-labile enterotoxin (LT-II) that activates adenylate cyclase in susceptible cells but is not neutralized by antisera against cholera toxin or type I heat-labile enterotoxin (LT-I). LT-I variants encoded by plasmids in ETEC from humans and pigs have amino acid sequences that are >= 95% identical. In contrast, LT-II toxins are chromosomally encoded and are much more diverse. Early studies characterized LT-IIa and LT-IIb variants, but a novel LT-IIc was reported recently. Here we characterized the LT-II encoding loci from 48 additional ETEC isolates. Two encoded LT-IIa, none encoded LT-IIb, and 46 encoded highly related variants of LT-IIc. Phylogenetic analysis indicated that the predicted LT-IIc toxins encoded by these loci could be assigned to 6 subgroups. The loci corresponding to individual toxins within each subgroup had DNA sequences that were more than 99% identical. The LT-IIc subgroups appear to have arisen by multiple recombinational events between progenitor loci encoding LT-IIc1- and LT IIc3-like variants. All loci from representative isolates encoding the LT-IIa, LT IIb, and each subgroup of LT-IIc enterotoxins are preceded by highly-related genes that are between 80 and 93% identical to predicted phage lysozyme genes. DNA sequences immediately following the B genes differ considerably between toxin subgroups, but all are most closely related to genomic sequences found in predicted prophages. Together these data suggest that the LT-II loci are inserted into lambdoid type prophages that may or may not be infectious. These findings raise the possibility that production of LT-II enterotoxins by ETEC may be determined by phage conversion and may be activated by induction of prophage, in a manner similar to control of production of Shiga-like toxins by converting phages in isolates of enterohemmorhagic E. coli. PMID- 22242187 TI - Genome-wide analyses of Nkx2-1 binding to transcriptional target genes uncover novel regulatory patterns conserved in lung development and tumors. AB - The homeodomain transcription factor Nkx2-1 is essential for normal lung development and homeostasis. In lung tumors, it is considered a lineage survival oncogene and prognostic factor depending on its expression levels. The target genes directly bound by Nkx2-1, that could be the primary effectors of its functions in the different cellular contexts where it is expressed, are mostly unknown. In embryonic day 11.5 (E11.5) mouse lung, epithelial cells expressing Nkx2-1 are predominantly expanding, and in E19.5 prenatal lungs, Nkx2-1 expressing cells are predominantly differentiating in preparation for birth. To evaluate Nkx2-1 regulated networks in these two cell contexts, we analyzed genome wide binding of Nkx2-1 to DNA regulatory regions by chromatin immunoprecipitation followed by tiling array analysis, and intersected these data to expression data sets. We further determined expression patterns of Nkx2-1 developmental target genes in human lung tumors and correlated their expression levels to that of endogenous NKX2-1. In these studies we uncovered differential Nkx2-1 regulated networks in early and late lung development, and a direct function of Nkx2-1 in regulation of the cell cycle by controlling the expression of proliferation related genes. New targets, validated in Nkx2-1 shRNA transduced cell lines, include E2f3, Cyclin B1, Cyclin B2, and c-Met. Expression levels of Nkx2-1 direct target genes identified in mouse development significantly correlate or anti correlate to the levels of endogenous NKX2-1 in a dosage-dependent manner in multiple human lung tumor expression data sets, supporting alternative roles for Nkx2-1 as a transcriptional activator or repressor, and direct regulator of cell cycle progression in development and tumors. PMID- 22242188 TI - Combinations of histone modifications mark exon inclusion levels. AB - Splicing is a complex process regulated by sequence at the classical splice sites and other motifs in exons and introns with an enhancing or silencing effect. In addition, specific histone modifications on nucleosomes positioned over the exons have been shown to correlate both positively and negatively with exon expression. Here, we trained a model of "IF ... THEN ..." rules to predict exon inclusion levels in a transcript from histone modification patterns. Furthermore, we showed that combinations of histone modifications, in particular those residing on nucleosomes preceding or succeeding the exon, are better predictors of exon inclusion levels than single modifications. The resulting model was evaluated with cross validation and had an average accuracy of 72% for 27% of the exons, which demonstrates that epigenetic signals substantially mark alternative splicing. PMID- 22242189 TI - Mucin depleted foci, colonic preneoplastic lesions lacking Muc2, show up regulation of Tlr2 but not bacterial infiltration. AB - Mucin depleted foci (MDF) are precancerous lesions of the colon in carcinogen treated rodents and humans at high risk. Since MDF show signs of inflammation we hypothesized that the defective mucous production would expose them to the risk of being penetrated by intestinal bacteria, which can be sensed by Toll-like receptors (Tlrs) and activate inflammatory pathways. To verify this hypothesis we tested the expression of 84 genes coding for Tlrs and associated pathways using RT-qPCR in MDF (n = 7) from 1,2-dimethylhydrazine (DMH)-treated rats. Among the 84 tested genes, 26 were differentially expressed in MDF with 5 genes significantly up-regulated and 21 down-regulated when compared to the normal mucosa. Tlr2, as well as other downstream genes (Map4k4, Hspd1, Irak1, Ube2n), was significantly up-regulated. Among the genes regulating the NFkB pathway, only Map4k4 was significantly up-regulated, while 19 genes were not varied and 6 were down-regulated. Tlr2 protein was weakly expressed both in normal mucosa and MDF. To determine whether inflammation observed in MDF could be caused by bacteria contacting or infiltrating crypts, we performed fluorescence in situ hybridization (FISH) experiments with a rRNA universal bacterial probe. None of the 21 MDF tested, showed bacteria inside the crypts, while among the colonic tumors (n = 15), only one had very few bacteria on the surface and on the surrounding normal mucosa. In conclusion, the up-regulation of Tlr2 in MDF, suggests a link between this receptor and carcinogenesis, possibly related to a defective barrier function of these lesions. The data of FISH experiments do not support the hypothesis that inflammation in MDF and tumors is stimulated by bacterial infiltration. PMID- 22242191 TI - Ultrasound biomicroscopy for longitudinal studies of carotid plaque development in mice: validation with histological endpoints. AB - Atherosclerosis is responsible for the death of thousands of Americans each year. The carotid constriction model of plaque development has recently been presented as a model for unstable plaque formation in mice. In this study we 1) validate ultrasound biomicroscopy (UBM) for the determination of carotid plaque size, percent stenosis, and plaque development in live animals, 2) determine the sensitivity of UBM in detecting changes in blood flow induced by carotid constriction and 3) test whether plaque formation can be predicted from blood flow parameters measured by UBM. Carotid plaques were induced by surgical constriction in Apo E-/- mice. Arteries were imaged bi-weekly by UBM, at which time PW-Doppler measurements of proximal blood flow, as well as plaque length and percent stenosis were determined. Histology was performed 9 weeks post surgery. When compared to whole mount post-mortem measurements, UBM accurately reported carotid plaque length. Percent stenosis, based on transverse B-mode UBM measurements, correlated well with that calculated from histological sections. PW Doppler revealed that constriction reduced maximum systolic velocity (v(max)) and duration of the systolic velocity peak (t(s)/t(t)). Pre-plaque (2 week post surgery) PW-Doppler parameters (v(max) and t(s)/t(t)) were correlated with plaque length at 9 weeks, and were predictive of plaque formation. Correlation of initiating PW-Doppler parameters (v(max) and t(s)/t(t)) with resulting plaque length established the degree of flow disturbance required for subsequent plaque development and demonstrated its power for predicting plaque development. PMID- 22242190 TI - Deletion of the RNaseIII enzyme dicer in thyroid follicular cells causes hypothyroidism with signs of neoplastic alterations. AB - Micro-RNAs (miRNAs) are small non-coding RNAs that regulate gene expression, mainly at mRNA post-transcriptional level. Functional maturation of most miRNAs requires processing of the primary transcript by Dicer, an RNaseIII-type enzyme. To date, the importance of miRNA function for normal organogenesis has been demonstrated in several mouse models of tissue-specific Dicer inactivation. However, the role of miRNAs in thyroid development has not yet been addressed. For the present study, we generated mouse models in which Dicer expression has been inactivated at two different stages of thyroid development in thyroid follicular cells. Regardless of the time of Dicer invalidation, the early stages of thyroid organogenesis, preceding folliculogenesis, were unaffected by the loss of small RNAs, with a bilobate gland in place. Nevertheless, Dicer mutant mice were severely hypothyroid and died soon after weaning unless they were substituted with T4. A conspicuous follicular disorganization was observed in Dicer mutant thyroids together with a strong down regulation of Nis expression. With increasing age, the thyroid tissue showed characteristics of neoplastic alterations as suggested by a marked proliferation of follicular cells and an ongoing de-differentiation in the center of the thyroid gland, with a loss of Pax8, FoxE1, Nis and Tpo expression. Together, our data show that loss of miRNA maturation due to Dicer inactivation severely disturbs functional thyroid differentiation. This suggests that miRNAs are mandatory to fine-tune the expression of thyroid specific genes and to maintain thyroid tissue homeostasis. PMID- 22242192 TI - Promoter polymorphism G-6A, which modulates angiotensinogen gene expression, is associated with non-familial sick sinus syndrome. AB - BACKGROUND: It is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non familial SSS. METHODS: In this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA). RESULTS: Association study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58 5.22, P = 0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54-4.57, P = 0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P<0.01). CONCLUSION: G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility. PMID- 22242194 TI - Renal function declines more in tenofovir- than abacavir-based antiretroviral therapy in low-body weight treatment-naive patients with HIV infection. AB - OBJECTIVE: To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naive patients with HIV infection. DESIGN: We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART. METHODS: The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model. RESULTS: The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152-2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339-3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (<=60 kg: adjusted HR = 2.771; 95%CI, 1.494-5.139; p = 0.001) (61-68 kg: adjusted HR = 1.908; 95%CI, 0.764-4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318-3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003). CONCLUSION: The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir. PMID- 22242193 TI - 1,25-dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells while maintaining their multipotent capacity. AB - 1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, beta-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence- and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging. PMID- 22242195 TI - Mirroring intentional forgetting in a shared-goal learning situation. AB - BACKGROUND: Intentional forgetting refers to the surprising phenomenon that we can forget previously successfully encoded memories if we are instructed to do so. Here, we show that participants cannot only intentionally forget episodic memories but they can also mirror the "forgetting performance" of an observed model. METHODOLOGY/PRINCIPAL FINDINGS: In four experiments a participant observed a model who took part in a memory experiment. In Experiment 1 and 2 observers saw a movie about the experiment, whereas in Experiment 3 and 4 the observers and the models took part together in a real laboratory experiment. The observed memory experiment was a directed forgetting experiment where the models learned two lists of items and were instructed either to forget or to remember the first list. In Experiment 1 and 3 observers were instructed to simply observe the experiment ("simple observation" instruction). In Experiment 2 and 4, observers received instructions aimed to induce the same learning goal for the observers and the models ("observation with goal-sharing" instruction). A directed forgetting effect (the reliably lower recall of to-be-forgotten items) emerged only when models received the "observation with goal-sharing" instruction (P<.001 in Experiment 2, and P<.05 in Experiment 4), and it was absent when observers received the "simple observation" instruction (P>.1 in Experiment 1 and 3). CONCLUSION: If people observe another person with the same intention to learn, and see that this person is instructed to forget previously studied information, then they will produce the same intentional forgetting effect as the person they observed. This seems to be a an important aspect of human learning: if we can understand the goal of an observed person and this is in line with our behavioural goals then our learning performance will mirror the learning performance of the model. PMID- 22242196 TI - Monitoring the mind: the neurocognitive correlates of metamemory. AB - Memory performance in everyday life is often far from perfect and therefore needs to be monitored and controlled by metamemory evaluations, such as judgments of learning (JOLs). JOLs support monitoring for goal-directed modification of learning. Behavioral studies suggested retrieval processes as providing a basis for JOLs. Previous functional imaging research on JOLs found a dissociation between processes underlying memory prediction, located in the medial prefrontal cortex (mPFC), and actual encoding success, located in the medial temporal lobe. However, JOL-specific neural correlates could not be identified unequivocally, since JOLs were given simultaneously with encoding. Here, we aimed to identify the neurocognitive basis of JOLs, i.e., the cognitive processes and neural correlates of JOL, separate from initial encoding. Using functional magnetic resonance imaging (fMRI), we implemented a face-name paired associative design. In general, we found that actual memory success was associated with increased brain activation of the hippocampi bilaterally, whereas predicted memory success was accompanied by increased activation in mPFC, orbital frontal and anterior cingulate cortices. Masking brain activation during predicted memory success with activation during retrieval success revealed BOLD increases of the mPFC. Our findings indicate that JOLs actually incorporate retrieval processes. PMID- 22242197 TI - Dynamic shift from CD85j/ILT-2 to NKG2D NK receptor expression pattern on human decidual NK during the first trimester of pregnancy. AB - During the first trimester of human pregnancy, Natural Killer (NK) cells of the maternal uterine mucosa (e.g. decidua) have a unique phenotype and are involved in crucial physiological processes during pregnancy. We investigated whether modifications of the NK receptor repertoire occur during the first trimester of pregnancy. We found significantly decreased expression of KIR2DL1/S1 and KIR2DL2/L3/S2 receptors, NKp30 and NKp44 activatory receptors, and the CD85j (ILT 2) inhibitory receptor. We also observed significantly increased expression of the NKG2D activatory receptor at the decidual NK cell surface. By flow cytometry, we further highlighted an evolution of NK subsets between 8 and 12 weeks of gestation, with a shift from the KIR2DL1/S1+/KIR2DL2/L3/S2+ subset towards the double negative subset, coupled with a decrease of the CD85j+/NKG2D- subset in favour of the CD85j-/NKG2D+ subset. Furthermore, cell surface expression of NK receptor ligands, including CD85j and NKG2D ligands, has been characterized by flow cytometry on decidual immune CD14+ and CD3+ cells. HLA-G, the high affinity ligand of CD85j, was detected on both cell types. In contrast, NKG2D ligands ULBP 2 ULBP-3 and MICA/B were not expressed on CD14+ and CD3+ cells, however a variable expression of ULBP-1 was observed. The ligand expression of KIR2DL1/S1 and KIR2DL2/L3/S2 was also analyzed: the HLA-C molecule was expressed at a low level on some CD14+ cells whereas it was not detected on CD3+ cell surface. NK receptor ligands are known to be also expressed on the invading placental trophoblast cells. Thus, the phenotypic evolutions of decidual NK cells described in this present study may preserve their activation/inhibition balance during the first trimester of pregnancy. PMID- 22242198 TI - Automatic portion estimation and visual refinement in mobile dietary assessment. AB - As concern for obesity grows, the need for automated and accurate methods to monitor nutrient intake becomes essential as dietary intake provides a valuable basis for managing dietary imbalance. Moreover, as mobile devices with built-in cameras have become ubiquitous, one potential means of monitoring dietary intake is photographing meals using mobile devices and having an automatic estimate of the nutrient contents returned. One of the challenging problems of the image based dietary assessment is the accurate estimation of food portion size from a photograph taken with a mobile digital camera. In this work, we describe a method to automatically calculate portion size of a variety of foods through volume estimation using an image. These "portion volumes" utilize camera parameter estimation and model reconstruction to determine the volume of food items, from which nutritional content is then extrapolated. In this paper, we describe our initial results of accuracy evaluation using real and simulated meal images and demonstrate the potential of our approach. PMID- 22242199 TI - Genetic factors of autoimmune thyroid diseases in Japanese. AB - Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by immune response to self-thyroid antigens and affect approximately 2-5% of the general population. Genetic susceptibility in combination with external factors, such as smoking, viral/bacterial infection, and chemicals, is believed to initiate the autoimmune response against thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITDs. Various techniques have been employed to identify genes contributing to the etiology of AITDs, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked to AITDs, and, in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to GD and HT and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. Known AITD-susceptibility genes are classified into three groups: HLA genes, non-HLA immune-regulatory genes (e.g., CTLA-4, PTPN22, and CD40), and thyroid-specific genes (e.g., TSHR and Tg). In this paper, we will summarize the latest findings on AITD susceptibility genes in Japanese. PMID- 22242200 TI - The dynamics of visual art dialogues: experiences to be used in hospital settings with visual art enrichment. AB - Objectives. Given that hospitals have environmental enrichment with paintings and visual art arrangement, it would be meaningful to develop and document how hospital art could be used by health professionals. Methods. The study was undertaken at an art site in Sweden. During 1-hour sessions, participants (n = 20) get together in an art gallery every second week five times. Results. According to the participants a new value was perceived. From qualitative analyses, three themes appear: raise association, mentally present, and door opener. In addition 72% of the participants reported makes me happy and gives energy and inspiration, and 52% reported that dialogues increase inspiration, make you involved, and stimulate curiosity. Conclusion. The present study supported the view that visual art dialogue could be used by health care professionals in a structured manner and that meaningful art stimulation, related to a person's experiences, could be of importance for the patients. Implementing art dialogues in hospital settings could be a fruitful working tool for nurses, a complementary manner of patient communication. PMID- 22242201 TI - Venous thrombosis in multiple sclerosis patients after high-dose intravenous methylprednisolone: the preventive effect of enoxaparin. AB - Aim. This study was designed to examine the possible role of high-dose intravenous methylprednisolone (IVMP) in the development of venous thrombosis (VT). The cerebral one anecdotally had been reported in patients with relapsing remitting multiple sclerosis (RRMS) in acute attacks and the possible preventive role of enoxaparin. Material and Methods. From a pool of 520 patients, 388 patients with definite RRMS who fulfilled entry characteristics were selected and randomly received either a 5-day course of daily 1 gr IVMP or the aforementioned plus 5 days of daily subcutaneous 40 units of enoxaparin according to a predefined protocol. Results. Mean age, gender ratio, mean relapse rate, and EDSS were similar in both groups of patients (P > 0.05). Finally, 366 patients remained in the study. Of 188 patients treated with IVMP with 855 relapses, 5 developed VT (0.37% per patient per year and 0.58% per each course of IVMP) within 3 to 15 days of starting therapy. None of the 178 patients who experienced 809 relapses who received IVMP plus enoxaparin developed such complications. Conclusion. The study implies that high-dose IVMP in MS exacerbation may increase the risk of VT and prophylactic anticoagulant treatment in this setting is warranted. PMID- 22242202 TI - Short-Term Relapse Quantitation as a Fully Surrogate Endpoint for Long-Term Sustained Progression of Disability in RRMS Patients Treated with Natalizumab. AB - Time to sustained worsening in the expanded disability status scale as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect. Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test. This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year. PMID- 22242203 TI - Lymphoscintigraphy defines new lymphatic pathways from cutaneous melanoma site: clinical implications and surgical management. AB - Sentinel lymph node biopsy is commonly applied as staging procedure of regional lymph nodes in patients with cutaneous melanoma. Dynamic lymphoscintigraphy defines the lymphatic pathways from a primary melanoma site and allows to identify the node receiving lymphatic drainage from the primary tumor, which is the sentinel lymph node. In rare cases, lymphoscintigraphy shows sites of lymphatic drainage in nonclassical basins never described in the past when lymphatic drainage was considered only according to the anatomical proximity of the tumor primary site. These peculiar sentinel nodes, so-called "uncommon/interval" nodes, must be surgically removed because they may contain micrometastatic disease and may be the only site of nodal involvement. PMID- 22242204 TI - Comparison between F-Fluorodeoxyglucose Positron Emission Tomography and Sentinel Lymph Node Biopsy for Regional Lymph Nodal Staging in Patients with Melanoma: A Review of the Literature. AB - Aim. to compare (18)F-Fluorodeoxyglucose positron emission tomography (FDG-PET) to sentinel lymph node biopsy (SLNB) for regional lymph nodal staging in patients with melanoma. Methods. We performed a literature review discussing original articles which compared FDG-PET to SLNB for regional lymph nodal staging in patients with melanoma. Results and Conclusions. There is consensus in the literature that FDG-PET cannot replace SLNB for regional lymph nodal staging in patients with melanoma. PMID- 22242205 TI - Use of clinical disease activity index score for assessment of disease activity in rheumatoid arthritis patients: an Indian experience. AB - Introduction. Serial objective assessment of disease activity in Rheumatoid Arthritis (RA) is imperative to achieve remission. The CDAI score appears more practical than DAS-28 in routine assessment of disease activity in RA patients. Objective. To evaluate correlation and agreement of the DAS-28 with CDAI in RA patients. Methods. A total of 200 patients of RA were evaluated by DAS-28 and CDAI and divided into 4 categories of disease activity i.e. Group-I: Remission (DAS-28 < 2.6; CDAI < 2.8), Group II: Low disease activity (DAS-28 = 2.6-3.2; CDAI = 2.8-10), Group III: Moderate disease activity (DAS-28 = 3.2- 5.1; CDAI = 10-22), Group IV: High disease activity (DAS-28 > 5.1; CDAI > 22). DAS-28 was compared to CDAI in each group using spearman correlation coefficient and kappa statistics. Results. Group I shows mean DAS-28 of 1.99 +/- 0.38; mean CDAI of 0.90 +/- 0.65, (P = 0.0001). Group II shows mean DAS-28 of 3.04 +/- 0.17; mean CDAI of 6.45 +/- 02.35, (P = 0.0001). Group III shows mean DAS-28 of 4.25 +/- 0.58; mean CDAI of 16.46 +/- 3.31 (P < 0.0001). Group IV shows mean DAS-28 of 6.38 +/- 0.87; mean CDAI of 38.56 +/- 11.88 (P < 0.0001). Kappa statistics (kappa) of the above comparison was 0.533. Conclusion. Our findings indicate that CDAI-a composite score that employs only clinical variables and omits assessment of Acute Phase Reactant (APR), has moderate to good correlation (Kappa value = 0.533) to DAS-28 for assessment of disease activity in RA patients. PMID- 22242206 TI - An in vitro study of differentiation of hematopoietic cells to endothelial cells. AB - Bone-marrow-derived endothelial progenitor cells (BM-EPCs) contribute to postnatal neovascularization and therefore are of great interest for cell therapies to treat ischemic diseases. However, their origin and characteristics are still in controversy. In this paper, we identified the origin/lineage of the BM-EPCs that were isolated from bone marrow mononuclear cells and differentiated with the induction of bone-marrow endothelial-cellconditioned medium (ECCM). BM EPCs were characterized in terms of phenotype, lineage potential, and their functional properties. Endothelial cell colonies derived from BM-EPC were cultured with ECCM for 3 months. Cultured EPC colony cells expressed endothelial cell markers and formed the capillary-like network in vitro. EPC colony cells expressed differential proliferative capacity; some of the colonies exhibited a high proliferative potential (HPP) capacity up to 20 population doublings. More importantly, these HPP-EPCs expressed hematopoietic marker CD45, exhibited endocytic activities, and preserved some of the myeloid cell activity. In addition, the HPP-EPCs secrete various growth factors including VEGF and GM-CSF into the culture medium. The results demonstrate that these EPCs were primarily derived from hematopoietic origin of early precursor cells and maintained high proliferative potential capacity, a feature with a significant potential in the application of cell therapy in ischemic diseases. PMID- 22242207 TI - Biosurveillance: a review and update. AB - Since the terrorist attacks and anthrax release in 2001, almost $32 billion has been allocated to biodefense and biosurveillance in the USA alone. Surveillance in health care refers to the continual systematic collection, analysis, interpretation, and dissemination of data. When attempting to detect agents of bioterrorism, surveillance can occur in several ways. Syndromic surveillance occurs by monitoring clinical manifestations of certain illnesses. Laboratory surveillance occurs by looking for certain markers or laboratory data, and environmental surveillance is the process by which the ambient air or environment is continually sampled for the presence of biological agents. This paper focuses on the ways by which we detect bioterrorism agents and the effectiveness of these systems. PMID- 22242208 TI - Evaluation of Drug Utilization Patterns during Initial Treatment in the Emergency Room: A Retroprospective Pharmacoepidemiological Study. AB - Background. We assessed the prescribing trends, average number of drugs per prescription, and cost per prescription during the initial contact of the patient with the physician in emergency room. Methods. This retro-prospective study was conducted over a period of six months. Medical records of two hundred patients were reviewed for prescribing patterns. Results. 52 different types of drugs (996 drugs) were prescribed in total 200 prescriptions during the mean time spent in emergency room of 2.8 +/- 1.4 hours. The average number of drugs per prescription was 4.2 +/- 1.2. 95% of drugs were prescribed by trade name. Average drugs cost per prescription was 784 +/- 134 rupees (17USD). Conclusion. Polypharmacy remains the main form of irrational prescribing. Prescribing patterns of drugs were knowledge based rather than WHO criteria for rational use of drugs. PMID- 22242209 TI - No Prognostic Impact of p53 and P-Glycoprotein Expression in Patients with Diffuse Large B-Cell Lymphoma. AB - The aim of this study was to determine the clinical significances of p53 and p glycoprotein (P-gp) expression on outcome predictors for patients with DLBC. We assessed the immunohistochemical expression of p53 and P-gp using formalin-fixed, paraffin-embedded specimens in 108 patients diagnosed with de novo DLBC. A high expression of p53 was found in 53.7% of the patients. No expression of P-gp was demonstrated in any of the specimens. There were no significant differences in the complete remission (CR) rate (P = 0.79), overall survival (OS) (P = 0.73), or disease-free survival (DFS) (P = 31) between the p53-positive and p53-negative groups. The final model from multivariate analysis that revealed poor performance status was significantly associated with CR (P < 0.001) and OS (P < 0.001). Moreover, the advanced stage was a significant predictor of DFS (P = 0.03). This study demonstrated no impact of the expression of p53 on either response or survival rates. PMID- 22242210 TI - Cardiovascular disease-related lifestyle factors and longevity. PMID- 22242211 TI - Imaging in acute coronary syndrome. PMID- 22242212 TI - Hypertension control and cardiometabolic risk: a regional perspective. AB - Background. We investigated the association between blood pressure control and common cardiometabolic risk factors from a global and regional perspective. Methods. In the present analysis of a large cross-sectional i-SEARCH study, 17.092 outpatients receiving antihypertensive treatment were included in 26 countries. According to clinical guidelines for the management of arterial hypertension, patients were classified based on the level of seated systolic/diastolic blood pressure (SBP/DBP). Uncontrolled hypertension was defined as SBP/DBP >=140/90 mmHg for non-diabetics, and >=130/80 mmHg for diabetics. Results. Overall, mean age was 63.1 years, 52.8% were male, and mean BMI was 28.9 kg/m(2). Mean SBP/DBP was 148.9/87.0 mmHg, and 76.3% of patients had uncontrolled hypertension. Diabetes was present in 29.1% with mean HbA1c of 6.8%. Mean LDL-cholesterol was 3.2 mmol/L, HDL-cholesterol 1.3 mmol/L, and triglycerides 1.8 mmol/L; 49.0% had hyperlipidemia. Patients with uncontrolled hypertension had a higher BMI (29.4 versus 28.6 kg/m(2)), LDL-cholesterol (3.4 versus 3.0 mmol/L), triglycerides (1.9 versus 1.7 mmol/L), and HbA1c (6.8 versus 6.7%) than those with controlled blood pressure (P < 0.0001 for all parameters). Conclusions. Among outpatients treated for arterial hypertension, three quarters had uncontrolled blood pressure. Elevated SBP/DBP and uncontrolled hypertension were associated with increasing BMI, LDL-cholesterol, triglycerides, and HbA1c, both globally and regionally. PMID- 22242214 TI - [Health behavior in diabetics in Uganda]. PMID- 22242213 TI - Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia. AB - Recent data have provided molecular evidence of high levels of endoplasmic reticulum stress in non-laboured placentas from cases of early-onset pre eclampsia. Endoplasmic reticulum stress is intricately linked to oxidative stress, and the two often share the same aetiology. In the case of pre-eclampsia this is likely to be placental malperfusion, secondary to deficient conversion of the spiral arteries. Endoplasmic reticulum stress activates a number of signalling pathways aimed at restoring homeostasis, but if these attempts fail then the apoptotic machinery may be activated. The potential consequences for placental development and function are numerous and diverse. Inhibition of protein synthesis results in lower levels of many kinases, growth factors and regulatory proteins involved in cell cycle control, and experiments in vitro reveal that endoplasmic reticulum stress slows cell proliferation. Chronic, low levels of stress during the second and third trimesters may therefore result in a growth restricted phenotype. Higher levels of endoplasmic reticulum stress lead to activation of pro-inflammatory pathways, a feature of pre-eclampsia that may contribute to maternal endothelial cell activation. These findings emphasise the complexity of cellular responses to stress, and the need to approach these in a holistic fashion when considering therapeutic interventions. PMID- 22242215 TI - Retraction of the article "Prevention of post-operative infection in spine surgery by wound irrigation with a solution of povidone-iodine and hydrogen peroxide". PMID- 22242216 TI - Northern Ireland disease surveillance, July to September 2011. PMID- 22242217 TI - Retraction. Human T-cell leukemia virus type I Tax down-regulates the expression of phosphatidylinositol 3,4,5-trisphosphate inositol phosphatases via the NF kappaB pathway. PMID- 22242218 TI - Orienting the demixion of a diblock copolymer using 193 nm interferometric lithography for the controlled deposition of nanoparticles. AB - DUV interferometric lithography and diblock copolymer self-organization have successfully been combined to provide a simple and highly collective nanopatterning technique enabling the organization of nanoparticles over several orders of magnitude, from nanometre to millimetre. The nanostructural changes at the surface of the polymer film after thermal annealing have been monitored by AFM and the process parameters optimized for obtaining a long-range organization of the lamellar domains. In particular, the impact of the annealing conditions and geometric parameters of the substrate patterns have been investigated. The nanopatterns resulting from the lamellar demixion of (PS-b-MMA) were used for a controlled deposition of nanoparticles. The affinity of the hydrophobic particles for the PS block was demonstrated, opening new doors towards the preparation of high-density arrays of nanoparticles with potential applications in data storage. PMID- 22242220 TI - Image of the month: herpes viral infection. PMID- 22242219 TI - Bridge funding: How to stay afloat. PMID- 22242221 TI - Image of the month: the three Ms of herpetic infection. PMID- 22242222 TI - Image of the month: Meckel's diverticulum in a 57-year-old man. PMID- 22242223 TI - Why the 'reason for encounter' should be incorporated in the analysis of outcome of care. PMID- 22242224 TI - Working as a high performing team. PMID- 22242225 TI - [N-acetylcysteine (NAC) inhibited pulmonary fibrosis in acute respiratory distress syndrome (ARDS)]. AB - OBJECTIVE: To investigate the effect of NAC treatment on lipopolysaccharide (LPS) treated human embryonic lung fibroblasts (HELF), in regard to oxidant injury and changes in indexes related to pulmonary fibrosis in ARDS. METHODS: Four groups of cultured HELF were treated with: vehicle, LPS(1 pg/ml), NAC (1 mmol/L)+LPS (1 pg/ml) and dexamethasone (DEX, 1 pmol/L)+LPS (1 pg/ml) for 24 hours. The content of collagen and the gamma-glutamylcysteinylglycine (GSH) in the cells were determined. RESULTS: As compared to the control group, the collagen content (pg/mg: 78.97+1.79 vs. 72.90+1.70)and GSH content (pg/mg: 23. 27 0. 92 vs. 26. 34+ 0. 83) in LPS group were significantly (P<0. 05) higher and lower, respectively; NAC and DEX both suppressed the effect of LPS on collagen content (72. 23 +/- 1.35, 73.64 1.89 vs. 78.97 + 1.79); and GSH content (26.52 0.62, 25.85 +/- 0.60 vs. 23.27+ 0.92)significantly (P < 0. 05 or P < 0. 01) in the treated cells. No significant difference was found between NAC+LPS and DEX+LPS group, either in the content of collagen or GSH. CONCLUSION: NAC can inhibit oxidant injury and pulmonary fibrosis in ARDS. PMID- 22242226 TI - TRPC6 in podocytes: questions and commentary on the article by Jiang et al., 'Over-expressing transient receptor potential cation channel 6 in podocytes induces cytoskeleton rearrangement through increases of intracellular Ca21 and RhoA activation'. PMID- 22242227 TI - Extension of statutory period for compensation for certain disabilities due to undiagnosed illnesses and medically unexplained chronic multi-symptom illnesses. Interim final rule. AB - The Department of Veterans Affairs (VA) is issuing this interim final rule to amend its adjudication regulation regarding compensation for disabilities suffered by veterans who served in the Southwest Asia Theater of Operations during the Persian Gulf War. This amendment is necessary to extend the period during which disabilities associated with undiagnosed illnesses and medically unexplained chronic multi-symptom illnesses must become manifest in order for a veteran to be eligible for compensation. PMID- 22242228 TI - Medical devices; ovarian adnexal mass assessment score test system; labeling; black box restrictions. Final rule. AB - The Food and Drug Administration (FDA) is amending the regulation classifying ovarian adnexal mass assessment score test systems to restrict these devices so that a prescribed warning statement that addresses a risk identified in the special controls guidance document must be in a black box and must appear in all labeling, advertising, and promotional material. The black box warning mitigates the risk to health associated with off-label use as a screening test, stand-alone diagnostic test, or as a test to determine whether or not to proceed with surgery. PMID- 22242229 TI - Revisions to labeling requirements for blood and blood components, including source plasma. Final rule. AB - The Food and Drug Administration (FDA) is revising the labeling requirements for blood and blood components intended for use in transfusion or for further manufacture by combining, simplifying, and updating specific regulations applicable to labeling and circulars of information. These requirements will facilitate the use of a labeling system using machine-readable information that would be acceptable as a replacement for the ''ABC Codabar'' system for the labeling of blood and blood components. FDA is taking this action as a part of its efforts to comprehensively review and, as necessary, revise its regulations, policies, guidances, and procedures related to the regulation of blood and blood components. This final rule is intended to help ensure the continued safety of the blood supply and facilitate consistency in labeling. PMID- 22242230 TI - Findings of research misconduct. PMID- 22242231 TI - Findings of research misconduct. PMID- 22242232 TI - Tribal child welfare. Interim final rule. AB - The Administration for Children and Families (ACF) is issuing this interim final rule to implement statutory provisions related to the Tribal title IV-E program. Effective October 1, 2009, section 479B(b) of the Social Security Act (the Act) authorizes direct Federal funding of Indian Tribes, Tribal organizations, and Tribal consortia that choose to operate a foster care, adoption assistance and, at Tribal option, a kinship guardianship assistance program under title IV-E of the Act. The Fostering Connections to Success and Increasing Adoptions Act of 2008 requires that ACF issue interim final regulations which address procedures to ensure that a transfer of responsibility for the placement and care of a child under a State title IV-E plan to a Tribal title IV-E plan occurs in a manner that does not affect the child's eligibility for title IV-E benefits or medical assistance under title XIX of the Act (Medicaid) and such services or payments; in-kind expenditures from third-party sources for the Tribal share of administration and training expenditures under title IV-E; and other provisions to carry out the Tribal-related amendments to title IV-E. This interim final rule includes these provisions and technical amendments necessary to implement a Tribal title IV-E program. PMID- 22242233 TI - Meeting of the Strategic Advisory Group of Experts on Immunization, November 2011 - conclusions and recommendations. PMID- 22242234 TI - Integrated preventive chemotherapy for neglected tropical diseases: estimation of the number of interventions required and delivered, 2009-2010. PMID- 22242235 TI - [Clinical study on dissociative disorders--the diagnosis and therapy]. PMID- 22242236 TI - [100 Years of the Japanese Journal of Psychiatry and Neurology--the year of 1911- cerebellopontine angle tumor]. PMID- 22242237 TI - [Present condition of electroconvulsive therapy in Japan--result of the field research by the committee for the Japanese Society of Psychiatry and Neurology]. PMID- 22242238 TI - [On plasticity of the brain]. PMID- 22242239 TI - [Palliative care. Allow active euthanasia when there is no hope of cure]. PMID- 22242240 TI - [New light over infectious endocarditis. Vascularization of heart valves can play a role in the pathogenesis]. PMID- 22242241 TI - [Primary health care a possible instance for millions with hazardous drinking habits]. PMID- 22242242 TI - [Less alcohol and more drugs trend of the time]. PMID- 22242243 TI - [Good effect of drug therapy against alcoholism]. PMID- 22242244 TI - [Biomarkers can detect early-stage alcohol problems]. PMID- 22242245 TI - [Treatment of alcohol dependence: time for non-specialists to take over]. PMID- 22242246 TI - [Drugs of abuse testing safer and safer and more complete]. PMID- 22242247 TI - [Pharmacological treatment of amphetamine dependence still on unsafe basis]. PMID- 22242248 TI - [Methadone and buprenorphine--attractive on the street and outside treatment programs]. PMID- 22242249 TI - [STRIDA in the fight against il(legal) Internet drugs]. PMID- 22242250 TI - [Ask all about exposure to violence]. PMID- 22242251 TI - [Alike are treated alike in palliative care too]. PMID- 22242252 TI - [EDS and the hypermobility syndrome. Common cause of reduced work capacity]. PMID- 22242253 TI - [Computer use and internet time in children]. PMID- 22242254 TI - [Psychopathology and achievement motivation in adolescents with pathological internet use]. AB - In Germany, the internet is used by 69.4% of the population or 49 million people, and 100% of adolescents (between 14 to 19 years of age) spend time in the internet at least occasionally. An excessive use of the internet may lead to negative psychosocial consequences and changes in behaviour. This phenomenon is named "pathological internet use". Until now, there are only few studies published that investigate mental well being in German adolescents with pathological internet use. 16 participants of an outpatient treatment program for pathological internet use and 16 healthy adolescents were compared on self reported levels of psychopathology (SPS-J), achievement motivation (FLM 7-13) and personal experience of attention deficit (FEDA). There were no differences in age, gender, intelligence or education between the two groups. Pathological internet users exhibited significantly elevated scores on self-esteem problems and the summary score of the SPS-J and significantly lower scores on FLM 7-13 dimensions "achievement ambition" and "perseverance/diligence" compared to controls. The results revealed that adolescents with pathological internet use report a higher level of psychopathology and lower levels of achievement motivation and drive. These findings should be taken into account when conceptualizing treatments for pathological internet users. PMID- 22242255 TI - [Correlates of cyberbullying and bullying--first results of a self-report study]. AB - If Li's assumption (2007) that the new phenomenon of cyberbullying is nothing else but "old wine in new old bottles" is true, cyberbullies (and cybervictims) will also be traditional bullies (and victims). Further aims of this study were to measure the prevalence of (cyber-bullying and to investigate the similarities and differences between both forms of bullying. An online-survey utilised the CAPI method with a sample of 838 students (11-17 years) who participated in whole classes. The data suggests that Li (2007) is right in principle, but there are also some important differences to traditional bullying: (1) cyberbullying seems to "level" the differences between gender; (2) cybervictims seem to be more ready to "strike back". PMID- 22242256 TI - [Violent video games and aggression: long-term impact and selection effects]. AB - This study applied social-cognitive models of aggression in order to examine relations between video game use and aggressive tendencies and biases in social information processing. To this end, 499 secondary school students (aged 12-16) completed a survey on two occasions one year apart. Hierarchical regression analysis probed media effects and selection effects and included relevant contextual variables (parental monitoring of media consumption, impulsivity, and victimization). Results revealed that it was not the consumption of violent video games but rather an uncontrolled pattern of video game use that was associated with increasing aggressive tendencies. This increase was partly mediated by a hostile attribution bias in social information processing. The influence of aggressive tendencies on later video game consumption was also examined (selection path). Adolescents with aggressive traits intensified their video game behavior only in terms of their uncontrolled video game use. This was found even after controlling for sensation seeking and parental media control. PMID- 22242257 TI - ["Treasure Hunt"--a cognitive-behavioural computer game]. AB - The development of video games promoting health related behaviour is increasing. This holds not only for chronic diseases like asthma and diabetes, but also for the field of child psychotherapy. At the Department of Child and Adolescent Psychiatry of Zurich University, the video game Treasure Hunt was developed to support psychotherapeutic treatment of children between eight and thirteen years of age. Treasure Hunt does not replace the therapist but supports treatment by offering attractive electronic work assignments. The scope of this article is an overview on health games for children and a description of Treasure Hunt. After the explanation of its therapeutic potentials, an evaluation based on questionnaires for therapists and children will be presented. 124 therapists answered a questionnaire on their impression of the game three months after download. 41 therapists were willing to participate in the further evaluation and sent questionnaires of 200 children with whom Treasure Hunt had been used. A limitation of these data is that a positive bias can not be excluded, as therapists with a positive attitude towards psychotherapeutic computer games were more likely to answer the questionnaire. 118 therapists (95.2%) considered Treasure Hunt a useful tool in child psychotherapy. 197 children (98.5%) report being satisfied with the use of the game during treatment. Treasure Hunt was predominantly used for the age group it is designed for and both, by very experienced and by young therapists. Eleven diagnostic categories reflect a broader range of indications than expected. PMID- 22242258 TI - [Hemodynamic crises from the standpoint of synergetics]. AB - This paper deals with the causes and mechanisms of exacerbation of cardiovascular disorders. The clinical aspects of this phenomenon and associated hemodymanic crisis are discussed in the light of the synergetic theory. Studies with the use of biodynamic models of exacerbation revealed pathways of transition of the disease from remission to unbalanced equilibrium. Resonance biodynamics and its role in alteration of the character of the disease are considered. The common signs of different pathogenetic variants of hemodynamic crises are described. PMID- 22242259 TI - [Diverticula in the digestive tract and their complications]. AB - This review concerns diverticula in different parts of the digestive tract (oesophagus, stomach, duoudenum, jejunum, ileum (including Meckel" diverticulum), and large intestine). Their origin, pathogenesis, and frequency are discussed, different forms of diverticula and diverticulosis are described with reference to major complications (diverticulitis, peridiverticulitis, ulceration, bleeding, perforation, obstruction, abscess, peritonitis, fistulas, etc.). Methods of clinical, instrumental and laboratory diagnostics and their informative value are considered along with indications and contraindications for surgical treatment. A new classification of diverticula and their complications is proposed. Debatable terminological problems are discussed. PMID- 22242260 TI - [Post-transplantational diabetes mellitus]. AB - Newly developed diabetes and impaired glucose tolerance are frequent post transplantation metabolic complications. In most reports, the incidence of newly diagnosed diabetes in such patients varies from 10 to 26%. They are at high risk of cardiovascular complications, infections, graft rejection, and impaired survival compared with recipients having normal blood glucose level. Some of the above risk factors are common for the general population (age, excess body weight, familial diabetes, afroamerican ethnicity, arterial hypertension, dyslipidemia). Specific risk factors characteristic of the post-transplantation period include the use of glucocorticoids and imunodepressants (especially tacrolimus and mTOR inhibitors) as well as infections (HCV and possibly cytomegalovirus). Screening for diabetes and evaluation of risk factors are recommended to all patients before and after transplantation. Patients of high risk groups should be treated using non-diabetogenic protocols of immunosuppression. Achievement of normoglycemia, control of lipid levels and arterial pressure, screening for diabetes complications are indispensable components of the treatment aimed at the improvement of clinical outcome in the patients developing diabetes after organ transplantation. PMID- 22242261 TI - [Oxidative stress and possibilities of its correction by melatonin]. AB - Oxidative stress plays an important role in pathogensis of many metabolic disorders; therefore, effective antioxidant therapy should be an essential component of their treatment. Meanwhile, the meta-analysis of 68 randomized trials do not confirm this inference. The reason is peroxynitrite rather than oxygen (as previously believed) plays the key part in the damage of cell structure. Peroxynitrite is generated in the interaction between nitric oxide and superoxide anion radical leading to lipid peroxidation, protein oxidation, and DNA damage. This mechanism involves activation of several transcription factors responsible for cytokine-induced chronic inflammation. Classical antioxidants do not neutralize peroxinitrite effects. Melatonin is a multifunctional indolamine that has marked beneficial effect on peroxinitrite-induced cellular toxicity confirmed in numerous experimental and clinical studies. It may be used alone or in combination with other therapeutic agents to inhibit nitrooxidative stress. PMID- 22242262 TI - [The role of N-terminal fragment of brain natriuretic peptide in patients with chronic cardiac insufficiency of ischemic genesis]. AB - The role of N-terminal pro-brain natriuretic peptide (NT-PBP) was analysed in 69 patients with chronic cardiac insufficiency (CCI) of ischemic genesis who developed CCI symptoms after myocardial infarction with the Q-wave on ECG and signed the informed consent. The NT-PBP level was determined in an immunoenzyme assay using Biomedica kits (Slovakia). Statistical treatment of the data was performed with the help of Statistica 7.0 program. The NT-PBP level positively correlated (p < 0.05) with patients' age (r = 0.35) and BMI (r = 0.38), heart rate (r = 0.55), CCI functional class (r = 0.46), CRP level (r = 0.55), left auricle end systolic size (r = 0.53), left ventricle end diastolic size (r = 0.40), left ventricle end diastolic and systolic end volume (r = 0.39 and 0.38), systoloc pressure in the pulmonary artery (r = 0.62), left ventricular myocardial mass (r = 0.58). NT-PBP negatively correlated (p < 0.05) with ejection fraction (r = -0.54). Based on NGT-PBP median, the patients were divided into 2 groups. Group 1 (n = 35) and group 2 (n = 34) comprised patients with NT-PBP levels below and above 120 pmol/ml respectively. Patients of group 2 were significantly older than in group 1 (p = 0.04), had a larger number of previous myocardial infarctions (p = 0.01), more frequent manifestations of CCI (p = 0.04), higher heart rate (p = 0.003) and CRP level (p = 0.005). Patients of group 2 had more frequent adverse events (p = 0.03), increased cholesterol level (p = 0.03), repeated myocardial infarction (p = 0.02), and fatal outcomes (p = 0.01). PMID- 22242263 TI - [About secondary phenothiazine-induced cardiomyopathy]. AB - A total of 830 autopsy protocols and medical histories of schizophrenic patients who died between 1952 and 2007 were analysed. Dilated cardiomyopathy (DCMP) occurred much more frequently than in the study of analogous material from the general population and patients with psychiatric disorders. The difference is attributed to the prolonged neuroleptic therapy with phenothiasine preparations in schizophrenics. This inference is confirmed by their significantly smaller heart mass compared with that in the period preceding this treatment. The frequency of DCMP in these patients significantly increased with duration of neuroleptic therapy. It is concluded that phenothiasine neuroleptics are etiological factors of DCMP. It is suggested to regard DCMP as an independent nosological form and call it phenothiasine-induced cardiomyopathy (FCMP). PMID- 22242264 TI - [Peculiarities of relationship between atrophic gastritis and stomach cancer in the population of East Siberia]. AB - The authors studied the relationship between atrophic gastritis and gastric cancer in Europeoid and Mongoloid populations of East Siberia. Screening for atrophic gastritis was carried out in parallel in Evenkia, Khakassia, and Tyva. 1492 Europeoids, 533 Khakasses, 493 Evenks, and 414 Tuvinians were examined by oesogastroduodenoscopy with simultaneous biopsy sampling. Morphological studies of gastric mucosa were performed by light microscopy of hematoxylin/eosin stained samples with evaluation of results based on the visual analogous scale. H.pylori was identified in Giemsa stain preparations. Immunoenzyme assay was used to detect IgG and IgG of H.pylori CagA. Gastric cancer morbidity was estimated using materials of local oncological dispensaries and autopsy data. The prevalence of antral atrophic gastritis was 25.8% in Europeoids, 15.2% in Khakasses, 14% in Evenks, and 25.8% in Tuvinians. The incidence of gastric cancer was 33.2 in Europeoids, 20.2 in Khakasses, and 50.7in Tuvinians per 100,000. The occurrence of H.pylori was similar in all these populations (roughly 90%). CagA strains were identified in 61.2% Europeoids, in 44% Khakasses, in 36.44% Evenks, and in 60% Tuvinians. The study revealed ethnic differences in the association between gastritis cancer and H.pylori CagA-related gastritis among populations of different regions of East Siberia. PMID- 22242265 TI - [Psychosomatic aspects of pathology of biliary passages]. AB - The work was designed to study psychological features of patients with hypomotor dysfunction of biliary passages, chronic non-calculous cholecystitis with and without opistorchosis and cholelithiasis before and after cholecystectomy. A total of 343 patients were examined between 1997 and 2007. The control group comprised 100 age- and sex-matched healthy subjects. All patients signed the informed consent. Significance of the difference between absolute and relative parameters was estimated using Student's t-test at three significance levels (0.05, 0.001, 0.001---??). There were no differences between psychological status of patients with biliary duct pathology, but they were significantly different from controls as regards this variable. Patients with different forms of biliary duct pathology showed unidirectional changes of psychological symptoms that deteriorated with severity of the main disease. The psychological portrait of the patients suggested emotionally labile, hypochondriac, irritable, self-confident, highly anxious and neurotic personality type. PMID- 22242266 TI - [Relationship between left ventricle dysfunction and the development of neuropathy in patients with type 2 diabetes mellitus]. AB - The prevalence of left ventricular diastolic dysfunction was evaluated in 127 patients aged 22-66 yr with type 2 diabetes mellitus (DM2) without CHD. 69 (54.3%) of them presented with arterial hypertension that increased severity of diastolic dysfunction and the frequency of left ventricular concentric hypertrophy. Diastolic dysfunction in the absence of arterial hypertension was related to poor compensation of DM2 (HbA1c 7.5%) associated with the risk of microangiopathy and demyelinating neuropathy. PMID- 22242267 TI - [Late results of high-dose immunosuppressive therapy with autotransplantation of hematopoietic stem cells in patients with severe refractory systemic lupus erythematosus]. AB - The aim of the study was to assess long-term results of high-dose immunosuppressive therapy with autoimplantation of hemopoietic stem cells in patients with severe systemic lupus erythematosus (SLE) resistant to standard immunosuppressive therapy and compare them with the outcome of the two modalities. The study and control groups comprised 15 women each aged 18-55 and 20-55 years respectively. The results were estimated 1 months after the onset of therapy and during the 45 +/- 10.4 (study) and 30 +/- 7.6 (control) month follow up. Combined treatment resulted in complete remission (SLEDAI below 3) in 6 (40%) and reduced SLE activity in 6 (40%) patients. The effect was absent in 1 (7%) patient, 2 others died. Remission and reduced SLE activity occurred in 1 (7%) and 1 (7%) patients of the control group respectively, 13 (87%) failed to benefit from therapy, and 1 (7%) died. Seven (47%) patients given combined treatment suffered recurrence of SLE, 3 (20%) had complete or partial remission, and 3 died during the long-term follow-up. Five-year survival rate was 80%. None of the patients in the control group showed remission in the late posttreatment period, SLE activity remained unaltered in 8 and progressed in 4; two patients died. Five year survival rate was 70%. It is concluded that high-dose immunosuppressive therapy with autoimplantation of hemopoietic stem cells is an efficacious tool for the treatment of lupus erythematosus resistant to standard therapy and has advantages over the latter. PMID- 22242268 TI - [Significance of correlation between weather factors and hemodynamic parameters in patients with arterial hypertension and coronary heart desease receiving traditional treatment and combined therapy with melatonin]. AB - The study included 2 groups of patients with arterial hypertension and coronary heart disease treated by traditional therapy or its combination with melatonin. All 31 patients aged 41-70 years underwent measurement of AP and pulse rate in morning and evening hours. Correlation analysis between hemodynamic parameters and weather factors (curtsey of Institute of Terrestrial Magnetism, Ionosphere and Radiowaves) was performed. The study revealed 64 significant correlations in patients given traditional treatment. Atmospheric pressure, air and dew point temperature proved to have the most pronounced effect on hemodynamic parameters. Morning pulse rate was especially sensitive to meteorological factors. Treatment with melaxene reduced the number of correlations to 35. Specifically, the influence of temperature on hemodynamics decreased whereas effects of dew point temperature, wind speed and direction on the cardiovascular system were totally absent. PMID- 22242269 TI - [Efficacy of reamberin in patients with acetic acid poisoning]. AB - Efficacy of reamberin infusion therapy was estimated in 38 patients with severe acetic acid intoxication. Reamberin was shown to have positive effect on certain end-points of the treatment, viz. caused a 2-fold decrease in duration of exotoxic shock (which allowed to use smaller volumes of infusion solutions), 3 fold decrease in the frequency of pneumonia, 5-fold reduction in the frequency of delirium and acute renal insufficiency in the early post-traumatic period. The use of reamberin allowed to reduce duration of patients' stay in intensive therapy and resuscitation wards by 1.2 times and mortality rate by 18.5%. PMID- 22242270 TI - [Efficacy of prolonged therapy of vascular dementia]. AB - This open study was designed to assess efficacy and safety of long-term therapy with cerebrolysin in 48 patients aged 59-77 years with mild and moderately severe vascular dementia. The slowdown in the progress of this condition during the 3 year treatment period was evaluated. The efficacy and safety of the drug was assessed clinically and with the use of standard scales and neuropsychological tests. The long-term therapy with cerebrolysin was shown to be safe and highly efficacious as indicated by the improvement of cognitive and motor functions both at early and late stages of the treatment regardless of the severity of the disease. It is concluded that long-term therapy with cerebrolysin slows down the progress of vascular dementia and prevent deterioration of cognitive abilities. PMID- 22242271 TI - [Peculiarities of immunomodulating therapy in an immunocompromised patient with allergies]. AB - The authors summarize recent data on the predisposition to, indications for, and efficacy of immunomodulating therapy of immunocompromised patients presenting with allergia. Clinical and immunological characteristic of pathology is presented including cytokine status before and after therapy. High efficacy of immunomodulators like interferons is exemplified by the most efficacious of them, cycloferon (meglumin acridonacetate). Disturbed immune reactivity promotes the development of pathological process. Results of the studies of various aspects of immunogenesis suggest desirability of inclusion of cycloferon therapy in the combined treatment of the disease under consideration. New aspects of clinical use of the immunomodulator cycloferon in combination with allergen-specific immunotherapy are discussed. PMID- 22242273 TI - [The doctor's word]. PMID- 22242272 TI - [The first case of acquired hemoglobinopathy H in Russia in a patient developing unclassified myelodysplastic syndrome/myeloproliferative disease]. AB - A 55 year-old man with hemolytic anemia is described. Careful clinical and laboratory studies showed that this condition was a manifestation of non hereditary hemoglobinopathy N. The clinical symptoms suggested acquired hemoglobinopathy N that devloped parallel to myelodysplastic syndrome/myeloproliferative disease. PMID- 22242274 TI - [Possibilities for quality analysis of diagnostic and therapeutic work based on the results of biopsy studies]. PMID- 22242275 TI - [Innovative approaches to diagnosis and treatment of occupational diseases (on joint diseases model)]. AB - The authors studies features of structure and functional state of knee joints in occupational diseases. Findings are peripheral circulatory disorders, changes in all hemostasis levels, with trend to increased platelets aggregation, hyperfibrinogenemia, hypercoagulation and fibrinolysis system disorders. Considering the diagnosis, the authors specified treatment algorithms for occupational osteoarthrosis. PMID- 22242276 TI - [Efficiency of early diagnosis and prevention of chronic obstructive pulmonary disease in industrial workers (prospective observation results)]. AB - Examination of workers engaged into major industrial enterprises of Novosibirsk demonstrated high prevalence of bronchial obstruction in individuals contacting industrial aerosol. The workers with long length of service proved high level of tobacco addiction and marked psychologic dependence on smoking. Based on the data obtained, the authors specified a program for early diagnosis and prevention of occupational bronchitis among the workers of major industrial enterprises. PMID- 22242277 TI - [Early markers of hypoxia in patients having respiratory system diseases caused to dust]. AB - Assessing state of various hemostasis levels in patients having pulmonary diseases caused by dust, in accordance with respiratory failure severity, enables to diagnose early changes confirming hypoxia. The most reliable parameters are changes in vascular and platelet hemostasis and in fibrinolysis system. PMID- 22242278 TI - [Possibile application of X-ray and high resolution CT in pneumoconiosis management]. AB - The article covers results of clinical and roentgenologic data analysis. The data were obtained in the study that covered 447 pneumoconiosis patients, 75 of which were subjected to high resolution CT. If compared to chest X-ray, high resolution CT helps more precise forecast of further course in pneumoconiosis. PMID- 22242280 TI - [Characteristics of arterial hypertension in psychoemotional burnout of emergency medical staffers]. AB - Medical profession requires not only skills, but also significant emotional dedication that leads to psychoemotional overstrain and frequently to emotional burnout influencing blood pressure level, cardiovascular state and arterial hypertension course. With this, studying influence of psycho-social factors in medical staffers' occupational life, in accordance with length of service, on cardiovascular system with arterial hypertension is topical. PMID- 22242279 TI - [Functional state of RBC and neutrophils in pneumoconiosis patients variable in tolerance to dust factor in after contact period]. AB - The article covers basic mechanisms and major pathogenetic factors of pneumoconiosis formation and course in after contact period. The authors provide results of metabolic disorders analysis in the patients vairable in tolerance to industrial aerosol, to forecast pneumoconiosis course after discontinued contact with the hazard. PMID- 22242281 TI - [Serum hormonal levels in diamond-extracting industry workers of Yakutia, with surface and underground type of work]. AB - The authors studied influence of work type (surface or underground) on serum hormonal levels in male workers of "International" mine within diamond-extracting complex of Yakutia-Sakha Republic. The results obtained show compensation and adaptation changes of endocrine system in males engaged into underground work vs. those of surface work. PMID- 22242282 TI - [Cognitive disorders in occupational diseases of after contact period, associated with cardiovascular problems]. AB - Vibration disease patients with chronic uranium intoxication in after contact period demonstrate moderate cognitive disorders of amnestic multifunctional type in 100% of cases. Individuals having occupational diseases due to physical, toxic and radiation hazards, associated with cardiovascular problems, in after contact period manifest mostly with visual-spatial functions, short-term, operative, visual and aural memory disorders. Visual-spatial functions, short-term, operative, visual and aural memory are decreased more in patients with remote period of chronic uranium intoxication. PMID- 22242283 TI - [State of hepatolienal circulation and liver functions in vibration disease under angioprotector treatment]. AB - The authors demonstrate that angioprotector therapy with Telmisartan in vibration disease patients caused positive effects on hepatolienal circulation, liver microcirculation and clinical functional parameters. PMID- 22242284 TI - [Prevalence and clinical manifestations of metabolic syndrome in vibration disease]. AB - Among 70 vibration disease patients (58 males and 12 females, average age 48 +/- 8.4 yr; 1 grade--85.7% and 2 grade--14.3%), prevalence of abdominal obesity equalled 34.3%. Arterial hypertension (with preferentially 3 grade, risk 3-4- 42.5%) was diagnosed in 94.3% of the examinees, of which 27.3% concurrent with IHD. Dyslipidemia were seen in 58.6%. Various combinations of metabolic syndrome were seen in 24.3% of the examinees. PMID- 22242285 TI - [Status of the autonomic nervous system and its correction in complex treatment of patients with occupational cervical dorsopathy]. AB - The authors studied features of vegetative regulation in patients with occupational cervical dorsopathy and specified differentiated rehabilitation programs proved to be more efficient than the conventional treatment. PMID- 22242286 TI - [Innovative approaches to postgraduate training of occupational therapy specialists: from knowledge to competency through activity]. AB - The authors studied innovative approaches in postgraduate training of occupational therapy specialists. Findings are that combination of technologic and research approaches provides guaranteed prevailing and development of creativity. PMID- 22242287 TI - [Simultaneous coronary artery bypass grafting and the ascending aorta to bifemoral bypass]. AB - OBJECTIVE: Coronary artery disease and arteriosclerosis obliterans (ASO) frequently coexist. Concomitant revascularization procedures may be required because harvest of the internal thoracic artery (ITA) in patients with ASO carries a risk of leg ischemia. This study reports our experience with combined coronary and femoral revascularization using the ascending aorta to bifemoral bypass. PATIENTS: Seven male patients (including 4 high aortic occlusions) underwent concomitant aorto-femoral bypass and coronary revascularization between 1990 and 2007. Mean age was 66 years old. RESULTS: Coronary artery bypass grafting (CABG) was performed on-pump in 5 cases and off-pump in 2 cases. The number of bypass grafts were 2.4 +/- 0.9. We harvested ITA in all cases. The prosthetic tube graft was positioned behind the muscles of the abnominal wall. One hospital death was related to mediastinitis. Perfect patency of the aorta femoral grafts was obtained in all cases. CONCLUSIONS: The ascending aorta is a good source of inflow to femoral arteries and the ascending aorta to bifemoral bypass did not require an intraperitoneal procedure. Therefore the simultaneous operation can be performed in shorter time, and it is an interesting alternative in cases with ischemic heart disease and leg ischemia. PMID- 22242288 TI - [Repair of pectus excavatum without the introduction of exogenous material]. AB - We review our experience of surgical repair for pectus excavatum without the introduction of exogenous material. Two hundred seven patients underwent surgical repair. Sterno-costal elevation was adopted for 196 patients. Sternal turnover was employed for 11 adult patients with severe asymmetric deformities. In sterno costal elevation, a section of the 3rd or 4th to the 7th costal cartilages were resected, and all of the cartilage stumps were resutured to the sternum. The secured ribs generate 0.5 to 12 kg of tension, pulling the sternum bilaterally, such that the resultant force causes the sternum to rise anteriorly and prevents flail chest. We've made modifications such as resection of the lower tip of the sternum below the 6th cartilage junction, or a diagonal groove on the sternal cortex to get better correction in any age group. There were neither operative death nor any severe complications, and in all cases the deformities were corrected satisfactorily. Patients resumed unlimited daily activities within 3 months after surgery. Our technique represents a less invasive procedure with low operative risk for the repair of pectus excavatum in any age group. PMID- 22242289 TI - [Comparative study between landiolol and amiodarone for therapeutic efficacy after open heart surgery]. AB - Tachyarrhythmia, especially atrial fibrillation, remains as a common complication after open heart surgery and sometimes leads to fatal condition. Many reports showed that landiolol (ultra short-acting beta one blocker) and amiodarone were effective against postoperative atrial fibrillation (POAF). However, there were few comparative studies between these 2 drugs as prophylactic agents, and no report mentioned the therapeutic efficacy. Our study suggests that landiolol be the 1st choice for rate control of tachyarrhythmia because of easy dose adjustment and mild side effects. Amiodarone may be useful for the patients whose left ventricular function is poor. PMID- 22242290 TI - [Postpneumonectomy syndrome treated with an air infusion through a central vein (CV) port]. AB - A 65-year-old woman underwent a right pneumonectomy 3 years before, because of lung cancer. Two years and 9 months after the operation, she developed a productive cough and complained of dyspnea At that time, the chest X-ray film showed a remarkable mediastinal shift to the right and herniation of the left lung. The computed tomography (CT) scan showed a marked rightward and posterior deviation of the mediastinum, and severe stenosis of the left main bronchus. A 18 gauge-silicon catheter was inserted into the right pleural cavity in order to inject air and 100 ml of air was infused through it. Immediately after injection, she was relieved from severe symptoms. A central vein (CV) port was implanted in the subcutaneous tissue at the right chest wall for periodic infusion of air with safety and ease. PMID- 22242291 TI - [Superior vena cava thrombosis in a case with low serum factor XII]. AB - The present case is 74 years old man who was hospitalized to treat lung tumor suspected of malignancy. Because the superior vena cava thrombus was also revealed by radiological examination, he was performed lobectomy and thrombectomy at the same time. He has past history of intravenous hyperalimentation for 15 days, and we supposed the event to be the cause of the thrombus. Venous thrombus has developed again in the left subclavian vein in spite of the anticoagulant therapy at the early postoperative period. The level of serum factor XII turned out to be low by the precise examination, of which possible contribution to thrombus formation was suspected. PMID- 22242292 TI - [Small size lung adenocarcinoma with rocal recurrence and port site recurrence 56 months after partial resection]. AB - A lobectomy with systemic lymphadenectomy is a standard surgical procedure for a resectable lung cancer. However there is not a consensus on the limited surgery. A 60-year-old man underwent left upper lobe partial resection for small size lung adenocarcinoma under video assisted thoracic surgery (VATS). Fifty-six months after the operation, a computed tomography (CT) scan showed a local recurrence on the staple-line. A positron emission tomography (PET) scan showed an additional port site recurrence, which wasn't showed by a CT scan. He underwent left upper lobectomy and port site resection. PMID- 22242293 TI - [Total arch replacement through a mediansternotomy for an aortic arch aneurysm with an aberrant right subclavian artery]. AB - The patient was a 77-year-old man. In 2004, he developed thrombosed aortic dissection extending from the distal aortic arch to the renal artery bifurcation. He was discharged after his condition improved with conservative treatment. He was followed up as an outpatient because there was an aneurysm, which measured 50 mm in diameter, at the aortic arch. Thereafter the aneurysm gradually enlarged. In May 2009, computed tomography (CT) showed that the aneurysm had increased to 10 cm in diameter and the patient began to have back pain. Thus, surgery was planned. CT revealed that the right subclavian artery originated distal to the left subclavian artery and coursed posterior to the esophagus and trachea. Surgery was performed using median sternotomy. Arch replacement and right subclavian artery reconstruction were performed under hypothermic circulatory arrest with selective cerebral perfusion. The right subclavian artery was controlled at the right border of the trachea, and cerebral perfusion was performed at this site. An end-to-side anastomosis to the reconstructed right common carotid artery was performed by an anterior tracheal approach. The patient had no cerebral complications and his postoperative course was uneventful. PMID- 22242295 TI - [Successful repair of left ventricular free wall rupture with repeated mydriasis and loss of light reflex]. AB - A 73-year-old woman was transferred to our hospital because of loss of consciousness. Cardiac catheterization showed a left ventricular free wall rupture (LVFWR) due to acute myocardial infarction at the posterolateral region. Shortly after cardiac catheterization, she lost her consciousness again and went into cardiogenic shock. Repeated mydriasis and loss of light reflex was recognized during establishment of cardiopulmonary bypass. Direct suture closure using equine pericardial strips and 4-0 polypropylene mattress sutures was performed under cardiac arrest. The suture site was covered with TachoComb and fibrin glue. Post-cardiac arrest brain injury was prevented by postoperative mild hypothermia. Surgical repair of LVFWR should be performed even when the signs of severe cerebral ischemia are apparent. PMID- 22242294 TI - [Hybrid endovascular repair with reconstruction of superior mesenteric and celiac arteries for thoracoabdominal and abdominal aortic aneurysms]. AB - A 79-year-old woman presented with sustained thoracolumbar back pain. Contrasted computed tomography (CT) showed a thoracoabdominal aortic aneurysm (TAAA: type I of Crawford classification) and an abdominal aortic aneurysm (AAA) that were not ruptured. Considering her age, the placement of an endovascular stent graft was performed for TAAA at the possible sacrifice of the celiac (CA) and superior mesenteric arteries (SMA). In order to prevent ischemic events, it was necessary that blood supply to the CA and SMA was maintained by placing a graft to each artery from the Y-shaped graft for replacement of AAA. Actually, only CA was sacrificed and coil embolization of CA was needed because of type 2 endoleak. The patient was discharged 17 days after surgery. A hybrid technique, endovascular repair with reconstruction of abdominal branches for TAAA and AAA, can be an alternative procedure for such high-risk operation with multiple aortic aneurysms including TAAA. PMID- 22242296 TI - [Coronary artery bypass grafting in a patient with systemic lupus erythematosus, scleroderma and secondary antiphospholipid syndrome]. AB - A 71-year-old patient with systemic lupus erythematosus, scleroderma and secondary antiphospholipid syndrome underwent coronary artery bypass grafting using cardiopulmonary bypass for angina pectoris. Postoperatively, new onset of thrombotic complications including neurological deficits was not recognized. She was discharged without any complications. PMID- 22242297 TI - [Coexistence of sarcoidosis and thymic carcinoid]. AB - We report a case of coexistence of sarcoidosis and thymic carcinoid. A 57-year old man was pointed out the anterior mediastinal tumor when his generator of pacemaker was exchanged. The tumor was diagnosed as atypical carcinoid by percutaneous needle biopsy. Chest computed tomography (CT) revealed the mediastinal and right hilar lymphadenopathy. Preoperative transbronchial aspiration cytology revealed no malignancy and extirpation of the anterior mediastinal tumor was carried out together with left diagraphmatic nerve and pericardium. The histopathological examination of the pretracheal lymph node was sarcoidosis. Postoperative radiation was performed because the thymic carcinoid invaded the pericardium. The right hilar lymph node was enlarged after the radiation. Five months later, follow-up chest CT showed reduction of the right lymph node. He has been alive without recurrence of the thymic carcinoid for 3 years. Simultaneous occurrence of sarcoidosis and thymic carcinoid is extremely rare. Assessment of mediastinal lymph node is difficult either preoperatively and postoperatively. Histological confirmation of the lymph node and careful follow up are necessary. PMID- 22242298 TI - [Cardiopulmonary arrest due to massive hemoptysis from bronchiectasis]. AB - A 61-year-old woman was admitted to our hospital because of hemosputum. When chest computed tomography (CT) was performed, sudden and massive hemoptysis occurred. She suffered cardiopulmonary arrest. After resuscitation, different lung ventilation was performed to control hemoptysis from the left lung. Bronchial artery embolization (BAE) was performed, however, hemoptysis recurred, and the left pneumonectomy was performed. She has been free from hemoptysis after operation, and has been discharged from the hospital 73 days after surgery. PMID- 22242299 TI - [Distal arch aneurysm and acute aortic dissection with bicuspid aortic valve; report of a case]. AB - A 49-year-old man was admitted to our institution with acute chest and back pain. Chest and abdominal computed tomography (CT) showed type A aortic dissection from the ascending aorta to the bilateral common iliac arteries and a distal arch aneurysm with a diameter of 65 mm. Echocardiogram showed a bicuspid aortic valve with severe regurgitation. We performed total arch replacement and aortic valve replacement. Pathological examination of the aortic wall revealed a typical cystic medial necrosis. After 3 months, we performed the 2nd stage operation for the distal arch aneurysm and descending aortic dissection. Here, we report a rare case of bileaflet aortic valve with aortic aneurysm and aortic dissection. PMID- 22242300 TI - [Emergent surgical treatment for purulent pericarditis associated with cardiac tamponade; report of a case]. AB - We describe a case of purulent pericarditis presented with cardiac tamponade. A 65-year-old man was admitted to our hospital with shock by cardiac tamponade and high grade fever. Transthoracic echocardiography revealed a large amount of pericardial effusion. Surgical drainage via median sternotomy was carried out in an emergent manner. Because culture of pericardial effusion showed positive for methicillin sensitive Staphylococcus aureus and thick white purulence covering over all pericardium, purulent pericarditis was diagnosed. Postoperative course was uneventful and discharged in a good condition. Special care should be taken of purulent pericaditis in differential diagnosis of cardiac tamponade. PMID- 22242301 TI - [Diaphragmatic endometriosis-associated pneumothorax triggered by abortion; report of a case]. AB - The patient was a 36-year-old woman. She had previously undergone surgery for hysteromyoma and endometriosis. At 8 week of pregnancy, the fetus's heart stopped beating, and the woman underwent abortion. On the same day, she began experiencing difficulty in breathing in the evening. After 4 days, she was referred to our hospital with dyspnea. Chest X-ray finding showed a right pneumothorax. Tube toracotomy was performed, and the right lung re-expanded immediately. Two months later, pneumothorax recurred without any association with the menstruation cycle. Thoracoscopic surgery was performed. No lesion was detected in the lung or visceral pleura, but a small hole and some thinned areas were noted in the diaphragm. Partial resection of the diaphragm was performed. Microscopic examination revealed endometriosis and localized lymphocyte infiltration in the resected diaphragm. It was suggested that the recurrence of pneumothorax without menstruation was caused by the thinning of the diaphragm due to endometriosis. PMID- 22242303 TI - [Bronchial fibroepithelial polyp completely resected by left upper sleeve lobectomy; report of a case]. AB - Cough and fever persisted in a 48-year-old female, and left pneumonia was diagnosed. A polyp-like lesion obstructing the left main bronchial lumen was observed on chest computed tomography (CT) and bronchoscopy. Since the root of the lesion could not be confirmed, treatment through the airway was considered difficult, and surgery was performed. Since continuation of the root of the lesion to the peripheral bronchus of the left superior lobe was observed during surgery, the left superior lobe was resected by sleeve lobectomy. The entire length of the excised lesion was about 8 cm, and the root arose from the bronchial wall of the left B(5) periphery. Pathologically, bronchogenic fibroepithelioma was definitely diagnosed. PMID- 22242302 TI - [Lung abscess which needed to be distinguished from lung cancer; report of a case]. AB - BACKGROUND: Differential diagnosis of lung abscess from lung cancer is sometimes difficult. CASE: In February 2009, a 57-year-old man consulted our hospital complaining of bloody sputum. Chest computed tomography (CT) demonstrated a 2.5 cm nodule with pleural indentation, spicula and vascular involvement in the right S(3). Bronchofiberscope could not establish a definitive diagnosis. Blood test showed no abnormality. Three months later, progression of the nodule to the adjacent middle lobe was demonstrated by follow-up CT, and F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) showed isotope accumulation in the nodule and hilar lymph node. A diagnosis of lung cancer was suspected and surgery was performed. The diagnosis of possible lung cancer was made by needle biopsy, and the patient underwent right upper lobectomy and partial resection of middle lobe with standard nodal dissection. The final pathological diagnosis was lung abscess. CONCLUSION: Lung abscess must be kept in mind as a possible differential diagnosis when abnormal shadow suspected of lung cancer is observed. PMID- 22242304 TI - [The current status and future perspective of tissue engineering and regenerative medicine]. PMID- 22242305 TI - [The history and current status of clinical applications of stem cells]. AB - Here, we summarize the history and current status of clinical applications of stem cells for regenerative medicine. Cultured autologous epidermal cells were successfully applied to treat human severe burn patients in 1980 for the first time ever. Then, several commercial tissue engineered products including skin and cartilage have been approved by the regulatory agencies, and many clinical trials are ongoing now in Europe and United States. Regenerative medicine achieved by tissue engineering with autologous and allogeneic stem cells including ES and iPS cells are highly promising, and more and more products are expected to come on the market in the near future. PMID- 22242306 TI - [Embryonic stem cell research]. AB - Research using human embryonic stem cell (hESC) lines has expanded dramatically because of two attractive capacity; self-renewal and differentiation into almost all cell types. For therapeutic purposes, many researchers are trying to establish methods for maintaining pluripotency in defined xeno-free conditions and scalable culture systems. Banking of hESC lines is important for the wide spread of personalized cell therapy and transplantation. We introduced the ongoing clinical trials using hESC-derived cells in patients with subacute spinal cord injury and Stargardt's macular dystrophy. We also discussed opportunities and an example for the use of hESC in drug discovery. Finally, we introduced transgenic hESC as a disease model. PMID- 22242307 TI - [Research for cell therapy by induced pluripotent stem cell]. AB - Induced pluripotent stem (iPS) cells, which are generated from somatic cells, are expected to be a hopeful source for cell therapy to treat intractable diseases due to its unlimited proliferation potential, differentiation potentials and the capability of autotransplantation characteristics. In this review, we have summarized the extension of iPS cell researches into cell therapy and the new researches associated with iPS cell technology. However, transplantation of iPS cell-derived tissue is considered to have a risk of tumorigenesis which is one of the major hurdles of using pluripotent stem cell in clinical application. This review is also focused on new strategies for reducing a risk of tumorigenesis. PMID- 22242308 TI - [Regenerative therapy using allogeneic mesenchymal stem cells]. AB - The use of mesenchymal stem cells (MSC) for tissue and organ regeneration offers advantages because the MSC contain multipotent progenitor cells and reported to be immunoprivileged as well as immunosuppressive. Therefore, cell therapy with allogeneic MSC has been reported as a promising treatment for severe acute graft versus host disease (GVHD). We reported a pilot study for GVHD treatments using a small number of allogeneic MSC. We also reported that MSC can show osteogenic differentiation capability when implanted in vivo as well as cultured in vitro. Based on these findings, we attempted to use allogeneic MSC for the treatment of genetic disorder of hypophosphatasia patient. Present paper summarizes our clinical experiences of allogeneic MSC for the purpose of regenerative medicine. PMID- 22242309 TI - [Tissue repairing cells that exist among mesenchymal stem cells; their potential for cell-based therapy]. AB - Although adult stem cells are generally known to generate the cell types of the tissue in which they reside, mesenchymal stem cells (MSCs) are unique in that they differentiate not only into the same mesodermal-lineage such as bone, cartilage, and adipocytes, but also into other lineages of ectodermal and endodermal cells. Furthermore, a subpopulation of MSCs are known to integrate into damaged sites, differentiate into cell types specific to the integrated tissue and contribute to the tissue repair. As MSCs comprise heterogeneous cell populations, however, the cells responsible for wide-ranging differentiation as well as for tissue repair have not been identified. Recent evidence suggests that a subpopulation of human MSCs, which were named Muse cells, were shown to have the ability to differentiate into trilineage cells and to function as tissue repairing cells in vivo. This review summarizes recent advances in MSC properties and discuss about future perspectives. PMID- 22242310 TI - [Hematopoietic stem cells and mature blood cells from pluripotent stem cells]. AB - Pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells could be good sources for obtaining massive hematopoietic stem cells (HSC) and mature blood cells. Coculture with feeder cells and embryoid body formation are two major strategies to induce hematopoietic differentiation from pluripotent stem cells. Derivation of HSC with ability of reconstituting human hematopoiesis in immunodeficient mice has been achieved. It is also possible to generate mature blood cells such as neutrophils, erythrocytes, and platelets from pluripotent stem cells. Their morphologies, phenotypes, and functions are usually very similar to those of normal counterparts. However, a breakthrough is needed to overcome the issue of "yield", which still stands as a high barrier to reach clinical applications. PMID- 22242311 TI - [Toward gene and cell therapy using human artificial chromosome]. AB - Human artificial chromosomes (HACs) exhibit several potential characteristics desired for an ideal gene delivery vector, including stable episomal maintenance and the capacity to carry large genomic loci with their regulatory elements, thus allowing the physiological regulation of the introduced gene. Stem cells, including hematopoietic stem cells, bone marrow-derived MSCs and iPS cells, can potentially avoid immune rejection due to their being obtained from the patient's own tissues. Recently, we succeeded the complete correction of a genetic deficiency in iPS cells derived from a human Duchenne muscular dystrophy patient using the HAC technology. Therefore, the combination of patient specific stem cells and HAC containing defective genes potentially represents a powerful tool for gene and cell therapies. PMID- 22242312 TI - [From cell therapy to organ regeneration therapy: generation of functional organs from pluripotent stem cells]. AB - Current stem cell therapy mainly targets diseases that can be treated by cell transplantation. The complexity of organogenesis hinders in vitro generation of organs derived from patient's pluripotent stem cells (PSCs), an ultimate goal of regenerative medicine. To address this issue, we attempted in vivo generation of PSC-derived pancreas using Pdx1(-/-) blastocysts(pancreatogenesis-disabled) and blastocyst complementation technique. When wild type rat PSCs were injected into mouse Pdx1(-/-) blastocysts, defective cells were totally replaced and pancreas was formed almost entirely by injected rat PSC derived cells. Chimeric mice of Pdx1(-/-) genotype survived to adulthood without any sign of diabetes. Generation of organs using blastocyst complementation in vivo provides a new strategy for understanding organogenesis and a novel approach for organ supply. PMID- 22242313 TI - [Advances of stem cell-based liver regeneration: science and the future]. AB - Liver transplants represent the only way to treat patients suffering from terminal liver failure, but they are associated with numerous problems, including a chronic shortage of donors, high cost, rejection, and side effects for the donor. It is anticipated that regenerative medicine will provide an alternative to liver transplants for such patients. An assortment of studies has documented their contribution in hepatogenic generation in vivo and in vitro. Preliminary results of only a few clinical studies on the administration of adult stem cells to liver cirrhotic patients seem to be very promising, but additional well designed and controlled studies are needed. We herein present the current knowledge what we obtained from differentiation of functional hepatocytes from several types of stem cells. PMID- 22242314 TI - [Potential usefulness of human iPS cells on the generation of platelets]. AB - Repetitive transfusion of platelets expressing HLA not corresponded to recipient matched often induces anti-HLA antibody-based undesired events including unresponsiveness in platelet transfusion therapy. It is desirable to use platelets derived from HLA-matched iPS cells. In this context, we have recently established an in vitro culture system whereby human pluripotent stem cells can be differentiated into'unique sac-like structures' (ES-/iPS-sacs) containing hematopoietic progenitors generating platelets. Among various iPS clones, we also found critical role of c-MYC in human megakaryopoiesis, leading to efficient platelet production with an intact in vivo functionality of hemostasis and thrombosis within the vessel. We propose that use of HLA-matched hiPS cells may be one of useful strategies for the treatment of thrombocytopenia in patients requiring repeated transfusion. PMID- 22242315 TI - [Stem cell therapy for intractable skin diseases]. AB - Previous studies have shown that bone marrow provides fibroblastic-like cells in the dermis and keratinocytes in the epithelia. Subsequent studies by us and other groups have demonstrated that both embryonic and postnatal transplantation of bone marrow cells in model mice of epidermolysis bullosa (EB), a heritable blistering skin disease due to genetic mutation of cutaneous basement membrane components, promote skin wound healing and correct the intrinsic basement membrane defect. We also reported that the source of the epithelial progenitors in mouse bone marrow was the nonhematopoietic, platelet-derived growth factor receptoralpha (PDGFRalpha)-positive bone marrow mesenchymal stem cell (MSC) population. In this review, recent progress as well as future perspectives of bone marrow MSC therapy for EB will be summarized. PMID- 22242316 TI - [Hematopoietic stem cell transplantation for hematologic disorders]. AB - There have been a great progress in hematopoietic stem cell transplantation (SCT) for hematologic malignancies in various aspects including stem cell sources, supportive care, infrastructure, stem cell mobilization, etc., which has lead SCT from experimental therapy to standard medical practice. The most prominent is the advent of SCT with reduced-intensity conditioning (RIC) regimen. It has not only expanded the eligibility for SCT to patients of older age or with co-morbidities, but also highlighted the impact of graft-versus-tumor (GVT) effects in some malignant disorders such as follicular lymphoma, peripheral T-cell lymphoma, and chronic myeloid or lymphocytic leukemia. RIC will provide a possibility for myriads of newly developed molecular-targeted or antibody-based agents to be incorporated in SCT as pre- or post-SCT therapies. PMID- 22242317 TI - [Recent advances of transplantation from bone marrow derived stem cells]. AB - The current progress of blood and marrow transplantation (except CBSCT) could be summarized as the followings; (1) HLA 1-haplo mismatched family donors have been recognized as suitable donor candidates under certain preconditioning regimens. On the other hand, the analysis of the relationship between HLA allele level match/mismatch and the outcomes of the unrelated bone marrow transplantation offered more sophisticated algorithm for donor selection. New devices and drugs to harvest stem cells are under clinical studies. The efficacy of intra bone marrow transplantation has been proved. (2) Fludarabine and i.v. busulfan has one of standards of preconditioning. New generation of drugs such as imatinib may be also beneficial to transplant outcome. (3) ATG, foscavil and other new drugs as well ex vivo manipulated DLI would contribute better outcomes. (4) Registration and follow up for patients and donors would be a global standard in near future. PMID- 22242318 TI - [Recent advances in cord blood stem cell transplantation]. AB - Cord blood stem cells are recognized as alternative donors for patients without HLA matched sibling donors in allogeneic stem cell transplantation, while limited number of stem cells are still associated with delayed or failed engraftment. To overcome this issue, clinical trials including reduced-intensity conditioning, double units transplantation, intrabone marrow injection as well as infusion of ex vivo expanded regulatory T cells have been performed. Chimerism analysis by multicolor flow cytometry is also valuable in monitoring the engraftment process. Future studies will test the potential application of cord blood stem cells to non-hematological disorders. PMID- 22242319 TI - [Strategy of surgical treatment for ischemic heart disease]. AB - The efficacy of regenerative cell therapy as strategy of cardiac functional recovery in patients with end-stage heart failure has been recently reported, and clinical applications of autologous skeletal myoblast cell transplantation has been already started in Europe and U.S. We developed cell-sheet technology with a temperature-responsive culture dish, which enabled cell-to-cell junction to retain, and started a clinical study of cardiac regenerative therapy using autologous skeletal myoblast cell sheet implantation. PMID- 22242320 TI - [Bone marrow stem cell therapy for stroke]. AB - Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow has been reported to ameliorate functional deficits in several CNS diseases in experimental animal models. The objectives of this study were to examine feasibility and safety of cell therapy using auto serum-expanded autologous MSCs in the stroke patients. Twelve (male and female) patients with stroke were enrolled. Cryopreserved MSCs were thawed and injected intravenously into patients over 30 min. Serial evaluations showed no severe adverse cell-related effects. In patients with cerebral infarcts, the intravenous administration of autologous MSCs appears to be feasible and safe, and merits further study as a therapy that may improve functional recovery. PMID- 22242321 TI - [Islet transplantation]. AB - In type 1 diabetes mellitus, islets are destroyed by the body's immune system. Clinical studies have shown that islet transplantation can support glucose homeostasis in type 1 diabetic patients and it carries the special advantages of being less invasive and resulting in fewer complications compared with pancreas transplantation. Islet transplantation shows short-term benefits of insulin independence, remarkable reductions in HbA(1c) levels, and elimination of severe hypoglycemic episodes. However, islet transplantation efforts have limitations such as the short supply of donor pancreata. The formation of new beta cells from stem/progenitor cells is an active area of investigation. Recent progress in the search for new sources of beta cells has opened up several possibilities for the development of new treatments for diabetes. PMID- 22242322 TI - [Inner ear cell therapy for hereditary deafness with multipotent stem cells]. AB - Congenital deafness affects about 1 in 1000 children and the half of them have genetic background such as connexin26 gene mutation. The strategy to rescue such hereditary deafness has not been developed yet. Inner ear cell therapy for hereditary deafness has been studied using some laboratory animals and multipotent stem cells, although the successful reports for the hearing recovery accompanied with supplementation of the normal functional cells followed by tissue repair and recovery of the cellular/molecular functions have been still few. To succeed in hearing recovery by inner ear cell therapy, appropriate cell type, surgical approach and the stem cell homing system to the niche are thought to be required. PMID- 22242323 TI - [An innovative disc repair for the degeneration]. AB - Experimental studies in various animals showed that using a coculture system with direct cell-to-cell contact with mesenchymal stem cells (MSCs) significantly upregulated the biological activity of nucleus pulposus (NP) cells. Activated NP cells can be reinserted into the disc to inhibit intervertebral disc degeneration. In human cells, the positive effects of the coculture system with direct cell-to-cell contact seen in animal studies were also evaluated and cell proliferation, DNA synthesis, and PG synthesis were significantly upregulated. Chromosome abnormalities and tumorigenesis were not observed in the activated NP cells. Then the authors have started the specially designed clinical trial under the control of Ministry of Health, Labour and Welfare and now post operative follow-up has been continued with expected good outcome. PMID- 22242324 TI - [Cell therapy for aseptic necrosis of femoral head]. AB - As the clinical application of mesenchymal stem cell (MSC), we have engaged in the development of cell transplantation therapy for aseptic necrosis of femoral head. Based on the results obtained by in vitro and in vivo preclinical experiments, we established the protocol for the clinical trial combining MSC with vascularized bone grafts. The protocol was approved by IRB on November 25, 2007, and the first case was operated on February 22, 2008. Since then 10 cases have been successfully treated and were followed at least 24 months with satisfactory results. PMID- 22242325 TI - [Oral surgery]. AB - Regenerative medicine is widely noticed as advanced medicine that treats acquired or congenital tissue defects. In the field of oral surgery, congenital anomalies, tissue defects caused by tumor excision or trauma, periodontal diseases, or loss of teeth are regarded as the subjects of regenerative medicine. A maxillofacial area is expected to be applied to early clinical application, since it is lightly loaded compared to limbs or trunk and needs no large tissues. In this chapter, we will explain the current situation and future prospects of regenerative medicine, concerning maxillofacial bones, nasal cartilages, and periodontal tissues, and teeth. PMID- 22242326 TI - [Regenerative medicine in cornea]. AB - Cornea is unique organ in its transparency. It consists of three different layers epithelium, stroma, and endothelium. Defect of each layers decrease the transparency resulting in blindness. Corneal transplant from donors is performed for these conditions. However it sometimes does not work because of immuno rejection and shortage of donors is still problem. Regenerative medicine resolves these problems. According to epithelium, we had succeeded in making epithelial sheet from oral mucosa epithelium. The sheet is clear and very resembles normal corneal epithelium in histology. We have auto transplantation of this epithelial sheet to severe corneal deficiency patients and obtained good clinical results. According to endothelium, we are trying to make the sheet from various stem sells including iPS cells. PMID- 22242327 TI - [Therapeutic angiogenesis by stem cell transplantation]. AB - The prevalence of peripheral arterial disease(PAD) is increasing with reference to the life style related disease. Up to one third of patients are not susceptible to traditional revascularization. Therefore, new strategies are needed to offer these patients a viable therapeutic option. The discovery of endothelial progenitor cells (EPCs) in human peripheral blood advanced the field of cell-based therapeutics for many pathological conditions. Bone-marrow derived stem and progenitor cells have been identified as a potential new therapeutic option to induce angiogenesis. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. The present study showed that angiogenic cytokines, especially IL-1beta, were associated with the response to treatment. It is likely that muscle cells but not implanted cells are a major source of angiogenic cytokines in ischemic limbs, thereby promoting neovascularization in ischemic tissues. PMID- 22242328 TI - [The Japanese government's prospects for stem cell research (highway program for realization of regenerative medicine)]. PMID- 22242329 TI - [Stem cell research and science and technology policy in Japan]. AB - In this paper I review the present condition of the regeneration medicine research using pluripotency and a somatic stem cell, and I describe the subject of the science and technology policy in Japan towards realization of regeneration medicine. The Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) supported research promotion by the prompt action in 2007 when establishment of the iPS cell was reported by Shinya Yamanaka. Although the hospitable support of the Japanese government to an iPS cell is continued still now, there are some problems in respect of the support to other stem cell researches, and industrialization of regeneration medicine. In order to win a place in highly competitive area of investigation, MEXT needs to change policy so that funds may be widely supplied also to stem cell researches other than iPS cell research. PMID- 22242330 TI - [Perspective on the treatment of myelodysplastic syndromes]. AB - The myelodysplastic syndromes (MDS) are acquired bone marrow disorders characterized by therapy-resistant cytopenias as a result of ineffective hematopoiesis and by preleukemic states. Diagnosis of MDS is done by clinical manifestations and hematological findings mainly according to the 4th WHO classification, but as it is sometimes difficult to discriminate MDS from other hematological diseases, a guideline for morphological evaluation is proposed. International Prognostic Scoring System is useful for choice of the treatment but this system is now under revision. Although most patients are fatal except the cases who receive successful stem cell transplantation, promising therapeutic drugs such as DNA hypomethylating agents and lenalidomide are developed and may alter the prognosis and quality of life of the patients suffering from MDS. PMID- 22242331 TI - [Progress in the management of multiple myeloma introduced by serum free light chain measurement]. AB - New immunoassay has been developed that allows the measurement of serum free light chains (FLC) more sensitive than currently available methods such as immunoelectrophoresis. This assay is useful especially in the diagnosis of BJP type multiple myeloma (MM), oligosecretory and nonsecretory MM. Baseline FLC value is the prognostic indicator of disease progression from MGUS and solitary plasmacytoma to symptomatic MM, and the prognostic factor of MM. In addition, uniform response criteria using FLC assay has been proposed by International Myeloma Working Group. This review summarized the recent information of the serum FLC assay in the diagnosis and management of MM. PMID- 22242332 TI - [Hypertension and insomnia]. AB - A total of 5747 workers (mean age: 43.8) were investigated to clarify the current state regarding insomnia and hypertension. Workers with hypertension were more likely to suffer from insomnia than those without hypertension, and workers with insomnia showed a significantly higher incidence of hypertension than those without insomnia, which suggested that insomnia and hypertension have a close relationship with each other. In addition, based on the results of this investigation, the following were clarified: many workers with insomnia do not spontaneously consult a physician, nor do they have interviews with a physician regarding sleep. They often remain untreated, or depend on nightcaps and/or over the-counter drugs according to their judgment, without receiving appropriate treatment with hypnotics. Diet and exercise therapies are important in the treatment of hypertension, but it is suggested that sleep therapy facilitating sufficient sleep is equally effective, and hypertension can be treated directly and indirectly through such therapy. PMID- 22242333 TI - Painful medicine. PMID- 22242334 TI - [Utilization of reinforced acetabular cages with caudal flange in reconstructing pelvic defect after acetabular tumor resection]. AB - OBJECTIVE: To evaluate the surgical procedure of reinforced acetabular cage with caudal flange in reconstruction of pelvic defect after acetabular tumor resection. METHODS: Between June 2003 and December 2009, 25 patients with Harrington class III pelvic defect underwent reconstruction with a reinforced acetabular cage with caudal flange and total hip arthroplasty (THA). There were 13 males and 12 females with an average age of 51.2 years (range, 13-73 years). The main clinical manifestations included hip pain and buttock pain, with a median disease duration of 6 months (range, 1-96 months). Pathological findings showed 18 cases of metastasis, 3 cases of multiple myeloma, 1 case of non Hodgkin's lymphoma, 1 case of grade I chondrosarcoma, 1 case of giant cell tumor, and 1 case of chondroblastoma. For the patient with chondroblastoma, THA with LINK RIBBED system was used. An artificial total hip system made in China was used in 6 patients and LINK SP II system was used in the other 18 patients. RESULTS: No patients died perioperatively. Deep infection and hip dislocations occurred in 1 and 2 patients, respectively. At last follow-up, 8 of 18 patients with metastasis died of cancer and the average survival time was 11 months. The other 10 who were alive were followed up 15 months on average. One patient with multiple myeloma died of pulmonary infection at 21 months after operation and the other 2 with multiple myeloma and 1 with lymphoma were alive with an average follow-up of 17 months. The patient with grade I chondrosarcoma and patient with chondroblastoma were followed up 58 and 12 months, respectively, without recurrence. Recurrence occurred in the patient with giant cell tumor at 19 months after operation. Loosening of implant occurred in 3 patients because of local tumor recurrence. For the 23 patients at 6 months after operation, the mean Musculoskeletal Tumor Society (MSTS) 93 score was 81% (range, 57%-93%). CONCLUSION: Reinforced acetabular cage with caudal flange could be used together with THA for reconstruction of Harrington class III pelvic defects after acetabular tumor resection, and low incidence of postoperative complication and good functional outcome could be expected. PMID- 22242335 TI - [Effectiveness evaluation of prosthetic revision for aseptic loosening in oncology prosthesis]. AB - OBJECTIVE: To evaluate the effectiveness of prosthetic revision using custom-made long stem prosthesis and allograft-prosthesis composite (APC) for aseptic loosening after bone tumor resection. METHODS: Between January 2002 and June 2008, 14 patients with aseptic loosening after bone tumor resection were treated. There were 8 males and 6 females, aged 21-70 years (mean, 43.9 years). The locations were distal femur (8 cases), proximal femur (2 cases), and proximal tibia (4 cases). Pain of the affected limb occurred after 6-31 years of prosthesis replacement and worsened when bearing and walking; 6 patients had shortened limb. The functional results were assessed quantitatively according to the functional rating system of the Musculoskeletal Tumor Society (MSTS). The MSTS score was 16.36 +/- 1.50 before revision. The X-ray films showed obvious prosthetic loosening and subsidence. The average time of symptom was 4.5 years (range, 3-9 years). In 7 patients having severe bone loss (the decrease of the thickness of cortical bone was more than 50%) and the prosthetic subsidence was more than 2 cm, the revision operation with the APC was performed; in 7 patients having less bone loss (the decrease of the thickness of cortical bone was less than 50%), the custom-made long stem prosthesis was performed. RESULTS: All wound healed by first intention. Two patients had temporary peroneal nerve paralysis and recovered after 3 months. All the patients were followed up 3.6 years on average (range, 2 years and 2 months- 7 years) after revision. After revision, pain was relieved and the range of joint was improved. The MSTS score was 23.43 +/- 2.56 at 12 months after revision showing significant difference when compared with the preoperative score (t = 8.910, P = 0.024). The X-ray films showed that lucency space line around stem cement in 2 patients at 12 months, and no prosthesis loosening and infection occurred. CONCLUSION: The prosthetic revision after limb salvage surgery with prosthesis for bone tumors was acceptable. The good functional results can be achieved by the revision with the APC or the custom-made long stem prosthesis according to the bone loss. PMID- 22242336 TI - [Reason analysis and treatment of acetabular component initial instability after primary total hip arthroplasty]. AB - OBJECTIVE: To analyze the main reasons of acetabular component initial instability after primary total hip arthroplasty (THA) and to discuss the prevention and management. METHODS: The clinical data were retrospectively analyzed from 19 patients undergoing revision for acetabular component initial instability after primary THA between January 2003 and June 2010. There were 11 males and 8 females, aged from 55 to 79 years (mean, 67.2 years). The locations were left hip in 9 cases and right hip in 10 cases. The cementless hip prosthesis was used in 12 cases and cement hip prosthesis in 7 cases. The revisions were performed at 3 weeks to 6 months after primary THA. The reasons of early failure were analyzed. Both the coverage rate of acetabulum-bone and the Harris hip score were compared between pre- and post-revision. RESULTS: The main reason of acetabular component initial instability after primary THA may be unsuitable treatment of acetabulum, improper selection of acetabular component, and incorrect place angle of acetabular component. Sciatic nerve palsy occurred in 1 case and recovered at 7 weeks after revision. Slight fracture of the acetabulum in 1 case and healed at 3 months after revision. All incisions healed by first intention. No infection, vessel injury, displacement of acetabular component, or deep vein thrombosis occurred. The patients were followed up 11-73 months (mean, 28 months). At last follow-up, no acetabular component instability was observed. The coverage rate of acetabulum-bone was increased from 67.9% +/- 5.5% before revision to 87.7% +/- 5.2% after revision, showing significant difference (t = 11.592, P = 0.003). The Harris hip score at last follow-up (84.4 +/- 4.6) was significantly higher than that at pre-revision (56.5 +/- 9.3) (t = 11.380, P = 0.005). CONCLUSION: Detailed surgical plan, proper choice of component, correct place angle and elaborative planning, and proficient surgical skill are necessary to achieve the initial stability of acetabular component in THA. PMID- 22242337 TI - [Application of acetabular tridimensional memory alloy-fixation system in treatment of old acetabular posterior wall fracture with bone defect]. AB - OBJECTIVE: To investigate the effectiveness of acetabular tridimensional memory alloy-fixation system (ATMFS) combined with autologous iliac bone in the treatment of old acetabular posterior wall fracture with bone defect. METHODS: Between January 2002 and February 2009, 17 patients with old acetabular posterior wall fracture and bone defect were treated, including 11 males and 6 females with an average age of 41.7 years (range, 20-60 years). The time from fracture to admission was 14-180 days (mean, 63 days). The displacement of the acetabular articular surface was more than or equal to 3 mm. According to the America Association of Orthopedic Surgeon (AAOS) acetabular fracture and defect classification standard, there were 4 cases of type I, 6 cases of type II, 5 cases of type III, and 2 cases of type IV. After the residual fracture fragments of the acetabular posterior wall and soft tissue hyperplasia were removed, the femoral head was reduced, and posterior wall defect was repaired with autologous iliac bone graft; ATMFS was used to fix acetabular posterior wall and artificial capsular ligament to reconstruct the hip so as to prevent re-dislocation of the femoral head. RESULTS: According to Matta imaging assessment standard, the results were excellent in 8 cases, good in 6 cases, fair in 2 cases, and poor in 1 case with an excellent and good rate of 82.3%. All incisions healed by first intention, and no sciatic nerve injury occurred. All patients were followed up 1 8 years (mean, 3.9 years). The mean time of fracture union was 3.6 months (range, 2-6 months). Avascular necrosis of femoral head occurred in 1 case, heterotopic ossification around the acetabulum in 1 case. According to Merle d'Aubigne-Postel scoring system evaluation, the clinical results were excellent in 9 cases, good in 6 cases, fair in 1 case, and poor in 1 case with an excellent and good rate of 88.2%. CONCLUSION: ATMFS combined with autologous iliac bone graft and artificial ligament reconstruction of the hip joint capsule is a good choice for the treatment of old acetabular posterior wall fractures with bone defect, which can resume the posterior hip joint stability and prevent re-dislocation of the femoral head. PMID- 22242338 TI - [Operative treatment of sacroiliac joint fracture and dislocation in Tile C pelvic fracture with Colorado 2 system]. AB - OBJECTIVE: To explore the effectiveness of Colorado 2 system in the stability reconstruction of sacroiliac joint fracture and dislocation in Tile C pelvic fracture. METHODS: Between February 2009 and January 2011, 8 cases of Tile C pelvic fracture were treated with Colorado 2 system. There were 3 males and 5 females with an average age of 34.4 years (range, 22-52 years). Fractures were caused by traffic accident in 3 cases, by falling from height in 3 cases, and by crash of heavy object in 2 cases. According to Tile classification, 5 cases were classified as C1-2, 2 cases as C1-3, and 1 case as C2. The time between injury and operation was 5-10 days (mean, 7 days). After skeletal traction reduction, Colorado 2 system was used to fix sacroiliac joint, and reconstruction plate or external fixation was selectively adopted. RESULTS: The postoperative X-ray films showed that the reduction of vertical and rotatory dislocation was satisfactory, posterior pelvic ring achieved effective stability. All the incisions healed by first intention, and no blood vessel or nerve injury occurred. Eight patients were followed up 6-24 months (mean, 12 months). No loosening or breakage of internal fixation was observed and no re-dislocation of sacroiliac joint occurred. The bone healing time was 6-12 months (mean, 9 months). According to Majeed's functional criterion, the results were excellent in 5 cases, good in 2 cases, and fair in 1 case at last follow-up. CONCLUSION: Colorado 2 system could provide immediate stability of pelvic posterior ring and good maintenance of reduction effect, which is an effective method in the therapy of sacroiliac joint fracture and dislocation in Tile C pelvic fracture. PMID- 22242339 TI - [Effectiveness of medial-lateral double plate internal fixation in treating type C distal humeral fractures]. AB - OBJECTIVE: To evaluate the effectiveness of open reduction and medial-lateral double plate internal fixation for type C distal humeral fractures. METHODS: Between June 2002 and January 2009, 32 patients with distal humeral intra articular fractures were treated. There were 19 males and 13 females, aged 19-70 years (mean, 43.3 years). The fracture was caused by falling in 7 cases, by traffic accident in 15 cases, by falling from height in 5 cases, by crush injury in 4 cases, and by machine injury in 1 case. The time from injury to operation was 8 hours-7 days (mean, 3.3 days). Of 32 patients, 1 had open fracture and 31 had closed fracture; 5 patients complicated by injury of ular nerve. According to AO/Association for the Study of Internal Fixation (AO/ASIF) classification, there were 9 cases of type C1, 16 of type C2, and 7 of type C3. Open reduction and medial-lateral double plate internal fixation were performed through posterior midline approach in 8 cases and through medial-lateral two-incision approaches in 24 cases. RESULTS: All incisions healed by first intention. The 32 cases were followed up 11-24 months (mean, 14 months). The X-ray films showed that all fractures healed at 3-6 months (mean, 3.8 months). According to Aitken et al. scoring system, the results were excellent in 22 cases, good in 6 cases, fair in 3 cases, and poor in 1 case with an excellent and good rate of 87.5%. In 5 patients with injury of ular nerve, 4 cases completely recovered at 6 months and 1 case still showed some symptoms after 1 year. CONCLUSION: Treatment of type C distal humeral fractures with open reduction and medial-lateral double plate internal fixation can get good clinical results. PMID- 22242340 TI - [Histomorphometric analysis of articular cartilage and subchondral bone from primary osteoarthritic knees]. AB - OBJECTIVE: To investigate the pathologic characteristics of the articular cartilage and subchondral bone from osteoarthritic knees, and to compare the structural parameters of articular cartilage and subchondral bone between the medial and lateral tibial plateau, so as to determine the role of calcified zone and subchondral bone in the pathogenesis of osteoarthritis (OA). METHODS: The tibial plateaus were taken from 30 patients undergoing total knee arthroplasty between October 2009 and May 2011. The subjects included 11 males and 19 females with an average age of 65.1 years (range, 55-78 years). The mean disease duration was 16.6 years (range, 10-25 years); the mean varus angle of the diseased knee was 9.3 degrees (range, 1-23 degrees). After gross observation, the cartilage bone samples were taken out from the most weight-bearing regions in the internal areas of the medial and lateral plateaus. The decalcified paraffin-embedded sections were prepared and stained with HE and Safranin O/fast green for cartilage assessment (Mankin score), staging, and bone histomorphometry; the pathologic features of the cartilage and subchondral bone were also observed. The thickness of total articular cartilage (TAC), articular calcified cartilage (ACC), subchondral bone plate (SCP), and the trabecular bone volume (BV/TV) were measured by Image Pro Plus 6.0 imaging system, then the ratio of ACC/TAC was calculated. RESULTS: Macroscopic results showed that articular cartilage degeneration was more severe in the medial plateau than in the lateral plateau; Mankin score of the medial plateau (12.4 +/- 1.1) was significantly higher than that of the lateral plateau (8.3 +/- 1.6) (t = 12.173, P = 0.000). In the 60 samples, 14 samples were at stage I, characterised by fissures within the superficial zone, duplicated tidemark, and thickened subchondral bone; 19 samples were at stage II, characterised by fissures extending into the deep zone, multiple subchondral bone resorption pits, and obviously thickened subchondral bone; and 27 samples were at stage III, characterised by full-thickness cartilage defects, endochondral ossification, and eburnated subchondral bone. The bone histomorphometric study showed that TAC thickness of the medial plateau was significantly lower than that of the lateral plateau (P < 0.05); the ratios of ACC/TAC, BV/TV, and SCP thickness of the medial plateau were significantly higher than those of the lateral plateau (P < 0.05). However, there was no significant difference in the ACC thickness between the medial and lateral plateaus (P > 0.05). CONCLUSION: The calcified zone and subchondral bone may play an important role in the initiation and progression of OA. PMID- 22242341 TI - [Effectiveness analysis of Vertex rod-screw system in cervical expansive open door laminoplasty]. AB - OBJECTIVE: To evaluate the clinical application value and short-term results of Vertex rod-screw system in cervical expansive open-door laminoplasty. METHODS: Between February 2008 and January 2010, 28 patients underwent Vertex rod-screw system fixation in cervical expansive open-door laminoplasty, including 15 cases of cervical spondylotic myelopathy, 5 cases of ossification of posterior longitudinal ligament, and 8 cases of cervical spondylosis with spinal stenosis. There were 16 males and 12 females, aged 42-77 years (mean, 61.3 years). The disease duration was 2 months to 11 years. The decompression range of cervical spine was from C3 to C7. The operation time, blood loss, Japanese Orthopedic Association (JOA) scores, and incidence of axial symptom were recorded. Pre- and postoperative curvature angles were demonstrated by the cross angle between posterior vertebral body margins of C2 and C7 on cervical X-ray films. The angle of the opened laminae was measured on CT scan at last follow-up. RESULTS: The operation time was (142.5 +/- 22.8) minutes, and the blood loss was (288.2 +/- 55.1) mL. All incisions healed by first intention. All patients were followed up 14-25 months (mean, 22 months). CT showed that no reclosed open-laminae or loosening and breakage of rod-screw system occurred at 1 week and 1 year after operation. The axial bony fusion rate was 89.3% (25/28). The improvement rate of JOA scores at 1 week after operation (29.5% +/- 15.0%) was significantly smaller than that at 1 year after operation (64.9% +/- 28.1%) (t = 0.810, P = 0.000). No case presented with C5 nerve root palsy. The cervical curvature angle was (24.29 +/- 5.04) degrees before operation, was (23.89 +/- 3.57) degrees at 1 week, and was (23.41 +/- 3.35) degrees at 1 year after operation, showing no significant difference between pre- and postoperative angles (P > 0.05). The angle of the opened laminae was (27.90 +/- 4.74) degrees at 1 week after operation, and was (28.07 +/- 4.21) degrees at 1 year after operation, showing no significant difference (P > 0.05). CONCLUSION: Vertex rod-screw system in cervical expansive open-door laminoplasty is effective in preventing reclosed open-laminae, which can reduce the loss of cervical curvature angle. PMID- 22242342 TI - [Anatomic study on percutaneous anterior transarticular screw fixation by CT three-dimensional imaging]. AB - OBJECTIVE: To improve the safety of the percutaneous anterior transarticular screw fixation (PATSF) by measuring the parameters related to PATSF. METHODS: Spiral CT scan and three-dimensional reconstructions of the atlanto-axis were performed in 50 adult volunteers. The section of inner margin of atlantal superior articular facet, the coronal plane vertebral artery cavity, and the sagittal plane of atlanto-axis were obtained with multiplanar reconstruction on helical CT. atlantoaxial vertebral structure and the direction of vertebral artery cavity were observed. The parameters related to PATSF measured and analysed. RESULTS: The suitable position of screw insertion was 4.0 mm from the midpoint of the axoidean anteroinferior margin. The maximum external angle of PATSF was (29.89 +/- 1.41) degrees; the minimum external angle was (4.37 +/- 0.87) degrees; the maximum backward angle was (32.41 +/- 1.66) degrees; the optimal external angle was (17.13 +/- 0.88) degrees; the optimal backward was (17.62 +/- 1.03) degrees; and the optimal screw length was (41.57 +/- 0.79) mm. The atlantoaxial articular facial diameter was (16.71 +/- 1.61) mm; the maximum distance of atlantal lateral displacement was (6.96 +/- 1.09) mm; and the ratio of them was 41.80% 5.69%. CONCLUSION: The optimal insertion of PATSF is safe and reliable. The screw can be inserted when the displacement the atlantal lateral mass is in a certain degree. PMID- 22242343 TI - [Surgical treatment of degenerative lumbar instability by minimally invasive transforaminal lumbar interbody fusion]. AB - OBJECTIVE: To investigate the effectiveness of surgical treatment for single level degenerative lumbar instability (DLI) by comparing traditional open transforaminal lumbar interbody fusion (TLIF) with minimally invasive TLIF. METHODS: Between March 2007 and May 2009, 87 patients with single-level DLI were treated by traditional open TLIF (group A, n = 45) and by minimally invasive TLIF (group B, n = 42), respectively. There was no significant difference in gender, age, disease duration, segment level, combined diseases of lumbar spine, or the proportion of uni- and bilateral symptom between 2 groups (P > 0.05). The indexes of surgical trauma, systemic inflammatory response, clinical outcomes, and paravertebral muscle injury were compared between 2 groups. RESULTS: Operation was performed successfully in all patients. The patients were followed up 2.9 years on average in group A and 2.8 years on average in group B. The incision, blood loss, and postoperative drainage in group B were significantly less than those in group A (P < 0.05), but the operation time in group B was significantly longer than that in group A (P < 0.05). There were significant differences (P < 0.05) in C-reactive protein, leucocyte count, and creatine kinase MM between 2 groups at 24 hours postoperatively as well as in C-reactive protein at 6 days postoperatively; group B was superior to group A. At last follow-up, the Oswestry disability index (ODI) and visual analogue score (VAS) were significantly improved when compared with the preoperative scores in 2 groups (P < 0.05). There were significant differences in ODI and back pain VAS score (P < 0.05), but no significant difference in leg pain VAS score (P > 0.05) between 2 groups. At last follow-up, no low back pain occurred in 8 and 18 cases, mild in 25 and 18 cases, moderate in 9 and 6 cases, and severe in 3 and 0 cases in groups A and B, respectively, showing that low back pain was significantly lighter in group B than in group A (Z = 2.574, P = 0.010). At last follow-up, the atrophy ratio of multifidus muscle was 37% +/- 13% in group A and was 15% +/- 7% in group B, showing significant difference (t = 12.674, P = 0.000). The multifidus muscle atrophy was rated as grade I in 18 and 44 sides, as grade II in 42 and 32 sides, and as grade III in 30 and 8 sides in groups A and B, respectively, showing significant difference (Z = -4.947, P = 0.000). CONCLUSION: Both traditional open TLIF and minimally invasive TLIF are the effective treatments for single-level DLI. Minimally invasive TLIF has less surgical trauma, slighter postoperative systemic inflammatory response, less paravertebral muscle injury, and lower incidence of postoperative back pain, but it has longer operation time. PMID- 22242344 TI - [Effect of low frequency pulsed electromagnetic fields on lumbar bone histomorphometry in ovariectomized osteoporosis rats]. AB - OBJECTIVE: To investigate the changes of lumbar bone histomorphometry after exposure to low frequency pulsed electromagnetic fields (PEMFs), and to further understand the effect of PEMFs on osteoporosis (OP) in ovariectomized OP rats. METHODS: Sixty-six 3-month-old Sprague Dawley rats were randomly divided into 4 groups: group A (n = 12), group B (n = 12), group C (n = 12), and group D (n = 30). In group A, the ovaries were not resected as sham-ovariectomy; in groups B, C, and D, the ovaries were resected. At 12 weeks after ovariectomy, the rats were exposed to PEMFs at 8 Hz, 3.8 mT, and 40 minutes/day for 30 days in group B; the rats were administered with premarin [0.065 mg/(kg x d) by gavage for 30 days] in group C; in group D, the rats were housed as ovariectomy control. The hair and activity of rats were observed; the levels of serum estradiol were determined. At 30 days after intervention, all rats were sacrificed to harvest the L4 vertebrae for bone histomorphometry. RESULTS: General observation showed hair loss and decreased activity in group D, and no abnormal appearances in groups A, B, and C. The level of serum estradiol in group A was significantly higher than that in group D [(54.93 +/- 23.52) pg/mL vs. (31.99 +/- 23.45) pg/mL] (t = 2.345, P = 0.029). Histological observation showed thinness of sclerotin, bigger medullary cavity, and sparse and thinner bone trabecula in group D; uniform bone trabecula with no breakage in groups A, B, and C at 30 days after intervention. The ratio of trabecular bone area in group B was significantly higher than that in group D (P < 0.05); it was higher than that in groups A and C, showing no significant difference (P > 0.05). The trabecular thickness in group B was significantly higher than that in group D (P < 0.05), but it was lower than that in groups A and C, showing no significant difference (P > 0.05). The trabecular number in group B was significantly lower than that in group D (P < 0.05), but it was higher than that in groups A and C, showing no significant difference (P > 0.05). The trabecular separation in group B was higher than that in group D and lower than that in groups A and C, showing no significant difference (P > 0.05). CONCLUSION: PEMFs at 8 Hz and 3.8 mT can significantly improve the character of bone microstructure in ovariectomized OP rats, increase the ratio of bone trabecular area and trabecular thickness, and decrease the trabecular number. PMID- 22242345 TI - [Dermal pedicled nasolabial flap with subdermal vascular network for repairing nasolabial skin defects]. AB - OBJECTIVE: To evaluate the effectiveness of the dermal pedicled nasolabial flap with subdermal vascular network for repairing nasolabial skin defects. METHODS: Between July 2008 and July 2011, 43 cases of nasolabial defects were repaired with dermal pedicled nasolabial flap with subdermal vascular network. There were 22 males and 21 females with a median age of 36 years (range, 6-68 years). All defects were caused by excision of lesions, including pigmented nevus in 23 cases, scar in 16 cases, and inflammatory granuloma in 4 cases. The disease duration was 3 months to 35 years. Lesions were located at the tip of the nose in 11 cases, at the alae of the nose in 10 cases, at the alae and tip of the nose in 10 cases, at the alar groove of the nose in 8 cases, and at upper lip in 4 cases. The defect size ranged from 0.7 cm x 0.5 cm to 1.2 cm x 1.0 cm. The flap size ranged from 1.0 cm x 0.7 cm to 1.5 cm x 1.2 cm. RESULTS: All flaps survived and incisions at donors and wound healed by first intention. After operation, 34 patients were followed up 6-12 months (mean, 10 months). The texture and color of the flap were similar to adjacent skin. No obvious scar was observed at donor sites. CONCLUSION: The dermal pedicled nasolabial flap with subdermal vascular network has the advantages of flexible flap transplantation, small damage to donor site, and low incidence of bloated subcutaneous tunnel. PMID- 22242346 TI - [V-U-shaped flaps for repairing soft tissue defect of fingertip]. AB - OBJECTIVE: To investigate the method and effectiveness of V-U-shaped flaps in repairing soft tissue defect of the fingertip. METHODS: Between January 2006 and February 2011, 47 patients (55 fingers) with soft tissue defect of fingertip were treated by using the V-U-shaped flaps. There were 25 males and 22 females, aged 18 to 35 years (mean, 26 years). The injury was caused by cuts in 21 cases and avulsion in 26 cases. The time between injury and admission was 1 to 6 hours with an average of 2.6 hours. The injured fingers included thumb (18 fingers), index finger (10 fingers), middle finger (10 fingers), ring finger (9 fingers), and little finger (8 fingers). Forty-one fingers had skin avulsion of the distal interphalangeal joint with phalanx exposure, and 14 fingers had distal dactylopodite defect and second phalanx exposure. The size of wound ranged from 1.1 cm x 1.0 cm to 1.9 cm x 1.7 cm. The time between injury and first-stage operation was 2 to 7 hours with an average of 5 hours. In the first-stage operation, the pedicled flap was used to repair the defect of dactylopodite. Then at 3 weeks after the first-stage operation, one U-shaped flap and two V-shaped flaps were prepared to cover defect of the fingertips in the second-stage operation. RESULTS: At 2 days after the second-stage operation, congestion and blisters occurred in 5 fingers, and were improved after symptomatic treatment. The other flaps survived, and wounds healed by first intention. Incisions at the donor site healed primarily. After the second-stage operation, 42 cases (50 fingers) were followed up 6 to 12 months (mean, 8.9 months). The appearance, texture, and color of the flaps were similar to normal skin. Injured fingers had tactile, pain, and thalposis, and the two point discrimination was 5-8 mm. At last follow-up, according to the functional assessment standards by the Chinese Medical Association Society of Hand Surgery of the upper limbs, the results were excellent in 46 fingers and good in 4 fingers. CONCLUSION: V-U-shaped flaps can be considered as an ideal method to repair soft tissue defect of the fingertip because of good appearance and function recovery. PMID- 22242347 TI - [Reconstruction of full-thickness chest wall defects]. AB - OBJECTIVE: To investigate the surgical techniques and effectiveness for reconstruction of severe full-thickness chest wall defects. METHODS: Between January 2006 and December 2010, 14 patients with full-thickness chest wall defects were treated, including 12 cases caused by giant chest wall malignant tumor excision, 1 case by thermocompression injury, and 1 case by radiation necrosis. There were 8 males and 6 females with an average age of 42 years (range, 23-65 years). The size of chest wall defects ranged from 8 cm x 5 cm to 26 cm x 14 cm. All patients complicated by rib defect (1-5 ribs), and 3 cases by sternum defect. Thoracic skeleton reconstruction was performed with Vicryl mesh or polytetrafluoroethylene mesh in 10 patients. Other 4 patients did not undergo thoracic skeleton reconstruction. The bilobed skin flaps, pectoralis major myocutaneous flap, latissimus dorsi myocutaneous flap, and rectus abdominis myocutaneous flap were utilized for repairing soft tissue defects. The size of the dissected flaps ranged from 10 cm x 7 cm to 25 cm x 13 cm. The donor sites were sutured directly or were repaired by free skin graft. RESULTS: Poor healing of incision occurred in 2 cases, which was cured after debridement, myocutaneous flap transfer, and skin graft. The other wounds healed by first intention. All patients were followed up 6-36 months (mean, 8 months). No tumor recurrence during follow-up, except 1 patient with osteosarcoma who died of liver metastasis at 6 months after operation. Transient slight paradoxical respiration occurred in 1 patient who did not undergo thoracic skeleton reconstruction at 5 days after operation. Integrity of chest wall in other patients was restored without paradoxical respiration and dyspnea. CONCLUSION: Depending on the cause, the size, and the location of defect, single or combination flaps could be used to repair soft tissue defect, and thoracic skeleton reconstruction should be performed when defect is severe by means of synthetic materials. PMID- 22242348 TI - [Clinical application of three-dimensional reconstruction of CT images in treating mandibular angle hypertrophy]. AB - OBJECTIVE: To investigate the clinical directive significance of three dimensional reconstruction of CT in treating mandibular angle hypertrophy. METHODS: Between March 2009 and January 2011, 18 patients with mandibular angle hypertrophy were treated using the three-dimensional reconstruction technology of CT. All patients were female, aged 20-36 years with an average of 25 years. Eighteen patients included: 14 single mandibular angle hypertrophy, 3 mandibular angle hypertrophy with masseter hypertrophy, and 1 mandibular angle hypertrophy with bilateral asymmetry; 6 cases of ptosis of mandibular angle, 9 cases of prominent mandibular angle, and 3 cases of introversive mandibular angle. According to the types of mandibular angle hypertrophy, the surgical methods could be correctly chosen. The procedure was planned and simulated; the osteotomy line was marked and the osteotomy was measured on the workstations of three dimensional reconstruction. RESULTS: No fracture of mandible occurred in the operation. Facial nerve temporary attack occurred in 1 case and recovered at 3 months after operation. All patients were followed up 6-12 months (mean, 7.6 months). After 6 months of operation, the effectiveness was satisfactory in 15 cases, basically satisfactory in 2 cases, and unsatisfactory in 1 case (bilateral asymmetry). CONCLUSION: Based on three-dimensional reconstruction technology of CT, surgical design performed on the model will promote the accuracy of operation. Basically symmetrical appearances can be achieved with satisfactory results. PMID- 22242349 TI - [Effectiveness of two-stage operation of auricular reconstruction in treatment of lobule-type microtia]. AB - OBJECTIVE: To investigate the method and effectiveness of two-stage operation of auricular reconstruction in treating lobule-type microtia. METHODS: Between March 2007 and April 2010, 19 patients (19 ears) of lobule-type microtia were treated. There were 13 males and 6 females, aged 5 to 27 years (mean, 12.6 years). Of 19 patients, 11 were less than or equal to 14 years old. The locations were left ear in 9 cases and right ear in 10 cases. Two-stage operation for auricular reconstruction of lobule-type microtia included fabrication and grafting of the costal cartilage framework at the first-stage operation and the ear elevation operation at the second-stage operation. RESULTS: Pseudomonas aeruginosa infection occurred in 1 patient after the first-stage operation, who was not given the second-stage operation. Skin necrosis occurred in 1 patient 8 days after the second-stage operation and healed after symptomatic treatment. Eighteen patients were followed up 6 months to 2 years (mean, 14 months). Retraction of cranioauricular angle and thoracic deformity occurred in 1 patient. The surgical results were satisfactory in the other 17 patients whose reconstructive ear had verisimilar shape and suitable cranioauricular angle. CONCLUSION: Two-stage operation of auricular reconstruction is considered to be an ideal method for lobule-type microtia. PMID- 22242350 TI - [Primary clinical application of high-intensity focused ultrasound on infant hemangiomas]. AB - OBJECTIVE: To explore the effectiveness and appropriate energy parameters of high intensity focused ultrasound (HIFU) in treating infant hemangiomas. METHODS: Between January 2009 and September 2010, 60 infants with hemangioma were treated. There were 23 boys and 37 girls, aged from 3 to 30 months with an average of 10 months. These hemangiomas were located at head and face (24 cases), trunk (15 cases), limb (16 cases), buttocks (2 cases), perineum (1 case), and multiple lesions (cervix, abdomen, and upper limbs, 2 cases). The size of hemangiomas ranged from 0.8 cm x 0.6 cm to 6.0 cm x 5.0 cm. The 60 infants were randomly divided into 3 groups: groups A, B, and C (n = 20) based on different ultrasound energies used in treatment. The lesion surface was irradiated with 3-5 mm/second for 5 continuously by ultrasonic therapeutic apparatus at a frequency of 9 MHz, impulse of 1 000, and 10% of scanning overlap; the powers of 3.5, 4.0, and 4.5 W were used in groups A, B, and C, respectively, 3 times as a course of treatment with 1 month interval. The effect and ulcer and scar risk in irradiation region were observed after 6 months of treatment. RESULTS: All cases were treated for one course. After 6 months of treatment, no significant difference in the effect was found among 3 groups based on hemangioma treatment judging criterion (P > 0.05). Neither ulcer nor scar occurred in group A; ulcer occurred in 4 cases (20%) of group B with superficial scars, and in 7 cases (35%) of group C with obvious scars. The rates of ulcer and scar in groups B and C were significantly higher than that in group A (P < 0.05). CONCLUSION: HIFU irradiating is one of effective methods for treating infant hemangioma, but the appropriate energy was below 3.5 W. PMID- 22242351 TI - [Experimental research of astragalus polysaccharides collagen sponge in enhancing angiogenesis and collagen synthesis]. AB - OBJECTIVE: Astragalus polysaccharide (APS) has promoting angiogenesis function. To explore the effects of APS collagen sponge on enhancing angiogenesis and collagen synthesis so as to provide evidence for the future tissue engineering application as a kind of angiogenic scaffold. METHODS: APS collagen sponges were prepared by covalent binding with collagen polypeptides by using of crosslinking agents at the ratio of 1 : 1 (W/W). Twenty 10-week-old Sprague Dawley rats (10 males and 10 females, and weighing 200-250 g) were selected. Longitudinal incision was made at both sides of the back to form subcutaneous pockets. APS collagen sponges of 5 mm x 5 mm x 5 mm at size were implanted into the left pockets as the experimental group, collagen sponges without APS of the same size into the right pockets as the control group. The general conditions were observed after operation. At 3, 7, 14, and 21 days, 5 rats were sacrificed and the samples were harvested to count the number of microvessels, to measure the contents of the hydroxyproline (Hyp), and to detect the mRNA expressions of angiopoietin 1 (Ang1), matrix metalloproteinases 9 (MMP-9), and tissue inhibitors of metalloproteinases 1 (TIMP-1). RESULTS: All rats were alive during experiment period. The number of microvessels increased gradually, and reached the peak at 14 days in 2 groups; the experimental group was significantly higher than the control group (P < 0.05). The contents of Hyp increased gradually in 2 groups, and the experimental group was significantly higher than the control group (P < 0.05). The mRNA expressions of Ang1 and MMP-9 in the experimental group were significantly higher than those in the control group at 3, 7, and 14 days (P < 0.05); the mRNA expression of TIMP-1 in the experimental group was significantly lower than that in the control group at 3 days and was significantly higher at 14 and 21 days (P < 0.05). CONCLUSION: The APS collagen sponges can improve angiogenesis and collagen synthesis in wound healing by regulating the expressions of Ang1, MMP-9, and TIMP-1. PMID- 22242352 TI - [Experimental study on osteogenic differentiation of adipose-derived stem cells treated with different concentrations of dexamethasone]. AB - OBJECTIVE: Dexamethasone is one of the basic agents which could induce osteogenic differentiation of mesenchymal stem cells. To investigate the optimal concentration of dexamethasone in osteogenic differentiation of adipose-derived stem cells (ADSCs) so as to provide the theoretical basis for further bone tissue engineering researches. METHODS: Five New Zealand rabbits (2-3 kg) of clean grade, aged 3 months and male or female, were obtained. ADSCs were isolated from the subcutaneous adipose tissue of inguinal region, and cultured with collagenase digestion, then were detected and identified by CD44, CD106 immunofluorescence staining and adipogenic differentiation. ADSCs at passage 3 were used and the cell density was adjusted to 1 x 10(5) cells/mL, then the cells were treated with common cultural medium (group A) and osteogenic induced medium containing 0 (group B), 1 x 10(-9) (group C), 1 x 10(-8) (group D), 1 x 10(-7) (group E), 1 x 10(-6) (group F), and 1 x 10(-5) mol/L (group G) dexamethasone, respectively. The cell proliferation and the mRNA expressions of osteocalcin (OC) and core binding factor alpha1 (Cbfalpha1) were detected by MTT and RT-PCR, respectively. The activity of alkaline phosphatase (ALP) was measured, and the percentage of mineral area was calculated. The mineral nodules were also detected by alizarin red staining. RESULTS: ADSCs mostly presented fusiform and polygon shape with positive expression of CD44 and negative expression of CD106. The result of oil red O staining was positive after ADSCs treated with adipogenic induced medium. The result of MTT revealed that the absorbance (A) value declined with the ascending of the concentration of dexamethasone, and there was significant difference in A value between groups D and E at 5 and 7 days after osteogenic induction (P < 0.05). The mRNA expressions of OC and Cbfal reached the peak in groups E and D at 7 days after osteogenic induction, respectively. The activity of ALP and the percentage of mineral area had the maximum value in group D at 14 days, then declined gradually. There was no significant difference in the mRNA expressions of OC and Cbfalpha1, the activity of ALP, and the percentage of mineral area between groups D and E (P > 0.05), but significant differences were found between groups D and E and other groups (P < 0.05). After 14 days, the cells of group G died, and the result of alizarin red staining was positive in groups B, C, D, E, and F. CONCLUSION: When the concentration of dexamethasone in osteogenic medium is 1 x 10(-8) mol/L, it could not only reduce the inhibitive effect on cells proliferation, but also induce osteogenic differentiation of ADSCs more efficiently. PMID- 22242353 TI - [Experimental study on ectopic bone formation of chitosan/phosphonic chitosan sponge combined with human umbilical cord mesenchymal stem cells]. AB - OBJECTIVE: To investigate the ectopic bone formation of the chitosan/phosphonic chitosan sponge combined with human umbilical cord mesenchymal stem cells (hUCMSCs) in vitro. METHODS: Phosphorous groups were introduced in chitosan molecules to prepare the phosphonic chitosan; 2% chitosan and phosphonic chitosan solutions were mixed at a volume ratio of 1 : 1 and freeze-dried to build the complex sponge, and then was put in the simulated body fluid for biomimetic mineralization in situ. The hUCMSCs were isolated by enzyme digestion method from human umbilical cord and were cultured. The chitosan/phosphonic chitosan sponge was cultured with hUCMSCs at passage 3, and the cell-scaffold composite was cultured in osteogenic medium. The growth and adhesion of the cells on the scaffolds were observed by light microscope and scanning electron microscope (SEM) at 1 and 2 weeks after culturing, respectively. The cell proliferation was detected by MTT assay at 1, 2, 3, 4, 5, and 6 days, respectively. Bilateral back muscles defects were created on 40 New Zealand rabbits (3-4 months old, weighing 2.1-3.2 kg, male or female), which were divided into groups A, B, and C. In group A, cell-scaffold composites were implanted into 40 right defects; in group B, the complex sponge was implanted into 20 left defects; and in group C, none was implanted into other 20 left defects. The gross and histological observations were made at 4 weeks RESULTS: The analysis results of phosphonic chitosan showed that the phosphorylation occurred mainly in the hydroxyl, and the proton type and chemical shifts intensity were conform to its chemical structure. The SEM results showed that the pores of the chitosan/phosphonic chitosan sponge were homogeneous, and the wall of the pore was thinner; the coating of calcium and phosphorus could be observed on the surface of the pore wall after mineralized with crystal particles; the cells grew well on the surface of the chitosan/phosphonic chitosan sponge. The MTT assay showed that the chitosan/phosphonic chitosan sponge could not inhibit the proliferation of hUCMSCs. The gross observation showed that the size and shape of the cell scaffold composite remained intact and texture was toughened in group A, the size of the complex sponge gradually reduced in group B, and the muscle defects wound healed with a little scar tissue in group C. The histological observation showed that part of the scaffold was absorbed and new blood vessels and new bone trabeculae formed in group A, the circular cavity and residual chitosan scaffolds were observed in group B, and the wound almost healed with a small amount of lymphocytes in group C. CONCLUSION: The chitosan/phosphonic chitosan sponge has good biocompatibility, the tissue engineered bone by combining the hUCMSCs with chitosan/phosphonic chitosan sponge has the potential of the ectopic bone formation in rabbit. PMID- 22242354 TI - [Effects of adipose-derived stem cells-hyaluronic acid composite on healing of wound combined with radiation injury]. AB - OBJECTIVE: To observe and explore the effects of adipose-derived stem cells (ADSCs)-hyaluronic acid (HA) composite on healing of wound combined with radiation injury. METHODS: The ADSCs were harvested from the fat tissue in groin of 10 inbred Sprague Dawley (SD) rats and were isolated and cultured by enzyme digestion. The ADSCs-HA composite was prepared with ADSCs (5 x 10(6) cells/mL) at passage 6 and HA (10 mg/mL). Thirty inbred SD rats, 15 males and 15 females, were randomly divided into groups A (n = 10), B (n = 10), and C (n = 10). A 2 cm x 2 cm full-thickness skin defect was made on the rat back before 20 Gy 60Co radiation exposure. One week after debridement, wounds were treated by petrolatum gauze in group A as the control group, by HA (0.4 mL) and petrolatum gauze in group B, and by ADSCs-HA composite (0.4 mL) and petrolatum gauze in group C. The microvessel density (MVD) and the distribution of CD90 positive cells were observed at 1st, 2nd, 3rd, and 4th weeks. RESULTS: The wound healing was slower, and wound did not heal at 4th week and still filled with granulation tissue in group A; the wound healing of group B was faster than that of group A, and the wound did not heal completely with depression in the center at 4th week; the wound healed completely with epidermilizated surface and no obvious depression at 4th week in group C. The histological observation showed that MVD was significantly higher in group C than in groups A and B at the 1st, 2nd, and 3rd weeks (P < 0.05), and in group B than in group A at the 3rd week (P < 0.05); MVD was significantly higher in groups B and C than in group A (P < 0.05), but no significant difference was found between groups B and C (P > 0.05) at 4th week. No CD90 positive cell was found in groups A and B; CD 90 positive cells were observed in group C and gradually decreased with time. CONCLUSION: ADSCs-HA composite can accelerate healing of wound combined with radiation injury by promoting and controlling wound angiogenesis. PMID- 22242355 TI - [Application of synovium-derived mesenchymal stem cells in tissue engineering]. AB - OBJECTIVE: To review the research application and advance of synovium-derived mesenchymal stem cells (SMSCs) in tissue engineering. METHODS: The recent related literature was reviewed, concerning isolation method, characteristics of SMSCs, and its application in tissue engineering. RESULTS: SMSCs are multipotent cell population with characteristics of easy isolation and high proliferation, which have been applicated in the cartilage, tendon, ligament, and bone tissue engineering. CONCLUSION: SMSCs is a new member of mesenchymal stem cells family. It appears to be promising seed cells for tissue engineering, but further research is needed. PMID- 22242356 TI - [Development of computer aided forming techniques in manufacturing scaffolds for bone tissue engineering]. AB - OBJECTIVE: To review recent advance in the research and application of computer aided forming techniques for constructing bone tissue engineering scaffolds. METHODS: The literature concerning computer aided forming techniques for constructing bone tissue engineering scaffolds in recent years was reviewed extensively and summarized. RESULTS: Several studies over last decade have focused on computer aided forming techniques for bone scaffold construction using various scaffold materials, which is based on computer aided design (CAD) and bone scaffold rapid prototyping (RP). CAD include medical CAD, STL, and reverse design. Reverse design can fully simulate normal bone tissue and could be very useful for the CAD. RP techniques include fused deposition modeling, three dimensional printing, selected laser sintering, three dimensional bioplotting, and low-temperature deposition manufacturing. These techniques provide a new way to construct bone tissue engineering scaffolds with complex internal structures. CONCLUSION: With rapid development of molding and forming techniques, computer aided forming techniques are expected to provide ideal bone tissue engineering scaffolds. PMID- 22242358 TI - [Magic! There is no difficult patient!]. PMID- 22242357 TI - [Application progress of subtalar arthroereisis for correction of pediatric flatfoot in children]. AB - OBJECTIVE: To review the application progress of subtalar arthroereisis for the correction of pediatric flatfoot in children and to analyze the problems at present as well as to predict the trend of development in the field. METHODS: Domestic and abroad literature concerning the methods of subtalar arthroereisis applied in pediatric flatfoot in recent years was reviewed extensively and thoroughly analyzed. RESULTS: Subtalar arthroereisis has proved to yield good results for correction of the flatfoot in children. In addition to the advantages of subtalar arthroereisis for pediatric flatfoot treatment (simple procedure, mature technology, and less complications), it allows further surgery if needed. CONCLUSION: Subtalar arthroereisis is a simple and effective way to treat flatfoot in children, however, its biomechanics mechanism and managements to complication need to explore further. PMID- 22242359 TI - [Federal cabinet adopts benchmarks. Nursing reform meets intense criticism from the opposition, unions and associations]. PMID- 22242360 TI - [Decision: nurses should be allowed to adopt physician responsibilities. Federal joint committee accepts model projects - minister must still approve]. PMID- 22242361 TI - ["Observing and Respecting Nursing" Statistics Symposium: experts present current figures. Noticing important developments]. PMID- 22242362 TI - [Deficiency symptoms in Crohn disease and ulcerative colitis. Nutrition in chronic inflammatory bowel diseases]. PMID- 22242363 TI - [Everyday challenge: the "difficult patient". It always takes two]. PMID- 22242364 TI - [Nursing care in malnutrition. Targeted intervention]. PMID- 22242365 TI - [Nutrition in patients with dementia. "I have already eaten"!]. PMID- 22242366 TI - [Family style meals in homes for the aged and nursing homes. Small changes can work wonders]. PMID- 22242367 TI - [A powerful team: nursing and facility administration stand united against malnutrition in nursing home residents. Cherry cake is sometimes better than sponge cake"]. PMID- 22242368 TI - [Vaccinations among students in health care professions]. AB - Incomplete vaccinations among students in health care professions lead to an increased risk for infections. Until now, only few studies related to this issue do exist. Therefore vaccinations and awareness regarding the importance of vaccinations among students in health care professions should be investigated. All 433 students of a regional college for health care professionals were asked to complete a standardized and anonymous questionnaire. Altogether 301 nursing students and 131 students of the other health care professions participated. About 66.1 percent of nursing students and 50.4 percent of students of other health care professions rated vaccination as "absolutely necessary". Different percentages of completed vaccinations were reported for tetanus (79.1 percent versus 64.4 percent), hepatitis B (78.7 percent versus 77.5 percent) and hepatitis A (74.1 percent versus 68.5 percent). 6.3 percent versus 15.4 percent did not know if they were vaccinated against tetanus, hepatitis B (5.3 percent versus 7.7 percent) and hepatitis A (5.6 percent versus 9.2 percent). While approximately half of the students reported "primary vaccination and booster" against mumps (59.5 percent versus 53.5 percent), measles (58.8 percent versus 54.6 percent) and rubella (58.3 percent versus 55.4 percent), this was reported less for pertussis (43.8 percent versus 39.8 percent) and varicella (32.4 percent versus 25.2 percent). The results indicate inadequate vaccination status in the investigated students. In addition, a gap between the awareness of the importance of vaccinations and personal preventive behavior became obvious. Therefore, education of these future health professionals still requires issues related to vaccinations. PMID- 22242369 TI - [Oral hygiene in patients with stroke. Do nursing interventions improve oral health?]. PMID- 22242370 TI - [A plea for a paradigm of mutual dependence. The future of nursing in the public hospital]. PMID- 22242371 TI - [Between self determination and nursing care. Force feeding of patients]. PMID- 22242372 TI - [Memory loss as presenting symptom. Shoes in the refrigerator]. PMID- 22242373 TI - [Nutritional status of Parkinson disease patients living at home]. PMID- 22242374 TI - [Strategies to manage food refusal. When residents do not want to eat]. PMID- 22242375 TI - [Study on mobile phone enabled wireless detection of saliva glucose]. AB - In this study, based on the correlation between the blood and saliva glucose, we proposed and developed a new conceptual method of using mobile phone to measure wirelessly the glucose concentration in saliva. According to the experiments on simulated saliva, the new system could draw, display, store and carry out calculation on the correlation curves between saliva glucose and electrical parameters. This demonstrates the feasibility and bright future of the new technique. PMID- 22242376 TI - [Study on the activity--heart rate prediction system for motion sensed rate responsive pacemakers]. AB - Focusing on the heart rate control mode of acceleration sensor based rate responsive pacemakers, this paper implemented the design of activity--heart rate prediction system. Bluetooth module was used as communication means in activity- heart rate prediction system, and the slave computer was used to complete the acceleration signal acquisition and processing, map from acceleration signal to the pacing rate signal, and achieve real-time transmission of acceleration signal and heart rate signal. The master computer fulfilled real-time display and recording of acceleration signal and heart rate signal, moreover, it achieved control function to the slave computer algorithm through classification of 6 parameters. The results of verification experiment showed that there was a significant relation between mapping heart rate and actual heart rate using linear mapping algorithm (R2 = 0.787, P < 0.001). PMID- 22242377 TI - [Image processing system of visual prostheses based on digital signal processor DM642]. AB - This paper employed a DSP platform to create the real-time and portable image processing system, and introduced a series of commonly used algorithms for visual prostheses. The results of performance evaluation revealed that this platform could afford image processing algorithms to be executed in real time. PMID- 22242378 TI - [Research of search strategy in the fields of double iron rotating electromagnetic locating/tracking method]. AB - This paper introduces a new search strategy on the basis of self-adaption step, aiming at solving the problem that primary double iron rotating electro-magnetic tracking method can not make a good balance of accuracy and efficiency. Through the emulation, we can conclude that this new strategy can sharply increase the efficiency, with the accuracy identical to that of the fixed-step (0.5 degrees). PMID- 22242379 TI - [The analysis of atrial cells conductivity based on epicardial mapping data of dog]. AB - This paper discusses the law of atrial electrical activity propagation (the timing of signal and the conduction velocity) under the sinus rhythm before and after AF caused by high-frequency electrical stimulation. The paper analyzes how different doses of acetylcholine affect the conductivity of the atrial cells of dogs. This result can also help the diagnoses and treatment of human's AF. PMID- 22242380 TI - [Research on intelligent fitness partner based on the acceleration and photoelectric sensors]. AB - Due to the drawbacks of the single function for the existing pedometers, this paper proposes an intelligent fitness partner based on the acceleration and photoelectric sensors.Through low-cost and single-chip three axles acceleration sensors MMA7260, it extracts and analysis the human's sports information. Furthermore, it detects and analyses the human's heart rate signal, by using the photoelectric sensor. Microcontroller PIC18F4520 is used to realize the algorithm of adaptive step counting model, and the heart rate detection circuit is also set up. The experimental results show that the proposed fitness partner can accurately display the heart rate wave of the testee, and the accurate rate is above 90%. PMID- 22242381 TI - [The research and design of non-invasive cardiac output detector based on pulse graph theory]. AB - This cardiac output detector uses AT89C52 as the core MCU, carries the pulse signal sampling from pulse sensor into the SCM after A/D conversion, and then figures out the cardiac output value and displays it on the LED. Software analysis works out the cardiac output value through five-point difference threshold for feature location of the pulse graph method theory. Experiment results show that the normal measured cardiac output is 5.411 L/min, the standard deviation of 0.873, while the catheter method as the gold standard of the mean 5.51 L/min, the standard deviation of 1.09. This system can meet the testing requirements of normal cardiac output. It is a non-invasive, convenient and new cardiac output measurement instrument with continuous testing, easy operation and low cost. PMID- 22242382 TI - [Development of a fully-automated biochemical analysis system intended for primay medical units]. AB - A fully-automated biochemical analysis system is developed, intending for primary medical units. It features high reliability, high usability, strong adaptability, low operation cost, low maintenance cost, and low requirements for operators. PMID- 22242383 TI - [Development of antibacterial plastic biliary stent coated with nano-silver]. AB - The common complications of the endoprosthesis are occlusion of the stents, and cholangitis. There are many bacterial colonies in the blocked stents. Some studies have proved that the silver in a low concentration has the antimicrobial efficacy .The plastic biliary stents coated with nano-silver were prepared by the chemical redox process with plastic stents as carriers and silver nitrate as material. Then the friction coefficient and elastic modulus of the stents were detected by use of scanning electron microscope (SEM), transmission electron microscopy (TEM) and Energy Dispersive X-ray analysis (EDXA), scanning tunneling microscope (STM). The result shows that the nano-sliver coating is high purity and the nanoparticle is well-distributed, range of size is 5-80 nm. Antibacterial plastic biliary stents coated with nano-sliver that its surface is smooth and elasticity is not obvious change. PMID- 22242384 TI - [The testing system for OCP of the digital X-ray machine]. AB - In this paper, we designed a testing system for operator control panel of a high voltage and high-frequency X-ray machine, and an online testing software for functional components, in order to help the testing engineers to improve their work efficiency. PMID- 22242385 TI - [The design of data transfer protocol for home and community tele-medical system]. AB - This article describes a design of physiological signal storage format and transfer protocol for the tele-medical system between home and community. The protocol is based on ASCII character, with frames as its basic structure. There are two kinds of frames: control frames and data frames. Control frames can start and stop data transfer, confirm the order, and ask for start. There are seven kinds of data frames, according to the different data types. Data is transferred in data frames. The protocol described in this article is simple and extensible. The design target has been accomplished in real system. PMID- 22242386 TI - [An approach to a negative pressure automatic control system in electronic endoscope]. AB - OBJECTIVE: The work presented here was to research into a kind of automatic control system that would be automatically linked to the working status of electronic endoscope. METHODS: The image video output signal and signal of negative pressure sensor were used to be a sampling signal of automatic control circuit. An electronic switch of automatic control circuit was challenged the manual control device of the negative pressure system. RESULTS: This system simplifies the operation procedures, enhances work efficiency, reduces energy consumption and improves the service life of the machine. CONCLUSION: The paper concludes that this negative pressure automatic control system has many strengths like stable performance, easy installation and strong versatility. It also can be widely applied in different brand and different types of electronic endoscope in China. PMID- 22242387 TI - [Design of a new type nasal-oral mask for noninvasive ventilation]. AB - To improve success rates of noninvasive ventilation, a new type nasal-oral mask was designed with high comfort level, high security and less leakage, which overcame the weak points of intolerance and poor treatment effect of the conventional nasal-oral mask. PMID- 22242388 TI - [Instruction of clinical testing method for medical devices]. AB - The article introduces the clinical testing method for the product of patient monitor, the definition of direct measurement and indirect measurement method, and the different testing methods. The clinical testing methods for none invasive blood pressure, pulse oxygen saturation and ECG analysis have significant value, which are important solutions to test the safety and effectiveness of medical devices by using the equivalent analysis method. These methods above are also provided as reference for other medical devices' clinical testing. PMID- 22242389 TI - [Study on IEC 60601-1-2: the standard of electromagnetic compatibility for medical electrical equipment]. AB - In this paper we did some comparisons between YY0505-2005 and IEC 60601-1-2 edition2.1, and concluded that they are identical in respects of testing items and methods, but significantly different in respects of classification, essential performance and risk analysis. Some suggestions about the transformation and implementation of edition 2.1 standards in our country were proposed. PMID- 22242390 TI - [Introduce a new vitro replacement method of skin irritation test]. AB - A series of new replacement methods of skin irritation test such as EpiSkin, EpiDermSIT (updated) and SkinEthicRHE have been validated by ECVAM. Due to it, animals are protected to the full extent. These provide more methods for biological evaluation of medical devices. PMID- 22242391 TI - [The risk analysis and strategy in medical equipment inspection and acceptance]. AB - Inspection and acceptance is an important part of medical equipment management. It is a major measure to ensure that the medical equipment purchased is in accordance with the quality and quantity of the intended standards and can be used in clinical treatment timely and safely. It is also a key step to inspect the performance of the contract and the implementation of tender documents. The medical equipment inspection and acceptance is classified based on the standards of equipment validity and safety. Furthermore these problems are analyzed deeply and the solution strategies are suggested. The objectives of our study are to ensure the equipment's quality, improve woke efficiency and induce the effects on manufactures. PMID- 22242392 TI - [Medical device software requirements and evaluation]. AB - This paper introduces the safety and effectiveness requirements of medical device software. And it discusses the methods on evaluating medical device software from two aspects, the design and development process of the software and software products. PMID- 22242393 TI - [Radiation output evaluation of kilovoltage cone beam CT unit]. AB - OBJECTIVE: To evaluate the radiation output and stability of linac-integrated kV cone beam CT unit. METHODS: Air kermas in radiographic mode were measured with 0.6 cc ion chamber and Unidos electrometer for Synergy-integrated XVI kV cone beam CT unit. Air kermas vs image frames were measured in fluoroscopic mode. Output stability and depth doses were measured. RESULTS: The air kerma increased quadratically with the increased tube voltage, while increasing linearly with the tube current, exposure time, and number of frames. The radiation output stability and its change with the gantry angle were within +/-1%. The percentage depth dose increased with higher tube voltage. CONCLUSION: The radiation output of XVI is stable. The radiation outputs change considerably with the preset parameters. Parameters should be optimally chosen to reduce the patient dose. PMID- 22242394 TI - [Daily quality assurance of linac radiation field]. AB - OBJECTIVE: To evaluate the clinical feasibility of daily quality assurance for linac radiation field by analyzing the trend of the daily testing data about parameter of radiation field. METHODS: Two-dimensional ion chamber array Daily QA3 was used to measure the difference between the practical value and the standard value of the parameter about radiation field before commencing daily treatment. Farmer type ionization chambers from IBA Co. with DOSE1 dosimeter was used for the absolute dosimetry of photon and electron beams. Light/radiation field coincidence was checked by using films every month. The daily testing data (from 11/28/2009 to 4/8/2011) were reviewed and analyzed. RESULTS: X-ray and electron output was increasing steadily; light/radiation field coincidence, beam flatness constancy and symmetry of X- ray and electron was keeping stable. CONCLUSION: The procedures for daily quality assurance of linac radiation field, which will provide reference for long term linac calibration, are feasible in our experience. PMID- 22242395 TI - [Discussion on logistics management of medical consumables]. AB - Management of medical consumables is an important part of modern hospital management. In modern medical behavior, drugs and medical devices act directly on the patient, and are important factors affecting the quality of medical practice. With the increasing use of medical materials, based on practical application, this article proposes the management model of medical consumables, and discusses the essence of medical materials logistics management. PMID- 22242396 TI - [Design and maintenance of the hospital-level external report]. AB - HIS external report provides convenience for statistical work in each hospital department, but the data of each department is not only relatively independent but also absolutely correlative. Besides, the numerous and complicated reports bring the hospital executive level inconvenience when they make a strategic policy. So the design of the hospital-level external report can resolve the problem mentioned above. Microsoft SQL Servers is used to write the procedures of external reports. We have written nearly 40 hospital-level external reports about outpatient, in-patient, medicine and etc., which satisfied the demand of the hospital leaders. This paper elaborates on the hospital-level external report in respects of: the design philosophy, the design process, and the maintenance tips and etc.? PMID- 22242397 TI - [A slight experience gained from life course and academic career]. PMID- 22242398 TI - [Research advances in the treatment of hyperhomocysteinemia]. AB - Homocysteine is an intermediate metabolite of methionine metabolism. Hyperhomocysteinemia which is caused by abnormal homocysteine metabolism has been confirmed to be related to cardio-cerebrovascular disease, peripheral vascular disorders, neurodegenerative diseases, diabetes, pregnancy-induced hypertension syndrome, liver cirrhosis, chronic kidney disease. In this paper, we first briefly introduced hyperhomocysteinemia and its pathogenesis, then summarized the treatment advances of hyperhomocysteinemia using folic acid, vitamin B6, B12, betaine, atorvastatin, isoflavones, taurine and some Chinese traditional medicine. Finally, the potential problems of the various treatment methods were analyzed. PMID- 22242399 TI - [The roles of microRNA in the diagnosis and therapy for cardiovascular diseases]. AB - Recent years, microRNAs (miRNAs) have attracted scholars' attention extensively. MiRNAs are a class of 21-25-nucleotide non-coding RNAs that have been implicated in regulating gene transcription and expression. Thus, alteration of miRNA is involved in many human activities and diseases. The function of miRNA is varied dependence on cell type and target mRNA. MiRNAs play important roles in the process of injury and repair through affecting cell phenotypes, such as development, division, proliferation, apoptosis and regeneration. Recently, miRNA based findings seem to be promising implications for diagnosis and therapy. PMID- 22242400 TI - [Progress of research on TLRs-mediated signaling pathway]. AB - TLRs belong to a family of pattern recognition receptors (PRRs) that recognize highly conserved microbial antigens termed pathogen associated molecular patterns (PAMPs). So far, ten TLRs have been identified in human genome. Each TLR senses a different set of microbial stimuli, and recruits various of adaptors and activates a series of distinct signaling cascades, and drives specific responses against the pathogens. TLRs bridged innate and adaptive immunity. The discoveries of Toll-like receptors guided the field of innate immunity to its present era of accelerated advancement. In this review, we will focus on the recent progresses of TLRs-mediated signaling. A better understanding of the immunological and molecular mechanisms mediated by TLRs will obviously facilitate the exploiting molecular targets of immunotherapy to control TLR-mediated diseases. PMID- 22242401 TI - [The role of mitochondrial dynamics in neurodegeneration]. AB - Mitochondria are highly dynamic organelles, which undergo continuous cycles of fission and fusion. Mitochondrial dynamics (fission and fusion) plays important roles in maintaining neuronal functions, including biogenesis, mitochondrial distribution and cell injury or death. Mfnl/2 and Opal mediate mitochondrial fusion, whereas Drp1 and Fis1 regulate mitochondrial fission. Mutations of Opal cause autosomal dominant optic atrophy, and mutations of Mfn2 lead to Charcot Marie-Tooth disease type 2A. Moreover, increasing evidences show that abnormal mitochondrial dynamics are involved in pathogenesis of late-onset neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. This paper reviews the current advances of abnormal mitochondrial dynamics relevant to neuronal loss in neurodegenerative diseases. PMID- 22242402 TI - [Relationship between neuroinflammation and neurodegenerative diseases]. AB - Over recent decade, studies have shown that inflammatory reaction characterized mainly by the activation of microglia in the brain is implicated in the pathogenesis and processes of neurodegenerative diseases. Neuroinflammation is a double-edged sword. On the one hand, it induces or aggravates the neurodegeneration in the nervous system, and on the other hand, it favors the recovery of the injured neurons in certain conditions. The activated glial cells release pro-inflammatory cytokines and reactive oxygen species, which mediate the neuroinflammation-induced neurodegenerative diseases. The anti-inflammatory cytokines synthesized by regulatory T cells and neuropeptides secreted by neurons protect the neurons against neuroinflammation, through which neurodegenerative diseases are alleviated. PMID- 22242403 TI - [Research proress of biological function of protein kinase D]. PMID- 22242404 TI - [Glycolysis participates in the mechanism of seizure energy supply and termination]. PMID- 22242405 TI - [New role of insulin in anti-inflammation: not only dependent of glycemic control]. PMID- 22242406 TI - [Functional diversity of GAPDH]. PMID- 22242407 TI - [The modulatory sites of P2X2 and P2X4 receptors]. PMID- 22242408 TI - [Protein tyrosine phosphatase SHP2 and respiratory diseases]. PMID- 22242409 TI - [Progress in embryonic stem cell phosphatase]. PMID- 22242410 TI - [Current understandings about the signaling mechanisms involved in disuse muscle atrophy]. PMID- 22242411 TI - [Omentin: a new adipokine]. PMID- 22242412 TI - [Effects of alpha cell in islets on beta cell function]. PMID- 22242413 TI - [Effects and mechanisms of autophagy in Alzheimer's disease]. PMID- 22242414 TI - [Research progress of salvianolic acid A]. AB - Salvianolic acid A is a water-soluble component from Danshen, which is frequently used in traditional Chinese medicine. High performance liquid chromatography was often used to analyze content of salvianolic acid A. The yield of salvianolic acid A increased by the technological improvement of extraction and separation. Salvianolic acid A possessed multiple pharmacological activities, including antioxidants, myocardial ischemic protection, antithrombatic, neuroprotection, anti fibrosis, prevention of diabetes and complications. Recently, preliminary pharmacokinetics characteristics of salvianolic acid A were clarified. Based on the research literature and study work from author's laboratory, this review will focus on recent developments concerning the chemistry, pharmacology and pharmacokinetic of salvianolic acid A, and prospect further research. PMID- 22242415 TI - [Study on liver protection, cholagogic effect and hepatotoxicity of Gardeniae fructus]. AB - Gardenia is widely used in clinical treatment to cure acute and chronic liver disease. But in recent two decades, hepatotoxicity has been reported from gardenia and major components. Based on literature research, the liver protection, cholagogic effect and hepatotoxicity have been discussed in-depth, with the purpose to provide a reference for rational usage in clinical and new drug development of gardenia. PMID- 22242416 TI - [Application of molecular pharmacognosy in research of Mongolian medicine]. AB - Molecular pharmacognosy has developed as a new borderline discipline. Using the method and technology of molecular pharmacognosy, a wide range of challenging problems were resolved, such as the identification of Mongolian medicinal raw materials, etiology of endangerment and protection of endangered Mongolian medicinal plants and animals, biosynthesis and bioregulation of active components in Mongolian medicinal plants, and characteristics and the molecular bases of Dao di Herbs. So molecular pharmacognosy will provide the new methods and insights for modernization of Mongolian medicine. PMID- 22242417 TI - [Status and prospective on nutritional physiology and fertilization of Panax notoginseng]. AB - Sanqi, Panax notoginseng, is a famous traditional Chinese herb, which has more than 400 years cultivation history in China. This paper has reviewed the studies on the suitable growing soil conditions for Sanqi, mineral nutrition effects on Sanqi, and the effects of nutrients uptake on the yield and quality of Sanqi by applying fertilizer. Thereafter, research needed to be put further efforts in the future has raised for discussion, and outlined the following topics for further research like the mechanism of mineral nutrition, methods of nutrients deficiency diagnosis on site, suitable cultivated soil grading special fertizer development, disease resistance, and fertilization recommended by soil testing. PMID- 22242418 TI - [Study on hydroxyproline tolerance of different cultivars of Chrysanthemum morifolium in vitro]. AB - OBJECTIVE: To investigate hydroxyproline tolerance of Chrysanthemum morifolium plantlets included " Boju", "Huaiju", "Chuju", "Gongju" and "Hangju",and provide references basis for excellent cultivar and breeding of Ch. morifolium. METHOD: Plantlets in vitro from five kinds of Ch. morifolium were inoculated on medium added with different concentrations of hydroxyproline. Free proline in leaves from plantlets was determined, then the damage index and survival rate were compared. RESULT AND CONCLUSION: The results showed that hydroxyproline tolerance of " Boju" and "Huaiju" were superior, the survival rates and free proline of them were higher, but the damage index was inferior. The hydroxyproline tolerance of "Hangju" was the worst, and the survival rate was minimum. The survival rate of "Chuju" and "Gongju" was between "Boju" and " Hangju", and the hydroxyproline tolerance of them was also medium. PMID- 22242420 TI - [Study on basic amino acid contents in Dendrobium officinale]. AB - OBJECTIVE: To investigate the contents of 16 basic amino acid and find out the variation of them in Dendrobium officinale with different germplasms and physiological ages, and then provide scientific basis for the quality evaluation and the breeding of D. officinale. METHOD: Thirty-three samples with 1-3 ages were collected from cultivated fields of Zhejiang. The samples were acid hydrolyzed, and then 16 basic amino acid contents of samples were determined by amino acid analyzer. RESULT: The average contents of 7 necessary amino acid were in 0.28 - 2.96 mg x g(-1), the average contents of other 9 basic amino acid were in 0.53 - 4.20 mg x g(-1). The contents of many amino acids were impacted by germplasms significantly, and contents of several amino acids were impacted by physiological ages significantly. CONCLUSION: There were rich basic amino acids in D. officinale. The breeding of D. officinale can increase the contents of essential amino acids and other basic amino acids. The relations among physiological age and amino acid contents were as follows: three years > two years > one year. The contents of Asp and Tyr have significantly negative correlation with magnesium, the content of Pro has significantly positive correlation with copper. PMID- 22242419 TI - [Correlation analysis soil nutrition as sell as yield and active compounds of Coptis teeta]. AB - The correlations between soil nutrition and yield as well as active compound contents of Coptis teeta were analyzed. The contents of 13 soil factors, rhizome biomass and the content of berberine, jatrorrhizine, and palmatine in rhizome of C. teeta were determined, and analyzed by factor analysis (FA) and correlation analysis (CA). FA showed that the first three factors accounted for 86.9% of the total variance. The contents of Ca, Mg, Fe, Mn, and Zn correlated with the first factor. The content of organic matter, N, available N, available P, and available K correlated with the second factor. CA showed that yield of C. teeta had a significant positive correlation with available P (r = 0.931) at 0.01 level, and available N (r = 0.703) at 0.05 level. The content of berberine of C. teeta had a significant positive correlation with available P (r = 0.680) at 0.05 level. The yield and berberine content of C. teeta were high in the soil with high contents of available N and available P. PMID- 22242421 TI - [Pollen germination in vitro and pollen tube growth of Scutellaria baicalensis]. AB - OBJECTIVE: To study the pollen germination in vitro and pollen tube growth of Scutellaria baicalensis. METHOD: Two years-old S. baicalensis that in the experiment field of Shangluo university were used as the materials. The effects of culture medium, sucrose, PEG, pH value, culture time and temperature on the pollen germination and tube growth of S. baicalensis were investigated using the method of liquid culture. RESULT AND CONCLUSION: The results showed that 100 g x L(-1) sucrose was helpful for the germination and growth of pollens. However, higher concentration of sucrose would inhibit strongly pollen germination and the growth of pollen tubes. PEG could accelerate pollen germination and tube growth, and the optimal concentration was 150 g x L(-1). The optimum culture medium was BK and BK + 10% sucrose + 150 g x L(-1) PEG (pH 5.8) , and the latter was more benefit for pollen germination and tube growth. The pollen of germination was better at 25-35 degrees C, and it was the best at 30 degrees C for 2-3 hours, while pollen tube growth was slower at 25 degrees C. PMID- 22242422 TI - [Comparative study on absorption kinetics in intestines of rats of epimedii foliunm of Xianlinggubao capsules prepared by different processes]. AB - OBJECTIVE: To study the characteristics of intestinal absorption of icariin and epimedin C of Xianlinggubao capsules, and compare the absorption of Xianlinggubao capsules prepared by different processes. METHOD: Non everted gut sac method was applied to investigate the influence of absorption sites and concentration on icariin and epimedin C, which were determined by HPLC. RESULT: The absorption rate constants of epimedin C in duodenum were absolutely more than that in jejunum and ileum (P < 0.05). The absorption rate constants of icariin in jejunum were absolutely less than that in duodenum and ileum (P < 0.05). The absorption rate constants of epimedin C and icariin kept at the same level when the concentrations of drug solution were at high, middle and low level. The Ka of epimedin C at three levels were 0.040, 0.058, 0.061 h(-1) , respectively, and the Ka of icariin at three levels were 0.002, 0.007, 0.003 h(-1), respectively. CONCLUSION: Intestinal absorption of icariin and epimedin C is not effected by concentrations. The absorption rate constants of icariin and epimedin C in new Xianlinggubao capsules are higher. PMID- 22242423 TI - [Comparison of essential oil enriched with ultrafiltration method and extraction method respectively from essential oil-in-water emulsion of Citri Reticulatae Pericarpium Viride by GC-MS]. AB - OBJECTIVE: To study on the separation from essential oil-in-water emulsion of Citri Reticulatae Pericarpium Viride by ultrafiltration and acetoacetate extraction methods respectively, and the comparison of the oil yields and chemical compositions. METHOD: Essential oil-in-water emulsion of Citri Reticulatae Pericarpium Viride was separated by ultrafiltration and acetoacetate extraction methods respectively, and the chemical compositions were analyzed and compared by GC-MS. RESULT: Ultrafiltration method could enrich essential oil more and its chemical compositions were more similar to the essential oil prepared by steam distillation method. CONCLUSION: Ultrafiltration method is a good medium to separate essential oil from essential oil-in-water emulsion of Citri Reticulatae Pericarpium Viride. PMID- 22242424 TI - [Determination of sulfur dioxide in traditional Chinese medicine by alkaline solution extraction and ion chromatography]. AB - OBJECTIVE: An ion chromatographic method was developed to analyze sulfur dioxide in traditional Chinese medicine (TCM). METHOD: The samples were extracted with alkaline solution and reacted with formaldehyde to form hydroxymethyl sulfonic acid. The extracts were cleaned by C18 column and SO3(2-) was determined with ion chromatography equipped with a conductance detector. In the method, AS11-HC chromatographic column was used and the mobile phase was 15 mmol x L(-1) KOH. RESULT: The calibration curve was in good linearity in the range of 1 to 100 microg (r =0.9992). The detection limit was 0.53 mg x kg(-1) and the average recovery was 103.7%. CONCLUSION: The method is simple, sensitive, precise, short time-consuming, and the random error is smaller, which is applicable to the testing of large quantity batches of TCM. PMID- 22242425 TI - [Study and comparison on HPLC fingerprints of flavonoids of frequently used Chinese materia medica in citrus]. AB - OBJECTIVE: To establish the HPLC fingerprint of flavonoids of the six clinical frequently used Chinese materia medica for regulating Qi flow,such as Citri grandis, C. grands, Citri Reticulatae Pericarpium, Citri Reticulatae Pericarpium Viride, Aurantii Fructus, and Aurantii Fructus Immaturus from Citrus, and analysis differences in the fingerprints to provide scientific basis for profile effect research and clinical reasonable use. METHOD: HPLC was performed on a C18 column with methanol-water (with acetic acid), to establish HPLC fingerprints of the six kinds of medicinal herbs on the same chromatograph condition. RESULT: The six frequently used Chinese materia medica were divided into naringin type and hesperidin type according to the method of phytochemotaxonomy. Based on the retention time of chromatograph peaks, C. grandis and C. grands had fifteen common peaks; Citri Reticulatae Pericarpium, Citri Reticulatae Pericarpium Viride, Aurantii Fructus and Aurantii Fructus Immaturus had ten common peaks. All herbs had five common peaks. Compared with mutual model, the holistic similarity of chromatograms of C. grandis and C. grands was in the range of 0.9285 - 0.9962. The degree of similarity was high. For Citri Reticulatae Pericarpium, Citri Reticulatae Pericarpium Viride and Aurantii Fructus Immaturus, it was in the range of 0.9221 - 0.9973 and high. But the similarity of Aurantii Fructus was only in 0.4547 - 0.7733 with the mutual model. CONCLUSION: The established fingerprints of flavonoids of the six common traditional Chinese medicines can be used to compare the differences intuitively. Meanwhile, the peak height and peak areas of characteristic peaks are different remarkably, but whether it is connected with the different function of regulating Qi flow of the six medical materials in clinical use, is still needed to be studied. PMID- 22242426 TI - [Study on antibacterial active components from Viola yedoensis]. AB - OBJECTIVE: Study on the antibacterial activity of Viola yedoensis and the antibacterial active compounds. METHOD: The chemical compositions were isolated by means of solvent extraction, column chromatography on silica gel, sephadex LH 20 and crystallization. The antibacterial activities were tested by Neo-Sensitab disk-diffusion method, nephelometric analysis and plating method. RESULT: One new compound (4) along with three known compounds were isolated from this plant for the first time and were identified as aesculetin (1), 6,7-dimethoxycoumarin (2), scopoletin (3) and 5-methoxy-7-hydroxymethylcoumarin (4), respectively. All the compounds showed antibacterial and antibactericidal activities at varying degree on Streptococcus Aureas, S. agalactiae, S. uberis, S. dysgalactiae, E. coli and Salmonella, of which 1 was most active with 0.031- 0.313 g x L(-1) of minimal inhibitory concentrations (MIC) and 0.313 - 0.625 g x L(-1) of minimal bactericidal concentrations (MBC). CONCLUSION: Viola yedoensis has a broad spectrum of antibacterial activity on animal pathogenic bacteria, and coumarins may be the main antibacterial activity ingredients. PMID- 22242427 TI - [Flavonoids and nor-sesquiterpenes of Pedicularis densispica]. AB - OBJECTIVE: To study the chemical constituents of the whole plants of Pedicularis densispica. METHOD: The chemical constituents were isolated by various chromatographic methods and their structures were determined by chemical evidences and spectral data. RESULT: Ten compounds were isolated and identified as acacetin (1), apigenin-7-0-beta-glucopyranoside (2), kaempferol-3,7-O-alpha dirhamnopyranoside (3), scutellarein-7-0-beta-glucopyranoside (4), chrysoeriol-7 O-beta-glucopyranoside (5), pedicutricone A (6), dearabinosyl pneumonanthoside (7), salidroside (8), darendoside B (9), and maltol-beta-D-glucopyranoside (10). CONCLUSION: These compounds were isolated from the titled plant for the first time. Except compounds 6 and 8, the others were obtained for the first time from the genus Pedicularis. PMID- 22242428 TI - [Studies on chemical constituents from leaves of Uraria lacei]. AB - OBJECTIVE: To study the chemical constituents from leaves of Uraria lacei. METHOD: Chemical constituents were isolated by silica gel column and Sephadex LH 20, and identified by physiochemical and spectral analyses and by comparison with the standard compounds. RESULT: Eleven compounds were isolated and identified as naringenin-7-0-beta-D-glucopyranside (1), (2S)-5, 7-dimethoxy-4'-hydroxyflavan (2), dalbergioidin (3), 5, 7-dihydroxy-2'-methoxy-3', 4' methylenedioxyisoflavanone (4), apigenin (5), 5, 7-dihydroxy-2', 4' dimethoxyisoflavanone (6), 5, 7, 2', 4'-tetrahydroxyisoflavone (7), emodin (8), saliylic acid (9), daucosterol (10), and tetracosane (11). CONCLUSION: All compounds were isolated from this plant for the first time. PMID- 22242429 TI - [Determination of longistylin A and longistylin C in Cajanus cajan]. AB - OBJECTIVE: To establish quality control criteria for medicinal herb Cajanus cajan based on the determination of longistylin A and longistylin C, two bioactive and specific stilbenes of the plant. METHOD: Longistylin A and longistylin C were obtained from the leaves of C. cajan by silica gel column chromatography and identified as marker compounds of this plant by spectroscopic analysis. A RP-HPLC method was established to determine the two compounds. RESULT: Longistylin A and longistylin C were well separated on a Thermo BDS Hypersil C18 column (4.6 mm x 250 mm, 5 microm) with a mobile phase methanol-water (8:2), and showed good linearity in the range of 0.00288 - 0.0576 microg and 0.0112 - 0.224 microg, respectively. The average recoveries were 98.9% and 97.2% with RSD of 2.4% and 2.2% for these two compounds, respectively. CONCLUSION: The established analysis method is simple and accurate, whicn can be used for quality control of C. cajan. PMID- 22242430 TI - [Screen for natural benzylisoquinoline alkaloids against tumor]. AB - OBJECTIVE: To search for natural benzylisoquinoline alkaloids against tumor. METHOD: In this study, taken DNA as target, a method was developed for screening of natural benzylisoquinoline alkaloids against tumor from traditional Chinese medicine by the use of centrifugal ultrafiltration combined with HPLC technology. The anti-tumor activity for the compounds screened was evaluated in vitro. RESULT: Nine compounds interacted with DNA were discovered and identified from Macleaya cordata, Chelidonium majus, Coptis chinensis, and the proliferation of four types of human solid cancer cell lines was markedly inhibited by these compounds. CONCLUSION: The developed method was considered to be suitable for screening of natural benzylisoquinoline alkaloids against tumor from traditional Chinese medicine. PMID- 22242431 TI - [Analysis of volatile components of flowers of Fritillaria thunbergii by GC-TOF MS]. AB - OBJECTIVE: To determine the structures and contents of the volatile components of flowers of Fritillaria thunbergii, and investigate the effects of operation modes on its volatile components. METHOD: The volatile oils were first obtained by the hydrodistillation assay and then submitted to gas chromatography-time-of flight mass spectrometry (GC-TOF-MS) analysis. RESULT: More than 60 peaks were resolved, and 39 of which were identified quantitatively and qualitatively based on high resolution spectra and compounds library screening. Among these identified components, the octadecatrienoic acid methyl esters were major components in the unprocessed flowers, while some aromatic aldehydes and ketones, such as benzeneacetaldehyde and 1-(2-hydroxy-5-methylphenyl)-ethanone, were prominent components in the flowers both dried in the fluidized bed and in shadow. In addition, the flowers dried in the fluidized bed were more fragrant than other flowers. CONCLUSION: The component and contents closely related to their processing mode, and the fluided bed drying may be a best choice to process the flowers of F. thunbergii. PMID- 22242432 TI - [Study on chromatography-efficacy relation of Zanthoxylum nitidum on gastric cancer cells]. AB - OBJECTIVE: To develop a method for elucidating " chromatography-efficacy" relation of the extract of Zanthoxylum nitidum on the gastric cancer cells. METHOD: After obtaining the tumor inhibition rate and fingerprint peak data through MTT and HPLC, "chromatography-efficacy" relation was established by an appropriate statistical method. RESULT: The gastric cancer "chromatography efficacy" relation of Z. nitidum was established by step-back technique. CONCLUSION: The "chromatography-efficacy" relation has statistically significant and practical significance, so it has reference value in some way. PMID- 22242433 TI - [Determination of harpagide and harpagoside in Scrophulariae Radix by HPLC-UV]. AB - OBJECTIVE: To develop a method for the determination of harpagide and harpagoside in Scrophulariae Radix (Xuanshen) by HPLC-UV under double wavelength, and to study the changes of these two constituents during processing, and to set the limitation of harpagide and harpagoside contents in crude drug and sliced pieces of Xuanshen. METHOD: The analyses were performed on an Agilent Technologies ZORBAX SB-C18 (4.6 mm x 250 mm, 5 microm) eluted with acetonitrile-water (containing 0.03% phosphoric acid) in gradient model. The flow rate was 1.0 mL x min(-1) . The column temperature was 25 degrees C. The UV detector wavelength was set at 210 nm before 13 min and then changed to 280 nm. RESULT: Harpagide and harpagoside were separated well. The linear calibration curves were obtained over of 0.0549 - 1.46 microg for harpagide (r = 0.9999, n =7) ,0.0225 - 0.900 microg for harpagoside (r = 0.9998, n = 9). The recoveries ( +/- RSD)% were 98.1 (+/- 2.4)% for harpagide and 98.8 (+/- 4.3)% for harpagoside. The contents of harpagide were 0. 277% - 0.620%, harpagoside were 0.078% - 0.362% in Xuanshen, and harpagide were 0.276% - 1.059%, harpagoside were 0. 059% - 0.183% in sliced Xuanshen, respectively. After the processing of Scrophulariae Radix, the content of harpagide increases 13.7% - 96.0%, while harpagoside decreases 11.0%-73.9%. CONCLUSION: This method is simple, accurate, and can be used for the quality control of Scrophulariae Radix. We propose that the total content of harpagide and harpagoside in either crude drug or sliced pieces of Scrophulariae Radix should not be less than 0.45%. PMID- 22242434 TI - [Influence of four parts of forming of Yiqi Qingwen Jidu Heji (YQQWJDHJ) to lung inflammatory cytokines of model rats infected with influenza virus FM1]. AB - OBJECTIVE: To observe the influence of the 4 parts of forming of Yiqi Qingwen Jidu Heji(YQQWJDHJ) to lung inflammatory cytokines of the model rats infected with influenza virus dynamically, and to discuss the mechanism of 4 parts of forming to anti-influenza immune injury and restoration. METHOD: At the different stages of infection with the model rats infected by FM1 influenza, expression in lung of TNF-alpha, IL-6, IL-1, IL-10 and IFN-gamma was detected after the intervention of 4 parts of forming using ELISA method. RESULT: The expression of TNF-alpha, IL-6, IL-1 and IFN-gamma of model rats infected by FM1 were higher than the control group, the expression of IL-10 did not change. The expression of TNF-alpha was significantly reduced in 3 to 5 days after infection. By the method of relieving superficies with acrid-cold, clearing away heat and poison and replenishing Qi, the lung expression of IFN-gamma was significantly increased in the stage after infection. The method of relieving superficies with acrid-warm significantly reduced lung expression of IL-6 after infection in 1 to 3 days and on the 7th day, decreased the expression of IL-1 in 3 to 7 days, increased IFN gamma expression on the 3rd day and the 7th day, and significantly increased the expression of IL-10 on the 1st day and in 5 to 7 days. The method of relieving superficies with acrid-cold reduced the expresssion of IL-6 after infection, and significantly increased the expression of IL-10. It could increase the expression of IL-1 after infection on the 3rd day, but reduced IL-1 expression after infection 7 days. The method of clearing away heat and poison reduced lung IL- 6 expression after infection in 3 to 7 days significantly, decreased the expression of IL-1 in 5 to 7 days, also increased the lung expression of IL-10 in 1 to 5 days significantly. The method of replenishing Qi significantly reduced the expression of IL-6 after infection on the 1st day and in 5 to 7 days, decreased the expression of IL-1 in 3 to 7 days, also significantly increased the lung IL 10 on the 5th day after infection. CONCLUSION: The method of clearing away heat and poison and replenishing Qi could be against the lung immune inflammatory damage and repair damage. The method of relieving superficies with acrid-warm demonstrated some immunity against lung injury on the 3rd day after infection and the method of relieving superficies with acrid-cold demonstrated some immunity against lung injury on the 5th days after infection. PMID- 22242435 TI - [Effect of water extract from traditional Chinese medicines Rehmannia glutinosa, Scrophularia ningpoensis, Asparagus cochinchinensis and Ophiopogon japonicas on contents of CYP450 and activities of CYP3A, CYP2E1 and CYP1A2 in rat]. AB - OBJECTIVE: To study the effects of the water extract of Rehmannia glutionsa, Scrophularia ningpoensis, Asparagus cochinchinensis and Ophiopogon japonicas, which are the drug from Tianwang Buxin Wan from nourishing vin, on the content of cytohrome P450 (CYP450) in rat and the activities of CYP3A, CYP2E1 and CYP1A2 to investigate the role of CYP450 in the biotransformation of Tianwang Buxin Wan. METHOD: The rats were killed after administrated with extracts once daily for consecutive 7 days, the livers were removed rapidly and weighed, liver microsomes were prepared with ultra-centrifuge method, the contents of liver microsomal CYP450, cytochrome b5 (Cytb5) and the activities of CYP3A were examined by ultraviolet spectrophotometry, the activities of CYP2E1 and CYP1A2 were determined by high performance liquid chromatography (HPLC). RESULT: All groups had no difference in the levels of liver indexe compared with normal sodium group. The water extract of R. glutionsa obviously decreased the contents of P450 (P < 0.01) and increased the activity of CYP3A (P < 0.01) and CYP1A2 (P <0.05). The water extract of S. ningpoensis decreased the contents of P450 (P < 0.05) and significantly increased CYP3A and CYP1A2 activities (P < 0.01). A. cochinchinensis increased content of Cytb5 (P < 0.05) in rat and increased the activity of CYP2E1 (P < 0.05) and CYP1A2 (P < 0.01). O. japonicas had no significant difference on the contents of CYP450 and Cytb5 while increased the activities of CYP3A (P < 0.05), CYP2E1 (P < 0.05) and CYP1A2 (P < 0.01). CONCLUSION: R. glutionsa and S. ningpoensis could decrease the content of CYP450 enzyme in rat liver and induct the activities of CYP3A and CYP1A2. A. cochinchinensis could induct the activities of CYP2E1 and CYP1A2. O. japonicus could induction the activities of CYP3A, CYP2E1 and CYP1A2 in Tianwang Buxin Wan. By inhibiting CYP450 activity to decrease the metabolism of other drugs, the effect of other functional groups in the compatibility of Tianwang Buxin Wan can be enhanced, and a theoretical basis on studying the compatible mechanism can be provided. PMID- 22242436 TI - [Study on effect of berberine on modulating lipid and CPT I A gene expression]. AB - OBJECTIVE: To investigate the modulating effect on lipid and gene expressions of CPT I A caused by berberine (Ber) in experimental hyperlipidemia rats. METHOD: Male SD rats were randomly divided into 5 groups according to the blood lipid values: normal group, hyperlipidemia group, 300 mg x kg(-1) x d(-1) Ber-treated group, 60 mg x kg(-1) x d(-1) Ber-treated group, and 7.2 mg x kg(-1) x d(-1) lovastatin-treated group. Normal group were fed with base diet and other groups were fed with high fat and cholesterol diet. 12 weeks after drugs were given the TC, TG, LDL-C, and HDL-C from rat blood samples were tested by automatic biochemistry analyzer. Gene expressions of CPT I A and PPARalpha were evaluated by RT-PCR and Western blot, respectively. RESULT: It was shown that Ber significantly decreased TC and LDL-C, but increased HDL-C in dose-dependent manner, elevated expressions of CPT I A mRNA and protein without influence on PPARalpha expression. Similar effects from lovastatin on lipidemia were observed except the Ber effect on CPT I A gene expression. CONCLUSION: Ber has modulating effect on the lipid metabolism, the mechanism of which may be by promoting the CPT I A gene expression. PMID- 22242437 TI - [TF-1 cell apoptosis-inducing effect of matrine and its effect on SALL4 expression]. AB - OBJECTIVE: To explore the mechanism of matrine (Mat) induced human erythroleukemia TF-1 cell apoptosis and its effect on SALL4 expression. METHOD: Different concentrations of the Mat (0.5, 1.0, 1.5, 2.0 g x L(-1) ) were cultured in vitro in TF-1 cells at different time (24, 48, 72 h). Cell proliferation was assayed by MTT. Cell cycle was determined by flow cytometry (FCM). Cell apoptosis was detected by Annexin V and PI double staining method. SALL4 mRNA expression was detected by reverse transcription RT-PCR (RTT-PCR). RESULT: Administrated with Mat (0.5-2.0 g x L(-1)) after 24, 48, 72 h, the proliferation of TF-1 cells were inhibited (P < 0.01) , and in dose- and time-dependent manner. Half inhibitory concentration (IC50 ) was 1.0 g L(-1) at 48 h. After 48 h that the Mat acted on TF-1 cells, the proportion of G0/G1 phase cells increased while compared with the control group, and S phase cells decreased (P < 0.01). Apoptosis were 8.6% , 11.21%, 15.26% , 17.63%, which showed statistically significant difference (P < 0.01) compared with the control group (5.05%). RT-PCR results showed the ratio between SALL4 mRNA expression and beta-actin (internal reference) expression significantly decreased (P < 0.01) with Mat dose increased. CONCLUSION: In a certain range of concentration and time, Mat can inhibit TFT-1 cells proliferation. The mechanism is to make the cells G0/G1 phase blocked, to inhibit SALL4 gene expression and induce cell apoptosis. PMID- 22242438 TI - [Effects of honey to acyclovir in the rabbit eye transport kinetics]. AB - OBJECTIVE: Using pharmacokinetics to explore the mechanism of honey to enhance the efficacy of acyclovir (ACV) treatment of herpes simplex keratitis (HSK), providing the basis for combination of the prescription of two drugs and dosage regimen designed. METHOD: Single dosages of 5% honey and 0% honey Meyasu eye ointment are injected into rabbit eyes. The aqueous humor of rabbit eye is measured at different times, specifically the content of ACV in aqueous humor by HPLC. Mathematical models are established, from which pharmacokinetic parameters are extracted and compared by mathematics and statistics methods. RESULT: Both the 5% and 0% honey Meyasu eye ointment in rabbit eyes are belong to a two compartment model. The absorption half-life of the 5% Meyasu eye ointment in aqueous humor is as 2.30 times longer, the distribution half-life is 2.12 times longer, the peak concentration is 1.17 times longer, the peak time is 1.36 times longer, AUC is 1.41 times longer when compared to the 0% Meyasu eye ointment. CONCLUSION: Honey can significantly increase the ACV concentration and bioavailability in the eye, extend the action time of ACV in target cells and increase the retention capacity of ACV in the target tissue; thereby improving treatment success. PMID- 22242439 TI - [Protective effect of purslane in a rat model of ulcerative colitis]. AB - OBJECTIVE: To evaluate the protective effect of purslane on the acute injury caused by intra-colonic administration of trinitrobenzenesulfonic acid (TNBS) in rats. METHOD: Seventy-two male SD rats were separated into 6 groups randomly. Rat model of ulcerative colitis was established by intra-colonic administration of trinitrobenzenesulfonic acid (TNBS). Purslane (2.5, 5, 10 g x kg(-1)) and sulfasalazine(0.5 g x kg(-1)) was administered by enemata, 3 days after TNBS instillation and daily during 10 days before killing the rats. Colons were removed for histological analysis and measurement of myeloperoxidase (MPO). RESULT: Rats treated with purslane (5 and 10 g x kg(-1)) were significantly healthier than TNBS-alone rats, as shown by improved food intake and reduced diarrhea, corrected the disorders in morphology associated to lesions, significantly reduced myeloperoxidase (MPO) levels. CONCLUSION: purslane exerts protective effect in experimental colitis, the effect seems to be related to relieving inflammatory reaction and repairing lesions. PMID- 22242440 TI - [Suggestions for improving quality control of extrinsic residues in crude drugs]. AB - To improve the impurity control of extrinsic residues in Chinese crude drugs and ensure the quality of crude drugs, relative suggestions should be provided. The present situation of extrinsic residues control in crude drugs was reviewed, and relative problems existed were analyzed. To develop the impurity control of extrinsic residues in Chinese crude drugs, more effort focus on strengthening basic research, improving analytical methods and optimizing the pattern of administration should be made. PMID- 22242441 TI - [Dissection of differences and similarities of botanical drugs in European Union, US and Canada]. AB - Because of the unique nature and treatment concept of traditional Chinese medicines (TCMs), TCMs have been respected again since 70s of last century. The regulatory agencies of some developed countries (the FDA, EMA and Health Canada etc) have published new guidance/guidelines/directives in recent years, such as the botanical drug product guidance of the FDA, the evidence for quality of finished natural health products guidance of the Health Canada and the guideline on quality of herbal medicinal products/ traditional herbal medicinal products of the EMA etc. All of the regulatory agencies are willing to scientifically evaluate the herbal medicines and accept it as therapeutic product. This paper analyzed the history of herbal medicine regulation and the similarities and differences of the regulatory requirements of the European Union, the United States and Canada, proposed possible future direction of the international development of Chinese medicine from the perspective of global regulatory affairs. PMID- 22242442 TI - [Speed up to formulate "National processing procedures of prepared slices of Chinese crude drugs", unified the national standards of prepared slices]. AB - The prepared slices of Chinese crude drugs are growing important in recent years, and faced with new developments and opportunities. The author analyzed the importance of formulate national processing procedures of prepared slices of Chinese crude drugs combined actual work, proposed the overall objectives and tasks for the formulation, and emphasized to need to correctly deal with several important factors during the process of formulate "National processing procedures of prepared slices of Chinese crude drugs", unified the national standards of prepared slices, solved the real problems that the prepared slices of Chinese crude drugs industry faced. PMID- 22242443 TI - [Chinese medicine adverse reactions' literature statistical analysis in recent five years]. AB - Since the state food and drug administration (SFDA) issued the first edition of adverse drug reaction(ADR) information in November, 2001, it has 32 edition, reported the drug 66 species of adverse reactions, involving the variety of 12 traditional Chinese medicines, it was effectively reminds all social concern of adverse drug reaction. For statistical analysis in recent years reported adverse drug reaction of prepared Chinese medicine, collected 462 literatures from 2005 09 CNKI Chinese journal full-text database of medicine health directory. In all the collections, about 94 literatures are closely related to adverse drug reaction report of prepared Chinese medicine. But there are only 7 references could identify traditional Chinese medicine and western medicine correctly in 72 literatures with the value of statistical analysis. That means only 8.9% of literatures can correctly identify western medicine and Chinese traditional medicine. So it proved that TCM workers' knowledge of ADR remains to be greatly improved. PMID- 22242444 TI - [Progress in the study of allergic disease drugs targeting on IgE/FcepsilonRI signaling pathway]. AB - Allergic diseases have become global social health problems. The binding of IgE with its high affinity receptor FcepsilonRI plays a key step in I-type allergy. Recently, more and more key molecules on the IgE/FcepsilonRI signaling transduction pathway were to be the drug candidates against allergic diseases, with in-depth study of FcepsilonRI signal pathway gradually. The main drugs include molecule antibodies, peptides, vaccines, fusion proteins, small molecules, and other drugs related to IgE/FcepsilonRI. The recent progress in the study of mechanisms of representative drugs targeting on IgE/FcepsilonRI signaling pathway was reviewed in this article. PMID- 22242446 TI - [Advances in the research of pregnane X receptor and constitutive androstane receptor]. AB - Nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are originally characterized as transcription factors regulating many target genes. Recent works have revealed that these nuclear receptors play critical roles in regulating genes that encode drug metabolism enzymes and modulating hepatic energy metabolism, such as down-regulating gluconeogenesis, fatty acid oxidation, and ketogenesis, as well as up-regulating lipogenesis. Studies on PXR and CAR have important implication on drug-drug interaction (DDI) and potential disease treatment targets. PMID- 22242445 TI - [Research progress of selective mGluR1 antagonists]. AB - As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade. PMID- 22242447 TI - [Effect of polyethylene glycol-lipid derivatives on the stability of grafted liposomes]. AB - It is reported that polyethylene glycol-lipid (PEG-lipid) derivatives increase liposomes stability, prolong the blood circulation of liposomes, enhance their tumor-targeting efficiency, and improve drug efficacy. Therefore, it is of great importance to investigate the influence of modified PEG-lipid derivatives on the physical, chemical, and biological characteristics of liposomes for the promotion of dealing with the existed problems, such as the accelerated blood clearance (ABC) phenomenon when repeated intravous injection at a certain time-interval, and developing novel targeted pharmaceutical preparations. In this review, the effects of modified PEG-lipid derivatives were summarized in many aspects. It indicats that the chemical bonds (amide, ether, ester, and disulfide) between PEG and lipid, as well as the species of lipids, such as the commonly used phosphatidylethanolamine, cholesterol, and diacylglycerol have substantial effects on the grafted liposomes stability in vitro and in vivo. Besides, the properties of lipids (the fatty acid chain length and saturation) and the groups (methoxy, carboxylic and amino) at the distal ends of the PEG chains were also considered to be important factors. In the end, the influence of the average molecular weight of PEG and the molar ratio of PEG-lipid derivatives in the total lipid were further focused. PMID- 22242448 TI - [Effect of anti-arrhythmia drugs on mouse arrhythmia induced by Bufonis Venenum]. AB - This study is to investigate the effects of phenytoin sodium, lidocaine (sodium channel blockers), propranolol (beta-adrenergic receptor antagonist), amiodarone (drugs prolonging the action potential duration) and verapamil (calcium channel blockers) on arrhythmia of mice induced by Bufonis Venenum (Chansu) and isolated mouse hearts lethal dose of Chansu. Arrhythmia of mice were induced by Chansu and then electrocardiograms (ECGs) were recorded. The changes of P-R interval, QRS complex, Q-T interval, T wave amplitude, heart rate (HR) were observed. Moreover, arrhythmia rate, survival rate and arrhythmia score were counted. Isolated mouse hearts were prefused, and the lethal dose of Chansu was recorded. Compared with control group, after pretreatment with phenytoin sodium, broadening of QRS complex and HR were inhibited, and the incidence of ventricular arrhythmia was reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with lidocaine, the prolongation of P-R interval and broadening of QRS complex were inhibited, and the incidences of ventricular arrhythmia were reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with propranolol, prolongation of P-R interval, broadening of QRS complex, prolongation of Q-T interval and HR were inhibited, and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically, while survival rate was improved. After pretreatment with amiodarone, HR was inhibited, the incidences of ventricular tachycardia were reduced dramatically. Lastly, after pretreatment with verapamil, the prolongation of P-R interval and Q-T interval were inhibited and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically; the isolated mouse hearts lethal dose of Chansu was reduced significantly. In in vivo experiments, phenytoin sodium was most effective against the mice arrhythmias induced by Chansu while cautious use of verapamil for Chansu inducing arrhythmia should be noted. It is also concluded that mice ventricular arrhythmias induced by Chansu might be most closely related to sodium channel, supraventricular arrhythmias might be related to beta-adrenergic receptor, and calcium channel plays an important role in conduction block. In in vitro experiments, phenytoin sodium was most effective, followed by lidocaine and propranolol, and amiodarone had no obvious effect and verapamil reduced the lethal dose of Chansu. PMID- 22242449 TI - [Anti-MDR tumor mechanism of CIP-36, a podophyllotoxin derivative]. AB - This study is to investigate the antitumor activity of CIP-36 on multidrug resistant human oral squamous carcinoma cell line (KBV200 cells) in vitro and the possible anticancer mechanisms. MTT assay, Hoechst fluorescein stain, RT-PCR and immunohistochemistry were carried out on KBV200 and KB cells. The growth of many tumor cells was obviously inhibited by CIP-36, especially the multidrug resistant cells KBV200. Obvious apoptosis could be observed in the Hoechst 33342 staining experiments. The results of RT-PCR showed that the levels of p53, p21, caspase-3 and bax mRNA increased, and meanwhile the expression of mdr-1 and bcl-2 mRNA decreased in a dose-dependent manner. The data were significantly different from that of vehicle. The expression of P-gp significantly decreased with the increasing dosage of CIP-36 examined by immunohistochemistry. It can be concluded that CIP-36 could change resistance-related genes and proteins to overcome multidrug resistance in the KBV200 cell line. PMID- 22242450 TI - [Protective effect of new adenosine analog B2 against serum deprivation-induced PC12 cell injury]. AB - This study is to investigate the effect of compound B2 on the damage of PC12 cells induced by serum deprivation and to explore its related mechanisms. The binding characteristics of B2 to rat striatum adenosine A2A receptor was studied by radioligand 3H-MSX-2 binding assay. Cell viability was detected by MTT assay. ROS formation was measured after DCFDA fluorescent staining. B2 has affinity to rat adenosine A2A receptor (K1 = 0.37 micromol x L(-1)). B2 remarkably increased PC12 cell survival rate in serum deprivation-induced PC12 cells. The percentage of serum deprivation-induced death of PC12 was 49.6%, and the treatment of B2 (0.1-100 micromol x L(-1)) increased the cell viability to 63.3%, 74.9%, 86.3% and 88.1%, respectively. Adenosine A2A receptor antagonist SCH 58261 could significantly block the protective effect of B2. The cell viability with 0.1 micromol x L(-1) SCH 58261 decreased by 16.1%, 24.0% and 19.8%, in the presence of B2 (0.1-10 micromol x L(-1)). Serum deprivation-induced ROS formation was 3.5 times more than that of control group, and treatment with B2 significantly and dose-dependently inhibited ROS over-formation. The protective effect of B2 may be related with adenosine A2A receptor. Decrease of serum-deprivation induced ROS formation may also be one of the mechanisms. PMID- 22242451 TI - [Pharmacokinetics of a fusion protein for human acidic fibroblast growth factor and transcriptional activator protein in rat and its penetration across blood brain barrier]. AB - This paper is to report the study of the pharmacokinetics of a fusion protein TAT haFGF(14-154) for human acidic fibroblast growth factor and transcriptional activator protein in rat plasma, and the investigation of their penetration across blood-brain barrier in mice and rats, in order to provide a basis for clinical development and treatment of Alzheimer's disease. Enzyme-linked immunosorbent assay (ELISA) was used to determine concentration of TAT-haFGF(14 154) in rat plasma and in mouse brain homogenate; and immunohistochemistry was used to analyze the distribution in brain. The concentration-time curve fitted two-compartment open model which was linear kinetics elimination after a single intravenous injection of TAT-haFGF(14-154) in rat at the dose of 300 microg x kg( 1). The half life time was 0.049 +/- 0.03 h for distribution phase and 0.55 +/- 0.05 h for elimination phase, and the weight was 1/C2. The result showed that TAT haFGF(14-154) could be detected in the brain by ELISA and immunohistochemistry, the elimination of TAT-haFGF(14-154) in rat was swift, and TAT-haFGF(14-154) could penetrate across the blood-brain barrier, distribute in pallium and hippocampus and locate in the nucleus. PMID- 22242452 TI - [Inhibitory activity of dioxy-pyrrolino [3', 4'-d]isoxazoline derivatives containing (1', 2'-O-cyclohexylidendioxyethyl) against Cdc25A and CD45]. AB - Fifteen 3-(1', 2'-di-O-cyclohexylidendioxyethyl)-5-aryl-3a, 6a-dihydro-4, 6-dioxo pyrrolino[3', 4'-d] isoxazoline derivatives (3a-3o) were synthesized by 1, 3 dipolar cycloaddition reaction of N-arylmaleimides and the nitrile oxide in situ generated from 2, 3-O-cyclohexylidene-D-glycerohydroximoyl chloride, in the presence of triethylamine. The structures of the target compounds 3a-3o were characterized by 1H NMR, IR and elemental analysis. The preliminary bioassay on the compounds showed that some compounds possess in vitro anticancer activity and the leukocyte common antigen activity to a different extent. The compounds 3e, 3h, 3j and 31 showed Cdc25A phosphatase inhibitory activity of 60.6%, 58.6%, 51.4% and 98.4% respectively at the test concentration of 20 microg x mL(-1), and among them 31 had inhibition rate of 86.97% even at the concentration as low as 5 microg x mL(-1), indicating worthy to be future studied. The compounds 3e, 31 and 3n showed an inhibitory activity of 57.7%, 74.4% and 77.3% on CD45 protein tyrosine phosphatase A, respectively, at the test concentration of 20 micromol x mL(-1). The structure-activity relationship of 3-(1', 2'-di-O cyclohexylidendioxyethyl)-5-aryl-3a, 6a- dihydro-4, 6-dioxo-pyrrolino[3', 4' d]isoxazoline derivatives was also discussed. PMID- 22242453 TI - [Synthesis and anti-tumor activity of oleanolic acid derivatives]. AB - Structural modifications were performed with natural product of oleanolic acid to search for novel anticancer drugs. Ten oleanolic acid derivatives were designed and obtained by the reaction of oxidation, acylation or hydrolyzation, etc. The cytotoxic activity of derivatives was evaluated against HeLa, HepG2 and BGC-823 cells in vitro by MTT assay, gefitinib and etoposide used as a positive control. The results showed that compound 5a was particularly active to inhibit HepG2 cells growth, and anti-tumor activity of compound 7 on HeLa cells was significantly stronger than oleanolic acid. They are worthy to be studied further. PMID- 22242454 TI - [Iridoid glycosides from buds of Jasminum officinale L. var. grandiflorum]. AB - The study on the buds of Jasminum officinale L. var. grandiflorum was carried out to look for anti-HBV constituents. The isolation and purification were performed by HPLC and chromatography on silica gel, polyamide and Sephadex LH-20 column. The structures were elucidated on the basis of physicochemical properties and spectral analysis. Six iridoid glycosides were identified as jasgranoside B (1), 6-O-methy-catalpol (2), deacetyl asperulosidic acid (3), aucubin (4), 8-dehydroxy shanzhiside (5), and loganin (6). Jasgranoside B (1) is a new compound. Compounds 2-6 were isolated from Jasminum officinale L. var. grandiflorum for the first time. PMID- 22242455 TI - [Electrochemical sensor for acetaminophen based on layer-by-layer self assembly technique]. AB - A novel type of carbon nanotube-coated Au nanoparticle and [bmim]BF4 composite modified glassy carbon electrode was fabricated by a layer-by-layer self-assembly technique. The electrochemical performance of acetaminophen (ACOP) on the modified electrode was investigated by cyclic voltammetry. The Nafion/GNPs/RTIL/MWNTs/GC electrode showed an excellent electrocatalytic activity for the oxidation of ACOP and accelerated electron transfer between the electrode and ACOP. For ACOP, the reversible electrochemical process was observed on the Nafion/GNPs/RTIL/MWNTs/GC electrode, while irreversible electrochemical process occurred on the GC electrode. For the Nafion/GNPs/RTIL/MWNTs/GC electrode, the anodic peak potential of ACOP was moved from 0.562 V to 0.413 V, with a potential drop of 149 mV. At the same time, the reduction peak potential was 0.384 V, and the potential difference was only 29 mV. It was shown that the modified electrode possessed higher electrocatalytic activity and more sensitive effect for the detection of ACOP than both MWNTs/GC electrode and GC electrode. The effects of the different experimental conditions on the electrochemical behaviors of ACOP were explored. Under the optimum conditions of preparation and experimental, the linear calibration curves of ACOP were obtained in a wide range of 2 x 10(-1) to 4.0 x 10(-4) mol x L(-1) with a correlation coefficient 0.999 2 and a detection limit of 2.6 x 10(-8) mol x L(-1) (the ratio of signal to noise, 3:1). The recovery rate was 97.9%-100.8%. This method can be used to determine ACOP in paracetamol tablets with satisfactory results. PMID- 22242456 TI - [Identification of chemical constituents in qiliqiangxin capsule by UPLC-Q TOF/MS(E)]. AB - In order to clarify the chemical constituents in Qiliqiangxin capsule, a rapid ultra-performance liquid chromatography/orthogonal acceleration time-of-flight mass spectrometry (UPLC-Q-TOF/MS(E)) method was established. Forty peaks were identified on line using this method. The herbal sources of these peaks were assigned. The results implied that triterpenoid saponins, flavonoid glycosides, C21-steroids and phenolic acids were included in the main components of Qiliqiangxin capsule. The method is simple and rapid for elucidation of the constituents of Qiliqiangxin capsule and the results are useful for the quality control of Qiliqiangxin capsule. PMID- 22242457 TI - [Simultaneous determination of seven flavonoids in Nervilia fordii with HPLC]. AB - The study is to develop an HPLC method for simultaneous determination of rhamnazin (1), rhamnocitrin (2), rhamnetin (3), rhamnazin-3-O-beta-D glucopyranoside (4), rhamnazin-3-O-beta-D-xylopyranosyl-(1-->4)-beta-D glucopyranoside (5), rhamnazin-3-O-beta-D-glucopyranosyl-(1-->4)-beta-D glucopyranoside (6), and rhamnocitrin-3-O-beta-D-glucopyranosyl-(1-->4)-beta-D glucopyranoside (7) in Nervilia fordii. The separation was performed on a Kromasil C18 column (250 mm x 4.6 mm, 5 microm) with 0.4% phosphoric acid acetonitrile as the mobile phase in a gradient elution at a flow rate of 1.0 mL x min(-1). The detect wavelength was set at 256 nm, and the column temperature was set at 40 degrees C. There were good linear relationships between the logarithm values of concentrations and those of the peak areas of seven flavonoids (1-7) in the range of 0.55-70.00 microg x mL(-1) (r = 0.9997), 0.86-110.00 microg x mL(-1) (r = 0.9997), 0.39-50.00 microg x mL(-1) (r = 0.999 7), 0.55-70.00 microg x mL( 1) (r = 0.999 5), 1.33-170.00 microg x mL(-1) (r = 0.9998), 1.33-170.00 microg x mL(-1) (r = 0.9998), 0.16-20.00 microg x mL(-1) (r = 0.9995), respectively. The recoveries of the seven flavonoids were between 97.19%-99.45%, the relative standard deviations (RSDs) were between 0.91%-2.69%. The established method is rapid, accurate with high repeatability, which could provide scientific evidence for the quality control of Nervilia fordii. PMID- 22242458 TI - Determinations of mifepristone and its metabolites and their pharmacokinetics in healthy female Chinese subjects. AB - The aim of this study is to establish an HPLC method for simultaneous determinations of mifepristone and its metabolites, mono-demethylated mifepristone, di-demethylated mifepristone and C-hydroxylated mifepristone in plasma and to evaluate the pharmacokinetic characteristics of mifepristone tablet. Twenty healthy female Chinese subjects were recruited and a series of blood samples were collected before and after 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 8.0, 12.0, 24.0, 48.0, 72.0 and 96.0 hours administration by a single oral dose of 75 mg mifepristone tablet. Mifepristone and its three metabolites were extracted from plasma using ethyl acetate and determined by high performance liquid chromatography. The main pharmacokinetic parameters of mifepristone and its metabolites, including Cmax, tmax, MRT, t(1/2), V, CL, AUC(0-96 h) and AUC(0 infinity), were calculated by Drug and Statistical Software Version 2.0. The simple, accurate and stable method allows the sensitive determinations of mifepristone and its metabolites in human plasma up to 4 days after oral administration of 75 mg mifepristone tablet and the clinical applications of their pharmacokinetic studies. PMID- 22242459 TI - [LC-MS/MS method for quantification and pharmacokinetic study of gabapentin in human plasma]. AB - A sensitive, rapid and specific liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for quantification of gabapentin in human plasma has been developed. After a single plasma protein precipitation with methanol, gabapentin and metformin (internal standard) were chromatographed on a Inertsil ODS-3 column (50 mm x 2.1 mm ID, 3 microm) with mobile phase consisting of methanol-0.2% formic acid aqueous solution (80:20, v/v) at a flow-rate of 0.2 mL x min(-1). Electrospray ionization (ESI) source was applied and operated in the positive ion mode. Multiple reaction monitoring (MRM) mode with the transitions of m/z 172 --> m/z 154 and m/z 130 --> m/z 71 were used to quantify gabapentin and metformin, respectively. The run time was 2.2 min. The linear calibration curve was obtained in the concentration range of 40.8-8.16x10(3) ng x mL(-1). The lower limit of quantification was 40.8 ng x mL(-1). The intra- and inter-day precision (RSD) was less than 12%, and the accuracy (RE) was within +/-6.4% calculated from quality control (QC) samples. The method was used to determine the concentration of gabapentin in human plasma after a single oral administration of 600 mg gabapentin capsule to 20 healthy male Chinese volunteers. The method was proved to be selective, sensitive, rapid and suitable for pharmacokinetic study of gabapentin in human plasma. PMID- 22242460 TI - Comparison of microcalorimetric fingerprint profiles of Lonicerae japonicae Flos and Lonicerae Flos. AB - To compare the microcalorimetric fingerprint profiles of Lonicerae japonicae Flos (Lj.F) and Lonicerae Flos (L.F), microcalormietry was applied to find the heat change regularity of Bacillus shigae (B. shigae) metabolism affected by Lj.F and L.F (we choose Lonicera macranthoides Hand.-Mazz in this paper) with different concentrations. The thermogenic curves and thermodynamics parameters were investigated as evaluation index, and then the date of experiment was studied by similarity analysis. All the results indicated that the Lj.F and Lonicera macranthoides Hand.-Mazz (L.m.H-M) significantly impacted the microbial growth and had good similarity in its inhibitory activities. The combination approach of chemical analysis with bioassay was developed and employed to ensure the safety and efficacy of Chinese herbal medicines. PMID- 22242461 TI - [Pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide]. AB - The pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide (ROP) was investigated in rats following i.v. or s.c. administration at three dose levels (9, 20, 50 mg x kg(-1)). A moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG was chosen to produce PEGylate ROP. The grafting degree of the prepared conjugate was 1.03, and the molecular mass of mPEG used was 20 kDa. High-performance gel permeation chromatorgraphy with fluorescein isothiocyanate prelabeling was established to determine levels of the conjugate in plasma. The results showed that the elimination half-life of the conjugate following s.c. administration was basically identical to that after iv administration. An accurate linear correlation was observed between administration doses and areas under the curve of plasma conjugate level vs. time profile, regardless of the administration route. The absolute bioavailability of the conjugate following sc administration was approximately 56%, and the mean in vivo residence time was 52.1 h, increased 2.4 times compared to those of iv administration. In general, linear pharmacokinetics was observed for the conjugate within the dose range studied, and sc should be a promising administration route for the conjugate. PMID- 22242462 TI - [Intestinal lymphatic transport of breviscapine orally administered in rat]. AB - Double cannulation model of conscious rat allowing simultaneous collection of mesenteric lymph and jugular venous blood was established to investigate the intestinal lymphatic transport of breviscapine orally administered in rat. The concentrations of breviscapine in plasma and lymph were determined by HPLC. The pharmacokinetics of breviscapine after oral and intravenous administration was evaluated in the conscious rat model. It was observed that scutellarin distributed from blood circulation to lymphatic system after intravenous injection. The cumulative lymphatic transport amount within 12 h was (2.78 +/- 0.25) microg, equivalent to 0.0792% of intravenous dose. After oral administration of scutellarin to double-cannulation rats, the cumulative lymphatic transport amount within 12 h was (0.92 +/- 0.08) microg, equal to 0.0083% of oral dose. The absolute bioavailability of breviscapine orally administered to double-cannulation rats was 4.91%, indicating that scutellarin was mainly absorbed into the bloodstream through the portal vein. Lymphatic transport of scutellarin appears to reflect high affinity for the lymph lipoproteins to chylomicron. This study provided a biopharmaceutics basis for developing oral lipid delivery system for the promotion of intestinal lymphatic transport to improve oral bioavailability of breviscapine. PMID- 22242463 TI - [Absorption dynamic characteristics of clopidogrel bisulfate polymorphs in rat]. AB - Four crystalline forms of clopidogrel bisulfate were characterized by analytical techniques. Aiming to research the absorption characteristics of clopidogrel bisulfate polymorphs after taken orally by rat, and to estimate the influence of crystal form to pharmacodynamic action, four crystalline forms of clopidogrel bisulfate were administered intragastrically to rats, and high performance liquid chromatography (HPLC) was used to measure the contents of clopidogrel bisulfate and its metabolite in rat plasma. The metabolite of clopidogrel bisulfate was detected in rat plasma. There were significant deviations among four crystalline forms in the areas under curve of the metabolite of clopidogrel bisulfate. We concluded that the different crystal forms of clopidogrel bisulfate showed different pharmacokinetic characteristics, which might affect pharmacodynamic action. PMID- 22242464 TI - [Cloning, expression and functional identification of a type III polyketide synthase gene from Huperzia serrata]. AB - A cDNA encoding novel type III polyketide synthase (PKS) was cloned and sequenced from young leaves of Chinese club moss Huperzia serrata (Thunb.) Trev. by RT-PCR using degenerated primers based on the conserved sequences of known CHSs, and named as H. serrata PKS2. The terminal sequences of cDNA were obtained by the 3'- and 5'-RACE method. The full-length cDNA of H. serrata PKS2 contained a 1212 bp open reading frame encoding a 46.4 kDa protein with 404 amino acids. The deduced amino acid sequence of H. serrata PKS2 showed 50%-66% identities to those of other chalcone synthase super family enzymes of plant origin. The recombinant H. serrata PKS2 was functionally expressed in Escherichia coli with an additional hexahistidine tag at the N-terminus and showed unusually versatile catalytic potency to produce various aromatic tetraketides, including chalcones, benzophenones, phloroglucinols, and acridones. In particular, the enzyme accepted bulky starter substrates N-methylanthraniloyl-CoA, and carried out three condensations with malonyl-CoA to produce 1, 3-dihydroxy-N-methylacridone. Interestingly, H. serrata PKS2 lacks most of the consensus active site sequences with acridone synthase from Ruta graveolens (Rutaceae). PMID- 22242465 TI - [Study of demonstrating main operative mark of transmastoid-epitympanum approach of the facial nerve using double oblique multi-planar reconstruction in multi slice CT]. AB - OBJECTIVE: To explore a method of demonstrating the facial nerve anatomical landmarks under transmastoid and epitympanum approach with multi-slice CT using double oblique multi-planar reconstruction (MPR). METHOD: Two temporal bone of a corpse were dissected, under transmastoid and epitympanum approach, to observe the anatomical landmarks of facial nerve. Based on that, the anatomical landmarks of facial nerve under transmastoid and epitympanum approach in 30 (60 ears) normal temporal bones of adult corpses were reconstructed using double oblique MPR in multi-slice CT. The achievement ratio was calculated and the differences among transverse plane, coronal plane, sagittal plane and double oblique were compared. RESULT: The different part of facial nerve, such as mastoid segment, tympanum segment, pyramid segment, geniculate ganglion and the outer labyrinthine segment could be exposed clearly with the main anatomical landmarks, such as horizontal semicircular canal, epitympanic recess and cochleariform process through transmastoid and epitympanum approach. The image of anatomical landmarks could be showed in the same sections by double oblique multi-planar reconstruction. The double oblique multi-planar reconstruction to show the landmarks of facial nerve displaying on the same imaging is better than transverse plane, coronal plane and sagittal plane. The achievement ratio of every section is 100%. CONCLUSION: Double oblique MPR is a new method to demonstrate anatomical landmarks through transmastoid and epitympanum approach in one slice. Combined with the operative approach and purpose, the reconstructive images with double oblique MPR can provide valuable information for operation. PMID- 22242466 TI - [The clinical characteristics and the treatment of external auditory canal cholesteatoma]. AB - OBJECTIVE: To evaluated the characteristics, stage classification and treatment of external auditory canal cholesteatoma (EACC). METHOD: Fifty-nine cases (60 ears) with EACC undergoing surgery were retrospectively analyzed in our study. RESULT: Hearing impairment, otalgia and otorrhea were common symptoms of EACC patients. A total of 60 ears were classified into 4 stages: Stage I (26 ears) underwent canaloplasty, stage II (14 cars) underwent both canaloplasty and tympanoplasty, stage III (19 ears) underwent mastoidectomy, and stage IV (1 ear) required both canaloplasty and neoplasty of capsula articularis articulations temporomandibular. CONCLUSION: Besides the lesion in external auditory canal, EACC also invaded into the middle ear and the temporal bone. Stage classification by the signs of the temporal bone computed tomography and the patients' clinical findings was helpful for surgery. PMID- 22242467 TI - [Diagnosis and treatment of esophagus perforation caused by esophageal foreign bodies]. AB - OBJECTIVE: Summarize the treatment skills of esophagus perforation caused by esophageal foreign bodies. METHOD: Retrospectively analyze the seven cases of esophagus foreign body perforation with various complications in our department. RESULT: Six cases recovered in 3 to 18 days after operation, on average 14.2 day, while one case recovered in 49 days by conservative method. CONCLUSION: Foreign bodies removing, fistulae repairing, abscess incising, effusion rinsing, effective antibiotics administrating and support treatment are effective to treat esophagus perforation caused by esophageal foreign bodies. It will take a relative long time to be treated only by conservative way. PMID- 22242468 TI - [Modified intranasal endoscopic dacryocystorhinostomy in chronic dacryocystitis]. AB - OBJECTIVE: To evaluate the technique and curative effect of modified intranasal endoscopic dacryocystorhinostomy (EDCR) for chronic dacryocystitis. METHOD: Twenty-two patients (Twenty-three eyes)with chronic dacryocystitis, undergoing modified intranasal EDCR were retrospectively analyzed in this study. RESULT: The follow-up period ranged from six months to ten months. Twenty eyes were cured successfully and two eyes had relieved symptoms. While one case failed. No serious complications were found. The total effective rate was 22/23 (95.7%). CONCLUSION: The modified intranasal EDCR is an effective method to treat chronic dacryocystitis. PMID- 22242469 TI - [Clinical analysis of reoperation for recurrence thyroid carcinoma in 87 cases]. AB - OBJECTIVE: To explore the cause and the methods of reoperation for recurrent thyroid carcinoma. METHOD: The clinicopathologic data of 87 cases were retrospectively analyzed. The diagnosis on recurrent thyroid carcinoma were confirmed after reoperative pathology. RESULT: Forty-three cases (49.4%) were confirmed as residual carcinoma by pathology. Among 87 cases, 65 cases (74.7%) had lymph node metastasis in group VI and 42 cases (48.3%) had lateral neck lymph nodes metastasis, 3 cases were in the presence of recurrent laryngeal nerve injury temporarily, 1 case was in the presence of recurrent laryngeal nerve injury permanently, 5 cases were convulsed by hypocalcemia. CONCLUSION: The nonstandard surgical procedure in the first operation is the main cause for the reoperation of thyroid carcinoma. Increased cognitive level of thyroid carcinoma and appropriate surgical technique may be the important keys to avoid reoperating. It is necessary to protect the parathyroid and recurrent laryngeal nerve in reoperation. PMID- 22242470 TI - [Long term observation of the effectiveness after tonsillectomy]. AB - OBJECTIVE: To observe the long-term effect of tonsillectomy and provide clinical evidence for tonsillectomy. METHOD: One hundred and one patients undergoing tonsillectomy in our department were included. Their satisfaction and symptom change were followed up by telephone. RESULT: 73.3% patients were satisfied with their surgery. Chief complaints such as pharyngalgia, fever, snoring were significantly decreased after surgery, while foreign body sensation still existed. Some patients complaint for dry throat, foreign body sensation or voice change after tonsillectomy. CONCLUSION: Most patients were satisfied with the tonsillectomy. While few of them had new complaints after tonsillectomy. PMID- 22242471 TI - [Use of silicon T-tube in laryngotracheal reconstruction]. AB - OBJECTIVE: To discuss the function and operative method of silicon T tube in laryngotracheal reconstruction. METHOD: Two hundred and ninety-seven patients of laryngotracheal stenosis were operated with laryngotracheal reconstruction in our department. All of patients were tracheostomy dependent before reconstruction and were placed a silicon T-tube stenting for 3 to 6 months after reconstruction. RESULT: Two hundred and eighty-nine patients (97.3%) were successfully decannulated with good airway patency and effective phonation. They were followed up from 1 to 10 years, and no recurrence was found. CONCLUSION: Silicon T-tube is an effective and safe stent for laryngotracheal reconstruction. Paying attention to some application details may avoid the complication and obtain a satisfactory effect. PMID- 22242472 TI - [Pathogenic bacteria distribution and drug susceptibility in children with acute otitis media in Pearl River Delta]. AB - OBJECTIVE: To investigate the pathogenic bacteria distribution and drug susceptibility in children with acute otitis media (AOM) in different age and different season in the Pearl River Delta region. METHOD: Four hundred and forty two children diagnosed as AOM were divided into three groups by age factor and four groups by season factor. Midge ear pus collecting and culturing were used for bacteria and antimicrobial susceptibility test. RESULT: (1) Strains of bacteria were isolated from 356 children with the positive rate of 80.5%. Streptococcus pneumoniae (39.2%), staphylococcus aureus (25.9%) and haemophilus influenzae (7.4%) were the most frequently isolated pathogens. (2) Streptococcus pneumoniae was the main pathogenic bacteria in 0-1 year group and > 1-3 years group (P < 0.05), staphylococcus aureus was the most frequently isolated pathogen in >3 years group (P < 0.05); (3) In the season groups, the number of children with AOM decreased significantly in July-September group. There was no significant difference of streptococcus pneumoniae distribution among the four groups (P > 0.05). Staphylococcus aureus was the main pathogen in January-March group (P < 0.05); (4) Drug sensitivity shown that linezolid and ofloxacin were most sensitive to streptococcus pneumoniae and staphylococcus aureus, and macrolides had a good therapy effect to haemophilus influenzae. CONCLUSION: The pathogens distribution and drug susceptibility in children with AOM were varies in different age and different season. As a result, a treatment should be done based on the climate, environment, and pathogens distribution of a region. PMID- 22242473 TI - [Petrositis due to acute otitis media: a case report and literature review]. AB - OBJECTIVE: To study the clinical features and conservative treatment of petrositis. METHOD: One case of petrositis was reported and literatures were reviewed. Opacificated air cells in CT, and anomalous, discontinuous hypersignal in MRI T1 and T2 provided evidence of infection of the apex of the petrous temporal bone. RESULT: The patient recovered totally after conservative treatment with intravenous antibiotic, glucocorticoid and neurotrophic therapy, and no recurrence occurred in 1 year follow-up. CT rescan showed the clear air cells of the petrous apex 4 months later. CONCLUSION: Petrositis can be diagnosed with specific clinical features, the image of CT and MRI. Conservative treatment could be a good choice. PMID- 22242474 TI - [Clinical analysis of cervical lymph node metastasis of hypopharyngeal carcinoma]. AB - OBJECTIVE: To investigate the pattern of cervical lymph node metastasis in hypopharyngeal carcinoma. METHOD: Forty-five cases of hypopharyngeal squamous cell carcinoma were analyzed retrospectively. RESULT: (1) The total rate of lymph node metastasis was 75.56%. 11.11% metastases for bilateral neck and 4.44% did unilateral neck in 10 bilateral neck dissection. The total distance metastasis rate out of lymph node were 79.41%. The rate of bilateral distance metastasis and unilateral distance metastasis were both 5.88% in 10 bilateral neck dissection. (2) 163 of 411 lymph nodes (39.66%) were positive. The percentage of positive lymph node were 0.61%, 49.08%, 25.77%, 21.47% and 3.07% in region I, II, III, IV and V respectively. The rates of lymph node metastasis were 3.57%, 62.02%, 37.17%, 42.17% and 8.62% in region I, II, III, NV and V respectively. (3) The statistical significant differences were found between region I + V and II + III and IV (P < 0.05), among II, III and IV (P < 0.05), between II and III + IV (P < 0.05), between II and III (P < 0.05), between II and IV (P < 0.05), among I, II, III, IV and II + III + IV (P < 0.05), among V, II, III, IV and II + III + IV (P < 0.05). There were not statistical significant differences in region between III and IV (P > 0.05), between I and V (P > 0.05). (4) There were not statistical significant differences in the rates of lymph node metastasis and capsule invasion between T1 + T2 and T3 + T4 (P > 0.05), among T1, T2, T3 and T4 (P > 0.05). (5) There were not statistical significant differences in the rates of lymph node metastasis and distance metastasis between pyriform sinus and out of it (P > 0.05). (6) There were not statistical significant differences in the rates of lymph node metastasis and distance metastasis between cervical esophagus invasion and not (P > 0.05). (7) There were not statistical significant differences in the rates of lymph node metastasis and distance metastasis among N1, N2, N3 (P > 0.05). (8) There were statistical significant differences in the rates of lymph node metastasis between clinical stage I + II + III and IV, between II and IV (P < 0.05). While there were not statistical significant differences in the rates of distance metastasis between III and IV (P > 0.05). CONCLUSION: The lymph node metastasis was mainly in the region II, III and IV, especially in the region II. T stage, primary site and cervical esophagus invasion were not related to neck lymph node metastasis and distance metastasis. N stage was not related to distance metastasis. Clinical stage IV had a higher lymph node metastasis rate. PMID- 22242475 TI - [Relationship between 3-d reconstruction of regenerated fibers and functional recovery after mastoid segment of facial nerve was repaired]. AB - OBJECTIVE: To explore the relationship between three-dimensional (3-D) reconstruction of regenerated fibers and functional recovery after mastoid segment of facial nerve was repaired with either end-to-end anastomosis or autogenous great auricular nerve grafting. METHOD: Thirty healthy adult New Zealand white rabbits were randomly divided into two groups: one was end-to-end anastomosis group and another was autogenous great auricular nerve grafting group. Only mastoid segment of right facial nerve of each animal was dissected and the contralateral nerve was as a control. Electromyogram (EMG) were recorded from 5 animals of each group at the 30th d, 90th d and 120th d after operation. After that the nerves were extracted, fixed, decalcified and embedded in paraffin. Samples was sectioned serially at 6 microm and stained with special trichrome stain. All the imagines were imported into Mimics software to reconstruct the 3-D model. RESULT: The significant differences were found in the regenerate fibers on 30 th d,and were found in amplitude of EMG on 30 th d and 90 th d. The image of 3-D reconstruction showed that the myelin sheath were thickening, connected from proximal to the distal gradually after repair. CONCLUSION: The 3-D reconstruction of regenerated nerve fibers partly conformed to the functional recovery after facial nerve trunk was repaired. The functional recovery of facial nerve was related with both the quantity and the quality of regenerated nerve fibers. PMID- 22242476 TI - [The expression of myosin heavy chain isoforms of human normal laryngeal muscles and the difference between the adductor and abductor]. AB - OBJECTIVE: To investigate the expression of myosin heavy chain (MHC) in normal laryngeal muscle and the difference between the adductor and abductor. METHOD: Seven patients with total laryngectomy were enrolled in this study. The adductor muscles were acquired from the lateral cricoarytenoid (LCA) muscle and the abductor muscles were acquired from the posterior cricoarytenoid (PCA) muscle. The expression of myosin heavy chain were detected with fluorescent quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining respectively. RESULT: (1) MHC-II b was expressed in laryngeal muscles at mRNA levels, and not expressed at the protein level; (2) At both mRNA level and protein level, the expression of MHC-I was higher in the PCA muscles than in the LCA muscles while MHC-II level was higher in the LCA muscles than in the PCA muscles. CONCLUSION: (1) MHC-II b protein was not expressed in human laryngeal muscles; (2) Phenotypic differences were significant in laryngeal adductor and abductor muscles based on their different functions. PCA contained larger percentage of MHC-I fibers, while LCA contained more MHC-II fibers. PMID- 22242477 TI - [Progress in Teflon AF LWCC/LCW applications]. AB - Teflon AF is chemically very inert, quite physically and optically stable, a highly vapor-permeable polymer with optical transparency through much of the UV Vis region and with an RI lower than that of water, so Teflon AF LWCC/LCW (Long path-length liquid waveguide capillary cell/liquid core waveguides) has been used with a range of different detection techniques, including absorbance spectroscopy, fluorescence spectroscopy, Raman spectroscopy, and gas sensor. The present article describes the properties and the aspects of Teflon AF LWCC/LCW instrumentation and applications. And finally,the future prospect and outlook of Teflon AF LWCC/LCW is also discussed. PMID- 22242478 TI - [Accurate optical parameters extracting of non-polar organic solvents in the terahertz range]. AB - Six kinds of non-polar organic solvents were measured by using terahertz time domain spectroscopy (THz-TDS), including positive hexane, cyclohexane, petroleum ether, carbon tetrachloride, carbon bisulfide, and toluene. These non-polar organic solvents are often used to solve other organics, so knowing the parameters of these non-polar organic solvents are important for studying optical properties of other organics in the frequency range of terahertz. The influence of the cuvette on THz signal was considered. Accurate optical parameters including refractive index and absorption coefficient were analyzed by the novel expression of the transfer function. In addition, according to the relationship among these absorption coefficients of five organic solvents, the polarity relationship can be determined. PMID- 22242479 TI - [Diagnostics of atmospheric-pressure radio-frequency capacitively coupled Ar/N2 plasma by optical emission spectroscopy]. AB - An atmospheric-pressure Ar/N2 glow discharge was achieved in a mode stricken between bare metal plate electrodes by radio-frequency power supply at 13.56 MHz. The rotational temperature was determined by using the Boltzmann plot of the OH (A 2sigma+ --> X 2pi) radical and the variation tendency of the gas temperature versus the input power was obtained. Furthermore, the measurement of the sequences of vibrational bands of N2 second positive system (C 3 pi(u) --> B 3 pi(g)) is made and the vibrational temperature was determined correspondingly. The experiment results showed that the emission peaks of N2 (C3 pi(u)) reached the maximum at the nitrogen flow rate of 80 mL x min(-1) with increasing addition of nitrogen, the gas temperature increased from 342 to 523 K when the input power increased from 30 to 210 W, and the vibrational temperature changed slightly when the gas flow rate of nitrogen increased from 30 to 140 mL x min(-1). PMID- 22242480 TI - [Study of a wire-to-plate positive pulsed corona discharge reactor by emission spectroscopy]. AB - In order to get extensive knowledge of wire-to-plate pulsed corona discharge reactor, the influences of different diameters of wire electrode, different wire to-plate and wire-to-wire spacing on OH radical generation were experimentally investigated under atmospheric pressure based on emission spectrum, and the spatial distribution of OH radicals in the electric field was also discussed in detail The results showed that OH radicals decrease along the X-axis, and the activation radius is approximately 20 mm; showing a trend of first increase and then decrease along the Y-axis, with the activation radius being more than 30 mm. OH radical has small change as the diameter of wire electrode changes below 2 mm, with a sharp decline as the diameter continues to increase. OH radical emission intensity increases as wire-to-wire spacing increases and decrease as wire-to plate spacing increases. PMID- 22242481 TI - [Analysis of streamer properties and emission spectroscopy of 2-D OH distribution of pulsed corona discharge]. AB - Streamer plays a key role in the process of OH radical generation. The propagation of primary and secondary streamers of positive wire-plate pulsed corona discharge was observed using a short gate ICCD in air environment. The influence of the applied voltage on the properties was investigated. It was shown that the primary streamer propagation velocity, electric coverage and length of secondary streamer increased significantly with increasing the applied voltage. Then 2-D OH distribution was investigated by the emission spectrum. With the analysis of the OH emission spectra, the distribution of OH radicals showed a trend of decreasing from the wire electrode to its circumambience. Compared with the streamer propagation trace, the authors found that OH radical distribution and streamer are in the same area. Both OH radical concentration and the intensity of streamer decreased when far away from the wire electrode. PMID- 22242482 TI - [Preparation and luminescent properties of a green Ca2SnO4 : Tb3+ phosphor]. AB - A novel green emitting phosphor, Tb(3+)-doped Ca2SnO4, was prepared by the solid state reaction. X-ray powder diffraction (XRD) analysis confirmed the formation of Ca2SnO4 : Tb3+. Photoluminescence measurements indicated that the phosphor exhibits bright green emission at about 543 nm under UV excitation. The excitation spectra of Ca(2-x)Tb(x)SnO4 appear to have a red shift with main peak from 254 to 260 nm. The emission spectra of Ca(2-x)Tb(x)SnO4 have four peaks ascribed to 5D4-7F(J) (where J = 6, 5, 4, 3) transitions of Tb3+ ions. Under the condition of low Tb3+ concentration, the 5D4-7F6 transition of Tb3+ showed a stark energy level split to three split peaks and the peak intensity of 481nm firstly increased with increasing Tb3+ concentration, then decreased. The dependence of luminescent intensity of Ca2 SnO4 : Tb3+ phosphor on the Tb3+ concentration was studied, and the results show that the luminescence intensity firstly increased with increasing Tb3+ concentration, then decreased, and reached the maximal value at 9 mol% Tb3+. According to the Dexter theory, the authors confirmed the concentration quenching mechanism of Tb3+ in Ca2 SnO4. The fluorescence lifetime of phosphor analysis shows that the average lifetime is 4.4 ms. The results indicated that Ca2 SnO4 : Tb3+ could be a potential candidate as a green-emitting powder phosphor. PMID- 22242483 TI - [Preparation and luminescence of single-host white-light-emitting BaSrMg(PO4)2 : Eu2+ phosphor for ultraviolet LEDs]. AB - A single-host white-light-emitting phosphor BaSrMg(PO4)2 : EU2+ was prepared by high temperature solid-state reaction method, and the luminescence characteristics and XRD pattern were investigated. The results showthat BaSrMg(PO4)2 phase was obtained by sintering at 1 200 degrees C for 3 hours. BaSrMg(PO4)2 = Eu2+ phosphor exhibits two main emission bands peaking at 424 and 585 nm, respectively. The emission band peaking at 424 nm is attributed to the 4f 6 5d1 --> 4f7 transition of Eu2+ substituting Sr2+, while the emission band peaking at 585 nm originates from the 4f 6 5d1 --> 4f7 transition of Eu2+ replacing Ba2+ in host lattice. The excitation spectra of the two emission peaks are range from 250 to 400 nm and both peaking at 360 nm. The effect of the proportion of Ba and Sr, and the Eu2+ doping concentration on the emission intensity were discussed in detail. Different chromaticity coordinates were obtained for each phosphor, that is, the chromaticity coordinates of the designed phosphor is tunable for the white-emitting LED or for special purpose. Quantum efficiency was also examined for the phosphors with different Eu2+ doping concentration, and concentration quenching took place obviously when Eu2+ doping concentration was lager than 6% in mole ratio. The obtained phosphor BaSrMg(PO4)2 : Eu2+ can be excited by near ultraviolet radiation effectively and emit full color lighting, which is a promising single-host white-light-emitting phosphor for white LED. PMID- 22242484 TI - [Cooperative downconversion in Tb (0.7 ) Yb (5) : FOV oxyfluoride nanophase vitroceramics]. AB - The present article reports the infrared quantum cutting study of the nanophase oxyfluoride vitroceramics Tb(0.7)Yb (5.0) : FOV. The visible to infrared fluorescence emission spectra, excitation spectra and fluorescence lifetime were measured carefully. The infrared quantum cutting phenomenon {1([5 D4 --> 7 F6](Tb3+), 2([2 F7/2 --> 2 F5/2](Yb3+)} was analyzed based on the above experiments. It was found that the theoretical quantum cutting efficiency is about 121.35% when 5D4 level is excited by 487.0nm light, and about 136.27% when (5D3, 5G6) levels are excited by 378.0 nm light respectively. Meanwhile, it is first time for the present paper to find a cooperative downconversion phenomenon {2([(5D3, 5G6) --> 5D4] (Tb3+), 1([2 F7/2 --> 2 F5/2] (Yb3+)}. That is, the authors found for the first time that the donor Tb3+ ion releases two pieces of energy [(5D3, 5G6) --> 5D4] of small energy photon to produce a middle energy photon [2 F5/2 --> 2 F7/2] of acceptor Yb3+ ion. PMID- 22242485 TI - [Excitation and relaxation of metastable state NaK(1 3Pi) at high vibrational levels]. AB - The authors have investigated collision vibrational energy transfer rate constants in NaK[1 3Pi(v)] and He system. Pump laser excitation of the spin forbidden band was used to produce very highly vibrationally excited metastable state NaK[1 3Pi (v = 22, 21, 20)]. The probe laser was used to excite the 1 3Pi (v = 22, 21, 20) to 5 3Pi(v'). Laser induced fluorescence (LIF) from 5 3Pi --> 1 3Sigma+ transition was used to follow the collision dynamics. The semilog plots of time-resolved LIF was obtained. The slopes yielded the effective lifetimes. From such data several Stern-Volmer plots could be constructed and the relaxation rate constants could be extracted for the sum of all processes that give rise to the decay of the prepared vibrational state. The rate constants (in units of 10( 11) cm3 x s(-1)) for v being 22, 21 and 20 are 1.4 +/- 0.1, 1.2 +/- 0.1 and 1.0 +/- 0.1, respectively. The vibrational relaxation rate is increasing with vibrational quantum number. In order to determine the importance of multiquantum relaxation, it is necessary to measure the relative population of both the prepared state and collisionally populated states. By the kinetic equations governing up to Delta(v) = 2 transitions, the time dependence of populations of the vibrational states were obtained. With the help of the integrating the population equations over all time, the importance of the two-quantum relaxation could be studied experimentally. By varying the delay between the pump and the probe laser, the He pressure dependent vibrational state specific decay could be measured. The time evolutions and relative intensities of the three states v = 22, 21 and 20 by preparing v = 22 were obtained. Using experimental data the rate constants (in units of 10(-11) cm3 x s(-1)) for v = 22 --> 21 and v = 22 --> 20 are 0.67 +/- 0.15 and 0.49 +/- 0.12, respectively. The single quantum relaxation accounts for only about 48% of the total relaxation out of v = 22. Multi-quantum relaxation (Delta(v) > 1) was found to be important at high vibrational states. PMID- 22242486 TI - [Analysis of alcoholic extracts of Cistanche deserticola by tri-step identification of Fourier transform infrared spectroscopy]. AB - Tri-step identification of Fourier transform infrared spectroscopy (FTIR) integrated with second derivative spectroscopy and two dimensional correlation infrared spectroscopy (2D-IR) were applied to analyze and evaluate the alcoholic extracts and corresponding residues of cistanche deserticola from the surface to what lies behind. It was found that active compounds including phenylethanoid glycosides were enriched effectively after alcoholic extraction and the extract by using 70% of alcohol had the highest concentration compared to the others. The technique of the tri-step identification holistically disclosed the profile of active compounds in cistanche deserticola extracted by a series of concentrations of ethanol and validated the rationality of the traditional alcoholic extraction method. It not only could be used in monitoring the process of the alcoholic extraction and the compositions of the extracts and residues, discriminating micro-differences among them, but also could provide a macroscopic guidance for medicinal and pharmacological studies. PMID- 22242487 TI - [Quantitative determination of parameters of substrate using near-infrared spectroscopy technique]. AB - Soilless culture has many virtues, such as space saving, time saving, etc.. It has become one of the technologies which developed fastest in agricultural products. The selection of substrate is one of the keys to determining the success of soilless culture. Therefore, it is important to rapidly determine the parameters of substrate. In the present paper, moisture, electronic conductivity and pH values of substrate were tested by near-infrared (NIR) spectroscopy. The spectra were preprocessed by baseline correction and derivative. Partial least squares (PLS) regression model was built using different wave bands. It was found that baseline drift was improved after correction. NIR spectroscopy can be used to determine EC value of substrate. The correlation coefficient r, root-mean square error of the cross validation (RMSECV), relative percent difference (RPD) and bias of the optimum PLS was 0.923 6, 634 micros x cm(-1), 3.11 and 19.8 micros x cm(-1), respectively, when the best wave band was 4 246.7 - 7 502.2 cm( 1) and the best factor was 7. NIR spectroscopy technique can also be used to predict moisture of substrate although the accuracy of model should be improved. However, it can not be used to predict pH value of substrate. PMID- 22242488 TI - [Identification of special quality eggs with NIR spectroscopy technology based on symbol entropy feature extraction method]. AB - Fast, nondestructive and accurate identification of special quality eggs is an urgent problem. The present paper proposed a new feature extraction method based on symbol entropy to identify near infrared spectroscopy of special quality eggs. The authors selected normal eggs, free range eggs, selenium-enriched eggs and zinc-enriched eggs as research objects and measured the near-infrared diffuse reflectance spectra in the range of 12 000-4 000 cm(-1). Raw spectra were symbolically represented with aggregation approximation algorithm and symbolic entropy was extracted as feature vector. An error-correcting output codes multiclass support vector machine classifier was designed to identify the spectrum. Symbolic entropy feature is robust when parameter changed and the highest recognition rate reaches up to 100%. The results show that the identification method of special quality eggs using near-infrared is feasible and the symbol entropy can be used as a new feature extraction method of near infrared spectra. PMID- 22242489 TI - [Prediction of chlorophyll content of greenhouse tomato using wavelet transform combined with NIR spectra]. AB - In quantitative analysis of spectral data, noises and background interference always degrade the accuracy of spectral feature extraction. The wavelet transform is multi-scale decomposition used to reduce the noise and improve the analysis precision. On the other hand, the wavelet transform denoising is often followed by destroying the efficiency information. The present research introduced two indexes to control the scale of decomposition, the smoothness index (SI) and the time shift index (TSI). When the parameters satisfied TSI < 0.01 and SI > 0.100 4, the noise of spectral characteristic was reduced. In the meanwhile, the reflection peaks of biochemical components were reserved. Through analyzing the correlation between denoised spectrum and chlorophyll content, some spectral characteristics parameters reflecting the changing tendency of chlorophyll content were chosen. Finally, the partial least squares regression (PLSR) was used to develop the prediction model of the chlorophyll content of tomato leaf. The result showed that the predictiong model, which used the values of absorbance at 366, 405, 436, 554, 675 and 693 nm as input variables, had higher predictive ability (calibration coefficient was 0. 892 6, and validation coefficient was 0.829 7) and better potential to diagnose tomato growth in greenhouse. PMID- 22242490 TI - [Quantitative estimation of CaO content in surface rocks using hyperspectral thermal infrared emissivity]. AB - The objective of the present paper is to study the quantitative relationship between the CaO content and the thermal infrared emissivity spectra. The surface spectral emissivity of 23 solid rocks samples were measured in the field and the first derivative of the spectral emissivity was also calculated. Multiple linear regression (MLR), principal component analysis (PCR) and partial least squares regression (PLSR) were modeled and the regression results were compared. The results show that there is a good relationship between CaO content and thermal emissivity spectra features; emissivities become lower when CaO content increases in the 10.3-13 mm region; the first derivative spectra have a better predictive ability compared to the original emissivity spectra. PMID- 22242491 TI - [Determination of acrylamide in PDA with near infrared reflectance spectroscopy]. AB - In the present study, near infrared reflectance spectroscopy(NIRS) was used as a rapid and accurate method to determine the residual of acrylamide monomer in the product of diallyl dimethyl ammonium chloride and acrylamide. In this experiment 38 products were used which were self-prepared in the laboratory, then near infrared spectra of the product were scanned, seven bands were selected, the characteristic peaks of each band were used as the independent variables, and the absorption peak was used as the dependent variable, using partial least squares (PLS) method to establish the mathematical conversion near infrared reflectance spectroscopy (NIRS) calibration model. In the analysis of the spectrum, using wavelet analysis as the method of reducing the noise of spectrum, and with comparison of the simulated value and measured value, the measured value was determined by using UV spectrum, the external validation determination coefficient was found to be 0.99, and the distribution trend forecast was good. Statistics showed that there was no significant difference between simulated value and measured value. The results show that using the calibration model established by the data of near infrared spectroscopy to predict the residual AM monomer in PDA is of high feasibility. PMID- 22242492 TI - [Influence factor for prediction of air-dry density of Eucalyptus pellita by near infrared spectroscopy]. AB - Near infrared spectroscopy(NIR)technique was applied to compare the influence factors of Eucalyptus pellita's air-dry density. Air-dry density of eucalypt wood was tested by direct measurement After collecting the near infrared reflectance spectra of samples in different section and with different thickness, moisture content and roughness, the NIR spectra were preprocessed with the second derivative and the regression models were built in certain spectra. The calibration models were established using 50-140 samples with the partial least squares method and validated with external validation method. The results showed that the predicted results were influenced by sample's section, thickness, roughness and moisture content. The best near infrared spectroscopy prediction model was built under the condition of transverse section, 2-5 mm thickness, 12% moisture content and meticulous roughness of wood. PMID- 22242493 TI - [Study of density functional theory for surface-enhanced Raman spectra of p aminothiophenol]. AB - In the present paper, DFT method at the B3LYP/6-31++G** (C, H, N, S)/LANL2DZ(Ag) level was used to optimize molecular configurations of p-aminothiophenol. Based on the optimized structure, the normal Raman scattering (NRS) spectrum of PATP and the surface-enhanced Raman scattering(SERS) spectrum of PATP adsorbed on Ag and Ag2 were both calculated, and were compared with the results of other literatures values. The calculation results indicated that a good conformity was found between the computed and experimental results. The results of PATP adsorbed on Ag2 were more approximate to the ever reported experimental data than those of PATP adsorbed on Ag. At the end, detailed analysis of the Raman spectrum and more comprehensive assignments of the vibration mode for p-aminothiophenol were studied by the software of GaussView. In comparison with SERS spectrum and NRS spectrum of PATP molecule, the authors observed the stretching vibration bands in the SERS spectrum at about 213 cm(-1), which is due to Ag-S stretching vibration mode. The work in this paper has greatly directive value in understanding and explaining some experiment phenomenon, and helps to study the mechanism of surface-enhanced Raman scattering of PATP. PMID- 22242494 TI - [Application of Raman spectroscopy to investigation of CVD-SIC fiber]. AB - The CVD-SiC fiber was studied by using laser Raman spectra. It was found that the sharp TO peak exists in the first SiC deposit layer, indicating the larger SiC grains. But the second SiC deposit layer is with small grains. Raman peak of carbon and silicon was detected respectively in the first and second layer. Compared with that of the single SiC fiber, the TO peaks move to the high wave number for the SiC fiber in SiC(f)/Ti-6Al-4V composite. It indicates that the compressive thermal residual stress is present in the SiC fiber during the fabrication of the composite because of the mismatched coefficient of thermal expansion between Ti-6Al-4V matrix and SiC fiber. The average thermal residual stress of the SiC fiber in SiC(f)/Ti-6Al-4V composite was calculated to be 318 MPa and the residual stress in first deposit layer is 436 MPa which is much higher than that in the second layer. PMID- 22242495 TI - [Raman spectral analysis of theanine]. AB - The L-theanine was tested using confocal Raman microscopy. Obvious Raman bands were showed in the range of 250 -1 700 and 2 800-3 000 cm(-1). The Raman bands were assigned with a preliminary analysis and the characteristic vibrational modes were gained in different range of wave numbers. Eight strong Raman bands were observed in the Raman spectra at 321, 900, 938, 1 153, 1 312, 1 358, 1 454 and 1 647 cm(-1), respectively. They are the characteristic Raman bands of L theanine. The results showed that Raman spectroscopy might be a new kind of precise, direct and fast detecting method for theanine. PMID- 22242496 TI - [Laser-induced fluorescence of 1-methylnaphthalene in a supersonic jet expansion]. AB - Laser-induced fluorescence excitation spectrum of S0 --> S1 transition of 1 methylnaphthalene was obtained in supersonic jet condition. Theoretical calculations were conducted to study the geometry and energy of 1 methylnaphthalene at the ground and first excited state. Geometry optimization for the ground state was performed by DFT/B3LYP methods using 6-311++G (d,p) basis set. CIS/6-311++G(d,p) method was used to study the excited state. The excitation spectrum of 1-methylnaphthalene was assigned with the help of calculated vibrational frequencies and vertical excitation energies predicted by TDDFT method. It was found that the oscillator strength of the S0 --> S1 transition was enhanced by substituting a hydrogen atom of naphthalene with the methyl group although the Herzberg-Teller vibronic coupling effect still existed. PMID- 22242498 TI - [Synthesis and fluorescence property of novel rare earth europium, terbium complexes with beta-diketone]. AB - A novel beta-diketone 1-(4-aminophenyl)-4,4,4-trifluorobutane-1, 3-dione(p-NBFA) was synthesized by Classical claisen condensation reaction. With p-NBFA as the first ligand and 1,10-phenanthroline(phen) as the secondary ligand, two new rare earth Eu(III), Tb(III) ternary complexes were prepared. Elemental analysis demonstrated that the compositions of the complexes were Eu(p-NBFA)3 phen and Tb(p-NBFA)3 phen. IR spectra indicated that rare earth ions were coordinated with oxygen atoms of the first ligand and two nitrogen atoms of the secondary ligand. UV spectra showed that the main absorption was from the first ligand in the complexes, the secondary ligand was acted as the synergistic coordination. Fluorescence spectra demonstrated that the emission intensity of Eu(p-NBFA)3 phen was obviously stronger than that of Tb(p-NBFA)3 phen. Further investigation showed that the emission intensity was influenced by the matching situation of energy level between the triplet state of ligand and the emission energy of rare earth ion. In Tb(p-NBFA)3phen, due to that the triplet state energy level of p NBFA was too near to the energy level of 5D4, then the energy transfered back to the ligand, most of the excitation energy was consumed, so the terbium complex showed lower luminescence intensity and competitive luminescence of p-NBFA also appeared. In Eu(p-NB-FA)3phen, the energy level difference was well matched and the emission of europium complex was characteristic and high. PMID- 22242497 TI - [The change of reflection spectra and fluorescence spectra of port wine stains during PDT]. AB - To analyze the change of optical property of PWS skin during photodynamic therapy, the reflection spectra and fluorescence spectra of PWS skin during PDT treatment were measured using mini-optical fiber spectrograph. The change of reflection spectra and fluorescence spectra were analyzed according to the histological structure of PWS skin and the absorption spectra of the main chromophores in skin (melanin and hemoglobin). The result showed that the spectra changed significantly at the wavelength at which melanin and hemoglobin have high absorption, or at which obvious difference existed in the absorption between HbO2 and Hb. The monitoring of reflection spectra and fluorescence spectra during PDT can provide information about the dynamic change of the optical property of PWS tissue. PMID- 22242499 TI - [Crystal structure and photoluminescence studies of ZnO nanocrystals doped with Eu3+ ions]. AB - The ZnO: Eu3+ crystal was prepared via coprecipitation with the starting materials Zn(OOCCH3)2 x 2H2O, Eu2O3 and NaOH. The X-ray diffraction patterns show that the samples are hexagonal wurtzite structure, No diffraction peaks from europium oxides are detectable. Comparing the ZnO and ZnO : Eu3+ Raman spectra, the new local vibrational modes were observed in ZnO : Eu3+. These phenomena show that Eu3+ ions have entered the lattice by doping. The SEM analysis exhibits that ZnO nanoparticles prepared by coprecipitation become smaller with Eu3+ doping. The excitation and emission spectra of ZnO : Eu3+ sample present a efficient energy transfer process between ZnO and Eu3+ ions. PMID- 22242500 TI - [Determination of the ofloxacin in the biologic samples by fluorescence microscopic imaging technique]. AB - The method of CTMAB-Al(3+)-OFLX ternary complex fluorescence microscopic imaging technique was established for the determination of ofloxacin based on the capillary effect of solvent on solid supports, and the concentration in the serum after the chicken was burdened with ofloxacin tablet, the concentration in the human urines and the percentage composition in the honeies, ofloxacin tablets and eye-drops were measured with satisfaction, respectively. In the presence of pH 9. 50 NH3-NH4Cl buffer solution and PVA-124, CTMAB-Al(3+)-OFLX ternary complex can form a self-ordered ring on the hydrophobic supports with the diameter of 1.63 mm and its ring belt width of 50 microm. When a 0.20 microL droplet was spotted, the fluorescence intensity of the ring had a favorable linear relation (r = 0.999 2) with the drug concentration in the range of 3.30 x 10(-13) - 1.65 x 10(-12) mol x ring(-1) (0.60-2.98 mg x L(-1)) and the limit of detection can reach 4.10 x 10( 15) mol x ring(-1) (7.41 microg x L(-1)) with three times of signal to noise ratio. This method has been applied to the average concentration of ofloxacin in the chicken serum with the recovery of 96.4%-101.2% after two hours of being burdened with ofloxacin tablet. Then the technique was applied to the determination of ofloxacin in the three healthy volunteer's urines after oral administration with recovery of 98.2% - 106.%. It was found that the concentrations of ofloxacin in urines were the highest after three hours of taking medicine; the result was similar to reports in the literature. The residues of ofloxacin in three different honey samples were satisfactorily determined with the recoveries of 98.2% - 106.1%, and RSD was less than 2.3%. The contents of active constituent in tablet samples and eye-drops sample were determined with recoveries of 93.5%-101.5% and 95.8%-104.2%, and RSD was 3.5% and 3.6%, respectively, which were similar to marked values. PMID- 22242501 TI - [Cucumber downy mildew prediction model based on analysis of chlorophyll fluorescence spectrum]. AB - In order to achieve quick and nondestructive prediction of cucumber disease, a prediction model of greenhouse cucumber downy mildew has been established and it is based on analysis technology of laser-induced chlorophyll fluorescence spectrum. By assaying the spectrum curve of healthy leaves, leaves inoculated with bacteria for three days and six days and after feature information extraction of those three groups of spectrum data using first-order derivative spectrum preprocessing with principal components and data reduction, principal components score scatter diagram has been built, and according to accumulation contribution rate, ten principal components have been selected to replace derivative spectrum curve, and then classification and prediction has been done by support vector machine. According to the training of 105 samples from the three groups, classification and prediction of 44 samples and comparing the classification capacities of four kernel function support vector machines, the consequence is that RBF has high quality in classification and identification and the accuracy rate in classification and prediction of cucumber downy mildew reaches 97.73%. PMID- 22242502 TI - [Multispectral remote sensing image denoising based on non-local means]. AB - The non-local mean denoising (NLM) exploits the fact that similar neighborhoods can occur anywhere in the image and can contribute to denoising. However, these current NLM methods do not aim at multichannel remote sensing image. Smoothing every band image separately will seriously damage the spectral information of the multispectral image. Then the authors promote the NLM from two aspects. Firstly, for multispectral image denoising, a weight value should be related to all channels but not only one channel. So for the kth band image, the authors use sum of smoothing kernel in all bands instead of one band. Secondly, for the patch whose spectral feature is similar to the spectral feature of the central patch, its weight should be larger. Bringing the two changes into the traditional non local mean, a new multispectral non-local mean denoising method is proposed. In the experiments, different satellite images containing both urban and rural parts are used. For better evaluating the performance of the different method, ERGAS and SAM as quality index are used. And some other methods are compared with the proposed method. The proposed method shows better performance not only in ERGAS but also in SAM. Especially the spectral feature is better reserved in proposed NLM denoising. PMID- 22242503 TI - [The Mie scattering lidar return signal denoising research based on EMD-DISPO]. AB - Lidar echo signal is a typical non-steady-state, non-stationary signal, and difficult to be dealt with by the traditional filtering methods. As a new signal processing theory proposed in recent years, empirical mode decomposition method can adaptively divide the lidar echo signal into different intrinsic mode function (IMF) components according to different time scale, and noise mainly concentrates in the high-frequency component. However, when filtered with simply removing high frequency component, the useful signal will be possibly reduced. In the present paper, a new method which combines empirical mode decomposition (EMD) with Savitzky-Golay filter is proposed. With experiments, it is indicated that our approach not only removes the noise component effectively but also maintains the useful signal, then will improve the accuracy in the next phase of data processing. PMID- 22242504 TI - [Narrow band multi-region level set method for remote sensing image]. AB - Massive redundant contours happen when the classical Chan-Vese (C-V) model is used to segment remote sensing images, which have interlaced edges. What's more, this model can't segment homogeneous objects with multiple regions. In order to overcome this limitation of C-V model, narrow band multiple level set method is proposed. The use of N-1 curves is required for the segmentation of N regions and each curve represents one region. First, the level set model to establish an independent multi-region region can eliminate the redundant contours and avoids the problems of vacuum and overlap. Then, narrow band approach to level set method can reduce the computational cost. Experimental results of remote image verify that our model is efficient and accurate. PMID- 22242505 TI - [Studies on the remote measurement of the emission of formaldehyde by mobile differential optical absorption spectroscopy]. AB - Formaldehyde (HCHO) is the most abundant carbonyl compounds that play an important role in atmospheric chemistry and photochemical reactions. Formaldehyde is an important indicator of atmospheric reactivity and urban atmospheric aerosol precursors. In the present paper, the emission of formaldehyde from chemical area was measured using the mobile differential optical absorption spectroscopy (DOAS). This instrument uses the zenith scattered sunlight as the light source with successful sampling in the area loop. Vertical column density was retrieved by this system, combined with the meteorological wind field and car speed information, the emission of formaldehyde in the area was estimated. The authors carried out the measuring experiment in one chemical plant in Beijing using this technology. The result showed that the average value of the flux of formaldehyde in this area was 605 kg x h(-1) during the measuring period. PMID- 22242506 TI - [Hyperspectral Bambusoideae discrimination based on Mann-Whitney non-parametric test and SVM]. AB - In the present study, based on the leaf-level hyperspectral data of MaoZhu, LeiZhu and XiaoShunZhu, We come up with two solutions to discrimination through the theory of non-parametric test and pattern recognition; the first one is that optimal discriminating band between bambusoideae species is extracted by Mann Whitney non-parametric test, the other is that bambusoideae species is discriminated by the support vector machine. The research results showed that (1) the optimal discriminating band between MaoZhu and LeiZhu is around 503-655, 689 732, 757-1 000, 1 038-1 084, 1 238-1 311, 1 404-1 591, 1682-1 800, 1 856-1 904, and 1 923-2 500 nm; the optimal discriminating band between MaoZhu and XiaoShunZhu is around 350-386, 731-1 430, 1 584-1 687, and 1 796-1 873 nm; the optimal discriminating band between LeiZhu and XiaoShunZhu is around 355-356, 498 662, 689-745, and 1 344-2 500 nm; and it can eliminate 30.0%, 57.7%, and 35.8% of the invalid distinction between bands by Mann-Whitney non-parametric test method. (2) In these optimal discriminating bands, we found that the accuracy of bambusoideae discrimination is 98.4%, 93.5%, and 95.1%, the generalization accuracy is 93.3%, 90.0%, and 86.7% by sequential minimal optimization algorithm. It indicates that this method is valid for selecting feature band and discriminating bambusoideae species. PMID- 22242507 TI - [Monte Carlo simulation of the determination of complex mixed solution with hyperspectral technique]. AB - In order to overcome the defects of overlapping spectrum and low signal-to-noise ratio in the analysis of the complex mixed solution with the traditional spectral method, the authors introduce hyperspectral technique to the analysis of complex mixed solution in the present article. The hyperspectral technique can use the information of the analytes carried by multi-mode photons to analyze the solution. Compared with the traditional methods that only use the absorption characteristics for analysis, the hyperspectral technique also use the space information to increase the spectral signal-to-noise ratio and to improve the modeling accuracy and reliability. To verify the feasibility of the analysis of complex mixed solution with hyperspectral technique, the authors take Monte Carlo simulation to simulate the distribution of the diffuse light of the Intralipid Ink model in the range of 650 -1 100 nm; the distribution of the diffuse light of the complex mixed solution is obviously different at different wavelengths. It is proved that the hyperspectral technique can use characteristic changes with the wavelengths of the analyte, greatly improve the signal to noise ratio, and has the potential to significantly enhance the ability of the component analysis of complex mixed solution. PMID- 22242508 TI - [The structure, shape, spectral characteristics and photochemical reaction of nano Eu : CaWO4]. AB - The samples were pretreated by controlling PH in the process of Pechini, and after sintering and grind, the nano Eu-doped tungstate with different granularity was obtained in the result. The structure was characterized by XRD, and the diffuse scattering spectra and the crystal microstructure were characterized by HRTEM and spectrometer. It was found from high efficient decomposition of rhodamine that the nano-materials obtained have good catalytic effect of light. PMID- 22242509 TI - [Spectroscopic characteristics of dissolved organic matter in water from typical area of Taihu Lake]. AB - Fluorescence spectroscopy, UV spectroscopy, and multiple UV parameters were applied to determine and analyze the dissolved organic matter (DOM) in water of Taihu Lake, in order to find out the sources and influencing factors of DOM in water from typical areas of Taihu Lake. The results showed that the components of DOM in water from different lake areas displayed some regional characteristics. The contents of macro-molecules matters with complex structures and humic substances in water from sampling points T1 (locates in the inflow river) and T2 (represents Zhu Shan Bay Lake) were in majority. This indicated that these areas were subjected to multiple sources, including biological sources, land-based sources, and domestic sewage. In the meanwhile, the complexities of DOM from sampling points T3 (Meiliang Bay Lake), T4 (Gonghu Bay Lake), and T5 (center of Taihu Lake) were relatively low. And protein-like materials with simple structures were in majority in water from sampling point T6 (East Taihu Lake), which suggested that this area was less influenced by the external environment. PMID- 22242510 TI - [The structure and spectral research on Mn2 [V12 B16 O52 (OH)6 ] (en) 2 (H3O)6 (H2O)5 (en = ethylenediamine)]. AB - A novel polyoxovanadium borate Mn2[V12B16O52 (OH)6](en)2 (H3O)6 (H2O)5 1(en = ethylenediamine) was hydrothermally synthesized and characterized by IR, two dimensional infrared (2D IR) correlation spectroscopy with magnetic and thermal perturbation, and single crystal X-ray diffraction. In 1, it is interesting that each [V12B16O52 (OH)6]14- units is connected by four [Mn(H2O)2]2+ to generate a 2D layer on the ab plane. Along c axis, these layers are further linked by H-bond to form a 3D framework. The response of the stretching vibrations of B-O, V-O-V and Mn-O-B was detected in the 2D IR correlation spectra with magnetic perturbation. In addition, the response of the stretching vibrations of B-OH, B O, V-O-V and Mn-O-B was detected in the 2D IR correlation spectra with thermal perturbation. PMID- 22242511 TI - [On-line and in-situ spectral analysis of multicomponent gas mixture with same molecular group]. AB - Aimed at the problem that Fourier transform infrared (FTIR) spectral analysis can't be used solely to analyze complex gas mxiture, in which there are many gas compositions, some compositions have same molecular group, and the concentrations of some compositions range greatly, in the present paper, a new spectral analysis method is proposed. For this method, the effects of gas temperature and gas pressure on the analysis result are taken into account, and feature variable extraction, recognition and correction of spectral disorder, robust modeling and multi-layer modeling with neural network (NN) are used to build gas mixture analysis models. At the end of this paper, on-line analysis of five alkane gases is taken as example to test the performance of the analysis method. CH4, C2 H6, Ca3 Ha8, iso-C4 H10 and n-C4 H10 are taken as object gases while iso-C5 H12 and n C5 H12 are looked as disturbing gases. The comparison results that analysis result curves of FTIR overlap that of gas chromatograph indicate that FTIR can be solely used in on-line and in-situ analysis of multicomponent gas mixture with same molecular group if the analysis method presented in this paper is used. PMID- 22242512 TI - [Spectral analysis of modified kaolinite filled with polypropylene]. AB - With wet surface modification of kaolinite, composite of PP/Kaolinite/PP-g-MAH was prepared by melt blending process. The kaolinite and composite were characterized by means of Flourier transform infrared (FTIR) spectroscopy, thermo gravimetric analyzer (TGA), X-ray diffraction (XRD) and scanning electron microscope (SEM), and mechanical, thermal performance test. The results indicated that the modifier reacted well with kaolinite and produced synergistic effect well with PP-g-MAH. The tensile strength increased by 10.6%, notched impact strength was better than unmodified kaolinite composite. XRD showed that the diffraction peaks of the composite didn't change evidently, and kaolinite had heterogeneous nucleation effect and increased the degree of crystallization greatly. The heat distortion temperature of the composite was increased by 18 degrees C. SEM analysis showed that the modified kaolinite particles were homogeneously dispersed in the PP matrix, and the modification effect of kaolin was increased. PMID- 22242513 TI - [Study on the interaction of pyronine G and sodium dodecyl sulfate by spectral method]. AB - In order to investigate the application of dyes in the field of textile dyeing, the interaction between pyronine G (PG) and sodium dodecyl sulfate (SDS) was studied by spectral method. The results showed that the fluorescence quenching of PG appeared when it reacted with the monomer of SDS. A new stronger fluorescence peak was obtained when it reacted with themicelle of SDS. Meanwhile, the influence of Na2SO4 and (NH2)2CO on the interaction between PG and SDS was investigated. The interaction between PG and SDS became stronger in the presence of Na2 SO4 but became weaker in the presence of (NH2)2CO. And the interaction mechanism was also discussed by absorption and fluorescence spectra. PMID- 22242514 TI - [Spectrum simulation based on data derived from red tide]. AB - The present paper utilizes the absorption data of red tide water measured during the growing and dying course to retrieve imaginary part of the index of refraction based on Mie theory, carries out the simulation and analysis of average absorption efficiency factors, average backscattering efficiency factors and scattering phase function. The analysis of the simulation shows that Mie theory can be used to reproduce the absorption property of Chaetoceros socialis with an average error of 11%; the average backscattering efficiency factors depend on the value of absorption whose maximum value corresponds to the wavelength range from 400 to 700 nanometer; the average backscattering efficiency factors showed a maximum value on 17th with a low value during the outbreak of red tide and the minimum on 21th; the total scattering, weakly depending on the absorption, is proportional to the size parameters which represent the relative size of cell diameter with respect to the wavelength, while the angle scattering intensity is inversely proportional to wavelength. PMID- 22242515 TI - [An integrated on-line processing method for spectrometric data based on wavelet transform and Gaussian fitting]. AB - Miniature mobile field spectrometry is pivotal equipment for qualitative and quantitative in-situ analysis of chemical substances. To solve the problem of spectrum signal interfered by complicated noise, overlapped and irregular peak shape recognition, and quick monitoring, an integrated on-line processing method for spectrometric data based on wavelet transform and Gaussian fitting was developed. In this way, toluene and perfluorotributylamine were processed, and the results shows that the integrated method can powerfully and effectively eliminate the noise, retain the original feature, and correct the overlapped and asymmetrical peaks, which can improve the analysis accuracy of instrument, and also achieve data compression. In addition, the method satisfies the requirement of on-site analysis for mobile field spectrometry. For the processing of mass spectra of toluene, at the characteristic peaks of 91 and 92, the SNR increased 1.3 times compared to that of moving average smoothing method, while the error between original peaks and theoretic peaks decreased 3.6 times. In addition, Gaussian fitting described the multipoint mass spectra data by three Gaussian parameters, and achieved data compression. For the processing of mass spectrogram of perfluorotributylamine, the ratio of compression was 197 : 1. PMID- 22242516 TI - The secondary structure of heated whey protein and its hydrolysates antigenicity. AB - Fourier transform infrared spectroscopy (FTIR) and circular dichroism (CD) were used to investigate the conformational changes of heated whey protein (WP) and the corresponding changes in the hydrolysates immunoreactivity were determined by competitive enzyme-linked immunosorbent assay (ELISA). Results showed that the contents of alpha- helix and beta-sheet of WP did not decrease much under mild heating conditions and the antigenicity was relatively high; when the heating intensity increased (70 degrees for 25 min or 75 degrees C for 20 min), the content of alpha- helix and beta-sheet decreased to the minimum, so was the antigenicity; However, when the WP was heated at even higher temperature and for a longer time, the beta-sheet associated with protein aggregation begun to increase and the antigenicity increased correspondingly. It was concluded that the conformations of heated WP and the antigenicity of its hydrolysates are related and the optimum structure for decreasing the hydrolysates antigeniity is the least content of alpha-helix and beta-sheet. Establishing the relationship between the WP secondary structure and WP hydrolysates antigenicity is significant to supply the reference for antigenicity reduction by enzymolysis. PMID- 22242517 TI - [Real-time measurement of detonation transient temperature]. AB - Based on the spectral characteristic of the detonation temperature, the present paper presents a measurement system of transient multi-wavelength pyrometry with the theory of multi-wavelength thermometry. The FPGA was applied as the hardware developing platform and the high-speed linear CCD was utilized. Each module was controlled by FPGA to achieve the process of real-time data acquisition, storage and transmission. Using the multiple regression analysis method, the dynamic spectral waveforms were calculated. The two laser spectral lines, 630 and 532 nm, were used to calibrate the corresponding pixel sequence numbers and the No. 175 and No. 270 were confirmed. In this paper, the halide tungsten light was measured. The results show that the system can sample continuous spectrum signal at several different times; the CCD can stably work with 40 MHz clock and the frame scanning frequency can achieve 73 kHz. PMID- 22242518 TI - [Research on extraction method of water body with DS spectral enhancement based on HJ-1 images]. AB - Natural disaster is one of the major global issues, and it is an important premise for disaster prevention and reduction to monitor it. In the present paper, multi-temporal HJ-1 images pre- and posto-typhoon Morakot were used. First, radiometric calibration and registration were done, then, decorrelation stretch (DS) was applied, and finally, maximum likelihood classification (MLC) was adopted to extract water body and monitor change of water body caused by typhoon Morakot. The results show that after DS spectral enhancement, the correlations among bands decrease and spectral differences increase, and it is helpful to identify surface features. The accuracy assessment demonstrates that the overall accuracies and Kappa coefficients of four phases are higher, above 96.0% and 0.94 respectively, than that of direct MLC without DS spectral enhancement. It is beneficial to scheduling flood discharge and ensuring the safety of reservoir downstream by comparing extracted multi-temporal water bodies. PMID- 22242519 TI - [The new method monitoring agricultural drought based on SWIR-Red spectrum feature space]. AB - Drought was a chronic, natural disaster, and Remote sensing drought monitoring had become a potential research field. In the present, short-wave infrared and red bands which sensitive to moisture variation were selected to monitor farmland drought conditions by analyzing the spectral characteristics of vegetation and soil. The goal of this paper was to provide a new method of drought monitoring- normalized drought monitoring index (NPDI), based on new constructed spectrum feature space by the difference of SWIR and Red and the sum of SWIR and Red. Field surveyed soil moisture verified NPDI model, and the result showed that NDPI and MPDI model could effectively monitor agricultural drought, and that had high correlation with soil moisture. The R2 was 0.583 and 0.438 with soil water of 10 cm. The monitoring effect of NPDI model was better than the MPDL. This model was further improvement to PDI and MPDI, and it could monitor the drought condition of different vegetation coverage and whole growing season. It has high application potential and popularization value. PMID- 22242520 TI - [Feasibility study on measuring composition concentration in turbid media by response variable transform method]. AB - The present paper primarily studied the feasibility of the measurement of composition concentration in turbid media using response variable transform (RVT) method. With intralipid as the subject, the simulation of Monte Carlo in conjunction with the IAD algorithm and the experiment of double-integrating sphere system combined with the IAD algorithm were conducted to verify the effectiveness to extract the scattering information. Furthermore, for the feasibility of the scattering coefficient to predict the concentration of intralipid, the results showed that measuring the component concentration in turbid media by means of RVT method is effective and feasible, and the relative error to predict the concentration with the linear relationship between scattering coefficient and concentration of intralipid is less than 10%. PMID- 22242521 TI - [Preparation and characterization of wood/methylolurea composite with in-situ polymerization]. AB - Wood/methylolurea composite was prepared with the in-situ polymerization. The green timber with high moisture content was impregnated by a pulse-dipping machine and then was dried in a hot-press drying kiln. The cross-linking reaction was taken under the heat treatment between the wood modifier and the wood composition, including cellulose, hemicelluloses, and lignin. The chemical composition was analyzed according to the Chinese standard, including X-ray photoelectron spectroscopy (XPS), nuclear magnetic resonance (NMR) and energy dispersive analysis of X-rays (EDXA). The changes in chemical composition of modified wood and carbon and nitrogen element were disused in the research The results showed that the content of water extraction and benzene alcohol extraction increased 187.43% and 230.87% respectively compared with the natural wood, while the lignin and holocellulose decreased 26.55% and 26.39% respectively. XPS showed that the concentrations of O and C atoms increased 9.4% and N element content increased 137.2%. 13C-NMR analysis showed that chemical reaction of the hydroxyl methyl urea with the hydroxyl in timber structure took place, with the reduction of hydroxyl content and increase in ether bond content. EDXA showed that the processing method can get impregnated modification wood and nitrogen element is evenly distributed in wood cell walls and intercellular space. PMID- 22242522 TI - [Characterization and analysis of direction extraction and precipitation of cerium loading organic phase by oxalic acid solution]. AB - In the condition of sodium hydroxide saponification, the test results using direction extraction and precipitation of cerium from P507 loading organic phase by oxalic acid solution were studied. Infared (IR) spectrum, X-ray diffraction (XRD), transmission electron microscope (TEM) and thermogravimetry (TG-DSC) were used to study and characterize organic cerium precipitates and the final calcined products. The results showed that organic cerium precipitates and final calcined products were spheric organic cerium coordination and spheric cube CeO2 crystal, respectively, showing their morphologies were successive. IR made out that the structures of organic cerium precipitates and final calcined products were different. TG-DSC indicated that the final calcined products weightlessness was 3.5% and chemical composing was CeO2 x 1/3H2O. PMID- 22242523 TI - [Multivariate analysis of heavy metal element concentrations in atmospheric deposition in Harbin City, northeast China]. AB - In order to understand the characteristics of atmospheric heavy metal deposition in Harbin City, 46 deposition samples were collected which were taken using bulk deposition samplers during the period of 2008-2009 (about 365 days). The samples were analyzed for heavy metal concentration by atomic fluorescence spectrometry (AFS) and inductively coupled plasma-atomic spectrometry (ICP-AES). The deposition flux was calculated. Sources analysis was made by the method of principal component analysis (PCA), Pearsons and enrichment factor (EF). The following points can be gained through multivariate analysis. Mn and Co are mostly from natural sources while the others may be brought by coal dust, vehicle emissions and metal smelting. PMID- 22242524 TI - [Study on the mineralogical origin of medicinal galamina based on phase and composition analysis]. AB - Based on the phase and composition analysis of 56 batches of samples, the present paper showed that hydrozincite, just as smithsonite, should be named as the mineralogical origin of medicinal galamina. Galamina was proved to be polymineral aggregation by electron probe micro-analysis, which was constituted by various mineral particulates, such as hydrozincite, smithsonite, zinc oxide, dolomite, etc. It is hydrozincite but not smithsonite that is the current mainstream mineral of commercial galamina. Both hydrozincite and smithsonite should be calcined to turn into zinc oxide when they were used as medicine. As a provider of medical galamina, essentially the zinc oxide, hydrozincite is appropriate. PMID- 22242525 TI - [Comparison of heavy metal elements between natural and plantation forests in a subtropical Montane forest]. AB - Heavy metals as one of major pollutants is harmful to the health of forest ecosystems. In the present paper, the concentrations of thirteen heavy metals (Fe, Al, Ti, Cr, Cu, Mn, V, Zn, Ni, Co, Pb, Se and Cd) were compared between natural and plantation forests in the Mt. Lushan by ICP-AES and atomic absorption spectroscopy. The results suggest that the soil of natural forest had higher concentrations of Fe, Al, Ti, Cu, Mn, V, Zn, Ni, Co, Pb, Se, and Cd than the plantation forest except for Cr. The soil of natural forest had a higher level of heavy metals than that of the plantation forest as a whole. This might be due to that the natural forest has longer age than the plantation forest, and fixed soil heavy metals take a longer period of time than the plantation forest. PMID- 22242526 TI - [Regional effect research of blood lead concentrations and isotopic fingerprints in four cities by ICP-MS]. AB - Blood lead is a reflection of environment lead in vivo, its concentration could be used to assess lead exposure of environment quantitatively, and its isotopic ratio could be used to fingerprint environment source qualitatively. In the present study, concentrations and isotopic ratios of blood lead (BPb) of four cities in China were measured by ICP-MS for the first time. The regional effects of BPb in four Chinese cities were observed in our study. The BPb levels of industrial cities (Taiyuan and Chengdu) are higher than that of non-industrial cities (Suzhou and Beijing), indicating that industrial pollution remains primary lead contamination factor. The BPb isotopic ratios are diverse with the different character of environment the individuals live in. Food-borne lead probably has replaced the air-borne lead to be the major source of BPb in Beijing. Besides, regional effect of BPb in some developed cities is partly weakened by diversity of vast majority of imported resources. PMID- 22242527 TI - [Determination of mineral elements utilization of Paeonia lactiflora Pall by ICP AES]. AB - The contents of K, Ca, Na, Mg, Fe, Cu and so on in the roots of Paeonia lactiflora Pall and in the soil in which they grew were determined by ICP-AES technique to study the mineral elements utilization of P. lactiflora Pall. The results indicate that the elements utilization rate of P. lactiflora Pall is different in different locations, so the contents of mineral elements in the roots of P. lactiflora Pall and even the quality of medicinal materials coming from them in different locations are different. The contents of Ca, Fe, Zn and so on in Chi Shao in Heilongjiang and Inner Mongolia are relatively high. The contents of mineral elements in soil influence not only themselves' utilization but also other mineral elements utilization of P. lactiflora Pall. PMID- 22242528 TI - [Analysis of the content of mineral elements in Scutellaria baicalensis, skullcap tea and its solution]. AB - The content of nine mineral elements in the root, stem and leaf of 1-3 years old Scutellaria baicalensis, skullcap tea, and its solution was determined by the inductively coupled plasma atomic emission spectrometry (ICP-AES). The results show that the main mineral elements in the root, stem and leaf are similar. The main mineral elements include K, Ca, Mg, P, Al and Fe. The content ratio of Zn, Mn, Cu, Fe, Al, P, Mg, Ca and K in the leaf of Scutellaria haicalensis is 1 : 3 : 6 : 15 : 18 19 : 41 : 333 : 423. The contents of Fe, Mn, P, Mg and Ca in the stems and leaves of Scutellaria baicalensis increase with the increase of cultivation period. There were K, Ca, Mg and other mineral elements in the skullcap tea, and Fe, Zn and Mg were easy to be dissolved, the dissolution rates were 61.8%, 55.4% and 61.4% respectively. This study can provide scientific basis for rational utilization of the above ground resources of Scutellaria baicalensis. PMID- 22242529 TI - [Mineral elements content of C. deserticola at different growth stages]. AB - ICP - AES technology was used to determine the mineral elements content of Cistanche deserticola Ma (C. deserticola). The results showed that: (1) At succulent stem stages, the content of K was the highest in 5 macroelements, it can reach to 9.45 mg x g(-1), and the proportion for K : Na : P : Ca : Mg was 12 : 3.4 : 1.6 : 1.4 : 1. Among 5 microelements, the content of Fe was the highest and can reach to 97.31 microg x g(-1), and the proportion for Fe : Cu : Mn: Zn : Cu : B was 25 : 3.7 : 3.5 : 1.2 : 1. (2) At reproductive growth stages, the contents of Ca, Mg, Fe, Zn, Cu, Mn and B at unearthed stage were significantly higher than that at the underearth stage, especially for the content of Fe and Mn, they can respectively reach to 697. 55 and 38.75 microg x g(-1) at capsule formative stage. The contents of Fe and Mn at capsule formative stage were almost 7.2 and 8.3 times than that at succulent stem stage. (3) At reproductive growth stages, the aerial part will exclude Na and accumulate P, K, Ca, Mg, Fe, Mn, Zn, Cu and B. This result of the study will be a scientific basis for evaluating the quality of C. deserticola. PMID- 22242530 TI - [Principal component analysis and cluster analysis of inorganic elements in sea cucumber Apostichopus japonicus]. AB - The present study is to investigate the feasibility of multi-elements analysis in determination of the geographical origin of sea cucumber Apostichopus japonicus, and to make choice of the effective tracers in sea cucumber Apostichopus japonicus geographical origin assessment. The content of the elements such as Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Cd, Hg and Pb in sea cucumber Apostichopus japonicus samples from seven places of geographical origin were determined by means of ICP-MS. The results were used for the development of elements database. Cluster analysis(CA) and principal component analysis (PCA) were applied to differentiate the sea cucumber Apostichopus japonicus geographical origin. Three principal components which accounted for over 89% of the total variance were extracted from the standardized data. The results of Q type cluster analysis showed that the 26 samples could be clustered reasonably into five groups, the classification results were significantly associated with the marine distribution of the sea cucumber Apostichopus japonicus samples. The CA and PCA were the effective methods for elements analysis of sea cucumber Apostichopus japonicus samples. The content of the mineral elements in sea cucumber Apostichopus japonicus samples was good chemical descriptors for differentiating their geographical origins. PMID- 22242531 TI - [Elimination of interference in the determination of selenium in high purity tellurium by HG-AFS]. AB - The samples were decomposed with HNCO3 +HCl, and Fe(3+)-citric acid mix solution was added to eliminate interferences. The elimination and mechanism of tellurium interference with selenium determination by HG-AFS were studied, and the residuary influence of NO3- and NO2- was investigated. The interference of ferric trichloride, hydrochloric acid, citric acid and PBH concentration with the fluorescence intensity of selenium was observed by the orthogonal test design combined with the mono-factor test. The detection limit was 0.15 microg x L(-1). The relative standard deviation of a solution containing 27.01 microg x L(-1) selenium in sample was in the range of 3.1%-4.2% (n = 11), and the recoveries of selenium were 96.1%-102.3%. The results obtained were satisfied, and the method was successfully applied to the determination of selenium in high purity tellurium samples. PMID- 22242532 TI - [Analysis of the adsorption properties of lead ion onto natural sand particles by flame atomic absorption spectrometry]. AB - The present research was aimed at the study of adsorption properties of lead ion on natural sand particle (NSP) by FAAS and at the development of NSP as an adsorbent used in the removal and preconcentration of lead(II) ion in aqueous solution by adsorption. Particle structure and size distribution, surface morphology, specific surface area, functional radical of NSP and adsorption properties of lead ion onto NSP and factors which affect the adsorption capacity were analyzed using FTIR, SEM, NSA and FAAS. The adsorption condition such as acidity of solution, flow rate and time etc were optimized. The 5.0 cm x 5 mm i. d. separation column was prepared by filling with the NSP as adsorbent. The experimental results showed that under the optimal adsorption conditions, such as the procedure was carried out at room temperature, pH of solution was 6, the flow rate was 2. 55 mL x min(-1), the maximum adsorption of Pb(II) onto NSP as adsorbent was 24. 9 mg x g(-1). Adsorption rate was 91.5%. Specific surface area and pore size were 7.60 m2 x g(-1) and 3.91 nm respectively. Using 0.10 mol x L( 1) chloride acid for desorption of Pb(II), the desorption rate reached 99%. At the same time the adsorption mechanism of Pb(II) was studied. PMID- 22242533 TI - [Determination of the content of eight metal elements in enteral nutritional powder (VIVONEX) by microwave digestion-AAS]. AB - Enteral nutritional powder (VIVONEX) is mainly used to provide nourishment for critical patients and those patients who have just undergone surgical operation. Microelements included in it exert significant influence on the patients' physical functioning. In the present paper, Enteral nutritional powder was digested with HNO3 by microwave digestion. After that, the content of eight metal elements in it, K, Na, Ca, Mg, Fe, Mn, Cu and Zn, was determined by FAAS. With the good linear correlations of standard curves (r = 0.999 2-0.999 8), the recovery (n = 6) ranging from 97% to 103%, and the RSD (n = 6) from 0.46% to 1.12%, the method can be applied to simultaneous determination of several metal elements in enteral nutritional powder, and offers advantages of low detection limit, high sensitivity, speediness and accuracy. The determination of metal elements in samples by this method gives satisfactory results. Hence, the method helps to guarantee quality control of this kind of medicine, and supplies statistical evidence for the safety of clinical drug use. PMID- 22242534 TI - [Nondestructive analysis of chemical composition, structure and mineral constitution of jadeite jade]. AB - The techniques of portable energy-dispersive X-ray fluorescence analysis (PXRF), proton induced X-ray emission spectroscopy (LRS) were employed to analyze the chemical composition, structure and mineral constitution of 12 samples. The results indicated that the chemical compositions determined by PXRF and PIXE are well comparable and most samples are constituted by almost pure jadeite with low concentration of secondary elements. One sample contains a little omphacite and one sample is composed only by omphacite. Raman characteristic peaks of jadeite occurred at 201, 372, 698, 985 and 1 037 cm(-1), while those of omphacite located at 680 and 1 017 cm(-1). By using laser Raman spectroscopy for testing the fissures of the samples, wax in 3 samples and epoxy resin in one sample were found. Raman characteristic peaks of wax located at 2 846 and 2 880 cm(-1) and those of epoxy resin occurred at 2 924 and 3 065 c(-1). The application of nondestructive techniques in jadeite jade broadens the range of samples for future study and provides technical support for jadeite jade's further study, identification and classification. PMID- 22242535 TI - [Chemical composition analysis of early neolithic pottery unearthed from Xiaohuangshang site, Zhejiang Province and Jiahu site, Henan Province by energy disperse X-ray fluorescence]. AB - The major elements in the early neolithic potteries unearthed from Xiaohuangshan site, Zhejiang Province and Jiahu site, Henan Province were determined by energy disperse X-ray fluorescence (EDXRF). The results show that the chemical compositions of the potteries from these two sites possess obvious regional features respectively. Compared with the specimen from Jiahu site, the potteries from Xiaohuangshan site have the common feature of ancient Chinese southern ceramics with high silicon and low aluminum contents. Simultaneously, the chemical composition of Xiaohuangshan pottery samples nearly unchanged from its early stage to the last stage. This phenomenon indicates that the source of the ceramic raw materials of Xiaohuangshan site was stable, and the continuous improvement of its pottery quality was mainly due to the progress in sintering techniques. However, the chemical composition of Jiahu potteries changed a lot in its three different periods. This change occurred because a large number of admixtures were added to the pottery bodies to improve their operating performances. These results also show that the improvements of pottery making techniques in different Chinese areas may have their own evolution directions respectively for the different geographical environments. PMID- 22242536 TI - [Preliminary study of zinc ion sensor with the function of imaging]. AB - A zinc ion fluorescence sensor with imaging was fabricated by using 1-(2 Pyridylazo)-2-naphthol and fluorescent reagent of rhodamine B together as the indication which was immobilized on an tip of gradient index lens by base catalyzed sol-gel method. Combined with improved metallographic microscope and laser, the measurement of zinc ion concentration and the view of sample morphology could be realized simultaneously by this system. The sensor has the linear range of zinc ion concentration from 0.1 to 1 mmol x L(-1). Moreover, it has the capabilities of imaging with the whole system's resolution of 18. 73 lp x mm(-1). This sensor with the function of imaging has the potential applications in biosensing. PMID- 22242537 TI - [Simulation and analysis of interference imaging spectrometer influenced by satellite vibration]. AB - During the spectral imaging course of interference imaging spectrometers, satellite platform's instability will bring serious impact on the imaging quality. Based on studying the degradation mechanism, a differential dynamic imaging simulation method is proposed here to simulate the process of spectral imaging degradation. And in this method, the mean ratio of doping is put forward, which combines the satellite motion parameters with the impacts on spectral imaging. And the quantitative relationship between them is deduced in detail With environmental resources satellite as an example, the degraded result is simulated, showing that the vibration affects the spectral imaging not only in the spatial resolution but also in spectrum, with the region of rich species having more serious influence. And through the simulation and analysis, the satellite attitudes' stability is requested accurately, below which the impacts of satellite vibration on spectral imaging should be significant and it's necessary to adopt corresponding compensation measures. PMID- 22242538 TI - [Near infrared spectroscopy system structure with MOEMS scanning mirror array]. AB - A method which uses MOEMS mirror array optical structure to reduce the high cost of infrared spectrometer is given in the present paper. This method resolved the problem that MOEMS mirror array can not be used in simple infrared spectrometer because the problem of imaging irregularity in infrared spectroscopy and a new structure for spectral imaging was designed. According to the requirements of imaging spot, this method used optical design software ZEMAX and standard specific aberrations of the optimization algorithm, designed and optimized the optical structure. It works from 900 to 1 400 nm. The results of design analysis showed that with the light source slit width of 50 microm, the spectrophotometric system is superior to the theoretical resolution of 6 nm, and the size of the available spot is 0.042 mm x 0.08 mm. Verification examples show that the design meets the requirements of the imaging regularity, and can be used for MOEMS mirror reflectance scan. And it was also verified that the use of a new MOEMS mirror array spectrometer model is feasible. Finally, analyze the relationship between the location of the detector and the maximum deflection angle of micro mirror was analyzed. PMID- 22242539 TI - [Spatial domain display for interference image dataset]. AB - The requirements of imaging interferometer visualization is imminent for the user of image interpretation and information extraction. However, the conventional researches on visualization only focus on the spectral image dataset in spectral domain. Hence, the quick show of interference spectral image dataset display is one of the nodes in interference image processing. The conventional visualization of interference dataset chooses classical spectral image dataset display method after Fourier transformation. In the present paper, the problem of quick view of interferometer imager in image domain is addressed and the algorithm is proposed which simplifies the matter. The Fourier transformation is an obstacle since its computation time is very large and the complexion would be even deteriorated with the size of dataset increasing. The algorithm proposed, named interference weighted envelopes, makes the dataset divorced from transformation. The authors choose three interference weighted envelopes respectively based on the Fourier transformation, features of interference data and human visual system. After comparing the proposed with the conventional methods, the results show the huge difference in display time. PMID- 22242540 TI - [Research on improving spectrum resolution of optimized Wollaston prism array]. AB - In order to not affect the image quality of interference fringes on the basis of the structure by increasing the structure angle of Wollaston prism to improve spectrum resolution, the authors optimized the structure of Wollaston prism. Calculating the function of the splitting angle and the structure angle, analysis indicated that taking the isosceles triangle prism with the same nature of the second wedge-shaped prism after the Wollaston prism, which makes the o and e light parallel to the optical axis, and alpha=0 degrees, the imaging interference fringes are no longer affected by changes in the splitting angle. Several optimized Wollaston prisms were made as an array to improve the spectral resolution. Experiments used traditional and optimized Wollaston prism array to detect the spectrum of the 980 nm laser. Experimental data showed that using optimized Wollaston prism array gets a clearer contrast of interference fringes, and the spectral data with Fourier transform are more accurate with DSP. PMID- 22242541 TI - Sensitive detection of intracellular sumoylation via SNAP tag-mediated translation and RNA polymerase-based amplification. AB - The covalent attachment of small ubiquitin-like modifier (SUMO) to target proteins, defined as sumoylation, is an important post-translational modification that regulates diverse cellular processes and many human diseases. However, functional analysis of sumo modification is usually hampered by the lack of sensitive methods for measuring extremely low abundance of specific sumoylated target in the cells. Here, we develop an ultrasensitive method for intracellular sumoylation assay based on SNAP tag (a mutant of O6-alkylguanine-DNA alkyltransferase)-mediated translation and RNA polymerase-based amplification. Intracellular sumo modification is first converted to the double-stranded DNA (dsDNA) containing the specific T7 promoter sequence via the covalent conjugation of SNAP tag with its substrate benzyl guanidine derivate; then, the dsDNA is extensively transcribed by T7 RNA polymerase to produce large amounts of RNAs, which are easily monitored using the RNA intercalating dye RiboGreen and a standard fluorometer. This method exhibits excellent specificity and high sensitivity and can detect as little as 5 pg of sumoylated p53 proteins, which has improved by as much as 1000-fold than that in the conventional Western blotting assay. Moreover, this method can measure intracellular sumoylation under different physiological conditions. Due to the common translation and amplification module, this method can be further extended to detect a variety of sumoylated proteins and other ubiquitin-like modifications in the cells and might provide a powerful tool for comprehensive analysis of the functions of sumoylation and other ubiquitin-like modifications in the fundamental biological processes and many human diseases. PMID- 22242542 TI - Fabrication of microfluidic devices containing patterned microwell arrays. AB - A rapid fabrication and prototyping technique to incorporate microwell arrays with sub-10 MUm features within a single layer of microfluidic circuitry is presented. Typically, the construction of devices that incorporate very small architecture within larger components has required the assembly of multiple elements to form a working device. Rapid, facile production of a working device using only a single layer of molded polydimethylsiloxane (PDMS) and a glass support substrate is achieved with the reported fabrication technique. A combination of conventional wet-chemical etching for larger (>=20 MUm) microchannel features and focused ion beam (FIB) milling for smaller (<=10 MUm) microwell features was used to fabricate a monolithic glass master mold. PDMS/glass hybrid chips were then produced using simple molding and oxygen plasma bonding methods. Microwell structures were loaded with 3 MUm antibody functionalized dye-encoded polystyrene spheres, and a sandwich immunoassay for common cytokines was performed to demonstrate proof-of-principle. Potential applications for this device include highly parallel multiplexed sandwich immunoassays, DNA/RNA hybridization analyses, and enzyme linked immunosorbent assay (ELISA). The fabrication technique described can be used for rapid prototyping of devices wherever submicrometer- to micrometer-sized features are incorporated into a microfluidic device. PMID- 22242543 TI - Preparation of boron-doped porous titania networks containing gold nanoparticles with enhanced visible-light photocatalytic activity. AB - The ability to decrease the electron/hole recombination rate, and decrease the band gap of titania to allow photoactivity on irradiation with visible light is attracting more and more attention. Here, boron doping of the titania, the deposition of gold nanoparticles, along with a meso-macroporous structure were obtained using a facile agarose gel templating process combined with sol-gel chemistry. The Au/B/TiO(2) nanocomposites were characterized using SEM, TEM, XRD, N(2) gas sorption, diffuse UV-vis, photoluminescence, and SIMS. The photocatalytic activity was assessed by degradation of an organic probe molecule (methylene blue) under visible light (lambda > 420 nm). The resulting materials achieved photocatalytic activities up to 50% greater than the commercial Degussa P25 under visible light. The enhancement in photocatalytic activity was primarily attributed to the decrease in band gap as a result of the boron doping and its influence on the anatase to rutile phase formation: The doped materials were highly crystalline and an optimum anatase to rutile ratio (3:1) was obtained with 0.25 wt % boron in the sample calcined at 650 degrees C. In addition, the presence of the gold nanoparticles decreased recombination between the photoexcited electrons and holes, which further improved the photocatalytic activity. PMID- 22242544 TI - Conformational characterization of synapse-associated protein 97 by nuclear magnetic resonance and small-angle X-ray scattering shows compact and elongated forms. AB - Synapse-associated protein 97 (SAP97) is a membrane-associated guanylate kinase protein that interacts with other proteins such as ion channels, subunits of glutamate receptors, and other cytoskeletal proteins and molecular scaffolds. The molecular diversity of SAP97 results from alternative splicing at the N-terminus, and in the U1 and U5 regions. There are two main N-terminal isoforms: the beta isoform has an L27 domain, whereas in the alpha-isoform, this is replaced by a palmitoylation motif. We have used multiangle light scattering, nuclear magnetic resonance, and small-angle X-ray scattering studies to characterize the conformation of a truncated form of the beta-isoform, hence mimicking the alpha isoform. This paper provides a comprehensive view of the small-angle X-ray scattering data, and the resulting data show that the scattering data are consistent with the presence of an ensemble of forms in dynamic equilibrium, with two prominent populations of compact and extended forms, with R(g) values of 38 +/- 7 A (52%) and 70 +/- 10 A (37%), respectively. The data show that without the L27 domain, the conformation of SAP97 is biased toward the compact form. We propose a hypothesis in which the overall conformation of SAP97 is determined by the nature of the N-terminus, which may, in turn, influence the specific role of a particular splice variant. PMID- 22242546 TI - Freshwater availability and water fetching distance affect child health in sub Saharan Africa. AB - Currently, more than two-thirds of the population in Africa must leave their home to fetch water for drinking and domestic use. The time burden of water fetching has been suggested to influence the volume of water collected by households as well as time spent on income generating activities and child care. However, little is known about the potential health benefits of reducing water fetching distances. Data from almost 200, 000 Demographic and Health Surveys carried out in 26 countries were used to assess the relationship between household walk time to water source and child health outcomes. To estimate the causal effect of decreased water fetching time on health, geographic variation in freshwater availability was employed as an instrumental variable for one-way walk time to water source in a two-stage regression model. Time spent walking to a household's main water source was found to be a significant determinant of under-five child health. A 15-min decrease in one-way walk time to water source is associated with a 41% average relative reduction in diarrhea prevalence, improved anthropometric indicators of child nutritional status, and a 11% relative reduction in under five child mortality. These results suggest that reducing the time cost of fetching water should be a priority for water infrastructure investments in Africa. PMID- 22242548 TI - Probing behavior of apterous and alate morphs of two potato-colonizing aphids. AB - Secondary host plant colonization by aphids involves alate and apterous morphs to spread in the population at a large scale by flying or, at a finer one, by walking. Macrosiphum euphorbiae Thomas (Hemiptera: Aphididae) and Myzus persicae Sulzer (Hemiptera: Aphididae) are two polyphagous aphids that cause serious losses on many crops, particularly on potato, Solanum tuberosum L. (Solanales: Solanaceae). When settlement of virginoparous alate aphids occurs, apterous individuals are produced and spread within the potato field. As these two potato colonizers originate from different areas and show different body length, this study compared probing behaviors of virginoparous alate and apterous M. persicae and M. euphorbiae on one of their secondary host plants, Solanum tuberosum. Non choice bioassays and electrical penetration graph (EPG) recordings were performed. Most M. euphorbiae of the two morphs rapidly accepted potato plants and exhibited long duration of probing, phloem sap salivation, and ingestion phases. In contrast, at the end of the experiment, most alates of M. persicae left the potato leaflet after brief gustative probes. Moreover, EPG experiments showed that the main difference between both morphs of the two species concerned the xylem ingestion parameter. Differences between species were also reported, such as an increased total duration of probing in both morphs and enhanced phloem ingestion duration in apterous M. euphorbiae. All the differences highlighted in this study are discussed according to the variations observed in aphid body size and to their historical association with Solanum species. PMID- 22242549 TI - Analytical measurement of PEGylated molecules. AB - Attachment of poly(ethylene glycol) (PEG) to proteins, peptides, liposomes, drugs, and nanoparticles can improve pharmaceutical pharmacokinetic properties and enhance in vivo biological efficacy. Since the first PEGylated product was approved by the Food and Drug Administration in 1990, increasing numbers of PEGylated compounds have entered clinical use. Successful clinical development of PEGylated pharmaceuticals requires accurate methods for the qualitative and quantitative analysis of intact PEG conjugates in biological fluids. In this article, we review assay methods that can be utilized for the detection and measurement of PEGylated pharmaceuticals in complex biological samples for determination of biodistribution and pharmacokinetic properties. In particular, we describe relevant colorimetric, chromatographic, radiolabeled, biological, and enzyme-linked immunosorbent assays for the pharmacokinetic study of PEGylated molecules. PMID- 22242550 TI - Protective effects of Ginkgo biloba extract on ligature-induced periodontitis in rats. AB - OBJECTIVE: The aim of this study was to test the hypothesis that the systemic administration of extract of Ginkgo biloba (EGb) would prevent excessive tissue destruction in ligature-induced periodontitis in a rat model. MATERIALS AND METHODS: Thirty-two male Wistar albino rats were used in the current study. The rats were randomly divided into four groups of eight rats each: (1) non-ligated treatment (NL) group, (2) ligature-only (LO) group, (3) ligature plus GB28 (28 mg/kg, daily for 11 days) group and (4) ligature plus GB56 (56 mg/kg, daily for 11 days) group. RESULTS: Measurement of alveolar bone loss in the mandibular molar tooth revealed significantly lower bone loss values in the LO group compared to groups NL, GB28 and GB56 (p < 0.05). CONCLUSION: The present results are the first data which suggests that host response in periodontitis can be modified by EGb administration. EGb minimized progression of periodontal disease. PMID- 22242553 TI - Automated method of content analysis: a device for psychotherapy process research. AB - The work presents a computer-aided method of content analysis applicable to verbatim transcripts of psychotherapy: the Automated Co-occurrence Analysis for Semantic Mapping (ACASM). ACASM is able to perform a context-sensitive strategy of analysis aimed at mapping the meanings of the text through a trans-theoretical procedure. The paper is devoted to the presentation of the method and testing its validity. To the latter end we have compared ACASM and independent blind human coders on two tasks of content analysis: (a) estimating the semantic similarity between two utterances; (b) the semantic classification of a set of utterances. Results highlight that: (a) ACASM's estimates of semantic similarity are consistent with the corresponding estimates provided by coders; (b) coders' agreement and coder-ACASM agreement on the task of semantic classification have the same magnitude. Results lead to the conclusion that the content analysis produced by ACASM is indistinguishable from that performed by human coders. PMID- 22242551 TI - Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists. AB - The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4 [(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6' dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance. PMID- 22242554 TI - Simultaneous surgery for primary colorectal cancer and metastatic lesions? AB - Approximately 20-25% of patients with colorectal cancer present with liver metastases at the time of diagnosis. Traditionally, resection of the primary tumor has been advocated in order to prevent complications of the primary tumor colorectal cancer in patients with synchronous liver metastases. The published data concerning long-term prognosis in this group of patients are discordant. Although some of the reports show survival benefits from resection of the primary tumor, these studies are retrospective with small number of patients and using single drug chemotherapy. For patients with resectable liver metastases, new studies indicate that progression-free survival is best in patients receiving perioperative chemotherapy. In patients with synchronous nonresectable liver metastases and colorectal cancer, there is no published prospective randomized study comparing initial surgery of the primary tumor with neoadjuvant chemotherapy. However, recent publications show that in patients receiving chemotherapy based on oxaliplatin or irinotecan combined with targeted treatments, the complications associated with the primary tumor are less than 10%. The conclusion should be that today prophylactic surgery of asymptomatic primary colorectal cancer in patients with liver metastases cannot be recommended. PMID- 22242555 TI - Metabolic discrimination of mango juice from various cultivars by band-selective NMR spectroscopy. AB - NMR-based metabolic analysis of foods has been widely applied in food science. In this study, we performed discrimination of five different mango cultivars, Awin, Carabao, Keitt, Kent, and Nam Dok Mai, using metabolic analysis with band selective excitation NMR spectra. A combination of unsupervised principal component analysis (PCA) with low-field region (1)H NMR spectra obtained by band selective excitation provided a good discriminant model of the five mango cultivars. Using F(2)-selective 2D NMR spectra, we also identified various minor components in the mango juice. Signal assignment of the minor components facilitated the interpretation of the loading plot, and it was found that arginine, histidine, phenylalanine, glutamine, shikimic acid, and trigonelline were important for classification of the five mango cultivars. PMID- 22242557 TI - Danusertib, an aurora kinase inhibitor. AB - INTRODUCTION: Drugs that interfere with the normal progression of mitosis belong to the most successful cytotoxic agents currently used for anticancer treatment. Aurora kinases are serine/threonine kinases that function as key regulators of mitosis and are frequently overexpressed in human cancers. The use of several small molecule aurora kinase inhibitors as potential anticancer therapeutic is being investigated. Danusertib (formerly PHA-739358) is a small ATP competitive molecule that inhibits aurora A, B and C kinases. Interestingly, danusertib also inhibits several receptor tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA. These tyrosine kinases are involved in the pathogenesis of a variety of malignancies and the observed multi-target inhibition may increase the antitumor activity resulting in extending the indication. Danusertib was one of the first aurora kinase inhibitors to enter the clinic and has been studied in Phase I and II trials. AREAS COVERED: This review provides an updated summary of preclinical and clinical experience with danusertib up to July 2011. EXPERT OPINION: Future studies with danusertib should focus on the possibility of combining this agent with other targeted anticancer agents, chemotherapy or radiotherapy. As a single agent, danusertib may show more promise in the treatment of leukemias than in solid tumors. PMID- 22242558 TI - Differences in treatment outcome among marijuana-dependent young adults with and without antisocial personality disorder. AB - BACKGROUND: Few studies have addressed comorbid antisocial personality disorder (ASPD) and marijuana dependence in young adults, and results from previous studies are inconsistent. OBJECTIVES: This study evaluated differences in pretreatment characteristics and treatment outcomes between marijuana-dependent young adults with and without ASPD. METHODS: Data for this study were derived from a randomized trial, in which marijuana-dependent young adults (n = 136) between 18 and 25 years of age were randomized to four behavioral conditions: (1) MET/CBT with CM, (2) MET/CBT without CM, (3) DC with CM, and (4) DC without CM. RESULTS: Forty-four percent of the participants met DSM-IV-TR criteria for ASPD. ASPD clients had significantly more lifetime alcohol dependence disorders, marijuana use in the 28 days pretreatment, arrests, and assault and weapon charges compared to those without ASPD. ASPD clients did not differ in retention or substance use outcomes at 8 weeks posttreatment or the 6-month follow-up. In general, both groups had more attendance in the voucher condition, but there were no significant ASPD by treatment interactions. CONCLUSIONS: These data suggest that marijuana-dependent young adults with comorbid ASPD do not necessarily have poorer retention or substance use outcomes compared with marijuana-dependent young adults who do not have ASPD when treated in a well-defined behavioral therapy protocol. SCIENTIFIC SIGNIFICANCE: Previous research has shown increased risks for clients with comorbid ASPD and marijuana dependence; however, our findings suggest that specialized programs for clients with ASPD may not be necessary if they are provided with empirically supported, structured treatments. PMID- 22242559 TI - Antenatal ultrasound assessment of placental/myometrial involvement in morbidly adherent placenta. AB - OBJECTIVES: To examine the usefulness of sonographic criteria in the assessment of the lateral extent and depth of myometrial involvement in morbidly adherent placenta. METHODS: From hospital records and a perinatal database, women with morbidly adherent placenta confirmed at delivery and antenatal ultrasound assessment in 2004-2007 were identified. The sonographic appearance at the time of antenatal assessment was compared with the clinical and histological findings at delivery. Following statistical analysis, useful sonographic features in the assessment of myometrial invasion were identified. RESULTS: Nine cases, including one case of placenta percreta, eight cases of accreta or increta of which one minor partial, were reviewed. The criteria useful for the assessment of the lateral placental/myometrial involvement were obliteration of retroplacental clear space, increased subplacental vascularity, placental-tissue interface disruption and vessels crossing the interface disruption site with the last 2 signs applicable for helpful for assessment of the parametrium; and for the assessment of the depth, bladder serosa-uterine wall interface hypervascularity, vessels extending from placenta to bladder, placental-tissue interface disruption and vessels crossing placental-tissue interface disruption. The myometrial vascular pattern was also helpful in assessing the extensiveness of myometrial involvement. There was bulging of the lower uterine wall in the case of placenta percreta. CONCLUSIONS: Assessment of the placental/myometrial involvement of morbidly adherent placenta is possible on antenatal ultrasound examination. Combinations of different criteria may be required in assessing the lateral extent and the depth of placental/myometrial involvement. PMID- 22242561 TI - Pharmacokinetic predictions for patients with renal impairment: focus on peptides and protein drugs. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Renal impairment may affect the pharmacokinetics of peptide and protein drugs. * Molecular size is a predictor. Small molecules are eliminated by the kidneys, whereas large molecules (>67 kDa) are not. * Urinary recovery of peptide and protein drugs in healthy volunteers is not predictive for pharmacokinetic changes in patients with renal impairment. WHAT THIS STUDY ADDS: * An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations as observed in patients with severe renal impairment or end-stage renal disease is described. * Potentially relevant pharmacokinetic changes were found for drugs with a molecular weight below 50 kDa. * Analysis of observed pharmacokinetics in patients with severe renal impairment may be a useful approach, especially when urinary recovery in healthy volunteers is not predictive. AIM: Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived. METHODS: Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid E(max) model was applied and fitted to the data and the prediction error was analyzed. RESULTS: Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life). CONCLUSION: An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients. PMID- 22242563 TI - Fractional systolic and diastolic pressures act as predictors of coronary artery disease. AB - AIMS: This study was designed to determine if fractional systolic/diastolic pressures act as predictors of the extent of coronary artery disease. PATIENTS AND METHODS: A total of 545 consecutive patients (305 men, 240 women, with mean age 54.2 years) were involved in the study. The patients were diagnosed with coronary and non-coronary artery disease confirmed by angiography. RESULTS: 353 patients were confirmed to have coronary artery disease, with 134 cases involving one vessel, 101 two vessels and 118 three vessels. There were significant differences between brachial and ascending aortic systolic blood pressures, fractional systolic blood pressures and fractional diastolic blood pressures in the patients with coronary artery disease compared with patients with non coronary artery disease. Blood pressure measured in the brachial artery was higher than the pressure measured in the ascending artery. Ascending aortic fractional systolic/diastolic pressures were associated with coronary Gensini score, and were significantly related to the number of diseased vessels. CONCLUSIONS: Fractional systolic and diastolic pressures in the ascending aorta were strong predictive factors for the extent of coronary artery disease. Central pressures measured invasively in the ascending aorta were more predictive than peripheral pressures for the evaluation of coronary artery disease. PMID- 22242562 TI - The role of DNA damage and caspase activation in cytotoxicity and genotoxicity of macrophages induced by bisphenol-A-glycidyldimethacrylate. AB - AIM: To evaluate the potential toxicological implications of BisGMA on murine macrophage cell line RAW264.7. METHODOLOGY: Lactate dehydrogenase release, flow cytometry, Western blot and fluorometric assays were used to detect cell viability, mode of cell death and caspase activities, respectively. In addition, alkaline single-cell gel electrophoresis and cytokinesis-block micronucleus assays were applied to detect genotoxicity. Statistical analyses were performed using anova followed by the Bonferroni's t-test for multi-group comparisons test. RESULTS: BisGMA demonstrated a cytotoxic effect on RAW264.7 cells in a dose dependent and a time-dependent manner (P < 0.05). BisGMA was found to induce two modes of cell death. The mode of cell death changed from apoptosis to necrosis as the concentrations of BisGMA elevated. Caspase-3, caspase-8 and caspase-9 activities were significantly induced by BisGMA in a dose-dependent manner (P < 0.05). Moreover, BisGMA exhibited genotoxicity via a dose-related increase in the numbers of micronucleus and DNA strand breaks (P < 0.05). CONCLUSIONS: Cytotoxicity and genotoxicity induced by BisGMA are mediated by DNA damage and caspase activation. PMID- 22242564 TI - Fumigant toxicity and oviposition deterrency of the essential oil from cardamom, Elettaria cardamomum, against three stored-product insects. AB - Use of insecticides can have disruptive effects on the environment. Replacing the chemical compounds in these insecticides with plant materials, however, can be a safe method with low environmental risk. In the current study, chemical composition and insecticidal activities of the essential oil from cardamom, Elettaria cardamomum L. (Maton) (Zingiberales: Zingiberaceae) on the adults of three stored product pests was investigated. Results indicated that essential oil of E. cardamomum toxic to the bruchid beetle, Callosobruchus maculatus Fabricius (Coleoptera: Bruchidae), the red flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae), and the flour moth, Ephestia kuehniella Zeller (Lepidoptera: Pyralidae). Adults of E. kuehniella were more sensitive than the Coleoptera. Also, the highest mortality of these insects was seen after 12 hours. Results of the LT50 tests showed that the lethal time of mortality occurred between 10-20 hours in various test concentrations. Essential oil of E. cardamomum had a good efficacy on oviposition deterrence of C. maculatus females, too. The chemical constituents of the essential oils were analyzed by gas chromatography-mass spectrometry. The major constituents of cardamom were identified as 1,8-cineol, alpha-terpinyl acetate, terpinene and fenchyl alcohol. These results suggest that essential oil of E. cardamomum is a good choice for control of stored product pests. PMID- 22242565 TI - Assessing clinical significance: proposed extensions to method. AB - Jacobson, Follette, and Revenstorf's (1984) proposal for assessing clinical significance provides a needed convention for psychotherapy outcome research. Several limitations that exists in this method (Jacobson & Revenstorf, 1988) are addressed in this paper and extensions are proposed. Specifically, limitations regarding the operationalization of the underlying social validation methodology in the derivation of normative samples and the resultant standards they set are discussed. Extensions and guidelines are proposed for specifying normative samples, determining the distinctness of these samples, and expanding procedures to accommodate multiple samples. This paper initially assumes a psychometric perspective and presents extensions, based on the Symptom Checklist 90-R. Then it shifts to a clinician perspective and applies reliable change estimates and cutoff scores to actual outcome data by analyzing the progress of four patients during and after therapy. The overall merit and utility of extensions to clinical significance are then discussed. PMID- 22242566 TI - A lacrimal sac mass with bloody discharge. AB - We report a 38-year-old man who presented with a 7-year history of a mass in the right medial canthal region. He had several episodes of dacryocystitis, epiphora and bloody discharge. A cystic lesion was defined on MRI. Lacrimal sac excision was performed and a dark red mass was extirpated. External dacryocystorhinostomy and bicanalicular silicone tube intubation was performed. The polypoid lesion was diagnosed as an inflammatory polyp. Benign and malignant tumors of the lacrimal sac may have similar clinical findings on presentation. Preoperative ancillary testing may help us to have an idea of the nature of the lesion but histopathological examination is still the gold standard. Ophthalmologists should remember this similarity and be careful especially while performing endoscopic or laser-assisted dacryocystorhinostomy. PMID- 22242567 TI - Motives and simultaneous sedative-alcohol use among past 12-month alcohol and nonmedical sedative users. AB - BACKGROUND: Simultaneous sedative-alcohol use (SSAU) is a matter of public health concern. It is important to address the various motives individuals may have for involvement in SSAU. OBJECTIVE: To explore the motives associated with SSAU. METHODS: Data were collected as part of the ongoing Prescription Drug Misuse, Abuse, and Dependence study in St. Louis. For this analysis, the sample included 173 participants who reported nonmedical sedative use for more than 5 days, and use of alcohol, in the past 12 months. SSAU was defined as past 12-month use of sedatives and alcohol together/at the same time. RESULTS: Past 12-month SSAU was reported by 61% of the sample. Multivariate logistic regression indicated that for every increment of one motive, participants were significantly more likely to report SSAU (adjusted odds ratio (aOR): 1.30; 95% confidence interval (CI): 1.12 1.52). Furthermore, reporting sedative use "to get high, to change mood, to relieve stress, to party, and 'just because' " was independently associated with the past 12-month SSAU. Past 12-month SSAU was also found to be significantly associated with simultaneous use of sedatives and cannabis in the past 12 months. CONCLUSION: A higher number of motives, as well as specific motives reported for sedative use, were found to be significantly associated with past 12-month SSAU. SCIENTIFIC SIGNIFICANCE: Findings underscore the need for considering motives in tailoring preventive interventions for reducing SSAU. It may be equally important to direct efforts toward decreasing the number of motives, as well as addressing the specific motives reported for sedative use. PMID- 22242568 TI - Metastatic colorectal cancer: current treatment and future options for improved survival. Medical approach--present status. AB - BACKGROUND: Metastatic colorectal cancer has a poor prognosis, and the majority of patients are left with palliative measures. The development seen using medical treatments are reviewed. MATERIAL AND METHODS: A systematic approach to the literature-based evidence of effects from palliative chemotherapy and targeted drugs was aimed at. RESULTS: The continuous improvements during the past 20-25 years have been documented in several large conclusive trials. At the end of the 1980s, the evidence that chemotherapy should be used at all was very limited, whereas presently most patients can be offered three lines of chemotherapy with or without a targeted drug based upon good scientific evidence. Median survival in trials has gradually improved from about 6 months to above 24 months in the most recent trials. Survival in the populations has, however, not improved to the same extent. Several important issues remain to be solved, such as the best sequence of treatments, what regimens to use in various situations, when to start and when to stop if a response is seen, whether cure may be possible in a small subset of patients, and socioeconomic issues. Integration of surgery and other local methods have further improved outcome for some individuals, but must be fine-tuned. CONCLUSIONS: Progress has been rapid in advanced colorectal cancer. This is likely a result of well-designed trials in collaboration between academy and industry, showing a great interest in the disease. A multi-professional approach and future collaborations may hopefully introduce new treatment concepts, further improving outcome. PMID- 22242570 TI - Integrating sphere setup for the traceable measurement of absolute photoluminescence quantum yields in the near infrared. AB - There is an increasing interest in chromophores absorbing and emitting in the near-infrared (NIR) spectral region, e.g., for applications as fluorescent reporters for optical imaging techniques and hence, in reliable methods for the characterization of their signal-relevant properties like the fluorescence quantum yield (Phi(f)) and brightness. The lack of well established Phi(f) standards for the NIR region in conjunction with the need for accurate Phi(f) measurements in transparent and scattering media encouraged us to built up an integrating sphere setup for spectrally resolved measurements of absolute fluorescence traceable to radiometric scales. Here, we present the design of this setup and its characterization and validation including an uncertainty budget for the determination of absolute Phi(f) in the visible and NIR. To provide the basis for better measurements of Phi(f) in the spectral window from ca. 600 to 1000 nm used, e.g., for optical imaging, the absolute Phi(f) of a set of NIR chromophores covering this spectral region are measured and compared to relative values obtained using rhodamine 101 as Phi(f) standard. Additionally, the absolute Phi(f) values of some red dyes that are among the most commonly used labels in the life sciences are presented as well as the absolute quantum yield of an optical probe for tumor imaging. PMID- 22242594 TI - Antitumor effect of a generation 4 polyamidoamine dendrimer/cyclooxygenase-2 antisense oligodeoxynucleotide complex on breast cancer in vitro and in vivo. AB - Cyclooxygenase (COX)-2 plays critical roles in tumorigenesis, tumor cell growth, and angiogenesis, and inhibiting the expression of COX-2 by gene therapy has showed promising prospects. Vectors are crucial for gene therapy. Polyamidoamine (PAMAM) dendrimers are one type of nano-vectors. In this study, we synthesized a generation 4 polyamidoamine (G4PAMAM) dendrimer/COX-2 antisense oligodeoxynucleotide complex (G4PAMAM/COX-2ASODN), determined the transfection rate of G4PAMAM/COX-2ASODN on cultured breast cancer cells, assessed the cell viability, cell cycle dynamics, and cell invasiveness after transfection, and investigated the effects of G4PAMAM/COX-2ASODN on the expression of COX-2 mRNA and protein and microvessel density (MVD) levels in the tumor tissues of a breast cancer nude mouse model. The results showed that G4PAMAM/COX-2ASODN had a high transfection rate, decreased the cell viability, induced apoptosis and G0/G1 cell cycle arrest, and suppressed cell invasiveness. After treatment with G4PAMAM/COX 2ASODN, the copy number of COX-2 mRNA and protein expression in the tumor tissue were decreased markedly, MVD in the tumor tissue was also decreased, and tumor growth was restrained (p<0. 05). We conclude that COX-2ASODN can be delivered into the cultured and transplanted breast cancer cells efficiently by G4PAMAM, can reduce the expression of COX-2 mRNA and protein, and can lower the MVD of tumor tissues. The G4PAMAM/COX-2ASODN complex has antitumor properties in vitro and in vivo. PMID- 22242595 TI - The effects of 12C6+ irradiation on cell cycle, apoptosis, and expression of caspase-3 in the human lung cancer cell line h1299. AB - INTRODUCTION: We aimed to investigate the effects of (12)C(6+) irradiation on the cell cycle and apoptosis as well as the associated mechanisms in the human lung cancer cell line H1299. METHODS: After irradiation with different doses of (12)C(6+) for varying lengths of incubation, the changes in H1299 cells were assayed by flow cytometry and the microculture tetrazolium test. The expression of caspase-3 was detected by immunocytochemistry, western blot, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The G(2)/M phase was blocked after treatment with 1 and 2 Gy at the 12-hour time point, and the most obvious block of G(2)/M occurred after treatment with 2 and 4 Gy at the 24-hour time point in a dose-dependent manner. The apoptosis rate increased with increasing radiation dose and reached a peak after the cells were irradiated with 2 Gy and incubated for 48 hours. In addition, the RT-PCR, western blot, and ICC results showed that irradiation with (12)C(6+) significantly increased the expression of caspase-3 compared with the control group (p<0.05). CONCLUSIONS: Irradiation of H1299 cells with (12)C(6+) induced apoptosis and significantly inhibited their growth through heavy ion irradiation-mediated activation of the caspase-3 pathway. Our results show that caspase-3 may play an important role in radiation-induced apoptosis through a p53-independent pathway. PMID- 22242596 TI - Sensing technique of silver nanoparticles as labels for immunoassay using liquid electrode plasma atomic emission spectrometry. AB - We report the use of liquid electrode plasma-atomic emission spectrometry (LEP AES) in protein sensing studies employing Ag nanoparticle labeling. LEP-AES requires no plasma gas and no high-power source and is suitable for onsite portable analysis. Human chorionic gonadotropin (hCG) was used as a model target protein, and the immunoreaction in which hCG is sandwiched between two antibodies, one of which is immobilized on the microwell and the second is labeled with Ag nanoparticles, was performed. Sensing occurs at the narrow pass in the center of a quartz chip following oxidative dissolution of the Ag nanoparticles by nitric acid. hCG was analyzed in the range from 10 pg/mL to 1 ng/mL, and the detection limit for hCG was estimated at 1.3 pg/mL (22.8 fM). The proposed detection method has a wide variety of promising applications in metal nanoparticle-labeled biomolecule detection. PMID- 22242597 TI - Stereospecific analysis of triacylglycerol and phospholipid fractions of five wild freshwater fish from Poyang Lake. AB - The fatty acids (FA) compositions and positional distributions in triacylglycerols (TAG) and phospholipids (PL) of five wild freshwater fish (Squaliobarbus curriculus, Erythroculter ilishaeformis, Pseudobagrus fulvidraco, Bostrichthys sinensis, and Siniperca kneri Garman) from Poyang Lake (the largest freshwater lake of China) were studied. For TAG, S. kneri German had the highest content (13.59%) of n - 3 polyunsaturated fatty acids (PUFA) and E. ilishaeformis had the lowest ratio of (n - 6)/(n - 3) (0.65). PL had a high content of PUFA, which declined in the order of phosphatidylethanolamine (PE) > phosphatidylcholine (PC) > TAG. 9c11t-18:2 accounted for 6.38-50.77% of total conjugated linoleic acids (CLA). The highest level of odd-branched chain fatty acids (OBCFA) was 26.7% in B. sinensis. The study revealed that the distribution of FA among the sn positions was not random: monounsaturated fatty acids (MUFA) and PUFA preferred positions 1 and 3 and saturated fatty acids (SFA) position 2 of TAG, while SFA and MUFA predominated over sn-1-PL and PUFA over sn-2-PL. PMID- 22242598 TI - Human CCAAT/enhancer-binding protein beta interacts with chromatin remodeling complexes of the imitation switch subfamily. AB - Transcription factor C/EBPbeta is involved in several cellular processes, such as proliferation, differentiation, and energy metabolism. This factor exerts its activity through recruitment of different proteins or protein complexes, including the ATP-dependent chromatin remodeling complex SWI/SNF. The C/EBPbeta protein is found as three major isoforms, C/EBPbeta1, -2, and -3. They are generated by translation at alternative AUG initiation codons of a unique mRNA, C/EBPbeta1 being the full-length isoform. It has been found that C/EBPbeta1 participates in terminal differentiation processes. Conversely, C/EBPbeta2 and -3 promote cell proliferation and are involved in malignant progression in a number of tissues. The mechanisms by which C/EBPbeta2 and -3 promote cell proliferation and tumor progression are not fully understood. In this work, we sought to identify proteins interacting with hC/EBPbeta using a proteomics approach. We found that all three isoforms interact with hSNF2H and hACF, components of ACF and CHRAC chromatin remodeling complexes, which belong to the imitation switch subfamily. Additional protein-protein interaction studies confirmed this finding and also showed that hC/EBPbeta directly interacts with hACF1. By overexpressing hC/EBPbeta, hSNF2H, and hACF1 in HepG2 cells and analyzing variations in expression of cyclin D1 and other C/EBPbeta target genes, we observed a functional interaction between C/EBPbeta and SNF2H/ACF1, characterized mainly by suppression of C/EBPbeta transactivation activity in the presence of SNF2H and ACF1. Consistent with these findings, induction of differentiation of HepG2 cells by 1% DMSO was accompanied by a reduction in the level of cyclin D1 expression and the appearance of hC/EBPbeta, hSNF2H, and hACF1 on the promoter region of this gene. PMID- 22242600 TI - Fracture resistance of root filled premolar teeth restored with direct composite resin with or without cusp coverage. AB - AIM: To evaluate the fracture resistance and fracture patterns of root filled maxillary first premolar teeth (with mesio-occlusal cavity preparation) restored with several composite restoration designs. METHODOLOGY: One hundred extracted sound human maxillary first premolars were randomly divided into five groups. Group 1 remained untreated (negative control). Conventional root canal treatment with additional mesial-occlusal cavity preparation was carried out on teeth in groups 2-5. In group 2, the teeth were restored intra-coronally with direct composite resin (positive control). In group 3, the palatal cusps of the teeth were reduced, and the cavities were restored with composite resin covering the palatal cusp (partial coverage). In group 4, the buccal and palatal cusps along with the distal marginal ridges were reduced; the cavities and cusps were restored with composite resin (conventional full coverage). In group 5, the buccal and palatal cusps were reduced but the distal marginal ridges were conserved. The cavities and the cusps were restored with composite resin (modified full coverage). All teeth were subjected to a progressive compressive loading parallel to their longitudinal axis until fracture. Fracture resistance was analysed using the one-way ANOVA and Fisher's LSD test. Fracture patterns were analyzed with chi-square test. The significance level was set at 0.05. RESULTS: The fracture resistance (mean +/- SD) of groups 1-5 was 1131 +/- 207N, 904 +/- 184N, 927 +/- 224N, 1095 +/- 289N and 1085 +/- 243N, respectively (groups 1, 4, 5 > groups 2, 3; P = 0.004). Cusp fractures were recorded as the fracture pattern in 20 (100%), 19 (95%), 16 (80%), 8 (40%) and 12 (60%) premolars in groups 1-5, respectively (groups 1, 2 > groups 4, 5; group 3 > group 4; P < 0.001). CONCLUSIONS: When direct composite resin was used to restore root filled maxillary first premolar teeth involving a proximal surface, those restored with full-coverage designs had greater fracture resistance. PMID- 22242602 TI - Single domain metallothioneins: supermetalation of human MT 1a. AB - Metallothioneins are a family of small, cysteine rich proteins that have been implicated in a range of roles including toxic metal detoxification, protection against oxidative stress, and as metallochaperones involved in the homeostasis of both essential zinc and copper. We report that human metallothionein 1a, well known to coordinate 7 Zn(2+) or Cd(2+) ions with 20 cysteinyl thiols, will bind 8 structurally significant Cd(2+) ions, leading to the formation of the supermetalated Cd(8)-betaalpha-rhMT 1a species, for which the structure is a novel single domain. ESI-mass spectrometry was used to determine the exact metalation status of the betaalpha-rhMT. The derivative-shaped CD envelope of Cd(7)-betaalpha-rhMT [peak extrema (+) 260 and (-) 239 nm] changed drastically upon formation of the Cd(8)-betaalpha-rhMT with the appearance of a sharp monophasic CD band centered on 252 nm, a feature indicative of the loss of cluster symmetry. The structural significance of the eighth Cd(2+) ion was determined from a combination of direct and indirect (113)Cd nuclear magnetic resonance (NMR) spectra. In the case of Cd(8)-betaalpha-rhMT, only four peaks were observed in the direct (113)Cd NMR spectrum. Significantly, while both of the isolated domains can be supermetalated forming Cd(4)-beta-rhMT and Cd(5) alpha-rhMT, Cd(8)-betaalpha-rhMT and not Cd(9)-betaalpha-rhMT was observed following addition of excess Cd(2+). We propose that both domains act in concert to coordinate the eighth Cd(2+) atom, and furthermore that this interaction results in a coalescence of the two domains leading to collapse of the two-domain structure. This is the first report of a possible single-"superdomain" metallothionein structure for Zn(2+) and Cd(2+) binding mammalian proteins. A computational model of a possible single-domain structure of Cd(8)-betaalpha-rhMT is described. PMID- 22242601 TI - Nanoparticles labeled with positron emitting nuclides: advantages, methods, and applications. AB - Over the past decade, positron emitter labeled nanoparticles have been widely used in and substantially improved for a range of diagnostic biomedical research. However, given growing interest in personalized medicine and translational research, a major challenge in the field will be to develop disease-specific nanoprobes with facile and robust radiolabeling strategies and that provide imaging stability, enhanced sensitivity for disease early stage detection, optimized in vivo pharmacokinetics for reduced nonspecific organ uptake, and improved targeting for elevated efficacy. This review briefly summarizes the major applications of nanoparticles labeled with positron emitters for cardiovascular imaging, lung diagnosis, and tumor theranostics. PMID- 22242603 TI - Mac-1 negative NK cells constitute the predominant subset in the livers of mice transvenously injected with tumor cells. AB - We evaluated age-related differences in hepatic natural killer (NK) cell phenotypes in juvenile (2-week-old) and adult (8-week-old) C57BL/6(B6) mice, and determined NK cell cytotoxicity and apoptosis in tumor inoculated mice. Juvenile mice had a preponderance of Mac-1(-) NK cells that exhibited significantly higher cytotoxicity levels. The Mac-1(-) NK cell population was the predominant subset in the liver of mice inoculated with the CMT-93 mouse rectum carcinoma cell line, which paralleled a dramatic decrease in the numbers of Mac-1(+) NK cells. The decrease in Mac-1(+) NK cells was driven by an apoptotic pathway. PMID- 22242605 TI - CO2 capture from cement plants using oxyfired precalcination and/or calcium looping. AB - This paper compares two alternatives to capture CO(2) from cement plants: the first is designed to exploit the material and energy synergies with calcium looping technologies, CaL, and the second implements an oxyfired circulating fluidized bed precalcination step. The necessary mass and heat integration balances for these two options are solved and compared with a common reference cement plant and a cost analysis exercise is carried out. The CaL process applied to the flue gases of a clinker kiln oven is substantially identical to those proposed for similar applications to power plants flue gases. It translates into avoided cost of of 23 $/tCO(2) capturing up to 99% of the total CO(2) emitted in the plant. The avoided cost of an equivalent system with an oxyfired CFBC precalcination only, goes down to 16 $/tCO(2) but only captures 89% of the CO(2) emitted in the plant. Both cases reveal that the application of CaL or oxyfired CFBC for precalcination of CaCO(3) in a cement plant, at scales in the order of 50 MWth (referred to the oxyfired CFB calciner) is an important early opportunity for the development of CaL processes in large scale industrial applications as well as for the development of zero emissions cement plants. PMID- 22242606 TI - Epitope mapping of BP230 leading to a novel enzyme-linked immunosorbent assay for autoantibodies in bullous pemphigoid. AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by circulating autoantibodies against BP180 and BP230. For BP180, the NC16A domain has previously been identified as the main antigenic target in BP, while data about the diagnostic value of epitopes on BP230 were inconclusive. OBJECTIVES: To identify the most appropriate epitopes on BP230 to be applied in a simple, sensitive, and highly specific enzyme-linked immunosorbent assay (ELISA) for routine detection of serum autoantibodies. METHODS: Ten overlapping linear fragments covering the whole length of BP230 were expressed in Escherichia coli. Based on Western blot analysis with sera from patients with BP (n = 49) and healthy controls (n = 94), the diagnostic performance of the fragments was compared by receiver operating characteristics curve analysis. The BP230-C3 fragment comprising the C-terminal portion (amino acids 2326-2649) was subsequently applied in a novel ELISA. The operating characteristics of this ELISA were analysed by probing sera from patients with BP (n = 118), pemphigus vulgaris (n = 50), rheumatoid arthritis and other inflammatory arthritides (n = 170), and systemic lupus erythematosus (n = 56), and from healthy blood donors (n = 483). RESULTS: Among all the fragments, BP230 C3 provided the best efficiency in serologically diagnosing BP by Western blot. An ELISA employing BP230-C3 revealed a diagnostic sensitivity of 56.8% and specificity of 97.6%. Its diagnostic added value amounted to 4.2% compared with the anti-BP180-NC16A-4X ELISA alone. CONCLUSIONS: Recombinant BP230-C3 is a suitable target antigen for the detection of serum autoantibodies against BP230. PMID- 22242607 TI - Editorial: transitions and new directions. PMID- 22242608 TI - Development of a therapist adherence/competence rating scale for supportive expressive dynamic psychotherapy: a preliminary report. AB - This paper reports on the development of the Penn Adherence/Competence Scale for Supportive-Expressive (SE) Dynamic Psychotherapy. The rating scale includes 45 items which are rated separately for both frequency (adherence) and quality (competence) of therapists' application. Audiotaped from four SE therapists who saw a total of 33 depressed patients were rated by two independent judges. The same judges also rated four cognitive (CT) therapists who saw a total of seven patients. Interjudge reliability for the six subscales and the two total scale scores ranged from .35 to .79, and internal consistency coefficients ranged from .62 to .95. While SE therapists used more expressive and interpretative techniques than did CT therapists, the two groups did not differ in their use of supportive and general techniques. In addition, SE therapists were judged to be more competent in their use of SE specific techniques than were CT therapists. SE therapists' adherence and competence were not associated with patients' level of psychiatric severity as indicated by pretreatment and concurrent levels of depression, comorbid personality disorder, or level of psychological health. Therapists' adherence and competence were unrelated to a concurrent measure of the therapeutic alliance. PMID- 22242609 TI - Vocabulary measures for the evaluation of therapy outcome: re-studying transcripts from the penn psychotherapy project. AB - In this study we investigated how vocabularies of patients, as well as therapists, are related to outcome of psychotherapeutic treatment. For this purpose 80 transcripts of the ten most and ten least improved patients of the Penn Psychotherapy Project (PPP) were included in the Ulm Textbank. In addition to the total amount of speech, different vocabulary measures, such as the "private vocabulary" and the "shared vocabulary" of patient and therapists, were applied to the transcripts. Furthermore, the "Regressive Imagery Dictionary" "RID" was applied as a content analytic approach, measuring primary and secondary process content in a given text. Significant correlations of these variables with the PPP outcome measure "residual gain" were found, indicating, that successful therapists tend to accommodate more to the language of their patients compared with their non-successful colleagues. PMID- 22242610 TI - Some comments on "assessing clinical significance". AB - The strategies for extending clinical significance (CS) methodology, suggested by Tingey et al., have considerable merit. They also serve to highlight the difficulties encountered with CS methodology in general. Problems encountered with the original methodology may be compounded, not solved, by such extensions. For example, problems around lack of agreement about the appropriateness of certain measures, and the questionable psychometric properties of measures, are likely to be exacerbated, not lessened, when attempting to measure social impact. Similarly, the proposal that multiple normative groups be identified to provide the impact factor does not resolve the original difficulty of identifying and discriminating more obviously diverse groups, such as functional and dysfunctional. Other problems with the proposed extensions, such as using criterion "c" (Jacobson and Truax, 1991) with non-normal distributions, are discussed. Some recommendations regarding these problems are made. PMID- 22242611 TI - The importance of the principle of clinical significance-defining significant to whom and for what purpose: a response to tingey, lambert, burlingame, and hansen. AB - Tingey, Lambert, Burlingame, and Hansen (1996) argue that although there are benefits and utility of clinical significance, extensions to the concept proposed a decade ago (Jacobson, Follette, & Revenstorf, 1984a) are necessary. The criticisms of the original paper and subsequent extensions are problematic and fail to appreciate the underlying principle of clinical significance, namely defining for whom and for what purpose significant change would be identified. This paper responds to several of the criticisms outlined in Tingey et al. with regard to operationalizing a comparison group, the perceived limitations of using two distributions, and the problems with their approach of specifying a method for determining whether groups are distinct. We then propose that there is a principle that underlies the concept of clinical significance that should be appreciated. We conclude by describing under what conditions "functional" distributions may be supplemented by including information to allow comparisons of outcomes with the current best available treatment alternative, but offer a cautionary statement about the potential risks run by extensions such as Tingey et al.'s that can obscure the concept of clinical significance to the point that researchers are no longer discussing change in terms meaningful to the client. PMID- 22242612 TI - Clinically significant change: practical indicators for evaluating psychotherapy outcome. AB - Developing procedures to evaluate the clinical significance of psychotherapy outcome is imperative. We see social validation as the most promising, viable methodology in this endeavor. Several concerns have been raised, however, about our proposed extensions. In this article, we illuminate and reassert the importance of generating and using multiple normative samples, and the utility of our statistical extensions. We address the limitations of procedural error and skewed sample distributions. Finally we see our commentary as a call for extensive study of the relationship between scores on standard outcome instruments and client's life functioning. We trust our commentary will continue to stimulate healthy dialogue on this crucial topic. PMID- 22242614 TI - Early postoperative complications in patients with Crohn's disease given and not given preoperative total parenteral nutrition. AB - OBJECTIVE: The effect of preoperative total parenteral nutrition (TPN) on the rate of early (within 30 days) postoperative complications in patients with moderate to severe Crohn's disease (CD) was examined. MATERIAL AND METHODS: A series of 15 consecutive patients with CD (mean CD activity index score, 270) given preoperative TPN for 18-90 days (mean, 46 days) and undergoing bowel resection and primary anastomosis was compared with matching controls (105 patients) consecutively selected from all CD patients operated in Stockholm County during a preceding 20-year period without preoperative TPN. RESULTS: During the preoperative TPN, all the patients studied displayed clinical remission of CD as reflected in improvement in their general well-being, relief of abdominal pain, and abatement of fever and diarrhea. There was no significant early postoperative complication in the TPN-treated group, whereas there were 29 patients with early postoperative complications in the control group, which means a significantly higher rate of postoperative complications when preoperative TPN was not provided. During the preoperative TPN, some crucial variables increased such as the body weight, the serum concentrations of albumin and triiodothyronine reflecting improved nutritional state, whereas the serum concentration of haptoglobin and the white cell count decreased reflecting decreased inflammatory activity. CONCLUSIONS: This study shows that preoperative TPN for at least 18 days may be recommended to be given to patients with moderate to severe CD until clinical remission is achieved in order to minimize the risk of early postoperative complications. PMID- 22242615 TI - Comparison of MELD, HVPG, and their changes to predict clinically relevant endpoints in cirrhosis. AB - AIM: Identification of predictors in the natural history of cirrhosis is based on determinations at a fixed time point. However, changes of these predictors may offer more information. To evaluate the predictive value of Model for End Stage Liver Disease (MELD) and hepatic venous pressure gradient (HVPG) and their changes in cirrhosis. METHODS: Patients with repeat HVPG measurements between January 2000 and December 2008 were considered for inclusion. Patients were followed until decompensation/death or July 2009. Multivariate Cox regression was used to analyze the predictive value of a single measurement of MELD and HVPG, and changes between measurements. Compensated and decompensated patients were analyzed separately. RESULTS: One hundred and seventeen patients were included (51 compensated, 66 decompensated). Median time between measurements and follow up was 13 (2-24) and 11 (6-38) months in compensated and 8 (1-16) and 10 (3-21) months in decompensated patients, respectively. Fifteen compensated patients developed decompensation while twelve decompensated patients died. On multivariate analysis, MELD (HR 1.12 (95% CI 1-1.24)) and HVPG (HR 1.16 (95% CI 1.04-1.29)) were independent predictors of decompensation in compensated, while MELD (HR 1.18 (95% CI 1.09-1.27)) was the only predictor of death in the decompensated. CONCLUSION: Single and repeat measurements of MELD and HVPG are associated to outcomes in cirrhosis. Use of repeat measurements does not seem to add further information. PMID- 22242613 TI - Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. AB - BACKGROUND AND AIMS: Atrophic gastritis (AG) results most often from Helicobacter pylori (H. pylori) infection. AG is the most important single risk condition for gastric cancer that often leads to an acid-free or hypochlorhydric stomach. In the present paper, we suggest a rationale for noninvasive screening of AG with stomach-specific biomarkers. METHODS: The paper summarizes a set of data on application of the biomarkers and describes how the test results could be interpreted in practice. RESULTS: In AG of the gastric corpus and fundus, the plasma levels of pepsinogen I and/or the pepsinogen I/pepsinogen II ratio are always low. The fasting level of gastrin-17 is high in AG limited to the corpus and fundus, but low or non-elevated if the AG occurs in both antrum and corpus. A low fasting level of G-17 is a sign of antral AG or indicates high intragastric acidity. Differentiation between antral AG and high intragastric acidity can be done by assaying the plasma G-17 before and after protein stimulation, or before and after administration of the proton pump inhibitors (PPI). Amidated G-17 will rise if the antral mucosa is normal in structure. H. pylori antibodies are a reliable indicator of helicobacter infection, even in patients with AG and hypochlorhydria. CONCLUSIONS: Stomach-specific biomarkers provide information about the stomach health and about the function of stomach mucosa and are a noninvasive tool for diagnosis and screening of AG and acid-free stomach. PMID- 22242616 TI - N-acetyl cysteine improves glycogenesis after segmental liver ischemia and reperfusion injury in pigs. AB - OBJECTIVE: N-acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion (IR). Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in IR injury. MATERIAL AND METHODS: In an experimental model, 80 min of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 min. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously. RESULTS: AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC-treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysates, indicating that NAC scavenges radical nitrosative species. CONCLUSIONS: NAC treatment improves glycogenesis after liver IR injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of radical nitrosative species. PMID- 22242617 TI - The role of antibiotic prophylaxis in endoscopic retrograde cholangiopancreatography; a retrospective single-center evaluation. AB - OBJECTIVE: Endoscopic retrograde cholangiopancreaticography (ERCP) can be complicated by post-ERCP cholangitis even when performed by experienced endoscopists. Therefore, antibiotic prophylaxis is recommended for certain patients, but controversy exists as to which patient groups really benefit from this strategy. We retrospectively evaluated the use of antibiotics in a primary teaching hospital in the Netherlands with regard to the incidence of post-ERCP cholangitis and cholecystitis. MATERIAL AND METHODS: Retrospective single-center evaluation in a primary teaching hospital. All consecutive ERCPs between 2000 and 2006 were studied. Primary end point was the incidence of post-ERCP cholangitis and cholecystitis, divided into four categories: definite, likely, possible and unlikely. Additionally, occurrence of complications such as pneumonia, post-ERCP pancreatitis, perforation of the duodenum, substantial bleeding and the need for re-ERCP within 5 days was scored. RESULTS: Five hundred forty ERCPs in 327 patients were screened. Of these, 292 ERCPs performed in 193 patients were included. Eight ERCPs (2.7%) of all ERCPs were followed by definite cholangitis and two ERCPs (0.7%) by likely cholangitis. The occurrence rate of ERCP-related complications remained low. CONCLUSIONS: This study shows that with our current policy of restricted use of antibiotic prophylaxis the overall incidence of biliary tract infections is low. PMID- 22242619 TI - The utility of mentoring homeless adolescents: a pilot study. AB - BACKGROUND: Despite the intuitive appeal and popularity of mentoring programs, mentoring has shown only limited success for positively impacting children's psychosocial functioning. Furthermore, we were not able to identify a study that examined the potential utility of mentoring for homeless adolescents. OBJECTIVE: The purpose of this pilot study was to examine the impact of mentoring among a group of homeless adolescents who were also receiving substance abuse treatment. METHODS: This pilot study examined the impact of mentoring among homeless adolescents (n = 90) between the ages of 14 and 20 years who also received substance abuse treatment. A longitudinal design was used in which adolescents were assessed at baseline, 3 months, and following the completion of treatment at 6 months postbaseline. RESULTS: Findings showed that adolescents with a history of physical or sexual abuse attended more mentoring sessions. Also, mentoring in addition to treatment was associated with a decrease in problem consequences associated with substance use. However, more mentoring with fewer treatment sessions was associated with an increase in internalizing behaviors. Only these two outcomes were associated with mentoring. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: While not providing resounding support for mentoring, this study suggests that examining the mentor/mentee relationship may be a fruitful line of future research given that significant variability among the mentor/mentee pairs was noted for some outcomes of interest. PMID- 22242622 TI - Co-electrospun nanofibrous membranes of collagen and zein for wound healing. AB - To develop biocompatible nanofibrous membranes for wound healing, we investigated the coelectrospinning of two proteins (collagen and zein) in aqueous acetic acid solution. It was found that the combination of zein could improve the electrospinnability of collagen. For the resultant electrospun membrane, its fiber diameter, surface wettability, mechanical, and in vitro degradable properties as well as cell adhesive ability could be modulated by the change of collagen/zein blending ratio. Moreover, berberine drug could be incorporated in situ into the electrospun nanofibrous membrane for its controlled release and antibacterial activity. The addition of berberine showed little effects on the fiber morphology and cell viability. In addition, the wound healing performance of the as-obtained nanofibrous membranes was examined in vivo by using female Sprague-Dawley rats and histological observation. PMID- 22242621 TI - Pharmacokinetics of linagliptin in subjects with hepatic impairment. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Linagliptin is an oral, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. * The elimination of linagliptin is primarily non-renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations. WHAT THIS STUDY ADDS: * This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. * No linagliptin dose adjustment is required in patients with any degree of hepatic impairment. AIM: To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability. METHOD: This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects. RESULTS: In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC(tau,ss) geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C(max,ss) GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC(tau,ss) GMR 85.5%, 90% CI 70.2%, 104.2% and C(max,ss) GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C(max) was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C(max) and renal excretion of unchanged linagliptin (<= 7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated. CONCLUSION: Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment. PMID- 22242623 TI - Intrinsic contribution of the 2'-hydroxyl to RNA conformational heterogeneity. AB - Canonical duplex RNA assumes only the A-form conformation at the secondary structure level while, in contrast, a wide range of noncanonical, tertiary conformations of RNA occur. Here, we show how the 2'-hydroxyl controls RNA conformational properties. Quantum mechanical calculations reveal that the orientation of the 2'-hydroxyl significantly alters the intrinsic flexibility of the phosphodiester backbone, favoring the A-form in duplex RNA when it is in the base orientation and facilitating sampling of a wide range of noncanonical, tertiary structures when it is in the O3' orientation. Influencing the orientation of the 2'-hydroxyl are interactions with the environment, as evidenced by crystallographic survey data, indicating the 2'-hydroxyl to sample more of the O3' orientation in noncanonical RNA structures. These results indicate that the 2'-hydroxyl acts as a "switch", both limiting the conformation of RNA to the A-form at the secondary structure level and allowing RNA to sample a wide range of noncanonical tertiary conformations. PMID- 22242624 TI - Does shape matter? Bioeffects of gold nanomaterials in a human skin cell model. AB - Gold nanomaterials (AuNMs) have distinctive electronic and optical properties, making them ideal candidates for biological, medical, and defense applications. Therefore, it is imperative to evaluate the potential biological impact of AuNMs before employing them in any application. This study investigates two AuNMs with different aspect ratios (AR) on mediation of biological responses in the human keratinocyte cell line (HaCaT) to model potential skin exposure to these AuNMs. The cellular responses were evaluated by cell viability, reactive oxygen species (ROS) generation, alteration in gene and protein expression, and inflammatory response. Gold nanospheres, nominally 20 nm in diameter and coated with mercaptopropane sulfonate (AuNS-MPS), formed agglomerates when dispersed in cell culture media, had a large fractal dimension (D(f) = 2.57 +/- 0.4) (i.e., tightly bound and densely packed) and were found to be nontoxic even at the highest dose of 100 MUg/mL. Highly uniform, 16.7 nm diameter, and 43.8 nm long polyethylene glycol-capped gold nanorods (AuNR-PEG) also formed agglomerates when dispersed into the cell culture media. However, the agglomerates had a smaller fractal dimension (D(f) = 1.28 +/- 0.08) (i.e., loosely bound) and were found to be cytotoxic to the HaCaT cells, with a significant decrease in cell viability occurring at 25 MUg/mL and higher. Moreover, AuNR-PEG caused significant ROS production and up-regulated several genes involved in cellular stress and toxicity. These results, combined with increased levels of inflammatory and apoptotic proteins, demonstrated that the AuNR-PEG induced apoptosis. Exposure to AuNS-MPS, however, did not show any of the detrimental effects observed from the AuNR-PEG. Therefore, we conclude that shape appears to play a key role in mediating the cellular response to AuNMs. PMID- 22242626 TI - Infrared laser ablation atmospheric pressure photoionization mass spectrometry. AB - In this paper we introduce laser ablation atmospheric pressure photoionization (LAAPPI), a novel atmospheric pressure ion source for mass spectrometry. In LAAPPI the analytes are ablated from water-rich solid samples or from aqueous solutions with an infrared (IR) laser running at 2.94 MUm wavelength. Approximately 12 mm above the sample surface, the ablation plume is intercepted with an orthogonal hot solvent (e.g., toluene or anisole) jet, which is generated by a heated nebulizer microchip and directed toward the mass spectrometer inlet. The ablated analytes are desolvated and ionized in the gas-phase by atmospheric pressure photoionization using a 10 eV vacuum ultraviolet krypton discharge lamp. The effect of operational parameters and spray solvent on the performance of LAAPPI is studied. LAAPPI offers ~300 MUm lateral resolution comparable to, e.g., matrix-assisted laser desorption ionization. In addition to polar compounds, LAAPPI efficiently ionizes neutral and nonpolar compounds. The bioanalytical application of the method is demonstrated by the direct LAAPPI analysis of rat brain tissue sections and sour orange (Citrus aurantium) leaves. PMID- 22242628 TI - Unusually high association of hypertrophic cardiomyopathy and complex heart defects in children with fasciculoventricular pathways. AB - INTRODUCTION: Fasciculoventricular pathways (FVPs) are rare causes of preexcitation that do not mediate tachycardias. We report a two-center experience of pediatric patients with FVP and an unexpectedly high association of complex congenital heart defects (CHDs), chromosomal anomalies, and hypertrophic cardiomyopathy. METHODS: A retrospective review of the electrophysiology database at two institutions was performed to identify patients with FVP from January 2000 to January 2011. Medical records of these patients were reviewed for clinical history and course, presence of comorbidities, and details of intracardiac electrophysiology (EP) study. RESULTS: A total of 17 patients were identified. The primary indication for EP study was a preexcitation pattern on electrocardiogram. The majority of patients, 12/17 (71%), were found to have associated cardiac and genetic anomalies. Hypertrophic cardiomyopathy was found in 5/17 (29%) patients, with genetic testing in two patients demonstrating the lysosomal-associated membrane protein 2 mutation (Danon syndrome). Underlying complex CHDs were present in 3/17 (18%) patients. One patient (6%) was status post (s/p) cardiac transplant, one patient had hypertension, and another had Trisomy 21. Other electrophysiologic substrates mediating tachycardia were found in 3/17 (18%) patients. Only 5/17 patients (29%) were otherwise healthy with structurally normal hearts. CONCLUSIONS: In this largest reported series of FVP in children, there is an unusually high association of FVP with complex CHDs, chromosomal anomalies, and hypertrophic cardiomyopathy. Any patient with such disorders and manifest preexcitation should be evaluated with a high index of suspicion for a FVP. PMID- 22242629 TI - Polybrominated diphenylethers (PBDEs) act as apoptotic factors in the corpus luteum in addition to having a short-term stimulatory effect on progesterone secretion by luteal cells. AB - To the best of our knowledge, there is a lack of data showing effect of polybrominated diphenyl ethers (PBDEs) on the corpus luteum (CL), a mini endocrine gland responsible for a normal estrous cycle and the maintenance of pregnancy. Luteal cells obtained from corpora lutea (8-10 days after ovulation) were exposed to PBDE 47, 99, and 100 at doses of 50, 250, and 500 ng/ml for 24 and 48 hours. The progesterone (P4) level in the culture medium and caspase-3, 8, and -9 activities in the cells were estimated by ELISA. CYP11A1 and 3beta-HSD protein expression were evaluated by western blot. A 2-fold increase in P4 secretion after 24 hours and no effect after 48 hours of exposure were observed. We demonstrated that the increase in P4 secretion was the result of the stimulatory action of all PBDEs on 3beta-HSD protein expression and additionally, PBDE 99 alone on 3beta-HSD activity (measured by the conversion of P5 into P4). In contrast, the activation of caspase-8 and -9 but not caspase-3 during 24 hours of exposure, and activation of all investigated caspases during 48 hours was observed. In conclusion, the present findings provide evidence that despite the initial stimulatory effect of PBDEs on the secretion of progesterone (due to the fact that the biochemical apparatus responsible for the conversion of cholesterol into pregnenolone remains uninterrupted). PBDEs are also a key executor of apoptosis (by activating both the extrinsic and intrinsic pathways of apoptosis after longer exposure periods) which can lead to premature dysfunction of the corpus luteum. PMID- 22242625 TI - Solution NMR of a 463-residue phosphohexomutase: domain 4 mobility, substates, and phosphoryl transfer defect. AB - Phosphomannomutase/phosphoglucomutase contributes to the infectivity of Pseudomonas aeruginosa, retains and reorients its intermediate by 180 degrees , and rotates domain 4 to close the deep catalytic cleft. Nuclear magnetic resonance (NMR) spectra of the backbone of wild-type and S108C-inactivated enzymes were assigned to at least 90%. (13)C secondary chemical shifts report excellent agreement of solution and crystallographic structure over the 14 alpha helices, C-capping motifs, and 20 of the 22 beta-strands. Major and minor NMR peaks implicate substates affecting 28% of assigned residues. These can be attributed to the phosphorylation state and possibly to conformational interconversions. The S108C substitution of the phosphoryl donor and acceptor slowed transformation of the glucose 1-phosphate substrate by impairing k(cat). Addition of the glucose 1,6-bisphosphate intermediate accelerated this reaction by 2-3 orders of magnitude, somewhat bypassing the defect and apparently relieving substrate inhibition. The S108C mutation perturbs the NMR spectra and electron density map around the catalytic cleft while preserving the secondary structure in solution. Diminished peak heights and faster (15)N relaxation suggest line broadening and millisecond fluctuations within four loops that can contact phosphosugars. (15)N NMR relaxation and peak heights suggest that domain 4 reorients slightly faster in solution than domains 1-3, and with a different principal axis of diffusion. This adds to the crystallographic evidence of domain 4 rotations in the enzyme, which were previously suggested to couple to reorientation of the intermediate, substrate binding, and product release. PMID- 22242630 TI - Pre-clinical evaluation of titanium nitride coated titanium material. AB - The titanium nitride coated titanium is a material intended for the fabrication of left ventricular assist device. As per International standards, a material is subjected to pre-clinical evaluation before fabrication of a device. Toxicity/biocompatibility studies such as acute systemic toxicity, intracutaneous irritation, in vitro haemolysis and implantation in muscle were studied as per international standards for the titanium nitride coated titanium. Acute systemic toxicity was studied in mice using physiological saline and cotton seed oil extracts of the material. Intracutaneous irritation was done by injecting the extracts of the test material and control intradermally into rabbits. Grading of erythema and oedema of test and control animals were recorded at 24, 48 and 72 h. In vitro haemolysis was carried out with material and extract of the material with rabbit blood. The muscle implantation was carried out in nine anesthetized rabbits. The implanted animals were sacrificed at the end of 1, 4 and 12 weeks, the tissue with the implanted materials were collected and subjected to histopathological analysis. The results of the study did not show any significant irritation or systemic toxicity with physiological saline and cotton seed oil extracts of the material. The percentage of hemolysis induced by the material and extract was under acceptable range. Results of the histopathological evaluation suggest that the test material did not produce any cellular changes. Hence the present study concluded that the test material is non-toxic, non-irritant, non haemolytic and biocompatible. PMID- 22242631 TI - Fin reduction is a novel and unexpected teratogenic effect of amikacin-treated zebrafish embryos. AB - We used zebrafish as a model to assess amikacin-induced embryotoxicity. We exposed zebrafish embryos to amikacin, using different amikacin doses (0-10 ppm), durations (12-48 h), and onsets (0, 24, 48 hpf). Amikacin-induced embryonic toxicity and reduced survival rate were found dependent on the exposure dose, duration and onset. Based on immunostaining with neuron-specific antibodies, amikacin reduced the number and size of zebrafish neuromasts. In addition, Amikacin caused pelvic, dorsal and anal fin defects in dose-dependent and duration-dependent manners. Proliferating cell nuclear antigen immunostaining revealed that amikacin-induced fin defects were not due to reduction of proliferating mesenchymal cells. TUNEL assay demonstrated that amikacin-induced fin defects might not associate with apoptosis. Therefore, further investigations are required to elucidate if other cell death pathways are involved in amikacin induced fin defects. PMID- 22242632 TI - "Foam Cone" exuding from the mouth and nostrils following heroin overdose. AB - A "foam cone" exuding the mouth and nostrils is a recognized consequence of anoxia following pulmonary edema. In this report, we illustrate and explain this phenomenon in victims of heroin overdose. PMID- 22242637 TI - Attention-deficit/hyperactivity disorder in childhood epilepsy: a neuropsychological and functional imaging study. AB - PURPOSE: Children with epilepsy have a significant risk for attention deficit/hyperactivity disorder (ADHD), which is often accompanied by deficits in working memory performance. However, it is not yet clear whether there are specific differences in the underlying mechanisms of working memory capability between children with epilepsy-related ADHD and those with developmental ADHD. There is evidence that methylphenidate can improve the behavioral difficulties in children with developmental ADHD. Whether this medication has the same effect on ADHD symptoms in patients with epilepsy is not yet well understood. The aim of the present study is, therefore, to evaluate whether boys with epilepsy-related ADHD and developmental ADHD share a common behavioral, pharmacoresponsive, and neurofunctional pathophysiology. METHODS: Seventeen boys with diagnosed combined epilepsy/ADHD, 15 boys with developmental ADHD, and 15 healthy controls (aged 8 14 years) performed on working memory tasks (N-back) while brain activation was recorded using functional magnetic resonance imaging. Each patient was tested twice: once after the intake of methylphenidate and once without in a counterbalanced order. KEY FINDINGS: On a behavioral level, we show that boys with epilepsy-related ADHD as well as those with developmental ADHD performed similarly poorly on tasks with high cognitive load when compared to healthy controls, and that intake of methylphenidate improved performance almost to normal levels in both ADHD groups. On the functional level, both patient groups showed similar reductions of activation in all relevant parts of the functional network of working memory when compared to controls. Of interest, intake of methylphenidate did not significantly alter this activity pattern. SIGNIFICANCE: Our data show strong similarities between epilepsy-related and developmental ADHD on the behavioral, pharmacoresponsive, and neural level, favoring the view that ADHD with and without epilepsy shares a common underlying neurobehavioral pathophysiology. PMID- 22242635 TI - Probing structural features of Alzheimer's amyloid-beta pores in bilayers using site-specific amino acid substitutions. AB - A current hypothesis for the pathology of Alzheimer's disease (AD) proposes that amyloid-beta (Abeta) peptides induce uncontrolled, neurotoxic ion flux across cellular membranes. The mechanism of ion flux is not fully understood because no experiment-based Abeta channel structures at atomic resolution are currently available (only a few polymorphic states have been predicted by computational models). Structural models and experimental evidence lend support to the view that the Abeta channel is an assembly of loosely associated mobile beta-sheet subunits. Here, using planar lipid bilayers and molecular dynamics (MD) simulations, we show that amino acid substitutions can be used to infer which residues are essential for channel structure. We created two Abeta(1-42) peptides with point mutations: F19P and F20C. The substitution of Phe19 with Pro inhibited channel conductance. MD simulation suggests a collapsed pore of F19P channels at the lower bilayer leaflet. The kinks at the Pro residues in the pore-lining beta strands induce blockage of the solvated pore by the N-termini of the chains. The cysteine mutant is capable of forming channels, and the conductance behavior of F20C channels is similar to that of the wild type. Overall, the mutational analysis of the channel activity performed in this work tests the proposition that the channels consist of a beta-sheet rich organization, with the charged/polar central strand containing the mutation sites lining the pore, and the C-terminal strands facing the hydrophobic lipid tails. A detailed understanding of channel formation and its structure should aid studies of drug design aiming to control unregulated Abeta-dependent ion fluxes. PMID- 22242638 TI - Highly sensitive molecularly imprinted electrochemical sensor based on the double amplification by an inorganic Prussian blue catalytic polymer and the enzymatic effect of glucose oxidase. AB - A novel strategy to improve the sensitivity of molecularly imprinted polymer (MIP) sensors was proposed. An electrocatalytic Prussian blue (PB) film was electrochemically polymerized on an electrode surface to fabricate an MIP electrochemical sensor using oxytetracycline (OTC) as a template. The OTC determination relied on a competition reaction between OTC and glucose-oxidase labeled OTC and the catalytic reduction of hydrogen peroxide by the modified PB film. Experimental results show that double amplification, which is based on the catalysis of inorganic PB films and the enzymatic effect of glucose oxidase, can remarkably increase the assay sensitivity. The main experimental conditions (including electrocatalysis of the PB film, pH effects, incubation and competition times, and anti-interference) were optimized. This novel MIP sensor can offer an femtomole detection limit for OTC. In addition, the feasibility of its practical applications has been demonstrated in the analysis of a series of real milk samples. PMID- 22242639 TI - An analytical solution describing the propagation of positive injury signals in an axon: effect of dynein velocity distribution. AB - A model describing the propagation of positive injury signals from the lesion site in an axon towards the neuron soma is described. It is assumed that these signals are driven by dynein molecular motors. An analytical solution that accounts for the probability density function (pdf) of a dynein velocity distribution is obtained. Two examples of pdf of dynein velocity distributions that follow from the results published in Ross et al. (2006, Processive bidirectional motion of dynein-dynactin complexes in vitro. Nat Cell Biol. 8:562 570) and Deinhardt et al. (2006, Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52:293-305) are considered. The effect of dynein velocity distribution on the rate of spreading of the signal wave is discussed. It is demonstrated that the obtained solution can be applied to the problem of how neurons measure the distance between the lesion site and the neuron soma. PMID- 22242640 TI - Interventions for treating oral lichen planus: a systematic review. AB - Oral lichen planus (OLP) is a common chronic inflammatory disease associated with cell-mediated immunological dysfunction. Symptomatic OLP is painful and complete healing is rare. The aim of this review was to assess the evidence for the efficacy and safety of treatments for symptomatic OLP. The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched in January 2011 to identify all randomized controlled trials (RCTs) evaluating any intervention for the treatment of symptomatic OLP. A total of 28 trials were included in this Cochrane review. There was no evidence from three RCTs that topical pimecrolimus is better than placebo in reducing pain from OLP. There was weak evidence from two RCTs that topical aloe vera may be associated with a reduction in pain compared with placebo. There was weak and unreliable evidence from two small trials, at high risk of bias, that topical ciclosporin may reduce pain and clinical signs of OLP. There was no evidence (from five trials each evaluating a different steroid and/or calcineurin inhibitor) that there is a difference between treatment with topical corticosteroids (TCSs) compared with topical calcineurin inhibitors with regard to reducing pain associated with OLP or that any specific steroid therapy is more or less effective at reducing pain. Although TCSs are considered to be the first-line treatment, we did not identify any RCTs that compared TCSs with placebo in patients with symptomatic OLP. From the 28 trials included in this systematic review, the wide range of interventions compared means there is insufficient evidence to support the superior effectiveness of any specific treatment. PMID- 22242642 TI - Development of the microbial electrolysis desalination and chemical-production cell for desalination as well as acid and alkali productions. AB - By combining the microbial electrolysis cell and the microbial desalination cell, the microbial electrolysis desalination cell (MEDC) becomes a novel device to desalinate salty water. However, several factors, such as sharp pH decrease and Cl(-) accumulation in the anode chamber, limit the MEDC development. In this study, a microbial electrolysis desalination and chemical-production cell (MEDCC) was developed with four chambers using a bipolar membrane. Results showed that the pH in the anode chamber of the MEDCC always remained near 7.0, which greatly enhanced the microbial activities in the cell. With applied voltages of 0.3-1.0 V, 62%-97% of Coulombic efficiencies were achieved from the MEDCC, which were 1.5 2.0 times of those from the MEDC. With 10 mL of 10 g/L NaCl in the desalination chamber, desalination rates of the MEDCC reached 46%-86% within 18 h. Another unique feature of the MEDCC was the simultaneous production of HCl and NaOH in the cell. With 1.0 V applied voltage, the pH values at 18 h in the acid production chamber and cathode chamber were 0.68 and 12.9, respectively. With the MEDCC, the problem with large pH changes in the anode chamber was resolved, and products of the acid and alkali were obtained. PMID- 22242643 TI - A comparison of attitudes toward opioid agonist treatment among short-term buprenorphine patients. AB - BACKGROUND: Obtaining data on attitudes toward buprenorphine and methadone of opioid-dependent individuals in the United States may help fashion approaches to increase treatment entry and improve patient outcomes. OBJECTIVES: This secondary analysis study compared attitudes toward methadone and buprenorphine of opioid dependent adults entering short-term buprenorphine treatment (BT) with opioid dependent adults who are either entering methadone maintenance treatment or not entering treatment. METHODS: The 417 participants included 132 individuals entering short-term BT, 191 individuals entering methadone maintenance, and 94 individuals not seeking treatment. Participants were administered an Attitudes toward Methadone scale and its companion Attitudes toward Buprenorphine scale. Demographic characteristics for the three groups were compared using chi(2) tests of independence and one-way analysis of variance. A repeated-measures multivariate analysis of variance with planned contrasts was used to compare mean attitude scores among the groups. RESULTS: Participants entering BT had significantly more positive attitudes toward buprenorphine than toward methadone (p < .001) and more positive attitudes toward BT than methadone-treatment (MT) participants and out-of-treatment (OT) participants (p < .001). In addition, BT participants had less positive attitudes toward methadone than participants entering MT (p < .001). CONCLUSIONS: Participants had a clear preference for a particular medication. Offering a choice of medications to OT individuals might enhance their likelihood of entering treatment. Treatment programs should offer a choice of medications when possible to new patients, and future comparative effectiveness research should incorporate patient preferences into clinical trials. SCIENTIFIC SIGNIFICANCE: These data contribute to our understanding of why people seek or do not seek effective pharmacotherapy for opioid addiction. PMID- 22242645 TI - Bioequivalence of two omega-3 fatty acid ethyl ester formulations: a case of clinical pharmacology of dietary supplements. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Omega-3 fatty acids are dietary components, present in the body with variable blood concentrations. * Bioavailability evaluations of ethyl ester preparations are hampered by the difficulty in achieving similar concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the preparations being compared. This may require questionable corrections for baseline concentrations. * If repeated doses are given, this may lead to errors because of variable dietary fish intake. If a single dose is selected, this needs to be large, since omega-3 LC-PUFA are present in many compartments. WHAT THIS STUDY ADDS: * We selected subjects with uniform omega-3 background concentrations, to obtain comparable results at the end of treatment. * Testing bioequivalence of two formulations with different EPA : DHA ratios led to single dose intakes of 12 g, which were well tolerated. * In spite of clear differences in EPA : DHA ratios between the two preparations, plasma ratios did not differ and bioequivalence could be well ascertained. AIM: To evaluate the bioequivalence of two omega-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA) ethyl ester preparations, previously shown not to be bioequivalent in healthy subjects, with the objective of providing a guideline for future work in this area. METHOD: A randomized double-blind crossover protocol was chosen. Volunteers with the lowest blood concentrations of n-3 LC PUFA were selected. They received the ethyl esters in a single high dose (12 g) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) blood concentrations were analyzed after fingerprick collection at intervals up to 24 h. RESULTS: Differently from a prior study, the pharmacokinetic analysis indicated a satisfactory bioequivalence: for the AUC(0,24 h) 90% CI of the ratio between the two formulations were in the range for bioequivalence (for EPA 0.98, 1.04 and for DHA 0.99, 1.04) and the same was true for C(max) and t(max) (90% CI were 0.95, 1.14 and 1.10, 1.25 for EPA and 0.88, 1.02 and 0.84, 1.24 for DHA). CONCLUSION: This study shows that, in order to obtain reliable bioequivalence data of products present in the daily diet, certain conditions should be met. Subjects should have low, homogeneous baseline concentrations and not be exposed to food items containing the product under evaluation, e.g. fish. Finally, as in the case of omega-3 fatty acids, selected doses should be high, eventually with appropriate conditions of intake. PMID- 22242646 TI - Cationic ruthenium(II) catalysts for oxidative C-H/N-H bond functionalizations of anilines with removable directing group: synthesis of indoles in water. AB - Cationic ruthenium(II) complexes enabled oxidative C-H bond functionalizations with anilines bearing removable directing groups. The C-H/N-H bond cleavages occurred most efficiently in water as a sustainable solvent and provided general access to various bioactive indoles. Mechanistic studies provided strong support for a novel reaction manifold. PMID- 22242647 TI - Upconversion fluorescence resonance energy transfer based biosensor for ultrasensitive detection of matrix metalloproteinase-2 in blood. AB - Matrix metalloproteinase-2 (MMP-2) is a very important biomarker in blood. Presently, sensitive and selective determination of MMP-2 directly in blood samples is still a challenging job because of the high complexity of the sample matrix. In this work, we reported a new homogeneous biosensor for MMP-2 based on fluorescence resonance energy transfer (FRET) from upconversion phosphors (UCPs) to carbon nanoparticles (CNPs). A polypeptide chain (NH(2)-GHHYYGPLGVRGC-COOH) comprising both the specific MMP-2 substrate domain (PLGVR) and a pi-rich motif (HHYY) was designed and linked to the surface of UCPs at the C terminus. The FRET process was initiated by the pi-pi interaction between the peptide and CNPs, which thus quenched the fluorescence of the donor. Upon the cleavage of the substrate by the protease at the amide bond between Gly and Val, the donor was separated from the acceptor while the pi-rich motif stayed on the acceptor. As a result, the fluorescence of the donor was restored. The fluorescence recovery was found to be proportional to the concentration of MMP-2 within the range from 10 500 pg/mL in an aqueous solution. The quantification limit of this sensor was at least 1 order of magnitude lower than that of other reported assays for MMP-2. The sensor was used to determine the MMP-2 level directly in human plasma and whole blood samples with satisfactory results obtained. Owing to the hypersensitivity of the method, clinical samples of only less than 1 MUL were needed for accurate quantification, which can be meaningful in MMP-2-related clinical and bioanalytical applications. PMID- 22242650 TI - Valuing comparisons. PMID- 22242648 TI - On the origin of multiphasic kinetics in peptide binding to phospholipid vesicles. AB - We critically examined a series of exact kinetic models for their ability to describe binding of a typical alpha-helical amphipathic peptide to lipid bilayers. Binding of the model peptide lysette-26 was measured through fluorescence resonance energy transfer from a Trp residue on the peptide to a fluorescently labeled acceptor lipid included in vesicles composed of 1-palmitoyl 2-oleoyl-sn-glycero-3-phosphocholine. Experimental data was collected varying peptide and lipid concentrations over an order of magnitude. The kinetic models were fit to all the experimental data simultaneously. Of the four models examined, the simplest one that is sufficient to correctly describe the experimental data includes two coupled equilibria, one between peptide monomers in solution and bound to the lipid membrane, and a second one between lipid-bound peptides that oligomerize to form dimers. We found that individual kinetic binding curves are insufficient to distinguish among kinetic models of peptide binding to lipid bilayers but that a number of models can be excluded based on inspection of a simple set of experiments. PMID- 22242652 TI - Intercountry assessment of the impact of severe premenstrual disorders on work and daily activities. AB - We explored the effects of premenstrual symptoms in women suffering from moderate to-severe premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD) on work productivity, absenteeism, and daily life activities in a large, worldwide exploratory study. Women aged 15-45 years from 19 countries in North America, Latin America, Europe, Asia, and Australia were screened for suspected PMS and PMDD and invited to participate in this 2-month web-based survey. Overall, 4,032 women completed all administered questionnaires and represent the analysis set. Women suffering from moderate-to-severe PMS/PMDD had increased work absenteeism and work productivity impairment due to premenstrual symptoms relative to those with mild PMS/no perceived symptoms. PMID- 22242651 TI - Development of a functional and emotional measure of dysmenorrhea (FEMD) in Chinese university women. AB - Primary dysmenorrhea, or cramps, causes pain, limits activity, and increases emotional tension in young women, but its measurement has not received enough research attention. We have developed a functional and emotional measure of dysmenorrhea (FEMD, 14 items), and trialed it with a sample of 833 Chinese university women. Two factors (scales) were extracted by principal component analysis (PCA) and subsequently approved by a confirmatory factor analysis (CFA). The two scales were intercorrelated and were correlated with experienced pain severity and, to a lesser degree, with the depressive tendency. We have demonstrated that FEMD has stable components that might help measure dysmenorrhea related dysfunctions. PMID- 22242653 TI - Body image among Turkish women during the first year postpartum. AB - In this study, we investigated the body image of Turkish women in their first year postpartum. We recruited 440 postpartum women who had applied to the outpatient clinics of the Maternity and Children's Hospital in the city of Ordu, Turkey. The mean of the women's body image scores was over the "middle level." The women's body image scale (BIS) score showed a significant negative relation with age, number of births, weight before pregnancy, weight gain, during pregnancy, weight soon after childbirth, present weight, postpartum weight gain, and postpartum body mass index (BMI). PMID- 22242654 TI - Sexual and reproductive health communication between mothers and their adolescent daughters in northern Nigeria. AB - We employed structured interviews and focus groups to investigate reproductive health (RH) communication practices among 184 mother-daughter pairs in Ungogo, northern Nigeria. Transcripts were analyzed using the grounded theory approach. A total of 136 mothers reported discussing RH issues with their daughters. The majority of daughters acquired RH education from their mothers. Parents were more likely to discuss marriage, menstruation, courtship, premarital sex, and sexually transmitted infections (STIs) than other sex education topics. Mothers in northern Nigeria need to be empowered with knowledge and skills to improve the scope and quality of home-based RH education. PMID- 22242655 TI - Understandings of prenatal nutrition among Argentine women. AB - Maternal nutrition is an important determinant of birth outcome and infant health. In this study, we sought to identify the current knowledge of prenatal nutrition among women in Tucuman, Argentina, to examine the extent to which knowledge was implemented and to identify opportunities for improvement in prenatal care and education. We conducted in-depth interviews with 10 women about their eating habits during pregnancy, prenatal nutrition education and knowledge, and attitudes about nutrition and pregnancy. Four major themes were identified: incomplete knowledge or practice, lack of comprehension, cultural beliefs, and noncompliance with medical advice. Suggested interventions are discussed. PMID- 22242656 TI - The roles of the father during childbirth: the lived experiences of Arab Syrian parents. AB - In our study, we explored the roles of a father during childbirth as perceived by Arab Syrian parents. A descriptive phenomenological approach was used to analyze transcripts from interviews and focus groups. Four themes emerged: (a) psychological and spiritual support, (b) being present and concerned, (c) being ready and alert, and (d) fulfilling social obligations. Most women preferred to have their mothers with them during childbirth instead of their husbands. Current health policies do not encourage fathers to play active roles during childbirth and need revision, within culturally acceptable parameters and norms, to meet the health needs of clients. PMID- 22242657 TI - Overweight and obese low-income women: restorative health behaviors under overwhelming conditions. AB - In this grounded theory study we used semistructured interviews to explore how 16 low-income uninsured Midwestern United States women who were overweight or obese felt about their condition. Using grounded theory, we identified a central problem-overwhelming conditions exemplified by numerous stressors in the lives of the participants. Despite these overwhelming conditions, the participants identified numerous restorative health behaviors in five dimensions: health, economics, environment, knowledge, and commitment. Health care providers should be cognizant of their patients' complex lives and support them in identifying, adopting, and maintaining health-restoring behaviors that work for them. PMID- 22242658 TI - Assessment of the effect of two occlusal concepts for implant-supported fixed prostheses by finite element analysis in patients with bruxism. AB - The aim of this study was to evaluate the effects of bruxing forces on implants configured under 2 different occlusal schemes by dynamic finite element analysis. A main model consisting of a 5-unit fixed partial denture supported by 3 implants was simulated with bone, implants, and superstructures. All calculations were made individually for each component, namely porcelain crowns, abutments, abutment screws, implants, and bone. Maximum stresses were found in the group function occlusion. Group-function loading may result excess stresses on the components compared with canine-guidance loading. According to the results of this study, use of canine guidance is encouraged in bruxers with implant supported prostheses. PMID- 22242660 TI - Evidence that the beta subunit of Chlamydia trachomatis ribonucleotide reductase is active with the manganese ion of its manganese(IV)/iron(III) cofactor in site 1. AB - The reaction of a class I ribonucleotide reductase (RNR) begins when a cofactor in the beta subunit oxidizes a cysteine residue ~35 A away in the alpha subunit, generating a thiyl radical. In the class Ic enzyme from Chlamydia trachomatis (Ct), the cysteine oxidant is the Mn(IV) ion of a Mn(IV)/Fe(III) cluster, which assembles in a reaction between O(2) and the Mn(II)/Fe(II) complex of beta. The heterodinuclear nature of the cofactor raises the question of which site, 1 or 2, contains the Mn(IV) ion. Because site 1 is closer to the conserved location of the cysteine-oxidizing tyrosyl radical of class Ia and Ib RNRs, we suggested that the Mn(IV) ion most likely resides in this site (i.e., (1)Mn(IV)/(2)Fe(III)), but a subsequent computational study favored its occupation of site 2 ((1)Fe(III)/(2)Mn(IV)). In this work, we have sought to resolve the location of the Mn(IV) ion in Ct RNR-beta by correlating X-ray crystallographic anomalous scattering intensities with catalytic activity for samples of the protein reconstituted in vitro by two different procedures. In samples containing primarily Mn(IV)/Fe(III) clusters, Mn preferentially occupies site 1, but some anomalous scattering from site 2 is observed, implying that both (1)Mn(II)/(2)Fe(II) and (1)Fe(II)/(2)Mn(II) complexes are competent to react with O(2) to produce the corresponding oxidized states. However, with diminished Mn(II) loading in the reconstitution, there is no evidence for Mn occupancy of site 2, and the greater activity of these "low-Mn" samples on a per-Mn basis implies that the (1)Mn(IV)/(2)Fe(III)-beta is at least the more active of the two oxidized forms and may be the only active form. PMID- 22242662 TI - Synergistic interactions between chemokine receptor elements in recognition of interleukin-8 by soluble receptor mimics. AB - Interleukin-8 (IL-8 or CXCL8), the archetypal member of the CXC chemokine subfamily, stimulates neutrophil chemotaxis by activating receptors CXCR1/IL8RA and CXCR2/IL8RB. Previous mutational studies have implicated both the N-terminal and third extracellular loop (E3) regions of these receptors in binding to IL-8. To investigate the interactions of these receptor elements with IL-8, we have constructed soluble proteins in which the N-terminal and E3 elements of either CXCR1 or CXCR2 are juxtaposed on a soluble scaffold protein; these are termed CROSS-N(X1)E3(X1) and CROSS-N(X2)E3(X2), respectively. Isothermal titration calorimetry and nuclear magnetic resonance spectroscopy were used to compare the IL-8 binding properties of the receptor mimics to those of control proteins containing only the N-terminal or E3 receptor element. CROSS-N(X2)E3(X2) bound to monomeric IL-8 with the same affinity and induced the same chemical shift changes as the control protein containing only the N-terminal element of CXCR2, indicating that the E3 element of CXCR2 did not contribute to IL-8 binding. In contrast, CROSS-N(X1)E3(X1) bound to IL-8 with ~10-fold increased affinity and induced different chemical shift changes compared to the control protein containing only the N-terminal element of CXCR1, suggesting that the E3 region of CXCR1 was interacting with IL-8. However, a chimeric protein containing the N terminal region of CXCR1 and the E3 region of CXCR2 (CROSS-N(X1)E3(X2)) bound to IL-8 with thermodynamic properties and induced chemical shift changes indistinguishable from those of CROSS-N(X1)E3(X1) and substantially different from those of CROSS-N(X2)E3(X2). These results indicate that the N-terminal and E3 regions of CXCR1 interact synergistically to achieve optimal binding interactions with IL-8. PMID- 22242659 TI - Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies. AB - PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes. PMID- 22242663 TI - Algal biomass constituent analysis: method uncertainties and investigation of the underlying measuring chemistries. AB - Algal biomass compositional analysis data form the basis of a large number of techno-economic process analysis models that are used to investigate and compare different processes in algal biofuels production. However, the analytical methods used to generate these data are far from standardized. This work investigated the applicability of common methods for rapid chemical analysis of biomass samples with respect to accuracy and precision. This study measured lipids, protein, carbohydrates, ash, and moisture of a single algal biomass sample at 3 institutions by 8 independent researchers over 12 separate workdays. Results show statistically significant differences in the results from a given analytical method among laboratories but not between analysts at individual laboratories, suggesting consistent training is a critical issue for empirical analytical methods. Significantly different results from multiple lipid and protein measurements were found to be due to different measurement chemistries. We identified a set of compositional analysis procedures that are in best agreement with data obtained by more advanced analytical procedures. The methods described here and used for the round robin experiment do not require specialized instrumentation, and with detailed analytical documentation, the differences between laboratories can be markedly reduced. PMID- 22242664 TI - Outdoor airborne fungal spora load in a suburb of Kolkata, India: its variation, meteorological determinants and health impact. AB - Our objective was to conduct an aeromycological and health survey (2002-2007) in a suburban area near Kolkata, India, with the aim of achieving the following goals: (i) to prepare a fungal spore calendar, (ii) to determine the influence of different meteorological parameters, and (iii) to study the respiratory health status of local population in relation to allergy. Airborne fungal spores from more than 50 taxa were found, of which at least 15 were allergenic. The spore concentration increased during early-winter and rainy season, and diminished during late-winter and mid-summer. Species-specific fluctuations had substantial influences from several meteorological parameters. The suburban area was found to be considerably contaminated with numerous allergenic air-spora, which caused health risk to the local population. Males were more susceptible to respiratory disorders irrespective of their age. In general, respiratory allergic patients in the 20-40 year age-group showed more frequent health problems due to aeroallergens. A positive correlation was found between the respiratory allergy cases and the air-spora concentrations. PMID- 22242666 TI - Supracerebellar transtentorial approach-resection of the tentorium instead of an opening-to provide broad exposure of the mediobasal temporal lobe: anatomical aspects and surgical applications: clinical article. AB - OBJECT: The aim of this study was to describe the surgical anatomy of the mediobasal aspect of the temporal lobe and the supracerebellar transtentorial (SCTT) approach performed not with an opening, but with the resection of the tentorium, as an alternative route for the neurosurgical management of vascular and tumoral lesions arising from this region. METHODS: Cadaveric specimens were used to illustrate the surgical anatomy of the mediobasal region of the temporal lobe. Demographic aspects, characteristics of lesions, clinical presentation, surgical results, follow-up findings, and outcomes were retrospectively reviewed for patients referred to receive the SCTT approach with tentorial resection. RESULTS: Ten patients (83%) were female and 2 (17%) were male. Their ages ranged from 6 to 59 years (mean 34.5 +/- 15.8 years). All lesions (3 posterior cerebral artery aneurysms, 3 arteriovenous malformations, 3 cavernous malformations, and 3 tumors) were completely excluded or resected. After a mean follow-up period of 143 months (range 10-240 months), the mean postoperative Glasgow Outcome Scale score was 4.9. CONCLUSIONS: Knowledge of the surgical anatomy provides improvement for microsurgical approaches. The evolution from a small opening to a resection of the tentorium absolutely changed the exposure of the mediobasal aspect of the temporal lobe. The SCTT approach with tentorial resection is an excellent alternative route to the posterior part of mediobasal aspect of the temporal lobe, and it was enough to achieve the best neurosurgical management of tumoral and vascular lesions located in this area. PMID- 22242667 TI - Delayed acute spinal cord injury following intracranial gunshot trauma: case report. AB - The authors report the case of a patient who presented with a hoarse voice and left hemiparesis following a gunshot injury with trajectory entering the left scapula, traversing the suboccipital bone, and coming to rest in the right lateral medullary cistern. Following recovery from the hemiparesis, abrupt quadriparesis occurred coincident with fall of the bullet into the anterior spinal canal. The bullet was retrieved following a C-2 and C-3 laminectomy, and postoperative MR imaging confirmed signal change in the cord at the level where the bullet had lodged. The patient then made a good neurological recovery. Bullets can fall from the posterior fossa with sufficient momentum to cause an acute spinal cord injury. Consideration for craniotomy and bullet retrieval should be given to large bullets lying in the CSF spaces of the posterior fossa as they pose risk for acute spinal cord injury. PMID- 22242668 TI - Identification of a dichotomy in morphological predictors of rupture status between sidewall- and bifurcation-type intracranial aneurysms. AB - OBJECT: Prediction of aneurysm rupture likelihood is clinically valuable, given that more unruptured aneurysms are being discovered incidentally with the increased use of imaging. The authors set out to evaluate the relative performance of morphological features for rupture status discrimination in the context of the divergent geometrical and hemodynamic characteristics of sidewall- and bifurcation-type aneurysms. METHODS: Catheter 3D rotational angiographic images of 271 consecutive aneurysms (101 ruptured, 135 bifurcation type) were used to assess the following parameters in 3D: maximum diameter (D(max)), height, height/width ratio, aspect ratio, size ratio, nonsphericity index, and inflow angle. Univariate statistics applied to the bifurcation, sidewall, and combined (bifurcation + sidewall) sets identified significant features for inclusion in multivariate analysis yielding area under the curve (AUC) and optimal thresholds in the receiver-operating characteristic. Furthermore, a computational fluid dynamics analysis was performed to evaluate the flow and wall shear stress conditions inside sidewall and bifurcation aneurysms at different inflow angles. RESULTS: The mean D(max), height, and inflow angle were significantly greater in ruptured sidewall aneurysms than in unruptured sidewall aneurysms, but showed no difference between ruptured and unruptured bifurcation lesions. There was a statistically significant difference between ruptured and unruptured aneurysms for all measured features in the combined set. Multivariate analysis identified the following: 1) nonsphericity index as the only rupture status discriminator in bifurcation lesions (AUC = 0.67); 2) height/width ratio, size ratio, and inflow angle as strong discriminators in sidewall lesions (AUC = 0.87); and 3) height/width ratio, inflow angle, and size ratio as intermediate discriminators in the combined group (AUC = 0.76). Computational fluid dynamics analysis showed that although increasing inflow angle in a sidewall model led to deeper penetration of flow, higher velocities, and higher wall shear stress inside the aneurysm dome, it produced the exact opposite results in a bifurcation model. CONCLUSIONS: Retrospective morphological and hemodynamic analysis point to a dichotomy between sidewall and bifurcation aneurysms with respect to performance of shape and size parameters in identifying rupture status, suggesting the need for aneurysm type-based analyses in future studies. The current most commonly used clinical risk assessment metric, D(max), was found to be of no value in differentiating between ruptured and unruptured bifurcation aneurysms. PMID- 22242669 TI - Hydrocephalus and radiotherapy. PMID- 22242670 TI - July effect. PMID- 22242671 TI - Use of (11)C-methionine PET parametric response map for monitoring WT1 immunotherapy response in recurrent malignant glioma. AB - OBJECT: Immunotherapy targeting the Wilms tumor 1 (WT1) gene product is a promising treatment modality for patients with malignant gliomas, and there have been reports of encouraging results. It has become clear, however, that Gd enhanced MR imaging does not reflect prognosis, thereby necessitating a more robust imaging evaluation system for monitoring response to WT1 immunotherapy. To meet this demand, the authors performed a voxel-wise parametric response map (PRM) analysis of (11)C-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OS(WT1)). METHODS: Fourteen patients with recurrent malignant glioma were included in the study, and OS(WT1) was compared with: 1) volume and length change in the contrast area of the tumor on Gd-enhanced MR images; 2) change in maximum uptake of (11)C-methionine; and 3) a more detailed voxel-wise PRM analysis of MET PET pre- and post-WT1 immunotherapy. RESULTS: The PRM analysis was able to identify the following 3 areas within the tumor core: 1) area with no change in (11)C-methionine uptake pre- and posttreatment; 2) area with increased (11)C methionine uptake posttreatment (PRM(+MET)); and 3) area with decreased (11)C methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OS(WT1) (p = 0.270 for Gd-enhanced MR imaging length, p = 0.960 for Gd-enhanced MR imaging volume, and p = 0.110 for MET-PET), the percentage of PRM(+MET) area showed excellent correlation (p = 0.008) with OS(WT1). CONCLUSIONS: This study describes the limited value of Gd-enhanced MR imaging and highlights the potential of voxel wise PRM analysis of MET-PET for monitoring treatment response in immunotherapy for malignant gliomas. Clinical trial registration no.: UMIN000002001. PMID- 22242672 TI - Lateral orbital wall approach to the cavernous sinus. AB - OBJECT: Lesions of the cavernous sinus remain a technical challenge. The most common surgical approaches involve some variation of the standard frontotemporal craniotomy. Here, the authors describe a surgical approach to access the cavernous sinus that involves the removal of the lateral orbital wall. METHODS: To achieve exposure of the cavernous sinus, a lateral canthal incision is performed, and the lateral orbital rim and anterior lateral wall are removed, for later replacement at closure. The posterior lateral orbital wall is removed to the region of the superior and inferior orbital fissures. With reflection of the dural covering of the lateral cavernous sinus and removal of the anterior clinoid process, the cavernous sinus is exposed. RESULTS: Exposure and details of the procedure were derived from anatomical study in cadavers. After the approach, with removal of the anterior clinoid process, the entire cavernous sinus from the superior orbital fissure anteriorly to the Meckel cave posteriorly is exposed. More exposure to the lateral middle fossa, foramen spinosum, and petrous carotid artery is obtained by further removal of the lateral sphenoid wing. An illustrative case example for approaching a cavernous sinus meningioma is presented. CONCLUSIONS: The translateral orbital wall approach provides a simple, rapid approach for lesions with primary or secondary involvement of the cavernous sinus. Advantages of this simple, extradural approach include the lack of brain retraction and no interruption of the temporalis muscle. PMID- 22242673 TI - Editorial: on the persisting difficulty of making predictions, especially about the future. PMID- 22242674 TI - Deep brain stimulation and seizures. PMID- 22242676 TI - Childbearing and the use of contraceptive methods among married adolescents in Bangladesh. AB - OBJECTIVES: To investigate the socioeconomic determinants of childbearing and contraceptive use among married adolescents in Bangladesh. METHODS: The study used the Bangladesh Demographic and Health Survey 2007 data. Both bivariate and multivariate statistical analyses were used to examine the association between the socioeconomic factors and childbearing and contraceptive use among married female adolescents. RESULTS: Overall, 69% of the married adolescents initiated childbearing and 25% of the most recent pregnancies were unintended. The current contraceptive prevalence rate was 42%. The multivariate logistic regression yielded a significantly increased risk of childbearing among adolescents with no formal education, those who were married-off before age 16, the poor and those who had ever used any contraceptive method. Inter-spousal communication on family planning (FP) appeared as the most single significant determinant of any contraceptive use. Number of living children, working status and visitations by FP workers are also important determinants of contraceptive use among the married female adolescents. CONCLUSIONS: Early childbearing, lower use rate of contraceptive methods and unintended pregnancies are common among married adolescents in Bangladesh. Expanded schooling and reproductive health programmes in Bangladesh should promote increased communication about FP within the couples in order to achieve successful contraception and better reproductive outcomes, particularly among adolescents. PMID- 22242677 TI - In situ study of the deposition of (ultra)thin organic phosphonic acid layers on the oxide of aluminum. AB - The interest in self-assembling monolayer deposition on various oxide substrate surfaces is steeply increasing in the last decades. Although many studies are being performed, literature does not come with a general insight in the adsorption of these layers on oxide surfaces. Also for the deposition of phosphonic acids on aluminum oxides, there is no global consensus. In this paper, we present an original in situ analysis in order to eludicate the real layer formation mechanism. First of all, the state of the phosphonic acid molecules was determined using DOSY NMR, making sure that no structures other than free molecules were present at the concentration used. With in situ atomic force microscopy and in situ visual ellipsometry, multilayers of phosphonic acids, showing 3D island growth, were determined. It was shown that using the variation of the in situ obtained roughness and bearing ratio, together with the equivalent thickness modeled by ellipsometry, the growth of the layers occurs in situ in three different stages. They consist of increasing number of islands growth, followed by filling up the gaps between islands. At last, within the adsorption time frame measured, the islands grow further in dimensions but not in numbers. This closely corresponds with the behavior of the octylphosphonic acid films analyzed by ex situ techniques. PMID- 22242675 TI - Strategies to potentiate antimicrobial photoinactivation by overcoming resistant phenotypes. AB - Conventional antimicrobial strategies have become increasingly ineffective due to the emergence of multidrug resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered the exploration of alternative treatments and unconventional approaches towards controlling microbial infections. Photodynamic therapy (PDT) was originally established as an anticancer modality and is currently used in the treatment of age-related macular degeneration. The concept of photodynamic inactivation requires cell exposure to light energy, typically wavelengths in the visible region that causes the excitation of photosensitizer molecules either exogenous or endogenous, which results in the production of reactive oxygen species (ROS). ROS produce cell inactivation and death through modification of intracellular components. The versatile characteristics of PDT prompted its investigation as an anti-infective discovery platform. Advances in understanding of microbial physiology have shed light on a series of pathways, and phenotypes that serve as putative targets for antimicrobial drug discovery. Investigations of these phenotypic elements in concert with PDT have been reported focused on multidrug efflux systems, biofilms, virulence and pathogenesis determinants. In many instances the results are promising but only preliminary and require further investigation. This review discusses the different antimicrobial PDT strategies and highlights the need for highly informative and comprehensive discovery approaches. PMID- 22242678 TI - Critical temperature threshold measurement for cold urticaria: a randomized controlled trial of H(1) -antihistamine dose escalation. AB - BACKGROUND: Cold urticaria is a rare but severe and potentially lethal condition. It is primarily treated symptomatically with H(1) -antihistamines. However, patients have a variable response to these drugs and, to date, it has not been possible to predict readily the response to therapy of individual patients. OBJECTIVES: To assess the severity of the cold urticaria in naive patients and the response to therapy of patients treated with increasing doses of an H(1) antihistamine by measurement of critical temperature thresholds (CTT) for producing weals on the forearm. METHODS: This was a two-centre, hospital-based, double-blind, randomized, parallel-group study of patients with a confirmed diagnosis of cold urticaria of at least 6 months' duration. Patient groups received either a constant dose of desloratadine 5 mg daily for 6 weeks (n = 13), or escalating doses of desloratadine: 5 mg daily for the first 2 weeks, 10 mg daily for the second 2 weeks and 20 mg daily for the final 2 weeks (n = 15). Only one adverse event that appeared to be drug related was reported: mild fatigue after treatment with desloratadine 10 mg that lasted for about 3 weeks and resolved at the end of the study. RESULTS: The desloratadine 5 mg daily dose produced a submaximal reduction of mean CTT which remained relatively constant over 6 weeks. Dose escalation increased efficacy, the reduction in mean CTT at four-times the standard daily dose being significantly greater (P = 0.03) than with the standard dose. Individually, no patient became symptom free (CTT < 4 degrees C) on 5 mg, while two became symptom free on 10 mg and a further three on 20 mg desloratadine daily. CONCLUSIONS: Measurement of CTT allows for individualized risk management and therapy in patients with cold urticaria. PMID- 22242679 TI - Development of an image-based technique to examine joint congruency at the elbow. AB - Identifying joint contact in articular joints is important for both the biomechanical investigation of joint mechanics and the study of osteoarthritis. The purpose of this study is to develop a proximity mapping technique to non invasively determine joint congruency, as a surrogate of joint contact. To illustrate the capabilities of this algorithm, a cadaveric upper extremity was positioned at varying degrees of elbow flexion. This technique was validated using a gold standard experimental casting technique. The pattern of the cast showed an excellent agreement with the generated proximity map using the inter bone distance algorithm. The results from this study agree with the results of previous studies examining joint contact at the elbow both in the location and in the tracking of the joint contact throughout elbow flexion. Ultimately, this technique will lead to an increased understanding of the effect of malalignment and instability of the joint on contact mechanics. PMID- 22242680 TI - Barriers to employment among unemployed drug users: age predicts severity. AB - BACKGROUND: Drug users in treatment or exiting treatment face many barriers to employment when entering the job market, such as low levels of education and technical skills, and low levels of interpersonal skills. As a result of these and other barriers, employment rates in these groups are generally low. OBJECTIVE: This article examines the existence and possible predictors of specific barriers to employment related to interpersonal and technical skills in a sample of participants enrolled in a therapeutic workplace intervention for substance abuse. METHODS: In Study I (N = 77), we characterized and examined predictors of participant scores on a staff-rated scale of interpersonal skills (Work Behavior Inventory). In Study II (N = 29), we examined whether participants had lower levels of computer knowledge than job seekers in the general population, and investigated possible predictors of computer knowledge in the sample. RESULTS: In general, participants in Study I displayed low levels of interpersonal skills, and participants in Study II scored lower on the computer knowledge test than job seekers in the general population. Older participants tended to have lower levels of interpersonal skills and lower levels of computer knowledge. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These results suggest that providers of workforce development services for drug users in treatment or exiting treatment should attend to these specific barriers to employment, which may also be more pronounced among older clients. PMID- 22242681 TI - Radiofrequency ablation does not induce apoptosis in the rat myocardium. AB - BACKGROUND: The mechanisms implicated in the genesis of delayed radiofrequency (RF) effects remain unclear, but may be related to extension of the lesion beyond the region of coagulative necrosis. The role of apoptosis in this process has not been previously reported. We assessed whether RF promotes apoptosis in the region surrounding acute ablation lesions in a rat model. METHODS: Wistar rats (n=30; weight 300 g) were anesthesized, the chest was opened, and the heart was exposed. A modified unipolar RF ablation (custom catheter 4.5-mm-tip diameter, 12 Watts, 10 seconds) was undertaken on the left ventricular anterolateral epicardial surface and the chest was closed. After 2 hours, animals were killed for histological (hematoxylin and eosin, TdT-mediated dUTP Nick End-Labeling [TUNEL] assay) and immunohistochemical (anti-BAD and anti-caspase 3 antibodies) analysis (n=18). Additional animals (n=12) were sacrificed at 2 (n=3), 24 (n=3), 48 (n=3), and 72 hours (n=3) after ablation exclusively for anti-BAD Western Blotting analysis. RESULTS: Lesions were characterized by well-defined regions of coagulative necrosis. In 18/18 (100%) animals, TUNEL assay revealed positive luminescent reaction cells in the region surrounding the lesion, extending up to 2 mm from the border zone. However, microscopic evaluation of the nuclei and immunohistochemical and anti-BAD Western Blotting analysis were negative in all (100%) rats. Thus, positive TUNEL reaction in the periphery of the ablation lesion likely reflects nonspecific DNA damage. CONCLUSION: RF ablation does not promote apoptosis in the periphery of the myocardial lesion. This finding may have implications for the elucidation of late lesion extension following RF ablation. PMID- 22242682 TI - Microfluidic cytometer for the characterization of cell lysis. AB - Blood cytometry and intercellular analysis typically requires lysis as a preparatory step, which can alter the results of downstream analyses. We fabricated a microfluidic cytometer to characterize erythrocyte lysis kinetics. Forward light scatter from erythrocytes was used for enumeration at specific locations on a microfluidic chip. Diffusive transport coupled with laminar flow was used to control the concentration and exposure time of the lysis reagent Zap OGLOBIN II to erythrocytes. Standard clinical practice is to expose erythrocytes to lysis reagent for 10 min. Under optimum conditions, we achieved complete erythrocyte lysis of a blood sample in 0.7 s. A maximum lysis reaction rate of 1.55 s(-1) was extrapolated from the data. Lysis began after 0.2 s and could be initiated with a lysis reagent concentration of 1.0% (68.5 mM). An equation that related lysis reagent concentration, [A], to erythrocyte lysis, [B], was determined to be [B] = -0.77[A](0.29)t. PMID- 22242683 TI - Cell-based proteome profiling of potential dasatinib targets by use of affinity based probes. AB - Protein kinases (PKs) play an important role in the development and progression of cancer by regulating cell growth, survival, invasion, metastasis, and angiogenesis. Dasatinib (BMS-354825), a dual Src/Abl inhibitor, is a promising therapeutic agent with oral bioavailability. It has been used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). Most kinase inhibitors, including Dasatinib, inhibit multiple cellular targets and do not possess exquisite cellular specificity. Recent efforts in kinase research thus focus on the development of large-scale, proteome-wide chemical profiling methods capable of rapid identification of potential cellular (on- and off-) targets of kinase inhibitors. Most existing approaches, however, are still problematic and in many cases not compatible with live-cell studies. In this work, we have successfully developed a cell-permeable kinase probe (DA-2) capable of proteome-wide profiling of potential cellular targets of Dasatinib. In this way, highly regulated, compartmentalized kinase-drug interactions were maintained. By comparing results obtained from different proteomic setups (live cells, cell lysates, and immobilized affinity matrix), we found DA-2 was able to identify significantly more putative kinase targets. In addition to Abl and Src family tyrosine kinases, a number of previously unknown Dasatinib targets have been identified, including several serine/threonine kinases (PCTK3, STK25, eIF-2A, PIM-3, PKA C-alpha, and PKN2). They were further validated by pull-down/immunoblotting experiments as well as kinase inhibition assays. Further studies are needed to better understand the exact relevance of Dasatinib and its pharmacological effects in relation to these newly identified cellular targets. The approach developed herein should be amenable to the study of many of the existing reversible drugs/drug candidates. PMID- 22242686 TI - Epilepsy control following intracranial monitoring without resection in young children. AB - PURPOSE: Intracranial monitoring (IM) is a key diagnostic procedure for select patients with treatment-resistant epilepsy (TRE). Seizure focus resection may improve seizure control in both lesional and nonlesional TRE. IM itself is not considered to have therapeutic potential. We describe a cohort of patients with improved seizure control following IM without resective surgery. METHODS: Over 12.5 years, 161 children underwent 496 surgeries including intracranial monitoring. We retrospectively reviewed the patients' charts, operative reports, and radiologic scans, under an institutional review board-approved protocol. KEY FINDINGS: Seventeen patients underwent only IM, without additional resective surgery, and seven had a dramatic improvement in their epilepsy; six of the seven patients are seizure-free (Engel class I), and one rarely has seizures (Engel class II). All seven patients had frequent seizures that led to IM: either daily (five patients) or 1-2 per week (two patients). The mean age (+/- standard deviation, SD) at seizure onset was 1.6 +/- 1.3 years (range 0.5-4 years). Etiologies were tuberous sclerosis (3 patients), trauma (1 patient), and unknown (3 patients). Mean age at surgery (+/- SD) was 4.1 +/- 2 years (range 1-7 years), and duration of epilepsy 2.5 +/- 1.1 years (range 0.5-4 years). Duration of IM was 11.7 +/- 5.6 days (5-19 days). Six patients had bilateral and one unilateral invasive electrodes. At last follow-up, four patients required fewer antiepileptic drugs (AEDs), one had the same medication but a higher dose, and two patients were taking additional AEDs. Follow-up was 30.6 +/- 9.5 months (range 19-41 months). SIGNIFICANCE: Although uncommon, patients with TRE may improve after IM alone. The explanation for this observation remains unclear; however, perioperative medications including steroids, direct cortical manipulation, or other factors may influence the epileptogenic network. PMID- 22242685 TI - Mechanism and kinetics of inducible nitric oxide synthase auto-S-nitrosation and inactivation. AB - Nitric oxide (NO), the product of the nitric oxide synthase (NOS) reaction, was previously shown to result in S-nitrosation of the NOS Zn(2+)-tetrathiolate and inactivation of the enzyme. To probe the potential physiological significance of NOS S-nitrosation, we determined the inactivation time scale of the inducible NOS isoform (iNOS) and found it directly correlates with an increase in the level of iNOS S-nitrosation. A kinetic model of NOS inactivation in which arginine is treated as a suicide substrate was developed. In this model, NO synthesized at the heme cofactor is partitioned between release into solution (NO release pathway) and NOS S-nitrosation followed by NOS inactivation (inactivation pathway). Experimentally determined progress curves of NO formation were fit to the model. The NO release pathway was perturbed through addition of the NO traps oxymyoglobin (MbO(2)) and beta2 H-NOX, which yielded partition ratios between NO release and inactivation of ~100 at 4 MUM MbO(2) and ~22000 at saturating trap concentrations. The results suggest that a portion of the NO synthesized at the heme cofactor reacts with the Zn(2+)-tetrathiolate without being released into solution. Perturbation of the inactivation pathway through addition of the reducing agent GSH or TCEP resulted in a concentration-dependent decrease in the level of iNOS S-nitrosation that directly correlated with protection from iNOS inactivation. iNOS inactivation was most responsive to physiological concentrations of GSH with an apparent K(m) value of 13 mM. NOS turnover that leads to NOS S-nitrosation might be a mechanism for controlling NOS activity, and NOS S-nitrosation could play a role in the physiological generation of nitrosothiols. PMID- 22242687 TI - Changes of blood endocannabinoids during anaesthesia: a special case for fatty acid amide hydrolase inhibition by propofol? AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Available data from animal studies suggest that the narcotic drug propofol interacts with the endocannabinoid system. Inhibition of enzymatic degradation of anandamide could explain some of the characteristics of propofol. Direct measurements have not been reported yet in humans. WHAT THIS STUDY ADDS: * Propofol does not change the time course of anandamide plasma concentrations during anaesthesia. Furthermore, propofol does not inhibit fatty acid amide hydrolase activity ex vivo or in vitro. Thus, specific characteristics of the narcotic drug propofol cannot be explained by peripheral inhibition of anandamide degradation in humans. AIMS: The aim of our study was to describe the time course of endocannabinoids during different anaesthesia protocols in more detail, and to challenge the hypothesis that propofol acts as a FAAH inhibitor. METHODS: Endocannabinoids were measured during the first hour of anaesthesia in 14 women and 14 men undergoing general anaesthesia with propofol and in 14 women and 14 men receiving thiopental/sevoflurane. We also incubated whole human blood samples ex vivo with propofol and the known FAAH inhibitor oloxa and determined FAAH enzyme kinetics. RESULTS: Plasma anandamide decreased similarly with propofol and thiopental/sevoflurane anaesthesia, and reached a nadir after 10 min. Areas under the curve for anandamide (mean and 95% CI) were 53.3 (47.4, 59.2) nmol l(-1) 60 min with propofol and 48.5 (43.1, 53.8) nmol l(-1) 60 min with thiopental/sevoflurane (P= NS). Anandamide and propofol plasma concentrations were not correlated at any time point. Ex vivo FAAH activity was not inhibited by propofol. Enzyme kinetics (mean +/- SD) of recombinant human FAAH were K(m) = 16.9 +/- 8.8 umol l(-1) and V(max) = 44.6 +/- 15.8 nmol mg(-1) min(-1) FAAH without, and K(m) = 16.6 +/- 4.0 umol l(-1) and V(max) = 44.0 +/- 7.6 nmol mg( 1 ) min(-1) FAAH with 50 umol l(-1) propofol (P= NS for both). CONCLUSIONS: Our findings challenge the idea that propofol anaesthesia and also propofol addiction are directly mediated by FAAH inhibition, but we cannot exclude other indirect actions on cannabinoid receptors. PMID- 22242693 TI - Comparison of implant-abutment interface misfits after casting and soldering procedures. AB - The aim of this study was to compare vertical and horizontal adjustments of castable abutments after conducting casting and soldering procedures. Twelve external hexagonal implants (3.75 * 10 mm) and their UCLA abutments were divided according their manufacturer and abutment type: PUN (plastic UCLA, Neodent), PUC (plastic UCLA, Conexao), PU3i (plastic UCLA, Biomet 3i), and PUTN (plastic UCLA with Tilite milled base, Neodent). Three infrastructures of a fixed partial implant-supported bridge with 3 elements were produced for each group. The measurements of vertical (VM) and horizontal (HM) misfits were obtained via scanning electron microscopy after completion of casting and soldering. The corresponding values were determined to be biomechanically acceptable to the system, and the results were rated as a percentage. Statistical analysis establishes differences between groups by chi-square after procedures, and McNeman's test was applied to analyze the influence of soldering over casting (alpha <= .05). For the values of VM and HM, respectively, when the casting process was complete, it was observed that 83.25% and 100% (PUTN), 33.3% and 27.75% (PUN), 33.3% and 88.8% (PUC), 33.3% and 94.35% (PU3i) represented acceptable values. After completing the requisite soldering, acceptable values were 50% and 94.35% (PUTN), 16.6% and 77.7% (PUN), 38.55% and 77.7% (PUC), and 27.75% and 94.35% (PU3i). Within the limitations of this study, it can be concluded that the premachined abutments presented more acceptable VM values. The HM values were within acceptable limits before and after the soldering procedure for most groups. Further, the soldering procedure resulted in an increase of VM in all groups. PMID- 22242694 TI - Effect of growth promotants on the occurrence of endogenous and synthetic steroid hormones on feedlot soils and in runoff from beef cattle feeding operations. AB - Supplements and growth promotants containing steroid hormones are routinely administered to beef cattle to improve feeding efficiency, reduce behavioral problems, and enhance production. As a result, beef cattle manure will contain both synthetic steroids as well as a range of endogenous steroids including androgens, estrogens, and progestogens. A two-year controlled study was conducted in which beef cattle were administered steroid hormones via subcutaneous implants and feed additives and the occurrence of 16 endogenous and synthetic steroid hormones and metabolites was evaluated in runoff from beef cattle feedlots and in manure and soil collected from feedlot surfaces. Samples were extracted and analyzed using liquid chromatography tandem mass spectrometryfor metabolites of the synthetic androgen trenbolone acetate, 17alpha-trenbolone, 17beta-trenbolone, for the nonsteroidal semisynthetic estrogen agonist, alpha-zearalanol, and the synthetic progesterone melengesterol acetate, as well as a wide range of endogeneous estrogens, androgens, and fusarium metabolites. Synthetic steroids including trenbolone metabolites and melengestrol acetate were detected in fresh manure and in feedlot surface soils from cattle administered synthetic steroids at concentrations up to 55 +/- 22 ng/g dry weight (dw) (17alpha-trenbolone) and 6.5 +/- 0.4 ng/g dw (melengesterol acetate). Melengesterol acetate was detected in 6% of runoff samples from feedlots holding cattle administered synthetic steroids at concentrations ranging up to 115 ng/L. The presence of melengesterol acetate in runoff from beef cattle feeding operations has not been previously reported. Synthetic steroids were not detected in manure or runoff from control cattle. A wide range of endogenous hormones were detected in runoff and feedlot surface soils and manure from cattle given synthetic steroids and from control cattle, with no statistically significant differences in concentration. These results indicate that runoff from confined animal production facilities is of environmental and public health concern regardless of the use of growth promotants. PMID- 22242695 TI - Phospha-Michael additions to activated internal alkenes: steric and electronic effects. AB - The addition of P(O)-H bonds to internal alkenes has been accomplished under solvent-free conditions without the addition of a catalyst or radical initiator. Using a prototypical secondary phosphine oxide, a range of substrates including cinnamates, crotonates, coumarins, sulfones, and chalcones were successfully functionalized. Highly activated acceptors such as isopropylidenemalononitrile and ethyl 2-cyano-3-methyl-2-butenoate underwent the phospha-Michael reaction upon simple trituration of the reagents at room temperature, whereas less activated substrates such as ethyl cinnamate and methyl crotonate required heating (>150 degrees C) in a microwave reactor to achieve significant consumption of the starting alkenes. For the latter alkenes, a competing reaction involving disproportionation of the ditolylphosphine oxide into ditolylphosphinic acid and ditolylphosphine was observed at the high temperatures needed to promote the addition reaction. PMID- 22242696 TI - Allenyl azide cycloaddition chemistry: application to the total synthesis of (+/ )-meloscine. AB - The pentacyclic alkaloid (+/-)-meloscine was prepared in 19 steps through a reaction sequence that features a putative azatrimethylenemethane intermediate, generated through cascade cyclization of an allenyl azide substrate, to deliver the core azabicyclo[3.3.0]octadiene substructure. Subsequent manipulation of the peripheral functionality then delivered (+/-)-meloscine. PMID- 22242697 TI - Characterization of carbon surface chemistry by combined temperature programmed desorption with in situ X-ray photoelectron spectrometry and temperature programmed desorption with mass spectrometry analysis. AB - The analysis of the surface chemistry of carbon materials is of prime importance in numerous applications, but it is still a challenge to identify and quantify the surface functional groups which are present on a given carbon. Temperature programmed desorption with mass spectrometry analysis (TPD-MS) and X-ray photoelectron spectroscopy with an in situ heating device (TPD-XPS) were combined in order to improve the characterization of carbon surface chemistry. TPD-MS analysis allowed the quantitative analysis of the released gases as a function of temperature, while the use of a TPD device inside the XPS setup enabled the determination of the functional groups that remain on the surface at the same temperatures. TPD-MS results were then used to add constraints on the deconvolution of the O1s envelope of the XPS spectra. Furthermore, a better knowledge of the evolution of oxygen functional groups with temperature during a thermal treatment could be obtained. Hence, we show here that the combination of these two methods allows to increase the reliability of the analysis of the surface chemistry of carbon materials. PMID- 22242698 TI - Inflammatory stimuli up-regulate transient receptor potential vanilloid-1 expression in human bronchial fibroblasts. AB - Lung fibroblasts are involved in interstitial lung disease, chronic asthma, and chronic obstructive pulmonary disease (COPD). The expanded fibroblast population in airway disease leads to airway remodeling and contributes to the inflammatory process seen in these diseases. The cation channel transient receptor potential vanilloid-1 (TRPV1) is activated by noxious stimuli, including capsaicin, protons, and high temperatures and is thought to have a role in inflammation. Although TRPV1 expression is primarily reported to be neuronal, some extraneuronal expression has been reported. The authors therefore sought to determine whether human primary bronchial fibroblasts (HPBFs) express TRPV1 and whether inflammatory mediators can induce TRPV1 expression. The authors show that fibroblasts are predominantly TRPV1 negative; however, following stimulation with 3 common inflammatory mediators, tumor necrosis factor alpha (TNF-alpha), lipopolysaccharide (LPS), and interleukin-1alpha (IL-1alpha), TRPV1 mRNA was observed at 24 and 48 hours post treatment with all 3 mediators. Using Western blotting an increase in TRPV1 expression with all 3 inflammatory mediators was detected with significant increases seen at 72 hours post LPS and IL-1alpha treatment. In stark contrast to the untreated fibroblasts, significant calcium signaling in response to capsaicin and resiniferatoxin in HPBFs treated for 24 and 48 hours with TNF-alpha, LPS, or IL-1alpha was also observed. These results indicate that TRPV1 can be expressed on bronchial fibroblasts in situations where an underlying inflammatory stimulus exists, as is the case in airway diseases such as asthma and COPD. PMID- 22242699 TI - Molecular response to ultraviolet radiation exposure in fish embryos: implications for survival and morphological development. AB - UVR exposure is known to cause developmental defects in a variety of organisms including aquatic species but little is known about the underlying molecular mechanisms. In this work we used zebrafish (Danio rerio) embryos as a model system to characterize the UVR effects on fish species. Larval viability was measured for embryos exposed to several UVR spectral treatments by using a solar simulator lamp and an array of UV cutoff filters under controlled conditions in the laboratory. Survival rate and occurrence of development abnormalities, mainly caudal (posterior) notochord bending/torsion, were seriously affected in UV exposed larvae reaching values of 53% and 72%, respectively, compared with non-UV exposed larvae after 6 days postfertilization (dpf). In order to elucidate the molecular mechanisms involved, a matricellular glycoprotein named osteonectin and the expression of a DNA-repair related gene, p53, were studied in relation to UVR exposure. The results indicate that osteonectin and p53 expression were increased under UVR exposure due to wavelengths shorter than 335 nm (i.e. mainly UVB) and 350 nm (i.e. short UVA and UVB), respectively. Furthermore, parallel experiments with microinjections of osteonectin-capped RNA showed that malformations induced by osteonectin overexpression were similar to those observed after a UVR exposure. Consequently this study shows a potential role of osteonectin in morphological deformities induced by solar UV radiation in zebrafish embryos. PMID- 22242701 TI - Effector-independent and effector-dependent sequence representations underlie general and specific perceptuomotor sequence learning. AB - Perceptuomotor sequence learning could be due to learning of effector-independent sequence information (e.g., response locations), effector-dependent information (e.g., motor movements of a particular effector), or both. Evidence also suggests that learning of statistical regularities in sequences (general-regularity learning) and specific sequences (specific-sequence learning) are dissociable. The authors examined the degree to which general and specific-sequence learning rely on effector-independent and effector-dependent representations. During training, participants typed sequences that followed a construction rule with a subset of sequences repeatedly processed. At test, effector-independent and effector-dependent learning was examined with respect to general-regularity and specific-sequence learning. Results suggest that general-regularity learning is subserved by effector-independent sequence representations, whereas specific sequence learning is subserved by effector-dependent sequence representations, further dissociating these types of learning. PMID- 22242702 TI - The new ILAE report on terminology and concepts for the organization of epilepsies: critical review and contribution. AB - This critical review refers to the new report on terminology and concepts for the organization of epilepsies by the Commission of the International League Against Epilepsy (ILAE). It is unfortunate that most of the proposals in the Commission's report are modified interpretations and nomenclature of previous ILAE classifications; new terms are not better than the old ones, and recent advances have not been incorporated. Hence, the new ILAE report met with considerable dissatisfaction from several expert epileptologists. The Commission abandoned (1) the disease-syndrome distinction, although "disease" is generally differentiated from "syndrome" in most medical texts as well as in the ILAE classification itself; (2) the distinction of "generalized" and "focal" for epileptic syndromes, despite maintaining this distinction for epileptic seizures and despite the fact that most epileptic syndromes manifest exclusively either with generalized or focal epileptic seizures; (4) the terms "idiopathic,""symptomatic," and "cryptogenic," although these terms have been well defined in the previous ILAE classifications; reiterating their true meaning would be sufficient. Genetic epilepsy could be a new category and (5) the designation of "benign" epilepsies, despite the recommendations of experts at the Monreale workshop. In addition, the Commission proposed that "age at onset" be used as a primary dimension for organizing the epilepsies. However, (a) this runs counter to classification efforts of other diseases in medicine and neurology; (b) syndromes that are likely to be linked together on the basis of electroclinical (and often genetic) evidence are now separated and intermixed with a number of heterogeneous epilepsies; and (c) a considerable number of epileptic syndromes have a wide range of age at onset from childhood to adulthood. Furthermore, epilepsy syndromes were given by name only, without definition; thus we remain dependent on previous ILAE definitions, which are often broad and imprecise. The ILAE should commission consensus of opinion from experts in specific fields in order to define each syndrome. Areas of certainties and uncertainties and of agreements and disagreements should be identified and explained. This approach may be the only way toward achieving a scientifically sound and clinically meaningful organizational system for the epileptic seizures and the epilepsies-a process that would incorporate the tremendous advances in our field and would be accepted by the wider community of clinicians and scientists. PMID- 22242700 TI - Developing a modified directly observed therapy intervention for hepatitis C treatment in a methadone maintenance program: implications for program replication. AB - BACKGROUND: Hepatitis C virus (HCV) is a prevalent chronic blood-borne infection among opioid-dependent patients on methadone maintenance treatment (MMT). Despite case reports and case-control studies, a randomized controlled trial (RCT) examining HCV treatment adherence in methadone-maintained patients is lacking and was the impetus for this ongoing RCT examining modified directly administered therapy for HCV treatment integrated within a MMT. METHODS: Subjects were randomized 1:1 to receive HCV treatment as modified directly observed therapy (mDOT) into the MMT program or at a liver specialty clinic as self-administered therapy (SAT). Randomization was stratified based on HIV status and HCV genotype. RESULTS: Twenty-one subjects to date have enrolled in this pilot study. The mDOT subjects have had greater success in starting treatment and 10 of the 12 mDOT subjects achieved early virologic response (EVR) at week 12 and 6 of those 10 achieved sustained virologic response (SVR). Of the nine SAT subjects, only three achieved EVR at week 12 and only one achieved SVR despite not completing the treatment. CONCLUSIONS: Hepatitis C treatment can be successfully integrated into a methadone maintenance clinic, and mDOT can be implemented with a methadone clinic's existing nursing and medical staff. Patients struggling with concurrent substance use and mental illness comorbidity may be successfully addressed in such settings and facilitate access to and completion of treatment through the utilization of on-site clinical services for HCV treatment and adherence support with mDOT. The exact importance of site of services and adherence support remains a significant area for future investigation. PMID- 22242704 TI - Hydrophobic drying and hysteresis at different length scales by molecular dynamics simulations. AB - We performed molecular dynamics simulations to investigate hydrophobic interactions between two parallel hydrophobic plates immersed in water. The two plates are separated by a distance D ranging from contact to a few nanometers. To mimic the attractive hydrophobic force measurement in a surface force experiment, a driving spring is used to measure the hydrophobic force between two hydrophobic plates. The force-distance curves, in particular the force variations from spontaneous drying to hydrophobic collapse are obtained. These details are usually not accessible in the surface force measurement due to the unstable jump into contact. The length-scale effect on the hydrophobic drying during normal approach and the hydrophobic hysteresis during retraction has been studied. We find that the critical distance at which a spontaneous drying occurs is determined by the shorter characteristic dimension of the plate, whereas the hydrophobic hysteresis is determined by the longer characteristic dimension of the plate. The variations of the potential of mean force versus separation during approach and retraction are also calculated. The results show that water confined between two parallel hydrophobic plates is in a thermodynamic metastable state. This comparably high energy state leads to the spontaneous drying at some critical distance. PMID- 22242703 TI - An SSR-based linkage map of yardlong bean (Vigna unguiculata (L.) Walp. subsp. unguiculata Sesquipedalis Group) and QTL analysis of pod length. AB - Yardlong bean (Vigna unguiculata (L.) Walp. subsp. unguiculata Sesquipedalis Group) (2n = 2x = 22) is one of the most important vegetable legumes of Asia. The objectives of this study were to develop a genetic linkage map of yardlong bean using SSR makers from related Vigna species and to identify QTLs for pod length. The map was constructed from 226 simple sequence repeat (SSR) markers from cowpea (Vigna unguiculata (L.) Walp. subsp. unguiculata Unguiculata Group), azuki bean (Vigna angularis (Willd.) Ohwi & Ohashi), and mungbean (Vigna radiata (L.) Wilczek) in a BC(1)F(1) ((JP81610 * TVnu457) * JP81610) population derived from the cross between yardlong bean accession JP81610 and wild cowpea (Vigna unguiculata subsp. unguiculata var. spontanea) accession TVnu457. The markers were clustered into 11 linkage groups (LGs) spanning 852.4 cM in total length with a mean distance between adjacent markers of 3.96 cM. All markers on LG11 showed segregation distortion towards the homozygous yardlong bean JP81610 genotype. The markers on LG11 were also distorted in the rice bean (Vigna umbellata (Thunb.) Ohwi & Ohashi) map, suggesting the presence of common segregation distortion factors in Vigna species on this LG. One major and six minor QTLs were identified for pod length variation between yardlong bean and wild cowpea. Using flanking markers, six of the seven QTLs were confirmed in an F(2) population of JP81610 * TVnu457. The molecular linkage map developed and markers linked to pod length QTLs would be potentially useful for yardlong bean and cowpea breeding. PMID- 22242705 TI - Stability of technetium and decontamination from ruthenium and molybdenum in determination of 99Tc in environmental solid samples by ICPMS. AB - A rapid and efficient method for the determination of (99)Tc in environmental solid samples was developed using chromatographic separation combined with inductively coupled plasma mass spectrometry (ICPMS) measurement. The volatility of technetium during sample ashing and solution evaporation was investigated to establish a reliable sample pretreatment procedure. A novel approach was developed to improve the removal of molybdenum and ruthenium in chromatographic separation using 30% H(2)O(2) pretreatment of the loading solution and extraction chromatographic separation using two serial small TEVA columns. The decontamination factors of more than 4 * 10(4) and 1 * 10(5) are achieved for molybdenum and ruthenium, respectively. Chemical yields of technetium in entire procedure range from 60% to 95% depending on the type and amount of samples, and the detection limit of 0.15 mBq/g for (99)Tc was obtained. The method has been successfully applied for the determination of (99)Tc in environmental solid samples. PMID- 22242707 TI - Minimum quality criteria are needed in the assessment and communication of unexpected drug safety findings of marketed products from randomized controlled trials. PMID- 22242708 TI - Effects of rosuvastatin on serum asymmetric dimethylarginine levels and atrial structural remodeling in atrial fibrillation dogs. AB - BACKGROUND: Circulating asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is increased in atrial fibrillation (AF). The purpose of this study was to investigate the effects of rosuvastatin on serum ADMA levels and atrial structural remodeling in AF dogs induced by chronic rapid atrial pacing. METHODS: Twenty dogs were randomly divided into the sham-operated (n=6), control (n=7), or rosuvastatin (n=7) groups. Sustained AF was induced by rapid pacing of the right atrium at 400 beats per minute for 6 weeks. Rosuvastatin was administered orally (1 mg/kg d) for 3 days before rapid pacing and was continued for 6 weeks. Transthoracic and transesophageal echocardiography were performed to detect left atrial structure and function. Serum levels of nitric oxide and ADMA were measured. Interstitial fibrosis and cardiomyocyte apoptosis in the atria were also identified. RESULTS: After 6 weeks, compared with the control group, dramatic smaller left atrium and left atrial appendage volumes and higher atrial contractile function were observed in the rosuvastatin group. Serum nitric oxide concentration was increased, whereas ADMA was decreased in the rosuvastatin group compared with the control group. The percentages of interstitial fibrosis and atrial apoptosis in the control group were significantly higher than those in the sham-operated group, and rosuvastatin attenuated these changes induced by atrial rapid pacing. CONCLUSION: A short course of rosuvastatin treatment decreased apoptosis and prevented atrial structural remodeling in association with a decrease in ADMA levels in AF dogs. PMID- 22242710 TI - Methylselenocysteine treatment leads to diselenide formation in human cancer cells: evidence from X-ray absorption spectroscopy studies. AB - The selenoamino acids methylselenocysteine (MeSeCys) and selenomethionine (SeMet) have disparate efficacies as anticancer agents. Herein, we use X-ray absorption spectroscopy to determine the chemical form of selenium in human neuroblastoma cells. Cells treated with MeSeCys contain a significant diselenide component, which is absent from SeMet-treated cells and suggests that metabolites of MeSeCys are capable of altering the redox status of the cells. The differences in the speciation of Se in the selenoamino acid-treated cells may provide insight into the differing anticancer activities of MeSeCys and SeMet. PMID- 22242711 TI - Sensitive luminometric method for protein quantification in bacterial cell lysate based on particle adsorption and dissociation of chelated europium. AB - A sensitive and rapid assay for the quantification of proteins, based on sample protein adsorption to Eu(3+)-chelate-labeled nanoparticles, was developed. The lanthanide ion of the surface-conjugated Eu(3+) chelate is dissociated at a low pH, decreasing the luminescence signal. The increased concentration of the sample protein prevents dissociation of the chelate, leading to a high luminescence signal due to the nanoparticle-bound protein. The assay sensitivity for the quantification of proteins was 130 pg for bovine serum albumin (BSA), which is an improvement of nearly 100-fold from the most sensitive commercial methods. The average coefficient of variation for the assay of BSA was 8%. The protein-to protein variability was sufficiently low; the signal values varied within a 28% coefficient of variation for nine different proteins. The developed method is relatively insensitive to the presence of contaminants, such as nonionic detergents commonly found in biological samples. The existing methods tested for the total protein quantification failed to measure protein concentration in the presence of bacterial cell lysate. The developed method quantified protein also in samples containing insoluble cell components reducing the need for additional centrifugal assay steps and making the concept highly attractive for routine laboratory work. PMID- 22242712 TI - Topical photodynamic therapy significantly reduces epidermal Langerhans cells during clinical treatment of basal cell carcinoma. AB - BACKGROUND: Topical photodynamic therapy (PDT) is a widely applied treatment for basal cell carcinoma (BCC). PDT-induced immunosuppression leading to reduced antitumour immune responses may be a factor in treatment failure. OBJECTIVES: To examine the impact of topical PDT on leucocyte trafficking following clinical treatment of BCC. METHODS: Superficial BCCs in eight white caucasian patients were treated with methyl aminolaevulinate (MAL)-PDT. Biopsies for immunohistochemical assessment were taken from BCCs pre-PDT, 1 h and 24 h post PDT and from untreated healthy skin. RESULTS: Treatment of BCC with MAL-PDT produced a rapid neutrophil infiltration, commencing by 1 h and significantly increased at 24 h post-PDT (P < 0.05 compared with baseline). An associated increase in the number of blood vessels expressing E-selectin was observed at 1 h and 24 h post-PDT (both P < 0.05 compared with baseline). In contrast, the number of epidermal Langerhans cells fell sharply by 1 h post-PDT, and remained significantly reduced at 24 h post-PDT (both P < 0.05 compared with baseline). CONCLUSIONS: Reduction of Langerhans cells during clinical treatment of BCC might potentially impact negatively on antitumour responses through reduced activation of tumour-specific effector cells. Investigation of modified PDT protocols with the aim to minimize immunosuppressive effects while maintaining antitumour efficacy is warranted. PMID- 22242713 TI - DNA-programmed modular assembly of cyclic and linear nanoarrays for the synthesis of two-dimensional conducting polymers. AB - Nanometer-scale arrays of conducting polymers were prepared on scaffolds of self assembling DNA modules. A series of DNA oligomers was prepared, each containing six 2,5-bis(2-thienyl)pyrrole (SNS) monomer units linked covalently to N4 atoms of alternating cytosines placed between leading and trailing 12-nucleobase recognition sequences. These DNA modules were encoded so the recognition sequences would uniquely associate through Watson-Crick assembly to form closed cycle or linear arrays of aligned SNS monomers. The melting behavior and electrophoretic migration of these assemblies showed cooperative formation of multicomponent arrays containing two to five DNA modules (i.e., 12-30 SNS monomers). The treatment of these arrays with horseradish peroxidase and H(2)O(2) resulted in oxidative polymerization of the SNS monomers with concomitant ligation of the DNA modules. The resulting cyclic and linear arrays exhibited chemical and optical properties typical of conducting thiophene-like polymers, with a red-end absorption beyond 1250 nm. AFM images of the cyclic array containing 18 SNS units revealed highly regular 10 nm diameter objects. PMID- 22242714 TI - A molecular peptide beacon for the ratiometric sensing of nucleic acids. AB - A pyrene-functionalized cationic oligopeptide 1 efficiently binds to double stranded DNA, as shown by different spectrophotochemical studies. Upon binding, the conformation of 1 changes from a folded to an extended form, which leads to a distinct change in the fluorescence properties. Thus, 1 functions as a molecular peptide beacon, and as it is easily taken up by cells, 1 can also be used for imaging of nucleic acids within cells. PMID- 22242715 TI - Confronting myths: the Native American experience in an academic inpatient palliative care consultation program. AB - BACKGROUND: Recent end-of-life (EOL) care literature in non-Native American (NA) populations has demonstrated the benefits of EOL discussions. EOL discussions are associated with less aggressive care at EOL, better patient self-assessed quality of life, and less caregiver depression after the patient is deceased. There is no literature assessing these issues in NA populations. However, common myths that may affect care include: 1) NA patients will not discuss death and dying, 2) severely ill NA patients and families will not choose do not resuscitate (DNR) status, and 3) NA patients and families will not utilize hospice services if offered. METHODS: Our study explored these issues utilizing a consultation database from the Palliative Care Consultation Service at University of New Mexico Hospital (UNMH). Statistical analyses were conducted using nonparametric Wilcoxon tests for continuous variables and Fisher's exact test for categorical variables. RESULTS AND CONCLUSION: Study results demonstrate that health care providers can hold EOL care discussions with NA patients and NA patients' care preferences are affected by these discussions. The result do not support our hypothesis that there would be a lower rate of post-consult DNR status in NA patients (compared with non-NA). NA and non-NA patients and families participated in family meetings and their code status was affected to a similar degree. Furthermore, NA patients and their families choose hospice services at rates similar to non-NA patients seen by the palliative care consultation service. PMID- 22242716 TI - Discussing religion and spirituality is an advanced communication skill: an exploratory structural equation model of physician trainee self-ratings. AB - BACKGROUND: Communication about religious and spiritual issues is fundamental to palliative care, yet little empirical data exist to guide curricula in this area. The goal of this study was to develop an improved understanding of physicians' perspectives on their communication competence about religious and spiritual issues. METHODS: We examined surveys of physician trainees (n=297) enrolled in an ongoing communication skills study at two medical centers in the northwestern and southeastern United States. Our primary outcome was self-assessed competence in discussing religion and spirituality. We used exploratory structural equation modeling (SEM) to develop measurement and full models for acquisition of self assessed communication competencies. RESULTS: Our measurement SEM identified two latent constructs that we label Basic and Intermediate Competence, composed of five self-assessed communication skills. The Basic Competence construct included overall satisfaction with palliative care skills and with discussing do not resuscitate (DNR) status. The Intermediate Competence construct included responding to inappropriate treatment requests, maintaining hope, and addressing fears about the end-of-life. Our full SEM model found that Basic Competence predicted Intermediate Competence and that Intermediate Competence predicted competence in religious and spiritual discussions. Years of clinical training directly influenced Basic Competence. Increased end-of-life discussions positively influenced Basic Competence and had a complex association with Intermediate Competence. Southeastern trainees perceived more competence in religious and spiritual discussions than northwestern trainees. CONCLUSION: This study suggests that discussion of religious and spiritual issues is a communication skill that trainees consider more advanced than other commonly taught communication skills, such as discussing DNR orders. PMID- 22242720 TI - A synthetic recursive "+1" pathway for carbon chain elongation. AB - Nature uses four methods of carbon chain elongation for the production of 2 ketoacids, fatty acids, polyketides, and isoprenoids. Using a combination of quantum mechanical (QM) modeling, protein-substrate modeling, and protein and metabolic engineering, we have engineered the enzymes involved in leucine biosynthesis for use as a synthetic "+1" recursive metabolic pathway to extend the carbon chain of 2-ketoacids. This modified pathway preferentially selects longer-chain substrates for catalysis, as compared to the non-recursive natural pathway, and can recursively catalyze five elongation cycles to synthesize bulk chemicals, such as 1-heptanol, 1-octanol, and phenylpropanol directly from glucose. The "+1" chemistry is a valuable metabolic tool in addition to the "+5" chemistry and "+2" chemistry for the biosynthesis of isoprenoids, fatty acids, or polyketides. PMID- 22242721 TI - Antiplatelet therapy for prevention of thromboembolic complications associated with coil embolization of unruptured cerebral aneurysms. AB - BACKGROUND: Antiplatelet agents are used during endovascular treatment of cerebral aneurysms to prevent thromboembolic complications. OBJECTIVE: The aim of this study was to investigate the efficacy of clopidogrel for the prevention of thromboembolic complications during elective coil embolization of unruptured cerebral aneurysms. METHODS: Sixty-three patients prospectively received oral clopidogrel 75 mg/day from 3 days before and for 1 day after the procedure at our institute (Kohnan Hospital, Sendai, Japan) during 2007. RESULTS: At 24 hours post coiling, significantly less high-intensity areas, detected by MRI with diffusion weighted imaging (MRI-DWI), were observed in clopidogrel-treated patients compared with a historical control cohort of aspirin (acetylsalicylic acid) treated patients (13/63 [20.6%] vs 27/69 [39.1%]; p = 0.02), primarily due to a statistically significantly lower rate during repair of small (<10 mm) lesions (p = 0.008). Also, the rate of periprocedural thromboembolic events was lower in the clopidogrel than the aspirin cohort (2/63 [3.2%] vs 5/69 [7.2%]; p = 0.3). CONCLUSIONS: Clopidogrel was generally well tolerated with no signs of hemorrhagic complications or liver dysfunction. PMID- 22242722 TI - Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs. AB - The world faces complex challenges for chemical hazard assessment. Microfluidic bioartificial organs enable the spatial and temporal control of cell growth and biochemistry, critical for organ-specific metabolic functions and particularly relevant to testing the metabolic dose-response signatures associated with both pharmaceutical and environmental toxicity. Here we present an approach combining a microfluidic system with (1)H NMR-based metabolomic footprinting, as a high throughput small-molecule screening approach. We characterized the toxicity of several molecules: ammonia (NH(3)), an environmental pollutant leading to metabolic acidosis and liver and kidney toxicity; dimethylsulfoxide (DMSO), a free radical-scavenging solvent; and N-acetyl-para-aminophenol (APAP, or paracetamol), a hepatotoxic analgesic drug. We report organ-specific NH(3) dose dependent metabolic responses in several microfluidic bioartificial organs (liver, kidney, and cocultures), as well as predictive (99% accuracy for NH(3) and 94% for APAP) compound-specific signatures. Our integration of microtechnology, cell culture in microfluidic biochips, and metabolic profiling opens the development of so-called "metabolomics-on-a-chip" assays in pharmaceutical and environmental toxicology. PMID- 22242723 TI - Diamond-blackfan anemia and isolated cleft palate. PMID- 22242724 TI - Clobazam for treatment of epilepsy. AB - INTRODUCTION: The landscape of antiepileptic drugs is constantly evolving with new compounds being released onto the market on a regular basis. Most new agents are, at least initially, approved for use as adjunctive treatment of localization related (focal) epilepsy, and only rarely are new medications released for other types of epilepsy. Though it has been in use in other countries, clobazam is now approved for use in the USA, and specifically in the treatment of Lennox-Gastaut syndrome, a type of (symptomatic or cryptogenic) generalized epilepsy. AREAS COVERED: This paper discusses the pharmacology of clobazam as well as the definition and nosologic boundaries of Lennox-Gastaut Syndrome. General (adult) neurologists are under the erroneous impression that Lennox-Gastaut syndrome is limited to childhood, and this common misconception indicates a lack of understanding of the group of generalized epilepsies. With this paper, readers will gain a better understanding of the limits of Lennox-Gastaut syndrome and how it evolves with age and what clobazam can contribute to its treatment. EXPERT OPINION: Clobazam offers a new treatment option for patients with refractory epilepsy. It has been found to be a safe, well-tolerated adjunctive antiepileptic medication that has had long-standing international experience in thousands of patients. It is unlikely that clobazam will change treatment strategies radically; nonetheless additional options are always welcome as individual patients can respond to different regimens. Physicians should be comfortable prescribing clobazam because it is a benzodiazepine and has been used extensively outside of the USA. PMID- 22242725 TI - Managing the combination of non-alcoholic fatty liver disease and metabolic syndrome. PMID- 22242728 TI - Progress in time-dependent density-functional theory. AB - The classic density-functional theory (DFT) formalism introduced by Hohenberg, Kohn, and Sham in the mid-1960s is based on the idea that the complicated N electron wave function can be replaced with the mathematically simpler 1-electron charge density in electronic structure calculations of the ground stationary state. As such, ordinary DFT cannot treat time-dependent (TD) problems nor describe excited electronic states. In 1984, Runge and Gross proved a theorem making TD-DFT formally exact. Information about electronic excited states may be obtained from this theory through the linear response (LR) theory formalism. Beginning in the mid-1990s, LR-TD-DFT became increasingly popular for calculating absorption and other spectra of medium- and large-sized molecules. Its ease of use and relatively good accuracy has now brought LR-TD-DFT to the forefront for this type of application. As the number and the diversity of applications of TD DFT have grown, so too has our understanding of the strengths and weaknesses of the approximate functionals commonly used for TD-DFT. The objective of this article is to continue where a previous review of TD-DFT in Volume 55 of the Annual Review of Physical Chemistry left off and highlight some of the problems and solutions from the point of view of applied physical chemistry. Because doubly-excited states have a particularly important role to play in bond dissociation and formation in both thermal and photochemistry, particular emphasis is placed on the problem of going beyond or around the TD-DFT adiabatic approximation, which limits TD-DFT calculations to nominally singly-excited states. PMID- 22242727 TI - Asymmetrical neural adaptation in lower leg muscles as a consequence of stereotypical motor training. AB - Despite well-authorized facts regarding asymmetrical architectural changes between different limbs after persistent participation in particular motor training, no studies have addressed the neural aspects to the present. The authors undertook the study to elucidate the possibility of neural adaptation on a limb-by-limb basis after repetitive engagement in a particular motor training routine. We investigated lower leg muscles in endurance-trained track runners who have been trained by routinely running on a track in counterclockwise direction on curved paths. Stretch reflex responses in the plantarflexor muscles (soleus [SOL], medial [MG], and lateral head of the gastrocnemius muscle) were evaluated bilaterally with participants sitting at rest. Comparisons were made between homonymous muscles of the right (corresponding to outside leg for track running) and left leg (inside leg, likewise) and with a group of nontrained controls. The result clearly demonstrated that the responses were prominently different between the legs (thus, asymmetrical) in the MG muscles and partially in the SOL muscles in the trained group. In contrast, no such differences were obtained in the nontrained control group. The result demonstrated that neural adaptation took place asymmetrically and that could be attributable to their repetitive engagement in the stereotypical motor task. PMID- 22242729 TI - Model catalysts: simulating the complexities of heterogeneous catalysts. AB - Surface-science investigations have contributed significantly to heterogeneous catalysis in the past several decades. Fundamental studies of reactive systems on metal single crystals have aided researchers in understanding the effect of surface structure on catalyst reactivity and selectivity for a number of important reactions. Recently, model systems, consisting of metal clusters deposited on planar oxide surfaces, have facilitated the study of metal particle size and support effects. These model systems not only are useful for carrying out kinetic investigations, but are also amenable to surface spectroscopic techniques, thus enabling investigations under realistic pressures and at working temperatures. By combining surface-science characterization methods with kinetic measurements under realistic working conditions, researchers are continuing to advance the molecular-level understanding of heterogeneous catalysis and are narrowing the pressure and material gap between model and real-world catalysts. PMID- 22242730 TI - Visualizing cell architecture and molecular location using soft x-ray tomography and correlated cryo-light microscopy. AB - Living cells are structured to create a range of microenvironments that support specific chemical reactions and processes. Understanding how cells function therefore requires detailed knowledge of both the subcellular architecture and the location of specific molecules within this framework. Here we review the development of two correlated cellular imaging techniques that fulfill this need. Cells are first imaged using cryogenic fluorescence microscopy to determine the location of molecules of interest that have been labeled with fluorescent tags. The same specimen is then imaged using soft X-ray tomography to generate a high contrast, 3D reconstruction of the cells. Data from the two modalities are then combined to produce a composite, information-rich view of the cell. This correlated imaging approach can be applied across the spectrum of problems encountered in cell biology, from basic research to biotechnological and biomedical applications such as the optimization of biofuels and the development of new pharmaceuticals. PMID- 22242732 TI - How good are we at diagnosing seizures based on semiology? AB - The accuracy of visual diagnosis of seizures based on semiologic features among different health care professionals is largely unknown. We evaluated the ability of health care professionals to correctly diagnose epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) from a random selection of 10 ES and 10 PNES videos. The 20 videos (without accompanying electroencephalography) were shown only once, in a random mix to different groups of health care professionals. These individuals, blinded to the diagnosis, were asked to classify the seizure as ES or PNES. We used summary receiver operating characteristic (SROC) curves to determine the accuracy for each group. Next we calculated the difference between the area under the curve (AUC) of SROC between neurologists (as the reference) and the other groups of health care professionals. Neurologists achieved significantly higher AUC results compared to other health care professionals. These results indicate a wide range of diagnostic accuracy among different health care professionals and have practical implications for the evaluation of patients with seizure disorders in acute settings. PMID- 22242731 TI - Deterministic assembly of functional nanostructures using nonuniform electric fields. AB - The force induced on anisotropic nanoparticles in a nonuniform electric field can be used to attract, orient, and position the nanoparticles with respect to microelectrodes on a surface. For polarizable nanomaterials, such as nanowires, carbon nanotubes, or graphene sheets suspended in solvent, this dielectrophoretic force results in movement to regions of highest electric field strength. This review discusses the origin of this force, its production by different microelectrode designs, and its use for nanomaterials assembly, with a focus on efforts toward heterogeneous integration with on-chip electronics for single particle characterization and device structures. PMID- 22242733 TI - Acute antioxidant supplementation improves endurance performance in trained athletes. AB - This study examined the acute effects of a single dose of an antioxidant (AO; Lactaway(r) containing pycnogenol) on time to fatigue (TTF). Nine trained cyclists [mean +/- SD age 35 +/- 10 yrs; body mass 71.6 +/- 10.2 kg; VO2 peak 63 +/- 11 ml/kg/min] performed on two separate occasions a continuous protocol of 5 min at 50% of peak power output (PPO), 8 min at 70% of PPO, and then cycled to fatigue at 95% PPO. Four hours prior to the exercise protocol, the subjects consumed the supplement or a placebo (counterbalanced, double blind protocol). Cyclists, on average, rode for 80 s more in the Lactaway trial than they did in the placebo trial. There was considerable evidence (chances >=94.5%) for substantial positive treatment effects for TTF and the other performance-related variables (excluding [BLa] at 95% PPO). Other studies are necessary to confirm these results and identify the mechanisms underlying the observed effects. PMID- 22242734 TI - VO2 response at the onset of heavy exercise is accelerated not by diathermic warming of the thigh muscles but by prior heavy exercise. AB - We investigated whether the elevated muscle temperature induced by the first bout influenced the VO2 response during a second-bout of heavy exercise. The control conditions were two consecutive 6-min leg cycling bouts (work rate: Delta50% between LT and VO2max) separated by a 6-min baseline at 20 W (L1-ex to L2-ex). In the experimental conditions prior to the main bout (H2-ex), the diathermic warming to the front thigh was substituted for the first-bout. The VO2 response for the second bout was significantly accelerated compared with the first bout (mean +/- SD of the tau by monoexponential fitting: L1-ex: 53.8 +/- 11.6, L2-ex: 38.7 +/- 7.9 s, P < 0.05). The diathermic warm-up, however, could not accelerate VO2 response for subsequent supra-LT leg exercise (tau for H2-ex: 52.3 +/- 7.7 s). It was concluded that the facilitation of [VO2 response during supra-LT exercise after prior heavy exercise does not seem to be caused by increased muscle temperature per se and its related factors. PMID- 22242735 TI - The effect of caffeine ingestion on field hockey skill performance following physical fatigue. AB - This study examined the impact of caffeine ingestion on field hockey skill performance following high-intensity fatigue. Thirteen male hockey players (mean age = 21.1 +/- 1.2 years) performed hockey sprint dribble and ball handling tests at rest and after a bout of total body fatigue (90% maximal capacity) following caffeine (5 mg kg(-1)) or placebo ingestion. Sprint dribble times were slower postfatigue compared with rest but were significantly faster postfatigue with caffeine compared with postfatigue with placebo ingestion (P < 0.01). Ball handling scores were higher at rest compared with postfatigue, but scores postfatigue were higher following caffeine than placebo ingestion (P < 0.01). Rating of perceived exhaustion (RPE) was lower (P < 0.01) and readiness to invest physical (P < 0.01) and mental effort (P = 0.01) were significantly higher in the caffeine condition. Caffeine ingestion may therefore be effective in offsetting decrements in skilled performance associated with fatigue. PMID- 22242736 TI - Review of Tai Chi as an effective exercise on falls prevention in elderly. AB - The risk of accidental falls and fall-related injuries increases with age. Regular physical exercises can delay the age-related changes affecting postural balance and reduce the risk of falls. Although Tai Chi (TC) has become a popular exercise among the elderly, does regular TC exercise lead to fewer falls and fall related injuries? Who would receive the most benefit from TC exercise? What style of TC is best for fall risk reductions? What is the minimum amount of TC exercise needed before its positive effect is observed? How does the effect of TC exercise compare to other physical exercises? The goal of this study is to conduct a systematic review of recent literature on TC's effectiveness for reducing fall risks in elders. A summary and analysis is provided for the following variables: targeted subject population, TC curriculum, comparative effect, and outcome measures. PMID- 22242737 TI - Demographic characteristics of 161-km ultramarathon runners. AB - Despite considerable recent growth in ultramarathon running, little is known about the characteristics of the participants. This work documents demographic characteristics of 161-km ultramarathoners. Surveys were completed by 489 of 674 runners entered in two of the largest 161-km ultramarathons in North America in 2009. Respondents had a mean (+/- SD) age of 44.5 +/- 9.8 years (range 20-72 years) and were generally men (80.2%), married (70.1%), had bachelor's (43.6%) or graduate (37.2%) degrees, and used vitamins and/or supplements (75.3%). They reported 2.8 +/- 20.2 days of work or school loss in the previous year from injury or illness. Body mass index (23.4 +/- 2.2 and 20.8 +/- 1.8 kg/m2 for men and women, respectively) was not associated with age. The findings indicate that 161-km ultramarathon participants are largely well-educated, middle-aged, married men who rarely miss work due to illness or injury, generally use vitamins and/or supplements, and maintain appropriate body mass with aging. PMID- 22242738 TI - Sural nerve injury in a footballer related to blunt leg trauma. AB - The sural nerve runs a superficial course in the posterior leg. Reported sural nerve injuries in athletes are very uncommon. This case report highlights the occurrence of numbness to the heel and lateral ankle of a footballer following direct trauma to the posterior calf. This led to a hematoma developing around the sural nerve and the combination of the hematoma and the direct nerve trauma resulted in the sural nerve dysfunction. Full sensation returned in this player's heel and lateral ankle after 2 weeks of rehabilitation. Athletes presenting with numbness to the heel and lateral ankle should be questioned about leg trauma, and sural nerve injury should be added to the list of differential diagnoses. PMID- 22242739 TI - Characterization of pyrogenic black carbon by desorption atmospheric pressure photoionization Fourier transform ion cyclotron resonance mass spectrometry. AB - We present a new method for molecular characterization of intact biochar directly, without sample preparation or pretreatment, on the basis of desorption atmospheric pressure photoionization (DAPPI) coupled to Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Conventional ionization methods (e.g., electrospray or atmospheric pressure photoionization) for characterization of natural organic matter have limited utility for the characterization of chars due to incomplete solubility in common solvents. Therefore, direct ionization techniques that do not require sample dissolution prior to analysis are ideal. Here, we apply DAPPI FTICR mass spectrometry to enable the first molecular characterization of uncharred parent oak biomass and after combustion (250 degrees C) or pyrolysis (400 degrees C). Parent oak is primarily composed of cellulose-, lignin-, and resin-like compounds. Oak combusted at 250 degrees C contains condensed aromatic compounds with low H/C and O/C ratios while retaining compounds with high H/C and O/C ratios. The bimodal distribution of aromatic and aliphatic compounds observed in the combusted oak sample is attributed to incomplete thermal degradation of lignin and hemicellulose. Pyrolyzed oak constituents exhibit lower H/C and O/C ratios: approximately three-quarters of the identified species are aromatic. DAPPI FTICR MS results agree with bulk elemental composition as well as functional group distributions determined by elemental analysis and solid state (13)C NMR spectroscopy. Complete molecular characterization of biomass upon thermal transformation may provide insight into the biogeochemical cycles of biochar and future renewable energy sources, particularly for samples currently limited by solubility, separation, and sample preparation. PMID- 22242740 TI - Hepatitis C knowledge and alcohol consumption among patients receiving methadone maintenance treatment in Shanghai, China. AB - OBJECTIVE: The aim was to investigate hepatitis C virus (HCV) knowledge and alcohol consumption among patients (n = 114) in a methadone maintenance treatment (MMT) clinic in Shanghai. METHODS: A cross-sectional survey was carried out in an MMT clinic. Structured questionnaires (HCV Knowledge Scale and Alcohol Use Disorders Identification Test (AUDIT)) and some open-ended questions were used to assess (i) HCV knowledge, (ii) HCV treatment received, (iii) awareness of HCV status, and (iv) alcohol consumption. RESULTS: Findings revealed the HCV-positive rate was 57.0%. There were significant gaps in knowledge about HCV and HCV treatment received. The group mean score of HCV knowledge was 11.3 out of 20 (SD = 2.1) and the mean score on the AUDIT was 3.2 (SD = 5.4). Most participants (68.4%) reported not knowing their HCV status. Among HCV-positive participants, only 15.3% had received HCV antivirus treatment and 18.4% expressed a need for counseling about HCV infection. CONCLUSIONS: Considering the limited HCV knowledge and low level of HCV treatment received, effective HCV education and intervention strategies should be developed to target patients in China's MMT clinics. Moreover, alcohol screening should also be part of the routine assessments within MMT programs. SCIENTIFIC SIGNIFICANCE: This study reveals the importance of HCV testing and education among drug users in MMT clinics. PMID- 22242741 TI - Use of dicarboxylic acids in type 2 diabetes. AB - Even-number, medium-chain dicarboxylic acids (DAs), naturally occurring in higher plants, are a promising alternative energy substrate. Unlike the homologous fatty acids, DAs are soluble in water as salts. They are beta-oxidized, providing acetyl-CoA and succinyl-CoA, the latter being an intermediate of the tricarboxylic acid cycle. Sebacic acid and dodecanedioic acid, DAs with 10 and 12 carbon atoms respectively, provide 6.6 and 7.2 kcal g-1 each; therefore, their energy density is intermediate between glucose and fatty acids. Dicarboxylic acids have been proved to be safe in both experimental animals and humans, and their use has recently been proposed in diabetes. Studies in animals and humans with type 2 diabetes showed that oral administration of sebacic acid improved glycaemic control, probably by enhancing insulin sensitivity, and reduced hepatic gluconeogenesis and glucose output. Moreover, dodecanedioic acid intake reduced muscle fatigue during exercise in subjects with type 2 diabetes, suggesting an improvement of energy utilization and 'metabolic flexibility'. In this article, we review the natural sources of DAs, their fate in animals and humans and their effect in improving glucose metabolism in type 2 diabetes. PMID- 22242764 TI - Ventricular "oversensing" in a biventricular pacemaker. PMID- 22242765 TI - The human ZIP4 transporter has two distinct binding affinities and mediates transport of multiple transition metals. AB - Zinc is the second most abundant transition metal in the body. Despite the fact that hundreds of biomolecules require zinc for proper function and/or structure, the mechanism of zinc transport into cells is not well-understood. The ZIP (Zrt- and Irt-like proteins; SLC39A) family of proteins acts to increase cytosolic concentrations of zinc. Mutations in one member of the ZIP family of proteins, the human ZIP4 (hZIP4; SLC39A4) protein, can result in the disease acrodermatitis enteropathica (AE). AE is characterized by growth retardation and diarrhea, as well as behavioral and neurological disturbances. While the cellular distribution of hZIP4 protein expression has been elucidated, the cation specificity, kinetic parameters of zinc transport, and residues involved in cation translocation are unresolved questions. Therefore, we have established a high signal-to-noise zinc uptake assay following heterologous expression of hZIP4 in Xenopus laevis oocytes. The results from our experiments have demonstrated that zinc, copper(II), and nickel can be transported by hZIP4 when the cation concentration is in the micromolar range. We have also identified a nanomolar binding affinity where copper(II) and zinc can be transported. In contrast, under these conditions, nickel can bind but is not transported by hZIP4. Finally, labeling of hZIP4 with maleimide or diethylpyrocarbonate indicates that extracellularly accessible histidine, but not cysteine, residues are required, either directly or indirectly, for cation uptake. The results of our experiments identify at least two coordination sites for divalent cations and provide a new framework for investigating the ZIP family of proteins. PMID- 22242766 TI - Polymeric coatings on silver nanoparticles hinder autoaggregation but enhance attachment to uncoated surfaces. AB - The propensity of silver nanoparticles (AgNPs) having two different polymer coatings (poly(vinylpyrrolidone), PVP, or gum arabic, GA) to aggregate, or to deposit to a reference surface (silica), was explored as a basis for differentiating the effect of surface coating on the stability of nanoparticles in aggregation and in deposition. Surface polymeric coatings stabilize nanoparticles against aggregation as shown by either an increased critical coagulation concentration as for PVP-coated AgNPs (AgPVP) or the absence of observable aggregation even at a high ionic strength as for GA-coated AgNPs (AgGA). In experiments of AgNPs deposition in a silica porous medium, dissimilar surfaces favored deposition, such as the case where polymer coatings were present on the AgNPs but were absent on the porous medium. The increased affinity of the AgNPs for the porous medium in this case may be explained by a shifted contact frontier where electrical double layer interaction is weaker. When coating polymers were introduced to the porous medium and allowed to preadsorb to the silica surfaces, the attachment efficiencies for both the AgPVP and AgGA were reduced due to steric and electrosteric stabilization, respectively. The results suggest that polymeric coatings that are usually deemed as stabilizers (as they indeed are in the case of autoaggregation) might not necessarily stabilize nanoparticles against deposition unless the collector surfaces are also coated with polymer. PMID- 22242767 TI - The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. AB - BACKGROUND: There is increased expression of type I interferon (IFN)-regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN-regulated gene expression pointing towards a possible underlying genetic defect. OBJECTIVES: To determine expression levels of five type I IFN-regulated genes that are highly expressed in SLE in the peripheral blood of patients with CLE and to correlate the expression levels with cutaneous disease activity. METHODS: Peripheral blood was obtained from 10 healthy controls and 30 patients with CLE, including eight with concomitant SLE. Total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real-time polymerase chain reaction. Gene expression was normalized to GAPDH, standardized to healthy controls and then summed to calculate an IFN score for each patient. Disease activity was assessed with the Cutaneous Lupus Area and Severity Index (CLASI). RESULTS: Patients with subacute CLE (SCLE) and discoid lupus erythematosus (DLE) had elevated IFN scores compared with healthy controls regardless of concomitant SLE (P < 0.01 with SLE and P < 0.05 without SLE). There was no difference between patients with tumid lupus erythematosus (TLE) and healthy controls. The IFN score correlated with CLASI scores (Spearman's rho = 0.55, P = 0.0017). CONCLUSIONS: Patients with SCLE and DLE have an IFN signature, as seen in SLE. The level of gene expression correlates with cutaneous disease activity. These findings support a shared pathogenesis between SLE and some subtypes of CLE. PMID- 22242769 TI - Efficient anodic and direct phenol-arene C,C cross-coupling: the benign role of water or methanol. AB - C,C cross-coupling reactions for the synthesis of nonsymmetrical biaryls represent one of the most significant transformations in contemporary organic chemistry. A variety of useful synthetic methods have been developed in recent decades, since nonsymmetrical biaryls play an evident role in natural product synthesis, as ligand systems in homogeneous catalysis and materials science. Transformation of simple arenes by direct C,H activation belongs to the cutting edge strategies for creating biaryls; in particular the 2-fold C,H activation is of significant interest. However, in most examples very costly noble metal catalysts, ligand systems, and significant amount of waste-producing oxidants are required. Electrochemical procedures are considered as inherently "green" methods, because only electrons are required and therefore, no reagent waste is produced. Here, we report a metal-free electrochemical method for cross-coupling between phenols and arenes using boron-doped diamond (BDD) anodes in fluorinated media. Our sustainable approach requires no leaving functionalities. Employing water or methanol as mediator represents the key improvement for achieving nonsymmetrical biaryls with superb selectivity and synthetic attractive yields. PMID- 22242771 TI - Single-walled polytetrazolate metal-organic channels with high density of open nitrogen-donor sites and gas uptake. AB - The self-assembly between zinc dimer and 1,3,5-tris(2H-tetrazol-5-yl)benzene (H(3)BTT), promoted by a urea derivative, leads to a highly porous 3D framework with a large percentage (67%) of N-donor sites unused for bonding with metals. The material exhibits high gas storage capacity (ca. 1.89 wt % H(2) at 77 K and 1 atm; 98 cm(3)/g CO(2) at 273 K and 1 atm), even in the absence of open metal sites. The high percentage of open N-donor sites, coupled with the low framework density resulting from single-walled channels, is believed to contribute to the high uptake capacity. PMID- 22242772 TI - Chemoselective intramolecular alkylation of the Blaise reaction intermediates: tandem one-pot synthesis of exo-cyclic enaminoesters and their applications toward the synthesis of N-heterocyclic compounds. AB - The intramolecular alkylative reactivity and N/C selectivity of the various Blaise reaction intermediates, which are formed from the reaction of the Reformatsky reagents with omega-chloroalkyl nitriles, did not reach the synthetic potential as an entry to exo-cyclic enaminoesters. To circumvent this issue, various additives were investigated, among which the addition of NaHMDS dramatically enhanced the reactivity and N/C selectivity. This modification provided a highly efficient route for the synthesis of various N-fused heterocyclic compounds, as it requires only two steps from nitriles. PMID- 22242773 TI - How are the costs of drug-related morbidity measured?: a systematic literature review. AB - BACKGROUND: Drug-related morbidity has been associated with increased healthcare costs and has been suggested as one of the leading causes of death. Previous reviews have identified heterogeneity in research methods in studies measuring the cost of drug-related morbidity. To date, no attempt has been made to analyse different methods and cost sources used when estimating the costs of drug-related morbidity. OBJECTIVE: The aim of this review was to evaluate and compare methods and data sources in cost estimates of drug-related morbidity. METHODS: A literature search was conducted in three electronic databases (CINAHL, EMBASE and MEDLINE) to identify peer-reviewed articles written in English and published between January 1990 and November 2011. Articles were included if estimating the direct or indirect costs of drug-related morbidity based on clinical data from general patient groups. The general patient groups were defined as patients visiting, being admitted to, treated at or discharged from a general hospital, excluding studies from nursing homes or specialized hospitals. Study information was collected using a standardized data collection sheet. Studies were categorized according to the type of costs included in the cost analysis. Thereafter, the cost analyses of included studies were reviewed regarding viewpoint, costing methods and adjustments for timing of costs. RESULTS: In total, 9569 articles were identified, of which 25 publications were included in this review, and four additional articles were identified from reference or citation lists of publications already included. Eighteen studies measured either the total or attributable costs of drug-related morbidity, while seven studies estimated the increased costs using matched controls or regression analyses. Six studies measured costs from a payer perspective, while the other 23 measured costs to the hospital. One study included costs resulting after discharge, and discounted future costs, while the remaining 28 studies measured costs during the initial admission only and involved no adjustment for timing of costs. CONCLUSIONS: The data sources and costs measured in the included studies varied considerably in terms of perspectives and use of data sources. Even though there is a trend towards more studies estimating costs from the payer perspective, the identified studies still focused on costs resulting from patients attending hospital, therefore underestimating the cost of drug-related morbidity. There is thus a need for more research on the costs of drug-related morbidity to providers other than hospitals, and costs occurring outside of hospitals and after the initial care episode. Such studies require clear descriptions of how the costs of drug-related morbidity are measured, and should adhere to published guidelines for observational studies and economic evaluation studies. PMID- 22242776 TI - Benthic bacterial diversity from freshwater tufas of the Iberian Range (Spain). AB - Aiming to characterize the bacterial diversity of modern tufa systems of the Iberian Range (Spain), we surveyed the 16S rRNA gene sequence diversity from 24 sites within three rivers (Anamaza, Mesa and Piedra). These tufas record substantial calcareous growth under different physicochemical conditions and are part of an important, regional landscape-building system. The bacterial community structure and composition, richness and diversity were quantified from denaturing gradient gel electrophoresis fingerprints. Retrieved DNA sequences could be assigned to 10 bacterial phyla and included a variety of phototrophic and heterotrophic groups. Cyanobacteria, mainly filamentous taxa, constituted 43% of all the retrieved sequences, followed by Firmicutes (11%), Gammaproteobacteria (10%), Alphaproteobacteria (7%), Acidobacteria (6%), Bacteroidetes (5%), Betaproteobacteria (4%), Planctomycetes (4%), Actinobacteria (3%) and Deltaproteobacteria (2%). Diatom and Xanthophyceae chloroplast sequences were also detected. Physicochemical variables measured at each site were modelled with multivariate statistics. Principal component analyses yielded the highest variance for salinity-related variables (conductivity; Na(+) , Cl(-) and SO4(2-) concentrations), which correlated negatively and significantly with diversity indices. However, the highest variance explained by individual principal components was relatively low (< 34%). Overall, we show that these young fluvial tufas are inhabited by a large variety of bacteria in diverse and widespread communities. PMID- 22242777 TI - Commitment or disaffection? Framing the forms, meanings, and predictors of youth civic engagement in Italy. PMID- 22242774 TI - Application of living free radical polymerization for nucleic acid delivery. AB - Therapeutic gene delivery can alter protein function either through the replacement of nonfunctional genes to restore cellular health or through RNA interference (RNAi) to mask mutated and harmful genes. Researchers have investigated a range of nucleic acid-based therapeutics as potential treatments for hereditary, acquired, and infectious diseases. Candidate drugs include plasmids that induce gene expression and small, interfering RNAs (siRNAs) that silence target genes. Because of their self-assembly with nucleic acids into virus-sized nanoparticles and high transfection efficiency in vitro, cationic polymers have been extensively studied for nucleic acid delivery applications, but toxicity and particle stability have limited the clinical applications of these systems. The advent of living free radical polymerization has improved the quality, control, and reproducibility of these synthesized materials. This process yields well-defined, narrowly disperse materials with designed architectures and molecular weights. As a result, researchers can study the effects of polymer architecture and molecular weight on transfection efficiency and cytotoxicity, which will improve the design of next-generation vectors. In this Account, we review findings from structure-function studies that have elucidated key design motifs necessary for the development of effective nucleic acid vectors. Researchers have used robust methods such as atom transfer radical polymerization (ATRP), reverse addition-fragmentation chain transfer polymerization (RAFT), and ring-opening metastasis polymerization (ROMP) to engineer materials that enhance extracellular stability and cellular specificity and decrease toxicity. In addition, we discuss polymers that are biodegradable, form supramolecular structures, target specific cells, or facilitate endosomal release. Finally, we describe promising materials with a range of in vivo applications from pulmonary gene delivery to DNA vaccines. PMID- 22242778 TI - The mediational role of values in linking personality traits to civic engagement in Italian youth. AB - In recent decades, given new forms of political participation, the involvement of young people in the civic domain begins to be a focus of many studies. The present study examined the role of personality traits and personal values in the prediction of civic engagement (CE) in Italian youth ranging in age from 19 to 29 years old involved in an ongoing longitudinal study. The multidimensionality of a scale tapping CE has been demonstrated with the examination of confirmatory factor analysis. Structural equation modeling corroborated a mediational model in which benevolence fully mediated the relationship of the traits of agreeableness and openness with civic associationism, whereas power fully mediated the relationship of the traits of agreeableness and openness with political associationism. In this mediational model men reported higher levels of power than women, whereas women reported higher levels of agreeableness and openness traits. Since basic personal traits have been identified as the root of any behavioral tendency and values have been recognized as the more flexible and changeable variables, future interventions aimed to foster CE in youth could be designed considering the strength relationship between the examined dimensions in the present study. PMID- 22242779 TI - A cross-cultural examination of adolescent civic engagement: comparing Italian and American community-oriented and political involvement. AB - The purpose of this study was to investigate community-oriented and political civic engagement activities and intentions among youth in Italy and the United States. Adolescents (N = 566) from academically rigorous schools in both countries completed surveys assessing frequency of civic activity participation, motivation for activity, evaluations of activity, and intentions for future civic engagement. Results suggest that youth in both countries were more likely to participate in community-oriented than political civic activities and that youth in both countries found their civic experiences to be meaningful. American youth reported more past civic activities of both types and higher intentions for future community-oriented civic engagement compared to Italian youth. Finally, a model was tested to examine links between peer and school contexts and civic activities and intentions. Findings highlighted that, in both countries, peer and school contexts had a stronger impact on community-oriented than on political civic activity. PMID- 22242780 TI - Family functioning's contributions to values and group participation in Italian late adolescents: a longitudinal study. AB - This longitudinal study aimed to investigate the contributions of family functioning (in terms of support and control) to the development of civic engagement in term of personal values (i.e., values related to health, school, religion, and disapproval of deviance) as well as participation in groups that pursue cultural, religious-volunteer, and sport goals. The study controlled for sociodemographic factors, such as parental level of education and integrity of the family. Two waves of data were collected among 175 Italian late adolescents at a one-year interval. Hierarchical regression analyses showed that the average level of parental support positively related to both health value and religion value; increased parental control positively related to health value and disapproval of deviance; and average levels of both parental support and control positively related to religious-volunteer group. However, increased parental support negatively related to participation in a cultural group. The discussion focused on the important role of the family in current Italian society for youth socialization in regard to civic engagement. PMID- 22242781 TI - Young adults and civic behavior: the psychosocial variables determining it. AB - The present work has a two-fold aim: (a) to verify the difference in civic behavior enacted by socially engaged young people in a lasting and structured form, sealed by membership in an organization, on the one hand, and in non engaged young people, on the other hand; (b) to identify a pattern of characteristics (personal, social, and familial) able to explain civic behavior. Participants, 577 young adults from ages 19 to 29, filled out a self-report questionnaire. The results of the t test for independent samples confirm the presence of the difference between means of scores on the civic behavior. Moreover, data confirm a model in which civic behavior is predicted by personal identity, engagement values, family discussion of current events, the quality of previous membership experiences in socially oriented groups (membership), and finally, in a mediator position, by sense of community. The present study has many implications for researchers and practitioners. PMID- 22242782 TI - "Volunteering by chance" to promote civic responsibility and civic engagement: does it work? AB - This study investigated the effectiveness of a program to promote civic responsibility and prevent antisocial behavior in a sample of Italian adolescents. Participants were 83 Italian male adolescents, attending the second year of high school (Mean age = 15.79; SD = 0.87). In order to test the efficacy of different strategies (in-classroom training and service activity in a voluntary organization) we divided students into two experimental groups--one classroom of students participated in both strategies (training + volunteering group) and another classroom only participated in the training (training only group)--and one control group. Process and efficacy evaluations were completed. Data were collected before and following the intervention. The process evaluation revealed that the program was highly accepted and appreciated by students. The efficacy evaluation revealed no intervention effects on civic responsibility. However, the training + volunteering group reported a significant decrease in antisocial behavior after the program. Thus, the program was effective in preventing antisocial behavior but not in promoting civic responsibility in our sample. PMID- 22242783 TI - Differences between men and women with a dismissing attachment style regarding their attitudes and behaviour in romantic relationships. AB - Research to date has revealed that the association between gender, attachment and the quality and functioning of intimate relationships is complex. This study examined the relationship between gender and attachment styles in attitudes to communication with one's partner and in the number of past relationships in a sample of 746 Spanish undergraduates. The Relationship Questionnaire was administered to them to determine the adult attachment style. The results revealed the existence of differences according to the adult attachment style and gender with regard to the two measured variables, and a significant effect of the interaction between gender and attachment. Dismissing men reported the highest average scores in the number of past relationships, with significant differences appearing when they were compared with secure and preoccupied men. However, dismissing women did not differ from the rest of the women with other attachment styles. When men and women with the same attachment styles were compared in this variable, the only significant differences were found between dismissing men and women (with the latter reporting fewer partners). In the case of attitudes to expressing feelings to one's partner, dismissing men reported the most negative attitudes, compared with secure and preoccupied men. Dismissing women, unlike the men, did not differ in their attitudes either from preoccupied or fearful women. Moreover, clear differences were shown between dismissing men and women in these attitudes (more negative in the case of men). PMID- 22242784 TI - Effect of different fertilizers on nitrogen isotope composition and nitrate content of Brassica campestris. AB - The effect of different fertilizers on the delta(15)N value, nitrate concentration, and nitrate reductase activity of Brassica campestris and the delta(15)N value of soil has been investigated through a pot experiment. The delta(15)N mean value of B. campestris at the seedling stage observed in the composted chicken treatment (+8.650/00) was higher than that of chemical fertilizer treatment (+5.730/00), compost-chemical fertilizer (+7.530/00), and control check treatment (+7.860/00). There were significantly different delta(15)N values (p < 0.05) between B. campestris cultivated with composted chicken manure treatment and with chemical fertilizer treatment. The similar results were also found at the middle stage and the terminal stage. The variation of delta(15)N value in soil for different treatments was smaller than that of B. campestris, which was +6.71-+8.120/00, +6.83-+8.240/00, and +6.85-8.40/00, respectively, at seedling stage, middle stage, and terminal stage. With the growth of B. campestris, the nitrate content decreased in all treatments, and the nitrate reductase activity in B. campestris increased except for the CK. Results suggested that the delta(15)N values of B. campestris and soil were more effected by the fertilizer than by the dose level, and the delta(15)N value analysis could be used as a tool to discriminate the B. campestris cultivated with composted manure or chemical fertilizer. PMID- 22242785 TI - Video game genre as a predictor of problem use. AB - This study assessed how problem video game playing (PVP) varies with game type, or "genre," among adult video gamers. Participants (n=3,380) were adults (18+) who reported playing video games for 1 hour or more during the past week and completed a nationally representative online survey. The survey asked about characteristics of video game use, including titles played in the past year and patterns of (problematic) use. Participants self-reported the extent to which characteristics of PVP (e.g., playing longer than intended) described their game play. Five percent of our sample reported moderate to extreme problems. PVP was concentrated among persons who reported playing first-person shooter, action adventure, role-playing, and gambling games most during the past year. The identification of a subset of game types most associated with problem use suggests new directions for research into the specific design elements and reward mechanics of "addictive" video games and those populations at greatest risk of PVP with the ultimate goal of better understanding, preventing, and treating this contemporary mental health problem. PMID- 22242786 TI - Effects of gigapascal level pressure on protein structure and function. AB - Information on very high pressure (VHP) effects on proteins is limited and therefore effects of VHP on chemistry, structure and function of two model proteins in medical use were studied. VHP (8 GPa) application to l-asparaginase (L-ASNase) resulted in faster mobility on clear native gels. VHP induced generation of lower-MW forms of L-ASNase but VHP treatment did not deteriorate asparaginase activity. Electrophoretic patterns in native and denaturing gels were comparable for untreated and pressurized recombinant human growth hormone (rhGH). rhGH function, however, was deteriorated as shown by a bioassay. In L ASNase and rhGH a series of protein modifications and amino acid exchanges (indicating cleavage of covalent bonds) were revealed that may probably lead to functional and conformational changes. The findings have implications in protein chemistry, structure, and function and are useful for designing biotechnological applications of protein products. PMID- 22242788 TI - Spectroscopic, structural, and conformational properties of (Z)-4,4,4-trifluoro-3 (2-hydroxyethylamino)-1-(2-hydroxyphenyl)-2-buten-1-one, C12H12F3NO3: a trifluoromethyl-substituted beta-aminoenone. AB - The (Z)-4,4,4-trifluoro-3-(2-hydroxyethylamino)-1-(2-hydroxyphenyl)-2-buten-1-one (C(12)H(12)F(3)NO(3)) compound was thoroughly studied by IR, Raman, UV-visible, and (13)C and (19)F NMR spectroscopies. The solid-state molecular structure was determined by X-ray diffraction methods. It crystallizes in the P2(1)/c space group with a = 12.1420(4) A, b = 7.8210(3) A, c = 13.8970(5) A, beta = 116.162(2) degrees , and Z = 4 molecules per unit cell. The molecule shows a nearly planar molecular skeleton, favored by intramolecular OH...O and NH...O bonds, which are arranged in the lattice as an OH...O bonded polymer coiled around crystallographic 2-fold screw-axes. The three postulated tautomers were evaluated using quantum chemical calculations. The lowest energy tautomer (I) calculated with density functional theory methods agrees with the observed crystal structure. The structural and conformational properties are discussed considering the effect of the intra- and intermolecular hydrogen bond interactions. PMID- 22242787 TI - Acentric 2-D ensembles of D-br-A electron-transfer chromophores via vectorial orientation within amphiphilic n-helix bundle peptides for photovoltaic device applications. AB - We show that simply designed amphiphilic 4-helix bundle peptides can be utilized to vectorially orient a linearly extended donor-bridge-acceptor (D-br-A) electron transfer (ET) chromophore within its core. The bundle's interior is shown to provide a unique solvation environment for the D-br-A assembly not accessible in conventional solvents and thereby control the magnitudes of both light-induced ET and thermal charge recombination rate constants. The amphiphilicity of the bundle's exterior was employed to vectorially orient the peptide-chromophore complex at a liquid-gas interface, and its ends were tailored for subsequent covalent attachment to an inorganic surface, via a "directed assembly" approach. Structural data, combined with evaluation of the excited state dynamics exhibited by these peptide-chromophore complexes, demonstrate that densely packed, acentrically ordered 2-D monolayer ensembles of such complexes at high in-plane chromophore densities approaching 1/200 A(2) offer unique potential as active layers in binary heterojunction photovoltaic devices. PMID- 22242789 TI - The pleasurability of scratching an itch: a psychophysical and topographical assessment. AB - BACKGROUND: Scratching an itch is perceived as being pleasurable. However, an analysis of topographical variations in itch intensity, the effectiveness of scratching to provide itch relief and the associated pleasurability has not been performed at different body sites. OBJECTIVES: To examine the role of scratching pleasurability in providing itch relief by investigating whether itch intensity is perceived differently at three different sites and to assess a potential correlation between the pleasurability and itch attenuation induced by scratching. METHODS: Itch was induced on the forearm, ankle and back using cowhage spicules in 18 healthy subjects. These sites were subsequently scratched by an investigator with a cytology brush immediately following itch induction. The intensity of itch with and without scratching at these sites and the pleasurability of scratching were recorded by taking visual analogue scale ratings at 30-s intervals. RESULTS: Mean itch intensity and scratching pleasurability ratings at the ankle and back were significantly higher than on the forearm. For the forearm and ankle, the greater the itch while scratching, the higher was the pleasurability. A higher baseline itch was linked to a higher itch reduction secondary to scratching in all tested areas. Pleasurability paralleled the curve of itch reduction for the back and forearm; however, scratching pleasurability at the ankle remained elevated and only slightly decreased while itch was diminishing. CONCLUSIONS: There are topographical differences in itch intensity, the effectiveness of scratching in relieving itch and the associated pleasurability. Experimental itch induced by cowhage was more intensely perceived at the ankle, while scratching attenuated itch most effectively on the back. PMID- 22242790 TI - Use of negative dielectrophoresis for selective elution of protein-bound particles. AB - In this paper with the aid of negative dielectrophoresis force in conjunction with shear force and at an optimal sodium hydroxide concentration we demonstrated a switchlike functionality to elute specifically bound beads from the surface. At an optimal flow rate and sodium hydroxide concentration, negative dielectrophoresis turned on results in bead detachment, whereas when negative dielectrophoresis is off, the beads remain attached. This platform offers the potential for performing a bead-based multiplexed assay where in a single channel various regions are immobilized with a different antibody, each targeting a different antigen. To develop the proof of concept and to demonstrate the switchlike functionality in eluting specifically bound beads from the surface we looked at two different protein interactions. We chose interactions that were in the same order of magnitude in strength as typical antibody-antigen interactions. The first was protein G-IgG interaction, and the second was the interaction between anti-IgG and IgG. PMID- 22242791 TI - Occurrence of fipronil and its biologically active derivatives in urban residential runoff. AB - Insecticides are commonly used around homes for controlling insects such as ants, termites, and spiders. Such uses have been linked to pesticide contamination and toxicity in urban aquatic ecosystems. Fipronil is a relatively new and popular urban-use insecticide that has acute toxicity to arthropods at low-ppb levels. In this study, we collected runoff water from 6 large communities, each consisting of 152 to 460 single-family homes, in Sacramento County and Orange County, California, and evaluated the occurrence of fipronil and its biologically active derivatives over 26 months under dry weather conditions. Statistical modeling showed that the levels of fipronil and derivatives in the runoff water were both spatially and temporally correlated. More than 10-fold differences were observed between the Sacramento and Orange County sites, with the much higher levels for Orange County (southern California) coinciding with heavier use. The median concentrations of combined fipronil and derivatives for the Orange County sites were 204-440 ng L(-1), with the 90th percentile levels ranging from 340 to 1170 ng L(-1). These levels frequently exceeded the LC50 values for arthropods such as mysid shrimp and grass shrimp. The highest levels occurred from April to October, while decreases were seen from October to December and from January to March, likely reflecting seasonal use patterns and the effect of rain-induced washoff. Fipronil and fipronil sulfone (oxidation derivative) each accounted for about 35% of the total concentrations, with desulfinyl fipronil (a photolytic product) contributing about 25%. Results of this study clearly established residential drainage as a direct source for pesticide contamination in urban waterways, and for the first time, identified fipronil as a new and widespread contaminant with potential ecotoxicological significance. PMID- 22242792 TI - The substance use among forensic psychiatric patients. AB - OBJECTIVES: The primary goal of this study was to examine the relative differences in the use of illegal substances (i.e., amphetamine, cannabis, opiates) among forensic patients who have committed a violent crime compared with the general population. The aim was also to find out if there were differences in substance use among forensic versus nonforensic patients with psychosis diagnosis. METHODS: The study population consisted of 190 persons, who were involuntarily ordered to hospital treatment as forensic patients in Finland. The information was compared with data from the national hospital discharge register. These results were also compared with national statistics from the general population. RESULTS: Among forensic patients, the lifetime prevalence of cannabis use was 2-fold, amphetamine use 40-fold, and opiate use over 60-fold higher than estimated from the general population in Finland. Cannabis use was 1.5-fold more common than amphetamine use among forensic patients and 1.3-fold more common among nonforensic patients. The prevalences of cannabis-related diagnoses were 4.7- and 3.7-fold more common than opiate use among forensic and nonforensic patients, respectively. CONCLUSIONS: Cannabis, amphetamine, and opiate use are associated with an increased risk of becoming a forensic psychiatric patient, but no substantial differences were observed among patients with psychosis diagnosis in the relative risk increase for cannabis versus amphetamine versus opiate use, indicating that none of these drugs are uniquely associated with violent offending among mentally ill. PMID- 22242793 TI - Medication review and reconciliation with cooperation between pharmacist and general practitioner and the benefit for the patient: a systematic review. AB - This article systematically reviews the literature on the impact of collaboration between pharmacists and general practitioners and describes its effect on patients' health. A systematic literature search provided 1041 articles. After first review of title and abstract, 152 articles remained. After review of the full text, 83 articles were included. All included articles are presented according to the following variables: (i) reference; (ii) design and setting of the study; (iii) inclusion criteria for patients; (iv) description of the intervention; (v) whether a patient interview was performed to involve patients' experiences with their medicine-taking behaviour; (vi) outcome; (vii) whether healthcare professionals received additional training; and (viii) whether healthcare professionals received financial reimbursement. Many different interventions are described where pharmacists and general practitioners work together to improve patients' health. Only nine studies reported hard outcomes, such as hospital (re)admissions; however, these studies had different results, not all of which were statistically significant. Randomized controlled trials should be able to describe hard outcomes, but large patient groups will be needed to perform such studies. Patient involvement is important for long-term success. PMID- 22242794 TI - Terminal interface conformations modulate dimer stability prior to amino terminal autoprocessing of HIV-1 protease. AB - The HIV-1 protease (PR) mediates its own release (autoprocessing) from the polyprotein precursor, Gag-Pol, flanked by the transframe region (TFR) and reverse transcriptase at its N- and C-termini, respectively. Autoprocessing at the N-terminus of PR mediates stable dimer formation essential for catalytic activity, leading to the formation of infectious virus. An antiparallel beta sheet interface formed by the four N- and C-terminal residues of each subunit is important for dimer stability. Here, we present the first high-resolution crystal structures of model protease precursor-clinical inhibitor (PI darunavir or saquinavir) complexes, revealing varying conformations of the N-terminal flanking (S(-4)FNF(-1)) and interface residues (P(1)QIT(4)). A 180 degrees rotation of the T(4)-L(5) peptide bond is accompanied by a new Q(2)-L(5) hydrogen bond and complete disengagement of PQIT from the beta-sheet dimer interface, which may be a feature for intramolecular autoprocessing. This result is consistent with drastically lower thermal stability by 14-20 degrees C of PI complexes of precursors and the mature PR lacking its PQIT residues (by 18.3 degrees C). Similar to the TFR-PR precursor, this deletion also results in a darunavir dissociation constant (2 * 10(4))-fold higher and a markedly increased dimer dissociation constant relative to the mature PR. The terminal beta-sheet perturbations of the dimeric structure likely account for the drastically poorer inhibition of autoprocessing of TFR-PR relative to the mature PR, even though significant differences in active site-PI interactions in these structures were not observed. The novel conformations of the dimer interface may be exploited to target selectively the protease precursor prior to its N-terminal cleavage. PMID- 22242795 TI - A comparative study of drug resistance mechanism associated with active site and non-active site mutations: I388N and D425G mutants of acetyl-coenzyme-A carboxylase. AB - A major concern in the development of acetyl-CoA carboxylase-inhibiting (ACCase; EC 6.4.1.2) herbicides is the emergence of resistance as a result of the selection of distinct mutations within the CT domain. Mutations associated with resistance have been demonstrated to include both active sites and non-active sites, including Ile-1781-Leu, Trp- 2027-Cys, Ile-2041-Asn, Asp-2078-Gly, and Gly 2096-Ala (numbered according to the Alopecurus myosuroides plastid ACCase). In the present study, extensive computational simulations, including molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) calculations, were carried out to compare the molecular mechanisms of active site mutation (I388N) and non-active site mutation (D425G) in Alopecurus myosuroides resistance to some commercial herbicides targeting ACCase, including haloxyfop (HF), diclofop (DF) and fenoxaprop (FR). All of the computational model and energetic results indicated that both I388N and D425G mutations have effects on the conformational change of the binding pocket. The pi-pi interaction between ligand and Phe377 and Tyr161' residues, which make an important contribution to the binding affinity, was decreased after mutation. As a result, the mutant-type ACCase has a lower affinity for the inhibitor than the wild-type enzyme, which accounts for the molecular basis of herbicidal resistance. The structural and mechanistic insights obtained from the present study will deepen our understanding of the interactions between ACCase and herbicides, which provides a molecular basis for the future design of a promising inhibitor with low resistance risk. PMID- 22242796 TI - Computational modeling methods for QSAR studies on HIV-1 integrase inhibitors (2005-2010). AB - The human immunodeficiency virus type 1 (HIV-1) integrase is an emerging target for novel antiviral drugs. Quantitative structure-activity relationship (QSAR) models for HIV-1 integrase inhibitors have been developed to understand the protein-ligand interactions to aid in the design of more effective analogs. This review paper presents a comprehensive overview of the computational modeling methods and results of QSAR models of HIV-1 integrase inhibitors published in 2005-2010. These QSAR models are classified according to the generation of molecular descriptors: 2D-QSAR, 3D-QSAR, and 4D-QSAR. Linear and non-linear modeling methods have been applied to derive these QSAR models, with the majority of the models derived from linear statistical methods such as multiple linear regression and partial least squares. While each of the published QSAR models have provided insight on the distinct chemical features of HIV-1 integrase inhibitors crucial for biological activity, only a few models have been used to propose and synthesize new HIV-1 integrase inhibitors. This study highlights the need for collaboration between computational and experimental chemists to utilize and improve these QSAR models to guide the design of the next generation of HIV-1 integrase inhibitors. PMID- 22242797 TI - Fragment-based development of HCV protease inhibitors for the treatment of hepatitis C. AB - A novel computational technology based on fragmentation of the chemical compounds has been used for the fast and efficient prediction of activities of prospective protease inhibitors of the hepatitis C virus. This study spans over a discovery cycle from the theoretical prediction of new HCV NS3 protease inhibitors to the first cytotoxicity experimental tests of the best candidates. The measured cytotoxicity of the compounds indicated that at least two candidates would be suitable further development of drugs. PMID- 22242798 TI - CoMFA and CoMSIA studies on aryl carboxylic acid amide derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors. AB - DHODH is a flavoenzyme that catalyzes the oxidation of dihydroorotate (DHO) to orotate (ORO) as part of the fourth and rate limiting step of the de novo pyrimidine biosynthetic pathway. Inhibitors of DHODHs have proven efficacy for the treatment of cancer, malaria and immunological disorders. 3D QSAR studies on some aryl carboxylic acid amide derivatives as hDHODH inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The alignment strategy was used for these compounds by means of Distill function defined in SYBYL X 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated coefficients (q2) of 0.636 and 0.604 and conventional coefficients (r2) of 0.993 and 0.950, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r2 pred) of 0.563 and 0.523 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Generated CoMFA and CoMSIA models provide useful information for the design of novel inhibitors with good hDHODH inhibitory. PMID- 22242799 TI - Modeling and simulation studies of human beta3 adrenergic receptor and its interactions with agonists. AB - beta3 adrenergic receptor (beta3AR) is known to mediate various pharmacological and physiological effects such as thermogenesis in brown adipocytes, lipolysis in white adipocytes, glucose homeostasis and intestinal smooth muscle relaxation. Several efforts have been made in this field to understand their function and regulation in different human tissues and they have emerged as potential attractive targets in drug discovery for the treatment of diabetes, depression, obesity etc. Although the crystal structures of Bovine Rhodopsin and beta2 adrenergic receptor have been resolved, to date there is no three dimensional structural information on beta3AR. Our aim in this study was to model 3D structure of beta3AR by various molecular modeling and simulation techniques. In this paper, we describe a refined predicted model of beta3AR using different algorithms for structure prediction. The structural refinement and minimization of the generated 3D model of beta3AR were done by Schrodinger suite 9.1. Docking studies of beta3AR model with the known agonists enabled us to identify specific residues, viz, Asp 117, Ser 208, Ser 209, Ser 212, Arg 315, Asn 332, within the beta3AR binding pocket, which might play an important role in ligand binding. Receptor ligand interaction studies clearly indicated that these five residues showed strong hydrogen bonding interactions with the ligands. The results have been correlated with the experimental data available. The predicted ligand binding interactions and the simulation studies validate the methods used to predict the 3D-structure. PMID- 22242800 TI - Multi-target QSAR and docking study of steroids binding to corticosteroid-binding globulin and sex hormone-binding globulin. AB - The QSAR and docking studies were performed on fifty seven steroids with binding affinities for corticosteroid-binding globulin (CBG) and eighty four steroids with binding affinities for sex hormone-binding globulin (SHBG). Since the steroidal compounds have binding affinity for both CBG and SHBG, multi-target QSAR approach was employed to establish a unique QSAR method for simultaneous evaluation of the CBG and SHBG binding affinities. The constitutional, geometrical, physico-chemical and electronic descriptors were computed for the examined structures by use of the Chem3D Ultra 7.0.0, the Dragon 6.0, the MOPAC2009, and the Chemical Descriptors Library (CDL) program. Partial least squares regression (PLSR) has been applied for selection of the most relevant molecular descriptors and QSAR models building. The QSAR (SHGB) model, QSAR model (CBG), and multi-target QSAR model (CBG, SHBG) were created. The multi-target QSAR model (CBG and SHBG) was found to be more effective in describing the CBG and SHBG affinity of steroids in comparison to the one target models (QSAR (SHGB) model, QSAR model (CBG)). The multi-target QSAR study indicated the importance of the electronic descriptor (Mor16v), steric/symmetry descriptors (Eig06_EA(ed)), 2D autocorrelation descriptor (GATS4m), distance distribution descriptor (RDF045m), and atom type fingerprint descriptor (CDL-ATFP 253) in describing the CBG and SHBG affinity of steroidal compounds. Results of the created multi-target QSAR model were in accordance with the performed docking studies. The theoretical study defined physicochemical, electronic and structural requirements for selective and effective binding of steroids to the CBG and SHBG active sites. PMID- 22242801 TI - Multiparametric analysis of intrinsically disordered proteins: looking at intrinsic disorder through compound eyes. AB - Intrinsically disordered proteins are highly abundant in various proteomes. They are different from ordered proteins at many levels, and their structural and functional characterization requires special experimental and computational tools. PMID- 22242803 TI - Insulin lispro protamine suspension in the treatment of patients with type 1 and type 2 diabetes mellitus: a systematic review of published data. AB - INTRODUCTION: Insulin lispro protamine suspension (ILPS) is a protamine-based insulin lispro formulation that allows 24-h coverage while limiting the number of daily injections. ILPS was developed to be the basal insulin component of premixed biphasic formulations with insulin lispro, i.e., the lispro/ILPS 25/75 and 50/50 mixed compounds, but has recently also been marketed as a basal insulin analog formulation, with an indication for the therapy of diabetic patients. AREAS COVERED: This article reviews the available literature on pharmacokinetics/pharmacodynamics (PK/PD), efficacy and safety of ILPS administered as basal insulin, or in premixed biphasic formulations, in patients with type 1 and type 2 diabetes mellitus. EXPERT OPINION: The results of this review suggest that ILPS may be associated with a favorable time-action profile, basal and postprandial glycemic control, and efficacy in terms of rates of patients reaching glycosylated hemoglobin targets; an increased risk of hypoglycemic episodes, compared to other basal insulins, seems to be related to the percentage of patients upgrading from once- to twice-daily injections. This increased risk might be linked with the concomitant use of insulin secretagogues in patients on higher daily dosages and is generally not observed in patients using one injection of ILPS a day. Thus, ILPS can be considered a valid option both as basal insulin and as basal component of the actual premixed formulations of lispro for the therapy of diabetic patients. PMID- 22242805 TI - Placebo-corrected efficacy of modern nonenzyme-inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis. AB - PURPOSE: Given serious concerns over the adverse effects of enzyme induction, modern nonenzyme-inducing antiepileptic drugs (AEDs) may be preferable, provided they have similar efficacy as enzyme-inducing AEDs. This is currently unclear. METHODS: Therefore, we performed a meta-analysis of the evidence to determine the placebo-corrected efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs versus modern enzyme-inducing AEDs that are on the market for refractory focal epilepsy. KEY FINDINGS: Of 322 potentially eligible articles reviewed in full text, 129 (40%) fulfilled eligibility criteria. After excluding 92 publications, 37 studies dealing with a total of 9,860 patients with refractory focal epilepsy form the basis for the evidence. The overall weighted pooled-risk ratio (RR) in favor of enzyme-inducing AEDs over placebo was 2.37 (95% confidence interval [CI] 1.77-3.18, p < 0.001) for at least 50% seizure reduction and 4.45 (2.26-8.76, p < 0.001) for seizure freedom. The corresponding weighted pooled RR in favor of nonenzyme-inducing AEDs over placebo was 2.28 (95% CI 2.03-2.57, p < 0.001) for at least 50% seizure reduction and 3.23 (95% CI 2.23-4.67, p < 0.001) for seizure freedom. In a meta-regression analysis in the same sample with at least 50% seizure reduction as outcome, the ratio of RRs for enzyme-inducing AEDs (eight studies) versus nonenzyme-inducing AEDs (29 studies) was 1.01 (95% CI 0.77 1.34, p = 0.92)). Similarly, the ratio of RRs for a seizure-free outcome for enzyme-inducing AEDs (six studies) versus nonenzyme-inducing AEDs (19 studies) was 1.38 (95% CI 0.60-3.16, p = 0.43). SIGNIFICANCE: Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs is similar to that of enzyme inducing AEDs. Given the negative consequences of enzyme induction, our data suggest that nonenzyme-inducing AEDs may be useful alternatives to enzyme inducing AEDs for treatment of refractory focal epilepsy. PMID- 22242806 TI - Prevention and pharmacovigilance: what should we do, what can we do? PMID- 22242808 TI - Synthesis of acyl pyrroles via palladium-catalyzed carbonylative amination of aryl and alkenyl iodides. AB - A palladium-catalyzed synthesis of acyl pyrroles from aryl and alkenyl iodides is reported. This carbonylative amination requires only atmospheric (balloon) pressure of carbon monoxide and proceeds with Pd(PPh(3))(4) and Pd-NHC catalysts. Aryl and heteroaryl iodides give the corresponding acyl pyrroles in good to excellent yields, while alkenyl iodides provide the corresponding acyl pyrroles in low to moderate yields. PMID- 22242809 TI - Metal-catalyzed reduction of HCONR'2, R' = Me (DMF), Et (DEF), by silanes to produce R'2NMe and disiloxanes: a mechanism unraveled. AB - We demonstrate that using Mo(CO)(6), Mo(CO)(5)NMe(3), and (eta(5) C(5)H(5))Mn(CO)(3) as catalysts for the silane, R(3)SiH, reduction of N,N dimethylformamide (DMF), and N,N-diethylformamide (DEF), we can observe, intercept, and isolate, the important siloxymethylamine intermediates, R(3)SiOCH(2)NR'(2), R' = Me, Et, for the first time. In the presence of excess DMF such intermediates thermally react with a variety of silanes to form the corresponding disiloxanes in the absence of a metal catalyst. We also show that the germanium hydrides, Et(3)GeH and Bu(3)GeH, also reduce DMF to form trimethylamine and the corresponding digermoxane but observe no intermediates R(3)GeOCH(2)NMe(2). Bu(3)SnH reduces DMF, but along with the low yields of Bu(3)SnOSnBu(3) (but no Bu(3)SnOCH(2)NMe(2)) significant side products are obtained including (Bu(3)Sn)(2) and Bu(4)Sn. In the absence of DMF the siloxymethylamines can undergo metal-catalyzed reactions with silanes, germanes and stannanes to form disiloxanes, and R(3)SiOER(3) E = Ge, Sn, respectively. To date, the most efficient catalyst for this latter process is (eta(5) C(5)H(5))Mo(CO)(3)CH(3) via a photochemical reaction. PMID- 22242811 TI - Amphiphilic building blocks for self-assembly: from amphiphiles to supra amphiphiles. AB - The process of self-assembly spontaneously creates well-defined structures from various chemical building blocks. Self-assembly can include different levels of complexity: it can be as simple as the dimerization of two small building blocks driven by hydrogen bonding or as complicated as a cell membrane, a remarkable supramolecular architecture created by a bilayer of phospholipids embedded with functional proteins. The study of self-assembly in simple systems provides a fundamental understanding of the driving forces and cooperativity behind these processes. Once the rules are understood, these guidelines can facilitate the research of highly complex self-assembly processes. Among the various components for self-assembly, an amphiphilic molecule, which contains both hydrophilic and hydrophobic parts, forms one of the most powerful building blocks. When amphiphiles are dispersed in water, the hydrophilic component of the amphiphile preferentially interacts with the aqueous phase while the hydrophobic portion tends to reside in the air or in the nonpolar solvent. Therefore, the amphiphiles aggregate to form different molecular assemblies based on the repelling and coordinating forces between the hydrophilic and hydrophobic parts of the component molecules and the surrounding medium. In contrast to conventional amphiphiles, supra-amphiphiles are constructed on the basis of noncovalent interactions or dynamic covalent bonds. In supra-amphiphiles, the functional groups can be attached to the amphiphiles by noncovalent synthesis, greatly speeding their construction. The building blocks for supra-amphiphiles can be either small organic molecules or polymers. Advances in the development of supra amphiphiles will not only enrich the family of conventional amphiphiles that are based on covalent bonds but will also provide a new kind of building block for the preparation of complex self-assemblies. When polymers are used to construct supra-amphiphiles, the resulting molecules are known as superamphiphiles. This Account will focus on the use of amphiphiles and supra-amphiphiles for self assembly at different levels of complexity. We introduce strategies for the fabrication of robust assemblies through self-assembly of amphiphiles. We describe the supramolecular approach for the molecular design of amphiphiles through the enhancement of intermolecular interaction among the amphiphiles. In addition, we describe polymerization under mild conditions to stabilize the assemblies formed by self-assembly of amphiphiles. Finally, we highlight self assembly methods driven by noncovalent interactions or dynamic covalent bonds for the fabrication of supra-amphiphiles with various topologies. Further self assembly of supra-amphiphiles provides new building blocks for complex structures, and the dynamic nature of the supra-amphiphiles endows the assemblies with stimuli-responsive functions. PMID- 22242812 TI - Chemoaffinity-mediated synthesis of NaRES2-based nanocrystals as versatile nano building blocks and durable nano-pigments. AB - In this article, we present a chemoaffinity-mediated synthetic strategy toward trivalent rare earth (RE) sulfides-based nanocrystals with poor affinity between cation and anion (i.e., RE(3+) and S(2-)). With the affinity mediation among multiple constituents based on hard and soft acid and base theory, we synthesized a series of monodisperse NaRES(2) nanocrystals (RE = La to Lu, Y). The revelation of the nanocrystal growth mechanism from both experimental evidence and crystal structure modeling has enabled a robust control over the sizes and morphologies of the nanocrystals. This principle of chemoaffinity has also promised the synthesis of well-defined but even more complex RE-based hetero-nanostructures (i.e. NaLaS(2)-Au, Au@NaLaS(2), NaLaS(2)@Ag(2)S, Au@NaLaS(2)@Ag(2)S) with tunable optical properties. Furthermore, this synthetic method has yielded durable NaCeS(2)-based red nano-pigments under ambient conditions, with superior brightness and permeability in polydimethylsiloxane. PMID- 22242813 TI - A novel alpha-thalassemia frameshift mutation: codon 8 (-C). AB - We report a novel alpha-thalassemia (alpha-thal) point mutation detected during newborn screening for hemoglobinopathies. Sequence analyses identified a frameshift mutation at codon 8 (-C) in exon 1 of the alpha2-globin gene. This mutation causes an alpha(+)-thal phenotype. PMID- 22242816 TI - A hypothesis on Microthrix parvicella proliferation in biological nutrient removal activated sludge systems with selector tanks. AB - The objective of this study was to evaluate the ability of Microthrix parvicella for long-chain fatty acids uptake under anaerobic, anoxic, and aerobic conditions as well as its ability to utilize volatile fatty acids and long-chain fatty acids under anoxic and aerobic conditions. According to the results, a hypothesis on the competition between floc-forming microorganisms and M. parvicella for long chain fatty acids uptake under aerobic, anoxic, and anaerobic conditions was formulated. According to this hypothesis, M. parvicella exhibits similar long chain fatty acids uptake capacity with floc-forming microorganisms even at relatively high floc loading values that are very often imposed at selector tanks. Following this hypothesis, the failure of selector tanks to provide for an effective M. parvicella control is evidenced. Based on the experimental results, the ability of M. parvicella to utilize long-chain fatty acids with rates comparable to those of floc formers, even in anoxic conditions, in conjunction with its lower acetate utilization rates, provides a good explanation regarding its preference to slowly biodegradable organic carbon compounds. PMID- 22242817 TI - Durable responses after donor lymphocyte infusion for patients with residual multiple myeloma following non-myeloablative allogeneic stem cell transplant. AB - The role of donor lymphocyte infusion (DLI) in mediating the graft-versus-myeloma (GvM) effect after allogeneic hematopoietic stem cell transplant (allo-HCT) is not clearly defined. We evaluated the safety and utility of DLI in patients with either persistent or recurrent multiple myeloma (MM) after allo-HCT. Twenty-three patients with MM received DLI after allo-HCT at the University of Texas M. D. Anderson Cancer Center between July 1996 and June 2008. Eight patients received preemptive DLI for residual disease (RD) while 15 patients received DLI for the treatment of recurrent or progressive disease (PD). We evaluated the response to DLI and the factors that may predict a response. Median DLI dose was 3.3 * 10(7) CD3 + cells (range 0.5-14.8 * 10(7)). Grade II-IV acute graft-versus-host disease (GvHD) was seen in five patients (22%). Median follow-up in surviving patients was 24 months. Five of 23 patients (22%) achieved a complete or a very good partial response (two CR, three VGPR), while eight patients (34%) had stable disease (SD) after the DLI. Patients who received DLI for RD had a higher response rate (>= VGPR 50% vs. 7%, p = 0.03), a longer overall survival (28.3 vs. 7.6 months, p = 0.03) and a trend toward longer progression-free survival (11.9 vs. 5.2 months, p = 0.1). In this largest single institution study, we conclude that the use of preemptive, non-manipulated DLI for RD after reduced-intensity conditioning allo-HCT is encouraging, and it was associated with a higher response rate and a longer overall survival when given preemptively. The role of DLI needs to be further explored in prospective clinical trials. PMID- 22242818 TI - Priapism as an initial presentation of chronic lymphocytic leukemia. PMID- 22242819 TI - Enteropathy-associated T-cell lymphoma in small intestine detected by capsule endoscopy. PMID- 22242820 TI - Reciprocal changes in regulatory T cells and Th17 helper cells induced by exercise in patients with chronic lymphocytic leukemia. PMID- 22242821 TI - Importance of inducible multidrug resistance 1 expression in HL-60 cells resistant to gemtuzumab ozogamicin. AB - Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO. PMID- 22242822 TI - Chemotherapy-related magnetic resonance imaging abnormalities mimicking disease progression following intraventricular liposomal cytarabine and high dose methotrexate for neurolymphomatosis. PMID- 22242823 TI - Improving quality of life in chronic lymphocytic leukemia. PMID- 22242824 TI - Survival trends in mantle cell lymphoma in the United States over 16 years 1992 2007. AB - A retrospective analysis was done using the Surveillance, Epidemiology, and End Results (SEER) database to determine the trends in overall survival and identify prognostic factors in patients with mantle cell lymphoma (MCL). In total 5367 cases of MCL identified from 1992 to 2007 were split into three cohorts, group 1(1992-1999), group 2 (2000-2003) and group 3 (2004-2007). Survival was analyzed using the Cox proportional hazards model to correct for age, gender and stage of disease. The proportion of patients with advanced disease at diagnosis, male gender and advanced age increased over time and these were all associated with increased mortality. The overall survival remained unchanged. However, when adjusted for the increased proportion of patients with poor prognostic features noted above, we found a significant improvement in survival. The adjusted model also showed an improvement in predicted survival over time in patients with advanced stage. No change in survival was seen in patients with localized disease. Although this analysis is not designed to evaluate specific treatment modalities, these data suggest that the development of new treatment strategies over the past decade may be impacting the survival of patients with advanced MCL despite the finding that the overall survival remains unchanged in the general US population. PMID- 22242825 TI - Antifungal activity of borrelidin produced by a Streptomyces strain isolated from soybean. AB - In this study, an endophytic Streptomyces sp. neau-D50 with strong antifungal activity against Phytophthora sojae was isolated from healthy soybean root, using an in vitro screening technique. A bioactivity-guided approach was then employed to isolate and determine the chemical identity of bioactive constituents with antifungal activity from strain neau-D50. The structure of the antifungal metabolite was elucidated as borrelidin on the basis of spectral analysis. To our knowledge, this is the first report that borrelidin has strong antifungal activity against dominant race 1 of P. sojae with EC(50) and EC(95) of 0.0056 and 0.026 mg/L, respectively. The values were respectively 62.5- and 262.3-fold lower than those of the commercial fungicide metalaxyl, which has been used to treat soybean seed for the control of P. sojae . The in situ bioassays demonstrated that borrelidin at 10 mg/L reduced P. sojae race 1 lesions on soybean seedlings by 94.72% without affecting root growth. Thus, borrelidin might be a promising candidate for new antifungal agents against P. sojae. PMID- 22242826 TI - Monomeric alpha-synuclein binds Congo Red micelles in a disordered manner. AB - The histological dye Congo Red (CR) previously has been shown to inhibit alpha synuclein (aS) fibrillation, but the mode of this inhibition remained unclear. Because of favorable exchange kinetics, interaction between CR and aS lends itself to a detailed nuclear magnetic resonance study, and relaxation dispersion measurements yield the bound fraction and time scales for the interaction of aS with CR. We find that at pH 6, CR exists as a micelle, and at a CR:aS molar ratio of ~1, only a small fraction of aS (~2%) is bound to these micelles. Rapid exchange (k(ex) ~ 3000 s(-1)) between the free and CR-bound states broadens and strongly attenuates resonances of aS by two processes: a magnetic field-dependent contribution, caused by the chemical shift difference between the two states, and a nearly field-independent contribution caused by slower tumbling of aS bound to the CR micelle. The salt dependence of the interaction suggests a predominantly electrostatic mechanism for the 60 N-terminal residues, while the weaker interaction between residues 61-100 and CR is mostly hydrophobic. Chemical shift and transferred NOE data indicate that aS becomes slightly more helical but remains largely disordered when bound to CR. Results indicate that inhibition of fibril formation does not result from binding of CR to free aS and, therefore, must result from interaction of aS fibrils or protofibrils with CR micelles. PMID- 22242827 TI - Family social support during the predeparture period: the experience of British migrants. AB - This study explored the stress, wellbeing and social support of predeparture British migrants to New Zealand. The main research questions addressed the relationship between family support and psychological outcomes, differences in migration desire between couples, and the impact of extended family support. A survey recruited 95 participants from online forums for migrants to New Zealand and results indicated that support from immediate family was related to better wellbeing and lower stress. Migrants who considered themselves the driving force behind the move reported significantly more stress and less family support than migrants who had partners who were equally enthusiastic about the move abroad. Sojourners perceived more support from extended family than did migrants who intended to leave permanently. The most difficult parts of the migration process were leaving loved ones, logistical demands, and uncertainty. The most positive parts of the process were adventure and becoming closer as a family. Overall, migration stress and coping began well before departure from the country of origin. This work was supported by a Victoria University of Wellington Faculty Strategic Research Grant. PMID- 22242829 TI - Lymphocyte subsets, granulocyte-colony-stimulating factor responsiveness and post stem cell transplantation infections: mucositis is the underestimated confounder? PMID- 22242828 TI - Five Japanese cases of antidesmoglein 1 antibody-positive and antidesmoglein 3 antibody-negative pemphigus with oral lesions. AB - BACKGROUND: Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the 'desmoglein (Dsg) compensation theory'. Dsg3 and Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti-Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti-Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus. OBJECTIVES: We present five Japanese patients with pemphigus who deviate from this theory, i.e. all patients showed oral lesions (three also had cutaneous lesions) and reacted only with Dsg1, but not with Dsg3, by enzyme linked immunosorbent assay. METHODS: To confirm whether the unique clinical phenotypes in our patients were due to a different immunological profile from that in classical pemphigus, we examined the reactivity of the patient sera by immunoprecipitation-immunoblotting analysis using five Dsg1/Dsg2 domain-swapped molecules. RESULTS: The sera of two patients who had only oral lesions tended to react with the extracellular (EC) 5 domain of Dsg1, the domain that is considered nonpathogenic in classical pemphigus foliaceus. Sera of three patients with mucocutaneous lesions reacted with EC1 domain or with both EC1 and EC2 domains of Dsg1, like classical pemphigus foliaceus. CONCLUSIONS: These results indicate that antigenic diversity of anti-Dsg1 antibodies in these patients may cause the unique oral mucosal and cutaneous lesions, although further studies are required to elucidate the pathomechanisms. PMID- 22242830 TI - Human umbilical cord mesenchymal stromal cells mitigate chemotherapy-associated tissue injury in a pre-clinical mouse model. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSC) have been shown to be a promising candidate for tissue regeneration and cancer therapy. However, their therapeutic potential against chemotherapy-induced side-effects remains unclear. METHODS: We treated murine Lewis lung carcinoma (LLC) and xenograft human colon tumors with adriamycin (ADM) for 3 consecutive days followed by one intravenous (i.v.) injection of human umbilical cord (hUC) MSC for several cycles. RESULTS: MSC treatment mitigated ADM-induced cardiomyopathy, reduced the extent of ADM induced apoptosis in intestinal crypts, suppressed body weight loss in mice treated with ADM and increased the survival rate of mice treated with a lethal dose of ADM. The examination of hematologic parameters indicated a moderate recovery in MSC-injected mice. Systemic administration of MSC did not increase the growth of murine LLC cells and human colon carcinoma in vivo while it strongly inhibited the lung metastases of LLC cells. CONCLUSIONS: We evaluated the prophylactic and therapeutic action of hUC MSC on the chemotherapy agent ADM induced side-effects in two different tumor models. Our observations suggest that MSC can be used as auxiliary means in chemotherapy for certain tumor types. PMID- 22242831 TI - In vivo enrichment of cytidine deaminase gene-modified hematopoietic cells by prolonged cytosine-arabinoside application. AB - BACKGROUND AIMS: Drug-resistance genes have been explored as powerful in vivo selection markers in hematopoietic cell gene therapy, and cytidine deaminase (CDD) represents a particularly attractive candidate given the virtual absence of non-hematopoietic side-effects after low/intermediate dose application of the associated drug cytosine-arabinoside (Ara-C). METHODS: We investigated the in vivo selection potential of CDD overexpression and prolonged low/intermediate dose Ara-C application in a murine model. Furthermore, non-transplanted mice were utilized to study Ara-C toxicity in different hematopoietic cell compartments. RESULTS: Significant protection of myelo- and thrombopoiesis and up to 6-fold in vivo enrichment of CDD-transduced hematopoietic cells was observed. Enrichment was most robust early after Ara-C application and was correlated with dosage and duration of chemotherapy. Enrichment remained significant for several weeks, indicating selection at the level of a progenitor population. This notion was supported by Ara-C toxicity studies, demonstrating profound hematotoxicity and a marked delay in hematopoietic recovery, specifically in the progenitor/stem cell compartment after low/intermediate-dose Ara-C. CONCLUSIONS: These data support the concept of CDD/Ara-C as a clinically applicable in vivo selection system in hematopoietic gene therapy. The data also demonstrate marked differences in hematotoxicity between alternative Ara-C dosing schemes and suggest thorough in vivo toxicity studies to optimize further Ara-C dosing en route to safe and stable enrichment of gene-corrected hematopoiesis. PMID- 22242832 TI - Distribution of functionalized gold nanoparticles between water and lipid bilayers as model cell membranes. AB - Lipid bilayers are biomembranes common to cellular life and constitute a continuous barrier between cells and their environment. Understanding the interaction of nanoparticles with lipid bilayers is an important step toward predicting subsequent biological effects. In this study, we assessed the affinity of functionalized gold nanoparticles (Au NPs) with sizes from 5 to 100 nm to lipid bilayers by determining the Au NP distribution between aqueous electrolytes and lipid bilayers. The Au NP distribution to lipid bilayers reached an apparent steady state in 24 h with smaller Au NPs distributing onto lipid bilayers more rapidly than larger ones. Au NPs distributed to lipid bilayers to a larger extent at lower pH. Tannic acid-functionalized Au NPs exhibited greater distribution to lipid bilayers than polyvinylpyrrolidone-functionalized Au NPs of the same size. Across the various Au NP sizes, we measure the lipid bilayer-water distribution coefficient (K(lipw) = C(lip)/C(w)) as 450 L/kg lipid, which is independent of dosimetric units. This work suggests that the nanoparticle-cell membrane interaction is dependent on solution chemistry and nanoparticle surface functionality. The K(lipw) value may be used to predict the affinity of spherical Au NPs across a certain size range toward lipid membranes. PMID- 22242834 TI - Self-organized anisotropic wrinkling of molecularly aligned liquid crystalline polymer. AB - Anisotropic wrinkling which utilizes the anisotropic nature of liquid crystalline polymer (LCP) is demonstrated as a means of physical self-assembly to produce periodic microstructures. Through the plasma treatment on the molecularly aligned LCP film surface, one-dimensionally ordered wrinkle pattern was spontaneously formed on glass substrates without employing external thin-film deposition or prestrain control of the system. Experimental results indicate that the directionality of the wrinkle pattern can be tailored by the structural ordering of LCP molecules in the bilayer system of a hard skin layer on a soft substrate. Studies on process variables, such as the plasma treatment time and the film thickness, were conducted to figure out the effect on the wrinkling morphology. Due to its spatial periodicity over a large area and undemanding requirement of the process, this approach can be a candidate for the microfabrication in various applications. PMID- 22242833 TI - Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions. AB - The nucleotide excision repair (NER) machinery, the primary defense against cancer-causing bulky DNA lesions, is surprisingly inefficient in recognizing certain mutagenic DNA adducts and other forms of DNA damage. However, the biochemical basis of resistance to repair remains poorly understood. To address this problem, we have investigated a series of intercalated DNA-adenine lesions derived from carcinogenic polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites that differ in their response to the mammalian NER apparatus. These stereoisomeric PAH-derived adenine lesions represent ideal model systems for elucidating the effects of structural, dynamic, and thermodynamic properties that determine the recognition of these bulky DNA lesions by NER factors. The objective of this work was to gain a systematic understanding of the relation between aromatic ring topology and adduct stereochemistry with existing experimental NER efficiencies and known thermodynamic stabilities of the damaged DNA duplexes. For this purpose, we performed 100 ns molecular dynamics studies of the lesions embedded in identical double-stranded 11-mer sequences. Our studies show that, depending on topology and stereochemistry, stabilizing PAH-DNA base van der Waals stacking interactions can compensate for destabilizing distortions caused by these lesions that can, in turn, cause resistance to NER. The results suggest that the balance between helix stabilizing and destabilizing interactions between the adduct and nearby DNA residues can account for the variability of NER efficiencies observed in this class of PAH-DNA lesions. PMID- 22242835 TI - Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. AB - PURPOSE: The mammalian target of rapamycin (mTOR) pathway has been implicated in contributing to progressive epileptogenesis in models of chronic epilepsy. Conversely, seizures themselves may directly cause acute activation of the mTOR pathway. To isolate the direct effects of seizures on the mTOR pathway, the time course and mechanisms of mTOR activation were investigated with acute seizures induced by pentylenetetrazole (PTZ), which does not lead to chronic epilepsy. METHODS: Western blot analysis was used to assay the phosphorylation of Akt and S6, as measures of activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR pathways, respectively, at various time points after PTZ-induced seizures in rats. The ability of wortmannin, a PI3K inhibitor, to inhibit PTZ seizure-induced activation of the mTOR pathway was tested. KEY FINDINGS: PTZ-induced seizures produced an immediate, transient mTOR activation lasting several hours, but no later, more chronic activation over days to weeks. This acute stimulation of the mTOR pathway by PTZ-induced seizures was mediated by upstream PI3K/Akt pathway activation and was blocked by a PI3K inhibitor. SIGNIFICANCE: Compared with models of chronic epilepsy that exhibit biphasic (acute and chronic) mTOR pathway activation, PTZ-induced seizures produce only acute, but not chronic, mTOR activation. These results in the PTZ seizure model highlight potential differences in the involvement of the mTOR pathway between self-limited seizures and progressive epileptogenesis. These findings also suggest a potential therapeutic role of PI3K inhibitors in epilepsy. PMID- 22242836 TI - The use of tumour volumetrics to assess response to therapy in anticancer clinical trials. AB - Serial evaluations of tumour burden using imaging, mainly computed tomography and magnetic resonance imaging, form the basis for assessing treatment response in many clinical trials of anticancer therapeutics. Traditionally, these evaluations have been based on linear measurements of tumour size. Such measurements have limitations related to variability in technical factors, tumour morphology and reader decisions. Measurements of entire tumour volumes may overcome some of the limitations of linear tumour measurements, improving our ability to detect small changes reliably and increasing statistical power per subject in a trial. Certain technical factors are known to affect the accuracy and precision of volume measurements, and work is in progress to define these factors more thoroughly and to qualify tumour volume as a biomarker for the purposes of drug development. PMID- 22242837 TI - Measurement and differentiation of ligand-induced calmodulin conformations by dual polarization interferometry. AB - In early drug discovery, knowledge about ligand-induced conformational changes and their influence on protein activity greatly aids the identification of lead candidates for medicinal chemistry efforts. Efficiently acquiring such information remains a challenge in the initial stages of lead finding. Here we investigated the application of dual polarization interferometry (DPI) as a method for the real-time characterization of low molecular weight (LMW) ligands that induce conformational changes. As a model system we chose calmodulin (CaM), which undergoes large and distinct structural rearrangements in response to calcium ion and small molecule inhibitors such as trifluoperazine (TFP). We measured concentration-dependent mass, thickness, and density responses of an immobilized CaM protein layer, which correlated directly with binding and conformational events. Calcium ion binding to CaM induced an increase in thickness (<=0.05 nm) and decrease in density (<=-0.03 g/cm(3)) whereas TFP induced an increase in both thickness (<=0.05 nm) and density (<=0.01 g/cm(3)). The layer measurements reported here show how DPI can be used to assess and differentiate ligands with distinct structural modes of action. PMID- 22242838 TI - Amplified detection of DNA through the enzyme-free autonomous assembly of hemin/G quadruplex DNAzyme nanowires. AB - An enzyme-free amplified detection platform is described using the horseradish peroxidase (HRP)-mimicking DNAzyme as an amplifying label. Two hairpin structures that include three-fourths and one-fourth of the HRP-mimicking DNAzyme in caged, inactive configurations are used as functional elements for the amplified detection of the target DNA. In the presence of the analyte DNA, one of the hairpins is opened, and this triggers the autonomous cross-opening of the two hairpins using the strand displacement principle. This leads to the formation of nanowires consisting of the HRP-mimicking DNAzyme. The resulting DNA nanowires act as catalytic labels for the colorimetric or chemiluminescent readout of the sensing processes (the term "enzyme-free" refers to a protein-free catalyst). The analytical platform allows the sensing of the analyte DNA with a detection limit corresponding to 1 * 10(-13) M. The optimized system acts as a versatile sensing platform, and by coaddition of a "helper" hairpin structure any DNA sequence may be analyzed by the system. This is exemplified with the detection of the BRCA1 oncogene with a detection limit of 1 * 10(-13) M. PMID- 22242839 TI - Contrasting reactions of ketones and thioketones with alkyllithiums: a coordinated experimental and computational investigation. AB - The reaction of ketones with organolithium reagents generally proceeds by addition of the organometallic to the electrophilic carbon of the C?O group to give the lithium salt of a tertiary alcohol. The seemingly analogous reaction of thioketones with organolithiums is a fundamentally different process: such reactions typically afford a variety of products, and addition of the organolithium to carbon of the C?S group to give a thiol is a relatively unimportant component. Reactions of the stable thioketone, adamantantanethione (1), with several alkyllithiums (MeLi, n-BuLi and t-BuLi) in a variety of solvents have been studied in the first comprehensive investigation of the reactions of organolithiums with a representative alkyl-substituted thione. Reactions of 1 with n-BuLi or t-BuLi afforded 2-adamantanethiol (2) as the major product. In an effort to explain the marked difference in behavior of ketones and thioketones in reactions with organolithiums, transition states for both the addition and reduction reactions have been located at the B3LYP/6-311+G* level using acetone and thioacetone as model substrates. The transition states for the addition of dimeric MeLi to the C?O and C?S carbons of acetone and thioacetone were significantly different as a result of the small bond angles preferred by divalent sulfur, and this accounts for the much slower addition to a C?S carbon vis-a-vis a C?O group. Transition states for reduction of acetone and thioacetone by EtLi were similar, but the greater exothermicity of the reduction of the thioketone results in an earlier transition state and lower activation energy for this process than that for the reduction of a ketone. The possible role of radical-mediated processes in this chemistry is also discussed. PMID- 22242841 TI - Cu(I)-catalyzed oxidative cyclization of alkynyl oxiranes and oxetanes. AB - In the presence of a Cu(I) catalyst and a pyridine oxide, alkynyl oxiranes and oxetanes can be converted into functionalized five- or six-membered alpha,beta unsaturated lactones or dihydrofuranaldehydes. This new oxidative cyclization is proposed to proceed via an unusual allenyloxypyridinium intermediate. PMID- 22242842 TI - Structural and solvent effects on the C-S bond cleavage in aryl triphenylmethyl sulfide radical cations. AB - Steady-state and laser flash photolysis (LFP) studies of a series of aryl triphenylmethyl sulfides [1, 3,4-(CH(3)O)(2)-C(6)H(3)SC(C(6)H(5))(3); 2, 4-CH(3)O C(6)H(4)SC(C(6)H(5))(3); 3, 4-CH(3)-C(6)H(4)SC(C(6)H(5))(3); 4, C(6)H(5)SC(C(6)H(5))(3); and 5, 4-Br-C(6)H(4)SC(C(6)H(5))(3)] has been carried out in the presence of N-methoxyphenanthridinium hexafluorophosphate in CH(3)CN, CH(2)Cl(2), CH(2)Cl(2)/CH(3)CN, and CH(2)Cl(2)/CH(3)OH mixtures. Products deriving from the C-S bond cleavage in the radical cations 1(*+)-5(*+) have been observed in the steady-state photolysis experiments. Time-resolved LFP showed first-order decay of the radical cations accompanied by formation of the triphenylmethyl cation. A significant decrease of the C-S bond cleavage rate constants was observed by increasing the electron-donating power of the arylsulfenyl substituent, that is, by increasing the stability of the radical cations. DFT calculations showed that, in 2(*+) and 3(*+), charge and spin densities are mainly localized in the ArS group. In the TS of the C-S bond cleavage an increase of the positive charge in the trityl moiety and of the spin density on the ArS group is observed. The higher delocalization of the charge in the TS as compared to the initial state is probably at the origin of the observation that the C-S bond cleavage rates decrease by increasing the polarity of the solvent. PMID- 22242844 TI - Editorial: the medicinal chemistry of novel approaches for the treatment of malaria. PMID- 22242845 TI - Back to the future: lessons learned in modern target-based and whole-cell lead optimization of antimalarials. AB - Antimalarial drug discovery has historically benefited from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. However over the past two decades there has been a shift in the pharmaceutical industry to move away from whole-cell screening to target-based approaches. As part of a Wellcome Trust and Medicines for Malaria Venture (MMV) funded consortium to discover new blood-stage antimalarials, we used both approaches to identify new antimalarial chemotypes, two of which have progressed beyond the lead optimization phase and display excellent in vivo efficacy in mice. These two advanced series were identified through a cell-based optimization devoid of target information and in this review we summarize the advantages of this approach versus a target-based optimization. Although the each lead optimization required slightly different medicinal chemistry strategies, we observed some common issues across the different the scaffolds which could be applied to other cell based lead optimization programs. PMID- 22242843 TI - Prenatal neurologic anomalies: sonographic diagnosis and treatment. AB - The low prevalence of fetal CNS anomalies results in a restricted level of exposure to, and limited experience for most obstetricians involved in, prenatal ultrasound. Sonographic guidelines for screening the fetal brain in a systematic way may increase the detection rate of fetal CNS anomalies, thus promoting correct referral to tertiary care centers offering patients a multidisciplinary approach to the condition. The aim of this review is to elaborate on the prenatal sonographic diagnosis and outcome of various CNS malformations. Detailed neurosonographic investigation has become available through high-resolution vaginal ultrasound probes and the development of a variety of 3-dimensional (3D) ultrasound modalities, such as ultrasound tomographic imaging. In addition, fetal magnetic resonance imaging is particularly helpful in the detection of gyration and neurulation anomalies, and disorders of the gray and white matter. Isolated mild ventriculomegaly is a rather common finding with good overall outcome. With an increasing diameter of the atria, however, and especially with the presence of associated malformations, long-term neurodevelopmental and behavioral outcome is disturbed in about 15% or more of cases. In view of recent developments in fetal therapy for neural tube defects, there is a clear need for a high level of ultrasound screening, work-up and counseling in tertiary care centers to identify those cases that might benefit from in utero intervention. The failure of prosencephalic midline induction and development results in midline defects ranging from alobar holoprosencephaly to isolated corpus callosum defects. The detection of callosal abnormaties is enhanced by 3D ultrasound, but counseling on neurodevelopmental outcome remains challenging. The Dandy-Walker spectrum includes isolated megacisterna magna, Blake's pouch cyst, hypoplasia of the vermis and Dandy-Walker malformation. Except for complete agenesis of the vermis associated with fourth ventricle cyst formation, data on long-term outcomes for the various conditions is largely lacking. Congenital cytomegalovirus (CMV) results in the highest incidence of children born with, or developing, long-term neurologic conditions. If proof of fetal infection has been delivered, microcephaly, cortical malformations, and intraparenchymal cysts show a strong correlation with poor outcome. Fetuses with CMV-related ultrasound abnormalities might benefit from maternal transplacental treatment. The aneurysm of the vein of Galen, a vascular malformation of the brain, often results in high cardiac output failure. After neonatal arterial embolization, survival is about 50% with normal neurologic development in 36% of cases. Over 50% of intracranial tumors are teratomata, presenting as fast-growing heterogeneous solid-cystic masses with calcifications. Most intracranial hemorrhages are related to the ventricular system, and prognosis is often poor, particularly in cases involving parenchymal and subdural bleeding. Proliferation disorders of the brain are often characterized by microcephaly. Their etiology is heterogeneous and prenatal diagnosis is often made late in gestation. PMID- 22242846 TI - Recent advances in plasmepsin medicinal chemistry and implications for future antimalarial drug discovery efforts. AB - Plasmepsins are the aspartic proteases of Plasmodium that play key roles in the survival of the parasite in its host. The plasmepsins of the digestive vacuole play an important role in hemoglobin degradation, providing the parasite with a vital source of nutrients. Recently, plasmepsin V has been shown to be an essential protease, processing hundreds of parasite proteins for export into the host erythrocyte. The functions of the remaining plasmepsins have yet to be discovered. Over the past decade, much effort has been placed towards developing plasmepsin inhibitors as antimalarial agents, particularly targeting the digestive vacuole. This review will highlight some of the recent work in this field with a particular focus on target druggability and strategies for identifying plasmepsins inhibitors as effective antimalarial drugs. Given recent advances in understanding the fundamental roles of the various plasmepsins, it is likely that the most effective antimalarial plasmepsin targets will be the non digestive vacuole plasmepsins. PMID- 22242847 TI - Synthetic peroxides as potent antimalarials. News and views. AB - The present review describes the development of synthetic cyclic peroxides, which are designed to surpass the antimalarial activity of the lead molecule, the natural product (+)-artemisinin and some of its C10 derivatives. To begin with, tricyclic and bicyclic 1,2,4-trioxanes are taken to show how the pharmacophore was identified and chirality proved to be irrelevant. The action of ferrous salts on trioxanes illustrates the structural elements that are needed so that reductive breaking of the peroxide bond leads to C-centered radicals, the alleged parasiticidal agents. Views are expressed on how heme, Plasmodium SERCA, and plain ferrous ions, either as targets or activators, could be implicated in the mode of action. Thereafter, news about 1,2,4-trioxolanes, 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, 1,2-dioxolanes, and 1,2-dioxanes is recounted, emphasizing aspects of design, mechanism, and the importance of the adamantane entity for buttressing activity. News about compounds made up of a trioxane covalently bound to aminoquinoline, so-called hybrid molecules, is reported together with a view that they might be better than mechanical mixtures. No new antimalarial can be considered without a word about the risk posed by the parasite developing resistance. The review is not intended to be exhaustive. Some gaps prior to 2009 are filled in, while the later literature up to the end of July 2011 has been covered. Artemisinin and its derivatives fall outside the scope of the review. Nevertheless, some mechanistic insights garnered from artemisinin, which are relevant to synthetic peroxides, are included. PMID- 22242849 TI - Falcipain inhibition as a promising antimalarial target. AB - Falcipains are Plasmodium falciparum cysteine proteases involved in different processes of the erythrocytic cycle of the malaria parasite like hydrolysis of host hemoglobin, erythrocyte invasion, and erythrocyte rupture. These proteases constitute promising targets in the search for novel therapies that would ease the burden caused by the increasing resistance to current antimalarial drugs. Despite biochemical characterization of four falcipains so far, the search for new falcipain inhibitors has been limited to falcipain-2 and/ or falcipain-3, due to their interesting hemoglobinase capacity and the ample availability of tools to study them. We describe progress towards the discovery of promising falcipain inhibitors, in the light of their drug-like properties and the effect of the inhibition of several of these cysteine proteases. Some important aspects to focus on future development of falcipain inhibition are also discussed. PMID- 22242848 TI - Reversed chloroquine molecules as a strategy to overcome resistance in malaria. AB - This short review tells the story of how Reversed Chloroquine drugs (RCQs) were developed. These are hybrid molecules, made by combining the quinoline nucleus from chloroquine (CQ) with moieties which are designed to inhibit efflux via known transporters in the membrane of the digestive vacuole of the malaria parasite. The resulting RCQ drugs can have potencies exceeding that of CQ, while at the same time having physical chemical characteristics that may make them favorable as partner drugs in combination therapies. The need for such novel antimalarial drugs will continue for the foreseeable future. PMID- 22242850 TI - Targeting protein kinases in the malaria parasite: update of an antimalarial drug target. AB - Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance. PMID- 22242851 TI - Current advances in therapeutic applications of nuclear receptors. PMID- 22242853 TI - Retinoid receptors and therapeutic applications of RAR/RXR modulators. AB - Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies. PMID- 22242854 TI - Current status of vitamin D signaling and its therapeutic applications. AB - Vitamin D and in particular its biologically most active metabolite, 1alpha,25 dihydroxyvitamin D3 (1alpha,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1alpha,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its molecular interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge number of synthetic 1alpha,25(OH)2D3 analogues, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1alpha,25(OH)2D3 analogues. PMID- 22242855 TI - Biology and therapeutic applications of peroxisome proliferator- activated receptors. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/ differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. Recent advances have attributed novel functions to PPARs in blood pressure regulation, neuroinflammation, nerve-cell protection, inflammatory pain reduction, and the hypothalamic control of metabolism. The abundant pleiotropic actions of PPARs suggest that PPAR agonists have enormous therapeutic potential. However, current PPAR-based therapies often have undesired side effects due to the concomitant activation of PPARs in non-target cells. There is therefore growing interest in the development of cell-specific PPAR agonists and improvement of the clinical use of PPAR ligands. This review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer. PMID- 22242856 TI - Update on cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology. AB - Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormonereceptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPARgamma plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAARgamma ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazone have been largely used so far in the clinical practice. They provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of hearth failure, which seem to be PPARgamma mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPARgamma-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 2 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPARgamma ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPARgamma modulators and/or dual PPARalpha/gamma agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed. PMID- 22242857 TI - Natural ligands for nuclear receptors: biology and potential therapeutic applications. AB - Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics. Research in the last two decades has focused to the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. The search for novel NRs agonists and antagonists with enhanced selectivity prompted the exploration of the extraordinary chemical diversity associated to natural products. In recent years a number of natural products were disclosed as ligands of NRs and proved to have remarkable affinity and in some cases peculiar mode of action. In this review the natural ligands of the subfamily NR1, NR2, and NR3 will be described with an emphasis to their mechanisms of action and pharmacological profiles. PMID- 22242852 TI - General molecular biology and architecture of nuclear receptors. AB - Nuclear receptors (NRs) regulate and coordinate multiple processes by integrating internal and external signals, thereby maintaining homeostasis in front of nutritional, behavioral and environmental challenges. NRs exhibit strong similarities in their structure and mode of action: by selective transcriptional activation or repression of cognate target genes, which can either be controlled through a direct, DNA binding-dependent mechanism or through crosstalk with other transcriptional regulators, NRs modulate the expression of gene clusters thus achieving coordinated tissue responses. Additionally, non genomic effects of NR ligands appear mediated by ill-defined mechanisms at the plasma membrane. These effects mediate potential therapeutic effects as small lipophilic molecule targets, and many efforts have been put in elucidating their precise mechanism of action and pathophysiological roles. Currently, numerous nuclear receptor ligand analogs are used in therapy or are tested in clinical trials against various diseases such as hypertriglyceridemia, atherosclerosis, diabetes, allergies and cancer and others. PMID- 22242858 TI - Molecular determinants of gastrointestinal and liver cancers: role of bile acid activated nuclear receptors. AB - Invasion and metastasis are critical determinants of gastrointestinal and liver cancers morbidity. Genes and molecules participating in these steps (e.g. growth factors and their receptors, cell cycle regulators, cell adhesion molecules, matrix degrading enzymes) have been progressively clarified. Activated Wnt signaling pathway has been found in these tumors. Mutations in one of the DNA mismatch repair genes, alterations in epigenetics, such as aberrant DNA methylation and histone modifications are associated with the progression of gastrointestinal and control liver neoplasies. Bile acids (BAs), the main constituents of bile, activate a family of nuclear receptors (NRs) that control critical steps in bile acid homeostasis, endo- and xenobiotics detoxification, glucose, lipid metabolism and innate immunity. BAs activated NRs are misregulated in gastrointestinal and liver cancers. The present review provides an overview on the molecular determinants involved in gastrointestinal and liver cancers and focuses on the role of BAs activated NRs in the pathogenesis of these tumors. PMID- 22242859 TI - Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders. AB - The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/ activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocyte's basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding sideeffects linked to FXR activation. PMID- 22242860 TI - PCR-free telomerase assay using chronocoulometry coupled with hexaammineruthenium(III) chloride. AB - An electrochemical method based on chronocoulometry coupled with hexaammineruthenium chloride (RuHex) is proposed for simple and rapid assay of telomerase without relying on PCR and gel electrophoresis. Thus, DNA extended by telomerase in extracts of as small as 5-1,000 HeLa cells on the TS primer immobilized electrodes was quantified successfully. This method is suitable for quick screening of drug candidates which inhibit telomerase. When 10 compounds were tested, the multiplicity of extension (x in (TTAGGG)(x)) varied from 11 to 0, suggesting that there is more than one mechanism of inhibition. IC(50) values of telomerase inhibitors TMPyP4 and PIPER were determined as 5.5 and 15 MUM, respectively, though their mechanisms of inhibition are different. This method is capable of discriminating two possible mechanisms of telomerase inhibition: direct binding of inhibitors to telomerase and indirect inhibition through their binding to the quadruplex generated by telomerase. As this method is easy and quick to run, it will be useful for high-throughput screening of drug candidates which inhibit telomerase. PMID- 22242861 TI - Clinical utility of the Bem Sex Role Inventory (BSRI) in the Spanish transsexual and nontranssexual population. AB - The aim of the study is to evaluate the usefulness of the Bem Sex Role Inventory (BSRI; Bem, 1974), an overall measurement of the cultural construct of masculinity and femininity, in the psychological assessment of Spanish transsexuals. Seventy male-to-female transsexuals (MF), 51 female-to-male transsexuals (FM), 77 control men, and 79 control women completed the Spanish version of the BSRI. Statistically significant differences between groups were only found on the femininity scale, on which MF transsexuals and control women scored significantly higher than FM transsexuals and control men. The results indicate that (a) only the femininity scale of the BSRI appears to be useful today for evaluating differences in the sex-role identification in Spanish controls and transsexuals; and (b) MF and FM transsexuals score as a function of their gender identity instead of their anatomical sex on the BSRI femininity scale. PMID- 22242862 TI - Reactivity of divalent germanium alkoxide complexes is in sharp contrast to the heavier tin and lead analogues. AB - The chemistry of beta-diketiminate germanium alkoxide complexes has been examined and shown to be in sharp contrast to its heavier congeners. For instance, (BDI)GeOR (BDI = [{N(2,6-(i)Pr(2)C(6)H(3))C(Me)}(2)CH], R = (i)Pr, (s)Bu, (t)Bu) does not react with carbon dioxide to form a metal carbonate complex. Addition of aliphatic electrophiles, such as methyl iodide or methyl triflate, results in the net oxidative addition to the germanium, giving cationic tetravalent germanium complexes, [(BDI)Ge(Me)OR][X] (X = I, OTf). An examination of the contrasting reactivities of the alkoxide ligand and the germanium loan pair with Lewis acids yielded the unusual germanium(II)-copper(I) adduct, {MU(2) Cu(2)I(2)}[(BDI)GeO(t)Bu](2). This complex not only displays a rare example of a divalent Ge-Cu bond, but is the first example in which a planar Cu(2)I(2) diamond core possesses a three-coordinate copper bound to another metal center. PMID- 22242864 TI - Root proteases: reinforced links between nitrogen uptake and mobilization and drought tolerance. AB - Integral subcellular and cellular functions ranging from gene expression, protein targeting and nutrient supply to cell differentiation and cell death require proteases. Plants have unique organelles such as chloroplasts composed of unique proteins that carry out the unique process of photosynthesis. Hence, along with proteases common across kingdoms, plants contain unique proteases. Improved knowledge on proteases can lead to a better understanding of plant development, differentiation and death. Because of their importance in multiple processes, plant proteases are actively studied. However, root proteases specifically are not as well studied. The associated rhizosphere, organic matter and/or inorganic matter make roots a difficult system. Yet recent research conclusively demonstrated the occurrence of endocytosis of proteins, peptides and even microbes by root cells, which, hitherto known for specialized pathogenesis or symbiosis, was unsuspected for nutrient uptake. These results reinforced the importance of root proteases in endocytosis or root exudate-mediated nutrient uptake. Rhizoplane, rhizosphere or in planta protease action on proteins, peptides and microbes generates sources of nitrogen, especially during abiotic stresses such as drought. This article highlights the recent research on root proteases for nitrogen uptake and the connection of the two to drought-tolerance mechanisms. Drought-induced proteases in rice roots, as known from rice expression databases, are discussed for future research on certain M50, Deg, FtsH, AMSH and deubiquitination proteases. The recent emphasis on linking drought and plant hydraulics to nutrient metabolism is illustrated and connected to the value of a systematic study of root proteases in crop improvement. PMID- 22242865 TI - Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. AB - BACKGROUND AIMS. TissueGene-C (TG-C) represents a cell-mediated gene therapy for localized delivery of allogeneic chondrocytes expressing transforming growth factor (TGF)-beta1 directly to the damaged knee joint. Untransduced human chondrocytes (hChonJ cells) have also been incorporated into the TG-C product at a 3:1 ratio with TGF-beta1-expressing chondrocytes (hChonJb#7) in order to help fill in the defect and as target cells for the actions of the expressed TGF beta1. METHODS: A phase I dose-escalating clinical trial was performed to evaluate the safety and biologic activity of TG-C in patients with advanced osteoarthritis of the knee joint (full thickness cartilage defect) that was refractory to existing non-operative therapies. Following a single intra articular injection into the joint space of the damaged knee, patients were monitored for safety, and an evaluation was performed to assess the pharmacokinetics and biologic activity of TG-C. RESULTS: There were no treatment related serious adverse events. Swelling, effusion and minor localized reactions such as warming sensation or itching were observed in a dose-dependent manner at the injection site. Knee evaluation scores seemed to indicate a dose-dependent trend toward efficacy; however, patient numbers were not sufficient to determine statistical significance. CONCLUSIONS: Overall, there were no significant safety issues related to the administration of TG-C, with only some minor injection site reactions observed. Additionally, knee scoring analyzes indicated a possibility that TG-C may contribute to improvement of arthritic symptoms. More study is warranted to evaluate further the safety and determine the potential efficacy of TG-C. PMID- 22242866 TI - An index-based approach to assessing recalcitrance and soil carbon sequestration potential of engineered black carbons (biochars). AB - The ability of engineered black carbons (or biochars) to resist abiotic and, or biotic degradation (herein referred to as recalcitrance) is crucial to their successful deployment as a soil carbon sequestration strategy. A new recalcitrance index, the R(50), for assessing biochar quality for carbon sequestration is proposed. The R(50) is based on the relative thermal stability of a given biochar to that of graphite and was developed and evaluated with a variety of biochars (n = 59), and soot-like black carbons. Comparison of R(50), with biochar physicochemical properties and biochar-C mineralization revealed the existence of a quantifiable relationship between R(50) and biochar recalcitrance. As presented here, the R(50) is immediately applicable to pre-land application screening of biochars into Class A (R(50) >= 0.70), Class B (0.50 <= R(50) < 0.70) or Class C (R(50) < 0.50) recalcitrance/carbon sequestration classes. Class A and Class C biochars would have carbon sequestration potential comparable to soot/graphite and uncharred plant biomass, respectively, whereas Class B biochars would have intermediate carbon sequestration potential. We believe that the coupling of the R(50), to an index-based degradation, and an economic model could provide a suitable framework in which to comprehensively assess soil carbon sequestration in biochars. PMID- 22242867 TI - QSAR and ANN for the estimation of water solubility of 209 polychlorinated trans azobenzenes. AB - Polychlorinated trans-azobenzenes (PCt-ABs) are less studied a highly toxic impurity in 2,3-dichloroaniline (2,3-D) and some herbicides and are compounds of environmental relevance lacking experimental physical and chemical properties data. In this study, to fulfill gaps on environmentally relevant partitioning properties of PCABs, the values of water solubility (MUg/L and log S) have been determined for 209 congeners of chloro-trans-azobenzene (Ct-AB) by means of quantitative structure - property relationship (QSPR) approach and artificial neural networks (ANN) predictive ability. The quantitative structure - property relationship (QSPR) approach used based on geometry optimalization and quantum chemical structural descriptors, which were computed on the level of density functional theory (DFT) using B3LYP functional and 6-311++G** basis set in Gaussian 03 and the semi-empirical quantum chemistry method for property parameterization (PM6) in the molecular orbital package (MOPAC) software. The predicted solubility of PCt-ABs by PM6 and DFT models and depending on a congener within a homologue class varied between 1995-11481 and 5370-15135 MUg/L for mono ; 170-5495 and 138-9332 MUg/L for di-; 36-1950 and 209-5248 MUg/L for tri-; 15 794 and 41-3715 MUg/L for tetra-; 5.5-209 and 39-1259 MUg/L for penta-; 1.8-98 and 3.5-1096 MUg/L for hexa-; 1.5-34 and 4.7-214 MUg/L for hepta-; 0.71-6.2 and 0.76-26 MUg/L for octa-; 0.83-1.7 and 0.69-1.2 MUg/L for nonaCt-ABs; and between 0.36 and 0.04 MUg/L for decaCt-AB, respectively. The calculations by PM6 were highly efficient and inexpensive compared to these by DFT, while both models gave data of similar accuracy. PMID- 22242868 TI - A simple and high collection efficiency sampling method for monitoring of carbonyl compounds in a workplace environment. AB - A simple and high collection efficiency sampling method was developed for the monitoring of carbonyl compounds, i.e., formaldehyde, acetaldehyde, benzaldehyde, acetone and butanone. The determination is based on the reaction of these compounds in a sensitive absorbing solution of 2,4-DNPH. After the completion of the reaction the derivatives were analyzed by the HPLC system without any post sample preparation. The operation conditions of the proposed method were optimized to obtain the highest sampling efficiency within a short analysis time. The collection efficiency for all compounds was in the range of 95 +/- 3 % to 99 +/- 4 % and the relative standard deviations (n = 15) were less than 10 %. This method was validated and applied to monitor carbonyl compounds in air samples from an occupational environment, the adhesive industry. Formaldehyde was found to be the most abundant carbonyl compound (64 +/- 8 to 250 +/- 20 ppbv), followed by acetaldehyde (ND to 24 +/- 6 ppbv), acetone (ND to 21 +/- 5 ppbv) and benzaldehyde (ND to 27 +/- 7 ppbv). The sampling of air directly into the absorbing solution was compared with the conventional method of using an adsorbent cartridge, and the results were in good agreement (P > 0.05). PMID- 22242869 TI - Analysis of haloacetic acids in water and air (aerosols) from indoor swimming pools using HS-SPME/GC/ECD. AB - A solid phase microextraction method was used for the analysis of nine haloacetic acids (HAAs) in water and air (aerosols) from indoor swimming pools (ISPs). The analysis is characterized by derivatization of HAAs to their methyl-esters with dimethyl sulphate, headspace solid phase microextraction (HS-SPME) with a Carboxen-polydimethylsiloxane (CAR-PDMS) fiber and gas chromatography - electron capture detector (GC/ECD). High correlation coefficients were obtained for esters mixture calibration lines and detection limits were found to be at the low ppb level. Repeatability was assessed and coefficients of variation varied from 10 to 20%. Reproducibility was also evaluated and coefficients of variation from 15 to 25% were obtained. Analytical results from four Portuguese ISPs showed that the mean concentration of total HAAs (THAAs) in water ranged from 10 +/- 2 to 183 +/- 28 MUg/L in which 55 +/- 20% corresponded to trichloroacetic and dichloroacetic acids (TCAA and DCAA). THAAs highest concentrations were directly related to higher ISPs' water organic matter content. In the lack of European specific regulation for water from ISPs and taking into consideration that ingestion is a form of exposure, THAAs concentration values were compared with drinking water maximum contamination level (MCL) of 60 MUg/L proposed by the US EPA for the sum of five HAAs. In 35% of water sampling campaigns the sum of MBAA (monobromoacetic acid), MCAA (monochloroacetic acid), DCAA and TCAA exceeded that MCL value. The concentrations obtained for THAAs in the ISPs' atmosphere ranged from 5 +/- 1 to 64 +/- 10 MUg/m(3) (T = 28 degrees C at 5 cm above the water surface) and were proportional to the aerosols' quantity, which was deeply related to indoor air ventilation system. PMID- 22242870 TI - Ecotoxicological evaluation of wastewater from 2.4.6-TNT production. AB - During the manufacture of explosives, large amounts of water are used to remove unwanted by-products generated. This water in turn, ends up in wastewater treatment plants or water bodies. The aim of this study was to evaluate the toxic potential of effluent generated by 2.4.6-Trinitrotoluene (TNT) production, yellow water, red water and mixture of yellow and red water, produced from a plant located in the Paraiba Valley, Sao Paolo state, Brazil. Daphnia similis, Danio rerio, Escherichia coli, Pseudomonas putida and Pseudokircheneriella subcaptata were used as test organisms. Physicochemical parameters such as color, pH, conductivity, total dissolved solids, dissolved oxygen, chemical oxygen demand (COD) and biochemical oxygen demand (BOD) were evaluated. Effluent from 2.4.6-TNT production was extremely toxic to all test organisms. The physicochemical parameters evaluated showed high levels of conductivity (from 41.533 to 42.344 MUS /cm) and chemical oxygen demand (COD of 8471 to 27.364 mg/L) for the effluents analyzed. PMID- 22242871 TI - Effect of feeding regime and the sludge age on the fate of acetate and the microbial composition in sequencing batch reactor. AB - The study investigated the effects of the feeding regime on the substrate metabolism under aerobic conditions. Throughout the study, two parallel sequencing batch reactors were operated using either short-term (pulse) or long term (almost continuous) feeding of acetate at two different sludge ages of two days and eight days. The microbial characterization studies showed that the feeding regime did not change the microbial composition as determined by the fluorescent in situ hybridization (FISH) analysis, however did strongly affect the substrate utilization mechanism. Additionally, the same microbial culture was able to utilize acetate with or without poly-beta-hydroxybutyrate (PHB) storage under pulse or continuous feeding, respectively. Conversely, the selected sludge ages induced significant changes in the microbial composition and floc structure, however, the well settling and bulking biomass selected at the sludge ages of eight days and two days, respectively, did not significantly affect the substrate utilization mechanism, where storage or growth prevailed as a result of either pulse or continuous feeding. PMID- 22242872 TI - Wastewater treatment in a submerged anaerobic membrane bioreactor. AB - Although most membrane bioreactors are used under aerobic conditions, over the last few years there has been increased interest in their application for anaerobic processes. This paper presents the results obtained when a bench-scale submerged anaerobic membrane bioreactor was used for the treatment of wastewaters generated in the agro-food industry. The reactor was fed with synthetic wastewater consisting of cheese whey and sucrose, and volumetric organic loading rates (OLRs) ranging from 1.5 to 13 kgCOD/(m(3)*d) were applied. Under the operating conditions studied, the maximum applicable OLR was between 6 and 10 gCOD/(g*L), which fell within the ranges of the high-rate anaerobic wastewater treatment systems, while high concentrations of volatile fatty acids were produced at higher OLR rates. With an OLR of 1.5-10 gCOD/(g*L), the reactor showed 94% COD removal, whereas this value dropped to 33% with the highest applied OLR of 13 gCOD/(g*L). The study therefore confirms that membrane bioreactors can be used for anaerobic wastewater treatment. PMID- 22242873 TI - De-colorization of textile wastewater by adsorption in a fluidized bed of locally available activated carbon. AB - The competency of a locally available granular activated carbon (GAC) in removing color from textile wastewater was studied in a fluidized bed. The characteristics of the fluidized bed with different GAC particles were obtained. A reactive dye was used to prepare the colored water of different dye concentrations. The effects of the GAC particle size, velocity and initial concentration of the colored water on dye removal were investigated. Equilibrium adsorption isotherm and breakthrough curves were generated to determine adsorption characteristics of activated carbon as well as mass transfer coefficients of the fluidized bed. The results of these experiments showed that an increase in liquid velocity and a decrease in particle size increased the color removal. The experiments were also carried out with industrial effluent and the de-colorization achieved was satisfactory. The mass transfer coefficient calculated for the fluidized bed was very low, which suggests that the GAC used in the local industries, although less expensive, may not be economically viable for de-colorization of industrial effluent. PMID- 22242874 TI - Modelling of the temperature-phased batch anaerobic digestion of raw sludge from an urban wastewater treatment plant. AB - The disposal of excess sludge from wastewater treatment plants is a serious problem that needs to be addressed. Temperature-phased anaerobic digestion (TPAD) which combines thermophilic and mesophilic processes in one, brings together the advantages of both systems. The aim of the present work was to develop a simple kinetic model to describe the TPAD of sewage sludge in batch completely stirred tank reactors (CSTRs) and to determine the kinetic parameters of both thermophilic and mesophilic stages. A zero-order kinetic equation described the thermophilic step after 2, 4 and 6 days of digestion time (experiment 1, 2 and 3, respectively), yet a first-order equation was found to be adequate to correlate the methane gas accumulated with time in the mesophilic step, the kinetic constant being 0.21 days(-1). The methane yield coefficient obtained was found to be almost proportional to the digestion time used in the thermophilic step with values of 0.067, 0.132 and 0.193 L CH(4) STP/g VS(added) for experiments 1, 2 and 3, respectively. By contrast, the kinetic constant of the mesophilic stage was not influenced by the digestion time used in the thermophilic phase. PMID- 22242875 TI - Solidification of Cd-bearing zeolitic tuff by reaction with lime. AB - This article aims to find a reliable procedure by which to remove Cd(2+) from water and store it safely. The proposed procedure includes Cd(2+) uptake by a zeolitic tuff, a natural cation exchanger, followed by stabilization of the contaminated solid in a hardened lime matrix. Several tuff-lime pastes were examined and their safety tested by cation leaching and mechanical strength measurement. It was demonstrated that a very cheap mixture, containing only 10% lime, is able to safely retain the harmful cation and may be disposed of in a segregated landfill. PMID- 22242876 TI - Isolation and identification of chromium-resistant bacteria: Test application for prevention of chromium toxicity in plant. AB - The purpose of this study was to isolate chromium resistant bacteria and characterize in depth before being applied for bioremediation or construction of chromium biosesnors. One of the major objectives was to identify the most useful strains with respect to chromium removal efficiency. Chromium resistant bacteria were isolated from tannery waste samples. These were characterized through biochemical tests and antibiotic assays. Cross metal reactivity, plasmid curing and cysteine quantifications were also performed. Gene sequencing was done for all the isolates and accession numbers received after submission to National Center for Biotechnology Information (NCBI). The removal capacity was also studied in broth cultures. The results were very encouraging since six new bacteria were recognised to withstand high concentrations of chromium. Out of these six bacteria, three i.e. Enterobacter aerogenes, Aeromonas sp., Acinetobacter sp. PD 12 performed very well by removing about 99% (average) from initial 19.8 ppm of Cr(VI) from a synthetic culture media. Enterobacter aerogenes, being the most efficient strain, was used to remediate hexavalent chromium from soil of potted plants- very encouraging results were obtained. These bacteria may be exploited for bioremediation of Cr (VI) and construction of microbial sensor in future. PMID- 22242877 TI - Statistical testing of input factors in the carbonation of brine impacted fly ash. AB - A D-optimal design was applied in the study of input factors: temperature, pressure, solid/liquid (S/L) ratio and particle size and their influence on the carbonation of brine impacted fly ash (FA) determined. Both temperature and pressure were at two levels (30 degrees C and 90 degrees C; 1 Mpa and 4 Mpa), S/L ratio was at three levels (0.1, 0.5 and 1) while particle size was at 4 levels (bulk ash, <20 MUm, 20 MUm -150 MUm and >150 MUm). Pressure was observed to have a slight influence on the % CaCO(3) yield while higher temperatures led to higher percentage CaCO(3) yield. The particle size range of 20 MUm - 150 MUm enhanced the degree of carbonation of the fly ash/brine slurries. This was closely followed by the bulk ash while the >150 MUm particle fraction had the least influence on the % CaCO(3). The effect of S/L ratio was temperature dependent. At low temperature, the S/L ratio of 1 resulted in the highest % CaCO(3) formation while at high temperature, the ratio of 0.5 resulted in the highest percentage CaCO(3) formation. Overall the two most important factors in the carbonation of FA and brine were found to be particle size and temperature. PMID- 22242878 TI - Studies on the removal of Lissamine Green B from clays and soil in comparison with contemporary approaches. AB - A combination of Fenton's reagent with electrochemistry has been demonstrated to be a efficient method for removing a dye (Lissamine Green B) from clays (kaolin, montmorillonite) and soil. The two-step approach described here involved quantitative extraction with hot water, followed by quantitative removal of the Lissamine Green dye by column chromatography using Octolig(r). The advantage of this procedure is success without the need for Fenton reagents or electricity. A disadvantage is the process would not work with polycyclic hydrocarbons such as phenanthrene, though the electro-Fenton degradation does. PMID- 22242879 TI - Performance of UASB reactor in the biotreatment of 1,1,2-Trichloroethane. AB - This article aims to examine the performance of bench-scale Upflow Anaerobic Sludge Blanket (UASB) reactor operated under varying operating conditions, during the treatment of simulated wastewater containing 1,1,2-Trichloroethane (TCA). Initially, reactor R1 (control) and reactor R2 (test) containing TCA were operated at 5 different Hydraulic Retention Times (HRTs) of 36, 30, 24, 18 and 12 hours. TCA removal decreased from 99.8% to 96.5%, when the HRT was reduced from 36 to 12 hours in discrete steps. Later, when the OLR was varied periodically from 1.5 to 3.1 kg COD/m(3).d to obtain a different substrate: co-substrate ratios; lower TCA removal efficiencies were observed at an OLR of 2.5 kg COD/ m(3).d and above. The average effluent concentrations of TCA and COD were 0.12 and 79 mg/L, respectively, at the optimum HRT of 24 hours; whereas the effluent TCA and COD concentrations at the substrate: co-substrate ratio of 50:1 was 0.06 mg/L and 48 mg/L, respectively. PMID- 22242880 TI - Electrokinetic transport of diesel-degrading microorganisms through soils of different textures using electric fields. AB - The mobilisation of diesel-degrading microorganisms in soils of three different textures (sandy, clay and silty) using electrokinetic techniques was studied. The mobilisation tests were performed using a laboratory-scale electrokinetic cell in which a synthetic soil column was inserted between the cathode and anode compartments. Microorganisms were located at the anode compartment at the beginning of each assay. A constant cell voltage was applied, and samples were taken from the cathode and anode compartments. Microbial transport through the soil strongly depended on soil particle size. Small particle sizes (silty and clay soil) travelled at low velocities (microbial transport rates of approximately 0.06 and 0.17 cm/min, respectively), while large particle sizes (sandy soil) led to high numbers of microorganisms passing through the soil column. In sandy soil, an increase in the voltage gradient did not increase the quantity of mobilised microorganisms (approximately 10(7) CFU/mL for every voltage gradient applied). For clay and silty soils, a higher voltage gradient led to a higher quantity of microorganisms mobilised to the cathodic compartment and a lower delay time for detecting the presence of microorganisms in the same compartment. PMID- 22242881 TI - A nutrient injection scheme for in situ bio-remediation. AB - Geological layers often have different hydraulic conductivities. This paper presents an innovative design for delivering aqueous substrates and nutrients to various stratified layers at desired rates during in-situ bio-stimulation. The new delivery system consists of intermittent porous tubes connected in series with impermeable polyethylene tubes that run horizontally in each stratified layer of a contaminated aquifer. Results of the tracer test indicated that the distribution of tritium through each porous tube was fairly uniform. A mathematical model was also developed to calculate the distribution of water flow through each porous tube. By controlling the permeability and the length of porous tubes placed in stratified layers, the new design provides a means to selectively deliver nutrients to various layers at desired rates according to aquifer heterogeneity. PMID- 22242882 TI - The effectiveness of sewage treatment processes to remove faecal pathogens and antibiotic residues. AB - Pathogens and antibiotics enter the aquatic environment via sewage effluents and may pose a health risk to wild life and humans. The aim of this study was to determine the levels of faecal bacteria, and selected antibiotic residues in raw wastewater and treated sewage effluents from three different sewage treatment plants in the Western Cape, South Africa. Sewage treatment plant 1 and 2 use older technologies, while sewage treatment plant 3 has been upgraded and membrane technologies were incorporated in the treatment processes. Coliforms and Escherichia coli (E. coli) were used as bioindicators for faecal bacteria. A chromogenic test was used to screen for coliforms and E. coli. Fluoroquinolones and sulfamethoxazole are commonly used antibiotics and were selected to monitor the efficiency of sewage treatment processes for antibiotic removal. Enzyme Linked Immunosorbent Assays (ELISAs) were used to quantitate antibiotic residues in raw and treated sewage. Raw intake water at all treatment plants contained total coliforms and E. coli. High removal of E. coli by treatment processes was evident for treatment plant 2 and 3 only. Fluoroquinolones and sulfamethoxazole were detected in raw wastewater from all sewage treatment plants. Treatment processes at plant 1 did not reduce the fluoroquinolone concentration in treated sewage effluents. Treatment processes at plant 2 and 3 reduced the fluoroquinolone concentration by 21% and 31%, respectively. Treatment processes at plant 1 did not reduce the sulfamethoxazole concentration in treated sewage effluents. Treatment processes at plant 2 and 3 reduced sulfamethoxazole by 34% and 56%, respectively. This study showed that bacteria and antibiotic residues are still discharged into the environment. Further research needs to be undertaken to improve sewage treatment technologies, thereby producing a better quality treated sewage effluent. PMID- 22242883 TI - Modified kraft lignin for bioremediation applications. AB - Kraft lignin (KL) from industrial pulping of E. globulus wood was subjected to the oxidative modification with the aim to produce sorbent mimicking humic matter for the bioremediation purposes. Lignin was oxidized by polyoxometalate Na(5)[PMo(10)V(2)O(40)] (POM), solely or in the presence of laccase, under pre selected aerobic conditions (50-60 degrees C, 1-2h, oxygen pressure 5 bar). The most pronounced lignin oxidation without its depolymerisation was observed in the reaction system POM/O(2). Modified lignins possessed increased amounts of COOH (up to 15 %) and CO (up to 500 %) groups, when compared to unmodified KL, and significantly higher molecular weights. Sorption capacity of KL before and after modification towards transition metals (cadmium (II) and mercury (II)) and triazine pesticide (atrazine) was assessed in batch experiments under equilibrium conditions. KL oxidation improved sorption capacity towards transition metals (up to 15 %) but not necessarily the uptake of atrazine that was higher for unmodified KL. PMID- 22242884 TI - A generalized model for transport of contaminants in soil by electric fields. AB - A generalized model applicable to soils contaminated with multiple species under enhanced boundary conditions during treatment by electric fields is presented. The partial differential equations describing species transport are developed by applying the law of mass conservation to their fluxes. Transport, due to migration, advection and diffusion, of each aqueous component and complex species are combined to produce one partial differential equation that describes transport of the total analytical concentrations of component species which are the primary dependent variables. This transport couples with geochemical reactions such as aqueous equilibrium, sorption, precipitation and dissolution. The enhanced model is used to simulate electrokinetic cleanup of lead and copper contaminants at an Army Firing Range. Acid enhancement is achieved by the use of adipic acid to neutralize the basic front produced for the cathode electrochemical reaction. The model is able to simulate enhanced application of the process by modifying the boundary conditions. The model showed that kinetics of geochemical reactions, such as metals dissolution/leaching and redox reactions, may be significant for realistic prediction of enhanced electrokinetic extraction of metals in real-world applications. PMID- 22242885 TI - Distribution and characteristics of total petroleum hydrocarbons in Jiuduansha tidal wetland and their potential impact on soil microbial respiration. AB - Microbial respiration is considered to be one of the most sensitive factors in soil; however, it might be altered by soil pollution. To clarify the potential impact of low levels of total petroleum hydrocarbons (TPHs) on soil microbial respiration (SMR) in tidal wetland in Jiuduansha, Shanghai, the distribution and characteristics of TPHs in the typical zones of the Jiuduansha Wetland and nearby watershed were analyzed, and the relationship between soil microbial respiration and TPH was studied. The results showed that the average concentration of TPHs in the soil was 23.98 mg.kg(-1), which was a relatively low pollution level. Moreover, the concentration of TPHs in the soil changed significantly with tidal elevation. The main petroleum pollutants in the soil were alkane and aromatic hydrocarbons with less than 10 carbons. The average concentration of TPHs of the surrounding watershed of Jiuduansha was about 0.26 mg.L(-1), indicating that it was grade III seawater. The concentration of the inner watershed was higher than that of the outer watershed, indicating that Jiuduansha wetland could enrich TPHs to some extent. Based on the results of regression analysis and a pot experiment, there was a relationship between TPHs and soil microbial respiration. The input of TPHs from the surrounding watershed over long term periods might improve the SMR of the Jiuduansha tidal wetland. PMID- 22242886 TI - Phototherapy in France: quantitative data from the National Health Insurance register. PMID- 22242888 TI - Ion transport in mesoporous silica SBA-16 thin films with 3D cubic structures. AB - Mesoporous silica SBA-16 thin films with highly ordered 3D cubic structures were synthesized on a Si substrate via the dip-coating method. After these films were filled with KCl aqueous solutions, the ionic current passing through the mesopores was measured by applying dc electric fields. At low ion concentrations, the measured I-V curves were nonlinear and the current increased exponentially with respect to voltage. As the ion concentration increased, the I-V curve approached linear behavior. The nonlinear behavior of I-V curves can be reasonably attributed to the electric potential barrier created in nanopores. PMID- 22242887 TI - Increased cortical BOLD signal anticipates generalized spike and wave discharges in adolescents and adults with idiopathic generalized epilepsies. AB - PURPOSE: Electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so-called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level-dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset. METHODS: Twenty-one patients with IGE underwent EEG-fMRI coregistration. EEG-related analyses were run both at the single-subject and at group level (random effect). The time-course analysis was conducted for 3 s time windows before, during, and after GSWDs, and they were included until no further BOLD signal changes were observed. KEY FINDINGS: Fifteen patients (nine female, mean age 28 years) had GSWDs during EEG-fMRI coregistration (262 total events, mean duration 4 s). Time-course group analysis showed BOLD increments starting approximately 10 s before GSWD onset located in frontal and parietal cortical areas, and especially in the precuneus-posterior cingulate region. At GSWD onset, BOLD increments were located in thalamus, cerebellum, and anterior cingulate gyrus, whereas BOLD decrements were observed in the DMN regions persisting until 9 s after onset. SIGNIFICANCE: Hemodynamic changes (BOLD increments) occurred in specific cortical areas, namely the precuneus/posterior cingulate, lateral parietal, and frontal cortices, several seconds before EEG onset of GSWD. A dysfunction of these brain regions, some of which belongs to the DMN, may be crucial in generating GSWDs in patients with IGE. PMID- 22242890 TI - Association between antidepressants and breast/ovarian cancer. AB - INTRODUCTION: Women are more vulnerable to the development of major depressive disorder (MDD) than men. Although several epidemiological studies have investigated the association between antidepressants and the risk of developing cancer, different methodologies were applied and as a result most of the results were inconsistent. A recent study by Cosgrove and colleagues at Harvard University investigated the relationship between prescriptions for antidepressants and breast/ovarian cancer, to determine whether such medications are associated with the development of cancer. AREAS COVERED: This paper discusses the relationship between the use of antidepressants and breast/ovarian cancer risk in the context of the potential limitations and significance of this recent research. EXPERT OPINION: Clinicians might need to be vigilant when treating female patients who require antidepressants, particularly those with other clinical risk factors in relation to breast/ovarian cancer; although more data will be necessary to evaluate the exact association between antidepressants and the development of such cancers. PMID- 22242891 TI - Improved synthesis of lysine- and arginine-derived Amadori and Heyns products and in vitro measurement of their angiotensin I-converting enzyme inhibitory activity. AB - The L-lysine- and L-arginine-derived Amadori and Heyns products consisting of N (1-deoxy-d-fructos-1-yl)amino acid and N-(2-deoxy-d-glucos-2-yl)amino acid were prepared by reaction of d-fructose and d-glucose with l-lysine hydrochloride and l-arginine hydrochloride using commercial zinc powder as deprotonating reagent and also as catalyst precursor in a simple synthetic route in high yield. These compounds were screened for angiotensin I-converting enzyme (ACE) inhibitory activity using a high-throughput colorimetric assay (utilizing porcine kidney ACE). The IC(50) values fall in the range of 1030-1175 MUM, with N(alpha)-(1 deoxy-d-fructos-1-yl)arginine showing the best IC(50) value (1030 +/- 38 MUM). This study demonstrates an improved synthetic method for simple Amadori and Heyns products and their moderate ACE inhibitor activity. PMID- 22242889 TI - Community structure of bacteria and fungi in aerosols of a pig confinement building. AB - Modern intensive husbandry practices can create poor indoor air quality, with high levels of airborne dust, endotoxins, ammonia, and microorganisms. Air in a sow breeding barn was investigated to determine the biomass composition of bioaerosols using molecular methods supplemented with microscopic and cultivation dependent approaches. A total of 2.7 +/- 0.7 * 10(7) bacterial cells m(-3) air and 1.2 +/- 0.3 * 10(6) fungi spores m(-3) were detected, corresponding to the fungal biovolume constituted 98% of the total microbial biovolume (fungal and bacterial). Fifty-two percent of all 4',6-diamidino-2-phenyl indole-stained cells were detectable with fluorescence in situ hybridization (FISH) with a general bacterial probe mixture. Quantitative FISH of the bacterial consortium revealed Firmicutes as the dominant group with Streptococcus as the major genus, while Actinobacteria constituted 10% of the detectable bacteria. Additionally, the study revealed an abundant and diverse fungal community including species not previously found in similar environments. The most abundant fungal 18S rRNA gene clone sequences identified affiliated with the Aspergillus-Eurotium cluster, but among others, species of Wallemia, Mucorales, and Russulales were detected. For both fungi and anaerobic bacteria, a hitherto undescribed diversity was found in bioaerosols from a modern sow breeding barn, which potentially could create poor indoor air quality, although their effect on the health of farmworkers and stock still is not resolved. PMID- 22242892 TI - Prenatal substance use, prenatal stress and offspring behavioural outcomes: considerations for future studies. AB - BACKGROUND: Numerous studies have been conducted in which the most common forms of maternal substance use during pregnancy (smoking, drinking or using cannabis) and maternal stress during pregnancy and her offspring's developmental or behavioural outcome have been the focus of interest. These studies seem to suggest that any perturbation caused by maternal substance use or maternal stress during fetal development may have (enduring) effects on offspring behaviour. However, recent developments in research methodology used to examine these associations question whether these prenatal influences actually cause altered offspring outcomes. AIMS: This review provides a short overview of previous studies in this field of research, some methodological issues particularly involved in studies that focus on the association between maternal substance use or stress during pregnancy and offspring's outcomes. Furthermore, it introduces several new approaches that have been applied recently to test these associations. RESULTS: Studies that applied these designs to disentangle prenatal influences from associated or inherited factors consistently show an effect of prenatal substance use exposure on birth weight, but yield little evidence for causal effects on behaviour. In contrast, prenatal stress may have a causal effect on some aspects of behaviour, although only one study thus far has been able to differentiate heritable factors from environmental factors. PMID- 22242893 TI - Role of individual histidines in the pH-dependent global stability of human chloride intracellular channel 1. AB - Chloride intracellular channel proteins exist in both a soluble cytosolic form and a membrane-bound form. The mechanism of conversion between the two forms is not properly understood, although one of the contributing factors is believed to be the variation in pH between the cytosol (~7.4) and the membrane (~5.5). We systematically mutated each of the three histidine residues in CLIC1 to an alanine at position 74 and a phenylalanine at positions 185 and 207. We examined the effect of the histidine-mediated pH dependence on the structure and global stability of CLIC1. None of the mutations were found to alter the global structure of the protein. However, the stability of H74A-CLIC1 and H185F-CLIC1, as calculated from the equilibrium unfolding data, is no longer dependent on pH because similar trends are observed at pH 7.0 and 5.5. The crystal structures show that the mutations result in changes in the local hydrogen bond coordination. Because the mutant total free energy change upon unfolding is not different from that of the wild type at pH 7.0, despite the presence of intermediates that are not seen in the wild type, we propose that it may be the stability of the intermediate state rather than the native state that is dependent on pH. On the basis of the lower stability of the intermediate in the H74A and H185F mutants compared to that of the wild type, we conclude that both His74 and His185 are involved in triggering the pH changes to the conformational stability of wild-type CLIC1 via their protonation, which stabilizes the intermediate state. PMID- 22242894 TI - Portable electrochemical surface-enhanced Raman spectroscopy system for routine spectroelectrochemical analysis. AB - A simple, portable electrochemical surface-enhanced Raman spectroscopy (SERS) system is reported, consisting of a small benchtop Raman spectrometer, a laptop computer, and a portable USB potentiostat. Screen printed electrodes modified with silver colloidal nanoparticles are used as the SERS-active electrode, which exhibit long-term stability once prepared. Spectroelectrochemical analyses of para-aminothiophenol and melamine as model systems was conducted. In both cases, an increase in SERS signal is observed upon modulation of the applied voltage, indicating an inherent benefit of such a system wherein the surface charge can be easily tuned. Given the low cost, rapid analysis time, and good sensitivity of this system, this simple setup could be implemented for many on-site sensing applications, ranging from food and drug analysis to environmental monitoring and to chemical and biological warfare agent detection. PMID- 22242895 TI - Authors' response to Hermann et al. Minimum quality criteria are needed in the assessment and communication of unexpected drug safety findings of marketed products from RCTs. PMID- 22242896 TI - The antioxidative effect of de novo generated vitamin B6 in Plasmodium falciparum validated by protein interference. AB - The malaria parasite Plasmodium falciparum is able to synthesize de novo PLP (pyridoxal 5'-phosphate), the active form of vitamin B6. In the present study, we have shown that the de novo synthesized PLP is used by the parasite to detoxify 1O2 (singlet molecular oxygen), a highly destructive reactive oxygen species arising from haemoglobin digestion. The formation of 1O2 and the response of the parasite were monitored by live-cell fluorescence microscopy, by transcription analysis and by determination of PLP levels in the parasite. Pull-down experiments of transgenic parasites overexpressing the vitamin B6-biosynthetic enzymes PfPdx1 and PfPdx2 clearly demonstrated an interaction of the two proteins in vivo which results in an elevated PLP level from 12.5 MUM in wild-type parasites to 36.6 MUM in the PfPdx1/PfPdx2-overexpressing cells and thus to a higher tolerance towards 1O2. In contrast, by applying the dominant-negative effect on the cellular level using inactive mutants of PfPdx1 and PfPdx2, P. falciparum becomes susceptible to 1O2. Our results demonstrate clearly the crucial role of vitamin B6 biosynthesis in the detoxification of 1O2 in P. falciparum. Besides the known role of PLP as a cofactor of many essential enzymes, this second important task of the vitamin B6 de novo synthesis as antioxidant emphasizes the high potential of this pathway as a target of new anti malarial drugs. PMID- 22242897 TI - Functionalized hydrophobic poly(glycerol-co-epsilon-caprolactone) depots for controlled drug release. AB - A limitation to many polymer-based drug delivery systems is the lack of ability to customize a particular polymer composition for tailoring drug release kinetics to a specific clinical application. In this study, we investigated the structure property effects of conjugating various hydrophobic biocompatible side chains to poly(glycerol-co-caprolactone) copolymers with the goal of achieving prolonged and controlled release of a chemotherapeutic agent. The choice of side chain significantly affected the resulting polymer properties including thermal transitions, relative crystallinity (DeltaH(f)), and hydrophobicity. Drug-loaded films cast from solutions of polymer and 10-hydroxycamptothecin demonstrated prolonged release from four to over seven weeks depending upon side chain structure without initial burst release behavior. Use of the stearic acid conjugated poly(glycerol-co-caprolactone) films afforded substantial anticancer activity in vitro for at least 50 days when exposed to fresh cultures of A549 human lung cancer cells over 24 h intervals, correlating well with the measured drug release kinetics. PMID- 22242898 TI - Signal amplification cytosensor for evaluation of drug-induced cancer cell apoptosis. AB - Apoptosis is involved in the pathology of a variety of diseases. The measurement of apoptosis will help us to evaluate the onset of disease and the effect of therapeutic interventions. In addition, the increased demand for understanding the early stages of apoptosis is pushing the envelope for solutions in early instance real-time monitoring of death kinetics. Here we present a novel electrochemiluminescent cytosensing strategy to quantitate apoptotic cell numbers, screen some anticancer drugs, and evaluate their effects on hepatocarcinoma cell line (HepG2) cells by utilizing the human antiphosphatidyl serine antibody (APSA) conjugated Ru(bpy)(3)(2+)-encapsulated silica nanoparticle (APSA-SiO(2)@Ru) as the detection probe. HepG2 cells were easily immobilized on the arginine-glycine-aspartic acid-serine (RGDS)-multiwalled carbon nanotubes (RGDS-MWCNTs) nanocomposite by the specific combination of RGD domains with integrin receptors on the cell surface. Then APSA-SiO(2)@Ru was introduced to the surface of apoptosis cells through the specific interaction between APSA and phosphatidylserine (PS) that distributed on the outer membrane of apoptotic cells. On the basis of the signal amplification of the APSA-SiO(2)@Ru nanoprobe, the cytosensor could respond as low as 800 cells mL(-1), showing very high sensitivity. In addition, the dynamic alterations of surface PS expression on HepG2 cells in response to drugs and the cell heterogeneity were also demonstrated. The strategy presented a promising platform for highly sensitive cytosensing and convenient screening of some clinically available anticancer drugs. PMID- 22242900 TI - Personality assessment screener in a primary care sample of low-income urban women. AB - The diagnostic efficiency of the Personality Assessment Screener (PAS; Morey, 1997) total score was evaluated using selected scales from the Patient Health Questionnaire (Spitzer, Kroenke, & Williams, 1999), the fourth edition of the Personality Diagnostic Questionnaire (Hyler, 1994), and the Alcohol Use Disorders Identification Test (Saunders, Aasland, Babor, DeLaFuente, & Grant, 1993) as reference standards. Complete data were collected from 110 women seeking treatment at an urban family medicine training clinic. Total PAS scores were effective in identifying patients with mood disorders, cluster B personality disorders, and alcohol use disorders, but the optimum cut scores were higher than the cut score of 19 recommended by Morey (1997). The 10 PAS element scores showed good convergent and discriminant correlations with the reference measures. These findings support the utility of the PAS to screen for major forms of psychopathology in an urban primary care setting. PMID- 22242901 TI - Short communication: Evaluation of GB virus C/hepatitis G viral load among HIV type 1-coinfected patients in Sao Paulo, Brazil. AB - Recent studies suggest that GB virus C/hepatitis G virus (GBV-C/HGV) infection in HIV-positive individuals is associated with a slower progression to AIDS, leading to a lower HIV viral load and higher counts of CD4(+) T cells, although many studies have failed to demonstrate these beneficial effects. We developed a Real Time PCR (TaqMan RT qPCR) to quantify the viral load of GBV-C/HGV in 102 HIV-1 infected patients, who were also evaluated for the presence of anti-E2. The prevalence of GBV-C/HGV infection was 21% among infected patients and the mean plasma viral load was 3.62 +/- 0.64 log(10) copies/ml. Despite the high prevalence, there was no statistical difference when we compared the mean viral load (p<=0.46) and the average count of CD4(+) (p<=0.29) and CD8(+) (p<=0.64) among patients infected by GBV-C/HGV and HIV and patients infected only by HIV. This fact can be explained by the number of patients included in the study. Nevertheless, compared to other studies, we observed a discrete number of patients with undetectable HIV load and lower median viral load in the group presenting GBV-C/HGV RNA. Our study suggests that there may be an impact on HIV viral load in GBV-C/HGV-coinfected patients. However, further studies are needed to elucidate the molecular and cellular mechanisms involved in this viral interaction, previously reported in other studies, with the aim of contributing to the development of new targets for drugs against HIV. PMID- 22242902 TI - Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (Addison's Disease). AB - BACKGROUND: Hypoglycemia can be a symptom in patients with Addison's disease. The common regimen of replacement therapy with oral glucocorticoids results in unphysiological low cortisol levels in the early morning, the time of highest insulin sensitivity. Therefore patients with Addison's disease are at risk for unrecognized and potentially severe nocturnal hypoglycemia also because of a disturbed counterregulatory function. Use of a continuous glucose monitoring system (CGMS) could help to adjust hydrocortisone treatment and to avoid nocturnal hypoglycemia in these patients. METHODS: Thirteen patients with Addison's disease were screened for hypoglycemia wearing a CGMS for 3-5 days. RESULTS: In one patient we identified a hypoglycemic episode at 3:45 a.m. with a blood glucose level of 46 mg/dL, clearly beneath the 95% tolerance interval of minimal glucose levels between 2 and 4 a.m. (53.84 mg/dL). After the hydrocortisone replacement scheme was changed, the minimum blood glucose level between 2 and 4 a.m. normalized to 87 mg/dL. CONCLUSIONS: Continuous glucose monitoring can detect nocturnal hypoglycemia in patients with primary adrenal insufficiency and hence prevent in these patients an impaired quality of life and even serious adverse effects. PMID- 22242903 TI - Senescence-associated proteases in plants. AB - Senescence is the final developmental stage of every plant organ, which leads to cell death. It is a highly regulated process, involving differential gene expression and outstanding increment in the rate of protein degradation. Senescence-associated proteolysis enables the remobilization of nutrients, such as nitrogen (N), from senescent tissues to developing organs or seeds. In addition to the nutrient recycling function, senescence-associated proteases are also involved in the regulation of the senescence process. Nearly, all protease families have been associated with some aspects of plant senescence, and numerous reports addressing the new identification of senescence-associated proteases are published every year. Here, we provide an updated report with the most recent information published in the field, focusing on senescence-associated proteases presumably involved in N remobilization. PMID- 22242904 TI - Synthesis, molecular and electronic structure of U(V)(O)[N(SiMe3)2]3. AB - Addition of 1 equiv of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to U(NR(2))(3) in hexanes affords U(O)(NR(2))(3) (2), which can be isolated in 73% yield. Complex 2 is a rare example of a terminal U(V) oxo complex. In contrast, addition of 1 equiv of Me(3)NO to U(NR(2))(3) (R = SiMe(3)) in pentane generates the U(IV) bridging oxo [(NR(2))(3)U](2)(MU-O) (3) in moderate yields. Also formed in this reaction, in low yield, is the U(IV) iodide complex U(I)(NR(2))(3) (4). The iodide ligand in 4 likely originates from residual NaI, present in the U(NR(2))(3) starting material. Complex 4 can be generated rationally by addition of 0.5 equiv of I(2) to a hexane solution of U(NR(2))(3), where it can be isolated in moderate yield as a tan crystalline solid. The solid-state molecular structures and magnetic susceptibilities of 2, 3, and 4 have been measured. In addition, the electronic structures of 2 and 3 have been investigated by density functional theory (DFT) methods. PMID- 22242905 TI - Synthesis and CO2 adsorption properties of molecularly imprinted adsorbents. AB - A series of molecularly imprinted adsorbents of CO(2) were developed by molecular self-assembly procedures, using ethanedioic acid, acrylamide, and ethylene glycol dimethacrylate as template, functional monomer, and cross-linker, respectively. Textural properties of these adsorbents were characterized by N(2) adsorption experiment, thermo-gravimetric analysis, and Fourier transform infrared spectroscopy. CO(2) adsorption capacities of adsorbents were investigated by thermo-gravimetric balance under 15% CO(2)/85% Ar atmosphere. Adsorption selectivity of CO(2) was studied by fixed-bed adsorption/desorption experiments. All the adsorbents displayed good thermal stability at 200 degrees C. Among them, MIP1b, with the higher amine content, exhibited the largest CO(2) capacity, which maintained steady after 50 adsorption-desorption cycles. Although MIP3 showed the highest specific surface, the CO(2) capacity was lower than that of MIP1b. CO(2) adsorption mechanism of molecularly imprinted adsorbents was determined to be physical sorption according to the adsorption enthalpies integrated from the DSC heatflow profiles. The calculated separation factors of CO(2) under 15% CO(2)/85% N(2) atmosphere were above 100 for all adsorbents. PMID- 22242906 TI - Crohn's disease and the mycobacterioses: a quarter century later. Causation or simple association? AB - It has been more than 25 years since Mycobacterium paratuberculosis was first proposed as an etiologic agent in Crohn's disease based on the isolation of this organism from several patients. Since that time, a great deal of information has been accumulated that clearly establishes an association between M. paratuberculosis and Crohn's disease. However, data are conflicting and difficult to interpret and the field has become divided into committed advocates and confirmed skeptics. This review is an attempt to provide a thorough and objective summary of current knowledge from both basic and clinical research from the views and interpretations of both the antagonists and proponents. The reader is left to draw his or her own conclusions related to the validity of the issues and claims made by the opposing views and data interpretations. Whether M. paratuberculosis is a causative agent in some cases or simply represents an incidental association remains a controversial topic, but current evidence suggests that the notion should not be so readily dismissed. Remaining questions that need to be addressed in defining the role of M. paratuberculosis in Crohn's disease and future implications are discussed. PMID- 22242907 TI - Uptake of dissolved organic carbon-complexed 65Cu by the green mussel Perna viridis. AB - Stable Cu isotope ((65)Cu) was complexed with various representative dissolved organic carbon (DOC) types, including coastal seawater DOC, fulvic acid (FA), cyanobacteria spirulina (SP) DOC, histidine (His), cysteine (Cys), and lipophilic diethyl dithiocarbamate (DDC) at different concentrations. The uptake of these dissolved Cu species by the coastal green mussel Perna viridis was quantified for the first time. Copper complexed with different DOC types were taken up in some measure by mussels, depending on the DOC types. However, complexation generally reduced Cu uptake as compared to that of inorganic Cu species, and DOC type specific negative relationships were found between DOC levels and Cu uptake. Strong Cu binding sites (including His and organic sulfur functional groups) within DOC appeared to control the inhibitory effects of DOC on Cu uptake, possibly due to the competitive binding of Cu between the dissolved phase and biological membranes. Therefore, differences in strong Cu binding site levels may explain the differences in bioavailability of Cu complexed with different types of DOC. At the same time, the variations in Cu-DOC uptake may also be partly attributed to the absorption of Cu-DOC complexes, especially for the small Cu-DOC complexes (e.g., Cu-Cys, Cu-His, or Cu-DDC). Our study highlights the importance of considering the specificity of Cu-DOC complexes when assessing biological exposure to dissolved Cu in natural waters, especially during events, such as phytoplankton bloom periods, that could modify DOC composition and concentrations. PMID- 22242908 TI - Growth mechanisms of fluorescent silver clusters regulated by polymorphic DNA templates: a DFT study. AB - The aggregation behaviors of silver atoms modulated by polymorphic DNA templates involving i-motif, G-quadruplex, and the Watson-Crick duplex, were investigated by using the density functional theory (DFT) calculations, combining with the experimental characterizations of CD, UV, fluorescence measurements and TEM, in order to understand the reason in the molecular level that polymorphic DNA templates affect the fluorescence emitting species of Ag nanomaterials. First, the affinity sites of silver ions on different DNA templates were analyzed by using DFT calculations, and the conformational variations of DNA templates caused by silver ions and atoms were disclosed. Second, the aggregation behaviors of silver atoms constrained by the polymorphic DNA templates were studied by DFT modeling, and distinct fluorescence property of nanosilvers templated by polymorphic DNA were evaluated using the time-dependent DFT calculations. It is illustrated that with the DNA template adopting i-motif or the duplex the silver atoms tend to aggregate inside the encapsulated spaces of nucleobases, and the formed silver nanoclusters are positively charged with high fluorescent spectral features; whereas with the template of the G-quadruplex the silver atoms are preferential to aggregate outside of the G-tetrad, which results in the formation of larger silver crystals without fluorescence property. The results obtained here are useful to explore the nucleation and growth mechanism of silver nanomaterials regulated by the structure-specific DNA templates, which is important to rational design of desirable fluorescent emitters for sensing in the field from biology to nanoscience. PMID- 22242909 TI - Hybrid polyion complex micelles formed from double hydrophilic block copolymers and multivalent metal ions: size control and nanostructure. AB - Hybrid polyion complex (HPIC) micelles are nanoaggregates obtained by complexation of multivalent metal ions by double hydrophilic block copolymers (DHBC). Solutions of DHBC such as the poly(acrylic acid)-block-poly(acrylamide) (PAA-b-PAM) or poly(acrylic acid)-block-poly(2-hydroxyethylacrylate) (PAA-b PHEA), constituted of an ionizable complexing block and a neutral stabilizing block, were mixed with solutions of metal ions, which are either monoatomic ions or metal polycations, such as Al(3+), La(3+), or Al(13)(7+). The physicochemical properties of the HPIC micelles were investigated by small angle neutron scattering (SANS) and dynamic light scattering (DLS) as a function of the polymer block lengths and the nature of the cation. Mixtures of metal cations and asymmetric block copolymers with a complexing block smaller than the stabilizing block lead to the formation of stable colloidal HPIC micelles. The hydrodynamic radius of the HPIC micelles varies with the polymer molecular weight as M(0.6). In addition, the variation of R(h) of the HPIC micelle is stronger when the complexing block length is increased than when the neutral block length is increased. R(h) is highly sensitive to the polymer asymmetry degree (block weight ratio), and this is even more true when the polymer asymmetry degree goes down to values close to 3. SANS experiments reveal that HPIC micelles exhibit a well defined core-corona nanostructure; the core is formed by the insoluble dense poly(acrylate)/metal cation complex, and the diffuse corona is constituted of swollen neutral polymer chains. The scattering curves were modeled by an analytical function of the form factor; the fitting parameters of the Pedersen's model provide information on the core size, the corona thickness, and the aggregation number of the micelles. For a given metal ion, the micelle core radius increases as the PAA block length. The radius of gyration of the micelle is very close to the value of the core radius, while it varies very weakly with the neutral block length. Nevertheless, the radius of gyration of the micelle is highly dependent on the asymmetry degree of the polymer: if the neutral block length increases in a large extent, the micelle radius of gyration decreases due to a decrease of the micelle aggregation number. The variation of the R(g)/R(h) ratio as a function of the polymer block lengths confirms the nanostructure associating a dense spherical core and a diffuse corona. Finally, the high stability of HPIC micelles with increasing concentration is the result of the nature of the coordination complex bonds in the micelle core. PMID- 22242910 TI - Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin induced lactic acidosis. AB - BACKGROUNDS AND PURPOSE: Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis. EXPERIMENTAL APPROACH: Blood lactate, pH and bicarbonate ion (HCO(3) (-) ) levels were evaluated during continuous administration of 3 mg.mL(-1) metformin in drinking water using Mate1 knockout (-/-), heterozygous (+/-) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg.kg(-1) metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin. KEY RESULTS: Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO(3) (-) levels were observed in Mate1(-/-) mice, but not in Mate1(+/-) mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg.kg(-1) , p.o.) the hepatic concentration of metformin was markedly higher in Mate1(-/-) mice than in Mate1(+/+) mice. CONCLUSION AND IMPLICATIONS: MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin induced lactic acidosis. PMID- 22242911 TI - Aromatase inhibitors and breast cancer prevention. AB - INTRODUCTION: Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. AREAS COVERED: This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. EXPERT OPINION: Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ. PMID- 22242912 TI - Calcified neurocysticercosis lesions and hippocampal sclerosis: potential dual pathology? AB - In areas where cysticercosis is endemic, calcified neurocysticercosis lesion(s) (CNL) and hippocampal sclerosis (HS) commonly coexist in patients with localization-related epilepsies. To understand the pathogenesis of HS associated with CNL, we compared the characteristics of three groups of patients with antiepileptic drug-resistant epilepsies: CNL with HS, CNL without HS (CNL alone), and HS without CNL (HS alone). In comparison to patients with CNL alone, those with CNL with HS had CNL more frequently located in the ipsilateral temporal lobe. Those with CNL with HS had a lower incidence of febrile seizures, older age at initial precipitating injury and at onset of habitual complex partial seizures, and more frequent clustering of seizures and extratemporal/bitemporal interictal epileptiform discharges as compared to patients with HS alone. Our study illustrates that HS associated with CNL might have a different pathophysiologic basis as compared to classical HS. PMID- 22242913 TI - Anthocyanin composition of wild Colombian fruits and antioxidant capacity measurement by electron paramagnetic resonance spectroscopy. AB - The qualitative and quantitative anthocyanin composition of four wild tropical fruits from Colombia was studied. Compounds of "mora pequena" ( Rubus megalococcus Focke.), "uva de arbol" ( Myrciaria aff. cauliflora O. Berg), coral, and motilon ( Hyeronima macrocarpa Mull. Arg.) fruits were separately extracted with methanol-acetic acid (95:5, v/v). The anthocyanin-rich extracts (AREs) were obtained by selective adsorption on Amberlite XAD-7. Each extract was analyzed by HPLC-PDA and HPLC-HRESI-MS(n) with LCMS-IT-TOF equipment in order to characterize the anthocyanin pigments and the coinjection in HPLC using standards allowed identifying the major constituents in each extract. The antioxidant activity was measured by electron paramagnetic resonance (EPR) and UV-vis spectroscopy, using ABTS and DPPH free radicals. The ARE of motilon ( H. macrocarpa Mull. Arg) exhibited the highest radical scavenging activity in comparison to the other extracts. A second-order kinetic model was followed in all of the cases. These results suggested that the studied fruits are promising not only as source of natural pigments but also as antioxidant materials for food industry. PMID- 22242914 TI - Suicidal and self-harm behaviour associated with adolescent attention deficit hyperactivity disorder-a study in the Northern Finland Birth Cohort 1986. AB - BACKGROUND: Suicidal behaviour, i.e. suicidal ideation and suicidal acts, as well as self-harm behaviour, are relatively common among adolescents. Depression and/or female gender seem to be risk factors for suicidal behaviour. However, the role of attention deficit hyperactivity disorder (ADHD) in these behaviours is still unclear. AIM: To study the effect of ADHD on suicidal or self-harm behaviour in adolescents from a general population sample. METHODS: The sample was derived from a population-based Northern Finland Birth Cohort 1986 (n = 9432). Based on the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime Version (Kiddie-SADS-PL) interview performed in a subpopulation (n = 457), the associations between suicidal behaviour and deliberate self-harm (DSH) and the diagnosis of ADHD were studied. RESULTS: Compared with adolescents without ADHD (n = 169), those with ADHD (n = 104) had more suicidal ideation (57% vs. 28%, P < 0.001) and DSH (69% vs. 32%, P < 0.001). In binary logistic models, the effect of ADHD on suicidal ideation remained strong (OR = 6.1) after controlling for several other predictors. Other contributing factors in suicidal behaviour included female gender, childhood emotional and behavioural problems, concurrent depression and anxiety, and, specifically in DSH, behavioural disorder, substance abuse and strains in family relations. DISCUSSION AND CLINICAL IMPLICATIONS: ADHD is a risk factor for suicidal ideation and DSH. These findings in a general population sample speak for a need to target mental health interventions at children and adolescents with relevant symptoms of ADHD. PMID- 22242915 TI - The guanine-nucleotide-exchange factor P-Rex1 is activated by protein phosphatase 1alpha. AB - P-Rex1 is a GEF (guanine-nucleotide-exchange factor) for the small G-protein Rac that is activated by PIP3 (phosphatidylinositol 3,4,5-trisphosphate) and Gbetagamma subunits and inhibited by PKA (protein kinase A). In the present study we show that PP1alpha (protein phosphatase 1alpha) binds P-Rex1 through an RVxF type docking motif. PP1alpha activates P-Rex1 directly in vitro, both independently of and additively to PIP3 and Gbetagamma. PP1alpha also substantially activates P-Rex1 in vivo, both in basal and PDGF (platelet-derived growth factor)- or LPA (lysophosphatidic acid)-stimulated cells. The phosphatase activity of PP1alpha is required for P-Rex1 activation. PP1beta, a close homologue of PP1alpha, is also able to activate P-Rex1, but less effectively. PP1alpha stimulates P-Rex1-mediated Rac-dependent changes in endothelial cell morphology. MS analysis of wild-type P-Rex1 and a PP1alpha-binding-deficient mutant revealed that endogenous PP1alpha dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165. Site-directed mutagenesis of Ser1165 to alanine caused activation of P-Rex1 to a similar degree as did PP1alpha, confirming Ser1165 as a dephosphorylation site important in regulating P-Rex1 Rac GEF activity. In summary, we have identified a novel mechanism for direct activation of P-Rex1 through PP1alpha-dependent dephosphorylation. PMID- 22242916 TI - Qualitative and quantitative analysis of tumor cell metabolism via stable isotope labeling assisted microfluidic chip electrospray ionization mass spectrometry. AB - In this work, a stable isotope labeling assisted microfluidic chip electrospray ionization mass spectrometry (SIL-chip-ESI-MS) platform for qualitative and quantitative analysis of cell metabolism was developed. Microfluidic cell culture, drug-induced cell apoptosis analysis, and cell metabolism measurements were performed simultaneously on the specifically designed device. MCF-7 cells were cultivated in vitro and exposed in anticancer agent (genistein and genistein d(2)) for cell-based drug assay. A dual-isotopic labeling was presented for effective qualitative analysis of multiplex metabolites. Interestingly, three coeluting pairs of isotopomers appeared with an m/z difference of two. Despite complex biological matrixes, they can be easily recognized and identified by chip ESI-MS/MS, which significantly facilitates candidate biomarker discovery. The quantitative performance of this system was evaluated using genistein as a model drug by means of stable isotope dilution analysis. The linear equation obtained is y = 0.06x - 3.38 * 10(-3) (R(2) = 0.995) at the dynamic range from 0.5 to 40 MUM. The detection limit is 0.2 MUM. The method shows an excellent stability of 2.2% relative standard deviation (RSD) and a good repeatability of 5.5% RSD. Our results have successfully demonstrated the capability of selective and quantitative analysis of cell-based drug absorption and metabolites with high stability, sensitivity, and repeatability on the chip-ESI-MS system. Consequently, the present device shows promise as a high-throughput, low-cost, and online platform for cell metabolism studies and drug screening processes. PMID- 22242918 TI - Prevalence of vitamin D deficiency and its related risk factor in a Spanish cohort of adult HIV-infected patients: effects of antiretroviral therapy. AB - We analyzed serum 25(OH) cholecalciferol [25(OH)D] levels and factors related to deficiency (<20 ng/ml) or insufficiency (<30 ng/ml) in a cohort of Spanish HIV infected patients and compared them with an age- and latitude-matched population from another study. We prospectively assessed 25(OH)D deficiency/insufficiency in a cohort of 352 HIV patients during 2009-2010. Predisposing factors were recorded and their relationship to low levels was assessed by logistic regression; a nutritional survey examined intake, nutritional status, and sunlight exposure in a subgroup of 92 patients. We studied the correlation of 25(OH)D with parathyroid hormone (PTH) and alkaline phosphatase. Age-, sex-, and race/ethnicity-adjusted vitamin D deficiency (<20 ng/ml) was 44.0% (95% CI, 38.8-49.4%) and insufficiency (<30 ng/ml) was 71.6% (95% CI, 66.9-76.3). Deficiency was 16.4% more prevalent in our sample than in non-HIV-infected Spaniards. Lower sunlight exposure was the only factor related to lower levels in the lifestyle and nutritional survey (p=0.045). In multiple logistic regression, higher body mass index (BMI), black race/ethnicity, lower seasonal sunlight exposure, men who have sex with men (MSM), and heterosexual transmission categories, efavirenz exposure and lack of HIV viral suppression were independently associated with deficiency/insufficiency. These variables predicted 79% of cases [AUC=0.872 (95% CI, 0.83-0.91)]. Patients receiving protease inhibitors (PIs) [OR 4.0 (95% CI, 1.3-12.3); p=0.014] or NNRTI [OR 3.6 (95% CI, 1.7-11.2); p=0.025] had higher odds of increased PTH levels; this was significant only in 25(OH)D-deficient patients (p=0.004). As in less insolated areas, the prevalence of vitamin D deficiency/insufficiency was high in HIV-infected patients in Spain; among treated patients, levels were higher with PIs than with efavirenz. PMID- 22242919 TI - Secondary and tertiary structure of bacteriorhodopsin in the SDS denatured state. AB - We characterized the structure of partially unfolded bacteriorhodopsin in sodium dodecyl sulfate (SDS) micelles and compared it with its in vitro refolded structure after reconstitution with dimyristoylphosphatidylcholine/3-[(3 cholamidopropyl)dimethylammonio]-1-propanesulfonate (DMPC/CHAPS). Intrahelical and interhelical distances were mapped in the protein using strategically located spin-label pairs at helical ends, assayed by pulsed electron paramagnetic resonance spectroscopy (double electron-electron spin resonance, DEER). We find that in SDS the intrahelical end-to-end distances exhibit broad distributions, suggesting a heterogeneous ensemble of conformations with differing secondary structures. Nevertheless, a majority of the denatured population retains end-to end distances similar to those in the native state. In contrast, the observed greatly increased interhelical distances, in addition to their very broad distributions, suggest that in the SDS micelles very little of the native tertiary structure remains. PMID- 22242920 TI - Electrochemical sensing of aptamer-facilitated virus immunoshielding. AB - Oncolytic viruses (OVs) are promising therapeutics that selectively replicate in and kill tumor cells. However, repetitive administration of OVs provokes the generation of neutralizing antibodies (nAbs) that can diminish their anticancer effects. In this work, we selected DNA aptamers against an oncolytic virus, vesicular stomatitis virus (VSV), to protect it from nAbs. A label-free electrochemical aptasensor was used to evaluate the degree of protection (DoP). The aptasensor was fabricated by self-assembling a hybrid of a thiolated ssDNA primer and a VSV-specific aptamer. Electrochemical impedance spectroscopy was employed to quantitate VSV in the range of 800-2200 PFU and a detection limit of 600 PFU. The aptasensor was also utilized for evaluating binding affinities between VSV and aptamer pools/clones. An electrochemical displacement assay was performed in the presence of nAbs and DoP values were calculated for several VSV aptamer pools/clones. A parallel flow cytometric analysis confirmed the electrochemical results. Finally, four VSV-specific aptamer clones, ZMYK-20, ZMYK 22, ZMYK-23, and ZMYK-28, showed the highest protective properties with dissociation constants of 17, 8, 20, and 13 nM, respectively. Another four sequences, ZMYK-1, -21, -25, and -29, exhibited high affinities to VSV without protecting it from nAbs and can be further utilized in sandwich assays. Thus, ZMYK-22, -23, and -28 have the potential to allow efficient delivery of VSV through the bloodstream without compromising the patient's immune system. PMID- 22242921 TI - In vitro stoichiometry of complexes between the soluble RANK ligand and the monoclonal antibody denosumab. AB - The in vitro binding stoichiometry of denosumab, an IgG2 fully human monoclonal therapeutic antibody, to RANK ligand was determined by multiple complementary size separation techniques with mass measuring detectors, including two solution based techniques (size-exclusion chromatography with static light scattering detection and sedimentation velocity analytical ultracentrifugation) and a gas phase analysis by electrospray ionization time-of-flight mass spectrometry from aqueous nondenaturing solutions. The stoichiometry was determined under defined conditions ranging from small excess RANK ligand to large excess denosumab (up to 40:1). High concentrations of denosumab relative to RANK ligand were studied because of their physiological relevance; a large excess of denosumab is anticipated in circulation for extended periods relative to much lower concentrations of free soluble RANKL. The studies revealed that an assembly including 3 denosumab antibody molecules bound to 2 RANKL trimers (3D2R) is the most stable complex in DPBS at 37 degrees C. This differs from the 1:1 binding stoichiometry reported for RANKL and osteoprotegerin (OPG), a soluble homodimeric decoy receptor which binds RANKL with high affinity. Denosumab and RANKL also formed smaller assemblies including 1 denosumab and 2 RANKL trimer molecules (1D2R) under conditions of excess RANKL, 3 denosumab molecules and 1 RANKL trimer (3D1R) under conditions of excess denosumab, and larger assemblies, but these intermediate species were only present at lower temperatures (4 degrees C), shortly after mixing denosumab and RANKL, and converted over time to the more stable 3D2R assembly. PMID- 22242922 TI - Seasonal association of thrombotic thrombocytopenic purpura. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy, is a clinical diagnosis, characterized by microangiopathic hemolytic anemia and thrombocytopenia without another likely explanation. Some initiators of the disease are well represented in the literature, such as certain drugs, malignancies, and viral illness; however, there are less objective factors still being investigated, with references to hormonal, stress, and seasonal variations considered anecdotally. A better insight of these factors would aid in understanding the pathophysiology of the disease. STUDY DESIGN AND METHODS: We performed a retrospective review of all idiopathic TTP cases treated with therapeutic plasma exchange at our institution from 1999 to 2008 to determine whether there was seasonal variation in TTP presentation. Seasons were defined as follows: winter = December to February; spring = March to May; summer = June to August; and fall = September to November. With the use of Poisson regression models, the incidence between seasons was compared. RESULTS: During this study period, a total of 97 cases were recorded. Summer had the highest occurrence of TTP (35%). This was significant compared to the fall (p = 0.012) and the winter (p = 0.019). There were more cases in the summer compared to the spring, but this was not significant. CONCLUSION: In our population, there was a significant difference in the number of TTP cases presenting in summer compared to fall and winter. This supports a possible environmental, infectious, or physiologic influence associated with the summer. PMID- 22242923 TI - Quantifying processes determining the free concentration of phenanthrene in Basal cytotoxicity assays. AB - Difficulties may arise when extrapolating in vitro derived toxicity data to in vivo toxicity data because of the high variability and occasional low sensitivity of in vitro results. Differences in the free concentration of a test compound between in vitro and in vivo systems and between different in vitro systems may in part explain this variability and sensitivity difference. The aim of this study was to determine what assay components influence the free concentration of phenanthrene in a Balb/c 3T3 and RTgill-W1 MTT assay. Partition coefficients of phenanthrene to serum, well plate plastic, cells, and headspace were measured and subsequently used to model the free concentration of the compound in vitro. The estimated free concentration was compared to the free concentration measured in the assays using solid phase microextraction (SPME). Results indicate that the free concentration of phenanthrene, a relatively volatile and hydrophobic compound, is significantly reduced in a typical in vitro setup as it binds to matrices such as serum protein and well plate plastic. A reduction in free concentration due to increasing serum protein levels is accompanied by an increase in the median effect concentration (EC(50)) and can be modeled, with the exception of evaporation, using the partition coefficients of the compound to assay components. PMID- 22242924 TI - Wetting-induced budding of vesicles in contact with several aqueous phases. AB - Osmotic deflation of vesicles enclosing two liquid phases can lead to bulging of one of the phases from the vesicle body. This budding process is preceded by a complete to partial wetting transition of one of the liquid phases on the membrane and depends on the membrane tensions and the tension of the interface between the enclosed liquid phases. These tensions dominate in different morphology regimes, the crossover of which initiates the budding process. In addition, the degree of budding can be controlled by aspiration via micropipets. We also demonstrate that the budding direction can be reversed if there are two external phases in contact with the vesicle. PMID- 22242925 TI - Patterning and electronic tuning of laser scribed graphene for flexible all carbon devices. AB - Engineering a low-cost graphene-based electronic device has proven difficult to accomplish via a single-step fabrication process. Here we introduce a facile, inexpensive, solid-state method for generating, patterning, and electronic tuning of graphene-based materials. Laser scribed graphene (LSG) is shown to be successfully produced and selectively patterned from the direct laser irradiation of graphite oxide films under ambient conditions. Circuits and complex designs are directly patterned onto various flexible substrates without masks, templates, post-processing, transferring techniques, or metal catalysts. In addition, by varying the laser intensity and laser irradiation treatments, the electrical properties of LSG can be precisely tuned over 5 orders of magnitude of conductivity, a feature that has proven difficult with other methods. This inexpensive method for generating LSG on thin flexible substrates provides a mode for fabricating a low-cost graphene-based NO(2) gas sensor and enables its use as a heterogeneous scaffold for the selective growth of Pt nanoparticles. The LSG also shows exceptional electrochemical activity that surpasses other carbon-based electrodes in electron charge transfer rate as demonstrated using a ferro /ferricyanide redox couple. PMID- 22242926 TI - Docosahexaenoic acid prevents trans-10, cis-12-conjugated linoleic acid-induced nonalcoholic fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation. AB - BACKGROUND: Concomitant supplementation with docosahexaenoic acid (22:6 n-3; DHA) prevented trans-10, cis-12-conjugated linoleic acid (CLA)-induced nonalcoholic fatty liver disease (NAFLD) and insulin resistance. The effective dose of DHA and mechanisms involved are poorly understood. METHODS: We examined the ability of DHA (0.5% and 1.5%) to prevent increases in NAFLD and homeostatic model assessment of insulin resistance (HOMA-IR) induced by CLA (0.5%) when fed concomitantly for 4 weeks to C57BL/6N female mice. We also examined changes in expression of hepatic genes involved in fatty acid synthesis and oxidation. RESULTS: CLA supplementation increased liver triglycerides (TG) and HOMA-IR by 221% and 547%, respectively, and decreased mass of different adipose depots by 65%-90% when compared to those in the control group. When fed concomitantly, DHA prevented CLA-induced increases in liver TG and circulating insulin with varying efficiency, but it did not prevent loss in adipose tissue mass. In the CLA+0.5% DHA group, the liver TG did not differ from those in the control group, but circulating insulin and HOMA-IR were 285% and 264%, respectively. In the CLA+1.5% DHA group, liver TG were 54% lower than those in the control group, but circulating insulin concentration and HOMA-IR did not differ between these two groups. CLA increased the expression of hepatic genes involved in fatty acid synthesis and decreased the expression of genes involved in fatty acid oxidation, and 1.5% DHA prevented changes in the expression of hepatic genes caused by CLA. CONCLUSIONS: Response of different tissues to CLA and DHA varied; CLA was more potent than DHA in altering depot fat and insulin concentrations. PMID- 22242927 TI - Meat consumption, cooking methods, mutagens, and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay. AB - The role of meat in squamous cell carcinoma of the esophagus (ESCC) has been considered conflictive. For this reason, we decided to conduct a case-control study on meat consumption and ESCC. Data included 234 newly diagnosed and microscopically examined ESCC and 2,020 controls with conditions not related to tobacco smoking nor alcohol drinking and without changes in their diets. We studied total meat, red meat, beef, lamb, processed meat, poultry, fish, total white meat, liver, fried meat, barbecued meat, boiled meat, heterocyclic amines, nitrosodimethylamine, and benzo[a]pyrene in relation with the risk of ESCC. Red meat, lamb, and boiled meat were directly associated with the risk of ESCC, whereas total white meat, poultry, fish, and liver were mainly protective against this malignancy. PMID- 22242928 TI - Treatment failure with new hepatitis C drugs. AB - INTRODUCTION: The combination of pegylated interferon-alpha plus ribavirin (pegIFNalpha-RBV) has been the only therapeutic option for patients with chronic hepatitis C virus (HCV) infection during the last decade. Unfortunately, it provides cure to less than a half of individuals infected with HCV genotype 1, which is by far the most prevalent worldwide. The recent introduction of new direct-acting antivirals (DAA) has revolutionized the hepatitis C field. The addition of any of the two recently approved HCV protease inhibitors, boceprevir or telaprevir, to pegIFNalpha-RBV results in the cure for two-thirds of HCV genotype 1, interferon-naive patients. AREAS COVERED: This paper reviews new antivirals for hepatitis C and HCV treatment failures, along with HCV drug resistance and rescue therapies. EXPERT OPINION: The application of early stopping rules may reduce the enrichment of drug-resistant viruses in patients failing first-generation HCV protease inhibitors, potentially allowing more chances of response to rescue interventions with other compounds within the same class in the near future. On the other hand, the advent of DAA belonging to distinct drug families may provide further opportunities for clearing definitively HCV in patients currently failing first-generation HCV protease inhibitors. Thus, hepatitis C has entered a new era that hopefully will end with its eradication. In the meantime, a wise use of DAA is warranted, including adequate selection of candidates for therapy, close monitoring of drug adherence, proper management of side effects and early application of stopping rules. PMID- 22242929 TI - Concentrations and composition profiles of benzotriazole UV stabilizers in municipal sewage sludge in China. AB - The environmental contamination and fate of benzotriazole UV stabilizers (BZTs) have received increasing attention due to their large production volume and wide usage in various consumer and industrial products. In the present work, 60 municipal sewage sludge samples from wastewater treatment plants (WWTPs) in 33 cities in China were collected to investigate the occurrence and distribution of 9 frequently used BZTs. The most dominant analogue was 2-[3,5-bis(1-methyl-1 phenylethyl)-2-hydroxyphenyl]benzotriazole (UV-234) at a median concentration of 116 ng/g (dry weight) and accounted on average for 27.2% of total BZTs. The abundance was successively followed by 2-(2-hydroxy-5-tert octylphenyl)benzotriazole (UV-329, average 24.3%), 2-(2-hydroxy-3-tert-butyl-5 methylphenyl)-5-chlorobenzotriazole (UV-326, average 22.2%), 2-(3,5-di-tert-amyl 2-hydroxyphenyl)benzotriazole (UV-328, average 17.7%), and 2-(2-hydroxy-5 methylphenyl)benzotriazole (UV-P, average 6.6%), with median concentrations of 66.8, 67.8, 57.3, and 20.6 ng/g, respectively. 5-Chloro-2-(3,5-di-tert-butyl-2 hydroxyphenyl)benzotriazole (UV-327) and 2-(3-sec-butyl-5-tert-butyl-2 hydroxyphenyl)benzotriazole (UV-350) had low detection frequency, while 2-(3,5-di tert-butyl-2-hydroxyphenyl)benzotriazole (UV-320) and 2-(5-tert-butyl-2 hydroxyphenyl)benzotriazole (UV-PS) were not detectable in any sample. To our knowledge, this is the first study reporting the occurrence of UV-234, UV-329, and UV-350 in sewage sludge in China. Significant correlations were found among the BZT concentrations and also with a WWTP characteristic (daily treatment volume). Furthermore, results from degradation prediction and multimedia fate simulation based on a quantitative structure-property relationship (QSPR) model at screening level also implied that the commercial BZT chemicals and their plausible transformation products might be persistent in the environment. PMID- 22242930 TI - Substrate selectivity of drug-metabolizing cytochrome P450s predicted from crystal structures and in silico modeling. AB - Enormous efforts toward predicting the metabolic fate of a drug have been driven by the high attrition rate in drug development. To accelerate such efforts, it is critical to elucidate the molecular mechanisms of drug recognition by drug metabolizing enzymes. Therefore, it is not surprising that an increasing number of crystal structures have been determined (by X-ray crystallography) and numerous insightful in silico (computational) models have been established for the most important metabolic enzymes, cytochrome P450s (CYPs). In this review, we provide a detailed analysis of the available crystal structures for CYPs to reveal the structural features and protein flexibility determining substrate selectivity. The ligand-based in silico models (including pharmacophore and molecular field analysis models) are also discussed, with a focus on their ability to characterize the structural features of the substrates for various CYP isoforms. PMID- 22242931 TI - Comparisons between in vitro whole cell imaging and in vivo zebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development. AB - Drug-induced liver injury (DILI) is a major cause of attrition during both the early and later stages of the drug development and marketing process. Reducing or eliminating drug-induced severe liver injury, especially those that lead to liver transplants or death, would be tremendously beneficial for patients. Therefore, developing new pharmaceuticals that have the highest margins and attributes of hepatic safety would be a great accomplishment. Given the current low productivity of pharmaceutical companies and the high costs of bringing new medicines to market, any early screening assay(s) to identify and eliminate pharmaceuticals with the potential to cause severe liver injury in humans would be of economic value as well. The present review discusses the background, proof of-concept, and validation studies associated with high-content screening (HCS) by two major pharmaceutical companies (Pfizer Inc and Jansen Pharmaceutical Companies of Johnson & Johnson) for detecting compounds with the potential to cause human DILI. These HCS assays use fluorescent-based markers of cell injury in either human hepatocytes or HepG2 cells. In collaboration with Evotec, an independent contract lab, these two companies also independently evaluated larval zebrafish as an early-stage in vivo screen for hepatotoxicity in independently conducted, blinded assessments. Details about this model species, the need for bioanalysis, and, specifically, the outcome of the phenotypic-based zebrafish screens are presented. Comparing outcomes in zebrafish against both HCS assays suggests an enhanced detection for hepatotoxicants of most DILI concern when used in combination with each other, based on the U.S. Food and Drug Administration DILI classification list. PMID- 22242933 TI - Development of surface-SFED models for polar solvents. AB - We developed surface grid-based solvation free energy density (Surface-SFED) models for 36 commonly used polar solvents. The parametrization was performed with a large and diverse set of experimental solvation free energies mainly consisting of combinations of polar solvent and multipolar solute. Therefore, the contribution of hydrogen bonds was dominant in the model. In order to increase the accuracy of the model, an elaborate version of a previous hydrogen bond acidity and basicity prediction model was introduced. We present two parametrizations for use with experimentally determined (Surface-SFED/HB(exp)) and empirical (Surface-SFED/HB(cal)) hydrogen bond acidity and basicity values. Our computational results agreed well with experimental results, and inaccuracy of empirical hydrogen bond acidity and basicity values was the main source of error in Surface-SFED/HB(cal). The mean absolute errors of Surface-SFED/HB(exp) and Surface-SFED/HB(cal) were 0.49 and 0.54 kcal/mol, respectively. PMID- 22242932 TI - Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. WHAT THIS STUDY ADDS: * This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. AIMS: The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS: The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS: The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied. PMID- 22242934 TI - Control of surface topography in biomimetic calcium phosphate coatings. AB - The behavior of cells responsible for bone formation, osseointegration, and bone bonding in vivo are governed by both the surface chemistry and topography of scaffold matrices. Bone-like apatite coatings represent a promising method to improve the osteoconductivity and bonding of synthetic scaffold materials to mineralized tissues for regenerative procedures in orthopedics and dentistry. Polycaprolactone (PCL) films were coated with calcium phosphates (CaP) by incubation in simulated body fluid (SBF). We investigated the effect of SBF ion concentration and soaking time on the surface properties of the resulting apatite coatings. CaP coatings were examined by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), and energy dispersive X-ray spectrometry (EDX). Young's modulus (E(s)) was determined by nanoindentation, and surface roughness was assessed by atomic force microscopy (AFM) and mechanical stylus profilometry. CaP such as carbonate-substituted apatite were deposited onto PCL films. SEM and AFM images of the apatite coatings revealed an increase in topographical complexity and surface roughness with increasing ion concentration of SBF solutions. Young's moduli (E(s)) of various CaP coatings were not significantly different, regardless of the CaP phase or surface roughness. Thus, SBF with high ion concentrations may be used to coat synthetic polymers with CaP layers of different surface topography and roughness to improve the osteoconductivity and bone-bonding ability of the scaffold. PMID- 22242935 TI - Evaluation of particle-induced X-ray emission and particle-induced gamma-ray emission of quartz grains for forensic trace sediment analysis. AB - The independent verification in a forensics context of quartz grain morphological typing by scanning electron microscopy was demonstrated using particle-induced X ray emission (PIXE) and particle-induced gamma-ray emission (PIGE). Surface texture analysis by electron microscopy and high-sensitivity trace element mapping by PIXE and PIGE are independent analytical techniques for identifying the provenance of quartz in sediment samples in forensic investigations. Trace element profiling of the quartz grain matrix separately from the quartz grain inclusions served to differentiate grains of different provenance and indeed went some way toward discriminating between different quartz grain types identified in a single sample of one known forensic provenance. These results confirm the feasibility of independently verifying the provenance of critical samples from forensic cases. PMID- 22242936 TI - Influence of a conservative sleep management strategy during a solo Pacific Ocean crossing on anxiety and perceived fatigue: a case study. AB - The aim of this case study was to determine whether a sailor's deliberate choice of a conservative strategy to manage sleep deprivation would allow him to cross the Pacific Ocean and to minimize his state of anxiety and perceived fatigue. The participant, who had more than 10 years' sailing experience in severe conditions, was tested on a small catamaran without any living quarters during a solo Pacific Ocean crossing. Estimations of sleep hours, state anxiety, and perceived fatigue were self-reported by the sailor on a daily basis using a specific questionnaire. The most important finding is that the sailor's deliberate sleep strategy, 5.4 h sleep per day (24% less than on-shore), was enough to keep his anxiety and perceived fatigue within acceptable limits and enabled him to achieve his goal, which was the first crossing of the Pacific Ocean on a catamaran of less than 6 m. In conclusion, our results suggest that the sailor observed in the present case study was able to minimize anxiety and perceived fatigue with adequate sleep to optimize his performance, security, and to achieve his goal. PMID- 22242937 TI - Reforming agricultural nonpoint pollution policy in an increasingly budget constrained environment. AB - Agricultural nonpoint source water pollution has long been recognized as an important contributor to U.S. water quality problems and the subject of an array of local, state, and federal initiatives to reduce the problem. A "pay-the polluter" approach to getting farmers to adopt best management practices has not succeeded in improving water quality in many impaired watersheds. With the prospects of reduced funding for the types of financial and technical assistance programs that have been the mainstay of agricultural water quality policy, alternative approaches need to be considered. Some changes to the way current conservation programs are implemented could increase their efficiency, but there are limits to how effective a purely voluntary approach can be. An alternative paradigm is the "polluter pays" approach, which has been successfully employed to reduce point source pollution. A wholesale implementation of the polluter-pays approach to agriculture is likely infeasible, but elements of the polluter-pays approach could be incorporated into agricultural water quality policy. PMID- 22242938 TI - The involvement of gap junctions in the delayed phase of the protection induced by cardiac pacing in dogs. AB - The present study has examined the role of GJ (gap junctions) in the delayed anti arrhythmic effect of cardiac pacing, with particular reference to the time-course changes in Cx43 (connexin43) expression both after pacing (4*5 min, at a rate of 240 beats/min) and 24 h later, when the dogs were subjected to a 25 min occlusion and reperfusion of the LAD (left anterior descending coronary artery). Compared with the SP (sham-paced) controls (n=20), in dogs paced 24 h previously (n=16) there were reductions in arrhythmia severity [e.g. number of VPB (ventricular premature beats) during occlusion 294+/-78 compared with 63+/-25; survival from the combined ischaemia/reperfusion insult 20% compared with 78%], and in other ischaemic changes [epicardial ST-segment, TAT (total activation time) and tissue impedance]. Pacing also prevented the ischaemia-induced structural impairment of the intercalated discs, and preserved GJ permeability and Cx43 phosphorylation, without modifying Cx43 protein content. Following cardiac pacing the membrane and total Cx43 protein contents were unchanged up to 6 h, but were significantly reduced 12 h later (preceded by a down-regulation of Cx43 mRNA at 6 h), and returned to normal by 24 h. Interestingly, dogs that were subjected to ischaemia 12 h after cardiac pacing showed increased arrhythmia generation. We conclude that cardiac pacing results in time-dependent changes in Cx43 expression, which may alter GJ function and influence arrhythmia generation during a subsequent ischaemia/reperfusion insult. This effect is manifested in protection 24 h after pacing, but of potential clinical interest is the finding that there is a time interval after pacing during which an ischaemic event may generate severe ventricular arrhythmias. PMID- 22242940 TI - Substitution reactions in dinuclear Ru-Hbpp complexes: an evaluation of through space interactions. AB - The synthesis of new dinuclear complexes of the general formula in,in {[Ru(II)(trpy)(L)](MU-bpp)[Ru(II)(trpy)(L')]}(3+) [bpp(-) is the bis(2-pyridyl) 3,5-pyrazolate anionic ligand; trpy is the 2,2':6',2"-terpyridine neutral meridional ligand, and L and L' are monodentate ligands; L = L' = MeCN, 3a(3+); L = L' = 3,5-lutidine (Me(2)-py), 3c(3+); L = MeCN, L' = pyridine (py), 4(3+)], have been prepared and thoroughly characterized. Further, the preparation and isolation of dinuclear complexes containing dinitrile bridging ligands of the general formula in,in-{[Ru(II)(trpy)](2)(MU-bpp)(MU-L-L)}(3+) [MU-L-L = 1,4 dicyanobutane (adiponitrile, adip), 6a(3+); 1,3-dicyanopropane (glutaronitrile, glut), 6b(3+); 1,2-dicyanoethane (succinonitrile; succ), 6c(3+)] have also been carried out. In addition, a number of homologous dinuclear complexes previously described, containing the anionic bis(pyridyl)indazolate (bid(-)) tridentate meridional ligand in lieu of trpy, have also been prepared for comparative purposes. In the solid state, six complexes have been characterized by X-ray crystallography, and in solution, all of them have been spectroscopically characterized by NMR and UV-vis spectroscopy. In addition, their redox properties have also been investigated by means of cyclic voltammetry and differential pulse voltammetry and show the existence of two one-electron waves assigned to the formation of the II,III and III,III species. Dinitrile complexes 6a(3+), 6b(3+), and 6c(3+) display a dynamic behavior involving their enantiomeric interconversion. The energy barrier for this interconversion can be controlled by the number of methylenic units between the dinitrile ligand. On the other hand, pyridyl complexes in,in-{[Ru(II)(T)(py)](2)(MU-bpp)}(n+) (T = trpy, n = 3, 3b(3+); T = bid(-), n = 1, 3b'(+)) and 3c(3+) undergo two consecutive substitution reactions of their monodentate ligands by MeCN.The substitution kinetics have been monitored by (1)H NMR and UV-vis spectroscopy and follow first order behavior with regard to the initial ruthenium complex. For the case of 3b(3+), the first-order rate constant k(1) = (2.9 +/- 0.3) * 10(-5) s(-1), whereas for the second substitution, the k obtained is k(2) = (1.7 +/- 0.7) * 10( 6) s(-1), both measured at 313 K. Their energies of activation at 298 K are 114.7 and 144.3 kJ mol(-1), respectively. Density functional theory (DFT) calculations have been performed for two consecutive substitution reactions, giving insight into the nature of the intermediates. Furthermore, the energetics obtained by DFT calculations of the two consecutive substitution reactions agree with the experimental values obtained. The kinetic properties of the two consecutive substitution reactions are rationalized in terms of steric crowding and also in terms of through-space interactions. PMID- 22242939 TI - Cancer somatic mutations disrupt functions of the EphA3 receptor tyrosine kinase through multiple mechanisms. AB - The Eph receptor tyrosine kinases make up an important family of signal transduction molecules that control many cellular processes, including cell adhesion and movement, cell shape, and cell growth. All of these are important aspects of cancer progression, but the relationship between Eph receptors and cancer is complex and not fully understood. Genetic screens of tumor specimens from cancer patients have revealed somatic mutations in many Eph receptors. The most highly mutated Eph receptor is EphA3, but its functional role in cancer is currently not well established. Here we show that many EphA3 mutations identified in lung, colorectal, and hepatocellular cancers, melanoma, and glioblastoma impair kinase activity or ephrin ligand binding and/or decrease the level of receptor cell surface localization. These results suggest that EphA3 has ephrin- and kinase-dependent tumor suppressing activities, which are disrupted by somatic cancer mutations. PMID- 22242943 TI - On a high note. PMID- 22242941 TI - Pattern-recognition receptors in human eosinophils. AB - The pattern-recognition receptor (PRR) family includes Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and the receptor for advanced glycation end products (RAGE). They recognize various microbial signatures or host-derived danger signals and trigger an immune response. Eosinophils are multifunctional leucocytes involved in the pathogenesis of several inflammatory processes, including parasitic helminth infection, allergic diseases, tissue injury and tumour immunity. Human eosinophils express several PRRs, including TLR1-5, TLR7, TLR9, NOD1, NOD2, Dectin-1 and RAGE. Receptor stimulation induces survival, oxidative burst, activation of the adhesion system and release of cytokines (interleukin-1beta, interleukin-6, tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor), chemokines (interleukin-8 and growth-related oncogene-alpha) and cytotoxic granule proteins (eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase and major basic protein). It is also evident that eosinophils play an immunomodulatory role by interacting with surrounding cells. The presence of a broad range of PRRs in eosinophils indicates that they are not only involved in defence against parasitic helminths, but also against bacteria, viruses and fungi. From a clinical perspective, eosinophilic PRRs seem to be involved in both allergic and malignant diseases by causing exacerbations and affecting tumour growth, respectively. PMID- 22242946 TI - Molecular origin of piezo- and pyroelectric properties in collagen investigated by molecular dynamics simulations. AB - Molecular dynamics simulations were used to study the effect of mechanical and thermal stimuli on the electrostatic properties of collagen model helices. Our model sequences were based on glycine proline and hydroxyproline amino acids. We find that longitudinal mechanical strain induces significant variation of the polarization of the collagen fibril. Such a phenomenon is determined by reorientation of the backbone polar groups, which are free to respond to the mechanical solicitation. This non-negligible effect is facilitated by the peculiar folding structure of the collagen helix, which is characterized by the absence of an extended hydrogen-bond network. The stretching/compression of the helix requires a concomitant winding/unwinding motion of the global structure; therefore, the shear components of the stress tensor are the components that most effectively induce structural modification associated to the piezoelectric response. The present calculations also report a pyroelectric response to thermal activation. Model calculations indicate that the pyroelectric effect is dominated by secondary components associated with the piezoelectric tensor. PMID- 22242942 TI - Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats. AB - BACKGROUND AND PURPOSE: Inflammation is involved in the development and/or progression of many diseases including diabetic complications. Investigations on novel anti-inflammatory agents may offer new approaches for the prevention of diabetic nephropathy. Our previous bioscreening of synthetic analogues of curcumin revealed C66 as a novel anti-inflammatory compound against LPS challenge in macrophages. In this study, we hypothesized that C66 affects high glucose (HG) induced inflammation profiles in vitro and in vivo and then prevents renal injury in diabetic rats via its anti-inflammatory actions. EXPERIMENTAL APPROACH: Primary peritoneal macrophages (MPM), prepared from C57BL/6 mice, were treated with HG in the presence or absence of C66. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and the effects of C66 (0.2, 1.0 or 5.0 mg.kg(-1) ), administered daily for 6 weeks, on plasma TNF-alpha levels and expression of inflammatory genes in the kidney were assessed. KEY RESULTS: Pretreatment of MPMs with C66 reduced HG-stimulated production of TNF-alpha and NO, inhibited HG induced IL-1beta, TNF-alpha, IL-6, IL-12, COX-2 and iNOS mRNA transcription, and the activation of JNK/NF-kB signalling. In vivo, C66 inhibited the increased plasma TNF-alpha levels and renal inflammatory gene expression, improved histological abnormalities and fibrosis of diabetic kidney, but did not affect the hyperglycaemia in these diabetic rats. CONCLUSIONS AND IMPLICATIONS: The anti inflammatory effects of C66 are mediated by inhibiting HG-induced activation of the JNK/NF-kappaB pathway, rather than by reducing blood glucose in diabetic rats. This novel compound is a potential anti-inflammatory agent and might be beneficial for the prevention of diabetic nephropathy. PMID- 22242947 TI - Amyloid-derived peptide forms self-assembled monolayers on gold nanoparticle with a curvature-dependent beta-sheet structure. AB - Using a combination of Fourier transform infrared (FTIR) spectroscopy and solid state nuclear magnetic resonance (SSNMR) techniques, the secondary structure of peptides anchored on gold nanoparticles of different sizes is investigated. The structure of the well-studied CALNN-capped nanoparticles is compared to the structure of nanoparticles capped with a new cysteine-terminated peptide, CFGAILSS. The design of that peptide is derived from the minimal amyloidogenic sequence FGAIL of the human islet polypeptide amylin. We demonstrate that CFGAILSS forms extended fibrils in solution. When constrained at a nanoparticle surface, CFGAILSS adopts a secondary structure markedly different from CALNN. Taking into account the surface selection rules, the FTIR spectra of CFGAILSS capped gold nanoparticles indicate the formation of beta-sheets which are more prominent for 25 nm diameter nanoparticles than for 5 nm nanoparticles. No intermolecular (13)C-(13)C dipolar coupling is detected with rotational resonance SSNMR for CALNN-capped nanoparticles, while CALNN is in a random coil configuration. Coupling is detected for CFGAILSS-capped gold nanoparticles, however, consistent with an intermolecular (13)C-(13)C distance of 5.0 +/- 0.3 A, in agreement with intermolecular hydrogen bonding in a parallel beta-sheet structure. PMID- 22242948 TI - Association of cyclooxygenase 2 single-nucleotide polymorphisms and hepatocellular carcinoma in Taiwan. AB - Hepatocellular carcinoma (HCC) is a worldwide neoplasm for which early diagnosis is difficult and the prognosis is usually poor. Overexpression of cyclooxygenase 2 (COX-2) has been suggested to be associated with hepatocarcinogenesis. Although several COX-2 inhibitors have been used in hepatoma therapy, the genetic background between COX-2 and HCC remains largely unknown. In this study, the association of genotypic polymorphisms in COX-2 with HCC was investigated. 298 patients with HCC and 298 healthy controls recruited from the China Medical Hospital in Taiwan were genotyped by a PCR-RFLP method. We have investigated six polymorphic variants of COX-2, including A-1195G, G- 765C, T+8473C, and variants in introns 1, 5 and 6, and analyzed the association of specific genotype(s) with susceptibility to HCC. The results showed that, for each of the six genotypes, no differences un distribution between the HCC and control groups were found. There was neither obvious joint effect of COX-2 G-765C/intron 6 haplotype nor its genotypes with smoking or alcohol consumption on HCC risk. Environmental factors, other than smoking and alcohol drinking, may affect the post-natal expression of COX-2 in the etiology of HCC, which is an outcome of complex genetic and environmental interactions. Moreover , our immunohistochemistrical results indicated that the COX-2 protein was significantly over-expressed in well differentiated HCC, but not significantly increased in expression in poorly differentiated HCC. We suggest that COX-2 may be a determinant of the differentiation grade of HCC. PMID- 22242949 TI - Exercise-induced changes in redox status of elite karate athletes. AB - Regular training has been claimed to increase the activity of antioxidant enzymes and, consequently, augments the resistance to oxidative stress; however, large volumes of training performed by elite sportsmen could lead to a chronic oxidative stress state. The aim of our study was to assess the oxidative status of elite athletes at the beginning of the preparatory and the beginning of the competition training phases, so that the influence of three months of programmed physical activity on redox status could be determined. The chronic effects of exercise on the redox state of the athletes were compared to the effects of a single bout of karate training. Thirty elite karate athletes, 16-30 years old, were subjected to maximal graded exercise test to estimate their aerobic capacity; blood sampling was also performed to measure levels of superoxide anion radical (O2-), hydrogen peroxide (H2O2), superoxide dismutase activity (SOD) and catalase activity (CAT). The only significant change after the three-month training process was found in the significantly decreased CAT activity (X +/- SE: 7.95 +/- 0.13 U/g Hb * 103 in the preparatory period, 6.65 +/- 0.28 U/g Hb * 103 in the competition stage; P < 0.01). After a single karate training session, there was statistically significant decrease of O2-(X +/- SE: 32.7 +/- 4.9 nmol/ml in the preparatory period, 24.5 +/- 2.5 nmol/ml in the competition stage; P < 0.05) and increase of H2O2(X +/- SE: 11.8 +/- 1.0 nmol/ml in the preparatory period, 14.2 +/- 0.9 nmol/ml in the competition stage; P < 0.01), as well as significant CAT increase (X +/- SE: 6.6 +/- 0.6 U/g Hb * 103 in the preparatory period, 8.5 +/- 0.5 U/g Hb * 103 in the competition stage; P < 0.05). Although the three-month training process induced, at the first sight, negative changes in the redox state, expressed through the decrease in CAT activity, adequate response of the antioxidant system of our athletes to acute exercise was preserved. PMID- 22242950 TI - Influence of zymosan A on the content of ascorbic acid in mice. AB - The aim of the study was to determine the effects of single intraperitoneal injections of zymosan A on changes in the content of ascorbic acid (ASC) in the brain, liver, spleen and kidneys of mature male mice, line Swiss. The experiments were carried out on 54 mice divided into 3 control groups and 6 experimental groups. Samples for analysis were collected after 3 h (experimental group I), 6 h (experimental group II) and 24 h (experimental group III) after the injection of zymosan A at the dose of 1 mg/kg body weight (b.w.). For groups IV, V and VI, the organs were removed at the same time as for the previous groups, but the animals were administered zymosan A at the dose of 100 mg/kg b.w. The content of ASC was then determined. The results showed that zymosan A significantly reduced the content of ASC in the brain of the mice in all the experimental groups, in the spleen in all the experimental groups except of group I (after 3 h since injection of zymosan A at 1 mg/kg b.w.), in the liver only in experimental groups IV, V and VI (after the injection of zymosan A at 100 mg/kg b.w.), while in the kidneys the effects were observed for groups III, V and VI. The data suggest that the observed decrease in the content of ASC is caused by the oxidative activity of zymosan A. PMID- 22242951 TI - Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats. AB - The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity. PMID- 22242952 TI - Expression of protein kinase C alpha and the MZF-1 and Elk-1 transcription factors in human breast cancer cells. AB - Recently, our research into hepatocellular carcinoma (HCC) has shown that the transcription factors Myeloid Zinc Finger-1 (MZF-1) and Ets-like-protein 1 are related to protein kinase C alpha (PKCalpha) expression. The purpose of this study was to determine the correlation of the expression of PKCalphawith the expressions of Elk-1 and MZF-1 in various differentiated breast cancer cell lines: MDA- MB-231, Hs57BT, SKBR3, MDA-MB-468 and MCF-7. The malignant potential in the five lines of breast cancer cells was examined by using a cell proliferation/migration/invasion assay and the protein and mRNA levels of PKCalpha, ElK-1 and MZF-1 were examined by Western blot and RT-PCR analysis, re- spectively. The results showed that there were obvious signs of migration and invasion of cells in MDA- MB-231 and Hs57BT cells, little signs of cell migration and invasion in MDA-MB-468 cells, and no sign in SKBR3 and MCF-7 cells. Moreover, the highest expression levels of PKCalpha, Elk-1 and MZF-1 were also observed in MDA-MB-231 and Hs57BT cells when compared to the other breast cancer cell lines. These findings confirm that elevated expression of PKCalphain breast cancer cells may be correlated with the potential of cell migration and invasion, and suggest an association between the expression of PKCalpha and the expression of the transcription factors Elk-1 and MZF-1. PMID- 22242953 TI - Anti-inflammatory effects of probiotic Lactobacillus paracasi on ventricles of BALB/C mice treated with ovalbumin. AB - Lactic acid bacteria (LAB) are microorganisms that benefit animals with allergic diseases and intestinal disorders such as inflammatory bowel disease. We propose that LAB can prevent cardiomyocytes inflammation and apoptosis in BALB/c mice using an ovalbumin (OVA)-induced allergy. Thirty-nine male BALB/c mice were divided into five groups: normal control, allergy control and three allergy groups each treated with Kefir I (Kefir I), Kefir II (Kefir II) or GM080 products (GM080). The myocardial architecture and apoptotic molecules in the excised left ventricle from these mice were investigated and post-treatment effects were evaluated. The inflammatory pathway, including toll-like receptor 4 (TLR4), phospholate-Jun-N-terminal kinase (p-JNK), JNK1/2 and tumor necrosis factor- alpha (TNF-alpha) and the mitochondria-dependent apoptosis phospholate-p38 (p p38), Bcl-2 associated agonist of cell death (Bad), Bcl-2 associated X (Bax) and activated caspase 3, were found to be significant- ly increased in the hearts of allergy mice. The expression of phospholate-nuclear factor-kappaB (p-NFkappaB), TNF-alpha, p-p38 and Bad protein products were reduced or retarded in the Kefir I or II-treated allergy group. The GM080-treated allergy group exhibited significantly lower p-JNK, JNK1/2, phospholate- Ikappa B (p-IkappaB), Bax and Bad protein products than the Kefir I and Kefir II allergy groups. These results indicate that LAB can reduce inflammation and prevent apoptosis of cardiomyocytes in the heart of OVA-induced allergy mice. PMID- 22242954 TI - Bone and joint protection ability of ceramic material with biological effects. AB - Ceramic materials with biological effects (bioceramic) have been found to modulate various biological effects, especially those effects involved in antioxidant activity and hydrogen peroxide scavenging. As arthropathy and osteopathy are the major chronic diseases of geriatric medicine, we explored the possible activity of bioceramic on these conditions using animal and cell models. Rabbits received intra-articular injections of lipopolysaccharides (LPS) to induce inflammation that mimic rheumatic arthritis. FDG isotopes were then IV injected for PET scan examinations at 16 hours and 7 days after the LPS injection. We examined and compared the bioceramic and control groups to see if bioceramic was capable of relieving inflammation in the joints by subtracting the final and initial uptake amount of FDG (max SUV). We studied the effects in prostaglandin E2 (PGE2) inhibition on the human chondrosarcoma (SW1353) cell line, and the effects on the murine osteoblast (MC3T3-E1) cell line under oxidative stress. All the subtractions between final and initial uptakes of FDG in the left knee joints of the rabbits after LPS injection indicated larger decreases in the bioceramic group than in the control group. This anti-arthritic or inflammatory effect was also demonstrated by the PGE2 inhibition of the SW1353 cells. We further proved that bioceramic treatment of the MC3T3-E1 cells resulted in increased viability of osteoblast cells challenged with hydrogen peroxide toxicity, and increased alkaline phosphatase activity and the total protein production of MC3T3-E1 cells under oxidative stress. Since LPS-induced arthritis is an experimental model that mimics RA, the potential therapeutic effects of bioceramic on arthropathy merit discussion. Bioceramic may contribute to relieving inflammatory arthritis and maintaining bone health. PMID- 22242955 TI - Expression of protein kinase C isoforms in cancerous breast tissue and adjacent normal breast tissue. AB - The role of protein kinase C (PKC) in the carcinogenesis of human breast tissue has been studied at the molecular level for more than two decades. In this study, we employed Western blotting to determine the presence of PKC isoforms in cancerous and normal breast tissues. The results indicate significant expression of a conventional PKC (PKCalpha) and two atypical PKCs (PKC zeta and lambda/iota) in both breast tumors and adjacent normal breast tissue. For the alpha,zeta and lambda/iota isoforms, the expression of individual isoforms was higher in the breast tumors than in the adjacent normal breast tissue. Although the correlation coefficient was low, significant linear correlation was found among the activities of the isoforms. The data suggest a potential new direction in cancer chemotherapy, namely the blockage of the signal transduction pathway of specific PKC isoforms. PMID- 22242956 TI - Facilitation of chronic intermittent hypobaric hypoxia on carotid sinus baroreflex in anesthetized rats. AB - Our previous study showed that chronic intermittent hypobaric hypoxia (CIHH) could prevent decreases in systemic arterial blood pressure (SABP) during acute hypoxia. However, the mechanism was not clear. The purpose of the present study was to observe whether the carotid sinus baroreflex (CSB) was involved in the antagonizing effect of CIHH on SABP decrease induced by acute hypoxia and to explore the underlying mechanism using perfusion technique in rat isolated carotid sinus area. After 14-day and 28-day CIHH exposure, the CSB in rats was enhanced markedly, manifesting as increases in PS and RD, and decreases in TP and SP. This facilitation of CSB was partly abolished by Glibenclamide (Gli, 10 MUM), a K ATP channel blocker, but was not influenced by L-NAME (100 MUM), a nitric oxide synthase (NOS) inhibitor. The results of the study suggested that CIHH facilitated CSB through opening the K ATP channels in carotid sinus of anesthetic rats and might be one of mechanisms of CIHH keeping SABP homeostasis during acute hypoxia. PMID- 22242957 TI - Anionic functionalized gold nanoparticle continuous full filling separations: importance of sample concentration. AB - Electrically driven separations which contain nanoparticles offer detection and separation advantages but are often difficult to reproduce. To address possible sources of separation inconsistencies, anionic functionalized gold nanoparticles are thoroughly characterized and subsequently included in continuous full filling capillary electrophoresis separations of varying concentrations of three small molecules. Citrate stabilized gold nanospheres are functionalized with 11 mercaptoundecanoic acid, 6-mercaptohexanoic acid, or thioctic acid self-assembled monolayers (SAMs) and characterized using dynamic light scattering, extinction spectroscopy, zeta potential, and X-ray photoelectron spectroscopy prior to use in capillary electrophoresis. Several important trends are noted. First, the stability of these anionic nanoparticles in the capillary improves with increased ligand packing density as indicated by a ratio of absorbance collected at 520 to 600 nm. Second, increasing nanoparticle concentration from 0 to 2 nM (0 0.002(5)%, w/w) minimally impacts analyte migration times; however, when higher nanoparticle concentrations are included within the capillary, nanoparticle aggregation occurs which induces separation inconsistencies. Third, analyte peak areas are most significantly impacted as their concentration decreases. These trends are attributed to both sample enrichment and electrostatic interactions between the anionic carboxylic acid functionalized gold nanoparticles and sample. These important findings suggest that sample concentration-induced conductivity differences between the sample matrix and separation buffer as well as SAM packing density are important parameters to both characterize and consider when nanoparticles are used during continuous full filling separations and their subsequent use to enhance spectroscopic signals to improve in-capillary analyte detection limits. PMID- 22242959 TI - Assessment of DDT relative bioavailability and bioaccessibility in historically contaminated soils using an in vivo mouse model and fed and unfed batch in vitro assays. AB - In this study, DDTr (DDTr = DDT + DDD + DDE) relative bioavailability in historically contaminated soils (n = 7) was assessed using an in vivo mouse model. Soils or reference materials were administered to mice daily over a 7 day exposure period with bioavailability determined using DDTr accumulation in adipose, kidney, or liver tissues. Depending on the target tissue used for its calculation, some variability in DDTr relative bioavailability was observed; however, it did not exceed 25% (range 2-25%). When DDTr bioaccessibility was determined using organic physiologically based extraction test (Org-PBET), unified BARGE method (UBM), and fed organic estimation human simulation test (FOREhST) in vitro assays, bioaccessibility was less than 4% irrespective of the assay utilized and the concentration of DDTr in the contaminated soil. Pearson correlations demonstrate a poor relationship between DDTr relative bioavailability and DDTr bioaccessibility (0.47, 0.38, and 0.28, respectively), illustrating the limitations of the static in vitro methods for predicting the dynamic processes of the mammalian digestive system for this hydrophobic organic contaminant. PMID- 22242960 TI - Hybrid polyethylenimine and polyacrylic acid-bound iron oxide as a magnetoplex for gene delivery. AB - Low transfection efficiency is always an issue when cationic polymers are used as a nonviral gene vector in the physiological condition, especially in the presence of proteins. A cationic magnetic nanoparticle (MNP) may be an alternative to solve this problem because a magnetic field can help to attract the MNP and internalize it into cells. The aim of this study was to determine the potency of polyethylenimine (PEI)-decorated MNPs for efficiently complexing and delivering plasmid DNA in vitro with the help of a magnetic field. PEI is associated with poly(acrylic acid)-bound superparamagnetic iron oxide (PAAIO) through electrostatic interactions (PEI-PAAIO). PEI-PAAIO formed stable polyplexes with pDNA in the presence and absence of 10% fetal bovine serum (FBS) and could be used for magnetofection. The effect of a static magnetic field on the cytotoxicity, cellular uptake, and transfection efficiency of PEI-PAAIO/pDNA was evaluated with and without 10% FBS. Magnetofection efficacy in HEK 293T cells and U87 cells containing 10% FBS was significantly improved in the presence of an external magnetic field. The amount of internalized iron was quantitatively measured using an inductively coupled plasma-optical emission spectrometer and directly visualized using Prussian blue staining. The internalized pDNA was visualized using a confocal laser scanning microscope. PMID- 22242961 TI - Ultrasensitive detection of bacteria by microchip electrophoresis based on multiple-concentration approaches combining chitosan sweeping, field-amplified sample stacking, and reversed-field stacking. AB - In this paper we describe an on-chip multiple-concentration method combining chitosan (CS) sweeping, reversed-field stacking, and field-amplified sample stacking for highly efficient detection of bacteria. Escherichia coli was selected as a model bacterium to investigate the efficiency of this multiple concentration method. CS was the most suitable sweeping agent for microchip electrophoresis, replacing the usually used cetyltrimethylammonium bromide for capillary electrophoresis. The additive taurine had a synergistic effect by enhancing the interaction between CS and the surface of the bacteria, thus improving the analysis sensitivity. All steps of the concentration method and related mechanisms are described and discussed in detail. A concentration enhancement factor of approximately 6000 was obtained using this concentration method under optimal conditions as compared to using no concentration step, and the detection limit of E. coli was 145 CFU/mL. The multiple-concentration methodology was also applied for the quantification of bacteria in surface water, and satisfactory results were achieved. The application of this methodology showed that the concentration enhancement of bacteria clearly conferred advantageous sensitivity, speed, and sample volume compared to established methods. PMID- 22242962 TI - There ought to be an equation for that. AB - An overriding interest in photosynthesis has propelled my wanderings from chemist to biochemist to plant physiologist and on to global topics. Equations and models have been organizing principles along the way. This fascination started as a reaction to difficulties with written communication, but it has proven to be quite useful in moving across different levels of organization. I conclude with some discussion of the importance of Earth system models for understanding and predicting how human activities may influence the climate, environment, and biota in the future, and some ideas about how disciplinary science might make larger contributions to this interdisciplinary problem. PMID- 22242963 TI - Autophagy: pathways for self-eating in plant cells. AB - Plants have developed sophisticated mechanisms to survive when in unfavorable environments. Autophagy is a macromolecule degradation pathway that recycles damaged or unwanted cell materials upon encountering stress conditions or during specific developmental processes. Over the past decade, our molecular and physiological understanding of plant autophagy has greatly increased. Most of the essential machinery required for autophagy seems to be conserved from yeast to plants. Plant autophagy has been shown to function in various stress responses, pathogen defense, and senescence. Some of its potential upstream regulators have also been identified. Here, we describe recent advances in our understanding of autophagy in plants, discuss areas of controversy, and highlight potential future directions in autophagy research. PMID- 22242964 TI - Understanding product specificity of protein lysine methyltransferases from QM/MM molecular dynamics and free energy simulations: the effects of mutation on SET7/9 beyond the Tyr/Phe switch. AB - The results of hybrid quantum mechanical/molecular mechanical (QM/MM) free energy (potential of mean force) simulations for methyl-transfer processes in SET7/9 and its Y245A mutant are compared to address the question concerning the change of the product specificity as well as catalytic efficiency due to the mutation. One of the key questions is whether or not the free energy profiles of methyl transfers may be used to predict the change of the product specificity as a result of the mutations for the residues that are not located at the Tyr/Phe switch position. The simulations show that while the wild-type SET7/9 is a monomethylase, the Y245->A mutation increases the ability of the enzyme to add more methyl groups on the target lysine (i.e., acting as a trimethylase). However, the first methyl-transfer process seems to become less efficient in the mutant compared to that in wild-type. All these results are consistent with experimental observations concerning the effects of the mutation on the product specificity and catalytic efficiency. Thus, the previous suggestion that the energetics of the methyl-transfer reactions may determine the product specificity, at least in some cases, is confirmed by the present work. Moreover, the dynamic information of the reactant complexes obtained from the QM/MM molecular dynamics simulations shows that the ability of the reactant complexes to form the reactive transition-state-like configurations may be used as an important indicator for the prediction of the product specificity of PKMTs, consistent with previous computational studies. PMID- 22242966 TI - Anti-collusion indices and averages for the evaluation of performances and judges. AB - In subjectively assessed artistic sports, judges sometimes collude. To avoid this, Federations adopt various strategies in their regulations. However, it is evident that these methods are often not sufficient to overcome collusions completely. The problem is especially difficult in cases where the judging panel consists of sub-commissions that deal with particular aspects of each performance and the scores of each sub-commission are summarized as mean values, which, in turn, are combined into a final mark. Therefore, the formulation of anti collusion indices would be useful to assess judges and take account of such scores, rejecting the less reliable ones. An anti-collusion index and related average, recently introduced, can be applied in fields other than sports. This article presents some useful considerations for the application of such instruments to the field of sport. PMID- 22242967 TI - The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate. AB - AIMS: To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS: Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double blind, randomized, cross-over fashion (>=7 day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120 h after co-administration. RESULTS: Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (C(max)), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC(0-tlqc)), AUC from time zero to infinity (AUC(0-infinity)), and terminal elimination half life for regimen A were 0.50 h, 308.6 ng ml-1, 1594.9 ng h ml-1, 1616.0 ng h ml-1 and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml-1, 1564.5 ng h ml-1, 1584.2 ng h ml-1 and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone C(max) , AUC(0-tlqc) and AUC(0-infinity) central values were 0.94 (0.89-1.00), 1.02 (1.00-1.04) and 1.02 (1.00-1.04), respectively. CONCLUSIONS: Co administration of febuxostat had no effect on rosiglitazone or N desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8. PMID- 22242968 TI - The association between -330T/G polymorphism of interleukin 2 gene and bladder cancer. AB - Bladder cancer is one of the most common cancers in the world. Studies have shown that genetic factors may play important roles in the development of this disease. Interleukin-2 (IL-2) is a cytokine involved in the regulation of proliferation and functional activities of T- and NK-cell. Recombinant IL-2 has been shown to be a promising agent for the activation of immune response against tumors. The aim of this study was to examine the effect of -330T/G polymorphism of the IL-2 gene on the development of bladder cancer in the Chinese population. IL-2 -330T/G polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 365 bladder cancer cases and 390 age-matched healthy controls. Data were analyzed using the Chi-square test. Results showed that individuals with TG genotype or GG genotype had significantly increased susceptibility to bladder cancer (odds ratio [OR]=1.48, 95% confidence interval [CI]: 1.08-2.02, p=0.014 and OR=2.22, 95%CI: 1.35-3.68, p=0.002). Also, the frequency of the G allele was significantly higher in bladder cancer cases compared with healthy controls (OR=1.40, 95%CI: 1.14-1.73, p=0.002). In conclusion, IL-2 -330T/G polymorphism may be involved in the etiology of bladder in Chinese population. PMID- 22242969 TI - DNA interaction studies of an antiviral drug, ribavirin, using different instrumental methods. AB - Interaction of ribavirin with CT-DNA was investigated by emission, absorption, circular dichroism, and viscosity studies to determine the binding mode and binding constant of this drug with DNA. The calculated binding constant, K(b), obtained from UV-vis absorption studies was 4.6 * 10(3) M(-1). In fluorimetric studies, the enthalpy (DeltaH<0) and entropy (DeltaS>0) of the reaction between ribavirin and CT-DNA showed a hydrophobic interaction. In addition, in the circular dichroism spectrum, the drug induces a B -> A structural transition of CT-DNA. These results demonstrate that ribavirin interacts with CT-DNA via the groove binding mode. It was observed that the drug has ability to cleave supercoiled plasmid DNA. PMID- 22242970 TI - Solid-state energetics and electrostatics: Madelung constants and Madelung energies. AB - The Madelung constants of ionic solids relate to their geometry and electrostatic interactions. Furthermore, because of issues in their evaluation, they are also of considerable mathematical interest. The corresponding Madelung (electrostatic, coulomb) energy is the principal contributor to the lattice energies of ionic systems, and these energies largely influence many of their physical properties. The Madelung constants are here defined and their properties considered. A difficulty with their application is that they may be defined relative to various lattice distances, and with various conventions for inclusion of the charges, leading to possible confusion in their use. Instead, the unambiguous Madelung energy, E(M), is to be preferred in chemistry. An extensive list of Madelung energies is presented. From this data set, it is observed that there is a strong linear correlation between the lattice energies of ionic solids, U(POT), and their Madelung energies: U(POT)/kJ mol(-1) = 0.8519E(M) + 293.9. This correlation establishes that the lattice energy, U(POT), for ionic solids is about 15% smaller than the attractive Madelung energy, the difference arising from the repulsions unaccounted for by the solely coulombic Madelung energy calculation. Correlations of U(POT) against E(M) for alkali metal hydrides and transition metal compounds, each having considerable covalency, show much reduced Madelung contributions to the lattice energy. These correlations permit ready estimation of lattice energies, and are the first to be based on actual data rather than a broad analysis. The independent volume-based thermodynamic (VBT) method, which relies on a separate correlation with the formula unit volume of the ionic material, complements these correlations. PMID- 22242972 TI - Bax/Bcl-2 protein expression ratio and leukocyte function are related to reduction of Walker-256 tumor growth after beta-hydroxy-beta-methylbutyrate (HMB) administration in Wistar rats. AB - This study investigated the mechanisms by which beta-hydroxy-beta-methylbutyrate (HMB) administration in rats reduces Walker-256 tumor growth. Male Wistar rats were supplemented with HMB (76 mg/kg/day) (HW), or a placebo (W), during 8 wk by gavage. At the 6th wk, rats were inoculated with a suspension of Walker 256 tumor cells (3 * 10(7)/mL). Fifteen days after inoculation, the HW group showed higher glycemia (109.4 +/- 5.53 vs. 89.87 +/- 7.02 mg/dL, P < 0.05) and lower spleen (1.35 +/- 0.05 vs. 1.65 +/- 0.12 g, P < 0.05) and tumor weights (9.64 +/- 1.07 vs. 13.55 +/- 1.19 g, P < 0.05) compared to the W group. Tumor cells extracted from the HMB-treated rats displayed a 36.9% decrement in rates of proliferation ex vivo and a significant increase in the Bax/Bcl-2 protein expression ratio in comparison to those extracted from the placebo-treated rats (P < 0.05). Both phagocytic capacity and H(2)O(2) production rates were higher in polymorphnuclear cells that were obtained from the blood of the HW rats in comparison to those from the W rats (P < 0.05). Reduction of necrotic regions and an intense infiltration of leukocytes and activated granulocytes in HW were evident by transmission electron microscopy. Our findings suggest that HMB supplementation decreases tumor burden by modifying the inner environment of tumor cells and by interfering with blood leukocyte function. PMID- 22242973 TI - Adefovir dipivoxil in chronic hepatitis B: history and current uses. AB - INTRODUCTION: The nucleotide analogue adefovir dipivoxil (ADV) was approved in 2002 for the treatment of chronic infection with hepatitis B virus (HBV), in both hepatitis B e antigen (HBeAg)-positive and -negative patients. ADV 10 mg daily has been associated with improved liver histology, decreased levels of HBV DNA and alanine aminotransferase (ALT), and seroconversion of HBeAg. AREAS COVERED: This paper reviews the use of ADV as a first-line treatment for chronic hepatitis B and as an add-on therapy in chronic HBV-infected patients with lamivudine resistance. In the years since its launch, clinical resistance to ADV has emerged, and tenofovir and entecavir have shown greater efficacy in reducing viral load. EXPERT OPINION: Many patients who started antiviral therapy with ADV (either as monotherapy or in combination with lamivudine) remain on this agent because they have undetectable viremia, but its future use will probably diminish because of the availability of more potent drugs. ADV is generally well tolerated, though the 10 mg dose is associated with low risk of nephrotoxicity. PMID- 22242974 TI - Multimodal action and selective toxicity of zerovalent iron nanoparticles against cyanobacteria. AB - Cyanobacteria pose a serious threat to water resources around the world. This is compounded by the fact that they are extremely resilient, having evolved numerous protective mechanisms to ensure their dominant position in their ecosystem. We show that treatment with nanoparticles of zerovalent iron (nZVI) is an effective and environmentally benign method for destroying and preventing the formation of cyanobacterial water blooms. The nanoparticles have multiple modes of action, including the removal of bioavailable phosphorus, the destruction of cyanobacterial cells, and the immobilization of microcystins, preventing their release into the water column. Ecotoxicological experiments showed that nZVI is a highly selective agent, having an EC(50) of 50 mg/L against cyanobacteria; this is 20-100 times lower than its EC(50) for algae, daphnids, water plants, and fishes. The primary product of nZVI treatment is nontoxic and highly aggregated Fe(OH)(3), which promotes flocculation and gradual settling of the decomposed cyanobacterial biomass. PMID- 22242976 TI - Evolution of public attitudes about mental illness: a systematic review and meta analysis. AB - OBJECTIVE: To explore whether the increase in knowledge about the biological correlates of mental disorders over the last decades has translated into improved public understanding of mental illness, increased readiness to seek mental health care and more tolerant attitudes towards mentally ill persons. METHOD: A systematic review of all studies on mental illness-related beliefs and attitudes in the general population published before 31 March 2011, examining the time trends of attitudes with a follow-up interval of at least 2 years and using national representative population samples. A subsample of methodologically homogeneous studies was further included in a meta-regression analysis of time trends. RESULTS: Thirty-three reports on 16 studies on national time trends met our inclusion criteria, six of which were eligible for a meta-regression analysis. Two major trends emerged: there was a coherent trend to greater mental health literacy, in particular towards a biological model of mental illness, and greater acceptance of professional help for mental health problems. In contrast, however, no changes or even changes to the worse were observed regarding the attitudes towards people with mental illness. CONCLUSION: Increasing public understanding of the biological correlates of mental illness seems not to result in better social acceptance of persons with mental illness. PMID- 22242975 TI - Natural and synthetic modulators of SK (K(ca)2) potassium channels inhibit magnesium-dependent activity of the kinase-coupled cation channel TRPM7. AB - BACKGROUND AND PURPOSE: Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an alpha-type protein kinase domain. TRPM7 is essential for proliferation and cell growth. Up-regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. The goal of this work was to identify non-toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells. EXPERIMENTAL APPROACH: We developed an aequorin bioluminescence based assay of TRPM7 channel activity and performed a hypothesis-driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments. KEY RESULTS: TRPM7 currents were inhibited by modulators of small conductance Ca2+ -activated K+ channels (K(Ca)2.1-2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC50 1.6 uM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg2+ -dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7-like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes. CONCLUSIONS AND IMPLICATIONS: This study reveals a tight overlap in the pharmacological profiles of TRPM7 and K(Ca)2.1-2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well-suited to study functional features and cellular roles of endogenous TRPM7. PMID- 22242977 TI - Changes in flavor precursors, pungency, and sugar content in short-day onion bulbs during 5-month storage at various temperatures or in controlled atmosphere. AB - Short-day onion bulbs (cv. TG 1015Y) were stored in 1% O(2,) 99% N(2) air at 5 degrees C (controlled atmosphere [CA]), or in ambient air at 5, 24, or 30 degrees C, for 5 mo. Changes in flavor precursors, pungency, and sugar content were investigated. After 5 mo of storage, 1-propenyl-L-cysteine sulfoxide concentrations increased continuously at 5 degrees C, gradually decreased in CA, slightly increased for 3 mo, and returned to initial levels at 24 degrees C and decreased below initial levels at 34 degrees C. Methyl-L-cysteine sulfoxide concentrations remained unchanged in all storage conditions. Onion pungency levels significantly increased at 5 degrees C, and decreased at 30 degrees C. Storage in CA and at 24 degrees C resulted in some fluctuations in pungency but the levels remained similar to initial levels. The calculated pyruvic acid concentrations were approximately 1.0 MUmole/mL higher than the measured concentrations, and showed an increase at 5 degrees C and a slight reduction at 30 degrees C, consistent with the pungency results. Storage at 5 degrees C and in CA resulted in slight increases in fructose and glucose concentrations for 3 to 4 mo with subsequent rapid decreases, while sucrose concentrations remained unchanged. However, at 24 and 30 degrees C, fructose and glucose concentrations continuously decreased, accompanied by a continuous increase in sucrose concentrations. Storage in CA maintained the quality of onions best, as evidenced by the smallest changes in flavor precursors, pungency, and sugar concentrations, while storage at 5 degrees C resulted in increased pungency. Storage at 24 and 30 degrees C was tested for the purpose of comparison only; these temperatures are not recommended for commercial storage. PMID- 22242978 TI - Klein tunneling of a quasirelativistic Bose-Einstein condensate in an optical lattice. AB - A proof-of-principle experiment simulating effects predicted by relativistic wave equations with ultracold atoms in a bichromatic optical lattice that allows for a tailoring of the dispersion relation is reported. We observe the analog of Klein tunneling, the penetration of relativistic particles through a potential barrier without the exponential damping that is characteristic for nonrelativistic quantum tunneling. Both linear (relativistic) and quadratic (nonrelativistic) dispersion relations are investigated, and significant barrier transmission is observed only for the relativistic case. PMID- 22242979 TI - Observation of high coherence in Josephson junction qubits measured in a three dimensional circuit QED architecture. AB - Superconducting quantum circuits based on Josephson junctions have made rapid progress in demonstrating quantum behavior and scalability. However, the future prospects ultimately depend upon the intrinsic coherence of Josephson junctions, and whether superconducting qubits can be adequately isolated from their environment. We introduce a new architecture for superconducting quantum circuits employing a three-dimensional resonator that suppresses qubit decoherence while maintaining sufficient coupling to the control signal. With the new architecture, we demonstrate that Josephson junction qubits are highly coherent, with T2 ~ 10 to 20 MUs without the use of spin echo, and highly stable, showing no evidence for 1/f critical current noise. These results suggest that the overall quality of Josephson junctions in these qubits will allow error rates of a few 10(-4), approaching the error correction threshold. PMID- 22242980 TI - Spin squeezing inequalities for arbitrary spin. AB - We determine the complete set of generalized spin squeezing inequalities, given in terms of the collective angular momentum components, for particles with an arbitrary spin. They can be used for the experimental detection of entanglement in an ensemble in which the particles cannot be individually addressed. We also present a large set of criteria involving collective observables different from the angular momentum coordinates. We show that some of the inequalities can be used to detect k-particle entanglement and bound entanglement. PMID- 22242981 TI - Experimental unconditional preparation and detection of a continuous bound entangled state of light. AB - Among the possibly most intriguing aspects of quantum entanglement is that it comes in free and bound instances. The existence of bound entangled states certifies an intrinsic irreversibility of entanglement in nature and suggests a connection with thermodynamics. In this Letter, we present a first unconditional, continuous-variable preparation and detection of a bound entangled state of light. We use convex optimization to identify regimes rendering its bound character well certifiable, and continuously produce a distributed bound entangled state with an extraordinary and unprecedented significance of more than 10 standard deviations away from both separability and distillability. Our results show that the approach chosen allows for the efficient and precise preparation of multimode entangled states of light with various applications in quantum information, quantum state engineering, and high precision metrology. PMID- 22242982 TI - Boson pairing and unusual criticality in a generalized XY model. AB - We discuss the unusual critical behavior of a generalized XY model containing both 2pi-periodic and pi-periodic couplings between sites, allowing for ordinary vortices and half-vortices. The phase diagram of this system includes both single particle condensate and pair-condensate phases. Using a field theoretic formulation and worm algorithm Monte Carlo simulations, we show that in two dimensions it is possible for the system to pass directly from the disordered (high temperature) phase to the single particle (quasi)condensate via an Ising transition, a situation reminiscent of the "deconfined criticality" scenario. PMID- 22242983 TI - Anderson localization or nonlinear waves: a matter of probability. AB - In linear disordered systems Anderson localization makes any wave packet stay localized for all times. Its fate in nonlinear disordered systems (localization versus propagation) is under intense theoretical debate and experimental study. We resolve this dispute showing that, unlike in the common hypotheses, the answer is probabilistic rather than exclusive. At any small but finite nonlinearity (energy) value there is a finite probability for Anderson localization to break up and propagating nonlinear waves to take over. It increases with nonlinearity (energy) and reaches unity at a certain threshold, determined by the initial wave packet size. Moreover, the spreading probability stays finite also in the limit of infinite packet size at fixed total energy. These results generalize to higher dimensions as well. PMID- 22242984 TI - Fluctuations of time averages for Langevin dynamics in a binding force field. AB - We derive a simple formula for the fluctuations of the time average x(t) around the thermal mean (eq) for overdamped brownian motion in a binding potential U(x). Using a backward Fokker-Planck equation, introduced by Szabo, Schulten, and Schulten in the context of reaction kinetics, we show that for ergodic processes these finite measurement time fluctuations are determined by the Boltzmann measure. For the widely applicable logarithmic potential, ergodicity is broken. We quantify the large nonergodic fluctuations and show how they are related to a superaging correlation function. PMID- 22242985 TI - Floating and sinking: the imprint of massive scalars around rotating black holes. AB - We study the coupling of massive scalar fields to matter in orbit around rotating black holes. It is generally expected that orbiting bodies will lose energy in gravitational waves, slowly inspiraling into the black hole. Instead, we show that the coupling of the field to matter leads to a surprising effect: because of superradiance, matter can hover into "floating orbits" for which the net gravitational energy loss at infinity is entirely provided by the black hole's rotational energy. Orbiting bodies remain floating until they extract sufficient angular momentum from the black hole, or until perturbations or nonlinear effects disrupt the orbit. For slowly rotating and nonrotating black holes floating orbits are unlikely to exist, but resonances at orbital frequencies corresponding to quasibound states of the scalar field can speed up the inspiral, so that the orbiting body sinks. These effects could be a smoking gun of deviations from general relativity. PMID- 22242986 TI - Black hole entropy and isolated horizons thermodynamics. AB - We present a statistical mechanical calculation of the thermodynamical properties of (nonrotating) isolated horizons. The introduction of the Planck scale allows for the definition of a universal horizon temperature (independent of the mass of the black hole) and a well-defined notion of energy (as measured by suitable local observers) proportional to the horizon area in Planck units. The microcanonical and canonical ensembles associated with the system are introduced. Black hole entropy and other thermodynamical quantities can be consistently computed in both ensembles and results are in agreement with Hawking's semiclassical analysis for all values of the Immirzi parameter. PMID- 22242988 TI - Exclusion of canonical weakly interacting massive particles by joint analysis of Milky Way dwarf galaxies with data from the Fermi Gamma-Ray Space Telescope. AB - Dwarf spheroidal galaxies are known to be excellent targets for the detection of annihilating dark matter. We present new limits on the annihilation cross section of weakly interacting massive particles based on the joint analysis of seven Milky Way dwarfs using a frequentist Neyman construction and Pass 7 data from the Fermi Gamma-Ray Space Telescope. We exclude generic weakly interacting massive particle candidates annihilating into bb with a mass less than 40 GeV that reproduce the observed relic abundance. To within 95% systematic errors on the dark matter distribution within the dwarfs, the mass lower limit can be as low as 19 GeV or as high as 240 GeV. For annihilation into tau+ tau-, these limits become 19, 13, and 80 GeV, respectively. PMID- 22242989 TI - Universal fermionic spectral functions from string theory. AB - We carry out the first holographic calculation of a fermionic response function for a strongly coupled d=3 system with an explicit D=10 or D=11 supergravity dual. By considering the supersymmetry current, we obtain a universal result applicable to all d=3 N=2 SCFTs with such duals. Surprisingly, the spectral function does not exhibit a Fermi surface, despite the fact that the system is at finite charge density. We show that it has a phonino pole and at low frequencies there is a depletion of spectral weight with a power-law scaling which is governed by a locally quantum critical point. PMID- 22242987 TI - Constraining dark matter models from a combined analysis of Milky Way satellites with the Fermi Large Area Telescope. AB - Satellite galaxies of the Milky Way are among the most promising targets for dark matter searches in gamma rays. We present a search for dark matter consisting of weakly interacting massive particles, applying a joint likelihood analysis to 10 satellite galaxies with 24 months of data of the Fermi Large Area Telescope. No dark matter signal is detected. Including the uncertainty in the dark matter distribution, robust upper limits are placed on dark matter annihilation cross sections. The 95% confidence level upper limits range from about 10(-26) cm3 s( 1) at 5 GeV to about 5*10(-23) cm3 s(-1) at 1 TeV, depending on the dark matter annihilation final state. For the first time, using gamma rays, we are able to rule out models with the most generic cross section (~3*10(-26) cm3 s( 1) for a purely s-wave cross section), without assuming additional boost factors. PMID- 22242991 TI - Constraints and tests of the OPERA superluminal neutrinos. AB - The superluminal neutrinos detected by OPERA indicate Lorentz invariance violation (LIV) of the neutrino sector at the order of 10(-5). We study the implications of the result in this work. We find that such a large LIV implied by OPERA data will make the neutrino production process pi -> MU + nu(MU) kinematically forbidden for a neutrino energy greater than about 5 GeV. The OPERA detection of neutrinos at 40 GeV can constrain the LIV parameter to be smaller than 3*10(-7). Furthermore, the neutrino decay in the LIV framework will modify the neutrino spectrum greatly. The atmospheric neutrino spectrum measured by the IceCube Collaboration can constrain the LIV parameter to the level of 10(-12). The future detection of astrophysical neutrinos of galactic sources is expected to be able to give an even stronger constraint on the LIV parameter of neutrinos. PMID- 22242990 TI - Search for differences in oscillation parameters for atmospheric neutrinos and antineutrinos at Super-Kamiokande. AB - We present a search for differences in the oscillations of antineutrinos and neutrinos in the Super-Kamiokande-I, -II, and -III atmospheric neutrino sample. Under a two-flavor disappearance model with separate mixing parameters between neutrinos and antineutrinos, we find no evidence for a difference in oscillation parameters. Best-fit antineutrino mixing is found to be at (Deltam2,sin2 2theta)=(2.0*10(-3) eV2, 1.0) and is consistent with the overall Super-K measurement. PMID- 22242993 TI - GHz Rabi flopping to Rydberg states in hot atomic vapor cells. AB - We report on the observation of Rabi oscillations to a Rydberg state on a time scale below 1 ns in thermal rubidium vapor. We use a bandwidth-limited pulsed excitation and observe up to 6 full Rabi cycles within a pulse duration of ~4 ns. We find good agreement between the experiment and numerical simulations based on a surprisingly simple model. This result shows that fully coherent dynamics with Rydberg states can be achieved even in thermal atomic vapor, thus suggesting small vapor cells as a platform for room-temperature quantum devices. Furthermore, the result implies that previous coherent dynamics in single-atom Rydberg gates can be accelerated by 3 orders of magnitude. PMID- 22242994 TI - Doppler cooling to the quantum limit. AB - Doppler cooling on a narrow transition is limited by the noise of single scattering events. It shows novel features, which are in sharp contrast with cooling on a broad transition, such as a non-gaussian momentum distribution, and divergence of its mean square value close to the resonance. We have observed those features using 1D cooling on an intercombination transition in strontium, and compared the measurements with theoretical predictions and Monte Carlo simulations. We also find that for very a narrow transition, cooling can be improved using a dipole trap, where the clock shift is canceled. PMID- 22242995 TI - Enhanced nonlinear double excitation of He in intense extreme ultraviolet laser fields. AB - Nonlinear, three-photon double excitation of He in intense extreme ultraviolet free-electron laser fields (~24.1 eV, ~5 TW/cm2) is presented. Resonances to the doubly excited states converging to the He+ N=3 level are revealed by the shot-by-shot photoelectron spectroscopy and identified by theoretical calculations based on the time-dependent Schrodinger equation for the two electron atom under a laser field. It is shown that the three-photon double excitation is enhanced by intermediate Rydberg states below the first ionization threshold, giving a greater contribution to the photoionization yields than the two-photon process by more than 1 order of magnitude. PMID- 22242996 TI - Control of molecular rotation with a chiral train of ultrashort pulses. AB - Trains of ultrashort laser pulses separated by the time of rotational revival (typically, tens of picoseconds) have been exploited for creating ensembles of aligned molecules. In this work we introduce a chiral pulse train--a sequence of linearly polarized pulses with the polarization direction rotating from pulse to pulse by a controllable angle. The chirality of such a train, expressed through the period and direction of its polarization rotation, is used as a new control parameter for achieving selectivity and directionality of laser-induced rotational excitation. The method employs chiral trains with a large number of pulses separated on the time scale much shorter than the rotational revival (a few hundred femtosecond), enabling the use of conventional pulse shapers. PMID- 22242997 TI - Measurement of a large chemical reaction rate between ultracold closed-shell 40Ca atoms and open-shell 174Yb+ ions held in a hybrid atom-ion trap. AB - Ultracold 174Yb+ ions and 40Ca atoms are confined in a hybrid trap. The charge exchange chemical reaction rate constant between these two species is measured and found to be 4 orders of magnitude larger than recent measurements in other heteronuclear systems. The structure of the CaYb+ molecule is determined and used in a calculation that explains the fast chemical reaction as a consequence of strong radiative charge transfer. A possible explanation is offered for the apparent contradiction between typical theoretical predictions and measurements of the radiative association process in this and other recent experiments. PMID- 22242998 TI - Light-assisted ion-neutral reactive processes in the cold regime: radiative molecule formation versus charge exchange. AB - We present a combined experimental and theoretical study of cold reactive collisions between laser-cooled Ca+ ions and Rb atoms in an ion-atom hybrid trap. We observe rich chemical dynamics which are interpreted in terms of nonadiabatic and radiative charge exchange as well as radiative molecule formation using high level electronic structure calculations. We study the role of light-assisted processes and show that the efficiency of the dominant chemical pathways is considerably enhanced in excited reaction channels. Our results illustrate the importance of radiative and nonradiative processes for the cold chemistry occurring in ion-atom hybrid traps. PMID- 22242999 TI - Dispersive optical interface based on nanofiber-trapped atoms. AB - We dispersively interface an ensemble of 1000 atoms trapped in the evanescent field surrounding a tapered optical nanofiber. This method relies on the azimuthally asymmetric coupling of the ensemble with the evanescent field of an off-resonant probe beam, transmitted through the nanofiber. The resulting birefringence and dispersion are significant; we observe a phase shift per atom of ~1 mrad at a detuning of 6 times the natural linewidth, corresponding to an effective resonant optical density per atom of 0.027. Moreover, we utilize this strong dispersion to nondestructively determine the number of atoms. PMID- 22243000 TI - Supercontinuum generation with femtosecond self-healing Airy pulses. AB - We report experiments and numerical simulations on supercontinuum generation with femtosecond Airy pulses in a highly nonlinear optical fiber. The ability of the Airy waveform to regenerate its dominant intensity peak results in the generation of distinct spectral features. Airy pulses and other self-healing temporal waveforms may be useful for the generation of spectra with desired properties. PMID- 22243001 TI - Trapped-ion state detection through coherent motion. AB - We demonstrate a general method for state detection of trapped ions that can be applied to a large class of atomic and molecular species. We couple a spectroscopy ion (27Al+) to a control ion (25Mg+) in the same trap and perform state detection through off-resonant laser excitation of the spectroscopy ion that induces coherent motion. The motional amplitude, dependent on the spectroscopy ion state, is measured either by time-resolved photon counting or by resolved sideband excitations on the control ion. The first method provides a simplified way to distinguish clock states in 27Al+, which avoids ground-state cooling and sideband transitions. The second method reduces spontaneous emission and optical pumping on the spectroscopy ion, which we demonstrate by nondestructively distinguishing Zeeman sublevels in the (1)S0 ground state of 27Al+. PMID- 22243002 TI - Chaos in symmetric phase oscillator networks. AB - Phase-coupled oscillators serve as paradigmatic models of networks of weakly interacting oscillatory units in physics and biology. The order parameter which quantifies synchronization so far has been found to be chaotic only in systems with inhomogeneities. Here we show that even symmetric systems of identical oscillators may not only exhibit chaotic dynamics, but also chaotically fluctuating order parameters. Our findings imply that neither inhomogeneities nor amplitude variations are necessary to obtain chaos; i.e., nonlinear interactions of phases give rise to the necessary instabilities. PMID- 22243003 TI - Memory effects are relevant for chaotic advection of inertial particles. AB - A systematic investigation of the effect of the history force on particle advection is carried out in a paradigmatic model flow of chaotic advection, the von Karman flow. All investigated properties turn out to heavily depend on the presence of memory when compared to previous studies neglecting this force. We find a weaker tendency for accumulation and for caustics formation. The Lyapunov exponent of transients becomes larger, the escape rates are strongly altered. Attractors are found to be suppressed by the history force, and periodic ones have a very slow, t(-1/2)-type convergence towards the asymptotic form. PMID- 22243004 TI - Stabilization of the resistive wall mode by a rotating solid conductor. AB - Stabilization of the resistive wall mode (RWM) by high-speed differentially rotating conducting walls is demonstrated in the laboratory. To observe stabilization intrinsic azimuthal plasma rotation must be braked with error fields. Above a critical error field the RWM frequency discontinuously slows (locks) and fast growth subsequently occurs. Wall rotation is found to reduce the locked RWM saturated amplitude and growth rate, with both static (vacuum vessel) wall locked and slowly rotating RWMs observed depending on the alignment of wall to plasma rotation. At high wall rotation RWM onset is found to occur at larger plasma currents, thus increasing the RWM-stable operation window. PMID- 22242992 TI - Wgamma production and limits on anomalous WWgamma couplings in pp collisions at sqrt[s] = 1.96 TeV. AB - We measure the cross section and the difference in rapidities between photons and charged leptons for inclusive W(->lnu) + gamma production in egamma and MUgamma final states. Using data corresponding to an integrated luminosity of 4.2 fb(-1) collected with the D0 detector at the Fermilab Tevatron Collider, the measured cross section times branching fraction for the process pp -> Wgamma + X -> lnugamma + X and the distribution of the charge-signed photon-lepton rapidity difference are found to be in agreement with the standard model. These results provide the most stringent limits on anomalous WWgamma couplings for data from hadron colliders: -0.4=0.7) of TJ-II plasmas. The temporal dynamics of the interaction displays an oscillatory behavior with a characteristic predator-prey relationship. The spatial evolution of this turbulence-flow oscillation pattern has been measured, showing both radial outward and inward propagation velocities of the turbulence flow front. The results indicate that the edge shear flow linked to the L-H transition can behave either as a slowing-down, damping mechanism of outward propagating turbulent-flow oscillating structures, or as a source of inward propagating turbulence-flow events. PMID- 22243008 TI - Mirror mode expansion in planetary magnetosheaths: Bohm-like diffusion. AB - Observed scale sizes of mirror modes in planetary magnetosheaths tend to be equal or larger than those that correspond to the maximum growth rate of the mirror instability: 9 rho(p) (proton gyroradius). These phenomena can be accounted for by introducing a diffusion process (Bohm) that shifts the spectra to lower wave numbers as the mode convects away from the source to the observation point. The theory is applied to data obtained in the magnetosheaths of Earth, Jupiter, Saturn, and the heliosheath, and shown to provide reasonable agreement to past spacecraft observations. Further observational tests of the theory are suggested. PMID- 22243009 TI - Unraveling the solid-liquid-vapor phase transition dynamics at the atomic level with ultrafast x-ray absorption near-edge spectroscopy. AB - X-ray absorption near-edge spectroscopy (XANES) is a powerful probe of electronic and atomic structures in various media, ranging from molecules to condensed matter. We show how ultrafast time resolution opens new possibilities to investigate highly nonequilibrium states of matter including phase transitions. Based on a tabletop laser-plasma ultrafast x-ray source, we have performed a time resolved (~3 ps) XANES experiment that reveals the evolution of an aluminum foil at the atomic level, when undergoing ultrafast laser heating and ablation. X-ray absorption spectra highlight an ultrafast transition from the crystalline solid to the disordered liquid followed by a progressive transition of the delocalized valence electronic structure (metal) down to localized atomic orbitals (nonmetal vapor), as the average distance between atoms increases. PMID- 22243010 TI - Soliton instabilities and vortex street formation in a polariton quantum fluid. AB - Exciton polaritons have been shown to be an optimal system in order to investigate the properties of bosonic quantum fluids. We report here on the observation of dark solitons in the wake of engineered circular obstacles and their decay into streets of quantized vortices. Our experiments provide a time resolved access to the polariton phase and density, which allows for a quantitative study of instabilities of freely evolving polaritons. The decay of solitons is quantified and identified as an effect of disorder-induced transverse perturbations in the dissipative polariton gas. PMID- 22243011 TI - Van der Waals interactions in ionic and semiconductor solids. AB - van der Waals (vdW) energy corrected density-functional theory [Phys. Rev. Lett. 102, 073005 (2009)] is applied to study the cohesive properties of ionic and semiconductor solids (C, Si, Ge, GaAs, NaCl, and MgO). The required polarizability and dispersion coefficients are calculated using the dielectric function obtained from time-dependent density-functional theory. Coefficients for "atoms in the solid" are then calculated from the Hirshfeld partitioning of the electron density. It is shown that the Clausius-Mossotti equation that relates the polarizability and the dielectric function is accurate even for covalently bonded semiconductors. We find an overall improvement in the cohesive properties of Si, Ge, GaAs, NaCl, and MgO, when vdW interactions are included on top of the Perdew-Burke-Ernzerhof or Heyd-Scuseria-Ernzerhof functionals. The relevance of our findings for other solids is discussed. PMID- 22243012 TI - Forced tearing of ductile and brittle thin sheets. AB - Tearing a thin sheet by forcing a rigid object through it leads to complex crack morphologies; a single oscillatory crack arises when a tool is driven laterally through a brittle sheet, while two diverging cracks and a series of concertinalike folds forms when a tool is forced laterally through a ductile sheet. On the other hand, forcing an object perpendicularly through the sheet leads to radial petallike tears in both ductile and brittle materials. To understand these different regimes we use a combination of experiments, simulations, and simple theories. In particular, we describe the transition from brittle oscillatory tearing via a single crack to ductile concertina tearing with two tears by deriving laws that describe the crack paths and wavelength of the concertina folds and provide a simple phase diagram for the morphologies in terms of the material properties of the sheet and the relative size of the tool. PMID- 22243013 TI - Quantum Hall superfluids in topological insulator thin films. AB - Three-dimensional topological insulators have protected Dirac-cone surface states. In this Letter we argue that gapped excitonic superfluids with spontaneous coherence between top and bottom surfaces can occur in the topological insulator (TI)-thin-film quantum Hall regime. We find that the large dielectric constants of TI materials increase the layer separation range over which coherence survives and decrease the superfluid sound velocity, but have little influence on the superfluid density or on the charge gap. The coherent state at total Landau-level filling factor nuT=0 is predicted to be free of edge modes, qualitatively altering its transport phenomenology compared to the widely studied case of nuT=1 in GaAs double-quantum wells. PMID- 22243014 TI - Nature of the band gap and origin of the conductivity of PbO2 revealed by theory and experiment. AB - Lead dioxide has been used for over a century in the lead-acid battery. Many fundamental questions concerning PbO2 remain unanswered, principally: (i) is the bulk material a metal or a semiconductor, and (ii) what is the source of the high levels of conductivity? We calculate the electronic structure and defect physics of PbO2, using a hybrid density functional, and show that it is an n-type semiconductor with a small indirect band gap of ~0.2 eV. The origin of electron carriers in the undoped material is found to be oxygen vacancies, which forms a donor state resonant in the conduction band. A dipole-forbidden band gap combined with a large carrier induced Moss-Burstein shift results in a large effective optical band gap. The model is supported by neutron diffraction, which reveals that the oxygen sublattice is only 98.4% occupied, thus confirming oxygen substoichiometry as the electron source. PMID- 22243015 TI - Few-particle Green's functions for strongly correlated systems on infinite lattices. AB - We show how few-particle Green's functions can be calculated efficiently for models with nearest-neighbor hopping, for infinite lattices in any dimension. As an example, for one-dimensional spinless fermions with both nearest-neighbor and second-nearest-neighbor interactions, we investigate the ground states for up to 5 fermions. This allows us not only to find the stability region of various bound complexes, but also to infer the phase diagram at small but finite concentrations. PMID- 22243016 TI - Quantum dynamics of a driven correlated system coupled to phonons. AB - Nonequilibrium interplay between charge, spin, and lattice degrees of freedom on a square lattice is studied for a single charge carrier doped in the t-J-Holstein model. In the presence of a static electric field we calculate the quasistationary state. With increasing electron-phonon (e-ph) coupling the carrier mobility decreases; however, we find increased steady state current due to e-ph coupling in the regime of negative differential resistance. We explore the distribution of absorbed energy between the spin and the phonon subsystem. For model parameters as relevant for cuprates, the majority of the gained energy flows into the spin subsystem. PMID- 22243017 TI - Observation of spin-selective tunneling in SiGe nanocrystals. AB - Spin-selective tunneling of holes in SiGe nanocrystals contacted by normal-metal leads is reported. The spin selectivity arises from an interplay of the orbital effect of the magnetic field with the strong spin-orbit interaction present in the valence band of the semiconductor. We demonstrate both experimentally and theoretically that spin-selective tunneling in semiconductor nanostructures can be achieved without the use of ferromagnetic contacts. The reported effect, which relies on mixing the light and heavy holes, should be observable in a broad class of quantum-dot systems formed in semiconductors with a degenerate valence band. PMID- 22243018 TI - Engineering negative differential conductance with the Cu(111) surface state. AB - Low-temperature scanning tunneling microscopy and spectroscopy are employed to investigate electron tunneling from a C60-terminated tip into a Cu(111) surface. Tunneling between a C60 orbital and the Shockley surface states of copper is shown to produce negative differential conductance (NDC) contrary to conventional expectations. NDC can be tuned through barrier thickness or C60 orientation up to complete extinction. The orientation dependence of NDC is a result of a symmetry matching between the molecular tip and the surface states. PMID- 22243019 TI - Lamellar solid-liquid mesophase nucleated by Josephson vortices at the melting of the vortex lattice in Bi2Sr2CaCu2O(8+delta) superconductor. AB - The local effect of the Josephson vortices on the vortex lattice melting process in Bi2Sr2CaCu2O(8+delta) crystals in the presence of an in-plane field H(ab) is studied by differential magneto-optical imaging. The melting process is found to commence along the Josephson vortex stacks, forming a mesomorphic phase of periodic liquid and solid lamellas, the direction and spacing of which are controlled by H(ab). The reduction of the local melting field H(m) along the Josephson vortex stacks is more than an order of magnitude larger than the reduction of the average bulk H(m) by HH(ab). PMID- 22243020 TI - Nanoscale electrostatic manipulation of magnetic flux quanta in ferroelectric/superconductor BiFeO3/YBa2Cu3O(7-delta) heterostructures. AB - Using heterostructures that combine a large-polarization ferroelectric (BiFeO3) and a high-temperature superconductor (YBa2Cu3O(7-delta)), we demonstrate the modulation of the superconducting condensate at the nanoscale via ferroelectric field effects. Through this mechanism, a nanoscale pattern of normal regions that mimics the ferroelectric domain structure can be created in the superconductor. This yields an energy landscape for magnetic flux quanta and, in turn, couples the local ferroelectric polarization to the local magnetic induction. We show that this form of magnetoelectric coupling, together with the possibility to reversibly design the ferroelectric domain structure, allows the electrostatic manipulation of magnetic flux quanta. PMID- 22243022 TI - Diagonal composite order in a two-channel Kondo lattice. AB - A novel type of symmetry breaking is reported for the two-channel Kondo lattice where conduction electrons have spin and orbital (channel) degrees of freedom. Using the continuous-time quantum Monte Carlo and the dynamical mean-field theory, a spontaneous breaking of the orbital symmetry is observed. The tiny breakdown of orbital occupation number, however, vanishes if the conduction electrons have the particle-hole symmetry. The proper order parameter instead is identified as a composite quantity representing the orbital-selective Kondo effect. The single-particle spectrum of the selected orbital shows insulating property, while the other orbital behaves as a Fermi liquid. This composite order is the first example of odd-frequency order other than off-diagonal order (superconductivity), and is a candidate of hidden order in f-electron systems. PMID- 22243021 TI - RKKY ferromagnetism with Ising-like spin states in intercalated Fe(1/4)TaS2. AB - We investigated the magnetic nature of Fe(1/4)TaS2 using x-ray absorption spectroscopy, photoemission spectroscopy, and first principles band calculations. The results show a large unquenched orbital magnetic moment (~1.0 MU(B)/Fe) at intercalated Fe sites, resulting in a gigantic magnetic anisotropy (H(A)?60 T). The magnetic coupling is well understood in terms of the Ruderman-Kittel-Kasuya Yosida (RKKY) interaction, suggesting a novel RKKY ferromagnet with Ising-type spin states. We also found that this indirect exchange coupling between the neighboring Fe spins is ferromagnetic and maximized at the Fe-Fe distance of 2*2 superstructure. PMID- 22243023 TI - Coherent longitudinal-optical ground-state phonon in CdSe quantum dots triggered by ultrafast charge migration. AB - We observe the CdSe longitudinal-optical ground-state phonon in the electron transfer system composed of CdSe quantum dots and methylviologen directly by femtosecond absorption spectroscopy. A significant phase shift indicates that the coherent oscillations are triggered by an ultrafast charge migration, which is the consequence of an electron transfer from the photoexcited quantum dot to the molecular acceptor methylviologen. In contrast, the observed coherent phonons in isolated quantum dots stem from the frequency modulation of the quantum dot excited-state spectrum. From the probe wavelength dependence of the longitudinal optical phonons in the electronic ground state and excited state it is possible to determine a biexciton binding energy of 35 meV. PMID- 22243024 TI - Evidence for confined tamm plasmon modes under metallic microdisks and application to the control of spontaneous optical emission. AB - We demonstrate strong confinement of the optical field by depositing a micron sized metallic disk on a planar distributed Bragg reflector. Confined Tamm plasmon modes are evidenced both experimentally and theoretically, with a lateral confinement limited to the disk area and strong coupling to TE polarized fields. Single quantum dots controllably coupled to these modes are shown to experience acceleration of their spontaneous emission when spectrally resonant with the mode. For quantum dots spectrally detuned from the confined Tamm plasmon mode, an inhibition of spontaneous emission by a factor 40+/-4 is observed, a record value in the optical domain. PMID- 22243025 TI - Sequence of four orthogonal smectic phases in an achiral bent-core liquid crystal: evidence for the SmAP(alpha) phase. AB - The mesomorphic properties of an achiral bent-core liquid crystal derived from 4 cyanoresorcinol are studied by polarizing optical microscopy, x-ray diffraction, and second harmonic electro-optic response. It shows a novel sequence of four nontilted or orthogonal smectic phases on cooling: SmA-SmAP(R)-SmAP(X)-SmAP(A). Here SmAP(X) is the new orthogonal polar uniaxial smectic phase. The electric field-induced transformations in the SmAP(X) phase give rise to two biaxial states separated by a uniaxial one. The second harmonic electro-optic response in this phase is interpreted in terms of the polar interaction with the electric field. A comparison of the experimental results with the next-nearest-neighbor model for the structure of the SmAP(X) phase shows it to be an SmAP(alpha) phase. PMID- 22243026 TI - Phase-transition-like properties of double-beam optical tweezers. AB - We report on double-beam optical tweezers that undergo previously unknown phase transition-like behavior resulting in the formation of more optical traps than the number of beams used to create them. We classify the optical force fields which produce multiple traps for a double-beam system including the critical behavior. This effect is demonstrated experimentally in orthogonally polarized (noninterfering) dual-beam optical tweezers for a silica particle of 2.32 MUm diameter. Phase transitions of multiple beam trapping systems have implications for hopping rates between traps and detection of forces between biomolecules using dual-beam optical tweezers. It is an example of a novel dynamic system with multiple states where force fields undergo a series of sign inversions as a function of parameters such as size and beam separation. PMID- 22243027 TI - Comment on "How water meets a very hydrophobic surface". PMID- 22243029 TI - Chemical patterns from surface grafted resists for directed assembly of block copolymers. AB - We demonstrate a direct e-beam patternable one-component block copolymer (BCP) resist to fabricate a chemical pattern for the directed assembly of a symmetric block copolymer. The resist consists of a low molecular weight poly(styrene-block methyl methacrylate) with a hydroxyl group at the PMMA chain end (PS-b-PMMA-OH), which anchors the chains to the surface. This short-tethered PMMA block provided sufficient sensitivity to allow scission by e-beam. The length of the untethered PS block was fine-tuned to impart the required contrast between the patterned and the unpatterned region for 1:1 assembly of an overlying BCP blend. Two BCP resists with a PS fraction of 0.25 (16SM) and 0.34 (18SM), with a total molecular weight less than 20K, were synthesized, and the assembly of a ternary BCP blend was studied. 16SM- and 18SM-anchored substrates showed nonpreferential and PS preferential surfaces, respectively. Both 18SM and 16SM could be patterned by e beam to fabricate a 1:1 chemical pattern with a line pitch of 70 nm for the assembly of a BCP ternary blend. 18SM gave fewer defects than 16SM due to an increased contrast in interfacial energies between adjacent stripes in the chemical surface pattern. Two additional PS-b-PMMA-OH polymers with a molecular weight of 39K (F(PS) = 0.76) and 69K (F(PS) = 0.83) were synthesized to study the effect of PS cross-linking upon exposure to e-beam. As the PS fraction increases, the line pattern becomes blurred and ultimately ineffective in guiding the BCP assembly. The blurring is attributed to cross-linking of adjacent PS chains. PMID- 22243030 TI - Promoting self-assembly of collagen-related peptides into various higher-order structures by metal-histidine coordination. AB - Collagen is an important and widely used biomaterial and therapeutic. The construction of large-scale collagen structures via the self-assembly of small collagen-related peptides has been extensively studied in the past decade. Here, we report a highly effective and simple means to assemble small synthetic collagen-related peptides into various higher-order structures by utilizing metal histidine coordination. In this work, two short collagen-related peptides in which histidine residues were incorporated as metal binding sites were designed and chemically synthesized: HG(PPG)(9)GH (X9) and HG(PPG)(4)(PHG)(PPG)(4)GH (PHG). Circular dichroism measurements indicated that these two peptides form only marginally stable collagen triple helices but that their stability can be increased upon the addition of metal ions. Dynamic light scattering analyses, turbidity measurements, TEM, and SEM results demonstrated the metal ion-dependent self-assembly of X9 and PHG into supramolecular structures ranging from various nanofibrils to microscale spherical, laminated, and granulated assemblies. The topology and size of these higher-order structures depends both on the metal ion identity and the location of the binding sites. Most intriguingly, the assembled fibrils show similar D-periodicity to that of natural collagen. Our results demonstrate that metal-histidine coordination can serve as an effective force to induce the self-assembly of unstable collagen-related peptides into higher-order structures. PMID- 22243032 TI - Thin layer chromatography/plasma assisted multiwavelength laser desorption ionization mass spectrometry for facile separation and selective identification of low molecular weight compounds. AB - A novel plasma assisted multiwavelength (1064, 532, and 355 nm) laser desorption ionization mass spectrometry (PAMLDI-MS) system was fabricated and applied in the analysis of low molecular weight compounds through combination with thin layer chromatography (TLC). The TLC/PAMLDI-MS system successfully integrated TLC, the multiwavelength laser ablation, and the excitated state plasma from direct analysis in real time (DART) and was proved to be effective in the facile separation and selective identification of low molecular weight compounds. An automated three-dimensional platform was utilized to facilitate the analysis procedures with all the parameters of the TLC/PAMLDI-MS systematically optimized, and the desorption/ionization mechanisms were discussed. The successful combination of three-wavelength laser with DART based system extended the range of the analytes and provided broad possibilities for the compound desorption from the TLC. The experimental results clearly showed that the laser desorption was wavelength dependent. The PAMLDI-MS system was successfully applied in the detection of low molecular weight compounds from different kinds of samples separated on a normal-phase silica gel, such as dye mixtures, drug standards, and tea extract, with the detection level of 5 ng/mm(2). PMID- 22243033 TI - Ultrahigh frequency voltammetry: effect of electrode material and frequency of alternating potential modulation on mass transport at hot-disk microelectrodes. AB - Ultrahigh frequency voltammetry involves low scan rate voltammetric measurements with microelectrodes polarized by high-frequency large-amplitude alternating potential. The method provides a simple means for studying electrothermal and dielectrophoretic effects, which are important in micro and nanofluidic systems. The method also allows for indirect measurements of electrode impedance at gigahertz frequencies. This increases the upper frequency limit in impedance measurements about 1000 times. In this work we demonstrated, for the first time, that the effect of dielectric relaxation of water can be observed in a simple voltammetric experiment. The paper focuses on the description of electrothermal convection at ac heated disk microelectrodes as a function of frequency and provides a comparison of numerical simulations with experimental results. PMID- 22243034 TI - Randomised clinical trial: an assessment of acupuncture on specific meridian or specific acupoint vs. sham acupuncture for treating functional dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD) is a common disease without an established optimal treatment. AIM: To determine (i) the effect of acupuncture in relieving FD symptoms and improving life quality; (ii) the effect difference between acupoint and non-acupoint; and (iii) the effect difference among different acupoints. METHODS: A total of 712 eligible patients were included and randomly assigned to six groups (Group A: specific acupoints of the stomach meridian; Group B: non-specific acupoints of the stomach meridian; Group C: specific acupoints of alarm and transport points; Group D: specific acupoints of the gallbladder meridian; Group E: sham acupuncture of non-acupoints; and Group F: itopride). A treatment period of 4 weeks (continuous five sessions per week), and a follow-up period of 12 weeks were arranged. The outcomes were the (i) patients' response, (ii) symptoms improvement measured using the Symptom Index of Dyspepsia and (iii) quality-of-life improvement based on Nepean Dyspepsia Index. RESULTS: All groups had an improvement in dyspepsia symptoms and the QoL at the end of treatment, and the improvement was sustained for 4 weeks and 12 weeks. The overall response rate was significantly higher in acupuncture group A (70.69%), and lower in sham acupuncture group (34.75%), compared with itopride and other acupuncture groups. Similarly, the difference in symptoms and QoL improvement was significant between group A and the other acupuncture groups. CONCLUSIONS: Acupuncture is effective in the treatment of functional dyspepsia, and is superior to non-acupoint puncture. The benefit of acupuncture relies on acupoint specificity. PMID- 22243035 TI - Effect of different operational conditions on biofilm development, nitrification, and nitrifying microbial population in moving-bed biofilm reactors. AB - In this study, the effect of different operational conditions on biofilm development and nitrification in three moving-bed biofilm reactors (MBBRs) was investigated: two reactors were operated in a continuously fed regime and one in sequencing-batch mode. The presence of organic carbon reduced the time required to form stable nitrifying biofilms. Subsequent stepwise reduction of influent COD caused a decrease in total polysaccharide and protein content, which was accompanied by a fragmentation of the biofilm, as shown by scanning electron microscopy, and by an enrichment of the biofilm for nitrifiers, as observed by fluorescent in situ hybridization (FISH) analysis. Polysaccharide and protein concentrations proved to be good indicators of biomass development and detachment in MBBR systems. Ammonium- and nitrite-oxidizing bacteria activities were affected when a pulse feeding of 4 g of NH(4)-N/(m(2).day) was applied. Free nitrous acid and free ammonia were likely the inhibitors for ammonium- and nitrite-oxidizing bacteria. PMID- 22243036 TI - Relationships between intrinsic motivation, physical self-concept and satisfaction with life: a longitudinal study. AB - In this study, we examined the relationships between intrinsic motivation, physical self-concept, and satisfaction with life using cross-lagged panel models analysed via structural equation models. The sample consisted of 293 participants (148 men, 145 women) aged 18-70 years who performed diverse types of physical exercise. Three alternative models were tested. The data were better represented by a model in which physical self-concept mediates the relationships between intrinsic motivation and satisfaction with life. Specifically, the direct effects of intrinsic motivation on physical self-concept, and of physical self-concept on satisfaction with life were significant, with the amount of explained variance increasing over time. In conclusion, people who perform physical exercise regularly, and who have fun over time will tend to have a better physical self perception and, consequently, more psychological well-being. PMID- 22243039 TI - Diagnostic criteria for schizoaffective disorder. PMID- 22243038 TI - Synthesis and structure of distanna and tristanna ansa half-sandwich complexes of ruthenium and nickel. AB - The synthesis and structural characterization of the first tin-bridged ansa half sandwich complexes via a two-step protocol from Na[eta(5)-C(5)H(5)Ru(CO)(2)] and in situ generated Na[eta(5)-C(5)H(5)Ni(CO)] are presented. Both compounds are characterized by multinuclear NMR spectroscopy and single-crystal diffraction. PMID- 22243040 TI - Are we missing opportunities for early intervention in bipolar disorder? PMID- 22243042 TI - The use of lisdexamfetamine dimesylate for the treatment of ADHD. AB - ADHD is a common neurobehavioral disorder characterized by significant impairment in attention, hyperactivity and impulsivity. Symptoms begin in childhood and can persist into adulthood. Current data suggest that abnormal functioning of the prefrontal cortex, cortical and subcortical regions of the brain have roles in ADHD. All currently approved drugs used to treat ADHD enhance dopamine and norepinephrine signals in these regions. Lisdexamfetamine dimesylate (LDX) is a long-acting amphetamine prodrug indicated for the treatment of ADHD and has been shown to be effective in children, adolescents and adults. The prodrug properties of LDX make it a desirable treatment because of its long duration of effect, and low intrasubject and intersubject pharmacokinetic variability, and attenuated response on measures of abuse liability when compared with immediate-release amphetamine. However, LDX is still classified as a controlled substance. In this article, the pharmacokinetic parameters and efficacy and safety of LDX are reviewed. PMID- 22243043 TI - Statins to treat Alzheimer's disease: an incomplete story. AB - The link between cholesterol and Alzheimer's disease (AD) has been explored for almost two decades. The link stems from the observation that atherosclerotic heart disease increases the risk for AD and that people expiring from coronary artery disease had AD changes in their brains. Cholesterol is a cofactor of amyloid deposition, with substantial evidence showing that high cholesterol diets in animal models can accelerate amyloidogenesis. This link led investigators to posit the use of cholesterol-lowering agents as treatments for AD and cognitive decline. Indeed, the epidemiological data suggest that cholesterol-lowering agents may reduce the risk of developing AD. Early pilot studies suggested that statins may be useful as treatments for AD because of a reduction in the rates of decline. Recent reports of simvastatin and atorvastatin assessed in large randomized, double-blind, placebo-controlled multicenter trials have not confirmed a clinically demonstrable cognitive benefit for statins in the treatment of AD. This article will discuss the results of one of these trials and explore the reasons behind why the multicenter trials may not have been positive and the growing disparity between preclinical/epidemiological benefit and a lack of clinical efficacy. PMID- 22243044 TI - Impact of transdermal drug delivery on treatment adherence in patients with Alzheimer's disease. AB - OBJECTIVE: As a part of a study investigating which strategies are effective to improve pharmacological compliance among nonadherent Alzheimer's disease patients, we assessed the impact of the galenic form (oral medications or patches) on treatment adherence in patients with dementia of Alzheimer's type (DAT). DESIGN AND METHODS: We performed a 6-month prospective, multicenter, observational study with three study visits (baseline, 3 months and 6 months). Patients with mild-to-moderately severe DAT receiving medication for >=3 months who were nonadherent to treatment were recruited. OUTCOME MEASURES: The main variable was adherence rate recorded at each visit. Patients were adherent if they missed <20% of the doses of their medication and they took it at the dose, manner and timing prescribed by the physician >80% of times. Secondary variables included strategies followed by physicians to improve adherence and reasons for nonadherence reported by patients. RESULTS: A total of 649 patients (35.2% men) were included. The percentage of adherent patients reached 73.6% at 3 months and rose to 85.9% at 6 months. The most common reasons for nonadherence were forgetfulness, avoidance of adverse events and refusal of treatment. Modification of treatment was the most frequent strategy followed by physicians for improving treatment adherence at baseline, and the only intervention that substantially improved adherence at the 3-month visit (the percentage of patients treated with patches increased from 6.1% at baseline to 64.8% at 3-month visit). Patients using patches were more likely to comply than patients using capsules/tablets, as demonstrated by logistic regression analysis. CONCLUSIONS: The results suggested that the transdermal patch may improve adherence, which may lead to an increase of treatment benefits in patients with DAT. PMID- 22243045 TI - Neurocognition and neuroimaging of persistent negative symptoms of schizophrenia. AB - Negative symptoms have been a conundrum to researchers and clinicians alike since having first been identified by Bleuler and Kraepelin. The term 'negative symptoms' has been scrutinized with regards to what it encompasses. Negative symptomatology has been categorized into distinct subdomains, including primary symptoms, secondary symptoms, deficit syndrome and, more recently, persistent negative symptoms (PNS). Although there have been some theories put forward with regards to negative symptoms, there are still discordant findings regarding PNS. Thus, this article aimed to review the structural, functional and cognitive correlates of PNS in an attempt to better understand these specific negative symptoms in schizophrenia. According to the reviewed literature, deficit syndrome appears to have similar neurocognitive and structural deficits as PNS; however, some minor distinctions may suggest that PNS are a separate subtype of negative symptoms. White matter decrements in the frontal lobe and gray matter reductions in the temporal lobe may be related more specifically to PNS. Furthermore, unlike deficit syndrome, structural abnormalities in the frontal and temporal lobe also appear to be related to PNS in patients with first-episode schizophrenia. Cognitive domains, such as memory, are impaired and appear to be predominantly related to PNS. Hence, PNS do appear to have neuroimaging and neurocognitive correlates and warrant further research. PMID- 22243046 TI - A 'family affair'? The impact of family psychoeducational interventions on depression. AB - Major depressive disorder is reported to be the most common mental disorder, and one of the leading causes of disability-adjusted life years. It causes high levels of family burden and of expressed emotions. Research interest in family functioning in mental disorders has recently shifted from schizophrenia to unipolar and bipolar affective disorders. However, studies on family burden and on the effect of family psychoeducational interventions on major depression are still very few in number and lack a rigorous methodology, clear outcome measures and adequate follow-ups. Despite this, the few available studies on the efficacy of psychoeducational family intervention in unipolar major depression have had promising results. A comprehensive management of unipolar major depression should include psychoeducational family intervention. PMID- 22243047 TI - Gene-expression studies in understanding the mechanism of action of lithium. AB - Lithium salts are among the drugs of choice for the treatment of bipolar disorder. Despite six decades of intensive research and an accumulating number of known cellular targets, lithium's mechanism of action still needs to be unraveled. The evolution of large-scale gene-expression analysis methodologies has provided a promising tool to understand the cellular events underlying the mood-stabilizing effect of the drug. However, despite great improvement achieved in transcriptome studies, findings of genes differentially expressed by lithium treatment exhibit, so far, a low reproducibility rate. This review discusses the different design and data analysis strategies applied in the studies and summarizes the possible reasons for the discrepancies among the reports. PMID- 22243049 TI - Analyzing the molecular basis of enzyme stability in ethanol/water mixtures using molecular dynamics simulations. AB - One of the drawbacks of nonaqueous enzymology is the fact that enzymes tend to be less stable in organic solvents than in water. There are, however, some enzymes that display very high stabilities in nonaqueous media. In order to take full advantage of the use of nonaqueous solvents in enzyme catalysis, it is essential to elucidate the molecular basis of enzyme stability in these media. Toward this end, we performed MUs-long molecular dynamics simulations using two homologous proteases, pseudolysin, and thermolysin, which are known to have considerably different stabilities in solutions containing ethanol. The analysis of the simulations indicates that pseudolysin is more stable than thermolysin in ethanol/water mixtures and that the disulfide bridge between C30 and C58 is important for the stability of the former enzyme, which is consistent with previous experimental observations. Our results indicate that thermolysin has a higher tendency to interact with ethanol molecules (especially through van der Waals contacts) than pseudolysin, which can lead to the disruption of intraprotein hydrophobic interactions and ultimately result in protein unfolding. In the absence of the C30-C58 disulfide bridge, pseudolysin undergoes larger conformational changes, becoming more open and more permeable to ethanol molecules which accumulate in its interior and form hydrophobic interactions with the enzyme, destroying its structure. Our observations are not only in good agreement with several previous experimental findings on the stability of the enzymes studied in ethanol/water mixtures but also give an insight on the molecular determinants of this stability. Our findings may, therefore, be useful in the rational development of enzymes with increased stability in these media. PMID- 22243050 TI - Kinetics of the terminal electron transfer step in cytochrome c oxidase. AB - Cytochrome c oxidase (cco) catalyzes the oxygen reduction reaction in most aerobically respiring organisms. Decades of research have uncovered many aspects relating to structure and function of this enzyme. However, the origin of the unusually fast terminal electron transfer step from heme a to heme a(3) in cco has been the subject of intense discussions over recent years. Yet, no satisfactory consensus has been achieved. Carrying out large-scale molecular dynamics simulation of the protein embedded in a solvated membrane, we obtain a reorganization free energy lambda = 0.57 eV. Evaluation of the quantized single mode rate equation using the experimental rate and the computed reorganization free energy gives a value of 1.5 meV for the average electronic coupling (H(ab)) between heme a and heme a(3). Thus, according to our calculations, the nanosecond electron transfer (ET) is due to a small but significant activation barrier (DeltaG(?) = 0.12 eV) in combination with effective electronic coupling between the two cofactors. The activation free energy is caused predominantly by collective reorganization of protein residues. We show that our results are consistent with the weak temperature dependence observed in experiment if one allows for very minor variations in the donor-acceptor distance as the temperature changes. PMID- 22243051 TI - Early cerebral manifestations in a young female with Fabry disease with skewed X inactivation. PMID- 22243052 TI - Transformation of sulfamethazine by manganese oxide in aqueous solution. AB - The transformation of the sulfonamide antimicrobial sulfamethazine (SMZ) by a synthetic analogue of the birnessite-family mineral vernadite (delta-MnO(2)) was studied. The observed pseudo-first-order reaction constants (k(obs)) decreased as the pH increased from 4.0 to 5.6, consistent with the decline in delta-MnO(2) reduction potential with increasing pH. Molecular oxygen accelerated SMZ transformation by delta-MnO(2) and influenced the transformation product distribution. Increases in the Na(+) concentration produced declines in k(obs). Transformation products identified by tandem mass spectrometry and the use of (13)C-labeled SMZ included an azo dimer self-coupling product and SO(2) extrusion products. Product analysis and density functional theory calculations are consistent with surface precursor complex formation followed by single-electron transfer from SMZ to delta-MnO(2) to produce SMZ radical species. Sulfamethazine radicals undergo further transformation by at least two pathways: radical-radical self-coupling or a Smiles-type rearrangement with O addition and then extrusion of SO(3). Experiments conducted in H(2)(18)O or in the presence of (18)O(2)(aq) demonstrated that oxygen both from the lattice of as-synthesized delta-MnO(2) and initially present as dissolved oxygen reacted with SMZ. The study results suggest that the oxic state and pH of soil and sediment environments can be expected to influence manganese oxide-mediated transformation of sulfonamide antimicrobials. PMID- 22243053 TI - Increased interleukin-1beta levels are associated with left ventricular hypertrophy and remodelling following acute ST segment elevation myocardial infarction treated by primary percutaneous coronary intervention. AB - OBJECTIVES: To assess the relationship between interleukin (IL)-1-related molecules, infarct size and left ventricular (LV) remodelling following acute myocardial infarction (MI). METHODS: Forty-two patients with first-time diagnosis of ST segment elevation MI (STEMI), with a single occluded vessel successfully revascularized by primary percutaneous coronary intervention (PCI), were recruited to this observational study conducted at a university teaching hospital and followed for 1 year. MAIN OUTCOME MEASURES: Plasma levels of IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-18 and caspase-1 were analysed before and 2 days, 1 week and 2 months after PCI. Serial cardiac magnetic resonance imaging (CMR) was used for the assessment of infarct size and LV remodelling. CMR findings at 1 year was the primary outcome variable. RESULTS: Univariate analysis showed that IL-1-related mediators were strongly (IL-1 beta), moderately (caspase 1) and weakly (IL-1Ra) associated with impaired myocardial function and noninfarct mass, but not infarct size, 1 year after reperfused STEMI. In multivariate analyses, troponin T predicted LV ejection fraction (LVEF), infarct size and LV end-diastolic (LVEDVi) and end-systolic volume index (LVESVi). However, significant additional variance was explained by IL-1beta, IL-18 and caspase-1. IL-1beta levels at 2 months, IL-18 at 2 days and pre-PCI caspase-1 were predictors of LVEF. Caspase-1 and in particular IL-1beta at 2 days were the only predictors of noninfarct mass. IL-1beta and IL-18 at 2 days were predictors of LVEDVi, whilst pre-PCI levels of IL-1beta contributed to prediction of LVESVi. By contrast, pro-B-type natriuretic peptide, C-reactive protein, IL-6 and transforming growth factor-beta1 (TGF-beta1) had no or only a weak (TGF-beta1) association with these CMR parameters in multivariate analyses. CONCLUSIONS: IL 1beta levels after STEMI were strongly associated with impaired myocardial function and noninfarct LV mass after 1 year, suggesting a potential role for IL 1beta as a predictor of maladaptive myocardial remodelling following reperfused MI. PMID- 22243054 TI - Protective effects of green and white tea against benzo(a)pyrene induced oxidative stress and DNA damage in murine model. AB - In the current investigation, the ameliorative effect of green tea (GT) and white tea (WT) against benzo(a)pyrene (BaP) induced oxidative stress and DNA damage has been studied in the livers and lungs of Balb/c mice. A single dose of BaP (125 mg/kg, b.w. orally) increased the levels of lipid peroxidation (LPO) and decreased endogenous antioxidants such as superoxide dismutase (SOD), glutahione reductase (GR), catalase (CAT), and glutathione (GSH) significantly. Pretreatment with GT and WT for 35 days before a single dose of BaP elevated the decreased activity of GR, SOD, and CAT in liver tissue and also tended to normalize the levels of GSH and LPO in both hepatic and pulmonary tissues. The percentage of DNA in comet tail and 8-hydroxy-2'-deoxyguanosine levels reflected the decreasing pattern of DNA damage from the BaP-treated group to the groups that received pretreatment with GT and WT. Our study concludes that both GT and WT are effective in combating BaP induced oxidative insult and DNA damage. However, WT was found to be more protective than GT with respect to CAT (only in the liver), percentage of DNA in comet tail (only in the lungs), GST activity, and GSH content in both the tissues. PMID- 22243055 TI - Coarse graining makes it hard to see micro-macro entanglement. AB - Observing quantum effects such as superpositions and entanglement in macroscopic systems requires not only a system that is well protected against environmental decoherence, but also sufficient measurement precision. Motivated by recent experiments, we study the effects of coarse graining in photon number measurements on the observability of micro-macro entanglement that is created by greatly amplifying one photon from an entangled pair. We compare the results obtained for a unitary quantum cloner, which generates micro-macro entanglement, and for a measure-and-prepare cloner, which produces a separable micro-macro state. We show that the distance between the probability distributions of results for the two cloners approaches zero for a fixed moderate amount of coarse graining. Proving the presence of micro-macro entanglement therefore becomes progressively harder as the system size increases. PMID- 22243056 TI - Demonstration of a controlled-phase gate for continuous-variable one-way quantum computation. AB - We experimentally demonstrate a controlled-phase gate for continuous variables using a cluster-state resource of four optical modes. The two independent input states of the gate are coupled with the cluster in a teleportation-based fashion. As a result, one of the entanglement links present in the initial cluster state appears in the two unmeasured output modes as the corresponding entangling gate acting on the input states. The genuine quantum character of this gate becomes manifest and is verified through the presence of entanglement at the output for a product two-mode coherent input state. By combining our gate with the recently reported module for single-mode Gaussian operations [R. Ukai et al., Phys. Rev. Lett. 106, 240504 (2011)], it is possible to implement any multimode Gaussian operation as a fully measurement-based one-way quantum computation. PMID- 22243057 TI - Nonperturbative gadget for topological quantum codes. AB - Many-body entangled systems, in particular topologically ordered spin systems proposed as resources for quantum information processing tasks, often involve highly nonlocal interaction terms. While one may approximate such systems through two-body interactions perturbatively, these approaches have a number of drawbacks in practice. In this Letter, we propose a scheme to simulate many-body spin Hamiltonians with two-body Hamiltonians nonperturbatively. Unlike previous approaches, our Hamiltonians are not only exactly solvable with exact ground state degeneracy, but also support completely localized quasiparticle excitations, which are ideal for quantum information processing tasks. Our construction is limited to simulating the toric code and quantum double models, but generalizations to other nonlocal spin Hamiltonians may be possible. PMID- 22243058 TI - Compressed quantum simulation of the Ising model. AB - Jozsa et al. [Proc. R. Soc. A 466, 809 2009)] have shown that a match gate circuit running on n qubits can be compressed to a universal quantum computation on log(n)+3 qubits. Here, we show how this compression can be employed to simulate the Ising interaction of a 1D chain consisting of n qubits using a universal quantum computer running on log(n) qubits. We demonstrate how the adiabatic evolution can be realized on this exponentially smaller system and how the magnetization, which displays a quantum phase transition, can be measured. This shows that the quantum phase transition of very large systems can be observed experimentally with current technology. PMID- 22243059 TI - Entanglement can completely defeat quantum noise. AB - We describe two quantum channels that individually cannot send any classical information without some chance of decoding error. But together a single use of each channel can send quantum information perfectly reliably. This proves that the zero-error classical capacity exhibits superactivation, the extreme form of the superadditivity phenomenon in which entangled inputs allow communication over zero-capacity channels. But our result is stronger still, as it even allows zero error quantum communication when the two channels are combined. Thus our result shows a new remarkable way in which entanglement across two systems can be used to resist noise, in this case perfectly. We also show a new form of superactivation by entanglement shared between sender and receiver. PMID- 22243060 TI - Additivity principle in high-dimensional deterministic systems. AB - The additivity principle (AP), conjectured by Bodineau and Derrida [Phys. Rev. Lett. 92, 180601 (2004)], is discussed for the case of heat conduction in three dimensional disordered harmonic lattices to consider the effects of deterministic dynamics, higher dimensionality, and different transport regimes, i.e., ballistic, diffusive, and anomalous transport. The cumulant generating function (CGF) for heat transfer is accurately calculated and compared with the one given by the AP. In the diffusive regime, we find a clear agreement with the conjecture even if the system is high dimensional. Surprisingly, even in the anomalous regime the CGF is also well fitted by the AP. Lower-dimensional systems are also studied and the importance of three dimensionality for the validity is stressed. PMID- 22243061 TI - Spin transport in the XXZ chain at finite temperature and momentum. AB - We investigate the role of momentum for the transport of magnetization in the spin-1/2 Heisenberg chain above the isotropic point at finite temperature and momentum. Using numerical and analytical approaches, we analyze the autocorrelations of density and current and observe a finite region of the Brillouin zone with diffusive dynamics below a cutoff momentum, and a diffusion constant independent of momentum and time, which scales inversely with anisotropy. Lowering the temperature over a wide range, starting from infinity, the diffusion constant is found to increase strongly while the cutoff momentum for diffusion decreases. Above the cutoff momentum diffusion breaks down completely. PMID- 22243062 TI - Transverse alignment of fibers in a periodically sheared suspension: an absorbing phase transition with a slowly varying control parameter. AB - Shearing solutions of fibers or polymers tends to align fiber or polymers in the flow direction. Here, non-Brownian rods subjected to oscillatory shear align perpendicular to the flow while the system undergoes a nonequilibrium absorbing phase transition. The slow alignment of the fibers can drive the system through the critical point and thus promote the transition to an absorbing state. This picture is confirmed by a universal scaling relation that collapses the data with critical exponents that are consistent with conserved directed percolation. PMID- 22243063 TI - Observational constraints on multimessenger sources of gravitational waves and high-energy neutrinos. AB - Many astronomical sources of intense bursts of photons are also predicted to be strong emitters of gravitational waves (GWs) and high-energy neutrinos (HENs). Moreover some suspected classes, e.g., choked gamma-ray bursts, may only be identifiable via nonphoton messengers. Here we explore the reach of current and planned experiments to address this question. We derive constraints on the rate of GW and HEN bursts based on independent observations by the initial LIGO and Virgo GW detectors and the partially completed IceCube (40-string) HEN detector. We then estimate the reach of joint GW+HEN searches using advanced GW detectors and the completed km(3) IceCube detector to probe the joint parameter space. We show that searches undertaken by advanced detectors will be capable of detecting, constraining, or excluding, several existing models with 1 yr of observation. PMID- 22243064 TI - Constraints on shift-symmetric scalar-tensor theories with a Vainshtein mechanism from bounds on the time variation of G. AB - We show that the current bounds on the time variation of the Newton constant G can put severe constraints on many interesting scalar-tensor theories which possess a shift symmetry and a nonminimal matter-scalar coupling. This includes, in particular, Galileon-like models with a Vainshtein screening mechanism. We underline that this mechanism, if efficient to hide the effects of the scalar field at short distance and in the static approximation, can in general not alter the cosmological time evolution of the scalar field. This results in a locally measured time variation of G which is too large when the matter-scalar coupling is of order one. PMID- 22243065 TI - Probing loop quantum gravity with evaporating black holes. AB - This Letter aims at showing that the observation of evaporating black holes should allow the usual Hawking behavior to be distinguished from loop quantum gravity (LQG) expectations. We present a full Monte Carlo simulation of the evaporation in LQG and statistical tests that discriminate between competing models. We conclude that contrarily to what was commonly thought, the discreteness of the area in LQG leads to characteristic features that qualify evaporating black holes as objects that could reveal quantum gravity footprints. PMID- 22243066 TI - Superluminal neutrinos at OPERA confront pion decay kinematics. AB - Violation of Lorentz invariance (VLI) has been suggested as an explanation of the superluminal velocities of muon neutrinos reported by OPERA. In this Letter, we show that the amount of VLI required to explain this result poses severe difficulties with the kinematics of the pion decay, extending its lifetime and reducing the momentum carried away by the neutrinos. We show that the OPERA experiment limits alpha=(nu(nu)-c)/c<4*10(-6). We then take recourse to cosmic ray data on the spectrum of muons and neutrinos generated in Earth's atmosphere to provide a stronger bound on VLI: (nu-c)/c<10(-12). PMID- 22243068 TI - Precise measurement of deuteron tensor analyzing powers with BLAST. AB - We report a precision measurement of the deuteron tensor analyzing powers T(20) and T(21) at the MIT-Bates Linear Accelerator Center. Data were collected simultaneously over a momentum transfer range Q=2.15-4.50 fm(-1) with the Bates Large Acceptance Spectrometer Toroid using a highly polarized deuterium internal gas target. The data are in excellent agreement with calculations in a framework of effective field theory. The deuteron charge monopole and quadrupole form factors G(C) and G(Q) were separated with improved precision, and the location of the first node of G(C) was confirmed at Q=4.19+/-0.05 fm(-1). The new data provide a strong constraint on theoretical models in a momentum transfer range covering the minimum of T(20) and the first node of G(C). PMID- 22243069 TI - 149Sm(n,alpha)146Nd cross sections in the MeV region. AB - We have measured the (149)Sm(n,alpha)(146)Nd cross section at 4.5, 5.0, 5.5, 6.0, and 6.5 MeV. Measurements were performed at the 4.5 MV Van de Graaff accelerator of Peking University with monoenergetic neutrons produced via the (2)H(d,n)(3)He reaction using a deuterium gas target. Alpha particles were detected with a double-section gridded ionization chamber having two back-to-back (149)Sm(2)O(3) samples attached to the common cathode. Absolute neutron flux was measured using a small (238)U fission chamber and monitored by a BF(3) long counter. These are the first reported cross sections for this reaction at these energies, except at 6.0 eV, where our new data are in good agreement with our earlier result. The present results help to much better constrain the (149)Sm(n,alpha)(146)Nd cross section in a region where its energy dependence is changing fairly rapidly and there are large differences between evaluated nuclear data libraries. PMID- 22243070 TI - Tunable multiple layered Dirac cones in optical lattices. AB - We show that multiple layered Dirac cones can emerge in the band structure of properly addressed multicomponent cold fermionic gases in optical lattices. The layered Dirac cones contain multiple copies of massless spin-1/2 Dirac fermions at the same location in momentum space, whose different Fermi velocity can be tuned at will. On-site microwave Raman transitions can further be used to mix the different Dirac species, resulting in either splitting of or preserving the Dirac point (depending on the symmetry of the on-site term). The tunability of the multiple layered Dirac cones allows us to simulate a number of fundamental phenomena in modern physics, such as neutrino oscillations and exotic particle dispersions with E~p(N) for arbitrary integer N. PMID- 22243071 TI - Circular dichroism in laser-assisted short-pulse photoionization. AB - A remarkable effect of circular dichroism, i.e., a difference in photoelectron spectra produced by right and left circularly polarized light in two-color multiphoton ionization of atoms, is predicted for the case when the atom is ionized by an extreme ultraviolet or x-ray femtosecond pulse in the field of a strong infrared laser pulse, both pulses being circularly polarized. We show that the sidebands formed in the spectra exhibit different circular dichroism often of different signs both in angle-resolved and angle-integrated experimental conditions. The effect can be used for detecting and measuring circular polarization of x rays in a spectral range where other methods are not effective. PMID- 22243072 TI - Indistinguishable photon pairs from independent true chaotic sources. AB - Indistinguishability of events in quantum mechanics is manifested by interference between their probability amplitudes. We report a unique kind of interference occurring between indistinguishable events of photon-pair emission, where each photon of the pair is emitted from a distinct true chaotic light source and has a different energy. The indistinguishability results in an interference which is observed as an ultrafast modulation of the second-order coherence function, measured on a femtosecond time scale by two-photon absorption in a semiconductor photomultiplier tube. PMID- 22243073 TI - Experimental realization of optimal noise estimation for a general Pauli channel. AB - We present the experimental realization of the optimal estimation protocol for a Pauli noisy channel. The method is based on the generation of 2-qubit Bell states and the introduction of quantum noise in a controlled way on one of the state subsystems. The efficiency of the optimal estimation, achieved by a Bell measurement, is shown to outperform quantum process tomography. PMID- 22243074 TI - Higher-order modulation instability in nonlinear fiber optics. AB - We report theoretical, numerical, and experimental studies of higher-order modulation instability in the focusing nonlinear Schrodinger equation. This higher-order instability arises from the nonlinear superposition of elementary instabilities, associated with initial single breather evolution followed by a regime of complex, yet deterministic, pulse splitting. We analytically describe the process using the Darboux transformation and compare with experiments in optical fiber. We show how a suitably low frequency modulation on a continuous wave field induces higher-order modulation instability splitting with the pulse characteristics at different phases of evolution related by a simple scaling relationship. We anticipate that similar processes are likely to be observed in many other systems including plasmas, Bose-Einstein condensates, and deep water waves. PMID- 22243076 TI - Vacuum in a strong magnetic field as a hyperbolic metamaterial. AB - As demonstrated by Chernodub, vacuum in a strong magnetic field behaves as Abrikosov vortex lattice in a type-II superconductor. We investigate electromagnetic behavior of vacuum in this state and demonstrate that vacuum behaves as a hyperbolic metamaterial. If the magnetic field is constant, low frequency extraordinary photons experience this medium as a (3+1) Minkowski spacetime in which the role of time is played by the spatial z coordinate. Variations of the magnetic field curve this spacetime, and may lead to formation of "electromagnetic black holes." Since hyperbolic metamaterials behave as diffractionless "perfect lenses," and large enough magnetic fields probably existed in the early Universe, the demonstrated hyperbolic behavior of early vacuum may have imprints in the large scale structure of the present-day Universe. PMID- 22243075 TI - Background-free nonlinear microspectroscopy with vibrational molecular interferometry. AB - We demonstrate a method for performing nonlinear microspectroscopy that provides an intuitive and unified description of the various signal contributions, and allows the direct extraction of the vibrational response. Three optical fields create a pair of Stokes Raman pathways that interfere in the same vibrational state. Frequency modulating one of the fields leads to amplitude modulations on all of the fields. This vibrational molecular interferometry technique allows imaging at high speed free of nonresonant background, and is able to distinguish between electronic and vibrational contributions to the total signal. PMID- 22243077 TI - Selection of spiral waves in excitable media with a phase wave at the wave back. AB - Universal relationships between the medium excitability and the angular velocity and the core radius of rigidly rotating spiral waves in excitable media are derived for situations where the wave front is a trigger wave and the wave back is a phase wave. Two universal limits restricting the region of existence of spiral waves in the parameter space are demonstrated. The predictions of the free boundary approach are in good quantitative agreement with results from numerical reaction-diffusion simulations performed on the Kessler-Levine model. PMID- 22243078 TI - Dissipative localized States with shieldlike phase structure. AB - A novel type of parametrically excited dissipative solitons is unveiled. It differs from the well-known solitons with constant phase by an intrinsically dynamical evolving shell-type phase front. Analytical and numerical characterizations are proposed, displaying quite a good agreement. In one spatial dimension, the system shows three types of stationary solitons with shell-like structure whereas in two spatial dimensions it displays only one, characterized by a pi-phase jump far from the soliton position. PMID- 22243067 TI - Measurements of higher order flow harmonics in Au+Au collisions at ?s(NN)=200 GeV. AB - Flow coefficients nu(n) for n=2, 3, 4, characterizing the anisotropic collective flow in Au+Au collisions at ?s(NN)=200 GeV, are measured relative to event planes Psi(n), determined at large rapidity. We report nu(n) as a function of transverse momentum and collision centrality, and study the correlations among the event planes of different order n. The nu(n) are well described by hydrodynamic models which employ a Glauber Monte Carlo initial state geometry with fluctuations, providing additional constraining power on the interplay between initial conditions and the effects of viscosity as the system evolves. This new constraint can serve to improve the precision of the extracted shear viscosity to entropy density ratio eta/s. PMID- 22243079 TI - Subwavelength position sensing using nonlinear feedback and wave chaos. AB - We demonstrate a position-sensing technique that relies on the inherent sensitivity of chaos, where we illuminate a subwavelength object with a complex structured radio-frequency field generated using wave chaos and nonlinear feedback. We operate the system in a quasiperiodic state and analyze changes in the frequency content of the scalar voltage signal in the feedback loop. This allows us to extract the object's position with a one-dimensional resolution of ~lambda/10,000 and a two-dimensional resolution of ~lambda/300, where lambda is the shortest wavelength of the illuminating source. PMID- 22243080 TI - Exploring classically chaotic potentials with a matter wave quantum probe. AB - We study an experimental setup in which a quantum probe, provided by a quasimonomode guided atom laser, interacts with a static localized attractive potential whose characteristic parameters are tunable. In this system, classical mechanics predicts a transition from regular to chaotic behavior as a result of the coupling between the different degrees of freedom. Our experimental results display a clear signature of this transition. On the basis of extensive numerical simulations, we discuss the quantum versus classical physics predictions in this context. This system opens new possibilities for investigating quantum scattering, provides a new testing ground for classical and quantum chaos, and enables us to revisit the quantum-classical correspondence. PMID- 22243081 TI - Hydrodynamics of superfluid helium in a single nanohole. AB - The flow of liquid helium through a single nanohole with radius smaller than 25 nm was studied. Mass flow was induced by applying a pressure difference of up to 1.4 bar across a 50 nm thick Si(3)N(4) membrane and was measured directly by means of mass spectrometry. In liquid He I, we experimentally show that the fluid is not clamped by the short pipe with diameter-to-length ratio D/L?1, despite the small diameter of the nanohole. This viscous flow is quantitatively understood by making use of a model of flow in short pipes. In liquid He II, a two-fluid model for mass flow is used to extract the superfluid velocity in the nanohole for different pressure heads at temperatures close to the superfluid transition. These velocities compare well to existing data for the critical superflow of liquid helium in other confined systems. PMID- 22243082 TI - Bifurcation to 3D helical magnetic equilibrium in an axisymmetric toroidal device. AB - We report the first direct measurement of the internal magnetic field structure associated with a 3D helical equilibrium generated spontaneously in the core of an axisymmetric toroidal plasma containment device. Magnetohydrodynamic equilibrium bifurcation occurs in a reversed-field pinch when the innermost resonant magnetic perturbation grows to a large amplitude, reaching up to 8% of the mean field strength. Magnetic topology evolution is determined by measuring the Faraday effect, revealing that, as the perturbation grows, toroidal symmetry is broken and a helical equilibrium is established. PMID- 22243083 TI - Model for incomplete reconnection in sawtooth crashes. AB - A model for incomplete reconnection in sawtooth crashes is presented. The reconnection inflow during the crash phase of sawteeth self-consistently convects the high pressure core toward the reconnection site, raising the pressure gradient there. Reconnection shuts off if the diamagnetic drift speed at the reconnection site exceeds a threshold, which may explain incomplete reconnection. The relaxation of magnetic shear after reconnection stops may explain the destabilization of ideal interchange instabilities reported previously. Proof-of principle two-fluid simulations confirm this basic picture. Predictions of the model compare favorably to data from the Mega Ampere Spherical Tokamak. Applications to transport modeling of sawteeth are discussed. The results should apply across tokamaks, including ITER. PMID- 22243084 TI - Controlled betatron x-ray radiation from tunable optically injected electrons. AB - The features of Betatron x-ray emission produced in a laser-plasma accelerator are closely linked to the properties of the relativistic electrons which are at the origin of the radiation. While in interaction regimes explored previously the source was by nature unstable, following the fluctuations of the electron beam, we demonstrate in this Letter the possibility to generate x-ray Betatron radiation with controlled and reproducible features, allowing fine studies of its properties. To do so, Betatron radiation is produced using monoenergetic electrons with tunable energies from a laser-plasma accelerator with colliding pulse injection [J. Faure et al., Nature (London) 444, 737 (2006)]. The presented study provides evidence of the correlations between electrons and x-rays, and the obtained results open significant perspectives toward the production of a stable and controlled femtosecond Betatron x-ray source in the keV range. PMID- 22243085 TI - Large-scale magnetic field generation by randomly forced shearing waves. AB - A rigorous theory for the generation of a large-scale magnetic field by random nonhelically forced motions of a conducting fluid combined with a linear shear is presented in the analytically tractable limit of low magnetic Reynolds number (Rm) and weak shear. The dynamo is kinematic and due to fluctuations in the net (volume-averaged) electromotive force. This is a minimal proof-of-concept quasilinear calculation aiming to put the shear dynamo, a new effect recently found in numerical experiments, on a firm theoretical footing. Numerically observed scalings of the wave number and growth rate of the fastest-growing mode, previously not understood, are derived analytically. The simplicity of the model suggests that shear dynamo action may be a generic property of sheared magnetohydrodynamic turbulence. PMID- 22243086 TI - Observation of Peregrine solitons in a multicomponent plasma with negative ions. AB - The experimental observation of Peregrine solitons in a multicomponent plasma with the critical concentration of negative ions is reported. A slowly amplitude modulated perturbation undergoes self-modulation and gives rise to a high amplitude localized pulse. The measured amplitude of the Peregrine soliton is 3 times the nearby carrier wave amplitude, which agrees with the theory. The numerical solution of the nonlinear Schrodinger equation is compared with the experimental results. PMID- 22243087 TI - Experimental realization of strong effective magnetic fields in an optical lattice. AB - We use Raman-assisted tunneling in an optical superlattice to generate large tunable effective magnetic fields for ultracold atoms. When hopping in the lattice, the accumulated phase shift by an atom is equivalent to the Aharonov Bohm phase of a charged particle exposed to a staggered magnetic field of large magnitude, on the order of 1 flux quantum per plaquette. We study the ground state of this system and observe that the frustration induced by the magnetic field can lead to a degenerate ground state for noninteracting particles. We provide a measurement of the local phase acquired from Raman-induced tunneling, demonstrating time-reversal symmetry breaking of the underlying Hamiltonian. Furthermore, the quantum cyclotron orbit of single atoms in the lattice exposed to the magnetic field is directly revealed. PMID- 22243088 TI - Spin diffusion in trapped clouds of cold atoms with resonant interactions. AB - We show that puzzling recent experimental results on spin diffusion in a strongly interacting atomic gas may be understood in terms of the predicted spin diffusion coefficient for a generic strongly interacting system. Three important features play a central role: (a) Fick's law for diffusion must be modified to allow for the trapping potential; (b) the diffusion coefficient is inhomogeneous, due to the density variations in the cloud; and (c) the diffusion approximation fails in the outer parts of the cloud, where the mean free path is long. PMID- 22243089 TI - Effect of the quantum zero-point atomic motion on the optical and electronic properties of diamond and trans-polyacetylene. AB - The quantum zero-point motion of the carbon atoms is shown to induce strong effects on the optical and electronic properties of diamond and trans polyacetylene, a conjugated polymer. By using an ab initio approach, we interpret the subgap states experimentally observed in diamond in terms of entangled electron-phonon states. These states also appear in trans-polyacetylene causing the formation of strong structures in the band structure that even call into question the accuracy of the band theory. This imposes a critical revision of the results obtained for carbon-based nanostructures by assuming the atoms frozen in their equilibrium positions. PMID- 22243090 TI - Large-scale simulations of a-Si:H: the origin of midgap states revisited. AB - Large-scale classical and quantum simulations are used to generate a-Si:H structures. The bond-resolved density of the occupied electron states discloses the nature of microscopic defects responsible for levels in the gap. Highly strained bonds give rise to band tails and midgap states. The latter originate mainly from stretched bonds, in addition to dangling bonds, and can act as hole traps. This study provides strong evidence for photoinduced degradation (Staebler Wronski effect) driven by strain, thus supporting recent work on a-Si, and sheds light on the role of hydrogen. PMID- 22243091 TI - Novel cooperative interactions and structural ordering in H2S-H2. AB - Hydrogen sulfide (H(2)S) and hydrogen (H(2)) crystallize into a 'guest-host' structure at 3.5 GPa and, at the initial formation pressure, the rotationally disordered component molecules exhibit weak van der Waals-type interactions. With increasing pressure, hydrogen bonding develops and strengthens between neighboring H(2)S molecules, reflected in a pronounced drop in S-H vibrational stretching frequency and also observed in first-principles calculations. At 17 GPa, an ordering process occurs where H(2)S molecules orient themselves to maximize hydrogen bonding and H(2) molecules simultaneously occupy a chemically distinct lattice site. Intermolecular forces in the H(2)S+H(2) system may be tuned with pressure from the weak hydrogen-bonding limit to the ordered hydrogen bonding regime, resulting in a novel clathrate structure stabilized by cooperative interactions. PMID- 22243092 TI - Insensitivity of sub-Kelvin electron-phonon coupling to substrate properties. AB - We have examined the role of the substrate on electron-phonon coupling in normal metal films of Mn-doped Al at temperatures below 1 K. Normal metal-insulator superconductor junctions were used to measure the electron temperature in the films as a function of Joule heating power and phonon temperature. Theory suggests that the distribution of phonons available for interaction with electrons in metal films may depend on the acoustic properties of the substrate, namely, that the electron-phonon coupling constant Sigma would be larger on the substrate with smaller sound speed. In contrast, our results indicate that within experimental error (typically +/-10%), Sigma is unchanged among the two acoustically distinct substrates used in our investigation. PMID- 22243093 TI - Visualization of hydrogen bonding and associated chirality in methanol hexamers. AB - Using a combination of scanning tunneling microscopy (STM) and density functional theory the hydrogen bond directionality and associated chirality of enantiopure clusters is visualized and controlled. This is demonstrated with methanol hexamers adsorbed on Au(111), which depending on their chirality, adopt two distinct molecular footprints on the surface. Controlled STM tip manipulations were used to interconvert the chirality of entire clusters and to break up metastable chain structures into hexamers. PMID- 22243094 TI - Janus-faced influence of Hund's rule coupling in strongly correlated materials. AB - We show that in multiband metals the correlations are strongly affected by Hund's rule coupling, which depending on the filling promotes metallic, insulating or bad-metallic behavior. The quasiparticle coherence and the proximity to a Mott insulator are influenced distinctly and, away from single- and half-filling, in opposite ways. A strongly correlated bad metal far from a Mott phase is found there. We propose a concise classification of 3d and 4d transition-metal oxides within which the ubiquitous occurrence of strong correlations in Ru- and Cr-based oxides, as well as the recently measured high Neel temperatures in Tc-based perovskites are naturally explained. PMID- 22243095 TI - Critical properties of the half-filled Hubbard model in three dimensions. AB - By means of the dynamical vertex approximation (DGammaA) we include spatial correlations on all length scales beyond the dynamical mean-field theory (DMFT) for the half-filled Hubbard model in three dimensions. The most relevant changes due to nonlocal fluctuations are (i) a deviation from the mean-field critical behavior with the same critical exponents as for the three dimensional Heisenberg (anti)ferromagnet and (ii) a sizable reduction of the Neel temperature (T(N)) by ~30% for the onset of antiferromagnetic order. Finally, we give a quantitative estimate of the deviation of the spectra between DGammaA and DMFT in different regions of the phase diagram. PMID- 22243096 TI - Exciton-Mott physics in a quasi-one-dimensional electron-hole system. AB - We investigate the correlation effect in the quasi-one-dimensional electron-hole (e-h) system under thermal equilibrium. A self-consistent screened T-matrix approximation developed here enables the description of an e-h pair under any ionization ratio, the portion of quasielectrons or quasiholes moving almost freely. Our phase diagram on the ionization ratio provides a unified description of exciton Mott physics from the low-density exciton gas towards the high-density electron-hole plasma, and predicts a first order transition at low temperature. The interband optical absorption-gain spectra are also evaluated, which succeeded in explaining semiquantitatively all aspects of the recent experimental observations in the strongly photoexcited quantum wires. PMID- 22243097 TI - Electrolyte gate-controlled Kondo effect in SrTiO3. AB - We report low-temperature, high-field magnetotransport measurements of SrTiO(3) gated by an ionic gel electrolyte. A saturating resistance upturn and negative magnetoresistance that signal the emergence of the Kondo effect appear for higher applied gate voltages. This observation, enabled by the wide tunability of the ionic gel-applied electric field, promotes the interpretation of the electric field-effect-induced 2D electron system in SrTiO(3) as an admixture of magnetic Ti(3+) ions, i.e., localized and unpaired electrons, and delocalized electrons that partially fill the Ti 3d conduction band. PMID- 22243098 TI - High-field transport in an electron-hole plasma: transition from ballistic to drift motion. AB - The time evolution of high-field carrier transport in bulk GaAs is studied with intense femtosecond THz pulses. While ballistic transport of electrons occurs in an n-type sample, a transition from ballistic to driftlike motion is observed in an electron-hole plasma. This onset of friction is due to the holes, which are heated by THz absorption. Theoretical calculations, which reproduce the data quantitatively, show that both electron-hole scattering and local-field effects in the electron-hole plasma are essential for the time-dependent friction. PMID- 22243099 TI - Two-dimensional topological insulator state and topological phase transition in bilayer graphene. AB - We show that gated bilayer graphene hosts a strong topological insulator (TI) phase in the presence of Rashba spin-orbit (SO) coupling. We find that gated bilayer graphene under preserved time-reversal symmetry is a quantum valley Hall insulator for small Rashba SO coupling lambda(R), and transitions to a strong TI when lambda(R)>?[U(2)+t(?)(2)], where U and t(?) are, respectively, the interlayer potential and tunneling energy. Different from a conventional quantum spin Hall state, the edge modes of our strong TI phase exhibit both spin and valley filtering, and thus share the properties of both quantum spin Hall and quantum valley Hall insulators. The strong TI phase remains robust in the presence of weak graphene intrinsic SO coupling. PMID- 22243100 TI - Nonequilibrium transport through a spinful quantum dot with superconducting leads. AB - We study the nonlinear cotunneling current through a spinful quantum dot contacted by two superconducting leads. Applying a general nonequilibrium Green function formalism to an effective Kondo model, we study the rich variation in the IV characteristics with varying asymmetry in the tunnel coupling to source and drain electrodes. The current is found to be carried, respectively, by multiple Andreev reflections in the symmetric limit, and by spin-induced Yu-Shiba Rusinov bound states in the strongly asymmetric limit. The interplay between these two mechanisms leads to qualitatively different IV characteristics in the crossover regime of intermediate symmetry, consistent with recent experimental observations of negative differential conductance and repositioned conductance peaks in subgap cotunneling spectroscopy. PMID- 22243101 TI - Near-field optical mapping of quantum Hall edge states. AB - We report on the mapping of quantum-Hall edge states by quasiresonant photovoltage measurements using a near-field scanning optical microscope. We have observed fine structures near sample edges that shift inward with an increase in magnetic field in accordance with the shift of the positions of the quantum-Hall edge states. We have found a transition from the weak disorder regime where compressible-incompressble strips are visible to the strong disorder regime where fluctuations smear out incompressible strips. PMID- 22243102 TI - Coupling a quantum dot, fermionic leads, and a microwave cavity on a chip. AB - We demonstrate a hybrid architecture consisting of a quantum dot circuit coupled to a single mode of the electromagnetic field. We use single wall carbon nanotube based circuits inserted in superconducting microwave cavities. By probing the nanotube dot using a dispersive readout in the Coulomb blockade and the Kondo regime, we determine an electron-photon coupling strength which should enable circuit QED experiments with more complex quantum dot circuits. PMID- 22243103 TI - Trap-assisted recombination in disordered organic semiconductors. AB - The trap-assisted recombination of electrons and holes in organic semiconductors is investigated. The extracted capture coefficients of the trap-assisted recombination process are thermally activated with an identical activation energy as measured for the hole mobility MU(p). We demonstrate that the rate limiting step for this mechanism is the diffusion of free holes towards trapped electrons in their mutual Coulomb field, with the capture coefficient given by (q/epsilon)MU(p). As a result, both the bimolecular and trap-assisted recombination processes in organic semiconductors are governed by the charge carrier mobilities, allowing predictive modeling of organic light-emitting diodes. PMID- 22243104 TI - One-Fe versus two-Fe Brillouin zone of Fe-based superconductors: creation of the electron pockets by translational symmetry breaking. AB - We investigate the physical effects of translational symmetry breaking in Fe based high-temperature superconductors due to alternating anion positions. In the representative parent compounds, including the newly discovered Fe-vacancy ordered K(0.8)Fe(1.6)Se(2), an unusual change of orbital character is found across the one-Fe Brillouin zone upon unfolding the first-principles band structure and Fermi surfaces, suggesting that covering a larger one-Fe Brillouin zone is necessary in experiments. Most significantly, the electron pockets (critical to the magnetism and superconductivity) are found only created with broken symmetry, advocating strongly its full inclusion in future studies, particularly on the debated nodal structures of the superconducting order parameter. PMID- 22243105 TI - Theory of half-metallic ferrimagnetism in double perovskites. AB - Double perovskites such as Sr(2)FeMoO(6) are rare examples of materials with half metallic ground states and a ferrimagnetic T(c) above room temperature. We present a comprehensive theory of the temperature and disorder dependence of their magnetic properties by deriving and validating a new effective spin Hamiltonian for these materials, amenable to large-scale three-dimensional simulations. We show how disorder, ubiquitous in these materials, affects T(c), the magnetization, and the conduction electron polarization. We conclude with a novel proposal to enhance T(c) without sacrificing polarization. PMID- 22243106 TI - Graphene as a reversible spin manipulator of molecular magnets. AB - One of the primary objectives in molecular nanospintronics is to manipulate the spin states of organic molecules with a d-electron center, by suitable external means. In this Letter, we demonstrate by first principles density functional calculations, as well as second order perturbation theory, that a strain induced change of the spin state, from S=1->S=2, takes place for an iron porphyrin (FeP) molecule deposited at a divacancy site in a graphene lattice. The process is reversible in the sense that the application of tensile or compressive strains in the graphene lattice can stabilize FeP in different spin states, each with a unique saturation moment and easy axis orientation. The effect is brought about by a change in Fe-N bond length in FeP, which influences the molecular level diagram as well as the interaction between the C atoms of the graphene layer and the molecular orbitals of FeP. PMID- 22243107 TI - Role of antisymmetric exchange in selecting magnetic chirality in Ba3NbFe3Si2O14. AB - We present an electron spin resonance (ESR) investigation of the acentric Ba(3)NbFe(3)Si(2)O(14), featuring a unique single-domain double-chiral magnetic ground state. Combining simulations of the ESR linewidth anisotropy and the antiferromagnetic-resonance modes allows us to single out the Dzyaloshinsky Moriya (DM) interaction as the leading magnetic anisotropy term. We demonstrate that the rather minute out-of-plane DM component d(c)=45 mK is responsible for selecting a unique ground state, which endures thermal fluctuations up to astonishingly high temperatures. PMID- 22243108 TI - Emergent rotational symmetries in disordered magnetic domain patterns. AB - Uniaxial systems often form labyrinthine domains that exhibit short-range order but are macroscopically isotropic and would not be expected to exhibit precise symmetries. However, their underlying frustration results in a multitude of metastable configurations of comparable energy, and driving such a system externally might lead to pattern formation. We find that soft x-ray speckle diffraction patterns of the labyrinthine domains in CoPd/IrMn heterostructures reveal a diverse array of hidden rotational symmetries about the magnetization axis, thereby suggesting an unusual form of emergent order in an otherwise disordered system. These symmetries depend on applied magnetic field, magnetization history, and scattering wave vector. Maps of rotational symmetry exhibit intriguing structures that can be controlled by manipulating the applied magnetic field in concert with the exchange bias condition. PMID- 22243109 TI - Domain-wall spin dynamics in kagome antiferromagnets. AB - We report magnetization and neutron scattering measurements down to 60 mK on a new family of Fe based kagome antiferromagnets, in which a strong local spin anisotropy combined with a low exchange path network connectivity lead to domain walls intersecting the kagome planes through strings of free spins. These produce unfamiliar slow spin dynamics in the ordered phase, evolving from exchange released spin flips towards a cooperative behavior on decreasing the temperature, probably due to the onset of long-range dipolar interaction. A domain structure of independent magnetic grains is obtained that could be generic to other frustrated magnets. PMID- 22243110 TI - Circular dichroism in the optical second-harmonic emission of curved gold metal nanowires. AB - Here we report the experimental observation of circular dichroism in the second harmonic field (800-400 nm conversion) generated by self-organized gold nanowire arrays with subwavelength periodicity (160 nm). Such circular dichroism, raised by a nonlinear optical extrinsic chirality, is the evident signature of the sample morphology. It arises from the curvature of the self-assembled wires, producing a lack of symmetry at oblique incidence. The results were compared, both in the optical linear and nonlinear regime, with a reference sample composed of straight wires. Despite the weak extrinsic optical chirality of our samples (not observable by our optical linear measurements), high visibility (more than 50%) was obtained in the second-harmonic generated field. PMID- 22243111 TI - Free-carrier generation in aggregates of single-wall carbon nanotubes by photoexcitation in the ultraviolet regime. AB - We present evidence for the generation of free carriers in aggregated single-wall carbon nanotubes by photoexcitation in the energetic range of the pi->pi(*) transition associated with the M saddle point of the graphene lattice. The underlying broad absorption culminating at 4.3 eV can be fit well with a Fano line shape that describes strong coupling of a saddle-point exciton to an underlying free electron-hole pair continuum. Moreover, it is demonstrated that transitions in this energetic region autoionize into the continuum by detecting features unique to the presence of free charges in the transient transmission spectra of the continuum-embedded second sub-band exciton, S(2). PMID- 22243112 TI - Chiral domains in cycloidal multiferroic thin films: switching and memory effects. AB - Cycloidal magnetic order occurring in some AMnO(3) perovskites is known to induce ferroelectricity. The polarization is perpendicular to the propagation vector direction of the cycloid and its chirality, and therefore it is directly related to the chiral domain structure. We show that the switching process of chiral domains is sensitively dependent on the magnetoelectric history of the sample. Moreover, by appropriate field cycling, magnetic order can display partial chiral memory. We argue that memory results from electric field coupling of cycloidal domain and nucleation and pinning of chiral domain walls, much like the domain structure in other ferroic systems. PMID- 22243113 TI - Interface control of emergent ferroic order in Ruddlesden-Popper Sr(n+1)Ti(n)O(3n+1). AB - We discovered from first principles an unusual polar state in the low n Sr(n+1)Ti(n)O(3n+1) Ruddlesden-Popper (RP) layered perovskites in which ferroelectricity is nearly degenerate with antiferroelectricity, a relatively rare form of ferroic order. We show that epitaxial strain plays a key role in tuning the "perpendicular coherence length" of the ferroelectric mode, and does not induce ferroelectricity in these low-dimensional RP materials as is well known to occur in SrTiO(3). These systems present an opportunity to manipulate the coherence length of a ferroic distortion in a controlled way, without disorder or a free surface. PMID- 22243114 TI - Fast and slow dynamics in a discotic liquid crystal with regions of columnar order and disorder. AB - Aromatic disk-shaped molecules tend to self-organize into a herringbone packing where the disks are inclined at angles +/-theta with respect to the axis of the column. In discotic liquid crystals this can introduce defects between stacks of limited length. In a C(3)-symmetric hexa-peri-hexabenzocoronene, solid-state NMR, x-ray scattering, and rheology identifies such a packing with theta=43 degrees and stacks of about seven disks. Disordered regions containing defects fill the space in between the ordered stacks. Biaxial intra- and intercolumnar dynamics differing by eight decades are identified. PMID- 22243115 TI - Scaling laws for melting ice avalanches. AB - This Letter describes an investigation of interfacial melting in ice-bearing granular flows. It is proposed that energy associated with granular collisions causes melting at an ice particle's surface, which can thus occur at temperatures well below freezing. A laboratory experiment has been designed that allows quantification of this process and its effect on the dynamics of a granular shear flow of ice spheres. This experiment employs a rotating drum, half filled with ice particles, situated in a temperature controlled laboratory. Capillary forces between the wetted melted particle surfaces lead to the clumping of particles and enhanced flow speeds, in turn leading to further melting. Dimensional analysis defines a parameter space for further experimentation. PMID- 22243116 TI - Leonardo's rule, self-similarity, and wind-induced stresses in trees. AB - Examining botanical trees, Leonardo da Vinci noted that the total cross section of branches is conserved across branching nodes. In this Letter, it is proposed that this rule is a consequence of the tree skeleton having a self-similar structure and the branch diameters being adjusted to resist wind-induced loads. PMID- 22243117 TI - In-plane dynamics of membranes with immobile inclusions. AB - Cell membranes are anchored to the cytoskeleton via immobile inclusions. We investigate the effect of such anchors on the in-plane dynamics of a fluid membrane and mobile inclusions (proteins) embedded in it. The immobile particles lead to a decreased diffusion coefficient of mobile ones and suppress the correlated diffusion of particle pairs. Because of the long-range, quasi-two dimensional nature of membrane flows, these effects become significant at a low area fraction (below 1%) of immobile inclusions. PMID- 22243118 TI - Cell motility resulting from spontaneous polymerization waves. AB - The crawling of cells on a substrate is in many cases driven by the actin cytoskeleton. How actin filaments and associated proteins are organized to generate directed motion is still poorly understood. Recent experimental observations suggest that spontaneous cytoskeletal waves might orchestrate the actin-filament network to produce directed motion. We investigate this possibility by studying a mean-field description of treadmilling filaments interacting with nucleating proteins, a system that is known to self-organize into waves. Confining the system by a boundary that shares essential features of membranes, we find that spontaneous waves can generate directional motion. We also find that it can produce lateral waves along the confining membrane as are observed in spreading cells. PMID- 22243119 TI - Criterion for extensional necking instability in polymeric fluids. AB - We study the linear instability with respect to necking of a filament of polymeric fluid undergoing uniaxial extension. Contrary to the widely discussed Considere criterion, we find the onset of instability to relate closely to the onset of downward curvature in the time (and so strain) evolution of the zz component of the molecular strain, for extension along the z axis. In establishing this result numerically across five of the most widely used models of polymer rheology, and by analytical calculation, we argue it to apply generically. Particularly emphasized is the importance of polymer chain stretching in partially mitigating necking. We comment finally on the relationship between necking and the shape of the underlying steady state constitutive curve for homogeneous extension. PMID- 22243120 TI - Comment on "Spaser action, loss compensation, and stability in plasmonic systems with gain". PMID- 22243122 TI - Comment on "Spaser action, loss compensation, and stability in plasmonic systems with gain". PMID- 22243124 TI - Supramolecular self-assembly induced graphene oxide based hydrogels and organogels. AB - We demonstrate the construction of three-dimensional graphene oxide based gel networks through the self-assembly of a series of amphiphilic molecules, which possess a polar carbohydrate headgroup attached to a nonpolar pyrene group. The gelation process can occur in both aqueous and organic solutions and be influenced by the gelators' molecular structure. The driving forces for the gelation process were determined as pi-pi stacking and hydrogen bonding interaction by using fluorescence and infrared spectroscopies. Rheometry was used to investigate the mechanical properties of the hydrogels and the organogels. The hydrogel was investigated to be applied to remove dye from aqueous solution. PMID- 22243126 TI - Growth speed of sporadic pheochromocytoma. PMID- 22243127 TI - Surface chemistry of quantum dots determines their behavior in postischemic tissue. AB - The behavior of quantum dots (QDs) in the microvasculature and their impact on inflammatory reactions under pathophysiological conditions are still largely unknown. Therefore, we designed this study to investigate the fate and effects of surface-modified QDs in postischemic skeletal and heart muscle. Under these pathophysiological conditions, amine-modified QDs, but not carboxyl-QDs, were strongly associated with the vessel wall of postcapillary venules and amplified ischemia-reperfusion-elicited leukocyte transmigration. Importantly, strong association of amine-QDs with microvessel walls was also present in the postischemic myocardium. As shown by electron microscopy and verified by FACS analyses, amine-modified QDs, but not carboxyl-QDs, were associated with endogenous microparticles. At microvessel walls, these aggregates were attached to endothelial cells. Taken together, we found that both the surface chemistry of QDs and the underlying tissue conditions (i.e., ischemia-reperfusion) strongly determine their uptake by endothelial cells in microvessels, their association to endogenous microparticles, as well as their potential to modify inflammatory processes. Thus, this study strongly corroborates the view that the surface chemistry of nanomaterials and the physiological state of the tissue are crucial for the behavior of nanomaterials in vivo. PMID- 22243128 TI - Gold nanoparticles with asymmetric polymerase chain reaction for colorimetric detection of DNA sequence. AB - We developed a novel strategy for rapid colorimetric analysis of a specific DNA sequence by combining gold nanoparticles (AuNPs) with an asymmetric polymerase chain reaction (As-PCR). In the presence of the correct DNA template, the bound oligonucleotides on the surface of AuNPs selectively hybridized to form complementary sequences of single-stranded DNA (ssDNA) target generated from As PCR. DNA hybridization resulted in self-assembly and aggregation of AuNPs, and a concomitant color change from ruby red to blue-purple occurred. This approach is simpler than previous methods, as it requires a simple mixture of the asymmetric PCR product with gold colloid conjugates. Thus, it is a convenient colorimetric method for specific nucleic acid sequence analysis with high specificity and sensitivity. Most importantly, the marked color change occurs at a picogram detection level after standing for several minutes at room temperature. Linear amplification minimizes the potential risk of PCR product cross-contamination. The efficiency to detect Bacillus anthracis in clinical samples clearly indicates the practical applicability of this approach. PMID- 22243129 TI - Ecological network analysis on global virtual water trade. AB - Global water interdependencies are likely to increase with growing virtual water trade. To address the issues of the indirect effects of water trade through the global economic circulation, we use ecological network analysis (ENA) to shed insight into the complicated system interactions. A global model of virtual water flow among agriculture and livestock production trade in 1995-1999 is also built as the basis for network analysis. Control analysis is used to identify the quantitative control or dependency relations. The utility analysis provides more indicators for describing the mutual relationship between two regions/countries by imitating the interactions in the ecosystem and distinguishes the beneficiary and the contributor of virtual water trade system. Results show control and utility relations can well depict the mutual relation in trade system, and direct observable relations differ from integral ones with indirect interactions considered. This paper offers a new way to depict the interrelations between trade components and can serve as a meaningful start as we continue to use ENA in providing more valuable implications for freshwater study on a global scale. PMID- 22243132 TI - Polypeptides and polyaminoacids in drug delivery. AB - INTRODUCTION: Advances achieved over the last few years in drug delivery have provided novel and versatile possibilities for the treatment of various diseases. Among the biomaterials applied in this field, it is worth highlighting the increasing importance of polyaminoacids and polypeptides. The appealing properties of these polymers are very promising for the design of novel compositions in a variety of drug delivery applications. AREAS COVERED: This review provides an overview on the general characteristics of polyaminoacids and polypeptides and briefly discusses different synthetic pathways for their production. This is followed by a detailed description of different drug delivery applications of these polymers, emphasizing those examples that already reached advanced preclinical development or have entered clinical trials. EXPERT OPINION: Polyaminoacids and polypeptides are gaining much attention in drug delivery due to their exceptional properties. Their application as polymers for drug delivery purposes has been sped up by the significant achievements related to their synthesis. Certainly, cancer therapy has benefited the most from these advances, although other fields such as vaccine delivery and alternative administration routes are also being successfully explored. The design of new entities based on polyaminoacids and polypeptides and the improved insight gained in drug delivery guarantee exciting findings in the near future. PMID- 22243131 TI - Nuclear resonance vibrational spectra of five-coordinate imidazole-ligated iron(II) porphyrinates. AB - Nuclear resonance vibrational spectra have been obtained for six five-coordinate imidazole-ligated iron(II) porphyrinates, [Fe(Por)(L)] (Por = tetraphenylporphyrinate, octaethylporphyrinate, tetratolylporphyrinate, or protoporphyrinate IX and L = 2-methylimidazole or 1,2-dimethylimidazole). Measurements have been made on both powder and oriented crystal samples. The spectra are dominated by strong signals around 200-300 cm(-1). Although the in plane and out-of-plane vibrations are seriously overlapped, oriented crystal spectra allow their deconvolution. Thus, oriented crystal experimental data, along with density functional theory (DFT) calculations, enable the assignment of key vibrations in the spectra. Molecular dynamics are also discussed. The nature of the Fe-N(Im) vibrations has been elaborated further than was possible from resonance Raman studies. Our study suggests that the Fe motions are coupled with the porphyrin core and peripheral groups motions. Both peripheral groups and their conformations have significant influence on the vibrational spectra (position and shape). PMID- 22243133 TI - Targeting the Hedgehog signaling pathway for cancer therapy. AB - INTRODUCTION: Hedgehog (Hh) signaling pathway plays key roles in embryonic development, formation and maintenance of cancer stem cells (CSCs) and acquisition of epithelial-to-mesenchymal transition (EMT). Since CSCs and EMT are important biological factors responsible for cancer cell invasion, metastasis, drug resistance and tumor recurrence, the Hh signaling pathway is believed to be an important target for cancer therapy. AREAS COVERED: In recent years, small molecule inhibitors of Hh signaling have been synthesized for cancer treatment. Clinical trials using these inhibitors are being conducted to determine their toxicity profiles and efficacies. In addition, nutraceuticals (such as isoflavones, curcumin, vitamin D, etc) have been shown to inhibit cancer growth through downregulation of Hh signaling. EXPERT OPINION: Inhibition of Hh signaling is important for suppression of cancer growth, invasion, metastasis and recurrence in cancer therapy. However, targeting only one molecule in Hh signaling may not be sufficient to kill cancer cells because cancers show deregulation of multiple signals. Therefore, utilizing new technologies to determine alterations in Hh and other signals for individuals and designing combination strategies with small-molecule Hh inhibitors, nutraceuticals and other chemotherapeutics in targeted personalized therapy could have a significant effect on improving the overall survival of patients with cancers. PMID- 22243135 TI - Reduction of matrix effects in liquid chromatography-electrospray ionization-mass spectrometry by dilution of the sample extracts: how much dilution is needed? AB - In this study, the relationship between matrix concentration and suppression of electrospray ionization (matrix effects) was investigated. Ion suppression of pesticides present in QuEChERS extracts was used as an example. Residue-free extracts of four different commodities, avocado, black tea, orange, and rocket (arugula), were fortified with 39 pesticides each. For many of the resulting 156 pesticide/matrix combinations, considerable matrix effects were observed if the coextracted matrix of 8 mg of equivalent sample (in the case of tea: 1.6 mg) was injected with the undiluted extracts. The reduction of these matrix effects was measured at 10 levels of dilution up to 1000-fold. The results obtained indicate a linear correlation between matrix effects and the logarithm of matrix concentration (or dilution factor) until the zero-effect level of further dilution was reached. Using the logarithmic equations, it could be shown that a dilution of extracts by a factor of 25-40 reduces ion suppression to less than 20% if the initial suppression is <=80%. For stronger matrix effects or complete elimination of suppression, higher dilution factors were needed. The observed correlation was independent from the two instrument platforms used, but the degree of matrix effects differed slightly between the two mass spectrometers in this study. PMID- 22243136 TI - Host-Epstein-Barr virus relationship affected by immunostimulation in HIV infected patients representing distinct progressor profile groups. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection with pronounced immunosuppression disrupts Epstein-Barr virus (EBV)-host balance with increased lymphoma risk. We explored whether different host responses to HIV are reflected in the EBV-host balance. METHODS: Eleven unvaccinated HIV-positive patients and 16 participants in a vaccine trial were included in the study. Blood samples were collected, B cells extracted, and EBV DNA load was determined using a semiquantitative polymerase chain reaction (PCR) method. RESULTS: Treatment-naive patients with a history of symptomatic primary HIV infection showed non significant, but higher EBV load compared to untreated long-term non-progressors. A significant difference in HIV RNA titres between these groups correlated weakly to EBV DNA load. Patients in the vaccine trial with recombinant HIV gp160 and/or adjuvant and with a history of symptomatic primary HIV infection, showed a 1-log increase in EBV load compared to patients with long-lasting HIV disease. CONCLUSION: Different host responses to HIV infection, especially in combination with vaccination, can be reflected in the EBV-host balance. PMID- 22243137 TI - Conformational dynamics of abasic DNA upon interactions with AP endonuclease 1 revealed by stopped-flow fluorescence analysis. AB - Apurinic/apyrimidinic (AP) sites are abundant DNA lesions arising from exposure to UV light, ionizing radiation, alkylating agents, and oxygen radicals. In human cells, AP endonuclease 1 (APE1) recognizes this mutagenic lesion and initiates its repair via a specific incision of the phosphodiester backbone 5' to the AP site. We have investigated a detailed mechanism of APE1 functioning using fluorescently labeled DNA substrates. A fluorescent adenine analogue, 2 aminopurine, was introduced into DNA substrates adjacent to the abasic site to serve as an on-site reporter of conformational transitions in DNA during the catalytic cycle. Application of a pre-steady-state stopped-flow technique allows us to observe changes in the fluorescence intensity corresponding to different stages of the process in real time. We also detected an intrinsic Trp fluorescence of the enzyme during interactions with 2-aPu-containing substrates. Our data have revealed a conformational flexibility of the abasic DNA being processed by APE1. Quantitative analysis of fluorescent traces has yielded a minimal kinetic scheme and appropriate rate constants consisting of four steps. The results obtained from stopped-flow data have shown a substantial influence of the 2-aPu base location on completion of certain reaction steps. Using detailed molecular dynamics simulations of the DNA substrates, we have attributed structural distortions of AP-DNA to realization of specific binding, effective locking, and incision of the damaged DNA. The findings allowed us to accurately discern the step that corresponds to insertion of specific APE1 amino acid residues into the abasic DNA void in the course of stabilization of the precatalytic complex. PMID- 22243138 TI - The overall reaction process of ozone with methacrolein and isoprene in the condensed phase. AB - The reaction of isoprene and methacrolein with ozone was investigated at different stages in the condensed phase at temperatures from 15 to 265 K by IR spectroscopy. The results revealed the following overall reaction process: the generation of primary ozonide (POZ), then its decomposition, and finally conversion into secondary ozonide (SOZ), which supported the Criegee mechanism. In the POZ and SOZ of isoprene, ozone cyclo-added preferentially to the double bond that is not substituted by the methyl group. For methacrolein, the mainly detected SOZ is claimed to be MACSII formed by recombination of the intermediate CH(2)OO radical with aldehyde carbonyl of methylglyoxal in stead of the ketone carbonyl group. Theoretical calculations were performed at the B3LYP//MP2/6 311++G (2d, 2p) level to analyze the resulting spectrum. The good agreement between the calculated infrared spectra of POZ and SOZ and the experimental spectra supports the above-described findings. PMID- 22243139 TI - Quantitative characterization of individual microdroplets using surface-enhanced resonance Raman scattering spectroscopy. AB - Surface-enhanced resonance Raman scattering (SERRS) spectroscopy is a highly sensitive optical technique capable of detecting multiple analytes rapidly and simultaneously. There is significant interest in SERRS detection in micro- and nanotechnologies, as it can be used to detect extremely low analyte concentrations in small volumes of fluids, particularly in microfluidic systems. There is also rapidly growing interest in the field of microdroplets, which promises to offer the analyst many potential advantages over existing technologies for both design and control of microfluidic assays. While there have been rapid advances in both fields in recent years, the literature on SERRS-based detection of individual microdroplets remains lacking. In this paper, we demonstrate the ability to quantitatively detect multiple variable analyte concentrations from within individual microdroplets in real time using SERRS spectroscopy. We also demonstrate the use of a programmable pump control algorithm to generate concentration gradients across a chain of droplets. PMID- 22243140 TI - Molecular dynamics simulations of silica nanoparticles grafted with poly(ethylene oxide) oligomer chains. AB - A molecular model of silica nanoparticles grafted with poly(ethylene oxide) oligomers has been developed for predicting the transport properties of nanoparticle organic-hybrid materials (NOHMs). Ungrafted silica nanoparticles in a medium of poly(ethylene oxide) oligomers were also simulated to clarify the effect of grafting on the dynamics of nanoparticles and chains. The model approximates nanoparticles as solid spheres and uses a united-atom representation for chains, including torsional and bond-bending interactions. The calculated viscosities from Green-Kubo relationships and temperature extrapolation are of the same order of magnitude as experimental data but show a smaller activation energy relative to real NOHMs systems. Grafted systems have higher viscosities, smaller diffusion coefficients, and slower chain dynamics than the ungrafted ones at high temperatures. At lower temperatures, grafted systems exhibit faster dynamics for both nanoparticles and chains relative to ungrafted systems, because of lower aggregation of particles and enhanced correlations between nanoparticles and chains. This agrees with the experimental observation that NOHMs have liquidlike behavior in the absence of a solvent. For both grafted and ungrafted systems at low temperatures, increasing chain length reduces the volume fraction of nanoparticles and accelerates the dynamics. However, at high temperatures, longer chains slow down nanoparticle diffusion. From the Stokes-Einstein relationship, it was determined that the coarse-grained treatment of nanoparticles leads to slip on the nanoparticle surfaces. Grafted systems obey the Stokes-Einstein relationship over the temperature range simulated, but ungrafted systems display deviations from it. PMID- 22243141 TI - Quantum electron self-interaction in a strong laser field. AB - The quantum state of an electron in a strong laser field is altered if the interaction of the electron with its own electromagnetic field is taken into account. Starting from the Schwinger-Dirac equation, we determine the states of an electron in a plane-wave field with inclusion, at leading order, of its electromagnetic self-interaction. On the one hand, the electron states show a pure quantum contribution to the electron quasimomentum, conceptually different from the conventional classical one arising from the quiver motion of the electron. On the other hand, the electron self-interaction induces a distinct dynamics of the electron spin, whose effects are shown to be measurable in principle with available technology. PMID- 22243142 TI - Two-dimensional imaging of gauge fields in optical lattices. AB - We propose a scheme to generate an arbitrary Abelian vector potential for atoms trapped in a two-dimensional optical lattice. By making the optical lattice potential dependent on the atomic state, we transform the problem into that of a two-dimensional imaging. It is shown that an arbitrarily fine pattern of the gauge field in the lattice can be realized without need of diffraction-limited imaging. PMID- 22243143 TI - Quantum simulation of quantum field theories in trapped ions. AB - We propose the quantum simulation of fermion and antifermion field modes interacting via a bosonic field mode, and present a possible implementation with two trapped ions. This quantum platform allows for the scalable add up of bosonic and fermionic modes, and represents an avenue towards quantum simulations of quantum field theories in perturbative and nonperturbative regimes. PMID- 22243144 TI - Greenberger-Horne-Zeilinger states and few-body Hamiltonians. AB - The generation of Greenberger-Horne-Zeilinger (GHZ) states is a crucial problem in quantum information. We derive general conditions for obtaining GHZ states as eigenstates of a Hamiltonian. We find that a necessary condition for an n-qubit GHZ state to be a nondegenerate eigenstate of a Hamiltonian is the presence of m qubit couplings with m>=[(n+1)/2]. Moreover, we introduce a Hamiltonian with a GHZ eigenstate and derive sufficient conditions for the removal of the degeneracy. PMID- 22243145 TI - Quantum filtering one bit at a time. AB - In this Letter we consider the purification of a quantum state using the information obtained from a continuous measurement record, where the classical measurement record is digitized to a single bit per measurement after the measurements have been made. Analysis indicates that efficient and reliable state purification is achievable for one- and two-qubit systems. We also consider quantum feedback control based on the discrete one-bit measurement sequences. PMID- 22243146 TI - Unequal twins: probability distributions do not determine everything. AB - It is the common lore to assume that knowing the equation for the probability distribution function (PDF) of a stochastic model as a function of time tells the whole picture defining all other characteristics of the model. We show that this is not the case by comparing two exactly solvable models of anomalous diffusion due to geometric constraints: the comb model and the random walk on a random walk. We show that though the two models have exactly the same PDFs, they differ in other respects, like their first passage time distributions, their autocorrelation functions, and their aging properties. PMID- 22243147 TI - Characterizing and quantifying frustration in quantum many-body systems. AB - We present a general scheme for the study of frustration in quantum systems. We introduce a universal measure of frustration for arbitrary quantum systems and we relate it to a class of entanglement monotones via an exact inequality. If all the (pure) ground states of a given Hamiltonian saturate the inequality, then the system is said to be inequality saturating. We introduce sufficient conditions for a quantum spin system to be inequality saturating and confirm them with extensive numerical tests. These conditions provide a generalization to the quantum domain of the Toulouse criteria for classical frustration-free systems. The models satisfying these conditions can be reasonably identified as geometrically unfrustrated and subject to frustration of purely quantum origin. Our results therefore establish a unified framework for studying the intertwining of geometric and quantum contributions to frustration. PMID- 22243148 TI - Do baryons trace dark matter in the early universe? AB - Baryon-density perturbations of large amplitude may exist if they are compensated by dark-matter perturbations such that the total density is unchanged. Primordial abundances and galaxy clusters allow these compensated isocurvature perturbations (CIPs) to have amplitudes as large as ~10%. CIPs will modulate the power spectrum of cosmic microwave background (CMB) fluctuations--those due to the usual adiabatic perturbations--as a function of position on the sky. This leads to correlations between different spherical-harmonic coefficients of the temperature and/or polarization maps, and induces polarization B modes. Here, the magnitude of these effects is calculated and techniques to measure them are introduced. While a CIP of this amplitude can be probed on large scales with existing data, forthcoming CMB experiments should improve the sensitivity to CIPs by at least an order of magnitude. PMID- 22243149 TI - Search for sub-eV mass solar axions by the CERN Axion Solar Telescope with 3He buffer gas. AB - The CERN Axion Solar Telescope (CAST) has extended its search for solar axions by using (3)He as a buffer gas. At T=1.8 K this allows for larger pressure settings and hence sensitivity to higher axion masses than our previous measurements with (4)He. With about 1 h of data taking at each of 252 different pressure settings we have scanned the axion mass range 0.39 eV?m(a)?0.64 eV. From the absence of excess x rays when the magnet was pointing to the Sun we set a typical upper limit on the axion-photon coupling of g(agamma)?2.3*10(-10) GeV(-1) at 95% C.L., the exact value depending on the pressure setting. Kim-Shifman-Vainshtein Zakharov axions are excluded at the upper end of our mass range, the first time ever for any solar axion search. In the future we will extend our search to m(a)?1.15 eV, comfortably overlapping with cosmological hot dark matter bounds. PMID- 22243153 TI - Trapping Rydberg atoms in an optical lattice. AB - Rubidium Rydberg atoms are laser excited and subsequently trapped in a one dimensional optical lattice (wavelength 1064 nm). Efficient trapping is achieved by a lattice inversion immediately after laser excitation using an electro-optic technique. The trapping efficiency is probed via analysis of the trap-induced shift of the two-photon microwave transition 50S->51S. The inversion technique allows us to reach a trapping efficiency of 90%. The dependence of the efficiency on the timing of the lattice inversion and on the trap laser power is studied. The dwell time of 50D(5/2) Rydberg atoms in the lattice is analyzed using lattice induced photoionization. PMID- 22243154 TI - Ultrafast dynamics of photoionized acetylene. AB - Acetylene cations [HCCH](+) produced in the A(2)Sigma(g)(+) state by extreme ultraviolet (XUV) photoionization are investigated theoretically, based on a mixed quantum-classical approach. We show that the decay of the A(2)Sigma(g)(+) state occurs via both ultrafast isomerization and nonradiative electronic relaxation. We find a time scale for hydrogen migration and electronic decay of about 60 fs, in good agreement with recent XUV-pump/XUV-probe time-resolved experiments on the same system [Phys. Rev. Lett. 105, 263002 (2010)]. Moreover, we predict an efficient vibrational energy redistribution mechanism that quickly transfers excess energy from the isomerization coordinates to slower modes in a few hundred femtoseconds, leading to a partial regeneration of acetylenelike conformations. PMID- 22243152 TI - Probing the high momentum component of the deuteron at high Q2. AB - The (2)H(e,e'p)n cross section at a momentum transfer of 3.5 (GeV/c)(2) was measured over a kinematical range that made it possible to study this reaction for a set of fixed missing momenta as a function of the neutron recoil angle theta(nq) and to extract missing momentum distributions for fixed values of theta(nq) up to 0.55 GeV/c. In the region of 35 degrees <=theta(nq)<=45 degrees recent calculations, which predict that final-state interactions are small, agree reasonably well with the experimental data. Therefore, these experimental reduced cross sections provide direct access to the high momentum component of the deuteron momentum distribution in exclusive deuteron electrodisintegration. PMID- 22243155 TI - Storage and adiabatic cooling of polar molecules in a microstructured trap. AB - We present a versatile electric trap for the exploration of a wide range of quantum phenomena in the interaction between polar molecules. The trap combines tunable fields, homogeneous over most of the trap volume, with steep gradient fields at the trap boundary. An initial sample of up to 10(8), CH(3)F molecules is trapped for as long as 60 s, with a 1/e storage time of 12 s. Adiabatic cooling down to 120 mK is achieved by slowly expanding the trap volume. The trap combines all ingredients for opto-electrical cooling, which, together with the extraordinarily long storage times, brings field-controlled quantum-mechanical collision and reaction experiments within reach. PMID- 22243156 TI - Exploiting the time-reversal operator for adaptive optics, selective focusing, and scattering pattern analysis. AB - We report on the experimental measurement of the backscattering matrix of a weakly scattering medium in optics, composed of a few dispersed gold nanobeads. The decomposition of the time-reversal operator is applied to this matrix and we demonstrate selective and efficient focusing on individual scatterers, even through an aberrating layer. Moreover, we show that this approach provides the decomposition of the scattering pattern of a single nanoparticle. These results open important perspectives for optical imaging, characterization, and selective excitation of nanoparticles. PMID- 22243157 TI - Homoclinic snaking of localized patterns in a spatially forced system. AB - Dissipative localized structures exhibit intricate bifurcation diagrams. An adequate theory has been developed in one space dimension; however, discrepancies arise with the experiments. Based on an optical feedback with spatially modulated input beam, we set up a 1D forced configuration in a nematic liquid crystal layer. We characterize experimentally and theoretically the homoclinic snaking diagram of localized patterns, providing a reconciliation between theory and experiments. PMID- 22243158 TI - Hydrodynamics of writing with ink. AB - Writing with ink involves the supply of liquid from a pen onto a porous hydrophilic solid surface, paper. The resulting linewidth depends on the pen speed and the physicochemical properties of the ink and paper. Here we quantify the dynamics of this process using a combination of experiment and theory. Our experiments are carried out using a minimal pen, a long narrow tube that serves as a reservoir of liquid, which can write on a model of paper, a hydrophilic micropillar array. A minimal theory for the rate of wicking or spreading of the liquid is given by balancing the capillary force that drives the liquid flow and the resistance associated with flow through the porous substrate. This allows us to predict the shape of the front and the width of the line laid out by the pen, with results that are corroborated by our experiments. PMID- 22243159 TI - Use of the Richtmyer-Meshkov instability to infer yield stress at high-energy densities. AB - We use the Richtmyer-Meshkov instability (RMI) at a metal-gas interface to infer the metal's yield stress (Y) under shock loading and release. We first model how Y stabilizes the RMI using hydrodynamics simulations with a perfectly plastic constitutive relation for copper (Cu). The model is then tested with molecular dynamics (MD) of crystalline Cu by comparing the inferred Y from RMI simulations with direct stress-strain calculations, both with MD at the same conditions. Finally, new RMI experiments with solid Cu validate our simulation-based model and infer Y~0.47 GPa for a 36 GPa shock. PMID- 22243150 TI - Search for a heavy toplike quark in pp collisions at ?s=1.96 TeV. AB - We present the results of a search for pair production of a heavy toplike (t') quark decaying to Wq final states using data corresponding to an integrated luminosity of 5.6 fb(-1) collected by the CDF II detector in pp collisions at ?s=1.96 TeV. We perform parallel searches for t'->Wb and t'->Wq (where q is a generic down-type quark) in events containing a lepton and four or more jets. By performing a fit to the two-dimensional distribution of total transverse energy versus reconstructed t' quark mass, we set upper limits on the t't' production cross section and exclude a standard model fourth-generation t' quark decaying to Wb (Wq) with mass below 358 (340) GeV/c(2) at 95% C.L. PMID- 22243160 TI - Rotation reversal bifurcation and energy confinement saturation in tokamak Ohmic L-mode plasmas. AB - Direction reversals of intrinsic toroidal rotation have been observed in diverted Alcator C-Mod Ohmic L-mode plasmas following electron density ramps. For low density discharges, the core rotation is directed cocurrent, and reverses to countercurrent following an increase in the density above a certain threshold. Such reversals occur together with a decrease in density fluctuations with 2 cm( 1)<=k(theta)<=11 cm(-1) and frequencies above 70 kHz. There is a strong correlation between the reversal density and the density at which the Ohmic L mode energy confinement changes from the linear to the saturated regime. PMID- 22243161 TI - Laser shaping of a relativistic intense, short Gaussian pulse by a plasma lens. AB - By 3D particle-in-cell simulation and analysis, we propose a plasma lens to make high intensity, high contrast laser pulses with a steep front. When an intense, short Gaussian laser pulse of circular polarization propagates in near-critical plasma, it drives strong currents of relativistic electrons which magnetize the plasma. Three pulse shaping effects are synchronously observed when the laser passes through the plasma lens. The laser intensity is increased by more than 1 order of magnitude while the initial Gaussian profile undergoes self-modulation longitudinally and develops a steep front. Meanwhile, a nonrelativistic prepulse can be absorbed by the overcritical plasma lens, which can improve the laser contrast without affecting laser shaping of the main pulse. If the plasma skin length is properly chosen and kept fixed, the plasma lens can be used for varied laser intensity above 10(19) W/cm(2). PMID- 22243162 TI - Tunable radiation source by coupling laser-plasma-generated electrons to a periodic structure. AB - Near-infrared radiation around 1000 nm generated from the interaction of a high density MeV electron beam, obtained by impinging an intense ultrashort laser pulse on a solid target, with a metal grating is observed experimentally. Theoretical modeling and particle-in-cell simulation suggest that the radiation is caused by the Smith-Purcell mechanism. The results here indicate that tunable terahertz radiation with tens GV/m field strength can be achieved by using appropriate grating parameters. PMID- 22243163 TI - Plasma damping effects on the radiative energy loss of relativistic particles. AB - The energy loss of a relativistic charge undergoing multiple scatterings while traversing an infinite, polarizable and absorptive plasma is investigated. Polarization and absorption mechanisms in the medium are phenomenologically modeled by a complex index of refraction. Apart from the known Ter-Mikaelian effect related to the dielectric polarization of matter, we find an additional, substantial reduction of the energy loss due to the damping of radiation. The observed effect is more prominent for larger damping and/or larger energy of the charge. A conceivable analog of this phenomenon in QCD could influence the study of jet quenching phenomena in ultrarelativistic heavy-ion collisions at RHIC and LHC. PMID- 22243164 TI - Observation of a superfluid component within solid helium. AB - We demonstrate by neutron scattering that a localized superfluid component exists at high pressures within solid helium in aerogel. Its existence is deduced from the observation of two sharp phonon-roton spectra which are clearly distinguishable from modes in bulk superfluid helium. These roton excitations exhibit different roton gap parameters than the roton observed in the bulk fluid at freezing pressure. One of the roton modes disappears after annealing the samples. Comparison with theoretical calculations suggests that the model that reproduces the observed data best is that of superfluid double layers within the solid and at the helium-substrate interface. PMID- 22243165 TI - Strain relaxation and vacancy creation in thin platinum films. AB - Synchrotron based combined in situ x-ray diffractometry and reflectometry is used to investigate the role of vacancies for the relaxation of residual stress in thin metallic Pt films. From the experimentally determined relative changes of the lattice parameter a and of the film thickness L the modification of vacancy concentration and residual strain was derived as a function of annealing time at 130 degrees C. The results indicate that relaxation of strain resulting from compressive stress is accompanied by the creation of vacancies at the free film surface. This proves experimentally the postulated dominant role of vacancies for stress relaxation in thin metal films close to room temperature. PMID- 22243166 TI - Geometrical frustration in nanowire growth. AB - Idealized nanowire geometries assume stable sidewalls at right angles to the growth front. Here we report growth simulations that include a mix of nonorthogonal facet orientations, as for Au-catalyzed Si. We compare these with in situ microscopy observations, finding striking correspondences. In both experiments and simulations, there are distinct growth modes that accommodate the lack of right angles in different ways--one through sawtooth-textured sidewalls, the other through a growth front at an angle to the growth axis. Small changes in conditions can reversibly switch the growth between modes. The fundamental differences between these modes have important implications for control of nanowire growth. PMID- 22243167 TI - Positive Tolman length in a lattice gas with three-body interactions. AB - We present a new method to determine the curvature dependence of the interface tension between coexisting phases in a finite volume from free energies obtained by Monte Carlo simulations. For the example of a lattice gas on a 3D fcc lattice with nearest neighbor three-body interactions, we demonstrate how to calculate the equimolar radius R(e) as well as the radius R(s) of the surface of tension and thus the Tolman length delta(R(s))=R(e)-R(s). Within the physically relevant range of radii, delta(R(s)) shows a pronounced R(s) dependence, such that the simple Tolman parametrization for the interface tension is refutable. For the present model, extrapolation of delta(R(s)) to R(s)->infinity by various methods clearly indicates a positive limiting value. PMID- 22243151 TI - Measurement of polarization and search for CP violation in B(s)0->phiphi decays. AB - We present the first measurement of polarization and CP-violating asymmetries in a B(s)(0) decay into two light vector mesons, B(s)(0)->phiphi, and an improved determination of its branching ratio using 295 decays reconstructed in a data sample corresponding to 2.9 fb(-1) of integrated luminosity collected by the CDF experiment at the Fermilab Tevatron collider. The fraction of longitudinal polarization is determined to be f(L)=0.348+/-0.041(stat)+/-0.021(syst), and the branching ratio B(B(s)(0)->phiphi)=[2.32+/-0.18(stat)+/-0.82(syst)]*10(-5). Asymmetries of decay angle distributions sensitive to CP violation are measured to be A(u)=-0.007+/-0.064(stat)+/-0.018(syst) and A(v)=-0.120+/-0.064(stat)+/ 0.016(syst). PMID- 22243168 TI - Mapping dynamical heterogeneity in structural glasses to correlated fluctuations of the time variables. AB - Dynamical heterogeneities--strong fluctuations near the glass transition--are believed to be crucial to explain much of the glass transition phenomenology. One hypothesis for their origin is that they emerge from soft (Goldstone) modes associated with a broken continuous symmetry under time reparametrizations. To test this hypothesis, we use numerical simulation data to construct coarse grained observables and decompose their fluctuations into two transverse components associated with the postulated soft modes and a longitudinal component unrelated to them. We find that as temperature is lowered and time scales are increased, the time reparametrization fluctuations become increasingly dominant, and that their correlation volumes grow together with those of the dynamical heterogeneities, while the correlation volumes for longitudinal fluctuations remain small. PMID- 22243170 TI - Peierls mechanism of the metal-insulator transition in ferromagnetic hollandite K2Cr8O16. AB - Synchrotron x-ray diffraction experiment shows that the metal-insulator transition occurring in a ferromagnetic state of a hollandite K(2)Cr(8)O(16) is accompanied by a structural distortion from the tetragonal I4/m to monoclinic P112(1)/a phase with a ?2*?2*1 supercell. Detailed electronic structure calculations demonstrate that the metal-insulator transition is caused by a Peierls instability in the quasi-one-dimensional column structure made of four coupled Cr-O chains running in the c direction, leading to the formation of tetramers of Cr ions below the transition temperature. This provides a rare example of the Peierls transition of fully spin-polarized electron systems. PMID- 22243169 TI - Electron-phonon coupling and the soft phonon mode in TiSe2. AB - We report high-resolution inelastic x-ray measurements of the soft phonon mode in the charge-density-wave compound TiSe(2). We observe a complete softening of a transverse optic phonon at the L point, i.e., q=(0.5, 0, 0.5), at T~T(CDW). Detailed ab initio calculations for the electronic and lattice dynamical properties of TiSe(2) are in quantitative agreement with experimental frequencies for the soft phonon mode. The observed broad range of renormalized phonon frequencies, (0.3, 0, 0.5)<=q<=(0.5, 0, 0.5), is directly related to a broad peak in the electronic susceptibility stabilizing the charge-density-wave ordered state. Our analysis demonstrates that a conventional electron-phonon coupling mechanism can explain a structural instability and the charge-density-wave order in TiSe(2) although other mechanisms might further boost the transition temperature. PMID- 22243171 TI - Electrical tuning of single nitrogen-vacancy center optical transitions enhanced by photoinduced fields. AB - We demonstrate precise control over the zero-phonon optical transition energies of individual nitrogen-vacancy (NV) centers in diamond by applying multiaxis electric fields, via the dc Stark effect. The Stark shifts display surprising asymmetries that we attribute to an enhancement and rectification of the local electric field by photoionized charge traps in the diamond. Using this effect, we tune the excited-state orbitals of strained NV centers to degeneracy and vary the resulting degenerate optical transition frequency by >10 GHz, a scale comparable to the inhomogeneous frequency distribution. This technique will facilitate the integration of NV-center spins within photonic networks. PMID- 22243172 TI - Reduced effective spin-orbital degeneracy and spin-orbital ordering in paramagnetic transition-metal oxides: Sr2IrO4 versus Sr2RhO4. AB - We discuss the notions of spin-orbital polarization and ordering in paramagnetic materials, and address their consequences in transition-metal oxides. Extending the combined density functional and dynamical mean field theory scheme to the case of materials with large spin-orbit interactions, we investigate the electronic excitations of the paramagnetic phases of Sr(2)IrO(4) and Sr(2)RhO(4). We show that the interplay of spin-orbit interactions, structural distortions and Coulomb interactions suppresses spin-orbital fluctuations. As a result, the room temperature phase of Sr(2)IrO(4) is a paramagnetic spin-orbitally ordered Mott insulator. In Sr(2)RhO(4), the effective spin-orbital degeneracy is reduced, but the material remains metallic, due to both, smaller spin-orbit and smaller Coulomb interactions. The corresponding spectra are in excellent agreement with photoemission data. Finally, we make predictions for the spectra of paramagnetic Sr(2)IrO(4). PMID- 22243173 TI - Hexadecapolar Kondo effect in URu2Si2? AB - We derive the coupling of a localized hexadecapolar mode to conduction electrons in tetragonal symmetry. The derivation can be easily adapted to arbitrary multipoles in an arbitrary environment. We relate our model to the two-channel Kondo (2CK) model and show that for an f(2) configuration a relevant crystal field splitting in addition to the 2CK interaction is intrinsic to tetragonal symmetry. We discuss possible realizations of a hexadecapolar Kondo effect in URu(2)Si(2). Solving our model we find good agreement with susceptibility and specific heat measurements in Th(1-x)U(x)Ru(2)Si(2) (x?1). PMID- 22243174 TI - Predicted signatures of the intrinsic spin Hall effect in closed systems. AB - We study a two-dimensional electron system in the presence of spin-orbit interaction. It is shown analytically that the spin-orbit interaction acts as a transversal effective electric field, whose orientation depends on the sign of the z-axis spin projection. This effect does not require any driving electrical field and is inherent to the spin-orbit interactions present in semiconductor materials. Therefore, it should manifest in both closed and open systems. An experiment is proposed to observe the intrinsic spin Hall effect in the far infrared absorption of an asymmetric semiconductor nanostructure. PMID- 22243175 TI - Evolution of the 7/2 fractional quantum Hall state in two-subband systems. AB - We report the evolution of the fractional quantum Hall state (FQHS) at a total Landau level (LL) filling factor of nu=7/2 in wide GaAs quantum wells in which electrons occupy two electric subbands. The data reveal subtle and distinct evolutions as a function of density, magnetic field tilt angle, or symmetry of the charge distribution. At intermediate tilt angles, for example, we observe a strengthening of the nu=7/2 FQHS. Moreover, in a well with asymmetric change distribution, there is a developing FQHS when the LL filling factor of the symmetric subband nu(S) equals 5/2 while the antisymmetric subband has a filling factor of 1phi(c) from above, consistent with a divergence at phi(c). epsilon(m) shows no characteristic length scale and has a nontrivial power-law form, epsilon(m)~R(-0.62), over almost the entire range of R at all phi. These results suggest that the force chains present in the spatial structure of the quenched stress may be governed by different physics than the anomalous elastic response near jamming. PMID- 22243185 TI - Forces and torques on rotating spirochete flagella. AB - Spirochetes are a unique group of motile bacteria that are distinguished by their helical or flat-wave shapes and the location of their flagella, which reside within the tiny space between the bacterial cell wall and the outer membrane (the periplasm). In Borrelia burgdorferi, rotation of the flagella produces cellular undulations that drive swimming. How these shape changes arise due to the forces and torques that act between the flagella and the cell body is unknown. It is possible that resistive forces come from friction or from fluid drag, depending on whether or not the flagella are in contact with the cell wall. Here, we consider both of these cases. By analyzing the motion of an elastic flagellum rotating in the periplasmic space, we show that the flagella are most likely separated from the bacterial cell wall by a lubricating layer of fluid. This analysis then provides drag coefficients for rotation and sliding of a flagellum within the periplasm. PMID- 22243186 TI - Two-dimensional microrheology of freely suspended liquid crystal films. AB - Smectic liquid crystals form freely-suspended, fluid films of highly uniform structure and thickness, making them ideal systems for studies of hydrodynamics in two dimensions. We have measured particle mobility and shear viscosity by direct observation of the gravitational drift of silica spheres and smectic islands included in these fluid membranes. In thick films, we observe a hydrodynamic regime dominated by lateral confinement effects, with the mobility of the inclusion determined predominantly by coupling of the fluid flow to the fixed boundaries of the film. In thin films, the mobility of inclusions is governed primarily by coupling of the fluid to the surrounding air, as predicted by Saffman-Delbruck theory. PMID- 22243187 TI - Thermal jamming of a colloidal glass. AB - We investigate the effect of temperature on structure and dynamics of a colloidal glass created by tethering polymers to the surface of inorganic nanoparticles. Contrary to the conventional assumption, an increase in temperature slows down glassy dynamics of the material, yet causes no change in its static structure factor. We show that these findings can be explained within the soft glassy rheology framework if the noise temperature X of the glass phase is correlated with thermodynamic temperature. PMID- 22243188 TI - Possible explanation of the atmospheric kinetic and potential energy spectra. AB - We hypothesize that the observed wave number spectra of kinetic and potential energy in the atmosphere can be explained by assuming that there are two related cascade processes emanating from the same large-scale energy source, a downscale cascade of potential enstrophy, giving rise to the k(-3) spectrum at synoptic scales and a downscale energy cascade giving rise to the k(-5/3) spectrum at mesoscales. The amount of energy which is going into the downscale energy cascade is determined by the rate of system rotation, with negligible energy going downscale in the limit of very fast rotation. We present a set of simulations of a system with strong rotation and stratification, supporting these hypotheses and showing good agreement with observations. PMID- 22243189 TI - Mean velocity profile in a sheared and thermally stratified atmospheric boundary layer. AB - A stability correction function phi(m)(zeta) that accounts for distortions to the logarithmic mean velocity profile (MVP) in the lower atmosphere caused by thermal stratification was proposed by Monin and Obukhov in the 1950s using dimensional analysis. Its universal character was established from many field experiments. However, theories that describe the canonical shape of phi(m)(zeta) are still lacking. A previous link between the spectrum of turbulence and the MVP is expanded here to include the effects of thermal stratification on the turbulent kinetic energy dissipation rate and eddy-size anisotropy. The resulting theory provides a novel explanation for the power-law exponents and coefficients already reported for phi(m)(zeta) from numerous field experiments. PMID- 22243190 TI - Mutations in the PDYN gene (SCA23) are not a frequent cause of dominant ataxia in Central Europe. PMID- 22243211 TI - Feasibility of a perfluorocarbon tracer based network to support monitoring, verification, and accounting of sequestered CO2. AB - Carbon capture and sequestration (CCS) will act as a bridging technology necessary to facilitate a transition from fossil fuels to a sustainable energy based economy. The Department of Energy (DOE) target leak rate for sequestration reservoirs is 1% of total sequestered CO(2) over the lifetime of the reservoir. This is 0.001% per year for a 1000 year lifetime of a storage reservoir. Effective detection of CO(2) leaks at the surface may require incorporation of a tracer tag into the sequestered CO(2). We applied a simple Gaussian Plume model to predict dispersion of a direct leak into the atmosphere and used the results to examine the requirements for designing a perfluorocarbon (PFT) monitoring network and tracer tagging strategy. Careful consideration must be given to the climate implications of using these compounds. The quantity of PFTs needed for tagging sequestered CO(2) is too large to be practical for routine monitoring. Tagging at a level that will result in 1.5 times background at a sampler 1 km from a leak of 0.01% per year will require 625 kg per year of PFT. This is a leak rate 10 times greater than the 1000 year DOE requirement and will require 19 tons of injected PFT over the 30 year lifetime of a 1000 mega watt coal fired plant. The utility of PFTs or any other tracer will be lost if the background levels are allowed to rise indiscriminately. A better use of PFTs is as a tool in sequestration research. Instead, geological surveys of sequestration sites will be necessary to locate potential direct pathways and develop targeted monitoring strategies. A global agreement on the use of tracers for monitoring CCS projects should be developed. PMID- 22243213 TI - Polymer single crystal-decorated superhydrophobic buckypaper with controlled wetting and conductivity. AB - Herein we report fabrication of uniform, free-standing nanohybrid buckypaper with high carbon nanotube (CNT) contents (13-70%) using polymer single crystal decorated CNTs as the precursor. Polyethylene single crystals were periodically grown on CNT surfaces, forming a nanohybrid shish kebab (NHSK) structure. Vacuum filtering a NHSK suspension led to polymer single crystal-decorated buckypaper (named as NHSK paper) with a wide range of CNT contents and uniform CNT dispersion. Porosity, surface roughness, and conductivity of NHSK paper can be controlled by tuning the polymer single crystal size. Because of the hierarchical roughness created by intra- and inter-NHSK nanostructure, NHSK paper with controlled kebab size exhibits both superhydrophobicity and high surface water adhesion, which mimics the rose petal effect. We anticipate that this unique NHSK paper can find applications in sensors, electrochemical devices, and coatings. PMID- 22243214 TI - The era of centenarians: mortality of the oldest old in Sweden. PMID- 22243215 TI - Prolactin measurement during inferior petrosal sinus sampling improves the localization of pituitary adenomas in Cushing's disease. AB - OBJECTIVE: Inferior petrosal sinus sampling (IPSS) distinguishes pituitary dependent Cushing's disease (CD) from ectopic ACTH syndrome with a high degree of certainty, but has not been reliable in predicting the location of an adenoma within the pituitary gland. We investigated whether prolactin measurements during IPSS would improve pituitary tumour localization. METHODS: Fifty-four patients with suspected ACTH-dependent Cushing's syndrome who underwent IPSS between 1997 and 2009 were studied retrospectively. Twenty-eight patients who had an identifiable tumour that stained for ACTH on histopathology are the subject of this study. Intersinus ACTH gradients before and after adjustment for prolactin were compared with surgical findings and pathology. RESULTS: Magnetic resonance imaging localized a pituitary adenoma in 17/28 (61%) patients. Using a maximum intersinus ACTH gradient of >=1.4 before or after CRH stimulation, we could diagnose the tumour location correctly in 15/28 (54%) patients. By comparison, tumour lateralization by means of a dominant (>=1.4) prolactin-adjusted ACTH intersinus gradient was correct in 21/28 (75%) patients (P = 0.041). Tumour localization was correct in 23/28 (82%) patients when MRI and prolactin-adjusted ratio data were combined. Fourteen patients with proper bilateral IPS venous sampling (as determined by concurrent IPS to peripheral prolactin ratio >=1.8) either had correct localization of the tumour (n = 12) or had a central lesion (n = 2). In none of these 14 patients was the dominant prolactin-adjusted ACTH ratio associated with a tumour on the opposite side of the gland. CONCLUSION: Prolactin measurement, during IPSS, improves our ability to correctly localize the pituitary adenoma site in CD. PMID- 22243216 TI - Lanthanide(III) complexes with ligands derived from a cyclen framework containing pyridinecarboxylate pendants. The effect of steric hindrance on the hydration number. AB - Two new macrocyclic ligands, 6,6'-((1,4,7,10-tetraazacyclododecane-1,7 diyl)bis(methylene))dipicolinic acid (H2DODPA) and 6,6'-((4,10-dimethyl-1,4,7,10 tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb(DODPA)](PF6).H2O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (q) obtained from luminescence lifetime measurements in aqueous solution of the Eu(III) and Tb(III) complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H2Me-DODPA are q = 0. The structure of the complexes in solution has been investigated by 1H and 13C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb(III) complex [Lambda(lambdalambdalambdalambda)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb(III)-induced paramagnetic 1H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd(Me-DODPA)]+ are typical of a complex with q = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd(DODPA)]+ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature 17O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd(DODPA)]+. The results show that this system is endowed with a relatively fast water exchange rate k(ex)(298) = 58 * 10(6) s(-1). PMID- 22243219 TI - Fluoride incorporation into apatite crystals delays amelogenin hydrolysis. AB - Enamel fluorosis has been related to an increase in the amount of amelogenin in fluorosed enamel compared with normal enamel in the maturation stage. In this study we tested the hypothesis that fluoride incorporated into carbonated apatite alters amelogenin hydrolysis. Recombinant human amelogenin (rh174) was allowed to bind to 0.15 mg of carbonated hydroxyapatite (CAP) or to fluoride-containing carbonated hydroxyapatite (F-CAP) synthesized to contain 100, 1,000, or 4,000 ppm F(-). After 3 h of digestion with recombinant human matrix metalloproteinase 20 (MMP20) or kallikrein-related peptidase 4 (KLK4), bound protein was characterized by reverse-phase high-performance liquid chromatography (HPLC). Proteolytic fragments of amelogenin formed after 24h of digestion with MMP20 of KLK 4 were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The hydrolysis, by both MMP20 and KLK4, of amelogenin bound to F100-CAP was significantly reduced in a dose-dependent manner compared with the hydrolysis of amelogenin bound to CAP. After 24 h of hydrolysis, a similar number of MMP20 cleavage sites was found for amelogenin bound to CAP and amelogenin bound to F100 CAP; however, 24 fewer KLK4 cleavage sites were identified for amelogenin bound to F100-CAP than for amelogenin bound to CAP. These results suggest that the reduced hydrolysis of amelogenins in fluorosed enamel may be partially caused by the increased fluoride content in fluoride-containing apatite, contributing to the hypomineralized enamel matrix phenotype observed in fluorosed enamel. PMID- 22243218 TI - Enhanced sensitivity for high spatial resolution lipid analysis by negative ion mode matrix assisted laser desorption ionization imaging mass spectrometry. AB - We have achieved enhanced lipid imaging to a ~10 MUm spatial resolution using negative ion mode matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry, sublimation of 2,5-dihydroxybenzoic acid as the MALDI matrix, and a sample preparation protocol that uses aqueous washes. We report on the effect of treating tissue sections by washing with volatile buffers at different pHs prior to negative ion mode lipid imaging. The results show that washing with ammonium formate, pH 6.4, or ammonium acetate, pH 6.7, significantly increases signal intensity and number of analytes recorded from adult mouse brain tissue sections. Major lipid species measured were glycerophosphoinositols, glycerophosphates, glycerolphosphoglycerols, glycerophosphoethanolamines, glycerophospho-serines, sulfatides, and gangliosides. Ion images from adult mouse brain sections that compare washed and unwashed sections are presented and show up to 5-fold increases in ion intensity for washed tissue. The sample preparation protocol has been found to be applicable across numerous organ types and significantly expands the number of lipid species detectable by imaging mass spectrometry at high spatial resolution. PMID- 22243220 TI - Fine mapping of dental fluorosis quantitative trait loci in mice. AB - Genetic factors underlie the susceptibility and the resistance to dental fluorosis (DF). The A/J (DF susceptible) and 129P3/J (DF resistant) mouse strains have previously been used to detect quantitative trait loci (QTLs) associated with DF on chromosome (Chr) 2 and Chr 11. In the present study, increased marker density genotyping followed by interval mapping was performed to narrow the QTL intervals and improve the logarithm of the odds (to the base 10) (LOD) scores. Narrower intervals were obtained on Chr 2 where LOD >= 6.0 (57-84 cM or ~ 51 Mb), LOD >= 7.0 (62-79 cM or ~ 32 Mb), and LOD >= 8.0 (65-74 cM or ~ 17 Mb); and on Chr 11 where LOD >= 6.0 (18-51 cM or ~ 53 Mb), LOD >= 7.0 (28-48 cM or ~ 34 Mb), and LOD >= 8.0 (31-45 cM or ~ 22 Mb). Haplotype analysis between A/J and 129P3/J mice further reduced the QTL intervals. Accn1 was selected as a candidate gene based upon its location near the peak LOD score on Chr 11 and distant homology with the Caenorhabditis elegans fluoride-resistance gene, flr1. The severity of DF between Accn1(-/-) and wild-type mice was not significantly different. Hence, the loss of ACCN1 function does not modify DF severity in mice. Narrowing the DF QTL intervals will facilitate additional candidate gene selections and interrogation. PMID- 22243221 TI - An in vitro scanning microradiography study of the reduction in hydroxyapatite demineralization rate by statherin-like peptides as a function of increasing N terminal length. AB - Enamel demineralization is slowed by salivary proteins that inhibit calcium hydroxyapatite (HA) demineralization. Statherin (StN43), a 43-residue phosphorylated salivary protein with primary sequence similarities to osteopontin and caseins, binds calcium and HA. The aim of this study was to identify the minimum length of the functional domain of the statherin molecule required for cariostatic function by measuring the efficacy of peptides of progressively shorter length (i.e. containing only the N-terminal 21 (StN21), 15 (StN15), 10 (StN10), or 5 (StN5) residues) to reduce HA demineralization rates (RD(HA) ). Porous HA blocks were used as enamel analogues, and were exposed to 0.1 M acetic acid at pH 4 for 120 h, rinsed, and treated with StN21, StN15, StN10, or StN5 peptides (1.88 * 10(-5) M) for 24 h, then demineralized for a further 120 h. The RD(HA) was measured, before and after peptide treatment, using scanning microradiography. Hydroxyapatite blocks treated with StN21 and StN15 demonstrated a 50-60% reduction in the RD(HA) . However, no reduction in the RD(HA) was observed following treatment with either StN10, StN5, or buffer only. The mechanism by which statherin-like peptides reduce RD(HA) may be associated with their binding to HA surfaces. Comparisons with previously published binding energies of statherin to HA also suggest that statherin-like peptides containing 15 N-terminal residues or more, are required for binding, suggesting a link between binding and demineralization reduction. PMID- 22243222 TI - Distribution of enamel crystallite orientation through an entire tooth crown studied using synchrotron X-ray diffraction. AB - The biomineralization of human dental enamel has resulted in a highly anisotropic and heterogeneous distribution of hydroxyapatite crystallites, which in combination with its high mineral content has resulted in one of the most durable and hardest tissues in the human body. In this study, we used position-sensitive synchrotron X-ray diffraction to quantify the spatial variation in the direction and magnitude of the preferred orientation of enamel crystallites across a whole tooth crown. Two-dimensional synchrotron X-ray diffraction images were collected with 300 MUm spatial resolution over a series of six sequential tooth sections obtained from a single maxillary first premolar and were analyzed using Rietveld refinement. Both the magnitude and the direction of the crystallite orientation were found to have a high spatial heterogeneity. Areas of high crystallite alignment were directed perpendicular to the biting surfaces, which is thought to meet the functional requirements of mastication. The results may assist in our understanding of the structure-function relationship and of the evolutionary development of enamel. PMID- 22243223 TI - Fluoride and caries. PMID- 22243224 TI - Molecular and circadian controls of ameloblasts. AB - Stage-specific expression of ameloblast-specific genes is controlled by differential expression of transcription factors. In addition, ameloblasts follow daily rhythms in their main activities (i.e. enamel protein secretion and enamel mineralization). This time-related control is orchestrated by oscillations of clock proteins involved in the regulation of circadian rhythms. Our aim was to identify the potential links between daily rhythms and developmental controls of ameloblast differentiation. The effects of the transcription factors distal-less homeobox 3 (Dlx3) and runt-related transcription factor 2 (Runx2), and the clock gene nuclear receptor subfamily 1, group D, member 1 (Nr1d1), on secretory and maturation ameloblasts [using stage-specific markers amelogenin (Amelx), enamelin (Enam), and kallikrein-related peptidase 4 (Klk4)] were evaluated in the HAT-7 ameloblast cell line. Amelx and Enam steady-state mRNA expression levels were down-regulated in Runx2 over-expressing cells and up-regulated in Dlx3 over expressing cells. In contrast, Klk4 mRNA was up-regulated by both Dlx3 and Runx2. Furthermore, a temporal and spatial relationship between clock genes and ameloblast differentiation markers was detected. Of interest, clock genes not only affected rhythmic expression of ameloblast-specific genes but also influenced the expression of Runx2. Multiscale mathematical modeling is being explored to further understand the temporal and developmental controls of ameloblast differentiation. Our study provides novel insights into the regulatory mechanisms sustaining ameloblast differentiation. PMID- 22243225 TI - Wnt-RhoA signaling is involved in dental enamel development. AB - Transgenic mice that express dominant-negative RhoA (RhoA(DN) ) in ameloblasts have hypoplastic enamel with defects in molar cusps. beta-catenin and Wnt5a were up-regulated in enamel organs of RhoA(DN) transgenic mice, which indicated that both canonical and non-canonical Wnt pathways are implicated in the process of enamel defect formation. It was hypothesized that expression of RhoA(DN) in ameloblasts interfered with normal enamel development through the pathways that were induced by fluoride. The Wnt and RhoA pathways were further investigated in an ameloblast-lineage cell line (ALC) by treatment with sodium fluoride (NaF). The activities of RhoA and Rho-associated protein kinase (ROCK) II decreased significantly by 8-12 hours, similar to decreased activity in RhoA(DN) transgenic mice. Both canonical and non-canonical Wnt pathways were activated by treatment with NaF, which was verified by western blotting and the beta-catenin-TCF/LEF (T cell factor lymphanoid/enhancer factor) reporter gene (TOPflash) assay. beta catenin localization to both cytoplasm and nucleus was up-regulated in NaF treated ALC, while Gsk-3beta, the negative regulator of the Wnt pathway, showed a decreased pattern of expression. The current results indicate that both Wnt and RhoA pathways are implicated in fluoride-induced signaling transductions in the ALC as well as in the development of enamel defects in RhoA(DN) transgenic mice. PMID- 22243226 TI - Tuft protein: protein cross-linking in enamel development. AB - Tuft protein is a material associated with enamel tufts, and resides in dental enamel primarily at the enamel-dentine junction. It is located primarily at prism peripheries and extends in a very attenuated form towards the enamel outer surface. While it appears to be a mixture of components, partial sequencing and antibody studies have demonstrated the presence of amelin, a protein associated with prism boundaries. Biochemical investigations have been seriously hampered by the fact that tuft protein is extremely insoluble in a range of solvents, including mineral acids, EDTA, chaotropic agents, and detergents including SDS. This raised the question as to whether it could be chemically cross-linked. Antibodies to gamma-glutamyl cross-linking peptide were used to determine the presence of a cross-linking isopeptide. In all cases examined, a positive response indicated that tuft protein does display chemical cross-linking, which may explain the insoluble nature of this material. This may be a mechanism to prevent protein degradation at the enamel-dentine junction during the degradation of enamel matrix, which occurs during amelogenesis. PMID- 22243227 TI - Biphasic influence of hypoxia on tuftelin expression in mouse mesenchymal C3H10T1/2 stem cells. AB - Tuftelin, an acidic protein, thought to play a role in the initial stages of ectodermal enamel mineralization, has since been detected in mesenchymal-derived tissues. During bone/cartilage development and regeneration, mesenchymal stem cells (MSCs) undergo an avascular period in a hypoxic environment, involving induction of hypoxia-inducible factor 1-alpha (HIF-1-alpha), a key component in this process. In the present study we investigated, in a mouse mesenchymal C3H10T1/2 stem cell model, the hypothesis that oxygen stress modulates tuftelin 1 expression in relation to HIF-1-alpha (Hif1a), in a mouse mesenchymal C3H10T1/2 stem cell model. The results of the present study showed a biphasic induction of tuftelin, similar to the pattern of HIF-1-alpha expression, in MSCs subjected to a hypoxic insult of 1% O(2) through a period of 2-24 h. Immunocytochemistry analysis of the cells exposed to hypoxic insult for 2-24 h revealed the same biphasic pattern of tuftelin protein expression. Tuftelin localization appears to be mainly in the cytoplasm, and concentrated at the perinuclear region of the cells by 24 h of hypoxic insult. Based on our previous studies using the neuronal PC12 cell model, in which tuftelin induction was mediated by Hif1a, we propose that tuftelin is a member of oxygen-sensitive genes and implicated in the adaptive mechanisms regulating MSC function. PMID- 22243228 TI - Cells, signaling, and enamel development. PMID- 22243229 TI - The role of amelogenin during enamel-crystallite growth and organization in vivo. AB - Amelogenin is critical for enamel formation, and human amelogenin gene (AMELX) mutations cause hypoplastic and/or hypomaturation enamel phenotypes. The Amelx null (AKO) mouse has a severe hypoplastic phenotype. This study evaluated the effect of amelogenin loss on enamel formation and crystallite morphology. Enamel from AKO and wild-type (WT) mice was used. The AKO mice were mated with transgenic mice expressing the most abundant known amelogenin isoform, TgM180-87, to rescue (KOM180-87) the enamel crystallite phenotype. Molar enamel was embedded, sectioned with a diamond microtome, and images were obtained by transmission electron microscopy. The crystallite sizes from multiple sections were measured using Image J. The mean thicknesses (WT = 26 nm, AKO = 16 nm, and KOM180-87 = 25 nm) and the mean widths (WT = 96 nm, AKO = 59 nm, KOM180-87 = 85 nm) of crystallites were measured. Despite a complete loss of amelogenin in AKO mice, a mineralized enamel layer with well-defined and organized crystallites is formed. In the absence of amelogenin, enamel crystallites were reduced in thickness and width. For the first time we show that introduction of the m180 amelogenin isoform into the AKO mouse through cross-breeding rescues the crystallite phenotype. We conclude that amelogenin is essential for the development of normal crystallite size. PMID- 22243230 TI - Rescue of the murine amelogenin null phenotype with two amelogenin transgenes. AB - The amelogenin proteins are required for normal enamel development, and the most abundant amelogenins expressed from alternatively spliced mRNAs are M180 and leucine-rich amelogenin protein (LRAP). The X-Chromosomal Amelogenin (Amelx) null [knockout (KO)] mouse has an enamel defect similar to human X-linked amelogenesis imperfecta. The disorganized enamel layer in KO mice is 10-20% of the thickness of wild-type (WT) enamel and lacks prismatic structures. When the KO mice were mated with mice that express the transgene M180-87, (TgM180-87) partial rescue of the phenotype was observed such that enamel thickness, volume, and density increased. A second transgene was introduced by mating TgM180 KO mice with TgLRAP mice, and male offspring were characterized for genotype and tooth phenotype was evaluated by scanning electron microscopy. The molar enamel thickness of TgM180 LRAP KO mice was further increased, and the structure was improved, with a more defined decussation pattern compared with singly rescued mice. We conclude that TgM180 provides significant rescue of the KO phenotype. Although the effectiveness of the LRAP transgene, alone, to rescue is less obvious, the addition of the LRAP transgene to the M180 transgene in KO enamel leads to an added improvement in both amount and structure and thus these transgenes function in a complementary manner. Together, the two most abundant amelogenins lead to the formation of obvious enamel decussation patterns. PMID- 22243231 TI - Self-assembly of amelogenin proteins at the water-oil interface. AB - Self-assembly of amelogenin plays a key role in controlling enamel biomineralization. Recently, we generated self-aligning nanoribbons of amelogenin in water-in-oil emulsions stabilized by the full-length protein (rH174). Here, we tested the hypothesis that the hydrophilic C-terminus is critical for self assembly of amelogenin into nanoribbons. The self-assembled structures of two amelogenin cleavage products, rH163 and rH146, were compared with structures of rH174 at different pH values and degrees of saturation using atomic force microscopy, electron microscopy, and dynamic light scattering. We observed that the number density of rH174 nanoribbons increased significantly when the initial pH was raised from 4.5 to 5.6. Nanoribbons, as well as unique helical nanostructures, were also readily observed when amelogenin rH146 was used, but showed little tendency for parallel alignment and did not bundle into fibrils like rH174. In contrast, rH163 rarely formed nanoribbons but predominantly assembled into nanospheres under the same conditions. We conclude that the presence of a hydrophilic C-terminus may not be a prerequisite for nanoribbon formation but may be critical for ribbon alignment and subsequent fibril formation. These results highlight the contribution of the hydrophobic domain in the self-assembly of elongated structures of amelogenins. Molecular mechanisms governing these processes based on the formation of reverse micelles are discussed. PMID- 22243232 TI - Recovery and identification of mature enamel proteins in ancient teeth. AB - Proteins in mineralized tissues provide a window to the past, and dental enamel is peculiar in being highly resistant to diagenesis and providing information on a very narrow window of time, such as the developing period; however, to date, complete proteins have not been extracted successfully from ancient teeth. In this work we tested the ability of a whole-crown micro-etch technique to obtain enamel protein samples from mature enamel of recently extracted (n = 2) and ancient (n = 2; ad 800 to 1100) third molars. Samples were analyzed using matrix assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI TOF/TOF) mass spectrometry, and the resulting spectra were searched against the Swiss-Prot protein database using the Mascot software for protein identification. In our protocol, the separation of proteins in gel is not necessary. Successful identification of specific enamel proteins was obtained after whole-crown superficial enamel etching with 10% HCl. Most protein fragments recovered from dry teeth and mummy teeth contained amino-terminal amelogenin peptides. Only one peptide specific for the amelogenin X-isoform was identified. In conclusion, the reported techniques allowed the successful recovery of proteins specific to dental enamel from samples obtained in a very conservative manner, which may also be important in forensic and/or archeological science. PMID- 22243233 TI - Amelogenin. PMID- 22243234 TI - Effect of phosphorylation on the interaction of calcium with leucine-rich amelogenin peptide. AB - Amelogenin undergoes self-assembly and plays an essential role in guiding enamel mineral formation. The leucine-rich amelogenin peptide (LRAP) is an alternative splice product of the amelogenin gene and is composed of the N terminus (containing the only phosphate group) and the C terminus of full-length amelogenin. This study was conducted to investigate further the role of phosphorylation in LRAP self-assembly in the presence and absence of calcium using small angle X-ray scattering (SAXS). Consistent with our previous dynamic light-scattering findings for phosphorylated (+P) and non-phosphorylated (-P) LRAP, SAXS analyses revealed radii of gyration (R(g)) for LRAP(-P) (46.3-48.0 A) that were larger than those for LRAP(+P) (25.0-27.4 A) at pH 7.4. However, added calcium (up to 2.5 mM) induced significant increases in the R(g) of LRAP(+P) (up to 46.4 A), while it had relatively little effect on LRAP(-P) particle size. Furthermore, SAXS analyses suggested compact folded structures for LRAP(-P) in the presence and absence of calcium, whereas the conformation of LRAP(+P) changed from an unfolded structure to a more compact structure upon the addition of calcium. We conclude that the single phosphate group in LRAP(+P) induces functionally important conformational changes, suggesting that phosphorylation may also influence amelogenin conformation and protein-mineral interactions during the early stages of amelogenesis. PMID- 22243235 TI - Regulation of calcium phosphate formation by amelogenins under physiological conditions. AB - Amelogenin is essential for proper enamel formation. The present in vitro study extends our previous work at low (10 mM) ionic strength (IS) by examining the effect of amelogenin on mineralization under higher (162 mM) IS conditions found in developing enamel. Full-length phosphorylated (P173) and non-phosphorylated (rP172) amelogenins were examined, along with P148 and rP147 that lack the hydrophilic C-terminus. Calcium phosphate formation was assessed by pH change, while the minerals formed were characterized using transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy. Amelogenin self assembly was also studied using dynamic light scattering and TEM. The results indicate that IS does not influence the effects of rP147, rP172, and P173 on mineralization. However, in contrast to the findings for low IS, where both P173 and P148 stabilize initially formed amorphous calcium phosphate (ACP) nanoparticles for >1 d, elongated hydroxyapatite crystals were observed after 24 h using P148 at high IS, unlike that seen with P173. Differences in self-assembly help explain these findings, which suggest that P173 and P148 may play different roles in regulating enamel mineral formation. The present data support the notion that proteolytic processing of P173 is required in vivo to induce the transformation of initial ACP phases to apatitic enamel crystals. PMID- 22243236 TI - Exclusion of all three calbindins from a calcium-ferry role in rat enamel cells. AB - It is widely accepted that healthy enamel formation depends on a steady supply of calcium, yet only fragmentary understanding exists about the mechanisms underlying transepithelial calcium transport. Several lines of evidence indicate that calcium principally follows a transcellular route, which classically is thought to be facilitated by cytosolic calcium-binding proteins termed calbindins. In enamel cells, however, this 'calcium-ferry' dogma appears to fail as we previously found that the major calbindin in murine enamel cells (calbindin 28 kDa) was down-regulated during the peak period of calcium transport and enamel was formed normally in mice lacking calbindin-28 kDa. It remains to be clarified whether the two other known calbindins could function as calcium ferries instead. This study used biochemical and proteomic approaches to obtain definitive identification and quantification of the 30-kDa calbindin (calretinin) and calbindin-9 kDa (S100-G) in enamel epithelium from rat. By establishing that both of these calbindins contribute insufficient calcium capacities in molars and incisors, our results render the calcium-ferry dogma untenable. Of significance to enamel defects and dental bioengineering, these findings support other evidence for an alternative organelle-based mode of calcium transport (calcium transcytosis) and also implicate S100-G/calbindin-9 kDa, but not calretinin, in a calcium-signaling role during enamel maturation. PMID- 22243237 TI - Relationships between dentin and enamel mineral at the dentino-enamel boundary: electron tomography and high-resolution transmission electron microscopy study. AB - To better understand the nature of the relationships between mineral phases at the dentino-enamel boundary (DEB), we performed electron tomography (ET) and high resolution transmission electron microscopy (HR-TEM) of the apical portions of rat incisors. The ET studies of the DEB at the secretory stage of amelogenesis revealed that nascent enamel crystals are co-aligned and closely associated with dentin crystallites in the mineralized von Korff fibers, with the distances between dentin and enamel crystals in the nanometer range. We have further studied the relationships between dentin and enamel crystals using HR-TEM lattice imaging of the DEB. Among dozens of high-resolution micrographs taken from the DEB we were able to identify only one case of lattice continuity between dentin and enamel crystals, indicating direct epitaxy. In other cases, although there was no direct continuity between the crystalline lattices, power spectra analysis of lattice images revealed a very high level of co-alignment between dentin and enamel crystals. Hence, we propose here that the high degree of alignment and integration between dentin and enamel mineral can be established either by epitaxy or without direct interactions between crystalline lattices, probably via regulation of mineral formation and organization by integrated organic matrices of dentin and enamel at the DEB. PMID- 22243238 TI - Relationships between protein and mineral during enamel development in normal and genetically altered mice. AB - The purpose of this study was to quantify and compare the amounts of volatiles (mostly protein) and mineral present in developing incisor enamel in normal mice and in those genetically engineered for absence of intact enamelin, ameloblastin, matrix metalloproteinase 20 (MMP20) or kallikrein-related peptidase 4 (KLK4). Data indicated that all mice showed peaks in the gross weight of volatiles and a similar weight of mineral at locations on incisors normally associated with early maturation. Thereafter, the content of volatiles on normal incisors declined rapidly by as much as 62%, but not by 100%, over 2 mm, accompanied by increases of ~ threefold in mineral weights. Enamelin heterozygous mice (lower incisors) showed a decrease in volatile content across the maturation stage, yet mineral failed to increase significantly. Mmp20 null mice showed no significant loss of volatiles from maturing enamel, yet the amount of mineral increased. Klk4 null mice showed normal mineral acquisition up to early maturation, but the input of new volatiles in mid to late maturation caused the final mineralization to slow below normal levels. These results suggest that it is not only the amount of protein but also the nature or type of protein or fragments present in the local crystallite environment that affects their volumetric expansion as they mature. PMID- 22243239 TI - Identification of a pH-responsive DNA region upstream of the transcription start site of human NBCe1-B. AB - In rodent incisors two distinct stages of enamel formation can be identified visually based on cell morphology: the secretory stage and the maturation stage. The expression profiles of many genes characterize both stages, including the bicarbonate transport protein NBCe1. Bicarbonate is a requirement for the mineralizing enamel matrix to buffer excessive protons that form as a consequence of hydroxyapatite formation. NBCe1-B mRNA is up-regulated during the maturation stage of amelogenesis, where hydroxyapatite formation predominates. In this study, a presumed 572-bp NBCe1-B promoter region was subcloned into a reporter construct, and within this 572-bp region of DNA we characterized a 285-bp segment that shows an increase of ~ 2.3-fold in gene-transcription activity when transfected into ameloblast-like cells and cultured in medium maintained at pH 6.8 (vs. pH 7.4). A presumed pH-responsive transcriptional factor-binding domain(s) thus resides in the 285-bp NBCe1-B promoter region where candidate domains include the nuclear factor of kappa light polypeptide gene enhancer in B cells1(NFKB1), jun proto-oncogene (JUN), and tumor protein p53(TP53)-binding sites. Mutagenesis studies identify that both the NFKB1- and TP53-binding sites are responsive to changes in the extracellular pH. These data help to explain how ameloblasts respond to the altered extracellular milieu of protons by changing their gene-expression profile throughout the stages of amelogenesis. PMID- 22243240 TI - Mineralization. PMID- 22243241 TI - Gene-expression analysis of early- and late-maturation-stage rat enamel organ. AB - Enamel maturation is a dynamic process that involves high rates of mineral acquisition, associated fluctuations in extracellular pH, and resorption of extracellular enamel proteins. During maturation, ameloblasts change from having a tall, thin, and highly polarized organization, characteristic of the secretory stage, to having a low columnar and widened morphology in the maturation stage. To identify potential differences in gene expression throughout maturation, we obtained enamel organ epithelial cells derived from the early- and late maturation stages of rat incisor and analyzed the global gene-expression profiles at each stage. Sixty-three candidate genes were identified as having potential roles in the maturation process. Quantitative PCR was used to confirm the results of this genome-wide analysis in a subset of genes. Transcripts enriched during late maturation (n = 38) included those associated with lysosomal activity, solute carrier transport, and calcium signaling. Also up-regulated were transcripts involved in cellular responses to oxidative stress, proton transport, cell death, and the immune system. Transcripts down-regulated during the late maturation stage (n =25) included those with functions related to cell adhesion, cell signaling, and T-cell activation. These results indicate that ameloblasts undergo widespread molecular changes during the maturation stage of amelogenesis and hence provide a basis for future functional investigations into the mechanistic basis of enamel mineralization. PMID- 22243242 TI - Enamel malformations associated with a defined dentin sialophosphoprotein mutation in two families. AB - Dentin sialophosphoprotein (DSPP) mutations cause dentin dysplasia type II (DD II) and dentinogenesis imperfecta types II and III (DGI-II and DGI-III, respectively). We identified two kindreds with DGI-II who exhibited vertical bands of hypoplastic enamel. Both families had a previously reported DSPP mutation that segregated with the disease phenotype. Oral photographs and dental radiographs of four affected and one unaffected participant in one family and of the proband in the second family were used to document the dental phenotypes. We aligned the 33 unique allelic DSPP sequences showing variable patterns of insertions and deletions (indels), generated a merged dentin phosphoprotein (DPP) sequence that includes sequences from all DSPP length haplotypes, and mapped the known DSPP mutations in this context. Analyses of the DSPP sequence changes and their probable effects on protein expression, as well as published findings of the dental phenotype in Dspp null mice, support the hypothesis that all DSPP mutations cause pathology through dominant-negative effects. Noting that Dspp is transiently expressed by mouse pre-ameloblasts during formation of the dentino enamel junction, we hypothesize that DSPP dominant-negative effects potentially cause cellular pathology in pre-ameloblasts that, in turn, causes enamel defects. We conclude that enamel defects can be part of the dental phenotype caused by DSPP mutations, although DSPP is not critical for dental enamel formation. PMID- 22243243 TI - Epithelial-specific knockout of the Rac1 gene leads to enamel defects. AB - The Ras-related C3 botulinum toxin substrate 1 (Rac1) gene encodes a 21-kDa GTP binding protein belonging to the RAS superfamily. RAS members play important roles in controlling focal adhesion complex formation and cytoskeleton contraction, activities with consequences for cell growth, adhesion, migration, and differentiation. To examine the role(s) played by RAC1 protein in cell-matrix interactions and enamel matrix biomineralization, we used the Cre/loxP binary recombination system to characterize the expression of enamel matrix proteins and enamel formation in Rac1 knockout mice (Rac1(-/-)). Mating between mice bearing the floxed Rac1 allele and mice bearing a cytokeratin 14-Cre transgene generated mice in which Rac1 was absent from epithelial organs. Enamel of the Rac1 conditional knockout mouse was characterized by light microscopy, backscattered electron imaging in the scanning electron microscope, microcomputed tomography, and histochemistry. Enamel matrix protein expression was analyzed by western blotting. Major findings showed that the Tomes' processes of Rac1(-/-) ameloblasts lose contact with the forming enamel matrix in unerupted teeth, the amounts of amelogenin and ameloblastin are reduced in Rac1(-/-) ameloblasts, and after eruption, the enamel from Rac1(-/-) mice displays severe structural defects with a complete loss of enamel. These results support an essential role for RAC1 in the dental epithelium involving cell-matrix interactions and matrix biomineralization. PMID- 22243244 TI - Enamel alterations in serotonin 2B receptor knockout mice. AB - The role of the serotonin 2B receptor (5-HT(2B) R) in enamel formation and mineralization was explored in adult 5HT(2B) R knockout (KO) mice compared with wild-type (WT) mice. In the molar, quantitative data obtained by micro-computed tomography imaging showed that the overall volume of the enamel layer was firmly reduced in KO mice. Defective mineralization was ascertained by energy-dispersive X-ray microanalysis. We also observed, using scanning electron microscopy, that parazones in the KO mice included two or three helicoidally twisted rods within Hunter-Schreger bands, instead of a single rod, as found in the WT mice. Minor disturbances were also detected in the incisors of KO mice. Structural modifications, thinner enamel crystallites, and porosities observed in KO mice indicate that the 5-HT(2B) R-mediated signaling pathways as part of the enamel formation process. These data provide a basis for evaluating the role of 5-HT(2B) R in ameloblast functions. Defects observed in the mineralization and structure of enamel in KO mice highlight that the 5-HT(2B) R interferes with the mechanisms directing amelogenesis. PMID- 22243245 TI - Developmental expression of solute carrier family 26A member 4 (SLC26A4/pendrin) during amelogenesis in developing rodent teeth. AB - Ameloblasts need to regulate pH during the formation of enamel crystals, a process that generates protons. Solute carrier family 26A member 4 (SLC26A4, or pendrin) is an anion exchanger for chloride, bicarbonate, iodine, and formate. It is expressed in apical membranes of ion-transporting epithelia in kidney, inner ear, and thyroid where it regulates luminal pH and fluid transport. We hypothesized that maturation ameloblasts express SLC26A4 to neutralize acidification of enamel fluid in forming enamel. In rodents, secretory and maturation ameloblasts were immunopositive for SLC26A4. Staining was particularly strong in apical membranes of maturation ameloblasts facing forming enamel. RT PCR confirmed the presence of mRNA transcripts for Slc26a4 in enamel organs. SLC26A4 immunostaining was also found in mineralizing connective tissues, including odontoblasts, osteoblasts, osteocytes, osteoclasts, bone lining cells, cellular cementoblasts, and cementocytes. However, Slc26a4-null mutant mice had no overt dental phenotype. The presence of SLC26A4 in apical plasma membranes of maturation ameloblasts is consistent with a potential function as a pH regulator. SLC26A4 does not appear to be critical for ameloblast function and is probably compensated by other pH regulators. PMID- 22243246 TI - Genes and development. PMID- 22243247 TI - Matrix metalloproteinase 20 promotes a smooth enamel surface, a strong dentino enamel junction, and a decussating enamel rod pattern. AB - Mutations of the matrix metalloproteinase 20 (MMP20, enamelysin) gene cause autosomal-recessive amelogenesis imperfecta, and Mmp20 ablated mice also have malformed dental enamel. Here we showed that Mmp20 null mouse secretory-stage ameloblasts maintain a columnar shape and are present as a single layer of cells. However, the maturation-stage ameloblasts from null mouse cover extraneous nodules of ectopic calcified material formed at the enamel surface. Remarkably, nodule formation occurs in null mouse enamel when MMP20 is normally no longer expressed. The malformed enamel in Mmp20 null teeth was loosely attached to the dentin and the entire enamel layer tended to separate from the dentin, indicative of a faulty dentino-enamel junction (DEJ). The enamel rod pattern was also altered in Mmp20 null mice. Each enamel rod is formed by a single ameloblast and is a mineralized record of the migration path of the ameloblast that formed it. The enamel rods in Mmp20 null mice were grossly malformed or absent, indicating that the ameloblasts do not migrate properly when backing away from the DEJ. Thus, MMP20 is required for ameloblast cell movement necessary to form the decussating enamel rod patterns, for the prevention of ectopic mineral formation, and to maintain a functional DEJ. PMID- 22243248 TI - Enamel proteins and proteases in Mmp20 and Klk4 null and double-null mice. AB - Matrix metalloproteinase 20 (MMP20) and kallikrein-related peptidase 4 (KLK4) are thought to be necessary to clear proteins from the enamel matrix of developing teeth. We characterized Mmp20 and Klk4 null mice to better understand their roles in matrix degradation and removal. Histological examination showed retained organic matrix in Mmp20, Klk4, and Mmp20/Klk4 double-null mouse enamel matrix, but not in the wild-type. X-gal histostaining of Mmp20 null mice heterozygous for the Klk4 knockout/lacZ knockin showed that Klk4 is expressed normally in the Mmp20 null background. This finding was corroborated by zymogram and western blotting, which discovered a 40-kDa protease induced in the maturation stage of Mmp20 null mice. Proteins were extracted from secretory-stage or maturation-stage maxillary first molars from wild-type, Mmp20 null, Klk4 null, and Mmp20/Klk4 double-null mice and were analyzed by SDS-PAGE and western blotting. Only intact amelogenins and ameloblastin were observed in secretory-stage enamel of Mmp20 null mice, whereas the secretory-stage matrix from Klk4 null mice was identical to the matrix from wild-type mice. More residual matrix was observed in the double-null mice compared with either of the single-null mice. These results support the importance of MMP20 during the secretory stage and of KLK4 during the maturation stage and show there is only limited functional redundancy for these enzymes. PMID- 22243249 TI - Kallikrein-related peptidase 4, matrix metalloproteinase 20, and the maturation of murine and porcine enamel. AB - The crowns of matrix metalloproteinase 20 (Mmp20) null mice fracture at the dentino-enamel junction (DEJ), whereas the crowns of kallikrein-related peptidase 4 (Klk4) null mice fracture in the deep enamel just above the DEJ. We used backscatter scanning electron microscopy to assess enamel mineralization in incisors from 9-wk-old wild-type, Klk4 null, and Mmp20 null mice, and in developing pig molars. We observed a line of hypermineralization along the DEJ in developing wild-type mouse and pig teeth. This line was discernible from the early secretory stage until the enamel in the maturation stage reached a similar density. The line was apparent in Klk4 null mice, but absent in Mmp20 null mice. Enamel in the Klk4 null mice matured normally at the surface, but was progressively less mineralized with depth. Enamel in the Mmp20 null mice formed as a mineral bilayer, with neither layer looking like true enamel. The most superficial mineral layer expanded during the maturation stage and formed irregular surface nodules. A surprising finding was the observation of electron backscatter from mid-maturation wild-type ameloblasts, which we attributed to the accumulation and release of iron. We conclude that enamel breaks in the deep enamel of Klk4 null mice because of decreasing enamel maturation with depth, and at the DEJ in Mmp20 null mice because of hypomineralization at the DEJ. PMID- 22243250 TI - Expression of kallikrein-related peptidase 4 in dental and non-dental tissues. AB - Kallikrein-related peptidase 4 (KLK4) is critical for proper dental enamel formation. Klk4 null mice, and humans with two defective KLK4 alleles have obvious enamel defects, with no other apparent phenotype. KLK4 mRNA or protein is reported to be present in tissues besides teeth, including prostate, ovary, kidney, liver, and salivary gland. In this study we used the Klk4 knockout/NLS lacZ knockin mouse to assay Klk4 expression using beta-galactosidase histochemistry. Incubations for 5 h were used to detect KLK4 expression with minimal endogenous background, while overnight incubations susceptible to false positives were used to look for trace KLK4 expression. Developing maxillary molars at postnatal days 5, 6, 7, 8, and 14, developing mandibular incisors at postnatal day 14, and selected non-dental tissues from adult wild-type and Klk4(lacZ/lacZ) mice were examined by X-gal histochemistry. After 5 h of incubation, X-gal staining was observed specifically in the nuclei of maturation stage ameloblasts in molars and incisors from Klk4(lacZ/lacZ) mice and was detected weakly in the nuclei of salivary gland ducts and in patches of prostate epithelia. We conclude that KLK4 is predominantly a tooth-specific protease with low expression in submandibular salivary gland and prostate, and with no detectable expression in liver, kidney, testis, ovary, oviduct, epididymis, and vas deferens. PMID- 22243252 TI - Proteinases. PMID- 22243251 TI - Characterization of kallikrein-related peptidase 4 glycosylations. AB - Kallikrein-related peptidase 4 (KLK4) is a glycosylated serine protease that functions in the maturation (hardening) of dental enamel. Pig and mouse KLK4 contain three potential N-glycosylation sites. We isolated KLK4 from developing pig and mouse molars and characterized their N-glycosylations. N-glycans were enzymatically released by digestion with N-glycosidase F and fluorescently labeled with 2-aminobenzoic acid. Normal-phase high-performance liquid chromatography (NP-HPLC) revealed N-glycans with no, or with one, two, or three sialic acid attachments in pig KLK4 and with no, or with one or two sialic acid attachments in mouse KLK4. The labeled N-glycans were digested with sialidase to generate the asialo N-glycan cores that were fractionated by reverse-phase HPLC, and their retention times were compared with similarly labeled glycan standards. The purified cores were characterized by mass spectrometric and monosaccharide composition analyses. We determined that pig and mouse KLK4 have NA2 and NA2F biantennary N-glycan cores. The pig triantennary core is NA3. The mouse triantennary core is NA3 with a fucose connected by an alpha1-6 linkage, indicating that it is attached to the first N-acetyglucosamine (NA3F). We conclude that pig KLK4 has NA2, NA2F, and NA3 N-glycan cores with no, or with one, two, or three sialic acids. Mouse KLK4 has NA2, NA2F, and NA3F N-glycan cores with no, or with one or two sialic acids. PMID- 22243253 TI - Molecular evolution of matrix metalloproteinase 20. AB - Dental enamel is a hypermineralized tissue, containing only trace amounts of organic components. During enamel formation, matrix metalloproteinase 20 (MMP20) processes proteins comprising enamel matrix and facilitates hypermineralization. In the human genome, 24 distinct MMP genes have been identified. Among these genes, MMP20 is clustered with eight other genes, including MMP13, and all these clustered genes show phylogenetically close relationships. In this study, we investigated MMP20 and closely related MMP genes in various tetrapods and in a teleost fish, fugu. In the genome of the chicken, a toothless tetrapod, we identified degraded exons of MMP20, which supports the previous proposition that MMP20 is important specifically for enamel formation. Nevertheless, for unknown reasons, we failed to identify MMP20 in the platypus genome. In the opossum, lizard, and frog genomes, MMP20 was found clustered with MMP13. Furthermore, in the fugu genome, we identified an MMP20-like gene located adjacent to MMP13, suggesting that MMP20 arose before the divergence of ray-finned fish and lobe finned fish. The teleost tooth surface is covered with enameloid, a hypermineralized tissue different from enamel. Thus, we hypothesize that MMP20 could have been used in an ancient hypermineralized tissue, which evolved into enameloid in teleosts and into enamel in tetrapods. PMID- 22243254 TI - Ameloblastin-rich enamel matrix favors short and randomly oriented apatite crystals. AB - Molecular evolution studies suggest that amelogenin (AMELX), the principal component of the mammalian enamel matrix, emerged considerably later than ameloblastin (AMBN), and enamelin. Here, we created a transgenic mouse model to ask the question how a conceivable basal enamel lacking AMELX and enriched in the more basal AMBN might compare with recent mouse enamel. To answer this question we overexpressed AMBN using a keratin 14 (K14) promoter and removed AMELX from the genetic background by crossbreeding with amelx(-/-) mice. Enamel coverings of amelx(-/-) mice and of the squamate Iguana iguana were used for comparison. Scanning electron microscopic analysis documented that AMBN transgenic (TG) * amelx(-/-) mouse molars were covered by a 5 MUm thin 'enameloid' layer resembling the thin enamel of the Iguana squamate. Transmission electron microscopy revealed that the enamel of developing AMBN TG * amelx(-/-) mouse molars contained short (approximately 70 nm) and randomly oriented crystals, while WT controls, AMBN overexpressors, and AMELX(-/-) mice all featured elongated and parallel oriented crystals measuring between 300 and 600 nm in average length. Together, these studies illustrate that AMBN promotes the growth of a crystalline enamel layer with short and randomly oriented crystals, but lacks the ability to facilitate the formation of long and parallel oriented apatite crystals. PMID- 22243255 TI - Biophysical characterization of recombinant human ameloblastin. AB - Ameloblastin (AMBN) is a protein expressed mainly during dental hard tissue development. Biochemically, it is classified as an intrinsically disordered protein (IDP). Its biological role remains largely unknown; however, the question of AMBN function will undoubtedly be connected to its structural properties and its potential for protein-protein and protein-cell interactions. A basic biophysical characterization of human recombinant ameloblastin (hrAMBN) and its N and C-terminal domains by means of circular dichroism spectroscopy and dynamic light scattering showed that under physiological conditions ameloblastin is an IDP with a prevalent polyproline-II (PPII) conformation. Both the N- and C terminal polypeptides, when expressed independently, showed different structural preferences upon heating as well as different behaviour in the presence of trifluoroethanol and CaCl(2) salt. The N-terminal peptide showed a more ordered structure with a strong tendency to adopt a helical conformation upon the addition of trifluorethanol, whereas the C-terminal domain seemed to be primarily responsible for the structural disorder of the entire AMBN molecule. PMID- 22243256 TI - Structure and function of ameloblastin as an extracellular matrix protein: adhesion, calcium binding, and CD63 interaction in human and mouse. AB - The functional significance of extracellular matrix proteins in the life of vertebrates is underscored by a high level of sequence variability in tandem with a substantial degree of conservation in terms of cell-cell and cell-matrix adhesion interactions. Many extracellular matrix proteins feature multiple adhesion domains for successful attachment to substrates, such as integrin, CD63, and heparin. Here we have used homology and ab initio modeling algorithms to compare mouse ameloblastin (mAMBN) and human ameloblastin (hABMN) isoforms and to analyze their potential for cell adhesion and interaction with other matrix molecules as well as calcium binding. Sequence comparison between mAMBN and hAMBN revealed a 26-amino-acid deletion in mAMBN, corresponding to a helix-loop-helix frameshift. The human AMBN domain (174Q-201G), homologous to the mAMBN 157E-178I helix-loop-helix region, formed a helix-loop motif with an extended loop, suggesting a higher degree of flexibility of hAMBN compared with mAMBN, as confirmed by molecular dynamics simulation. Heparin-binding domains, CD63 interaction domains, and calcium-binding sites in both hAMBN and mAMBN support the concept of AMBN as an extracellular matrix protein. The high level of conservation between AMBN functional domains related to adhesion and differentiation was remarkable when compared with only 61% amino acid sequence homology. PMID- 22243257 TI - Ameloblastin regulates cell attachment and proliferation through RhoA and p27. AB - The matrix adhesion protein ameloblastin (AMBN) is one of the unique components of the mineralizing matrix of bones and teeth. Here we focused on two types of cells expressing AMBN - mouse dental follicle cells (mDF) and mouse periodontal ligament cells (mPDL) - to decipher AMBN function in developing dental, periodontal, and bone tissues. To test AMBN function, cell culture dishes of mDF and mPDL were exposed to either full-length or C-terminal (amino acids 137-407) recombinant Ambn protein. Alternatively, cells were subjected to transient transfection using an Ambn-small hairpin (sh) RNA vector. Our cell culture studies documented that dishes coated with full-length AMBN promoted the attachment of mPDL and mDF cells as early as 1 h after seeding. In order to identify potential intermediaries that might aid the effect of AMBN on adhesion, RhoA expression levels in AMBN-coated and uncoated control dishes were assessed. These studies indicated that AMBN induced RhoA expression 4 h after seeding, especially in mPDL cells. After 4 h of culture, the cell cycle inhibitor p27 was also up-regulated. In addition, exogenous AMBN and its C-terminal fragment reduced the proliferation of mDF and mPDL. Finally, transient transfection of mDF and mPDL cells with the Ambn-shRNA vector resulted in the down-regulation of p27 in mPDL cells. Together, these data indicate that AMBN affects cell adhesion via RhoA and cell cycle progression through p27. PMID- 22243259 TI - Evolution and ameloblastin. PMID- 22243258 TI - Ameloblastin upstream region contains structural elements regulating transcriptional activity in a stromal cell line derived from bone marrow. AB - Ameloblastin (AMBN) was originally described as a tooth-specific extracellular matrix protein, but current data have shown that AMBN is present in many different tissues of mesenchymal origin. The identification of regulatory elements in the promoter region of the Ambn gene would assist in identifying potential mesenchymal-specific transcriptional factors. In this study we subcloned a 3,788-bp region upstream (and a 54-bp region downstream) of the mouse Ambn transcriptional start site into a LacZ reporter construct and called this construct 3788-Ambn-lacZ. In silico analysis of the 3,788-bp Ambn promoter region identified 50 potential cis-regulatory elements, 29 of which are known to be functional in cell populations of mesenchymal origin. The reporter construct was activated in transfected bone marrow cells, and the promoter activity was induced in cell cultures following addition of recombinant AMBN, interferon-gamma, serotonin, or dexamethasone. We discuss the relative significance of the potential cis-acting gene-regulatory elements of Ambn in relation to bone morphogenesis. Knowledge of Ambn gene-regulatory elements will be of importance when developing strategies for bone repair and replacement in a clinical surgical setting. PMID- 22243260 TI - Identification of amelotin- and ODAM-interacting enamel matrix proteins using the yeast two-hybrid system. AB - The formation of dental enamel is a prototype of functional tissue development through biomineralization. Amelotin (AMTN) is a recently discovered secreted enamel protein predominantly expressed during the maturation stage of enamel formation. It accumulates in a basal lamina-like structure at the interface between ameloblasts and enamel mineral and it co-localizes with another recently described enamel protein, odontogenic ameloblast-associated protein (ODAM). The purpose of this study was to determine whether AMTN and ODAM bind to each other and/or to other well-established enamel matrix proteins. The coding sequences of all enamel proteins were cloned into appropriate vectors of the GAL4-based Matchmaker Gold Yeast Two-Hybrid System. The growth of yeast cells on selective media and color induction were used as indicators for reporter gene expression through protein-protein interactions in combinations of prey and bait constructs. We found that AMTN interacts with itself and with ODAM, but not with amelogenin (AMEL), ameloblastin (AMBN), or enamelin (ENAM). Using ODAM as bait, the interaction with AMTN was confirmed. Furthermore, ODAM was found to bind to itself and to AMBN, as well as weakly to AMEL but not to ENAM. We propose a model where the distinct expression of AMTN and ODAM and their interaction are involved in defining the enamel microstructure at the enamel surface. PMID- 22243261 TI - Enamel extracellular matrix. PMID- 22243263 TI - A novel mutation in the AMELX gene and multiple crown resorptions. AB - Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders with regard to genetic aetiology and clinical phenotype and affects tooth enamel with no other non-oral syndromic conditions. X-linked AI is caused by mutations in the amelogenin (AMELX) gene, the only AI candidate gene located on the X chromosome. To date, 15 mutations in the AMELX gene have been found to cause AI. We identified a proband with generalized hypoplastic enamel and unusual multiple crown resorption in premolars and molars. Pedigree analysis suggested an X-linked hereditary pattern. We performed mutational analysis for the AMELX gene based on the candidate gene approach. Sequencing analysis revealed a novel mutation in exon 6 (g.4090delC, c.517delC, p.Pro173LeufsX16). This frameshift mutation produces a premature stop codon within exon 6 and is predicted to replace 33 amino acids at the C-terminus with 15 novel amino acids if the mutant mRNA escapes the nonsense-mediated decay system. Although crown resorptions occur frequently in patients with the hypoplastic type of A1, an association with the AMELX mutation has not been previously reported. We believe that these findings will broaden our understanding of the clinical phenotype and pathogenesis of X linked AI. PMID- 22243262 TI - Target gene analyses of 39 amelogenesis imperfecta kindreds. AB - Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred. PMID- 22243265 TI - Amelogenesis imperfecta. PMID- 22243264 TI - Cell proliferation and apoptosis in enamelin null mice. AB - Enamelin is a secreted glycoprotein that is critical for dental enamel formation. Ameloblasts in enamelin (Enam) null mice develop atypical features that include the absence of a Tomes' process, expanded endoplasmic reticulum, apparent loss of polarity, and pooling of extracellular matrix in all directions, including between ameloblasts and the stratum intermedium. We hypothesized that ameloblast pathological changes may be associated with increased cell apoptosis. Our objective was to assess apoptotic activity in maxillary first molars of wild type, Enam(+/-), and Enam(-/-) mice at postnatal days 5, 7, 9, 14, and 17. Mouse maxillae were characterized by light microscopy after terminal deoxynucleotidyl transferase (TdT)-mediated biotin-dUTP nick-end labelling (TUNEL) or 5-bromo-2' deoxyuridine (BrdU) staining. Following the initial deposition of dentin matrix, ameloblasts became highly dysplastic and no enamel crystal ribbons were deposited. Ameloblast apoptosis was observed in the Enam null mice starting in the secretory stage and with no apparent alteration in cell proliferation. We conclude that in the absence of enamelin and subsequent shutdown of enamel formation, ameloblasts undergo pathological changes early in the secretory stage that are evident as radically altered cell morphology, detachment from the tooth surface, apoptosis, and formation of ectopic calcifications both outside and inside the dystrophic enamel organ. PMID- 22243266 TI - Is the 32-kDa fragment the functional enamelin unit in all species? AB - Enamelin is an extracellular enamel matrix protein essential for normal amelogenesis. After secretion, porcine enamelin is processed to generate several enamelin-degradation products. The cumulative 32-kDa enamelin is the most abundant enamelin present, and various roles for this molecule have been suggested. However, the proteolytic cleavage sites in porcine enamelin that generate the 32-kDa enamelin are not conserved across species, and the 32-kDa enamelin analogue may not be present in all species. To explore this we studied rat enamelin biochemistry using western blotting with anti-peptide IgGs to porcine 32-kDa enamelin and to the putative rat 32-kDa enamelin analogue. The dominant enamelins in secretory-stage rat enamel migrated at around 60-70 kDa. In contrast, the dominant enamelins in secretory-stage porcine enamel migrated at around 32 kDa. In contrast, secretory-stage porcine-enamel enamelins were dominated by the 32-kDa enamelin. Rat enamelin was completely removed from maturation-stage enamel without any accumulation of 32-kDa enamelin. We suggest that a discrete 32-kDa enamelin is not essential for normal amelogenesis in all species, and in pig it may be a processing product of a larger functional enamelin molecule. The pig may be an atypical model in terms of enamelin biochemistry and function, and caution should be exercised when assigning functional roles to the 32-kDa enamelin as a discrete enamel matrix entity. PMID- 22243267 TI - Amelogenin-enamelin association in phosphate-buffered saline. AB - The structures and interactions among macromolecules in the enamel extracellular matrix play vital roles in regulating hydroxyapatite crystal nucleation, growth, and maturation. We used dynamic light scattering (DLS), circular dichroism (CD), fluorescence spectroscopy, and transmission electron microscopy (TEM) to investigate the association of amelogenin and the 32-kDa enamelin, at physiological pH 7.4, in phosphate-buffered saline (PBS). The self-assembly behavior of amelogenin (rP148) was altered following addition of the 32-kDa enamelin. Dynamic light scattering revealed a trend for a decrease in aggregate size in the solution following the addition of enamelin to amelogenin. A blue shift and intensity increase of the ellipticity minima of rP148 in the CD spectra upon the addition of the 32-kDa enamelin, suggest a direct interaction between the two proteins. In the fluorescence spectra, the maximum emission of rP148 was red-shifted from 335 to 341 nm with a marked intensity increase in the presence of enamelin as a result of complexation of the two proteins. In agreement with DLS data, TEM imaging showed that the 32-kDa enamelin dispersed the amelogenin aggregates into oligomeric particles and stabilized them. Our study provides novel insights into understanding the possible cooperation between enamelin and amelogenin in macromolecular co-assembly and in controlling enamel mineral formation. PMID- 22243268 TI - Human osteoblastic cells discriminate between 20-kDa amelogenin isoforms. AB - Enamel matrix derivative (EMD) is used to stimulate healing of alveolar bone after destructive marginal periodontitis; however, the roles of the different EMD constituents are unclear. The aim here was to compare the effect of two EMD fractions (A1 and A2) on primary human osteoblasts cultured in the presence of 50 MUg ml(-1) of A1, A2, or EMD. SDS-PAGE showed that A1 and A2 were comprised of amelogenins migrating at around 20 kDa. Fourier transform infrared (FTIR) analysis revealed that A1 and A2 had different secondary structures, and matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) identified different peptide mass values. Osteoblasts responded differently to A1 and A2. Whereas A1 enhanced the proliferation [measured by the incorporation of 5-bromo 2'-deoxyuridine (BrdU)] of osteoblasts, the expression of runt-related transcription factor-2 (RUNX2) mRNA, and the secretion of interleukin 6 (IL-6) into the cell culture medium, exposure to A2 resulted in increased alkaline phosphatase (ALP) activity, increased expression of CD44 mRNA, and increased secretion of osteoprotegrin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL). The level of osteocalcin in the cell culture medium was increased after all treatments, while A2 stimulated the expression of dentin matrix protein 1 (DMP1) mRNA. The results suggest that both A1 and A2 participate in the observed effect of EMD, but have different effects on the expression of osteoblast mRNA and the secretion of osteoblast protein, and thus might facilitate the differentiation of a different phenotype. PMID- 22243270 TI - Matrix and cells. PMID- 22243269 TI - Enamel matrix derivative stimulates expression and secretion of resistin in mesenchymal cells. AB - In this study we wanted to identify the effect of enamel matrix derivative (EMD) on adipocytokines, so-called adipokines. Primary human cells of mesenchymal origin (osteoblasts, periodontal ligament cells, mesenchymal stem cells, and pulp cells) and hematopoietic origin (monocytes) were incubated with EMD. The levels of adipokines in cell culture medium were quantified using the Lincoplex human adipocyte panel (Luminex) and by real-time PCR of mRNA isolated from cell lysates. Rats were injected with 2 mg of EMD or saline intramuscularly every third day for 14 d. Blood samples were taken before and after injections, and the level of resistin in rat plasma was measured by ELISA. We found a dramatic increase in the secretion of resistin from mesenchymal stem cells, and verified this result in all the cells of mesenchymal origin tested. However, we observed no significant changes in the amount of resistin secreted from monocytes exposed to EMD compared with the control. Injections of EMD significantly enhanced the circulating levels of resistin in rats, and EMD also significantly enhanced the activity of the resistin promoter in transfected mesenchymal stem cells, indicating a direct effect on resistin expression. Our results indicate that resistin may play a role in mediating the biological effect of EMD in mesenchymal tissues. PMID- 22243271 TI - Enamel biology and future research directions. PMID- 22243274 TI - Enamel VIII foreword. PMID- 22243278 TI - Activated leukocyte cell adhesion molecule modulates neurotrophin signaling. AB - Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been shown to modulate growth factor signaling and follow complex trafficking pathways in neurons. Similarly, several growth factors, including members of the neurotrophin family, undergo axonal retrograde transport that is required to elicit their full signaling potential in neurons. We sought to determine whether IgCAMs that enter the axonal retrograde transport route co-operate with neurotrophin signaling. We identified activated leukocyte cell adhesion molecule (ALCAM), a protein involved in axon pathfinding and development of the neuromuscular junction, to be associated with an axonal endocytic compartment that contains neurotrophins and their receptors. Although ALCAM enters carriers that are transported bidirectionally in motor neuron axons, it is predominantly co-transported with the neurotrophin receptor p75(NTR) toward the cell body. ALCAM was found to specifically potentiate nerve growth factor (NGF)-induced differentiation and signaling. The extracellular domain of ALCAM is both necessary and sufficient to potentiate NGF-induced neurite outgrowth, and its homodimerization is required for this novel role. Our findings indicate that ALCAM synergizes with NGF to induce neuronal differentiation, raising the possibility that it functions not only as an adhesion molecule but also in the modulation of growth factor signaling in the nervous system. PMID- 22243279 TI - A complete record from colonization to extinction reveals density dependence and the importance of winter conditions for a population of the silvery blue, Glaucopsyche lygdamus. AB - Butterflies in the family Lycaenidac are often the focus of conservation efforts. However, our understanding of lycaenid population dynamics has been limited to relatively few examples of long-term monitoring data that have been reported. Here, factors associated with population regulation are investigated using a complete record of a single population of the silvery blue, Glaucopsyche lygdamus Doubleday (Lepidoptera: Lycaenidae). Adults of G. lygdamus were first observed in an annual grassland near Davis, California, in 1982 and were last seen in 2003. Relationships between inter-annual variation in abundance and climatic variables were examined, accounting for density dependent effects. Significant effects of both negative density dependence and climatic variation were detected, particularly precipitation and temperature during winter months. Variation in precipitation, the strongest predictor of abundance, was associated directly and positively with butterfly abundance in the same year. Winter temperatures had a negative effect in the same year, but had a lagged, positive effect on abundance in the subsequent year. Mechanistic hypotheses are posed that include climatic effects mediated through both larval and adult plant resources. PMID- 22243280 TI - Internalization of fresh produce by foodborne pathogens. AB - Recent studies addressing the internalization of fresh produce by foodborne pathogens arose in response to the growing number of recent and high profile outbreaks involving fresh produce. Because chemical sanitizing agents used during harvest and minimal processing are unlikely to reach enteric pathogens residing within plant tissue, it is imperative that paths for pathogen entry be recognized and minimized. Using both microscopy and microbial enumeration tools, enteric pathogens have been shown to enter plant tissues through both natural apertures (stomata, lateral junctions of roots, flowers) and damaged (wounds, cut surfaces) tissue. In studies revealing preharvest internalization via plant roots or leaf stomata, experimental conditions have primarily involved exposure of plants to high pathogen concentrations (>= 6 log g-1 soil or 6 log ml-1 water), but those pathogens internalized appear to have short-term persistence. Postharvest internalization of pathogens via cut surfaces may be minimized by maintaining effective levels of sanitizing agents in waters during harvesting and minimal processing. PMID- 22243281 TI - Lessons learned. AB - The paper discusses my early years, education, and life experiences, including aspects of my career at McCormick & Co., Inc. A major intensive effort, one that greatly influenced my career, was helping the flavor industry cope with the passage of the Food Additives Amendment to the Food, Drug, and Cosmetic Act. It resulted in a program now in its 51st year that is unique in the food industry. Other activities took me further into the fields of toxicology, structure/activity relationships, food safety, nutrition, and biotechnology. The paper closes with some observations on current challenges, and the steps that, in my opinion, we must take to meet them. PMID- 22243282 TI - Detection and quantification of bacterial autofluorescence at the single-cell level by a laboratory-built high-sensitivity flow cytometer. AB - Cellular autofluorescence can affect the sensitivity of fluorescence microscopic or flow cytometric assays by interfering with or even precluding the detection of low-level specific fluorescence. Here we developed a method to detect and quantify bacterial autofluorescence in the green region of the spectrum at the single-cell level using a laboratory-built high-sensitivity flow cytometer (HSFCM). The detection of the very weak bacterial autofluorescence was confirmed by analyzing polystyrene beads of comparable and larger size than bacteria in parallel. Dithionite reduction and air re-exposure experiments verified that the green autofluorescence mainly originates from endogenous flavins. Bacterial autofluorescence was quantified by calibrating the fluorescence intensity of nanospheres with known FITC equivalents, and autofluorescence distribution was generated by analyzing thousands of bacterial cells in 1 min. Among the eight bacterial strains tested, it was found that bacterial autofluorescence can vary from 80 to 1400 FITC equivalents per cell, depending on the bacterial species, and a relatively large cell-to-cell variation in autofluorescence intensity was observed. Quantitative measurements of bacterial autofluorescence provide a reference for the background signals that can be expected with bacteria, which is important in guiding studies of low-level gene expression and for the detection of low-abundance biological molecules in individual bacterial cells. This paper presents the first quantification of bacterial autofluorescence in FITC equivalents. PMID- 22243283 TI - Infrared multiple photon dissociation spectroscopy of cationized histidine: effects of metal cation size on gas-phase conformation. AB - The gas phase structures of cationized histidine (His), including complexes with Li(+), Na(+), K(+), Rb(+), and Cs(+), are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy utilizing light generated by a free electron laser, in conjunction with quantum chemical calculations. To identify the structures present in the experimental studies, measured IRMPD spectra are compared to spectra calculated at B3LYP/6-311+G(d,p) (Li(+), Na(+), and K(+) complexes) and B3LYP/HW*/6-311+G(d,p) (Rb(+) and Cs(+) complexes) levels of theory, where HW* indicates that the Hay-Wadt effective core potential with additional polarization functions was used on the metals. Single point energy calculations were carried out at the B3LYP, B3P86, and MP2(full) levels using the 6-311+G(2d,2p) basis set. On the basis of these experiments and calculations, the only conformation that reproduces the IRMPD action spectra for the complexes of the smaller alkali metal cations, Li(+)(His) and Na(+)(His), is a charge solvated, tridentate structure where the metal cation binds to the backbone carbonyl oxygen, backbone amino nitrogen, and nitrogen atom of the imidazole side chain, [CO,N(alpha),N(1)], in agreement with the predicted ground states of these complexes. Spectra of the larger alkali metal cation complexes, K(+)(His), Rb(+)(His), and Cs(+)(His), have very similar spectral features that are considerably more complex than the IRMPD spectra of Li(+)(His) and Na(+)(His). For these complexes, the bidentate [CO,N(1)] conformer in which the metal cation binds to the backbone carbonyl oxygen and nitrogen atom of the imidazole side chain is a dominant contributor, although features associated with the tridentate [CO,N(alpha),N(1)] conformer remain, and those for the [COOH] conformer are also clearly present. Theoretical results for Rb(+)(His) and Cs(+)(His) indicate that both [CO,N(1)] and [COOH] conformers are low-energy structures, with different levels of theory predicting different ground conformers. PMID- 22243284 TI - Mutational analysis of PMP22, GJB1 and MPZ in Greek Charcot-Marie-Tooth type 1 neuropathy patients. PMID- 22243285 TI - Small mesh size hydrogel for functional photocontrol of encapsulated enzymes and small probe molecules. AB - Previously, we developed the "protein activation and release from cage by external light" (PARCEL) method for controlling the function of proteins by encapsulating them in a photodegradable hydrogel and subsequently releasing them by ultraviolet (UV) irradiation of the gel. However, controlling small proteins is difficult because small proteins can leak from the gap (ca. 12.4 nm) of the mesh structure of the hydrogel without irradiation. Here, we developed a photodegradable gel with a smaller mesh size (~3.6 nm) and used the new gel to control the function of three small enzymes (trypsin, chymotrypsin, and elastase) and several small nonprotein molecules. The new gel showed reduced leakage of the proteins without irradiation, and tryptic activity increased approximately 78 fold upon irradiation of gel-encapsulated trypsin. The new gel also permitted encapsulation and release of 4',6-diamidino-2-phenylindole (DAPI, molecular weight 277), a small DNA-specific fluorescent probe. After irradiation to the gel encapsulated DAPI and subsequent addition of DNA, strong fluorescence of the DAPI DNA complex was observed. Our results indicate that reducing the gel mesh size from 12.4 to 3.6 nm should allow the encapsulation of various proteins and small molecules in an inactive state and their subsequent light-induced release. We expect this method to be useful in preparation of photoactivated biosensors, drug delivery systems, and catalysis. PMID- 22243287 TI - The challenge of cervical screening: to find and treat high-grade cervical intraepithelial neoplasia at risk of progression in women of childbearing age. PMID- 22243288 TI - Type 1 and type 2 cervical carcinomas: some cervical cancers are more difficult to prevent with screening. AB - Although the Papanicolaou (Pap) smear is medical history's most successful cancer screening test, some cervical cancers are more difficult to prevent with screening than others. Cervical cancers that are difficult to prevent are seen disproportionately among interval cancers arising in previously screened women and in Pap test litigation. These include (i) rapidly progressing cervical cancers; (ii) cervical cancers in younger women; (iii) glandular cervical cancers; and (iv) cervical cancers in elderly women. Screening protocols have generally been designed to optimize prevention of slower-growing cervical squamous carcinomas in middle-aged women. To focus further attention on the heterogeneous screening challenges posed by different cervical cancers, we designate the more screening preventable majority as type 1 cervical cancers and the more difficult to prevent minority as type 2 cervical cancers. We review available data on why some cervical cancers are more difficult to prevent with screening and newer methods that may improve prevention. PMID- 22243289 TI - Review of cytology and histopathology as part of the NHS Cervical Screening Programme audit of invasive cervical cancers. AB - OBJECTIVE: To audit pathology slide reporting in the Cervical Screening Programme in England by reviewing cytology and histology slides from women subsequently diagnosed with invasive cervical cancer. METHODS: Between April 2007 and March 2010, 6113 women diagnosed with cervical cancer were identified. Cervical cytology and histology slides taken within 10 years of diagnosis were identified and where possible reviewed after a nationally agreed protocol. Reviewers were not blinded to the original reading of each sample. Most cytology samples before 2005 were conventional, most after 2007 liquid based. RESULTS: Of 13,745 cytology results from women developing cervical cancer, 55% were reviewed. The review result was identical for 55% of slides. Of 3759 originally normal slides, only 45% were normal on review: 11% were inadequate, 21% low grade (borderline or mild dyskaryosis) and 23% high grade (moderate dyskaryosis or worse). Of tests originally normal taken over 5.5 years before diagnosis, 14% were upgraded to high grade compared with 37% within 3.5 years of diagnosis. Of 5159 histology specimens recorded within 10 years of diagnosis of a cancer, 3895 were reviewed. Overall, 94% of samples reviewed retained the original diagnosis. One per cent (33/3012) of cancers were downgraded and 5% (6/112) of negative samples were upgraded to cancer upon review (four of which were taken within 2 months of diagnosis). In comparison, 15% (14/91) of cervical glandular intraepithelial neoplasia (CGIN) and 12% (38/314) of cervical intraepithelial neoplasia grade 3 (CIN3) were upgraded to cancer. CONCLUSIONS: In spite of the excellent quality of cytology in England, a high proportion of negative cytology taken up to three and a half years before diagnosis were considered to contain abnormal cells by reviewers informed of the subsequent cancer. Continuing these reviews, with a strong focus on education, will ensure a clear understanding of these slides and further reduce the risk of developing cervical cancer. PMID- 22243291 TI - Trapped two-dimensional condensates with synthetic spin-orbit coupling. AB - We study trapped 2D atomic Bose-Einstein condensates with spin-independent interactions in the presence of an isotropic spin-orbit coupling, showing that a rich physics results from the nontrivial interplay between spin-orbit coupling, confinement and interatomic interactions. For low interactions two types of half vortex solutions with different winding occur, whereas strong-enough repulsive interactions result in a stripe-phase similar to that predicted for homogeneous condensates. Intermediate interaction regimes are characterized for large enough spin-orbit coupling by an hexagonally-symmetric phase with a triangular lattice of density minima similar to that observed in rapidly rotating condensates. PMID- 22243292 TI - Quantum nonlocality in weak-thermal-light interferometry. AB - In astronomy, interferometry of light collected by separate telescopes is often performed by physically bringing the optical paths together in the form of Young's double-slit experiment. Optical loss severely limits the efficiency of this so-called direct detection method, motivating the fundamental question of whether one can achieve a comparable performance using separate optical measurements at the two telescopes before combining the measurement results. Using quantum mechanics and estimation theory, here I show that any such spatially local measurement scheme, such as heterodyne detection, is fundamentally inferior to coherently nonlocal measurements, such as direct detection, for estimating the mutual coherence of bipartite thermal light when the average photon flux is low. This surprising result reveals an overlooked signature of quantum nonlocality in a classic optics experiment. PMID- 22243293 TI - Probing the quantum state of a 1D Bose gas using off-resonant light scattering. AB - We present a theoretical treatment of coherent light scattering from an interacting 1D Bose gas at finite temperatures. We show how this can provide a nondestructive measurement of the atomic system states. The equilibrium states are determined by the temperature and interaction strength, and are characterized by the spatial density-density correlation function. We show how this correlation function is encoded in the angular distribution of the fluctuations of the scattered light intensity, thus providing a sensitive, quantitative probe of the density-density correlation function and therefore the quantum state of the gas. PMID- 22243294 TI - Swallowtail band structure of the superfluid Fermi gas in an optical lattice. AB - We investigate the energy band structure of the superfluid flow of ultracold dilute Fermi gases in a one-dimensional optical lattice along the BCS to Bose Einstein condensate (BEC) crossover within a mean-field approach. In each side of the crossover region, a loop structure (swallowtail) appears in the Bloch energy band of the superfluid above a critical value of the interaction strength. The width of the swallowtail is largest near unitarity. Across the critical value of the interaction strength, the profiles of density and pairing field change more drastically in the BCS side than in the BEC side. It is found that along with the appearance of the swallowtail, there exists a narrow band in the quasiparticle energy spectrum close to the chemical potential, and the incompressibility of the Fermi gas consequently experiences a profound dip in the BCS side, unlike in the BEC side. PMID- 22243295 TI - Entanglement witness operator for quantum teleportation. AB - The ability of entangled states to act as a resource for teleportation is linked to a property of the fully entangled fraction. We show that the set of states with their fully entangled fraction bounded by a threshold value required for performing teleportation is both convex and compact. This feature enables the existence of Hermitian witness operators, the measurement of which could distinguish unknown states useful for performing teleportation. We present an example of such a witness operator illustrating it for different classes of states. PMID- 22243296 TI - Capabilities of a perturbed toric code as a quantum memory. AB - We analyze the effect of typical, unknown perturbations on the 2D toric code when acting as a quantum memory, incorporating the effects of error correction on readout. By transforming the system into a 1D transverse Ising model undergoing an instantaneous quench, and making extensive use of Lieb-Robinson bounds, we prove that for a large class of perturbations, the survival time of stored information grows at least logarithmically with the system size. A uniform magnetic field saturates this scaling behavior. We show that randomizing the stabilizer strengths gives a polynomial survival time with a degree that depends on the strength of the perturbation. PMID- 22243297 TI - Practical limitations on astrophysical observations of methanol to investigate variations in the proton-to-electron mass ratio. AB - The possibility of using astrophysical observations of rotational transitions in the methanol molecule to measure, or constrain temporal and spatial variations in the proton-to-electron mass ratio (MU) has recently been investigated by several groups. Here we outline some of the practical considerations of making such observations, including both the instrumental and astrophysical limitations which exist at present. This leads us to conclude that such observations are unlikely to be able to improve evidence either for, or against the presence of variations in the proton-to-electron mass ratio by more than an order of magnitude beyond current limits. PMID- 22243298 TI - Molecular gas sensing below parts per trillion: radiocarbon-dioxide optical detection. AB - Radiocarbon ((14)C) concentrations at a 43 parts-per-quadrillion level are measured by using saturated-absorption cavity ringdown spectroscopy by exciting radiocarbon-dioxide ((14)C(16)O(2)) molecules at the 4.5 MUm wavelength. The ultimate sensitivity limits of molecular trace gas sensing are pushed down to attobar pressures using a comb-assisted absorption spectroscopy setup. Such a result represents the lowest pressure ever detected for a gas of simple molecules. The unique sensitivity, the wide dynamic range, the compactness, and the relatively low cost of this table-top setup open new perspectives for ^{14}C tracing applications, such as radiocarbon dating, biomedicine, or environmental and earth sciences. The detection of other very rare molecules can be pursued as well thanks to the wide and continuous mid-IR spectral coverage of the described setup. PMID- 22243299 TI - Wormholes in dilatonic Einstein-Gauss-Bonnet theory. AB - We construct traversable wormholes in dilatonic Einstein-Gauss-Bonnet theory in four spacetime dimensions, without needing any form of exotic matter. We determine their domain of existence, and show that these wormholes satisfy a generalized Smarr relation. We demonstrate linear stability with respect to radial perturbations for a subset of these wormholes. PMID- 22243301 TI - Clipping the cosmos: the bias and bispectrum of large scale structure. AB - A large fraction of the information collected by cosmological surveys is simply discarded to avoid length scales which are difficult to model theoretically. We introduce a new technique which enables the extraction of useful information from the bispectrum of galaxies well beyond the conventional limits of perturbation theory. Our results strongly suggest that this method increases the range of scales where the relation between the bispectrum and power spectrum in tree-level perturbation theory may be applied, from k(max) ~ 0.1 to ~0.7 hMpc(-1). This leads to correspondingly large improvements in the determination of galaxy bias. Since the clipped matter power spectrum closely follows the linear power spectrum, there is the potential to use this technique to probe the growth rate of linear perturbations and confront theories of modified gravity with observation. PMID- 22243302 TI - Possibility of a dark matter interpretation for the excess in isotropic radio emission reported by ARCADE. AB - The ARCADE 2 Collaboration has recently measured an isotropic radio emission which is significantly brighter than the expected contributions from known extra galactic sources. The simplest explanation of such excess involves a "new" population of unresolved sources which become the most numerous at very low (observationally unreached) brightness. We investigate this scenario in terms of synchrotron radiation induced by weakly interacting massive particle (WIMP) annihilations or decays in extra-galactic halos. Intriguingly, for light-mass WIMPs with a thermal annihilation cross section, the level of expected radio emission matches the ARCADE observations. PMID- 22243303 TI - Determination of weak amplitudes using Bose symmetry and Dalitz plots. AB - We present a new method using Dalitz plots and Bose symmetry of pions that allows the complete determination of the magnitudes and phases of weak decay amplitudes. We apply the method to processes such as B->K*pi, with the subsequent decay of K* >Kpi. Our approach enables the additional measurement of an isospin amplitude without any theoretical assumption. This advance will help in measuring the weak phase and probing for new physics beyond the standard model with fewer assumptions. PMID- 22243300 TI - Directional limits on persistent gravitational waves using LIGO S5 science data. AB - The gravitational-wave (GW) sky may include nearby pointlike sources as well as stochastic backgrounds. We perform two directional searches for persistent GWs using data from the LIGO S5 science run: one optimized for pointlike sources and one for arbitrary extended sources. Finding no evidence to support the detection of GWs, we present 90% confidence level (C.L.) upper-limit maps of GW strain power with typical values between 2-20*10(-50) strain(2) Hz(-1) and 5-35*10(-49) strain(2) Hz(-1) sr(-1) for pointlike and extended sources, respectively. The latter result is the first of its kind. We also set 90% C.L. limits on the narrow band root-mean-square GW strain from interesting targets including Sco X-1, SN 1987A and the Galactic center as low as ~7*10(-25) in the most sensitive frequency range near 160 Hz. PMID- 22243308 TI - Generating molecular rovibrational coherence by two-photon femtosecond photoassociation of thermally hot atoms. AB - The formation of diatomic molecules with rotational and vibrational coherence is demonstrated experimentally in free-to-bound two-photon femtosecond photoassociation of hot atoms. In a thermal gas at a temperature of 1000 K, pairs of magnesium atoms, colliding in their electronic ground state, are excited into coherent superpositions of bound rovibrational levels in an electronically excited state. The rovibrational coherence is probed by a time-delayed third photon, resulting in quantum beats in the UV fluorescence. A comprehensive theoretical model based on ab initio calculations rationalizes the generation of coherence by Franck-Condon filtering of collision energies and partial waves, quantifying it in terms of an increase in quantum purity of the thermal ensemble. Our results open the way to coherent control of a binary reaction. PMID- 22243309 TI - Exploring interatomic Coulombic decay by free electron lasers. AB - To exploit the high intensity of laser radiation, we propose to select frequencies at which single-photon absorption is of too low energy and two or more photons are needed to produce states of an atom that can undergo interatomic Coulombic decay (ICD) with its neighbors. For Ne(2) it is explicitly demonstrated that the proposed multiphoton absorption scheme is much more efficient than schemes used until now, which rely on single-photon absorption. Extensive calculations on Ne(2) show how the low-energy ICD electrons and Ne(+) pairs are produced for different laser intensities and pulse durations. At higher intensities the production of Ne(+) pairs by successive ionization of the two atoms becomes competitive and the respective emitted electrons interfere with the ICD electrons. It is also shown that a measurement after a time delay can be used to determine the contribution of ICD even at high laser intensity. PMID- 22243310 TI - Laser cooling and optical detection of excitations in a LC electrical circuit. AB - We explore a method for laser cooling and optical detection of excitations in a room temperature LC electrical circuit. Our approach uses a nanomechanical oscillator as a transducer between optical and electronic excitations. An experimentally feasible system with the oscillator capacitively coupled to the LC and at the same time interacting with light via an optomechanical force is shown to provide strong electromechanical coupling. Conditions for improved sensitivity and quantum limited readout of electrical signals with such an "optical loud speaker" are outlined. PMID- 22243311 TI - Rogue waves in a multistable system. AB - Clear evidence of rogue waves in a multistable system is revealed by experiments with an erbium-doped fiber laser driven by harmonic pump modulation. The mechanism for the rogue wave formation lies in the interplay of stochastic processes with multistable deterministic dynamics. Low-frequency noise applied to a diode pump current induces rare jumps to coexisting subharmonic states with high-amplitude pulses perceived as rogue waves. The probability of these events depends on the noise filtered frequency and grows up when the noise amplitude increases. The probability distribution of spike amplitudes confirms the rogue wave character of the observed phenomenon. The results of numerical simulations are in good agreement with experiments. PMID- 22243307 TI - First use of high charge states for mass measurements of short-lived nuclides in a Penning trap. AB - Penning trap mass measurements of short-lived nuclides have been performed for the first time with highly charged ions, using the TITAN facility at TRIUMF. Compared to singly charged ions, this provides an improvement in experimental precision that scales with the charge state q. Neutron-deficient Rb isotopes have been charge bred in an electron beam ion trap to q=8-12+ prior to injection into the Penning trap. In combination with the Ramsey excitation scheme, this unique setup creating low energy, highly charged ions at a radioactive beam facility opens the door to unrivaled precision with gains of 1-2 orders of magnitude. The method is particularly suited for short-lived nuclides such as the superallowed beta emitter 74Rb (T(1/2)=65 ms). The determination of its atomic mass and an improved Q(EC) value are presented. PMID- 22243312 TI - Reacting particles in open chaotic flows. AB - We study the collision probability p of particles advected by open flows with chaotic advection. We show that p scales with the particle size (or, alternatively, reaction distance) delta as a power law whose coefficient is determined by the fractal dimensions of the invariant sets defined by the advection dynamics. We also argue that this same scaling also holds for the reaction rate of active particles in the low-density regime. These analytical results are compared to numerical simulations, and they are found to agree very well. PMID- 22243313 TI - Ionization by drift and ambipolar electric fields in electronegative capacitive radio frequency plasmas. AB - Unlike alpha- and gamma-mode operation, electrons accelerated by strong drift and ambipolar electric fields in the plasma bulk and at the sheath edges are found to dominate the ionization in strongly electronegative discharges. These fields are caused by a low bulk conductivity and local maxima of the electron density at the sheath edges, respectively. This drift-ambipolar mode is investigated by kinetic particle simulations, experimental phase-resolved optical emission spectroscopy, and an analytical model in CF(4). Mode transitions induced by voltage and pressure variations are studied. PMID- 22243314 TI - Confinement and lattice quantum-electrodynamic electric flux tubes simulated with ultracold atoms. AB - We propose a method for simulating (2+1)D compact lattice quantum electrodynamics, using ultracold atoms in optical lattices. In our model local Bose-Einstein condensates' (BECs) phases correspond to the electromagnetic vector potential, and the local number operators represent the conjugate electric field. The well-known gauge-invariant Kogut-Susskind Hamiltonian is obtained as an effective low-energy theory. The field is then coupled to external static charges. We show that in the strong coupling limit this gives rise to "electric flux tubes" and to confinement. This can be observed by measuring the local density deviations of the BECs, and is expected to hold even, to some extent, outside the perturbative calculable regime. PMID- 22243315 TI - Dynamical theory of superfluidity in one dimension. AB - A theory accounting for the dynamical aspects of the superfluid response of one dimensional (1D) quantum fluids is reported. In long 1D systems, the onset of superfluidity is related to the dynamical suppression of quantum phase slips at low temperatures. The effect of this suppression as a function of frequency and temperature is discussed within the framework of the experimentally relevant momentum response function. Applications of these results to the understanding of the superfluid properties of helium confined in 1D pores with nanometer diameter, dislocations in solid 4He, and ultracold atomic gases are also briefly discussed. PMID- 22243316 TI - Laser excitation of a fracture source for elastic waves. AB - We show that elastic waves can be excited at a fracture inside a transparent sample by focusing laser light directly onto this fracture. The associated displacement field, measured by a laser interferometer, has pronounced waves that are diffracted at the fracture tips. We confirm that these are tip diffractions from direct excitation of the fracture by comparing them with tip diffractions from scattered elastic waves excited on the exterior of the sample. Being able to investigate fractures-in this case in an optically transparent material-via direct excitation opens the door to more detailed studies of fracture properties in general. PMID- 22243305 TI - Measurement of the B(s)0 lifetime in fully and partially reconstructed B(s)0 >D(s)(-)(phipi(-))X decays in p-p collisions at ?s=1.96 TeV. AB - We present a measurement of the B(s)(0) lifetime in fully and partially reconstructed B(s)(0)->D(s)(-)(phipi(-))X decays in 1.3 fb(-1) collected in pp - collisions at ?s=1.96 TeV by the CDF II detector at the Fermilab Tevatron. We measure tau(B(s)(0))=1.518+/-0.041(stat)+/-0.027(syst) ps. The ratio of this result and the world average B(0) lifetime yields tau(B(s)(0))/tau(B(0))=0.99+/ 0.03, which is in agreement with recent theoretical predictions. PMID- 22243317 TI - Extreme value statistics distributions in spin glasses. AB - We study the probability distribution of the pseudocritical temperature in a mean field and in a short-range spin-glass model: the Sherrington-Kirkpatrick and the Edwards-Anderson (EA) model. In both cases, we put in evidence the underlying connection between the fluctuations of the pseudocritical point and the extreme value statistics of random variables. For the Sherrington-Kirkpatrick model, both with Gaussian and binary couplings, the distribution of the pseudocritical temperature is found to be the Tracy-Widom distribution. For the EA model, the distribution is found to be the Gumbel distribution. Being the EA model representative of uniaxial magnetic materials with quenched disorder like Fe(0.5)Mn)0.5)TiO(3) or Eu(0.5)Ba(0.5)MnO(3), its pseudocritical point distribution should be a priori experimentally accessible. PMID- 22243318 TI - Preparation and relaxation of very stable glassy states of a simulated liquid. AB - We prepare metastable glassy states in a model glass former made of Lennard-Jones particles by sampling biased ensembles of trajectories with low dynamical activity. These trajectories form an inactive dynamical phase whose "fast" vibrational degrees of freedom are maintained at thermal equilibrium by contact with a heat bath, while the "slow" structural degrees of freedom are located in deep valleys of the energy landscape. We examine the relaxation to equilibrium and the vibrational properties of these metastable states. The glassy states we prepare by our trajectory sampling method are very stable to thermal fluctuations and also more mechanically rigid than low-temperature equilibrated configurations. PMID- 22243319 TI - Suppression effect on explosive percolation. AB - Percolation transitions (PTs) of networks, leading to the formation of a macroscopic cluster, are conventionally considered to be continuous transitions. However, a modified version of the classical random graph model was introduced in which the growth of clusters was suppressed, and a PT occurs explosively at a delayed transition point. Whether the explosive PT is indeed discontinuous or continuous becomes controversial. Here, we show that the behavior of the explosive PT depends on detailed dynamic rules. Thus, when dynamic rules are designed to suppress the growth of all clusters, the discontinuity of the order parameter tends to a finite value as the system size increases, indicating that the explosive PT could be discontinuous. PMID- 22243320 TI - Dielectric breakdown and avalanches at nonequilibrium metal-insulator transitions. AB - Motivated by recent experiments on the finite temperature Mott transition in VO(2) films, we propose a classical coarse-grained dielectric breakdown model where each degree of freedom represents a nanograin which transitions from insulator to metal with increasing temperature and voltage at random thresholds due to quenched disorder. We describe the properties of the resulting nonequilibrium metal-insulator transition and explain the universal characteristics of the resistance jump distribution. We predict that by tuning voltage, another critical point is approached, which separates a phase of boltlike avalanches from percolationlike ones. PMID- 22243321 TI - Terahertz radiation driven chiral edge currents in graphene. AB - We observe photocurrents induced in single-layer graphene samples by illumination of the graphene edges with circularly polarized terahertz radiation at normal incidence. The photocurrent flows along the sample edges and forms a vortex. Its winding direction reverses by switching the light helicity from left to right handed. We demonstrate that the photocurrent stems from the sample edges, which reduce the spatial symmetry and result in an asymmetric scattering of carriers driven by the radiation electric field. The developed theory based on Boltzmann's kinetic equation is in a good agreement with the experiment. We show that the edge photocurrents can be applied for determination of the conductivity type and the momentum scattering time of the charge carriers in the graphene edge vicinity. PMID- 22243322 TI - Advanced simulation of conductance histograms validated through channel-sensitive experiments on indium nanojunctions. AB - We demonstrate a self-contained methodology for predicting conductance histograms of atomic and molecular junctions. Fast classical molecular-dynamics simulations are combined with accurate density functional theory calculations predicting both quantum transport properties and molecular-dynamics force field parameters. The methodology is confronted with experiments on atomic-sized indium nanojunctions. Beside conductance histograms the distribution of individual channel transmission eigenvalues is also determined by fitting the superconducting subgap features in the I-V curves. The remarkable agreement in the evolution of the channel transmissions demonstrates that the simulated ruptures are able to reproduce a realistic statistical ensemble of contact configurations, whereas simulations on selected ideal geometries show strong deviations from the experimental observations. PMID- 22243323 TI - Unusual Nernst effect suggesting time-reversal violation in the striped cuprate superconductor La(2-x)Ba(x)CuO4. AB - The striped cuprate La(2-x)Ba(x)CuO(4) (x=1/8) undergoes several transitions below the charge-ordering temperature T(co)=54 K. From Nernst experiments, we find that, below T(co), there exists a large, anomalous Nernst signal e(N,even)(H,T) that is symmetric in field H, and remains finite as H->0. The time reversal violating signal suggests that, below T(co), vortices of one sign are spontaneously created to relieve interlayer phase frustration. PMID- 22243324 TI - Metamagnetic behavior and Kondo breakdown in heavy-fermion CeFePO. AB - We report that nonmagnetic heavy-fermion (HF) iron oxypnictide CeFePO with two dimensional XY-type anisotropy shows a metamagnetic behavior at the metamagnetic field H(M)?4 T perpendicular to the c axis and that a critical behavior is observed around H(M). Although the magnetic character is entirely different from that in other Ce-based HF metamagnets, H(M) in these metamagnets is linearly proportional to the inverse of the effective mass, or to the temperature where the susceptibility shows a peak. This finding suggests that H(M) is a magnetic field breaking the local Kondo singlet, and the critical behavior around H(M) is driven by the Kondo breakdown accompanied by the Fermi-surface instability. PMID- 22243325 TI - Quantum many-body calculation of mixed-parity pairing in the Sr2RuO4 superconductor induced by spin-orbit coupling. AB - The unusual superconducting state in Sr(2)RuO(4) has long been viewed as being analogous to a superfluid state in liquid (3)He. Nevertheless, calculations based on this odd-parity state are presently unable to completely reconcile the properties of Sr(2)RuO(4). Using a self-consistent quantum many-body scheme that employs realistic parameters, we are able to model several signature properties of the normal and superconducting states of Sr(2)RuO(4). We find that the dominant component of the model superconducting state is of even parity and closely related to superconducting state for the high-T(c) cuprates although a smaller odd-parity component is induced by spin-orbit coupling. This mixed pairing state gives a more complete representation of the complex phenomena measured in Sr(2)RuO(4). PMID- 22243326 TI - Frustration and glassiness in spin models with cavity-mediated interactions. AB - We show that the effective spin-spin interaction between three-level atoms confined in a multimode optical cavity is long-ranged and sign changing, like the RKKY interaction; therefore, ensembles of such atoms subject to frozen-in positional randomness can realize spin systems having disordered and frustrated interactions. We argue that, whenever the atoms couple to sufficiently many cavity modes, the cavity-mediated interactions give rise to a spin glass. In addition, we show that the quantum dynamics of cavity-confined spin systems is that of a Bose-Hubbard model with strongly disordered hopping but no on-site disorder; this model exhibits a random-singlet glass phase, absent in conventional optical-lattice realizations. We briefly discuss experimental signatures of the realizable phases. PMID- 22243327 TI - Dicke quantum spin glass of atoms and photons. AB - Recent studies of strongly interacting atoms and photons in optical cavities have rekindled interest in the Dicke model of atomic qubits coupled to discrete photon cavity modes. We study the multimode Dicke model with variable atom-photon couplings. We argue that a quantum spin-glass phase can appear, with a random linear combination of the cavity modes superradiant. We compute atomic and photon spectral response functions across this quantum phase transition, both of which should be accessible in experiments. PMID- 22243328 TI - Silo clogging reduction by the presence of an obstacle. AB - We present experimental results on the effect that inserting an obstacle just above the outlet of a silo has on the clogging process. We find that, if the obstacle position is properly selected, the probability that the granular flow is arrested can be reduced by a factor of 100. This dramatic effect occurs without any remarkable modification of the flow rate or the packing fraction above the outlet, which are discarded as the cause of the change in the clogging probability. Hence, inspired by previous results of pedestrian crowd dynamics, we propose that the physical mechanism behind the clogging reduction is a pressure decrease in the region of arch formation. PMID- 22243329 TI - Irreversible electrokinetic repulsion at zero-Reynolds-number sedimentation. AB - Stokes-flow reversibility is violated in electrolyte solutions by a streaming potential mechanism, where nonuniform convective currents within Debye layers surrounding charged particles induce electric fields in the electroneutral Ohmic bulk. We demonstrate the irreversibility consequences of this phenomenon for the problem of particle-pair sedimentation, where the two particles experience a repulsive force driven by bulk Maxwell stresses. At small separations the force scales inversely with the third power of separation distance. This singular behavior is associated with the counterrotation of the two torque-free particles, which leads through a lubrication mechanism to an intense electric field in the narrow gap between them. At large separations the force follows an inverse dependence upon the fourth power of separation, now associated with rectilinear particle motion. PMID- 22243330 TI - Free energy of multiple overlapping chains. AB - How accurate is pair additivity in describing interactions between soft polymer based nanoparticles? Using numerical simulations we compute the free energy cost required to overlap multiple chains in the same region of space, and provide a quantitative measure of the effectiveness of pair additivity as a function of chain number and length. Our data suggest that pair additivity can indeed become quite inadequate as the chain density in the overlapping region increases. We also show that even a scaling theory based on polymer confinement can only partially account for the complexity of the problem. In fact, we unveil and characterize an isotropic to star-polymer crossover taking place for large number of chains, and propose a revised scaling theory that better captures the physics of the problem. PMID- 22243331 TI - Comment on "Zeeman-driven Lifshitz transition: a model for the experimentally observed Fermi-surface reconstruction in YbRh2Si2". PMID- 22243334 TI - Quantifying particle coatings using high-precision mass measurements. AB - We present a general method to quantify coatings on microparticle surfaces based on the additional mass. Particle buoyant mass is determined in a solution with a density that is nearly equivalent to that of the core particle, reducing the magnitude and uncertainty of the measurement. Under these conditions, added material with a different density than that of the core is a larger fraction of the total buoyant mass of the coated particle. This method can resolve a buoyant mass difference between uncoated and coated particles of ~1 fg. For the protein layer on the 3 MUm polystyrene spheres measured herein, this is equivalent to 1/10th of a full layer. PMID- 22243335 TI - Quantification of dystrophin immunofluorescence in dystrophinopathy muscle specimens. AB - AIMS: Duchenne muscular dystrophy (DMD) is usually associated with absent or nearly absent dystrophin expression at the sarcolemmal membrane. Quantification of very low levels of dystrophin signal in immunofluorescent studies of muscle biopsy sections presents a technical challenge. This is particularly true in the setting of proof-of-principle drug trials, in which the detection and quantification of what may be significant changes in levels of expression is important, even if absolute dystrophin levels remain low. METHODS: We have developed a method of image analysis that allows reliable and semi-automated immunofluorescent quantification of low-level dystrophin expression in sections co-stained for spectrin. Using a custom Metamorph script to create a contiguous region spectrin mask, we quantify dystrophin signal intensity only at pixels within the spectrin mask that presumably represent the sarcolemmal membrane. Using this method, we analysed muscle biopsy tissue from a series of patients with DMD, Becker muscular dystrophy, intermediate muscular dystrophy and normal control tissue. RESULTS: Analysis of serial sections on multiple days confirms reproducibility, and normalized dystrophin:spectrin intensity ratios (expressed as a percentage of normal control tissue) correlate well with the dystrophin expression levels as determined by Western blot analysis. CONCLUSION: This method offers a robust and reliable method of biomarker detection for trials of DMD therapies. PMID- 22243336 TI - Influence of organic matter content and human activities on the occurrence of organic pollutants in antarctic soils, lichens, grass, and mosses. AB - Banned pesticides such as HCB and p,p'-DDE, and other legacy and ongoing pollutants such as PCBs and PAHs, were measured in different vegetation types and soil samples collected at selected areas from Antarctic Peninsula (Deception and Livingstone Islands, Southern Shetlands). Two Antarctic expeditions (in 2005 and 2009) were carried out to assess POPs levels at remote areas, and close to current and abandoned Antarctic research settlements, to assess potential sources of pollutants. Overall, the patterns in lichens, mosses, and grass were dominated by low molecular PCB congeners and PAHs and the presence of HCB and p,p'-DDE rather than heavier compounds, suggesting the importance of long-range atmospheric transport of POPs as the main vector for the introduction of these chemicals to Antarctica. Statistically significant correlations (p-level < 0.05) between concentrations in vegetation of PCBs, p,p'-DDE, and the more volatile PAHs with lipid content were found with r(2) of 0.22-0.52 for PCBs, 0.42 for p,p' DDE, and 0.44-0.72 for the more volatile PAHs. Thus, lipid content is an important factor controlling POPs in Antarctic lichens, mosses, and grass. A strong significant dependence of HCB (r(2) = 0.83), p,p'-DDE (r(2) = 0.60), and PCBs (r(2) = 0.36-0.47) concentrations in soil on its organic carbon content was also observed, indicating the important role of soil organic matter (SOM) in the retention of PCBs and OCPs in Polar Regions, where SOM content is low. Penguin colonies enhance the SOM content in some areas which is reflected in higher concentrations of all POPs, especially of persistent compounds such as p,p'-DDE. Higher concentrations of PCBs and PAHs found at the currently active Byers Camp (in an Antarctic Specially Protected Area) were explained by higher SOM content, thus indicating that Antarctic regulations are being successfully fulfilled in this small research area. On the other hand, PAHs in soils proximate to current Juan Carlos I research station show that even small human settlements are an important source of PAHs to the local environment. Therefore, even though the concentrations in Antarctica are low, there is evidence of local hotspots of contamination. PMID- 22243337 TI - Inducible alkylation of DNA by a quinone methide-peptide nucleic acid conjugate. AB - The reversibility of alkylation by a quinone methide intermediate (QM) avoids the irreversible consumption that plagues most reagents based on covalent chemistry and allows for site specific reaction that is controlled by the thermodynamics rather than kinetics of target association. This characteristic was originally examined with an oligonucleotide QM conjugate, but broad application depends on alternative derivatives that are compatible with a cellular environment. Now, a peptide nucleic acid (PNA) derivative has been constructed and shown to exhibit an equivalent ability to delivery the reactive QM in a controlled manner. This new conjugate demonstrates high selectivity for a complementary sequence of DNA even when challenged with an alternative sequence containing a single T/T mismatch. Alternatively, alkylation of noncomplementary sequences is only possible when a template strand is present to colocalize the conjugate and its target. For efficient alkylation in this example, a single-stranded region of the target is required adjacent to the QM conjugate. Most importantly, the intrastrand self-adducts formed between the PNA and its attached QM remained active and reversible over more than 8 days in aqueous solution prior to reaction with a chosen target added subsequently. PMID- 22243338 TI - Exploring the role of topological frustration in actin refolding with molecular simulations. AB - Actin plays crucial roles in the life of the cell while being notorious for its inability to reach a functional conformation without the help of assistant proteins. In eukaryotes, for example, the cytosolic chaperonin containing TCP-1 (CCT) and prefoldin (PFD) are required for actin folding assistance and prevention of protein aggregation in the crowded cellular environment. The folding of non-native actin is known to occur in a number of steps, but the reasons underlying its folding difficulty are unknown. Because a full, atomistic level, investigation of the kinetics and thermodynamics of folding of such a large molecule is beyond computational reach, we focused our investigation on the role of topological frustration on the folding of actin. Namely, we studied the (re)folding of actin using simulations of a variant self-organized polymer model (SOP-DH) starting from a stretched state, leading to results that correlate well with experimentally driven conclusions and allowing us to make a number of testable predictions. Primarily, our simulations reveal that the successful refolding of the C-terminus end of actin occurs through a zipping process in which the alpha-helices wind up turn by turn upon formation of their native tertiary contacts. In turn, an early formation of the helical structure in this region of the chain has deleterious effects for actin's refolding fitness. Moreover, the C-terminus refolding is a very rare event in our simulations, in agreement with the large activation barrier predicted on the basis of experimental studies of actin unfolding in EDTA. We also discovered that subdomain 4 has a low refolding probability, which can help explain why many of the non-native actin target binding sites for CCT and PFD are located within this subdomain. PMID- 22243339 TI - Derivatization of bichromic cyclometalated Ru(II) complexes with hydrophobic substituents. AB - The syntheses and physical properties of cyclometalated Ru(II) complexes containing a triphenylamine (TPA) unit bearing aliphatic groups are reported. Each member of the series consists of an octahedral Ru(II) center coordinated by a tridentate polypyridyl ligand and a tridentate cyclometalating ligand. One of the chelating ligands contains electron-deficient methyl ester groups, while a TPA unit is attached to the central ring of the adjacent chelating ligand through a thiophene bridge. This study builds on our previous work (Inorg. Chem. 2011, 50, 6019-6028; Inorg. Chem. 2011, 50, 5494-5508) by (i) outlining a synthetic protocol for installing aliphatic groups on the TPA substituents, (ii) examining the role that terminal -O-hexyl and -S-hexyl groups situated on the TPA have on the electrochemical properties, and (iii) demonstrating the potential benefit of installing the TPA on the neutral chelating ligand rather than the anionic chelating ligand. The results reported herein provide important synthetic advances for our broader goal of developing bis-tridentate cyclometalated Ru(II) complexes for light-harvesting applications. PMID- 22243359 TI - Lewy body-related alpha-synucleinopathy in the spinal cord of cases with incidental Lewy body disease. AB - Incidental Lewy body disease (ILBD) represents the early asymptomatic phase of Lewy body diseases (LBD), including idiopathic Parkinson's disease (PD). Although pathological disturbances in the spinal cord, which connects the brain to the peripheral nervous system, plays an important role, the pathology of ILBD has not been adequately examined. Eighteen ILBD and eight age-matched LBD cases were enrolled in the present study. LB-related pathology was immunohistochemically evaluated using anti-phosphorylated alpha-synuclein (palphaSyn) antibodies, revealing LB-related pathology in the spinal cords of 15 (83.3%) of the ILBD cases. Attempts were made to identify the early pattern of palphaSyn deposition in the spinal cord by comparing the cervical, thoracic, lumbar and sacral segments in detail. Most palphaSyn-positive structures were distributed in and around the autonomic nuclei of the spinal cord. The intermediolateral nuclei in the thoracic segments (Th/IML) were the most frequently and severely affected region, suggesting that Th/IML are the first structures affected. Furthermore, following analysis of the distribution pattern of the palphaSyn-positive structures, it is suspected that LB-related pathology progresses toward the caudal vertebrae by involving neurons in the spinal cord that are vulnerable to alphaSyn. It should be noted that the ILBD cases enrolled in the present study were in an earlier stage than the PD cases enrolled in the previous study, and that the present study provides new, previously undescribed information. PMID- 22243360 TI - Is Hardikar syndrome distinct from Kabuki (Niikawa-Kuroki) syndrome? PMID- 22243362 TI - Carbon dioxide in 1-butyl-3-methylimidazolium acetate. I. Unusual solubility investigated by Raman spectroscopy and DFT calculations. AB - The unusual solubility of carbon dioxide in 1-butyl-3-methylimidazolium acetate (Bmim Ac) has been studied by Raman spectroscopy and DFT calculations. It is shown that the solubility results from the existence of two distinct solvation regimes. In the first one (CO(2) mole fraction <= 0.35), the usual Fermi dyad is not observed, a fact never reported before for binary mixtures with organic liquids or ionic liquids (IL). Strong experimental evidence complemented by effective DFT modeling shows that this regime is dominated by a chemical reaction leading to the carboxylation of the imidazolium ring accompanied by acetic acid formation. The reactive scheme proposed involves two concerted mechanisms, which are a proton exchange process between the imidazolium cation and the acetate anion and the carboxylation process itself initiated from the formation of "transient" CO(2)-1-butyl-3-methylimidazole 2-ylidene carbene species. In that sense, CO(2) triggers the carboxylation reaction. Moreover, this dynamic picture circumvents consideration of a long-lived carbene formation in dense phase. The second regime is characterized by the detection of the CO(2) Fermi dyad showing that the carboxylation reaction has been strongly moderated. This finding has been interpreted as due to the interaction of the acetic acid molecules with the COO group of acetate anions involved in monodentate forms with the cation. The observation of the Fermi doublet allows us to infer that CO(2) essentially preserves its linear geometry and that the nature and strength of the interactions with its environment should be comparable to those existing in organic liquids and other IL as well. These results have been supported by DFT calculations showing that the CO(2) molecule interacts with energetically equivalent coexisting structures and that its geometry departs only slightly from the linearity. Finally, we find that the CO(2) solvation in Bmim Ac and 1-butyl-3 methylimidazolium trifluoroacetate (Bmim TFA) cannot be straightforwardly compared neither in the first regime due to the existence of a chemical reaction nor in the second regime because CO(2) interacts with a variety of environments not only consisting of ions pairs like in Bmim TFA but also with carboxylate and acetic acid molecule. PMID- 22243363 TI - The relationship of electrocardiographic left ventricular hypertrophy to decreased serum potassium. AB - BACKGROUND: Low serum potassium (K) is associated with increased blood pressure, impaired cardiac function and renal dysfunction. Although lower serum K is associated with cardiac hypertrophy in animal models, the relationship of low serum K to the presence and severity of electrocardiographic left ventricular hypertrophy (LVH) is unclear. METHODS: Baseline and yearly Cornell product LVH levels were examined in relation to low serum K (serum K <= 3.90 mEq/l, the lowest quartile of baseline K levels) in 8586 patients with baseline K levels. Patients were randomized to losartan-vs atenolol-based treatment and additional hydrochlorothiazide (HCTZ) therapy as needed. RESULTS: After adjusting for age, sex, race, prior antihypertensive treatment, losartan vs atenolol therapy, HCTZ use, baseline diastolic and systolic pressure, body mass index, serum creatinine and urine albumin/creatinine ratio, baseline serum K <= 3.90 was associated with significantly higher mean baseline Cornell product LVH (2898 vs 2801 mm*ms, p = 0.001) and a 24% higher risk of Cornell product LVH > 2440 mm*ms at baseline (OR 1.24, 95% CI 1.11-1.38, p < 0.001). After also adjusting for baseline Cornell product and changes in diastolic and systolic pressure between baseline and each year of measurement, in-treatment serum K <= 3.90 determined yearly was associated with significantly higher mean Cornell product LVH at years 1-3 and with statistically significant 16-32% increased risks of LVH by Cornell product at years 1-4. CONCLUSIONS: A low serum K is independently associated with a greater likelihood and severity of Cornell product LVH during antihypertensive therapy. PMID- 22243364 TI - Studies on the influence of host plants and effect of chemical stimulants on the feeding behavior in the muga silkworm, Antheraea assamensis. AB - The feeding habits of Antheraea assamensis, Helfer (Lepidoptera: Saturniidae) larvae towards the leaves of its four different host plants, Persea bombycina King ex. Hook (Laurales: Lauraceae), Litsea polhantha Jussieu, L. salicifolia Roxburgh ex. Nees and L. citrata Blume, and the chemical basis of feeding preference were investigated. Nutritional superiority of young and medium leaves with respect to soluble protein, total phenol and phenylalanine ammonia lyase activity was observed in the leaves of P. bombycina compared to other host plants. Attraction and feeding tests with detached leaves and artificial diet with different chemical stimulants revealed that a mixture of the flavonoids, myrcetin, and 7, 2', 4' trimethoxy dihydroxy flavone with sterol compound beta sitosterol elicited the most biting behavior by A. assamensis larvae. While linalyl acetate alone attracted larvae towards the leaves of the host plants, a mixture of caryophyllene, decyl aldehyde and dodecyl aldehyde was found to both attract them to the host leaves and cause biting behavior. Azaindole was found to deter them from the host plants. PMID- 22243366 TI - The boreal forest as a cultural landscape. AB - Because of its generally low density of humans and few settlements, the circumpolar boreal forest is often viewed as an untouched wilderness. However, archeological evidence indicates that humans have inhabited the region since the continental glaciers disappeared 8,000-12,000 years ago. This paper discusses the ecological impacts that humans have had on the boreal forest ecosystem through their activities in prehistoric, historic, and recent times and argues that the boreal forest has always been a cultural landscape with a gradient of impacts both spatially and temporally. These activities include hunting, trapping, herding, agriculture, forestry, hydroelectric dam projects, oil and natural gas development, and mining. In prehistoric times, human impacts would generally have been more temporary and spatially localized. However, the megafaunal extinctions coincident with arrival of humans were very significant ecological impacts. In historic times, the spread of Europeans and their exploitation of the boreal's natural resources as well as agricultural expansion has altered the composition and continuity of the boreal forest ecosystem in North America, Fennoscandia, and Asia. Particularly over the last century, these impacts have increased significantly (e.g., some hydroelectric dams and tar sands developments that have altered and destroyed vast areas of the boreal forest). Although the atmospheric changes and resulting climatic changes due to human activities are causing the most significant changes to the high-latitude boreal forest ecosystem, any discussion of these impacts are beyond the limits of this paper and therefore are not included. PMID- 22243365 TI - Microglial neurotransmitter receptors trigger superoxide production in microglia; consequences for microglial-neuronal interactions. AB - Microglia express three isoforms of the NADPH oxidase, Nox1, Nox2 and Nox4, with the potential to produce superoxide (O(2) (-) ). Microglia also express neurotransmitter receptors, which can modulate microglial responses. In this study, microglial activity of Nox1, Nox2 and Nox4 in primary rat cultured microglia or the rodent BV2 cell line were altered by microglial neurotransmitter receptor modulation. Glutamate, GABA or ATP triggered microglial O(2) (-) production via Nox activation. Nox activation was elicited by agonists of metabotropic mGlu3 receptors and by group III receptors, by GABA(A) but not GABA(B) receptors, and by purinergic P2X(7) or P2Y(2/4) receptors but not P2Y(1) receptors, and inhibited by metabotropic glutamate receptor 5 antagonists. The neurotransmitters also modulated Nox mRNA expression and NADPH activity. The activation of Nox by BzATP or GABA promoted a neuroprotective phenotype whilst the activation of Nox by glutamate promoted a neurotoxic phenotype. Taken together, these data indicate that microglial neurotransmitter receptors can signal via Nox to promote neuroprotection or neurotoxicity. This has implications for the subsequent neurotoxic profile of microglia when neurotransmitter levels may become skewed in neurodegeneration. PMID- 22243368 TI - 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene induces substantial hyperplasia in fibrotic mouse liver. AB - The proliferative response of hepatocytes in vivo can be induced by two mechanisms: severe damage to hepatic tissue results in regenerative growth and so called primary hepatocyte mitogens can initiate liver cell proliferation without preceding loss of parenchyma. The regulation of the two responses is quite different. The decreased regenerative response of cirrhotic/fibrotic liver is well known, and is a severe obstacle to surgery of the diseased liver. In the present experiments we investigated the efficiency of a primary hepatocyte mitogen 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOB) on two different liver cirrhosis/fibrosis models in mice induced by chronic administration of CCl(4) and thioacetamide respectively. BrdU incorporation and cyclin A expression established clearly that there is a reduced but still powerful mitogenic response of the fibrotic livers. Therefore, primary hepatocyte mitogens appear to be suitable to be used to rescue the regenerative response of cirrhotic livers. PMID- 22243393 TI - GC/MS method for positive detection of Bacillus anthracis endospores. AB - A simple method was developed for detection of Bacillus anthracis (BA) endospores and for differentiation of them from other species in the Bacillus cereus group. Chemical profiles that include lipids (i.e., fatty acids), carbohydrates (i.e., sugars), and the spore-specific biomarker, dipicolinic acid, were generated by one-step thermochemolysis (TCM) at 140 degrees C in 5 min to provide specific biomarker signatures. Anthrose, which is a biomarker characteristic of the B. cereus group of bacteria, was determined from a fragment produced by TCM. Surprisingly, several virulent BA strains contained very low levels of anthrose, which confounded their detection. A statistical discrimination algorithm was constructed using a combination of biomarkers, which was robust against different growth conditions (medium and temperature). Fifteen endospore-forming Bacillus species were confirmed in a statistically designed test (~90%) using the algorithm, including six BA strains (four virulent isolates), five B. thuringiensis (BT) isolates, and one isolate each for B. cereus (BC), B. mycoides (BM), B. atrophaeus (BG), and B. subtilis (BS). The detection limit for B. anthracis was found to be 50,000 endospores, on the basis of the GC/MS detection limits for 3-methyl-2-butenoic acid methyl ester, which is the biomarker derived from TCM of anthrose. PMID- 22243395 TI - Animal experimentation and the labelling of drugs. PMID- 22243396 TI - A computer experiment model to investigate the effects of drug dosage in animals, for use in pharmacological education and research. AB - The ACD-IDEA database, which was originally developed by the authors in 2004, is an ongoing compilation of existing data on the in vivo doses of compounds at which various responses in certain animal species have been observed. It can provide an infrastructure for various research/educational efforts, and creates a synergy for new applications. In this paper, some of these applications are described. Specific interfaces within the database are designed for users who are not computer specialists. Users can search the database to find the answer to a query, or they can design a simple virtual animal experiment. In the second case, the interface is used to undertake a dialogue with the system, in order to test the user's knowledge regarding an experiment under consideration, and to allow the user to glean additional information on better experimental planning. The use of this virtual experimental tool should lead to savings in time, animals, materials, and monetary costs, while the effective learning outcomes of pharmacological experiments are maintained or enhanced. PMID- 22243397 TI - Lessons from chimpanzee-based research on human disease: the implications of genetic differences. AB - Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98-99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis C virus infection in the two species, the lack of correlation in the efficacy of vaccines and treatments between chimpanzees and humans, and the fact that chimpanzees are not useful for research on human cancer. The major molecular differences underlying these inter species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and chimpanzee genetic sequences is of little consequence for biomedical research. The extrapolation of biomedical data from the chimpanzee to the human is therefore highly unreliable, and the use of the chimpanzee must be considered of little value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to science. PMID- 22243398 TI - Estimation of the acute inhalation hazards of chemicals based on route-to-route and local endpoint extrapolation: experience from bulk maritime transport. AB - Data on acute lethal inhalation toxicity from animal studies are commonly required for assessing the hazards to human health of volatile, gaseous and dusty chemicals or their mixtures. The International Maritime Organisation (IMO) made the provision of acute inhalation toxicity data a mandatory requirement for the carriage of bulk liquid chemicals transported by sea in tank ships, thereby creating the need for inhalation data on many hundreds of chemicals in bulk maritime transport. Taking note of previously published proposals for estimating acute inhalation toxicity hazards for chemicals, and the paucity of measured experimental data, an extrapolation method has been developed by the Group of Experts on the Scientific Aspects of Marine Environmental Protection (GESAMP) to partly fulfil this need. This method should be seen as a pragmatic approach to the challenge of missing measured experimental test data, with the added benefit of reducing tests in experimental animals. The method is based on a route-to route (i.e. between-route) extrapolation of information on acute oral and/or dermal toxicity, in combination with data on the potential for irritation and/or corrosion to skin and eyes. The validation of this method was based on the individual evaluation of inhalation toxicity studies for 330 chemicals, including mixtures and many important chemical groups, for which the IMO holds public and industry-confidential data. The authors contend that this extrapolation method offers a reliable basis for hazard evaluation in the context of bulk maritime transport, and the 'GESAMP inhalation toxicity extrapolation method' has become part of the IMO regulatory system for the carriage of bulk liquids (i.e. noxious liquid substances) on board tank ships. PMID- 22243399 TI - Willingness to spare animals in undergraduate medical education in Southern India: a preliminary questionnaire-based investigation. AB - Animal experiments continue to play an integral role in Indian undergraduate medical education, even though alternatives are becoming increasingly available. In this context, this study aimed to assess the perceptions of pharmacology faculty members from medical colleges in southern India regarding the use of animals and alternatives in experimental pharmacology, and to determine the association between these perceptions and the socio-demographic characteristics of the participants. Data were collected from 59 faculty members of 15 medical colleges in southern India. The response rate was 84.3%. A 30-statement, five domain questionnaire was used, with a global score of 120. The mean +/- SD global score was 60.9 +/- 17.3. Significant differences were observed in domain scores and individual statement scores with respect to the extent of teaching experience. There were no statistically significant differences in perceptions with respect to age, gender or educational qualifications. All the participating colleges were conducting at least 3-8 animal experiments per year on the rabbit, rat, mouse and frog/toad. The pharmacology faculty members in the southern India medical colleges included in the study (especially the more experienced teachers) supported animal use in undergraduate medical education, in spite of being aware of the drawbacks of animal experiments and the availability of alternatives. PMID- 22243401 TI - Role of p53-dependent placental apoptosis in the reproductive and developmental toxicities of caffeine in rodents. AB - The aim of the present study was to evaluate the role of placental apoptosis in mediating the reproductive and developmental toxicity of caffeine in rodents. Female Kunming mice were treated with caffeine (60, 120 and 240 mg/kg per day) before and during pregnancy. The conception rate, maternal bodyweight gain, placental weight and indices of fetal developmental, including the rate of intrauterine growth retardation (IUGR; i.e. the actual number of fetuses exhibiting IUGR as a percentage of the total number of fetuses), were determined on gestational day (GD) 18. Female Wistar rats were treated with caffeine (20, 60 and 180 mg/kg per day) from GD11 to GD20. The IUGR rate, maternal plasma angiotensin (Ang) II and prolactin concentrations, placental pathology, expression of angiotensin AT(1) and AT(2) receptors and apoptosis-related proteins were measured on GD20. In mice, caffeine treatment dose-dependently reduced the total conception rate, delayed conception and decreased maternal bodyweight gain, placental weight, fetal bodyweight and fetal body and tail lengths, whereas the IUGR rate was increased. In rats, caffeine treatment dose dependently decreased placental weight and fetal bodyweight and increased the IUGR rate. Abnormal placental structures and decreased maternal plasma prolactin concentrations were observed following 180 mg/kg per day caffeine treatment, which resulted in increases in renin-angiotensin system (RAS) activity, including maternal plasma AngII concentrations and placental AT(1B) and AT(2) receptor expression, and Bax and p53 expression, but decreases in placental Bcl-2 expression. On the basis of the results of the present study, it appears that caffeine ingestion has detrimental effects on the reproductive system and fetal development in rodents that are associated with chronic activation of the maternal and placental RAS, and induction of p53-dependent placental apoptosis. PMID- 22243402 TI - Fate of brominated flame retardants and organochlorine pesticides in urban soil: volatility and degradation. AB - As the uses of polybrominated diphenyl ethers (BDEs) are being phased out in many countries, soils could become a secondary emission source to the atmosphere. It is also anticipated that the demand for alternative brominated flame retardants (BFRs) will grow, but little is known about their environmental fate in soils. In this study, the volatility and degradation of BFRs and organochlorine pesticides (OCPs) in soil was investigated. A low organic carbon (5.6%) urban soil was spiked with a suite of BFRs and OCPs, followed by incubation under laboratory condition for 360 days. These included BDE- 17, -28, -47, -99; alpha- and beta 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH), beta-1,2,5,6 tetrabromocyclooctane (TBCO), and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE), OCPs: alpha-hexachlorocyclohexane (alpha-HCH) and (13)C(6)-alpha-HCH, trans-chlordane (TC), and (13)C(10)-TC. The volatility of spiked chemicals was investigated using a fugacity meter to measure the soil-air partition coefficient (K(SA)). K(SA) of some spiked BFRs and OCPs increased from Day 10 to 60 or 90 and leveled off afterward. This suggests that the volatility of BFRs and OCPs decreases over time as the chemicals become more strongly bound to the soil. Degradation of alternative BFRs (alpha- and beta-TBECH, beta-TBCO, DPTE), BDE-17, and alpha-HCH ((13)C-labeled and nonlabeled) was evident in soils over 360 days, but no degradation was observed for the BDE-28, -47, -99, and TC ((13)C-labeled and nonlabeled). A method to separate the enantiomers of alpha-TBECH and beta TBCO was developed and their degradation, along with alpha-HCH ((13)C-labeled and nonlabeled) was enantioselective. This is the first study which reports the enantioselective degradation of chiral BFRs in soils. Discrepancies between the enantiomer fraction (EF) of chemicals extracted from the soil by dichloromethane (DCM) and air were found. It is suggested that DCM removes both the sequestered and loosely bound fractions of chemicals in soil, whereas air accesses only the loosely bound fraction, and these two pools are subject to different degrees of enantioselective degradation. This calls for caution when interpreting EFs obtained from DCM extraction of soil with EFs in ambient air. PMID- 22243403 TI - Evidence in support of lysine 77 and histidine 96 as acid-base catalytic residues in saccharopine dehydrogenase from Saccharomyces cerevisiae. AB - Saccharopine dehydrogenase (SDH) catalyzes the final reaction in the alpha aminoadipate pathway, the conversion of l-saccharopine to l-lysine (Lys) and alpha-ketoglutarate (alpha-kg) using NAD+ as an oxidant. The enzyme utilizes a general acid-base mechanism to conduct its reaction with a base proposed to accept a proton from the secondary amine of saccharopine in the oxidation step and a group proposed to activate water to hydrolyze the resulting imine. Crystal structures of an open apo form and a closed form of the enzyme with saccharopine and NADH bound have been determined at 2.0 and 2.2 A resolution, respectively. In the ternary complex, a significant movement of domain I relative to domain II that closes the active site cleft between the two domains and brings H96 and K77 into the proximity of the substrate binding site is observed. The hydride transfer distance is 3.6 A, and the side chains of H96 and K77 are properly positioned to act as acid-base catalysts. Preparation of the K77M and H96Q single mutant and K77M/H96Q double-mutant enzymes provides data consistent with their role as the general acid-base catalysts in the SDH reaction. The side chain of K77 initially accepts a proton from the epsilon-amine of the substrate Lys and eventually donates it to the imino nitrogen as it is reduced to a secondary amine in the hydride transfer step, and H96 protonates the carbonyl oxygen as the carbinolamine is formed. The K77M, H976Q, and K77M/H96Q mutant enzymes give 145-, 28-, and 700-fold decreases in V/E(t) and >103-fold increases in V2/K(Lys)E(t) and V2/K(alpha-kg)E(t) (the double mutation gives >105-fold decreases in the second-order rate constants). In addition, the K77M mutant enzyme exhibits a primary deuterium kinetic isotope effect of 2.0 and an inverse solvent deuterium isotope effect of 0.77 on V2/K(Lys). A value of 2.0 was also observed for (D)(V2/K(Lys))(D2O) when the primary deuterium kinetic isotope effect was repeated in D2O, consistent with a rate-limiting hydride transfer step. A viscosity effect of 0.8 was observed on V2/K(Lys), indicating the solvent deuterium isotope effect resulted from stabilization of an enzyme form prior to hydride transfer. A small normal solvent isotope effect is observed on V, which decreases slightly when repeated with NADD, consistent with a contribution from product release to rate limitation. In addition, V2/K(Lys)E(t) is pH-independent, which is consistent with the loss of an acid-base catalyst and perturbation of the pK(a) of the second catalytic group to a higher pH, likely a result of a change in the overall charge of the active site. The primary deuterium kinetic isotope effect for H96Q, measured in H2O or D2O, is within error equal to 1. A solvent deuterium isotope effect of 2.4 is observed with NADH or NADD as the dinucleotide substrate. Data suggest rate-limiting imine formation, consistent with the proposed role of H96 in protonating the leaving hydroxyl as the imine is formed. The pH-rate profile for V2/K(Lys)E(t) exhibits the pK(a) for K77, perturbed to a value of ~9, which must be unprotonated to accept a proton from the epsilon-amine of the substrate Lys so that it can act as a nucleophile. Overall, data are consistent with a role for K77 acting as the base that accepts a proton from the epsilon-amine of the substrate lysine prior to nucleophilic attack on the alpha-oxo group of alpha-ketoglutarate, and finally donating a proton to the imine nitrogen as it is reduced to give saccharopine. In addition, data indicate a role for H96 acting as a general acid-base catalyst in the formation of the imine between the epsilon-amine of lysine and the alpha-oxo group of alpha-ketoglutarate. PMID- 22243404 TI - General LC-MS/MS method approach to quantify therapeutic monoclonal antibodies using a common whole antibody internal standard with application to preclinical studies. AB - Ligand binding assays (LBAs) are widely used for therapeutic monoclonal antibody (mAb) quantification in biological samples. Major limitations are long method development times, reagent procurement, and matrix effects. LC-MS/MS methods using signature peptides are emerging as an alternative approach, which typically use a stable isotope labeled signature peptide as the internal standard (IS). However, a new IS has to be generated for every candidate, and the IS may not correct for variations at all processing steps. We have developed a general LC MS/MS method approach employing a uniformly heavy-isotope labeled common whole mAb IS and a common immunocapture for sample processing. The method was streamlined with automation for consistency and throughput. Method qualification of four IgG(2) and four IgG(1) mAbs showed sensitivity of 0.1 MUg/mL and linearity of 0.1-15 MUg/mL. Quality control (QC) data of these eight mAbs were accurate and precise. The QC performance of the whole molecule labeled IS was better than those of synthetic labeled IS peptides tested. The pharmacokinetic results of two mAbs (an IgG(2) and IgG(1) candidate) dosed in rats were comparable to those of LBA. The general LC-MS/MS method approach overcomes the limitations of current methods to reduce time and resources required for preclinical studies. PMID- 22243405 TI - Direct venous spinal reabsorption of cerebrospinal fluid: a new concept with serial magnetic resonance cisternography in rabbits. AB - OBJECT: For nearly 100 years it has been believed that the main reabsorption of CSF occurs in arachnoid projections into the superior sagittal sinus, but a significant number of experiments and cases conflict with this hypothesis. According to recently published studies, CSF is permanently produced and absorbed in the whole CSF system. Clusters of arachnoidal villi, which are speculated to have a role in the reabsorption of CSF, have recently been revealed in the dorsal root of the spinal nerves. Huge absorptive surface areas of microvessels have been suggested to serve a putative role in reabsorption. The authors' aim was to observe direct venous connections between the subarachnoid space and the perispinal veins. METHODS: Eleven adult (6 months old) New Zealand white male rabbits weighing approximately 3.0 kg each were used in this experiment. After obtaining precontrast MR cisternography images, subarachnoid access was gained percutaneously via a cisternal approach by using a 20-gauge intravenous indwelling cannula. One rabbit died as a result of brainstem trauma during percutaneous cannulation before contrast administration, but contrast agent was still injected to see the possible MR imaging results of spinal CSF reabsorption after death. Magnetic resonance imaging was performed at 15, 60, 120, and 180 minutes after the administration of contrast agent. After intramuscular injections of anesthetic, 2 rabbits died 120 and 150 minutes after contrast injection, but the MR imaging study at 180 minutes after contrast injection was still performed. RESULTS: Direct connections between the subarachnoid space and the perispinal veins were observed in all rabbits during serial MR cisternography. The enhancement power was not affected by the amount of injected contrast agent or by cervical or lumbar penetration but was increased at higher contrast concentrations or upon seizure (physical activity). CONCLUSIONS: Extracranial reabsorption of CSF has been finally proved with direct radiological confirmation of spinal venous reabsorption of CSF using serial MR cisternography. The authors believe that this study can help to develop a more accurate model of CSF dynamics, which will allow understanding of many CSF-related diseases, as well as the development of new strategies for treatment. PMID- 22243406 TI - Coarse-grained molecular dynamics simulations of the phase behavior of the 4 cyano-4'-pentylbiphenyl liquid crystal system. AB - In this paper, with the aim to establish a rational coarse-grained (CG) model for the 4-cyano-4'-pentylbiphenyl (5CB) molecule, we construct three possible CG models (5P, 6P, and 7P) and then determine the bonded and nonbonded interaction parameters separately. For the intramolecular bonded interactions, the bond and angle distributions of the 5CB bulk phase are used as the target properties. For the nonbonded interactions between CG particles, we combine the structure-based and thermodynamic quantities-based methods for the parametrization of CG interaction potentials and attempt to use several fragment molecular systems to derive the CG nonbonded interaction parameters in order to maintain the transferability of our CG models to some extent. Finally, we fix the optimal nonbonded LJ parameters between CG bead pairs such that the results from CG simulations not only correctly reproduce the experimental density and the nematic LC state at 300 K and 1 atm but also reasonably approximate the local structural properties calculated from the underlying atomistic model. Through comparison of the resulting CG data with target properties, the 6P model is found to be the best one among the three, and then we use this model to investigate the phase behavior and dynamic properties. Our results show that the phase transition temperature from nematic to isotropic phase and the diffusion coefficients are reproduced very well, demonstrating the rationality of the 6P model. Our coarse grained process should have implications for constructing CG models for nCB series or molecules with similar architectures. PMID- 22243408 TI - Studies on serum 8-hydroxy guanosine (8-OHdG) as reliable biomarker for psoriasis. AB - BACKGROUND: Oxidative stress was implicated in the psoriasis disease development and may damage DNA leading to keratinocytes cell death. No serum biomarker was available for the oxidative DNA damage. OBJECTIVES: To evaluate the 8-OHdG (8 Hydroxy guanosine) as reliable biomarker for the oxidative stress in psoriatic patients with severity. METHODS: A total of 30 patients were considered for the study and graded according to the Psoriasis Area Severity Index (PASI) and 10 healthy controls. Blood was collected under aseptic condition, and serum was separated. Serum 8-OHdG and total antioxidant capacity was measured by competitive enzyme linked immunosorbent assay using '8-OHdG Check' and PAO kit (JaICA, Fukuroi City, Japan). RESULTS: The average serum 8-OHdG level in the control, mild, moderate and severe groups were 1.18 +/- 0.93 ng/mL, 3.46 +/- 0.82 ng/mL, 3.68 +/- 0.67 ng/mL and 4.86 +/- 1.7 ng/mL respectively. There was no significant difference in the average level of total antioxidant capacity of control, mild, moderate and severe groups, and the values presented were 295.88 +/- 206 MUmol/L, 1392.20 +/- 225 MUmol/L, 1199.57 +/- 257 MUmol/L and 1184.24 +/- 207 MUmol/L respectively. CONCLUSION: Serum 8-OHdG levels could be used as good biomarker for the early diagnosis of psoriasis and its management. PMID- 22243409 TI - Red cell distribution width in patients with prehypertension and hypertension. AB - OBJECTIVE: Red cell distribution width (RDW) which is reported as part of complete blood count in routine clinical practice, is a measure of variability in size of the erythrocytes in the circulation. It is a novel predictor of mortality both in unselected populations and in some selected group of patients. We aimed to search whether RDW values differ between the healthy population and the patients with pre-hypertension and hypertension who are otherwise healthy, considering the widely accepted role of RDW as a prognostic marker especially for mortality. PATIENTS AND METHODS: Patients who were diagnosed with prehypertension or hypertension for the first time according to the Joint National Committee (JNC) 7 criteria and otherwise healthy were enrolled to the study. One-hundred and twenty-eight patients with hypertension, 74 patients with prehypertension and 36 healthy controls participated in the study. Complete blood count, biochemistry and erythrocyte sedimentation rates were measured by standard methods. Hemoglobin, white blood cell count, mean corpuscular volume, platelet count and RDW were recorded. RESULTS: After adjustment for age, hemoglobin level, presence of anemia, serum uric acid level, erythrocyte sedimentation rate and mean corpuscular volume, mean RDW values were 15.26 +/- 0.82, 16.54 +/- 0.91 and 13.87 +/- 0.94 in prehypertensive, hypertensive and control groups, respectively (p < 0.05). Systolic and diastolic blood pressures were strongly correlated with RDW (r = 0.848 and r = 0.748, respectively; p < 0.01). CONCLUSION: RDW is higher in prehypertensive and hypertensive patients compared with healthy controls independently of age, inflammatory status and anemia. Higher RDW values are strongly correlated with higher systolic and diastolic blood pressures. PMID- 22243411 TI - Diagnosis and management of oviductal disease in three red-eared slider turtles (Trachemys scripta elegans). AB - Three mature, female, red-eared slider turtles (Trachemys scripta elegans) were individually, and separately, diagnosed with different forms of oviductal disease. Case 1 presented with acute cloacal bleeding and was diagnosed with acute oviductal rupture and ectopic eggs in the coelom. Case 2 presented for repeated scratching in the direction of the cloaca and was diagnosed with chronic oviductal impaction and coelomitis. Both cases were treated successfully by endoscopy-assisted complete ovariosalpingectomy via a bilateral prefemoral approach. Case 3 presented with a reduced appetite and signs of nesting behaviour and was diagnosed with obstructive dystocia associated with bacterial salpingitis. Successful treatment consisted of transcloacal egg removal and systemic antibiotics. Complete recovery was achieved in all three turtles, which remained disease-free 23 to 33 months later. Oviductal disease can present with a variety of clinical signs, and an accurate diagnosis can be made based on a thorough history, physical examination and appropriate diagnostic techniques. PMID- 22243412 TI - Lighting up the brain's reward circuitry. AB - The brain's reward circuit is critical for mediating natural reward behaviors including food, sex, and social interaction. Drugs of abuse take over this circuit and produce persistent molecular and cellular alterations in the brain regions and their neural circuitry that make up the reward pathway. Recent use of optogenetic technologies has provided novel insights into the functional and molecular role of the circuitry and cell subtypes within these circuits that constitute this pathway. This perspective will address the current and future use of light-activated proteins, including those involved in modulating neuronal activity, cellular signaling, and molecular properties in the neural circuitry mediating rewarding stimuli and maladaptive responses to drugs of abuse. PMID- 22243413 TI - Structure guided development of novel thymidine mimetics targeting Pseudomonas aeruginosa thymidylate kinase: from hit to lead generation. AB - Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC(50) = 58 MUM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP(5)A in a PaTMK homology model. This hit (1) was cocrystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC(50) = 100-200 nM) were synthesized using computer-aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs but not with human TMK, which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray cocrystal structures, homology models, and structure-activity relationship results. PMID- 22243414 TI - Integrated lateral flow test strip with electrochemical sensor for quantification of phosphorylated cholinesterase: biomarker of exposure to organophosphorus agents. AB - An integrated lateral flow test strip with an electrochemical sensor (LFTSES) device with rapid, selective, and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of postexposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of the total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. The proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows a linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with a detection limit of 0.02 nM. On the basis of this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective, and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents. PMID- 22243415 TI - Synthesis and structural characterization of oaklin-catechins. AB - Condensation reactions of procyanidin dimer B4 with two representative oak wood cinnamic aldehydes (coniferaldehyde and sinapaldehyde) were conducted in winelike model solutions. Coniferaldehyde led to the formation of guaiacylcatechin pyrylium-catechin (GCP-catechin, 737 m/z), whereas sinapaldehyde led to the formation of syringylcatechin-pyrylium-catechin (SCP-catechin, 767 m/z). The former was also structurally characterized by 1D and 2D NMR, allowing an elucidation of the formation mechanism of these oaklin-catechin adducts and demonstrating the importance of procyanidins in the formation of colored compounds through the reaction with cinnamic aldehydes extracted from oaks during storage. PMID- 22243416 TI - Mining and characterization of sequence tagged microsatellites from the brown planthopper Nilaparvata lugens. AB - The brown planthopper, Nilaparvata lugens (Stal) (Hemiptera: Delphacidae), is an important pest of rice. To better understand the migration pattern and population structure of the Chinese populations of N. lugens, we developed and characterized 12 polymorphic microsatellites from the expressed sequence tags database of N. lugens. The occurrence of these simple sequence repeats was assessed in three populations collected from three provinces of China. The number of alleles per locus ranged from 3 to 13 with an average of 6.5 alleles per locus. The mean observed heterozygosity of the three populations ranged from 0.051 to 0.772 and the expected heterozygosity ranged from 0.074 to 0.766. The sequences of the 12 markers were highly variable. The polymorphism information content of the 12 markers was high and ranged from 0.074 to 0.807 (mean = 0.503). Sequencing of microsatellite alleles revealed that the fragment length differences were mainly due to the variation of the repeat motif. Significant genetic differentiation was detected among the three N. lugens populations as the Fst ranged from 0.034 to 0.273. Principle coordinates analysis also revealed significant genetic differentiation between populations of different years. We conclude that these microsatellite markers will be a powerful tools to study the migration routine of the N. lugens. PMID- 22243417 TI - Depression as a mediator of the association between substance abuse and negative parenting of fathers. AB - OBJECTIVE: The role of substance abuse (SA) and depression on paternal parenting has recently gained attention in the research literature. Both SA and depression have been associated with negative parenting in fathers, but studies to date have not examined the mediating role that depression may play in the association of SA and fathering. METHODS: SA, depression, and parenting data were reported by 87 fathers presenting for SA evaluation. Bootstrap mediation modeling was conducted to determine the role of depression on the association between SA and negative parenting. RESULTS: Depression is a significant mediator of the relationship between the severity of fathers' drug use and hostile-aggressive parenting behaviors. Fathers who had concerns about parenting or wanted help to improve the parent-child relationship had significantly higher symptoms of depression. CONCLUSIONS: Depressive symptoms in fathers entering SA treatment have implications for both the severity of drug abuse and negative parenting behaviors. PMID- 22243418 TI - High-throughput analysis of ligand-induced internalization of beta2-adrenoceptors using the coiled-coil tag-probe method. AB - Receptor internalization is a useful indicator of the activity of ligands. The N terminus of the beta(2)-adrenergic receptor expressed on the cell surface was labeled with fluorophores using a novel coiled-coil labeling system. Endocytosis of the receptors was automatically detected using a fluorescence image analyzer by evaluating (1) translocation of the receptor from cell-surface to intracellular regions and (2) acidification in endosomes. Both parameters increased upon agonist stimulation in a dose-dependent manner. The extent of endocytosis was significantly dependent on the agonist used, indicating the presence of a biased signaling for endocytosis. The receptor antagonists can also be screened by competitive inhibition of agonist-induced endocytosis. The image analysis approach has proven to be useful for high-throughput characterization and screening of GPCR ligands. PMID- 22243419 TI - Different effect of hydrogelation on antifouling and circulation properties of dextran-iron oxide nanoparticles. AB - Premature recognition and clearance of nanoparticulate imaging and therapeutic agents by macrophages in the tissues can dramatically reduce both the nanoparticle half-life and delivery to the diseased tissue. Grafting nanoparticles with hydrogels prevents nanoparticulate recognition by liver and spleen macrophages and greatly prolongs circulation times in vivo. Understanding the mechanisms by which hydrogels achieve this "stealth" effect has implications for the design of long-circulating nanoparticles. Thus, the role of plasma protein absorption in the hydrogel effect is not yet understood. Short circulating dextran-coated iron oxide nanoparticles could be converted into stealth hydrogel nanoparticles by cross-linking with 1-chloro-2,3-epoxypropane. We show that hydrogelation did not affect the size, shape and zeta potential, but completely prevented the recognition and clearance by liver macrophages in vivo. Hydrogelation decreased the number of hydroxyl groups on the nanoparticle surface and reduced the binding of the anti-dextran antibody. At the same time, hydrogelation did not reduce the absorption of cationic proteins on the nanoparticle surface. Specifically, there was no effect on the binding of kininogen, histidine-rich glycoprotein, and protamine sulfate to the anionic nanoparticle surface. In addition, hydrogelation did not prevent activation of plasma kallikrein on the metal oxide surface. These data suggest that (a) a stealth hydrogel coating does not mask charge interactions with iron oxide surface and (b) the total blockade of plasma protein absorption is not required for maintaining iron oxide nanoparticles' long-circulating stealth properties. These data illustrate a novel, clinically promising property of long-circulating stealth nanoparticles. PMID- 22243420 TI - Concomitant use of clopidogrel and statins and risk of major adverse cardiovascular events following coronary stent implantation. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The CYP3A4 inhibition by lipophilic statins may attenuate the effectiveness of clopidogrel. * No studies have measured drug exposure in a time-varying manner that detects discontinuation and restart of clopidogrel and statin therapy, allowing clinical quantification of the interaction effect. WHAT THIS STUDY ADDS: * Clopidogrel and CYP3A4 metabolizing statin use were each associated with a substantially reduced rate of major adverse cardiovascular events within 12 months after coronary stent implantation. * Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of major adverse cardiovascular events in patients using clopidogrel after coronary stent implantation. AIMS: To examine whether CYP3A4-metabolizing statin use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation, using time-varying drug exposure ascertainment. METHODS: We conducted this population-based cohort study in Western Denmark (population: 3 million) using medical databases. We identified all 13 001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12 months of follow-up, we tracked the use of clopidogrel and CYP3A4-metabolizing statins and the rate of MACE. We used Cox regression to compute hazard ratios (HRs) controlling for potential confounders. RESULTS: The rate of MACE per 1000 person years was 104 for concomitant clopidogrel and statin use, 130 for clopidogrel without statin use, 108 for statin without clopidogrel use and 446 for no use of either drug. The adjusted HR comparing clopidogrel use with non-use was 0.68 (95% confidence interval (CI) 0.58, 0.79) among statin users and 0.34 (95% CI 0.29, 0.40) among statin non users, yielding an interaction effect (i.e. relative rate increase) of 1.97 (95% CI 1.59, 2.44). The adjusted HR for MACE comparing statin use with non-use was 0.97 (95% CI 0.83, 1.13) among clopidogrel users and 0.49 (95% CI 0.42, 0.57) among clopidogrel non-users. CONCLUSIONS: Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of MACE within 12 months after coronary stent implantation. Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of MACE in patients using clopidogrel after coronary stent implantation. PMID- 22243423 TI - A sensitive chromatographic strip test for the rapid detection of enrofloxacin in chicken muscle. AB - A sensitive colloidal gold immunochromatography assay using a specific monoclonal antibody was developed for the rapid detection of enrofloxacin (ENR) residues in chicken muscles. Anti-ENR antibodies with high sensitivity and specificity are generated by immunising BALB/c mice with well-characterised ENR-bovine serum albumin conjugate. An orthogonal L9(3)3 test was designed, and various parameters that influenced the assay performance were investigated and optimised. Under the optimised conditions, the cut-off limits of semi-quantitative test strips for ENR were found to be 3 ng/mL in phosphate-buffered saline and 8 ug/kg in chicken muscle. The ENR test strips showed a 6% cross-reactivity with ciprofloxacin, 3% with norfloxacin, less than 1% with ofloxacin and sarafloxacin and 0.1% with the other eight fluoroquinolones including enoxacin, difloxacin, danofloxacin, pefloxacin, lomefloxacin, sparfloxacin, oxolinic acid and flumequine. Consistent results are produced from the parallel analysis of ENR-contaminated chicken muscle extracts using test strips and ELISA. PMID- 22243424 TI - Erysipelas-like erythema as the presenting feature of familial Mediterranean fever. AB - BACKGROUND: 'Erysipelas-like' erythema (ELE) is a well recognized, although uncommon, manifestation of familial Mediterranean fever (FMF), which is frequently mistaken for infectious erysipelas, especially when forming the initial disease presentation. AIM: To clinically and genetically characterize ELE as the first manifestation of FMF. METHODS: FMF patients with ELE as the first disease presentation (study group), were compared with FMF patients with ELE, appearing during the disease course (control group I), and to those FMF patients who never had ELE (control group II). RESULTS: Patients of the study group were comparable to patients without ELE with respect to all demographic, clinical and genetic features studied, and yet differed from patients with ELE appearing later in the disease course in disease severity score (1.7 +/- 0.4 vs. 2.4 +/- 0.6, P = 0.01), length of diagnosis delay (7.2 +/- 6.4 vs. 2.3 +/- 3.3 years, P=0.037), age of FMF onset (24.8 +/- 19.9 vs. 5.6 +/- 5.7 years of age, P=0.014) and rate of homozygosity to the M694V mutation (14.3% vs. 68.7% respectively). ELE traits in the study and control groups were alike. CONCLUSIONS: FMF with ELE as the first disease manifestation form an uncommon subgroup, clinically and genetically diverging from the rest of the FMF-ELE patients. PMID- 22243422 TI - Mapping general anesthetic binding site(s) in human alpha1beta3 gamma aminobutyric acid type A receptors with [3H]TDBzl-etomidate, a photoreactive etomidate analogue. AB - The gamma-aminobutyric acid type A receptor (GABA(A)R) is a target for general anesthetics of diverse chemical structures, which act as positive allosteric modulators at clinical doses. Previously, in a heterogeneous mixture of GABA(A)Rs purified from bovine brain, [3H]azietomidate photolabeling of alphaMet-236 and betaMet-286 in the alphaM1 and betaM3 transmembrane helices identified an etomidate binding site in the GABA(A)R transmembrane domain at the interface between the beta and alpha subunits [Li, G. D., et.al. (2006) J. Neurosci. 26, 11599-11605]. To further define GABA(A)R etomidate binding sites, we now use [3H]TDBzl-etomidate, an aryl diazirine with broader amino acid side chain reactivity than azietomidate, to photolabel purified human FLAG-alpha1beta3 GABA(A)Rs and more extensively identify photolabeled GABA(A)R amino acids. [3H]TDBzl-etomidate photolabeled in an etomidate-inhibitable manner beta3Val-290, in the beta3M3 transmembrane helix, as well as alpha1Met-236 in alpha1M1, a residue photolabeled by [3H]azietomidate, while no photolabeling of amino acids in the alphaM2 and betaM2 helices that also border the etomidate binding site was detected. The location of these photolabeled amino acids in GABA(A)R homology models derived from the recently determined structures of prokaryote (GLIC) or invertebrate (GluCl) homologues and the results of computational docking studies predict the orientation of [3H]TDBzl-etomidate bound in that site and the other amino acids contributing to this GABA(A)R intersubunit etomidate binding site. Etomidate-inhibitable photolabeling of beta3Met-227 in betaM1 by [3H]TDBzl etomidate and [3H]azietomidate also provides evidence of a homologous etomidate binding site at the beta3-beta3 subunit interface in the alpha1beta3 GABA(A)R. PMID- 22243426 TI - TD-DFT/molecular mechanics study of the Photinus pyralis bioluminescence system. AB - This is the first report of a computational study of the bioluminescence of ligand-bound Photinus pyralis luciferase. A time-dependent PBE0/molecular mechanics approach was used to study the interaction between excited-state oxyluciferin (Keto-(-1)) and neighboring active site molecules. The results of these calculations demonstrated that the most important intermolecular interactions are: blue-shifting ionic interactions, red-shifting pi-pi stacking, and red/blue shifting hydrogen bonding. Subsequent molecular dynamics simulations further supported these conclusions. PMID- 22243427 TI - Advancing interpersonal therapy for substance use disorders. AB - BACKGROUND AND AIMS: Interpersonal psychotherapy (IPT) for substance use disorders has received little research attention over the past two decades, despite a suggested adaptation for substance use treatment. This article explores the potential reasons for the limited attention and suggests further adaptations that have the potential to increase the usefulness of IPT in treating substance use. The goal of this exploration is to renew interest in the use of IPT for substance use disorders and spark research to assess this type of intervention. MATERIALS AND METHODS: First, the published literature on the use of IPT for treating substance abuse is reviewed. Subsequently, substance use research commenting on the relational aspects of substance abuse is examined and used in order to develop and support suggested adaptations to IPT for substance abuse treatment. RESULTS: Suggested adaptations include incorporating relational elements from motivational interviewing, focusing on the importance of developing meaningful roles in society, encouraging social bonding with non-users, and using the therapeutic relationship to develop the capacity to self-soothe. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: It is expected that the suggested adaptations for IPT will enable IPT treatment to be more effective. Scientific evaluation of IPT for substance abuse is encouraged with the adoption of these proposed adaptations. PMID- 22243428 TI - Comment on "predominance of aqueous Tl(I) species in the river system downstream from the abandoned Carnoules mine (Southern France)". PMID- 22243431 TI - Beneficial effects of blueberries in experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune disease that presents with pathological and clinical features similar to those of multiple sclerosis (MS) including inflammation and neurodegeneration. This study investigated whether blueberries, which possess immunomodulatory, anti inflammatory, and neuroprotective properties, could provide protection in EAE. Dietary supplementation with 1% whole, freeze-dried blueberries reduced disease incidence by >50% in a chronic EAE model (p < 0.01). When blueberry-fed mice with EAE were compared with control-fed mice with EAE, blueberry-fed mice had significantly lower motor disability scores (p = 0.03) as well as significantly greater myelin preservation in the lumbar spinal cord (p = 0.04). In a relapsing remitting EAE model, blueberry-supplemented mice showed improved cumulative and final motor scores compared to control diet-fed mice (p = 0.01 and 0.03, respectively). These data demonstrate that blueberry supplementation is beneficial in multiple EAE models, suggesting that blueberries, which are easily administered orally and well-tolerated, may provide benefit to MS patients. PMID- 22243432 TI - Validated UV-spectrophotometric method for the evaluation of the efficacy of makeup remover. AB - A UV-spectrophotometric method for the analysis of makeup remover was developed and validated according to ICH guidelines. Three makeup removers for which the main ingredients consisted of vegetable oil (A), mineral oil and silicone (B) and mineral oil and water (C) were sampled in this study. Ethanol was the optimal solvent because it did not interfere with the maximum absorbance of the liquid foundation at 250 nm. The linearity was determined over a range of makeup concentrations from 0.540 to 1.412 mg mL-1 (R2 = 0.9977). The accuracy of this method was determined by analysing low, intermediate and high concentrations of the liquid foundation and gave 78.59-91.57% recoveries with a relative standard deviation of <2% (0.56-1.45%). This result demonstrates the validity and reliability of this method. The reproducibilities were 97.32 +/- 1.79, 88.34 +/- 2.69 and 95.63 +/- 2.94 for preparations A, B and C respectively, which are within the acceptable limits set forth by the ASEAN analytical validation guidelines, which ensure the precision of the method under the same operating conditions over a short time interval and the inter-assay precision within the laboratory. The proposed method is therefore a simple, rapid, accurate, precise and inexpensive technique for the routine analysis of makeup remover efficacy. PMID- 22243433 TI - Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion. PMID- 22243434 TI - Topical anesthetics for dermatologic procedures: a review. AB - BACKGROUND: Practitioners are increasingly using topical anesthetics to decrease the pain associated with superficial dermatologic, aesthetic, and laser procedures. Numerous lidocaine-containing products are available, but comprehensive reviews are lacking regarding their relative safety profiles and appropriate dermatologic uses. MATERIALS AND METHODS: A literature review of currently available topical anesthetics, their safety profiles, and dermatologic uses was conducted. RESULTS: Factors that should be considered to reduce the risk of side effects associated with the use of topical anesthetics include the amount of product used, body location, size of the surface area, and duration of product application. Many case reports document adverse outcomes associated with the use of compounded products that the Food and Drug Administration has not approved that have inappropriately high anesthetic concentrations and from the use of topical anesthetics on excessively large skin surface areas during laser treatments. CONCLUSIONS: Lidocaine-containing products play an integral role in cutaneous anesthesia by providing patient comfort with minimal side effects. Careful attention must be paid to the particular anatomic location, the total surface area covered, and the duration of anesthetic skin contact. PMID- 22243435 TI - Adsorptive stripping voltammetry of hen-egg-white-lysozyme via adsorption desorption at an array of liquid-liquid microinterfaces. AB - Electrochemical adsorption and voltammetry of hen-egg-white-lysozyme (HEWL) was studied at an array of microinterfaces between two immiscible electrolyte solutions (MUITIES). Adsorption of the protein was achieved at an optimal applied potential of 0.95 V, after which it was desorbed by a voltammetric scan to lower potentials. The voltammetric peak recorded during the desorption scan was dependent on the adsorption time and on the aqueous phase concentration of HEWL. The slow approach to saturation or equilibrium indicated that protein reorganization at the interface was the rate-determining step and not diffusion to the interface. For higher concentrations and longer adsorption times, a HEWL multilayer surface coverage of 550 pmol cm(-2) was formed, on the basis of the assumption that a single monolayer corresponded to a surface coverage of 13 pmol cm(-2). Implementation of adsorption followed by voltammetric detection as an adsorptive stripping voltammetric approach to HEWL detection demonstrated a linear dynamic range of 0.05-1 MUM and a limit of detection of 0.03 MUM, for 5 min preconcentration in unstirred solution; this is a more than 10-fold improvement over previous HEWL detection methods at the ITIES. These results provide the basis for a new analytical approach for label-free protein detection based on adsorptive stripping voltammetry. PMID- 22243437 TI - Additional role of O-acetylserine as a sulfur status-independent regulator during plant growth. AB - O-acetylserine (OAS) is one of the most prominent metabolites whose levels are altered upon sulfur starvation. However, its putative role as a signaling molecule in higher plants is controversial. This paper provides further evidence that OAS is a signaling molecule, based on computational analysis of time-series experiments and on studies of transgenic plants conditionally displaying increased OAS levels. Transcripts whose levels correlated with the transient and specific increase in OAS levels observed in leaves of Arabidopsis thaliana plants 5-10 min after transfer to darkness and with diurnal oscillation of the OAS content, showing a characteristic peak during the night, were identified. Induction of a serine-O-acetyltransferase gene (SERAT) in transgenic A. thaliana plants expressing the genes under the control of an inducible promoter resulted in a specific time-dependent increase in OAS levels. Monitoring the transcriptome response at time points at which no changes in sulfur-related metabolites except OAS were observed and correlating this with the light/dark transition and diurnal experiments resulted in identification of six genes whose expression was highly correlated with that of OAS (adenosine-5'-phosphosulfate reductase 3, sulfur deficiency-induced 1, sulfur-deficiency-induced 2, low-sulfur-induced 1, serine hydroxymethyltransferase 7 and ChaC-like protein). These data suggest that OAS displays a signalling function leading to changes in transcript levels of a specific gene set irrespective of the sulfur status of the plant. Additionally, a role for OAS in a specific part of the sulfate response can be deduced. PMID- 22243436 TI - Enzyme-linked immunosorbent assay-based method to quantify the association of small molecules with aggregated amyloid peptides. AB - This paper describes a simple enzyme linked immunosorbent assay (ELISA) protocol for quantifying the binding of small molecules to aggregated beta-amyloid (Abeta) peptides. Amyloid-targeting small molecules have attracted wide interest as potential agents for the treatment or diagnosis of neurodegenerative disorders such as Alzheimer's disease. The lack of general methods to evaluate small molecule-amyloid binding interactions, however, has significantly limited the number of amyloid-targeting molecules that have been studied to date. Here, we demonstrate a general method to quantify small molecule-amyloid binding interactions via a modified quantitative ELISA protocol. A key feature of this protocol is the treatment of commercial ELISA plates with an air plasma to help maintain the desired beta-sheet content of the aggregated Abeta upon immobilization of these peptides on to the polystyrene surface. We developed an ELISA-based competition assay on these air plasma-treated plates and evaluated the binding of five previously known amyloid-binding small molecules to aggregated Abeta. We show that this general ELISA-based competition assay can be used to quantify small molecule-amyloid binding interactions in the low nanomolar to low micromolar range, which is the typical range of affinities for many amyloid-targeting diagnostic agents under current development. This simple protocol for quantifying the interaction of small molecules with aggregated Abeta peptides overcomes many limitations of previously reported spectroscopic or radioactivity assays and may, therefore, facilitate the screening and evaluation of a more structurally diverse set of amyloid-targeting agents than had previously been possible. PMID- 22243438 TI - Isolation and characterization of lipase-producing bacteria in the intestine of the silkworm, Bombyx mori, reared on different forage. AB - The silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), an oligophagous insect that mainly feeds on mulberry leaves, is susceptible to entomopathogen infection when reared with tricuspid cudrania leaves. A total of 56 dominant bacterial strains, classified into 12 phylotypes based on bacteriological properties and analysis of 16S rRNA genes, were isolated from the intestine of the fourth and fifth instar silkworm larvae. Ten and seven phylotypes exist in the intestine of the silkworm larvae reared with mulberry leaves and tricuspid cudrania leaves, respectively. Four of them are common in the intestine of the two treatment groups. By screening their lipolytic ability on a Rhodamine B agar plate, nine lipase-producing bacterial strains were obtained and classified into six genera, including Bacillus, Brevibacterium, Corynebacterium, Staphylococcus, Klebsiella, and Stenotrophomonas. Except for Stenotrophomonas, which is common in both, the other genera only exist in the intestine of the silkworm larvae fed with mulberry leaves. In addition, by culture and fermentation in vitro, the maximum cell density and lipase activity of lipase-producing bacteria were examined at about 48 hours. The results indicate that diet has a significant impact on the gut bacterial community, especially lipase-producing bacteria. We suggest that the difference of lipase-producing bacterial diversity might be related to disease resistance of the silkworm. PMID- 22243440 TI - The effect of genetically enriched (E)-beta-ocimene and the role of floral scent in the attraction of the predatory mite Phytoseiulus persimilis to spider mite induced volatile blends of torenia. AB - Plants under herbivore attack emit mixtures of volatiles (herbivore-induced plant volatiles, HIPVs) that can attract predators of the herbivores. Although the composition of HIPVs should be critical for the attraction, most studies of transgenic plant-emitted volatiles have simply addressed the effect of trans volatiles without embedding in other endogenous plant volatiles. We investigated the abilities of transgenic wishbone flower plants (Torenia hybrida and Torenia fournieri) infested with spider mites, emitting a trans-volatile ((E)-beta ocimene) in the presence or absence of endogenous volatiles (natural HIPVs and/or floral volatiles), to attract predatory mites (Phytoseiulus persimilis). In both olfactory- and glasshouse-based assays, P. persimilis females were attracted to natural HIPVs from infested wildtype (wt) plants of T. hybrida but not to those of T. fournieri. The trans-volatile enhanced the ability to attract P. persimilis only when added to an active HIPV blend from the infested transgenic T. hybrida plants, in comparison with the attraction by infested wt plants. Intriguingly, floral volatiles abolished the enhanced attractive ability of T. hybrida transformants, although floral volatiles themselves did not elicit any attraction or avoidance behavior. Predator responses to trans-volatiles were found to depend on various background volatiles (e.g. natural HIPVs and floral volatiles) endogenously emitted by the transgenic plants. PMID- 22243439 TI - Plasma pencil atmospheric mass spectrometry detection of positive ions from micronutrients emitted from surfaces. AB - Analysis and detection of micronutrients is important for the reduction of the global burden of malnutrition-related disease. A relatively new technique, plasma pencil atmospheric mass spectrometry (PPAMS) was applied in a comprehensive evaluation for rapid, simultaneous detection of the key micronutrients zinc, iron, folate, vitamin A, and iodine. PPAMS was performed through the coupling of a low-temperature plasma pencil to an atmospheric mass spectrometer. The effectiveness of the PPAMS system was demonstrated through the generation of characteristic mass spectra and tandem mass spectra on neat micronutrient powders suspended on double-sided tape. The analytical performance and ability to qualitatively separate out the nutrients from a complex biological solution and each other was then assessed through the application of PPAMS on a sample matrix of micronutrients in porcine plasma in which nutrient concentration is varied from high blood level concentrations (HBLCs) to low blood level concentrations (LBLCs). A multivariate analysis method, principal component analysis (PCA), was then used to qualitatively separate the fragments obtained by nutrient type. The resulting plots of PCA scores of the positive-ion spectra from each mixed sample showed excellent separation of HBLCs and LBLCs of single nutrients at the 95% confidence level (Wagner et al. Langmuir 2001, 17, 4649-4660). The associated plots of PCA loadings showed that key loadings could be attributed to the expected micronutrient fragments. The PPAMS technique was successfully demonstrated and compared with traditional MS techniques: time-of-flight secondary ion mass spectrometry (ToF-SIMS) and electrospray ionization mass spectrometry (ESI-MS). Separation of the nutrients at concentrations relevant for human blood-based nutrient detection was possible by both ESI-MS and PPAMS. However, only PPAMS could detect the nutrients at physiological concentrations from porcine plasma. ToF-SIMS could detect the nutrients from plasma solution but required 5 to 1000-times higher concentrations of folate, vitamin A, and iodine to achieve adequate separation of the micronutrients by PCA. PMID- 22243442 TI - Long term use of drugs affecting the renin-angiotensin system and the risk of cancer: a population-based case-control study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * A recent meta-analysis has suggested an increased risk of cancer among users of angiotensin receptor blockers. WHAT THIS STUDY ADDS: * Within the limitations of an observational study there is no difference in the cancer incidence between users of drugs affecting the renin angiotensin system and users of other antihypertensives. * No consistent dose or duration dependency could be demonstrated for angiotensin reeptor blockers and angiotensin converting enzyme inhibitors. AIMS: A recent meta-analysis of clinical trials has demonstrated a small excess of cancers in persons who had been allocated to angiotensin receptor blockers (ARBs). We undertook this observational study to look at dose-response and dose-duration effects and look for specificity with respect to outcome. Use of angiotensin converting enzyme inhibitors (ACEIs) was included in the main analysis since ACEIs share pharmacological properties with ARBs. METHODS: We identified 149 417 incident cancer cases in Denmark during the period 2000-2005. Four controls, matched by age and gender, were selected for each case by a risk-set sampling. Data on medication were retrieved from the Danish National Prescription Registry. We defined long term exposure as at least 1000 defined daily doses redeemed within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS: The odds ratio (OR) associating long term drug use with incident cancer was 1.12 (95% CI 1.06, 1.18), 1.17 (95% CI 1.14, 1.20), 1.23 (95% CI 1.20, 1.26), 1.18 (95% CI 1.14, 1.22), 1.25 (95% CI 1.22, 1.28), 1.37 (95% CI 1.21, 1.54), 1.29 (95% CI 1.22, 1.37) for ARBs, ACEIs, calcium channel blockers, beta adrenoceptor blockers, thiazide diuretics and alpha-adrenoceptor blockers. No consistent dose-duration or dose-response association could be demonstrated for ARBs or ACEIs. CONCLUSIONS: The indication or possibly threshold for prescribing antihypertensives appears to be related to a small increase in cancer risk. The ARB-cancer association is probably too weak to be addressed in observational studies, given their limitations. PMID- 22243444 TI - Producing a sulfamethazine quality control material under the framework of ISO/CD Guide 80. AB - The increasing use of antimicrobial agents such as sulfonamides by the pig industry is of concern, since residues in both pork and its by-products, when derived from animals treated improperly, can endanger human health. The aim of this study was to establish the production conditions and to evaluate the homogeneity and the stability of sulfamethazine in porcine liver quality control material, produced 'in-house' for use in ring tests of the laboratory network of residues and contaminants of the Ministry of Agriculture, Livestock and Food Supply, Brazil. In the process of preparing the material, a FOSS blender was used, where the samples were ground to obtain a homogeneous mass, which was packed in polypropylene bottles. The material resulting from this process of homogenisation was sampled and analysed by LC/MS/MS. The analytical results were statistically evaluated by one-way ANOVA. According to statistical evaluation, the material produced was considered homogeneous, with 95% confidence. Stability tests were performed with the bottles stored under the specified storage conditions. They were randomly selected and analysed in duplicate by the same analytical method as the homogeneity study. The analytical results were statistically evaluated by the procedures for a stability check described in ISO 13528:2005, indicating that the material was unstable under the conditions of storage. PMID- 22243446 TI - The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data. AB - Twins have always fascinated medical research even before the discovery of DNA and the understanding of the differences between identical and non-identical twins. Dermatology with the benefit of being able to visualize phenotypes was one of the first specialities reporting on the fascinating concordance in identical (MZ) twins in the 1920's. Over the last 20 years, the heritability of skin diseases using twins has been clearly demonstrated, across a wide variety of traits including melanoma, polymorphic light eruption, psoriasis, eczema and acne. Other rarer diseases have also been shown to have a significant genetic basis such as lupus, sarcoidosis and lichen sclerosus. Following evidence of heritability for many skin disease the next step was Genome-Wide Association Studies (GWAS) which are uncovering new genes in large twin cohorts. The twin model is also ideal for the new field of epigenetics, investigating subtle differences in DNA methylation within discordant MZ pairs for a disease, as well as differences in CNVs. Twins are also valuable for examining differences in gene function via RNA expression in twins discordant for a skin trait or disease. PMID- 22243443 TI - Thermodynamics of coupled folding in the interaction of archaeal RNase P proteins RPP21 and RPP29. AB - We have used isothermal titration calorimetry (ITC) to identify and describe binding-coupled equilibria in the interaction between two protein subunits of archaeal ribonuclease P (RNase P). In all three domains of life, RNase P is a ribonucleoprotein complex that is primarily responsible for catalyzing the Mg2+ dependent cleavage of the 5' leader sequence of precursor tRNAs during tRNA maturation. In archaea, RNase P has been shown to be composed of one catalytic RNA and up to five proteins, four of which associate in the absence of RNA as two functional heterodimers, POP5-RPP30 and RPP21-RPP29. Nuclear magnetic resonance studies of the Pyrococcus furiosus RPP21 and RPP29 proteins in their free and complexed states provided evidence of significant protein folding upon binding. ITC experiments were performed over a range of temperatures, ionic strengths, and pH values, in buffers with varying ionization potentials, and with a folding deficient RPP21 point mutant. These experiments revealed a negative heat capacity change (DeltaC(p)), nearly twice that predicted from surface accessibility calculations, a strong salt dependence for the interaction, and proton release at neutral pH, but a small net contribution from these to the excess DeltaC(p). We considered potential contributions from protein folding and burial of interfacial water molecules based on structural and spectroscopic data. We conclude that binding-coupled protein folding is likely responsible for a significant portion of the excess DeltaC(p). These findings provide novel structural and thermodynamic insights into coupled equilibria that allow specificity in macromolecular assemblies. PMID- 22243475 TI - Qualitative approaches in occupational therapy research. AB - OBJECTIVE: Development of research in occupational therapy requires a continuous critical discussion concerning methodological approaches. In this paper the authors wish to contribute to such a discussion by introducing the formal data structure analysis approach (FDSA) as a method for understanding people's experiences. METHODS AND RESULTS: A review of selected publications from occupational therapy journals between 2003 and 2005 illustrated that qualitative articles within occupational therapy publications were mainly descriptive in nature. This finding raises questions about how to develop new knowledge that contributes to occupational therapy. CONCLUSIONS: In this paper the authors suggest that it is possible to apply the FDSA approach not only when describing and categorizing qualitative phenomena, but also when aiming to reach an in-depth understanding of issues related to human meaning-making; for example, how we understand engagement in occupations or living with a disability. Examples of the application of the FDSA approach are included and discussed. PMID- 22243304 TI - Search for a vectorlike quark with charge 2/3 in t+Z events from pp collisions at ?s=7 TeV. AB - A search for pair-produced heavy vectorlike charge-2/3 quarks, T, in pp collisions at a center-of-mass energy of 7 TeV, is performed with the CMS detector at the LHC. Events consistent with the flavor-changing-neutral-current decay of a T quark to a top quark and a Z boson are selected by requiring two leptons from the Z-boson decay, as well as an additional isolated charged lepton. In a data sample corresponding to an integrated luminosity of 1.14 fb(-1), the number of observed events is found to be consistent with the standard model background prediction. Assuming a branching fraction of 100% for the decay T->tZ, a T quark with a mass less than 475 GeV/c(2) is excluded at the 95% confidence level. PMID- 22243476 TI - Proteomics signature profiling (PSP): a novel contextualization approach for cancer proteomics. AB - Traditional proteomics analysis is plagued by the use of arbitrary thresholds resulting in large loss of information. We propose here a novel method in proteomics that utilizes all detected proteins. We demonstrate its efficacy in a proteomics screen of 5 and 7 liver cancer patients in the moderate and late stage, respectively. Utilizing biological complexes as a cluster vector, and augmenting it with submodules obtained from partitioning an integrated and cleaned protein-protein interaction network, we calculate a Proteomics Signature Profile (PSP) for each patient based on the hit rates of their reported proteins, in the absence of fold change thresholds, against the cluster vector. Using this, we demonstrated that moderate- and late-stage patients segregate with high confidence. We also discovered a moderate-stage patient who displayed a proteomics profile similar to other poor-stage patients. We identified significant clusters using a modified version of the SNet approach. Comparing our results against the Proteomics Expansion Pipeline (PEP) on which the same patient data was analyzed, we found good correlation. Building on this finding, we report significantly more clusters (176 clusters here compared to 70 in PEP), demonstrating the sensitivity of this approach. Gene Ontology (GO) terms analysis also reveals that the significant clusters are functionally congruent with the liver cancer phenotype. PSP is a powerful and sensitive method for analyzing proteomics profiles even when sample sizes are small. It does not rely on the ratio scores but, rather, whether a protein is detected or not. Although consistency of individual proteins between patients is low, we found the reported proteins tend to hit clusters in a meaningful and informative manner. By extracting this information in the form of a Proteomics Signature Profile, we confirm that this information is conserved and can be used for (1) clustering of patient samples, (2) identification of significant clusters based on real biological complexes, and (3) overcoming consistency and coverage issues prevalent in proteomics data sets. PMID- 22243478 TI - Adsorption characteristics of (-)-epigallocatechin gallate and caffeine in the extract of waste tea on macroporous adsorption resins functionalized with chloromethyl, amino, and phenylamino groups. AB - According to the Friedel-Crafts and amination reaction, a series of macroporous adsorption resins (MARs) with novel structures were synthesized and identified by the Brunauer-Emmett-Teller (BET) method and Fourier transform infrared (FTIR) spectra, and corresponding adsorption behaviors for (-)-epigallocatechin gallate (EGCG) and caffeine (CAF) extracted from waste tea were systemically investigated. Based on evaluation of adsorption kinetics, the kinetic data were well fitted by pseudo-second-order kinetics. Langmuir, Freundlich, Temkin-Pyzhev, and Dubinin-Radushkevich isotherms were selected to illustrate the adsorption process of EGCG and CAF on the MARs. Thermodynamic parameters were adopted to explain in-depth information of inherent energetic changes associated with the adsorption process. The effect of temperature on EGCG and CAF adsorption by D101 3 was further expounded. Van der Waals force, hydrogen bonding, and electrostatic interaction were the main driving forces for the adsorption of EGCG and CAF on the MARs. This study might provide a scientific reference point to aid the industrial large-scale separation and enrichment of EGCG from the extracts of waste tea using modified MARs. PMID- 22243479 TI - Relationships between soil organic matter, nutrients, bacterial community structure, and the performance of microbial fuel cells. AB - Microbial fuel cells (MFCs) offer the potential for generating electricity, mitigating greenhouse gas emissions, and bioremediating pollutants through utilization of a plentiful renewable resource: soil organic carbon. We analyzed bacterial community structure, MFC performance, and soil characteristics in different microhabitats within MFCs constructed from agricultural or forest soils in order to determine how soil type and bacterial dynamics influence MFC performance. Our results indicated that MFCs constructed from agricultural soil had power output about 17 times that of forest soil-based MFCs and respiration rates about 10 times higher than forest soil MFCs. Agricultural soil MFCs had lower C:N ratios, polyphenol content, and acetate concentrations than forest soil MFCs. Bacterial community profile data indicate that the bacterial communities at the anode of the high power MFCs were less diverse than in low power MFCs and were dominated by Deltaproteobacteria, Geobacter, and to a lesser extent, Clostridia, while low-power MFC anode communities were dominated by Clostridia. These results suggest that the presence of organic carbon substrate (acetate) was not the major limiting factor in selecting for highly electrogenic bacterial communities, while the quality of available organic matter may have played a significant role in supporting high performing bacterial communities. PMID- 22243480 TI - Statin use and the risk of gallstone disease: a population-based case-control study. AB - OBJECTIVE: The aim of this study was to investigate whether the use of statins was associated with a decreased risk of gallstone disease. METHODS: We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of gallstone disease or cholecystectomy for the period between 2005 and 2009. The controls were matched to cases by age, sex and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. RESULTS: We examined 1014 gallstone disease cases and 1014 controls. The unadjusted ORs for any statin prescription was 1.06 (95% CI 0.86 to 1.29), and the adjusted OR was 1.14 (95% CI 0.90 to 1.43). Compared with no use of statins, the adjusted ORs were 1.05 (95% CI 0.72 to 1.54) for the group having been prescribed statins with cumulative defined daily doses (DDDs) below 41.53, 1.12 (95% CI 0.84 to 1.50) for the group with cumulative dose between 41.54 and 334.81 DDD, and 1.30 (95% CI 0.86 to 1.95) for the group with cumulative statin use of 334.81 DDDs or more. CONCLUSIONS: This study does not provide support for a beneficial association between usage of statin and gallstone disease. PMID- 22243482 TI - Sublimation of new matrix candidates for high spatial resolution imaging mass spectrometry of lipids: enhanced information in both positive and negative polarities after 1,5-diaminonapthalene deposition. AB - Matrix sublimation has demonstrated to be a powerful approach for high-resolution matrix-assisted laser desorption ionization (MALDI) imaging of lipids, providing very homogeneous solvent-free deposition. This work presents a comprehensive study aiming to evaluate current and novel matrix candidates for high spatial resolution MALDI imaging mass spectrometry of lipids from tissue section after deposition by sublimation. For this purpose, 12 matrices including 2,5 dihydroxybenzoic acid (DHB), sinapinic acid (SA), alpha-cyano-4-hydroxycinnamic acid (CHCA), 2,6-dihydroxyacetphenone (DHA), 2',4',6'-trihydroxyacetophenone (THAP), 3-hydroxypicolinic acid (3-HPA), 1,8-bis(dimethylamino)naphthalene (DMAN), 1,8,9-anthracentriol (DIT), 1,5-diaminonapthalene (DAN), p-nitroaniline (NIT), 9-aminoacridine (9-AA), and 2-mercaptobenzothiazole (MBT) were investigated for lipid detection efficiency in both positive and negative ionization modes, matrix interferences, and stability under vacuum. For the most relevant matrices, ion maps of the different lipid species were obtained from tissue sections at high spatial resolution and the detected peaks were characterized by matrix-assisted laser desorption ionization time-of-flight/time of-flight (MALDI-TOF/TOF) mass spectrometry. First proposed for imaging mass spectrometry (IMS) after sublimation, DAN has demonstrated to be of high efficiency providing rich lipid signatures in both positive and negative polarities with high vacuum stability and sub-20 MUm resolution capacity. Ion images from adult mouse brain were generated with a 10 MUm scanning resolution. Furthermore, ion images from adult mouse brain and whole-body fish tissue sections were also acquired in both polarity modes from the same tissue section at 100 MUm spatial resolution. Sublimation of DAN represents an interesting approach to improve information with respect to currently employed matrices providing a deeper analysis of the lipidome by IMS. PMID- 22243483 TI - Evaluation of Nd:YAG and Er:YAG irradiation, antibacterial photodynamic therapy and sodium hypochlorite treatment on Enterococcus faecalis biofilms. AB - AIM: To compare the antimicrobial efficacy of two-high power lasers (Nd:YAG and Er:YAG) and two commercial antimicrobial photodynamic therapy (aPDT) systems with that of sodium hypochlorite (NaOCl) action on Enterococcus faecalis biofilms grown on dentine discs. METHODOLOGY: Enterococcus faecalis biofilms were grown on dentine discs in a microtiter plate, incubated for 24 h and subjected to the following treatments: aPDT (Denfotex and Helbo system), Er:YAG laser irradiation (2940 nm, 50 mJ or 100 mJ, 15 Hz, 40 s), Nd:YAG laser irradiation (1064 nm, 2 W, 15 Hz, 40 s) and immersion in 2.5% (w/v) NaOCl for 1, 5, 10 and 30 min. Surviving bacteria were harvested, and the number of CFU per disc was determined by plate counting. RESULTS: Significant reductions (anova, P <= 0.05) in viable counts were observed for aPDT (Helbo) (2 log(10) reduction), Er:YAG irradiation using 100 mJ pulses (4.3 log(10) reduction) and all NaOCl treatments (>6 log(10) reduction). NaOCl (2.5%) for 5 min effectively eliminated all bacteria. aPDT (Denfotex), Er:YAG irradiation using 50 mJ pulses and Nd:YAG treatment caused a reduction in the viable counts of <1 log(10) unit; these results were not significantly different from the untreated controls. CONCLUSION: Within the limitations of this particular laboratory set-up, NaOCl was the most effective in E. faecalis biofilm elimination, while Er:YAG laser treatment (100 mJ pulses) also resulted in high reductions in viable counts. The use of both commercial aPDT systems resulted in a weak reduction in the number of E. faecalis cells. Nd:YAG irradiation was the least effective. PMID- 22243484 TI - Long-term effectiveness and safety of small gel particle hyaluronic acid for hand rejuvenation. AB - BACKGROUND: Fillers to reverse the effects of fat atrophy can help restore the hands' youthful appearance. OBJECTIVE: To evaluate the effectiveness and safety of small gel particle hyaluronic acid (SGP-HA) for hand rejuvenation through 1 year. MATERIALS AND METHODS: A prospective open-label study recruited adults with moderate to severe vascular, bony, and tendon prominence. After a topical anesthetic was applied, SGP-HA (maximum dose of 4.0 mL) was injected into the dorsum using a threading technique and distributed by massage. RESULTS: There were 16 patients with a mean +/- SD age of 60.1 +/- 5.3. Two weeks after treatment, vascular, tendon, and bony prominence and skin turgor were improved by 60.9%, 65.2%, 73.7%, and 26.3%, respectively. Substantial or complete global aesthetic improvement was rated in 75% of patients by investigators and in 56% by self-report; 81% of patients were satisfied or very satisfied. Five needed a touch-up (maximum 1.0 mL/hand). Improvements were largely maintained at 6 months, with 85% patient satisfaction, and assessments approached pretreatment levels at 1 year, with 50% patient satisfaction. One patient reported itching on one hand, which was judged to be unrelated to treatment. CONCLUSION: SGP-HA produced lasting improvements in aging hands and was safe and well tolerated. PMID- 22243485 TI - NcoI TNF-beta gene polymorphism and TNF expression are associated with an increased risk of developing Barrett's esophagus and esophageal adenocarcinoma. AB - OBJECTIVE: Esophageal cancer development is a sequence that starts with reflux esophagitis (RE), followed by Barrett's esophagitis (BE), dysplasia, and finally esophageal adenocarcinoma (EAC). Tumor necrosis factor (TNF) is a potent anti neoplastic agent, hence DNA polymorphisms that reduce TNF levels potentially enhance the development of BE and EAC. The aim of the study was to determine the impact of TNF gene variation on the RE-BE-EAC cascade. METHODS: DNA from 887 Caucasian participants (197 controls, 305 RE, 257 BE, 128 EAC) was tested for the gene polymorphism TNF-beta NcoI, and TNF production was determined by TNF-alpha specific immunohistochemistry on esophageal biopsies from these BE (n = 31) and EAC (n = 4) patients. RESULTS: As compared with healthy controls, the TNF-beta NcoI A/A genotype was significantly more prevalent in BE (p = 0.04) and EAC patients (p = 0.02), but not in RE patients (p = 0.1). While TNF-alpha protein levels were invariably high in esophageal biopsies from EAC patients, most esophageal BE samples showed low to moderate TNF levels. CONCLUSIONS: Chronic inflammation, like in BE, markedly increase the risk of malignant transformation. In this study, the significantly higher frequency of the TNF-beta NcoI A/A genotype and the local TNF expression indicate that the pro-inflammatory cytokine TNF plays a role in the development of BE and EAC. PMID- 22243486 TI - HIV sex-risk behaviors among in- versus out-of-treatment heroin-addicted adults. AB - BACKGROUND: Relatively limited empirical evidence exists comparing the impact on HIV sex risk behavior for patients admitted to methadone treatment programs (MTPs) as compared with nontreatment seekers. METHODS: This longitudinal cohort study examined HIV sex-risk behavior among 164 out-of-treatment heroin-dependent adults recruited from the street and 351 newly admitted MTP patients. The AIDS Risk Assessment was administered at baseline, 6 months, and 12 months. Generalized linear mixed model and generalized estimating equation analyses were used to examine the changes in sex risk behavior over time. RESULTS: The participants mean age was 41.5 years, 74.8% were African-American, 24.3% were White, and 54.4% were men. There were no significant differences between the groups in age, race, or gender. At baseline, the out-of-treatment group compared with the in-treatment group reported more sex partners (p < .001) and higher frequency of sex (p = .001). There was a group x time interaction for three of the sex-risk items and the out-of-treatment group reported having significantly more sex partners at both follow-up time points and having significantly more frequent unprotected sex while high at 6 months (all values of p < .01). CONCLUSIONS: Nontreatment seekers are at higher HIV risk than those entering MTPs and should be a focus of sex-risk reduction interventions, even if they are not interested in treatment at that time. PMID- 22243487 TI - Antifeedant activity of citrus waste wax and its fractions against the dry wood termite, Cryptotermes brevis. AB - The wood protective action of citrus wax, a waste from the citrus industry that is a mixture of citrus fruit epicuticular waxes and essential oils, was evaluated against the termite Cryptotermes brevis Walker (Isoptera: Kalotermitidae). The antifeedant index (AI) of the total wax and fractions was calculated. The total citrus wax exhibited an AI50 value of 24.69 mg/cm3, the wax after hydrodistillation showed the strongest antifeedant property (AI50 11.68 mg/cm3). Fractionation of the wax and gas chromatography-mass spectrometric analysis allowed the identification of coumarins and furancoumarins as the active compounds. These results suggest the potential use of these industrial residues as a natural approach to termite control. PMID- 22243488 TI - Detection of femtomolar proteins by nonfluorescent ZnS nanocrystal clusters. AB - Cation exchange (CX) in the nonfluorescent ZnS nanocrystal clusters (NCCs) was employed to detect trace biomolecules with immunoassays. The NCCs were porous and allowed fast cation exchange reaction to release an ultralarge number of Zn(2+) from each cluster that turned on the Zn-responsive dyes for fluorescence detection. The ZnS NCCs were highly stable in biological buffers and more biocompatible than quantum dots. Zn(2+) release efficiency and target binding by NCCs with average diameters of 44 nm, 86 nm, and 144 nm were investigated. The smallest NCCs exhibited the highest CX efficiency because of its larger surface area and bigger pores inside the cluster structure, and 71.0% of the enclosed Zn(2+) were freed by CX with 2-min microwave irradiation. They also experienced the least space hindrance and the fastest rate when binding to target molecules immobilized on surface. When the 44-nm NCCs were used to detect IgE in a sandwich assay, the limit of detection (LOD) was 5 pg/mL (33 fM), 1,000 times better than that of ELISA. Our results well demonstrate that CX in the ZnS NCCs is superior to the conventional signaling strategies in its high amplification efficiency, robustness, and biocompatibility. PMID- 22243489 TI - 1,4-dioxane, a suitable scaffold for the development of novel M3 muscarinic receptor antagonists. AB - In this study the modulation of the pharmacological profile from agonist to antagonist was successfully obtained by replacing the methyl group in position 6 of the 1,4-dioxane scaffold of the potent M(2)/M(3) muscarinic agonist 1 with bulkier groups. In particular, the 6,6-diphenyl substitution provided the potent M(3) preferring antagonist (+/-)-17, which in in vivo study proved to be effective in reducing the volume-induced contractions of rat urinary bladder and was devoid of cardiovascular effects. PMID- 22243490 TI - Migration of polyolefin oligomeric saturated hydrocarbons (POSH) into food. AB - POSH are polyolefin oligomeric saturated hydrocarbons, such as oligomers from polyethylene or polypropylene. POSH that have migrated into foods are easily mistaken for mineral oil-saturated hydrocarbons (MOSH). In fact, both POSH and MOSH largely consist of highly isomerised branched and possibly cyclic hydrocarbons, both forming humps of unresolved components in gas chromatography. Chromatograms are reported to show typical elution patterns of POSH and help analysts distinguishing POSH from MOSH as far as possible. Since the structures of the POSH are not fundamentally different from those of the MOSH, it would be prudent to apply the evaluation of the MOSH. However, the migration is frequently beyond that for which safety has been demonstrated. This is shown for a few examples, particularly for powdered formula for babies. PMID- 22243491 TI - Examining nursing vital signs documentation workflow: barriers and opportunities in general internal medicine units. AB - AIMS: To characterise the nursing practices of vital signs collection and documentation in a general internal medicine environment to inform strategies for improving workflow design. BACKGROUND: Clinical workflow analysis is critical to identify barriers and opportunities in current processes. Analysis can guide the design and development of novel technological solutions to produce greater efficiencies and effectiveness in healthcare delivery. Research surrounding vital signs documentation workflow in general internal medicine environments has received very little attention making it difficult to compare the effectiveness of new technologies. DESIGN: Qualitative ethnographic analyses and quantitative time-motion study were conducted. METHODS: Workflows of 24 nurses at three hospitals in five general internal medicine environments were captured, and timeliness of vital signs assessment and documentation was measured. RESULTS: Clinical assessment of vital signs was consistent, but the documentation process was highly variable within groups and between hospitals. Two themes characterised workflow barriers surrounding point-of-care documentation. First, a lack of standardised documentation methods for vital signs resulted in higher rates of transcription, increasing not only the likelihood of errors but delays in recording and accessibility of information. Second, despite advancements in electronic documentation systems, the observed system was not conducive to point of-care documentation. Average electronic documentation was significantly longer than paper documentation. Nurses developed ad hoc workarounds that were inefficient and undermined the intent of electronic documentation. CONCLUSION: We have identified barriers and opportunities to improve the efficiency of nursing vital signs documentation. Changes in technology, workflows and environmental design allow for significant improvements and deserve further exploration. RELEVANCE TO CLINICAL PRACTICE: Attention to clinical practice and environments can improve the workflow of prompt vital signs documentation and increase clinical productivity and timeliness of information for clinical decisions, as well as minimising transcription errors leading to safer patient care. PMID- 22243492 TI - Activation of defense against Phytophthora infestans in potato by down-regulation of syntaxin gene expression. AB - The oomycete Phytophthora infestans is the causal agent of late blight, the most devastating disease of potato. The importance of vesicle fusion processes and callose deposition for defense of potato against Phytophthora infestans was analyzed. Transgenic plants were generated, which express RNA interference constructs targeted against plasma membrane-localized SYNTAXIN-RELATED 1 (StSYR1) and SOLUBLE N-ETHYLMALEIMIDE-SENSITIVE FACTOR ADAPTOR PROTEIN 33 (StSNAP33), the potato homologs of Arabidopsis AtSYP121 and AtSNAP33, respectively. Phenotypically, transgenic plants grew normally, but showed spontaneous necrosis and chlorosis formation at later stages. In response to infection with Phytophthora infestans, increased resistance of StSYR1-RNAi plants, but not StSNAP33-RNAi plants, was observed. This increased resistance correlated with the constitutive accumulation of salicylic acid and PR1 transcripts. Aberrant callose deposition in Phytophthora infestans-infected StSYR1-RNAi plants coincided with decreased papilla formation at penetration sites. Resistance against the necrotrophic fungus Botrytis cinerea was not significantly altered. Infiltration experiments with bacterial solutions of Agrobacterium tumefaciens and Escherichia coli revealed a hypersensitive phenotype of both types of RNAi lines. The enhanced defense status and the reduced growth of Phytophthora infestans on StSYR1-RNAi plants suggest an involvement of syntaxins in secretory defense responses of potato and, in particular, in the formation of callose-containing papillae. PMID- 22243493 TI - Regulated exocytosis: novel insights from intravital microscopy. AB - Regulated exocytosis is a fundamental process that every secretory cell uses to deliver molecules to the cell surface and the extracellular space by virtue of membranous carriers. This process has been extensively studied using various approaches such as biochemistry, electrophysiology and electron microscopy. However, recent developments in time-lapse light microscopy have made possible imaging individual exocytic events, hence, advancing our understanding of this process at a molecular level. In this review, we focus on intravital microscopy (IVM), a light microscopy-based approach that enables imaging subcellular structures in live animals, and discuss its recent application to study regulated exocytosis. IVM has revealed differences in regulation and modality of regulated exocytosis between in vitro and in vivo model systems, unraveled novel aspects of this process that can be appreciated only in in vivo settings and provided valuable and novel information on its molecular machinery. In conclusion, we make the case for IVM being a mature technique that can be used to investigate the molecular machinery of several intracellular events under physiological conditions. PMID- 22243494 TI - Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS * This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. AIM: Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS: In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 * 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 * 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 * 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS: Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-infinity)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96). CONCLUSION: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. PMID- 22243515 TI - Thin-film fixed-bed reactor (TFFBR) for solar photocatalytic inactivation of aquaculture pathogen Aeromonas hydrophila. AB - BACKGROUND: Outbreaks of infectious diseases by microbial pathogens can cause substantial losses of stock in aquaculture systems. There are several ways to eliminate these pathogens including the use of antibiotics, biocides and conventional disinfectants, but these leave undesirable chemical residues. Conversely, using sunlight for disinfection has the advantage of leaving no chemical residue and is particularly suited to countries with sunny climates. Titanium dioxide (TiO2) is a photocatalyst that increases the effectiveness of solar disinfection. In recent years, several different types of solar photocatalytic reactors coated with TiO2 have been developed for waste water and drinking water treatment. In this study a thin-film fixed-bed reactor (TFFBR), designed as a sloping flat plate reactor coated with P25 DEGUSSA TiO2, was used. RESULTS: The level of inactivation of the aquaculture pathogen Aeromonas hydrophila ATCC 35654 was determined after travelling across the TFFBR under various natural sunlight conditions (300-1200 W m(-2)), at 3 different flow rates (4.8, 8.4 and 16.8 L h(-1)). Bacterial numbers were determined by conventional plate counting using selective agar media, cultured (i) under conventional aerobic conditions to detect healthy cells and (ii) under conditions designed to neutralise reactive oxygen species (agar medium supplemented with the peroxide scavenger sodium pyruvate at 0.05% w/v, incubated under anaerobic conditions), to detect both healthy and sub-lethally injured (oxygen-sensitive) cells. The results clearly demonstrate that high sunlight intensities (>= 600 W m(-2)) and low flow rates (4.8 L h(-1)) provided optimum conditions for inactivation of A. hydrophila ATCC 3564, with greater overall inactivation and fewer sub-lethally injured cells than at low sunlight intensities or high flow rates. Low sunlight intensities resulted in reduced overall inactivation and greater sub-lethal injury at all flow rates. CONCLUSIONS: This is the first demonstration of the effectiveness of the TFFBR in the inactivation of Aeromonas hydrophila at high sunlight intensities, providing proof-of-concept for the application of solar photocatalysis in aquaculture systems. PMID- 22243516 TI - Integrated vector management for malaria control in Uganda: knowledge, perceptions and policy development. AB - BACKGROUND: Integrated vector management (IVM) is increasingly being recommended as an option for sustainable malaria control. However, many malaria-endemic countries lack a policy framework to guide and promote the approach. The objective of the study was to assess knowledge and perceptions in relation to current malaria vector control policy and IVM in Uganda, and to make recommendations for consideration during future development of a specific IVM policy. METHODS: The study used a structured questionnaire to interview 34 individuals working at technical or policy-making levels in health, environment, agriculture and fisheries sectors. Specific questions on IVM focused on the following key elements of the approach: integration of chemical and non-chemical interventions of vector control; evidence-based decision making; inter-sectoral collaboration; capacity building; legislation; advocacy and community mobilization. RESULTS: All participants were familiar with the term IVM and knew various conventional malaria vector control (MVC) methods. Only 75% thought that Uganda had a MVC policy. Eighty percent (80%) felt there was inter-sectoral collaboration towards IVM, but that it was poor due to financial constraints, difficulties in involving all possible sectors and political differences. The health, environment and agricultural sectors were cited as key areas requiring cooperation in order for IVM to succeed. Sixty-seven percent (67%) of participants responded that communities were actively being involved in MVC, while 48% felt that the use of research results for evidence-based decision making was inadequate or poor. A majority of the participants felt that malaria research in Uganda was rarely used to facilitate policy changes. Suggestions by participants for formulation of specific and effective IVM policy included: revising the MVC policy and IVM-related policies in other sectors into a single, unified IVM policy and, using legislation to enforce IVM in development projects. CONCLUSION: Integrated management of malaria vectors in Uganda remains an underdeveloped component of malaria control policy. Cooperation between the health and other sectors needs strengthening and funding for MVC increased in order to develop and effectively implement an appropriate IVM policy. Continuous engagement of communities by government as well as monitoring and evaluation of vector control programmes will be crucial for sustaining IVM in the country. PMID- 22243517 TI - Processing and storage effect on berry polyphenols: challenges and implications for bioactive properties. AB - Anthocyanins and tannins in blueberries, blackberries and black raspberries are susceptible to degradation during processing, with juices showing the greatest losses due to physical removal of skins and seeds. Anthocyanins and procyanidins are also degraded in processed products stored at ambient temperature with losses accompanied by increased polymeric pigments (PPs). Using chokeberry as a model, formation of PPs occurred in both pasteurized and aged juices and pasteurized juice contained a greater proportion of low molecular weight PPs than aged juice, while aged juice contained a greater proportion of higher molecular PPs. Formation of PP accounts for some of the losses of anthocyanins and procyanidins during processing and storage, but the complete fate of anthocyanins remains unclear. In this review we highlight the steps in processing where significant losses of polyphenols occur, and discuss potential mechanisms responsible for losses, methods to mitigate losses, and implications on bioactive properties. PMID- 22243519 TI - Mitochondrial ATP synthase catalytic mechanism: a novel visual comparative structural approach emphasizes pivotal roles for Mg2+ and P-loop residues in making ATP. AB - The mitochondrial ATP synthase (F(o)F(1)) is one of the most abundant, important, and complex enzymes found in animals and humans. In earlier studies, we used the photosensitive phosphate analogue vanadate (V(i)) to study the enzyme's mechanism in the transition state. Significantly, these studies showed that Mg(2+) plays an important role in transition state formation during ATP synthesis. Additionally, in both MgADP.V(i)-F(1) and MgV(i)-F(1) complexes, photoactivation of orthovanadate (V(i)) induced cleavage at the third residue within the P-loop (GGAGVGKT), i.e., betaA158, suggesting its proximity to the gamma-phosphate during transition state formation. However, despite our recent release of the F(1)-ATPase structure containing V(i), the structural details regarding the role of Mg(2+) have remained elusive. Therefore, in this study, we sought to improve our understanding of the essential role of Mg(2+) during transition state formation. We utilized Protein Data Bank structural data representing different conformational intermediates of key steps in ATP synthesis to assemble a database of positional relationships between landmark residues of the catalytic site and the bound ligand. Applying novel bioinformatics methods, we combined the resulting interatomic spatial data with an animated model of the catalytic site to visualize the exact nature of the changes in these positional relationships during ATP synthesis. The results of these studies reported here show that the absence of Mg(2+) results in migration of inorganic phosphate (P(i)) from betaA158 to a more medial position in the P-loop binding pocket, thereby disrupting essential placement and orientation of the P(i) needed to form the transition state structure and therefore MgATP. PMID- 22243518 TI - Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn. AB - BACKGROUND: Paw carrageenan induces activation of phosphatidylinositol 3-kinase (PI-3K) and Akt in dorsal horn neurons in addition to induction of pain behavior. Spinal PI-3K activation is also thought to be required for inflammation-induced trafficking of GluA1, AMPA receptor subunits, into plasma membranes from cytosol. Phosphorylation of Akt has a unique time course. It occurs first in the superficial dorsal horn (0.75 h), then soon dissipates and is followed an hour later by Akt phosphorylation in deeper dorsal horn laminae, primarily lamina V. Initially, we wished to determine if Akt phosphorylation in the deeper laminae were dependent on the presence of lamina I, neurokinin receptor bearing projection neurons. As the study progressed, our aims grew to include the question, whether carrageenan-induced GluA1 subunit trafficking was downstream of Akt phosphorylation. RESULTS: Rats pretreated with spinal saporin conjugated to a stabilized form of substance P had substantial loss of neurons with neurokinin 1 receptors throughout their superficial, but not deep dorsal horns. Animals pre treated with substance P-saporin exhibited no change in locomotor ability and a small, but significant decrease in carrageenan-induced mechanical allodynia when compared to animals pre-treated with spinal saporin alone. Importantly, carrageenan-induced phosphorylation of Akt was blocked, in the substance P saporin treated group, throughout the spinal cord grey matter. In marked contrast, carrageenan induced-trafficking of the GluA1 receptor subunit increased equivalently in both treatment groups. CONCLUSIONS: We infer from these data that 1) phosphorylation of Akt in the deep dorsal horn is dependent on prior activation of NK1 receptor bearing cells in superficial dorsal horn, and 2) there are parallel spinal intracellular cascades initiated by the carrageenan injection downstream of PI-3K activation, including one containing Akt and another involving GluA1 trafficking into neuronal plasma membranes that separately lead to enhanced pain behavior. These results imply that the two pathways downstream of PI-3K can be activated separately and therefore should be able to be inhibited independently. PMID- 22243520 TI - Impedance nadir values correlate with barium bolus amount. AB - We examined the value of impedance monitoring in measuring bolus volume compared with videoesophagram. Eighty consecutive subjects were studied with simultaneous impedance-manometry-videoesophagram. A catheter with both an impedance electrode pair and a pressure transducer at four sites (5, 10, 15, 20 cm above lower esophageal sphincter) was passed per nares. Six 10-cc boluses of 45% barium mixed with 0.9% NaCl were swallowed at 20- to 30-second intervals. When impedance fell to below 1000 ohms, other than that occurring during administered swallows, the videofluoroscopic image corresponding to the time of impedance nadir was reviewed. If barium was present at the impedance site, barium area was calculated. The video was reviewed for the cause of abnormal barium transit causing barium presence. We found 38/80 subjects had a total of 169 impedance falls to below 1000 ohms. Ninety-seven percent (164/169) of impedance falls had barium present at the impedance site, and there was good correlation (r = 0.83, P < 0.001) between impedance nadir value and barium area. The impedance nadir value : barium area relationship was similar for the three causes of barium presence identified by video: failed bolus clearing; gastroesophageal reflux; and esophageal escape. Impedance nadir values 700-999 ohms usually had a small barium area. In contrast, nadir values <400 ohms had a large barium area covering all or most of the catheter and filling the esophagus at the impedance site. Impedance falls from >1000 ohms to a low nadir value from all forms of abnormal esophageal bolus transit imply a large bolus amount. PMID- 22243522 TI - Oral health of 65-year olds in Sweden and Norway: a global question and ICF, the latest conceptual model from WHO. AB - OBJECTIVE: The aims of this study were to identify explanatory factors of satisfaction with oral health among Norwegian and Swedish 65 year olds in terms of items from four different domains of ICF and to compare the strengths of the various ICF domains in explaining satisfaction with oral health. Further it was to assess whether the explanatory factors of ICF domains vary between Norway and Sweden. MATERIALS AND METHODS: In 2007, standardized questionnaires were mailed to all the residents in certain counties of Sweden and Norway who were born in 1942. Response rates were 73.1% (n = 6078) in Sweden and 56.0% (n = 4062) in Norway. RESULTS: In total, 33 questions based on four different ICF domains were chosen to explain satisfaction with oral health. Logistic regression showed that four different ICF domains in terms of body function, body structure, activity/participation and environmental factors explained, respectively, 53%, 31%, 12% and 34% of the explanatory variance in the satisfaction with oral health. In the final analysis, only nine items were statistically significant (p < 0.05). CONCLUSION: This study indicates that ICF as a conceptual model could cover a broad spectrum of factors embedded in OHRQoL measured by a global question in Sweden and Norway. Nine items, representing four ICF domains, were important in the final model for explaining satisfaction with oral health. PMID- 22243521 TI - Proteomic analysis (GeLC-MS/MS) of ePFT-collected pancreatic fluid in chronic pancreatitis. AB - Chronic pancreatitis is characterized by inflammation, fibrosis, pain, and loss of exocrine function of the pancreas. We aimed to identify differentially expressed proteins in the ePFT-collected pancreatic fluid from individuals with chronic pancreatitis (CP; n = 9) and controls with chronic abdominal pain not associated with the pancreas (NP; n = 9). Using GeLC-MS/MS techniques, we identified a total of 1391 different proteins in 18 pancreatic fluid samples. Of these proteins, 257 and 413 were identified exclusively in the control and chronic pancreatitis cohorts, respectively, and 721 were identified in both cohorts. Spectral counting and statistical analysis thereof revealed an additional 38 and 77 proteins that were up- or down-regulated, respectively, in the pancreatic fluid from individuals with chronic pancreatitis. As expected, gene ontology analysis illustrated that the largest percentage of differentially regulated proteins was secreted/extracellular in origin. In addition, proteins that were down-regulated with statistical significance in the chronic pancreatitis cohort were determined to have biological function of proteases, corresponding to the canonical pancreatic insufficiency associated with chronic pancreatitis. Proteins enriched in the pancreatic fluid of chronic pancreatitis patients had roles in fibrosis, inflammation, and pain, whereas digestive enzymes were significantly less abundant. Our workflow provided a mass spectrometry-based approach for the further study of the pancreatic fluid proteome, which may lead to the discovery potential biomarkers of chronic pancreatitis. PMID- 22243524 TI - Nasopharyngeal carriage rate of Streptococcus pneumoniae in Ugandan children with sickle cell disease. AB - BACKGROUND: Nasopharyngeal carriage of Streptococcus pneumoniae is a determinant for invasive pneumococcal disease, which often complicates homozygous sickle cell disease. Here, we determined the nasopharyngeal carriage rate of S. pneumoniae in Ugandan children with homozygous sickle cell disease, who attended the outpatient Sickle Cell Clinic at Mulago National Referral hospital in Kampala, Uganda. RESULTS: S. pneumoniae occurred in 27 of the 81 children with homozygous sickle cell disease (giving a carriage rate of 33%, 27/81). Twenty three children were previously hospitalized of whom S. pneumoniae occurred in only two (9%, 2/23), while among the 58 who were not previously hospitalized it occurred in 25 (43%, 25/58, chi2 = 8.8, p = 0.003), meaning there is an association between high carriage rate and no hospitalization. Two children previously immunized with the pneumococcal conjugate vaccine did not carry the organism. Prior antimicrobial usage was reported in 53 children (65%, 53/81). There was high resistance of pneumococci to penicillin (100%, 27/27) and trimethoprime-sulfamethoxazole (97%, 26/27), but low resistance to other antimicrobials. Of the 70 children without sickle cell disease, S. pneumoniae occurred in 38 (54%, 38/70) of whom 43 were males and 27 females (53% males, 23/43, and 56% females, 15/27). CONCLUSION: Nasopharyngeal carriage of penicillin resistant pneumococci in Ugandan children with homozygous sickle cell disease is high. While nasopharyngeal carriage of S. pneumoniae is a determinant for invasive pneumococcal disease, pneumococcal bacteremia is reportedly low in Ugandan children with sickle cell disease. Studies on the contribution of high carriage rates to invasive pneumococcal disease in these children will be helpful. This is the first report on pneumococcal carriage rate in Ugandan children with sickle cell disease. PMID- 22243525 TI - Patient with tracheostomy parasitized in hospital by larvae of the screwworm, Cochliomyia hominivorax. AB - Myiasis is the infestation of living vertebrates by fly larvae that feed for at least part of their development on the host's dead or living tissues, body substances, or ingested food. The occurrences of traumatic myiasis in humans and animals in urban and rural environments represent serious economic and public health concerns. This study reports a 49-year-old tracheostomized man undergoing chemotherapy treatment who was parasitized in the hospital in Sao Goncalo, Rio de Janeiro, Brazil, by larvae of the screwworm, Cochliomyia hominivorax (Coquerel) (Diptera: Calliphoridae) in the thoracic cavity. PMID- 22243526 TI - Bacteriocin-producing oral streptococci and inhibition of respiratory pathogens. AB - The use of bacteria as probiotics is in continuous development, thanks to their capacity to maintain or restore a host's natural microbiome by interference with and/or inhibition of other microorganisms mediated by antimicrobial peptide production such as bacteriocins. In the oral cavity, Streptococcus salivarius, a non-pathogenic and predominant oral species, is one of the major bacteriocin producers that is able to coexist in this environment and reduce the frequency of colonization of the main pathogens involved in upper respiratory tract infections. The aim of this study was to screen oral bacteria colonizing healthy children for their use as potential oral probiotics. Eighty-one alpha-hemolytic streptococci isolated from nasal and/or pharyngeal swabs of 31 healthy children aged between two and twelve years were isolated. Among them, 13 alpha-hemolytic streptococci were selected for their bacteriocin-like inhibitory activity against potential pathogens. These strains were tested for bacteriocin production and assayed for their capacity to adhere to HEp-2 cell lines. Our data showed that 13 bacteriocin producer strains were able to inhibit different gram-positive pathogens. Among them one strain, S. salivarius 24SMB, deposited as DSM 23307, was selected as a potential oral probiotic, thanks to its safety assessment, ability to inhibit Streptococcus pneumoniae and the absence of virulence and antibiotic resistance genes. PMID- 22243528 TI - Synthesis and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton coupled folate transporter over the reduced folate carrier. AB - We previously reported the selective transport of classical 2-amino-4-oxo-6 substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a three- (3a) and four-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells. While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and l-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5, and 6) substitutions on the thienoyl ring and with acetylenic insertions in the four-atom bridge were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRalpha and PCFT over RFC. PMID- 22243529 TI - Soil phosphate stable oxygen isotopes across rainfall and bedrock gradients. AB - The stable oxygen isotope compositions of soil phosphate (delta(18)O(p)) were suggested recently to be a tracer of phosphorus cycling in soils and plants. Here we present a survey of bioavailable (resin-extractable or resin-P) inorganic phosphate delta(18)O(p) across natural and experimental rainfall gradients, and across soil formed on sedimentary and igneous bedrock. In addition, we analyzed the soil HCl-extractable inorganic delta(18)O(p), which mainly represents calcium bound inorganic phosphate. The resin-P values were in the range 14.5-21.20/00. A similar range, 15.6-21.30/00, was found for the HCl-extractable inorganic delta(18)O(p), with the exception of samples from a soil of igneous origin that show lower values, 8.2-10.90/00, which indicate that a large fraction of the inorganic phosphate in this soil is still in the form of a primary mineral. The available-P delta(18)O(p) values are considerably higher than the values we calculated for extracellular hydrolysis of organic phosphate, based on the known fractionation from lab experiments. However, these values are close to the values expected for enzymatic-mediated phosphate equilibration with soil-water. The possible processes that can explain this observation are (1) extracellular equilibration of the inorganic phosphate in the soil; (2) fractionations in the soil are different than the ones measured at the lab; (3) effect of fractionation during uptake; and (4) a flux of intercellular-equilibrated inorganic phosphate from the soil microbiota, which is considerably larger than the flux of hydrolyzed organic-P. PMID- 22243530 TI - Accuracy in documentation of peripheral venous catheters in paediatric care: an intervention study in electronic patient records. AB - AIMS: The aim of this study is to compare the accuracy and completeness in the recording of peripheral venous catheters before and after implementing a template in the electronic patient record in paediatric care. BACKGROUND: As a basis for quality improvement and research purposes and to ensure patient safety, accurate clinical data need to be easily accessible in patient records. Several studies have concluded that the relation between performed care and what is documented in patient records is poor. DESIGN: Before and after study. METHOD: The study took place at a large paediatric university hospital in Sweden. Inclusion criteria were patients who were admitted to one of the included wards, had one or several peripheral venous catheters and were available at the ward at the time for data collection. Data were collected by observations and record audits before and then four and 10 months after the introduction of a template for recording peripheral venous catheters in a structured and standardised way. RESULTS: A significant increase in peripheral venous catheters with complete recording was observed after as compared with before the intervention. The percentage of peripheral venous catheters with recording of any kind was relatively stable (85-93%). The overall recording of peripheral venous catheters insertion did not improve, but there was an increase in the recording of side and size after the intervention. One of the 22 complications observed before the intervention was documented and none of the complications (n = 17 and n = 9) after. CONCLUSION: The electronic patient record did not provide accurate data on peripheral venous catheters in paediatric care neither before nor after the intervention. RELEVANCE TO CLINICAL PRACTICE: Further efforts to increase the documentation of catheter-related complications are needed. Integrated decision support systems in electronic patient records that remind nurses to inspect peripheral venous catheters regularly could be one solution. PMID- 22243546 TI - Synthesis of 5- and 6-N-heterocyclic methylenebisphosphonate derivatives and evaluation of their cytogenetic activity in normal human lymphocyte cultures. AB - Methods for the preparation of various aminomethylene bisphosphonates were developed. The required bisphosphonates were obtained by applying tetraethyl methylenebisphosphonate reagent to different types of oxazinones and the relevant Schiff base derivatives. Based on the prediction results (Pass program), we further estimated the sister chromatid exchange frequency and proliferation rate index values of human lymphocyte cultures after the administration of four newly synthesized bisphosphonates in order to evaluate their cytotoxic/cytostatic and possible antineoplastic potency. The results showed that all four bisphosphonates cause a dose-dependent increase in sister chromatid exchange frequency, followed by a decrease in proliferation rate index in both experiments compared to the control. PMID- 22243547 TI - Morphological and genetic distinctiveness of metallicolous and non-metallicolous populations of Armeria maritima s.l. (Plumbaginaceae) in Poland. AB - Patterns of morphological, genetic and epigenetic variation (DNA methylation pattern) were investigated in metallicolous (M) and non-metallicolous (NM) populations of Armeria maritima. A morphological study was carried out using plants from six natural populations grown in a greenhouse. Morphological variation was assessed using seven traits. On the basis of this study, three representative populations were selected for molecular analyses using metAFLP to study sequence- and methylation-based DNA variation. Only one morphological trait (length of outer involucral bracts) was common to both metallicolous populations studied; however, the level of variation was sufficient to differentiate between M and NM populations. Molecular analyses showed the existence of naturally occurring epigenetic variation in A. maritima populations, as well as structuring into distinct between and within population components. We show that patterns of population genetic structure differed depending on the information used in the study. Analysis of sequence-based information data demonstrates the presence of three well-defined and genetically differentiated populations. Methylation-based data show that two major groups of individuals are present, corresponding to the division into M and NM populations. These results were confirmed using different analytical approaches, which suggest that the DNA methylation pattern is similar in both M populations. We hypothesise that epigenetic processes may be involved in microevolution leading to development of M populations in A. maritima. PMID- 22243548 TI - Application of time-of-flight aerosol mass spectrometry for the online measurement of gaseous molecular iodine. AB - Here we present a new application of a time-of-flight aerosol mass spectrometer (TOF-AMS) for the measurement of atmospheric trace gases in real-time. Usually, TOF-AMS instruments are not sensitive to gas-phase species due to the aerodynamic particle focusing inlet system which reduces the gas phase species by a factor of about 10(7) relative to the particle phase. This efficient removal of the gas phase and the resulting high relative enrichment of particles is one reason for the very high sensitivity of TOF-AMS instruments for particle phase compounds (detection limits in the sub-MUg/m(3)-range for online measurements with 1 min integration time), which allows application of the instruments even under clean atmospheric conditions. Here we use artificially generated particles as sampling probes to transfer selected atmospheric trace gases into the particle phase before entering the AMS (gaseous compound trapping in artificially generated particles-AMS, GTRAP-AMS). The sampling probe particles are mixed with the gaseous analytes upstream of the TOF-AMS in a 0.5 L flow tube. As an exemplary application of the method, the measurement of trace levels of gaseous molecular iodine is demonstrated. alpha-Cyclodextrin (alpha-CD/NH(4)Br) particles are used as selective sampling probes to transfer molecular iodine into the AMS. A detection limit in the subparts-per-billion (sub-ppb) range was achieved. The method was compared to a recently developed off-line method that combines denuder sampling of gaseous I(2) and gas chromatography/mass spectrometry (GC/MS) analysis. To demonstrate the usability of the method, temporally resolved I(2) emission profiles from a brown algae species (Laminaria saccharina) under exposure of ambient ozone levels were investigated. Total I(2) release rates of 36.5 pmol min(-1) grams fresh weight (gFW)(-1) at 100 pbb O(3) and 33.4 pmol min( 1) gFW(-1) at 50 ppb O(3) were obtained within the first hour of ozone exposure. PMID- 22243549 TI - Fibromyalgia: a critical digest of the recent literature. AB - Fibromyalgia is a common syndrome characterised by widespread pain and a constellation of other symptoms and overlapping conditions that contribute to complicate the diagnosis, the assessment and the treatment. Furthermore, the etiological causes for the moment only consist of assumptions, and the underlying pathogenetic mechanisms still remain to be clarified. For the above-mentioned reasons, with the present review we sought to provide an overview of the literature on fibromyalgia from both the pre-clinical and clinical studies indexed in PubMed during the last year, classifying original articles and reviews into etiopathogenesis, assessment and therapy. PMID- 22243550 TI - Patient and spouse appraisals of health status in rheumatoid arthritis and fibromyalgia: discrepancies and associations with invalidation. AB - OBJECTIVES: The health problems of patients with rheumatoid arthritis and fibromyalgia are mostly invisible to others, which can lead to a discrepancy between patients' and spouses' appraisals of the severity of the health problems. As a consequence, some patients may feel 'invalidation' from their spouse, such as not being understood and believed. Aim of this study was to compare patients' and spouses' appraisals of the health status of patients with rheumatoid arthritis and patients with fibromyalgia, and to examine whether discrepancies in these appraisals are associated with invalidation experiences of the patient. METHODS: Eighty-four patients with rheumatoid arthritis and 95 patients with fibromyalgia filled out a health status questionnaire (MOS short-form general health survey, SF-20) and a questionnaire on invalidation by the spouse (Illness Invalidation Inventory, 3*I). The spouses appraised the patients' health status independently from the patients using a spouse version of the SF-20. RESULTS: Patients with fibromyalgia and their spouses appraised the patients' health status significantly worse than patients with rheumatoid arthritis and their spouses. The agreement between patients and spouses was generally fair with somewhat more agreement in rheumatoid arthritis than in fibromyalgia. Patient spouse discrepancies in health status appraisals were not associated with invalidation experiences. CONCLUSIONS: The invisibility of health problems in fibromyalgia and rheumatoid arthritis is not accompanied by large patient-spouse discrepancies of health status appraisals, which suggests that invalidation by spouses is not dependent on observable evidence such as clinical signs of damage or pathology. PMID- 22243306 TI - Search for dilepton resonances in pp collisions at ?s=7 TeV with the ATLAS detector. AB - This Letter reports on a search for narrow high-mass resonances decaying into dilepton final states. The data were recorded by the ATLAS experiment in pp collisions at ?s=7 TeV at the Large Hadron Collider and correspond to a total integrated luminosity of 1.08 (1.21) fb(-1) in the e(+)e(-) (MU(+)MU(-)) channel. No statistically significant excess above the standard model expectation is observed and upper limits are set at the 95% C.L. on the cross section times branching fraction of Z' resonances and Randall-Sundrum gravitons decaying into dileptons as a function of the resonance mass. A lower mass limit of 1.83 TeV on the sequential standard model Z' boson is set. A Randall-Sundrum graviton with coupling k/M(Pl)=0.1 is excluded at 95% C.L. for masses below 1.63 TeV. PMID- 22243551 TI - Relationship of severity of depression, anxiety and stress with severity of fibromyalgia. AB - OBJECTIVES: Negative affects like depression, anxiety and stress are frequently observed in patients with fibromyalgia (FMS). Understanding the association between FMS and negative affects is likely to help in deciding the choice of treatment. The aim of this study was to determine the correlation between the severity of FMS with the severity of depression, anxiety and stress. METHODS: Sixty patients with fibromyalgia and 60 healthy controls were included in the study. Fibromyalgia Impact Questionnaire Revised (FIQR), and Depression, Anxiety and Stress Scale (DASS21) were administered to both the groups. The mean age of study population was 40.4+/-9.9 and 36+/-8.7 for FMS and control groups respectively. Most of the patients were females (93.3%). RESULTS: In subjects without FMS, depression was seen in 5% and was significantly associated with all three components of FIQR (p<0.01), namely pain, symptoms and functional impairment. However, patients with FMS suffered more from all three components assessed in FIQR than those without FMS. In patients with FMS the severity of depression, anxiety and stress were found significantly associated with the severity of all three components of FIQR, namely pain, function and symptoms (p<0.01). CONCLUSIONS: Results suggest that FMS is associated with depression, anxiety and stress and in FMS magnitude of negative affects is significantly correlated with FIQR. However, depression alone in absence of FMS can also give rise to all three components of FIQR. PMID- 22243552 TI - Lifetime post-traumatic stress symptoms are related to the health-related quality of life and severity of pain/fatigue in patients with fibromyalgia. AB - OBJECTIVES: The aim of the present study was to investigate the impact of lifetime potentially traumatic events, including losses, and of post-traumatic stress symptoms on the severity of illness and health-related quality of life in patients with fibromyalgia (FM). METHODS: Seventy patients with FM, diagnosed according to the American College of Rheumatology criteria, were consecutively enrolled at the Unit of Rheumatology of the University of Pisa, Italy. Assessments included: SCID-I/P; the Fibromyalgia Impact Questionnaire (FIQ) and the Medical Outcomes Study Short Form-36 Health Survey (MOS SF-36), for the severity of pain; the Health-Related Quality of Life (HRQoL); the Trauma and Loss Spectrum Self-Report (TALS-SR) life-time version. RESULTS: The FIQ total score was related to the number of loss events (Domain I) and to symptoms of grief reactions (Domain II) and re-experiencing (Domain V) of the TALS-SR. The 'VAS fatigue' scores (FIQ) were significantly related to the TALS-SR symptoms of grief reactions (Domain II) and re-experiencing (Domain V). The Mental Component Summary and Bodily Pain scores of the MOS SF-36 were significantly related to all TALS-SR domains, the latter with the exception of the VIII (Arousal). CONCLUSIONS: Our results corroborate the presence of a relationship between the lifetime exposure to potentially traumatic events, in particular loss events, and lifetime post-traumatic stress symptoms and the severity of illness and HRQoL in patients with FM. PMID- 22243556 TI - Effectiveness of multidisciplinary therapy on symptomatology and quality of life in women with fibromyalgia. AB - OBJECTIVES: To study the effects of a 3-month multidisciplinary intervention based on exercise and psychological therapy on symptomatology and quality of life in women with fibromyalgia. METHODS: Seventy-five women with fibromyalgia volunteered to participate and were allocated to a 3-month (3-times/week) multidisciplinary (pool, land-based and psychological session based on the Acceptance and Commitment Therapy) intervention (n=41), or to a usual care group (n=34). Sixty-five women with fibromyalgia completed the study protocol (n=33 multidisciplinary intervention, aged 51.4+/-7.4 years and n=32 usual care group, aged 50.0+/-7.3 years). The outcomes variables were Fibromyalgia Impact Questionnaire (FIQ), Short Form Health Survey 36 (SF-36), Hospital Anxiety and Depression Scale, Vanderbilt Pain Management Inventory and Rosenberg Self-Esteem Scale. RESULTS: We observed a significant interaction effect (group*time) for the FIQ total score, the subscales fatigue, stiffness, anxiety and depression, and the subscales of SF-36 physical role, bodily pain, vitality and social functioning. Post-hoc analysis revealed significant improvements in total score of FIQ (p<0.001), fatigue (p=0.001), stiffness (p<0.001), anxiety (p=0.011), depression (p=0.008), physical role (p=0.002), bodily pain (p<0.001), vitality (p<0.001) and social functioning (p<0.001) in the intervention group, whereas in the control group, there was a significant worsening in the subscale depression (p=0.006) and social functioning (p=0.019). CONCLUSIONS: A 3-month low-moderate intensity multidisciplinary intervention improved fibromyalgia symptomatology and quality of life in women with fibromyalgia. PMID- 22243554 TI - Fibromyalgia in patients with rheumatoid arthritis: driven by depression or joint damage? AB - OBJECTIVES: Studies have shown an increased incidence of fibromyalgia (FMS) in RA patients. The aims of this study were to explore the effect of mood and disease damage on the prevalence of FMS. METHODS: RA patients underwent a standardised clinical assessment, including disease activity (DAS-28), disease damage (mechanical joint score, MJS), fibromyalgia tender point assessment and the Hospital Anxiety and Depression Scale (HADS) and Health Assessment Questionnaire (HAQ). Patients were classified with FMS using two criteria a) tender-swollen joint count was >=7 or b) tender point score of >=11/18. RESULTS: 44/285 (15%) patients were classified as having FMS using the joint count difference of >=7, compared to 18/285 (6%) using the tender point score of >11. Using the joint count difference to classify patients as having FMS, those with FMS had higher HAQ scores than those without FMS (2.12 vs. 1.5, p<0.0001). Although the DAS-28 was higher in this group (5.4 vs. 3.82, p<0.0001), the MJS was similar (8 vs. 7, p=0.19), suggesting similar levels of joint damage. Those classified as having FMS were more likely to have HAD-D scores of >11 (25% vs. 6%, p=0.0001). CONCLUSIONS: Coexistent FMS was common in our cohort, although using the tender point count to define FMS classified fewer patients with FMS. Within this group those with FMS had higher levels of depression but similar scores for joint damage indicating that in this cohort FMS and poorer physical functioning is mediated by low mood rather than joint damage. PMID- 22243555 TI - Sleep quality in fibromyalgia and rheumatoid arthritis: associations with pain, fatigue, depression, and disease activity. AB - OBJECTIVES: The aim of this study was to compare the sleep quality in patients with rheumatoid arthritis (RA) and fibromyalgia syndrome (FMS); and to evaluate the relationship between sleep quality and pain, fatigue, depression, and disease activity in patients with RA and FMS. METHODS: Forty RA, 40 FMS and 40 healthy controls were enrolled in the study. Disease activity and disease duration were reported in patients. Pain by visual analogue scale (VAS), fatigue by Multidimensional Assesment of Fatigue (MAF), depression by Beck Depression Index (BDI), and sleep quality by Pittsburgh Sleep Quality Index (PSQI) were gathered in all participants. RESULTS: All participants were aged between 20 and 65 years, with a mean age of 42.97+/-10.75 years. There was no significant difference with respect to demographic characteristics among the three study groups. Patients reported more depression than controls, but BDI scores were similar in FMS and RA patients. VAS pain scores and MAF scores were significantly different in the three groups (p<0.001). FMS and RA patients had poor sleep quality (p<0.001). FMS patients had daytime dysfunction due to sleep disorder and had worse habitual sleep efficiency than RA patients (p<0.05). In patients, positive correlations were found between PSQI and clinic assessment variables except disease duration. CONCLUSIONS: FMS and RA may have poor sleep quality when compared to subjects without rheumatologic disorders. The quality of sleep can be impaired by pain, fatigue, depression, and disease activity in such patients. PMID- 22243557 TI - Misdiagnosis in fibromyalgia: a multicentre study. AB - BACKGROUND: Fibromyalgia (FM) is the second most common cause of visits to rheumatologists after osteoarthritis, and may be difficult to diagnose in many patients. It is associated with various rheumatic disorders such as rheumatoid arthritis, spondyloarthropathies (SpA) and connective tissue disease (CTD), and a late diagnosis or misdiagnosis is a common and underestimated problem. OBJECTIVES: The aim of this study was to investigate the 'underdiagnosis' of FM, and which rheumatic diseases tend to be confused with it. METHODS: The following data were collected at baseline: symptoms, disease duration, physical examination findings, previous and current investigations and management, laboratory tests, tender point count, tender and swollen joint counts, and spinal pain. The clinimetric evaluation included the Fibromyalgia Impact Questionnaire (FIQ) and Fibromyalgia Assessment Status (FAS). RESULTS: The study population consisted of 427 outpatients (418 females and 9 males; mean age 49.3 years; mean disease duration 8.5 years). Fifty-seven patients (13.3%) had been previously misdiagnosed as having other musculoskeletal disorders (MSDs); 370 patients had been previous correctly diagnosed as having FM, or were diagnosed as having it during the course of the study. The FM and MSD groups were comparable in terms of demographic data and referral patterns. Disease duration was longer and the erythrocyte sedimentation rate was higher in the MSD patients, who also had less severe FIQ and lower pain visual analogue scale scores. Moreover, the FIQ and FAS scores correlated in the MS group. CONCLUSIONS: The findings of this study suggest that, although FM is a wellknown clinical entity, differential diagnosis with SpA, CTD and inflammatory arthritis can still be a challenge for rheumatologists and general practitioners. PMID- 22243553 TI - Fibromyalgia: prevalence, course, and co-morbidities in hospitalized patients in the United States, 1999-2007. AB - OBJECTIVES: To evaluate hospitalisation data for patients with a primary or secondary fibromyalgia (FM) diagnosis. We estimated the number of men and women with an FM diagnostic code and compared them across a number of demographic and hospitalisation characteristics; examined age-specific, population-based FM hospitalisation rates; and determined the most common co-morbid diagnoses when FM was either the primary or secondary diagnostic code. METHODS: Hospital discharge data from the Nationwide Inpatient Sample (NIS) were used. Records were evaluated between 1999 and 2007 that contained the International Classification of Diseases, 9th Revision, Clinical Modification FM diagnostic code (729.1, Myositis and Myalgia, unspecified), the FM criterion used in large-scale health services studies. RESULTS: There were 1,727,765 discharges with a 729.1 diagnostic code (FM) during this nine-year span, 213,034 men (12.3%) and 1,513,995 women (87.6%). Discharges coded for FM increased steadily each year. The population-based rate of male FM discharges rose gradually across the lifespan; the rate for women rose sharply but then declined after age 64. Few differences between men and women across demographic and hospitalisation characteristics were evident. The most common co-morbidities with FM as the primary diagnosis were non-specific chest pain, mood disorders, and Spondylosis/intervertebral disc disorders/other back problems. Most common primary diagnoses, with FM as a secondary diagnosis, were essential hypertension, disorders of lipid metabolism, coronary atherosclerosis/other heart disease, and mental disorders. CONCLUSIONS: A substantial number of U.S. residents with FM were hospitalised over the study period. Further analysis of hospitalisation data from patients with FM may provide guidance for both research and treatment, with the goal of improved care for FM patients. PMID- 22243558 TI - Brain imaging in fibromyalgia syndrome. AB - Fibromyalgia (FM) is a chronic musculoskeletal pain syndrome which is characterised by clinical pain as well as widespread hyperalgesia/allodynia to mechanical, thermal, electrical, and chemical stimuli. Lack of consistent tissue abnormalities in FM patients has more and more shifted the focus away from peripheral factors and towards central nervous system abnormalities including central sensitisation as well as aberrant pain facilitation and inhibition. Besides quantitative sensory testing, functional brain imaging has been increasingly utilised to characterise the abnormal pain processing of FM patients. Whereas initial work in FM patients identified abnormally increased pain-related brain activity within the thalamus, insula, anterior cingulate, S1, and prefrontal cortex (so-called 'pain matrix'), more recent research focused on altered 'connectivity' between multiple interconnected brain networks in these patients. Additionally, magnetic resonance spectroscopy studies demonstrated high concentration of the excitatory neurotransmitter glutamate in FM patients in pain related brain areas which correlated not only with experimental but also with clinical pain ratings. Overall, functional brain imaging studies have provided compelling evidence for abnormal pain processing in FM, including brain activity that correlated with patients' augmented pain sensitivity (hyperalgesia/allodynia), temporal summation of pain, and prolonged pain aftersensations. Future imaging work needs to focus on identifying the neural correlates of FM patients' abnormal endogenous pain modulation which will likely not only shed more light on this important pain regulatory mechanism but may also provide useful information for future treatments of FM symptoms. PMID- 22243559 TI - Chronic widespread pain and fibromyalgia: could there be some relationships with infections and vaccinations? AB - Chronic widespread pain (CWP) is a common symptom within the community, and may be part of or arise as a result of various diseases or conditions. Fibromyalgia (FM) is probably the most common and best known disease whose cardinal symptom is CWP. Many authors, however, indistinctively describe pain as 'widespread', 'diffuse' or 'generalised', and this may lead to misunderstandings about true clinical or scientific significance. Widespread pain has been variously defined, over the years, beginning from the American College of Rheumatology (ACR) classification criteria for FM in 1990, and the CWP Manchester definition in 1996. A comprehensive and brief core sets for CWP was developed in 2003, by the WHO International Classification of Functioning Consensus Conference, and finally, the ACR proposed new preliminary diagnostic criteria for FM in 2010. Research into CWP and/or FM is therefore difficult and can lead to conflicting results. CWP and (particularly) FM are multifactorial disorders. There is increasing evidence that they may be triggered by environmental factors, and many authors have highlighted a relationship with various infectious agents and some have suggested that vaccinations may play a role. This review analyses the available data concerning the relationships between FM and widespread pain (in its various meanings) with infections and vaccinations, from the earliest report to the most recent contributions. Considering all scientific papers, various levels of possible associations emerge. There is no clear-cut evidence of FM or CWP due to infections or vaccinations, no correlations with persistent infection, and no proven relationship between infection, antimicrobial therapies and pain improvement. A higher prevalence of FM and chronic pain has been found in patients with Lyme disease, and HIV or HCV infection, and, perhaps, also in patients with mycoplasmas, HBV, HTLV I, and parvovirus B19 infections. Some unconfirmed evidence and case reports suggest that vaccinations may trigger FM or chronic pain. PMID- 22243560 TI - Frequency of juvenile fibromyalgia syndrome in children with familial Mediterranean fever: effects on depression and quality of life. AB - OBJECTIVES: To determine the prevalence of juvenile fibromyalgia syndrome (JFMS) in children with familial Mediterranean fever (FMF) and to evaluate quality of life (QoL) and depression. METHODS: Ninety-one FMF patients (M/F: 44/47) who fulfilled the Livneh criteria and 60 healthy children (M/F: 27/33) were enrolled in the study. Yunus and Masi's criteria were used for diagnosis of JFMS. Depression was assessed with Children's Depression Inventory (CDI) and QoL was evaluated with child and parent reports of Paediatric Quality of Life Inventory 4.0 (PedsQLTM). RESULTS: While 20 (21.9%) of 91 FMF patients fulfilled JFMS criteria, 2 (3.3%) of the control group met the diagnostic criteria of JFMS (p=0.002). PedsQLTM scores (child self-report and parent-report) of the FMF patients were significantly lower and the depression scores were significantly higher than the healthy controls (p<0.001 for all). When the FMF patients were assigned to two groups as FMF with or without JFMS, patients with JFMS were found to have a higher depression score (p=0.007) and child and parent reports of PedsQLTM 4.0 were lower in the children with JFMS than in the patients without JFMS (p=0.001, p=0.003, respectively). CONCLUSIONS: We have determined that JFMS frequency was higher in children with FMF and patients with FMF and JFMS had a poor QoL and were more susceptible to depression. FMF patients with widespread and persistent pain should be evaluated for JFMS in order to avoid unnecessary investigations and inappropriate treatment. PMID- 22243561 TI - Patterns of operative mortality following esophagectomy. AB - Esophagectomy has one of the highest mortality rates among all surgical procedures. We investigated the type and frequency of complications associated with perioperative mortality after esophagectomy. We performed a retrospective review of all perioperative deaths following esophagectomy for esophageal cancer at the Mayo Clinic, Rochester from 1993 through 2009. Of 1522 esophagectomies, perioperative mortality occurred in 45 (3.0%). The majority who died were male (82%); median age was 72 years (range 46-92). The median age-adjusted Charlson comorbidity score was 6. Twenty-three (51%) underwent neoadjuvant chemoradiotherapy. The type of esophagectomy was transthoracic in 27 patients (60%), transhiatal in eight (18%), tri-incisional in seven (16%), left thoracoabdominal in one (2%), and transabdominal in one (2%). A mean of 3.2 major complications occurred prior to death (median 2.5, range 1-8), with the most common being pulmonary complications occurring in 30 patients (67%) and anastomotic complications in 20 (44%). The primary underlying cause of death was pulmonary complications and anastomotic complications in 18 patients (40%) each, respectively, abdominal sepsis in three (7%), fatal hemorrhage in three (7%), and pulmonary embolism, stroke and multisystem organ failure in one each (2%), respectively. Patients died a median of 19 days (range 3-98) following esophagectomy. Most patients who died following esophagectomy experienced multiple serious complications rather than a single causative event. Major pulmonary and anastomotic complications were implicated in the vast majority of perioperative mortality, and should remain the focus of efforts to improve clinical outcomes. PMID- 22243562 TI - Addressing the complexity and diversity of agricultural plant volatiles: a call for the integration of laboratory- and field-based analyses. AB - As the sophistication and sensitivity of chemical instrumentation increase, so does the number of applications. Correspondingly, new questions and opportunities for systems previously studied also arise. As with most plants, the emission of volatiles from agricultural products is complex and varies among commodities. Volatiles are indicative of characteristics such as food quality, cultivar type, phenological stage, and biotic and abiotic stressors; thus, their systematic and accurate evaluation is important. Early volatile analyses entailed removal of the sample matrix in question, transport to the laboratory, and subsequent investigation. More recently, scientists are moving the laboratory to the field to obtain realistic emission patterns of the sample in its natural environment. This perspective proposes that a methodical and collaborative approach to the complex relationship between volatiles and agricultural commodities and their various phenological stages, oxidative degradation products, and fungal contamination is needed in order to fully comprehend the sample and associated relationships as a whole. These methodical approaches should incorporate both in situ and ex situ investigations of the sample. Ultimately, there exists an opportunity for development of methodologies that integrate both laboratory- and field-based collection of volatiles to explore and address the complex biological interactions of agricultural systems. PMID- 22243564 TI - Evaluation of the effect of wheat aleurone-rich foods on markers of antioxidant status, inflammation and endothelial function in apparently healthy men and women. AB - Observational data show an inverse association between the consumption of whole grain foods, and inflammation and related diseases. Although the underlying mechanisms are unclear, whole grains, and in particular the aleurone layer, contain a wide range of components with putative antioxidant and anti inflammatory effects. We evaluated the effects of a diet high in wheat aleurone on plasma antioxidants status, markers of inflammation and endothelial function. In this parallel, participant-blinded intervention, seventy-nine healthy, older, overweight participants (45-65 years, BMI>25 kg/m2) incorporated either aleurone rich cereal products (27 g aleurone/d), or control products balanced for fibre and macronutrients, into their habitual diets for 4 weeks. Fasting blood samples were taken at baseline and on day 29. Results showed that, compared to control, consumption of aleurone-rich products provided substantial amounts of micronutrients and phytochemicals which may function as antioxidants. Additionally, incorporating these products into a habitual diet resulted in significantly lower plasma concentrations of the inflammatory marker, C-reactive protein (P = 0.035), which is an independent risk factor for CVD. However, no changes were observed in other markers of inflammation, antioxidant status or endothelial function. These results provide a possible mechanism underlying the beneficial effects of longer-term whole-grain intake. However, it is unclear whether this effect is owing to a specific component, or a combination of components in wheat aleurone. PMID- 22243563 TI - Naltrexone does not attenuate the effects of intravenous Delta9 tetrahydrocannabinol in healthy humans. AB - Although a wealth of preclinical evidence indicates an interplay between the MU opioid (MOR) and cannabinoid 1 receptor (CB1R) systems, the precise nature of the cross modulation in humans is unclear. The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist, naltrexone, on the subjective, behavioural and cognitive effects of the CB1R agonist, Delta9 tetrahydrocannabinol (THC), in healthy human subjects. Healthy human subjects, screened carefully for any medical or psychiatric illness, were administered either placebo or active naltrexone (25 mg) orally on each test day, followed 45 min later by placebo and 165 min later by active i.v. THC (0.025 mg/kg) in a randomized, fixed-order, double-blind manner. Subjective, behavioural and cognitive effects were assessed before and at several points after each drug administration. THC produced expected effects, including euphoria, anxiety, transient perceptual alterations, transient psychotomimetic effects and cognitive impairments. However, naltrexone did not produce any effects alone, nor did it attenuate any of THC's effects. Thus, in healthy human subjects who use cannabis intermittently, MOR antagonism does not modulate the common acute subjective, behavioural and cognitive effects of THC. PMID- 22243565 TI - Indications and considerations of foot and ankle arthrodesis. AB - This article discusses the introductory physiology of bone healing with respect to arthrodesis. The joints of the foot and ankle can suffer many trials and tribulations in an otherwise normal life, and must adapt to instances such as fractures, dislocations, and congenital problems. When adaptation leads to a malformation in the unit structure, surgical intervention is required to restore the foot and ankle complex to a working device. Primary indications for regarding any joint fusion in the human body include deformity, instability, and pain. An overview of the indications for performing joint fusions at the foot and ankle is presented. PMID- 22243566 TI - Complications of arthrodesis and nonunion. AB - Complications of joint fusions can include those applicable to any surgery such as bone and/or soft-tissue infection, wound dehiscence, and failure of fixation. Other complications are specific to fusion procedures and would include malalignment, proximal or distal joint deterioration, and delayed union or nonunion. The latter negative outcomes can occur from medical comorbidities, patient noncompliance, or inappropriate fixation. This article addresses many of these complications including techniques for evaluation, accurate diagnosis, and current treatment options. Special attention is paid to the subject of nonunion, as it is one of the most common and difficult adverse outcomes of arthrodesis procedures. PMID- 22243567 TI - Master techniques in digital arthrodesis. AB - This is a comprehensive review of various techniques of digital fusion. Evolution of the technique has afforded today's surgeons a valuable repertoire of surgical options. Ultimately, patient factors and surgeon preference determine the most appropriate method of fixation. PMID- 22243569 TI - Lisfranc arthrodesis. AB - Lisfranc fracture-dislocations are complex injuries that require a high skill set from foot and ankle surgeons to diagnose and treat. Conservative treatment is seldom an option for treatment of Lisfranc injuries. The authors believe that even subtle injuries require surgical intervention. The comparison between open reduction internal fixation, partial arthrodesis, and complete arthrodesis is discussed, as well as various fixation techniques to accomplish these procedures when approaching a Lisfranc injury. PMID- 22243568 TI - First metatarsophalangeal joint arthrodesis. AB - Arthrodesis of the first metatarsophalangeal joint (MTPJ) is used primarily for end-stage hallux rigidus whereby pain, crepitus, and limitation of motion is noted at the joint. Arthrodesis at the first MTPJ also has it uses as a primary procedure for rheumatoid arthritis when severe deformity is present, as well as for salvage procedures for failed joint arthroplasties with or without implant, fractures with intra-articular extension, avascular necrosis, and infection management. A first MTPJ arthrodesis should provide stable fixation, attain suitable positioning for a reasonable gait, maintain adequate length, and create a stable platform for a plantigrade foot type. PMID- 22243570 TI - Subtalar joint arthrodesis. AB - Isolated subtalar joint arthrodesis has gained popularity more recently. Research has shown that it preserves rearfoot motion, does not increase the risk of arthritis in adjacent joints, and is not an especially complex operative procedure. It decreases the chance of midtarsal joint nonunion and malunion postoperatively. This article takes an in-depth approach to isolated talocalcaneal fusions. Anatomy and biomechanics of the subtalar joint are reviewed. Clinical presentation and radiologic evaluation are discussed. Conservative treatment, operative technique, and postoperative management are included. PMID- 22243572 TI - Triple arthrodesis. AB - A triple arthrodesis is a fusion of the talocalcaneal, calcaneal cuboid, and talonavicular joints. The purpose is to create a well-aligned, plantigrade, and stable foot for patients with deformity or progressive neurologic and arthritic conditions. This article is a comprehensive overview of the procedure. However effective, triple arthrodesis is a challenging procedure for even the most skilled surgeon. PMID- 22243571 TI - Calcaneocuboid arthrodesis. AB - The calcaneocuboid joint is stable, although multiple conditions might affect the joint, including arthritis, fracture, subluxation, and dislocation. Calcaneocuboid arthrodesis is more commonly performed as an adjunct procedure with other rearfoot procedures such as triple arthrodesis and is less used as isolated fusion. This article reviews the main conditions of the lateral column and calcaneocuboid joint in particular. The surgical technique for isolated calcaneocuboid arthrodesis is discussed. PMID- 22243573 TI - Ankle arthrodesis. AB - This article presents an overview of current ankle arthrodesis techniques. Surgical indications, pathophysiology of the ankle joint, preoperative assessment of the patient, surgical techniques for ankle fusion, and complications/sequelae are discussed. The surgical techniques section focuses on crossed screws arthrodesis and intramedullary nailing for tibiotalocalcaneal arthrodesis. Other techniques, including arthroscopic fusion, are also discussed. PMID- 22243574 TI - Salvage arthrodesis for charcot arthropathy. AB - The principles of fusion of a Charcot joint arise from the assertion that successful fusion requires removal of all cartilage, debris, and sclerotic bone. The authors believe that reconstruction can prevent amputation in patients who have unbraceable or unstable deformities, or recurrent ulcerations. The goal with any Charcot reconstruction procedure is to achieve a plantigrade foot free of ulceration, and to prevent any future collapse, deformity, or ulcerations. The authors strongly believe arthrodesis of unstable joints of the Charcot neuropathic foot can lead to limb salvage and better quality of life. PMID- 22243575 TI - First metatarsophalangeal joint arthrodiastasis and biologic resurfacing with external fixation: a case report. AB - The primary goal in the treatment of arthritic joints is elimination of pain associated with limited motion. Several surgical techniques have been developed to treat varying degrees of hallux rigidus of any cause. This case report details an alternative surgical approach to address hallux rigidus and associated hallux valgus deformity through a combination of joint debridement, resurfacing, and arthrodiastasis. PMID- 22243576 TI - Surgical soft tissue closure of severe diabetic foot infections: a combination of biologics, negative pressure wound therapy, and skin grafting. AB - Creative surgical strategies are often warranted for long-term closure of diabetic foot wounds. This article provides a case report describing the successive use of negative pressure wound therapy, advanced biologics, and split thickness skin grafting for healing an extensive surgical wound. Although the success of these therapies is enticing, their use should be based on careful patient selection in a multidisciplinary setting. PMID- 22243577 TI - Arthrodesis of the foot and ankle. Foreword. PMID- 22243578 TI - Clinics in Podiatric Medicine and Surgery. Preface. PMID- 22243580 TI - Quality control in aminoacyl-tRNA synthesis its role in translational fidelity. AB - Accurate translation of mRNA into protein is vital for maintenance of cellular integrity. Translational fidelity is achieved by two key events: synthesis of correctly paired aminoacyl-tRNAs by aminoacyl-tRNA synthetases (aaRSs) and stringent selection of aminoacyl-tRNAs (aa-tRNAs) by the ribosome. AaRSs define the genetic code by catalyzing the formation of precise aminoacyl ester-linked tRNAs via a two-step reaction. AaRSs ensure faithful aa-tRNA synthesis via high substrate selectivity and/or by proofreading (editing) of noncognate products. About half of the aaRSs rely on proofreading mechanisms to achieve high levels of accuracy in aminoacylation. Editing functions in aaRSs contribute to the overall low error rate in protein synthesis. Over 40 years of research on aaRSs using structural, biochemical, and kinetic approaches has expanded our knowledge of their cellular roles and quality control mechanisms. Here, we review aaRS editing with an emphasis on the mechanistic and kinetic details of the process. PMID- 22243581 TI - Termination and post-termination events in eukaryotic translation. AB - Translation termination in eukaryotes occurs in response to a stop codon in the ribosomal A-site and requires two release factors (RFs), eRF1 and eRF3, which bind to the A-site as an eRF1/eRF3/GTP complex with eRF1 responsible for codon recognition. After GTP hydrolysis by eRF3, eRF1 triggers hydrolysis of the polypeptidyl-tRNA, releasing the completed protein product. This leaves an 80S ribosome still bound to the mRNA, with deacylated tRNA in its P-site and at least eRF1 in its A-site, which needs to be disassembled and released from the mRNA to allow further rounds of translation. The first step in recycling is dissociation of the 60S ribosomal subunit, leaving a 40S/deacylated tRNA complex bound to the mRNA. This is mediated by ABCE1, which is a somewhat unusual member of the ATP binding cassette family of proteins with no membrane-spanning domain but two essential iron-sulfur clusters. Two distinct pathways have been identified for subsequent ejection of the deacylated tRNA followed by dissociation of the 40S subunit from the mRNA, one executed by a subset of the canonical initiation factors (which therefore starts the process of preparing the 40S subunit for the next round of translation) and the other by Ligatin or homologous proteins. However, although this is the normal sequence of events, there are exceptions where the termination reaction is followed by reinitiation on the same mRNA (usually) at a site downstream of the stop codon. The overwhelming majority of such reinitiation events occur when the 5'-proximal open reading frame (ORF) is short and can result in significant regulation of translation of the protein coding ORF, but there are also rare examples, mainly bicistronic viral RNAs, of reinitiation after a long ORF. Here, we review our current understanding of the mechanisms of termination, ribosome recycling, and reinitiation after translation of short and long ORFs. PMID- 22243582 TI - Quality control of mRNA decoding on the bacterial ribosome. AB - The ribosome is a major player in providing accurate gene expression in the cell. The fidelity of substrate selection is tightly controlled throughout the translation process, including the initiation, elongation, and termination phases. Although each phase of translation involves different players, that is, translation factors and tRNAs, the general principles of selection appear surprisingly similar for very different substrates. At essentially every step of translation, differences in complex stabilities as well as induced fit are sources of selectivity. A view starts to emerge of how the ribosome uses local and global conformational switches to govern induced-fit mechanisms that ensure fidelity. This review describes the mechanisms of tRNA and mRNA selection at all phases of protein synthesis in bacteria. PMID- 22243583 TI - Control of gene expression by translational recoding. AB - Like all rules, even the genetic code has exceptions: these are generically classified as "translational recoding." Almost every conceivable mode of recoding has been documented, including signals that redefine translational reading frame and codon assignation. While first described in viruses, it is becoming clear that sequences that program elongating ribosomes to shift translational reading frame are widely used by organisms in all domains of life, thus expanding both the coding capacity of genomes and the modes through which gene expression can be regulated at the posttranscriptional level. Instances of programmed ribosomal frameshifting and stop codon reassignment are opening up new avenues for treatment of numerous inborn errors of metabolism. The implications of these findings on human health are only beginning to emerge. PMID- 22243585 TI - Posttranscriptional recoding by RNA editing. AB - The posttranscriptional recoding of nuclear RNA transcripts has emerged as an important regulatory mechanism during eukaryotic gene expression. In particular the deamination of adenosine to inosine (interpreted by the translational machinery as a guanosine) is a frequent event that can recode the meaning of amino acid codons in translated exons, lead to structural changes in the RNA fold, or may affect splice consensus or regulatory sequence sites in noncoding exons or introns and modulate the biogenesis of small RNAs. The molecular mechanism of how the RNA editing machinery and its substrates recognize and interact with each other is not understood well enough to allow for the ab initio delineation of bona fide RNA editing sites. However, progress in the identification of various physiological modification sites and their characterization has given important insights regarding molecular features and events critical for productive RNA editing reactions. In addition, structural studies using components of the RNA editing machinery and together with editing competent substrate molecules have provided information on the chemical mechanism of adenosine deamination within the context of RNA molecules. Here, I give an overview of the process of adenosine deamination RNA editing and describe its relationship to other RNA processing events and its currently established roles in gene regulation. PMID- 22243586 TI - Fidelity and quality control in gene expression. Preface. PMID- 22243597 TI - The Society of Urologic Oncology's reply to the US Preventative Services Task Force's recommendation on PSA testing. PMID- 22243598 TI - Conjugation reactions involving maleimides and phosphorothioate oligonucleotides. AB - Phosphorothioate diester oligonucleotides proved to be fully compatible with maleimides in the context of two different conjugation reactions: (a) reaction of (5')diene-[phosphorothioate oligonucleotides] with maleimido-containing compounds to afford the Diels-Alder cycloadduct; (b) conjugation of (5')maleimido [phosphorothioate oligonucleotides] with thiol-containing compounds. No evidence of reaction between phosphorothioate diesters and maleimides was found in any of these processes. Importantly, in the preparation of (5')maleimido [phosphorothioate oligonucleotides] from [protected maleimido]-[phosphorothioate oligonucleotides], which requires the maleimide to be deprotected by retro-Diels Alder reaction (heating for 3-4 h in toluene at 90 degrees C), no addition of phosphorothioate diester to the maleimide was found either. Finally, maleimide [phosphorothioate monoester] conjugation was also explored for comparison purposes. PMID- 22243599 TI - Presence of Not5 and ubiquitinated Rps7A in polysome fractions depends upon the Not4 E3 ligase. AB - In this study, we determine that Saccharomyces cerevisiae Not4 E3 ligase ubiquitinates Rps7A in vivo and in vitro, but not its paralogue, Rps7B. Ubiquitinated Rps7A is detectable only in 80S and polysomes, but not in free 40S fractions. A different role of the Rps7 paralogues in vivo is supported by the observation that the deletion of Rps7A but not Rps7B is sensitive to translational inhibitors and leads to an accumulation of aggregated proteins. An important accumulation of aggregated proteins that include ribosomal proteins and ribosome-associated chaperones is also observed in cells lacking Not4. A contribution of Not4 to ribosomal function extending beyond Rps7A ubiquitination is supported by the observation that the deletion of Not4 displays a synthetic slow growth phenotype when combined with the deletion of either one of the two Rps7 paralogues. Not4 is detectable in polysome fractions, as are other subunits of the Ccr4-Not complex such as Not5. The optimal presence of Not5 in polysomes is dependent upon Not4 and the deletion of Not5 leads to a dramatic reduction of polysomes. These results lead us to suggest that Not4 contributes to normal polysome levels and is important for cellular protein solubility maybe in part by ubiquitination of Rps7A. PMID- 22243600 TI - Lessons learned from the Australian Home Medicine Review program. PMID- 22243584 TI - The tmRNA ribosome-rescue system. AB - The bacterial tmRNA quality control system monitors protein synthesis and recycles stalled translation complexes in a process termed "ribosome rescue." During rescue, tmRNA acts first as a transfer RNA to bind stalled ribosomes, then as a messenger RNA to add the ssrA peptide tag to the C-terminus of the nascent polypeptide chain. The ssrA peptide targets tagged peptides for proteolysis, ensuring rapid degradation of potentially deleterious truncated polypeptides. Ribosome rescue also facilitates turnover of the damaged messages responsible for translational arrest. Thus, tmRNA increases the fidelity of gene expression by promoting the synthesis of full-length proteins. In addition to serving as a global quality control system, tmRNA also plays important roles in bacterial development, pathogenesis, and environmental stress responses. This review focuses on the mechanism of tmRNA-mediated ribosome rescue and the role of tmRNA in bacterial physiology. PMID- 22243601 TI - Pharmacists' counseling protocols for minor ailments: a structure-based analysis. AB - BACKGROUND: Self-medication is an important component of health care. To optimize pharmacists' over-the-counter counseling, there are several guidelines and protocols used in practice. In a self-care environment, protocols should comprise items related to patients' autonomy. The structure of self-medication protocols, among other elements, should present steps to facilitate patients' participation. OBJECTIVE: To analyze structural differences between existing community pharmacy minor ailment protocols, including those related to patient autonomy and empowerment in self-medication conditions. METHODS: The study design followed a cross-sectional descriptive approach. Self-medication protocols were systematically collected from 3 different professional sources (Pharmaceutical Society [OF], National Pharmacies Association [ANF], and Grupo Holon [GH]). A structural-based analysis, by comparison with the general self-medication OF standard protocol, produced outcome measures such as frequencies of flowchart critical steps, active pharmaceutical substances, dosage forms, and posologies. Simple scores were computed to assess protocols' structural quality, as well as differences between protocols, produced by each professional organization. RESULTS: Forty-four protocols presented on average 8 counseling steps toward 10 different active substances, 7 dosages forms, and 14 posologic schemes. From a maximum of 30 critical items, 1 protocol scored 24, 7 scored 23, and 5 scored less than 15 items. Significant differences were found between protocols' structural components from different sources, particularly between GHs' protocols compared with those produced by OF and ANF. CONCLUSIONS: In general, all protocols matched the OF standard for ailment characterization but fell short on steps related to medicine information and selection. Steps for patient participation and agreement were absent, as was pharmacists' expected role of outcomes monitoring. It might be appropriate to redesign self-medication protocols, preferably through a consensus process that includes not only professionals' but also patients' preferences, starting from the prevalent conditions in Portuguese pharmacy practice. PMID- 22243602 TI - 3-fluoro- and 3,3-difluoro-3,4-dideoxy-KRN7000 analogues as new potent immunostimulator agents: total synthesis and biological evaluation in human invariant natural killer T cells and mice. AB - We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies. The fluoro 3,4-dideoxy-GalCer analogues appears as partial agonists compared to KRN7000 for iNKT cell activation, inducing T(H)1 or T(H)2 biases that strongly depend of the mode of antigen presentation, including human vs mouse differences. We evidenced that if a sole fluorine atom is not able to balance the loss of the 3-OH, the presence of a difluorine group at C3 of the sphingosine can significantly restore human iNKT activation. PMID- 22243603 TI - The relation between chronic kidney disease and cerebral microbleeds: difference between patients with and without diabetes. AB - BACKGROUND: Cerebral microbleeds are an important radiologic marker of bleeding prone brain and have been reported to be associated with the increased risk of intracerebral haemorrhage. AIMS: We sought to examine the association of chronic kidney disease with cerebral microbleeds, and determine whether the association differs between patients with and without diabetes. METHODS: A total of 909 patients with ischemic stroke who were consecutively admitted to our hospital were included in this study. We collected demographic, clinical, and laboratory data (including serum creatinine levels) and documented the presence and numbers of microbleeds. Kidney function was estimated by using the Modification of Diet in Renal Disease formula. We categorized estimated glomerular filtration rates into moderate to severe, mild, and normal (<60, 60-90, and >90 ml/min/1.73 m(2), respectively). RESULTS: Cerebral microbleeds is most frequent in the moderate-to severe chronic kidney disease group (45.6%). In patients without diabetes, mild and moderate-to-severe chronic kidney disease was found to be independently associated with the presence of cerebral microbleeds (adjusted odds ratio, 1.68; 95% confidence interval, 1.04-2.71 and adjusted odds ratio, 3.74; 95% confidence interval, 1.87-7.47) compared with normal kidney function. In patients with diabetes, however, this relationship was not found. Furthermore, ordinal logistic regression analysis revealed that an increased serum creatinine level and a reduced kidney function were associated with the number of cerebral microbleeds. CONCLUSION: We found that chronic kidney disease is independently associated with cerebral microbleeds in patients without diabetes but not in patients with diabetes. PMID- 22243604 TI - Oocyte meiotic-stage-specific differences in spindle depolymerization in response to temperature changes monitored with polarized field microscopy and immunocytochemistry. AB - OBJECTIVE: To compare the polymerization status of mouse oocyte spindles exposed to various temperatures at various stages of meiosis. DESIGN: Experimental animal study. SETTING: University animal laboratory. ANIMAL(S): CF1 mice. INTERVENTION(S): Immature oocytes matured to metaphase I (MI), telophase I (TI), and metaphase II (MII) were incubated at 37 degrees C (control), room temperature (RT), or 4 degrees C for 0, 10, 30, and 60 minutes. Spindle analysis subsequently was performed using polarized field microscopy and immunocytochemistry. Spindles of TI and MII oocytes that underwent vitrification and warming were analyzed also by immunocytochemistry. MAIN OUTCOME MEASURE(S): Detection of polymerized meiotic spindles. RESULT(S): At RT, and after 60 minutes at 4 degrees C, a significant time-dependent decrease in the percentage of polymerized meiotic spindles was observed in MI and MII oocytes, but not in TI oocytes. The polymerization of TI spindles at 4 degrees C was similar to that of TI spindles at 4 degrees C that underwent vitrification and warming. CONCLUSION(S): Significant differences in the microtubule dynamics of MI, TI, and MII oocytes incubated at different temperatures were observed. In particular, meiotic spindles in TI oocytes exhibited less depolymerization than did metaphase spindles. PMID- 22243605 TI - Effects of acupuncture on pregnancy rates in women undergoing in vitro fertilization: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effect of acupuncture on in vitro fertilization (IVF) outcomes. DESIGN: Systematic review and meta-analysis. PATIENT(S): Women undergoing IVF in randomized controlled trials (RCTs) who were evaluated for the effects of acupuncture on IVF outcomes. SETTING: Not applicable. INTERVENTION(S): The intervention groups used manual, electrical, and laser acupuncture techniques. The control groups consisted of no, sham, and placebo acupuncture. MAIN OUTCOME MEASURE(S): The major outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR). Heterogeneity of the therapeutic effect was evaluated with a forest plot analysis. Publication bias was assessed by a funnel plot analysis. RESULT(S): Twenty-four trials (a total of 5,807 participants) were included in this review. There were no significant publication biases for most of the comparisons among these studies. The pooled CPR (23 studies) from all of the acupuncture groups was significantly greater than that from all of the control groups, whereas the LBR (6 studies) was not significantly different between the two groups. The results were different when the type of control was examined in a sensitivity analysis. The CPR and LBR differences between the acupuncture and control groups were more obvious when the studies using the Streitberger control were ignored. Similarly, if the underlying effects of the Streitberger control were excluded, the LBR results tended to be significant when the acupuncture was performed around the time of oocyte aspiration or controlled ovarian hyperstimulation. CONCLUSION(S): Acupuncture improves CPR and LBR among women undergoing IVF based on the results of studies that do not include the Streitberger control. The Streitberger control may not be an inactive control. More positive effects from using acupuncture in IVF can be expected if an appropriate control and more reasonable acupuncture programs are used. PMID- 22243620 TI - Antioxidant and photoprotective responses to elevated CO(2) and heat stress during holm oak regeneration by resprouting, evaluated with NIRS (near-infrared reflectance spectroscopy). AB - Photosynthetic, photoprotective and antioxidant responses during high temperature stress were determined in leaves of evergreen holm oak (Quercus ilex L.), the main species in Mediterranean forests, during resprouting under elevated CO(2) (750 MUl.l(-1) ). Leaf chemicals, chloroplast pigments and non-enzymatic antioxidants were quantified in a single measurement using NIRS (near-infrared spectroscopy), a rapid and suitable method for ecophysiological purposes. Resprouts from plants grown under elevated CO(2) (RE) showed photosynthetic down regulation, higher starch content and lower stomatal conductance, but similar stomatal density, than plants grown under current CO(2) concentrations (350 MUl.l(-1) ) (RA). The photosynthetic sink reduction and need for more antioxidants and photoprotection in RE were reflected in an increased concentration of ascorbate (Asc) and phenolic compounds and in the contribution of the xanthophyll (Z/VAZ) and lutein epoxide cycles to excess energy dissipation as heat, and also reflected in chlorophyll fluorescence measurements. CO(2) assimilation parameters were stable from 25 to 35 degrees C in RE and RA, declining thereafter in RA in spite of a 2.3 degrees C lower leaf temperature. RE showed a more marked decline in photorespiration above 35 degrees C and less sensitive stomatal responses to high temperature stress than RA. During heat stress, RE had higher Asc, Z/VAZ and phenolics content, together with delayed enhancement of chloroplast lipophilic antioxidant compounds (carotenes and tocopherols). The high contribution of photoprotective systems and high temperature tolerance in resprouts developed under elevated CO(2) would mitigate the effect of photosynthesis acclimation during the regeneration of Q. ilex plants under climate change. PMID- 22243621 TI - Characterization of the biotin uptake system encoded by the biotin-inducible bioYMN operon of Corynebacterium glutamicum. AB - BACKGROUND: The amino acid-producing Gram-positive Corynebacterium glutamicum is auxotrophic for biotin although biotin ring assembly starting from the precursor pimeloyl-CoA is still functional. It possesses AccBC, the alpha-subunit of the acyl-carboxylases involved in fatty acid and mycolic acid synthesis, and pyruvate carboxylase as the only biotin-containing proteins. Comparative genome analyses suggested that the putative transport system BioYMN encoded by cg2147, cg2148 and cg2149 might be involved in biotin uptake by C. glutamicum. RESULTS: By comparison of global gene expression patterns of cells grown with limiting or excess supply of biotin or with dethiobiotin as supplement replacing biotin revealed that expression of genes coding for enzymes of biotin ring assembly and for the putative uptake system was regulated according to biotin availability. RT PCR and 5'-RACE experiments demonstrated that the genes bioY, bioM, and bioN are transcribed from one promoter as a single transcript. Biochemical analyses revealed that BioYMN catalyzes the effective uptake of biotin with a concentration of 60 nM biotin supporting a half-maximal transport rate. Maximal biotin uptake rates were at least five fold higher in biotin-limited cells as compared to cells grown with excess biotin. Overexpression of bioYMN led to an at least 50 fold higher biotin uptake rate as compared to the empty vector control. Overproduction of BioYMN alleviated biotin limitation and interfered with triggering L-glutamate production by biotin limitation. CONCLUSIONS: The operon bioYMN from C. glutamicum was shown to be induced by biotin limitation. Transport assays with radio-labeled biotin revealed that BioYMN functions as a biotin uptake system. Overexpression of bioYMN affected L-glutamate production triggered by biotin limitation. PMID- 22243623 TI - In situ molecular analysis of plant tissues by live single-cell mass spectrometry. AB - We report the development of a rapid, direct molecular analysis of live, single plant cells viewed under a video microscope in their natural environment. A nanoelectrospray tip was used to extract the contents of a single leaf, stem, or petal cell from Pelargonium zonale, and the samples were analyzed on an Orbitrap mass spectrometer by nanoelectrospray ionization. Around a thousand m/z peaks belonging to metabolites and other compounds in each sample were obtained and processed by using statistical tools to find the cell specific molecular peaks. Hybrid high-resolution mass spectrometry analysis was performed to confirm the structure of specific metabolites from the analyzed samples. This method is useful for identifying specific molecules in live single cells from plant tissue and will allow different cell types and stages from different sites in the plant to be compared with morphological observations. PMID- 22243622 TI - Hand washing with soap and water together with behavioural recommendations prevents infections in common work environment: an open cluster-randomized trial. AB - BACKGROUND: Hand hygiene is considered as an important means of infection control. We explored whether guided hand hygiene together with transmission limiting behaviour reduces infection episodes and lost days of work in a common work environment in an open cluster-randomized 3-arm intervention trial. METHODS: A total of 21 clusters (683 persons) were randomized to implement hand hygiene with soap and water (257 persons), with alcohol-based hand rub (202 persons), or to serve as a control (224 persons). Participants in both intervention arms also received standardized instructions on how to limit the transmission of infections. The intervention period (16 months) included the emergence of the 2009 influenza pandemic and the subsequent national hand hygiene campaign influencing also the control arm. RESULTS: In the total follow-up period there was a 6.7% reduction of infection episodes in the soap-and water arm (p = 0.04). Before the onset of the anti-pandemic campaign, a statistically significant (p = 0.002) difference in the mean occurrence of infection episodes was observed between the control (6.0 per year) and the soap-and-water arm (5.0 per year) but not between the control and the alcohol-rub arm (5.6 per year). Neither intervention had a decreasing effect on absence from work. CONCLUSIONS: We conclude that intensified hand hygiene using water and soap together with behavioural recommendations can reduce the occurrence of self-reported acute illnesses in common work environment. Surprisingly, the occurrence of reported sick leaves also increased in the soap-and water-arm. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981877 SOURCE OF FUNDING: The Finnish Work Environment Fund and the National Institute for Health and Welfare. PMID- 22243624 TI - Influence of enterococcal surface protein (esp) on the transport of Enterococcus faecium within saturated quartz sands. AB - Enterococcus was selected by US EPA as a Gram-positive indicator microorganism for groundwater fecal contamination. It was recently reported that enterococcal surface protein (esp) was more prevalent in Enterococcus from human sources than in Enterococcus from nonhuman sources and esp could potentially be used as a source tracking tool for fecal contamination (Scott et al., 2005). In this research, we performed laboratory column transport experiments to investigate the transport of Enterococcus faecium within saturated quartz sands. Particularly, we used a wild type strain (E1162) and a mutant (E1162Deltaesp) to examine the influence of esp on the transport behavior of E. faecium. Our results showed that esp could significantly enhance the attachment of E. faecium cells onto the surface of silica sands and thus lower the mobility of E. faecium within sand packs. Cell surface properties (e.g., zeta potential) were determined and the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory was applied to explain the effects of esp on the retention of E. faecium. Overall, our results suggested that E. faecium strains with esp could display lower mobility within saturated sand packs than E. faecium strains without esp. The disparity in the transport behavior of E. faecium with and without esp could limit the effectiveness of esp as a source tracking tool within the groundwater system. PMID- 22243625 TI - Exposure assessment of radon in the drinking water supplies: a descriptive study in Palestine. AB - BACKGROUND: Radon gas is considered as a main risk factor for lung cancer and found naturally in rock, soil, and water. The objective of this study was to determine the radon level in the drinking water sources in Nablus city in order to set up a sound policy on water management in Palestine. METHODS: This was a descriptive study carried out in two phases with a random sampling technique in the second phase. Primarily, samples were taken from 4 wells and 5 springs that supplied Nablus city residents. For each source, 3 samples were taken and each was analyzed in 4 cycles by RAD 7 device manufactured by Durridge Company. Secondly, from the seven regions of the Nablus city, three samples were taken from the residential tap water of each region. Regarding the old city, ten samples were taken. Finally, the mean radon concentration value for each source was calculated. RESULTS: The mean (range) concentration of radon in the main sources were 6.9 (1.5-23.4) Becquerel/liter (Bq/L). Separately, springs and wells' means were 4.6 Bq/L and 9.5 Bq/L; respectively. For the residential tap water in the 7 regions, the results of the mean (range) concentration values were found to be 1.0 (0.9-1.3) Bq/L. For the old city, the mean (range) concentration values were 2.3 (0.9-3.9) Bq/L. CONCLUSIONS: Except for Al-Badan well, radon concentrations in the wells and springs were below the United State Environmental Protection Agency maximum contaminated level (U.S EPA MCL). The level was much lower for tap water. Although the concentration of radon in the tap water of old city were below the MCL, it was higher than other regions in the city. Preventive measures and population awareness on radon's exposure are recommended. PMID- 22243626 TI - Wild bitter gourd improves metabolic syndrome: a preliminary dietary supplementation trial. AB - BACKGROUND: Bitter gourd (Momordica charantia L.) is a common tropical vegetable that has been used in traditional or folk medicine to treat diabetes. Wild bitter gourd (WBG) ameliorated metabolic syndrome (MetS) in animal models. We aimed to preliminarily evaluate the effect of WBG supplementation on MetS in Taiwanese adults. METHODS: A preliminary open-label uncontrolled supplementation trial was conducted in eligible fulfilled the diagnosis of MetS from May 2008 to April 2009. A total of 42 eligible (21 men and 21 women) with a mean age of 45.7 +/- 11.4 years (23 to 63 years) were supplemented with 4.8 gram lyophilized WBG powder in capsules daily for three months and were checked for MetS at enrollment and follow-up monthly. After supplementation was ceased, the participants were continually checked for MetS monthly over an additional three-month period. MetS incidence rate were analyzed using repeated-measures generalized linear mixed models according to the intention-to-treat principle. RESULTS: After adjusting for sex and age, the MetS incidence rate (standard error, p value) decreased by 7.1% (3.7%, 0.920), 9.5% (4.3%, 0.451), 19.0% (5.7%, 0.021), 16.7% (5.4%, 0.047), 11.9% (4.7%, 0.229) and 11.9% (4.7%, 0.229) at visit 2, 3, 4, 5, 6, and 7 compared to that at baseline (visit 1), respectively. The decrease in incidence rate was highest at the end of the three-month supplementation period and it was significantly different from that at baseline (p = 0.021). The difference remained significant at end of the 4th month (one month after the cessation of supplementation) (p = 0.047) but the effect diminished at the 5th and 6th months after baseline. The waist circumference also significantly decreased after the supplementation (p < 0.05). The WBG supplementation was generally well-tolerated. CONCLUSION: This is the first report to show that WBG improved MetS in human which provides a firm base for further randomized controlled trials to evaluate the efficacy of WBG supplementation. PMID- 22243627 TI - Intergroup contact, attitudes toward homosexuality, and the role of acceptance of gender non-conformity in young adolescents. AB - This study explored how contact with gay and lesbian persons affects adolescents' attitudes toward them, and whether this association is mediated or moderated by one's acceptance of gender non-conformity. We analyzed survey responses from 456 Dutch adolescents aged 12-15 who reported having no same-sex attractions. Data were collected in 2008 at 8 schools in Amsterdam, the Netherlands. Preliminary analyses showed that contact with lesbian/gay persons outside of school was positively associated with attitudes toward lesbians and gay men. Multilevel analyses showed that acceptance of gender non-conformity mediated rather than moderated the relationship between intergroup contact and sexual prejudice in males. The effect of intergroup contact on females' attitudes toward lesbian women was no longer significant in multilevel analyses. The findings suggest that attention to both intergroup contact and acceptance of gender non-conformity would enhance our understanding of attitudes toward homosexuality in adolescents. PMID- 22243628 TI - Determination of perfluorochemicals in cow's milk using liquid chromatography tandem mass spectrometry. AB - This study describes a new method developed for detection of 10 different perfluorochemicals (PFCs) in cow's milk, seven perfluorinated carboxylates and three perfluorinated sulfonate salts. After attempting multiple methods employing both acidic and basic extractions, a basic extraction using 10 mM sodium hydroxide in methanol digestion along with weak anion-exchange solid-phase extraction was employed. Vortex mixing and varying sonication times were compared as part of sample processing. Results show that sonication during sample processing yield decreased recovery of longer chain perfluorinated carboxylates. The final method developed was used to determine the concentration of PFCs in 12 raw and 49 retail milk samples from across the United States. With the exception of a single raw milk sample obtained from a dairy farm that had applied PFC containing biosolids to its fields, there were no milk samples containing PFCs. PMID- 22243631 TI - Extraesophageal gastroesophageal reflux disease (GERD) symptoms are not more frequently associated with proximal esophageal reflux than typical GERD symptoms. AB - Extraesophageal (EE) symptoms such as cough and throat clearing are common in patients referred for reflux testing, but are less commonly associated with gastroesophageal reflux disease (GERD). Patients with reflux associated EE symptoms often lack typical GERD symptoms of heartburn and regurgitation. Our aim was to compare the frequency of proximal esophageal reflux between esophageal (typical) symptoms and EE (atypical) symptoms. Combined multichannel intraluminal impedance-pH (MII-pH) tracings were blinded by an investigator so that symptom markers were relabeled with a number without disclosure of symptom type. We selected 40 patients with at least five reflux-related symptom events for one of four symptoms (heartburn, regurgitation, cough, or throat clearing). A blinded investigator analyzed all 200 reflux episodes, reporting the proximal esophageal extent of the reflux for all symptoms. The percentage of symptom-related reflux extending proximally to 17 cm above the LES was similar among all four symptom types. At least 50% of all symptoms were associated with proximal esophageal reflux to 17 cm, with regurgitation having the highest frequency at 60%. Our data indicate that EE symptoms are not more frequently associated with proximal esophageal reflux than typical esophageal symptoms. PMID- 22243632 TI - SATgenepsilon dietary model to implement diets of differing fat composition in prospectively genotyped groups (apoE) using commercially available foods. AB - Response to dietary fat manipulation is highly heterogeneous, yet generic population-based recommendations aimed at reducing the burden of CVD are given. The APOE epsilon genotype has been proposed to be an important determinant of this response. The present study reports on the dietary strategy employed in the SATgenepsilon (SATurated fat and gene APOE) study, to assess the impact of altered fat content and composition on the blood lipid profile according to the APOE genotype. A flexible dietary exchange model was developed to implement three isoenergetic diets: a low-fat (LF) diet (target composition: 24 % of energy (%E) as fat, 8 %E SFA and 59 %E carbohydrate), a high-saturated fat (HSF) diet (38 %E fat, 18 %E SFA and 45 %E carbohydrate) and a HSF-DHA diet (HSF diet with 3 g DHA/d). Free-living participants (n 88; n 44 E3/E3 and n 44 E3/E4) followed the diets in a sequential design for 8 weeks, each using commercially available spreads, oils and snacks with specific fatty acid profiles. Dietary compositional targets were broadly met with significantly higher total fat (42.8 %E and 41.0 %E v. 25.1 %E, P <= 0.0011) and SFA (19.3 %E and 18.6 %E v. 8.33 %E, P <= 0.0011) intakes during the HSF and HSF-DHA diets compared with the LF diet, in addition to significantly higher DHA intake during the HSF-DHA diet (P <= 0.0011). Plasma phospholipid fatty acid analysis revealed a 2-fold increase in the proportion of DHA after consumption of the HSF-DHA diet for 8 weeks, which was independent of the APOE genotype. In summary, the dietary strategy was successfully implemented in a free-living population resulting in well-tolerated diets which broadly met the dietary targets set. PMID- 22243633 TI - Enriched pathways for major depressive disorder identified from a genome-wide association study. AB - Major depressive disorder (MDD) has caused a substantial burden of disease worldwide with moderate heritability. Despite efforts through conducting numerous association studies and now, genome-wide association (GWA) studies, the success of identifying susceptibility loci for MDD has been limited, which is partially attributed to the complex nature of depression pathogenesis. A pathway-based analytic strategy to investigate the joint effects of various genes within specific biological pathways has emerged as a powerful tool for complex traits. The present study aimed to identify enriched pathways for depression using a GWA dataset for MDD. For each gene, we estimated its gene-wise p value using combined and minimum p value, separately. Canonical pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and BioCarta were used. We employed four pathway based analytic approaches (gene set enrichment analysis, hypergeometric test, sum square statistic, sum-statistic). We adjusted for multiple testing using Benjamini & Hochberg's method to report significant pathways. We found 17 significantly enriched pathways for depression, which presented low-to intermediate crosstalk. The top four pathways were long-term depression (p?1*10 5), calcium signalling (p?6*10-5), arrhythmogenic right ventricular cardiomyopathy (p?1.6*10-4) and cell adhesion molecules (p?2.2*10-4). In conclusion, our comprehensive pathway analyses identified promising pathways for depression that are related to neurotransmitter and neuronal systems, immune system and inflammatory response, which may be involved in the pathophysiological mechanisms underlying depression. We demonstrated that pathway enrichment analysis is promising to facilitate our understanding of complex traits through a deeper interpretation of GWA data. Application of this comprehensive analytic strategy in upcoming GWA data for depression could validate the findings reported in this study. PMID- 22243635 TI - Using operational research to ensure that immunisation benefits are enjoyed by all. PMID- 22243634 TI - Nanomolar cellular antisense activity of peptide nucleic acid (PNA) cholic acid ("umbrella") and cholesterol conjugates delivered by cationic lipids. AB - Limited cellular uptake and low bioavailability of peptide nucleic acids (PNAs) have restricted widespread use of PNAs as antisense/antigene agents for cells in culture and not least for in vivo applications. We now report the synthesis and cellular antisense activity in cultured HeLa pLuc705 cells of cholesterol and cholic acid ("umbrella") derivatives of splice correction antisense PNA oligomers. While the conjugates alone were practically inactive up to 1 MUM, their activity was dramatically improved when delivered by a cationic lipid transfection agent (LipofectAMINE2000). In particular, PNAs, conjugated to cholesterol through an ester hemisuccinate linker or to cholic acid, exhibited low nanomolar activity (EC(50) ~ 25 nM). Excellent sequence specificity was retained, as mismatch PNA conjugates did not show any significant antisense activity. Furthermore, we show that increasing the transfection volume improved transfection efficiency, suggesting that accumulation (condensation) of the PNA/lipid complex on the cellular surface is part of the uptake mechanism. These results provide a novel, simple method for very efficient cellular delivery of PNA oligomers, especially using PNA-cholic acid conjugates which, in contrast to PNA-cholesterol conjugates, exhibit sufficient water solubility. The results also question the generality of using cholic acid "umbrella" derivatives as a delivery modality for antisense oligomers. PMID- 22243636 TI - Invasive pneumococcal disease in western Sydney, 2002-2010. PMID- 22243637 TI - Aboriginal identification in Hunter New England infants. PMID- 22243638 TI - Why are children on the NSW North Coast not being vaccinated against chickenpox? PMID- 22243639 TI - The seroepidemiology of pertussis in NSW: fluctuating immunity profiles related to changes in vaccination schedules. AB - The pertussis epidemic experienced in NSW in 2008-2009 was likely to be in part due to changes in diagnostic practice since 2007, which amplified disease notifications. We used population-based seroepidemiology as a less biased means of interpreting age-specific pertussis infection patterns in NSW from three serosurveys undertaken in 1997-98 (during an epidemic), 2002 (post-epidemic) and 2007 (inter-epidemic), using a standardised pertussis toxin IgG enzyme-linked immunosorbent assay (ELISA). There was a decrease in the proportion of high anti pertussis toxin IgG titres (>62.5ELISAUnits/mL) across all age groups in the 2007 serosurvey compared to the previous two serosurveys. In the 2007 serosurvey, the proportion of undetectable (<5ELISAUnits/mL) anti-pertussis toxin IgG titres increased in many age groups. The seroepidemiological profiles of the three serosurveys demonstrate fluctuating immunity profiles related to changes in vaccination schedules. PMID- 22243640 TI - Influenza immunisation program at three tertiary paediatric hospitals in NSW in 2010. AB - This is a report of an innovative influenza immunisation program in three tertiary paediatric hospitals in NSW. A targeted once-off program of influenza immunisation funded by NSW Health was offered during 2010 at the Children's Hospital at Westmead, Sydney Children's Hospital and the John Hunter Children's Hospital. Authorised immunisers offered influenza immunisation to paediatric patients, outpatients and relatives of children with chronic illnesses. Influenza immunisation was administered to 3458 people, 1251 (36%) of whom were children with chronic conditions. In 2009 before the program, 420 influenza vaccines were prescribed for children in two of these hospitals. This number increased to 949 in 2010, the year of the program. Dedicated vaccination clinics at tertiary paediatric hospitals provide additional opportunities to ensure that children at high risk of severe influenza disease and its complications are vaccinated. The information obtained from the hospital vaccination program contributed to the national investigation of febrile convulsions following influenza vaccines in children in 2010. PMID- 22243642 TI - Bug breakfast in the Bulletin. Pertussis in NSW and its prevention in infants and children. PMID- 22243643 TI - Bug Breakfast in the Bulletin. Tickborne diseases. PMID- 22243644 TI - Communicable Diseases Report, NSW, September and October 2011. PMID- 22243645 TI - Otolaryngological aspects of sudden infant death syndrome. AB - INTRODUCTION: Sudden infant death syndrome (SIDS) is characterized by the sudden death of an apparently otherwise healthy infant, typically during sleep, and with no obvious case after a thorough post-mortem and scene death examination. OBJECTIVE: To address the problem from the otolaryngologist's perspective, describe relevant pathologies, discuss controversies and suggest preventive measures in high-risk populations. METHODOLOGY: A MEDLINE search and hand search were conducted to identify reports published between 1969 and 2011 in the English language on the pathophysiology of SIDS related to the head and neck organs. Search terms included SIDS (MeSH term), SIDS and pathophysiology (text words), and SIDS and autopsy (text words). DISCUSSION: A growing number of reports suggested head and neck organs involvement in SIDS autopsies. Laryngeal, oropharyngeal, maxillofacial, otologic, cervical vascular abnormalities and infectious etiologies, were recognized and discussed. CONCLUSIONS: Otolaryngologists should be aware of relevant pathologies, as some are treatable, if identified early enough in infancy. A proactive risk-management approach is warranted in infants presenting with certain abnormalities reviewed here. PMID- 22243646 TI - Subglottic cyst: the role of narrow-band imaging. AB - A subglottic cyst is a rare cause of neonatal upper airway obstruction, which may be misinterpreted as a subglottic hemangioma. With the advent of narrow-band imaging, the application of its unique features in analyzing the mucosa surface's vascular structures in pediatric subglottic lesions remains to be investigated. Here, we report the case of a preterm baby who developed two subglottic cysts when he was 3-months old. Both traditional endoscopic examination and narrow-band imaging were performed pre-operatively. Both the potential impact of this new technique and the diagnosis and management of this disease are discussed. PMID- 22243647 TI - Magnetic resonance imaging susceptibility artifact due to pigmented intraorbital silicone prosthesis. AB - Magnetic resonance imaging (MRI) findings of two cases with intracranial disease and pigmented intraorbital prosthetics are presented. A brown prosthetic (Case 1) caused a significant magnetic susceptibility artifact, which necessitated removal to properly image the brain. The artifact observed on MRI images is likely due to ferromagnetic pigments used for coloring. A black prosthetic (Case 2) caused no imaging artifact. The carbon-based pigments used to color the black prosthetic implant do not appear to cause imaging artifact. The pigments currently used to color the brown pigmented orbital prostheses cause significant magnetic susceptibility artifact and may require removal to evaluate the brain and surrounding structures completely. PMID- 22243648 TI - New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and beta-amyloid-reducing properties. AB - By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and beta-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4 tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS permeable properties. PMID- 22243649 TI - Involvement of consumers in studies run by the Medical Research Council Clinical Trials Unit: results of a survey. AB - BACKGROUND: We aimed to establish levels of consumer involvement in randomised controlled trials (RCTs), meta-analyses and other studies carried out by the UK Medical Research Council (MRC) Clinical Trials Unit across the range of research programs, predominantly in cancer and HIV. METHODS: Staff responsible for studies that were included in a Unit Progress Report (MRC CTU, April 2009) were asked to complete a semi-structured questionnaire survey regarding consumer involvement. This was defined as active involvement of consumers as partners in the research process and not as subjects of that research. The electronic questionnaires combined open and closed questions, intended to capture quantitative and qualitative information on whether studies had involved consumers; types of activities undertaken; recruitment and support; advantages and disadvantages of involvement and its perceived impact on aspects of the research. RESULTS: Between October 2009 and April 2010, 138 completed questionnaires (86%) were returned. Studies had been conducted over a 20 year period from 1989, and around half were in cancer; 30% in HIV and 20% were in other disease areas including arthritis, tuberculosis and blood transfusion medicine. Forty-three studies (31%) had some consumer involvement, most commonly as members of trial management groups (TMG) [88%]. A number of positive impacts on both the research and the researcher were identified. Researchers generally felt involvement was worthwhile and some felt that consumer involvement had improved the credibility of the research. Benefits in design and quality, trial recruitment, dissemination and decision making were also perceived. Researchers felt they learned from consumer involvement, albeit that there were some barriers. CONCLUSIONS: Whilst most researchers identified benefits of involving consumers, most of studies included in the survey had no involvement. Information from this survey will inform the development of a unit policy on consumer involvement, to guide future research conducted within the MRC Clinical Trials Unit and beyond. PMID- 22243650 TI - Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis. AB - BACKGROUND: Central nervous system disease is the most serious form of tuberculosis, and is associated with high mortality and severe neurological sequelae. Though recent clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with central nervous system disease, the microbial virulence factors required have not been described previously. RESULTS: We screened 398 unique M. tuberculosis mutants in guinea pigs to identify genes required for central nervous system tuberculosis. We found M. tuberculosis pknD (Rv0931c) to be required for central nervous system disease. These findings were central nervous system tissue-specific and were not observed in lung tissues. We demonstrated that pknD is required for invasion of brain endothelia (primary components of the blood-brain barrier protecting the central nervous system), but not macrophages, lung epithelia, or other endothelia. M. tuberculosis pknD encodes a "eukaryotic-like" serine-threonine protein kinase, with a predicted intracellular kinase and an extracellular (sensor) domain. Using confocal microscopy and flow cytometry we demonstrated that the M. tuberculosis PknD sensor is sufficient to trigger invasion of brain endothelia, a process which was neutralized by specific antiserum. CONCLUSIONS: Our findings demonstrate a novel in vivo role for M. tuberculosis pknD and represent an important mechanism for bacterial invasion and virulence in central nervous system tuberculosis, a devastating and understudied disease primarily affecting young children. PMID- 22243651 TI - Driving habits in glaucoma patients. AB - PURPOSE: Glaucoma is a progressive optic neuropathy leading to loss of visual function beginning with the peripheral visual field. One large population-based study found that individuals with visual impairment reported difficulties in performing most vision-dependent daily activities, including difficulty with driving. The objective of this retrospective cohort study was to investigate the driving habits of glaucoma patients and to determine the conformance of their visual acuity and visual fields with driving regulations. METHODS: The charts of 20 patients followed in the Ophthalmology Department of Foch Hospital, Suresnes, Paris, France, with open angle glaucoma (mean visual field mean deviation of the worse eye: -15.5 dB; range -1.97 to -27 dB) and still driving, were reviewed. Data collected included visual acuity, type of glaucoma, slit lamp and fundus examination, most recent standard automated perimetry, and binocular visual field test results. Each patient was asked if he or she still drove on highways, and if he or she still drove at night. RESULTS: The driving habits of glaucoma patients were analyzed, and visual acuity and binocular visual fields were compared to French and European legal driving criteria. Thirteen patients (65%) with glaucoma were still driving on highways, and five (25%) at night. Seven patients (35%) were below French legal minimum visual acuity or visual field criteria. CONCLUSION: Glaucoma patients appear to self-regulate their driving habits by avoiding potentially difficult driving situations. Further studies with larger sample size are necessary to determine relationships between severity of visual impairment, severity of visual field defects, and the cessation of driving. PMID- 22243652 TI - [Corneal intraepithelial neoplasia]. PMID- 22243653 TI - [Alzheimer's disease and visual impairment]. AB - Alzheimer disease is the most prevalent cause of cognitive decline in older adults. The typical presentation of Alzheimer disease is memory dysfunction, however, presentations with impairment in other domains may occur. Visual symptoms may be the first manifestation of Alzheimer disease. The purpose of this article is to review the spectrum of visual system disturbances found in Alzheimer disease. PMID- 22243654 TI - Carbohydrate-active enzymes revealed in Coptotermes formosanus (Isoptera: Rhinotermitidae) transcriptome. AB - Coptotermes formosanus is one of the most destructive wood-feeding termites. To understand the molecular mechanisms that regulate the development of the termite, a normalized C. formosanus cDNA library was constructed using mixed RNA isolated from workers, soldiers, nymphs and alates of both sexes. The sequencing of this library generated 131 636 expressed sequence tags (ESTs) and 25 939 assembled unigenes. The carbohydrate-active enzymes (CAZymes) revealed in this library were analysed in the present report. A total of 509 putative CAZymes were identified. Diverse cellulolytic enzymes were uncovered from both the host termite and from symbionts harboured by the termite, which were possibly the result of the high efficiency of cellulose utilization. CAZymes associated with trehalose biosynthetic and metabolic pathways were also identified, which are potential regulators of the physiological activities of trehalose, an important insect blood sugar. Representative CAZyme coding genes in glycoside hydrolase family 1 (GH1) were quantitatively analysed. The results showed that the five GH1 beta glucosidase genes were expressed differentially among different castes and one of them was female alate-specific. Overall, the normalized EST library provides a comprehensive genetic resource of C. formosanus and will serve a diverse range of research areas. The CAZymes represent one of the repositories of enzymes useful for physiological studies and applications in sugar-based biofuel production. PMID- 22243655 TI - Chemical and morphological characterization of Costa Rican papaya (Carica papaya L.) hybrids and lines with particular focus on their genuine carotenoid profiles. AB - Papaya (Carica papaya L.) F1 hybrids and inbred lines grown in Costa Rica were screened for morphological and nutritionally relevant fruit traits. The qualitative composition of carotenoids showed great similarity, being mostly composed of free and esterified beta-cryptoxanthins accompanied by beta-carotene, lycopene, and biosynthetic precursors. High levels of (all-E)-lycopene and its isomers were distinctive for red-fleshed hybrids, whereas yellow-fleshed fruits were virtually devoid of lycopenes. Because carotenoid levels among the investigated hybrids and lines differed significantly, this study supports the hypothesis of an exploitable genetic variability, and a potential heterotic effect regarding carotenoid expression may be instrumental in papaya-breeding programs. Due to significantly higher levels of provitamin A carotenoids and coinciding high levels of total lycopene, particularly red-fleshed hybrids might represent prospective sources of these compounds. Furthermore, the nutritional value of some genotypes was boosted by substantial amounts of ascorbic acid (up to 73 mg/100 g of fresh weight), which correlated to total soluble solids (R(2) = 0.86). PMID- 22243656 TI - Health care expenditure for hospital-based delivery care in Lao PDR. AB - BACKGROUND: Delivery by a skilled birth attendant (SBA) in a hospital is advocated to improve maternal health; however, hospital expenses for delivery care services are a concern for women and their families, particularly for women who pay out-of-pocket. Although health insurance is now implemented in Lao PDR, it is not universal throughout the country. The objectives of this study are to estimate the total health care expenses for vaginal delivery and caesarean section, to determine the association between health insurance and family income with health care expenditure and assess the effect of health insurance from the perspectives of the women and the skilled birth attendants (SBAs) in Lao PDR. METHODS: A cross-sectional study was carried out in two provincial hospitals in Lao PDR, from June to October 2010. Face to face interviews of 581 women who gave birth in hospital and 27 SBAs was carried out. Both medical and non-medical expenses were considered. A linear regression model was used to assess influencing factors on health care expenditure and trends of medical and non medical expenditure by monthly family income stratified by mode of delivery were assessed. RESULTS: Of 581 women, 25% had health care insurance. Health care expenses for delivery care services were significantly higher for caesarean section (270 USD) than for vaginal delivery (59 USD). After adjusting for the effect of hospital, family income was significantly associated with all types of expenditure in caesarean section, while it was associated with non-medical and total expenditures in vaginal delivery. Both delivering women and health providers thought that health insurance increased the utilisation of delivery care. CONCLUSIONS: Substantially higher delivery care expenses were incurred for caesarean section compared to vaginal delivery. Three-fourths of the women who were not insured needed to be responsible for their own health care payment. Women who had higher family incomes were able to pay for more non-medical care expenses. The effect of health insurance on service utilization was noted by women and SBAs. To achieve the goal of utilizing delivery care in the hospitals, coverage of health insurance needs to be expanded. PMID- 22243657 TI - Reducing sodium levels in frankfurters using naturally brewed soy sauce. AB - Sodium chloride (NaCl; salt) serves important functions in processed meats, contributing to desirable quality and food safety characteristics; however, renewed interest exists in reducing sodium in the human diet despite sodium being a required component of the diet for physiological regulation. This study investigated consumer sensory and quality impacts from replacement of normally added NaCl (flake salt) with naturally brewed soy sauce (SS). Varying levels of SS were used with NaCl and/or potassium chloride (KCl) to comprise treatments (TRT) which investigated flake salt replacement (Phase I) and sodium reduction (Phases II and III). Phase I identified a 50% replacement of NaCl with SS as the baseline for subsequent phases. Phase II indicated that the inclusion of SS could allow for a 20% NaCl reduction without adverse effects on quality or sensory attributes. Phase III results demonstrated that it was feasible to reduce NaCl by 35% via the inclusion of KCl in SS containing frankfurters without major quality or sensory changes. PMID- 22243660 TI - Neonatal non-contact respiratory monitoring based on real-time infrared thermography. AB - BACKGROUND: Monitoring of vital parameters is an important topic in neonatal daily care. Progress in computational intelligence and medical sensors has facilitated the development of smart bedside monitors that can integrate multiple parameters into a single monitoring system. This paper describes non-contact monitoring of neonatal vital signals based on infrared thermography as a new biomedical engineering application. One signal of clinical interest is the spontaneous respiration rate of the neonate. It will be shown that the respiration rate of neonates can be monitored based on analysis of the anterior naris (nostrils) temperature profile associated with the inspiration and expiration phases successively. OBJECTIVE: The aim of this study is to develop and investigate a new non-contact respiration monitoring modality for neonatal intensive care unit (NICU) using infrared thermography imaging. This development includes subsequent image processing (region of interest (ROI) detection) and optimization. Moreover, it includes further optimization of this non-contact respiration monitoring to be considered as physiological measurement inside NICU wards. RESULTS: Continuous wavelet transformation based on Debauches wavelet function was applied to detect the breathing signal within an image stream. Respiration was successfully monitored based on a 0.3 degrees C to 0.5 degrees C temperature difference between the inspiration and expiration phases. CONCLUSIONS: Although this method has been applied to adults before, this is the first time it was used in a newborn infant population inside the neonatal intensive care unit (NICU). The promising results suggest to include this technology into advanced NICU monitors. PMID- 22243661 TI - Body fat and blood pressure: comparison of blood pressure measurements in Chinese children with different body fat levels. AB - Children in China are experiencing a rapid increase in the prevalence of obesity, which is associated with hypertension. To compare the effect of body fat on blood pressure (BP) with that of the normal physical growth, we compared BP levels in Chinese children with different body fat levels. In the present population-based study, 13 972 children in the highest-skinfold-thickness-quartile group were individually matched to 13 972 children in the lowest-skinfold-thickness-quartile group by height and weight. Similarly, 5103 children in the highest-waist circumference-quartile group were matched to the same number of children in the lowest-waist-circumference-quartile group. The high- and low-fat groups had similar height and weight but the high-fat group had significantly higher skinfold and waist circumference measurements. The differences in systolic BP (SBP) between the high- and low-skinfold-thickness groups were small: 0.01 (95 % CI -0.41, 0.44) mmHg in boys and 0.20 (95 % CI -0.15, 0.54) mmHg in girls. The differences in diastolic BP (DBP) were also small (0.39 and 0.38 mmHg for boys and girls, respectively) but were statistically significant. The differences in both SBP and DBP between the high- and low-waist-circumference groups were small but not statistically significant. For a given body size as measured by height and weight, relative body fat had little impact on BP levels in these children. Fat mass and lean mass may have a similar quantitative impact on BP in healthy weight children. PMID- 22243663 TI - Bone marrow micrometastases in esophageal carcinoma: a 10-year follow-up study. AB - Detection of bone marrow micrometastases (BMMs) in patients with esophageal carcinoma may indicate a metastatic phenotype. We assessed if the presence of BMMs had adverse prognostic significance in a 10-year follow-up study. Patients undergoing surgery for esophageal cancer were prospectively recruited between February 1999 and August 2000. Bone marrow aspirates were obtained from the iliac crest of patients under general anesthesia at the time of surgery. Immunocytochemical analysis using anticytokeratin antibodies CAM 5.2 and AE1/AE3 was undertaken to determine the presence of BMMs. Union International Contre le Cancer staging was recorded for all patients. Patient follow-up was completed over a 10-year period through analysis of the Northern Ireland Cancer Registry. Forty-two patients (male = 35) were included, with a mean age of 67.2 years (range 39-83). BMMs were detected in 19 patients (45.2%). International Contre le Cancer tumor staging was stage I = 6, stage II = 10, stage III = 24, and stage IV = 2. BMMs were associated with lymphovascular invasion (P= 0.02) and advanced T stage (P= 0.02). Overall, 10-year survival was 21.4% (n= 9), with a median follow up of 877.5 days (interquartile range 391.5-2546.3). There was no statistically significant difference between the survival of patients with or without BMMs (1451.4 vs. 1431.6 days, P= 0.99). Univariate analysis demonstrated a trend toward decreased survival for patients with positive lymph nodes (P= 0.07), an increased T stage (P= 0.06), and lymphovascular invasion (P= 0.07). Multivariate analysis demonstrated that none of the variables were significant predictors of mortality. Although the presence of BMMs correlates with recognized adverse tumor characteristics in patients with esophageal cancer, micrometastases detected in the bone marrow at time of surgery does not influence long-term survival. PMID- 22243662 TI - The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice. AB - The purpose of this study was to explore how genetic deletion and pharmacological antagonism of the P2X7 receptor (P2rx7) alter mood-related behaviour, gene expression and stress reactivity in the brain. The forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperlocomotion (AH) tests were used in wild-type (P2rx7(+/+)) and P2rx7-deficient (P2rx7(-/-)) mice. Biogenic amine levels were analysed in the amygdala and striatum, adrenocorticotropic hormone (ACTH) and corticosterone levels were measured in the plasma and pituitary after restraint stress. Chimeric mice were generated by bone marrow transplantation. A whole genome microarray analysis with real-time polymerase chain reaction validation was performed on the amygdala. In the absence of P2rx7s decreased behavioural despair in the FST, reduced immobility in the TST and attenuated amphetamine-induced hyperactivity were detected. Basal norepinephrine levels were elevated in the amygdala, whereas stress-induced ACTH and corticosterone responses were alleviated in P2rx7(-/-) mice. Sub-acute treatment with the selective P2rx7 antagonist, Brilliant Blue G, reproduced the effect of genetic deletion in the TST and AH test in P2rx7(+/+) but not P2rx7(-/-) mice. No change in behavioural phenotype was observed in chimeras lacking the P2rx7 in their haematopoietic compartment. Whole genome microarray analysis indicated a widespread up- and down-regulation of genes crucial for synaptic function and neuroplasticity by genetic deletion. Here, we present evidence that the absence of P2rx7s on non-haematopoietic cells leads to a mood-stabilizing phenotype in several behavioural models and suggest a therapeutic potential of P2rx7 antagonists for the treatment of mood disorders. PMID- 22243664 TI - Site-specific PEGylation at histidine tags. AB - The efficacy of protein-based medicines can be compromised by their rapid clearance from the blood circulatory system. Achieving optimal pharmacokinetics is a key requirement for the successful development of safe protein-based medicines. Protein PEGylation is a clinically proven strategy to increase the circulation half-life of protein-based medicines. One limitation of PEGylation is that there are few strategies that achieve site-specific conjugation of PEG to the protein. Here, we describe the covalent conjugation of PEG site-specifically to a polyhistidine tag (His-tag) on a protein. His-tag site-specific PEGylation was achieved with a domain antibody (dAb) that had a 6-histidine His-tag on the C terminus (dAb-His(6)) and interferon alpha-2a (IFN) that had an 8-histidine His tag on the N-terminus (His(8)-IFN). The site of PEGylation at the His-tag for both dAb-His(6)-PEG and PEG-His(8)-IFN was confirmed by digestion, chromatographic, and mass-spectral studies. A methionine was also inserted directly after the N-terminal His-tag in IFN to give His(8)Met-IFN. Cyanogen bromide digestion studies of PEG-His(8)Met-IFN were also consistent with PEGylation at the His-tag. By using increased stoichiometries of the PEGylation reagent, it was possible to conjugate two separate PEG molecules to the His-tag of both the dAb and IFN proteins. Stability studies followed by in vitro evaluation confirmed that these PEGylated proteins retained their biological activity. In vivo PK studies showed that all of the His-tag PEGylated samples displayed extended circulation half-lives. Together, our results indicate that site-specific, covalent PEG conjugation at a His-tag can be achieved and biological activity maintained with therapeutically relevant proteins. PMID- 22243665 TI - Indicators for research performance evaluation: an overview. PMID- 22243666 TI - The phantom menace of prostate cancer screening. PMID- 22243667 TI - Organ-preserving surgery for testicular tumours. PMID- 22243668 TI - Protection of commercial opportunity. PMID- 22243669 TI - Expression of GSK-3beta in renal allograft tissue and its significance in pathogenesis of chronic allograft dysfunction. AB - OBJECTIVE: To explore the expression of Glycogen synthase kinase 3 beta (GSK 3beta) in renal allograft tissue and its significance in the pathogenesis of chronic allograft dysfunction. METHODS: Renal allograft biopsy was performed in all of the renal allograft recipients with proteinuria or increased serum creatinine level who came into our hospital from January 2007 to December 2009. Among them 28 cases was diagnosed as chronic allograft dysfunction based on pahtological observation, including 21 males with a mean age of 45 +/- 10 years old and 7 females with a mean age of 42 +/- 9 years old. The time from kidney transplantation to biopsy were 1-9 (3.5) years. Their serum creatinine level were 206 +/- 122 umol/L. Immunohistochemical assay and computer-assisted genuine color image analysis system (imagepro-plus 6.0) were used to detect the expression of GSK-3beta in the renal allografts of 28 cases of recipients with chronic allograft dysfunction. Mean area and mean integrated optical density of GSK-3beta expression were calculated. The relationship between expression level of GSK 3beta and either the grade of inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft was analyzed. Five specimens of healthy renal tissue were used as controls. RESULTS: The expression level of the GSK-3beta was significantly increased in the renal allograft tissue of recipients with chronic allograft dysfunction, compared to normal renal tissues, and GSK 3beta expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue. CONCLUSION: There might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3beta expression in renal allograft tissue. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/9924478946162998. PMID- 22243670 TI - Neuraminidase H275Y and hemagglutinin D222G mutations in a fatal case of 2009 pandemic influenza A (H1N1) virus infection. AB - Oseltamivir-resistant 2009 H1N1 influenza virus infections associated with neuraminidase (NA) H275Y have been identified sporadically. Strains possessing the hemagglutinin (HA) D222G mutation have been detected in small numbers of fatal 2009 H1N1 cases. We report the first clinical description of 2009 H1N1 virus infection with both NA-H275Y and HA-D222G mutations detected by pyrosequencing of bronchioalveolar lavage fluid obtained on symptom day 19. The 59-year-old immunosuppressed patient had multiple conditions conferring higher risk of prolonged viral replication and severe illness and died on symptom day 34. Further investigations are needed to determine the significance of infection with strains possessing NA-H275Y and HA-D222G. PMID- 22243672 TI - Metabolomic plasticity in GM and non-GM potato leaves in response to aphid herbivory and virus infection. AB - An important aspect of ecological safety of genetically modified (GM) plants is the evaluation of unintended effects on plant-insect interactions. These interactions are to a large extent influenced by the chemical composition of plants. This study uses NMR-based metabolomics to establish a baseline of chemical variation to which differences between a GM potato line and its parent cultivar are compared. The effects of leaf age, virus infection, and aphid herbivory on plant metabolomes were studied. The metabolome of the GM line differed from its parent only in young leaves of noninfected plants. This effect was small when compared to the baseline. Consistently, aphid performance on excised leaves was influenced by leaf age, while no difference in performance was found between GM and non-GM plants. The metabolomic baseline approach is concluded to be a useful tool in ecological safety assessment. PMID- 22243671 TI - Characterisation of a cell wall-anchored protein of Staphylococcus saprophyticus associated with linoleic acid resistance. AB - BACKGROUND: The Gram-positive bacterium Staphylococcus saprophyticus is the second most frequent causative agent of community-acquired urinary tract infections (UTI), accounting for up to 20% of cases. A common feature of staphylococci is colonisation of the human skin. This involves survival against innate immune defenses including antibacterial unsaturated free fatty acids such as linoleic acid which act by disrupting bacterial cell membranes. Indeed, S. saprophyticus UTI is usually preceded by perineal skin colonisation. RESULTS: In this study we identified a previously undescribed 73.5 kDa cell wall-anchored protein of S. saprophyticus, encoded on plasmid pSSAP2 of strain MS1146, which we termed S. saprophyticus surface protein F (SssF). The sssF gene is highly prevalent in S. saprophyticus clinical isolates and we demonstrate that the SssF protein is expressed at the cell surface. However, unlike all other characterised cell wall-anchored proteins of S. saprophyticus, we were unable to demonstrate a role for SssF in adhesion. SssF shares moderate sequence identity to a surface protein of Staphylococcus aureus (SasF) recently shown to be an important mediator of linoleic acid resistance. Using a heterologous complementation approach in a S. aureus sasF null genetic background, we demonstrate that SssF is associated with resistance to linoleic acid. We also show that S. saprophyticus strains lacking sssF are more sensitive to linoleic acid than those that possess it. Every staphylococcal genome sequenced to date encodes SssF and SasF homologues. Proteins in this family share similar predicted secondary structures consisting almost exclusively of alpha-helices in a probable coiled-coil formation. CONCLUSIONS: Our data indicate that SssF is a newly described and highly prevalent surface-localised protein of S. saprophyticus that contributes to resistance against the antibacterial effects of linoleic acid. SssF is a member of a protein family widely disseminated throughout the staphylococci. PMID- 22243673 TI - VPA: an R tool for analyzing sequencing variants with user-specified frequency pattern. AB - BACKGROUND: The massive amounts of genetic variant generated by the next generation sequencing systems demand the development of effective computational tools for variant prioritization. FINDINGS: VPA (Variant Pattern Analyzer) is an R tool for prioritizing variants with specified frequency pattern from multiple study subjects in next-generation sequencing study. The tool starts from individual files of variant and sequence calls and extract variants with user specified frequency pattern across the study subjects of interest. Several position level quality criteria can be incorporated into the variant extraction. It can be used in studies with matched pair design as well as studies with multiple groups of subjects. CONCLUSIONS: VPA can be used as an automatic pipeline to prioritize variants for further functional exploration and hypothesis generation. The package is implemented in the R language and is freely available from http://vpa.r-forge.r-project.org. PMID- 22243674 TI - Publication ethics: Its importance to readers, authors, and the profession. PMID- 22243675 TI - Prehypertension: a literature-documented public health concern. AB - PURPOSE: To provide nurse practitioners (NPs) with an overview of prehypertension identification and management. Additionally, the article serves to highlight the prevalence and impact of prehypertension in the United States. DATA SOURCES: A comprehensive review of the literature was conducted using multiple databases, including PubMed, Medline, CINAHL, and SAGE Health Sciences databases. The review was not limited by discipline, year of publication, or type of research. Key words used to obtain relevant articles included prehypertension, nurse practitioner, health promotion, disease prevention, hypertension, and chronic disease. CONCLUSIONS: Approximately 70 million individuals have been recognized as prehypertensive in the United States, placing them at increased risk for hypertension and cardiovascular disease. Identifying and managing prehypertension has been recognized in national health policy as a priority to improve public health. Prehypertension is managed primarily by eliminating risk factors and implementing lifestyle modification. IMPLICATIONS FOR PRACTICE: Health promotion and disease prevention form the cornerstone of the NP role. The designation of prehypertension serves as an opportunity for NPs to assist in decreasing the burden on the health system from chronic disease and improve patient quality of life. PMID- 22243676 TI - Defining NP scope of practice and associated regulations: focus on acute care. AB - PURPOSE: Although the nurse practitioner (NP) role has been in existence for over 40 years, there continues to be uncertainty about the essential components that define NP scope of practice. The purpose of this article is to review definitions and concepts related to NP scope of practice with an emphasis on NPs working in acute care. DATA SOURCES: A synthesis literature review was conducted on defining NP scope of practice. Simultaneous review of authoritative resources including National Council of State Board of Nursing, individual state board of nursing language, and NP scope and standards of practice documents was conducted. CONCLUSIONS: Scope of practice is a legal term used by states to define what activities an individual professional can undertake. The Consensus Model for Advanced Practice Registered Nurse (APRN) Regulation outlines that licensure and scope of practice are based on graduate education within a defined patient population for the APRN role. The APRN Consensus Model further identifies that the services provided by APRNs are not defined or limited by setting but rather by patient care needs. For the acute care NP, this is especially significant, as patient acuity and care requirements can vary across settings. When implemented, the Consensus Model will help to standardize regulation for APRNs as well as ensure congruence between licensure, accreditation, certification, and education. IMPLICATIONS FOR PRACTICE: Providing clarification of the NP scope of practice, especially as it pertains to NPs working in acute care settings, remains needed to support practice based on educational preparation, licensure, certification, and focus of practice. PMID- 22243677 TI - Exercise-induced bronchospasm: a case study in a nonasthmatic patient. AB - PURPOSE: To provide an overview of the clinical presentation, diagnosis, and management of exercise-induced bronchospasm (EIB) without underlying asthma. DATA SOURCES: Case presentation and review of the EIB Landmark Survey. CONCLUSIONS: EIB is a common and well-described occurrence in patients with asthma, as well as in patients with no overt respiratory condition. Treatment with a short-acting beta-agonist before starting exercise is effective, yet this treatment approach is underutilized in the majority of patients with asthma. IMPLICATIONS FOR PRACTICE: This case highlights the implications of undermanaged EIB and the disconnect between healthcare provider recommendations and the beliefs and behaviors in patients with EIB. Inhaled short-acting beta-agonists can attenuate EIB in 80%-95% of patients and are effective during 2-3 h of exercise. Patients with a compromised level of physical activity because of EIB who do not respond to conventional treatment strategies should be referred to a respiratory specialist for diagnostic evaluation and confirmation of underlying asthma. Nurse practitioners should remain vigilant to identify untreated EIB and ensure that affected patients understand the condition and appropriate treatment options. PMID- 22243678 TI - Nurse-managed health centers: safety-net care through advanced nursing practice. AB - PURPOSE: To describe the nurse-managed health center (NMHC) as a model for effective health delivery in providing safety-net care to medically underserved populations. DATA SOURCES: Although the literature regarding outcomes of the model is still building, mounting evidence shows that NMHCs provide quality and cost-effective care to their target populations. The Division of Nursing of the Health Resources and Services Administration has ample data to support the findings that NMHCs are a significant component of the primary healthcare system in providing access particularly for medically underserved and vulnerable populations. Furthermore, NMHCs are a powerful source of clinical experiences to train nurses and nurse practitioners as part of the healthcare workforce. CONCLUSIONS: The financial challenges facing NMHCs are significant; it will take an enormous push from organized fronts of the NMHC movement to give individual NMHCs a fighting chance to survive within the competitive healthcare climate. IMPLICATIONS FOR PRACTICE: Policy changes are essential to assure that NMHCs are an integral part of the primary healthcare safety net for America's vulnerable populations, and that advance practice nurses are at the forefront of policy initiatives. PMID- 22243679 TI - Perceived weight gain, risk, and nutrition in pregnancy in five racial groups. AB - OBJECTIVE: Examine perceived pregnancy weight gain needed, perceived risks to mother, and infant of excessive weight and underweight, perceptions of actual, ideal, realistic body size, nutritional intake in five racial/ethnic groups. DESIGN: Cross-sectional Setting: Physicians' offices Participants: A total of 54 women <20 weeks gestation. METHODS: Questionnaires-perceived weight gain needed, risks of weight gain for mother, infant, perceptions of body size, food frequency. RESULTS: A total of 39% of women are overweight or obese (57% Caribbean Black, 50% African American). Perceived pregnancy weight gain needed highest in Central American Hispanic women, lowest Caribbean Black women. African American women had low perceived risk for mother and infant of gaining too much pregnancy weight, highest perceived risk for both of gaining too little. Caribbean Black women perceived highest risk to mother of gaining too much pregnancy weight, highest risk to infant of gaining too little. White Non Hispanic women reported smaller prepregnant, ideal, realistic body sizes than other four groups. Daily caloric intake ranged from 599 to 5856 calories. African American women had significantly more calories; protein, total fats, monounsaturated, polyunsaturated, and saturated fats; carbohydrates, sugar; and iron than White Non-Hispanic women. Women in each racial/ethnic group had less than recommended intake of protein, carbohydrates, calcium, iron, folate, and fiber. CONCLUSIONS: Education is needed to raise awareness of risks of prepregnancy weight and excessive weight gain for mother and infant. The need for prenatal nutritional counseling to reduce the intake of calories, fats, sweets, and snacks; increase intake of vegetables, fruits, foods with iron, folate, and fiber. PMID- 22243680 TI - Behavior changes in patients with diabetes and hypertension after experiencing shared medical appointments. AB - PURPOSE: This project examined recently implemented shared medical appointments (SMAs) at a free clinic for patients with diabetes and/or hypertension. Changes in patients' self-managing behaviors, specifically exercise and goal-setting activity, were explored after participating in SMAs for 4 months. DATA SOURCES: The study employed a pretest-posttest quasi-experimental design. Participants completed a questionnaire of their self-managing behaviors and a behavioral action plan at each SMA. The SMAs were facilitated in English, Spanish, and bilingually (English and Spanish) with a total of 37 participants. CONCLUSIONS: Descriptive analysis showed a significant increase in exercise time with a mean increase of 86 min per week at post-SMA (p= .002, 95% confidence interval [CI]). Each participant identified a measurable goal, and 97% of participants reported achieving or almost achieving their goals. Males reported a significantly (p= .002, 95% CI) larger increase in exercise time than women. Variance of self managing behaviors among the English, Spanish, and bilingual SMAs was statistically not significant. IMPLICATIONS FOR PRACTICE: Though much evidence exists demonstrating that SMAs provide effective quality care, literature is lacking in examining patients' self-managing behaviors after participation in language-specific SMAs. Understanding patients' response to programs that address the needs of the individual leads to more effective programs. PMID- 22243681 TI - Primary palliative care clinic pilot project demonstrates benefits of a nurse practitioner-directed clinic providing primary and palliative care. AB - PURPOSE: The purpose of the Primary Palliative Care Pilot Project was to determine if patients with a life-limiting illness who receive their primary care and palliative care from a consistent provider via a nurse practitioner (NP) founded and-directed Primary Palliative Care Clinic at a public hospital would have improved symptom management and decreased emergency department utilization over time. DATA SOURCES: All patients followed in the Harborview Primary Palliative Care Clinic from January to March 2010. CONCLUSIONS: The results of this project demonstrate that patients with a life-limiting illness who receive their primary care and palliative care in an NP-founded and -directed Primary Palliative Care Clinic have decreased utilization of the emergency department, and some experience improvement in symptom assessment scores. IMPLICATIONS FOR PRACTICE: Palliative care providers and administrators should explore opportunities to expand outpatient palliative care clinics with an emphasis on primary care and continuity of care. NPs by experience and education are ideally suited to manage both primary and palliative care needs for people at the end of life. PMID- 22243682 TI - Patient-centered outcomes research and nurse practitioners' role in shared decision making. AB - This article provides a brief overview of a new program from the Agency for Healthcare Research and Quality (AHRQ) called the Effective Healthcare Program. This program has supported more than 70 research projects since its inception and published more than 50 products, including guides for clinicians and patients that provide a comprehensive analysis of treatment options for common, chronic illnesses. Research summaries are also available for mobile devices. PMID- 22243683 TI - Cyanidin-3-O-beta-glucoside regulates fatty acid metabolism via an AMP-activated protein kinase-dependent signaling pathway in human HepG2 cells. AB - BACKGROUND: Hepatic metabolic derangements are key components in the development of fatty liver disease. AMP-activated protein kinase (AMPK) plays a central role in controlling hepatic lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase 1 (CPT-1) pathway. In this study, cyanidin-3-O-beta-glucoside (Cy-3-g), a typical anthocyanin pigment was used to examine its effects on AMPK activation and fatty acid metabolism in human HepG2 hepatocytes. RESULTS: Anthocyanin Cy-3-g increased cellular AMPK activity in a calmodulin kinase kinase dependent manner. Furthermore, Cy-3-g substantially induced AMPK downstream target ACC phosphorylation and inactivation, and then decreased malonyl CoA contents, leading to stimulation of CPT-1 expression and significant increase of fatty acid oxidation in HepG2 cells. These effects of Cy-3-g are largely abolished by pharmacological and genetic inhibition of AMPK. CONCLUSION: This study demonstrates that Cy-3-g regulates hepatic lipid homeostasis via an AMPK-dependent signaling pathway. Targeting AMPK activation by anthocyanin may represent a promising approach for the prevention and treatment of obesity-related nonalcoholic fatty liver disease. PMID- 22243686 TI - Trivalent ultrashort lipopeptides are potent pH dependent antifungal agents. AB - The activity of antimicrobial peptides (AMPs) that contain a large proportion of histidine residues (pK(a) ~ 6) depends on the physiological pH environment. Advantages of these AMPs include high activity in slightly acidic areas of the human body and relatively low toxicity in other areas. Also, many AMPs are highly active in a multivalent form, but this often increases toxicity. Here we designed pH dependent amphiphilic compounds consisting of multiple ultrashort histidine lipopeptides on a triazacyclophane scaffold, which showed high activity toward Aspergillus fumigatus and Cryptococcus neoformans at acidic pH, yet remained nontoxic. In vivo, treatment with a myristic acid conjugated trivalent histidine histidine dipeptide resulted in 55% survival of mice (n = 9) in an otherwise lethal murine lung Aspergillus infection model. Fungal burden was assessed and showed completely sterile lungs in 80% of the mice (n = 5). At pH 5.5 and 7.5, differing peptide-membrane interactions and peptide nanostructures were observed. This study underscores the potential of unique AMPs to become the next generation of clinical antimicrobial therapy. PMID- 22243687 TI - Dietary Approaches to Stop Hypertension (DASH) eating pattern and risk of elevated blood pressure in adolescent girls. AB - Dietary determinants of adolescent blood pressure (BP) are poorly understood. The goal of the present study was to assess the effects of an eating pattern similar to that from the Dietary Approaches to Stop Hypertension (DASH) study on adolescent BP. Data from 2185 girls followed-up over 10 years (until the girls were 18-20 years of age) in the National Heart Lung and Blood Institute's Growth and Health Study were used in this analysis. Diet was assessed during eight examination cycles using 3 d dietary records; girls were classified according to their consumption of foods associated with a DASH-style eating pattern. Analysis of covariance modelling, multiple logistic regression and longitudinal mixed models were used to control for potential confounding by age, race, socio economic status, height, physical activity, television viewing time and other dietary factors. Girls who consumed >= 2 daily servings of dairy and >= 3 servings of fruits and vegetables (FV) had a 36 % lower risk (95 % CI: 0.43, 0.97) of elevated BP (EBP) in late adolescence. In longitudinal modelling, two dietary factors were associated with a lower systolic BP throughout adolescence: higher (>= 2 daily servings) dairy intakes (P < 0.0001) and a DASH-style pattern (P = 0.0002). Only the DASH-style pattern led to consistently lower diastolic BP levels (P = 0.0484). Adjustment for BMI did not appreciably modify the results. In this study, adolescent girls whose diets were rich in dairy products and FV during the early- and mid-adolescent years were less likely to have EBP levels in later adolescence. PMID- 22243688 TI - Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. AB - The aim of the present clinical positron emission tomography study was to examine if the 5-HTT is a common target, both for tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Serotonin transporter (5-HTT) occupancy was estimated during treatment with TCA, SSRI and mirtazapine in 20 patients in remission from depression. The patients were recruited from out patient units and deemed as responders to antidepressive treatment. The radioligand [11C]MADAM was used to determine the 5-HTT binding potential. The mean 5-HTT occupancy was 67% (range 28-86%). There was no significant difference in 5-HTT occupancy between TCA (n=5) and SSRI (n=14). 5-HTT affinity correlated with the recommended clinical dose. Mirtazapine did not occupy the serotonin transporter. The results support that TCAs and SSRIs have a shared mechanism of action by inhibition of 5-HTT. PMID- 22243689 TI - Novel cyanine dyes with vinylsulfone group for labeling biomolecules. AB - Novel vinylsulfone cyanine dyes (em. 550-850 nm) were designed and synthesized for fluorescent labeling of biomolecules via 1,2-addition reaction in aqueous conditions. Due to the virtue of chemical structures of both fluorophore and reactive group, these dyes could be significantly stable and reactive in various aqueous/organic conditions. A wide variety of pH, temperature, buffer concentration, and protein were tested for the optimal labeling condition. PMID- 22243690 TI - Slovakian Arthroplasty Register. Review of the annual report of the Slovakian Arthroplasty Register - 2010. AB - This annual report of Slovakian Arthroplasty Register (SAR) is an official document dealing with all arthroplasty procedures performed in Slovakia from January 1st until December 30th, 2010. During that period the population of Slovakia reached 5,435,273. During the observed period 4,970 primary arthroplasties and 457 revision arthroplasties were performed. In general, the number of arthroplasty procedures depends on the demographic growth of the population. This annual report is divided into two main parts - arthroplasty of the hip joint and the arthroplasty of the knee joint: it contains summary statistics from all surgical departments performing arthroplasty procedures. In the hip joint section, it evaluates data from 40 orthopaedic and traumatology departments in 2010, the incidence of primary total hip arthroplasty (THA) was 91.42 per 100,000 inhabitants. From the year 2003, when the incidence was 39.39 per 100,000 inhabitants, the percentage growth has been 232%. In 2010, the revision rate reached 9.20%, representing annual increase of 1.1%. The revision rate in whole observed period 2003-2010 reached 9.15%.The mean age of all patients undergoing primary THA was 64.66 years. Sixty percent were female and 40% male. Primary coxarthrosis was the main indication for the surgery in 57.75%. Compared to 2003, when it was 54.33% the increase was minimal. In 2003, dysplasia was as the main indication in 10.01% and in 2010 this figure reached 11.39%. In 19.68% the indication was femoral neck fracture. Regarding the type of the arthroplasty, total hip arthroplasty was used in 86.78% of all cases, unipolar hemiarthroplasty was used in 12.45% cases and bipolar hemiarthroplasty accounted for only 0.76% of all cases. Cement was used for all components in 35.45% of all arthoplasties, 53.25% were uncemented and 11.28% were hybrids. We have observed significant growth in the uncemented type of fixation. In 2003, the uncemented type of fixation was used in only 23.07% of all cases. The SAR started with data collection in total knee arthroplasty (TKA) on January 1st, 2006. In 2010, TKA was practised in 28 surgical departments, in which 2,198 primary and 97 revision arthroplasties were performed. Females comprised 67.38% and males 32.62%. The incidence of TKA was 40.44 per 100,000 of population. In 2010, the revision rate reached 4.41%, representing an annual growth of 0.04% compared to 2009. During the period 2003-2010, the overall TKA revision rate was 3.62%. In 2010, primary bicondylar arthroplasty was the chosen TKA technique in 85.53% of all cases: 97.04% of all implants were fixed with bone cement, 1.36% were uncemented and 1.59% of all knees were hybrids. PMID- 22243691 TI - The management of transitional cell carcinoma (TCC) in a European regional renal transplant population. AB - In the West, transitional cell carcinoma (TCC) in renal transplant patients is uncommon, but aggressive. Conversely, it appears to be frequent in the Far East, necessitating aggressive surgical approaches such as prophylactic nephroureterectomy. There are few European case series to date. TCC in the present population was predominantly low-grade and superficial, with no progression in patients with those tumours. Endoscopic management was sufficient for most patients. The behaviour of TCC in the present population was much less aggressive than that described in the Far East. Altering immunosuppression regimes may have a role to play in managing bladder cancer in renal transplant patients. OBJECTIVE: To examine the clinical characteristics, management and long term outcomes of patients with transitional cell carcinoma (TCC) who also have had renal transplantation. PATIENTS AND METHODS: A retrospective case note review was performed for the 15-year period 1995-2009. Searches from three different urological centres in the UK, using multiple sources, yielded 1647 patients with renal transplants, 12 of whom had TCC. Eight cases were identified who developed de novo TCC after transplantation (0.48%). Four patients had pre-existing TCC who then had renal transplantation. The current literature was reviewed. RESULTS: In the eight de novo TCC cases, the bladder was the site in all with no upper tract TCC; seven were superficial (pTa/T1) and five were low grade (G1/2). The mean time to development of TCC after transplant was 5 years, with a mean follow-up of 11 years. There was no progression in low-grade superficial disease that was managed endoscopically. The 5- and 10-year overall survival was 83% and 72%, respectively. In patients with pre-existing TCC prophylactic bilateral nephroureterectomy before transplantation was performed once. There was progression of superficial disease whilst on immunosuppression in one patient. Sirolimus was used in patients with TCC and reports suggest this may have a role to play in modifying malignancy in this setting. The number of patients involved in studies particularly focusing on TCC in renal transplantation is small (136 patients), with 60% from China/Taiwan where there is a high incidence of upper tract TCC and high-grade muscle-invasive disease. CONCLUSIONS: Although this is one of the largest European case series of renal transplant patients with TCC, the numbers are small making clear conclusions difficult. The frequency of TCC in our renal transplant population is low, consistent with previous studies. However, contrary to prior studies, TCC after renal transplantation in this European population was predominantly superficial, low-grade, non-progressive and confined to the bladder. Altering immunosuppression regimes in patients with TCC may have a role to play, although further work is required to clarify and substantiate this. PMID- 22243692 TI - Questionnaire layout and wording influence prevalence and risk estimates of respiratory symptoms in a population cohort. AB - OBJECTIVE: Results of epidemiological studies are greatly influenced by the chosen methodology. The study aims to investigate how two frequently used questionnaires (Qs), with partly different layout, influence the prevalence of respiratory symptoms. STUDY DESIGN AND SETTING: A booklet containing two Qs, the Global Allergy and Asthma European Network Q and the Obstructive Lung Disease in Northern Sweden Q, was mailed to 30,000 subjects aged 16-75years in West Sweden; 62% responded. Sixteen questions were included in the analysis: seven identical between the Qs, four different in set-up and five with the same layout but different wording. Comparisons were made using differences in proportions, observed agreement and Kappa statistics. RESULTS: Identical questions yielded similar prevalences with high observed agreement and kappa values. Questions with different set-up or differences in wording resulted in significantly different prevalences with lower observed agreement and kappa values. In general, the use of follow-up questions, excluding subjects answering no to the initial question, resulted in 2.9-6.7% units lower prevalence. CONCLUSION: The question set-up has great influences on epidemiological results, and specifically questions that are set up to be excluded based on a previous no answer leads to lower prevalence compared with detached questions. Therefore, Q layout and exact wording of questions has to be carefully considered when comparing studies. PMID- 22243693 TI - Early experiences of vasodilators and hypotensive anesthesia in children. AB - The physiological application of OHMS LAW explains the basis of hypotensive anesthesia. V = IR translates into: Pressure = Flow * Resistance or Blood pressure = Cardiac Output * Peripheral Resistance. If peripheral resistance is reduced by a vasodilator such as sodium nitroprusside (a short acting, vascular smooth muscle relaxant) or phenoxybenzamine (a long acting alpha adrenoreceptor antagonist), blood pressure will fall and vasoconstriction and bleeding will be reduced. A less desirable alternative to lowering blood pressure could be to reduce cardiac output by suppressing myocardial contractility using a beta(1) adrenoceptor antagonist or an inhalational agent such as isoflurane. PMID- 22243694 TI - A genomics approach to understanding the role of auxin in apple (Malus x domestica) fruit size control. AB - BACKGROUND: Auxin is an important phytohormone for fleshy fruit development, having been shown to be involved in the initial signal for fertilisation, fruit size through the control of cell division and cell expansion, and ripening related events. There is considerable knowledge of auxin-related genes, mostly from work in model species. With the apple genome now available, it is possible to carry out genomics studies on auxin-related genes to identify genes that may play roles in specific stages of apple fruit development. RESULTS: High amounts of auxin in the seed compared with the fruit cortex were observed in 'Royal Gala' apples, with amounts increasing through fruit development. Injection of exogenous auxin into developing apples at the start of cell expansion caused an increase in cell size. An expression analysis screen of auxin-related genes involved in auxin reception, homeostasis, and transcriptional regulation showed complex patterns of expression in each class of gene. Two mapping populations were phenotyped for fruit size over multiple seasons, and multiple quantitative trait loci (QTLs) were observed. One QTL mapped to a region containing an Auxin Response Factor (ARF106). This gene is expressed during cell division and cell expansion stages, consistent with a potential role in the control of fruit size. CONCLUSIONS: The application of exogenous auxin to apples increased cell expansion, suggesting that endogenous auxin concentrations are at least one of the limiting factors controlling fruit size. The expression analysis of ARF106 linked to a strong QTL for fruit weight suggests that the auxin signal regulating fruit size could partially be modulated through the function of this gene. One class of gene (GH3) removes free auxin by conjugation to amino acids. The lower expression of these GH3 genes during rapid fruit expansion is consistent with the apple maximising auxin concentrations at this point. PMID- 22243697 TI - Associations between frequency of tea consumption and health and mortality: evidence from old Chinese. AB - Tea consumption may be associated with reduced risk of morbidity and mortality; however, this association is not conclusive and has rarely been investigated among very old adults. The present study examines how self-reported frequency of tea consumption in daily life is associated with health and mortality among very old adults in China. The data are from a national longitudinal data set that included 32 606 individuals (13 429 men and 19 177 women) aged 65 years and older: 11 807 respondents aged 65 to 84 years and 20 799 respondents aged 85 years and older. A total of four measurements between 1998 and 2005 resulted in 51 668 observations. Hazard regressions showed that men who drink tea almost every day have a 10-20 % lower risk of death compared to their counterparts who seldom drink tea, after adjusting for numerous confounders including baseline health. This relationship was stronger in younger male elders aged 65 to 84 years than in the oldest-old men aged 85 years and older. However, frequency of tea consumption was not significantly associated with mortality in women. Our analyses further show that high frequency of tea consumption is significantly associated with reduced OR of disability in activities of daily living, cognitive impairment, self-rated poor health, cumulative health deficits and CVD in both young elders and the oldest-old, and in both men and women. These results suggest that the health benefit of drinking tea is universal. We conclude that frequent tea consumption probably helps one achieve healthy longevity and that men benefit more from such lifestyles. PMID- 22243696 TI - Different means, same end-heterochromatin formation by RNAi and RNAi-independent RNA processing factors in fission yeast. AB - The assembly of heterochromatin in eukaryotic genomes is critical for diverse chromosomal events including regulation of gene expression, silencing of repetitive DNA elements, proper segregation of chromosomes and maintenance of genomic integrity. Previous studies have shown that noncoding RNAs and the RNA interference (RNAi) machinery promote the assembly of heterochromatin that serves as a multipurpose platform for targeting effectors involved in various chromosomal processes. Recent work has revealed that RNAi-independent mechanisms, involving RNA processing activities that utilize both noncoding and coding RNAs, operate in the assembly of heterochromatin. These findings have established that, in addition to coding for proteins, mRNAs also function as signaling molecules that modify chromatin structure by targeting heterochromatin assembly factors. PMID- 22243698 TI - Homobivalent ligands of the atypical antipsychotic clozapine: design, synthesis, and pharmacological evaluation. AB - To date all typical and atypical antipsychotics target the dopamine D(2) receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D(2) receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D(2) receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine. PMID- 22243699 TI - Experimental study of leflunomide on renal protective effect and on inflammatory response of streptozotocin induced diabetic rats. AB - AIM: To further reveal the effects of leflunomide on renal protection and on inflammatory response using streptozotocin (STZ) induced diabetic rats. METHODS: Male Wistar rats were randomly divided into normal control group (NC), diabetic group (DM) and leflunomide treatment group (LEF). LEF group rats were given leflunomide (5 mg/kg) once daily. At the end of the 12th week, general biochemical parameters in three groups were determined. The renal histopathology was observed by light microscopy and electron microscopy. Further biochemical analysis of the gene and protein expression of nuclear factor kappa B (NF kappaB), tumour necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and ED-1 positive cells in renal tissue were provided using real-time reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: Compared with NC group rats, systolic blood pressure, blood glucose (BG), glycohemoglobin (HbAlc), renal hypertrophy index, urine albumin excretion rate (AER) and serum creatinine were increased in DM group rats (P < 0.05). Treatment with leflunomide can improve these parameters except systolic blood pressure, BG and HbAlc. Creatinine clearance rate (Ccr) in the DM group was significantly lower than that of the NC group, and leflunomide can increase its level. Compared with DM group rats, the pathological damages were significantly relieved in LEF group rats. Compared with NC group rats, the gene and protein expressions of NF-kappaB, TNF-alpha, MCP-1 and ED-1 positive cells in renal tissue of DM group rats were highly upregulated (P < 0.01). Leflunomide suppressed their high expressions in renal tissue of diabetic rats. CONCLUSIONS: Leflunomide can ameliorate the kidney structure and function injury of diabetic rats through suppressing the expression of NF-kappaB, TNF-alpha, MCP 1 and macrophage infiltration in renal tissue. PMID- 22243700 TI - beta-conglycinin combined with fenofibrate or rosuvastatin have exerted distinct hypocholesterolemic effects in rats. AB - BACKGROUND: There is increasing interest in non-pharmacological control of cholesterol and triglyceride levels in the plasma and diet-drug association represent an important area of studies. The objective of this study was to observe the hypocholesterolemic effect of soybean beta-conglycinin (7S protein) alone and combined with fenofibrate and rosuvastatin, two hypolipidemic drugs. METHODS: The protein and drugs were administered orally once a day to rats and the effects were evaluated after 28 days. Wistar rats were divided into six groups (n = 9): hypercholesterolemic diet (HC), HC+7S protein (300 mg.kg-1 day-1) (HC-7S), HC+fenofibrate (30 mg.kg-1 day-1)(HC-FF), HC+rosuvastatin (10 mg.kg-1 day-1)(HC-RO), HC+7S+fenofibrate (HC-7S-FF) and HC+7S+rosuvastatin (HC-7S-RO). RESULTS: Animals in HC-7S, HC-FF and HC-RO exhibited reductions of 22.9, 35.8 and 18.8% in total plasma cholesterol, respectively. In HC-7S-FF, animals did not show significant alteration of the level in HC+FF while the group HC-7S-RO showed a negative effect in comparison with groups taking only protein (HC-7S) or drug (HC-RO). The administration of the protein, fenofibrate and rosuvastatin alone caused increases in the plasma HDL-C of the animals, while the protein-drug combinations led to an increase compared to HC-FF and HC-RO. The plasma concentration of triacylgycerides was significantly reduced in the groups without association, while HC-7S-FF showed no alteration and HC-7S-RO a little reduction. CONCLUSION: The results of our study indicate that conglycinin has effects comparable to fenofibrate and rosuvastatin on the control of plasma cholesterol, HDL-C and triacylglycerides, when given to hypercholesterolemic rats, and suggests that the association of this protein with rosuvastatin alters the action of drug in the homeostasis of cholesterol. PMID- 22243701 TI - Increase of ABCG2/BCRP+ side population stem cells in myocardium after ventricular unloading. AB - BACKGROUND: A significant decrease in mean cardiomyocyte DNA content and increased numbers of diploid cardiomyocytes after unloading has been demonstrated, suggesting a numerical increase of cardiomyocytes. Despite a thorough search in that study, no mitoses explaining a potential net increase of cardiomyocytes has been observed. The heart harbors several stem cell populations, including c-kit (CD117)(+) stem cells and side population cells (SPC), which may proliferate after unloading and thus contribute to the generation of diploid cardiomyocytes. In this study we sought to determine, whether there is an increase of ABCG2(+) SPC and CD117(+) stem cells after unloading. METHODS: In paired myocardial samples (prior to and after LVAD), the number of cells with immunoexpression of ABCG2, c-kit/CD117 and MEF-2 was assessed by immunohistochemistry. Their number was morphometrically determined and these data were correlated with the mean cardiomyocyte DNA content. RESULTS: A significant increase of SPC and cells with coexpression of c-kit and MEF-2 after unloading was observed from 0.00013% in CHF to 0.0011%, and 0.013% to 0.035%, respectively after unloading (p = 0.001). A significant positive correlation between both SPC and cells with coexpression of c-kit and MEF-2 expression was observed (p = 0.007 and 0.01). No correlation was found between the number of SPC and the mean cardiomyocyte DNA content. CONCLUSIONS: SPC are increased significantly in the myocardium after ventricular unloading, suggesting a role for stem cell proliferation during "reverse cardiac remodeling." These cells might proliferate and commit to different cell lineages, such as cardiomyocytes or endothelium, and thus ameliorate cardiac function. PMID- 22243702 TI - Survival after biventricular mechanical circulatory support: does the type of device matter? AB - BACKGROUND: Biventricular support can be achieved using paracorporeal biventricular assist devices (BiVADs), the total artificial heart (TAH), and implantable VADs. This study evaluated the influence of the device on patient survival. METHODS: Data from 383 patients (321 men [84%]) undergoing primary, planned biventricular support using durable devices between 2000 and 2010 were extracted from the French multicentric Groupe de Reflexion sur l'Assistance Mecanique (GRAM) registry. Mean age was 41.6 +/- 14.0 years. Patients were classified as group 1, 255 (67%) with paracorporeal BiVADs; group 2, 90 (24%) with TAH; and group 3, 38 (10%) with implantable BiVADs. RESULTS: Mean patient support duration was 82.8 +/- 107.4 days and similar among groups (p = 0.53). Bridging to transplantation was successful in 211 patients (55%) and to recovery in 23 (6%). Mortality on device was similar among groups (p = 0.16). TAH patients had a significantly lower stroke rate (p < 0.0001). Actuarial estimates for survival while on support were 75.2% +/- 2.3%, 64.4% +/- 2.7%, 61.1% +/- 2.8%, and 56.8% +/- 3.1% at 30, 60, 90, and 180 days, respectively, and were similar among groups. However, TAH patients undergoing prolonged support (>=90 days) showed a trend toward improved survival (p = 0.08). Actuarial post-transplant survival estimates were, respectively, 81.7 +/- 2.7, 75.3 +/- 3.0, 73.0 +/- 3.0, and 64.7 +/- 3.7 at 1 month and 1, 3, and 5 years and were similar among groups (p = 0.84). CONCLUSION: Survival while on support and after heart transplantation did not differ significantly in patients supported with paracorporeal BiVADs, implantable BiVADs, or the TAH. Patients undergoing prolonged support (>90 days) tended to have improved survival when supported with TAH compared with BiVADs, which may be related to a lower incidence of neurologic events. PMID- 22243703 TI - Humanism through the Lens of the Academic Pediatric Association. PMID- 22243704 TI - Ethics and Academic Pediatrics. PMID- 22243705 TI - A shot in the arm: not as simple as it would seem. PMID- 22243706 TI - Dr and Mrs. PMID- 22243707 TI - The intersection of flexibility and outcomes in pediatric education. PMID- 22243708 TI - Increasing adult Tdap vaccination rates by vaccinating infant caregivers in the pediatric office. AB - OBJECTIVE: To increase adult caregiver Tdap vaccination rates by offering Tdap vaccine during infant well-child visits. METHODS: We developed a pilot vaccine initiative wherein pediatricians offered Tdap vaccine to mothers and non-mother caregivers attending the 2-week well-child visit at a hospital-based clinic serving predominantly low-income families. We evaluated this initiative by asking mothers and caregivers to participate in a survey after the 2-week visit to determine self-reported Tdap vaccination status, demographics, and the source of their adult primary care. RESULTS: Seventy (69%) participants received the Tdap vaccine during the newborns' 2-week well-child visit. Forty-six percent of the infants' 152 adult household contacts were vaccinated through this initiative. Of those mothers and caregivers, more caregivers reported not having insurance (38% vs 15%, P < .001), and no routine medical care (23% vs 8%, P = .007). CONCLUSIONS: Through this pilot initiative, we vaccinated 69% of mothers and non mother caregivers presenting to the 2-week well-child visit. A large proportion of caregivers did not receive routine medical care or have insurance, which suggests that they otherwise may have poor access to the vaccine. Tdap vaccination in the pediatric office represents a substantial opportunity to increase vaccination rates. PMID- 22243709 TI - Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study. AB - BACKGROUND: Elective single-embryo transfer has been proposed as a strategy to reduce the risk of multiple birth and adverse pregnancy outcomes after in-vitro fertilisation (IVF). Whether this approach should be restricted to young women is unclear. METHODS: In a prospective study of UK Human Fertilisation and Embryology Authority data, we investigated whether perinatal livebirth outcomes varied by the number of embryos transferred in relation to maternal age. We compared rates of livebirth, multiple births, low birthweight (<2.5 kg), preterm birth (<37 weeks), and severe preterm birth (<33 weeks) in women younger than 40 years and those aged 40 years or older. We used logistic and binomial regression methods to assess, respectively, relative risk and absolute differences in risk. FINDINGS: We assessed 124,148 IVF cycles overall, which yielded 33,514 livebirths. The odds ratios of livebirth were higher in women aged 40 years or older than in those younger than 40 years when two embryos were transferred compared with one embryo (3.12, 95% CI 2.58-3.77 [corrected] vs 2.33, 2.20-2.46; p=0.0006 for interaction), but the absolute difference in risk of livebirth was smaller (0.090, 0.080-0.099 for women >=40 years vs 0.156, 0.148-0.163 for those <40 years; p<0.0001). The odds ratios and absolute risk differences for multiple birth, preterm birth, and low birthweight were all smaller in older than in younger women (analyses were done in 32,732 cycles in which a livebirth had resulted and data on gestational age and birthweight were complete). Livebirth rates did not increase with transfer of three embryos, but the risk of adverse perinatal outcomes did increase. INTERPRETATION: Transfer of three or more embryos at any age should be avoided. The decision to transfer one or two embryos should be based on prognostic indicators, such as age. FUNDING: None. PMID- 22243710 TI - Number of embryos to transfer: better safe than sorry? PMID- 22243711 TI - Emergency care. Editorial. PMID- 22243712 TI - Measuring emergency department nurses' attitudes towards deliberate self-harm using the Self-Harm Antipathy Scale. AB - The emergency department is an important gateway for the treatment of self-harm patients. Nurses' attitudes towards patients who self-harm can be negative and often nurses experience frustration, helplessness, ambivalence and antipathy. Patients are often dissatisfied with the care provided, and meeting with positive or negative attitudes greatly influences whether they seek additional help. A quantitative design was utilised to measure emergency department nurses' attitudes towards deliberate self-harm. The 'Self-Harm Antipathy Scale', a validated questionnaire, was administered to a random sample of nurses in four emergency departments in the Republic of Ireland. A total of 87 questionnaires were returned (87% response rate). Results reveal that nurses show slightly negative antipathy overall, indicating positive attitudes towards self-harming patients. Attitudes were significantly different in accordance with a nurse's age. Education and social judgment also contribute to the way nurses view, interact and make moral decisions regarding self-harm patients. Evidence indicates there is need to improve the training, supervision and support of nurses caring for patients who self-harm, and that practical strategies should be implemented to manage the alienation process and inform practice. PMID- 22243713 TI - Jordanian nurses' perceptions of their preparedness for disaster management. AB - AIM: To assess Jordanian RNs' perceptions regarding their knowledge, skills, and preparedness for disaster management. BACKGROUND: Current disaster knowledge, skills, and preparedness levels need to be evaluated to guide plans for effective educational programs. There is also a need to know where RNs received their knowledge, skills, and preparation, to enhance or improve future educational opportunities. METHODS: Cross-sectional survey where the Disaster Preparedness Evaluation Tool (DPET((r))) was distributed to Jordanian RNs who work in three randomly selected Ministry of Health hospitals and two university hospitals. RESULTS: Four hundred and seventy-four participants completed the survey. Sixty five per cent of respondents described their current disaster preparedness as weak: 18% medium: 12% good; and 5% felt their preparation was very good. Thirty one per cent received disaster education in undergraduate programs; 8% in graduate nursing programs; 31% in facility drills, and 22% in continuing education courses. Eleven per cent had participated in a real disaster. Four hundred and thirty RNs wanted to learn more about RNs role in disasters, including knowledge and skills. CONCLUSION: Knowledge,skills, and disaster preparedness need continual reinforcement to improve self efficacy for disaster management. RECOMMENDATIONS: There is a need for a consistent national nursing curriculum for disaster preparedness and nationwide drills to increase disaster knowledge, skills, preparedness, and confidence. PMID- 22243714 TI - Quality of the handover of patient care: a comparison of pre-Hospital and Emergency Department notes. AB - AIM: The aim of this audit was to evaluate the accuracy of patient information transfer from pre-hospital reports to Emergency Department (ED) documentation. METHODS: The records of 100 patients seen in the ED resuscitation room of a UK hospital were compared using a pro-forma designed by the research team. Sections of the ambulance service patient report form and the ED documentation were compared for differences. The history of the event leading to the 999 call, the patient's previous medical history, prescribed medications, allergies and any treatment carried out by the ambulance crew were analysed. RESULTS: Of the 100 records, 26 had at least one instance where information recorded by the ambulance crew was either omitted or altered during transfer. These fell into various categories including the previous medical history of the patient, the timings of the event bringing them to hospital, frequency of the event occurring, allergies and medications. CONCLUSION: This audit quantifies the number of patient encounters where written information changes or is lost when care is passed from pre-hospital to hospital staff in the resuscitation room. We have not investigated other parts of the ED or the verbal transfer of information. Further work investigating the causes of these changes in information, any impact on patient care and whether this occurs in other parts of an ED is suggested. PMID- 22243715 TI - Evaluation of nurses' theoretical knowledge in Basic Life Support: a study in a district Greek hospital. AB - OBJECTIVE: Nurses are usually the first-responders in cases of in-hospital cardiac arrest. Their competence in Basic Life Support (BLS) is important in improving patient outcome. The purpose of this study was to evaluate the nurses' BLS knowledge in a small district hospital. METHODS: Data was collected by an anonymous questionnaire, distributed to all nursing personnel in this hospital. DATA/RESULTS: The failure rate of the BLS theoretical questionnaire was 84%. Regarding self-assessment 10.3% of the participants rated their BLS knowledge as very good, whereas 31.2%, 44.2% and 14.3% of them rated it as good, moderate or not good respectively. This self-assessment did not correlate significantly with the final performance in the written test. No difference regarding the performance in the written test was observed between nurses who had participated in a refresher BLS course after graduation and those who had not. The nurses without any previous personal experience in the BLS had a higher probability to pass the written test. CONCLUSIONS: Our results indicate a low level of BLS knowledge among the study participants. Having an occasional refresher BLS course, or prior experience in BLS, does not affect the level of knowledge. PMID- 22243716 TI - To handle the unexpected - the meaning of caring in pre-hospital emergency care. AB - The patient's voice has not been present to the same degree as the professional perspective in caring research in a pre-hospital context. In order to further develop and improve pre-hospital care, it is therefore important to explore patients' situations not only in life threatening but also in non-traumatic situations. This is especially important as these patients might be defined as inappropriate attendees of ambulance services. The aim of this study was to interpret and explain experiences of caring in pre-hospital care situations that are not defined as traumatic or life threatening. Twenty informants aged between 34 and 82 years were interviewed. The design of the study was exploratory, and it used an interpretative approach in order to understand the meaning of pre hospital caring. The findings show that pre-hospital caring can be understood and explained as a matter of interplay between carer(s) and patient with potentials for positive as well as negative outcomes. Our conclusion is that the initial meeting is of vital importance in how patients experience pre-hospital care. It is suggested that general public information on the development of Swedish pre hospital care received in turn may facilitate the first encounter between patient and carer(s). PMID- 22243717 TI - Antipathy towards self-harm patients and nurse education. PMID- 22243719 TI - Placental villous expression of TNFalpha and IL-10 and effect of oxygen tension in euploid early pregnancy failure. AB - PROBLEM: The objective was to investigate placental inflammation in chromosomally normal miscarriages in vivo and in vitro. METHOD OF STUDY: Chorionic villous tissue was collected from missed miscarriages and normal gestation-matched controls and cultured at 6 and 20% O(2) concentrations. Tissue was karyotyped. Flowcytometric bead arrays and real-time PCR were carried out for protein and gene expression studies. RESULTS: The levels of TNFalpha and IL-10 were significantly (P < 0.005 and P < 0.05) higher, and the levels of TNF-R1 and TNF R2 were significantly (P < 0.01 and P < 0.05) lower in culture conditioned medium of villous explants of miscarriages compared to control group. Villous tissue homogenates from miscarriages contained significantly (P < 0.005) lower levels of TNF-R1. There was a significant O(2) -dependent increase in the secretion of IL 10 (P < 0.01) and decrease in TNFalpha/IL-10 ratio (P < 0.005) in the culture medium in both groups. CONCLUSION: Increased levels of TNFalpha and decreased levels of receptors in miscarriage villous tissue confirm an excessive placental inflammation in miscarriage patients. PMID- 22243720 TI - [Breast implants and anaplastic large cell lymphoma: What do we know?]. AB - There is a new concern about a possible association between anaplastic large cell lymphoma (ALCL) and breast implants. The purpose of this review was to identify and analyze all reported cases of ALCL occurring in patients with breast implants. Therefore, we reviewed all articles published concerning this subject between 1991 and 2011. We found 41 cases of ALCL. The mean age of the patients was 51 years old with an average of 108 months between the implantation and the diagnosis. Over 60 % of the reported cases were aesthetic augmentations. However, none of the published study managed to highlight a correlation between the prosthesis and this lymphoma. Therefore, we believe that for the moment, we can reassure our patients, but we must be aware of this association if a late seroma or a tumefaction occur on prosthesis. The surgical management seems to be essential for the diagnosis and the treatment, especially by the negative ALK and CD 30 expression of this lymphoma. PMID- 22243721 TI - Solar cheilosis: an ominous precursor: part I. Diagnostic insights. AB - Squamous cell carcinoma (SCC) of the lower lip is a deadly nonmelanoma skin cancer. Its precursor, a distinctive cutaneous neoplasia analogous to cervical dysplasia, is known by the confusing term actinic cheilitis. Solar cheilosis (SC) is a more appropriate designation. It represents incipient SCC in situ. SC is widely recognized as an ultraviolet light-induced precancer of the lower lip that is typically seen in light-skinned individuals and others with poorly pigmented lower lips. Lip SCC is one of the most common malignancies of the oral cavity. SCC is much more likely to metastasize from the lip than cutaneous surfaces, with a 5-year overall survival rate of less than 75%. SC results from long-term exposure to ultraviolet radiation. The occurrence of SC is dose-dependent and is influenced by the patient's solar exposure, age, genetic predisposition, geographic latitude of residence, occupation, leisure activities, and use of lip protective agents. Molecular abnormalities of SC are similar to those of actinic keratosis and facilitate the evolution to SCC. A high degree of clinical suspicion should be maintained, given the malignant nature of this condition. Ulceration and nodularity often indicate progression to SCC. We performed a Medline and Google Scholar search for all articles related to actinic cheilitis, actinic cheilosis, SC, actinic keratosis, solar keratosis, premalignant oral disease, and lip SCC, and have also evaluated many other articles and book chapters. One hundred forty-two peer-reviewed articles were identified as being of particular value. Pertinent facts were selected and analyzed. PMID- 22243722 TI - Solar cheilosis: an ominous precursor part II. Therapeutic perspectives. AB - The differential diagnosis of SC includes malignant, premalignant, metastatic, inflammatory, and eczematoid disorders, along with photodermatoses and a few rare but important disorders of the lower lip. Current treatment options include topical, ablative, and surgical therapies. Several clinical challenges are also addressed, including the issue of obtaining a high-yield diagnostic biopsy specimen while minimizing patient morbidity, field-directed treatment for SC, and strategies for combination therapy. PMID- 22243723 TI - Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know. AB - The entry of biosimilar forms of biopharmaceutical therapies for the treatment of psoriasis and other immune-mediated disorders has provoked considerable interest. Although dermatologists are accustomed to the use of a wide range of generic topical agents, recognition of key differences between original agent (ie, the name brand) and the generic or biosimilar agent is necessary to support optimal therapy management and patient care. In this review we have summarized the current state of the art related to the impending introduction of biosimilars into dermatology. Biosimilars represent important interventions that are less expensive and hence offer the potential to deliver benefit to large numbers of patients who may not currently be able to access these therapies. But the development of biosimilars is not equivalent to that of small molecule generic therapies because of differences in molecular structure and processes of manufacture. The planned regulatory guidelines and path to approval may not encompass all of these potentially important differences and this may have clinical relevance to the prescriber and patient. Consequently, we have identified a series of key issues that should be considered to support the full potential of biosimilars for the treatment of psoriasis; ie, that of increased access to appropriate therapy for the psoriasis population worldwide. PMID- 22243724 TI - Limitations of the "spaghetti technique". PMID- 22243725 TI - Segmentally grouped melanocytic nevi and melanoma risk. PMID- 22243727 TI - Long-term prognosis of vitiligo patients on narrowband UVB phototherapy. PMID- 22243728 TI - Randomized study of topical tacrolimus ointment as possible treatment for resistant idiopathic pruritus ani. PMID- 22243729 TI - Infliximab as a steroid-sparing agent in refractory cutaneous sarcoidosis: single center retrospective study of 9 patients. PMID- 22243730 TI - Grover disease may result from the impairment of keratinocytic cholinergic receptors. PMID- 22243731 TI - Phaeohyphomycosis caused by Phaeoacremonium species in a patient taking infliximab. PMID- 22243732 TI - Use of a hydrocolloid dressing to aid in the closure of surgical wounds in patients with fragile skin. PMID- 22243733 TI - JAAD Grand Rounds quiz. A 46-year-old man with agminated papules on the buttock. Reed syndrome. PMID- 22243734 TI - JAAD grand rounds quiz. A 40-year-old man with hyperkeratotic palms and soles. Papillone-Lefevre syndrome. PMID- 22243735 TI - JAAD grand rounds quiz. Red, purple, and brown skin lesions in a 2-month-old boy. Phakomatosis pigmentovascularis type V. PMID- 22243738 TI - Precursor uptake assays and metabolic analyses in isolated tomato fruit chromoplasts. AB - BACKGROUND: Carotenoids are the most widespread group of pigments found in nature. In addition to their role in the physiology of the plant, carotenoids also have nutritional relevance as their incorporation in the human diet provides health benefits. In non-photosynthetic tissues, carotenoids are synthesized and stored in specialized plastids called chromoplasts. At present very little is known about the origin of the metabolic precursors and cofactors required to sustain the high rate of carotenoid biosynthesis in these plastids. Recent proteomic data have revealed a number of biochemical and metabolic processes potentially operating in fruit chromoplasts. However, considering that chloroplast to chromoplast differentiation is a very rapid process during fruit ripening, there is the possibility that some of the proteins identified in the proteomic analysis could represent remnants no longer having a functional role in chromoplasts. Therefore, experimental validation is necessary to prove whether these predicted processes are actually operative in chromoplasts. RESULTS: A method has been established for high-yield purification of tomato fruit chromoplasts suitable for metabolic studies. Radiolabeled precursors were efficiently incorporated and further metabolized in isolated chromoplast. Analysis of labeled lipophilic compounds has revealed that lipid biosynthesis is a very efficient process in chromoplasts, while the relatively low incorporation levels found in carotenoids suggest that lipid production may represent a competing pathway for carotenoid biosynthesis. Malate and pyruvate are efficiently converted into acetyl-CoA, in agreement with the active operation of the malic enzyme and the pyruvate dehydrogenase complex in the chromoplast. Our results have also shown that isolated chromoplasts can actively sustain anabolic processes without the exogenous supply of ATP, thus suggesting that these organelles may generate this energetic cofactor in an autonomous way. CONCLUSIONS: We have set up a method for high yield purification of intact tomato fruit chromoplasts suitable for precursor uptake assays and metabolic analyses. Using targeted radiolabeled precursors we have been able to unravel novel biochemical and metabolic aspects related with carotenoid and lipid biosynthesis in tomato fruit chromoplasts. The reported chromoplast system could represent a valuable platform to address the validation and characterization of functional processes predicted from recent transcriptomic and proteomic data. PMID- 22243739 TI - Molecular epidemiology of livestock rabies viruses isolated in the northeastern Brazilian states of Paraiba and Pernambuco from 2003 - 2009. AB - BACKGROUND: Limited or no epidemiological information has been reported for rabies viruses (RABVs) isolated from livestock in the northeastern Brazilian states of Paraiba (PB) and Pernambuco (PE). The aim of this study was to clarify the molecular epidemiology of RABVs circulating in livestock, especially cattle, in these areas between 2003 and 2009. FINDINGS: Phylogenetic analysis based on 890 nt of the nucleoprotein (N) gene revealed that the 52 livestock-derived RABV isolates characterized here belonged to a single lineage. These isolates clustered with a vampire bat-related RABV lineage previously identified in other states in Brazil; within PB and PE, this lineage was divided between the previously characterized main lineage and a novel sub-lineage. CONCLUSIONS: The occurrences of livestock rabies in PB and PE originated from vampire bat RABVs, and the causative RABV lineage has been circulating in this area of northeastern Brazil for at least 7 years. This distribution pattern may correlate to that of a vampire bat population isolated by geographic barriers. PMID- 22243740 TI - Regulated shuttling of the histone deacetylase HDAC5 to the nucleus may put a brake on cocaine addiction. AB - The histone deacetylase HDAC5 has been shown to regulate behavioral adaptations to cocaine. In this issue of Neuron, Taniguchi et al. (2012) describe a cAMP dependent signaling pathway that regulates nuclear accumulation of HDAC5, suggesting a mechanism to couple cocaine with changes in HDAC5 function. PMID- 22243741 TI - Spontaneous neurotransmission: a SNARE for the rest. AB - In addition to activity-dependent neurotransmission, neurons can undergo spontaneous activity-independent neurotransmitter release with low probability. In this issue of Neuron, Ramirez et al. (2012) now identify the noncanonical endosomal SNARE Vps10p-tail-interactor1a (Vti1a) as a regulator of spontaneously fusing vesicles. PMID- 22243742 TI - Adaptive switches in midbrain circuits. AB - In this issue of Neuron, Mysore and Knudsen (2012) describe a simple, anatomically supported circuit that can categorize stimuli into "strongest" and "others," regardless of their absolute strength. Such flexible categorization cannot be achieved by lateral inhibition alone but also requires that the inhibitory neurons reciprocally inhibit each other. PMID- 22243743 TI - The challenges and promise of neuroimaging in psychiatry. AB - Neuroimaging is central to the quest for a biological foundation of psychiatric diagnosis but so far has not yielded clinically relevant biomarkers for mental disorders. This review addresses potential reasons for this limitation and discusses refinements of paradigms and analytic techniques that may yield improved diagnostic and prognostic accuracy. Neuroimaging can also be used to probe genetically defined biological pathways underlying mental disorders, for example through the genetic imaging of variants discovered in genome-wide association studies. These approaches may ultimately reveal mechanisms through which genes contribute to psychiatric symptoms and how pharmacological and psychological interventions exert their effects. PMID- 22243744 TI - Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. AB - Over the past two decades, research has identified extrasynaptic GABA(A) receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability. The importance of this tonic inhibition in regulating states of consciousness is highlighted by the fact that extrasynaptic GABA(A) receptors (GABA(A)Rs) are believed to be key targets for anesthetics, sleep-promoting drugs, neurosteroids, and alcohol. The neurosteroid sensitivity of these extrasynaptic GABA(A)Rs may explain their importance in stress-, ovarian cycle-, and pregnancy-related mood disorders. Moreover, disruptions in network dynamics associated with schizophrenia, epilepsy, and Parkinson's disease may well involve alterations in the tonic GABA(A)R-mediated conductance. Extrasynaptic GABA(A)Rs may therefore present a therapeutic target for treatment of these diseases, with the potential to enhance cognition and aid poststroke functional recovery. PMID- 22243745 TI - Cell-type-based analysis of microRNA profiles in the mouse brain. AB - MicroRNAs (miRNA) are implicated in brain development and function but the underlying mechanisms have been difficult to study in part due to the cellular heterogeneity in neural circuits. To systematically analyze miRNA expression in neurons, we have established a miRNA tagging and affinity-purification (miRAP) method that is targeted to cell types through the Cre-loxP binary system in mice. Our studies of the neocortex and cerebellum reveal the expression of a large fraction of known miRNAs with distinct profiles in glutamatergic and GABAergic neurons and subtypes of GABAergic neurons. We further detected putative novel miRNAs, tissue or cell type-specific strand selection of miRNAs, and miRNA editing. Our method thus will facilitate a systematic analysis of miRNA expression and regulation in specific neuron types in the context of neuronal development, physiology, plasticity, pathology, and disease models, and is generally applicable to other cell types and tissues. PMID- 22243746 TI - Otic mesenchyme cells regulate spiral ganglion axon fasciculation through a Pou3f4/EphA4 signaling pathway. AB - Peripheral axons from auditory spiral ganglion neurons (SGNs) form an elaborate series of radially and spirally oriented projections that interpret complex aspects of the auditory environment. However, the developmental processes that shape these axon tracts are largely unknown. Radial bundles are comprised of dense SGN fascicles that project through otic mesenchyme to form synapses within the cochlea. Here, we show that radial bundle fasciculation and synapse formation are disrupted when Pou3f4 (DFNX2) is deleted from otic mesenchyme. Further, we demonstrate that Pou3f4 binds to and directly regulates expression of Epha4, Epha4-/- mice present similar SGN defects, and exogenous EphA4 promotes SGN fasciculation in the absence of Pou3f4. Finally, Efnb2 deletion in SGNs leads to similar fasciculation defects, suggesting that ephrin-B2/EphA4 interactions are critical during this process. These results indicate a model whereby Pou3f4 in the otic mesenchyme establishes an Eph/ephrin-mediated fasciculation signal that promotes inner radial bundle formation. PMID- 22243748 TI - Integrins establish dendrite-substrate relationships that promote dendritic self avoidance and patterning in drosophila sensory neurons. AB - Dendrites achieve characteristic spacing patterns during development to ensure appropriate coverage of territories. Mechanisms of dendrite positioning via repulsive dendrite-dendrite interactions are beginning to be elucidated, but the control, and importance, of dendrite positioning relative to their substrate is poorly understood. We found that dendritic branches of Drosophila dendritic arborization sensory neurons can be positioned either at the basal surface of epidermal cells, or enclosed within epidermal invaginations. We show that integrins control dendrite positioning on or within the epidermis in a cell autonomous manner by promoting dendritic retention on the basal surface. Loss of integrin function in neurons resulted in excessive self-crossing and dendrite maintenance defects, the former indicating a role for substrate interactions in self-avoidance. In contrast to a contact-mediated mechanism, we find that integrins prevent crossings that are noncontacting between dendrites in different three-dimensional positions, revealing a requirement for combined dendrite dendrite and dendrite-substrate interactions in self-avoidance. PMID- 22243747 TI - Integrins regulate repulsion-mediated dendritic patterning of drosophila sensory neurons by restricting dendrites in a 2D space. AB - Dendrites of the same neuron usually avoid each other. Some neurons also repel similar neurons through dendrite-dendrite interaction to tile the receptive field. Nonoverlapping coverage based on such contact-dependent repulsion requires dendrites to compete for limited space. Here we show that Drosophila class IV dendritic arborization (da) neurons, which tile the larval body wall, grow their dendrites mainly in a 2D space on the extracellular matrix (ECM) secreted by the epidermis. Removing neuronal integrins or blocking epidermal laminin production causes dendrites to grow into the epidermis, suggesting that integrin-laminin interaction attaches dendrites to the ECM. We further show that some of the previously identified tiling mutants fail to confine dendrites in a 2D plane. Expansion of these mutant dendrites in three dimensions results in overlap of dendritic fields. Moreover, overexpression of integrins in these mutant neurons effectively reduces dendritic crossing and restores tiling, revealing an additional mechanism for tiling. PMID- 22243749 TI - Assembly and maintenance of nodes of ranvier rely on distinct sources of proteins and targeting mechanisms. AB - VIDEO ABSTRACT: We have investigated the source(s) and targeting of components to PNS nodes of Ranvier. We show adhesion molecules are freely diffusible within the axon membrane and accumulate at forming nodes from local sources, whereas ion channels and cytoskeletal components are largely immobile and require transport to the node. We further characterize targeting of NF186, an adhesion molecule that pioneers node formation. NF186 redistributes to nascent nodes from a mobile, surface pool. Its initial accumulation and clearance from the internode require extracellular interactions, whereas targeting to mature nodes, i.e., those flanked by paranodal junctions, requires intracellular interactions. After incorporation into the node, NF186 is immobile, stable, and promotes node integrity. Thus, nodes assemble from two sources: adhesion molecules, which initiate assembly, accumulate by diffusion trapping via interactions with Schwann cells, whereas ion channels and cytoskeletal components accumulate via subsequent transport. In mature nodes, components turnover slowly and are replenished via transport. PMID- 22243750 TI - Histone deacetylase 5 limits cocaine reward through cAMP-induced nuclear import. AB - Chromatin remodeling by histone deacetylases (HDACs) is a key mechanism regulating behavioral adaptations to cocaine use. We report here that cocaine and cyclic adenosine monophosphate (cAMP) signaling induce the transient nuclear accumulation of HDAC5 in rodent striatum. We show that cAMP-stimulated nuclear import of HDAC5 requires a signaling mechanism that involves transient, protein phosphatase 2A (PP2A)-dependent dephosphorylation of a Cdk5 site (S279) found within the HDAC5 nuclear localization sequence. Dephosphorylation of HDAC5 increases its nuclear accumulation, by accelerating its nuclear import rate and reducing its nuclear export rate. Importantly, we show that dephosphorylation of HDAC5 S279 in the nucleus accumbens suppresses the development, but not expression, of cocaine reward behavior in vivo. Together, our findings reveal a molecular mechanism by which cocaine regulates HDAC5 function to antagonize the rewarding impact of cocaine, likely by putting a brake on drug-stimulated gene expression that supports drug-induced behavioral changes. PMID- 22243751 TI - Vti1a identifies a vesicle pool that preferentially recycles at rest and maintains spontaneous neurotransmission. AB - Recent studies suggest that synaptic vesicles (SVs) giving rise to spontaneous neurotransmission are distinct from those that carry out evoked release. However, the molecular basis of this dichotomy remains unclear. Here, we focused on two noncanonical SNARE molecules, Vps10p-tail-interactor-1a (vti1a) and VAMP7, previously shown to reside on SVs. Using simultaneous multicolor imaging at individual synapses, we could show that compared to the more abundant vesicular SNARE synaptobrevin2, both vti1a and VAMP7 were reluctantly mobilized during activity. Vti1a, but not VAMP7, showed robust trafficking under resting conditions that could be partly matched by synaptobrevin2. Furthermore, loss of vti1a function selectively reduced high-frequency spontaneous neurotransmitter release detected postsynaptically. Expression of a truncated version of vti1a augmented spontaneous release more than full-length vti1a, suggesting that an autoinhibitory process regulates vti1a function. Taken together, these results support the premise that in its native form vti1a selectively maintains spontaneous neurotransmitter release. PMID- 22243752 TI - NMDA receptor-mediated PIP5K activation to produce PI(4,5)P2 is essential for AMPA receptor endocytosis during LTD. AB - NMDA receptor activation leads to clathrin-dependent endocytosis of postsynaptic AMPA receptors. Although this process controls long-term depression (LTD) induction in the hippocampus, how it is regulated by neuronal activities is not completely clear. Here, we show that Ca2+ influx through the NMDA receptor activates calcineurin and protein phosphatase 1 to dephosphorylate phosphatidylinositol 4-phosphate 5-kinasegamma661 (PIP5Kgamma661), the major phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-producing enzyme in the brain. Bimolecular fluorescence complementation analysis revealed that the dephosphorylated PIP5Kgamma661 became associated with the clathrin adaptor protein complex AP-2 at postsynapses in situ. NMDA-induced AMPA receptor endocytosis and low-frequency stimulation-induced LTD were completely blocked by inhibiting the association between dephosphorylated PIP5Kgamma661 and AP-2 and by overexpression of a kinase-dead PIP5Kgamma661 mutant in hippocampal neurons. Furthermore, knockdown of PIP5Kgamma661 inhibited the NMDA-induced AMPA receptor endocytosis. Therefore, NMDA receptor activation controls AMPA receptor endocytosis during hippocampal LTD by regulating PIP5Kgamma661 activity at postsynapses. PMID- 22243753 TI - Identification of an inhibitory circuit that regulates cerebellar Golgi cell activity. AB - Here we provide evidence that revises the inhibitory circuit diagram of the cerebellar cortex. It was previously thought that Golgi cells, interneurons that are the sole source of inhibition onto granule cells, were exclusively coupled via gap junctions. Moreover, Golgi cells were believed to receive GABAergic inhibition from molecular layer interneurons (MLIs). Here we challenge these views by optogenetically activating the cerebellar circuitry to determine the timing and pharmacology of inhibition onto Golgi cells and by performing paired recordings to directly assess synaptic connectivity. In contrast to current thought, we find that Golgi cells, not MLIs, make inhibitory GABAergic synapses onto other Golgi cells. As a result, MLI feedback does not regulate the Golgi cell network, and Golgi cells are inhibited approximately 2 ms before Purkinje cells, following a mossy fiber input. Hence, Golgi cells and Purkinje cells receive unique sources of inhibition and can differentially process shared granule cell inputs. PMID- 22243755 TI - Inferotemporal cortex subserves three-dimensional structure categorization. AB - We perceive real-world objects as three-dimensional (3D), yet it is unknown which brain area underlies our ability to perceive objects in this way. The macaque inferotemporal (IT) cortex contains neurons that respond selectively to 3D structures defined by binocular disparity. To examine the causal role of IT in the categorization of 3D structures, we electrically stimulated clusters of IT neurons with a similar 3D-structure preference while monkeys performed a 3D structure categorization task. Microstimulation of 3D-structure-selective IT clusters caused monkeys to choose the preferred structure of the 3D-structure selective neurons considerably more often. Microstimulation in IT also accelerated the monkeys' choice for the preferred structure, while delaying choices corresponding to the nonpreferred structure of a given site. These findings reveal that 3D-structure-selective neurons in IT contribute to the categorization of 3D objects. PMID- 22243754 TI - Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. AB - The response of cortical neurons to a sensory stimulus is shaped by the network in which they are embedded. Here we establish a role of parvalbumin (PV) expressing cells, a large class of inhibitory neurons that target the soma and perisomatic compartments of pyramidal cells, in controlling cortical responses. By bidirectionally manipulating PV cell activity in visual cortex we show that these neurons strongly modulate layer 2/3 pyramidal cell spiking responses to visual stimuli while only modestly affecting their tuning properties. PV cells' impact on pyramidal cells is captured by a linear transformation, both additive and multiplicative, with a threshold. These results indicate that PV cells are ideally suited to modulate cortical gain and establish a causal relationship between a select neuron type and specific computations performed by the cortex during sensory processing. PMID- 22243756 TI - Neural activities in v1 create a bottom-up saliency map. AB - The bottom-up contribution to the allocation of exogenous attention is a saliency map, whose neural substrate is hard to identify because of possible contamination by top-down signals. We obviated this possibility using stimuli that observers could not perceive, but that nevertheless, through orientation contrast between foreground and background regions, attracted attention to improve a localized visual discrimination. When orientation contrast increased, so did the degree of attraction, and two physiological measures: the amplitude of the earliest (C1) component of the ERP, which is associated with primary visual cortex, and fMRI BOLD signals in areas V1-V4 (but not the intraparietal sulcus). Significantly, across observers, the degree of attraction correlated with the C1 amplitude and just the V1 BOLD signal. These findings strongly support the proposal that a bottom-up saliency map is created in V1, challenging the dominant view that the saliency map is generated in the parietal cortex. PMID- 22243757 TI - Reciprocal inhibition of inhibition: a circuit motif for flexible categorization in stimulus selection. AB - As a precursor to the selection of a stimulus for gaze and attention, a midbrain network categorizes stimuli into "strongest" and "others." The categorization tracks flexibly, in real time, the absolute strength of the strongest stimulus. In this study, we take a first-principles approach to computations that are essential for such categorization. We demonstrate that classical feedforward lateral inhibition cannot produce flexible categorization. However, circuits in which the strength of lateral inhibition varies with the relative strength of competing stimuli categorize successfully. One particular implementation- reciprocal inhibition of feedforward lateral inhibition--is structurally the simplest, and it outperforms others in flexibly categorizing rapidly and reliably. Strong predictions of this anatomically supported circuit model are validated by neural responses measured in the owl midbrain. The results demonstrate the extraordinary power of a remarkably simple, neurally grounded circuit motif in producing flexible categorization, a computation fundamental to attention, perception, and decision making. PMID- 22243758 TI - Genetic etiology of the common liability to drug dependence: evidence of common and specific mechanisms for DSM-IV dependence symptoms. AB - BACKGROUND: We investigated the etiological nature of comorbid alcohol, tobacco, and cannabis DSM-IV dependence symptoms in late adolescence and young adulthood while accounting for gender differences in the magnitude of genetic and environmental influences. METHODS: Univariate and multivariate twin modeling was used to determine the heritability of each substance and the etiology of multiple drug problems in a sample of 2484 registrants of the Center for Antisocial Drug Dependence who provided data at the second wave of an ongoing longitudinal study. We report on mean and prevalence levels of whole-life DSM-IV dependence symptoms that were assessed with the Composite International Diagnostic Interview Substance Abuse Module. Biometrical analyses were limited to age-adjusted DSM-IV dependence symptom counts from a subset of twins that reported using alcohol, tobacco, or cannabis in their lifetime. RESULTS: Male and female alcohol, tobacco, and cannabis DSM-IV symptoms are indicators of a heritable unidimensional latent continuous trait. Additive genetic factors explain more than 60% of the common liability to drug dependence. A larger proportion of the variation in each substance is attributable to substance-specific genetic and environmental factors. CONCLUSIONS: These data suggest that both common and substance-specific genetic and environmental factors contribute to individual differences in the levels of DSM-IV alcohol, tobacco, and cannabis dependence symptoms. PMID- 22243760 TI - Predicting metastasized seminoma using gene expression. AB - Treatment options for testis cancer depend on the histological subtype as well as on the clinical stage. An accurate staging is essential for correct treatment. The 'golden standard' for staging purposes is CT, but occult metastasis cannot be detected with this method. Currently, parameters such as primary tumour size, vessel invasion or invasion of the rete testis are used for predicting occult metastasis. Last year the association of these parameters with metastasis could not be validated in a new independent cohort. Gene expression analysis in testis cancer allowed discrimination between the different histological subtypes (seminoma and non-seminoma) as well as testis cancer and normal testis tissue. In a two-stage study design we (i) screened the whole genome (using human whole genome microarrays) for candidate genes associated with the metastatic stage in seminoma and (ii) validated and quantified gene expression of our candidate genes (real-time quantitative polymerase chain reaction) on another independent group. Gene expression measurements of two of our candidate genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2]) examined in primary testis cancers made it possible to discriminate the metastasis status in seminoma. The discriminative ability of the genes exceeded the predictive significance of currently used histological/pathological parameters. Based on gene expression analysis the present study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance. OBJECTIVE: To evaluate the usefulness of gene expression profiling for predicting metastatic status in testicular seminoma at the time of first diagnosis compared with established clinical and pathological parameters. PATIENTS AND METHODS: Total RNA was isolated from testicular tumours of metastasized patients (12 patients, clinical stage IIa-III), non-metastasized patients (40, clinical stage I) and adjacent 'normal' tissue (n = 36). The RNA was then converted into cDNA and real-time quantitative polymerase chain reaction was run on 94 candidate genes selected from previous work. Normalised gene expression of these genes and histological variables, e.g. tumour size and rete testis infiltration, were analysed using logistic regression analysis. RESULTS: Expression of two genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2], P = 0.005 and 0.024 in separate analysis and P = 0.004 and 0.016 when combining both genes, respectively) made it possible to significantly discriminate the metastasis status. Concordance increased from 77.9% (DRD1) and 72.3% (FAM71F2) in separate analysis and up to 87.7% when combining both genes in one model. Only primary tumour size in separate analysis (continuous or categorical with tumour size >6 cm) was significantly associated with metastasis (P = 0.039/P = 0.02), but concordance was lower (61%). When we combined tumour size with our two genes in one model there was no further statistical improvement or increased concordance. CONCLUSION: Based on gene expression analysis our study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance. PMID- 22243761 TI - Diabetes: the prototypical non-communicable disease. PMID- 22243759 TI - A new criterion for acquisition of nicotine self-administration in rats. AB - BACKGROUND: Acquisition of nicotine self-administration in rodents is relatively difficult to establish and measures of acquisition rate are sometimes confounded by manipulations used to facilitate the process. This study examined acquisition of nicotine self-administration without such manipulations and used mathematical modeling to define the criterion for acquisition. METHODS: Rats were given 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined for individual rats by the higher likelihood of reinforcers obtained across sessions fitting a logistic over a constant function according to the corrected Akaike Information Criterion (AICc). RESULTS: For rats that acquired self administration, an AICc-based multi-model comparison demonstrated that the asymptote (highest number of reinforcers/session) and mid-point of the acquisition curve (h; the number of sessions necessary to reach half the asymptote) varied by nicotine dose, with both exhibiting a negative relationship (the higher the dose, the lower number of reinforcers and the lower h). CONCLUSIONS: The modeling approach used in this study provides a way of defining acquisition of nicotine self-administration that takes advantage of all data from individual subjects and the procedure used is sensitive to dose differences in the absence of manipulations that influence acquisition (e.g., food restriction, prior food reinforcement, conditioned reinforcers). PMID- 22243762 TI - Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers. AB - In previous research, nicotine-dependent men exhibited lower putamen D2/D3 dopamine-receptor availability than non-smokers (Fehr et al. 2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non smokers) were tested for differences due to sex and smoking in striatal D(2)/D(3) dopamine-receptor availability, using positron emission tomography with [(18)F]fallypride. Receptor availability was determined using a reference region method, in striatal volumes and in whole-brain, voxel-wise analysis. Significant sex * smoking interactions were observed in the caudate nuclei and putamen. Post hoc t tests showed that male smokers had significantly lower D(2)/D(3) dopamine receptor availability than female smokers (-17% caudate, -21% putamen) and male non-smokers (-15% caudate, -16% putamen). Female smokers did not differ from non smokers. Whole-brain analysis demonstrated no statistically significant voxels or clusters. These results suggest that low receptor availability may confer vulnerability to nicotine dependence or that smoking selectively affects D2/D3 receptor down-regulation in men but not women. PMID- 22243763 TI - The nurse education imperative. PMID- 22243764 TI - Risks of developing psychiatric disorders in pediatric patients with psoriasis. AB - BACKGROUND: Symptoms of psoriasis can be embarrassing and distressing, and may increase risk of developing psychiatric disorders in young people. OBJECTIVE: We sought to compare incidences of psychiatric disorders between pediatric patients with psoriasis and psoriasis-free control subjects. METHODS: Patients (<18 years) with continuous health plan enrollment 6 months before and after first psoriasis diagnosis (index date) were selected (Thomson Reuters MarketScan database, 2000 2006 [Thomson Reuters, New York, NY]). Patients with psoriasis (N = 7404) were matched 1:5 on age and sex to psoriasis-free control subjects (N = 37,020). Patients were followed from index date to first diagnosis of a psychiatric disorder (ie, alcohol/drug abuse, depression, anxiety disorder, bipolar disorder, suicidal ideation, eating disorder), end of data availability, or disenrollment. Patients with psychiatric diagnoses or psychotropic medication use before the index date were excluded. Cox proportional hazard models controlling for age, sex, and comorbidities were used to estimate the effect of psoriasis on risks of developing psychiatric disorders. RESULTS: Patients with psoriasis were significantly more at risk of developing psychiatric disorders versus control subjects (5.13% vs 4.07%; P = .0001; hazard ratio = 1.25; P = .0001), especially depression (3.01% vs 2.42%; P = .0036; hazard ratio = 1.25; P = .0053) and anxiety (1.81% vs 1.35%; P = .0048; hazard ratio = 1.32; P = .0045). LIMITATIONS: Retrospective, observational studies of medical claims data are typically limited by overall quality and completeness of data and accuracy of coding for diagnoses and procedures. CONCLUSIONS: Pediatric patients with psoriasis had an increased risk of developing psychiatric disorders, including depression and anxiety, compared with psoriasis-free control subjects. PMID- 22243765 TI - Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow-up. AB - BACKGROUND: Rituximab induces depletion of B cells and has shown efficacy in antibody-mediated autoimmune disorders. In studies on small series of patients with pemphigus, rituximab administration results in significant improvement. However, differences in inclusion criteria, treatment protocols, and follow-up make it difficult to derive uniform conclusions. OBJECTIVES: We sought to test the efficacy and tolerability of rituximab as adjuvant therapy to corticosteroids in the treatment of pemphigus. METHODS: In all, 42 patients with pemphigus were treated with rituximab and followed up for up to 5 years. No additional immunosuppressive agents were used. Steroids were rapidly tapered. Outcomes were the proportion of patients who achieved a complete response on or off therapy, the rate of discontinuation of corticosteroid within 6 months, length of remission, time to relapses, and occurrence of adverse events. RESULTS: In all, 36 of 42 patients (86%; 95% confidence interval 75%-96%) achieved a complete response on or off therapy and discontinued steroids within 6 months from induction therapy. Six patients had a complete response off therapy with an additional infusion of rituximab 6 months after initial treatment. Twenty patients experienced a total of 34 relapses; the time to relapse was 8 to 64 months. Every relapse was treated with rituximab (500 mg) without corticosteroids, which induced a new complete response. No serious adverse events were observed. LIMITATIONS: Lack of a control group is a limitation. CONCLUSIONS: Rituximab therapy induces prolonged clinical remission in patients with pemphigus. Coadministration of other immunosuppressive agents is not necessary. Relapses can be managed with additional infusions administered on demand. PMID- 22243766 TI - Correlates of systemic disease in adult Henoch-Schonlein purpura: a retrospective study of direct immunofluorescence and skin lesion distribution in 87 patients at Mayo Clinic. AB - BACKGROUND: Detection of IgM in lesional skin of adult patients with Henoch Schonlein purpura via direct immunofluorescence (DIF) has been associated with the presence of renal disease. OBJECTIVE: We sought to examine whether DIF findings of skin biopsy specimens and distribution of skin lesions were associated with the presence of systemic disease, including renal, gastrointestinal tract, and joint involvement. METHODS: We performed a retrospective review of adult patients with Henoch-Schonlein purpura seen at Mayo Clinic between 1992 and 2011. RESULTS: Of the 87 patients (mean age, 46.1 years), 51 (59%) were male. A total of 39 patients (45%) had renal disease; 32 (37%), gastrointestinal tract involvement; 39 (45%), joint involvement; and 65 (75%), some systemic involvement. In all, 61 patients (70%) had cutaneous lesions above the waist. The DIF findings showed the presence of IgA in all 87 patients (100%). In addition, findings were positive for IgM in 32 patients (37%); IgG in 3 patients (3%); C3 in 75 patients (87%); and fibrinogen in 78 patients (92%). IgM was not found to be significantly associated with renal disease (P = .10); however, absence of fibrinogen was correlated with presence of renal involvement (P = .04). No other correlations were detected between DIF findings and systemic disease. Lesions above the waist were not significantly associated with renal (P = .12) or any (P = .76) systemic involvement. LIMITATIONS: This study is retrospective. CONCLUSIONS: Neither IgM in lesional skin nor distribution of skin lesions above the waist was a reliable indicator of renal or systemic disease in adults with Henoch-Schonlein purpura. PMID- 22243767 TI - Clinicopathologic study of 85 cases of melanoma of the female genitalia. AB - BACKGROUND: Melanoma of the female genitalia has poor overall prognosis. OBJECTIVE AND METHODS: To examine prognostic factors influencing survival, the Duke Melanoma and Tumor Registry Databases were queried for patients who had received their clinical care at Duke University Medical Center, with a diagnosis of melanoma of the female genitalia, including vulva, vagina, and cervix, between 1970 and 2009. From this group, any available histopathologic specimens were procured for further review. RESULTS: Eighty-five patients were identified. The median follow-up time was 8.8 years with 60% of the patients experiencing melanoma-related mortality at last follow-up. Survival rates at 1, 5, and 10 years were 85%, 51%, and 30%, respectively. The available histopathologic specimens from 36 cases were reviewed by a dermatopathologist (M.A.S.). Fifteen of 36 cases were notable for the presence of atypical melanocytic hyperplasia adjacent to the primary melanoma. Breslow depth, lymph node status, systemic therapy, and surgery were also examined for differences in survival distributions using the log-rank test. In general, survival was inversely correlated with Breslow depth, extent of nodal involvement, and provision of systemic therapy. A higher survival rate was observed among those who received wide local excision. Log-rank test demonstrated that survival between different decades of diagnosis was not significantly different. LIMITATIONS: Because of its small sample size, this study may be underpowered. CONCLUSION: Despite new treatments developed and attempted, there is no evidence that survival has improved over the past 40 years. In summary, patients with thinner melanomas amenable to surgical resection had a better prognosis than those with more extensive, metastatic disease at presentation. PMID- 22243768 TI - The effect of different pulse durations in the treatment of nail psoriasis with 595-nm pulsed dye laser: a randomized, double-blind, intrapatient left-to-right study. AB - BACKGROUND: Several studies have proven the efficacy of pulsed dye laser (PDL) in the treatment of plaque type psoriasis. However, only two published studies indicate the effectiveness of PDL on nail psoriasis. OBJECTIVE: We sought to study the effect of different pulse durations in the treatment of nail psoriasis with the 595-nm PDL to determine the optimal pulse duration. METHODS: Twenty patients with bilateral fingernail psoriasis were recruited and completed a 6 month trial. PDL was applied on the proximal and lateral nailfolds based on random assignment. Forty nails were treated with 6-millisecond pulse duration and 9 J/cm(2) whereas 39 nails were treated with 0.45-millisecond pulse duration and 6 J/cm(2). Patients were blinded to pulse durations. One blinded dermatologist used the Nail Psoriasis Severity Index (NAPSI) to assess the clinical outcome from pretreatment and posttreatment photographs. Patients were monitored for adverse events. Pain was evaluated after the procedure using a visual analog scale assessed by the patient. RESULTS: After 6 months of first treatment, there was a significant reduction in overall NAPSI, nail matrix NAPSI, and nail bed NAPSI scores from baseline in both groups; however, no significant difference was found between the two pulse duration groups. Side effects were mild including transient petechiae and hyperpigmentation. LIMITATIONS: There was no placebo group. CONCLUSIONS: PDL was found to be an effective and well-tolerated option in the treatment of nail psoriasis. No significant difference in terms of efficacy was found between the longer and shorter pulse duration treatment groups. PMID- 22243769 TI - Application of mobile teledermatology for skin cancer screening. AB - BACKGROUND: With advancements in mobile technology, cellular phone-based store and-forward teledermatology may be applied to skin cancer screening. OBJECTIVE: We sought to determine diagnostic and management concordance between in-person and teledermatology evaluations for patients at skin cancer screening whose clinical images and history were transmitted through mobile phones. METHODS: A total of 86 patients with 137 skin lesions presented to a skin cancer screening event in California. These patients' clinical history and skin images were captured by a software-enabled mobile phone. Patients were assessed separately by an in-person dermatologist and a teledermatologist, who evaluated the mobile phone-transmitted history and images. Diagnostic and management concordance was determined between the in-person and teledermatology evaluations. RESULTS: The primary categorical diagnostic concordance was 82% between the in-person dermatologist and the teledermatologist (95% confidence interval 0.73-0.89), with a Kappa coefficient of 0.62 indicating good agreement. The aggregated diagnostic concordance between the in-person dermatologist and the teledermatologist was 62% (95% confidence interval 0.51-0.71), with Kappa coefficient of 0.60 indicating good agreement. Management concordance between the in-person dermatologist and the teledermatologist was 81% (95% confidence interval 0.72-0.88), with a Kappa coefficient of 0.57, which indicates moderate agreement between the dermatologists. Multivariate analysis showed that older age and presentation of atypical nevus were significantly associated with disagreement in diagnosis between the teledermatologist and in-person dermatologist, after adjusting for other factors. LIMITATIONS: Dermatoscopic images were not captured via mobile phones, which might improve diagnostic accuracy. CONCLUSION: Mobile teledermatology using cellular phones is an innovative and convenient modality of providing dermatologic consultations for skin cancer screening. PMID- 22243770 TI - Predictors of the development of myocarditis or acute renal failure in patients with leptospirosis: an observational study. AB - BACKGROUND: Leptospirosis has a varied clinical presentation with complications like myocarditis and acute renal failure. There are many predictors of severity and mortality including clinical and laboratory parameters. Early detection and treatment can reduce complications. Therefore recognizing the early predictors of the complications of leptospirosis is important in patient management. This study was aimed at determining the clinical and laboratory predictors of myocarditis or acute renal failure. METHODS: This was a prospective descriptive study carried out in the Teaching Hospital, Kandy, from 1st July 2007 to 31st July 2008. Patients with clinical features compatible with leptospirosis case definition were confirmed using the Microscopic Agglutination Test (MAT). Clinical features and laboratory measures done on admission were recorded. Patients were observed for the development of acute renal failure or myocarditis. Chi-square statistics, Fisher's exact test and Mann-Whitney U test were used to compare patients with and without complications. A logistic regression model was used to select final predictor variables. RESULTS: Sixty two confirmed leptospirosis patients were included in the study. Seven patients (11.3%) developed acute renal failure and five (8.1%) developed myocarditis while three (4.8%) had both acute renal failure and myocarditis. Conjunctival suffusion - 40 (64.5%), muscle tenderness - 28 (45.1%), oliguria - 20 (32.2%), jaundice - 12 (19.3%), hepatomegaly - 10 (16.1%), arrhythmias (irregular radial pulse) - 8 (12.9%), chest pain - 6 (9.7%), bleeding - 5 (8.1%), and shortness of breath (SOB) 4 (6.4%) were the common clinical features present among the patients. Out of these, only oliguria {odds ratio (OR) = 4.14 and 95% confidence interval (CI) 1.003-17.261}, jaundice (OR = 5.13 and 95% CI 1.149-28.003), and arrhythmias (OR = 5.774 and 95% CI 1.001-34.692), were predictors of myocarditis or acute renal failure and none of the laboratory measures could predict the two complications. CONCLUSIONS: This study shows that out of clinical and laboratory variables, only oliguria, jaundice and arrhythmia are strong predictors of development of acute renal failure or myocarditis in patients with leptospirosis presented to Teaching Hospital of Kandy, Sri Lanka. PMID- 22243771 TI - Removal of dinitrotoluenes in wastewater by sono-activated persulfate. AB - Oxidative degradation of dinitrotoluenes (DNTs) in wastewater was performed using persulfate anions combined with ultrasonic irradiation, wherein a synergistic effect is observed. The batch-wise experiments were carried out to elucidate the influence of various operating parameters on sono-activated persulfate oxidation, including ultrasonic power intensity, persulfate anion concentration, reaction temperature and acidity of wastewater. It is noteworthy that the nitrotoluene contaminants could be almost completely eliminated by virtue of sono-activated persulfate oxidation, wherein sulfate radicals serve as principal oxidants, of which amounts are significantly enhanced via addition of sodium sulfate. Based on the results given by gas chromatograph-mass spectrometer (GC-MS), it is postulated that the methyl group of DNTs preliminarily underwent oxidation pathway into dinitrobenzoic acid, followed by decarboxylation to form 1,3 dinitrobenzene (DNB). In sum, the sono-activated persulfate oxidation is a promising method for treatment of nitrotoluenes in wastewater. PMID- 22243772 TI - Sex-specific association of ACAT-1 rs1044925 SNP and serum lipid levels in the hypercholesterolemic subjects. AB - BACKGROUND: Acyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme in cellular cholesterol homeostasis and in atherosclerosis. The cellular cholesterol efflux correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations has shown to be impaired in hyperlipidemic mice. The present study was carried out to clarify the association of ACAT-1 rs1044925 single nucleotide polymorphism (SNP) and serum lipid levels in the hyperlipidemic subjects. METHODS: A total of 821 unrelated subjects (hyperlipidemia, 476; normolipidemia, 345) aged 15-80 were included in the study. Genotyping of the ACAT-1 rs1044925 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: There was no significant difference in the genotypic and allelic frequencies of ACAT-1 rs1044925 SNP between the normolipidemic and hyperlipidemic subjects. The levels of total cholesterol (TC), HDL-C and apolipoprotein (Apo) AI in hyperlipidemic subjects were different between the AA and AC/CC genotypes in male but not in female (P < 0.05-0.01), the C allele carriers had higher serum TC, HDL-C and ApoAI levels than the C allele noncarriers. The association of genotypes and serum HDL-C and ApoAI levels in hyperlipidemia was found mainly in the male subjects with hypercholesterolemia but not in those with hypertriglyceridemia. There were no significant differences in serum lipid levels between the AA and AC/CC genotypes in the normolipidemic subjects. CONCLUSIONS: The present study shows that the C allele carriers of ACAT 1 rs1044925 SNP in male hyperlipidemic subjects had higher serum TC, HDL-C and ApoAI levels than the C allele noncarriers. There is a sex (male)-specific association of ACAT-1 rs1044925 SNP and serum HDL-C and ApoAI levels in the hypercholesterolemic subjects. PMID- 22243773 TI - A phase II trial of second-line pemetrexed in adults with advanced/metastatic osteosarcoma. AB - BACKGROUND: Osteosarcoma is the most common primary malignant tumour in young adults. An effective treatment strategy for relapsed patients is still not defined. Pemetrexed is a multitargeted antifolate with a mode of action similar to, and a range of action broader than that of methotrexate. The primary objective of this phase II study was to determine tumour response rate in patients with high-grade, advanced/metastatic osteosarcoma. Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety. METHODS: Pemetrexed 500mg/m(2) was administered on day 1 of 21-day cycles with folic acid and vitamin B(12) supplementation. At least 5 tumour responses in a targeted population of 32 were required to consider further investigation. RESULTS: Thirty-two patients (median age, 43.3 years; range, 18.6-76.0) with 1 prior chemotherapy regimen for high-grade advanced/metastatic osteosarcoma were enrolled. Thirty (93.8%) patients had an ECOG performance status <= 1 and 29 (90.6%) had metastases in the lung. One patient had partial response (3.1%) and 5 (15.6%) had stable disease. Median PFS and OS were 1.4 months (95% CI: 1.4-1.7) and 5.5 months (95% CI: 2.3-10.5), respectively. The most common drug-related grade 3/4 toxicities were leukopaenia, asthaenia and elevated alanine aminotransferase in 3 (9.4%) patients each. One patient died due to multi-organ failure considered possibly related to the study drug. CONCLUSIONS: Pemetrexed 500mg/m(2) administered on day 1 of 21-day cycles as second-line treatment to patients with advanced/metastatic high-grade osteosarcoma was generally well tolerated but did not meet minimal response expectations for further investigation in this patient population. PMID- 22243774 TI - A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. AB - PURPOSE: S-1 or capecitabine plus oxaliplatin are considered active and tolerable in gastric cancer patients. We conducted a randomized phase II trial in gastric cancer patients to compare the activity and safety of these combinations. METHODS: The patients received S-1 at 80 mg/m2 for 14 days, followed by a 7-day rest period within a 3-week schedule in the S-1/oxaliplatin (SOX) arm, and capecitabine at 2000 mg/m2 for 14 days, followed by a 7-day rest period within a 3-week schedule in the capecitabine/oxaliplatin (CAPOX) arm. Oxaliplatin 130 mg/m2 was administered every 3 weeks in both arms. RESULTS: One hundred twenty nine patients were randomly assigned to SOX (N=65) or CAPOX (N=64). The median time to progression and the overall survival were 6.2 and 12.4 months with SOX, respectively; and 7.2 and 13.3 months with CAPOX, respectively. The overall response rates were 40% and 44% for SOX and CAPOX, respectively. The most frequent grade 3 or 4 toxicities were thrombocytopenia (15.4%) for SOX and neutropenia (18.8%) for CAPOX. The median time to 10% deteriorations in global health scores was similar in both arms (SOX, 4.3 months, CAPOX, 4.9 months). CONCLUSION: Both the SOX and CAPOX regimens were equally active and well tolerated in advanced gastric cancer patients. PMID- 22243775 TI - Attenuation of colonic inflammation by partial replacement of dietary linoleic acid with alpha-linolenic acid in a rat model of inflammatory bowel disease. AB - Increasing prevalence of inflammatory bowel disease may be due to imbalance in the intake of n-6 and n-3 PUFA in the diet. This study investigates the impact of varying ratios of dietary linoleic acid (LA, 18 : 2n-6) to alpha-linolenic acid (ALA, 18 : 3n-3) on the inflammatory response in dextran sulphate sodium (DSS) induced colitis. Weanling male Sprague-Dawley rats were divided into five groups: a non-colitic group with a LA:ALA ratio of 215 (CON-215), and colitic groups with LA:ALA ratios of 215 (DSS-215), 50 (DSS-50), 10 (DSS-10) and 2 (DSS-2). Blends of groundnut, palmolein and linseed oils were used to provide varying LA:ALA ratios. All the rats were fed the respective experimental isoenergetic diets containing 10 % fat for 90 d and DSS was administered during the last 11 d. Colonic inflammation was evaluated by clinical, biochemical and histological parameters. The results showed attenuation of colitis in the DSS-2 group as evidenced by significant reductions in disease activity index, mucosal myeloperoxidase activity (P < 0.05), alkaline phosphatase activity (P < 0.01) and increase in colon length (P < 0.01) compared to the groups fed with higher ratios (DSS-215). This was accompanied by significant reductions in mucosal proinflammatory cytokines TNF-alpha (P < 0.01) and IL-1beta (P < 0.01) and improvement in the histological score. Further, ALA supplementation increased long-chain (LC) n-3 PUFA and decreased LC n-6 PUFA in colon structural lipids. These data suggest that substitution of one-third of LA with ALA (LA:ALA ratio 2) mitigates experimental colitis by down-regulating proinflammatory mediators. PMID- 22243776 TI - FOXP3(+) regulatory and TIA-1(+) cytotoxic T lymphocytes in HIV-associated Hodgkin lymphoma. AB - Human immunodeficiency virus (HIV) infects CD4(+) lymphocytes, leading to a development of malignant lymphomas, such as HIV-associated Hodgkin Lymphoma (HIV HL). This study aimed to assess the differences in cellular composition of the inflammatory reactive background of HIV-HLs. We examined infiltrating T lymphocytes, specifically regulatory T cells, cytotoxic cells, Epstein-Barr virus (EBV) related antigens and HIV-receptor CCR5. In all HIV-HL cases, Hodgkin and Reed-Sternberg (HRS) cells showed EBER1 expression, LMP-1 staining positivity and EBNA-2 staining negativity, except for one case which showed LMP-1 staining negativity. Our histological findings indicate the percentage of CD8(+) , TIA 1(+) lymphocytes was significantly higher in HIV-HL than in non-HIV-HL cases (P < 0.05). On the other hand, the percentage of CD4(+) , FOXP3(+) lymphocytes was significantly lower in HIV-HL than in non-HIV-HL cases (P < 0.05) but present. The percentage of CCR5(+) lymphocytes was significantly lower in HIV-HL than in non-HIV-HL cases (P < 0.05). Usually, CD4(+) and CCR5(+) lymphocytes are reported to be rarely detected in HIV-associated non-Hodgkin lymphomas, but the presence of CD4(+) and/or FOXP3(+) lymphocytes may be implicated in the pathogenesis of HL. In addition, although additional CD8(+) lymphocytes are probably not EBV-LMP specific cytotoxic T-cells, these lymphocytes may also well be involved in the pathogenesis of HIV-HL. PMID- 22243777 TI - Histone H1 expression in human prostate cancer tissues and cell lines. AB - Histone H1, one of the histone superfamilies, is known to determine chromatin structure and alter gene expression. It also contributes to regulation of cell proliferation in breast cancer. We hypothesized a similar association in prostate cancer, and therefore examined relationships between histone H1 expression and Gleason pattern, Ki-67 and androgen receptor levels in a series of prostate cancer tissues and cell lines. Histone H1 positive cancer cells increased with the Gleason pattern. Gleason pattern 3 tumors were divided into two groups, one with high histone H1 positivity (H1-high cases, 60-100% positivity) and the other with low histone H1 positivity (H1-low cases, 0-20% positivity). Ki-67 or androgen receptor positivity in H1-high cases was significantly higher than in H1 low cases. PC3 cells demonstrated more frequent histone H1 and Ki-67 positivity as compared to LNCaP cells. Silencing of histone H1 by siRNA transfection significantly reduced cell proliferation in LNCaP and PC3. These findings suggest that histone H1 expression is associated with the Gleason pattern, cell proliferation and androgen receptor expression in prostate cancers. PMID- 22243778 TI - Characterization of chromosomal aberrations in thymic MALT lymphoma. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma arising in the thymus is a rare disorder that shows a strong association with autoimmune disease. Several MALT lymphoma-specific and -associated chromosomal abnormalities, including t(11;18), t(14;18), t(1;14), trisomy 3 and trisomy 18, are known to occur. The former translocation results in apoptosis inhibitor 2 gene (API2)-MALT lymphoma associated translocation 1 (MALT1) fusion. In this study, we examined 14 cases of thymic MALT lymphomas for API2-MALT1 fusion using multiplex reverse transcription polymerase chain reaction and looked for trisomy 3, trisomy 18 and abnormalities of MALT1 and IGH genes using fluorescence in situ hybridization. Thymic MALT lymphoma cases had a high frequency of trisomy 3 (7/14 cases), a very low incidence of trisomy 18 (1/14) and no detectable MALT1-associated (0/13) or IGH associated (0/13) gene abnormalities including t(11;18). A review of the literature showed that the pattern of chromosomal aberrations in thymic MALT lymphoma was similar to those of thyroid and salivary gland MALT lymphomas. Although frequently detected, trisomy 3 was not associated with any of the clinicopathological factors analyzed, suggesting that trisomy 3 may play a role in lymphoma development. In conclusion, the present study showed that thymic MALT lymphoma has a characteristic pattern of chromosomal aberrations that may be similar to those of other autoimmune-associated MALT lymphomas. PMID- 22243779 TI - Analysis of the pathological lesions of the lung in a mouse model of cutaneous infection with Streptococcus pyogenes. AB - Invasive diseases such as toxic shock syndrome caused by Streptococcus pyogenes (S. pyogenes) are re-emerging infectious diseases. The mechanism of pathogenesis is not completely understood although the virulence of this organism has been analyzed using animal model systems, particularly using mice. The analysis of the progression of infection, however, is difficult. Computed tomography (CT) scanning is an extremely powerful technique that we applied to the mouse model of cutaneous infection with S. pyogenes. Two or three days after subcutaneous administration of bacteria, high density reticular areas were detected in the lung by CT. Histopathological examination of the lung was performed to examine the results of CT. Increased numbers of cytokeratin-positive epithelial cells, probably alveolar type II epithelial cells, were detected but no remarkable increase of inflammatory cell infiltrates was observed. Our results show that the pathological lesions of the lung in this model, wherein relatively few numbers of neutrophils were in the alveoli, are well correlated with the lung of a part of streptococcal toxic shock syndrome patients. Therefore, CT may be useful in assessing the progression of S. pyogenes infection, particularly in the pathological lesions of the lung in this model. PMID- 22243780 TI - Indoleamine 2,3-dioxygenase expression in early keratocyte neoplasia of the lower lip correlates to the degree of cell atypia. AB - Actinic cheilitis (AC) is an early keratocyte neoplasia with inflammation that occurs in the lip vermillion with the potential to develop into invasive squamous cell carcinoma (SCC). The expression of the intracellular enzyme indoleamine 2,3 dioxygenase (IDO) by antigen-presenting cells and/or tumor cells has been described to arrest T cell proliferation by degrading the essential amino acid tryptophan from the environment. The expression of IDO in AC may support cancer progression by inhibiting T cell-mediated rejection responses. The aim of this study was to identify the cellular nature and extent of IDO expression in early keratocye neoplasia of the lower lip (n=25), and to correlate IDO expression to the severity of epithelial atypia (KIN I degrees - KIN III degrees ) and to the extent of actinic inflammation. The expression of IDO was analyzed together with expression markers for T-cells (CD3), myeloid DCs (S100, CD11c), macrophages (CD68, CD11c), and Langerhans cells (CD1a) by immunohistochemistry and immunofluorescence analysis. Analyses showed that IDO was expressed in myeloid S100(+) CD11c(+) DCs. The expression of IDO correlated significantly with the degree of epithelial atypia (P=0.0005) but not to the extent of inflammation (P=0.4283). Expression of IDO in early atypic skin epithelial conditions might be a predictor to promote carcinogenesis. PMID- 22243781 TI - Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. AB - Gastric cancer (GC) is one of the most common malignancies worldwide. Recently, cancer stem cells (CSCs) in tumors were found to possess the ability to sustain tumor self-renewal, initiate tumor progression, and possibly also contribute to cancer metastasis. We immunohistochemically examined expression and distribution of representative CSC markers ALDH1, CD44, and CD133 in primary tumors and lymph node metastasis of GC. Among 190 GC primary tumors, 104 (55%) were positive for ALDH1, 117 (62%) were positive for CD44, and 18 (9%) were positive for CD133. Expression of these three CSC markers was significantly associated with advanced clinicopathologic factors. Patients with CD44- and CD133-positive GC had a poorer survival rate than patients with CD44- and CD133-negative GC (CD44: P < 0.001, CD133: P= 0.006). Univariate and multivariate Cox proportional hazards analysis revealed tumor node metastasis stage, CD44 expression, and CD133 expression to be independent predictors of survival in patients with GC. Comparison of CSC markers in primary and metastatic sites showed ALDH1 positivity to be significantly higher in diffuse-type lymph node metastasis than in the primary tumor (P < 0.001). These results indicate that these CSC markers are important in tumor invasion and metastasis and may be good markers indicating long-term survival in patients with GC. PMID- 22243782 TI - Comparative study of histological features between core needle biopsy and surgical excision in phyllodes tumor. AB - We analyzed histopathological features of core needle biopsy (CNB) and surgical excision specimen comparatively in 129 patients with surgically proven phyllodes tumor (PT). Stromal characteristics including cellularity, atypia, mitosis, overgrowth, tissue fragmentation, and the tumor margin were assessed. Benign/borderline/malignant phyllodes tumor (PT) were diagnosed in 90 (69.8%)/30 (23.3%)/9 (7.0%) patients. Among the 90 cases of benign PTs, 67 cases (74.4%) were diagnosed concordantly in CNB. For borderline and malignant PTs, three out of eight (26.6%) and four out of nine (44.4%) cases were diagnosed concordantly in CNBs. All 50 cases of discordant diagnosis were underestimated in matched CNBs, especially in their stromal cellularity and mitosis. The size of tumor is larger in discordant cases of PT (P= 0.013). The concordant rate of diagnosis between CNB and surgical excision was about 60% and accordingly, grading of PT based on the histological findings in CNBs has limitation. The discordance comes from heterogeneous stromal properties of PTs. PMID- 22243783 TI - RON is associated with tumor progression via the inhibition of apoptosis and cell cycle arrest in human gastric cancer. AB - The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed in epithelial cancers, including gastric cancer. The aims of the present study were to evaluate whether RON affects tumor cell behaviors and oncogenic signaling pathways, and to document the relationship of its expression with various clinicopathological parameters in gastric cancer. The biological role of RON in tumor cell behaviors and oncogenic signaling pathways was investigated by using small interfering RNA in gastric cancer cell lines including AGS and MKN28. The expression of RON in gastric cancer tissues was investigated by using reverse transcription polymerase chain reaction and immunohistochemistry. Knockdown of RON suppressed tumor cell migration and invasion in AGS and MKN28, induced apoptosis through modulation of anti-apoptotic and pre-apoptotic genes and induced cell cycle arrest by decreasing cyclin D1, cyclin D3 and CDK4, and by inducing p21 and p27 expression. Signaling cascades, including Akt and mitogen activated protein kinase (MAPK), were significantly blocked by knockdown of RON. Expression of RON was significantly associated with tumor size, depth of invasion, lymph node metastasis, tumor stage and poor survival. These results indicate that RON is associated with tumor progression via the inhibition of apoptosis and cell cycle arrest in human gastric cancer. PMID- 22243784 TI - Clear cell variant of squamous cell carcinoma originating in the esophagus: report of a case with immunohistochemical and oncogenetic analyses. AB - The cutaneous clear cell squamous cell carcinoma (SCC) is a rare tumor thought to be associated with hair follicle or skin appendage differentiation. We report herein a rare variant case of a clear cell SCC originating in the esophagus. A 70 year-old Japanese man was found to have a tumor in the esophagus. The excised neoplasm showed dominance of clear cell over conventional SCC components; the two components in an apparent continuum. The clear cells, regular in size with a moderate nuclear/cytoplasmic ratio and relatively hyperchromatic and centrally located nuclei, were compactly arranged in sheets. Glycogen deposition was apparent on PAS staining with or without diastase digestion and under the electron microscope. The clear cell SCC components were positive for cytokeratin (CK)7, CK8, CK18 and CK19, but were negative for CK5/6 or CK14. Reciprocal staining patterns of CKs were apparent in conventional SCC components. The present case and cutaneous clear cell SCC counterparts share some histopathologic characteristics whereas CKs expression differs between the two. Overexpression of p53 protein, without evidence of any mutation, and reduced p16(INK4a) were noted in both clear cell and conventional SCC components. No mutations of Kras, BRAF or beta-catenin genes were found in both tumor components. PMID- 22243785 TI - Successful salvage treatment of steroid-refractory bronchiolar COP with low-dose macrolides. AB - Cryptogenic organizing pneumonia (COP) is an idiopathic interstitial pneumonia characterized by fibroblastic tissues that occupy the lumina of alveoli and alveolar ducts or respiratory bronchioles. Although adequate doses and durations of glucocorticoids can improve its condition, COP is sometimes resistant to glucocorticoid therapy and is often lethal.Herein, a very rare case of 'bronchiolar COP' that was confined to the respiratory bronchioles is reported. This case indicates that macrolides may act as anti-inflammatory agents in patients with COP. Timely and precise pathological diagnosis may corroborate clinician diagnoses and eventually improve chances to overcome the disease. PMID- 22243786 TI - Case report of Mammary Analog Secretory Carcinoma of the parotid gland. AB - Mammary Analog Secretory Carcinoma (MASC) is a new entity of malignant salivary gland tumors that morphologically resembles mammary secretory carcinoma and carries the identical ETV6-NTRK3 fusion gene. We report our first case of MASC in Japan occurring in the parotid gland of a 37-year-old female patient with a t (12; 15) (p13; q25) translocation. Histologically, the tumor was composed of monomorphic cuboidal cells with low-grade vesicular nuclei and pale eosinophilic cytoplasm, and formed microcystic and tubular spaces with periodic acid-Schiff positive secretion. Immunohistochemically, the tumor cells tested positive for cytokeratin, vimentin, and S-100 protein. MASC is a morphological mimicker of acinic cell carcinoma, but is a distinct neoplasm characterized by a specific chromosomal translocation. An accumulation of similar case studies is mandatory in order to clarify biological behaviors. PMID- 22243787 TI - Adenomatoid tumor of the liver. PMID- 22243788 TI - A novel voltammetric sensor for amoxicillin based on nickel-curcumin complex modified carbon paste electrode. AB - The electrocatalytic oxidation of amoxicillin was investigated on a nickel-based (Ni(II)-curcumin) chemically modified electrode. This modified electrode was prepared by electropolymerization of complex (curcumin = 1,7-bis[4-hydroxyl-3 methoxyphenyl]-1,6-heptadiene-3,5-dione) in alkaline solution. For the first time, the catalytic oxidation of amoxicillin was demonstrated by cyclic voltammetry, chronoamperometry, chronocoulometry and amperometry methods at the surface of this modified carbon paste electrode. The obtained results showed that NiOOH acts as an electrocatalyst for oxidation of amoxicillin. This electrocatalytic oxidation exhibited a good linear response for amoxicillin concentration over the range of 8 * 10-6-1*10-4 M with a detection limit of 5 * 10-6 M. Therefore, this electrocatalytic method was used as a simple, selective and rapid method able to determine amoxicillin in pharmaceutical preparations and biological media. PMID- 22243789 TI - Electron transfer and electrocatalytics of cytochrome c and horseradish peroxidase on DNA modified electrode. AB - A bio-interphase composed of DNA, cytochrome c (Cyt c) and horseradish peroxidase (HRP) was developed by layer-by-layer assembling Cyt c, DNA and Cyt c-HRP on biocompatible 11-mercaptoundecanoic acid--6-mercapto-1-hexanol modified gold electrode. The new bio-interphase was used as a model system to mimic the electron transfer and electrocatalytic performance of two proteins in living organisms. Results showed that the electron transfer rate at bi-protein bio interphase was faster than those at the single protein bio-interphase, indicating a synergistic interaction between the two proteins occurred in the electron transfer. Moreover, the mixed proteins modified electrode exhibited good electrocatalytic response to reduction of hydrogen peroxide (H2O2) and oxygen (O2), suggesting that it could be used as a sensor for H2O2 and O2 detection. The properties of the bio-interphase, together with the bioelectrocatalytic activity, could make it useful in the development of bioelectronic devices, and investigation of electrochemistry of other heme proteins at functional interphase. It would also provide a new strategy for further study on the electron transfer of other multi-proteins in a bio-interphase and the development of biosensors. PMID- 22243790 TI - High points and hurdles in the translation of genomics. PMID- 22243792 TI - Prematurity in mice leads to reduction in nephron number, hypertension, and proteinuria. AB - The nephron number at birth is a quantitative trait that correlates inversely with the risk of hypertension and chronic kidney disease later in life. During kidney development, the nephron number is controlled by multiple factors including genetic, epigenetic, and environmental modifiers. Premature birth, which represents more than 12% of annual live births in the United States, has been linked to low nephron number and the development of hypertension later in life. In this report, we describe the development of a mouse model of prematurity induced reduction of nephron number. Premature mice, delivered 1 and 2 days early, have 17.4 +/- 2.3% (n = 6) and 23.6 +/- 2% (n = 10) fewer nephrons, respectively, when compared with full-term animals (12,252 +/- 571 nephrons/kidney, n = 10). After 5 weeks of age, the mice delivered 2 days premature show lower real-time glomerular filtration rate (GFR, 283 +/- 13 vs 389 +/- 26 MUL/min). The premature mice also develop hypertension (mean arterial pressure [MAP], 134 +/- 18 vs 120 +/- 14 mm Hg) and albuminuria (286 +/- 83 vs 176 +/- 59 MUg albumin/mg creatinine). This mouse model provides a proof of concept that prematurity leads to reduced nephron number and hypertension, and this model will be useful in studying the pathophysiology of prematurity-induced nephron number reductions and hypertension. PMID- 22243791 TI - Molecular genetic studies of complex phenotypes. AB - The approach to molecular genetic studies of complex phenotypes evolved considerably during the recent years. The candidate gene approach, which is restricted to an analysis of a few single-nucleotide polymorphisms (SNPs) in a modest number of cases and controls, has been supplanted by the unbiased approach of genome-wide association studies (GWAS), wherein a large number of tagger SNPs are typed in many individuals. GWAS, which are designed on the common disease common variant hypothesis (CD-CV), identified several SNPs and loci for complex phenotypes. However, the alleles identified through GWAS are typically not causative but rather in linkage disequilibrium (LD) with the true causal variants. The common alleles, which may not capture the uncommon and rare variants, account only for a fraction of heritability of the complex traits. Hence, the focus is being shifted to rare variants-common disease (RV-CD) hypothesis, surmising that rare variants exert large effect sizes on the phenotype. In conjunctional with this conceptual shift, technologic advances in DNA sequencing techniques have dramatically enhanced whole genome or whole exome sequencing capacity. The sequencing approach affords identification of not only the rare but also the common variants. The approach-whether used in complementation with GWAS or as a stand-alone approach-could define the genetic architecture of the complex phenotypes. Robust phenotyping and large-scale sequencing studies are essential to extract the information content of the vast number of DNA sequence variants (DSVs) in the genome. To garner meaningful clinical information and link the genotype to a phenotype, the identification and characterization of a large number of causal fields beyond the information content of DNA sequence variants would be necessary. This review provides an update on the current progress and limitations in identifying DSVs that are associated with phenotypic effects. PMID- 22243793 TI - The combined ratios of L-arginine and asymmetric and symmetric dimethylarginine as biomarkers in spontaneously hypertensive rats. AB - Hypertension and hypertensive end-organ damage have been associated with decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) both can inhibit NO availability by competition with L-arginine (L-Arg). However, whether a combined analysis of these 3 parameters can serve as an ideal biomarker of hypertension remains unclear. We measured the plasma and renal levels of L-Arg, ADMA, and SDMA in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) control rats at 3 stages: 4 weeks old (prehypertensive), 12 weeks old (hypertensive), and 24 weeks old (end-organ damage). The plasma and renal L-Arg/ADMA ratio (AAR) and the ADMA/SDMA ratio (ASR) were computed for all 3 age stages. Our results revealed an ADMA level increase, and an AAR decrease in plasma and kidneys may develop early on, even before the onset of hypertension in 4-week-old SHRs. The renal ADMA level and AAR were restored in SHRs at 24 weeks of age, which might protect SHRs against kidney injury. We found that the plasma AAR is superior to the levels of L-Arg and ADMA in plasma, and it predicted blood pressure and urinary NOx levels. Renal AAR is a strong independent marker of renal dimethylarginine dimethylaminohydrolase (DDAH) activity. The plasma ASR was correlated strongly to blood pressure. However, renal DDAH activity was related to the renal ASR but not the plasma ASR. In conclusion, the AAR and ASR may serve as better markers for disease activity and progression than each individual parameter. Clinical use of these ratios to elucidate the role of ADMA in hypertension awaits further validation. PMID- 22243794 TI - Enhanced induction of heme oxygenase-1 suppresses thrombus formation and affects the protein C system in sepsis. AB - Heme oxygenase-1 (HO-1) displays anti-inflammatory and cytoprotective activities in sepsis. Here, we investigated the effects of HO-1 on thrombus formation and the protein C system in a septic C57BL/6 mouse model induced by cecal ligation and perforation (CLP). Septic mice were either preinjected with the vehicle, pretreated with hemin (an HO-1 inducer) or zinc protoporphyrin IX (ZnPP, an HO-1 inhibitor), or given a combination of hemin + ZnPP. CLP increased significantly the hepatic expression of HO-1; increased thrombosis in livers, kidneys, and lungs; shortened the prothrombin time (PT) and activated partial thromboplastin time (APTT); elevated the levels of tumor necrosis factor-1alpha (TNF-1alpha), interleukin-6 (IL-6), and thrombomodulin (TM); reduced the levels of protein C (PC) and activated protein C (aPC); and downregulated hepatic expression of PC and TM. The preadministration of hemin to septic mice increased the expression and activity of HO-1; inhibited thrombosis in the preceding 3 organs; prolonged PT and APTT; inhibited the production of TNF-alpha and IL-6; upregulated the expression of PC and TM in livers; elevated the plasma levels of PC and aPC; and reduced the plasma levels of TM. In contrast, ZnPP showed opposite effects to hemin and reversed the effects of hemin by inhibiting the activity of HO-1. The administration of tricarbonyl dichloro ruthenium (II) dimer (CORM-2), which is a CO-releasing molecule, had a similar effect to hemin on thrombosis and the protein C system. The data indicate that the enhanced induction of HO-1 inhibits thrombus formation and affects the protein C system in sepsis. PMID- 22243795 TI - Mild hypothermia reduces ventilator-induced lung injury, irrespective of reducing respiratory rate. AB - In the era of lung-protective mechanical ventilation using limited tidal volumes, higher respiratory rates are applied to maintain adequate minute volume ventilation. However, higher respiratory rates may contribute to ventilator induced lung injury (VILI). Induced hypothermia reduces carbon dioxide production and might allow for lower respiratory rates during mechanical ventilation. We hypothesized that hypothermia protects from VILI and investigated whether reducing respiratory rates enhance lung protection in an in vivo model of VILI. During 4 h of mechanical ventilation, VILI was induced by tidal volumes of 18 mL/kg in rats, with respiratory rates set at 15 or 10 breaths/min in combination with hypothermia (32 degrees C) or normothermia (37 degrees C). Hypothermia was induced by external cooling. A physiologic model was established. VILI was characterized by increased pulmonary neutrophil influx, protein leak, wet weights, histopathology score, and cytokine levels compared with lung protective mechanical ventilation. Hypothermia decreased neutrophil influx, pulmonary levels, systemic interleukin-6 levels, and histopathology score, and it tended to decrease the pulmonary protein leak. Reducing the respiratory rate in combination with hypothermia did not reduce the parameters of the lung injury. In conclusion, hypothermia protected from lung injury in a physiologic VILI model by reducing inflammation. Decreasing the respiratory rate mildly did not enhance protection. PMID- 22243796 TI - Link between leptin and interleukin-6 levels in the initial phase of obesity related inflammation. AB - The mechanisms underlying the pathogenesis of obesity-related atherosclerosis remain to be clarified. To investigate the preclinical phase, interleukin-6 (IL 6) plasma levels were analyzed together with clinical, anthropometric, inflammatory, and metabolic variables in a well-defined cohort of 677 young and middle-aged overweight/obese and normal-weight subjects. In the juvenile and adult overweight/obese study group, IL-6 levels were increased significantly compared with normal-weight, age-matched controls (P < 0.001). In both juveniles and adults, higher levels of IL-6 were observed in obese compared with overweight participants. Subjects with metabolic syndrome (MS) had significantly higher IL-6 levels than those without MS. In juveniles, leptin, and in adults, the waist-to height ratio, turned out to be the best predictor of IL-6 plasma levels in a multiple stepwise regression model. Taken together, in every age group, interleukin-6 is associated positively with the grade of overweight. Interestingly, leptin, which is the best known adipokine, is associated predictively with interleukin-6 plasma levels only in juveniles, which may indicate an important role of this molecule in the initiation of obesity-related inflammation. PMID- 22243797 TI - Multifunctional QD-based co-delivery of siRNA and doxorubicin to HeLa cells for reversal of multidrug resistance and real-time tracking. AB - Co-delivery of siRNA and chemotherapeutic agents has been developed to combat multidrug resistance in cancer therapy. Recently, we developed a series of quantum dots (QDs) functionalized by beta-cyclodextrin (beta-CD) coupled to amino acids, some of which can be used to facilitate the delivery of siRNA. In this study, two CdSe/ZnSe QDs modified with beta-CD coupled to L-Arg or L-His were used to simultaneously deliver doxorubicin (Dox) and siRNA targeting the MDR1 gene to reverse the multidrug resistance of HeLa cells. In this co-delivery system, Dox was firstly encapsulated into the hydrophobic cavities of beta-CD, resulting in bypass of P-glycoprotein (P-gp)-mediated drug efflux. After complex formation of the mdr1 siRNA with Dox-loaded QDs via electrostatic interaction, significant down-regulation of mdr1 mRNA levels and P-gp expression was achieved as shown by RT-PCR and Western blotting experiments, respectively. The number of apoptotic HeLa cells after treatment with the complexes substantially exceeded the number of apoptotic cells induced by free Dox only. The intrinsic fluorescence of the QDs provided an approach to track the system by laser confocal microscopy. These multifunctional QDs are promising vehicles for the co delivery of nucleic acids and chemotherapeutics and for real-time tracking of treatment. PMID- 22243798 TI - Magnetite-loaded fluorine-containing polymeric micelles for magnetic resonance imaging and drug delivery. AB - Magnetite (Fe(3)O(4)) - loaded polymer micelles (denoted as "magnetomicelles") are produced by self-assembly of fluorine-containing amphiphilic poly(HFMA-g PEGMA) copolymers with oleic acid modified Fe(3)O(4) nanoparticles in an aqueous medium. The oleic acid modified Fe(3)O(4) nanoparticles form small clusters in the poly(HFMA-g-PEGMA) micelles with a mean diameter of 100 nm and the magnetomicelles show high stability in an aqueous medium due to the high hydrophobic fluorine segments in graft copolymers enhance the stability of the micelles. The magnetomicelles also show good cytocompatibility based on the MTT cytotoxicity assay and possess paramagnetic properties with saturation magnetization of 17.14 emu/g.Their good stability, cytocompatibility, and paramagnetic properties render the materials attractive in drug delivery and in vivo magnetic resonance imaging (MRI) applications. Controlled release of hydrophobic drug-5-fluorouracil is achieved from the magnetomicelles with a loading efficiency of 20.94 wt%. The magnetomicelles have transverse relaxivity rates (r(2)) of 134.27 mM(-1) s(-1) and exhibit high efficacy as a negative MRI agent in T(2)-weighted imaging. In vivo MRI studies demonstrate that the contrast between liver and spleen is enhanced by the magnetomicelles. These favorable properties suggest clinical use as nanocarriers in drug delivery applications and contrast agents in MRI. PMID- 22243799 TI - Gene transfer by chemical vectors, and endocytosis routes of polyplexes, lipoplexes and lipopolyplexes in a myoblast cell line. AB - Chemical vectors are widely developed for providing safe DNA delivery systems. It is well admitted that their endocytosis and intracellular trafficking are critical for the transfection efficiency. Here, we have compared the endocytic pathways of lipoplexes, polyplexes and lipopolyplexes formed with carriers of various chemical compositions. Engineered C2C12 mouse myoblast cells expressing Rab5-EGFP, Rab7-EGFP or Cav1-GFP were used to monitor the location of the plasmid DNA into the endocytic compartments by real time fluorescence confocal microscopy. We observed that (i) DNA complexes made with dioleyl succinyl paromomycin:O,O-dioleyl-N-histamine phosphoramidate (DOSP/MM27) liposomes or histidinylated lPEI (His-lPEI) allowing the highest transfection efficiency displayed a positive zeta potential and were internalized by clathrin-mediated endocytosis, (ii) DOSP/MM27 lipoplexes were 6-times more internalized than His lPEI polyplexes, (iii) all negatively charged DNA complexes lead to less efficient transfection and entered the cells via caveolae and (iv) lipopolyplexes allowing high transfection efficiency were weakly internalized via caveolae. Our results indicate that the transfection efficiency is better correlated with the nature of the endocytic pathway than with the uptake efficacy. This study shows also that engineered cells expressing specific fluorescent compartments are convenient tools to monitor endocytosis of a fluorescent plasmid DNA by real time fluorescence confocal microscopy. PMID- 22243800 TI - The effect of long-term release of Shh from implanted biodegradable microspheres on recovery from spinal cord injury in mice. AB - After spinal cord injury (SCI), loss of cells and damage to ascending and descending tracts can result in paralysis. Current treatments for SCI are based on patient stabilization, and much-needed regenerative therapies are still under development. To activate and instruct stem and progenitor cells or injured tissue to aid SCI repair, it is important to modify the injury environment for a protracted period, to allow time for cell activation, proliferation and appropriate fate differentiation. Shh plays a critical role in spinal cord formation, being involved in multiple processes: it promotes production of motor neurons and oligodendrocytes from ventral cord progenitor cells and serves as an axon guidance molecule. Hence Shh is a candidate pleiotropic beneficial environmental factor for spinal cord regeneration. Here we show that administration of biodegradable microspheres that provide sustained, controlled delivery of Shh resulted in significant functional improvement in two different mouse models of SCI: contusion and dorsal hemioversection. The mechanism is multifactorial, involving increased proliferation of endogenous NG2+ oligodendrocyte lineage cells, decreased astrocytic scar formation and increased sprouting and growth of corticospinal (CST) and raphespinal tract (RST) fibers. Thus, long-term administration of Shh is a potential valuable therapeutic intervention for SCI. PMID- 22243801 TI - Transplantation of platelet gel spiked with cardiosphere-derived cells boosts structural and functional benefits relative to gel transplantation alone in rats with myocardial infarction. AB - The emerging field of stem cell therapy and biomaterials has begun to provide promising strategies for the treatment of ischemic cardiomyopathy. Platelet gel and cardiosphere-derived cells (CDCs) are known to be beneficial when transplanted separately post-myocardial infarction (MI). We hypothesize that pre seeding platelet gel with CDCs can enhance therapeutic efficacy. Platelet gel and CDCs were derived from venous blood and heart biopsies of syngeneic rats, respectively. In vitro, the viability, growth, and morphology of CDCs cultured in platelet gel were characterized. When delivered into infarcted rat hearts, platelet gel pre-seeded with CDCs was more efficiently populated with endogenous cardiomyocytes and endothelial cells than platelet gel alone. Recruitment of endogenous c-kit positive cells was enhanced in the hearts treated with gel with CDC. At 3 weeks, the hearts treated with CDC-seeded platelet gel exhibited the greatest attenuation of adverse left ventricular (LV) remodeling and the highest cardiac function (i.e., LV ejection fraction) as compared to hearts transplanted with Gel only or vehicle controls. Histological analysis revealed that, though some transplanted CDCs differentiated into cardiomyocytes and endothelial cells in the recipients' hearts, most of the incremental benefit arose from CDC mediated endogenous repair. Pre-seeding platelet gel with CDCs enhanced the functional benefit of biomaterial therapy for treating myocardial infarction. PMID- 22243802 TI - Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. AB - Complexing agents such as diethylene triamine pentaacetic acid (DTPA) are known to disrupt intestinal tight junctions and inhibit intestinal proteases by chelating divalent metal ions. This study attempts to incorporate these benefits of DTPA in functional nanoparticles (NPs) for oral insulin delivery. To maintain the complexing agent concentrated on the intestinal mucosal surface, where the paracellular permeation enhancement and enzyme inhibition are required, DTPA was covalently conjugated on poly(gamma-glutamic acid) (gammaPGA). The functional NPs were prepared by mixing cationic chitosan (CS) with anionic gammaPGA-DTPA conjugate. The gammaPGA-DTPA conjugate inhibited the intestinal proteases substantially, and produced a transient and reversible enhancement of paracellular permeability. The prepared NPs were pH-responsive; with an increasing pH, CS/gammaPGA-DTPA NPs swelled gradually and disintegrated at a pH value above 7.0. Additionally, the biodistribution of insulin orally delivered by CS/gammaPGA-DTPA NPs in rats was examined by confocal microscopy and scintigraphy. Experimental results indicate that CS/gammaPGA-DTPA NPs can promote the insulin absorption throughout the entire small intestine; the absorbed insulin was clearly identified in the kidney and bladder. In addition to producing a prolonged reduction in blood glucose levels, the oral intake of the enteric-coated capsule containing CS/gammaPGA-DTPA NPs showed a maximum insulin concentration at 4 h after treatment. The relative oral bioavailability of insulin was approximately 20%. Results of this study demonstrate the potential role for the proposed formulation in delivering therapeutic proteins by oral route. PMID- 22243803 TI - Efficient in vitro RNA interference and immunofluorescence-based phenotype analysis in a human parasitic nematode, Brugia malayi. AB - BACKGROUND: RNA interference (RNAi) is an efficient reverse genetics technique for investigating gene function in eukaryotes. The method has been widely used in model organisms, such as the free-living nematode Caenorhabditis elegans, where it has been deployed in genome-wide high throughput screens to identify genes involved in many cellular and developmental processes. However, RNAi techniques have not translated efficiently to animal parasitic nematodes that afflict humans, livestock and companion animals across the globe, creating a dependency on data tentatively inferred from C. elegans. RESULTS: We report improved and effective in vitro RNAi procedures we have developed using heterogeneous short interfering RNA (hsiRNA) mixtures that when coupled with optimized immunostaining techniques yield detailed analysis of cytological defects in the human parasitic nematode, Brugia malayi. The cellular disorganization observed in B. malayi embryos following RNAi targeting the genes encoding gamma-tubulin, and the polarity determinant protein, PAR-1, faithfully phenocopy the known defects associated with gene silencing of their C. elegans orthologs. Targeting the B. malayi cell junction protein, AJM-1 gave a similar but more severe phenotype than that observed in C. elegans. Cellular phenotypes induced by our in vitro RNAi procedure can be observed by immunofluorescence in as little as one week. CONCLUSIONS: We observed cytological defects following RNAi targeting all seven B. malayi transcripts tested and the phenotypes mirror those documented for orthologous genes in the model organism C. elegans. This highlights the reliability, effectiveness and specificity of our RNAi and immunostaining procedures. We anticipate that these techniques will be widely applicable to other important animal parasitic nematodes, which have hitherto been mostly refractory to such genetic analysis. PMID- 22243804 TI - Transcranial Doppler and cerebral augmentation in acute ischemic stroke. AB - BACKGROUND: Collateral flow augmentation using partial aortic occlusion may improve cerebral perfusion in acute stroke. We assessed the effect of partial aortic occlusion on arterial flow velocities of acute stroke patients. METHODS: Patients with neurological deficits following thrombolysis were treated with partial aortic occlusion. Transcranial Doppler ultrasound (TCD) was used to measure arterial flow velocities at baseline, before and during balloon inflation. The augmented mean flow velocity (MFV), peak systolic velocity (PSV), and end diastolic velocity flow percentages (aMFV%, aPSV%, aEDV%) were calculated and compared based on outcome. RESULTS: Of 11 patients, 3 did not have a temporal window and thus were excluded from our analysis. Six of the remaining 8 patients had middle cerebral artery (MCA) occlusions; the final 2 had terminal internal carotid artery (TICA) occlusions. Three of these 8 patients had good outcome at 90 days (mRS < 3). Before intra-aortic balloon inflation (IABI), the mean affected artery MFV was 23 +/- 11 cm/s; during the procedure it was 26 +/- 12 cm/s (P = .2). Mean affected artery PSV at baseline and during balloon inflation were 37 +/- 16 and 46 +/- 23, respectively (P = .1). Mean augmented affected artery MFV% in patients with good long-term outcome was 65.4 +/- 46, while the result in those with poor outcome was -3.7 +/- 21 (P = .03). Three patients developed anterior cross-filling, and of these 2 had good long-term outcome. CONCLUSION: TCD monitoring of patients treated with IABI may help in predicting outcome in this novel device. PMID- 22243806 TI - Central obesity as measured by waist circumference is predictive of severity of lower urinary tract symptoms. AB - Study Type - Prognosis (cohort). Level of Evidence 2a. What's known on the subject? and What does the study add? The metabolic syndrome, or Syndrome X, has traditionally been associated with an increased risk of cardiovascular disease and sexual dysfunction. Emerging data however now suggest that the metabolic syndrome may also have a heretofore unrecognized negative effect on voiding function as well. Weight loss through either behavioural modification or bariatric surgery has been shown to lead to improvement in stress and urge incontinence as well as LUTS. A potential relationship may be drawn between obesity and BPH. This study adds the knowledge that WC can represent a simple metric not only for elements of the metabolic syndrome but also for worsened voiding. These obese men may be at high risk of male pelvic dysfunction. OBJECTIVES: * To determine if central obesity as measured by waist circumference (WC) is a risk factor in metabolic dysfunction, which includes hypertension, dyslipidaemia and type 2 diabetes (DM2). * To test the hypothesis that central obesity and WC are associated with and predictive of the severity of voiding dysfunction. METHODS: * Men aged >= 40 years with moderate or severe lower urinary tract symptoms (LUTS, International Prostate Symptom Score >= 8) with no previous treatment were included for study. * Subjects were divided into three groups according to WC (<90, 90-99 and >= 100 cm). * Baseline parameters including International Prostate Symptom Score, prostate volume, serum prostate specific antigen, presence of erectile dysfunction and ejaculatory dysfunction, and the prevalence of hypertension, coronary artery disease and DM2 were compared among the three WC categories. * The association between WC and all parameters assessed was tested using multivariate logistic regression analysis. RESULTS: * In the 409 consecutive men analysed, WC was significantly and positively associated with prostate volume, serum prostate-specific antigen and International Prostate Symptom Score. * Higher WCs were also significantly associated with a greater prevalence of hypertension, coronary artery disease, DM2 and obesity as well as the presence of erectile dysfunction and ejaculatory dysfunction. CONCLUSIONS: * Increased WC is associated with worsened voiding. * There was a significantly increased prevalence of components of the metabolic syndrome in patients with higher WC. * Obese men, in particular those with other features of the metabolic syndrome, are at increased risk of male pelvic dysfunction and can be easily recognized by measurement of WC. PMID- 22243807 TI - Valproic acid up-regulates melatonin MT1 and MT2 receptors and neurotrophic factors CDNF and MANF in the rat brain. AB - We have reported that clinically relevant concentrations of valproic acid (VPA) up-regulate the G-protein-coupled melatonin MT1 receptor in rat C6 glioma cells. To determine whether this effect occurs in vivo, the effects of chronic VPA treatment on the expression of both melatonin receptor subtypes, MT1 and MT2, were examined in the rat brain. Reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR analyses revealed significant increases in MT1 and MT2 mRNA expression in the hippocampus, following VPA (4 mg/ml drinking water) treatment for 17 d. Increases in the mRNA and protein expression of the novel neurotrophic factors, conserved dopamine neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor, were detected in the hippocampus and/or striatum. In addition, significant changes in persephin, glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor mRNA expression were observed. The robust multi-fold induction of MT1 and MT2 receptors in the hippocampus suggests a role for the melatonergic system in the psychotropic effects of VPA. PMID- 22243808 TI - Spider: an R package for the analysis of species identity and evolution, with particular reference to DNA barcoding. AB - Spider: SPecies IDentity and Evolution in R is a new R package implementing a number of useful analyses for DNA barcoding studies and associated research into species delimitation and speciation. Included are functions essential for generating important summary statistics from DNA barcode data, assessing specimen identification efficacy, and for testing and optimizing divergence threshold limits. In terms of investigating evolutionary and taxonomic questions, techniques for assessing diagnostic nucleotides and probability of reciprocal monophyly are also provided. Additionally, a sliding window function offers opportunities to analyse information across a gene, essential for marker design in degraded DNA studies. Spider capitalizes on R's extensible ethos and offers an integrated platform ideal for the analysis of both nucleotide and morphological data. The program can be obtained from the comprehensive R archive network (CRAN, http://cran.r-project.org) and from the R-Forge package development site (http://spider.r-forge.r-project.org/). PMID- 22243809 TI - Situs inversus totalis: the association of Kartagener's syndrome with diffuse bronchiolitis and azoospermia. AB - Kartagener's syndrome (KS) is characterised by bronchiectasis, paranasal sinusitis and situs inversus totalis (SIT). Association of diffuse bronchiolitis (DB) with KS has been documented from Japan only. Fourteen patients with SIT were seen in one unit over 7 years. All patients underwent a similar work up which included high resolution computed-tomography (HRCT) of thorax and CT-paranasal sinuses. Semen analysis was done in 2/3 adult males. Eleven patients (6 males and 5 females) had KS while 3 adult females had SIT alone. HRCT-thorax detected bronchiectasis in 10/11 patients with KS. HRCT-thorax confirmed DB in 6/11 patients with KS. One adult male had total sperm count of 2.5 million/ml without sperm motility while the other had no sperms. This series documents the largest number of patients with SIT/KS from India and highlights for the first time, the association of DB with KS from India. PMID- 22243810 TI - A convenient method for simultaneous quantification of multiple phytohormones and metabolites: application in study of rice-bacterium interaction. AB - BACKGROUND: Simultaneous analysis of multiple functional-related phytohormones and their metabolites will improve our understanding of interactions among different hormones in the same biologic process. RESULTS: A method was developed for simultaneous quantification of multiple phytohormones, abscisic acid, indole 3-acetic acid (IAA), jasmonic acid (JA), and salicylic acid, hormone conjugates, IAA-aspartic acid, JA-isoleucine, and methyl JA, and phytoalexins, momilactone A, naringenin, and sakuranetin. This method combines a convenient procedure for preparing filtrated crude extracted samples and a sensitive quantification assay using ultra fast liquid chromatography-electrospray ionization tandem mass spectrometry (UFLC-ESI-MS). With this method, we determined the dynamic profiles of defense-related phytohormones, hormone metabolites, and phytoalexins in the interaction of rice with Xanthomonas oryzae pv. oryzae (Xoo), which causes bacterial blight, one of the most devastating diseases of rice worldwide. CONCLUSION: This UFLC-ESI-MS method is convenient, sensitive, reliable, and inexpensive for quantification of multiple phytohormones and metabolites compared to current methods. The results obtained by application of this method in studying rice-bacterial interaction provide a basis for understanding the molecular mechanisms of rice defense responses. PMID- 22243811 TI - Silicone breast implants: lessons from the USA. PMID- 22243812 TI - The continuing fight against cancer. PMID- 22243813 TI - WHO and Margaret Chan: the next 5 years. PMID- 22243814 TI - Increasing requests for vitamin D measurement: costly, confusing, and without credibility. PMID- 22243815 TI - End-of-life decisions in Argentina. PMID- 22243817 TI - Elodie Ghedin: intrepid gene hunter. PMID- 22243818 TI - Overdose deaths and Vancouver's supervised injection facility. PMID- 22243820 TI - Pelvic floor muscle training after prostate surgery. PMID- 22243821 TI - Pelvic floor muscle training after prostate surgery. PMID- 22243822 TI - Pelvic floor muscle training after prostate surgery. PMID- 22243823 TI - Pelvic floor muscle training after prostate surgery. PMID- 22243825 TI - An unusual presentation of recurrent pneumonia. PMID- 22243826 TI - Exon-skipping therapy for Duchenne muscular dystrophy. PMID- 22243829 TI - Suicide bombing: how to prevent death in civilians? PMID- 22243830 TI - Efficacy and safety of a fully covered esophageal stent: a prospective study. PMID- 22243831 TI - Jejunal tube extensions via percutaneous endoscopic gastrostomy and delayed small bowel perforations: a case series. PMID- 22243832 TI - Catheter application, insertion vein and length of ICU stay prior to insertion affect the risk of catheter-related bloodstream infection. AB - BACKGROUND: The Dutch PREZIES surveillance scheme for catheter-related bloodstream infection (CR-BSI) collects data on infection rates and related risk factors. AIM: To evaluate risk factors for CR-BSI. METHODS: Hospitals collected data for intensive care units (ICU) or for the entire hospital. All short-term central venous catheters (CVC), including Swan-Ganz catheters, present for >=48h were surveyed, except in cases when bacteraemia was present at insertion. CVCs were monitored until infection, removal or death for up to 28 days. Data were collected on 3750 CVCs and 29,003 CVC-days. FINDINGS: Of the CVCs surveyed, 1.6% [95% confidence interval (CI) 1.2-2.0] resulted in CR-BSI, representing 2.0/1000 CVC-days (95% CI 1.6-2.6). Multi-variate analysis revealed that the length of ICU stay prior to CVC insertion, insertion in the jugular or femoral vein, and use of the CVC to deliver total parenteral nutrition increased the risk of CR-BSI, whereas use of the CVC to deliver antibiotics decreased the risk of CR-BSI. CONCLUSION: Attention to these risks has the potential to reduce the incidence of CR-BSI. PMID- 22243833 TI - A DNA resequencing array for genes involved in Parkinson's disease. AB - Parkinson's disease (PD) is aetiologically complex with both familial and sporadic forms. Familial PD results from rare, highly penetrant pathogenic mutations whereas multiple variants of low penetrance may contribute to the risk of sporadic PD. Common variants implicated in PD risk appear to explain only a minor proportion of the familial clustering observed in sporadic PD. It is therefore plausible that combinations of rare and/or common variants in genes already implicated in disease pathogenesis may help to explain the genetic basis of PD. We have developed a CustomSeq Affymetrix resequencing array to enable high throughput sequencing of 13 genes (44 kb) implicated in the pathogenesis of PD. Using the array we sequenced 269 individuals, including 186 PD patients and 75 controls, achieving an overall call rate of 96.5% and 93.6%, for two respective versions of the array, and >99.9% accuracy for five samples sequenced by capillary sequencing in parallel. We identified modest associations with common variants in SNCA and LRRK2 and a trend suggestive of an overrepresentation of rare variants in cases compared to controls for several genes. We propose that this technology offers a robust and cost-effective alternative to targeted sequencing using traditional sequencing methods, and here we demonstrate the potential of this approach for either routine clinical investigation or for research studies aimed at understanding the genetic aetiology of PD. PMID- 22243834 TI - Genetic analysis of HLA-DRA region variation in Taiwanese Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder comprising both motor and cognitive disability. The pathogenesis of the disease is still unclear; however, neuroinflammation seemed to play a role. A recent genome-wide association study (GWAS) reported an association between HLA-DRA rs3129882 and the development of PD in Caucasian populations. In this study, we observe no association between this single nucleotide polymorphism and PD in a Taiwanese population. The possible reasons include different ethnicity with genomic differences and environmental factors in different geographical regions. PMID- 22243835 TI - The Q10 questionnaire for detection of wearing-off phenomena in Parkinson's disease. AB - In Parkinson's disease (PD), wearing-off can be difficult to detect as it is very variable and may affect motor and non-motor symptoms. The Wearing-Off Questionnaire, WOQ-32 (Stacy et al., 2005), was introduced to help identify wearing-off and proved to be very efficient. Two short versions of the questionnaire (WOQ-19 or QUICK and WOQ-9) were later developed to decrease the respondent burden without loss of efficacy in terms of sensitivity. The objective of the present study was to check the ability of a new 10-item QUICK version, Q10, to identify patients with wearing-off. Q10 items were selected from the QUICK validation study data set through statistical analysis and it was then tested on a sample of 162 PD patients, 64.8% with wearing-off. Sensitivity, specificity, and accuracy were 96%, 63%, and 85% respectively with one positive response and 90%, 70%, and 83% respectively with two positive responses. The correlation with the gold standard (neurologist diagnosis of wearing-off) was substantial (kappa = 0.62-0.64). Comparison with the QUICK and WOQ-9 shows that the Q10 can be a new tool for detection of wearing-off with satisfactory properties and a good balance between brevity and performance. PMID- 22243836 TI - Inulin and fructo-oligosaccharides have divergent effects on colitis and commensal microbiota in HLA-B27 transgenic rats. AB - Modulation of intestinal microbiota by non-digestible carbohydrates may reduce inflammation in inflammatory bowel disease (IBD). The aim of the present study was to assess the effects of inulin and fructo-oligosaccharides (FOS) on intestinal microbiota and colitis in HLA-B27 transgenic rats, a well-validated rodent model for IBD. In this study, 4-week-old rats were fed 8 g/kg body weight inulin or FOS for 12 weeks, or not. Faeces were collected at 4 and 16 weeks of age; and caecal samples were collected at necropsy. The effects of inulin and FOS on chronic intestinal inflammation were assessed using a gross gut score, histology score and levels of mucosal IL-1beta. Intestinal microbiota were characterised by quantitative PCR and denaturing gradient gel electrophoresis. Colitis was significantly reduced in all FOS-fed rats compared to the control diet, whereas inulin decreased chronic intestinal inflammation in only half the number of animals. Quantitative analysis of caecal microbiota demonstrated that inulin increased the numbers of total bacteria and the Bacteroides-Prevotella Porphyromonas group, FOS increased bifidobacteria, and both fructans decreased Clostridium cluster XI. In the faecal samples, both inulin and FOS decreased total bacteria, Bacteroides-Prevotella-Porphyromonas group, and Clostridium clusters XI and XIVa. FOS increased Bifidobacterium spp., and mediated a decrease of gene copies of Enterobacteriaceae and Clostridium difficile toxin B in faeces. SCFA concentrations in the faecal and caecal samples were unaffected by the diets. In conclusion, FOS increased the abundance of Bifidobacterium spp., whereas both fructans reduced Clostridium cluster XI and C. difficile toxin gene expression, correlating with a reduction of chronic intestinal inflammation. PMID- 22243838 TI - TaWIR1 contributes to post-penetration resistance to Magnaporthe oryzae, but not Blumeria graminis f. sp. tritici, in wheat. AB - Members of the Wheat-Induced Resistance 1 (TaWIR1) gene family are highly induced in response to a wide range of pathogens. Homologues have been identified in barley, but not in Brachypodium, whereas, in rice, only distant WIR1 candidates are known. Phylogenetic analysis placed TaWIR1a and TaWIR1b within a distinct clade of wheat transcripts, whereas TaWIR1c clustered with HvWIR1 genes. Transcripts of all three TaWIR1 genes were strongly induced by a wheat-adapted isolate of Magnaporthe oryzae. Virus-induced gene silencing of the TaWIR1 gene family had no effect on the initial penetration of epidermal cells by M. oryzae. However, following the establishment of an infection site, the fungus was able to grow more extensively within the leaf tissue, relative to control leaves, indicating a role for the TaWIR1 gene family in the cell-to-cell movement of M. oryzae. In contrast, the silencing of TaWIR1 transcripts had no effect on epidermal cell penetration by a wheat-adapted isolate of Blumeria graminis, or on the subsequent growth of hyphae. Differential transcription of TaWIR1 genes was also seen in epidermal peels, relative to the remaining leaf tissue, following inoculation with M. oryzae. PMID- 22243837 TI - Identification of differentially accumulated proteins associated with embryogenic and non-embryogenic calli in saffron (Crocus sativus L.). AB - BACKGROUND: Somatic embryogenesis (SE) is a complex biological process that occurs under inductive conditions and causes fully differentiated cells to be reprogrammed to an embryo like state. In order to get a better insight about molecular basis of the SE in Crocus sativus L. and to characterize differentially accumulated proteins during the process, a proteomic study based on two dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry has been carried out. RESULTS: We have compared proteome profiles of non-embryogenic and embryogenic calli with native corm explants. Total soluble proteins were phenol-extracted and loaded on 18 cm IPG strips for the first dimension and 11.5% sodium dodecyl sulfate-polyacrylamide gels for the second dimension. Fifty spots with more than 1.5-fold change in abundance were subjected to mass spectrometry analysis for further characterization. Among them 36 proteins could be identified, which are classified into defense and stress response, protein synthesis and processing, carbohydrate and energy metabolism, secondary metabolism, and nitrogen metabolism. CONCLUSION: Our results showed that diverse cellular and molecular processes were affected during somatic to embryogenic transition. Differential proteomic analysis suggests a key role for ascorbate metabolism during early stage of SE, and points to the possible role of ascorbate-glutathione cycle in establishing somatic embryos. PMID- 22243839 TI - Occupational stress. PMID- 22243840 TI - Correlation of arterial blood pressure and compliance with left ventricular structure and function in the very elderly. AB - There are very few data on the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), arterial compliance, and left ventricular structure and function, particularly left ventricular hypertrophy (LVH), in the very elderly (>75 years). SBP and arterial stiffness increase with age, and the question is: which of the two is the main stimulus to LVH? This is a cross sectional study to compare blood pressure and arterial stiffness measures with regard to their correlations with echocardiographic parameters of LV structure and function, controlling for age and cardiovascular risk factors, in a very elderly population. Arterial stiffness was determined by radial pulse waveform using pulse contour analysis. LV dimensions were measured by transthoracic M-mode echocardiography, and diastolic function by tissue Doppler measurements of diastolic mitral annular velocities. There were 179 subjects, all male, with a mean age of 81.8 years. Using age-adjusted partial correlations, SBP, DBP, and mean arterial pressure (MAP) were correlated with parameters of LV structure and function. Correlation coefficients were: SBP versus left ventricular mass index (LVMI), r = 0.246; SBP versus early diastolic mitral annular velocity (MAV), r = 0.179; DBP versus LVMI, r = 0.199; DBP versus MAV, r = -0.199; MAP versus LVMI, r = 0.276; and MAP versus MAV, r = -0.206, all with P < .05. However, neither capacitative nor reflective arterial compliance was significantly correlated with any parameter of LV structure and function. After controlling for age and 10 cardiovascular and metabolic risk factors, the correlation between blood pressure and the measured LV parameters was substantially unchanged, as was the lack of correlation between indices of arterial compliance and the LV indices. Arterial blood pressure is correlated with LV structure and function in the very elderly, but arterial stiffness, as measured by diastolic pulse contour analysis, is not. PMID- 22243841 TI - Effect of long-term equilibration on the toxicity of molybdenum to soil organisms. AB - To determine if long-term equilibration may alleviate molybdenum toxicity, earthworms, enchytraeids, collembolans and four plant species were exposed to three soils freshly spiked with Na(2)MoO(4).2H(2)O and equilibrated for 6 or 11 months in the field with free drainage. Total Mo concentrations in soil decreased by leaching, most (up to 98%) in sandy soil and less (54-62%) in silty and clayey soils. Changes in residual Mo toxicity with time were inconclusive in sandy soil. In the other two soils, toxicity of residual total Mo was significantly reduced after 11 months equilibration with a median 5.5-fold increase in ED50s. Mo fixation in soil, i.e. the decrease of soil solution Mo concentrations at equivalent residual total soil Mo, was maximally a factor of 2.1 only. This experiment shows natural attenuation of molybdate ecotoxicity under field conditions is related to leaching of excess Mo and other ions as well as to slow ageing reactions. PMID- 22243842 TI - Effects of multigenerational cadmium exposure of insects (Spodoptera exigua larvae) on anti-oxidant response in haemolymph and developmental parameters. AB - Biochemical and organismal indices of metal tolerance were studied in Spodoptera exigua exposed to a cadmium-contaminated diet for one or many (33 or 61) generations. Reduced and oxidised glutathione, protein thiols, total anti-oxidant capacity level, glutathione transferase activity, and Cd accumulation were assayed in the haemolymph of the last instar larvae. The cadmium concentration in the whole larval body as well as larval survival, larval duration time and last instar body weight were also measured. Elevated cadmium concentration in the whole body, higher mortality and longer duration of the larval stage in one generation exposed insects in comparison with those exposed for many generations suggest that metal tolerance builds over time. For the larvae from multigeneration metal treatment, the higher cadmium concentration in larval haemolymph positively correlated with glutathione oxidation and total anti oxidant capacity. One-generation exposed insects had lower metal concentration in haemolymph than did 33-generation exposed insects. PMID- 22243843 TI - Development of a methodology examining the behaviours of VOCs source apportionment with micro-meteorology analysis in an urban and industrial area. AB - During summer 2009, online measurements of 25 Volatile Organic Compounds (VOCs) from C6 to C10 as well as micro-meteorological parameters were simultaneously performed in the industrial city of Dunkerque. With the obtained data set, we developed a methodology to examine how the contributions of different source categories depend on atmospheric turbulences, and the results provided identification of emission modes. Eight factors were resolved by using Positive Matrix Factorization model and three of them were associated with mixed sources. The observed behaviours of contributions with turbulences lead to attribute some factors with sources at ground level, and some other factors with sources in the upper part of surface layer. The impact of vertical turbulence on the pollutant dispersion is also affected by the distance between sources and receptor site. PMID- 22243844 TI - Potential influence of CO2 release from a carbon capture storage site on release of trace metals from marine sediment. AB - One of the main risks of CCS (Carbon Capture and Storage) is CO(2) leakage from a storage site. The influence of CO(2) leakage on trace metals leaching from contaminated marine sediment in a potential storage area (Northern Spain) is addressed using standardized leaching tests. The influence of the pH of the leaching solution on the leachates is evaluated using deionized water, natural seawater and acidified seawater at pH = 5, 6 and 7, obtained by CO(2) bubbling. Equilibrium leaching tests (EN 12457) were performed at different liquid-solid ratios and the results of ANC/BNC leaching test (CEN/TS 15364) were modeled using Visual Minteq. Equilibrium tests gave values of the final pH for all seawater leachates between 7 and 8 due to the high acid neutralization capacity of the sediment. Combining leaching test results and geochemical modeling provided insight in the mechanisms and prediction of trace metals leaching in acidified seawater environment. PMID- 22243845 TI - Comparative tissue and body compartment accumulation and maternal transfer to eggs of perfluoroalkyl sulfonates and carboxylates in Great Lakes herring gulls. AB - The comparative accumulation of C(4)-C(15) perfluorinated sulfonates (PFSAs) and carboxylates (PFCAs), and several precursors (e.g., perfluorooctane sulfonamide, N-methyl-FOSA, and fluorotelomer unsaturated acids and alcohols) was examined in tissues (liver, brain, muscle, and adipose), plasma/red blood cells (RBCs) and whole egg clutches (yolk and albumen) of female herring gulls collected in 2010 from Chantry Island, Lake Huron of the Laurentian Great Lakes. Highest mean ?PFSA concentrations were in yolk, followed by adipose, liver, plasma, muscle, RBCs, and brain. Highest mean ?PFCA concentrations were in yolk, followed by brain, plasma, liver, RBC, adipose and muscle. PFOS accounted for >88% of ?PFSA in all samples; the liver, plasma/RBCs, muscle and adipose PFCA patterns were dominated by C(8)-C(11) PFCAs, whereas C(10)-C(15) PFCAs in brain and yolk. Among PFSAs and PFCAs there is tissue-specific accumulation, which could be due to a number of pharmacokinetic processes. PMID- 22243846 TI - Preliminary insights into delta15N and delta18O of nitrate in natural mosses: a new application of the denitrifier method. AB - Natural mosses have been employed as reactive and accumulative indicators of atmospheric pollutants. Using the denitrifier method, the concentration, delta(15)N and delta(18)O of moss nitrate (NO(3)(-)) were measured to elucidate the sources of NO(3)(-) trapped in natural mosses. Oven drying at 55-70 degrees C, not lyophilization, was recommended to dry mosses for NO(3)(-) analyses. An investigation from urban to mountain sites in western Tokyo suggested that moss [NO(3)(-)] can respond to NO(3)(-) availability in different habitats. NO(3)(-) in terricolous mosses showed isotopic ratios as close to those of soil NO(3)(-), reflecting the utilization of soil NO(3)(-). Isotopic signatures of NO(3)(-) in corticolous and epilithic mosses elucidated atmospheric NO(3)(-) sources and strength from the urban (vehicle NO(x) emission) to mountain area (wet-deposition NO(3)(-)). However, mechanisms and isotopic effects of moss NO(3)(-) utilization must be further verified to enable the application of moss NO(3)(-) isotopes for source identification. PMID- 22243848 TI - Fluorescent characteristics and metal binding properties of individual molecular weight fractions in municipal solid waste leachate. AB - Molecular weight (MW) is a fundamental property of dissolved organic matter (DOM), which potentially affects the binding behavior between DOM and metals. Here, a combined approach of ultrafiltration fractionation, fluorescence excitation-emission matrix quenching and parallel factor analysis (PARAFAC) was employed to elucidate fluorescent characteristics and metal binding properties of individual MW fractions of DOM in landfill leachate. Four humic-like and two protein-like components were identified by PARAFAC. Among them, a fulvic acid like component was found to be responsible for Cd(II) binding while Cu(II) inclined to complex with humic-like components rather than protein-like ones. Apart from that, MW was found to exert less influence on metal binding than that of specific metals or components. Key components distributed within various fractions of DOM were the main influence on the impact of MW on metal binding. PMID- 22243847 TI - Investigation of antibiotics in mollusks from coastal waters in the Bohai Sea of China. AB - This study focused on the presence and distribution of 22 antibiotics, including eight quinolones, nine sulfonamides and five macrolides in mollusks from the Bohai Sea of China. 190 samples of eleven species were collected in 2006, 2007 and 2009. Laboratory analyses revealed that antibiotics were widely distributed in the mollusks with quinolones as the major compounds with concentrations of 0.71~1575.10 MUg/kg, which were up to two orders of magnitude higher than those of sulfonamides (0~76.75 MUg/kg) and macrolides (0~36.21 MUg/kg). The contents of quinolones and macrolides did not show significant changes from 2006, 2007 to 2009, while sulfonamides decreased significantly from 2006 to 2009. Compared with other sites, the city of Dalian was more polluted with quinolones, while Beidaihe was more contaminated with erythromycin and sulfapyridine. In addition, Mactra veneriformis and Meretrix merehjgntrix Linnaeus contained higher concentrations of quinolones and sulfamonomethoxine, while Mytilus edulis had higher levels of erythromycin and sulfapyridine. PMID- 22243849 TI - Ozone weekend effect in Santiago, Chile. AB - The study examined weekday-weekend differences in ozone, NO(x) (NO and NO(2)) and VOC concentrations in Santiago, Chile, from 1999 to 2007. The results provide evidence for the occurrence of an atmospheric phenomenon that produces higher ozone concentrations during weekends despite lower concentrations of ozone precursors. This phenomenon is known as the weekend effect (WE). The overall ozone decrease since the spring of 2004 was a consequence of the implementation of several urban pollution control measures. Although these measures caused a decline in the number of days that exceed the national standard from two-thirds to one-third of summer days, the WE, which became statistically significant beginning in September 2004, could not be eliminated. Furthermore, VOC/NO(x) ratios decreased during the same period (2004), especially in the most industrialized area of Santiago. Similarly, under these regimes, the VOC/NO(x) ratios were higher on Sundays than on weekdays and caused higher ozone concentrations on Sundays. PMID- 22243850 TI - Indicating atmospheric sulfur by means of S-isotope in leaves of the plane, osmanthus and camphor trees. AB - Foliar delta(34)S values of three soil-growing plant species (Platanus Orientalis L., Osmanthus fragrans L. and Cinnamomum camphora) have been analyzed to indicate atmospheric sulfur. The foliar delta(34)S values of the three plant species averaged -3.11+/-1.940/00, similar to those of both soil sulfur (-3.73+/ 1.040/00) and rainwater sulfate (-3.07+/-2.740/00). This may indicate that little isotopic fractionation had taken place in the process of sulfur uptake by root or leaves. The delta(34)S values changed little in the transition from mature leaves to old/senescing leaves for both the plane tree and the osmanthus tree, suggestive of little isotope effect during sulfur redistribution in plant tissues. Significantly linear correlation between delta(34)S values of leaves and rainwater sulfate for the plane and osmanthus trees allowed the tracing of temporal variations of atmospheric sulfur by means of foliar sulfur isotope, while foliage delta(34)S values of the camphor is not an effective indicator of atmospheric sulfur. PMID- 22243851 TI - Development of aquatic life criteria for nitrobenzene in China. AB - Nitrobenzene is a toxic pollutant and was the main compound involved in the Songhuajiang accident in 2007, one of the largest water pollution accidents in China in the last decade. No aquatic life criteria for nitrobenzene have previously been proposed. In this study, published toxicity data of nitrobenzene to Chinese aquatic species were gathered, and six resident Chinese aquatic organisms were used in toxicity tests to supplement the existing toxicity data for nitrobenzene. Seventeen genuses mean acute values, three genuses mean chronic values to freshwater aquatic animals, and six genus toxicity values to aquatic plants were collected in total. A criterion maximum concentration of 0.018 mg/L and a criterion continuous concentration of 0.001 mg/L were developed based on these data, according to the U.S. Environmental Protection Agency guidelines. These criteria may be useful in the determination of water quality standard of nitrobenzene. PMID- 22243852 TI - Toxicity assessment of simulated urban runoff containing polycyclic musks and cadmium in Carassius auratus using oxidative stress biomarkers. AB - The objective of this study was to assess potential toxic effects of simulated urban runoff on Carassius auratus using oxidative stress biomarkers. The activity of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), and the content of malondialdehyde (MDA) in the liver of C. auratus were analyzed after a 7-, 14- and 21-day exposure to simulated urban runoff containing galaxolide (HHCB) and cadmium (Cd). The results showed that the activity of antioxidant enzymes and the content of MDA increased significantly exposed to the simulated urban runoff containing HHCB alone or mixture of HHCB and Cd. The activity of the investigated enzymes and the content of MDA then returned to the blank level over a longer period of exposure. The oxidative stress could be obviously caused in the liver of C. auratus under the experimental conditions. This could provide useful information for toxic risk assessment of urban runoff. PMID- 22243853 TI - Distribution of antibiotic resistance in urban watershed in Japan. AB - Antibiotic-resistant E. coli concentrations showed large spatial and temporal variations, with greater concentrations observed in tributaries and downstream than in the upstream and midstream. Twenty percent of the geometric mean concentrations of antibiotic-resistant E. coli in the Tama River basin (Japan) exceeded the maximum acceptable concentration of indicator E. coli established by the USEPA. The indicator E. coli concentrations were positively correlated with those of antibiotic-resistant E. coli and multiple-antibiotic-resistant E. coli (resistance to more than two kinds of antibiotics), respectively, but not the detection rate of antibiotic-resistant E. coli, implying that use of antibiotic resistant E. coli concentration rather than the detection rate can be a better approach for water quality assessment. Multiple-antibiotic-resistant E. coli is a useful indicator for estimating the resistance diffusion, water quality degradation and public health risk potential. This assessment provides beneficial information for setting national regulatory or environmental standards and managing integrated watershed areas. PMID- 22243854 TI - The functional response of a freshwater benthic community to cadmium pollution. AB - Theory predicts that in freshwater communities under chemical stress secondary production will decrease while the rate of biomass turnover (P/B) will increase. However, this concept has never been tested on organisms of smaller size (bacteria, protozoans, small metazoans), although they form the basis of the heterotrophic food web. The present work describes the results of a 7-month microcosm study, in which the effects of low and high toxic stress on an entire sediment community were examined, with cadmium (Cd) as the model pollutant (50 and 400mg Cd kg(-1) dry sediment). While metazoans and protozoans generally followed the expected trend, in bacteria both production and P/B decreased under Cd stress. These observations provide new insights into the functioning of freshwater ecosystems and demonstrate the functional consequences of toxicants on biological systems. PMID- 22243855 TI - PAH diagnostic ratios for the identification of pollution emission sources. AB - Polycyclic aromatic hydrocarbon (PAH) diagnostic ratios have recently come into common use as a tool for identifying and assessing pollution emission sources. Some diagnostic ratios are based on parent PAHs, others on the proportions of alkyl-substituted to non-substituted molecules. The ratios are applicable to PAHs determined in different environmental media: air (gas + particle phase), water, sediment, soil, as well as biomonitor organisms such as leaves or coniferous needles, and mussels. These ratios distinguish PAH pollution originating from petroleum products, petroleum combustion and biomass or coal burning. The compounds involved in each ratio have the same molar mass, so it is assumed they have similar physicochemical properties. Numerous studies show that diagnostic ratios change in value to different extents during phase transfers and environmental degradation. The paper reviews applications of diagnostic ratios, comments on their use and specifies their limitations. PMID- 22243856 TI - Pollutant plume delineation from tree core sampling using standardized ranks. AB - There are currently contradicting results in the literature about the way chloroethene (CE) concentrations from tree core sampling correlate with those from groundwater measurements. This paper addresses this issue by focusing on groundwater and tree core datasets in CE contaminated site, Czech Republic. Preliminary analyses revealed strongly and positively skewed distributions for the tree core dataset, with an intra-tree variability accounting for more than 80% of the total variability, while the spatial analyses based on variograms indicated no obvious spatial pattern for CE concentration. Using rank transformation, it is shown how the results were improved by revealing the initially hidden spatial structure for both variables when they are handled separately. However, bivariate analyses based on cross-covariance functions still failed to indicate a clear spatial correlation between groundwater and tree core measurements. Nonetheless, tree core sampling and analysis proved to be a quick and inexpensive semi-quantitative method and a useful tool. PMID- 22243857 TI - Composting of waste paint sludge containing melamine resin as affected by nutrients and gypsum addition and microbial inoculation. AB - Melamine formaldehyde resins have hard and durable properties and are found in many products, including automobile paints. These resins contain high concentrations of nitrogen and, if properly composted, can yield valuable products. We evaluated the effects of starter compost, nutrients, gypsum and microbial inoculation on composting of paint sludge containing melamine resin. A bench-scale composting experiment was conducted at 55 degrees C for 91 days and then at 30 degrees C for an additional 56 days. After 91 days, the composts were inoculated with a mixed population of melamine-degrading microorganisms. Melamine resin degradation after the entire 147 days of composting varied between 73 and 95% for the treatments with inoculation of microorganisms compared to 55-74% for the treatments without inoculation. Degradation was also enhanced by nutrients and gypsum additions. Our results infer that large scale composting of melamine resins in paint sludge is possible. PMID- 22243858 TI - Long-term persistence of polychlorinated dibenzo-p-dioxins and dibenzofurans in air, soil and sediment around an abandoned pentachlorophenol factory in China. AB - Air, soils and sediments surrounding an abandoned pentachlorophenol (PCP) factory were sampled to determine the levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), unintentionally formed during PCP production. The mean concentration of PCDD/Fs in ambient air was one order of magnitude higher than that of the reference site. A trend of decreasing concentrations with increasing distance from the factory was observed, suggesting this site has a significant influence on the regional ambient air. As for soil samples collected within 3 km from the factory and sediment samples from the adjacent rivers, high levels of contamination were found with WHO-TEQ concentrations of 193 +/- 211 pg/g and 667 +/- 978 pg/g, respectively. The PCDD/F homologue profiles of all samples were consistent with those found in the technical product of PCP, with OCDD as the dominant congener. These results indicate PCDD/Fs in the historical contaminated site pose a long-term impact on surrounding environment. PMID- 22243859 TI - Indoor and outdoor poly- and perfluoroalkyl substances (PFASs) in Korea determined by passive air sampler. AB - Despite concerns to their increasing contribution to ecological and human exposure, the atmospheric levels of poly- and perfluoroalkyl substances (PFASs) have been determined mainly in Europe and North America. This study presents the indoor and outdoor air concentrations of volatile PFASs [fluorotelomer alcohols (FTOHs), and perfluoroalkyl sulfonamides/sulfonamidoethanols/sulfonamide ethyl acetate (FOSAs/FOSEs/FOSEA)] for the first time in Korean cities. In contrast to the good agreement observed for indoor FTOHs levels in Korea and Europea/North America, FOSAs/FOSEs levels were 10-100-fold lower in Korean indoor air, representing a cultural difference of indoor source. Korean outdoor air contained higher PFAS levels than indoor air, and additionally showed different PFAS composition profile from indoor air. Thus, indoor air would not likely be a main contributor to atmospheric PFAS contamination in Korea, in contrast to western countries. Inhalation exposure of volatile PFASs was estimated to be a minor contributor to PFOA and PFOS exposure in Korea. PMID- 22243860 TI - Chromate removal as influenced by the structural changes of soil components upon carbonization at different temperatures. AB - Surface fire could induce heat transferring into the soil, creating a carbonized environment, which may alter the chemical compositions of soil organic matters (SOM). In the study, a surface soil was carbonized at up to 600 degrees C with limited air to simulate soils experiencing a surface fire, and Cr(VI) removal on the carbonized soils was investigated. NMR and FTIR analyses demonstrated a remarkable change of SOM structures at 300-400 degrees C. TGA-MS spectra indicated that (e.g. C(2)H(4), CH(3)OH and C(3)H(8)) were the major components in the evolved gases from the pyrolyzed soil. A maximum amount of Cr(VI) removal (ca. 4 mg g(-1) soil) occurred for the 200 degrees C-carbonized soils, attributed mainly to a significant increase of Cr(VI) reduction by 0.1 M KCl extractable organic carbon (EOC) with abundant carboxylic groups. Nonetheless, the formation of aromatic C upon carbonization of the soil at >400 degrees C may be responsible for Cr(VI) reduction. PMID- 22243861 TI - Continental scale inverse modeling of common organic water contaminants in European rivers. AB - The paper presents an analysis of measured riverine concentrations of 16 common organic water contaminants. From observed concentrations we back-calculate emissions and chemical half lives through a simple inverse model. The analysis does not allow identifying a single half life/emission factor combination, but a set of combinations which are Pareto-optimal (or "non-dominated"). The approach is shown to provide a rational basis for the screening of chemicals in rivers: with reference to the 16 chemicals considered here, estimated emission factors and half lives are consistent with the ones reported in other studies. For more precise estimates, prior knowledge about either emission factors or half lives is necessary. For the considered chemicals, loads to European seas can be subsequently estimated with an uncertainty usually within a factor of 2. The approach can be proposed for the inventorying of catchment-specific chemical pollutant emissions required for European environmental policies. PMID- 22243862 TI - Assessment of N and P status at the landscape scale using environmental models and measurements. AB - We assessed the compliance of a Dutch landscape, dominated by dairy farming, with environmental quality standards using a combination of model calculations and measurements. The total ammonia emission of 2.4 kton NH(3) yr(-1) does not exceed the environmental quality standard (2.6 kton NH(3) yr(-1)). Nevertheless, the total N deposition (on average 24.4 kg N ha(-1) yr(-1)) is such that critical N loads are exceeded at 53% of the nature areas. The deposited N mainly results from non-agricultural sources and agricultural sources outside the area (72%). The calculated average NO(3)(-) concentration in the upper groundwater does not exceed the 50 mg l(-1) threshold. Calculated annual average N-total and P-total concentrations in discharge water are relatively high but these cannot be directly compared with thresholds for surface water. The results suggest that compliance monitoring at the landscape scale needs to include source indicators and cannot be based on state indicators alone. PMID- 22243863 TI - Investigating a high ozone episode in a rural mountain site. AB - A very high ozone episode with observed hourly values above 350 MUg m(-3) occurred in July 2005 at the Lamas d'Olo air quality monitoring station, located in a mountainous area in the north of Portugal. Aiming to identify the origin and formation of this ozone-rich episode, a statistical analysis and a modelling approach were applied. A cross-spectrum analysis in the frequency domain and a synoptic analysis of the meteorological and air quality time series were performed. In order to go further in this analysis, a numerical modelling approach was applied. The results indicate that the transport of ozone and its precursors is the main responsible for the high ozone concentrations. Together with the local mountain breeze and subsidence conditions, the sea-breeze circulation transporting pollutants from the coastal urban and industrialized areas that reach the site during late afternoon turn out to be the driving forces for the ozone peaks. PMID- 22243865 TI - Reducing total mercury and methylmercury accumulation in rice grains through water management and deliberate selection of rice cultivars. AB - Rice consumption has been identified as a major route of methylmercury (MeHg) exposure in some areas of inland China. We investigated two potential mitigation methods (water management and deliberate selection of rice cultivars) to reduce the amount of total mercury (Hg) and MeHg within the grain. Rice grown aerobically had markedly reduced total Hg and MeHg concentrations as well as a much lower proportion of MeHg in the grain. Remarkably, there were considerable variations in the total Hg and MeHg concentrations as well as the proportion of MeHg in the grain among the 24 cultivars grown in the same paddy soil. The Hg tolerance index (expressed as % mean of control root growth) also varied substantially among the different cultivars. Furthermore, negative correlations were found between the total Hg and MeHg concentrations (P<0.05) of grain and the proportion of MeHg in the grain (P<0.01). PMID- 22243866 TI - Increased atmospheric deposition of mercury in reference lakes near major urban areas. AB - Atmospheric deposition of Hg is the predominant pathway for Hg to reach sensitive ecosystems, but the importance of emissions on near-field deposition remains unclear. To better understand spatial variability in Hg deposition, mercury concentrations were analyzed in sediment cores from 12 lakes with undeveloped watersheds near to (<50 km) and remote from (>150 km) several major urban areas in the United States. Background and focusing corrected Hg fluxes and flux ratios (modern to background) in the near-urban lakes (68 +/- 6.9 MUg m(-2) yr(-1) and 9.8 +/- 4.8, respectively) greatly exceed those in the remote lakes (14 +/- 9.3 MUg m(-2) yr(-1) and 3.5 +/- 1.0) and the fluxes are strongly related to distance from the nearest major urban area (r(2) = 0.87) and to population and Hg emissions within 50-100 km of the lakes. Comparison to monitored wet deposition suggests that dry deposition is a major contributor of Hg to lakes near major urban areas. PMID- 22243864 TI - The contribution of microbial mats to the arsenic geochemistry of an ancient gold mine. AB - The ancient Zloty Stok (SW Poland) gold mine is such an environment, where different microbial communities, able to utilize inorganic arsenic species As(III) and As(V), are found. The purpose of the present study was to (i) estimate prokaryotic diversity in the microbial mats in bottom sediments of this gold mine, (ii) identify microorganisms that can metabolize arsenic, and (iii) estimate their potential role in the arsenic geochemistry of the mine and in the environment. The oxidation/reduction experiments showed that the microbial mat community may significantly contribute to arsenic contamination in groundwater. The presence of both arsenite oxidizing and dissimilatory arsenate reducing bacteria in the mat was confirmed by the detection of arsenite oxidase and dissimilatory arsenate reductase genes, respectively. This work also demonstrated that microorganisms utilizing other compounds that naturally co-occur with arsenic are present within the microbial mat community and may contribute to the arsenic geochemistry in the environment. PMID- 22243867 TI - Bioaccumulation of Fe2O3(magnetic) nanoparticles in Ceriodaphnia dubia. AB - While nano-Fe(2)O(3)(magnetic) is generally considered non-toxic, it could serve as a carrier of other toxic chemicals such as As(V) and enhance their toxicity. The bioaccumulation of nano-Fe(2)O(3)(m) with different exposure times, NP concentrations, and pH conditions was investigated using Ceriodaphnia dubia (C. dubia) as the model organism. Under natural pH conditions, C. dubia significantly accumulated nano-Fe(2)O(3)(m) in the gut, with the maximum accumulation being achieved after 6 h of exposure. The concentration of nano-Fe(2)O(3) also impacted its accumulation, with the maximum uptake occurring at 20 mg/L or more. In addition, the highest bioaccumulation occurred in a pH range of 7-8 where the highest feeding rate was reported, confirming that the ingestion of NPs is the main route of nano-Fe(2)O(3)(m) bioaccumulation. In a clean environment without NPs, depuration of nano-Fe(2)O(3)(m) occurred, and food addition accelerated the depuration process. PMID- 22243868 TI - Modelling nitrous oxide emissions from grazed grassland systems. AB - Grazed grassland systems are an important component of the global carbon cycle and also influence global climate change through their emissions of nitrous oxide and methane. However, there are huge uncertainties and challenges in the development and parameterisation of process-based models for grazed grassland systems because of the wide diversity of vegetation and impacts of grazing animals. A process-based biogeochemistry model, DeNitrification-DeComposition (DNDC), has been modified to describe N(2)O emissions for the UK from regional conditions. This paper reports a new development of UK-DNDC in which the animal grazing practices were modified to track their contributions to the soil nitrogen (N) biogeochemistry. The new version of UK-DNDC was tested against datasets of N(2)O fluxes measured at three contrasting field sites. The results showed that the responses of the model to changes in grazing parameters were generally in agreement with observations, showing that N(2)O emissions increased as the grazing intensity increased. PMID- 22243869 TI - Parasitism can be a confounding factor in assessing the response of zebra mussels to water contamination. AB - Biological responses measured in aquatic organisms to monitor environmental pollution could be also affected by different biotic and abiotic factors. Among these environmental factors, parasitism has often been neglected even if infection by parasites is very frequent. In the present field investigation, the parasite infra-communities and zebra mussel biological responses were studied up- and downstream a waste water treatment plant in northeast France. In both sites, mussels were infected by ciliates and/or intracellular bacteria, but prevalence rates and infection intensities were different according to the habitat. Concerning the biological responses differences were observed related to the site quality and the infection status. Parasitism affects both systems but seemed to depend mainly on environmental conditions. The influence of parasites is not constant, but remains important to consider it as a potential confounding factor in ecotoxicological studies. This study also emphasizes the interesting use of integrative indexes to synthesize data set. PMID- 22243870 TI - Arsenic in cooked rice: effect of chemical, enzymatic and microbial processes on bioaccessibility and speciation in the human gastrointestinal tract. AB - Rice, used as staple food for half of the world population, can easily accumulate arsenic (As) into its grain, which often leads to As contamination. The health risk induced by presence of As in food depends on its release from the food matrix, i.e., its bioaccessibility. Using an in vitro gastrointestinal simulator, we incubated two types of cooked rice (total As: 0.389 and 0.314 mg/kg). Arsenic bioaccessibility and speciation changes were determined upon gastrointestinal digestion. Washing with deionized water and cooking did not result in changes of As speciation in the rice although the arsenic content dropped by 7.1-20.6%. Arsenic bioaccessibility of the cooked rice in the small intestine ranged between 38 and 57%. Bioaccessibility slightly increased during digestion in the simulated small intestine and decreased with time in the simulated colon. Significant speciation changes were noted in the simulated colon, with trivalent monomethylarsonate (MMA(III)) becoming an important species. PMID- 22243871 TI - Ecotoxicology and macroecology--time for integration. AB - Despite considerable progress in ecotoxicology, it has become clear that this discipline cannot answer its central questions, such as, "What are the effects of toxicants on biodiversity?" and "How the ecosystem functions and services are affected by the toxicants?". We argue that if such questions are to be answered, a paradigm shift is needed. The current bottom-up approach of ecotoxicology that implies the use of small-scale experiments to predict effects on the entire ecosystems and landscapes should be merged with a top-down macroecological approach that is directly focused on ecological effects at large spatial scales and consider ecological systems as integral entities. Analysis of the existing methods in ecotoxicology, ecology, and environmental chemistry shows that such integration is currently possible. Therefore, we conclude that to tackle the current pressing challenges, ecotoxicology has to progress using both the bottom up and top-down approaches, similar to digging a tunnel from both ends at once. PMID- 22243872 TI - Adsorption of mercury on lignin: combined surface complexation modeling and X-ray absorption spectroscopy studies. AB - Adsorption of mercury (Hg) on lignin was studied at a range of pH values using a combination of batch adsorption experiments, a surface complexation model (SCM) and synchrotron X-ray absorption spectroscopy (XAS). Surface complexation modeling indicates that three types of acid sites on lignin surfaces, namely aliphatic carboxylic-, aromatic carboxylic- and phenolic-type surface groups, contributed to Hg(II) adsorption. The bond distance and coordination number of Hg(II) adsorption samples at pH 3.0, 4.0 and 5.5 were obtained from extended X ray absorption fine structure (EXAFS) spectroscopy analysis. The results of SCM and XAS combined reveal that the predominant adsorption species of Hg(II) on lignin changes from HgCl(2)(0) to monodentate complex -C-O-HgCl and then bidentate complex -C-O-Hg-O-C- with increasing pH value from 2.0 to 6.0. The good agreement between SCM and XAS results provides new insight into understanding the mechanisms of Hg(II) adsorption on lignin. PMID- 22243873 TI - Polybrominated diphenyl ethers and decabromodiphenylethane in sediments from twelve lakes in China. AB - Sediment cores from 12 Chinese lakes were analyzed to investigate the historical inputs of polybrominated diphenyl ethers (PBDEs) and decabromodiphenylethane (DBDPE) during the past few decades. Concentrations of SigmaPBDE(1) (sum of tri- to hepta-BDEs), SigmaPBDE(2) (sum of nona- to deca-BDEs) and DBDPE in the surface sediments were 0.02-0.29 ng g(-1), 0.46-46.6 ng g(-1) and 1.02-3.64 ng g(-1), respectively. The temporal trends of PBDEs and DBDPE followed a general increase from the bottom to the surface. The calculated fluxes for SigmaPBDE(1), SigmaPBDE(2) and DBDPE were 0.001-0.09, 0.03-4.24, and 0.05-0.31 ng cm(-2) yr( 1), and the inventories were 0.09-7.86, 0.91-461, and 3.83-24.6 ng cm(-2), respectively. The urbanization and industrialization are highly related to the contamination of PBDEs and DBDPE in sediments. The DBDPE input in recent years was still lower than SigmaPBDE(2) but the temporal trends indicated that the contamination would increase with the increasing usage of DBDPE in the future. PMID- 22243874 TI - Regional variation and possible sources of brominated contaminants in breast milk from Japan. AB - This study focuses on the regional trends and possible sources of brominated organic contaminants accumulated in breast milk from mothers in southeastern (Okinawa) and northwestern (Hokkaido) areas of Japan. For persistent brominated flame retardants, polybrominated diphenyl ethers (PBDEs; major components, BDE-47 and BDE-153) were distributed at higher levels in mothers from Okinawa (mean, 2.1 ng/g lipid), while hexabromobenzene (HeBB) and its metabolite 1,2,4,5 tetrabromobenzene were more abundantly detected in mothers from Hokkaido (0.86 and 2.6 ng/g lipid), suggesting that there are regional differences in their exposure in Japan. We also detected naturally produced brominated compounds, one of which was identified as 2'-methoxy-2,3',4,5'-tetrabromodiphenyl ether (2'-MeO BDE68) at higher levels in mothers from Okinawa (0.39 ng/g lipid), while the other was identified as 3,3',4,4'-tetrabromo-5,5'-dichloro-2,2'-dimethyl-1,1' bipyrrole in mothers from Hokkaido (0.45 ng/g lipid). The regional variation may be caused by source differences, i.e. southern seafood for MeO-PBDEs and northern biota for halogenated bipyrroles in the Japanese coastal water. PMID- 22243875 TI - Ozone uptake by adult urban trees based on sap flow measurement. AB - The O(3) uptake in 17 adult trees of six urban species was evaluated by the sap flow-based approach under free atmospheric conditions. The results showed very large species differences in ground area scaled whole-tree ozone uptake (F(o)3), with estimates ranging from 0.61 +/- 0.07 nmol m(-2) s(-1) in Robinia pseudoacacia to 4.80 +/- 1.04 nmol m(-2) s(-1) in Magnolia liliiflora. However, average F(o)3by deciduous foliages was not significantly higher than that by evergreen ones (3.13 vs 2.21 nmol m(-2) s(-1), p = 0.160). Species of high canopy conductance for O(3) (G(o)3) took up more O(3) than those of low G(o)3, but that their sensitivity to vapour pressure deficit (D) were also higher, and their F(o)3decreased faster with increasing D, regardless of species. The responses of F(o)3to D and total radiation led to the relative high flux of O(3) uptake, indicating high ozone risk for urban tree species. PMID- 22243876 TI - Freely dissolved PBDEs in water and porewater of an urban estuary. AB - Polyethylene passive samplers (PE) were deployed in Narragansett Bay, RI, to examine freely dissolved concentrations of polybrominated diphenyl ethers (PBDEs) in surface, bottom, and sediment porewater. PBDE congeners in the water column and porewater were below 3 pg L(-1). In the surface water, only PBDE congeners containing up to 5 bromines were detected, while in the deeper water congeners 153 and 154 (6 bromines) were also detected. Activity ratios of surface-bottom water and porewater-bottom water suggested that lower brominated (di-tetra) congeners reached Narragansett Bay from surface waters and sediments. PBDEs in the surface water probably originated from a combination of air-water exchange, freshwater runoff, rivers, and wastewater treatment plants. It is suggested that deep water was the source of higher brominated PBDEs to the Bay implying that the more hydrophobic PBDEs reached depth on particles and/or that these congeners were degraded in sediments. On-going sources supply PBDEs to Narragansett Bay. PMID- 22243878 TI - Dechlorination of p,p'-DDTs coupled with sulfate reduction by novel sulfate reducing bacterium Clostridium sp. BXM. AB - A novel non-dsrAB (without dissimilatory sulfite reductase genes) sulfate reducing bacterium (SRB) Clostridium sp. BXM was isolated from a paddy soil. Incubation experiments were then performed to investigate the formation of reduced sulfur compounds (RSC) by Clostridium sp. BXM, and RSC-induced dechlorination of p,p'-DDT in culture medium and soil solution. The RSCs produced were 5.8 mM and 4.5 mM in 28 mM sulfate amended medium and soil solution respectively after 28-day cultivation. The p,p'-DDT dechlorination ratios were 74% and 45.8% for 5.8mM and 4.5 mM RSCs respectively at 6h. The metabolites of p,p'-DDT found in the two reaction systems were identified as p,p'-DDD and p,p' DDE. The dechlorination pathways of p,p'-DDT to p,p'-DDD and p,p'-DDE were proposed, based on mass balance and dechlorination time-courses. The results indicated that RSC-induced natural dechlorination may play an important role in the fate of organochlorines. PMID- 22243877 TI - Using a two site-reactive model for simulating one century changes of Zn and Pb concentration profiles in soils affected by metallurgical fallout. AB - Predicting the transfer of contaminants in soils is often hampered by lacking validation of mathematical models. Here, we applied Hydrus-2D software to three agricultural soils for simulating the 1900-2005 changes of zinc and lead concentration profiles derived from industrial atmospheric deposition, to validate the tested models with plausible assumptions on past metal inputs to reach the 2005 situation. The models were set with data from previous studies on the geochemical background, estimated temporal metal deposition, and the 2005 metal distributions. Different hypotheses of chemical reactions of metals with the soil solution were examined: 100% equilibrium or partial equilibrium, parameterized following kinetic chemical extractions. Finally, a two-site model with kinetic constant values adjusted at 1% of EDTA extraction parameters satisfactory predicted changes in metal concentration profiles for two arable soils. For a grassland soil however, this model showed limited applicability by ignoring the role of earthworm activity in metal incorporation. PMID- 22243879 TI - Diffuse urban pollution increases metal tolerance of natural heterotrophic biofilms. AB - This study is a first attempt to investigate the impact of urban contamination on metal tolerance of heterotrophic river biofilms using a short-term test based on beta-glucosidase activity. Tolerance levels to Cu, Cd, Zn, Ni and Pb were evaluated for biofilms collected at three sites along an urban gradient in the Seine river (France). Metallic pollution increased along the river, but concentrations remained low compared to environmental quality standards. Biofilm metal tolerance increased downstream from the urban area. Multivariate analysis confirmed the correlation between tolerance and contamination and between multi metallic and physico-chemical gradients. Therefore, tolerance levels have to be interpreted in relation to the whole chemical and physical characteristics and not solely metal exposure. We conclude that community tolerance is a sensitive biological response to urban pressure and that mixtures of contaminants at levels lower than quality standards might have a significant impact on periphytic communities. PMID- 22243880 TI - Hydrogen fluoride damage to vegetation from peri-urban brick kilns in Asia: a growing but unrecognised problem? AB - The rapid urbanisation of many cities in south and south-east Asia has increased the demand for bricks, which are typically supplied from brick kilns in peri urban areas. We report visible foliar damage to mango, apricot and plum trees in the vicinity of traditional Bull's Trench brick kilns in Peshawar, Pakistan. Visible injury symptoms, hydrogen fluoride concentrations in air, and foliar fluoride concentrations were all greater in the vicinity of brick kilns than at more distant sites, indicating that fluoride emissions from brick kilns were the main cause of damage. Interviews with local farmers established the significant impact of this damage on their livelihoods. Since poorly regulated brick kilns are often found close to important peri-urban agricultural areas, we suggest that this may be a growing but unrecognised environmental problem in regions of Asia where emission control in brick kilns has not been improved. PMID- 22243882 TI - Dorsi-ventral leaf reflectance properties of Carpinus betulus L.: an indicator of urban habitat quality. AB - The objective of this paper is to give an account of the evaluation of the effect of urban habitat quality on dorsi-ventral leaf reflectance asymmetry to bio monitor urban habitat pollution. Reflectance in the RGB bands of a reflex camera is measured at the adaxial and abaxial sides of Carpinus betulus L. leaves for two contrasting urban habitats, e.g.; suburban green and industrial habitats in the city of Gent (Belgium). Abaxial leaf reflectance is consistently higher than adaxial leaf reflectance. We quantified leaf dorsi-ventral reflectance asymmetry with a newly defined Normalized Dorsi-ventral Asymmetry Index (NDAI). The NDAI is significantly higher in industrial habitats as opposed to suburban green ones. Our optical observations indicate that changes in Carpinus betulus L. leaf morphology are related to urban habitat quality. Hence, we suggest that leaf dorsi-ventral reflectance asymmetry allows the estimation of the magnitude and spatial extent of environmental pollution in urban environments. PMID- 22243881 TI - Biological effects and bioaccumulation of steroidal and phenolic endocrine disrupting chemicals in high-back crucian carp exposed to wastewater treatment plant effluents. AB - Endocrine disrupting chemicals (EDCs) found in wastewater treatment plant (WWTP) effluents have been shown to cause adverse effects, but the uptake of EDCs from effluents (measured in fish muscle) are not known. In this study, the biological effects and bioaccumulation of steroidal and phenolic EDCs were assessed in high back crucian carp (Carassius auratus) exposed to WWTP effluents for 141 days. Compared with fish controls caged in Dianchi Lake, a significant reduction in gonadosomatic index (GSI) and increase in hepatosomatic index (HSI) and plasma vitellogenin (VTG) levels were observed in effluent-exposed fish. The concentrations of steroids and phenols in effluent-exposed fish showed time dependent increase during the exposure. In addition, bioconcentration factors (BCFs) for steroids and phenols were between 17 and 59 on day 141. The results confirm that steroids and phenols bioconcentrate in fish muscle and this accumulation may account for the biological effects associated with exposures to WWTP effluents. PMID- 22243883 TI - Regionalization of soil base cation weathering for evaluating stream water acidification in the Appalachian Mountains, USA. AB - Estimation of base cation supply from mineral weathering (BC(w)) is useful for watershed research and management. Existing regional approaches for estimating BC(w) require generalized assumptions and availability of stream chemistry data. We developed an approach for estimating BC(w) using regionally specific empirical relationships. The dynamic model MAGIC was used to calibrate BC(w) in 92 watersheds distributed across three ecoregions. Empirical relationships between MAGIC-simulated BC(w) and watershed characteristics were developed to provide the basis for regionalization of BC(w) throughout the entire study region. BC(w) estimates extracted from MAGIC calibrations compared reasonably well with BC(w) estimated by regression based on landscape characteristics. Approximately one third of the study region was predicted to exhibit BC(w) rates less than 100 meq/m(2)/yr. Estimates were especially low for some locations within national park and wilderness areas. The regional BC(w) results are discussed in the context of critical loads (CLs) of acidic deposition for aquatic ecosystem protection. PMID- 22243885 TI - Canopy interaction with precipitation and sulphur deposition in two boreal forests of Quebec, Canada. AB - The interaction of atmospheric sulphur (S) was investigated within the canopies of two boreal forests in Quebec, Canada. The net canopy exchange approach, i.e. the difference between S-SO(4) in throughfall and precipitation, suggests high proportion of dry deposition in winter (up to 53%) as compared to summer (1-9%). However, a 3.50/00 decrease in delta(18)O-SO(4) throughfall in summer compared to incident precipitation points towards a much larger proportion of dry deposition during the warm season. We suggest that a significant fraction of dry deposition (about 1.2 kg ha(-1) yr(-1), representing 30-40% of annual wet S deposition) which contributed to the decreased delta(18)O-SO(4) in throughfall was taken up by the canopy. Overall, these results showed that, contrary to what is commonly considered, S interchanges in the canopy could be important in boreal forests with low absolute atmospheric S depositions. PMID- 22243886 TI - Nitrate leaching, direct and indirect nitrous oxide fluxes from sloping cropland in the purple soil area, southwestern China. AB - This study provides a combined dataset on N loss pathways and fluxes from sloping cropland in the purple soil area, southwestern China. A lysimeter experiment was conducted to quantify nitrate leaching (May 2004-May 2010) and N(2)O emission (May 2009-May 2010) losses. Nitrate leaching was the dominant N loss pathway and annual leaching fluxes ranged from 19.2 to 53.4 kg N ha(-1), with significant differences between individual observation years (P < 0.05). Direct N(2)O emissions due to N fertilizer use were 1.72 +/- 0.34 kg N ha(-1) yr(-1), which corresponds to an emission factor of 0.58 +/- 0.12%. However, indirect N(2)O emissions caused by nitrate leaching and surface runoff N losses, may contribute another 0.15-0.42 kg N ha(-1) yr(-1). Our study shows that nitrate leaching lowered direct N(2)O emissions, highlighting the importance for a better understanding of the tradeoff between direct and indirect N(2)O emissions for the development of meaningful N(2)O emission strategies. PMID- 22243887 TI - Effects of silicon on the distribution of cadmium compartmentation in root tips of Kandelia obovata (S., L.) Yong. AB - The Effects of silicon (Si) on the distribution of cadmium (Cd) compartmentation in root tips of Kandelia obovata (S., L.) Yong were investigated by pot experiments. Cd concentrations in the apoplastic saps and symplastic fractions of the root tips of K. obovata seedlings were decreased at both Si-supplied treatments. Si addition reduced the concentrations of BaCl(2-)extractable cell wall-Cd in root tips, but increased the concentrations of Na(3)citrate extractable cell-wall-Cd and HCl-extractable cell-wall-Cd in root tips. The total root-tip contents of Cd were mainly distributed in the apoplast and most of the Cd in the apoplast was bound to the cell wall. Our experiment found that Si increased the ratio of apoplast Cd (>87.08%) and reduced the ratio of Cd in the symplast (<12.92%). This suggested that Si enhanced binding of Cd to the cell walls and restricted the apoplastic transport of Cd. PMID- 22243888 TI - Changes in hydrocarbon groups, soil ecotoxicity and microbiology along horizontal and vertical contamination gradients in an old landfarming field for oil refinery waste. AB - Horizontal and vertical contaminant gradients in an old landfarming field for oil refinery waste were characterised with the aim to assess parallel changes in hydrocarbon groups and general, microbiological and ecotoxicological soil characteristics. In the surface soil polar compounds were the most prevalent fraction of heptane-extractable hydrocarbons, superseding GC-FID-resolvable and high-molar-mass aliphatics and aromatics, but there was no indication of their relatively higher mobility or toxicity. The size of the polar fraction correlated poorly with soil physical, chemical and microbiological properties, which were better explained by the total heptane-extractable and total petroleum hydrocarbons (TPH). Deleterious effects on soil microbiology in situ were observed at surprisingly low TPH concentrations (0.3%). Due to the accumulation of polar and complexed degradation products, TPH seems an insufficient measure to assess the quality and monitor the remediation of soil with weathered hydrocarbon contamination. PMID- 22243889 TI - Brominated flame retardants in three terrestrial passerine birds from South China: geographical pattern and implication for potential sources. AB - Polybrominated diphenyl ethers (PBDEs), decabromodiphenyl ethane (DBDPE), polybrominated biphenyls (PBBs) and pentabromotoluene (PBT) were investigated in light-vented bulbul (LVB), long-tailed shrike (LTS) and oriental magpie-robin (OMR) collected from seven sampling sites in South China. ?PBDEs, DBDPE, PBB 153, and PBT levels ranged from 35 to 15,000, no detected (nd)-130, nd-6800, and nd 6.8 ng/g lipid weight, respectively. Positive correlations were found between delta(15)N values and brominated flame retardant (BFR) concentrations. The BFR geographic pattern indicated that PBDEs were linked to e-waste recycling and local industry activities as well as urbanization; PBB 153 was derived from e waste; DBDPE was mainly come from local industry activities; and no specific source was observed for PBT. PBDE congener profiles were found to be depended on bird species and sampling sites with relatively high abundances of lower brominated congeners in e-waste site and significantly higher abundance of BDE153 in LTS and OMR than in LVB. PMID- 22243884 TI - Betaproteobacteria dominance and diversity shifts in the bacterial community of a PAH-contaminated soil exposed to phenanthrene. AB - In this study, the PAH-degrading bacteria of a constructed wetland collecting road runoff has been studied through DNA stable isotope probing. Microcosms were spiked with (13)C-phenanthrene at 34 or 337 ppm, and bacterial diversity was monitored over a 14-day period. At 337 ppm, PAH degraders became dominated after 5 days by Betaproteobacteria, including novel Acidovorax, Rhodoferax and Hydrogenophaga members, and unknown bacteria related to Rhodocyclaceae. The prevalence of Betaproteobacteria was further demonstrated by phylum-specific quantitative PCR, and was correlated with a burst of phenanthrene mineralization. Striking shifts in the population of degraders were observed after most of the phenanthrene had been removed. Soil exposed to 34 ppm phenanthrene showed a similar population of degraders, albeit only after 14 days. Results demonstrate that specific Betaproteobacteria are involved in the main response to soil PAH contamination, and illustrate the potential of SIP approaches to investigate PAH biodegradation in soil. PMID- 22243890 TI - Does consumption of leafy vegetables grown in peri-urban agriculture pose a risk to human health? AB - Concentrations of potentially toxic elements were measured in soils and five contrasting tropical leafy vegetables grown in a replicated field trial at five contaminated urban agriculture sites in Kampala City, Uganda. Soil contamination at each site could be tentatively ascribed to known waste disposal practices. There was considerable variation in metal uptake between vegetable types. Washing leafy vegetables reduced chromium and lead concentrations but exogenous contamination of leaves also depended on vegetable type, with Gynandropsis gynandra L. showing a marked tendency to accumulate Pb and Cr. For the worst case scenario of children consuming unwashed vegetables, some metal 'hazard quotient' (HQ) limits (1.0) were violated at four of the five sites studied. For the 25 'site-vegetable' combinations assessed, the HQ for Pb exceeded 1.0 in 36% of cases. A vegetable-specific site screening tool based on soil extraction with 0.01 M CaCl(2) and extrapolation to provide HQ values was assessed. PMID- 22243891 TI - The effect of EDTA, NTA and picolinic acid on Th(IV) mobility in a ternary system with natural sand. AB - Organic complexing agents, such as ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA) and picolinic acid, have been widely used at nuclear sites and are therefore found as common co-contaminants in radioactive contaminated land. This study has explored the mechanisms by which these three complexing agents affect the sorption of Th(IV) to pure silica and a natural sand. EDTA, NTA and, to a lesser extent, picolinic acid decreased the sorption of Th to silica, demonstrating the formation and solubility of Th complexes. However, Th sorption to sand was kinetically controlled and complexation enhanced the rate of Th sorption. EDTA and NTA did not sorb significantly to the sand, and metal desorption indicated that the mechanism involved exchange with sand associated metals. At equilibrium, however, Th sorption was not affected by the presence of the ligands, and modelling suggested that the interaction between Th and the surface binding sites controlled Th sorption thermodynamically. PMID- 22243892 TI - Tissue-specific assimilation, depuration and toxicity of nickel in Mytilus edulis. AB - The tissue-specific accumulation and time-dependent depuration of radioactive (63)Ni by the byssus, gut, foot, gills, kidney, adductor muscle and faeces of Mytilus edulis has been investigated using a pulse-chase technique. The rate and extent of depuration of (63)Ni varied between tissues and, after 168 h, the concentration factors and assimilation efficiencies ranged from 1 to 35 L kg(-1) and 5%-13%, respectively. Mussels were also exposed to a range of environmentally realistic concentrations of dissolved Ni, prior to the analysis of biological endpoints. The clearance rate was concentration-dependent and at the highest concentration decreased by 30%. Neutral red retention (NRR) assays indicated a cytotoxic response and DNA strand breaks were observed in the haemocytes. The association of DNA damage with that of physiological and cytotoxic effects suggests that Ni exerts a significant impact on Mytilus edulis at cellular and genetic levels. PMID- 22243893 TI - Evaluation of dissipation gradients of polycyclic aromatic hydrocarbons in rice rhizosphere utilizing a sequential extraction procedure. AB - The aim of this study was to evaluate the spatial dissipation gradient of PAHs, including phenanthrene, pyrene, and benzo[a]pyrene, with various bioavailability represented with sequential extraction. Dissipation rates of PAHs in the rhizosphere were greater than those in the bulk soil. The n-butanol extracted fraction showed a general trend of dissipation during phytoremediation. Moreover, the formation of bound PAH residues was inhibited in the rhizosphere. While concerning the PAH toxicity, the reduction rates of PAH toxicity were significantly greater than total soil PAH concentrations. Microbial biomass was the highest at four mm away from the root surface. However, the PAH dissipation rates were the highest at one mm and two mm away from the root surface in high and low PAH treatments, respectively. These results suggest that rhizoremediation with rice is a useful approach to reduce the toxicity of PAHs in soil. PMID- 22243894 TI - Quality of roof-harvested rainwater--comparison of different roofing materials. AB - The objective of the study reported in this paper was to assess the quality of harvested rainwater on the basis of the roofing materials used and the presence of lichens/mosses on the roofing surface. Four pilot structures with different roofing materials (i.e., wooden shingle tiles, concrete tiles, clay tiles [Gi-Wa] and galvanized steel) were installed in a field. The galvanized steel was found to be the most suitable for rainwater harvesting applications, with their resulting physical and chemical water quality parameters meeting the Korean guidelines for drinking water quality (e.g., pH (5.8-8.5), TSS <500 mg/L, NO(3)( ) < 10 mg/L, SO(4)(2-) < 200 mg/L, Al < 0.2 mg/L, Cu < 1 mg/L, Fe < 0.3 mg/L, Pb < 0.05 mg/L, Zn < 1 mg/L, and E. coli (No detection)). In the galvanized steel case, the relatively high water quality was probably due to ultraviolet light and the high temperature effectively disinfecting the harvested rainwater. It was also found that the presence of lichens and mosses may adversely affect the physical, chemical and microbiological quality of rainwater. PMID- 22243895 TI - DNA-damage effect of polycyclic aromatic hydrocarbons from urban area, evaluated in lung fibroblast cultures. AB - This study was designed to biomonitor the effect of PAH extracts from urban areas on the DNA of lung cell cultures. The analyses of the polycyclic aromatic hydrocarbons (PAHs) were performed in atmospheric PM(2.5) and PM(10) collected at three sampling sites with heavy traffic located in the Metropolitan Area of Porto Alegre (MAPA) (Brazil). The concentrations of 16 major PAHs were determined according to EPA. Comet assay on V79 hamster lung cells was chosen for genotoxicity evaluation. Temperature, humidity, and wind speed were recorded. With regard to the damage index, higher levels were reported in the extract of particulate matter samples from the MAPA during the summer. High molecular weight compounds showed correlation with DNA damage frequency and their respective carcinogenicity. PMID- 22243896 TI - Does mercury contamination reduce body condition of endangered California clapper rails? AB - We examined mercury exposure in 133 endangered California clapper rails (Rallus longirostris obsoletus) within tidal marsh habitats of San Francisco Bay, California from 2006 to 2010. Mean total mercury concentrations were 0.56 MUg/g ww in blood (range: 0.15-1.43), 9.87 MUg/g fw in head feathers (3.37-22.0), 9.04 MUg/g fw in breast feathers (3.68-20.2), and 0.57 MUg/g fww in abandoned eggs (0.15-2.70). We recaptured 21 clapper rails and most had low within-individual variation in mercury. Differences in mercury concentrations were largely attributed to tidal marsh site, with some evidence for year and quadratic date effects. Mercury concentrations in feathers were correlated with blood, and slopes differed between sexes (R(2) = 0.58-0.76). Body condition was negatively related to mercury concentrations. Model averaged estimates indicated a potential decrease in body mass of 20-22 g (5-7%) over the observed range of mercury concentrations. Our results indicate the potential for detrimental effects of mercury contamination on endangered California clapper rails in tidal marsh habitats. PMID- 22243897 TI - Longitudinal study comparing the dynamics of Clostridium difficile in conventional and antimicrobial free pigs at farm and slaughter. AB - Clostridium difficile is the leading cause of nosocomial diarrhea in humans and a major cause of enteritis in neonatal piglets, foals and calves. The aim of this longitudinal study was to determine and compare the prevalence, antimicrobial susceptibility, and toxinotype profiles of C. difficile isolated from pigs and their environment in the indoor conventional and outdoor antimicrobial free (ABF) production systems. Ten conventional and eight ABF cohorts of 35 pigs each and their environment were sampled at different stages of production at farm and slaughter. C. difficile prevalence in pigs was highest at the farrowing stage in both conventional (34%, 120/350) and ABF (23%, 56/244) systems, and decreased with age. This reduction in C. difficile prevalence in pigs at later stages of production mirrored the decreased prevalence in the farm environment. At slaughter, C. difficile was isolated at a low frequency from the carcasses and processing environment in both production systems. All but three isolates were resistant to ciprofloxacin (99%, 505/508), while 1.0% (5/508) and 6.0% (23/508) of isolates exhibited resistance to tetracycline and erythromycin, respectively. Toxinotype V (tcdA(+)tcdB(+)) was the predominant strain identified in both systems (conventional: 94%, 376/401; ABF: 82%, 88/107), while the rest were toxinotype XIII (tcdA(+)tcdB(+)). To conclude, we isolated antimicrobial resistant C. difficile regardless of antimicrobial use on the farm. Based on the phenotypic and genotypic similarity of C. difficile isolated in this study, we conclude that the unique production practices employed in conventional and ABF production systems have no impact on the pathogen population. PMID- 22243898 TI - The antiviral defense mechanisms in mandarin fish induced by DNA vaccination against a rhabdovirus. AB - Plasmid DNAs containing Siniperca chuatsi rhabdovirus (SCRV) glycoprotein gene (pcDNA-G) and nucleoprotein gene (pcDNA-N) were constructed, and used to determine the antiviral immune response elicited by DNA vaccination in mandarin fish. In vitro and in vivo expression of the plasmid constructs was confirmed in transfected cells and muscle tissues of vaccinated fish by Western blot, indirect immunofluorescence or RT-PCR analysis. Fish injected with pcDNA-G exhibited protective effect against SCRV challenge with a relative percent survival (RPS) of 77.5%, but no significant protection (RPS of 2.5%) was observed in fish vaccinated with pcDNA-N. Immunohistochemical analysis showed that vaccination with pcDNA-G decreased histological lesions and suppressed the virus replication in fish target organs, e.g. kidney, liver, spleen, gill and heart. Transcriptional analysis further revealed that the expression levels of type I IFN system genes including interferon regulation factor-7 (IRF-7) gene, myxovirus resistance (Mx) gene and virus inhibitory protein (Viperin) gene were strongly up regulated after injection with pcDNA-G, whereas the level of transcription of immunoglobulin M (IgM) gene did not show a statistically significant change. These results reveal that type I IFN antiviral immune response is rapidly triggered by the plasmid DNA containing rhabdovirus glycoprotein gene in fish, which offers an explanation of molecular mechanisms for DNA vaccination inducing mandarin fish resist to SCRV disease. PMID- 22243900 TI - Partnerships for progress in active living: from research to action. PMID- 22243899 TI - Influence of membrane ion channel in pituitary somatotrophs by hypothalamic regulators. AB - The secretion of growth hormone (GH) from somatotrophs located within the anterior pituitary gland is stimulated by endogenous hypothalamic growth hormone releasing hormone (GHRH) and the GH secretagogue (GHS) ghrelin, and inhibited by somatotropin-releasing inhibitory factor (SRIF, also known as somatostatin). These factors bind to specific G-protein-coupled receptors on the cell membrane, and directly or indirectly modify the properties of ion channels and second messenger systems. Ultimately this results in a change in intracellular free Ca(2+) concentration ([Ca(2+)](i)) and the secretion of GH. Somatotrophs possess a variety of ion channels on their membranes, and modification of these ion channels, especially Ca(2+), K(+), and Na(+) channels, is tightly linked to intracellular Ca(2+) levels and therefore hormone secretion. Various issues regarding receptor distribution, role of ion channels, alteration of membrane potential, and involvement of intracellular signaling system in the control of GH secretion are discussed in this review. In particular, this work will focus on ion channels and [Ca(2+)](i) in somatotrophs. PMID- 22243901 TI - Developing and implementing the Active Design Guidelines in New York City. AB - Physical inactivity is a leading cause of death in the United States and globally and is also associated with several additional leading causes of death, including obesity, high blood pressure and high blood glucose. The built environment plays a critical role in promoting or discouraging physical activity among adults and children. To create a healthier and more physically active city, a working group comprising several New York City agencies, including the Departments of Design and Construction, Health and Mental Hygiene, Transportation and City Planning, and in collaboration with design organizations and academics, published the Active Design Guidelines (ADG; ) in January 2010. The ADG is a manual of evidence-based and best-practice strategies for increasing physical activity in the design and construction of neighborhoods, streets and buildings. The commentary discusses key activities and events leading up to the publication as well as current implementation activities. It also shares the lessons learned that could assist other communities interested in improving their built environments in developing and implementing similar activities and initiatives. PMID- 22243902 TI - The impact of state safe routes to school-related laws on active travel to school policies and practices in U.S. elementary schools. AB - This study examined the relationship between state laws requiring minimum bussing distances, hazardous route exemptions, sidewalks, crossing guards, speed zones, and traffic control measures around schools and active travel to school (ATS) policies/practices in nationally representative samples of U.S. public elementary schools between 2007-2009. The state laws and school data were compiled through primary legal research and annual mail-back surveys of principals, respectively. Multivariate logistic and zero-inflated poisson regression indicated that all state law categories (except for sidewalks) relate to ATS. These laws should be considered in addition to formal safe routes to school programs as possible influences on ATS. PMID- 22243903 TI - Program practices and demographic factors associated with federal funding for the Safe Routes to School program in the United States. AB - In 2005, the United States Congress authorized $612 million for use in implementing the US Safe Routes to School program to address physical inactivity, air quality, safety and traffic near schools. Each US state developed administrative practices to implement the program. Based on state-specific annual obligations, on average, states have obligated 44% of available funds. State project obligations were directly associated with programmatic factors, including broader adherence to federal agency administrative guidance objectives and the number of years for which the states obligated new projects and indirectly associated with student enrollment and state child poverty. Research and policy recommendations are discussed. PMID- 22243904 TI - Impact of a pilot walking school bus intervention on children's pedestrian safety behaviors: a pilot study. AB - Walking school buses (WSB) increased children's physical activity, but impact on pedestrian safety behaviors (PSB) is unknown. We tested the feasibility of a protocol evaluating changes to PSB during a WSB program. Outcomes were school level street crossing PSB prior to (Time 1) and during weeks 4-5 (Time 2) of the WSB. The protocol collected 1252 observations at Time 1 and 2548 at Time 2. Mixed model analyses yielded: intervention schoolchildren had 5-fold higher odds (p<0.01) of crossing at the corner/crosswalk but 5-fold lower odds (p<0.01) of stopping at the curb. The protocol appears feasible for documenting changes to school-level PSB. PMID- 22243905 TI - Impact and cost-effectiveness of family Fitness Zones: a natural experiment in urban public parks. AB - We evaluated the impact of outdoor exercise equipment (FZ, Fitness Zones) in 12 parks serving diverse populations. We used the System for Observing Play and Recreation in Communities (SOPARC) to assess use and estimate energy expenditure prior to and twice after FZ installation. Park use increased more in FZ parks than in 10 control parks that did not get equipment, but the difference was not statistically significant. However, self-reports of being a new park user increased more in FZ parks, and estimated energy expenditure in FZ parks was higher at both follow-ups than at baseline. Installing Fitness Zones appears to be cost-effective (10.5 cents/MET increase) and most successful in parks in densely populated areas with limited facilities. Longer-term follow-up measures are needed to determine if the early increases in physical activity associated with the Fitness Zone installations are sustained. PMID- 22243906 TI - A study of community design, greenness, and physical activity in children using satellite, GPS and accelerometer data. AB - This study examined relationships between greenness exposure and free-living physical activity behavior of children in smart growth and conventionally designed communities. Normalized Difference Vegetation Index (NDVI) was used to quantify children's (n=208) greenness exposure at 30-s epoch accelerometer and GPS data points. A generalized linear mixed model with a kernel density smoothing term for addressing spatial autocorrelation was fit to analyze residential neighborhood activity data. Excluding activity at home and during school-hours, an epoch-level analysis found momentary greenness exposure was positively associated with the likelihood of contemporaneous moderate-to-vigorous physical activity (MVPA). This association was stronger for smart growth residents who experienced a 39% increase in odds of MVPA for a 10th to 90th percentile increase in exposure to greenness (OR=1.39, 95% CI 1.36-1.44). An individual-level analysis found children who experienced >20 min of daily exposure to greener spaces (>90th percentile) engaged in nearly 5 times the daily rate of MVPA of children with nearly zero daily exposure to greener spaces (95% CI 3.09-7.20). PMID- 22243907 TI - Neighborhood factors influence physical activity among African American and Hispanic or Latina women. AB - This study investigated the relationship between neighborhood street-scale elements, such as traffic lights and crossing aids, and physical activity (PA) adoption and maintenance in African American and Hispanic or Latina women. Women (N=309) participated in a 6-month intervention and completed baseline and post intervention assessments of PA. Trained field assessors completed the Pedestrian Environment Data Scan in participants' neighborhoods. Adjusted linear regression models found attractiveness for bicycling significantly predicted post intervention accelerometer-measured PA. Greater traffic control devices and crossing aids were associated with greater PA among women assigned to the PA intervention group, and greater street amenities were associated with greater PA among those in the comparison group. Neighborhood factors may interact favorably with behavioral interventions to promote PA adoption and maintenance, and should be considered in health promotion efforts. PMID- 22243908 TI - Hispanic maternal and children's perceptions of neighborhood safety related to walking and cycling. AB - This study examined neighborhood safety as perceived by children (mean age=10 years) and their mothers, and its association with children's physical activity. For all eight safety items examined, children perceived their environment as less dangerous than mothers (p<0.05). None of the multiple regression models predicting children's physical activity by safety perceptions were significant (p>0.10). The maternal perception model explained the highest percentage of variance (R(2)=0.26), compared to the children's perception model (R(2)=0.22). Findings suggest that future studies should explore relations between self reported and objectively measured safety barriers to Hispanic youth walking and cycling. PMID- 22243909 TI - Investigating the impact of a smart growth community on the contexts of children's physical activity using Ecological Momentary Assessment. AB - This quasi-experimental research used Ecological Momentary Assessment with electronic surveys delivered through mobile phones to determine whether children change the type of contexts (i.e., settings) where they engage in physical activity after a recent move to a smart growth (SG) community in the U.S. as compared to children living in conventional low-to-medium density U.S. suburban communities (controls). SG vs. control children engaged in a greater proportion of physical activity bouts with friends, a few blocks from home, and at locations to which they walked. Over six months, the proportion of physical activity bouts reported at home (indoors) and in high traffic locations decreased among SG but not control children. Six-month increases in daily moderate-to-vigorous physical activity did not significantly differ by group. Children might have altered the type of contexts where they engage in physical activity after moving to SG communities, yet more time may be necessary for these changes to impact overall physical activity. PMID- 22243910 TI - Page Avenue health impact assessment: building on diverse partnerships and evidence to promote a healthy community. AB - The Page Avenue health impact assessment (HIA) was focused on a redevelopment in Missouri. This case study describes a comprehensive HIA led by an interdisciplinary academic team with community partners, as well as compliance with North American HIA Practice Standards. Some of the key lessons learned included: (1) interdisciplinary teams are valuable but they require flexibility and organization; (2) engaging community stakeholders and decision-makers prior to, during, and following the HIA is critical to a successful HIA; and (3) HIA teams should not be too closely affiliated with decision-makers. It is hoped that this case study will inform future HIAs. PMID- 22243911 TI - Exploring walking differences by socioeconomic status using a spatial agent-based model. AB - We use an exploratory agent-based model of adults' walking behavior within a city to examine the possible impact of interventions on socioeconomic differences in walking. Simulated results show that for persons of low socioeconomic status, increases in walking resulting from increases in their positive attitude towards walking may diminish over time if other features of the environment are not conducive to walking. Similarly, improving the safety level for the lower SES neighborhoods may be effective in increasing walking, however, the magnitude of its effectiveness varies by levels of land use mix, such that effects of safety are greatest when persons live in areas with a large mix of uses. PMID- 22243913 TI - Diverse viewpoints on partnerships for active living research and action. PMID- 22243912 TI - Toward environments and policies that promote injury-free active living--it wouldn't hurt. AB - Although being active is vital to the health and well-being of children, increases in physical activity can lead to an elevated risk of injury, which is a leading cause of childhood mortality globally. This article provides an overview of the evidence base concerning unintentional injuries associated with popular forms of physical activities for youth, and describes how injury prevention and child obesity professionals can work together to prevent injuries while promoting active lifestyles. Policy and environmental interventions that are beneficial to both outcomes are highlighted and recommendations for future research for these complementary areas are also provided. PMID- 22243914 TI - Active living research: partnerships that count. AB - There is growing recognition that partnerships with policy-makers and practitioners are critical, if active living research has any chance of being translated into policy and practice. These partnerships provide researchers insight into policy-relevant research questions; create an appetite for the research findings amongst policy-makers; and help create 'champions' for the research who can assist in advocating for the findings to be translated. Drawing on experience, this commentary describes partnerships that have worked in Australia, and reflects on lessons that have contributed to success. PMID- 22243915 TI - The role of partnerships in promoting physical activity: the experience of Agita Sao Paulo. AB - Strategic partnership is a logical approach to face some of the public health problems. However, its application is somewhat more complex. In this paper our experience with three networks (Agita Sao Paulo, Physical Activity Network of Americas, and Agita Mundo Network) was described. In the case of Agita Sao Paulo even the name was a consequence of a partnership with a marketing company, and is an idiomatic expression that means much more than just to move your body. It also means to move psychologically and socially, with the concept of "active citizenship". Among the important features of that intervention, we highlighted: (a) national and international intellectual partnership; (b) strong institutional partnerships, including government in one hand, and non-governmental and private sector in the other hand, in a so called: "two-hats approach"; (c) minimal formalization/maximal flexibility; (d) a signed letter of agreement: an active symbol of institutional commitment; (e) use the "mobile management" adaptation of the ecological model, in which attention was given to intrapersonal, social, and physical environmental factors, in a dynamic way; (f) attention to inter-sectoral as well as to intra-sectoral partners, in which creates incentives for participation of more than one representative from each sector; (g) the inclusion principle, that was not restricted to the institution, but affected the program actions, materials, and particularly the messages; (h) a high level of legitimacy of the coordination institution in the leadership; (i) special attention to improve environment supports for physical activity, such as: strategic partnerships established with the Metro System, that serves over 1 million persons/day; the Truck Drivers Radio Station; the State Secretariat of Environment, that built a walking path around its main building; the city of Sao Caetano do Sul, with the healthy sidewalk program; the city of Santana do Parnaiba building a walking path around the outpatients clinic, as well as the establishment of a fitness room in the basic unit of health; and Sorocaba, a city of 600,000 inhabitants, that after 4 years of the program of building walk and bike pathways, and parks, found a decrease in hospitalization of 50% by stroke, and 57% of diabetes type 2. A recent paper has shown that sedendarism has declined relatively about 70% from 2002 to 2008 in the State of Sao Paulo, and World Bank has reported that Agita represents a saving of 310 million US dollars per year in the health sector of Sao Paulo. All this scenario strongly suggests that the social issue in the developing countries facilitates the success of strategic partnerships. PMID- 22243916 TI - 3T magnetic resonance neurography of tibial nerve pathologies. AB - Diagnosis of tibial neuropathy has been traditionally based on clinical examination and electrodiagnostic studies; however, cross-sectional imaging modalities have been used to increase the diagnostic accuracy and provide anatomic mapping of the abnormalities. In this context, magnetic resonance neurography (MRN) offers high-resolution imaging of the tibial nerve (TN), its branches and the adjacent soft tissues, and provides an objective assessment of the neuromuscular anatomy, abnormality, and the surrounding pathology. This review describes the pathologies affecting the TN and illustrates their respective 3 Tesla (T) MRN appearances with relevant case examples. PMID- 22243918 TI - Acute myocardial infarction for thrombotic occlusion in patient with elevated coagulation factor VIII. PMID- 22243919 TI - Evidence of alphaherpesvirus infections in Alaskan caribou and reindeer. AB - BACKGROUND: The reindeer (Rangifer tarandus tarandus) industry in Alaska began with animals imported from Siberia (Russia) in the 1890's. Cervid herpes virus 2 (CvHV2) is endemic in reindeer in Scandinavia. We sought to determine if the same virus, or similar herpesviruses, were circulating in Alaskan reindeer and caribou (Rangifer tarandus granti). Serum samples from 292 reindeer were collected during annual reindeer handlings (1988-2005) near Nome, Alaska. In 2005, swab samples were collected from 40 calves from this herd, near Nome, Alaska. In 2007, ocular and nasal swab samples were collected from 30 apparently healthy reindeer calves near Wales, Alaska. Samples of plasma and white blood cells were collected from three Alaskan caribou herds, Mulchatna (n = 24), Teshekpuk (n = 34) and the Western Arctic (n = 87) in 2009. RESULTS: Of 292 reindeer samples tested by ELISA for antibodies against alphaherpesvirus (bovine herpesvirus 1 as antigen), seroprevalence was 47% (136/292) and adult reindeer had higher seroprevalence than yearlings. The overall seroprevalence for caribou was 60% (87/145), with no significant differences among caribou herds. A virus neutralization test of 20 samples from both reindeer and caribou showed that ELISA positive samples always neutralized CvHV2 to a greater extent than BoHV1 or elk herpesvirus (ElkHV), indicating that CvHv2 is the most likely virus circulating. PCR of nasal and ocular swabs sampled from 30 reindeer calves in Wales, Alaska (2007) yielded four CvHV2 positive samples. PCR amplicons of the expected size (294 bp) were obtained from 2 of the 36 buffy coats samples from caribou, and the amplicon sequences were consistent with CvHV2. CONCLUSIONS: This study shows that Alaskan reindeer and Caribou are infected with an alphaherpesvirus. Based on sequence similarity, CvHV-2 is the most likely virus. Further studies should be conducted to determine the impact of this infection on the health of these animals. PMID- 22243921 TI - Medical home and pediatric primary care utilization among children with special health care needs. AB - INTRODUCTION: The medical home model seeks to improve health care delivery by enhancing primary care. This study examined the relationship between the presence of a medical home and pediatric primary care office visits by children with special health care needs (CSHCN) using the data from 2005-2006 National Survey of Children with Special Healthcare Needs. METHOD: Survey logistic regression was used to analyze the relationship. RESULTS: When CSHCN age, gender, ethnicity/race, functional status, insurance status, household education, residence, and income were included in the model, CSHCN with a medical home were 1.6 times more likely to have six or more annual pediatric primary care office visits than were children without a medical home [odds ratio = 1.60, 95% confidence interval = (1.47, 1.75)]. Female CSHCN, younger CSHCN, children with public health insurance, children with severe functional limitations, and CSHCN living in rural areas also were more likely to have a larger number of visits. DISCUSSION: By controlling for child sociodemographic characteristics, this study provides empirical evidence about how medical home availability affects primary care utilization by CSHCN. PMID- 22243922 TI - Childhood obesity and dental caries in homeless children. AB - INTRODUCTION: Childhood obesity and dental caries are increasing epidemics, especially among children who are living below the poverty level. This study was conducted to determine the relationship between body mass index (BMI) and caries in homeless children. METHODS: A secondary data analysis with a correlational design was used. A convenience sample of 157 children was recruited from a homeless shelter. RESULTS: Pearson's and partial correlations were used to explore the relationships among age, BMI, and caries. Most of the children were girls and were African American. Slightly more than half of the children were overweight (19.7%) or obese (30.6%) and had caries (50.3%). Significant positive correlations between age and BMI (p = .03) as well as between age and caries (p = .003) were found. As BMI increased, so did caries (p = .08). DISCUSSION: Consistent with reports from the Centers for Disease Control and Prevention, homeless children had higher BMI and caries rates than the national averages. Although a definitive conclusion between obesity and dental caries cannot be drawn, these two health issues are important areas for all pediatric health care providers to address at every visit. PMID- 22243920 TI - R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes. AB - BACKGROUND: Toll-like receptors (TLR) 7 and 8 are important in single-stranded viral RNA recognition and may play a role in HIV infection and disease progression. We analyzed TLR7/8 expression and signaling in monocytes from HIV infected and uninfected subjects to investigate a pathway with new potential for the suppression of HIV replication. METHODS: Eighty-one HIV-infected and uninfected subjects from Liaoning and Henan provinces in China participated in this study. Monocytes were isolated from subjects' peripheral blood mononuclear cells by magnetic bead selection. TLR7 and TLR8 mRNA was measured using quantitative real-time reverse transcriptase PCR. R-848 (resiquimod) was used as a ligand for TLR7 and TLR8 in order to 1) assess TLR7/8-mediated monocyte responsiveness as indicated by IL-12 p40 and TNF-alpha secretion and 2) to examine HIV replication in cultured monocytes in the presence of R-848. RESULTS: We found that expression of TLR7/8 mRNA in peripheral blood monocytes decreased with disease progression. TLR7 expression was decreased with stimulation with the TLR7/8 agonist, R-848, in vitro, whereas TLR8 expression was unaffected. Following R-848 stimulation, monocytes from HIV-infected subjects produced significantly less TNF-alpha than those from uninfected subjects, but trended towards greater production of IL-12 than stimulated monocytes from uninfected subjects. R-848 stimulation also suppressed HIV replication in cultured monocytes. CONCLUSIONS: Our study provides evidence that the TLR7 and TLR8 triggering can suppress HIV replication in monocytes and lead to postpone HIV disease progression, thereby offering novel targets for immunomodulatory therapy. PMID- 22243923 TI - Model development and parameter estimation for a hybrid submerged membrane bioreactor treating Ametryn. AB - A lab-scale membrane bioreactor (MBR) was used to remove Ametryn from synthetic wastewater. It was found that concentrations of MLSS and extra-cellular polymeric substances (EPS) in MBR mixed liquor fluctuated (production and decay) differently for about 40 days (transition period) after the introduction of Ametryn. During the subsequent operations with higher organic loading rates, it was also found that a low net biomass yield (higher death rate) and a higher rate of fouling of membrane (a very high rate during the first 48 h) due to increased levels of bound EPS (eEPS) in MBR mixed liquor. A mathematical model was developed to estimate the kinetic parameters before and after the introduction of Ametryn. This model will be useful in simulating the performance of a MBR treating Ametryn in terms of flux, rate of fouling (in terms of transmembrane pressure and membrane resistance) as well as treatment efficiency. PMID- 22243924 TI - Fibre size does not appear to influence the ease of enzymatic hydrolysis of organosolv-pretreated softwoods. AB - To determine the effect of fibre size on enzymatic hydrolysis, organosolv pretreated lodgepole pine was size-fractionated into six substrates ranging in average size from 0.20 to 3.4mm. Other than the fines fraction (<0.2mm) which contained most of the lignin, the fractionated substrates were more readily hydrolyzed than the original substrate with nearly complete hydrolysis after 72 h at 5 FPU g(-1) cellulose. Surprisingly, fibre size was found to have little influence on enzymatic hydrolysis likely due to similarities in the substrates' chemical composition, accessible surface area, cellulose crystallinity and degree of polymerization. To determine the influence of the fines on enzymatic hydrolysis, their content was artificially increased (from 8.9% to 55.4%) however; this did not have a noticeable effect. These results show that within the range of fibre sizes tested, other substrate characteristics likely play a more significant role in the ease of hydrolysis of pretreated substrates. PMID- 22243925 TI - Biodegradation characteristics and bioaugmentation potential of a novel quinoline degrading strain of Bacillus sp. isolated from petroleum-contaminated soil. AB - Quinoline and its derivatives are widely considered to be environmental pollutants. In this study, the biodegradation characteristics and bioaugmentation potential for a novel strain were described. The strain, named Q2, which could utilize quinoline as the sole carbon, nitrogen and energy source, was isolated and identified as a Bacillus sp. The optimum temperature, initial pH and shaker rotary speed for quinoline degradation were 30 degrees C, pH 8-10 and 100-200 rpm, respectively. During the biodegradation process, the quinoline-N was released as ammonium and the culture broth became yellow, pink and brown in turn, which indicated that several intermediates were generated. GC/MS analysis showed that 2(1H)-quinolinone and 8-hydroxycoumarin were produced. Furthermore, the bioaugmentation of Q2 into the sludge consortium, which was taken from refinery wastewater treatment plant, to degrade quinoline was investigated. The results showed that it could coexist with the other microbes and the remarkably enhanced quinoline biodegradation ability was achieved. PMID- 22243926 TI - Removal of Cr(VI) from low-temperature micro-polluted surface water by tannic acid immobilized powdered activated carbon. AB - In this study, food-grade tannic acid-immobilized powdered activated carbon (TA PAC) was prepared, and adsorption of Cr(VI) (0.500 mg/L) onto TA-PAC as a function of pH, contact time, adsorption capacities and adsorption isotherms at 280 K was investigated. The results indicated that the immobilization process introduced abundant acid functional groups. The adsorption capacity of TA-PAC was found to be pH-dependent, and the optimal pH value was found to be 4.0. The equilibrium time was 240 min for TA-PAC. Adsorption data for total chromium were modeled using both two-parameter and three-parameter isotherm models. Freundlich and linear forms of three-parameter models yielded the best results for all of the data. Desorption studies of immobilized material suggested that the immobilization of food-grade tannic acid is steady. The adsorption mechanism of Cr(VI) on TA-PAC was assumed to be a comprehensive process consisting of surface reduction of Cr(VI), esterification between catechol and chromate, and ion exchange. PMID- 22243927 TI - A study on experimental characteristic of microwave-assisted pyrolysis of microalgae. AB - The microwave-assisted pyrolysis of Chlorella vulgaris was carried out under different microwave power levels, catalysts and contents of activated carbon and solid residue. The products, pyrolysis temperature and temperature rising rate were analyzed in order to obtain the optimal conditions. The results indicated that the higher the microwave power level was, the higher the maximum temperature rising rate and pyrolysis temperature were. The maximum bio-oil yield (35.83 wt.%) and gas yield (52.37%) were achieved under the microwave power of 1500 W and 2250 W, respectively. And 2250 W was the optimal power to obtain bio-fuel product. High microwave power level and catalyst can enhance the production of gas. Catalysts can promote the pyrolysis of C. vulgaris, and activated carbon was the best among the tested catalysts followed by the solid residue. The optimal content of activated carbon is 5% with the maximum bio-fuel yield of 87.47%. PMID- 22243928 TI - Allothermal gasification of biomass using micron size biomass as external heat source. AB - An allothermal biomass gasification system using biomass micron fuel (BMF) as external heat source was developed. In this system, heat supplied to gasifier was generated from combustion of BMF. Biomass feedstock was gasified with steam and then tar in the produced gas was decomposed in a catalytic bed with NiO/gamma Al(2)O(3) catalyst. Finally the production gas was employed as a substitute for civil fuel gas. An overall energy analysis of the system was also investigated. The results showed that the lower heating value of the product gas reached more than 12 MJ/Nm(3). The combusted BMF accounted for 26.8% of the total energy input. Allothermal gasification based on the substituted BMF for conventional energy was an efficient and economical technology to obtain bioenergy. PMID- 22243929 TI - Toxic organic micro-pollutants removal mechanisms in long-term operated membrane bioreactor treating municipal solid waste leachate. AB - The performance of two-stage membrane bioreactor (MBR) in term of toxic organic micro-pollutants removal was continuously monitored for 300 days under long sludge age condition. The phenolic compounds and phthalic acid esters (PAEs) in landfill leachate and treated water from MBR unit were quantified by solid phase extraction and gas chromatography-mass spectrometry. Priority pollutants in landfill leachate were phenolics and their degradation products i.e. 4-methyl-2,6 di-tert-butylphenol, bisphenol A at higher concentrations above 100 MUg/l, PAEs i.e. dimethyl phthalate, diethyl phthalate, di-n-butyl phthalate, di-n-octyl phthalate, and di (2-ethylhexyl) phthalate. It was found that MBR could remove phenolic compounds and PAEs by 77-96%. Biodegradation and adsorption mechanisms were responsible for their removals in MBR. Additionally, the retention of compounds during filtration through the fouled membrane was also found significant. This research shows that the removal of organic micro-pollutants in landfill leachate was improved under higher biomass concentration and longer sludge age conditions. PMID- 22243930 TI - Ecological factors related to the widespread distribution of sylvatic Rhodnius ecuadoriensis populations in southern Ecuador. AB - BACKGROUND: Chagas disease transmission risk is a function of the presence of triatomines in domestic habitats. Rhodnius ecuadoriensis is one of the main vectors implicated in transmission of Trypanosoma cruzi in Ecuador. This triatomine species is present in domestic, peridomestic and sylvatic habitats in the country. To determine the distribution of sylvatic populations of R. ecuadoriensis and the factors related to this distribution, triatomine searches were conducted between 2005 and 2009 in southern Ecuador. METHODS: Manual triatomine searches were conducted by skilled bug collectors in 23 communities. Sylvatic searched sites were selected by a) directed sampling, where microhabitats were selected by the searchers and b) random sampling, where sampling points where randomly generated. Domiciliary triatomine searches were conducted using the one man-hour method. Natural trypanosome infection was determined by microscopic examination and PCR. Generalized linear models were used to test the effect of environmental factors on the presence of sylvatic triatomines. RESULTS: In total, 1,923 sylvatic individuals were collected representing a sampling effort of 751 man-hours. Collected sylvatic triatomines were associated with mammal and bird nests. The 1,219 sampled nests presented an infestation index of 11.9%, a crowding of 13 bugs per infested nest, and a colonization of 80% of the nests. Triatomine abundance was significantly higher in squirrel (Sciurus stramineus) nests located above five meters from ground level and close to the houses. In addition, 8.5% of the 820 examined houses in the same localities were infested with triatomines. There was a significant correlation between R. ecuadoriensis infestation rates found in sylvatic and synanthropic environments within communities (p = 0.012). Parasitological analysis revealed that 64.7% and 15.7% of the sylvatic bugs examined (n = 300) were infected with Trypanosoma cruzi and T. rangeli respectively, and 8% of the bugs presented mixed infections. CONCLUSIONS: The wide distribution of sylvatic R. ecuadoriensis populations may jeopardize the effectiveness of control campaigns conducted to eliminate domestic populations of this species. Also, the high T. cruzi infection rates found in sylvatic R. ecuadoriensis populations in southern Ecuador could constitute a risk for house re-infestation and persistent long-term Chagas disease transmission in the region. PMID- 22243931 TI - Fabrication of a Layered Microstructured Polymeric Microspheres as a Cell Carrier for Nucleus Pulposus Regeneration. AB - This study aimed to investigate the feasibility of nanostructured 3D poly(lactide co-glycolide) (PLGA) constructs, which are loaded with dexamethasone (DEX) and growth factor embedded hepaiin/poly(L-lysine) nanoparticles by a layer-by-layer system, to serve as an effective scaffold for nucleus pulposus (NP) tissue engineering. Our results demonstrated that the microsphere constructs were capable of simultaneously releasing basic fibroblast growth factor and DEX with approximately zero-order kinetics. The dual bead microspheres showed no cytotoxicity, and promoted the proliferation of the rat mesenchymal stem cells (rMSCs) by lactate dehydrogenase assay and CCK-8 assay. After 4 weeks of culture in vitro, the rMSCs- scaffold hybrids contained significantly higher levels of sulfated GAG/DNA and type-II collagen than the control samples. Moreover, quantity real-time PCR analysis revealed that the expression of disc-matrix proteins, including type-II collagen, aggrecan and versican, in the rMSCs scaffold hybrids was significantly higher than the control group, whereas the expression of osteogenic differentiation marker type-I collagen was decreased. Taken together, these data indicate that the heparin bound bFGF-coated and DEX loaded PLGA microsphere constructs is an effective bioactive scaffold for the regeneration of NP tissue. PMID- 22243933 TI - Sirolimus-eluting stents reduce long-term mortality compared with bare metal stents in ST-segment elevation myocardial infarction: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Sirolimus-eluting stents (SES) have demonstrated more favorable outcomes compared with bare metal stents (BMS) for ST-segment elevation myocardial infarction (STEMI) within medium term follow up in randomized controlled trials (RCT). However, long-term outcomes remain unknown. METHODS: We conducted a meta-analysis of RCT comparing SES with BMS in STEMI patients at long term follow up, defined as 2 years or more after primary percutaneous coronary intervention (PCI). The clinical end points of our interest were death, recurrent myocardial infarction (MI), definite stent thrombosis (ST), and target lesion revascularization (TLR). We calculated the pooled estimate based on a fixed effects model using Peto odds ratio (OR) for rare events. If heterogeneity was observed across an individual RCT, an analysis based on a random-effects model was performed. RESULTS: Four RCT were included in this study, involving 1304 patients (656 patients randomized to SES and 648 patients to BMS). Up to 4 years, SES showed a significant reduction in not only TLR (OR: 0.44, 95% confidence interval (CI): 0.31 to 0.62, p<0.001) but also mortality (OR: 0.62, 95% CI: 0.39 to 1.00, p=0.049) compared with BMS. In contrast, the proportions of recurrent MI (OR: 0.82, 95% CI: 0.52 to 1.28, p=0.378) and definite ST (OR: 1.13, 95% CI: 0.56 to 2.27, p=0.740) were comparable between the 2 groups. CONCLUSIONS: In this meta analysis of long-term RCT, primary PCI for STEMI patients with SES was associated with a decrease in mortality as well as TLR without an increase in recurrent MI or definite ST compared with BMS. PMID- 22243932 TI - Novel immune-modulator identified by a rapid, functional screen of the parapoxvirus ovis (Orf virus) genome. AB - BACKGROUND: The success of new sequencing technologies and informatic methods for identifying genes has made establishing gene product function a critical rate limiting step in progressing the molecular sciences. We present a method to functionally mine genomes for useful activities in vivo, using an unusual property of a member of the poxvirus family to demonstrate this screening approach. RESULTS: The genome of Parapoxvirus ovis (Orf virus) was sequenced, annotated, and then used to PCR-amplify its open-reading-frames. Employing a cloning-independent protocol, a viral expression-library was rapidly built and arrayed into sub-library pools. These were directly delivered into mice as expressible cassettes and assayed for an immune-modulating activity associated with parapoxvirus infection. The product of the B2L gene, a homolog of vaccinia F13L, was identified as the factor eliciting immune cell accumulation at sites of skin inoculation. Administration of purified B2 protein also elicited immune cell accumulation activity, and additionally was found to serve as an adjuvant for antigen-specific responses. Co-delivery of the B2L gene with an influenza gene vaccine significantly improved protection in mice. Furthermore, delivery of the B2L expression construct, without antigen, non-specifically reduced tumor growth in murine models of cancer. CONCLUSION: A streamlined, functional approach to genome-wide screening of a biological activity in vivo is presented. Its application to screening in mice for an immune activity elicited by the pathogen genome of Parapoxvirus ovis yielded a novel immunomodulator. In this inverted discovery method, it was possible to identify the adjuvant responsible for a function of interest prior to a mechanistic study of the adjuvant. The non specific immune activity of this modulator, B2, is similar to that associated with administration of inactivated particles to a host or to a live viral infection. Administration of B2 may provide the opportunity to significantly impact host immunity while being itself only weakly recognized. The functional genomics method used to pinpoint B2 within an ORFeome may be more broadly applicable to screening for other biological activities in an animal. PMID- 22243934 TI - Extremely high coronary artery calcium score is associated with a high cancer incidence. PMID- 22243935 TI - Myocardial perfusion defects detected by cardiopulmonary exercise testing: role of VE/VCO2 slope in patients with chest pain suspected of coronary artery disease. PMID- 22243936 TI - Cardiac myxoma the great imitators: comprehensive histopathological and molecular approach. AB - Cardiac myxomas are rare benign and slowly proliferating neoplasms of uncertain histogenesis with heterogeneous histomorphology and variable and sometimes clinically quite malignant pathological manifestations. Majority of cardiac myxoma occur sporadically while a relatively small proportion of diagnosed cases develop as a part of Carney complex syndrome with established familial pattern of inheritance. Although histologically indistinguishable these two forms of cardiac myxoma exhibit distinct cytogenetic make-up and apparent pathological differences important for their clinical presentation and prognosis. Additional problem is presented with secondary lesions with more aggressive histology and significantly faster cell proliferation suggesting their successive malignant alteration. Surgical resection of cardiac myxoma is currently the only treatment of choice. However, to avoid potentially hazardous operating procedures and possible postoperative complications and to prevent recurrence of the neoplastic lesions it is necessary to develop alternative approaches and identify a possible drug targets for their successful pharmacological treatment. Due to the rarity of the disease, a small number of cases in one institution and lack of comprehensive experimental data particularly concerning the cases of metastatic dissemination and secondary lesions with malignant nature, a comprehensive multi-institutional approach is required for better understanding of their molecular pathology and illumination of key molecular, genetic as well as epigenetic markers and regulatory pathways responsible for their development. In this article we provide comprehensive pathohistological, molecular and cytogenetic overview of sporadic cardiac myxoma cases restating the major hypothesis concerning their histogenesis and emphasizing potential approaches for their further reexamination. PMID- 22243937 TI - Clinical consideration of cardiac pacemaker implantation through a persistent left superior vena cava with an absent right superior vena cava. PMID- 22243938 TI - Hypertonic saline solution for prevention of renal dysfunction in patients with decompensated heart failure. AB - BACKGROUND: Renal dysfunction is associated with increased mortality in patients with decompensated heart failure. However, interventions targeted to prevention in this setting have been disappointing. We investigated the effects of hypertonic saline solution (HSS) for prevention of renal dysfunction in decompensated heart failure. METHODS: In a double-blind randomized trial, patients with decompensated heart failure were assigned to receive three-day course of 100mL HSS (NaCl 7.5%) twice daily or placebo. Primary end point was an increase in serum creatinine of 0.3mg/dL or more. Main secondary end point was change in biomarkers of renal function, including serum levels of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin-NGAL and the urinary excretion of aquaporin 2 (AQP2), urea transporter (UT-A1), and sodium/hydrogen exchanger 3 (NHE3). RESULTS: Twenty-two patients were assigned to HSS and 12 to placebo. Primary end point occurred in two (10%) patients in HSS group and six (50%) in placebo group (relative risk 0.3; 95% CI 0.09-0.98; P=0.01). Relative to baseline, serum creatinine and cystatin C levels were lower in HSS as compared to placebo (P=0.004 and 0.03, respectively). NGAL level was not statistically different between groups, however the urinary expression of AQP2, UT-A1 and NHE3 was significantly higher in HSS than in placebo. CONCLUSIONS: HSS administration attenuated heart failure-induced kidney dysfunction as indicated by improvement in both glomerular and tubular defects, a finding with important clinical implications. HSS modulated the expression of tubular proteins involved in regulation of water and electrolyte homeostasis. PMID- 22243939 TI - Do patients with chronic heart failure have chest pain? AB - OBJECTIVE: In questionnaire surveys, patients with chronic heart failure frequently report "pain" as a symptom. We investigated the prevalence of chest pain as a possible cause for pain, particularly in patients with prior myocardial infarction. DESIGN: Questionnaire survey. SETTING: Community heart failure clinic. PATIENTS: 1 786 patients with heart failure due to left ventricular systolic dysfunction (mean +/- SD age 70.1 +/- 11.0 years; 73% male; left ventricular ejection fraction (LVEF) 35.3 +/- 9.9%; 65.6 with underlying ischaemic heart disease (IHD)). INTERVENTION: Patients with chronic heart failure completed a questionnaire. MAIN OUTCOME MEASURES: Answers to the questions: (1) "In the last week, how many days did you get angina chest pain?"; and "In the last month, how much did the following affect you:" (2) "chest pains at rest"; (3) "chest pains during normal activity". RESULTS: 73% of those with IHD, and 84% of those without had had no angina in the previous week; 79% and 82%, respectively, had at most "little" chest pain at rest; 67% and 76%, respectively, had at most "little" chest pain during exertion. Angina increased with NYHA class, but there was no relation between angina and sex of patient, age or LVEF. There was a weak relation between chest pain and an adverse outcome in the patients with ischaemic heart disease. CONCLUSIONS: Although pain is commonly reported in patients with chronic heart failure, it seems unlikely that the pain is due to angina, even in patients with underlying coronary heart disease. PMID- 22243940 TI - The coexistence of comorbidities at admission is an independent predictor of 30 day mortality of patients hospitalized with acute myocardial infarction: analysis of 5523 cases in China. PMID- 22243941 TI - Two-dimensional speckle tracking echocardiography: a novel approach to evaluate left atrial mechanical function. PMID- 22243942 TI - The use of a combination of computer-assisted structure prediction and SHAPE probing to elucidate the secondary structures of five viroids. AB - The elucidation of the structures of viroids, noncoding infectious RNA species, is paramount to obtain an understanding of the various aspects of their life cycles (including replication, transport and pathogenesis). In general, the secondary structures of viroids have been predicted using computer software programs which have been shown to possess several important limitations. Clearly, the predicted structure of a viroid needs to receive physical support prior to its use in the accurate interpretation of any mechanistic studies. Here, SHAPE probing coupled to computer-assisted structure prediction using the RNAstructure software program was employed to determine the structures of five viroids. These species belong to four genera of the Pospiviroidae family, and none have had their structure characterized in solution. In addition, several interesting questions were addressed by either studying various sequence variants or varying the SHAPE conditions. More importantly, this approach is novel in the study of viroids, and should be of significant aid in the determination of the structures of other RNA species. PMID- 22243943 TI - Effect of the protein:carbohydrate ratio in hypoenergetic diets on metabolic syndrome risk factors in exercising overweight and obese women. AB - Overweight and obesity are growing problems both in Canada and around the world. Obesity is associated with a number of chronic diseases including type 2 diabetes and CVD, which puts a tremendous burden on the health care systems in place. The present study sought to investigate whether there were differences in the effectiveness of three low-fat, hypo- and isoenergetic diets differing in protein:carbohydrate ratio, low protein (LP, 1 g protein:4 g carbohydrate), normal protein (NP, 1 g protein:2 g carbohydrate) or high protein (HP, 1 g protein:1 g carbohydrate), on weight loss and markers of the metabolic syndrome (MetS) in overweight women. Subjects were randomly assigned to receive one of three intervention diets, all of which included a 60 min exercise programme three times/week for 12 weeks. Of the total subjects, fifty-four overweight and obese local women with MetS risk factors completed the study. All groups had similar improvements in body weight, insulin sensitivity, lipid profile, blood pressure and fitness. Subjects reported that the NP diet was easier to comply with and achieved better improvements in body fat, waist circumference and waist:hip ratio, and preservation of lean mass compared with the other two diets. In conclusion, energy restriction and exercise both facilitate weight loss in overweight and obese subjects and reduce symptoms of the MetS. A diet with a 1:2 protein:carbohydrate ratio promoted better improvements than either the LP or HP diets, and may be superior in reducing long-term chronic disease risk in this population. PMID- 22243944 TI - Potential interaction between sevelamer and fat-soluble vitamins: a hypothesis. PMID- 22243945 TI - Hyponatremia and mortality in patients with cancer: the devil is in the details. PMID- 22243946 TI - Commentary on 'The DOPPS practice monitor for US dialysis care: trends through April 2011': no surprises yet. PMID- 22243948 TI - Metabolic alkalosis due to hypercalcemia. PMID- 22243949 TI - Potassium and metabolic alkalosis. PMID- 22243951 TI - Predialysis care: intertwined roles of nephrologists and dietitians. PMID- 22243952 TI - What dominates living donor kidney transplantation: altruism or loss of dignity? PMID- 22243954 TI - Bound by a promise: advance directives and "uninformed consent". PMID- 22243955 TI - Quiz page February 2012: acute kidney injury in an adolescent with a family history of autoimmune disorders. PMID- 22243956 TI - Musculoskeletal examination and junior doctors: cause for concern? PMID- 22243957 TI - Working towards a new psychiatry - neuroscience, technology and the DSM-5. AB - This Editorial introduces the thematic series on 'Toward a New Psychiatry: Philosophical and Ethical Issues in Classification, Diagnosis and Care' http://www.biomedcentral.com/series/newpsychiatry. PMID- 22243958 TI - Worsening dyspnea in a man with 2 hearts. AB - We report a case of dyspnea in a 71-year-old man who underwent heterotopic heart transplantation in 2003. At presentation, electrocardiography showed ventricular fibrillation of the native heart and then a progression to both donor and recipient hearts. Synchronized electrical cardioversion restored sinus rhythm and relieved the patient from his symptoms. PMID- 22243959 TI - Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: a randomized controlled trial. AB - STUDY OBJECTIVE: We assess the efficacy of intravenous ketamine compared with intravenous morphine in reducing pain in adults with significant out-of-hospital traumatic pain. METHODS: This study was an out-of-hospital, prospective, randomized, controlled, open-label study. Patients with trauma and a verbal pain score of greater than 5 after 5 mg intravenous morphine were eligible for enrollment. Patients allocated to the ketamine group received a bolus of 10 or 20 mg, followed by 10 mg every 3 minutes thereafter. Patients allocated to the morphine alone group received 5 mg intravenously every 5 minutes until pain free. Pain scores were measured at baseline and at hospital arrival. RESULTS: A total of 135 patients were enrolled between December 2007 and July 2010. There were no differences between the groups at baseline. After the initial 5-mg dose of intravenous morphine, patients allocated to ketamine received a mean of 40.6 mg (SD 25 mg) of ketamine. Patients allocated to morphine alone received a mean of 14.4 mg (SD 9.4 mg) of morphine. The mean pain score change was -5.6 (95% confidence interval [CI] -6.2 to -5.0) in the ketamine group compared with -3.2 (95% CI -3.7 to -2.7) in the morphine group. The difference in mean pain score change was -2.4 (95% CI -3.2 to -1.6) points. The intravenous morphine group had 9 of 65 (14%; 95% CI 6% to 25%) adverse effects reported (most commonly nausea [6/65; 9%]) compared with 27 of 70 (39%; 95% CI 27% to 51%) in the ketamine group (most commonly disorientation [8/70; 11%]). CONCLUSION: Intravenous morphine plus ketamine for out-of-hospital adult trauma patients provides analgesia superior to that of intravenous morphine alone but was associated with an increase in the rate of minor adverse effects. PMID- 22243960 TI - Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine binding protein. AB - Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the alpha7 and alpha4beta2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes. PMID- 22243961 TI - Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2 carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles. AB - A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure-activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2 carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC(50) 0.026-0.209 MUM) against Plasmodium falciparum. PMID- 22243962 TI - Synthesis and evaluation of aza-peptidyl inhibitors of the lysosomal asparaginyl endopeptidase, legumain. AB - Legumain or asparaginly endopeptidase (AEP) is a lysosomal cysteine protease with a high level of specificity for cleavage of protein substrates after an asparagine residue. It is also capable of cleaving after aspartic acids sites when in the acidic environment of the lysosome. Legumain expression and activity is linked to a number of pathological conditions including cancer, atherosclerosis and inflammation, yet its biological role in these pathologies is not well-understood. Highly potent and selective inhibitors of legumain would not only be valuable for studying the functional roles of legumain in these conditions, but may have therapeutic potential as well. We describe here the design, synthesis and in vitro evaluation of selective legumain inhibitors based on the aza-asparaginyl scaffold. We synthesized a library of aza-peptidyl inhibitors with various non-natural amino acids and different electrophilic warheads, and characterized the kinetic properties of inactivation of legumain. We also synthesized fluorescently labeled inhibitors to investigate cell permeability and selectivity of the compounds. The inhibitors have second order rate constants of up to 5 * 10(4)M(-1)s(-1) and IC(50) values as low as 4 nM against recombinant mouse legumain. In addition, the inhibitors are highly selective toward legumain and have little or no cross-reactivity with cathepsins. Overall, we have identified several valuable new inhibitors of legumain that can be used to study legumain function in multiple disease models. PMID- 22243963 TI - 2-(2-phenylethyl)chromones from Chinese eaglewood. AB - 2-(2-Phenylethyl) chromones and a 2-(2-phenylethenyl) chromone, were isolated from the ethanolic extract of Chinese eaglewood. Their structures were determined on the basis of extensive analyses of spectroscopic data. Among those, one showed significant neuroprotective activities against both glutamate-induced and corticosterone-induced neurotoxicity in P12 pheochromocytoma and human U251 glioma cells at a concentration of 10 MUM and increased cell viability by 82.2% and 86.9%, respectively. PMID- 22243964 TI - Five years of GWAS discovery. AB - The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section. PMID- 22243965 TI - Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. AB - Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum. PMID- 22243966 TI - Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis. AB - We investigated a family in which the index subject presented with severe congenital lactic acidosis and dysmorphic features associated with a cytochrome c oxidase (COX)-assembly defect and a specific decrease in the synthesis of COX I, the subunit that nucleates COX assembly. Using a combination of microcell mediated chromosome transfer, homozygosity mapping, and transcript profiling, we mapped the gene defect to chromosome 12 and identified a homozygous missense mutation (c.88G>A) in C12orf62. C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype. Furthermore, siRNA-mediated knockdown of C12orf 62 recapitulated the biochemical defect in control cells and exacerbated it in subject cells. C12orf62 is apparently restricted to the vertebrate lineage. It codes for a very small (6 kDa), uncharacterized, single transmembrane protein that localizes to mitochondria and elutes in a complex of ~110 kDa by gel filtration. COX I, II, and IV coimmunoprecipated with an epitope tagged version of C12orf62, and 2D blue-native-polyacrylamide-gel-electrophoresis analysis of newly synthesized mitochondrial COX subunits in subject fibroblasts showed that COX assembly was impaired and that the nascent enzyme complex was unstable. We conclude that C12orf62 is required for coordination of the early steps of COX assembly with the synthesis of COX I. PMID- 22243967 TI - PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. AB - Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia). PMID- 22243969 TI - Cavernous carotid pseudoaneurysm following transsphenoidal surgery. AB - Pseudoaneurysm of the internal carotid artery (ICA) as a result of injury during transsphenoidal surgery is a rare but serious complication. We present a review of this subject, identifying 22 such cases in the literature, and contribute an unusual case of our own. Among our cohort, 23% of patients had no evidence of vascular injury or hemorrhage during the initial transsphenoidal operation, and presented at an average of 83 days after surgery. The average time to diagnosis for patients with intraoperative bleeding was 64 days after surgery. Epistaxis was the most common initial presenting symptom, seen in 41% of patients, and traditional angiography was employed in every case to make the diagnosis of pseudoaneurysm. Though complete occlusion of the ICA was ultimately required in 41% of patients, the remainder were treated with a variety of modalities. While intraoperative hemorrhage is certainly the most predictive indicator of iatrogenic vascular damage, in its absence, other signs such as postoperative bruits may be predictive of pseudoaneurysm formation as well. The continued accumulation of these unique cases will hopefully provide definitive recommendations on the early recognition and treatment of this serious condition, especially regarding the emerging role of endovascular therapy in its management. PMID- 22243968 TI - A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. AB - Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor beta and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth. PMID- 22243971 TI - Comparison of Rater's reliability on perceptual evaluation of different types of voice sample. AB - OBJECTIVE/HYPOTHESIS: The objective of this study was to determine whether different types of voice samples affect rater reliability and which type of sample can be rated most reliably, with particular reference to two types of connected speech-passage reading and conversational speech. STUDY DESIGN: Prospective reliability study. METHODS: One hundred fifty voice samples from 40 speakers were presented to 14 speech pathologists experienced in managing voice disorders. Each speaker contributed three types of voice samples: sustained vowels, passage reading, and conversational speech. Ratings were made on four vocal parameters--overall severity, roughness, breathiness, and strain--on a 10 point equal-appearing interval scale. RESULTS: Differences in intrarater reliability across the three types of voice samples were noted. Higher intrarater reliability was achieved with connected speech than with sustained vowel samples. Interrater reliability showed no statistically significant difference across the three types but increased with the severity of dysphonia. CONCLUSIONS: This study reveals that raters give internally more reliable ratings for connected speech samples. Results also indicate that voices with severe disorders appear to be rated more reliably. PMID- 22243970 TI - Placental malaria is associated with attenuated CD4 T-cell responses to tuberculin PPD 12 months after BCG vaccination. AB - BACKGROUND: Placental malaria (PM) is associated with prenatal malaise, but many PM+ infants are born without symptoms. As malaria has powerful immunomodulatory effects, we tested the hypothesis that PM predicts reduced T-cell responses to vaccine challenge. METHODS: We recruited healthy PM+ and PM- infants at birth. At six and 12 months, we stimulated PBMCs with tuberculin purified protein derivative (PPD) and compared expression of CD154, IL-2 and IFNgamma by CD4 T cells to a negative control using flow cytometry.We measured the length, weight and head circumference at birth and 12 months. RESULTS: IL-2 and CD154 expression were low in both groups at both timepoints, without discernable differences. Expression of IFNgamma was similarly low at 6 months but by 12 months, the median response was higher in PM- than PM + infants (p = 0.026). The PM+ infants also had a lower weight (p = 0.032) and head circumference (p = 0.041) at 12 months, indicating lower growth rates.At birth, the size and weight of the PM+ and PM- infants were equivalent. By 12 months, the PM+ infants had a lower weight and head circumference than the PM- infants. CONCLUSIONS: Placental malaria was associated with reduced immune responses 12 months after immune challenge in infants apparently healthy at birth. PMID- 22243972 TI - Fundamental frequency and perturbation measures of sustained vowels in Malaysian Malay children between 7 and 12 years old. AB - OBJECTIVE: The study is going to investigate the fundamental frequency (F(0)) and perturbation measures of sustained vowels in 360 native Malaysian Malay children aged between 7 and 12 years using acoustical analysis. METHODS: Praat software (Boersma and Weenink, University of Amsterdam, The Netherlands) was used to analyze the F(0) and perturbation measures of the sustained vowels. Statistical analyses were conducted to determine the significant differences in F(0) and perturbation measures across the vowels, sex, and age groups. RESULTS: The mean F(0) of Malaysian Malay male and female children were reported at 240+/-34.88 and 254.48+/-23.35Hz, respectively. The jitter (Jitt), relative average perturbation (RAP), five-point period perturbation quotient (PPQ5), shimmer (Shim), and 11 point amplitude perturbation quotient (APQ11) of Malaysian male children were reported at 0.43+/-0.26%, 0.25+/-0.16%, 0.26+/-0.15%, 2.48+/-1.61%, and 1.75+/ 1.04%, respectively. As for female children, the Jitt, RAP, PPQ5, Shim, and APQ11 were reported at 0.42+/-0.22%, 0.25+/-0.14%, 0.25+/-0.13%, 2.47+/-1.53%, and 1.75+/-1.10%, respectively. CONCLUSIONS: No significant differences in F(0) were reported across the Malay vowels for both males and females. Malay females had significantly higher F(0) than that in Malay males at the age of 8, 10, and 12 years. Malaysian Malay children underwent the nonsystematic decrement in F(0) across the age groups. Significant differences in F(0) were found across the age groups. Significant differences in perturbation measures were observed across the vowels in certain age groups of Malay males and females. Generally, no significant differences in perturbation measures between the sex were observed in all the age groups and vowels. No significant differences in all the perturbation measures across the age groups were reported in both Malaysian Malay male and female children. PMID- 22243973 TI - Creating a mastery experience during the voice evaluation. AB - OBJECTIVES: Adherence to treatment is a common challenge when working with patients with voice disorders. Improving their self-efficacy through a mastery experience has the potential to improve treatment adherence. An ideal mastery experience gives early and quick evidence that the patient will be successful with the treatment and works for a broad range of patients. This study sought to test whether a brief stimulability trial of forward focused voice could produce sufficient change in acoustic analysis measures to provide visibly improved objective results and, thus, be a potentially useful mastery experience. STUDY DESIGN: Prospective, repeated measures, pre- and posttreatment. METHODS: Twenty four consecutive patients with varying diagnoses referred for a voice evaluation participated in this study. Acoustic analysis was completed before and after a short stimulability trial of forward focused voice. Acoustic analysis parameters evaluated include fundamental frequency, jitter, shimmer, noise-to-harmonic ratio, and voice turbulence index. Data pre- and posttreatment were analyzed for change and compared with normative values. RESULTS: Results demonstrated a significant change from pre- to posttrial, as indicated by the objective measure transitioning from being outside to within normal limits, in 75% of patients (P=0.000). When less rigid criterion of a positive change in one or more of the three acoustic measures of interest is used, improvement was noted in 96% of patients. CONCLUSION: Pairing a trial therapy with acoustic analysis during a voice evaluation is a possible mastery experience. Future research is needed to determine if this mastery experience improves self-efficacy, treatment adherence, and treatment outcomes. PMID- 22243974 TI - Vocal folds analysis using global energy tracking. AB - INTRODUCTION: Detection and quantification of oscillatory irregularities in laryngeal videostroboscopy can be particularly difficult for the human expert. Accordingly, there is a wide interest in automated methods for recovering the folds' temporal trajectory. Unfortunately, current methods typically provide only crude glottal measurements. OBJECTIVES: An automated procedure for consistently tracking the entire vocal folds' boundary in laryngeal stroboscopy videos, even when the glottal opening is closed. METHODS: A preprocessing frame-by-frame crude midpoint identification is followed by an active contour evolution to detect the global boundary in each frame independently. A global energy active contour is then jointly defined over the entire video sequence, and the full glottal boundary is detected throughout the video via standard energy minimization. RESULTS: The vocal folds' boundary is accurately tracked in normal and abnormal stroboscopy videos collected in a clinical setting, and that exhibit a varied range of visual characteristics (eg, lighting conditions). A proof-of-concept evaluation based on the analysis of the waveform of the location of points along the boundary separates between a normal and two markedly different abnormal subjects, and automatically provides a hypothesized localization of the abnormality. CONCLUSION: The first method for automatically tracing the temporal trajectory of all points along the vocal folds' boundary in all frames of a stroboscopy video is presented. The approach opens the door for novel analysis of all regions of the contour, which in turn may lead to automated localization of pathologies. PMID- 22243975 TI - Correlation between p38 mitogen-activated protein kinase and human telomerase reverse transcriptase in sarcomas. AB - BACKGROUND: One of the major components of telomerase is the human telomerase reverse transcriptase (hTERT) as the catalytic protein. hTERT mRNA expression are reported to be associated with prognosis and tumor progression in several sarcomas. However, there is no clear understanding of the mechanisms of hTERT in human sarcomas. Recent studies have suggested that signals transmitted through p38 mitogen-activated protein kinase (MAPK) can increase or decrease hTERT transcription in human cells. The purpose of this study was to analyse the correlation between p38 MAPK and hTERT in sarcoma samples. METHODS: We investigated 36 soft tissue malignant fibrous histiocytomas (MFH), 24 liposarcomas (LS) and 9 bone MFH samples for hTERT and p38 MAPK expression. Quantitative detection of hTERT and p38 MAPK was performed by RT-PCR. RESULTS: There was a significant positive correlation between the values of hTERT and p38 MAPK in all samples (r = 0.445, p = 0.0001), soft tissue MFH (r = 0.352, p = 0.0352), LS (r = 0.704, p = 0.0001) and bone MFH samples (r = 0.802, p = 0.0093). Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis than other patients (p = 0.0036). CONCLUSIONS: p38 MAPK may play a role in up-regulation of hTERT, and therefore, p38 MAPK may be a useful marker in the assessment of hTERT and patients' prognosis in sarcomas. PMID- 22243976 TI - A brief historicity of the Diagnostic and Statistical Manual of Mental Disorders: issues and implications for the future of psychiatric canon and practice. AB - The Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association, currently in its fourth edition and considered the reference for the characterization and diagnosis of mental disorders, has undergone various developments since its inception in the mid-twentieth century. With the fifth edition of the DSM presently in field trials for release in 2013, there is renewed discussion and debate over the extent of its relative successes - and shortcomings - at iteratively incorporating scientific evidence on the often ambiguous nature and etiology of mental illness. Given the power that the DSM has exerted both within psychiatry and society at large, this essay seeks to analyze variations in content and context of various editions of the DSM, address contributory influences and repercussion of such variations on the evolving landscape of psychiatry as discipline and practice over the past sixty years. Specifically, we document major modifications in the definition, characterization, and classification of mental disorders throughout successive editions of the DSM, in light of shifting trends in the conceptualization of psychopathology within evolving schools of thought in psychiatry, and in the context of progress in behavioral and psychopharmacological therapeutics over time. We touch upon the social, political, and financial environments in which these changes took places, address the significance of these changes with respect to the legitimacy (and legitimization) of what constitutes mental illness and health, and examine the impact and implications of these changes on psychiatric practice, research, and teaching. We argue that problematic issues in psychiatry, arguably reflecting the large-scale adoption of the DSM, may be linked to difficulties in formulating a standardized nosology of psychopathology. In this light, we highlight 1) issues relating to attempts to align the DSM with the medical model, with regard to increasing specificity in the characterization of discrete mental disease entities and the incorporation of neurogenetic, neurochemical and neuroimaging data in its nosological framework; 2) controversies surrounding the medicalization of cognition, emotion, and behavior, and the interpretation of subjective variables as 'normal' or 'abnormal' in the context of society and culture; and 3) what constitutes treatment, enablement, or enhancement - and what metrics, guidelines, and policies may need to be established to clarify such criteria. PMID- 22243977 TI - "Doing it blindfolded"-successful administration of enfuvirtide by a person living with HIV and blindness: a case study of treatment access and disability. PMID- 22243980 TI - The effect of a mindful restaurant eating intervention on weight management in women. AB - OBJECTIVE: To evaluate the effect of a Mindful Restaurant Eating intervention on weight management. DESIGN: Randomized control trial. SETTING: Greater metropolitan area of Austin, Texas. PARTICIPANTS: Women (n = 35) 40-59 years old who eat out at least 3 times per week. INTERVENTION: The intervention, using 6 weekly 2-hour, small group sessions, focused on reducing calorie and fat intake when eating out through education, behavior change strategies, and mindful eating meditations. MAIN OUTCOME MEASURES: Weight, waist circumference, self-reported daily calorie and fat intake, self-reported calories and fat consumed when eating out, emotional eating, diet related self-efficacy, and barriers to weight management when eating out. ANALYSIS: General linear models examined change from baseline to final endpoint to determine differences in outcomes between the intervention and control group. RESULTS: Participants in the intervention group lost significantly more weight (P =.03), had lower average daily caloric (P = .002) and fat intake (P = .001), had increased diet-related self-efficacy (P = .02), and had fewer barriers to weight management when eating out (P = .001). CONCLUSIONS AND IMPLICATIONS: Mindful Restaurant Eating intervention was effective in promoting weight management in perimenopausal women. PMID- 22243981 TI - Family mealtime conversations in context. PMID- 22243982 TI - The nature of methadone diversion in England: a Merseyside case study. AB - BACKGROUND: Methadone maintenance treatment (MMT) is a key element in treatment for opiate addiction; however concerns about the diversion of methadone remain. More current empirical data on methadone diversion are required. This research investigated the market for diverted methadone in Merseyside, UK, in order to provide a case study which can be transferred to other areas undertaking methadone maintenance treatment on a large scale. METHODS: Questionnaires were completed (in interview format) with 886 past year users of methadone recruited both in and out of prescribing agencies. Topic areas covered included current prescribing, obtaining and providing methadone, reasons for using illicit methadone and other drug use. RESULTS: Large proportions of participants had obtained illicit methadone for use in the past year with smaller proportions doing so in the past month. Proportions of participants buying and being given methadone were similar. Exchange of methadone primarily took place between friends and associates, with 'dealers' rarely involved. Gender, age, whether participant's methadone consumption was supervised and whether the aims of their treatment had been explained to them fully, influenced the extent to which participants were involved in diverting or using diverted methadone. CONCLUSION: Methadone diversion is widespread although drug users generally do not make use of illicit methadone regularly (every month). The degree of altruism involved in the exchange of methadone does not negate the potential role of this action in overdose or the possibility of criminal justice action against individuals. Treatment agencies need to emphasise these risks whilst ensuring that treatment aims are effectively shared with clients to ensure adherence to treatment. PMID- 22243983 TI - Glycaemic, insulin and ghrelin responses to traditional South Asian flatbreads in diabetic and healthy subjects. AB - In the South-East Asian subcontinent, flatbreads contribute the main portion of carbohydrate to a meal. There are no specific data on the effect of different flatbreads on satiety and recurrent hunger, as indicated by the duration of ghrelin suppression after a meal. The present study was designed to examine the glycaemic, insulin and ghrelin responses to traditional subcontinental breads in type 2 diabetic subjects and healthy volunteers. For this purpose, twelve normoglycaemic healthy volunteers and ten type 2 diabetic patients, in the fasting state, consumed one of five common flatbreads on consecutive days. Capillary blood glucose was examined in the fasting state and serially for 5 h after a meal. Serum insulin and ghrelin levels were determined at hourly intervals for 5 h after the consumption of bran and plain chapatti flatbreads. The incremental area under the curve (iAUC) was calculated for glycaemic and insulin responses, while the net AUC was used to assess the ghrelin response. The results showed that glycaemic and insulin iAUC were lowest for bran chapatti, and highest for plain chapatti. Furthermore, bran chapatti showed maximum ghrelin suppression in both normal and diabetic groups. In conclusion, the low-glycaemic index bran chapatti flatbread had a lower postprandial glycaemic excursion and insulin response, and a more prolonged suppression of ghrelin levels, compared with the plain chapatti flatbread, and in each case, the difference was greater for the diabetic subjects than for the normal subjects. The inclusion of these flatbreads in the diabetic/weight-reducing diet may help weight loss by promoting satiety and reducing hyperinsulinaemia. PMID- 22243984 TI - The effect of Zhangfei on the unfolded protein response and growth of cells derived from canine and human osteosarcomas. AB - The objective of this study was to determine whether the protein Zhangfei could suppress the unfolded protein response (UPR) and growth of osteosarcoma cells. Dog (D-17) and a human (Saos-2) osteosarcoma cells were infected with adenovirus vectors expressing either Zhangfei or the control protein beta- galactosidase. We monitored cell growth as well as levels of UPR gene transcripts and proteins. We found that Zhangfei suppressed the growth of both D-17 and Saos-2 cells. Zhangfei expressing D-17 cells displayed large vacuoles containing culture medium and expressed phosphatidylserine on their external surface suggesting that Zhangfei induced macropinocytosis and apoptosis in these cells. While Zhangfei inhibited the growth of both D-17 and Saos-2 cells, it inhibited thapsigargin-induced UPR, as detected by a decrease in transcripts for UPR genes, and HERP and GRP78 proteins, only in D-17 cells, suggesting that the ability of Zhangfei to suppress the UPR and tumour cells growth may not be linked. PMID- 22243985 TI - Epidemiological investigations in regard to porcine reproductive and respiratory syndrome (PRRS) in Quebec, Canada. Part 1: biosecurity practices and their geographical distribution in two areas of different swine density. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a considerable threat to the swine industry and implementing biosecurity measures is essential for the control of its transmission. The aims of this study were: (1) to describe biosecurity practices in production sites located in a moderate density (MD) and a high density (HD) pig area according to production type; (2) to group sites in different patterns according to their biosecurity practices; and (3) to determine the geographical distribution of sites according to biosecurity patterns. Biosecurity practices were selected based on PRRS epidemiology. A questionnaire was completed on 125 breeding sites (MD=54; HD=71) and 120 growing (HD) sites, between 2005 and 2008. Depending on area and production type, the frequency of biosecurity practices used ranged from 0 to 2% for barrier at site entrance, 0 to 19% for use of shower, 25 to 35% for washing truck between loads of pigs, 51 to 57% for absence of rendering or rendering without access to the site, and 26 to 51% for absence of gilt purchase or purchase with quarantine. Better practices pertaining to entrance protocol (i.e. "no-entry" sign, shower, >=24 h downtime) were reported more frequently on breeding sites in the MD than the HD area (P<0.05). In the HD area, growing sites had in general a lower level of biosecurity than breeding sites. Using a two-step clustering procedure performed separately for breeding and growing sites, two different patterns were obtained for each production type, which corresponded to a high and low level of biosecurity. For breeding sites, a higher biosecurity level was observed at sites located away from other pig sites, set at more than 300 m from the public road, having higher sow inventory, or being part of an integrated production (P<0.05). Spatial clusters of sites for each biosecurity pattern were detected. This study identified some shortcomings regarding biosecurity that should be addressed before implementing any PRRSV regional control. Vicinity of sites with different biosecurity levels also suggests difficulties in planning priorities of intervention based on geographical distribution of sites. PMID- 22243986 TI - Assessment of the utility of routinely collected cattle census and disposal data for syndromic surveillance. AB - Census and disposal data provide a multipurpose source of information on cattle mortality. The retrospective analyses we conducted on the data gathered in the National Cattle Register produced relevant information for describing and modelling the cattle mortality baseline and evaluating the impact of the 2007 2008 Blue Tongue epidemic on the French cattle population. This work was conducted retrospectively but showed that monitoring cattle mortality near real time could help detecting unexpected events. We are thus currently working on a timely and automated system to monitor cadaver disposal requests received by rendering plants, thanks to a data interchange system recently implemented between the Ministry of Agriculture and the fallen stock companies. Besides technical and methodological challenges, using these data for surveillance purposes raises epidemiological questions that still need to be answered. The question remains notably as to whether an abnormal increased mortality is a sensitive and timely signal for detecting unexpected health events. It appears also very challenging to identify the most adequate surveillance scale (time, space and population) and the most adequate anomaly detection algorithms to apply when the characteristics of the signals to be detected (shape, amplitude, etc.) are not known a priori. In Human health, similar systems have not yet proven their ability to detect unexpected events earlier than classical surveillance systems currently in place, but they have already demonstrated their value for real time assessment of identified and potentially dangerous events. Combined with traditional surveillance systems, we think that monitoring routinely collected data could improve the surveillance of the animal population health. Even if not used for detection purposes, cattle mortality monitoring could be used to rapidly produce information on the impact and evolution of identified events, what would facilitate decision-making regarding management measures and improve the communication. PMID- 22243987 TI - Computerized gait analysis in Legg-Calve-Perthes disease--analysis of the sagittal plane. AB - Current follow-up- and outcome-evaluations of Legg-Calve-Perthes disease (LCPD) are based on subjective measures of function, clinical and radiological parameters. The objective of this study was to evaluate the sagittal plane kinematics and the effect on hip joint loading on the affected hip in children with LCPD. MATERIALS AND METHODS: Computerized gait analysis was performed in 49 LCPD patients aged >= 5 years with unilateral hip involvement. Sagittal plane kinematics and kinetics were compared to a group of healthy children (n=30). RESULTS: Kinematics: a significantly increased anterior tilt and range of motion (ROM) of the pelvis combined with a marked reduction of the extension of the involved hip joint compared to the control group was observed. The increased ROM of the contralateral hip results from increased maximum flexion. Power generation: overall significantly decreased on the involved side during florid stage. Global hip function: significantly reduced hip flexor index of the involved hip; 46.2% of the patients in advanced stage, although having no significant changes in kinematics - except increased anterior pelvic tilt - had a pathologic HFI. CONCLUSION: Sagittal plane hip function is significantly impaired in florid and advanced LCPD. The results of this study will lead to further investigations into whether this development can be prevented by conservative or operative treatment thus improving function and long-term prognosis. PMID- 22243988 TI - Online control of anticipated postural adjustments in step initiation: evidence from behavioral and computational approaches. AB - Anticipatory postural adjustments (APAs) prior to step execution are thought to be immutable once released. Here we challenge this assumption by testing whether APAs can be modified online if a body perturbation occurs during execution. Two directions of perturbation (resisting and assisting) relative to the body weight transfer were used during the execution of APAs. We found that APAs are modified online (increase in both ground pressure and muscle activity) to compensate for resisting perturbations. The outcomes of a biomechanical model confirmed that the early changes in the APAs resulted from an active control of the APAs and were not merely mechanical consequences of the perturbation. However, no modification of the initial feedforward command was observed for assisting perturbations. The motor command changes for the resisting perturbation may originate from the mismatch between passively originated forces and those actively specified by the central command when acting in the opposite direction. The absence of a mismatch in the assisting perturbation might explain why the central nervous system was not prompted to modify the APAs in this condition. PMID- 22243989 TI - The mirror sign: a reflection of cognitive decline? PMID- 22243990 TI - Wernicke's encephalopathy in a patient with hyperemesis gravidarum. PMID- 22243991 TI - Impact of clinical severity index, infective pathogens, and initial empiric antibiotic use on hospital mortality in patients with ventilator-associated pneumonia. AB - BACKGROUND: The prompt initial use of appropriate antibiotics should improve mortality rates in adults with ventilator-associated pneumonia (VAP). However, the incidence of multidrug-resistant (MDR) pathogen infections is on the rise, and the choice of the initial empiric antibiotic may be challenging. We investigated whether appropriate initial antibiotic therapy, infective pathogens, and the clinical severity index influence hospital mortality in patients with VAP and determined independent risk factors for the same. METHODS: This study evaluated 163 adult patients (aged >= 18 years) at Chang Gung Memorial Hospital, Kaohsiung, Taiwan, from January 1, 2007, to January 31, 2008. Eligibility was evaluated based on criteria for VAP. Sequential Organ Failure Assessment (SOFA) scores, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) scores, oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis. RESULTS: Ninety-two patients survived from a total 163 patients with VAP during the course of their confinement in the intensive care unit. Multivariable logistic regression analysis identified that a pre-existing Charlson Comorbidity Index score (P = .011), initial oxygenation index (P = .025), SOFA score (P = .043), VAP caused by Acinetobacter baumanii (P = .030), and infection with MDR pathogens (P = .003) were independent risk factors for hospital mortality in patients with VAP. CONCLUSION: High Charlson Comorbidity Index score, high initial oxygenation index, high SOFA score, and infection with Acinetobacter baumannii or MDR pathogens significantly affect hospital mortality in patients with VAP. PMID- 22243992 TI - Is a head CT necessary after uncomplicated coiling of unruptured intracranial aneuryms? AB - In this study, we sought to determine whether routine head computed tomographies (CTs) after uncomplicated coil embolization of intracranial aneurysms can add any significant clinical value. METHODS: We retrospectively reviewed the medical records of 139 patients with unruptured aneurysms who underwent 150 elective coiling procedures between January 2008 and June 2010. A total of 6 head CTs were obtained emergently after intraprocedural complications and 122 head CTs were obtained routinely after uncomplicated coil embolization of intracranial aneurysms. RESULTS: The 122 head CTs that were obtained routinely after uncomplicated coil embolization of unruptured intracranial aneurysms did not show any acute or subacute changes. CONCLUSION: A head CT after uncomplicated coil embolization of an intracranial aneurysm does not add any significant clinical value and should not be ordered routinely. PMID- 22243993 TI - How uniquely irreducible is consciousness? Defining the limits of biological reductionism: a commentary on Neuroontology, neurobiological naturalism, and consciousness: a challenge to scientific reduction and a solution, by Todd E. Feinberg, MD. PMID- 22243994 TI - The six most essential questions in psychiatric diagnosis: a pluralogue part 1: conceptual and definitional issues in psychiatric diagnosis. AB - In face of the multiple controversies surrounding the DSM process in general and the development of DSM-5 in particular, we have organized a discussion around what we consider six essential questions in further work on the DSM. The six questions involve: 1) the nature of a mental disorder; 2) the definition of mental disorder; 3) the issue of whether, in the current state of psychiatric science, DSM-5 should assume a cautious, conservative posture or an assertive, transformative posture; 4) the role of pragmatic considerations in the construction of DSM-5; 5) the issue of utility of the DSM - whether DSM-III and IV have been designed more for clinicians or researchers, and how this conflict should be dealt with in the new manual; and 6) the possibility and advisability, given all the problems with DSM-III and IV, of designing a different diagnostic system. Part I of this article will take up the first two questions. With the first question, invited commentators express a range of opinion regarding the nature of psychiatric disorders, loosely divided into a realist position that the diagnostic categories represent real diseases that we can accurately name and know with our perceptual abilities, a middle, nominalist position that psychiatric disorders do exist in the real world but that our diagnostic categories are constructs that may or may not accurately represent the disorders out there, and finally a purely constructivist position that the diagnostic categories are simply constructs with no evidence of psychiatric disorders in the real world. The second question again offers a range of opinion as to how we should define a mental or psychiatric disorder, including the possibility that we should not try to formulate a definition. The general introduction, as well as the introductions and conclusions for the specific questions, are written by James Phillips, and the responses to commentaries are written by Allen Frances. PMID- 22243995 TI - Why do results conflict regarding the prognostic value of the methylation status in colon cancers? The role of the preservation method. AB - BACKGROUND: In colorectal carcinoma, extensive gene promoter hypermethylation is called the CpG island methylator phenotype (CIMP). Explaining why studies on CIMP and survival yield conflicting results is essential. Most experiments to measure DNA methylation rely on the sodium bisulfite conversion of unmethylated cytosines into uracils. No study has evaluated the performance of bisulfite conversion and methylation levels from matched cryo-preserved and Formalin-Fixed Paraffin Embedded (FFPE) samples using pyrosequencing. METHODS: Couples of matched cryo preserved and FFPE samples from 40 colon adenocarcinomas were analyzed. Rates of bisulfite conversion and levels of methylation of LINE-1, MLH1 and MGMT markers were measured. RESULTS: For the reproducibility of bisulfite conversion, the mean of bisulfite-to-bisulfite standard deviation (SD) was 1.3%. The mean of run-to run SD of PCR/pyrosequencing was 0.9%. Of the 40 DNA couples, only 67.5%, 55.0%, and 57.5% of FFPE DNA were interpretable for LINE-1, MLH1, and MGMT markers, respectively, after the first analysis. On frozen samples the proportion of well converted samples was 95.0%, 97.4% and 87.2% respectively. For DNA showing a total bisulfite conversion, 8 couples (27.6%) for LINE-1, 4 couples (15.4%) for MLH1 and 8 couples (25.8%) for MGMT displayed significant differences in methylation levels. CONCLUSIONS: Frozen samples gave reproducible results for bisulfite conversion and reliable methylation levels. FFPE samples gave unsatisfactory and non reproducible bisulfite conversions leading to random results for methylation levels. The use of FFPE collections to assess DNA methylation by bisulfite methods must not be recommended. This can partly explain the conflicting results on the prognosis of CIMP colon cancers. PMID- 22243996 TI - Controlling disease outbreaks in wildlife using limited culling: modelling classical swine fever incursions in wild pigs in Australia. AB - Disease modelling is one approach for providing new insights into wildlife disease epidemiology. This paper describes a spatio-temporal, stochastic, susceptible- exposed-infected-recovered process model that simulates the potential spread of classical swine fever through a documented, large and free living wild pig population following a simulated incursion. The study area (300 000 km2) was in northern Australia. Published data on wild pig ecology from Australia, and international Classical Swine Fever data was used to parameterise the model. Sensitivity analyses revealed that herd density (best estimate 1-3 pigs km-2), daily herd movement distances (best estimate approximately 1 km), probability of infection transmission between herds (best estimate 0.75) and disease related herd mortality (best estimate 42%) were highly influential on epidemic size but that extraordinary movements of pigs and the yearly home range size of a pig herd were not. CSF generally established (98% of simulations) following a single point introduction. CSF spread at approximately 9 km2 per day with low incidence rates (< 2 herds per day) in an epidemic wave along contiguous habitat for several years, before dying out (when the epidemic arrived at the end of a contiguous sub-population or at a low density wild pig area). The low incidence rate indicates that surveillance for wildlife disease epidemics caused by short lived infections will be most efficient when surveillance is based on detection and investigation of clinical events, although this may not always be practical. Epidemics could be contained and eradicated with culling (aerial shooting) or vaccination when these were adequately implemented. It was apparent that the spatial structure, ecology and behaviour of wild populations must be accounted for during disease management in wildlife. An important finding was that it may only be necessary to cull or vaccinate relatively small proportions of a population to successfully contain and eradicate some wildlife disease epidemics. PMID- 22243997 TI - Assessment of a Chitosan/Hyaluronan Injectable Composite for Fat Reconstruction. AB - The long-term success of autologous fat transplants is dependent on numerous factors including tissue quality, tissue survivability and the expansion of the implanted cells. The addition of a biomaterial filler to an injectable gel implant matrix provides an anchor and scaffold for proliferating cells as well as a carrier for syringe delivery. Building on the tissue reconstruction concept which we first disclosed, i.e., an injectable composite comprised of beads in a gel, the present study uses an injectable composite comprised of fatty-acid loaded chitosan/gelatin (FA-CG) beads (i.e., a degradable filler material with tissue bulking potential) and hyaluronic acid (HA, a matrix). Human and bovine preadipocytes were considered independently; however, in both cases the cells proliferated and differentiated equally when grown with the FA-CG/HA composite, as demonstrated by the production of lipids and triglycerides, as well as expression of the human adipocyte marker aP2. The preadipocyte/FA-CG/HA injectables formed stable complexes that remained intact, with little degradation and no measurable immune response, for 4 months after implantation into mice. These results suggest that FA-CG/HA composite is a suitable injectable matrix for preadipocyte transplantation, providing the basis for further studies investigating the suitability of this technique for larger-scale tissue implantation and regeneration. PMID- 22243998 TI - Transvaginal ultrasound ovarian diathermy: sheep as an experimental model. AB - BACKGROUND: Some techniques of transvaginal ovarian drilling have been previously described. Nevertheless a monopolar transvaginal ovarian cauterization, that use the expertise and safety of transvaginal puncture for oocyte captation seems to be an easier and feasible approach. The aim of this study was to develop a minimally invasive ovarian cauterization technique under transvaginal ultrasound control, and to evaluate the safety of the transvaginal ovarian monopolar cauterization, female sheep at reproductive age were used as an experimental model. FINDINGS: An experimental study was performed in a university research center. Seventeen female sheep (15 Corriedale e 2 Suffolk) in reproductive age were submitted to transvaginal ovarian cauterization with a monopolar Valleylab Force 2 electrocautery. Macroscopic and microscopic lesions were assessed. Ovarian size were 1.31 cm2 +/- 0,43 (Corriedale) and 3.41 cm2 +/- 0,64 (Suffolk). From 30 ovaries from Corriedale sheep punctured, only 3 were cauterized, presenting macroscopic and typical microscopic lesion. In the Suffolk sheep group, only one ovary was cauterized. No lesion could be found in the needle path. CONCLUSIONS: This is the first experimental animal model described for ovarian cauterization needle guided by transvaginal ultrasound. The sheep does not seem to be the ideal animal model to study this technique. Another animal model, whose ovaries are better identified by transvaginal ultrasound should be sought for this technique, theoretically less invasive, before it could be offered safely to women with polycystic ovary syndrome. PMID- 22243999 TI - Ejection fraction change and coronary artery disease severity: a vasodilator contrast stress-echocardiography study. AB - BACKGROUND: An important goal of noninvasive stress testing is the identification of patients with left main coronary artery or three-vessel disease, because coronary artery disease extension and severity are major prognostic factors in ischemic heart disease. Wall motion abnormalities during vasodilator stress echocardiography become apparent in more than one coronary territory only in a small number of patients with multivessel disease. The aim of this study was to assess the value of change in left ventricular ejection fraction change (DeltaLVEF) to identify patients with multivessel obstructive coronary artery disease during dipyridamole stress echocardiography. METHODS: All dipyridamole stress echocardiographic studies performed at the authors' institution from October 2007 through March 2010 were retrospectively reviewed, and 150 patients who underwent coronary angiography within the next 60 days were selected. Left ventricular end-diastolic volume and end-systolic volume were measured at baseline and at the end of high-dose dipyridamole; DeltaLVEF was calculated as stress ejection fraction minus rest ejection fraction. Patients were divided into four groups (controls and patients with single-vessel, two-vessel, and three vessel disease) on the basis of coronary angiographic results. RESULTS: The mean LVEF increased significantly from rest to peak stress in all groups except the three-vessel disease group. Mean DeltaLVEF was negative in patients with three vessel or left main coronary artery disease (-2.8 +/- 5.1%) and significantly lower compared with all other angiographic groups (10.2 +/- 5.1% and 6.2 +/- 4.1%, respectively, for single-vessel and two-vessel disease). The negative value of DeltaLVEF for three-vessel disease was due mainly to increased end-systolic volume at peak stress. Receiver operating characteristic curves demonstrated excellent accuracy of DeltaLVEF compared with change in wall motion score index in identifying patients with multivessel disease, with areas under the curves of 0.96 and 0.62, respectively. CONCLUSIONS: DeltaLVEF is significantly lower in patients with severe coronary artery disease compared with those with single vessel or two-vessel disease; reduced DeltaLVEF identifies high-risk patients, who are likely to benefit from a more aggressive therapeutic strategy. PMID- 22244000 TI - In vitro atrial septal ablation using high-intensity focused ultrasound. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) has been applied clinically as a noninvasive therapeutic tool. Atrial septostomy is a palliative treatment for pulmonary artery hypertension. The purpose of this study was to assess the feasibility of atrial septal ablation in vitro using HIFU. METHODS: Fourteen sections of atrial septum from pig hearts were treated. Focused ultrasound energy was applied with an operating frequency of 5.25 MHz at the nominal focal point intensity of 4.0 kW/cm(2) for 0.4 sec in 1-sec intervals. RESULTS: Lesions were created with ultrasonic exposures ranging from 40 to 120 pulses. There were significant relationships between HIFU exposure time and lesion area on the exposed site (R(2) = 0.3389, P < .0001) and lesion volume (R(2) = 0.6161, P < .0001). CONCLUSIONS: HIFU has the potential to create focal perforations without direct tissue contact. This method may prove useful for noninvasive atrial septostomy. PMID- 22244001 TI - The incremental value of valvuloarterial impedance in evaluating the results of transcatheter aortic valve implantation in symptomatic aortic stenosis. AB - BACKGROUND: Valvuloarterial impedance (Z(va)) can estimate the global hemodynamic load on the left ventricle in patients with severe aortic stenosis better than the standard indexes, as shown in previous studies. In fact, Z(va) can estimate global left ventricular hemodynamic load as the sum of valvular and vascular loads. The aim of this study was to evaluate the acute improvement of left ventricular performance in patients with symptomatic aortic stenosis after transcatheter aortic valve implantation (TAVI) using Z(va). METHODS: One hundred two consecutive patients who underwent TAVI were submitted to transthoracic echocardiography immediately before and after aortic valve implantation, together with invasive hemodynamic measurements. RESULTS: After TAVI, immediate reductions in the transaortic peak pressure gradient (P < .0001) and mean pressure gradient (P < .0001) and a concomitant increase in aortic valve area (P < .0001) were seen on echocardiography. Left ventricular ejection fraction significantly increased immediately after TAVI in all patients (from 48.9 +/- 10.3% to 52.1 +/- 11.1%, P < .0001). Regarding global left ventricular hemodynamic load, acute and significant reductions in end-systolic meridional wall stress (from 82.7 +/- 42.6 to 57.8 +/- 30.1 kdyne . cm(-2), P < .0001) and in Z(va) (from 6.81 +/- 2.51 to 5.38 +/- 2.13 mm Hg . mL(-1) . m(-2), P < .0001) were observed. Furthermore, patients who died at 6-month follow-up had higher baseline Z(va) values compared with those who were alive at 6-month follow-up (8.13 +/- 3.08 vs 6.41 +/- 2.12 mm Hg . mL(-1) . m(-2), P < .004). CONCLUSIONS: TAVI is characterized by an immediate enhancement of global left ventricular hemodynamic performance, as demonstrated by an acute Z(va) improvement, even in patients with low baseline ejection fractions. PMID- 22244002 TI - The pre-hospital epidemiology and management of spinal cord injuries in New South Wales: 2004-2008. AB - CONTEXT: Patients who have sustained a traumatic spinal cord injury require appropriate management in the immediate post-injury period for both survival and to reduce the chances of costly and disabling permanent neurological deficits. Emerging time-critical neuroprotective therapies require the prompt recognition and transfer of patients to a specialised centre for early intervention. METHODS: The Ambulance Research Institute, with the New South Wales State Spinal Cord Injury Service retrospectively linked prehospital data to spinal cord injury unit (SCIU) outcome data for all 324 patients transported by ambulance and subsequently admitted to a SCIU with a persisting traumatic spinal cord injury (SCI) between January 2004 and June 2008, with the aim of identifying factors that impact on the provision of timely and appropriate care. RESULTS: Paramedics appropriately managed 88% of SCI patients. Only 4.9% of patients had initial vital signs potentially indicative of neurological injury. The median time to a SCIU was 12h, with 60% of patients undergoing multiple transfers. The odds of reaching a SCIU in over 24h were 1.71 times greater for patients injured in a major city (95% CI 1.00-2.90) in comparison to other areas of NSW. More SCI patients with multiple trauma experienced delays in reaching a SCIU (59%), compared to patients with isolated SCI (40%; p=0.039). Patients initially transported to a designated major trauma centre were more likely to be delayed in reaching a SCIU, regardless of whether their injury was an isolated SCI or associated with multiple trauma, compared with other patients. Patients who took greater than 24h to reach a SCIU were 2.5 times more likely to develop a secondary complication (95% CI 1.51-4.17, p=0.0004). Patients who sustained their SCI as a result of a low fall were older and less likely to have their SCI identified and treated early, with less than half of this group reaching a SCIU within 24h compared with other SCI patients (OR 0.42, 95% CI 0.19-0.93, p=0.004). CONCLUSION: Early recognition, appropriate prehospital management, triage, timely and appropriate interfacility transfers of all SCI patients are critical for access to specialised care and reducing preventable complications. Elderly fallers present particular challenges to early identification. PMID- 22244003 TI - State-of-the-art review about basophil research in immunology and allergy: is the time right to treat these cells with the respect they deserve? PMID- 22244004 TI - Clinical and laboratory characteristics of children positive for antiphospholipid antibodies. AB - BACKGROUND: It is difficult to estimate the actual prevalence of antiphospholipid syndrome (APS) in the paediatric population since there are no standardised criteria. We aimed to assess clinical and laboratory characteristics of a cohort of children positive for antiphospholipid antibodies (aPL) to contribute to the understanding of the heterogeneous aPL-related features in childhood. MATERIALS AND METHODS: Forty-four patients with prolonged activated partial thromboplastin time were enrolled and assigned to group I ("transiently positive") or group II ("persistently positive"), based on the detection of elevated aPL plasma levels [lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2-glycoprotein I (anti-beta2GPI) antibodies] on, respectively, one or more occasions, at least 12 weeks apart, by standard procedures. The clinical history and symptoms of all patients were recorded. RESULTS: Thirty-three (75%) patients were assigned to group I, while the other 11 (25%) formed group II. Major associated diseases in group I were urticarial vasculitis (21%), acute infections (18%) and thalassaemia (12%). Five subjects (15%) were asymptomatic. Four out of the 11 subjects (36%) in group II had thrombotic events; they were all persistently aPL-positive and two of them had concomitant systemic lupus erythematosus. The rate of detection of LA-positivity was not significantly different between the two groups (76% vs 91%, p>0.05), whereas the percentage of patients positive for overall aCL was higher in group II than in group I (54% vs 42%, respectively; p<0.05). Specifically, aCL IgG and anti-beta2GPI IgM subtypes were significantly more represented in group II than in group I (100% vs 62% and 75% vs 33%, respectively; p<0.05). DISCUSSION: Our study shows that aPL-positive children have different features that should be taken into account in the classification of criteria for paediatric APS. PMID- 22244005 TI - GeneXpert in the diagnosis of risk factors for thrombophilia: evaluation of its use in a small laboratory. PMID- 22244006 TI - Comparison of myocardial and hepatic iron loading, assessed by MRI T2*, in patients with myelodysplastic syndromes, thalassaemia major and controls. PMID- 22244007 TI - Plasma-derived medicines: access and usage issues. PMID- 22244008 TI - Are intravenous immunoglobulins really inappropriate in acquired von Willebrand syndrome? PMID- 22244010 TI - Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti-factor Xa levels. AB - BACKGROUND: Unfractionated heparin (UFH) is a widely used anticoagulant. Current American College of Chest Physicians guidelines for infants extrapolated from adults recommend 28 U kg(-1) h(1) of UFH to achieve an anti-factor Xa level of 0.35-0.7 IU mL(-1). OBJECTIVE: To assess the profile of anti-FXa-based UFH dosing guidelines in infants. PATIENTS/METHODS: We included all infants aged < 6 months treated with per-protocol intravenous UFH at the Hospital for Sick Children, Toronto, over a 3.5-year period. RESULTS: Of 100 infants, 11% achieved sustained therapeutic anti-FXa levels with current dose recommendations. Only 15% achieved target anti-FXa levels within 24 h with per-protocol dose escalations. Seventeen per cent of patients never achieved therapeutic anti-FXa levels, despite up to 60 days of therapy and triple the recommended dose. The median dose needed to achieve therapeutic anti-FXa levels in the remaining 83 infants was 33 U kg(-1) h(-1) (interquartile range, 30-36). Two in three infants had decreased thrombus size at completion of therapy and no thrombus progression/recurrence, and 11/100 infants suffered major bleeding. Without exclusion of extracorporeal membrane oxygenation patients, an activated partial thromboplastin time (APTT) of > 180 s was detected as a risk factor for major bleeding. CONCLUSIONS: UFH monitoring is challenging in infants. Despite their delay in reaching therapeutic anti-FXa levels, infants monitored with the adult-based anti-FXa range have a high thrombus resolution rate, no thrombus progression, but a relatively high bleeding rate. Extreme APTT elevation may contribute to this bleeding risk, particularly in critically ill patients. Current UFH guidelines for young infants may still be inadequate, and laboratory methods with age-appropriate ranges may be required to further improve clinical outcomes within this population. PMID- 22244012 TI - American Association of Heart Failure Nurses' mission, vision, and strategic plan: what do these mean to me--the member? PMID- 22244013 TI - [Liver and heart T2* measurement in secondary haemochromatosis]. AB - OBJECTIVE: To determine whether there is iron overload by calculating the T2* value in the liver and myocardium in patients with secondary haemochromatosis. To analyse the correlation of the values obtained with the iron levels in blood, with the liver iron concentration (LIC) calculated using magnetic resonance (MR) imaging, and the correlation between them. MATERIAL AND METHODS: A total of 16 patients (13 males, 3 females), with a mean age of 61 years, were included and evaluated in the years 2008 and 2009. Fifteen of them had received multiple transfusions, and one was diagnosed with hereditary sideroblastic anaemia. The measurements included, blood ferritin, LIC by MRI, cardiac function using MRI and the T2* value by means of multi-echo sequences in the liver (TR/TE1/DeltaTE/No of echos/alpha: 21/1,18/1.0/20/35 degrees ) and myocardium (26/1.04/0.8/30/60 degrees ). A correlation-regression analysis was performed by comparing the cardiac and liver T2* values with the ferritin, LIC and between each of them. RESULTS: A total of 13 patients had ferritin values greater than 1000ng/ml (median/minimum/maximum: 1762/294/3785ng/ml). An increased LIC greater than 80MUmol/g (median/minimum/maximum: 125.4/41.2/241.5MUmol/g) was observed in 13 patients. In all cases cardiac function was conserved, and in 15 cases the liver T2* value was less than 6.3ms. The myocardium T2* value was less than 20ms. in only one case. A high correlation was observed between the liver T2* values and the LIC (r:-0.912). The correlation was statistically significant between the liver T2* value and ferritin (r:-0.541). The correlations between myocardium T2* and ferritin, myocardium T2* and LIC, and myocardium T2* and liver T2* were not statistically significant. CONCLUSIONS: The liver T2* showed a high correlation with LIC and a statistically significant correlation with ferritin. No association was observed between the myocardium T2* values and ferritin in blood, the LIC or the liver T2* value. PMID- 22244014 TI - beta2-1 Fructans have a bifidogenic effect in healthy middle-aged human subjects but do not alter immune responses examined in the absence of an in vivo immune challenge: results from a randomised controlled trial. AB - beta2-1 fructans are considered to be prebiotics. Current literature indicates that beta2-1 fructans may modulate some aspects of immune function, improve the host's ability to respond to certain intestinal infections, and modify some inflammatory outcomes in human subjects. However, there is a need to find out more about the modulation of immune markers by beta2-1 fructans in humans. Healthy human subjects aged 45-65 years were randomly allocated to beta2-1 fructans (Orafti(r) Synergy1; 8 g/d; n 22) or the digestible carbohydrate maltodextrin as placebo (n 21) for 4 weeks. Blood, saliva and faecal samples were collected at study entry and after 4 weeks. Immune parameters were measured using the blood and saliva samples and bifidobacteria were measured in the faecal samples. Faecal bifidobacteria numbers increased in the Orafti(r) Synergy1 group (P < 0.001) and were different at 4 weeks from numbers in the placebo group (P = 0.001). There was no significant effect of Orafti(r) Synergy1 on any of the immune parameters measured (blood immune cell subsets, total serum Ig, salivary IgA, neutrophil and monocyte phagocytosis of Escherichia coli and respiratory burst in response to E. coli or phorbol ester, natural killer cell activity, T cell activation and proliferation, production of six cytokines by T cells). It is concluded that, compared with maltodextrin, Orafti(r) Synergy1 has a bifidogenic effect in healthy middle-aged human subjects but does not alter immune responses examined in the absence of an in vivo immune challenge. PMID- 22244015 TI - Oral health related quality of life in pregnant and post partum women in two social network domains; predominantly home-based and work-based networks. AB - BACKGROUND: Individuals connected to supportive social networks have better general and oral health quality of life. The objective of this study was to assess whether there were differences in oral health related quality of life (OHRQoL) between women connected to either predominantly home-based and work based social networks. METHODS: A follow-up prevalence study was conducted on 1403 pregnant and post-partum women (mean age of 25.2 +/- 6.3 years) living in two cities in the State of Rio de Janeiro, Brazil. Women were participants in an established cohort followed from pregnancy (baseline) to post-partum period (follow-up). All participants were allocated to two groups; 1. work-based social network group--employed women with paid work, and, 2. home-based social network group--women with no paid work, housewives or unemployed women. Measures of social support and social network were used as well as questions on sociodemographic characteristics and OHRQoL and health related behaviors. Multinomial logistic regression was performed to obtain OR of relationships between occupational contexts, affectionate support and positive social interaction on the one hand, and oral health quality of life, using the Oral Health Impacts Profile (OHIP) measure, adjusted for age, ethnicity, family income, schooling, marital status and social class. RESULTS: There was a modifying effect of positive social interaction on the odds of occupational context on OHRQoL. The odds of having a poorer OHIP score, >= 4, was significantly higher for women with home-based social networks and moderate levels of positive social interactions [OR 1.64 (95% CI: 1.08-2.48)], and for women with home-based social networks and low levels of positive social interactions [OR 2.15 (95% CI: 1.40-3.30)] compared with women with work-based social networks and high levels of positive social interactions. Black ethnicity was associated with OHIP scores >= 4 [OR 1.73 (95% CI: 1.23-2.42)]. CONCLUSIONS: Pregnant and post-partum Brazilian women in paid employment outside the home and having social supports had better OHRQoL than those with home-based social networks. PMID- 22244016 TI - Time to reflect on surgery and neuro-intervention for intracranial atherosclerotic diseases. AB - In view of the early results and halt of recruitment from both the Carotid Occlusion Surgery Study (COSS) and Stenting and the Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study we should seize this opportunity to reflect on future directions, rather than abandoning these procedures, during this period of disillusionment. We here suggest the reasons for the failure of these two clinical trials and review future directions for researche in cerebral revascularization. PMID- 22244017 TI - Anatomic differences in early blindness: a deformation-based morphometry MRI study. AB - BACKGROUND AND PURPOSE: This study aims to investigate the regional changes in the early onset of blindness using the deformation-based morphometry (DBM) method. METHODS: A total of 15 early blindness and 30 gender- and age-matched sighted control subjects were recruited for the study. Statistically significant changes in regional volume were analyzed using DBM through HAMMER registration. Using this technique, changes in regional tissue volume can be detected on the basis of the deformation field derived from the warping subject to the template image. A voxelwise estimation of the morphological differences between the two groups can be acquired after applying a threshold (P < .001, uncorrected) to the statistic maps. RESULTS: Regions with enlarged volume in the brains of blind subjects are mainly localized in the left associated visual cortex, posterior cingulated cortex, and cerebellum, whereas volume reductions are primarily localized in the left early visual cortex. CONCLUSIONS: DBM is an effective method for detecting entire brain structural changes in blindness. Visual deprivation actually alters the local structural organization during the early critical periods of neurodevelopment. Volume increases outside the occipital lobe detected with DBM may suggest compensatory adaptations. PMID- 22244018 TI - Space-time clustering of childhood central nervous system tumours in Yorkshire, UK. AB - BACKGROUND: We specifically tested the aetiological hypothesis that a factor influencing geographical or temporal heterogeneity of childhood central nervous system (CNS) tumour incidence was related to exposure to a transient environmental agent. METHODS: Information was extracted on individuals aged 0-14 years, diagnosed with a CNS tumour between the 1st January 1974 and 31st December 2006 from the Yorkshire Specialist Register of Cancer in Children and Young People. Ordnance Survey eight-digit grid references were allocated to each case with respect to addresses at the time of birth and the time of diagnosis, locating each address to within 0.1 km. The following diagnostic groups were specified a priori for analysis: ependymoma; astrocytoma; primitive neuroectodermal tumours (PNETs); other gliomas; total CNS tumours. We applied the K-function method for testing global space-time clustering using fixed geographical distance thresholds. Tests were repeated using variable nearest neighbour (NN) thresholds. RESULTS: There was statistically significant global space-time clustering for PNETs only, based on time and place of diagnosis (P = 0.03 and 0.01 using the fixed geographical distance and the variable NN threshold versions of the K-function method respectively). CONCLUSIONS: There was some evidence for a transient environmental component to the aetiology of PNETs. However, a possible role for chance cannot be excluded. PMID- 22244019 TI - Role of moxifloxacin for the treatment of community-acquired [corrected] complicated intra-abdominal infections in Taiwan. AB - Complicated intra-abdominal infections (cIAIs) are common yet serious infections that can potentially lead to substantial morbidity and morbidity. As an essential adjunct to source control, the goals of antimicrobial therapy are to promote patient recovery, reduce recurrence risk, and prevent antimicrobial resistance. The current international guidelines on the empirical treatment of community acquired complicated IAIs were published by the Infectious Diseases Society of America (IDSA) and Surgical Infections Society (SIS) in 2010. These guidelines all recommend the use of a fluoroquinolone (ciprofloxacin or levofloxacin) plus metronidazole for mild-to-moderate- and high-severity cases. Moxifloxacin monotherapy is recommended by the current IDSA/SIS guidelines for the treatment of mild-to-moderate complicated IAIs. Moxifloxacin has demonstrated a broad spectrum coverage of both aerobic and anaerobic pathogens, good tissue penetration into the gastrointestinal tract, and a good tolerability profile. Clinical data have demonstrated that moxifloxacin is at least as effective as other standard therapeutic regimens recommended by current clinical guidelines. Due to the high rates of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and fluoroquinolone-resistant Enterobacteriaceae among isolates causing community-acquired IAIs in Asia, any fluoroquinolones (including moxifloxacin) are not recommended as drugs of choice for the empirical treatment of community-acquired IAIs, particularly in countries (China, India, Thailand, and Vietnam) with fluoroquinolone resistance rates among Escherichia coli isolates of >20%. Given the low rates of fluoroquinolone-resistant (<20%) and extended-spectrum beta-lactamase (ESBL)-producing (<10%) Enterobacteriaceae isolates associated community-acquired IAIs in Taiwan, it appears that moxifloxacin is considered an appropriate first-line therapy for patients with community-acquired complicated IAIs in this country. PMID- 22244020 TI - The impact of omega-3 fatty acids on depressive disorders and suicidality: can we reconcile 2 studies with seemingly contradictory results? PMID- 22244021 TI - Increased risk of diabetes mellitus among persons with psychotic symptoms: results from the WHO World Health Survey. AB - OBJECTIVE: To analyze with a symptom-based approach the relationship between psychosis and diabetes mellitus in the general population. METHOD: Nationally representative samples from the World Health Organization (WHO) World Health Survey, totaling 224,743 randomly selected adults 18 years and older from 52 countries worldwide, were interviewed to establish the presence of psychotic symptoms and diabetes mellitus. Presence of psychotic symptoms was established using questions pertaining to positive symptoms from the psychosis screening module of the Composite International Diagnostic Interview. Presence of diabetes was established with a response of "yes" to the question, "Have you ever been diagnosed with diabetes (high blood sugar)?" The World Health Survey was conducted between 2002 and 2004. RESULTS: An increasing number of psychotic symptoms was related to increasing likelihood of diabetes mellitus (OR = 1.27; 95% CI, 1.24-1.30). As compared to no symptoms, at least 1 psychotic symptom substantially elevated the risk (OR = 1.71; 95% CI, 1.61-1.81). In people with a lifetime diagnosis of schizophrenia or psychosis, the prevalence of diabetes was higher in those with current psychotic symptoms (7.3% vs 5.2%; OR = 1.65; 95% CI, 1.21-2.26), suggesting that the persistence of symptoms over time could play a central role. After controlling for different potential confounders, there was a clear increase in the probability of having diabetes as the number of psychotic symptoms increased. The relationship between psychotic symptoms and diabetes was tested with multiple mediation models and path analyses for categorical outcomes. Only body mass index appeared as a relevant mediator in a model with a good fit (ie, chi21 = 3.2, P = .0742; comparative fit index = 0.999). CONCLUSIONS: Psychotic symptoms are related to increased rates of diabetes mellitus in nonclinical samples, independent of several potential confounders-including a clinical diagnosis of psychosis or schizophrenia, previous antipsychotic treatment, depression, lifestyle, and individual or country socioeconomic status. The findings highlight the worldwide relevance of the problem and the importance of identifying the specific paths of this association. PMID- 22244022 TI - Problematic video game use scale: initial psychometric properties with psychiatrically hospitalized adolescents. AB - OBJECTIVE: Excessive video game use among youth has been a growing concern in the United States and elsewhere. The aims of this study are to establish validity of a video game measure in a large adolescent inpatient sample, identify clinical factors underlying problem video game use, and identify associations with measures of psychopathology. METHOD: Three hundred eighty participants admitted to an adolescent inpatient psychiatric unit between November 2007 and March 2009 were administered a battery of self-report measures, including a questionnaire developed for this study that assessed reinforcers and consequences of past-year video game use (ie, Problematic Video Game Use Scale). Factor analysis was used to identify the underlying structure of behaviors associated with problem video game use. RESULTS: A factor analysis of the Problematic Video Game Use Scale indicated 2 primary factors. One was associated with engaging in problem behaviors that impaired the adolescent's functioning as a result of playing video games and one reflected the reinforcing effects of playing video games. Both factors were associated with measures of psychopathology, although associations were generally stronger for impairment in functioning than for reinforcing effects. Both factors were significantly correlated with self-reported daily video game use (P < .001). CONCLUSIONS: Two underlying factors emerged to account for problem video game playing: impairment in functioning and reinforcing effects. Initial evidence of the content validity of the video game measure was established. Findings highlight the importance of assessing video game use among an adolescent population, the factors associated with video game use, and associations with symptoms of psychopathology. Limitations include a common reporter for multiple measures and cross-sectional data that do not allow for causal links to be made. PMID- 22244023 TI - Mid-term and long-term efficacy and effectiveness of antipsychotic medications for schizophrenia: a data-driven, personalized clinical approach. AB - OBJECTIVE: Our aim in this article is 2-fold: first, to examine the mid-term to long-term data on efficacy, from controlled and naturalistic and other studies, in order to determine if they are consistent with the quantitative meta-analyses of mostly short-term, randomized controlled trials Our second (and most important) aim is to use these and other data to provide guidance about the potential relationship of these differences among antipsychotics to the individual patient's own experience with antipsychotic drugs in the process of shared decision-making with the patients and their significant others. DATA SOURCES: A search of PubMed, Embase, and PsychINFO was conducted for articles published in English between January 1, 1999, and April 2011, using the search terms double-blind AND randomized AND olanzapine AND (ziprasidone OR risperidone OR quetiapine OR haloperidol OR fluphenazine OR perphenazine OR aripiprazole). STUDY SELECTION: Studies with a duration 3 months or longer, including patients with schizophrenia or schizoaffective disorder, reporting survival analysis for all-cause discontinuation and relapse or dropout due to poor efficacy were selected. DATA EXTRACTION: We extracted the number of patients relapsed due to poor efficacy and hazard rates for relapses. DATA SYNTHESIS: Overall, the efficacy patterns of both controlled effectiveness and observational long-term studies closely parallel the efficacy observed in the short-term, controlled studies. The results of Phase 1 Clinical Antipsychotic Trials of Intervention Effectiveness are very similar to, but not identical with, the controlled short term efficacy studies, the European First-Episode Schizophrenia Trial, and naturalistic studies. The mid-term and long-term data suggest that olanzapine is more effective than risperidone and that both of these are better than the other first- and second-generation antipsychotics except for clozapine, which is the most efficacious of all. Further large differences emerged regarding the specific mid-term and long-term safety profiles of individual antipsychotics. CONCLUSIONS: Despite intraclass differences and the complexities of antipsychotic choice, the second-generation antipsychotics are important contributions not only to the acute phase but, more importantly, to the maintenance treatment of schizophrenia. PMID- 22244024 TI - A case of agranulocytosis secondary to rechallenge with clozapine following severe neutropenia during previous therapy. PMID- 22244025 TI - Efficacy of antidepressants for late-life depression: a meta-analysis and meta regression of placebo-controlled randomized trials. AB - OBJECTIVE: Late-life depression is an important public health issue, given the growing proportion of the elderly relative to the general population in the developed world. The purpose of this study was to examine the efficacy of antidepressants for the treatment of major depressive disorder (MDD) in elderly patients. DATA SOURCES: PubMed/MEDLINE was searched for randomized, double-blind, placebo-controlled trials of antidepressants for treatment of both adult (nonelderly) MDD (patients aged < 65 years) and late-life MDD (patients aged >= 55 years). The search was limited to articles published between January 1, 1980, and March 3, 2010 (inclusive). The year 1980 was used as a cutoff in our search to decrease diagnostic variability, since the DSM-III was introduced in 1980. Our search cross-referenced the term placebo with each of the following antidepressants: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. We also reviewed the reference lists of all studies identified through the PubMed/MEDLINE search. STUDY SELECTION: Articles were selected that reported on randomized, double blind, placebo-controlled trials of antidepressants used as monotherapy for treatment of MDD and that met numerous a priori criteria pertaining to MDD diagnosis criteria, study duration, study design, drug formulation, original data, age thresholds, primary and secondary outcome measures, and exclusions of other disorders. Final inclusion of articles was determined by consensus between the authors. Seventy-four articles were found eligible for inclusion in our analysis (15 late-life MDD trials and 59 adult MDD trials). RESULTS: Antidepressants were found to be efficacious for late-life MDD (age 55 and older; P < .0001), although there was evidence for heterogeneity across studies (Q22 = 67.302, P < .001). However, antidepressants were not found to be efficacious in the subset of studies using age thresholds of 65 years or older (older late-life MDD) (P = .265). Finally, when we controlled for study design characteristics, antidepressant but not placebo response rates were lower among late-life MDD patients than among adult MDD patients. CONCLUSIONS: The present meta-analysis suggests that antidepressants are efficacious in late-life MDD, but significant study heterogeneity suggests that other factors may contribute to these findings. A secondary analysis raises the possibility that efficacy of these agents may be reduced in trials involving patients aged 65 years or older. Why antidepressants may be less efficacious in elderly versus younger subjects remains unclear. PMID- 22244027 TI - Antidepressant use and risk for suicide attempts in bipolar disorder. PMID- 22244026 TI - Variants of the serotonin transporter gene, selective serotonin reuptake inhibitors, and bone mineral density in risperidone-treated boys: a reanalysis of data from a cross-sectional study with emphasis on pharmacogenetics. AB - OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may reduce bone mineral density (BMD). Here, we investigate whether variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene moderate this association in boys. METHOD: Between November 2005 and August 2009, medically healthy boys, aged 7 to 17 years, were enrolled in a cross sectional study exploring the effect of risperidone-induced hyperprolactinemia on BMD. Volumetric BMD of the ultradistal radius was measured using peripheral quantitative computed tomography, and areal BMD of the lumbar spine was estimated using dual energy x-ray absorptiometry. Multiple linear regression analysis tested whether the 5-HTTLPR genotypes interacted with SSRI treatment status to affect BMD, adjusting for relevant confounders. Participant enrollment was conducted at the University of Iowa, Iowa City. RESULTS: Of 108 boys (mean +/- SD age = 11.7 +/- 2.8 years), with DSM-IV clinical diagnoses based on chart review, 52% (n = 56) had been taking an SSRI for a median duration of 2.8 years. After adjusting for pubertal development, anthropometric measures, physical activity, calcium intake, and prolactin concentration, there was a significant 5-HTTLPR genotype * SSRI treatment interaction effect on total lumbar spine BMD z score (P < .05) in non-Hispanic whites. The interaction effect on BMD at the ultradistal radius failed to reach statistical significance. Among LS genotype carriers, those treated with SSRIs had lower lumbar BMD z score and trabecular BMD at the radius compared to those not treated (P < .02 and P < .008, respectively). CONCLUSIONS: These findings add to the growing evidence implicating the serotonin system in bone metabolism. They suggest the potential use of 5-HTTLPR genotypes to guide the safer long-term prescribing of SSRIs in youths. However, prospective confirmation in a controlled matched population is warranted. PMID- 22244029 TI - Predicting suicide attempt risk: logistic regression requires large sample sizes. PMID- 22244032 TI - Using algorithms and computerized decision support systems to treat major depression. AB - The American Psychiatric Association practice guidelines for treating major depressive disorder advocate using measurement-based care and treatment algorithms, which have been shown to be effective strategies in improving patient outcomes. However, in practice, clinicians may avoid using algorithms and guidelines due to barriers such as lack of time, lack of staff support, and the perceived inflexibility of algorithms. Computerized decision support systems (CDSS) are one approach to increasing guideline adherence. A CDSS can make measurement-based care strategies accessible and user-friendly for physicians and staff, individualize treatment options according to each patient's circumstances, and provide guideline information at the point of care. In addition, a CDSS can be merged with electronic health record systems, which should simplify implementation and increase guideline adherence. PMID- 22244033 TI - Clinical impact of updated diagnostic and research criteria for Alzheimer's disease. AB - Almost 30 years ago, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (more commonly known as the Alzheimer's Association) developed the original clinical diagnostic criteria for Alzheimer's disease (AD). Recently, the National Institute on Aging and the Alzheimer's Association released updated research and diagnostic criteria for AD. The new criteria establish that AD exists on a continuum and is comprised of not only dementia but also a preclinical phase and a phase of mild cognitive impairment due to AD. The new criteria also describe advancements in biomarker evidence, which is still being researched and is not yet ready for clinical settings. Additionally, the American Psychiatric Association is currently revising the Diagnostic and Statistical Manual of Mental Disorders, which will include updated diagnostic criteria for AD and other neurocognitive disorders. PMID- 22244034 TI - Presentation and diagnosis of fibromyalgia. AB - Because of substantial symptomatic overlap with several other conditions, fibromyalgia is difficult to detect and diagnose. The hallmark symptom of fibromyalgia is widespread pain, but patients often complain of only specific or localized pain symptoms, complicating the diagnosis. Assessing pain symptoms is the first step in the diagnostic process and must include performing a differential diagnosis and identifying comorbid illnesses. New diagnostic criteria for fibromyalgia allow primary care physicians to bypass a time consuming 18-point physical examination and, instead, use assessment tools. PMID- 22244035 TI - Effects of swimming training on blood pressure and vascular function in adults >50 years of age. AB - Swimming is ideal for older adults because it includes minimum weight-bearing stress and decreased heat load. However, there is very little information available concerning the effects of regular swimming exercise on vascular risks. We determined if regular swimming exercise would decrease arterial blood pressure (BP) and improve vascular function. Forty-three otherwise healthy adults >50 years old (60 +/- 2) with prehypertension or stage 1 hypertension and not on any medication were randomly assigned to 12 weeks of swimming exercise or attention time controls. Before the intervention period there were no significant differences in any of the variables between groups. Body mass, adiposity, and plasma concentrations of glucose and cholesterol did not change in either group throughout the intervention period. Casual systolic BP decreased significantly from 131 +/- 3 to 122 +/- 4 mm Hg in the swimming training group. Significant decreases in systolic BP were also observed in ambulatory (daytime) and central (carotid) BP measurements. Swimming exercise produced a 21% increase in carotid artery compliance (p <0.05). Flow-mediated dilation and cardiovagal baroreflex sensitivity improved after the swim training program (p <0.05). There were no significant changes in any measurements in the control group that performed gentle relaxation exercises. In conclusion, swimming exercise elicits hypotensive effects and improvements in vascular function in previously sedentary older adults. PMID- 22244037 TI - Nonlinear dimensionality reduction combining MR imaging with non-imaging information. AB - We propose a framework for the extraction of biomarkers from low-dimensional manifolds representing inter-subject brain variation. Manifold coordinates of each image capture information about structural shape and appearance and, when a phenotype exists, about the subject's clinical state. Our framework incorporates subject meta-information into the manifold learning step. Apart from gender and age, information such as genotype or a derived biomarker is often available in clinical studies and can inform the classification of a query subject. Such information, whether discrete or continuous, is used as an additional input to manifold learning, extending the Laplacian Eigenmap objective function and enriching a similarity measure derived from pairwise image similarities. The biomarkers identified with the proposed method are data-driven in contrast to a priori defined biomarkers derived from, e.g., manual or automated segmentations. They form a unified representation of both the imaging and non-imaging measurements, providing a natural use for data analysis and visualization. We test the method to classify subjects with Alzheimer's Disease (AD), mild cognitive impairment (MCI) and healthy controls enrolled in the ADNI study. Non imaging metadata used are ApoE genotype, a risk factor associated with AD, and the CSF-concentration of Abeta(1-42), an established biomarker for AD. In addition, we use hippocampal volume as a derived imaging-biomarker to enrich the learned manifold. Our classification results compare favorably to what has been reported in a recent meta-analysis using established neuroimaging methods on the same database. PMID- 22244038 TI - MIPHENO: data normalization for high throughput metabolite analysis. AB - BACKGROUND: High throughput methodologies such as microarrays, mass spectrometry and plate-based small molecule screens are increasingly used to facilitate discoveries from gene function to drug candidate identification. These large scale experiments are typically carried out over the course of months and years, often without the controls needed to compare directly across the dataset. Few methods are available to facilitate comparisons of high throughput metabolic data generated in batches where explicit in-group controls for normalization are lacking. RESULTS: Here we describe MIPHENO (Mutant Identification by Probabilistic High throughput-Enabled Normalization), an approach for post-hoc normalization of quantitative first-pass screening data in the absence of explicit in-group controls. This approach includes a quality control step and facilitates cross-experiment comparisons that decrease the false non-discovery rates, while maintaining the high accuracy needed to limit false positives in first-pass screening. Results from simulation show an improvement in both accuracy and false non-discovery rate over a range of population parameters (p < 2.2 * 10(-16)) and a modest but significant (p < 2.2 * 10(-16)) improvement in area under the receiver operator characteristic curve of 0.955 for MIPHENO vs 0.923 for a group-based statistic (z-score). Analysis of the high throughput phenotypic data from the Arabidopsis Chloroplast 2010 Project (http://www.plastid.msu.edu/) showed ~ 4-fold increase in the ability to detect previously described or expected phenotypes over the group based statistic. CONCLUSIONS: Results demonstrate MIPHENO offers substantial benefit in improving the ability to detect putative mutant phenotypes from post-hoc analysis of large data sets. Additionally, it facilitates data interpretation and permits cross dataset comparison where group-based controls are missing. MIPHENO is applicable to a wide range of high throughput screenings and the code is freely available as Additional file 1 as well as through an R package in CRAN. PMID- 22244039 TI - The removal of Pluto from the class of planets and homosexuality from the class of psychiatric disorders: a comparison. AB - We compare astronomers' removal of Pluto from the listing of planets and psychiatrists' removal of homosexuality from the listing of mental disorders. Although the political maneuverings that emerged in both controversies are less than scientifically ideal, we argue that competition for "scientific authority" among competing groups is a normal part of scientific progress. In both cases, a complicated relationship between abstract constructs and evidence made the classification problem thorny. PMID- 22244040 TI - The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation. AB - OBJECTIVE: A common gain-of-function LPL variant, LPLS447X, has favorable clinical features and involves a C->G base change at nucleotide 1595 of the LPL cDNA, along with a haplotype, which includes other non-coding SNPs. The mechanism for the LPL gain-in-function is not clear. LPL translation is regulated by epinephrine by an RNA-protein complex, consisting of PKA subunits and an A kinase anchoring protein (AKAP), which targets the 3'UTR. METHODS: To examine LPL translation of the LPLS447X variant, in vitro translation of LPL mRNA constructs was studied in the presence of cytoplasmic extracts from 3T3-F442A adipocytes treated with/without epinephrine. RESULTS: When the C->G base change at nucleotide 1595 was introduced, LPL mRNA was less susceptible to inhibition by the adipocyte extract. Similarly, a lessened susceptibility to translation inhibition occurred when the complete haplotype was constructed in the full length 3.6 kb LPL mRNA, when an irrelevant coding sequence was introduced into the LPL mRNA construct, and in response to the use of components of the RNA binding complex (PKA C and R subunits, and KH region of AKAP149). CONCLUSION: These studies suggest that the LPLS447X gain of function may be due to the base change in the LPL mRNA resulting in a decreased susceptibility to translational inhibition. PMID- 22244041 TI - Retinal vessel diameter, obesity and metabolic risk factors in school children (JuvenTUM 3). AB - BACKGROUND: The prevalence of childhood obesity is high and its association with future cardiovascular disease in adulthood is well established. The cross sectional data presented analyze the prevalence of obesity and the association between metabolic risk factors, physical inactivity and retinal vessel diameter in young school children. METHODS: The examination included 578 school children aged 11.1+/-0.6 years from secondary schools in the District of Munich, Germany. Anthropometric measurements and blood sampling were conducted using standard protocols for children. Physical activity was evaluated by use of a questionnaire. Retinal microvascular diameters and the arteriolar to venular ratio (AVR) were assessed with a non-mydriatic vessel analyser (SVA-T) using a computer-based program. RESULTS: In our population, 128 (22.2%) children were overweight (ow) or obese (ob). The mean retinal arteriolar and venular calibres were 208.0+/-15.6 MUm and 236.2+/-16.2 MUm, respectively, with a mean AVR of 0.88+/-0.01. Girls had significantly wider arteriolar and venular diameters compared to boys (p<0.001). ow and ob children had a lower AVR compared to normal weight (nw) children (mean(95% CI); nw: 0.89(0.88-0.89); ow: 0.87(0.86-0.88); ob: 0.85(0.83-0.87); p<=0.05). Wider venular diameters were independently associated with higher BMI and higher hsCRP. Blood pressure was associated with retinal vessel constriction. Higher physical inactivity and BMI were independently associated with a reduced AVR (p=0.032 and p<0.001, respectively). CONCLUSIONS: Cardiometabolic risk factors and physical inactivity are associated with retinal microvascular alterations in young children, comparable to associations in adults. Retinal vessel imaging seems to be a feasible assessment for the detection of microvascular impairments in children at risk of developing cardiovascular disease in adulthood. PMID- 22244042 TI - Is the bioresorbable scaffold a sealing device? PMID- 22244043 TI - Molecular characterization of familial hypercholesterolemia in Spain. AB - Familial hypercholesterolemia (FH), characterized by isolated elevation of plasmatic low-density lipoprotein (LDL) cholesterol and premature coronary heart disease (CHD), is associated with mutations in three major genes: LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin 9 (PCSK9). We have analyzed 5430 Spanish index cases and 2223 relatives since 2004 with LIPOchip((r)) genetic diagnostic platform, a microarray for the detection of Spanish common mutations in these three genes, including copy number variation (CNV) in LDLR, followed by sequencing analysis of the coding regions of LDLR and exon 26 of APOB, when the result is negative. Samples were received from hospitals of all around Spain. The preferred clinical criterion to diagnose FH was Dutch Lipid Clinic Network (DLCN) score. Our results show that there is a broad spectrum of mutations in the LDLR gene in Spain since about 400 different mutations were detected, distributed along almost the whole LDLR gene. Mutations in APOB (mainly p.Arg3527Gln) covered 6.5% of positive cases and only one PCSK9 mutation was detected. We found correlation between more severe mutations and the clinical diagnosis but also that 28% of FH patients harboring mutations do not have a definite clinical diagnosis. This study analyzes the mutation spectrum in Spain, remarks the importance of genetic diagnosis of FH patients, as well as the cascade screening, and shows how it is being carried out in Spain. PMID- 22244044 TI - Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction. AB - OBJECTIVE: To investigate the involvement of Toll-like receptor 4 (TLR4) expression on two monocyte subsets in the pathologic processes related to acute coronary syndrome. How monocytes, which have recently been shown to comprise two distinct subsets, mediate the process of coronary plaque rupture remains to be fully elucidated. Recent studies have shown that TLR4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis. METHODS: We enrolled 65 patients with acute myocardial infarction (AMI, n=22), unstable angina pectoris (UAP, n=16), and stable angina pectoris (SAP, n=27) who underwent coronary angiography and 15 healthy controls. The expression of TLR4 on two monocyte subsets (CD14(+)CD16(-) and CD14(+)CD16(+)) was measured by flow cytometry. RESULTS: In patients with AMI, TLR4 was more expressed on circulating CD14(+)CD16(+) monocytes than on CD14(+)CD16(-) monocytes (p<0.001). The expression levels of TLR4 on CD14(+)CD16(+) monocytes were significantly elevated in patients with AMI compared with other 3 groups. TLR4 expression levels on CD14(+)CD16(+) monocytes were significantly elevated at the culprit site compared with the systemic level (p=0.044). The up-regulation of TLR4 on admission was remarkably decreased 12 days after AMI (p<0.001). In addition, plasma levels of tumor necrosis factor-alpha were positively correlated with TLR4 expression levels on monocytes in patients with AMI (r=0.47, p=0.027). CONCLUSION: TLR overexpression on CD14(+)CD16(+) monocytes in AMI, as demonstrated both in the circulation and at the coronary culprit site, might be associated with the pathogenesis of AMI. PMID- 22244045 TI - International Atherosclerosis Research School (iARS) 2011 in Prague, Czech Republic. PMID- 22244046 TI - Intravenous Lacosamide in refractory nonconvulsive status epilepticus. AB - BACKGROUND: Many patients present with refractory Status epilepticus (SE) despite multiple anti-epileptic drugs (AEDs). Lacosamide (LCM) was recently approved as an adjunct AED for partial-onset seizures. It has unique mechanism of modulating voltage-gated sodium channels by enhancing their slow inactivation. LCM has demonstrated efficacy in animal models of pharmacoresistant seizures. To date, there are isolated anecdotal reports of LCM use in SE. OBJECTIVE: To report a single center experience with IV Lacosamide in patients with NCSE. METHODS: Pharmacy records were reviewed to identify patients with SE who received IV LCM in our institution. Data on demographics, response to therapy and adverse effects/outcomes were analyzed. All patients had continuous EEG monitoring. RESULTS: 10 patients (4 men, 6 women), age 16-90 years with refractory SE were given LCM. Eight patients were in focal non-convulsive SE (NCSE), 2 were in generalized non-convulsive SE. The etiologies included anoxic brain injury, idiopathic, encephalitis, tumor, posterior reversible encephalopathy syndrome (PRES), stroke, and AVM. IV LCM was added after traditional AEDs, including drug induced coma in some, failed to control the SE. NCSE resolved in 7/10 patients whereas 1/10 patient showed partial response with cessation of NCSE but still frequent electrographic seizures and 2/10 patients were resistant to therapy. CONCLUSIONS: LCM is a useful adjunct in refractory NCSE. The IV formulation allows prompt administration in the intensive care unit setting. Response was seen especially in focal SE. Similar to other AEDs, response was poor in patients with postanoxic injury. Our data is limited by the small number of patients. Larger controlled studies are necessary to assess accurately the efficacy of IV LCM as an early treatment of SE. PMID- 22244047 TI - Electrospun Poly(L-Lactic Acid)-co-Poly(epsilon-Caprolactone) Nanofibres Containing Silver Nanoparticles for Skin-Tissue Engineering. AB - Silver nanoparticles (AgNPs) and silver ions (Ag(+)) show growth-inhibitory activity against microorganisms and have been used for decades as antibacterial agents in various fields. To fabricate a nanofibrous scaffold which is antibacterial against bacteria and non-toxic to cells, we electrospun composite poly(L-lactic acid)-co-poly(epsilon-caprolactone) nanofibres containing silver nanoparticles (PLLCL-AgNPs) with different concentrations (0.25, 0.50 and 0.75 wt%) of silver nitrate (AgNO3) in PLLCL. The diameters of the electrospun PLLCL AgNPs nanofibres decreased with the increase of AgNO3 concentration in PLLCL solutions. Human skin fibroblasts cultured on the scaffolds showed that the PLLCL nanofibres containing lesser amounts of AgNPs (0.25 wt%) had better cell proliferation and retained the cell morphology similar to the phenotype observed on tissue culture plates (control). The antibacterial activity of AgNPs in PLLCL nanofibres was investigated against Staphylococcus aureus and Salmonella enterica and the antimicrobial activity was found to increase with the increasing concentration of nanoparticles present in the scaffold. Based on our studies, we propose that PLLCL nanofibres containing 0.25 wt% AgNO3 or PLLCL-Ag(25), favors cell proliferation and inhibits bacteria and could be a suitable substrate for wound healing. PMID- 22244048 TI - Biomechanical approaches to understanding the potentially injurious demands of gymnastic-style impact landings. AB - Gymnasts are exposed to a high incidence of impact landings due to the execution of repeated dismount performances. Biomechanical research can help inform recent discussions surrounding a proposed rule change in potentially injurious gymnastic dismounting. The review examines existing understanding of the mechanisms influencing the impact loads incurred in gymnastic-style landings achieved using biomechanical approaches. Laboratory-based and theoretical modelling research of inherent and regulatory mechanisms is appraised. The integration of the existing insights into injury prevention interventions studies is further considered in the appraisals. While laboratory-based studies have traditionally been favoured, the difficulty in controlling and isolating mechanisms of interest has partially restricted the understanding gained. An increase in the use of theoretical approaches has been evident over the past two decades, which has successfully enhanced insight into less readily modified mechanisms. For example, the important contribution of mass compositions and 'tuned' mass coupling responses to impact loading has been evidenced. While theoretical studies have advanced knowledge in impact landing mechanics, restrictions in the availability of laboratory-based input data have suppressed the benefits gained. The advantages of integrating laboratory-based and theoretical approaches in furthering scientific understanding of loading mechanisms have been recognised in the literature. Since a multi-mechanism contribution to impact loading has been evident, a deviation away from studies examining isolated mechanisms may be supported for the future. A further scientific understanding of the use of regulatory mechanisms in alleviating a performer's inherent injury predisposition may subsequently be gained and used to inform potential rule changes in gymnastics. While the use of controlled studies for providing scientific evidence for the effectiveness of gymnastics injury counter measures has been advocated over the past decade, a lack of information based on randomised controlled studies or actual evaluation of counter measures in the field setting has been highlighted. The subsequent integration of insight into biomechanical risk factors of landing with clinical practice interventions has been recently advocated. PMID- 22244049 TI - Intra-anal Iferanserin 10 mg BID for hemorrhoid disease: a prospective, randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Despite the prevalence of internal hemorrhoid disease (HD), there are few pharmacologic options. Iferanserin, a selective serotonin receptor antagonist, is being studied for use in the treatment of HD. OBJECTIVE: This Phase IIb study evaluated the efficacy and tolerability of 10-mg twice-daily iferanserin intra-anal ointment for the cessation of bleeding and other symptoms associated with internal HD. METHODS: This randomized, double-blind, placebo controlled study was conducted at 5 sites in Germany. Outpatients with Goligher grade I, II, and/or III hemorrhoids and bleeding were randomly assigned to receive iferanserin ointment 10 mg or inactive vehicle (placebo) BID for 14 days. During treatment, patients rated the severity of HD symptoms daily on a 10-point scale using a diary form. At enrollment and study end, physicians recorded the frequency and intensity of HD symptoms, adverse events, and results from blood and urine analyses on clinical-report forms. RESULTS: Of the 121 patients enrolled in the study, 118 were evaluable for tolerability and 111 for efficacy. The mean age of the tolerability population was 52.7 years, 78.9% were male, and all were white. The 2 groups had similar HD symptoms at baseline, but overall, patients in the placebo group had numerically higher grades of HD than did patients in the iferanserin group. Compared with placebo, iferanserin was associated with significantly lower patient-reported severity ratings of daily bleeding and itching, beginning at day 1 for bleeding and at day 2 for itching (P < 0.05), but not with reduced ratings for severity of other HD symptoms, including pain, tenderness, difficulty with defecation, fullness, throbbing, and gas. In the physician assessments, iferanserin was associated with significantly reduced bleeding frequency by day 14 compared with placebo (P < 0.05). Adverse events were mild and infrequent, with no significant differences in prevalences between the 2 treatment groups and no clinically significant changes in laboratory values in any patient. CONCLUSION: Compared with placebo, intra-anal iferanserin was associated with significantly reduced patient-reported severity of bleeding and itching and physician-assessed bleeding frequency in these patients presenting with grade I, II, and/or III internal hemorrhoids and bleeding at 5 sites in Germany. ClinicalTrials.gov identifier: 01483833. PMID- 22244050 TI - Biosimilars: impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. AB - BACKGROUND: Biosimilars are defined as biologic products that are highly similar to reference products, notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences between the biologic product and the reference product in terms of safety profile, purity, and potency. Due to the high cost of innovator biologics, as well as an increase in the number of these products reaching patent expiry, the development of a process for approving biosimilar products has become a crucial regulatory issue in the United States. OBJECTIVE: This commentary explores the relationship between structural/biophysical variation and the risk/benefit profile of biosimilars and reference biologics that have undergone process changes in the context of the most recent biophysical, nonclinical, and clinical data available. METHODS: The search strategy used PubMed, EMBASE, and MEDLINE for the retrieval of documents pertaining to biologic manufacturing, comparative analysis of biosimilars and originator biologics, and relevant review articles on biosimilars. For regulatory documents pertaining to the processes of the approval of biosimilars, biologics, and generics, a search for legislative decisions, briefing summaries, concept papers, guidance, and evaluations of approved and rejected applications for biosimilars published by the World Health Organization, US Food and Drug Administration, European Medicines Agency (EMA), and other national regulatory authorities was conducted. Selected articles from key opinion leaders and manufacturers were also reviewed. These searches were conducted to provide a review of historical and contemporary issues in the consideration of the current status of worldwide biosimilar use and regulation. RESULTS: A total of 18 marketing applications covering 9 development programs were surveyed. Of these, 14 applications were approved and 4 were rejected by the EMA. None of the biosimilars were reported to have evidence of significant clinical variation relative to reference compounds in the absence of corresponding differences in biophysical properties. A single biosimilar (Omnitrope((r)) [somatropin]) was reported to have evidence of significant variation in both biophysical and clinical parameters in premarketing studies. Biophysical variation in the absence of relevant differences in the efficacy and safety profiles compared with the reference brands was noted for 2 biosimilar epoetin products. CONCLUSIONS: This commentary provides evidence that current EU guidelines have resulted in the approval of biosimilar therapeutics with comparable efficacy and safety profiles for the recommended indications of their respective reference originator biologics. It is anticipated that these precedents will serve as a starting point in the development of a process for approving biosimilars in the United States and worldwide to provide efficacious and tolerable biotherapeutics with a significant cost advantage for national health care programs and consumers. PMID- 22244051 TI - Two decades of experience with the Haemophilus influenzae serotype b conjugate vaccine in the United Kingdom. AB - BACKGROUND: The Haemophilus influenzae serotype b (Hib) conjugate vaccine was introduced into the UK national childhood immunization program in 1992 after clinical trials reported the vaccine to be highly immunogenic in infants as young as two months of age. OBJECTIVE: The goal of this study was to describe and comment on the impact of routine Hib immunization on the epidemiology of invasive Hib disease in the United Kingdom. In addition, the development of Hib polysaccharide and conjugate vaccines was reviewed. METHODS: A literature search was conducted of PubMed for invasive Hib disease epidemiology in the United Kingdom. The UK Health Protection Agency Web site was also searched for relevant publications. RESULTS: The incidence of invasive Hib incidence in children aged <5 years fell from 21/100,000 to 44/100,000 in the prevaccine era to 0.63/100,000 in 1998, with an estimated vaccine failure rate of 2.2/100,000 vaccinees. After 1999, however, invasive Hib disease increased, particularly in toddlers, and peaked in 2003. Potential reasons for the resurgence included a greater-than expected decline in Hib antibodies after primary immunization, waning of herd immunity offered by the initial catch-up campaign, and use of a less immunogenic Hib combination vaccine containing acellular pertussis in 2000-2001. In response to the resurgence, a Hib combination vaccine containing whole-cell pertussis was reintroduced in 2002, followed by a childhood Hib booster campaign in 2003. In 2004, the recommended infant vaccine was changed to a different Hib/acellular pertussis combination vaccine containing inactivated polio, which had a satisfactory Hib response, was less reactogenic, and eliminated the risk of vaccine-associated paralytic poliomyelitis. This action was followed by introduction of a routine 12-month Hib booster in 2006. Together, these measures led to a decline in invasive Hib disease across all age groups. In 2010, there were only 30 invasive Hib cases, with 6 reported in children aged <5 years and no deaths in this age group since 2007. CONCLUSIONS: Control of Hib disease is currently the best that has been achieved since the introduction of the routine Hib vaccination almost 20 years ago. PMID- 22244052 TI - Effect of statins on total cholesterol concentrations, cardiovascular morbidity, and all-cause mortality in chronic obstructive pulmonary disease: a population based cohort study. AB - BACKGROUND: The benefit of statin use on total cholesterol (TC) concentration has not been studied previously in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: Our study aimed to evaluate statin-associated TC concentration reduction and subsequent risk for cardiovascular (CV) morbidity and mortality in COPD. METHODS: We performed a population-based cohort study using a record-linkage database in Tayside, Scotland. A total of 1017 COPD patients who had at least 2 separate TC measurements between 1993 and 2007 were studied. They were categorized into statin-exposed and statin-unexposed groups according to their statin use status during follow-up. Main outcomes were TC-concentration change from baseline, CV events, and all-cause mortality during follow-up. Multivariate Cox regression models with a time-dependent variable for statins were used to assess risk for outcomes. RESULTS: Statin-associated TC concentrations decreased by 0.86 mmol/L (16%) in patients treated for primary prevention (PP) (n = 1274) and 0.52 mmol/L (11%) in patients treated for secondary prevention (SP) (n = 443), from 5.30 mmol/L and 4.68 mmol/L at baseline, respectively. TC concentrations also declined by 2% in patients free from established CV disease and by 5% in patients with established CV disease in the statin-unexposed groups. A risk reduction of recurrent CV events with statins was observed (adjusted hazard ratio [HR] = 0.35; 95% CI, 0.15-0.87), but not for PP (adjusted HR = 0.84; 95% CI, 0.37-1.89). Statins reduced CV mortality (adjusted HR = 0.32; 95% CI, 0.13-0.77) in SP but not PP. There were statistically significant reductions in all-cause mortality in both PP (adjusted HR = 0.61; 95% CI, 0.43-0.85) and SP (adjusted HR = 0.58; 95% CI, 0.35-0.97). CONCLUSIONS: In patients with COPD, statins were protective from CV events and CV mortality in SP but not PP, and statins improved all-cause mortality in both PP and SP. PMID- 22244054 TI - [A vertex lesion]. PMID- 22244053 TI - A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model. AB - Prostate cancer (PCa) has been linked to fat intake, but the effects of both different dietary fat levels and types remain inconsistent and incompletely characterised. The effects on PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model of an elevated fat (20 % of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20 % of energy as soyabean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8 % of energy as soyabean oil) diet. Mice, starting at 8 weeks of age, consumed one of the three different diets ad libitum; and prostates, livers and blood were obtained after 9, 18 or 24 weeks of feeding. No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumour weight and growth rate were reduced in the walnut diet group. Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks, while no statistically significant prostate weight differences by diet were seen at 9 or 24 weeks. Multiple metabolites in the livers differed by diet at 9 and 18 weeks. The walnut diet's beneficial effects probably represent the effects of whole walnuts' multiple constituents and not via a specific fatty acid or tocopherols. Moreover, as the two HF diets had dissimilar effects on prostate tumour growth rate and size, and yet had the same total fat and tocopherol composition and content, this suggests that these are not strongly linked to PCa growth. PMID- 22244055 TI - Heparin promotes soluble vascular enothelial growth factor receptor expression in human placental villi: a rebuttal. PMID- 22244057 TI - Measurement of in vivo tendon function. AB - Chronic tendon pathologies (eg, rotator cuff tears, Achilles tendon ruptures) are common, painful, debilitating, and a significant source of medical expense. Treatment strategies for managing tendon pathologies vary widely in invasiveness and cost, with little scientific basis on which to base treatment selection. Conventional techniques for assessing the outcomes of physical therapy or surgical repair typically rely on patient-based assessments of pain and function, physical measures (eg, strength, range of motion, or stability), and qualitative assessments using magnetic resonance imaging or ultrasound. Unfortunately, these conventional techniques provide only an indirect assessment of tendon function. The inability to make a direct quantitative assessment of the tendon's mechanical capabilities may help to explain the relatively high rate of failed tendon repairs and has led to an interest in the development of tools for directly assessing in vivo tendon function. The purpose of this article is to review methods for assessing tendon function (ie, mechanical properties and capabilities) during in vivo activities. This review will describe the general principles behind the experimental techniques and provide examples of previous applications of these techniques. In addition, this review will characterize the advantages and limitations of each technique, along with its potential clinical utility. Future efforts should focus on developing broadly translatable technologies for quantitatively assessing in vivo tendon function. The ability to accurately characterize the in vivo mechanical properties of tendons would improve patient care by allowing for the systematic development and assessment of new techniques for treating tendon pathologies. PMID- 22244058 TI - Basic mechanisms of tendon fatigue damage. AB - Pathologic processes intrinsic and extrinsic to the tendons have been proposed as the underlying cause of rotator cuff disease, but the precise etiology is not known. Tear formation is, in part, attributable to the accumulation of subrupture tendon fatigue damage. We review the molecular, mechanical, and structural changes induced in tendons subjected to controlled amounts of fatigue loading in an animal model of early tendinopathy. The distinct tendon responses to low and moderate levels of loading, as opposed to high levels, provide insight into the potential mechanisms for the therapeutic benefits of exercise in the treatment of rotator cuff tendinopathy. The progression of damage accumulation leading to fiber rupture and eventual tendon tearing seen with higher loading illustrates the progression from tendinopathy to full-thickness tearing. We hope that this more realistic animal model of tendon fatigue damage will allow better assessment of biologic, mechanical, tissue-engineering, and rehabilitation strategies to improve repair success. PMID- 22244059 TI - Muscle degeneration in rotator cuff tears. AB - Rotator cuff tears are among the most common injuries seen by orthopedic surgeons. Although small- and medium-sized tears do well after arthroscopic and open repair, large and massive tears have been shown to develop marked muscle atrophy and fatty infiltration within the rotator cuff muscles. These pathologic changes have been found to be independent predictors of failed surgical repair with poor functional outcomes. To understand the pathophysiology of rotator cuff disease, we must first develop an understanding of the changes that occur within the cuff muscles themselves. The purpose of this review is to summarize the molecular pathways behind muscular degeneration and emphasize new findings related to the clinical relevance of muscle atrophy and fatty infiltration seen with rotator cuff tears. Understanding these molecular pathways will help guide further research and treatment options that can aim to alter expression of these pathways and improve outcomes after surgical repair of massive rotator cuff tears. PMID- 22244060 TI - Mechanisms of fatty degeneration in massive rotator cuff tears. AB - Fatty degeneration of chronically injured muscle is a commonly recognized consequence of massive rotator cuff tears. Current surgical treatments are unable to alter or reverse the progression of fatty degeneration and are associated with poor functional outcomes in these patients. Therefore, a better understanding of the pathophysiology of fatty degeneration is required. As such, recent discoveries in stem cell biology and new animal models have significantly advanced our understanding of the cellular and molecular basis of fatty degeneration. Future studies will facilitate development of novel treatments to prevent the progression of fatty degeneration and improve muscle regeneration in patients with massive rotator cuff tears. PMID- 22244061 TI - Biologic approaches to enhance rotator cuff healing after injury. AB - BACKGROUND: Despite the advances in surgical procedures to repair the rotator cuff, there is a high incidence of failure. Biologic approaches, such as growth factor delivery and stem cell and gene therapy, are potential targets for optimization to improve the outcome of rotator cuff therapies and reduce rates of reinjury. This article outlines the current evidence for growth factor and stem cell therapy in tendon healing and the augmentation of rotator cuff repair. METHODS: Literature on the PubMed-National Center for Biotechnology Information database was searched using the keywords growth factor, factor, gene therapy, stem cell, mesenchymal, or bone marrow in combination with rotator cuff, supraspinatus, or infraspinatus. Articles that studied growth factors or stem cells alone in rotator cuff repair were selected. Only 3 records showed use of stem cells in rotator cuff repair; thus, we expanded our search to include selected studies on stem cells and Achilles or patellar tendon repairs. Bibliographies and proceedings of meetings were searched to include additional applicable studies. We also included hitherto unpublished data by our group on the use of stem cell transplantation for rotator cuff therapy. RESULTS: More than 70 articles are summarized, with focus on recent original research papers and significant reviews that summarized earlier records. CONCLUSIONS: Use of growth factors, stem cell therapy, and other tissue-engineering means serve to augment classical surgical rotator cuff repair procedures. The combination of stem cells and growth factors resulted in enhanced repair that emulated uninjured tissue, but the literature search reflected paucity of research in this field. Preclinical evidence from gene therapy and stem cell studies can be used as a start to move therapy from the experimental phase to clinical translation in patients. PMID- 22244062 TI - Lessons we can learn from gene expression patterns in rotator cuff tears and tendinopathies. AB - Persistently high failure rates that are reported after rotator cuff repairs have encouraged greater understanding of the pathophysiology that underlies rotator cuff tears. Biologic changes that contribute to the pathogenesis of rotator cuff tears and tendinopathies, as well as adaptation after these changes, have been well described. A subset of patients with a genetic predisposition to early onset of rotator cuff tears and earlier symptom and disease progression have been identified. Many biologic changes occurring at the gene level have been identified. Pathways that are believed to contribute to rotator cuff tendinopathies include extracellular matrix remodeling, angiogenesis, changes in metabolism, apoptosis, and stress-related genes. Metaplasia of rotator cuff cells is contributed to by changes in gene expression. Modification of these gene changes may be possible through mechanical loading, drugs, or cellular manipulation. Gene changes may offer greater insight into why certain tears fail to heal and help to identify therapeutic targets. PMID- 22244063 TI - Metalloproteases and rotator cuff disease. AB - The molecular changes occurring in rotator cuff tears are still unknown, but much attention has been paid to better understand the role of matrix metalloproteinases (MMP) in the development of tendinopathy. These are potent enzymes that, once activated, can completely degrade all components of the connective tissue, modify the extracellular matrix (ECM), and mediatethe development of painful tendinopathy and tendon rupture. To control the local activity of activated proteinases, the same cells produce tissue inhibitors of metalloproteinases (TIMP) that bind to the enzymes and prevent degradation. The balance between the activities of MMPs and TIMPs regulates tendon remodeling, whereas an imbalance produces a collagen dis-regulation and disturbances intendons. ADAMs (a disintegrin and metalloproteinase) are cell membrane-linked enzymes with proteolytic and cell signaling functions. ADAMTSs (ADAM with thrombospondin motifs) are secreted into the circulation, and constitute a heterogenous family of proteases with both anabolic and catabolic functions. Biologic modulation of endogenous MMP activity to basal levels may reduce pathologic tissue degradation and favorably influence healing after rotator cuff repair. Further studies are needed to better define the mechanism of action, and whether these new strategies are safe and effective in larger models. PMID- 22244064 TI - Potential of collagen cross-linking therapies to mediate tendon mechanical properties. AB - Collagen cross-links are fundamental to the mechanical integrity of tendon, with orderly and progressive enzymatic cross-linking being central to healthy development and injury repair. However, the nonenzymatic cross-links that form as we age are associated with increased tendon brittleness, diminished mechanical resistance to injury, and impaired matrix remodeling. Collagen cross-linking thus sits at the center of tendon structure and function, with important implications to age, disease, injury, and therapy. The current review touches on these aspects from the perspective of their potential relevance to the shoulder surgeon. We first introduce the most well-characterized endogenous collagen cross-linkers that enable fibrillogenesis in development and healing. We also discuss the glycation-mediated cross-links that are implicated in age- and diabetes-related tendon frailty and summarize work toward therapies against these disadvantageous cross-links. Conversely, we discuss the introduction of exogenous collagen cross links to augment the mechanical properties of collagen-based implants or native tendon tissue. We conclude with a summary of our early results using exogenous collagen cross-linkers to prevent tendon tear enlargement and eventual failure in an in vitro model of partial tendon tear. PMID- 22244065 TI - Cytokines in rotator cuff degeneration and repair. AB - The pathogenesis of rotator cuff degeneration remains poorly defined, and the incidence of degenerative tears is increasing in the aging population. Rates of recurrent tear and incomplete tendon-to-bone healing after repair remain significant for large and massive tears. Previous studies have documented a disorganized, fibrous junction at the tendon-to-bone interface after rotator cuff healing that does not recapitulate the organization of the native enthesis. Many biologic factors have been implicated in coordinating tendon-to-bone healing and maintenance of the enthesis after rotator cuff repair, including the expression and activation of transforming growth factor-beta, basic fibroblast growth factor, platelet-derived growth factor-beta, matrix metalloproteinases, and tissue inhibitors of metalloproteinases. Future techniques to treat tendinopathy and enhance tendon-to-bone healing will be driven by our understanding of the biology of this healing process after rotator cuff repair surgery. The use of cytokines to provide important signals for tissue formation and differentiation, the use of gene therapy techniques to provide sustained cytokine delivery, the use of stem cells, and the use of transcription factors to modulate endogenous gene expression represent some of these possibilities. PMID- 22244067 TI - The role of nitric oxide in tendon healing. AB - Nitric oxide (NO) is a small free radical that is generated by a family of enzymes called the nitric oxide synthases (NOS). There are 3 isoforms of NOS: endothelial NOS (eNOS), brain or neuronal NOS (bNOS), and inducible NOS (iNOS). In experiments performed during the last 20 years, we have shown that NO is induced by all 3 isoforms of NOS after tendon injury and that NOS activity is upregulated in tendinopathy. In normal uninjured tendons, there is very little NOS activity. In injured rat and human tendons, NOS activity was found in healing fibroblasts in a temporal fashion. In animal models, competitive inhibition of NOS resulted in reduced tendon healing, whereas the addition of NO resulted in enhanced tendon healing. In cultured human cells, the addition of NO via chemical means and adenovirus transfection resulted in enhanced collagen synthesis. We performed 3 randomized, double-blinded clinical trials that demonstrated a significant positive beneficial effect of NO treatment on clinical symptoms and function in patients with Achilles tendinopathy, tennis elbow, and supraspinatus tendonitis. NO was delivered via glyceryl trinitrate (GTN) patches. We also conducted a 3-year prospective follow-up that demonstrated significant long-term efficacy of GTN patches in treating noninsertional Achilles tendinopathy. In a 5 year prospective comparison treating lateral epicondylitis, we found no additional benefits of GTN vs placebo at 5 years. The use of a new GTN patch, OrthoDerm, demonstrated no evidence for efficacy in treating chronic lateral epicondylitis. PMID- 22244066 TI - The role of mechanobiology in tendon healing. AB - Mechanical cues affect tendon healing, homeostasis, and development in a variety of settings. Alterations in the mechanical environment are known to result in changes in the expression of extracellular matrix proteins, growth factors, transcription factors, and cytokines that can alter tendon structure and cell viability. Loss of muscle force in utero or in the immediate postnatal period delays tendon and enthesis development. The response of healing tendons to mechanical load varies depending on anatomic location. Flexor tendons require motion to prevent adhesion formation, yet excessive force results in gap formation and subsequent weakening of the repair. Excessive motion in the setting of anterior cruciate ligament reconstruction causes accumulation of macrophages, which are detrimental to tendon graft healing. Complete removal of load is detrimental to rotator cuff healing; yet, large forces are also harmful. Controlled loading can enhance healing in most settings; however, a fine balance must be reached between loads that are too low (leading to a catabolic state) and too high (leading to microdamage). This review will summarize existing knowledge of the mechanobiology of tendon development, homeostasis, and healing. PMID- 22244068 TI - Fiber-aligned polymer scaffolds for rotator cuff repair in a rat model. AB - BACKGROUND: Repair techniques of rotator cuff tendon tears have improved in recent years; nonetheless, the failure rate remains high. Despite the availability of various graft materials for repair augmentation, there has yet to be a biomechanical study using fiber-aligned scaffolds in vivo. The objective of this study was to evaluate the efficacy of fiber-aligned nanofibrous polymer scaffolds as a potential treatment-delivery vehicle in a rat rotator cuff injury model. MATERIALS AND METHODS: Scaffolds with and without sacrificial fibers were fabricated via electrospinning and implanted to augment supraspinatus repair in rats. Repairs without scaffold augmentation were also performed to serve as controls. Rats were sacrificed at 4 and 8 weeks postoperatively, and repairs were evaluated histologically and biomechanically. RESULTS: Both scaffold formulations remained in place, with more noticeable cellular infiltration and colonization at 4 and 8 weeks after injury and repair for scaffolds lacking sacrificial fibers. Specimens with scaffolds were larger in cross-sectional area compared with controls. Biomechanical testing revealed no significant differences in structural properties between the groups. Some apparent material properties were significantly reduced in the scaffold groups. These reductions were due to increases in cross-sectional area, most likely caused by the extra thickness of the implanted scaffold material. No differences were observed between the 2 scaffold groups. CONCLUSIONS: No adverse effect of surgical implantation of overlaid fiber-aligned scaffolds on structural properties of supraspinatus tendons in rat rotator cuff repair was demonstrated, validating this model as a platform for targeted delivery. PMID- 22244069 TI - Scaffold devices for rotator cuff repair. AB - Rotator cuff tears affect 40% or more of those aged older than 60 years, and repair failure rates of 20% to 70% remain a significant clinical challenge. Hence, there is a need for repair strategies that can augment the repair by mechanically reinforcing it, while at the same time biologically enhancing the intrinsic healing potential of the tendon. Tissue engineering strategies to improve rotator cuff repair healing include the use of scaffolds, growth factors, and cell seeding, or a combination of these approaches. Currently, scaffolds derived from mammalian extracellular matrix, synthetic polymers, and a combination thereof, have been cleared by the U.S. Food and Drug Administration and are marketed as medical devices for rotator cuff repair in humans. Despite the growing clinical use of scaffold devices for rotator cuff repair, there are numerous questions related to their indication, surgical application, safety, mechanism of action, and efficacy that remain to be clarified or addressed. This article reviews the current basic science and clinical understanding of commercially available synthetic and extracellular matrix scaffolds for rotator cuff repair. Our review will emphasize the host response and scaffold remodeling, mechanical and suture-retention properties, and preclinical and clinical studies on the use of these scaffolds for rotator cuff repair. We will discuss the implications of these data on the future directions for use of these scaffolds in tendon repair procedures. PMID- 22244071 TI - Cell- and gene-based approaches to tendon regeneration. AB - Repair of rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches, including platelet-rich plasma, bone marrow aspirate, growth factor supplements, and cell- and gene modified cell therapy. Despite added complexity, cell-based therapies form an important part of enhanced repair, and combinations of carrier vehicles, growth factors, and implanted cells provide the best opportunity for robust repair. Bone marrow-derived mesenchymal stem cells provide a stimulus for repair in flexor tendons, but application in rotator cuff repair has not shown universally positive results. The use of scaffolds such as platelet-rich plasma, fibrin, and synthetic vehicles and the use of gene priming for stem cell differentiation and local anabolic and anti-inflammatory impact have both provided essential components for enhanced tendon and tendon-to-bone repair in rotator cuff disruption. Application of these research techniques in human rotator cuff injury has generally been limited to autologous platelet-rich plasma, bone marrow concentrate, or bone marrow aspirates combined with scaffold materials. Cultured mesenchymal progenitor therapy and gene-enhanced function have not yet reached clinical trials in humans. Research in several animal species indicates that the concept of gene-primed stem cells, particularly embryonic stem cells, combined with effective culture conditions, transduction with long-term integrating vectors carrying anabolic growth factors, and development of cells conditioned by use of RNA interference gene therapy to resist matrix metalloproteinase degradation, may constitute potential advances in rotator cuff repair. This review summarizes cell- and gene-enhanced cell research for tendon repair and provides future directions for rotator cuff repair using biologic composites. PMID- 22244070 TI - Biomimetic scaffold design for functional and integrative tendon repair. AB - Rotator cuff tears represent the most common shoulder injuries in the United States. The debilitating effect of this degenerative condition coupled with the high incidence of failure associated with existing graft choices underscores the clinical need for alternative grafting solutions. The 2 critical design criteria for the ideal tendon graft would require the graft to not only exhibit physiologically relevant mechanical properties but also be able to facilitate functional graft integration by promoting the regeneration of the native tendon to-bone interface. Centered on these design goals, this review will highlight current approaches to functional and integrative tendon repair. In particular, the application of biomimetic design principles through the use of nanofiber- and nanocomposite-based scaffolds for tendon tissue engineering will be discussed. This review will begin with nanofiber-based approaches to functional tendon repair, followed by a section highlighting the exciting research on tendon-to bone interface regeneration, with an emphasis on implementation of strategic biomimicry in nanofiber scaffold design and the concomitant formation of graded multi-tissue systems for integrative soft-tissue repair. This review will conclude with a summary and discussion of future directions. PMID- 22244072 TI - Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones. AB - An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum. PMID- 22244073 TI - Posterior and open anterior components separations: a comparative analysis. AB - BACKGROUND: Anterior components separation (ACS) creates large lipocutaneous flaps to release the external oblique fascia often leading to major wound complications. Posterior components separation (PCS) involves the release of the posterior rectus sheath and transversus abdominis muscles. We hypothesized that PCS provides effective fascial advancement while reducing wound morbidity during abdominal wall reconstructions. METHODS: A retrospective review of consecutive components separation performed by a single surgeon over 5 years. RESULTS: One hundred eleven patients (56 ACS/55 PCS) were analyzed. The mean defect size was 472 and 531 cm(2), respectively (P = .28). Five patients in each group required a bridging repair. Wound complications occurred in significantly more ACS than PCS patients (48.2% vs 25.5%, P = .01). The recurrence rate was also higher in the ACS group (14.3% vs 3.6%, P = .09). CONCLUSIONS: PCS provides equivalent myofascial advancement with significantly less wound morbidity when compared with ACS. Although further studies are needed, PCS has evolved as an important addition to the armamentarium of surgeons undertaking complex abdominal wall reconstructions. PMID- 22244074 TI - Getting back to zero with nucleated red blood cells: following trends is not necessarily a bad thing. AB - BACKGROUND: The presence of nucleated red blood cells (NRBCs) has been identified as a poor prognostic indicator. We investigated the relationship of NRBC trends in patients with and without trauma. METHODS: We retrospectively reviewed surgical intensive care unit admissions over 4 years, categorizing trauma and nontrauma patients and subdividing them into 3 groups: group A, all-zero NRBC; group B, positive NRBC value returning to zero; and group C, positive NRBC value that did not return to zero. We analyzed all groups for outcomes of length of stay and mortality. RESULTS: Group A was the largest and had the shortest length of stay and least mortality. Group C had the highest mortality rate. No statistical difference was observed with mortality. CONCLUSIONS: Any positive NRBC was associated with poor outcome, and increasing NRBC was associated with increasing mortality. Trends in NRBC values showed that returning to zero was protective. PMID- 22244075 TI - CT characteristics of primary hepatic mass lesions in dogs. AB - Little information is available on the relationship between computed tomography (CT) imaging findings and the pathologic diagnosis of canine hepatic tumors. Our purpose was to clarify the characteristic features of CT findings in liver tumors in dogs. Data from 33 dogs with either a hepatocellular carcinoma, n = 14, hepatocellular adenoma, n = 14, or nodular hyperplasia, n = 5 were summarized from medical records. CT features for each histologic diagnosis were characterized and analyzed statistically. Common findings in hepatocellular carcinoma included central (79%, P = 0.0030) and marginal enhancement (93%, P = 0.00043) in the arterial phase, cyst-like lesions (93%), capsule formation (93%), and hypoattenuation in the portal (86%), and equilibrium phases (93%). Hepatic adenoma was characterized by a characteristic diffuse enhancement pattern during the arterial phase (57%, P = 0.013), which was also found in nodular hyperplasia (60%), but never in hepatocellular carcinoma. Nodular hyperplasia was less likely to have a capsule structure (20%, P = 0.0087). Mass size was significantly smaller in nodular hyperplasia than in hepatocellular carcinoma and hepatic adenoma (P = 0.0033 and 0.038, respectively). Hyperattenuation in the arterial and the portal phase i.e. contrast retention, was more frequent in hepatic adenoma than in the other groups (P = 0.037 and 0.037, respectively). Nodular hyperplasia was more frequently isoattenuating in the equilibrium phase (P = 0.043). PMID- 22244076 TI - Second-line treatment of stage III/IV non-small-cell lung cancer (NSCLC) with pemetrexed in routine clinical practice: evaluation of performance status and health-related quality of life. AB - BACKGROUND: Second-line treatment of advanced non-small-cell lung cancer (NSCLC) improves overall survival. There is a lack of data regarding the impact on patients' overall health condition. This prospective, non-interventional study evaluated performance status (PS) and health-related quality of life (HR-QoL) during second-line pemetrexed treatment in routine clinical practice. METHODS: Stage III/IV NSCLC patients who initiated second-line pemetrexed (standard vitamin and dexamethasone supplementation) were observed for a maximum of 9 treatment cycles. The primary objective was to evaluate the proportion of patients achieving improvement of Karnofsky Index (KI) of >= 10% (absolute) or maintaining KI >= 80% after the second treatment cycle ("KI benefit response"). HR-QoL was self-rated using the EuroQoL-5D questionnaire (EQ-5D). Factors potentially associated with KI benefit response were evaluated using logistic regression models. RESULTS: Of 521 eligible patients (73.5% Stage IV, median age 66.3 yrs, 36.1% >= 70 yrs, 62.0% with KI >= 80%), 471 (90.4%) completed at least 2 treatment cycles. 58.0% (95%CI 53.6%;62.2%) achieved KI benefit response after the second cycle. Patients with baseline KI >= 80%, no Grade 3/4 toxicities during the first 2 cycles, or combination regimen as prior first-line therapy were more likely to achieve a KI benefit response. EQ-5D scores improved over time. Grade 3/4 toxicities were reported in 23.8% of patients (mainly fatigue/asthenia 15.9%, neutropenia 8.7%). CONCLUSIONS: In this large prospective, non-interventional study of second-line pemetrexed treatment in patients with advanced NSCLC, including 36% elderly patients ( >= 70 years), physician-rated PS and self-rated HR-QoL were maintained or improved in the majority of patients. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT00540241) on October 4, 2007. PMID- 22244077 TI - Trauma induced eagle syndrome. AB - Eagle syndrome is characterized by secondary calcification and elongation of the styloid process. Eagle syndrome is often associated with sharp, intermittent pain along the path of the glossopharyngeal nerve located in the hypopharynx and at the base of the tongue. In some cases, the stylohyoid apparatus can compress the internal and/or the external carotid arteries and their perivascular sympathetic fibres, resulting in a persistent pain radiating throughout the carotid territory. The pathogenesis of the syndrome is not understood. The authors report the case of a 52-year-old woman with post traumatic Eagle syndrome-like pain and pseudoarthrosis of the stylohyoid ligament. PMID- 22244078 TI - Microbiological investigation of retrodiscal tissues from patients with advanced internal derangement of the temporomandibular joint. AB - The aim of this study was to investigate the presence of bacteria in samples of retrodiscal tissues taken from patients suffering from advanced internal derangement of the temporomandibular joint (TMJ). 12 fresh retrodiscal tissue samples were taken from 12 consecutive patients who underwent unilateral TMJ discectomy for advanced TMJ internal derangement (Wilkes stage IV). The retrodiscal tissue samples were stained and cultured for the presence of micro organisms in microbiology laboratories. No evidence of bacteria or other micro organisms was found in any of the tissue specimens procured from the TMJ. This study failed to identify the presence of bacteria or other micro-organisms in fresh retrodiscal tissue specimens of the TMJ in patients with advanced TMJ internal derangement. PMID- 22244079 TI - Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease. AB - Statistically, significant numbers of central bone specimens of suppurative osteomyelitis of the jaws (SOJ), bisphosphonate induced osteonecrosis of the jaws (BIONJ), and osteoradionecrosis of the jaws (ORNJ) were compared. All three evidenced the common finding of necrotic bone with empty osteocytic lacunae, Haversian and Volkmann canals, but each showed a distinctive histopathologic pattern indicating a different disease mechanism and treatment options. Suppurative osteomyelitis was characterized by intense marrow inflammation and marrow vessel thrombosis with retention of viable osteoclasts and periosteum. Bisphosphonate induced osteonecrosis was characterized by an empty marrow space with empty Howship's lacunae and an absence of osteoclasts but viable periosteum. Osteoradionecrosis was characterized by a collagenous hypocellular, hypovascular marrow space and nonviable periosteum. Histologic evidence in SOJ indicates a microorganism provoked intense inflammation and marrow vascular thrombosis creating an environment conducive to continual bacterial proliferation. BIONJ is seen as a non-inflammatory drug toxicity to bone by osteoclastic death leading to over suppression of bone renewal, and ORN as another non-inflammatory condition caused by a high linear energy transfer that impairs or kills numerous cell types in the field of radiation including periosteum, bone, and all soft tissue. PMID- 22244080 TI - Microbubble ultrasound-guided targeted delivery to tumors. PMID- 22244081 TI - Respiratory carbon fluxes in leaves. AB - Leaf respiration is a major metabolic process that drives energy production and growth. Earlier works in this field were focused on the measurement of respiration rates in relation to carbohydrate content, photosynthesis, enzymatic activities or nitrogen content. Recently, several studies have shed light on the mechanisms describing the regulation of respiration in the light and in the dark and on associated metabolic flux patterns. This review will highlight advances made into characterizing respiratory fluxes and provide a discussion of metabolic respiration dynamics in relation to important biological functions. PMID- 22244082 TI - Hormone signaling in plant development. AB - Hormone signaling plays diverse and critical roles during plant development. In particular, hormone interactions regulate meristem function and therefore control formation of all organs in the plant. Recent advances have dissected commonalities and differences in the interaction of auxin and cytokinin in the regulation of shoot and root apical meristem function. In addition, brassinosteroid hormones have recently been discovered to regulate root apical meristem size. Further insights have also been made into our understanding of the mechanism of crosstalk among auxin, cytokinin, and strigolactone in axillary meristems. PMID- 22244083 TI - Law and ethics of deep brain stimulation. AB - Deep brain stimulation (DBS) is a non-destructive, adjustable, and mainly reversible method of continuously giving electrical impulses into a small area of the brain via implanted electrodes. It has been established as a standard form of treatment for specific cases of Parkinson's disease, essential tremor and dystonia. It is currently being evaluated for several mental disorders, dementia and even alcoholism. In spite of its growing practical importance, the legal issues have so far undergone almost no analysis. The article outlines both the essential legal questions of DBS from the perspective of German Law as well as major issues of the current ethical debate, and the correlation of both fields. PMID- 22244084 TI - Psychopharmacological enhancement: a conceptual framework. AB - The availability of a range of new psychotropic agents raises the possibility that these will be used for enhancement purposes (smart pills, happy pills, and pep pills). The enhancement debate soon raises questions in philosophy of medicine and psychiatry (eg, what is a disorder?), and this debate in turn raises fundament questions in philosophy of language, science, and ethics. In this paper, a naturalistic conceptual framework is proposed for addressing these issues. This framework begins by contrasting classical and critical concepts of categories, and then puts forward an integrative position that is based on cognitive-affective research. This position can in turn be used to consider the debate between pharmacological Calvinism (which may adopt a moral metaphor of disorder) and psychotropic utopianism (which may emphasize a medical metaphor of disorder). I argue that psychiatric treatment of serious psychiatric disorders is justified, and that psychotropics are an acceptable kind of intervention. The use of psychotropics for sub-threshold phenomena requires a judicious weighing of the relevant facts (which are often sparse) and values. PMID- 22244085 TI - Convergent evolution in structural elements of proteins investigated using cross profile analysis. AB - BACKGROUND: Evolutionary relations of similar segments shared by different protein folds remain controversial, even though many examples of such segments have been found. To date, several methods such as those based on the results of structure comparisons, sequence-based classifications, and sequence-based profile profile comparisons have been applied to identify such protein segments that possess local similarities in both sequence and structure across protein folds. However, to capture more precise sequence-structure relations, no method reported to date combines structure-based profiles, and sequence-based profiles based on evolutionary information. The former are generally regarded as representing the amino acid preferences at each position of a specific conformation of protein segment. They might reflect the nature of ancient short peptide ancestors, using the results of structural classifications of protein segments. RESULTS: This report describes the development and use of "Cross Profile Analysis" to compare sequence-based profiles and structure-based profiles based on amino acid occurrences at each position within a protein segment cluster. Using systematic cross profile analysis, we found structural clusters of 9-residue and 15-residue segments showing remarkably strong correlation with particular sequence profiles. These correlations reflect structural similarities among constituent segments of both sequence-based and structure-based profiles. We also report previously undetectable sequence-structure patterns that transcend protein family and fold boundaries, and present results of the conformational analysis of the deduced peptide of a segment cluster. These results suggest the existence of ancient short-peptide ancestors. CONCLUSIONS: Cross profile analysis reveals the polyphyletic and convergent evolution of beta-hairpin-like structures, which were verified both experimentally and computationally. The results presented here give us new insights into the evolution of short protein segments. PMID- 22244086 TI - Regulation of basic helix-loop-helix transcription factors Dec1 and Dec2 by RORalpha and their roles in adipogenesis. AB - DEC1 and DEC2, members of the basic helix-loop-helix superfamily, are involved in various biological phenomena including clock systems, cell differentiation and metabolism. In clock systems, Dec1 and Dec2 expression are up-regulated by the CLOCK:BMAL1 heterodimer via E-box (CACGTG), exhibiting a circadian rhythm in the suprachiasmatic nucleus (SCN), the central circadian pacemaker and other peripheral tissues. In this study, using assays of luciferase reporters, electrophoretic mobility shift and chromatin immunoprecipitation, we identified novel nuclear receptor response elements, ROR response elements (RORE), in Dec1 and Dec2 promoters. These ROREs responded to the transcriptional activator RORalpha, but not to the repressor REVERBalpha, although the Bmal1 promoter responded to both RORalpha and REVERBalpha. Therefore, RORalpha, but not REVERBalpha, is involved in the regulation of Dec1 and Dec2 expression without significantly affecting their rhythmicity. Since RORalpha, DEC1 and DEC2 reportedly suppressed adipogenic differentiation, we examined expression of Roralpha, Dec1, Dec2 and other clock-controlled genes in differentiating 3T3-L1 adipocytes. The results suggested that RORalpha suppresses adipogenic differentiation at a later stage of differentiation by RORE-mediated stimulation of Dec1 and Dec2 expression. PMID- 22244088 TI - Quantitative EEG and LORETA: valuable tools in discerning FTD from AD? AB - Drawing a clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease (AD) is tricky, particularly at the early stages of disease. This study evaluates the possibility in differentiating 39 FTD, 39 AD, and 39 controls (CTR) by means of power spectral analysis and standardized low resolution brain electromagnetic tomography (sLORETA) within delta, theta, alpha 1 and 2, beta 1, 2, and 3 frequency bands. Both analyses revealed in AD patients, relative to CTR, higher expression of diffuse delta/theta and lower central/posterior fast frequency (from alpha1 to beta2) bands. FTD patients showed diffuse increased theta power compared with CTR and lower delta relative to AD patients. Compared with FTD, AD patients showed diffuse higher theta power at spectral analysis and, at sLORETA, decreased alpha2 and beta1 values in central/temporal regions. Spectral analysis and sLORETA provided complementary information that might help characterizing different patterns of electroencephalogram (EEG) oscillatory activity in AD and FTD. Nevertheless, this differentiation was possible only at the group level because single patients could not be discerned with sufficient accuracy. PMID- 22244087 TI - A review of the epidemiology of oral and pharyngeal carcinoma: update. AB - Oral and pharyngeal cancers are the sixth most common cancers internationally. In the United States, there are about 30,000 new cases of oral and pharyngeal cancers diagnosed each year. Furthermore, survival rates for oral and pharyngeal cancers have not significantly improved over the last three decades. This review examines the scientific literature surrounding the epidemiology of oral and pharyngeal cancers, including but not limited to risk factors, disparities, preventative factors, and the epidemiology in countries outside the United States. The literature review revealed that much of the research in this field has been focused on alcohol, tobacco, and their combined effects on oral and pharyngeal cancers. The literature on oral and pharyngeal cancer disparities among racial groups also appears to be growing. However, less literature is available on the influence of dietary factors on these cancers. Finally, effective interventions for the reduction of oral and pharyngeal cancers are discussed. PMID- 22244089 TI - Body mass index is associated with biological CSF markers of core brain pathology in Alzheimer's disease. PMID- 22244090 TI - Sleep modulates word-pair learning but not motor sequence learning in healthy older adults. AB - Sleep benefits memory across a range of tasks for young adults. However, remarkably little is known of the role of sleep on memory for healthy older adults. We used 2 tasks, 1 assaying motor skill learning and the other assaying nonmotor/declarative learning, to examine off-line changes in performance in young (20-34 years), middle-aged (35-50 years), and older (51-70 years) adults without disordered sleep. During an initial session, conducted either in the morning or evening, participants learned a motor sequence and a list of word pairs. Memory tests were given twice, 12 and 24 hours after training, allowing us to analyze off-line consolidation after a break that included sleep or normal wake. Sleep-dependent performance changes were reduced in older adults on the motor sequence learning task. In contrast, sleep-dependent performance changes were similar for all 3 age groups on the word pair learning task. Age-related changes in sleep or networks activated during encoding or during sleep may contribute to age-related declines in motor sequence consolidation. Interestingly, these changes do not affect declarative memory. PMID- 22244091 TI - Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys. AB - Lipofuscin is a cytologic hallmark of aging in metabolically active postmitotic cells including neurons, cardiac muscle cells, and the retinal pigment epithelium (RPE). High levels of lipofuscin are involved in the pathogenesis of age-related macular degeneration (AMD), the main cause of blindness in the elderly population in the western world. Degradation and exocytosis of lipofuscin by RPE cells have not been observed in vivo until now, and no drug is known to eliminate the intracellular amount of lipofuscin. Here, we show that in monkeys treated with a small molecule belonging to the tetrahydropyridoethers class (n = 36 of 48 monkeys), RPE cells significantly release lipofuscin. In 4 eyes, macrophages were detected which had taken up lipofuscin. They were located between the Bruch's membrane and the RPE, and in the choroid. The quantification of pigment granules was performed by transmission electron microscopy. Our findings open the way to develop therapeutic strategies to remove lipofuscin from RPE cells, which may have implications for the treatment of age-related macular degeneration in which lipofuscin accumulation in cells is a causative factor. PMID- 22244092 TI - The influence of oral health conditions, socioeconomic status and home environment factors on schoolchildren's self-perception of quality of life. AB - BACKGROUND: The objective this study was to investigate the influence of clinical conditions, socioeconomic status, home environment, subjective perceptions of parents and schoolchildren about general and oral health on schoolchildren's oral health-related quality of life (OHRQoL). METHODS: A sample of 515 schoolchildren, aged 12 years was randomly selected by conglomerate analysis from public and private schools in the city of Juiz de Fora, Brazil. The schoolchildren were clinically examined for presence of caries lesions (DMFT and dmft index), dental trauma, enamel defects, periodontal status (presence/absence of bleeding), dental treatment and orthodontic treatment needs (DAI). The SiC index was calculated. The participants were asked to complete the Brazilian version of Child Perceptions Questionnaire (CPQ11-14) and a questionnaire about home environment. Questions were asked about the presence of general diseases and children's self perception of their general and oral health status. In addition, a questionnaire was sent to their parents inquiring about their socioeconomic status (family income, parents' education level, home ownership) and perceptions about the general and oral health of their school-aged children. The chi-square test was used for comparisons between proportions. Poisson's regression was used for multivariate analysis with adjustment for variances. RESULTS: Univariate analysis revealed that school type, monthly family income, mother's education, family structure, number of siblings, use of cigarettes, alcohol and drugs in the family, parents' perception of oral health of schoolchildren, schoolchildren's self perception their general and oral health, orthodontic treatment needs were significantly associated with poor OHRQoL (p < 0.001). After adjusting for potential confounders, variables were included in a Multivariate Poisson regression. It was found that the variables children's self perception of their oral health status, monthly family income, gender, orthodontic treatment need, mother's education, number of siblings, and household overcrowding showed a strong negative effect on oral health-related quality of life. CONCLUSIONS: It was concluded that the clinical, socioeconomic and home environment factors evaluated exerted a negative impact on the oral health-related quality of life of schoolchildren, demonstrating the importance of health managers addressing all these factors when planning oral health promotion interventions for this population. PMID- 22244093 TI - The speed of sound through trabecular bone predicted by Biot theory. AB - Cancellous bone is a highly porous material filled with fluid. The mechanical properties of cancellous bone determine whether the bone is normal or osteoporotic. Wave propagation can be used to measure the elastic constants of cancellous bone. Recently, poroelasticity theory has been used to predict the elastic constants of cancellous bone from the wave velocities. In this study, it is shown that the fast wave, predicted by the Biot theory, corresponds to the wave penetrating the trabeculae, while the slow wave is determined by the interaction between the trabeculae and the fluid. The trabecular shape does not affect the wave velocity significantly when using the variable, which is determined by the microstructure, and the slow wave velocity decreases after the porosity reaches 80%. PMID- 22244094 TI - Dietary silk protein, sericin, improves epidermal hydration with increased levels of filaggrins and free amino acids in NC/Nga mice. AB - Epidermal hydration is maintained primarily by natural moisturising factors (NMF), of which free amino acids (AA) are major constituents that are generated by filaggrin degradation. To identify dietary sources that may improve skin dryness of atopic dermatitis (AD), we investigated dietary effects of silk proteins, sericin and fibroin, on epidermal levels of hydration, filaggrins and free AA, as well as PPARgamma, peptidylarginine deiminase-3 (PAD3) and caspase-14 proteins involved in filaggrin expression and degradation processes. NC/Nga mice, an animal model of AD, were fed a control diet (group CA: atopic control) or diets with 1 % sericin (group S) or fibroin (group F) for 10 weeks. In group S, epidermal levels of hydration, total filaggrins and total free AA, as well as PPARgamma, PAD3 and caspase-14, which were reduced in group CA, were increased to higher or similar levels of a normal control group of BALB/c mice (group C). Furthermore, profilaggrin, a precursor with multiple filaggrin repeats, and three repeat intermediates were increased, while two repeat intermediates and filaggrin were decreased in parallel with increased levels of glutamate and serine, major AA of NMF in group S. Despite increased levels of total filaggrins, total free AA, PPARgamma and PAD3, epidermal levels of hydration, glutamate, serine and caspase-14 were not increased, but other minor AA of NMF were highly detected in group F. Dietary sericin improves epidermal hydration in parallel with enhancing profilaggrin expression and degradation into free AA that is coupled with elevated levels of PPARgamma, PAD3 and caspase-14 proteins. PMID- 22244095 TI - A Porous Hydroxyapatite/Gelatin Nanocomposite Scaffold for Bone Tissue Repair: In Vitro and In Vivo Evaluation. AB - In this study, a nano-structured scaffold was designed for bone repair using hydroxapatite and gelatin as its main components. The scaffold was prepared via layer solvent casting combined with freeze-drying and lamination techniques and characterized by the commonly used bulk techniques. The biocompatibility and osteoconductivity of this scaffold and its capacity to promote bone healing were also evaluated. Osteoblast-like cells were seeded on these scaffolds and their proliferation rate, intracellular alkaline phosphatase (ALP) activity and ability to form mineralized bone nodules were compared with those osteoblasts grown on cell culture plastic surfaces. Also, the scaffolds were implanted in a critical bone defect created on rat calvarium. Engineering analyses show that the scaffold posses a three dimensional interconnected homogenous porous structure with a porosity of about 82% and pore sizes ranging from 300 to 500 MUm. Mechanical indices are in the range of spongy bones. The results obtained from biological assessment show that this scaffold does not negatively affect osteoblasts proliferation rate and improves osteoblasts function as shown by increasing the ALP activity and calcium deposition and formation of mineralized bone nodules. In addition, the scaffold promoted healing of critical size calvarial bone defect in rats. It could be concluded that this scaffold fulfills all the main requirements to be considered as a bone substitute. PMID- 22244096 TI - Our new journal: Arthroscopy Techniques. PMID- 22244097 TI - Outcome score validation. PMID- 22244099 TI - Problems with "Validation of a measurement device for instrumented quantification of anterior translation and rotational assessment of the knee". PMID- 22244100 TI - Computer-assisted modeling of osseous impingement and resection in femoroacetabular impingement. AB - PURPOSE: The purpose of this study was to evaluate the utility of computer assisted 3-dimensional modeling in diagnosing and treating symptomatic hip impingement. METHODS: Eight patients with symptomatic, focal cam and/or pincer impingement lesions underwent high-resolution computed tomography scans and computer-assisted, 3-dimensional modeling of the involved hip. Cam location, alpha angle, neck-shaft angle, femoral version, and acetabular version at the 12 o'clock through 3-o'clock positions were measured. The model was subsequently dynamized to define the preoperative range of motion and location of impingement with hip flexion, internal rotation, and internal rotation at 90 degrees of hip flexion. Virtual cam and pincer osteoplasty was performed to establish normal head-neck offset and head sphericity and to eliminate focal rim impingement lesions. Range of motion and location of impingement were reassessed after resection in the defined area of impingement. RESULTS: The cam lesion was located between the 12-o'clock and 4-o'clock positions in all cases. The mean alpha angle was 66.4 degrees (range, 53 degrees to 80 degrees ). Mean femoral version was 14.6 degrees (range, 5 degrees to 23 degrees ). Mean preoperative hip flexion was 109.7 degrees (range, 87.5 degrees to 125.5 degrees ), and mean internal rotation at 90 degrees of hip flexion was 16.2 degrees (range, 1.7 degrees to 25.5 degrees ). The location of impingement was unique in each case and not predictable based on radiographic measures alone. Virtual osteoplasty in the defined regions of impingement resulted in significant improvements in both hip flexion and internal rotation (P < .05). CONCLUSIONS: Computed tomography-based computer modeling can localize regions of anticipated mechanical impingement in symptomatic patients with hip pain. Computer-assisted navigation may be a valuable surgical tool to more accurately and reliably eliminate offending impingement lesions. LEVEL OF EVIDENCE: Level IV, diagnostic study. PMID- 22244101 TI - Anterior cruciate ligament reconstruction with bone-patellar tendon-bone graft: comparison of autograft, fresh-frozen allograft, and gamma-irradiated allograft. AB - PURPOSE: To compare clinical follow-up results of anterior cruciate ligament (ACL) reconstruction using (1) autologous, (2) fresh-frozen allogeneic, and (3) gamma-irradiated allogeneic bone-patellar tendon-bone (BPTB). METHODS: From February 2002 to January 2006, 187 patients received BPTB ACL reconstruction at our center. One hundred forty-two consecutive patients who had received single bundle BPTB ACL reconstruction were included in this study. Of these patients, 41 had autografts, 33 had fresh-frozen allografts, and 68 had gamma-irradiated allografts. Clinical results were evaluated with the KT-1000 maximum displacement test (MEDmetric, San Diego, CA), Lachman test, and Lysholm, Irrgang, and Larson activity scales. RESULTS: The mean duration of follow-up was 6.7 +/- 1.5 years (range, 4.2 to 8.2 years). There were 3 cases of acute synovitis due to immunologic rejection (fresh-frozen allografts) and 6 cases of failure (gamma irradiated allografts). KT-1000 examination showed more anterior laxity in the gamma-irradiated allograft group compared with the autograft and fresh-frozen allograft groups (P < .05). The Lysholm, Irrgang, and Larson activity scales showed no difference among the 3 groups (P > .05). CONCLUSIONS: The study showed a statistically poorer KT-1000 result and higher failure rate in the gamma irradiated allograft group compared with the autograft and fresh-frozen allograft groups. This may suggest that gamma-irradiated allograft is not a good candidate graft for ACL reconstruction. Power analysis showed that the study was underpowered, so further research and longer follow-up study are needed to make this point clearer. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 22244102 TI - Evidence-based indications for elbow arthroscopy. AB - PURPOSE: The purpose was to review the literature on the outcomes of elbow arthroscopy and to make evidence-based recommendations for or against elbow arthroscopy for the treatment of various conditions. Our hypothesis was that the evidence would support the use of elbow arthroscopy in the management of common elbow conditions. METHODS: A literature search was performed by use of the PubMed database in October 2010. All therapeutic studies investigating the results of treatment with elbow arthroscopy were analyzed for outcomes and complications. The literature specific to common elbow arthroscopy indications was summarized and was assigned a grade of recommendation based on the available evidence. RESULTS: There is fair-quality evidence for elbow arthroscopy in the treatment of rheumatoid arthritis of the elbow and lateral epicondylitis (grade B recommendation). There is poor-quality evidence for, rather than against, the arthroscopic treatment of degenerative arthritis, osteochondritis dissecans, radial head resection, loose bodies, post-traumatic arthrofibrosis, posteromedial impingement, excision of a plica, and fractures of the capitellum, coronoid process, and radial head (grade C(f) recommendation). There is insufficient evidence to give a recommendation for or against the arthroscopic treatment of posterolateral rotatory instability and septic arthritis (grade I recommendation). CONCLUSIONS: The available evidence supports the use of elbow arthroscopy in the management of the majority of conditions where it is currently used. The quality of the evidence, however, is generally fair to poor. LEVEL OF EVIDENCE: Level IV, systematic review of Level II-IV studies. PMID- 22244103 TI - Surgical treatment of chronic retrocalcaneal bursitis. AB - PURPOSE: The purpose of this systematic review was to analyze the results of surgical treatments for chronic retrocalcaneal bursitis (RB). METHODS: Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase, and the Cochrane Library (1945 to December 2010) were systematically searched for the following terms: calcaneal AND (prominence OR exostosis) OR ((retrocalcaneal OR calcan(*)) AND (burs(*) OR exosto(*) OR prominence)) OR Haglund[tw] OR Haglund's[tw] OR ((retrocalcaneal OR calcan(*)) AND (ostectom(*) OR osteotom(*) OR resect(*))). Therapeutic studies on 10 or more subjects with RB were eligible. Quality was assessed by use of the GRADE scale and Downs and Black scale. RESULTS: Of 876 reviewed abstracts, 15 trials met our inclusion criteria evaluating 547 procedures in 461 patients. Twelve trials reported an open surgical technique; three studies evaluated endoscopic techniques. Differences in patient satisfaction favored the endoscopic technique. The complication rate differed substantially, favoring endoscopic surgery over open surgery. CONCLUSIONS: There are many different surgical techniques to treat RB. Regardless of technique, resecting sufficient bone is essential for a good outcome. Even though the level of evidence of included studies is relatively low, it can be concluded that endoscopic surgery is superior to open intervention for RB. More evidence is a necessity to be more conclusive regarding the best surgical treatment. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 22244104 TI - Popliteal venotomy during posterior cruciate ligament reconstruction in the setting of a popliteal artery bypass graft. AB - Injury to the vascular structures in the popliteal fossa during arthroscopic cruciate ligament reconstruction can be limb threatening or even life threatening. We present the first report, to our knowledge, of an isolated injury to a popliteal vein during arthroscopic posterior cruciate ligament reconstruction. Unfortunately, the venotomy led to cardiopulmonary arrest and flash pulmonary edema in this patient. Preoperative planning is paramount to assess risk of injury to vascular structures, which may be increased in patients who have had prior procedures on the affected knee. Furthermore, vascular surgery consultation preoperatively after a magnetic resonance angiogram or venogram and avoiding the use of epinephrine in the arthroscopy fluid should be considered when performing these higher-risk procedures. PMID- 22244105 TI - Synergistic control of joint angle variability: influence of target shape. AB - Reaching movements are often used to study the effectiveness of motor control processes with respect to the final position of arm and hand. Empirical evidence shows that different targets can be grasped with similar final position accuracy. However, movements that achieve similar accuracy at their final position may nevertheless be controlled differently. In particular, control strategies may differ in the control of the abundant degrees of freedom with respect to the task specific costs. The objective of the present study was to investigate whether the applied control strategy was influenced by the shape of the target to be grasped. It was investigated whether mechanical constraints, imposed on final hand orientation or final hand position by the shape of the targets, affected the synergistic coordination of the kinematic degrees of freedom of the arm. Subjects were asked to grasp either a cylindrical or a spherical target, which imposed different constraints on final hand orientation and position. Besides temporal movement aspects, variability of the joint angles of the arm, as well as variability of hand orientation and hand position was analyzed over the whole time course of movement execution, using the uncontrolled manifold method. Overall movement duration differed between cylindrical and spherical target condition, due to differences in deceleration duration. Reaching movements towards the cylindrical target, which was more constraint in final hand orientation and position, took longer than movements towards the spherical target. Analysis further revealed that the degrees of freedom of the arm were synergistically coordinated to stabilize both hand orientation and hand position, when grasping either the spherical or the cylindrical target. This suggests that the applied control strategy in natural reaching movements can simultaneously account for multiple task constraints. The analysis further revealed that stabilization of hand orientation was stronger when reaching towards a cylindrical target, which imposed more constraints on final hand orientation. In contrast, hand position was more strongly stabilized in the spherical target shape condition, where stronger constraints on final hand position were applied. This suggests that different target shapes do influence the control strategy of reaching movements even though variability at movement end was not affected. PMID- 22244106 TI - An EMG-driven musculoskeletal model of the shoulder. AB - This paper aims to develop an EMG-driven model of the shoulder that can consider possible muscle co-contractions. A musculoskeletal shoulder model (the original model) is modified such that measured EMGs can be used as model-inputs (the EMG driven model). The model is validated by using the in-vivo measured glenohumeral joint reaction forces (GH-JRFs). Three patients carrying instrumented hemi arthroplasty were asked to perform arm abduction and forward-flexion up to maximum possible elevation, during which motion data, EMG, and in-vivo GH-JRF were measured. The measured EMGs were normalized and together with analyzed motions served as model inputs to estimate the GH-JRF. All possible combinations of input EMGs ranging from a single signal to all EMG signals together were tested. The 'best solution' was defined as the combination of EMGs which yielded the closest match between the model and the experiments. Two types of inconsistencies between the original model and the measurements were observed including a general GH-JRF underestimation and a GH-JRF drop above 90 degrees elevation. Both inconsistencies appeared to be related to co-contraction since inclusion of EMGs could significantly (p<.05) improve the predicted GH-JRF (up to 45%). The developed model has shown the potential to successfully take the existent muscle co-contractions of patients into account. PMID- 22244107 TI - Effects of sterilization and disinfection procedures on the corrosion of orthodontic ligature cutters. AB - OBJECTIVE: The objective of our study was to investigate the corrosion resistance of orthodontic ligature cutters subjected separately to two different sterilization procedures, namely, autoclaving and chemical disinfection with main focus on the cutting section of each instrument. MATERIALS AND METHODS: Twenty four ligature cutters were obtained from three different manufacturers: Hu Friedy, ETM, and Nadir & Co. The study included a control group (G0) and four experimental groups (G1-4). G1 was subjected to 50 autoclave sterilization cycles. G2, G3, and G4 were subjected to 50 chemical disinfection cycles using, respectively, Peridiol E, Hexanios G+R, and Steranios 2%. Manufacturer recommendations were followed. The instruments' blades were studied via SEM and X ray microanalysis (EDX spectrum). RESULTS: These cutters have inserts made from various resistant alloys. SEM micrographs revealed different forms of corrosion depending on whether autoclaving or chemical disinfectant sterilization procedures were used, and depending on the alloys present. Chemical disinfection is more aggressive than autoclave sterilization, and is responsible for localized corrosion in the form of pitting. This is more detrimental to the lifespan of orthodontic cutters. CONCLUSION: Sterilization/disinfection procedures should be adapted to the chemical profile of the metal alloys present. Recommendations for use published by instrument manufacturers must be followed. PMID- 22244109 TI - Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer. AB - BACKGROUND: The multicellular tumor spheroid (MCTS) is an in vitro model associating malignant-cell microenvironment and 3D organization as currently observed in avascular tumors. METHODS: In order to evaluate the relevance of this model for pre-clinical studies of drug combinations, we analyzed the effect of gemcitabine alone and in combination with the CHIR-124 CHK1 inhibitor in a Capan 2 pancreatic cell MCTS model. RESULTS: Compared to monolayer cultures, Capan-2 MCTS exhibited resistance to gemcitabine cytotoxic effect. This resistance was amplified in EGF-deprived quiescent spheroid suggesting that quiescent cells are playing a role in gemcitabine multicellular resistance. After a prolonged incubation with gemcitabine, DNA damages and massive apoptosis were observed throughout the spheroid while cell cycle arrest was restricted to the outer cell layer, indicating that gemcitabine-induced apoptosis is directly correlated to DNA damages. The combination of gemcitabine and CHIR-124 in this MCTS model, enhanced the sensitivity to the gemcitabine antiproliferative effect in correlation with an increase in DNA damage and apoptosis. CONCLUSIONS: These results demonstrate that our pancreatic MCTS model, suitable for both screening and imaging analysis, is a valuable advanced tool for evaluating the spatio temporal effect of drugs and drug combinations in a chemoresistant and microenvironment-depending tumor model. PMID- 22244110 TI - Molecular epidemiology of mycobacteriosis in wildlife and pet animals. AB - The ecology of mycobacteria is shifting in accordance with environmental change and new patterns of interaction between wildlife, humans, and nondomestic animals. Infection of vertebrate hosts throughout the world is greater now than ever and includes a growing prevalence in free ranging and captive wild animals. Molecular epidemiologic studies using standardized methods with high discriminatory power are useful for tracking individual cases and outbreaks, identifying reservoirs, and describing patterns of transmission and are used with increasing frequency to characterize disease wildlife. This review describes current features of mycobacteriosis in wildlife species based on traditional descriptive studies and recent molecular applications. PMID- 22244111 TI - Mycobacterial lesions in fish, amphibians, reptiles, rodents, lagomorphs, and ferrets with reference to animal models. AB - Mycobacteriosis is a serious disease across many animal species. Approximately more than 120 species are currently recognized in the genus Mycobacterium. This article describes the zoonotic potential of mycobacteria and mycobacteriosis in fish, amphibians, rodents, rabbits, and ferrets. It considers clinical signs; histology; molecular methods of identification, such as polymerase chain reaction and DNA sequencing; routes of infection; and disease progression. Studying the disease in animals may aid in understanding the pathogenesis of mycobacterial infections in humans and identify better therapy and preventative options such as vaccines. PMID- 22244112 TI - Pathology of mycobacteriosis in birds. AB - Avian mycobacteriosis is a disease that affects companion, captive exotic, wild, and domestic birds. The disease in birds is generally caused by Mycobacterium avium subsp avium but more than 10 other species of mycobacteria infect birds. Oral route of infection appears to be the primary mode of transmission. In some cases, the extensive involvement of the respiratory system suggests an airborne mode of transmission. Molecular diagnostic techniques have improved the ability to confirm the disease. Avian mycobacteriosis is an important veterinary and economic risk in birds and mammals. Exposure of humans to infected birds may cause a zoonotic infection. PMID- 22244113 TI - Taking a rational approach in the treatment of avian mycobacteriosis. AB - Treatment for avian mycobacteriosis is still in its infancy and based on extrapolations from human medicine. The optimum drug choice, dose, or length of treatment has yet to be determined for most exotic animal species. Treatment should include multiple drugs for extended periods of time with appropriate monitoring of both drug levels and overall animal health. Risk to owners and handlers needs to be minimized through appropriate identification of the species of mycobacteri causing disease. More research is necessary on the pharmacokinetics of these drugs in other animal species and antibiotic resistance. Currently, euthanasia remains the most common action in the face of active mycobacteriosis. PMID- 22244114 TI - Diagnosis of mycobacterial infections in the exotic pet patient with emphasis on birds. AB - The term "mycobacteriosis" encompasses a variety of infectious diseases of animals caused by bacteria of the genus Mycobacterium, which are chronic and debilitating diseases. More than 35 Mycobacterium spp can cause mycobacteriosis. The wide range of possible clinical signs and physical exam findings can make the antemortem diagnosis inconsistent and challenging. Proper sample collection and test modality in relation to the state of the disease process are essential. Clinicians can determine a presumptive diagnosis of mycobacteriosis, but the definitive etiologic diagnosis of mycobacteriosis relies on the correct identification of the mycobacteria through microbiological and molecular diagnostic methods. PMID- 22244115 TI - Mycobacteriosis in the rabbit and rodent. AB - Spontaneous mycobacteriosis is rare in rabbits and rodents with the exception of the pygmy rabbit, and there are only a handful of reported cases involving other rodents. Mycobacterium avium complex was the most commonly identified organism in reports of spontaneous mycobacteriosis involving rabbits and rodents. The resistance of rabbits and rodents to mycobacterial disease has been useful in understanding the disease in humans and other animals. Preventing or controlling Mycobacterium sp transmission from wildlife to domestic animals will require collaboration between agriculture, wildlife, environmental, and political entities. Understanding the ecology and epidemiology of mycobacteria is needed for better worldwide management of tuberculosis. PMID- 22244116 TI - Mycobacterial infections in reptiles. AB - Mycobacteriosis is an important disease worldwide. Although commonly associated with higher vertebrates, including humans, it has been reported in only a handful of reptile cases. The purpose of this article is to review the literature as it relates to mycobacteriosis in reptiles. Knowledge of the epidemiology of this disease can be useful to veterinarians working with these animals, especially when working on a diagnosis and making recommendations to clients regarding the need for case follow-up to rule in or rule out the potential presence of these pathogens in pet reptiles and best handling practices to minimize their exposure. PMID- 22244117 TI - Amphibian mycobacteriosis. AB - Amphibians are commonly kept in laboratory and zoological facilities and are becoming more frequent as pets. However, many amphibian species are declining in the wild owing to a variety of infectious and noninfectious diseases. This article reviews the current state of knowledge of mycobacteriosis in amphibian species, including pathogenesis, clinical signs, appropriate diagnostics, treatment options, and zoonotic potential and prevention. It is hoped this review will provide clinical veterinarians and scientists the tools they need to provide better care for amphibian species suffering mycobacteriosis, as well as serve to stimulate additional research into amphibians affected by mycobacterosis. PMID- 22244118 TI - Mycobacterial infection in the ferret. AB - Mycobacteriosis is an important disease in the feral ferret (Mustela putorius furo) of New Zealand; elsewhere, reports of tuberculosis in the ferret are sporadic. Genus Mycobacterium consists of aerobic, non-spore-forming, gram positive, nonmotile bacteria that characteristically feature a cell wall rich in mycolic acids and esters. The epidemiology of mycobacteriosis in the ferrets of New Zealand involves complex interactions between ferrets, possums, and livestock. Investigators have shown that the ferret is highly susceptible only to Mycobacterium bovis infection and is more resistant to infection by other Mycobacterium spp. The principal site of all mycobacterial infection in the ferret is the gastrointestinal tract. PMID- 22244119 TI - Mycobacteriosis. PMID- 22244120 TI - The AJT report: news and issues that affect organ and tissue transplantation. Missing the mark: hospital-wide electronic medical record systems don't always accommodate transplantation's specific needs. PMID- 22244121 TI - Literature watch implications for transplantation. The anti-infectious role of the IL-17 pathway. PMID- 22244122 TI - Maastricht type 2 donors: unrealized opportunities. PMID- 22244123 TI - Posttransplant lymphoproliferative disorder presenting as multiple cystic lesions in a renal transplant recipient. AB - We report a case of a 67-year-old man who experienced allograft dysfunction following a renal transplantation from a donation after cardiac death. The postoperative course was initially complicated by episodes of E. coli urinary sepsis causing pyrexia and a raised creatinine level. Ultrasound scanning 5 weeks posttransplant revealed mild hydronephrosis with several parenchymal cystic areas measuring up to 2 cm with appearances suggestive of fungal balls. Aspirated fluid again grew Escherichia coli, and this was treated with the appropriate antimicrobial therapy. The patient continued to have episodes of culture-negative sepsis; therefore, a computed tomography scan was performed 6 months posttransplant, which revealed multiple lesions in the renal cortex as well as liver and spleen. Subsequent biopsy revealed an Epstein-Barr virus-driven lymphoproliferation consistent with a polymorphic posttransplantation lymphoproliferative disorder (PTLD). This rare case of PTLD presenting as multiple renal, hepatic and splenic lesions emphasizes the need for a high index of clinical suspicion for this condition. Abnormal para-renal allograft masses should be biopsied to allow swift and effective management of a disease that can disseminate and become significantly more challenging to manage. PMID- 22244124 TI - Legionellosis--United States, 2000-2009. PMID- 22244125 TI - Fever and suprapubic tenderness ten days after kidney transplantation. PMID- 22244126 TI - Causes and ecological effects of resuspended contaminated sediments (RCS) in marine environments. AB - Sediments act as a net sink for anthropogenic contaminants in marine ecosystems and contaminated sediments may have a range of toxicological effects on benthic fauna and associated species. When resuspended, however, particulate-bound contaminants may be remobilised into the water column and become bioavailable to an additional assemblage of species. Such resuspension occurs through a range of natural and anthropogenic processes each of which may be thought of as pulsed disturbances resulting in pulsed exposures to contaminants. Thus, it is important to understand not only the toxicological responses of organisms to resuspended contaminated sediments (RCS), but also the frequency, magnitude and duration of sediment disturbance events. Such information is rarely collected together with toxicological data. Rather, the majority of published studies (>50% of the articles captured in this review) have taken the form of fixed-duration laboratory-based exposures with individual species. While this research has clearly demonstrated that resuspension of contaminated sediments can liberate sediment-bound contaminants leading to toxicity and bioaccumulation under controlled conditions, the potential for ecological effects in the field is often unclear. Monitoring studies suggest that recurrent natural disturbances such as tides and waves may cause the majority of contaminant release in many environments. However, various processes also act to limit the spatial and temporal scales across which contaminants are remobilised to the most toxic dissolved state. Various natural and anthropogenic disturbances of contaminated sediments have been linked to both community-level and sub-lethal responses in exposed populations of invertebrates and fish in the field. Together these findings suggest that resuspension of contaminated sediments is a frequently recurring ecological threat in contaminated marine habitats. Further consideration of how marine communities respond to temporally variable exposures to RCS is required, as well as research into the relative importance of various disturbances under field conditions. PMID- 22244127 TI - Cardiovascular mortality and heart failure risk score for patients after ST segment elevation acute myocardial infarction treated with primary percutaneous coronary intervention (Data from the Leiden MISSION! Infarct Registry). AB - The risk scores developed for the prediction of an adverse outcome in patients after ST-segment elevation myocardial infarction (STEMI) have mostly addressed patients treated with thrombolysis and evaluated solely all-cause mortality as the primary end point. Primary percutaneous coronary intervention in patients with STEMI has improved the outcome significantly and might have changed the relative contribution of different risk factors. Our patient population included 1,484 consecutive patients admitted with STEMI who had undergone primary percutaneous coronary intervention. The clinical, angiographic, and echocardiographic data obtained during hospitalization were used to derive a risk score for the prediction of short-term (30-day) and long-term (1- and 4-year) cardiovascular mortality and hospitalization for heart failure. During a median follow-up of 30 months, 87 patients (6%) died from cardiovascular mortality or were hospitalized for heart failure. Multivariate Cox regression analyses identified age >=70 years, Killip class >=2, diabetes, left anterior descending coronary artery as the culprit vessel, 3-vessel disease, peak cardiac troponin T level >=3.5 MUg/L, left ventricular ejection fraction <=40%, and heart rate at discharge >=70 beats/min as relevant factors for the construction of the risk score. The discriminatory power of the model as assessed using the areas under the receiver operating characteristic curves was good (0.84, 0.83, and 0.81 at 30 days and 1 and 4 years, respectively), and the patients could be allocated to low , intermediate-, or high-risk categories with an event rate of 1%, 6%, and 24%, respectively. In conclusion, the current risk model demonstrates for the first time that 8 parameters readily available during the hospitalization of patients with STEMI treated with primary percutaneous coronary intervention can accurately stratify patients at long-term follow-up (<=4 years after the index infarction) into low-, intermediate-, and high-risk categories. PMID- 22244128 TI - Baseline and post-exercise N-terminal pro-B-type natriuretic peptide values are associated with body mass index. PMID- 22244129 TI - Alcoholic cirrhosis and coronary artery disease. PMID- 22244130 TI - Not all exercises are created equal. PMID- 22244131 TI - PyElph - a software tool for gel images analysis and phylogenetics. AB - BACKGROUND: This paper presents PyElph, a software tool which automatically extracts data from gel images, computes the molecular weights of the analyzed molecules or fragments, compares DNA patterns which result from experiments with molecular genetic markers and, also, generates phylogenetic trees computed by five clustering methods, using the information extracted from the analyzed gel image. The software can be successfully used for population genetics, phylogenetics, taxonomic studies and other applications which require gel image analysis. Researchers and students working in molecular biology and genetics would benefit greatly from the proposed software because it is free, open source, easy to use, has a friendly Graphical User Interface and does not depend on specific image acquisition devices like other commercial programs with similar functionalities do. RESULTS: PyElph software tool is entirely implemented in Python which is a very popular programming language among the bioinformatics community. It provides a very friendly Graphical User Interface which was designed in six steps that gradually lead to the results. The user is guided through the following steps: image loading and preparation, lane detection, band detection, molecular weights computation based on a molecular weight marker, band matching and finally, the computation and visualization of phylogenetic trees. A strong point of the software is the visualization component for the processed data. The Graphical User Interface provides operations for image manipulation and highlights lanes, bands and band matching in the analyzed gel image. All the data and images generated in each step can be saved. The software has been tested on several DNA patterns obtained from experiments with different genetic markers. Examples of genetic markers which can be analyzed using PyElph are RFLP (Restriction Fragment Length Polymorphism), AFLP (Amplified Fragment Length Polymorphism), RAPD (Random Amplification of Polymorphic DNA) and STR (Short Tandem Repeat). The similarity between the DNA sequences is computed and used to generate phylogenetic trees which are very useful for population genetics studies and taxonomic classification. CONCLUSIONS: PyElph decreases the effort and time spent processing data from gel images by providing an automatic step-by-step gel image analysis system with a friendly Graphical User Interface. The proposed free software tool is suitable for researchers and students which do not have access to expensive commercial software and image acquisition devices. PMID- 22244132 TI - Endogenous and exogenous hydrogen influence on amorphous silicon thin films analysis by pulsed radiofrequency glow discharge optical emission spectrometry. AB - During the last decade the photovoltaic industry has been growing rapidly. One major strategy to reduce the production costs is the use of thin film solar cells based on hydrogenated amorphous silicon (a-Si:H). The potential of pulsed radiofrequency glow discharge coupled to optical emission spectrometry (rf-PGD OES) for the analysis of such type of materials has been investigated in this work. It is known that when hydrogen is present in the argon discharge, even in small quantities, significant changes can occur in the emission intensities and sputtering rates measured. Therefore, a critical comparison has been carried out by rf-PGD-OES, in terms of emission intensities, penetration rates and depth resolution for two modes of hydrogen introduction in the discharge, manually external hydrogen in gaseous form (0.2% H(2)-Ar) or internal hydrogen, sputtered as a sample constituent. First, a comparative optimisation study (at 600 Pa and 50 W) was performed on conducting materials and on a silicon wafer varying the pulse parameters: pulse frequency (500 Hz-20 kHz) and duty cycle (12.5-50%). Finally, 600 Pa, 50 W, 10 kHz and 25% duty cycle were selected as the optimum conditions to analyse three types of hydrogenated samples: an intrinsic, a B doped and a P-doped layer based on a-Si:H. Enhanced emission intensities have been measured for most elements in the presence of hydrogen (especially for silicon) despite the observed reduced sputtering rate. The influence of externally added hydrogen and that of hydrogen sputtered as sample constituent from the analysed samples has been evaluated. PMID- 22244133 TI - Green chemistry and the evolution of flow analysis. A review. AB - Flow analysis has achieved its majority as a well-established tool to solve analytical problems. Evolution of flow-based approaches has been analyzed by diverse points of view, including historical aspects, the commutation concept and the impact on analytical methodologies. In this overview, the evolution of flow analysis towards green analytical chemistry is demonstrated by comparing classical procedures implemented with different flow approaches. The potential to minimize reagent consumption and waste generation and the ability to implement processes unreliable in batch to replace toxic chemicals are also emphasized. Successful applications of greener approaches in flow analysis are also discussed, focusing on the last 10 years. PMID- 22244134 TI - Surface-bonded ionic liquid stationary phases in high-performance liquid chromatography--a review. AB - Ionic liquids (ILs) are a class of ionic, nonmolecular solvents which remain in liquid state at temperatures below 100 degrees C. ILs possess a variety of properties including low to negligible vapor pressure, high thermal stability, miscibility with water or a variety of organic solvents, and variable viscosity. IL-modified silica as novel high-performance liquid chromatography (HPLC) stationary phases have attracted considerable attention for their differential behavior and low free-silanol activity. Indeed, around 21 surface-confined ionic liquids (SCIL) stationary phases have been developed in the last six years. Their chromatographic behavior has been studied, and, despite the presence of a positive charge on the stationary phase, they showed considerable promise for the separation of neutral solutes (not only basic analytes), when operated in reversed phase mode. This aspect points to the potential for truly multimodal stationary phases. This review attempts to summarize the state-of-the-art about SCIL phases including their preparation, chromatographic behavior, and analytical performance. PMID- 22244135 TI - Arsenic speciation in edible alga samples by microwave-assisted extraction and high performance liquid chromatography coupled to atomic fluorescence spectrometry. AB - Twelve commercially available edible marine algae from France, Japan and Spain and the certified reference material (CRM) NIES No. 9 Sargassum fulvellum were analyzed for total arsenic and arsenic species. Total arsenic concentrations were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) after microwave digestion and ranged from 23 to 126 MUg g(-1). Arsenic species in alga samples were extracted with deionized water by microwave-assisted extraction and showed extraction efficiencies from 49 to 98%, in terms of total arsenic. The presence of eleven arsenic species was studied by high performance liquid chromatography-ultraviolet photo-oxidation-hydride generation atomic-fluorescence spectrometry (HPLC-(UV)-HG-AFS) developed methods, using both anion and cation exchange chromatography. Glycerol and phosphate sugars were found in all alga samples analyzed, at concentrations between 0.11 and 22 MUg g(-1), whereas sulfonate and sulfate sugars were only detected in three of them (0.6-7.2 MUg g( 1)). Regarding arsenic toxic species, low concentration levels of dimethylarsinic acid (DMA) (<0.9 MUg g(-1)) and generally high arsenate (As(V)) concentrations (up to 77 MUg g(-1)) were found in most of the algae studied. The results obtained are of interest to highlight the need to perform speciation analysis and to introduce appropriate legislation to limit toxic arsenic species content in these food products. PMID- 22244136 TI - Usefulness of capability indices in the framework of analytical methods validation. AB - Analytical methods capability evaluation can be a useful methodology to assess the fitness of purpose of these methods for their future routine application. However, care on how to compute the capability indices have to be made. Indeed, the commonly used formulas to compute capability indices such as Cpk, will highly overestimate the true capability of the methods. Especially during methods validation or transfer, there are only few experiments performed and, using in these situations the commonly applied capability indices to declare a method as valid or as transferable to a receiving laboratory will conduct to inadequate decisions. In this work, an improved capability index, namely Cpk-tol and the corresponding estimator of proportion of non-conforming results (pi(Cpk-tol)) have been proposed. Through Monte-Carlo simulations, they have been shown to greatly increase the estimation of analytical methods capability in particular in low sample size situations as encountered during methods validation or transfer. Additionally, the usefulness of this capability index has been illustrated through several case studies covering applications commonly encountered in the pharmaceutical industry. Finally a methodology to determine the optimal sample size required to validate analytical methods is also given using the proposed capability metric. PMID- 22244137 TI - Prediction of some quality attributes of lamb meat using near-infrared hyperspectral imaging and multivariate analysis. AB - The goal of this study was to explore the potential of near-infrared (NIR) hyperspectral imaging in combination with multivariate analysis for the prediction of some quality attributes of lamb meat. In this study, samples from three different muscles (semitendinosus (ST), semimembranosus (SM), longissimus dorsi (LD)) originated from Texel, Suffolk, Scottish Blackface and Charollais breeds were collected and used for image acquisition and quality measurements. Hyperspectral images were acquired using a pushbroom NIR hyperspectral imaging system in the spectral range of 900-1700 nm. A partial least-squares (PLS) regression, as a multivariate calibration method, was used to correlate the NIR reflectance spectra with quality values of the tested muscles. The models performed well for predicting pH, colour and drip loss with the coefficient of determination (R(2)) of 0.65, 0.91 and 0.77, respectively. Image processing algorithm was also developed to transfer the predictive model in every pixel to generate prediction maps that visualize the spatial distribution of quality parameter in the imaged lamb samples. In addition, textural analysis based on gray level co-occurrence matrix (GLCM) was also conducted to determine the correlation between textural features and drip loss. The results clearly indicated that NIR hyperspectral imaging technique has the potential as a fast and non-invasive method for predicting quality attributes of lamb meat. PMID- 22244138 TI - Annular diffusion denuder for simultaneous removal of gaseous organic compounds and air oxidants during sampling of carbonaceous aerosols. AB - A specially designed annular diffusion denuder for simultaneous removal of organic gaseous compounds and atmospheric oxidants in carbonaceous aerosol sampling is presented. Various kinds of denuder coatings were compared with respect to the collection efficiency of both organic gaseous compounds and NO(2) and ozone. The optimum sorbent is a mixture of activated charcoal and sulfite on molecular sieve. To ensure high collection efficiency over long-term field operation, two annular diffusion denuders are combined in series. The first half of the first denuder is filled with Na(2)SO(3) on molecular sieve (23 cm long layer) while the second half of the first denuder and the whole second denuder are filled with activated charcoal (the total length of the charcoal section is 67 cm). At a flow rate of 16.6 L min(-1), the collection efficiency of organic gaseous compounds and atmospheric oxidants in the annular diffusion denuder is better than 95%. Only small losses of aerosol particles (<3.6% in number concentration) were observed in the size range 0.12-2.26 MUm. The annular diffusion denuder is compatible with the collection of aerosols on 47-mm diameter quartz fiber filters at a flow rate of 16.6 L min(-1). The use of this denuder enables one to sample carbonaceous aerosols on filters without positive sampling artefacts from volatile organic compounds and interferences from atmospheric oxidants. The annular diffusion denuder has been applied successfully for the sampling of carbonaceous aerosols during field campaigns of typically 1 month each at urban and forested sites in Europe. PMID- 22244139 TI - Evaluation of single-walled carbon nanohorns as sorbent in dispersive micro solid phase extraction. AB - A new dispersive micro solid-phase extraction method which uses single-walled carbon nanohorns (SWNHs) as sorbent is proposed. The procedure combines the excellent sorbent properties of the nanoparticles with the efficiency of the dispersion of the material in the sample matrix. Under these conditions, the interaction with the analytes is maximized. The determination of polycyclic aromatic hydrocarbons was selected as model analytical problem. Two dispersion strategies were evaluated, being the functionalization via microwave irradiation better than the use of a surfactant. The extraction was accomplished by adding 1 mL of oxidized SWHNs (o-SWNHs) dispersion to 10 mL of water sample. After extraction, the mixture was passed through a disposable Nylon filter were the nanoparticles enriched with the PAHs were retained. The elution was carried out with 100 MUL of hexane. The limits of detection achieved were between 30 and 60ngL(-1) with a precision (as repeatability) better than 12.5%. The recoveries obtained for the analytes in three different water samples were acceptable in all instances. The performance of o-SWNHs was favourably compared with that provided by carboxylated single-walled carbon nanotubes and thermally treated carbon nanocones. PMID- 22244140 TI - Comparison of ultrasound-assisted emulsification and dispersive liquid-liquid microextraction methods for the speciation of inorganic selenium in environmental water samples using low density extraction solvents. AB - Herein, ultrasound-assisted emulsification microextraction (USAEME) and dispersive liquid-liquid microextraction (DLLME) methods based on applying low density organic solvents have been critically compared for the speciation of inorganic selenium, Se(IV) (selenite) and Se(VI) (selenate) in environmental water samples by gas chromatography-flame ionization detection (GC-FID). At pH 2 and T=75 degrees C for 7 min, only Se(IV) was able to form the piazselenol complex with 4-nitro-o-phenylenediamine. Piazselenol was extracted using an extraction solvent and was injected into a GC-FID instrument for the determination of Se(IV). Conveniently, Se(VI) remained in the aqueous phase. Total inorganic selenium was determined after the reduction of Se(VI) to Se(IV) and prior to the above procedures. The Se(VI) concentration was calculated as the difference between the measured total inorganic selenium and Se(IV) content. The effect of various experimental parameters on the efficiencies of the two methods and their optimum values were studied with the aid of response surface methodology and experimental design. Under the optimal conditions, the limit of detections (LODs) for Se(IV) obtained by USAEME-GC-FID and DLLME-GC-FID were 0.05 and 0.11 ng mL(-1), respectively. The relative standard deviations (RSDs, n=6) for the measurement 10 ng mL(-1) of Se(IV) were 5.32% and 4.57% with the enrichment factors of 2491 and 1129 for USAEME-GC-FID and DLLME-GC-FID, respectively. Both methods were successfully applied to the analysis of inorganic selenium in different environmental water samples and certified reference material (NIST SRM 1643e). PMID- 22244141 TI - Application of sulfur microparticles for solid-phase extraction of polycyclic aromatic hydrocarbons from sea water and wastewater samples. AB - The application of sulfur microparticles as efficient adsorbents for the solid phase extraction (SPE) and determination of trace amounts of 10 polycyclic aromatic hydrocarbons (PAHs) was investigated in sea water and wastewater samples using high performance liquid chromatography coupled with an ultraviolet detector (HPLC-UV). Parameters influencing the preconcentration of PAHs such as the amount of sulfur, solution flow rate and volume, elution solvent, type and concentration of organic modifier, and salt effect were examined. The results showed that at a flow rate of 10 mL min(-1) for the sample solutions (100mL), the PAHs could be adsorbed on the sulfur microparticles and then eluted by 2.0 mL of acetonitrile. For HPLC-UV analysis of extracted PAHs, the calibration curves were linear in the range of 0.05-80.0 MUg L(-1); the coefficients of determinations (r(2)) were between 0.9934 and 0.9995. The relative standard deviations (RSDs) for eight replicates at two concentration levels (0.5 and 4.0 MUg L(-1)) of PAHs were lower than 7.3%, under optimized conditions. The limits of detection (LODs, S/N = 3) of the proposed method for the studied PAHs were 0.007-0.048 MUg L(-1). The recoveries of spiked PAHs (0.5 and 4 MUg L(-1)) in the wastewater and sea water samples ranged from 78% to 108%. The simplicity of experimental procedure, high extraction efficiency, short sample analysis, and using of low cost sorbent demonstrate the potential of this approach for routine trace PAH analysis in water and wastewater samples. PMID- 22244142 TI - Effect of standard phase differences between gas and liquid and the resulting experimental bias in the analysis of gaseous volatile organic compounds. AB - Liquid- or gas-phase standards can be used for the analysis of VOCs in air. Once the accuracy is secured in the standard preparation stage, the use of gas-phase standard should be more reliable with the least matrix effect. However, it is not difficult to find that the liquid-phase standard is used more preferably in many laboratories for several reasons (e.g., low expense, easy handling, etc.). As such, one needs to accurately evaluate any possible bias stemming from the use of different standard phases. To this end, standards for 8 VOCs consisting of 4 aromatic compounds (benzene (B), toluene (T), styrene (S) and p-xylene (p-X)) and 4 others (methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), butyl acetate (BuAc), and isobutyl alcohol (i-BuAl)) were prepared in both liquid and gas phases. Each standard was analyzed by the initial collection on the adsorption tube and by the combined application of thermal-desorption-gas chromatography mass spectrometry (TD/GC/MS). The results indicated that experimental bias between the two phases, if expressed in terms of percent difference (PD), was very low in many target VOCs (B (1.09%), T (2.41%), p-X (3.64%), MEK (6.76%), and MIBK (0.17%)), while it was not in some targets (e.g., >10%: e.g., S, i-BuAl, and BuAc). In an ancillary experiment, biases were evaluated further by (1) calibrating gaseous samples against liquid phase standard and via (2) comparison between two different types of gas phase standards. In conclusion, treatment of different standards (e.g., between the same or different phases) will inevitably induce biases in most VOCs, although certain volatiles (e.g., benzene, MIBK, etc.) are virtually unaffected by such variables in a practical sense. PMID- 22244143 TI - Microprobe sampling--photo ionization-time-of-flight mass spectrometry for in situ chemical analysis of pyrolysis and combustion gases: examination of the thermo-chemical processes within a burning cigarette. AB - A microprobe sampling device (MU-probe) has been developed for in situ on-line photo ionization mass spectrometric analysis of volatile chemical species formed within objects consisting of organic matter during thermal processing. With this approach the chemical signature occurring during heating, pyrolysis, combustion, roasting and charring of organic material within burning objects such as burning fuel particles (e.g., biomass or coal pieces), lit cigarettes or thermally processed food products (e.g., roasting of coffee beans) can be investigated. Due to its dynamic changes between combustion and pyrolysis phases the cigarette smoking process is particularly interesting and has been chosen as first application. For this investigation the tip of the MU-probe is inserted directly into the tobacco rod and volatile organic compounds from inside the burning cigarette are extracted and real-time analyzed as the glowing front (or coal) approaches and passes the MU-probe sampling position. The combination of micro sampling with photo ionization time-of-flight mass spectrometry (PI-TOFMS) allows on-line intrapuff-resolved analysis of species formation inside a burning cigarette. Monitoring volatile smoke compounds during cigarette puffing and smoldering cycles in this way provides unparalleled insights into formation mechanisms and their time-dependent change. Using this technique the changes from pyrolysis conditions to combustion conditions inside the coal of a cigarette could be observed directly. A comparative analysis of species formation within a burning Kentucky 2R4F reference cigarette with MU-probe analysis reveals different patterns and behaviors for nicotine, and a range of semi-volatile aromatic and aliphatic species. PMID- 22244144 TI - Amperometric L-lactate biosensor based on screen-printed carbon electrode containing cobalt phthalocyanine, coated with lactate oxidase-mesoporous silica conjugate layer. AB - A novel amperometric biosensor for the measurement of L-lactate has been developed. The device comprises a screen-printed carbon electrode containing cobalt phthalocyanine (CoPC-SPCE), coated with lactate oxidase (LOD) that is immobilized in mesoporous silica (FSM8.0) using a polymer matrix of denatured polyvinyl alcohol; a Nafion layer on the electrode surface acts as a barrier to interferents. The sampling unit attached to the SPCE requires only a small sample volume of 100 MUL for each measurement. The measurement of l-lactate is based on the signal produced by hydrogen peroxide, the product of the enzymatic reaction. The behavior of the biosensor, LOD-FSM8.0/Naf/CoPC-SPCE, was examined in terms of pH, applied potential, sensitivity and operational range, selectivity, and storage stability. The sensor showed an optimum response at a pH of 7.4 and an applied potential of +450 mV. The determination range and the response time for L lactate were 18.3 MUM to 1.5 mM and approximately 90s, respectively. In addition, the sensor exhibited high selectivity for L-lactate and was quite stable in storage, showing no noticeable change in its initial response after being stored for over 9 months. These results indicate that our method provides a simple, cost effective, high-performance biosensor for l-lactate. PMID- 22244145 TI - Ion chromatographic determination of hydrolysis products of hexafluorophosphate salts in aqueous solution. AB - In this work, hydrolysis of three different hexafluorophosphate salts in purified water was investigated. Aqueous samples of lithium hexafluorophosphate (LiPF(6)), sodium hexafluorophosphate (NaPF(6)) and potassium hexafluorophosphate (KPF(6)) were prepared and stored for different times. Ion chromatography (IC) with UV as well as non-suppressed and suppressed conductivity detection was used for the analysis of the reaction products. For the detection and identification of the formed decomposition products, an IC method using IonPac AS14A 250 mm * 4.0 mm i.d. column and 2.5 mM KHCO(3)-2.5 mM K(2)CO(3) eluent was established. Besides hexafluorophosphate, four other anionic species were detected in fresh and matured aqueous solutions. The hydrolysis products fluoride (F(-)), monofluorophosphate (HPO(3)F(-)), phosphate (HPO(4)(2-)) and difluorophosphate (PO(2)F(2)(-)) were found and were unambiguously identified by means of standards or electrospray ionization mass spectrometry (ESI-MS). It was shown that stability of hexafluorophosphate solutions depends on the nature of the counter ion and decreases in the order potassium>sodium>lithium. PMID- 22244146 TI - Dual polarization interferometric and capillary electrophoretic analysis of supported lipid bilayer constructed on silica-based surface: evaluation of its anti-protein adsorption effect. AB - Supported lipid bilayer (SLB) has been demonstrated as a model of cell membranes with prospective bioanalytical or biotechnological applications. In this study, the formation of SLB and their potential biofunctionality against protein adsorption were investigated by Dual Polarization Interferometry (DPI) and Capillary Electrophoresis (CE). DPI studies on different formulations of double chained, zwitterionic phospholipidlipids, allow the process of bilayer formation to be followed in situ and in real time. Furthermore the anti-protein adsorption effect provided by the various formulated SLBs was examined by DPI. In addition, the SLB coatings of the same lipid formulations were subsequently employed in CE experiments as a pseudo-stationary phase for demonstrating more efficient separation of alkaline protein standard mixtures. SLB-assisted CE was found to be capable of separating 4 alkaline proteins (protonated at neutral pH). This study demonstrates the applicability of DPI to monitor the process of SLB formation; and our findings, obtained by both DPI and CE, confirm that the presence of the SLB reduced drastically the problematic interactions between cationic, alkaline proteins and the negatively charged silica capillary wall, leading to better recovery and efficient separation of the proteins under investigation. PMID- 22244147 TI - The role of miRNA in stem cell pluripotency and commitment to the vascular endothelial lineage. AB - Vascular endothelial cells derived from human pluripotent stem cells have substantial potential for the development of novel vascular therapeutics and cell based therapies for the repair of ischemic damage. To gain maximum benefit from this source of cells, a complete understanding of the changes in gene expression and how they are regulated is required. miRNAs have been demonstrated to play a critical role in controlling stem cell pluripotency and differentiation and are important for mature endothelial cell function. Specific miRNAs that determine stem cell fate have been identified for a number of different cell lineages; however, in the case of differentiation and specification of vascular endothelial cells, this is yet to be fully elucidated. PMID- 22244148 TI - Recognition rights, mental health consumers and reconstructive cultural semantics. AB - INTRODUCTION: Those in mental health-related consumer movements have made clear their demands for humane treatment and basic civil rights, an end to stigma and discrimination, and a chance to participate in their own recovery. But theorizing about the politics of recognition, 'recognition rights' and epistemic justice, suggests that they also have a stake in the broad cultural meanings associated with conceptions of mental health and illness. RESULTS: First person accounts of psychiatric diagnosis and mental health care (shown here to represent 'counter stories' to the powerful 'master narrative' of biomedical psychiatry), offer indications about how experiences of mental disorder might be reframed and redefined as part of efforts to acknowledge and honor recognition rights and epistemic justice. However, the task of cultural semantics is one for the entire culture, not merely consumers. These new meanings must be negotiated. When they are not the result of negotiation, group-wrought definitions risk imposing a revision no less constraining than the mis-recognizing one it aims to replace. Contested realities make this a challenging task when it comes to cultural meanings about mental disorder. Examples from mental illness memoirs about two contested realities related to psychosis are examined here: the meaninglessness of symptoms, and the role of insight into illness. They show the magnitude of the challenge involved--for consumers, practitioners, and the general public--in the reconstruction of these new meanings and realities. CONCLUSION: To honor recognition rights and epistemic justice acknowledgement must be made of the heterogeneity of the effects of, and of responses to, psychiatric diagnosis and care, and the extent of the challenge of the reconstructive cultural semantics involved. PMID- 22244149 TI - Stalled Poleta at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1. AB - DNA polymerase eta (Poleta), whose gene mutation is responsible for the inherited disorder xeroderma pigmentosum variant (XP-V), carries out accurate and efficient translesion synthesis (TLS) across cyclobutane pyrimidine dimer (CPD). As Poleta interacts with REV1, and REV1 interacts with other TLS polymerases including Poliota, Polkappa and Polzeta, Poleta may play a role in recruitment of these TLS polymerases at lesion site. But it is unclear whether UV sensitivity of XP-V patients is caused not only by defect of Poleta activity but also by dysfunction of network between Poleta and other TLS polymerases. Here, we examined whether the TLS polymerase network via Poleta is important for replicative bypass of CPDs and DNA damage tolerance induced by UV in mouse cells. We observed that UV sensitivity of Poleta-deficient mouse cells was moderately rescued by the expression of a catalytically inactive Poleta. Moreover, this recovery of cellular UV sensitivity was mediated by the interaction between Poleta and REV1. However, expression of the inactive mutant Poleta was not able to suppress the incidence of UV-induced mutation observed in Poleta-deficient cells. We propose the model that REV1 and Polkappa are involved in DNA damage tolerance via Poleta REV1 interaction when Poleta fails to bypass its cognate substrates. PMID- 22244150 TI - Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. AB - BACKGROUND: The complications of prostate needle biopsy (PNB) are important when considering the benefits and harms of prostate cancer screening. Studies from the United States and Canada have recently reported increasing numbers of hospitalizations for infectious complications after PNB. OBJECTIVE: Examine the risk of infectious complications and hospital admissions after PNB in a European screening trial. DESIGN, SETTING, AND PARTICIPANTS: From 1993 to 2011, 10 474 PNBs were performed in the European Randomized Study of Screening for Prostate Cancer (Rotterdam section). Prophylaxis originally consisted of trimethoprim sulfamethoxazole. Beginning in 2008, it was changed to ciprofloxacin. MEASUREMENTS: Febrile complications and hospital admissions were assessed by questionnaires 2 wk after PNB. Logistic regression was used to identify risk factors for biopsy-related fever and hospital admission. RESULTS AND LIMITATIONS: Fever and hospital admission were reported on 392 of 9241 questionnaires (4.2%) and 78 of 9198 questionnaires (0.8%), respectively. Although most fevers were managed on an outpatient basis, 81% of hospital admissions were for infection. Of the 56 available blood cultures, 34 were positive with Escherichia coli as the predominant organism. On multivariable analysis, prostate enlargement and diabetes were significantly associated with an increased risk of fever after PNB, whereas later year of biopsy was the only factor significantly associated with an increased risk of hospital admission. CONCLUSIONS: In a European screening trial, <5% PNBs resulted in febrile complications. Significant risk factors included diabetes and prostatic enlargement. Although most fevers were managed on an outpatient basis, infection remained the leading cause of hospital admission after PNB. Consistent with prior international reports, the frequency of hospital admissions after PNB significantly increased over time. Nevertheless, the absolute frequency of hospital admissions related to PNB was low and should not dissuade healthy men who would benefit from early prostate cancer diagnosis from undergoing biopsy when clinically indicated. PMID- 22244151 TI - Predictors of attendance for prostate-specific antigen screening tests and prostate biopsy. AB - BACKGROUND: Little is known about factors influencing men's decisions to undergo screening and diagnostic tests for prostate cancer (PCa). OBJECTIVE: Identify predictors of attendance for prostate-specific antigen (PSA) testing and prostate biopsy. DESIGN, SETTING, AND PARTICIPANTS: Literature searches and interviews with men undergoing PSA testing and prostate biopsy formed the basis of a self report questionnaire designed to identify predictors of health behaviour, which was completed by men eligible for PSA invitation and prostate biopsy. Multitrait scaling analyses established the final questionnaire content. This revised instrument was distributed to a new cohort of men before PSA testing and biopsy invitations were received. Ethical committee approval was obtained from Trent Multicentre Research Ethics Committee (MREC/01/4/025-21/06/2001). MEASUREMENTS: Predictors of health behaviour and attendance rates for PSA test or prostate biopsy were measured. Associations between questionnaire scores and health behaviour (PSA and prostate biopsy attendance) were examined using logistic regression. RESULTS AND LIMITATIONS: The provisional 49-item health behaviour questionnaire was completed by 468 of 810 men (57.8%). Multitrait scaling refined the questionnaire to 26 items in six scales (A: health benefits, B: threats to health, C: barriers to testing, D: health intentions, E: external influences, F: current general health). A total of 1455 of 2657 men (54.8%) completed the revised instrument before invitations for PSA test or biopsy were received; 395 (43.4%) and 434 (91.6%) attended. Strong associations between men's health intentions (scale D) and PSA and biopsy attendance (odds ratio: 1.56 or 3.67, respectively; p<0.001) were observed with modest associations between the other five scales and attendance for PSA testing. Average questionnaire response rates represent the major limitation of this study. CONCLUSIONS: Knowledge and beliefs about PCa and testing predict men's intentions and attendance for PSA testing and prostate biopsy. Understanding men's health behaviour is important for the management of patients seeking PSA testing in general practice. PMID- 22244153 TI - Correlative microscopy: providing new understanding in the biomedical and plant sciences. AB - Correlative microscopy is the application of two or more distinct microscopy techniques to the same region of a sample, generating complementary morphological, structural and chemical information that exceeds what is possible with any single technique. As a variety of complementary microscopy approaches rather than a specific type of instrument, correlative microscopy has blossomed in recent years as researchers have recognised that it is particularly suited to address the intricate questions of the modern biological sciences. Specialised technical developments in sample preparation, imaging methods, visualisation and data analysis have also accelerated the uptake of correlative approaches. In light of these advances, this critical review takes the reader on a journey through recent developments in, and applications of, correlative microscopy, examining its impact in biomedical research and in the field of plant science. This twin emphasis gives a unique perspective into use of correlative microscopy in fields that often advance independently, and highlights the lessons that can be learned from both fields for the future of this important area of research. PMID- 22244152 TI - Functional characterisation of bovine interleukin 8 promoter haplotypes in vitro. AB - Interleukin 8 (IL-8) is a major mediator of the innate immune response and polymorphisms in this gene are associated with susceptibility to inflammatory disease in humans. The aim of this study was to characterise the promoter region of the bovine IL8 gene towards understanding its regulation and the effect of promoter polymorphisms on gene expression levels. Twenty-nine polymorphic sites were identified across a 2.1kb upstream promoter region of the IL8 gene including two insertion/deletion polymorphisms. Sequence analysis and SNP genotyping identified two distinct promoter haplotypes (IL8-h1 and IL8-h2), which were present at significantly different frequencies in two divergently selected cattle breeds - Holstein-Friesian and Norwegian Red (IL8-h1 at 48% and 80% respectively). IL8-h1 was functionally less responsive in unstimulated mammary epithelial cells and in response to stimulation with LPS or bovine TNF. Serial deletion analysis and in silico transcription-factor binding site analysis indicated that allele specific binding of the transcriptional repressor Oct-1 may account for the reduced sensitivity of IL8-h1. Our finding of genetic variation in the bovine IL8 promoter that differentially regulates its expression has significant functional implications for IL8 expression in vitro and which may impact on susceptibility to bovine infectious disease and inflammation. PMID- 22244155 TI - Human papillomavirus 18 E6 inhibits phosphorylation of p53 expressed in HeLa cells. AB - BACKGROUND: In HPV infected cells p53 function is abrogated by E6 and even ectopically expressed p53 is unable to perform tumor suppressor functions. In addition to facilitating its degradation, E6 may also inhibit p53 transactivity, though the mechanisms are still poorly understood. It has been reported that inhibition of p300, an acetyltransferase responsible for p53 acetylation is inactivated by E6. Activation of overexpressed p53 to cause cell growth inhibition is facilitated by its phosphorylation. Previously, we reported that non-genotoxically overexpressed p53 in HeLa cells needs to be phosphorylated to perform its cell growth inhibitory functions. Since over expressed p53 by itself was not activated, we hypothesized an inhibitory role for E6. RESULTS: Majority of reports proposes E6 mediated degradation of p53 as a possible reason for its inactivation. However, results presented here for the first time demonstrate that overexpressed p53 is not directly associated with E6 and therefore free, yet it is not functionally active in HPV positive cells. Also, the stability of overexpressed p53 does not seem to be an issue because inhibition of proteasomal degradation did not increase the half-life of overexpressed p53, which is more than endogenous p53. However, inhibition of proteasomal degradation prevents the degradation of endogenous p53. These findings suggest that overexpressed p53 and endogenous p53 are differentially subjected to proteasomal degradation and the reasons for this discrepancy remain unclear. Our studies demonstrate that p53 over expression has no effect on anchorage independent cell-growth and E6 nullifies its cell growth inhibitory effect. E6 overexpression abrogates OA induced p53 occupancy on the p21 promoter and cell death as well. E6 did not decrease p53 protein but phospho-p53 level was significantly reduced. CONCLUSION: We report for the first time that E6 de-activates p53 by inhibiting its phosphorylation. This prevents p53 binding to p21 promoter and thereby restraining its cell-growth inhibitory functions. Our study provides new evidence indicating that viral protein E6 inhibits p53 transactivity by mechanism independent of degradation pathway. PMID- 22244156 TI - Life begins when the sea lion is ashore: microhabitat use by a louse living on a diving mammal host. AB - Among Anoplura, the family Echinophthiriidae includes species that infest pinnipeds and otters. Previous evidence obtained from pinnipeds infested by echinophthiriids, specifically from seals, indicates that flippers are the preferred infestation sites, while lice from fur seals select areas in the pelage. We studied habitat selection of Antarctophthirus microchir on South American sea lion pups (Otaria flavescens Shaw, 1800) from Patagonia, Argentina, during the austral summer of 2009. We found a clear pattern of habitat selection: eggs are laid on the dorsal surface; nymphs 1 hatch there and then migrate to the belly, where they develop into adults and copulate; and then ovigerous females return to the dorsal surface. On the one hand, nymphs 1 are characterised by their low locomotory ability; therefore, the fact that they migrate as soon as they hatch suggests a clear pressure leading to microhabitat restriction. On the other hand, the described pattern of microhabitat selection seems to respond to the physiological requirements of each stage, which vary according to the physiological process considered, e.g. oviposition, morphogenesis, hatching and development. Accordingly, it appears that A. microchir would prefer the host's ventral area for development and copulation and the dorsal area for oviposition. However, the causes of this pattern are not clear, and many factors could be involved. Considering that sea lion pups periodically soak at high tides, and that prolonged immersion and very high humidity are known to be lethal for lice eggs, selecting the dorsal area would be advantageous for oviposition because it dries much faster. Furthermore, because humidity should be retained for longer periods on the ventral surface of the pup, wetter conditions on the sea lion would prevent desiccation of the nymphs in the very arid environment where O. flavescens breeds. PMID- 22244157 TI - The future of the dental hygiene profession. PMID- 22244158 TI - From the incoming Editor-in-Chief. PMID- 22244159 TI - The controlling effect of temperature in the application of permeation tube devices in standard gas generation. AB - In this study, the performance of permeation tube (PT) devices for the generation of VOC calibration gas was examined by successively generating BTX gas at five temperatures (30, 50, 70, 80, and 100 degrees C) and two flow rates (400 and 800 mL min-1). A distinct relationship was observed between temperatures and permeation rates (PR) (or generated BTX concentrations). We examined the reliability of the manufacturer's PR formula when operating at chamber temperatures different from the manufacturer reference temperatures for each PT device. Bias of the actual PR from the theoretical PR values became significant as PT devices were operated at temperatures beyond their optimum operating range (e.g., maximum bias of BTX as 141%, 87.2%, and 85%, respectively). Through a derivation of empirical formula, we were able to predict PR values of the target compounds more accurately as evidenced by significant bias reduction at all temperature points (e.g., maximum bias of BTX as 10.9%, 21.1% and 20.6%, respectively). PMID- 22244160 TI - Transarterial chemoembolization plus or minus intravenous bevacizumab in the treatment of hepatocellular cancer: a pilot study. AB - BACKGROUND: Stimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE. METHODS: 30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab. RESULTS: Among the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm (p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm (p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post TACE. CONCLUSIONS: IV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14. TRIAL REGISTRATION: ClinicalTrials.gov NCT00049322. PMID- 22244161 TI - Usefulness of oblique axial scan in magnetic resonance imaging evaluation of anterior talofibular ligament in ankle sprain. AB - The purpose of the present study was to clarify the usefulness of the oblique axial scan parallel to the course of the anterior talofibular ligament in magnetic resonance imaging of the anterior talofibular ligament in patients with chronic ankle instability. We evaluated this anterior talofibular ligament view and routine axial magnetic resonance imaging planes of 115 ankles. We diagnosed the grade of the anterior talofibular ligament injury and confirmed full-length views of the anterior talofibular ligament. Associated lesions were also checked. The subjective diagnostic convenience of associated problems was determined. The full-length view of the anterior talofibular ligament was checked in 85 (73.9%) patients in the routine axial view and 112 (97.4%) patients in the anterior talofibular ligament view. The grade of injury increased in the anterior talofibular ligament view in 26 (22.6%) patients compared with the routine axial view. There were 64 associated injuries. The anterior inferior tibiofibular ligament, posterior inferior tibiofibular ligament, and posterior tibialis tendinitis were more easily diagnosed on the routine axial view than on the anterior talofibular ligament view. An additional anterior talofibular ligament view is useful in the evaluation of the anterior talofibular ligament in patients with chronic ankle instability. PMID- 22244162 TI - Validation of a Greek version of the oral health impact profile (OHIP-14) for use among adults. AB - BACKGROUND: To test the validity of the short form of the Oral Health Impact Profile (OHIP-14) for use among adults in Greece. METHODS: The original English version of the OHIP-14 was translated using the forward-backward technique, pilot tested, and then applied to 211 adults aged 35 years and above. The questionnaire was filled out during face-to-face interviews conducted by one dentist, while individuals were asked to undergo a clinical examination. The internal consistency of the questionnaire was evaluated using Cronbach's alpha (alpha) coefficient and inter-item and item-total correlations. Discriminant and convergent validities were assessed. RESULTS: Cronbach's alpha was estimated to be 0.90. Inter-item correlations coefficients ranged from 0.10 to 0.83, while item-total correlations coefficients from 0.44 to 0.76. Significant associations were found between OHIP-14 and the decayed, missing and filled teeth (DMFT) and oral hygiene, supporting the ability of the questionnaire to discriminate between individuals with and without impacts. The OHIP-14 total score was highly associated with self-perceived oral health status (r(s) = 0.57; p = 0.01), as well as with self-assessment of oral satisfaction (r(s) = 0.55;p = 0.01). Similar results were observed by investigating the relationship between the latter questions and each domain score as well as in various sub-groups analyses. CONCLUSIONS: The OHIP-14 is a reliable and valid questionnaire for the assessment of OHRQoL among adults in Greece. PMID- 22244163 TI - Functionalized gold nanoparticle supported sensory mechanisms applied in detection of chemical and biological threat agents: a review. AB - There is a great necessity for development of novel sensory concepts supportive of smart sensing capabilities in defense and homeland security applications for detection of chemical and biological threat agents. A smart sensor is a detection device that can exhibit important features such as speed, sensitivity, selectivity, portability, and more importantly, simplicity in identifying a target analyte. Emerging nanomaterial based sensors, particularly those developed by utilizing functionalized gold nanoparticles (GNPs) as a sensing component potentially offer many desirable features needed for threat agent detection. The sensitiveness of physical properties expressed by GNPs, e.g. color, surface plasmon resonance, electrical conductivity and binding affinity are significantly enhanced when they are subjected to functionalization with an appropriate metal, organic or biomolecular functional groups. This sensitive nature of functionalized GNPs can be potentially exploited in the design of threat agent detection devices with smart sensing capabilities. In the presence of a target analyte (i.e., a chemical or biological threat agent) a change proportional to concentration of the analyte is observed, which can be measured either by colorimetric, fluorimetric, electrochemical or spectroscopic means. This article provides a review of how functionally modified gold colloids are applied in the detection of a broad range of threat agents, including radioactive substances, explosive compounds, chemical warfare agents, biotoxins, and biothreat pathogens through any of the four sensory means mentioned previously. PMID- 22244164 TI - Ionic liquid-modified materials for solid-phase extraction and separation: a review. AB - In recent years, materials science has propelled to the research forefront. Ionic liquids with unique and fascinating properties have also left their footprints to the developments of materials science during the last years. In this review we highlight some of their recent advances and provide an overview at the current status of ionic liquid-modified materials applied in solid-phase extraction, liquid and gas chromatography and capillary electrochromatography with reference to recent applications. In addition, the potential of ionic liquids in the modification of capillary inner wall in capillary electrophoresis is demonstrated. The main target material modified with ionic liquids is silica, but polymers and monoliths have recently joined the studies. Although imidazolium is still clearly the most commonly used ionic liquid for the covalently modification of materials, the exploitation of pyridinium and phosphonium will most probably increase in the future. PMID- 22244165 TI - Detection of an aberrant methylation of CDH4 gene in PCR product by ferrocenylnaphthalene diimide-based electrochemical hybridization assay. AB - Hybridization behavior of 24-meric and 105-meric single stranded DNAs derived from CDH4 gene related to cadherin cell-adhesive protein was tested with 24-meric DNA probe in a ferrocenylnaphthalene diimide (FND)-based hybridization assay. Hybridization efficiency in this system was also clarified using chronocoulometric (CC) measurement with Hexaammineruthenium (III) probe (RuHx). This is first example to calculate hybridization efficiency of PCR product with a DNA probe immobilized on the electrode. Although hybridization efficiency was really small for the PCR product as expected (20% for 105-meric PCR product), PCR products carrying aberrant methylation were discriminated from the wild one due to the electrochemical signal of FND. It was possible since FND possessed high preference for double stranded DNA, especially on the electrode. When applied to aberrant methylation detection for the fragment of CDH4 gene, this system can discriminate over 0.5 ng MUL(-1) sample DNA, which is superior to bisulfite sequencing or MSP and COBRA assays. PMID- 22244166 TI - Multi-channel purge and trap system coupled with ion chromatography for the determination of alkylamines in cosmetics. AB - A new multi-channel purge and trap system coupled with ion chromatography for the determination of six alkylamines in cosmetics was developed. The proposed method, based on purge and trap of the volatile alkylamines, involved in a miniaturization and multi-channel integration of classical steam distillation and a simple approach for routine labs. The procedure was rapidly achieved within 10 min and the matrix interferences could be effectively eliminated. Sample pretreatment frequency was higher than 40 h(-1). The linear ranges were 0.1-15 mg L(-1) and the detection limits varied from 0.023 to 0.038 mg L(-1). This method was successfully utilized to determine the amounts of alkylamines in cosmetics with recoveries ranging from 80.3 to 105.5% and the relative standard deviations (RSDs) ranging from 0.78 to 7.5%. It was proved to be accurate, time-saving, and suitable for the determination of large numbers of cosmetics in a short time. PMID- 22244167 TI - Development of a chromatographic low pressure flow injection system: application to the analysis of methylxanthines in coffee. AB - In this work, the coupling of a commercial monolithic column to a traditional low pressure FIA system is proposed for the analysis of theobromine, theophylline and caffeine in coffee brewed samples using UV detection. The parameters mobile phase composition, flow rate and loop volume were evaluated and discussed considering the various chromatographic parameters in order to enable resolution of the methylxanthines studied within the coffee brewed sample matrix. The analyses of methylxanthines in coffee brewed samples by the proposed methodology were in good agreement with those obtained by the reference procedure based on HPLC. Relative errors were below 6% for all samples analyzed. Detection limits in the selected experimental conditions were within 10(-6)M range for theobromine and theophylline, and 10(-5) M for caffeine. The determination rate of the three methylxanthines for coffee brewed samples was ca of 10 h(-1). The main advantage of the proposed flow system was the possibility to perform chromatographic separations in low pressure flow systems. This substantial improvement was achieved due to the compatibility of monolithic columns within the flow injection system surpassing in this way one of the main handicaps of traditional flow analysis systems. Additional features of the strategy presented were low cost, efficiency, high versatility and low reagent consumption comparing to HPLC methodologies usually followed in the case study herein presented. PMID- 22244168 TI - Ultrahigh performance liquid chromatography-triple quadrupole mass spectrometry inhibitors fishing assay: a novel method for simultaneously screening of xanthine oxidase inhibitor and superoxide anion scavenger in a single analysis. AB - Xanthine oxidase (XOD) inhibitors and superoxide anion scavengers play an important role in the treatment of gout and the inhibition of many diseases related to superoxide anion. The respective quantitation of uric acid and superoxide anion by traditional spectroscopic methods is routine in XOD inhibitors and superoxide anion scavengers screening at laboratories worldwide. In the present study, we established an ultrahigh performance liquid chromatography and triple quadrupole mass spectrometry (UHPLC-TQ-MS) method of higher accuracy and speed that combines screening of superoxide anion scavenger and XOD inhibitor in a single analysis by adding WST-1 (2-(4-iodophenyl)-3-(4 nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium sodium salt) to the enzymatic reaction. We applied the established method to determine the XOD inhibitory activities and superoxide scavenging activities of some herbal extracts and compounds from natural products, which could be classified into six groups based on the results of the assay. Our innovative protocol is fast, accurate and robust. Moreover, it can eliminate false positive and false negative results which may occur in the traditional spectroscopic methods. PMID- 22244169 TI - Optimization of solid-phase extraction and liquid chromatography-tandem mass spectrometry for the determination of domoic acid in seawater, phytoplankton, and mammalian fluids and tissues. AB - We previously reported a solid-phase extraction (SPE) method for determination of the neurotoxin domoic acid (DA) in both seawater and phytoplankton by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the purpose of sample desalting without DA pre-concentration. In the present study, we optimized the SPE procedure with seawater and phytoplankton samples directly acidified with aqueous formic acid without addition of organic solvents, which allowed sample desalting and also 20-fold pre-concentration of DA in seawater and phytoplankton samples. In order to reduce MS contamination, a diverter valve was installed between LC and MS to send the LC eluant to waste, except for the 6-min elution window bracketing the DA retention time, which was sent to the MS. Reduction of the MS turbo gas temperature also helped to maintain the long-term stability of MS signal. Recoveries exceeded 90% for the DA-negative seawater and the DA positive cultured phytoplankton samples spiked with DA. The SPE method for DA extraction and sample clean-up in seawater was extended to mammalian fluids and tissues with modification in order to accommodate the fluid samples with limited available volumes and the tissue extracts in aqueous methanol. Recoveries of DA from DA-exposed laboratory mammalian samples (amniotic fluid, cerebrospinal fluid, plasma, placenta, and brain) were above 85%. Recoveries of DA from samples (urine, feces, intestinal contents, and gastric contents) collected from field stranded marine mammals showed large variations and were affected by the sample status. The optimized SPE-LC-MS method allows determination of DA at trace levels (low pg mL(-1)) in seawater with/without the presence of phytoplankton. The application of SPE clean-up to mammalian fluids and tissue extracts greatly reduced the LC column degradation and MS contamination, which allowed routine screening of marine mammalian samples for confirmation of DA exposure and determination of fluid and tissue DA concentrations in experimental laboratory animals. PMID- 22244170 TI - A novel dichromate-sensitive fluorescent nano-chemosensor using new functionalized SBA-15. AB - A novel fluorescence nano-chemosensor for Cr(2)O(7)(2-) anion has been developed by assembly of fluorescent aluminum complex of 8-hydroxyquinoline (AlQ(x)) within the channels of modified SBA-15. SBA-SPS-AlQ(x) shows a fluorescence emission at 486 nm. The observed remarkable fluorescence of SBA-SPS-AlQ(x) quenches in presence of Cr(2)O(7)(2-) anion. The results showed that this fluorescent nano material can be a useful chemo-sensor for determination of dichromate anions in aqueous solutions. The linear detecting range of fluorescent nano-chemosensor for Cr(2)O(7)(2-) anion was 0.16-2.9 MUmol L(-1). The lowest limit of detection (LDL) was also found to be 0.2 ng mL(-1) in aqueous solutions. SBA-SPS-AlQ(x) showed selectively and sensitively fluorescent quenching response toward Cr(2)O(7)(2-) ion in comparison with I(3)(-), NO(3)(-), CN(-), CO(3)(2-), Br(-), Cl(-), F(-), H(2)PO(4)(-) and SO(4)(2-) ions, which was because of the higher stability of its inorganic complex with dichromate ion. PMID- 22244171 TI - Electrochemiluminescence biosensor for the assay of small molecule and protein based on bifunctional aptamer and chemiluminescent functionalized gold nanoparticles. AB - An electrochemiluminescence (ECL) biosensor for simultaneous detection of adenosine and thrombin in one sample based on bifunctional aptamer and N (aminobutyl)-N-(ethylisoluminol) functionalized gold nanoparticles (ABEI-AuNPs) was developed. A streptavidin coated gold nanoparticles modified electrode was utilized to immobilize biotinylated bifunctional aptamer (ATA), which consisted of adenosine and thrombin aptamer. The ATA performed as recognition element of capture probe. For adenosine detection, ABEI-AuNPs labeled hybridization probe with a partial complementary sequence of ATA reacted with ATA, leading to a strong ECL response of N-(aminobutyl)-N-(ethylisoluminol) enriched on ABEI-AuNPs. After recognition of adenosine, the hybridization probe was displaced by adenosine and ECL signal declined. The decrease of ECL signal was in proportion to the concentration of adenosine over the range of 5.0*10(-12)-5.0*10(-9) M with a detection limit of 2.2*10(-12) M. For thrombin detection, thrombin was assembled on ATA modified electrode via aptamer-target recognition, another aptamer of thrombin tagged with ABEI-AuNPs was bounded to another reactive site of thrombin, producing ECL signals. The ECL intensity was linearly with the concentration of thrombin from 5*10(-14)M to 5*10(-10) M with a detection limit of 1.2*10(-14) M. In the ECL biosensor, adenosine and thrombin can be detected when they coexisted in one sample and a multi-analytes assay was established. The sensitivity of the present biosensor is superior to most available aptasensors for adenosine and thrombin. The biosensor also showed good selectivity towards the targets. Being challenged in real plasma sample, the biosensor was confirmed to be a good prospect for multi-analytes assay of small molecules and proteins in biological samples. PMID- 22244172 TI - Electrochemical genosensor array for the simultaneous detection of multiple high risk human papillomavirus sequences in clinical samples. AB - An electrochemical genosensor array for the simultaneous detection of three high risk human papillomavirus (HPV) DNA sequences, HPV16, 18 and 45, exhibiting high sensitivity and selectivity is presented. The electrodes of a 4*4 array were modified via co-immobilization of a 1:100 (mol/mol) mixture of a thiolated probe and an oligoethyleneglycol-terminated bipodal thiol. Detection of synthetic and PCR products was carried out in a sandwich type format, with the target hybridized between a surface immobilized probe and a horseradish peroxidase labelled secondary reporter probe. The detection limits obtained in the detection of each individual target were in the pM range, allowing the application of this sensor for the detection of samples obtained from PCR amplification of cervical scrape samples. The results obtained exhibited an excellent correlation with the HPV genotyping carried out within a hospital laboratory. Multiplexing and cross reactivity studies demonstrated high selectivity over potential interfering sequences, facilitating application of the developed platform for the high throughput screening of multiple high-risk DNA sequences. PMID- 22244173 TI - Seed-mediated synthesis of copper nanoparticles on carbon nanotubes and their application in nonenzymatic glucose biosensors. AB - In this paper, for the first time, Cu nanoparticles (CuNPs) were prepared by seed mediated growth method with Au nanoparticles (AuNPs) playing the role of seeds. Carbon nanotubes (CNTs) and AuNPs were first dropped on the surface of glassy carbon (GC) electrode, and then the electrode was immersed into growth solution that contained CuSO(4) and hydrazine. CuNPs were successfully grown on the surface of the CNTs. The modified electrode showed a very high electrochemical activity for electrocatalytic oxidation of glucose in alkaline medium, which was utilized as the basis of the fabrication of a nonenzymatic biosensor for electrochemical detection of glucose. The biosensor can be applied to the quantification of glucose with a linear range covering from 1.0*10(-7) to 5*10( 3)M and a low detection limit of 3*10(-8)M. Furthermore, the experiment results also showed that the biosensor exhibited good reproducibility and long-term stability, as well as high selectivity with no interference from other oxidable species. PMID- 22244174 TI - Generation of anti-azoxystrobin monoclonal antibodies from regioisomeric haptens functionalized at selected sites and development of indirect competitive immunoassays. AB - Azoxystrobin is a modern strobilurin fungicide used around the world to combat prime diseases affecting highly valuable crops. Accordingly, residues of this chemical are frequently found in food, even though mostly under maximum tolerated levels. We herein describe the development of an indirect competitive immunoassay for the determination of azoxystrobin residues. A panel of monoclonal antibodies displaying subnanomolar affinity to azoxystrobin was generated using, as immunizing haptens in mice, four functionalized derivatives carrying the same spacer arm located at different rationally chosen positions. This collection of antibodies was thoroughly characterized with homologous and heterologous antigens, and the immunoassay consisting of monoclonal antibody AZo6#49 and the coating conjugate OVA-AZb6, which displayed an IC(50) value of 0.102 MUg L(-1) and a LOD of 0.017 MUg L(-1), was eventually optimized. The response to different pH and ionic strength conditions of the specific assay was studied using a biparametric approach. In addition, the influence of Tween 20 and organic solvents over the assay parameters was also evaluated. After optimization, the developed immunochemical assay was applied to the analysis of azoxystrobin in spiked juices of relevant fruits and vegetables, showing excellent recoveries between 2 and 500 MUg L(-1). PMID- 22244175 TI - Mixed hemimicelles solid-phase extraction of chlorophenols in environmental water samples with 1-hexadecyl-3-methylimidazolium bromide-coated Fe3O4 magnetic nanoparticles with high-performance liquid chromatographic analysis. AB - In this paper, 1-hexadecyl-3-methylimidazolium bromide (C(16)mimBr)-coated Fe(3)O(4) magnetic nanoparticles (NPs) as an adsorbent of mixed hemimicelles solid-phase extraction was investigated for the preconcentration of two chlorophenols (CPs) in environmental water samples prior to HPLC with UV detection at 285 nm. The high surface area and excellent adsorption capacity of the Fe(3)O(4) NPs after modification with C(16)mimBr were utilized adequately in the SPE process. By the rapid isolation of Fe(3)O(4) NPs through placing a strong magnet on the bottom of beaker, the time-consuming preconcentration process of loading large volume sample in conventional SPE method with a column can be avoided. A comprehensive study of the adsorption conditions such as the zeta potential of Fe(3)O(4) NPs, added amounts of C(16)mimBr, pH value, standing time and maximal extraction volume were also presented. Under optimized conditions, two analytes of 2,4-dichlorophenol (2,4-DCP) and 2,4,6-trichlorophenol (2,4,6 TCP) were quantitatively determined. The method was then used to determine the two CPs in real environmental water samples. The accuracy of method was evaluated by recovery measurements on spiked samples. Good recovery results (74-90%) were achieved. It is important to note that satisfactory preconcentration factors and extraction recoveries for the two CPs were obtained with only a small amount of Fe(3)O(4) NPs (40 mg) and C(16)mimBr (24 mg). PMID- 22244176 TI - Interim results from the international trial of Second Sight's visual prosthesis. AB - PURPOSE: This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration. DESIGN: Single-arm, prospective, multicenter clinical trial. PARTICIPANTS: Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years. METHODS: The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface. MAIN OUTCOME MEASURES: The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks. RESULTS: Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications. CONCLUSIONS: The long term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it. PMID- 22244177 TI - The effect of adding fish oil to parenteral nutrition on hepatic mononuclear cell function and survival after intraportal bacterial challenge in mice. AB - BACKGROUND: Parenteral nutrition (PN) is indispensable for meeting caloric and substrate needs of patients who cannot receive adequate amounts of enteral nutrition; however, PN impairs hepatic immunity. We examined the effects of omega 3 and -6 polyunsaturated fatty acids, added individually to fat-free PN, on hepatic immunity in a murine model. We focused on serum liver enzymes, cytokine production, histopathology, and the outcomes after intraportal bacterial challenge. METHODS: Male Institute of Cancer Research mice were randomized into 4 groups; ad libitum chow (CHOW), fat-free PN (FF-PN), PN + fish oil (FO-PN), or PN + safflower oil (SO-PN). After the mice had been fed for 5 days, hepatic mononuclear cells (MNCs) were isolated. The number of MNCs was counted and cytokine production (tumor necrosis factor [TNF]-alpha and interleukin [IL]-10) by hepatic MNCs in response to lipopolysaccharide (LPS) was measured. Blood samples were analyzed for hepatobiliary biochemical parameters. Moreover, 1.0 * 10(7) pseudomonas aeruginosa were delivered by intraportal injection. Survival and histology were examined. RESULTS: Hepatic MNC numbers were significantly less in the FO-PN and FF-PN than in the CHOW group, whereas the SO-PN group showed moderate recovery of hepatic MNC numbers. The CHOW, FO-PN, and SO-PN groups showed LPS dose-dependent increases in TNF-alpha levels. These increases were blunted in the FF-PN group. IL-10 levels were increased LPS dose-dependently in the CHOW and FO-PN groups, but no marked changes were observed with LPS stimulation in the SO-PN and FF-PN groups. Plasma levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were significantly greater in the FF-PN than in the FO- and SO-PN and CHOW groups. The FO-PN group showed significantly improved survival compared with the SO-PN and FF PN groups, showing essentially no morphologic hepatic abnormalities. CONCLUSION: Addition of fish oil to PN was advantageous in terms of reversing PN-induced deterioration of hepatic immunity, as reflected by altered cytokine production. Fish oil administration was also useful for preventing PN-induced hepatobiliary dysfunction. These changes seem to result in better survival and to protect against severe tissue damage after intraportal bacterial challenge. This therapy may have the potential to ameliorate PN-induced impairment of host immunity and thereby decrease morbidity and mortality. PMID- 22244178 TI - Novel use of electronic whiteboard in the operating room increases surgical team compliance with pre-incision safety practices. AB - BACKGROUND: Despite evidence that use of a checklist during the pre-incision time out improves patient morbidity and mortality, compliance with performing the required elements of the checklist has been low. In an effort to improve compliance, a standardized time out interactive Electronic Checklist System [iECS] was implemented in all hospital operating room (OR) suites at 1 institution. The purpose of this 12-month prospective observational study was to assess whether an iECS in the OR improves and sustains improved surgical team compliance with the pre-incision time out. METHODS: Direct observational analyses of preprocedural time outs were performed on 80 cases 1 month before, and 1 and 9 months after implementation of the iECS, for a total of 240 observed cases. Three observers, who achieved high interrater reliability (kappa = 0.83), recorded a compliance score (yes, 1; no, 0) on each element of the time out. An element was scored as compliant if it was clearly verbalized by the surgical team. RESULTS: Pre-intervention observations indicated that surgical staff verbally communicated the core elements of the time out procedure 49.7 +/- 12.9% of the time. After implementation of the iECS, direct observation of 80 surgical cases at 1 and 9 months indicated that surgical staff verbally communicated the core elements of the time out procedure 81.6 +/- 11.4% and 85.8 +/- 6.8% of the time, respectively, resulting in a statistically significant (P < .0001) increase in time out procedural compliance. CONCLUSION: Implementation of a standardized, iECS can dramatically increase compliance with preprocedural time outs in the OR, an important and necessary step in improving patient outcomes and reducing preventable complications and deaths. PMID- 22244179 TI - The state of performance on the American Board of Surgery Qualifying Examination and Certifying Examination and the effect of residency program size on program pass rates. PMID- 22244180 TI - Video-assisted thoracoscopic surgery for esophageal cancer attenuates postoperative systemic responses and pulmonary complications. AB - BACKGROUND: Less invasive operations such as laparoscopic surgery have been developed for treating gastrointestinal malignancies. However, the advantages of video-assisted thoracoscopic surgery for esophageal cancer (VATS-e) with regard to postoperative morbidity and mortality remains controversial. METHODS: We investigated the postoperative clinical course of patients who underwent esophagectomy for esophageal cancer in terms of systemic inflammatory response syndrome (SIRS) induced by VATS-e (VATS-e group) or conventional open surgery (OS group) combined with laparoscopic gastric tube reconstruction. RESULTS: Compared with the OS group (n = 27), the VATS-e group (n = 22) had a greater thoracic operation time (VATS-e versus OS, 181 +/- 56 vs 143 +/- 45 minutes, respectively), and lesser duration of stay in the intensive care unit (17 +/- 2 vs 32 +/- 21 hours, respectively). The VATS-e group also had a lesser SIRS duration (1.5 vs 4.3 days), a lesser incidence of SIRS, a lesser number of positive SIRS criteria, and lesser serum interleukin-6 levels immediately after operation and on postoperative day (POD) 1. The heart rate in the VATS-e group was less than that in the OS group on POD 3. The respiratory rate in the VATS-e group was significantly less than that in the OS group on PODs 3, 5, and 7. Although no difference was observed in the frequencies of postoperative complications between the 2 groups, the VATS-e group had less postoperative pneumonia. CONCLUSION: VATS-e attenuates postoperative SIRS, and is therefore a potentially less invasive operative procedure. PMID- 22244181 TI - Prognostic impact of marginal resection for patients with solitary hepatocellular carcinoma: evidence from 570 hepatectomies. AB - BACKGROUND: During resection of a hepatocellular carcinoma, surgeons encounter occasionally a situation where marginal resection is inevitable because of a close association between the hepatocellular carcinoma and major vasculature and/or underlying impaired liver function. We investigated the impact of marginal resection on recurrence-free survival after a resection of a solitary hepatocellular carcinoma. METHODS: The data of 570 patients who underwent macroscopically curative hepatectomy for a solitary hepatocellular carcinoma in our institution between 1990 and 2007 were analyzed. Marginal resection and non marginal resection were defined as a cancer-negative surgical margin of <= 1 mm and a surgical margin of >1 mm, respectively. The macroscopic appearance of the hepatocellular carcinoma was classified as the simple nodular type or non-simple nodular type based on the classification of the Liver Cancer Study Group of Japan, and patients were categorized into 4 groups: group A, simple nodular type with cirrhosis; group B, simple nodular type without cirrhosis; group C, non simple nodular type with cirrhosis; and group D, non-simple nodular type without cirrhosis. RESULTS: The surgical margins were diagnosed as cancer-positive in 31 patients, as marginal resection in 165 patients, and as non-marginal resection in 374 patients. The marginal resection group showed a better recurrence-free survival than the positive surgical margin group (P = .001), and also a worse recurrence-free survival than the non-marginal resection group (P = .003). In groups A, B, and C, the recurrence-free survival rates were similar between marginal resection and non-marginal resection patients (P = .458), while in group D, marginal resection was a significant poor prognostic factor of recurrence-free survival in both univariate and multivariate analyses. CONCLUSION: Marginal resection is acceptable in group A, B, and C patients, because it did not negatively affect postoperative recurrence-free survival. PMID- 22244182 TI - Capturing the teachable moment: a grounded theory study of verbal teaching interactions in the operating room. AB - BACKGROUND: Teaching in the operating room is one of the major cornerstones of surgical education. As time available for intraoperative resident teaching diminishes, such teaching time becomes increasingly precious. We studied how surgeons communicate with residents during an operation, with the goal of enhancing intraoperative teaching opportunities. METHODS: Grounded theory methodology was used to investigate intraoperative verbal communication during four videotaped surgical procedures. Utterance-by-utterance analysis was performed to generate codes for each surgeon-resident interaction. Interactions were then analyzed to determine the percentage time spent in verbal teaching, number of topics covered, times each topic was visited, and time per topic. RESULTS: Four main types of teaching surgeon-resident verbal interaction were identified from 1306 interactions. Instrumental interactions were intended solely to move the operation forward. Pure teaching interactions served to educate the trainee, shape judgment, or enhance performance. Instrumental and Teaching interactions were directive but also contained teaching. Banter was discussion unrelated to the operation. Analysis of a subset of the operations demonstrated 13-29 topics covered per procedure, with each topic addressed between 1 and 8 times, and 25-330 seconds spent per topic. Most teaching instances were prompted by errors in resident performance. CONCLUSION: Instances of verbal teaching were numerous, arose opportunistically in this study, and focused typically on multiple points. To maximize teaching opportunities, the authors propose a structured approach to intraoperative teaching that involves identification of a limited set of specific learning objectives, followed by intraoperative teaching and postoperative debriefing targeted to those objectives. PMID- 22244183 TI - Screening and assessing ideas and delusions of reference using a semi-structured interview scale: a validation study of the Ideas of Reference Interview Scale (IRIS) in early psychosis patients. AB - BACKGROUND: Ideas and delusions of reference (IOR/DOR) are an important but underrecognized research target. Difficulty in their reliable assessment has been a barrier. A screening and assessment tool incorporating a self-information processing framework, the Ideas of Reference Interview Scale (IRIS), was developed and validated in patients with early psychosis. METHODS: Comprehensive review of IOR/DOR phenomena in the literature and pilot interviews were conducted for scale item development. Self-referential themes were summarized into 15 items. A consecutive sample of 137 outpatients with early psychosis was interviewed using IRIS. Their IOR/DOR experiences were also rated independently by clinicians on the Scale for the Assessment of Positive Symptoms (SAPS) and self-rated using the IOR subscale on the Schizotypal Personality Questionnaire (SPQ). Inter-rater reliability of IRIS was examined in a subsample of 15 participants. RESULTS: IRIS demonstrated good internal consistency (Cronbach's alpha 0.80), inter-rater reliability (intraclass correlation coefficient 0.95), and divergent validity with other symptoms. IRIS correlated satisfactorily with the IOR/DOR item or subscale on SAPS and SPQ (Spearman's rho = 0.71 and 0.47, respectively). DISCUSSION: IRIS provided a reliable high-resolution tool for progressing single-symptom research into IOR/DOR, a potential target feature of schizophrenia. The scale allows future investigation into self-referential processing and detailed phenomenological comparison in different clinical, subclinical, and healthy populations. PMID- 22244185 TI - Olfaction, "olfiction," and the schizophrenia-spectrum: an updated meta-analysis on identification and acuity. AB - Olfaction deficits in individuals with schizophrenia are well documented. A meta analysis conducted nearly a dozen years ago on the topic revealed a deficit of a full standard deviation in magnitude compared to nonpatient controls. Recent efforts have been attempted to determine whether deficits in olfactory identification and acuity reflect a vulnerability marker of schizophrenia spectrum pathology. To address this issue, the present study conducted a meta analysis of 16 studies of individuals with schizotypy, defined in terms of a) "ultra-high risk" status, b) having an affected biological family member, or c) having extreme scores on a schizotypy questionnaire. We also conducted an updated meta-analysis of 40 studies of olfactory functioning in schizophrenia. Consistent with the prior meta-analysis, patients with schizophrenia showed impairments in olfaction identification on a full standard deviation in magnitude (d = -.99). Individuals with schizotypy showed much more subtle (d = -.24) differences in olfaction, though the effect sizes were higher for studies examining individuals at "ultra-high risk" (d = -.67) versus studies examining individuals with psychometrically-defined (d = -.14) schizotypy. Differences in olfactory acuity, relative to their respective control groups, were small for both the schizophrenia (d = -.45) and schizotypy (d = -.38) studies but were similar in magnitude. The present findings argue against the notion that deficits in olfaction identification are a vulnerability marker of schizophrenia. Suggestions for future research are recommended. PMID- 22244184 TI - Structural abnormalities in the cuneus associated with Herpes Simplex Virus (type 1) infection in people at ultra high risk of developing psychosis. AB - It has been suggested that some cases of schizophrenia may be caused by an interaction between physiological risk factors and exposure to certain neurotropic infectious agents such as Herpes Simplex Virus type 1 (HSV1). This study investigated whether HSV1 exposure was associated with structural brain abnormalities in individuals who, because of genetic or other factors, were deemed at ultra high risk (UHR) of developing psychosis. Twenty-five UHR individuals with a history of HSV1 exposure (HSV1+), 33 UHR participants without a history of HSV1 exposure (HSV1-) and 19 healthy controls participated in the study. All participants underwent a T1-weighted structural MRI scan, and HSV1 exposure was determined based on the presence of IgG class antibodies in the blood serum. Voxel based morphometry revealed that the HSV1+ participants exhibited volumetric gray matter reductions in the cuneus, relative to both the HSV1--and healthy control participants (p<0.05, small volume corrected for familywise error). The results of the study suggest that a history of HSV1 infection is associated with volumetric gray matter reductions in individuals at ultra-high risk for developing psychosis, and are consistent with previous studies that have identified structural gray matter abnormalities in HSV1 infected patients with established schizophrenia. PMID- 22244186 TI - Molecular characterization of Italian Candida parapsilosis isolates reveals the cryptic presence of the newly described species Candida orthopsilosis in blood cultures from newborns. AB - The authors report the molecular characterization of Candida parapsilosis isolates recovered from the blood and venous central catheter tips of patients admitted to different care units of the Polyclinic Hospital, University of Messina, Italy. Among 97 presumed C. parapsilosis isolates examined, 94 were identified as C. parapsilosis sensu stricto and the remaining 3 isolates were found to belong to the cryptic species Candida orthopsilosis which was recovered only from blood cultures of neonates (<30 days old) born prematurely. No C. metapsilosis was found in this study. This study emphasizes the role of C. parapsilosis as an important nosocomial pathogen, and it also describes, for the first time, the occurrence of C. orthopsilosis in newborns. PMID- 22244188 TI - Functional and proteomic analysis of submandibular saliva in rats exposed to chronic stress by immobilization or constant light. AB - OBJECTIVE: In this study, we have evaluated the effects of stress on functional and proteomic changes in submandibular saliva of rats. DESIGN: Male adult rats were divided in three groups: IMO (2 h/day of immobilization for 7 days), LL (constant light during 20 days), C (unstressed controls submitted to 14 h light 10h dark cycle). Body weight, food intake and the dry weight of submandibular gland were recorded. Saliva samples, collected under anaesthesia following i.p. administration of isoproterenol and pilocarpine (5 mg/kg), were assayed for total proteins (TP), amylase activity and SDS-PAGE electrophoresis. RESULTS: Body weight, food intake and the dry weight of submandibular gland of IMO rats were lower than those of C and LL groups. The salivary volumes secreted in IMO and LL rats, were significantly higher than in controls. The TP output (MUg protein/MUg saliva/mg of dry tissue) and amylase activity output (AU/MUg of saliva/mg of dry tissue) in IMO were significantly higher than in C and LL animals. The electrophoretic pattern of saliva proteins of LL rats, revealed the absence of a protein band of approximately 25 kDa. This band was composed by the common salivary protein-1 and a prolactin-induced protein as identified by peptide mass fingerprinting. CONCLUSIONS: Differences in body weight and food intake between IMO and LL might be attributed to the sort and intensity of stressors stimuli. The changes in the volume of secreted saliva could be a compensatory mechanism in response to stressors. The increase of total protein in IMO rats and the absence of 25 kDa proteins in LL, would suggest that the submandibular glands respond to the sympathetic nervous system stimuli induced by the stress with an increase of activity of the sympathetic nerves in IMO and a reduction in LL rats. PMID- 22244187 TI - Evolution, expansion and expression of the Kunitz/BPTI gene family associated with long-term blood feeding in Ixodes Scapularis. AB - BACKGROUND: Recent studies of the tick saliva transcriptome have revealed the profound role of salivary proteins in blood feeding. Kunitz/BPTI proteins are abundant in the salivary glands of ticks and perform multiple functions in blood feeding, such as inhibiting blood coagulation, regulating host blood supply and disrupting host angiogenesis. However, Kunitz/BPTI proteins in soft and hard ticks have different functions and molecular mechanisms. How these differences emerged and whether they are associated with the evolution of long-term blood feeding in hard ticks remain unknown. RESULTS: In this study, the evolution, expansion and expression of Kunitz/BPTI family in Ixodes scapularis were investigated. Single- and multi-domain Kunitz/BPTI proteins have similar gene structures. Single-domain proteins were classified into three groups (groups I, II and III) based on their cysteine patterns. Group I represents the ancestral branch of the Kunitz/BPTI family, and members of this group function as serine protease inhibitors. The group I domain was used as a module to create multi domain proteins in hard ticks after the split between hard and soft ticks. However, groups II and III, which evolved from group I, are only present and expanded in the genus Ixodes. These lineage-specific expanded genes exhibit significantly higher expression during long-term blood feeding in Ixodes scapularis. Interestingly, functional site analysis suggested that group II proteins lost the ability to inhibit serine proteases and evolved a new function of modulating ion channels. Finally, evolutionary analyses revealed that the expansion and diversification of the Kunitz/BPTI family in the genus Ixodes were driven by positive selection. CONCLUSIONS: These results suggest that the differences in the Kunitz/BPTI family between soft and hard ticks may be linked to the evolution of long-term blood feeding in hard ticks. In Ixodes, the lineage specific expanded genes (Group II and III) lost the ancient function of inhibiting serine proteases and evolved new functions to adapt to long-term blood feeding. Therefore, these genes may play a profound role in the long-term blood feeding of hard ticks. Based our analysis, we propose that the six genes identified in our study may be candidate target genes for tick control. PMID- 22244189 TI - Lubricin in human temporomandibular joint disc: an immunohistochemical study. AB - AIMS: To evaluate, immunohistochemically, the presence and distribution of lubricin in human temporomandibular joint (TMJ) discs without any degenerative changes, obtained from autopsies, in order to elucidate the TMJ lubrication system and disc tribology. METHODS: Immunohistochemistry for lubricin detection was carried out on 34 TMJ discs. Any disc had signs of degenerative or inflammatory joint disease nor disc were displaced. Sections were incubated with diluted rabbit polyclonal anti-lubricin antibody and scored according to the percentage of lubricin immunopositive cells. Three different TMJ disc tissue compartments taken from the intermediate zone were analysed, namely: the central region as well as the temporal (superior) and condylar (inferior) disc surfaces. The Friedman test, was used to compare lubricin at a protein level expression, amongst the regions of disc specimens. RESULTS: Staining was noted within the TMJ disc cell populations in every disc tissue sample, however, the number of disc cells immunolabelled varied according to disc tissue regions. The percentage of immunostained cells, was statistically significant lower in the central region than in each disc surface (p<0.0001), whilst any statistically significant difference was found when comparing the two surfaces one another. CONCLUSIONS: Lubricin is present in several location of TMJ disc being significantly more expressed at disc surfaces than in the central part. PMID- 22244190 TI - Subungual exostosis: a simple surgical technique. PMID- 22244191 TI - Detection of infectious symptoms from VA emergency department and primary care clinical documentation. AB - OBJECTIVE: The majority of clinical symptoms are stored as free text in the clinical record, and this information can inform clinical decision support and automated surveillance efforts if it can be accurately processed into computer interpretable data. METHODS: We developed rule-based algorithms and evaluated a natural language processing (NLP) system for infectious symptom detection using clinical narratives. Training (60) and testing (444) documents were randomly selected from VA emergency department, urgent care, and primary care records. Each document was processed with NLP and independently manually reviewed by two clinicians with adjudication by referee. Infectious symptom detection rules were developed in the training set using keywords and SNOMED-CT concepts, and subsequently evaluated using the testing set. RESULTS: Overall symptom detection performance was measured with a precision of 0.91, a recall of 0.84, and an F measure of 0.87. Overall symptom detection with assertion performance was measured with a precision of 0.67, a recall of 0.62, and an F measure of 0.64. Among those instances in which the automated system matched the reference set determination for symptom, the system correctly detected 84.7% of positive assertions, 75.1% of negative assertions, and 0.7% of uncertain assertions. CONCLUSION: This work demonstrates how processed text could enable detection of non-specific symptom clusters for use in automated surveillance activities. PMID- 22244192 TI - Biocontrol of Salmonella Typhimurium in RTE foods with the virulent bacteriophage FO1-E2. AB - Foodborne Salmonella infections are a major public health concern worldwide. Bacteriophages offer highly specific and effective biocontrol of such pathogens. We evaluated the broad host range, virulent phage FO1-E2 for reduction of Salmonella Typhimurium in different RTE foods. Samples were spiked with 1*103 Salmonella cells and treated with 3*108 pfu/g phage, and incubated for 6 days at 8 degrees C or 15 degrees C. At 8 degrees C, no viable cells remained following FO1-E2 application, corresponding to a more than 3 log10 unit reduction. At 15 degrees C, application of phage lowered S. Typhimurium counts by 5 log units on turkey deli meat and in chocolate milk, and by 3 logs on hot dogs and in seafood. In egg yolk, an effect was observed only after 2 days, but not after 6 days. Phage particles retained their infectivity, although they were readily immobilized by the food matrix, resulting in loss of their ability to diffuse and infect target cells. At the end of the incubation period, phage resistant Salmonella strains appeared which, however, were not able to compensate for the initial killing effect. Altogether, our data show that virulent phages such as FO1-E2 offer an effective biocontrol measure for Salmonella in foods. PMID- 22244193 TI - An optimization algorithm for estimation of microbial survival parameters during thermal processing. AB - Isothermal microbial survival curves are usually described by either linear or nonlinear time-dependent models, from which non-isothermal survival curves can be generated if the parameters describing the survival kinetics of the microbial population are known. In order to estimate these parameters, an algorithm based on the steepest decent optimization method was developed. The algorithm searches the values of the survival parameters which minimize the sum of the squared differences between the experimental data and the calculated values provided by the model. The difference of the proposed algorithm with a typical optimization technique is that each data point used is not necessarily coming from the same thermal treatment; instead, data from different non-isothermal processes can be used. The developed algorithm was tested by using published non-isothermal survival data of Salmonella. The data showed that the survival curves can be described by the Weibull model, an already accepted and frequently used nonlinear model. Salmonella's survival parameters were estimated from the end points and all data points, respectively, of three non-isothermal survival curves. The results obtained showed that the number of survival data points must be sufficiently large to obtain true or statistically sound values of the survival parameters. A suitable way to achieve this is to implement the algorithm using all data points of multiple non-isothermal survival curves or a large number of end points of non-isothermal treatments. Mathematically, the developed algorithm should be applicable to any microbial survival kinetics accurately describing the inactivation of the microorganisms because no specific survival kinetics has to be pre-assumed to run the algorithm. PMID- 22244194 TI - Uranium distribution and radon exhalation from Brazilian dimension stones. AB - This paper provides evaluations of the radiometric behavior and exhalation patterns of radon gas in decorative and dimension stones explored in the Brazilian states of Minas Gerais and Espirito Santo, given the importance of determining radon gas concentrations in human-inhabited environments. A total of 10 silicate rock types were studied, featuring different petrographic/petrophysical characteristics given by seven magmatic rocks (three of which are granitic pegmatites) and three metamorphic rocks. The study, comprising radiometric data of U and monitoring of (222)Rn gas exhalation, shows a strong correlation between petrographic parameters and the physical properties of rocks. U levels ranged between 2.9 and 37 ppm, revealing a good coherence between the presence and the absence of radioactive element-bearing accessory minerals for each rock type. The rate of radon exhalation from the stones is related to the petrographic/petrophysical features of each material. By comparing the (222)Rn level generated by a rock to the amount effectively emanated by it, the rate of emanated gas proves to be insignificant; also, a rock that produces more Rn will not always emanate more. Simulations performed to estimate the radon levels inside residences or any given indoor environment showed that nine samples attained values below the 4 pCi/L EPA limit, whereas one was above that limit. PMID- 22244195 TI - On the stochastic dependence between photomultipliers in the TDCR method. AB - The TDCR method (Triple to Double Coincidence Ratio) is widely implemented in National Metrology Institutes for activity primary measurements based on liquid scintillation counting. The detection efficiency and thereby the activity are determined using a statistical and physical model. In this article, we propose to revisit the application of the classical TDCR model and its validity by introducing a prerequisite of stochastic independence between photomultiplier counting. In order to support the need for this condition, the demonstration is carried out by considering the simple case of a monoenergetic deposition in the scintillation cocktail. Simulations of triple and double coincidence counting are presented in order to point out the existence of stochastic dependence between photomultipliers that can be significant in the case of low-energy deposition in the scintillator. It is demonstrated that a problem of time dependence arises when the coincidence resolving time is shorter than the time distribution of scintillation photons; in addition, it is shown that this effect is at the origin of a bias in the detection efficiency calculation encountered for the standardization of (3)H. This investigation is extended to the study of geometric dependence between photomultipliers related to the position of light emission inside the scintillation vial (the volume of the vial is not considered in the classical TDCR model). In that case, triple and double coincidences are calculated using a stochastic TDCR model based on the Monte-Carlo simulation code Geant4. This stochastic approach is also applied to the standardization of (51)Cr by liquid scintillation; the difference observed in detection efficiencies calculated using the standard and stochastic models can be explained by such an effect of geometric dependence between photomultiplier channels. PMID- 22244196 TI - Determination of the natural radioactivity levels in north west of Dukhan, Qatar using high-resolution gamma-ray spectrometry. AB - This study is aimed at the determination of the activity concentrations of naturally occuring and technologically enhanced levels of radiation in 34 representative soil samples that have been collected from an inshore oil field area which was found to have, in a previous study, the highest observed value of 226Ra concentration among 129 soil samples. The activity concentrations of 238U and 226Ra have been inferred from gamma-ray transitions associated with their decay progenies and measured using a hyper-pure germanium detector. Details of the sample preparation and the gamma-ray spectroscopic analysis techniques are presented, together with the values of the activity concentrations associated with the naturally occuring radionuclide chains for all the samples collected from NW Dukhan. Discrete-line, gamma-ray energy transitions from spectral lines ranging in energy from ~100 keV up to 2.6 MeV have been associated with characteristic decays of the various decay products within the 235.8U and 232Th radioactive decay chains. These data have been analyzed, under the assumption of secular equilibrium for the U and Th decay chains. Details of the sample preparation and the gamma-ray spectroscopic analysis techniques are presented. The weighted mean value of the activity concentrations of 226Ra in one of the samples was found to be around a factor of 2 higher than the values obtained in the previous study and approximately a factor of 10 higher than the accepted worldwide average value of 35 Bq/kg. The weighted mean values of the activity concentrations of 232Th and 40K were also deduced and found to be within the worldwide average values of 30 and 400 Bq/kg, respectively. Our previous study reported a value of 201.9+/-1.5Stat.+/-13Syst.Bq/kg for 226Ra in one sample and further investigation in the current work determined a measured value for 226Ra of 342.00+/-1.9Stat.+/-25Syst.Bq/kg in a sample taken from the same locality. This is significantly higher than all the other investigated soil samples in the current and previous works. Notably, the Th levels in the same sample are within the worldwide average expectations, implying that the increased 226Ra concentration arises from TENORM processes. PMID- 22244197 TI - QTL/microarray approach using pathway information. AB - BACKGROUND: A combined quantitative trait loci (QTL) and microarray-based approach is commonly used to find differentially expressed genes which are then identified based on the known function of a gene in the biological process governing the trait of interest. However, a low cutoff value in individual gene analyses may result in many genes with moderate but meaningful changes in expression being missed. RESULTS: We modified a gene set analysis to identify intersection sets with significantly affected expression for which the changes in the individual gene sets are less significant. The gene expression profiles in liver tissues of four strains of mice from publicly available microarray sources were analyzed to detect trait-associated pathways using information on the QTL regions of blood concentrations of high density lipoproteins (HDL) cholesterol and insulin-like growth factor 1 (IGF-1). Several metabolic pathways related to HDL levels, including lipid metabolism, ABC transporters and cytochrome P450 pathways were detected for HDL QTL regions. Most of the pathways identified for the IGF-1 phenotype were signal transduction pathways associated with biological processes for IGF-1's regulation. CONCLUSION: We have developed a method of identifying pathways associated with a quantitative trait using information on QTL. Our approach provides insights into genotype-phenotype relations at the level of biological pathways which may help to elucidate the genetic architecture underlying variation in phenotypic traits. PMID- 22244198 TI - Rabbit haemorrhagic disease: are Australian rabbits (Oryctolagus cuniculus) evolving resistance to infection with Czech CAPM 351 RHDV? AB - Rabbit haemorrhagic disease is a major tool for the management of introduced, wild rabbits in Australia. However, new evidence suggests that rabbits may be developing resistance to the disease. Rabbits sourced from wild populations in central and southeastern Australia, and domestic rabbits for comparison, were experimentally challenged with a low 60 ID50 oral dose of commercially available Czech CAPM 351 virus - the original strain released in Australia. Levels of resistance to infection were generally higher than for unselected domestic rabbits and also differed (0-73% infection rates) between wild populations. Resistance was lower in populations from cooler, wetter regions and also low in arid regions with the highest resistance seen within zones of moderate rainfall. These findings suggest the external influences of non-pathogenic calicivirus in cooler, wetter areas and poor recruitment in arid populations may influence the development rate of resistance in Australia. PMID- 22244199 TI - Characterization of a single-stranded DNA-binding protein from Klebsiella pneumoniae: mutation at either Arg73 or Ser76 causes a less cooperative complex on DNA. AB - Single-stranded DNA-binding protein (SSB) plays an important role in DNA metabolism, such as in processes like DNA replication, repair and recombination, and is essential for cell survival. Here, we characterized the ssDNA-binding properties of Klebsiella pneumoniae SSB (KpSSB) by using fluorescence-quenching measurements, electrophoretic mobility shift analysis (EMSA) and site-directed mutagenesis. Analysis of purified KpSSB by gel-filtration chromatography showed a stable tetramer in solution. In fluorescence titrations, KpSSB bound to 25-40 nucleotides (nt) per tetramer depending on the salt concentration. Using EMSA, we characterized the stoichiometry of KpSSB complexed with a series of ssDNA homopolymers, and the size of the binding site was determined to be 26 +/- 1 nt. Mutation at either Arg73 or Ser76 of KpSSB caused a less cooperative complex on DNA. Arg73 forms an intermolecular hydrogen bond with Ser76, and this appears to be a likely driving force that directs the self-assembly of SSB on DNA. PMID- 22244200 TI - Golgi protein 73 versus alpha-fetoprotein as a biomarker for hepatocellular carcinoma: a diagnostic meta-analysis. AB - BACKGROUNDS: There have been conflicting reports about serum golgi protein 73 (GP73) as one of the most promising serum markers for the diagnosis of hepatocellular carcinoma (HCC). This study was to make a systematic review about the diagnostic accuracy of serum GP73 versus alpha-fetoprotein (AFP) for HCC. METHODS: After a systematic review of related studies, sensitivity, specificity and other measures about the accuracy of serum GP73 and AFP in the diagnosis of HCC were pooled using random-effects models. Summary receiver operating characteristic curve analysis was used to summarize the overall test performance. RESULTS: Eight studies were included in our meta-analysis. The summary estimates for serum GP73 and AFP in diagnosing HCC in the studies included were as follows: sensitivity, 76% (95% confidence interval (CI) 51-91%) vs. 70% (47-86%); specificity, 86% (95%CI 65-95%) vs. 89% (69-96%); diagnostic odds ratio (DOR), 18.59 (95%CI 5.33-64.91) vs. 18.00(9.41-34.46); and area under sROC, 0.88 (95%CI 0.77-0.99) vs. 0.86 (95%CI 0.84-0.87). CONCLUSIONS: The current evidence indicates that serum GP73 has a comparable accuracy to AFP for the diagnosis of HCC, while the value of serum GP73 in combination with AFP for HCC detection deserves further investigation. PMID- 22244201 TI - Biodistribution and Tumor Localization of PEG-Modified Dendritic Poly(L-Lysine) Oligonucleotide Complexes. AB - A poly(ethylene glycol) (PEG)-modified dendritic poly(L-lysine) (PEG-WeKG6) containing tryptophan residues in its core was synthesized as an oligonucleotide carrier to tumors after systemic injection. PEG- WeKG6 formed a stable complex with double-stranded deoxyoligonucleotide (ODN). The size and the zeta-potential of the complex were smaller than those of a dendritic poly(L-lysine) without PEG (WeKG6). To study the biodistribution of the complexes in tumor-bearing mice after intravenous injection, the den- drimers and the oligonucleotide were labeled with gadolinium and Cy5, respectively. Our results show that PEG modification of the dendrimer improved the stability of ODN in blood circulation. Effective accumulation of the PEG-WeKG6/ODN complex in the tumor tissue was found 24 h after the injection. These results indicate that PEG-WeKG6 is suitable for forming a complex with any genetic or therapeutic material for efficient delivery to tumors. PMID- 22244202 TI - RNAa-mediated overexpression of WT1 induces apoptosis in HepG2 cells. AB - AIM: Recent studies have reported that double-stranded RNA (dsRNA) can activate gene expression by targeting promoter sequence in a process termed RNA activation. The present study was conducted to evaluate the potential of WT1 induction by small activating RNA targeting the WT1 promoter (dsWT1) in the treatment of hepatocellular carcinoma. METHODS: The human hepatocellular carcinoma cell line HepG2 was transfected with dsRNA by liposomes. The expression of mRNA and protein in cells were investigated using real-time reverse real-time quantitative PCR and Western blot, respectively. Cell viability and clonogenicity were determined by MTT assay and clonogenicity assay, respectively. Cell apoptosis was evaluated by flow-cytometric analysis. RESULTS: Expressions of WT1 mRNA and protein in dsWT1 treated HepG2 cells were significantly elevated. Inhibition of cell viability by dsWT1 was dose-dependent and time-dependent. Reduction of the number and size of colonies formed were found in dsWT1 treated cells. dsWT1 induced significant apoptosis in HepG2 cells. The decreased anti apoptotic protein Bcl-2 and elevated pro-apoptotic protein Bak expression were detected in dsWT1 treated cells. The level of pro-caspase-3 remarkably decreased and cleaved caspase-3 and PARP fragment were also detected in dsWT1 treated cells. CONCLUSION: These data show that RNAa-mediated overexpression of WT1 may have therapeutic potential in the treatment of hepatocellular carcinoma. PMID- 22244203 TI - Bacterial sepsis after living donor liver transplantation: the impact of early enteral nutrition. AB - BACKGROUND: Bacterial sepsis is a significant problem that must be addressed after living donor liver transplantation (LDLT). STUDY DESIGN: A retrospective analysis of 346 adult-to-adult LDLT patients was performed. RESULTS: Forty-six patients (13.3%) experienced bacterial sepsis, with primary and secondary origins in 23.9% and 76.1%, respectively. Gram-negative bacteria accounted for 71.7% of the bacteria isolated. The 2-year cumulative graft survival rate in patients with bacterial sepsis was 45.7%. Patients with bacterial sepsis secondary to pneumonia (n = 12) had poorer 2-year graft survival rates (16.7%) than did those with primary or other types of secondary sepsis (p = 0.004). Multivariate analysis showed that intraoperative massive blood loss >10L (p < 0.001) and no enteral feeding started within 48 hours after transplantation (p = 0.005) were significant risk factors for bacterial sepsis. Among patients who received enteral nutrition, the incidences of bacterial sepsis in patients who received enteral nutrition within 48 hours (n = 135) or later than 48 hours (n = 57) were 5.9% and 21.0%, respectively (p = 0.002). The incidence of early graft loss was 8 fold higher in recipients with massive intraoperative blood loss without early enteral nutrition (p < 0.001). CONCLUSIONS: Early enteral nutrition was associated with significantly reduced risk of developing bacterial sepsis after LDLT. PMID- 22244204 TI - Statins in abdominal surgery: a systematic review. PMID- 22244205 TI - Total mesorectal excision with intraoperative assessment of internal anal sphincter innervation provides new insights into neurogenic incontinence. AB - BACKGROUND: The aim of this prospective study was to assess internal anal sphincter (IAS) innervation in patients undergoing total mesorectal excision (TME) by intraoperative neuromonitoring (IONM). STUDY DESIGN: Fourteen patients underwent TME. IONM was carried out through pelvic splanchnic nerve stimulation under continuous electromyography of the IAS. Anorectal function was assessed with the digital rectal examination scoring system and a standardized questionnaire. RESULTS: Nine of 11 patients who underwent low anterior resection had positive IONM results, with stimulation-induced increased IAS electromyographic amplitudes (median 0.23 MUV (interquartile range [IQR] 0.05, 0.56) vs median 0.89 MUV (IQR 0.64, 1.88), p < 0.001) after TME. The patients with the positive IONM results were continent after stoma closure. Of 2 patients with negative IONM results, 1 had fecal incontinence after closure of the defunctioning stoma and received a permanent sigmoidostomy. In the other patient the defunctioning stoma was deemed permanent due to decreased anal sphincter function. In 3 patients who underwent abdominoperineal excision, IONM assessed denervation of the IAS after performance of the abdominal part. CONCLUSIONS: This study demonstrated that IONM of IAS innervation in rectal cancer patients is feasible and may predict neurogenic fecal incontinence. PMID- 22244206 TI - A systematic review and meta-analysis of diagnostic screening criteria for blunt cerebrovascular injuries. AB - BACKGROUND: Despite progress in diagnosing and managing blunt cerebrovascular injury (BCVI), controversy remains regarding the appropriate population to screen. A systematic review of published literature was conducted to summarize the overall incidence of BCVI and the various screening criteria used to detect BCVI. A meta-analysis was performed to evaluate which screening criteria may be associated with BCVI. Goals were to confirm inclusion of certain criteria in current screening protocols and possibly eliminate criteria not associated with BCVI. STUDY DESIGN: Studies published between January 1995 and April 2011 using digital subtraction angiography or CT angiography as a diagnostic modality and reporting overall BCVI incidence or prevalence of BCVI for specific screening criteria were examined. Screening criteria were analyzed using a random effects model to determine if an association with BCVI was present. RESULTS: The incidence range of BCVI was between 0.18% and 2.70% among approximately 122,176 blunt trauma admissions. The meta-analysis encompassed 418 BCVI and 22,568 non BCVI patients. Of the 9 screening criteria analyzed, cervical spine (odds ratio [OR] 5.45; 95% CI 2.24 to 13.27; p < 0.0001) and thoracic (OR 1.98; 95% CI 1.35 to 2.92; p = 0.001) injuries demonstrated a significant association with BCVI. CONCLUSIONS: Patients with cervical spine and thoracic injuries had significantly greater likelihoods of BCVI compared with patients without these injuries. All patients with either injury should be screened for BCVI. Multivariate logistic regression analysis is needed to elucidate the possible impact of the combined presence of screening criteria, but it was not possible in our study due to limitations in data presentation. Standardized reporting of BCVI data is not established and is recommended to permit future collaboration. PMID- 22244207 TI - Management of papillary breast lesions diagnosed on core-needle biopsy: clinical pathologic and radiologic analysis of 276 cases with surgical follow-up. AB - BACKGROUND: Clinical management of papillary breast lesions (PBLs) remains controversial. The objective of this study was to identify pathologic and radiologic predictors of malignancy from a large cohort of PBLs diagnosed on core needle biopsy (CNB). STUDY DESIGN: Retrospective review of the institutional pathology database identified all PBLs diagnosed from 2001 to 2009 and surgically excised within 6 months of diagnosis. PBLs were divided into intraductal papilloma (IDP) and IDP associated with atypical ductal or lobular hyperplasia (ADH/ALH). Surgical pathology of all lesions was reviewed and upgrade was defined as a change to a lesion of greater clinical significance, including ALH, ADH, lobular, or ductal carcinoma in situ (LCIS or DCIS), and invasive ducal carcinoma (IDC). RESULTS: We identified 276 patients (mean age 56 years; range 23 to 88 years) with PBLs on CNB. Seventy-nine patients (28.6%) upgraded to a lesion of greater clinical significance. Of the 234 (84.7%) had IDP only, 42 (17.9%) upgraded to ADH, and 21 (8.9%) to DCIS or IDC. Of the 42 (15.3%) patients with associated ADH or ALH on CNB, 16 (38.0%) upgraded to DCIS or IDC. The majority of patients (n = 173, 62.6%) had no breast symptoms. All patients had an abnormal mammogram and/or ultrasound that prompted the CNB. Among all clinical and radiographic variables analyzed, older age alone was predictive of upgrade. CONCLUSIONS: Frequent upgrade to a high-risk lesion or cancer is observed with IDPs diagnosed on CNB without adequate identifiable clinical and radiographic risk factors. Surgical excision should be performed for all IDPs to delineate subsequent clinical management. PMID- 22244208 TI - AUDIT-C alcohol screening results and postoperative inpatient health care use. AB - BACKGROUND: Alcohol screening scores >=5 on the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) up to a year before surgery have been associated with postoperative complications, but the association with postoperative health care use is unknown. This study evaluated whether AUDIT-C scores in the year before surgery were associated with postoperative hospital length of stay, total ICU days, return to the operating room, and hospital readmission. STUDY DESIGN: This cohort study included male Veterans Affairs patients who completed the AUDIT-C on mailed surveys (October 2003 through September 2006) and were hospitalized for nonemergent noncardiac major operations in the following year. Postoperative health care use was evaluated across 4 AUDIT C risk groups (scores 0, 1 to 4, 5 to 8, and 9 to 12) using linear or logistic regression models adjusted for sociodemographics, smoking status, surgical category, relative value unit, and time from AUDIT-C to surgery. Patients with AUDIT-C scores indicating low-risk drinking (scores 1 to 4) were the referent group. RESULTS: Adjusted analyses revealed that among eligible surgical patients (n = 5,171), those with the highest AUDIT-C scores (ie, 9 to 12) had longer postoperative hospital length of stay (5.8 [95% CI, 5.0-6.7] vs 5.0 [95% CI, 4.7 5.3] days), more ICU days (4.5 [95% CI, 3.2-5.8] vs 2.8 [95% CI, 2.6-3.1] days), and increased probability of return to the operating room (10% [95% CI, 6-13%] vs 5% [95% CI, 4-6%]) in the 30 days after surgery, but not increased hospital readmission within 30 days postdischarge, relative to the low-risk group. CONCLUSIONS: AUDIT-C screening results could be used to identify patients at risk for increased postoperative health care use who might benefit from preoperative alcohol interventions. PMID- 22244209 TI - Argon beam coagulator: an effective adjunct to stapled pulmonary tractotomy to control hemorrhage in penetrating pulmonary injuries. PMID- 22244210 TI - [Acute myocardial infarction associated to oral contraceptives: a case report]. PMID- 22244211 TI - [Quality indicators in a respiratory intensive care unit. Initial analysis of the DEDUCIR database]. PMID- 22244212 TI - [Temporary endocavitary pacemaker implantation]. PMID- 22244213 TI - [Abdominal compartment syndrome and acute intestinal distress syndrome]. AB - Seriously ill patients frequently present intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) as complications, and the associated mortality is very high. This review offers an update on the most controversial aspects of these entities: factors favoring their appearance, the most common causes, prognosis, and methods of measuring intra-abdominal pressure (IAP), physiopathological consequences in relation to the different organs and systems, and the currently accepted treatment measures (medical and/or surgical). Simultaneously to the strictly physical mechanisms of injury, such as direct compression of intra-abdominal organs and vessels, the transmission of IAP to other compartments, and the drop in cardiac output, a series of immune inflammatory mediators generated in the intestine itself may also intervene. Hypoperfusion, sustained ischemia and the ischemia-reperfusion phenomenon, would act upon the microbiota, intestinal epithelium and intestinal immune system, triggering a systemic inflammatory response and multiorgan dysfunction that appears in the final stages of ACS. PMID- 22244214 TI - [Continuous propofol perfusion in critically ill children]. AB - OBJECTIVE: To describe sedation with continuous perfusion of propofol in critically ill children. DESIGN: A retrospective, descriptive observational study was carried out. SETTING: A pediatric intensive care unit. PATIENTS: Pediatric patients requiring sedoanalgesia between October 1, 2009 and September 30, 2010. INTERVENTIONS: None. DATA COLLECTED: Demographic, clinical and laboratory test variables, diagnosis, treatment, complications and evolution in each patient. In addition, the potential adverse effects associated with propofol administration were analyzed. RESULTS: Midazolam, fentanyl and propofol were the most commonly used sedative and analgesic drugs. Seventy-one out of 222 patients (32%) received propofol in continuous infusion. The average dose was 2.1 mg/kg/h (SD 1.3, range: 0.5 to 6), and the average duration of treatment was of 6.7 days (SD 8.5 range 0.5-40). Fifty-two percent were males, and the mean patient age was 45.8 months (median: 24; interquartile range: 7-65). No patient developed propofol infusion syndrome or other serious drug-related adverse effects. Patients treated with propofol showed more abnormal laboratory test findings, although no relationship to drug administration could be demonstrated. There were no significant differences in lactate level or in the incidence of infection in either group. CONCLUSIONS: Propofol at a dose of 1 to 4 mg/kg/h is a safe alternative for sustained sedation in critically ill children. However, further studies are needed to assess its effects and safety profile. PMID- 22244215 TI - E. coli O104:H4 outbreak and haemolytic-uraemic syndrome. AB - BACKGROUND: The first cases of the European epidemic of Shiga toxin-producing Escherichia coli O104:H4 (STEC-O104:H4) infection were reported in Germany in April 2011. OBJECTIVES: To characterize the 2011 STEC-O104:H4 outbreak and its management. A literature review is made to assess the state of the art in STEC haemolytic-uraemic syndrome (HUS) epidemiology, pathogenesis, management and prognosis, focusing on critically ill adults. METHODS: References were obtained from the European Center for Disease Control and World Health Organization epidemiological updates, in addition to a PubMed search covering the period from 1980 to August 2011, including all published work on STEC-014:H4 and reviews on HUS management and prognosis. RESULTS: The epidemic originated from a bean and seed sprouts farm in Lower Saxony, and was caused by the O104:H4 strain - a highly antibiotic resistant, hybrid enteroaggregative - Shiga toxin producing E. coli strain (STEC). The infection was characterized by increased HUS (25%) and a higher mortality rate. STEC enteritis and HUS are associated with significant mortality and morbidity, especially amongst patients with severe renal and neurological disorders. Management should center on prompt kidney protection by maintaining adequate renal perfusion, in addition to avoiding diuretics and nephrotoxic agents. CONCLUSIONS: The published studies regarding antibiotic treatment lack good quality evidence. However, recent data suggest a potential modulating effect that explains the conflicting data but moreover suggests that azithromycin might be of use. Neutralizing monoclonal antibodies are a promising new therapy for STEC-HUS, with currently ongoing studies. Other treatments have not been shown to be superior to supportive therapy alone. PMID- 22244216 TI - [Pilot plan for training in life support and CPR in schools]. PMID- 22244217 TI - Structural differences between soluble and membrane bound cytochrome P450s. AB - The superfamily of cytochrome P450s forms a large class of heme monooxygenases with more than 13,000 enzymes represented in organisms from all biological kingdoms. Despite impressive variability in sizes, sequences, location, and function, all cytochrome P450s from various organisms have very similar tertiary structures within the same fold. Here we show that systematic comparison of all available X-ray structures of cytochrome P450s reveals the presence of two distinct structural classes of cytochrome P450s. For all membrane bound enzymes, except the CYP51 family, the beta-domain and the A-propionate heme side chain are shifted towards the proximal side of the heme plane, which may result in an increase of the volume of the substrate binding pocket and an opening of a potential channel for the substrate access and/or product escape directly into the membrane. This structural feature is also observed in several soluble cytochrome P450s, such as CYP108, CYP151, and CYP158A2, which catalyze transformations of bulky substrates. Alternatively, both beta-domains and the A propionate side chains in the soluble isozymes extend towards the distal site of the heme. This difference between the structures of soluble and membrane bound cytochrome P450s can be rationalized through the presence of several amino acid inserts in the latter class which are involved in direct interactions with the membrane, namely the F'- and G'-helices. Molecular dynamics using the most abundant human cytochrome P450, CYP3A4, incorporated into a model POPC bilayer reveals the facile conservation of a substrate access channel, directed into the membrane between the B-C loop and the beta domain, and the closure of the peripheral substrate access channel directed through the B-C loop. This is in contrast to the case when the same simulation is run in buffer, where no such channel closing occurs. Taken together, these results reveal a key structural difference between membrane bound and soluble cytochrome P450s with important functional implications induced by the lipid bilayer. PMID- 22244218 TI - How useful are landmarks when learning a route in a virtual environment? Evidence from typical development and Williams syndrome. AB - The ability to learn a route through a virtual environment was assessed in 19 older children and adults with Williams syndrome (WS) and 40 typically developing (TD) children aged 6-9 years. In addition to comparing route-learning ability across groups, we were interested in whether participants show an adult-like differentiation between "useful" and "less useful" landmarks when learning a route and the relative salience of landmark position versus landmark identity. Each virtual environment consisted of a brick wall maze with six junctions. There were 16 landmarks in the maze, half of which were on the correct path and half on incorrect paths. Results showed that both groups could learn each route to criterion (two successful completions of a route without error). During the learning phase, the WS group produced more errors than the TD group and took longer to reach criterion. This was predominantly due to the large number of perseverative errors (i.e., errors that were made at the same choice point on consecutive learning trials) made by the WS group relative to the TD children. We suggest that this reflects a difficulty in inhibiting erroneous responses in WS. During the test phase, the TD group showed stronger recall of landmarks adjacent to junctions (more useful landmarks) than of landmarks along path sections (less useful landmarks) independent of each individual's level of nonverbal ability. This pattern was also evident in the WS group but was related to level of nonverbal maturation; the differentiation between recall of junction and path landmarks increased as nonverbal ability increased across WS participants. Overall, the results demonstrate that individuals with WS can learn a route but that the development of this ability is atypical. PMID- 22244219 TI - Neurobrucellosis developing unilateral oculomotor nerve paralysis. AB - Brucellosis is a zoonotic infectious disease that is common around the world. Its clinical course demonstrates great diversity as it can affect all organs and systems. However, the central nervous system is rarely affected in the pediatric population. Neurobrucellosis is most frequently observed with meningitis and has numerous complications, including meningocephalitis, myelitis, cranial nerve paralyses, radiculopathy, and neuropathy. Neurobrucellosis affects the second, third, sixth, seventh, and eighth cranial nerves. Involvement of the oculomotor nerves is a very rare complication in neurobrucellosis although several adult cases have been reported. In this article, we present the case of a 9-year-old girl who developed unilateral nerve paralysis as a secondary complication of neurobrucellosis and recovered without sequel after treatment. This case is notable because it is a very rare, the first within the pediatric population. Our article emphasizes that neurobrucellosis should be considered among the distinguishing diagnoses in every case that is admitted for nerve paralysis in regions where Brucella infection is endemic. PMID- 22244220 TI - Bedside ultrasound evaluation of tendon injuries. AB - OBJECTIVE: The primary purpose of this study was to investigate the overall accuracy of bedside extremity tendon ultrasound performed by emergency physicians in the emergency department. We also sought to investigate whether or not bedside tendon ultrasonography can be used to expedite the diagnosis and discharge planning in patients with suspected tendon injuries. METHODS: This was a prospective study conducted at 2 academic level 1 trauma centers. Thirty-four patients were enrolled and underwent a comprehensive physical examination of the injured extremity, followed by a bedside ultrasound evaluation to look for tendon disruption. Results of the tendon ultrasound were compared against the findings seen during wound exploration in the emergency department, wound exploration in the operating room, or results from an extremity magnetic resonance imaging (MRI). RESULTS: There were 6 finger injuries, 11 hand injuries, 6 arm injuries, 6 forearm injuries, and 5 lower extremity injuries. Of the 34 total patients, 4 patients had partial tendon injuries, 9 suffered from 100% tendon laceration or rupture, and 21 had no tendon injury noted on exploration or MRI. Bedside ultrasound had a sensitivity, specificity, and accuracy of 100%, 95%, and 97%, respectively. Physical examination had a sensitivity, specificity, and accuracy of 100%, 76%, and 85%, respectively. Average time to bedside ultrasound was 46.3 minutes compared with 138.6 minutes for wound irrigation and exploration, MRI, or surgery consultation. CONCLUSION: Bedside ultrasound is more sensitive and specific than physical examination for detecting tendon lacerations, and takes less time to perform than traditional wound exploration techniques or MRI. PMID- 22244222 TI - Evaluating the risk of venous thromboembolism in medical patients: which criteria? PMID- 22244221 TI - Is inadequate human immunodeficiency virus care associated with increased ED and hospital utilization? A prospective study in human immunodeficiency virus positive ED patients. AB - BACKGROUND: There is a lack of data on the effect(s) of suboptimal human immunodeficiency virus (HIV) care on subsequent health care utilization among emergency department (ED) patients with HIV. Findings on their ED and inpatient care utilization patterns will provide information on service provision for those who have suboptimal access to HIV-related care. METHODS: A pilot prospective study was conducted on HIV-positive patients in an ED. At enrollment, participants were interviewed regarding health care utilization. Participants were followed up for 1 year, during which time data on ED visits and hospitalizations were obtained from their patient records. Inadequate HIV care (IHC) was defined according to Infectious Diseases Society of America recommendations as less than 3 scheduled clinic visits for HIV care in the year before enrollment. Cox regression models were used to evaluate whether IHC was associated with increased hazard of health care utilization. RESULTS: Of 107 subjects, 36% were found to have IHC. Inadequate HIV care did not predict more frequent ED visits but was significantly associated with fewer hospitalizations (adjusted incidence rate ratio, 0.61 [95% CI: 0.43-0.86]). Inadequate HIV care did not significantly increase the hazard for earlier ED visit or hospitalization. However, further stratification analysis found that IHC increased the hazard of hospitalization for subjects without comorbid diseases (adjusted hazard ratio, 2.50 [95% CI: 1.10-5.68]). CONCLUSIONS: In our setting, IHC does not appear to be associated with earlier or more frequent ED visits but may lead to earlier hospitalization, particularly among those without other chronic diseases. PMID- 22244223 TI - Circadian variation of acute myocardial infarction in young people. AB - AIMS: The aim was to investigate the circadian and weekly variation in Chinese young patients with acute myocardial infarction (AMI). METHODS: This was a 10 year retrospective cohort study. We studied patients (>18 to <45 years of age) with a first attack of AMI from the emergency departments of 3 university teaching hospitals in Taiwan from January 1, 2001, to December 31, 2010. We analyzed patients in the standard circadian fashion using 6-hour intervals (00:01 06:00, 06:01-12:00, 12:01-18:00, and 18:01-24:00). We also did an analysis by day of week. RESULTS: The database had 505 patients with AMI with complete data. The percentage of total AMIs that occurred in the 6-hour intervals were as follows: 00:01 to 06:00, 30.9%; 06:01 to 12:00, 23.4%; 12:01 to 18:00, 25.9%; and 18:01 to 24:00, 19.8%. The percentage of AMIs between 00:01 and 06:00 was significant higher compared with that in the other three 6-hour intervals (df = 3, chi(2) = 91.7, P < .001). However, there was no significant weekly variation for these patients in the present study. CONCLUSIONS: There was a significant circadian variation with a peak from 00:01 to 06:00 in Chinese young patients with AMI. However, there was no significant weekly variation in these patients. The circadian periodicity may create new possibilities for disease prevention and medication prescription. PMID- 22244224 TI - The use of a 4-step algorithm in the electrocardiographic diagnosis of ST-segment elevation myocardial infarction by novice interpreters. AB - The electrocardiographic (ECG) diagnosis of ST-segment elevation myocardial infarction (STEMI) represents a challenge to all health care providers, particularly so for the novice ECG interpreter. We have developed--and present in this article--a 4-step algorithm that will detect STEMI in most instances in the prehospital and other nonemergency department (ED) settings. The algorithm should be used in adult patients with chest pain or equivalent presentation who are suspected of STEMI. It inquires as to the presence of ST-segment elevation as well as the presence of STEMI confounding/mimicking patterns; the algorithm also makes use of reciprocal ST-segment depression as an adjunct in the ECG diagnosis of STEMI. If STEMI is detected by this algorithm, then management decisions can be made based upon this ECG diagnosis. If STEMI is not detected using this algorithm, then we can only note that STEMI is not "ruled in"; importantly, STEMI is not "ruled out." In fact, more expert interpretation of the ECG will be possible once the patient (and/or the ECG) arrive in the ED where ECG review can be made with the more complex interpretation used by expert physician interpreters. PMID- 22244225 TI - 5-Hydroxyindoleacetic acid in appendicitis: the importance of test selection. PMID- 22244226 TI - Comment on "Dental pain as a risk factor for accidental acetaminophen overdose: a case-control study". PMID- 22244227 TI - EZ-IO in the ED: an observational, prospective study comparing flow rates with proximal and distal tibia intraosseous access in adults. AB - INTRODUCTION: Intraosseous (IO) access is an important alternative to conventional intravenous access when intravenous access is difficult. METHODS: A nonrandomized, prospective, observational study comparing flow rates with distal and proximal tibia IO access in adults using the EZ-IO-powered drill device. The proximal tibia was the first site of insertion, and a second IO was inserted in the distal tibia if clinically indicated. Intravenous saline infusion was started for all patients, initially without, then with a pressure bag device applied. RESULTS: From September 19, 2008 to November 3, 2010, 22 patients were recruited, with 20 proximal tibial and 22 distal tibia insertions. Two patients had only distal tibia IO insertions. Five distal tibia and 3 proximal tibia insertions had no flow when initiating normal saline infusion without pressure. Upon comparing the mean flow rates without pressure bag, it is significantly faster in the proximal tibia, 4.96 mL/min, compared with distal tibia, 2.07 ml/min, difference of 2.89 ml/min (95% CI 1.20-4.58). Flow rates with pressure bags also revealed a similar result. Flow rates in the proximal tibia were significantly faster, 7.70 ml/min to that of distal tibia, 3.80 ml/min, difference of 3.89 ml/min (95% CI 1.68-6.10). In both proximal and distal tibia groups, the flow rates are also significantly faster with pressure bags compared with without. CONCLUSION: Flow rates are significantly faster in the proximal tibia compared with the distal tibia. In addition, flow rates with pressure bags are significantly faster than without pressure bags in both groups. PMID- 22244228 TI - ED ultrasound diagnosis of a type B aortic dissection using the suprasternal view. AB - Aortic dissection (AD) is one of the most challenging diagnoses in emergency medicine. This is due, in part, to its variable presentation, ranging from abrupt tearing chest pain in a hemodynamically unstable patient to back pain in a stable patient, as well as its high mortality rates. (1) With the expanding role of ultrasound (U/S) performed by emergency physicians, it is possible to make the diagnosis of AD at the bedside before any other imaging modality has been accessed. (2) In this case report, we describe the use of emergency department (ED) bedside U/S and specifically highlight the use of the suprasternal view in the diagnosis of AD. PMID- 22244229 TI - Mechanisms of allergic sensitization to foods: bypassing immune tolerance pathways. AB - The default response of the mucosal immune system to antigens derived from food is one of active immune tolerance carried out by regulatory T cells and induced by dendritic cells residing in the intestinal mucosa. This tolerance response must be inhibited or bypassed to generate allergic sensitization in experimental food allergy and this has been achieved by 3 main approaches: genetic modifications, experimental adjuvants, and bypassing oral tolerance by administering the antigen through alternative routes. This article discusses the implications of these approaches for understanding the mechanisms of sensitization to food allergens in human disease. PMID- 22244231 TI - The epidemiology of IgE-mediated food allergy and anaphylaxis. AB - The rise in food allergy prevalence in developed countries is evident from anecdotal reports but has been difficult to document and until recently good quality prevalence data were lacking. Although most emerging risk factors seem related to the "modern lifestyle" the reasons for the rise in food allergy prevalence remain poorly understood. The incidence of food allergy-related anaphylaxis is rising particularly in children younger than 5 years of age. Emerging studies are better designed to assess the true prevalence of IgE mediated food allergy using formal population sampling frames, standardized and objective outcome data including use of the gold standard oral food challenge, and the capacity to adjust for potential selection bias. PMID- 22244232 TI - Can we prevent food allergy by manipulating the timing of food exposure? AB - Prevention of food allergies by maternal and infant feeding practices serves as a simple, inexpensive approach to address the growing number of subjects with food allergies in comparison with any emerging interventional therapies for existing food allergies, such as oral immunotherapy. This article provides a careful evaluation of the rationale and existing data on the effect of timing of the introduction of food allergens (during pregnancy, lactation, and early childhood) on the development of specific food allergies. PMID- 22244230 TI - Determinants of food allergy. AB - Food allergy is an emerging epidemic in the United States and the Western world. The determination of factors that make certain foods allergenic is still not clearly understood. Only a tiny fraction of thousands of proteins and other molecules is responsible for inducing food allergy. In this review, the authors present 3 examples of food allergies with disparate clinical presentations: peanut, soy, and mammalian meat. The potential relationships between allergen structure and function, emphasizing the importance of cross-reactive determinants, immunoglobulin E antibodies to the oligosaccharides, and the immune responses induced in humans are discussed. PMID- 22244233 TI - Eosinophilic esophagitis: diagnosis and management. AB - Eosinophilic esophagitis is a clinicopathologic disease that can present with a constellation of upper gastrointestinal symptoms and endoscopic findings in conjunction with significant infiltration of the esophageal tissue with eosinophils. Clinical and histologic resolution of the disease can be seen with dietary restriction therapies and systemic and topical corticosteroids. Because most patients have an atopic background and the disease seems to have an underlying T-helper type 2 pathogenesis, allergists and gastroenterologists need to be familiar with the diagnosis and management of this disease. In this review, clinical characteristics, endoscopic and histologic findings, and available therapy options are discussed. PMID- 22244234 TI - Mental health and quality-of-life concerns related to the burden of food allergy. AB - As food allergy increases, more research is devoted to its influence on patient and family mental health and quality of life (QoL). This article discusses the effects on parent and child QoL, as well as distress, while appraising the limitations of knowledge given the methods used. Topics include whether QoL and distress are affected compared with other illnesses, assessment of distress and QoL in parents compared with children, concerns about food allergy-related bullying, and the necessity for evidence-based interventions. Suggestions are offered for how to improve QoL and reduce distress on the way to better coping with food allergy. PMID- 22244235 TI - Beyond skin testing: state of the art and new horizons in food allergy diagnostic testing. AB - Food allergy affects approximately 1% to 10.8% of the general population, and its prevalence seems to be increasing. An accurate diagnosis is particularly important because a misdiagnosis could lead to life-threatening reactions or to unnecessary restrictive diets. However, allergy tests currently used in clinical practice have limited accuracy, and an oral food challenge, considered as the gold standard, is often required to confirm or exclude a food allergy. This article reviews several promising novel approaches for the diagnosis of food allergy, such as new molecular diagnostic technologies and functional assays, along with their potential clinical applications. PMID- 22244236 TI - Oral immunotherapy and anti-IgE antibody-adjunctive treatment for food allergy. AB - One of the most promising therapies for food allergy is oral immunotherapy (OIT), in which small amounts of allergen are administered in increasing amounts, with the immediate goal of desensitization and the long-term goal of tolerance. However, safety and standardization concerns prevent its widespread use, and a subgroup of patients may experience severe allergic reactions. These concerns might be addressed by another promising therapy involving anti-IgE monoclonal antibodies (mAb), which can reduce allergic reactions associated with food administration. A recent pilot study combining anti-IgE mAb with OIT suggests that anti-IgE mAb might improve the safety, rapidity, and efficacy of OIT. PMID- 22244237 TI - Alternative and complementary treatment for food allergy. AB - Despite increased consumer interest in complementary and alternative medicine (CAM) for the treatment of food allergy, there remains a relative paucity of knowledge regarding the clinical efficacy, mechanisms of action, and safety of most CAM treatments available to consumers. This article focuses on recent advances in CAM for food allergy, including acupuncture, herbal medicine, probiotics, and alternative approaches to allergen immunotherapy. The mechanism of action of several novel approaches to treatment of food allergy is reviewed, but FAHF-2 is the only investigational herbal formulation currently validated for use in human clinical trials. PMID- 22244238 TI - Paradigm shift in the management of milk and egg allergy: baked milk and egg diet. AB - Heat treatment of several foods, including all types of cooking, has been mainly used to minimize the number of viable microbes, reduce pathogenicity, and destroy the undesirable enzymes, maintaining food quality. In addition, food processing improves sensory, nutritional, and physical properties of the foods, due to food protein denaturation. Heat-induced alterations of food proteins can attenuate allergenicity. In this article, the authors review the important role of thermal processing on milk and egg proteins, which comprise the commonest food allergies in infancy and early childhood. PMID- 22244240 TI - Is food allergy giving me a headache? PMID- 22244241 TI - Food allergy guidelines and beyond. PMID- 22244239 TI - Food-induced anaphylaxis. AB - Food-induced anaphylaxis (FIA) is a serious allergic reaction that may cause death rapidly in otherwise healthy individuals. There is no universal agreement on its definition or criteria for diagnosis. Hospital admissions for FIA have more than doubled in the last decade. Food is one of the most common causes of anaphylaxis, with most surveys indicating that food-induced reactions account for 30% to 50% of cases. The most commonly implicated foods are peanut, tree nuts, milk, eggs, sesame seeds, fish, and shellfish. The only life-saving treatment for anaphylaxis is allergen avoidance, and epinephrine injection if an anaphylactic event occurs. PMID- 22244242 TI - Progressive histopathological changes and beta-cell loss in the pancreas of a new spontaneous rat model of type 2 diabetes. AB - The eSMT rat is a new spontaneous model of type 2 diabetes that develops a progressive diabetic syndrome with a stronger incidence in males than in females. We decide to investigate the progression of the pancreatic histopathological changes during the lifespan of the eSMT rat, especially those associated with islet cell populations. Besides that, some plasmatic parameters were evaluated in order to correlate them with the morphological findings. Male eSMT and Sprague Dawley control rats were used. The results showed a dramatic decrease of the volume density (VD) of endocrine tissue in the eSMT rats without evidence of insulitis. Islets became fragmented structures with strong presence of interstitial fibrosis. Consequently, plasma insulin levels showed a significant decrease, while plasma glucose, cholesterol and triglyceride levels were increased. Normal rats showed no significant changes in the VD of endocrine tissue, except for the older animals, where the VD of beta-cell population was increased. Early derangements observed in islets, together with the progressive decrease of endocrine tissue and the metabolic disorders described, would be responsible for an irreversible pathologic condition which avoids the animal survival beyond about 18 months of age. However, there is still a need to investigate the causes of endocrine tissue decrease and its possible association with an inflammatory process that it could be associated with the development and progression of fibrosis. PMID- 22244244 TI - Characterization of the glass-to-vitroceramic transition in yttrium aluminum borate laser glasses using solid state NMR. AB - The crystallization of laser glasses in the system (Y(2)O(3))(0.2){((Al(2)O(3))(x))(B(2)O(3))(0.8-x)} (0.15 <= x <= 0.40) doped with 0.5 mol% of ytterbium oxide has been investigated by x-ray powder diffraction, and various solid state NMR techniques. The crystallization process has been analyzed in a quantitative fashion by high-resolution solid state (11)B, (27)Al, and (89)Y NMR spectroscopy as well as (11)B{(27)Al} and (27)Al{(11)B} rotational echo double resonance (REDOR) experiments. The homogeneous glasses undergo major phase segregation processes resulting in crystalline Al(5)BO(9) (historically denoted as Al(18)B(4)O(33)), YBO(3), crystalline YAl(3)(BO(3))(4), residual glassy B(2)O(3), and an additional yet not identified crystalline phase ("X phase"). PMID- 22244243 TI - Molecular evolution of Drosophila Sex-lethal and related sex determining genes. AB - BACKGROUND: Sex determining mechanisms are evolutionarily labile and related species often use different primary signals and gene regulatory networks. This is well illustrated by the sex determining cascade of Drosophila fruitflies, which have recruited Sex-lethal as the master switch and cellular memory of sexual identity, a role performed in other insects by the gene transformer. Here we investigate the evolutionary change in the coding sequences of sex determining genes associated with the recruitment of Sex-lethal. We analyze sequences of Sex lethal itself, its Drosophila paralogue sister-or-Sex-lethal and downstream targets transformer and doublesex. RESULTS: We find that the recruitment of sister-or-Sex-lethal was associated with a number of adaptive amino acid substitutions, followed by a tightening of purifying selection within the Drosophila clade. Sequences of the paralogue sister-or-Sex-lethal, in contrast, show a signature of rampant positive selection and relaxation of purifying selection. The recruitment of Sex-lethal as top regulator and memory gene is associated with a significant release from purifying selection in transformer throughout the Drosophila clade. In addition, doublesex shows a signature of positive selection and relaxation of purifying selection in the Drosophila clade. A similar pattern is seen in sequences from the sister Tephritidae clade. CONCLUSIONS: The pattern of molecular evolution we observe for Sex-lethal and its paralogue sister-or-Sex-lethal is not characteristic of a duplication followed by neo-functionalization. Rather, evidence suggests a sub-functionalization scenario achieved through the evolution of sophisticated splicing. As expected, we find that transformer evolves under relaxed purifying selection after the recruitment of Sex-lethal in Drosophila. Finally, the observation of doublesex adaptation in both Drosophila and Tephritidae suggests that these changes are due to ongoing adaptation of downstream sex-specific regulation, rather than being associated the recruitment of Sex-lethal and the resulting change in the topology of the sex determining cascade. PMID- 22244246 TI - Effect of fluid collections on long-term outcome after lower limb amputation. AB - OBJECTIVE: To ascertain the long-term outcome for individuals found to have fluid collections in residual limbs after amputation. DESIGN: Prospective cohort study. SETTING: Outpatient follow-up at a prosthetic rehabilitation unit. PARTICIPANTS: Successive lower limb amputations (N=105) scanned for fluid collections after operation and followed up after 3 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Survival; secondary outcomes of prosthetic limb use, hours of prosthetic limb-wearing, anxiety and depression levels. RESULTS: After 3 years, 70 individuals were alive, of whom 21 (30%) had fluid collections originally. There was no significant difference at follow-up between the group that had fluid collections in their residual limbs after surgery and the group that did not in terms of survival (chi(2)(1)=.21, P=.64), numbers wearing prosthetic limb (chi(2)(1)=.102, P=.75), hours of limb wearing (t(37)=.35, P=.72), anxiety (chi(2)(1)=.77, P=.78), and depression (chi(2)(1)=1.98, P=.16). A multivariable logistic regression confirmed that presence of fluid collection was not associated with survival. CONCLUSIONS: Fluid collections in residual limbs after amputation are common, but patients can be reassured that their long-term outcomes are not affected. PMID- 22244247 TI - Biomechanical and clinical outcomes with shock-absorbing insoles in patients with knee osteoarthritis: immediate effects and changes after 1 month of wear. AB - OBJECTIVES: To examine the effectiveness of shock-absorbing insoles in the immediate reduction of knee joint load, as well as reductions in knee joint load, pain, and dysfunction after 1 month of wear, in individuals with knee osteoarthritis (OA). DESIGN: Pre-post design with participants exposed to 2 conditions (normal footwear, shock-absorbing insoles) with a 1-month follow-up. SETTING: University laboratory for testing and general community for intervention. PARTICIPANTS: Community-dwelling individuals (N=16; 6 men, 10 women) with medial compartment knee OA. INTERVENTION: Participants were provided with sulcus length shock-absorbing insoles to be inserted into their everyday shoes. MAIN OUTCOME MEASURES: Primary outcome measures included the peak, early stance peak, and late stance peak external knee adduction moment (KAM); the KAM impulse (positive area under the KAM curve); and peak tibial vertical acceleration. Secondary outcomes included walking pain, the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale and total score, and a timed stair climb task. RESULTS: There was a significant reduction in the late stance peak KAM with shock-absorbing insoles (P=.03) during follow-up compared with the baseline test session. No other immediate or longitudinal significant changes (P>.05) in the other KAM parameters or peak tibial acceleration after use of a shock-absorbing insole were observed. However, significant improvements in all measures of pain and function (P<.05) were observed. CONCLUSIONS: Shock absorbing insoles produced significant reductions in self-reported knee joint pain and physical dysfunction with 1 month of wear in patients with knee OA despite no consistent changes in knee joint load. Further research using randomized controlled trials, with larger sample sizes and explorations into long term use of shock-absorbing insoles and their effect on disease progression, is warranted. PMID- 22244248 TI - Is there a dose response for valgus unloader brace usage on knee pain, function, and muscle strength? AB - OBJECTIVE: To examine whether there was a dose response for valgus unloader brace wear on knee pain, function, and muscle strength in participants with medial compartment knee osteoarthritis. DESIGN: In this single-group study, participants with medial compartment knee osteoarthritis were followed for approximately 6 months. SETTING: Recruitment was conducted in the general community, and testing was performed at a university laboratory. PARTICIPANTS: A convenience sample of patients (N=32) who were prescribed a valgus unloader brace agreed to participate, met the inclusion criteria, and completed the baseline data collection. Twenty-four participants (20 men, 4 women) completed baseline and follow-up collections. INTERVENTION: Participants wore their valgus unloader brace as needed. MAIN OUTCOME MEASURES: Knee extensor, flexor, and plantar flexor strength was tested at baseline and follow-up. Participants filled out Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Medical Outcomes Study 36-Item Short-Form Health Survey questionnaires to assess pain and function. Self-selected walking velocity and stride length were objective measures of function. Brace usage (dose) and activity (step count) were recorded at least 4 days/week for the study duration. RESULTS: Positive relationships existed between brace wear usage and percent change in step count (r=.59, P=.006) and percent change in hamstrings strength (r=.37, P=.072). At follow-up, there was significant improvement in hamstrings strength (P=.013), and trends toward improvements in WOMAC pain (P=.059) and WOMAC function (P=.089). CONCLUSIONS: Our results indicate that greater brace use may positively affect physical activity level, but there was minimal effect of brace wear dosage on lower-limb muscle strength. Only knee flexion showed a positive relationship. Our finding of no decreased muscle strength indicates that increased brace use over a 6-month period does not result in muscle impairment. PMID- 22244249 TI - Treatment of posttraumatic bone defects by the induced membrane technique. AB - INTRODUCTION: Among bone reconstruction techniques, the induced membrane technique, proposed in 1986 by Masquelet, has rarely been studied or evaluated in the surgical literature until recently. The 2010 French Society of Orthopaedic Surgery and Traumatology (SoFCOT) Annual Convention symposium was the occasion to evaluate a large cases series having used this technique. PATIENTS AND METHODS: This retrospective study included 84 posttraumatic diaphyseal long bone reconstructions using the induced membrane technique (1988-2009). The series included 79 men and five women (mean age 32-year-old). In 89% of cases, the initial trauma was an open fracture. The leg was involved in 70% of cases. The mean delay between the accident and treatment of bone defects (BD) was 8 months. In 50% of the cases, infection was present. Bone defects were larger than 5cm in 57% of the cases. RESULTS: Union was obtained in 90% of cases, a mean 14.4 months after the first stage of the reconstruction. A mean 6.11 interventions were necessary to obtain union. Malalignment was present in 17% of cases. Delayed interventions to correct deformities mostly of the foot were necessary in 16% of the cases. Eight failures (10%) involved severe leg traumas associating extensive bone defects, soft tissue lesions and infection and required amputation in six cases. DISCUSSION: This series emphasizes the severity of open fractures of the leg, especially those with primary or secondary infection. The induced membrane technique has been shown to be effective in treating bone defects, regardless of their magnitude. In a two-step procedure, this simple but demanding technique, which may be more complicated when repair of soft tissue is necessary, provides successful treatment in case of initial infection and fulfills the goal of controlling infection before bone reconstruction. Moreover, the induced membrane technique can be integrated in hybrid reconstruction procedures. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 22244250 TI - Posterior tibial slope changes after opening- and closing-wedge high tibial osteotomy: a comparative prospective multicenter study. AB - INTRODUCTION: Valgus high tibial osteotomy is considered to be an effective treatment for unicompartmental medial osteoarthritis. It is generally admitted that tibial slope increases after open-wedge high tibial osteotomy and decreases after closing-wedge high tibial osteotomy. However, the effects on posterior tibial slope of closing- or opening-wedge osteotomies remain controversial. HYPOTHESIS: We analyzed the modifications of tibial slope after opening- and closing-wedge high tibial osteotomies and compared the results of these two procedures. We hypothesized that there was no difference in postoperative tibial slope between opening and closing-wedge osteotomies. PATIENTS AND METHODS: This prospective consecutive nonrandomized multicenter study was conducted between January 2008 and March 2009 and included 321 patients: 205 men and 116 women. A total of 224 patients underwent an opening-wedge high tibial osteotomy and 97 a closing-wedge osteotomy. The mean age was 52 years +/- 9 and the mean body mass index was 28kg/m(2) +/- 5. The main etiology was primary arthritis. Posterior tibial slope was measured preoperatively and at the last follow-up on a lateral radiograph in relation to the posterior tibial cortex. RESULTS: In the opening wedge group, a definite 0.6 degrees increase in tibial slope (P=0.016) was observed. In the closing-wedge group, a definite 0.7 degrees decrease in tibial slope (P=0.02) was found. Fourteen percent of the opening-wedge osteotomies increased tibial slope by 5 degrees or more versus only 2% of the closed-wedge osteotomies (P<0.001). Twelve percent of the closing-wedge high tibial osteotomies led to a decrease of 5 degrees or more of the tibial slope versus 7% of the opening-wedge osteotomies (P<0.02). DISCUSSION AND CONCLUSION: These results confirm what is generally reported in the literature, i.e., an increase in tibial slope in opening-wedge high tibial osteotomy and a decrease in the slope in closing-wedge osteotomies. These tibial slope changes appear to be very limited in this series, less than 1 degrees on average. However, there was a bias since the open-wedge technique was preferred in cases with substantial varus deformity. We emphasize the importance of surgical technique to avoid alteration of the tibial slope, particularly in opening-wedge high tibial osteotomy for which we recommend a release of posterior soft tissue and a complete osteotomy of the posterior cortex of the tibia. LEVEL OF EVIDENCE: III. Prospective consecutive nonrandomized multicenter study. PMID- 22244251 TI - Malignant glioma grade 3 and 4: how relevant is timing of radiotherapy? AB - AIMS AND BACKGROUND: The aim of this study is to determine prognostic factors that influence further outcome in patients with glioma. METHODS: Between 01/2002 and 08/2008, 153 patients with malignant gliomas of WHO-grade 3 or 4 who were treated with external beam radiotherapy with or without chemotherapy. RESULTS: In univariate analysis, following factors were ascertained as statistically significant prognostic parameters: grade (p = 0.000), time between operation and radiotherapy >24 days (p = 0.044) for progression-free survival; grade (p = 0.000), age<58 years (p = 0.001), extent of surgery (p = 0.011), time between operation and radiotherapy >24 days (p = 0.009), overall treatment time >68 days (p = 0.003), use of chemotherapy (p = 0.015) for overall survival. A longer time period between resection and start of radiotherapy showed to be associated with improved outcome. After multivariate analysis, only grade (p = 0.000) remained a statistically significant factor for progression-free and grade (p = 0.000) and use of chemotherapy (p = 0.031) for overall survival. CONCLUSIONS: We were able to recognize grade and use of chemotherapy as statistically significant prognostic determinants, but not time intervals or overall treatment time. PMID- 22244252 TI - Stabbing headache in patients with autoimmune disorders. AB - Stabbing headache is a relatively rare type of chronic "primary" headache with distinctive features with respect to more common forms of paroxysmal headache, such as cluster headache and trigeminal neuralgia. Drug treatment is empirical because of the lack of knowledge on the pathophysiology of stabbing headache. We examined 26 patients recruited over 10 years, who met the diagnostic criteria for stabbing headache. Interestingly, more than half of these patients had autoimmune disorders, including multiple sclerosis, Sjogren's disease, Systemic Lupus Erythematosus, Behcet's disease, autoimmune vasculitis, and antiphospholipid antibody syndrome. We speculate that stabbing headache may develop as a result of neuroinflammation and, at least in some cases, may be an epiphenomenon of focal demyelinating lesions of the upper or lower brain stem. PMID- 22244253 TI - A simple and consistent technique for ventricular catheter insertion using a tripod. AB - OBJECTIVE: For long-term preservation of ventriculo-peritoneal (VP) shunt function, it is essential to place the ventricular catheter tip above the foramen of Monro. But the free-hand technique for ventricular catheter passage is not consistent. METHODS: Supposing that a convex of skull matches to a sphere, in which the foramen of Monro is the center, a perpendicular direction from the surface of the sphere to inside always directs toward the center. The authors identified the range of skull where corresponded to the sphere by magnetic resonance imaging assessment and utilized tripod to achieve exactly perpendicular insertion of ventricular catheter. And an optimal length of catheter insertion was investigated by navigation system. RESULTS: The anterior-posterior range of the spherical portion was from coronal suture to 20mm anterior, and the lateral range of it was between 15 and 35mm lateral from sagittal suture. The optimal catheter length for insertion was between 55 and 58mm from the brain surface. Ideal placement of a ventricular catheter tip was achieved in more than 90% of cases (31/34) with this technique. CONCLUSION: Tripod-guided ventricular catheter insertion is a simple and reliable method for VP shunt at any angle of head rotation. PMID- 22244254 TI - Cerebral alveolar echinococcosis: a report of two cases. PMID- 22244255 TI - Pet dogs--a transmission route for human noroviruses? AB - BACKGROUND: Human noroviruses (HuNoVs) are one of the leading causes of diarrhoeal diseases worldwide in all age groups. Virus transmission can occur via the faecal-oral route from person to person or via contaminated food, water, or surfaces. The most common NoV strains circulating among humans belong to genogroup GII. Thus far, to our knowledge, no HuNoVs have been detected in pets. OBJECTIVES: We investigated whether pet dogs could serve as carriers for HuNoVs and thereby transmit the infection to humans. STUDY DESIGN: Ninety-two faecal samples of indoor pet dogs were obtained. The main criteria for sample collection were that the dog or humans in the household had suffered from diarrhoea or vomiting. All samples were screened for HuNoV genogroups GI, GII, and GIV by real time one-step RT-PCR. RESULTS: We detected HuNoV in four faecal samples from pet dogs that had been in direct contact with symptomatic persons. Three of the positive samples contained genotype GII.4 variant 2006b or 2008 and one GII.12. All NoV-positive dogs lived in households with small children and two dogs showed mild symptoms. CONCLUSIONS: Our results suggest that HuNoVs can survive in the canine gastrointestinal tract. Whether these viruses can replicate in dogs remains unresolved, but an association of pet dogs playing a role in transmission of NoVs that infect humans is obvious. PMID- 22244256 TI - Assessment of immunovirological features in HIV related non-Hodgkin lymphoma patients and their impact on outcome. AB - BACKGROUND: Despite the era of highly active antiretroviral therapy, non-Hodgkin lymphoma (NHL) remains one of the main causes of death in HIV-infected patients, with a wide variation on the outcome. OBJECTIVES: We investigated immunological status and EBV, HHV8, HIV viral load in a group of HIV-infected patients at diagnosis of NHL to evaluate their prognostic significance. STUDY DESIGN: Eighty one consecutive HIV+ NHL patients were studied. CD4 and CD8 cell counts, HHV8 DNA, EBV DNA, HIV RNA and HIV DNA were assessed at diagnosis and at 3 months after chemotherapy initiation. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of disease free survival (DFS) and overall survival (OS) were computed according to CD4 and CD8 cell counts, EBV DNA, HIV RNA and HIV DNA. HRs were, thereafter, computed also for continuous variation of CD4, CD8 cell counts and EBV DNA. RESULTS: In the multivariate analysis, CD4<160 and CD8<590 cell/MUl and EBV DNA>=300 c/ml were independently associated to DFS (HR=2.98; 95%CI: 1.26-7.03; HR=2.65, 95%CI: 1.13-6.19; HR=4.01; 95%CI: 1.81-8.91) and OS (HR=3.32; 95%CI: 1.41-7.83; HR=4.62, 95%CI: 1.91-11.19; HR=3.11, 95%CI: 1.42-6.80). HRs for DFS and OS decreased continuously with increasing CD4 and CD8 cell counts, while they increased continuously with increasing EBV DNA levels. CONCLUSIONS: The association with survival of low CD4 and CD8 cell counts and detectable EBV viremia, measured at lymphoma's diagnosis, identified three independent prognostic biomarkers that might help in the management of NHL HIV+ patients, offering complementary information in the ascertainment of their outcome. PMID- 22244257 TI - Reproducibility of a food menu to measure energy and macronutrient intakes in a laboratory and under real-life conditions. AB - Given the limitations associated with the measurement of food intake, we aimed to determine the reliability of a food menu to measure energy intake (EI) and macronutrient intake within the laboratory and under free-living conditions. A total of eight men and eight women (age 25.74 (sd 5.9) years, BMI 23.7 (sd 2.7) kg/m2) completed three identical in-laboratory sessions (ILS) and three out-of laboratory sessions (OLS). During the ILS, participants had ad libitum access to a variety of foods, which they chose from a menu every hour, for 5 h. For the OLS, the foods were chosen from the menu at the start of the day and packed into containers to bring home. There were no significant differences in total EI (6118.6 (sd 2691.2), 6678.8 (sd 2371.3), 6489.5 (sd 2742.9) kJ; NS) between the three ILS and three OLS (6816.0 (sd 2713.2), 6553.5 (sd 2364.5), 6456.4 (sd 3066.8) kJ; NS). Significant intraclass correlations (ICC) for total energy (r 0.77, P<0.0001), carbohydrate (r 0.81, P<0.0001), dietary fat (r 0.54, P<0.0001) and protein (r 0.81, P<0.0001) intakes for the ILS and significant ICC for total energy (r 0.85, P<0.0001), carbohydrate (0.85, P<0.0001), dietary fat (0.72 P<0.0001) and protein (0.80, P<0.0001) intakes for the OLS were noted. The average within-subject CV for total EI was 18.3 (sd 10.0) and 16.1 (sd 10.3) % for the ILS and OLS, respectively, with a pleasantness rating for foods consumed of 124 (sd 14) mm out of 150 mm (83 %). Overall, the food menu produces a relatively reliable measure of EI inside and outside the laboratory. The results also underscore the difficulties in capturing a representative image of food intake given the relatively high day-to-day variation in the amount and composition of foods consumed. PMID- 22244258 TI - Beyond apoptosis: caspase regulatory mechanisms and functions in vivo. AB - The caspases, a family of cysteine proteases, function as central regulators of cell death. Recently, caspase activity and caspase substrates identified in the absence of cell death have sparked strong interest in caspase functions in nonapoptotic cellular responses; these functions suggest that caspases may be activated without inducing or before apoptosis, thus leading to the cleavage of a specific subset of substrates. This review focuses primarily on the caspase enzymatic activity. Detailed genetic analyses of caspase-deficient Caenorhabditis elegans, Drosophila, and mice have shown that caspases are essential, not only for controlling the number of cells involved in sculpting or deleting structures in developing animals, but also for dynamic, nonapoptotic cell processes, such as innate immune response, tissue regeneration, cell-fate determination, stem-cell differentiation and neural activation. Our understanding of the spatio-temporal caspase activation mechanisms has advanced, primarily through the study of Drosophila developmental processes. This review will discuss current findings regarding caspase functions in cytoskeletal modification, morphogenetic regulation of cell shape, cell migration and the production of mechanical force during embryogenesis. PMID- 22244259 TI - Evaluation of an opa gene-based nucleic acid amplification test for detection of Neisseria gonorrhoeae in urogenital samples in North India. AB - Due to the poor positive predictive value of nucleic acid amplification tests (NAATs) for gonorrhoea when applied to a low-prevalence setting, current guidelines recommend the use of supplementary polymerase chain reaction (PCR) targeting a different gene for confirmation of true positives in urogenital specimens. This study sought to standardize and evaluate performance of an in house opa gene-based PCR assay for gonorrhoea compared to assays targeting the porA pseudogene and 16S rRNA gene. Four hundred samples (300 endocervical, 100 urethral swabs) from patients attending STD clinics in New Delhi, India were used. The sensitivity, specificity, positive predictive value and negative predictive value of the opa-based PCR were 100%, 97.9%, 89.5% and 100%, respectively. In females, the use of NAATs provided enhanced diagnosis of gonorrhoea. PMID- 22244260 TI - Estimates of carbon stored in harvested wood products from the United States forest service northern region, 1906-2010. AB - BACKGROUND: Global forests capture and store significant amounts of CO2 through photosynthesis. When carbon is removed from forests through harvest, a portion of the harvested carbon is stored in wood products, often for many decades. The United States Forest Service (USFS) and other agencies are interested in accurately accounting for carbon flux associated with harvested wood products (HWP) to meet greenhouse gas monitoring commitments and climate change adaptation and mitigation objectives. This paper uses the Intergovernmental Panel on Climate Change (IPCC) production accounting approach and the California Forest Project Protocol (CFPP) to estimate HWP carbon storage from 1906 to 2010 for the USFS Northern Region, which includes forests in northern Idaho, Montana, South Dakota, and eastern Washington. RESULTS: Based on the IPCC approach, carbon stocks in the HWP pool were increasing at one million megagrams of carbon (MgC) per year in the mid 1960s, with peak cumulative storage of 28 million MgC occurring in 1995. Net positive flux into the HWP pool over this period is primarily attributable to high harvest levels in the mid twentieth century. Harvest levels declined after 1970, resulting in less carbon entering the HWP pool. Since 1995, emissions from HWP at solid waste disposal sites have exceeded additions from harvesting, resulting in a decline in the total amount of carbon stored in the HWP pool. The CFPP approach shows a similar trend, with 100-year average carbon storage for each annual Northern Region harvest peaking in 1969 at 937,900 MgC, and fluctuating between 84,000 and 150,000 MgC over the last decade. CONCLUSIONS: The Northern Region HWP pool is now in a period of negative net annual stock change because the decay of products harvested between 1906 and 2010 exceeds additions of carbon to the HWP pool through harvest. However, total forest carbon includes both HWP and ecosystem carbon, which may have increased over the study period. Though our emphasis is on the Northern Region, we provide a framework by which the IPCC and CFPP methods can be applied broadly at sub-national scales to other regions, land management units, or firms. PMID- 22244261 TI - A critical re-evaluation of the regression model specification in the US D1 EQ-5D value function. AB - BACKGROUND: The EQ-5D is a generic health-related quality of life instrument (five dimensions with three levels, 243 health states), used extensively in cost utility/cost-effectiveness analyses. EQ-5D health states are assigned values on a scale anchored in perfect health (1) and death (0).The dominant procedure for defining values for EQ-5D health states involves regression modeling. These regression models have typically included a constant term, interpreted as the utility loss associated with any movement away from perfect health. The authors of the United States EQ-5D valuation study replaced this constant with a variable, D1, which corresponds to the number of impaired dimensions beyond the first. The aim of this study was to illustrate how the use of the D1 variable in place of a constant is problematic. METHODS: We compared the original D1 regression model with a mathematically equivalent model with a constant term. Comparisons included implications for the magnitude and statistical significance of the coefficients, multicollinearity (variance inflation factors, or VIFs), number of calculation steps needed to determine tariff values, and consequences for tariff interpretation. RESULTS: Using the D1 variable in place of a constant shifted all dummy variable coefficients away from zero by the value of the constant, greatly increased the multicollinearity of the model (maximum VIF of 113.2 vs. 21.2), and increased the mean number of calculation steps required to determine health state values. DISCUSSION: Using the D1 variable in place of a constant constitutes an unnecessary complication of the model, obscures the fact that at least two of the main effect dummy variables are statistically nonsignificant, and complicates and biases interpretation of the tariff algorithm. PMID- 22244264 TI - Current management of short bowel syndrome. PMID- 22244265 TI - Radical prostatectomy: positive surgical margins matter. AB - OBJECTIVE: A positive surgical margin (PSM) in the radical prostatectomy (RP) specimen is associated with biochemical recurrence (BCR) and the need for adjuvant radiation therapy, and is a surrogate for surgical quality. We review the available data describing the identification, anatomy, and management of PSM after RP. METHODS: A PubMed search (using English language as a filter) was performed to identify factors affecting PSMs and their management. RESULTS: PSMs are associated with an increased likelihood of BCR after RP. The most common location for a PSM is the apex, followed by the posterolateral edge of the prostate. The risk of recurrence in a patient with a PSM is associated with the location, length, and Gleason score of the PSM. The management of a patient with a PSM remains controversial, with some recommending adjuvant radiation therapy for all PSMs and others suggesting only salvage radiation therapy for men who experience BCR. CONCLUSIONS: PSMs are associated with an increased likelihood of BCR and often result in initiation of adjuvant treatment. Therefore, the goal of surgery should be to minimize the likelihood of a PSM. PMID- 22244266 TI - Binge eating, purging and non-purging compensatory behaviours decrease from adolescence to adulthood: A population-based, longitudinal study. AB - BACKGROUND: Subclinical forms of eating disorders (ED) are highly prevalent, but relatively little is known about age trends, gender differences and distinctions among symptoms. This study investigates age trends and gender difference in binge eating, purging and non-purging compensatory behaviours (CB) and the relationship of such behaviours to psychosocial problems. METHODS: Data from the national representative longitudinal study "Young in Norway" (ages 14-34 years) were analysed using chi(2) tests, logistic random intercept models and analyses of covariance. RESULTS: For both genders, a decrease was found in the prevalence of CB from age 14-16 years to 23 years and over. For binging, however, a significant decrease was found only for females, whose binge eating also declined more markedly over time than did males'. A significant gender difference was detected for purging, with females at higher risk. Purging was related to particularly serious symptoms of psychosocial problems: Those who purged had significantly higher levels of appearance dissatisfaction, anxiety and depressive symptoms, alcohol consumption, self-concept instability and loneliness than those with symptoms of other forms of disordered eating. CONCLUSIONS: Individuals affected by purging need to be targeted as a high-risk group. The distinction in severity among the subclinical ED may indicate the need for the reformulation of the eating disorder not otherwise specified category in the Diagnostic and Statistical Manual of Mental Disorders-V. PMID- 22244267 TI - Does innovation in obesity drugs affect stock markets? An event study analysis. AB - OBJECTIVE: This study empirically analyzes the effects of public information about the pharmaceutical R&D process on the market valuation of the sponsoring firm. We examined the market's response to scientific news and regulatory decisions about an antiobesity drug, rimonabant, and the effects on the sponsoring company (Sanofi-Aventis) and its incumbent competitors (Abbott and Roche). METHODS: Event study methodology was used to test the null hypothesis of no market response. We covered the full life cycle of rimonabant (1994-2008), using a data set of daily closing price and volume. RESULTS: The results suggest that scientific news in the initial stages of the drug R&D process (i.e., drug discovery, preclinical and clinical trials) had no significant effects. However, news related to regulatory decisions, such as recall or safety warning, had significant negative effects on the company's market value. No spillover/contagion effects on competitor firms were detected. CONCLUSION: Market reactions occur at the time when the regulator takes decisions about drugs. Scientific news, even those of high-impact, may pass unnoticed. PMID- 22244268 TI - Relationship between physician and industry in Aragon (Spain). AB - OBJECTIVE: To describe the relationship between industry and physicians and to analyze the physician characteristics associated with the probability of receiving benefits from industry in Aragon (Spain). METHODS: We carried out an observational, cross-sectional study in which Aragonese physicians (north-east region in Spain) from public and private settings completed an anonymous questionnaire on a web page between June and November 2008. Visits/month with industry, samples, gifts, reimbursements and payments were used as dependant variables in the regression analyses. Year of medical license, specialty, work setting, time spent on direct care, articles read/month and being a resident's tutor were used as independent variables. RESULTS: A total of 659 questionnaires were considered valid for the analysis. Overall, 87% (n=573) of the respondents reported they had received some benefit in the previous year and 90.1% (n=593) reported having held meetings with industry representatives monthly. Non-clinical specialists received fewer gifts (odds ratio [OR]=0.38; 95% confidence interval [95%CI]: 0.18-0.77), reimbursements (OR=0.14; 95%CI: 0.06-0.35) and payments (OR=0.30; 95%CI: 0.13-0.74) than their clinical colleagues. The probability of receiving reimbursements (OR=0.37; 95%CI: 0.15-0.89) and payments (OR=0.39; 95%CI: 0.20-0.77) was lower in primary care physicians. CONCLUSIONS: This study, performed in a sample of physicians from a southern European region, demonstrates differences in the intensity of the physician-industry relationship depending on physician specialty and work setting. These results provide important information for improving transparency and for future research on the appropriateness and efficiency of prescription in Spain and other countries with similar health systems. PMID- 22244269 TI - [Gender inequalities in occupational health in Spain]. AB - OBJECTIVES: To analyze gender inequalities in employment and working conditions, the work-life balance, and work-related health problems in a sample of the employed population in Spain in 2007, taking into account social class and the economic sector. METHODS: Gender inequalities were analyzed by applying 25 indicators to the 11,054 workers interviewed for the VI edition of the National Working Conditions Survey. Multivariate logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CI), stratifying by occupational social class and economic sector. RESULTS: More women than men worked without a contract (OR=1.83; 95% CI: 1.51-2.21) and under high-effort/low reward conditions (1.14:1.05-1.25). Women also experienced more sexual harassment (2.85:1.75-4.62), discrimination (1.60:1.26-2.03) and musculoskeletal pain (1.38:1.19-1.59). More men than women carried out shift work (0.86:0.79-0.94), with high noise levels (0.34:0.30-0.40), and high physical demands (0.58:0.54 0.63). Men also suffered more injuries due to occupational accidents (0.67:0.59 0.76). Women white-collar-workers were more likely than their male counterparts to have a temporary contract (1.34:1.09-1.63), be exposed to psychosocial hazards and discrimination (2.47:1.49-4.09) and have occupational diseases (1.91:1.28 2.83). Gender inequalities were higher in the industry sector. CONCLUSIONS: There are substantial gender inequalities in employment, working conditions, and work related health problems in Spain. These gender inequalities are influenced by social class and the economic sector, and should be considered in the design of public policies in occupational health. PMID- 22244270 TI - Transcriptomic analysis of Chinese bayberry (Myrica rubra) fruit development and ripening using RNA-Seq. AB - BACKGROUND: Chinese bayberry (Myrica rubra Sieb. and Zucc.) is an important subtropical fruit crop and an ideal species for fruit quality research due to the rapid and substantial changes that occur during development and ripening, including changes in fruit color and taste. However, research at the molecular level is limited by a lack of sequence data. The present study was designed to obtain transcript sequence data and examine gene expression in bayberry developing fruit based on RNA-Seq and bioinformatic analysis, to provide a foundation for understanding the molecular mechanisms controlling fruit quality changes during ripening. RESULTS: RNA-Seq generated 1.92 G raw data, which was then de novo assembled into 41,239 UniGenes with a mean length of 531 bp. Approximately 80% of the UniGenes (32,805) were annotated against public protein databases, and coding sequences (CDS) of 31,665 UniGenes were determined. Over 3,600 UniGenes were differentially expressed during fruit ripening, with 826 up regulated and 1,407 down-regulated. GO comparisons between the UniGenes of these two types and interactive pathways (Ipath) analysis found that energy-related metabolism was enhanced, and catalytic activity was increased. All genes involved in anthocyanin biosynthesis were up-regulated during the fruit ripening processes, concurrent with color change. Important changes in carbohydrate and acid metabolism in the ripening fruit are likely associated with expression of sucrose phosphate synthase (SPS) and glutamate decarboxylase (GAD). CONCLUSIONS: Mass sequence data of Chinese bayberry was obtained and the expression profiles were examined during fruit ripening. The UniGenes were annotated, providing a platform for functional genomic research with this species. Using pathway mapping and expression profiles, the molecular mechanisms for changes in fruit color and taste during ripening were examined. This provides a reference for the study of complicated metabolism in non-model perennial species. PMID- 22244271 TI - Trimethoprim: kinetic and mechanistic considerations in photochemical environmental fate and AOP treatment. AB - Trimethoprim (TMP), a bacteriostatic antibiotic, has recently been detected in wastewater and surface waters. In this study the sunlight mediated photochemical fate, and treatment using advanced oxidation and reduction (free radical) processes, have been investigated with respect to their effect on TMP. Photochemical fate, in the presence of humic acid, and advanced oxidation treatment both involve the hydroxyl radical (OH) as one of the reactive species of interest. Another reactive oxygen species, singlet oxygen (1O2), may also be important in the photochemical fate of TMP. The bimolecular reaction rate constants of TMP with 1O2 and OH were evaluated to be (3.2+/-0.2)*10(6) M(-1) s( 1) and 8.66*10(9) M(-1) s(-1), respectively. The reaction kinetics for the sub structural moieties of TMP, 1,2,3-trimethoxybenzene (TMBz) and 2,4 diaminoprimidine (DAP), was evaluated to facilitate an understanding of the loss mechanisms. For TMBz and DAP the reaction rate constants with 1O2 were <1.0*10(4) and (3.0+/-0.1)*10(6) M(-1) s(-1), while with OH they were 8.12*10(9) and 1.64*10(9) M(-1) s(-1), respectively. The data suggests that the 1O2 attacks the DAP and the OH radical attacks the TMBz moiety. However, for TMP, 1O2 and OH reactions accounted for only ~19% and ~6%, of its total photodegradation, respectively. Therefore, the reaction of TMP with excited state natural organic matter is postulated as a significant degradation pathway for the loss of TMP in sunlit waters containing natural organic matter. There was no effect of pH on the direct or indirect photolysis of TMP. To complete the study for reductive treatment processes, the solvated electron reaction rates for the destruction of TMP, TMBz and DAP were also evaluated. The absolute bimolecular reaction rates obtained were, (13.6+/-0.01)*10(9), (6.36+/-0.11)*10(7) and (10.1+/-0.01)*10(9) M(-1) s(-1), respectively. PMID- 22244272 TI - Fate of N-nitrosodimethylamine in recycled water after recharge into anaerobic aquifer. AB - Laboratory and field experiments were undertaken to assess the fate of N nitrosodimethylamine (NDMA) in aerobic recycled water that was recharged into a deep anaerobic pyritic aquifer, as part of a managed aquifer recharge (MAR) strategy. Laboratory studies demonstrated a high mobility of NDMA in the Leederville aquifer system with a retardation coefficient of 1.1. Anaerobic degradation column and (14)C-NDMA microcosm studies showed that anaerobic conditions of the aquifer provided a suitable environment for the biodegradation of NDMA with first-order kinetics. At microgram per litre concentrations, inhibition of biodegradation was observed with degradation half-lives (260+/-20 days) up to an order of magnitude greater than at nanogram per litre concentrations (25-150 days), which are more typical of environmental concentrations. No threshold effects were observed at the lower ng L(-1) concentrations with NDMA concentrations reduced from 560 ng L(-1) to <6 ng L(-1) over a 42 day 14C-NDMA aerobic microcosm experiment. Aerobic (14)C-NDMA microcosm studies were also undertaken to assess potential aerobic degradation, likely to occur close to the recharge bore. These microcosm experiments showed a faster degradation rate than anaerobic microcosms, with a degradation half-life of 8+/-2 days, after a lag period of approximately 10 days. Results from a MAR field trial recharging the Leederville aquifer with aerobic recycled water showed that NDMA concentrations reduced from 2.5+/-1.0 ng L(-1) to 1.3+/-0.4 ng L(-1) between the recharge bore and a monitoring location 20 m down gradient (an estimated aquifer residence time of 10 days), consistent with data from the aerobic microcosm experiment. Further down gradient, in the anaerobic zone of the aquifer, NDMA degradation could not be assessed, as NDMA concentrations were too close to their analytical detection limit (<1 ng L(-1)). PMID- 22244273 TI - A field study to evaluate runoff quality from green roofs. AB - Green (vegetated) roofs are emerging as practical strategies to improve the environmental quality of cities. However, the impact of green roofs on the storm water quality remains a topic of concern to city planners and environmental policy makers. This study investigated whether green roofs act as a source or a sink of various metals (Na, K, Ca, Mg, Al, Fe, Cu, Cd, Pb, Zn, Mn, Cr, Ni, Li and Co), inorganic anions (NO3-, NO2-, PO4(3-), SO4(2-), Cl-, F- and Br-) and cation (NH4+). A series of green roof assemblies were constructed. Four different real rain events and several artificial rain events were considered for the study. Results showed that concentrations of most of the chemical components in runoff were highest during the beginning of rain events and subsided in the subsequent rain events. Some of the important components present in the runoff include Na, K, Ca, Mg, Li, Fe, Al, Cu, NO3-, PO4(3-) and SO4(2-). However, the concentration of these chemical components in the roof runoff strongly depends on the nature of substrates used in the green roof and the volume of rain. Based on the USEPA standards for freshwater quality, we conclude that the green roof used in this study is reasonably effective except that the runoff contains significant amounts of NO3- and PO4(3-). PMID- 22244274 TI - Ultra-short courses of adjuvant breast radiotherapy: promised land or primrose path? PMID- 22244275 TI - Postradiotherapy neck dissection: an obsolete treatment paradigm? PMID- 22244276 TI - Response to "Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy." (Int J Radiat Oncol Biol Phys 2011;80:398-402). PMID- 22244279 TI - Response to "The correlation of osteoradionecrosis and dental events with dosimetric parameters in intensity-modulated radiation therapy (IMRT) for head and-neck cancer." (Int J Radiat Oncol Biol Phys 2011;81:e207-e213.). PMID- 22244280 TI - Stereotactic radiotherapy of primary lung cancer and other targets: results of consultant meeting of the International Atomic Energy Agency (Int J Radiat Oncol Biol Phys 2011;79:660-669). PMID- 22244284 TI - Treatment for pathologic stage I lung cancer--are models reliable? PMID- 22244286 TI - Indian and United States paramedic students: comparison of examination performance for the American Heart Association Advanced Cardiovascular Life Support (ACLS) training. AB - BACKGROUND: The American Heart Association (AHA) Advanced Cardiovascular Life Support (ACLS) course is taught worldwide. The ACLS course is designed for consistency, regardless of location; to our knowledge, no previous study has compared the cognitive performance of international ACLS students to those in the United States (US). STUDY OBJECTIVES: As international health educational initiatives continue to expand, an assessment of their efficacy is essential. This study assesses the AHA ACLS curriculum in an international setting by comparing performance of a cohort of US and Indian paramedic students. METHODS: First-year paramedic students at the Emergency Management and Research Institute, Hyderabad, India, and a cohort of first-year paramedic students from the United States comprised the study population. All study participants had successfully completed the standard 2-day ACLS course, taught in English. Each student was given a 40-question standardized AHA multiple-choice examination. Examination performance was calculated and compared for statistical significance. RESULTS: There were 117 Indian paramedic students and 43 US paramedic students enrolled in the study. The average score was 86% (+/- 11%) for the Indian students and 87% (+/- 6%) for the US students. The difference between the average examination scores was not statistically significant in an independent means t-test (p=0.508) and a Wilcoxon test (p=0.242). CONCLUSION: Indian paramedic students demonstrated excellent ACLS cognitive comprehension and performed at a level equivalent to their US counterparts on an AHA ACLS written examination. Based on the study results, the AHA ACLS course proved effective in an international setting despite being taught in a non-native language. PMID- 22244287 TI - Inter-rater reliability of sonographic measurements of the inferior vena cava. AB - BACKGROUND: Bedside ultrasound is emerging as a useful tool in the assessment of intravascular volume status by examining measurements of the inferior vena cava (IVC). Many previous studies do not fully describe their scanning protocol. OBJECTIVES: The objective of this study was to evaluate which of three commonly reported IVC scanning methods demonstrates the best inter-rater reliability. METHODS: Three physicians visualized the IVC in three common views and utilized M mode to measure the maximal and minimal diameter during quiet respiration. Pairwise correlation coefficients were determined using Pearson product-moment correlation. RESULTS: The most reliable pair of measurements (inspiratory and expiratory) was found to be using the anterior midaxillary line longitudinal view with a Kappa value for both at 0.692. CONCLUSION: Imaging with the anterior midaxillary longitudinal approach using the liver as an acoustic window provides the best inter-rater reliability when measuring the IVC. Our findings demonstrate that IVC measurements differ based on anatomic location. PMID- 22244288 TI - Implementation of transvaginal ultrasound in an emergency department residency program: an analysis of resident interpretation. AB - BACKGROUND: Emergency physicians are increasingly performing transvaginal ultrasound (TVUS) to rule out ectopic pregnancy. However, little is known about appropriate educational pathways to train emergency medicine residents in TVUS. STUDY OBJECTIVES: To evaluate the ability of Emergency Medicine (EM) residents who underwent a training program in TVUS to detect the presence or absence of an intrauterine pregnancy (IUP) in patients of < 13 weeks gestation with vaginal bleeding or abdominal pain, as compared to the final interpretation of each study as determined by the Emergency Department (ED) Director of Ultrasound. METHODS: This was a prospective, observational study in a single residency program. Training included a lecture, competency examination, and 10 supervised TVUSs. The EM residents then performed TVUSs with the goal of determining the presence or absence of an IUP without input from an attending physician. Correlation with the ED Director of Ultrasound was assessed for the cohort, and stratified by year of training. RESULTS: There were 22 residents who performed 75 TVUSs over 17 months. Correlation with the ED Director of Ultrasound was 93.3%. Differences in correlation with the ED Director of Ultrasound were noted when compared by year of training: post-graduate year (PGY)-3 (93.3%), PGY-2 (92.1%), and PGY-1 (100%); p < 0.001. CONCLUSION: Residents were able to perform TVUSs to determine the presence or absence of an IUP in patients in whom the diagnosis of ectopic pregnancy was being considered with a high degree of correlation with the ED Director of Ultrasound after a brief training program. Correlation with the ED director of ultrasound was influenced by year of training. PMID- 22244289 TI - Adult intussusception: presentation, management, and outcomes of 148 patients. AB - BACKGROUND: Intussusception is a predominantly pediatric diagnosis that is not well characterized among adults. Undiagnosed cases can result in significant morbidity, making early recognition important for clinicians. STUDY OBJECTIVES: We describe the presentation, clinical management, disposition, and outcome of adult patients diagnosed with intussusception during a 13-year period. METHODS: A retrospective study of consecutive adult patients diagnosed with intussusception at a tertiary academic center was carried out from 1996 to 2008. Cases were identified using International Classification of Diseases, 9(th) Revision codes and a document search engine. Data were abstracted in duplicate by two independent authors. RESULTS: Among 148 patients included in the study, the most common symptoms at presentation were abdominal pain (72%), nausea (49%), and vomiting (36%). Twenty percent were asymptomatic. Sixty percent of cases had an identifiable lead point. Patients presenting to the emergency department (ED) (31%) had higher rates of abdominal pain (relative risk [RR] 5.7) and vomiting (RR 3.4), and were more likely to undergo surgical intervention (RR 1.8) than patients diagnosed elsewhere. There were 77 patients who underwent surgery within 1 month; patients presenting with abdominal pain (RR 2.2), nausea (RR 1.7), vomiting (RR 1.4), and bloody stool (RR 1.9) were more likely to undergo surgery. CONCLUSIONS: Adult intussusception commonly presents with abdominal pain, nausea, and vomiting; however, approximately 20% of cases are asymptomatic and seem to be diagnosed by incidental radiologic findings. Patients presenting to an ED with intussusception due to a mass as a lead point or in an ileocolonic location are likely to undergo surgical intervention. PMID- 22244290 TI - Oral thromboprophylaxis in pelvic trauma: a standardized protocol. AB - BACKGROUND: Thromboprophylaxis for deep vein thrombosis (DVT) after lower extremity trauma could include rivaroxaban, an oral medication that does not need laboratory monitoring. OBJECTIVE: To assess rivaroxaban's efficacy in preventing DVTs after pelvic trauma compared to its historical incidence. MATERIALS AND METHODS: All patients admitted with pelvic fractures in a 12-month period followed a standardized thromboprophylaxis protocol: 1) rivaroxaban 10 mg/day within 24 h of injury or upon hemodynamic stability; 2) pre-operative, post operative, and 30-day extremity ultrasound; 3) ventilation-perfusion scintigraphy for clinical signs of pulmonary embolus; and 4) a 45-, 90-, and 120-day re evaluation. Rivaroxaban administration ceased the day of surgery and restarted 12 h post-operatively or upon hemodynamic stability, continuing for 30 days. Excluded patients had severe neurological or hepatosplenic injuries, heparin hypersensitivity, or hemodynamic instability. RESULTS: Of 113 patients assessed, 84 patients (66 males), average age 46.6 years (range 19-69 years), were included. They had isolated pelvic trauma (n = 37), associated lower limb injuries (n = 47), average Injury Severity Score 21.4 (range 16-50), and average Glasgow Coma Scale score 13.6 (range 9-15). Patients receiving thromboprophylaxis soon after their fracture (n = 64) had a lower incidence of DVT than those receiving delayed thromboprophylaxis (n = 20) (p = 0.02). One patient (1.2%) died from a pulmonary embolus; 13 had asymptomatic below-the-knee DVTs. Rivaroxaban did not increase intra- or post-operative bleeding in surgical wounds. CONCLUSIONS: DVT incidence after pelvic fractures is reduced by administering antithrombotics within 24 h of injury or, if the patient is hemodynamically unstable, 24 h after stabilization. Rivaroxaban is a safe and effective method of providing this thromboprophylaxis. PMID- 22244291 TI - "Lipid rescue" for tricyclic antidepressant cardiotoxicity. AB - BACKGROUND: Tricyclic antidepressant (TCA) toxicity results predominantly from myocardial sodium-channel blockade. Subsequent ventricular dysrhythmias, myocardial depression, and hypotension cause cardiovascular collapse. Animal studies have demonstrated the effectiveness of intravenous lipid-emulsion in treating TCA cardiotoxicity. CASE REPORT: We report a case of dothiepin (tricyclic antidepressant) overdose causing refractory cardiovascular collapse, which seemed to be successfully reversed with lipid-emulsion therapy (Intralipid((r)); Fresenius, Cheshire, UK). CONCLUSIONS: Lipid emulsions are a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Research is required into the role of lipid emulsion in the management of poisoning by oral lipophilic agents. PMID- 22244292 TI - Hidden attraction: a menacing meal of magnets and batteries. AB - BACKGROUND: Magnet and button battery ingestions are increasingly common, and can result in significant morbidity. Timely identification of hazardous foreign body ingestions can be difficult in non-verbal and non-disclosing children. OBJECTIVES: We aim to present a case that demonstrates some of the challenges around identifying and correctly locating magnets and batteries, and the importance of prompt identification and removal. CASE REPORT: We describe an older child with the covert ingestion of multiple magnets and batteries, with magnets that attracted across the stomach and a loop of jejunum. Mild symptoms and signs resulted in a delayed diagnosis and serious consequences. Radiographs suggested a gastric location of the foreign bodies. CONCLUSION: Health care workers should consider the possibility of battery or magnet ingestions in children with vomiting and abdominal pain, even when well-appearing. Like esophageal batteries, multiple gastrointestinal magnets and combined magnet battery ingestions can cause significant morbidity, and prompt identification is important. Providers should ask verbal children for ingestion histories, and consider radiographs when symptoms are atypical or persistent. Like esophageal batteries, gastrointestinal magnet-battery ingestions should be removed promptly to prevent complications. Caregivers should supervise or limit the use of toys that include magnets and batteries. PMID- 22244293 TI - Thallium-201 for cardiac stress tests: residual radioactivity worries patients and security. AB - BACKGROUND: A 47-year-old man presented to the Emergency Department (ED) in duress and stated he was "highly radioactive." There were no reports of nuclear disasters, spills, or mishaps in the local area. OBJECTIVES: This report discusses the potential for thallium-201 (Tl-201) patients to activate passive radiation alarms days to weeks after nuclear stress tests, even while shielded inside industrial vehicles away from sensors. Characteristics of Tl-201, as used for medical imaging, are described. CASE REPORT: This patient was twice detained by Homeland Security Agents and searched after he activated radiation detectors at a seaport security checkpoint. Security agents deemed him not to be a threat, but they expressed concern regarding his health and level of personal radioactivity. The patient was subsequently barred from his job and sent to the hospital. Tl-201 is a widely used radioisotope for medical imaging. The radioactive half-life of Tl-201 is 73.1h, however, reported periods of extended personal radiation have been seen as far out as 61 days post-administration. CONCLUSION: This case describes an anxious, but otherwise asymptomatic patient presenting to the ED with detection of low-level personal radiation. Documentation should be provided to and carried by individuals receiving radionuclides for a minimum of five to six half-lives of the longest-lasting isotope provided. Patients receiving Tl-201 should understand the potential for security issues; reducing probable tense moments, confusion, and anxiety to themselves, their employers, security officials, and ED staff. PMID- 22244294 TI - Tension viscerothorax after blunt abdominal trauma: a case report and review of the literature. AB - BACKGROUND: Tension viscerothorax is herniation of abdominal viscera into the thorax. Tension viscerothorax can simulate tension pneumothorax. Immediate decompression with a nasogastric tube is required for hemodynamic stabilization. OBJECTIVE: A case of tension viscerothorax is reported along with a review of the literature to highlight this rare complication of blunt abdominal trauma, and to emphasize the importance of nasogastric tube decompression in tension viscerothorax. CASE REPORT: A 10-year-old boy with a remote history of trauma related to a motor vehicle crash was brought into the Emergency Department with a 3-day history of vomiting, epigastric pain, and dyspnea. By physical examination and chest X-ray study, tension gastrothorax was diagnosed. Nasogastric tube placement was difficult and delayed, and the patient deteriorated into cardiac arrest, but after successful cardiopulmonary resuscitation and nasogastric tube insertion, the patient was stabilized. Laparotomy was performed and primary repair of a ruptured diaphragm was done. The patient made an uneventful recovery. CONCLUSION: Acute tension viscerothorax should be considered in the differential diagnosis of tension pneumothorax, and its initial resuscitation should include nasogastric tube insertion for immediate decompression. PMID- 22244295 TI - Impact of physician-assisted triage on timing of antibiotic delivery in patients admitted to the hospital with community-acquired pneumonia (CAP). AB - BACKGROUND: Time to antibiotic delivery in patients with diagnosis of pneumonia is a publicly reported quality measure. OBJECTIVE: We aim to describe the impact of emergency department (ED) physician-assisted triage (PAT) on The Joint Commission (TJC) and Centers for Medicare and Medicaid Services (CMS) pneumonia core quality measures of timing to antibiotic delivery. METHODS: Retrospective case series studies of patients admitted to the hospital through the ED with diagnosis of community-acquired pneumonia were identified over a period of 48 months. Patients were included in the study if they met TJC/CMS PN-5 (antibiotic timing) criteria. We compared antibiotic delivery timing before and after implementation of PAT in moderate-acuity patients using Wilcoxon rank sum tests. A linear regression analysis was done to account for age, sex, ED volume, and acuity level. RESULTS: A total of 659 patients were identified: 497 patients and 162 patients enrolled pre- and post-implementation of a PAT, respectively. The median antibiotic delivery times for moderate-acuity patients during open hours of operation of PAT were 180min (pre) and 195min (post), p=0.027; this was unchanged when ED volume, age, sex, and acuity level were accounted for. A total of 43 patients (9%) and 13 patients (8%) failed to receive antibiotics within 6h of ED presentation before and after implementation of PAT, respectively. CONCLUSION: In this study, implementation of PAT did not result in overall decrease in antibiotic delivery time in patients admitted to the hospital with CAP. We postulate several explanations for this delay in antibiotic delivery time. PMID- 22244296 TI - Intramural esophageal hematoma: an unusual complication of endotracheal intubation. PMID- 22244297 TI - Introduction: the cognitive neuroscience of thought. PMID- 22244298 TI - Novel polymer-layered silicate intercalated composite beads for drug delivery. AB - Core-shell structured beads were fabricated from chitosan (CS)/organic rectorite (OREC) composites and alginate (ALG) in Ca(2+) aqueous solutions with different mixing ratios by a cross-linking process. The mechanical properties, surface and internal morphology, intercalation structure between CS and OREC, porosity and pore size distribution, bovine serum albumin (BSA) encapsulation efficiency and its controllable release ability were investigated. Optical microscopy, scanning electron microscopy and transmission electron microscopy showed that the core shell structure was generated in the beads. The Fourier transform infrared spectra results implied the presence of electrostatic and hydrogen-bonding interaction between CS and OREC. The energy-dispersive X-ray and X-ray photoelectron spectroscopy results verified the existence of OREC in the beads. Small-angle X-ray diffraction results confirmed that the interlayer of OREC was intercalated by CS chains successfully, and the interlayer distance increased from 2.42 to 2.60 nm. The BSA encapsulation and release test indicated that the beads released the drug continuously. OREC could not only avoid the burst release phenomenon in the first period but also improve the utilization efficacy of the drug. When the ratio of CS/OREC was 6:1 and CS-OREC/ALG was 2:1, the beads were better for drug released in stomach, and when CS/OREC was 12:1 and CS-OREC/ALG was 2:1, the beads were better for drug released in stomach than in intestine. PMID- 22244299 TI - Chitosan-solid lipid nanoparticles as carriers for topical delivery of tretinoin. AB - Tretinoin (TRE) or all-trans retinoic acid is employed in the topical treatment of various skin diseases including acne and psoriasis. However, its use is strongly limited by side effects and high chemical instability. TRE encapsulation in nanostructured systems reduces these problems. Chitosan is a biopolymer that exhibits a number of interesting properties such as bioadhesion and antibacterial activity. The aim of this work was to prepare and characterize solid lipid nanoparticles (SLN) containing TRE, with and without addition of chitosan, to assess their in vitro cytotoxicity in keratinocytes and to evaluate their antibacterial activity against bacteria related to acne. SLN without (SLN-TRE) and with (SLN-chitosan-TRE) chitosan were prepared by hot high pressure homogenization. The hydrodynamic mean diameter and zeta potential were 162.7+/ 1.4 nm and -31.9+/-2.0 mV for SLN-TRE, and 284.8+/-15.0 nm and 55.9+/-3.1 mV for SLN-chitosan-TRE. The SLN-chitosan-TRE exhibited high encapsulation efficiency, high physical stability in the tested period (one year), were not cytotoxic to keratinocytes and showed high antibacterial activity against P. acnes and S. aureus. Therefore chitosan-SLN can be good candidates to encapsulate TRE and to increase its therapeutic efficacy in the topical treatment of acne. PMID- 22244300 TI - Surface modification of poly(propylene carbonate) by aminolysis and layer-by layer assembly for enhanced cytocompatibility. AB - Poly(propylene carbonate) (PPC) is a biodegradable polymer with desirable mechanical properties for bone and cartilage repair. However, the poor biocompatibility impedes its applications in tissue engineering. The aim of this study was to evaluate the effect of surface modification of PPC on the improvement of its cytocompatibility. The combination of aminolysis and layer-by layer (LBL) assembly techniques was used to modify the PPC surface. The results of ATR-FTIR measurement demonstrated that PPC was aminolyzed by polyethylenimine (PEI) at specific reaction conditions and the degree of aminolyzation was quantitatively determined by ninhydrin method. Positively charged PEI and negatively charged gelatin were alternatively deposited on the aminolyzed PPC membranes at pH 7.4, which formed polyelectrolyte multilayers surface with gelatin as the outermost layer. The presence of amino groups on the aminolyzed PPC and gelatin on the multilayers had significant impact on enhancing the hydrophilicity of PPC. Fibroblast and primary human osteoblasts (HOBs) were used to assess the cytocompatibility of PPC. The deposition of PEI and gelatin bilayers on PPC remarkably promoted both fibroblast and HOBs cell attachment, spreading and growth. In particular, the osteogenic gene expression of HOBs cultured on the multilayers modified PPC was substantially increased. The aminolysis followed by LBL assembly is a convenient and cost effective technique for enhancing cell attachment and proliferation. The product has high potential for musculoskeletal tissue engineering applications due to its desirable mechanical strength and tunable cytocompatibility. PMID- 22244301 TI - The influence of powder properties on the imbibation rate. AB - Mixing of powders into liquids is a common unit operation. Mixing can be divided into several steps, imbibation of the powder into the liquid being the first. Under some circumstances, such as when the powder has poor wetting properties, imbibation can be the rate-determining step. The effects of different powder properties on the imbibation rate were evaluated using an experimental imbibation model based on the imbibing process employed in an industrial powder-in-liquid mixer. A multivariate analysis of the results suggests that bulk density and capillary penetration rate, and to some extent cohesivity, play an important role in determining the powder imbibation rate. The results also suggest that the capillary penetration rate is increasing on a large particle radius, slow solubilisation of the particles and a low ability of the particles to generate viscosity. PMID- 22244302 TI - New pathway to prepare gold nanoparticles and their applications in catalysis and surface-enhanced Raman scattering. AB - As shown in the literature, additional energies are necessary for the reduction of positively charged noble metal ions to prepare metal nanoparticles (NPs). In this work, we report a new green pathway to prepare Au NPs in neutral 0.1M NaCl aqueous solutions from bulk Au substrates without addition of any stabilizer and reductant just via aid of natural chitosan (Ch) at room temperature. Au- and Ch containing complexes in aqueous solution were electrochemically prepared. The role of Ch is just an intermediate to perform electron transfer with Au NPs. The stability of these prepared Au NPs is well maintained by Au NPs themselves with slightly positively charged Au remained on the surface of Au NPs. The particle size of prepared spherical Au (111) NPs is ca. 15 nm in diameter. Moreover, increasing the pH of preparation solutions can be contributive to preparing concentrated Au NPs in solutions. The prepared Au NPs are surface-enhanced Raman scattering (SERS)-active for probe molecules of Rhodamine 6G. They also demonstrate significantly catalytic activity for decomposition of acetaldehyde in rice wine. PMID- 22244303 TI - Impact of comorbidities and surgery on health related transitions in pancreatic cancer admissions: a multi state model. AB - AIM: Pancreatic cancer is one of the least common tumors, nevertheless it is one of the most lethal. This lethality is mainly due to the fact that the vast majority of patients are diagnosed in an advanced stage. The objective of this work is investigate how different covariates affect the transition to death after a first admission due to pancreatic cancer. METHODS: We analyze the impact of different factors on health related transitions after a first hospital admission related to pancreatic cancer based on a multi state model. RESULTS: Transitions of interest include the transition to death (i.e. survival time), but also the time between a first admission and discharge or between discharge and readmission. We consider comorbidities, the type of admission, and especially the performance of pancreas surgery as covariates with a potential effect on the transition intensities. CONCLUSION: The multi state model allows for a very detailed analysis since all covariate effects may change depending on the current state of the patient. PMID- 22244305 TI - Effects of pre- and postnatal protein malnutrition in hypoxic-ischemic rats. AB - Neonatal hypoxic-ischemic encephalopathy (HI) is a major cause of nervous system damage and neurological morbidity. Perinatal malnutrition affects morphological, biochemical and behavioral aspects of neural development, including pathophysiological cascades of cell death triggered by ischemic events, so modifying resulting brain damage. Female Wistar rats were subjected to protein restriction during pregnancy and lactation (control group: 25% soybean protein; malnourished group: 7%). Seven days after delivery (PND7), their offspring were submitted to unilateral cerebral HI; rats were then tested for sensorimotor (PND7 and PND60) and memory (PND60) functions. Offspring of malnourished mothers showed marked reduction in body weight starting in lactation and persisting during the entire period of observation. There was a greater sensorimotor deficit after HI in malnourished (M) animals, in righting reflex and in home bedding task, indicating an interaction between diet and hypoxia-ischemia. At PND60, HI rats showed impaired performance when compared to controls in training and test sessions of rota-rod task, however there was no effect of malnutrition per se. In the open field, nourished HI (HI-N) presented an increase in crossings number; this effect was not present in HI-M group. Surprisingly, HI-M rats presented a better performance in inhibitory avoidance task and a smaller hemispheric brain damage as compared to HI-N animals. Our data points to a possible metabolic adaptation in hypoxic-ischemic animals receiving protein malnutrition during pregnancy and lactation; apparently we observed a neuroprotective effect of diet, possibly decreasing the brain energy demand, under a hypoxic-ischemic situation. PMID- 22244304 TI - Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. AB - We examined gene expression in the lumbar spinal cord and the specific response of motoneurons, intermediate gray and proprioceptive sensory neurons after spinal cord injury and exercise of hindlimbs to identify potential molecular processes involved in activity dependent plasticity. Adult female rats received a low thoracic transection and passive cycling exercise for 1 or 4weeks. Gene expression analysis focused on the neurotrophic factors: brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and their receptors because of their potential roles in neural plasticity. We also examined expression of genes involved in the cellular response to injury: heat shock proteins (HSP) -27 and 70, glial fibrillary acidic protein (GFAP) and caspases -3, -7, and -9. In lumbar cord samples, injury increased the expression of mRNA for TrkB, all three caspases and the HSPs. Acute and prolonged exercise increased expression of mRNA for the neurotrophic factors BDNF and GDNF, but not their receptors. It also increased HSP expression and decreased caspase-7 expression, with changes in protein levels complimentary to these changes in mRNA expression. Motoneurons and intermediate gray displayed little change in mRNA expression following injury, but acute and prolonged exercise increased levels of mRNA for BDNF, GDNF and NT 4. In large DRG neurons, mRNA for neurotrophic factors and their receptors were largely unaffected by either injury or exercise. However, caspase mRNA expression was increased by injury and decreased by exercise. Our results demonstrate that exercise affects expression of genes involved in plasticity and apoptosis in a cell specific manner and that these change with increased post-injury intervals and/or prolonged periods of exercise. PMID- 22244306 TI - Role of thioproline on seed germination: interaction ROS-ABA and effects on antioxidative metabolism. AB - In this work we investigate the effect of the imbibition of pea seeds with different thioproline (TP) concentrations on the germination percentage and the early growth of the seedlings. The interaction between TP and hydrogen peroxide (H2O2) treatments is also analysed in order to test if any synergy in germination and growth occurs. Although the imbibition of pea seeds in the presence of TP did not significantly improve the germination percentage, TP and/or H2O2 pre treatments increased seedlings growth. This increase in seedling growth was reduced by abscisic acid (ABA) addition. Imbibition of pea seeds in the presence of ABA also reduced the endogenous H2O2 contents of pea seedlings in control and TP-treated seeds. The incubation of pea seeds with TP and/or H2O2 in presence or absence of ABA decreased the activity of H2O2-scavenging enzymes. The increase of the endogenous H2O2 contents observed in TP and/or H2O2 treatments in absence of ABA could be correlated with the decrease in these activities. Finally, the hormone profile of pea seedlings was investigated. The results show that the increase in seedling growth is correlated with a decrease in ABA in samples pre treated with H2O2 and TP + H2O2. Nevertheless, no significant differences in endogenous ABA concentration were observed with the TP pre-treatment. This paper suggests a relationship between endogenous H2O2 contents and plant growth, so reinforcing the intricate crosstalk between reactive oxygen species (ROS) and plant hormones in seed germination signalling and early seedling development. PMID- 22244307 TI - Quality of life in Alzheimer's disease: different factors associated with complementary ratings by patients and family carers. AB - BACKGROUND: Quality of life (QoL) in dementia is a complex construct and factors that predict QoL ratings are unclear. We designed this study to determine: (1) the agreement in QoL ratings between community-dwelling patients with mild to moderate dementia and family carers; and (2) the factors associated with self reported and two types of carer-reported QoL ratings: carer-carer perspective and carer-patient perspective. METHODS: A cross-sectional study was carried out of 80 community-dwelling patients with the diagnosis of probable Alzheimer's disease (AD) of mild or moderate severity according to NINCDS-ADRD criteria, and their 80 family carers. The QoL-AD was the primary outcome measure. We collected patients' self-reported QoL ratings and two types of carer-reported QoL ratings: carer patient and carer-carer perspectives. Explanatory variables included demographics, lifestyle, and clinical information from patients and carers, along with cognition, awareness, psychopathology, burden-of-care, and functionality in daily life. Bland-Altman plots guided the interpretation of agreement by visualizing the distribution of all the ratings. Univariate and multivariate regression analyses were conducted to examine the contribution of candidate explanatory factors. RESULTS: Patients and their carers showed good agreement in their QoL ratings, although the total scores of carers (regardless of perspective) were lower than the scores of patients. Depression, insight and use of anti-dementia agents were associated with QoL self-ratings, whereas cognitive function was directly associated and depression inversely associated with carers' QoL ratings. CONCLUSION: Mild to moderate community-dwelling AD patients and their carers (with different perspectives) agree within an acceptable range in QoL ratings but the ratings are driven by different factors, and consequently are not interchangeable but complementary. They provide valuable information when used separately, not in a composite score. PMID- 22244308 TI - Trends in dietary energy, fat, carbohydrate and protein intake in Chinese children and adolescents from 1991 to 2009. AB - Few studies have examined nutrition transition in children in China. Our aim, in the present study, was to examine temporal trends in dietary energy, fat, carbohydrate and protein intake in Chinese children aged 7-17 years. The analysis used individual level, consecutive 3 d dietary recall data from seven rounds of the China Health and Nutrition Surveys in 1991 (n 2714), 1993 (n 2542), 1997 (n 2516), 2000 (n 2142), 2004 (n 1341), 2006 (n 1072) and 2009 (n 996). Mixed-effect models were constructed to obtain adjusted means and to examine trends after adjusting for intra-class correlation within clusters and for covariates including age, sex, urban/rural residence and income. From 1991 to 2009, daily energy intake steadily declined from 9511.0 to 7658.2 kJ (P<0.0001). There was a steady decline in daily carbohydrate intake from 382.5 to 254.1 g (P<0.0001), and in the proportion of energy from carbohydrate from 66.7 to 56.8 % (P<0.0001). In contrast, daily fat intake steadily increased from 54.8 to 66.0 g (P<0.0001), as did the proportion of energy from fat from 21.5 to 30.0 % (P<0.0001). The proportion of children who consumed a diet with more than 30 % of energy from fat increased from 20.1 to 49.4 % (P<0.0001). The proportion of energy from protein increased from 11.8 to 13.1 % (P<0.0001), although daily protein intake dropped from 66.2 to 58.0 g (P<0.0001). Our data suggest that Chinese children have been undergoing a rapid nutrition transition to a high-fat diet. PMID- 22244309 TI - Online use of error-related potentials in healthy users and people with severe motor impairment increases performance of a P300-BCI. AB - OBJECTIVE: To investigate whether error-related potentials can be used to increase information transfer rate of a P3 brain-computer interface (BCI) in healthy and motor-impaired individuals. METHODS: Extraction and classification of the error-related potential was performed offline on data recorded from six amyotrophic lateral sclerosis (ALS) patients. An online study with 17 healthy and six motor impaired participants followed, using a modified P3 speller to provide explicit feedback of spelled letters. On recognition of error-related potentials, the interface informed users that the incorrect letter was automatically deleted. RESULTS: The offline cross-validation estimate of P3 speller data of six ALS patients increased bit rate by 0.44 bit/trial. During online copy spelling, the participants increased their bit rate by 0.52 bit/trial with the error correction system (ECS). Some participants performed free spelling and were able to increase their bit rate. Finally, we demonstrated that healthy participants could increase their bit rate by using a classifier pre-trained on other users' data. CONCLUSIONS: Error-related potentials as a secondary source of information can be used to increase overall bit rate in a P3 BCI. SIGNIFICANCE: The method should be made available to any patient using the P3 BCI for communication. PMID- 22244310 TI - Metal work-function-dependent barrier height of Ni contacts with metal-embedded nanoparticles to 4H-SiC. AB - Metal, typically gold [Au], nanoparticles [NPs] embedded in a capping metal contact layer onto silicon carbide [SiC] are considered to have practical applications in changing the barrier height of the original contacts. Here, we demonstrate the use of silver [Ag] NPs to effectively lower the barrier height of the electrical contacts to 4H-SiC. It has been shown that the barrier height of the fabricated SiC diode structures (Ni with embedded Ag-NPs) has significantly reduced by 0.11 eV and 0.18 eV with respect to the samples with Au-NPs and the reference samples, respectively. The experimental results have also been compared with both an analytic model based on Tung's theory and physics-based two dimensional numerical simulations. PMID- 22244312 TI - Facilitator versus preceptor: which offers the best support to undergraduate nursing students? AB - INTRODUCTION: There is an abundance of literature regarding factors that influence student learning within the clinical environment. Within this discourse, there is a paucity of research on the impact of supervision models on the learning support needs of students. This paper presents the results of research that focused on nursing students' perceptions about the effectiveness of the support they received during their work integrated learning (WIL) experience. BACKGROUND: The majority of students placed within health care facilities are in groups. The group model incorporates a facilitator who supervises the students who are placed across a number of wards. At the ward level students are then assigned a Registered Nurse (RN) who is their mentor. This occurs on a shift by shift basis. Another model of clinical supervision involves preceptorship. This approach is via a one-on-one supervision of students. Within the preceptorship model, students are supervised by a RN who is responsible for supporting them during their WIL experience and for completing their assessment. METHODS: This study compared two models of clinical supervision to better understand the learning support needs as perceived by undergraduate nursing students during their WIL experience. Survey method using a self reporting online questionnaire developed by the researchers was used to collect data. RESULTS: 159 undergraduate nursing students enrolled in a Bachelor level programme of study completed the on line survey. When comparing the two models of supervision, students supervised within the facilitator model were statistically more likely to be challenged to reflect, think, build on existing skills and knowledge and to problem-solve issues. Notably, all factors integral to RN education. Overall, students considered the quality of support to be the most important facet of supervision. CONCLUSIONS: The findings of this study demonstrate that the facilitator model is the better approach for the development of critical thinking, but both models enable the development of a student's professional identity and the development of their role within nursing. This highlights the significance of clinical experiences during undergraduate nursing education. PMID- 22244311 TI - The genetic control of growth rate: a systems biology study in yeast. AB - BACKGROUND: Control of growth rate is mediated by tight regulation mechanisms in all free-living organisms since long-term survival depends on adaptation to diverse environmental conditions. The yeast, Saccharomyces cerevisiae, when growing under nutrient-limited conditions, controls its growth rate via both nutrient-specific and nutrient-independent gene sets. At slow growth rates, at least, it has been found that the expression of the genes that exert significant control over growth rate (high flux control or HFC genes) is not necessarily regulated by growth rate itself. It has not been determined whether the set of HFC genes is the same at all growth rates or whether it is the same in conditions of nutrient limitation or excess. RESULTS: HFC genes were identified in competition experiments in which a population of hemizygous diploid yeast deletants were grown at, or close to, the maximum specific growth rate in either nutrient-limiting or nutrient-sufficient conditions. A hemizygous mutant is one in which one of any pair of homologous genes is deleted in a diploid, These HFC genes divided into two classes: a haploinsufficient (HI) set, where the hemizygous mutants grow slower than the wild type, and a haploproficient (HP) set, which comprises hemizygotes that grow faster than the wild type. The HI set was found to be enriched for genes involved in the processes of gene expression, while the HP set was enriched for genes concerned with the cell cycle and genome integrity. CONCLUSION: A subset of growth-regulated genes have HFC characteristics when grown in conditions where there are few, or no, external constraints on the rate of growth that cells may attain. This subset is enriched for genes that participate in the processes of gene expression, itself (i.e. transcription and translation). The fact that haploproficiency is exhibited by mutants grown at the previously determined maximum rate implies that the control of growth rate in this simple eukaryote represents a trade-off between the selective advantages of rapid growth and the need to maintain the integrity of the genome. PMID- 22244313 TI - Application of neurodevelopmental screening to a sample of South American infants: the Bayley Infant Neurodevelopmental Screener (BINS). AB - OBJECTIVE: To evaluate the utility of the Bayley Infant Neurodevelopmental Screener (BINS), standardized in the US, for South American infants, 3-24 months of age. METHODS: Thirty-five physicians administered the BINS to 2471 South American infants recruited during routine well-child visits, 578 (23%) from Brazil and 1893 (77%) from six other South American countries. The BINS was translated into Spanish and Portuguese and participating physicians were trained to administer the BINS. Physician inter-rater agreement with training tapes was 84.4%; test-retest reliability for age item sets ranged from 0.80 to 0.93 (Pearson's r). Infants were classified into being at low, moderate, or high risk for developmental delay or neurological impairment based on their total BINS score. The sample was stratified by infant's age, sex and language (Spanish and Portuguese). The BINS scores were compared to the scores of the US infant sample used to standardize the BINS. RESULTS: Female infants performed higher than male at 16-20 months and 21-24 months; male infant scores were more variable at 5-6 months. Scores on only two items were significantly different between Spanish and Portuguese speaking participants. South American scores were typically significantly higher than the US sample, and a lower proportion of infants were classified as being at high risk in the South American sample than in the US standardization sample. CONCLUSION: Overall, the results of this study indicate that the BINS is feasible and appropriate for neurodevelopmental screening in South America. Further studies are needed to confirm the BINS utility in South America, including its use with a clinical sample. PMID- 22244315 TI - Socioeconomic factors associated with drug consumption in prison population in Mexico. AB - BACKGROUND: Consumption of illegal drugs is a public health problem in Mexico, and the prison population is a vulnerable group with higher rates of prevalence than in the general population. The objective of this study was to determine the main socioeconomic variables associated with drug consumption in the prison population. METHODS: Utilizing data from the Second Incarcerated Population Survey carried out by the Centre of Research and Teaching of Economics (CIDE) in Mexico, a logistic model in two stages was developed. The first stage analyzed the determinants of habitual drug consumption by prisoners (prior to admittance into prisons), while the second stage of the model addressed drug consumption within prisons. RESULTS: Prevalence of drug consumption previous to incarceration was 28.5%, although once people were imprisoned this figure dropped to 7.4%. The characteristics that most heavily influenced against the possibility of habitual drug consumption prior to admittance to prison were: preparatory school or higher, being employed and having children; while the variables associated negatively were: male gender, childhood home shared with adults who consumed illegal drugs; abandoning childhood home; and having previous prison sentences. Once in prison, the negative conditions in there are associated with drug consumption. CONCLUSIONS: Work and study during incarceration, in addition to being instruments for rehabilitation, seem to exert an important positive association against drug consumption. However, this correlation seems to be minimized in the face of negative conditions of the penal institution; thus, public policies are necessary to improve the prisoner's environment. PMID- 22244314 TI - Sequence based polymorphic (SBP) marker technology for targeted genomic regions: its application in generating a molecular map of the Arabidopsis thaliana genome. AB - BACKGROUND: Molecular markers facilitate both genotype identification, essential for modern animal and plant breeding, and the isolation of genes based on their map positions. Advancements in sequencing technology have made possible the identification of single nucleotide polymorphisms (SNPs) for any genomic regions. Here a sequence based polymorphic (SBP) marker technology for generating molecular markers for targeted genomic regions in Arabidopsis is described. RESULTS: A ~3X genome coverage sequence of the Arabidopsis thaliana ecotype, Niederzenz (Nd-0) was obtained by applying Illumina's sequencing by synthesis (Solexa) technology. Comparison of the Nd-0 genome sequence with the assembled Columbia-0 (Col-0) genome sequence identified putative single nucleotide polymorphisms (SNPs) throughout the entire genome. Multiple 75 base pair Nd-0 sequence reads containing SNPs and originating from individual genomic DNA molecules were the basis for developing co-dominant SBP markers. SNPs containing Col-0 sequences, supported by transcript sequences or sequences from multiple BAC clones, were compared to the respective Nd-0 sequences to identify possible restriction endonuclease enzyme site variations. Small amplicons, PCR amplified from both ecotypes, were digested with suitable restriction enzymes and resolved on a gel to reveal the sequence based polymorphisms. By applying this technology, 21 SBP markers for the marker poor regions of the Arabidopsis map representing polymorphisms between Col-0 and Nd-0 ecotypes were generated. CONCLUSIONS: The SBP marker technology described here allowed the development of molecular markers for targeted genomic regions of Arabidopsis. It should facilitate isolation of co dominant molecular markers for targeted genomic regions of any animal or plant species, whose genomic sequences have been assembled. This technology will particularly facilitate the development of high density molecular marker maps, essential for cloning genes based on their genetic map positions and identifying tightly linked molecular markers for selecting desirable genotypes in animal and plant breeding experiments. PMID- 22244317 TI - [Meningococcemia revealed by acute febrile polyarthritis: a case report]. PMID- 22244318 TI - [Childhood spastic diplegia: experience of the Marrakech University Hospital]. PMID- 22244319 TI - [Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management]. AB - MCAD deficiency is the most common fatty acid oxidation disorder, with the prevalence varying from 1/10,000 to 1/27,000 in the countries adjacent to France. As the High Authority for Health has recently proposed including MCAD deficiency in the panel of diseases neonatally screened for in France, a consensus was written for the management of MCAD deficiency diagnosed either clinically or by neonatal screening. Patients may present acutely with hyperammonemia, hypoglycemia, encephalopathy, and hepatomegaly, mainly after a prolonged fast of intercurrent infection. Sudden death related to heartbeat disorders may also occur. The diagnosis of MCAD deficiency is suspected on the plasma acylcarnitine and/or the urinary organic acid profile. The diagnosis is confirmed by molecular biology and the enzymatic activity for patients who are not homozygous for the main mutation c.985A>G. However, some MCAD-deficient individuals may remain asymptomatic throughout life. The mainstay of treatment consists in avoiding prolonged fast and prescribing l-carnitine for patients who exhibit a deficiency in plasma carnitine. This management has radically modified the natural history of MCAD deficiency. This consensus will allow homogeneous management of these patients once the neonatal screening of MCAD deficiency has been introduced in France. PMID- 22244320 TI - [Acute consciousness disorders]. PMID- 22244321 TI - Visit with a veteran: a lesson in open listening. PMID- 22244322 TI - Using visual displays to communicate risk of cancer to women from diverse race/ethnic backgrounds. AB - OBJECTIVE: This study evaluated how well women from diverse race/ethnic groups were able to take a quantitative cancer risk statistic verbally provided to them and report it in a visual format. METHODS: Cross-sectional survey was administered in English, Spanish or Chinese, to women aged 50-80 (n=1160), recruited from primary care practices. The survey contained breast, colorectal or cervical cancer questions regarding screening and prevention. Women were told cancer-specific lifetime risk then shown a visual display of risk and asked to indicate the specific lifetime risk. Correct indication of risk was the main outcome. RESULTS: Correct responses on icon arrays were 46% for breast, 55% for colon, and 44% for cervical; only 25% correctly responded to a magnifying glass graphic. Compared to Whites, African American and Latina women were significantly less likely to use the icon arrays correctly. Higher education and higher numeracy were associated with correct responses. Lower education was associated with lower numeracy. CONCLUSIONS: Race/ethnic differences were associated with women's ability to take a quantitative cancer risk statistic verbally provided to them and report it in a visual format. PRACTICE IMPLICATIONS: Systematically considering the complexity of intersecting factors such as race/ethnicity, educational level, poverty, and numeracy in most health communications is needed. PMID- 22244324 TI - Cysteine 38 holds the key to NF-kappaB activation. AB - The importance of parallel signaling pathways controlling NF-kappaB subunit posttranslational modifications is demonstrated by Sen et al. (2012), who reveal that RelA (p65) sulfhydration, at its highly conserved cysteine 38 residue, regulates association with the coactivator RPS3, DNA binding, and antiapoptotic gene expression. PMID- 22244325 TI - Get back TFIIF, don't let me Gdown1. AB - In this issue of Molecular Cell, papers by the Price and Roeder labs reveal how the Gdown1 protein antagonizes the general transcription factor TFIIF during RNAPII initiation and elongation and how the Mediator complex intervenes in this molecular tug-of-war to activate RNAPII. PMID- 22244323 TI - Health literacy and cancer prevention: two new instruments to assess comprehension. AB - OBJECTIVES: Ability to understand spoken health information is an important facet of health literacy, but to date, no instrument has been available to quantify patients' ability in this area. We sought to develop a test to assess comprehension of spoken health messages related to cancer prevention and screening to fill this gap, and a complementary test of comprehension of written health messages. METHODS: We used the Sentence Verification Technique to write items based on realistic health messages about cancer prevention and screening, including media messages, clinical encounters and clinical print materials. Items were reviewed, revised, and pre-tested. Adults aged 40-70 participated in a pilot administration in Georgia, Hawaii, and Massachusetts. RESULTS: The Cancer Message Literacy Test-Listening is self-administered via touchscreen laptop computer. No reading is required. It takes approximately 1 hour. The Cancer Message Literacy Test-Reading is self-administered on paper. It takes approximately 10min. CONCLUSIONS: These two new tests will allow researchers to assess comprehension of spoken health messages, to examine the relationship between listening and reading literacy, and to explore the impact of each form of literacy on health related outcomes. PRACTICE IMPLICATIONS: Researchers and clinicians now have a means of measuring comprehension of spoken health information. PMID- 22244326 TI - A novel antirecombinase gains PARIty. AB - In this issue, Moldovan et al. (2012) report the identification of PARI, a putative human ortholog of the yeast Srs2 protein, which potentially regulates homologous recombination repair via its ability to disrupt the function of RAD51. PMID- 22244327 TI - Ramping up mitosis: an AMPKalpha2-regulated signaling network promotes mitotic progression. AB - In the December 23rd issue of Molecular Cell, Banko et al. (2011) describe a chemical genetic screen that identified 28 novel AMPKalpha2 direct substrates. A subset of these substrates comprise a signaling network by which AMPK, seemingly independent of cellular energy status, promotes mitotic progression. PMID- 22244328 TI - SIRT1 regulation-it ain't all NAD. AB - SIRT1 is a phylogenetically conserved energy sensor. The molecular mechanisms that regulate its catalytic activity, however, are incompletely understood. Gerhart-Hines et al. (2011) have identified beta-adrenergic/cAMP signaling as a regulatory input that rapidly controls SIRT1 activity and fatty acid oxidation. PMID- 22244329 TI - Hydrogen sulfide-linked sulfhydration of NF-kappaB mediates its antiapoptotic actions. AB - Nuclear factor kappaB (NF-kappaB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-kappaB are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-alpha treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-kappaB, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H(2)S acts by sulfhydrating the p65 subunit of NF kappaB at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-alpha treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-kappaB are markedly diminished. Thus, sulfhydration of NF-kappaB appears to be a physiologic determinant of its antiapoptotic transcriptional activity. PMID- 22244330 TI - Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIalpha and PKCdelta signaling. AB - BIK protein is an initiator of mitochondrial apoptosis, and BIK expression is induced by proapoptotic signals, including DNA damage. Here, we demonstrate that 3' end processing and expression of BIK mRNA are controlled by the nuclear PI4,5P(2)-regulated poly(A) polymerase Star-PAP downstream of DNA damage. Nuclear PKCdelta is a key mediator of apoptosis, and DNA damage stimulates PKCdelta association with the Star-PAP complex where PKCdelta is required for Star-PAP dependent BIK expression. PKCdelta binds the PI4,5P(2)-generating enzyme PIPKIalpha, which is essential for PKCdelta interaction with the Star-PAP complex, and PKCdelta activity is directly stimulated by PI4,5P(2). Features in the BIK 3' UTR uniquely define Star-PAP specificity and may block canonical PAP activity toward BIK mRNA. This reveals a nuclear phosphoinositide signaling nexus where PIPKIalpha, PI4,5P(2), and PKCdelta regulate Star-PAP control of BIK expression and induction of apoptosis. This pathway is distinct from the Star-PAP mediated oxidative stress pathway indicating signal-specific regulation of mRNA 3' end processing. PMID- 22244331 TI - Functional association of Gdown1 with RNA polymerase II poised on human genes. AB - Most human genes are loaded with promoter-proximally paused RNA polymerase II (Pol II) molecules that are poised for release into productive elongation by P TEFb. We present evidence that Gdown1, the product of the POLR2M gene that renders Pol II responsive to Mediator, is involved in Pol II elongation control. During in vitro transcription, Gdown1 specifically blocked elongation stimulation by TFIIF, inhibited the termination activity of TTF2, and influenced pausing factors NELF and DSIF, but did not affect the function of TFIIS or the mRNA capping enzyme. Without P-TEFb, Gdown1 led to the production of stably paused polymerases in the presence of nuclear extract. Supporting these mechanistic insights, ChIP-Seq demonstrated that Gdown1 mapped over essentially all poised polymerases across the human genome. Our results establish that Gdown1 stabilizes poised polymerases while maintaining their responsiveness to P-TEFb and suggest that Mediator overcomes a Gdown1-mediated block of initiation by allowing TFIIF function. PMID- 22244332 TI - Transcriptional regulation by Pol II(G) involving mediator and competitive interactions of Gdown1 and TFIIF with Pol II. AB - Pol II(G) is a distinct form of RNA polymerase II that contains the tightly associated Gdown1 polypeptide (encoded by POLR2M). Unlike Pol II, Pol II(G) is highly dependent upon Mediator for robust activator-dependent transcription in a biochemically defined in vitro system. Here, in vitro studies show that Gdown1 competes with TFIIF for binding to the RPB1 and RPB5 subunits of Pol II, thereby inhibiting an essential function of TFIIF in preinitiation complex assembly, but also that Mediator can actually facilitate Pol II(G) binding to the promoter prior to subsequent Mediator functions. Complementary ChIP and RNAi analyses reveal that Pol II(G) is recruited to promoter regions of subsets of actively transcribed genes, where it appears to restrict transcription. These and other results suggest that Pol II(G) may act to modulate some genes while simultaneously, as a poised (noninitiated) polymerase, setting the stage for Mediator-dependent enhancement of their activity. PMID- 22244333 TI - Ars2 promotes proper replication-dependent histone mRNA 3' end formation. AB - Ars2 is a component of the nuclear cap-binding complex that contributes to microRNA biogenesis and is required for cellular proliferation. Here, we expand on the repertoire of Ars2-dependent microRNAs and determine that Ars2 regulates a number of mRNAs, the largest defined subset of which code for histones. Histone mRNAs are unique among mammalian mRNAs because they are not normally polyadenylated but, rather, are cleaved following a 3' stem loop. A significant reduction in correctly processed histone mRNAs was observed following Ars2 depletion, concurrent with an increase in polyadenylated histone transcripts. Furthermore, Ars2 physically associated with histone mRNAs and the noncoding RNA 7SK. Knockdown of 7SK led to an enhanced ratio of cleaved to polyadenylated histone transcripts, an effect dependent on Ars2. Together, the data demonstrate that Ars2 contributes to histone mRNA 3' end formation and expression and these functional properties of Ars2 are negatively regulated by interaction with 7SK RNA. PMID- 22244334 TI - RNase H and postreplication repair protect cells from ribonucleotides incorporated in DNA. AB - The chemical identity and integrity of the genome is challenged by the incorporation of ribonucleoside triphosphates (rNTPs) in place of deoxyribonucleoside triphosphates (dNTPs) during replication. Misincorporation is limited by the selectivity of DNA replicases. We show that accumulation of ribonucleoside monophosphates (rNMPs) in the genome causes replication stress and has toxic consequences, particularly in the absence of RNase H1 and RNase H2, which remove rNMPs. We demonstrate that postreplication repair (PRR) pathways MMS2-dependent template switch and Pol zeta-dependent bypass-are crucial for tolerating the presence of rNMPs in the chromosomes; indeed, we show that Pol zeta efficiently replicates over 1-4 rNMPs. Moreover, cells lacking RNase H accumulate mono- and polyubiquitylated PCNA and have a constitutively activated PRR. Our findings describe a crucial function for RNase H1, RNase H2, template switch, and translesion DNA synthesis in overcoming rNTPs misincorporated during DNA replication, and may be relevant for the pathogenesis of Aicardi-Goutieres syndrome. PMID- 22244336 TI - Initial recovery trajectories among patients with hip fracture: a conceptual approach to exploring comparative effectiveness in postacute care. AB - OBJECTIVE: To assess whether clusters of patients with hip fracture and with distinct initial recovery trajectories (IRT) could be identified by using practice-based evidence data and to examine the validity of these data. DESIGN: Analysis of multisite prospective observational cohort study database. SETTING: Eighteen skilled nursing and inpatient rehabilitation facilities. PATIENTS: Patients with hip fractures (N = 226) treated with joint replacement and admitted to skilled nursing or inpatient rehabilitation facilities, subset (n = 85), with telephone follow-up results approximately 8 months after rehabilitation discharge. Patients' ages were 76.8 +/- 11.4 years; the majority were women (78%) and white (87%). METHODS: Measurements included medical severity by using the Comprehensive Severity Index and functional levels by using Functional Independence Measure (FIM). The IRT was calculated for each patient as the rate of change in function from the time of surgery to rehabilitation admission. We used cluster analysis to partition patients into subsets that shared common IRT scores. Validity was explored by comparing subgroups across patient characteristics and treatment patterns. Significance was defined as P <= .05. MAIN OUTCOMES MEASUREMENTS: IRT grouping, Comprehensive Severity Index, FIM, discharge location, living location at follow-up. RESULTS: We identified 3 patient clusters with differentiated IRT scores: group 1: 4.96 +/- 2.45 (range, 0.4-8.6) FIM point change per day; group 2: 12.42 +/- 2.51 (range, 8.9-17.0); group 3: 26.80 +/- 13.78 (range, 17.5-70.0). Clinical group validation was established from statistically different Comprehensive Severity Index scores on admission; FIM scores at admission, discharge, and follow-up; and discharge and 8 month living settings. Calculation of IRT recovery curves by using FIM scores and associated time in days through logarithmic regression curves confirmed each group's IRT remained distinct through rehabilitation and follow-up. CONCLUSIONS: The IRT concept appears to be valid in patients with hip fracture who were treated with hip arthroplasty, and may assist in evaluating and comparing the effectiveness of postacute rehabilitation services. PMID- 22244335 TI - H2B ubiquitylation controls the formation of export-competent mRNP. AB - Histone H2B ubiquitylation is a transcription-dependent modification that not only regulates nucleosome dynamics but also controls the trimethylation of histone H3 on lysine 4 by promoting ubiquitylation of Swd2, a component of both the histone methyltransferase COMPASS complex and the cleavage and polyadenylation factor(CPF). We show that preventing either H2B ubiquitylation or H2B-dependent modification of Swd2 results in nuclear accumulation of poly(A) RNA due to a defect in the integrity and stability of APT, a subcomplex of the CPF. Ubiquitin-regulated APT complex dynamics is required for the correct recruitment of the mRNA export receptor Mex67 to nuclear mRNPs. While H2B ubiquitylation controls the recruitment of the different Mex67 adaptors to mRNPs, the effect of Swd2 ubiquitylation is restricted to Yra1 and Nab2, which, in turn, controls poly(A) tail length. Modification of H2B thus participates in the crosstalk between cotranscriptional events and assembly of mRNPs linking nuclear processing and mRNA export. PMID- 22244339 TI - Preparation and characterisation of solid state forms of paracetamol-O glucuronide. AB - The synthesis and crystallisation of the pharmaceutically important metabolite, paracetamol-O-glucuronide, is described. Hydrated and anhydrous forms of the target molecule have been characterised by PXRD, DSC and TGA. In addition, a methanol solvate has been analysed, including single crystal analysis, which represents the first structure solution for this system. PMID- 22244340 TI - Structure and gene cluster of the O-antigen of Escherichia coli O41. AB - The acidic O-polysaccharide (O-antigen) of Escherichia coli O41 was studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy, and the following structure of the branched hexasaccharide repeating unit was established: This structure is unique among the known structures of bacterial polysaccharides. The O-antigen gene cluster of E. coli O41 was sequenced. The gene functions were tentatively assigned by a comparison with sequences in the available databases and found to be in full agreement with the E. coli O41 O polysaccharide structure. PMID- 22244341 TI - Fast and efficient removal of mercury from water samples using magnetic iron oxide nanoparticles modified with 2-mercaptobenzothiazole. AB - Mercury in the lowest levels of concentrations is dangerous for human health due to its bioaccumulation in body and toxicity. This investigation shows the effective removal of mercury (II) ions from contaminated surface waters by modified magnetic iron oxide nanoparticles (M-MIONPs) with 2 mercaptobenzothiazole as an efficient adsorbent. The proposed method is fast, simple, cheap, effective and safe for treatment of mercury polluted waters. Preparation of adsorbent is easy and removal time is short. Non-modified magnetic iron oxide nanoparticles (MIONPs) can adsorb up to 43.47% of 50 ngmL(-1) of Hg (II) ions from polluted water, but modified magnetic ironoxide nanoparticles (M MIONPs) improved the efficiency up to 98.6% for the same concentration. The required time for complete removal of mercury ions was 4 min. Variation of pH and high electrolyte concentration (NaCl) of the solution do not have considerable effect on the mercury removal efficiency. Loading capacity of adsorbent for Hg ions is obtained to be 590 MUgg(-1). PMID- 22244342 TI - Recovery comparisons--hot nitrogen Vs steam regeneration of toxic dichloromethane from activated carbon beds in oil sands process. AB - The regeneration experiments of dichloromethane from activated carbon bed had been carried out by both hot nitrogen and steam to evaluate the regeneration performance and the operating cost of the regeneration step. Factorial Experimental Design (FED) tool had been implemented to optimize the temperature of nitrogen and the superficial velocity of the nitrogen to achieve maximum regeneration at an optimized operating cost. All the experimental results of adsorption step, hot nitrogen and steam regeneration step had been validated by the simulation model PROSIM. The average error percentage between the simulation and experiment based on the mass of adsorption of dichloromethane was 2.6%. The average error percentages between the simulations and experiments based on the mass of dichloromethane regenerated by nitrogen regeneration and steam regeneration were 3 and 12%, respectively. From the experiments, it had been shown that both the hot nitrogen and steam regeneration had regenerated 84% of dichloromethane. But the choice of hot nitrogen or steam regeneration depends on the regeneration time, operating costs, and purity of dichloromethane regenerated. A thorough investigation had been made about the advantages and limitations of both the hot nitrogen and steam regeneration of dichloromethane. PMID- 22244343 TI - Characterization and detoxification of a mature landfill leachate using a combined coagulation-flocculation/photo Fenton treatment. AB - The aim of the present work was to characterize and treat a mature landfill leachate using a coagulation/flocculation process followed by a photo-Fenton oxidation treatment. The leachate was obtained from a landfill in Tetlama, Morelos (Mexico) during the drought season and was characterized in terms of its major pollutants. Considerable levels of chemical oxygen demand (COD), total carbon (TC) and NH4+ were identified, as well as high concentrations of Hg, Pb, and As. Other heavy metals such as Ni, Co, Zn, Cd, and Mn were detected at trace levels. The lethal concentration (LC50) of the leachate, evaluated on Artemia salina, was 12,161+/-11 mg/L of COD, demonstrating an antagonistic interaction among the leachate's components. The treatment of this effluent consisted of a coagulation-flocculation process using an optimal dose of FeCl3 . 6H2O of 300 mg/L. The supernatant was treated using a photo-Fenton process mediated with FeCl2 . 4H2O and H2O2 in a compound parabolic concentrator (CPC) photo-reactor operating in batch mode using an R ratio (R=[H2O2]/[Fe2+]) of 114. The global removal efficiencies after treatment were 56% for the COD, 95% for TC, and 64% for NH4+. The removal efficiencies for As, Hg, and Pb were 46%, 9%, and 85%, respectively. PMID- 22244344 TI - UVA-induced melanogenesis and modulation of glutathione redox system in different melanoma cell lines: the protective effect of gallic acid. AB - Oxidative stress has been suggested to play a role in ultraviolet A (UVA) mediated melanogenesis. Glutathione (GSH) and GSH-related enzymes including gamma glutamate cysteine ligase (gamma-GCL) and glutathione S-transferase (GST) are important antioxidant defenses responsible for maintaining cellular redox balance. Hence, improving GSH redox system to cope with oxidative insults may be essential for attenuation of abnormal melanin production. Gallic acid (GA), a dietary phenolic, has been shown to provide beneficial effects against hyperpigmentation possibly through its antioxidant properties. This study thus aimed to assess the antimelanogenic action of GA with regard to modulation of GSH GCL system and GST in two melanoma cell lines, lightly pigmented G361 human melanoma and more pigmented B16F10 mouse melanoma cells, irradiated with UVA. G361 cells were shown to have lower basal GSH content and GST activity than B16F10 cells. Moreover, GA provided antimelanogenic effects in correlation with promotion of GSH levels, GST activity as well as gamma-GCL and GST mRNA in both G361 and B16F10 cells at 2-h post-irradiation. In summary, GA exhibits protective effects on UVA-mediated melanogenesis possibly through improvement of GSH-related antioxidant defenses. Furthermore, different redox state in G361 and B16F10 cells may affect the responses of melanoma cells to GA. PMID- 22244345 TI - Binding of fullerol to human serum albumin: spectroscopic and electrochemical approach. AB - The potential impact of human exposure to carbonaceous nanomaterials in the environment becomes a concerning issue. Here we report on the interaction of fullerol with human serum albumin (HSA) using spectroscopic and electrochemical methods. The water-soluble fullerene derivative (fullerol) was synthesized and characterized by IR, (1)H NMR, TG-DSC, XRD, HR-TEM, etc. The spectroscopic methods show that the fluorescence quenching of HSA by fullerol is the result of the formation of an HSA-fullerol complex. Binding parameters such as DeltaG, DeltaH and DeltaS were calculated, and the quenching constant K(a) at different temperatures was determined using the modified Stern-Volmer equation. The electrochemical experiments further confirmed the conclusions. In addition, the influences of coexisting heavy metal ions have also been studied in the present system. The circular dichroism spectra (CD), 3D fluorescence spectra and FT-IR spectra results suggest that the secondary structure of HSA was changed by fullerol. Based on the site marker competitive experiments, we can predict the possible binding position of fullerol on the HSA was located at the site of sub domain II A. Furthermore, the distance r between donor (HSA) and acceptor (fullerol) was obtained according to the famous fluorescence resonance energy transfer (FRET) mechanism. PMID- 22244346 TI - A population-based study of sport and recreation-related head injuries treated in a Canadian health region. AB - OBJECTIVES: To report the rates of SR-related HIs presenting to EDs in a Canadian population-based sample. DESIGN: Descriptive epidemiology study. METHODS: Using administrative data, sport and recreation-related emergency department presentations for persons 0-35 years of age, from April 1997 through March 2008, were obtained from the Edmonton Zone (formerly the Capital Health Region), Alberta Health Services through the Ambulatory Care Classification System. RESULTS: Of the 3,230,890 visits to the emergency departments of the five hospitals in Edmonton, 63,219 sport and recreation-related injury records and 4935 sport and recreation-head injury records were identified. Head injuries were most frequently treated for the activities of hockey (20.7%), cycling (12.0%), and skiing/snowboarding/sledding. Males accounted for 71.9% (n=3546) and patients less than 18 years of age sustained 3446 (69.8%) sport and recreation-head injuries. CONCLUSIONS: Sport and recreation-related head injuries most frequently treated in emergency departments involve common activities such as hockey, cycling, skiing/snowboarding/sledding, and soccer. Males and those less than 18 years of age sustain the majority of sport and recreation-related head injuries treated in emergency departments. These findings underscore the importance of sport-specific policies and safety promotion for the prevention of head injuries, in sports and recreational activities. PMID- 22244347 TI - Organizational structure and processes in pediatric heart transplantation: a survey of practices. AB - Despite emerging literature on pediatric heart transplantation, there continues to be variation in current practices. The degree of variability among heart transplant programs has not been previously characterized. The purpose of this study was to evaluate organizational structure and practices of pediatric heart transplant programs. The UNOS database was queried to identify institutions according to volume. Coordinators from 50 institutions were invited to participate with a 70% response rate. Centers were grouped by volume into four categories. Some institutional practices were dominated by clear volume trends. Ninety-five percent of larger centers routinely transplant patients with known antibody sensitization and report a broader range and acuity of recipients. Ninety-four percent report problems with non-adherence. Sixty-nine percent of centers routinely require prospective crossmatches. There was dramatic variation in the use of steroids across all centers. Sixty-five percent of centers transition adolescents to an adult program. Prophylaxis protocols were also highly inconsistent. This survey provided a comprehensive insight into current practices at pediatric heart transplant programs. The results delineated remarkably variable strategies for routine aspects of care. Analysis of divergence along with uniformity across protocols is a valuable exercise and may serve as a stepping-stone toward ongoing cooperation and clarity for evidence based practice protocols. PMID- 22244348 TI - Relationship of age and gender to the prevalence and correlates of psychological distress in later life. AB - BACKGROUND: As populations age, psychological distress in late life will become of increasing public health and social importance. This study seeks to bridge the gap in information that exists about psychological distress in late life, by exploring the prevalence of psychological distress among a very large sample of older adults to determine the impact of age and gender, and the modifying effect of these factors on the associations between measures of psychological distress and sociodemographic and comorbid conditions. METHODS: We analyzed self-reported data from 236,508 men and women in the New South Wales 45 and Up Study, to determine the impact of age and gender, and the modifying effects of these factors on associations between psychological distress and sociodemographic and comorbid conditions. RESULTS: Higher education, married status, and higher income were associated with lower risk of psychological distress. Although overall prevalence of psychological distress is lower at older ages, this increases after age 80, and is particularly associated with physical disabilities. Some older people (such as those requiring help because of disability and those with multiple comorbid health conditions) are at increased risk of psychological distress. CONCLUSION: These findings have implications for both healthcare providers and policy-makers in identifying and responding to the needs of older people in our aging society. PMID- 22244349 TI - Effect of long-term intermittent supplementation with multiple micronutrients compared with iron-and-folic acid supplementation on Hb and micronutrient status of non-anaemic adolescent schoolgirls in rural Bangladesh. AB - The present study examined whether long-term supplementation with once- and twice weekly multiple micronutrients (MMN-1 and MMN-2) can improve Hb and micronutrient status more than twice-weekly Fe-folic acid (IFA-2) supplementation in non anaemic adolescent girls in Bangladesh. An equal number of 324 rural schoolgirls aged 11-17 years were given MMN-1 or MMN-2 or IFA-2 supplements for 52 weeks in a randomised, double-blind trial. Blood samples were collected at baseline, and at 26 and 52 weeks of supplementation. The girls receiving IFA-2 supplements were more likely to be anaemic than the girls receiving MMN-2 supplements for 26 weeks (OR 5.1, 95% CI 1.3, 19.5; P = 0.018). All three supplements reduced Fe deficiency effectively. Both the MMN-1 and MMN-2 groups showed significantly greater improvements in vitamins A, B(2) and C status than the girls in the IFA-2 group, as might be expected. Receiving a MMN-1 supplement was found to be less effective than MMN-2 supplement in improving Fe, vitamins A, B(2) and folic acid status. Receiving micronutrient supplements beyond 26 weeks showed little additional benefit in improving micronutrient status. In conclusion, given twice weekly for 26 weeks, MMN supplements can improve micronutrient status effectively with no significant increase in Hb concentration compared with IFA supplements in non-anaemic Bangladeshi adolescent girls. However, it significantly reduces the risk of anaemia. Before any recommendations can be made, further research, including into cost-effectiveness, is needed to see whether MMN supplementation has any additional longer-term health benefits over that of IFA supplementation in this population. PMID- 22244350 TI - Towards a genuinely medical model for psychiatric nosology. AB - Psychiatric nosology is widely criticized, but solutions are proving elusive. Planned revisions of diagnostic criteria will not resolve heterogeneity, comorbidity, fuzzy boundaries between normal and pathological, and lack of specific biomarkers. Concern about these difficulties reflects a narrow model that assumes most mental disorders should be defined by their etiologies. A more genuinely medical model uses understanding of normal function to categorize pathologies. For instance, understanding the function of a cough guides the search for problems causing it, and decisions about when it is expressed abnormally. Understanding the functions of emotions is a foundation missing from decisions about emotional disorders. The broader medical model used by the rest of medicine also recognizes syndromes defined by failures of functional systems or failures of feedback control. Such medical syndromes are similar to many mental diagnoses in their multiple causes, blurry boundaries, and nonspecific biomarkers. Dissatisfaction with psychiatric nosology may best be alleviated, not by new diagnostic criteria and categories, but by more realistic acknowledgment of the untidy landscape of mental and other medical disorders. PMID- 22244351 TI - Cleavage of pyrene-stabilized RNA bulge loops by trans-(+/-)-cyclohexane-1,2 diamine. AB - Chemical agents that cleave HIV genome can be potentially used for anti-HIV therapy. In this report, the cleavage of the upper stem-loop region of HIV-1 TAR RNA was studied in a variety of buffers containing organic catalysts. trans-(+/-) Cyclohexane-1,2-diamine was found to cleave the RNA with the highest activity (31%, 37 degrees C, 18 h). Cleavage of the RNA in trans-(+/-)-cyclohexane-1,2 diamine buffer was also studied when the RNA was hybridized with complementary DNAs. A pyrene-modified C3 spacer was incorporated to the DNA strand to facilitate the formation of a RNA bulge loop in the RNA/DNA duplex. In contrast, unmodified DNAs cannot efficiently generate RNA bulge loops, regardless of the DNA sequences. The results showed that the pyrene-stablized RNA bulge loops were efficiently and site-specifically cleaved by trans-(+/-)-cyclohexane-1,2-diamine. PMID- 22244353 TI - Arsenic species in poultry feather meal. AB - Organoarsenical drugs are widely used in the production of broiler chickens in the United States. Feathers from these chickens are processed into a meal product that is used as an animal feed additive and as an organic fertilizer. Research conducted to date suggests that arsenical drugs, specifically roxarsone, used in poultry production result in the accumulation of arsenic in the keratinous material of poultry feathers. The use of feather meal product in the human food system and in other settings may result in human exposures to arsenic. Consequently, the presence and nature of arsenic in twelve samples of feather meal product from six US states and China were examined. Since arsenic toxicity is highly species-dependent, speciation analysis using HPLC/ICPMS was performed to determine the biological relevance of detected arsenic. Arsenic was detected in all samples (44-4100 MUg kg(-1)) and speciation analyses revealed that inorganic forms of arsenic dominated, representing 37 - 83% of total arsenic. Roxarsone was not detected in the samples (<20 MUg As kg(-1)). Feather meal products represent a previously unrecognized source of arsenic in the food system, and may pose additional risks to humans as a result of its use as an organic fertilizer and when animal waste is managed. PMID- 22244354 TI - Multi-molecular markers and metals as tracers of organic matter inputs and contamination status from an Environmental Protection Area in the SW Atlantic (Laranjeiras Bay, Brazil). AB - The sources and concentrations of aliphatic hydrocarbons (AHs) and polycyclic aromatic hydrocarbons (PAHs), faecal and biogenic sterols, and trace metals at 10 sampling sites located in Laranjeiras Bay, a large Environmental Protection Area in the southern Atlantic region of Brazil, were determined to assess the sources of organic matter and the contamination status of estuarine sediments. Organic compounds were determined by GC-FID and GC-MS, and ICP-OES was used to evaluate trace metals. The total AHs concentration ranged from 0.28 to 8.19 MUg g(-1), and n-C(29) and n-C(31) alkanes were predominant, indicating significant inputs from higher terrestrial plants. Unresolved complex mixtures (UCM) were not detected at any site, suggesting that the study area was not significantly contaminated by fossil fuels. The total PAH concentration varied from 3.85 to 89.2 ng g(-1). The ratio between selected PAH isomers showed that combustion of biomass, coal, and petroleum is the main source of PAHs in the study area. The concentrations of the faecal sterols coprostanol and epicoprostanol were below the detection limits, suggesting that sewage was not a significant contributor to sedimentary organic matter. The concentrations of the trace metals (As, Cr, Cu, Ni, Pb and Zn) were low, except near sites located at the mouths of rivers that discharge into the study area and near urbanised regions (Paranagua city and the adjoining harbour). In general, the concentrations of PAHs were below the threshold effect concentrations (TEL) levels. Although the As, Cr and Ni concentrations were above the TEL levels, the study area can be considered as preserved from human activities. PMID- 22244355 TI - A state-wide survey in Oregon (USA) of trace metals and organic chemicals in municipal effluent. AB - Oregon's Senate Bill 737, enacted in 2007, required the state's 52 largest municipal wastewater treatment plants (WWTP) and water pollution control facilities (WPCF) to collect effluent samples in 2010 and analyze them for persistent organic pollutants. These facilities are located state-wide and represent a variety of treatment types, service population sizes, geographic areas, and flow conditions. Of the 406 chemicals ultimately analyzed, 114 were detected above the level of quantification (LOQ) in at least one sample. Few persistent pollutants were found possibly because of their diversion from effluent via sorption to sludge (solids phase) or high LOQs for certain chemicals. Several pesticides, as well as benzene and phenol degradation products, all previously unreported in effluent, were detected. Ten polychlorinated biphenyls (PCB) congeners were present at low concentrations in <= 10 samples, while polychlorinated naphthalenes and dioxins/furans were not detected at all. Twenty-one polybrominated diphenyl ether (PBDE) congeners were found, nine of which have been reported in Osprey eggs in Oregon and Washington. Methylmercury was present in 65% of samples, with average and maximum concentrations of 0.18 and 1.36 ng/L, respectively. Although they are generally assumed to be innocuous by-products of sewage treatment, additional research is needed on potential impacts to aquatic ecosystems of high loadings of coprostanol and cholesterol. These results suggest that effluent, rather than just receiving waters, should itself be analyzed for a wide range of contaminants in order to understand how upstream sources, conveyed through WWTPs and WPCFs, could be impacting aquatic ecosystems. PMID- 22244352 TI - Characterisation of full-length cDNA sequences provides insights into the Eimeria tenella transcriptome. AB - BACKGROUND: Eimeria tenella is an apicomplexan parasite that causes coccidiosis in the domestic fowl. Infection with this parasite is diagnosed frequently in intensively reared poultry and its control is usually accorded a high priority, especially in chickens raised for meat. Prophylactic chemotherapy has been the primary method used for the control of coccidiosis. However, drug efficacy can be compromised by drug-resistant parasites and the lack of new drugs highlights demands for alternative control strategies including vaccination. In the long term, sustainable control of coccidiosis will most likely be achieved through integrated drug and vaccination programmes. Characterisation of the E. tenella transcriptome may provide a better understanding of the biology of the parasite and aid in the development of a more effective control for coccidiosis. RESULTS: More than 15,000 partial sequences were generated from the 5' and 3' ends of clones randomly selected from an E. tenella second generation merozoite full length cDNA library. Clustering of these sequences produced 1,529 unique transcripts (UTs). Based on the transcript assembly and subsequently primer walking, 433 full-length cDNA sequences were successfully generated. These sequences varied in length, ranging from 441 bp to 3,083 bp, with an average size of 1,647 bp. Simple sequence repeat (SSR) analysis identified CAG as the most abundant trinucleotide motif, while codon usage analysis revealed that the ten most infrequently used codons in E. tenella are UAU, UGU, GUA, CAU, AUA, CGA, UUA, CUA, CGU and AGU. Subsequent analysis of the E. tenella complete coding sequences identified 25 putative secretory and 60 putative surface proteins, all of which are now rational candidates for development as recombinant vaccines or drug targets in the effort to control avian coccidiosis. CONCLUSIONS: This paper describes the generation and characterisation of full-length cDNA sequences from E. tenella second generation merozoites and provides new insights into the E. tenella transcriptome. The data generated will be useful for the development and validation of diagnostic and control strategies for coccidiosis and will be of value in annotation of the E. tenella genome sequence. PMID- 22244356 TI - Gentamicin supplemented polyvinylidenfluoride mesh materials enhance tissue integration due to a transcriptionally reduced MMP-2 protein expression. AB - BACKGROUND: A beneficial effect of gentamicin supplemented mesh material on tissue integration is known. To further elucidate the interaction of collagen and MMP-2 in chronic foreign body reaction and to determine the significance of the MMP-2-specific regulatory element (RE-1) that is known to mediate 80% of the MMP 2 promoter activity, the spatial and temporal transcriptional regulation of the MMP-2 gene was analyzed at the cellular level. METHODS: A PVDF mesh material was surface modified by plasma-induced graft polymerization of acrylic acid (PVDF+PAAc). Three different gentamicin concentrations were bound to the provided active sites of the grafted mesh surfaces (2, 5 and 8 MUg/mg). 75 male transgenic MMP-2/LacZ mice harbouring the LacZ reporter gene under control of MMP-2 regulatory sequence -1241/+423, excluding the RE-1 were randomized to five groups. Bilateral of the abdominal midline one of the five different meshes was implanted subcutaneously in each animal. MMP-2 gene transcription (anti-beta galactosidase staining) and MMP-2 protein expression (anti-MMP-2 staining) were analyzed semiquantitatively by immunohistochemistry 7, 21 and 90 days after mesh implantation. The collagen type I/III ratio was analyzed by cross polarization microscopy to determine the quality of mesh integration. RESULTS: The perifilamentary beta-galactosidase expression as well as the collagen type I/III ratio increased up to the 90th day for all mesh modifications, whereas no significant changes could be observed for MMP-2 protein expression between days 21 and 90. Both the 5 and 8 MUg/mg gentamicin group showed significantly reduced levels of beta-galactosidase expression and MMP-2 positive stained cells when compared to the PVDF group on day 7, 21 and 90 respectively (5 MUg/mg: p < 0.05 each; 8 MUg/mg: p < 0.05 each). Though the type I/III collagen ratio increased over time for all mesh modifications significant differences to the PVDF mesh were only detected for the 8 MUg/mg group at all 3 time points (p < 0.05 each). CONCLUSIONS: Our current data indicate that lack of RE-1 is correlated with increased mesh induced MMP-2-gene expression for coated as well as for non-coated mesh materials. Gentamicin coating reduced MMP-2 transcription and protein expression. For the 8 MUg/mg group this effect is associated with an increased type I/III collagen ratio. These findings suggest that gentamicin is beneficial for tissue integration after mesh implantation, which possibly is mediated via RE 1. PMID- 22244357 TI - Impact of sleep apnea on economics. AB - Obstructive sleep apnea syndrome (OSA) alters sleep quality and is associated with sleepiness and decreased cognitive functioning. It has therefore always been recognized as a major public health issue with potential societal consequences: accidents, increased morbidity, and cognitive deficits impairing work efficiency. The number of patients diagnosed and treated for OSA has increased drastically in the last few years. In response to this epidemic, health authorities have encouraged studies investigating how patients cope with OSA and also its diagnosis, comparing ambulatory to hospital-based polysomnography. Based on epidemiological knowledge, this review aims to carefully describe the possible links between sleep apnea and public health concerns along with identifying the certitudes and missing data concerning the consequences of sleep apnea on accidents, work, economics and health-related quality of life. PMID- 22244358 TI - Stent grafting for aneurysmal degeneration of chronic descending thoracic aortic dissections. AB - OBJECTIVE: The objective of this study was to examine the results of thoracic endovascular aneurysm repair (TEVAR) for chronic descending thoracic aortic (DTA) dissections with aneurysmal degeneration. METHODS: Over 70 months at a single institution, 27 patients underwent TEVAR for aneurysms related to chronic (>6 weeks) DTA dissections. RESULTS: Mean patient age was 67.5 +/- 9.6 years; 18 were men. Primary indications for repair were aneurysm size (n = 20), rapid aneurysmal growth (n = 5), saccular aneurysm (n = 1), and rupture (n = 1). Preoperative false lumen status was patent in 18 patients, partially thrombosed in 8 patients, and unknown in the patient whose aneurysm ruptured. The proximal entry tear was covered in all 27 patients. Fourteen patients required coverage of the left subclavian artery, of which 9 patients underwent prophylactic revascularization. On completion angiogram, no patient had antegrade perfusion of the aneurysmal false lumen. There were three procedural complications: 2 patients sustained paraparesis (one resolved and one improved), and 1 patient had an access injury requiring stent graft placement. Thirty-day mortality was 3.7% (1 of 27); the one death was in the patient whose aneurysm ruptured. Of the 26 surviving patients, 23 (88.5%) had thrombosis of the aneurysmal false lumen. Twenty-two patients (84.6%) had stability or decrease in maximal aneurysm diameter on last radiographic follow-up at 18 +/- 20 months. Three-year Kaplan-Meier survival was 90.3% +/- 6.5% in the 26 patients who survived to hospital discharge, with a mean follow-up of 27.3 +/- 22.1 months. In patients with preoperatively partially thrombosed false lumens (n = 8), 3-year survival was 100%. CONCLUSIONS: TEVAR for aneurysms due to chronic dissections of the DTA can be performed safely and effectively at midterm follow-up according to this single-institution study. Stent graft therapy may be of particular benefit in patients presenting with partially thrombosed false lumens. PMID- 22244359 TI - Does stress contribute to the incubation of craving? PMID- 22244360 TI - Chronic rotavirus infection in an infant with severe combined immunodeficiency: successful treatment by hematopoietic stem cell transplantation. PMID- 22244361 TI - Engineering better biomass-degrading ability into a GH11 xylanase using a directed evolution strategy. AB - BACKGROUND: Improving the hydrolytic performance of hemicellulases on lignocellulosic biomass is of considerable importance for second-generation biorefining. To address this problem, and also to gain greater understanding of structure-function relationships, especially related to xylanase action on complex biomass, we have implemented a combinatorial strategy to engineer the GH11 xylanase from Thermobacillus xylanilyticus (Tx-Xyn). RESULTS: Following in vitro enzyme evolution and screening on wheat straw, nine best-performing clones were identified, which display mutations at positions 3, 6, 27 and 111. All of these mutants showed increased hydrolytic activity on wheat straw, and solubilized arabinoxylans that were not modified by the parental enzyme. The most active mutants, S27T and Y111T, increased the solubilization of arabinoxylans from depleted wheat straw 2.3-fold and 2.1-fold, respectively, in comparison to the wild-type enzyme. In addition, five mutants, S27T, Y111H, Y111S, Y111T and S27T-Y111H increased total hemicellulose conversion of intact wheat straw from 16.7%tot. xyl (wild-type Tx-Xyn) to 18.6% to 20.4%tot. xyl. Also, all five mutant enzymes exhibited a better ability to act in synergy with a cellulase cocktail (Accellerase 1500), thus procuring increases in overall wheat straw hydrolysis. CONCLUSIONS: Analysis of the results allows us to hypothesize that the increased hydrolytic ability of the mutants is linked to (i) improved ligand binding in a putative secondary binding site, (ii) the diminution of surface hydrophobicity, and/or (iii) the modification of thumb flexibility, induced by mutations at position 111. Nevertheless, the relatively modest improvements that were observed also underline the fact that enzyme engineering alone cannot overcome the limits imposed by the complex organization of the plant cell wall and the lignin barrier. PMID- 22244362 TI - Dual-task motor performance with a tongue-operated assistive technology compared with hand operations. AB - BACKGROUND: To provide an alternative motor modality for control, navigation, and communication in individuals suffering from impairment or disability in hand functions, a Tongue Drive System (TDS) has been developed that allows for real time tracking of tongue motion in an unobtrusive, wireless, and wearable device that utilizes the magnetic field generated by a miniature disk shaped magnetic tracer attached to the tip of the tongue. The purpose of the study was to compare the influence of a concurrent motor or cognitive task on various aspects of simple movement control between hand and tongue using the TDS technology. METHODS: Thirteen young able-bodied adults performed rapid and slow goal-directed movements of hand and tongue (with TDS) with and without a concurrent motor (hand or tongue) or cognitive (arithmetic and memory) task. Changes in reaction time, completion time, speed, correctness, accuracy, variability of displacement, and variability of time due to the addition of a concurrent task were compared between hand and tongue. RESULTS: The influence of an additional concurrent task on motor performance was similar between the hand and tongue for slow movement in controlling their displacement. In rapid movement with a concurrent motor task, most aspects of motor performance were degraded in hand, while tongue speed during rapid continuous task was maintained. With a concurrent cognitive task, most aspects of motor performance were degraded in tongue, while hand accuracy during the rapid discrete task and hand speed during the rapid continuous task were maintained. CONCLUSION: Rapid goal-directed hand and tongue movements were more consistently susceptible to interference from concurrent motor and cognitive tasks, respectively, compared with the other movement. PMID- 22244363 TI - Multi-micronutrient-fortified biscuits decreased the prevalence of anaemia and improved iron status, whereas weekly iron supplementation only improved iron status in Vietnamese school children. AB - In Vietnam, nutrition interventions do not target school children despite a high prevalence of micronutrient deficiencies. The present randomised, placebo controlled study evaluated the impact of providing school children (n 403) with daily multiple micronutrient-fortified biscuits (FB) or a weekly Fe supplement (SUP) on anaemia and Fe deficiency. Micronutrient status was assessed by concentrations of Hb, and plasma ferritin (PF), transferrin receptor (TfR), Zn and retinol. After 6 months of intervention, children receiving FB or SUP had a significantly better Fe status when compared with the control children (C), indicated by higher PF (FB: geometric mean 36.9 (95% CI 28.0, 55.4) MUg/l; SUP: geometric mean 46.0 (95% CI 33.0, 71.7) MUg/l; C: geometric mean 34.4 (95% CI 15.2, 51.2) MUg/l; P < 0.001) and lower TfR concentrations (FB: geometric mean 5.7 (95% CI 4.8, 6.52) mg/l; SUP: geometric mean 5.5 (95% CI 4.9, 6.2) mg/l; C: geometric mean 5.9 (95% CI 5.1, 7.1) mg/l; P = 0.007). Consequently, body Fe was higher in children receiving FB (mean 5.6 (sd 2.2) mg/kg body weight) and SUP (mean 6.1 (sd 2.5) mg/kg body weight) compared with the C group (mean 4.2 (sd 3.3) mg/kg body weight, P < 0.001). However, anaemia prevalence was significantly lower only in the FB group (1.0%) compared with the C group (10.4%, P = 0.006), with the SUP group being intermediate (7.4%). Children receiving FB had better weight-for-height Z-scores after the intervention than children receiving the SUP (P = 0.009). Vitamin A deficiency at baseline modified the intervention effect, with higher Hb concentrations in vitamin A-deficient children receiving FB but not in those receiving the SUP. This indicates that vitamin A deficiency is implicated in the high prevalence of anaemia in Vietnamese school children, and that interventions should take other deficiencies besides Fe into account to improve Hb concentrations. Provision of biscuits fortified with multiple micronutrients is effective in reducing anaemia prevalence in school children. PMID- 22244364 TI - Impact of diabetes, high triglycerides and low HDL cholesterol on risk for ischemic cardiovascular disease varies by LDL cholesterol level: a 15-year follow up of the Chinese Multi-provincial Cohort Study. AB - AIMS: A large proportion of ischemic cardiovascular disease occur in people without hypercholesterolemia. We aimed to investigate whether risk factors other than low-density lipoprotein cholesterol (LDL-C) have different impacts on cardiovascular risk in people with low verses high LDL-C levels. METHODS: A total of 30,378 participants (35-64 years) were followed for 15 years in the Chinese Multi-provincial Cohort Study. Associations of coronary heart disease (CHD) and ischemic stroke with risk factors other than LDL-C were assessed in participants with low (<130 mg/dL) and high (>=130 mg/dL) LDL-C levels. RESULTS: During the follow-up, 65.5% of CHD and 70.2% of ischemic stroke events occurred in participants with low LDL-C. High triglycerides predicted CHD (HR=1.74, 95% CI 1.25-2.42, P=0.001), and low HDL-C predicted ischemic stroke (HR=1.54, 95% CI 1.18-2.03, P=0.002) only in participants with low LDL-C. Diabetes predicted CHD in participants with high LDL-C (HR=2.38, 95% CI 1.31-4.34, P=0.005), but not in those with low LDL-C. Older age, male, hypertension, central obesity, and smoking had similar effects on the risk in both groups. CONCLUSIONS: Triglycerides and low HDL-C should be addressed in the management of dyslipidemia in people with low LDL-C. When LDL-C is high, tighter management of glycemia and LDL-C is warranted. PMID- 22244365 TI - Musculoskeletal pain in patients with type 2 diabetes. AB - AIMS: The aims were to investigate the prevalence of musculoskeletal pain in patients with type 2 diabetes and demonstrate possible associated factors. METHODS: Nine hundred fifty-one patients completed a validated questionnaire used in The Danish Health and Morbidity Survey and results were compared to data for 2923 matched subjects from the Danish population. Musculoskeletal pain was self reported Pain in the shoulder and neck; Low-back pain; and Pain in the arm, hand, knee and/or hip. RESULTS: Compared to the age, gender and region matched controls patients reported musculoskeletal pain 1.7-2.1 times as frequent (p<0.001). Pain was more frequently reported in women (p<0.001). Low-back pain and Pain in the arm, hand, knee and/or hip was associated with body mass index (p<0.005). Low back pain was associated with a sedentary life style, impaired quality of life and reduced physical function (p<0.05). CONCLUSIONS: The prevalence of musculoskeletal pain was seriously increased in patients with type 2 diabetes. It was associated with body mass index, reduced quality of life, low physical function and the ability to be physical active. Focus on musculoskeletal pain in clinical practice is therefore of major importance in lifestyle interventions in type 2 diabetes. PMID- 22244366 TI - Management of status dystonicus in children. Cases report and review. AB - Status dystonicus (SD) is a medical emergency weighed by a relevant morbidity and mortality. It mainly affects patients with primary or secondary dystonia and is often triggered by events such as fever, infections, exposure medications or their abrupt cessation. We report on three patients presenting with SD. Two of them were affected by a static encephalopathy and the other one by a neurodegenerative disorder such as megalencephalic leukoencephalopathy with subcortical cysts (MLC). To our knowledge this is the first patient affected by MLC presenting with SD. All our patients underwent continuous infusion of midazolam, in association with pimozide and trihexyphenidyl, which led to complete resolution of muscular spasms in two patients. In the other one a complete cessation of dystonic spasms was obtained after intrathecal baclofen. From a therapeutic point of view there are no evidence-based management guidelines in SD. The approach is empiric and based on very limited anecdotal reports. On the basis of our observations and an extensive review of the literature we delineated a possible therapeutic strategy of SD in children. PMID- 22244368 TI - NOD2/CARD15 gene mutations in patients with familial Mediterranean fever. AB - OBJECTIVE: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/CARD15 gene mutations in the FMF disease phenotype was never studied before. PATIENTS AND METHODS: The cohort consisted of 103 consecutive children with FMF, followed in a single referral center. NOD2/CARD15 genotypes were analyzed in all patients and 299 ethnically matched unaffected controls. Demographic data, clinical characteristics, and disease course of FMF patients with and without NOD2/CARD15 mutation were compared. RESULTS: A single NOD2/CARD15 mutation was detected in 10 (9.7%) FMF patients and 26 (8.7%) controls. No homozygous or compound heterozygous subjects were discovered in the 2 groups. FMF patients carrying a NOD2/CARD15 mutation had a higher rate of erysipelas-like erythema and acute scrotum attacks, a trend for a higher rate of colchicine resistance and a more severe disease as compared with patients without mutations. CONCLUSIONS: NOD2/CARD15 mutations are not associated with an increased susceptibility to develop FMF. Nevertheless, the presence of these mutations in FMF patients appears to be associated with a trend to a more severe disease. PMID- 22244367 TI - Genome-wide association scan and phased haplotype construction for quantitative trait loci affecting boar taint in three pig breeds. AB - BACKGROUND: Boar taint is the undesirable smell and taste of pork meat derived from some entire male pigs. The main causes of boar taint are the two compounds androstenone and skatole (3-methyl-indole). The steroid androstenone is a sex pheromone produced in the testis of the boars. Skatole is produced from tryptophan by bacteria in the intestine of the pigs. In many countries pigs are castrated as piglets to avoid boar taint, however, this is undesirable for animal welfare reasons. Genetic variations affecting the level of boar taint have previously been demonstrated in many breeds. In the study presented in this paper, markers and haplotypes, which can be applied to DNA-based selection schemes in order to reduce or eliminate the boar taint problem, are identified. RESULTS: Approximately 30,000 SNPs segregating in 923 boars from three Danish breeds; Duroc, Landrace, and Yorkshire, were used to conduct genome wide association studies of boar taint compounds. At 46 suggestive quantitative trait loci (QTL), 25 haplotypes and three single markers with effects were identified. Furthermore, 40% of the haplotypes mapped to previously identified regions. Haplotypes were also analysed for effects of slaughter weight and meat content. The most promising haplotype was identified on Sus scrofa chromosome 1. The gain in fixed effect of having this haplotype on level of androstenone in Landrace was identified to be high (1.279 MUg/g). In addition, this haplotype explained 16.8% of the phenotypic variation within the trait. The haplotype was identified around the gene CYB5A which is known to have an indirect impact on the amount of androstenone. In addition to CYB5A, the genes SRD5A2, LOC100518755, and CYP21A2 are candidate genes for other haplotypes affecting androstenone, whereas, candidate genes for the indolic compounds were identified to be SULT1A1 and CYP2E1. CONCLUSIONS: Despite the small sample size, a total of 25 haplotypes and three single markers were identified including genomic regions not previously reported. The haplotypes that were analysed showed large effects on trait level. However, little overlap of QTL between breeds was observed. PMID- 22244369 TI - Meta-analysis on the performance of sonography for the diagnosis of carpal tunnel syndrome. AB - OBJECTIVE: We aimed to review and pool recent large methodological studies evaluating the diagnosis performance of ultrasonography vs electrodiagnostic testing (EDX). METHODS: Using the keywords: "carpal tunnel syndrome", "ultrasound", and "validity", recent articles evaluating ultrasonography compared with a reference including EDX were selected from 4 databases (PubMed, Embase, Web of science, and BDSP) and from previous review for older articles, after 2 rounds. Relevant data for different thresholds of cross-sectional area of the median nerve were extracted from the articles to calculate the pooled sensitivity, specificity, and likelihood ratios. Different analyses were also performed to study potential sources of heterogeneity, such as calculation of area under the curve, using summary receiver operating characteristic curve. RESULTS: Among the 189 articles found, 13 articles were included. A cross sectional area of the median nerve between 9.5 and 10.5 mm(2) (study included once only), found for 11 studies, gave the pooled sensitivity as 0.84 [0.81 to 0.87] and the likelihood ratio for a negative test as 0.21 [0.17 to 0.27]. Specificity (0.78 [0.69-0.88]) and the likelihood ratio for a positive test (3.74 [2.30-6.10]) were heterogeneous. For a threshold at 7.0 to 8.5 mm(2), pooled sensitivity was 0.94 [0.87 to 1.00], and for 11.5 to 13.0 mm(2) specificity was 0.97 [0.91 to 1.00]. The only significant variable on potential sources of heterogeneity was the cross-sectional area of the median nerve threshold and area under the curve was 0.87 (asymmetric). CONCLUSIONS: Pooling recent articles seems to confirm that sonography using cross-sectional area of the median nerve could not be an alternative to EDX for diagnosis of carpal tunnel syndrome but could give complementary results. PMID- 22244370 TI - Screening of anti-dengue activity in methanolic extracts of medicinal plants. AB - BACKGROUND: Dengue fever regardless of its serotypes has been the most prevalent arthropod-borne viral diseases among the world population. The development of a dengue vaccine is complicated by the antibody-dependent enhancement effect. Thus, the development of a plant-based antiviral preparation promises a more potential alternative in combating dengue disease. METHODS: Present studies investigated the antiviral effects of standardised methanolic extracts of Andrographis paniculata, Citrus limon, Cymbopogon citratus, Momordica charantia, Ocimum sanctum and Pelargonium citrosum on dengue virus serotype 1 (DENV-1). RESULTS: O. sanctum contained 88.6% of total flavonoids content, an amount that was the highest among all the six plants tested while the least was detected in M. charantia. In this study, the maximum non-toxic dose (MNTD) of the six medicinal plants was determined by testing the methanolic extracts against Vero E6 cells in vitro. Studies also determined that the MNTD of methanolic extract was in the decreasing order of M. charantia >C. limon >P. citrosum, O. sanctum >A. paniculata >C. citratus. Antiviral assay based on cytopathic effects (CPE) denoted by degree of inhibition upon treating DENV1-infected Vero E6 cells with MNTD of six medicinal plants showed that A. paniculata has the most antiviral inhibitory effects followed by M. charantia. These results were further verified with an in vitro inhibition assay using MTT, in which 113.0% and 98.0% of cell viability were recorded as opposed to 44.6% in DENV-1 infected cells. Although methanolic extracts of O. sanctum and C. citratus showed slight inhibition effect based on CPE, a significant inhibition was not reflected in MTT assay. Methanolic extracts of C. limon and P. citrosum did not prevent cytopathic effects or cell death from DENV-1. CONCLUSIONS: The methanol extracts of A. paniculata and M. charantia possess the ability of inhibiting the activity of DENV-1 in in vitro assays. Both of these plants are worth to be further investigated and might be advantageous as an alternative for dengue treatment. PMID- 22244371 TI - Systematic review of the effectiveness of non-pharmacological interventions to improve quality of life of people with dementia. AB - BACKGROUND: People with dementia report lower quality of life, but we know little about what interventions might improve it. METHODS: We systematically reviewed 20 randomized controlled trials reporting the effectiveness of non-pharmacological interventions in improving quality of life or well-being of people with dementia meeting predetermined criteria. We rated study validity with a checklist. We contacted authors for additional data. We calculated standardized mean differences (SMD) and, for studies reporting similar interventions, pooled standardized effect sizes (SES). RESULTS: Pooled analyses found that family carer coping strategy-based interventions (four studies, which did not individually achieve significance; n = 420; SES 0.24 (range 0.03-0.45)) and combined patient activity and family carer coping interventions (two studies, not individually significant; n = 191; SES 0.84 (range 0.54-1.14)) might improve quality of life. In one high-quality study, a care management system improved quality of life of people with dementia living at home. Group Cognitive Stimulation Therapy (GCST) improved quality of life of people with dementia in care homes. CONCLUSION: Preliminary evidence indicated that coping strategy-based family carer therapy with or without a patient activity intervention improved quality of life of people with dementia living at home. GCST was the only effective intervention in a higher quality trial for those in care homes, but we did not find such evidence in the community. Few studies explored whether effects continued after the intervention stopped. Future research should explore the longer-term impact of interventions on, and devise strategies to increase, life quality of people with dementia living in care homes or at home without a family carer. PMID- 22244372 TI - Psychomotor symptoms in depressed elderly patients: assessment of the construct validity of the Dutch CORE by accelerometry. AB - BACKGROUND: Psychomotor symptoms are putative distinguishing features of melancholia that may guide treatment decisions. Hence, there is a need for valid instruments to assess psychomotor symptoms. The objective of this study is to examine the construct validity of the CORE, an observational instrument designed to quantify psychomotor symptoms in depression. METHODS: Associations between CORE scores and levels of motor activity measured by accelerometry were examined in a sample of 25 elderly depressed in-patients, for various time intervals, during 24h of follow-up. RESULTS: Total CORE scores (as well as CORE retardation and agitation sub-scale scores) were negatively correlated with activity scores, with depression severity increasing the correlational strength substantively. For total CORE scores and retardation sub-scale scores, the highest associations were quantified across morning intervals. LIMITATIONS: Given the nature of the study mild levels of depression were overrepresented, monitoring of motor activity lasted only 24h and non-motor activity items in the CORE were not measured. CONCLUSION: Associations between CORE total scores and retardation sub-scale scores support the validity of the CORE as well as quantifying associations between severity of psychomotor disturbance and clinical depression severity. Study results also support the application of accelerometry tools in quantifying components of clinical depression. PMID- 22244373 TI - The effects of progress monitoring on subsequent readmission to psychiatric care: a six-month follow-up. AB - BACKGROUND: Monitoring patient progress and providing feedback to clinicians and patients about progress during therapy reduce depressive symptoms at treatment completion. However, the effects of feedback on patient outcomes following treatment completion are unknown. Accordingly, the current study aimed to examine the effect of feedback on readmission to psychiatric hospital following completion of a group psychotherapy program. METHOD: This naturalistic historical follow-up study compared the risk of readmission to a psychiatric hospital for two patient cohorts examined by Newnham et al. (2010a,b); the first cohort received feedback (n=408) during a group psychotherapy program, whereas the second cohort did not receive feedback (n=439). The sample included inpatients and day patients, with primarily depressive and anxiety disorders who routinely completed the World Health Organization's Wellbeing Index. RESULTS: Feedback was associated with fewer readmissions over the six months following completion of the therapy program for patients who, at the point of feedback, were on track to make clinically meaningful improvement by treatment termination. DISCUSSION: The findings suggest feedback could result in cost saving and is associated with improved outcomes following treatment completion for patients deemed on track during therapy. PMID- 22244374 TI - Seasonal influences on admissions for mood disorders and schizophrenia in a teaching psychiatric hospital in Egypt. AB - BACKGROUND: Distinct seasonal variation in hospital admission and various associations with the climatic parameters for mood disorders and schizophrenia have been previously reported in several world regions. There are, however, no North-African studies on this association. METHODS: The charts of 1987 patients with mood disorders (mania 1181, depression 806) and 1359 patients with schizophrenia admitted from 2003 to 2007 from an university hospital at Mansoura, Egypt, were reviewed. Seasonality was assessed with Cosinor Analysis. Correlations of the rate of admissions for affective disorders and schizophrenia to climatic variables were performed, including lagged and differenced data. RESULTS: There was a significant seasonal variation in the monthly admission frequencies both for mania (peak in June) and for depression (peak in December) but no significant seasonal variation was found in admissions with diagnosis of schizophrenia. The number of admissions for mania was positively correlated to indicators of temperature and luminosity, but inversely correlated to relative humidity. Quite the opposite, the number of admissions for depression showed a negative correlation to temperature and luminosity, but a positive correlation to relative humidity. 55-57% of the monthly variance of the number of admissions for mood disorders was explained by climatic variables. CONCLUSIONS: Seasonality of admissions for mood disorders, but not for schizophrenia, has been demonstrated, in an African Mediterranean region with a fairly constant climate. The association between admission rates and climatic variables found in this study could pave the way for further studies aiming at exploration of the biological mechanism of this association as well as tailoring of treatment interventions on mood disorders. PMID- 22244376 TI - Intrusive memories and depression following recent non-traumatic negative life events in adolescents. AB - BACKGROUND: Research in adults suggests that intrusive memories are not just found in individuals with post-traumatic stress disorder (PTSD), yet there is little evidence concerning the phenomenology of intrusive memories in children and adolescents. The present study investigated the frequency of intrusive memories following a recent negative event in an adolescent school sample, and considered the application of cognitive theory to understanding the maintenance of intrusive memories of recent negative events, and their role in maintaining depression. METHODS: High school students (aged 11-18 years; n=231) completed questionnaires concerning affect experienced during a recent negative event, the frequency of subsequent intrusive memories, memory quality, thought suppression, post-traumatic stress and depressive symptoms. RESULTS: Most participants had experienced at least one intrusive memory in the previous week, at similar rates for traumatic events and life events. In non-trauma exposed youth, peri-event affect and memory quality accounted for unique variance in a regression model of intrusive memory frequency, while peri-event affect, memory quality, and intrusive memory frequency accounted for unique variance in a regression model of depression. LIMITATIONS: The study needs replication in younger children. Interview methods may be required to ensure that intrusive memories are being assessed and not intrusive thoughts or ruminations. CONCLUSIONS: Intrusive memories are common reaction to negative events in adolescents, and may be involved in maintaining subsequent depressed mood. The nature of event memories may have a role in the maintenance of such psychopathology, and may be a target for psychological interventions in this age group. PMID- 22244375 TI - Depression as a disease of modernity: explanations for increasing prevalence. AB - There has been much speculation about modern environments causing an epidemic of depression. This review aims to (1) determine whether depression rates have increased and (2) review evidence for possible explanations. While available data indicate rising prevalence and an increased lifetime risk for younger cohorts, strong conclusions cannot be drawn due to conflicting results and methodological flaws. There are numerous potential explanations for changing rates of depression. Cross-cultural studies can be useful for identifying likely culprits. General and specific characteristics of modernization correlate with higher risk. A positive correlation between a country's GDP per capita, as a quantitative measure of modernization, and lifetime risk of a mood disorder trended toward significance (p=0.06). Mental and physical well-being are intimately related. The growing burden of chronic diseases, which arise from an evolutionary mismatch between past human environments and modern-day living, may be central to rising rates of depression. Declining social capital and greater inequality and loneliness are candidate mediators of a depressiogenic social milieu. Modern populations are increasingly overfed, malnourished, sedentary, sunlight deficient, sleep-deprived, and socially-isolated. These changes in lifestyle each contribute to poor physical health and affect the incidence and treatment of depression. The review ends with a call for future research and policy interventions to address this public health crisis. PMID- 22244377 TI - Low trait anxiety, high resilience, and their interaction as possible predictors for treatment response in patients with depression. AB - BACKGROUND: Although many demographic and clinical characteristics have been suggested to predict treatment outcome of depression, they provide only a weak prediction for clinical response. Based on the predictive values of trauma and biological markers involved in stress response, we investigated the roles of baseline trait anxiety and resilience, which were assumed as vulnerability and resilience factors, respectively, in predicting treatment response in naturalistically treated outpatients with depressive disorders. METHODS: A total of 178 outpatients with depressive disorders were consecutively recruited and completed measures of trauma experiences, psychological symptoms, and resilience at baseline. Response was defined by Clinical Global Impression (CGI)-Improvement score <=2 at last visit during a 6month-treatment period. Univariate analyses and multiple logistic regression analysis were performed to determine predictors of treatment response. RESULTS: Among demographic and clinical variables, treatment response was associated with increased age, longer treatment duration, higher resilience, and lower trait anxiety. In logistic regression analysis, resilience, trait anxiety, and their interaction significantly predicted treatment response after adjusting for age and treatment duration. Interaction between resilience and trait anxiety remained significant in the final model. Examining the interaction between the two, patients with low trait anxiety were only significantly affected by the level of resilience in response rate. CONCLUSIONS: Low trait anxiety, high resilience, and their interaction might contribute to better treatment response in depressed patients. Our result suggested that individual differences in responding to stress might be important in predicting treatment outcome of depression in addition to other demographic and clinical factors. PMID- 22244378 TI - Parieto-temporal alpha EEG band power at baseline as a predictor of antidepressant treatment response with repetitive Transcranial Magnetic Stimulation: a preliminary study. AB - BACKGROUND: The aim of this preliminary study was to determine the predictive value of absolute alpha band power measured during the rest EEG eyes closed task for responses to 20 sessions of high frequency repetitive transcranial stimulation (rTMS) in the left dorsolateral prefrontal cortex in patients with pharmacoresistant major depressive episode. METHODS: 13 major depressive disorders (8 males) and 8 bipolar disorders (6 males) were included (mean age 58years). Spearman correlations between pretreatment alpha band power in height regions of analysis and absolute improvement in Beck Depression Inventory Short Form (DeltaBDI-SF) were analyzed. The predictive value of alpha band power for classifying patients as responders and non-responders to rTMS was determined using Receiver Operating Characteristic (ROC) curve. RESULTS: Spearman correlation analysis revealed that DeltaBDI-SF correlated significantly and negatively with alpha band power on the right (r=-.673, p=.001) and left parieto temporal regions (r=-.638, p=.002). The area under the ROC curve for the right parieto-temporal was .815, p=.0037. The cut-off point that maximized both sensitivity and specificity was 1.49MUV. Sensitivity, specificity, positive and negative predictive values were 100, 66, 80, 100% respectively. LIMITATIONS: The population was small and lacked homogeneity concerning affective disorders (unipolar and bipolar disorder). The use of a self-rating subjective scale (BDI SF) to measure the severity of depression could be criticized. CONCLUSIONS: Pretreatment alpha band power on parieto-temporal regions could be a predictor for response to rTMS in patients with homogenous demographic/clinical features. The association between electrical activity and the perfusion under each electrode need to be examined. PMID- 22244379 TI - Psychometric validation and clinical validity of the Minor Melancholia Mood Checklist (MMCL-32). AB - BACKGROUND: The Minor Melancholia Mood Checklist (MMCL-32) was developed to identify sub-threshold states of major depression. The MMCL-32 can be considered as the counterpole to the Hypomanic Check List (HCL-32). METHODS: Principal component analysis (PCA) without rotation was used to identify a bidirectorial principal component. To evaluate the clinical validity of the bidirectorial factors, with reference to brief recurrent depression, the Bech-Rafaelsen Melancholia Scale was used. RESULTS: We included 59 patients with bipolar I disorder (SCID criteria) and 57 patients with unipolar depression (more than one major depressive episode without hypomanic or manic episodes). They were all outpatients, but had recently been discharged from inpatient treatment. The PCA identified two contrasting factors: 17 items with negative loadings (psychasthenic depression factor) and 15 items with positive loadings (cognitive depression factor). When PCA was applied exclusively to the bipolar patients, 5 items within the cognitive factor were identified. When applied exclusively to the unipolar patients, 5 items within the psychasthenic factor were identified. The non-remitted bipolar patients scored higher on the cognitive factor (P=0.01) than the remitted. On the psychasthenic factor (P=0.06), the non-remitted unipolar patients scored higher than the remitted patients. CONCLUSION: The MMCL 32 was found psychometrically valid in measuring sub-threshold states of major depression with rather specific factors for bipolar and unipolar depression. Focusing on these factors could be a clinical aid to distinguish patients at risk of developing a bipolar course. PMID- 22244380 TI - Role of polar and nonpolar residues at the active site for PPIase activity of FKBP22 from Shewanella sp. SIB1. AB - FKBP22 from the psychotropic bacterium Shewanella sp. SIB1 is a homodimeric protein with peptidyl prolyl cis-trans isomerase (PPIase) activity. According to a tertiary model, several nonpolar residues including Trp157 and Phe197 form a substrate-binding cavity, and Asp137 and Arg142, which form a salt bridge, are located at the edge of this cavity. To analyze the role of these residues, nine single (D137A, R142A, W157A/F/Y, F197A/L/Y/W) and one double (D137A/R142A) mutant protein of SIB1 FKBP22 were constructed. The far- and near-UV CD spectra of these mutant proteins suggest that the mutations at Asp137 and Arg142 do not seriously affect the protein structure, while those at Trp157 and Phe197 cause a local conformational change around the mutation site. Each mutation decreased the PPIase activities of SIB1 FKBP22 for peptide and protein substrates similarly without seriously affecting chaperone function. This result indicates that SIB1 FKBP22 does not require PPIase activity for chaperone function. The PPIase activities of R142A, D137A and D137A/R142A decreased in this order, suggesting that Asp137 and Arg142 play a principal and auxiliary role in catalytic function, respectively, but Arg142 can function as a substitute of Asp137. Because the PPIase activity of SIB1 FKBP22 was not fully lost by the removal of all polar residues around the active site, the desolvation effect may also contribute to the enzymatic activity. However, the mutations of Trp157 to Phe or Phe197 to Leu greatly decrease the enzymatic activity, suggesting that the shape of the substrate-binding cavity is also important for enzymatic activity. PMID- 22244381 TI - Diabetes mellitus, myocardial reperfusion, and outcome in patients with acute ST elevation myocardial infarction treated with primary angioplasty (from HORIZONS AMI). AB - Diabetes mellitus (DM) increases mortality in acute ST-segment elevation myocardial infarction (STEMI) but the responsible mechanism is not fully elucidated. We compared the rate of successful myocardial reperfusion measured by tissue myocardial perfusion grade (TMPG) and outcomes in patients with and without DM undergoing primary percutaneous coronary intervention (PCI) for STEMI. Patients enrolled in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS AMI) trial were analyzed according to presence of DM with respect to TMPG after PCI and outcomes at 30 days and 3 years. Multivariable logistic regression was performed to identify the independent contribution to mortality of DM and TMPG and the interaction between the 2 was assessed. Complete data were available for 3,265 patients, of whom 533 (16.3%) had DM. Diabetic patients were significantly older and heavier and had more risk factors for coronary disease and more previous MI, revascularization, and heart failure. There were no differences in rates of Thrombolysis In Myocardial Infarction grade 3 flow after PCI in the infarct artery or TMPG 2/3 between patients with and without DM. Compared to nondiabetics, mortality was significantly higher at 30 days and at 3 years in the DM group (1.8% vs 4.5%, p = 0.0002 and 5.4% vs 11.0%, p <0.0001, respectively). DM and TMPG were significantly associated with 3-year mortality, but there was no statistical interaction between DM and TMPG (p = 0.70). In conclusion, DM is associated with a significantly higher risk of death but this association is not mediated by impaired epicardial or myocardial reperfusion. PMID- 22244382 TI - Functional health status in adult survivors of operative repair of tetralogy of fallot. AB - We aimed to determine late functional health status of the growing adult population with repaired tetralogy of Fallot (TOF). We studied all 840 patients with TOF born from 1927 through 1984 who survived to adulthood (> 18 years of age). Clinical follow-up was by chart review, telephone interview (n = 706), and echocardiographic reports (n = 339). Functional health status was assessed using Short Form-36 (SF-36) surveys (n = 396) indexed to normative data. Risk of reoperation was low (~ 1%/year) but increased beyond age 40 years. At latest follow-up moderate or severe pulmonary regurgitation was common (54%) and right ventricular outflow tract stenosis presented in 1/3. Consequently, evidence of right ventricular dilatation and dysfunction and tricuspid regurgitation was typical. Left-sided abnormalities were also common: hypertrophy (p < 0.0001) and outflow tract dilation (p < 0.0001) with at least mild aortic regurgitation in > 50%. Cardiorespiratory symptoms were reported in 45% (palpitations 27%, dyspnea 21%, chest pain 17%). SF-36 scores were significantly below normal for 4 physical domains (p < 0.001). Decrements in physical functioning were associated particularly with older age at follow-up (p < 0.0001), associated syndromes/lesions, reoperations, ventricular dysfunction, tricuspid regurgitation, residual septal defects, and cardiorespiratory symptomatology. Echocardiographic abnormalities were more common in older patients (p < 0.0001). All 3 SF-36 domains specific to psychosocial well-being were normal. In conclusion, despite excellent survival prospects, physical compromise is common in adults with repaired TOF. Greater decrements in older patients may reflect late deterioration with advancing age or cohort effects related to historical management. Efforts to limit ventricular and outflow tract dysfunction may translate into improved late functional status. PMID- 22244383 TI - The Anatomische Gesellschaft and National Socialism - A preliminary analysis based on the society proceedings. AB - The Anatomische Gesellschaft (AG) is an international society for the anatomical sciences and at the same time the main organising body for German anatomists. This study analyses how the AG went through the years of National Socialism. As the society does not possess archival material from that time, the analysis is mainly based on the society proceedings (Verhandlungen der Anatomischen Gesellschaft) published annually after each meeting from 1934 to 1939 and again in 1950. During the period of National Socialism, the AG kept its international status against demands to make it a purely German society. It did not introduce anti-Jewish regulations or the Fuhrer principle into its bylaws. The membership directories reveal that it was at least possible for members whose career was disrupted by Nazi policies to remain on the membership lists throughout the Nazi period. However, in contrast to later assumptions that no persecuted member of the AG was ever struck from its register, 17 of 57 persecuted members left the society between 1933 and 1939. The membership of six of these members was cancelled, officially for unpaid fees. However, other members with much longer arrears were not cancelled. To date, no additional historical information is available to assess the circumstances of these cancellations. In general, it remains remarkable that, in contrast to many other societies, the AG did not follow the path of preemptive obedience towards the new rulers. More archival sources need to be uncovered to elucidate the external influences and internal negotiations behind the published documents. PMID- 22244384 TI - Bone level change of extraction sockets with Bio-Oss collagen and implant placement: a clinical study. AB - AIMS: To compare the reaction of the alveolar bone to the preservation of the extraction socket by Bio-Oss Collagen with and without combination of implant treatment. To evaluate whether early implant insertion 8-10weeks thereafter could be a suitable time point for long term bone stability around the implant. METHODS: A total of 25 patients were divided into three groups: The first group (seven patients) received Bio-Oss Collagen after extraction and 8-10weeks later an implant, the second group (eight patients) received only Bio-Oss Collagen without implantation thereafter, while the third group was considered as a control (eleven patients), where the sockets healed without any treatment. The change in the vertical bone level of the alveolar crests were measured from panoramic radiographs and statistically analysed. RESULTS: Bone level change was significantly less for Group 1 than Group 3 (P<0.001), while was not significantly different for Group 2 and Group 3 (P=0.23). However, the rate of bone level change per year was statistically smaller for Group 1 compared to Group 3 (P=0.019) and as well as for Group 1 than for Group 2 (P=0.003), whereas the change per year was not significantly different for Group 2 vs. Group 3 (P=0.122). CONCLUSION: Bone level preservation of extraction sockets using Bio Oss Collagen with implantation is significantly better compared to using Bio-Oss Collagen only and untreated sockets. Implant insertion 8-10weeks after extraction is a suitable time point after socket augmentation. PMID- 22244385 TI - Health care quality, access, cost, workforce, and surgical education: the ultimate perfect storm. AB - The discussions on health care reform over the past two years have focused on cost containment while trying to maintain quality of care. Focusing on just cost and quality unfortunately does not address other very important factors that impact on our health care delivery system. Availability of a well-trained workforce, maintaining the sophisticated medical/surgical education system, and ultimately access to quality care by the public are critical to maintaining and enhancing our health care delivery system. Unfortunately, all five of these components are under at risk. Thus, we have evolving the ultimate perfect storm affecting our health care delivery system. Although not ideal and given the uniqueness of our population and their expectations, our current delivery system is excellent compared to other countries. However, the cost of our current system is rising at an alarming rate. Currently, health care consumes 17% of our gross domestic product. If our system is not revised this will continue to rise and by 2025 it will consume 48%. The dilemma, given the current state of our overall economy and rising debt, is how to address this major problem. Unfortunately, the Affordable Care Act, which is now law, does not address most of the issues and the cost was initially grossly under estimated. Furthermore, the law does not address the issues of workforce, maintaining our medical education system or ultimately, access. A major revision of our system will be necessary to truly create a system that protects and enhances all five of the components of our health care delivery system. To effectively accomplish this will require addressing those issues that lead to wasteful spending and diversion of our health care dollars to profit instead of care. Improved and efficient delivery systems that reduce complications, reduction of duplication of tertiary and quaternary programs or services within the same markets (i.e. regionalization of care), health insurance reform, and tort reform collectively could save hundreds of billion dollars per year! These changes may not be easy to accomplish politically but will be essential to save what is likely the best health care system in the world. PMID- 22244386 TI - Notes on the early development of pediatric surgery in the United States. AB - This lecture addresses the leadership roles in American surgery. PMID- 22244387 TI - Regenerative medicine strategies. AB - Applications of regenerative medicine technology may offer novel therapies for patients with injuries, end-stage organ failure, or other clinical problems. Currently, patients suffering from diseased and injured organs can be treated with transplanted organs. However, there is a severe shortage of donor organs that is worsening yearly as the population ages and new cases of organ failure increase. Scientists in the field of regenerative medicine and tissue engineering are now applying the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. The stem cell field is also advancing rapidly, opening new avenues for this type of therapy. For example, therapeutic cloning and cellular reprogramming may one day provide a potentially limitless source of cells for tissue engineering applications. While stem cells are still in the research phase, some therapies arising from tissue engineering endeavors have already entered the clinical setting successfully, indicating the promise regenerative medicine holds for the future. PMID- 22244388 TI - The history of paediatric surgery in the United Kingdom and the influence of the national health service on its development. AB - Details of the modern history of paediatric surgery in the United Kingdom with particular emphasis on the 3 main training centres in England in the 1960s to 1970s are discussed. The genesis of the National Health Service and of the British Association of Paediatric Surgeons and their influence on the establishment and sitting of regional centres, education and training, and centralization of rare conditions is highlighted. PMID- 22244389 TI - Microcystic congenital pulmonary airway malformation with hydrops fetalis: steroids vs open fetal resection. AB - BACKGROUND/PURPOSE: Congenital pulmonary airway malformations (CPAM) are rare lesions often diagnosed during routine prenatal ultrasound. The presence of hydrops fetalis is an indicator of poor prognosis. Here we present a retrospective review of fetuses undergoing either open fetal surgery or steroids for predominantly microcystic CPAM with hydrops fetalis. METHOD: A retrospective review of patients undergoing open fetal surgery or steroids for CPAM at our institution was performed. The primary outcome was survival. RESULTS: A retrospective review of all patients referred to our institution with the diagnosis of CPAM was performed. Fetuses with predominantly microcystic CPAM and the presence of hydrops fetalis treated with steroid or surgery were included. Thirteen patients were treated with steroids, and 11 patients underwent open fetal surgery. In the steroid group 12 (92%) of 13 fetuses survived to delivery versus 9 (82%) of 11 in the open fetal surgery group. Only 5 (56%) of 9 of the patients in the open fetal surgery group survived to neonatal discharge compared to 10 (83%) of 12 in the steroid group. CONCLUSIONS: In the present retrospective study, improved survival was seen in fetuses with hydrops fetalis and predominantly microcystic CPAM treated with steroids when compared with open fetal surgery. Steroids should be considered for first-line therapy in these cases. PMID- 22244390 TI - Defining hydrops and indications for open fetal surgery for fetuses with lung masses and vascular tumors. AB - PURPOSE: The aim of this study was to identify the most accurate prenatal predictors of outcomes and need for fetal surgery for fetuses with high-risk lung masses and vascular tumors. METHODS: The records of all fetuses with high-risk lung mass (congenital cystic adenomatoid malformation-volume ratio > 1.6 or findings of hydrops) and vascular tumor evaluated between July 2001 and March 2011 were reviewed retrospectively. Hydrops was defined as accumulation of fluid in 2 or more compartments. RESULTS: Of fetuses with high-risk lung mass, hydrops was identified in 46% (11/24). Fetuses with hydrops and an abnormal echocardiogram (n = 8) demonstrated poor survival without fetal surgery (13%) compared with 100% survival in fetuses with hydrops and a normal echocardiogram (n = 3; P = .02). Of 21 fetuses with vascular tumor (11 sacrococcygeal and 8 cervical teratomas; 2 hemangioendotheliomas), hydrops was identified in 29% and an abnormal echocardiogram in 57%. All fetuses with hydrops had an abnormal echocardiogram and either died (n = 5) or required fetal surgery (n = 1). However, all fetuses with abnormal echocardiograms alone (n = 7) survived without fetal intervention. CONCLUSIONS: For fetuses with lung mass, an abnormal echocardiogram in the setting of hydrops is the best predictor of mortality and need for fetal surgery. For fetuses with vascular tumor, hydrops in the setting of high-output physiology best predicts demise and need for fetal surgery. PMID- 22244391 TI - Tracheoesophageal displacement index and predictors of airway obstruction for fetuses with neck masses. AB - PURPOSE: There are no established selection guidelines to determine which fetuses with giant neck masses may benefit from delivery using an ex utero intrapartum treatment procedure. The purposes of this study were to describe the tracheoesophageal displacement index (TEDI), a novel measurement of fetal airway displacement, and to correlate this measurement and other prenatal findings to the extent of airway obstruction at birth. METHODS: The medical records of all fetuses with giant neck masses evaluated between 2001 and 2011 were reviewed. At birth, each infant's airway was categorized as uncomplicated or complicated. Prenatal variables were correlated with airway difficulty. RESULTS: There were 24 fetuses with large neck masses (11 lymphatic malformations, 10 teratomas, 3 others). One fetus died in utero, and 3 underwent pregnancy termination. Variables associated with a complicated airway at birth included polyhydramnios, teratoma diagnosis, and tracheoesophageal displacement index. Tracheoesophageal displacement index greater than 12 correlated strongly with a complicated airway (area under the curve = 0.80). All fetuses classified with an uncomplicated airway (n = 7) had a diagnosis other than teratoma and normal amniotic fluid volume. CONCLUSION: In fetuses with giant neck masses, the presence of polyhydramnios, teratoma diagnosis, or tracheoesophageal displacement index greater than 12 are predictive of a complicated airway at birth. Our data suggest that fetuses without any of these findings may be delivered safely without an ex utero intrapartum treatment approach. PMID- 22244392 TI - Long-term morbidity after fetal endoscopic surgery for severe twin-to-twin transfusion syndrome. AB - BACKGROUND/PURPOSE: Severe twin-to-twin transfusion syndrome (TTTS) leads to 80% to 100% dual mortality. Endoscopic laser coagulation of connecting vessels improves outcome to 80% survival of at least 1 twin. There is limited long-term follow-up of surviving TTTS patients. The aim of this study was to analyze gestational age-stratified, long-term morbidity in these patients. METHODS: A retrospective case-control study of TTTS surviving patients (38 patients, 72% follow-up rate) from one center. Perinatal and pediatric records were reviewed, and outcomes were compared with published reports and gestational age-matched controls. RESULTS: Forty percent (15/38) had at least 1 major sequela, all but 6 of which were fully resolved at a median follow-up of 4.4 years. There were no permanent cardiac, genitourinary, renal, or respiratory sequelae. All major complications were in patients born <29 weeks. There were no significant differences in complications between this cohort of patients and gestational age (GA)-matched control patients. CONCLUSIONS: The long-term morbidity of monochorionic twins after fetal laser surgery for severe TTTS is 13%. At a median follow-up of more than 4 years, these children fare no worse than gestational age matched, non-operated twins and singletons. The degree of prematurity at birth is the best predictor of temporary or permanent sequela in this group of patients. PMID- 22244393 TI - The congenital diaphragmatic hernia composite prognostic index correlates with survival in left-sided congenital diaphragmatic hernia. AB - PURPOSE: We developed the congenital diaphragmatic hernia congenital prognostic index (CDH-CPI) to incorporate all known prognostic variables into a single composite index to improve prognostic accuracy. The purpose of this study is to examine the ability of the CDH-CPI to predict survival in patients with left sided congenital diaphragmatic hernia and to determine if the index has a stronger correlation with survival than each of the individual components. METHODS: A retrospective review of patients with left-sided congenital diaphragmatic hernia between 2004 and 2010 was conducted. Ten prenatal parameters of the CDH-CPI were collected, total score was tabulated, and patients stratified according to total score and survival. RESULTS: Sixty-four patients with a prenatal diagnosis of left-sided congenital diaphragmatic hernia were identified. Patients with a CDH-CPI score of 8 or higher had a significantly higher survival than patients with a CDH-CPI score of lower than 8. The CDH-CPI has the strongest correlation with survival compared with the individual parameters measured. The CDH-CPI correlates with extracorporeal membrane oxygenation use, and 75% of patients with a score of 5 or lower were placed on extracorporeal membrane oxygenation. CONCLUSIONS: The CDH-CPI accurately stratifies survival in left sided congenital diaphragmatic hernia. The amalgamation of 10 prenatal parameters of the CDH-CPI may be a better prenatal predictor than any single prognostic variable currently used. PMID- 22244394 TI - Improved survival in venovenous vs venoarterial extracorporeal membrane oxygenation for pediatric noncardiac sepsis patients: a study of the Extracorporeal Life Support Organization registry. AB - BACKGROUND/PURPOSE: There are few studies comparing venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation (ECMO) in pediatric noncardiac sepsis patients. METHODS: Following approval, we reviewed the Extracorporeal Life Support Organization registry data from 1990 to 2008 for patients 0 to 18 years with a diagnosis of sepsis and without diagnosis of congenital heart disease. Survival to discharge was compared between VA and VV ECMO using chi(2) analysis and multivariable logistic regression. RESULTS: Four thousand three hundred thirty-two ECMO runs were reviewed, 3256 VA (75%) and 1076 VV (25%). A majority of VA modality was noted in each decade studied. Overall survival was 68% and was higher in VV (79%) than in VA ECMO (64%, P < .001). Survival decreased with increasing age (73% in newborns <= 1 month, 40% in children 1 month to 12 years, and 32% in adolescents >12 years, P < .001). VA ECMO had increased mortality risk after adjustment for age, use of vasoactive agents, and advanced respiratory support (odds ratio, 2.06; 95% confidence interval, 1.74-2.44; P < .001). CONCLUSIONS: These data demonstrate improved survival in VV vs. VA ECMO in select pediatric septic patients without congenital heart disease. When technically feasible, physicians should consider VV ECMO as first therapeutic choice in this patient population. PMID- 22244395 TI - Extracorporeal membrane oxygenation cannulation trends for pediatric respiratory failure and central nervous system injury. AB - BACKGROUND: Guidelines regarding arterial cannula site and cannula site-specific risks of central nervous system (CNS) injury for pediatric patients requiring extracorporeal membrane oxygenation (ECMO) support are lacking. We reviewed cannulation trends for pediatric respiratory failure and evaluated CNS complication rates by cannulation site and mode of support. METHODS: The Extracorporeal Life Support Organization (ELSO) registry was queried for all pediatric respiratory failure patients <18 years treated from 1993-2007. The primary outcome was radiographic evidence of CNS injury. RESULTS: Venoarterial (VA) support was used in 62% of 2617 ECMO runs. The carotid artery was used in 93% of VA patients. Femoral artery use increased in patients >5 years of age and >20 kg. Venovenous (VV) ECMO was used in >50% of children >10 years. No significant difference was identified in CNS injury between carotid and femoral cannulation in any age group but the femoral group was small (4.4%). VA support was independently associated with increased odds of CNS injury compared to VV cannulation (OR, 1.6). CONCLUSION: VA ECMO is the most common mode of support in pediatric respiratory failure patients. Although no significant difference in CNS injury was noted between carotid and femoral artery cannulation, the odds of injury were significantly higher than VV support. PMID- 22244396 TI - Utility of neuroradiographic imaging in predicting outcomes after neonatal extracorporeal membrane oxygenation. AB - BACKGROUND: The need for routine neuroimaging after extracorporeal membrane oxygenation (ECMO) and the optimal radiographic study remains unclear. We sought to evaluate the correlation between findings on head ultrasound (HUS) and magnetic resonance imaging (MRI) and determine the association of these findings to neurodevelopmental outcome. METHODS: A retrospective review was performed (2003-2010) to identify neonates who had a MRI after ECMO. Each MRI was reviewed by a single pediatric neuroradiologist. Neurodevelopmental data was collected from the high-risk neonatal follow-up clinic. RESULTS: Fifty neonates had a MRI (venoarterial 37, venovenous 13) after ECMO. HUS was abnormal in 24%, whereas MRI was abnormal in 62%. All infants with an abnormal HUS had an abnormal MRI, but an additional 50% of patients with a normal HUS had an abnormal MRI. Venoarterial ECMO was significantly associated with an abnormal MRI. Follow-up data was available for 26 neonates. The only predictor of abnormal neurodevelopment was the need for supplemental tube feeds at discharge. CONCLUSIONS: MRI identified significantly more abnormalities compared to routine HUS after neonatal ECMO. However, neither MRI nor HUS findings correlated with early neurodevelopmental outcome. Feeding ability at discharge was the overall best predictor of neurologic impairment in survivors. PMID- 22244397 TI - Split abdominal wall muscle flap repair vs patch repair of large congenital diaphragmatic hernias. AB - PURPOSE: Large congenital diaphragmatic hernias are commonly repaired with a prosthetic patch. We hypothesized that a split abdominal wall muscle flap would reduce the risk of recurrence. METHODS: A retrospective review of neonates with congenital diaphragmatic hernia in whom primary repair was not possible was performed. Kaplan-Meier analyses and Cox proportional hazards modeling were performed. RESULTS: Of 153 patients, 46 could not have repair with primary closure of the diaphragm. Thirty-three survived to discharge and were subjected to analysis for recurrence. Ten underwent repair with a patch, whereas 23 had a muscle flap (internal oblique and transversalis) patch. The groups were similar with regard to demographics, need for extracorporeal membrane oxygenation, repair on extracorporeal membrane oxygenation, and size of the defect. Fifty percent of patch repairs recurred with a median time of 0.5 years. Only one (4.3%) of the patients who had muscle flap patch developed a recurrence. This was significant on Kaplan-Meier analysis (P = .0009) and had a hazard ratio of 14.3 on Cox regression (P = .018). Median follow-up exceeded 4 years. No children required surgery for an abdominal wall hernia. CONCLUSIONS: The split abdominal wall muscle flap allows for closure of large congenital diaphragmatic hernia defects with autologous tissue. This approach is associated with significantly fewer recurrences than patch repairs. PMID- 22244398 TI - Congenital lung anomalies: can we postpone resection? AB - BACKGROUND/PURPOSE: The management of asymptomatic congenital lung lesions is controversial. It is unclear whether elective resection provides a significant benefit. We sought to determine whether early vs delayed resection of asymptomatic congenital lung malformations resulted in complications. METHODS: Institutional billing records were queried for patients with lung malformations over a 10-year period. Medical records were reviewed for demographics, type of anomaly, symptoms, management, and procedural or disease-related complications. RESULTS: Eighty-seven patients were identified. The diagnoses included congenital cystic adenomatoid malformation (41%), bronchogenic cyst (19.3%), sequestration (13.2%), and congenital lobar emphysema (12.0%). Fifty patients were observed for some period. Eleven became symptomatic, and 47 underwent resection at a mean age of 11 months. There was no difference in the type of resection, length of hospitalization, or complication rate between patients who underwent early vs delayed resection. There were no occurrences of malignancy or death. CONCLUSIONS: In our series, there was no difference in measurable outcomes between early and delayed resection of congenital lung lesions. These data provide some support for a management strategy that might include observation with delayed resection for asymptomatic patients. PMID- 22244399 TI - Pyloromyotomy: randomized control trial of laparoscopic vs open technique. AB - PURPOSE: Open pyloromyotomy remains as the criterion standard treatment for hypertrophic pyloric stenosis with the laparoscopic approach rapidly gaining adoption. We present a prospective, randomized trial between the 2 approaches. METHODS: After institutional review board approval, 98 patients with hypertrophic pyloric stenosis were consecutively randomized to either open or laparoscopic pyloromyotomy. Postoperative and hospital course were evaluated by review of the hospital records and long-term follow-up with scripted telephone survey using Likert scales. The length of operating room time, surgical procedure, postoperative stay, time to refeeding, and complications were evaluated. Secondary outcomes of cosmetic results and parental satisfaction were determined. RESULTS: Ninety-eight patients were enrolled during a 4-year period. There were no significant differences between 2 groups on all primary outcomes. There were 3 complications in the open group-a wound dehiscence, a surgical site infection, and a gastric serosal tear-and 2 complications in the laparoscopic group-mucosal perforation and a suture granuloma. In long-term follow-up on 72 patients (56 months), parents described significant cosmetic results with laparoscopic approach. CONCLUSIONS: There was no difference in operating time, hospital stay, or refeeding patterns between open and laparoscopic pyloromyotomy. The complication rates were similar between the 2 methods. However, long-term cosmetic results were significantly superior in the laparoscopic group. PMID- 22244400 TI - A novel antireflux procedure: gastroplasty with restricted antrum to control emesis (GRACE). AB - PURPOSE: Nissen fundoplication is the most commonly performed operation to treat gastroesophageal reflux disease and vomiting in children with neurologic impairment. However, failure rates of Nissen fundoplication in this population are higher, and alternatives to Nissen fundoplication have technical and functional disadvantages. We hypothesize that the novel gastroplasty with restricted antrum to control emesis (GRACE) would be more effective than Nissen fundoplication at reducing emetic reflux. METHODS: To compare the GRACE with Nissen fundoplication, 15 canine subjects were randomized to Nissen fundoplication or GRACE. All subjects underwent gastrostomy tube placement. Baseline gastric emptying, electrogastrography, and induced vomiting studies were performed. Nissen fundoplication or GRACE was then performed. Postoperatively, gastric emptying and vomiting studies were repeated. RESULTS: Gastric emptying before and after antireflux procedures was not significantly different between groups. Both Nissen fundoplication (38%, P = .04) and GRACE (69%, P < .01) procedures prevented reflux compared with baseline. However, the GRACE procedure significantly reduced reflux when compared with Nissen fundoplication (P = .03). CONCLUSIONS: In this canine model, GRACE appears to be significantly more effective than Nissen fundoplication at reducing emetic reflux. This novel procedure preserves gastric function and is well tolerated. The GRACE procedure may provide an alternative to Nissen fundoplication as a primary or repeat antireflux procedure for children with neurologic impairment. PMID- 22244401 TI - Agency for Healthcare Research and Quality pediatric indicators as a quality metric for surgery in children: do they predict adverse outcomes? AB - BACKGROUND/PURPOSE: The pediatric quality indicators (PDIs) were developed by the Agency for Healthcare Research and Quality to compare patient safety and quality of pediatric care. These are being considered for mandatory reporting as well as pay-for-performance efforts. The present study evaluates the PDIs' predictive value for surgical outcomes in children. METHODS: A cross-sectional study was performed using nationwide inpatient data from 1988 to 2007. Patients younger than 18 years with an inpatient surgical procedure were included and evaluated for 10 PDIs. Odds ratios for mortality, increase in length of stay, and total charges were calculated using multivariate regression adjusting for age, sex, race, region, hospital type, and comorbidities. RESULTS: A total of 1,964,456 pediatric discharges were included. Mortality rates were 5.4% for patients with at least 1 PDI and 0.6% for those with none. Multivariate analysis showed that occurrence of any PDI was associated with a 20% increased risk of mortality. The PDIs were associated with an increased length of stay and total hospital charges. CONCLUSION: The present study shows that PDIs are associated with increased mortality risk as well as increased hospital stay and total hospital charges. This provides positive evidence for the utility of these indicators as metrics for quality and patient safety. PMID- 22244402 TI - Quality improvement and patient care checklists in intrahospital transfers involving pediatric surgery patients. AB - BACKGROUND: Intrahospital transfers are necessary but hazardous aspects of pediatric surgical care. Plan-Do-Study-Act processes identify risks during hospitalization and improve care systems and patient safety. METHODS: A multidisciplinary team developed a checklist that documented patient data and handoffs for all intrahospital transfers involving pediatric surgical inpatients. The checklist summarized major clinical events and provided concurrent summaries by 3-month quarters (Q) over 1 year. RESULTS: There were 903 intrahospital transfers involving 583 inpatients undergoing surgery. Total handoffs were documented in 436 (75% of 583), with greater than 1 handoff in 202 (46% of 436). Documented problems occurred in 31 transfers (3.4%), the most during Q1 (19/191; 9.9%). Incidence fell to 3.5% (9/260) in Q2, 0.4% (1/243) in Q3, and 1.0% (2/209) in Q4 (P < .001). Patient care issues (14/31; 45%) were most common, followed by documentation (10, 32%) and process problems (7, 23%). The quality improvement team was able to resolve patient instability during transport (5 in Q1, none in Q3, Q4) and poor pain control (3 in Q2, 1 in Q3, Q4). Of the patients, 3.2% had identified problems with patient care during intrahospital transfer. CONCLUSIONS: Plan-Do-Study-Act review emphasizes ongoing process analysis by multidisciplinary teams. Checklists reinforce communication and provide feedback on whether system goals are being achieved. PMID- 22244403 TI - The jury is still out: changes in gastroschisis management over the last decade are associated with both benefits and shortcomings. AB - PURPOSE: Management of gastroschisis has shifted from early primary closure to preformed silo placement and delayed closure. We aimed to identify how closure techniques have changed and how outcomes have been affected. METHODS: Records of patients undergoing gastroschisis closure at a single institution from 2000 to 2009 were reviewed. Patient characteristics and outcomes were collected and compared among those undergoing primary closure vs preformed silo placement. Outcomes were also compared in an era when primary closure predominated (2000 2002) vs one when primary silo predominated (2003-2009). RESULTS: From 2000 to 2009, 203 patients underwent gastroschisis closure. Primary closure was performed in 50% of patients from 2000 to 2002 vs 12.3% from 2003 to 2009. Preformed silos were placed in 34.7% of patients from 2000 to 2002 vs 84.4% from 2003 to 2009. Patients treated from 2000 to 2002 experienced shorter hospital stays and shorter time to achievement of full enteral nutrition. Patients treated from 2003 to 2009 developed fewer ventral hernias and wound infections and required less ventilator days. Patients undergoing early primary closure developed ventral hernias at higher rates compared with those treated with preformed silos. Intensive care unit stay was longer for patients receiving preformed silos. CONCLUSION: Change in our management strategy has resulted in prolonged intensive care unit stay and time to full feeds but reduced postoperative hernias and wound infections. PMID- 22244404 TI - Long-term neurodevelopmental outcomes in children born with gastroschisis: the tiebreaker. AB - PURPOSE: We evaluated 2-year neurodevelopmental outcomes in children with gastroschisis. METHODS: We reviewed the records of children with gastroschisis treated between August 2001 and July 2008. Children discharged from the neonatal intensive care unit were referred to the state-sponsored Developmental Tracking Infant Progress Statewide (TIPS) program. We reviewed TIPS assessments performed before age 2 years. School districts evaluated children referred by TIPS and determined their eligibility for early intervention services. Poor outcomes were defined as scores of "failure" or "moderate/high risk" on the screening assessment or enrollment in early intervention services by 2 years. Children with gastroschisis were compared with case-matched nonsurgical, nonsyndromic children of similar gestational age and birth weight. RESULTS: One hundred five children were born with gastroschisis, and 46 were followed up with TIPS. There was no statistically significant difference in performance on screening assessments or in the rate of enrollment in early intervention services between the gastroschisis children and controls. CONCLUSIONS: Children born with gastroschisis have similar 2-year neurodevelopmental outcomes as nonsurgical, nonsyndromic neonatal intensive care unit children of similar gestational age and birth weight. Both groups of children have a higher rate of enrollment in early intervention than their healthy peers. These data suggest that neurodevelopmental outcomes in gastroschisis children are delayed secondary to prematurity rather than the presence of the surgical disease. PMID- 22244405 TI - Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism. AB - PURPOSE: To determine the outcome of patients who underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy to the remaining normal pancreatic body and tail for the treatment of a focal lesion in the pancreatic head causing congenital hyperinsulinism (HI). METHODS: One hundred thirty-eight patients underwent pancreatic resection for focal HI between 1998 and 2010. Twenty-three patients in the group underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy. RESULTS: There were 13 females and 10 males. Median age and weight at surgery were 8 weeks and 5.8 kg, respectively. Twenty-one patients had a near-total pancreatic head resection, and 2 patients had a pylorus preserving Whipple procedure. The pancreaticojejunostomy anastomosis was performed with interrupted fine monofilament sutures such that the transected end of the pancreatic body was tucked within the end of the Roux-en-Y jejunal limb. Median hospital stay was 22 days. All patients were cured of HI. CONCLUSION: We conclude that pancreatic head resection with Roux-en-Y pancreaticojejunostomy is a safe and effective procedure for the treatment of the HI patient with a large focal lesion in the pancreatic head that is not amenable to local resection alone. PMID- 22244406 TI - Development of an endoluminal intestinal lengthening capsule. AB - PURPOSE: Prior studies demonstrated the ability of a spring to lengthen intestinal segments. We made two innovations to this device. First, we employed a degradable capsule to control the deployment of the spring. Second, we decreased the spring force to allow slower expansion of the intestinal segment. METHODS: Nitinol springs with varying forces were compressed and placed in gelatin capsules. These capsules were coated with a degradable polymer and were placed in isolated segments of rat jejunum. Serial x-rays were used to determine the rate of spring expansion. Retrieved jejunal segments were analyzed histologically. RESULTS: Using the polymer-coated capsule, the spring was reliably deployed between 24 and 48 hours. Intestinal segments were lengthened from 1.0 cm to 3.6 cm after 14 days. The optimal spring for the gradual expansion of jejunal segments had a spring constant of 0.0010 N/mm. Villus height was preserved, but crypt depth was significantly greater in the lengthened intestine. CONCLUSION: Use of a low-force spring resulted in a nearly four-fold lengthening of jejunal segments. The use of a polymer-coated capsule provided a reliable way to control the timing of spring deployment. This capsule may be useful for the endoscopic placement of the spring in patients with short bowel syndrome. PMID- 22244407 TI - Evaluation of intestinal viability using 3-charge coupled device image enhancement technology in a pediatric laparoscopic appendectomy model. AB - BACKGROUND: Intraoperative laparoscopic determination of intestinal viability is currently limited to subjective visible cues. Adjunctive modalities are neither widely available nor practical. Three-charge coupled device (3-CCD) imaging directly correlates the amount of light detected by CCDs to tissue oxygenation. We hypothesize that application of 3-CCD image enhancement detects bowel ischemia in a pediatric laparoscopic appendectomy model. METHODS: We recorded 10 laparoscopic appendectomies for appendicitis. Offline analysis involved selecting regions of interest (ROIs) in the appendix, adjacent colon, and nonappendiceal fat and calculating mean intensity values in selected images before and after division of the mesoappendix. The colon was used as a control, and the intensity values were normalized to fat. RESULTS: As an indicator of decreased perfusion, the mean appendix ROI intensity values decreased over time (R(2) = 0.92) compared with the colon mean ROI intensity values, which remained stable. There was a statistically significant difference between fat-normalized intensity values for ischemic and nonischemic appendix after 1 minute. CONCLUSION: We have demonstrated proof of principle for the determination of bowel ischemia using 3 CCD image enhancement. By quantitatively identifying areas of ischemia, this technique has the potential to significantly change the management of ischemic bowel in the future. PMID- 22244408 TI - Epidural vs patient-controlled analgesia for postoperative pain after pectus excavatum repair: a prospective, randomized trial. AB - PURPOSE: Management of postoperative pain is a challenge after the minimally invasive repair of pectus excavatum. Pain is usually managed by either a thoracic epidural or patient-controlled analgesia with intravenous narcotics. We conducted a prospective, randomized trial to evaluate the relative merits of these 2 pain management strategies. METHODS: After obtaining permission/assent (Institutional Review Board no. 06 08 128), patients were randomized to either epidural or patient-controlled analgesia with fixed protocols for each arm. The primary outcome variable was length of stay with a power of .8 and alpha of .05. RESULTS: One hundred ten patients were enrolled. There was no difference in length of stay between the 2 arms. A longer operative time, more calls to anesthesia, and greater hospital charges were found in the epidural group. Pain scores favored epidural for the few days and favored patient-controlled analgesia thereafter. The epidural catheter could not be placed or was removed within 24 hours in 12 patients (22%). CONCLUSIONS: There is longer operating room time, increase in calls to anesthesia, and greater hospital charges with epidural analgesia after repair of pectus excavatum. Pain scores favor the epidural approach early in the postoperative course and patient-controlled analgesia later. PMID- 22244409 TI - Magnetic mini-mover procedure for pectus excavatum III: safety and efficacy in a Food and Drug Administration-sponsored clinical trial. AB - PURPOSE: The magnetic mini-mover procedure (3MP) uses magnetic force to gradually remodel pectus excavatum deformity. A magnet is implanted on the sternum and coupled with an external magnetic brace. Under Investigational Device Exemption and Institutional Review Board approval, we performed a pilot study of safety, probable efficacy, and cost-effectiveness of this new treatment of an orphan disease using an implantable pediatric device. METHODS: Ten otherwise healthy patients, ages 8 to 14 years, with severe pectus excavatum (pectus severity index [PSI] > 3.5) underwent 3MP treatment (mean, 18.8 +/- 2.5 months). Safety was assessed by postimplant and postexplant electrocardiograms and monthly chest x rays. Efficacy was assessed by change in pectus severity index as measured using pretreatment and posttreatment computed tomographic scan. Cost of 3MP was compared with that of standard procedures. RESULTS: The 3MP device had no detectable ill effect. Device weld failure or malpositioning required revision in 5 patients. Average wear time was 16 h/d. Pectus severity index improved in patients in the early or mid puberty but not in patients with noncompliant chest walls. Average cost for 3MP was $46,859, compared with $81,206 and $81,022 for Nuss and Ravitch, respectively. CONCLUSION: The 3MP is a safe, cost-effective, outpatient alternative treatment for pectus excavatum that achieves good results for patients in early and midpuberty stages. PMID- 22244410 TI - Optoelectronic plethysmography demonstrates abrogation of regional chest wall motion dysfunction in patients with pectus excavatum after Nuss repair. AB - PURPOSE: We previously demonstrated that patients with pectus excavatum (PE) have significantly decreased chest wall motion at the pectus defect compared with the rest of the chest vs unaffected individuals and use abdominal respiratory contributions to compensate for decreased upper chest wall motion. We hypothesize that PE repair will reverse chest wall motion dysfunction. METHODS: A prospective, institutional review board-approved study compared patients with PE before and after Nuss repair. Informed consent was obtained before motion analysis. Sixty-four patients with uncorrected PE ages 10 to 21 years underwent optoelectronic plethysmography analysis. Repeat analysis was performed in 42 patients 6 months postoperative (PO). RESULTS: Volume of the chest wall and its subdivisions were calculated. Total chest wall volume at rest was significantly increased after repair and in each thoracic compartment. PO patients developed increased midline marker excursion at the pectus defect and significantly decreased excursion at the level of the umbilicus. CONCLUSIONS: Optoelectronic plethysmography kinematic analysis demonstrates that chest wall remodeling during Nuss repair results in increased thoracic volume. Chest wall motion dysfunction at the pectus defect is reversed after Nuss repair. Abdominal respiratory contributions are also markedly decreased. These findings may help to explain why patients with PE report an improvement in endurance after the Nuss procedure. PMID- 22244411 TI - Lessons from a liver hemangioma registry: subtype classification. AB - PURPOSE: A previously proposed classification of hepatic hemangioma postulated 3 types of lesions: focal, multifocal, and diffuse. A registry (www.liverhemangioma.org) was created to track patients to validate this classification scheme. METHODS: Registry records entered between 1995 and 2010 were reviewed. RESULTS: Of 121 patients with hepatic hemangioma, 119 were focal (n = 33), multifocal (n = 68), and diffuse (n = 18). Two patients shared features of multifocal and diffuse. The focal group had a balanced sex distribution, whereas multifocal and diffuse were more common in women (66.2% and 70.0%, respectively). Hepatic hemangioma was detected prenatally in 30% (9/30) of patients with focal disease. Detection was not possible in multifocal or diffuse hepatic hemangioma, indicating postnatal proliferation typical of common cutaneous infantile hemangioma. Cutaneous hemangiomas accompanied 77.4% (48/62) of multifocal hepatic hemangioma, 53.3% (8/15) of diffuse hepatic hemangioma, and 15.3% (4/26) of focal hepatic hemangioma. Hypothyroidism was documented in all (16/16) patients with diffuse hepatic hemangioma, 21.4% (9/42) with multifocal hepatic hemangioma, but in no patients with focal hepatic hemangioma (0/17). CONCLUSIONS: Analysis of the Liver Hemangioma Registry confirms that focal lesions are biologically distinct from multifocal and diffuse hepatic hemangioma. Feared diffuse hepatic hemangioma may evolve from previously undetected multifocal hepatic hemangioma. Screening ultrasounds in infants with multiple cutaneous infantile hemangioma may allow for earlier detection and therapy. PMID- 22244412 TI - Circulating thyrotropin receptor messenger RNA for evaluation of thyroid nodules and surveillance of thyroid cancer in children. AB - PURPOSE: The aim of this study was to determine the role of thyrotropin receptor messenger RNA as a novel blood test for evaluation of thyroid nodules and cancer in children. METHODS: We reviewed thyroid disease management of patients younger than 18 years with thyrotropin receptor messenger RNA measurements identified from a prospective, institutional review board-approved registry during 2008 to 2010. RESULTS: Thirty-nine thyrotropin receptor messenger RNA measurements were made in 21 female patients (12-17 years old; median, 16 years). Four patients with fine-needle aspiration only had benign thyroid cytology, and 3 of 4 had undetectable thyrotropin receptor messenger RNA. Seventeen patients underwent 22 thyroid operations. Preoperative thyrotropin receptor messenger RNA was measured in 9 patients: 3 of 4 with thyroid cancer had elevated levels and 3 of 5 with goiters undetectable. Postthyroidectomy surveillance (median, 16 months; range, 6 24) of 11 thyroid cancer patients (8 papillary, 3 follicular) showed that thyrotropin receptor messenger RNA was concordant with thyroglobulin in 14 (73%) of 19 measurements. In 3 (16%) of 19 measurements, thyrotropin receptor messenger RNA was the only blood test useful for disease assessment because of elevated antithyroglobulin antibodies. Overall, to predict thyroid cancer, thyrotropin receptor messenger RNA demonstrated 73% sensitivity, 82% specificity, 62% positive predictive value, 88% negative predictive value, and 79% accuracy. CONCLUSION: Thyrotropin receptor messenger RNA provides complementary evaluation to thyroglobulin and fine-needle aspiration for pediatric thyroid nodule management. PMID- 22244413 TI - Novel zebrafish model reveals a critical role for MAPK in lymphangiogenesis. AB - PURPOSE: Lymphatic disorders are poorly understood with few animal models. We designed a novel assay to measure lymphatic development using transgenic zebrafish with fluorescently labeled endothelial cells. Two major branches of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were examined: the MAPK and PI3K pathways. METHODS: Direct visualization of lymphatic development was performed in control embryos or under chemical inhibition. Treatment involved a 6-hour pulse of inhibitor at 3 days postfertilization. Fish were analyzed for the presence of the thoracic duct (TD) at 4 days postfertilization (n > 100 specimens). RESULTS: Thoracic duct formation was prevented using selective inhibitors against kinases (MAPK, PI3K/TOR, or VEGFR). These kinases were important for TD formation because the lymphatic vessel failed to form in most of treated animals. Remarkably, MAPK pathway inhibition most robustly reduced lymphangiogenesis, demonstrated by a lack of lymphatic endothelial cells. CONCLUSION: We conclude that MAPK pathway function downstream of the VEGFRs is crucial at the early stages of TD development. This study provides a novel animal model and a potential target pathway for further investigation. We suggest further examination of MAPK pathway deregulation as a potential mechanism underlying lymphatic disease in humans. PMID- 22244414 TI - Rapamycin-induced tumor vasculature remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. AB - PURPOSE: Rapamycin inhibits vascular endothelial growth factor expression. Vascular endothelial growth factor is a tumor-elaborated protein that stimulates neovascularization. This inhibition can cause transient "normalization" of the generally dysfunctional tumor vasculature, resulting in improved tumor perfusion and oxygenation. We hypothesized that this may potentiate the antitumor effects of adjuvant ionizing radiation. METHODS: Mice bearing orthotopic Rh30 alveolar rhabdomyosarcomas were treated with rapamycin (5 mg/kg intraperitoneally daily *5). Tumors were then evaluated for changes in intratumoral oxygenation, perfusion, vessel permeability, and microvessel density. Additional tumor-bearing mice were treated with 5 doses of rapamycin, irradiation (4 Gy), or 5 doses of rapamycin with irradiation administered on the first or sixth day of rapamycin treatment. RESULTS: Although tumor vessel permeability changed only minimally, microvessel density decreased (3153 +/- 932 vs 20,477 +/- 3717.9 pixels per high power field), whereas intratumoral oxygenation increased significantly (0.0385 +/ 0.0141 vs 0.0043 +/- 0.0023 mm Hg/mm(3)) after 5 doses of rapamycin. Contrast enhanced ultrasound demonstrated a significantly increased rate of change of signal intensity after 5 days of rapamycin, suggesting improved intratumoral perfusion. Tumor volume 14 days after treatment was smallest in mice treated with the combination of rapamycin given before irradiation. CONCLUSION: Combination therapy with rapamycin given before irradiation to normalize the tumor vasculature, thereby improving tumor oxygenation, increased the sensitivity of alveolar rhabdomyosarcoma xenografts to adjuvant irradiation. PMID- 22244415 TI - A multicenter evaluation of the role of mechanical bowel preparation in pediatric colostomy takedown. AB - BACKGROUND: In response to studies in adults that have failed to demonstrate a benefit for mechanical bowel preparation in colonic surgery, we sought to evaluate the utility of mechanical bowel preparation in a multicenter, retrospective study of children who underwent colostomy takedown. METHODS: The records of 272 children who underwent colostomy takedown at 3 large children's hospitals were reviewed, and the utilization of mechanical bowel preparation and perioperative antibiotics was noted. Length of stay and the incidences of wound, anastomotic, and other complications were compared. RESULTS: A polyethylene glycol bowel prep was administered to 187 children. All subjects received perioperative, intravenous antibiotics, and 52% of those with bowel preps received preoperative oral antibiotics. Subjects in the bowel prep group had a significantly higher incidence of wound infection (P = .04) and longer length of stay (P = .05). Oral antibiotics did not affect outcome. CONCLUSIONS: The use of a mechanical bowel preparation in children before colostomy takedown was associated with a greater risk for wound infection, no protection from other complications, and a longer length of stay. This suggests that bowel preparation may be safely omitted in many children who undergo colonic surgery, thereby reducing cost and discomfort. PMID- 22244416 TI - Hepatocyte growth factor and omega-3-enriched feeds have a synergistic effect on mucosal mass in an animal model of inflammatory bowel disease. AB - BACKGROUND: Hepatocyte growth factor (HGF) decreases intestinal inflammation and cytokine levels in an animal model of inflammatory bowel disease (IBD). Luminal omega-3 (OM-3) is anti-angiogenic, reduces inflammation, and may decrease symptoms in patients with Crohn's disease. This study evaluates the synergism of HGF and OM-3. METHODS: Twenty adult female transgenic HLA-B27 rats were divided into 4 groups: group 1: regular feeds, IV saline; group 2: OM-3-enriched feeds, IV saline; group 3: regular feeds, IV HGF (150 ug/kg per day); and group 4: OM-3 enriched feeds, IV HGF(150 ug/kg per day). Rats were killed at 14 days after pump placement. Small and large bowel mucosa was harvested, and DNA and protein were extracted and quantified. Statistical analysis was done by analysis of variance with post-hoc Tukey's HSD test. RESULTS: Content of protein and DNA in the ileum were significantly increased by supplementation of HGF (P < .001, P < .01, respectively) alone. OM-3 significantly increased protein content but not DNA (P = .02, P = 0.3, respectively). Combined, they had a synergistic effect greater than either supplement alone (P = .0001, P = .002, respectively). In the colon, HGF and OM-3 did not significantly increase protein or DNA content individually or together. CONCLUSIONS: This is the first demonstration of the synergistic effect of a growth factor (HGF) and a dietary supplement (OM-3) in an immunologic model of IBD. PMID- 22244418 TI - Restorative proctocolectomy without diverting ileostomy in children with ulcerative colitis. AB - PURPOSE: The safety of performing a restorative proctocolectomy (RP) and J-pouch ileoanal anastomosis (IPAA) without diverting ileostomy for children with ulcerative colitis (UC) is a subject of extensive debate. Our goal was to examine pediatric outcomes of RP and IPAA without ileostomy. METHODS: We performed a single-institution review of UC patients who had RP and IPAA with (+Ostomy) or without (-Ostomy) diverting ileostomy from 2002 to 2010. Surgeon and patient preference determined ileostomy decision. The study included 50 patients (28 +Ostomy, 22 -Ostomy). RESULTS: Preoperative demographics were similar between 2 groups in age (13.5 +/- 3.5 years -Ostomy, 14.3 +/- 3 years +Ostomy), serum albumin (3.6 +/- 0.7 -Ostomy, 3.6 +/- 0.7 +Ostomy), body mass index (20.8 +/- 6.9 -Ostomy, 21.3 +/- 8.6 +Ostomy), and daily corticosteroid dose (22.4 +/- 17.7 mg Ostomy, 23.5 +/- 13.7 mg +Ostomy). Operating time was less in -Ostomy with mean times of 6:22 +/- 2:04 vs 9:07 +/- 2:57. The -Ostomy group required fewer ileoanal anastomotic dilations per patient (0.4 +/- 0.8 vs 1.4 +/- 1.9). Functional outcomes were not significantly different regarding pouchitis episodes per patient (0.6 +/- 1.1 -Ostomy, 0.6 +/- 1.1 +Ostomy), daily bowel movements (5.5 +/- 1.9 -Ostomy, 6.7 +/- 4.0 +Ostomy), and daily postoperative loperamide dose (8.4 +/- 4.3 mg -Ostomy, 6.8 +/- 4.0 mg +Ostomy). CONCLUSION: Short- and long-term outcomes can be equivalent in patients with and without diverting ileostomy, but questions remain regarding patient selection and quality of life impact. PMID- 22244417 TI - Pediatric chronic ulcerative colitis: does infliximab increase post-ileal pouch anal anastomosis complications? AB - BACKGROUND: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is a common surgical approach to chronic ulcerative colitis (CUC). Preoperative use of Infliximab (IFX) has raised concern of increased postoperative complications. We sought to compare outcomes of pediatric patients (<= 18 years) who were treated with IFX before IPAA to those who did not. METHODS: Patients (<= 18 years of age) who underwent IPAA from 2003 to 2008 for CUC were included, and their records were retrospectively reviewed for preoperative medications, operative technique, and 1-year postoperative complications (leak, wound infection, small bowel obstruction, pouchitis). Subjects were divided into 2 groups--those who received IFX preoperatively and those who did not. RESULTS: Eleven patients received IFX preoperatively, and 27 children did not. All complications following IPAA were more frequent in the IFX group compared to controls (55% vs 26%). Small bowel obstruction was significantly higher in the IFX group (55% vs 7%). Long-term complications occurred in 64% of the IFX group and 61% of the controls. CONCLUSION: Children that were treated with IFX prior to IPAA suffered twice as many postoperative complications. Long-term outcomes are similar. Currently, we recommend colectomy with end ileostomy for patients that receive IFX within 8 weeks of colectomy for CUC. PMID- 22244419 TI - Is daily dilatation by parents necessary after surgery for Hirschsprung disease and anorectal malformations? AB - BACKGROUND/PURPOSE: Most surgeons recommend daily dilatation after surgery for Hirschsprung disease and anorectal malformations. Our goal was to critically evaluate the potential risks and benefits of this practice. METHODS: A retrospective chart review was carried out of all children undergoing repair of Hirschsprung disease or anorectal malformation over 5 years. Patients with long segment Hirschsprung disease or anal stenosis were excluded. RESULTS: There were 95 patients, of which 34 had Hirschsprung disease and 61 had an anorectal malformation. Postoperatively, 65 underwent routine dilatation by parents; and 30 underwent weekly calibration by the surgeon, with daily dilatation by the parents only if the anastomosis was felt to be narrow. Of the 30 children undergoing weekly calibration, only 5 (17%) developed late narrowing that required conversion to the daily parental dilatation approach. There were no significant differences between the 2 approaches with respect to stricture development, anastomotic disruption, perineal excoriation, or enterocolitis. CONCLUSION: Weekly calibration by the surgeon is associated with similar outcomes to daily dilatation by the parents. Because this approach is kinder to the parents and the child, it should be seriously considered for the postoperative management of children with Hirschsprung disease or anorectal malformations. PMID- 22244420 TI - Pediatric hernia repair: 1-stop shopping. AB - PURPOSE: Multiple visits for the evaluation, treatment, and follow-up of straightforward surgical problems are inconvenient, can result in lost work for the parents, and missed school for the child. We hypothesized that with proper previsit screening, patients with select diagnoses can be evaluated in an outpatient clinic setting and undergo operation the same day. METHODS: Criteria were developed to identify straightforward referrals to our surgical practice for umbilical, epigastric, or inguinal hernias. Scripting was created to offer families the option of consultation and, if indicated, surgical treatment on the same day. Data collected included number of patients, cases performed, insurance status, and consultation reimbursement and surgical fees. Families were surveyed postoperatively. RESULTS: Sixty-one patient candidates participated. The diagnosis and indication for surgery were confirmed in 56 (92%), of which 50 underwent repair the day of their consultation. Seventy-two percent of patients had commercial insurance, whereas 28% had Medicaid. The preoperative consultation fee was reimbursed in 39 (78%) of 50 encounters (57% Medicaid, 86% commercial). All surgical cases were reimbursed. Patient and family satisfaction was high. CONCLUSIONS: We conclude that it is feasible to provide same-day evaluation and service for straightforward pediatric hernias with acceptable financial reimbursement and high parent satisfaction. PMID- 22244421 TI - Overnight observation in former premature infants undergoing inguinal hernia repair. AB - BACKGROUND: Overnight observation for apneic events is standard practice in former preterm infants. However, the literature supporting current protocols is dated. Therefore, we retrospectively evaluated the post-anesthetic risks in these patients. METHODS: A retrospective review was conducted on former preterm infants admitted after an inguinal herniorrhaphy between 1/00 and 10/09. The protocol for overnight admission was for patients born before 37 weeks gestation who are less than 60 weeks post-conceptional age (PCA). RESULTS: There were 363 patients, of which 23 were <40 weeks PCA (group 1), 244 were 40 to 49.9 weeks PCA (group 2), and 96 were 50 to 60 weeks PCA (group 3). Events registered by alarms occurred in 4 patients (1.1%), 2 from group 1 and 2 from group 2. In Group 1, one occurred during nasogastric tube placement and resolved spontaneously. In group 2, one was apnea-induced bradycardia that resolved spontaneously, and one was in a patient on home monitors with an event similar to home reports. There were no events in group 3. CONCLUSION: Conservative guidelines for overnight observation after inguinal hernia repair could be set for patients born before 37 weeks gestation who are under 50 weeks PCA. PMID- 22244422 TI - Using robotic telecommunications to triage pediatric disaster victims. AB - PURPOSE: During a disaster, hospitals may be overwhelmed and have an insufficient number of pediatric specialists available to care for injured children. The aim of this study was to determine the feasibility of remotely providing pediatric expertise via a robot to treat pediatric victims. METHODS: In 2008, Los Angeles County held 2 drills involving telemedicine. The first was the Tri-Hospital drill in which 3 Los Angeles County hospitals, one being a pediatric hospital, participated. The disaster scenario involved a Metrolink train crash, resulting in a large surge of traumatic injuries. The second drill involved multiple agencies and was called the Great California Shakeout, a simulated earthquake exercise. The telemedicine equipment installed is an InTouch Health, Inc, Santa Barbara, CA robotic telecommunications system. We used mixed-methods to evaluate the use of telemedicine during these drills. RESULTS: Pediatric specialists successfully provided remote triage and treatment consults of victims via the robot. The robot proved to be a useful means to extend resources and provide expert consult if pediatric specialists were unable to physically be at the site. CONCLUSION: Telemedicine can be used in the delayed treatment areas as well as for training first receivers to collaborate with specialists in remote locations to triage and treat seriously injured pediatric victims. PMID- 22244423 TI - Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. AB - OBJECTIVE: The aim of this study was to review evidence-based data addressing key clinical questions regarding parenteral nutrition-associated cholestasis (PNAC) and parenteral nutrition-associated liver disease (PNALD) in children. DATA SOURCE: Data were obtained from PubMed, Medicine databases of the English literature (up to October 2010), and the Cochrane Database of Systematic Reviews. STUDY SELECTION: The review of PNAC/PNALD has been divided into 4 areas to simplify one's understanding of the current knowledge regarding the pathogenesis and treatment of this disease: (1) nonnutrient risk factors associated with PNAC, (2) PNAC and lipid emulsions, (3) nutritional (nonlipid) considerations in the prevention of PNAC, and (4) supplemental medications in the prevention and treatment of PNAC. RESULTS: The data for each topic area relevant to the clinical practice of pediatric surgery were reviewed, evaluated, graded, and summarized. CONCLUSIONS: Although the conditions of PNAC and PNALD have been well recognized for more than 30 years, only a few concrete associations and treatment protocols have been established. PMID- 22244424 TI - Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. AB - PURPOSE: Necrotizing enterocolitis (NEC) is the most common acquired disease of the gastrointestinal tract in preterm infants, whereas probiotic supplementation might reduce NEC risk and potentially provide benefits to preterm infants. We performed an updated meta-analysis of all relevant randomized, controlled trials to assess the benefits of probiotic supplementation for preterm very low-birth weight (VLBW) infants. METHODS: We searched in PubMed, Embase, and Chinese BioMedical Literature Database (CBM) databases, and 20 randomized, controlled trials (a total of 3816 preterm VLBW infants) were finally included into this meta-analysis. Incidence and relative risk (RR) were calculated using a random effects or fixed-effects model depending on the heterogeneity of the included studies. RESULTS: Probiotic supplement was associated with a significantly decreased risk of NEC in preterm VLBW infants (RR = 0.33; 95% confidence interval [CI], 0.24-0.46; P < .00001). Risk of death was also significantly reduced in the probiotic group (RR = 0.56; 95% CI, 0.43-0.73; P < .0001). There was no difference in the risk of sepsis between the probiotic group and placebo group (RR = 0.90; 95% CI, 0.71-1.15; P = .40). CONCLUSIONS: Probiotic supplement can reduce risk of NEC and mortality in preterm VLBW infants. However, the optimum type of probiotic supplement and the long-term effects need further study. PMID- 22244425 TI - Trichoblastoma: management of a rare skin lesion. AB - A 15-year-old girl presented with a 2-year history of an enlarging parietal scalp lesion. Excisional biopsy revealed trichoblastoma, a benign secondary tumor arising from a nevus sebaceous. There is no consensus in the literature about the surgical management of nevus sebaceous in children owing to the low incidence of secondary malignancy. There is a 20% lifetime risk of transformation to a soft tissue neoplasm, most of which are benign; but malignant neoplasms have also been reported. At minimum, these lesions need to be followed clinically over the patient's lifetime if left in situ. Recurrence after excision is rare. PMID- 22244426 TI - Gastroportal shunt for portal hypertension in children. AB - PURPOSE: Extrahepatic portal venous obstruction is the most common cause of portal hypertension in children. The Rex shunt has been used successfully to treat patients with extrahepatic portal hypertension. In the conventional Rex shunt, the internal jugular vein is used as a venous graft. Inevitably, such a procedure requires neck exploration and sacrifice of internal jugular vein. The authors describe a novel adaptation of gastroportal shunt, successfully carried out in 8 children with extrahepatic portal hypertension. METHODS: The mean age of the 8 patients (6 boys and 2 girls) was 66.6 months at the time of operation. All children had portal hypertension. Seven had a history of upper gastrointestinal bleeding, and 4 had splenomegaly and hypersplenism. Gastroportal shunt was performed in all patients. The left gastric vein was mobilized and anastomosed to left portal vein. In 1 patient, the left gastric vein was not of adequate length and required a venous graft (the inferior mesenteric vein). All patients were followed up for 3 to 20 months (median, 9 months). RESULTS: The gastroportal shunt was successfully performed in all patients. The median operative time was 265 minutes (range, 205-360 minutes). Operative blood loss was 21 +/- 7.4 mL, and the length of hospital stay varied from 9 to 19 days (median, 15 days). Intraoperative portal venous angiography demonstrated the patency of the shunt in all patients. Postoperatively, the complete blood count normalized, and the biochemistry tests were within reference range. Postoperative ultrasound confirmed shunt patency and satisfactory flow in the gastroportal shunt in each patient. The size of spleen decreased. There was no recurrence of variceal bleeding. CONCLUSIONS: The gastroportal shunt is an effective treatment of extrahepatic portal hypertension. PMID- 22244427 TI - Simplified technique for minimally invasive repair of congenital diaphragmatic hernia using hollow-needle snare and transthoracic traction stitches. AB - BACKGROUND: Minimally invasive (MI) congenital diaphragmatic hernia (CDH) repair can be challenging. Placing rib-anchoring stitches without creating skin incisions and closing wider defects are some of the difficulties. In Bochdaleck hernia repair, maintaining visceral reduction and minimizing pneumothorax use are additional obstacles. We describe the use of hollow-needle snares (HNS) and transthoracic traction stitches (TTS) to overcome these challenges. METHODS: Hollow-needle snares is assembled by passing a prolene stitch through a hollow needle creating a retractable snare, which is used to extract the placed anchoring stitches by passing it over the ribs but through the same stitch's skin entrance site. In Bochdaleck hernia, the early placement of TTS using HNS can facilitate visceral reduction, patch lay down, and tension-free closure of possible residual V-shaped defects. RESULTS: Between July 2009 and April 2011, we performed 10 consecutive MI CDH repairs for 9 patients, including 7 Bochdaleck and 3 Morgagni hernias. The median age was 8 days (range, 3-172 days), and the mean operative time was 148.5 +/- 37.8 minutes for Bochdaleck hernia repairs. For Morgagni hernia, the median age was 18.3 months (range, 10.5-37 months), and the mean operative time was 100 +/- 26.5 minutes. All cases were completed without conversion. One patient had a hernia recurrence and was repaired similarly, whereas the others had uneventful recovery at a median follow-up of 5.8 months (range, 1.1-23.7 months). CONCLUSION: Hollow-needle snare and TTS are simple and available tools that can facilitate MI repair of CDH. This initial experience demonstrates the technique's effectiveness and its excellent cosmetic outcomes. PMID- 22244428 TI - A rare case of ovarian juvenile granulosa cell tumor without precocious pseudopuberty in an 11-month-old infant. PMID- 22244429 TI - Successful management of congenital bronchial stenosis using an expandable stent. AB - Congenital bronchial stenosis is a very rare cause of neonatal dyspnea. Surgical management remains challenging in small children. We report successful implantation of a bronchial stent in a 3-month-old female infant presenting with congenital right bronchial stenosis and 18 months of follow-up. Use of stents in children remains controversial because of the problem of size mismatch as the child grows. Nevertheless, expandable stent implantation could be an interesting alternative to complex surgery for localized bronchial stenosis in neonates. PMID- 22244430 TI - Poland syndrome with extracorporeal intercostal liver herniation and thoracic myelomeningocele. AB - Poland syndrome is characterized by hypoplastic unilateral chest wall structures. These chest wall deformities may be associated with upper extremity anomalies. The association of Poland syndrome with either intercostal liver herniation or a spinocerebral deformity has been described, but there is no report of both findings encountered simultaneously. This is the first report of a newborn child with Poland syndrome associated with an intercostal liver segment herniation and thoracic myelomeningocele with features of an Arnold-Chiari II cerebral malformation. PMID- 22244431 TI - Ulcerative colitis of the neovagina as a postsurgical complication of persistent cloaca. AB - Persistent cloaca is characterized by a common vestibule connected to the bladder, uterus, and rectum and a single perineal orifice to the exterior. Treatment can involve vaginal reconstruction with sigmoid/descending colon. We report a case of an 8-year-old girl who, as an infant, underwent vaginoplasty using sigmoid colon for persistent cloaca and developed a fulminant colitis that also affected the colonic neovagina 2 years after her reconstruction. PMID- 22244432 TI - Partial nephrectomy for a large renal lymphatic malformation in a child presenting with hypertension. AB - A 9-year-old girl had hypertension (systolic blood pressure of 125 mm Hg) noted at an annual well child visit. An ultrasound study demonstrated a large right renal cystic mass. A partial nephrectomy was performed. The surgical specimen was 9.7 * 9.4 * 6.4 cm and weighed 413.2 g. The tumor stained diffusely positive for smooth muscle actin and focally positive for factor VIII. Final histologic diagnosis was primary intrarenal lymphatic malformation. The case is unusual because of the presentation, size of the mass, as well as the therapeutic approach of partial nephrectomy. PMID- 22244433 TI - Preduodenal portal vein, malrotation, and high jejunal atresia: a case report. AB - Preduodenal portal vein (PDPV) is a rare congenital anomaly. In most patients, it is associated with other congenital defects including situs inversus, malrotation, and biliary atresia or occurs as part of the heterotaxia syndrome or polysplenia syndrome. We describe a newborn affected by high jejunal atresia, malrotation, and a complex cardiac anomaly, in whom PDPV was diagnosed at early relaparotomy because of stenosis of the jejunal anastomosis. Occurrence of PDPV with intestinal atresia has not been previously reported in the literature. PMID- 22244434 TI - Esophageal bronchus in an infant--a rare cause of recurrent pneumonia. AB - A 4-month-old female infant presented to our institute with recurrent pneumonia and was diagnosed with a right lower lobe esophageal bronchus. This congenital anomaly is extremely rare with very few cases reported in the literature. We describe the diagnostic workup and management that led to a successful outcome. PMID- 22244435 TI - Solitary Langerhans cell histiocytosis arising from sternum: a case report. AB - Langerhans cell histiocytosis (LCH) is a rare idiopathic benign disease characterized by proliferation of Langerhans cells, most commonly in the skull. In extremely rare cases, the tumor can occur in the sternum. A 4-year-old girl presented to our institution with a firm, nontender mass in her anterior chest that had indolently enlarged to approximately 2 cm in diameter over the previous several months. Computed tomography, magnetic resonance imaging, and F18 flurodeoxy-glucose positron emission tomography computed tomography were performed for preoperative diagnosis, but the findings were inconclusive. Therefore, we performed surgical excision under general anesthesia, followed by microscopic and immunohistochemical analysis of the excised specimen. The mass was eventually diagnosed as a LCH arising from the sternum. No postoperative oncological treatment was given, and follow-up has continued for 1 year until the time of writing without any tumor recurrence. To our knowledge, only 10 cases of LCH arising from the sternum have been reported in the medical literature. Among them, surgical approaches including curettage and partial sternotomy were performed in only 6 cases. Without exception, all patients experienced excellent clinical outcomes. Therefore, additional clinical experiences are required. No standard treatment of choice for this disease currently exists. In our experience, curettage of the involved soft tissue mass and bone followed by appropriate reconstruction of the defect is considered a good option for the treatment of solitary LCH of the sternum. In addition, LCH should be considered in the differential diagnoses when a sharp delineated osteolytic mass is detected in the sternum. PMID- 22244436 TI - Biliary reconstruction when the liver hilum is inaccessible: the anterior approach. AB - OBJECTIVE: This paper focuses on a novel approach to biliary reconstruction after previous extensive liver surgery. SUMMARY BACKGROUND DATA: Bile leak and subsequent biliary strictures are not uncommon after extensive liver surgery. Biliary reconstruction is then required, but the liver hilum is usually inaccessible for further surgical intervention. METHODS: A novel surgical technique is described in two patients with biliary stenosis after previous extensive liver surgery. Access to the biliary tree was obtained using an anterior approach. A previously inserted PTC drain was used as guidance to the bile duct suitable for creating a biliary-digestive anastomosis. RESULTS: The described technique proved to cause complete biliary drainage in both patients. There was no treatment-related morbidity nor was further biliary intervention needed during follow-up. PMID- 22244437 TI - Two-stage hepatectomy: who will not jump over the second hurdle? AB - BACKGROUND: Two-stage hepatectomy uses compensatory liver regeneration after a first noncurative hepatectomy to enable a second curative resection in patients with bilobar colorectal liver metastasis (CLM). OBJECTIVE: To determine the predictive factors of failure of two-stage hepatectomy. METHOD: Between 2000 and 2010, 48 patients with irresectable CLM were eligible for two-stage hepatectomy. The planned strategy was a) cleaning of the left hepatic lobe (first hepatectomy), b) right portal vein embolisation and c) right hepatectomy (second hepatectomy). Six patients had occult CLM (n = 5) or extra-hepatic disease (n = 1), which was discovered during the first hepatectomy. Thus, 42 patients completed the first hepatectomy and underwent portal vein embolisation in order to receive the second hepatectomy. Eight patients did not undergo a second hepatectomy due to disease progression. RESULTS: Upon univariate analysis, two factors were identified that precluded patients from having the second hepatectomy: the combined resection of a primary tumour during the first hepatectomy (p = 0.01) and administration of chemotherapy between the two hepatectomies (p = 0.03). An independent association with impairment to perform the two-stage strategy was demonstrated by multivariate analysis for only the combined resection of the primary colorectal cancer during the first hepatectomy (p = 0.04). CONCLUSION: Due to the small number of patients and the absence of equivalent conclusions in other studies, we cannot recommend performance of an isolated colorectal resection prior to chemotherapy. However, resection of an asymptomatic primary tumour before chemotherapy should not be considered as an outdated procedure. PMID- 22244438 TI - Radioactive seed migration after transperineal interstitial prostate brachytherapy and associated development of small-cell lung cancer. AB - PURPOSE: We report a case of lung carcinoma developing in the location of a migrated prostate brachytherapy seed. METHODS AND MATERIALS: A 57-year-old male nonsmoker was originally diagnosed with prostate adenocarcinoma Group IIB in October 1999. Treatment was completed at an outside local hospital and consisted of hormone suppression, pelvic external beam radiation, and transperineal interstitial permanent prostate brachytherapy with loose iodine-125 seeds. RESULTS: The treatment was unremarkable for any complications, and immediate postimplant evaluation did not reveal any loose seeds. The patient remained clinically without evidence of disease and was asymptomatic until an isolated episode of hematuria in December 2009. Radiographic evaluation noted an incidental right lower lobe lung mass with a 4-mm hyperdensity slightly off center. Biopsy confirmed Stage IB limited-stage small-cell lung cancer, and he underwent thoracic radiation with concurrent systemic chemotherapy. The mass remained mildly avid on a positron emission tomographic scan after treatment, and he underwent surgical evaluation with final pathology demonstrating no residual tumor but a metal rod-like implant consistent with a migrated radioactive brachytherapy seed. CONCLUSIONS: To our knowledge, this is the first case of a long-term adverse sequela seen in the location of a migrated brachytherapy seed. Although reported incidence of pulmonary seed emboli remains low with little measurable consequence on pulmonary function, we must appreciate that a theoretical risk for secondary malignancy remains not only locally within the periprostatic region but also at any site of seed migration. PMID- 22244439 TI - White matter microstructural alterations in migraine: a diffusion-weighted MRI study. AB - Migraine is a common and disabling neurological disease. The pathomechanism that underlies the disorder is not entirely understood, and reliable biomarkers are missing. In the current analysis we looked for microstructural alterations of the brain white matter in migraine patients by means of diffusion-weighted magnetic resonance imaging. The measurements were carried out with a novel approach based on fine-tuned nonlinear registration and nonparametric permutation test in an alignment-invariant tract representation (Tract-Based Spatial Statistics). We found reduced fractional anisotropy in the right frontal white matter cluster of migraine patients. In the same region we also found increased mean diffusivity and increased radial diffusivity. The probabilistic tractography showed connection of this cluster to other parts of the pain network (orbitofrontal cortex, insula, thalamus, dorsal midbrain). We speculate that these findings reflect maladaptive plastic changes or white matter disintegration. PMID- 22244440 TI - The challenges of prognosis in cancer pain. PMID- 22244442 TI - Fear avoidance and neuroimaging: falsification or just failure to confirm? PMID- 22244441 TI - Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. AB - The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano sensitivity of chemotherapy-naive rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naive control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention. PMID- 22244443 TI - Pain-related bias in the classification of emotionally ambiguous facial expressions in mothers of children with chronic abdominal pain. AB - This study sought to determine whether mothers of young people with chronic abdominal pain (CAP) compared to mothers of pain-free children show a pain recognition bias when they classify facial emotional expressions. One hundred demographically matched mothers of children with CAP (n=50) and control mothers (n=50) were asked to identify different emotions expressed by adults in 2 experiments. In experiment 1, participants were required to identify the emotion in a series of facial images that depicted 100% intensity of the following emotions: Pain, Sadness, Anger, Fear, Happiness, and Neutral. In experiment 2, mothers were required to identify the predominant emotion in a series of computer interpolated ("morphed") facial images. In this experiment, pain was combined with Sad, Angry, Fearful, Happy, and Neutral facial expressions in different proportions-that is, 90%:10%, 70%:30%, 50%:50%, 30%:70%, 10%:90%. All participants completed measures of state and trait anxiety, depression, and anxiety sensitivity. In experiment 1, there was no difference in the performance of the 2 groups of mothers. In experiment 2, it was found that overall mothers of children with CAP were classifying ambiguous emotional expressions predominantly as pain. Mean response times for CAP and control groups did not differ significantly. Mothers of children with CAP did not report more anxiety, depression, and anxiety sensitivity compared to control mothers. It is concluded that mothers of children with CAP show a pain bias when interpreting ambiguous emotional expressions, which possibly contributes to the maintenance of this condition in children via specific parenting behaviours. PMID- 22244444 TI - Oxysterols as non-genomic regulators of cholesterol homeostasis. AB - Tight regulation of cellular and plasma cholesterol is crucial to proper cellular functioning because excess free cholesterol is toxic to cells and is associated with atherosclerosis and heart disease. Cellular cholesterol homeostasis is regulated by enzymatically formed oxygenated cholesterol derivatives termed oxysterols. Although the effects of oxysterols on transcriptional pathways are well described, the non-transcriptional mechanisms through which oxysterols acutely modulate cellular cholesterol levels are less well understood. We present emerging evidence suggesting that the membrane biophysical properties of oxysterols underlie their acute cholesterol-regulatory functions and discuss the relevance of these acute effects to cholesterol overload in physiological and pathophysiological states. PMID- 22244445 TI - Molecular prediction for atherogenic risks across different cell types of leukocytes. AB - BACKGROUND: Diagnosing subclinical atherosclerosis is often difficult since patients are asymptomatic. In order to alleviate this limitation, we have developed a molecular prediction technique for predicting patients with atherogenic risks using multi-gene expression biomarkers on leukocytes. METHODS: We first discovered 356 expression biomarkers which showed significant differential expression between genome-wide microarray data of monocytes from patients with familial hyperlipidemia and increased risk of atherosclerosis compared to normal controls. These biomarkers were further triaged with 56 biomarkers known to be directly related to atherogenic risks. We also applied a COXEN algorithm to identify concordantly expressed biomarkers between monocytes and each of three different cell types of leukocytes. We then developed a multi gene predictor using all or three subsets of these 56 biomarkers on the monocyte patient data. These predictors were then applied to multiple independent patient sets from three cell types of leukocytes (macrophages, circulating T cells, or whole white blood cells) to predict patients with atherogenic risks. RESULTS: When the 56 predictor was applied to the three patient sets from different cell types of leukocytes, all significantly stratified patients with atherogenic risks from healthy people in these independent cohorts. Concordantly expressed biomarkers identified by the COXEN algorithm provided slightly better prediction results. CONCLUSION: These results demonstrated the potential of molecular prediction of atherogenic risks across different cell types of leukocytes. PMID- 22244446 TI - High hepatitis B virus load is associated with hepatocellular carcinomas development in Chinese chronic hepatitis B patients: a case control study. AB - BACKGROUND: Persistent hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) development. This study aimed to clarify whether the high HBV DNA level is associated with HCC development by comparing HBV DNA levels between HBV infected patients with and without HCC. RESULTS: There were 78 male and 12 female patients in each group and there was no statistical difference between these two group patients' average ages. The HBV DNA level in the HCC patients was 4.73 +/- 1.71 Log10 IU/ml while 3.90 +/- 2.01 Log10 IU/ml in non-HCC patients (P < 0.01). The HBeAg positive rate was 42.2% (38/90) in the HCC group while 13.3% (12/90) in the non-HCC group (P < 0.001). Compared with patients with HBV DNA level of < 3 Log10 IU/ml, the patients with level of 3 to < 4, 4 to < 5, 5 to < 6, or >= 6 Log10 IU/ml had the odds ratio for HCC of 1.380 (95% CI, 0.544 3.499), 3.671 (95% CI, 1.363-9.886), 5.303 (95% CI, 1.847-15.277) or 3.030 (95% CI, 1.143-8.036), respectively. CONCLUSIONS: HBV-related HCC patients had higher HBV DNA level than non-HCC counterparts. Our findings imply that active HBV replication is associated with the HCC development. PMID- 22244447 TI - Homocysteine-lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta-analysis of randomised, controlled trials. AB - The efficacy of homocysteine (Hcy)-lowering therapy in reducing the risk of CVD among patients with chronic kidney disease (CKD) remains controversial. We performed a meta-analysis to determine whether pooling the data from the few small randomised, controlled trials that address this topic would improve the statistical power of the analysis and resolve some of the inconsistencies in the results. Randomised, controlled clinical trials (RCT) were identified from MEDLINE, EMBASE, www.clinicaltrials.gov, the Cochrane Controlled Clinical Trials Register Database and Nephrology Filters. Independent extraction of articles was performed using predefined data fields. The primary outcome was relative risk (RR) of CVD, CHD, stroke and all-cause mortality for the pooled trials. A stratified analysis was planned, assessing the RR for cardiovascular events between the patients on and not on dialysis. Overall, ten studies met the inclusion criteria. The estimated RR were not significantly different for any outcomes, including CHD (RR 1.00, 95 % CI 0.75, 1.31, P = 0.97), CVD (RR 0.94, 95 % CI 0.84, 1.05, P = 0.30), stroke (RR 0.83, 95 % CI 0.57, 1.19, P = 0.31) and all-cause mortality (RR 1.00, 95 % CI 0.92, 1.09, P = 0.98). In the stratified analysis, the estimated RR were not significantly different for cardiovascular events regardless of dialysis or in combination with vitamin B therapy or the degree of reduction in Hcy levels. Our meta-analysis of RCT supports the conclusion that Hcy-lowering therapy was not associated with a significant decrease in the risk for CVD events, stroke and all-cause mortality among patients with CKD. PMID- 22244448 TI - Abnormal accumulation of human transmembrane (TMEM)-176A and 176B proteins is associated with cancer pathology. AB - Transmembrane (TMEM)-176A and 176B proteins belong to the MS4A family of proteins whose function in the immune system remains unclear. TMEM176A transcripts were previously shown to be elevated in liver cancer or kidney tissue with proteinuria, while marked changes in TMEM176B transcripts have been found in tolerated tissue allografts and neoplastic fibroblasts. To study the functional relationship between human TMEM176A and 176B and their putative link to cancer, we used polymerase chain reaction and biochemical assays. Here, we show that TMEM176A and 176B are widely expressed in all human tissues examined. Co immunoprecipitation of heterologously expressed TMEM176A and 176B revealed direct physical interaction. To determine the relevance of such interaction to cancer pathology, we analyzed biopsied tissue samples from a variety of normal and cancer tissues. Our data reveal that human TMEM176A and 176B protein levels are significantly elevated in lymphoma, but not in normal tissues. The protein levels of TMEM176A are also significantly increased in lung carcinoma. Finally, analysis of the protein expression ratio of TMEM176A over 176B showed significant differences between normal and cancer tissues of the breast, lymph, skin, and liver, which indicates that both TMEM proteins could be potential useful markers for certain human cancers. PMID- 22244449 TI - An immunohistochemical study of interleukin-8 (IL-8) in breast cancer. AB - The use of prognostic markers for breast cancer is important for routine diagnosis and research. Interleukin-8 is a chemotactic cytokine produced by several cell types in response to inflammation, however, its expression, regulation and function are poorly understood. Recent studies have associated angiogenesis and inflammatory processes with tumor malignancy. The present study investigated the correlation between interleukin-8 expression and breast cancer prognosis. Interleukin-8 expression was assessed in 72 women with mammary neoplasia by immunohistochemistry and the results were statistically correlated with clinical-pathological findings. There was an inverse correlation between interleukin-8 expression and metastasis (p=0.03) and/or local recurrence (p=0.02). In the patient group that received post-surgery chemotherapy and radiotherapy, a lower interleukin-8 expression was found in those women that showed local recurrence (p=0.01). Multivariate logistic regression showed estrogen receptor negativity, progesterone positivity and metastasis with increased risk of death (p<0.05). The data reflect the complexity of the role of interleukin-8 in tumor microenvironment and support its classification as a possible prognostic marker, although more studies are necessary for its inclusion in clinical practice. PMID- 22244450 TI - Attitudes toward integrative paediatrics: a national survey among youth health are physicians in The Netherlands. AB - BACKGROUND: Integrative Medicine (IM) is an emerging field in paediatrics, especially in the USA. The purpose of the present study was to assess the attitudes and beliefs of Youth Health Care (YHC) physicians in the Netherlands toward IM in paediatrics. METHODS: In October 2010, a link to an anonymous, self reporting, 30-item web-based questionnaire was mailed to all members of the Dutch Organisation of YHC physicians. The questionnaire included questions on familiarity with IM, attitudes towards Integrative Paediatrics (IP), use and knowledge of Complementary and Alternative Medicine (CAM), demographic and practice characteristics. RESULTS: A total of 276 YHC physicians (response rate of 27%) responded to the survey. Of the respondents, 52% was familiar with IM and 56% had used some kind of CAM therapy during the past 2 years, of which self medicated herbal and/or homeopathic remedies (61%) and supplements (50%) were most frequently mentioned. Most of the YHC physicians (62%) seldom asked parents of clients about CAM use. One third of the YHC physicians recommended CAM to their clients. In general, about 50% or more of the respondents had little knowledge of CAM therapies. Predictors for a positive attitude towards IP were familiarity with IM, own CAM use, asking their clients about CAM use and practising one or more forms of CAM therapy. Logistic regression analysis showed that the following factors were associated with a higher recommendation to CAM therapies: own CAM use (odds ratio (OR) = 3.8; 95% confidence interval (CI) = 2.1 6.9, p = 0.001) and practising CAM (OR 4.4; 95% CI = 1.6-11.7, p = 0.003). CONCLUSIONS: In general Dutch YHC physicians have a relative positive attitude towards IP; more than half of the respondents used one or more forms of CAM and one third recommended CAM therapies. However, the majority of YHC physicians did not ask their clients about CAM use and seemed to have a lack of knowledge regarding CAM. PMID- 22244451 TI - Low-gradient single-sided NMR sensor for one-shot profiling of human skin. AB - This paper describes a shimming approach useful to reduce the gradient strength of the magnetic field generated by single-sided sensors simultaneously maximizing its uniformity along the lateral directions of the magnet. In this way, the thickness of the excited sensitive volume can be increased without compromising the depth resolution of the sensor. By implementing this method on a standard U shaped magnet, the gradient strength was reduced one order of magnitude. In the presence of a gradient of about 2 T/m, slices of 2mm could be profiled with a resolution that ranges from 25 MUm at the center of the slice to 50 MUm at the borders. This sensor is of particular advantage for applications, where the scanning range is of the order of the excited slice. In those cases, the full profile is measured in a single excitation experiment, eliminating the need for repositioning the excited slice across the depth range to complete the profile as occurs with standard high gradient sensors. Besides simplifying the experimental setup, the possibility to move from a point-by-point measurement to the simultaneous acquisition of the full profile led to the shortening of the experimental time. A further advantage of performing the experiment under a smaller static gradient is a reduction of the diffusion attenuation affecting the signal decay measured with a CPMG sequence, making it possible to measure the T(2) of samples with high diffusivity (comparable to the water diffusivity). The performance of the sensor in terms of resolution and sensitivity is first evaluated and compared with conventional singled-sided sensors of higher gradient strength using phantoms of known geometry and relaxation times. Then, the device is used to profile the structure of human skin in vivo. To understand the contrast between the different skin layers, the distribution of relaxation times T(2) and diffusion coefficients is spatially resolved along the depth direction. PMID- 22244453 TI - Long-term simulations of the 137Cs dispersion from the Fukushima accident in the world ocean. AB - The LAMER calculation code was used for simulation of the distribution of (137)Cs released after the Fukushima accident into the Pacific and Indian Oceans. The maximum (137)Cs concentration predicted for surface waters of the open NW Pacific Ocean in 2012 (21 Bq/m(3) at 38 degrees N, 164 degrees E) will be comparable to that observed during the early 1960s after atmospheric nuclear weapons tests. The (137)Cs in surface waters of the Pacific Ocean will reach the US coast 4-5 y after the accident, however, the levels will be low (<3 Bq/m(3)). All the North Pacific Ocean will be labeled with Fukushima (137)Cs 10 y after the accident with concentrations below 1 Bq/m(3). Thirty years after the accident the (137)Cs levels in the Pacific and Indian Oceans will be below 0.1 Bq/m(3), i.e. undetectable on the present global fallout background. The effective dose commitment with ingestion of marine biota found in 2012 in the open NW Pacific Ocean was estimated to be 1.7 MUSv/y, mostly delivered by (134,137)Cs. The estimated dose is by about a factor of 500 lower than the present dose limit for the public. PMID- 22244452 TI - Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. AB - CTCF-binding locations represent regulatory sequences that are highly constrained over the course of evolution. To gain insight into how these DNA elements are conserved and spread through the genome, we defined the full spectrum of CTCF binding sites, including a 33/34-mer motif, and identified over five thousand highly conserved, robust, and tissue-independent CTCF-binding locations by comparing ChIP-seq data from six mammals. Our data indicate that activation of retroelements has produced species-specific expansions of CTCF binding in rodents, dogs, and opossum, which often functionally serve as chromatin and transcriptional insulators. We discovered fossilized repeat elements flanking deeply conserved CTCF-binding regions, indicating that similar retrotransposon expansions occurred hundreds of millions of years ago. Repeat-driven dispersal of CTCF binding is a fundamental, ancient, and still highly active mechanism of genome evolution in mammalian lineages. PMID- 22244454 TI - Indirect closing of elytra by the prothorax in beetles (Coleoptera): general observations and exceptions. AB - Voluntary movements of the prothorax and the elytra in tethered flying beetles and manually induced movements of these parts in fresh dead beetles were recorded in 30 species representing 14 families. Participation of prothoracic elevation in the closing of the elytra was demonstrated in three ways. (i) The elevation was always simultaneous with elytral closing, in contrast to depression and elytral opening; a rare exception occurred in Lucanus cervus, whose elytra sometimes started to close before the cessation of wing strokes and the elevation of the prothorax. (ii) The manipulated elevation always induced closing of the spread elytra; the mechanical interaction between the hind edge of the pronotum and the roots of the elytra is a universal mechanism of closing the elytra in beetles. (iii) The prevention of pronoto-elytral contact in live beetles by the excision of the hind edge of the pronotum in front of the root prevented elytral closing after normal flight. Exceptions to this rule included some beetles that were able to close their elytra after such an excision: tiger beetles and diving beetles (seldomly) and rose chafers (always). This ability in Adephaga may be explained by attachments of the muscle actuating the 4th axillary plate, which differ from the attachments in Polyphaga. Cetoniinae open their elytra only by a small amount. It is proposed that their small direct adductors in combination with the elasticity of the sclerites are enough to achieve elytral closing without additional help from the prothorax. PMID- 22244455 TI - The need for speed: testing acceleration for estimating animal travel rates in terrestrial dead-reckoning systems. AB - Numerous methods are currently available to track animal movements. However, only one of these, dead-reckoning, has the capacity to provide continuous data for animal movements over fine scales. Dead-reckoning has been applied almost exclusively in the study of marine species, in part due to the difficulty of accurately measuring the speed of terrestrial species. In the present study we evaluate the use of accelerometers and a metric known as overall dynamic body acceleration (ODBA) as a proxy for the measurement of speed for use in dead reckoning. Data were collated from previous studies, for 10 species locomoting on a treadmill and their ODBA measured by an attached data logger. All species except one showed a highly significant linear relationship between speed and ODBA; however, there was appreciable inter- and intra-specific variance in this relationship. ODBA was then used to estimate speed in a simple trial run of a dead-reckoning track. Estimating distance travelled using speed derived from prior calibration for ODBA resulted in appreciable errors. We describe a method by which these errors can be minimised, by periodic ground-truthing (e.g., by GPS or VHF telemetry) of the dead-reckoned track and adjusting the relationship between speed and ODBA until actual known positions and dead-reckoned positions accord. PMID- 22244456 TI - Prey handling using whole-body fluid dynamics in batoids. AB - Fluid flow generated by body movements is a foraging tactic that has been exploited by many benthic species. In this study, the kinematics and hydrodynamics of prey handling behavior in little skates, Leucoraja erinacea, and round stingrays, Urobatis halleri, are compared using kinematics and particle image velocimetry. Both species use the body to form a tent to constrain the prey with the pectoral fin edges pressed against the substrate. Stingrays then elevate the head, which increases the volume between the body and the substrate to generate suction, while maintaining pectoral fin contact with the substrate. Meanwhile, the tip of the rostrum is curled upwards to create an opening where fluid is drawn under the body, functionally analogous to suction-feeding fishes. Skates also rotate the rostrum upwards although with the open rostral sides and the smaller fin area weaker fluid flow is generated. However, skates also use a rostral strike behavior in which the rostrum is rapidly rotated downwards pushing fluid towards the substrate to potentially stun or uncover prey. Thus, both species use the anterior portion of the body to direct fluid flow to handle prey albeit in different ways, which may be explained by differences in morphology. Rostral stiffness and pectoral fin insertion onto the rostrum differ between skates and rays and this corresponds to behavioral differences in prey handling resulting in distinct fluid flow patterns. The flexible muscular rostrum and greater fin area of stingrays allow more extensive use of suction to handle prey while the stiff cartilaginous rostrum of skates lacking extensive fin insertion is used as a paddle to strike prey as well as to clear away sand cover. PMID- 22244457 TI - Classification of patients with multiple injuries--is the polytrauma patient defined adequately in 2012? PMID- 22244458 TI - Non-traditional markers of metabolic risk in prepubertal children with different levels of cardiorespiratory fitness. AB - OBJECTIVE: To assess classical and non-classical metabolic risk biomarkers in prepubertal children with different levels of cardiorespiratory fitness (CRF). DESIGN: CRF was assessed by the 20 m shuttle run test. To estimate physical activity, participants were observed while engaged in an after-school programme. Additionally, a short test based on a validated questionnaire was used to obtain information about physical activity practice and sedentary habits. Anthropometric parameters, blood pressure, and classical and non-traditional metabolic risk biomarkers--plasma lipid profile, glucose and insulin, homeostasis model assessment-insulin resistance index (HOMA-IR), plasma uric acid, transaminases and C-reactive protein (CRP)--were measured. SETTING: The study was conducted in local elementary schools in Cordoba, Spain. SUBJECTS: One hundred and forty-one healthy children (eighty-eight boys, fifty-three girls) aged 7-12 years, in Tanner stage I, were recruited. They were divided into two groups after they performed the 20 m shuttle run test: equal or higher cardiovascular fitness (EHCF) group and low cardiovascular fitness (LCF) group. RESULTS: The LCF group displayed significantly higher TAG (P = 0.004) and lower HDL cholesterol levels (P = 0.001), as well as significantly lower values for the non-traditional lipid marker apo-A1 (P = 0.001) compared with the EHCF group. The LCF children displayed higher plasma glucose (P = 0.003) and insulin levels, higher HOMA-IR scores (P < 0.001) and higher plasma uric acid and CRP levels (P < 0.05). After adjustment for BMI, age and sex, no statistically significant differences were found between groups for the biomarkers analysed. CONCLUSIONS: The study provides new information to understand the role not only of weight status but also of the level of CRF on the metabolic health profile of prepubertal children. PMID- 22244459 TI - Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. AB - We report the successful use of abatacept and sodium thiosulfate in a patient with severe recalcitrant juvenile dermatomyositis complicated by ulcerative skin disease and progressive calcinosis. This combination therapy resulted in significant reductions in muscle and skin inflammation, decreased corticosteroid dependence, and halted the progression of calcinosis. PMID- 22244460 TI - Use of technology with health care providers: perspectives from urban youth. AB - OBJECTIVE: To evaluate urban youths' use of and access to technology and solicit their opinions about using technology with healthcare providers. STUDY DESIGN: Urban youth (aged 14-24 years) were invited to participate in focus groups in which a trained focus group facilitator used a survey and a structured guide to elicit responses regarding the foregoing objective. All sessions were audiotaped and transcribed. Emergent themes were determined with the assistance of Atlas TI. Survey data were analyzed in SPSS (SPSS Inc, Chicago, Illinois). RESULTS: Eight focus groups including 82 primarily low-income urban African-American adolescents and young adults (mean age, 18.5 years) were completed. The participants reported fairly high access to and use of technology. However, they expressed some concerns regarding the use of technology with healthcare providers. Many worried about the confidentiality of conversations conducted using technology. Face-to face meetings with a healthcare provider were preferred by most participants, who felt that the information provided would be better tailored to their individual needs and more credible. CONCLUSION: Although urban youth were high users of technology, they expressed reservations about using technology with health care providers. When developing new technology communication and information dissemination strategies, it is critical to understand and address these concerns while involving young people in the research and development process. PMID- 22244462 TI - Improving detection by pediatric residents of endotracheal tube dislodgement with capnography: a randomized controlled trial. AB - OBJECTIVE: The authors sought to determine if capnography could improve time to correction of a simulated endotracheal tube (ETT) dislodgement by pediatric residents. STUDY DESIGN: Pediatric residents attended a didactic session that included interpretation of capnography. A randomized controlled study was then performed using patient simulators. Residents were randomized to standard monitoring (control group) or standard monitoring plus capnography (intervention group). The primary outcome was time to correction of ETT dislodgement. Correction of dislodgement prior to decline in pulse oximetry was our secondary outcome. RESULTS: Twenty-seven subjects completed the simulation. Subjects in the intervention group corrected the ETT dislodgement faster than those in the control group (2.38 minutes vs 3.92 minutes, P = .02). There were no differences in time to correction based on postgraduate year, clinical experiences, or comfort with capnography. Two subjects corrected the dislodgement prior to changes in pulse oximetry, both from the intervention group. Fifty-nine percent of subjects had seen capnography used in the past and 82% felt very or somewhat comfortable with capnography. CONCLUSION: Capnography decreased time to correction of ETT dislodgement by pediatric residents. Capnography should be considered as an essential monitoring device for intubated patients to enhance patient safety. PMID- 22244461 TI - The child as proband for future parental cardiometabolic disease: the 26-year prospective Princeton Lipid Research Clinics Follow-up Study. AB - OBJECTIVE: To evaluate children's cardiovascular disease (CVD) risk factors as predictors of parents' subsequent CVD, type 2 diabetes mellitus (T2DM), and high blood pressure (HBP). STUDY DESIGN: We conducted a 26-year prospective follow-up of 852 5- to 19-year-old black and white schoolchildren (mean age, 12 years; Lipid Research Clinics, 1973-8), and parents (mean age, 40 years) from 519 families in Princeton Schools, Cincinnati, Ohio. Schoolchildren were reassessed in the Princeton Follow-up study 1999-2003 at mean age 39 years; CVD, T2DM, and HBP history of their 1038 parents were reassessed by mean age 66 years. We assessed relationships of childhood risk factors with parental CVD, T2DM, and HBP. Child-probands identified with triglyceride (TG) levels, blood pressure, low density lipoprotein cholesterol levels, body mass index (BMI), and glucose level greater than and high-density lipoprotein cholesterol levels less than established cutoff points. RESULTS: Pediatric HBP (P=.006) and low high-density lipoprotein cholesterol (P=.018) were predictive of parental CVD at age <=50 years. Pediatric HBP (P=.02) and high TG (P=.03) were predictive of parental CVD at age <=60 years. Pediatric high TG (P=.009) and high low-density lipoprotein cholesterol (P=.04) were predictive of parental CVD by age 66 years. Pediatric high BMI (P=.0006) were predictive of parental T2DM. Pediatric high BMI (P=.003) and black race (P=.004) were predictive of parental HBP. CONCLUSIONS: Pediatric risk factors identify families with parents at increased risk for CVD, T2DM, and HBP, emphasizing the usefulness of the child as proband. PMID- 22244464 TI - Growth in children and adolescents with type 1 diabetes. AB - OBJECTIVE: To investigate the effect of type 1 diabetes on growth and adult height. STUDY DESIGN: Data from 22 651 children (10 494 females) with type 1 diabetes documented at onset of the disease from specialized centers in Germany and Austria were analyzed. Patients of non-German and non-Austrian origin and patients with celiac disease were excluded from the analysis. Near-adult height data were available in 1685 patients. RESULTS: At the time of diagnosis of type 1 diabetes, the mean age of the 22 651 children was 8.8 +/- 4.2 years, with a mean height SDS of 0.22 +/- 1.0. The 1685 patients with diabetes onset before age 11 years reached a mean adult height of -0.16 +/- 1.0 SDS. Mean adult height was was 167.1 +/- 6.2 cm (-0.16 +/- 0.97 SDS) in females (n = 846) and 179.6 +/- 7.1 cm ( 0.17 +/- 1.0 SDS) in males (n = 839). Mean duration of diabetes was 9.1 +/- 2.6 years, and mean Hemoglobin A1c concentration was 7.9% +/- 1.2% (63 +/- 10 mmol/mol). In a multivariate regression model, adult height was positively correlated with height at onset of diabetes (P < .0001) and negatively with mean Hemoglobin A1c (P < .0001) and duration of diabetes (P = .0015). CONCLUSION: Height at the time of diagnosis of type 1 diabetes is above average. Even with intensive insulin therapy, growth and adult height remain indicators of metabolic diabetes control in the 21st century. PMID- 22244463 TI - Cancer in children with nonchromosomal birth defects. AB - OBJECTIVE: To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies. STUDY DESIGN: We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies. RESULTS: Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors. CONCLUSION: Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer. PMID- 22244465 TI - Transitional changes in cardiac and cerebral hemodynamics in term neonates at birth. AB - OBJECTIVE: To describe cardiac function, cerebral regional oxygen saturation (rSO(2)), and cerebral blood flow (CBF) that correspond to changes in arterial oxygen saturation (SaO(2)) in normal term neonates immediately after birth and after the transition. STUDY DESIGN: In this prospective observational study, cardiac function and cerebral hemodynamics were assessed by echocardiography and Doppler ultrasonography 3 times during the first 20 minutes after vaginal delivery, then again at 24-48 hours after delivery. Cerebral rSO(2) (by near infrared spectroscopy) and preductal SaO(2) (by pulse oximetry) were assessed continuously. RESULTS: In 20 neonates, SaO(2) increased progressively from 65% at 1 minute after birth to 97% at 17 minutes after birth. Cerebral rSO(2) increased from 47% at 1 minute to 83% at 8 minutes, then decreased progressively to 73% at 20 minutes. Middle cerebral artery mean velocity decreased from 34 cm/s at 7 minutes to 25 cm/s at 14 minutes. The patent ductus arteriosus (PDA) shunt was balanced at 5 minutes but became increasingly left to right. Left ventricular stroke volume was increased. Middle cerebral artery mean velocity demonstrated an inverse relationship with the PDA shunt. Further hemodynamic changes were noted on the posttransitional assessment. CONCLUSION: After birth, ductal shunting rapidly changes from balanced to left to right, with a responsive increase in left ventricular stroke volume. Cerebral rSO(2) increases as SaO(2) rises during the first 8 minutes, subsequently, it decreases due to a drop in CBF and despite a further increase in SaO(2). The reduction in CBF is likely due to an increase in arterial O(2) content, PDA shunting, or both. PMID- 22244466 TI - Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. AB - OBJECTIVE: To determine the long-term effects of iron deficiency on the neural correlates of recognition memory. STUDY DESIGN: Non-anemic control participants (n=93) and 116 otherwise healthy formerly iron-deficient anemic Chilean children were selected from a larger longitudinal study. Participants were identified at 6, 12, or 18 months as iron-deficient anemic or non-anemic and subsequently received oral iron treatment. This follow-up was conducted when participants were 10 years old. Behavioral measures and event-related potentials from 28 scalp electrodes were measured during an new/old word recognition memory task. RESULTS: The new/old effect of the FN400 amplitude, in which new words are associated with greater amplitude than old words, was present within the control group only. The control group also showed faster FN400 latency than the formerly iron-deficient anemic group and larger mean amplitude for the P300 component. CONCLUSIONS: Although overall behavioral accuracy is comparable in groups, the results show that group differences in cognitive function have not been resolved 10 years after iron treatment. Long-lasting changes in myelination and energy metabolism, perhaps especially in the hippocampus, may account for these long-term effects on an important aspect of human cognitive development. PMID- 22244467 TI - [Postobstructive pulmonary edema]. PMID- 22244468 TI - [Cerebral metastasis of a "ghost" bronchopulmonary tumor]. AB - Carcinoma of unknown primary (CUP) is the metastasis of epithelial malignancy whose origin remains unknown. Bronchial carcinoma is the most common cause (45%), however, in more than a quarter of cases, its origin is unknown and the choice of therapy often justifies a histopathological precision brought by the immuno histochemistry. We present a rare case of cerebral metastasis, revealing an unknown lung cancer after a comprehensive review. This is a patient aged 53 years, chronic smoker, who presented a year and a half ago a sudden loss of consciousness with afebrile tonic-clonic seizure of spontaneous resolution. Clinical examination was unremarkable. Brain imaging by MRI has objectified the presence of two parietal tissue formations, which stereotactic biopsy with histological and immuno-histochemical favored metastasis of lung adenocarcinoma origin. An etiologic in search of the primitive lung remained negative (chest X ray of face, chest CT and bronchoscopy with sampling upper gastrointestinal endoscopy). The rest of the etiologic, looking for another primitive, remained negative. The diagnosis of a bronchogenic carcinoma with brain metastasis is therefore withheld. The patient received two brain radiotherapies (gamma kniff) with regression of the two nodular formations. We have not given specific treatment and have called for very close monitoring of the patient who remained stable after 18 months. Through this observation, we stress the interest of the histology and immuno-histochemistry of carcinoma of unknown primary (CUP) to the diagnosis, guide therapy and determine prognosis. PMID- 22244469 TI - Fear of the unknown: ionizing radiation exposure during pregnancy. AB - Ionizing radiation during pregnancy can negatively impact a fetus. In light of the Fukushima nuclear plant disaster in Japan, we discuss existing knowledge on the health effects of radiation and preventive measures for pregnant women. Overall, the risk of exposure to radiation is limited but severe defects can result from fetal radiation exposure >100 mGy equivalent to 10 rad (>1000 chest x rays). While such high-level exposure rarely occurs during single medical diagnostic procedures, caution should be exercised for pregnant women. As a protective public health measure in light of a disaster, evacuation, shielding, and elimination of ingested radioactive isotopes should all be considered. Detailed radiation reports with health effects and precautionary measures should be available for a population exposed to more than background radiation. PMID- 22244470 TI - Inhibition of uterine contractility with various tocolytics with and without progesterone: in vitro studies. AB - OBJECTIVE: Various tocolytics are used to suppress uterine contractility in patients in preterm labor. Progesterone (P4) is used in patients at high risk for preterm delivery. In this study, we evaluated the effects of various tocolytics with and without P4 to examine effects on uterine contractility. STUDY DESIGN: Uterine tissues (n = 280) from women undergoing cesarean at term were exposed in vitro to various agents (vehicle, magnesium sulfate [MgSO(4)], nifedipine, indomethacin, or pinacidil-all with and without P4). Contractility was measured before and after addition of the various agents. RESULTS: P4 alone at 10(-5) mol/L concentration has little effect to inhibit contractility (P >= .05). MgSO(4) (2-8 * 10(-3) mol/L) inhibits uterine contractility (P < .05) but there is no change when combined with P4 (P > .05). Nifedipine (10(-8) mol/L) and indomethacin (10(-5) mol/L) inhibit contractions alone (P < .05) and to a greater extent when combined with P4 (P < .05). P4 significantly (P < .05) reduced the effects of pinacidil (10(-6.5) mol/L). CONCLUSION: Combinations of P4 with nifedipine or indomethacin, but not MgSO(4), might be used to effectively suppress preterm labor. PMID- 22244471 TI - Timing of delivery and pregnancy outcomes among laboring nulliparous women. AB - OBJECTIVE: The objective of the study was to compare pregnancy outcomes by completed week of gestation after 39 weeks with outcomes at 39 weeks. STUDY DESIGN: Secondary analysis of a multicenter trial of fetal pulse oximetry in spontaneously laboring or induced nulliparous women at a gestation of 36 weeks or longer. Maternal outcomes included a composite (treated uterine atony, blood transfusion, and peripartum infections) and cesarean delivery. Neonatal outcomes included a composite of death, neonatal respiratory and other morbidities, and neonatal intensive care unit admission. RESULTS: Among the 4086 women studied, the risks of the composite maternal outcome (P value for trend < .001), cesarean delivery (P < .001), and composite neonatal outcome (P = .047) increased with increasing gestational age from 39 to 41 or more completed weeks. Adjusted odds ratios (95% confidence interval) for 40 and 41 or more weeks, respectively, compared with 39 weeks were 1.29 (1.03-1.64) and 2.05 (1.60-2.64) for composite maternal outcome, 1.28 (1.05-1.57) and 1.75 (1.41-2.16) for cesarean delivery, and 1.25 (0.86-1.83) and 1.37 (0.90-2.09) for composite neonatal outcome. CONCLUSION: Risks of maternal morbidity and cesarean delivery but not neonatal morbidity increased significantly beyond 39 weeks. PMID- 22244473 TI - The 5-tier system of assessing fetal heart rate tracings is superior to the 3 tier system in identifying fetal acidemia. AB - OBJECTIVE: Electronic fetal heart rate monitoring was developed to identify fetuses at risk of acidemia for intervention before adverse outcomes. Our objective was to compare the 3-tier system with a 5-tier system in evaluation of fetal acidemia. STUDY DESIGN: Retrospective case-control study of patients with a fetal arterial pH <7 matched to the next birth that resulted in a pH >7.2. Tracings were categorized into 3- and 5-tier systems by a single reviewer. Sensitivities and specificities were calculated for each. RESULTS: Twenty-four cases and 24 controls were identified. The sensitivity for an orange or red tracing was higher than for category III, with more of these in the pH <7 group compared with controls (P <= .001). There were significantly more green, blue, and yellow tracings in the normal pH group compared with the pH <7 group (P = .033, P = .008, P = .023), respectively. CONCLUSION: The 5-tier system had a better sensitivity than the 3-tier system. PMID- 22244472 TI - The estimated annual cost of uterine leiomyomata in the United States. AB - OBJECTIVE: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications. STUDY DESIGN: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed. RESULTS: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually. CONCLUSION: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors. PMID- 22244474 TI - Prevalence of hyperprolactinemia in adolescents and young women with menstruation related problems. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence of hyperprolactinemia in adolescents and young women with menstrual problems. STUDY DESIGN: This study included 1704 young women with menstruation-related problems. The patients were classified into group I (age, 11-20 years) or group II (age, 21 30 years); the prevalence of hyperprolactinemia was analyzed according to age and categories of menstruation-related problems. RESULTS: For primary amenorrhea and oligomenorrhea, the prevalence of hyperprolactinemia was low in both groups. However, hyperprolactinemia was a relatively common cause of secondary amenorrhea (5.5% for group I and 13.8% for group II, respectively); it was more frequent in group II (P = .001); the prevalence of prolactinoma was also higher in group II (P = .015). For abnormal uterine bleeding, hyperprolactinemia was more common in group II (2.6% for group I and 9.4% for group II; P < .001), but causes were similar. CONCLUSION: Hyperprolactinemia is not rare in young women with menstruation-related problems; its prevalence varies according to age and manifestations. PMID- 22244476 TI - Effect of experimental genital mycoplasmosis on gene expression in the fetal brain. AB - Neurodevelopmental disorders may have their origins during intrauterine development. We used a well-defined animal model to test whether hematogenous infection with genital mycoplasma would alter the expression of genes associated with autism spectrum disorders (ASD). In a preliminary experiment, rats were exposed at 14 days gestation (GD14) to Mycoplasma pulmonis or sterile broth and sacrificed at GD18. Infection and inflammation status of the pups was ascertained by culture and cytokine ELISA. Intra-cardiac injection of 10(6)CFU M. pulmonis resulted in amniotic infection of 100% of the pups and was accompanied by higher levels of IL-1beta in amniotic fluids. In a second experiment, animals were infected in a similar manner but dams and their litters were sacrificed at GD18, GD21 or postpartum day 3 (PPD3). Expression of proinflammatory cytokines and neurodevelopmental genes in the fetal brains was evaluated. M. pulmonis infection significantly increased the expression of IL-1beta, TNF-alpha and COX-2 in fetal and neonatal brains. Expression of GFAP and CD11b, markers for activation on astrocytes and microglial cells, respectively, was also increased for infected animals. M. pulmonis significantly increased SHANK-3 gene expression at GD21 and PPD3 and PCP-2 expression at GD21. No effect of M. pulmonis infection on Reelin, PTEN, BDNF or HGF was detected. These data suggest that M. pulmonis infection at GD14 increases the expression of proinflammatory genes in the perinatal brain. Further studies with earlier time-points of infection and ones that use behavioral outcomes are needed to better understand the potential role of genital mycoplasmosis on pychopathology. PMID- 22244477 TI - Impact of elevated serum glycated albumin levels on contrast-induced acute kidney injury in diabetic patients with moderate to severe renal insufficiency undergoing coronary angiography. AB - BACKGROUND: Glycated albumin (GA) has been shown to be a better indicator than glycosylated hemoglobin A1c (HbA1c) in terms of severity of renal impairment in patients with type 2 diabetes mellitus (T2DM). This study aimed to determine whether elevated serum GA levels are associated with an increased risk for contrast-induced acute kidney injury (CI-AKI) and worse clinical outcome in patients with T2DM and at least moderate renal insufficiency (RI) undergoing coronary angiography. METHODS: Serum levels of fasting blood glucose (FBG), HbA1c and GA were measured in 1030 patients with T2DM and moderate to severe RI (eGFR 15-59 mL/min/1.73 m(2)). CI-AKI was defined as >= 25% increase in serum creatinine within 72 h after the procedure. Receiver-operating characteristic curve was constructed to assess the predictive value of GA, HbA1c and FBG for CI AKI. Multivariable logistic regression model was developed to identify risk factors for CI-AKI, and Kaplan-Meier curve analysis was used to compare the rates of dialysis and major adverse cardiac events (MACE) during one-year follow-up. RESULTS: The overall rate of CI-AKI was 11.1%. GA was significantly higher in patients with CI-AKI than in those without, and correlated positively with changes of renal function after the procedure. After adjusting for age, sex, left ventricular ejection fraction, multi-vessel disease, type and volume of contrast media, FBG, and HbA1c, GA remained an independent risk factor for CI-AKI. GA >= 21% was associated with increased rates of dialysis and MACE during one-year follow-up in patients with or without CI-AKI. CONCLUSIONS: Increased GA level serves as a valuable risk factor for CI-AKI and indicates poor one-year clinical outcome in patients with T2DM and moderate to severe RI. PMID- 22244478 TI - Comparison of inverse Gaussian distribution with survival analysis in advanced chronic heart failure patients. PMID- 22244479 TI - Myocardial oxidative stress in patients with active infective endocarditis. AB - BACKGROUND: Infective endocarditis (IE) induces the rise of pro-inflammatory cytokines. Some of them can stimulate oxidants production in myocardium with subsequent peroxidative damage to various biomolecules. We compared indices of oxidative stress: H2O2, thiobarbituric acid-reactive substances (TBARs), thiols in myocardium specimens between patients with active IE and those with valvular heart disease (VHD) of rheumatic etiology who underwent surgical valve replacement. METHODS: 17 left ventricle papillary muscle specimens and 28 specimens of auricle of the right heart were collected from 45IE patients, and 16 papillary muscle and 12 auricle specimens from 28 VHD patients, respectively. Patients groups had similar NYHA functional class and majority of echocardiographic indices of heart morphology. H2O2 and TBARs were determined fluorometrically in myocardium homogenates whereas thiols with photometric method. Between and within groups comparisons and mutual correlations between variables were analyzed. RESULTS: H2O2 generation from all myocardium specimens and auricles was 2.14- and 2.59- times higher (p<0.001) in IE patients than in VHD group. Auricles had the highest H2O2 levels within IE group. TBARs were 10 times higher (p<0.05) in IE when compared to VHD group in auricles and papillary muscles. Thiols did not differ between groups. H2O2 positively correlated with TBARs and negatively with thiols in all IE myocardium specimens (r=0.31 and r= 0.46, p<0.05) and auricles (r=0.58 and r=-0.67, p<0.05), respectively. No such associations were noted in VHD specimens. CONCLUSIONS: Active IE induces enhanced myocardial production of H2O2 and formation of TBARs which proves occurrence of oxidative stress in the heart. PMID- 22244480 TI - Initial clinical experience with an everolimus eluting platinum chromium stent (Promus Element) in unselected patients from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). AB - BACKGROUND: The safety and efficacy of the Promus Element stent have been recently demonstrated in a selected population from one randomized trial. The aim of this study was to describe the initial clinical experience with the everolimus eluting platinum chromium stent (Promus Element) in unselected patients from a real life nationwide registry. METHODS: The Promus Element DES was compared to all other DES implanted in Sweden (with more than 500 implants) from November 2009 to March 2011. The results were assessed using Cox regression. RESULTS: A total of 13,577 stents (Promus Element, n=2724, Cypher, n=782; Endeavor, n=747; Taxus Liberte, n=1393, Xience V/Promus, n=4832, Resolute, n=1566, Xience Prime, n=4832) were implanted at 8375 procedures. At one year the restenosis rate in the Promus Element was not significantly different from the overall DES group (2.8% vs. 2.7%, adjusted HR:1.17, 95% CI: 0.75-1.75). A significantly lower restenosis rate was observed in the Promus Element when compared with Endeavor (2.8% vs. 5.8%; adjusted HR: 0.44; 95% CI: 0.26-0.74). The stent thrombosis (ST) rate at one year was not significantly different in the Promus Element as compared with the overall DES group (0.2% vs. 0.5% adjusted HR: 0.59; 95% CI: 025-1.40). ST rate was significantly lower as compared with Endeavor stent (0.2% vs. 0.8%; HR: 0.24; 95% CI: 0.08-0.67). CONCLUSIONS: In a large unselected population the Promus Element stent appears to be safe and effective with a low risk of restenosis and ST. PMID- 22244481 TI - Immunoglobulin treatment ameliorates myocardial injury in experimental autoimmune myocarditis associated with suppression of reactive oxygen species. AB - AIMS: We tested the hypothesis that immunoglobulin ameliorated experimental autoimmune myocarditis (EAM) in mice attributing to the suppression of reactive oxygen species (ROS)-mediated myocardial injury. METHODS: We intraperitoneally administered intact type of human immunoglobulin (Ig) or F(ab')2 fragments of human immunoglobulin, 1g/kg/day daily for 3 weeks, to male BALB/c mice with heart failure due to EAM. RESULTS: The results showed that intact type of Ig, but not F(ab')2 type, reduced the severity of myocarditis by comparing the heart weight/body weight and lung weight/body weight ratios, pericardial effusion score, macroscopic and microscopic scores. Tissue superoxide production was marked in untreated mice with EAM, which was suppressed by the treatment of immunoglobulins. The cytotoxic activities of lymphocytes in mice with EAM treated with Ig were reduced compared with untreated controls. The shift from Th1 toward Th2 cytokine balance was demonstrated by the treatment of immunoglobulins both in vitro and in vivo. CONCLUSION: ROS may be involved in the development of myocarditis. Intact Ig ameliorates myocardial damage in mice with myocarditis associated with suppression of ROS and cytotoxic activity of lymphocytes. PMID- 22244482 TI - Repeated sauna therapy improves myocardial perfusion in patients with chronically occluded coronary artery-related ischemia. AB - BACKGROUND: Repeated low-temperature sauna (Waon) therapy relieves ischemic symptoms in patients with peripheral arterial disease. We investigated whether Waon therapy could improve myocardial perfusion in patients with ischemia related to chronic total occlusion (CTO) of coronary arteries. METHODS: Twenty-four patients who had ischemia in the CTO-related area were examined. The severity of ischemia was quantified by thallium-201 myocardial perfusion scintigraphy with adenosine. The Waon group (n=16) was treated daily for three weeks with a 60 degrees C far infrared-ray dry sauna bath for 15 min and then kept in a bed covered with blankets for 30 min. The control group (n=8) underwent myocardial perfusion scintigraphy twice with a three-week interval. RESULTS: In the control group, neither summed stress score (SSS) nor summed difference score (SDS) of myocardial scintigraphy changed. However, Waon therapy improved both SSS (16 +/- 7 to 9 +/- 6, p<0.01) and SDS (7 +/- 4 to 3 +/- 2, p<0.01), and the improvement was greater in patients with higher SSS and SDS scores at the baseline. Waon therapy extended treadmill exercise time (430 +/- 185 to 511 +/- 192s, p<0.01) and improved flow-mediated dilation of the brachial artery (4.1 +/- 1.3 to 5.9 +/ 1.8%, p<0.05), but tended to decrease the number of circulating CD34-positive bone marrow-derived cells. CONCLUSIONS: Waon therapy improves CTO-related myocardial ischemia in association with improvement of vascular endothelial function. This therapy could be a complementary and alternative tool in patients with severe coronary lesions not suitable for coronary intervention. PMID- 22244483 TI - Impaired coronary flow reserve after a recent myocardial infarction: correlation with infarct size and extent of microvascular obstruction. AB - BACKGROUND: The exact relationship between the coronary flow reserve (CFR) and infarct size remains unknown. In this prospective study the relationship between the CFR both in the infarcted and remote myocardium and infarct size was investigated. Furthermore, the diagnostic value of the CFR to predict the extent of microvascular obstruction (MO) was evaluated. METHODS: In thirty patients the CFR was measured with a Doppler guide wire 6 +/- 3 days after a first myocardial infarction (MI) in the infarct related and in a reference coronary artery. MO and infarct size were determined with magnetic resonance imaging. RESULTS: The CFR was inversely related to infarct size in the infarcted and remote myocardium (respectively, r=-0.60, p<0.01 and r=-0.62, p<0.01). In the infarcted myocardium the extent of MO was strongly related to the infarct size and was in a multivariate analysis the single significant determinant of the CFR and the hyperaemic flow. In the remote myocardium no relationship was present between infarct size and hyperaemic flow, but the baseline flow increased as the infarct size became larger (r=0.58, p<0.01). In a receiver operator characteristic (ROC) analysis, a CFR value <= 2 in the infarct related coronary artery offered the best sensitivity (65%) and specificity (71%) to detect the presence of MO (p<0.05). CONCLUSIONS: After MI, the CFR both in the infarcted and remote myocardium is inversely related to infarct size. In the infarcted myocardium, a CFR value <= 2 predicts the presence of MO with moderate sensitivity and specificity. PMID- 22244485 TI - 2012: a time for change. PMID- 22244484 TI - Peak oxygen consumption and prognosis in heart failure: 14 mL/kg/min is not a "gender-neutral" reference. AB - BACKGROUND: Peak oxygen consumption (VO2) predictive authority in heart failure (HF) has been established from male cohorts. We evaluated the gender impact on the prognostic meaning of low peak VO2. METHODS: We followed 529 HF patients (116 female), with peak VO2 <= 14 mL/kg/min, until cardiovascular death (CVD) and urgent heart transplantation. RESULTS: During follow up, 156 (29%) patients had cardiac events. Female gender, age, left ventricular ejection fraction, peak VO2, peak systolic blood pressure, and beta-blocker treatment all contributed to increase the risk ability of the hierarchical multivariate model. Two-year survival was higher in women: 85 vs 66%; chi(2)=15.7, p<0.0001. Peculiarly, outcome results were similar when only CVD was considered. Females showed a multivariate adjusted hazard ratio (HR) of 0.46. Since a 1-mL/kg/min increment in peak VO2 was equated with a 12% improvement in prognosis, the same gender adjusted HR was achieved when mean peak VO2 was reduced by 5 units in women: thus, a HF woman with peak VO2 of 9 mL/kg/min has the same 2-year outcome as a HF man with peak VO2 of 14 mL/kg/min. CONCLUSIONS: Although HF women have a comparatively lower peak VO2 than men, they live longer. We discovered that the traditional cut point value for peak VO2, i.e. <= 14 mL/kg/min is not a "gender neutral" reference since lumping HF men and women together with the same VO2 value is unlikely to describe the true risk. These preliminary findings do underline the need to assimilate gender-specific issues into clinical practice in HF, when appropriate. PMID- 22244486 TI - Proposed career pathway for clinical academic general dental practitioners. PMID- 22244488 TI - Should dentists be concerned about the weight of their patients? AB - This opinion paper considers obesity and its relationship to dental practice. Twenty-three per cent of people in England are estimated to be obese, a figure that is predicted to continue rising. It follows that obese patients are frequently encountered in general dental practice. The authors review the links between obesity and dental health, the possible barriers and challenges to providing dental care for obese people, and how these may be overcome. They also report the findings of a London survey investigating the current provision of specialist dental services for obese patients who cannot be treated in a standard dental chair. Services across London were highly variable and in some areas no provision was identified. The implications of the rising prevalence of obesity for service planners and practitioners are also discussed. PMID- 22244489 TI - An investigation of West Sussex general dental practitioners' awareness, attitudes and adherence to NICE dental recall guidelines. AB - AIMS: The overall aim of this study was to determine whether general dental practitioners (GDPs) in West Sussex were aware of and followed National Institute for Health and Clinical Excellence (NICE) guidelines on dental recalls. The study also aimed to identify factors in the GDPs' practice of dentistry that could affect their adherence to NICE guidelines and to gain some insight into their views on this topic and how these might affect their adherence. METHODS: A postal questionnaire, which had previously been piloted, and an explanatory letter were sent to a random sample of 195 GDPs representing 50% of the GDPs contracted to the West Sussex Primary Care Trust. Those who did not respond were sent the questionnaire and letter for a second time. The questionnaire consisted of 50 questions that covered awareness of, attitudes towards and adherence to the NICE guidelines on dental recalls, risk factors, and the GDPs' practising profile. Resulting data were entered into a database and, where appropriate, statistically tested with the chi-square test, with the level of statistical probability set at P<0.5. RESULTS: Data were obtained from the 50 questions in the questionnaires. Only key results are presented in this abstract. Ten of the 195 GDPs had either moved away from the area or were orthodontists. The final sample was therefore 185, of whom 117 returned questionnaires, a response rate of 63%. Seventy-three per cent of the respondents had qualified in United Kingdom. Sixty-five per cent were male. The mean age of respondents was 43 years. Seventy-one per cent worked as GDPs within the General Dental Services (GDS) or Personal Dental Services. Concerning NICE recall guidelines, 94% stated that they were aware of them, 61% said they agreed with them, and 64% that they adhered to them. Female GDPs were statistically far more likely to state that they followed NICE guidelines ( P =0.0043). Seventy per cent of GDPs reported that they still recalled their patients at six-month intervals and only 3% that they recalled their patients according to need. Eighty-five per cent reported taking radiographs at two-year intervals and/or according to patient need, and 68% that they gave oral hygiene advice six monthly or at every recall. Risk assessments were reported as being always carried out by 65% of responding GDPs for caries, 83% for periodontal disease, and 81% for oral cancer. Ninety per cent reported that they thought risk factors were relevant when setting the recall interval and 82% thought that six monthly recalls allowed appropriate screening to take place. CONCLUSIONS: Only 3% of responding GDPs recalled their patients according to patient need, in line with NICE recall guidelines, although the majority of GDPs agreed with the guidelines and stated that they adhered to them; however, this was in contrast to the 70% of GDPs who continued to recall at six-month intervals. The majority of GDPs thought that less frequent recalls would not allow for early caries, periodontal disease and oral malignancy diagnosis, and did not think that access to NHS dentistry would be improved. They also did not believe that excessive NHS money was spent on over-frequent dental examinations. There would appear to be significant obstacles to altering the recall habits of dentists because of the way that dentists practise. PMID- 22244490 TI - A baseline audit of referral and treatment delivered to patients in the intermediate minor oral surgery service in Croydon PCT. AB - INTRODUCTION: Patients attending for primary dental care may require oral surgery procedures beyond the capability of a generalist and thus need to be treated by a dentist with greater expertise. In the United Kingdom, it is increasingly accepted that such care may be provided in primary care settings by specialists or dentists with a special interest. In response to local pressures, an intermediate minor oral surgery (IMOS) service has been established in Croydon, south west London, to provide oral surgery treatment for non-urgent patients on referral. AIM: To audit the appropriateness and quality of oral surgery referrals after triage to an IMOS service in Croydon and to set standards for future audits on this topic. METHODS: An audit tool was developed in line with the local referral guidelines and agreed with local stakeholders. Information on 501 (10%) triaged referrals to IMOS practices over a 24-month period was obtained through the referral management centre. A 10% sample of referrals per month to each practice was calculated and IMOS providers randomly selected the relevant patient records. Using an agreed audit pro forma, information on the indications for referral, treatment provided, and dates relating to patient management, in addition to the age and sex of patients, was collected from the IMOS providers by one investigator. Descriptive analysis of the data was performed. RESULTS: Of the 501 patient records that were examined, 99% of patients were treated in IMOS practices, with only three (less than 1%) patients being referred on to hospital consultant services. The largest proportion (237; 40%) of referrals was for the extraction of teeth considered to have special difficulty, followed by lower third molars (154; 26%). Almost one-third (159; 32%) of patients were referred for more than one procedure. One in eight (72; 13%) teeth removed by the IMOS providers were recorded as a simple extraction without medical complications. CONCLUSIONS: In general, patients were referred appropriately to the primary care oral surgery service in Croydon, with only a minority recorded as receiving simple care that should not have required referral. The clinician-led triage process using a referral management system worked well in selecting appropriate patients for treatment by IMOS providers in primary care and reduced referrals to hospital. Suggested standards for future audits of IMOS referrals have been set. PMID- 22244491 TI - Negotiation: a necessary art for dental practice. AB - This brief paper explains why the art of negotiation has become far more important for general dental practitioners. It explains that negotiations take place with patients, with practice staff, and with funding agencies such as Primary Care Trusts. It sets out the principles for successful negotiation and gives two examples of how they can be applied. It concludes that negotiation is a skill that can be learned and that it will be a key skill as the profession faces future challenges. PMID- 22244492 TI - Oral and dental manifestations in Rubinstein-Taybi syndrome: report of a rare case. AB - Rubinstein-Taybi syndrome, or broad thumb-hallux syndrome, is a well-defined rare congenital disorder characterised by postnatal growth deficiency, craniofacial dysmorphism, broad thumbs and great toes, and mental retardation (intellectual disability). Occurrence may be either sporadic or through autosomal dominant inheritance. Reports of Rubinstein-Taybi syndrome are scarce in the literature. This case report describes the oral and dentofacial findings of Rubinstein-Taybi syndrome affecting a 13-year-old Indian female, including the uncommon presence of talon cusps and an unerupted supernumerary tooth. PMID- 22244493 TI - An introduction to research for primary dental care clinicians: part 7: stage 8. Collecting data. PMID- 22244495 TI - Electrons for single molecule diffraction and imaging. AB - We demonstrate the potential of electrons for single molecule diffraction and imaging using C60 molecules confined inside single-walled carbon nanotubes (C60s@SWCNT or peapod) as a model system. A 25 nm diameter electron beam from a field emission gun source is used to record diffraction patterns from individual peapods using imaging plates. The electron beam illuminates about 25 C60 molecules. Experimentally, we found that the molecules diffract inside ~15% of the host nanotubes. With the help of simulations, we explore the limits of electron molecular diffraction and its sensitivity to the molecular configurations. We show that the combination of electron diffraction and electron direct imaging provides the best approach to single molecule imaging. PMID- 22244494 TI - Prenatal dichlorodiphenyldichloroethylene (DDE) exposure and child growth during the first year of life. AB - BACKGROUND: Due to its long-term persistence in the environment and its ability to cross the placental barrier, prenatal p,p'-dichlorodiphenyldichloroethene (DDE) exposure continues to be a public health concern. This study aimed to evaluate the association between prenatal DDE exposure and child growth, at birth and during the first year of life. METHODS: 253 pregnant women were recruited between January 2001 and June 2005 in a prospective cohort in Morelos, Mexico. Serum levels of DDE were measured during each trimester of pregnancy by gas chromatography with an electron capture detector. Using the generalized mixed effects models, the association between DDE and child growth parameters (weight for-age, length-for-age, weight-for-length, BMI-for-age and head circumference for-age Z-scores) from birth to 1 year of age was assessed. Maternal dietary intake was considered as covariable among others. RESULTS: DDE levels were 6.3+/ 2.8 ng/mL (first trimester), 6.6+/-2.9 ng/mL (second trimester), and 7.6+/-2.9 ng/mL (third trimester). After adjusting for potential confounder variables, no significant associations were observed with prenatal DDE exposure and each of the selected parameters. CONCLUSIONS: Our results show no evidence of an association between prenatal DDE exposure and child growth during the first year of life. PMID- 22244497 TI - BarraCUDA - a fast short read sequence aligner using graphics processing units. AB - BACKGROUND: With the maturation of next-generation DNA sequencing (NGS) technologies, the throughput of DNA sequencing reads has soared to over 600 gigabases from a single instrument run. General purpose computing on graphics processing units (GPGPU), extracts the computing power from hundreds of parallel stream processors within graphics processing cores and provides a cost-effective and energy efficient alternative to traditional high-performance computing (HPC) clusters. In this article, we describe the implementation of BarraCUDA, a GPGPU sequence alignment software that is based on BWA, to accelerate the alignment of sequencing reads generated by these instruments to a reference DNA sequence. FINDINGS: Using the NVIDIA Compute Unified Device Architecture (CUDA) software development environment, we ported the most computational-intensive alignment component of BWA to GPU to take advantage of the massive parallelism. As a result, BarraCUDA offers a magnitude of performance boost in alignment throughput when compared to a CPU core while delivering the same level of alignment fidelity. The software is also capable of supporting multiple CUDA devices in parallel to further accelerate the alignment throughput. CONCLUSIONS: BarraCUDA is designed to take advantage of the parallelism of GPU to accelerate the alignment of millions of sequencing reads generated by NGS instruments. By doing this, we could, at least in part streamline the current bioinformatics pipeline such that the wider scientific community could benefit from the sequencing technology.BarraCUDA is currently available from http://seqbarracuda.sf.net. PMID- 22244498 TI - Treatment and follow up of children with chronic hepatitis C in Albania. AB - BACKGROUND: Treatment of Hepatitis C in children has a better outcome than in adults, and for this reason the treatment had different views. However, in pediatric age hepatitis C is seen to have an evolution towards chronicity. Today is a normal option to treat chronic hepatitis C as early as possible according to certain criteria. The aim of this study is to show the results of treatment with interferon and ribavirin and the follow-up of children diagnosed with chronic hepatitis C in our service. PATIENTS AND METHODS: This is a prospective study which has included children 3 up to 15 years old (13 boys and 4 girls) diagnosed with chronic hepatitis C. All patients underwent a certain protocol, including liver biopsy prior to treatment. Treatment consisted in use for 48 weeks of INF alpha-2b, 3 MIU/m2 three times a week s/c and ribavirin 15 mg/kg orally divided bid. Two patients were treated with PEGINF alpha-2b with dose 1.5 mcg/kg once a week s/c and ribavirin 15 mg/kg. After the treatment all patients have stayed under our control for an average period of 24 weeks. RESULTS: At the end of the treatment we detected a patient with HCV-RNA positive. End Treatment Viral Response was 94%. Six months later we found three patients who showed relapse of disease. Sustained Viral Response was approximately 83% CONCLUSION: The combination therapy of interferon with Ribavirin in treatment of children with chronic hepatitis C provides a higher SVR when treatment is initiated at the earliest stages of hepatic changes. Side effects of therapy are insignificant in comparison with results obtained. PMID- 22244500 TI - The major soyabean allergen P34 resists proteolysis in vitro and is transported through intestinal epithelial cells by a caveolae-mediated mechanism. AB - Soya is considered to be one of the eight most significant food allergens. Among the allergenic soya proteins determined to date, P34 has been identified as one of the immunodominant soya antigens. Sensitisation to a specific food antigen like P34 generally follows the transit of intact antigens across the intestinal barrier and usually occurs in infants, who are most susceptible to food allergies. In the present study, we used the intestinal epithelial cell line IPEC J2, which was originally derived from the jejunum of a neonatal piglet, to recapitulate the infant intestinal epithelium and study the binding and uptake of P34 protein. P34 was partially resistant to degradation in an in vitro proteolysis assay. IPEC-J2 cells were able to endocytose intact P34, as shown by immunofluorescence and immunoelectronmicroscopy methods. P34 associated with lipid raft microdomains of IPEC-J2 cells, and disruption of caveolae/lipid raft microdomains using methyl-beta-cyclodextrin abolished P34 endocytosis, indicating that the observed endocytosis was mediated by caveolae. Using IPEC-J2 cells grown on Transwell filters, we further demonstrated that P34 is transported through the epithelial monolayer by transcytosis. Piglets frequently show hypersensitivity to soya antigens, and in this study, we show that healthy adult pigs with dietary exposure to soya protein mount an antibody response to soyabean protein P34, suggesting that this protein has entered the body, probably through gastrointestinal uptake. In summary, our data suggest that soya P34 resists proteolysis in the gastrointestinal tract and is transported through the intestinal epithelial barrier, thereby allowing sensitisation of immune cells in the sub-epithelial compartment. PMID- 22244502 TI - The relationship between plasma concentrations of ionized calcium and magnesium with cardiac energetics and systemic oxygen transport in neonates after the Norwood procedure. AB - OBJECTIVE: We sought to determine the relationship between plasma calcium and magnesium concentrations with postoperative systemic hemodynamics and oxygen transport in neonates after the Norwood procedure. METHODS: Postoperative systemic oxygen consumption was continuously measured using respiratory mass spectrometry for 72 hours in 17 neonates. Arterial, superior vena caval and pulmonary venous blood gases and pressures, plasma calcium, and lactate levels were measured at 2- to 4-hour intervals to calculate cardiac output, rate pressure product, cardiac power output, systemic oxygen delivery, and oxygen extraction ratio. Plasma magnesium levels were measured at 2- to 8-hour intervals. RESULTS: Plasma calcium levels decreased in the first 8 hours from 1.08+/-0.13 mmol/L to 0.98+/-0.08 mmol/L, followed by an increase to 1.10+/-0.26 mmol/L at 72 hours (P<.0001). Mg2p change was significantly related to time after logarithmic transformation, rapidly decreasing from 1.62+/-0.25 mg/L to 0.90+/ 0.15 mg/L in the first 40 hours and further decreasing slowly thereafter to 0.64+/-0.13 mg/L at 72 hours (P<.0001). Plasma magnesium levels had a significant positive correlation with cardiac output (P=.008) and cardiac power output (P=.01), and a negative correlation with heart rate (P=.05). Plasma magnesium levels correlated positively with systemic oxygen delivery and negatively with systemic oxygen consumption (P=.08 for both), resulting in significant negative correlations with oxygen extraction ratio (P=.04) and lactate levels (P=.05). For a given cardiac power output, plasma magnesium showed a significantly negative correlation with rate pressure product (P=.01). Plasma calcium levels showed the opposite trend, which was statistically insignificant except for lactate (P=.007). CONCLUSIONS: Plasma magnesium may exert favorable effects on myocardial energetics and systemic oxygen transport in neonates after the Norwood procedure, whereas plasma calcium may be harmful. Maintaining a relatively high level of plasma magnesium and a low level of plasma calcium may improve myocardial work efficiency and the balance of systemic and myocardial oxygen transport. PMID- 22244503 TI - Do we increase the operative risk by adding the Cox Maze III procedure to aortic valve replacement and coronary artery bypass surgery? AB - OBJECTIVE: Recent reports from Europe and the United States have suggested that patients presenting for open surgery with a significant history of atrial fibrillation (AF) have inferior early and late outcomes if AF is left untreated. On the other hand, there is reluctance among surgeons to treat AF surgically, especially when atriotomies may be required otherwise, which is the case with aortic valve replacement (AVR) or coronary artery bypass grafting (CABG). The objective of this study was to explore the potential impact of the addition of the Cox Maze III procedure on short- and long-term outcomes of patients when combined with AVR or CABG. METHODS: Since 2005, 485 patients have undergone the Cox Maze III procedure at Inova Heart and Vascular Institute, 95 of whom had a full Cox Maze III with an AVR or CABG (Cox Maze III/AVR = 30; Cox Maze III/CABG = 47; Cox Maze III/AVR/CABG = 18). In addition, 4255 patients with no history of AF underwent AVR or CABG without surgical ablation (AVR = 422; CABG = 3518; AVR/CABG = 315). Data from our CABG, valve, and AF registries were used for analyses. Patients with and without the Cox Maze III were propensity score matched using a 0.10 caliper to improve balance on clinical and demographic variables. Differences in perioperative and postoperative outcomes by group were evaluated using the Fisher exact test, and a Kaplan-Meier survival analysis was completed. Health-related quality of life (Short Form 12) was obtained at baseline and 6 months post-surgery (n = 72). RESULTS: All 95 patients who underwent the Cox Maze III were propensity score matched with patients who did not undergo the Cox Maze III. Mean age (t = 0.3, P = .79) and European System for Cardiac Operative Risk Evaluation score (t = -1.8, P = .07) were similar between the groups. There were no significant differences in major postoperative morbidities between the groups despite the Cox Maze III group being on bypass longer (164.4 vs 108.8 minutes; t = -9.8, P < .001). Pacemaker implantation was significantly higher in the Cox Maze III group (P = .03). Survival during follow-up (mean = 35 months) was not different between patients who did and did not undergo the Cox Maze III procedure (log rank = 0.49, P = .48). Improvement in physical health-related quality of life was similar for both groups (F = 0.01, P = .94). At 1 year, 94% of the patients (60/64) who underwent the Cox Maze III procedure were in sinus rhythm (81% off class I and III antiarrhythmic drugs). CONCLUSIONS: The addition of the Cox Maze III procedure to AVR or CABG did not convey an increase in major morbidity and perioperative risk. Patients who underwent the Cox Maze III procedure demonstrated similar survival over time with improvement in health related quality of life. The Cox Maze III should not be denied to patients in whom the cardiac surgical procedure does not include atriotomies because of the perceived increased operative risk. The Cox Maze III may significantly improve their outcome. PMID- 22244504 TI - Expression of TRAIL, DR4, and DR5 in bladder cancer: correlation with response to adjuvant therapy and implications of prognosis. AB - OBJECTIVES: To explore the interrelationship of human tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and its death receptors DR4 and DR5 expressions level with patient prognosis and the response to adjuvant therapy in bladder cancer, the synergism function that is between chemotherapy and TRAIL on apoptosis induction in tumor cells. METHODS: The expression of TRAIL, DR4, and DR5 was studied using immunohistochemistry of paraffin-embedded tumor specimens from 229 bladder cancer patients who had undergone transurethral resection. RESULTS: Cytoplasmic TRAIL, DR4, and DR5 expressions were detected in 35%, 75.1%, and 74.2% of bladder cancer patients, respectively. Patients with bladder cancer with either high DR4 or DR5 expression had a significantly longer postoperative recurrence-free rate than those with low expression of both during the 10-year follow-up. Multivariate analysis revealed that the expression of DR4 (P < .001), DR5 (P < .001) and epirubicin therapy (P = .034) were independent prognostic indicators of bladder cancer. Furthermore, epirubicin therapy significantly improved recurrence-free rate for the patients with DR4-high (P = .006) or DR5 high (P = .042) tumor. CONCLUSIONS: The results of the present study have shown for the first time that a combination of DR4 and DR5 expression have significant value in predicting the prognosis of bladder cancer. In addition, patients with high expression of both DR4 and DR5 might benefit from epirubicin therapy. PMID- 22244505 TI - Estimating insulin sensitivity from glucose levels only: Use of a non-linear mixed effects approach and maximum a posteriori (MAP) estimation. AB - Insulin Sensitivity is an important parameter for the management of Diabetes. It can be derived for a particular patient using data derived from some glucose challenge tests using measured glucose and insulin levels at various times. Whilst a useful approach, deriving insulin sensitivities to inform insulin dosing in other settings such as Intensive Care Units can be more challenging - especially as insulin levels have to be assayed in a laboratory, not at the bedside. This paper investigates an approach to measure insulin sensitivity from glucose levels only. Estimates of mean and between individual parameter variances are used to derive conditional estimates of insulin sensitivity. The method is demonstrated to perform reasonably well, with conditional estimates comparing well with estimates derived from insulin data as well. PMID- 22244506 TI - Descemet stripping automated endothelial keratoplasty in a child after failed penetrating keratoplasty. AB - Use of Descemet stripping automated endothelial keratoplasty (DSAEK) has been reported in children for the treatment of postoperative endothelial decompensation and Descemet membrane break after forceps delivery. Rapid visual recovery and minimally induced postoperative astigmatism make DSAEK preferable to penetrating keratoplasty for the management of isolated endothelial disorders in this age group. We present a case of DSAEK in a 4-year-old boy for the management of irreversible endothelial rejection after penetrating keratoplasty. Three months after the procedure, the cornea remained clear with the donor button in place. PMID- 22244507 TI - Posterior capsular plaque in bilateral congenital cataracts. AB - BACKGROUND: Many cases of unilateral congenital cataract have an associated posterior capsular plaque. Observations such as this have led to the hypothesis that posterior capsular plaque is caused by persistent fetal vasculature, generally a unilateral condition, even if no obvious hyaloid remnant is visible. We investigated the incidence of posterior capsular plaque associated with bilateral congenital cataracts. METHODS: Children with bilateral congenital cataracts were identified from three surgical practices. Children were included if lensectomies were performed prior to age 7 months. Surgical videos were evaluated for cataract morphology. RESULTS: Fourteen children with bilateral cataracts were identified. Surgical videos were available for 24 eyes. Five eyes (21%) had evidence of persistent hyaloid remnants. Of the remaining 19 eyes, cataracts were categorized as nuclear in 10 cases, nuclear with cortical extension in 6 cases, and posterior cortical in 3 cases. Evidence of posterior capsular plaque was seen in seven cases (37%) on video review. CONCLUSIONS: Video review revealed a much lower incidence of posterior capsular plaque in eyes with bilateral congenital cataracts compared to unilateral congenital cataracts, lending presumptive evidence to the hypothesis that most unilateral lens opacities arise from persistent fetal vasculature. PMID- 22244508 TI - Semantic interference during object naming in agrammatic and logopenic primary progressive aphasia (PPA). AB - This study examined the time course of object naming in 21 individuals with primary progressive aphasia (PPA) (8 agrammatic (PPA-G); 13 logopenic (PPA-L)) and healthy age-matched speakers (n=17) using a semantic interference paradigm with related and unrelated interfering stimuli presented at stimulus onset asynchronies (SOAs) of -1000, -500, -100 and 0 ms. Results showed semantic interference (SI) (i.e. significantly slower RTs in related compared to unrelated conditions) for all groups at -500, -100 and 0 ms, indicating timely spreading activation to semantic competitors. However, both PPA groups showed a greater magnitude of SI than normal across SOAs. The PPA-L group and six PPA-G participants also evinced SI at -1000 ms, suggesting an abnormal time course of semantic interference resolution, and concomitant left hemisphere cortical atrophy in brain regions associated with semantic processing. These subtle semantic mapping impairments in non-semantic variants of PPA may contribute to the anomia of these patients. PMID- 22244509 TI - Importance of factors determining the effective lifetime of a mass, long-lasting, insecticidal net distribution: a sensitivity analysis. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) reduce malaria transmission by protecting individuals from infectious bites, and by reducing mosquito survival. In recent years, millions of LLINs have been distributed across sub-Saharan Africa (SSA). Over time, LLINs decay physically and chemically and are destroyed, making repeated interventions necessary to prevent a resurgence of malaria. Because its effects on transmission are important (more so than the effects of individual protection), estimates of the lifetime of mass distribution rounds should be based on the effective length of epidemiological protection. METHODS: Simulation models, parameterised using available field data, were used to analyse how the distribution's effective lifetime depends on the transmission setting and on LLIN characteristics. Factors considered were the pre-intervention transmission level, initial coverage, net attrition, and both physical and chemical decay. An ensemble of 14 stochastic individual-based model variants for malaria in humans was used, combined with a deterministic model for malaria in mosquitoes. RESULTS: The effective lifetime was most sensitive to the pre intervention transmission level, with a lifetime of almost 10 years at an entomological inoculation rate of two infectious bites per adult per annum (ibpapa), but of little more than 2 years at 256 ibpapa. The LLIN attrition rate and the insecticide decay rate were the next most important parameters. The lifetime was surprisingly insensitive to physical decay parameters, but this could change as physical integrity gains importance with the emergence and spread of pyrethroid resistance. CONCLUSIONS: The strong dependency of the effective lifetime on the pre-intervention transmission level indicated that the required distribution frequency may vary more with the local entomological situation than with LLIN quality or the characteristics of the distribution system. This highlights the need for malaria monitoring both before and during intervention programmes, particularly since there are likely to be strong variations between years and over short distances. The majority of SSA's population falls into exposure categories where the lifetime is relatively long, but because exposure estimates are highly uncertain, it is necessary to consider subsequent interventions before the end of the expected effective lifetime based on an imprecise transmission measure. PMID- 22244510 TI - Tibial rotation in anterior cruciate ligament reconstructed knees during single limb hop and drop landings. AB - BACKGROUND: Alterations in knee joint kinematics have been suggested as a potential mechanism that influences the development of osteoarthritis of the knee after anterior cruciate ligament reconstruction. Whilst previous work has shown changes in internal-external tibial rotation during level walking, many patients aim to return to high impact activities following surgery. This study examined tibial rotation during single limb hop and drop landings in anterior cruciate ligament reconstructed knees compared to a control group, and also evaluated the influence of graft type (hamstring or patellar tendon). METHODS: In 48 participants (17 patellar tendon graft, 18 hamstring graft and 13 controls) internal-external rotation was measured during single limb hop and drop landings in a gait laboratory at mean of 10 months after surgery. FINDINGS: There was no difference between the two graft types and both patient groups had less internal rotation when compared to the control group. For 60% of patients, internal rotation values were at least 5 degrees less than the control group mean. INTERPRETATION: Anterior cruciate ligament reconstructed knees with both hamstring tendon and patellar tendon grafts show altered rotational kinematic patterns during high impact dynamic load activities. PMID- 22244511 TI - A comparative biomechanical study of a novel integrated plate spacer for stabilization of cervical spine: an in vitro human cadaveric model. AB - BACKGROUND: Integrated plate-spacer may provide adequate construct stability while potentially lowering operative time, decreasing complications, and providing less mechanical obstruction. The purpose of the current study was to compare the biomechanical stability of an anatomically profiled 2-screw integrated plate-spacer to a traditional spacer only and to a spacer and anterior cervical plate construct. In addition, the biomechanical stability of 2-screw integrated plate-spacer was compared to a commercially available 4-screw integrated plate-spacer. METHODS: Two groups, each of nine cervical cadaver spines (C2-C7), were tested under pure moments of 1.5Nm. Range of motion was recorded at C5-C6 in all loading conditions (flexion, extension, lateral bending, and axial rotation) for the following constructs: 1) Intact; 2) 2-screw or 4 screw integrated plate-spacer; 3) spacer and anterior cervical plate; and 4) spacer only. FINDINGS: All fusion constructs significantly reduced motion compared to the intact condition. Within the instrumented constructs, spacer and anterior cervical plate, 2-screw and 4-screw integrated plate-spacer resulted in reduced motion compared to the spacer only construct. No significant differences were found in motion between any of the instrumented conditions in any of the loading conditions. INTERPRETATION: The application of integrated plate-spacer for anterior cervical discectomy and fusion is based on several factors including surgical ease-of-use, biomechanical characteristics, and surgeon preference. The study suggests that integrated plate-spacer provide biomechanical stability comparable to traditional spacer and plate constructs in the cervical spine. Clinical studies on integrated plate spacer devices are necessary to understand the performance of these devices in vivo. PMID- 22244512 TI - Comparison of peak knee adduction moment and knee adduction moment impulse in distinguishing between severities of knee osteoarthritis. AB - BACKGROUND: The peak knee adduction moment is a valid proxy for medial knee joint loading. However as it only measures load at one instance of stance, knee adduction moment impulse, a measure that takes into account both the magnitude and duration of the stance phase, may provide more comprehensive information. This study directly compared the abilities of peak knee adduction moment and knee adduction moment impulse to distinguish between knee osteoarthritis severities. METHODS: 169 participants with medial knee osteoarthritis completed radiographic and magnetic resonance imaging, the Western Ontario and McMaster Universities Arthritis Index to assess pain and a three-dimensional gait analysis. Participants were classified using four dichotomous classifications: Kellgren Lawrence grading, alignment, medial tibiofemoral bone marrow lesions, and pain. FINDINGS: When using Kellgren-Lawrence grade and alignment classifications, the area under the receiver operator curves were significantly greater for knee adduction moment impulse than for peak knee adduction moment. Based on analysis of covariance, knee adduction moment impulse was significantly different between Kellgren-Lawrence grade and alignment groups while peak knee adduction moment was not significantly different. Both peak knee adduction moment and knee adduction moment impulse distinguished between bone marrow lesion severities while neither measure was significantly different between pain severity groups. INTERPRETATIONS: Findings suggest knee adduction moment impulse is more sensitive at distinguishing between disease severities and may provide more comprehensive information on medial knee joint loading. Future studies investigating biomechanics of knee osteoarthritis should include knee adduction moment impulse in conjunction with peak knee adduction moment. PMID- 22244513 TI - Whole body kinematics and knee moments that occur during an overhead catch and landing task in sport. AB - BACKGROUND: Athletes suffering an anterior cruciate ligament injury tend to exhibit similar body postures that in sidestep cutting are associated with increased knee moments. This relationship, however, has not been investigated in landing. Catching a ball in different overhead positions may affect landing postures and knee joint moments. This study investigated these possible relationships. It was anticipated that some joint postures would be associated increased knee loads during the landing task. METHODS: Twenty-five healthy male team sports athletes performed four variations of a landing task. Full body kinematics were identified at initial contact. Peak flexion, valgus and internal rotation moments at the knee, measured during early landing, were normalized to mass and height and statistically compared. Intra-participant correlations were performed between all kinematics and each moment. Mean slopes for each correlation were used to identify the existence of relationships between full body kinematics and knee joint moments. Findings Landing after an overhead catch when the ball moved towards a player's support leg resulted in increased peak valgus moments. These increased valgus moments were correlated with increased knee flexion, hip flexion, and torso lean, as well as torso rotation towards the support leg, and foot and knee external rotation. Increased internal rotation moments were correlated with reduced hip abduction and external rotation, increased ankle inversion, knee external rotation and torso lean away from the support leg. Interpretation Learning to land with techniques that do not reflect postures associated with high knee moments may reduce an athlete's risk of non contact anterior cruciate ligament injury. PMID- 22244514 TI - Sensorimotor gating and D2 receptor signalling: evidence from a molecular genetic approach. AB - Converging evidence from pharmacological investigations, genetic association studies and schizophrenia research indicates an important influence of the dopamine system on sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response. In particular, D2 receptor agonists have been shown to disrupt PPI in humans and rodents. In the present study, we investigated the associations of two functional DRD2 related single nucleotide polymorphisms (rs4648317 and rs1800497, the latter also known as DRD2/ANKK1 Taq1A) with PPI in two independent healthy human samples (overall n=197; Munich n=101; London n=96). Taq1A is a prominent marker of striatal D2 receptor signalling and was therefore hypothesized to impact on PPI. In line with our hypothesis, we report here reduced PPI levels in individuals with higher striatal D2 receptor signalling as indicated by the Taq1A genotype. Meta-analysis across both samples confirmed this finding. In contrast, an association between rs4648317 and PPI found in the Munich sample could not be confirmed in the London sample. Overall, the present study helps to bridge the gap between pharmacological manipulations of PPI and molecular genetics of the dopaminergic system. PMID- 22244515 TI - Serum brain-derived neurotrophic factor level in relation to illness severity and episode duration in patients with major depression. AB - BACKGROUND: Since there are few data on the possible association between BDNF levels and characteristics of major depression, the present study assesses brain derived neurotrophic factor (BDNF) levels in three drug-free patient samples, and explores whether episode duration, and severity correlate with serum BDNF levels. METHOD: Serum BDNF levels were measured in 42 drug-free patients with major depression. The duration of the index episode and the presence of psychotic features were assessed with the Schedule for Affective Disorders and Schizophrenia, and the severity of depression was measured with the 17-item Hamilton Rating Scale for Depression. The sample was divided into three groups: severely depressed inpatients without psychotic features, severely depressed inpatients with psychotic features, and moderately depressed outpatients. RESULTS: Mean serum BDNF level in the total sample was 18.0 +/- 2.8 ng/ml, with no significant difference between the three patient samples (F = 1.80, df = 2, p = 0.18). Mean serum BDNF level was significantly lower in patients with an index episode over one year, compared with patients who had a shorter index episode (F = 4.90, df = 1, p = 0.033). CONCLUSION: These data show that patients with a long index episode have significantly lower serum BDNF levels. We found no influence of the presence of psychotic features and severity of depression on serum BDNF levels. PMID- 22244516 TI - Outcomes in young South Asian Canadians after acute myocardial infarction. AB - BACKGROUND: South Asians have a high prevalence of ischemic heart disease and experience high incident acute myocardial infarction (AMI) rates at younger ages than their white counterparts. The aim of this study was to compare outcomes after AMI in a Canadian population of South Asian and white patients, aged 20 to 55 years. METHODS: Using hospital discharge abstract administrative data, we included patients with incident AMI, residing in British Columbia and the Calgary Health Region, between April 1, 1995 and March 31, 2002. The cohort was followed for up to 8 years (mean 4.2 years) to determine outcomes of mortality, recurrent AMI, and congestive heart failure (CHF) requiring hospitalization. South Asian ethnicity was determined using validated surname analysis. Baseline demographic characteristics and comorbidities were adjusted using Cox proportional hazard models. RESULTS: Of 7135 young patients with AMI, 487 were of South Asian ancestry. Compared with white patients, South Asian patients were more likely to have diabetes (25% vs. 12%) and hypertension (24% vs. 20%). After adjustment for sociodemographic and comorbidity variables, there were no significant differences in rates of 30-day mortality (risk adjusted hazard ratio [aHR] 0.90; 95% confidence interval [CI], 0.38-2.10), long-term mortality (aHR 0.81; 95% CI, 0.53 1.26), recurrent AMI (aHR 1.07; 95% CI, 0.89-1.29), or CHF (aHR 0.90; 95% CI, 0.51-1.59) between the 2 groups. CONCLUSIONS: Despite the recognition of increased cardiovascular mortality among young South Asian patients, our Canadian sample demonstrated similar rates of fatal and nonfatal outcomes among young South Asian and white patients with AMI. PMID- 22244517 TI - Microsatellites in immune-relevant regions and their associations with Maedi Visna and ovine pulmonary adenocarcinoma viral diseases. AB - Maedi-Visna (MV) and ovine pulmonary adenocarcinoma (OPA) are two retroviral diseases occurring worldwide that affect adult sheep. Differences in incidence, which may be related to sheep-rearing and housing choices, as well as to genetics, and disease progression have been reported for both diseases. In this work four microsatellites located in immune-relevant regions, the major histocompatibility complex (MHC) region, interferon-gamma and interleukin-12p35, were genotyped to determine their association with disease progression. The analysed sample included Latxa sheep with and without OPA and MV-characteristic lesions in their lungs. The microsatellites in the MHC were the most diverse, while the ones located in the cytokines were the less polymorphic. In the case of IFN-gamma the results suggested the presence of null alleles. Significant results were detected for several microsatellite alleles in the association analysis carried out by logistic regression. All statistical analyses included a flock effect adjustment to avoid false positives due to genetic structuration. MHC Class I microsatellite alleles OMHC1*205 and OMHC1*193 were associated with disease progression for Maedi and OPA, respectively. Moreover, MHC Class II microsatellite allele DRB2*275 was associated with presence of lesions in Maedi. Furthermore, the MHC microsatellites were combined for a bioinformatic haplotype inference with the PHASE software. In total, 73 haplotypes were detected, 18 of them in more than 6 animals. After standard and weighted logistic regression analysis, two of them were significantly associated with susceptibility: OMHC1*205-DRB2*271 for Maedi and OMHC1*193-DRB2*271 for OPA, both with the Class I microsatellite alleles associated in the marker by marker study. Although more extensive analyses are needed to disentangle the relationship between host genetics and disease, as far as we know this is the first study demonstrating a significant association between sheep MHC Class I microsatellite alleles and susceptibility to Maedi-Visna and OPA viral diseases. PMID- 22244518 TI - Suppression of canine myeloid cells by soluble factors from cultured canine tumor cells. AB - BACKGROUND: Cancer profoundly affects immunity and causes immunosuppression that contributes to tumor escape, metastases and resistance to therapy. The mechanisms by which cancer cells influence immune cells are not fully known but both innate and adaptive immune cells can be altered by cancer. Myeloid cells are innate immune cells that comprise the mononuclear phagocytic system (MPS) and include monocytes, macrophages, dendritic cells (DCs) and their progenitors. Myeloid cells play important roles in both the promotion and regulation of immune responses. Dysregulated myeloid cells are increasingly being recognized as contributing to cancer-related immunosuppression. This study investigated whether soluble factors produced by canine tumor cells inhibited canine myeloid cell function. METHODS: These studies investigated the utility of using the canine DH82 cell line for assessment of canine myeloid responses to tumor-derived soluble factors (TDSFs). Phenotypic comparisons to canine bone marrow-derived DCs (BM-DCs) and bone marrow-derived macrophages (BM-MPhis) were performed and expression of myeloid cell markers CD11b, CD11c, CD80, and major histocompatibility complex (MHC) class II were evaluated by flow cytometry. Phenotypic and functional changes of DC populations were then determined following exposure to tumor-conditioned media (TCM) from canine osteosarcoma, melanoma and mammary carcinoma cell lines. RESULTS: We found that the canine BM DCs and the DH82 cell line shared similar CD11b, CD11c and MHC II expression and morphologic characteristics that were distinct from canine BM-MPhis. Myeloid cells exposed to TDSFs showed decreased expression of MHC class II and CD80, had reduced phagocytic activity and suppressed the proliferation of responder immune cells. CONCLUSION: These results show that soluble factors secreted from canine tumor cells suppress the activation and function of canine myeloid cells. Our results suggest that, similar to humans, dysregulated myeloid cells may contribute to immunosuppression in dogs with cancer. PMID- 22244519 TI - Prevalence of livestock diseases and their impact on livelihoods in Central Equatoria State, Southern Sudan. AB - A participatory epidemiological (PE) study was conducted in Kajo Keji and Yei Counties, Central Equatoria State, southern Sudan to assess the impact of livestock diseases on livelihoods. A serological survey of tick-borne diseases was conducted to supplement the PE study. PE data collection tools consisted primarily of focus group interviews and key informant interviews supplemented by observation. Information was collected on the social context, history and species of livestock kept. Constraints in livestock keeping were explored through description and probing. Proportional piling on the importance of different diseases and relative incidence scoring were also conducted. 243 sera were collected from cattle and tested for antibodies to Anaplasma marginale, Babesia bigemina, B. bovis, Theileria mutans and T. parva by ELISA. Additionally, 173 blood samples were collected for a PCR assay of T. parva. Livestock diseases were ranked as the most important constraint to livestock keeping. While East Coast fever was ranked as the most important disease in Kajo Keji, diarrhoea in small ruminants was reported as the most important disease in Yei. Serological analyses of the sera indicated that A. marginale, B. bigemina, T. mutans and T. parva were most prevalent. Prevalence of B. bovis was found to be low (4.0% and 7.4% in Kajo Keji and Yei, respectively). 35% of the samples screened with the T. parva p104 gene nested PCR assay were positive. The study concludes that while ECF is the most important disease in Kajo Keji, it was not the case in Yei. Additional epidemiological studies are proposed before control strategies are recommended. PMID- 22244520 TI - Six-transmembrane epithelial antigen of prostate 4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with rheumatoid arthritis. AB - OBJECTIVES: Human six-transmembrane epithelial antigen of prostate 4 (STEAP4) is one of the STEAP family as a homologue of mouse tumour necrosis factor-alpha induced adipose-related protein (TIARP). Recently, we reported that the TIARP gene expression was remarkably increased in spleen and joints of glucose-6 phosphate isomerise (GPI)-induced arthritis model, suggesting pivotal association to arthritis. The aim of the present study was to assess the expression, localisation and function of STEAP4 in peripheral blood of patients with rheumatoid arthritis (RA). METHODS: Peripheral blood was obtained from seven patients with RA, the surface expression of STEAP4 was detected by flow cytometry. The number of neutrophils was compared with the expression of STEAP4 mRNA derived from peripheral blood of patients with RA. Neutrophils were introduced by HL60 with retinoic acid, and were transfected with GFP-STEAP4 plasmid DNA, then the migration of neutrophil-like HL60 was determined by transwell assay. In addition, the fluctuation of STEAP4 mRNA was analysed before and after treatment with infliximab in 40 patients with RA. RESULTS: STEAP4 was expressed on monocytes and neutrophils in peripheral blood in RA. The number of neutrophils and expression of STEAP4 mRNA was positively correlated. Migration of neutrophil-like HL60 was down-regulated by over-expression of STEAP4. Expression of STEAP4 Mrna was significantly decreased after infliximab treatment in patients with RA, especially in good responders. CONCLUSIONS: STEAP4 is expressed on monocytes and neutrophils in peripheral blood, regulates cell migration, is down regulated by TNF antagonist, and might be a possible predictor of response to TNF antagonist. PMID- 22244521 TI - Application of deglycosylation to SDS PAGE analysis improves calibration of influenza antigen standards. AB - Each year the production of seasonal influenza vaccines requires antigen standards to be available for the potency assessment of vaccine batches. These are calibrated and assigned a value for haemagglutinin (HA) content. The calibration of an antigen standard is carried out in a collaborative study amongst a small number of national regulatory laboratories which are designated by WHO as Essential Regulatory Laboratories (ERLs) for the purposes of influenza vaccine standardisation. The calibration involves two steps; first the determination of HA protein in a primary liquid standard by measurement of total protein in a purified influenza virus preparation followed by determination of the proportion of HA as determined by PAGE analysis of the sample; and second, the calibration of the freeze-dried reference antigen against the primary standard by single radial immunodiffusion (SRD) assay. Here we describe a collaborative study to assess the effect of adding a deglycosylation step prior to the SDS-PAGE analysis for the assessment of relative HA content. We found that while the final agreed HA value of the samples tested was not significantly different with or without deglycosylation, the deglycosylation step greatly improved between-laboratory agreement. PMID- 22244523 TI - Clinical features of 121 patients with diffuse unilateral subacute neuroretinitis. AB - PURPOSE: To describe the determinant clinical signs to diagnose diffuse unilateral subacute neuroretinitis (DUSN) and the main features related to identification of the live worm. DESIGN: Retrospective study performed at the Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil, between 2003 and 2008. METHODS: Patients with early- or late-stage diffuse unilateral subacute neuroretinitis were included. All patients underwent complete ophthalmologic examination and had a minimum of 6 months of follow-up. RESULTS: A total of 121 patients were included. Most patients were younger than 20 years (69.42%). Visual acuity was 20/400 or worse in 86 patients (71.7%). Nine patients (7.43%) presented in the early stage and 112 (92.57%) patients presented in the late stage. Subretinal tracks (91.7%), focal alterations of the retinal pigment epithelium (89.3%), small white spots (80.2%), and optic nerve atrophy (76.9%) were the most frequent clinical features. The subretinal worm was identified in 48 patients (39.66%), and laser treatment to destroy it was performed in all cases. The most common location of the nematode was the posterior pole (21 patients). It was observed that the younger the age, the higher the indices of larvae identification (P=.022). Multifocal yellow-white lesions and vitritis were correlated with identification of the worm (P=.001). Mean logarithm of the minimal angle of resolution visual acuity was 1.466 (20/600) and 1.281 (20/400) before and after laser treatment, respectively (P<.005). CONCLUSIONS: Identification of clinical signs and diagnosis of diffuse unilateral subacute neuroretinitis in its early stage, followed by prompt location and destruction of the worm by photocoagulation, may improve the vision of affected patients. PMID- 22244522 TI - Postoperative complications in the Tube Versus Trabeculectomy (TVT) study during five years of follow-up. AB - PURPOSE: To describe postoperative complications encountered in the Tube Versus Trabeculectomy (TVT) Study during 5 years of follow-up. DESIGN: Multicenter randomized clinical trial. METHODS: SETTINGS: Seventeen clinical centers. STUDY POPULATION: Patients 18 to 85 years of age who had previous trabeculectomy and/or cataract extraction with intraocular lens implantation and uncontrolled glaucoma with intraocular pressure (IOP) >=18 mm Hg and <=40 mm Hg on maximum tolerated medical therapy. INTERVENTIONS: Tube shunt (350-mm(2) Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC 0.4 mg/mL for 4 minutes). MAIN OUTCOME MEASURES: Surgical complications, reoperations for complications, visual acuity, and cataract progression. RESULTS: Early postoperative complications occurred in 22 patients (21%) in the tube group and 39 patients (37%) in the trabeculectomy group (P = .012). Late postoperative complications developed in 36 patients (34%) in the tube group and 38 patients (36%) in the trabeculectomy group during 5 years of follow-up (P = .81). The rate of reoperation for complications was 22% in the tube group and 18% in the trabeculectomy group (P = .29). Cataract extraction was performed in 13 phakic eyes (54%) in the tube group and 9 phakic eyes (43%) in the trabeculectomy group (P = .43). CONCLUSIONS: A large number of surgical complications were observed in the TVT Study, but most were transient and self-limited. The incidence of early postoperative complications was higher following trabeculectomy with MMC than tube shunt surgery. The rates of late postoperative complications, reoperation for complications, and cataract extraction were similar with both surgical procedures after 5 years of follow-up. PMID- 22244524 TI - The effect of general anesthesia and strabismus surgery on the intellectual abilities of children: a pilot study. AB - PURPOSE: To determine the influence of general anesthesia and strabismus surgery on children's intellectual abilities. DESIGN: Prospective, observational study. METHODS: SETTINGS: Institutional. PATIENTS: Children 5 to 10 years of age receiving general anesthesia with sevoflurane and undergoing strabismus surgery were included. Intellectual abilities were examined before and 4 weeks after surgery using the Kaufman Assessment Battery for Children. Four subtests representing intellectual abilities related to complex cortical function were examined: identification of objects in a partially completed picture, reproduction of a presented design by using rubber triangles, selecting a picture that completes or is similar to another picture, and memory for location of pictures presented on a page. MAIN OUTCOME MEASURES: Preoperative and postoperative age-adjusted scores of the 4 subtests of the Kaufman Assessment Battery for Children. RESULTS: The study group consisted of 21 children who underwent strabismus surgery under general anesthesia (mean duration, 51.3 minutes). The mean preoperative total score of the 4 subtests was 49.4+/-6.2. The mean postoperative total score adjusted for potential learning effects and test retest reliability was 48.1+/-7.7. There was no significant postoperative change in the total score (P=.108). However, the triangle test score decreased significantly after operation (P=.019), particularly in patients with decreased stereoacuity after surgery. CONCLUSIONS: General anesthesia with sevoflurane and strabismus surgery generally do not affect the intellectual abilities of complex cortical function in children 5 to 10 years of age at 4 weeks after surgery. Cortical functions related to hand-eye coordination may be affected by transient changes in postoperative stereoacuity. PMID- 22244525 TI - Long-term outcome of macular microstructure assessed by optical coherence tomography in eyes with spontaneous resolution of macular hole. AB - PURPOSE: To evaluate the long-term anatomic features as assessed by optical coherence tomography (OCT) in patients with spontaneously closed full-thickness macular hole (MH). DESIGN: Retrospective, noncomparative, observational case series. METHODS: Six eyes of 6 patients who eventually showed spontaneous resolution of idiopathic MH were studied. The best-corrected visual acuity (BCVA) and OCT images of the fovea were examined before and until at least 3 years after spontaneous resolution. RESULTS: The MH closed spontaneously 1 to 4 months after the initial examination. There were 2 distinct macular abnormalities in the early period after spontaneous closure: 4 eyes showed outer foveal defects and the remaining 2 eyes showed persistent foveal detachment. However, the fovea regained its normal configuration and the photoreceptor inner segment/outer segment (IS/OS) junction recovered completely in all eyes. Although all 6 eyes showed visual improvement after the hole closure, the BCVA in the 4 eyes that showed delayed recovery of the IS/OS junction and foveal detachment was limited to 20/25 or worse. CONCLUSION: Spontaneous closure of MH could acquire complete anatomic reconstruction. However, delayed restoration of the IS/OS junction and persistent foveal detachment after spontaneous closure might influence the functional outcomes. PMID- 22244526 TI - [Hepatocarcinoma, an uncommon cause of right-sided heart failure]. PMID- 22244527 TI - [Disseminated painful nodules]. PMID- 22244529 TI - Response rates of standard interferon therapy in chronic HCV patients of Khyber Pakhtunkhwa (KPK). AB - BACKGROUND: Interferon based therapy is used to eradicate the Hepatitis C Virus from the bodies of the infected individuals. HCV is highly prevalent in Khyber Pakhtunkhwa (KPK) that is why it is important to determine the response of standard interferon based therapy in Chronic HCV patients of the region. STUDY DESIGN: A total of 174 patients were selected for interferon based therapy. The patients were selected from four different regions of KPK. After confirmation of active HCV infection by Real Time PCR, standard interferon with ribavirn was given to patients for 6 months. After completion of therapy, end of treatment virologic response (ETR) was calculated. RESULTS: Out of total 174 patients, 130 (74.71%) showed ETR and 44 (25.28%) did not show ETR. In district Bunir, out of 52 patients, 36 (69.23%) showed ETR and 16 (30.79%) did not show ETR. In district Mardan, out of the total 74 patients, 66 (89.18%) were negative for HCV RNA and 8 (10.81%) were resistant to therapy. In Peshawar, out of 22, 16 (60%) were negative and 6 (40%) were positive for HCV RNA at the end of 6 months therapy. In the Federally Administered Tribal Area (FATA), out of 18 only 10 (55.5%) were negative and 8 (44.45%) were positive for active HCV infection. CONCLUSION: It is concluded that the response of antiviral therapy against HCV infection in chronic HCV patients of KPK province is 74.71%. The high response rate may be due to the prevalence of IFN-responsive HCV genotypes (2 and 3) in KPK. PMID- 22244528 TI - Central nervous system mechanisms linking the consumption of palatable high-fat diets to the defense of greater adiposity. AB - The central nervous system (CNS) plays key role in the homeostatic regulation of body weight. Satiation and adiposity signals, providing acute and chronic information about available fuel, are produced in the periphery and act in the brain to influence energy intake and expenditure, resulting in the maintenance of stable adiposity. Diet-induced obesity (DIO) does not result from a failure of these central homeostatic circuits. Rather, the threshold for defended adiposity is increased in environments providing ubiquitous access to palatable, high-fat foods, making it difficult to achieve and maintain weight loss. Consequently, mechanisms by which nutritional environments interact with central homeostatic circuits to influence the threshold for defended adiposity represent critical targets for therapeutic intervention. PMID- 22244530 TI - [Characterisation of a CTX-M-15-producing Shigella sonnei in a Spanish patient who had not travelled abroad]. AB - One hundred and seven Shigella spp. strains were isolated in our laboratory during the years 2000 to 2010. One Shigella sonnei harboured the genes that coded the beta-lactamases TEM-1 and CTX-M-15, identifying the structure, ISEcp1+bla(CTX M-15)+orf477, in their genetic environment. The strain also carried a class 2 integron with the gene cassettes dfrA1+sat+aadA1. A plasmid group IncI1 ST31 (CC 31) was detected and its mobilization by conjugation was demonstrated. We describe for the first time a S. sonnei strain producing a CTX-M-15 beta lactamase recovered from a Spanish patient who had not travelled abroad. PMID- 22244531 TI - [Nosocomially transmitted neonatal Listeriosis]. PMID- 22244532 TI - Managing anthelmintic resistance--use of a combination anthelmintic and leaving some lambs untreated to slow the development of resistance to ivermectin. AB - A field study was conducted to test the hypotheses that use of a combination anthelmintic and/or increasing the pool of unselected worms 'in refugia' by leaving a proportion of lambs untreated would slow the development of resistance to ivermectin. Twelve suites of four paddocks (farmlets) were seeded with a mixture of resistant and susceptible isolates of both Trichostrongylus colubriformis and Teladorsagia (Ostertagia) circumcincta calculated to yield a 95% reduction in faecal nematode egg count (FEC) after treatment with ivermectin. Each year for three years the farmlets were stocked in the spring with mobs of lambs which were treated five times at 28-day intervals with either ivermectin or an ivermectin+levamisole combination. In addition, in half the mobs the heaviest 10% of lambs remained untreated at each treatment occasion, resulting in a 2 * 2 factorial treatment structure (i.e. two drench types * two percentage treated) with three complete replicates. The development of resistance to ivermectin, and at the end to levamisole, was measured by larval development assays (LDA) and worm counts from treated and untreated tracer lambs. For T. colubriformis the development of resistance to ivermectin, as measured by tracer lamb worm burdens, was delayed by treatment with the combination and by leaving 10% of lambs untreated. In addition, the interaction between these factors approached significance (p=0.052). Similarly, results of the LDAs indicated a slower development of resistance when lambs were treated with the combination and when 10% of lambs were left untreated. For T. circumcincta, results were compromised by the rapid development of resistance, which appears to be the result of low viability in the field of the susceptible isolate used to contaminate the pastures. Although a small delay in the development of resistance to ivermectin was indicated, this was off-set by an increase in the level of resistance to levamisole. A post-study modelling experiment simulating the conditions of the field study and the starting efficacies for the two nematode species produced equivalent outputs to those measured in the field. Overall, results support the conclusions that use of combination anthelmintics and deliberately increasing 'refugia' of unselected genotypes will slow the development of anthelmintic resistance. However, as indicated in modelling studies, once resistance to all the constituent actives is well developed (efficacy<70%) the value of combinations for slowing the development of resistance is largely lost. PMID- 22244533 TI - Acaricidal activity of extract from Eupatorium adenophorum against the Psoroptes cuniculi and Sarcoptes scabiei in vitro. AB - The possible acaricidal activity of Eupatorium adenophorum was analyzed using extracts created by water decocting, ethanol thermal circumfluence, and steam distillation. The toxic effect of each extract was tested against Psoroptes cuniculi and Sarcoptes scabiei in vitro. Ethanol thermal circumfluence extract had strong toxicity against mites, killing all S. scabiei at 0.5 and 1.0 g/ml (w/v) concentration, while 1g/ml extract was also found to kill all P. cuniculi within a 4-h period. Similarly, 0.25, 0.5 and 1.0 g/ml concentration of extract had strong toxicity against S. scabiei, with median lethal time (LT(50)) values at 0.866, 0.785 and 0.517 h, respectively. 0.5 g/ml and 1g/ml showed strong acaricidal action against P. cuniculi; the LT(50) values were 0.93 h and 1.29 h, respectively. The median lethal concentration (LC(50)) values were 0.22 g/ml for Scabies mite and 0.64 g/ml for P. cuniculi in 1h. The results indicated that E. adenophorum contains potent acaricidal ingredients; as a first step in the potential development of novel drugs, it may provide new acaricidal compounds for the effective control of animal acariasis. PMID- 22244534 TI - Experimental inoculation of Neospora caninum in pregnant water buffalo. AB - The aim of this study was to characterize the pathogenesis of Neospora caninum in experimentally inoculated pregnant water buffalo (Bubalus bubalis). Twelve Mediterranean female water buffaloes ranging in age from 4 to 14 years old and seronegative to N. caninum by indirect fluorescent antibody test (IFAT) were involved. Ten females were intravenously inoculated with 10(8) tachyzoites of NC 1 strain at 70 (n=3) or 90 (n=7) days of pregnancy (dp). Two control animals were inoculated with placebo at 70 and 90 dp, respectively. Serum samples were obtained weekly following inoculation to the end of the experiment. Three animals inoculated at 70 dp were slaughtered at 28 days post inoculation (dpi), three animals inoculated at 90 dp were slaughtered at 28 dpi and the remaining four animals inoculated at 90 dp were slaughtered at 42 dpi. Fetal fluids from cavities and tissue samples were recovered for IFAT and histopathology, immunohistochemistry and PCR, respectively. Genomic DNA from fetal tissues was used for parasite DNA detection and microsatellite genotyping in order to confirm the NC-1 specific-infection. Dams developed specific antibodies one week after the inoculation and serological titers did not decrease significantly to the end of the experiment. No abortions were recorded during the experimental time; however, one fetus from a dam inoculated at 70 dp was not viable at necropsy. Specific antibodies were detected in only two fetuses from dams inoculated at 90 dp that were slaughtered at 42 dpi. No macroscopic changes in the placentas and organs of viable fetuses were observed. Nonsuppurative placentitis was a common microscopic observation in Neospora-inoculated specimens. Microscopic fetal lesions included nonsuppurative peribronchiolar interstitial pneumonia, epicarditis and myocarditis, interstitial nephritis, myositis and periportal hepatitis. Positive IHC results were obtained in two fetuses from dams inoculated at 70 dp and slaughtered at 28 dpi. N. caninum DNA was detected in placentas and fetuses from all inoculated animals. The pattern of amplified microsatellites from placental and fetal tissues resembled the NC-1 strain. Water buffaloes, like cattle, are susceptible to experimental inoculation with N. caninum at early pregnancy. PMID- 22244535 TI - Farmed wild boars exposed to Toxoplasma gondii and Trichinella spp. AB - The meat of wild boar (Sus scrofa L.) can be a source of human infections with zoonotic parasites Toxoplasma gondii and Trichinella spp. We screened 197 wild boar sera collected at slaughter from 25 Finnish farms in 2007-2008 for serological evidence of infections with these parasites. Using a commercial direct agglutination test at a serum dilution of 1:40, T. gondii-specific IgG antibodies were detected in 65 (33.0%) samples, on 14 (56.0%) farms. Females, animals older than 24 months, animals of small herds, and animals originating from south-western parts of Finland were more often T. gondii-seropositive than were males, younger animals, animals of larger herds, and animals originating from the north and east, respectively. Four (2.0%) of the sera, originating from three (12.0%) farms, tested Trichinella-seropositive with an in-house ELISA and a conservative cut-off for seropositivity. One farm had both T. gondii- and Trichinella-seropositive animals. Taken together, an infection source had been present on 16 (64.0%) farms, and 69 (35.0%) of the 197 farmed wild boars intended for human consumption had specific serological evidence of exposure to a zoonotic parasite. PMID- 22244536 TI - Bivalve larvae transport and connectivity within the Ahe atoll lagoon (Tuamotu Archipelago), with application to pearl oyster aquaculture management. AB - Patterns of bivalve larvae dispersal in the deep Ahe atoll lagoon was studied by using a numerical 3D transport model (MARS3D) coupled with a vertical swimming sub-model, forced mainly by tide and wind-induced currents. The simulations were validated against observations of larval dispersal monitored several days throughout the lagoon. Connectivity matrices describing larval exchanges inside the lagoon were inferred. Larvae displayed a significant dispersal capacity at the lagoon scale, especially with dominant eastern winds. With southeastern winds, larvae mostly remained in their origin sector. The total export rate of the larvae, toward the ocean through the pass and shallow lagoon borders, was independent of the wind conditions, with 1% of the total concentration exported per day. However, the tide-driven currents efficiently flushed larvae in sectors close to the pass. Connectivity matrices suggest that the south and west sectors were more suitable for spat collecting and that central sectors would be efficient sanctuaries if genitors were accumulated. PMID- 22244537 TI - Suppression of matrix metalloproteinase-9 expression by andrographolide in human monocytic THP-1 cells via inhibition of NF-kappaB activation. AB - There is much evidence indicating that human leukemic cells and monocytes/macrophages synthesize, and secrete, several matrix metalloproteinases (MMPs), and participate in the degradation of extracellular matrix components in tissue lesions. In this study, we investigated the effects and mechanisms of andrographolide, extracted from the herb Andrographis paniculata, on human monocytic MMPs expression and activation. Andrographolide (1-50 MUM) exhibited concentration-dependent inhibition of MMP-9 activation, induced by either tumor necrosis factor-alpha (TNF-alpha), or lipopolysaccharide (LPS), in THP-1cells. In addition, andrographolide did not present an inhibitory effect on MMP-9 enzymatic activity at a concentration of 50 MUM. By contrast, enzyme-linked immunosorbent assay (ELISA) showed that andrographolide partially affect TIMP-1 levels. Western blot analysis showed that both TNF-alpha, and LPS stimulators attenuated MMP-9 protein expression in a concentration-dependent manner. Using reverse transcription polymerase chain reaction (RT-PCR), we found that andrographolide suppressed expression of MMP-9 messenger RNA. Furthermore, we also found that andrographolide could significantly inhibit the degradation of inhibitor-kappaB alpha (IkappaB-alpha) induced by TNF-alpha. We used electrophoretic mobility shift assay and reporter gene detection to show that andrographolide also markedly inhibited NF-kappaB signaling, anti-translocation and anti-activation. In conclusion, we demonstrate that andrographolide attenuates MMP-9 expression, and its main mechanism might involve the NF-kappaB signal pathway. These results provide new opportunities for the development of new anti-inflammatory and leukemic therapies. PMID- 22244539 TI - Variations in T(2)* and fat content of murine brown and white adipose tissues by chemical-shift MRI. AB - PURPOSE: The purpose was to compare T(2)* relaxation times and proton density fat fraction (PDFF) values between brown (BAT) and white (WAT) adipose tissue in lean and ob/ob mice. MATERIALS AND METHODS: A group of lean male mice (n=6) and two groups of ob/ob male mice placed on similar 4-week (n=6) and 8-week (n=8) ad libitum diets were utilized. The animals were imaged at 3 T using a T(2)* corrected chemical-shift-based water-fat magnetic resonance imaging (MRI) method that provides simultaneous estimation of T(2)* and PDFF on a voxel-wise basis. Regions of interest were drawn within the interscapular BAT and gonadal WAT depots on co-registered T(2)* and PDFF maps. Measurements were assessed using analysis of variance, Bonferroni-adjusted t test for multigroup comparisons and the Tukey post hoc test. RESULTS: Significant differences (P<.01) in BAT T(2)* and PDFF were observed between the lean and ob/ob groups. The ob/ob animals exhibited longer BAT T(2)* and greater PDFF than lean animals. However, only BAT PDFF was significantly different (P<.01) between the two ob/ob groups. When comparing BAT to WAT within each group, T(2)* and PDFF values were consistently lower in BAT than WAT (P<.01). The difference was most prominent in the lean animals. In both ob/ob groups, BAT exhibited very WAT-like appearances and properties on the MRI images. CONCLUSION: T(2)* and PDFF are lower in BAT than WAT. This is likely due to variations in tissue composition. The values were consistently lower in lean mice than in ob/ob mice, suggestive of the former's greater demand for BAT thermogenesis and reflective of leptin hormone deficiencies and diminished BAT metabolic activity in the latter. PMID- 22244540 TI - A preliminary study of blood-oxygen-level-dependent MRI in patients with chronic kidney disease. AB - BACKGROUND: Blood-oxygen-level-dependent (BOLD) magnetic resonance imaging (MRI) can provide regional measurements of oxygen content using deoxyhemoglobin paramagnetic characteristics. The apparent relaxation rate or R2*(=1/T2*) can be determined from the slope of log (intensity) versus echo time and is directly proportional to the tissue content of deoxyhemoglobin. Thus, as the level of deoxyhemoglobin increases, T2* will decrease, leading to an increase in R2*. Chronic kidney disease (CKD) can affect oxygenation levels in renal parenchyma, which influences the clinical course of the disease. The goal of this study was to detect and assess renal oxygenation levels in CKD using BOLD MRI. METHODS: Fifteen healthy subjects and 11 patients with CKD underwent a renal scan using multigradient-recalled-echo sequence with eight echoes. R2* (1/s) of the renal cortex and medulla was measured on BOLD images. Of the 11 patients, nine had biopsy-proven chronic glomerulonephritis, and two had a similar diagnosis based on clinical symptoms and investigations. RESULTS: Mean medullary R2* (MR2*) and cortex R2* (CR2*) levels were significantly higher in patients (22 kidneys, MR2*=24.79+/-4.84 s(-1), CR2*=18.97+/-2.72 s(-1)) than in controls (30 kidneys, MR2*=19.98+/-1.19 s(-1), CR2*=16.03+/-1.23 s(-1)) (P<.01), and MR2* was increased more than CR2*. Medullary to cortical R2* ratios (MCR2*) of patients were significantly increased when compared with those of controls (P<.01). In the patient group, estimated glomerular filtration rate levels were greater than or equal to 60 ml/min/1.73 m(2) in six patients (12 kidneys), whose MR2* and CR2* were also significantly higher than those of controls (P<.01). Serum creatinine levels were normal in seven patients (14 kidneys), whose MR2*, CR2* and MCR2* were also higher than those of controls (P<.01). CONCLUSIONS: BOLD MRI can be used to evaluate changes in renal oxygenation in CKD, suggesting that it has the potential to be an excellent noninvasive tool for the evaluation of renal function. PMID- 22244541 TI - Simultaneous 3D localization of multiple MR-visible markers in fully reconstructed MR images: proof-of-concept for subsecond position tracking. AB - PURPOSE: To determine whether a greatly reduced spatial resolution of fully reconstructed projection MR images can be used for the simultaneous 3D localization of multiple MR-visible markers and to assess the feasibility of a subsecond position tracking for clinical purposes. MATERIALS AND METHODS: Miniature, inductively coupled RF coils were imaged in three orthogonal planes with a balanced steady-state free precession (SSFP) sequence and automatically localized using a two-dimensional template fitting and a subsequent three dimensional (3D) matching of the coordinates. Precision, accuracy, speed and robustness of 3D localization were assessed for decreasing in-plane resolutions (0.6-4.7 mm). The feasibility of marker tracking was evaluated at the lowest resolution by following a robotically driven needle on a complex 3D trajectory. RESULTS: Average 3D precision and accuracy, sensitivity and specificity of localization ranged between 0.1 and 0.4 mm, 0.5 and 1.0 mm, 100% and 95%, and 100% and 96%, respectively. At the lowest resolution, imaging and localization took ~350 ms and provided an accuracy of ~1.0 mm. In the tracking experiment, the needle was clearly depicted on the oblique scan planes defined by the markers. CONCLUSION: Image-based marker localization at a greatly reduced spatial resolution is considered a feasible approach to monitor reference points or rigid instruments at subsecond update rates. PMID- 22244542 TI - The effect of gradient sampling schemes on diffusion metrics derived from probabilistic analysis and tract-based spatial statistics. AB - PURPOSE: The purpose was to systematically evaluate the effect of diffusion gradient encoding scheme on estimated fractional anisotropy (FA), mean diffusivity (MD) and the voxel-wise probability of identifying crossing fibers in the brain. MATERIALS AND METHODS: Eight healthy volunteers (mean age 26.5+/-1.3 years, 5 males, 3 females) were imaged using a Spin-Echo Echo-Planar-Imaging sequence acquired with two signal averages [number of signals averaged (NSA)], 127 diffusion directions, and b-values of 750 s/mm(2) and 1500 s/mm(2). The number of diffusion gradient directions (N(d)) was reduced from the original value whilst maintaining a homogeneous gradient distribution enabling direct comparison of subsampled data sets with N(d)=15, 28, 43, 84, 112 and 127. FA and MD maps were generated and analyzed using tract-based spatial statistics. Effect of N(d) on estimated FA and MD was tested with voxel-wise statistics in 13 regions of interest. The number of voxels supporting two fiber populations (NV(2)) at different N(d) values was estimated using Bayesian estimation of diffusion parameters. RESULTS: Low FA values decreased significantly with increasing N(d) and with increasing NSA. MD was only marginally sensitive to N(d) and NSA. NV(2) increased significantly with N(d) but not with NSA. Thus, we conclude that accurate estimation of standard diffusion metrics FA and MD is mainly dependent on the signal-to-noise ratio (SNR), whereas the ability to differentiate multiple fiber populations requires a high diffusion sampling density. PMID- 22244543 TI - Depth and orientational dependencies of MRI T(2) and T(1rho) sensitivities towards trypsin degradation and Gd-DTPA(2-) presence in articular cartilage at microscopic resolution. AB - Depth and orientational dependencies of microscopic magnetic resonance imaging (MRI) T(2) and T(1rho) sensitivities were studied in native and trypsin-degraded articular cartilage before and after being soaked in 1 mM Gd-DTPA(2-) solution. When the cartilage surface was perpendicular to B(0), a typical laminar appearance was visible in T(2)-weighted images but not in T(1rho)-weighted images, especially when the spin-lock field was high (2 kHz). At the magic angle (55 degrees ) orientation, neither T(2)- nor T(1rho)-weighted image had a laminar appearance. Trypsin degradation caused a depth- and orientational-dependent T(2) increase (4%-64%) and a more uniform T(1rho) increase at a sufficiently high spin lock field (55%-81%). The presence of the Gd ions caused both T(2) and T(1rho) to decrease significantly in the degraded tissue (6%-38% and 44%-49%, respectively) but less notably in the native tissue (5%-10% and 16%-28%, respectively). A quantity Sensitivity was introduced that combined both the percentage change and the absolute change in the relaxation analysis. An MRI experimental protocol based on two T(1rho) measurements (without and with the presence of the Gd ions) was proposed to be a new imaging marker for cartilage degradation. PMID- 22244544 TI - CNS prophylaxis in diffuse large B-cell lymphoma: if, when, how and for whom? AB - Central nervous system (CNS) relapse is an uncommon devastating complication of diffuse large B-cell lymphoma (DLBCL) that usually occurs within 2 years from initial diagnosis. Its pathophysiology is poorly understood and there is no consensus on the definition of high-risk patients for CNS relapse. Consequently, an empirical and highly variable practice of chemoprophylaxis is employed. In this review we critically appraise the available literature in order to address issues related to ineffectiveness of current paradigms of chemoprophylaxis. The commonly used prophylaxis is derived from past experience with childhood acute leukemia where most early CNS relapses are leptomeningeal. In contrast, CNS involvement in DLBCL affects brain parenchyma in almost 60% of cases and thus intrathecal prophylaxis remains ineffective. We propose that CNS relapse in DLBCL is sometimes related to occult malignant cells present in the CNS at diagnosis. In others, CNS relapse is likely due to a later acquisition of CNS-penetrating subtypes of malignant clones. With lack of evidence for occult CNS involvement no strong indication currently exist that any form of chemoprophylaxis is beneficial. Future directions for evaluation and treatment of CNS disease are outlined. This complex and intriguing topic should be ideally investigated by prospective trials. PMID- 22244546 TI - Emergency medical services triage using the emergency severity index: is it reliable and valid? AB - INTRODUCTION: Efficient communication between emergency medical services (EMS) and ED providers using a common triage system may enable more effective transfers when EMS arrives in the emergency department. We sought (1) to evaluate inter rater reliability between Emergency Severity Index (ESI) assignments designated by EMS personnel and emergency triage nurses (registered nurses [RNs]) and (2) to evaluate the validity of EMS triage assignments using the ESI instrument. METHODS: This prospective, observational study evaluated inter-rater reliability in ESI scores assigned by prehospital personnel and RNs. EMS providers were trained to use the ESI by the same methods used for nurse training. EMS personnel assigned triage scores to patients independent of assignments by the RN. Inter rater reliability, differences based on provider experience, and validity of EMS triage assignments (sensitivity and specificity) were evaluated. RESULTS: Seventy five paired, blinded triages were completed. Overall concordance between EMS providers and RNs was 0.409 (95% confidence interval [CI], 0.256-0.562). Agreement for EMS providers with less experience was 0.519 (95% CI, 0.258-0.780), whereas concordance for those with more experience was 0.348 (95% CI, 0.160 0.536; chi(2) = 1.413, df = 1, P = .235). Sensitivity ranged from 0% to 67.86%. Specificity ranged from 68.09% to 97.26%. CONCLUSIONS: We observed moderate concordance between EMS and RN ESI triage assignments. EMS sensitivity for correct acuity assignment was generally poor, whereas specificity for correctly not assigning a particular level was better. Additional research investigating the potential causes of the poor agreement that we observed is warranted. PMID- 22244547 TI - Logistics and lessons learned: ED redesign 3 years later--a follow-up to "How to create a new emergency department in 21 days or less". PMID- 22244548 TI - Evaluation of a flexible acute admission unit: effects on transfers to other hospitals and patient throughput times. AB - INTRODUCTION: To prevent overcrowding of the emergency department, a flexible acute admission unit (FAAU) was created, consisting of 15 inpatient regular beds located in different departments. We expected the FAAU to result in fewer transfers to other hospitals and in a lower length of stay (LOS) of patients needing hospital admission. METHODS: A before-and-after interventional study was performed in a level 1 trauma center in the Netherlands. Number of transfers and LOS of admitted ED patients in a 4-month period in 2008 (control period) and a 4 month period in 2009 (intervention period) were analyzed. RESULTS: Of 1,619 regular admission patients, 768 were admitted in the control period and 851 in the intervention period. The number of transfers decreased from 80 (10.42%) to 54 (6.35%) (P = .0037). The mean ED LOS of both the non-admitted patients and the admitted patients needing special care significantly increased (105 minutes vs 117 minutes [P = .022] and 176 minutes vs 191 minutes [P < .001], respectively). However, the mean LOS of FAAU-admissible patients was unaltered (226 minutes vs 225 minutes, P = .865). CONCLUSIONS: The FAAU reduced the number of transfers of admitted patients to other hospitals. The increase in LOS for special care patients and non-admitted patients was not observed for regular, FAAU-admissible patients. Flexible bed management might be useful in preventing overcrowding. PMID- 22244549 TI - Raised erythrocyte creatine in patients with pulmonary arterial hypertension- evidence for subclinical hemolysis. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) has been associated with hemolytic conditions such as sickle cell disease but the possible role of hemolysis in the pathogenesis or pathophysiology of other forms of PAH has not been studied. Erythrocyte lifespan is the gold-standard test of hemolysis and may be measured by assaying erythrocyte creatine (EC) levels. EC decreases as the erythrocyte ages, so patients with hemolysis have high EC levels. METHODS: We measured EC and other parameters of hemolysis in patients with idiopathic and connective tissue associated PAH and normal controls. RESULTS: In patients with PAH (n = 40), EC levels were higher than in controls n = 30 (patients EC 1.72 mcmol/g HgB 95%CI[1.51, 1.96], controls EC 1.05 mcmol/g HgB [0.93, 1.19], p < 0.0001). High levels of EC correlated with worse 6 min walk (r = -0.42, p < 0.0001) and worse functional class (p = 0.002). Other indirect indices of hemolysis (total lactate dehydrogenase, red cell distribution width) were also increased in patients with PAH relative to controls. CONCLUSIONS: There is evidence of subclinical hemolysis in patients with PAH, and higher levels of hemolysis are associated with poorer exercise capacity. PMID- 22244550 TI - [Hemoglobin: simply a laboratory value or a powerful predictor of risk in patients with acute coronary syndrome?]. AB - INTRODUCTION: Anemia has been shown to be associated with a worse prognosis, especially higher mortality in various pathological conditions. However, few studies have specifically examined its impact in acute coronary syndrome (ACS) patients. The purpose of our study was to assess the association between different quartiles of hemoglobin on admission and short- and long-term prognosis in patients with ACS. METHODS: We performed a retrospective analysis of 1303 consecutive ACS patients admitted to a coronary care unit and analyzed the association between baseline hemoglobin and morbidity and mortality, in-hospital and at 12-month follow-up. The population was divided into groups according to quartiles of hemoglobin concentration (Hb): Q1: <10.8g/dl; Q2: 10.8-12.2g/dl; Q3: 12.3-13.2g/dl; Q4: >=13.3g/dl. Logistic regression analysis was used to identify independent predictors of short- and long-term mortality. RESULTS: Hypertension and diabetes mellitus were more common in the lower Hb quartiles, while the prevalence of smoking and physical inactivity increased with higher Hb. A higher proportion of patients in the lower quartiles had congestive heart failure, peripheral artery disease and previous stroke or transient ischemic attack. Anemic patients tended to be older, with worse renal function and left ventricular systolic function. Patients in Q1 had significantly higher levels of troponin I and blood glucose on admission. Anemic patients showed significantly higher in-hospital mortality (Q1: 9.8%; Q2: 6.3%; Q3: 4.1%; Q4: 3.6%, p<0.001), longer hospital stay (Q1: 6.1+/-4.4; Q2: 5.2+/-3.0; Q3: 4.9+/-2.7; Q4 4.3+/-2.1 days, p<0.001) and higher 1-year mortality (Q1: 23.6%; Q2: 11.6%; Q3: 10.6%; Q4: 5.5%, p<0.001). In multivariate analysis, the only independent predictor of in hospital mortality was Killip class >1 at admission. The independent predictors of long-term mortality were age >=69.5 years, Killip class >1 at admission, diabetes mellitus, ST-segment depression on admission ECG and Hb <10.8g/dl. DISCUSSION AND CONCLUSIONS: Low baseline hemoglobin is associated with more comorbidities and can accurately predict 1-year mortality after an acute coronary syndrome. PMID- 22244551 TI - Evolving progress in oncologic and operative outcomes for esophageal and junctional cancer: lessons from the experience of a high-volume center. AB - OBJECTIVE: Modern series from high-volume esophageal centers report an approximate 40% 5-year survival in patients treated with curative intent and postoperative mortality rates of less than 4%. An objective analysis of factors that underpin current benchmarks within high-volume centers has not been performed. METHODS: Three time periods were studied, 1990 to 1998 (period 1), 1999 to 2003 (period 2), and 2004 to 2008 (period 3), in which 471, 254, and 342 patients, respectively, with esophageal cancer were treated with curative intent. All data were prospectively recorded, and staging, pathology, treatment, operative, and oncologic outcomes were compared. RESULTS: Five-year disease specific survival was 28%, 35%, and 44%, and in-hospital postoperative mortality was 6.7%, 4.4%, and 1.7% for periods 1 to 3, respectively (P < .001). Period 3, compared with periods 1 and 2, respectively, was associated with significantly (P < .001) more early tumors (17% vs 4% and 6%), higher nodal yields (median 22 vs 11 and 18), and a higher R0 rate in surgically treated patients (81% vs 73% and 75%). The use of multimodal therapy increased (P < .05) across time periods. By multivariate analysis, age, T stage, N stage, vascular invasion, R status, and time period were significantly (P < .0001) associated with outcome. CONCLUSIONS: Improved survival with localized esophageal cancer in the modern era may reflect an increase of early tumors and optimized staging. Important surgical and pathologic standards, including a higher R0 resection rate and nodal yields, and lower postoperative mortality, were also observed. PMID- 22244553 TI - Impact of pressure load caused by right ventricular outflow tract obstruction on right ventricular volume overload in patients with repaired tetralogy of Fallot. AB - OBJECTIVES: In correction of tetralogy of Fallot (TOF), surgical strategies to minimize right ventricular outflow tract (RVOT) enlargement have recently been preferred. However, we may be confronted with residual pulmonary stenosis (PS) combined with pulmonary regurgitation (PR), and how the pressure load affects these patients is not evident. METHODS: We compared 51 patients with PR and significant PS (PR with PS group) with 87 patients with PR without significant PS (PR group) using echocardiography and cardiac magnetic imaging. We evaluated the differences in parameters derived by magnetic resonance imaging between the 2 groups and the influence of the pressure load on right ventricular (RV) volume and function. RESULTS: Although the PR fraction was similar between the 2 groups, the PR with PS group showed significantly smaller RV end-diastolic volume (136.7 +/- 26.5 mL/m(2) vs 151.2 +/- 34.7 mL/m(2); P = .01), RV end-systolic volume (68.1 +/- 23.7 mL/m(2) vs 80.2 +/- 27.5 mL/m(2); P = .01), and slightly better RV ejection fraction (51.1% +/- 9.8% vs 47.6% +/- 8.9%; P = .03) than the PR group. For influence of the pressure load, PR fraction (r = -0.18, P = .03), RV end diastolic volume (r = -0.25, P = .003), and RV end-systolic volume (r = -0.24, P = .005) were decreased as peak pressure gradient of PS was higher. Linear regression analysis revealed that both PR fraction and peak pressure gradient of PS were independent predictors for RV volume. CONCLUSIONS: Our study demonstrated that the RV pressure load prevented RV dilatation from chronic PR without systolic dysfunction. It is suggested that a proper relief of RVOT obstruction with acceptable residual stenosis is more advantageous than aggressive RVOT enlargement in the long-term outcome of repaired TOF. PMID- 22244554 TI - Thoracic empyema in patients with liver cirrhosis: clinical characteristics and outcome analysis of thoracoscopic management. AB - OBJECTIVE: Thoracic empyema in cirrhotic patients is a challenging situation, and the clinical characteristics are rarely reported. The objective of this study was to report the clinical characteristics among this group and to evaluate whether thoracoscopic intervention would affect clinical outcomes. METHODS: Between 2001 and 2010, we retrospectively reviewed the clinical characteristics, bacteriologic studies, and treatment outcomes of 63 cirrhotic patients with thoracic empyema. A propensity-score based process, matched on age, sex, diabetes mellitus, malignancy, cause, and Child-Pugh classification (A, B, or C), was performed to equalize potential prognostic factors in thoracoscopy and nonthoracoscopy groups. The Kaplan-Meier curve and log-rank test were applied to compare the survival to discharge between the 2 matched groups. RESULTS: The median patient age was 61 years. Thirty-two patients (51%) underwent thoracoscopic management, and the remaining patients underwent thoracocentesis or tube thoracostomy. The median hospital stay was 28 days, and 19 patients (30%) had in-hospital mortality. Multivariate analysis showed that Child-Pugh C disease and positive blood cultures were risk factors for in-hospital mortality (P = .016 and .027, respectively), whereas thoracoscopic management may be favorable for survival (P = .041). The propensity score-matched analysis showed a significant reduction in intensive care unit stay (P = .044) in the thoracoscopy group. Kaplan-Meier survival analysis revealed a higher survival to discharge, favoring thoracoscopy over non-thoracoscopy treatment (P = .035). CONCLUSIONS: Management of thoracic empyema in cirrhotic patients is complicated and associated with a high mortality. With proper patient selection, thoracoscopic management is feasible and may provide a better chance of survival. PMID- 22244555 TI - Prognostic value of myocardial fibrosis in patients with severe aortic valve stenosis. AB - OBJECTIVE: To evaluate whether myocardial fibrosis influences left ventricular performance in severe aortic stenosis and to assess its effect on long-term survival after aortic valve replacement. METHODS: Myocardial fibrosis was evaluated in biopsy specimens taken from the interventricular septum in 99 patients undergoing aortic valve replacement because of severe or prevalent aortic stenosis. Clinical and echocardiographic evaluations were performed at a mean follow-up of 6.2 +/- 3.0 years. The patients were classified according to the myocardial fibrosis severity (none or mild in 28, moderate in 52, and severe in 19). RESULTS: Patients with severe myocardial fibrosis had a dilated left ventricle and positive association between the left ventricular end-diastolic diameter (R = 0.77, P < .001), left ventricular end-systolic diameter (R = 0.78, P < .001), left ventricular end-systolic wall stress (R = 0.74, P < .001) and the degree of myocardial fibrosis. Myocardial fibrosis was inversely related to left ventricular fractional shortening (R = -0.64, P < .001), left ventricular ejection fraction (R = -0.53, P < .001), and left ventricular relative wall thickness (R = -0.70, P < .001). Patients with a higher grade of myocardial fibrosis had a significantly lower freedom from cardiac death at 10 years (42% +/ 19% vs 89% +/- 6%, P = .002), with congestive heart failure the most common cause of death. At Cox regression analysis, patient age (P = .012), low preoperative transvalvular gradient less than 40 mm Hg (P = .040), preoperative end-systolic wall stress (P = .046), and preoperative myocardial fibrosis grade (P = .034) emerged as the strongest independent predictors of mortality. CONCLUSIONS: In patients with severe aortic valve stenosis, the amount of myocardial fibrosis appears to have significant effect on clinical status and long-term survival after aortic valve replacement. From these results, we believe that new strategies for the earlier detection of myocardial fibrosis are needed to achieve a better prognostic outcome. PMID- 22244556 TI - Outcomes of less invasive J-incision approach to aortic valve surgery. AB - OBJECTIVE: Less invasive approaches to aortic valve surgery are increasingly used; however, few studies have investigated their impact on outcome. We sought to compare clinical outcomes after these approaches with full sternotomy using propensity-matching methods. METHODS: From January 1995 to January 2004, a total of 2689 patients underwent isolated aortic valve surgery, 1193 via upper J hemisternotomy and 1496 via full sternotomy. Because of important differences in patient characteristics between these groups, a propensity score based on 42 variables was used to obtain 832 well-matched patient pairs (70% of possible cases). RESULTS: In-hospital mortality was identical for propensity-matched patients, 0.96% (8 in each). Occurrences of stroke (P > .9), renal failure (P = .8), and myocardial infarction (P = .7) were similar. However, 24-hour mediastinal drainage was a third less after less invasive surgery (median, 250 vs 350 mL; P < .0001), and fewer patients received transfusions (24% vs 34%; P < .0001). More patients undergoing less invasive surgery were extubated in the operating room (12% vs 1.6%; P < .0001), postoperative forced 1-second expiratory volume was higher (P = .009), and fewer had respiratory failure (P = .01). Early after operation, pain scores were lower (P < .0001) after less-invasive surgery and postoperative length of stay shorter (P < .0001). CONCLUSIONS: Within that portion of the spectrum of isolated aortic valve surgery where propensity matching was possible, minimally invasive aortic valve surgery had not only cosmetic advantages, but blood product use, respiratory, pain, and resource utilization advantages over full sternotomy, and no apparent detriments. Less invasive aortic valve surgery should be considered for most aortic valve operations. PMID- 22244557 TI - Surgical treatment of residual systolic anterior motion after otherwise successful percutaneous transluminal septal myocardial ablation: a case report. PMID- 22244559 TI - Modified aortoplasty for discrete congenital supravalvular aortic stenosis. PMID- 22244560 TI - A simplified technique for total anomalous pulmonary venous connection repair associated with functional single ventricle. PMID- 22244558 TI - Effects of alcohol on pericardial adhesion formation in hypercholesterolemic swine. AB - OBJECTIVE: Reoperative cardiac surgery is complicated in part because of extensive adhesions encountered during the second operation. The purpose of this study was to examine the effects of alcohol with and without resveratrol (red wine vs vodka) on postoperative pericardial adhesion formation in a porcine model of hypercholesterolemia and chronic myocardial ischemia. METHODS: Male Yorkshire swine were fed a high-cholesterol diet to simulate conditions of coronary artery disease followed by surgical placement of an ameroid constrictor to induce chronic ischemia. Postoperatively, control pigs continued their high-cholesterol diet alone, whereas the 2 experimental groups had diets supplemented with red wine or vodka. Seven weeks after ameroid placement, all animals underwent reoperative sternotomy. RESULTS: Compared with controls, pericardial adhesion grade was markedly reduced in the vodka group, whereas there was no difference in the wine group. Intramyocardial fibrosis was significantly reduced in the vodka group compared with controls. There was no difference in expression of proteins involved in focal adhesion formation between any groups (focal adhesion kinase, integrin alpha-5, integrin beta-1, paxillin, vinculin, protein tyrosine kinase 2, protein kinase C epsilon, and phosphorylated protein kinase C epsilon). The wine group exhibited elevated C-reactive protein levels versus the control and vodka groups. CONCLUSIONS: Postoperative vodka consumption markedly reduced the formation of pericardial adhesions and intramyocardial fibrosis, whereas red wine had no effect. Analysis of protein expression did not reveal any obvious explanation for this phenomenon, suggesting a post-translational effect of alcohol on fibrous tissue deposition. The difference in adhesion formation in the vodka versus wine groups may be due to increased inflammation in the wine group. PMID- 22244561 TI - Prophylactic tricuspid annuloplasty in patients with dilated tricuspid annulus undergoing mitral valve surgery. AB - OBJECTIVE: Progression of functional tricuspid regurgitation is not uncommon after mitral valve surgery and is associated with poor outcomes. We tested the hypothesis that concomitant tricuspid valve annuloplasty in patients with tricuspid annulus dilatation (>=40 mm) prevents tricuspid regurgitation progression after mitral valve surgery. METHODS: We enrolled 44 patients undergoing mitral valve surgery (both repair or replacement) showing less than moderate (<=+2) tricuspid regurgitation and dilated tricuspid annulus (>=40 mm) at preoperative echocardiography. They were randomized to receive (n = 22) or not receive (n = 22) concomitant tricuspid annuloplasty (Cosgrove-Edwards annuloplasty ring; Edwards Lifesciences, Irvine, Calif) at the time of mitral valve surgery. Clinical and echocardiographic follow-up was 100% completed at 12 months after surgery. RESULTS: Preoperative clinical and echocardiographic characteristics were comparable in the 2 groups. Operative mortality was 4.4% (1 death in each group). At 12 months follow-up, tricuspid regurgitation was absent in 71% (n = 15) versus 19% (n = 4) of patients in the treatment and control groups, respectively (P = .001). Moderate to severe tricuspid regurgitation (>=+3) was present in 0% versus 28% (n = 6) of patients in the treatment and control groups, respectively (P = .02). Pulmonary artery systolic pressure significantly decreased from baseline in all cases (P < .001) and was comparable in the 2 groups (41 +/- 8 mm Hg vs 40 +/- 5 mm Hg; P = .4). Right ventricular reverse remodeling was marked in the treatment group (right ventricular long axis: 71 +/- 7 mm vs 65 +/- 8 mm; P = .01; short axis: 33 +/- 4 mm vs 27 +/- 5 mm; P = .001) but only minimal in the control group (right ventricular long axis: 72 +/- 6 mm vs 70 +/- 7 mm; P = .08; short axis: 34 +/- 5 mm vs 33 +/- 5 mm; P = .1). The 6-minute walk test improved from baseline in both groups (P < .001), but this improvement was greater in the treatment group (+115 +/- 23 m from baseline vs +75 +/- 35 m; P = .008). CONCLUSIONS: Prophylactic tricuspid valve annuloplasty in patients with dilated tricuspid annulus undergoing mitral valve surgery was associated with a reduced rate of tricuspid regurgitation progression, improved right ventricular remodeling, and better functional outcomes. PMID- 22244562 TI - Impairment of pericardial leaflet structure from balloon-expanded valved stents. AB - OBJECTIVE: Malpositioning is one of the major problems in transcatheter aortic valve implantation. To evaluate the influence of mechanical balloon inflation on aortic valve stent positioning, the expansion process and the impact on the valve leaflet's structure were investigated. METHODS: Custom-made stents were laser cut from a 22-mm diameter stainless steel tube and mounted with a glutaraldehyde treated bovine pericardial valve. The valved stents were crimped onto a standard balloon catheter and expanded by inflation of the balloon with 2 bar for 3 seconds. Expansion was studied using a high-speed camera, and the histology of the pericardial tissue was analyzed. RESULTS: The valved stents were fully expanded within 3 seconds. Balloon inflation was observed to be asymmetric starting proximally. At the beginning of expansion, the valved stents were pulled proximally. During further inflation, the stents slipped distally on the balloon and experienced a total displacement of 13.5 mm. Macroscopic examination showed severe imprinting of the stent struts into the pericardial tissue. Histology revealed disrupted tissue layers and collagen fibers. CONCLUSIONS: Analysis of valved stent expansion showed a displacement of the stent on the catheter during balloon inflation. Therefore, precise placement of the valved stent cannot be accomplished. Histologic analysis of the expanded pericardial tissue revealed disruption of collagen fibers. Disruption of pericardial tissue structures due to balloon expansion may result in early functional valve failure. PMID- 22244563 TI - Fifteen-year single-center experience with the Norwood operation for complex lesions with single-ventricle physiology compared with hypoplastic left heart syndrome. AB - OBJECTIVE: The Norwood procedure, the first surgical step of staged palliation for hypoplastic left heart syndrome, is also applied for other complex single ventricle lesions with systemic outflow tract obstruction or aortic arch hypoplasia. We reviewed our 15-year institutional experience with the Norwood procedure for patients with and without hypoplastic left heart syndrome. METHODS: A total of 41 patients without hypoplastic left heart syndrome and 212 patients with hypoplastic left heart syndrome who underwent a Norwood procedure between January 1996 and December 2010 were enrolled. Full medical records were reviewed to assess the determinants of outcome. RESULTS: Early failure (death or cardiac transplantation) was 7% in patients without hypoplastic left heart syndrome and 13% in patients with hypoplastic left heart syndrome (P = .29). Frequency of postoperative complications, duration of postoperative ventilation, and length of vasoactive drug treatment were not different between groups. Transplant-free survival until the second operative step trended to be higher for patients without hypoplastic left heart syndrome (92% vs 80%, P = .067). Recurrent aortic arch obstruction was more common in patients without hypoplastic left heart syndrome (15/39 vs 32/171, P = .008), but there were 4 patients with stenosis of the proximal aortic arch. In subsequent procedures, 31 patients without hypoplastic left heart syndrome underwent superior cavopulmonary anastomosis and 5 biventricular repair. Overall transplant-free survival was not different between groups (P = .119) but trended to be higher in patients with a systemic or substantial left ventricle remnant contributing to cardiac output (P = .082). CONCLUSIONS: Early and long-term survivals and postoperative complications were similar between patients with and without hypoplastic left heart syndrome undergoing a Norwood operation. Recurrent aortic arch obstruction was common in both groups but more prevalent in patients without hypoplastic left heart syndrome. PMID- 22244564 TI - Pulmonary reperfusion injury after the unifocalization procedure for tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries. AB - OBJECTIVE: The aims of our study are to describe the incidence, clinical profile, and risk factors for pulmonary reperfusion injury after the unifocalization procedure for tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries. We hypothesized the following: (1) Pulmonary reperfusion injury is more likely to occur after unifocalization procedures in which a septated circulation is not achieved, (2) pulmonary reperfusion injury is directly related to the severity of stenosis in major aortopulmonary collateral arteries, and (3) pulmonary reperfusion injury leads to longer intubation time and longer hospitalization. METHODS: Consecutive patients with tetralogy of Fallot/pulmonary atresia/major aortopulmonary collateral arteries who underwent unifocalization procedures over a 5-year period were identified in our institutional database. Chest radiographs before the unifocalization procedure, from postoperative days 0 to 4, and from 2 weeks after the unifocalization procedure or at discharge were evaluated by a pediatric radiologist for localized pulmonary edema. Determination of stenosis severity was based on review of preoperative angiograms. Statistical analyses using multivariate repeated measures analyses were performed with generalized estimating equations. RESULTS: Pulmonary reperfusion injury was present after 42 of 65 (65%) unifocalization procedures. In 36 of 42 cases of reperfusion injury, unilateral injury was present. Risk factors for the development of reperfusion injury included bilateral unifocalization (P = .01) and degree of stenosis (P = .03). We did not identify an association between pulmonary reperfusion injury and time to tracheal extubation or hospital discharge. CONCLUSIONS: Pulmonary reperfusion injury is common after the unifocalization procedure for tetralogy of Fallot/pulmonary atresia/major aortopulmonary collateral arteries. Severity of stenosis and bilateral unifocalization are associated with the development of reperfusion injury. PMID- 22244565 TI - The ethical dilemma of Thoracic Surgery recertification. PMID- 22244566 TI - Operative techniques in robotic thoracic surgery for inferior or posterior mediastinal pathology. AB - OBJECTIVE: Thoracic surgeons are performing robotic resections for anterior mediastinal tumors; however, tumors located in the posterior and especially the inferior chest can be difficult to approach robotically. The objective of this study was to evaluate the efficacy of the robot for resection of these tumors. METHODS: We performed a retrospective review of the evolution and outcomes of our surgical technique for inferior or posterior mediastinal pathology. RESULTS: During a 30-month period, 153 patients underwent robotic surgery for pathology in the mediastinum, located in the inferior or posterior mediastinum in 75 of these patients. The most common indications for surgery were posterior mediastinal mass or lymph node in 41 patients, esophageal or bronchogenic cysts in 11 patients, esophageal leiomyoma in 7 patients, and diaphragmatic elevation in 7 patients. The median tumor size was 4.4 cm, and the median length of stay was 1 day. One patient was converted to thoracotomy, but no patients were converted for bleeding. Morbidity occurred in 9 patients (12%), major in 1 patient (a delayed esophageal leak after epiphrenic diverticulectomy). There was no mortality. Technical improvements included using robotic arm 3 posteriorly for retraction, side-docking, or coming over the back of the patient for tumors inferior to the inferior pulmonary vein and for diaphragmatic plication and using the lateral decubitus position for extraction of tumors larger than 3 cm via an access port over the tenth rib above the diaphragmatic fibers. CONCLUSIONS: The robot affords safe access using a completely portal approach for resection of and surgical intervention for inferior and posterior chest pathology and for anterior tumors. Specific techniques can be used to improve the operation. PMID- 22244568 TI - Serum creatinine as a perioperative biomarker: a challenge for perioperative management and an opportunity for the Cardiothoracic Surgery Trials Network. PMID- 22244567 TI - Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: a randomized controlled trial. AB - OBJECTIVE: Cardiopulmonary bypass is associated with ischemia-reperfusion injury to multiple organs. We aimed to evaluate whether remote ischemic preconditioning performed the day before surgery for congenital heart disease with cardiopulmonary bypass attenuates the postoperative inflammatory response and myocardial dysfunction. METHODS: This was a prospective, randomized, single blind, controlled trial. Children allocated to remote ischemic preconditioning underwent 4 periods of 5 minutes of lower limb ischemia by a blood pressure cuff intercalated with 5 minutes of reperfusion. Blood samples were collected 4, 12, 24, and 48 hours after cardiopulmonary bypass to evaluate nuclear factor kappa B activation in leukocytes by quantification of mRNA of I kappa B alpha by real time quantitative polymerase chain reaction and for interleukin-8 and 10 plasma concentration measurements by enzyme-linked immunosorbent assay. Myocardial dysfunction was assessed by N-terminal pro-B-type natriuretic peptide and cardiac troponin I plasma concentrations, measured by chemiluminescence, and clinical parameters of low cardiac output syndrome. RESULTS: Twelve children were allocated to remote ischemic preconditioning, and 10 children were allocated to the control group. Demographic data and Risk Adjustment for Congenital Heart Surgery 1 classification were comparable in both groups. Remote ischemic preconditioning group had lower postoperative values of N-terminal pro-B-type natriuretic peptide, but cardiac troponin I levels were not significantly different between groups. Interleukin-8 and 10 concentrations and I kappa B alpha gene expression were similar in both groups. Postoperative morbidity was similar in both groups; there were no postoperative deaths in either group. CONCLUSIONS: Late remote ischemic preconditioning did not provide clinically relevant cardioprotection to children undergoing cardiopulmonary bypass. PMID- 22244571 TI - Association of feeding modality with interstage mortality after single-ventricle palliation. AB - OBJECTIVE: Interstage mortality has been reported in 10% to 25% of hospital survivors after single-ventricle palliation. The purpose of this study was to examine the impact of feeding modality at discharge after single-ventricle palliation on interstage mortality. METHODS: We conducted a retrospective review of all neonates undergoing single-ventricle palliation from January 2003 to January 2010. A total of 334 patients (90%) survived to hospital discharge, comprising the study group. Preoperative, operative, and postoperative variables were examined, including feeding method at discharge. Multivariate Poisson regression models were constructed to estimate the relative risk of interstage mortality. RESULTS: Of 334 patients, 56 (17%) underwent gastrostomy tube +/- Nissen. There was a statistically significant increase in interstage mortality for patients who underwent gastrostomy tube +/- Nissen compared with patients who did not (relative risk, 2.38; 95% confidence interval, 1.05-5.40; P = .04]). Of the 278 patients who were not fed via a gastrostomy tube +/- Nissen, 190 (68%) were fed with nasogastric feedings and 88 (32%) were fed entirely by mouth. There was no difference in interstage mortality between these 2 groups (relative risk, 0.92; 95% confidence interval, 0.31-2.73; P = .89). CONCLUSIONS: Neonates undergoing single-ventricle palliation who require gastrostomy tube +/- Nissen are at an increased risk of interstage mortality. The need for gastrostomy tube +/- Nissen in this population may be a marker for other unmeasured comorbidities that place them at an increased risk of interstage mortality. Discharge with nasogastric feeds does not increase the risk of interstage mortality. PMID- 22244569 TI - Evaluation of the use of an induced puripotent stem cell sheet for the construction of tissue-engineered vascular grafts. AB - OBJECTIVE: The development of a living, tissue-engineered vascular graft (TEVG) holds great promise for advancing the field of cardiovascular surgery. However, the ultimate source and time needed to procure these cells remain problematic. Induced puripotent stem (iPS) cells have recently been developed and have the potential for creating a pluripotent cell line from a patient's own somatic cells. In the present study, we evaluated the use of a sheet created from iPS cell-derived vascular cells as a potential source for the construction of TEVG. METHODS: Male mouse iPS cells were differentiated into embryoid bodies using the hanging-drop method. Cell differentiation was confirmed by a decrease in the proportion of SSEA-1-positive cells over time using fluorescence-activated cell sorting. The expression of endothelial cell and smooth muscle cell markers was detected using real-time polymerase chain reaction (PCR). The differentiated iPS cell sheet was made using temperature-responsive dishes and then seeded onto a biodegradable scaffold composed of polyglycolic acid-poly-l-lactide and poly(l lactide-co-epsilon-caprolactone) with a diameter of 0.8 mm. These scaffolds were implanted as interposition grafts in the inferior vena cava of female severe combined immunodeficiency/beige mice (n = 15). Graft function was serially monitored using ultrasonography. The grafts were analyzed at 1, 4, and 10 weeks with histologic examination and immunohistochemistry. The behavior of seeded differentiated iPS cells was tracked using Y-chromosome fluorescent in situ hybridization and SRY real-time PCR. RESULTS: All mice survived without thrombosis, aneurysm formation, graft rupture, or calcification. PCR evaluation of iPS cell sheets in vitro demonstrated increased expression of endothelial cell markers. Histologic evaluation of the grafts demonstrated endothelialization with von Willebrand factor and an inner layer with smooth muscle actin- and calponin positive cells at 10 weeks. The number of seeded differentiated iPS cells was found to decrease over time using real-time PCR (42.2% at 1 week, 10.4% at 4 weeks, 9.8% at 10 weeks). A fraction of the iPS cells were found to be Y chromosome fluorescent positive at 1 week. No iPS cells were found to co-localize with von Willebrand factor or smooth muscle actin-positive cells at 10 weeks. CONCLUSIONS: Differentiated iPS cells offer an alternative cell source for constructing TEVG. Seeded iPS cells exerted a paracrine effect to induce neotissue formation in the acute phase and were reduced in number by apoptosis at later time points. Sheet seeding of our TEVG represents a viable mode of iPS cell delivery over time. PMID- 22244572 TI - Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 and Streptococcus pneumoniae R6 by microglial cells. AB - The ability of microglial cells to phagocytose bacteria after stimulation with the endocannabinoid palmitoylethanolamide (PEA) was studied in vitro. PEA increased the phagocytosis of unencapsulated Streptococcus pneumoniae R6 and encapsulated Escherichia coli K1 by murine microglial cells significantly after 30 min of microglial stimulation. This suggested that stimulation of microglial cells by PEA can increase the resistance of the brain against CNS infections. PMID- 22244574 TI - No evidence for an anti-inflammatory effect of escitalopram intervention in healthy individuals with a family history of depression. AB - Inflammation may contribute to the pathogenesis of depression and antidepressants are hypothesised to have an anti-inflammatory effect. In this randomised double blinded trial we investigated the cytokine levels in supernatants of stimulated whole blood samples from first degree relatives to patients with depression randomised to a single daily dose of either 10mg escitalopram or placebo for four weeks. No significant differences were found in any of the cytokine levels between the participants treated with escitalopram (n=21) or placebo (n=23). Our data does thus not support the hypothesis of a global anti-inflammatory effect of escitalopram on cytokines in healthy subjects. PMID- 22244573 TI - Stress and the anti-influenza immune response: repeated social defeat augments clonal expansion of CD8(+)T cells during primary influenza A viral infection. AB - Social disruption stress (SDR) prior to primary influenza A virus (IAV) infection augments memory to IAV re-challenge in a T cell-specific manner. However, the effect of SDR on the primary anti-viral immune response has not been elucidated. In this study, SDR-infected (INF) mice terminated viral gene expression earlier and mounted an enhanced pulmonary IAV-specific CD8(+)T cell response versus controls. Additionally, SDR-INF mice had a more pro-inflammatory lung profile prior to and during infection and an attenuated corticosterone response. These data demonstrate neuroendocrine modification of the lung microenvironment and increased antigen-specific T cell activation, clonal expansion and viral control in stress-exposed mice. PMID- 22244575 TI - Studies with Listeria monocytogenes lead the way. PMID- 22244576 TI - Interactions of Listeria monocytogenes with the autophagy system of host cells. AB - Macrophages are immune cells that participate in the host defense against bacterial pathogens. These cells mediate bacterial clearance by internalizing bacteria into a phagosome, which ultimately fuses with lysosomes to kill bacteria. One bacterial strategy to evade killing in the phagosome is to escape from this compartment prior to lysosomal fusion. Listeria monocytogenes is a classic example of a "cytosol-adapted pathogen" in that it can rapidly escape from the phagosome in macrophages (and other cell types) and replicate rapidly in the cytosol. Phagosome escape also enables cell-to-cell spread by the bacteria through a bacterial driven actin-based motility mechanism. How the bacteria escape the phagosome and evade host cellular defenses, including autophagy, will be discussed in this review. We also discuss an underappreciated population of L. monocytogenes that can replicate in macrophage vacuoles and how these may be important for the establishment of chronic infections. PMID- 22244577 TI - Virulence factors that modulate the cell biology of Listeria infection and the host response. AB - The Gram-positive bacterial pathogen Listeria monocytogenes has become one of the best studied models in infection biology. This review will update our knowledge of Listeria virulence factors and highlight their role during the Listeria infection process. PMID- 22244578 TI - Dendritic cells in Listeria monocytogenes infection. AB - Dendritic cells (DCs) represent a unique collection of innate immune cells present throughout the body as distinct subpopulations generally sharing the functions of pathogen recognition, cytokine production, and antigen presentation. A large body of work in recent years has examined DC functions during infection with Listeria monocytogenes (Lm), particularly in the murine model. Here, I review several aspects of DC biology in this model, with particular emphasis on the role DCs play in the establishment of a productive Lm infection and the role of DCs as cytokine producers and antigen-presenting cells in this system. PMID- 22244579 TI - Probing CD8 T cell responses with Listeria monocytogenes infection. AB - CD8 T cells play a critical role in the control and eradication of intracellular pathogens. Increased understanding of CD8 T cell biology provides insight that can be translated into improved vaccination strategies. The intracellular bacterium, Listeria monocytogenes, has been used as a model organism to study every phase of the CD8 T cell response to intracellular bacterial infection. Infection of laboratory mice with L. monocytogenes has provided insight into the factors that are involved in primary T cell responses, memory CD8 T cell generation, maintenance, functionality, and diversification following repeated pathogenic challenges. In this review, we will focus on work from our laboratories utilizing the murine model of L. monocytogenes to investigate the characteristics of CD8 T cell responses to infection. This model has profoundly advanced our understanding of the CD8 T cell response to infection and is likely to continue to provide invaluable basic insights that can be translated into the development of effective vaccination strategies to protect against pathogens. PMID- 22244580 TI - Listeria monocytogenes and its products as agents for cancer immunotherapy. AB - This review covers the use of Listeria monocytogenes and its virulence factors as cancer immunotherapeutics. We describe their development as vectors to carry protein tumor antigen and eukaryotic DNA plasmids to antigen-presenting cells and efforts to harness their tumor-homing properties. We also describe their use as vectors of angiogenic molecules to induce an immune response that will destroy tumor vasculature. The background knowledge necessary to understand the biology behind the rationale to develop Listeria as a vaccine vector for tumor immunotherapy is included as well as a brief summary of the major therapies that have used this approach thus far. PMID- 22244581 TI - Monocyte-mediated immune defense against murine Listeria monocytogenes infection. AB - Infection of mice with Listeria monocytogenes induces a robust innate inflammatory response that restricts bacterial growth in the liver and spleen prior to the development of protective T cell responses. Ly6C(hi) monocytes contribute to the innate immune response following L. monocytogenes infection and in their absence, mice rapidly succumb to infection. Emigration of Ly6C(hi) monocytes from the bone marrow into the circulation is the first step in their recruitment to sites of L. monocytogenes infection and is triggered by CCL2- and CCL7-mediated stimulation of CCR2 chemokine receptors on monocytes. CCL2 expression by mesenchymal stem cells in the bone marrow, in response to TLR stimulation, drives monocyte emigration from cellular compartments into vascular sinuses of the bone marrow. In addition to TLR ligands, type I interferon mediated signals can also drive monocyte emigration from the bone marrow during L. monocytogenes infection. Once Ly6C(hi) monocytes enter the bloodstream, trafficking to sites of infection in the liver and spleen is CCR2 independent. In the liver, CD11b on the monocyte and ICAM-1 on the surface of endothelial cells target Ly6C(hi) monocytes to foci of L. monocytogenes infection. At the site of infection, Ly6C(hi) monocytes undergo MyD88-dependent differentiation into TNF and iNOS-producing dendritic cells (TipDCs) and express MHC class II, B7.1, and CD40 on their cell surface. How TipDCs mediate bacterial clearance during early L. monocytogenes infection remains an active area of investigation. PMID- 22244582 TI - Innate immune pathways triggered by Listeria monocytogenes and their role in the induction of cell-mediated immunity. AB - Acquired cell-mediated immunity to Listeria monocytogenes is induced by infection with live, replicating bacteria that grow in the host cell cytosol, whereas killed bacteria, or those trapped in a phagosome, fail to induce protective immunity. In this chapter, we focus on how L. monocytogenes is sensed by the innate immune system, with the presumption that innate immunity affects the development of acquired immunity. Infection by L. monocytogenes induces three innate immune pathways: an MyD88-dependent pathway emanating from a phagosome leading to expression of inflammatory cytokines; a STING/IRF3-dependent pathway emanating from the cytosol leading to the expression of IFN-beta and coregulated genes; and very low levels of a Caspase-1-dependent, AIM2-dependent inflammasome pathway resulting in proteolytic activation and secretion of IL-1beta and IL-18 and pyroptotic cell death. Using a combination of genetics and biochemistry, we identified the listerial ligand that activates the STING/IRF3 pathway as secreted cyclic diadenosine monophosphate, a newly discovered conserved bacterial signaling molecule. We also identified L. monocytogenes mutants that caused robust inflammasome activation due to bacteriolysis in the cytosol, release of DNA, and activation of the AIM2 inflammasome. A strain was constructed that ectopically expressed and secreted a fusion protein containing Legionella pneumophila flagellin that robustly activated the Nlrc4-dependent inflammasome and was highly attenuated in mice, also in an Nlrc4-dependent manner. Surprisingly, this strain was a poor inducer of adaptive immunity, suggesting that inflammasome activation is not necessary to induce cell-mediated immunity and may even be detrimental under some conditions. To the best of our knowledge, no single innate immune pathway is necessary to mount a robust acquired immune response to L. monocytogenes infection. PMID- 22244583 TI - Mechanisms and immunological effects of apoptosis caused by Listeria monocytogenes. AB - Infection with Listeria monocytogenes shows an early stage of lymphocyte apoptosis. This is an obligatory stage the extent of which depends on infective dose. Lymphocyte apoptosis occurs early and is rapidly superseded, yet it has a strong biological consequence. The immunological effect of lymphocyte apoptosis following infection is increased susceptibility to L. monocytogenes infection due, in part, to upregulation of IL-10 on macrophages and DC. Lymphocyte apoptosis is dependent on bacterial expression of the pore-forming toxin listeriolysin O (LLO). Also, purified LLO can lead to the induction of death pathways similar to infection, demonstrating that it is a killer agent generated by L. monocytogenes. Signaling through the type I interferon receptor potentiates cell death induced by the bacteria or LLO. Infection with L. monocytogenes also causes death of phagocytic cells, the nature and significance of which is not clear at present. Infection with L. monocytogenes is a tractable model to examine pathogen-induced cell death pathways and their possible immunological consequences in multiple cell types following infection. PMID- 22244584 TI - The detection of plasma levels of connective tissue growth factor in rheumatoid arthritis patients. PMID- 22244585 TI - Mental rotation of letters, body parts and complex scenes: separate or common mechanisms? AB - This study compares mental rotation with three stimuli: letters, body parts and complex scenes. Twenty-four subjects saw letters and judged whether they were mirror-reversed or not (task LETTER), saw pictures of a hand and indicated whether it was a right or a left one (task HAND), and saw drawings of a person at a table on which a weapon and a rose laid and decided whether the weapon was to the person's right or left (task SCENE). Stimuli were presented in canonical orientation or rotated by up to 180 degrees . Our analyses focused on intra subject correlations between reaction times of the different tasks. We found that reaction times for stimuli in canonical orientation co-varied in HAND and LETTER, the increase of reaction times with increasing object rotation co-varied in HAND and SCENE, and reaction times for 180 degrees rotations co-varied between all tasks. We suggest that basic processes like visual perception and decision-making are distinct for scenes versus letters and body parts, that the mechanism for mental rotation of letters is distinct from that for mental self- and body part rotation, and suggest an extra mechanism for 180 degrees rotations that shared among all tasks. These findings confirm and expand hypotheses about mental rotation that were based on comparisons of between-subject means. PMID- 22244586 TI - The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of patients with resectable colorectal liver metastases: a meta-analysis. AB - BACKGROUND: The role of staging laparoscopy (SL) with laparoscopic ultrasound (LUS) in patients with resectable colorectal liver metastases (CRLM) remains controversial. METHODS: A meta-analysis of all studies (from 1998 to the present) on the effect of SL/LUS in patients with potentially resectable CRLM with respect to alteration in surgical management was performed. RESULTS: Twelve studies satisfied the inclusion criteria. A total of 1,047 patients underwent SL/LUS. The true yield of SL/LUS for CRLM was 19% (95% confidence interval [CI], 16%-22%), with a diagnostic odds ratio of 132 (95% CI, 56-310) and an overall sensitivity of 59% (95% CI, 53%-65%). Subgroup analysis for detection of other liver and peritoneal lesions showed a sensitivity of 59% (95% CI, 49%-67%) and 75% (95% CI, 63%-85%) respectively. There was major between-study heterogeneity for all analyses, with no obvious cause revealed by meta-regression. CONCLUSIONS: The true benefit of using SL/LUS universally seems limited. It appears more useful as an adjunct in patients when peritoneal disease is suspected. PMID- 22244587 TI - Joint recognition-expression impairment of facial emotions in Huntington's disease despite intact understanding of feelings. AB - Patients with Huntington's disease (HD), a neurodegenerative disorder that causes major motor impairments, also show cognitive and emotional deficits. While their deficit in recognising emotions has been explored in depth, little is known about their ability to express emotions and understand their feelings. If these faculties were impaired, patients might not only mis-read emotion expressions in others but their own emotions might be mis-interpreted by others as well, or thirdly, they might have difficulties understanding and describing their feelings. We compared the performance of recognition and expression of facial emotions in 13 HD patients with mild motor impairments but without significant bucco-facial abnormalities, and 13 controls matched for age and education. Emotion recognition was investigated in a forced-choice recognition test (FCR), and emotion expression by filming participants while they mimed the six basic emotional facial expressions (anger, disgust, fear, surprise, sadness and joy) to the experimenter. The films were then segmented into 60 stimuli per participant and four external raters performed a FCR on this material. Further, we tested understanding of feelings in self (alexithymia) and others (empathy) using questionnaires. Both recognition and expression were impaired across different emotions in HD compared to controls and recognition and expression scores were correlated. By contrast, alexithymia and empathy scores were very similar in HD and controls. This might suggest that emotion deficits in HD might be tied to the expression itself. Because similar emotion recognition-expression deficits are also found in Parkinson's Disease and vascular lesions of the striatum, our results further confirm the importance of the striatum for emotion recognition and expression, while access to the meaning of feelings relies on a different brain network, and is spared in HD. PMID- 22244588 TI - Synthesis and biological evaluation of conjugates of deoxypodophyllotoxin and 5 FU as inducer of caspase-3 and -7. AB - In order to generate compounds with superior antitumor activity and reduced toxicity, a series of conjugates of deoxypodophyllotoxin and 5-FU were synthesized by coupling 4'-demethyl-4-dexoypodophyllotoxin with N-(5-fluorouracil N(1)-ly acetic)- amino acids (or 5-fluorouracil-N(1)-ly acetic acid). The cytotoxic activity of these compounds against four human cancer cell lines (HL 60, A-549, HeLa and SiHa) were evaluated, and results indicated that these compounds were more potent in terms of cytotoxicity than either parent compound DPT or anticancer drug VP-16 and 5-FU. In addition, we found that 14d induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells, and 14d activated caspase-3 and -7. These results suggested that caspase-mediated pathways are involved in 14d induced apoptosis. PMID- 22244589 TI - Preparation and optimization of PIT solid lipid nanoparticles via statistical factorial design. AB - The objective of this study was the preparation, physico-chemical characterization and statistical optimization of cationic solid lipid nanoparticles (SLN) prepared by the PIT method as potential carrier for gene therapy, emphasizing the application of factorial design in such a kind of studies. The preliminary screening from a physico-chemical point of view on three cationic lipids (CTAB, DDAB and DOTAP), selected on the basis of their different chemical structure and increasing lipophilicity, allowed us to select SLN with DOTAP, due to its higher zeta potential and smaller particle size. Afterward, a 2(2) full factorial experimental design was developed in order to study the effects of two independent variables (amount of DOTAP and concentration of lipid matrix) and their interaction on mean particle size and zeta potential values. The factorial planning was validated by ANOVA analysis; the correspondence between the predicted values of size and zeta and those measured experimentally confirmed the validity of the design and the equation applied for its resolution. The factorial design showed a significant influence of the independent variables on the selected parameters; in particular, a higher effect of DOTAP was observed on zeta potential value. Different dilutions of the optimized SLN containing 7% w/w of cutina CP and 1% w/w of DOTAP, with size and zeta potential values respectively of 462.9 nm and 50.8 mV, were in vitro examined to evaluate the possible cytotoxicity on two models of cell cultures: human prostate cancer androgen-non-responsive DU-145 cells and primary cultures of rat astrocytes. PMID- 22244590 TI - Topological sub-structural molecular design approach: radical scavenging activity. AB - In the last decades phenolic compounds have gained enormous interest because of their beneficial health effects such as anti-inflammatory, anticancer, or antiviral activities. The pharmacological effects of phenolic compounds are mainly due to their antioxidant activity and their inhibition of certain enzymes. This antoxidant activity is related to the structure and has been extensively reported throught SAR or QSAR models. These studies confirmed that the number and position of hydroxyl groups, the related glycosylation and other substitutions in the phenolic ring largely determined radical scavenging activity. Most of these models are based on certain families of chemicals (flavonoids, cinnamic acids, etc...) and the model by itself is not useful for other substances of a different family. In this study we developed a QSAR model for a heterogeneous group of substances with TOPS-MODE descriptors for an interpretation of the antioxidant activity of these compounds in the form of bond contributions. The model developed, able to describe more than 90% of the variance in the experimental activity, also has a good predictive ability and stability. The information extracted from the QSAR model revealed that the major driving forces for radical scavenging activity are hydrogen bond donation and polarity. With this work we have managed to unify the different families of antioxidants in a single model with sufficient capacity to make predictions of radical scavenging activity for unknown substances. PMID- 22244591 TI - Increased serum placenta growth factor level is significantly associated with progression, recurrence and poor prognosis of oral squamous cell carcinoma. AB - We recently found that the expression of placenta growth factor (PlGF) in oral squamous cell carcinoma (OSCC) specimens is correlated with the progression and prognosis of OSCC. In this study, serum samples were obtained from 72 OSCC patients before and 3 months after surgical cancer excision and from 30 normal controls. Serum PlGF levels were determined by enzyme-linked immunosorbent assay (ELISA). The mean serum PlGF levels were significantly higher in pre-surgery OSCC patients than in normal controls (19.1+/-10.7 vs. 10.1+/-4.5, P<0.001). Serum PlGF levels dropped to near the normal control levels after surgical cancer removal. Higher pre-surgery serum PlGF levels were significantly associated with larger tumor size (P=0.015), positive lymph node metastasis (P=0.001), more advanced clinical stages (P=0.002), and loco-regional recurrence (P=0.037). The serum PlGF level was identified as an independent unfavorable prognosis factor by multivariate Cox regression analyses (P=0.014). Kaplan-Meier curve showed that OSCC patients with a higher serum PlGF level had a significantly poorer cumulative recurrence-free survival than those with a lower serum PlGF level (log rank test, P=0.009). When we used the serum PlGF level of 19.1 pg/ml (mean normal control value plus 2 standard deviations) as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence was 80%, 56% and 78%, respectively. We conclude that the serum PlGF level may be a valuable biomarker for prediction of therapeutic effect, progression, recurrence and prognosis of OSCC. PMID- 22244592 TI - Progress of environmental management and risk assessment of industrial chemicals in China. AB - With China's rapid economic growth, chemical-related environmental issues have become increasingly prominent, and the environmental management of chemicals has garnered increased attention from the government. This review focuses on the current situation and the application of risk assessment in China's environmental management of industrial chemicals. The related challenges and research needs of the country are also discussed. The Chinese government promulgated regulations for the import and export of toxic chemicals in 1994. Regulations for new chemical substances came into force in 2003, and were revised in 2010 based on the concept of risk management. In order to support the implementation of new regulations, Guidance for Risk Assessment of Chemicals is under development in an attempt to provide the concepts and techniques of risk assessment. With increasing concern and financial support from Chinese government, China is embarking on the fast track of research and development in environmental management of industrial chemicals. PMID- 22244594 TI - The Wisconsin approach to newborn screening for severe combined immunodeficiency. AB - Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable with hematopoietic cell transplantation if detected early. Population-based screening for SCID using the T-cell receptor excision circle (TREC) assay began in Wisconsin in 2008; 5 infants with SCID or other forms of severe T-cell lymphopenia (TCL) have been detected, and no infants with SCID have been missed. This review will provide an overview of the TREC screening assay and an update of the findings from Wisconsin on all infants screened from January 1, 2008, until December 31, 2010. Importantly, we give practical recommendations regarding newborn population-based screening using the TREC assay, including the evaluation and care of infants detected. PMID- 22244595 TI - Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: looking at the published evidence. AB - In allergen immunotherapy there is debate as to whether polysensitized patients are best treated with many allergens simultaneously (chosen according to the sensitization profile, a predominantly North American approach) or a single allergen (chosen according to the most clinically problematic allergy, a predominantly European approach). In patients seeking treatment for moderate-to severe respiratory allergies, polysensitization is more prevalent (range, 50% to 80%) than monosensitization in both the United States and Europe. Safe, effective, single-allergen preparations will most likely have been tested in polysensitized patients. In robust, large-scale clinical trials of grass pollen sublingual tablets, polysensitized patients benefited at least as much from allergen immunotherapy as monosensitized patients. A recent review of multiallergen immunotherapy concluded that simultaneous delivery of multiple unrelated allergens can be clinically effective but that there was a need for additional investigation of therapy with more than 2 allergen extracts (particularly in sublingual allergen immunotherapy). More work is also required to determine whether single-allergen and multiallergen immunotherapy protocols elicit distinct immune responses in monosensitized and polysensitized patients. Sublingual and subcutaneous multiallergen immunotherapy in polysensitized patients requires more supporting data to validate its efficacy in practice. PMID- 22244597 TI - The risk of allergic reactions to allergen extracts in personnel. PMID- 22244598 TI - Nationwide cohort study of the leukotriene receptor antagonist montelukast and incident or recurrent cardiovascular disease. AB - BACKGROUND: The leukotriene pathway has been associated with an increased cardiovascular risk. However, the effects of the antileukotriene treatment used in asthmatic patients on cardiovascular outcomes have remained largely unexplored. OBJECTIVE: We sought to examine a potential protective role of the leukotriene receptor antagonist montelukast on future risk of incident and recurrent myocardial infarction and ischemic stroke. METHODS: A nationwide population-based cohort of approximately 7 million persons integrating data from the Prescribed Drug, Patient, Cause of Death, Income, Educational, and Emigration Registers was followed from July 1, 2005, to December 31, 2008. Analyses were performed in the whole population after exclusion of subjects with a prior cardiovascular diagnosis (incident events; sample size, n = 6,910,923 for myocardial infarction and n = 6,932,578 for stroke) and in subjects with a prior diagnosis (recurrent events; n = 153,937 and n = 132,291 for stroke and myocardial infarction, respectively). RESULTS: Cox proportional hazard ratios (HRs) did not reveal an association of montelukast use with incident events. In contrast to these findings, montelukast use was associated with a lower risk for recurrent stroke (HR, 0.62; 95% CI, 0.38-0.99) accounting for age, sex, education level, and yearly income. Adjusting the latter finding also for respiratory and cardiovascular medications and diagnoses revealed similar point estimates (HR, 0.62; 95% CI, 0.39-1.0). Post hoc analyses revealed a significant association of montelukast use with a lower risk for recurrent myocardial infarction in male subjects (HR, 0.65; 95% CI, 0.43-0.99). CONCLUSION: These data provide a first indication for a potential role of the antiasthma drug montelukast for secondary prevention of cardiovascular disease. PMID- 22244599 TI - Development and validation of the Composite Asthma Severity Index--an outcome measure for use in children and adolescents. AB - BACKGROUND: Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included. OBJECTIVE: Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk, and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma. METHODS: Twenty-six established asthma investigators, who are part of the National Institutes of Health-supported Inner City Asthma Consortium, participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma by using the Asthma Control Evaluation trial. CASI was validated by using the Inner City Anti-IgE Therapy for Asthma trial. RESULTS: CASI scores include 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At Asthma Control Evaluation trial enrollment, CASI ranged from 0 to 17, with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than did symptoms alone. CONCLUSION: CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity and provide a composite clinical characterization of asthma. PMID- 22244600 TI - Obesity is not linked to increased whole-body mast cell burden in children. PMID- 22244601 TI - Delay in spinal cord injury diagnosis due to sedation: a case report. AB - BACKGROUND: In the United States, the incidence of traumatic spinal cord injury is estimated to be approximately 40 per one million persons per year. The most common causes of traumatic spinal cord injury are motor vehicle collisions, falls, gunshot wounds, and sports accidents. OBJECTIVE: To report signs, symptoms, clinical presentation, diagnostic modalities, acute management, and treatment of an acute spinal cord injury. CASE REPORT: A case of traumatic cervical spine injury that was not immediately apparent upon presentation is reported. Diagnostic confirmation was possible after obtaining magnetic resonance imaging and after the sedative effects of medications resolved, allowing for a better physical examination. CONCLUSION: Neurogenic shock should be considered in patients with hypotension of unknown or unclear etiology. A ground-level fall is sufficient to cause traumatic spinal cord injury in elderly patients, and a cervical spine computed tomography scan without clear fracture does not exclude this pathology. PMID- 22244602 TI - Cleft palate secondary to an ingested foreign body: a learning experience. AB - BACKGROUND: Cleft palate has usually been described as a congenital anomaly. Acquired clefting of the palate is rare and is usually due to penetrating trauma. OBJECTIVE: To report a case of cleft palate developing after ingestion of a coin due to prolonged impaction in the nasopharynx. CASE REPORT: A 4 1/2-year-old child presented with nasal regurgitation and nasal twang of voice. The parents reported a history of ingestion of a coin 2 years prior, which was undetectable on neck and chest X-ray study done at that time. Examination revealed a triangular cleft of soft palate. A diagnosis was made of an acquired cleft palate secondary to prolonged impaction of the coin in the nasopharynx. Under general anesthesia, the palatal defect was repaired in three layers. CONCLUSION: The case highlights the fact that ingested foreign bodies can get lodged in the nasopharynx and that nasopharynx X-ray study should always be done in cases of a disappearing foreign body in the aerodigestive tract. PMID- 22244603 TI - Hypermagnesemia in a constipated female. AB - BACKGROUND: Hypermagnesemia is a rare condition that is usually iatrogenic. Magnesium oxide (MgO) ingestion by constipated patients with prolonged colonic retention contributes to hypermagnesemia. Treatment of hypermagnesemia includes discontinuation of the magnesium use, gastrointestinal (GI) decontamination, and removal of magnesium from the serum by dialysis. Calcium acts as an antagonist in hypermagnesemia. CASE REPORT: A 72-year-old woman presented with constipation and MgO ingestion. The patient was brought to our department due to altered mental status and progressive general weakness. Laboratory tests showed a magnesium level of 6.2 mEq/L. Bradycardia and hypotension developed with rebound hypermagnesemia after incomplete dialysis. Abdomen computed tomography showed hyperdense MgO tablets retained in the colon. A magnesium-free laxative was used for GI decontamination. Despite the use of high-dose inotropics and an elevated trigger for transcutaneous pacing, the cardiac performance improved minimally. Although our patient responded to calcium administration with hemodynamic improvement, prolonged hypotension and decreased perfusion led to hypoxic encephalopathy. CONCLUSION: This report demonstrates that MgO tablets retained in the GI tract without adequate decontamination result in continuous absorption and rebound of hypermagnesemia. This report also addresses the importance of GI decontamination in the treatment of hypermagnesemia. PMID- 22244604 TI - Issues to address in burn care for ethnic minority children: a qualitative study of the experiences of health care staff. AB - INTRODUCTION: Numerous studies have shown that ethnic minority children in the developed world are at greater risk of sustaining burns compared to children from non-ethnic minority backgrounds. However, little is known about the experiences of hospital health care staff with ethnic minority children and parents. A qualitative interview study was conducted to gain more insight into burn care for ethnic minority children and the potential challenges this presents. METHODS: Semi-structured interviews on burn care for ethnic minority children were conducted in 2009 with health care staff (N=17) working in two burn centers in the Netherlands. Interviews were transcribed and analyzed using a framework method. RESULTS: Health care staff identified the following issues in burn care for ethnic minority children and their parents: (1) linguistic barriers to communication with parents about pressure garments, dressing changes, skin grafting procedures, and psychosocial support; (2) biological/genetic features of differing pigmentation of skin and skin healing; (3) cultural differences between parents and health care staff; (4) insecurity or irritation about linguistic and cultural barriers. CONCLUSIONS: Burn health care staff should have knowledge of biological/genetic features of dark skin, awareness of cultural differences, and transcultural communication skills to deliver culturally competent care tailored to the needs of ethnic minority children and their parents. PMID- 22244605 TI - Post burn pruritus--a review of current treatment options. AB - Post burn pruritus is a well recognised symptom in almost all burn patients. Yet, there is insufficient awareness about the etiopathogenesis and a lack of a systematic approach in the assessment and treatment of this distressing symptom. The current standard therapies include antihistamines, which are effective as sole therapy in only 20% patients, and emollients. There is a lacunae of clear consensus on the care of patients not responding to antihistamines. We review the literature on the etiology and pathogenesis of post burn pruritus, which has both central and peripheral pathways. The published studies on the currently available therapeutic options to treat itch in burns are discussed. On the basis of current evidence in literature, gabapentin used in the treatment of neuropathic pain, has demonstrated great promise, and is suggested as the next option for this subset of patients, not relieved with antihistamines. PMID- 22244606 TI - Thermodynamics, formamide, and the origin of life: Comment on "Formamide and the origin of life" by R. Saladino et al. PMID- 22244607 TI - Stress during childhood and adolescence: how to combat? PMID- 22244608 TI - Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. AB - The effects on long-term post-operative quality of life (QoL) and disease-control in malignant pleural mesothelioma (MPM) of extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are compared. Seventy-seven patients affected by early-stage MPM received EPP (40) or P/D (37) associated with multimodal treatment between 1998 and 2009 at our institution. The last consecutive 39 (19 EPP and 20 P/D) were asked to answer the EORTC-QLQ-C30 questionnaire at baseline and at 6- and 12-months after treatment completion to evaluate the impact on QoL of both procedures. QoL evaluation was stopped at recurrence demonstration. Twenty-five (62%) EPP vs 9 (24%) P/D patients (p = 0.002) had in-hospital major complications, and 2/40 (5%) EPP vs no one P/D patients died after surgery. Both procedures caused a significant impairment of all the considered variables of the EORTC-QLQ-C30 questionnaire after treatment completion; only P/D patients returned at baseline levels after 12 months. EPP patients had a worse long-term post-operative QoL when compared with P/D. Median post-operative disease-free period was longer for EPP patients (14 vs 11 months) whereas the residual life to death period after recurrence detection was significantly longer for P/D patients (13 vs 9 months) (p = 0.01). Median long-term survival was longer, even not significant, for P/D patients (25 vs 20 months). MPM patients submitted to EPP had a higher post-operative complication rate, a worse long-term QoL, a shorter residual life time after recurrent disease, despite a similar long-term survival when compared to P/D. PMID- 22244609 TI - Serious ocular complications of cosmetic iris implants in 14 eyes. AB - PURPOSE: To report the presentation and subsequent management of a series of patients presenting with cosmetic iris implants. SETTING: New York Eye and Ear Infirmary, New York, New York, USA. DESIGN: Case series. METHODS: In this evaluation of patients with NewColorIris cosmetic iris implants, data collected included patient demographics, visual acuity, intraocular pressure (IOP), endothelial cell count, and slitlamp examination findings at presentation. Medical and surgical interventions and the postoperative course were recorded. RESULTS: Fourteen eyes of 7 patients (ages 22 to 60; 71% men) were identified. Nine eyes (64%) presented with decreased visual acuity, 7 (50%) had elevated IOP, 5 (36%) had corneal edema, and 5 (36%) had anterior uveitis. All 14 eyes had explantation of the iris prosthesis (range 4 to 33 months after placement). The minimum follow-up after implant removal in all eyes was 2 months (range 2 to 28 months). Intraoperative complications included suprachoroidal hemorrhage during explantation in 1 eye. Postoperative complications included corneal edema (8 eyes), cataract (9 eyes), and increased IOP/glaucoma (7 eyes). Secondary surgeries included Descemet-stripping automated endothelial keratoplasty (5 eyes), cataract extraction with intraocular lens placement (7 eyes), trabeculectomy (3 eyes), glaucoma drainage implant placement (3 eyes), and penetrating keratoplasty (1 eye). CONCLUSIONS: The cosmetic iris implants may result in severe ocular morbidity. Complications in our series included uveitis, glaucoma, corneal edema, and decreased visual acuity. Although explantation helped stabilize symptoms, additional medical and surgical intervention to control IOP and corneal decompensation was required in many cases. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22244610 TI - Using artificial intelligence to predict the risk for posterior capsule opacification after phacoemulsification. AB - PURPOSE: To apply artificial intelligence models to predict the occurrence of posterior capsule opacification (PCO) after phacoemulsification. SETTING: Farabi Eye Hospital, Tehran, Iran. DESIGN: Clinical-based cross-sectional study. METHODS: The posterior capsule status of eyes operated on for age-related cataract and the need for laser capsulotomy were determined. After a literature review, data polishing, and expert consultation, 10 input variables were selected. The QUEST algorithm was used to develop a decision tree. Three back propagation artificial neural networks were constructed with 4, 20, and 40 neurons in 2 hidden layers and trained with the same transfer functions (log sigmoid and linear transfer) and training protocol with randomly selected eyes. They were then tested on the remaining eyes and the networks compared for their performance. Performance indices were used to compare resultant models with the results of logistic regression analysis. RESULTS: The models were trained using 282 randomly selected eyes and then tested using 70 eyes. Laser capsulotomy for clinically significant PCO was indicated or had been performed 2 years postoperatively in 40 eyes. A sample decision tree was produced with accuracy of 50% (likelihood ratio 0.8). The best artificial neural network, which showed 87% accuracy and a positive likelihood ratio of 8, was achieved with 40 neurons. The area under the receiver-operating-characteristic curve was 0.71. In comparison, logistic regression reached accuracy of 80%; however, the likelihood ratio was not measurable because the sensitivity was zero. CONCLUSION: A prototype artificial neural network was developed that predicted posterior capsule status (requiring capsulotomy) with reasonable accuracy. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22244611 TI - Results of laser in situ keratomileusis performed using solid-state laser technology. AB - PURPOSE: To evaluate and report the visual, refractive, and aberrometry outcomes of laser in situ keratomileusis (LASIK) to correct low to moderate myopia using a commercial solid-state laser. SETTING: Oftalmar, Medimar International Hospital, Alicante, Spain. DESIGN: Prospective case series. METHODS: This study evaluated consecutive eyes with low to moderate myopia that had LASIK performed using a Pulzar Z1 solid-state laser. Visual, refractive, and aberrometry changes as well as potential complications were evaluated. RESULTS: The study enrolled 60 eyes (34 patients). The mean follow-up was 8.5 months (range 6 to 13 months). There was a significant improvement in logMAR uncorrected distance visual acuity (UDVA) postoperatively (P<.01). No significant change was detected in logMAR corrected distance visual acuity (CDVA) (P=.21). The postoperative logMAR UDVA was 0.1 (approximately 20/25) or better in 57 eyes (95.00%). The mean overall efficacy index was 0.99 and the mean safety index, 1.02. Postoperatively, 1 eye (1.67%) lost lines (1 line) of CDVA. The postoperative spherical equivalent was within +/ 0.50 diopter in 58 eyes (96.67%). There was a small, but statistically significant increase in the primary coma root mean square (0.17 MUm) and in the magnitude of primary spherical aberration (0.09 MUm). No severe complications occurred. CONCLUSION: Laser in situ keratomileusis using the solid-state laser provided predictable correction of low to moderate myopia, minimizing the induction of higher-order aberrations and preserving CDVA. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22244612 TI - 3D ultrastructure of the nuclear pore complex. AB - Nuclear pore complexes (NPCs) perforate the double-layered nuclear envelope and form the main gateway for molecular exchange between nucleus and cytoplasm of the eukaryotic cell. Because NPCs are extraordinarily complex and large, thus challenging to investigate on a molecular level, they are still rather poorly understood, despite their pivotal role in cellular homeostasis. To decipher the NPC structure at high resolution, the prerequisite to fully understand its function, a tailored approach is necessary that feeds from complimentary data, obtained at largely different spatial resolutions. The problem is further complicated by the dynamic nature of the NPC, manifested in flexible regions and dynamic components. Here we summarize the current state of these structural efforts, describe the breakthroughs of recent years, point out the existing disputes in the field, and give an outlook of what we should expect to happen in the near future. PMID- 22244613 TI - Modelling of a downdraft gasifier fed by agricultural residues. AB - A non-stoichiometric model for a downdraft gasifier was developed in order to simulate the overall gasification process. Mass and energy balances of the gasifier were calculated and the composition of produced syngas was predicted. The capacity of the modeled gasifier was assumed to be 0.5 MW, with an Equivalence Ratio (EQ) of 0.45. The model incorporates the chemical reactions and species involved, while it starts by selecting all species containing C, H, and O, or any other dominant elements. Olive wood, miscanthus and cardoon were tested in the formulated model for a temperature range of 800-1200 degrees C, in order to examine the syngas composition and the moisture impact on the supplied fuel. Model results were then used in order to design an olive wood gasification reactor. PMID- 22244614 TI - Belgian MSWI fly ashes and APC residues: a characterisation study. AB - Municipal Solid Waste Incineration (MSWI) produces different sorts of residues, bottom ash, fly ashes and Air Pollution Control (APC) residues. Generally, fly ashes and APC residues are mixed at the MSWI plant and manage as a sole residue. In this study, fly ashes and APC residues have been sampled separately at different Belgian MSWI plant and analysed by X-ray fluorescence in order to highlight the composition differences that may appear between the solids. Ca and Cl are found to be the major elements in most of the samples. Lithophilic elements, such as Al and Si, are richer in furnace and boiler ashes, as can be expected. Leaching tests also show differences between the residues; leachates from furnace and boiler ashes are alkaline while those from bag filter residues present a pH value of 6, which impacts the leaching of heavy metals (Pb and Zn). The results suggest that it could be advantageous to manage fly ashes and APC residues separately by adjusting the treatment to their specificities. PMID- 22244615 TI - Soluble salt removal from MSWI fly ash and its stabilization for safer disposal and recovery as road basement material. AB - Fly ash from municipal solid waste incinerators (MSWI) is classified as hazardous in the European Waste Catalogue. Proper stabilization processes should be required before any management option is put into practice. Due to the inorganic nature of MSWI fly ash, cementitious stabilization processes are worthy of consideration. However, the effectiveness of such processes can be severely compromised by the high content of soluble chlorides and sulphates. In this paper, a preliminary washing treatment has been optimized to remove as much as possible soluble salts by employing as little as possible water. Two different operating conditions (single-step and two-step) have been developed to this scope. Furthermore, it has been demonstrated that stabilized systems containing 20% of binder are suitable for safer disposal as well as for material recovery in the field of road basement (cement bound granular material layer). Three commercially available cements (pozzolanic, limestone and slag) have been employed as binders. PMID- 22244616 TI - Parent-child relations and psychological adjustment among high-achieving Chinese and European American adolescents. AB - Chinese American students are often perceived as problem-free high achievers. Recent research, however, suggests that high-achieving Chinese American students can experience elevated levels of stress, especially comparing to their peers from other ethnic groups. In this paper, we examine how family dynamics may influence psychological adjustment among a group of high-achieving adolescents. Drawing on survey data collected on 295 Chinese American and 192 European American 9th graders attending a highly selective magnet school, our findings show that Chinese American adolescents reported significantly lower levels of psychological adjustment (d = -.31), and significantly less family cohesion (d = .34) and more conflict (d = .56) than their European American peers. Further, the ethnic differences on adjustment disappeared after controlling for perceptions of family cohesion and conflict, indicating that such perceptions may be a key factor in understanding the high academic achievement/low psychological adjustment paradoxical pattern of development among Chinese American adolescents. PMID- 22244617 TI - Iatrogenic headaches: giving everyone a sore head. PMID- 22244618 TI - Obtaining informed consent for clinical trials - seldom easy, often difficult, and sometimes impossible. PMID- 22244619 TI - What's new in obstetric anesthesia: the 2011 Gerard W. Ostheimer lecture. AB - The Gerard W. Ostheimer lecture is delivered at the Society for Obstetric Anesthesia and Perinatology Annual Meeting. The lecture provides a comprehensive review of the previous year's literature in obstetric anesthesia, obstetrics, perinatology, and health services research relevant for obstetric anesthesiologists. This article covers several of the major themes that emerged from the 2010 literature. PMID- 22244620 TI - FGF-2 induces proliferation of human periodontal ligament cells and maintains differentiation potentials of STRO-1(+)/CD146(+) periodontal ligament cells. AB - The presence of human STRO-1(+)/CD146(+) periodontal ligament (PDL) cells has been reported, but obtaining a large amount of these cells is difficult. The purpose of this study was to evaluate the percentages of STRO-1(+)/CD146(+) cells in PDL cells and determine the effects of FGF-2 on the proliferation and multilineage differentiation potency of these cells. Human PDL (HPDL) cells were individually prepared from 15 extracted teeth. HPDL cells were cultured with or without FGF-2, and the percentages of STRO-1(+)/CD146(+) cells in each HPDL cell culture was examined using FACSAriaTM. The STRO-1(+)/CD146(+) cells were sorted with FACSAriaTM, and the mRNA expression and differentiation potency of the sorted cells were subsequently examined. The numbers of the STRO-1(+)/CD146(+) cells in the FGF-2 cultures were significantly higher than those cultured in the absence of FGF-2. The sorted STRO-1(+)/CD146(+) cells expressed mRNA of PDL markers and differentiated into adipocytes and osteoblast-like cells. The present study shows that FGF-2 augmented the proliferation of the STRO-1(+)/CD146(+) cells in the HPDL cultures whilst retaining adipogenic and osteogenic differentiation potentials. Thus, it may be useful to culture HPDL cells with FGF 2 for the application of the human STRO-1(+)/CD146(+) PDL cells in periodontal tissue regeneration. PMID- 22244621 TI - Meiofaunal and bacterial community response to diesel additions in a microcosm study. AB - Effects of low PAH-containing diesel were studied in a 60-day microcosm experiment at PAH concentrations 130, 1300 and 13,000MUg/kg sediment. Nutrient fluxes, potential nitrification and meiofaunal community composition were analysed at three time points. Changed ?NOx-fluxes indicated reduced sediment nitrification in Medium and High with time, in agreement with lowered potential nitrification rates in all treatments. Reduction in silicate and phosphate fluxes over time suggested severe effects on activity of meiofauna. Reduced activity increased the anoxic sediment layer, which could have contributed to the changed ?NOx-fluxes. There were significant differences in meiofaunal community composition after 30 and 60days in Medium and High. Changes were due to increasing numbers of harpacticoids and the foraminiferan group Rotaliina, as well as decreasing numbers of Nematodes and the foraminiferan group Reophax. In spite of the low PAH-level, small additions of this diesel can still have pronounced effects on meiofaunal and bacterial communities. PMID- 22244622 TI - Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. AB - OBJECTIVES: To assess the safety and efficacy of long-term treatment with rituximab (RTX) in patients with systemic sclerosis (SSc). METHODS: Eight patients with SSc-associated interstitial lung disease (ILD) received 4 cycles of RTX and had a follow-up of 2 years. Lung involvement was assessed by pulmonary function tests and chest HRCT. Skin involvement was assessed both clinically and histologically. RESULTS: We found a linear improvement of lung function and skin thickening over the 2 years of RTX treatment. There was a significant increase of FVC at 2 years compared to baseline (mean +/- SEM: 77.13+/-7.13 vs. 68.13+/-6.96, respectively, p<0.0001). Similarly, DLco increased significantly at 2 years compared to baseline (mean +/- SEM: 63.13+/-7.65 vs. 52.25+/-7.32, respectively, p<0.001). Skin thickening, assessed with the MRSS, improved significantly at 2 years compared to baseline (mean +/- SEM: 4.87+/-0.83 vs. 13.5+/-2.42, respectively, p<0.0001). A reduction in myofibroblast score was seen histologically following RTX treatment. CONCLUSIONS: Our results indicate that long-term treatment with RTX may favourably affect lung function and skin fibrosis in patients with SSc. Larger scale, multicentre, randomised, controlled studies are needed to further explore the efficacy of RTX in SSc. PMID- 22244623 TI - Possible horizontal transmission of Salmonella via reusable egg trays in Thailand. AB - Salmonella contamination of eggshells, egg contents, reusable egg trays, and various environmental samples was assessed. Although the overall Salmonella contamination rate from egg farms was low (3.2%), over a quarter (26.7%) of egg trays from farms and more than one third (36.7%) of trays from the market were contaminated. Salmonella strains isolated from reusable egg trays were analyzed by serotyping, antimicrobial susceptibility test and XbaI pulsed-field gel electrophoresis (PFGE) typing. Five serovars (S. Braenderup, S. Emek, S. Weltevreden, S. Stanley, and S. Derby) were isolated, and half of the strains assessed were found to be resistant to one or more of the six antimicrobial agents examined. The overall resistance rates to nalidixic acid, trimethoprim sulfamethoxazole, tetracycline, and ampicillin were 40.7%, 36.0%, 26.7% and 3.5%, respectively. The PFGE types were matched against sample location and drug resistance. S. Braenderup PFGE type A2 (susceptible to all tested drugs) was isolated from all sample sites; PFGE type A2 (resistant to nalidixic acid) was isolated from Farm C and the market. S. Braenderup PFGE type A1 (resistant to four drugs) was isolated from Farms A and C. S. Weltevreden PFGE type C3 (susceptible to all tested drugs) was isolated from Farms A and B and type C4 (susceptible to all tested drugs) was isolated from Farm A and the market. The distribution of the related genotypes and resistance patterns of Salmonella in egg farms and the market indicate drug-resistant strains of Salmonella may be spread on reusable egg trays. PMID- 22244624 TI - Does a combination of two radiographs increase accuracy in detecting acid-induced periapical lesions and does it approach the accuracy of cone-beam computed tomography scanning? AB - INTRODUCTION: The purpose of this study was to determine whether the use of a combination of 2 images (storage phosphor plates [SPPs] and F-speed films [Eastman Kodak, Rochester, NY]) with a 10 degrees difference in horizontal beam angulation resulted in better detectability of chemically created periapical defects than when only 1 image was used and whether a detectability as good as that achieved by limited cone-beam computed tomography (LCBCT) scanning could be achieved. METHODS: Lesions were created by 1, 1.5, and 2 hours of acid application apical to extracted teeth in jaw specimens. After repositioning, teeth were radiographed with Accu-I-Tomo LCBCT, Digora Optime SPP system, and F speed films. The SPPs and films were exposed at 0 degrees and 10 degrees horizontal angulations. The diagnostic accuracy (Az) was compared using 2-way analysis of variance; pair-wise comparisons were performed using the post hoc t test. Kappa was used to measure interobserver agreement. RESULTS: A combination of 2 exposures with a 10 degrees difference in horizontal angulation caused an increase, although not statistically significant, in the accuracy of both films and SPPs for all acid durations (P > .05) compared with when only 1 exposure was used. The accuracy did not approach that of LCBCT. CONCLUSIONS: Using a combination of 2 exposures instead of 1 did not significantly increase the accuracy in detecting acid-induced lesions at the apices of single-rooted premolars. The accuracy of LCBCT was superior. PMID- 22244625 TI - A survey of dental residents' expectations for regenerative endodontics. AB - INTRODUCTION: The objective was to survey a group of dental residents regarding their expectations for using regenerative endodontic procedures as part of future dental treatments. METHODS: After institutional review board approval, the opinions of 32 dentists who were having postgraduate residency training to become specialists in a dental school were surveyed. The survey had 40 questions about professional status, ethical beliefs, judgment, and clinical practice. RESULTS: It was found that 83.9% of dentists had no continuing education or training in stem cells or regenerative endodontic procedures. Results showed that 96.8% of dentists are willing to receive training to be able to provide regenerative endodontic procedures for their patients. Of the total group, 49.1% of dentists already use membranes, scaffolds, or bioactive materials to provide dental treatment. It was determined that 47.3% of dentists agree that the costs of regenerative procedures should be comparable with current treatments. It was also found that 55.1% of dentists were unsure whether regenerative procedures would be successful. CONCLUSIONS: Dentists are supportive of using regenerative endodontic procedures in their dental practice, and they are willing to undergo extra training and to buy new technology to provide new procedures. Nevertheless, dentists also need more evidence for the effectiveness and safety of regenerative treatments before they will be recommended for most patients. PMID- 22244626 TI - The variability of electric pulp response threshold in premolars: a clinical study. AB - INTRODUCTION: This study was designed to determine the variability of the electric pulp response threshold in premolars and the relationship between the response threshold and age. METHODS: Ninety-seven volunteers were recruited, ranging from 20-72 years old. The volunteers were categorized into 6 age groups: group 1, 20-29 years; group 2, 30-39 years; group 3, 40-49 years; group 4, 50-59 years; group 5, 60-69 years; and group 6, 70-79 years. All intact premolars present in each dental arch were tested. Three sites (the tip of the buccal cusp, the center of the middle, and cervical third of the buccal surface) on each tooth crown were tested. RESULTS: In total, 1965 measurements were done. A progressive increase of mean threshold value was observed from groups 1 to 6. The response threshold value showed significant differences among the 6 age groups. The effect of age was more intense in mandibular premolars. In first and second mandibular premolars the cusp tip required the lowest current to evoke a response. In maxillary premolars no significant differences among the sites were found. Also, the mean threshold value of the mandibular premolars was lower than that of the maxillary premolars in subjects of the same age, and the mean threshold value of the first premolars was lower than that of the second premolars. The buccal cusp tip of the first mandibular premolars responded more quickly than any other tested site. CONCLUSIONS: Age is related with higher response threshold values. The optimum site for testing the lower premolars is the buccal cusp tip. PMID- 22244627 TI - Effects of 3-dimensional conformal or intensity-modulated radiotherapy on dental pulp sensitivity during and after the treatment of oral or oropharyngeal malignancies. AB - INTRODUCTION: Radiation therapy (RT) of malignant tumors in the head and neck area may have damaging effects on surrounding tissues. The aim of this investigation was to evaluate the effects of RT delivered by 3-dimensional conformal radiotherapy (3D-RT) or intensity-modulated radiotherapy (IMRT) on dental pulp sensitivity. METHODS: Twenty patients with oral or oropharyngeal cancer receiving RT with 3D-RT or IMRT underwent cold thermal pulp sensitivity testing (PST) of 2 teeth each at 4 time points: before RT (TP1), the beginning of RT with doses between 30 and 35 Gy (TP2), the end of RT with doses between 60 and 70 Gy (TP3), and 4 to 5 months after the start of RT (TP4). RESULTS: All 40 teeth showed positive responses to PST at TP1 (100%) and 9 at TP2 (22.5%; 3/16 [18.8%] for 3D-RT and 6/24 [25.0%] for IMRT). No tooth responded to PST at TP3 and TP4 (0%). A statistically significant difference existed in the number of positive pulp responses between different time points (TP1 through TP4) for all patients receiving RT (P <= .05), IMRT (P <= .05), and 3D-RT (P <= .05). No statistically significant differences in positive sensitivity responses were found between 3D RT and IMRT at any time point (TP1, TP3, TP4, P = 1.0; TP2, P = .74). A statistically significant correlation existed between the location of the tumor and PST at TP2 for IMRT (P <= .05) but not for 3D-RT (P = .14). CONCLUSIONS: RT decreased the number of teeth responding to PST after doses greater than 30 to 35 Gy. The type of RT (3D-RT or IMRT) had no influence on the pulp responses to PST after the conclusion of RT. PMID- 22244628 TI - Endodontic application of cone-beam computed tomography in South Korea. AB - INTRODUCTION: This study aimed to investigate the incidence of cone-beam computed tomography (CBCT) associated with endodontic procedures during 2009 in South Korea and to retrospectively evaluate information from CBCT with large field of view (FOV), which is popular in South Korea. METHODS: The Health Insurance Review and Assessment agency, which reviews all medical and dental expenses covered under the Korean National Health Insurance (NHI) system, was queried for data on the nationwide number of CBCTs associated with some treatment procedures. To compare digital periapical radiography and CBCT retrospectively, 470 roots of 257 root canal-infected teeth were enrolled. RESULTS: In total, 13,209 cases of NHI covered CBCT were performed in South Korea during 2009, excluding cases for implant restoration and orthodontics. In total, 1253 and 95 CBCT cases were combined with root canal length measuring and apicoectomy, respectively. In a retrospective comparison, CBCT with large FOV provided more information about the presence of apical periodontitis, distortion of cortical bone, and identification of root compared with digital periapical radiography. CONCLUSIONS: CBCT with large FOV is useful in nonsurgical endodontic treatment and provides more information compared with digital periapical radiography. PMID- 22244629 TI - Clustering behavior in microbial communities from acute endodontic infections. AB - INTRODUCTION: Acute endodontic infections harbor heterogeneous microbial communities in both the root canal (RC) system and apical tissues. Data comparing the microbial structure and diversity in endodontic infections in related ecosystems, such as RC with necrotic pulp and acute apical abscess (AAA), are scarce in the literature. The aim of this study was to examine the presence of selected endodontic pathogens in paired samples from necrotic RC and AAA using polymerase chain reaction (PCR) followed by the construction of cluster profiles. METHODS: Paired samples of RC and AAA exudates were collected from 20 subjects and analyzed by PCR for the presence of selected strict and facultative anaerobic strains. The frequency of species was compared between the RC and the AAA samples. A stringent neighboring clustering algorithm was applied to investigate the existence of similar high-order groups of samples. A dendrogram was constructed to show the arrangement of the sample groups produced by the hierarchical clustering. RESULTS: All samples harbored bacterial DNA. Porphyromonas endodontalis, Prevotella nigrescens, Filifactor alocis, and Tannerela forsythia were frequently detected in both RC and AAA samples. The selected anaerobic species were distributed in diverse small bacteria consortia. The samples of RC and AAA that presented at least one of the targeted microorganisms were grouped in small clusters. CONCLUSIONS: Anaerobic species were frequently detected in acute endodontic infections and heterogeneous microbial communities with low clustering behavior were observed in paired samples of RC and AAA. PMID- 22244630 TI - Effect of guided tissue regeneration on newly formed bone and cementum in periapical tissue healing after endodontic surgery: an in vivo study in the cat. AB - INTRODUCTION: The purpose of this study was to evaluate the influence of anorganic bovine bone as a grafted biomaterial on newly formed bone and cementum in periapical regions after surgical endodontic treatment in cats. METHODS: After inducing apical periodontitis in 9 cats, root canal and surgical endodontic treatment were performed on 72 roots of first and second maxillary premolars. Bone defects were treated with biomaterial particles + a membrane, biomaterial only, a membrane only, or left unfilled (control). Histomorphometry on nondecalcified sections were performed at 3 and 6 months after surgery. Analysis of variance with repeated measures was used within 2 and 3 subject factors to analyze newly formed bone, cementum, biomaterial conduction, and resorption. RESULTS: At each time period, bone formation was greater at the grafted membrane protected sites than in the grafted-unprotected sites. At 6 months, the bone area fraction at membrane nongrafted sites was greater than in the grafted-protected sites. The new cementum was significantly greater at 6 months than at 3 months and greater at the grafted membrane-protected sites over the unprotected ones at 6 months. Statistically, the grafted biomaterial, the membrane, and the time contributed significantly to the amount of new bone (P<.05) with no significant interaction. Biomaterial osteoconduction was significantly affected by the time. All 3 variables showed a significant interaction on new cementum. CONCLUSIONS: There was significantly more bone formation after surgical endodontic treatment when membrane and bone grafts were used as compared with bone grafts only or unfilled control sites. However, it appears that the key factor to the enhanced tissue regeneration is the membrane and not the grafted biomaterial. PMID- 22244631 TI - Mineralized tissue formation by bone morphogenetic protein-7-transfected pulp stem cells. AB - INTRODUCTION: Recombinant human bone morphogenetic protein-7 (BMP-7) is a well established agent to induce bone and dentin formation. Little is understood until now whether BMP-7 could be used to genetically modify human dental pulp stem cells for tissue engineering applications. METHODS: This study was to determine the feasibility of mineralized tissue formation from human dental pulp-derived stem cells (DPSCs) transfected with adenoviral-mediated human BMP-7 gene through in vitro and in vivo evaluations. RESULTS: In vitro results of alkaline phosphatase, calcium content, and real-time polymerase chain reaction showed that BMP-7-transfected cells had the ability to differentiate towards the odontoblast phenotype and produce a calcified extracellular matrix. Transfected cell were seeded onto a porous ceramic scaffold and implanted subcutaneously in mice. Samples were retrieved after 4 and 8 weeks for histology evaluation. The results indicated that only the cultures with BMP-7 gene transfection showed obvious hard tissue generation. CONCLUSIONS: Our data suggest that adenovirus-mediated BMP-7 expression can induce odontogenic differentiation of human DPSCs and show effectively mineralized tissue formation in vivo, which may provide support for gene therapy candidate of BMP-7 in dental tissue engineering. PMID- 22244632 TI - Expressional alterations of fibrillin-1 during wound healing of human dental pulp. AB - INTRODUCTION: The degradation of fibrillins, the major constituents of microfibrils, is known to facilitate the release of active transforming growth factor-beta (TGF-beta), a signaling molecule contributing to mineralized tissue barrier formation in exposed dental pulps. To examine the involvement of fibrillins in the barrier formation, we examined the temporospatial expression of (1) genes and proteins of fibrillins and (2) factors possibly associated with fibrillin degradation and cytodifferentiation in exposed human pulps. Human pulp slice cultures were also examined for the role of fibrillins in mineralization. METHODS: Clinically healthy pulps were mechanically exposed and capped with mineral trioxide aggregate. After 7 to 42 days, the teeth were processed for immunohistochemical and cytochemical staining of fibrillin-1, fibrillin-2, latent TGF-beta-binding protein (LTBP)-1, matrix metalloproteinase-3 (MMP-3), alkaline phosphatase (ALP), and in situ hybridization of fibrillin-1. Pulp tissue slices cultured with beta-glycerophosphate were analyzed for fibrillin-1, fibrillin-2, and ALP with the immunohistochemical/cytochemical staining and quantitative reverse-transcriptase polymerase chain reaction. RESULTS: Fibrillin-1 immunoreactivity was seen until 7 days but turned into undetectable since 14 days in the pulpal area just beneath the exposure site. MMP-3-immunoreaction was transiently detected at 14 days. At 42 days when the mineralized barrier was evident, fibrillin-1-immunoreactivity and fibrillin-1 expression remained down regulated. Fibrillin-2, LTBP-1, and ALP were constantly detected in the fibrillin 1-undetectable area. Pulp slices cultured with beta-glycerophosphate showed mineralization with up-regulation of ALP and down-regulation of fibrillin-1. CONCLUSIONS: Degradation and down-regulation of fibrillin-1 expression took place during the mineralized tissue barrier formation in exposed pulps in vivo and beta glycerophosphate-induced pulpal mineralization in vitro. PMID- 22244633 TI - Expression analysis of wound healing genes in human periapical granulomas of progressive and stable nature. AB - INTRODUCTION: Wound healing process involves the activation of extracellular matrix components, remodeling enzymes, cellular adhesion molecules, growth factors, cytokines and chemokines genes. However, the molecular patterns underlying the healing process at the periapical environment remain unclear. Here we hypothesized that endodontic infection might result in an imbalance in the expression of wound healing genes involved in the pathogenesis of periapical lesions. Furthermore, we suggest that differential expression of wound healing markers in active and latent granulomas could account for different clinical outcomes for such lesions. METHODS: Study samples consisted of 93 periapical granulomas collected after endodontic surgeries and 24 healthy periodontal ligament tissues collected from premolars extracted for orthodontic purposes as control samples. Of these, 10 periapical granulomas and 5 healthy periapical tissues were used for expression analysis of 84 wound healing genes by using a pathway-specific real-time polymerase chain reaction array. The remaining 83 granulomas and all 24 control specimens were used to validate the obtained array data by real-time polymerase chain reaction. Observed variations in expression of wound healing genes were analyzed according to the classification of periapical granulomas as active/progressive versus inactive/stable (as determined by receptor activator for nuclear factor kappa B ligand/osteoprotegerin expression ratio). RESULTS: We observed a marked increase of 5-fold or greater in SERPINE1, TIMP1, COL1A1, COL5A1, VTN, CTGF, FGF7, TGFB1, TNF, CXCL11, ITGA4, and ITGA5 genes in the periapical granulomas when compared with control samples. SERPINE1, TIMP1, COL1A1, TGFB1, and ITGA4 mRNA expression was significantly higher in inactive compared with active periapical granulomas (P < .001), whereas TNF and CXCL11 mRNA expression was higher in active lesions (P < .001). CONCLUSIONS: The identification of novel gene targets that curb the progression status of periapical lesions might contribute to a more accurate diagnosis and lead to treatment modalities more conducive to endodontic success. PMID- 22244635 TI - Comparison of the effect of various irrigants on apically extruded debris after root canal preparation. AB - INTRODUCTION: Several factors can influence the amount of apically extruded debris. The aim was to quantitatively compare the amount of debris extruded apically from root canals when 3 different irrigants were used during canal preparation with rotary instruments. METHODS: Ninety-one extracted single-rooted human mandibular premolar teeth with straight root canals were used. The teeth were randomly divided into 1 control group (group 1, n = 4) and 3 experimental groups of 29 teeth each. Hero 642 instruments were used for root canal preparation in all teeth, and 3 different irrigants were used (group 2, 2% chlorhexidine; group 3, 5.25% sodium hypochlorite; group 4, 2.5% sodium hypochlorite). Seven Eppendorf tubes served as a second control group. Debris extruded from the apical foramen during root canal preparation was collected into preweighed Eppendorf tubes. The weight of the dry extruded debris was established by subtracting the preinstrumentation and postinstrumentation weight of the Eppendorf tubes for each group. The data obtained were analyzed by using one-way analysis of variance and Tukey honestly significant difference. RESULTS: Group 3 (sodium hypochlorite 5.25%) had the highest amount of extruded debris, which was significantly different from the other groups (P < .05). CONCLUSIONS: The type of irrigant used can affect the amount of apically extruded debris. The 5.25% solution of sodium hypochlorite had the greatest amount of debris. PMID- 22244634 TI - Effects of the antioxidant agent tempol on periapical lesions in rats with doxorubicin-induced cardiomyopathy. AB - INTRODUCTION: Cardiovascular diseases have been associated with increased risk of endodontic complications. This study evaluated the effects of the antioxidant agent tempol on periapical lesions in rats with doxorubicin-induced cardiomyopathy in comparison with control animals. METHODS: Forty male Wistar rats were divided into 4 groups: (1) naive rats orally treated with saline solution (10 mL/kg, during 21 days after periapical lesion induction); (2) naive rats treated with tempol (30 and 50 mg/kg, during 21 days after periapical lesion induction) by oral pathway; (3) rats with doxorubicin-induced cardiomyopathy treated with saline solution by oral route (10 mL/kg, from day 3 to day 10 after initiating treatment with doxorubicin); and (4) rats with doxorubicin-induced cardiomyopathy orally treated with tempol (30 and 50 mg/kg, from day 3 to day 10 after initiating treatment with doxorubicin). Periapical lesions were induced on the first right mandibular molar tooth. After 21 days of apical periodontitis induction, the animals were killed, and the mandibles were collected for radiographic and histologic analysis. RESULTS: The oral administration of tempol (50 mg/kg) was able to significantly prevent the establishment of periapical lesions in either control animals or rats submitted to the model of doxorubicin induced cardiomyopathy, according to radiographic and histologic evaluation. Nevertheless, the protective effects of tempol were virtually greater in control animals in comparison with doxorubicin-treated rats, as indicated by histologic inflammatory assessment, which might be related to the increased production of free radicals under cardiomyopathy. CONCLUSIONS: We provide novel evidence on the beneficial systemic effects of the antioxidant tempol on apical periodontitis in both control animals and rats with doxorubicin-elicited cardiomyopathy. PMID- 22244636 TI - Dynamic movement of intracanal gas bubbles during cleaning and shaping procedures: the effect of maintaining apical patency on their presence in the middle and cervical thirds of human root canals-an in vivo study. AB - INTRODUCTION: The vapor lock effect has been shown to limit the penetration of irrigating solutions into the apical third of root canals both in vivo and in vitro; however, little attention has been given to gas bubbles in the remainder of the root canal system. METHODS: Seventy-one human root canals were randomly divided into 4 groups. Apical patency was maintained in 2 groups in both small (PS) (n = 21) and big canals (PB) (n = 15) during shaping and cleaning procedures with a 10 K-file 1 mm beyond working length but not in the other 2 groups: no patency, small canals (NPS) (n = 19) and no patency, big canals (NPB) (n = 16). Irrigation was performed with 1 mL of a solution prepared with a radiopaque contrast medium and sodium hypochlorite 5.25%. Digital images were taken, and a calibrated reader determined the presence or absence of gas bubbles in the middle and cervical thirds of the root canal system. RESULTS: When a patency file was not used, 40% of the root canals presented gas bubbles; when a patency file was used, 25% of the cases exhibited gas bubbles. CONCLUSIONS: The presence of gas bubbles in the middle and cervical thirds of the root canal system during cleaning and shaping procedures is a common finding regardless of whether a patency file was used, although maintaining apical patency significantly leads to minimizing the presence of gas bubbles in big canals (P < .05). PMID- 22244637 TI - Chemical and ultramorphologic effects of ethylenediaminetetraacetic acid and sodium hypochlorite in young and old root canal dentin. AB - OBJECTIVES: The objectives of this study were to evaluate and compare the time dependent chemical and ultramorphologic effects of ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite (NaOCl) in young and old dentin. METHODS: Sixty-four teeth scheduled for extraction were collected from young (<30 years) and old (>60 years) patients. In 48 teeth, the dentin was reduced to a powder state and treated with EDTA or EDTA + NaOCl for 1 and 10 minutes, respectively. X ray diffraction analysis was used to determine the changes in the composition of dentin through dissolution of hydroxyapatite (HAp). In the remaining teeth (n = 16), the root canals were prepared, bisected, and subjected to the same time dependent treatment regimens. The changes in the number and area of dentinal tubules were calculated by image analysis. The data were analyzed statistically by paired t test and one-way analysis of variance, followed by Tukey honestly significant difference test at P = .05. RESULTS: In both young and old dentin, EDTA significantly decreased the HAp intensity at 1 and 10 minutes, whereas EDTA + NaOCl only decreased that of old dentin at 10 minutes. Pair-wise comparisons revealed that in old dentin, the reduction in HAp intensity after treatment with EDTA and EDTA + NaOCl was significantly greater at 10 minutes than at 1 minute, whereas in young dentin, a significant decrease was only observed in the EDTA/10 minute subgroup. Compared with their 1-minute counterparts, 10-minute treatment with EDTA + NaOCl significantly increased the tubular diameter and tubular area of old dentin. In young dentin, the tubular area and diameter values were not affected by treatment time (P > .05). CONCLUSIONS: In young root dentin, 10 minute treatment with EDTA + NaOCl does not significantly alter the chemical and ultramorphologic structure and thus appears to be unnecessary. In old dentin, extended treatment time with EDTA + NaOCl should be avoided owing to excessive demineralization and erosion. In both types of dentin, EDTA was not effective in complete removal of the smear layer. PMID- 22244638 TI - The challenge of C-shaped canal systems: a comparative study of the self adjusting file and ProTaper. AB - INTRODUCTION: C-shaped canals are anatomic features that present the clinician with both diagnostic and operational challenges. The aim of this study was to compare the efficacy of the Self-Adjusting File (SAF; ReDent, Ra'anana, Israel) in shaping C-shaped canals with that of the rotary ProTaper file system (Dentsply Maillefer, Ballaigues, Switzerland). METHODS: Sixteen mandibular second molars and 4 maxillary second molars with C-shaped canals were obtained, originating from native Chinese population. They were divided into 2 equal groups of 10 teeth each, based on similar canal morphology as presented in preliminary micro computed tomography-derived images. One group was shaped using the SAF, whereas the other was shaped using the ProTaper file system. Reconstructed micro-computed tomographic images before and after treatment were superimposed over each other, and the percentage of the canal wall unaffected by the procedure was calculated. Comparison of the 2 groups for this parameter was performed using the Student t test. RESULTS: When treated with the SAF, 41% +/- 14% of the canal walls remained unaffected by the procedure, whereas 66% +/- 6% of the wall area was unaffected when using ProTaper, which was significantly higher than that of the SAF-treated group (P < .001). CONCLUSIONS: The SAF was more effective than the ProTaper file system in shaping the walls of C-shaped root canals. PMID- 22244639 TI - Comparison between the effect of plasma and chemical treatments on fiber post surface. AB - INTRODUCTION: The aim of the present study was to evaluate the fiber post surface after plasma and usual treatments and the adhesion between treated fiber posts and Rely X Unicem resin cement (3M ESPE, St Paul, MN). METHODS: Flat fiber posts were divided into 6 groups according to surface treatment: silane, hydrofluoric acid, hydrofluoric acid plus silane, plasma polymerization with argon, ethylenediamine plasma (EDA), and the control group. A goniometer was used to measure the contact angle between the groups with water or resin cement. Scanning electron microscopy and electron dispersive spectroscopy were used to examine the topography and chemical changes in the post surfaces after treatment. Push-out tests were performed using a universal testing machine to evaluate the adhesion strength between treated fiber posts and resin cement. RESULTS: In the contact angle with water, the most hydrophilic surface was observed in samples treated with argon plasma, followed by treatments with silane and hydrofluoric acid plus silane. The hydrophobic characteristic was observed with EDA and hydrofluoric acid. The contact angle with dual resin cement showed lower values with argon and EDA, followed by silane and hydrofluoric acid plus silane. Electron dispersive spectroscopy analyses showed chemical modifications in the surface after different treatments although topographic changes were verified only with EDA plasma compared with the control. Push-out results did not show differences between groups compared with the control, except for EDA plasma treatment. CONCLUSIONS: Plasma treatment favored the wettability of the post surface by modifying it chemically. Adhesion improvement was only observed after EDA treatment. PMID- 22244640 TI - Dentin bond strength of two mineral trioxide aggregate-based and one epoxy resin based sealers. AB - INTRODUCTION: This study aimed at evaluating the bond strength to root dentin of 2 mineral trioxide aggregate (MTA)-based sealers (Endo-CPM sealer and MTA Fillapex) and of 1 epoxy resin-based sealer (AH Plus sealer). METHODS: Forty-five extracted human teeth with single roots were prepared by using the step-back technique. Irrigation with 2.5% NaOCl and a final rinse with 17% ethylenediaminetetraacetic acid and distilled water were performed. Canals were filled by using Endo-CPM sealer, MTA Fillapex, or AH Plus sealer by means of the gutta-percha lateral condensation technique. After 7 days, the roots were sectioned perpendicularly to its long axis, and the push-out test was carried out. The data were analyzed by using the Kruskal-Wallis and Dunn post hoc tests. RESULTS: Endo-CPM sealer showed the highest values of bond strength to root dentin (8.265 MPa) (P < .05). The values of push-out test were similar for MTA Fillapex (2.041 MPa) and AH Plus (3.034 MPa). CONCLUSIONS: On the basis of the findings presented herein and within the limitations of this study, Endo-CPM sealer presented advantages when a post preparation was required. MTA Fillapex presented acceptable resistance to dislodgement, which was similar to that observed in samples filled with AH Plus sealer. PMID- 22244641 TI - Experimental evaluation on the influence of autoclave sterilization on the cyclic fatigue of new nickel-titanium rotary instruments. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of autoclave sterilization on cyclic fatigue resistance of rotary endodontic instruments made of traditional and new nickel-titanium (NiTi) alloys. METHODS: Four NiTi rotary endodontic instruments of the same size (tip diameter 0.40 mm and constant .04 taper) were selected: K3, Mtwo, Vortex, and K3 XF prototypes. Each group was then divided into 2 subgroups, unsterilized instruments and sterilized instruments. The sterilized instruments were subjected to 10 cycles of autoclave sterilization. Twelve files from each different subgroup were tested for cyclic fatigue resistance. Means and standard deviations of number of cycles to failure (NCF) and fragment length of the fractured tip were calculated for each group, and data were statistically analyzed (P < .05). RESULTS: Comparing the results between unsterilized and sterilized instruments for each type of file, differences were statistically significant (P < .05) only between sterilized and unsterilized K3XF files (762 versus 651 NCF). The other instruments did not show significant differences (P > .05) in the mean NCF as a result of sterilization cycles (K3, 424 versus 439 NCF; Mtwo, 409 versus 419 NCF; Vortex, 454 versus 480 NCF). Comparing the results among the different groups, K3 XF (either sterilized or not) showed a mean NCF significantly higher than all other files (P < .05). CONCLUSIONS: Repeated cycles of autoclave sterilization do not seem to influence the mechanical properties of NiTi endodontic instruments except for the K3 XF prototypes of rotary instruments that demonstrated a significant increase of cyclic fatigue resistance. PMID- 22244642 TI - Efficacy of the self-adjusting file system on cleaning and shaping oval canals: a microbiological and microscopic evaluation. AB - INTRODUCTION: The shaping ability of root canal instruments is determined by a complex interrelationship of parameters such as cross-sectional design and the ability to remove debris and the smear layer. The self-adjusting file (SAF) consists of a hollow, flexible instrument in the form of a compressible, thin walled, pointed cylinder. The aim of this study was to compare the SAF with the ProTaper rotary file system, evaluating debris and smear layer removal and the presence of bacteria by using microbiological and scanning electron microscopy (SEM) evaluation. METHODS: Fifty maxillary premolars were inoculated with Enterococcus faecalis for 30 days and then randomly distributed into 2 groups. Group 1 was prepared with ProTaper rotary instruments and irrigated with 30-gauge side-vented needles. Group 2 was prepared by using the SAF system with continuous irrigation. Bacteriologic samples were taken before and after preparation. All samples were then longitudinally split and analyzed under scanning electron microscopy. The scoring was carried out by 3 blinded evaluators. RESULTS: In group 1, 40% of samples had negative cultures with postinstrumentation samples taken with paper points (S2a) and 45% with postinstrumentation dentin samples (S2b). In group 2, 20% of samples had negative cultures with S2a and 15% with S2b. Intragroup analyses evaluating the reduction in the number of colony-forming units (CFUs) from S1 to S2a and S2b demonstrated both preparation techniques were highly effective (P < .01). Further reduction of CFUs was observed when comparing S2a and S2b in group 1 (P < .05), whereas no difference was observed in group 2. Intergroup analysis demonstrated a statistically significant difference of CFUs at S2a and S2b (P < .05). SEM scores were consistent with the microbiology findings. CONCLUSIONS: The SAF system does not allow control of the apical enlargement, thus limiting the ability of the irrigants to achieve effective and predictable disinfection. PMID- 22244643 TI - Dentinal microcrack formation during root canal preparations by different NiTi rotary instruments and the self-adjusting file. AB - INTRODUCTION: The purpose of this study was to compare dentinal microcrack formation while using hand files (HFs), 4 brands of nickel-titanium (NiTi) rotary files and the self-adjusting file. METHODS: One hundred forty mandibular first molars were selected: 20 teeth were left unprepared and served as control, and the remaining 120 teeth were divided into 6 groups. HFs, HERO Shaper (HS; Micro Mega, Besancon, France), Revo-S (RS, Micro-Mega), Twisted File (TF; SybronEndo, Orange, CA), ProTaper (PT, Dentsply Maillefer), and SAFs were used to prepare the 2 mesial canals. Roots were then sectioned 3, 6, and 9 mm from the apex, and the cut surface was observed under a microscope and checked for the presence of dentinal microcracks. RESULTS: The control, HF, and SAF groups did not show any microcracks. In roots prepared with the HS, RS, TF, and PT, dentinal microcracks were observed in 60%, 25%, 44%, and 30% of teeth, respectively. There was a significant difference between the control/HF/SAF group and the 4 NiTi rotary instrument groups (P < .0001). However, no significant difference was found among the 4 NiTi rotary instruments (P > .005). CONCLUSIONS: All rotary files created microcracks in the root dentin, whereas the SAF file and hand instrumentation presented with satisfactory results with no dentinal microcracks. PMID- 22244644 TI - Comparison of in vivo and in vitro readings when testing the accuracy of the Root ZX apex locator. AB - INTRODUCTION: The purpose of the study was to compare the accuracy of the Root ZX electronic apex locator (J Morita Corp, Tokyo, Japan) between an in vivo and an in vitro model. METHODS: The working length (WL) was determined electronically for 46 root canals of human teeth with a 15 K-file using both in vitro (n = 23) and in vivo (n = 23) models. The files were fixed at the WL. The apical 4 mm of each canal was trimmed to expose the file tip. The samples were observed under a scanning electron microscope, and the distance from the file tip to the point 0.5 mm coronal to the major foramen (the final WL) was measured. The data were analyzed using the Student t test, and significance was set at P <= .05. RESULTS: The statistical analysis revealed no significant differences between the in vivo group and in vitro group with respect to the accuracy of the Root ZX device in determining the final WL. The mean distance from the final WL to the file tip was 0.23 +/- 0.39 mm for the in vivo group and 0.29 +/- 0.32 mm for the in vitro group. In determining the final WL, the Root ZX was accurate 78.3% of the time to +/-0.5 mm and 100% of the time to +/-1 mm in the in vivo group, whereas it was accurate 74% of the time to +/-0.5 mm and 100% of the time to +/-1 mm in the in vitro group. CONCLUSIONS: No statistically significant differences were observed between the in vivo group and the in vitro group. PMID- 22244645 TI - Dentin moisture conditions affect the adhesion of root canal sealers. AB - INTRODUCTION: The purpose of this study was to evaluate the effects of intraradicular moisture conditions on the push-out bond strength of root canal sealers. METHODS: Eighty root canals were prepared using rotary instruments and, thereafter, were assigned to 4 groups with respect to the moisture condition tested: (1) ethanol (dry): excess distilled water was removed with paper points followed by dehydration with 95% ethanol, (2) paper points: the canals were blot dried with paper points with the last one appearing dry, (3) moist: the canals were dried with low vacuum by using a Luer adapter for 5 seconds followed by 1 paper point for 1 second, and (4) wet: the canals remained totally flooded. The roots were further divided into 4 subgroups according to the sealer used: (1) AH Plus (Dentsply-Tulsa Dental, Tulsa, OK), (2) iRoot SP (Innovative BioCeramix Inc, Vancouver, Canada), (3) MTA Fillapex (Angelus Industria de Produtos Odontologicos S/A, Londrina, Brasil), and (4) Epiphany (Pentron Clinical Technologies, Wallingford, CT). Five 1-mm-thick slices were obtained from each root sample (n = 25 slices/group). Bond strengths of the test materials to root canal dentin were measured using a push-out test setup at a cross-head speed of 1 mm/min. The data were analyzed statistically by two-way analysis of variance and Tukey tests at P = .05. RESULTS: Irrespective of the moisture conditions, iRoot SP displayed the highest bond strength to root dentin. Statistical ranking of bond strength values was as follows: iRoot SP > AH Plus > Epiphany >= MTA Fillapex. The sealers displayed their highest and lowest bond strengths under moist (3) and wet (4) conditions, respectively. CONCLUSIONS: The degree of residual moisture significantly affects the adhesion of root canal sealers to radicular dentin. For the tested sealers, it may be advantageous to leave canals slightly moist before filling. PMID- 22244646 TI - The effect of acidity on dislodgment resistance of mineral trioxide aggregate and bioaggregate in furcation perforations: an in vitro comparative study. AB - INTRODUCTION: The aim of this study was to compare the effect of acidic environment on the dislodgement resistance of mineral trioxide aggregate (MTA) and Bioaggregate (Innovative BioCeramix, Vancouver, Canada) when used as perforation repair materials. METHODS: Eighty, human, mandibular molars were used. Perforations were made in the furcation of each molar and enlarged to #4 Pesso drills. After perforation repair, specimens of each material were randomly divided into 4 groups (n = 10) according to storage media and time: group A: phosphate-buffered saline (PBS) (pH = 7.4) for 4 days, group B: acetic acid (pH = 5.4) for 4 days, group C: PBS for 34 days, and group D: acetic acid (pH = 5.4) for 4 days followed by exposure to PBS for 30 days. Dislodgment resistance was then measured using a universal testing machine, and then the specimens were vertically split to examine the perforated dentin wall using scanning electron microscopy. RESULTS: MTA resisted dislodgement more efficiently than BA after 4 days in PBS (P < .05). The dislodgment resistance of MTA was significantly reduced (P < .05) after exposure to acetic acid, whereas BA was not affected (P > .05). There was an increase in the dislodgment resistance with the increase in the storage time to 34 days (P < .01). After 34 days, there was a statistically significant difference among groups; the MTA D group had significantly the highest bond strength, and the BA D group D had the lowest (P < .05). CONCLUSIONS: MTA is more influenced by acidic pH than BA. Storage for 30 days in PBS can reverse the affected bond of MTA by the acidic environment. PMID- 22244647 TI - Dentinal tubule infection as the cause of recurrent disease and late endodontic treatment failure: a case report. AB - INTRODUCTION: This article describes a case of recurrent post-treatment apical periodontitis and late failure after endodontic retreatment performed in a single visit. METHODS: The patient presented with a tooth exhibiting inadequate endodontic treatment and a large periradicular lesion that extended laterally to the root. Retreatment was performed in a single visit and involved chemomechanical preparation using 5.25% NaOCl as the irrigant and root canal obturation by Schilder's vertical compaction technique. A large lateral canal was radiographically revealed after obturation. After 2 years, the lesion was no longer radiographically discernible, a condition that was confirmed 9 years after retreatment procedures. Nonetheless, after 12 years, radiographs revealed recurrent disease. Apical surgery was performed, and the root apex, including the area of the large lateral canal, was resected with care to maintain the lesion attached to it. The biopsy specimen was subjected to histopathologic and histobacteriologic analyses. RESULTS: Longitudinal sections of the apical root specimen revealed a heavy dentinal tubule infection surrounding the area of the lateral canal. Bacteria were not found in any other area of the specimen. No other possible reason for the inflammatory periradicular lesion, such as root fracture, coronal leakage, or foreign-body reaction, was evident. CONCLUSIONS: A persistent intraradicular infection caused by bacteria located within dentinal tubules is the most reasonable explanation for resurgence of the apical periodontitis lesion. This case report stresses the importance of attaining proper disinfection of the root canal system for a predictable long-term outcome of the treatment. PMID- 22244648 TI - Endodontic management in a patient with vitamin D-resistant Rickets. AB - INTRODUCTION: Hypophosphatemic vitamin D-resistant rickets (VDRRs) is a metabolic bone disease caused by abnormalities in the vitamin D receptive system or in phosphate and calcium metabolism. This condition occurs in growing skeleton affecting bone and dentin mineralization, resulting in systemic and oral manifestations. METHODS: A 15-year-old boy was referred to the private clinic for endodontic treatment in #9. His medical history revealed VDRR disease. The dental findings were multiple periapical lesions in several teeth without obvious reason such as caries or trauma. The radiographic examination showed short roots, enlarged pulp chambers with longer pulp horns, thin dentin and enamel, missing or poorly defined lamina dura, and abnormalities in the cementoenamel junction, all pathognomonic features of the disorder. Conservative endodontic treatment was completed in all teeth with pulp necrosis and rarefactions. RESULTS: A 6-month, 1 year, and 2-year follow-up radiographic examination revealed progressive improvement with bone reconstruction without any clinical symptoms. CONCLUSIONS: Early diagnosis, conventional treatment, and continuous radiographic examination are important factors in improving dental alterations in patients with VDRRs. PMID- 22244649 TI - Large-animal models of acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is characterized by an acute inflammatory response that compromises alveolar-capillary membrane integrity. Clinical symptoms include refractory hypoxemia, noncardiogenic edema, and decreased lung compliance. The purpose of this review is to summarize the different ARDS large-animal models in terms of similarity to the clinical disease and underlying pathophysiology. The repeated lavage, oleic acid, endotoxin, and smoke/burn ARDS models will be discussed in this review. While each model has significant benefits, none is without weaknesses. Thus, the choice of large animal ARDS model must be carefully considered based upon the study focus and investigative team experience. PMID- 22244650 TI - Vascular risk factors, apolipoprotein E, and hippocampal decline on magnetic resonance imaging over a 10-year follow-up. AB - BACKGROUND: Decline of hippocampal volume on magnetic resonance imaging (MRI) may be considered as a surrogate biomarker of accumulating Alzheimer disease (AD) pathology. Previously, we showed in the prospective population-based Rotterdam Scan Study that a higher rate of decline of hippocampal volume on MRI precedes clinical AD or memory decline. We studied potential risk factors for decline of hippocampal volume. METHODS: At baseline (1995-1996), 518 nondemented elderly subjects were included, and the cohort was re-examined in 1999 and in 2006. At each examination, hippocampal volume was determined using an automated segmentation procedure. In all, 301 persons had at least two three-dimensional MRI scans to assess decline in hippocampal volume. RESULTS: Persons carrying the apolipoprotein E (APOE) E4 allele had lower hippocampal volumes than persons with the E3/E3 genotype, but the rate of decline was not influenced by APOE genotype. In persons who did not use antihypertensive treatment, both a high (>90 mm Hg) and a low (<70 mm Hg) diastolic blood pressure were associated with a faster decline in hippocampal volume. Also, white matter lesions on baseline MRI were associated with a higher rate of decline in hippocampal volume. CONCLUSIONS: In a nondemented elderly population, persons with the APOE E4 allele have a smaller hippocampal volume but not a higher rate of decline. Rate of decline of hippocampal volume was influenced by white matter lesions and diastolic blood pressure, supporting their hypothesized role in the pathogenesis of AD. PMID- 22244651 TI - Relationship between muscle coordination and forehand drive velocity in tennis. AB - This study aimed at investigating the relationship between trunk and upper limb muscle coordination and stroke velocity during tennis forehand drive. The electromyographic (EMG) activity of ten trunk and dominant upper limb muscles was recorded in 21 male tennis players while performing five series of ten crosscourt forehand drives. The forehand drive velocity ranged from 60% to 100% of individual maximal velocity. The onset, offset and activation level were calculated for each muscle and each player. The analysis of muscle activation order showed no modification in the recruitment pattern regardless of the velocity. However, the increased velocity resulted in earlier activation of the erector spinae, latissimus dorsi and triceps brachii muscles, as well as later deactivation of the erector spinae, biceps brachii and flexor carpi radialis muscles. Finally, a higher level of activation was observed with the velocity increase in the external oblique, latissimus dorsi, middle deltoid, biceps brachii and triceps brachii. These results might bring new knowledge for strength and tennis coaches to improve resistance training protocols in a performance and prophylactic perspective. PMID- 22244652 TI - Optimization of conventional Fenton and ultraviolet-assisted oxidation processes for the treatment of reverse osmosis retentate from a paper mill. AB - According to current environmental legislation concerned with water scarcity, paper industry is being forced to adopt a zero liquid effluent policy. In consequence, reverse osmosis (RO) systems are being assessed as the final step of effluent treatment trains aiming to recover final wastewater and reuse it as process water. One of the most important drawbacks of these treatments is the production of a retentated stream, which is usually highly loaded with biorecalcitrant organic matter and inorganics; and this effluent must meet current legislation stringent constraints before being ultimately disposed. The treatment of biorefractory RO retentate from a paper mill by several promising advanced oxidation processes (AOPs) - conventional Fenton, photo-Fenton and photocatalysis - was optimized considering the effect and interaction of reaction parameters; particularly using response surface methodology (RSM) when appropriate (Fenton processes). The economical cost of these treatments was also comparatively assessed. Photo-Fenton process was able to totally remove the COD of the retentate, and resulted even operatively cheaper at high COD removal levels than conventional Fenton, which achieved an 80% reduction of the COD at best. In addition, although these optimal results were produced at pH=2.8, it was also tested that Fenton processes are able to achieve good COD reduction efficiencies (>60%) without adjusting the initial pH value, provided the natural pH of this wastewater was close to neutral. Finally, although TiO(2) photocatalysis showed the least efficient and most expensive figures, it improved the biodegradability of the retentate, so its combination with a final biological step almost achieved the total removal of the COD. PMID- 22244653 TI - Action to preserve WHO's core functions cannot wait for organisational reform. PMID- 22244655 TI - Behavioural problems from perinatal and neonatal insults. PMID- 22244654 TI - Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. AB - BACKGROUND: Neonatal interventions are largely focused on reduction of mortality and progression towards Millennium Development Goal 4 (child survival). However, little is known about the global burden of long-term consequences of intrauterine and neonatal insults. We did a systematic review to estimate risks of long-term neurocognitive and other sequelae after intrauterine and neonatal insults, especially in low-income and middle-income countries. METHODS: We searched Medline, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, and Embase for studies published between Jan 1, 1966, and June 30, 2011, that reported neurodevelopmental sequelae after preterm or neonatal insult. For unpublished studies and grey literature, we searched Dissertation Abstracts International and the WHO library. We reviewed publications that had data for long-term outcome after defined neonatal insults. We summarised the results with medians and IQRs, and calculated the risk of at least one sequela after insult. FINDINGS: Of 28,212 studies identified by our search, 153 studies were suitable for inclusion, documenting 22,161 survivors of intrauterine or neonatal insults. The overall median risk of at least one sequela in any domain was 39.4% (IQR 20.0 54.8), with a risk of at least one severe impairment in any insult domain of 18.5% (7.7-33.3), of at least one moderate impairment of 5.0% (0.0-13.3%), and of at least one mild impairment of 10.0% (1.4-17.9%). The pooled risk estimate of at least one sequela (weighted mean) associated with one or more of the insults studied (excluding HIV) was 37.0% (95% CI 27.0-48.0%) and this risk was not significantly affected by region, duration of the follow-up, study design, or period of data collection. The most common sequelae were learning difficulties, cognition, or developmental delay (n=4032; 59%); cerebral palsy (n=1472; 21%); hearing impairment (n=1340; 20%); and visual impairment (n=1228; 18%). Only 40 (26%) studies included data for multidomain impairments. These studies included 2815 individuals, of whom 1048 (37%) had impairments, with 334 (32%) having multiple impairments. INTERPRETATION: Intrauterine and neonatal insults have a high risk of causing substantial long-term neurological morbidity. Comparable cohort studies in resource-poor regions should be done to properly assess the burden of these conditions, and long-term outcomes, such as chronic disease, and to inform policy and programme investments. FUNDING: The Bill & Melinda Gates Foundation, Saving Newborn Lives, and the Wellcome Trust. PMID- 22244656 TI - Eye can see a nest of worms! PMID- 22244657 TI - [Mitral regurgitation of unknown etiology in a 20-year-old patient]. PMID- 22244658 TI - The epidemiology of endometrial and ovarian cancer. AB - This review highlights similarities in the epidemiology of endometrial and ovarian cancer, including highly correlated incidence rates and similar risk factor profiles. Factors that decrease risk for both cancers include a late menarche, early age at first birth, giving birth and breastfeeding, and use of oral contraceptives. Short or irregular cycles and late menopause are associated with increased risk for both. Other risk factors that appear to operate in a similar direction include decreased risk associated with IUD use or a tubal ligation, and increased risk associated with obesity, lack of exercise, and use of talc powders in genital hygiene. Estrogen excess is proposed as the underlying mechanism for most endometrial cancers, whereas incessant ovulation has been suggested as the explanation for ovarian cancer. However, an increased number of estimated ovulatory cycles correlates directly with risk for both endometrial and ovarian cancer, suggesting that reproductive tissue turnover with an accumulation of PTEN or p53 mutations represents a possible common mechanism. An immune-based explanation involving mucin proteins represents another common mechanism that could explain additional risk factors. Maintenance of ideal weight, breastfeeding children, use of oral contraceptives, and avoidance of talc powders in genital hygiene are measures that could lower the risk for both types of cancer. Careful selection of patients for prophylactic oophorectomy for those women who are coming to hysterectomy for benign disease is an additional measure to consider for ovarian cancer. PMID- 22244660 TI - Management of cervical precancers: a global perspective. AB - Cervical cancer incidence and mortality have decreased dramatically over the past 50 years in countries with access and resources to provide frequent screening, evaluation, and treatment of high-grade cervical cancer precursors. For countries with fewer resources and many competing health concerns, cervical cancer remains one of the most lethal and common cancers among women. With the advent of newer technology, such as low-cost HPV vaccines and self-administered HPV tests, followed by simple well-known techniques such as VIA and cryotherapy, cervical cancer rates may well start to decrease worldwide. PMID- 22244661 TI - Current management of vulvar cancer. AB - 1. Vulvar cancer is surgically staged. 2. Imaging such as CT of the abdomen and pelvis should be performed for women with tumors 2 cm or larger or to detect lymph node or other metastases. 3. Staging should include evaluation of factors related to prognosis: tumor size, depth of invasion, lymph node involvement, and presence of distant metastases. 4. Inguinofemoral lymph node metastasis is the most important predictor of overall prognosis. 5. Inguinofemoral lymphadenectomy or sentinel lymph node evaluation can be omitted for lesions 2 cm or smaller and depth of invasion less than 1 mm. 6. Sentinel node biopsy seems to be a reliable means to pathologically assess inguinofemoral lymph node metastasis. 7. All tumors larger than 2 cm require pathologic inguinofemoral lymph node evaluation. 8. Radical local excision or modified radical vulvectomy is appropriate for most stage I and II lesions located on the lateral or posterior aspects of the vulva. 9. A tumor-free surgical margin of at least 1 cm decreases the risk of local recurrence. 10. Chemoradiation therapy is the preferred approach for most patients with very advanced vulvar cancer. PMID- 22244659 TI - Genetic risk and gynecologic cancers. AB - Although most gynecologic malignancies are sporadic, hereditary cancer syndromes cause a substantial portion of these cancers. Given that the diagnosis of these syndromes has prognostic and therapeutic implications for the patient, as well as preventive implications for her family members, genetic testing is now an accepted part of the management of the patient who has gynecologic cancer. PMID- 22244662 TI - Surgical management of cervical carcinoma. AB - Surgical management for cervical carcinoma uses a wide variety of procedures for all stages of disease, ranging from the most conservative excisional biopsy to aggressive extirpative surgery with sophisticated reconstruction. Innovative surgical procedures have given fertility-sparing treatment options to women of reproductive age, and refinement and use of minimally invasive surgical approaches have minimized operative morbidity without sacrificing outcomes. Conservative staging procedures are being evaluated to improve survival in locally advanced disease. There have been many breakthroughs in the treatment of cervical carcinoma over recent years, which have improved not only survival but also the quality of ensuing life for women afflicted by this disease. PMID- 22244663 TI - Current surgical management of endometrial cancer. AB - It is reasonable to perform complete lymphadenectomy in patients at significant risk of lymph node metastases, and use the results to guide adjuvant treatment decisions.(24,25) Criteria for staging based on intraoperative pathology should be determined in consultation with the pathologist, preferably with an institution-specific quality-assurance review.(34) Patients with more aggressive histologies should undergo a staging procedure including an omental biopsy whenever possible, with the understanding that most require systemic adjuvant therapy. Minimally invasive surgery is associated with shorter recovery and fewer postoperative complications than open endometrial cancer staging,(4,5,45) with preliminary data showing similar oncologic outcomes (Walker and colleagues, late breaking abstract SGO 2010 Annual Meeting). Whenever feasible, patients should be offered minimally invasive surgery for endometrial cancer staging. Retrospective data support an attempt at complete cytoreduction in patients with advanced endometrial cancer and a good performance status.(8-12) The decision to perform aggressive cytoreductive surgery should be individualized, taking into account the patient's comorbidities, her performance status, her symptoms, and the risks associated with more aggressive surgical procedures. PMID- 22244664 TI - Current surgical management of ovarian cancer. AB - Surgical management of ovarian cancer requires excellent judgment and mastery of a wide array of procedures. Involvement of a gynecologic oncologist improves outcomes. Staging of apparent stage I disease is important. Minimally invasive techniques provide advantages. Primary debulking surgery provides the best long term survival of any strategy in advanced ovarian cancer. Aggressive surgical paradigms have the greatest success. Further cytoreductive surgery may be appropriate. Most relapsed patients require management of bowel obstruction at some point. Palliative intervention can enhance quality of life. Surgical correction may extend survival. For end-stage patients with progressive disease, the treating gynecologic oncologist must manage expectations. PMID- 22244665 TI - Current management of gestational trophoblastic neoplasia. AB - Gestational trophoblastic neoplasms are malignant lesions that arise from placental villous and extravillous trophoblast. Four clinicopathologic conditions make up this entity: invasive mole (IM), choriocarcinoma (CCA), placental-site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). IM and CCA, which make up the majority of these tumors, are highly responsive to chemotherapy with an overall cure rate exceeding 90%, making it usually possible to achieve cure while preserving reproductive function. PSTT and ETT, which rarely occur, are relatively resistant to chemotherapy, making surgery the primary treatment modality, chemotherapy being used only when the disease has metastasized. PMID- 22244666 TI - New biologic agents for the treatment of gynecologic cancers. AB - The discovery of new biologic targeted agents and appropriately matching them to specific gynecologic tumor types either based on histology or the genetic make-up of the cancer is an exciting new chapter in the treatment of gynecologic malignancies. Therapeutic targets of multiple pathways are currently in study, and combinations with chemotherapy as well as combinations of pathway inhibitors are currently in development. PMID- 22244667 TI - Advances in the use of radiation for gynecologic cancers. AB - Radiation plays an integral role in the management of gynecologic cancers. The specific regimen must be carefully coordinated based on the details of a patient's personal history and pathologic findings. An integrated multidisciplinary approach that merges pathology, radiology, medical oncology, gynecologic oncology, and radiation oncology results in a greater understanding and, ideally, better outcomes for women suffering from gynecologic cancer. PMID- 22244669 TI - Gynecologic cancer. PMID- 22244670 TI - Phenylene-ethynylene trication as an efficient fluorescent signal transducer in an aptasensor for potassium ion. AB - A tricationic phenylene-ethynylene (N(3+)) fluorophore is investigated as a fluorescent transducer in homogeneous aptasensing system for potassium ion (K(+)) assay in aqueous media. The enhancement of the fluorescent signal of N(3+) by three K(+) aptamers consisting of 12, 15, and 21 nucleotides are observed and used for the determination of N(3+)-aptamer binding affinities. The binding affinities increase with the length of the aptameric oligonucleotides and are proven to be important to the sensitivity and selectivity of the aptasensors. The enhanced fluorescent signal of each N(3+)-aptamer solution is selectively quenched by K(+) due to the ability of K(+) in stabilizing the G-quadruplex structure of the aptamer. Among three aptamers, the 15-base aptamer provides optimal sensitivity and selectivity over other ions such as Li(+), Na(+), NH(4)(+), Mg(2+), Ca(2+) and Sr(2+). The sensing system shows the detection limit of 1 MUM of K(+) in clean buffered solution and 30 MUM of K(+) in the solution containing 4800-fold excess of Na(+), with wide linear dynamic ranges of micro- to millimolar concentration. This label-free fluorescence aptasensor is conveniently and effectively applicable for analysis of K(+) in urine samples. PMID- 22244671 TI - Microfluidic heavy metal immunoassay based on absorbance measurement. AB - A simple and rapid flow-based multioperation immunoassay for heavy metals using a microfluidic device was developed. The antigen-immobilized microparticles in a sub-channel were introduced as the solid phase into a main channel structures through a channel flow mechanism and packed into a detection area enclosed by dam like structures in the microfluidic device. A mixture of a heavy metal and a gold nanoparticle-labeled antibody was made to flow toward the corresponding metal through the main channel and make brief contact with the solid phase. A small portion of the free antibody was captured and accumulated on the packed solid phase. The measured absorbance of the gold label was proportional to the free antibody portion and, thus, to the metal concentration. Each of the monoclonal antibodies specific for cadmium-EDTA, chromium-EDTA, or lead-DTPA was applied to the single-channel microfluidic device. Under optimized conditions of flow rate, volume, and antibody concentration, the theoretical (antibody K(d)-limited) detection levels of the three heavy metal species were achieved within only 7 min. The dynamic range for cadmium, chromium, and lead was 0.57-60.06 ppb, 0.03 0.97 ppb, and 0.04-5.28 ppb, respectively. An integrated microchannel device for simultaneous multiflow was also successfully developed and evaluated. The multiplex cadmium immunoassay of four samples was completed within 8 min for a dynamic range of 0.42-37.48 ppb. Present microfluidic heavy metal immunoassays satisfied the Japanese environmental standard for cadmium, chromium and, lead, which provided in the soil contamination countermeasures act. PMID- 22244668 TI - Contemporary quality of life issues affecting gynecologic cancer survivors. AB - Regardless of cancer origin or age of onset, the disease and its treatment can produce short- and long-term sequelae (ie, sexual dysfunction, infertility, or lymphedema) that adversely affect quality of life (QOL). This article outlines the primary contemporary issues or concerns that may affect QOL and offers strategies to offset or mitigate QOL disruption. These contemporary issues are identified within the domains of sexual functioning, reproductive issues, lymphedema, and the contribution of health-related QOL in influential gynecologic cancer clinical trials. PMID- 22244673 TI - Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats. AB - OBJECTIVE: Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and -5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats. DESIGN: Arthritis was induced in adult male Wistar rats by an intradermal injection of 4 mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300 MUg/kg of rhGH or 200 MUg/kg of rhIGF or saline was administrated 18 and 3h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot. RESULTS: Arthritis decreased serum IGF-I and IGF mRNA in liver (P<0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P<0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P<0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats. CONCLUSIONS: Short-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle. PMID- 22244672 TI - Sequencing our way towards understanding global eukaryotic biodiversity. AB - Microscopic eukaryotes are abundant, diverse and fill critical ecological roles across every ecosystem on Earth, yet there is a well-recognized gap in understanding of their global biodiversity. Fundamental advances in DNA sequencing and bioinformatics now allow accurate en masse biodiversity assessments of microscopic eukaryotes from environmental samples. Despite a promising outlook, the field of eukaryotic marker gene surveys faces significant challenges: how to generate data that are most useful to the community, especially in the face of evolving sequencing technologies and bioinformatics pipelines, and how to incorporate an expanding number of target genes. PMID- 22244675 TI - The impact of myelodysplastic syndromes on quality of life: lessons learned from 70 voices. AB - BACKGROUND: Little is known about the impact of myelodysplastic syndromes (MDS) on the quality of life (QOL) of those living with the disease. OBJECTIVES: The purpose of this qualitative study was to explore this phenomenon. METHODS: Seventy patients with MDS participated in five focus groups conducted throughout the United States. Transcripts from recordings of focus group sessions were coded and emerging themes identified using thematic analysis. RESULTS: Findings revealed a multifaceted description of how MDS affects QOL. MDS was found to cause a substantial and sustained decrease in ability to function. QOL was adversely affected by work expended on managing the disease. The emotional impact was often viewed as more problematic than the physical impact; emotional reactions included shock, anger, depression, and anxiety. In contrast, spiritual well-being was often enhanced, with a renewed appreciation for life, relationships, and faith. CONCLUSIONS: Data from this study suggest that MDS has a substantial, often negative impact on patients' lives and clinicians should be cognizant of this impact. Attention must be directed at providing more comprehensive support for the patient throughout the illness trajectory. LIMITATIONS: The method of subject recruitment may have limited participation to individuals who are more proactive in obtaining information about their illness. The focus groups convened only once; thus, purposive sampling and repeated assessments were not possible. PMID- 22244674 TI - Managing side effects of tyrosine kinase inhibitor therapy to optimize adherence in patients with chronic myeloid leukemia: the role of the midlevel practitioner. AB - In the last decade, the development of imatinib, a tyrosine kinase inhibitor, has brought about unprecedented change in the way newly diagnosed, chronic-phase chronic myeloid leukemia patients are treated. Two next-generation tyrosine kinase inhibitors, nilotinib and dasatinib, were initially indicated for imatinib resistant or imatinib-intolerant chronic myeloid leukemia patients and recently received approval from the Food and Drug Administration for treatment of newly diagnosed, chronic-phase chronic myeloid leukemia patients. In comparison with the previous standards of care, benefits with these three tyrosine kinase inhibitors have included more rapid response rates, increased survival, and fewer side effects. The improved long-term outcomes have altered the approach to management of chronic myeloid leukemia from a progressive fatal disease with a poor prognosis to a chronic condition similar to diabetes or hypertension. Prolonged survival increases the need for patient education, support, monitoring, and assistance with adverse event management. Even low-grade side effects can adversely affect patients' quality of life and, therefore, require prompt attention to prevent long-term complications or suboptimal outcomes. New evidence has indicated that patient adherence to tyrosine kinase inhibitor therapy is essential to successful treatment. Midlevel practitioners can help to optimize outcomes by educating patients regarding the importance of adherence, performing regular monitoring, helping patients to understand their test results, and aggressively managing treatment-related side effects. PMID- 22244676 TI - What is the role of lymphadenectomy in surgical management of patients with endometrial carcinoma? AB - The role of lymphadenectomy in the management of endometrial carcinoma remains controversial in gynecologic oncology. Comprehensive pelvic and paraaortic lymphadenectomy should be performed in patients with intermediate- and high-risk endometrial cancer. PMID- 22244678 TI - Hybrid sliding mode position control for a piston air motor ball screw table. AB - Air motors have been generally applied in the automation industry. Since air motors operate without electricity, they will not produce sparks, explosions or short circuit phenomenon. The purpose of this paper is to analyze the behavior of a ball screw table actuated by a piston air motor and design a hybrid (backstepping and fuzzy) sliding mode controller for accomplishing accurate position performance. The experimental results validate the proposed position control strategy. PMID- 22244677 TI - State-of-the-art classification and multimodality treatment of malignant thymoma. AB - Thymomas are the most common tumors of the anterior mediastinum. Classification, treatment options and understanding of the pathophysiology of thymoma have changed over the past years. It is hoped that novel therapeutic strategies will lead to a survival benefit in these patients. It has turned out that patients with thymoma are best treated with multimodality therapy. In this review, a pathologist, an immunologist, a surgeon, a radiotherapist, a pneumologist and oncologists discuss the current status of classification and strategies for the treatment of thymoma patients. PMID- 22244679 TI - Taming the hydra of specialized metabolism: how systems biology and comparative approaches are revolutionizing plant biochemistry. AB - Specialized (traditionally called 'secondary') metabolism can be thought of as a hydra with hundreds of thousands of compounds produced by thousands of enzymes across the entire plant kingdom. Until recently, plants that produce the most interesting and valuable metabolites were recalcitrant to modern molecular biology approaches for gene and pathway discovery. Recent advances in technologies for genomic, transcriptomic, proteomic, and metabolomic methods now allow for deployment of 'systems biology' approaches to help elucidate unknown steps in specialized metabolite pathways, for example through co-expression analyses. Inexpensive transcriptome and whole genome sequencing (WGS) promises to provide direct access to metabolic pathways in plants not currently used as reference organisms. For example, WGS has uncovered cases of physical proximity of genes of specialized metabolism. Further integration of multiple 'omics' datasets through advances in bioinformatics tools will increase our knowledge of pathway architecture and regulation at an ever-increasing rate. As such the era of systems biology is rapidly providing a broader and deeper understanding of plant specialized metabolism. PMID- 22244681 TI - Development of a clinical Multiple-Lunge Test to predict falls in older adults. AB - OBJECTIVE: To develop a new Multiple-Lunge Test to distinguish between fallers and nonfallers in community-dwelling older adults. DESIGN: A cross-sectional design was used to establish the sensitivity and specificity of the test to predict faller status based on retrospective self-reported fall history. SETTING: Local retirement villages. PARTICIPANTS: Community-dwelling older adults (N=130; mean age +/- SD, 77+/-7y) with (n=40) and without (n=90) a history of falls. INTERVENTIONS: The Multiple-Lunge Test required individuals to lunge forward to a step length determined as 60% of their leg length, and return to start, for 5 consecutive repetitions. Interday and intraday test-retest reliability of the Multiple-Lunge Test was established across 2 testing occasions. MAIN OUTCOME MEASURES: Number of steps performed correctly, total time to complete 5 steps. RESULTS: The Multiple-Lunge Test was found to be reliable across trials (Intraday: intraclass correlation coefficient [ICC]=.79-.81 for steps, ICC=.86 .88 for time; Interday: ICC=.77 for steps; ICC=.84 for time). Sensitivity and specificity values were calculated as 73% and 63%, respectively, for predicting multiple fallers using the measure of all 5 steps done correctly. CONCLUSIONS: The test is easily administered and because of its challenging nature, it may be well suited to detect subtle differences in abilities of higher functioning, community-dwelling older adults. A practitioner can be confident in 7 of 10 cases that an older adult who cannot complete all 5 steps of the Multiple-Lunge Test is at high risk of falls. The results suggest that there is potential for the Multiple-Lunge Test to be used in clinical practice; however, additional research on how to further increase its validity appears warranted. PMID- 22244680 TI - Dosing of renal replacement therapy in acute kidney injury. AB - The impact of the intensity of renal replacement therapy on outcomes in patients with acute kidney injury has been studied intensively during the past decade. In this review, we consider the concept of dose of renal replacement therapy in acute kidney injury and summarize the recent clinical trials addressing this topic. Although several single-center trials suggest that more intensive therapy is associated with improved outcomes, 2 large multicenter randomized trials do not find a benefit with higher doses of therapy. Based on these studies, we provide recommendations for the delivered intensity of renal replacement therapy in acute kidney injury. PMID- 22244682 TI - Lymphadenectomy increases the prognostic value of the revised 2009 FIGO staging system for endometrial cancer: a multi-center study. AB - BACKGROUND: We investigated whether pelvic or para-aortic lymphadenectomy increases the prognostic value of the revised 2009 FIGO staging system in patients with endometrial cancer (EC). METHODS: We reviewed 786 patients with EC from six tertiary medical centers between July 1996 and June 2008. All patients were classified according to the 1988 FIGO staging system: IA (n = 234); IB (n = 270); IC (n = 109); IIA (n = 35); IIB (n = 29); IIIA (n = 37); IIIB (n = 3); IIIC (n = 69), and the revised 2009 FIGO staging system was also applied to divide them: IA (=542); IB (=125); II (n = 29); IIIA (n = 18); IIIB (n = 3); IIIC1 (n = 43); IIIC2 (n = 26). Prognostic values between the 1988 and the revised 2009 FIGO staging systems were compared by multivariate Cox's proportional hazard analysis. RESULTS: The 1988 FIGO stage IC, IIB, IIIA + IIIB and IIIC, and the revised 2009 FIGO stage IB, II, IIIA + IIIB and IIIC2 diseases were prognostic factors for poor PFS, whereas the 1988 FIGO stage IIB and IIIC, and the revised 2009 FIGO stage II, IIIA + IIIB and IIIC2 diseases were unfavorable prognostic factors for OS. Although these results were similar to those in 595 patients who underwent pelvic or para-aortic lymphadenectomy, the revised 2009 FIGO stage IIIC1 disease was an additional prognostic factor for poor PFS and OS (adjusted HRs, 4.19 and 11.25; 95% CIs, 1.39-12.60 and 2.23-36.74). CONCLUSIONS: The revised 2009 FIGO staging system had a higher prognostic value than the 1988 FIGO staging system, and pelvic or para-aortic lymphadenectomy increased the prognostic value of the revised 2009 FIGO staging system for EC. PMID- 22244683 TI - [Reference guidelines for the 12-Item Short-Form Health Survey version 2 based on the Catalan general population]. AB - BACKGROUND AND OBJECTIVE: The SF-12 health survey is the short version of the SF 36. The main interpretation strategy for these health related quality of life (HRQL) questionnaires is the use of population based reference values. This study aims to obtain the population based norms for the Spanish version of SF-12 version 2 (SF-12v2), to evaluate its construct validity and to compare the scores obtained by the standard and the specific method of calculation. SUBJECTS AND METHODS: We analyzed a subsample of the Catalan Health Interview Survey (n=4,261), representative of the general non-institutionalized population. Median and percentiles were calculated for each of the 8 dimensions and for the component summaries, stratified by sex and age groups. The construct validity was evaluated by comparing known groups, applying ANOVA. RESULTS: The results for the known groups analysis supported the hypothesis established a priori (P<.001): worse physical health for persons with mobility problems (EQ-5D) (37.8 vs 52), with restriction in activities (41.8 vs 51.2), and with greater number of chronic disorders (from 43.2 to 53.9); and worse mental health with problems of anxiety/depression (EQ-5D) (42.2 vs 51.9). The scores obtained by the 2 different methods of calculation were similar, except for General Health and Vitality. CONCLUSIONS: The SF-12v2 is a valid instrument to measure HQRL in our environment. The obtained norms facilitate the interpretation of SF-12v2 scores in the clinical practice, research and health policy. We recommend the use of the specific method of calculation for national HRQL comparison and the standard one for international comparison. PMID- 22244684 TI - Preface to first special issue on Fukushima. PMID- 22244685 TI - Correlations of natural radionuclides in soil with those in sediment from the Danube and nearby irrigation channels. AB - The correlation between activity concentrations of some natural radionuclides ((238)U, (226)Ra, (232)Th, (40)K) measured in soil and in sediment taken from the Danube River and nearby irrigation channels was studied. The soil samples were collected from the northern part of Serbia and the sediment from the Serbian part of the Danube River and from the surrounding irrigation channels. The correlation between (238)U and other natural radionuclides in irrigation channel sediments was not as good as in the Danube. One of the possible explanations for this weak correlation can be the different chemical dynamics of (238)U in the irrigation channel sediment or changes of the (238)U activity concentration in irrigation channel sediment due to some human activities. The evaluation of ratios of activity concentrations of some natural radionuclides could be a more sensitive method for the determination of contaminant, rather than the straightforward analysis of activity concentrations. PMID- 22244686 TI - Effect of triage on waiting time for community rehabilitation: a prospective cohort study. AB - OBJECTIVE: To investigate how the allocation of referrals for a community rehabilitation service to triage categories affects waiting time from referral to first appointment, and whether other factors also contribute to variance in waiting time. DESIGN: A prospective cohort study. SETTING: A multidisciplinary outpatient community rehabilitation program within a large metropolitan health service. PARTICIPANTS: Consecutive adult patients (N=379) commencing rehabilitation over a 3-month period. INTERVENTION: Allocation of referrals to a triage category of 1 (most urgent) to 4 (least urgent) by allied health clinicians guided by a written protocol. MAIN OUTCOME MEASURE: The primary outcome was waiting time from referral to service commencement. RESULTS: The small group of patients (4%) allocated to the most urgent category had significantly shorter mean waiting times than the other 3 categories (mean, 4.8d vs 19.6, 26.6, and 19.4d for categories 2, 3, and 4, respectively). Regression analysis indicated that approximately 11% of the variance in waiting time was accounted for by the triage categories. Site of treatment (home or center) and diagnosis also made small contributions (4% combined) to variance in waiting time. CONCLUSIONS: The triage process ensured rapid service for a small number of urgent referrals, but made little difference to the waiting time of the vast majority of patients. Given the resources required for triaging patients, the results of this study lead us to question the value of the triage system in this setting. PMID- 22244688 TI - Analysis of immune-related gene expression in chicken peripheral blood mononuclear cells following Salmonella enterica serovar Enteritidis infection in vitro. AB - We examined mRNA expression of eight genes, TLR4, TLR5, TLR15, interleukin (IL) 1beta, IL-6, transforming growth factor-beta4 (TGF-beta4), CXCLi2, and a macrophage inflammatory protein (MIP) family chemokine called CCLi2, in peripheral blood mononuclear cells (PBMCs) isolated from the blood of chickens after in vitro exposure to Salmonella enterica serovar Enteritidis (SE). The chickens of four Chinese native lines, Qingjiaoma, Sanhuang, Wugu, and Xueshanma, were evaluated for mRNA expression levels at 2 and 4h post-infection using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). TLR4 and TLR15 mRNA were in particular highly expressed in PBMCs of Wugu and Xueshanma chickens exposed to SE, while TLR5 was expressed less in the Sanhuang chickens than in others. Breed effect was significant (P<0.05) for IL-1beta, IL-6, CXCLi2, and CCLi2 mRNA expression, all of which were expressed to a greater extent in Wugu and Xueshanma than in the other two lines. These findings demonstrate the difference of mRNA expression profiles for innate immune molecules in PBMCs infected to SE among different lines. PMID- 22244687 TI - New directions for patient-centred care in scleroderma: the Scleroderma Patient centred Intervention Network (SPIN). AB - Systemic sclerosis (SSc), or scleroderma, is a chronic multisystem autoimmune disorder characterised by thickening and fibrosis of the skin and by the involvement of internal organs such as the lungs, kidneys, gastrointestinal tract, and heart. Because there is no cure, feasibly-implemented and easily accessible evidence-based interventions to improve health-related quality of life (HRQoL) are needed. Due to a lack of evidence, however, specific recommendations have not been made regarding non-pharmacological interventions (e.g. behavioural/psychological, educational, physical/occupational therapy) to improve HRQoL in SSc. The Scleroderma Patient-centred Intervention Network (SPIN) was recently organised to address this gap. SPIN is comprised of patient representatives, clinicians, and researchers from Canada, the USA, and Europe. The goal of SPIN, as described in this article, is to develop, test, and disseminate a set of accessible interventions designed to complement standard care in order to improve HRQoL outcomes in SSc. PMID- 22244689 TI - Vaccinia viruses isolated from skin infection in horses produced cutaneous and systemic disease in experimentally infected rabbits. AB - The susceptibility of rabbits to two isolates of Vaccinia virus (VACV) recovered from cutaneous disease in horses in Southern Brazil was investigated. Rabbits were inoculated in the ear skin with both VACV isolates, either in single or mixed infection. All inoculated animals presented local skin lesions characterized by hyperaemia, papules, vesicles, pustules and ulcers. Infectious virus was detected in the lungs and intestine of rabbits that died during acute disease. Histological examination of the skin revealed changes characteristic of those associated with members of the genus Orthopoxvirus. These results demonstrate that rabbits develop skin disease accompanied by systemic signs upon intradermal inoculation of these two equine VACV isolates, either alone or in combination, opening the way for using rabbits to study selected aspects of the biology and pathogenesis of VACV infection. PMID- 22244690 TI - When single cell technology meets omics, the new toolbox of analytical biotechnology is emerging. PMID- 22244691 TI - Stroke literacy, behavior, and proficiency in a South Florida population. AB - BACKGROUND: Our goal was to assess stroke literacy, behavior, and proficiency in our South Florida service population. METHODS: Data were obtained from the 2006 to 2010 Cleveland Clinic Florida annual "stroke prevention screening" questionnaires. "Stroke risk factor awareness" was attributed to participants correctly identifying at least 5 out of the 7 stroke risk factors presented. "Stroke symptom awareness" was assigned if one correctly selected all 5 listed stroke symptoms and not any of the 3 inappropriate responses. Participants had "stroke literacy" if they: (1) demonstrated stroke risk factor awareness; (2) demonstrated stroke symptom awareness; and (3) they correctly identified the brain as where a stroke occurs. To assess appropriate "stroke behavior," respondents had to choose "call 911 immediately" if one were to experience stroke symptoms. "Stroke proficiency" was attributed to individuals showing both stroke literacy and appropriate stroke behavior. RESULTS: There were a total of 298 participants. Sixty-seven percent of participants correctly identified the brain as the organ where stroke occurs. Almost three-fourths (74.2%) demonstrated stroke risk factor awareness, 28.2% had stroke symptom awareness, 17.8% had stroke literacy, 87.9% declared appropriate stroke behavior, and 16.1% had stroke proficiency. CONCLUSIONS: Stroke behavior and stroke proficiency are useful novel concepts in stroke epidemiology. Although our South Florida community is relatively well-educated and affluent, there are tangible gaps in knowledge, attitudes, and behavior as it pertains to stroke, similar to that seen in less advantaged populations. We recommend intensified usage of the media with information provided by qualified health professionals in a variety of formats and languages appropriate to the ethnic and cultural diversities that define this population. PMID- 22244692 TI - Chemical proteomics. PMID- 22244693 TI - Prebiotics in foods. AB - A wealth of information has been gathered over the past 15 years on prebiotics through experimental, animal and human studies, with the aim to understand the mechanism of actions and elucidate their beneficial health effects to the human host. Significant amount of evidence exists for their ability to increase the bioavailability of minerals and stimulate the immune system, although there is less clear evidence so far for their prophylactic or therapeutic role in gastrointestinal infections. Moreover, the effect of the food delivery vehicle on the efficacy of prebiotics is an area that has been hardly investigated. Besides their beneficial effects, prebiotics influence the textural and organoleptic properties of the food products, such as dairy and baked products. To do this however, they need to be stable during food processing, in particular under conditions of high temperature and low pH. PMID- 22244694 TI - Endothelialization and patency of RGD-functionalized vascular grafts in a rabbit carotid artery model. AB - To address the growing demand of small-diameter vascular grafts for cardiovascular disease, it is necessary to develop substitutes with bio functionalities, such as anticoagulation, rapid endothelialization, and smooth muscle regeneration. In this study, the small-diameter tubular grafts (2.2 mm) were fabricated by electrospinning of biodegradable polymer polycaprolactone (PCL) followed by functional surface coating with an arginine-glycine-aspartic acid (RGD)-containing molecule. The healing characteristics of the grafts were evaluated by implanting them in rabbit carotid arteries for 2 and 4 weeks. Results showed that at both time points, all 10 of the RGD-modified PCL grafts (PCL-RGD) were patent, whereas 4 of the 10 non-modified PCL grafts were occluded due to thrombus formation. Scanning electron microscopy (SEM) data showed abundant platelets adhering on the surface of the midportion of the PCL grafts. In contrast, only few platelets were observed on the PCL-RGD surface, suggesting that RGD modification significantly improved the hemocompatibility of the PCL grafts. Histological analysis demonstrated enhanced cell infiltration and homogeneous distribution within the PCL-RGD grafts in comparison with the PCL grafts. Furthermore, immunofluorescence staining also showed a 3-fold increase of endothelial coverage of the PCL-RGD grafts than that of PCL grafts at those two time points. After 4-week implantation, 65.3 +/- 7.6% of the surface area of the PCL-RGD grafts was covered by smooth muscle cell layer, which is almost 23% more than that on the PCL grafts. The present study indicates that RGD-modified PCL grafts exhibit an improved remodeling and integration capability in revascularization. PMID- 22244695 TI - The use of an in vitro 3D melanoma model to predict in vivo plasmid transfection using electroporation. AB - A large-scale in vitro 3D tumor model was generated to evaluate gene delivery procedures in vivo. This 3D tumor model consists of a "tissue-like" spheroid that provides a micro-environment supportive of melanoma proliferation, allowing cells to behave similarly to cells in vivo. This functional spheroid measures approximately 1 cm in diameter and can be used to effectively evaluate plasmid transfection when testing various electroporation (EP) electrode applicators. In this study, we identified EP conditions that efficiently transfect green fluorescent protein (GFP) and interleukin 15 (IL-15) plasmids into tumor cells residing in the 3D construct. We found that plasmids delivered using a 6-plate electrode applying 6 pulses with nominal electric field strength of 500 V/cm and pulse-length of 20 ms produced significant increase of GFP (7.3-fold) and IL-15 (3.0-fold) expression compared to controls. This in vitro 3D model demonstrates the predictability of cellular response toward delivery techniques, limits the numbers of animals employed for transfection studies, and may facilitate future developments of clinical trials for cancer therapies in vivo. PMID- 22244696 TI - Non-invasive imaging of transplanted human neural stem cells and ECM scaffold remodeling in the stroke-damaged rat brain by (19)F- and diffusion-MRI. AB - Transplantation of human neural stem cells (hNSCs) is emerging as a viable treatment for stroke related brain injury. However, intraparenchymal grafts do not regenerate lost tissue, but rather integrate into the host parenchyma without significantly affecting the lesion cavity. Providing a structural support for the delivered cells appears important for cell based therapeutic approaches. The non invasive monitoring of therapeutic methods would provide valuable information regarding therapeutic strategies but remains a challenge. Labeling transplanted cells with metal-based (1)H-magnetic resonance imaging (MRI) contrast agents affects the visualization of the lesion cavity. Herein, we demonstrate that a (19)F-MRI contrast agent can adequately monitor the distribution of transplanted cells, whilst allowing an evaluation of the lesion cavity and the formation of new tissue on (1)H-MRI scans. Twenty percent of cells labeled with the (19)F agent were of host origin, potentially reflecting the re-uptake of label from dead transplanted cells. Both T(2)- and diffusion-weighted MRI scans indicated that transplantation of hNSCs suspended in a gel form of a xenogeneic extracellular matrix (ECM) bioscaffold resulted in uniformly distributed cells throughout the lesion cavity. However, diffusion MRI indicated that the injected materials did not yet establish diffusion barriers (i.e. cellular network, fiber tracts) normally found within striatal tissue. The ECM bioscaffold therefore provides an important support to hNSCs for the creation of de novo tissue and multi-nuclei MRI represents an adept method for the visualization of some aspects of this process. However, significant developments of both the transplantation paradigm, as well as regenerative imaging, are required to successfully create new tissue in the lesion cavity and to monitor this process non-invasively. PMID- 22244697 TI - The role of non-covalent interactions in anticancer drug loading and kinetic stability of polymeric micelles. AB - A new series of acid- and urea-functionalized polycarbonate block copolymers were synthesized via organocatalytic living ring-opening polymerization using methoxy poly(ethylene glycol) (PEG) as a macroinitiator to form micelles as drug delivery carriers. The micelles were characterized for critical micelle concentration, particle size and size distribution, kinetic stability and loading capacity for a model anticancer drug, doxorubicin (DOX) having an amine group. The acid/urea groups were placed in block forms (i.e. acid as the middle block or the end block) or randomly distributed in the polycarbonate block to investigate molecular structure effect. The micelles formed from the polymers in both random and block forms provided high drug loading capacity due to strong ionic interaction between the acid in the polymer and the amine in DOX. However, the polymers with acid and urea groups placed in the block forms formed micelles with wider size distribution (two size populations), and their DOX-loaded micelles were less stable. The number of acid/urea groups in the random form was further varied from 5 to 8, 13 and 19 to study its effects on self-assembly behaviors and DOX loading. An increased number of acid/urea groups yielded DOX-loaded micelles with smaller size and enhanced kinetic stability because of improved inter molecular polycarbonate-polycarbonate (urea-urea and urea-acid) hydrogen-bonding and polycarbonate-DOX (acid-amine) ionic interactions. However, when the number of acid/urea groups was 13 or higher, micelles aggregated in a serum-containing medium, and freeze-dried DOX-loaded micelles were unable to re-disperse in an aqueous solution. Among all the polymers synthesized in this study, 1b with 8 acid/urea groups in the random form had the optimum properties. In vitro release studies showed that DOX release from 1b micelles was sustained over 7 h without significant initial burst release. MTT assays demonstrated that the polymer was not toxic towards HepG2 and HEK293 cells. Importantly, DOX-loaded micelles were potent against HepG2 cells with IC(50) of 0.26 mg/L, comparable to that of free DOX (IC(50): 0.20 mg/L). In addition, DOX-loaded 1b micelles yielded lower DOX content in the heart tissue of the tested mice as compared to free DOX formulation after i.v. injection. These findings signify that 1b micelles may be a promising carrier for delivery of anticancer drugs that contain amine groups. PMID- 22244698 TI - The RhoA-ROCK-PTEN pathway as a molecular switch for anchorage dependent cell behavior. AB - The proliferation of anchorage-dependent cells of mesenchymal origin requires the attachment of the cells to substrates. Thus, cells that are poorly attached to substrates exhibit retarded cell cycle progression or apoptotic death. A major disadvantage of most polymers used in tissue engineering is their hydrophobicity; hydrophobic surfaces do not allow cells to attach firmly and, therefore, do not allow normal proliferation rates. In this study, we investigated the molecular mechanism underlying the reduced proliferation rate of cells that are poorly attached to substrates. There was an inverse relationship between the activity of the small GTPase RhoA (RhoA) and the cell proliferation rate. RhoA activity correlated inversely with the strength of cell adhesion to the substrates. The high RhoA activity in the cells poorly attached to substrates caused an increase in the activity of Rho-associated kinase (ROCK), a well-known effector of RhoA that upregulated the activity of phosphatase and tensin homolog (PTEN). The resulting activated PTEN downregulated Akt activity, which is essential for cell proliferation. Thus, the cells that were poorly attached to substrates showed low levels of cell proliferation because the RhoA-ROCK-PTEN pathway was hyperactive. In addition, RhoA activity seemed to be related to focal adhesion kinase (FAK) activity. Weak FAK activity in these poorly attached cells failed to downregulate the high RhoA activity that restrained cell proliferation. Interestingly, reducing the expression of any component of the RhoA-ROCK-PTEN pathway rescued the proliferation rate without physico-chemical surface modifications. Based on these results, we suggest that the RhoA-ROCK-PTEN pathway acts as a molecular switch to control cell proliferation and determine anchorage dependence. In cells that are poorly attached to substrates, its inhibition is sufficient to restore cell proliferation without the need for physico-chemical modification of the material surface. PMID- 22244703 TI - Protein expression changes during cotton fiber elongation in response to low temperature stress. AB - Low temperature stress is one of the major abiotic stresses limiting the formation of cotton (Gossypium hirsutum L.) fiber qualities, especially fiber length. To investigate the molecular adaptation mechanisms of cotton fiber elongation to low temperature stress, two cotton cultivars, Kemian 1 (low temperature-tolerant) and Sumian 15 (low temperature-sensitive), were planted in the field at two sowing dates (25 April and 10 June). The two sowing dates resulted in different growing conditions and the main environmental difference between them was temperature, particularly the mean daily minimum temperature (MDTmin). When the sowing date was delayed, the MDTmin decreased from 26.9 degrees C (25 April) to 20.6 degrees C (10 June). Low temperature stress (MDTmin of 20.6 degrees C) shortened the fiber length significantly in two cultivars, but the decreased extent was larger in Sumian 15 than that in Kemian 1. Proteomic analysis of three developmental stages (10, 15 and 20 days post-anthesis [DPA]) showed that 37 spots changed significantly (p<0.05) in abundance under low temperature stress and they were identified using mass spectrometry. These proteins were involved in malate metabolism, soluble sugar metabolism, cell wall loosening, cellulose synthesis, cytoskeleton, cellular response, and redox homeostasis. The results suggest that the enhancement of osmoticum maintenance, cell wall loosening, cell wall components biosynthesis, and cytoskeleton homeostasis plays important roles in the tolerance of cotton fibers to low temperature stress. Moreover, low levels of PEPCase, expansin, and ethylene signaling proteins may potentially lead to the low temperature sensitivity of Sumian 15 at the proteomic level. PMID- 22244704 TI - A review of the validity and reliability of smokeless tobacco dependence measures. AB - INTRODUCTION: With the growing marketing of alternate tobacco products, advocacy of harm reduction, and smoke free air policies, an overall increase in Smokeless Tobacco (ST) use has been observed since the 1970s. Numerous studies have been published addressing nicotine dependence measures for smokers; however, research in the field of ST dependence measures is scarce. PURPOSE: The aim of this study is to summarize the psychometric properties of ST dependence measures by evaluating the reliability and validity of these scales through peer review research. METHODS: A systematic literature search was conducted within the databases of PubMed and OVID Medline. Four publications reporting on the psychometric properties of ST dependence measures were identified; two regarding FTQ based scales, one regarding an FTND based scale, and one comparing two of these modified scales. A predefined set of criteria was used to assess the psychometric properties of these measures. RESULTS: ST dependence measures depend heavily on two underlying factors, heaviness of tobacco use and withdrawal. The internal consistency of the measures was low to moderate, Cronbach's alpha ranging from 0.30 to 0.52 Cotinine was used as criterion variable to validate the results of the dependence measures. Concurrent validity against DIS-IV-ND based diagnosis was not established for modified FTQ scale. Predictive validity of these ST dependence scales was measured as abstinence of ST use at three and six months. FTQ-ST was predictive of abstinence at three months however failed to predict six months abstinence. CONCLUSION: FTQ and FTND based measures have inherited shortcomings and have limited psychometric properties. With ease of use and wide application in tobacco research, these measures provide preliminary foundation for studying ST dependence. However, the complexity of tobacco dependence requires a multidimensional measure with high validity and reliability for effective prevention care and for research purposes. PMID- 22244705 TI - The relationship of alexithymia to emotional dysregulation within an alcohol dependent treatment sample. AB - Difficulties regulating emotions have implications for the development, maintenance, and recovery from alcohol problems. One construct thought to impede the regulation of emotion is alexithymia. Alexithymia is characterized by difficulties identifying, differentiating and expressing feelings, a limited imagination and fantasy life, and an externally-oriented thinking style (e.g., prefer talking about daily activities rather than feelings). Given that poor emotion regulation skills have been found to predict posttreatment levels of alcohol use, and that several defining characteristics of alexithymia bear similarity to deficits in emotion regulation skills, it is possible that alexithymia may predict poorer alcohol treatment outcomes. Thus, the present study first examined the relationship of alexithymia to several other emotion regulation measures and then investigated the impact of alexithymia on attrition and alcohol treatment outcomes in men and women (N=77) enrolled in a 12-week cognitive-behavioral intervention for alcohol dependence. At baseline, higher scores on alexithymia were associated poorer emotion regulation skills, fewer percent days abstinent, greater alcohol dependence severity, and several high risk drinking situations. Alexithymia was unrelated to attrition and to level of alcohol consumption at posttreatment. Overall, the construct of alexithymia is shown to be related to several theoretically-related constructs (e.g., emotion regulation, mindfulness) but demonstrated a limited relationship to drinking outcomes in those seeking treatment for alcohol dependence. PMID- 22244706 TI - Extended duration therapy with transdermal nicotine may attenuate weight gain following smoking cessation. AB - AIM: People who quit smoking often gain 11-12 lb, on average, which can frequently lead to a relapse to smoking. This study evaluated whether extended vs. standard duration treatment with nicotine patch helps those able to quit smoking to reduce cessation-induced weight gain and explored nicotine patch adherence as a mediator of treatment effects. DESIGN AND SETTING: We examined data from a completed randomized placebo-controlled clinical trial of extended (24 weeks) vs. standard (8 weeks plus 16 weeks of placebo) transdermal nicotine patch therapy. Changes in measured weight over 24 weeks were compared across the two treatment arms, controlling for gender, baseline smoking rate, and previous weight. Adherence to patch use was assessed using self-report of daily use over 24 weeks. PARTICIPANTS: 139 clinical trial participants who were confirmed to be abstinent at weeks 8 and 24. FINDINGS: Compared to participants who received 8 weeks of nicotine patch therapy, participants who received 24 weeks of treatment showed significantly less weight gain from pre-treatment to week 24 (beta=-4.76, 95% CI: -7.68 to -1.84, p=.002) and significantly less weight gain from week 8 to week 24 (beta=-2.31, 95% CI: -4.39 to -0.23, p=.03). Extended treatment increased patch adherence which, in turn, reduced weight gain; patch adherence accounted for 20% of the effect of treatment arm on weight gain. CONCLUSION: Compared to 8 weeks of transdermal nicotine therapy, 24 weeks of patch treatment may help to reduce the weight gain that is typical among smokers who are able to achieve abstinence from tobacco use. Extended treatment increased nicotine patch adherence which, in turn, reduced weight gain. PMID- 22244708 TI - Study of the risk factors associated with Neospora caninum seroprevalence in Algerian cattle populations. AB - Bovine abortions due to Neospora caninum infection were reported worldwide. The situation in Algeria was unknown. For the evaluation of the prevalence of N. caninum and its associated risk factors, 799 cattle belonging to 87 farms of the north and northeast of Algeria were analyzed. The cattle were divided into imported cattle, local cattle and improved cattle corresponding to breeding between imported and local cattle. Sera were examined for the presence of N. caninum antibodies by indirect fluorescence antibody test. The overall seroprevalence for the 87 farms was 52.87% (41.28-62.71%). The overall animal seroprevalence was 19.64% (16.82-22.45%). The seroprevalence of N. caninum in local cattle (34.28%) was significantly higher (p<0.05) than in modern (16.04%) and improved (18.64%) cattle. The risk factors analysis indicated that cattle population, geographical location, dog presence, season, global farm hygiene or the presence of abortion were significantly associated with seroprevalence. PMID- 22244707 TI - Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection. AB - Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p=0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p=0.0132) and a trend toward a significant reduction in INR levels from baseline (p=0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients. PMID- 22244709 TI - A comparative study of chronic kidney disease in dogs and cats: induction of cyclooxygenases. AB - The present study investigated whether renal cyclooxygenase (COX) induction is associated with the severity of chronic kidney disease (CKD) in dogs and cats. The collected kidneys were examined histopathologically and immunohistochemically. The immunoreactivities of COX-1 and COX-2 were evaluated quantitatively, and the correlations to the plasma creatinine concentrations, glomerular size, glomerulosclerosis, interstitial fibrosis, and interstitial cell infiltration were evaluated statistically. Immunoreactivities for COX-1 were heterogeneously observed in the medullary distal tubules and collecting ducts; no correlations with the severity of renal damage were detected. Immunoreactivities for COX-2 were heterogeneously observed in the macula densa (MD) regions. In dogs, the percentage of COX-2-positive MD was significantly correlated with the glomerular size. In cats, glomeruli with COX-2-positive MD had significantly higher sclerosis scores than those with COX-2-negative MD. In conclusion, renal COX-2 is induced in canine and feline CKD, especially in relation to the glomerular changes. PMID- 22244710 TI - Sample blank subtraction outreachs hemoglobin interferences in flurorometric methods for DBS. PMID- 22244711 TI - Antithrombotic management of stroke patients before colonoscopy. AB - BACKGROUND: Uncertainty exists regarding the management of antithrombotic medications in ischemic stroke and transient ischemic attack (TIA) patients around the time of colonoscopy. We sought to evaluate whether there was a difference in adverse events among patients who continued medications and those who had temporary discontinuation. METHODS: Using a hospital administrative database, electronic charts of patients with a diagnostic code for stroke or TIA and a procedural code for colonoscopy were reviewed. Information collected included baseline demographics, medical history, and antithrombotic medications. Outcome measures were stroke (ischemic and hemorrhagic), myocardial infarction, venous thromboembolism, and major systemic bleeding (i.e., requiring transfusion) up to 4 weeks after the procedure among patients who had medications continued versus temporarily discontinued. RESULTS: One hundred seventy-seven patients met inclusion criteria. Antithrombotic medication was temporarily discontinued in 42 patients and continued in 135 patients. Comparing patients who had medications held to those who had medications continued, stroke occurred in 1 (2.4%) versus 0 (0%; P = .237) patients; myocardial infarction in no patients in either group; venous thromboembolism in 0 (0%) versus 1 (0.7%; P > .99) patients; and major system bleeding in 2 (4.8%) versus 4 (3.0%; P = .628) patients. CONCLUSIONS: In this retrospective analysis, there was no significant difference in the occurrence of stroke, myocardial infarction, venous thromboembolism, and major bleeding between patients who had medications continued around the time of colonoscopy versus those who had temporary discontinuation. A prospective, randomized controlled study is warranted to further elucidate this issue. PMID- 22244712 TI - Correlation of elevated troponin and echocardiography in acute ischemic stroke. AB - BACKGROUND: Previous research has revealed a higher prevalence of elevated cardiac troponin T or I levels amongst patients admitted with stroke, which has been associated with increased cardiovascular events, higher mortality rates, and poor inpatient prognosis. Because cardiac comorbidities account for almost 20% of deaths after ischemic stroke, it is important to understand the relationship between troponin elevation, cardiac events, and acute ischemic stroke (AIS). METHODS: We evaluated 137 consecutive patients >= 18 years of age who presented within 48 hours of AIS onset. All patients had laboratory markers drawn on admission, including troponin and brain natriuretic peptide, along with transthoracic echocardiogram with Doppler. The mean age of our study population was 71.7 +/- 14.6 years. RESULTS: Twenty-four of 137 patients (17.5%) had a positive troponin level. Sixteen of 24 (67%) patients with a positive troponin level had a new wall motion abnormality on echocardiogram that was suggestive of unstable atherosclerotic disease. On statistical analysis, we found a significant association between troponin and brain natriuretic peptide elevation with positive segmental wall motion abnormality on echocardiogram. CONCLUSIONS: These study findings represent a new paradigm of interpreting elevated cardiac biomarkers and may help with risk stratification and diagnosis of patients presenting with AIS. PMID- 22244713 TI - Transoral carotid ultrasonography using a micro convex probe with B-flow imaging for extracranial internal carotid artery dissection. AB - We report on transoral carotid ultrasonography using a micro convex probe with B flow imaging for determining spontaneous extracranial internal carotid artery dissection just below the petrous portion. A 49-year-old man suffered cortical and subcortical infarction in the region of the right middle cerebral artery. Magnetic resonance angiography on the third day of admission revealed spontaneous recanalization of the right internal carotid artery associated with an intimal flap-like structure at the petrous portion. Transoral carotid ultrasonography using a micro convex probe revealed right extracranial internal carotid artery dissection, showing an increased diameter of the right extracranial internal carotid artery with double lumen formation, stenosis of the true lumen, and a mobile intimal flap in B-flow imaging. Transoral carotid ultrasonography using a micro convex probe was helpful to attempt a self-expanding stent for recanalizing right extracranial internal carotid artery dissection. The patient recovered and was discharged ambulatory. The size of the micro convex probe was optimum for transoral carotid ultrasonography in our patient. Micro convex probe is more commonly used than the standard transoral carotid ultrasonography probe, which lacks versatility. We consider that transoral carotid ultrasonography using a micro convex probe could be routinely used for ultrasonographic evaluation of extracranial internal carotid artery dissection. PMID- 22244715 TI - Low-normal systolic blood pressure and secondary stroke risk. AB - A recent observational study of >20,000 patients with recent ischemic stroke suggested that systolic blood pressure (SBP) maintained in a low-normal range may be associated with increased risk of recurrent stroke, especially within the first 6 months after the first stroke. Using a distinct cohort, the current study aimed to independently evaluate the relationship between low-normal SBP levels and risk of recurrent stroke through analysis of a trial dataset involving 3680 patients with recent noncardioembolic ischemic stroke aged >= 35 years recruited from 56 centers between September 1996 and May 2003 and followed for 2 years. Subjects were categorized based on their mean in-trial SBP value as low-normal (<120 mm Hg), high-normal (120 to <140 mm Hg), or high (>140 mm Hg). The primary outcome was stroke. Multivariate analyses used competing-risks Cox regression models. The rate of recurrent stroke was 9.1% in the low-normal group, 6.7% in the high-normal group, and 10% in the high group. The difference in recurrent stroke rate between the low-normal and high-normal groups was more prominent within the first 6 months (low-normal, 4.5%; high-normal, 2.5%; high, 3.4%) than after 6 months (low-normal, 4.6%; high-normal, 4.2%; high, 6.6%). Over the study period, compared with the high-normal group, the risk of the primary outcome trended higher in the low-normal group (adjusted hazard ratio, 1.47; 95% confidence interval, 0.94-2.29; P = .09) and was higher in the high group (adjusted hazard ratio, 1.39; 95% confidence interval, 1.08-1.79; P = .01). These results support the recently described pattern of increased risk of recurrent stroke in patients with low-normal SBP levels, especially within the first 6 months after first stroke. However, this study likely was not sufficiently powered to detect more than a strong statistical trend underlying this relationship. PMID- 22244714 TI - von Willebrand factor genetic variant associated with hematoma expansion after intracerebral hemorrhage. AB - BACKGROUND: Hematoma expansion, the leading cause of neurologic deterioration after intracerebral hemorrhage (ICH), remains one of the few modifiable risk factors for poor outcome. In the present study, we explored whether common genetic variants within the hemostasis pathway were related to hematoma expansion during the acute period after ICH. METHODS: Patients with spontaneous ICH who were admitted to the institutional Neuro-ICU between 2009 and 2011 were enrolled in the study, and clinical data were collected prospectively. Hematoma size was measured in patients admitted on or before postbleed day 2. Baseline models for hematoma growth were constructed using backwards stepwise logistic regression. Genotyping of single-nucleotide polymorphisms for 13 genes involved in hemostasis was performed, and the results were individually included in the above baseline models to test for independent association of hematoma expansion. RESULTS: During the study period, 82 patients were enrolled in the study and had complete data. The mean age was 65.9 +/- 14.9 years, and 38% were female. Only von Willebrand factor was associated with absolute and relative hematoma growth in univariate analysis (P < .001 and P = .007, respectively); von Willebrand factor genotype was independently predictive of relative hematoma growth but only approached significance for absolute hematoma growth (P = .002 and P = .097, respectively). CONCLUSIONS: Our genomic analysis of various hemostatic factors identified von Willebrand factor as a potential predictor of hematoma expansion in patients with ICH. The identification of von Willebrand factor single-nucleotide polymorphisms may allow us to better identify patients who are at risk for hematoma enlargement and will benefit the most from treatment. The relationship of von Willebrand factor with regard to hematoma enlargement in a larger population warrants further study. PMID- 22244717 TI - Recalled pain scores are not reliable after acute trauma. AB - INTRODUCTION: Pain research in emergency settings can be problematic, as data collection is logistically difficult and pain levels are often poorly documented. Short-term recall of acute pain has been evaluated in postoperative, labour and procedural pain, with variable reported accuracy. The reliability of pain recall in trauma resuscitation patients is unknown. This study aims to determine the accuracy of short-term pain recall 1-2 days after trauma. METHODS: Prospective, cohort study of trauma resuscitation patients transported by ambulance to a major trauma centre. Patients with haemodynamic instability (SBP<90, HR>120) or GCS<14 on arrival were excluded. Momentary pain scores were measured on an 11-point verbal numerical rating scale by paramedics during prehospital management. Patients were evaluated within 48 h of injury on the recall of their initial pain, pain during transport, and lowest pain score achieved by prehospital analgesia. Spearman's rank correlation and Bland-Altman tests were used to compare ambulance and hospital data. RESULTS: 88 trauma resuscitation patients (mean age 44 years +/- 18 SD, male 74%, mean ISS: 7 +/- 5 SD) were enrolled over a 5 month study period. Comparison of immediate and recalled pain scores produced Spearman's correlation coefficients of 0.71 for initial pain, 0.56 for pain during transport, and 0.45 for minimum pain scores. DISCUSSION: In our study patients did not accurately recall their pain levels 1-2 days after acute trauma. The results suggest that retrospective pain ratings are not reliable in trauma patients. PMID- 22244716 TI - Alterations in cardiovascular autonomic function tests in idiopathic hyperhidrosis. AB - We performed cardiovascular autonomic function tests to assess sympathetic and parasympathetic functions in patients with idiopathic hyperhidrosis. We studied 35 patients with idiopathic hyperhidrosis and 35 age- and sex-matched controls. A thermoregulatory sweat test (TST) was performed in all subjects. Sweating was qualitatively (Minor's test at 22 degrees C) and quantitatively (skin conductance) evaluated. Orthostatism, tilt to 65 degrees , cold pressor test, deep breathing, Valsalva maneuver and hyperventilation were performed in patients and controls. A greater fall in blood pressure values was observed in patients than in controls in the upright tests (p<0.05). In particular, postural hypotension was present in a subgroup of patients (34%), in whom changes in lying to-standing blood pressure and heart rate were greater (p<0.001) than those of the remaining patients. The TST revealed that the total body sweat rate (ml/cm(2)/min) was more pronounced in patients with postural hypotension (p<0.001) than in the other patients and controls. The skin conductance values of patients with postural hypotension were higher (p<0.001) than those of the remaining patients. A positive correlation was found between skin conductance values and postural hypotension. Dehydration and poor water intake may play a role in postural hypotension in patients with severe hyperhidrosis and pronounced thermoregulatory sweating. A significantly marked increase in parasympathetic function was observed in patients. Responses to deep breathing, Valsalva maneuver and hyperventilation were significantly greater in patients (p<0.001) than in controls. Idiopathic hyperhidrosis seems to be a complex dysfunction that involves autonomic pathways other than those related to sweating. PMID- 22244718 TI - The impact of snow on orthopaedic trauma referrals. AB - Adverse weather has been shown to increase orthopaedic referrals and place strain on services. This retrospective study undertaken at a teaching hospital concerned referrals between April 2009 and April 2010 comparing days when snow fell to days when it did not. Referrals increased significantly on snow days (to 74.9 per day) in comparison to normal weather days (33.5 per day). During snow days there were significant increases in the number of distal radius and ankle fractures referred but not of fractured necks of femur. Complications during the snow fall period were related to procedures performed outside of the trauma unit with further difficulties related to a lack of operating equipment and implant availability. As a result of our study, we recommend that during periods of heavy snow fall orthopaedic and trauma units should place senior orthopaedic trainees in Accident and Emergency to review patients as a triage service, organise trauma lists related to surgeon specific expertise and avoid sending trauma patients outside the unit for operation. PMID- 22244719 TI - Special issue part II: Illegalization and embodied vulnerability in health. PMID- 22244720 TI - Griseofulvin-induced photo-onycholysis. PMID- 22244721 TI - [Kidney allograft: a target for systemic disease]. AB - Recurrence of disease after transplantation is frequent and represents the third cause of allograft loss. Recurrence of lupus nephritis after transplantation is rare. Kidney transplantation in patients with antiphospholipid syndrome or lupus anticoagulant is challenging due to the high risk of immediate post-transplant thrombosis and bleeding risk associated to the subsequent anticoagulation. Moreover, vascular changes associated to the presence of antiphospholipid antibodies negatively impact allograft rate survival. Recurrence of pauci immune glomerulonephritis or Goodpasture syndrome is exceptional. PMID- 22244722 TI - Advantages and limits of ADAMTS13 testing in the prognostic assessment of thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare but severe disease characterized by mechanical hemolytic anemia and consumptive thrombocytopenia leading to disseminated microvascular thrombosis that causes signs and symptoms of organ ischemia and functional damage. After the elucidation of the pathophysiology of TTP, thanks to the demonstration of the congenital or acquired (autoimmune) plasma deficiency of the von Willebrand factor cleaving metalloprotease A Disintegrin And Metalloprotease with ThromboSpondin 1 repeats (ADAMTS13), a number of laboratory assays for measuring ADAMTS13 and related autoantibodies have been developed. Current knowledge on the diagnostic and prognostic value of ADAMTS13 and anti-ADAMTS13 assays is summarized in this review. PMID- 22244723 TI - [The analysis of a mobile mental health outreach team activity: from psychiatric emergencies on the street to practice of hospitalization at home for homeless people]. AB - CONTEXT AND OBJECTIVE: Since their creation in 2005 in France, mobile mental health outreach teams (EMPP) have been working to improve the health of the homeless who, for 30 to 50% of them, present severe mental disorders. Their missions are defined by ministerial circular's specifications. Few studies have been undertaken in France to analyze the practices of these teams' professionals, nor the characteristics of the populations with whom they are involved. The EMPP described in this paper had in 2010 a greater staff than other French EMPPs. It has 15 full-time staff, including four doctors (two psychiatrists, one GP, one house physician), two nurses, two educators, one social worker, three peer workers, one secretary and two coordinators. The article analyzes the way of support developed within the range of EMPP's missions defined by the ministerial circular. METHODS: Descriptive statistical analysis was carried out using standardized data from four different sources (round sheet, record of activity, record of hospitalization, housing information, interviews conducted by medical and social professionals with patients). Another source of data consists of records describing the operation of the team (reference framework) and annual activities (annual report). RESULTS: The method of care was developed based on a street working, involving a full medical and its relationship with the hospital and a place to live in a semi-community context. The Mobile Mental Health Outreach team documented 318 rounds in 2010, describing 666 contacts among whom 87.9% were followed regularly thereafter. It focuses to a target population. The team actively followed 198 people including 161 for whom a psychiatric diagnosis was done: 48.5% of the patients followed presented schizophrenic-type disorders, 21.8% bipolar disorders and other mood-linked problems, 13% behavioral disorders and 6.2% substance-use disorders. A percentage of 44.9 presented with a physical disease. Among the 89 hospitalizations, 86.5% were motivated by psychiatric disorders and 43% were forced. In about one third of the cases, hospitalizations were motivated by a double indication - psychiatric and physical - and in 13.5% for only a physical indication. Thirty people of the actively followed people had stayed in a halfway house as an alternative to hospitalization, restoring a continuity of care and allowing to resolve social problems that had until then been hopeless. PERSPECTIVES: The strategies developed by this Mobile Health Outreach Team ensure local community medical, psychiatric and social care for "hard to reach" people. The results confirm the interest of the link between the street work, the hospital and the halfway home, both as a living facility and an alternative to hospitalization. They suggest the importance of a critical minimum size for these EMPP that allows them a street work with doctors providing guidance. The presence of a GP is another welcome development because of the severity and the entanglement of somatic and psychiatric problems of these populations. PMID- 22244724 TI - [Kidney diseases: new issues]. AB - Chronic kidney disease (CKD) affects two to four million people in France and most of them are not aware of their disease. CKD is a major, independent risk factor of cardiovascular mortality and morbidity; the cardiovascular risk increases with the severity of renal failure. Evaluation of renal function (GFR) relies on MDRD and CKD-EPI equations. The French CKD-REIN cohort with more than 3000 patients followed for 5 years, will hopefully provide substantial advances in the knowledge of CKD epidemiology, of risk factors and mechanisms of CKD progression and medical practices. Improving CKD screening based on blood pressure, proteinuria (microalbuminuria in diabetic patients) and serum creatinine, is a national duty in high risk patients (with diabetes, hypertension and cardiovascular diseases). A major research goal is to identify new therapeutic targets and biomarkers, in order to treat kidney diseases before the occurrence of renal insufficiency, to halt their progression and to decrease cardiovascular risk. Careful therapeutic education of patients is required to successfully implement established guidelines, appropriate diets and new therapeutic strategies. PMID- 22244726 TI - [Vascular nephropathies: a fresh look at a systemic disease]. AB - Hypertensive nephropathy represents the most prevalent cause of end-stage renal disease in France. Renal lesions are unspecific. Nephroangiosclerosis diagnosis is overestimated due to non standardized clinical criteria and available histological analysis. Other factors than hypertension contribute to vascular lesions.MYH9 and APOL1 polymorphisms are strongly associated with kidney diseases including hypertensive nephropathy. Elevated blood pressure levels are associated with CKD progression. Treatment includes angiotensin blockers which have a synergic effect on blood pressure reduction and lowering urinary protein excretion with sodium restriction and diuretics. PMID- 22244725 TI - [Renal disorders associated with monoclonal gammopathies: diagnostic and therapeutic progress]. AB - Various renal disorders are associated with monoclonal gammopathies, secondary to tissue deposition or precipitation of a monoclonal immunoglobulin (Ig) or a fragment thereof (isolated Ig light chain or heavy chain). They are classified according to the localization of renal lesions, either glomerular or tubular and to the pattern of ultrastructural organization of Ig deposits. Renal disease in monoclonal gammopathies may be isolated, or associated with various systemic symptoms particularly in AL amyloidosis, Randall-type monoclonal Ig deposition disease and monoclonal cryoglobulinemias. Except for myeloma cast nephropathy, which occurs in the setting of high-mass myeloma and is recognized after electrophoretic analysis of proteinuria and AL amyloidosis, which diagnosis is usually made after pathological examination of non-invasive tissue specimens (i.e. abdominal fat or minor salivary glands), a kidney biopsy is required to identify the other types of renal disorders associated with monoclonal gammopathies and to estimate renal prognosis. Renal pathological diagnosis is difficult and relies on careful examination of kidney biopsy samples, by light microscopy, immunofluorescence studies using conjugates specific for Ig light and heavy chains, IgG sub-classes and heavy chain constant domains and by electron microscopy. In some cases, additional studies are required to identify the nature of deposits, such as immuno-electron microscopy or mass spectrometric-based proteomic analysis after laser dissection. In patients with renal disorders related to Ig light chain precipitation or deposition (myeloma cast nephropathy, AL amyloidosis, Randall-type light chain deposition disease), measurement of serum free light chains at baseline and throughout follow-up is mandatory to evaluate clonal response to chemotherapy. A more than or equal to 50% decrease in serum free light chain levels is associated with increased renal and patient survival. In AL amyloidosis, serum levels of markers of cardiac disease (NT proBNP and troponin) are also closely associated with prognosis. Efficient chemotherapy, tailored to the underlying plasma cell or lymphoproliferative disorder and adapted to renal function, should be promptly introduced, even in the absence of overt malignant haematological disease. Renal prognosis and patient survival (particularly in AL amyloidosis and cast nephropathy) are closely associated with the rapid achievement of an haematological response. The combination of melphalan plus dexamethasone (MDex) is currently used as first line chemotherapy in systemic AL amyloidosis. Bortezomib-based regimens are commonly employed as first-line treatment in myeloma cast nephropathy and Randall type monoclonal Ig deposition disease and as second line therapy in AL amyloidosis patients with advanced cardiomyopathy or refractory to previous chemotherapy. Solid organ transplantation (heart and kidney) should be considered in patients with AL amyloidosis or Randall-type monoclonal Ig deposition disease and advanced cardiac or renal failure. Prolonged graft and patient survival may be obtained, providing that recipients do not have other severe organ involvement or symptomatic myeloma and that haematological remission has been achieved with chemotherapy before or after organ transplantation. PMID- 22244727 TI - [Prevalence of Helicobacter pylori infection in anemia by vitamin B12 deficiency in Marrakech (Morocco)]. PMID- 22244728 TI - Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer. AB - Thrombotic microangiopathy (TMA) has multiple etiologies. In the four disorders described in this review, the primary organ involved is the kidney. Drug associated TMA can be an acute, immune-mediated disorder or the result of gradual, dose-dependent toxicity. TMA may occur in patients with advanced HIV infection, possibly mediated by angio-invasive infections. TMA following allogeneic hematopoietic stem cell transplantation may also be caused by drug toxicity; the pathogenesis may involve inhibition of vascular endothelial cell growth factor in renal podocytes. Malignancies of many types with systemic microvascular involvement may cause TMA. Recognition that these syndromes may mimic TTP is important to provide appropriate management and to avoid the inappropriate use of plasma exchange treatment. PMID- 22244729 TI - [Results of the 2011 national ranking in France]. PMID- 22244730 TI - Identification of Genistein and Biochanin A by THz (far-infrared) vibrational spectra. AB - The temperature dependent vibrational spectra of Genistein and Biochanin A, major components in Mongolian medicines Agi, in the range of 0.5-4.5 THz (16.7-150 cm( 1)) are presented for the first time. Over the temperature range from 295 to 77K, 12 highly resolved spectral features for the Genistein and 13 features for Biochanin A were measured by THz-TDS and display strong linewidth narrowing and frequency blue-shift with cooling. Such narrow-line THz fingerprint spectra provide a rapid, nondestructive and reliable method for the identification of these Chinese traditional medicines. PMID- 22244731 TI - Flow injection photometric determination of NaCl, KCl and glucose in injectable drugs exploiting Schlieren signals. AB - A flow injection photometric system that exploits Schlieren signals for analytical measurement is described. The system was designed to be used as a new strategy for determining the contents of sodium chloride, potassium chloride and glucose, each respectively in injectable drugs. The proposed methodology was based on the difference between the refractive indices of the sample zone and of the carrier stream. With this perspective, a lab-made photometer based on LED phototransistor technology was employed as a detection system to investigate the different analytical profiles related to the Schlieren effect in low flow rate conditions. The parameters of the flow system, such as flow-rate, optical path length, and sampling loop, were adjusted in order to obtain suitable Schlieren profiles for the measurements. Data evaluation was performed with the application of partial least squares regression (PLS-1). The obtained results demonstrated the predictive ability of the constructed PLS models, and the predicted concentration values were in agreement with the reference values, with a 95% confidence level. PMID- 22244732 TI - A clinical evaluation of all-ceramic bridges placed in patients attending UK general dental practices: three-year results. AB - OBJECTIVES: To report the results at year three of an evaluation of fixed-fixed all-ceramic bridges, constructed in a yttria oxide stabilized tetragonal zirconium oxide polycrystal (Y-TZP) substructure, placed in adult patients in UK general dental practices and luted using a self-adhesive resin-based cement. METHODS: Ethical approval was obtained. Four UK general dental practitioners were asked to recruit patients in accordance with the trial protocol. After obtaining informed written consent, appropriate vitality and radiographic assessments were completed and the pre-operative status of the gingival tissues noted. The teeth were prepared and bridges constructed in accordance with the manufacturer's instructions. Each bridge was reviewed annually within 3 months of the anniversary of its placement by a calibrated examiner, together with the clinician who had placed the restoration. The examiners evaluated the integrity of the restoration, its anatomic form, marginal adaptation, surface quality, sensitivity, the condition of the adjacent gingivae, and the presence or absence of secondary caries. RESULTS: A total of 34 bridges were examined at the three year review. All Y-TZP frameworks were intact and no bridge retainers had debonded. Two veneering ceramic chips, in total, were detected over the three year period of observation: the patients in whom this had occurred were unconcerned. A further abutment tooth had been successfully endodontically treated, through an occlusal access cavity, in addition to the two already reported at year one. SIGNIFICANCE: At year three, the 34 Lava Y-TZP fixed-fixed bridges, placed in patients attending UK general dental practices, were found to be performing satisfactorily. PMID- 22244733 TI - [Percutaneous mandibular nerve block using neuro-stimulation guiding through the sigmoid indentation in facial surgery]. AB - INTRODUCTION: Mandibular nerve block is a simple and effective but rarely used technique. It decreases peri-operative pain in mandibular osteotomy. It improves surgical field visibility by decreasing bleeding. Mandibular nerve block allows cutaneous surgery without general anesthesia and is one of the alternative treatments for chronic facial pain. TECHNICAL NOTE: The mandibular nerve is located using a needle connected to a neurostimulator. After local disinfection, a neurostimulation needle is inserted below the zygomatic arch, between the coronoid apophysis in front, and the condyle process in back, with a 45 to 60 degrees angle. The needle is pushed to a 40 mm depth. Masticator muscle contraction confirms mandibular nerve stimulation. After a careful negative aspiration, 5 mL of ropivacaine 0.5% are injected slowly, and in increments. DISCUSSION: The complications with this technique, such as failure or arterial puncture, are rare and limited if a nerve stimulator is used. Patient's comfort is improved by intravenous remifentanil sedation in target control infusion mode, associated to prior use of prilocaine and lidocaine cutaneous cream. PMID- 22244734 TI - A coordination polymer nanobelt (CPNB)-based aptasensor for sulfadimethoxine. AB - A polymer-based aptasensor, which consisted of fluorescein amidite (FAM)-modified aptamers and coordination polymer nanobelts (CPNBs), was developed utilizing the fluorescence quenching effect to detect sulfadimethoxine residue in food products. A single-stranded DNA (ssDNA) aptamer, which was a specific bio-probe for sulfadimethoxine (Su13; 5'-GAGGGCAACGAGTGTTTATAGA-3'), was discovered by a magnetic bead-based systematic evolution of ligands by exponential enrichment (SELEX) technique, and the fluorescent quenchers CPNBs were produced by mixing AgNO(3) and 4,4'-bipyridine. This aptasensor easily and sensitively detected sulfadimethoxine in solution with a limit of detection (LOD) of 10ng/mL. Furthermore, the antibiotic dissolved in milk was also effectively detected with the same LOD value. In addition, this aptamer probe offered high specificity for sulfadimethoxine compared to other antibiotics. These valuable results provide ample evidence that the CPNB-based aptasensor can be used to quantify sulfadimethoxine residue in food products. PMID- 22244735 TI - Stability of reference proteins in human placenta: general protein stains are the benchmark. AB - The stability of reference proteins in semi-quantitative Western blot experiments in normal and diseased placenta has never been studied. This study aims to determine the stability of five reference proteins and two general protein stains in placentas from preeclampsia, gestational diabetes mellitus and matched control pregnancies. The stability of the reference proteins was analysed using indicators of inter-group (P value) and intra-group (coefficient of variation) stability. The effect of different normalization strategies was determined by normalizing serotonin transporter (SERT) expression against the different reference protein markers. Results show significant expression variability of beta-actin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), hypoxanthine phosphoribosyltransferase 1 (HPRT1), peptidylprolyl isomerase A (PPIA) and alpha tubulin, and that amido black staining is the most stable reference protein marker. Furthermore, results show that SERT expression significantly differs according to the reference protein markers used for its normalization. The present study demonstrated the importance of using stable reference protein markers and normalization strategy in order to get correct results in semi quantitative Western blot experiments in placental tissues. PMID- 22244736 TI - Higher levels of soluble Fas ligand and transforming growth factor-beta after omalizumab treatment: a case report. AB - A skewed T-helper (T(h))1/T(h)2 immune response is considered to be the major cause of allergic disorders. Overproduction of T(h)2 cytokines, which promote recruitment and activation of mast cells and eosinophils, plays a key part in the pathogenesis of allergic asthma. The mechanisms by which omalizumab is effective in asthma treatment are not yet fully understood. A 16-year-old girl who was experiencing frequent asthma attacks in spite of daily administration of budesonide (640 MUg) and montelukast (10mg) was given omalizumab (375 mg) at intervals of 2 weeks, to prevent a visit to the emergency room. Plasma levels of T(h)1 cytokines [interferon (IFN)-gamma and interleukin (IL)-12p70], T(h)2 cytokines (IL-4 and IL-13), other proinflammatory and regulatory cytokines [IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta], chemokines [monocyte chemotactic protein (MCP)-1, chemokine ligand (CCL)7, and CCL17], and soluble Fas ligand (sFasL) were measured before treatment and after treatment for 8 weeks. She showed a good clinical response to omalizumab: her lung function parameters improved and the use of beta2-agonist decreased. No emergency room visits were required after omalizumab treatment for 8 weeks. Plasma levels of sFasL and TGF-beta showed obvious increases after omalizumab therapy. IL-12p70 levels were decreased as compared to the corresponding baseline levels. These findings suggest that the effects of omalizumab in asthma treatment are not restricted to the regulation of the skewed T(h)1/T(h)2 cytokine immune response, and sFasL-mediated apoptosis and regulatory T-cell (Treg)-mediated TGF-beta seem to have important roles in the therapeutic effects of omalizumab. PMID- 22244737 TI - Self-injury in people with intellectual disability and epilepsy: a matched controlled study. AB - We aimed to identify the presence of self-injurious behavior in a sample of 158 people with intellectual disability and epilepsy as compared with a control sample consisting of 195 people with intellectual disability without epilepsy. The Italian Scale for the Assessment of self-injurious behaviors was used to describe self-injurious behavior in both groups. The groups were matched for ID degree: mild/moderate (20 and 20 respectively), severe/profound (45 in both samples) and unknown (4 in both samples). Seventy-four percent of the first sample were diagnosed with symptomatic partial epilepsy. The prevalence of self injurious behaviors was 44% in the group with intellectual disability and epilepsy and 46.5% in the group with intellectual disability without epilepsy (difference not significant). The areas most affected by self-injurious behaviors in both samples were the hands, the mouth and the head. The most frequent types of self-injurious behaviors were self-biting, self-hitting with hands and with objects. Self-injurious behavior is frequently observed in individuals with epilepsy and intellectual disability. Our study does not suggest that the presence of epilepsy is a risk factor for self-injurious behavior in this patient group. PMID- 22244739 TI - [Oral appliances or maxillomandibular advancement osteotomy for severe obstructive sleep apnoea in patients refusing CPAP]. AB - OBJECTIVES: The management of patients with severe obstructive sleep apnea syndrome (OSAS) refusing or not tolerating continuous positive pressure ventilation (CPAP) remains problematic. We evaluated the effectiveness of oral appliances and of maxillomandibular advancement osteotomy. METHODS: One hundred and two patients with severe OSAS were included between 2001 and 2006. Maxillo mandibular advancement osteotomy was proposed to patients less than 60 years of age, non obese and without comorbidities. The other patients were treated with oral appliances. All patients underwent polysomnography at 3 months. RESULTS: Group A: 25 patients with mean apnea-hypopnea index (AHI) at 45/h were treated by maxillo-mandibular advancement. Three months after the surgery, AHI had decreased from 45 to 7. The success rate was 89% when AHI was less than 15/h and 74% when AHI was less than 10/h. Sixteen patients performed a polysomnography one year after surgery with similar results. There were no major postoperative complications. Group B: 77 patients with a mean AHI at 41/h were treated with oral appliances. Only 23 patients underwent polysomnography at 3 months. The mean AHI had decreased from 41/h to 22/h. The success rate was 56% when AHI was less than 15/h and 30% when AHI was less than 10/h. DISCUSSION: We are confronted with an increasing number of severe OSAS patients with CPAP failure or intolerance. Surgery for maxillo-mandibular advancement is an effective alternative. However, it is not always indicated or accepted by the patient. So an oral appliance remains a useful therapeutic option despite its moderate success rate. PMID- 22244738 TI - Alterations in in vivo knee joint kinematics following a femoral nerve branch block of the vastus medialis: Implications for patellofemoral pain syndrome. AB - BACKGROUND: A potential source of patellofemoral pain, one of the most common problems of the knee, is believed to be altered patellofemoral kinematics due to a force imbalance around the knee. Although no definitive etiology for this imbalance has been found, a weak vastus medialis is considered a primary factor. Therefore, this study's purpose was to determine how the loss of vastus medialis obliquus force alters three-dimensional in vivo knee joint kinematics during a volitional extension task. METHODS: Eighteen asymptomatic female subjects with no history of knee pain or pathology participated in this IRB approved study. Patellofemoral and tibiofemoral kinematics were derived from velocity data acquired using dynamic cine-phase contrast MRI. The same kinematics were then acquired immediately after administering a motor branch block to the vastus medialis obliquus using 3-5ml of 1% lidocaine. A repeated measures analysis of variance was used to test the null hypothesis that the post- and pre-injection kinematics were no different. FINDINGS: The null hypothesis was rejected for patellofemoral lateral shift (P=0.003, max change=1.8mm, standard deviation=1.7mm), tibiofemoral lateral shift (P<0.001, max change=2.1mm, standard deviation=2.9mm), and tibiofemoral external rotation (P<0.001, max change=3.7 degrees , standard deviation=4.4 degrees ). INTERPRETATION: The loss of vastus medialis obliquus function produced kinematic changes that mirrored the axial plane kinematics seen in individuals with patellofemoral pain, but could not account for the full extent of these changes. Thus, vastus medialis weakness is likely a major factor in, but not the sole source of, altered patellofemoral kinematics in such individuals. PMID- 22244741 TI - Neural specializations for small target detection in insects. AB - Despite being equipped with low-resolution eyes and tiny brains, many insects show exquisite abilities to detect and pursue targets even in highly textured surrounds. Target tracking behavior is subserved by neurons that are sharply tuned to the motion of small high-contrast targets. These neurons respond robustly to target motion, even against self-generated optic flow. A recent model, supported by neurophysiology, generates target selectivity by being sharply tuned to the unique spatiotemporal profile associated with target motion. Target neurons are likely connected in a complex network where some provide more direct output to behavior, whereas others serve an inter-regulatory role. These interactions may regulate attention and aid in the robust detection of targets in clutter observed in behavior. PMID- 22244740 TI - The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine induced changes in striatal dopamine but not self-administration in squirrel monkeys. AB - Extrasynaptic glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway, which plays an important role in the behavioral pharmacology of psychostimulants. Basal levels of glutamate are primarily regulated by the cystine-glutamate transporter and provide glutamatergic tone on extrasynaptic glutamate receptors. The present study examined the effects of a cystine-glutamate transporter enhancer on the neurochemical and behavioral effects of cocaine and amphetamine in nonhuman primates. It was hypothesized that augmenting extrasynaptic glutamate release with N-acetyl-L-cysteine (NAC), a cystine prodrug, would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant and reinforcing effects. In vivo microdialysis was used to evaluate cocaine-induced changes in extracellular dopamine (DA) in the caudate nucleus (n=3). NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine (n=4). Separate groups of subjects were either trained on a fixed-interval schedule of stimulus termination (n=6) or on a second-order schedule of self-administration (n=5) to characterize the behavioral-stimulant and reinforcing effects of psychostimulants, respectively. Systemic administration of NAC did not alter the behavioral-stimulant effects of either cocaine or amphetamine. Furthermore, cocaine self-administration and reinstatement of previously extinguished cocaine self-administration were not altered by pretreatment with NAC. Hence, drug interactions on caudate neurochemistry in vivo were not reflected in behavioral measures in squirrel monkeys. The present results in nonhuman primates do not support the use of NAC as a pharmacotherapy for cocaine abuse, although rodent and clinical studies suggest otherwise. PMID- 22244742 TI - Global navigation in migratory birds: tracks, strategies, and interactions between mechanisms. AB - The advancing development of tracking techniques has led to fascinating new insights into avian migration, documenting the immense diversity, complexity, and flexibility of this phenomenon. Tracking studies so far have confirmed many findings from ringing recoveries and cage studies, for example, the change from flying innate compass courses in the first migration to true navigation, as experienced migrants head toward familiar goals. First attempts to analyze the navigational mechanisms by tracking manipulated migrants indicate strong parallels to those of homing pigeons. Findings suggesting that the magnetic compass of migrants is regularly calibrated by the pattern of polarized light could not be replicated with a number of other birds, pointing out differences between species and possibly region and phases of migration. Tracking has become a valuable tool, complimenting traditional methods by documenting migration behavior in the wild; whether it can be used to further unveil the navigational mechanisms of migrants and the factor used remains an open question. PMID- 22244743 TI - Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. AB - PURPOSE: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Chemonaive patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed >=3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p=0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p=0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p=0.9526). No new safety signals were detected. CONCLUSION: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338). PMID- 22244745 TI - Associations of variants of CNR1 with obesity and obesity-related traits in Chinese women. AB - The aim of this study was to investigate associations of two candidate gene SNPs of the endocannabinoid receptor type 1 gene (CNR1) with overweight, obesity and obesity-related traits in Chinese retired women. The study subjects were a subsample of the Taizhou Retiree Women Cohort, consisting of 2812 retired women aged 50-64 years recruited from Taizhou, Jiangsu, China. Neither rs2023239 nor rs806381 polymorphism was significantly associated with body mass index-defined overweight and obesity or waist-to-hip-ratio-defined obesity. For obesity-related traits, rs2023239 was significantly associated with glutamate pyruvate transaminase (GPT) (median, 18.00 vs 17.00 for TT and TC genotypes, respectively, P=0.043). The rs806381 also showed significant association with triglyceride (TG) (mean+/-SD, 1.46+/-0.20 vs 1.53+/-0.20 for GA and GG+AA genotypes, respectively, P=0.013) under the dominant genetic model. In conclusion, the rs2023239 and rs806381 polymorphisms of CNR1 were not associated with increased overweight and obesity risk. But the rs2023239 polymorphism was significantly associated with GPT, and the rs806381 polymorphism was significantly associated with TG. PMID- 22244744 TI - Putative function of TAP63alpha during endochondral bone formation. AB - P63, a member of the P53 tumor suppressor family, is known to play important functions in cancer and development. Interestingly, previous studies have shown that p63 null mice are absent or have truncated limbs, while mutations in human P63 cause several skeletal syndromes that also show limb and digit abnormalities, suggesting its essential role in long bone development. Indeed, we detected increased level of p63 transcript in hypertrophic MCT cells (an established cell model of chondrocyte maturation) than in proliferative MCT cells. To investigate the in vivo role of P63 upon endochondral bone formation, we have established transgenic mouse lines in which HA- and Flag-tagged TAP63alpha (the longest P63 isoform) is driven by the hypertrophic chondrocyte-specific Col10a1 regulatory elements. Skeletal staining of Col10a1-TAP63alpha transgenic mice at either embryonic day 17.5 (E17.5) or postnatal day 1 (P1) observed accelerated ossification in long bone, digit and tail bones compared to their wild-type littermates, suggesting a putative function of P63 during skeletal development. We also detected decreased level of Sox9 and Bcl-2 transcripts, while Alp and Ank are slightly upregulated in Col10a1-TAP63alpha transgenic mouse limbs. Further immunohistochemical analysis confirmed the decreased Sox9 expression in the proliferative and hypertrophic zone of these mice. Von Kossa staining suggests increased mineralization in hypertrophic zone of transgenic mice compared to littermate controls. Together, our results suggest a role of TAP63alpha upon skeletal development. TAP63a may promote endochondral ossification through interaction with genes relevant to matrix mineralization and chondrocyte maturation or apoptosis. PMID- 22244746 TI - Integrated analysis of mRNA and microRNA expression in mature neurons, neural progenitor cells and neuroblastoma cells. AB - Mature neurons (MNs), neural progenitor cells (NPCs) and neuroblastoma cells (NBCs) are all neural-derived cells. However, MNs are unable to divide once differentiated; NPCs are able to divide a limited number of times and differentiate to normal brain cell types; whereas NBCs can divide an unlimited number of times but rarely differentiate. Here, we perform whole transcriptome (mRNA, miRNA) profiling of these cell types and compare expression levels of each cell type to the others. Integrated mRNA-miRNA functional analyses reveal that: 1) several very highly expressed genes (e.g., Robo1, Nrp1, Epha3, Unc5c, Dcc, Pak3, Limk4) and a few under-expressed miRNAs (e.g., miR-152, miR-146b, miR-339 5p) in MNs are associated with one important cellular process-axon guidance; 2) some very highly expressed mitogenic pathway genes (e.g., Map2k1, Igf1r, Rara, Runx1) and under-expressed miRNAs (e.g., miR-370, miR-9, miR-672) in NBCs are associated with cancer pathways. These results provide a library of negative mRNAmiRNA networks that are likely involved in the cellular processes of differentiation and division. PMID- 22244747 TI - Corticosterone reduces brain mitochondrial function and expression of mitofusin, BDNF in depression-like rodents regardless of exercise preconditioning. AB - Both chronic mild stress and an injection of corticosterone induce depression like states in rodents. To further link mitochondrial dysfunction to the pathophysiology of major depression, here we describe two rat models of a depressive-like state induced by chronic unpredictable mild stress (CUMS) or corticosterone treatment (CORT). It is also a model that allows the simultaneous study of effects of exercise preconditioning on behavioral, electrophysiological, biochemical and molecular markers in the same animal. Exercise preconditioning ahead of CUMS and CORT treatment prevents many behavioral abnormalities resulted from CUMS. The changes in mitochondrial activity in brain and reduced expressions of superoxide dismutase (SOD1, SOD2), mitofusin (Mfn1, Mfn2) as well as brain derived neurotrophic factor (BDNF) suggest that both CORT and CUMS may impair mitochondrial function and/or expressions of mitofusion and antioxidant enzymes that, in turn, may increase oxidative stress and reduce energy production in brain with depression-like behaviors. These findings suggest an underlying mechanism by which CORT, as well as CUMS, induces brain mitochondrial dysfunction that is associated with depressive-like states. Remarkably, physical exercise is identified as a helpful and preventive measure to promote mitochondrial function and expressions of mitofusin, BDNF and antioxidant enzymes in brain, so as to protect brain energy metabolism against CUMS, rather than the compound of corticosterone. PMID- 22244750 TI - The rise of oxygen and aerobic biochemistry. AB - Analysis of conserved protein folding domains across extant genomes by Kim et al. in this issue of Structure provides insights into the timing of some of the earliest aerobic metabolisms to arise on Earth. PMID- 22244749 TI - Verapamil does not modify catalytic activity of CYP450 in rainbow trout after long-term exposure. AB - Little is known about the effects of the cardiovascular drug verapamil (VRP) on metabolic processes in fish. Most calcium channel blockers including VRP are metabolized by cytochrome P450 (CYP450) enzymes. In this study we investigated the in vivo effect of VRP on some CYP450-mediated reactions in juvenile rainbow trout (Oncorhynchus mykiss). Fish were exposed to sublethal concentrations of VRP (0.5, 27 and 270 MUg l(-1)) for 0, 21, and 42 day. The following CYP450-mediated reactions were studied in hepatic microsomes: O-dealkylation of ethoxyresorufin, methoxyresorufin, and pentoxyresorufin, hydroxylation of coumarin, tolbutamide, and p-nitrophenol, and O-debenzylation of 7-benzyloxy-4-trifluoromethylcoumarin. The amounts of products of these reactions did not differ among fish exposed to different levels of VRP and control fish. This suggests that the levels of VPR used did not alter catalytic activity of the selected CYP450 enzymes. In conclusion, none of the investigated CYP450-mediated reactions has potential as a biomarker to monitor VRP contamination of the aquatic environment. PMID- 22244748 TI - Social subordination produces distinct stress-related phenotypes in female rhesus monkeys. AB - Social subordination in female macaques is imposed by harassment and the threat of aggression and produces reduced control over one's social and physical environment and a dysregulation of the limbic-hypothalamic-pituitary-adrenal axis resembling that observed in people suffering from psychopathologies. These effects support the contention that this particular animal model is an ethologically relevant paradigm in which to investigate the etiology of stress induced psychological illness related to women. Here, we sought to expand this model by performing a discriminate analysis (DA) on 33 variables within three domains; behavioral, metabolic/anthropomorphic, and neuroendocrine, collected from socially housed female rhesus monkeys in order to assess whether exposure to social subordination produces a distinct phenotype. A receiver operating characteristic (ROC) curve was also calculated to determine each domain's classification accuracy. DA found significant markers within each domain that differentiated dominant and subordinate females. Subordinate females received more aggression, showed more submissive behavior, and received less of affiliation from others than did dominant females. Metabolic differences included increased leptin, and reduced adiponectin in dominant compared to subordinate females. Dominant females exhibited increased sensitivity to hormonal stimulation with higher serum LH in response to estradiol, cortisol in response to ACTH, and increased glucocorticoid negative feedback. Serum oxytocin, CSF DOPAC and serum PACAP were all significantly higher in dominant females. ROC curve analysis accurately predicted social status in all three domains. Results suggest that socially house rhesus monkeys represent a cogent animal model in which to study the physiology and behavioral consequences of chronic psychosocial stress in humans. PMID- 22244751 TI - Couple dynamics: PPARgamma and its ligand partners. AB - Ligand-regulated transcriptional activity is the most important property of nuclear receptors, including PPARgamma. In this issue of Structure, Hughes et al. determined how the dynamic conformations of ligands and the receptor contribute to the degree of ligand-dependent activation of PPARgamma, which provide further insights into design of PPARgamma-based anti-diabetic drugs. PMID- 22244752 TI - Computational design of membrane proteins. AB - Membrane proteins are involved in a wide variety of cellular processes, and are typically part of the first interaction a cell has with extracellular molecules. As a result, these proteins comprise a majority of known drug targets. Membrane proteins are among the most difficult proteins to obtain and characterize, and a structure-based understanding of their properties can be difficult to elucidate. Notwithstanding, the design of membrane proteins can provide stringent tests of our understanding of these crucial biological systems, as well as introduce novel or targeted functionalities. Computational design methods have been particularly helpful in addressing these issues, and this review discusses recent studies that tailor membrane proteins to display specific structures or functions and examines how redesigned membrane proteins are being used to facilitate structural and functional studies. PMID- 22244753 TI - Telomerase and telomere-associated proteins: structural insights into mechanism and evolution. AB - Recent advances in our structural understanding of telomerase and telomere associated proteins have contributed significantly to elucidating the molecular mechanisms of telomere maintenance. The structures of telomerase TERT domains have provided valuable insights into how experimentally identified conserved motifs contribute to the telomerase reverse transcriptase reaction. Additionally, structures of telomere-associated proteins in a variety of organisms have revealed that, across evolution, telomere-maintenance mechanisms employ common structural elements. For example, the single-stranded 3' overhang of telomeric DNA is specifically and tightly bound by an OB-fold in nearly all species, including ciliates (TEBP and Pot1a), fission yeast (SpPot1), budding yeast (Cdc13), and humans (hPOT1). Structures of the yeast Cdc13, Stn1, and Ten1 proteins demonstrated that telomere maintenance is regulated by a complex that bears significant similarity to the RPA heterotrimer. Similarly, proteins that specifically bind double-stranded telomeric DNA in divergent species use homeodomains to execute their functions (human TRF1 and TRF2 and budding yeast ScRap1). Likewise, the conserved protein Rap1, which is found in budding yeast, fission yeast, and humans, contains a structural motif that is known to be critical for protein-protein interaction. In addition to revealing the common underlying themes of telomere maintenance, structures have also elucidated the specific mechanisms by which many of these proteins function, including identifying a telomere-specific domain in Stn1 and how the human TRF proteins avoid heterodimerization. In this review, we summarize the high-resolution structures of telomerase and telomere-associated proteins and discuss the emergent common structural themes among these proteins. We also address how these high-resolution structures complement biochemical and cellular studies to enhance our understanding of telomere maintenance and function. PMID- 22244754 TI - NMR structure of a heterodimeric SAM:SAM complex: characterization and manipulation of EphA2 binding reveal new cellular functions of SHIP2. AB - The sterile alpha motif (SAM) for protein-protein interactions is encountered in over 200 proteins, but the structural basis for its interactions is just becoming clear. Here we solved the structure of the EphA2-SHIP2 SAM:SAM heterodimeric complex by use of NMR restraints from chemical shift perturbations, NOE and RDC experiments. Specific contacts between the protein surfaces differ significantly from a previous model and other SAM:SAM complexes. Molecular dynamics and docking simulations indicate fluctuations in the complex toward alternate, higher energy conformations. The interface suggests that EphA family members bind to SHIP2 SAM, whereas EphB members may not; correspondingly, we demonstrate binding of EphA1, but not of EphB2, to SHIP2. A variant of EphB2 SAM was designed that binds SHIP2. Functional characterization of a mutant EphA2 compromised in SHIP2 binding reveals two previously unrecognized functions of SHIP2 in suppressing ligand induced activation of EphA2 and in promoting receptor coordinated chemotactic cell migration. PMID- 22244755 TI - Mechanism of regulation of receptor histidine kinases. AB - Bacterial transmembrane receptors regulate an intracellular catalytic output in response to extracellular sensory input. To investigate the conformational changes that relay the regulatory signal, we have studied the HAMP domain, a ubiquitous intracellular module connecting input to output domains. HAMP forms a parallel, dimeric, four-helical coiled coil, and rational substitutions in our model domain (Af1503 HAMP) induce a transition in its interhelical packing, characterized by axial rotation of all four helices (the gearbox signaling model). We now illustrate how these conformational changes are propagated to a downstream domain by fusing Af1503 HAMP variants to the DHp domain of EnvZ, a bacterial histidine kinase. Structures of wild-type and mutant constructs are correlated with ligand response in vivo, clearly associating them with distinct signaling states. We propose that altered recognition of the catalytic domain by DHp, rather than a shift in position of the phospho-accepting histidine, forms the basis for regulation of kinase activity. PMID- 22244756 TI - Protein domain structure uncovers the origin of aerobic metabolism and the rise of planetary oxygen. AB - The origin and evolution of modern biochemistry remain a mystery despite advances in evolutionary bioinformatics. Here, we use a structural census in nearly 1,000 genomes and a molecular clock of folds to define a timeline of appearance of protein families linked to single-domain enzymes. The timeline sorts out enzymatic recruitment, validates patterns in metabolic history, and reveals that the most ancient reaction of aerobic metabolism involved the synthesis of pyridoxal 5'-phosphate or pyridoxal and appeared 2.9 Gyr ago. The oxygen source for this primordial reaction was probably Mn catalase, which appeared at the same time and could have generated oxygen as a side product of hydrogen peroxide detoxification. Finally, evolutionary analysis of transferred groups and metabolite fragments revealed that oxidized sulfur did not participate in metabolism until the rise of oxygen. The evolutionary patterns we uncover in molecules and chemistries provide strong support for the coevolution of biochemistry and geochemistry. PMID- 22244757 TI - The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. AB - Uncontrolled fibroblast growth factor (FGF) signaling can lead to human malignancies necessitating multiple layers of self-regulatory control mechanisms. Fibroblast growth factor receptor (FGFR) autoinhibition mediated by the alternatively spliced immunoglobulin (Ig) domain 1 (D1) and the acid box (AB) containing linker between D1 and Ig domain 2 (D2) serves as the first line of defense to minimize inadvertent FGF signaling. In this report, nuclear magnetic resonance and surface plasmon resonance spectroscopy are used to demonstrate that the AB subregion of FGFR electrostatically engages the heparan sulfate (HS) binding site on the D2 domain in cis to directly suppress HS-binding affinity of FGFR. Furthermore, the cis electrostatic interaction sterically autoinhibits ligand-binding affinity of FGFR because of the close proximity of HS-binding and primary ligand-binding sites on the D2 domain. These data, together with the strong amino acid sequence conservation of the AB subregion among FGFR orthologs, highlight the universal role of the AB subregion in FGFR autoinhibition. PMID- 22244758 TI - Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors. AB - The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. pestis FabV in complex with its cofactor reveals that the enzyme features the common architecture of the short-chain dehydrogenase reductase superfamily, but contains additional structural elements that are mostly folded around the usually flexible substrate-binding loop, thereby stabilizing it in a very tight conformation that seals the active site. The structures of FabV in complex with NADH and two newly developed 2-pyridone inhibitors provide insights for the development of new lead compounds, and suggest a mechanism by which the substrate-binding loop opens to admit the inhibitor, a motion that could also be coupled to the interaction of FabV with the acyl-carrier protein substrate. PMID- 22244760 TI - Computational reconstruction of multidomain proteins using atomic force microscopy data. AB - Classical structural biology techniques face a great challenge to determine the structure at the atomic level of large and flexible macromolecules. We present a novel methodology that combines high-resolution AFM topographic images with atomic coordinates of proteins to assemble very large macromolecules or particles. Our method uses a two-step protocol: atomic coordinates of individual domains are docked beneath the molecular surface of the large macromolecule, and then each domain is assembled using a combinatorial search. The protocol was validated on three test cases: a simulated system of antibody structures; and two experimentally based test cases: Tobacco mosaic virus, a rod-shaped virus; and Aquaporin Z, a bacterial membrane protein. We have shown that AFM-intermediate resolution topography and partial surface data are useful constraints for building macromolecular assemblies. The protocol is applicable to multicomponent structures connected in the polypeptide chain or as disjoint molecules. The approach effectively increases the resolution of AFM beyond topographical information down to atomic-detail structures. PMID- 22244761 TI - The transmembrane protein KpOmpA anchoring the outer membrane of Klebsiella pneumoniae unfolds and refolds in response to tensile load. AB - In Klebsiella pneumoniae the transmembrane beta-barrel forming outer membrane protein KpOmpA mediates adhesion to a wide range of immune effector cells, thereby promoting respiratory tract and urinary infections. As major transmembrane protein OmpA stabilizes Gram-negative bacteria by anchoring their outer membrane to the peptidoglycan layer. Adhesion, osmotic pressure, hydrodynamic flow, and structural deformation apply mechanical stress to the bacterium. This stress can generate tensile load to the peptidoglycan-binding domain (PGBD) of KpOmpA. To investigate how KpOmpA reacts to mechanical stress, we applied a tensile load to the PGBD and observed a detailed unfolding pathway of the transmembrane beta-barrel. Each step of the unfolding pathway extended the polypeptide connecting the bacterial outer membrane to the peptidoglycan layer and absorbed mechanical energy. After relieving the tensile load, KpOmpA reversibly refolded back into the membrane. These results suggest that bacteria may reversibly unfold transmembrane proteins in response to mechanical stress. PMID- 22244759 TI - Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824. AB - Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F(420) deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F(420) and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data. PMID- 22244762 TI - A master switch couples Mg2+-assisted catalysis to domain motion in B. stearothermophilus tryptophanyl-tRNA Synthetase. AB - We demonstrate how tryptophanyl-tRNA synthetase uses conformation-dependent Mg(2+) activation to couple catalysis of tryptophan activation to specific, functional domain movements. Rate acceleration by Mg(2+) requires ~-6.0 kcal/mol in protein?Mg(2+) interaction energy, none of which arises from the active site. A highly cooperative interaction between Mg(2+) and four residues from a remote, conserved motif that mediates the shear of domain movement (1) destabilizes the pretransition state conformation, thereby (2) inducing the Mg(2+) to stabilize the transition state for k(cat) by ~-5.0 kcal/mol. Cooperative, long-range conformational effects on the metal therefore convert an inactive Mg(2+) coordination into one that can stabilize the transition state if, and only if, domain motion occurs. Transient, conformation-dependent Mg(2+) activation, analogous to the escapement in mechanical clocks, explains vectorial coupling. PMID- 22244763 TI - Ligand and receptor dynamics contribute to the mechanism of graded PPARgamma agonism. AB - Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor gamma (PPARgamma) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARgamma modulators. PMID- 22244764 TI - Structural basis for molecular interactions involving MRG domains: implications in chromatin biology. AB - MRG15 is a member of the mortality family of transcription factors that targets a wide variety of multiprotein complexes involved in transcription regulation, DNA repair, and alternative splicing to chromatin. The structure of the apo-MRG15 MRG domain implicated in interactions with diverse proteins has been described, but not in complex with any of its targets. Here, we structurally and functionally characterize the interaction between MRG15 and Pf1, two constitutively associated subunits of the histone deacetylase-associated Rpd3S/Sin3S corepressor complex. The MRG domain adopts a structure reminiscent of the apo state, whereas the Pf1 MRG-binding domain engages two discrete hydrophobic surfaces on the MRG domain via a bipartite motif comprising an alpha-helix and a segment in an extended conformation, both of which are critical for high-affinity interactions. Multiple MRG15 interactors share an FxLP motif in the extended segment, but equivalent sequence/helical motifs are not readily evident, implying potential diversity in MRG-recognition mechanisms. PMID- 22244765 TI - Assembly of the eukaryotic PLP-synthase complex from Plasmodium and activation of the Pdx1 enzyme. AB - Biosynthesis of vitamins is fundamental to malaria parasites. Plasmodia synthesize the active form of vitamin B(6) (pyridoxal 5'-phosphate, PLP) using a PLP synthase complex. The EM analysis shown here reveals a random association pattern of up to 12 Pdx2 glutaminase subunits to the dodecameric Pdx1 core complex. Interestingly, Plasmodium falciparum PLP synthase organizes in fibers. The crystal structure shows differences in complex formation to bacterial orthologs as interface variations. Alternative positioning of an alpha helix distinguishes an open conformation from a closed state when the enzyme binds substrate. The pentose substrate is covalently attached through its C1 and forms a Schiff base with Lys84. Ammonia transfer between Pdx2 glutaminase and Pdx1 active sites is regulated by a transient tunnel. The mutagenesis analysis allows defining the requirement for conservation of critical methionines, whereas there is also plasticity in ammonia tunnel construction as seen from comparison across different species. PMID- 22244767 TI - Animal models of vascular calcification. PMID- 22244766 TI - Structural basis for recognition of H3T3ph and Smac/DIABLO N-terminal peptides by human Survivin. AB - Survivin is an inhibitor of apoptosis family protein implicated in apoptosis and mitosis. In apoptosis, it has been shown to recognize the Smac/DIABLO protein. It is also a component of the chromosomal passenger complex, a key player during mitosis. Recently, Survivin was identified in vitro and in vivo as the direct binding partner for phosphorylated Thr3 on histone H3 (H3T3ph). We have undertaken structural and binding studies to investigate the molecular basis underlying recognition of H3T3ph and Smac/DIABLO N-terminal peptides by Survivin. Our crystallographic studies establish recognition of N-terminal Ala in both complexes and identify intermolecular hydrogen-bonding interactions in the Survivin phosphate-binding pocket that contribute to H3T3ph mark recognition. In addition, our calorimetric data establish that Survivin binds tighter to the H3T3ph-containing peptide relative to the N-terminal Smac/DIABLO peptide, and this preference can be reversed through structure-guided mutations that increase the hydrophobicity of the phosphate-binding pocket. PMID- 22244768 TI - White blood cell count is associated with carotid and femoral atherosclerosis. AB - OBJECTIVE: Chronic low-grade inflammation is associated with atherosclerosis. Ultrasound imaging allows measurement of intima-media thickness (IMT) and plaque. We investigated the association between inflammatory markers and carotid and femoral atherosclerosis. METHODS: We studied 554 subjects with primary dyslipidemia (57% men, median age 49 years) and 246 age- and sex-matched normolipidemic subjects. Carotid and femoral arteries were imaged bilaterally with a standardized protocol. Mean and maximum common carotid IMT (CC-IMT and MaxCC-IMT) and common femoral IMT (F-IMT and MaxF-IMT), and carotid and femoral plaque were assessed. Carotid atherosclerosis was defined by CC-IMT and/or plaque height >75th percentile of a reference population. White blood cell count (WBCC) was measured in all subjects. High-sensitivity C-reactive protein (CRP) was measured in 330 dyslipidemic subjects. RESULTS: The age- and sex-adjusted probability of carotid atherosclerosis and femoral plaque increased by 20% (odds ratio [OR] 1.20; 95% CI, 1.10-1.31) and 25% (1.25; 1.13-1.38), respectively, for each 1000/mm(3) WBCC increment. WBCC was associated with age- and sex-adjusted CC IMT and MaxCC-IMT (p<0.05, both), and F-IMT and MaxF-IMT (p<0.001, both). Adjustment for cardiovascular risk factors did not influence these associations. CRP was associated with CC-IMT and MaxCC-IMT (p<0.05, both), but the associations disappeared after adjustment for body mass index. CRP was unrelated to carotid plaque or measures of femoral atherosclerosis. CONCLUSIONS: WBCC, but not CRP, related to early and advanced measures of atherosclerosis independently of risk factors. Our findings support using the heretofore undervalued WBCC as an easy-to measure, low-cost diagnostic marker of atherosclerosis. PMID- 22244769 TI - Con: topical head cooling should not be used during deep hypothermic circulatory arrest. PMID- 22244770 TI - Pro: topical hypothermia should be used during deep hypothermic circulatory arrest. PMID- 22244771 TI - Differences in prevalence and severity of coronary artery disease by three metabolic syndrome definitions. AB - BACKGROUND: People with metabolic syndrome (MS) are at increased risk for cardiovascular disease-associated morbidity and all-cause mortality. However, predicting the severity of coronary artery disease (CAD) according to different MS definitions is controversial. This study explores the prevalence and severity of CAD according to different MS definitions, focusing on their predictive value. METHODS: We enrolled 690 Taiwanese adults with CAD in this study. Coronary artery lesions were classified by the modified American Heart Association-American College of Cardiology grading system. MS was diagnosed in 3 groups of randomly assigned subjects according to World Health Organization (WHO), International Diabetes Federation (IDF), and revised Adult Treatment Panel III (rATP III) criteria. RESULTS: More MS components and more severe CAD were identified in the WHO group. Prevalence of MS in the WHO, IDF, and rATP III groups was 33.9%, 47.4%, and 52.8%, respectively (P < 0.001). Mean lesion and culprit vessel numbers were slightly higher in WHO-group patients. The WHO group had more complex stenoses with type C classification than did the IDF and rATP III groups (32.7%, 26.3%, and 28.1%; P = 0.041) and significantly more calcified stenoses (21.5%, 16.2%, and 16.4%; P = 0.027). In a comparison of CAD severity by complex morphology lesions, the area under the receiver operating characteristic curve was higher in the WHO group (0.552; 95% confidence interval, 0.509-0.595; P = 0.019). CONCLUSION: Compared with IDF and rATP III definitions, the WHO definition of MS has superior predictive value of CAD severity in Taiwanese patients. PMID- 22244772 TI - Development of atrial fibrillation in recipients of cardiac resynchronization therapy: the role of atrial reverse remodelling. PMID- 22244773 TI - Angina in the broken heart syndrome: emotional or physical chest pain? PMID- 22244774 TI - The sympathetic nervous system and new nonpharmacologic approaches to treating hypertension: a focus on renal denervation. AB - The sympathetic nervous system is activated in a variety of cardiovascular and metabolic diseases. This is particularly the case for essential hypertension, in which various indices of adrenergic activity, such as plasma norepinephrine, norepinephrine spillover, and sympathetic nerve firing rate, are all well above the reference range of values, thereby documenting sympathetic overdrive. Evidence is available that sympathetic neural factors participate in disease progression, as well as in the development of cardiac and renal organ damage. These findings represent the rationale for therapeutic interventions that counteract the adrenergic overdrive in the hypertensive state. This paper, after reviewing the key findings of the neuroadrenergic abnormalities occurring in hypertension, examines the rationale and the technical details, as well as the results achieved so far, with the use of a new technique that allows the elimination of afferent and efferent innervation of the kidney in resistant hypertension, ie, the ablation of renal nerves. Strengths and potential limitations of the renal denervation approach are briefly addressed. PMID- 22244775 TI - Elevated endothelin-1 vasoconstrictor tone in prehypertensive adults. AB - BACKGROUND: Prehypertension (blood pressure [BP] 120-139/80-89 mm Hg) is an independent risk factor for hypertension and cardiovascular disease. Currently, it is unknown whether endothelin (ET)-1-mediated vasoconstrictor tone is elevated with BP in the prehypertensive range. The aims of this study were to determine whether ET-1 vasoconstrictor tone is elevated in prehypertensive adults and, if so, whether ET-1-mediated vasoconstriction contributes to endothelial vasodilator dysfunction in this population. METHODS: Forearm blood flow responses to selective ET(A) receptor blockade (BQ-123; 100 nmol/min) were determined in 26 normotensive adults (age 55 +/- 1 years; BP 112 +/- 1/72 +/- 1 mm Hg) and 30 prehypertensive adults (57 +/- 1 years; BP 130 +/- 1/80 +/- 1 mm Hg). In a subset of participants, forearm blood flow responses to nonselective ET-1 receptor blockade (BQ-123 + BQ-788) were determined. Endothelium-dependent vasodilation to acetylcholine (8.0-32.0 MUg/100 mL tissue/min) was measured in the absence and presence of selective ET(A) receptor blockade. RESULTS: BQ-123 elicited a significantly greater increase in forearm blood flow in prehypertensive (approximately 20%) than in normotensive (approximately 5%) adults. Addition of BQ-788 resulted in a further increase (P < 0.05) in forearm blood flow in prehypertensive but not in normotensive adults. Forearm blood flow responses to acetylcholine were lower (P < 0.05) in prehypertensive (4.6 +/- 0.3 to 12.6 +/- 0.5 mL/100 mL tissue/min) than in normotensive (4.9 +/- 0.3 to 14.7 +/- 0.8 mL/100 mL tissue/min) adults. Co-infusion of BQ-123 did not affect acetylcholine induced vasodilation in normotensive adults but resulted in an approximately 20% increase (P < 0.05) in prehypertensive adults. CONCLUSIONS: ET-1-mediated vasoconstrictor tone is elevated with prehypertension, contributing to impaired endothelium-dependent vasodilation. ET-1 vasoconstriction may underlie the increased risk of hypertension and cardiovascular disease in prehypertensive adults. PMID- 22244776 TI - Study on the interaction between cyanobacteria FBP/SBPase and metal ions. AB - Fructose-1,6-/sedoheptulose-1,7-bisphosphatase (FBP/SBPase) is a potential important target enzyme for finding inhibitors to solve harmful algal bloom. In this paper, the interactions between FBP/SBPase and metal ions were studied by enzyme activity analysis, fluorescence and molecular modeling method. The enzyme activity analysis showed that FBP/SBPase can be activated by Mg2+ or Mn2+ but cannot be activated by Ca2+ or Zn2+. Spectroscopic analysis of emission quenching showed that quenching mechanism of FBP/SBPase with Mg2+ or Mn2+ was static quenching mechanism while that of Ca2+ or Zn2+ was dynamic quenching process. Hydrogen bonds and van der Waals interaction might be the predominant intermolecular forces in stabilizing FBP/SBPase-Mg2+ while hydrophobic forces were the predominant intermolecular forces in stabilizing FBP/SBPase-Mn2+. Microenvironment and conformation of FBP/SBPase were changed in binding reaction. The effect of metal ions and important amino acid residues on FBP/SBPase-metal ion complex was also discussed by molecular modeling study. PMID- 22244778 TI - Percutaneous nephrolithotomy in the United kingdom: results of a prospective data registry. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) is commonly used in the management of large upper renal tract stones. It is highly effective but carries a greater risk of significant morbidity than less invasive treatment options such as ureteroscopy or extracorporeal shock wave lithotripsy. OBJECTIVE: Evaluate the current practice and outcomes of PCNL using a national prospective data registry. DESIGN, SETTING, AND PARTICIPANTS: All surgeons undertaking PCNL in the United Kingdom were invited to submit data to an online registry. MEASUREMENTS: Effectiveness was assessed by stone-free rates and safety according to complications including blood transfusion, fever, and sepsis rates. RESULTS AND LIMITATIONS: Since January 2010, data on 987 patients who had 1028 PCNL procedures were collected. A total of 299 of 1012 procedures (30%) were for staghorn calculi, 299 (30%) for stones >2 cm, 329 (33%) for stones 1-2 cm, and 89 (9%) for stones <1cm. There were no significant differences in rates of failed access or complications according to whether a urologist or radiologist obtained renal access. There was a nonsignificant trend to a higher transfusion rate with balloon dilatation (7 of 222 [3.2%]) compared with serial dilatation (2 of 245 [0.8%]) of the renal tract (p = 0.093). Totally tubeless procedures were not associated with higher complication rates but did lead to a significant reduction in median length of stay (3 d vs 1.5 d; p<0.0001). Intraoperatively, 78% of patients were believed to be stone free, which was confirmed in 68% with postoperative imaging. Blood transfusion was required in 24 of 968 patients (2.5%). The incidence of postoperative fever was 16% and of sepsis was 2.4%. CONCLUSIONS: The PCNL data registry is a unique resource providing vital information on current practice and critical outcome data. Using the registry, endourologists can audit their practice against national outcome data for this benchmark procedure. It will help surgeons counsel patients during consent for this complex endourologic procedure about the possible outcome in their hands. PMID- 22244779 TI - Antimicrobial susceptibility and molecular characteristics of 857 methicillin resistant Staphylococcus aureus isolates from 16 medical centers in Japan (2008 2009): nationwide survey of community-acquired and nosocomial MRSA. AB - This study is a nationwide survey of all clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, including community-acquired MRSA (CA MRSA), in Japan. A total of 857 MRSA clinical isolates were collected from the 16 institutions throughout Japan that participated in the survey (2008-2009). The drug susceptibility and staphylococcal cassette chromosome mec (SCCmec) typing and the presence of specific pathogenic genes were evaluated. The isolates comprised SCCmec type II (73.6%), type IV (20%), and type I (6%). The percentage of SCCmec type IV isolates was significantly higher in outpatients than in inpatients. Most of the isolated strains were sensitive to vancomycin (VCM, MIC <=2 MUg/mL), linezolid (MIC <=4 MUg/mL), and teicoplanin (MIC <=8 MUg/mL). Although most strains were sensitive to VCM, the MIC value of VCM for SCCmec type II strains was higher than that for SCCmec type IV strains. Only 4 (2.3%) of 171 SCCmec type IV strains were Panton-Valentine leukocidin (lukS/F-PV)-positive. Thus, this result indicates a unique feature of SCCmec type IV strains in Japan. The information in this study not only is important in terms of local public health but will also contribute to an understanding of epidemic clones of CA MRSA. PMID- 22244780 TI - [Oral combined contraception: is there any difference between ethinyl-estradiol and estradiol?]. AB - Estradiol 17-beta, which is the natural estrogen in women, offers an alternative to ethinyl-estradiol to be used in combined oral contraceptives. Thanks to its biochemical structure, estradiol has a far lesser impact on the synthesis of hepatic proteins than ethinyl-estradiol, which is likely to result in a better metabolic and vascular profile. However and until lately, the different clinical trials that had investigated estradiol-containing oral contraceptives were limited by bleeding disturbances, with breakthrough and irregular bleeding and higher rates of discontinuation. Development of anti-gonadotropic progestins with a potent endometrial activity is likely to make possible their combination with estradiol in oral contraceptives. The objective of this current review is to provide an overview of the development of combined oral contraceptives containing natural estrogen from the respective biochemical and pharmacological characteristics of ethinyl-estradiol and estradiol. PMID- 22244781 TI - A randomized assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer. AB - OBJECTIVE: To compare the efficacy and safety of highly purified menotropin (hphMG) and recombinant FSH (rFSH) for controlled ovarian stimulation in a GnRH antagonist cycle with compulsory single-blastocyst transfer. DESIGN: Randomized, open-label, assessor-blind, parallel groups, multicenter, noninferiority trial. SETTING: Twenty-five infertility centers in seven countries. PATIENT(S): Seven hundred forty-nine women. INTERVENTION(S): Controlled ovarian stimulation with hphMG or rFSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer on day 5 in one fresh or subsequent frozen blastocyst replacement in natural cycles initiated within 1 year of each patient's start of treatment. MAIN OUTCOME MEASURE(S): Ongoing pregnancy (primary end point) and live birth rates, as well as pharmacodynamic parameters. RESULT(S): The ongoing pregnancy rate after a fresh cycle was 30% with hphMG versus 27% with rFSH for the per-protocol (PP) population and 29% versus 27% for the intention-to-treat (ITT) population. Noninferiority of hphMG compared to rFSH was established. Considering frozen cycles initiated within 1 year, the cumulative live birth rate for a single stimulation cycle was 40% and 38% for women treated with hphMG and rFSH, respectively (both PP and ITT). Significant differences in pharmacodynamic end points were found between the two gonadotropin preparations. CONCLUSION(S): Highly purified hMG is at least as effective as rFSH in GnRH antagonist cycles with compulsory single-blastocyst transfer. CLINICAL TRIAL REGISTRATION NUMBER: NCT00884221. PMID- 22244782 TI - The association between circulating levels of antimullerian hormone and follicle number, androgens, and menstrual cycle characteristics in young women. AB - OBJECTIVE: To investigate the association between serum antimullerian hormone (AMH) and other reproductive parameters in young women. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): Population-based cohort of 256 women: 180 were users and 76 were nonusers of hormonal contraceptives. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Antral follicles, androgens, age at menarche, and duration and regularity of menstrual cycle. RESULT(S): AMH levels were lower among users of hormonal contraceptives compared to nonusers. Among nonusers, women with AMH levels in the upper tertile had 55% (95% confidence interval [CI]: 22%-99%) higher levels of total T and 8% (95% CI = 2% 15%) longer menstrual cycles than women with AMH levels in the lower tertile. An increase of 1 ng/mL in AMH was associated with 45% (95% CI = 6%-97%) higher prevalence of irregular menstrual cycles. These associations were not seen among users of hormonal contraceptives. A strong relationship between AMH and follicle number was found in both users and nonusers. CONCLUSION(S): AMH measurements were found to be applicable in evaluation of the reproductive function of young women. However, there may be differences in the way that serum AMH levels can be interpreted depending on whether the woman uses hormonal contraceptives or not. PMID- 22244783 TI - CD11c+HLADR+ dendritic cells are present in human ovarian follicular fluid, and their maturity correlates with serum estradiol levels in response to gonadotropins. AB - OBJECTIVE: To determine whether dendritic cells (DCs), innate immune cells that specialize in initiation and modulation of immune responses, are present in ovarian follicular fluid (FF) and whether their abundance and maturation state correlate with ovarian response to gonadotropins. DESIGN: Observational study. SETTING: IVF unit and laboratory for reproductive immunology. PATIENT(S): Patients undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): FF was collected from the first follicle aspirated in each patient, and cellular content was analyzed by flow cytometry. DCs were defined as CD45(+)CD11c(+)HLADR(+) cells, and the intensity of HLADR expression indicated DC maturity. RESULT(S): The CD45(+)-hematopoietic cell compartment in FFs (n = 30) contained a significant fraction of CD11c(+)HLADR(+) DCs (15.4% +/- 2.9%). The mean fluorescence intensity (MFI) of HLADR expression, which reflects DC maturity, correlated positively with ovarian response to gondotropins, as determined by serum levels of E(2) on the day of hCG administration (r = 0.38). CONCLUSION(S): DCs make up a significant fraction of hematopoietic cells in the FF. Furthermore, DC maturation correlates positively with the ovarian response to gonadotropins. It is therefore conceivable that DCs contribute to the sterile inflammatory process in the follicle that leads to ovulation. PMID- 22244784 TI - Nitric oxide synthase and tyrosine nitration in idiopathic asthenozoospermia: an immunohistochemical study. AB - OBJECTIVE: To characterize the expression pattern of constitutive and inducible nitric oxide synthase (NOS) in spermatozoa isolated from normospermic fertile donors and asthenozoospermic infertile patients, by means of immunohistochemistry. Also to evaluate the immunohistochemical expression of citrulline, a marker of NOS activity, and nitrotyrosine, which indicates the formation of peroxynitrite, which may affect sperm functionality through its cytotoxic action. DESIGN: Prospective study. SETTING: Academic male infertility center. PATIENT(S): Twenty-nine infertile patients affected by idiopathic asthenozoospermia and 26 age-matched normospermic fertile donors. INTERVENTION(S): Sperm parameters were evaluated, and immunohistochemical analysis was performed in isolated spermatozoa. MAIN OUTCOME MEASURE(S): Semen analyses, to ascertain volume, sperm count, motility, and morphology. Immunohistochemical expression of NOS isoforms, citrulline, and nitrotyrosine. RESULT(S): Constitutive NOS expression was greater in spermatozoa isolated from normospermic fertile donors. In contrast, the immunohistochemical expression of inducible NOS and nitrotyrosine was higher in asthenozoospermic samples. Our data concerning citrulline indicated enhanced NOS activity in sperm from idiopathic asthenozoospermic patients. CONCLUSION(S): Our results support the hypothesis that increased NOS activity and an excess of tyrosine nitration may affect the functional characteristics of spermatozoa in idiopathic asthenozoospermia. PMID- 22244785 TI - [Editorial. Tropical neurology]. PMID- 22244786 TI - Origin, evolution, and phylogeography of recent epidemic CHIKV strains. AB - Chikungunya virus (CHIKV) is an arthropod-borne virus of the Alphavirus genus, which is transmitted to humans by Aedes spp. mosquitoes and was firstly identified in Tanzania in the mid 1950s. In this article, the findings of a phylogenetic and phylogeographic analysis of the recent CHIKV pandemic are reported. We estimated time of origin of the ancestral virus, time and place of occurrence of A226V mutation, and the flow of viral strains from an area to the other. The Bayesian phylogenetic and phylogeographic analysis was performed on the whole dataset, which consisted of 195 E1 (envelope 1) CHIKV sequences, and on a subset (D2), including 146 of the 195 previous sequences. Using the relaxed clock model, we estimated a CHIKV E1 mean evolutionary rate (in the whole dataset) of 1.4 * 10(-3)substitution/site/year (95% highest posterior density interval HPD 6.4 * 10(-4)-2.5 * 10(-3)), and of 2.2 * 10(-3) (95% HPD 9.6 * 10( 4)-3.8 * 10(-3)) in the D2 subset, including only the strains involved in the recent Indian Ocean epidemic. The phylogeographical analysis suggested an African origin of CHIKV with a tMRCA of 146 years corresponding to 1863 (95% HPD 1741 1941). Moreover D2 subset most probably originated in Kenya, with a tMRCA corresponding to the year 2002 (95% HPD 2000-2004), then spread following two distinct routes: one throughout the Indian Ocean (Reunion, Comoros) and the other moving from India then scattered in the South East Asia and reached Italy. In conclusion, we reconstructed the geographic spread of CHIKV during the last epidemic wave, which showed an eastward path from Africa to Indian Ocean island to India, and from there to other South East Asian countries. Whether A226V variants followed the same migration path remains undefined, since local independent mutations, followed by fixation due to selective advantage conferred by better adaptation to local vectors of infection, cannot be excluded. PMID- 22244787 TI - Visceral fat mass is always, but adipokines (adiponectin and resistin) are diversely associated with insulin resistance in Chinese type 2 diabetic and normoglycemic subjects. AB - AIMS: The present study investigated alteration of abdominal visceral fat mass (VFM) and its relationship to adipokines and insulin resistance (IR) in obese and non-obese type 2 diabetes and normoglycemic subjects. METHODS: Twenty-two diabetic patients and 37 normoglycemic controls were subgrouped into obese and non-obese according to their BMI. VFM was quantified by computed tomography. Plasma adiponectin and resistin, two adipokines exert contrary effects on insulin sensitivity were measured. Insulin sensitivity was evaluated by an established HOMA model. RESULTS: Obese subjects showed remarkably expanded VFM, while non obese diabetes obtained more abundant VFM than non-obese controls (104 +/- 50 cm(2)vs. 77 +/- 26 cm(2), P<0.05). Plasma adiponectin was only significantly decreased in obese diabetes. Plasma resistin was increased in diabetes, but compared between obese and non-obese subjects. Diabetic patients and obese controls were significantly insulin resistant. HOMA-IR index positively correlated to VFM in both groups (r=0.563, P=0.011 for diabetes and r=0.671, P=0.000 for controls). In diabetes but not controls, plasma adiponectin negatively related to VFM (r=-0.687, P=0.000) and HOMA-IR index (r=-0.659, P=0.002), while resistin had no relation to IR and VFM in both groups. CONCLUSIONS: Increased VFM may lead to IR by mechanisms beyond adipokines in Chinese type 2 diabetic and normoglycemic subjects. PMID- 22244788 TI - Systems and synthetic metabolic engineering for amino acid production - the heartbeat of industrial strain development. AB - With a world market of more than four million tons per year, l-amino acids are among the most important products in industrial biotechnology. The recent years have seen a tremendous progress in the development of tailor-made strains for such products, intensively driven from systems metabolic engineering, which upgrades strain engineering into a concept of optimization on a global scale. This concept seems especially valuable for efficient amino acid production, demanding for a global modification of pathway fluxes - a challenge with regard to the high complexity of the underlying metabolism, superimposed by various layers of metabolic and transcriptional control. PMID- 22244789 TI - Integrating C4 photosynthesis into C3 crops to increase yield potential. AB - The growth rate of the human population is faster than improvements in crop yields. To feed people in the future, multiple strategies are required. One proposed approach is to raise the yield potential of C(3) crops by modifying photosynthesis to the more efficient C(4) pathway. Owing to complex changes associated with C(4) photosynthesis, it is no understatement to define this conversion as one of the Grand Challenges for Biology in the 21st Century. Here we outline the challenges of installing a C(4) system and assess how new approaches and knowledge may help achieve this goal. PMID- 22244790 TI - Heterologous production of polyketides by modular type I polyketide synthases in Escherichia coli. AB - Heterologous production of polyketide compounds, an important class of natural products with complex chemical structures, was first demonstrated with Streptomyces parvulus in 1984. Although Streptomyces strains are good first options for heterologous polyketide biosynthesis, their slow growth kinetics prompt other hosts to also be considered. Escherichia coli provides key elements of an ideal host in terms of the growth rate, culture conditions, and available recombinant DNA tools. Here we review the current status and potential for metabolic engineering of polyketides in E. coli. PMID- 22244791 TI - Strategies to mitigate N2O emissions from biological nitrogen removal systems. AB - N2O emissions from the biological treatment of sewage, manure, landfill leachates and industrial effluents have gained considerable interest among policy makers and environmental scientists. Estimated global emission rates from these sources can contribute up to 10% of the anthropogenic N2O emissions. Particularly at the level of a treatment plant, the N2O impact can be very significant and reach up to 80% of the operational CO2 footprint. Imperfect nitritation by an imbalance in the two-step nitritation metabolism of ammonia-oxidizing bacteria is considered as the main contributor to N2O production with hydroxylamine and particularly nitrite as key precursors. Monitoring of these compounds is warranted to understand and abate N2O emissions. Mitigation strategies should also comprise optimizations of the process parameters as well as bio-augmentative approaches empowered to restore the functional capacity and to deal with unwanted accumulation of intermediates. These strategies require validation for their effectiveness and costs at full-scale. PMID- 22244792 TI - [Mycoplasma pneumoniae encephalitis associated with basal ganglia necrosis]. AB - INTRODUCTION: Severe central nervous system diseases, such as encephalitis, have been reported in association with Mycoplasma pneumoniae infections. CASE REPORT: A previously healthy 5-year-old boy presented with an atypical pneumonia; he rapidly developed encephalitis revealed by lethargy, generalized status epilepticus. MRI showed abnormal signals in the basal ganglia, typical of bilateral striatal necrosis. Serologic tests for M. pneumoniae were positive, the child recovered almost completely. CONCLUSION: M. pneumoniae infection should be considered in all cases of acute encephalopathy; yet the pathogenesis of the disorder is unknown and the treatment uncertain. PMID- 22244793 TI - [Rhomboencephalitis due to enterovirus]. PMID- 22244794 TI - [Mortality in patients with osteolysis of lymphatic origin: a review of the experience with 54 patients and the literature]. AB - INTRODUCTION: Osteolysis of lymphatic origin is a rare disease with a high mortality which is difficult to attribute whether it is due to the disease itself or the therapeutic morbidity. The aim of this study is to review the causes of mortality in our group of patients with osteolysis of lymphatic origin, compared with the group of patients previously reported in the medical literature. PATIENTS AND METHODS: We reviewed all patients with osteolysis of lymphatic origin and treated in our department who had died in the last 15 years, and we reviewed all published cases of death with this disease since the 1950's. RESULTS: A total of 57 patients with osteolysis of lymphatic origin had been studied at our institution, of whom three died, two from sepsis, and one from acute respiratory distress syndrome. All of them suffered severe malnutrition from massive lymphatic loss and 2 had bilateral chylothorax. Among the 51 cases reviewed in the literature between 1954 - 2010, 19 had bilateral chylothorax, 15 had right side involvement and only 2 had an exclusive left chylothorax. Eleven patients had complications, such as respiratory distress and pneumonia. Ten of them suffered from pathological fractures, and 10 from chylopericardium and/or chylous ascites. The most common cause of death was respiratory failure in 25 patients, followed by pneumonia and sepsis. The publications do not specify the ultimate cause of respiratory failure. CONCLUSIONS: Patients with severe osteolysis of lymphatic origin suffer three main disorders with overlapping comorbidity: the lymphatic malformation of soft tissue, the bone resorption and the chylothorax. While mortality in the first two is exceptional, the mortality of the chylothorax is common, especially when it is bilateral and does not respond to different therapies. Respiratory failure and infection are aggravated by immunosuppression, malnutrition and the non-restrictive use of central catheters. Unlike respiratory failure, which is difficult to control after the failure of medical and surgical treatment, morbidity from infections can be reduced through careful nutritional support, rational antibiotic prophylaxis and a reduction to a minimum in the use of central catheters and total parenteral nutrition. PMID- 22244795 TI - Symptoms of behavioural anapyrexia--reverse fever as a defence response of snails to fluke invasion. AB - The subject of the research was the thermal preferences of Planorbarius corneus individuals infected by larvae of digenetic trematodes. Snails were obtained over two consecutive years, 2009 and 2010, from 10 water bodies located in central Poland. The relationship between the seasons and the occurrence of patent invasions in hosts found in the shore-zone of lakes was observed. Behavioural experiments conducted on P. corneus individuals placed in a thermal gradient demonstrated that parasite infection had an impact on the thermal preferences of the snails. Individuals that shed cercariae of Bilharziella polonica, Cotylurus sp., Notocotylus ephemera, Rubenstrema exasperatum/Neoglyphe locellus, Rubenstrema opisthovitellinum, or Tylodelphys excavata displayed symptoms of behavioural anapyrexia, similarly to experimentally injured snails. This response increased the survival of infected individuals while simultaneously prolonging the period of shedding of dispersive forms of parasites. This point of view was upheld by the observation that infected snails bred at 19 degrees C lived longer than at 26 degrees C and the shedding rate of cercariae at a lower temperature was lower than at a higher one. PMID- 22244796 TI - Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: a retrospective cohort study. AB - BACKGROUND: Accelerated vascular calcification contributes to cardiovascular disease burden in patients with chronic kidney disease (CKD). We hypothesized that bisphosphonate therapy would reduce the risk of mortality and cardiovascular events in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult women with stage 3 or 4 CKD receiving primary care in a large rural integrated health care system in 2004-2010. EXPOSURE: Time-dependent exposure status based on outpatient prescription for any medication within the bisphosphonate class, obtained from electronic health records. OUTCOMES: Time to death and first cardiovascular event (composite of myocardial infarction, heart failure, or stroke). RESULTS: Data from 9,604 eligible female patients with CKD were analyzed; 3,234 were treated with bisphosphonate therapy. During a median follow-up of 3.9 (25th-75th percentile, 2.3-5.4) years, there were 286 versus 881 deaths and 206 versus 571 cardiovascular events (treated vs not-treated groups, respectively). In a multivariate Cox proportional hazard model, the adjusted HR for death (treated vs not treated) was 0.78 (95% CI, 0.67-0.91; P = 0.003). In Cox modeling adjusted for similar baseline covariates, treatment with bisphosphonates was not associated with a lower risk of the composite cardiovascular outcome (adjusted HR, 1.14; 95% CI, 0.94-1.39; P = 0.2). LIMITATIONS: Residual confounding by unidentified factors, exclusion of male patients, and lack of information about longitudinal drug adherence. CONCLUSIONS: For female patients with CKD, treatment with bisphosphonates is associated with a lower risk of death, but not cardiovascular events. Confirmatory studies and investigations of potential causal mechanisms are warranted. PMID- 22244797 TI - The return of the variance: intraspecific variability in community ecology. AB - Despite being recognized as a promoter of diversity and a condition for local coexistence decades ago, the importance of intraspecific variance has been neglected over time in community ecology. Recently, there has been a new emphasis on intraspecific variability. Indeed, recent developments in trait-based community ecology have underlined the need to integrate variation at both the intraspecific as well as interspecific level. We introduce new T-statistics ('T' for trait), based on the comparison of intraspecific and interspecific variances of functional traits across organizational levels, to operationally incorporate intraspecific variability into community ecology theory. We show that a focus on the distribution of traits at local and regional scales combined with original analytical tools can provide unique insights into the primary forces structuring communities. PMID- 22244798 TI - Validation of self-reported khat chewing amongst khat chewers: an exploratory study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Khat chewing amongst the UK communities originating from Yemen and the East African coast is suggested to create dependency through its main stimulant components (cathinone, norephedrine and norpseudoephedrine) on the central nervous system. AIMS OF THE STUDY: To validate self-reported khat chewing behaviours by measuring levels of cathinone, norephedrine and norpseudoephedrine in saliva and to explore their associations with self-reported khat chewing dependency. MATERIALS AND METHODS: Face-to-face interviews were conducted amongst 30 male UK-resident khat chewers. Saliva samples were collected from each participant and high-performance liquid chromatography (HPLC) employed to extract and quantify the levels of the biomarkers. RESULTS: The mean (SD) for cathinone and the composite norephedrine and norpseudoephedrine levels were 33.93 (+/-39.20) and 29.28 (+/-26.32)MUg/mL respectively. These biomarkers were significantly associated (p<=0.05) with khat chewing dependency. CONCLUSIONS: Validation of self-reported khat chewing is possible. Khat chewing dependency correlates significantly with biomarker levels in saliva. Replication is required. PMID- 22244799 TI - The stress-response dampening hypothesis: how self-esteem and stress act as mechanisms between negative parental bonds and alcohol-related problems in emerging adulthood. AB - The stress dampening model (Marlatt, 1987; Sayette, 1993; Sher, 1987) suggests certain individuals may use alcohol to escape from their negative life experiences. Pathological reasons for drinking (e.g., using alcohol as a means to cope) reflect the degree to which individuals are motivated to use alcohol in order to dampen or alleviate the stress they are experiencing (Johnson, Schwitters, Wilson, Nagoshi, & McClearn, 1985). Direct and mediational links among parental bonds (rejection, care, overprotection, autonomy, and neglect), self-esteem, stress, pathological reasons for drinking, and alcohol-related problems were explored. A Structural Equation Model with (405 students; 164 women, 241 men) college students was examined. Three path mediational analyses revealed several mediated pathways. Greater feelings of perceived father/mother neglectfulness (i.e., offspring feeling parents do not show up for them) were indirectly linked to more alcohol-related problems (e.g., indicative of alcohol use or dependence in emerging adulthood) through increased stress and pathological reasons for drinking. Furthermore, higher levels of father rejection (i.e., perception of feeling unwanted) were indirectly linked to more pathological reasons for drinking through low self-esteem and increased stress. However, greater feelings of mother care (affectionate and attentive) were indirectly linked to fewer pathological reasons for drinking through higher self esteem and lower levels of stress. Moreover, high self-esteem was found to be indirectly linked to fewer alcohol-related problems through decreased stress and pathological reasons for drinking. These findings suggest several specific pathways for using alcohol to self-medicate (i.e., consume alcohol for a specific purpose) or dampen feelings of stress. PMID- 22244800 TI - Financial incentives and weight control. AB - This paper reviews research studies evaluating the use of financial incentives to promote weight control conducted between 1972 and 2010. It provides an overview of behavioral theories pertaining to incentives and describes empirical studies evaluating specific aspects of incentives. Research on financial incentives and weight control has a history spanning more than 30 years. Early studies were guided by operant learning concepts from Psychology, while more recent studies have relied on economic theory. Both theoretical orientations argue that providing financial rewards for losing weight should motivate people to engage in behaviors that produce weight loss. Empirical research has strongly supported this idea. However, results vary widely due to differences in incentive size and schedule, as well as contextual factors. Thus, many important questions about the use of incentives have not yet been clearly answered. Weight-maintenance studies using financial incentives are particularly sparse, so that their long-term efficacy and thus, value in addressing the public health problem of obesity is unclear. Major obstacles to sustained applications of incentive in weight control are funding sources and acceptance by those who might benefit. PMID- 22244801 TI - Phase II study of biweekly cetuximab in combination with irinotecan as second line treatment in patients with platinum-resistant gastro-oesophageal cancer. AB - BACKGROUND: The purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma. PATIENTS AND METHODS: Patients with failure to first-line platinum-based chemotherapy received cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) every second week until disease progression. Toxicity was evaluated according to The Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 3.0. Antitumour activity was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v. 1.0. RESULTS: Sixty three patients were enrolled, median age was 60 years, median performance status was 1 (0-1), 35 patients had two or more organs involved. The median number of courses was 5 (range 1-25). Response rate was 11% (6 partial response (PR)) and 37% had stable disease. Median progression free survival was 2.8 months and overall survival (OS) was 6.1 months. Grade 3-4 toxicity included: diarrhoea (6%), fatigue (5%), vomiting (5%) and neutropenia (16%). Two patients developed febrile neutropenia. Forty-six patients (73%) had developed grade 1-2 skin rash. Patients developing skin rash had a prolonged survival with an OS at 7.1 months. CONCLUSIONS: The combination of cetuximab and irinotecan is active as second-line therapy in patients with gastro-oesophageal cancer. Cetuximab induced skin rash was associated with prolonged survival. PMID- 22244802 TI - Effect of cigarette smoking on quality of life in small cell lung cancer patients. AB - BACKGROUND: Continued cigarette smoking after small cell lung cancer (SCLC) diagnosis has been shown to shorten patients' survival, but little is known about the impact of smoking and cessation on quality of life (QOL) profile (e.g., overall QOL, pain, fatigue, cough, dyspnea, appetite change, and performance status) in SCLC survivors (who survived at least 6 months post initial diagnosis). In this study, we sought to evaluate the relationship between cigarette smoking and QOL profiles in SCLC patients. METHODS: A total of 223 survivors were classified into five groups: never smokers, former smokers (quit more than 1 year prior to diagnosis), recent quitters (quit within 1 year surrounding diagnosis), late quitters (quit after 1 year post diagnosis) and never quitters. One hundred and sixty-eight of these survivors were matched with 334 lung-cancer-free controls on age, gender, and smoking status for comparative analysis. QOL scales were scored from 0 (worse) to 100 (best). Conditional logistic regression, linear mixed-effect models, and Wilcoxon signed rank tests were used. RESULTS: SCLC survivors consistently showed a significant deficit in QOL profile; e.g., mean overall QOL in patients was 17.5 points worse than the controls (p<0.0001). Among all smokers, former smokers reported the best QOL profile, while late or never quitters reported the worst. The recent quitters showed an improving trend in QOL profile and lower percent of reduced appetite (an average of 43%) compared to the late or never quitters (58%). CONCLUSIONS: Our study confirmed the negative impact of smoking on SCLC survivors' QOL and found that smoking cessation surrounding the time of diagnosis could improve overall QOL and symptoms. The findings of this study provide evidence for oncologists to recommend smoking cessation to their SCLC patients. PMID- 22244803 TI - Trucut biopsy of breast lesions: the first step toward international standards in developing countries. AB - The new concept in breast cancer diagnosis and treatment is based on a less invasive, more accurate and effective strategy, with a multidisciplinary approach in a specialised breast unit. When indicated, conservative surgery has replaced mastectomy with sentinel-node biopsy substituting routine axillary dissection. But the key factor in respect of these new standards is to confirm the cancer before going to the operating room. Trucut biopsy is performed instead of incisional or excisional biopsy and frozen section. The technique is reliable, simple, and reproducible, and not at all expensive; it can be adapted even for low-income developing countries. MATERIALS AND METHODS: Between March 2006 and June 2010, 764 patients under clinical suspicion of cancer and/or with BIRADS (Breast Imaging Reporting and Data System) III-V in imaging in one university and one private hospital in Tehran, Iran underwent trucut biopsy (60% palpable and 40% non-palpable lesions). Cancer was found in 30.8% of the cases. In benign pathology, in concordance with clinical and imaging suspicion, surgery was omitted with short-term follow-up. For palpable symptomatic benign lesions surgery was performed to relieve the patient's symptoms. When the pathology report was not in concordance with clinical/imaging suspicion (1.8%), and in the presence of moderate and severe hyperplasia with or without atypia, in lobular and papillary lesions (4.9%) open biopsy was done to rule out cancer (10 added cancers, 1.3%; total cancers 32.1%). Cancer surgery was done as a single procedure in 89.8% of cases. CONCLUSION: Trucut biopsy for breast lesion assessment is the first step toward a new concept in breast cancer care. It is simple, reduces the number of surgeries (no surgery for non-symptomatic benign lesions and one surgery for cancer), and avoids diagnostic errors with full respect for the patient's rights. We insist on its routine use to extend international guidelines while decreasing the total cost of this common disease in all low-resource countries. PMID- 22244804 TI - Structural identification and biological activity of positional isomers of long acting and mono-PEGylated recombinant human granulocyte colony-stimulating factor with trimeric-structured methoxy polyethylene glycol N-hydroxysuccinimidyl functional group. AB - The individual positional isomers from the mono-PEGylated recombinant human granulocyte colony-stimulating factor (rhG-CSF) were successfully isolated with additional strong cation exchange chromatography using Source 15S. The three isolated individual positional isomers were found to be homogeneous by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), analytical size exclusion high-performance liquid chromatography (SE-HPLC), and analytical cation exchange HPLC (CIE-HPLC) and were also characterized with respect to site of PEGylation by enzymatic digestion with endoproteinase Lys-C and N-terminal sequencing. In addition, in vitro biological activity was determined by cell proliferation assay. It was determined that the three isolated individual positional isomers were PEGylated at Lys35, Met(N-terminal), and Lys17 of the rhG CSF molecule with a 23-kDa trimer-structured methoxy polyethylene glycol N hydroxysuccinimidyl functional group (mPEG-NHS). All individual positional isomers (Lys35-PEGylated rhG-CSF, Met(N-terminal)-PEGylated rhG-CSF, and Lys17 PEGylated rhG-CSF) retained in vitro biological activity and were found to be 18.5%, 37.6%, and 7.1%, respectively, compared with the rhG-CSF molecule. The significantly different in vitro biological activities observed in the individual positional isomers could be presumably due to interference of receptor binding or active sites on the rhG-CSF molecule. In conclusion, the individual positional isomers isolated from the mono-PEGylated rhG-CSF were well characterized with respect to the site of PEGylation involving Lys35, Met(N-terminal), and Lys17. This characterization of the individual positional isomers would be critical to provide a basis for establishing consistency in the manufacturing process. PMID- 22244805 TI - A rapid and quantitative coat protein complex II vesicle formation assay using luciferase reporters. AB - The majority of protein export from the endoplasmic reticulum (ER) is facilitated by coat protein complex II (COPII). The COPII proteins deform the ER membrane into vesicles at the ER exit sites. During the vesicle formation step, the COPII proteins load cargo molecules into the vesicles. Formation of COPII vesicles has been reconstituted in vitro in yeast and in mammalian systems. These in vitro COPII vesicle formation assays involve incubation of microsomal membranes and purified COPII proteins with nucleotides. COPII vesicles are separated from the microsomes by differential centrifugation. Interestingly, the efficiency of the COPII vesicle formation with purified recombinant mammalian COPII proteins is lower than that with cytosol, suggesting that an additional cytosolic factor(s) is involved in this process. Indeed, other studies have also implicated additional factors. To facilitate biochemical identification of such regulators, a rapid and quantitative COPII vesicle formation assay is necessary because the current assay is lengthy. To expedite this assay, we generated luciferase reporter constructs. The reporter proteins were packaged into COPII vesicles and yielded quantifiable luminescent signals, resulting in a rapid and quantitative COPII vesicle formation assay. PMID- 22244806 TI - In-microbe formation of nucleotide sugars in engineered Escherichia coli. AB - Numerous different nucleotide sugars are used as sugar donors for the biosynthesis of glycans by bacteria, humans, fungi, and plants. However, many of these nucleotide sugars are not available either in their native form or with the sugar portion labeled with a stable or radioactive isotope. Here we demonstrate the use of Escherichia coli metabolically engineered to contain genes that encode proteins that convert monosaccharides into their respective monosaccharide-1 phosphates and subsequently into the corresponding nucleotide sugars. In this system, which we designated "in-microbe", reactions occur within 2 to 4 h and can be used to generate nucleotide sugars in amounts ranging from 5 to 12.5 MUg/ml cell culture. We show that the E. coli can be engineered to produce the seldom observed nucleotide sugars UDP-2-acetamido-2-deoxy-glucuronic acid (UDP-GlcNAcA) and UDP-2-acetamido-2-deoxy-xylose (UDP-XylNAc). Using similar strategies, we also engineered E. coli to synthesize UDP-galacturonic acid (UDP-GalA) and UDP galactose (UDP-Gal). 13C- and 15N-labeled NDP-sugars are formed using [13C] glucose as the carbon source and with [15N]NH4Cl as the nitrogen source. PMID- 22244807 TI - Advantage of menadione-catalyzed chemiluminescent assay for the determination of viable mammalian cell number. AB - A chemiluminescent assay composed of TCPO [bis(2,4,6-trichlorophenyl)oxalate] and harmless rhodamine B is proposed to be superior in the determination of menadione catalyzed hydrogen peroxide (H2O2) production by viable mammalian cells to that composed of TCPO and harmful pyrene [Anal. Biochem. 207 (1992) 255-260]. In tests, the proposed assay showed that the measurable concentration of H2O2 and the viable cell number ranged from 10-9 to 10-3 M and from 2 * 102 to 2 * 106 cells/100 MUl/well in the presence of 10% bovine serum, respectively. The measuring time was approximately 10 min. On the other hand, the measurable cell numbers by the colorimetric WST-1 and MTT assays requiring several hours ranged only from 103 to 104 cells/100 MUl/well and from 104 to 105 cells/100 MUl/well, respectively. The cytotoxicity of sodium dodecyl sulfate was also observed at intervals of 1 min by the proposed assay, but not by the above colorimetric assays. PMID- 22244808 TI - Quantitative Forster resonance energy transfer analysis for kinetic determinations of SUMO-specific protease. AB - Forster resonance energy transfer (FRET) technology has been widely used in biological and biomedical research, and it is a very powerful tool for elucidating protein interactions in either dynamic or steady state. SUMOylation (the process of SUMO [small ubiquitin-like modifier] conjugation to substrates) is an important posttranslational protein modification with critical roles in multiple biological processes. Conjugating SUMO to substrates requires an enzymatic cascade. Sentrin/SUMO-specific proteases (SENPs) act as an endopeptidase to process the pre-SUMO or as an isopeptidase to deconjugate SUMO from its substrate. To fully understand the roles of SENPs in the SUMOylation cycle, it is critical to understand their kinetics. Here, we report a novel development of a quantitative FRET-based protease assay for SENP1 kinetic parameter determination. The assay is based on the quantitative analysis of the FRET signal from the total fluorescent signal at acceptor emission wavelength, which consists of three components: donor (CyPet-SUMO1) emission, acceptor (YPet) emission, and FRET signal during the digestion process. Subsequently, we developed novel theoretical and experimental procedures to determine the kinetic parameters, k(cat), K(M), and catalytic efficiency (k(cat)/K(M)) of catalytic domain SENP1 toward pre-SUMO1. Importantly, the general principles of this quantitative FRET-based protease kinetic determination can be applied to other proteases. PMID- 22244809 TI - Metabolism, excretion, and pharmacokinetics of [14c]-radiolabeled aleglitazar: a phase I, nonrandomized, open-label, single-center, single-dose study in healthy male volunteers. AB - BACKGROUND: Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-alpha/gamma agonist with a balanced activity (similar half-maximal effective concentrations) toward PPAR-alpha and -gamma that is in clinical development for the treatment of patients who have experienced an acute coronary syndrome and have type 2 diabetes mellitus. OBJECTIVE: This study aimed to characterize the metabolic profile and the routes and rates of elimination of aleglitazar and its major metabolites in humans. METHODS: In this Phase I, nonrandomized, open-label, single-center, single-dose study, 6 healthy male subjects each received a single oral dose of 300 MUg [(14)C]-labeled aleglitazar. Total urine and feces were collected for up to 15 days. Venous blood samples were collected to determine the plasma concentrations of aleglitazar and its metabolites and for radioactivity counting. RESULTS: The median age (range) and mean (SD) body mass index of subjects were 48 (41-60) years and 24.8 (3.0) kg/m(2), respectively. Recovery of total radioactivity, as a percentage of the dose administered, was high (93 [3]%). Aleglitazar was predominantly eliminated in feces (mean, 66% [range, 55%-74%]), with only 28% (range, 22%-36%) of the radioactivity recovered in urine. Only a mean (SD) of 1.8 (0.8)% of aleglitazar was eliminated unchanged as parent compound in feces and only 0.3 (0.4)% was eliminated in urine. Almost all excreted drug-related material could be attributed to its 2 main metabolites, M1 (21%) and M6 (38%). Treatment with aleglitazar was well tolerated, and no serious adverse events were reported. CONCLUSIONS: In healthy volunteers, aleglitazar was excreted mainly in the form of inactive metabolites, mostly M1 and M6, with only a small proportion eliminated unchanged. PMID- 22244810 TI - Purification and characterization of a novel antimicrobial peptide from Brevibacillus laterosporus strain A60. AB - A novel antimicrobial peptide, with molecular mass of 1602.0469Da, produced by Brevibacillus laterosporus strain A60 was isolated and purified from the soil of mango plants. The purification procedure consisted of ammonium sulfate precipitation, cation exchange chromatography on an HiTrap SP HP column, thin layer chromatography and High Performance Liquid Chromatography (HPLC) on C18 reversed-phase column. After the four isolation procedures, one peptide with antimicrobial activity was obtained and named BL-A60. The determination of the complete amino acid sequences of this peptide showed that it contains eleven amino acid residues, L-Y-K-L-V-K-V-V-L-N-M, and a choline connected to the N terminal and a tenuazonic acid modified of the C-terminal. This peptide shows relatively low identification to other antimicrobial peptides from bacteria. Purified BL-A60 showed high pH and thermal stability and a strong inhibition of different stages of the life cycle of Phytophthora capsici, including mycelial growth, sporangia formation and cystospore germination, with EC(50) values of 7.89, 0.60 and 21.96 MUg ml(-1), respectively. PMID- 22244811 TI - Distribution of somatostatin receptor 5 in mouse and bullfrog retinas. AB - Somatostatin (SRIF), as a neuroactive peptide in the CNS, may act as a neuromodulator through activation of five specific receptor subtypes (sst(1) sst(5)). In this work we conducted a comparative study of the expression of sst(5) in mouse and bullfrog retinas by immunofluorescence double labeling. Basically, the expression profiles of sst(5) in the retinas of the two species were similar. That is, in the inner retina sst(5) was localized to dopaminergic and cholinergic amacrine cells, stained by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) respectively, and cells in the ganglion cell layer, whereas in the outer retina immunostaining for sst(5) was observed in horizontal cells. However, a more widespread, abundant distribution of labeling for sst(5), as compared to mouse retina, was seen in bullfrog retina: strong labeling for sst(5) was diffusely distributed in both outer and inner plexiform layers (OPL and IPL) in the bullfrog retina, but the labeling was only observed in the IPL of the mouse retina. In addition, bullfrog photoreceptors, both rods and cones, but not mouse ones, were labeled by sst(5). In combination with the experiments showing that SRIF-immunoreactivity was mainly found in the inner retina, our results suggest that SRIF, released from SRIF-containing cells in the inner retina, may play a neuromodulatory role in both outer and inner retina mediated by volume transmission via sst(5) in bullfrog retina, while the SRIF action may be largely restricted to the mouse inner retina. PMID- 22244812 TI - Urotensin II and urocortin trigger the expression of myostatin, a negative regulator of cardiac growth, in cardiomyocytes. AB - Urotensin II (UII) and urocortin (UCN) are potent contributors to the physiopathology of heart failure. Our study investigated the effects of UII and UCN on the expression of myostatin (Mstn) in primary culture of adult cardiomyocytes. Adult rat cardiomyocytes were stimulated for 48 h with UII and UCN. Cell size and protein content were determined. Mstn gene expression was determined by real time quantitative polymerase chain reaction. Treatment with UII and UCN stimulates hypertrophy of adult cardiomyocytes. This effect was associated with a twofold increase of Mstn gene expression. We have established for the first time that the two hypertrophic peptides UII and UCN stimulate the expression of Mstn. PMID- 22244813 TI - Extracellular signal-regulated kinase 1/2 activation is involved in intermedin1 53 attenuating myocardial oxidative stress injury induced by ischemia/reperfusion. AB - Intermedin (IMD)(1-53) is a novel member of the calcitonin gene-related peptide superfamily and has potent cardioprotective effects against myocardial injury induced by ischemia-reperfusion (I/R). To explore the mechanism of the IMD(1-53) cardioprotective effect, we studied the anti-oxidant effects of IMD(1-53) on myocardial injury induced by I/R in vivo in rat and H(2)O(2) treatment in vitro in rat cardiomyocytes. Compared with sham treatment, I/R treatment induced severe lipid peroxidation injury in rat myocardium: plasma malondialdehyde (MDA) content and myocardial LDH activity was increased by 34% and 85% (all P<0.01); Mn superoxide dismutase (Mn-SOD) and catalase (CAT) activity was reduced 80% and 86% (all P<0.01), respectively, and the protein levels of the NADPH oxidase complex subunits gp91(phox) and p47(phox) were markedly increased, by 86% (P<0.05) and 95% (P<0.01), respectively; IMD(1-53) treatment ameliorated lipid peroxidation injury: plasma MDA content and myocardial LDH activity was decreased by 30% (P<0.05) and 36% (P<0.01); Mn-SOD and CAT activity was elevated 1.0- and 4.3-fold (all P<0.01), respectively; and the protein levels of gp91(phox) and p47(phox) were reduced, by 28% and 36% (both P<0.05), respectively. Concurrently, IMD(1-53) treatment markedly promoted cell viability and inhibited apoptosis in cardiomyocytes as compared with H(2)O(2) treatment alone. Furthermore, IMD(1-53) increased the ratio of p-ERK to ERK by 66% (P<0.05) as compared with I/R alone, and the protective effect of IMD(1-53) on H(2)O(2)-induced apoptosis was abolished by preincubation with PD98059, a MEK inhibitor. IMD(1-53) may improve the oxidative stress injury induced by I/R via inhibiting the production of reactive oxygen species and enhancing ERK phosphorylation. PMID- 22244815 TI - The influence of a carbon layer deposited on a zirconia surface on the retention of polar analytes in an organic rich mobile phase. AB - Hydrophilic interaction liquid chromatography (HILIC) represents a modern MS friendly approach to the analysis of polar compounds. To date especially silica based HILIC stationary phases are utilized. Recently the papers concerning retention of polar analytes on unmodified titania and zirconia as well as a polybutadiene modified zirconia stationary phase under HILIC conditions have been published. In this work the investigation of a highly hydrophobic carbon-coated zirconia column under HILIC conditions was reported. The influence of buffer concentration, buffer type, pH and temperature on the elution and chromatographic efficiency were studied. The processes participating on the retention of polar compounds showed a multimodal character. The retention was governed rather by surface adsorption than phase partition in high ACN mobile phases. The ligand exchange remained an important retention force although the access of the analytes to the active surface was significantly hindered by the carbon coating. Besides ligand exchange and hydrophilic interactions also the hydrophobic carbon layer was involved in the retention of carboxylic acids and especially xanthines in the organic rich mobile phase. PMID- 22244814 TI - Enhanced antifungal and insect alpha-amylase inhibitory activities of Alpha-TvD1, a peptide variant of Tephrosia villosa defensin (TvD1) generated through in vitro mutagenesis. AB - TvD1 is a small, cationic, and highly stable defensin from the weedy legume, Tephrosia villosa with demonstrated in vitro antifungal activity. We show here peptide modifications in TvD1 that lead to enhanced antifungal activities. Three peptide variants, S32R, D37R, and Alpha-TvD1 (-G-M-T-R-T-) with variations in and around the beta2-beta3 loop region that imposes the two beta-strands, beta2 and beta3 were generated through in vitro mutagenesis. Alpha-TvD1 exhibited enhanced antifungal activity against the fungal pathogens, Fusarium culmorum and Fusarium oxysporum with respective IC(50) values of 2.5 MUM and 3.0 MUM, when compared to S32R (<5.0 MUM and >5.0 MUM), D37R (5.5 MUM and 4.5 MUM), and the wild type TvD1 (6.5 MUM). Because of the enhanced antifungal activity, this variant peptide was characterized further. Growth of F. culmorum in the presence of Alpha-TvD1 showed deformities in hyphal walls and nuclear damage. With respect to the plant pathogenic bacterium, Pseudomonas syringae pv. tomato strain DC3000, both Alpha TvD1 and the wild type TvD1 showed comparable antibacterial activity. Both wild type TvD1 and Alpha-TvD1 displayed inhibitory activity against the alpha-amylase of the mealworm beetle, Tenebrio molitor (TMA) with the latter showing enhanced activity. The human salivary as well as barley alpha-amylase activities were not inhibited even at concentrations of up to 50 MUM, which has been predicted to be due to differences in the pocket size and the size of the interacting loops. Present study shows that the variant Alpha-TvD1 exhibits enhanced antifungal as well as insect alpha-amylase inhibitory activity. PMID- 22244816 TI - Evaluating metabolic stress and plasmid stability in plasmid DNA production by Escherichia coli. AB - In the context of recombinant DNA technology, the development of feasible and high-yielding plasmid DNA production processes has regained attention as more evidence for its efficacy as vectors for gene therapy and DNA vaccination arise. When producing plasmid DNA in Escherichia coli, a number of biological restraints, triggered by plasmid maintenance and replication as well as culture conditions are responsible for limiting final biomass and product yields. This termed "metabolic burden" can also cause detrimental effects on plasmid stability and quality, since the cell machinery is no longer capable of maintaining an active metabolism towards plasmid synthesis and the stress responses elicited by plasmid maintenance can also cause increased plasmid instability. The optimization of plasmid DNA production bioprocesses is still hindered by the lack of information on the host metabolic responses as well as information on plasmid instability. Therefore, systematic and on-line approaches are required not only to characterise this "metabolic burden" and plasmid stability but also for the design of appropriate metabolic engineering and culture strategies. The monitoring tools described to date rapidly evolve from laborious, off-line and at line monitoring to online monitoring, at a time-scale that enables researchers to solve these bioprocessing problems as they occur. This review highlights major E. coli biological alterations caused by plasmid maintenance and replication, possible causes for plasmid instability and discusses the ability of currently employed bioprocess monitoring techniques to provide information in order to circumvent metabolic burden and plasmid instability, pointing out the possible evolution of these methods towards online bioprocess monitoring. PMID- 22244817 TI - Oncology team members' perceptions of a virtual navigation tool for cancer patients. AB - OBJECTIVES: The Internet has become an important source of health information for patients and health care providers (HCPs) alike. Whereas studies have begun to document the effects of the internet on health behaviors and outcomes, surprisingly few studies have explored HCPs' perceptions of the internet as a key resource accessed by patients. However, as HCPs are seen as pivotal in guiding patients toward these resources, it is timely to study their perceptions. Therefore, the present inquiry explores HCPs' views of a recently developed high quality virtual navigation tool called the Oncology Interactive NavigatorTM (OIN). DESIGN: Using a qualitative approach, in-depth interviews were conducted with 16 members of a multidisciplinary colorectal oncology team and volunteers at a large Cancer Centre in Montreal, Quebec, Canada. RESULTS: Content analysis revealed emerging themes centering on key benefits including: perceptions of a highly accessible, comprehensive high quality repository of cancer information; a means to further enhance HCP-patient communication and trust; and a significant catalyst to patient-family communication and support. Perceived drawbacks included patient (e.g., socio-demographic profile) and system's (e.g., professional roles and time constraints) characteristics that may limit OINTM full implementation and uptake. CONCLUSIONS: The findings underscore the relevance of virtual navigation tools to ensure optimal person-centred care in cancer. Findings also suggest how virtual tools such as the OINTM can best be used in practice as well as they guide strategies to adopt to optimize implementation of similar innovations in health care. PMID- 22244818 TI - Record completeness and data concordance in an anesthesia information management system using context-sensitive mandatory data-entry fields. AB - BACKGROUND: Use of an anesthesia information management system (AIMS) does not insure record completeness and data accuracy. Mandatory data-entry fields can be used to assure data completeness. However, they are not suited for data that is mandatory depending on the clinical situation (context sensitive). For example, information on equal breath sounds should be mandatory with tracheal intubation, but not with mask ventilation. It was hypothesized that employing context sensitive mandatory data-entry fields can insure high data-completeness and accuracy while maintaining usability. METHODS: A commercial off-the-shelf AIMS was enhanced using its built-in VBScript programming tool to build event-driven forms with context-sensitive mandatory data-entry fields. One year after introduction of the system, all anesthesia records were reviewed for data completeness. Data concordance, used as a proxy for accuracy, was evaluated using verifiable age-related data. Additionally, an anonymous satisfaction survey on general acceptance and usability of the AIMS was performed. RESULTS: During the initial 12 months of AIMS use, 12,241 (99.6%) of 12,290 anesthesia records had complete data. Concordances of entered data (weight, size of tracheal tubes, laryngoscopy blades and intravenous catheters) with patients' ages were 98.7 99.9%. The AIMS implementation was deemed successful by 98% of the anesthesiologists. Users rated the AIMS usability in general as very good and the data-entry forms in particular as comfortable. LIMITATIONS: Due to the complexity and the high costs of implementation of an anesthesia information management system it was not possible to compare various system designs (for example with or without context-sensitive mandatory data entry-fields). Therefore, it is possible that a different or simpler design would have yielded the same or even better results. This refers also to the evaluation of usability, since users did not have the opportunity to work with different design approaches or even different computer programs. CONCLUSIONS: Using context-sensitive mandatory fields in an anesthesia information management system was associated with high record completeness rate and data concordance. In addition, the system's usability was rated as very good by its users. PMID- 22244819 TI - Postoperative information needs and communication barriers of esophageal cancer patients. AB - OBJECTIVE: Given the poor prognosis of esophageal cancer and the impact of surgery on health-related quality of life (HRQL), addressing patients' postoperative information needs is important. This study aimed to examine (1) the content and type of patients' information needs and (2) patient perceived facilitators and barriers to patient participation. METHODS: Interviews were conducted with 20 purposefully selected esophageal cancer patients. Open and structured questions were alternated. The transcribed interviews were analysed inductively and deductively, using MAXqda. RESULTS: Patients' post-operative information needs concerned HRQL, medical care and prognosis, covering several sub-domains. Different types of needs were identified, e.g., requests for information about cause, course and self-management. Barriers to patient participation mostly reflected beliefs and skills, and could be categorized into agenda and communication barriers. Facilitators of patient participation reflected physician, patient and interaction characteristics, companion support and pre-visit preparation. Many patients saw merit in pre-visit preparation interventions; few endorsed skill-building interventions. CONCLUSION: This study listed the postoperative information needs of esophageal cancer patients. Moreover, it gained insight into patient-perceived barriers and facilitators of patient participation. PRACTICE IMPLICATIONS: The findings demonstrate what information physicians should have available and informs interventions to support patients in meeting their information needs. PMID- 22244821 TI - Morin inhibits interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes. AB - It is well known that the inflammatory cytokines play important roles in osteoarthritis (OA). In the present study, we investigated the anti-inflammatory properties of morin in chondrocytes. The nitric oxide (NO) production was determined by Griess method, the prostaglandin E2 (PGE(2)) production was detected by Enzyme-linked immunosorbent assay (ELISA). The expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 were investigated by quantitative real-time PCR and western blot. In addition, western blotting and immunofluorescence staining were performed to investigate the protein level of inhibitor of nuclear factor-kappaB (IkappaB-alpha) and the translocation of nuclear factor kappa B (NF-kappaB). For the in vivo study, morin was administered by intra-articular injection in rats, and the gene expression of iNOS and COX-2 was assessed. We showed that morin inhibited the production of NO and PGE(2) as well as the expression of iNOS and COX-2 in interleukin-1-beta (IL-1beta)-induced chondrocytes. In addition, morin suppressed the degradation of IkappaB-alpha as well as the translocation of NF-kappaB. In vivo study, morin exerted anti inflammatory properties in an IL-1beta-induced rat OA model. Our data suggest that morin possess potential value in the treatment of OA. PMID- 22244820 TI - Double strand binding-single strand incision mechanism for human flap endonuclease: implications for the superfamily. AB - Detailed structural, mutational, and biochemical analyses of human FEN1/DNA complexes have revealed the mechanism for recognition of 5' flaps formed during lagging strand replication and DNA repair. FEN1 processes 5' flaps through a previously unknown, but structurally elegant double-stranded (ds) recognition/single stranded (ss) incision mechanism that both selects for 5' flaps and selects against ss DNA or RNA, intact dsDNA, and 3' flaps. Two major DNA binding interfaces, including a K(+) bridge between the DNA and the H2TH motif, are spaced one helical turn apart and together select for substrates with dsDNA. A conserved helical gateway and a helical cap protects the two-metal active site and selects for ss flaps with free termini. Structures of substrate and product reveal an unusual step between binding substrate and incision that involves a double base unpairing with incision occurring in the resulting unpaired DNA or RNA. Ordering of the active site requires a disorder-to-order transition induced by binding of an unpaired 3' flap, which ensures that the product is ligatable. Comparison with FEN superfamily members, including XPG, EXO1, and GEN1, identifies superfamily motifs such as the helical gateway that select for ss-dsDNA junctions and provides key biological insights into nuclease specificity and regulation. PMID- 22244823 TI - PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy? AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease are characterized by inappropriate constriction of the airway smooth muscle. In this context, the physiological response of the human airways to selective relaxant agonists like PGE(2) is highly relevant. The aim of this study was thus to characterize the PGE(2) receptor subtypes (EP(2) or EP(4)) involved in the relaxation of human bronchial preparations. METHODS: Human bronchial preparations cut as rings were mounted in organ baths for isometric recording of tension and a pharmacological study was performed using selective EP(2) or EP(4) ligands. RESULTS: In the presence of a thromboxane TP receptor antagonist and indomethacin, PGE(2) induced the relaxation of human bronchi (E(max) = 86 +/- 04% of papaverine response; pEC(50) value = 7.06 +/- 0.13; n = 6). This bronchodilation was significantly blocked by a selective EP(4) receptor antagonist (GW627368X, 1 and 10 MUmol/L) with a pK(B) value of 6.38 +/- 0.19 (n = 5). In addition, the selective EP(4) receptor agonists (ONO-AE1-329; L-902688), but not the selective EP(2) receptor agonist (ONO-AE1-259), induced potent relaxation of bronchial preparations pre contracted with histamine or anti-IgE. CONCLUSION: PGE(2) and EP(4) agonists induced potent relaxations of human bronchial preparations via EP(4) receptor. These observations suggest that EP(4) receptor agonists could constitute therapeutic agents to treat the increased airway resistance in asthma. PMID- 22244824 TI - Comparative acute toxicity of twenty-four insecticides to earthworm, Eisenia fetida. AB - In this study, we used two different types of bioassay, a contact filter paper toxicity bioassay and a soil toxicity bioassay, to compare the acute toxicity of twenty-four insecticides belonging to six chemical categories on earthworm species, Eisenia fetida. Results of the contact filter paper toxicity bioassay indicated that neonicotinoids were super toxic to E. fetida (48 h-LC(50) value ranged from 0.0088 to 0.45 MUg cm(-2)), pyrethroids were very toxic (48 h-LC(50) values ranged from 10.55 to 25.7 MUg cm(-2)) and insect growth regulators (IGRs) were moderately toxic (48 h-LC(50) values ranged from 117.6 to 564.6 MUg cm(-2)) to the worms. However, antibiotics, carbamates and organophosphates induced variable toxicity responses in E. fetida, and were very to extremely toxic (48 h LC(50) values ranged from 3.64 to 75.75 MUg cm(-2)). Results of the soil toxicity bioassays showed a different pattern of toxicity except that neonicotinoids were the most toxic even under the soil toxicity bioassay system. The acute toxicity of neonicotinoids was higher than those of antibiotics, carbamates, IGRs and organophosphates. In contrast, pyrethroids were the least toxic to the worms under the soil toxicity bioassay system. It was concluded that irrespective of bioassay systems, earthworms were more susceptible to neonicotinoids than other modern synthetic insecticides. PMID- 22244825 TI - Diablo/SMAC: a novel biomarker of pollutant exposure in European flounder (Platichthys flesus). AB - Diablo (or SMAC) is a protein released from mitochondria following apoptotic stimuli and inhibits the actions of Inhibitors of Apoptosis (IAP) proteins. IAPs regulate the activity of caspases and NFkB, the primary executioners of apoptosis and of inflammation, respectively. Thus, Diablo is important for the regulation of cellular responses to damage. In Northern Europe, statutory governmental marine monitoring programs measure various biomarkers in flounder to indicate biological effects of pollutant exposure. More recently transcriptomic techniques have been applied in flounder to gain a more comprehensive understanding of pollutant effects, and to discover novel biomarkers. In most of these studies utilising flounder, Diablo was amongst the most highly increased transcripts identified. The aim of this study was to further examine piscine Diablo, at the gene level and mRNA level, after exposure to prototypical pollutants, and in flounder caught from polluted environments. The results show that two genes encoding Diablo exist in fish species, and in flounder one of these genes is increased in liver after exposure to polyaromatic hydrocarbons and polychlorinated biphenyls, and also in livers from fish living on contaminated estuarine sediments. Therefore, Diablo measurement has potential as a biomarker of pollutant exposure, and could indicate damaging effects of chemical contaminants. PMID- 22244826 TI - Primary treatment and prognostic factors of small cell neuroendocrine carcinoma of the uterine cervix: a Taiwanese Gynecologic Oncology Group study. AB - BACKGROUND: Our aims were to investigate the treatment and clinicopathological variables in relation to prognosis in small cell neuroendocrine cervical carcinoma (SCNECC). PATIENTS AND METHODS: Clinical data of SCNECC patients with International Federation of Gynaecology and Obstetrics (FIGO) stages I-IV treated between 1987 and 2009 at member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed. RESULTS: Of the 179 eligible patients, 104 were of FIGO stage I, 19 stage IIA, 23 stage IIB, 9 stage III, and 24 stage IV. The median failure-free survival (FFS) was 16.0 months, and the median cancer-specific survival (CSS) was 24.8 months. In multivariate analysis, FIGO stage and lymph node metastasis were selected as independent variables in stages I-IV. In stages IIB-IVB, primary treatment containing etoposide and platinum for at least 5 cycles (EP5+) (n=16) was associated with significantly better 5-year FFS (42.9% versus 11.8%, p=0.041) and CSS (45.6% versus 17.1%, p=0.035) compared to other treatments (n=40). Furthermore, concurrent chemoradiation with EP5+ (CCRT-EP5+) was associated with even better 5-year FFS (62.5% versus 13.1%, p=0.025) and CSS (75.0% versus 16.9%, p=0.016). CONCLUSIONS: FIGO stage and lymph node metastasis are significant prognostic factors in SCNECC. In stages IIB-IVB, CCRT-EP5+ might be the treatment of choice, which could be also true for earlier stages. Despite limitations of a retrospective study spanning a long time period and heterogeneous managements, the results provide an important basis for designing future prospective studies. PMID- 22244827 TI - A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour specific p53 overexpression through E1A-dependent p21 and MDM2 suppression. AB - Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP 702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP 301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301 resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome. PMID- 22244828 TI - A DNA methylation signature associated with aberrant promoter DNA hypermethylation of DNMT3B in human colorectal cancer. AB - Altered promoter DNA methylation, one of the most important molecular alterations in cancer, is proposed to correlate with deregulation of DNA methyltransferases, although the molecular mechanisms implicated are still poorly understood. Here we show that the de novo DNA methyltransferase DNMT3B is frequently repressed in human colorectal cancer cell lines (CCL) and primary tumours by aberrant DNA hypermethylation of its distal promoter. At the epigenome level, DNMT3B promoter hypermethylation was associated with the hypomethylation of gene promoters usually hypermethylated in the healthy colon. Forced DNMT3B overexpression in cancer cells restored the methylation levels of these promoters in the healthy colon. Our results show a new molecular mechanism of aberrant DNMT3B regulation in colon cancer and suggest that its expression is associated with the methylation of constitutively hypermethylated promoters in the healthy colon. PMID- 22244829 TI - Prognostic stratification for children with hepatoblastoma: the SIOPEL experience. AB - PURPOSE: To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. PATIENTS AND METHODS: Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). RESULTS: In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP >= 1.2 * 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 * 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%. CONCLUSION: Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology. PMID- 22244830 TI - Simultaneous inhibition of Src and Aurora kinases by SU6656 induces therapeutic synergy in human synovial sarcoma growth, invasion and angiogenesis in vivo. AB - Synovial sarcoma is an obstinate, high-grade malignancy because of its modest responses to radiotherapy and chemotherapy; the identification of effective therapeutics for this sarcoma is therefore necessary. Inhibition of Src family kinases (SFKs) suppresses the proliferation of synovial sarcoma cells in vitro, as we have previously reported. In this study, to validate the efficacy of Src inhibition in vivo, we employed SU6656, which was originally identified as a specific SFK inhibitor. SU6656 treatment significantly impaired the growth of established, existing tumours formed by synovial sarcoma cells in mice. Tumour cell invasion into the surrounding tissues was also abolished by SU6656. It is noteworthy that SU6656 but not PP2 induced a defect in cleavage furrow formation during cytokinesis, resulting in G2/M accumulation and subsequent apoptosis. Intriguingly, SU6656 abrogated the catalytic activities of Aurora kinases and led to the down-regulation of phosphorylated histone H3 coincidently with p53 accumulation, as did the Aurora kinase inhibitor VX-680. Structural comparison indicated an extensive similarity between the catalytic domains of SFKs and Aurora kinases. The structural analysis also revealed the potential binding mode of SU6656 to the ATP-binding cleft of Aurora B via four hydrogen bonds. SU6656 prevented angiogenesis within the tumours by attenuating vascular endothelial growth factor (VEGF) production by tumour cells and the subsequent chemotaxis of endothelial cells; these effects were the result of the inhibition of SFKs but not Aurora kinases. Based on these results, we hereby report a novel property of SU6656 as a dual inhibitor of SFKs and Aurora kinases, the suppression of both of which effectively abrogates tumour development and the progression of synovial sarcoma in vivo. PMID- 22244831 TI - Contrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation. AB - BACKGROUND: Magnetic resonance imaging (MRI) studies suggest that antipsychotic treated patients with schizophrenia show a decrease in gray-matter volumes, whereas lithium-treated patients with bipolar disorder show marginal increases in gray-matter volumes. Although these clinical data are confounded by illness, chronicity, and other medications, they do suggest that typical antipsychotic drugs and lithium have contrasting effects on brain volume. METHODS: Rodent models offer a tractable system to test this hypothesis, and we therefore examined the effect of chronic treatment (8 weeks) and subsequent withdrawal (8 weeks) with clinically relevant dosing of an antipsychotic (haloperidol, HAL) or lithium (Li) on brain volume using longitudinal in vivo structural MRI and confirmed the findings postmortem using unbiased stereology. RESULTS: Chronic HAL treatment induced decreases in whole brain volume (-4%) and cortical gray matter (-6%), accompanied by hypertrophy of the corpus striatum (+14%). In contrast, chronic Li treatment induced increases in whole-brain volume (+5%) and cortical gray matter (+3%) without a significant effect on striatal volume. Following 8 weeks of drug withdrawal, HAL-induced changes in brain volumes normalized, whereas Li-treated animals retained significantly greater total brain volumes, as confirmed postmortem. However, the distribution of these contrasting changes was topographically distinct: with the haloperidol decreases more prominent rostral, the lithium increases were more prominent caudal. CONCLUSIONS: The implications of these findings for the clinic, potential mitigation strategies, and further drug development are discussed. PMID- 22244832 TI - Hb S-Sao Paulo: a new sickling hemoglobin with stable polymers and decreased oxygen affinity. AB - Hb S-Sao Paulo (SP) [HBB:c.20A>T p.Glu6Val; c.196A>G p.Lys65Glu] is a new double mutant hemoglobin that was found in heterozygosis in an 18-month-old Brazilian male with moderate anemia. It behaves like Hb S in acid electrophoresis, isoelectric focusing and solubility testing but shows different behavior in alkaline electrophoresis, cation-exchange HPLC and RP-HPLC. The variant is slightly unstable, showed reduced oxygen affinity and also appeared to form polymers more stable than the Hb S. Molecular dynamics simulation suggests that the polymerization is favored by interfacial electrostatic interactions. This provides a plausible explanation for some of the reported experimental observations. PMID- 22244833 TI - Noxa1 as a moderate activator of Nox2-based NADPH oxidase. AB - Noxa1 was discovered as an activating factor for Nox1, an O(2)(-)-generating enzyme. Subsequent studies have shown that Noxa1 is colocalized with Nox2 in several cell types, including vascular cells. Nox2 activation by Noxa1 has been examined in reconstituted model cells. However, little is known about the kinetic properties of Noxa1 in Nox2 activation. In the present study, we used purified cyt.b(558) (Nox2 plus p22(phox)), Rac(Q61L), and Noxo1 to examine the ability of Noxa1 to activate Nox2. In the pure reconstitution system, Noxa1 activated Nox2 with lower efficiency than p67(phox), a canonical activator of Nox2. The EC(50) value of Noxa1 was considerably higher than that of p67(phox). The V(max) value with Noxa1 and Noxo1 was one-third of that with p67(phox) and p47(phox). The EC(50) value of Noxo1 or Rac(Q61L) was also higher when Noxa1 was used. The affinity of FAD for the oxidase and the stability of the active complex were remarkably low when Noxa1 and Noxo1 were used compared with p67(phox) and p47(phox). The stability was not improved by fusion of Noxa1 with Rac(Q61L). These findings show that Noxa1 has quite different kinetic properties from p67(phox) and suggest that Noxa1 may function as a moderate activator of Nox2. PMID- 22244834 TI - Selection of antibodies from synthetic antibody libraries. AB - More than 2 dozen years had passed since the field of antibody engineering was established, with the first reports of bacterial [1-3] and mammalian cells [4] expression of recombinant antibody fragments, and in that time a lot of effort was dedicated to the development of efficient technological means, intended to assist in the creation of therapeutic monoclonal antibodies (mAbs). Research focus was given to two intertwined technological aspects: the selection platform and the recombinant antibody repertoires. In accordance with these areas of interest, it is the goal of this chapter to describe the various selection tools and antibody libraries existing, with emphasis on the later, and their applications. This chapter gives a far from exhaustive, subjective "historic account" of the field, describing the selection platforms, the different formats of antibody repertoires and the applications of both for selecting recombinant antibodies. Several excellent books provide detailed protocols for constructing antibody libraries and selecting antibodies from those libraries [5-13]. Such books may guide a newcomer to the field in the fine details of antibody engineering. We would like to offer advice to the novice: although seemingly simple, effective library construction and antibody isolation provide best benefits in the hands of professionals. It is an art as much as it is science. PMID- 22244835 TI - Cognitive conflict in a syllable identification task causes transient activation of speech perception area. AB - It has previously been shown that task performance and frontal cortical activation increase after cognitive conflict. This has been argued to support a model of attention where the level of conflict automatically adjusts the amount of cognitive control applied. Conceivably, conflict could also modulate lower level processing pathways, which would be evident as trial-to-trial changes in domain specific activation. The present fMRI experiment used a syllable identification task where conflict is manipulated by presenting recently ignored syllables. Results showed that on trials following a high conflict trial, activation increased primarily in the planum temporale region of the left temporal cortex, an area believed to be involved in syllable discrimination. The experiment thus showed a transient, domain specific attention effect that was modulated on a trial-to-trial basis. We argue that this indicates a self regulating system where increased levels of conflict directs resources in order to improve performance. PMID- 22244836 TI - Pure versus guided mirror exposure to reduce body dissatisfaction: a preliminary study with university women. AB - While effectiveness of mirror exposure to reduce body dissatisfaction has been demonstrated, the exposure was almost always combined with other interventions. The aim of the study was to evaluate the effectiveness of a pure mirror exposure intervention compared with a guided mirror exposure (participants are guided to describe their body shape in a non-evaluative manner) and an imagery exposure intervention (participants are guided to describe their body through mental representation). Thirty-one women with high body dissatisfaction received five sessions of treatment under one of the three conditions. All interventions reduced body dissatisfaction, but only the mirror exposures successfully reduced the frequency of negative thoughts and feelings of ugliness. Pure mirror exposure was more effective than guided exposure for reducing body discomfort within and between sessions. Pure mirror exposure, based on the traditional extinction paradigm, led to strong emotional activation followed by a fast decrease in emotional reactivity. PMID- 22244837 TI - Restoration of the behavioral rates and lifespan in clk-1 mutant nematodes in response to exogenous coenzyme Q(10). AB - The clk-1 gene encodes demethoxyubiquinone mono-oxygenase that is necessary for the biosynthesis of coenzyme Q (CoQ), which is an electron transporter in the respiratory chain of mitochondria. Therefore, clk-1 mutant nematodes that have loss-of-function mutations in the clk-1 gene lack endogenous CoQ(9) and exhibit slowed behavioral rates and an extended lifespan compared with wild-type animals when they are fed standard bacteria containing endogenous CoQ(8). This finding suggests that clk-1 regulates behavioral rates and the lifespan through CoQ in nematodes; however, the effects of exogenous CoQ on the regulation of these biological processes have been incompletely evaluated. In this study, we found that adding 10 MUM water-soluble CoQ(10) to the culture medium of clk-1 mutant nematodes that were fed a diet of standard bacteria restored the pharyngeal pumping, defecation and the lifespan to levels that were comparable to those of wild-type animals. The results indicate that both behavioral rates and lifespan are regulated by the clk-1 gene through the action of CoQ in nematodes. PMID- 22244838 TI - Mastoid: a vestigial function in humans? AB - At the present time, the function of the mastoid remains unknown. One of the main hypotheses accredited in the literature interprets the mastoid as a pressure buffer. Other theories underline the role of the mastoid mucosa in pressure regulation by transmucosal gas exchanges. The question is what advantage does air reabsorption and the creation of a certain degree of negative pressure that mastoid seems to produce, bring to the middle ear and hearing? In the authors' opinion, it is possible that the mastoid, or, in general, every kind of mucosa contained in the middle ear of mammals, would act to create a quite constant, although slight, negative pressure to obtain favorable compliance and impedance conditions in the middle ear to hear and transmit high frequency sounds and ultrasounds. The Eustachian tube, in this perspective, would compensate excessive values of negative pressure. Clearly, that function of mastoid pneumatization in humans would have lost its role, due to the absence of a sensorineural system to analyse ultrasounds. PMID- 22244839 TI - Lipodystrophy and adrenal insufficiency: potential mediators of peripheral neuropathy in HIV infection? AB - The mechanisms behind certain co-morbid conditions associated with chronic HIV disease still remain elusive. HIV-associated peripheral neuropathy is one among those rarely studied manifestations in HIV-1 infection. Numerous underlying factors associated with peripheral neuropathy have been described in HIV disease. Herein, we hypothesized certain heretofore undescribed potential mechanisms that lead to HIV associated neuropathy. Being a multifactoral manifestation, HIV associated neuropathy is presumed to have an association with physiological factors namely, adrenal inadequacy/steroid resistance and lipodystrophy-induced cushion-effect loss in peripheral nerves. Therefore, management of the adrenals with steroids at the time-point of high inflammatory burden thereby preventing lipodystrophy by selecting the optimum treatment regimen could markedly alleviate the severity of HIV-associated neuropathic manifestations. PMID- 22244841 TI - Recent progress and perspectives on the toxicity of carbon nanotubes at organism, organ, cell, and biomacromolecule levels. AB - A wide application of carbon nanotubes (CNTs) is on the way owing to their unique structural, optical, mechanical and electronic properties, high specific surface area, and facile functionalization. As a result, human beings will inevitably be exposed to CNTs, especially when the tubes are utilized as diagnostic and therapeutic tools to better understand, detect, and treat human diseases. Therefore the new subject of nanotoxicology, which is the study of the toxicity of nanomaterials, is now gaining public concern. This review provides an overview and comments on recent advances (mostly within the last 3 years) in the toxicology of CNTs, including their toxicity targeted to cells, organs, tissues and the whole organism, including mammals and other species (e.g. aquatic species, plants, and bacteria). Not only these traditional subjects of toxicological study but the interaction of CNTs and biomacromolecules is also covered so that the mechanism of their toxicity may be understood and their undesirable properties are more likely to be avoided. PMID- 22244840 TI - Enhanced port-wine stain lightening achieved with combined treatment of selective photothermolysis and imiquimod. AB - BACKGROUND: Pulsed dye laser (PDL) is the gold standard for treatment of port wine stain (PWS) birthmarks but multiple treatments are required and complete resolution is often not achieved. Posttreatment vessel recurrence is thought to be a factor that limits efficacy of PDL treatment of PWS. Imiquimod 5% cream is an immunomodulator with antiangiogenic effects. OBJECTIVE: We sought to determine if application of imiquimod 5% cream after PDL improves treatment outcome. METHODS: Healthy individuals with PWS (n = 24) were treated with PDL and then randomized to apply posttreatment placebo or imiquimod 5% cream for 8 weeks. Chromameter measurements (Commission Internationale de l'Eclairage L*a*b* colorspace) for 57 PWS sites (multiple sites per patient) were taken at baseline and compared with measurements taken 8 weeks posttreatment. The Deltaa* (change in erythema) and DeltaE (difference in color between normal-appearing skin and PWS skin) were measured to quantify treatment outcome. RESULTS: Two patients developed minor skin irritation. Other adverse effects were not noted. Average ?a* was 0.43 for PDL + placebo sites (n = 25) and 1.27 for PDL + imiquimod sites (n = 32) (P value = .0294) indicating a greater reduction in erythema with imiquimod. Average ?E was 2.59 for PDL + placebo and 4.08 for PDL + imiquimod (P value = .0363), again indicating a greater color improvement with imiquimod. LIMITATIONS: Effects were evaluated after a single treatment and duration of effect is unknown. CONCLUSION: Combined selective photothermolysis and antiangiogenic therapy may enhance PWS treatment efficacy. PMID- 22244842 TI - Regulation of connexin expression by transcription factors and epigenetic mechanisms. AB - Gap junctions are specialized cell-cell junctions that directly link the cytoplasm of neighboring cells. They mediate the direct transfer of metabolites and ions from one cell to another. Discoveries of human genetic disorders due to mutations in gap junction protein (connexin [Cx]) genes and experimental data on connexin knockout mice provide direct evidence that gap junctional intercellular communication is essential for tissue functions and organ development, and that its dysfunction causes diseases. Connexin-related signaling also involves extracellular signaling (hemichannels) and non-channel intracellular signaling. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. In recent years, it has become clear that epigenetic processes are also essentially involved in connexin gene expression. In this review, we summarize recent knowledge on regulation of connexin expression by transcription factors and epigenetic mechanisms including histone modifications, DNA methylation, and microRNA. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions. PMID- 22244843 TI - Regulation of respiration in muscle cells in vivo by VDAC through interaction with the cytoskeleton and MtCK within Mitochondrial Interactosome. AB - This review describes the recent experimental data on the importance of the VDAC cytoskeleton interactions in determining the mechanisms of energy and metabolite transfer between mitochondria and cytoplasm in cardiac cells. In the intermembrane space mitochondrial creatine kinase connects VDAC with adenine nucleotide translocase and ATP synthase complex, on the cytoplasmic side VDAC is linked to cytoskeletal proteins. Applying immunofluorescent imaging and Western blot analysis we have shown that beta2-tubulin coexpressed with mitochondria is highly important for cardiac muscle cells mitochondrial metabolism. Since it has been shown by Rostovtseva et al. that alphabeta-heterodimer of tubulin binds to VDAC and decreases its permeability, we suppose that the beta-tubulin subunit is bound on the cytoplasmic side and alpha-tubulin C-terminal tail is inserted into VDAC. Other cytoskeletal proteins, such as plectin and desmin may be involved in this process. The result of VDAC-cytoskeletal interactions is selective restriction of the channel permeability for adenine nucleotides but not for creatine or phosphocreatine that favors energy transfer via the phosphocreatine pathway. In some types of cancer cells these interactions are altered favoring the hexokinase binding and thus explaining the Warburg effect of increased glycolytic lactate production in these cells. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism. PMID- 22244844 TI - Brain glycogen and its role in supporting glutamate and GABA homeostasis in a type 2 diabetes rat model. AB - The number of people suffering from diabetes is hastily increasing and the condition is associated with altered brain glucose homeostasis. Brain glycogen is located in astrocytes and being a carbohydrate reservoir it contributes to glucose homeostasis. Furthermore, glycogen has been indicated to be important for proper neurotransmission under normal conditions. Previous findings from our laboratory suggested that glucose metabolism was reduced in type 2 diabetes, and thus we wanted to investigate more specifically how brain glycogen metabolism contributes to maintain energy status in the type 2 diabetic state. Also, our objective was to elucidate the contribution of glycogen to support neurotransmitter glutamate and GABA homeostasis. A glycogen phosphorylase (GP) inhibitor was administered to Sprague-Dawley (SprD) and Zucker Diabetic Fatty (ZDF) rats in vivo and after one day of treatment [1-13C]glucose was used to monitor metabolism. Brain levels of 13C labeling in glucose, lactate, alanine, glutamate, GABA, glutamine and aspartate were determined. Our results show that inhibition of brain glycogen metabolism reduced the amounts of glutamate in both the control and type 2 diabetes models. The reduction in glutamate was associated with a decrease in the pyruvate carboxylase/pyruvate dehydrogenase ratio in the control but not the type 2 diabetes model. In the type 2 diabetes model GABA levels were increased suggesting that brain glycogen serves a role in maintaining a proper ratio between excitatory and inhibitory neurotransmitters in type 2 diabetes. Both the control and the type 2 diabetic states had a compensatory increase in glucose-derived 13C processed through the TCA cycle following inhibition of glycogen degradation. Finally, it was indicated that the type 2 diabetes model might have an augmented necessity for compensatory upregulation at the glycolytic level. PMID- 22244845 TI - Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. AB - T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORgammat)-driven IL-17 expression in vitro. CNS2 deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17 Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2 deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells. PMID- 22244847 TI - Alzheimer's disease risk factor complement receptor 1 is associated with depression. AB - Variation in the complement receptor 1 gene (CR1) has been identified in recent genome-wide association studies as a risk factor for Alzheimer's disease. Here, we show that two Alzheimer's disease-associated CR1 variants, rs6656401 and rs3818361, are associated with major recurrent depression in females in a population-based cohort using individuals from the Generation Scotland: Scottish Family Health Study. PMID- 22244846 TI - RAE1epsilon ligand expressed on pancreatic islets recruits NKG2D receptor expressing cytotoxic T cells independent of T cell receptor recognition. AB - The mechanisms by which cytotoxic T lymphocytes (CTLs) enter and are retained in nonlymphoid tissue are not well characterized. With a transgenic mouse expressing the NKG2D ligand retinoic acid early transcript 1epsilon (RAE1epsilon) in beta islet cells of the pancreas, we found that RAE1 expression was sufficient to induce the recruitment of adoptively transferred CTLs to islets. This was dependent on NKG2D expression by the CTLs and independent of antigen recognition. Surprisingly, the recruitment of CTLs resulted in the subsequent recruitment of a large number of endogenous lymphocytes. Whereas transgenic mice did not develop diabetes, RAE1 expression was sufficient to induce insulitis in older, unmanipulated transgenic mice that was enhanced by viral infection and pancreatic inflammation. These results demonstrate that the expression of an NKG2D ligand in islets is sufficient to recruit CTLs regardless of their antigen specificity and to induce insulitis. PMID- 22244848 TI - Current and future applications of dried blood spots in viral disease management. AB - Almost five decades after their first application in diagnostics, dried blood spot (DBS) cards remain to be of key interest in many research areas and clinical applications. The advantages of sample stability during transport and storage, can now be combined with the high sensitivity of novel diagnostic techniques for the measurement and analysis of nucleic acids, proteins and small molecules which may overcome the limitations of the small samples sizes in DBS cards. Here we present a survey of the literature on the use of DBS cards for diagnosis, monitoring and epidemiological studies of virus infections other than HIV, including CMV, HBV, HCV, HAV, HEV, HTLV, EBV, HSV, measles-, rubella- and dengue virus. The minimal invasiveness of sampling and the relative ease of handling and storing DBS cards is expected to offer additional opportunities to measure and analyze biomarkers of viral disease in resource poor settings or when limited amount of blood can be obtained. Large retrospective studies of virus infections in newborns using stored DBS cards have already been undertaken for screening of congenital infections. In addition, DBS cards have been used prospectively for prevalence studies, outbreak surveillance, mass screening for viral infections, follow-up of chronic infection and its treatment in resource-limited areas. We do not expect that current wet sampling techniques of plasma or serum will be replaced by DBS sampling but it allows extension of sampling in persons and settings that are currently difficult to access or that lack suitable storage facilities. In conclusion, DBS card sampling and storage will aid adequate outbreak management of existing and emerging viral diseases. PMID- 22244849 TI - Individuals at high-risk for pancreatic cancer development: management options and the role of surgery. AB - Pancreatic cancer (PC) is a highly lethal disease. Despite advances regarding the safety and long-term results of pancreatectomies, early diagnosis remains the only hope for cure. This necessitates the implementation of an intensive screening program (based mainly on modern imaging), which - given the incidence of PC - is not cost effective for the general population. However, this screening program is recommended for individuals at high-risk for PC development. Indications for screening include the following three clinical settings: hereditary cancer predisposition syndromes associated with PC, hereditary pancreatitis and familial pancreatic cancer syndrome. The aim of this strategy is to identify pre-invasive (precursor) lesions, which are curable. Surgery is recommended in the presence of recognizable lesion on imaging lesions. Partial (anatomic) pancreatectomy - depending on the location of the suspicious lesion - is the most widely accepted type of surgical intervention in this setting; occasionally, however, total pancreatectomy may be required, in carefully selected patients. Despite that experience still remains limited, there is evidence that this aggressive strategy allows early detection of neoplastic lesions, thereby improving the effectiveness of surgery and prognosis. PMID- 22244850 TI - Validation of diagnostic algorithm to differentiate between tuberculous meningitis and acute bacterial meningitis. AB - BACKGROUND: Discrimination between tuberculous and acute bacterial meningitis is difficult by clinical features alone and laboratory methods may only supplement the clinical suspicion. We aimed to validate the diagnostic criteria by Thwaites et al. [1] and construct our own diagnostic predictors based on the clinical and laboratory features. METHODS: 380 patients of acute bacterial meningitis (ABM) and 210 patients of tuberculous meningitis (TBM) were enrolled retrospectively from June 2004 to June 2007 and prospectively from July 2007 to September 2008. HIV positive patients were excluded. Detailed history, clinical examination CSF analysis, haematological, biochemical investigations and imaging was performed in all patients. RESULTS: Factors associated with the diagnosis of TBM in the present study included rural area of residence, longer duration of disease, presence of clear CSF, lower percentage of CSF neutrophils, presence of diplopia and hemiparesis. On validation, age did not appear as a significant factor in our population. The diagnostic algorithm from our study group had a sensitivity of 95.71% and specificity of 97.63%. CONCLUSIONS: The diagnostic criterion has a fair validation in our population when the age factor is excluded. The rule is useful in HIV negative patients with low CSF sugar and negative organism yield in the CSF. PMID- 22244851 TI - Subcellular distribution of the human putative nucleolar GTPase GNL1 is regulated by a novel arginine/lysine-rich domain and a GTP binding domain in a cell cycle dependent manner. AB - GNL1, a putative nucleolar GTPase, belongs to the MMR1-HSR1 family of large GTPases that are emerging as crucial coordinators of signaling cascades in different cellular compartments. Members of this family share very closely related G-domains, but the signals and pathways regulating their subcellular localization with respect to cell growth remain unknown. To understand the nuclear transport mechanism of GNL1, we have identified a novel arginine/lysine rich nucleolar localization signal in the NH(2)-terminus that is shown to translocate GNL1 and a heterologous protein to the nucleus/nucleolus in a pathway that is independent of importin-alpha and importin-beta. In addition, the present investigation provided evidence that GNL1 localized to the nucleus and the nucleolus only in G2 stage, in contrast to its cytoplasmic localization in the G1 and S phases of the cell cycle. Using heterokaryon assay, we have demonstrated that GNL1 shuttles between the nucleus and the cytoplasm and that the motif between amino acids 201 and 225 is essential for its export from the nucleus by a signal-mediated CRM1-independent pathway. Alanine-scanning mutagenesis of conserved residues within G-domains suggests that the G2 motif is critical for guanine nucleotide triphosphate (GTP) binding of GNL1 and further showed that nucleolar retention of GNL1 is regulated by a GTP-gating-mediated mechanism. Expression of wild-type GNL1 promotes G2/M transition, in contrast to the G domain mutant (G2m), which fails to localize to the nucleolus. These data suggest that nucleolar translocation during G2 phase may be critical for faster M-phase transition during cell proliferation. Replacement of conserved residues within the G5 motif alters the stability of GNL1 without changing GTP binding activity. Finally, our data suggest that ongoing transcription is essential for the efficient localization of GNL1 to the nucleolus. Overall, the results reported here demonstrate that multiple mechanisms are involved in the translocation of GNL1 to the nucleolus in a cell cycle-dependent manner to regulate cell growth and proliferation. PMID- 22244852 TI - Arginine changes the conformation of the arginine attenuator peptide relative to the ribosome tunnel. AB - The fungal arginine attenuator peptide (AAP) is a regulatory peptide that controls ribosome function. As a nascent peptide within the ribosome exit tunnel, it acts to stall ribosomes in response to arginine (Arg). We used three approaches to probe the molecular basis for stalling. First, PEGylation assays revealed that the AAP did not undergo overall compaction in the tunnel in response to Arg. Second, site-specific photocross-linking showed that Arg altered the conformation of the wild-type AAP, but not of nonfunctional mutants, with respect to the tunnel. Third, using time-resolved spectral measurements with a fluorescent probe placed in the nascent AAP, we detected sequence-specific changes in the disposition of the AAP near the peptidyltransferase center in response to Arg. These data provide evidence that an Arg-induced change in AAP conformation and/or environment in the ribosome tunnel is important for stalling. PMID- 22244853 TI - A cyclic peptide inhibitor of apoC-II peptide fibril formation: mechanistic insight from NMR and molecular dynamics analysis. AB - The misfolding and aggregation of proteins to form amyloid fibrils is a characteristic feature of several common age-related diseases. Agents that directly inhibit formation of amyloid fibrils represent one approach to combating these diseases. We have investigated the potential of a cyclic peptide to inhibit fibril formation by fibrillogenic peptides from human apolipoprotein C-II (apoC II). Cyc[60-70] was formed by disulfide cross-linking of cysteine residues added to the termini of the fibrillogenic peptide comprising apoC-II residues 60-70. This cyclic peptide did not self-associate into fibrils. However, substoichiometric concentrations of cyc[60-70] significantly delayed fibril formation by the fibrillogenic, linear peptides apoC-II[60-70] and apoC-II[56 76]. Reduction of the disulfide bond or scrambling the amino acid sequence within cyc[60-70] significantly impaired its inhibitory activity. The solution structure of cyc[60-70] was solved using NMR spectroscopy, revealing a well-defined structure comprising a hydrophilic face and a more hydrophobic face containing the Met60, Tyr63, Ile66 and Phe67 side chains. Molecular dynamics (MD) studies identified a flexible central region within cyc[60-70], while MD simulations of "scrambled" cyc[60-70] indicated an increased formation of intramolecular hydrogen bonds and a reduction in the overall flexibility of the peptide. Our structural studies suggest that the inhibitory activity of cyc[60-70] is mediated by an elongated structure with inherent flexibility and distinct hydrophobic and hydrophilic faces, enabling cyc[60-70] to interact transiently with fibrillogenic peptides and inhibit fibril assembly. These results suggest that cyclic peptides based on amyloidogenic core peptides could be useful as specific inhibitors of amyloid fibril formation. PMID- 22244855 TI - Inhibition of amyloid formation. AB - Amyloid is aggregated protein in the form of insoluble fibrils. Amyloid deposition in human tissue-amyloidosis-is associated with a number of diseases including all common dementias and type II diabetes. Considerable progress has been made to understand the mechanisms leading to amyloid formation. It is, however, not yet clear by which mechanisms amyloid and protein aggregates formed on the path to amyloid are cytotoxic. Strategies to prevent protein aggregation and amyloid formation are nevertheless, in many cases, promising and even successful. This review covers research on intervention of amyloidosis and highlights several examples of how inhibition of protein aggregation and amyloid formation has been achieved in practice. For instance, rational design can provide drugs that stabilize a native folded state of a protein, protein engineering can provide new binding proteins that sequester monomeric peptides from aggregation, small molecules and peptides can be designed to block aggregation or direct it into non-cytotoxic paths, and monoclonal antibodies have been developed for therapies towards neurodegenerative diseases based on inhibition of amyloid formation and clearance. PMID- 22244857 TI - The number of patent tibial vessels does not influence primary patency after nitinol stenting of the femoral and popliteal arteries. AB - OBJECTIVE: Initial TransAtlantic Inter-Society consensus (TASC) II classification has been shown to influence the patency of stented femoral and popliteal arteries. Although several studies have shown the effect of the number of runoff vessels on the durability of infrainguinal angioplasty without stenting, the influence of tibial vessel runoff on the patency of primarily stented femoral and popliteal arteries has not been as well defined. The purpose of this study was to determine whether the number of patent tibial vessels affects primary patency after primary stenting of the femoral and popliteal arteries. METHODS: The records of all patients undergoing angioplasty and primary nitinol stenting of the femoral and popliteal arteries, by or under the supervision of one vascular surgeon, were reviewed. Results were analyzed by both the number of patent tibial vessels documented on periprocedural angiography and by using a modified Society for Vascular Surgery runoff score. TASC II classification was also recorded. Kaplan-Meier survival curves were plotted and differences between groups tested by log-rank method. Fisher exact and chi(2) tests were used to compare categoric factors. RESULTS: During a 7-year period, 289 limbs in 236 patients underwent primary stenting of the femoral and popliteal arteries. Overall primary patency was 70.3% at 12 months, 52.4% at 24 months, and 39.1% at 36 months. Limbs classified as TASC A or B had significantly better patency rates than those classified as TASC C or D (P < .001). While the number of runoff vessels decreased with worsening of the TASC classification (P = .024), overall (P = .355), and within individual TASC classes (P >= .092 for each), there was no difference in the primary patency of stented segments with good runoff and those with compromised runoff. Limbs with poor runoff (one or no vessels) were no more likely to fail with occlusion than their counterparts with two or three patent tibial vessels (P = .383). The number of patent tibial vessels at the time of initial stenting did not impact ultimate limb salvage (P = .063). CONCLUSIONS: The number of patent tibial vessels does not influence the primary patency of primarily stented femoral and popliteal arteries. TASC II classification appears to be significantly more predictive of initial failure after angioplasty and stenting of these vessels. PMID- 22244858 TI - Self-reported symptoms on questionnaires and anatomic lesions on duplex ultrasound examinations in patients with peripheral arterial disease. AB - OBJECTIVE: Whether a typical patient and symptom profile is associated with proximal or distal lesions in lower extremity peripheral arterial disease (PAD) is unknown. Knowing which patient characteristics, exertional leg symptoms, and cardiovascular risk profile accompany the anatomic lesion location may facilitate a more tailor-made management of PAD. METHODS: This cross-sectional study comprised 701 patients from two vascular surgery outpatient clinics with new onset symptoms of PAD (Fontaine 2) who underwent duplex ultrasound (DUS) examinations from March 2006 to March 2011. The main outcome measures were patient characteristics, self-reported leg symptoms, and cardiovascular risk factors as documented from questionnaires and medical records. Peripheral lesion information, categorized by proximal and distal lesions, was obtained from DUS examinations. Multivariable logistic regression analyses were performed of proximal vs nonproximal lesions, distal vs nondistal lesions, and proximal and distal vs absence of having both lesions to assess relationships between patient characteristics, leg symptom categories (typical vs atypical leg symptoms), cardiovascular risk factors, and anatomic lesion location. RESULTS: Lesions were proximal in 270 (38.5%), distal in 441 (62.9%), and proximal and distal in 94 (13.4%). Patients with proximal lesions were younger (odds ratio [OR], 0.94; P < .0001) and less likely to be obese (OR, 0.34; P < .0001) than those without proximal lesions. Older age (OR, 1.07; P < .0001), male sex (OR, 1.96; P = .003), being without a partner (OR, 2.24; P = .004), and lower anxiety scores (OR, 0.42; P = .003) were associated with distal lesions. Patients with both lesions were more likely to be single (OR, 2.30; P = .010) and less likely to be obese (OR, 0.24; P = .009). No distinguishing leg symptom pattern was observed for patients with proximal lesions. Intermittent claudication was more frequently reported in those with distal lesions (P = .011). Although buttock and thigh pain seemed to be somewhat more present in proximal lesions (P < .01) and calf pain more in distal lesions (P < .001), patients still reported pain at a variety of levels throughout their legs, regardless of the anatomic lesion location. CONCLUSIONS: Two distinctive PAD phenotypes-each with its own characteristics and risk factors emerged by anatomic lesion location; however, PAD-specific leg symptoms did not always reflect the anatomic lesion location. These findings may open new opportunities to better tailor PAD management to these two PAD subgroups and may raise awareness about not relying on self-reported symptoms to guide further diagnostic imaging and peripheral lesion management. PMID- 22244854 TI - The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. AB - Transthyretin (TTR) is one of the many proteins that are known to misfold and aggregate (i.e., undergo amyloidogenesis) in vivo. The process of TTR amyloidogenesis causes nervous system and/or heart pathology. While several of these maladies are associated with mutations that destabilize the native TTR quaternary and/or tertiary structure, wild-type TTR amyloidogenesis also leads to the degeneration of postmitotic tissue. Over the past 20 years, much has been learned about the factors that influence the propensity of TTR to aggregate. This biophysical information led to the development of a therapeutic strategy, termed "kinetic stabilization," to prevent TTR amyloidogenesis. This strategy afforded the drug tafamidis which was recently approved by the European Medicines Agency for the treatment of TTR familial amyloid polyneuropathy, the most common familial TTR amyloid disease. Tafamidis is the first and currently the only medication approved to treat TTR familial amyloid polyneuropathy. Here we review the biophysical basis for the kinetic stabilization strategy and the structure based drug design effort that led to this first-in-class pharmacologic agent. PMID- 22244859 TI - Early experience with the snorkel technique for juxtarenal aneurysms. AB - OBJECTIVE: The lack of readily available branched and fenestrated endovascular aneurysm repair (EVAR) options has created an opportunity for creative deployment of endograft components to treat juxtarenal aneurysms. We present our early experience with "snorkel" or "chimney" techniques in the endovascular management of complex aortic aneurysms. METHODS: We retrospectively reviewed planned snorkel procedures for juxtarenal aneurysms performed from September 2009 to August 2011. Our standardized technique included axillary or brachial cutdown for delivery of covered snorkel stents and mostly percutaneous femoral access for the main body endograft. RESULTS: Fifty-six snorkel grafts were successfully placed in 28 consecutive patients (mean age, 75 years) with juxtarenal aneurysms. Mean aneurysm size was 64.8 mm (range, 53-87 mm). The snorkel configuration extended the proximal seal zone from an unsuitable infrarenal neck for standard EVAR (median diameter, 33.5 mm; length, 0.0 mm) to a median neck diameter of 24.5 mm and length of 18.0 mm. Five patients had unilateral renal snorkels, 17 had bilateral renal snorkels, and six had celiac/superior mesenteric artery/renal combinations. Technical success of snorkel placements was 98.2%, with loss of wire access leading to one renal stent deployment failure. Thirty-day mortality was 7.1%: one patient was readmitted 1 week postoperatively with pneumonia and died of sepsis; one patient died at 1 week of a right hemispheric stroke. Other major complications included perinephric hematomas, 7.1%; permanent hemodialysis, 3.6%; iliac artery injury requiring endoconduit placement, 3.6%; and brachial plexus nerve injury, 3.6%. Cardiac complications included self-limited arrhythmias (14.3%) and one non-Q-wave myocardial infarction (3.6%), with all recovering without coronary intervention. Mean follow-up was 10.7 months (range, 3-25 months). One patient died of nonaneurysmal-related causes at 3 months (89.3% survival). Postoperative imaging revealed one renal snorkel graft occlusion occurring at 3 months (98.2% overall primary patency). Seven (25%) early endoleaks were noted on the first follow-up computed tomography angiography: two type I, three type II, and two type III (25%), leading to one secondary intervention (3.6%) with bridging cuff placement (type III). The small type Ia endoleaks and other type III endoleak resolved at the 6-month scan. Mean sac regression at the latest follow-up was 7.3 mm. No aneurysm has enlarged on postoperative imaging. CONCLUSIONS: Early success with the snorkel technique for juxtarenal aneurysms has made it our procedure of choice for complex short-neck to no-neck EVAR. Although long-term follow-up is needed, the flexibility of the snorkel technique and lack of requirement for custom-built devices may make this approach more attractive than branched or fenestrated stent grafts. PMID- 22244860 TI - Aspirin prevents resistin-induced endothelial dysfunction by modulating AMPK, ROS, and Akt/eNOS signaling. AB - BACKGROUND: Resistin, an adipocytokine, plays a potential role in cardiovascular disease and may contribute to increased atherosclerotic risk by modulating the activity of endothelial cells. A growing body of evidence suggests that aspirin is a potent antioxidant. We investigated whether aspirin mitigates resistin induced endothelial dysfunction via modulation of reactive oxygen species (ROS) generation and explored the role that AMP-activated protein kinase (AMPK), a negative regulator of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, plays in the suppressive effects of aspirin on resistin-induced endothelial dysfunction. METHODS: Human umbilical vein endothelial cells (HUVECs) were pretreated with various doses of aspirin (10-500 MUg/mL) for 2 hours and then incubated with resistin (100 ng/mL) for an additional 48 hours. Fluorescence produced by the oxidation of dihydroethidium (DHE) was used to quantify the production of superoxide in situ; superoxide dismutase (SOD) and catalase activities were determined by an enzymatic assay; and protein levels of AMPK mediated downstream signaling were investigated by Western blot. RESULTS: Treatment of HUVECs with resistin for 48 hours resulted in a 2.9-fold increase in superoxide production; however, pretreatment with aspirin resulted in a dose dependent decrease in production of superoxide (10-500 MUg/mL; n = 3 experiments; all P < .05). Resistin also suppressed the activity of superoxide dismutase and catalase by nearly 50%; that result, however, was not observed in HUVECs that had been pretreated with aspirin at a concentration of 500 MUg/mL. The membrane translocation assay showed that the levels of NADPH oxidase subunits p47(phox)and Rac-1 in membrane fractions of HUVECs were threefold to fourfold higher in cells that had been treated with resistin for 1 hour than in untreated cells; however, pretreatment with aspirin markedly inhibited resistin-induced membrane assembly of NADPH oxidase via modulating AMPK-suppressed PKC-alpha activation. Application of AMPKalpha1-specific siRNA resulted in increased activation of PKC-alpha and p47(phox). In addition, resistin significantly decreased AMPK-mediated downstream Akt/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling and induced the phosphorylation of p38 mitogen-activated protein kinases, which in turn activated NF-kappaB-mediated inflammatory responses such as the release of interleukin (IL)-6 and IL-8, the overexpression of adhesion molecules, and stimulation of monocytic THP-1 cell attachment to HUVECs (2.5-fold vs control; n = 3 experiments). Furthermore, resistin downregulated eNOS and upregulated inducible NO synthase (iNOS) expression, thereby augmenting the formation of NO and protein nitrosylation. Pretreatment with aspirin, however, exerted significant cytoprotective effects in a dose-dependent manner (P < .05). CONCLUSIONS: Our findings suggest a direct connection between adipocytokines and endothelial dysfunction and provide further insight into the protective effects of aspirin in obese individuals with endothelial dysfunction. PMID- 22244861 TI - Repetitive progressive thermal preconditioning hinders thrombosis by reinforcing phosphatidylinositol 3-kinase/Akt-dependent heat-shock protein/endothelial nitric oxide synthase signaling. AB - OBJECTIVE: We compared the effects of modified progressive thermal preconditioning (PTP) and whole-body thermal preconditioning (TP) on stress responses, oxidative stress biomarkers, and arterial thrombosis formation, and explored their possible actions through phosphatidylinositol 3-kinase (PI3K)/Akt dependent heat-shock protein (Hsp)/endothelial nitric oxide synthase (eNOS) pathways. METHODS: We divided four groups of 249 male Wistar rats into nonimmersed controls, TP, and one (1-PTP) and three consecutive cycles (3-PTP) of PTP in a 42 degrees C water bath. We evaluated the stress responses, including hemodynamics, total energy transfer, endoplasmic reticulum (ER) stress marker glucose-regulated protein (GRP78), and blood reactive oxygen species level during TP or PTP treatment. We compared 1-PTP, 3-PTP, or TP effects on oxidative stress, intercellular adhesion molecule 1 (ICAM-1), Hsp70, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) activity, and vascular phosphorylated Akt (p-Akt) and eNOS (p-eNOS) expressions in a model of topical ferric chloride (FeCl(3))-induced carotid artery thrombosis. RESULTS: PTP significantly (P < .05) induced less hemodynamic fluctuations, total energy transfer, ER, and oxidative stress than TP did. After 24 or 72 hours of treatment, 1-PTP, 3-PTP, and TP significantly (P < .05) elevated carotid arterial Hsp70, p-Akt, and p-eNOS expression, significantly (P < .05) depressed FeCl(3) enhanced vascular 2',7'-dichlorodihydrofluorescein diacetate, chemokine (C-X3-C motif) ligand 1 (CX3CL1), 3-nitrotyrosine, 4-hydroxynonenal, and ICAM-1 stain, PAI-1, and t-PA activity, leukocyte infiltration and thrombus size, and significantly (P < .05) delayed thrombus formation compared with controls. 3-PTP and TP had a higher (P < .05) protection than 1-PTP. PI3K/Akt, Hsp70, or N(G) nitro-l-arginine methyl ester hydrochloride (L-NAME) inhibitors significantly (P < .05) depressed 3-PTP and TP-induced vascular protection. CONCLUSIONS: Repetitive PTP is better than single PTP to hinder thrombosis formation via reinforcing PI3K/Akt-dependent Hsp70/eNOS signaling. PMID- 22244863 TI - Association between periodontal disease and stroke. AB - OBJECTIVE: Periodontitis is a very common human infection. There is evidence that periodontitis is associated with cerebrovascular disease (CVD) and stroke. The aim of this study is to examine the relationship between periodontal disease and CVD in observational studies. METHODS: An electronic search of the English literature using PubMed was conducted. A meta-analysis of the studies reporting on the risk of stroke in patients with periodontitis was performed. RESULTS: Six prospective and seven retrospective studies met the inclusion criteria. Patients with both hemorrhagic and ischemic cerebrovascular events, fatal and nonfatal, were included. Definition of periodontitis was taken directly from included studies. Most studies have been adjusted for common cardiovascular risk factors. Separate statistical analysis was performed for prospective and retrospective studies. Overall adjusted risk of stroke in subjects with periodontitis was 1.47 times higher than in subjects without (95% confidence interval, 1.13-1.92;P = .0035) in prospective and 2.63 times (95% confidence interval, 1.59-4.33;P = .0002) in retrospective studies. The application of the trim and fill algorithm does not change the initial significant inference. CONCLUSIONS: There is evidence that periodontitis is associated with increased risk of stroke. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity of the studies as well as the differences in periodontitis definition. PMID- 22244864 TI - Bioinspired Au/TiO2 photocatalyst derived from butterfly wing (Papilio Paris). AB - The reticular hierarchical structure of butterfly wings (Papilio Paris) is introduced as template for Au/TiO(2) photocatalyst by depositing the Au nanoparticles on TiO(2) matrix, which is carried out by a water-ethanol sol-gel procedure combined with subsequent calcination. The obtained Au/TiO(2) nanocomposites present the reticular hierarchical structure of butterfly wings, and Au nanoparticles with an average size of 7 nm are homogeneously dispersed in TiO(2) substrate. Benefiting from such unique reticular hierarchical structure and composition, the biomorphic Au/TiO(2) exhibits high-harvesting capability and presents superior photocatalytic activity. Especially, the biomorphic Au/TiO(2) at the nominal content of gold to titanium of 8 wt% shows the highest photocatalytic activity and can completely decompose methyl orange within 80 min, which is obviously higher than that of commercial Degussa P25 powders. PMID- 22244865 TI - Neutron reflectivity study of substrate surface chemistry effects on supported phospholipid bilayer formation on (11 20) sapphire. AB - Oxide-supported phospholipid bilayers (SPBs) used as biomimetic membranes are significant for a broad range of applications including improvement of biomedical devices and biosensors, and in understanding biomineralization processes and the possible role of mineral surfaces in the evolution of pre-biotic membranes. Continuous-coverage and/or stacked SPBs retain properties (e.g., fluidity) more similar to native biological membranes, which is desirable for most applications. Using neutron reflectivity, we examined the role of oxide surface charge (by varying pH and ionic strength) and of divalent Ca(2+) in controlling surface coverage and potential stacking of dipalmitoylphosphatidylcholine (DPPC) bilayers on the (11 20) face of sapphire (alpha-Al(2)O(3)). Nearly full bilayers were formed at low to neutral pH, when the sapphire surface is positively charged, and at low ionic strength (I=15 mM NaCl). Coverage decreased at higher pH, close to the isoelectric point of sapphire, and also at high I>=210 mM, or with addition of 2mM Ca(2+). The latter two effects are not additive, suggesting that Ca(2+) mitigates the effect of higher I. These trends agree with previous results for phospholipid adsorption on alpha-Al(2)O(3) particles determined by adsorption isotherms and on single-crystal (10 10) sapphire by atomic force microscopy, suggesting consistency of oxide surface chemistry-dependent effects across experimental techniques. PMID- 22244866 TI - Poor patient knowledge regarding family history of colon polyps: implications for the feasibility of stratified screening recommendations. AB - BACKGROUND: In 2008, the American College of Gastroenterology (ACG) modified its colorectal screening guidelines regarding patients with family histories of colorectal polyps, specifically highlighting the importance of obtaining detailed history that includes the number, type, and size of adenomas found in a patient's relative. This information is then used to guide screening recommendations for these patients. OBJECTIVE: To assess the proportion of patients undergoing screening colonscopy for a family history of polyps who have knowledge of their family members' colonoscopy findings. DESIGN: Retrospective, single-center cohort pilot study. SETTING: Tertiary care medical center. PATIENTS: Patients who presented for screening colonoscopy between 2008 and 2010 with an indication of family history of polyps. INTERVENTIONS: Obtain detailed history regarding patient's family history of polyps, including which family member, age of family member at diagnosis, size, type and number of polyps found. MAIN OUTCOME MEASUREMENTS: Knowledge of family history. RESULTS: Seventy-three patients were included in the study. Their knowledge of their family histories of polyps showed the following: 23.2% (17/73; 95% CI, 14%-35%) did not know which family member had polyps, 42.5% (31/73; 95% CI, 31%-55%) did not know the age at diagnosis, 71.2% (52/73; 95% CI, 59%-81%) did not know the polyp type, 90.4% (66/73; 95% CI, 81%-96%) did not know the number of polyps found, and 97.3% (71/73; 95% CI, 90% 100%) did not know the polyp size. LIMITATIONS: Retrospective study at a single tertiary referral center. CONCLUSIONS: Patients' knowledge regarding the details of their family histories of polyp data appears often unknown or incomplete. Thus, at present, it may not appear feasible or practical to incorporate this level of information in colon cancer screening guidelines. PMID- 22244867 TI - Muscle ultrasonography: a diagnostic tool for amyotrophic lateral sclerosis. AB - OBJECTIVE: In a prospective study we tested whether muscle ultrasonography can differentiate between amyotrophic lateral sclerosis (ALS) and mimics. Furthermore, we assessed the ability of ultrasonography to identify subclinical lower motor neuron involvement. METHODS: In 59 patients, suspected for adult onset motor neuron disease, ultrasound scans were made of 12 different muscle groups. Echo intensity was determined and each muscle was screened for fasciculations. Ultrasonography was considered diagnostic for ALS when echo intensity was 1.5 SD above normal in at least two muscles and fasciculations were present in at least four muscles. RESULTS: Ultrasonography differentiated between ALS and mimics with 96% sensitivity and 84% specificity. In the 27 ALS patients, ultrasonography detected 15 regions with lower motor neuron involvement that were negative using either clinical examination or needle EMG. CONCLUSIONS: Muscle ultrasound can differentiate between amyotrophic lateral sclerosis and mimics with high sensitivity and specificity, and is a sensitive tool to screen for regional lower motor neuron involvement. SIGNIFICANCE: Muscle ultrasonography is a promising tool in the diagnostic work up of ALS. PMID- 22244868 TI - Comparison of a row-column speller vs. a novel lateral single-character speller: assessment of BCI for severe motor disabled patients. AB - OBJECTIVE: Non-invasive brain-computer interface (BCI) based on electroencephalography (EEG) offers a new communication channel for people suffering from severe motor disorders. This paper presents a novel P300-based speller called lateral single-character (LSC). The LSC performance is compared to that of the standard row-column (RC) speller. METHODS: We developed LSC, a single character paradigm comprising all letters of the alphabet following an event strategy that significantly reduces the time for symbol selection, and explores the intrinsic hemispheric asymmetries in visual perception to improve the performance of the BCI. RC and LSC paradigms were tested by 10 able-bodied participants, seven participants with amyotrophic lateral sclerosis (ALS), five participants with cerebral palsy (CP), one participant with Duchenne muscular dystrophy (DMD), and one participant with spinal cord injury (SCI). RESULTS: The averaged results, taking into account all participants who were able to control the BCI online, were significantly higher for LSC, 26.11 bit/min and 89.90% accuracy, than for RC, 21.91 bit/min and 88.36% accuracy. The two paradigms produced different waveforms and the signal-to-noise ratio was significantly higher for LSC. Finally, the novel LSC also showed new discriminative features. CONCLUSIONS: The results suggest that LSC is an effective alternative to RC, and that LSC still has a margin for potential improvement in bit rate and accuracy. SIGNIFICANCE: The high bit rates and accuracy of LSC are a step forward for the effective use of BCI in clinical applications. PMID- 22244869 TI - Is female sex a risk factor for red blood cell alloimmunization after transfusion? A systematic review. AB - Large scale red blood cell (RBC) antigen genotyping of donors is currently well developed. There is scarce information, however, to select patients who might benefit from preemptive extended RBC antigen-matched transfusions. Female sex has been proposed as a risk factor for RBC alloimmunization after transfusion. To asses whether females respond differently to RBC alloantigens compared with males, we conducted a literature review on RBC alloimmunization. Clinical studies on RBC alloimmunization incidence were searched for in databases from 1950 through 2011. Studies were included when data were available to calculate the female-to-male risk ratio for alloimmunization. Based on the reported age, adult patients (>18 years) were distinguished from pediatric patients (<=18 years), and articles were analyzed according to disease categories. Thirty articles fulfilled the inclusion criteria. The Mantel-Haenszel risk ratio estimate of combined adult studies showed that women with sickle cell disease had an increased relative risk (27%) on RBC alloantibodies compared with men. Other groups showed equal alloimmunization risk in women and men. Women slightly more often than men possess RBC antibodies. This is likely explained by more exposure to immunizing events through pregnancy and/or transfusions in females with sickle cell disease. The results support the current policy implemented in many countries for Rhesus/Kell matching in patients with a hemoglobinopathy irrespective of sex. Thus, based solely on sex difference, the results do not justify recommending additional matching for women, besides preemptive K and c antigen matching for women during the (pre-) fertile age, as already applied in many European countries for the prevention of fetal morbidity. PMID- 22244870 TI - Diphenyl diselenide diet intake improves spatial learning and memory deficits in hypothyroid female rats. AB - Cognitive deficits have been observed in different animal models of adult-onset hypothyroidism. Thus, this study was delineated to evaluate whether diphenyl diselenide, an organoselenium compound with neuroprotective and antioxidant properties, could afford protection against the detrimental effects of hypothyroidism on behavioral parameters. Hypothyroidism condition was induced in female rats by continuous exposure to methimazole (MTZ) at 20 mg/100 ml in the drinking water, during 3 months. MTZ-induced hypothyroid rats were fed with either standard or a diet containing 5 ppm of diphenyl diselenide for 3 months. Behavioral assessments were performed monthly, in the following order: elevated plus maze, open field and Morris water maze. The levels of thyroid hormones in the animals exposed to MTZ were lower than control until the end of experimental period. The rats exposed to MTZ had a significant weight loss from the first month, which was not modified by diphenyl diselenide supplementation. In elevated plus maze test, MTZ exposure caused a reduction on the number of entries of animals in closed arms, which was avoided by diphenyl diselenide supplementation. In Morris water maze, the parameters latency to reach the platform and distance performed to find the escape platform in the test session were significantly greater in MTZ group when compared to control. These cognitive deficits observed in MTZ-induced hypothyroid rats were restored by dietary diphenyl diselenide. The group fed with diphenyl diselenide alone exhibited a better spatial learning and memory capability in some parameters of Morris water maze when compared to the control group. In summary, our data provide evidence of the effectiveness of dietary diphenyl diselenide in improving the performance of control and hypothyroid rats in the water maze test. PMID- 22244871 TI - Formation of tRNA granules in the nucleus of heat-induced human cells. AB - The stress response, which can trigger various physiological phenomena, is important for living organisms. For instance, a number of stress-induced granules such as P-body and stress granule have been identified. These granules are formed in the cytoplasm under stress conditions and are associated with translational inhibition and mRNA decay. In the nucleus, there is a focus named nuclear stress body (nSB) that distinguishes these structures from cytoplasmic stress granules. Many splicing factors and long non-coding RNA species localize in nSBs as a result of stress. Indeed, tRNAs respond to several kinds of stress such as heat, oxidation or starvation. Although nuclear accumulation of tRNAs occurs in starved Saccharomyces cerevisiae, this phenomenon is not found in mammalian cells. We observed that initiator tRNA(Met) (Meti) is actively translocated into the nucleus of human cells under heat stress. During this study, we identified unique granules of Meti that overlapped with nSBs. Similarly, elongator tRNA(Met) was translocated into the nucleus and formed granules during heat stress. Formation of tRNA granules is closely related to the translocation ratio. Then, all tRNAs may form the specific granules. PMID- 22244872 TI - Pharmacophore modeling for hERG channel facilitation. AB - Human ether-a-go-go-related gene (hERG) channels play a critical role in cardiac action potential repolarization. The unintended block of hERG channels by compounds can prolong the cardiac action potential duration and induce arrhythmia. Several compounds not only block hERG channels but also enhance channel activation after the application of a depolarizing voltage step. This is referred to as facilitation. In this study, we tried to extract the property of compounds that induce hERG channel facilitation. We first examined the facilitation effects of structurally diverse hERG channel blockers in Xenopus oocytes. Ten of 13 assayed compounds allowed facilitation, suggesting that it is an effect common to most hERG channel blockers. We constructed a pharmacophore model for hERG channel facilitation. The model consisted of one positively ionizable feature and three hydrophobic features. Verification experiments suggest that the model well describes the structure-activity relationship for facilitation. Comparison of the pharmacophore for facilitation with that for hERG channel block showed that the spatial arrangement of features is clearly different. It is therefore conceivable that two different interactions of a compound with hERG channels exert two pharmacological effects, block and facilitation. PMID- 22244873 TI - F-spondin regulates the differentiation of human cementoblast-like (HCEM) cells via BMP7 expression. AB - Cementum plays an important role in the attachment of connective tissue to the root surface. However, the detailed mechanism of cementum formation has not yet been clarified. We previously established human cementoblast-like cell lines (HCEM) and human periodontal ligament cell lines (HPL) by infection of hTERT gene. Using those cell lines, we compared the gene expression of them and identified F-spondin as a cementoblast specific gene. In this study, to clarify the role of F-spondin in the differentiation of periodontal ligament cells to cementoblasts, we compared the gene expression of F-spondin-overexpressed HPL (HPL-spondin) cells with HPL parent cells. We found that several genes expressed higher level in HPL-spondin cells than in HPL cells, such as heparin sulfate 6 sulfotranferase, calcitonin-related polypeptide beta, bone morphogenetic proteins 7 (BMP7), BMP2 and BMP8B. Among those genes, we focused on BMP7 and examined the interaction between F-spondin and BMP7, because BMP7 was reported to enhance cementoblast function. Moreover, we further examined the effect of BMP7 peptide on the expression of mineralization-associated genes in HCEM cells. RT-PCR and real-time PCR analyses showed that HPL-spondin expressed BMP7, but not HPL cells. And BMP7 and phospho-Smad1/5/8 protein production were detected in HPL-spondin by Western blot. siSPON1 inhibited expression of type I collagen, runt-related transcription factor 2 (RUNX2) and bone sialoprotein (BSP) mRNA in HCEM cells. And the mineralization tended to be decreased in siSPON1 treated cells by ALZ staining and the quantification analysis. Moreover, we examined the effect of BMP7 peptide on the gene expressions of HCEM cells by RT-PCR. Increase of the osteopontin and BSP mRNA was observed in BMP7 treated HCEM cells. These findings indicate that F-spondin regulates the differentiation of HCEM cells via BMP7 expression. PMID- 22244874 TI - Increase of L-type Ca2+ current by protease-activated receptor 2 activation contributes to augmentation of spontaneous uterine contractility in pregnant rats. AB - We evaluated the effects of protease-activated receptor (PAR)-2 on spontaneous myometrial contraction (SMC) in isolated term pregnant myometrial strips of rat, and elucidated the cellular mechanisms of this effect using a conventional voltage-clamp method. In isometric tension measurements, trypsin and SL-NH(2), PAR-2 agonists, significantly augmented SMC in frequency and amplitude; however, boiled trypsin (BT) and LR-NH(2) had no effect on SMC. These stimulatory effects of PAR-2 agonists on SMC were nearly completely occluded by pre-application of Bay K 8644, an L-type voltage-gated Ca(2+) channel activator, thus showing the involvement of L-type voltage-gated Ca(2+) channels in PAR-2-induced augmentation of SMC. In addition, PAR-2 agonists significantly enhanced L-type voltage-gated Ca(2+) currents (I(Ca-L)), as measured by a conventional voltage-clamp method, and this increase was primarily mediated by activation of phospholipase C (PLC) and protein kinase C (PKC) via G-protein activation. Taken together, we have demonstrated that PAR-2 may actively regulate SMC during pregnancy by modulating Ca(2+) influx through L-type voltage-gated Ca(2+) channels, and that this increase of I(Ca-L) may be primarily mediated by PLC and PKC activation. These results suggest a cellular mechanism for the pathophysiological effects of PAR-2 activation on myometrial contractility during pregnancy and provide basic and theoretical information about developing new agents for the treatment of premature labor and other obstetric complications. PMID- 22244875 TI - Influence of heart failure on nucleolar organization and protein expression in human hearts. AB - We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n=38) and DCM (n=27) patients, undergoing heart transplantation and control donors (n=6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p<0.05) and DCM (141%, p<0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p<0.05) and DCM (1.70-fold, p<0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p<0.0001), and it was increased in pathological hearts (p<0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p<0.05 and 131%, p<0.001) and DCM (56%, p<0.01 and 69%, p<0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p<0.001), perinucleolar chromatin (p<0.01) and dense fibrillar components (p<0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p<0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein. PMID- 22244876 TI - Extracellular acidosis accelerates bone resorption by enhancing osteoclast survival, adhesion, and migration. AB - Acidic extracellular pH promotes osteoporotic bone loss by osteoclast activation. However, the change of osteoclastic cell behavior in acidosis-stimulated bone resorption process is unknown. We found that lowering extracellular pH induced an increase in the survival, adhesion, and migration of mature osteoclasts with a full actin ring, leading to enhanced pit formation on dentine slices. Acidosis upregulated osteopontin, which is an Arg-Gly-Asp (RGD) motif-containing matrix protein secreted from osteoclasts and acts as a common modulator for their survival, adhesion, and migration. A synthetic RGD peptide treatment blocked acidosis-induced osteoclast adhesion and migration, likely by competing with the RGD motif-containing extracellular matrix proteins for cell surface integrin binding. We finally observed that acidosis was associated with activation of osteoclast survival/adhesion/migration-related Pyk2, Cbl-b, and Src signals. Collectively, the findings indicate that extracellular acidosis stimulates bone resorption by extending osteoclast survival and facilitating osteoclast adhesion and migration. PMID- 22244877 TI - Anti-aggressive activity of methyl jasmonate and the probable mechanism of its action in mice. AB - This study examines the anti-aggressive activity of methyl jasmonate (MJ) and its probable mechanism of action in mice. Male mice that showed aggression after housing individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated with MJ, vehicle or haloperidol (HP) 60 min before the test for aggression. Effects of p-chlorophenylalanine (PCPA) or fluoxetine (FL) given alone or in combination with MJ were also investigated. In the interaction studies, PCPA or FL was given to the animals 30 min after MJ injection and aggression testing was carried out 30 min later. Parameters assessed in the study were latency to attack, frequency of attacks, aggressive postures, lateral threats, tail rattling and pursuit frequency. MJ (1, 5, 10 mg/kg) produced a significant dose-dependent decrease in offensive aggressive behaviors. MJ did not impair the defensive mechanisms of the animals and its anti-aggressive effect was not accompanied by sedation or catalepsy. PCPA (50 mg/kg), an inhibitor of 5 hydroxytryptamine (5-HT) biosynthesis, produced a significant increase in aggressive responses and reversed the anti-aggressive effect of MJ. Additionally, FL (10 mg/kg), a 5-HT reuptake inhibitor, produced a significant suppression of aggressive behaviors and also enhanced the antiaggressive effect of MJ. Taken together, these findings suggest that methyl jasmonate exhibits specific anti offensive aggressive activity and may be relevant in the treatment of reactive aggression in humans. Although, it appears that MJ may be affecting 5-HT(1B) receptors, additional data are needed to clearly define the mechanism(s) by which MJ exhibit antiaggressive activity. PMID- 22244878 TI - Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. AB - STUDY OBJECTIVE: Patients receiving warfarin who experience minor head injury are at risk of intracranial hemorrhage, and optimal management after a single head computed tomography (CT) scan is unclear. We evaluate a protocol of 24-hour observation followed by a second head CT scan. METHODS: In this prospective case series, we enrolled consecutive patients receiving warfarin and showing no intracranial lesions on a first CT scan after minor head injury treated at a Level II trauma center. We implemented a structured clinical pathway, including 24-hour observation and a CT scan performed before discharge. We then evaluated the frequency of death, admission, neurosurgery, and delayed intracranial hemorrhage. RESULTS: We enrolled and observed 97 consecutive patients. Ten refused the second CT scan and were well during 30-day follow-up. Repeated CT scanning in the remaining 87 patients revealed a new hemorrhage lesion in 5 (6%), with 3 subsequently hospitalized and 1 receiving craniotomy. Two patients discharged after completing the study protocol with 2 negative CT scan results were admitted 2 and 8 days later with symptomatic subdural hematomas; neither received surgery. Two of the 5 patients with delayed bleeding at 24 hours had an initial international normalized ratio greater than 3.0, as did both patients with delayed bleeding beyond 24 hours. The relative risk of delayed hemorrhage with an initial international normalized ratio greater than 3.0 was 14 (95% confidence interval 4 to 49). CONCLUSION: For patients receiving warfarin who experience minor head injury and have a negative initial head CT scan result, a protocol of 24-hour observation followed by a second CT scan will identify most occurrences of delayed bleeding. An initial international normalized ratio greater than 3 suggests higher risk. PMID- 22244879 TI - Snoring effects on the baroreflex: an animal model. AB - Baroreflex sensitivity (BRS) is reduced in humans during snoring, however the mechanisms are unknown. We used an anaesthetised rabbit induced snoring (IS) model, to test: (1) whether IS was associated with reduced BRS; and (2) if snoring related vibration transmission to peri-carotid tissues influenced BRS levels. BRS was quantified using the spontaneous sequence technique. During IS, BRS fell by 40%, without any associated change in blood pressure (BP) but accompanied by an increase in heart rate (HR). Direct application of a snore frequency and intensity matched vibratory stimulus to the peri-carotid tissues of non-snoring tracheostomised rabbits had no effect on BRS, HR or BP. In conclusion, IS induced depression of BRS is likely mediated via a HR driven change in BRS operating point that is unrelated to snoring-related vibration transmission to carotid baroreceptors. The anaesthetised IS rabbit provides a model in which mechanistic interactions between snoring and BRS can be further explored. PMID- 22244880 TI - Oxygen-glucose deprivation (OGD) and interleukin-1 (IL-1) differentially modulate cathepsin B/L mediated generation of neuroprotective perlecan LG3 by neurons. AB - Brain extracellular matrix (ECM) is highly degraded after cerebral ischemia. The perlecan c-terminal fragment LG3 is generated at increased levels by proteolytic processing as long as 3 days after ischemia. It has previously been shown that oxygen-glucose deprivation (OGD), reperfusion and interleukin-1 alpha (IL-1alpha) stimulate brain cells to yield increased levels of LG3. This LG3, in turn, is neuroprotective against OGD, and may therefore represent one of the brain's defenses against ischemic injury. Here, we investigate whether, in neurons, this increased LG3 is the result of increased perlecan generation and cellular release, increased protease release (to generate LG3 from previous extracellularly deposited perlecan) or both. We found that pre-synthesized perlecan may be exocytosed by neurons during OGD and de novo synthesis of perlecan is increased during reperfusion, even 24 h after OGD. Furthermore, while cathepsin L activity was seen to be marginally important to generate LG3 during normoxic conditions, cathepsin B activity was found to be important to generate increased levels of LG3 following OGD and reperfusion. On the other hand, IL 1alpha treatment raised levels of cathepsin L in neuronal media, and both cathepsin L and cathepsin B were demonstrated to be important for increasing LG3 levels after IL-1alpha treatment. PMID- 22244881 TI - Involvement of NADPH oxidase and glutathione in zinc-induced dopaminergic neurodegeneration in rats: similarity with paraquat neurotoxicity. AB - An association between excessive zinc (Zn) accumulation in brain and incidences of Parkinson's disease (PD) has been shown in several epidemiological and experimental investigations. The involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and glutathione (GSH) in the pathogenesis of PD has also been proposed in a few studies. Despite the implicated role of oxidative stress in PD, the entire mechanism of Zn-induced dopaminergic neurodegeneration has not yet been clearly understood. The present study aimed to investigate the involvement of NADPH oxidase and GSH in Zn-induced dopaminergic neurodegeneration and also to assess its similarity with paraquat (PQ)-induced rat model of PD. Male Wistar rats were treated either with Zn (20 mg/kg; i.p.) or PQ (5 mg/kg; i.p.) in the presence and absence of NADPH oxidase inhibitor, apocynin (10 mg/kg; i.p.) and a GSH precursor, N-acetyl cysteine (NAC; 200 mg/kg; i.p.) either alone or in combination along with the respective controls. Apocynin and/or NAC pre treatment significantly alleviated Zn- and PQ-induced changes in neurobehavioral deficits, number of dopaminergic neurons and contents of the striatal dopamine and its metabolites. Apocynin and/or NAC also mitigated Zn- and PQ-induced alterations in oxidative stress, NADPH oxidase activation and cytochrome c release, caspases-9 and -3 activation and CD11b expression. The results obtained thus suggest that Zn induces oxidative stress via the activation of NADPH oxidase and depletion of GSH, which in turn activate the apoptotic machinery leading to dopaminergic neurodegeneration similar to PQ. PMID- 22244882 TI - Characterizing short read sequencing for gene discovery and RNA-Seq analysis in Crassostrea gigas. AB - Advances in DNA sequencing technology have provided opportunities to produce new transcriptomic resources for species that lack completely sequenced genomes. However, there are limited examples that rely solely on ultra-short read sequencing technologies (e.g. Solexa, SOLiD) for transcript discovery and gene expression analysis (i.e. RNA-Seq). Here we use SOLiD sequencing to examine gene expression patterns in Pacific oyster (Crassostrea gigas) populations exposed to varying degrees of anthropogenic impact. Novel transcripts were identified and RNA-Seq analysis revealed several hundred differentially expressed genes. Gene enrichment analysis determined that in addition to biological processes predicted to be associated with anthropogenic influences (e.g. immune response), other processes play important roles including cell recognition and cell adhesion. To evaluate the effectiveness of restricting characterization solely to short read sequences, mapping and RNA-Seq analysis were also performed using publicly available transcriptome sequence data as a scaffold. This study demonstrates that ultra-short read sequencing technologies can effectively generate novel transcriptome information, identify differentially expressed genes, and will be important for examining environmental physiology of non-model organisms. PMID- 22244883 TI - Comparative defense-associated responses in salmon skin elicited by the ectoparasite Lepeophtheirus salmonis. AB - Susceptibility among salmonids to the ectoparasite Lepeophtheirus salmonis is related to inflammatory reactions at the site of parasite attachment. Salmon from two susceptible (Salmo salar, Oncorhynchus keta) and one resistant (Oncorhynchus gorbuscha) species were exposed to adult L. salmonis. After 24 and 48h, skin samples directly below the attachment site and at non-attachment sites were assessed for transcriptomic profiles of select innate defense genes. Abrasion of the skin permitted comparisons between abrasion-associated injury and louse associated injury. Infection responses were consistently higher than those caused by abrasion. Temporal patterns of expression were evident in all species for the transcription factor CCAAT/enhancer-binding protein beta (C/EBP-beta), the cytokine interleukin-6 (IL-6) and the enzyme prostaglandin D synthase (PGDS) at attachment sites. O. gorbuscha was the highest responder in a number of genes while there was an absence of C-reactive protein (CRP) gene expression in S. salar and O. keta, indicating an altered acute-phase response. Moreover, O. keta displayed distinct interleukin-8 (IL-8) and serum amyloid P (SAP) responses. Impaired genetic expression or over-expression in these pathways may be evidence for species-specific pathways of susceptibility to the parasite. At L. salmonis attachment sites, reduced expression compared to non-attachment sites was observed for C/EBP-beta (S. salar), CRP (S. salar), SAP (S. salar, O. gorbuscha, O. keta), PGDS (S. salar, O. gorbuscha, O. keta), and major histocompatibility class II (MH class II, S. salar), suggesting local immunodepression. PMID- 22244884 TI - Management of recurrent cervical cancer: a review of the literature. AB - OBJECTIVE: The aim of this narrative review is to update the current knowledge on the treatment of recurrent cervical cancer based on a literature review. MATERIAL AND METHODS: A web based search in Medline and CancerLit databases has been carried out on recurrent cervical cancer management and treatment. All relevant information has been collected and analyzed, prioritizing randomized clinical trials. RESULTS: Cervical cancer still represents a significant problem for public health with an annual incidence of about half a million new cases worldwide. Percentages of pelvic recurrences fluctuate from 10% to 74% depending on different risk factors. Accordingly to the literature, it is suggested that chemoradiation treatment (containing cisplatin and/or taxanes) could represent the treatment of choice for locoregional recurrences of cervical cancer after radical surgery. Pelvic exenteration is usually indicated for selected cases of central recurrence of cervical cancer after primary or adjuvant radiation and chemotherapy with bladder and/or rectum infiltration neither extended to the pelvic side walls nor showing any signs of extrapelvic spread of disease. Laterally extended endopelvic resection (LEER) for the treatment of those patients with a locally advanced disease or with a recurrence affecting the pelvic wall has been described. CONCLUSIONS: The treatment of recurrences of cervical carcinoma consists of surgery, and of radiation and chemotherapy, or the combination of different modalities taking into consideration the type of primary therapy, the site of recurrence, the disease-free interval, the patient symptoms, performance status, and the degree to which any given treatment might be beneficial. PMID- 22244885 TI - Increased incidence of anti-GBM disease in Fcgamma receptor 2b deficient mice, but not mice with conditional deletion of Fcgr2b on either B cells or myeloid cells alone. AB - Fcgamma receptor 2b (Fcgr2b) is the only inhibitory Fcgamma receptor in both humans and mice, and is implicated in both antibody production and effector responses to antibody complexes. Reduced function of Fcgr2b has previously been associated with anti-glomerular basement membrane antibody (anti-GBM) disease in mice. However, the mice used had 129 genetic elements flanking the deleted Fcgr2b gene, which are known to increase susceptibility to autoimmunity. In order to confirm a role for Fcgr2b in protection from anti-GBM disease, wild type (WT) mice, mice lacking Fcgr2b on a pure C57BL/6 background, or mice lacking Fcgr2b on a C57BL/6 background with 129 flanking sequences, were immunized with the recombinant NC1 domain of alpha 3 Type IV collagen. Twenty two weeks after immunization, there was a higher incidence of crescentic glomerulonephritis, macrophage infiltration and renal dysfunction in both groups of Fcgr2b-/- mice, indicating an important role of Fcgr2b in regulating the development of anti-GBM disease, on both genetic backgrounds. In order to determine the cellular origin of the Fcgr2b-associated effect, disease was induced in mice with deficiency of Fcgr2b on either B cells alone (CD19Cre), or a subset of myeloid cells (LysozymeMCre). Neither B cell nor myeloid specific knockout mice developed crescentic glomeruonephritis with higher incidence than WT mice indicating that Fcgr2b deficiency on either B cells or a subset of myeloid cells alone is not sufficient to increase susceptibility to anti-GBM disease, but that a combination of cell types, or deficiency of Fcgr2b in a different cell type, is also required. PMID- 22244886 TI - Physical exercise reverses glutamate uptake and oxidative stress effects of chronic homocysteine administration in the rat. AB - The influence of physical exercise on the effects elicited by homocysteine on glutamate uptake and some parameters of oxidative stress, namely thiobarbituric acid-reactive substances, 2',7'-dichlorofluorescein (H(2)DCF) oxidation, as well as enzymatic antioxidant activities, superoxide dismutase, catalase and glutathione peroxidase in rat cerebral cortex were investigated. Wistar rats received subcutaneous administration of homocysteine or saline (control) from the 6th to 29th day of life. The physical exercise was performed from the 30th to 60th day of life; 12 h after the last exercise session animals were sacrificed and the cerebral cortex was dissected out. It is shown that homocysteine reduces glutamate uptake increases thiobarbituric acid-reactive substances and disrupts enzymatic antioxidant defenses in cerebral cortex. Physical activity reversed the homocysteine effects on glutamate uptake and on antioxidant enzymes activities; although the increase in thiobarbituric acid-reactive substances was only partially reversed by exercise. These findings allow us to suggest that physical exercise may have a protective role against homocysteine-induced oxidative imbalance and brain damage to the glutamatergic system. PMID- 22244887 TI - Reduction of serotonergic neurons in the dorsal raphe due to chronic prenatal administration of a tryptophan-free diet. AB - Serotonin (5-HT) is a widely studied neurotransmitter which plays an important role in the development and proper functioning of the organism throughout life. The appearance of 5-HT system early in ontogeny suggests the hypothesis that 5-HT plays a regulatory role in neurodevelopment. This study investigated the effect of administration of a tryptophan deficient diet during prenatal development on the morphology and cell population of the dorsal raphe. The experimental diet, containing balanced amounts of carbohydrates, lipids and proteins, was provided to a time-mated group of rats from gestational day 5 until delivery. Control groups were fed with (i) the experimental diet formulation with 0.2% tryptophan added to the mixture, or (ii) a regular chow diet. At delivery, five pups per dam were euthanized. Body and brain weight was measured and brain sections were processed for immunohistochemistry for tryptophan hydroxylase (TrpH) and whole brain 5-HT analysis. Sections containing dorsal raphe were photographed with a light microscope and TrpH positive neurons quantified. Brain weights in the tryptophan deprived group showed no difference as compared with controls while body weights were reduced by 25%. Total numbers of serotonergic neurons at the dorsal raphe in the prenatal tryptophan deficient pups were reduced by 35%. A regional analysis of the dorsal raphe indicated a marked cellular reduction in the medial and caudal sections of the nucleus, which contains the majority of serotonergic neurons, in the tryptophan deprived condition. Quantitative 5-HT analysis showed that the brain concentration was similar among conditions. In conclusion, gestational tryptophan deprivation exerts adverse effects on the development of the 5-HT system, particularly in the dorsal raphe, manifested by decreased numbers of serotonergic neurons as well as altered topography in this important nucleus. PMID- 22244888 TI - A subpopulation of endothelial progenitor cells with low aldehyde dehydrogenase activity attenuates acute ischemic brain injury in rats. AB - Previous studies have examined the therapeutic effect of endothelial progenitor cells (EPCs) during the chronic phase of cerebral infarction in rats; however, few studies have investigated the effects of EPCs during the acute phase of infarction. In this study, we evaluated the therapeutic effect of EPCs with low aldehyde dehydrogenase activity (Alde-Low EPCs) in rats with acute cerebral infarction, and our results provide insight that may help to identify a therapeutic mechanism of EPCs for acute cerebral infarction. The administration of Alde-Low EPCs into rats with acute cerebral infarction results in the accumulation and migration of the Alde-Low EPCs into the infarct area and the subsequent decrease of infarct volume. Moreover, we found that the stromal cell derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) signaling pathway may regulate the accumulation of Alde-Low EPCs. The transplantation of Alde-Low EPCs may represent a potential treatment strategy for acute cerebral infarction. PMID- 22244889 TI - CRKL plays a pivotal role in tumorigenesis of head and neck squamous cell carcinoma through the regulation of cell adhesion. AB - The signaling adapter protein CRK is an indispensable molecule involved in regulating the malignant potential of human cancers. CRK-like (CRKL) is a hematopoietic cell-dominant homologue of CRK that is reported to be phosphorylated by BCR-ABL tyrosine kinase in chronic myelogenous leukemia patients, but its biological function in non-hematopoietic tumors remains unclear. In this study, we explored the tumorigenic role of CRKL in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Immunoprecipitation analysis of HNSCC cell line, HSC-3 cells, showed that the dominant binding partner for C3G was CRKL, not CRK. To clarify the molecular function of CRKL, we established lentiviral shRNA-mediated CRKL-knockdown HNSCC cell lines. In CRKL knockdown HSC-3 and HSC-4 cells, cell growth and motility were diminished compared to control cells. Cell adhesion assays showed that cell attachment onto both fibronectin- and collagen-coated dishes was significantly suppressed in CRKL knockdown HSC-3 cells, while no significant change was observed for poly-l-lysine coated dishes. Immunofluorescence staining revealed that focal adhesion was reduced in CRKL-knockdown HSC-3 cells. With a pulldown assay, CRKL-knockdown HSC 3 cells showed decreased amounts of active Rap1 compared to control cells. Moreover, in an in vivo assay, tumor formation of CRKL-knockdown HSC-3 cells in nude mice was significantly abrogated. Our results indicate that CRKL regulates HNSCC-cell growth, motility, and integrin-dependent cell adhesion, suggesting that CRKL plays a principal role in HNSCC tumorigenicity. PMID- 22244890 TI - MNT inhibits the migration of human hepatocellular carcinoma SMMC7721 cells. AB - Max binding protein (MNT) is a member of the Myc/Max/Mad network that plays a role in cell proliferation, differentiation and apoptosis. We previously observed that MNT was differentially expressed in hepatocellular carcinoma (HCC) and interacted with Nck1 by 2-DE. Nck family adaptor proteins function to couple tyrosine phosphorylation signals, regulate actin cytoskeletal reorganization and lead to cell motility. In order to investigate the regulatory role of MNT in HCC migration, we used transient transfection with a MNT expressing vector to overexpress MNT protein in SMMC7721 cells, and MNT siRNA to knockdown MNT expression. Rho Family Small GTPase activation assay, Western blots and transwell assay were used to determine the migration potential of cells. We found that knockdown of MNT expression might promote SMMC7721 cell migration, while the overexpressed MNT could significantly inhibit cell migration. It further emphasized the role of MNT in inhibition of cell migration that might be a promising target for HCC chemotherapy. PMID- 22244891 TI - Augmented glutathione synthesis decreases acrolein toxicity. AB - We have shown recently that acrolein is more strongly involved in cell damage than reactive oxygen species during brain infarction. Thus, we tried to isolate cells with reduced susceptibility to acrolein toxicity to clarify how acrolein is detoxified under cell culture conditions. The IC(50) of acrolein in mouse mammary carcinoma FM3A cells and in neuroblastoma Neuro2a cells was 2.6 and 4.2MUM, respectively, but in acrolein toxicity-decreasing FM3A (FM3A-ATD) cells and Neuro2a (Neuro2a-ATD) cells, it was 7.6 and 8.4MUM, respectively. In both FM3A ATD and Neuro2a-ATD cells, the concentration of glutathione (GSH) was increased, so that detoxification occurred through acrolein conjugation with GSH. In FM3A ATD cells, the level of a rate-limiting enzyme of GSH synthesis, gamma glutamylcysteine ligase catalytic unit (GCLC), was increased through the reactivation of one inactive allele of GCLC genes in FM3A cells. In Neuro2a-ATD cells, phosphorylation of transcription factors (c-Jun and NF-kappaB) necessary for expression of genes for GCLC and glutathione synthetase (GSHS) involved in GSH synthesis was stimulated, so that transcription of two genes increased in Neuro2a-ATD cells. Phosphorylation of JNK (c-Jun N-terminal kinase), which catalyzes phosphorylation of c-Jun and NF-kappaB p65, was also increased in Neuro2a-ATD cells, suggesting that activation of JNK kinase is responsible for the increase in GSH. These results support the idea that GSH plays important roles in detoxification of acrolein, because GSH is increased in both FM3A-ATD and Neuro2a-ATD cells. PMID- 22244892 TI - Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest. AB - Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal sensitization mechanisms. These results may contribute to the development of Sal based chemotherapy for cancer patients treated with antimitotic drugs. PMID- 22244894 TI - In situ quantification of mitochondrial respiration in permeabilized fibers of a marine invertebrate with low aerobic capacity. AB - The aim of this study was to design a protocol to allow the assessment of normal and alternative pathways for electron transport in mitochondria using an in situ approach (on permeabilized fibers) in high-resolution respirometry. We measured the oxygen consumption of permeabilized fibers from Nereis (Neanthes) virens with different substrates and the presence of ADP. To estimate the alternative oxidase (AOX) activity, antimycin A was introduced in order to inhibit complex III. Moreover, the apparent complex IV (COX) excess capacity was evaluated using different substrates to assess the implication of this complex in the partitioning of electrons during its progressive inhibition. Our in situ method enabled to quantify the activity of the normal COX pathway as well as the AOX pathway when different substrates were oxidized by either complex I, complex II or both. Using this approach, we confirmed that according to the substrates used, each pathway has a different role and consequently is otherwise involved in the partitioning of electrons through the electron transport system, and suggested that the AOX activity is triggered not only by the redox state of the cell but also by the type of substrates provided to mitochondria. PMID- 22244893 TI - ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response. AB - The intracellular domain of ErbB4 receptor tyrosine kinase is known to translocate to the nucleus of cells where it can regulate p53 transcriptional activity. The purpose of this study was to examine whether ErbB4 can localize to the nucleus of adult rat ventricular myocytes (ARVM), and regulate p53 in these cells. We demonstrate that ErbB4 does locate to the nucleus of cardiac myocytes as a full-length protein, although nuclear location occurs as a full-length protein that does not require Protein Kinase C or gamma-secretase activity. Consistent with this we found that only the non-cleavable JM-b isoform of ErbB4 is expressed in ARVM. Doxorubicin was used to examine ErbB4 role in regulation of a DNA damage response in ARVM. Doxorubicin induced p53 and p21 was suppressed by treatment with AG1478, an EGFR and ErbB4 kinase inhibitor, or suppression of ErbB4 expression with small interfering RNA. Thus ErbB4 localizes to the nucleus as a full-length protein, and plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes. PMID- 22244895 TI - Impact of price and thickness on consumer selection of ribeye, sirloin, and top loin steaks. AB - Consumers (n=316) were recruited from college football picnickers to select ribeye, sirloin, and top loin steaks from 3 price groups based on thickness (n=10 steaks per price/type combination). Constant weight steaks were assigned to these groups: P1, thinnest, $19.80/kg ribeye and top loin, $10.99/kg sirloin; P2, average thickness, $22.00/kg ribeye and top loin, $13.19/kg sirloin; P3, thickest, $24.21/kg ribeye and top loin, $15.40/kg sirloin. Consumers selected 3 steaks per type and ranked selection criteria (price, color, marbling, thickness, texture). Percentage of steaks chosen from each price group did not differ (P>0.05), but consumers tended to select thinner ribeye steaks (P1 and P2) and thicker sirloin steaks (P2 and P3). Across all steak types, a greater number of consumers reported that marbling, color, and thickness were more important than price and visual texture. Data indicate that consumers may select steaks that display their preferred attributes, even if the steaks cost more. PMID- 22244896 TI - Cathepsin D is released after severe tissue trauma in vivo and is capable of generating C5a in vitro. AB - In response to severe tissue trauma several danger sensing and signalling cascades are activated, including the complement and the apoptosis systems. In polytrauma patients, both the early activation of the complement cascade with an excessive generation of the potent anaphylatoxin C5a and the induction of apoptosis have been shown to modulate the post-traumatic immune response. However, little is known about a direct interaction between the complement and apoptosis systems after severe tissue trauma. Therefore the focus of the present study was to elucidate the interplay between the central complement component C5 and the pro-apoptotic aspartic protease cathepsin D. In vivo, the cathepsin D plasma concentration of multiple injured patients was markedly increased when compared to healthy volunteers. In vitro incubation of C5 with cathepsin D resulted in a concentration- and time-dependent generation of C5a, which was inhibited by the aspartate protease inhibitor pepstatin A. Immunoblotting and sequencing analysis indicated that the C5 cleavage product represents the native form of human C5a, also exhibiting chemotactic activity for human neutrophils. In conclusion, these data show for the first time that cathepsin D is increased in plasma early after severe tissue injury. Furthermore, the results provide in vitro evidence of cleavage of C5 by an aspartic protease with subsequent generation of functional C5a, which represents a new path of complement activation. PMID- 22244898 TI - Synthesis and characterization of agar-based silver nanoparticles and nanocomposite film with antibacterial applications. AB - This study describes the synthesis and characterization of silver nanoparticles and nanocomposite material using agar extracted from the red alga Gracilaria dura. Characterization of silver nanoparticles was carried out based on UV-Vis spectroscopy (421 nm), transmission electron microscopy, EDX, SAED and XRD analysis. The thermal stability of agar/silver nanocomposite film determined by TGA and DSC analysis showed distinct patterns when compared with their raw material (agar and AgNO(3)). The TEM findings revealed that the silver nanoparticles synthesized were spherical in shape, 6 nm in size with uniform dispersal. The synthesized nanoparticles had the great bactericidal activity with reduction of 99.9% of bacteria over the control value. The time required for synthesis of silver nanoparticles was found to be temperature dependent and higher the temperature less the time for nanoparticles formation. DSC and XRD showed approximately the same crystalline index (CI(DSC) 0.73). PMID- 22244897 TI - Cyclic, alternating methane and nitrogen limitation increases PHB production in a methanotrophic community. AB - To identify feast-famine strategies that favor PHB accumulation in Type II methanotrophic proteobacteria, three sequencing batch reactors seeded with a defined inoculum of Type II methanotrophs were subjected to 24-h cycles consisting of (1) repeated nitrogen limitation, (2) repeated nitrogen and oxygen limitation, and (3) repeated nitrogen and methane limitation. PHB levels within each reactor and capacity to produce PHB in offline batch incubations were monitored over 11 cycles. PHB content increased only in the reactor limited by both nitrogen and methane. This reactor became dominated by Methylocystis parvus OBBP with no detectable minority populations. It was concluded that repeated nitrogen and methane limitations favored PHB accumulation in strain OBBP and provided it with a competitive advantage under the conditions imposed. PMID- 22244899 TI - Enhanced co-production of S-adenosylmethionine and glutathione by an ATP-oriented amino acid addition strategy. AB - Effects of amino acids on co-production of S-adenosylmethionine (SAM) and glutathione (GSH) with Candida utilis CCTCC M 209298 were investigated. Both methionine and cysteine showed positive effects on improving intracellular SAM and GSH content simultaneously. Batch fermentative co-production of SAM and GSH was conducted in a 5L stirred fermentor, where the co-production of SAM and GSH was enhanced by 71.3% and 71.5% with 6g/L methionine and 6 mmol/L cysteine, respectively. Based on these results together with intracellular ATP levels during batch cultivation of C. utilis CCTCC M 209298, a two-stage amino acid addition strategy was developed by adding 6g/L methionine at 0 h and 6 mmol/L cysteine at 21 h. Under this ATP-oriented strategy, SAM and GSH biosynthesis was further promoted, and the co-production of SAM and GSH reached 669.3mg/L, which was increased by 124.6% compared to that without amino acid addition. PMID- 22244900 TI - Combination of biological pretreatment with liquid hot water pretreatment to enhance enzymatic hydrolysis of Populus tomentosa. AB - A novel stepwise pretreatment of combination of fungal treatment with liquid hot water (LHW) treatment was conducted to enhance the enzymatic hydrolysis of Populus tomentosa. The results showed that lignin and cellulose increased with the elevating temperature, while significant amount of hemicellulose was degraded during the LHW pretreatment. A highest hemicellulose removal of 92.33% was observed by combination of Lenzites betulina C5617 with LHW treatment at 200 degrees C, which was almost 2 times higher than that of sole LHW treatment at the same level. Saccharification of poplar co-treated with L. betulina C5617 and LHW at 200 degrees C resulted in a 2.66-fold increase of glucose yield than that of sole LHW treatment, and an increase (2.25-fold) of glucose yield was obtained by the combination of Trametes ochracea C6888 with LHW. The combination pretreatment performed well at accelerating the enzymatic hydrolysis of poplar wood. PMID- 22244901 TI - Optimization of clean fractionation processing as a pre-treatment technology for prairie cordgrass. AB - The main objective of this study was to fractionate prairie cordgrass (PCG) obtaining the highest cellulose digestibility. Following clean fractionation (CF) processing, the PCG lignocellulosic biomass was fractionated into three main building blocks: cellulose, hemicellulose and lignin. Effects of processing factors such as time, temperature, catalyst concentration and organic solvent mixture composition were evaluated. Organic solvent-aqueous mixture contained methyl isobutyl ketone (MIBK), ethanol and water in different proportions. Sulfuric acid was used as a catalyst. In order to evaluate the degree of pre treatment, enzymatic saccharification was employed on the cellulose fraction obtained from the CF process. Response surface methodology was used for process optimization and statistical analysis. Optimal conditions (39 min, 154 degrees C, 0.69% catalyst and 9% MIBK) resulted in 84% glucose yield and 87% acid insoluble lignin (AIL). PMID- 22244902 TI - Characteristics of cationic Red X-GRL biosorption by anaerobic activated sludge. AB - Anaerobic activated sludge (AAS) was employed for the adsorption of cationic Red X-GRL (X-GRL) from aqueous solutions. The X-GRL uptakes decreased with increases in temperature and salinity, while it was improved with increase in pH. The adsorption of X-GRL by AAS had a better agreement with a fractal-like Langmuir isotherm than a typical Langmuir isotherm. The adsorption rate coefficients at different time had a power-law relationship with time. The surface dimension was positively related to the X-GRL uptakes. The X-GRL uptake by the EPS accounted for only ~ 19% of the total adsorption. The X-GRL adsorption was therefore largely attributed to the active groups on the cell wall. FTIR analysis showed that -CH(2) and -NH(2) groups were not responsible for the adsorption, which indicated chemical adsorption was negligible. PMID- 22244903 TI - Sodium borohydrate (NaBH4) pretreatment for efficient enzymatic saccharification of wheat straw. AB - In this study, the aim was to examine bioethanol production of wheat straw residues using an alternative chemical, sodium borohydrate (NaBH(4)) in chemical pretreatment step. The obtained results showed that sodium hydroxide (NaOH) and NaBH(4) treated straw resulted in 87.8% and 83.3% glucan conversion in enzymatic hydrolysis, but hydrogen peroxide (H(2)O(2)) (74.7%) and sulfuric acid (H(2)SO(4)) (71.7%) had lower glucan conversion. The highest ethanol yield from untreated straw (115 g/kg) was observed for 4% NaBH(4) pretreated sample (60 min) and the theoretical yield (86.9%) was also calculated to be highest for the sample. PMID- 22244904 TI - Studies on the properties of graphene oxide-alkaline protease bio-composites. AB - Graphene oxide (GO) nanosheets as functional material have a unique planar structure and intriguing mechanical that have attracted intensive interests recently. A method was developed for the immobilization protease on GO sheets using glutaraldehyde as cross-linking reagent. The results showed that the thermostability and reusability of immobilized protease have been obviously improved compared to the free enzyme. However, there was no significant change in optimum pH value between the free and immobilized protease. The immobilized protease exhibited good operational stability. The apparent K(m) and V(max) for free and immobilized alkaline protease were determined, and the bio-catalytic activity was not impaired by immobilization. PMID- 22244905 TI - Gasification of biomass in a fixed bed downdraft gasifier--a realistic model including tar. AB - This study presents a model for fixed bed downdraft biomass gasifiers considering tar also as one of the gasification products. A representative tar composition along with its mole fractions, as available in the literature was used as an input parameter within the model. The study used an equilibrium approach for the applicable gasification reactions and also considered possible deviations from equilibrium to further upgrade the equilibrium model to validate a range of reported experimental results. Heat balance was applied to predict the gasification temperature and the predicted values were compared with reported results in literature. A comparative study was made with some reference models available in the literature and also with experimental results reported in the literature. Finally a predicted variation of performance of the gasifier by this validated model for different air-fuel ratio and moisture content was also discussed. PMID- 22244906 TI - The effects of irradiation and microfiltration on the cells growing and total lipids production in the cultivation of Rhodotorula glutinis. AB - The results of this study indicate that the irradiation could enhance the cells growing of Rhodotorula glutinis to 54.2 +/- 1.6g/L as compared to the control (without irradiation) of 38.3 +/- 1.2g/L. However, different wavelength of LEDs' (red, green, blue and white) had no significant impacts on the growth and on the lipid content. The accumulation of potential inhibitive metabolic products probably impedes growth, which restricts more biomass accumulated in the fed batch operation with irradiation. The combining of the fed-batch operation with irradiation and microfiltration can successfully improve the growth of R. glutinis to the maximum of 72.4 +/- 0.6g/L and 51.2 +/- 4.9% of lipid content obtained. Conclusively, the integration process of a fed-batch operation, irradiation and microfiltration can effectively enhance cell growth in R. glutinis, without any reimbursement of lipid contents. This finding might be useful when applied to the commercialized cultivation of R. glutinis for biodiesel production. PMID- 22244907 TI - Invasive extramammary Paget's disease and the risk for secondary tumours in Europe. AB - The aim of this study was to determine the incidence and survival of Extramammary Paget's disease (EMPD) and to describe the possible increased risk of tumours after EMPD. All invasive cases diagnosed between 1990 and 2002 were selected from the RARECARE database. Incidence was expressed in European standardized rates. Relative survival was calculated for the period 1995-1999, with a follow-up until 31st December 2003. Standardized incidence ratios of second primary tumours were calculated to reveal possible increased risk after EMPD. European age standardized Incidence of EMPD within Europe is 0.6 per 1000,000 person years. Five-year relative survival for invasive EMPD was 91.2% (95%CI; 83.5-95.4), 8.6 percent of the EMPD patients developed other malignancies. The highest increased risk of developing a second primary tumour was found in the first year of follow up (SIR:2.0 95%CI; 1.3-2.9), living in the South European region (SIR:2.3 95%CI; 1.5-3.5) or being female (SIR:1.5 95%CI; 1.1-1.9). Female genital organs displayed greatest increased risk of developing a second primary tumour after EMPD (SIR:15,1 95%CI; 0.38-84.23). Due to the increased risk of a second primary tumour after EMPD a thorough search for other tumours during their follow-up is recommended. PMID- 22244908 TI - Extent of lymph node resection does not increase perioperative morbidity and mortality after surgery for stage I lung cancer in the elderly. AB - BACKGROUND & OBJECTIVES: Pathologic evaluation of > 10 lymph nodes (LNs) is considered necessary for accurate lung cancer staging. However, physicians have concerns about increased risk in perioperative mortality (POM) and morbidity with more extensive LN sampling, particularly in the elderly. In this study, we compared the outcomes in elderly patients with stage I non-small cell lung cancer (NSCLC) undergoing extensive (> 10 nodes) and limited (<= 10 nodes) LN resections. METHODS: Using data from the Surveillance, Epidemiology and End Results registry linked to Medicare records, we identified 4975 patients >= 65 years of age with stage I NSCLC who underwent a lobectomy between 1992 and 2002. Risk of perioperative morbidity and POM after the evaluation of <= 10 vs. >10 LNs was compared among patients after adjusting for propensity scores. RESULTS: Multiple regression analysis showed similar POM between the two groups (OR, 1,01; 95% CI, 0,71-1,44). Other postoperative complications were similar across groups except for thromboembolic events, which were more common among patients undergoing resection of > 10 LNs (OR, 1,72; 95% CI, 1,12-2,63). CONCLUSIONS: These data suggest that evaluation of > 10 LNs, which allows for more accurate staging, appears to be safe in the elderly patients undergoing lobectomy for stage I NSCLC without compromising postoperative recovery. PMID- 22244909 TI - Class I versus class III radical hysterectomy in stage IB1-IIA cervical cancer. A prospective randomized study. AB - OBJECTIVE: The standard treatment for stage IB-IIA cervical cancer over the past three decades has been the Piver-Rutledge type III radical hysterectomy. This surgery implies a high rate of urologic morbidity. The objective was to determine the role of class I radical hysterectomy compared to class III radical hysterectomy in terms of morbidity, overall survival, DFS and patterns of relapse in patients undergoing primary surgery. MATERIALS AND METHODS: 125 patients with stage IB1 and IIA cervical cancer <= 4 cm were randomized between type I and type III hysterectomy. Clinical, pathologic and follow-up data were prospectively collected. Adjuvant radiotherapy was administered when indicated. Univariate and multivariate analyses were carried out. RESULTS: Sixty-two patients were randomized to class I surgery and 63 to class III. No significant differences were observed regarding pathologic findings and adjuvant treatment. Morbidity rates were higher after class III surgery (84% versus 45%). Pelvic recurrences were equal in both groups (8 cases each one). Fifteen-year overall survival rate was 90 and 74% respectively (p = 0.11) and 76 and 80% when cervical size is <= 3 cm (p = 0.88). CONCLUSIONS: There are no significant differences in terms of both recurrence rate and overall survival among patients with stage IB-IIA cervical cancer undergoing simple extrafascial hysterectomy (class I) or radical hysterectomy (class III). Morbidity is proportional to the extent of radicality. These data confirm the need of tailoring the extent of resection to the characteristics of the cervical neoplasia and open new interesting pathways to upcoming protocols for the conservative management of these tumors. PMID- 22244910 TI - Age- and gender-related differences in the use of secondary medical prevention after primary vascular surgery: a nationwide follow-up study. AB - OBJECTIVE: This study examined the possible age- and gender-related differences in the use of secondary medical prevention following primary vascular reconstruction in a population-based long-term follow-up study. METHODS: Using information from nationwide Danish registers, we identified all patients undergoing primary vascular reconstruction in-between 1996 and 2006 (n = 20,761). Data were obtained on all filled prescriptions 6 months and 3, 5 and 10 years after primary vascular reconstruction. Comparisons were made across age and gender groups, using men 40-60 years old as a reference. RESULTS: Compared to current guidelines the overall use of secondary medical prevention was moderate to low (e.g., lipid-lowering drugs 49.5%, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists (ACE/ATII) 43.4%, combination of lipid-lowering drugs and anti-platelet therapy and any anti-hypertensive therapy 44.7%). A decline was observed between 6 months and 3 years after surgery. Patients >80 years old were less likely to be prescribed lipid-lowering drugs and combination therapy (e.g.: adjusted risk ratio (RR) 5 years after surgery for men and women 0.63 (95% confidence interval (CI): 0.39-1.02) and 0.48 (95%CI: 0.31-0.75), respectively, whereas smaller and statistical non-significant gender-related differences were observed. The age- and gender-related differences appeared eliminated or substantially reduced in the latest part of the study period (2001-2007). CONCLUSION: We found moderate to low use of secondary medical prevention in Denmark compared with recommendations from clinical guidelines. However, the use has increased in recent years and age- and gender-related differences have been reduced or even eliminated. PMID- 22244912 TI - American Society of Metabolic and Bariatric Surgery patient safety committee policy statement on the qualifications of expert witnesses in bariatric surgery medicolegal matters. PMID- 22244913 TI - A West Nile virus CD4 T cell epitope improves the immunogenicity of dengue virus serotype 2 vaccines. AB - Flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), are among the most prevalent human disease-causing arboviruses world-wide. As they continue to expand their geographic range, multivalent flavivirus vaccines may become an important public health tool. Here we describe the immune kinetics of WNV DNA vaccination and the identification of a CD4 epitope that increases heterologous flavivirus vaccine immunogenicity. Lethal WNV challenge two days post-vaccination resulted in 90% protection with complete protection by four days, and was temporally associated with a rapid influx of activated CD4 T cells. CD4 T cells from WNV vaccinated mice could be stimulated from epitopic regions in the envelope protein transmembrane domain. Incorporation of this WNV epitope into DENV-2 DNA and virus-like particle vaccines significantly increased neutralizing antibody titers. Incorporating such potent epitopes into multivalent flavivirus vaccines could improve their immunogenicity and may help alleviate concerns of imbalanced immunity in multivalent vaccine approaches. PMID- 22244914 TI - The role of theorem proving in systems biology. AB - Theorems offer a rarity in biology, a guarantee that something will always be true if certain conditions are met. We show that modeling and theorem proving are distinct while playing mutually supporting roles in understanding cellular phenomena. Using two recently proven theorems from systems biology as examples, we demonstrate that theorems are not an alternative to mechanistic models. Rather, theorem proving, in conjunction with conventional mathematical (mechanistic) modeling, is an essential tool for a deeper understanding in systems biology. PMID- 22244911 TI - O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems. AB - Gliomas are the most frequent adult primary brain tumor, and are invariably fatal. The most common diagnosis glioblastoma multiforme (GBM) afflicts 12,500 new patients in the U.S. annually, and has a median survival of approximately one year when treated with the current standard of care. Alkylating agents have long been central in the chemotherapy of GBM and other gliomas. The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT), the principal human activity that removes cytotoxic O(6)-alkylguanine adducts from DNA, promotes resistance to anti-glioma alkylators, including temozolomide and BCNU, in GBM cell lines and xenografts. Moreover, MGMT expression assessed by immunohistochemistry, biochemical activity or promoter CpG methylation status is associated with the response of GBM to alkylator-based therapies, providing evidence that MGMT promotes clinical resistance to alkylating agents. These observations suggest a role for MGMT in directing adjuvant therapy of GBM and other gliomas. Promoter methylation status is the most clinically tractable measure of MGMT, and there is considerable enthusiasm for exploring its utility as a marker to assign therapy to individual patients. Here, we provide an overview of the biochemical, genetic and biological characteristics of MGMT as they relate to glioma therapy. We consider current methods to assess MGMT expression and discuss their utility as predictors of treatment response. Particular emphasis is given to promoter methylation status and the methodological and conceptual impediments that limit its use to direct treatment. We conclude by considering approaches that may improve the utility of MGMT methylation status in planning optimal therapies tailored to individual patients. PMID- 22244915 TI - An overlapping genetic code for frameshifted overlapping genes in Drosophila mitochondria: antisense antitermination tRNAs UAR insert serine. AB - Mitochondrial Drosophila genomes possess at least one antisense antiterminator (suppressor) tRNA matching stop codons UAR: antitermination might enable translation after ribosomal frameshift. Proteins translated from samestrand frameshifted and antisense sequences match 26 Genbank proteins (16 are samestrand). Natural frameshifted sequences match more Genbank proteins than after randomizing synonymous codons, suggesting optimization for overlap coding, but some genes avoid overlap coding. Alignments reassign serine to UAR: translational activity by antitermination tRNAs defines a new, presumably stopless overlapping genetic code. Cloverleaf formation by antisense suppressor tRNAs UAA and UAG coevolve with overlapping samestrand and antisense genes, respectively. Coevolution between suppressor tRNAs and sense as well as antisense overlapping genes increases with relative abundances of corresponding sense and antisense (m)RNAs, strong functional evidence for this parallel coding system. Antisense tRNA abundances converge with computed adaptations of antisense tRNAs for translation. Some short frameshifted coding regions are apparently programmed frameshifts putatively producing altered forms of the known main frame protein; most overlapping genes apparently code for unknown proteins. Overlap coding increases gene density without increasing genome size, but decreases with genome size. Parallel genetic systems coded by an additional mitochondrial genetic code in Drosophila confirm similar phenomena in primate mitochondria. PMID- 22244916 TI - Purification and characterization of phytase from Klebsiella pneumoniae 9-3B. AB - Phytase, an enzyme that catalyzes the hydrolysis of phytate, was purified from Klebsiella pneumoniae 9-3B. The isolate was preferentially selected in a medium which contains phytate as a sole carbon and phosphate source. Phytic acid was utilized for growth and consequently stimulated phytase production. Phytase production was detected throughout growth and the highest phytase production was observed at the onset of stationary phase. The purification scheme including ion exchange chromatography and gel filtration resulted in a 240 and 2077 fold purification of the enzyme with 2% and 15% recovery of the total activity for liberation of inorganic phosphate and inositol, respectively. The purified phytase was a monomeric protein with an estimated molecular weight of 45kDa based on size exclusion chromatography and SDS-PAGE analyses. The phytase has an optimum pH of 4.0 and optimum temperature of 50 degrees C. The phytase activity was slightly stimulated by Ca(2+) and EDTA and inhibited by Zn(2+) and Fe(2+). The phytase exhibited broad substrate specificity and the K(m) value for phytate was 0.04mM. The enzyme completely hydrolyzed myo-inositol hexakisphosphate (phytate) to myo-inositol and inorganic phosphate. The properties of the enzyme prove that it is a good candidate for the hydrolysis of phytate for industrial applications. PMID- 22244917 TI - Common variation in genes related to immune response and risk of childhood leukemia. AB - An abnormal immune response to common infection(s) may be a plausible etiological mechanism in childhood leukemia. We investigated whether 931 tagging single nucleotide polymorphisms (SNPs) selected in gene regions related to immune response are associated with childhood leukemia susceptibility in a hospital based case-control study (63 cases and 148 controls) conducted among Korean children. The AT or TT genotype of rs7939734 in Fas-associated protein with death domain (FADD) was associated with increased risk of childhood leukemia compared with the AA genotype (odds ratio [OR] = 2.26, 95% confidence interval [95% CI] = 1.20-4.25, p(trend) = 0.0007, min p = 0.002, false discovery rate [FDR] p = 0.17). The CG or GG genotype of rs2301696 in TRPM5 was associated with decreased risk of childhood leukemia compared with the CC genotype (OR = 0.30, 95% CI = 0.14-0.63, p(trend) = 0.002, min p = 0.004, FDR p = 0.17). Our findings suggest that genetic polymorphisms in immune response genes might play a role in childhood leukemia development with limited biologic evidence. PMID- 22244918 TI - High frequency of human leukocyte antigen class II DRB1*1602 haplotype in Greek patients with myelodysplastic syndrome and of DRB1*1501 in the low-risk subgroup. AB - Myelodysplastic syndromes (MDS) comprise a heterogenous group of clonal hematopoietic disorders in which the immune-mediated pathogenetic mechanisms are under investigation. Overrepresentation of human leukocyte antigen (HLA)-DR2 and its serologic split HLA-DR15 has been associated with low-risk MDS in certain ethnic groups and has been proposed as a predictive factor for a favorable response to immunomodulatory treatment. Because the HLA-DRB1*15 haplotype does not predominate in the Greek population, we investigated the frequency of HLA DRB1 alleles among 114 patients of Greek origin suffering from various types of MDS: 36 refractory anemia (RA), 24 refractory anemia with ringed sideroblasts (RARS), 19 refractory anemia with excess of blasts (RAEB), 14 refractory anemia with excess of blasts in transformation (RAEB-t), 14 chronic myelomonocytic leukemia, and 7 hypoplastic MDS patients. HLA-DRB1 molecular typing was performed with polymerase chain reaction-sequence specific oligonucleotides and results were compared with that from a previously reported control Greek population. HLA DRB1*1602 was the only allele that was significantly overrepresented in Greek MDS patients as a whole, whereas HLA-DRB1*1501 allele frequency was significantly higher in Greek patients with low-risk myelodysplasia. Our results suggest the possible value of HLA-DR15 and HLA-DR16 as determinants for immunomodulatory interventions, at least for Greek patients with low-risk MDS. PMID- 22244919 TI - Detection of HLA-DRB1 microchimerism using nested polymerase chain reaction and single-strand conformation polymorphism analysis. AB - For the detection of microchimerism, molecular methods detecting donor-specific HLA-DRB1 alleles in the recipient are most commonly used. Nested polymerase chain reaction sequence specific primer (nested PCR-SSP) methods widely used to increase the sensitivity of detection have been reported to give frequent false positive reactions. We have developed a new method combining nested PCR with single-strand conformation polymorphism analysis (nested PCR-SSCP) and tested the 1 to 0.00001% level of microchimerism for 27 different HLA-DRB1 alleles. For most (26/27) of the HLA-DRB1 alleles tested, this method could detect 0.01 to 0.001% of microchimerism and its sensitivity was equal to or better than that of nested PCR-SSP tested in parallel. Its specificity was verified by visualizing particular DRB1-specific SSCP bands under test. Nested PCR-SSP indicated frequent false-positive reactions, mainly caused by nonspecific amplification of DRB3/B4/B5 alleles present in the major (recipient) DNAs. We have compared a real time quantitative PCR for non-human leukocyte antigen (HLA) target (insertion/deletion marker) using a commercial kit (AlleleSEQR Chimerism assay), and its microchimerism detection sensitivity (around 0.1%) was 1 step (10 times) lower than that of nested PCR-SSP or -SSCP methods for HLA-DRB1 alleles. We validated that the newly designed nested PCR-SSCP affords good sensitivity and specificity and may be useful for studying microchimerism in clinical settings. PMID- 22244921 TI - Arsenite promotes apoptosis and dysfunction in microvascular endothelial cells via an alteration of intracellular calcium homeostasis. AB - Vascular endothelium has been considered as a target for arsenic-induced cardiovascular toxicity. The present study demonstrated that arsenite caused slow and sustained elevation of intracellular free calcium levels ([Ca2+]i) in HMEC-1, a human microvessel-derived endothelial cell line, in a concentration-dependent manner. Pretreatment with U-73122 (a specific PLC inhibitor) or 2-APB (a specific IP3 receptor antagonist) attenuated this effect, suggesting that PLC/IP3 signaling cascade is involved in arsenite-induced elevation of [Ca2+]i. Cytotoxic concentrations of arsenite (5 and 10 MUM) significantly enhanced endothelial nitric oxide synthase (eNOS) phosphorylation, nitric oxide (NO) production and apoptosis after 24-h exposure. Additionally, 2-APB attenuated eNOS phosphorylation and apoptosis induced by arsenite, indicating that Ca2+ -mediated eNOS activation participates in arsenite-induced endothelial cell apoptosis. Moreover, we also found that non-apoptotic concentrations of arsenite (0.5 and 1 MUM) dramatically mitigated thrombin-induced rapid transient rise of [Ca2+]i, eNOS phosphorylation and NO production, suggesting functional disruption of endothelial by arsenite, and these effects occurred without an alteration of PLC beta1 and thrombin receptor levels. Altogether, the results reveal that arsenite induces apoptotic cell death and endothelial dysfunction as indicated by the reduction of thrombin responses, particularly related to an alteration of intracellular Ca2+ homeostasis. PMID- 22244920 TI - Penaeus monodon tropomyosin induces CD4 T-cell proliferation in shrimp-allergic patients. AB - Shellfish allergy affects approximately 2% of the population and can cause immediate hypersensitivity reactions such as urticaria, swelling, difficulty breathing, and, in some cases, anaphylaxis. Tropomyosin is the major shrimp allergen and binds IgE in two-thirds of patients. A total of 38 shrimp-allergic patients and 20 negative control subjects were recruited and evaluated on the basis of history, skin prick testing, specific immunoglobulin E (IgE) levels, and peripheral blood mononuclear cell proliferation in response to shrimp tropomyosin or shrimp tropomyosin-derived peptides. Of the classically allergic patients by history, 59% tested positive for serum shrimp IgE antibodies. Of patients with shrimp-specific IgE in sera, 70% also had significant IgE levels specific for shrimp tropomyosin. Peripheral blood mononuclear cells from classically shrimp allergic patients proliferated in a dose-dependent manner in response to to tropomyosin. In addition, a T-cell line derived from a shrimp-allergic patient proliferated specifically in response to tropomyosin-derived peptides. These studies suggest a strategy for immunotherapy using a tropomyosin-derived T-cell epitope vaccination. PMID- 22244922 TI - Evaluation of the novel in vitro systems for hepatic drug clearance and assessment of their predictive utility. AB - A valuable strategy for the assessment of in vitro systems is proposed which involves a tiered approach consisting of four levels valuable for both selection of probe compounds and designing experiments for evaluation. At level 1, a Preliminary Assessment is used to triage novel systems based on existing information generated using the methods employed in the development of the system. There is no special requirement for specific probes or experimental conditions. At level 2, Metabolic and Transporter Competence and Cellular Integrity are investigated with a number of specific probes which are generally accepted as appropriate. The information obtained at this level (as with level 1) is largely qualitative in nature. At level 3, Quantitative Utility is established by kinetic studies conducted with specific probes under standard conditions of linearity with respect to time and protein concentration. It is essential that the latter be adhered to if subsequent scale up of the output metrics for uptake and clearance are to have appropriate (scalable) units. Finally level 4, Predictive Utility, is the most detailed level of evaluation involving several model compounds for which in vivo correlates are available. Model compounds have been collated that cover a wide range of metabolic clearance values, and it is important that comparisons are made with existing in vitro systems in order to show the added value of a novel approach including modelling and familiarity with in vivo investigations. PMID- 22244923 TI - Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist. AB - Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0 mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03 mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen. PMID- 22244924 TI - Traveling in the dark: the legibility of a regular and predictable structure of the environment extends beyond its borders. AB - The physical structure of the surrounding environment shapes the paths of progression, which in turn reflect the structure of the environment and the way that it shapes behavior. A regular and coherent physical structure results in paths that extend over the entire environment. In contrast, irregular structure results in traveling over a confined sector of the area. In this study, rats were tested in a dark arena in which half the area contained eight objects in a regular grid layout, and the other half contained eight objects in an irregular layout. In subsequent trials, a salient landmark was placed first within the irregular half, and then within the grid. We hypothesized that rats would favor travel in the area with regular order, but found that activity in the area with irregular object layout did not differ from activity in the area with grid layout, even when the irregular half included a salient landmark. Thus, the grid impact in one arena half extended to the other half and overshadowed the presumed impact of the salient landmark. This could be explained by mechanisms that control spatial behavior, such as grid cells and odometry. However, when objects were spaced irregularly over the entire arena, the salient landmark became dominant and the paths converged upon it, especially from objects with direct access to the salient landmark. Altogether, three environmental properties: (i) regular and predictable structure; (ii) salience of landmarks; and (iii) accessibility, hierarchically shape the paths of progression in a dark environment. PMID- 22244925 TI - Identification and classification of conopeptides using profile Hidden Markov Models. AB - Conopeptides are small toxins produced by predatory marine snails of the genus Conus. They are studied with increasing intensity due to their potential in neurosciences and pharmacology. The number of existing conopeptides is estimated to be 1 million, but only about 1000 have been described to date. Thanks to new high-throughput sequencing technologies the number of known conopeptides is likely to increase exponentially in the near future. There is therefore a need for a fast and accurate computational method for identification and classification of the novel conopeptides in large data sets. 62 profile Hidden Markov Models (pHMMs) were built for prediction and classification of all described conopeptide superfamilies and families, based on the different parts of the corresponding protein sequences. These models showed very high specificity in detection of new peptides. 56 out of 62 models do not give a single false positive in a test with the entire UniProtKB/Swiss-Prot protein sequence database. Our study demonstrates the usefulness of mature peptide models for automatic classification with accuracy of 96% for the mature peptide models and 100% for the pro- and signal peptide models. Our conopeptide profile HMMs can be used for finding and annotation of new conopeptides from large datasets generated by transcriptome or genome sequencing. To our knowledge this is the first time this kind of computational method has been applied to predict all known conopeptide superfamilies and some conopeptide families. PMID- 22244926 TI - Kis antitoxin couples plasmid R1 replication and parD (kis,kid) maintenance modules. AB - The coupling between the replication and parD (kis, kid) maintenance modules of R1 has been revisited here by the isolation of a significant collection of conditional replication mutants in the pKN1562 mini-R1 plasmid, and in its derivative, pJLV01, specifically affected in the RNase activity of the Kid toxin. This new analysis aims to identify key factors in this coupling. For this purpose we have quantified and characterized the restriction introduced by parD to isolate conditional replication mutants of this plasmid, a signature of the modular coupling. This restriction depends on the RNase activity of the Kid toxin and it is relieved by either over-expression of the Kis antitoxin or by preventing its degradation by Lon and ClpAP proteases. Based on these data and on the correlation between copy numbers and parD transcriptional levels obtained in the different mutants, it is proposed that a reduction of Kis antitoxin levels in response to inefficient plasmid replication is the key factor for coupling plasmid replication and parD modules. PMID- 22244927 TI - The peptidoglycan hydrolase TcpG is required for efficient conjugative transfer of pCW3 in Clostridium perfringens. AB - Peptidoglycan hydrolases that are specifically associated with bacterial conjugation systems are postulated to facilitate the assembly of the transfer apparatus by creating a temporally and spatially controlled local opening in the peptidoglycan layer. To date little is known about the role of such enzymes in conjugation systems from Gram-positive bacteria. Conjugative plasmids from the Gram-positive pathogen Clostridium perfringens all encode two putative peptidoglycan hydrolases, TcpG and TcpI, within the conserved tcp transfer locus. Mutation and complementation analysis was used to demonstrate that a functional tcpG gene, but not the tcpI gene, was required for efficient conjugative transfer of pCW3. Furthermore, it was also shown that each of the two predicted catalytic domains of TcpG was functional in C. perfringens and that the predicted catalytic site residues, E-111, D-136, and C-238, present within these functional domains were required for optimal TcpG function. Escherichia coli cells producing TcpG demonstrated a distinctive autoagglutination phenotype and partially purified recombinant TcpG protein was shown to have peptidoglycan hydrolase-like activity on cognate peptidoglycan from C. perfringens. Based on these results it is suggested that TcpG is a functional peptidoglycan hydrolase that is required for efficient conjugative transfer of pCW3, presumably by facilitating the penetration of the pCW3 translocation complex through the cell wall. PMID- 22244929 TI - Clinical performance of the carbohydrate-deficient transferrin (CDT) assay by the Sebia Capillarys2 system in case of cirrhosis. Interest of the Bio-Rad %CDT by HPLC test and Siemens N-Latex CDT kit as putative confirmatory methods. AB - BACKGROUND: The CDT assay used to detect chronic alcohol abuse is difficult with cirrhotic patients. This article describes the performances of several CDT assays in case of cirrhosis. The CDT-Capillarys assay by capillary zone electrophoresis was used for initial testing. Two additional methods were tested as putative confirmatory methods. METHODS: 110 patients with known hepatic status had their CDT measured by the Capillarys2 or alternative methods. Self-reported alcohol intake was used to assess the performances of CDT assays. RESULTS: Capillarys2 performance was lower in case of cirrhosis, many electropherograms displaying various abnormalities. We used the proper separation of the di- and tri sialotransferrin peaks to select reliable profiles. This selection led to the classification of cirrhotic and non-cirrhotic patients in abusers and abstainers with similar performances. However, no interpretation was available for 54% of the cirrhotic patients and neither the BioRad %CDT by HPLC test, nor the Siemens N-Latex CDT kit was suitable as confirmatory methods for these samples. CONCLUSIONS: An attentive profile examination is required for the validation of Capillarys CDT results of cirrhotic patients. Reliability is significantly improved when samples with an improper separation are excluded. To date, no commercial test can confirm the excluded samples. PMID- 22244928 TI - The nicotine metabolite, cotinine, attenuates glutamate (NMDA) antagonist-related effects on the performance of the five choice serial reaction time task (5C-SRTT) in rats. AB - Cotinine, the most predominant metabolite of nicotine in mammalian species, has a pharmacological half-life that greatly exceeds its precursor. However, until recently, relatively few studies had been conducted to systematically characterize the behavioral pharmacology of cotinine. Our previous work indicated that cotinine improves prepulse inhibition of the auditory startle response in rats in pharmacological impairment models and that it improves working memory in non-human primates. Here we tested the hypothesis that cotinine improves sustained attention in rats and attenuates behavioral alterations induced by the glutamate (NMDA) antagonist MK-801. The effects of acute subcutaneous (dose range 0.03-10.0 mg/kg) and chronic oral administration (2.0 mg/kg/day in drinking water) of cotinine were evaluated in fixed and variable stimulus duration (VSD) as well as variable intertrial interval (VITI) versions of a five choice serial reaction time task (5C-SRTT). The results indicated only subtle effects of acute cotinine (administered alone) on performance of the 5C-SRTT (e.g., decreases in timeout responses). However, depending on dose, acute treatment with cotinine attenuated MK-801-related impairments in accuracy and elevations in timeout responses, and it increased the number of completed trials. Moreover, chronic cotinine attenuated MK-801-related impairments in accuracy and it reduced premature and timeout responses when the demands of the task were increased (i.e., by presenting VSDs or VITIs in addition to administering MK-801). These data suggest that cotinine may represent a prototype for compounds that have therapeutic potential for neuropsychiatric disorders (i.e., by improving sustained attention and decreasing impulsive and compulsive behaviors), especially those characterized by glutamate receptor alterations. PMID- 22244930 TI - Meta-analysis for cyclin E in lung cancer survival. AB - BACKGROUND: To assess the prognosis value of cyclin E expression in survival of patients with lung cancer (LC), we performed a systematic review of the literature with meta-analysis. METHODS: Electronic databases were used to identify published studies before August 2011. Pooled hazard ratio (HR) with 95% confidence interval (95% CI) was used to estimate the strength of the association of cyclin E expression with survival of LC patients. Heterogeneity and publication bias were also assessed. RESULTS: Fourteen studies (2606 cases) were eligible and subjected to analysis. Cyclin E over-expression was found to be a strong predictor of poor prognosis in LC patients (HR: 1.38, 95% CI: 1.07-1.79; P=0.014). When only non-small cell lung cancer (NSCLC) was considered, the combined HR was 1.53 (95% CI: 1.19-1.97, P=0.001). A significant association was also evident when the analysis was limited to studies involving adenocarcinoma (AD), but not squamous cell carcinoma (SQ). Publication bias was absent. Sensitivity analyses suggested that the summary statistics obtained should approximate the actual average. PMID- 22244931 TI - Effects of hemoglobin C, D, E, and S traits on measurements of HbA1c by six methods. PMID- 22244933 TI - Visual computed tomographic scoring of emphysema and its correlation with its diagnostic electrocardiographic sign: the frontal P vector. AB - BACKGROUND: Verticalization of the frontal P vector in patients older than 45 years is virtually diagnostic of pulmonary emphysema (sensitivity, 96%; specificity, 87%). We investigated the correlation of P vector and the computed tomographic visual score of emphysema (VSE) in patients with established diagnosis of chronic obstructive pulmonary disease/emphysema. METHODS: High resolution computed tomographic scans of 26 patients with emphysema (age, >45 years) were reviewed to assess the type and extent of emphysema using the subjective visual scoring. Electrocardiograms were independently reviewed to determine the frontal P vector. The P vector and VSE were compared for statistical correlation. Both P vector and VSE were also directly compared with the forced expiratory volume at 1 second. RESULTS: The VSE and the orientation of the P vector (AP) had an overall significant positive correlation (r = +0.68; P = .0001) in all patients, but the correlation was very strong in patients with predominant lower-lobe emphysema (r = +0.88; P = .0004). Forced expiratory volume at 1 second and AP had almost a linear inverse correlation in predominant lower lobe emphysema (r = -0.92; P < .0001). CONCLUSION: Orientation of the P vector positively correlates with visually scored emphysema. Both AP and VSE are strong reflectors of qualitative lung function in patients with predominant lower-lobe emphysema. A combination of more vertical AP and predominant lower-lobe emphysema reflects severe obstructive lung dysfunction. PMID- 22244932 TI - Electrocardiographic patterns of proximal left anterior descending artery occlusion in ST-elevation myocardial infarction may be modified by 3-vessel coronary artery disease. AB - BACKGROUND: The electrocardiographic (ECG) pattern of ST-segment deviation in myocardial infarction is integral to the proper assessment of the location, extent, and functional significance of the infarct but may be modified by the underlying coronary artery anatomy. METHODS: We describe the ECG findings in 2 cases of proximal left anterior descending (LAD) artery occlusion in ST-elevation myocardial infarction (STEMI) associated with 3-vessel coronary artery disease. RESULTS: Both patients had atypical ECG patterns of ST-segment elevation in leads V(2), I, and aVL and ST-segment depression with positive T waves suggestive of extensive subendocardial ischemia in leads II, III, aVF, and V(3) through V(6); acute proximal LAD occlusion and concomitant 3-vessel coronary artery disease were observed angiographically. CONCLUSION: Electrocardiographic changes in proximal LAD STEMI may be modified by the presence of significant atherosclerotic disease elsewhere in the coronary vasculature. Recognition of this ECG pattern may aid the clinician in the rapid identification of high-risk STEMI. PMID- 22244934 TI - Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS. AB - About 5% of amyotrophic lateral sclerosis (ALS) cases are known to be familial (fALS) and mutations in SOD1 and other genes are found in more than 20% of fALS patients and in 2%-4% of apparently sporadic ALS (sALS) cases. However, there are few reports on the proportion of fALS and the frequency of mutations in Korean patients with ALS. We screened mutations in the SOD1, FUS, TARDBP, ANG, and OPTN genes in 258 consecutively enrolled Korean patients with ALS from October 2006 to November 2010. The frequency of fALS was estimated to be 3.5% (9/258), and mutations were identified in 88.9% (8/9) of fALS patients but only in 2.8% (7/249) of sALS patients. Seven fALS and 3 sALS patients had mutations in SOD1 gene while all the others had FUS gene. The proportion of fALS was lower than that reported in Caucasian populations but the frequency of SOD1 gene mutations in Korean fALS patients (77.8%, 7/9) was much higher than that reported in other ethnic groups. These findings might suggest that there is an ethnic difference in the proportion of fALS and the genetic background of ALS. PMID- 22244935 TI - Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. AB - Cell surface proteins Hfe, Tfr2, hemojuvelin and Tmprss6 play key roles in iron homeostasis. Hfe and Tfr2 induce transcription of hepcidin, a small peptide that promotes the degradation of the iron transporter ferroportin. Hemojuvelin, a co receptor for bone morphogenic proteins, induces hepcidin transcription through a Smad signaling pathway. Tmprss6 (also known as matriptase-2), a membrane serine protease that has been found to bind and degrade hemojuvelin in vitro, is a potent suppressor of hepcidin expression. In order to examine if Hfe and Tfr2 are substrates for Tmprss6, we generated mice lacking functional Hfe or Tfr2 and Tmprss6. We found that double mutant mice lacking functional Hfe or Tfr2 and Tmprss6 exhibited a severe iron deficiency microcytic anemia phenotype mimicking the phenotype of single mutant mice lacking functional Tmprss6 (Tmprss6msk/msk mutant) demonstrating that Hfe and Tfr2 are not substrates for Tmprss6. Nevertheless, the phenotype of the mice lacking Hfe or Tfr2 and Tmprss6 differed from Tmprss6 deficient mice alone, in that the double mutant mice exhibited much greater erythropoiesis. Hfe and Tfr2 have been shown to play important roles in the erythron, independent of their role in regulating liver hepcidin transcription. We demonstrate that lack of functional Tfr2 and Hfe allows for increased erythropoiesis even in the presence of high hepcidin expression, but the high levels of hepcidin levels significantly limit the availability of iron to the erythron, resulting in ineffective erythropoiesis. Furthermore, repression of hepcidin expression by hypoxia was unaffected by the loss of functional Hfe, Tfr2 and Tmprss6. PMID- 22244936 TI - On metabolic shift to lactate consumption in fed-batch culture of mammalian cells. AB - Fedbatch culture is the prevalent cell cultivation method in producing protein therapeutics. A metabolic shift to lactate consumption in late stage of cultivation has been shown to extend the culture viability and increase product concentrations. To better understand the factors, which trigger metabolic shift we performed transcriptome and metabolic flux analysis on a fedbatch culture of mouse myeloma cell line (NS0) and developed a mechanistic kinetic model for energy metabolism. Experimental observation indicates that the shift to lactate consumption occurs upon the cessation of rapid growth and under conditions of low glycolysis flux and high extracellular lactate concentrations. Although the transition is accompanied by a general down regulation of enzymes in energy metabolism, that alone was insufficient to elicit a metabolic shift. High lactate level has been reported to exert an inhibitory effect on glycolysis enzyme phosphofructokinase; model simulation suggests that a high lactate level can contribute to reduced glycolytic flux as well as providing a driving force for its conversion to pyruvate. The transcriptome data indicate that moderate alteration in the transcript levels of AKT1 and P53 signaling pathways genes occurs in the late stage of culture. These signaling pathways are known to regulate glycolytic activity. Model simulations further suggest that AKT1 signaling plays a key role in facilitating lactate consumption. Collectively, our results strongly suggest that lactate consumption in fedbatch culture is an outcome of reduced glycolysis flux, which is a product of lactate inhibition and regulatory action of signaling pathway caused by reduced growth rate. PMID- 22244937 TI - Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. AB - In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF. PMID- 22244938 TI - Discovery of GS-9256: a novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity. AB - A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV. PMID- 22244939 TI - [18F]GE-180: a novel fluorine-18 labelled PET tracer for imaging Translocator protein 18 kDa (TSPO). AB - A series of tricyclic compounds have been synthesised and evaluated in vitro for affinity against Translocator protein 18 kDa (TSPO) and for preferred imaging properties. The most promising of the compounds were radiolabelled and evaluated in vivo to determine biodistribution and specificity for high expressing TSPO regions. Metabolite profiling in brain and plasma was also investigated. Evaluation in an autoradiography model of neuroinflammation was also carried out for the best compound, 12a ([(18)F]GE-180). PMID- 22244940 TI - Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents. AB - SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40 MUM), stronger inhibition of nuclear import (0.5:1.3 MUM), and viral replication in HIV-1-infected TZM-bl cells (24.6:100 MUM), human peripheral blood mononuclear cells (PMBCs) (30.1 MUM: toxic). Different spectra of inhibitory activities against infected three healthy humans macrophages with high (donor A) and low (donor B and C) amounts of virus were also observed. Thus 16 showed 10-times stronger activity than 1 (16:1; 0.1:<1.0 MUM) in the case of A, while 16 and 1 showed comparable activities in the cases of B and C (>0.01 and >0.00 1MUM). The comparison of the inhibition of viral p24 antigen production was clearly indicated that compound 16 is at least twofold more potent anti-viral activity than 1. Thus, structures and actions of deoxy analogs particularly 16 could provide valuable information for the development of a novel class of anti HIV-1 agents. PMID- 22244941 TI - Guided plate wave scattering at vertical stiffeners and its effect on source location. AB - This paper examines guided wave transmission characteristics of plate stiffeners and their influence on the performance of acoustic noise source location. The motivation for this work is the detection of air leaks in manned spacecraft. The leaking air is turbulent and generates noise that can be detected by a contact coupled acoustic array to perform source location and find the air leak. Transmission characteristics of individual integral stiffeners are measured across a frequency range of 50-400kHz for both high and low aspect-ratio rectangular stiffeners, and comparisons are made to model predictions which display generally good agreement. It is demonstrated that operating in frequency ranges of high plate wave stiffener transmission significantly improves the reliability of noise source location in the plate. A protocol is presented to enable the selection of an optimal frequency range for leak location. PMID- 22244942 TI - Substance P activates ADAM9 mRNA expression and induces alpha-secretase-mediated amyloid precursor protein cleavage. AB - Altered levels of Substance P (SP), a neuropeptide endowed with neuroprotective and anti-apoptotic properties, were found in brain areas and spinal fluid of Alzheimer's disease (AD) patients. One of the hallmarks of AD is the abnormal extracellular deposition of neurotoxic beta amyloid (Abeta) peptides, derived from the proteolytic processing of amyloid precursor protein (APP). In the present study, we confirmed, the neurotrophic action of SP in cultured rat cerebellar granule cells (CGCs) and investigated its effects on APP metabolism. Incubation with low (5 mM) potassium induced apoptotic cell death of CGCs and amyloidogenic processing of APP, whereas treatment with SP (200 nM) reverted these effects via NK1 receptors. The non-amyloidogenic effect of SP consisted of reduction of Abeta(1-42), increase of sAPPalpha and enhanced alpha-secretase activity, without a significant change in steady-state levels of cellular APP. The intracellular mechanisms whereby SP alters APP metabolism were further investigated by measuring mRNA and/or steady-state protein levels of key enzymes involved with alpha-, beta- and gamma-secretase activity. Among them, Adam9, both at the mRNA and protein level, was the only enzyme to be significantly down regulated following the induction of apoptosis (K5) and up-regulated after SP treatment. In addition to its neuroprotective properties, this study shows that SP is able to stimulate non-amyloidogenic APP processing, thereby reducing the possibility of generation of toxic Abeta peptides in brain. PMID- 22244943 TI - Short-term individual housing induced social deficits in female Mongolian gerbils: attenuation by chronic but not acute imipramine. AB - Mongolian gerbils are highly sensitive to manipulations of their social environments. Housing females individually for short periods (in the order of 7 21 days) has been shown to produce robust and reliable impairments of their subsequent social behaviour. These effects are typified by a marked reduction in the social investigation of an unfamiliar male in a neutral arena and/or a marked increases in levels of freezing whilst and only whilst they are being socially investigated (Immobile in contact). These responses demonstrate housing induced impaired motivation to socially interact. These effects have also been shown to be sensitive to treatment with chronic (but not acute) administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. It was therefore of interest to know if similar effects would be produced by treatment with the tricyclic antidepressant Imipramine. This mixed NA/5-HT reuptake inhibitor first developed in the 1950's is a commonly used standard in animal models of depression and remains in clinical use today. Female gerbils were individually housed for 7 days or maintained in single-sex groups of 4 for the same period. All animals were then randomly allocated to be administered with either 0, 10 or 20 mg/kg imipramine. Acute administration did not reverse the social impairments produced by the individual housing but did produce non-specific stimulant effects on locomotion in both housing conditions. These social impairments were however reduced after a further 14 days chronic treatment with 10 or 20 mg/kg imipramine and stimulant effects were no longer seen. Following chronic administration in group-housed animals locomotor stimulation was replaced with sedation, which resulted in a reduction in social behaviour. That is, opposite to the effect seen in Individual housed animals. It is therefore concluded that chronic treatment with imipramine serves to increase social behaviour but only in those animals with a pre-existing social deficit. PMID- 22244944 TI - Outcomes and bleb-related complications of trabeculectomy. AB - PURPOSE: To determine rates of success and complications of trabeculectomy surgery. DESIGN: Case series. PARTICIPANTS: Consecutive patients undergoing trabeculectomy by 2 surgeons between May 2000 and October 2008. INTERVENTION: By using the Wilmer Institute's billing database, we identified all patients at least 12 years of age coded as having undergone trabeculectomy between May 2000 and October 2008 by 1 of 2 glaucoma surgeons and whose surgery was not combined with another operation. From the chart, we abstracted demographic information on the patients and clinical characteristics of the eyes. The Kaplan-Meier product limit method and Cox proportional hazard models were used to look at success rates and characteristics associated with inadequate intraocular pressure (IOP) reduction. Complications were tabulated. MAIN OUTCOME MEASURES: (1) Success rate of trabeculectomy, as determined by the achievement of each of 4 different IOP goals, with or without IOP-lowering medications; and (2) incidence of surgical complications. RESULTS: During the study period, 797 eyes of 634 persons underwent trabeculectomy without concurrent surgery. The success rates 4 years after surgery, with or without the use of IOP-lowering eye drops, were 70%, 72%, 60%, and 44%, for achievement of target IOP, <=18 mmHg and >=20% IOP reduction, <=15 mmHg and >=25% reduction, and <=12 mmHg and >=30% reduction, respectively. Increased chance of success was associated with European-derived race; use of mitomycin C (MMC); higher concentrations of MMC, when used; and higher preoperative IOP. Age and previous intraocular surgery were not associated with surgical success. Complications included worsening lens opacity in 242 of 443 phakic eyes (55%), loss of >=3 lines of acuity (Snellen) in 161 eyes (21%), surgery for bleb-related problems in 70 eyes (8.8%), and infection occurring >6 weeks after surgery in 27 eyes (3.4%). A total of 101 eyes of 94 patients had at least 1 subsequent operation for inadequate IOP control. CONCLUSIONS: Trabeculectomy surgery performed by 2 experienced glaucoma specialists achieved target IOP at 4 years in 70% of those operated and was associated with progressive cataract and small risks of bleb-related complications. These results are comparable to those reported in smaller series. PMID- 22244945 TI - Epidemiologic characteristics of intraocular pressure in the Korean and Mongolian populations: the Healthy Twin and the GENDISCAN study. AB - PURPOSE: The purpose of this study was to demonstrate a negative association between intraocular pressure (IOP) and age in 2 Asian populations. In addition, we evaluated genetic and nongenetic factors associated with IOP. DESIGN: Family based cohort study. PARTICIPANTS: Study subjects >10 years of age from one Korean (The Healthy Twin; n = 1431) and 2 Mongolian populations (The GENDISCAN; n = 859 and 806) with IOP values. METHODS: The IOP values were measured with a noncontact tonometer. Each participant received a standard health examination and received questionnaires, which include candidate risk factors on IOP. Mixed models were used to identify risk factors for IOP. Variance-component methods were applied to estimate the heritability of IOP. MAIN OUTCOME MEASURES: The negative trend of IOP with aging and evaluation of impact of genetic and nongenetic components on IOP. RESULTS: The mean ages were 43.6, 34.1, and 36.3 years for the Korean, Orhontuul, and Dashbalbar populations, respectively. The mean IOPs were 14.4 mmHg (95% confidence interval [CI], 14.3-14.6) in the Koreans and 14.1 mmHg (95% CI, 13.9-14.3) and 12.6 mmHg (95% CI, 12.4-12.9) in the Orhontuul and Dashbalbar populations, respectively. In the 3 populations, the IOP decreased as age increased. We replicated an association of systolic blood pressure (SBP) with IOP. In addition, components of the metabolic syndrome (MS), such as plasma glucose, lipid level, and body mass index, showed positive associations with IOP, after adjusting for age and SBP. The IOP also had strong genetic contributions in all populations (heritability, 0.47-0.51). CONCLUSIONS: Negative associations between age and IOP were observed in all 3 populations, which cannot be explained by the increasing prevalence of myopia in the younger generation. The different age trend in IOP may in part be responsible for differences in the prevalence of glaucoma subtypes. Our findings suggest that associations between IOP and MS components were independent of established risk factors such as SBP or age. In addition, the importance of inherited risks requires further genetic dissection of IOP determinants for biological understandings of underlying pathophysiology. PMID- 22244946 TI - Development of a non-heart-beating lung donor program with "Bithermia Preservation", and results after one year of clinical experience. AB - The number of lung transplantations that are performed in Spain continues to grow, with 235 transplant recipients 2010. Non-heart-beating donations have contributed to this upward progression. Our Lung Transplant Unit began its activity in October 2008 and during these last three years 97% of the transplant interventions performed have been successful. In order to increase the number of donations, we have developed a non-heart-beating donor program as part of the existing organs program in our hospital. In doing so, the development of a multi organic preservation method (lung, liver and kidney), which we call "Bithermia Preservation", was necessary. This paper presents this methodology as well as the first year of clinical application experience. During this time, 3 patients have been transplanted using such non-heart-beating donations. None of them developed primary graft dysfunction; all the patients have been discharged and lead active lives without any evidence of bronchiolitis obliterans syndrome. PMID- 22244947 TI - Video-assisted thoracoscopic lung biopsy in the diagnosis of interstitial lung disease: a prospective, multi-center study in 224 patients. AB - OBJECTIVES: To evaluate whether the location and number of lung biopsies obtained by video-assisted thoracoscopy (VAT) influence the diagnosis of diffuse interstitial lung disease (ILD). To assess the applicability of an Ambulatory Surgery Program (ASP). METHODS: Prospective, multicenter study of VAT lung biopsies due to suspected ILD from January 2007 to December 2009, including 224 patients from 13 Spanish centers (mean age 57.1 years; 52.6% females). Data were prospectively collected in every institution and sent to the coordination center for analysis. RESULTS: The most affected areas in high resolution chest CT were the lower lobes (55%). Bronchoscopy was performed in 84% and transbronchial biopsy in 49.1%. In 179 cases (79.9%), more than one biopsy was performed, with a diagnostic agreement of 97.2%. A definitive histopathologic diagnosis was obtained in 195 patients (87%). Idiopathic pulmonary fibrosis was the most frequent diagnosis (26%). There were no statistically significant factors that could predict a greater diagnostic yield (neither anatomical location nor number of biopsies). Seventy patients (31.3%) were included in an ASP. After discharge, there were complications in 12 patients (5.4%), similar between patients admitted postoperatively (9/154: 5.8%) and those included in an ASP (3/70: 4.3%). CONCLUSIONS: Anatomical location and number of lung biopsy specimens did not seem to influence the diagnosis. The patients included in an ASP had a complication rate comparable to that of the hospitalized, so this procedure can be included in a surgical outpatient program. Lung biopsy obtained by VAT is a powerful and safe tool for diagnosis of suspected ILD, resulting in a definitive diagnosis for the majority of patients with a low morbidity rate. PMID- 22244948 TI - Nitric oxide in the exhaled breath condensate of healthy volunteers collected with a reusable device. AB - BACKGROUND: The analysis of exhaled breath condensate (EBC) is a non-invasive technique that enables the determination of several volatile and nonvolatile substances produced in the respiratory tract, whose measurement may be useful for the diagnosis and monitoring of several respiratory diseases. OBJECTIVE: The aim of this study was to produce a low-cost reusable device in order to sample exhaled breath condensate in healthy adult volunteers, and to determine the concentration of nitric oxide in the sample collected. MATERIAL AND METHODS: The apparatus was made with a U-shaped tube of borosilicate glass. The tube was placed in a container with ice, and unidirectional respiratory valves were fitted to the distal end. Afterwards, nitric oxide was measured in the exhaled breath condensate (EBC) by chemiluminescence. RESULTS: The total cost of the device was $120.20. EBC samples were obtained from 116 volunteers of both sexes, aged between 20 and 70. The mean volume of exhaled breath condensate collected during 10 minutes was 1.0 +/- 0.6 mL, and the mean level of nitric oxide was 12.99 +/- 14.38 MUM (median 8.72 MUM). There was no correlation between the nitric oxide levels in the exhaled breath condensate and age or gender. CONCLUSION: We demonstrate that it is possible to fabricate a low-cost, efficient, reusable device in order to collect and determine nitric oxide levels in EBC. We have identified no correlation between the nitric oxide levels present in the EBC obtained with this method with either age or sex. PMID- 22244949 TI - Quantitative assessment of the embryotoxic potential of NSO-heterocyclic compounds using zebrafish (Danio rerio). AB - Heterocyclic aromatic compounds (NSO-HET) have frequently been detected in the environment. Several studies have concluded that NSO-HET pose a threat to organisms in waters, sediments and soils. However, few publications are available assessing the ecotoxicology of NSO-HET. The present study aims to assess the embryo toxicity of heterocycles using Danio rerio. A combination of the Fish Embryo Toxicity Test and analytical quantification should aid to determine the hazard potential. Changes of the total concentrations due to sorption or volatility were quantified by GC/MS. Loss of compounds during the test was observed primarily for volatile or hydrophobic NSO-HET. The LC50 calculated with nominal concentrations underestimates the toxicity by a factor up to 16 (2 h), demonstrating that a chemical analysis for comparing nominal and measured concentrations is essential for such investigations. PMID- 22244950 TI - Developmental exposure to valproate and ethanol alters locomotor activity and retino-tectal projection area in zebrafish embryos. AB - Given the minimal developmental neurotoxicity data available for the large number of new and existing chemicals, there is a critical need for alternative methods to identify and prioritize chemicals for further testing. We outline a developmental neurotoxicity screening approach using zebrafish embryos. Embryos were exposed to nominal concentrations of either valproate or ethanol then examined for lethality, malformation, nervous system structure and locomotor activity. Developmental valproate exposure caused locomotor activity changes at concentrations that did not result in malformations and showed a concentration dependent decrease in retino-tectal projection area in the optic tectum. Developmental ethanol exposure also affected retino-tectal projection area at concentrations below those concentrations causing malformations. As both valproate and ethanol are known human developmental neurotoxicants, these results add to the growing body of evidence showing the potential utility of zebrafish in screening compounds for mammalian developmental neurotoxicity. PMID- 22244951 TI - Performance of a commercial-scale DiCOM demonstration facility treating mixed municipal solid waste in comparison with laboratory-scale data. AB - The current paper describes the performance of a commercial-scale (20,000 tpa) demonstration facility of the DiCOM process, a biological treatment for the organic fraction of municipal solid waste (OFMSW). The 21-d process combines aerobic composting and high-solids (30%DM), thermophilic (55 degrees C) anaerobic digestion (AD), within a single vessel. Mechanically sorted OFMSW, derived from mixed household MSW (324 t), was exposed to sequential aerobic/anaerobic/aerobic treatment. The AD, initiated by adding anaerobic inoculum from a previous trial, was stable (without pH intervention) and the onset of methanogenesis, rapid (<3 h). Volatile fatty acids formed during AD (including propionate) were exhausted prior to reuse of the inoculum. As measured by an electron flux from solids to gaseous end-products, AD accounted for the greatest portion of solids degradation (86%=160 m(3)CH(4)/drytOFMSW). However, unlike laboratory trials, limited degradation occurred during initial aerobic treatment. The discharged solids were classified as a composted soil conditioner. PMID- 22244952 TI - Hydrogen production from the steam reforming of bio-butanol over novel supported Co-based bimetallic catalysts. AB - This paper reports the hydrogen production through the steam reforming of a bioresource-derived butanol mixture (butanol:acetone:ethanol=6:3:1 mass ratio) over supported cobalt-based catalysts. The support plays an important role for the catalytic behavior and Co/ZnO exhibits the best catalytic performance compared to Co/TiO(2) and Co/CeO(2). Moreover, a higher hydrogen yield is obtained over bimetallic Co-Ir/ZnO, which shows an increase in H(2) selectivity and a decrease in CH(4) selectivity under steam reforming conditions, compared to Co/ZnO. Raman results of the used catalysts indicate that the addition of Ir could prevent the coke formation to prolong the catalyst stability. PMID- 22244953 TI - Autohydrolysis and organosolv process for recovery of hemicelluloses, phenolic compounds and lignin from grape stalks. AB - A combination of two environment-friend processes for hemicelluloses and lignin recovery from red grape stalks were investigated: an autohydrolysis pretreatment at 180 degrees C for 30 min followed by a non-catalysed ethanol organosolv step at 180 degrees C for 90 min. Hemicelluloses were precipitated by ethanol addition to autohydrolysis liquor, while lignin was tentatively precipitated by acidification of liquors from both the processes. Results suggest that stalks hemicelluloses can be easily hydrolysed requiring a milder treatment to reduce sugar degradation, while the organosolv process did not give a consistent delignification. Autohydrolysis allowed a recovery of 2% (on stalks d.m.) of total phenols in the liquor. Organosolv liquor had a higher concentration of phenols (corresponding to 0.72% of stalks d.m.) which almost completely precipitated with lignin. PMID- 22244954 TI - Elucidation of cellulose accessibility, hydrolysability and reactivity as the major limitations in the enzymatic hydrolysis of cellulose. AB - The precipitous decline in the rates of enzymatic hydrolysis of cellulose with conversion is one of the major limitations to the commercialization of second generation biofuel. In this work, various rate-limiting factors (fractal kinetics, changes in crystallinity, accessibility, reactivity and hydrolysable fraction, enzyme clogging, and degree of polymerization) were investigated employing experimental as well as computational studies. Model-guided experiments showed cellulose accessibility and the hydrolysable fraction of accessible substrate (a previously undefined and unreported quantity) to decrease steadily until a conversion level of nearly 70%, while cellulose reactivity, defined in terms of hydrolytic activity per amount of actively adsorbed cellulase, remained constant. Substrate depletion, accessibility and hydrolysability decrease accounted for approximately 90% of rate retardation up to 70% conversion. Faster restart rates were observed on partially converted cellulose as compared to uninterrupted hydrolysis rates, supporting an enzyme clogging phenomenon that could possibly be responsible for the additional rate decrease. PMID- 22244955 TI - Behavior of autotrophic denitrification and heterotrophic denitrification in an intensified biofilm-electrode reactor for nitrate-contaminated drinking water treatment. AB - An intensified biofilm-electrode reactor (IBER) was developed to treat nitrate contaminated drinking water. Different running conditions were conducted to investigate the behavior of autotrophic denitrification (AD) and heterotrophic denitrification (HD) in the IBER. In AD process, the nitrate nitrogen coulomb reduction rate was used to evaluate the performance of the reactor. The maximum NO(3)(-)-N removal efficiency was 6.8% at the current of 60 mA, while nitrate nitrogen coulomb-reduction rate was 0.024 mg C(-1). The optimum conditions for HD process were C/N=0.8 and HRT=8h, under which complete NO(3)(-)-N removal and no NO(2)(-)-N accumulation were observed. With the cooperative effect of AD and HD in the heterotrophic and autotrophic denitrification (HAD) process, large treatment capacity, high denitrification efficiency, and low nitrite and ammonia accumulation were achieved. The results proved that HAD process was superior to single AD and HD for nitrate removal in the IBER. PMID- 22244956 TI - Statistical optimization of microalgae Pavlova lutheri cultivation conditions and its fermentation conditions by yeast, Candida rugopelliculosa. AB - In this study, sequential strategy based design was applied to optimize the microalgae, Pavlova lutheri mass culture conditions and fermentation conditions of the cultured algae by proteolytic yeast Candidia rugopelliculosa to obtain small peptide chains. This optimization of culture and fermentation conditions by response surface methodology (RSM) finally leads to effective purification of a bioactive peptide MPGPLSPL (793.01 Da) with hydroxyl radical scavenging activity. Collectively, these results indicated that microalgae P. lutheri can enhance the hydroxyl radical inhibiting effect through protein hydrolysis process under RSM optimal condition. PMID- 22244957 TI - Parametric study of a brewery effluent treatment by microalgae Scenedesmus obliquus. AB - This work analyses the potential of using microalgae Scenedesmus obliquus (So) for a brewery wastewater treatment and biomass production. The chemical oxygen demand (COD), total nitrogen (TN) and total carbon (TC) was followed in time, and the influence of light exposure, light intensity and culture aeration was studied. Results show that the most adequate conditions for cultivating So in this effluent are the aerated cultures, exposed to a 12h period of daily light, at 12000 Lux intensity. At these conditions it is obtained a maximum of 0.9 g of dry biomass per liter of culture, after 9 days, for a maximum reduction of 57.5% and 20.8% of COD and TN, respectively, after 14 days, and 56.9% of TC, after 13 days, corresponding to the final values of 1692 mg O(2)/L COD, 47 mg N/L TN, and 1mg C/L TC. PMID- 22244958 TI - High pressure treatment as a tool for engineering of enzymatic reactions in cellulosic fibres. AB - Ultrahigh hydrostatic pressure (UHP) was applied to enhance the enzymatic hydrolysis of xylan in cellulosic fibers. The pretreatment improved xylan accessibility in the fiber cell wall and a 5-10-fold increase in the initial hydrolysis rate of xylan by xylanase was observed when Eucalyptus globulus kraft bleached pulp was pretreated at hydrostatic pressures of 300-400 MPa for 15-45 min. The rate and the extent of hydrolysis can be controlled by varying the pressure and the exposure time of UHP treatment prior to enzymatic hydrolysis. Sequential UHP pretreatment and hydrolysis by xylanase disaggregated the hydrated cellulose fibrils and led to the gelation of cell wall regions accessible to enzymatic attack. UHP could therefore become a tool for the engineering of enzymatic reactions within cellulosic fibers to obtain products with tailored properties. PMID- 22244959 TI - High yield bio-butanol production by solvent-producing bacterial microflora. AB - Highly efficient butanol-producing bacterial microflora were isolated from hydrogen-producing sludge of a sewage treatment plant. Based on denaturing gradient gel electrophoresis (DGGE) analysis and 16s rDNA comparison, four strains from the butanol-producing microflora were identified as Clostridium saccharoperbutylacetonicum, Clostridium butylicum, Clostridium beijernckii, and Clostridium acetobutylicum. The effects of glucose, FeSO(4) . 7H(2)O and yeast extract concentrations on the butanol production by the mixture culture were investigated on batch mode. The medium composition for bio-butanol production was optimized using the Box-Behnken design and response surface methodology (RSM). The maximum butanol production rate (0.25 +/- 0.02 g/L-h) and concentration (12.4 g/L) were obtained under the condition of glucose concentration, 60 g/L; FeSO(4) . 7H(2)O, 0.516 g/L; yeast extract concentration, 5.13 g/L. Addition of 6.0 g/L butyric acid significantly increased the butanol titer to 17.51 +/- 0.49 g/L. Pressurized fermentation strategy (employed with a 5L fermentor) further enhanced the butanol concentration to 21.35 g/L, along with a maximum butanol rate of 1.25 g/L-h. PMID- 22244960 TI - Oral ACTH (H.P. Acthar((r))Gel) inhibits IL-1 and IL-17 secretion in humans. AB - OBJECTIVE: We have shown that oral corticotropin hormone (ACTH) decreased clinical score, inflammatory foci and T(eff) IL-17 in fed and adoptive transferred recipient mice with experimental autoimmune encephalomyelitis (EAE). Therefore, we determined whether oral administration of ACTH had immunological and endocrinological effects and was safe in humans. METHODS: Three groups of three healthy adult volunteers were assayed for total serum ACTH, cortisol and a set of pro-inflammatory and counter-regulatory cytokines after ingested dose(s) of ACTH 4 IU (n=3), 41 IU (n=3), or 123 IU (n=3) over 5 days. RESULTS: There were no safety issues during the trial. There was no increase in total ACTH levels after day 1 or day 5. There was no significant increase in total cortisol among the groups comparing day 1 to day 5. There were significant decreases in the inflammatory cytokine IL-1 and IL-17 secretion at day 6 compared to baseline with the 123 IU dose but not after the 4 IU and 41 IU doses. CONCLUSIONS: These data provide evidence for the safety and an immunological effect of oral ACTH in humans. It is unknown if the change in IL-1 and IL-17 reflects a local GI mediated effect or effects following systemic absorption of ACTH. PMID- 22244961 TI - Effect of immunosuppressive drugs on DNA repair in human peripheral blood mononuclear cells. AB - INTRODUCTION: Cancer is a major cause of mortality among transplant recipients. Immunosuppressive treatment is a modifiable factor contributing to this phenomenon. Cyclosporine in kidney transplant recipients was associated with reduced UV-induced DNA repair by peripheral blood mononuclear cells (PBMC) and increased cancer rate. H(2)O(2) is a common cellular reactive oxygen species (ROS), which induces DNA damage followed by DNA repair. AIM: To investigate the effect of currently used immunosuppressive drugs on DNA repair. METHODS: H(2)O(2) induced DNA repair by human PBMC was tested in vitro in the presence of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus, mycophenolic acid (MPA), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus, at low to high non-toxic concentrations. The effect of combination therapy at maintenance levels was also tested. RESULTS: Cyclosporine and tacrolimus suppressed DNA repair throughout the tested dose range. In contrast, MPA, sirolimus and everolimus did so only at the high doses. Maintenance doses of a combination of tacrolimus and MPA, the most frequent treatment regimen, reduced DNA repair, while MPA with sirolimus or everolimus did not. CONCLUSION: In an attempt to reduce the risk of post-transplantation malignancy, treatment protocols may be modified by reducing CNI dose. PMID- 22244962 TI - Lung cancer alters the hydrolysis of nucleotides and nucleosides in platelets. AB - BACKGROUND: The nucleotides and nucleosides of adenine are signaling molecules related to thromboregulation and modulation of immune responses in patients with malignancies. Thus, this study aims to determine NTPDase, 5'-nucleotidase, ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) and adenosine deaminase (ADA) activities in the platelets of patients with lung cancer. METHODS: We collected blood samples from patients (n=33) previously treated for lung cancer with chemotherapy. Patients were classified as stage IIIb and IV according to the Union for International Cancer Control (UICC). RESULTS: Patients showed a significant decrease in the hydrolysis of adenosine diphosphate (ADP) and adenosine, whereas the adenosine monophosphate (AMP) hydrolysis and platelet aggregation were significantly increased in this group. Adenosine triphosphate (ATP) hydrolysis did not show significant results between the group of patients and the control group. CONCLUSIONS: We may suggest that ectonucleotidases as well as ADA are enzymes involved in thromboembolic events but especially here we may see that they are also directly involved in the generation of adenosine formation in the cancer patient circulation. PMID- 22244963 TI - A systematic-analysis of predicted miR-21 targets identifies a signature for lung cancer. AB - INTRODUCTION: The well-known oncomiR-miR-21 was previously reported oncogenic activity in lung cancer. We sought to determine the expression of all predicted target genes of miR-21 and their potential function, pathways and networks, which are involved in the biological behavior of lung cancer. METHODS: After a systematic review of English language studies of lung cancer-related molecules were pooled; genes were classified in three functional groups by gene ontology (GO) analysis. The key molecules were indentified by establishing lung cancer related networks and pathways. MiR-21 targets were predicted by computational method, followed by screening for matched gene symbols in NCBI human sequences and GO, pathway and network analysis. MiR-21 targets and their network, which are involved in the malignant mechanisms of lung cancer, were obtained by the final integrative analysis. RESULT: We indentified the potential functions, pathways and networks of lung cancer relating molecules and miR-21 targets respectively in the initial analysis. In the final integrative analysis of lung cancer related miR-21-targets analysis, 24 hub genes were identified by overlap calculation, suggesting that miR-21 may play an important role in the development and progression of lung cancer through JAK/STAT signal pathway, MAPK signaling pathway, Wnt signaling pathway, cell cycle, PPAR signaling pathway, apoptosis pathway and other pathways. CONCLUSION: Our data may help researchers to predict the molecular mechanisms of miR-21 in the development and progression of lung cancer comprehensively. Moreover, the present data indicate that miR-21-targets may be a series of promising candidates as biomarkers for lung cancer. PMID- 22244964 TI - LPS and TNF-alpha induce expression of sphingosine-1-phosphate receptor-2 in human microvascular endothelial cells. AB - Sphingosine-1-phosphate (S1P) is a bioactive sophospholipid with various S1P receptor (S1PR) expression profiles in cells of different origin. S1PR1, R3 and - to a lesser extent - R2 were the main receptors expressed in most of endothelial cells (ECs). The balances in the expression and activation of S1PR1, R2 and R3 help to maintain the physiological functions of ECs. Reverse transcription-PCR and Western blotting were used to detect the mRNA transcript level and protein expression of S1PR. Endothelial barrier function was measured by transflux of tracer protein through endothelial monolayer. Human dermal microvascular ECs predominantly expressed S1PR1 and S1PR3. Lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) significantly upregulated S1PR2 mRNA and protein levels. The application of S1PR2 antagonist JTE-013 decreased the endothelial monolayer hyper-permeability response induced by LPS and TNF-alpha. Inflammatory mediators LPS and TNF-alpha induce S1PR2 expression in endothelium, suggesting that S1PR2 up-regulation may be involved in LPS and TNF-alpha elicited endothelial barrier dysfunction. PMID- 22244965 TI - The physiological and activity demands experienced by Australian female basketball players during competition. AB - OBJECTIVES: To describe the physiological and activity demands experienced by Australian female basketball players during competition. DESIGN: A between subjects (positional comparison) repeated measures (playing periods) observational experimental design was followed. METHODS: State-level basketball players (n=12; age: 22.0+/-3.7 yr; body mass: 72.9+/-14.2 kg; stature: 174.2+/ 6.9 cm; body fat: 17.2+/-5.6%; estimated VO(2max):43.3+/-5.7 ml kg-1 min-1) volunteered to participate. Heart rate (HR) and blood lactate concentration ([BLa]) were collected across eight competitive matches. Overall and positional player activity demands were calculated across three matches using time-motion analysis methodology. Activity frequencies, total durations and total distances were determined for various activity categories. RESULTS: Mean (+/-SD) HR responses of 162+/-3b min-1 (82.4+/-1.3% HR(max)) and 136+/-6b min-1 (68.6+/-3.1% HR(max)) were evident across live and total time during matches. A mean [BLa] of 3.7+/-1.4 mmol L-1 was observed across competition. Player activity demands were unchanged across match periods, with 1752+/-186 movements performed and 5214+/ 315 m travelled across total live match time. Furthermore, 39+/-3%, 52+/-2%, 5+/ 1% and 4+/-1% of total live time was spent performing low-intensity, moderate intensity, high-intensity and dribbling activity. Positional comparisons revealed backcourt players performed more ball dribbling (p<0.001) and less standing/walking (p<0.01) and running (p<0.05) than frontcourt players. CONCLUSIONS: Together, these findings highlight the high intermittent demands and important contributions of both anaerobic and aerobic metabolic pathways during state-level female basketball competition. PMID- 22244966 TI - Upper limb impairments and their impact on activity measures in children with unilateral cerebral palsy. AB - BACKGROUND: Insights in upper limb impairments and their relationship with activity measures in children with unilateral cerebral palsy (CP) are important to optimize treatment interventions. AIMS: (1) To investigate upper limb impairments and activity limitations in children with unilateral CP; (2) to compare these according to the Manual Ability Classification System (MACS), timing of lesion (congenital/acquired) and age; (3) to determine the impact of impairments on activity measures. METHODS: Eighty-one children with unilateral CP aged 5-15 years (mean 9 years 11 months; congenital N=69, acquired N=12) were recruited. Body function measurements included passive range of motion (PROM), muscle tone, strength and sensibility. At activity level, the Melbourne Assessment, Assisting Hand Assessment (AHA) and Abilhand-Kids were assessed. RESULTS: Most PROM limitations were found for elbow extension and supination. Increased tone and weakness were most prominent in distal muscles. Stereognosis and two-point discrimination were mostly affected. Children with a lower MACS level or acquired lesion had significantly more impairments and activity limitations. In children with congenital lesions, best predictors for unimanual capacity (Melbourne Assessment) were wrist strength, stereognosis and proprioception, and for bimanual performance (AHA) wrist strength and grip strength, explaining 76% of the variance. For the Abilhand-Kids, wrist strength and stereognosis predicted 46% of the variance. CONCLUSIONS: Classification according to MACS and timing of lesion is important to differentiate within the wide range of impairments and activity limitations. In children with congenital lesions, unimanual capacity and bimanual performance are highly determined by distal strength, supporting the additional use of impairment-based interventions. PMID- 22244967 TI - Aggregation and deposition kinetics of carboxymethyl cellulose-modified zero valent iron nanoparticles in porous media. AB - Transport and deposition of carboxymethyl cellulose (CMC)-modified nanoparticles of zero-valent iron (NZVI) were investigated in laboratory-scale sand packed columns. Aggregation resulted in a change in the particle size distribution (PSD) with time, and the changes in average particle size were determined by nanoparticle tracking analysis (NTA). The change in PSD over time was influenced by the CMC-NZVI concentration in suspension. A particle-particle attachment efficiency was evaluated by fitting an aggregation model with NTA data and subsequently used to predict changes in PSD over time. Changes in particle sizes over time led to corresponding changes in single-collector contact efficiencies, resulting in altered particle deposition rates over time. A coupled aggregation colloid transport model was used to demonstrate how changes in PSD can reduce the transport of CMC-NZVI in column experiments. The effects of particle concentrations in the range of 0.07 g L(-1) to 0.725 g L(-1) on the transport in porous media were evaluated by comparing the elution profiles of CMC-NZVI from packed sand columns. Changes in PSD over time could reasonably account for a gradual increase in effluent concentration between 1 and 5 pore volumes (PVs). Processes such as detachment of deposited particles also likely contributed to the gradual increase in effluent concentrations. The particle-collector attachment efficiency increased with CMC-NZVI particle concentration due to a rise in dissolved Na(+) concentration with increased addition of Na-CMC. This inadvertent change in ionic strength led to decreased effluent concentrations at higher CMC-NZVI concentrations. PMID- 22244968 TI - Is the future blue-green? A review of the current model predictions of how climate change could affect pelagic freshwater cyanobacteria. AB - There is increasing evidence that recent changes in climate have had an effect on lake phytoplankton communities and it has been suggested that it is likely that Cyanobacteria will increase in relative abundance under the predicted future climate. However, testing such a qualitative prediction is challenging and usually requires some form of numerical computer model. Therefore, the lake modelling literature was reviewed for studies that examined the impact of climate change upon Cyanobacteria. These studies, taken collectively, generally show an increase in relative Cyanobacteria abundance with increasing water temperature, decreased flushing rate and increased nutrient loads. Furthermore, they suggest that whilst the direct effects of climate change on the lakes can change the timing of bloom events and Cyanobacteria abundance, the amount of phytoplankton biomass produced over a year is not enhanced directly by these changes. Also, warmer waters in the spring increased nutrient consumption by the phytoplankton community which in some lakes caused nitrogen limitation later in the year to the advantage of some nitrogen-fixing Cyanobacteria. Finally, it is also possible that an increase in Cyanobacteria dominance of the phytoplankton biomass will lead to poorer energy flow to higher trophic levels due to their relatively poor edibility for zooplankton. PMID- 22244969 TI - Distribution and disinfection of bacterial loadings associated with particulate matter fractions transported in urban wet weather flows. AB - Urban runoff is a resource for reuse water. However, runoff transports indicator and pathogenic organisms which are mobilized from sources of fecal contamination. These organisms are entrained with particulate matter (PM) that can serve as a mobile substrate for these organisms. Within a framework of additional treatment for reuse of treated runoff which requires the management of PM inventories in unit operations and drainage systems there is a need to characterize organism distributions on PM and the disinfection potential thereof. This study quantifies total coliform, Escherichia coli, fecal streptococcus, and enterococcus generated from 25 runoff events. With the ubiquity and hetero-dispersivity of PM in urban runoff this study examines organism distributions for suspended, settleable and sediment PM fractions differentiated based on PM size and transport functionality. Hypochlorite is applied in batch to elaborate inactivation of PM associated organisms for each PM fraction. Results indicate that urban runoff bacterial loadings of indicator organisms exceed U.S. wastewater reuse, recreational contact, and Australian runoff reuse criteria as comparative metrics. All monitored events exceeded the Australian runoff reuse criteria for E. coli in non-potable residential and unrestricted access systems. In PM differentiated events, bacteriological mobilization primarily occurred in the suspended PM fraction. However, sediment PM shielded PM-associated coliforms at all hypochlorite doses, whereas suspended and settleable PM fractions provide less shielding resulting in higher inactivation by hypochlorite. PMID- 22244970 TI - Strategies for lipids and phenolics degradation in the anaerobic treatment of olive mill wastewater. AB - Strategies are proposed for the anaerobic treatment of lipid and phenolic-rich effluents, specifically the raw olive mill wastewater (OMW). Two reactors were operated under OMW influent concentrations from 5 to 48 g COD L(-1) and Hydraulic Retention Time between 10 and 5 days. An intermittent feeding was applied whenever the reactors showed a severe decay in the methane yield. This strategy improved the mineralization of oleate and palmitate, which were the main accumulated Long-Chain Fatty Acids (LCFA), and also promoted the removal of resilient phenolic compounds, reaching remarkable removal efficiencies of 60% and 81% for two parallel reactors at the end of a feed-less period. A maximum biogas production of 1.4m(3)m(-3)d(-1) at an Organic Loading Rate of 4.8 kg COD m(-3)d( 1) was obtained. Patterns of individual LCFA oxidation during the OMW anaerobic digestion are presented and discussed for the first time. The supplementation of a nitrogen source boosted immediately the methane yield from 21 and 18 to 76 and 93% in both reactors. The typical problems of sludge flotation and washout during the anaerobic treatment of this oily wastewater were overcome by biomass retention, according to the Inverted Anaerobic Sludge Blanket (IASB) reactor concepts. This work demonstrates that it is possible to avoid a previous detoxification step by implementing adequate operational strategies to the anaerobic treatment of OMW. PMID- 22244971 TI - Membrane vis-LED photoreactor for simultaneous penicillin G degradation and TiO2 separation. AB - The hybrid membrane photoreactor (MPR) combining a photoreactor irradiated with visible-light-emitting diode (vis-LED) and a cross-flow microfiltration (MF) membrane module was investigated in both closed-loop and continuous flow-through modes for the simultaneous degradation of penicillin G (PG) and separation of visible-light responsive TiO(2) particles, namely C-sensitized-N-doped TiO(2) (T300) and C-N-S tridoped TiO(2) (T0.05-450). The turbidity of permeate water was <0.2 NTU for both T300 and T0.05-450 suspensions in the MPR system operated at different transmembrane pressures (TMPs) and cross-flow velocities (CFVs), indicating effective separation of TiO(2) particles by the MF membrane. The operations at a higher TMP or lower CFV were more prone to induce TiO(2) deposition on the membrane surface without backwashing, which resulted in the membrane fouling, the loss of TiO(2) from the photoreactor and the decrease of PG photocatalytic degradation efficiency. 75% and 84% of PG were degraded in the closed-loop MPR without backwashing operated at 10 kPa and 0.15 m s(-1) after 4 h of vis-LED irradiation using 1.0 g L(-1) of T300 and T0.05-450, respectively. With backwashing of the membrane, the PG photocatalytic degradation efficiencies in the closed-loop MPR could be significantly enhanced to achieve 93% and 95% using 1.0 g L(-1) of T300 and T0.05-450, respectively, which were almost comparable to those achieved in the batch photoreactor. Due to its shorter hydraulic residence time in the photoreactor, the PG degradation efficiency in the continuous flow-through MPR with backwashing was lower than that achieved in the closed-loop MPR. PMID- 22244972 TI - Nano-magnetic particles as multifunctional microreactor for deep desulfurization. AB - Oxidation of dibenzothiophene with hydrogen peroxide using a recyclable amphiphilic catalyst has been studied. The catalyst was synthesized by surfacely covering magnetic silica nanospheres (MSN) with the complexes between 3 (trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride (AEM) and phosphotungstic acid (PTA). The morphology and components of the composite material were characterized by TEM, EDX, XPS, FT-IR, and VSM, respectively. The effects of several factors on desulfurization reactivity were systematically investigated. The results showed that the composite nanospheres have core/shell structure with the properties of amphiphilicity and superparamagnetism. The composite nanospheres have high catalytic activity in the oxidation of dibenzothiophene to corresponding sulfones by hydrogen peroxide under mild reaction conditions. The sulfur level could be lowered from 487 ppm to less than 0.8 ppm under optimal conditions. Additionally, the amphiphilic catalyst and the oxidized product could be simultaneously separated from medium by external magnetism, and the recovered composite material could be recycled for three times with almost constant activity. PMID- 22244973 TI - Volatility and mixing states of ultrafine particles from biomass burning. AB - Fine and ultrafine carbonaceous aerosols produced from burning biomasses hold enormous importance in terms of assessing radiation balance and public health hazards. As such, volatility and mixing states of size-selected ultrafine particles (UFP) emitted from rice straw, oak, and pine burning were investigated by using volatility tandem differential mobility analyzer (VTDMA) technique in this study. Rice straw combustion produced unimodal size distributions of emitted aerosols, while bimodal size distributions from combustions of oak (hardwood) and pine (softwood) were obtained. A nearness of flue gas temperatures and a lower CO ratio of flaming combustion (FC) to smoldering combustion (SC) were characteristic differences found between softwood and hardwood. SC emitted larger mode particles in higher numbers than smaller mode particles, while the converse was true for FC. Rice straw open burning UFPs exhibited a volatilization behavior similar to that between FC and SC. In addition, internal mixing states were observed for size-selected UFPs in all biomasses for all combustion conditions, while external mixing states were only observed for rice straw combustion. Results for FC and open burning suggested there was an internal mixing of volatile organic carbon (OC) and non-volatile core (e.g., black carbon (BC)), while the SC in rice straw produced UFPs devoid of non-volatile core. Also, it was found that volatility of constituting OC in FC and SC particles was different. PMID- 22244975 TI - Tests and models of nociception and pain in rodents. AB - Nociception and pain is a large field of both neuroscience and medical research. Over time, various tests and models were developed in rodents to provide tools for fundamental and translational research on the topic. Tests using thermal, mechanical, and chemical stimuli, measures of hyperalgesia and allodynia, models of inflammatory or neuropathic pain, constitute a toolbox available to researchers. These tests and models allowed rapid progress on the anatomo molecular basis of physiological and pathological pain, even though they have yet to translate into new analgesic drugs. More recently, a growing effort has been put forth trying to assess pain in rats or mice, rather than nociceptive reflexes, or at studying complex states affected by chronic pain. This aids to further improve the translational value of preclinical research in a field with balanced research efforts between fundamental research, preclinical work, and human studies. This review describes classical tests and models of nociception and pain in rodents. It also presents some recent and ongoing developments in nociceptive tests, recent trends for pain evaluation, and raises the question of the appropriateness between tests, models, and procedures. PMID- 22244974 TI - Effects of long-term moderate ethanol and cholesterol on cognition, cholinergic neurons, inflammation, and vascular impairment in rats. AB - There is strong evidence that vascular risk factors play a role in the development of Alzheimer's disease (AD) or vascular dementia (vaD). Ethanol (EtOH) and cholesterol are such vascular risk factors, and we recently showed that hypercholesterolemia causes pathologies similar to AD [Ullrich et al. (2010) Mol Cell Neurosci 45, 408-417]. The aim of this study was to investigate the effects of long-term (12 months) EtOH treatment (20% v/v in drinking water) alone or long-term 5% cholesterol diet alone or a combination (mix) in adult Sprague Dawley rats. Long-term EtOH treatment (plasma EtOH levels 58+/-23 mg/dl) caused significant impairment of spatial memory, reduced the number of choline acetyltransferase- and p75 neurotrophin receptor-positive nucleus basalis of Meynert neurons, decreased cortical acetylcholine, elevated cortical monocyte chemoattractant protein-1 and tissue-type plasminogen activator, enhanced microglia, and markedly induced anti-rat immunoglobulin G-positive blood-brain barrier leakage. The effect of long-term hypercholesterolemia was similar. Combined long-term treatment of rats with 20% EtOH and 5% cholesterol (mix) did not potentiate treatment with EtOH alone, but instead counteracted some of the EtOH-associated effects. In conclusion, our data show that vascular risk factors EtOH and cholesterol play a role in cognitive impairment and possibly vaD. PMID- 22244976 TI - The effects of metabotropic glutamate receptor 7 allosteric agonist N,N' dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 mitogen activated protein kinase signaling pathway. AB - The present study was designed to evaluate the possible neuroprotective effects of metabotropic glutamate receptor (mGluR7) allosteric agonist N,N' dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) on developmental sevoflurane neurotoxicity. To achieve the objective, hippocampal cultures (7 DIV, 7 day in vitro) were treated with different doses of L-(+)-2-amino-4 phosphonobutyric acid (L-AP4, an agonist of group III mGluRs), (RS)-alpha Methylserine-O-phosphate (MSOP, an antagonist of group III mGluRs), AMN082 or cis 2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanecarboxylic acid (VU0155041, an agonist of mGluR4) before exposed to sevoflurane. Cell apoptosis were determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-staining. For in vivo study, rat pups (7 PND, 7 postnatal day) were injected with AMN082, L-AP4 or saline before sevoflurane exposure. Extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, caspase-3, Bcl-2, and Bax were detected by Western blot. The locomotor activity and cognitive functions were evaluated by open-field test and Morris water maze (MWM), respectively. We found that L-AP4 prevented sevoflurane induced cell apoptosis, but MSOP promoted. Specially, application of AMN082 contributed to the relief of sevoflurane-induced apoptosis in vitro, whereas VU0155041 did not. In addition, sevoflurane treatment led to a decrease of Bcl-2 and an increase of caspase-3 and Bax, which were mitigated by AMNO82 in vivo. Moreover, we showed that sevoflurane treatment resulted in a remarkable suppression of phospho-ERK1/2, which was restored by AMN082. Application of U0126 (an inhibitor of MEK) abolished the neuroprotective effects of AMN082 on sevoflurane neurotoxicity both in vitro and in vivo. In addition, sevoflurane exposure also led to an increase of phospho-JNK, but SP600125 (an inhibitor of JNK) did not attenuate sevoflurane-induced apoptosis. The total and phosphorylated p38 remained unchanged in sevoflurane-treated rat pups. Finally, AMN082 improved the learning and memory defects caused by postnatal sevoflurane exposure without alternations in emotion or locomotor activity. These preliminary data indicate that AMN082 may protect immature brain against sevoflurane neurotoxicity, and the ERK1/2 MAP kinase signaling is likely to be involved. Further studies are needed to fully assess the neuroprotective role of mGluR7 agonist AMN082 in developmental anesthetic neurotoxicity. PMID- 22244977 TI - A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice. AB - Delayed activation of tissue plasminogen activator (tPA) can lead to the disruption of the blood-brain barrier (BBB), resulting in hemorrhagic complications. In the present study, we focused on tight junction proteins (TJPs), occludin, zona occludens (ZO)-1, and claudin-5, which are important structural components of the BBB, and investigated whether inhibition of matrix metalloproteinases (MMPs) provides a protective effect against hemorrhagic complications induced by tPA. We subjected mice to 6-h filamental middle cerebral artery occlusion (MCAO) with vehicle, delayed tPA alone, or combined tPA (10 mg/kg, i.v.) plus GM6001 (100 mg/kg, i.p.), a broad-spectrum MMP inhibitor. We evaluated brain hemoglobin and the expression of MMP-9 and TJPs by immunoblotting. GM6001 significantly reduced tPA-elevated brain hemoglobin, MMP 9, and inhibited the degradation of occludin and ZO-1 induced by tPA, but not claudin-5. Treatment with GM6001 also significantly prevented the decrease in the survival rate and the reduction in locomotor activity caused by tPA at 7 days after ischemia/reperfusion. Furthermore, GM6001 treatment also significantly prevented cell damage, determined by release of lactase dehydrogenase (LDH) activity, and the decrease in transendothelial electrical resistance (TEER) induced by tPA. These findings indicate that GM6001 prevented the hemorrhagic complications and improved the behavioral abnormalities induced by tPA, partly via protection of TJPs. This suggests that GM6001 may be a useful candidate for combination therapy against the hemorrhagic complications induced by tPA. PMID- 22244978 TI - A simple method for detection of food foraging behavior in the rat: involvement of NMDA and dopamine receptors in the behavior. AB - Food foraging behavior involves food removing, hoarding, and competitive preying upon other animals. It is also associated with high cognitive functions such as investing effort into decision making, but no established laboratory model is available to detect the behaviors. In the present study, we have developed a novel laboratory rodent model to detect competitive, non-competitive, and no hurdle foraging conditions that can mimic the corresponding environment in nature. We found that normal rats consistently foraged the food from a food container to the field and spread food into piles in the open field. There was no difference between male and female rats in the amount of foraged food in the competitive, non-competitive, and no-hurdle food foraging tests. The amount of foraged food was consistent each day for five consecutive days with a slight increase in following days. There was no significant difference in the amount of food foraged in the presence or absence of bedding materials. A dramatic decrease of foraged food was found in the rats after administration of haloperidol (dopamine D2 receptor antagonist) in the competitive, non-competitive, and no hurdle food foraging tests. Treatment with MK-801 (non-competitive N-methy-D aspartate receptor antagonist) reduced the foraged food in the competitive food foraging test, but did not affect the foraged food in the non-competitive and no hurdle food foraging tests. Our study provides a simple but consistent analogue of natural food foraging behavior. Our study also suggests that dopaminergic and glutaminergic systems are differentially involved in the food foraging behaviors. PMID- 22244980 TI - Myxomavirus as a vector for the immunisation of sheep: protection study against challenge with bluetongue virus. AB - Recombinant poxviruses are well suited for the development of new vaccine vectors. Our previous data supported the idea that Myxomavirus (MYXV) is efficient at priming antibody responses in sheep. To provide definitive evidence on the potential of MYXV for vaccination against infectious diseases in ruminants, we investigated the immune protection provided by recombinant MYXV against bluetongue, a devastating disease in sheep. To test this concept, sheep were injected twice with an MYXV expressing the immunodominant VP2 protein (SG33 VP2). The SG33-VP2 vector promoted the production of neutralising antibodies and partially protected sheep against disease after challenge with a highly virulent strain of serotype-8 bluetongue virus (BTV-8). In contrast, an MYXV expressing both VP2 and VP5 proteins (SG33-VP2/5) elicited very little protection. The expression levels of the VP2 and VP5 proteins suggested that, greater than the co expression of the VP5 protein which was previously thought to favour anti-VP2 antibody response, the high expression of VP2 may be critical in the MYXV context to stimulate a protective response in sheep. This highlights the requirement for a careful examination of antigen expression before any conclusion can be drawn on the respective role of the protective antigens. As a proof of principle, our study shows that an MYXV vaccine vector is possible in ruminants. PMID- 22244979 TI - Drug treatment combined with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium tuberculosis. AB - Bacillus-Calmette-Guerin (BCG), the only human tuberculosis vaccine, primes a partially protective immune response against Mycobacterium tuberculosis infection in humans and animals. In guinea pigs, BCG vaccination slows the progression of disease and reduces the severity of necrotic granulomas, which harbor a population of drug-tolerant bacilli. The objective of this study was to determine if reducing disease severity by BCG vaccination of guinea pigs prior to M. tuberculosis challenge enhanced the efficacy of combination drug therapy. At 20 days of infection, treatment of vaccinated and non-vaccinated animals with rifampin, isoniazid, and pyrizinamide (RHZ) was initiated for 4 or 8 weeks. On days 50, 80 and 190 of infection (10 weeks after drug were withdrawn), treatment efficacy was evaluated by quantifying clinical condition, bacterial loads, lesion severity, and dynamic changes in peripheral blood and lung leukocyte numbers by flow cytometry. In a separate, long-term survival study, treatment efficacy was evaluated by determining disease reactivation frequency post-mortem. BCG vaccination alone delayed pulmonary and extra-pulmonary disease progression, but failed to prevent dissemination of bacilli and the formation of necrotic granulomas. Drug therapy either alone or in combination with BCG, was more effective at lessening clinical disease and lesion severity compared to control animals or those receiving BCG alone. Fewer residual lesions in BCG vaccinated and drug treated animals, equated to a reduced frequency of reactivation disease and improvement in survival even out to 500 days of infection. The combining of BCG vaccination and drug therapy was more effective at resolving granulomas such that fewer animals had evidence of residual infection and thus less reactivation disease. PMID- 22244981 TI - Statistics of N-terminal alignment as a guide for refining prokaryotic gene annotation. AB - Identification of a correct N-terminus of a protein is an important step in genome annotation. However, we sometimes encounter incorrectly annotated N termini in genomic databases. We analyzed statistics of surplus or missing N terminal amino acid residues in tentatively translated coding sequence of cyanobacterial database entries, and found that, on average, about 8-9% of the aligned proteins have a putative incorrect N-terminus, although the percentage was dependent on the database entry. In an attempt to find more plausible N termini for these proteins, we were able to estimate a better-aligning N-terminus in 90% of the cases. TTG was found as a putative initiation codon in most cases of recessed N-termini. This statistical approach, applicable to any group of prokaryotes, will help identify a plausible translation initiation site for each protein-coding gene in newly sequenced genomes, and also is a method of refining the N-terminus of proteins in already published genomes. PMID- 22244982 TI - Isolation of cyanophycin from tobacco and potato plants with constitutive plastidic cphATe gene expression. AB - A chimeric cyanophycin synthetase gene composed of the cphATe coding region from the cyanobacterium Thermosynechococcus elongatus BP-1, the constitutive 35S promoter and the plastid targeting sequence of the integral photosystem II protein PsbY was transferred to the tobacco variety Petit Havanna SRI and the commercial potato starch production variety Albatros. The resulting constitutive expression of cyanophycin synthetase leads to polymer contents in potato leaf chloroplasts of up to 35 mg/g dry weight and in tuber amyloplasts of up to 9 mg/g dry weight. Both transgenic tobacco and potato were used for the development of isolation methods applicable for large-scale extraction of the polymer. Two different procedures were developed which yielded polymer samples of 80 and 90% purity, respectively. PMID- 22244983 TI - Nanogel scavengers for drugs: local anesthetic uptake by thermoresponsive nanogels. AB - The use of functional nanogels based on poly(N-isopropylacrylamide) for effectively scavenging compounds (here, the model drug bupivacaine) is demonstrated using an in vitro cell-based assay. Nanogels containing higher loadings of acidic functional groups or more core-localized functional group distributions bound more bupivacaine, while nanogel size had no significant effect on drug binding. Increasing the dose of nanogel applied also facilitated more bupivacaine binding for all nanogel compositions tested. Binding was driven predominantly by acid-base interactions between the nanogels (anionic) and bupivacaine (cationic) at physiological pH, although both non-specific absorption and hydrophobic partitioning also contributed to drug scavenging. Nanogels exhibited minimal cytotoxicity to multiple cell types and were well tolerated in vivo via peritoneal injections, although larger nanogels caused limited splenic toxicity at higher concentrations. The cell-based assay described herein is found to facilitate more robust drug uptake measurements for nanogels than conventional centrifugation-based assays, in which nanogels can be compressed (and thus drug released) during the measurement. PMID- 22244985 TI - Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. AB - BACKGROUND: The large quantity of systematic reviews of magnetic resonance imaging studies in schizophrenia challenges their meaningful interpretation. This meta-review synthesises the available information from systematic reviews of structural alteration in both chronic and first-episode schizophrenia. METHODS: Systematic reviews were identified using electronic databases. Review methodological quality was assessed according to the Assessment of Multiple Systematic Reviews checklist. Data were extracted in duplicate and quality assessed for consistency and precision, guided by Grading of Recommendations Assessment, Development and Evaluation recommendations. RESULTS: Integration of volumetric and voxel-based estimates allowed critical assessment of the magnitude and location of anatomical differences. There is evidence for grey matter reductions of anterior cingulate, frontal (particularly medial and inferior) and temporal lobes, hippocampus/amygdala, thalamus, and insula that may be magnified over time. Other regional alterations appear specific to illness stage or medication status. CONCLUSIONS: There is limited high quality evidence supporting grey or white matter changes in schizophrenia, which has previously been obscured by a large volume of conflicting lower quality evidence. PMID- 22244984 TI - An N-halamine-based rechargeable antimicrobial and biofilm controlling polyurethane. AB - An N-halamine precursor, 5,5-dimethylhydantoin (DMH), was covalently linked to the surface of polyurethane (PU) with 1,6-hexamethylene diisocyanate (HDI) as the coupling agent. The reaction pathways were investigated using propyl isocyanate (PI) as a model compound. The results suggested that the imide and amide groups of DMH have very similar reactivities toward the isocyanate groups on PU surfaces activated with HDI. After bleach treatment the covalently bound DMH moieties were transformed into N-halamines. The new N-halamine-based PU provided potent antimicrobial effects against Staphylococcus aureus (Gram-positive bacterium), Escherichia coli (Gram-negative bacterium), methicillin-resistant Staphylococcus aureus (MRSA, drug-resistant Gram-positive bacterium), vancomycin-resistant Enterococcus faecium (VRE, drug-resistant Gram-positive bacterium), and Candida albicans (fungus), and successfully prevented bacterial and fungal biofilm formation. The antimicrobial and biofilm controlling effects were stable for longer than 6 months under normal storage in open air. Furthermore, if the functions were lost due to prolonged use they could be recharged by another chlorination treatment. The recharging could be repeated as needed to achieve long-term protection against microbial contamination and biofilm formation. PMID- 22244986 TI - Comparison of four current 25-hydroxyvitamin D assays. AB - OBJECTIVES: The performance of recently developed vitamin D total assays (ADVIA Centaur and Elecsys) was compared to that of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LIASON 25-OH Vitamin D total assays. DESIGN AND METHODS: A total of 157 clinical samples and standard reference material (SRM) 972 were analyzed. RESULTS: The correlations of LC-MS/MS with the three immunoassays were acceptable. However, compared to LC-MS/MS, LIAISON and ADVIA Centaur showed negative bias, and Elecsys showed positive bias. There was a lack of agreement among the four methods with only LC-MS/MS results close to the certified values of SRM 972. The prevalence of vitamin D insufficiency (<50 nmol/L) was higher with ADVIA Centaur (51.6%) and LIAISON (52.2%) and lower with Elecsys (37.6%), compared with that of LC-MS/MS (44.6%). CONCLUSION: The new, automated total vitamin D assays show acceptable correlation with LC-MS/MS, and could be used in routine laboratories. However, standardization of vitamin D assays and consideration of assay-specific decision limits should be addressed. PMID- 22244987 TI - Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats. AB - Although hepatic expression of cytochrome P450 (CYP) changes markedly in diabetes, the role of ketone bodies in the regulation of CYP in diabetes is controversial. The present study was performed to determine the expression and activity of CYP in non-obese type II diabetic Goto-Kakizaki (GK) rats with normal levels of ketone bodies. In the present study, basal serum glucose levels increased 1.95-fold in GK rats, but acetoacetate and beta-hydroxybutyrate levels were not significantly different. Hepatic expression of CYP reductase and CYP3A2 was up-regulated in the GK rats, and consequently, activities of CYP reductase and midazolam 4-hydroxylase, mainly catalyzed by CYP3A2, increased. In contrast, hepatic expression of CYP1A2 and CYP3A1 was down-regulated and the activities of 7-ethoxyresorufin-O-deethylase and 7-methoxyresorufin-O-demethylase, mainly catalyzed by CYP1A, also decreased in GK rats. Hepatic levels of microsomal protein and total CYP and hepatic expression of cytochrome b(5), CYP1B1, CYP2B1 and CYP2C11 were not significantly different between the GK rats and normal Wistar rats. Moreover, the expression and activity of CYP2E1, reported to be up regulated in diabetes with hyperketonemia, were not significantly different between GK rats and control rats, suggesting that elevation of ketone bodies plays a critical role in the up-regulation of hepatic CYP2E1 in diabetic rats. Our results showed that the expression of hepatic CYP is regulated in an isoform specific manner. The present results also show that the GK rat is a useful animal model for the pathophysiological study of non-obese type II diabetes with normal ketone body levels. PMID- 22244988 TI - Enhanced recognition and recall of new words in 7- and 12-year-olds following a period of offline consolidation. AB - Recent studies of adults have found evidence for consolidation effects in the acquisition of novel words, but little is known about whether such effects are found developmentally. In two experiments, we familiarized children with novel nonwords (e.g., biscal) and tested their recognition and recall of these items. In Experiment 1, 7-year-olds were then retested on either the same day or the following day to examine changes in performance after a short delay compared with a longer delay that included sleep. Experiment 2 used two age groups (7- and 12 year-olds), with all participants being retested 24h later. The 12-year-olds accurately recognized the novel nonwords immediately after exposure, as did the 7 year-olds in Experiment 2 (but not in Experiment 1), suggesting generally good initial rates of learning. Experiment 1 revealed improved recognition of the novel nonwords after both short (3- to 4-h) and longer (24-h) delays. In contrast, recall was initially poor but showed improvements only when children were retested 24h later, not after a 3- to 4-h delay. Similar improvements were observed in both age groups despite better overall performance in 12-year-olds. We argue that children, like adults, exhibit offline consolidation effects on the formation of novel phonological representations. PMID- 22244989 TI - Population genetic data for 16 STR loci (PowerPlex ESX-17 kit) in El Salvador. PMID- 22244990 TI - Complex interaction of circadian and non-circadian effects of light on mood: shedding new light on an old story. AB - In addition to its role in vision, light exerts strong effects on behavior. Its powerful role in the modulation of mood is well established, yet remains poorly understood. Much research has focused on the effects of light on circadian rhythms and subsequent interaction with alertness and depression. The recent discovery of a third photoreceptor, melanopsin, expressed in a subset of retinal ganglion cells, allows major improvement of our understanding of how photic information is processed. Light affects behavior in two ways, either indirectly through the circadian timing system, or directly through mechanisms that are independent of the circadian system. These latter effects have barely been studied in regard to mood, but recent investigations on the direct effects of light on sleep and alertness suggest additional pathways through which light could influence mood. Based on our recent findings, we suggest that light, via melanopsin, may exert its antidepressant effect through a modulation of the homeostatic process of sleep. Further research is needed to understand how these mechanisms interplay and how they contribute to the photic regulation of mood. Such research could improve therapeutic management of affective disorders and influence the management of societal lighting conditions. PMID- 22244991 TI - [Costs and cost effectiveness analysis of preferred GESIDA regimens for initial antiretroviral therapy]. PMID- 22244992 TI - First cases of Neisseria gonorrhoeae resistant to ceftriaxone in Catalonia, Spain, May 2011. PMID- 22244993 TI - [Bilateral micronodular lung infiltrates in a patient with advanced AIDS]. PMID- 22244994 TI - An integrated performance assessment framework for water treatment plants. AB - An innovative framework for the performance assessment of a traditional water treatment plant (WTP) is presented that integrates the concepts of reliability, robustness, and Quantitative Microbial Risk Assessment (QMRA). Performance assessment for a WTP comprised of three units (i.e., unit 1: Coagulation/Flocculation and Sedimentation; unit 2: Filtration, and unit 3: Disinfection) was conducted. Performance functions for units 1, 2, and units 1 and 2 combined, were constructed by integrating turbidity robustness indices. Performance function for chlorine disinfection was developed based on the difference between achieved and required CT values. A health-based performance function was developed by comparing the target daily infection rate to the site specific infection rate. It was used to identify whether the health-based target was met during the failures of units 1 to 3. Results obtained from the proposed performance functions can be used by operators to ensure that multiple barriers perform successfully under variable conditions. PMID- 22244995 TI - Evaluation of a quantitative H2S MPN test for fecal microbes analysis of water using biochemical and molecular identification. AB - The sensitivity and specificity of the H(2)S test to detect fecal bacteria in water has been variable and uncertain in previous studies, partly due to its presence-absence results. Furthermore, in groundwater samples false-positive results have been reported, with H(2)S-positive samples containing no fecal coliforms or Escherichia coli. False-negative results also have been reported in other studies, with H(2)S-negative samples found to contain E. coli. Using biochemical and molecular methods and a novel quantitative test format, this research identified the types and numbers of microbial community members present in natural water samples, including fecal indicators and pathogens as well as other bacteria. Representative water sources tested in this study included cistern rainwater, a protected lake, and wells in agricultural and forest settings. Samples from quantitative H(2)S tests of water were further cultured for fecal bacteria by spread plating onto the selective media for detection and isolation of Aeromonas spp., E. coli, Clostridium spp., H(2)S-producers, and species of Salmonella and Shigella. Isolates were then tested for H(2)S production, and identified to the genus and species level using biochemical methods. Terminal Restriction Fragment Length Polymorphisms (TRFLP) was the molecular method employed to quantitatively characterize microbial community diversity. Overall, it was shown that water samples testing positive for H(2)S bacteria also had bacteria of likely fecal origin and waters containing fecal pathogens also were positive for H(2)S bacteria. Of the microorganisms isolated from natural water, greater than 70 percent were identified using TRFLP analysis to reveal a relatively stable group of organisms whose community composition differed with water source and over time. These results further document the validity of the H(2)S test for detecting and quantifying fecal contamination of water. PMID- 22244996 TI - Do compensation processes impair mental health? A meta-analysis. AB - BACKGROUND: Victims who are involved in a compensation processes generally have more health complaints compared to victims who are not involved in a compensation process. Previous research regarding the effect of compensation processes has concentrated on the effect on physical health. This meta-analysis focuses on the effect of compensation processes on mental health. METHOD: Prospective cohort studies addressing compensation and mental health after traffic accidents, occupational accidents or medical errors were identified using PubMed, EMBASE, PsycInfo, CINAHL, and the Cochrane Library. Relevant studies published between January 1966 and 10 June 2011 were selected for inclusion. RESULTS: Ten studies were included. The first finding was that the compensation group already had higher mental health complaints at baseline compared to the non-compensation group (standardised mean difference (SMD)=-0.38; 95% confidence interval (CI) 0.66 to -0.10; p=.01). The second finding was that mental health between baseline and post measurement improved less in the compensation group compared to the non compensation group (SMD=-0.35; 95% CI -0.70 to -0.01; p=.05). However, the quality of evidence was limited, mainly because of low quality study design and heterogeneity. DISCUSSION: Being involved in a compensation process is associated with higher mental health complaints but three-quarters of the difference appeared to be already present at baseline. The findings of this study should be interpreted with caution because of the limited quality of evidence. The difference at baseline may be explained by a selection bias or more anger and blame about the accident in the compensation group. The difference between baseline and follow-up may be explained by secondary gain and secondary victimisation. Future research should involve assessment of exposure to compensation processes, should analyse and correct for baseline differences, and could examine the effect of time, compensation scheme design, and claim settlement on (mental) health. PMID- 22244997 TI - The shock index: a further simple tool of triage in combat casualties. PMID- 22244998 TI - Marine viruses exploit their host's two-component regulatory system in response to resource limitation. AB - Phosphorus (P) availability, which often limits productivity in marine ecosystems, shapes the P-acquisition gene content of the marine cyanobacteria Prochlorococcus [1-4] and its viruses (cyanophages). As in other bacteria, in Prochlorococcus these genes are regulated by the PhoR/PhoB two-component regulatory system that is used to sense and respond to P availability and is typical of signal transduction systems found in diverse organisms. Replication of cyanophage genomes requires a significant amount of P, and therefore these phages could gain a fitness advantage by influencing host P acquisition in P-limited environments. Here we show that the transcription of a phage-encoded high affinity phosphate-binding protein gene (pstS) and alkaline phosphatase gene (phoA)-both of which have host orthologs-is elevated when the phages are infecting host cells that are P starved, relative to P-replete control cells. We further show that the phage versions of these genes are regulated by the host's PhoR/PhoB system. This not only extends this fundamental signaling mechanism to viruses but is also the first example of regulation of lytic phage genes by nutrient limitation in the host. As such, it reveals an important new dimension of the intimate coevolution of phage, host, and environment in the world's oceans. PMID- 22244999 TI - The HSF-like transcription factor TBF1 is a major molecular switch for plant growth-to-defense transition. AB - BACKGROUND: Induction of plant immune responses involves significant transcription reprogramming that prioritizes defense over growth-related cellular functions. Despite intensive forward genetic screens and genome-wide expression profiling studies, a limited number of transcription factors have been found that regulate this transition. RESULTS: Using the endoplasmic-reticulum-resident genes required for antimicrobial protein secretion as markers, we identified a heat shock factor-like transcription factor that specifically binds to the TL1 (GAAGAAGAA) cis element required for the induction of these genes. Surprisingly, plants lacking this TL1-binding factor, TBF1, respond normally to heat stress but are compromised in immune responses induced by salicylic acid and by microbe associated molecular pattern, elf18. Genome-wide expression profiling indicates that TBF1 plays a key role in the growth-to-defense transition. Moreover, the expression of TBF1 itself is tightly regulated at both the transcriptional and translational levels. Two upstream open reading frames encoding multiple aromatic amino acids were found 5' of the translation initiation codon of TBF1 and shown to affect its translation. CONCLUSIONS: Through this unique regulatory mechanism, TBF1 can sense the metabolic changes upon pathogen invasion and trigger the specific transcriptional reprogramming through its target genes expression. PMID- 22245000 TI - CDK-dependent potentiation of MPS1 kinase activity is essential to the mitotic checkpoint. AB - Accurate chromosome segregation relies upon a mitotic checkpoint that monitors kinetochore attachment toward opposite spindle poles before enabling chromosome disjunction [1]. The MPS1/TTK protein kinase is a core component of the mitotic checkpoint that lies upstream of MAD2 and BubR1 both at the kinetochore and in the cytoplasm [2, 3]. To gain insight into the mechanisms underlying the regulation of MPS1 kinase, we undertook the identification of Xenopus MPS1 phosphorylation sites by mass spectrometry. We mapped several phosphorylation sites onto MPS1 and we show that phosphorylation of S283 in the noncatalytic region of MPS1 is required for full kinase activity. This phosphorylation potentiates MPS1 catalytic efficiency without impairing its affinity for the substrates. By using Xenopus egg extracts depleted of endogenous MPS1 and reconstituted with single point mutants, we show that phosphorylation of S283 is essential to activate the mitotic checkpoint. This phosphorylation does not regulate the localization of MPS1 to the kinetochore but is required for the recruitment of MAD1/MAD2, demonstrating its role at the kinetochore. Constitutive phosphorylation of S283 lowers the number of kinetochores required to hold the checkpoint, which suggests that CDK-dependent phosphorylation of MPS1 is essential to sustain the mitotic checkpoint when few kinetochores remain unattached. PMID- 22245001 TI - Maternal control of nutrient allocation in plant seeds by genomic imprinting. AB - Imprinted genes are commonly expressed in mammalian placentas and in plant seed endosperms, where they exhibit preferential uniparental allelic expression. In mammals, imprinted genes directly regulate placental function and nutrient distribution from mother to fetus; however, none of the >60 imprinted genes thus far reported in plants have been demonstrated to play an equivalent role in regulating the flow of resources to the embryo. Here we show that imprinted Maternally expressed gene1 (Meg1) in maize is both necessary and sufficient for the establishment and differentiation of the endosperm nutrient transfer cells located at the mother:seed interface. Consistent with these findings, Meg1 also regulates maternal nutrient uptake, sucrose partitioning, and seed biomass yield. In addition, we generated an imprinted and nonimprinted synthetic Meg1 ((syn)Meg1) dosage series whereby increased dosage and absence of imprinting both resulted in an unequal investment of maternal resources into the endosperm. These findings highlight dosage regulation by genomic imprinting as being critical for maintaining a balanced distribution of maternal nutrients to filial tissues in plants, as in mammals. However, unlike in mammals, Meg1 is a maternally expressed imprinted gene that surprisingly acts to promote rather than restrict nutrient allocation to the offspring. PMID- 22245002 TI - Lead transformation to pyromorphite by fungi. AB - Lead (Pb) is a serious environmental pollutant in all its chemical forms [1]. Attempts have been made to immobilize lead in soil as the mineral pyromorphite using phosphate amendments (e.g., rock phosphate, phosphoric acid, and apatite [2 5]), although our work has demonstrated that soil fungi are able to transform pyromorphite into lead oxalate [6, 7]. Lead metal, an important structural and industrial material, is subject to weathering, and soil contamination also occurs through hunting and shooting [8, 9]. Although fungi are increasingly appreciated as geologic agents [10-12], there is a distinct lack of knowledge about their involvement in lead geochemistry. We examined the influence of fungal activity on lead metal and discovered that metallic lead can be transformed into chloropyromorphite, the most stable lead mineral that exists. This is of geochemical significance, not only regarding lead fate and cycling in the environment but also in relation to the phosphate cycle and linked with microbial transformations of inorganic and organic phosphorus. This paper provides the first report of mycogenic chloropyromorphite formation from metallic lead and highlights the significance of this phenomenon as a biotic component of lead biogeochemistry, with additional consequences for microbial survival in lead contaminated environments and bioremedial treatments for Pb-contaminated land. PMID- 22245003 TI - CRAC channels drive digital activation and provide analog control and synergy to Ca(2+)-dependent gene regulation. AB - Ca(2+)-dependent gene expression is critical for cell growth, proliferation, plasticity, and adaptation [1-3]. Because a common mechanism in vertebrates linking cytoplasmic Ca(2+) signals with activation of protein synthesis involves the nuclear factor of activated T cells (NFAT) family of transcription factors [4, 5], we have quantified protein expression in single cells following physiological Ca(2+) signals by using NFAT-driven expression of a genetically encoded fluorescent protein. We find that gene expression following CRAC channel activation is an all-or-nothing event over a range of stimulus intensities. Increasing agonist concentration recruits more cells but each responding cell does so in an essentially digital manner. Furthermore, Ca(2+)-dependent gene expression shows both short-term memory and strong synergy, where two pulses of agonist, which are ineffectual individually, robustly activate gene expression provided that the time interval between them is short. Such temporal filtering imparts coincidence detection to Ca(2+)-dependent gene activation. The underlying molecular basis mapped to time-dependent, nonlinear accumulation of nuclear NFAT. Local Ca(2+) near CRAC channels has to rise above a threshold level to drive gene expression, providing analog control to the digital activation process and a means to filter out fluctuations in background noise from activating transcription while ensuring robustness and high fidelity in the excitation transcription coupling mechanism. PMID- 22245004 TI - Effects of the bHLH domain on axial coordination of heme in the PAS-A domain of neuronal PAS domain protein 2 (NPAS2): conversion from His119/Cys170 coordination to His119/His171 coordination. AB - Neuronal PAS domain protein 2 (NPAS2), which is a CO-dependent transcription factor, consists of a basic helix-loop-helix domain (bHLH), and two heme containing PAS domains (PAS-A and PAS-B). In our previous study on the isolated PAS-A domain, we concluded that His119 and Cys170 are the axial ligands of the ferric heme, while Cys170 is replaced by His171 upon reduction of heme (Uchida et al., J. Biol. Chem. 270, (2005) 21358-21368.). Recently, we characterized the PAS A domain combined with the N-terminal bHLH domain, and found that some spectroscopic features were different from those of the isolated PAS-A domain (Mukaiyama et al., FEBS J. 273, (2006) 2528-2539.). Therefore, we reinvestigated the coordination structure of heme in the bHLH-PAS-A domain and prepared four histidine and one cysteine mutants. Resonance Raman spectrum of the Cys170Ala mutant is the same as that of wild type with a dominant 6-coordinate heme in the ferric form. In contrast, His119Ala and His171Ala mutants significantly increase amounts of the 5-coordinate species, indicating that His119 and His171, not Cys170, are axial ligands of the ferric heme in the bHLH-PAS-A domain. We had confirmed that the coordination structure of the isolated PAS-A domain is in equilibrium between Cys-Fe-His and His-Fe-His coordinated species but newly found that interaction of the PAS-A domain with the bHLH domain shifts the equilibrium toward the latter structure. Such flexibility in the heme coordination structure seems to be in favor of signal transduction in NPAS2. PMID- 22245005 TI - Comprehension of concrete and abstract words in patients with selective anterior temporal lobe resection and in patients with selective amygdalo-hippocampectomy. AB - The role of the anterior temporal lobe (ATL) in semantic memory is now firmly established. There is still controversy, however, regarding the specific role of this region in processing various types of concepts. There have been reports of patients suffering from semantic dementia (SD), a neurodegenerative condition in which the ATL is damaged bilaterally, who present with greater semantic impairment for concrete concepts than for abstract concepts, an effect known as reversal of the concreteness effect. This effect has previously been interpreted as reflecting degraded visual-perceptual features of objects due to damage to the inferior temporal lobes such as is observed in SD. Temporal lobe atrophy in SD, however, is bilateral even if it usually predominates to the left ATL, and it has been found to extend beyond the ATL, throughout the temporal lobes including medial and posterior temporal lobe regions. The question therefore remains whether greater impairment for concrete concepts results from damage to the ATL or from damage to the visual association cortex, and if unilateral damage can produce such a deficit. The aim of the present study was to investigate the processing of concrete and abstract words in rare patients who underwent a selective ATL surgical resection, and to compare their performance with that of patients with selective medial temporal lobe damage sparing the ATL region. Seven patients with a selective unilateral anterior temporal resection (ATL), 15 patients with a selective unilateral amygdalo-hippocampectomy (SeAH), and 15 healthy age- and education-matched controls underwent detailed neuropsychological assessment and carried out a semantic similarity judgment task evaluating their comprehension of concrete and abstract words. Results showed that both ATL and SeAH groups were significantly impaired on the semantic task relative to the control group. Within the patient groups, however, comprehension of concrete words was significantly more impaired than that of abstract words in the ATL group, while comprehension of abstract and concrete words was equally affected in the SeAH group. Results of this study suggest that the ATL region may play a critical role in processing concrete concepts, and that the reversal of the concreteness effect observed in ATL patients may result from damage to a categorical organization underlying the representation of concrete concepts. PMID- 22245006 TI - A review on sex differences in processing emotional signals. AB - Interest in sex-related differences in psychological functioning has again come to the foreground with new findings about their possible functional basis in the brain. Sex differences may be one way how evolution has capitalized on the capacity of homologous brain regions to process social information between men and women differently. This paper focuses specifically on the effects of emotional valence, sex of the observed and sex of the observer on regional brain activations. We also discuss the effects of and interactions between environment, hormones, genes and structural differences of the brain in the context of differential brain activity patterns between men and women following exposure to seen expressions of emotion and in this context we outline a number of methodological considerations for future research. Importantly, results show that although women are better at recognizing emotions and express themselves more easily, men show greater responses to threatening cues (dominant, violent or aggressive) and this may reflect different behavioral response tendencies between men and women as well as evolutionary effects. We conclude that sex differences must not be ignored in affective research and more specifically in affective neuroscience. PMID- 22245007 TI - Language lateralisation in late proficient bilinguals: a lexical decision fMRI study. AB - Approximately half the world's population can now speak more than one language. Understanding the neural basis of language organisation in bilinguals, and whether the cortical networks involved during language processing differ from that of monolinguals, is therefore an important area of research. A main issue concerns whether L2 (second language) is processed using the same neural mechanisms that mediate L1 (first language) processing. Moderating factors include the age of L2 acquisition and the level of proficiency. Here we used a lexical decision task with five conditions during functional magnetic resonance imaging (fMRI) to investigate language processing in eight late proficient bilinguals when using Macedonian (L1) and English (L2). Bilinguals had greater bilateral activation during both L1 and L2 processing, and therefore weaker language lateralisation, compared to matched control English monolinguals. A greater amount of overall activation was also seen in bilinguals, especially during L2 conditions. Late proficient bilinguals living in their L2 environment employ a more extensive neural network than monolinguals when processing their second language. PMID- 22245008 TI - N300 indexes deficient integration of orthographic and phonological representations in children with dyslexia. AB - In transparent orthographies, like German, children with developmental dyslexia (DD) are mainly characterized by a reading fluency deficit. The reading fluency deficit might be traced back to a scarce integration of orthographic and phonological representations. In order to address this question, the present study used EEG to investigate the N300, an ERP component which has been associated with the integration of orthographic and phonological representations. Twenty children without DD and 18 children with DD performed a phonological (P) orthographic (O) matching task (P-O condition), which tapped the integration of orthographic and phonological representations. A control task was applied which did not require the integration of orthographic and phonological representations and consisted only of orthographic information (O-O condition). The O-O condition revealed a similar N300 distribution between groups with a bilateral activity over fronto-temporal electrodes. However, in the P-O condition N300 differentiated the 2 groups of children. The control group revealed greater activity over left fronto-temporal electrodes, whereas the N300 was distributed bilaterally in the group of children with DD suggesting deficient integration of orthographic and phonological representations. These findings might be related to the reading fluency deficit as it was also observed that better reading fluency was correlated with higher (r=-.36) and earlier peaking (r=-.33) N300 amplitudes in the left hemisphere and attenuated N300 amplitudes (r=.45) in the right hemisphere. Standardized low-resolution electromagnetic tomography analysis (sLORETA) revealed that children with DD rely more on right temporo-parietal brain areas compared to children without DD. Furthermore, in order to rule out that earlier deficient processes might influence the group differences found in the N300, we analyzed the N170 for group differences. We did not find significant differences between children without DD and children with DD. In conclusion the results suggest deficient integration of orthographic and phonological representations in dyslexia, as indexed by the N300, and further highlight how this activity is relevant for fluent reading. PMID- 22245010 TI - Superior haptic-to-visual shape matching in autism spectrum disorders. AB - A weak central coherence theory in autism spectrum disorder (ASD) proposes that a cognitive bias toward local processing in ASD derives from a weakness in integrating local elements into a coherent whole. Using this theory, we hypothesized that shape perception through active touch, which requires sequential integration of sensorimotor traces of exploratory finger movements into a shape representation, would be impaired in ASD. Contrary to our expectation, adults with ASD showed superior performance in a haptic-to-visual delayed shape-matching task compared to adults without ASD. Accuracy in discriminating haptic lengths or haptic orientations, which lies within the somatosensory modality, did not differ between adults with ASD and adults without ASD. Moreover, this superior ability in inter-modal haptic-to-visual shape matching was not explained by the score in a unimodal visuospatial rotation task. These results suggest that individuals with ASD are not impaired in integrating sensorimotor traces into a global visual shape and that their multimodal shape representations and haptic-to-visual information transfer are more accurate than those of individuals without ASD. PMID- 22245009 TI - Age-related differences in memory and executive functions in healthy APOE E4 carriers: the contribution of individual differences in prefrontal volumes and systolic blood pressure. AB - Advanced age and vascular risk are associated with declines in the volumes of multiple brain regions, especially the prefrontal cortex, and the hippocampus. Older adults, even unencumbered by declining health, perform less well than their younger counterparts in multiple cognitive domains, such as episodic memory, executive functions, and speed of perceptual processing. Presence of a known genetic risk factor for cognitive decline and vascular disease, the E4 allele of the apolipoprotein E (APOE) gene, accounts for some share of those declines; however, the extent of the joint contribution of genetic and physiological vascular risk factors on the aging brain and cognition is unclear. In a sample of healthy adults (age 19-77), we examined the effects of a vascular risk indicator (systolic blood pressure, SBP) and volumes of hippocampus (HC), lateral prefrontal cortex (lPFC), and prefrontal white matter (pFWM) on processing speed, working memory (WM), and recognition memory. Using path analyses, we modeled indirect effects of age, SBP, and brain volumes on processing speed, WM, and memory and compared the patterns of structural relations among those variables in APOE E4 carriers and E3 homozygotes. Among E4 carriers, age differences in WM were explained by increase in SBP, reduced FWM volume, and slower processing. In contrast, lPFC and FWM volumes, but not BP, explained a share of age differences in WM among E3 homozygotes. Thus, even in healthy older carriers of the APOE E4 allele, clinically unremarkable increase in vascular risk may be associated with reduced frontal volumes and impaired cognitive functions. PMID- 22245011 TI - Neural activity in readiness for incidental and explicitly timed actions. AB - Voluntary, self-initiated actions are preceded by slowly increasing neural activity in pre-motor regions of the brain, beginning up to 2s before the onset of muscle movement. This activity is commonly seen in the scalp-recorded readiness potential, and is an index of movement preparation involving both motor programming and non-motor or cognitive processes such as attention. The specific contribution of cognitive processes, thought to occur during the earliest stage of planning, remains somewhat unclear. We suggest that attention to the timing of movement is a key voluntary process contributing to early-stage cortical activity. As a novel approach to examining this, we recorded EEG throughout a time reproduction task in which participants replicated the interval between two tones with two button-press actions. The first action, i.e. the beginning of the reproduced interval, was somewhat incidental to the task of time reproduction and required minimal attention to the time of initiation, while the second action required explicit attention to the time of initiation. Pre-movement neural activity preceding the first, relatively unattended movement was greatly reduced in amplitude and almost absent in the early stage, in contrast with readiness potentials typically seen prior to voluntary movement. Neural activity preceding explicitly timed movements was significantly larger, with effects emerging in the early component of pre-movement activity over frontal and right frontal scalp regions. We propose that attention to movement timing, i.e. the process of orienting attention in time towards the moment of movement initiation, is a key component of voluntary action preparation that is reflected in the early-stage neural activity we typically see prior to voluntary movement. PMID- 22245012 TI - Electrophysiological and behavioral measures of phonological processing of auditory nonsense V-CV-VCV stimuli. AB - An event-related potential, the Phonological Mapping Negativity (PMN), has been reported to reflect recognition of phonological mismatches in speech stimuli. The purpose of the present study was to explore how the PMN response to the auditory nonsense syllable reflects phonological processing in isolation without the letter prime or lexical/semantic context. Sixty-four nonsense syllable stimuli were composed for each of three stimulus conditions: phonological match (PM), phonological mismatch with similar sound (PMMS), and phonological mismatch with different sound (PMMD), making a total of 192 stimuli. The PMN was measured from fourteen normal-hearing listeners. Electroencephalogram (EEG) activity was recorded while subjects were listening to the stimuli and responding behaviorally. Subjects were asked to determine what vowel-consonant-vowel (VCV) (e.g. /apa/) would be formed from the combination of the preceding vowel (V) (e.g. /a/) and consonant-vowel (CV) (e.g. /pa/), and press a 'correct' or 'incorrect' response button as soon as they decided whether the target VCV stimulus matched their expectation. In this way, along with the PMN, behavioral response accuracy and reaction times were obtained. The results were as follows: (1) PMN amplitude was not different by stimulus condition, (2) PMN amplitude was larger over frontal and central than posterior regions, but not different between the left versus right hemisphere, (3) PMN was detected in the absence of N400, and (4) behavioral responses were more accurate and faster in PMMD than PM and PMMS. Results indicate that the PMN can reflect phonological processing of auditory nonsense syllables in isolation. The scalp distribution of PMN is most dominant in the fronto-central regions without lateralization. Lastly, behavioral response accuracy and reaction times appear to be influenced by the extent of the task difficulty or processing demand rather than by the extent of phonological violation. PMID- 22245013 TI - Selective alignment of brain responses by task demands during semantic processing. AB - The way the brain binds together words to form sentences may depend on whether and how the arising cognitive representation is to be used in behavior. The amplitude of the N400 effect in event-related brain potentials is inversely correlated with the degree of fit of a word's meaning into a semantic representation of the preceding discourse. This study reports a double dissociation in the latency characteristics of the N400 effect depending on task demands. When participants silently read words in a sentence context, without issuing a relevant overt response, greater temporal alignment over recording sites occurs for N400 onsets than peaks. If however a behavior is produced - here pressing a button in a binary probe selection task - exactly the opposite pattern is observed, with stronger alignment of N400 peaks than onsets. The peak amplitude of the N400 effect correlates best with the latency characteristic showing less temporal dispersion. These findings suggest that meaning construction in the brain is subtly affected by task demands, and that there is complex functional integration between semantic combinatorics and control systems handling behavioral goals. PMID- 22245015 TI - Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. AB - We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-alpha, interferon-gamma, and interleukin (IL)-6 knockout (-/-) mice showed that the IL-6(-/-) mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6(-/-) mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus. These effects were more pronounced in the IL-6(-/-) mice than in wild-type controls. In addition, the ability of TMT to induce nuclear translocation of Nrf2 and upregulation of heme oxygenase-1 and gamma-glutamylcysteine ligase was significantly decreased in IL 6(-/-) mice. Treatment of IL-6(-/-) mice with recombinant IL-6 protein (rIL-6) restored these effects of TMT. Treatment with rIL-6 also significantly attenuated the TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling, thereby increasing phosphorylation of Bad (Bcl-xL/Bcl-2-associated death promoter protein), expression of Bcl-xL and Bcl-2, and the interaction between p-Bad and 14-3-3 protein and decreasing Bax expression and caspase-3 cleavage. Furthermore, in IL-6(-/-) mice, rIL-6 provided significant protection against TMT-induced neuronal degeneration; this effect of rIL-6 was counteracted by the PI3K inhibitor LY294002. These results suggest that activation of Nrf2-dependent glutathione homeostasis and PI3K/Akt signaling is required for the neuroprotective effects of IL-6 against TMT. PMID- 22245014 TI - fMRI evidence for strategic decision-making during resolution of pronoun reference. AB - Pronouns are extraordinarily common in daily language yet little is known about the neural mechanisms that support decisions about pronoun reference. We propose a large-scale neural network for resolving pronoun reference that consists of two components. First, a core language network in peri-Sylvian cortex supports syntactic and semantic resources for interpreting pronoun meaning in sentences. Second, a frontal-parietal network that supports strategic decision-making is recruited to support probabilistic and risk-related components of resolving a pronoun's referent. In an fMRI study of healthy young adults, we observed activation of left inferior frontal and superior temporal cortex, consistent with a language network. We also observed activation of brain regions not associated with traditional language areas. By manipulating the context of the pronoun, we were able to demonstrate recruitment of dorsolateral prefrontal cortex during probabilistic evaluation of a pronoun's reference, and orbital frontal activation when a pronoun must adopt a risky referent. Together, these findings are consistent with a two-component model for resolving a pronoun's reference that includes neuroanatomic regions supporting core linguistic and decision-making mechanisms. PMID- 22245017 TI - [Kidney and HIV infection]. AB - Screening of chronic kidney disease (CKD) that includes estimation of the glomerular filtration rate (GFR) and evaluation proteinuria should be performed in all HIV-infected patients and these parameters have to be monitored annually in patients at higher risk for CKD. Black patients have a genetic predisposition to develop HIV-associated nephropathy. Suppression of HIV viral replication with antiretroviral therapy prevents the development of HIV-associated nephropathy or halts its progression. Kidney biopsy remains the most informative diagnosis test to differentiate various forms of kidney diseases in HIV-infected patients. Dosing antiretroviral agents with kidney metabolism should be adjusted when eGFR is bellow 50 mL/min/1.73 m(2). eGFR and serum phosphorus at baseline and during treatment should be carefully assessed in patients receiving tenofovir. Proximal renal tubular toxicity must be further evaluated in the presence of eGFR decrease and/or hypophosphatemia under tenofovir therapy. PMID- 22245018 TI - Synthesis and antimicrobial activity of 2,3-bis(bromomethyl)quinoxaline derivatives. AB - We synthesized 12 derivatives of 2,3-bis(bromomethyl)quinoxaline with substituents at the 6- and/or 7-positions, and evaluated their activities against bacteria and fungi. Of the 12 compounds, nine (1a-h, 1j, and 1k) showed antibacterial activity. The derivative 1g, which bears a trifluoromethyl group at the 6-position, showed the highest activity against Gram-positive bacteria, while 1c, which has a fluoro-group at the 6-position, showed the widest antifungal activity spectrum. However, only the derivative with an ethyl ester substitution, 1k showed activity against Gram-negative bacteria. PMID- 22245019 TI - Substrate specificity in thiamin diphosphate-dependent decarboxylases. AB - Thiamin diphosphate (ThDP) is the biologically active form of vitamin B(1), and ThDP-dependent enzymes are found in all forms of life. The catalytic mechanism of this family requires the formation of a common intermediate, the 2alpha-carbanion enamine, regardless of whether the enzyme is involved in C-C bond formation or breakdown, or even formation of C-N, C-O and C-S bonds. This demands that the enzymes must screen substrates prior to, and/or after, formation of the common intermediate. This review is focused on the group for which the second step is the protonation of the 2alpha-carbanion, i.e., the ThDP-dependent decarboxylases. Based on kinetic data, sequence/structure alignments and mutagenesis studies the factors involved in substrate specificity have been identified. PMID- 22245020 TI - Molecular and immune toxicity of CoCr nanoparticles in MoM hip arthroplasty. AB - Theoretical, desirable features of second-generation metal-on-metal (MoM) hip prostheses have led to their widespread use. However, the bearing surfaces, consisting of complex cobalt-chromium alloys, are subject to wear and the release of cobalt and chromium (CoCr) nanoparticles. These nanoparticles can reduce cellular viability, induce DNA damage, lead to chromosomal aberrations, and possibly stimulate increased metal hypersensitivity. Clinically, the effects can be both local (soft-tissue reactions) and systemic (arthroprosthetic cobaltism). This review assesses the literature concerning the in vitro and in vivo cytotoxic, genotoxic, and immunotoxic effects of CoCr wear particles, which is increasingly important in view of the large number of MoM arthroplasties performed. PMID- 22245016 TI - Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for "double trouble" overlapping syndromes. AB - We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient's muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient. PMID- 22245021 TI - Long-term results of pediatric cataract surgery after delayed diagnosis. AB - PURPOSE: To report the long-term rates of visual impairment in children who underwent cataract surgery after late diagnosis. METHODS: The records of children who underwent cataract surgery in northern China between January 1994 and December 2009 were retrospectively reviewed. Age at surgery, surgical approach, postoperative best-corrected visual acuity, and compliance with amblyopia treatment were evaluated. Visual impairment was defined as best-corrected visual acuity <20/60. RESULTS: Of 486 children included in this study, 2 (0.4%) had surgery by age 3 months and 68 (14%) by age 6 months. Of the 536 eyes of 331 patients with visual acuity recorded at final follow-up, 151 eyes (37%) had bilateral cataract and 82 (65%) had unilateral cataract, with a total of 233 (45%) considered visually impaired. In children who had surgery before 36 months of age for bilateral cataracts, there was no significant difference in rates of visual impairment with versus without primary IOL implantation. In patients with unilateral cataract, visual impairment occurred regardless of age at surgery or whether IOL was primarily implanted. Postoperatively, compliance with amblyopia treatment was good in 30% of patients, fair in 45%, and poor in 31%. CONCLUSIONS: The long-term visual acuity was unfavorable in approximately half of children diagnosed and treated for pediatric cataracts after 3 months of age. Contributing factors included age at presentation and absence of effective training for postoperative vision rehabilitation. PMID- 22245022 TI - Hypertensive retinopathy in a child caused by pheochromocytoma: identification after a failed school vision screening. AB - A 7-year-old girl was referred for ophthalmological examination after the result of a routine school vision screening identified unilateral vision loss. Fundus examination showed bilateral but markedly asymmetric macular exudates and optic disk edema. After the results of two blood pressure measurements were within normal limits, a third markedly elevated measurement revealed malignant hypertension and led to a diagnosis of pheochromocytoma, a rare catecholamine secreting tumor. The tumor was resected, and 6 months later the patient's blood pressure had normalized; however, although visual acuity had improved to 20/20 in the right eye, it remained 20/200 in the left eye, with decreased disk edema but the persistence of the macular exudates. The identification of an abdominal malignancy through a school vision screening may have saved this child's life. The need for repeated blood pressure measurement is also highlighted. PMID- 22245023 TI - Fellowship training in retinopathy of prematurity. PMID- 22245024 TI - Quetiapine-induced frequent premature ventricular contraction. AB - A 17-year-old female diagnosed with bipolar II disorder was treated for emotional lability with quetiapine. Two-lead electrocardiography revealed frequent monomorphic premature ventricular contraction (PVC) during an electroencephalography examination. Twenty-four-hour Holter electrocardiography revealed 0.6% uniform frequent PVCs and indicated that the readministration and second-time withdrawal of quetiapine markedly increased (7.1%) and decreased the frequency of PVC (1.1%), respectively. This case indicates that quetiapine can cause PVC as a serious side effect. PMID- 22245025 TI - WITHDRAWN: Auditory hallucination and agitation due to memantine in a patient with Alzheimer's disease: a case report. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22245026 TI - Switching to aripiprazole in subjects with pervasive developmental disorders showing tolerability issues with risperidone. AB - BACKGROUND: Subjects with Pervasive Developmental Disorders (PDD) often exhibit behavioral symptoms such as aggressiveness and irritability, which are targets of psychopharmacologic intervention. This retrospective study was designed to examine children and adolescents with PDD experiencing tolerability issues with risperidone treatment, and thereby assess the efficacy and tolerability of switching to aripiprazole. METHODS: This naturalistic study included 23 subjects with PDD (16 males, 7 females, age range 9-24 years, mean age 15.1+/-3.9 years) diagnosed according to DSM-IV criteria and followed up for 14.9+/-8.4 weeks after switching to aripiprazole from risperidone. Outcome measures were the Clinical Global Impression-Severity (CGI-S) and CGI Improvement (CGI-I) scales. RESULTS: The mean CGI-S scores of pre-aripiprazole treatment and post-aripiprazole treatment were, respectively 4.7+/-1.4 and 4.6+/-1.3. Mean maintenance dosages of risperidone and aripiprazole were, respectively, 0.7+/-0.5mg/day and 2.8+/ 1.3mg/day. The mean CGI-I score, which shows the difference induced by switching from risperidone to aripiprazole, was 3.4+/-0.8 for the whole sample, suggesting that the efficacy of risperidone for treating behavioral problems of PDD was maintained by aripiprazole. Some improvement of safety/tolerability issues such as increased appetite, somnolence, hyperprolactinemia, and amenorrhea occurred after switching to aripiprazole. CONCLUSION: Results show that switching to aripiprazole might be generally well tolerated and might constitute an alternative treatment for subjects with PDD who experience tolerability issues with risperidone treatment. Additional long-term controlled studies of PDD subjects should be undertaken to evaluate the efficacy and safety of switching to aripiprazole from other antipsychotics. PMID- 22245027 TI - Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in rats. AB - TAK-285, an investigational, orally active HER2/EGRF inhibitor is in clinical development for potential use in HER2 over-expressing metastatic breast cancer. The objective of the present work was to verify the presence of unbound TAK-285 in the rat brain after oral administration by a microdialysis technique with simultaneous sampling of blood and brain. In a pilot microdialysis experiment no detectable amount of TAK-285 was found in the brain dialysate samples after oral administration of the drug (50 mg/kg). A conventional pharmacokinetic study was performed simultaneously with the pilot microdialysis study using the same dosing suspension. TAK-285 was detected in the brain even at the last time point when the samples were taken from the animal at the end-point of the microdialysis experiment. The apparent absence of TAK-285 in blood and brain dialysate samples might be explained by a very low recovery of microdialysis probes for TAK-285 and/or by the adsorption of the compound to the outflow tubing of the microdialysis probes. Results of an in vitro recovery study with TAK-285 were indicative of the strong adsorption of the compound to the microdialysis tubings. Adding bovine serum albumin (4%, w/v) in perfusion fluids and reducing perfusion flow rate (from 1.0 MUL/min to 0.5 MUL/min) in in vitro experiments substantially improved the detectability of TAK-285 in dialysate samples. Application of new perfusion conditions resulted in a manifold increase of the relative recovery of the microdialysis set-up for TAK-285 (from 1.6% to 47%). Subsequent in vivo microdialysis experiments were performed using the modified perfusion conditions in animals dosed with TAK-285 (75 mg/kg, p.o.). Detectable level of unbound TAK 285 was found in the extracellular space in the brain as long as 24-28 h after administration of the drug. The brain-to-blood ratios of the unbound TAK-285 were 0.18 and 0.24 (calculated from the C(max) values or from the area under the curve [AUC] values) similarly to the brain-to-blood ratios of total TAK-285. On the basis of substantial brain penetration of unbound TAK-285, it is concluded that TAK-285 might have the potential in the treatment of brain metastases of HER2 over-expressing metastatic breast cancer. The methodological approach described here might help to solve similar problems in determination of brain penetration of other substances with strong adsorption to the tubing of microdialysis setups. PMID- 22245028 TI - Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro. AB - Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD seem to be related to oxidative stress, excitotoxicity and misbalance in energetic metabolism. In this study we evaluated the potential relationship between energetic impairment, excitotoxicity and oxidative stress in rat striatal slices exposed to quinolinic acid (QA; as an excitotoxic model), 3-nitropropionic acid (3-NP; as an inhibitor of mitochondrial succinate dehydrogenase), as well as a combined model produced by the co-administration of these two toxins at subtoxic concentrations. We took advantage of the direct antioxidant/scavenger properties of Probucol in order to investigate the role of reactive oxygen species (ROS) in mediating the toxicity of both compounds alone or in association. Experiments with MK-801 (a NMDA type glutamate receptor antagonist) and succinate (an energy precursor agent) were also performed in an attempt to better comprehend the mechanisms of damage and neuroprotection. QA (1 mM), 3-NP (1 mM) and QA plus 3-NP (0.1 mM of both) significantly induced mitochondrial dysfunction and produced an increase in ROS generation, as well as a significant increase in lipid peroxidation in striatal slices. Probucol (10 and 30 MUM) prevented ROS formation and lipid peroxidation in all used models, but did not protect against the mitochondrial dysfunction induced by 3-NP (only by QA or QA plus 3-NP). Sodium succinate (1 mM) protected the striatal slices only against 3-NP-induced mitochondrial dysfunction. On the other hand, MK-801 protected against mitochondrial dysfunction in all used models. Our data suggest that the two studied toxic models (QA and 3-NP) or the combined model (QA plus 3-NP) can generate complex patterns of damage, which involve metabolic compromise, ROS formation, and oxidative stress. Moreover, a partial inhibition of SDH by subtoxic 3-NP and moderate excitotoxicty by subtoxic QA are potentiated when both agents are associated. The toxic action of QA plus 3-NP seems to be involved with Ca2+ metabolism and ROS formation, and can be prevented or attenuated by antioxidant/scavenger compounds and NMDAr antagonists. PMID- 22245029 TI - Gaze step distributions reflect fixations and saccades: a comment on. AB - In three experimental tasks Stephen and Mirman (2010) measured gaze steps, the distance in pixels between gaze positions on successive samples from an eyetracker. They argued that the distribution of gaze steps is best fit by the lognormal distribution, and based on this analysis they concluded that interactive cognitive processes underlie eye movement control in these tasks. The present comment argues that the gaze step distribution is predictable based on the fact that the eyes alternate between a fixation state in which gaze is steady and a saccade state in which gaze position changes rapidly. By fitting a simple mixture model to Stephen and Mirman's gaze step data we reveal a fixation distribution and a saccade distribution. This mixture model captures the shape of the gaze step distribution in detail, unlike the lognormal model, and provides a better quantitative fit to the data. We conclude that the gaze step distribution does not directly suggest processing interaction, and we emphasize some important limits on the utility of fitting theoretical distributions to data. PMID- 22245031 TI - Integrating constraints for learning word-referent mappings. AB - Learning word-referent mappings is complex because the word and its referent tend to co-occur with multiple other words and potential referents. Such complexity has led to proposals for a host of constraints on learning, though how these constraints may interact has not yet been investigated in detail. In this paper, we investigated interactions between word co-occurrence constraints and cross situational statistics in word learning. Analyses of child-directed speech revealed that when both object-referring and non-referring words occurred in the utterance, referring words were more likely to be preceded by a determiner than when the utterance contained only referring words. In a word learning study containing both referring and non-referring words, learning was facilitated when non-referring words contributed grammatical constraints analogous to determiners. The complexity of multi-word utterances provides an opportunity for co-occurrence constraints to contribute to word-referent mapping, and the learning mechanism is able to integrate these multiple sources of information. PMID- 22245030 TI - A funny thing happened on the way to articulation: N400 attenuation despite behavioral interference in picture naming. AB - We measured Event-Related Potentials (ERPs) and naming times to picture targets preceded by masked words (stimulus onset asynchrony: 80 ms) that shared one of three different types of relationship with the names of the pictures: (1) Identity related, in which the prime was the name of the picture ("socks" - ), (2) Phonemic Onset related, in which the initial segment of the prime was the same as the name of the picture ("log" - ), and (3) Semantically related in which the prime was a co-category exemplar and associated with the name of the picture ("cake" - ). Each type of related picture target was contrasted with an Unrelated picture target, resulting in a 3*2 design that crossed Relationship Type between the word and the target picture (Identity, Phonemic Onset and Semantic) with Relatedness (Related and Unrelated). Modulation of the N400 component to related (versus unrelated) pictures was taken to reflect semantic processing at the interface between the picture's conceptual features and its lemma, while naming times reflected the end product of all stages of processing. Both attenuation of the N400 and shorter naming times were observed to pictures preceded by Identity related (versus Unrelated) words. No ERP effects within 600 ms, but shorter naming times, were observed to pictures preceded by Phonemic Onset related (versus Unrelated) words. An attenuated N400 (electrophysiological semantic priming) but longer naming times (behavioral semantic interference) were observed to pictures preceded by Semantically related (versus Unrelated) words. These dissociations between ERP modulation and naming times suggest that (a) phonemic onset priming occurred late, during encoding of the articulatory response, and (b) semantic behavioral interference was not driven by competition at the lemma level of representation, but rather occurred at a later stage of production. PMID- 22245032 TI - Comparing pluralities. AB - What does it mean to compare sets of objects along a scale, for example by saying "the men are taller than the women"? We explore comparison of pluralities in two experiments, eliciting comparison judgments while varying the properties of the members of each set. We find that a plurality is judged as "bigger" when the mean size of its members is larger than the mean size of the competing plurality. These results are incompatible with previous accounts, in which plural comparison is inferred from many instances of singular comparison between the members of the sets (Matushansky & Ruys, 2006). Our results suggest the need for a type of predication that ascribes properties to plural entities, not just individuals, based on aggregate statistics of their members. More generally, these results support the idea that sets and their properties are actively represented as single units. PMID- 22245033 TI - Does learning to count involve a semantic induction? AB - We tested the hypothesis that, when children learn to correctly count sets, they make a semantic induction about the meanings of their number words. We tested the logical understanding of number words in 84 children that were classified as "cardinal-principle knowers" by the criteria set forth by Wynn (1992). Results show that these children often do not know (1) which of two numbers in their count list denotes a greater quantity, and (2) that the difference between successive numbers in their count list is 1. Among counters, these abilities are predicted by the highest number to which they can count and their ability to estimate set sizes. Also, children's knowledge of the principles appears to be initially item-specific rather than general to all number words, and is most robust for very small numbers (e.g., 5) compared to larger numbers (e.g., 25), even among children who can count much higher (e.g., above 30). In light of these findings, we conclude that there is little evidence to support the hypothesis that becoming a cardinal-principle knower involves a semantic induction over all items in a child's count list. PMID- 22245034 TI - Improved real-time PCR detection of 'Candidatus Liberibacter asiaticus' from citrus and psyllid hosts by targeting the intragenic tandem-repeats of its prophage genes. AB - 'Candidatus Liberibacter asiaticus' (CLas) is a Gram-negative alpha proteobacterium, and the prominent species of Liberibacter associated with a devastating worldwide citrus disease known as huanglongbing (HLB). This fastidious bacterium resides in phloem sieve cells of host plants and is vectored by the Asian citrus psyllid (Diaphorina citri). Due to its uneven distribution in planta and highly variable bacterial titers, detection of HLB bacteria can be challenging. Here we demonstrated a new utility of nearly identical tandem repeats of two CLas prophage genes for real-time PCR by SYBR Green 1 (LJ900fr) and TaqMan((r)) (LJ900fpr). When compared with conventional 16S rDNA-based real time PCR, targeting the repeat sequence reduced the relative detectable threshold by approximately 9 and 3 real-time PCR cycles for LJ900fr and LJ900fpr, respectively. Additionally, both LJ900 methods detected CLas from otherwise non detectable samples by other methods. CLas was also detected from globally derived samples including psyllids, various citrus varieties, periwinkle, dodder, and orange jasmine, suggesting the new detection method can be applicable worldwide. Additionally, we demonstrated the presence of the hyv(I)/hyv(II) repeat sequence within the 'Ca. Liberibacter americanus' strain. The method thereby provides sensitive HLB detection with broad application for scientific, regulatory, and citrus grower communities. PMID- 22245035 TI - Non-high-density lipoprotein cholesterol is a practical predictor of long-term cardiac death after coronary artery bypass grafting. AB - BACKGROUND: Recent studies have demonstrated that non-high-density lipoprotein cholesterol (non-HDL-C) can predict the risk of cardiovascular events among general population without coronary heart disease (CHD). However, few studies have investigated the predictive value of non-HDL-C for long-term prognosis in patients with CHD. The purpose of this study was to investigate whether non-HDL-C can predict long-term cardiovascular events in patients with CHD who underwent coronary artery bypass grafting (CABG). METHODS: We enrolled 1074 consecutive patients who underwent CABG at Juntendo University Hospital between 1984 and 1994, and obtained mortality data through 2000. We divided the patients into 2 groups by the median non-HDL-C level at baseline (180 mg/dL) and used Kaplan Meier method with log-rank test for survival analyses. Cox proportional-hazard regression model was used to calculate the relative risk (RR) of cardiac death. RESULTS: The mean follow-up period was 10.6+/-3.5 years. The survival rate of cardiac death was significantly lower in the high non-HDL-C group than that in the low non-HDL-C group (log-rank test; p=0.006). Furthermore, in proportional regression analysis adjusted for conventional coronary risk factors, metabolic syndrome, statin treatment, and use of artery bypass graft, the increased levels of non-HDL-C were significant and independent predictor of cardiac death beyond other lipid parameters (RR1.22; by 10 mg/dL non-HDL-C increasing, 95% confidence interval 1.03-1.44; p<0.05). CONCLUSIONS: The increased levels of non-HDL-C were significantly associated with an increased risk of cardiac death. Baseline non HDL-C levels may be a practical predictor of long-term cardiac death in patients with CHD after CABG. PMID- 22245036 TI - The potent different risk factors for cerebral infarction in young patients with and without type 2 diabetes: subanalysis of the Young Cerebral Infarction Study (YCIS). AB - BACKGROUND: To compare risk factors, stroke characteristics, and short-term prognosis between diabetic and nondiabetic young ischemic stroke patients to provide information for patient management, counseling, and future research in these patient groups. METHODS: All consecutive patients between the ages of 18 and 45 years with first-ever cerebral infarction during 2001-2010 were recruited to participate in the study. Using multivariate logistic regression modeling, demographic characteristics, cerebrovascular risk factors, clinical events, stroke subtypes, and outcome in ischemic stroke patients with and without diabetes were compared. RESULTS: Logistic regression analysis adjusted for confounders confirmed the following independent susceptibility markers: in a substudy of young patients with and without diabetes, the predictors of short term outcome were more likely to be TOAST subtype, initial stroke severity and serum uric acid, and age at onset, dyslipidemia, initial stroke severity and serum fibron levels correlate with a higher risk for incident stroke in young with diabetes. CONCLUSION: Our findings suggest that diabetic and nondiabetic ischemic stroke patients exhibit a distinct risk-factor and etiologic profile and may help clinicians to assess prognosis more accurately. PMID- 22245037 TI - The Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) study: prevalence and risk factors. AB - BACKGROUND AND PURPOSE: The ongoing population-based Barcelona-Asymptomatic Intracranial Atherosclerosis (Barcelona-AsIA) study is a prospective study that plans to investigate the natural history of asymptomatic intracranial atherosclerosis (AsIA) in a Caucasian-Mediterranean population, which remains unknown until now. The present study aims to determine the prevalence of AsIA and associated risk factors in the final study cohort. METHODS: Crossover, population based study of a representative sample (randomly selected from our reference population) older than 50 with a moderate-high vascular risk assessed by the vascular equation REGICOR and prior history of neither stroke nor ischemic heart disease. Anthropometric, demographic, clinical data and blood samples were collected at baseline. All individuals underwent a complete extracranial and transcranial color-coded duplex (TCCD) examination. TCCD criteria were used to identify and classify the degree of intracranial stenoses. RESULTS: A total of 933 subjects (64% men, mean age 66.3 years) were included in the study. One or more intracranial stenoses were detected at baseline in 80 subjects (8.6%) of whom 31 (3.3%) had moderate-severe lesions. The higher the REGICOR scores the greater the prevalence of AsIA (6.6%, 10.2% and 25% for REGICOR scores 5-9, 10-14 and >=15, p<0.001). Diabetes (OR 2.95; 95% CI (1.68-5.18); p<0.001), age (OR 1.05; 95% CI (1.02-1.08); p=0.001) and hypertension (OR 1.78; 95% CI (1.02-3.13); p=0.04) were independently associated with any degree of AsIA, while diabetes (OR 2.85; 95% CI (1.16-6.96); p=0.02) and age kept independently associated with moderate-severe AsIA. CONCLUSION: The prevalence of AsIA and moderate-severe AsIA in stroke-free Caucasians with a moderate-high vascular risk were 8.6% and 3.3% respectively. Diabetes and age were independently associated with moderate-severe AsIA. PMID- 22245038 TI - Serum albumin as a determinant of cortisol release in patients with acute ischemic stroke. AB - OBJECTIVE: Animal studies demonstrated that protein malnutrition increases pituitary-adrenorcortical activity and leads to excessive cortisol release. The aim of our study was to determine the association between serum albumin and cortisol level in patients with acute ischemic stroke. METHODS: Fifty-nine patients with first-ever ischemic stroke were included. Serum albumin level was measured within 36 h after stroke symptoms onset. Serum cortisol was measured between 36 and 72 h after stroke onset at 6 a.m., 10 a.m., 6 p.m. and 10 p.m. RESULTS: The patients in upper tertile of serum albumin had significantly lower cortisol level measured at 6 a.m. (median with interquartiles: 549.0 [430.4 667.7] nmol/L vs 590.4 [482.8-918.7] nmol/L, P=0.047) and 10 a.m. (402.8 [344.9 510.4] nmol/L vs 634.6 [482.8-827.7] nmol/L, P<0.01) than patients in lower and middle tertiles. On logistic regression analysis adjusted for age and stroke severity, patients in lower and middle tertile of serum albumin had about 7-times higher risk of hypercortisolemia than patients in upper tertile (P<0.01). CONCLUSIONS: Low serum albumin level in patients with ischemic stroke is associated with higher serum cortisol level and predisposes to hypercortisolemia. PMID- 22245039 TI - Circulating endothelial and platelet derived microparticles reflect the size of myocardium at risk in patients with ST-elevation myocardial infarction. AB - OBJECTIVES: Microparticles (MP) are small membrane vesicles, released from activated, damaged and apoptotic endothelial cells (EMP) or platelets (PMP) that may actively modulate inflammation, coagulation and vascular function. We tested the hypothesis that the number of circulating EMP or PMP in acute myocardial infarction correlates with the myocardium at risk (MaR) and infarct size (IS). METHODS: EMP were quantified in plasma samples of 36 patients (age: 63+/-10 years) with first time ST-elevation myocardial infarction (STEMI) using flow cytometry. EMP were defined as CD31(+)/CD42(-) MP and CD144(+) MP and PMP as CD31(+)/CD42(+) MP. MaR and IS was determined by cardiovascular magnetic resonance imaging one week after the index event. RESULTS: Plasma levels of CD31(+)/CD42(-) EMP were 251.0+/-178.8/MUl and CD144(+) 106.3+/-33.7/MUl. PMP levels were 579.2+/-631.8/MUl. MaR was 31.0+/-11.2% of the left ventricle and IS was 11.4+/-7.1% of the left ventricle. Patients with STEMI in the left anterior descending artery had higher levels of CD31(+)/CD42(-) EMP and PMP than those with other infarct-related arteries (p<0.05). The numbers of CD31(+)/CD42(-) EMP and PMP correlated to MaR, but not to IS. CONCLUSIONS: Circulating EMP and PMP correlate to the size of MaR in patients with STEMI suggesting that they reflect the severity of the endothelial injury and platelet activation during myocardial ischemia. PMID- 22245040 TI - Laparoscopic promontofixation for the treatment of recurrent sigmoid neovaginal prolapse: case report and systematic review of the literature. AB - Prolapse of a sigmoid neovagina, created in patients with congenital vaginal aplasia, is rare. In correcting this condition, preservation of coital function and restoration of the vaginal axis should be of primary interest. A 34-year-old woman with vaginal agenesis underwent vaginoplasty using sigmoid colon. Almost 6 years after the initial operation, she started complaining of a bearing-down sensation and an increase in vaginal discharge. She underwent 2 open surgeries and one vaginal surgery to treat the prolapse with no success. She came to our service and at vaginal examination the neovagina protruded approximately 5 cm beyond the hymen. The prolapse was treated successfully using a laparoscopic approach to suspend the neovagina to the sacral promontory (laparoscopic promontofixation). Prolapse of an artificially created vagina is a rare occurrence, without a standard treatment. Laparoscopy may be an alternative approach to restore the neovagina without compromising its function. PMID- 22245041 TI - Standardizing pneumoperitoneum for laparoscopic entry. Time, volume, or pressure: which is best? AB - STUDY OBJECTIVE: To establish whether time, pressure, or volume is the most reliable indicator of adequate pneumoperitoneum and, hence, the best parameter to use for safe trocar entry. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: Department of Endogynecology, Royal Hospital for Women, Sydney, Australia. PATIENTS: One hundred thirty-three consecutive patients having gynecologic laparoscopy were recruited for the study. Of these, 100 patients were included in the analysis, and 33 were excluded. INTERVENTION: Laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: After umbilical Veress needle entry, pressure and volume were recorded every 20 seconds until insufflation pressure of 20 mm Hg was reached. Following trocar entry, the gas was then expelled with the patient lying flat. The depth of pneumoperitoneum was measured at intra-abdominal pressure of 5, 10, 15, and 20 mm Hg. Random effects models were used to predict the depth of pneumoperitoneum based on pressure, time, and volume. A comparison was made of the standard deviation of pneumoperitoneum distance produced at pressure of 20 mm Hg (8.56 +/- 0.59) compared with that produced by a volume of 3 L (4.96 +/- 1.13). Compared with volume, pressure was significantly more reliable in estimating depth of pneumoperitoneum (p < .001) because it exhibited the least variance. Further comparison was made of the standard deviation of pneumoperitoneum distance produced at pressure of 20 mm Hg (8.56 +/- 0.59) compared with that produced at 3 minutes (7.82 +/- 1.19). Compared with time, pressure was significantly more reliable in depth of pneumoperitoneum (p < .001) because it exhibited the least variance. These results demonstrate that, compared with volume and time, pressure is the most reliable predictor of pneumoperitoneum depth because it exhibits the least variance (p < .001). CONCLUSION: Pressure is the most reliable predictor of pneumoperitoneum before trocar entry in laparoscopic surgery. PMID- 22245042 TI - Laparoscopic intracorporeal cinch knots: changing the square knot paradigm. AB - Reliable knot tying is a cornerstone of surgical technique, and the square knot and surgeon's knot constitute the greatest part of most surgeons' knot-tying skills. Traditionally, laparoscopic intracorporeal knot tying of a square knot or surgeon's knot is a direct translation from an open instrument tying technique. Given the technical and mechanical challenges imposed by standard laparoscopic instrumentation, performance of such a basic task is sometimes difficult and elusive, even for accomplished surgeons. Consequently, myriad technologies and techniques are used as work-arounds for this basic surgical task. However, the sometimes necessary tying of a snug and reliable intracorporeal knot is unavoidable. That laparoscopic intracorporeal knot tying must be translated from a 2-handed open surgical technique using flat knots deserves reassessment. Cinch knots, with unusual sliding and tightening properties, are currently used in surgery. With apparent complexity and exacting construction requirements, however, primary intracorporeal knot tying has not been described. Described herein is a technique for doing so. Also included is a review of cinch knot mechanics, an understanding of a fundamental scheme for their construction, and basic instrument maneuvers that enable easier intracorporeal tying of a most reliable knot, useful for multiport and, in particular, single-port laparoscopic knot tying. PMID- 22245044 TI - Serum activin A does not predict ectopic pregnancy as a single measurement test, alone or as part of a multi-marker panel including progesterone and hCG. AB - BACKGROUND: To evaluate the diagnostic accuracy of activin A alone or in a multi marker panel for the prediction of ectopic pregnancy (EP). METHODS: A retrospective analysis was performed on a cohort of 289 women who presented to the emergency department (ED) with vaginal bleeding and/or abdominal pain/cramping and were diagnosed with EP, spontaneous abortion, or viable intrauterine pregnancy. Serum progesterone, hCG, and activin A concentrations were measured on the samples obtained in the ED. Statistical analysis was performed to determine the clinical utility of these biomarkers as single measurement and as a multi-marker panel test for ectopic pregnancy. Women >=18 y with vaginal bleeding or abdominal pain/cramping. RESULTS: Progesterone (<10 ng/ml), hCG (<6,699 IU/l), and activin A (<0.26 ng/ml) cutoffs were optimized by ROC analysis. These demonstrated sensitivities of 62.9%, 74.2%, and 59.6%, and specificities of 60.5%, and 63.0%, and 61.0% respectively for detecting EP. The multi-marker panel utilizing all three biomarkers had a sensitivity of 70% and specificity of 69%. CONCLUSION: Serum activin A cannot be used as a single measurement or in a multi-marker panel with progesterone and hCG to predict EP. PMID- 22245045 TI - Plectin promotes migration and invasion of cancer cells and is a novel prognostic marker for head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is usually found at a late stage and distant metastasis occurs at high frequency; therefore, novel prognostic markers are needed. This study was aimed to identify novel tumor markers in HNSCC. We identified 65 proteins which were significantly increased or decreased in the tumors by 2D-DIGE using 12 HNSCC and adjacent non-cancer tissues. Western blotting and immunohistochemical analysis confirmed that the expression of plectin was significantly increased in most cancer tissues as compared with non cancer tissues. Strikingly, the suppression of endogenous plectin using siRNA inhibited the proliferation, migration and invasion of HNSCC cells and down regulated Erk 1/2 kinase. Furthermore, immunohistochemistry using paraffin embedded tissues from 62 patients showed not only that the frequency of recurrence was correlated with the plectin expression but that the prognosis of patients with a high plectin was extremely poor. Moreover, the survival rate of patients with a high plectin was significantly lower than that of patients with low E-cadherin levels, which is known to correlate with the poor prognosis of HNSCC. Our findings suggest that plectin promotes the migration and invasion of HNSCC cells through activation of Erk 1/2 kinase and is a potential prognostic biomarker of HNSCC. PMID- 22245043 TI - Developmental origins of adult diseases and neurotoxicity: epidemiological and experimental studies. AB - To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers at this symposium presented their research results on different neurotoxic chemicals relating to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to inorganic mercury and methylmercury, and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-dose human equivalent gestational lead exposure produces late-onset obesity only in male mice that is associated with neurodegeneration. Didima de Groot presented results on prenatal exposure of rats to methylazoxymethanol and discussed the results in light of the etiology of western Pacific amyotrophic lateral sclerosis and Parkinson-dementia complex. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following acute 24 h exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment. The results indicate that developmental neurotoxicity results in permanent changes, thus emphasizing the need to prevent such toxicity. PMID- 22245046 TI - Comparative proteomic analysis of salt response proteins in seedling roots of two wheat varieties. AB - A comparative proteomic analysis was made of salt response in seedling roots of wheat cultivars Jing-411 (salt tolerant) and Chinese Spring (salt sensitive) subjected to a range of salt stress concentrations (0.5%, 1.5% and 2.5%) for 2 days. One hundred and ninety eight differentially expressed protein spots (DEPs) were located with at least two-fold differences in abundance on 2-DE maps, of which 144 were identified by MALDI-TOF-TOF MS. These proteins were involved primarily in carbon metabolism (31.9%), detoxification and defense (12.5%), chaperones (5.6%) and signal transduction (4.9%). Comparative analysis showed that 41 DEPs were salt responsive with significant expression changes in both varieties under salt stress, and 99 (52 in Jing-411 and 47 in Chinese Spring) were variety specific. Only 15 and 9 DEPs in Jing-411 and Chinese Spring, respectively, were up-regulated in abundance under all three salt concentrations. All dynamics of the DEPs were analyzed across all treatments. Some salt responsive DEPs, such as guanine nucleotide-binding protein subunit beta-like protein, RuBisCO large subunit-binding protein subunit alpha and pathogenesis related protein 10, were up-regulated significantly in Jing-411 under all salt concentrations, whereas they were down-regulated in salinity-stressed Chinese Spring. PMID- 22245047 TI - Structure-activity relationships for the interaction of 5,10-dihydroindeno[1,2 b]indole derivatives with human and bovine carbonic anhydrase isoforms I, II, III, IV and VI. AB - Several 5,10-dihydroindeno[1,2-b]indole derivatives incorporating methoxy, hydroxyl, and halogen (F, Cl, and Br) moieties on the indene fragment of the molecule were prepared and tested against five carbonic anhydrase (CA, EC 4.2.1.1) isoforms. The inhibitory potencies of these compounds against the human (h) isoforms hCA I, II, IV, VI and bovine (b) isoform bCA III were assessed. Most of them exhibited low micromolar inhibition of these enzymes. K(I) values of these compounds against hCA I and hCA II were in the range of 2.14-16.32 MUM, and 0.34-2.52 MUM, respectively. Isozyme hCA IV was inhibited with K(I)-s in the range of 0.435-5.726 MUM, while hCA VI with K(I)-s of 1.92-12.84 MUM bCA III was inhibited with K(I)-s in the range of 2.13-17.83 MUM. The structurally related compounds, 1,2-dimethoxybenzene, catechol and indole were also tested in order to understand the structure activity relationship. In silico docking studies of some derivatives within the active site of hCA I and II were also carried out in order to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. PMID- 22245048 TI - Bakuchiol derivatives as novel and potent cytotoxic agents: a report. AB - A library of 28 compounds comprising of acyl, amino, halo, nitro, styryl and cyclized derivatives of bakuchiol have been evaluated against a panel of eight human cancer cell lines. Bioevaluation studies have resulted in the identification of potent cytotoxic molecules exhibiting concentration dependent growth inhibition against leukemia cancer cells with best results observed for compounds 17 and 22 exhibiting IC(50) 1.8 and 2.0 MUM respectively. As evident from various biological end-points, inhibition of cell proliferation by inducing G2/M cell cycle arrest, mitochondrial membrane disruption followed by DNA fragmentation and apoptosis is demonstrated. PMID- 22245049 TI - New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy 1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold. AB - Based on some structural analogies with leflunomide and brequinar, two well-known inhibitors of dihydroorotate dehydrogenase (DHODH), a new series of products was designed, by joining the substituted biphenyl moiety to the 4-hydroxy-1,2,5 oxadiazol-3-yl scaffold through an amide bridge. The compounds were studied for their DHODH inhibitory activity on rat liver mitochondrial/microsomal membranes. The activity was found to be closely dependent on the substitution pattern at the biphenyl system; the most potent products were those bearing two or four fluorine atoms at the phenyl adjacent to the oxadiazole ring. A molecular modeling study suggested that these structures might have a brequinar-like binding mode. The greater potency of fluorinated analogs may depend partly on enhanced interactions with the hydrophobic ubiquinone channel, and partly on the role of fluorine in stabilizing the putative bioactive conformation. PMID- 22245050 TI - Aortic stiffness and distensibility in top-level athletes. AB - BACKGROUND: Although cardiac adaptation to different sports has been extensively described, the potential relationship of training with aortic root (AR) elastic properties and diameters in top-level athletes remains not fully investigated. The aims of this study were to compare AR morphology and stiffness between highly trained athletes and sedentary subjects and to assess the independent determinants of AR stiffness and distensibility in athletes. METHODS: Four hundred ten elite athletes (220 endurance-trained athletes [ATE] and 190 strength trained athletes [ATS]; 290 men; mean age, 28.3 +/- 13.6 years; age range, 18-40 years) and 240 healthy controls underwent standardized comprehensive transthoracic echocardiography, including Doppler studies. End-diastolic AR diameters were measured at four locations: the aortic annulus, the sinuses of Valsalva, the sinotubular junction, and the maximal diameter of the proximal ascending aorta. The aortic distensibility index was calculated as 2 * (systolic proximal ascending aortic diameter - diastolic proximal ascending aortic diameter)/(diastolic proximal ascending aortic diameter) * (pulse pressure) (cm( 2).dyn(-1).10(-6)). AR stiffness index was defined as (systolic blood pressure/diastolic blood pressure)/(systolic proximal ascending aortic diameter - diastolic proximal ascending aortic diameter)/diastolic proximal ascending aortic diameter. Analysis of variance was performed to evaluate differences among groups. RESULTS: Left ventricular (LV) mass index did not significantly differ between the two groups of athletes but was lower in controls. ATS showed higher body surface area, sum of wall thickness (septum plus LV posterior wall), and circumferential end-systolic stress, while LV stroke volume and LV end-diastolic volume were greater in ATE. AR diameters at all levels and AR stiffness were significantly greater in ATS than in ATE and controls, while AR distensibility was significantly higher in ATE. However, AR dilatation was observed only in four male power athletes (1%). By multivariate analyses, in the overall population of athletes, age, LV stroke volume, endurance training, and duration of training were the only independent determinant of higher AR distensibility. On the other hand, age, circumferential end-systolic stress, strength training, and duration of training were independently associated with AR stiffness in ATS. CONCLUSIONS: AR diameters and stiffness were significantly greater in strength-trained athletes, while aortic distensibility was higher in endurance athletes compared with age- and sex-matched healthy controls. PMID- 22245051 TI - Prognostic value of tricuspid annular tissue Doppler velocity in heart failure with atrial fibrillation. AB - BACKGROUND: Right ventricular function is associated with long-term outcomes of heart failure (HF), particularly with atrial fibrillation (AF). The aim of this study was to evaluate the prognostic value of Doppler tissue imaging at the mitral and tricuspid annuli in patients with HF and AF. METHODS: In this prospective observational study, 457 patients (mean age, 67 years; 283 men) referred for HF with AF were enrolled and underwent conventional echocardiography including pulsed-wave Doppler tissue imaging. Systolic (s') and early diastolic (e') velocities of the tricuspid and mitral annuli were recorded from the apical four-chamber view. The development of clinical adverse events during the follow up period was defined as the composite of cardiac death and readmission for HF. RESULTS: During the follow-up period (median, 20 months), 37 patients reached the primary end point (nine deaths and 28 cases of HF). Patients with cardiac events were significantly older and more often had previous HF admissions and diuretic use, higher New York Heart Association classes, and greater average ratios of peak early diastolic mitral inflow to annular velocity. Additionally, Doppler tissue imaging of s' and e' at the tricuspid, septal, and lateral mitral annuli were all reduced. Multivariate analysis showed that tricuspid s' and septal e' remained significant predictors of cardiac events. By Kaplan-Meier analysis, the occurrence of cardiac events was more frequent when tricuspid s' was <9.0 cm/sec (P < .001) and when septal e' was <7.3 cm/sec (P < .001). CONCLUSIONS: In patients with HF and AF with a high risk for cardiac events, tricuspid s' and septal e' can be independent risk predictors of outcomes. PMID- 22245053 TI - Organized living: formation mechanisms and functions of plasma membrane domains in yeast. AB - Plasma membrane proteins and lipids organize into lateral domains of specific composition. Domain formation is achieved by a combination of lipid-lipid and lipid-protein interactions, membrane-binding protein scaffolds and protein fences. The resulting domains function in membrane protein turnover and homeostasis, as well as in cell signaling. We review the mechanisms generating plasma membrane domains and the functional consequences of this organization, focusing on recent findings from research on the yeast model system. PMID- 22245054 TI - Traumatic optic nerve avulsion: A case report. AB - INTRODUCTION: Case report of a traumatic optic nerve avulsion. OBSERVATION: We report the case of a traumatic right optic nerve avulsion in an 11-year-old boy as a result of a contusion with a surfboard. On initial examination, the patient exhibited bilateral mydriasis with a right afferent pupillary defect. Visual acuity was no light perception. A moderate microhyphema was noted along with intraocular pressure of 12mmHg and no open globe. Fundus examination revealed retinal ischemia with white retinal edema, attenuated arteries and segmentally occluded vasculature. In place of the optic nerve, there was a hole with associated vitreous hemorrhage. Non-contrast CT and MRI demonstrated vitreous prolapse into the optic nerve sheath, which still appeared securely attached to the globe. Spectral domain OCT and visual evoked potentials confirmed disruption of the ganglion cell layer. DISCUSSION: While obvious in the presence of clear media, an avulsion may remain undetected in the case of associated vitreous hemorrhage. Orbital imaging may clarify the diagnosis. CONCLUSION: Although rare, optic nerve avulsions exhibit the same risk profile as open globe injuries and arterial occlusions. PMID- 22245052 TI - Slit/Robo-mediated axon guidance in Tribolium and Drosophila: divergent genetic programs build insect nervous systems. AB - As the complexity of animal nervous systems has increased during evolution, developmental control of neuronal connectivity has become increasingly refined. How has functional diversification within related axon guidance molecules contributed to the evolution of nervous systems? To address this question, we explore the evolution of functional diversity within the Roundabout (Robo) family of axon guidance receptors. In Drosophila, Robo and Robo2 promote midline repulsion, while Robo2 and Robo3 specify the position of longitudinal axon pathways. The Robo family has expanded by gene duplication in insects; robo2 and robo3 exist as distinct genes only within dipterans, while other insects, like the flour beetle Tribolium castaneum, retain an ancestral robo2/3 gene. Both Robos from Tribolium can mediate midline repulsion in Drosophila, but unlike the fly Robos cannot be down-regulated by Commissureless. The overall architecture and arrangement of longitudinal pathways are remarkably conserved in Tribolium, despite it having only two Robos. Loss of TcSlit causes midline collapse of axons in the beetle, a phenotype recapitulated by simultaneous knockdown of both Robos. Single gene knockdowns reveal that beetle Robos have specialized axon guidance functions: TcRobo is dedicated to midline repulsion, while TcRobo2/3 also regulates longitudinal pathway formation. TcRobo2/3 knockdown reproduces aspects of both Drosophila robo2 and robo3 mutants, suggesting that TcRobo2/3 has two functions that in Drosophila are divided between Robo2 and Robo3. The ability of Tribolium to organize longitudinal axons into three discrete medial-lateral zones with only two Robo receptors demonstrates that beetle and fly achieve equivalent developmental outcomes using divergent genetic programs. PMID- 22245055 TI - [Comparing central corneal thickness measured using ultrasound pachymetry and the Pentacam in healthy subjects and patients with primary open-angle glaucoma]. AB - PURPOSE: To determine the capacity for measurement of central corneal thickness by ultrasound pachymetry and by Pentacam (pachymetry at the pupillary axis and minimum corneal pachymetry) to discriminate between healthy controls and patients with primary open-angle glaucoma. METHODS: Measurements of the left eyes of 123 control subjects and 128 glaucomatous patients were taken. Differences between the two data sets for each variable were identified using a t-test for independent samples. Three univariate binary logistic regression models (to discriminate between glaucoma and controls) were constructed, in which the predictive variables were the determinations of corneal thickness. RESULTS: All variables showed a normal distribution. Controls and patients failed to differ significantly in terms of ultrasound pachymetry but did differ in terms of pupillary axis thickness (mean difference 22.01MUm in favour of controls; 95% CI: 5.61-34.15) and minimum corneal thickness (mean difference 21.65MUm in favour of controls; 95% CI: 3.05-32.25). The logistic regression model for ultrasound pachymetry was not significant (P=0.051) but significant discriminatory capacity was shown for pupillary axis thickness (expB=0.987; 95% CI: 0.99-0.993; sensitivity: 58.5%; specificity: 64.8%) and minimum corneal thickness (expB=0.987; 95% CI: 0.981-0.994; sensitivity: 61.9%; specificity: 63.1%). CONCLUSIONS: Central corneal thickness measurement by Pentacam, while not an ad hoc diagnostic test for glaucoma, showed a similar yet not inappreciable capacity to discriminate between glaucoma patients and controls. PMID- 22245056 TI - [Astigmatism correction by femtosecond laser]. AB - Through the creation of astigmatic keratotomies, femtosecond laser can correct congenital or post-surgical astigmatism. We have been using an optimized treatment nomogram, which offers superior and more predictable results than manual incisional techniques. Femtosecond arcuate incisions allow a reduction of over 50% of the preoperative astigmatism. Nonetheless, the efficacy can likely be improved further by refining these nomograms specific to the femtosecond laser. PMID- 22245057 TI - Silica nanoparticles and silver-doped silica nanoparticles induce endoplasmatic reticulum stress response and alter cytochrome P4501A activity. AB - Engineered silica nanoparticles (SiO(2)-NPs) find widespread application and may lead to exposure of humans and the environment. Here we compare the effects of SiO(2)-NPs and SiO(2)-NPs doped with silver (SiO(2)-Ag-NPs) on survival and cellular function of human liver cells (Huh7) and Pimephales promelas (fathead minnow) fibroblast cells (FMH). In Huh7 cells we investigate effects on the endoplasmatic reticulum (ER), including ER stress, and interactions of nanoparticles (NPs) with metabolizing enzymes and efflux transporters. The NPs formed agglomerates/aggregates in cell culture media as revealed by SEM and TEM. SiO(2) and SiO(2)-1% Ag-NPs were taken up into cells as demonstrated by agglomerates occurring in vesicular-like structures or freely dispersed in the cytosol. Cytotoxicity was more pronounced in Huh7 than in FMH cells, and increased with silver content in silver-doped NPs. Dissolved silver was the most significant factor for cytotoxicity. At toxic and non-cytotoxic concentrations SiO(2)-NPs and SiO(2)-1% Ag-NPs induced perturbations in the function of ER. In Huh7 cells NPs induced the unfolded protein response (UPR), or ER stress response, as demonstrated in induced expression of BiP and splicing of XBP1 mRNA, two selective markers of ER stress. Additionally, SiO(2)-1% Ag-NPs and AgNO(3) induced reactive oxygen species. Pre-treatment of Huh7 cells with SiO(2)-1% Ag NPs followed by exposure to the inducer benzo(a)pyrene caused a significant reduced induction of CYP1A activity. NPs did not alter the activity of ABC transporters. These data demonstrate for the first time that SiO(2)-NPs and SiO(2)-1% Ag-NPs result in perturbations of the ER leading to the ER stress response. This represents a novel and significant cellular signalling pathway contributing to the cytotoxicity of NPs. PMID- 22245058 TI - Assessment of the abiotic transformation of 17beta-estradiol in the presence of vegetable matter--II: the role of molecular oxygen. AB - This study characterizes the effect of oxygen in the abiotic transformation of estrogens when they are contacted with a surrogate of the vegetable wastes found in sewage. 17beta-Estradiol (E2) and 17beta-(14)C(4)-estradiol ((14)C-E2) were utilized as model compounds. Batch experiments were run under both oxic and anoxic conditions. In order to accomplish an accurate mass balance of the target estrogen, two analyses were performed simultaneously: first, radioactivity counting, and second, quantitation of E2 and (14)C-E2, as well as their transformation product estrone and (14)C(4)-estrone, by Liquid Chromatography tandem Mass Spectrometry. Under oxic conditions, the total concentration of (14)C E2 was found to decrease by 78% in 72 h (15% and 7% remained in the liquid and solid phases, respectively). Conversely, when the estrogens were contacted with the synthetic influent under anoxic conditions, E2 was quantitatively recovered after 72 h (70% and 22% in aqueous and solid matrices, correspondingly). These results suggest that when the concentration of dissolved oxygen is null or limited, catalysis through an oxidative coupling mechanism is halted. Moreover, it was confirmed that the catalytic reaction occurred solely in the presence of the solid phase of the model vegetable matter. PMID- 22245059 TI - Aerobic degradation of tetrabromobisphenol-A by microbes in river sediment. AB - This study investigated the aerobic degradation of tetrabromobisphenol-A (TBBPA) and changes in the microbial community in river sediment from southern Taiwan. Aerobic degradation rate constants (k(1)) and half-lives (t(1/2)) for TBBPA (50 MUg g(-1)) ranged from 0.053 to 0.077 d(-1) and 9.0 to 13.1 d, respectively. The degradation of TBBPA (50 MUg g(-1)) was enhanced by adding yeast extract (5 mg L( 1)), sodium chloride (10 ppt), cellulose (0.96 mg L(-1)), humic acid (0.5 g L( 1)), brij 30 (55 MUM), brij 35 (91 MUM), rhamnolipid (130 mg L(-1)), or surfactin (43 mg L(-1)), with rhamnolipid yielding a higher TBBPA degradation than the other additives. For different toxic chemicals in the sediment, the results showed the high-to-low order of degradation rates were bisphenol-A (BPA) (50 MUg g(-1))>nonylphenol (NP) (50 MUg g(-1))>4,4'-dibrominated diphenyl ether (BDE-15) (50 MUg g(-1))>TBBPA (50 MUg g(-1))>2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) (50 MUg g(-1)). The addition of various treatments changed the microbial community in river sediments. The results also showed that Bacillus pumilus and Rhodococcus ruber were the dominant bacteria in the process of TBBPA degradation in the river sediments. PMID- 22245060 TI - Isolation of mesotrione-degrading bacteria from aquatic environments in Brazil. AB - Mesotrione is a benzoylcyclohexane-1,3-dione herbicide that inhibits 4 hydroxyphenyl pyruvate dioxygenase in target plants. Although it has been used since 2000, only a limited number of degrading microorganisms have been reported. Mesotrione-degrading bacteria were selected among strains isolated from Brazilian aquatic environments, located near corn fields treated with this herbicide. Pantoea ananatis was found to rapidly and completely degrade mesotrione. Mesotrione did not serve as a sole C, N, or S source for growth of P. ananatis, and mesotrione catabolism required glucose supplementation to minimal media. LC MS/MS analyses indicated that mesotrione degradation produced intermediates other than 2-amino-4-methylsulfonyl benzoic acid or 4-methylsulfonyl-2-nitrobenzoic acid, two metabolites previously identified in a mesotrione-degrading Bacillus strain. Since P. ananatis rapidly degraded mesotrione, this strain might be useful for bioremediation purposes. PMID- 22245061 TI - Responses of Hyalella azteca and phytoplankton to a simulated agricultural runoff event in a managed backwater wetland. AB - We assessed the aqueous toxicity mitigation capacity of a hydrologically managed floodplain wetland following a synthetic runoff event amended with a mixture of sediments, nutrients (nitrogen and phosphorus), and pesticides (atrazine, S metolachlor, and permethrin) using 48-h Hyalella azteca survival and phytoplankton pigment, chlorophyll a. The runoff event simulated a 1h, 1.27 cm rainfall event from a 16 ha agricultural field. Water (1L) was collected every 30 min within the first 4h, every 4h until 48 h, and on days 5, 7, 14, 21, and 28 post-amendment at distances of 0, 10, 40, 300 and 500 m from the amendment point for chlorophyll a, suspended sediment, nutrient, and pesticide analyses. H. azteca 48-h laboratory survival was assessed in water collected at each site at 0, 4, 24, 48 h, 5 d and 7 d. Greatest sediment, nutrient, and pesticide concentrations occurred within 3h of amendment at 0m, 10 m, 40 m, and 300 m downstream. Sediments and nutrients showed little variation at 500 m whereas pesticides peaked within 48 h but at <15% of upstream peak concentrations. After 28 d, all mixture components were near or below pre-amendment concentrations. H. azteca survival significantly decreased within 48 h of amendment up to 300 m in association with permethrin concentrations. Chlorophyll a decreased within the first 24h of amendment up to 40m primarily in conjunction with herbicide concentrations. Variations in chlorophyll a at 300 and 500 m were associated with nutrients. Managed floodplain wetlands can rapidly and effectively trap and process agricultural runoff during moderate rainfall events, mitigating impacts to aquatic invertebrates and algae in receiving aquatic systems. PMID- 22245062 TI - BDE-47 sorption and desorption to soil matrix in single- and binary-solute systems. AB - Three loamy-clay soil samples (LC1-3) with different properties were collected as the geosorbents to preliminarily investigate the sorption and desorption of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in single system and binary system with the presence of decabromodiphenyl ether (BDE-209), which can provide information in order to further understand the sorption mechanisms and evaluate the adsorption sites. A concentration of 10 MUg L(-1) BDE-209 suppressed the sorption of BDE-47, and the trend became more and more significant with the increase of BDE-47 equilibrium concentration, however, BDE-47 caused no competitive effect on BDE-209 sorption, which was related with the better accessibility of more hydrophobic molecules to adsorption sites. In the binary system, nonlinearity of the BDE-47 sorption isotherms for the three samples changed in different ways, which originated from the varied soil properties. Desorption hysteresis was observed in all cases, which was estimated due to irreversible surface adsorption between sorbent and sorbate. BDE-209 made desorption of BDE-47 more hysteretic from soil samples, which was estimated to be ascribed to the accelerated sorbent state transition and new sites creation caused by BDE-209 sorption. PMID- 22245063 TI - Presence of urotensin-II receptors at the cell nucleus: specific tissue distribution and hypoxia-induced modulation. AB - Urotensin II (UII) and its receptor UT, are widely expressed in the cardiovascular and central nervous system, where they exert regulatory actions under both physiological and pathological conditions. Our study, aimed at investigating the presence of functional nuclear UT in various rat and monkey tissues as well as in human cell lines, demonstrated for the first time by Western blot analysis and confocal immunofluorescence a tissue-specific nuclear expression of this receptor (heart and central nervous system). This nuclear UT was further characterized pharmacologically through radioligand binding studies using specific ligands of the urotensinergic system, as well as somatostatin. In 2D-gel experiments, we observed the presence of different post-translational modifications between membrane and nuclear UT receptors in brain extracts. Transcription initiation assays showed de novo RNA synthesis caused by UII and Urotensin-related peptide (URP) which were inhibited by an UT antagonist urantide. In hypoxic/ischemic conditions, UT receptors were differentially modulated in regard to subcellular localization. Thus, the unique regiospecificity of the nuclear UT receptor along with its particular modulation under hypoxic conditions could indicate a specific and complementary physiological role that could be correlated with pro-angiogenic and/or neuromodulatory actions of UII, both in the cardiovascular and central nervous system. PMID- 22245064 TI - Dual specificity phosphatases 10 and 16 are positive regulators of EGF-stimulated ERK activity: indirect regulation of ERK signals by JNK/p38 selective MAPK phosphatases. AB - We have explored the possible role of dual specificity phosphatases (DUSPs) on acute EGF-mediated ERK signalling using high content imaging and a delayed MEK inhibition protocol to distinguish direct and indirect effects of the phosphatases on ERK activity. Using siRNAs, we were unable to find evidence that any of the MAPK phosphatases (MKPs) expressed in HeLa cells acts directly to dephosphorylate ppERK1/2 (dual phosphorylated ERKs 1 and/or 2) in the acute time frame tested (0-14 min). Nevertheless, siRNAs against two p38/JNK MKPs (DUSPs 10 and 16) inhibited acute EGF-stimulated ERK activation. No such effect was seen for acute effects of the protein kinase C activator PDBu (phorbol 12,13 dibutyrate) on ERK activity, although effects of EGF and PDBu on ERK-dependent transcription (Egr-1 luciferase activity) were both reduced by siRNA targeting DUSPs 10 and 16. Inhibition of EGF-stimulated ERK activity by these siRNAs was reversed by pharmacological inhibition of p38 MAPK and single cell analysis revealed that the siRNAs did not influence the nuclear-cytoplasmic distribution of ppERK1/2. Thus, DUSPs 10 and 16 are positive regulators of activation, apparently acting by modulating cross-talk between the p38 and ERK pathways. A simplified mathematical model of this scenario accurately predicted the experimental data, supporting the conclusion that the major mechanism by which MKPs influence acute EGF-stimulated ERK responses is the negative regulation of p38, resulting in the positive regulation of ERK phosphorylation and activity. PMID- 22245065 TI - A review of female genital schistosomiasis. AB - In a review of the studies on genital schistosomiasis, the cervix, the Fallopian tubes, and the vagina are the most common gynaecological sites to harbour Schistosoma haematobium. Lesions are caused by host responses to dead or viable schistosomiasis eggs and may render women with genital schistosomiasis susceptible to HIV. The typical genital changes, such as sandy patches and pathological blood vessels may make women susceptible to super-infection, cause contact bleeding, decreased fertility, abortions, discharge and bleeding. Further research is needed to find simple, low-tech diagnostic methods, treatment for chronic lesions, and to explore the preventive effects of mass drug administration on symptoms, sandy patches, HPV and the HIV epidemic. PMID- 22245066 TI - Melatonin and cardiovascular disease: myth or reality? PMID- 22245068 TI - Senescence: a new weapon for cancer therapy. AB - Senescence is a stable cell cycle arrest that can be activated by oncogenic signaling and manifests with changes in cellular organization and gene expression, such as the induction of a complex secretome. Importantly, senescence limits tumor progression and determines the outcome of conventional anticancer therapies. In recent years, therapeutic approaches such as p53 reactivation, inhibition of c-MYC in addicted tumors or treatment with cyclin-dependent kinase (CDK) inhibitors have proven effective by invoking a senescence response. The possibility of using prosenescence therapies for cancer treatment has provoked considerable interest. We propose that the senescence secretome can be a source of novel targets for prosenescence therapies, as it has tumor suppressive actions. Overall, tailored prosenescence therapies have the potential to be used for treating cancer and other pathologies. PMID- 22245067 TI - Low sociability in BTBR T+tf/J mice is independent of partner strain. AB - Inbred mouse strains differ greatly in social behaviors, making them a valuable resource to study genetic and non-genetic mechanisms underlying social deficits relevant to autism spectrum disorders. A hallmark symptom of autism is a lack of ability to understand other people's thoughts and intentions, which leads to impairments in adjusting behaviors in response to ever-changing social situations in daily life. We compared the ability of BTBR T+tf/J (BTBR), a strain with low sociability, and C57BL/6J (B6), a strain with high sociability, for their abilities to modulate responses to social cues from different partners in the reciprocal social interaction test. Results indicate that BTBR exhibited low sociability toward different partners and displayed minimal ability to modify behaviors toward different partners. In contrast, B6 showed high sociability toward different partners and was able to modify social behaviors toward different partners. Consistent results were found in two independent cohorts of different ages, and in both sexes. In the three-chambered test, high sociability in B6 and low sociability in BTBR were independent of strain of the novel mouse. Since social deficits in BTBR could potentially be caused by physical disabilities in detecting social olfactory cues, or in cognitive abilities, we tested BTBR and B6 mice on measures of olfaction and cognition. BTBR mice displayed more sniffing of social odors emitted by soiled bedding than of an odorless novel object, but failed to show a preference for a live novel mouse over a novel object. On olfactory habituation/dishabituation to a sequence of odors, BTBR displayed discrimination abilities across three non-social and two social odors. However, as compared to B6, BTBR displayed less sniff time for both non-social and social odors, and no significant dishabituation between cage odors from two different novel mouse strains, findings that will be important to investigate further. BTBR was generally normal in spatial acquisition on the Morris water maze test, but showed deficits in reversal learning. Time spent freezing on contextual and cued fear conditioning was lower in BTBR than in B6. Our findings suggest that BTBR has poor abilities to modulate its responses to different social partners, which may be analogous to social cognition deficits in autism, adding to the value of this strain as a mouse model of autism. PMID- 22245069 TI - Oocysts and high seroprevalence of Neospora caninum in dogs living in remote Aboriginal communities and wild dogs in Australia. AB - Canines are definitive hosts of Neospora caninum (Apicomplexa). For horizontal transmission from canines to occur, viable oocysts of N. caninum must occur in the environment of susceptible intermediate hosts. Canids in Australia include wild dogs and Aboriginal community dogs. Wild dogs are those dogs that are not dependent on humans for survival and consist of the dingo, feral domestic dog and their hybrid genotypes. Aboriginal community dogs are dependent on humans, domesticated and owned by a family, but are free-roaming and have free access throughout the community. In this study the extent of N. caninum infection was determined in a total of 374 dogs (75 wild dogs and 299 Aboriginal community dogs) using a combination of microscopic, molecular and serological techniques. Oocysts of N. caninum were observed in the faeces of two juvenile Aboriginal community dogs (2/132; 1.5%). To estimate N. caninum prevalence, a new optimised cut-off of 18.5% inhibition for a commercial competitive ELISA was calculated using a two-graph receiver-operating characteristic (TG-ROC) analysis and IFAT as the gold standard resulting in equal sensitivity and specificity of 67.8%. Of the 263 dog sera tested the true prevalence of N. caninum antibodies was 27.0% (95% confidence limit: 10.3-44.1%). The association between the competitive ELISA results in dogs less than 12 month old and older dogs was significant (P=0.042). To our knowledge this is the first large scale parasitological survey of the Aboriginal community dogs and wild dogs from Australia. The high prevalence of N. caninum infection in Aboriginal community dogs illustrates that horizontal transmission of N. caninum is occurring in Australia. These results demonstrated that N. caninum in dogs is widespread, including the semi-arid to arid regions of north-western New South Wales and the Northern Territory. The populations of free ranging dogs are likely to be important contributors to the sylvatic life cycle of N. caninum. PMID- 22245070 TI - In vitro lethal effect of ajowan (Trachyspermum ammi L.) essential oil on hydatid cyst protoscoleces. AB - Various chemical scolicidal agents have been used for inactivation of hydatid cyst protoscolices, but most of them are associated with adverse side effects. Since ajowan (Trachyspermum ammi) has been shown to have a number of medicinal properties, in this study the scolicidal effect of the essential oil (EO) from the fruits of this herbal plant was investigated. Ajowan EO was obtained by hydrodistillation method. Gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were employed to determine the chemical composition of the EO. Protoscoleces were exposed to various concentrations of EO (3, 5 and 10mg/mL) for 10, 20, 30, and 60 min. Viability of protoscolices was confirmed by 0.1% eosin staining. A total of 18 compounds representing 99.54% of the total oil, were identified. Thymol (50.07%), gamma-terpinene (23.92%), and p-cymene (22.9%) were found to be the major EO constituents. While the mortality rate of protoscolices in the control group was 6.67%, scolicidal power of ajowan EO at concentration of 3mg/mL was 31.34, 35.98, 45.17, and 51.58% after 10, 20, 30, and 60 min, respectively. The EO at concentration of 5mg/mL killed 51.89, 72.20, 88.64, and 100% of protoscolices after 10, 20, 30, and 60 min, respectively. One hundred percent scolicidal activity was observed with ajowan EO at concentration of 10mg/mL after 10 min of exposure. The results of this study revealed that the EO of ajowan is rich in thymol, gamma-terpinene and p-cymene, has high scolicidal power and it may be used as a natural scolicidal agent. PMID- 22245071 TI - Apparent lack of a domestic animal reservoir in Gambiense sleeping sickness in northwest Uganda. AB - The role played by domestic animals in the transmission of gambiense Human African Trypanosomosis remains uncertain. Northwest Uganda is endemic for Trypanosoma brucei gambiense. Of the 3267 blood samples from domestic animals in four counties examined by hematocrit centrifugation technique (HCT), 210 (6.4%) were positive for trypanosomes. The prevalence of animal trypanosomosis was estimated at 13.8% in Terego County, 4.2% in East Moyo County, 3.1% in Koboko County, and zero in West Moyo County. The trypanosome infection rates varied from 0.2% in goats, 3.5% in dogs, 5.0% in sheep, 7.5% in cattle, to 15.5% in pigs. DNA was extracted from the blood samples by Chelex method, Sigma and Qiagen DNA extraction Kits. A total of 417(12.8%) DNA samples tested positive by polymerase chain reaction (PCR) using T. brucei species specific primers (TBR) indicating that the DNA was of Trypanozoon trypanosomes while 2850 (87.2%) samples were TBR PCR negative. The T. brucei infection rates based on TBR-PCR were highest in pigs with 21.7%, followed by cattle (14.5%), dogs (12.4%), sheep (10.8%), and lowest in goats with 3.2%, which indicated that pigs were most bitten by infected tsetse than other domestic animals. TBR-PCR detected 6.3% more infected domestic animals that had been missed, and confirmed the 6.4% cases detected by HCT in the field. Statistical analysis done using one-way ANOVA Kruskal-Wallis test (Prism version 5.0) showed no significant difference in trypanosome infections among domestic animals using both HCT and TBR-PCR techniques in the different counties (Confidence Interval of 95%, p-values >0.05). All the 417 trypanosome DNA samples were negative by PCR using two sets of primers specific for the T. b. gambiense specific glycoprotein gene and serum resistance associated gene of T. b. rhodesiense, indicating that they were probably not from the two human infective trypanosomes. Polymerase chain reaction using primers based on ribosomal internal transcribed spacer-1 region (ITS-PCR) resolved the 417 DNA of trypanosome samples into 323 (77.5%) as single trypanosome infections due to T. brucei and 39 (9.4%) mixed infections but missed detecting 55 (13.1%) samples, possibly because of the low sensitivity of ITS-PCR as compared to TBR-PCR. The 31 mixed infections were due to T. brucei (T.b) and T. vivax (T.v); while 8 mixed infections were of T. congolense (T.c) and T. brucei but no mixed trypanosome infections with T. congolense, T. brucei, and T. vivax were detected. Statistical analysis done using one way ANOVA Kruskal-Wallis test (Prism version 5.0) to compare single and mixed trypanosome infections showed no significant difference in trypanosome infections due to single (T.v, T.b, T.c) and mixed (T.v+T.b; T.v+T.c; T.b+T.c; T.v+T.b+T.c) trypanosome species among domestic animals in the different counties using ITS-PCR technique (Confidence Interval of 95%, p-values >0.05). It was concluded that domestic animals in northwest Uganda were probably not reservoirs of T. b. gambiense and there was no infection, as yet, with T. b. rhodesiense parasites. PMID- 22245072 TI - The investigation of lipid peroxidation, anti-oxidant levels and some hematological parameters in sheep naturally infested with Wohlfahrtia magnifica larvae. AB - Wohlfahrtia magnifica is the main agent of traumatic myiasis in many central and eastern European countries as well as in the Mediterranean basin and Asian countries. The present study was aimed to investigate the effect of myiasis infestation on lipid peroxidation, antioxidant levels and several hematological parameters in the sheep naturally infested with W. magnifica larvae. A total of 38 sheep, including 19 awassi sheep naturally infested with W. magnifica larvae and 19 clinically healthy awassi sheep, were studied. The infected animals were divided into three groups depending on the number of larvae (Group 1: <50 larvae; Group 2: 50-100 larvae; Group 3: >100 larvae). In blood samples, red blood cell counts, hemoglobin, hematocrit concentration and white blood cell, neutrophil, lymphocyte, eosinophil, basophil counts, plasma malondialdehyde, erythrocyte glutathione levels and erythrocyte glutathione peroxidase activity were studied. The results revealed a marked decrease in red blood cell counts and hemoglobin concentrations along with a significant increase in white blood cell and neutrophil counts. The elevation in plasma malondialdehyde levels, a function of lipid peroxidation, established a significant difference between the control group and groups 2, 3. Decreased activity of erythrocyte glutathione peroxidase was found significant in the control group and all parasitemia. We conclude that in natural infestations with W. magnifica, as in infestation with Lucilia cuprina, there is a notable increase in inflammatory activities resulting from the movements, secretions, and toxins of the larvae and form the toxins secreted by the bacteria - which leads to an impression of anemia - and that the tissue injury results in an increase in level of free radicals in the organism. PMID- 22245073 TI - The role of combination anthelmintic formulations in the sustainable control of sheep nematodes. AB - Combinations of anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (1) to enable the effective control of nematodes in the presence of single or multiple drug resistance, and (2) to slow the development of resistance to the component anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow the development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the anthelmintics in the combination. Combinations slow the development of a resistant parasite population by reducing the number of resistant genotypes which survive treatment, because multiple alleles conferring resistance to all the component anthelmintic classes must be present in the same parasite for survival. Individuals carrying multiple resistance alleles are rarer than those carrying single resistance alleles. This enhanced efficacy leads to greater dilution of resistant genotypes by the unselected parasites in refugia, thus reducing the proportion of resistant parasites available to reproduce with other resistant adults that have survived treatment. Concerns over the use of anthelmintic combinations include the potential to select for resistance to multiple anthelmintic classes concurrently if there are insufficient parasites in refugia; the potential for shared mechanisms of resistance between chemical classes; and the pre-existing frequency of resistance alleles may be too high on some farms to warrant the introduction of certain combinations. In conclusion, anthelmintic combinations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable anthelmintic use. PMID- 22245074 TI - Phytoremediation of pyrene contaminated soils amended with compost and planted with ryegrass and alfalfa. AB - Ryegrass (Lolium perenne) and alfalfa (Medicago sativa) were planted in pots to remediate pyrene contaminated quartz sand (as a control group), alluvial and red soils amended with and without compost. The pyrene degradation percentages in quartz sand, alluvial soil, and red soil amended with compost (5%, w/w) and planted with ryegrass and alfalfa for 90 d growth were 98-99% and 97-99%, respectively, while those of pyrene in the corresponding treatments amended without compost but planted with ryegrass and alfalfa were 91-96% and 58-89%, respectively. Further, those of pyrene in the respective treatments amended with and without compost but unplanted were 54-77% and 51-63%, respectively. Pyrene contents in both roots and aboveground parts of ryegrass and alfalfa after 90 d growth in quartz sand and the two soils amended with or without compost were trace amounts. Statistical analyses for the parameters of ryegrass planted in red and alluvial soils including the concentrations of total water-soluble volatile low molecular weight organic acids, microbial population, pyrene degradation percentage, and spiked pyrene concentration show significant correlations at 5% and mostly 1% probability levels, by the analysis of variance. It was thus suggested that the interactions among the consortia of plant root exudates, microorganisms, and amended compost in rhizosphere soils could facilitate bioavailability of pyrene and subsequently enhance its dissipation. PMID- 22245075 TI - Characteristics of oxytetracycline sorption and potential bioavailability in soils with various physical-chemical properties. AB - Veterinary antibiotics are widely used for disease treatment, prevention and animal growth promoting. Frequent detection of veterinary antibiotics in environments, caused by land application of untreated or even treated antibiotics containing animal wastes, has posed the growing concern of their adverse effect on natural ecosystems. Oxytetracycline (OTC) is one of the most widely-used veterinary antibiotics in livestock industry. OTC present as a cation, zwitterions, or net negatively charged ion in soils complicates predicting its sorption characteristics and potential bioavailability and toxicity. This study was to identify soil properties influencing OTC sorption and its subsequent bioavailability in five soils with various physical-chemical properties. A solution used to determine bioavailable analytes in soils and sediments, 1 M MgCl(2) (pH 8.5), was chosen to desorb the potentially bioavailable fraction of OTC sorbed onto soils. Our results demonstrated that soils with higher illite content and permanent cation exchange capacity have higher OTC sorption capacity, but increase the availability of sorbed OTC indicated by higher release of sorbed OTC from soils into aqueous phase in 1 M MgCl(2) (pH 8.5). Reversely, soil organic matter (SOM), clay, kaolinite, variable cation exchange capacity, DCB-Fe and -Al have lower OTC sorption capacity, but decrease the release of sorbed OTC from soils into 1 M MgCl(2). These findings indicate that SOM and clay greatly influence OTC adsorption and potential availability. This study contributes significantly to our understanding of the potential bioavailability of sorbed OTC and the effects of soil properties on OTC sorption behaviors in soils. PMID- 22245076 TI - QSAR models for the removal of organic micropollutants in four different river water matrices. AB - Ozonation is an advanced water treatment process used to remove organic micropollutants (OMPs) such as pharmaceuticals and personal care products (PPCPs). In this study, Quantitative Structure Activity Relationship (QSAR) models, for ozonation and advanced oxidation process (AOP), were developed with percent-removal of OMPs by ozonation as the criterion variable. The models focused on PPCPs and pesticides elimination in bench-scale studies done within natural water matrices: Colorado River, Passaic River, Ohio River and Suwannee synthetic water. The OMPs removal for the different water matrices varied depending on the water quality conditions such as pH, DOC, alkalinity. The molecular descriptors used to define the OMPs physico-chemical properties range from one-dimensional (atom counts) to three-dimensional (quantum-chemical). Based on a statistical modeling approach using more than 40 molecular descriptors as predictors, descriptors influencing ozonation/AOP were chosen for inclusion in the QSAR models. The modeling approach was based on multiple linear regression (MLR). Also, a global model based on neural networks was created, compiling OMPs from all the four river water matrices. The chemically relevant molecular descriptors involved in the QSAR models were: energy difference between lowest unoccupied and highest occupied molecular orbital (E(LUMO)-E(HOMO)), electron affinity (EA), number of halogen atoms (#X), number of ring atoms (#ring atoms), weakly polar component of the solvent accessible surface area (WPSA) and oxygen to carbon ratio (O/C). All the QSAR models resulted in a goodness-of-fit, R(2), greater than 0.8. Internal and external validations were performed on the models. PMID- 22245077 TI - Removal of silver nanoparticles in simulated wastewater treatment processes and its impact on COD and NH(4) reduction. AB - The increasing utilization of silver nanoparticles in industrial and consumer products has raised concern to wastewater treatment utilities due to its antimicrobial activity. In this work, the removal of citrate stabilized silver nanoparticles (Ag-NPs) during the wastewater treatment processes and its impact on treatment performance were examined. During simulated primary clarification, over 90% of the Ag-NPs remained in the wastewater, indicating that the majority of silver nanoparticles in sewage would enter the subsequent treatment units. During sequencing batch reactor processes, silver nanoparticles were effectively removed in each cycle throughout the 15-d experimental duration. Continuous input of silver nanoparticles into the wastewater did not significantly alter chemical oxygen demand (COD) removal. NH(4) removal was reduced at the beginning of the SBR experiment but quickly recovered at the later stage of the experiment. This study demonstrated that in the near future it is unlikely that citrate-stabilized Ag-NPs released into sewage will cause significant adversary effects on the COD and NH(4) removal of activated sludge processes in municipal wastewater treatment plants. PMID- 22245079 TI - Physalin B from Physalis angulata triggers the NOXA-related apoptosis pathway of human melanoma A375 cells. AB - Melanoma is a lethal form of skin cancer that can metastasize rapidly. While surgery and radiation therapy provide palliative therapy for local tumor growth, systemic therapy is the mainstay of treatment for metastatic melanoma. However, limited chemotherapeutic agents are available for melanoma treatment. In this study, we investigated the anti-melanoma effect of physalin B, the major active compound from a widely used herb medicine, Physalis angulata L. This study demonstrated that physalin B exhibits cytotoxicity towards v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma A375 and A2058 cells (the IC50 values are lower than 4.6 MUg/ml). Cytotoxicity is likely resulted from apoptosis since the apoptotic marker phosphatidylserine are detected immediately under physalin B treatment and apoptotic cells formation. Further examination revealed that physalin B induces expression of the proapoptotic protein NOXA within 2 h and later triggers the expression of Bax and caspase-3 in A375 cells. These results indicate that physalin B can induce apoptosis of melanoma cancer cells via the NOXA, caspase-3, and mitochondria-mediated pathways, but not of human skin fibroblast cells and myoblastic cells. Thus, physalin B has the potential to be developed as an effective chemotherapeutic lead compound for the treatment of malignant melanoma. PMID- 22245078 TI - Index of the transmissible common liability to addiction: heritability and prospective associations with substance abuse and related outcomes. AB - BACKGROUND: Substance use disorders (SUDs) are highly comorbid and exhibit a relatively late onset. As such, many behaviors and personality traits present prior to the initiation of substance use can be used to predict later SUDs. The transmissible liability index (TLI) is a quantitative measure of such behaviors that indexes the common liability to SUDs. We examined the predictive utility and heritability of the TLI in a large community twin sample. METHODS: Using the Minnesota Twin Family Study (N=2510), we estimated TLI scores from mother, child, and teacher reports of symptom and personality measures assessed at age 11. We then estimated the genetic and environmental contributions to the association between TLI scores at age 11 and composite measures of substance abuse and behavioral disinhibition (antisocial behavior) at age 17. RESULTS: For both male and female twins, TLI scores were highly heritable (.76) and exhibited moderate associations with adolescent substance abuse (r=.29) and behavioral disinhibition (r=.40). Genetic factors accounted for the association between TLI scores and the adolescent outcomes. CONCLUSIONS: Findings support the utility of the TLI as a measure of the inherited, common liability to SUDs. PMID- 22245080 TI - Oral biodrug delivery using cell-penetrating peptide. AB - During the past few decades, the novel biotherapeutic agents such as peptides and proteins have been contributed to the treatment of several diseases. However, their oral absorption is significantly limited due to their poor delivery through the intestinal mucosa. Therefore, the feasible approaches are needed for improving the oral bioavailability of biodrugs. Recently, cell-penetrating peptides (CPPs) such as HIV-1 Tat, penetratin and oligoarginine are considered as a useful tool for the intracellular delivery of therapeutic macromolecules. Hence, it was expected that the ability of CPPs may be applicable to enhance the absorption of biodrugs through intestinal epithelial membrane. CPPs are likely to become powerful tools for overcoming the low permeability of therapeutic peptides and proteins through the intestinal membrane, the major barrier to their oral delivery. Further advantage of this promising strategy is that this successful intestinal absorption could be achieved by more convenient methodology, coadministration of CPP with drugs via intermolecular interaction among them. Hereafter, the further establishment of delivery system based on CPPs is required to realize the development of the oral forms of therapeutic peptides and proteins. The aim here is to introduce our vision focusing on oral biodrug delivery by the use of CPPs as potential peptide carrier in order to provide new information in the design and development of new oral delivery systems for novel biotherapeutics. PMID- 22245081 TI - Antiparasitic antioxidant phenylpropanoids and iridoid glycosides from Tecoma mollis. AB - A radical scavenging guided phytochemical study on the stem bark of Tecoma mollis afforded seven active phenylpropanoid glycosides (1-7), including a new one (4), and one iridoid (8). The structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Compounds (1-7) displayed promising antioxidant activity (DPPH assay) in relation to ascorbic acid (positive control). The antimicrobial activity for compounds (1 8) was evaluated against five bacterial and five fungal strains. The isolated compounds exhibited nonselective weak to moderate antimicrobial activity. The highest antileishmanial activity against Leishmania donovani was observed for compound (7) with an IC50 value of 6.71 MUg/ml, using pentamidine and amphotericin B as drug controls. Compound (5) exhibited moderate antimalarial activity (45% inhibition) against chloroquine sensitive (D6) clones of Plasmodium falciparum. PMID- 22245082 TI - Trichalasins C and D from the plant endophytic fungus Trichoderma gamsii. AB - Two new cytochalasans, trichalasins C (1) and D (2) together with known cytochalasans aspochalasins D (3), M (4) and P (5) were isolated from one endophytic fungus Trichoderma gamsii inhabiting in traditional medicinal plant Panax notoginseng (BurK.) F.H.Chen. The structures for the new compounds 1 and 2 were determined by NMR and HRESIMS, and their relative configurations were established by analysis of coupling constants and NOESY correlations. Compound 3 displaying inhibitory activity with EC50 value 5.72 MUM, whereas the EC50 values for compounds 1, 2 and 4, 5 are more than 40 MUM. PMID- 22245083 TI - Ent-trachyloban-19-oic acid isolated from Iostephane heterophylla as a promising antibacterial agent against Streptococcus mutans biofilms. AB - From the roots of Iostephane heterophylla, six known compounds, namely, ent trachyloban-19-oic acid (1), the mixture of ent-kaur-16-en-19-oic acid (2) and ent-beyer-15-en-19-oic acid (3), xanthorrhizol (4), 16alpha-hydroxy-ent-kaurane (5) and 16alpha-hydroxy-ent-kaur-11-en-19-oic acid (6) were isolated using a bioassay-guided fractionation method. The known compounds (1-6) were identified by comparison of their spectroscopic data with reported values in the literature. In an attempt to increase the resultant antimicrobial activity of 1 and 4, a series of reactions was performed on ent-trachyloban-19-oic acid (1) and xanthorrhizol (4), to obtain derivatives 1a, 1b, and 4a-4d. All the isolated compounds (1-6) and the derivatives 1a, 1b, and 4a-4d were evaluated for their antimicrobial activity against two oral pathogens, Streptococcus mutans and Porphyromonas gingivalis associated with caries and periodontal disease, respectively. Compounds 1, 1b, 2+3, 4 and 4d inhibited the growth of S. mutans with concentrations ranging from 4.1 MUg/mL to 70.5 MUg/mL. No significant activity was found on P. gingivalis except for 4 with an MIC of 6.8 MUg/mL. The ability of 1, 1b, 2+3, 4 and 4d to inhibit biofilm formation by S. mutans was evaluated. It was found that 1, 1b, 4 and 4d interfered with the establishment of S. mutans biofilms, inhibiting their development at 32.5, 125.0, 14.1 and 24.4 MUg/mL, respectively. PMID- 22245084 TI - Pharmacokinetic study of baicalein after oral administration in monkeys. AB - Baicalein, a flavonoid originally isolated from the root of Scutellaria baicalensis Georgi, has numerous pharmacological activities. Up to now, several studies regarding the pharmacokinetic profiles of baicalein have been described, while there is no such study reported in monkey, the species which is more similar to human. The purpose of this study was to investigate the pharmacokinetic profiles of baicalein after oral administration in monkeys. After orally administrating three doses of baicalein in monkeys, multi-peaks of the plasma concentration-time curves were observed and the non-linear pharmacokinetics for baicalein and its metabolite baicalin were found at doses of 50-500mg/kg. In order to calculate the absolute bioavailability, the intravenous pharmacokinetic study was also carried out after intravenous administration of 10mg/kg baicalein. The absolute bioavailability of baicalein in different doses was ranged from 13.1% to 23.0%. In this study, baicalein and baicalin were determined by LC-MS method. The chromatographic separation was performed on Agilent Poroshell 120 SB-C18 column (2.7MUm, 2.1*50mm). Baicalein and baicalin were detected by single quadrupole mass spectrometer equipment with electrospray ionization interface with the selected ion monitoring mode. The assay was linear for both baicalein and baicalin with the correlation coefficients>0.99. The intra and inter-day precisions for baicalein and baicalin were all less than 15% by relative standard deviation. The analytes were stable during samples storage and handling, and no matrix effects were observed. The method we developed in this study was sensitive, precise, stable and producible. PMID- 22245085 TI - Synergistic antibiotic activity of volatile compounds from the essential oil of Lippia sidoides and thymol. AB - Lippia sidoides Cham. (Verbenaceae) is used in the folk medicine as topical antiseptic in skin and mucous membranes and its therapeutic effect is attributed to the thymol presence. The objective of this work was to verify the chemical composition and antibiotic modifying activity of the essential oil extracted from the leaves of L. sidoides and its major component thymol. The essential oil was obtained by hydrodistillation and analyzed by GC/MS. The synergistic activity was evaluated using gaseous contact method. The essential oil was obtained (yield of 1.06%) and the GC/MS analysis identified the main constituents: thymol (84.9%) and p-cymene (5.33%). The antibiotic modifying activity was verified using the minimal inhibitory dose method and gaseous contact. It verified the interference of essential oil and thymol against all tested aminoglycosides. There were no statistical differences between the activity of the essential oil and thymol against Pseudomonas aeruginosa, indicating this to be the responsible composition for such activity. However, the oil was shown more effective when compared to the thymol against Staphylococcus aureus. The essential oil of L. sidoides and its major component thymol influence the activity of aminoglycosides and may be used as adjuvant in antibiotic therapy against respiratory tract bacterial pathogens. PMID- 22245086 TI - Sesquiterpenes inhibiting NO production from Celastrus orbiculatus. AB - Two new (1 and 2) and one known (3) beta-dihydroagarofuran sesquiterpenes were isolated from the fruits of Celastrus orbicultus Thunb. Their structures were elucidated as 1beta,13-diacetoxy-8beta,9beta-dibenzoyloxy-beta-dihydroagarofuran (1), 1beta,13-diacetoxy-8alpha-hydroxy-9beta-benzoyloxy-beta-dihydroagarofuran (2), and 1beta,6alpha,13-triacetoxy-9alpha-benzoyloxy-beta-dihydroagarofuran (3), on the basis of spectroscopic data analyses. All the compounds exhibited inhibitory effects on LPS-induced nitric oxide production in murine microglial BV 2 cells. PMID- 22245087 TI - Chemical constituents from the fruits of Gardenia jasminoides Ellis. AB - A new lignan glucoside, (+)-(7S,8R,8'R)-lyoniresinol 9-O-beta-D-(6"-O-trans sinapoyl)glucopyranoside (1), and a new iridoid glucoside, 10-O-trans sinapoylgeniposide (2), together with eight known compounds, were isolated from the fruits of Gardenia jasminoides Ellis. The structures of the isolates were elucidated by extensive spectroscopic studies, including UV, IR, 1D and 2D NMR, ESI-MS, HR-ESI-MS, and CD experiments. The short-term-memory-enhancement activities of some compounds were evaluated on an Abeta transgenic drosophila model. PMID- 22245088 TI - Antiproliferative steroidal glycosides from Digitalis ciliata. AB - Two new compounds, a furostanol glycoside (1) and a pregnane glycoside (4), along with eight known compounds, belonging to the classes of spirostane (2,3), pregnane (5-7) and cardenolide (8-10) glycosides, were isolated from the seeds of Digitalis ciliata. Their structures were elucidated by 1D and 2D-NMR experiments as well as ESI-MS analysis. For the first time pregnane glycosides of the diginigenin series have been isolated from D. ciliata. The cytotoxic effects of compounds 1-10 on cell viability of several cancer cell lines, namely human breast cancer (MCF-7), human glioblastoma (T98G), human lung adenocarcinoma (A549), human colon carcinoma (HT-29), and human prostate cancer (PC-3) cell lines were evaluated. Compounds 1, 4, 7 and 8 showed antiproliferative effects against MCF-7, HT-29 and A549 cancer cells with IC50 values ranging from 8.3 to 20 MUM. The effects of compounds 1-10 on cell proliferation were evaluated on these three cancer cell lines by cell cycle analysis of DNA content using flow cytometry. Compounds 7, 8 and 10 induced significant changes in G2/M cell cycle phase of all analyzed cells. The obtained results indicate that compounds 7, 8 and 10 are cytostatic compounds effective in reducing cell proliferation by inducing accumulation of the cells in the G2/M phase of the cell cycle. PMID- 22245089 TI - Isolation, stability and bioactivity of Jatropha curcas phorbol esters. AB - Jatropha curcas seed oil, which can be utilized for biodiesel production upon transesterification, is also rich in phorbol esters (PEs). In this study, PEs from J. curcas oil (Jatropha factors C1 and C2 (purified to homogeneity), Jatropha factors C3 and (C4+C5) (obtained as mixtures) and PE-rich extract (containing all the above stated Jatropha factors) were investigated. The concentrations of Jatropha PEs were expressed equivalent to Jatropha factor C1. In the snail (Physa fontinalis) bioassay, the order of potency (EC50, MUg/L) was: PE-rich extractmRNA->condition' at the post-transcriptional level. PMID- 22245100 TI - Non-obstructive low attenuation coronary plaque predicts three-year acute coronary syndrome events in patients with hypertension: multidetector computed tomographic study. AB - BACKGROUND: Arterial hypertension is an established risk factor for acute coronary syndrome (ACS). Multidetector computed tomography (MDCT) is an accurate and less invasive technique for assessment of the degree of coronary artery luminal narrowing and characterization of coronary atherosclerosis. We therefore aimed to investigate the predictive power of MDCT for future ACS events and compared with traditional parameters in patients with hypertension. METHODS: One hundred and thirty-four patients (93 men, mean age 70+/-11 years) with hypertension underwent MDCT for evaluation of coronary artery disease. MDCT analysis focused on the presence of plaques, the degree of stenosis, and the plaque characteristics. Traditional parameters included Framingham risk score, carotid intima-media thickness, and left ventricular mass index. RESULTS: During a mean follow-up of 39+/-10 months, ACS events occurred in 10 patients, including myocardial infarction (n=3) and unstable angina (n=7). Multivariate analysis identified total number of low attenuation plaques as an independent predictor of ACS events (p<0.001). CONCLUSION: We demonstrated that non-obstructive low attenuation coronary plaques on MDCT predicted more accurately future ACS events in patients with hypertension than traditional parameters. PMID- 22245101 TI - Prolonged hypocalcemia after zoledronic acid in a patient with metastatic prostate carcinoma: did zoledronic acid trigger osteoblastic activity and avid calcium uptake? PMID- 22245102 TI - Protein kinase D1 stimulates proliferation and enhances tumorigenesis of MCF-7 human breast cancer cells through a MEK/ERK-dependent signaling pathway. AB - Protein kinase D1, PKD1, is a novel serine/threonine kinase whose altered expression and dysregulation in many tumors as well as its activation by several mitogens suggest that this protein could regulate proliferation and tumorigenesis. Nevertheless, the precise signaling pathways used are still unclear and the potential direct role of PKD1 in tumor development and progression has not been yet investigated. In order to clarify the role of PKD1 in cell proliferation and tumorigenesis, we studied the effects of PKD1 overexpression in a human adenocarcinoma breast cancer cell line, MCF-7 cells. We demonstrated that overexpression of PKD1 specifically promotes MCF-7 cell proliferation through accelerating G0/G1 to S phase transition of the cell cycle. Moreover, inhibition of endogenous PKD1 significantly reduced cell proliferation. Taken together, these results clearly strengthen the regulatory role of PKD1 in cell growth. We also demonstrated that overexpression of PKD1 specifically diminished serum- and anchorage-dependence for proliferation and survival in vitro and allowed MCF-7 cells to form tumors in vivo. Thus, all these data highlight the central role of PKD1 in biological processes which are hallmarks of malignant transformation. Analysis of two major signaling pathways implicated in MCF-7 cell proliferation showed that PKD1 overexpression significantly increased ERK1/2 phosphorylation state without affecting Akt phosphorylation. Moreover, PKD1 overexpression-stimulated cell proliferation and anchorage-independent growth were totally impaired by inhibition of the MEK/ERK kinase cascade. However, neither of these effects was affected by blocking the PI 3-kinase/Akt signaling pathway. Thus, the MEK/ERK signaling appears to be a determining pathway mediating the biological effects of PKD1 in MCF-7 cells. Taken together, all these data demonstrate that PKD1 overexpression increases the aggressiveness of MCF-7 breast cancer cells through enhancing their oncogenic properties and would, therefore, define PKD1 as a potentially new promising anti-tumor therapeutic target. PMID- 22245103 TI - Variability of gait is dependent on direction of progression: implications for active control. AB - Typical healthy walking displays greater variability in the mediolateral direction compared to the anteroposterior direction. This greater variability is thought to represent increased uncertainty in movement. As a result, it has been postulated that the mediolateral direction of gait requires more active control by the central nervous system while the anteroposterior direction is controlled through passive actions. However, this theory has only been tested on gait where progression occurs in the anteroposterior direction. Therefore, the purpose of this study was to investigate how the amount of variability is affected if progression occurs in the mediolateral direction using a lateral stepping gait. Results showed the anteroposterior direction had a significantly greater amount of variability than the mediolateral direction (p<0.001). The results do not support current models of a partition of active control to different anatomical planes. Rather, it seems that other physical entities involved in motion, such as momentum and inertia, are able to decrease the dependence on active control from the central nervous system. In a lateral stepping gait, such physical entities were no longer assisting in the anteroposterior direction but had a larger impact in the mediolateral direction as it was the direction of progression. As a result variability in the anteroposterior direction increased. Thus, it is possible to infer increased reliance on active control from the central nervous system in the direction orthogonal to progression. PMID- 22245104 TI - Delirium: a review of the nurses role in the intensive care unit. AB - AIM: This article aims to review current literature into the use of assessment tools for the diagnosis of delirium and the implications of care for the patient with delirium. BACKGROUND: Delirium is a common often misdiagnosed, unrecognised and misunderstood condition in the critical care setting that has been associated with increased mortality and cognitive dysfunction. RELEVANCE TO CLINICAL PRACTICE: Delirium has implications for increasing cost to the National Health Service as it is linked to prolonged ventilation and the associated risks and increased hospital stay. CONCLUSION: Nurses play a key role in identification of delirium using CAM-ICU, a valid and reliable tool and identifying modifiable risks to improve the delirious ICU patient's outcome. PMID- 22245105 TI - Nuclear organization and chromatin dynamics in yeast: biophysical models or biologically driven interactions? AB - Over the past decade, tremendous progress has been made in understanding the spatial organization of genes and chromosomes. Nuclear organization can be thought of as information that is not encoded in DNA, but which nevertheless impacts gene expression. Nuclear organizational influences can be cell-specific and are potentially heritable. Thus, nuclear organization fulfills all the criteria necessary for it to be considered an authentic level of epigenetic information. Chromosomal nuclear organization is primarily dictated by the biophysical properties of chromatin. Diffusion models of polymers confined in the crowded nuclear space accurately recapitulate experimental observation. Diffusion is a Brownian process, which implies that the positions of chromosomes and genes are not defined deterministically but are likely to be dictated by the laws of probability. Despite the small size of their nuclei, budding yeast have been instrumental in discovering how epigenetic information is encoded in the spatial organization of the genome. The relatively simple organization of the yeast nucleus and the very high number of genetically identical cells that can be observed under fluorescent microscopy allow statistically robust definitions of the gene and chromosome positions in the nuclear space to be constructed. In this review, we will focus on how the spatial organization of the chromatin in the yeast nucleus might impact transcription. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. PMID- 22245106 TI - Determination of ganciclovir in human plasma by ultra performance liquid chromatography-UV detection. AB - OBJECTIVES: Implement a sensitive UHPLC method for the assay of ganciclovir in human plasma. DESIGN AND METHODS: We developed and validated a chromatographic method coupled to ultraviolet detection for quantification of ganciclovir, with a short run time using a small volume of human plasma. Comparison of system performance was made with respect to analysis time, efficiency and sensitivity. RESULTS: Correlation coefficients (r) of the calibration curves ranged from 0.999744 to 0.999784. Within-day and between-day imprecision and inaccuracy, specificity and recovery were also evaluated for validation. The method was precise and accurate and the retention time was 0.7 min. The calibration curves were linear between 0.5 and 30 MUg/mL. There was a good correlation between HPLC and UHPLC techniques. CONCLUSIONS: We developed a method that is currently applied in a clinical study assessing GCV plasma concentration variability after ganciclovir and valganciclovir administration. PMID- 22245107 TI - Clastogenic and mutagenic effects of bisphenol A: an endocrine disruptor. AB - Bisphenol A (BPA) is a well-known endocrine disruptor (ED) which represents a major toxicological and public health concern due to its widespread exposure to humans. BPA has been reported to induce DNA adduct and aneuploidy in rodents. Recent studies in humans depicted its association with recurrent miscarriages and male infertility due to sperm DNA damage indicating that BPA might have genotoxic activity. Hence, the present study was designed to determine genotoxic and mutagenic effects of BPA using in-vivo and in-vitro assays. The adult male and female rats were orally administered with various doses of BPA (2.4 MUg, 10 MUg, 5mg and 50mg/kgbw) once a day for six consecutive days. Animals were sacrificed, bone marrow and blood samples were collected and subjected to series of genotoxicity assay such as micronucleus, chromosome aberration and single cell gel electrophoresis (SCGE) assay respectively. Mutagenicity was determined using tester strains of Salmonella typhimurium (TA 98, TA 100 and TA 102) in the presence and absence of metabolically active microsomal fractions (S9). Further, we estimated the levels of 8-hydroxydeoxyguanosine, lipid per-oxidation and glutathione activity to decipher the potential genotoxic mechanism of BPA. We observed that BPA exposure caused a significant increase in the frequency of micronucleus (MN) in polychromatic erythrocytes (PCEs), structural chromosome aberrations in bone marrow cells and DNA damage in blood lymphocytes. These effects were observed at various doses tested except 2.4 MUg compared to vehicle control. We did not observe the mutagenic response in any of the tester strains tested at different concentrations of BPA. We found an increase in the level of 8 hydroxydeoxyguanosine in the plasma and increase in lipid per-oxidation and decrease in glutathione activity in liver of rats respectively which were exposed to BPA. In conclusion, the data obtained clearly documents that BPA is not mutagenic but exhibit genotoxic activity and oxidative stress could be one of the mechanisms leading to genetic toxicity. PMID- 22245108 TI - Combination effects of chronic cadmium exposure and gamma-irradiation on the genotoxicity and cytotoxicity of peripheral blood lymphocytes and bone marrow cells in rats. AB - This work investigated the effects of chronic cadmium (Cd) exposure combined with gamma-ray irradiation on the cytotoxicity and genotoxicity of peripheral blood cells and bone marrow cells in rats. Results showed that when the rats were exposed to low dose (LD) Cd of 0.1mg CdCl2/(kgd) for 8 and 12 weeks, the Cd concentration in blood reached to 135-140 MUg/L and no toxic effects on peripheral blood lymphocytes, white blood cells (WBC) and granulocyte-monocyte (GM) progenitor cells were observed except polychromatic erythrocytes (PCE) of bone marrow. Moreover, this chronic LD Cd exposure significantly decreased irradiation-induced micronucleus (MN) formation and hypoxanthine-guanine phosphoribosyl transferase (hprt) mutation in lymphocytes and PCE, while the combination of LD Cd exposure and irradiation induced the additive metallothionein (MT) protein expression in bone marrow cells. When the rats were exposed to a high dose (HD) Cd of 0.5mg CdCl/2(kgd) for 8 and 12 weeks, the blood Cd level approached to 458-613 MUg/L and an inflammatory response was induced, meanwhile, MN formation and hprt mutation were markedly increased, and the ratio of PCE/NCE (normochromatic erythrocyte) was significantly decreased. Furthermore, when the rats were exposed to HD Cd plus 2 Gy irradiation, additive toxic effects on MN formation, hprt mutation, PCE damage and GM progenitor cell proliferation were observed, while this combination treatment resulted in an obvious reduction of MT protein compared to HD Cd group. In conclusion, chronic exposure to LD Cd induced the adaptive response to irradiation in the genotoxicity of peripheral blood lymphocytes and PCE of bone marrow by the up-regulation of Cd-induced MT protein, but the combination of HD Cd exposure and irradiation generated the additive effects on the cytotoxicity and genotoxicity in peripheral blood lymphocytes and bone marrow cells. PMID- 22245109 TI - Environmental exposure to benzene, micronucleus formation and polymorphisms in DNA-repair genes: a pilot study. AB - This report is part of a biomarker study conducted in an Italian population with exposure to environmental benzene ranging from 1.43 to 31.41 MUg/m3 (values from personal sampling). DNA damage induced by benzene is the crucial mechanism of its genotoxicity, which leads to chronic benzene poisoning, haematotoxicity and leukaemia. Therefore, genetic variation in DNA-repair genes may modulate susceptibility to benzene-induced DNA damage. In light of this, the effects of polymorphisms in DNA-repair genes (APEX1, hOGG1, NBS1, XPD, XRCC1, and XRCC3) on micronucleus (MN) formation as a biomarker of early biological effects were evaluated. A significantly higher median MN frequency was recorded in traffic wardens than in controls. However, none of the analysed polymorphisms was significantly associated with the median MN frequency. A gene-gender interaction was observed for the APEX1 genotype. The APEX1 variant genotype was associated with significantly lower median MN frequency in men, not in women. Statistical analysis did not reveal any association between the score of the protective alleles - hypothetically pushing the pathway towards optimal DNA-damage repair - and MN. Even though there are some limitations in the study, our results indicate that the general population may be exposed to benzene concentrations higher than the threshold level for air-quality standards in the European Union of 10 MUg/m3. Furthermore, urban traffic wardens are exposed to significantly higher levels of benzene than individuals spending most of the time indoors. This higher exposure may contribute to DNA damage, suggesting that benzene might be implicated both as an environmental and occupational risk factor in leukaemia and other haematological diseases. In conclusion, this study suggest the need for (i) regular monitoring of traffic wardens for possible exposure to benzene, as a precautionary step to reduce the associated health risks, and (ii) more comprehensive studies in order to better elucidate the involvement of APEX1 genotypes in benzene genotoxicity. PMID- 22245110 TI - The effect of mother-infant skin-to-skin contact on infants' response to the Still Face Task from newborn to three months of age. AB - The effect of mother-infant skin-to-skin contact on infants' developing social expectations for maternal behavior was investigated longitudinally over infants' first 3 months. Infants with and without skin-to-skin contact engaged with their mothers in the Still Face Task at ages 1 week, 1 month, 2 months, and 3 months. Infants with skin-to-skin contact began responding to changes in their mothers' behavior with their affect at 1 month; infants without skin-to-skin contact did so at 2 months. At 3 months, infants with skin-to-skin contact increased their non-distress vocalizations during the still face phase, suggesting social bidding to their mothers. Skin-to-skin contact accelerated infants' social expectations for their mothers' behavior and enhanced infants' awareness of themselves as active agents in social interactions. PMID- 22245111 TI - Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. AB - Lysine-specific demethylase 1 (GeneID 23028), a flavin-dependent monoamine oxidoreductase and a histone demethylase, serves as an epigenetic coregulator of transcription. Lysine-specific demethylase 1 is up-regulated in neuroblastoma and in bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers, and its overexpression drives the cell cycle of otherwise nontransformed human cells, suggesting oncogenic properties. Lysine-specific demethylase 1 was recently reported to be also overexpressed in several different mesenchymal tumors. We investigated lysine-specific demethylase 1 expression in over 500 sarcomas by gene expression profiling and tissue microarray-coupled immunohistochemical analyses and confirmed lysine-specific demethylase 1 overexpression in rhabdomyosarcoma and synovial sarcoma. We also show for the first time that lysine-specific demethylase 1 is also overexpressed in chondrosarcoma, Ewing's sarcoma, and osteosarcoma wherein it localizes in cell nuclei. We further show that a US Food and Drug Administration-approved drug that inhibits lysine specific demethylase 1 also inhibits chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma cell growth in vitro. These data suggest that lysine-specific demethylase 1 plays a role in sarcoma pathology and that lysine specific demethylase 1 inhibition strategies might represent a novel means to inhibiting growth of lysine-specific demethylase 1-overexpressing sarcomas. PMID- 22245112 TI - Mouse germ cell clusters form by aggregation as well as clonal divisions. AB - After their arrival in the fetal gonad, mammalian germ cells express E-cadherin and are found in large clusters, similar to germ cell cysts in Drosophila. In Drosophila, germ cells in cysts are connected by ring canals. Several molecular components of intercellular bridges in mammalian cells have been identified, including TEX14, a protein required for the stabilization of intercellular bridges, and several associated proteins that are components of the cytokinesis complex. This has led to the hypothesis that germ cell clusters in the mammalian gonad arise through incomplete cell divisions. We tested this hypothesis by generating chimeras between GFP-positive and GFP-negative mice. We show that germ cell clusters in the fetal gonad arise through aggregation as well as cell division. Intercellular bridges, however, are likely restricted to cells of the same genotype. PMID- 22245113 TI - A model-based tool to predict the propagation of infectious disease via airports. AB - Epidemics of novel or re-emerging infectious diseases have quickly spread globally via air travel, as highlighted by pandemic H1N1 influenza in 2009 (pH1N1). Federal, state, and local public health responders must be able to plan for and respond to these events at aviation points of entry. The emergence of a novel influenza virus and its spread to the United States were simulated for February 2009 from 55 international metropolitan areas using three basic reproduction numbers (R(0)): 1.53, 1.70, and 1.90. Empirical data from the pH1N1 virus were used to validate our SEIR model. Time to entry to the U.S. during the early stages of a prototypical novel communicable disease was predicted based on the aviation network patterns and the epidemiology of the disease. For example, approximately 96% of origins (R(0) of 1.53) propagated a disease into the U.S. in under 75 days, 90% of these origins propagated a disease in under 50 days. An R(0) of 1.53 reproduced the pH1NI observations. The ability to anticipate the rate and location of disease introduction into the U.S. provides greater opportunity to plan responses based on the scenario as it is unfolding. This simulation tool can aid public health officials to assess risk and leverage resources efficiently. PMID- 22245114 TI - The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases. AB - GNAS mutations have been implicated in the development of fibrous dysplasia and multiple endocrinopathies of the Albright-McCune syndrome. To investigate the diagnostic utility of GNAS mutations in patients with fibrous dysplasia, we performed mutational analyses of histologically confirmed fibrous dysplasia and conducted a meta-analysis of the literature. We collected 48 cases of fibrous dysplasia from 3 institutions from 2002 to 2011 and performed polymerase chain reaction and direct bidirectional sequencing of exons 8 and 9 of GNAS using paraffin-embedded tissues. We searched MEDLINE, PubMed, and the KoreaMed databases from 1997 to 2011 and included an additional 155 cases of fibrous dysplasia from 8 representative studies to conduct a meta-analysis. In our sample, 28 (58.3%) of 48 cases showed point mutations of codon 201 at exon 8. Twenty-five cases had a substitution of arginine at codon 201 for histidine (p.R201H), and 3 cases had a substitution for cysteine (p.R201C). One case had a new mutation at codon 224 (p.V224A). The incidence of GNAS mutations was significantly greater in cases that involved long bones than in cases that involved flat bones (P = .017) and was higher in polyostotic cases than in monostotic cases (P = .067). In meta-analysis, 9 studies and 203 patients were included. The overall positive rate of GNAS mutation in fibrous dysplasia was 71.9% (146/203). The major types of mutations were missense mutations such as R201H (66.4%) and R201C (30.8%). As a result, the detection of GNAS mutation could be a valuable adjunct to conventional histopathologic diagnosis of fibrous dysplasia. PMID- 22245115 TI - Reflections on a challenging year. PMID- 22245116 TI - Monocyte-derived dendritic cells enhance cell proliferation and porcine circovirus type 2 replication in concanavalin A-stimulated swine peripheral blood lymphocytes in vitro. AB - Dendritic cells (DCs) are professional antigen presenting cells cooperating with other immune cells for the activation of innate and adaptive immune responses. The objective of the present study was to investigate the replication activity of porcine circovirus type 2 (PCV2) in DCs and/or lymphocytes during their cross talk and its possible mechanism. Two models were set, herein. Swine blood monocyte (Mo)-derived DCs (MoDCs) or peripheral blood lymphocytes (PBLs) were inoculated with PCV2 prior to their co-cultivation. Bacterial lipopolysaccharide (LPS) and concanavalin A (Con A) were used to stimulate MoDCs and PBLs, respectively. During 6 days of cultivation, a high PCV2 antigen-containing rate without detectable intranuclear signals and a slight but significant increase in the copy number of PCV2 genome were detected in PCV2-inoculated MoDCs. The presence of LPS alone or PCV2-free PBLs, however, had no effect on the location of PCV2 antigens or copy number of PCV2 genome in PCV2-inoculated MoDCs. On the contrary, active PCV2 replication occurred in Con A-stimulated PCV2-inoculated PBLs. When compared with blood Mos, MoDCs induced significantly higher cell proliferation and intensified PCV2 replication in Con A-stimulated PCV2 inoculated PBLs, for which direct contact between MoDCs and lymphocytes was required. Among the cytokines secreted by Con A-activated PBLs, interleukin (IL) 2, but not IL-4 or interferon-gamma, could induce cell proliferation and PCV2 replication in PCV2-inoculated PBLs. The findings suggest that although MoDCs support only limited PCV2 replication in themselves, their accessory cell function is required for cell proliferation and PCV2 replication in PCV2-infected lymphocytes. PMID- 22245117 TI - Nosocomial outbreak of Pantoea agglomerans bacteraemia associated with contaminated anticoagulant citrate dextrose solution: new name, old bug? AB - We describe an outbreak investigation of Pantoea agglomerans bacteraemia associated with anticoagulant citrate-dextrose 46% (ACD) solution prepared in house. A healthy man presented with septic shock during plasmapheresis for granulocyte donation. The solution used for priming and blood samples were sent for culture. Identification of the isolate to species level was performed by gyrB sequencing. Typing was performed by pulsed-field gel electrophoresis (PFGE). In total, eight cases were identified during a three-week period. P. agglomerans was also cultured from six ACD solution bags. Isolates from patients and ACD bags were identical by PFGE. All isolates were susceptible to ampicillin, cephazolin, gentamicin, ciprofloxacin, cefepime and imipenem. PMID- 22245118 TI - Providing strong evidence of nosocomial outbreak of hepatitis B virus infection. PMID- 22245119 TI - Isolation, expansion and characterisation of alloreactive human Th17 and Th1 cells. AB - Interleukin 17 producing T helper cells (Th17) and IFNgamma producing Th1 cells are distinct subsets of effector memory CD4(+) T cells that are crucial to host immunity and have been linked to the pathology of certain inflammatory autoimmune diseases. We have developed a method for the isolation and long term culture of human Th17 and Th1 cells. Using allogeneic stimulation we have cultured homogeneous populations of Th17 and Th1 cells to large cell numbers. These alloreactive cell lines were established from CD4(+)CD45RO(+) memory T cells expressing, or lacking, CCR6 and CCR4. The Th17 cells were derived only from cells expressing both CCR6 and CCR4 whereas the Th1 cells, secreting IFNgamma, were derived from cells lacking CCR6 and CCR4. The CCR6(+) and CCR4(+) memory T cells also gave rise to a third population of polyfunctional cells expressing both IL-17 and IFNgamma. All cell populations expressed the TCR alphabeta and the Th17 cells characteristically expressed CCR6, CCR4 and CD161. The use of this protocol will ultimately allow for the comparative analysis of the Th17 and Th1 cells. PMID- 22245120 TI - Alterations in c-Src/HER1 and estrogen receptor alpha signaling pathways in mammary gland and tumors of hexachlorobenzene-treated rats. AB - Hexachlorobenzene (HCB) is an organochlorine pesticide that acts as an endocrine disruptor in humans and rodents. The development of breast cancer strongly depends on endocrine conditions modulated by environmental factors. We have demonstrated that HCB is a tumor co-carcinogen in rats and an inducer of proliferation in MCF-7 cells, in an estrogen receptor alpha (ERalpha)-dependent manner, and of migration in MDA-MB-231 breast cancer cell line. In the present study, we examined HCB effect on c-Src/human epidermal growth factor receptor (HER1) and ERalpha signaling pathways in mammary glands and in N-nitroso-N methylurea (NMU)-induced mammary tumors in rats. Furthermore, we evaluated histopathological changes and serum hormone levels. Rats were separated into four groups: control, HCB (100 mg/kg b.w.), NMU (50 mg/kg b.w.) and NMU-HCB. Our data show that HCB increases c-Src and HER1 activation, c-Src/HER1 association, and Y699-STAT5b and ERK1/2 phosphorylation in mammary glands. HCB also enhances Y537 ERalpha phosphorylation and ERalpha/c-Src physical interaction. In tumors, HCB also induces c-Src and HER1 activation, c-Src/HER1 association, as well as T308 Akt and Y699-STAT5b phosphorylation. In addition, the pesticide increases ERalpha protein content and decreases p-Y537-ERalpha levels and ERalpha/c-Src association in tumors. HCB increases serum 17-beta estradiol and prolactin contents and decreases progesterone, FSH and LH levels in rats without tumors, while the opposite effect was observed in rats with tumors. Taken together, our results indicate that HCB induces an estrogenic effect in mammary gland, increasing c Src/HER1 and ERalpha signaling pathways. HCB stimulates c-Src/HER1 pathway, but decreases ERalpha activity in tumors, appearing to shift them towards a higher malignancy phenotype. PMID- 22245121 TI - Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from increased expression of xenosensor nuclear receptors PPARalpha and CAR/PXR. AB - The present study investigated the potential role for activation of PPARalpha and CAR/PXR by potassium PFOS (K+ PFOS) with respect to the etiology of hepatic hypertrophy and hepatocellular adenoma in rats. Male Sprague-Dawley rats were fed K+ PFOS (20 or 100 ppm) for either 1, 7, or 28 days. Wyeth 14,643 (Wy 14,643, 50 ppm) and phenobarbital (PB, 500 ppm) were the controls for PPARalpha and CAR/PXR activation, respectively. Measurements included: plasma ALT, AST, cholesterol, triglycerides, and glucose; liver protein and DNA content; liver activities of palmitoyl CoA oxidase (ACOX), Cyp4A, CYP2B, and CYP3A; induction of liver CYP4A1, CYP2E1, CYP2B1/2, and CYP3A1 proteins (SDS-PAGE and Western blots); liver and thyroid microscopic histopathology, apoptotic index, and cell proliferation index. Terminal body weight was decreased by K+ PFOS (100 ppm) and Wy 14,643. All test-compound treatments increased liver weight. Plasma lipids were decreased by both PFOS and Wy 14,643. After treatment for 1 day, K+ PFOS (100 ppm), PB, and Wy 14,643 increased mean hepatic DNA concentration and total hepatic DNA, and total DNA remained elevated after treatment for 7 days and 28 days (PB and Wy 14,643 only). Hepatic P450 concentration was elevated after 7 and 28 days by K+ PFOS and by PB. K+ PFOS and Wy 14,643 increased liver activities of ACOX and CYP4A as well as increased liver CYP4A1 protein. By 28 days of treatment, K+ PFOS and PB increased liver activities of CYP2B and CYP3A as well as increased liver CYP2B1/2 and CYP3A1 proteins, and Wy 14,643 increased CYP2B enzyme activity to a slight extent. All test compounds increased the liver cell proliferative index and decreased the liver apoptotic index. No histological changes of the thyroid were noted; however, PB and WY increased thyroid follicular cell proliferation index (seven-day treatment only), while K+ PFOS did not. The thyroid follicular cell apoptotic index did not differ between groups. The hepatomegaly and hepatocellular adenoma observed after dietary exposure of Sprague-Dawley rats to K+ PFOS likely are due to the increased expression of xenosensor nuclear receptors PPARalpha and CAR/PXR. Given the markedly lower or absent response of human hepatocytes to the proliferative stimulus from activation of PPARalpha and CAR/PXR, the hepatocellular proliferative response from activation of these receptors by PFOS observed in rats is not expected to be of human relevance. PMID- 22245122 TI - Effects of isolation in adulthood on frustration and anxiety. AB - In consummatory successive negative contrast (cSNC), when rats receive 32% of sweetened water and are unexpectedly exposed to 4% of the same solution, they consume less than those who received 4% regularly. In consummatory extinction (cE), rats receiving a 32% or 4% sugar solution stop lapping when presented with an empty tube. In both cases, these situations trigger an aversive emotional reaction similar to fear and anxiety called frustration or negative contrast effect. Isolation conditions in adulthood increase anxiety responses. We describe an experiment in which isolated or grouped rats in adulthood are evaluated in an elevated plus maze (EPM), in cSNC and cE. Results show that rats in groups express less anxiety and activity in EPM and more persistence in cE than isolated rats. There are no differences between the two housing conditions in cSNC. We discuss these results on the basis of frustration theories. PMID- 22245123 TI - Advanced age and comorbidity increase the risk for adverse events after revision total hip arthroplasty. AB - With the institution of quality-assurance parameters in health care, physicians must accurately measure and report the true baseline rates of adverse events (AEs) after complex surgical interventions. To better quantify the risk of AEs for revision total hip arthroplasty (THA), we divided a cohort of 306 patients (322 procedures) into age groups: group I (<65 years, n = 138), group II (65-79 years, n = 119), and group III (>=80 years, n = 65). Ninety-day rates of major AE were 9%, 19%, and 34% in the groups, respectively. Group III had an increased chance of experiencing major AE compared with groups I and II. Age and Charlson Comorbidity Index independently predicted major complications, whereas body mass index, sex, and type of revision did not. PMID- 22245124 TI - Patient perception of physician reimbursement in elective total hip and knee arthroplasty. AB - The purpose of this study was to evaluate patient perception of orthopedic surgeon reimbursement for total hip (THA) and knee (TKA) arthroplasty. A total of 1120 consecutive patients were asked what they believed a surgeon should be paid for performing THA and TKA. Patients were then asked to estimate what Medicare actually reimbursed for each of these procedures. On average, patients thought that surgeons should receive $14,358 for THA and $13,332 for TKA. Patients estimated actual Medicare reimbursement to be $8212 for THA and $7196 for TKA. Most of the patients stated that Medicare reimbursement was "much lower" than what it should be. Many patients commented that given this discrepancy, surgeons may drop Medicare, which may decrease access to quality hip and knee arthroplasties. PMID- 22245126 TI - Improving acetabular cup orientation in total hip arthroplasty by using smartphone technology. AB - Acetabular cup placement in total hip arthroplasty is often difficult to assess, especially in the lateral position and using the posterior approach. Conventional techniques and computer-assisted surgery are the 2 most popular methods for proper placement of the acetabular cup in Lewinnek's safe zone of orientation (anteversion 15 degrees +/- 10 degrees and lateral inclination 40 degrees +/- 10 degrees ). We developed a system that uses the accelerometer and camera function of the iPhone. A level indicator application and protractor application were downloaded to the iPhone and used to improve acetabular cup placement. This system has proven to be accurate and quick. Our series of 50 prospective cases showed good results with all our acetabular cups being placed within a narrow range in the safe zone and with less than 5% difference between the preoperative, intraoperative, and postoperative acetabular inclinations. PMID- 22245125 TI - Low rates of heterotopic ossification after resurfacing hip arthroplasty with use of prophylactic radiotherapy in select patients. AB - Recent reports have noted higher rates of heterotopic ossification (HO) with surface replacement arthroplasty (SRA) than with traditional total hip arthroplasty in the absence of postoperative HO prophylaxis. This study reports rates and grades of HO in 44 SRA patients with at least 1 year of follow-up. Heterotopic ossification prophylaxis was used in 32 (73%) of 44 cases. Heterotopic ossification prophylaxis consisted of radiotherapy (22/32), nonsteroidal anti-inflammatory drugs (8/32), or both (2/32). One case of clinically significant HO was documented in the no-prophylaxis group. This strategy of selective HO prophylaxis in patients felt by orthopedic surgeons to be at high risk of HO resulted in low rates of clinically relevant HO after SRA (1/44, 2.3%). Further study is needed to establish optimal selection criteria for HO prophylaxis after SRA. PMID- 22245127 TI - Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS- and mitochondria-mediated pathway. AB - Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II) induced renal cytotoxicity. PMID- 22245128 TI - Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice. AB - Epileptic seizures and status epilepticus (SE) induced by the poisoning with organophosphorus nerve agents (OP), like soman, are accompanied by neuroinflammation whose role in seizure-related brain damage (SRBD) is not clear. Antagonists of the NMDA glutamate ionotropic receptors are currently among the few compounds able to arrest seizures and provide neuroprotection even during refractory status epilepticus (RSE). Racemic ketamine (KET), in combination with atropine sulfate (AS), was previously shown to counteract seizures and SRBD in soman-poisoned guinea-pigs. In a mouse model of severe soman-induced SE, we assessed the potentials of KET/AS combinations as a treatment for SE/RSE-induced SRBD and neuroinflammation. When starting 30min after soman challenge, a protocol involving six injections of a sub-anesthetic dose of KET (25mg/kg) was evaluated on body weight loss, brain damage, and neuroinflammation whereas during RSE, anesthetic protocols were considered (KET 100mg/kg). After confirming that during RSE, KET injection was to be repeated despite some iatrogenic deaths, we used these proof-of-concept protocols to study the changes in mRNA and related protein contents of some inflammatory cytokines, chemokines and adhesion molecules in cortex and hippocampus 48h post-challenge. In both cases, the KET/AS combinations showed important neuroprotective effects, suppressed neutrophil granulocyte infiltration and partially suppressed glial activation. KET/AS could also reduce the increase in mRNA and related pro-inflammatory proteins provoked by the poisoning. In conclusion, the present study confirms that KET/AS treatment has a strong potential for SE/RSE management following OP poisoning. The mechanisms involved in the reduction of central neuroinflammation remain to be studied. PMID- 22245129 TI - Induction of activation of the antioxidant response element and stabilization of Nrf2 by 3-(3-pyridylmethylidene)-2-indolinone (PMID) confers protection against oxidative stress-induced cell death. AB - The antioxidant response elements (ARE) are a cis-acting enhancer sequence located in regulatory regions of antioxidant and detoxifying genes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a member of the Cap 'n' Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE-containing genes. Under oxidative stress, Nrf2/ARE induction is fundamental to defense against reactive oxygen species (ROS) and serves as a key factor in the protection against toxic xenobiotics. 3-(3 Pyridylmethylidene)-2-Indolinone (PMID) is a derivative of 2-indolinone compounds which act as protein kinase inhibitors and show anti-tumor activity. However, the role of PMID in the oxidative stress remains unknown. In the present study, we showed that PMID induced the activation of ARE-mediated transcription, increased the DNA-binding activity of Nrf2 and then up-regulated the expression of antioxidant genes such as HO-1, SOD, and NQO1. The level of Nrf2 protein was increased in cells treated with PMID by a post-transcriptional mechanism. Under CHX treatment, the stability of Nrf2 protein was enhanced by PMID with decreased turnover rate. We showed that PMID reduced the ubiquitination of Nrf2 and disrupted the Cullin3 (Cul3)-Keap1 interaction. Furthermore, cells treated with PMID showed resistance to cytotoxicity by H(2)O(2) and pro-oxidant 6-OHDA. PMID also up-regulated the antioxidant level in BALB/c mice. Taken together, the compound PMID induces the ARE-mediated gene expression through stabilization of Nrf2 protein and activation of Nrf2/ARE pathway and protects against oxidative stress-mediated cell death. PMID- 22245130 TI - Genetic contribution to sour taste preference. AB - Genetic contribution to individual differences in sour taste perception and preference was investigated in a cohort of young adult Finnish twins (n=328, 21 25 years) including 46 complete monozygotic and 92 dizygotic twin pairs and 52 twin individuals without their co-twin. Responses to sour taste were recorded as pleasantness and intensity ratings of orange juice with added citric acid (4.2g/L) relative to untainted orange juice (sensory traits). Pleasantness and use-frequency of 21 food items varying in sourness were rated in a questionnaire. Three food categories emerged in factor analysis: sour berries and fruits, less sour berries and fruits, and sour dairy products (questionnaire traits). The contribution of genetic and environmental factors to variation and co-variation of the traits were analyzed using quantitative genetic modeling. Genetic factors played a larger role than shared environment, explaining 14% and 31% of the variation in pleasantness and intensity of sour taste, respectively, and 34-50% of the variation in pleasantness and use-frequency of sour foods. Relatively large genetic correlations existed between sensory traits and between questionnaire traits. These results demonstrate a genetic contribution to preference for sour foods. PMID- 22245131 TI - Orofacial reactivity to the sight and smell of food stimuli. Evidence for anticipatory liking related to food reward cues in overweight children. AB - Whether food liking may be a risk factor of overconsumption and overweight/obesity remains a controversial issue. So far, most studies used subjective reports to assess consummatory behavior, approaches that might overlook subtle or implicit hedonic changes to sensory properties of foods. Therefore, we used a cue-exposure approach by recording different measures of hedonic processes (orofacial reactivity, self-rated pleasantness, food preference) in 6-11 years old overweight (n=20) and normal-weight (n=20) children. Children were exposed to the smell and sight of high and low-energy density food stimuli and to non-food stimuli during pre- and post-prandial states. Their facial and verbal responses were videotaped and parent's reports of children's eating styles and appetitive traits were collected using the Children's Eating Behavior Questionnaire (CEBQ). Results showed that orofacial reactivity, as an objective measure of anticipatory liking, was more discriminative than self reports, with overweight children displaying more lip sucking than normal-weight children when exposed to high energy food pictures and to food odorants. Orofacial reactivity to food cues was also associated with BMI and children's eating styles (food responsiveness, emotional overeating, and desire to drink). Finally, overweight children classified more frequently non food odorants as members of the food category during the pre-prandial state than during the post-prandial state, suggesting a possible influence of affective/motivational bias on odor categorization. Our findings suggest that orofacial responsiveness may be relevant to assess the sensitivity to energy dense food reward cues in overweight children and for signaling, as an index of anticipatory liking, a potential risk for the development of overweight/obesity. PMID- 22245132 TI - Development and pilot of a group skills-and-support intervention for mothers of children with feeding problems. AB - Child feeding problems are often associated with parental factors which may influence and maintain difficulties. This paper reports the development, pilot and preliminary evaluation of a group intervention for mothers of children with feeding problems. Themes for the group were derived from a survey of parents and professionals. Three pilot interventions were conducted in order to make an assessment of the feasibility, acceptability and potential for achieving change in levels of maternal mood, parenting stress and concerns related to feeding. While single case analysis revealed little change in standardised measures of mood and parenting stress, participants valued the social and emotional support offered by the group and reported improvements in concerns and maladaptive behaviours related to feeding. An intervention which provides support and a sense of a shared experience appears to have beneficial effects for mothers of children with feeding problems and therefore, may offer a constructive means of supporting this population. PMID- 22245133 TI - Overcoming picky eating. Eating enjoyment as a central aspect of children's eating behaviors. AB - Picky eating is a relatively common problem during childhood, and parents lack clear strategies with which to decrease picky eating. This study examined whether increasing eating enjoyment and cooking enjoyment might give opportunities to decrease picky eating. Parents (n=305), mainly mothers with children between 6 and 12 years of age (53.8% boys; 46.2% girls), completed a questionnaire on pressure and restriction, eating enjoyment, and picky eating, and cooking enjoyment. Path analyses were performed to examine the mediating role of eating enjoyment. The final model provided a good fit to the data and explained 33% variance in picky eating. A strong inverse association between eating enjoyment and picky eating was found (beta=-.44). Significant direct effects were found between cooking enjoyment and picky eating (beta=-.16) and restriction and picky eating (beta=.18). Eating enjoyment partly mediated the association between cooking enjoyment and picky eating. Results showed pressure had only an indirect effect on picky eating through eating enjoyment. Eating enjoyment serves as an important and central factor in children's picky-eating behavior. High controlling practices might create a negative environment around food and healthy eating and so decrease eating enjoyment and increase picky eating. PMID- 22245134 TI - The weight of the container influences expected satiety, perceived density, and subsequent expected fullness. AB - We report a study designed to investigate the influence of the weight of the container on expected satiety prior to tasting the food within and on the perceived density of the food and any feelings of fullness expected to follow consumption (expected satiation). The results demonstrate that the contents of a heavier container are expected to be more satiating than when exactly the same contents are presented in a visually-identical, but physically lighter, container (even before the food has been tasted). In addition, we were able to validate a "weight-density" illusion, since the weight of the container was shown to influence the perceived density of the sample. Put simply, the heavier the container, the denser the food sample was perceived to be. PMID- 22245135 TI - Links between maternal feeding practices and children's eating difficulties. Validation of French tools. AB - The main objectives of the present study were to validate measures of young children's eating difficulties and maternal feeding practices in a French sample, as well as to assess the links between these practices and children's eating difficulties. Mothers (n=502) of French children aged 20-36 months completed four questionnaires that were validated using a Structural Equation Modelling approach. Links between children and maternal components were investigated using a PLS regression. The Children's Eating Difficulties Questionnaire yielded a 4 dimension solution: Neophobia, Pickiness, Low Appetite and Low Enjoyment in food. The Feeding Style Questionnaire assessed three dimensions: Authoritarian, Authoritative and Permissive Styles. The Feeding Strategy Questionnaire, designed to evaluate strategies used by mothers to make their child taste rejected foods, resulted in four factors: Coercion, Explanation, Contingency and Preference. The Questionnaire relating to Parental Motivations when buying food for children presented a 6-dimension solution: Convenience, Weight-control, Natural, Health concern, Preference and Price. The factors associated positively with the four dimensions of the Children's Eating Difficulties Questionnaire were on the one hand Permissive Style and Practices to fulfil child's desires, and on the other hand Authoritarian Style, Contingent and Coercive Practices aimed at forcing children to taste rejected foods. PMID- 22245136 TI - A de novo balanced t(2;6)(p15;p22.3) in a patient with West Syndrome disrupts a lnc-RNA. AB - In a male patient with West Syndrome we identified a perfectly balanced, de novo balanced translocation 46,XY,t(2;6)(p15;p22.3). No known protein coding genes were disrupted by the translocation and positional effects on nearby genes were excluded by expression studies. A putative long non-coding RNA, BX118339, spans the breakpoint on chromosome 6. It can be hypothesized that disruption of this non-coding transcript plays a role in the pathogenesis of the patient. PMID- 22245137 TI - Non-resective surgery and radiosurgery for treatment of drug-resistant epilepsy. AB - Epilepsy surgery is an effective treatment for properly selected patients with intractable seizures. However, many patients with medically intractable epilepsy are not excellent candidates for surgical resection of the epileptogenic zone. Due to recent advances in computer technology and bioengineering, several novel techniques are receiving increasing interest for their role in the care of people with epilepsy. Neuromodulation is an emerging surgical option to be used when conventional resective surgery is not indicated. We review the indications and expected outcomes of neuromodulatory treatments currently available for the treatment of refractory epilepsy, i.e., vagus nerve stimulation, deep brain stimulation, stereotactic radiosurgery, and multiple subpial transections. PMID- 22245139 TI - Central and peripheral release of oxytocin following chronic homotypic stress in rats. AB - Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Centrally released oxytocin has anxiolytic and anti-stress effects. We have recently shown that impaired gastric and colonic motility observed in acute restraint stress was restored following repeated restraint stress for 5 consecutive days (chronic homotypic stress) in mice and rats. Chronic homotypic stress upregulates oxytocin mRNA expression and downregulates corticotrophin releasing factor (CRF) mRNA expression at the hypothalamus. However, it still remains unclear whether stress responses induced by chronic homotypic stress are accompanied by the central or peripheral release of oxytocin. Adult male SD rats were chronically implanted with microdialysis probes at the hypothalamic paraventricular nucleus (PVN) and jugular vein catheters. Microdialysis and blood sampling were performed following 1st, 3rd and 5th of chronic homotypic stress. Oxytocin levels in the dialysates and plasma were measured by radioimmunoassay (RIA). On day 1 of chronic homotypic stress, oxytocin release was slightly, but not significantly, increased in the PVN and plasma. Oxytocin release was significantly increased in the PVN on day 3 (12.7 +/- 1.3 pg/sample, n=5, P<0.05) and day 5 (28.2 +/- 2.4 pg/sample, n=5, P<0.05) from basal (6.9 +/- 1.8 pg/sample, n=5). In contrast, there were no significant changes observed in the plasma on day 3 and day 5. This suggests that central, but not peripheral, release of oxytocin plays an important role in response to chronic homotypic stress in rats. PMID- 22245138 TI - Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin. AB - Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1% O(2), 4h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca(2+) currents were acquired immediately after hypoxic exposure or after 48h recovery in 95% air/5% CO(2). Maximal Ca(2+) current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca(2+) currents were unchanged. The half-maximal potentials of activation and steady-state inactivation were unchanged. The calcineurin inhibitors FK-506 (in the recording pipette) or cyclosporine A (during hypoxia) prevented the post-hypoxic increase in HVA Ca(2+) currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca(2+) for calcineurin activation, as nimodipine during hypoxia prevented post hypoxic enhancement. Hypoxia transiently potentiated L-type VGCC currents via calcineurin, suggesting a positive feedback loop to amplify neuronal calcium signaling that may contribute to seizure generation. PMID- 22245140 TI - The BRCA1 alternative splicing variant Delta14-15 with an in-frame deletion of part of the regulatory serine-containing domain (SCD) impairs the DNA repair capacity in MCF-7 cells. AB - The BRCA1 gene codes for a protein involved in the DNA double strand break (DDSB) repair. Alongside the dominant full-length splicing form of BRCA1, numerous endogenously expressed alternative splicing variants of unknown significance have been described in various tissues. Some of them retain the original BRCA1 reading frame but lack several critical BRCA1 structural domains, suggesting an altered function of the resulting protein in the BRCA1-regulated processes. To characterize the effect of the BRCA1Delta14-15 splicing variant (with an in-frame deletion affecting the regulatory serine-containing domain) on the DDSB repair, we constructed the MCF-7 clones stably expressing the analyzed variant with/without a shRNA-mediated downregulation of the endogenous full-length wild type BRCA1 expression. Our results show that the expression of the BRCA1Delta14 15 variant delays the gamma-radiation-induced DDSB repair, alters the kinetics of irradiation-induced foci formation/decomposition and reduces the non-homologous end-joining capacity in MCF-7 cells. Therefore, the BRCA1Delta14-15 is not able to functionally replace the full-length wt BRCA1 in the DDSB repair. Our findings indicate that the endogenously expressed BRCA1 alternative splicing variants may negatively influence genome stability and support the growing evidence of the pathological potential of the sequence variants generated by an altered or misregulated alternative splicing in the process of mammary malignant transformation. PMID- 22245141 TI - BCL11B tumor suppressor inhibits HDM2 expression in a p53-dependent manner. AB - BCL11B is a C2H2 zinc finger transcription factor that acts as a haploinsufficient tumor suppressor. Mutations and deletion in the human orthologue BCL11B have been identified in human T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of thymic lymphomas. Bcl11b(KO/+)p53(KO/+) doubly heterozygous mice, but not Bcl11b(KO/+) heterozygous mice, spontaneously develop thymic lymphomas at a high frequency, suggesting cooperativity of BCL11B and p53 in cancer development. In this study, we have examined whether or not BCL11B directly affects the p53 signaling pathway including HDM2, a ubiquitin ligase for p53 degradation. The p53 pathway regulates cell proliferation and the response to DNA damages to maintain genome integrity. Here we show that BCL11B binds to human HDM2-P2 promoter by ChIP (chromatin immuno-precipitation) assay and inhibits HDM2 expression in a p53-dependent manner. Deletion of the distal p53 responsive element in HDM2 promoter region or the lack of p53 in HCT116 cells greatly reduced the repressive effect of BCL11B on HDM2-P2 promoter activity. The repressive activity was alleviated in gamma-ray induced DNA damage conditions that activate p53, suggesting interaction between BCL11B and p53 for HDM2 expression. These date suggest that BCL11B affects the activity of the p53-HDM2 feedback loop in basal and irradiated conditions. This may be a mechanism underlying the leukemic transformation in T-ALL and in Bcl11b(KO/+)p53(KO/+) mouse thymocytes. PMID- 22245142 TI - Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells. AB - Our recent study have shown that resveratrol (RV), a natural plant polyphenol found in red grape skins as well as other food product, induced apoptosis via the downstream factors, caspase-independent AIF and to lesser extent caspase-9, of intrinsic apoptosis pathway in human lung adenocarcinoma (ASTC-a-1) cells. This report is designed to explore the roles of the upstream mediators of the intrinsic pathway, such as Bak/Bax, Bim, Puma and Noxa, during RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines. RV treatment remarkably induced the activation of Bak but not Bax, and silencing Bak but not Bax by shRNA almost completely prevented RV-induced cell death, mitochondrial dysfunction and also largely prevented RV-induced AIF release, demonstrating the preferential engagement of Bak but not Bax during RV-induced apoptosis. In addition, although RV treatment induced a significant degradation of Mcl-1, knockdown of Mcl-1 by shRNA only modestly increased RV-induced Bak activation. Interestingly, silencing Bim but not Puma and Noxa remarkably attenuated RV-induced cell death, loss of mitochondrial membrane potential, and Bak activation, suggesting the important roles of Bim. Collectively, our findings for the first time demonstrate that RV induces apoptosis dominantly via a Bak- but not Bax-mediated AIF-dependent mitochondrial apoptotic signaling pathway in which Bim but not Puma and Noxa may supply the force to trigger Bak activation and subsequent apoptosis in both ASTC-a-1 and A549 cell lines. PMID- 22245144 TI - Creating a movement heuristic for voluntary action: electrophysiological correlates of movement-outcome learning. AB - Performance of voluntary behavior requires the selection of appropriate movements to attain a desired goal. We propose that the selection of voluntary movements is often contingent on the formation of a movement heuristic or set of internal rules governing movement selection. We used event-related potentials (ERPs) to identify the electrophysiological correlates of the formation of movement heuristics during movement-outcome learning. In two experiments, ERPs from non learning control tasks were compared to a movement-learning task in which a movement heuristic was formed. We found that novelty P3 amplitude was negatively correlated with improved performance in the movement-learning task. Additionally, enhancement of novelty P3 amplitude was observed during learning even after controlling for memory, attentional and inter-stimulus interval parameters. The feedback correct-related positivity (fCRP) was only elicited by sensory effects following intentional movements. These findings extend previous studies demonstrating the role of the fCRP in performance monitoring and the role of the P3 in learning. In particular, the present study highlights an integrative role of the fCRP and the novelty P3 for the acquisition of movement heuristics. While the fCRP indicates that the goal of intentional movements has been attained, the novelty P3 engages stimulus-driven attentional mechanisms to determine the primary aspects of movement and context required to elicit the sensory effect. PMID- 22245143 TI - The "beta-clasp" model of apolipoprotein A-I--a lipid-free solution structure determined by electron paramagnetic resonance spectroscopy. AB - Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and plays a central role in cholesterol metabolism. The lipid free/lipid-poor form of apoA-I is the preferred substrate for the ATP-binding cassette transporter A1 (ABCA1). The interaction of apoA-I with ABCA1 leads to the formation of cholesterol laden high density lipoprotein (HDL) particles, a key step in reverse cholesterol transport and the maintenance of cholesterol homeostasis. Knowledge of the structure of lipid-free apoA-I is essential to understanding its critical interaction with ABCA1 and the molecular mechanisms underlying HDL biogenesis. We therefore examined the structure of lipid-free apoA I by electron paramagnetic resonance spectroscopy (EPR). Through site directed spin label EPR, we mapped the secondary structure of apoA-I and identified sites of spin coupling as residues 26, 44, 64, 167, 217 and 226. We capitalize on the fact that lipid-free apoA-I self-associates in an anti-parallel manner in solution. We employed these sites of spin coupling to define the central plane in the dimeric apoA-I complex. Applying both the constraints of dipolar coupling with the EPR-derived pattern of solvent accessibility, we assembled the secondary structure into a tertiary context, providing a solution structure for lipid-free apoA-I. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). PMID- 22245145 TI - How do our brain hemispheres cooperate to avoid false memories? AB - Memories are not always as reliable as they may appear. The occurrence of false memories can be reduced, however, by enhancing the cooperation between the two brain hemispheres. Yet is the communication from left to right hemisphere as helpful as the information transfer from right to left? To address this question, 72 participants were asked to learn 16 word lists. Applying the Deese-Roediger McDermott paradigm, the words in each list were associated with an unpresented prototype word. In the test condition, learned words and corresponding prototypes were presented along with non-associated new words, and participants were asked to indicate which of the words they recognized. Crucially, both study and test words were projected to only one hemisphere in order to stimulate each hemisphere separately. It was found that false recognitions occurred significantly less often when the right hemisphere studied and the left hemisphere recognized the stimuli. Moreover, only the right-to-left direction of interhemispheric communication reduced false memories significantly, whereas left-to-right exchange did not. Further analyses revealed that the observed reduction of false memories was not due to an enhanced discrimination sensitivity, but to a stricter response bias. Hence, the data suggest that interhemispheric cooperation does not improve the ability to tell old and new apart, but rather evokes a conservative response tendency. Future studies may narrow down in which cognitive processing steps interhemispheric interaction can change the response criterion. PMID- 22245146 TI - Single-grain OSL chronologies for Middle Palaeolithic deposits at El Mnasra and El Harhoura 2, Morocco: implications for Late Pleistocene human-environment interactions along the Atlantic coast of northwest Africa. AB - Optically stimulated luminescence (OSL) measurements were made on individual, sand-sized grains of quartz from Middle Palaeolithic deposits at two cave sites (El Harhoura 2 and El Mnasra) on the Atlantic coast of Morocco. We were able to calculate OSL ages for 32 of the 33 samples collected from the Middle Palaeolithic deposits, including the earliest and latest Aterian levels at both sites. These ages reveal periods of occupation between about 110 and 95 ka (thousands of years ago), and at ~75 ka. A late Middle Palaeolithic occupation of El Harhoura 2 is also recorded at ~55 ka. Our single-grain OSL chronologies largely support previous age estimates from El Mnasra and other sites along the Atlantic coast of Morocco, but are generally more precise, reproducible and stratigraphically more coherent (i.e., fewer age reversals). We compare the single-grain ages for El Harhoura 2 and El Mnasra with those obtained from single and multi-grain OSL dating of Middle Palaeolithic deposits in the nearby sites of Contrebandiers and Dar es-Soltan 1 and 2, and with records of past regional environments preserved in sediment cores collected from off the coast of northwest Africa. A conspicuous feature of the new chronologies is the close correspondence between the three identified episodes of human occupation and periods of wetter climate and expanded grassland habitat. Owing to the precision of the single-grain OSL ages, we are able to discern gaps in occupation during Marine Isotope Stages 5 and 4, which may represent drier periods with reduced vegetation cover. We propose that these climatic conditions can be correlated with events in the North Atlantic Ocean that exert a major control on abrupt, millennial-scale fluctuations between wet and dry periods in northwest and central North Africa. PMID- 22245147 TI - Spatial analysis and mapping of malaria risk in an endemic area, south of Iran: a GIS based decision making for planning of control. AB - Bashagard district is one of the important malaria endemic areas in southern Iran. From this region a total of 16,199 indigenous cases have been reported in recent years. The aim of this study was to determine the situation of the disease and provide the risk map for the area. ArcGIS9.2 was used for mapping spatial distribution of malaria incidence. Hot spots were obtained using evidence-based weighting method for transmission risk. Environmental factors including temperature, relative humidity, altitude, slope and distance to rivers were combined by weighted multi criteria evaluation for mapping malaria hazard area at the district level. Similarly, risk map was developed by overlaying weighted hazard, land use/land cover, population density, malaria incidence, development factors and intervention methods. Our results reveal that the disease mainly occurs in north and east of the study area. Consequently the district is divided into three strata. Appropriate interventions are recommended for each stratum based on national malaria policy. Malaria hazard and risk map, stratification based on relevant information and data analyzing provide a useful method preparedness and early warning system for malaria control, although regular updating is required timely. PMID- 22245149 TI - Development of a magnetic bead fluorescence microscopy immunoassay to detect and quantify Leptospira in environmental water samples. AB - Climate change, world population growth, and poverty have led to an increase in the incidence of leptospirosis. Leptospirosis is caused by pathogenic spirochaete bacteria that belong to the genus Leptospira. The bacteria are maintained in the renal tubules of the reservoir hosts (typically a rodent), then shed into the environment via the urine. Water is key for environmental survival and transmission, as leptospires can survive for several weeks in a moist environment. Therefore, environmental epidemiological studies are needed to study the contamination of environmental water sources. However, few such studies have been performed using cultivation of the isolates and PCR assays. But, leptospira cultivation can be easily contaminated by other organisms and takes usually several weeks. Moreover, PCR is a complex and costly analysis for the underdeveloped countries that have the highest incidence of leptospirosis. In this study, we describe two modifications of a fluorescence microscopy assay based on immuno-magnetic separation (IMS) to detect leptospires in environmental water samples that mainly differ in fluorescent dye staining. The first type uses acridine orange fluorescent dye staining combined with multiplexed IMS for sample screening. The detection limit ranged from 10(2) to 10(3) organisms per mL and largely depended on the capture efficiency (CE) of the immuno-magnetic particles. The second type uses serogroup-specific immuno-particles and direct fluorescence antibody staining (DFA) to detect leptospires; the detection limit of this second assay was approximately 10(1) cells per mL. Both assay types were applied to natural and experimentally infected water samples, which were also analysed with DFM and real-time PCR. Our data show that the fluorescent microscopy immunoassay successfully identified experimental leptospire contamination and was as sensitive as PCR. This modified immune-fluorescence assay may therefore enable epidemiological studies of leptospirosis. PMID- 22245148 TI - Urine heme dipsticks are useful in monitoring the impact of praziquantel treatment on Schistosoma haematobium in sentinel communities of Delta State, Nigeria. AB - Nigeria is highly endemic for infection with Schistosoma haematobium, which most commonly manifests itself with blood in urine. To monitor the impact of annual mass drug administration (MDA) with Praziquantel for S. haematobium in Delta State, Nigeria, cross-sectional hematuria surveys of school children were conducted in 8 sentinel villages (SVs) at baseline (n=240) and after two annual doses (n=402). We assessed the comparability of three assessments of hematuria (child's reported history, nurse visual diagnosis (NVD) and dipstick) to determine the need for mass treatment. Dipstick was considered to be the gold standard. Prior to treatment, history and NVD each identified only the 3 most highly prevalent SVs, and overall this represented just 37.5% of the 8 SVs in need of treatment. Following treatment, after dipstick prevalence decreased by 88.5% (p<0.001), and history and NVD identified only one of two villages still needing treatment. The study suggests that dipsticks should be the recommended method for launching and monitoring mass treatment for S. haematobium. PMID- 22245150 TI - A well-fixed femoral stem facing a failed acetabular component: to exchange or not? A 5- to 15-year follow-up study. AB - INTRODUCTION: There is no consensus about the necessity of exchanging a stable femoral component during revision total hip arthroplasty (RTHA) when only the acetabular component requires replacement. Sparing the femoral component reduces morbidity, but can make acetabular replacement technically more difficult. Moreover, the outcome of the retained femoral component is also a question, especially with older implants. HYPOTHESIS: Isolated acetabular component RTHA results in lower surgical morbidity, and does not increase the risk of later femoral complications. PATIENTS AND METHODS: Eighty-nine patients, mean age 68, underwent surgery (anterior approach on traction table) for isolated acetabular component revision between 1994 and 2005. The femoral component had been implanted a mean 10.5 years before revision. RESULTS: Fifteen patients died, mean age 84.5. Eleven patients, mean age 81.3, were lost to follow-up and four underwent revision due to a subsequent infection (range 14 months - 11 years). Fifty-nine patients were evaluated after a mean 8.6 years (range 4 - 15 years). At follow-up the mean Harris score was 89.2 [IC=6.89; 44 - 100] and the mean Merle d'Aubigne score was 15.3 [IC=1.57; 11 - 18]. Five patients (5.6%) underwent surgery again due to postoperative dislocation. Six patients underwent surgery for recurrent acetabular loosening due to allograft resorption. The size of the bone defects did not increase the risk of these failures (P>0.6). Fractures occurred in two femoral components 6 and 9 years after revision. Polyethylene wear occurred in three patients requiring two repeat revisions at 6 and 7 years. In both cases the femoral component included a titanium head, which caused the wear. Implant survival at 8.6 years was 85.16 +/- 0.117% all causes of revision combined, 88.47 +/- 0.113% if infectious causes were excluded and 93.6 +/- 0.07% if only cases of acetabular component failure were taken into account. CONCLUSION: Intermediate term outcomes are satisfactory if stable femoral components are retained. Nevertheless, this procedure should be performed in situations of correctly oriented modular components. In single piece (monoblock) femoral implants, or in implants with a history of failure, this technique should be restricted to elderly and/or fragile patients. LEVEL OF EVIDENCE: Level IV, Retrospective study. PMID- 22245151 TI - Mutation of a raft-targeting signal in the transmembrane region retards transport of influenza virus hemagglutinin through the Golgi. AB - Inclusion of proteins into membrane-rafts favours interactions required for virus assembly but has also been proposed to facilitate vesicular transport of proteins. The hemagglutinin (HA) of influenza virus contains a raft-targeting sequence in the outer leaflet of its transmembrane region. We report that its mutation enhances co-localization of HA with a cis-Golgi marker and retards Golgi localized processing, such as acquisition of Endo-H resistant carbohydrates and proteolytic cleavage. In contrast, trimerization of the molecule in the ER and transport to the apical membrane were not affected. The second signal for raft targeting, S-acylation at cytoplasmic cysteines, did not retard HA transport. PMID- 22245152 TI - Hypoxia-induced SM22alpha in A549 cells activates the IGF1R/PI3K/Akt pathway, conferring cellular resistance against chemo- and radiation therapy. AB - Chemo- or radiation-resistance in tumors caused by hypoxia often undermines efficacy of cancer therapy. Thus, therapies that overcome cellular resistance during hypoxia are necessary. SM22alpha is an actin-binding protein found in smooth muscle, fibroblasts, and some epithelium. We demonstrate that SM22alpha is induced in A549 non-small cell lung carcinoma cells by hypoxia and its overexpression increased chemo- and radiation-resistance. Hypoxia-mediated induction of SM22alpha expression is hypoxia-inducible factor-independent. Moreover, SM22alpha overexpression enhances tumor cell growth and activates the IGF1R/PI3K/Akt pathway via direct interaction with IGF1Rbeta. Our results suggest SM22alpha as a novel regulator of hypoxic survival pathway of A549 NSCLC cells. PMID- 22245153 TI - SNPs of hemocyanin C-terminal fragment in shrimp Litopenaeus vannamei. AB - In this study, we identified a variable region in the C-terminus of hemocyanin from the shrimp Litopenaeus vannamei (2288-2503bp, HcSC) by sequence alignments. A total of 13 SNPs were identified by PCR-SSCP and HcSC clone sequencing. The SSCP patterns of HcSC could be modulated in Vibro parahaemolyticus-treated shrimps. A novel SSCP band with four SNP sites was identified in V. parahaemolyticus-resistant shrimps. More importantly, three of these four SNPs introduced variations in amino acid sequence and possibly secondary structure of the HcSC polypeptide and resulted in a higher agglutinative activity against seven pathogenic bacteria. These results suggest that the C-terminus of shrimp L. vannamei hemocyanin possesses SNPs, which may be related to shrimp resistance to different pathogens. PMID- 22245154 TI - Activation of macrophage-stimulating protein by human airway trypsin-like protease. AB - Macrophage-stimulating protein (MSP) circulates as a proform protein and requires proteolytic processing for activation. Respiratory ciliated cells express the MSP receptor, recepteur d'origine nantais (RON), at the apical surface, which reportedly has an important role in ciliary function. Like RON, human airway trypsin-like protease (HAT) is also expressed at the apical surface of ciliated cells. Here we show that HAT cleaves proMSP at the physiological activation site, Arg483-Val484. MSP processed by HAT could induce chemotactic responses and morphological changes of peritoneal macrophages. In human respiratory epithelial cells, knock down of HAT expression reduced proMSP processing and RON autophosphorylation. We suggest that HAT is important for MSP-RON signaling in the respiratory tract. PMID- 22245155 TI - PEDV ORF3 encodes an ion channel protein and regulates virus production. AB - Several studies suggest that the open reading frame 3 (ORF3) gene of porcine epidemic diarrhea virus (PEDV) is related to viral infectivity and pathogenicity, but its function remains unknown. Here, we propose a structure model of the ORF3 protein consisting of four TM domains and forming a tetrameric assembly. ORF3 protein can be detected in PEDV-infected cells and it functions as an ion channel in both Xenopus laevis oocytes and yeast. Mutation analysis showed that Tyr170 in TM4 is important for potassium channel activity. Furthermore, viral production is reduced in infected Vero cells when ORF3 gene is silenced by siRNA. Interestingly, the ORF3 gene from an attenuated PEDV encodes a truncated protein with 49 nucleotide deletions, which lacks the ion channel activity. PMID- 22245156 TI - Predicting orally disintegrating tablets formulations of ibuprophen tablets: an application of the new SeDeM-ODT expert system. AB - This article provides a new innovative tool for pharmaceutical preformulation to predict whether a disintegrant excipient or mixture of powder containing API+excipients is suitable to obtain a bucodispersible tablet by direct compression or not. This innovative tool is the new model SeDeM-ODT that provides the Index of Good Compressibility and Bucodispersibility (IGCB index), which is based on the previous SeDeM expert system that indicates the aptitude of a powder to be compressed. The IGCB index is composed of six main factors (from 15 pharmaceutical raw parameters), which indicate whether a mixture of powder has the aptitude to be compressed by direct compression and at the same time indicates whether these tablets are suitable to be used as a bucodispersible tablet (disintegration time lower than 3 min). PMID- 22245157 TI - Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction. AB - A human neural stem cell (NSC) line over-expressing human choline acetyltransferase (ChAT) gene was generated and these F3.ChAT NSCs were transplanted into the brain of rat Alzheimer disease (AD) model which was induced by application of ethylcholine mustard aziridinium ion (AF64A) that specifically denatures cholinergic nerves and thereby leads to memory deficit as a salient feature of AD. Transplantation of F3.ChAT human NSCs fully recovered the learning and memory function of AF64A animals, and induced elevated levels of acetylcholine (ACh) in cerebrospinal fluid (CSF). Transplanted F3.ChAT human NSCs were found to migrate to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and astrocytes. The present study demonstrates that brain transplantation of human NSCs over expressing ChAT ameliorates complex learning and memory deficits in AF64A cholinotoxin-induced AD rat model. PMID- 22245159 TI - High-frequency water quality time series in precipitation and streamflow: from fragmentary signals to scientific challenge. AB - Eighteen months of 7-hourly analyses of rainfall and stream water chemistry are presented, spanning a wide range of chemical determinands and building on over 20 years of weekly records for the moorland headwaters of the river Severn. The high frequency time series data show that hydrochemical responses to major hydrological and biological drivers of short-term variability in rainfall and rivers are not captured by conventional low-frequency monitoring programmes. A wealth of flow related, flow independent, diurnal, seasonal and annual fluctuations indicate a cacophony of interactions within the catchment and stream. The complexity of the chemical dynamics is visually obvious, although there appears to be no clear way of translating this complexity into a simple algorithm. The work provides a proof of concept for the complex structure of catchment functioning revealed by extensive high-frequency measurements coupled with high analytical sensitivity and reproducibility. It provides new insights into hydrogeochemical functioning and a novel resource for catchment modelling. PMID- 22245158 TI - Endogenous opioid-dopamine neurotransmission underlie negative CBV fMRI signals. AB - Previous studies showed noxious unilateral forepaw electrical stimulation surprisingly evoked negative blood-oxygenation-level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) fMRI responses in the bilateral striatum whereas the local neuronal spike and c-Fos activities increased. These negative responses are associated with vasoconstriction and appeared to override the increased hemodynamic responses that typically accompanied with increased neural activity. The current study aimed to investigate the role of MU-opioid system in modulating vasoconstriction in the striatum associated with noxious stimulation on a 4.7-Tesla MRI scanner. Specifically, we investigated: i) how morphine (a MU-opioid receptor agonist) affects the vasoconstriction in the bilateral striatum associated with noxious electrical forepaw stimulation in rats, and ii) how naloxone (an opioid receptor antagonist) and eticlopride (a dopamine D(2)/D(3) receptor antagonist) modulates the morphine effects onwards. Injection of morphine enhanced the negative striatal CBV responses to noxious stimulation. Sequential injection of naloxone in the same animals abolished the stimulus-evoked vasoconstriction. In a separate group of animals, injection of eticlopride following morphine also reduced the vasoconstriction. Our findings suggested that noxious stimulation endogenously activated opioid and dopamine receptors in the striatum and thus leading to vasoconstriction. PMID- 22245160 TI - Integrating Saharan dust forecasts into a regional chemical transport model: a case study over Northern Italy. AB - The Po Valley in Northern Italy is frequently affected by high PM10 concentrations, where both natural and anthropogenic sources play a significant role. To improve air pollution modeling, 3D dust fields, produced by means of the DREAM dust forecasts, were integrated as boundary conditions into the mesoscale 3D deterministic Transport Chemical Aerosol Model (TCAM). A case study of the TCAM and DREAM integration was implemented over Northern Italy for the period May 15-June 30, 2007. First, the Saharan dust impact on PM10 concentration was analyzed for eleven remote PM10 sites with the lowest level of air pollution. These remote sites are the most sensitive to Saharan dust intrusions into Northern Italy, because of the absence of intensive industrial pollution. At these remote sites, the observed maxima in PM10 concentration during dust events is evidence of dust aerosol near the surface in Northern Italy. Comparisons between modeled PM10 concentrations and measurements at 230 PM10 sites in Northern Italy, showed that the integrated TCAM-DREAM model more accurately reproduced PM10 concentration than the base TCAM model, both in terms of correlation and mean error. Specifically, the correlation median increased from 0.40 to 0.65, while the normalized mean absolute error median dropped from 0.5 to 0.4. PMID- 22245161 TI - Carcinogenic potencies of polycyclic aromatic hydrocarbons for back-door neighbors of restaurants with cooking emissions. AB - In the present study, 21 polycyclic aromatic hydrocarbon (PAH) congeners were measured in the exhaust stack of 3 types of restaurants: 9 Chinese, 7 Western, and 4 barbeque (BBQ). The total PAH concentration of BBQ restaurants (58.81 +/- 23.89 MUg m(-3)) was significantly higher than that of Chinese (20.99 +/- 13.67 MUg m(-3)) and Western (21.47 +/- 11.44 MUg m(-3)) restaurants. The total benzo[a]pyrene potency equivalent (B[a]P(eq)) concentrations, however, were highest in Chinese restaurants (1.82 +/- 2.24 MUg m(-3)), followed by Western (0.86 +/- 1.43 MUg m(-3), p<0.01) and BBQ-type restaurants (0.59 +/- 0.55 MUg m( 3), p<0.01). We further developed a probabilistic risk model to assess the incremental lifetime cancer risk (ILCR) for people exposed to carcinogenic PAHs. Because the exhaust stack directly affected the back-door neighbors of these restaurants, we were concerned with the real exposure of groups near the exhaust stack outlets of these restaurants. The ILCRs for total exposure of the neighbors (inhalation+dermal contact+ingestion) were 2.6-31.3, 1.5-14.8, and 1.3-12.2 * 10( 6) in Chinese, Western, and BBQ restaurants, respectively. We suggest that the maximum acceptable exposure time to the exhaust stack outlet area for Chinese, Western, and BBQ restaurants ranges between 5-19, 17-42, and 18-56 h month(-1), respectively, based on an ILCR of less than 10(-6). PMID- 22245162 TI - Effects of bench step exercise on arterial stiffness in post-menopausal women: contribution of IGF-1 bioactivity and nitric oxide production. AB - OBJECTIVE: To examine the effect of bench step exercise on arterial pulse wave velocity (PWV) and the associated contribution of insulin-like growth factor (IGF)-1 bioactivity and nitric oxide (NO). DESIGN: Twenty-six elderly (post menopausal) women were randomly allocated to a bench step exercise group or a control group. The participants in the bench step exercise group practiced a 12 week home-based bench step exercise for 10-20min, 3 times daily (i.e., for a total of 140min/week at the intensity level of lactate threshold (LT)). In addition to conventional risk factors of atherosclerosis, PWV, IGF-1/IGF binding protein (IGFBP)-3 molar ratio (an index for IGF-1 bioactivity), and urinary nitrite/nitrate (NO(x)) excretion were measured before and after the intervention. RESULTS: BMI, systolic blood pressure, fasting plasma glucose, low density lipoprotein cholesterol, LT, and PWV were significantly improved in the bench step exercise group. A significant positive correlation between changes in PWV and IGF-1/IGFBP-3 molar ratio, and a significant negative correlation between changes in IGF-1/IGFBP-3 molar ratio and urinary NO(x) excretion were found in the bench step exercise group. CONCLUSION: The bench step exercise leads to improvements in not only the classical risk factors of atherosclerosis but also the arterial stiffness in elderly women, partly through NO production via IGF-1 bioactivity. PMID- 22245163 TI - Enhanced somatosensory information decreases postural sway in older people. AB - The somatosensory system plays an important role in balance control and age related declines in somatosensory function have been implicated in falls incidence. Different types of insole devices have been developed to enhance somatosensory information and improve postural stability. However, they are often too complex and expensive to integrate into daily life and textured insole surfaces may provide an inexpensive and accessible means to enhance somatosensory input. This study investigated the effects of textured insole surfaces on postural sway in ten younger and seven older participants performing standing balance tests on a force plate under three insole surface conditions: (1) barefoot; (2) with hard; and (3), soft textured insole surfaces. With each insole surface, participants were tested under two vision conditions (eyes open, closed) on two standing surfaces (firm, foam). Four 30s trials were collected for different combinations of insole surface, standing surface and vision. Centre of pressure measurements included the range and standard deviation of anterior posterior and medial-lateral displacement, path length and the 90% confidence elliptical area. Results revealed a significant Group*Surface*Insole interaction for five of the dependent variables. Compared to younger individuals, postural sway was greater in older people on both standing surfaces in the barefoot condition. However, both textured insole surfaces reduced postural sway for the older group especially in the eyes closed condition on a foam surface. These findings suggest that textured insole surfaces can reduce postural sway in older people, particularly during more challenging balance tasks. Textured insole surfaces may afford a low-cost means of decreasing postural sway, providing an important intervention in falls prevention. PMID- 22245164 TI - BodyWorks: a parent-focused program to promote healthful eating and physical activity for children and adolescents. PMID- 22245166 TI - Occurrence of Mycobacterium avium subsp. paratuberculosis in milk at dairy cattle farms: a systematic review and meta-analysis. AB - Presence of Mycobacterium avium subsp. paratuberculosis (MAP) in milk for human consumption is a concern due to its possible relationship with Crohn's disease in humans. Pasteurization effectively reduces the MAP load by four to five logs, but the efficacy depends on the MAP concentration, which depends on the prevalence among contributing herds and individuals. Considerable variation of MAP in bulk tank milk (BTM) and individual cow's milk (IM) is reported, but factors associated with MAP occurrence in milk at farm level have not been described. This study systematically reviewed published studies aiming at estimating the occurrence of MAP in on-farm BTM and IM by meta-analysis. A total of 692 articles were identified through electronic databases and initially screened using title and abstract. The quality of the 61 potentially relevant articles was assessed using full text and 31 articles were eventually included in the meta-analysis. The apparent prevalence (AP) of MAP in BTM and IM on farm were summarized in relation to strata defined by the test used to identify MAP and the infection status of the herds/animals. There was considerable inconsistency in the reporting, resulting in missing information potentially explaining the dispersion in the estimated AP. The overall AP and 95% confidence intervals based on PCR and culture of MAP were summarized to 0.10 (0.04-0.22) in BTM and 0.20 (0.12-0.32) in IM. Quantifying the MAP load in test-positive milk samples was not possible because very few articles provided quantitative information on individual samples. PMID- 22245167 TI - Feeding and mandibular distraction osteogenesis in children with Pierre Robin sequence: a case series of functional outcomes. AB - INTRODUCTION: In addition to upper airway obstruction, many patients with micrognathia and Pierre Robin sequence also have swallowing abnormalities and reflux. Many studies have demonstrated the effectiveness in alleviating the airway symptoms with mandibular distraction osteogenesis, but very few studies have focused on feeding and reflux outcomes. METHODS: A retrospective chart review was performed to identify patients with Pierre Robin sequence who underwent mandibular distraction osteogenesis with completed pre- and post operative upper gastroesophageal series and videofluoroscopic swallow assessments. RESULTS: All six children in our series demonstrated significant improvements in both airway obstructive symptoms and feeding abnormalities. More specifically, all patients showed clinical and objective improvements in reflux and swallowing function after distraction surgery. CONCLUSION: Objective and symptomatic improvements in swallowing function and reflux disease can be seen after mandibular distraction osteogenesis in children with Pierre Robin sequence. PMID- 22245168 TI - Effect of topical anesthetic agents and ethanol on corneoepithelial wound healing in an ex vivo whole-globe porcine model. AB - PURPOSE: To assess the impact of topical anesthetic agents and ethanol on ocular surface wound healing using an ex vivo whole-globe porcine model. SETTING: Department of Ophthalmology, Inselspital, University of Bern, Bern, Switzerland. DESIGN: Experimental study. METHODS: Standardized corneoepithelial lesions (5.0 mm diameter, 40 MUm depth) were created with excimer laser light in freshly enucleated porcine eyes. The globes (6 per group) were exposed to different concentrations of ethanol (2.0% to 99.0%), cocaine (2.0% to 10.0%), procaine hydrochloride (0.4%), tetracaine (0.5% to 1.0%), or lidocaine (2.0%), 3 drops/hour for 3 hours. Control solutions were physiologic saline, balanced salt solution, and tissue-culture medium. After 20 to 26 hours, wound-healing response was compared by measuring the diameter of each corneoepithelial lesion. RESULTS: The mean diameter of corneoepithelial lesions exposed to physiologic saline decreased from 4.78 mm +/- 0.19 (SD) to 4.44 +/- 0.17 mm between 20 and 26 hours. After 24 hours, the mean lesion size, compared with physiological saline, was larger after cocaine 5.0% (5.20 +/- 0.26 mm) and 10.0% (5.39 +/- 0.12 mm), tetracaine 0.5% (5.59 +/- 0.35 mm) and 1.0% (5.55 +/- 0.27 mm), and procaine hydrochloride 0.4% (5.76 +/- 0.12 mm), but not after lidocaine 2.0% (5.01 +/- 0.17 mm). Balanced salt solution, tissue-culture medium, ethanol 2.0% to 99.0%, and cocaine 2.0% did not inhibit the wound-healing response. CONCLUSIONS: In an ex vivo whole-globe porcine model, lidocaine 2.0% and cocaine 2.0% were the least toxic anesthetic agents. At all concentrations, ethanol had no impact on wound healing. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22245165 TI - Onset and risk factors for anxiety and depression during the first 2 years after lung transplantation. AB - OBJECTIVE: Anxiety disorders are prominent in chronic lung disease; lung transplant recipients may therefore also be at high risk for these disorders. We sought to provide the first prospective data on rates and risk factors for anxiety disorders as well as depressive disorders during the first 2 years after transplantation. METHOD: A total of 178 lung recipients and a comparison group (126 heart recipients) received psychosocial and Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition assessments at 2, 7, 12, 18 and 24 months posttransplant. Survival analysis determined onset rates and risk factors. RESULTS: The panic disorder rate was higher (P<.05) in lung than heart recipients (18% vs. 8%). Lung and heart recipients did not differ on rates of transplant-related posttraumatic stress disorder (15% vs. 14%), generalized anxiety disorder (4% vs. 3%) or major depression (30% vs. 26%). Risk factors for disorders included pretransplant psychiatric history, female gender, longer wait for transplant, and early posttransplant health problems and psychosocial characteristics (e.g., poorer caregiver support and use of avoidant coping). CONCLUSIONS: Heightened vigilance for panic disorder in lung recipients and major depression in all cardiothoracic recipients is warranted. Strategies to prevent psychiatric disorder should target recipients based not only on pretransplant characteristics but on early posttransplant characteristics as well. PMID- 22245169 TI - Epidemiology of postoperative endophthalmitis in an Asian population: 11-year incidence and effect of intracameral antibiotic agents. AB - PURPOSE: To describe the incidence of postoperative endophthalmitis after cataract surgery in a multiethnic Asian population over an 11-year period, compare the endophthalmitis rates before and after the use of intracameral antibiotic agents, and identify potential risk factors for endophthalmitis. SETTING: Department of Ophthalmology, Tan Tock Seng Hospital, Singapore. DESIGN: Cohort study. METHODS: The incidence and risk factors for postoperative endophthalmitis in patients who had cataract surgery over 11 years were reviewed. Subconjunctival antibiotic agents only were administered over 7 years; in the subsequent 4 years, intracameral cefazolin (1.0 mg/0.1 mL) was used. RESULTS: The overall incidence of postoperative endophthalmitis in 50,177 was 0.042%. Over the 7 years without intracameral antibiotics, the endophthalmitis rate was 0.064% (19/29,539). With the use of intracameral cefazolin, the incidence decreased to 0.01% (2/20,638) (multivariate odds ratio [OR], 13.6; 95% confidence interval [CI], 3.15-58.58; P<.001). The independent risk factors for endophthalmitis were age (OR, 1.05; 95% CI, 1.01-1.09; P=.025) and male sex (0.06% versus 0.02%; OR, 2.96; 95% CI; 1.15-7.65; P=.025). CONCLUSIONS: There was a significant reduction in the rate of postoperative endophthalmitis in a multiethnic Asian population with the use of intracameral cefazolin. Men and older patients were at a higher risk for endophthalmitis. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22245170 TI - Long-term visual outcome after cataract surgery: comparison of healthy eyes and eyes with age-related macular degeneration. AB - PURPOSE: To compare the long-term longitudinal visual acuity outcomes after cataract surgery in eyes with age-related macular degeneration (AMD) at surgery and eyes without comorbidity. SETTING: University-based eye clinic. DESIGN: Longitudinal cohort study. METHODS: Patients having cataract surgery were evaluated over 1 year. A clinical eye examination and corrected distance visual acuity (CDVA) measurement were performed preoperatively and postoperatively as well as 5 and 10 years postoperatively for eligible patients. The patients were divided into functional groups depending on postoperative signs of macular degeneration and postoperative CDVA. RESULTS: The study evaluated 810 patients. The rate of CDVA decline with age was faster in AMD patients than in patients without comorbidity. The slope of the visual acuity decline was similar in the 2 subgroups with AMD (almost normal CDVA and reduced CDVA postoperatively). After adjustment for age, there was a mean loss of 2.3 logMAR letters in patients with no comorbidity and 6.4 letters in patients with AMD at surgery for each decade of increasing age. More than 75% of AMD patients had better CDVA 10 years after surgery than before surgery. CONCLUSIONS: Patients with signs of AMD at cataract surgery had a longitudinally worse visual outcome than patients without clinical signs of AMD. However, there is no reason to discourage patients with concurrent visually significant cataract and AMD from having surgery because most AMD patients had better CDVA 10 years after surgery than before surgery. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 22245171 TI - Impact of a national hospital evaluation program using clinical performance indicators on the use of surgical antibiotic prophylaxis in Korea. AB - OBJECTIVES: Clinical performance measurement in surgical antibiotic prophylaxis (SAP) was implemented as part of a national hospital evaluation program (NHEP) in Korea in 2007. This study investigated changes in SAP quality before and after the implementation of clinical performance measurement. METHODS: The medical records of patients who underwent three types of surgery that were included for assessment in the NHEP (NHEP surgery) - arthroplasty, gastrectomy, and hysterectomy - and two other types of non-NHEP assessment surgery - craniotomy and spine surgery (non-NHEP surgery) - at six hospitals, from August to October in 2006-2008, were retrospectively reviewed. Three clinical indicators of SAP (antibiotic selection, timing of administration of the first dose, and duration) and the development of surgical site infections (SSIs) were compared before and after implementation. RESULTS: A total of 1949 patients were enrolled: 356 arthroplasty, 273 gastrectomy, 615 hysterectomy, 168 craniotomy, and 537 spinal surgery. There were no significant changes in age, gender, wound class, or ASA score for each surgery during the study period. From 2007, SAP quality was significantly improved in NHEP surgery for the three clinical indicators. The timing of administration of the first dose was most markedly improved. SAP quality was also improved in non-NHEP surgery, but not as much as in NHEP surgery. Changes in the SSI rates for each surgery were not significant. CONCLUSIONS: Hospital evaluation using clinical performance indicators can considerably improve the use of SAP. Further studies are warranted to investigate whether this hospital evaluation will decrease the development of SSIs. PMID- 22245172 TI - Honoring nobel laureate Dr. Marshall Nirenberg on decoding brain memory. Preface. PMID- 22245173 TI - Comparative study of the mesostructure of natural and synthetic polyisoprene by size exclusion chromatography-multi-angle light scattering and asymmetrical flow field flow fractionation-multi-angle light scattering. AB - This paper presents results from the first analyses of the mesostructure of natural rubber (NR) by asymmetrical flow field flow fractionation (AF4). The results are compared with those obtained by size exclusion chromatography (SEC) in terms of average molar masses, radius of gyration and insoluble part (or gel quantity). Comparable results were obtained for the sample not containing gel. Conversely, for samples with gel, significant differences were found due to the presence of microaggregates. Contrary to SEC, AF4 fractionation enables partial fractionation of polyisoprene chains and microaggregates in a single run without preliminary treatment. The results presented here also highlight the special structure (very compact spheres) of microaggregates in NR compared to chemical crosslinked microaggregates in synthetic polyisoprene. The advantages and drawbacks of both techniques for analysing NR samples are also discussed. PMID- 22245174 TI - Method development for the characterization of biofuel intermediate products using gas chromatography with simultaneous mass spectrometric and flame ionization detections. AB - Accurate analytical methods are required to develop and evaluate the quality of new renewable transportation fuels and intermediate organic liquid products (OLPs). Unfortunately, existing methods developed for the detailed characterization of petroleum products, are not accurate for many of the OLPs generated from non-petroleum feedstocks. In this study, a method was developed and applied to the detailed characterization of complex OLPs formed during triacylglyceride (TG) pyrolysis which is the basis for generating one class of emerging biofuels. This method uses gas chromatography coupled simultaneously with flame ionization and mass spectrometry detectors (GC-FID/MS). The FID provided accurate quantification of carbonaceous species while MS enabled identification of unknown compounds. A programed temperature vaporizer using a 25 degrees C, 0.1 min, 720 degrees C min(-1), 350 degrees C, 5 min temperature program is employed which minimizes compound discrimination better than the more commonly utilized split/splitless injector, as verified with injections at 250 and 350 degrees C. Two standard mixtures featuring over 150 components are used for accurate identification and a designed calibration standard accounts for compound discrimination at the injector and differing FID responses of various classes of compounds. This new method was used to identify and quantify over 250 species in OLPs generated from canola oil, soybean oil, and canola methyl ester (CME). In addition to hydrocarbons, the method was used to quantify polar (upon derivatization) and unidentified species, plus the unresolved complex mixture that has not typically been determined in previous studies. Repeatability of the analytical method was below 5% RSD for all individual components. Using this method, the mass balance was closed for samples derived from canola and soybean oil but only ca. 77 wt% of the OLP generated from CME could be characterized. The ability to close the mass balance depended on sample origin, demonstrating the need for an accurate quantification method for biofuels at various stages of production. PMID- 22245176 TI - Right-sizing testing for pulmonary embolism: recognizing the risks of detecting any clot. PMID- 22245175 TI - Selection of stationary phase particle geometry using X-ray computed tomography and computational fluid dynamics simulations. AB - The X-ray computed tomography (CT) is used to determine local parameters related to the column packing homogeneity and hydrodynamics in columns packed with spherically and irregularly shaped particles of same size. The results showed that the variation of porosity and axial dispersion coefficient along the column axis is insignificant, compared to their radial distribution. The methodology of using the data attained by CT measurements to perform a CFD simulation of a batch separation of model binary mixtures, with different concentration and separation factors is demonstrated. The results of the CFD simulation study show that columns packed with spherically shaped particles provide higher yield in comparison to columns packed with irregularly shaped particles only below a certain value of the separation factor. The presented methodology can be used for selecting a suited packing material for a particular separation task. PMID- 22245177 TI - Can emergency physicians safely increase the proportion of patients with community-acquired pneumonia who are treated in the outpatient setting? PMID- 22245178 TI - Work, visible and invisible. PMID- 22245179 TI - Do medical interventions for traumatic hyphema reduce the risk of vision loss? PMID- 22245180 TI - Evaluation of a multiplex real time reverse transcription PCR assay for the detection and quantitation of the most common human rotavirus genotypes. AB - Group A rotaviruses (RVs) are important pathogens that cause acute, dehydrating gastroenteritis in infants and young children. In this study, a multiplex real time polymerase chain reaction protocol using primers and TaqMan((r)) probes specific for viral VP4 and VP7 genes was evaluated. This assay offers simultaneous genotyping and quantification of the most common RV genotypes G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. It was compared to the molecular typing results provided by conventional PCR. A total of 92 archived stool specimens obtained from children younger than 5 years old with the diagnosis of acute gastroenteritis were examined. Real-time PCR assay detected rotavirus strains among the most common genotype combinations G4P[8] (70.7%), G1P[8] (10.9%), G2P[4] (5.4%), G9P[8] (2.2%). This new assay described has an acceptable sensitivity (low limit 6.3*10(2)copies/g of stool). PMID- 22245181 TI - Mosaic down syndrome with a marker: molecular cytogenetic characterization of the marker chromosome. AB - Down syndrome is a complex disorder characterized by well defined and distinctive phenotypic features. Approximately 2-3% of all live-born Down individuals are mosaics. Here we report a boy with suspected Down syndrome showing mosaicism for two different cell lines where one cell line is unexpected. The cytogenetic analysis by G-banding revealed a karyotype of 47 XY+21 [20]/46,X+marker [30]. Further, molecular cytogenetic analysis with spectral karyotyping identified the marker as a derivative of Y chromosome. The delineation of Y chromosomal DNA was done by quantitative real-time PCR and aneuploidy detection by quantitative fluorescence PCR. The Y-short tandem repeats typing was performed to estimate the variation in quantity as well as to find out the extent of deletion on Y chromosome using STR markers. Fluorescence in situ hybridization using Y centromeric probe was also performed to confirm the origin of the Y marker. Further fine mapping of the marker was carried out with three bacterial artificial chromosome clones RP11-20H21, RP11-375P13, RP11-71M14, which defined the hypothetical position of the deletion. In our study we defined the extent of deletion of the marker chromosome and also discussed it in relation with mosaicism. This is the first report of mosaic Down syndrome combined with a second de novo mosaic marker derived from the Y chromosome. PMID- 22245182 TI - Associations between two novel rSNPs in 5'-flanking region of the bovine casein gene cluster and milk performance traits. AB - Ten evolutionary conservative sequences with high identity level to homological sequences in other mammal species were revealed in 5'-flanking region of casein's genes cluster. Five novel SNPs located inside of the evolutionary conservative regions were identified. The binding sites were revealed to be present in one allelic variant of four detected SNPs. So these SNPs were considered as rSNPs. Significant differences of allelic frequencies were revealed between beef cow's group and dairy cow's group in two rSNPs (NCE4, NCE7, p<0.001). Different alleles of those two rSNPs were shown to be associated with some milk performance traits in Black-and-White Holstein dairy cows. Significant difference of protein percentage has been found between cows with G/G and A/A genotypes (P<0.05) and A/G and A/A genotypes (P<0.05) for NCE4 polymorphism. The groups of animals with genotypes G/G and A/G for NCE7 polymorphism were significantly different in milk yield at the first lactation (kg) (P<0.01), milk fat yield (kg) (P<0.05) and milk protein yield (kg) (P<0.01). For the last trait the difference was significant also between cows with genotypes G/G and A/A for rSNP NCE7 (P<0.05). PMID- 22245184 TI - Chemical modification of triplex-forming oligonucleotide to promote pyrimidine motif triplex formation at physiological pH. AB - Extreme instability of pyrimidine motif triplex DNA at physiological pH severely limits its use in wide variety of potential applications, such as artificial regulation of gene expression, mapping of genomic DNA, and gene-targeted mutagenesis in vivo. Stabilization of pyrimidine motif triplex at physiological pH is, therefore, crucial for improving its potential in various triplex formation-based strategies in vivo. To this end, we investigated the effect of 3' amino-2'-O,4'-C-methylene bridged nucleic acid modification of triplex-forming oligonucleotide (TFO), in which 2'-O and 4'-C of the sugar moiety were bridged with the methylene chain and 3'-O was replaced by 3'-NH, on pyrimidine motif triplex formation at physiological pH. The modification not only significantly increased the thermal stability of the triplex but also increased the binding constant of triplex formation about 15-fold. The increased magnitude of the binding constant was not significantly changed when the number and position of the modification in TFO changed. The consideration of the observed thermodynamic parameters suggested that the increased rigidity of the modified TFO in the free state resulting from the bridging of different positions of the sugar moiety with an alkyl chain and the increased hydration of the modified TFO in the free state caused by the introduction of polar nitrogen atoms may significantly increase the binding constant at physiological pH. The study on the TFO viability in human serum showed that the modification significantly increased the resistance of TFO against nuclease degradation. This study presents an effective approach for designing novel chemically modified TFOs with higher binding affinity of triplex formation at physiological pH and higher nuclease resistance under physiological condition, which may eventually lead to progress in various triplex-formation based strategies in vivo. PMID- 22245183 TI - Differential requirement for the N-terminal catalytic domain of the DNA polymerase epsilon p255 subunit in the mitotic cell cycle and the endocycle. AB - In Drosophila, the 255kDa catalytic subunit (dpolepsilonp255) and the 58kDa subunit of DNA polymerase epsilon (dpolepsilonp58) have been identified. The N terminus of dpolepsilonp255 carries well-conserved six DNA polymerase subdomains and five 3'->5' exonuclease motifs as observed with Polepsilon in other species. We here examined roles of dpolepsilonp255 during Drosophila development using transgenic fly lines expressing double stranded RNA (dsRNA). Expression of dpolepsilonp255 dsRNA in eye discs induced a small eye phenotype and inhibited DNA synthesis, indicating a role in the G1-S transition and/or S-phase progression of the mitotic cycle. Similarly, expression of dpolepsilonp255 dsRNA in the salivary glands resulted in small size and endoreplication defects, demonstrating a critical role in endocycle progression. In the eye disc, defects induced by knockdown of dpolepsilonp255 were rescued by overexpression of the C terminal region of dpolepsilonp255, indicating that the function of this non catalytic domain is conserved between yeast and Drosophila. However, this was not the case for the salivary gland, suggesting that the catalytic N-terminal region is crucial for endoreplication and its defect cannot be complemented by other DNA polymerases. In addition, several genetic interactants with dpolepsilonp255 including genes related to DNA replication such as RFC, DNA primase, DNA poleta, Mcm10 and Psf2 and chromatin remodeling such as Iswi were also identified. PMID- 22245185 TI - The association between early autistic traits and psychotic experiences in adolescence. AB - BACKGROUND: There has been growing interest in the clinical and biological links between autistic spectrum disorder and psychotic disorders, and between symptoms of these disorders that exist below diagnostic thresholds. Whilst autism and schizophrenia are regarded as distinct disorders, recent studies support an overlap in the genetic architecture across these conditions. Although early neurodevelopmental impairment is associated with psychotic disorders in later life, evidence from longitudinal studies of the relationship between autistic traits and psychotic experiences is limited. Aims The aim of the study is to explore whether children with early autistic traits (social interaction and communication problems, and restricted, repetitive interests and behaviours) are more likely to present with psychotic experiences in early adolescence. METHOD: Longitudinal study using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The mothers of 8232 children were asked about autistic traits in their children as part of the Development and Well-Being Assessment (DAWBA) at the age of 7. Of those, 6439 children completed a semi-structured clinical assessment for psychotic experiences at the age of 12. RESULTS: Children whose mothers had concerns about autistic traits in early life, in particular with regard to speech development or 'rituals'/'habits', were more likely to develop psychotic experiences in early adolescence. The greater the number of early autistic traits a child had, the greater their risk of developing psychotic experiences. These associations were not confounded by IQ, family history of depression or schizophrenia, gender or socio-demographic characteristics. CONCLUSIONS: Childhood autistic traits, and particularly speech problems and odd rituals or unusual habits, are associated with psychotic experiences in adolescence. This may be a result of a shared aetiology or because autistic traits may also be an early precursor of psychotic experiences. PMID- 22245186 TI - Clinical and cognitive correlates of insight in first-episode schizophrenia. AB - This study aims to explore the relationship between clinical symptoms and cognitive functions with different insight dimensions in patients with first episode schizophrenia. Seventy-nine patients were assessed following six months of treatment. Insight was assessed using the abridged version of Scale of Unawareness of Mental Disorder (SUMD). Symptoms were assessed using Positive and Negative Syndrome Scale (PANSS). Cognitive functions were assessed using the Modified Wisconsin Card Sorting Test (MWCST), semantic verbal fluency and the letter-number sequencing (LNS) test from the Wechsler Adult Intelligence Scale (WAIS). Positive, negative and disorganized symptoms were found to be correlated with overall insight and all three general insight dimensions. Only perseverative errors and categories completed of MWCST were correlated with overall insight. Perseverative errors and non-perseverative errors of MWCST were correlated with the awareness of medication effects; perseverative errors of MWCST were also correlated with the awareness of social consequence of the illness. These support the link between poor insight and impaired executive function particularly measured by MWCST. The specific correlation of cognitive functions and different dimensions of insight suggests different underlying mechanism within each dimension of insight. The combined model of symptomatology and cognitive function explained 20.6% to 36.4% of the variance in the lack of insight within the different dimensions. The modest combined relationship of clinical and cognitive function with insight suggests that the exploration of other models in relationship to different insight dimensions is important. PMID- 22245187 TI - A new brain positron emission tomography scanner with semiconductor detectors for target volume delineation and radiotherapy treatment planning in patients with nasopharyngeal carcinoma. AB - PURPOSE: We compared two treatment planning methods for stereotactic boost for treating nasopharyngeal carcinoma (NPC): the use of conventional whole-body bismuth germanate (BGO) scintillator positron emission tomography (PET(CONV)WB) versus the new brain (BR) PET system using semiconductor detectors (PET(NEW)BR). METHODS AND MATERIALS: Twelve patients with NPC were enrolled in this study. [(18)F]Fluorodeoxyglucose-PET images were acquired using both the PET(NEW)BR and the PET(CONV)WB system on the same day. Computed tomography (CT) and two PET data sets were transferred to a treatment planning system, and the PET(CONV)WB and PET(NEW)BR images were coregistered with the same set of CT images. Window width and level values for all PET images were fixed at 3000 and 300, respectively. The gross tumor volume (GTV) was visually delineated on PET images by using either PET(CONV)WB (GTV(CONV)) images or PET(NEW)BR (GTV(NEW)) images. Assuming a stereotactic radiotherapy boost of 7 ports, the prescribed dose delivered to 95% of the planning target volume (PTV) was set to 2000 cGy in 4 fractions. RESULTS: The average absolute volume (+/-standard deviation [SD]) of GTV(NEW) was 15.7 ml (+/-9.9) ml, and that of GTV(CONV) was 34.0 (+/-20.5) ml. The average GTV(NEW) was significantly smaller than that of GTV(CONV) (p = 0.0006). There was no statistically significant difference between the maximum dose (p = 0.0585) and the mean dose (p = 0.2748) of PTV. The radiotherapy treatment plan based on the new gross tumor volume (PLAN(NEW)) significantly reduced maximum doses to the cerebrum and cerebellum (p = 0.0418) and to brain stem (p = 0.0041). CONCLUSION: Results of the present study suggest that the new brain PET system using semiconductor detectors can provide more accurate tumor delineation than the conventional whole-body BGO PET system and may be an important tool for functional and molecular radiotherapy treatment planning. PMID- 22245189 TI - A treatment planning and acute toxicity comparison of two pelvic nodal volume delineation techniques and delivery comparison of intensity-modulated radiotherapy versus volumetric modulated arc therapy for hypofractionated high risk prostate cancer radiotherapy. AB - PURPOSE: To perform a comparison of two pelvic lymph node volume delineation strategies used in intensity-modulated radiotherapy (IMRT) for high risk prostate cancer and to determine the role of volumetric modulated arc therapy (VMAT). METHODS AND MATERIALS: Eighteen consecutive patients accrued to an ongoing clinical trial were identified according to either the nodal contouring strategy as described based on lymphotropic nanoparticle-enhanced magnetic resonance imaging technology (9 patients) or the current Radiation Therapy Oncology Group (RTOG) consensus guidelines (9 patients). Radiation consisted of 45 Gy to prostate, seminal vesicles, and lymph nodes, with a simultaneous integrated boost to the prostate alone, to a total dose of 67.5 Gy delivered in 25 fractions. Prospective acute genitourinary and gastrointestinal toxicities were compared at baseline, during radiotherapy, and 3 months after radiotherapy. Each patient was retrospectively replanned using the opposite method of nodal contouring, and plans were normalized for dosimetric comparison. VMAT plans were also generated according to the RTOG method for comparison. RESULTS: RTOG plans resulted in a significantly lower rate of genitourinary frequency 3 months after treatment. The dosimetric comparison showed that the RTOG plans resulted in both favorable planning target volume (PTV) coverage and lower organs at risk (OARs) and integral (ID) doses. VMAT required two to three arcs to achieve adequate treatment plans, we did not observe consistent dosimetric benefits to either the PTV or the OARs, and a higher ID was observed. However, treatment times were significantly shorter with VMAT. CONCLUSION: The RTOG guidelines for pelvic nodal volume delineation results in favorable dosimetry and acceptable acute toxicities for both the target and OARs. We are unable to conclude that VMAT provides a benefit compared with IMRT. PMID- 22245188 TI - Effect of gold marker seeds on magnetic resonance spectroscopy of the prostate. AB - PURPOSE: Magnetic resonance stereoscopic imaging (MRSI) of the prostate is an emerging technique that may enhance targeting and assessment in radiotherapy. Current practices in radiotherapy invariably involve image guidance. Gold seed fiducial markers are often used to perform daily prostate localization. If MRSI is to be used in targeting prostate cancer and therapy assessment, the impact of gold seeds on MRSI must be investigated. The purpose of this study was to quantify the effects of gold seeds on the quality of MRSI data acquired in phantom experiments. METHODS AND MATERIALS: A cylindrical plastic phantom with a spherical cavity 10 centimeters in diameter wss filled with water solution containing choline, creatine, and citrate. A gold seed fiducial marker was put near the center of the phantom mounted on a plastic stem. Spectra were acquired at 1.5 Tesla by use of a clinical MRSI sequence. The ratios of choline + creatine to citrate (CC/Ci) were compared in the presence and absence of gold seeds. Spectra in the vicinity of the gold seed were analyzed. RESULTS: The maximum coefficient of variation of CC/Ci induced by the gold seed was found to be 10% in phantom experiments at 1.5 T. CONCLUSION: MRSI can be used in prostate radiotherapy in the presence of gold seed markers. Gold seeds cause small effects (in the order of the standard deviation) on the ratio of the metabolite's CC/Ci in the phantom study done on a 1.5-T scanner. It is expected that gold seed markers will have similar negligible effect on spectra from prostate patients. The maximum of 10% of variation in CC/Ci found in the phantom study also sets a limit on the threshold accuracy of CC/Ci values for deciding whether the tissue characterized by a local spectrum is considered malignant and whether it is a candidate for local boost in radiotherapy dose. PMID- 22245190 TI - Craniocaudal safety margin calculation based on interfractional changes in tumor motion in lung SBRT assessed with an EPID in cine mode. AB - PURPOSE: To evaluate setup error and interfractional changes in tumor motion magnitude using an electric portal imaging device in cine mode (EPID cine) during the course of stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC) and to calculate margins to compensate for these variations. MATERIALS AND METHODS: Subjects were 28 patients with Stage I NSCLC who underwent SBRT. Respiratory-correlated four-dimensional computed tomography (4D-CT) at simulation was binned into 10 respiratory phases, which provided average intensity projection CT data sets (AIP). On 4D-CT, peak-to-peak motion of the tumor (M-4DCT) in the craniocaudal direction was assessed and the tumor center (mean tumor position [MTP]) of the AIP (MTP-4DCT) was determined. At treatment, the tumor on cone beam CT was registered to that on AIP for patient setup. During three sessions of irradiation, peak-to-peak motion of the tumor (M-cine) and the mean tumor position (MTP-cine) were obtained using EPID cine and in-house software. Based on changes in tumor motion magnitude (?M) and patient setup error (?MTP), defined as differences between M-4DCT and M-cine and between MTP-4DCT and MTP-cine, a margin to compensate for these variations was calculated with Stroom's formula. RESULTS: The means (+/-standard deviation: SD) of M-4DCT and M cine were 3.1 (+/-3.4) and 4.0 (+/-3.6) mm, respectively. The means (+/-SD) of ?M and ?MTP were 0.9 (+/-1.3) and 0.2 (+/-2.4) mm, respectively. Internal target volume-planning target volume (ITV-PTV) margins to compensate for ?M, ?MTP, and both combined were 3.7, 5.2, and 6.4 mm, respectively. CONCLUSION: EPID cine is a useful modality for assessing interfractional variations of tumor motion. The ITV PTV margins to compensate for these variations can be calculated. PMID- 22245191 TI - Functional image-guided radiotherapy planning in respiratory-gated intensity modulated radiotherapy for lung cancer patients with chronic obstructive pulmonary disease. AB - PURPOSE: To investigate the incorporation of functional lung image-derived low attenuation area (LAA) based on four-dimensional computed tomography (4D-CT) into respiratory-gated intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) in treatment planning for lung cancer patients with chronic obstructive pulmonary disease (COPD). METHODS AND MATERIALS: Eight lung cancer patients with COPD were the subjects of this study. LAA was generated from 4D-CT data sets according to CT values of less than than -860 Hounsfield units (HU) as a threshold. The functional lung image was defined as the area where LAA was excluded from the image of the total lung. Two respiratory-gated radiotherapy plans (70 Gy/35 fractions) were designed and compared in each patient as follows: Plan A was an anatomical IMRT or VMAT plan based on the total lung; Plan F was a functional IMRT or VMAT plan based on the functional lung. Dosimetric parameters (percentage of total lung volume irradiated with >=20 Gy [V20], and mean dose of total lung [MLD]) of the two plans were compared. RESULTS: V20 was lower in Plan F than in Plan A (mean 1.5%, p = 0.025 in IMRT, mean 1.6%, p = 0.044 in VMAT) achieved by a reduction in MLD (mean 0.23 Gy, p = 0.083 in IMRT, mean 0.5 Gy, p = 0.042 in VMAT). No differences were noted in target volume coverage and organ-at risk doses. CONCLUSIONS: Functional IGRT planning based on LAA in respiratory guided IMRT or VMAT appears to be effective in preserving a functional lung in lung cancer patients with COPD. PMID- 22245192 TI - Electron irradiation of conjunctival lymphoma--Monte Carlo simulation of the minute dose distribution and technique optimization. AB - PURPOSE: External beam radiotherapy is the only conservative curative approach for Stage I non-Hodgkin lymphomas of the conjunctiva. The target volume is geometrically complex because it includes the eyeball and lid conjunctiva. Furthermore, the target volume is adjacent to radiosensitive structures, including the lens, lacrimal glands, cornea, retina, and papilla. The radiotherapy planning and optimization requires accurate calculation of the dose in these anatomical structures that are much smaller than the structures traditionally considered in radiotherapy. Neither conventional treatment planning systems nor dosimetric measurements can reliably determine the dose distribution in these small irradiated volumes. METHODS AND MATERIALS: The Monte Carlo simulations of a Varian Clinac 2100 C/D and human eye were performed using the penelope and penEasyLinac codes. Dose distributions and dose volume histograms were calculated for the bulbar conjunctiva, cornea, lens, retina, papilla, lacrimal gland, and anterior and posterior hemispheres. RESULTS: The simulated results allow choosing the most adequate treatment setup configuration, which is an electron beam energy of 6 MeV with additional bolus and collimation by a cerrobend block with a central cylindrical hole of 3.0 cm diameter and central cylindrical rod of 1.0 cm diameter. CONCLUSIONS: Monte Carlo simulation is a useful method to calculate the minute dose distribution in ocular tissue and to optimize the electron irradiation technique in highly critical structures. Using a voxelized eye phantom based on patient computed tomography images, the dose distribution can be estimated with a standard statistical uncertainty of less than 2.4% in 3 min using a computing cluster with 30 cores, which makes this planning technique clinically relevant. PMID- 22245193 TI - Is short-interval mammography necessary after breast conservation surgery and radiation treatment in breast cancer patients? AB - PURPOSE: The optimum timing and frequency of mammography in breast cancer patients after breast-conserving therapy (BCT) are controversial. The American Society of Clinical Oncology recommends the first posttreatment mammogram 1 year after diagnosis but no earlier than 6 months after completion of radiotherapy. The National Comprehensive Cancer Network recommends annual mammography. Intermountain Healthcare currently follows a more frequent mammography schedule during the first 2 years in BCT patients. This retrospective study was undertaken to determine the cancer yield mammography during the first 2 years after BCT. METHODS AND MATERIALS: 1,435 patients received BCT at Intermountain Healthcare between 2003 and 2007, inclusive. Twenty-three patients had bilateral breast cancer (1,458 total breasts). Patients were followed up for 24 months after diagnosis. The 1- and 2-year mammography yields were determined and compared with those of the general screening population. RESULTS: 1,079 breasts had mammography at less than 1 year, and two ipsilateral recurrences (both noninvasive) were identified; 1,219 breasts had mammography during the second year, and nine recurrences (three invasive, six noninvasive) were identified. Of the 11 ipsilateral recurrences during the study, three presented with symptoms and eight were identified by mammography alone. The mammography yield was 1.9 cancers per 1,000 breasts the first year and 4.9 per 1,000 the second year. CONCLUSIONS: These data demonstrate that the mammography yield during the first 2 years after BCT is not greater than that in the general population, and they support the policy for initiating followup mammography at 1 year after BCT. PMID- 22245194 TI - Respiration-correlated image guidance is the most important radiotherapy motion management strategy for most lung cancer patients. AB - PURPOSE: The purpose of this study was to quantify the effects of four dimensional computed tomography (4DCT), 4D image guidance (4D-IG), and beam gating on calculated treatment field margins in a lung cancer patient population. MATERIALS AND METHODS: Images were acquired from 46 lung cancer patients participating in four separate protocols at three institutions in Europe and the United States. Seven patients were imaged using fluoroscopy, and 39 patients were imaged using 4DCT. The magnitude of respiratory tumor motion was measured. The required treatment field margins were calculated using a statistical recipe (van Herk M, et al. Int J Radiat Oncol Biol Phys 2000;474:1121-1135), with magnitudes of all uncertainties, except respiratory peak-to-peak displacement, the same for all patients, taken from literature. Required margins for respiratory motion management were calculated using the residual respiratory tumor motion for each patient for various motion management strategies. Margin reductions for respiration management were calculated using 4DCT, 4D-IG, and gated beam delivery. RESULTS: The median tumor motion magnitude was 4.4 mm for the 46 patients (range 0-29.3 mm). This value corresponded to required treatment field margins of 13.7 to 36.3 mm (median 14.4 mm). The use of 4DCT, 4D-IG, and beam gating required margins that were reduced by 0 to 13.9 mm (median 0.5 mm), 3 to 5.2 mm (median 5.1 mm), and 0 to 7 mm (median 0.2 mm), respectively, to a total of 8.5 to 12.4 mm (median 8.6 mm). CONCLUSION: A respiratory management strategy for lung cancer radiotherapy including planning on 4DCT scans and daily image guidance provides a potential reduction of 37% to 47% in treatment field margins. The 4D image guidance strategy was the most effective strategy for >85% of the patients. PMID- 22245195 TI - Factors associated with chest wall toxicity after accelerated partial breast irradiation using high-dose-rate brachytherapy. AB - PURPOSE: The purpose of this analysis was to evaluate dose-volume relationships associated with a higher probability for developing chest wall toxicity (pain) after accelerated partial breast irradiation (APBI) by using both single-lumen and multilumen brachytherapy. METHODS AND MATERIALS: Rib dose data were available for 89 patients treated with APBI and were correlated with the development of chest wall/rib pain at any point after treatment. Ribs were contoured on computed tomography planning scans, and rib dose-volume histograms (DVH) along with histograms for other structures were constructed. Rib DVH data for all patients were sampled at all volumes >=0.008 cubic centimeter (cc) (for maximum dose related to pain) and at volumes of 0.5, 1, 2, and 3 cc for analysis. Rib pain was evaluated at each follow-up visit. Patient responses were marked as yes or no. No attempt was made to grade responses. Eighty-nine responses were available for this analysis. RESULTS: Nineteen patients (21.3%) complained of transient chest wall/rib pain at any point in follow-up. Analysis showed a direct correlation between total dose received and volume of rib irradiated with the probability of developing rib/chest wall pain at any point after follow-up. The median maximum dose at volumes >=0.008 cc of rib in patients who experienced chest wall pain was 132% of the prescribed dose versus 95% of the prescribed dose in those patients who did not experience pain (p = 0.0035). CONCLUSIONS: Although the incidence of chest wall/rib pain is quite low with APBI brachytherapy, attempts should be made to keep the volume of rib irradiated at a minimum and the maximum dose received by the chest wall as low as reasonably achievable. PMID- 22245196 TI - How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. AB - PURPOSE: To verify how the classification according to the American Society for Therapeutic Radiation Oncology (ASTRO) consensus statement (CS) for the application of accelerated partial breast irradiation (APBI) fits patients treated with intraoperative radiotherapy with electrons (ELIOT) at a single institution. METHODS AND MATERIALS: The study included 1,822 patients treated with ELIOT as the sole radiation modality outside of a clinical trial at the European Institute of Oncology after breast-conserving surgery for invasive breast cancer, who were classified into CS groups of suitable, cautionary, and unsuitable. The outcome in terms of ipsilateral breast recurrence, regional node relapse, distant metastases, progression free-survival, cause-specific survival, and overall survival were assessed. RESULTS: All the 1,822 cases except for 25 could be classified according to ASTRO CS: 294 patients met the criteria for inclusion into the suitable group, 691 patients into the cautionary group, and 812 patients into the unsuitable group. The 5-year rate of ipsilateral breast recurrence for suitable, cautionary, and unsuitable groups were 1.5%, 4.4%, and 8.8%, respectively (p = 0.0003). Whereas the regional node relapse showed no difference, the rate of distant metastases was significantly different in the unsuitable group compared with the suitable and cautionary groups, having a significant impact on survival. CONCLUSION: In the context of patients treated with ELIOT, the ASTRO guidelines identify well the groups for whom APBI might be considered as an effective alternative to whole breast radiotherapy and also identify groups for whom APBI is not indicated. PMID- 22245197 TI - Protons offer reduced normal-tissue exposure for patients receiving postoperative radiotherapy for resected pancreatic head cancer. AB - PURPOSE: To determine the potential role for adjuvant proton-based radiotherapy (PT) for resected pancreatic head cancer. METHODS AND MATERIALS: Between June 2008 and November 2008, 8 consecutive patients with resected pancreatic head cancers underwent optimized intensity-modulated radiotherapy (IMRT) treatment planning. IMRT plans used between 10 and 18 fields and delivered 45 Gy to the initial planning target volume (PTV) and a 5.4 Gy boost to a reduced PTV. PTVs were defined according to the Radiation Therapy Oncology Group 9704 radiotherapy guidelines. Ninety-five percent of PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Normal tissue constraints were as follows: right kidney V18 Gy to <70%; left kidney V18 Gy to <30%; small bowel/stomach V20 Gy to <50%, V45 Gy to <15%, V50 Gy to <10%, and V54 Gy to <5%; liver V30 Gy to <60%; and spinal cord maximum to 46 Gy. Optimized two- to three field three-dimensional conformal proton plans were retrospectively generated on the same patients. The team generating the proton plans was blinded to the dose distributions achieved by the IMRT plans. The IMRT and proton plans were then compared. A Wilcoxon paired t-test was performed to compare various dosimetric points between the two plans for each patient. RESULTS: All proton plans met all normal tissue constraints and were isoeffective with the corresponding IMRT plans in terms of PTV coverage. The proton plans offered significantly reduced normal tissue exposure over the IMRT plans with respect to the following: median small bowel V20 Gy, 15.4% with protons versus 47.0% with IMRT (p = 0.0156); median gastric V20 Gy, 2.3% with protons versus 20.0% with IMRT (p = 0.0313); and median right kidney V18 Gy, 27.3% with protons versus 50.5% with IMRT (p = 0.0156). CONCLUSIONS: By reducing small bowel and stomach exposure, protons have the potential to reduce the acute and late toxicities of postoperative chemoradiation in this setting. PMID- 22245198 TI - Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. AB - PURPOSE: The outcome of recurrent ependymoma in children is dismal. Reirradiation has been proposed as an effective modality for ependymoma at relapse. However, the toxicity and outcome benefits of this approach have not been well established. METHODS AND MATERIALS: We conducted a retrospective population-based study of all patients with recurrent ependymoma treated between 1986 and 2010 in our institution. Demographic, treatment, and outcome data were analyzed for the entire cohort. RESULTS: Of 113 patients with intracranial ependymoma, 47 patients relapsed. At the time of relapse, 29 patients were treated with surgical resection and/or chemotherapy, and 18 patients received full-dose (>= 54 Gy focal and/or craniospinal) reirradiation with or without surgery at recurrence. Reirradiation was tolerated well with no severe acute complications noticed. Three-year overall survival was 7% +/- 6% and 81% +/- 12% for nonreirradiated and reirradiated patients, respectively (p < 0.0001). Time to second progression after reirradiation was significantly longer than time to first progression. This surprising phenomenon was associated with improved progression-free survival for tumors with evidence of DNA damage (n = 15; p = 0.002). At a mean follow-up of 3.73 years, only 2/18 patients had endocrine dysfunction, and 1 patient required special education support. However, a decline in intellectual function from pre- to postreirradiation assessment was observed. CONCLUSIONS: Reirradiation is an effective treatment that may change the natural history of recurrent ependymoma in children. However, this change may be associated with increased neurocognitive toxicity. Additional follow-up is needed to determine the risk of late recurrence, secondary radiation-induced tumors, and long-term functional outcome of these patients. PMID- 22245199 TI - Impact of statistical learning methods on the predictive power of multivariate normal tissue complication probability models. AB - PURPOSE: To study the impact of different statistical learning methods on the prediction performance of multivariate normal tissue complication probability (NTCP) models. METHODS AND MATERIALS: In this study, three learning methods, stepwise selection, least absolute shrinkage and selection operator (LASSO), and Bayesian model averaging (BMA), were used to build NTCP models of xerostomia following radiotherapy treatment for head and neck cancer. Performance of each learning method was evaluated by a repeated cross-validation scheme in order to obtain a fair comparison among methods. RESULTS: It was found that the LASSO and BMA methods produced models with significantly better predictive power than that of the stepwise selection method. Furthermore, the LASSO method yields an easily interpretable model as the stepwise method does, in contrast to the less intuitive BMA method. CONCLUSIONS: The commonly used stepwise selection method, which is simple to execute, may be insufficient for NTCP modeling. The LASSO method is recommended. PMID- 22245200 TI - High and low LET radiation differentially induce normal tissue damage signals. AB - PURPOSE: Radiotherapy using high linear energy transfer (LET) radiation is aimed at efficiently killing tumor cells while minimizing dose (biological effective) to normal tissues to prevent toxicity. It is well established that high LET radiation results in lower cell survival per absorbed dose than low LET radiation. However, whether various mechanisms involved in the development of normal tissue damage may be regulated differentially is not known. Therefore the aim of this study was to investigate whether two actions related to normal tissue toxicity, p53-induced apoptosis and expression of the profibrotic gene PAI-1 (plasminogen activator inhibitor 1), are differentially induced by high and low LET radiation. METHODS AND MATERIALS: Cells were irradiated with high LET carbon ions or low LET photons. Cell survival assays were performed, profibrotic PAI-1 expression was monitored by quantitative polymerase chain reaction, and apoptosis was assayed by annexin V staining. Activation of p53 by phosphorylation at serine 315 and serine 37 was monitored by Western blotting. Transfections of plasmids expressing p53 mutated at serines 315 and 37 were used to test the requirement of these residues for apoptosis and expression of PAI-1. RESULTS: As expected, cell survival was lower and induction of apoptosis was higher in high -LET irradiated cells. Interestingly, induction of the profibrotic PAI-1 gene was similar with high and low LET radiation. In agreement with this finding, phosphorylation of p53 at serine 315 involved in PAI-1 expression was similar with high and low LET radiation, whereas phosphorylation of p53 at serine 37, involved in apoptosis induction, was much higher after high LET irradiation. CONCLUSIONS: Our results indicate that diverse mechanisms involved in the development of normal tissue damage may be differentially affected by high and low LET radiation. This may have consequences for the development and manifestation of normal tissue damage. PMID- 22245201 TI - High-dose radiotherapy with or without androgen deprivation therapy for intermediate-risk prostate cancer: cancer control and toxicity outcomes. AB - PURPOSE: To evaluate the impact of short-course androgen deprivation therapy (ADT) on cancer control outcomes and toxicity in intermediate-risk prostate cancer treated with dose-escalated external beam radiotherapy (high-dose radiotherapy [HDRT]). METHODS AND MATERIALS: Demographic, disease, and treatment characteristics of prostate cancer patients at 2 institution consortiums were charted. Of 296 men with intermediate-risk prostate cancer (defined as >=T2b, prostate-specific antigen level >10 ng/mL, or Gleason score [GS] of 7, with none of the following: >=T3, prostate-specific antigen level >20 ng/mL, GS >=8, or positive nodes) treated with HDRT to a dose of 72 Gy or greater, 123 received short-course ADT and 173 did not. Univariate and multivariate analyses on biochemical failure-free survival (BFFS) (including subset analysis by disease factors) and on overall survival (OS) were performed, as were comparisons of gastrointestinal (GI) and genitourinary (GU) toxicity rates. RESULTS: For the whole group, the median dose was 75.6 Gy; the minimum follow-up was 2 years, and the median follow-up was 47.4 months. For ADT vs. no ADT, the 5-year BFFS rate was 86% vs. 79% (p = 0.138) and the 5-year OS rate was 87% vs. 80% (p = 0.159). On multivariate analysis, percent positive cores (PPC) (p = 0.002) and GS (p = 0.008) were significantly associated with BFFS, with ADT showing a trend (p = 0.055). The impact of ADT was highest in the subsets with PPC greater than 50% (p = 0.019), GS 4+3 (p = 0.078), and number of risk factors greater than 1 (p = 0.022). Only intensity-modulated radiotherapy use (p = 0.012) and GS (p = 0.023) reached significance for OS, and there were no significant differences in GU or GI toxicity. CONCLUSIONS: Although the use of ADT with HDRT did not influence BFFS, our study suggests a benefit in patients with PPC greater than 50%, GS 4+3, or multiple risk factors. No OS benefit was shown, and ADT was not associated with additional radiotherapy-related GI or GU toxicity. PMID- 22245202 TI - Formulation of the multi-hit model with a non-Poisson distribution of hits. AB - PURPOSE: We proposed a formulation of the multi-hit single-target model in which the Poisson distribution of hits was replaced by a combination of two distributions: one for the number of particles entering the target and one for the number of hits a particle entering the target produces. Such an approach reflects the fact that radiation damage is a result of two different random processes: particle emission by a radiation source and interaction of particles with matter inside the target. METHODS AND MATERIALS: Poisson distribution is well justified for the first of the two processes. The second distribution depends on how a hit is defined. To test our approach, we assumed that the second distribution was also a Poisson distribution. The two distributions combined resulted in a non-Poisson distribution. We tested the proposed model by comparing it with previously reported data for DNA single- and double-strand breaks induced by protons and electrons, for survival of a range of cell lines, and variation of the initial slopes of survival curves with radiation quality for heavy-ion beams. RESULTS: Analysis of cell survival equations for this new model showed that they had realistic properties overall, such as the initial and high-dose slopes of survival curves, the shoulder, and relative biological effectiveness (RBE) In most cases tested, a better fit of survival curves was achieved with the new model than with the linear-quadratic model. The results also suggested that the proposed approach may extend the multi-hit model beyond its traditional role in analysis of survival curves to predicting effects of radiation quality and analysis of DNA strand breaks. CONCLUSIONS: Our model, although conceptually simple, performed well in all tests. The model was able to consistently fit data for both cell survival and DNA single- and double-strand breaks. It correctly predicted the dependence of radiation effects on parameters of radiation quality. PMID- 22245203 TI - Radioprotective effect of lidocaine on function and ultrastructure of salivary glands receiving fractionated radiation. AB - PURPOSE: Radiation-induced xerostomia still represents a common side effect after radiotherapy for head-and-neck malignancies. The aim of the present study was to examine the radioprotective effect of lidocaine hydrochloride during fractionated radiation in an experimental animal model. METHODS AND MATERIALS: To evaluate the influence of different radiation doses on salivary gland function and the radioprotective effect of lidocaine, rabbits were irradiated with 15, 25, 30, and 35 Gy (equivalent doses in 2-Gy fractions equivalent to 24, 40, 48, and 56 Gy, respectively). Lidocaine hydrochloride (10 and 12 mg/kg) was administered before every radiation fraction in the treatment groups. Salivary gland function was assessed by flow sialometry and sialoscintigraphy, and the morphologic changes were evaluated using transmission electron microscopy. RESULTS: Functional impairment was first observed after 35 Gy and pretreatment with lidocaine improved radiation tolerance of both parotid and submandibular glands. The use of 12 mg/kg lidocaine was superior and displayed significant radioprotection with regard to flow sialometry and sialoscintigraphy. The ultrastructure was largely preserved after pretreatment with both lidocaine doses. CONCLUSIONS: Lidocaine represents an effective radioprotective agent and a promising approach for clinical application to avoid radiation-induced functional impairment of salivary glands. PMID- 22245204 TI - Standardizing naming conventions in radiation oncology. AB - PURPOSE: The aim of this study was to report on the development of a standardized target and organ-at-risk naming convention for use in radiation therapy and to present the nomenclature for structure naming for interinstitutional data sharing, clinical trial repositories, integrated multi-institutional collaborative databases, and quality control centers. This taxonomy should also enable improved plan benchmarking between clinical institutions and vendors and facilitation of automated treatment plan quality control. MATERIALS AND METHODS: The Advanced Technology Consortium, Washington University in St. Louis, Radiation Therapy Oncology Group, Dutch Radiation Oncology Society, and the Clinical Trials RT QA Harmonization Group collaborated in creating this new naming convention. The International Commission on Radiation Units and Measurements guidelines have been used to create standardized nomenclature for target volumes (clinical target volume, internal target volume, planning target volume, etc.), organs at risk, and planning organ-at-risk volumes in radiation therapy. The nomenclature also includes rules for specifying laterality and margins for various structures. The naming rules distinguish tumor and nodal planning target volumes, with correspondence to their respective tumor/nodal clinical target volumes. It also provides rules for basic structure naming, as well as an option for more detailed names. Names of nonstandard structures used mainly for plan optimization or evaluation (rings, islands of dose avoidance, islands where additional dose is needed [dose painting]) are identified separately. RESULTS: In addition to its use in 16 ongoing Radiation Therapy Oncology Group advanced technology clinical trial protocols and several new European Organization for Research and Treatment of Cancer protocols, a pilot version of this naming convention has been evaluated using patient data sets with varying treatment sites. All structures in these data sets were satisfactorily identified using this nomenclature. CONCLUSIONS: Use of standardized naming conventions is important to facilitate comparison of dosimetry across patient datasets. The guidelines presented here will facilitate international acceptance across a wide range of efforts, including groups organizing clinical trials, Radiation Oncology Institute, Dutch Radiation Oncology Society, Integrating the Healthcare Enterprise, Radiation Oncology domain (IHE-RO), and Digital Imaging and Communication in Medicine (DICOM). PMID- 22245206 TI - Individualized dose prescription for hypofractionation in advanced non-small-cell lung cancer radiotherapy: an in silico trial. AB - PURPOSE: Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various hypofractionation schemes delivered with intensity-modulated radiation therapy. METHODS AND MATERIALS: For 38 Stage III NSCLC patients, the dose level of an existing curative treatment plan with standard fractionation (66 Gy) was rescaled based on dose constraints for the lung, spinal cord, esophagus, brachial plexus, and heart. The effect on tumor total dose (TTD) and biologic tumor effective dose in 2-Gy fractions (TED) corrected for overall treatment time (OTT) was compared for isotoxic and maximally tolerable schemes given in 15, 20, and 33 fractions. Rescaling was accomplished by altering the dose per fraction and/or the number of fractions while keeping the relative dose distribution of the original treatment plan. RESULTS: For 30 of the 38 patients, dose escalation by individualized hypofractionation yielded therapeutic gain. For the maximally tolerable dose scheme in 33 fractions (MTD(33)), individualized dose escalation resulted in a 2.5-21% gain in TTD. In the isotoxic schemes, the number of fractions could be reduced with a marginal increase in TED. For the maximally tolerable dose schemes, the TED could be escalated up to 36.6%, and for all patients beyond the level of the isotoxic and the MTD(33) schemes (range, 3.3-36.6%). Reduction of the OTT contributed to the therapeutic gain of the shortened schemes. For the maximally tolerable schemes, the maximum esophageal dose was the dominant dose limiting constraint in most patients. CONCLUSIONS: This modeling study showed that individualized dose prescription for hypofractionation in NSCLC radiotherapy, based on scaling of existing treatment plans up to normal tissue dose constraints, enables dose escalation with therapeutic gain in 79% of the cases. PMID- 22245205 TI - Predicting the risk of secondary lung malignancies associated with whole-breast radiation therapy. AB - PURPOSE: The risk of secondary lung malignancy (SLM) is a significant concern for women treated with whole-breast radiation therapy after breast-conserving surgery for early-stage breast cancer. In this study, a biologically based secondary malignancy model was used to quantify the risk of secondary lung malignancies (SLMs) associated with several common methods of delivering whole-breast radiation therapy (RT). METHODS AND MATERIALS: Both supine and prone computed tomography simulations of 15 women with early breast cancer were used to generate standard fractionated and hypofractionated whole-breast RT treatment plans for each patient. Dose-volume histograms (DVHs) of the ipsilateral breast and lung were calculated for each patient on each plan. A model of spontaneous and radiation-induced carcinogenesis was used to determine the relative risks of SLMs for the different treatment techniques. RESULTS: A higher risk of SLMs was predicted for supine breast irradiation when compared with prone breast irradiation for both the standard fractionation and hypofractionation schedules (relative risk [RR] = 2.59, 95% confidence interval (CI) = 2.30-2.88, and RR = 2.68, 95% CI = 2.39-2.98, respectively). No difference in risk of SLMs was noted between standard fractionation and hypofractionation schedules in either the supine position (RR = 1.05, 95% CI = 0.97-1.14) or the prone position (RR = 1.01, 95% CI = 0.88-1.15). CONCLUSIONS: Compared with supine whole-breast irradiation, prone breast irradiation is associated with a significantly lower predicted risk of secondary lung malignancy. In this modeling study, fractionation schedule did not have an impact on the risk of SLMs in women treated with whole-breast RT for early breast cancer. PMID- 22245207 TI - How effective are clinical pathways with and without online peer-review? An analysis of bone metastases pathway in a large, integrated National Cancer Institute-Designated Comprehensive Cancer Center Network. AB - PURPOSE: Clinical pathways are an important tool used to manage the quality in health care by standardizing processes. This study evaluated the impact of the implementation of a peer-reviewed clinical pathway in a large, integrated National Cancer Institute-Designated Comprehensive Cancer Center Network. METHODS: In 2003, we implemented a clinical pathway for the management of bone metastases with palliative radiation therapy. In 2009, we required the entry of management decisions into an online tool that records pathway choices. The pathway specified 1 or 5 fractions for symptomatic bone metastases with the option of 10-14 fractions for certain clinical situations. The data were obtained from 13 integrated sites (3 central academic, 10 community locations) from 2003 through 2010. RESULTS: In this study, 7905 sites were treated with 64% of courses delivered in community practice and 36% in academic locations. Academic practices were more likely than community practices to treat with 1-5 fractions (63% vs. 23%; p < 0.0001). The number of delivered fractions decreased gradually from 2003 to 2010 for both academic and community practices (p < 0.0001); however, greater numbers of fractions were selected more often in community practices (p < 0.0001). Using multivariate logistic regression, we found that a significantly greater selection of 1-5 fractions developed after implementation online pathway monitoring (2009) with an odds ratio of 1.2 (confidence interval, 1.1-1.4) for community and 1.3 (confidence interval, 1.1-1.6) for academic practices. The mean number of fractions also decreased after online peer review from 6.3 to 6.0 for academic (p = 0.07) and 9.4 to 9.0 for community practices (p < 0.0001). CONCLUSION: This is one of the first studies to examine the efficacy of a clinical pathway for radiation oncology in an integrated cancer network. Clinical pathway implementation appears to be effective in changing patterns of care, particularly with online clinical peer review as a valuable aid to encourage adherence to evidence-based practice. PMID- 22245208 TI - Phase I trial using the proteasome inhibitor bortezomib and concurrent chemoradiotherapy for head-and-neck malignancies. AB - PURPOSE: Advanced head-and-neck cancer (HNC) remains a difficult disease to cure. Proteasome inhibitors such as bortezomib have the potential to improve survival over chemoradiotherapy alone. This Phase I dose-escalation study examined the potential of bortezomib in combination with cisplatin chemotherapy and concurrent radiation in the treatment of locally advanced and recurrent HNC. METHODS AND MATERIALS: Eligible patients received cisplatin once weekly at 30 mg/m(2) per week and bortezomib along with concurrent radiation. Bortezomib was given on Days 1, 4, 8, and 11 every 3 weeks, with an initial starting dose of 0.7 mg/m(2) and escalation levels of 1.0 and 1.3 mg/m(2). Dose escalation was performed only after assessment to rule out any dose-limiting toxicity. RESULTS: We enrolled 27 patients with HNC, including 17 patients with recurrent disease who had received prior irradiation. Patients received bortezomib dose levels of 0.7 mg/m(2) (7 patients), 1.0 mg/m(2) (10 patients), and 1.3 mg/m(2) (10 patients). No Grade 5 toxicities, 3 Grade 4 toxicities (all hematologic and considered dose-limiting toxicities), and 39 Grade 3 toxicities (in 20 patients) were observed. With a median follow-up of 7.4 months, the overall median survival was 24.7 months (48.4 months for advanced HNC patients and 15.4 months for recurrent HNC patients). CONCLUSION: Bortezomib in combination with radiation therapy and cisplatin chemotherapy is safe in the treatment of HNC with a bortezomib maximum tolerated dose of 1.0 mg/m(2) in patients previously treated for HNC and 1.3 mg/m(2) in radiation-naive patients. PMID- 22245209 TI - Proton therapy for spinal ependymomas: planning, acute toxicities, and preliminary outcomes. AB - PURPOSE: To report acute toxicities and preliminary outcomes for pediatric patients with ependymomas of the spine treated with proton beam therapy at the MD Anderson Cancer Center. METHODS AND MATERIALS: Eight pediatric patients received proton beam irradiation between October 2006 and September 2010 for spinal ependymomas. Toxicity data were collected weekly during radiation therapy and all follow-up visits. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS: All patients had surgical resection of the tumor before irradiation (7 subtotal resection and 1 gross total resection). Six patients had World Health Organization Grade I ependymomas, and two had World Health Organization Grade II ependymomas. Patients had up to 3 surgical interventions before radiation therapy (range, 1-3; median, 1). Three patients received proton therapy after recurrence and five as part of their primary management. The entire vertebral body was treated in all but 2 patients. The mean radiation dose was 51.1 cobalt gray equivalents (range, 45 to 54 cobalt gray equivalents). With a mean follow-up of 26 months from the radiation therapy start date (range, 7-51 months), local control, event-free survival, and overall survival rates were all 100%. The most common toxicities during treatment were Grade 1 or 2 erythema (75%) and Grade 1 fatigue (38%). No patients had a Grade 3 or higher adverse event. Proton therapy dramatically reduced dose to all normal tissues anterior to the vertebral bodies in comparison to photon therapy. CONCLUSION: Preliminary outcomes show the expected control rates with favorable acute toxicity profiles. Proton beam therapy offers a powerful treatment option in the pediatric population, where adverse events related to radiation exposure are of concern. Extended follow-up will be required to assess for late recurrences and long-term adverse effects. PMID- 22245210 TI - Dosimetric predictors of radiation-induced acute nausea and vomiting in IMRT for nasopharyngeal cancer. AB - PURPOSE: We wanted to investigate dosimetric parameters that would predict radiation-induced acute nausea and vomiting in intensity-modulated radiation therapy (IMRT) for undifferentiated carcinoma of the nasopharynx (NPC). METHODS AND MATERIALS: Forty-nine consecutive patients with newly diagnosed NPC were treated with IMRT alone in this prospective study. Patients receiving any form of chemotherapy were excluded. The dorsal vagal complex (DVC) as well as the left and right vestibules (VB-L and VB-R, respectively) were contoured on planning computed tomography images. A structure combining both the VB-L and the VB-R, named VB-T, was also generated. All structures were labeled organs at risk (OAR). A 3-mm three-dimensional margin was added to these structures and labeled DVC+3 mm, VB-L+3 mm, VB-R+3 mm, and VB-T+3 mm to account for physiological body motion and setup error. No weightings were given to these structures during optimization in treatment planning. Dosimetric parameters were recorded from dose-volume histograms. Statistical analysis of parameters' association with nausea and vomiting was performed using univariate and multivariate logistic regression. RESULTS: Six patients (12.2%) reported Grade 1 nausea, and 8 patients (16.3%) reported Grade 2 nausea. Also, 4 patients (8.2%) complained of Grade 1 vomiting, and 4 patients (8.2%) experienced Grade 2 vomiting. No patients developed protracted nausea and vomiting after completion of IMRT. For radiation-induced acute nausea, V40 (percentage volume receiving at least 40Gy) to the VB-T and V40>=80% to the VB-T were predictors, using univariate analysis. On multivariate analysis, V40>=80% to the VB-T was the only predictor. There were no predictors of radiation-induced acute vomiting, as the number of events was too small for analysis. CONCLUSIONS: This is the first study demonstrating that a V40 to the VB T is predictive of radiation-induced acute nausea. The vestibules should be labeled as sensitive OARs, and weightings should be considered for dose sparing during optimization in the treatment planning of IMRT. PMID- 22245211 TI - Determination of radium isotopes in environmental samples by gamma spectrometry, liquid scintillation counting and alpha spectrometry: a review of analytical methodology. AB - Radium (Ra) isotopes are important from the viewpoints of radiation protection and environmental protection. Their high toxicity has stimulated the continuing interest in methodology research for determination of Ra isotopes in various media. In this paper, the three most routinely used analytical techniques for Ra isotope determination in biological and environmental samples, i.e. low background gamma-spectrometry, liquid scintillation counting and alpha spectrometry, were reviewed, with emphasis on new methodological developments in sample preparation, preconcentration, separation, purification, source preparation and measurement techniques. The accuracy, selectivity, traceability, applicability and minimum detectable activity (MDA) of the three techniques were discussed. It was concluded that the MDA (0.1mBqL(-1)) of the alpha-spectrometry technique coupled with chemical separation is about two orders of magnitude lower than that of low-background HPGe gamma-spectrometry and LSC techniques. Therefore, when maximum sensitivity is required, the alpha-spectrometry technique remains the first choice. PMID- 22245212 TI - Application of density functional theory (DFT) to study the properties and degradation of natural estrogen hormones with chemical oxidizers. AB - Estrone (E1), 17beta-estradiol (E2), estriol (E3), equilin (EQ) and 17alpha estradiol (17alpha) estrogen hormones are released by humans and animals and have been detected in the environment and municipal wastewater treatment plants. The structural and electronic properties of natural hormone molecules are investigated by performing density functional theory calculations and used to predict their properties and chemical behavior. Quantitative structure property relationship (QSPR) approach is applied to correlate the estrogenicity associated with the natural estrogen hormones according to their molecular properties. The obtained relationship reveals the importance of the frontier molecular orbital energy in the interpretation of estrogenic activity of hormones, which is consistent with the previous research. Moreover, the obtained molecular descriptors also aid determination of the degradability of hormones, and to rationalize degradation pathways, with chemical oxidizers such as ozone and hydroxyl radical. Both types of interactions belong to the orbital-controlled reactions. The active sites determined by Fukui functions for the estrogen hormone molecules confirm the reaction pattern that initiates the attack of the aromatic ring for both ozone and hydroxyl radical. The reactive sites of the molecules are mapped with subsequent reaction intermediates and compared with experimental data obtained from the literature. PMID- 22245213 TI - Nitrogen deposition and climate effects on soil nitrogen availability: influences of habitat type and soil characteristics. AB - The amount of plant-available nitrogen (N) in soil is an important indicator of eutrophication of semi-natural habitats, but previous studies have shown contrasting effects of N deposition on mineralisable N in different habitats. The stock of readily mineralisable N (N(rm)) was measured in 665 locations across Britain from a range of intensively and extensively managed habitats, allowing N availability to be studied in relation to soil and vegetation type, and also to variation in climate and in reactive N deposition from the atmosphere. Mineralisable N contents were correlated with deposition in extensively managed habitats but not in intensively managed habitats. The following statements apply only to extensively managed habitats. All habitats showed a similar increase in N(rm) with N deposition. However, soil characteristics affected the relationship, and soil carbon content in particular was a major control on mineralisation. The N(rm) stock increased more with N deposition in organic than in mineral soils. The nitrate proportion of N(rm) also increased with N deposition but, conversely, this increase was greater in mineral than in organic soils. The measurements could be used as indicators of eutrophication, e.g. deposition rates of over 20 kg N ha(-1) y(-1) are associated with nitrate proportions of >41% in a mineral soil (2% carbon), and with N(rm) stocks of over 4.8 kg N ha(-1) in an organic soil (55% carbon). Both N(rm) and nitrate proportion increased with mean annual temperature of the sampling location, despite consistent incubation temperature, suggesting that increasing temperatures are likely to increase the eutrophying effects of N pollution on semi-natural ecosystems. PMID- 22245214 TI - Deficiency of interleukin-1 receptor antagonist promotes spontaneous femoral artery aneurysm formation in mice. AB - Femoral artery aneurysms (FAAs) are very rare, and their natural history is not well understood. In this study, we sought to analyze the pathogenesis of inflammatory FAAs in interleukin-1 receptor antagonist-deficient (IL-1Ra(-/-)) B6 mice. Systolic arterial pressures and plasma lipid levels of IL-1Ra(-/-) mice and wild-type (WT) mice did not differ significantly. However, IL-1Ra(-/-) mice spontaneously developed fusiform FAAs. Real-time PCR of 9-month-old IL-1Ra(-/-) mice revealed significantly increased mRNA levels of IL-1beta (6.6-fold), tumor necrosis factor-alpha (TNF-alpha) (12.4-fold), and matrix metalloproteinase-9 (6.0-fold) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the FAAs in IL-1Ra(-/-) mice, and elastin staining showed destruction of both the internal and external elastic lamina in IL-1Ra(-/ ) mice. Afterward, macrophage function was studied. After lipopolysaccharide (1 MUg/mL) stimulation, IL-1Ra-deficient macrophages produced much higher levels of TNF-alpha than those from WT mice. Finally, we performed bone marrow cell transplantation. FAAs with many inflammatory cells in the adventitia were detected in several WT mice that received bone marrow cells from IL-1Ra(-/-) mice (44%), but not from WT mice (0%). Our study is the first to demonstrate that IL 1Ra deficiency in inflammatory cells disrupts immune system homeostasis and induces inflammatory FAAs in IL-1Ra(-/-) B6 mice. We believe that these mice will provide much information about the natural history and management of FAAs. PMID- 22245215 TI - Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. AB - Development of personalized treatment regimens is hampered by lack of insight into how individual animal models reflect subsets of human disease, and autoimmune and inflammatory conditions have proven resistant to such efforts. Scleroderma is a lethal autoimmune disease characterized by fibrosis, with no effective therapy. Comparative gene expression profiling showed that murine sclerodermatous graft-versus-host disease (sclGVHD) approximates an inflammatory subset of scleroderma estimated at 17% to 36% of patients analyzed with diffuse, 28% with limited, and 100% with localized scleroderma. Both sclGVHD and the inflammatory subset demonstrated IL-13 cytokine pathway activation. Host dermal myeloid cells and graft T cells were identified as sources of IL-13 in the model, and genetic deficiency of either IL-13 or IL-4Ralpha, an IL-13 signal transducer, protected the host from disease. To identify therapeutic targets, we explored the intersection of genes coordinately up-regulated in sclGVHD, the human inflammatory subset, and IL-13-treated fibroblasts; we identified chemokine CCL2 as a potential target. Treatment with anti-CCL2 antibodies prevented sclGVHD. Last, we showed that IL-13 pathway activation in scleroderma patients correlated with clinical skin scores, a marker of disease severity. Thus, an inflammatory subset of scleroderma is driven by IL-13 and may benefit from IL-13 or CCL2 blockade. This approach serves as a model for personalized translational medicine, in which well-characterized animal models are matched to molecularly stratified patient subsets. PMID- 22245216 TI - Integrative molecular profiling reveals asparagine synthetase is a target in castration-resistant prostate cancer. AB - The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells. PMID- 22245217 TI - Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and low-metastatic tumors. AB - An important concept in tumor angiogenesis is that tumor endothelial cells (TECs) are genetically normal and homogeneous. However, we previously reported that TECs differ from normal ECs. Whether the characteristics of TECs derived from different tumors differ remains unknown. To elucidate this, in this study, we isolated two types of TECs from high-metastatic (HM) and low-metastatic (LM) tumors and compared their characteristics. HM tumor-derived TECs (HM-TECs) showed higher proliferative activity and invasive activity than LM tumor-derived TECs (LM-TECs). Moreover, the mRNA expression levels of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF) receptors 1 and 2, VEGF, and hypoxia inducible factor-1alpha, were higher in HM-TECs than in LM-TECs. The tumor blood vessels themselves and the surrounding area in HM tumors were exposed to hypoxia. Furthermore, HM-TECs showed higher mRNA expression levels of the stemness-related gene stem cell antigen and the mesenchymal marker CD90 compared with LM-TECs. HM TECs were spheroid, with a smoother surface and higher circularity in the stem cell spheroid assay. HM-TECs differentiated into osteogenic cells, expressing activated alkaline phosphatase in an osteogenic medium at a higher rate than either LM-TECs or normal ECs. Furthermore, HM-TECs contained more aneuploid cells than LM-TECs. These results indicate that TECs from HM tumors have a more pro angiogenic phenotype than those from LM tumors. PMID- 22245218 TI - MicroRNAs in Parkinson's disease. AB - Besides the classic mutations in coding regions of genes, the critical role of gene expression regulators in disease states is increasingly recognized. The network of small non-coding microRNAs is crucial for the normal development and survival of distinct neuronal populations that are vulnerable in various neurodegenerative disorders. In midbrain dopaminergic neurons, which degenerate in Parkinson's disease (PD) causing motor signs and symptoms, disruption of this network results in their progressive loss associated with impaired motor activity in Drosophila and mouse models. Studies of families with dominantly inherited PD linked to multiplication of the alpha-synuclein gene locus indicate that the amount of this key pathogenic protein in neurons is an important determinant of its tendency to aggregate pathologically and increase neuronal susceptibility. Recent reports demonstrate that the alpha-synuclein mRNA is under negative control by at least two microRNAs, miR-7 and miR-153. In addition to studying the regulation of candidate genes by specific microRNA species, different profiling approaches are uncovering variations in the abundance of certain microRNAs that may prove to be relevant to the disease. For example, miR-133b is deficient in the PD midbrain as well as in mouse models, and miR-34b/34c are decreased in several affected brain regions in PD and incidental Lewy body disease. Polymorphisms in the 3'-untranslated region of microRNA target mRNAs, including in the gene encoding alpha-synuclein found in Genome Wide Association studies, are another potential reason for variations in the rate of protein production and thus disease risk. And finally, the impact of a disease associated gene product, and in particular LRRK2, on the microRNA network compounds the complexity of the interplay between the microRNA system and pathogenic proteins. The wealth of knowledge accumulating from these studies in a few short years holds considerable promise to harness its potential and translate it into therapeutic strategies for PD. PMID- 22245219 TI - Psychosis, apathy, depression and anxiety in Parkinson's disease. AB - Psychiatric symptoms are important non-motor features in PD, which occur at high frequency and have significant impact on health related quality of life. This review concentrates on the prevalence, pathophysiology, diagnosis and treatment of depression, anxiety, apathy and psychosis. The pathophysiology of these disorders is complex, reflecting the widespread brainstem and cortical pathology in PD, with involvement of several neurotransmitters, including dopaminergic, serotonergic, noradrenergic and cholinergic systems. The diagnosis of psychiatric conditions, in particular affective disorders, is challenging because of the overlap of somatic features of psychiatric disorders and underlying movement disorder. The pathogenesis is likely to differ considerably from non-PD patients, and treatments used in general psychiatry services may not be as effective in PD and will require clearer clarification in well-designed clinical studies. Management strategies include adjustment of dopaminergic medication, use of psychotropic treatments and behavioural and psychological approaches. However, the future challenge will be to develop treatments developed specifically for the pathogenesis of these disorders in PD. PMID- 22245220 TI - Differences in spectral sensitivity within and among species of darters (genus Etheostoma). AB - We examined variation in the visual system both within and among seven species of darters, colorful freshwater fishes of the genus Etheostoma. Using microspectrophotometry, we found that darters possess rod photoreceptor cells, single cone photoreceptor cells containing middle wavelength sensitive (MWS) visual pigments, and twin photoreceptor cells containing (LWS) visual pigments. No variation in peak sensitivity was detected among species or individuals in the rod class. In the MWS class, significant variation was detected among species and a strong statistical trend suggests differences among individuals. By contrast, all differences in the LWS class could be attributed to variation among individuals. Patterns of variation detected among species, among individuals, and among cone classes suggest that complex patterns of selection may be shaping the visual system of these fishes. Further, differences among individuals may have important consequences for visually based behaviors. PMID- 22245221 TI - Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging. AB - Raman spectroscopy was implemented successfully as a non-invasive and rapid process analytical technology (PAT) tool for in-line quantitative monitoring of functional coating. Coating experiments were performed at which diprophylline tablets were coated with a sustained release formulation based on Kollicoat SR 30 D. Using PLS a multivariate model was constructed by correlating Raman spectral data with the mean dissolution time as determined by dissolution testing and the coating thickness as measured by terahertz pulsed imaging. By performing in-line measurements it was possible to monitor the progress of the coating process and to detect the end point of the process, where the acquired coating amount was achieved for the desired MDT or coating thickness. PMID- 22245222 TI - Platelet-leukocyte deregulated interactions foster sterile inflammation and tissue damage in immune-mediated vessel diseases. AB - Platelets and leukocytes co-localize and interact at sites of vessel injury, haemorrhage, thrombosis and inflammation. Recent studies have highlighted the role of local cues in the interaction between the two cell populations, including the exposure of anionic phospholipids and the release of Damage Associated Molecular Patterns (DAMPs) by activated platelets, the release of the prototypical tissue pentraxin PTX3 by neutrophils, as well as the generation of polarized clusters of neutrophil beta(2) integrins. In turn, the reciprocal activatory cross-talk between platelets and leukocytes contributes to the generation of thrombo-inflammatory lesions and of vascular injury. Here we will discuss the implications of these results for the pathogenesis and the clinical features of self-sustaining immune-mediated vessel diseases. PMID- 22245223 TI - Evaluation of the Stratus CS Acute Care D-dimer assay (DDMR) using the Stratus CS STAT Fluorometric Analyzer: a prospective multisite study for exclusion of pulmonary embolism and deep vein thrombosis. AB - BACKGROUND: D-dimer testing is an integral part of the diagnostic algorithm in excluding patients with venous thromboembolism. In this study, we prospectively evaluated the Stratus DDMR D-dimer test in patients suspected of pulmonary embolism (PE) and deep vein thrombosis (DVT). METHODS: Patients suspected of venous thromboembolism were prospectively enrolled at four different clinical sites, with sodium citrate and lithium heparin plasma was tested using the DDMR D dimer test on the Stratus CS analyzer. RESULTS: 1,012 patients were enrolled for analysis, with 85/603 (14.1%) patients with PE and 80/443 (18.1%) with DVT, and four of the patients (0.4%) with PE and DVT. For the samples collected in 3.2% sodium citrate, the DDMR method had a sensitivity, specificity, and negative predictive value for VTE of 98.0%, 38.1%, and 99.1%, respectively. For the samples collected in lithium heparin, the DDMR method had a sensitivity, specificity, and negative predictive value (NPV) for VTE of 98.9%, 28.8%, and 99.4%, respectively. In PE, DDMR testing on citrate plasma had a sensitivity, specificity, and NPV of 98.8%, 39.5%, and 99.6%, respectively, while heparin samples had a sensitivity, specificity, and NPV for PE of 98.0%, 28.4%, and 99.1%, respectively. In DVT, citrate plasma had a sensitivity, specificity, and NPV for DVT of 97.5%, 32.0%, and 98.3%, respectively, while heparin samples had a sensitivity, specificity, and NPV for DVT of 100%, 27.8%, and 100%, respectively. CONCLUSION: The Stratus CS DDMR D-dimer can be used in those patients with non high clinical pre-test probability for the exclusion of PE. PMID- 22245224 TI - The effect of total hip/knee replacement surgery and prophylactic dabigatran on thrombin generation and coagulation parameters. AB - INTRODUCTION: Total hip/knee replacement surgery (THR/TKR respectively) is associated with an increased risk of venous thromboembolism. Dabigatran is recommended as a thromboprophylactic agent post orthopaedic surgery. The aim of this study was to assess the post-operative (Day-1 and Day-2) effect of prophylactic Dabigatran on: the thrombin generation (TG) assay; prothrombin fragment 1.2 (F1.2); thrombin-antithrombin complexes (TAT); D-dimer (D-D); and other coagulation parameters. METHODS AND SAMPLES: Nineteen patients (12 THR, 7 TKR) who received 110 mg dabigatran 4 hours post-operatively, then 220 mg the following day, were recruited. Blood was collected: pre-operatively (Pre-); peri operatively (Peri-); 19 hours after 110 mg dabigatran (Day-1); and 17 hours after 220 mg dabigatran (Day-2). The TG assay was measured using the Calibrated Automated Thrombogram and a low concentration of tissue factor. Other coagulation parameters measured included activated partial thromboplastin time (APTT), thrombin-time (TT), ecarin-clotting time (ECT) and Hemoclot tests. RESULTS: From Pre- to Peri-, ETP/peak-thrombin, F1.2, TAT and D-D increased significantly. From Peri- to Day-1 and Day-2: TAT reduced progressively; D-D increased; F1.2 did not change significantly; lag-time and time-to-peak prolonged; ETP/Peak-thrombin increased spuriously, due to Dabigatran interfering with the alpha-2 macroglobulin:thrombin complex in the TG assay. APTT, TT, ECT and Hemoclot increased progressively post-operatively; good correlations were seen between these tests. CONCLUSION: The effect of dabigatran on the TG assay, showed a spurious increase in ETP and Peak-thrombin due to its interference with the TG assay. Dabigatran reduced TAT, but not F1.2, suggesting that thrombin was still being generated after surgery, but was blocked by Dabigatran. PMID- 22245226 TI - Sensitivity of the OLGA and VCM models to erroneous marker placement: effects on 3D-gait kinematics. AB - Gait data need to be reliable to be valuable for clinical decision-making. To reduce the impact of marker placement errors, the Optimized Lower Limb Gait Analysis (OLGA) model was developed. The purpose of this study was to assess the sensitivity of the kinematic gait data to a standard marker displacement of the OLGA model compared with the standard Vicon Clinical Manager (VCM) model and to determine whether OLGA reduces the errors due to the most critical marker displacements. Healthy adults performed six gait sessions. The first session was a standard gait session. For the following sessions, 10mm marker displacements were applied. Kinematic data were collected for both models. The root mean squares of the differences (RMS) were calculated for the kinematics of the displacement sessions with respect to the first session. The results showed that the RMS values were generally larger than the stride-to-stride variation except for the pelvic kinematics. For the ankle, knee and hip kinematics, OLGA significantly reduced the averaged RMS values for most planes. The shank, knee and thigh anterior-posterior marker displacements resulted in RMS values exceeding 10 degrees . OLGA reduced the errors due to the knee and thigh marker displacements, but not the errors due to the ankle marker displacements. In conclusion, OLGA reduces the effect of erroneous marker placement, but does not fully compensate all effects, indicating that accurate marker placement remains of crucial importance for adequate 3D-gait analysis and subsequent clinical decision-making. PMID- 22245225 TI - A sample extraction method for faster, more sensitive PCR-based detection of pathogens in blood culture. AB - Three mechanistically different sample extraction methodologies, namely, silica spin columns, phenol-chloroform, and an automated magnetic capture of polymer complexed DNA (via an Automate Express instrument), were compared for their abilities to purify nucleic acids from blood culture fluids for use in TaqMan assays for detection of Staphylococcus aureus. The extracts from silica columns required 100- to 1000-fold dilutions to sufficiently reduce the powerful PCR inhibitory effects of the anticoagulant sodium polyanetholsulfonate, a common additive in blood culture media. In contrast, samples extracted by either phenol chloroform or the Automate Express instrument required little or no dilution, respectively, allowing for an approximate 100-fold improvement in assay sensitivity. Analysis of 60 blood culture bottles indicated that these latter two methodologies could be used to detect lower numbers of pathogens and that a growing S. aureus culture could be detected 2 hours earlier than when using silica columns. Of the three tested methodologies, the Automate Express instrument had the shortest time to result, requiring only approximately 80 minutes to process 12 samples. These findings highlight the importance of considering the mechanism when selecting a DNA extraction methodology, given that certain PCR inhibitors act in a similar fashion to DNA in certain chemical environments, resulting in copurification, whereas other methodologies use different chemistries that have advantages during the DNA purification of certain types of samples. PMID- 22245227 TI - Gait and menstrual cycle: ovulating women use sexier gaits and walk slowly ahead of men. AB - Previous research has demonstrated that women's physical appearance or sexual interest is different across the menstrual cycle. However, the nonverbal behavior of women toward men according to their menstrual cycle has not been previously explored. In this study, the gait of women walking ahead a male confederate was recorded with the help of a spy-camera. The amount of time that women spent walking was the first dependent variable whereas the extent to which the women were perceived to be sexually attractive by two judges was the second dependent variable. Comparisons were performed according to the women's ovulation phase measured with an LH salivary test. Near ovulation, it was found that women walked slower and their gait was subjectively rated as sexier. Such behaviors were interpreted as unconscious desires of women near ovulation to reinforce their attractiveness in order to attract more men and to increase their choice of a partner. PMID- 22245228 TI - Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin mediated repair of oxidized proteins and cell survival. AB - Eukaryotic 2-Cys peroxiredoxins (Prx) are abundant antioxidant enzymes whose thioredoxin peroxidase activity plays an important role in protecting against oxidative stress, aging, and cancer. Paradoxically, this thioredoxin peroxidase activity is highly sensitive to inactivation by peroxide-induced Prx hyperoxidation. However, any possible advantage in preventing Prx from removing peroxides under oxidative stress conditions has remained obscure. Here we demonstrate that, in cells treated with hydrogen peroxide, the Prx Tpx1 is a major substrate for thioredoxin in the fission yeast Schizosaccharomyces pombe and, as such, competitively inhibits thioredoxin-mediated reduction of other oxidized proteins. Consequently, we reveal that the hyperoxidation of Tpx1 is critical to allow thioredoxin to act on other substrates ensuring repair of oxidized proteins and cell survival following exposure to toxic levels of hydrogen peroxide. We conclude that the inactivation of the thioredoxin peroxidase activity of Prx is important to maintain thioredoxin activity and cell viability under oxidative stress conditions. PMID- 22245229 TI - Short-term increase of body weight triggers immunological variables in dogs. AB - Overweight in dogs is, as in other companion animals, a major risk factor for several metabolic disorders. However, it is not yet known whether immunity is challenged by increased body weight in dogs. The aim of this study was to investigate the effect of a short-term increase in body weight on immunological variables in adult healthy beagle dogs. Sixteen dogs, divided into a control group (CG) and weight gain group (WGG), were included. During a period of 13 weeks, the CG was fed at maintenance energy requirement (MER), whereas the WGG received a double amount of food. After 13 weeks, blood samples were taken for immunological and biochemical analyses. Weight gain and increased body condition score in the WGG were accompanied by a significant higher leptin concentration. Weight gain increased the number of lymphocytes and immunoglobulins A and M and was responsible for a higher proliferation of peripheral blood mononuclear cells (PBMC). Short-term increase of body weight thus seems to trigger immunological variables in dogs. PMID- 22245230 TI - Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents. AB - Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology. PMID- 22245231 TI - Fetal myocardial tissue Doppler indices before birth physiologically change in proportion to body size adjusted for gestational age in low-risk term pregnancies. AB - BACKGROUND: Few studies have investigated the relationship between myocardial tissue Doppler parameters and fetal size adjusted for gestational age and its trend has been controversial. AIMS: To investigate fetal cardiac function before birth using tissue Doppler imaging (TDI: indicated by the prime symbol (')) in low-risk term pregnancies by comparing the TDI parameters with gestational age specific birth weight percentiles and z scores. STUDY DESIGN AND MEASUREMENTS: Interventricular septum, left and right ventricular myocardial peak early diastolic (E'), late diastolic (A') and systolic (S') velocities, E'/A' ratios, myocardial performance index (MPI') and umbilical artery pulsatility index were measured within three days before birth in 76 low-risk term pregnancies, including appropriate for gestational age (AGA, n=50), small for gestational age (SGA, n=10), and large for gestational age (LGA, n=16) subjects. RESULTS: Myocardial peak velocities showed higher in the LGA and lower in the SGA compared with the AGA group, and All S' positively correlated with birth weight (r=0.51 0.57). All z scores of S' demonstrated a positive correlation with birth weight z score (Spearman r=0.45-0.53). MPI' was significantly higher in the SGA and lower in the LGA compared with the AGA group. All MPI' negatively correlated with birth weight (r=-0.55 to -0.65). All z scores of MPI' showed a negative correlation with birth weight z score (Spearman r=-0.40 to -0.56). CONCLUSIONS: Fetal myocardial peak velocities and MPI' physiologically changed in proportion to body size adjusted for gestational age in low-risk term pregnancies. PMID- 22245232 TI - What is in the best interest of the infant? PMID- 22245233 TI - Thermal detection thresholds in 5-year-old preterm born children; IQ does matter. AB - BACKGROUND: Experiencing pain at newborn age may have consequences on one's somatosensory perception later in life. Children's perception for cold and warm stimuli may be determined with the Thermal Sensory Analyzer (TSA) device by two different methods. AIM: This pilot study in 5-year-old children born preterm aimed at establishing whether the TSA method of limits, which is dependent of reaction time, and the method of levels, which is independent of reaction time, would yield different cold and warm detection thresholds. The second aim was to establish possible associations between intellectual ability and the detection thresholds obtained with either method. STUDY DESIGN: A convenience sample was drawn from the participants in an ongoing 5-year follow-up study of a randomized controlled trial on effects of morphine during mechanical ventilation. METHODS: Thresholds were assessed using both methods and statistically compared. Possible associations between the child's intelligence quotient (IQ) and threshold levels were analyzed. RESULTS: The method of levels yielded more sensitive thresholds than did the method of limits, i.e. mean (SD) cold detection thresholds: 30.3 (1.4) versus 28.4 (1.7) (Cohen'sd=1.2, P=0.001) and warm detection thresholds; 33.9 (1.9) versus 35.6 (2.1) (Cohen's d=0.8, P=0.04). IQ was statistically significantly associated only with the detection thresholds obtained with the method of limits (cold: r=0.64, warm: r=-0.52). DISCUSSION: The TSA method of levels, is to be preferred over the method of limits in 5-year-old preterm born children, as it establishes more sensitive detection thresholds and is independent of IQ. PMID- 22245234 TI - Maternal nicotine effects on vascular endothelial growth factor expression and morphometry in rat lungs. AB - AIMS: Maternal smoking during pregnancy may impair pulmonary function in infants, and the exact mechanisms underlying these changes are unknown. We evaluated the effects of maternal nicotine exposure on lung VEGF expression and morphometry during the postnatal period in rats. METHODS AND RESULTS: Timed pregnant Sprague Dawley rats were injected subcutaneously with nicotine at a dose of 2 mg/kg/day from Day 3 to Day 21 of gestation. A control group was injected with saline. Body weight, lung weight, and lung volume were comparable between control and nicotine exposed rats. Plasma vascular endothelial growth factor (VEGF) levels and lung VEGF mRNA expression decreased with advancing age, and nicotine exposure insignificantly decreased plasma VEGF levels and lung VEGF mRNA expression, compared with the control rats during the study period. Nicotine exposure caused a significant decrease in vascular endothelial growth factor receptor (VEGFR)-2 mRNA expression, compared with the level of the control rats on Postnatal Day 1. On Postnatal Day 1, nicotine-exposed rats exhibited a significantly lower volume fraction of alveolar airspace and alveolar surface area and a significantly higher alveolar wall volume fraction than did the control rats. CONCLUSIONS: Maternal nicotine exposure during pregnancy decreases VEGF and VEGFR-2 mRNA expression and alters lung structure in the lungs of postnatal rats. Because angiogenesis is vital for alveolarization during normal lung development, these results suggest that decreased VEGF expression might be involved in the structural alterations of the developing lung after exposure to antenatal nicotine. PMID- 22245235 TI - The metabolic effects of two different lipid emulsions used in parenterally fed premature infants--a randomized comparative study. AB - OBJECTIVE: To compare the effects of two different lipid emulsions, based on soybean oil and olive oil respectively on plasma lipid concentrations and acylcarnitine profile of very low birth weight infants. DESIGN: Randomized comparative study. PATIENTS AND METHODS: Forty very low birth weight infants, <=32 weeks of gestational age and receiving at least 40% of the calorie taken by parenteral nutrition from lipid solution at 14th day of life were evaluated. Group I (n=20) received soybean oil based lipid emulsion (Intralipid(r)) and Group II (n=20) received olive oil based lipid emulsion (Clinoleic(r)). MAIN OUTCOME MEASURES: Plasma lipid concentrations and acylcarnitine profile were assessed. RESULTS: Triglyceride, cholesterol, high and low density lipoprotein levels, liver function tests were similar between two groups whereas very low density lipoprotein level was statistically lower in Group I (p<0.05). Free carnitine levels were 15.73+/-10.67 in Group I and 34.25+/-22.18 MUM in Group II (p=0.012) and hexanoyl carnitine levels 2.18+/-2.10 in Group I and 0.38+/-0.12 MUM in Group II, respectively (p=0.005). Plasma medium chain acylcarnitine levels were significantly higher in Group I. CONCLUSIONS: Low levels of very low density lipoprotein in Group I may be a way of hemostasis to keep the serum triglyceride within normal levels. Lower free carnitine levels in soybean oil-based group is the result of carnitine need during the mitochondrial transport of long chain fatty acids. In Group I, due to the inefficient transport of medium chain fatty acids into the mitochondria, medium chain acylcarnitines accumulate in plasma. This may be the reason of lower carnitine levels in Group I. We suggest that higher levels of hexanoyl carnitine, reflecting defective mitochondrial transport of hexanoyl which leads immunsupression, may be the cause of higher sepsis risk in Group I. PMID- 22245236 TI - Association of IL28B gene polymorphism with development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C virus infection. AB - IL28B single nucleotide polymorphisms (SNPs) are associated with spontaneous and treatment-induced elimination of hepatitis C virus (HCV). To assess whether the IL28B rs8099917 SNP also affects the progression of chronic HCV infection, we genotyped 511 Japanese HCV patients, including 69 with hepatocellular carcinoma (HCC). The T/T genotype of rs8099917 was not associated with the development of HCC (p = 0.623), although stepwise logistic regression analysis showed that liver cirrhosis, age greater than 68 years, and serum albumin <4.2 mg/dl were associated with HCC onset. It appears that the IL28B SNP does not directly influence hepatocarcinogenesis in chronic HCV infection. PMID- 22245237 TI - Angiotensin-converting enzyme insertion/deletion polymorphism is a risk factor for thoracic aortic aneurysm in patients with bicuspid or tricuspid aortic valves. AB - OBJECTIVE: The angiotensin-converting enzyme (ACE) is highly expressed in the aneurysmal vascular wall, in both animal models and human disease. Genetic variations in ACE could be crucial in determining the risk of thoracic aortic aneurysm (TAA). The aim of the present study was to examine the role of ACE insertion/deletion polymorphism on the risk of TAA in patients with bicuspid aortic valves or tricuspid aortic valves. METHODS: We enrolled 216 patients (158 men; age, 58.9+/-14.9 years) with TAA, associated with bicuspid aortic valves (n=105) and tricuspid aortic valves (n=111) compared with 312 patients (252 men; age, 54.6+/-11.0 years) with angiographically proven coronary artery disease and 300 healthy controls (91 men; age, 40.4+/-10.5 years). RESULTS: The genotype distribution of ACE insertion/deletion was significantly different between the patients with TAA compared with both the control group (P=.0005) and the coronary artery disease group (P=.03). The genotypes were not different between the control group and the coronary artery disease group (P=.3). Compared with the controls, both the bicuspid aortic valve patients (P=.0008) and tricuspid aortic valve patients (P<.0001) had a greater frequency of allele D. The aortic diameters were significantly different among the three genotypes (48.3+/-6.6, 45.3+/-8.9, 39.9+/-8.7 for the DD, DI, and II genotypes, respectively; P=.0002). A synergistic effect between the ACE D allele and hypertension was found for both an increased aortic diameter (P=.003) and the risk of TAA (P<.001). On multivariate logistic regression analysis, D allele (odds ratio, 3.0; 95% confidence interval, 1.1-8.1; P=.03) was a significant predictor of TAA. CONCLUSIONS: ACE insertion/deletion polymorphism represents a genetic biomarker for TAA. These findings could have a significant effect on both the early detection and effective pharmacologic treatment of aortic disease. PMID- 22245238 TI - HeartWare continuous-flow ventricular assist device thrombosis: the Bad Oeynhausen experience. PMID- 22245240 TI - Bilateral internal thoracic artery grafting improves long-term survival in patients with reduced ejection fraction: a propensity-matched study with 30-year follow-up. AB - OBJECTIVE: Bilateral internal thoracic artery (BITA) grafting has been shown to improve long-term survival after coronary artery bypass grafting. However, there has been reluctance to use this technique in higher-risk patients. Patients with reduced ejection fraction (EF) have been shown to present a higher operative risk and reduced long-term survival. We studied the perioperative and long-term results of BITA versus single internal thoracic artery grafting (SITA) in a large population of patients with reduced EF in whom BITA grafting was broadly applied. METHODS: Between February 1972 and May 1994, 4537 consecutive patients in whom EF was recorded underwent SITA (2340) or BITA (2197) grafting. Prospectively collected clinical data recorded EF categorically as less than 0.30 (group I; n = 233), 0.30 to 0.50 (group II; n = 1256), or greater than 0.50 (group III; n = 3048). Multivariable analyses were performed to determine correlates of operative and late mortality. Optimal matching using propensity scoring was used to create matched SITA and BITA cohorts: group I, SITA and BITA, n = 87 each; group II, SITA and BITA, n = 448 each; group III, SITA and BITA, n = 1137 each. Equality of survival distribution was tested by the log-rank algorithm. RESULTS: There was no difference in operative mortality between matched SITA and BITA groups (group I: SITA vs BITA, 10.3% vs 6.9%, P = .418; group II: 4.7% vs 4.5%, P = .873; group III: 3.2% vs 2.0%, P = .086). SITA versus BITA was not a predictor of operative mortality on logistic regression analysis. There was no difference in freedom from any postoperative complication, including sternal wound infection, between matched SITA and BITA groups. Late survival was significantly enhanced with the use of BITA grafting in groups II and III (10- and 20-year survival, SITA vs BITA, in group II: 57.7% +/- 0.3% and 19% +/- 2.5% vs 62.0% +/- 2.3% and 33.1% +/ 3.4%, respectively, P = .016; and in group III: 67.1% +/- 1.4% and 35.8% +/- 1.7% vs 74.6% +/- 1.3% and 38.1% +/- 2.1%, respectively, P = .012). Likewise, choice of SITA versus BITA was a significant predictor of late mortality on Cox regression in both groups II (P < .007) and III (P < .001). CONCLUSIONS: Broadly applied BITA compared with SITA grafting in propensity-matched patients provides enhanced long-term survival with no increase in operative mortality or morbidity for patients with normal and reduced EF. The expanded use of BITA grafting should be seriously considered. PMID- 22245242 TI - Experience with more than 100 total artificial heart implants. AB - OBJECTIVE: The SynCardia Total Artificial Heart (SynCardia Systems Inc, Tucson, Ariz) has been used as a bridge to cardiac transplantation in 930 patients worldwide and in 101 patients in our program. Our experience with SynCardia Total Artificial Heart implantation documents its indications, safety, and efficacy. METHODS: Data regarding preoperative condition, mortality, and morbidity have been reviewed and analyzed. RESULTS: From January 1993 to December 2009, 101 patients had bridge to transplant procedures with the SynCardia Total Artificial Heart. Ninety-one percent of cases were Interagency Registry for Mechanically Assisted Circulatory Support profile 1, and the remaining 9% of cases were failing medical therapy on multiple inotropic medications. The mean support time was 87 days (median, 53 days; range, 1-441 days). Pump outputs during support were 7 to 9 L/min. Adverse events included strokes in 7.9% of cases and take-back for hemorrhage in 24.7% of cases. Survival to transplantation was 68.3%. Causes of death of 32 patients on device support included multiple organ failure (13), pulmonary failure (6), and neurologic injury (4). Survival after transplantation at 1, 5, and 10 years was 76.8%, 60.5%, and 41.2%, respectively. The longest-term survivor is currently alive 16.4 years postimplantation. CONCLUSIONS: These patients were not candidates for left ventricular assist device therapy and were expected to die. The SynCardia Total Artificial Heart offers a real alternative for survival with a reasonable complication rate in appropriate candidates who otherwise might have been assigned to hospice care. PMID- 22245243 TI - PDE4 regulates tissue plasminogen activator expression of human brain microvascular endothelial cells. AB - INTRODUCTION: Factors regulating brain tissue plasminogen activator (tPA) are pertinent for stroke. Recent observations have suggested a role for the phosphodiesterase-4 (PDE4) pathway in stroke pathogenesis, via an uncertain mechanism. We studied PDE4 regulation of tPA expression by human brain microvascular endothelial cells in a variety of conditions, including an in vitro model of ischemia. MATERIALS AND METHODS: We analyzed tPA antigen and mRNA of human brain microvascular endothelial cells (HBECs) during normoxia and oxygen glucose deprivation (OGD) following inhibition of PDE4 and PDE4D, using HBEC monocultures and co-cultures with astrocytes and pericytes, and analyzed relevant signal transduction pathways. RESULTS: PDE4 inhibitor rolipram enhanced OGD effects on endothelial tPA release in endothelial monocultures and co-cultures with astrocytes; there was a 54+/-10% (p<0.001) reduction of tPA release in astrocyte-endothelial co-cultures under OGD. PDE4D siRNA reduced endothelial tPA mRNA to 40-55% of control (p<0.05). Use of Epac inducer mimicked, while use of Epac siRNA inhibited, these effects. CONCLUSIONS: Inhibition of PDE4 and PDE4D reduced expression of tPA by HBEC via Epac pathway. PMID- 22245245 TI - Multidrug-resistant organisms in a community living facility: tracking patient interactions and time spent in common areas. AB - Contact precautions in community living facilities (CLF) are used to reduce the transmission of multidrug-resistant organisms (MDRO). However, this policy does not address the contamination of shared spaces, devices (eg, wheelchairs), and interactions with other patients. Using a real-time surveillance system, this study examines the time MDRO-positive patients spend interacting with others in communal areas. The findings from this study may be used to tailor MDRO policies and practices to the specific needs of CLF. PMID- 22245244 TI - Characteristics of fibrin formation and clot stability in individuals with congenital type IIb protein C deficiency. AB - Many studies have shown that unregulated or excessive thrombin formation is potentially a cause of thrombosis; however, studies examining processes that contribute to fibrin stabilization in individuals predisposed to thrombosis are limited. In this study, we investigate a family with familial thrombosis via type IIb protein C (PC) deficiency. Using contact pathway inhibited whole blood, thrombin generation, fibrin clot formation and factor (f)XIII activation were monitored over time in control (n=5) and PC deficient (n=4, 34 - 69% PC by activity) subjects. The dynamics of thrombin generation varied significantly with the time required to reach the maximal rate of thrombin-antithrombin formation being much shorter in PC deficiency (5.8 +/- 0.4 minutes) than in controls (9.7 +/- 0.4 minutes; p < 0.001). PC deficient clots were significantly heavier than control clots (p < 0.001) and this difference could not be contributed exclusively to differences in fibrinogen levels between groups. FXIII was consumed faster in PC deficient subjects (23.7 +/- 2.0 nM/minute) than in controls (5.1 +/- 1.5 nM/minute; p < 0.0001) suggesting increased fXIII activation and incorporation of fXIIIa substrates into the clot. In plasma, the clot lysis time was increased in PC deficiency by both TAFIa dependent and independent mechanisms. Since PC deficient clots are both denser and show a greater degree of resistance to fibrinolysis, these clots would likely resist fibrinolysis and potentiate fibrin deposition observed in thrombosis. PMID- 22245246 TI - Investigating Jordanian nurses' handwashing beliefs, attitudes, and compliance. AB - BACKGROUND: Low rates of handwashing compliance among nurses are still reported in literature. Handwashing beliefs and attitudes were found to correlate and predict handwashing practices. However, such an important field is not fully explored in Jordan. OBJECTIVES: This study aims at exploring Jordanian nurses' handwashing beliefs, attitudes, and compliance and examining the predictors of their handwashing compliance. METHODS: A cross-sectional multicenter survey design was used to collect data from registered nurses and nursing assistants (N = 198) who were providing care to patients in governmental hospitals in Jordan. Data collection took place over 3 months during the period of February 2011 to April 2011 using the Handwashing Assessment Inventory. RESULTS: Participants' mean score of handwashing compliance was 74.29%. They showed positive attitudes but seemed to lack knowledge concerning handwashing. Analysis revealed a 5 predictor model, which accounted for 37.5% of the variance in nurses' handwashing compliance. Nurses' beliefs relatively had the highest prediction effects (beta = .309, P < .01), followed by skin assessment (beta = .290, P < .01). CONCLUSION: Jordanian nurses reported moderate handwashing compliance and were found to lack knowledge concerning handwashing protocols, for which education programs are recommended. This study raised the awareness regarding the importance of complying with handwashing protocols. PMID- 22245247 TI - Use of the point of origin code from a universal billing form, UB-04, to efficiently identify hospitalized patients admitted from other health care facilities. AB - BACKGROUND: Recent exposure to health care facilities is a risk factor for carriage of multidrug-resistant organisms, but identification of hospitalized patients admitted from other health care facilities is often inefficient. METHODS: At an acute care hospital, we utilized a standard point of origin code from a universal billing form (UB-04) to categorize hospitalized patients as admitted from any health care facility (long-term care facility vs acute care facility). In a prospective study, the point of origin code and information obtained from physician-documented history were validated against patient self report. RESULTS: Admission source for 523 patients was assessed. For identifying admission from any health care facility, the point of origin code had 86% sensitivity (95% confidence interval [CI]: 77-92) and 98% specificity (95% CI: 97 99). Physician-documented history had 75% sensitivity (95% CI: 65-84) and 98% specificity (95% CI: 96-99). For identifying patients from long-term care facilities, the sensitivities of the point of origin code and physician history were 50% (95% CI: 23-77) and 71% (95% CI: 42-92), respectively. For identifying patients admitted from acute care facilities, the sensitivities of the point of origin code and physician history were 93% (95% CI: 84-98) and 76% (95% CI: 64 85), respectively. CONCLUSION: The point of origin code is an accurate method of identifying patients admitted from another health care facility that is comparable with physician-documented history. PMID- 22245248 TI - Sorption of copper(II) ions in the biomass of alga Spirogyra sp. AB - Sorption of copper ions by the alga Spirogyra sp. was investigated to determine the influence of experimental conditions and the methods of sample preparation on the process. The experiments were carried out both under the static and the dynamic conditions. Kinetics and equilibrium parameters of the sorption were evaluated. In addition, the influence was studied of the algae preparation methods on the conductivity of demineralized water in which the algae samples were immersed. The static experiments showed that the sorption of Cu(2+) ions reached equilibrium in about 30 min, with approximately 90% of the ions adsorbed in the initial 15 min. The sorption capacity determined from the Langmuir isotherms appeared highly uncertain (SD=+/-0.027 mg/g dry mass or +/-11%, for the live algae). Under static conditions, the slopes of the Langmuir isotherms depended on the ratio of the alga mass to the volume of solution. The conductometric measurements were proven to be a simple and fast way to evaluate the quality of algae used for the experiments. PMID- 22245249 TI - Characterization of channel-forming peptide nanostructures. AB - We have prepared fluorescent analogs of known ion-channel-forming synthetic peptide nanostructures. These analogs were designed as probes to gain insight about the mechanism by which self-assembling amphiphilic peptides interact with lipid membranes. Conformational studies demonstrated that the labeled analogs retain their propensity to adopt a strong helical conformation in 2,2,2 trifluoroethanol and lipid bilayers. Attenuated total reflectance results indicated that the fluorescent peptide nanostructures are under an incorporation equilibrium between two forms, adsorbed at the surface or incorporated within the bilayer, similar to their unlabeled counterparts. However, when using a HeLa mimicking membrane, the proportion of peptide nanostructures in the transmembrane orientation decreases significantly. Finally, we were able to show by confocal microscopy studies that fluorescent analogs internalized into HeLa cells and localized into both the membranes of inner organelles and the cell membrane. PMID- 22245250 TI - The retinoic acid-induced up-regulation of insulin-like growth factor 1 and 2 is associated with prolidase-dependent collagen synthesis in UVA-irradiated human dermal equivalents. AB - BACKGROUND: Ultraviolet (UV) A irradiation causes the degeneration of extracellular matrix in the skin dermis, mainly due to disrupted collagen homeostasis, resulting in the photo-aging of human skin. All-trans retinoic acid (ATRA) improves photo-aged human skin in vivo. OBJECTIVES: Although the effects of ATRA on collagen synthesis and MMP regulation are well known, the effects of ATRA on other collagen homeostasis-associated genes have not been elucidated. This study was aimed to study the factors that are pharmacologically associated with the effect of ATRA on collagen homeostasis. METHODS: The gene transcription profile of collagen homeostasis-associated genes was systematically evaluated in three-dimensional human dermal equivalents (HDEs) following UVA-irradiation and/or ATRA treatment. RESULTS: In addition to the expected changes in MMPs and collagen synthesis in HDEs in response to ATRA, prolidase, an important enzyme in the recycling of proline and hydroxyproline from degraded collagen molecules, was significantly decreased by UVA irradiation, and its down-regulation was antagonized by ATRA. Transfection with a prolidase-specific siRNA led to a significant decrease in procollagen synthesis in human fibroblasts. ATRA inhibited the UVA irradiation-induced decrease in prolidase activity through an insulin-like growth factor (IGF) receptor signaling pathway in HDEs. ARTA increased IGF1 and IGF2 production in HDEs, and neutralizing IGFs with anti-IGF antibodies abolished the effect of ATRA on proliase activity. CONCLUSIONS: These data demonstrate that ATRA regulates prolidase activity in HDEs via IGF receptor signaling, suggesting one of the pharmacological mechanisms by which improves photo-aged human skin. PMID- 22245251 TI - Minocycline prevents paraquat-induced cell death through attenuating endoplasmic reticulum stress and mitochondrial dysfunction. AB - Paraquat (PQ) was demonstrated to induce dopaminergic neuron death and is used as a Parkinson's disease (PD) mimetic; however, its mechanism remains contradictory. Alternatively, minocycline is a second-generation tetracycline and is undergoing clinical trials for treating PD with an unresolved mechanism. We thus investigated the molecular mechanism of minocycline in preventing PQ-induced cytotoxicity. In this study, minocycline was effective in preventing PQ-induced apoptotic cell death, which involves the cleavages of poly (ADP-ribose) polymerase (PARP) and caspase 3 and increased fluorescence intensity of annexin V FITC. In addition, PQ also quickly induced alterations of unfolded protein responses (UPRs) and subsequently dysfunction of the mitochondria (such as the decrease in membrane potential and increase in membrane permeability and superoxide formation). Finally, the mechanism of minocycline in preventing PQ induced apoptosis might be mediated by attenuating endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which respectively results in caspase-12 activation and the release of H2O2, HtrA2/Omi, and Smac/Diablo. Thus, minocycline could possibly be used to treat other neurodegenerative disorders with similar pathologic mechanisms. PMID- 22245252 TI - Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway. AB - Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In this study, we used in vitro and in vivo assays to examine the inhibitory effects of oroxylin A, one of the main bioactive flavonoid extracted from Scutellaria radix, on the human breast carcinoma cell MDA-MB-231 invasion and migration. We found that oroxylin A can suppress cell adhesion, invasion and migration in a concentration-dependent manner. Moreover, oroxylin A led to the reduction of the activity and expression levels of MMP-2 and MMP-9 in gelatin zymography, real-time PCR and western blotting analysis. Further elucidation of the mechanism revealed that oroxylin A increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of MMP 2, and repressed the phorbol-12-myristate-13-acetate (PMA)-induced translocation of protein kinase Cdelta (PKCdelta), phosphorylation of extracellular signal regulated kinase (ERK1/2) and binding activity of the transcription factor activator protein-1 (AP-1) which are upstream signaling molecules in MMP-9 expression. Our results also indicated that oroxylin A inhibited the lung metastasis of murine melanoma cell B16-F10 in vivo. Therefore, we proposed that oroxylin A might be developed as a therapeutic potential candidate for the treatment of cancer metastasis. PMID- 22245253 TI - B cell increases and ex vivo IL-2 production as secondary endpoints for the detection of sensitizers in non-radioisotopic local lymph node assay using flow cytometry. AB - Non-radioisotopic local lymph node assay (LLNA) using 5-bromo-2'-deoxyuridine (BrdU) with flow cytometry (FCM) is gaining attention since it is free from the regulatory issues in traditional LLNA (tLLNA) accompanying in vivo uses of radioisotope, (3)H-thymidine. However, there is also concern over compromised performance of non-radioisotopic LLNA, raising needs for additional endpoints to improve the accuracy. With the full 22 reference substances enlisted in OECD Test Guideline No. 429, we evaluated the performance of LLNA:BrdU-FCM along with the concomitant measurements of B/T cell ratio and ex vivo cytokine production from isolated lymph node cells (LNCs) to examine the utility of these markers as secondary endpoints. Mice (Balb/c, female) were topically treated with substances on both ears for 3 days and then, BrdU was intraperitoneally injected on day 5. After a day, lymph nodes were isolated and undergone FCM to determine BrdU incorporation and B/T cell sub-typing with B220+ and CD3e+. Ex vivo cytokine production by LNCs was measured such as IL-2, IL-4, IL-6, IL-12, IFN-gamma, MCP 1, GM-CSF and TNFalpha. Mice treated with sensitizers showed preferential increases in B cell population and the selective production of IL-2, which matched well with the increases in BrdU incorporation. When compared with guinea pig or human data, BrdU incorporation, B cell increase and IL-2 production ex vivo could successfully identify sensitizers with the accuracy comparable to tLLNA, suggesting that these markers may be useful for improving the accuracy of LLNA:BrdU-FCM or as stand-alone non-radioisotopic endpoints. PMID- 22245254 TI - The possible mechanism of silver nanoparticle impact on hippocampal synaptic plasticity and spatial cognition in rats. AB - Silver nanoparticles (Ag-np) are very promising engineered nanomaterials which play an important role in the world biomedical, healthcare and in general nanotechnology applications. With the most impressive effect in antibacterial and many other broad-spectrum biotechnological advantages, Ag-np in real applications is still a controversial issue. This study investigated effects of the Ag-np on hippocampal synaptic plasticity and spatial cognition in rats and followed with the research on their possible mechanism. In this study, twenty-four adult male Wister rats were randomly divided into 3 groups: control group, low-dose group (Ag-np, 3 mg/kg) and high-dose group (Ag-np, 30 mg/kg). After two-week exposure to Ag-np through the nasal administration, Morris water maze (MWM) test was performed for the spatial cognition, followed by the long-term potentiation (LTP) recording and reactive oxygen species (ROS) detection in hippocampal homogenate. Results showed that compared with the control group, both LTP and MWM were abnormal in low-dose group and high-dose group. The quantity of ROS in hippocampal homogenate was increased significantly in low-dose group and high dose group, which may be the reason of the neural damage caused by Ag-np. PMID- 22245255 TI - Neurochemical and behavioral analyses of the lateral hypothalamic syndrome: a look back. AB - Philip Teitelbaum is one of the great physiological psychologists of his generation. His early research clarified key issues regarding the effects of electrolytic lesions of the ventromedial or ventrolateral hypothalamus on food intake in rats, a subject of paramount interest during the 1950s and 1960s. Perhaps best known were his extensive studies of the lateral hypothalamic syndrome in rats, which focused on the complex and changing array of symptoms after experimental brain damage. It soon became clear from later work that his research interests were not in the brain's control of food intake but in the effects of lesions to fragment behavior and thereby allow investigators to view its components. He was the foremost proponent of the use of exquisite behavioral analysis to reveal details in movement that allowed insights into brain function, and that approach - old fashioned physiological psychology made modern and at its finest - has infiltrated the entire field of experimental psychology, including studies of ingestive behavior, even while the new field of behavioral neuroscience emerged. He extended his analytic approach to neurological issues such as autism in humans, a promising arena that fully occupied his attention during the later phases of his career. But his influence on his scientific colleagues went well beyond his careful and powerful thinking; his articles and books have been models of clarity and concision. I write in behalf of a grateful field to salute his many great contributions. PMID- 22245256 TI - Discrimination learning with light stimuli in restrained American lobster. AB - Operant discrimination learning has been extensively utilized in the study on the perceptual ability of animals and their higher order brain functions. We tested in this study whether American lobster Homarus americanus, which was previously found to possess ability of operant learning with claw gripping, could be trained to discriminate light stimuli of different intensities. For the current purpose, we newly developed a PC-controlled operant chamber that allowed the animal under a body-fixed condition to perform operant reward learning with claw gripping. Lobsters were first reinforced when they gripped the sensor bar upon presentation of a light cue. Then they were trained to grip the bar only when the light stimulus of a specific intensity was presented to obtain food reward while the stimuli of three different intensities including the reinforced one were presented in a random order. Finally, they were re-trained to grip the bar only when the light stimulus of another intensity that was not rewarded in the preceding training to obtain food while other intensities including the one that was rewarded previously were not rewarded any more. In these training procedures, the operant behavior occurred more frequently in response to the rewarded cue than to the non-rewarded one. The action latency for the reinforced stimuli showed a significant decrease in the course of training. These data demonstrate that lobsters can be trained with the light cues of different intensity as discriminative stimuli under a restrained condition that would allow application of electrophysiological techniques to the behaving subjects. PMID- 22245257 TI - Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain. AB - For many patients, chronic pain is often accompanied, and sometimes amplified, by co-morbidities such as anxiety and depression. Although it represents important challenges, the establishment of appropriate preclinical behavioral models contributes to drug development for treating chronic inflammatory pain and associated psychopathologies. In this study, we investigated whether rats experiencing persistent inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) developed anxiety-like behaviors, and whether clinically used analgesic and anxiolytic drugs were able to reverse CFA-induced anxiety-related phenotypes. These behaviors were evaluated over 28 days in both CFA- and saline-treated groups with a variety of behavioral tests. CFA-induced mechanical allodynia resulted in increased anxiety-like behaviors as evidenced by: (1) a significant decrease in percentage of time spent and number of entries in open arms of the elevated-plus maze (EPM), (2) a decrease in number of central squares visited in the open field (OF), and (3) a reduction in active social interactions in the social interaction test (SI). The number of entries in closed arms in the EPM and the distance traveled in the OF used as indicators of locomotor performance did not differ between treatments. Our results also reveal that in CFA-treated rats, acute administration of morphine (3mg/kg, s.c.) abolished tactile allodynia and anxiety-like behaviors, whereas acute administration of diazepam (1mg/kg, s.c) solely reversed anxiety-like behaviors. Therefore, pharmacological treatment of anxiety-like behaviors induced by chronic inflammatory pain can be objectively evaluated using multiple behavioral tests. Such a model could help identify/validate alternative potential targets that influence pain and cognitive dimensions of anxiety. PMID- 22245258 TI - Magnetic nanocomposite of anti-human IgG/COOH-multiwalled carbon nanotubes/Fe3O4 as a platform for electrochemical immunoassay. AB - An electrochemical immunosensing method was developed based on a magnetic nanocomposite. The multiwalled carbon nanotubes (MWCNTs) were treated with nitric acid to produce carboxyl groups at the open ends. Then, Fe3O4 nanoparticles were deposited on COOH-MWCNTs by chemical coprecipitation of Fe2+ and Fe3+ salts in an alkaline solution. Goat anti-human IgG (anti-hIgG) was covalently attached to magnetic nanocomposite through amide bond formation between the carboxylic groups of MWCNTs and the amine groups of anti-hIgG. The prepared bio-nanocomposite was used for electrochemical sensing of human tetanus IgG (hIgG) as a model antigen. The anti-hIgG magnetic nanocomposite was fixed on the surface of a gold plate electrode using a permanent magnet. The hIgG was detected using horseradish peroxidase (HRP)-conjugated anti-hIgG in a sandwich model. Electrochemical detection of hIgG was carried out in the presence of H2O2 and KI as substrates of HRP. Using this method, hIgG was detected in a concentration range from 30 to 1000 ng ml-1 with a correlation coefficient of 0.998 and a detection limit of 25 ng ml-1 (signal/noise=3). The designed immunosensor was stable for 1 month. PMID- 22245259 TI - Multivariate pattern classification of gray matter pathology in multiple sclerosis. AB - Univariate analyses have identified gray matter (GM) alterations in different groups of MS patients. While these methods detect differences on the basis of the single voxel or cluster, multivariate methods like support vector machines (SVM) identify the complex neuroanatomical patterns of GM differences. Using multivariate linear SVM analysis and leave-one-out cross-validation, we aimed at identifying neuroanatomical GM patterns relevant for individual classification of MS patients. We used SVM to separate GM segmentations of T1-weighted three dimensional magnetic resonance (MR) imaging scans within different age- and sex matched groups of MS patients with either early (n=17) or late MS (n=17) (contrast I), low (n=20) or high (n=20) white matter lesion load (contrast II), and benign MS (BMS, n=13) or non-benign MS (NBMS, n=13) (contrast III) scanned on a single 1.5 T MR scanner. GM patterns most relevant for individual separation of MS patients comprised cortical areas of all the cerebral lobes as well as deep GM structures, including the thalamus and caudate. The patterns detected were sufficiently informative to separate individuals of the respective groups with high sensitivity and specificity in 85% (contrast I), 83% (contrast II) and 77% (contrast III) of cases. The study demonstrates that neuroanatomical spatial patterns of GM segmentations contain information sufficient for correct classification of MS patients at the single case level, thus making multivariate SVM analysis a promising clinical application. PMID- 22245261 TI - Prolactin and blood vessels: a comparative endocrinology perspective. AB - The hormone prolactin (PRL), fundamental for lactation in mammals, is known to exert a wide diversity of actions in the various vertebrate groups. Blood vessels are surfacing as important PRL targets, contributing to these hormonal functions. PRL promotes the growth of new blood vessels (angiogenesis) and is proteolytically cleaved to vasoinhibins, a family of peptides (including 16-kDa PRL) with potent antiangiogenic and blood vessel regression effects. These opposing actions point to the regulation of the proteases responsible for PRL cleavage as an efficient way to balance blood vessel growth and involution. This review briefly summarizes the effects of PRL and vasoinhibins on blood vessels in mammals and discusses whether similar vascular actions could contribute to the effects of PRL on the development, growth, and reproduction of lower vertebrates. A comparative study in diverse species may lead to a better understanding of blood vessels as a driving force for the biological actions of PRL. PMID- 22245260 TI - A reliable protocol for the manual segmentation of the human amygdala and its subregions using ultra-high resolution MRI. AB - The measurement of the volume of the human amygdala in vivo has received increasing attention over the past decade, but existing methods face several challenges. First, due to the amorphous appearance of the amygdala and the difficulties in interpreting its boundaries, it is common for protocols to omit sizable sections of the rostral and dorsal regions of the amygdala comprising parts of the basolateral complex (BL) and central nucleus (Ce), respectively. Second, segmentation of the amgydaloid complex into separate subdivisions is challenging due to the resolution of routinely acquired images and the lack of standard protocols. Recent advances in technology have made ultra-high resolution MR images available, and in this study we provide a detailed segmentation protocol for manually tracing the whole amygdala that incorporates a greater portion of the rostral and dorsal sections with techniques illustrated in detail to maximize reproducibility. In addition, we propose a geometrically-based protocol for segmenting the amygdala into four component subregions of interest (sROI), which correspond largely to amygdala subnuclear divisions: the BL sROI, centromedial (CM) sROI, basomedial (BM) sROI, and the amygdaloid cortical (ACo) sROI. We performed an intra- and inter-rater reliability study of our methods in 10 adults (5 young adults and 5 older adults). The results indicate that both protocols can be implemented with a high degree of reliability (the majority of intra-rater and inter-rater correlations were > 0.81). This protocol should aid further research into the alterations in amygdala anatomy, connectivity, and function that accompany normal aging and pathology associated with neuropsychiatric disorders. PMID- 22245262 TI - Ambiguities in the relationship between gonadal steroids and reproduction in axolotls (Ambystoma mexicanum). AB - Axolotls (Ambystoma mexicanum) are aquatic salamanders that are widely used in research. Axolotls have been bred in laboratories for nearly 150 years, yet little is known about the basic biology of reproduction in these animals. We investigated the effects of changing day length, time of year, and food availability on levels of circulating estradiol and androgens in adult female and male axolotls, respectively. In addition, we examined the effects of these variables on the mass of ovaries, oviducts, and eggs in females and on mass of testes in males relative to each individual's body weight, to calculate a form of gonadosomatic index (GSI). In both sexes, GSI was not correlated with levels of circulating steroids. In female axolotls, estradiol levels were influenced by food availability, changes in day length, and season, even when animals were held at a constant temperature and day length was decorrelated with calendar date. In addition, the mass of ovaries, oviducts, and eggs varied seasonally, peaking in the winter months and declining during the summer months, even though our animals were not breeding and shedding eggs. In males, levels of androgens appeared to vary independently of external conditions, but GSI varied dramatically with changes in day length. These results suggest that reproduction in axolotls may vary seasonally, as it does in many other ambystomid species, although both male and female axolotls are capable of reproducing several times each year. The physiological basis of this ability remains enigmatic, given the indications of seasonality contained in our data. PMID- 22245263 TI - Effects of photoperiod and food restriction on the reproductive physiology of female California mice. AB - Many temperate-zone animals use changes in photoperiod to time breeding. Shorter term cues, like food availability, are integrated with photoperiod to adjust reproductive timing under unexpected conditions. Many mice of the genus Peromyscus breed in the summer. California mice (Peromyscus californicus), however, can breed year round, but tend to begin breeding in the winter. Glial cells may be involved in transduction of environmental signals that regulate gonadotrophin releasing hormone I (GnRH) activity. We examined the effects of diet and photoperiod on reproduction in female California mice. Mice placed on either short days (8L:16D) or long days (16L:8D) were food restricted (80% of normal intake) or fed ad libitum. Short day-food restricted mice showed significant regression of the reproductive system. GnRH-immunoreactivity was increased in the tuberal hypothalamus of long day-food restricted mice. This may be associated with the sparing effect long days have when mice are food restricted. The number of GFAP-immunoreactive fibers in proximity to GnRH nerve terminals correlated negatively with uterine size in ad libitum but not food restricted mice, suggesting diet may alter glial regulation of the reproductive axis. There was a trend towards food restriction increasing uterine expression of c-fos mRNA, an estrogen dependent gene. Similar to other seasonally breeding rodents, short days render the reproductive system of female California mice more susceptible to effects of food restriction. This may be vestigial, or it may have evolved to mitigate consequences of unexpectedly poor winter food supplies. PMID- 22245266 TI - Colloid chemistry of nanocatalysts: a molecular view. AB - Recent advances of a colloidal chemistry can offer great opportunities to fabricate and design nanocatalysts. Comprehensive understanding of a basic concept and theory of the colloidal synthetic chemistry facilitates to engineer elaborate nano-architectures such as bi- or multi-metallic, heterodimers, and core/shell. This colloidal solution technique not only enables to synthesize high surface mesoporous materials, but also provides a versatile tool to incorporate nanoparticles into mesoporous materials or onto substrates. For green chemistry, catalysis research has been pursued to design and fabricate a catalyst system that produces only one desired product (100% selectivity) at high turnover rates to reduce the production of undesirable wastes. Recent studies have shown that several molecular factors such as the surface structures, composition, and oxidation states affect the turnover frequency and reaction selectivity depending on the size, morphology, and composition of metal nanoparticles. Multipath reactions have been utilized to study the reaction selectivity as a function of size and shape of platinum nanoparticles. In the past, catalysts were evaluated and compared with characterizations before and after catalytic reaction. Much progress on in situ surface characterization techniques has permitted real-time monitoring of working catalysts under various conditions and provides molecular information during the reaction. PMID- 22245265 TI - Oxidative stress and endosome recycling are complementary mechanisms reorganizing the T-cell receptor signaling complex in SLE. PMID- 22245264 TI - DNA-responsive inflammasomes and their regulators in autoimmunity. AB - Upon sensing microbial and self-derived DNA, DNA sensors initiate innate immune responses. These sensors include the interferon (IFN)-inducible Toll-like receptor 9 (TLR9) and PYHIN proteins. Upon sensing DNA, cytosolic (murine Aim2 and human AIM2) and nuclear (IFI16) PYHIN proteins recruit an adaptor protein (ASC) and pro-caspase-1 to form an inflammasome, which activates caspase-1. The activated caspase-1 cleaves pro-IL-1beta and pro-IL-18 to generate active forms. However, upon sensing cytosolic DNA, the IFI16 protein recruits STING to induce the expression of type I IFN. Recognition of self DNA by innate immune cells contributes to the production of increased levels of type I IFN. Given that the type I IFNs modulate the expression of inflammasome proteins and that the IFN inducible proteins inhibit the activity of DNA-responsive inflammasomes, an improved understanding of the molecular mechanisms that regulate the activity of DNA-responsive inflammasomes is likely to identify new therapeutic targets to treat autoimmune diseases. PMID- 22245267 TI - Excision of a submandibular gland: a safe day case procedure? AB - There are considerable benefits, both for patients and hospitals, if operations are done as day case procedures. Excision of a submandibular gland is a relatively common operation and it is usual practice for surgeons to be cautious, admit the patient for an overnight stay, and leave a drain in place. To assess the amount of postoperative bleeding into the wound (and hence potential risk to the airway) we have studied prospectively the amount of drainage that occurs. Sixty consecutive patients admitted for overnight postoperative monitoring after excision of a submandibular gland had a suction drain placed as part of the procedure. Drainage was measured by departmental staff at regular intervals during the following 24h. Nearly all the patients drained 40ml or less (mean 18ml) and in all cases there was a clear decrease in the volumes drained over the first 6-8h postoperatively. Drainage then became negligible. The plateau in drainage was evident regardless of the initial volume drained. Surgeons should be confident that drainage will cease after 6-8h in most patients, and residual drainage is negligible. PMID- 22245268 TI - Nasolabial symmetry and aesthetics in children with complete unilateral cleft lip and palate. AB - The objective of this study was to evaluate the association between nasolabial symmetry and aesthetics in children with complete unilateral cleft lip and palate (CUCLP). Frontal and basal photographs of 60 consecutively treated children with CUCLP (cleft group: 41 boys and 19 girls, mean (SD) age 11 (2) years) and 44 children without clefts (control group: 16 boys and 28 girls, mean (SD) age 11(2) years), were used for evaluation of nasolabial symmetry and aesthetics. Nasal and labial measurements were made to calculate the coefficient of asymmetry (CA). The 5-grade aesthetic index described by Asher-McDade et al. was used to evaluate nasolabial appearance. Correlation and regression analysis were used to identify an association between aesthetics and CA, sex, and the presence of CUCLP. Ten measurements in the cleft, and 2 in the control, group differed significantly between the cleft and non-cleft (or right and left) sides, respectively. The significantly higher values of 9 of 11 CA in the children with CUCLP indicated that they had more asymmetrical nasolabial areas than children without clefts. However, the regression analyses showed that only a few CA were associated with nasolabial aesthetics. In conclusion, nasolabial aesthetics and nasolabial symmetry seem to be only weakly associated in patients with CUCLP. PMID- 22245269 TI - Multilevel predictors of smoking initiation among adolescents: findings from the Minnesota Adolescent Community Cohort (MACC) study. AB - OBJECTIVE: To understand how factors at multiple levels of influence impact adolescent smoking initiation. METHOD: Data from the Minnesota Adolescent Community Cohort, a population-based cohort, were analyzed. Adolescents were recruited from randomly selected geopolitical units (GPUs) in Minnesota at ages 12 to 13 (n=1953), and were surveyed every six months (2000-2006) until 18. The association between baseline social factors and smoking initiation was analyzed using logistic regression. Linear regression was used to analyze predictors and age of initiation among smokers (n=603). RESULTS: Higher proportion of 15-16 year olds who smoke at the area-level (GPU) was associated with younger initiation (15.47 vs 15.87, p<.05). Higher proportion of the population employed and higher median household income were associated with older initiation (15.90 vs. 15.56 p<.05). Parent education, living with parents or siblings who smoke, living in homes that allow smoking, and having friends who smoke at baseline were associated with smoking initiation or younger initiation (p<.05). Participants whose parents had less than a high school education were 1.6 times more likely than those with college educated parents to have smoked at least a whole cigarette (CI=1.06, 2.26). CONCLUSION: Factors at multiple levels of influence effect adolescent smoking initiation. Smoking by older age peers and lower SES predicts earlier smoking. PMID- 22245270 TI - Involvement of transcription factor GATA-4 in regulation of CYP19 gene during folliculogenesis and luteinization in buffalo ovary. AB - CYP19 gene encode aromatase, the key enzyme of estrogen biosynthesis, is regulated in species- and tissue-specific manner by alternate use of different promoters. Previously, we have reported the cloning and characterization of tissue-specific promoter and transcripts in buffalo ovary and placenta. In human and rat ovary, FSH induces the phosphorylation of transcription factor CREB (cAMP response element binding protein) through PKA pathway which binds to cAMP response element like sequence (CLS) in CYP19 gene ovarian promoter. However, in buffalo as well as in bovine, in silico analysis of ovary specific promoter sequence identified a single base pair deletion in CLS site and is designated as CLS-like sequence. To understand if CLS with a point mutation is still a functional cis-element and is involved in FSH stimulated transactivation of CYP19 gene in buffalo ovary, the present study was thus aimed to functionally characterize the role of buffalo CLS in CYP19 gene transactivation. We also studied the involvement of GATA-4, having consensus binding sites in CYP19 gene ovarian promoter in the vicinity of CLS during different stages of the buffalo estrus cycle. Reporter construct analyses and EMSA results showed that CLS is playing no significant role in CYP19 gene regulation in buffalo ovary. Real time absolute quantification of GATA-4 showed the differential expression of GATA-4 mRNA during folliculogenesis and luteinization with significantly higher transcript abundance in large follicle in comparison to other tissues. Western blot analysis of granulosa cells nuclear protein isolated from different stage of follicular development (small and large follicles) and differentiation (corpus luteum) showed that abundance of phosphorylated GATA-4 (Ser261) was significantly higher in granulosa cell nuclear protein of large follicles as compared to small follicles and corpora lutea. Interestingly, binding studies using ChIP showed significantly enhanced binding to the CYP19 gene promoter in large follicle which was seen to be declined in the luteal tissue. Similar results were obtained in the in vitro experiments as well. Finally, RNAi experiments were performed to validate the involvement of GATA-4 in CYP19 gene regulation. Results of RNAi showed that knockdown of GATA-4 mRNA significantly declined CYP19 gene mRNA as well as 17beta-estradiol contents. In conclusion, result of the present study indicated that that in the absence of consensus CRE (cAMP response element); GATA 4 could be a downstream effector of cAMP/PKA pathway in regulation of CYP19 gene during folliculogenesis and luteinization. PMID- 22245271 TI - Ocular melanoma metastasis to the cervical spine. AB - Ocular melanoma is a rare type of malignant melanoma. Melanoma metastatic to the spine typically arises within the vertebral column, presents with back pain, and has a poor prognosis. We present a patient with a unique disease course: ocular melanoma metastasis occurred after an extended latency period of 14 years, attained a large size within the spinal intradural space, presented with severe neurological deficits without additional central nervous system disease, and the tumor was amenable to surgical intervention. We also review the literature on melanoma spine metastasis. PMID- 22245272 TI - Regression of a meningioma during paclitaxel and bevacizumab therapy for breast cancer. AB - Meningiomas often are not amenable to total resection, and subtotally resected meningiomas often recur. Recurrent meningiomas present a clinical dilemma, particularly when surgical and radiotherapy options are exhausted, as there are no chemotherapeutic options that demonstrate consistent, significant efficacy. We report a patient with the regression of a recurrent World Health Organization grade I meningioma during combination chemotherapy with bevacizumab and paclitaxel for breast cancer. This chemotherapy regimen has never been explored for recurrent meningiomas. While further data are necessary, we suggest that combination chemotherapy with bevacizumab and paclitaxel may be an option for treatment of recurrent meningiomas when no further surgical or radiotherapy options exist. PMID- 22245273 TI - Delayed post-traumatic bilateral abducens nerve palsy with complete recovery. AB - Isolated bilateral abducens (sixth) nerve palsy is rare in the setting of trauma. To date, most cases have been reported in patients who sustain cranial fractures or have other acute intracranial pathologies, including acute hemorrhage. We describe the case of a 41-year-old man who presented with bilateral abducens nerve palsy in the setting of acute head trauma without evidence of cranial fractures or other acute intracranial pathology. Six months after the initial injury, he regained bilateral function of his abducens nerves with intact extraocular muscle movements. Full recovery is the natural history in the majority of traumatic abducens nerve palsies, and this is an important consideration when counseling patients with such injuries. PMID- 22245274 TI - Use of a synthetic dural substitute to prevent ventral retethering in the management of diastematomyelia. AB - Diastematomyelia is a congenital condition where the spinal cord is split by a bony or cartilaginous septum. Neurological signs and symptoms arise when this septum tethers the spinal cord. Surgical detethering often improves symptoms; however, recurrent tethering of the cord is increasingly recognised as a long term complication. In order to prevent retethering many techniques have been used, including early patient mobilisation and sectioning of the cord. Dorsal expansile duroplasty, using synthetic grafts, is a commonly used technique to prevent recurrent dorsal tethering. We present a 31-year-old woman with recurrent ventral tethering of the cord where we used expanded polytetrafluoroethylene (Gore Preclude MVP Dura Substitute; WL Gore and Associates, Flagstaff, AZ, USA) to cover the ventral dural surface, separating the cord from its dural site of tethering. This technique may be useful to prevent ventral retethering in diastematomyelia. PMID- 22245275 TI - Technique for decompressive craniectomy using Seprafilm as a dural substitute and anti-adhesion barrier. AB - Surgeons in abdominal and gynecological fields have pioneered the use of Seprafilm (a chemically modified sodium hyaluronate/carboxymethylcellulose absorbable adhesion barrier, Genzyme Biosurgery, Cambridge, MA, USA) to prevent adhesion but its use outside these specialties is not well documented. The authors have used Seprafilm for craniectomy closure in several patients as a dural substitute and anti-adhesion barrier. During emergent craniectomy, the dura mater is reapproximated and a layer of Seprafilm is placed over the dura as an onlay and anti-adhesion barrier. During subsequent surgery for bone flap replacement, dissection between the dural plane and overlying tissues has been completed easily. There has been minimal adhesion to the underlying Seprafilm/dural layer. The Seprafilm has been incorporated into the surrounding dural plane. No postoperative complications have been noted. Seprafilm's anti adhesive properties and biodegradable characteristics make it useful as a dural onlay for craniectomy in which a second surgery is planned. PMID- 22245276 TI - Hyperprolactinaemia and the empty sella. AB - Hyperprolactinaemia is an endocrine abnormality seen not infrequently in the population with empty sella; a radiological and anatomical diagnosis of a deformed and enlarged sella turcica. Often there is no associated pathology within the pituitary gland itself, lending to the hypothesis that the empty sella syndrome per se has a yet-to-be defined role in hyperprolactinemia. We report a patient who presented initially with non-specific symptoms of meningeal irritation and viral illness on a long background of galactorrhoea. The patient demonstrated elevated serum prolactin, and a diagnosis of empty sella was made on the basis of MRI findings. PMID- 22245277 TI - Seizure or syncope: lessons over time. AB - A 25-year-old woman with recurrent syncopal episodes presented with a first time generalized tonic clonic (GTC) seizure. She had experienced two prior fainting spells lasting seconds and associated with diet pills and dehydration. She had another similar spell prior to falling, sustaining a laceration to the right posterior occiput, and having a witnessed GTC seizure. Her scalp electroencephalography (EEG) showed left temporal slowing with sharp features. T1 weighted and T2-weighted MRI revealed two moderately enhancing focal lesions within the left frontal and temporal regions. These findings raised the possibility of an underlying seizure focus. Repeat imaging studies of this patient 1 month later, however, demonstrated resolution of these findings and an area of encephalomalacia, consistent with a traumatic coup contrecoup injury. A repeat EEG was normal. Therefore, the cause of the loss of consciousness was due to syncope with the consequent head injury giving rise to an isolated seizure. Understanding the underlying cause of a seizure is important in dictating treatment. In this setting the patient was not initiated on seizure medication and has done well. PMID- 22245278 TI - Age over 80 years is not associated with increased hemorrhagic transformation after stroke thrombolysis. AB - Thrombolysis trials have recruited few patients aged >=80 years, which has led to uncertainty about the likely risk-to-benefit profile in the elderly. Leukoaraiosis (LA) has been associated with hemorrhagic transformation (HT) and increases with advanced age. We tested whether there were any independent associations between age, LA and HT. Consecutive patients treated with intravenous (IV) tissue plasminogen activator (tPA) were identified from a prospective database. LA on baseline CT scans was assessed by two independent raters using the modified Van Swieten Score (mVSS) (maximum score 8, severe >4). HT was assessed on routine 24 hour to 48 hour CT /MRI scans using the European Cooperative Acute Stroke Study criteria for hemorrhagic infarct (HI) or parenchymal hematoma (PH) and judged symptomatic by the treating neurologist as per Safe Implementation of Thrombolysis in Stroke criteria. There were 206 patients treated with IV tPA (mean age: 71.0 years; range: 24-92 years), of whom 65/206 (32%) were aged >=80 years. Overall, HT occurred in 41/206 patients (20%), HI in 31, PH1 in four (one symptomatic) and PH2 in six (three symptomatic). Age was not associated with HT (any HT: odds ratio [OR]=1.01; 95% confidence interval [CI]=0.5-2.08; p=0.99; PH: OR=0.53; 95% CI=0.12-2.3; p=0.51). There was one patient with PH1 and one patient with PH2 in 65 patients >=80 years, both asymptomatic. LA was present in 112/208 (54%), and severe in 16.5%. LA increased with age (p<0.001) but was not associated with PH (any LA: OR=0.83; 95% CI=0.25 2.8; p=0.99; severe LA: OR=0.54, 95% CI=0.09-3.5; p=0.99). Age >=80 years or LA did not increase the risk of HT (including PH) after thrombolysis, although LA increased with age. Neither factor should exclude otherwise eligible patients from tPA treatment. PMID- 22245279 TI - Headache after substance abuse: a diagnostic dilemma. AB - An 18-year-old man inhaled a substance containing synthetic cannabinoids and 1 hour later developed a severe global headache. Imaging revealed a perimesencephalic subarachnoid haemorrhage. An angiogram suggested that a small superior cerebellar artery aneurysm was the culprit. This report discusses the, as yet undefined, relationship between "herbal highs" and intracranial haemorrhage. PMID- 22245280 TI - [Posterior interosseous nerve palsy. A series of 18 cases and literature review]. AB - OBJECTIVES: Posterior interosseous nerve palsy is a rare syndrome frequently unrecognized, while the clinical presentation is characteristic: finger extension paresis associated with wrist extension in radially deviated position. Here, we assessed our results of surgical treatment. METHODS: A 20-year retrospective study was carried out in our unit. Analysis of causes and an assessment of postoperative functional outcome were performed. Our study was compared with literature data. RESULTS: Eighteen cases were treated with a predominance in men manual workers. The etiology of the posterior interosseous nerve palsy was tumor in four cases, traumatic in two cases, iatrogenic in two cases and idiopathic in ten cases. In seven of these ten cases, compression under the arch of the extensor carpi radialis brevis was found. The postoperative results were satisfactory with full recovery in nine out of fifteen cases treated by neurolysis, depending on the duration of the paralysis. In the literature, we found 264 cases over 50 years through a variety of clinical cases and five case series. A predominance of tumor etiology was found. CONCLUSION: Ignorance of the clinical presentation of a posterior interosseous nerve palsy frequently leads to misdiagnosis. Early complete neurolysis enables a satisfactory functional recovery. PMID- 22245281 TI - [Midcarpal fusion using break-away compression screw]. AB - Indication of midcarpal fusion is SNAC or SLAC wrist grade 3. The main complication of circular plate (most common technique) is non-union. In this context, the purpose of our work was to propose the use of break-away compression screws to decrease the rate of non-union. Our series included ten patients. The fusion was fixed using two break-away compression screws (2mm diameter). No bone graft was used. As assessment, subjective (pain, Quick-DASH) and objective (strength, mobility) criteria were reviewed at follow-up. All the criteria were significantly improved after operation except mobility. Among the complications, we noticed one delayed bone-healing with a good outcome and a radiological consolidation. Midcarpal fusion by dorsal approach using break-away compression screws appears to us a technique of interest, not requiring a bone graft, with good cost effectiveness. PMID- 22245282 TI - One-step microsurgery for acquired anterior glottic web. PMID- 22245283 TI - Analysis of antibodies to surface epitopes of contactin-2 in multiple sclerosis. AB - Contactin-2 was recently identified as an autoantigen targeted by T-cells and autoantibodies in multiple sclerosis (MS). Here we analyzed the frequency of antibodies to contactin-2 (contactin-2-ab) by a cell-based assay in the serum from 105 MS patients and at least 5 years of follow-up (19 clinically isolated syndromes, 51 relapsing-remitting, 20 secondary-progressive, and 15 primary progressive). Contactin-2-ab were detected in 4 (7.8%) relapsing-remitting patients. Clinical and magnetic resonance imaging characteristics were not significantly different from the rest of relapsing-remitting patients. In conclusion, contactin-2-ab are identified in a minority of MS patients but their presence is not associated with a particular clinical-radiological profile. PMID- 22245284 TI - Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network. AB - The concomitant production of IL-17A and IL-9, both Th17 cytokines, has not been compared in MS patients. We show that IL-17A but not IL-9 expression by CD3(+) cells was increased during a MS relapse. Co-expression of IL-17A and IL-9 was marginal. In addition to Th1 and Th2 cytokines, IL-17A, IL-6 and IL-23p19 were down-regulated by ivMP, but Foxp3 was not, while an increase in IL-10, TGF-beta1 and IL-27p28 mRNA was observed. This change in the Th17, Treg and IL-10 balance could be an additional mechanism by which corticosteroids shorten the duration of a MS relapse and promote recovery. PMID- 22245285 TI - Human T cell expansion and experimental autoimmune encephalomyelitis inhibited by Lenaldekar, a small molecule discovered in a zebrafish screen. AB - Immune-mediated diseases [multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE)] are driven by proliferating, highly activated autoreactive T-cells that are unresponsive to in vivo immunoregulatory mechanisms. The compound Lenaldekar (LDK) was identified in a zebrafish screen by inhibiting T-cell expansion. By monitoring mitogen- and antigen-driven proliferation, we found that LDK inhibited human and murine T-cell expansion in a non-cytolytic manner. This suppressive activity directly correlated with the degree of activation/proliferation of the T-cells. In testing LDK in an EAE model of MS, exacerbations were suppressed in treated animals. Therefore, LDK represents a novel therapeutic approach to T-cell-mediated autoimmune diseases. PMID- 22245286 TI - Mediatophore regulates acetylcholine release from T cells. AB - Immunological stimulation of T cells by phytohemagglutinin (PHA) enhances the synthesis and release of acetylcholine (ACh), suggesting a role for the lymphocytic cholinergic system in the regulation of immune function. In the present study, we used two human leukemic T cell lines as models to investigate whether mediatophore, a homooligomer of a 16-kDa subunit homologous to the proteolipid subunit c of vacuolar H(+)-ATPase (V-ATPase), is involved in mediating ACh release from T cells. Immunohistochemical analysis revealed the presence of mediatophore in the cytoplasm and on the plasma membrane of both T cell lines. Mediatophore gene expression was up-regulated by immunological T cell activation by PHA. Transfection of anti-mediatophore small interference RNA down regulated mediatophore gene expression and significantly reduced ACh release. These results suggest that T cells express mediatophore, which then plays a key role in mediating ACh release, and that mediatophore expression is regulated by immunological stimulation. PMID- 22245287 TI - Loss of class I MHC function alters behavior and stress reactivity. AB - The importance of the classical immune molecule, class I major histocompatibility complex to central nervous system function is one of the most surprising discoveries related to neuroimmunology in the past decade. Mice lacking both beta 2microglobulin and transporter associated with antigen processing (beta2M-/-TAP-/ ) showed differences in basal behavior. In response to saline injection, beta2M-/ TAP-/- mice showed a significant hypothalamic pituitary adrenal activation that was not observed in wild type mice, while lipopolysaccharide-induced cytokine expression in the hypothalamus was similar in beta2M-/-TAP-/- and wild type mice. Overall, these data show that class I MHC plays an important role in behavior and stress reactivity. PMID- 22245288 TI - Basic principles for the development of a common standardised method for determining the radon diffusion coefficient in waterproofing materials. AB - Paper presents the principles for unified test methods for determining the radon diffusion coefficient in waterproof materials in order to increase the accuracy, repeatability and reproducibility of the results. We consider this very important, because an assessment of the radon diffusion coefficient is required by several national technical standards when waterproofing acts as a radon-proof membrane. The requirements for key parameters for one test method performed under non-stationary conditions and for two methods performed under stationary conditions are described in this paper. PMID- 22245289 TI - Mathematical modeling of a survey-meter used to measure radioactivity in human thyroids: Monte Carlo calculations of the device response and uncertainties. AB - This paper presents results of Monte Carlo modeling of the SRP-68-01 survey meter used to measure exposure rates near the thyroid glands of persons exposed to radioactivity following the Chernobyl accident. This device was not designed to measure radioactivity in humans. To estimate the uncertainty associated with the measurement results, a mathematical model of the SRP-68-01 survey meter was developed and verified. A Monte Carlo method of numerical simulation of radiation transport has been used to calculate the calibration factor for the device and evaluate its uncertainty. The SRP-68-01 survey meter scale coefficient, an important characteristic of the device, was also estimated in this study. The calibration factors of the survey meter were calculated for (131)I, (132)I, (133)I, and (135)I content in the thyroid gland for six age groups of population: newborns; children aged 1 yr, 5 yr, 10 yr, 15 yr; and adults. A realistic scenario of direct thyroid measurements with an "extended" neck was used to calculate the calibration factors for newborns and one-year-olds. Uncertainties in the device calibration factors due to variability of the device scale coefficient, variability in thyroid mass and statistical uncertainty of Monte Carlo method were evaluated. Relative uncertainties in the calibration factor estimates were found to be from 0.06 for children aged 1 yr to 0.1 for 10-yr and 15-yr children. The positioning errors of the detector during measurements deviate mainly in one direction from the estimated calibration factors. Deviations of the device position from the proper geometry of measurements were found to lead to overestimation of the calibration factor by up to 24 percent for adults and up to 60 percent for 1-yr children. The results of this study improve the estimates of (131)I thyroidal content and, consequently, thyroid dose estimates that are derived from direct thyroid measurements performed in Belarus shortly after the Chernobyl accident. PMID- 22245290 TI - Defining the contribution of select neuropeptides and their receptors in regulating sesquiterpenoid biosynthesis by Drosophila melanogaster ring gland/corpus allatum through RNAi analysis. AB - The larval ring gland and adult corpus allatum (CA) of Drosophila melanogaster produce at least three sesquiterpenoid products: methyl farnesoate (MF), juvenile hormone III (JHIII), and JHIII bisepoxide (JHB(3)). Our understanding of neuropeptide regulation of sesquiterpenoid biosynthesis in D. melanogaster has been hampered by uncertainty over the biosynthetic pathway and the sites of action of regulators. As an approach to defining the neuropeptide regulators, we have used in vivo gene-specific silencing (RNAi). D. melanogaster strains containing an inducible UAS-RNAi construct made to either PheGlyLeu-NH(2) allatostatin (FGLa/AST) and its cognate receptors Dar-1 and Dar-2 or PISCF allatostatin (PISCF/AST) or its cognate receptors Drostar-1 or Drostar-2 were expressed in vivo. MF, JHIII and JHB(3) production was measured in ring glands of 3rd instars or corpora allata (CA) of adult females using the radiochemical assay. Reduction in FGLa/AST and Dar-1 or Dar-2 mRNA levels had no effect on MF, JHIII, or JHB(3) production in larvae or adults. Inhibition of Drostar-1 expression resulted in a significant decrease in MF and JHB(3) production in 3rd instars with little effect on JHIII biosynthesis. In contrast, inhibition of Drostar-1 in adult females led to a significant increase in MF and JHIII production. Inhibition of Drostar-2 also reduced MF biosynthesis in 3rd instars. In adults, inhibition of Drostar-2 led to a significant increase in MF and JHIII production but showed no effect on JHB(3). PISCF/AST had no effect on sesquiterpenoid biosynthesis when incubated with 3rd instar ring glands but was stimulatory when incubated with adult glands. Inhibition of short neuropeptide F (sNPF) expression by RNAi or application of sNPF to ring glands had no effect on MF, JHIII, or JHB3 biosynthesis in larvae or adults. Reduction in the neuropeptide Y receptor (NepYr) or neuropeptide F receptor (NPF-R) inhibited JHIII and JHB(3) production in 3rd instars but only reduction in NepYr resulted in JHB(3) reduction in adults. PMID- 22245291 TI - Apoptotic and survival signaling mediated through death receptor members during metamorphosis in the African clawed frog Xenopus laevis. AB - The tumor necrosis factor (TNF) superfamily includes death receptor (DR) ligands, such as TNF-alpha, FasL, and TRAIL. Death receptors (DRs) induce intracellular signaling upon engagement of their cognate DR ligands, either leading to apoptosis, survival, or proinflammatory responses. The DR signaling is mediated by the recruitment of several death domain (DD)-containing molecules such as Fas associated death domain (FADD) and receptor-interacting protein (RIP) 1. In this review, we describe DR signaling in mammals, and describe recent findings of DR signaling during metamorphosis in the African clawed frog Xenopus laevis. Specifically, we focus on the cell fate (apoptosis or survival) mediated through a DR ligand, TNF-alpha or TRAIL in endothelial cells or red blood cells (RBCs). In addition, we discuss relationships between thyroid hormone-induced metamorphosis and DR signaling. PMID- 22245292 TI - Pure mini-laparoscopic transperitoneal pyeloplasty in an adult population: feasibility, safety, and functional results after one year of follow-up. AB - OBJECTIVE: To report the results of mini-laparoscopic pyeloplasty (mLP) in an adult population. The feasibility of pure mLP has been previously reported in children. MATERIAL AND METHODS: From April 2009 to February 2010, 10 patients with ureteropelvic junction obstruction (UPJO) were enrolled in this prospective study and underwent pure mLP (using only 3-mm instruments) according to the Anderson-Hynes technique. Inclusion criteria were: age >18 years, body mass index <25, primary UPJO, and no previous surgery on the affected kidney or a history of major abdominal surgery. Demographic and perioperative data, as well as 1-, 3-, 6 , and 12-month follow-up data were collected. RESULTS: The mean operative time was 134 minutes, and blood loss was negligible. All procedures but one were completed using only 3.9-mm ports and 3-mm instruments. No perioperative complications occurred, and no patients had computed tomography evidence of hydronephrosis at 6 months after surgery. No functional obstructions were visualized with renal scintigraphy at 12 months after surgery. All patients were satisfied with the intervention and with their cosmetic results, as assessed by the Patient Scar Assessment Questionnaire and Scoring System. CONCLUSIONS: The results of our study suggest that pure mLP in an adult population is feasible and seems to be safe and effective in the treatment of UPJO. Furthermore, the patients tolerated the procedure well and appreciated its excellent cosmetic results. Further studies are required to determine the true advantages of mLP over standard laparoscopy. PMID- 22245293 TI - Histologic inflammatory changes on the prostatic gland due to immunosuppression for kidney transplantation. AB - OBJECTIVE: To determine the incidence of type IV prostatitis in patients with kidney transplantation receiving an immunosuppression regimen and to compare it with that of a nonimmunosuppressed control group. METHODS: We retrospectively reviewed 216 electronic charts of patients who had undergone surgical treatment for benign prostatic hyperplasia from August 2000 to January 2006. Of the 216 patients, 183 did not receive immunosuppressive therapy and were included in the control group (group 1). The other 33 patients had undergone kidney transplantation and were included in the study group (group 2). The patient data were accessed for age at surgery, International Prostate Symptom Score, prostate volume, preoperative serum prostate-specific antigen level, history of acute urinary retention, and surgical approach (open vs transurethral resection of prostate). Histologic findings from the surgical specimens were also recorded. RESULTS: The mean age at surgery, mean serum prostate-specific antigen level, mean prostate volume, and mean International Prostate Symptom Score were not significantly different between both groups. However, histologic evidence of chronic prostatitis was obtained in 145 surgical specimens (78%) from group 1 and in just 3 specimens from group 2 (9%; P < .001). Moreover, nonimmunosuppressed patients had a 38.2 times greater risk of presenting with prostatitis than did the immunosuppressed patients. CONCLUSION: Immunosuppression therapy in kidney transplantation has a protective factor in the prostatitis incidence. PMID- 22245294 TI - Role of spinal cord in regulating mouse kidney: a virally mediated trans-synaptic tracing study. AB - OBJECTIVE: To determine the spinal innervation and neuronal connections is important for studying renal metabolic responses. MATERIALS AND METHODS: In this study, the spinal cords of 10 adult male C57BL/6J strain mice were mapped retrograde using injections of pseudorabies virus (PRV)-614. The virus, injected into the kidney, was specifically transported to the spinal cord. RESULTS: At 5 days after injection of the PRV-614, PRV-614-positive cells were found in the intermediolateral cell column, the intercalates nucleus, or the central autonomic nucleus of spinal cord segments T4-L1, and most PRV-614-labeled cells were found in the T9 segment. CONCLUSION: Our results revealed neuroanatomical circuits between kidney and the spinal intermediolateral cell column neurons. PMID- 22245296 TI - Unilateral exophthalmos revealing metastatic prostate cancer. AB - Prostate cancer, when metastatic, typically involves the axial skeleton. Sphenoidal metastasis is uncommon. We report a rare case of a 75-year-old man who presented with isolated unilateral exophthalmos. Digital rectal examination and serum prostate-specific antigen level were suggestive of metastatic prostate cancer. The prostate biopsy and imaging findings confirmed the source of the exophthalmos as a sphenoidal metastasis of an aggressive prostate adenocarcinoma. PMID- 22245295 TI - Factors influencing urologist treatment preference in surgical management of stone disease. AB - OBJECTIVE: To assess the surgeon factors influencing the surgical treatment decisions for symptomatic stone disease. The factors influencing the selection of shock wave lithotripsy (SWL), ureteroscopy, or percutaneous nephrolithotomy to treat symptomatic stone disease are not well studied. METHODS: Electronic surveys were sent to urologists with American Medical Association membership. Information on training, practice, and ideal treatment of common stone scenarios was obtained and statistically analyzed. RESULTS: In November 2009, 600 surveys were sent and 180 were completed. High-volume SWL practices (>100 cases annually) were more common in community practice (P < .01), and high-volume ureteroscopy and percutaneous nephrolithotomy practices were more common in academic practice (P = .03). Community practice was associated with SWL selection for proximal urolithiasis and upper pole nephrolithiasis (P < .005). An increasing time since urologic training was associated with SWL selection for proximal urolithiasis and upper pole nephrolithiasis (P < .01). Urologists reporting shock wave lithotriptor ownership were 3-4 times more likely to select SWL for urolithiasis or nephrolithiasis compared with urologists who did not own a lithotripter (P < .01). Routine concern for stent pain and rigid ureteroscope preference (vs flexible) were associated with SWL selection (P < .03). CONCLUSION: Surgeon factors significantly affected urolithiasis treatment selection. SWL was associated with community urology practice, increasing time since training, shock wave lithotriptor ownership, concern for stent pain, and ureteroscope preference. PMID- 22245297 TI - Mullerian remnant malignancy. AB - Mixed gonadal dysgenesis is a disorder of sexual differentiation, characterized by mosaicism, ambiguous external genitalia, and both Wolffian and Mullerian internal genitalia. These patients are at a known increased risk of germ cell cancer, specifically gonadoblastoma; however, in this report we describe a case of adenocarcinoma of a remnant Mullerian structure. PMID- 22245298 TI - Long-term results of small intestinal submucosa graft in bulbar urethral reconstruction. AB - OBJECTIVE: To retrospectively report the long-term results of the use of a small intestinal submucosa (SIS) graft in bulbar urethral repair. METHODS: From 2003 to 2007, 25 men (mean age 40.5 years) with bulbar strictures underwent patch graft urethroplasty using SIS placed on the dorsal or ventral or dorsal plus ventral surface of the urethra. The mean follow-up period was 71 months (range 52-100). The clinical outcome was considered a failure when any postoperative instrumentation, including dilation, was needed. RESULTS: Of the 25 cases, 19 (76%) were successful and 6 (24%) were failures. No postoperative complications were related to the use of heterologous graft material, such as infection or rejection. The failure rate was 14% for strictures <4 cm and 100% for strictures >4 cm. CONCLUSION: At long-term follow-up, in bulbar stricture repair, SIS grafts showed similar results to penile skin grafts but were less effective than buccal mucosa grafts. The use of SIS as graft material should not be the first choice but represents an alternative option for patients with bulbar strictures that are not long and who refuse the harvesting or are not ideal candidates for buccal mucosa or penile skin grafts. Larger series of patients with longer follow-up are needed before widespread use can be advocated. PMID- 22245299 TI - Pressure transmission through ureteric stents: a novel in vivo human study. AB - OBJECTIVE: To document, in an in vivo study, the pressure transmission from the urinary bladder to the upper tract through ureteric stents in human patients. Stents have acquired special importance in the urological armamentarium. Flank pain and hydronephrosis are associated with stenting in 50% and 18% of cases, respectively. Pressure transmission from urinary bladder to the upper tract through the stent is the logical explanation for loin pain and hydronephrosis. METHODS: This study was conducted in a prospective manner. We did not select patients or modify their management; instead, we studied patients who, during the course of urological management of some upper tract disease, are left with both a ureteric stent and a nephrostomy tube. Twenty patients fulfilled our criteria. After written consent, a pressure-flow study was done monitoring pressure changes in the renal pelvis during different phases of bladder filling in sitting and recumbent positions. RESULTS: Pressure-flow curves showed almost equal transmission of pressure from the bladder to the renal pelvis throughout all phases of bladder filling and emptying. Any voluntary and involuntary rise of pressure in the bladder was instantly and almost equally transmitted to the renal pelvis. A subgroup of patients with infravesical obstruction resulting from benign prostatic hyperplasia also showed equal transmission of the elevated intravesical pressure during voiding to the renal pelvis. CONCLUSION: Pressure from the lower urinary tract is transmitted to the upper tract through the stent, posing a threat to the renal parenchyma and function. Stent placement, when indicated, should be used for the shortest period possible, in sterile urine. PMID- 22245300 TI - Pre- and postoperative urodynamic findings in patients after a bulbourethral composite suspension with intraoperative urodynamically controlled sling tension adjustment for postprostatectomy incontinence. AB - OBJECTIVES: To compare pre- and postoperative urodynamic findings in patients with a bulbourethral composite suspension and intraoperative urodynamically controlled sling tension adjustment. METHODS AND PATIENTS: All data were prospectively collected from 10 patients (mean age 66 years) who successfully underwent bulbourethral composite suspension for moderate to severe postprostatectomy incontinence. Patients were evaluated preoperatively and 3-6 months postoperatively by urodynamic measurements, including urethra pressure profiles (UPPs) and pressure flow studies (PFSs). Clinical outcome was evaluated by patient-reported pad use and questionnaires (ICIQ-UI SF and I-QOL). Intraoperatively sling tension was adjusted under repeated urodynamic measurements of abdominal leak point pressure. Data were evaluated using the Kruskal-Wallis Wilcoxon test. RESULTS: Sling implantation was successful in all patients. Pre- to postoperative pad use decreased significantly (P < .005). Five patients were pad-free, 3 used 1 pad, and 2 used 2 pads per day. Continence and quality of life improved significantly (ICIQ-UI SF: pre-op 17 vs post-op 4.9; I QOL: pre-op 66 vs post-op 91; P < .05 for both). Urodynamic parameters during the filling phase remained unchanged. UPPs revealed a significant increase of the maximal urethral closure pressure (pre-op 40 cm H(2)O vs post-op 58 cm H(2)O) and functional length (pre-op 31 mm vs post-op 40 mm; P < .05 for both). Postoperatively, urodynamic maximal flow rates were slightly reduced from 16 mL/s to 12 mL/s (P = .4). PFSs revealed an unobstructed voiding in all patients. CONCLUSIONS: According to the present evaluation, a bulbourethral composite suspension with intraoperative urodynamically controlled sling tension adjustment improves continence without causing prolonged clinically or urodynamically significant voiding obstruction. PMID- 22245301 TI - The effect of extralumenal safety wires on ureteral injury and insertion force of ureteral access sheaths: evaluation using an ex vivo porcine model. AB - OBJECTIVE: To evaluate the effect that a safety wire (SW) had on insertion force and direct ureteral trauma using ureteral access sheaths (UAS) in an ex vivo porcine model. MATERIAL AND METHODS: UASs were advance into 20 fresh ex vivo porcine kidney-ureters, either with or without SWs. The average and max force of insertion were recorded. Retrograde saline injection was used to identify the presence of lacerations. RESULTS: For SW vs no SW, the mean insertion force (1.79 vs 0.67, P = .0003, respectively) and max insertion force (2.29 kg vs 1.00, P = .0007) was greater in the SW group. There were 9 lacerations, 6 of which were partial and 3 complete. Of the partial injuries, 2 were in the no SW group and 4 were in the SW group. Of the complete lacerations, 2 occurred in the no SW group and 1 in the SW group. However, there was no significant difference in the total number of lacerations (P = 1.00), the number of partial lacerations (P = .628), or the number of complete lacerations (P = 1.00) between the 2 groups. CONCLUSIONS: The use of an SW significantly increases the force required to insert a UAS; however, it does not appear to affect the force or the degree of ureteral injury. PMID- 22245302 TI - Biomechanical properties of human pelvic organs. AB - OBJECTIVE: To comparatively define the biomechanical characteristics of the pelvic organs (the vagina, bladder, and rectum), which are crucial for the maintenance of pelvic support. Despite minimal fundamental studies, meshes are increasingly implanted into the vesicovaginal and rectovaginal spaces to replace disrupted native tissues and to treat pelvic organ prolapse. However, the mechanical characteristics of these materials have not yet been compared with those of the "functional unit," the vagina, bladder, and rectum. METHODS: Samples from 5 fresh female cadavers without prolapse were collected. Uniaxial tension tests under monotonic and cyclic loading were performed and the stress-strain curves obtained. RESULTS: The biomechanical properties of the vaginal, bladder, and rectal tissues differed significantly. We were able to demonstrate a nonlinear relationship between the stress and strain and a visco-hyperelastic behavior with a Mullins effect of damage of the tissues examined. Comparable rigidity was found between the investigated tissues at low strains; however, at large strain levels, marked differences could be observed. The vagina was much more rigid and less extendible than the rectal tissue, which, in turn, was more rigid than the bladder tissue. The anterior and posterior vagina revealed a different stiffness, and the bladder tissue was anisotropic at large strain levels. CONCLUSION: Our results underline the pivotal role of the vaginal tissue for the maintenance of pelvic support. The observed differences with respect to tissue rigidity should have pronounced effects on the physiologic organ function, pointing to the necessity of a differentiated view on using the same prosthetic material for different anatomic locations. PMID- 22245303 TI - Long-term outcomes of open radical retropubic prostatectomy for clinically localized prostate cancer in the prostate-specific antigen era. AB - OBJECTIVE: To determine long-term oncological outcomes and complication rates for patients with clinically organ confined prostate adenocarcinoma (PCa) treated with open radical retropubic prostatectomy and pelvic lymph node dissection (RRP/PLND) in the prostate-specific antigen (PSA) era. METHODS: Outcomes data were obtained from a prospectively maintained prostate cancer database. Patients with cT1/cT2 PCa undergoing RRP/PLND without neoadjuvant therapy between July 1988 and June 2008 were included. Kaplan-Meier and Cox proportional regression models were used to evaluate factors influencing biochemical recurrence, clinical recurrence, and overall survival (OS). RESULTS: A total of 2487 patients met inclusion criteria, and median follow-up was 7.2 years (range 1-21 years). Of the patients, 49.7% were low risk, 33.2% intermediate risk, and 16.1% high risk by D'Amico criteria, and 6% were LN+. The 10-year biochemical recurrence-free survival (BCRFS) for low-, intermediate-, and high-risk patients was 92%, 83%, and 76%, respectively (P < .001), and 10 year OS was 91%, 83%, and 74%, respectively (P < .001). BCRFS at 10 years was 76% and 88% for patients with positive and negative margins, respectively (P < .001). Of the 2487 patients, 11% developed BCR, and 3.7% experienced CR, with 9 local recurrences. The overall complication rate was 2.3%, and the cancer specific mortality rate was 2%. CONCLUSION: D'Amico risk group, margin status, and LN status are significantly correlated with outcomes in patients undergoing RRP/PLND for clinically localized PCa. Local recurrence and death from prostate cancer are rare in patients undergoing open RRP/PLND for clinically organ confined disease in the PSA era. PMID- 22245305 TI - Relationship between procalcitonin levels and presence of vesicoureteral reflux during first febrile urinary tract infection in children. AB - OBJECTIVE: To investigate the association between the procalcitonin (PCT) level during the first febrile urinary tract infection (UTI) in children and the presence of vesicoureteral reflux (VUR). VUR-associated UTI is among the primary causes of chronic renal failure in Turkey. METHODS: From March 2008 to November 2009, patients admitted with their first febrile UTI were included in the present prospective hospital-based study. The serum concentrations of C-reactive protein, complete blood count, and PCT were measured. All patients underwent renal ultrasonography and voiding cystourethrography. RESULTS: Of the 66 patients who were diagnosed with UTI, 18 had VUR. The geometric mean of the PCT levels was significantly greater in the children with VUR than in those without (P = .006). After logistic regression adjustment, the association between the PCT levels and the presence of VUR remained significant (odds ratio 5.08, 95% confidence interval [CI] 1.43-18.02). A PCT level >0.56 ng/mL had 66.7% sensitivity (95% CI 41-86.6) and 77.1% specificity (95% CI 62.7-88) for diagnosing VUR. The area under the receiver operating characteristic curve for PCT was 0.715 (95% CI, 0.56 0.86, P = .007), and the area under the curve for C-reactive protein was 0.723 (95% CI 0.58-0.86, P = .006). CONCLUSION: A PCT-guided strategy could help in detecting patients with VUR. Large cohort studies are needed to define an accurate cutoff value for children who are at risk of VUR, which increases the risk of renal damage and subsequent scarring. PMID- 22245304 TI - Durability of antireflux effect of ureteral reimplantation for primary vesicoureteral reflux: findings on long-term cystography. AB - OBJECTIVE: To evaluate the long-term durability of successful ureteral reimplantation (UR) for vesicoureteral reflux (VUR) through a review of late cystography (LC) findings. MATERIALS AND METHODS: We performed a retrospective chart review of all children with primary VUR who underwent successful open UR (grade 0 VUR into the reimplanted ureter[s] on initial cystogram) at our institution from January 1990 to December 2002. We identified successful UR patients who underwent LC >= 1 year after UR and reviewed the results for the presence of recurrent VUR into the reimplanted ureter(s). RESULTS: Seven-hundred ninety-four patients underwent successful open UR for primary VUR, of whom 60 (7.6%) had a subsequent LC. Preoperative VUR grade was <= II in 20 (34.5%) and >= III in 38 (65.5%). Median age at UR was 3.5 years (IQR 1.3-6.2 years); 51 (85%) were female. UR was intravesical in 45 (75%) and bilateral in 19 (32%). LC was performed at a median of 38.7 months after UR (IQR 19.6-66.1 months). Indication for LC was febrile urinary tract infection (UTI) in 16 (27%), nonfebrile UTIs in 15 (25%), follow-up of contralateral VUR in 16 (27%), and other clinical indications in 13 (21%). The recurrence rate was 0%; of the 79 reimplanted ureters, 100% (95% CI 95.4-100) had no VUR (grade 0). CONCLUSION: Among children who underwent successful open UR for primary VUR, there was no VUR recurrence on extended follow-up. This suggests that the late durability of open antireflux surgery is excellent. PMID- 22245306 TI - Understanding variation in primary prostate cancer treatment within the Veterans Health Administration. AB - OBJECTIVE: To examine the variation in prostate cancer treatment in the Veterans Health Administration (VHA)--a national, integrated delivery system. We also compared the care for older men in the VHA with that in fee-for-service Medicare. METHODS: We used data from the Veterans Affairs Central Cancer Registry linked with administrative data and Surveillance, Epidemiology, and End Results-Medicare data to identify men with local or regional prostate cancer diagnosed during 2001 to 2004. We used multinomial logistic and hierarchical regression models to examine the patient, tumor, and facility characteristics associated with treatment in the VHA and, among older patients, used propensity score methods to compare primary therapy between the VHA and fee-for-service Medicare. RESULTS: The rates of radical prostatectomy and radiotherapy varied substantially across VHA facilities. Among the VHA patients, older age, black race/ethnicity, and greater comorbidity were associated with receiving neither radical prostatectomy nor radiotherapy. Facilities with more black patients with prostate cancer had lower rates of radical prostatectomy, and those with less availability of external beam radiotherapy had lower radiotherapy rates. The adjusted rates of radiotherapy (39.7% vs 52.0%) and radical prostatectomy (12.1% vs 15.8%) were lower and the rates of receiving neither treatment greater (48.2% vs 32.2%) in the VHA versus fee-for-service Medicare (P < .001). CONCLUSIONS: In the VHA, the treatment rates varied substantially across facilities, and black men received less aggressive prostate cancer treatment than white men, suggesting factors other than patient preferences influence the treatment decisions. Also, primary prostate cancer therapy for older men is less aggressive in the VHA than in fee for-service Medicare. PMID- 22245307 TI - Is there any role for urodynamic study in children with high-grade vesicoureteral reflux? AB - OBJECTIVE: To determine the clinical symptoms and urodynamic characteristics among children with primary high-grade vesicoureteral reflux (VUR). MATERIALS AND METHODS: We prospectively studied clinical symptoms and urodynamic parameters in 147 consecutive patients <= 12 years old with idiopathic high-grade VUR referred to our hospital. RESULTS: Of 147 patients with high-grade VUR, 139 cases with mean age of 5.3 years met our inclusion criteria (88.5% females, 11.5% males). The most common symptom was recurrent urinary tract infection (57%) and urgency (59%) followed by enuresis (31.6%) and frequency (26.6%). Normal urodynamic findings were observed in 23% of patients. Overactive bladder (74%), high-end filling pressure (72.7%), low-compliance bladder (56%), and low bladder capacity (51%) were the most common urodynamic reports in this study. Other urodynamic findings were underactive bladder (1.5%), hypersensitive bladder (1.5%), hyposensitive bladder (3%), and high capacity bladder (2.2%). CONCLUSION: Proper management of VUR is very important because of its harmful potential effects on kidney function in children. With regard to the issue that most children with grade III and higher VUR had overactive bladder, high-end filling pressure, and other urodynamic disorders in their urodynamic study, it seems that these urodynamic disorders could be the basic cause of reflux. PMID- 22245308 TI - Re: Bas W.G. van Rhijn, Theo H. van der Kwast, Sultan S. Alkhateeb, et al. A new and highly prognostic system to discern T1 bladder cancer substage. Eur Urol 2012;61:378-84. PMID- 22245309 TI - Plasmodium vivax gametocyte protein Pvs230 is a transmission-blocking vaccine candidate. AB - The malaria transmission-blocking vaccine (TBV) aims to interfere the development of malaria parasite in the mosquito and prevent further transmission in the community. So far only two TBV candidates have been identified in Plasmodium vivax; ookinete surface proteins Pvs25 and Pvs28. The pvs230 (PVX_003905) is reported as an ortholog of Pfs230, a gametocyte/gamete stage TBV candidate in Plasmodium falciparum, however its candidacy for TBV has never been tested. Therefore here, we have investigated whether Pvs230 can be a TBV candidate using P. vivax samples obtained from Thailand. The mouse antiserum raised against the plasmid expressing CRDs I-IV of Pvs230 detected Pvs230 protein in the lysate of P. vivax gametocyte in western blot analysis under non-reducing condition. From the localization of Pvs230 on the outer most regions of gametocyte in the immunofluorescence assay, it appears that Pvs230 is localized on the surface of gametes. Importantly, the anti-Pvs230 mouse serum significantly reduced the number of P. vivax oocysts developed in the mosquito midgut. Moreover, the polymorphism in Pvs230 CRDs I-IV is limited suggesting that it may not be an impediment for the utilization of Pvs230 as an effective TBV candidate. In conclusion, our results show that Pvs230 is a transmission-blocking vaccine candidate of P. vivax. PMID- 22245310 TI - Persistence of long-term immunity to hepatitis B among adolescents immunized at birth. AB - The long-term duration of recombinant hepatitis B vaccine-induced immunity among persons vaccinated starting at birth is still not well understood. Waning of vaccine-induced immunity could leave young adults at risk of hepatitis B virus infection due to behavioral or occupational exposures. We followed a cohort of children immunized starting at birth with a 3-dose regimen of recombinant hepatitis B vaccine (5 mcg, 2.5 mcg, 2.5 mcg). They were challenged with a booster dose of the hepatitis B vaccine 10 and 15 years after vaccination to assess anamnestic response as a measure of persistence of protection. Among 108 participants who had lost protective antibody levels against hepatitis B, the majority (>70%) had an anamnestic response to the booster dose; response rates did not decline significantly between 10 and 15 years follow-up periods. A high antibody concentration following primary vaccination was independently associated with an anamnestic response later on in life. Nonetheless, ~20-30% of participants were unable to mount an immune response after boosting. Hepatitis B revaccination might be required for persons vaccinated starting at birth if opportunities for hepatitis B virus exposure exist. Future vaccine recommendations should be based on studies ascertaining protection against clinically significant disease. PMID- 22245311 TI - Undescended testis in inguinal canal detected incidentally on fluorodeoxyglucose PET/CT imaging. AB - The differential diagnosis at the inguinal region is very important for hypermetabolic foci because of the possibility of metastasis at this level in cancer patients ongoing PET imaging for detection of metastases. It is important to distinguish this activity from other possible malignant and benign conditions such as lymph node activity, testicular cancer, metastatic disease activity, inflammation and urine skin contamination artefact. A 66-year-old male patient with operated colon cancer and liver metastasis was referred for PET/CT examination for re-staging because of suspicious metastases. Findings of PET/CT imaging with undescended testis detected incidentally was presented. PMID- 22245313 TI - Developmental experiences and the oxytocin receptor system. AB - The long-term effects of developmental experiences on social behavior, and the neuropeptide systems such as oxytocin which subserve the behavior, are still little understood. In this article, we review various types of early experience, including normal development, knockout models, pharmacological exposures, and early social experiences. We consider the processes by which experience can affect oxytocin receptor binding, and what is known about the directionality of experience effects on oxytocin receptors. Finally, we attempt to synthesize the literature into a predictive model as to the direction of early experience effects on oxytocin receptor binding potential, and whether these changes have functional significance. These predictions are relevant to current human health practice, given proposals to use chronic intranasal oxytocin to treat developmental disorders including autism and schizophrenia. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22245312 TI - Patterns of heroin and cocaine injection and plasma HIV-1 RNA suppression among a long-term cohort of injection drug users. AB - BACKGROUND: Previous studies suggest that active drug use may compromise HIV treatment among HIV-positive injection drug users (IDU). However, little is known about the differential impacts of cocaine injection, heroin injection, and combined cocaine and heroin injection on plasma HIV-1 RNA suppression. METHODS: Data were derived from a longstanding open prospective cohort of HIV-positive IDU in Vancouver, Canada. Kaplan-Meier methods and Cox proportional hazards regression were used to examine the impacts of different drug use patterns on rates of plasma HIV-1 RNA suppression. RESULTS: Between May 1996 and April 2008, 267 antiretroviral (ART) naive participants were seen for a median follow-up duration of 50.6 months after initiating ART. The incidence density of HIV-1 RNA suppression was 65.2 (95%CI: 57.0-74.2) per 100 person-years. In Kaplan-Meier analyses, compared to those who abstained from injecting, individuals injecting heroin, cocaine, or combined heroin/cocaine at baseline were significantly less likely to achieve viral suppression (all p<0.01). However, none of the drug use categories remained associated with a reduced rate of viral suppression when considered as time-updated variables (all p>0.05). CONCLUSIONS: Active injecting at the time of ART initiation was associated with lower plasma HIV-1 RNA suppression rates; however, there was no difference in suppression rates when drug use patterns were examined over time. These findings imply that adherence interventions for active injectors should optimally be applied at the time of ART initiation. PMID- 22245314 TI - The contributions of oxytocin and vasopressin pathway genes to human behavior. AB - Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22245315 TI - The impact of interspecific competition on lineage evolution and a rapid peak shift by interdemic genetic mixing in experimental bacterial populations. AB - Epistatic interactions between genes in the genome constrain the accessible evolutionary paths of lineages. Two factors involving epistasis that can affect the evolutionary path and fate of lineages were investigated. The first factor concerns the impact of competition with another species lineage that has different epistatic constraints. Five enteric bacterial populations were evolved by point mutation in medium containing a single limiting resource. Single-species and two-species cultures were used to determine whether different asexual lineages have different capacities for producing variants due to epistatic constraints, and whether their survival is determined by local inter-lineage competition with different species. Local inter-lineage competition quickly resulted in one successful lineage, with another lineage becoming extinct before finding a higher peak. The second factor concerns a peak-shifting process, and whether the sexual recombination between different demes can cause peak shifts was investigated. An Escherichia coli population consisting of a male (Hfr) and female strain (F(-)) was evolved in a single limiting resource and compared to evolving populations containing the male or female strain alone. The E. coli sexual lineage was successful due to its ability to escape lower peaks and reach a higher peak, not because of a rapid approach to the nearest local peak the male or female asexual lineage could reach. The data in this study demonstrate that lineage survivability can be determined by the ability to produce beneficial mutations and checked by local competition between lineages of different species. Interspecific competition may prevent a population from evolving through crossing fitness valleys or adaptive ridges if it requires many generations to achieve peak shifts. The data also show that genomic recombination between different conspecific lineages can rapidly carry the combined lineage to a higher peak. PMID- 22245316 TI - Whole brain N-acetylaspartate concentration is conserved throughout normal aging. AB - We hypothesize that normal aging implies neuronal durability, reflected by age independent concentrations of their marker--the amino acid derivative N acetylaspartate (NAA). To test this, we obtained the whole-brain and whole-head N acetylaspartate concentrations (WBNAA and WHNAA) with proton magnetic resonance (MR) spectroscopy; and the fractional brain parenchyma volume (fBPV)--a metric of atrophy, by segmenting the magnetic resonance image (MRI) from 42 (18 male) healthy young (31.9 +/- 5.8 years old) and 100 (64 male, 72.6 +/- 7.3 years old) cognitively normal elderly. The 12.8 +/- 1.9 mM WBNAA of the young was not significantly different from the 13.1 +/- 3.1 mM in the elderly (p > 0.05). In contrast, both fBPV (87.3 +/- 4.7% vs. 74.8 +/- 4.8%) and WHNAA (11.1 +/- 1.7 mM vs. 9.8 +/- 2.4 mM) were significantly higher in the young (approximately 14%; p < 0.0001 for both). The similarity in mean WBNAA between 2 cohorts 4 decades of normal aging apart suggests that neuronal integrity is maintained across the lifespan. Clinically, WBNAA could be used as a marker for normal (hence, also abnormal) brain aging. In contrast, WHNAA and fBPV seem age-related suggesting that brain atrophy may occur without compromising the remaining tissue. PMID- 22245318 TI - Chondrogenesis in scaffolds with surface modification of elastin and poly-L lysine. AB - A tissue engineering cartilage is of great importance in the current diarthrodial surgery. This study presents the formation of neocartilage by cultivating chondrocytes in elastin- and poly-L-lysine-modified scaffolds. The hybrid bulk biomaterials used contained polyethylene oxide, chitin, and chitosan and were fabricated by crosslinking, pre-freezing, and lyophilization. Bovine knee chondrocytes were seeded in the scaffolds and cultured in a spinner-flask bioreactor over 4 weeks. Surface elastin showed a better efficiency in the adhesion and proliferation of bovine knee chondrocytes in the scaffolds than surface poly-L-lysine. In addition, elastin-modified constructs yielded higher quantities of secreted glycosaminoglycans and produced collagen than poly-L lysine-modified constructs. The surface morphology demonstrated a thriving chondrogenesis in the two kinds of constructs. The staining images revealed that elastin induced larger amounts of regenerated bovine knee chondrocytes, glycosaminoglycans, and type II collagen in the constructs than poly-L-lysine. Elastin- and poly-L-lysine-grafted polyethylene oxide/chitin/chitosan scaffolds are effective in producing cartilaginous components. PMID- 22245317 TI - Nuclear localization of Klotho in brain: an anti-aging protein. AB - Klotho is a putative age-suppressing gene whose overexpression in mice results in extension of life span. The Klotho gene encodes a single-pass transmembrane protein whose extracellular domain is shed and released into blood, urine, and cerebrospinal fluid, potentially functioning as a humoral factor. The extracellular domain of Klotho has an activity that increases the expression of antioxidant enzymes and confers resistance to oxidative stress in cultured cells and in whole animals. The transmembrane form of the Klotho protein directly binds to multiple fibroblast growth factor receptors and modifies their ligand affinity and specificity. The purpose of the present study was to determine the precise cellular localization of Klotho in the mouse brain. Using light microscopic immunohistochemical methods, we found the highest levels of Klotho immunoreactivity in 2 brain regions: the choroid plexus, and cerebellar Purkinje cells. In the choroid plexus cells, Klotho was found not only on the plasma membrane but also in large amounts near the nuclear membrane. Likewise, in the Purkinje cell Klotho was found throughout the cell including dendrites, axon and soma with large amounts near the nuclear membrane. Using immunoelectron microscopy, we found Klotho in the cell membrane, but the highest concentration was localized in the peripheral portion of the nucleus and the nucleolus in both cell types. This new finding suggests that in addition to Klotho being secreted from cells in brain, it also has a nuclear function. PMID- 22245319 TI - Reduced maternal and cord nerve growth factor levels in preterm deliveries. AB - Nerve growth factor (NGF) is a neurotrophin, which exerts an important role in the development and function of the central and peripheral nervous system. There is limited information regarding the levels of NGF during pregnancy and its role in fetal development. We have earlier reported increased oxidative stress in pregnancy complications. The present study examines the levels of NGF in maternal and cord samples in preterm deliveries and its association with oxidative stress marker. A total number of 96 women delivering preterm (<37 weeks gestation) and 94 women delivering at term (control group) (>=37 weeks gestation) were recruited. Plasma NGF levels were measured in both mother and cord plasma using the Emax Immuno Assay System Promega kit. Maternal and cord plasma NGF levels were significantly reduced (p<0.05 for both) in women delivering preterm as compared to term. There was a positive association between maternal and cord plasma NGF levels (p=0.022). Maternal NGF levels were negatively (p=0.017) associated with maternal malondialdehyde (MDA) levels. Reduced cord NGF levels may affect fetal growth in preterm deliveries which may have implications for the neurodevelopmental pathologies in later life. Circulating maternal NGF levels in preterm pregnancies may be a useful marker to predict NGF levels in the neonate. PMID- 22245320 TI - Editorial comment. PMID- 22245321 TI - Does prolonged warm ischemia after partial nephrectomy under pneumoperitoneum cause irreversible damage to the affected kidney? AB - PURPOSE: We determined the effects of warm ischemia time on the recovery of renal function after partial nephrectomy under pneumoperitoneum. MATERIALS AND METHODS: In this prospective study 37 consecutive patients who underwent laparoscopic partial nephrectomy or robot-assisted partial nephrectomy between June 2008 and May 2009 to remove a single cT1 renal tumor were evaluated using (99m)Tc diethylenetriamine pentaacetic acid renal scintigraphy preoperatively, and at 3 and 12 months postoperatively. RESULTS: The most significant reduction in the glomerular filtration rate of the affected kidney at 3 and 12 months after surgery (p = 0.018, p = 0.036, respectively) was seen for a warm ischemia time cutoff of 28 minutes. The glomerular filtration rate of the affected kidney was consistently and significantly reduced at 3 and 12 months postoperatively (-22.4% to -30.6%, p <0.001) in patients with a warm ischemia time greater than 28 minutes. In contrast, no significant glomerular filtration rate change was seen in patients with a warm ischemia time of 28 minutes or less. In terms of the contributional change of the affected kidney to total renal function, there is a trend toward a recovery after an initial decrease in both groups with a warm ischemia time greater than 28 minutes vs 28 minutes or less. On multivariate analysis warm ischemia time was a strong independent predictor of glomerular filtration rate reduction even 12 months after surgery (beta = -1.3; 95% CI -1.8, -0.7; p <0.001). CONCLUSIONS: If the warm ischemia time is greater than 28 minutes during laparoscopic partial nephrectomy or robot-assisted partial nephrectomy, the functional damage to the affected kidney progresses even up to 1 year after surgery. PMID- 22245322 TI - Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer. AB - PURPOSE: Whether race influences bone loss and fracture risk during androgen deprivation therapy for prostate cancer is unknown. Using data from a prospective clinical trial we compared bone mineral density and fracture between African American and Caucasian men receiving androgen deprivation therapy. MATERIALS AND METHODS: A total of 516 subjects were in the placebo group of a 2-year randomized placebo controlled fracture prevention trial, and were African-American (68) or Caucasian (448). We compared baseline characteristics, changes in bone mineral density and rates of new fractures between races. RESULTS: Compared to Caucasian men, African-American men had higher baseline hip bone mineral density (mean +/- SD 0.98 +/- 0.15 vs 0.91 +/- 0.15 gm/m(2), p = 0.001) and similar spine bone mineral density (1.09 +/- 0.22 vs 1.11 +/- 0.22, p = 0.51). There was no difference in prevalent vertebral fractures between African-American and Caucasian men (7.4% vs 15.0%, p = 0.13). The percentage change in hip bone mineral density at 2 years was similar between African-American and Caucasian men (mean +/- SE -2.21% +/- 0.59% vs -2.54% +/- 0.26%, p = 0.65). Changes in bone mineral density of the lumbar spine were also similar between African-American and Caucasian men (-1.74% +/- 0.69% vs -1.30% +/- 0.33%, p = 0.64). No new vertebral fractures were reported in African-American men but 2 fractures were reported in Caucasian men. CONCLUSIONS: In a clinical trial African-American men receiving androgen deprivation therapy for prostate cancer have a greater hip bone mineral density and tended to have fewer prevalent vertebral fractures than Caucasian men. Despite a lower baseline risk of osteoporosis and fracture, African-American men experience a decrease in bone mineral density similar to that of Caucasian men. PMID- 22245323 TI - Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. AB - PURPOSE: Widespread prostate specific antigen screening together with the increase in the number of biopsy cores has led to increased prostate cancer incidence. Standard diagnostic tools still cannot unequivocally predict prostate cancer progression, which often results in a significant overtreatment rate. We present recent findings on PCA3 and TMPRSS:ERG fusion, and describe their clinical implications and performance. MATERIALS AND METHODS: The PubMed(r) database was searched for reports on PCA3 (130 articles), TMPRSS:ERG and ETS fusion (180 publications) since 1999. RESULTS: In recent years advances in genetics and biotechnology have stimulated the development of noninvasive tests to detect prostate cancer. Serum and urine molecular biomarkers have been identified, of which PCA3 has already been introduced clinically. The identification of prostate cancer specific genomic aberrations, ie TMPRSS2:ERG gene fusion, might improve diagnosis and affect prostate cancer treatment. CONCLUSIONS: Although several recently developed markers are promising, often showing increased specificity for prostate cancer detection compared to that of prostate specific antigen, their clinical application is limited. The only 2 true prostate cancer specific biomarkers identified to date remain PCA3 and TMPRSS2:ERG gene fusion. PMID- 22245324 TI - Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread. AB - PURPOSE: Bladder plasmacytoid carcinoma is an invasive urothelial carcinoma subtype that is emphasized for its morphological overlap with plasma cells and metastatic carcinoma. Our experience suggests frequent intraperitoneal spread that is not typical of conventional urothelial carcinoma. MATERIALS AND METHODS: We identified cases of plasmacytoid urothelial carcinoma diagnosed on radical cystectomy. Patient age, gender, American Joint Committee on Cancer (7th edition) stage, metastatic spread/recurrence sites and clinical disease status at last followup were recorded. RESULTS: A total of 10 male and 5 female patients 42 to 81 years old were identified. One tumor was pT2, 11 pT3 and 3 pT4. Six of 15 patients (40%) presented with lymph node metastasis and 5 (33%) had intraperitoneal metastasis at cystectomy. These initial sites of metastatic spread included the prerectal space, ovary and vagina, ovary and fallopian tube, bowel serosa, and omentum and bowel serosa in 1 case each. Three patients had subsequent metastasis involving the prerectal space, pleural fluid and small bowel serosa, and bowel serosa in 1 each. Eight patients had followup information available, including 3 who died of disease, 3 with disease and 2 with no evidence of disease. CONCLUSIONS: Of the patients 33% with the plasmacytoid variant of urothelial carcinoma presented with intraperitoneal disease spread and 20% had subsequent metastasis involving serosal surfaces. The possibility of noncontiguous intraperitoneal spread involving serosal surfaces should be recognized to ensure proper intraoperative staging and clinical followup for patients with plasmacytoid carcinoma. PMID- 22245325 TI - Use of fluorescence in situ hybridization to predict response to bacillus Calmette-Guerin therapy for bladder cancer: results of a prospective trial. AB - PURPOSE: No reliable methods currently exist to predict patient response to intravesical immunotherapy with bacillus Calmette-Guerin given after transurethral resection for high risk nonmuscle invasive bladder cancer. We initiated a prospective clinical trial to determine whether fluorescence in situ hybridization results during bacillus Calmette-Guerin immunotherapy can predict therapy failure. MATERIALS AND METHODS: Candidates for standard of care bacillus Calmette-Guerin were offered participation in a clinical trial. Fluorescence in situ hybridization was performed before bacillus Calmette-Guerin, and at 6 weeks, 3 months and 6 months during bacillus Calmette-Guerin therapy with maintenance. Cox proportional hazards regression was used to assess the relationship between fluorescence in situ hybridization results and tumor recurrence or progression. The Kaplan-Meier product limit method was used to estimate recurrence-free and progression-free survival. RESULTS: A total of 126 patients participated in the study. At a median followup of 24 months 31% of patients had recurrent tumors and 14% experienced disease progression. Patients who had positive fluorescence in situ hybridization results during bacillus Calmette-Guerin therapy were 3 to 5 times more likely than those who had negative fluorescence in situ hybridization results to experience recurrent tumors and 5 to 13 times more likely to have disease progression (p <0.01). The timing of positive fluorescence in situ hybridization results also affected outcomes. For example, patients with a negative fluorescence in situ hybridization result at baseline, 6 weeks and 3 months demonstrated an 8.3% recurrence rate compared to 48.1% for those with a positive result at all 3 points. CONCLUSIONS: Fluorescence in situ hybridization results can identify patients at risk for tumor recurrence and progression during bacillus Calmette-Guerin immunotherapy. This information may be used to counsel patients about alternative treatment strategies. PMID- 22245326 TI - Pretreatment expectations of patients undergoing robotic assisted laparoscopic or open retropubic radical prostatectomy. AB - PURPOSE: We previously found that patients undergoing robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy had a higher likelihood of not being satisfied, independent of side effect profile. We hypothesized that differential preoperative expectations might contribute to this finding. In the current study we compared expectations of patients undergoing robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy. MATERIALS AND METHODS: A questionnaire on expectations regarding recovery was administered to 171 patients electing to undergo robotic assisted laparoscopic radical prostatectomy or radical retropubic prostatectomy from 2008 to 2010. We prospectively collected data on patient expectations before surgery. Differences between patients undergoing robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy were assessed with adjusted proportional odds models. RESULTS: Patients who underwent robotic assisted laparoscopic radical prostatectomy (97) did not differ significantly from those treated with radical retropubic prostatectomy (74) in age, race, income, time between survey and surgery, and prostate specific antigen (p >=0.4). Patients who underwent radical retropubic prostatectomy had significantly higher clinical stage and Gleason grade disease (p <=0.007). After adjusting for socioeconomic factors, clinical stage and grade on multivariate analysis, patients who underwent robotic assisted laparoscopic radical prostatectomy expected a significantly shorter length of stay (OR 0.07, p <0.001) and earlier return to physical activity (OR 0.36, p = 0.005). The choice of robotic assisted laparoscopic radical prostatectomy (OR 0.41, p = 0.012), younger age (OR 0.49, p = 0.001) and higher preoperative International Index of Erectile Function-5-item version score (OR 0.60, p = 0.017) were independently associated with the expectation of earlier return of erections but not of continence on multivariate analysis. CONCLUSIONS: The body of evidence surrounding robotic assisted laparoscopic radical prostatectomy supports shorter hospitalization but there is no conclusive evidence that the robotic approach results in earlier return to physical activity or improved disease specific outcomes. Nonetheless we found that patients who underwent robotic assisted laparoscopic radical prostatectomy had higher expectations regarding these outcomes, particularly that of erectile function recovery, than did their radical retropubic prostatectomy counterparts. PMID- 22245327 TI - Comprehensive assessment of quality of life and psychosocial adjustment in patients with renal tumors undergoing open, laparoscopic and nephron sparing surgery. AB - PURPOSE: We prospectively evaluated the general and cancer specific quality of life, and psychosocial adjustment of patients with a renal mass treated with radical vs partial nephrectomy via a laparoscopic or an open approach. MATERIALS AND METHODS: A total of 172 patients with renal tumors completed questionnaires before surgery, and 3 weeks, and 2, 3, 6 and 12 months postoperatively. We assessed general quality of life using SF-36TM and cancer specific quality of life using the Cancer Rehabilitation Evaluation System-Short Form, in addition to intrusive thoughts, avoidance behaviors and fear of recurrence. We used mixed model regression analysis to compare these measures across surgery types during the study course, adjusted for tumor size, histology, stage and renal function. RESULTS: The SF-36 physical component score differed significantly by surgery type with time (p = 0.04). Patients treated with laparoscopy improved by month 2 while those treated with open surgery had poorer quality of life until month 3. Better cancer specific quality of life was reported in patients who underwent radical vs partial nephrectomy. Age also had a significant effect on outcomes. CONCLUSIONS: We report one of the most comprehensive patient reported prospective quality of life studies in patients with renal cell carcinoma. There were significant differences in quality of life and psychosocial adjustment outcomes during 1 year among patients treated with 1 of 4 commonly accepted surgical renal procedures. These outcomes must be evaluated in the context of tumor characteristics, cancer specific outcomes and renal function. These quality of life issues may be important to consider when choosing surgical procedures for patients with renal tumors. PMID- 22245328 TI - External validation of a biomarker based pre-cystectomy algorithm to predict nonorgan confined urothelial cancers. AB - PURPOSE: The role of neoadjuvant chemotherapy before surgery in patients with muscle invasive bladder cancer remains debated and the need for tools to identify patients who would benefit from chemotherapy is pertinent. We previously published a preoperative algorithm to predict nonorgan confined disease. This algorithm included tumor markers (CEA, CA 125 and CA 19-9) as well as clinical parameters. In this study we validated the accuracy of this algorithm in an independent, external cohort. MATERIALS AND METHODS: We used the Toronto Biobank to measure preoperative serum levels of CEA, CA 125 and CA 19-9 in 76 consecutive patients with clinically organ confined bladder cancer (cT2 or less) who underwent radical cystectomy. Clinical parameters were retrieved from our prospective bladder information system database and incorporated into our marker based algorithm. A numerical score was generated for each patient and a previously published cutoff was used to predict the presence of nonorgan confined disease. The accuracy of the model was quantified with the area under the curve, and the positive and negative predictive values were calculated. RESULTS: On pathological evaluation 38 patients (50%) had nonorgan confined tumors. The AUC of the algorithm was 0.79 (95% CI 0.69-0.89). The positive and negative predictive values were 79% (95% CI 71-87) and 74% (95% CI 66-82), respectively. CONCLUSIONS: We externally validated a pre-cystectomy model to predict pathological stage. The algorithm may possibly aid in selecting patients who would benefit from neoadjuvant chemotherapy before cystectomy. PMID- 22245329 TI - p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study. AB - PURPOSE: We assessed the prognostic role of p16(INK4a) expression in penile cancer with respect to cancer specific survival. MATERIALS AND METHODS: Based on a multi-institutional collaboration wax embedded tissues from 92 surgically treated patients, including 27 with total and 65 with partial penectomy, were retrospectively evaluated. After a central histopathological review by 1 pathologist a tissue microarray was constructed for p16(INK4a) immunostaining. Two independent pathologists evaluated p16(INK4a) expression, which was correlated with cancer specific survival. The kappa statistic was used to assess interobserver variability. Univariate and multivariate Cox proportional hazards analysis was applied to assess the independent effects of prognostic factors on cancer specific survival during a median postoperative followup of 32 months (IQR 6-66). RESULTS: The kappa statistic revealed excellent interobserver agreement (kappa 0.934, p <0.001). Two and 5-year cancer specific survival rates for the entire study cohort were 86% and 74%, respectively. The 2 and 5-year rates for patients without and with p16(INK4a) expression differed significantly (73% and 57% vs 95% and 85%, respectively, p = 0.011). Univariate analysis revealed p16(INK4a) expression as a significant prognostic factor with respect to cancer specific survival (p = 0.018). Multivariate analysis identified koilocytosis (HR 0.24, 95% CI 0.07-0.83, p = 0.024), p16(INK4a) expression (HR 0.44, 95% CI 0.23 0.84, p = 0.013), and histological stage (HR 3.54, 95% CI 1.88-6.67, p <0.001) and grade (HR 2.47, 95% CI 1.00-6.09, p = 0.049) as independent prognostic factors for cancer specific survival. CONCLUSIONS: Results show that p16(INK4a) seems to be a prognostic parameter for primary invasive penile cancer with excellent interobserver reproducibility. At pathology laboratories without antibodies against p16(INK4a) conventional histological determination of koilocytosis by the pathologist also appears to provide important prognostic information for cancer specific survival. PMID- 22245330 TI - Chemokine and chemokine receptor expression in kidney tumors: molecular profiling of histological subtypes and association with metastasis. AB - PURPOSE: Molecular characterization of renal cell carcinoma may help differentiate benign oncocytoma from malignant renal cell carcinoma subtypes and predict metastasis. Chemokines, eg IL-8 and chemokine receptors such as CXCR4 and 7, promote inflammation and metastasis. SDF-1 is a CXCR4 and 7 ligand with 6 known isoforms. We evaluated the expression of these chemokines and chemokine receptors in kidney specimens. MATERIALS AND METHODS: Using quantitative polymerase chain reaction we measured mRNA levels of IL-8, CXCR4 and 7, and SDF1 isoforms alpha, beta and gamma in a total of 166 specimens from 86 patients, including 86 tumor samples and 80 matched normal kidney samples. Mean +/- SD followup was 18.9 +/- 12 months (median 19.5). Renal cell carcinoma specimens included the clear cell, papillary and chromophobe subtype in 65, 10 and 5 cases, respectively, and oncocytoma in 6. A total of 17 cases were positive for metastasis. RESULTS: Median CXCR4 and 7, and SFD1-gamma levels were increased twofold to tenfold. SDF1-alpha and beta were unchanged or lower in clear cell renal cell carcinoma and papillary tumors than in normal tissue. Median SDF1 gamma, IL-8, and CXCR4 and 7 were increased threefold to fortyfold in chromophobe tumors compared to oncocytoma. CXCR4 and 7 were increased in tumors less than 4 cm (mean 3,057 +/- 2,230 and 806 +/- 691) compared to oncocytoma (336 +/- 325 and 201 +/- 281, respectively, p <=0.016). On multivariate analysis CXCR4 (p = 0.01), CXCR7 (p = 0.02) and SDF1-beta (p = 0.005) were independently associated with metastasis. Combined CXCR7 plus SDF1-alpha and CXCR7 plus IL-8 markers showed the highest sensitivity (71% to 81%) and specificity (75% to 80%) of all individual or combined markers. CONCLUSIONS: Chemokines and chemokine receptors differentiate renal cell carcinoma and oncocytoma. Combined SDF1-alpha plus CXCR7 and IL-8 plus CXCR7 markers have about 80% accuracy for predicting renal cell carcinoma metastasis. PMID- 22245331 TI - Prognostic value of the Leibovich prognosis score supplemented by vascular invasion for clear cell renal cell carcinoma. AB - PURPOSE: We assessed whether supplementing the Leibovich prognosis score with vascular invasion would improve prognostic value to predict metastatic disease in patients with nonmetastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: We retrospectively evaluated the pathology records of 1,754 patients with nonmetastatic clear cell renal cell carcinoma treated with surgery between 1984 and 2006 at a single tertiary academic center. The Leibovich prognosis score was supplemented by additional scoring for vascular invasion. Metastasis-free survival was assessed using the Kaplan-Meier method for each score category. A Cox regression model was used for multivariate testing. Predictive accuracy was determined by the Harrell concordance index and decision curve analysis. RESULTS: Median followup was 84 months. Ten-year metastasis-free survival probability for a score of 0 to 1 and 2 to 8 or greater was 95%, 83%, 78%, 81%, 69%, 51%, 15% and 13%, respectively. The concordance index was 0.792 compared to 0.778 from our external validation of the Leibovich prognosis score using routine pathological findings (p <0.05). Decision curve analysis also favored the predictive ability of the novel model. CONCLUSIONS: Adding vascular invasion improved the predictive accuracy of our validation data by 1.4% over that of the Leibovich prognosis score. Patients with a score of 7 or greater had a more than 85% probability of metastatic disease at 10 years. Thus, they could be considered candidates for adjuvant treatment trials. PMID- 22245332 TI - Early detection of carcinoma in situ of the bladder: a comparative study of white light cystoscopy, narrow band imaging, 5-ALA fluorescence cystoscopy and 3 dimensional optical coherence tomography. AB - PURPOSE: We compared the efficacy and potential limitations of white light cystoscopy, narrow band imaging, 5-ALA fluorescence cystoscopy and 3-dimensional optical coherence tomography for early diagnosis of bladder carcinoma in situ. MATERIALS AND METHODS: By expressing simian virus 40T antigen in the urothelium carcinoma in situ typically develops in SV40T transgenic mice in about 8 to 20 weeks and then frank high grade papillary urothelial carcinoma starts to emerge. A total of 18 control and 29 SV40T mice were examined during weeks 8 to 22 by white light cystoscopy, fluorescence cystoscopy, narrow band imaging and 3 dimensional optical coherence tomography. Results were validated by histology. Newly improved algorithms for computer aided detection were applied to acquired 3 dimensional optical coherence tomography images to enhance the quantitative diagnosis of carcinoma in situ in near real time. RESULTS: Of 29 carcinoma in situ samples 27 were detected by 3-dimensional optical coherence tomography, 1 by white light cystoscopy, 26 by narrow band imaging and 13 by fluorescence cystoscopy. Of the 18 histologically confirmed benign cases 17 were detected by 3 dimensional optical coherence tomography, 14 by white light cystoscopy, 5 by narrow band imaging and 18 by fluorescence cystoscopy. The diagnostic sensitivity of white light cystoscopy (3.4%) and fluorescence cystoscopy (44.8%), and the specificity of narrow band imaging (27.8%) were significantly enhanced by 3 dimensional optical coherence tomography to 93.1% and 94.4%, respectively (p <0.01). CONCLUSIONS: Three-dimensional optical coherence tomography with quantitative computer aided detection can significantly enhance the sensitivity of white light cystoscopy and fluorescence cystoscopy, and the specificity of narrow band imaging for early diagnosis of carcinoma in situ. This suggests the potential of narrow band imaging guided 3-dimensional optical coherence tomography for future clinical detection of carcinoma in situ when effective image guidance is desirable. PMID- 22245333 TI - Genome-wide identification and characterization of a panel of house-keeping genes in Schistosoma japonicum. AB - Quantitative real-time polymerase chain reaction (qPCR), as one of the most sensitive and precise gene expression analysis methods, is frequently used to validate data obtained in high-through-put assays. qPCR requires reference genes with stable transcription for accurate normalization. However, no systematic studies on such genes have been performed in the genus Schistosoma japonicum. In this study, eight novel candidate genes selected from a microarray analysis and four commonly used reference genes were systematically validated in a series of qPCR experiments. Based on the results of geNorm, Normfinder, BestKeeper, and the comparative delta-cycle threshold (DeltaCT) integrated analysis, the genes PSMD4, NDUFV2, and TPC2L were found to be most stably expressed in all S. japonicum developmental stages; meanwhile, ACTB and TUBA were found as the least stably expressed genes. This study provided, at the first time, data for genes that can be explored as reliable references in transcriptomic analysis of S. japonicum. PMID- 22245334 TI - Metabolic oligosaccharide engineering of Plasmodium falciparum intraerythrocytic stages allows direct glycolipid analysis by mass spectrometry. AB - A recent addition to the arsenal of tools for glycome analysis is the use of metabolic labels that allow covalent tagging of glycans with imaging probes. In this work we show that N-azidoglucosamine was successfully incorporated into glycolipidic structures of Plasmodium falciparum intraerythrocytic stages. The ability to tag glycoconjugates selectively with a fluorescent reporter group permits TLC detection of the glycolipids providing a new method to quantify dynamic changes in the glycosylation pattern and facilitating direct mass spectrometry analyses. Presence of glycosylphosphatidylinositol and glycosphingolipid structures was determined in the different extracts. Furthermore, the fluorescent tag was used as internal matrix for the MALDI experiment making even easier the analysis. PMID- 22245336 TI - Client education experiences and expectations of women at the first level of maternal and child care in Kaduna state, Nigeria. AB - PURPOSE: to explore the client education experiences of women at first level maternal and child health-care facilities in Kaduna State Nigeria. The lack of access to appropriate information to assist women in making decisions about their health and utilize available services is recognized as a major contributory factor to the unabated high maternal and child mortality rates in Nigeria. DESIGN: a qualitative descriptive study was conducted. Nine focus group discussions were held with 65 women across the three senatorial zones of Kaduna State, Nigeria. Participants were recruited using maximum variation sampling technique. Audio recordings of the discussions were transcribed and the content analysed. The themes were determined by a priory approach and findings compared across groups through manually developed data matrices. FINDINGS: midwives were the major source of useful health information to the women who wished the midwives could cover more issues. The information provided by the midwives was skewed towards children and postnatal care, and some midwives ignored, or considered some of the women's questions interrupting. The harshness of midwives in emphasizing the need for prompt care, to women who came late to register or deliver, kept some women away. Women who never delivered in the facilities were not aware that the 'nurses' at the clinics were midwives, and desired to know more about midwifery in the facilities being tired of traditional birth attendants. CONCLUSION: the desire of women for more information and to know the 'midwife' suggests a gap between what the women expected and what they were provided. IMPLICATION FOR PRACTICE: it is important to expand the scope of client education to include critical pregnancy and labour related issues and friendly midwifery practices in the facility. PMID- 22245337 TI - k-space and q-space: combining ultra-high spatial and angular resolution in diffusion imaging using ZOOPPA at 7 T. AB - There is ongoing debate whether using a higher spatial resolution (sampling k space) or a higher angular resolution (sampling q-space angles) is the better way to improve diffusion MRI (dMRI) based tractography results in living humans. In both cases, the limiting factor is the signal-to-noise ratio (SNR), due to the restricted acquisition time. One possible way to increase the spatial resolution without sacrificing either SNR or angular resolution is to move to a higher magnetic field strength. Nevertheless, dMRI has not been the preferred application for ultra-high field strength (7 T). This is because single-shot echo planar imaging (EPI) has been the method of choice for human in vivo dMRI. EPI faces several challenges related to the use of a high resolution at high field strength, for example, distortions and image blurring. These problems can easily compromise the expected SNR gain with field strength. In the current study, we introduce an adapted EPI sequence in conjunction with a combination of ZOOmed imaging and Partially Parallel Acquisition (ZOOPPA). We demonstrate that the method can produce high quality diffusion-weighted images with high spatial and angular resolution at 7 T. We provide examples of in vivo human dMRI with isotropic resolutions of 1 mm and 800 MUm. These data sets are particularly suitable for resolving complex and subtle fiber architectures, including fiber crossings in the white matter, anisotropy in the cortex and fibers entering the cortex. PMID- 22245335 TI - A novel type of allosteric regulation: functional cooperativity in monomeric proteins. AB - Cooperative functional properties and allosteric regulation in cytochromes P450 play an important role in xenobiotic metabolism and define one of the main mechanisms of drug-drug interactions. Recent experimental results suggest that ability to bind simultaneously two or more small organic molecules can be the essential feature of cytochrome P450 fold, and often results in rich and complex pattern of allosteric behavior. Manifestations of non-Michaelis kinetics include homotropic and heterotropic activation and inhibition effects depending on the stoichiometric ratios of substrate and effector, changes in the regio- and stereospecificity of catalytic transformations, and often give rise to the clinically important drug-drug interactions. In addition, functional response of P450 systems is modulated by the presence of specific and non-specific effector molecules, metal ions, membrane incorporation, formation of homo- and hetero oligomers, and interactions with the protein redox partners. In this article we briefly overview the main factors contributing to the allosteric effects in cytochromes P450 with the main focus on the sources of cooperative behavior in xenobiotic metabolizing monomeric heme enzymes with their conformational flexibility and extremely broad substrate specificity. The novel mechanism of functional cooperativity in P450 enzymes does not require substantial binding cooperativity, rather it implies the presence of one or more binding sites with higher affinity than the single catalytically active site in the vicinity of the heme iron. PMID- 22245338 TI - Early development of arterial spin labeling to measure regional brain blood flow by MRI. AB - Two major avenues of work converged in the late 1980's and early 1990's to give rise to brain perfusion MRI. The development of anatomical brain MRI quickly had as a major goal the generation of angiograms using tricks to label flowing blood in macroscopic vessels. These ideas were aimed at getting information about microcirculatory flow as well. Over the same time course the development of in vivo magnetic resonance spectroscopy had as its primary goal the assessment of tissue function and in particular, tissue energetics. For this the measurement of the delivery of water to tissue was critical for assessing tissue oxygenation and viability. The measurement of the washin/washout of "freely" diffusible tracers by spectroscopic based techniques pointed the way for quantitative approaches to measure regional blood flow by MRI. These two avenues came together in the development of arterial spin labeling (ASL) MRI techniques to measure regional cerebral blood flow. The early use of ASL to measure brain activation to help verify BOLD fMRI led to a rapid development of ASL based perfusion MRI. Today development and applications of regional brain blood flow measurements with ASL continues to be a major area of activity. PMID- 22245340 TI - Targeting the functional properties of cortical neurons using fMR-adaptation. AB - The introduction of functional brain imaging based on BOLD-fMRI, twenty years ago, has revolutionized the field of human brain research. However, right from its inception it became clear that the BOLD signal suffers from a serious limitation--it reflects the averaged activity of large neuronal populations and hence can not, on its own, index the functional properties of individual neurons. The method of fMR-adaptation (also termed repetition suppression) was developed to circumvent this problem and use the BOLD signal to assess functional specializations at the individual neuron level. The approach is based on the tendency of cortical neurons to reduce their activity upon stimulus repetition. By examining the sensitivity of the adaptation effect to stimulus manipulation, insight can be gained about the invariant and selective properties of neuronal networks. It has been argued that the adaptation effect occurs at the level of synaptic inputs--and hence may be mislocalized. However, it is critical to consider the adaptation effect in the context of the cortical network architecture. This cortical anatomical organization, dominated by short range intrinsic connections, ensures that the fMR-adaptation largely reflects the response profile of the neurons located within the imaged voxel proper. PMID- 22245341 TI - The role of physiological noise in resting-state functional connectivity. AB - Functional connectivity between different brain regions can be estimated from MRI data by computing the temporal correlation of low frequency (<0.1Hz) fluctuations in the MRI signal. These correlated fluctuations occur even when the subject is "at rest" (not asked to perform any particular task) and result from spontaneous neuronal activity synchronized within multiple distinct networks of brain regions. This estimate of connectivity, however, can be influenced by physiological noise, such as cardiac and respiratory fluctuations. This brief review looks at the effect of physiological noise on estimates of resting-state functional connectivity, discusses ways to remove physiological noise, and provides a personal recollection of the early developments in these approaches. This review also discusses the importance of physiological noise correction and provides a summary of evidence demonstrating that functional connectivity does have a neuronal underpinning and cannot purely be the result of physiological noise. PMID- 22245339 TI - Dynamic models of BOLD contrast. AB - This personal recollection looks at the evolution of ideas about the dynamics of the blood oxygenation level dependent (BOLD) signal, with an emphasis on the balloon model. From the first detection of the BOLD response it has been clear that the signal exhibits interesting dynamics, such as a pronounced and long lasting post-stimulus undershoot. The BOLD response, reflecting a change in local deoxyhemoglobin, is a combination of a hemodynamic response, related to changes in blood flow and venous blood volume, and a metabolic response related to oxygen metabolism. Modeling is potentially a way to understand the complex path from changes in neural activity to the BOLD signal. In the early days of fMRI it was hoped that the hemodynamic/metabolic response could be modeled in a unitary way, with blood flow, oxygen metabolism, and venous blood volume-the physiological factors that affect local deoxyhemoglobin-all tightly linked. The balloon model was an attempt to do this, based on the physiological ideas of limited oxygen delivery at baseline and a slow recovery of venous blood volume after the stimulus (the balloon effect), and this simple model of the physiology worked well to simulate the BOLD response. However, subsequent experiments suggest a more complicated picture of the underlying physiology, with blood flow and oxygen metabolism driven in parallel, possibly by different aspects of neural activity. In addition, it is still not clear whether the post-stimulus undershoot is a hemodynamic or a metabolic phenomenon, although the original venous balloon effect is unlikely to be the full explanation, and a flow undershoot is likely to be important. Although our understanding of the physics of the BOLD response is now reasonably solid, our understanding of the underlying physiological relationships is still relatively poor, and this is the primary hurdle for future models of BOLD dynamics. PMID- 22245342 TI - Local head gradient coils: window(s) of opportunity. AB - At the Medical College of Wisconsin (MCW), prior to the 1991 announcement of the discovery of BOLD fMRI, all of the technical pieces that were needed for efficient BOLD fMRI imaging were assembled for other applications, allowing MCW to jump into the fMRI business just days after the announcement. Central among these pieces was single shot EPI, implemented at MCW using a three axis local head gradient coil. This article describes the development of local gradient coil technology at MCW, and a historical perspective on local head gradient coils in general. PMID- 22245344 TI - Ultra high resolution fMRI at ultra-high field. AB - In this short review article I will summarize the path we took over the years towards increasing the spatial resolution of fMRI. To fully capitalize on the fMRI technique, a better understanding of the origin of the hemodynamic signals, and what factors are governing their spatial control is necessary. Here, I will briefly describe the studies and developments that ultimately led to our successful effort in mapping orientation columns in humans that is considered by many as the current state-of-the-art for fMRI studies. PMID- 22245345 TI - Coupling between gamma oscillation and fMRI signal in the rat somatosensory cortex: its dependence on systemic physiological parameters. AB - The simultaneous recordings of neuronal and hemodynamic signals have revealed a significant involvement of high frequency bands (e.g., gamma range, 25-70 Hz) in neurovascular coupling. However, the dependence on a physiological parameter is unknown. In this study, we performed simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings in 12 Wistar rats using a conventional forepaw stimulation paradigm and concurrently monitored the systemic physiological parameters of the partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, pH, mean arterial blood pressure, and heart rate through the rat femoral artery. The high frequency bands in the artifact-free EEG signals, especially those in the gamma range, demonstrated a maximum correlation with fMRI signals in the rat somatosensory cortex. A multiple linear regression analysis demonstrated that the correlation coefficient between the gamma power and fMRI signal depended on the actual values of the physiological parameters (R(2)=0.20, p<0.05), whereas the gamma power and fMRI signal by itself were independent. Among the parameters, the heart rate had a statistically significant slope (95% CI: 0.00027-0.0016, p<0.01) in a multiple linear regression model. These results indicate that neurovascular coupling is mainly driven by gamma oscillations, as expected, but coupling or potential decoupling is strongly influenced by systemic physiological parameters, which dynamically reflect the baseline vital status of the subject. PMID- 22245343 TI - A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer's disease in the ADNI cohort. AB - The underlying genetic etiology of late onset Alzheimer's disease (LOAD) remains largely unknown, likely due to its polygenic architecture and a lack of sophisticated analytic methods to evaluate complex genotype-phenotype models. The aim of the current study was to overcome these limitations in a bi-multivariate fashion by linking intermediate magnetic resonance imaging (MRI) phenotypes with a genome-wide sample of common single nucleotide polymorphism (SNP) variants. We compared associations between 94 different brain regions of interest derived from structural MRI scans and 533,872 genome-wide SNPs using a novel multivariate statistical procedure, parallel-independent component analysis, in a large, national multi-center subject cohort. The study included 209 elderly healthy controls, 367 subjects with amnestic mild cognitive impairment and 181 with mild, early-stage LOAD, all of them Caucasian adults, from the Alzheimer's Disease Neuroimaging Initiative cohort. Imaging was performed on comparable 1.5 T scanners at over 50 sites in the USA/Canada. Four primary "genetic components" were associated significantly with a single structural network including all regions involved neuropathologically in LOAD. Pathway analysis suggested that each component included several genes already known to contribute to LOAD risk (e.g. APOE4) or involved in pathologic processes contributing to the disorder, including inflammation, diabetes, obesity and cardiovascular disease. In addition significant novel genes identified included ZNF673, VPS13, SLC9A7, ATP5G2 and SHROOM2. Unlike conventional analyses, this multivariate approach identified distinct groups of genes that are plausibly linked in physiologic pathways, perhaps epistatically. Further, the study exemplifies the value of this novel approach to explore large-scale data sets involving high-dimensional gene and endophenotype data. PMID- 22245346 TI - Subspace-based Identification Algorithm for characterizing causal networks in resting brain. AB - The resting brain has been extensively investigated for low frequency synchrony between brain regions, namely Functional Connectivity (FC). However the other main stream of brain connectivity analysis that seeks causal interactions between brain regions, Effective Connectivity (EC), has been little explored. Inherent complexity of brain activities in resting-state, as observed in BOLD (Blood Oxygenation-Level Dependant) fluctuations, calls for exploratory methods for characterizing these causal networks. On the other hand, the inevitable effects that hemodynamic system imposes on causal inferences in fMRI data, lead us toward the methods in which causal inferences can take place in latent neuronal level, rather than observed BOLD time-series. To simultaneously satisfy these two concerns, in this paper, we introduce a novel state-space system identification approach for studying causal interactions among brain regions in the absence of explicit cognitive task. This algorithm is a geometrically inspired method for identification of stochastic systems, purely based on output observations. Using extensive simulations, three aspects of our proposed method are investigated: ability in discriminating existent interactions from non-existent ones, the effect of observation noise, and downsampling on algorithm performance. Our simulations demonstrate that Subspace-based Identification Algorithm (SIA) is sufficiently robust against above-mentioned factors, and can reliably uncover the underlying causal interactions of resting-state fMRI. Furthermore, in contrast to previously established state-space approaches in Effective Connectivity studies, this method is able to characterize causal networks with large number of brain regions. In addition, we utilized the proposed algorithm for identification of causal relationships underlying anti-correlation of default-mode and Dorsal Attention Networks during the rest, using fMRI. We observed that Default-Mode Network places in a higher order in hierarchical structure of brain functional networks compared to Dorsal Attention Networks. PMID- 22245347 TI - Phase synchrony in the early preterm EEG: development of methods for estimating synchrony in both oscillations and events. AB - Development of neuronal connections relies on proper neuronal activity, and it starts during the time when early preterm babies are treated in the neonatal intensive care units. While synchrony has been a key element in visual assessment of neonatal EEG signals, there has been no unambiguous definitions for synchrony, and no objective measures available for neonatal signals. Estimation of phase locking value (PLV) has been an established paradigm in adults, but many unique characteristics of the neonatal EEG have precluded its applicability in them. In the present paper, we developed the existing PLV-based methods further to be applicable for neonatal signals at two different temporal scales, oscillations and events, where the latter refers technically to quantitating phase synchrony (PS) between band-specific amplitude envelopes (bafPS). In addition, we present a measure for quantitation based on assessing cumulative proportion of time with statistically significant synchrony between the given signal pair. The paper uses real EEG examples and the prior neurobiological knowledge in the process of defining optimal parameters in each step of the procedure. Finally, we apply the method to a set of dense array EEG recordings from very early preterm babies, recorded at conceptional age of less than 30 weeks. By comparing PS and bafPS from babies without and with major cerebrovascular lesion, we show that the effects of brain lesions may be selective both in space and in frequency. These findings do by nature escape visual detection in the conventional EEG reading, however they have intriguing correlates in the current concept of how somatosensory networks are thought to develop and/or become disorganized in the early preterm babies. PMID- 22245348 TI - Diffusion modulation of the fMRI signal: early investigations on the origin of the BOLD signal. AB - The early 1990s was a very special period for functional MRI (fMRI). Many original concepts were formed during that period which helped set up the foundations for modern neuroimaging development. I was fortunate to be in graduate school at the time. I was even more fortunate to be enrolled in one of the pioneer groups in fMRI at the Medical College of Wisconsin, and witnessed some of the early fMRI experiments taking place in the lab. Under the daily influence and steady guidance by the extraordinarily talented researchers there, I also began my own work on the contrast mechanisms of fMRI. In particular, I was developing diffusion weighted strategies to investigate the origin of the functional signal using blood oxygenation level dependent (BOLD) contrast. Our results, that there was significant BOLD signal in large veins and their vicinities at low field strengths (e.g. 1.5T), played an immediate role in moving fMRI applications to higher fields (3T and above) where small vessels (e.g. capillaries) contribute more significantly to improve the neuronal specificity of the BOLD signal. This manuscript gathers some of my own recollections concerning this particular development. PMID- 22245349 TI - How challenges in auditory fMRI led to general advancements for the field. AB - In the early years of fMRI research, the auditory neuroscience community sought to expand its knowledge of the underlying physiology of hearing, while also seeking to come to grips with the inherent acoustic disadvantages of working in the fMRI environment. Early collaborative efforts between prominent auditory research laboratories and prominent fMRI centers led to development of a number of key technical advances that have subsequently been widely used to elucidate principles of auditory neurophysiology. Perhaps the key imaging advance was the simultaneous and parallel development of strategies to use pulse sequences in which the volume acquisitions were "clustered," providing gaps in which stimuli could be presented without direct masking. Such sequences have become widespread in fMRI studies using auditory stimuli and also in a range of translational research domains. This review presents the parallel stories of the people and the auditory neurophysiology research that led to these sequences. PMID- 22245350 TI - The PRESTO technique for fMRI. AB - In the early days of BOLD fMRI, the acquisition of T(2)(*) weighted data was greatly facilitated by rapid scan techniques such as EPI. The latter, however, was only available on a few MRI systems that were equipped with specialized hardware that allowed rapid switching of the imaging gradients. For this reason, soon after the invention of fMRI, the scan technique PRESTO was developed to make rapid T(2)(*) weighted scanning available on standard clinical scanners. This method combined echo shifting, which allows for echo times longer than the sequence repetition time, with acquisition of multiple k-space lines per excitation. These two concepts were combined in order to achieve a method fast enough for fMRI, while maintaining a sufficiently long echo time for optimal contrast. PRESTO has been primarily used for 3D scanning, which minimized the contribution of large vessels due to inflow effects. Although PRESTO is still being used today, its appeal has lessened somewhat due to increased gradient performance of modern MRI scanners. Compared to 2D EPI, PRESTO may have somewhat reduced temporal stability, which is a disadvantage for fMRI that may not outweigh the advantage of reduced inflow effects provided by 3D scanning. In this overview, the history of the development of the PRESTO is presented, followed by a qualitative comparison with EPI. PMID- 22245351 TI - Spin-echo fMRI: The poor relation? AB - Spin-echo fMRI offers a potentially better intrinsic functional spatial resolution than its gradient echo counterpart, as well as the elimination of signal dropouts in the image. This comes at the price of a significant loss in sensitivity. In this article the main methods for measuring spin-echo fMRI are presented: HASTE, SSFP, RASER and most importantly spin-echo EPI. Their relative merits and limitations are discussed. The BOLD contrast mechanisms responsible for spin echo fMRI are summarised, and the spatial origin of the signal within the neocortex discussed. The major publications concerning the use of spin echo fMRI are examined. At present the most promising application for this methodology would appear to be in the examination of cortical layers and columns. The balance of experimental and theoretical evidence accumulated to date leads the author to propose that: (i) There is little point in conducting spin-echo fMRI at main magnetic field strengths of 3T and below; (ii) There are fundamental limitations to acquiring spin-echo BOLD data at 7T and above; (iii) Whole brain coverage with SE-BOLD at very high static magnetic field strengths could prove valuable; and (iv) SE-BOLD is probably better suited to study cortical columns than cortical layers. Recently gradient-echo approaches for high spatial resolution fMRI have been demonstrated that employ special techniques to avoid the effects of larger post capillary vessels. The coming years will show whether spin-echo techniques can remain the method of choice for high spatial resolution studies, and whether they can extend their range of application at 7T and above. PMID- 22245352 TI - A history of randomized task designs in fMRI. AB - In the early days of fMRI, data were acquired using methods adapted mainly from PET imaging. Sets of similar stimuli were presented in extended blocks, with stimulus conditions changing from block to block. While this method provided optimum statistical power, it also presented a variety of potential confounds, including changes in attention, alertness, expectancy, and practice effects within and between blocks. Event-related paradigms using unpredictable, randomized stimulus sequences had been used in EEG studies for over 50 years before the development of fMRI, and provided a means to overcome these issues. However, the temporal dispersion of BOLD fMRI activity resulted in responses to successive stimuli adding together, making it difficult to perform rapid event related paradigms using fMRI. Here we describe the background and history of methods developed to overcome this limitation, allowing rapid, randomized stimulus sequences to be used with fMRI. The advantages and disadvantages of this technique and how these methods have been applied in a variety of experimental settings are discussed. PMID- 22245353 TI - The characterization of dynamic susceptibility effects. AB - Understanding and quantifying dynamic susceptibility contrast, which arises from compartmentalized magnetic field perturbers (e.g., deoxyhemoglobin, contrast agents) that affect the water around them, formed the basis of a significant part of the author's fMRI-related research in the early 90's. This short note describes how the scientific work used to help understand and quantify dynamic injections of contrast agents, primarily designed for clinical MRI, was adapted to help quantify and explain BOLD imaging. PMID- 22245354 TI - Taste laterality studied by means of umami and salt stimuli: an fMRI study. AB - Aim of the present study was to investigate laterality of the gustatory system in the human brain for the taste qualities elicited by MSG (monosodium glutamate) and NaCl (sodium chloride). A total of 23 subjects participated in a block-design functional magnetic resonance imaging (fMRI) study. Liquid stimuli were presented at supra-threshold concentrations and delivered by means of a computer controlled gustometer. Left and right sides of the mouth were stimulated separately in order to correlate statistical parametrical maps to both the site of the stimulus and the specific taste quality. Following the effects of the site of stimulation through primary and secondary gustatory cortices an effort was made to explore the laterality of the gustatory pathways. Our results showed for both tastants a predominance of ipsilateral connections at the thalamus level. Insula left and right regions were both involved for both tastants. In these regions we found a high proportion of ipsilateral connection again for both the tastants. Considering orbitofrontal/prefrontal cortex, left-sided stimulation with NaCl or MSG produced left-sided activation of the orbito-frontal cortex clearly indicating the presence of an ipsilateral path. Finally, the hypothesis of frontal operculum as primary gustatory cortex and lateral prefrontal cortex as secondary was also supported by the results from dynamic causal modeling. PMID- 22245355 TI - The future of the human connectome. AB - The opportunity to explore the human connectome using cutting-edge neuroimaging methods has elicited widespread interest. How far will the field be able to progress in deciphering long-distance connectivity patterns and in relating differences in connectivity to phenotypic characteristics in health and disease? We discuss the daunting nature of this challenge in relation to specific complexities of brain circuitry and known limitations of in vivo imaging methods. We also discuss the excellent prospects for continuing improvements in data acquisition and analysis. Accordingly, we are optimistic that major insights will emerge from human connectomics in the coming decade. PMID- 22245356 TI - Integration of shape and motion cues in biological motion processing in the monkey STS. AB - To correctly perceive biological actions, the movement pattern generated in the course of the action has to be linked to the configuration of the actor. Recently, we showed that in humans, motion and configuration cues are processed separately in occipito-temporal cortex, and that both cues are integrated in the extrastriate (EBA) and fusiform (FBA) body areas (Jastorff and Orban, 2009). Using the same factorial design as in our human study, we performed fMRI experiments in awake monkeys to compare biological motion processing in the two species. Point-light displays of monkeys engaged in various actions were presented in a 2*2 factorial design. One factor manipulated the configuration of the stimuli, the other, the kinematics. As in humans, the two factors were anatomically segregated in the superior temporal sulcus (STS) rostral to the MT/V5 complex, with the effect of configuration significant along the lower bank and that of kinematics significant in the fundus and the upper bank of the STS. Moreover, voxels showing a significant interaction between the two factors were mainly confined to body-selective patches within the STS, mimicking our human findings. Importantly, this study reports for the first time differential activation for biological actions presented as point-light displays in the monkey. Moreover, our results suggest that the processing mechanisms of biological actions are remarkably similar in humans and macaque monkeys, and provide the basis for linking existing and future single-cell physiology in the monkey with human functional imaging. PMID- 22245357 TI - Brain state regulation during normal development: Intrinsic activity fluctuations in simultaneous EEG-fMRI. AB - Brain maturation in adolescence is mirrored by the EEG as a pronounced decrease in low frequency activity. This EEG power attenuation parallels reductions of structural and metabolic markers of neuronal maturation (i.e., gray matter loss and decrease of absolute cerebral glucose utilization). However, it is largely unknown what causes these electrophysiological changes, and how this functional reorganization relates to other functional measures such as the fMRI BOLD signal. In this study, we used simultaneously recorded EEG and fMRI to localize hemodynamic correlates of fluctuating EEG oscillations and to study the development of this EEG-BOLD coupling. Furthermore, the maturational EEG power attenuation was directly compared to BOLD signal power maturation. Both analyses were novel in their developmental perspective and aimed at providing a functional lead to EEG maturation. Data from 19 children, 18 adolescents and 18 young adults were acquired in 10 min eyes-open/eyes-closed resting states. Our results revealed that both EEG and BOLD amplitudes strongly decrease between childhood and adulthood, but their functional coupling remains largely unchanged. The global reduction of absolute amplitude of spontaneous slow BOLD signal fluctuation is a novel marker for brain maturation, and parallels the globally decreasing trajectories of EEG amplitudes, gray matter and glucose metabolism during adolescence. Further, the absence of thalamocortical EEG-BOLD coupling in children together with age-related normalized thalamic BOLD power increase indicated maturational changes in brain state regulation. PMID- 22245358 TI - Phylogenetically informative rearrangements in mitochondrial genomes of Coleoptera, and monophyly of aquatic elateriform beetles (Dryopoidea). AB - Mitochondrial gene order in Coleoptera has been thought to be conservative but a survey of 60 complete or nearly complete genomes revealed a total of seven different gene rearrangements (deletions, gene order reversals), mainly affecting tRNA genes. All of these were found to be limited to a single taxon or a subclade of Coleoptera. The phylogenetic distribution of a translocation of tRNA(Pro) in three species of elateriform beetles was investigated further by sequencing three nearly complete mitochondrial genomes (Dascillidae, Byrrhidae, Limnichidae) and ten additional individuals for a ~1370 bp diagnostic fragment spanning the relevant region. Phylogenetic analysis consistently recovered the monophyly of families previously grouped in the contentious superfamily Dryopoidea, a group of approximately 10 beetle families with mainly aquatic lifestyles. The Byrrhidae (moss beetles) were not part of this lineage, although they may be its sister group, to recover the widely accepted Byrrhoidea. The tRNA(Pro) translocation was present in all members of Dryopoidea, but not in any other Elateriformia, providing independent support for this lineage and for a single origin of aquatic habits. PMID- 22245359 TI - Kinetic, structural and molecular docking studies on the inhibition of tyrosinase induced by arabinose. AB - Tyrosinase plays a central role in biological pigment formation, and hence knowledge of tyrosinase catalytic mechanisms and regulation may have medical, cosmetic, and agricultural applications. We found in this study that arabinose significantly inhibited tyrosinase, and this was accompanied by conformational changes in enzyme structure. Kinetic analysis showed that arabinose-mediated inactivation followed first-order kinetics, and single and multiple classes of rate constants were measured. Arabinose displayed a mixed-type inhibitory mechanism with K(i)=0.22+/-0.07 mM. Measurements of intrinsic and ANS-binding fluorescence showed that arabinose induced tyrosinase to unfold and expose inner hydrophobic regions. We simulated the docking between tyrosinase and arabinose (binding energies were -26.28 kcal/mol for Dock6.3 and -2.02 kcal/mol for AutoDock4.2) and results suggested that arabinose interacts mostly with His61, Asn260, and Met280. The present strategy of predicting tyrosinase inhibition by simulation of docking by hydroxyl groups may prove useful in screening for potential tyrosinase inhibitors, as shown here for arabinose. PMID- 22245360 TI - Sex differences in reported pain across 11,000 patients captured in electronic medical records. AB - Clinically recorded pain scores are abundant in patient health records but are rarely used in research. The use of this information could help improve clinical outcomes. For example, a recent report by the Institute of Medicine stated that ineffective use of clinical information contributes to undertreatment of patient subpopulations--especially women. This study used diagnosis-associated pain scores from a large hospital database to document sex differences in reported pain. We used de-identified electronic medical records from Stanford Hospital and Clinics for more than 72,000 patients. Each record contained at least 1 disease associated pain score. We found over 160,000 pain scores in more than 250 primary diagnoses, and analyzed differences in disease-specific pain reported by men and women. After filtering for diagnoses with minimum encounter numbers, we found diagnosis-specific sex differences in reported pain. The most significant differences occurred in patients with disorders of the musculoskeletal, circulatory, respiratory and digestive systems, followed by infectious diseases, and injury and poisoning. We also discovered sex-specific differences in pain intensity in previously unreported diseases, including disorders of the cervical region, and acute sinusitis (P = .01, .017, respectively). Pain scores were collected during hospital encounters. No information about the use of pre encounter over-the-counter medications was available. To our knowledge, this is the largest data-driven study documenting sex differences of disease-associated pain. It highlights the utility of electronic medical record data to corroborate and expand on results of smaller clinical studies. Our findings emphasize the need for future research examining the mechanisms underlying differences in pain. PERSPECTIVE: This article highlights the potential of electronic medical records to conduct large-scale pain studies. Our results are consistent with previous studies reporting pain differences between sexes and also suggest that clinicians should pay increased attention to this idea. PMID- 22245362 TI - Awareness of temperature and pain sensation. AB - Evoked potentials (EPs) to radiant or contact heat pain stimuli reflect the synchronization of brain activity to noxious inputs. However, we do not know how they relate to conscious awareness (AW) of a sensation. In healthy volunteers, we determined the time of AW for thermal noxious and non-noxious sensory inputs and examined its correlation to parametric measures of vertex EPs. Subjects had to report the position of the hand of a Libet's clock at the moment they perceived either a laser or a thermode stimulus. AW was determined after subtracting the position of the clock hand at the moment of stimulus delivery from the one reported by the subject, in ms. Subjects estimated AW in all single trials, including those in which no EPs could be identified. Mean AW was estimated earlier than the corresponding EP latency for both types and intensities of stimuli. There was a weak but significant negative correlation of AW to EPs amplitude, which was higher than the correlation of AW to EPs latency. Our results indicate that the timing of AW is influenced by the subjective relevance of sensory inputs. This feature could be used for the analysis of cognitive aspects of pain processing. PERSPECTIVE: This article presents a way to measure the subjective awareness of the sensation induced by a noxious heat stimulus, either radiant or contact, in healthy human subjects. This method could be used for the analysis of cognitive aspects of pain processing. PMID- 22245361 TI - Physical activity, sustained sedentary behavior, and pain modulation in women with fibromyalgia. AB - Fibromyalgia (FM) has been conceptualized as a disorder of the central nervous system, characterized by augmented sensory processing and an inability to effectively modulate pain. We previously reported that physical activity is related to brain processing of pain, providing evidence for a potential mechanism of pain management. The purpose of this study was to extend our work by manipulating pain modulation and determining relationships to both physical activity and sustained sedentary behavior. Eleven women with FM completed accelerometer measures of physical activity and underwent functional magnetic resonance imaging of painful heat, administered alone and during distracting cognitive tasks. Results showed that physical activity was significantly (P < .005) and positively related to brain responses during distraction from pain in regions implicated in pain modulation including the dorsolateral prefrontal cortex (DLPFC), the dorsal posterior cingulate, and the periaqueductal grey. A significant negative relationship occurred in the left anterior insula. For sedentary time, significant negative relationships were observed in areas involved in both pain modulation and the sensory-discriminative aspects of pain including the DLPFC, thalamus, and superior frontal and pre- and post-central gyri. These results suggest that physical activity and sedentary behaviors are related to central nervous system regulation of pain in FM. PERSPECTIVE: Our results support a promising benefit of physical activity and highlight the potentially deleterious effects of sustained sedentary behavior for pain regulation in FM. Studies aimed at increasing physical activity or reducing sedentary behavior and determining the impact of these on pain regulation are warranted. PMID- 22245363 TI - Measurements and model calculations of activation cross sections for (n,p) reactions on 152Sm isotope between 13.57 and 14.83 MeV neutrons. AB - The activation cross sections were measured at six neutron energies from 13.57 and 14.83 MeV for (152)Sm(n,p)(152 g)Pm, (152)Sm(n,p)(152 m)Pm reactions. The production of short-lived activity and the spectra accumulation have been carried out by the cyclic activation method. Statistical model calculations, which the pre-equilibrium emission effects were taken into consideration were also performed (STAPRE code). The cross sections were compared with works in the literature, model calculation results, and evaluation data bases (ENDF/B-VII, JENDL-3.3, JEFF-3.1). PMID- 22245364 TI - X-ray diffraction imaging with the Multiple Inverse Fan Beam topology: principles, performance and potential for security screening. AB - The steadily increasing number of explosive threat classes, including home-made explosives (HMEs), liquids, amorphous and gels (LAGs), is forcing up the false alarm rates of security screening equipment. This development can best be countered by increasing the number of features available for classification. X ray diffraction intrinsically offers multiple features for both solid and LAGs explosive detection, and is thus becoming increasingly important for false-alarm and cost reduction in both carry-on and checked baggage security screening. Following a brief introduction to X-ray diffraction imaging (XDI), which synthesizes in a single modality the image-forming and material-analysis capabilities of X-rays, the Multiple Inverse Fan Beam (MIFB) XDI topology is described. Physical relationships obtaining in such MIFB XDI components as the radiation source, collimators and room-temperature detectors are presented with experimental performances that have been achieved. Representative X-ray diffraction profiles of threat substances measured with a laboratory MIFB XDI system are displayed. The performance of Next-Generation (MIFB) XDI relative to that of the 2nd Generation XRD 3500TM screener (Morpho Detection Germany GmbH) is assessed. The potential of MIFB XDI, both for reducing the exorbitant cost of false alarms in hold baggage screening (HBS), as well as for combining "in situ" liquid and solid explosive detection in carry-on luggage screening is outlined. PMID- 22245365 TI - Bioevaluation study of 32P-CP-PLLA particle brachytherapy in a rabbit VX2 lung tumor model. AB - OBJECTIVE: The purpose of this study was to investigate the therapy effects of intratumoral administration of (32)P-CP-PLLA particles in a rabbit VX2 lung tumor model. METHODS: 16 rabbits with tumors were randomly divided into 4 groups. 4 rabbits served as untreated controls, and others received intratumoral administration of (32)P-CP-PLLA particles with CT guidance. The total radioactivities in treated groups were as follows: a low activity was 93 MBq (n=4) (group 1), a medium activity was 185 MBq (n=4) (group 2) and a high activity was 370 MBq (n=4) (group 3). Brachytherapy treated VX2 tumors underwent (18)F-FDG PET/CT at 0 day, 3 day, 7 day and 14 day postinjection. In control group, (18)F-FDG PET/CT images were acquired at the same time points but without any treatment. Bremsstrahlung SPECT images were performed at 14 days after intratumoral brachytherapy in treated groups. After Bremsstrahlung SPECT and last (18)F-FDG PET/CT imagings, the rabbits were euthanized and the tumors were removed for histological examination. RESULTS: Bremsstrahlung SPECT images study indicated that there was no leakage of (32)P out of the injection site at 14 days after treatment. Compared with the control, the tumor volumes in treated groups significantly decreased, and (32)P-CP-PLLA particle produced a reduction in maximum or mean SUV of VX2 tumor (p<0.05). The percentage changes in maximum and mean SUV gradually decreased in group 1 and group 2 from day 3 to day 14 (p<0.05). A transient increase in (18)F-FDG accumulation at group 3 occurred due to the inflammatory reaction elements. Activity dependence was seen in HE and PCNA staining after 14 days treatment among three treated groups (p<0.05). CONCLUSIONS: Our data suggested that (32)P-CP-PLLA particle localized on the injecting sites. This novel brachytherapy device efficiently suppressed the growth of the VX2 tumors implanted in the rabbit. PMID- 22245366 TI - Effect of ultrasound treatment on steady and dynamic shear properties of glucomannan based salep dispersions: optimization of amplitude level, sonication time and temperature using response surface methodology. AB - The present study investigated effect of different amplitude levels (40, 70 and 100%), sonication temperatures (40, 50 and 60 degrees C) and exposure times (3, 7 and 11 min) on steady shear properties; apparent viscosity (eta), shear stress (sigma), consistency coefficient (K), flow behavior index (n) and dynamic shear properties; storage modulus (G'), loss modulus (G"), complex viscosity (eta(*)), complex modulus (G(*)) and loss tangent (tan delta) values of glucomannan based salep solution (SS) and salep drink (SD) samples. In addition, the steady and dynamic shear properties were optimized using ridge analysis in terms of amplitude level, sonication temperature and exposure times levels. Increasing amplitude level and sonication time decreased considerably the eta, sigma, K, G', G" and eta* values of salep dispersions (SS and SD samples). However, sonication temperature did not have a remarkable effect on these properties. PMID- 22245368 TI - Gas chromatographic-mass spectrometric investigation of volatile and extractable compounds of crude royal jelly. AB - Using headspace solid-phase microextraction (HS-SPME) followed by diethyl ether and methanol extraction, it was possible to isolate as many as 185 organic compounds out of 17 samples of crude royal jelly (RJ). Of the above compound number, 169 compounds were positively identified by means of gas chromatography mass spectrometry. The volatile fraction of RJ consists of 25 different compounds where approximately 47% of the total ion current (TIC) of volatile compound chromatograms were composed of substances characterized by bactericidal (phenols) and repelling (octanoic acid and 2-heptanone) activities. Preliminary investigations have shown that RJ stored for 10 months at -18 degrees C and 4 degrees C keeps its composition of volatile compounds unchanged, however, at the same time at room temperature RJ phenol contents is decreased twice, whereas the fraction of aliphatic acids is increased 2.8 times due to the presence of both acetic and butyric acids. The chromatogram of RJ ether extracts showed 85 different compounds, however about 88% of TIC consisted exclusively of 8 compounds, i.e. 10-hydroxy-2-decenoic, 10-hydroxydecanoic, 3,10 dihydroxydecanoic, 8-hydroxyoctanoic, 2-decene-1,10-dioc and (Z)-9-hydroxy-2 decenoic acids. Nine aliphatic acids, which were detected for the first time, are the homologues of hydroxy- and oxo-acids identified earlier in RJ. In the RJ methanol extracts 82 compounds were identified, mainly carbohydrates and their derivatives. Approximately 87% of TIC consisted of fructose, glucose and sucrose. Special attention was paid to discrepancies between obtained and literature data concerning the presence of free amino acids in RJ. It was suggested that these inconsistencies can be explained by the differences in the methods of RJ collection and/or sample preparation. PMID- 22245369 TI - [Management of pregnancy in patients with systemic lupus erythematosus]. AB - Patients with systemic lupus erythematosus are exposed to a remarkably high number of maternal-fetal complications during pregnancy. Knowledge regarding the reciprocal influence between lupus and pregnancy is the starting point to assure that these patients are correctly monitored. It is also important to carry out comprehensive preconception evaluation to individually evaluate the risk of each patient. The immunological profile, history of nephritis, presence of chronic damage and disease activity are the basic data that will determine the specific individual risk profile. Finally, correct drug management must be assured during this period, based on the safety profile of the different treatments during pregnancy and lactation. PMID- 22245370 TI - Poly(4-vinylpyridinium)hydrogen sulfate: a novel and efficient catalyst for the synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes under conventional heating and ultrasound irradiation. AB - A simple and convenient procedure for the synthesis of 14-aryl-14H dibenzo[a,j]xanthenes is described through a one-pot condensation of 2-naphthol with aryl aldehydes in the presence of poly(4-vinylpyridinium)hydrogen sulfate as an efficient, cheap, readily synthesized and eco-friendly catalyst in a solvent free media using conventional heating and ultrasound irradiation. PMID- 22245367 TI - Developmental changes in the protein composition of Manduca sexta lipid droplets. AB - The lipid droplets (LDs) are intracellular organelles mainly dedicated to the storage and provision of fatty acids. To accomplish these functions the LDs interact with other organelles and cytosolic proteins. In order to explore possible correlations between the physiological states of cells and the protein composition of LDs we have determined and compared the proteomic profiles of lipid droplets isolated from the fat bodies of 5th-instar larvae and adult Manduca sexta insects and from ovaries. These LD-rich tissues represent three clearly distinct metabolic states in regard to lipid metabolism: 1) Larval fat body synthesizes fatty acids (FA) and accumulates large amounts as triglyceride (TG); 2) Fat body from adult insects provides FA to support reproduction and flight; 3) Ovaries do not synthesize FA, but accumulate considerable amounts of TG in LDs. Major qualitative and semi-quantitative variations in the protein compositions of the LDs isolated from these three tissues were observed by MS/MS and partially validated by immuno-blotting. The differences observed included changes in the abundance of lipid droplet specific proteins, cytosolic proteins, mitochondrial proteins and also proteins associated with the machinery of protein synthesis. These results suggest that changes in the interaction of LDs with other organelles and cytosolic proteins are tightly related to the physiological state of cells. Herein, we summarize and compare the protein compositions of three subtypes of LDs and also describe for the first time the proteomic profile of LDs from an insect ovary. The compositions and compositional differences found among the LDs are discussed to provide a platform for future studies on the role of LDs, and their associated proteins, in cellular metabolism. PMID- 22245371 TI - High-frequency ultrasound treatment of sludge: combined effect of surfactants removal and floc disintegration. AB - Ultrasounds represent an effective technology in many research fields. In sewage sludge treatment, low-frequency ultrasound, particularly at 20 kHz, are widely used for sludge disintegration before the anaerobic digestion, while in the last years novel application of high-frequency ultrasound regards the decontamination of water and wastewater through sonochemical reactions. The innovative approach presented in this paper is the treatment of sewage sludge with ultrasound at 200 kHz for obtaining efficient sludge disintegration and the removal of the linear alkylbenzenesulphonates (LAS) at the same time. Results of the sonolysis experiments showed that native LAS degradation up to 40% can be achieved with low power input in less than 1h. The degradation pattern was different for each LAS homologue (from C10 to C13), because of their physical-chemical properties, in particular as regards the alkyl chain length. This high-frequency ultrasound irradiation resulted effective also in terms of floc disintegration and soluble organic matter release, in particular for energy inputs higher than 30,000 kJ/kg TS. The disrupting effect of the 200 kHz treatment was also evaluated by microscope analyses and determination of the extracellular polymeric substances release in the liquid phase. PMID- 22245373 TI - Molting dynamics and juvenile hormone titer profiles in the nymphal stages of a lower termite, Cryptotermes secundus (Kalotermitidae)--signatures of developmental plasticity. AB - Termites are social cockroaches and this sociality is founded on a high plasticity during development. Three molting types (progressive, stationary and regressive molts) are fundamental to achieve plasticity during alate/sexual development, and they make termites a major challenge to any model on endocrine regulation in insect development. As the endocrine signatures underpinning this plasticity are barely understood, we studied the developmental dynamics and their underlying juvenile hormone (JH) titers in a wood-dwelling termite, Cryptotermes secundus, which is characterized by an ancestral life style of living in dead wood and individuals being totipotent in development. The following general pattern elements could be identified during winged sexual development (i) regressive molts were accompanied by longer intermolt periods than other molting types, (ii) JH titers decreased gradually during the developmental transition from larva (immatures without wing buds), to nymph (immatures with wing buds), to winged adult, (iii) in all nymphal stages, the JH titer rose before the next molt and dropped thereafter within the first week, (iv) considerable variation in JH titers occurred in the midphase of the molting cycle of the 2nd and 3rd nymphal instar, inferring that this variation may reflect the underlying endocrine signature of each of the three molting types, (v) the 4th nymphal instar, the shortest of all, seems to be a switch point in development, as nymphs in this stage mainly developed progressively. When comparing these patterns with endocrine signatures seen in cockroaches, the developmental program of Cryptotermes can be interpreted as a co-option and repetitive use of hormonal dynamics of the post dorsal-closure phase of cockroach embryonic development. PMID- 22245374 TI - Steatohepatitis and liver cirrhosis in Chanarin-Dorfman syndrome with a new ABDH5 mutation. AB - Chanarin-Dorfman syndrome (CDS) is an autosomal recessive neutral lipid storage disease. It is very rare and characterized by ichtiosis, intracellular fat droplets in leucocytes (Jordan anomaly) and involvement of multiple tissues (skeletal muscle, central nervous system, bone marrow, eye and ear) mainly the liver. Our patients were diagnosed as CDS because they had ichtiosis, Jordon anomaly of leucocytes in peripheral blood smear, liver involvement and presence of homozygous 88 insertion C frame shift mutation on exon 4 of ABHD5/CGI-58 gene in genetic analysis. Our cases were two sisters. One of them developed severe steatohepatitis on age 19 and the other one was diagnosed as decompensated cirrhosis when she was 26 years old. We report here a new mutation in comparative gene identification-58 (CGI-58) gene causing syndactyly and steatohepatitis induced early cirrhosis. PMID- 22245372 TI - The vestibular system: multimodal integration and encoding of self-motion for motor control. AB - Understanding how sensory pathways transmit information under natural conditions remains a major goal in neuroscience. The vestibular system plays a vital role in everyday life, contributing to a wide range of functions from reflexes to the highest levels of voluntary behavior. Recent experiments establishing that vestibular (self-motion) processing is inherently multimodal also provide insight into a set of interrelated questions. What neural code is used to represent sensory information in vestibular pathways? How do the interactions between the organism and the environment shape encoding? How is self-motion information processing adjusted to meet the needs of specific tasks? This review highlights progress that has recently been made towards understanding how the brain encodes and processes self-motion to ensure accurate motor control. PMID- 22245375 TI - A complementary approach to identifying and assessing the remediation potential of hydrocarbonoclastic bacteria. AB - The isolation and assessment of hydrocarbonoclastic bacteria often represents a key strategy in the bioremediation of hydrocarbon-contaminated sites. However the isolation and assessment of such bacteria is often a lengthy and expensive procedure. The aim of this study was to identify potential isolates for use in the remediation of hydrocarbon contaminated sites using a combination of selective isolation plating, the Biolog system and subsequent multivariate analyses. The use of weathered oil as the main C source restricted the number of isolates growing to 5*10(2)CFUg soil(-1). Isolates (n=96) were then assessed individually using Biolog MT2 plates with seven different hydrocarbons (dodecane, tridecane, hexadecane, octadecane, eicosane, naphthalene and phenanthrene). The results indicated that all isolates were able to grow on at least one hydrocarbon from the seven chosen. This confirmed that the isolation media developed was selective in isolating hydrocarbonoclastic bacteria only. Cluster analysis of Biolog data separated the isolates into two discrete clusters with cluster 2 identifying hydrocarbonoclastic bacteria that are effective in degrading a variety of contaminants. Further study on the isolates from cluster 2 was carried out based on their phylogenetic analysis. Phylogenetic analysis of 28 bacterial isolates from cluster 2 based on the 1500bp sequences from 16S rDNA genes using MRBAYES confirmed all isolates as being hydrocarbonoclastic, providing supportive evidence that isolates from cluster 2 have a potential use in bioremediation. This approach could improve both the speed and efficiency of the commercial bioremediation process. PMID- 22245376 TI - Approaches to the safety assessment of engineered nanomaterials (ENM) in food. AB - A systematic, tiered approach to assess the safety of engineered nanomaterials (ENMs) in foods is presented. The ENM is first compared to its non-nano form counterpart to determine if ENM-specific assessment is required. Of highest concern from a toxicological perspective are ENMs which have potential for systemic translocation, are insoluble or only partially soluble over time or are particulate and bio-persistent. Where ENM-specific assessment is triggered, Tier 1 screening considers the potential for translocation across biological barriers, cytotoxicity, generation of reactive oxygen species, inflammatory response, genotoxicity and general toxicity. In silico and in vitro studies, together with a sub-acute repeat-dose rodent study, could be considered for this phase. Tier 2 hazard characterisation is based on a sentinel 90-day rodent study with an extended range of endpoints, additional parameters being investigated case-by case. Physicochemical characterisation should be performed in a range of food and biological matrices. A default assumption of 100% bioavailability of the ENM provides a 'worst case' exposure scenario, which could be refined as additional data become available. The safety testing strategy is considered applicable to variations in ENM size within the nanoscale and to new generations of ENM. PMID- 22245377 TI - Safety evaluation of a natural eggshell membrane-derived product. AB - Natural Eggshell Membrane (NEM(r)) is a novel dietary ingredient that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. NEM(r) was evaluated for safety via in vitro and in vivo toxicological studies. This included testing for cytotoxicity, genotoxicity, acute oral toxicity, and 90-day repeated-dose oral toxicity. NEM(r) did not exhibit any cytotoxic effects at a dose of 100 MUg in an in vitro human cell viability assay after incubation for up to 20 h. NEM(r) did not exhibit any genotoxic effects in an in vitro assay of four strains of histidine-dependent Salmonella typhimurium and one strain of tryptophan-dependent Escherichia coli at a dose of up to 5000 MUg/plate. NEM(r) did not exhibit any signs of acute toxicity in rats at a single oral dose of up to 2000 mg/kg body weight, nor signs of toxicity (via urinalysis, hematology, clinical chemistry, or histopathological evaluation) in rats at a repeated oral dose of up to 2000 mg/kg body weight per day for 90 days. The results of these studies suggest that NEM(r) may be safe for human consumption. PMID- 22245378 TI - Evaluation of protective efficacy of CC-2 formulation against topical lethal dose of T-2 toxin in mice. AB - T-2 toxin is the type-A trichothecene and a common contaminant of food and cereals, produced by Fusarium species. T-2 toxin easily penetrates skin due to its lipophilic nature and causes skin irritation and blisters in humans. Physical protection of the skin and airway is the only proven effective method of protection. To date, no chemical antidotes are available to prevent T-2 induced lethality. In the present study, we evaluated the protective efficacy of 20% N,N' dichloro-bis(2,4,6-trichlorophenyl) urea (CC-2) formulation against lethal topical exposure dose of T-2 toxin in mice. None of the animals exposed to only T 2 toxin at lethal dose of 2 and 4 LD50 (11.8 and 23.76 mg/kg body weight) survived beyond 36 and 16 h, respectively. CC-2 application at 5 and 15 min post exposure protected mice 100% from lethality at 2 LD50. Survival rate was 100% and 50% at 4LD50 dose if CC-2 was applied dermally within 5 and 15 min post-exposure. Recovery profile of surviving animals after 2LD50 T-2 toxin exposure at 1, 3, 7, and 14 days was assessed in terms of hepatic GSH, lipid peroxidation, serum ALP, ALT and AST. Hepatic lipid peroxidation significantly increased in all groups exposed to T-2 toxin by 3 day but normalized by day 7. A delayed GSH depletion was noted in surviving animals on day 7 but recovered by day 14. ALT and AST levels were elevated in all CC-2 protected mice on day 1 and normalized by day 3. ALP level decreased till day 7 in all protected groups. The biochemical variables recovered to control values by 14th day. GC-MS analysis after in vitro interaction of CC-2 formulation with T-2 toxin had shown that nearly 86% of T-2 toxin is decontaminated in 5 min but 8-10% of T-2 toxin was still present even after 60 min of interaction. Results of our study suggest that CC-2 may be an effective dermal decontaminant against lethal topical exposure of T-2 toxin. PMID- 22245380 TI - Effects of mechanical forces and stretch on intercellular gap junction coupling. AB - Mechanical forces provide fundamental physiological stimulus in living organisms. Recent investigations demonstrated how various types of mechanical load, like strain, pressure, shear stress, or cyclic stretch can affect cell biology and gap junction intercellular communication (GJIC). Depending on the cell type, the type of mechanical load and on strength and duration of application, these forces can induce hypertrophic processes and modulate the expression and function of certain connexins such as Cx43, while others such as Cx37 or Cx40 are reported to be less mechanosensitive. In particular, not only expression but also subcellular localization of Cx43 is altered in cardiomyocytes submitted to cyclic mechanical stretch resulting in the typical elongated cell shape with an accentuation of Cx43 at the cell poles. In the heart both cardiomyocytes and fibroblasts can alter their GJIC in response to mechanical load. In the vasculature both endothelial cells and smooth muscle cells are subject to strain and cyclic stretch resulting from the pulsatile flow. In addition, vascular endothelial cells are mainly affected by shear stress resulting from the blood flow parallel to their surface. These mechanical forces lead to a regulation of GJIC in vascular tissue. In bones, osteocytes and osteoblasts are coupled via gap junctions, which also react to mechanical forces. Since gap junctions are involved in regulation of cell growth and differentiation, the mechanosensitivity of the regulation of these channels might open new perspectives to explain how cells can respond to mechanical load, and how stretch induces self-organization of a cell layer which might have implications for embryology and the development of organs. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions. PMID- 22245382 TI - Special issue part I: 'Deservingness' and the politics of health care. PMID- 22245381 TI - Feeding her children, but risking her health: the intersection of gender, household food insecurity and obesity. AB - This paper investigates one explanation for the consistent observation of a strong, negative correlation in the United States between income and obesity among women, but not men. We argue that a key factor is the gendered expectation that mothers are responsible for feeding their children. When income is limited and households face food shortages, we predict that an enactment of these gendered norms places mothers at greater risk for obesity relative to child-free women and all men. We adopt an indirect approach to study these complex dynamics using data on men and women of childrearing age and who are household heads or partners in the 1999-2003 waves of the Panel Study of Income Dynamics (PSID). We find support for our prediction: Food insecure mothers are more likely than child free men and women and food insecure fathers to be overweight or obese and to gain more weight over four years. The risks are greater for single mothers relative to mothers in married or cohabiting relationships. Supplemental models demonstrate that this pattern cannot be attributed to post-pregnancy biological changes that predispose mothers to weight gain or an evolutionary bias toward biological children. Further, results are unchanged with the inclusion of physical activity, smoking, drinking, receipt of food stamps, or Women, Infants and Children (WIC) nutritional program participation. Obesity, thus, offers a physical expression of the vulnerabilities that arise from the intersection of gendered childcare expectations and poverty. PMID- 22245379 TI - The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor. AB - The molecular mechanisms responsible for the transition of some prostate cancers from androgen ligand-dependent to androgen ligand-independent are incompletely established. Molecules that are ligands for G protein coupled receptors (GPCRs) have been implicated in ligand-independent androgen receptor (AR) activation. The purpose of this study was to examine whether CXCL12, the ligand for the GPCR, CXCR4, might mediate prostate cancer cell proliferation through AR-dependent mechanisms involving functional transactivation of the AR in the absence of androgen. The results of these studies showed that activation of the CXCL12/CXCR4 axis promoted: The nuclear accumulation of both wild-type and mutant AR in several prostate epithelial cell lines; AR-dependent proliferative responses; nuclear accumulation of the AR co-regulator SRC-1 protein; SRC-1:AR protein:protein association; co-localization of AR and SRC-1 on the promoters of AR-regulated genes; AR- and SRC-1 dependent transcription of AR-regulated genes; AR-dependent secretion of the AR-regulated PSA protein; P13K-dependent phosphorylation of AR; MAPK-dependent phosphorylation of SRC-1, and both MAPK- and P13K-dependent secretion of the PSA protein, in the absence of androgen. Taken together, these studies identify CXCL12 as a novel, non-steroidal growth factor that promotes the growth of prostate epithelial cells through AR-dependent mechanisms in the absence of steroid hormones. These findings support the development of novel therapeutics targeting the CXCL12/CXCR4 axis as an ancillary to those targeting the androgen/AR axis to effectively treat castration resistant/recurrent prostate tumors. PMID- 22245383 TI - Sweden--socioeconomic factors and health. PMID- 22245384 TI - Conservation of Gbx genes from EHG homeobox in bivalve molluscs. AB - Homeobox-containing genes encode a set of transcription factors that have been shown to control spatial patterning mechanisms in bilaterian organism development. The homeobox gene Gbx, included in the EHGbox cluster, is implicated in the development of the nervous system. In this study, we surveyed five different families of Bivalvia for the presence of Gbx genes by means of PCR with degenerate primers. We were able to recover seven Gbx gene fragments from five bivalve species: Solen marginatus, Mimachlamys varia, Venerupis pullastra, Ostrea edulis and Mytilus galloprovincialis (the derived amino acid sequence were designated Sma-Gbx, Cva-Gbx, Vpu-Gbx, Oed-Gbx and Mga-Gbx, respectively). These genes are orthologous to various Gbx genes present in bilaterian genomes. The Gbx genes in four Bivalvia families, namely Solenidae, Veneridae, Ostreidae and Mytilidae, are newly reported here and we also showed additional information of the Gbx genes of Pectinidae. The phylogenetic analyses by neighbour-joining, UPGMA, maximum parsimony and Bayesian analysis clearly indicated that the Gbx sequences formed a well supported clade and assigned these Gbx genes to the Gbx family. These data permit to confirm that the homeodomain of the Gbx family is highly conserved among these five distinct families of bivalve molluscs. PMID- 22245385 TI - Repeated sodium hyaluronate injections following multiple arthrocenteses in the treatment of early stage reducing disc displacement of the temporomandibular joint: a preliminary report. AB - PURPOSE: The aim of this study was to assess the safety and clinical utility of intraarticular injection of sodium hyaluronate for the treatment of symptoms associated with internal derangement of the temporomandibular joint (TMJ). PATIENTS AND METHODS: Twenty patients, who have early stage temporomandibular dysfunction (TMD), were treated with intraarticular sodium hyaluronate injection and arthrocentesis. The patients received sodium hyaluronate (15 mg/ml) (1 ml) injections two times a week first following arthrocentesis with 200 ml Ringer's Lactate and the second without. The procedure was repeated for three times at weekly intervals for 3 weeks. Pre- and postinjection pain intensity, the presence of joint sounds, and interincisial distance were recorded. These data were evaluated by visual analog scale (VAS). RESULTS: The follow-up period was 6 months. There was a statistically significant reduction of pain intensity (p < 0.001) and joint sound (p < 0.001) in all patients. Initial measurement of maximal mouth opening (MMO) was 33.40 +/- 3.75 mm. At the end of the follow-up period, the same measurements were repeated and interincisal distance was 49.3 +/ 3.74 mm. The difference between these measurements was statistically significant (p < 0.001). CONCLUSION: We suggest that repeated sodium hyaluronate injections following multiple arthrocenteses with Ringer's Lactate is an effective and safe method for the treatment of early stage reducing disc displacement of TMJ. PMID- 22245386 TI - Needle-free jet injection using real-time controlled linear Lorentz-force actuators. AB - Needle-free drug delivery by jet injection is achieved by ejecting a liquid drug through a narrow orifice at high pressure, thereby creating a fine high-speed fluid jet that can readily penetrate skin and tissue. Until very recently, all jet injectors utilized force- and pressure-generating principles that progress injection in an uncontrolled manner with limited ability to regulate delivery volume and injection depth. In order to address these shortcomings, we have developed a controllable jet injection device, based on a custom high-stroke linear Lorentz-force motor that is feed-back controlled during the time-course of an injection. Using this device, we are able to monitor and modulate continuously the speed of the drug jet, and regulate precisely the volume of drug delivered during the injection process. We demonstrate our ability to control injection depth (up to 16mm) and repeatably and precisely inject volumes of up to 250MUL into transparent gels and post-mortem animal tissue. PMID- 22245387 TI - Downregulation of cholesterol biosynthesis genes in the forebrain of ERCC1 deficient mice. AB - Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. These phenotypes are recapitulated in Ercc1-knockout mice, which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocampal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying central nervous system abnormalities caused by inherited defects in NER. In the cerebellum, the most prominent change was the upregulation of genes associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, the transcripts whose downregulation is associated with Purkinje cell loss were mostly unaffected by the knockout of Ercc1. In the hippocampus, there was extensive downregulation of genes related to cholesterol biosynthesis. Reduced expression of these genes was also present in the neocortex of adult mice with reduced expression of ERCC1. These changes were accompanied by reduced mRNA expression of the transcription factor Sterol Regulatory Element Binding Transcription Factor-2 (SREBF2) which is a master regulator of cholesterol biosynthesis. The downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Reduced cholesterol biosynthesis may contribute to the neurodevelopmental disruption that is associated with ERCC1 defects and several other NER deficiencies including Cockayne syndrome. In addition, this reduction may negatively affect the function of mature synapses. PMID- 22245388 TI - Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures. AB - Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. In this context, anti-diabetic agents such as rosiglitazone and glucagon-like peptide (GLP)-1 have been reported to reduce pathologies associated with AD, including tau hyperphosphorylation, suggesting that such agents might be used to treat AD. One such anti-diabetic agent is sitagliptin, which acts through inhibition of dipeptidyl peptidase (DPP)-IV to increase GLP-1 levels. Given this action, sitagliptin would be predicted to reduce AD pathology. Accordingly, we investigated whether sitagliptin is effective in attenuating AD pathologies, focusing on tau phosphorylation in the OLETF type 2 diabetic rat model. Unexpectedly, we found that sitagliptin was not effective against pathological tau phosphorylation in the hippocampus of OLETF type 2 diabetes rats, and instead aggravated it. This paradoxically increased tau phosphorylation was attributed to activation of the tau kinase, GSK3beta (glycogen synthase kinase 3beta). Sitagliptin also increased ser-616 phosphorylation of the insulin receptor substrate (IRS)-1, suggesting increased insulin resistance in the brain. These phenomena were recapitulated in primary rat cortical neurons treated with sitagliptin, further confirming sitagliptin's effects on AD-related pathologies in neurons. These results highlight the need for caution in considering the use of sitagliptin in AD therapy. PMID- 22245391 TI - Understanding the role of oxygen in acute coronary syndromes. PMID- 22245390 TI - Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs. AB - The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at alpha5-, alpha2-, and alpha3- but low intrinsic efficacy at alpha1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 MUg/kg pyridostigmine bromide 30 min prior to 2* LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2* LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity. PMID- 22245389 TI - Cellular immune response parameters that influence IgE sensitization. AB - In vitro basophil responses have long been used in mechanistic studies to help assess the human allergic diathesis, particularly during therapeutic intervention. Recent evidence points to the use of dendritic cells (DCs) in also being valuable in evaluating therapies aimed at lessening disease through immunomodulation. This review article therefore takes a look at some of the recent advances in old and new assays employing both basophils and DCs, with the added perception that the responses mediated by two cell types are insightful towards understanding immune cell mechanisms underlying allergic disease. PMID- 22245393 TI - The ENA Lantern Award: the process and the celebration. PMID- 22245394 TI - Sex and the older adult. PMID- 22245395 TI - Early recognition and treatment of the septic patient in the emergency department. PMID- 22245396 TI - Lateral violence in nursing. PMID- 22245397 TI - Working toward perfection on the pneumonia core measure. PMID- 22245398 TI - Redesign of an urban academic emergency department: action research can make a difference. PMID- 22245399 TI - Oral rehydration of the pediatric patient with mild to moderate dehydration. PMID- 22245400 TI - Stenotrophomonas maltophilia--the most worrisome threat among unusual non fermentative gram-negative bacilli from hospitalized patients: a prospective multicenter study. AB - OBJECTIVES: Isolation rates of unusual non-fermentative Gram-negative bacilli (i.e. other than Pseudomonas aeruginosa and Acinetobacter baumannii) are increasing but studies are limited to few observations. We aimed at determining risk factors for infection and influence of antibiotic treatment on the outcome. METHODS: A six-month (December 1, 2008-May 31, 2009) prospective multicenter cohort study was conducted in nine French teaching hospitals. Characteristics of patients colonized or infected by unusual NF-GNB, adequacy of antimicrobial therapies, and outcome were analyzed. RESULTS: Analysis of 158 patients (median age, 62.7 years) was conducted. Stenotrophomonas maltophilia was the predominant bacterial species isolated (39%) followed by Achromobacter group (15%) and non baumannii Acinetobacter species (13%). Compared to colonized patients, infected ones were more frequently immunocompromised [relative risk (RR) = 1.63, (95% confidence interval (CI) = 1.02-2.60, P = 0.05)], hospitalized within the last three months [RR 1.67 (95% CI 1.09-2.58, P = 0.02)], admitted in an intensive care unit with central venous catheter [RR 1.74 (95% CI 1.15-2.63, P = 0.01)]. The overall hospital mortality concerned 28 patients (18%) but no association with inadequate antimicrobial treatment was found except in the group of S. maltophilia infected cases [RR 2.81 (95% CI 1.01-7.83, P = 0.02)]. CONCLUSION: Naturally carbapenems-resistant S. maltophilia is the main unusual NF-GNB pathogen in hospitalized patients, leading to inappropriate empirical antibiotic treatment at the time of emerging extended-spectrum beta-lactamase-producing bacteria. PMID- 22245401 TI - Oral co-administration of live attenuated Salmonella enterica serovar Typhimurium expressing chicken interferon-alpha and interleukin-18 enhances the alleviation of clinical signs caused by respiratory infection with avian influenza virus H9N2. AB - The combined use of cytokines has shown synergistic and/or additive effects in controlling several viral infections of livestock animals. However, little is known concerning the practical use of chicken cytokine combinations to control avian diseases. Here, we investigated the antiviral efficacy of oral co administration of chicken interferon-alpha (chIFN-alpha) and chicken interleukin 18 (chIL-18) using attenuated Salmonella enterica serovar Typhimurium in chickens infected with avian influenza virus (AIV) H9N2. Our results demonstrate that oral co-administration of S. enterica serovar Typhimurium expressing chIFN-alpha and chIL-18 produced a greater alleviation of clinical signs caused by respiratory infection with AIV H9N2 in chickens, when compared to administration of S. enterica serovar Typhimurium expressing either chIFN-alpha or chIL-18 alone. Mortality, clinical symptom severity, and feed and water intake were used to access treatment effectiveness. This enhancement of antiviral immunity was further confirmed by evidence of reduced rectal shedding and decreased replication of AIV H9N2 in several different tissues of challenged chickens including trachea, lung, cecal tonsil, and brain. Furthermore, oral co administration of chIFN-alpha and chIL-18 more efficiently modulated the immune responses of chickens against AIV H9N2 by enhancing both humoral and Th1-biased cell-mediated immunity, compared to single administration of either construct. Therefore, our results suggest that the combined administration of two chicken cytokines, chIFN-alpha and chIL-18, using attenuated S. enterica serovar Typhimurium as an oral carrier, provides an effective means for controlling respiratory disease caused by AIV H9N2 infection. PMID- 22245402 TI - Mutations in the genome of the highly pathogenic porcine reproductive and respiratory syndrome virus potentially related to attenuation. AB - A live-attenuated highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRS) virus (HP-PRRSV) TJM vaccine strain was derived from the HP-PRRSV TJ strain by passage 92 times in the African green monkey kidney epithelial cell line Marc-145. We found that the virulence of the TJ strain to piglets was decreased greatly from passage 19. To identify mutations associated with attenuation of the TJM vaccine strain, we determined the nucleotide changes that arose during Marc-145 passage of the HP-PRRSV TJ virus. The TJM strain contains a 360 nucleotide (120 amino acids) deletion and a 118 nucleotide mutation that resulted in 48 amino acid changes. Analysis of the complete nucleotide sequences of intermediate passage-level viruses F19, F46 and F78 showed that 31 (64.6%) of the 48 amino acid mutations occurred in F19, 7 (14.6%) occurred in F46, 7 (14.6%) occurred in F78 and 3 (6.3%) occurred in F92. The 120 amino acid deletion occurred from F19 to TJM. Therefore, we hypothesized that the 31 amino acid mutations distributed in nsp1beta, nsp2-nsp5, nsp7, nsp9, nsp10, GP4 and GP5 and the continuous 120 amino acid deletion in the nsp2 region from F19 provide a strong potential molecular basis for the observed attenuated phenotype. PMID- 22245403 TI - Study of methicillin resistant Staphylococcus aureus (MRSA) in Danish pigs at slaughter and in imported retail meat reveals a novel MRSA type in slaughter pigs. AB - Methicillin-resistant Staphylococcus aureus (MRSA), especially CC398, have emerged in livestock worldwide. We investigated the occurrence of MRSA in pigs at slaughter and in retail meat. During 2009, nasal swabs (n=789) were taken from pigs at slaughter. Moreover, 866 meat samples [Danish: pork (153), broiler meat (121), beef (142) and; imported: pork (173), broiler meat (193), and beef (84)] were randomly collected in retail stores and outlets. MRSA was isolated from nasal swabs or from meat samples after preenrichment (Mueller Hinton broth with 6.5% NaCl), selective enrichment (tryptone soya broth with 4 mg/L cefoxitine and 75 mg/L aztreonam) and selective plating on Brilliance Chromogenic MRSA agar. The presence of mecA was confirmed by PCR and the MRSA isolates were spa typed. Novel MRSA spa types were characterized by MLST, PFGE and SCCmec typing. Thirteen percent (101/789) of the pigs had MRSA. Based on spa types 93% corresponded to CC398 (spa t011, t034, t1451, t2876, t2974), 4% to CC30 (t1333) and one isolate to CC1 (t0127). The spa type t1333 (CC30), which is common among methicillin susceptible S. aureus (MSSA) from pigs in Denmark, contained a SCCmec cassette type V and czrC zinc resistance gene. Imported broiler meat had the highest occurrence (18%) of MRSA, followed by imported pork (7.5%) and Danish pork (4.6%). MRSA ST398 was found for the first time in Danish beef (1.4%). The finding of MRSA CC30 (spa t1333) suggest possible spread of the SCCmec cassette normally associated with ST398 into another S. aureus lineage common in pigs. PMID- 22245404 TI - Mitral annular calcium, inducible myocardial ischemia, and cardiovascular events in outpatients with coronary heart disease (from the Heart and Soul Study). AB - We sought to determine whether mitral annular calcium (MAC) is associated with inducible myocardial ischemia and adverse cardiovascular outcomes in ambulatory patients with coronary artery disease (CAD). MAC is associated with cardiovascular disease (CVD) in the general population, but its association with CVD outcomes in patients with CAD has not been evaluated. We examined the association of MAC with inducible ischemia and subsequent cardiovascular events in 1,020 ambulatory patients with CAD who were enrolled in the Heart and Soul Study. We used logistic regression to determine the association of MAC with inducible ischemia and Cox proportional hazards models to determine the association with CVD events (myocardial infarction, heart failure, stroke, transient ischemic attack or death). Models were adjusted for age, gender, race, smoking, history of heart failure, blood pressure, high-density lipoprotein, and estimated glomerular filtration rate. Of the 1,020 participants 192 (19%) had MAC. Participants with MAC were more likely than those without MAC to have inducible ischemia (adjusted odds ratio 2.06, 95% confidence interval 1.41 to 3.01, p = 0.0002). During an average of 6.26 +/- 2.11 years of follow-up, there were 310 deaths, 161 hospitalizations for heart failure, 118 myocardial infarctions, and 55 cerebrovascular events. MAC was associated with an increased rate of cardiovascular events (adjusted hazard ratio 1.39, 95% confidence interval 1.08 to 1.79, p = 0.01). In conclusion, we found that MAC was associated with inducible ischemia and subsequent CVD events in ambulatory patients with CAD. MAC may indicate a high atherosclerotic burden and identify patients at increased risk for adverse cardiovascular outcomes. PMID- 22245406 TI - Influence of gender on long-term mortality in patients presenting with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention. AB - Although an invasive strategy has predominately been studied in men with non-ST segment elevation acute coronary syndromes (NSTE-ACSs), its role in low-risk women is unclear. We sought to examine gender differences in a real-world registry of patients with NSTE-ACS who underwent percutaneous coronary intervention (PCI). Patients with NSTE-ACS undergoing PCI at the Cleveland Clinic, Cleveland, Ohio from 2003 through 2007 (n = 1,874) were included. In hospital and long-term mortalities were assessed. Cox proportional hazards models were constructed to study the influence of gender on mortality. Interactions with age and biomarker status were examined. Women were older and had a higher incidence of co-morbid conditions compared to men. They had a smaller reference vessel diameter compared to men. Despite these characteristics there was no overall difference in in-hospital (1.4% vs 1.6%) or long-term (14.6% vs 15.8%) mortality between men and women. However, there was evidence of a significant effect modification by age (p = 0.012) and troponin status (p = 0.0073) for long term mortality such that women <60 years of age, especially those who were troponin negative, had more than a twofold increase in long-term mortality compared to men (p = 0.007). In conclusion, although overall mortality rates are similar between men and women undergoing PCI for NSTE-ACS, women <60 years old with negative biomarkers have a higher mortality than their men peers. PMID- 22245405 TI - Comparison of percutaneous coronary intervention safety before and during the establishment of a transradial program at a teaching hospital. AB - This study sought to examine the safety of percutaneous coronary intervention (PCI) before and during de novo establishment of a transradial (TR) program at a teaching hospital. TR access remains underused in the United States, where cardiology fellowship programs continue to produce cardiologists with little TR experience. Establishment of TR programs at teaching hospitals may affect PCI safety. Starting in July 2009 a TR program was established at a teaching hospital. PCI-related data for academic years 2008 to 2009 (Y1) and 2009 to 2010 (Y2) were prospectively collected and retrospectively analyzed. Of 1,366 PCIs performed over 2 years, 0.1% in Y1 and 28.7% in Y2 were performed by TR access. No major complications were identified in 194 consecutive patients undergoing TR PCI, and combined bleeding and vascular complication rates were lower in Y2 versus Y1 (0.7% vs 2.0%, p = 0.05). Patients treated in Y2 versus Y1 and by TR versus transfemoral approach required slightly more fluoroscopy but similar contrast volumes and had similar procedural durations, lengths of stay, and predischarge mortality rates. PCI success rates were 97% in Y1, 97% in Y2, and 98% in TR cases. TR PCIs were performed by 13 cardiology fellows and 9 attending physicians, none of whom routinely performed TR PCI previously. In conclusion, de novo establishment of a TR program improved PCI safety at a teaching hospital. TR programs are likely to improve PCI safety at other teaching hospitals and should be established in all cardiology fellowship training programs. PMID- 22245408 TI - Effect of embolic particles during coronary interventional procedures on regional wall motion in patients with stable angina pectoris. AB - Microembolization during percutaneous coronary intervention (PCI) causes minor myocardial injury, and a Doppler guidewire can detect embolic particles as high intensity transient signals (HITS). The present study investigated the effect of microembolization during PCI on regional wall motion using a Doppler guidewire and myocardial strain analysis. We performed PCI to the left anterior descending coronary artery in 25 patients (18 men and 7 women, 68 +/- 8 years old) with stable angina pectoris. Coronary flow spectrums were obtained with a Doppler guidewire to count the total number of HITS throughout the PCI procedures. On the days before and after PCI, we recorded echocardiography and measured the longitudinal peak systolic strain, peak strain rate, and early diastolic strain rate in the left anterior descending territory using a 2-dimensional speckle tracking method. PCI was successfully performed, and 10 +/- 6 HITS (range 0 to 22, median 9) were recognized during PCI. The echocardiographic study showed no visible wall motion abnormalities in the left anterior descending territory either after or before PCI. In cases in which the total number of HITS was >=10, the peak systolic strain, peak strain rate, and early diastolic strain rate worsened on the day after PCI compared with those on the day before PCI (p <0.01). The rates of change in peak systolic strain and early diastolic strain rate, defined as the ratios of those parameters after PCI to those before PCI, had modest to strong inverse correlations with the total number of HITS (R(2) = 0.35 and R(2) = 0.46, respectively). In conclusion, periprocedural microembolization during PCI reduces subclinical cardiac function in patients with stable angina pectoris. PMID- 22245407 TI - A pulmonary hypertension gas exchange severity (PH-GXS) score to assist with the assessment and monitoring of pulmonary arterial hypertension. AB - Submaximal exercise gas analysis may be a useful method to assess and track pulmonary arterial hypertension (PAH) severity. The aim of the present study was to develop an algorithm, using exercise gas exchange data, to assess and monitor PAH severity. Forty patients with PAH participated in the study, completing a range of clinical tests and a novel submaximal exercise step test, which lasted 6 minutes and incorporated rest (2 minutes), exercise (3 minutes), and recovery (1 minute) ventilatory gas analysis. Using gas exchange data, including breathing efficiency, end-tidal carbon dioxide, oxygen saturation, and oxygen pulse, a pulmonary hypertension gas exchange severity (PH-GXS) score was developed. Patients were retested after about 6 months. There was significant separation between healthy controls and patients with moderate PAH (World Health Organization [WHO] class I/II) and those with more severe PAH (WHO class III/IV) for breathing efficiency, end-tidal carbon dioxide, oxygen saturation, and oxygen pulse. The PH-GXS score was significantly correlated with WHO class (r = 0.51), 6 minute walking distance (r = -0.59), right ventricular systolic pressure (r = 0.49), log N-terminal pro-B-type natriuretic peptide (r = 0.54), and pulmonary vascular resistance (r = 0.71). The PH-GXS score remained unchanged in 22 patients retested (1.50 +/- 0.92 vs 1.48 +/- 0.94), as did WHO class (2.3 +/- 0.8 vs 2.3 +/- 0.8) and 6-minute walking distance (455 +/- 120 vs 456 +/- 103 m). Small individual changes were observed in the PH-GXS score, with 8 patients improving and 8 deteriorating. In conclusion, the PH-GXS score differentiated between patients with PAH and was correlated with traditional clinical measures. The PH-GXS score was unchanged in our cohort after 6 months, consistent with traditional clinical metrics, but individual differences were evident. A PH-GXS score may be a useful way to track patient responses to therapy. PMID- 22245409 TI - Usefulness of minimal luminal coronary area determined by intravascular ultrasound to predict functional significance in stable and unstable angina pectoris. AB - Little is known about the intravascular ultrasound (IVUS) minimal lumen area (MLA) criteria and their accuracy in lesion subsets assorted according to vessel type, lesion location, vessel size, and clinical settings. We therefore assessed the accuracy of subgroup-specific cut-off values in predicting fractional flow reserve (FFR) <0.80. In total 692 consecutive patients with 784 coronary lesions were assessed by IVUS and FFR before intervention. All patients had >=1 target vessel with a de novo lesion (30% to 90% diameter stenosis). For prediction of FFR <0.80 in the group overall, the best cut-off value of MLA was 2.4 mm(2) (sensitivity 84% and specificity 63%). Overall diagnostic accuracy was only 69%. In the subgroup analysis, the MLA cutoff was 2.4 mm(2) for the left anterior descending coronary artery, 1.6 mm(2) for the left circumflex coronary artery, and 2.4 mm(2) for the right coronary artery. By lesion location, the optimal cutoff was 2.6 mm(2) for proximal, 2.3 mm(2) for mid, and 1.9 mm(2) for distal segments. Furthermore, the cutoffs were 3.2 mm(2) in lesions with a larger RLD >3.5 mm and 1.9 mm(2) in lesions with a smaller RLD <2.75 mm. Nevertheless, diagnostic accuracies of all subgroup-specific criteria were <80%. In conclusion, because IVUS-measured MLA is only 1 of many factors affecting coronary flow hemodynamics, even subgroup-specific criteria were inaccurate in identifying ischemia-inducible stenosis. In conclusion, direct functional assessment is therefore essential in guiding treatment strategies for coronary lesions. PMID- 22245410 TI - Age-specific gender differences in in-hospital mortality by type of acute myocardial infarction. AB - Younger women hospitalized with an acute myocardial infarction (MI) have a poorer prognosis than men. Whether this is true for patients with acute ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI) is not extensively studied. Using the MarketScan 2004 to 2007 Commercial and Medicare supplemental admission databases, we assessed gender differences in in-hospital mortality according to age in 91,088 patients (35,899 with STEMI, 55,189 with NSTEMI) who were 18 to 89 years old and had acute MI as their primary diagnosis. Patients with STEMI had significantly higher in-hospital mortality than those with NSTEMI (4.35% vs 3.53%, p <0.0001). Compared to men women were older, had higher co-morbidity scores, and were less likely to undergo revascularization during hospitalization in the STEMI and NSTEMI populations. In patients with STEMI the unadjusted women to-men odds ratio for in-hospital mortality was 2.29 (95% confidence interval 1.48 to 3.55) for the 18- to 49-year age group, 1.68 (1.28 to 2.21) for 50 to 59, 1.48 (1.17 to 1.88) for 60 to 69, 1.28 (1.06 to 1.57) for 70 to 79, and 1.01 (0.83 to 1.23) for 80 to 89. Corresponding unadjusted odds ratios were 1.51 (0.87 to 2.61), 1.46 (1.11 to 1.92), 1.29 (1.04 to 1.61), 0.83 (0.70 to 0.99) and 0.82 (0.70 to 0.94) for patients with NSTEMI. After adjustment for potential confounding factors, excess risk for in-hospital mortality in younger women versus their men counterparts (<60 years old) persisted in STEMI. In patients with NSTEMI the difference between younger women and younger men was not statistically significant; however, older women (>=70 years old) had better survival than men. In conclusion, higher risk of in-hospital mortality in younger women compared to younger men is more evident in patients with STEMI. PMID- 22245411 TI - Relation between estimated glomerular filtration rate and composition of coronary arterial atherosclerotic plaques. AB - It is well known that chronic kidney disease is a risk factor for atherosclerosis. The present study was conducted to identify any relation between the estimated glomerular filtration rate (eGFR) and coronary plaque characteristics using integrated backscatter intravascular ultrasound (IB-IVUS), which can detect coronary plaque composition. We performed IB-IVUS for 201 consecutive patients undergoing percutaneous coronary intervention, and they were divided into 3 groups according to the eGFR values (group 1 [n = 20], >=90 ml/min/1.73 m(2); group 2 [n = 123], 60 to 90 ml/min/1.73 m(2); and group 3 [n = 58], <60 ml/min/1.73 m(2)). Coronary plaques in nonculprit lesions on 3 dimensional analysis were evaluated using IB-IVUS. The baseline characteristics were similar, except for older age and a greater prevalence of men in group 3. IB IVUS showed a percentage of lipid volume of 44.7 +/- 5.0% in group 1, 53.6 +/- 6.2% in group 2, and 63.5 +/- 6.2% in group 3 (p <0.01), with a corresponding percentage of fibrous volume of 53.9 +/- 4.9%, 45.1 +/- 6.0%, and 35.3 +/- 6.1%, respectively (p <0.01). The eGFR correlated significantly with both parameters (r = -0.68, p <0.001 and r = 0.68, p <0.001, respectively). In conclusion, lower eGFR levels were associated with greater lipid and lower fibrous contents, contributing to coronary plaque vulnerability. PMID- 22245412 TI - United States national prevalence of electrocardiographic abnormalities in black and white middle-age (45- to 64-Year) and older (>=65-Year) adults (from the Reasons for Geographic and Racial Differences in Stroke Study). AB - A United States national sample of 20,962 participants (57% women, 44% blacks) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study provided general population estimates for electrocardiographic (ECG) abnormalities among black and white men and women. The participants were recruited from 2003 to 2007 by random selection from a commercially available nationwide list, with oversampling of blacks and those from the stroke belt, with a cooperation rate of 49%. The measurement of risk factors and 12-lead electrocardiograms (centrally coded using Minnesota code criteria) showed 28% had >=1 major ECG abnormality. The prevalence of abnormalities was greater (>=35%) for those >=65 years old, with no differences between blacks and whites. However, among men <65 years, blacks had more major abnormalities than whites, most notably for atrial fibrillation, major Q waves, and left ventricular hypertrophy. Men generally had more ECG abnormalities than women. The most common ECG abnormalities were T-wave abnormalities. The average heart rate-corrected QT interval was longer in women than in men, similar in whites and blacks, and increased with age. However, the average heart rate was greater in women than in men and in blacks than in whites and decreased with age. The prevalence of ECG abnormalities was related to the presence of hypertension, diabetes, blood pressure, and age. In conclusion, black men and women in the United States have a significantly greater prevalence of ECG abnormalities than white men and women at age 45 to 64 years; however, these proportions, although larger, tended to equalize or reverse after age 65. PMID- 22245413 TI - Meta-analysis of randomized controlled trials comparing intracoronary and intravenous administration of glycoprotein IIb/IIIa inhibitors in patients with ST-elevation myocardial infarction. AB - Glycoprotein IIb/IIIa receptor inhibitors (GPIs) have been widely adopted as an adjuvant regimen during primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction, but whether intracoronary administration of these potent antiplatelet agents conveys better efficacy and safety over the intravenous route has not been well addressed. A meta-analysis was performed by a systematic search of the published research for randomized controlled trials comparing intracoronary versus intravenous administration of GPIs in patients with ST-segment elevation myocardial infarction. Eight studies involving 686 patients in the intracoronary arm and 660 in the intravenous arm met the inclusion criteria. Postprocedural Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.08 to 1.98, p <0.05) and myocardial reperfusion grade 2 or 3 (OR 1.78, 95% CI 1.29 to 2.46, p <0.001) were markedly more often achieved in patients who received intracoronary boluses of GPIs than those receiving the intravenous strategy. Intracoronary administration resulted in a reduced incidence of mortality (OR 0.44, 95% CI 0.21 to 0.92, p <0.05), target vessel revascularization (OR 0.53, 95% CI 0.29 to 0.99, p <0.05), and the composite end point of major adverse cardiac events (OR 0.48, 95% CI 0.31 to 0.76, p <0.005) at 30-day follow-up. No significant difference was found in terms of major or minor bleeding (OR 1.14, p = 0.71, and OR 0.86, p = 0.47 respectively). In conclusion, intracoronary administration of GPIs yielded favorable outcomes in postprocedural blood flow restoration and 30-day clinical prognosis in patients with ST-segment elevation myocardial infarction. The intracoronary use of GPIs can be recommended as a preferred regimen during primary percutaneous coronary intervention. PMID- 22245414 TI - Six year follow-up after catheter ablation of atrial fibrillation: a palliation more than a true cure. AB - Long-term outcomes after pulmonary vein isolation for atrial fibrillation (AF) remain uncertain. In particular, the influence of rigorous arrhythmia monitoring on outcomes is not yet clear. In this study, 103 patients with symptomatic AF who underwent catheter ablation at a single academic medical center from 2002 to 2006 were evaluated, with a median follow-up time of 6 years. The primary end point was the success rate of catheter ablation, defined as the absence of any atrial arrhythmia recurrence lasting >10 seconds at the clinical visit and electrocardiographic or long-term cardiac rhythm recording after a single procedure and after the last procedure. In all, 153 procedures were performed, with a median of 1 (interquartile range 1 to 2) per patient as follows: 61 had 1, 35 had 2, 6 had 3, and 1 had 4 catheter ablations. Freedom from all atrial arrhythmias was present in 23% of patients at 6 years after a single procedure and in 39% of patients after the last procedure. No clinical predictors of AF recurrence were recognized after a single procedure, whereas after the last procedure, in univariate and multivariate Cox regression analysis, only nonparoxysmal AF (hazard ratio 1.92, 95% confidence interval 1.07 to 3.47, p = 0.02) was a predictor of recurrence. In conclusion, AF recurrence at 6-year follow-up after catheter ablation in a selected group of patients with symptomatic drug-refractory AF was relatively high, with 2/3 of AF relapses occurring in the first year of follow-up. Strict clinical surveillance after catheter ablation should be considered to help guide clinical decisions. PMID- 22245415 TI - Light-harvesting complexes from purple sulfur bacteria Allochromatium minutissimum assembled without carotenoids. AB - Effect of carotenoid (Car) biosynthesis inhibitor diphenylamine (DPA) on purple sulfur bacteria Allochromatium (Alc) minutissimum cell growth has been investigated. Cell growth in the presence of maximum concentration of DPA results in practically complete suppression (~99%) of carotenoids (Cars) according to the spectrophotometric, HPLC and CD data. Phytoene does not replace the colored carotenoids in these cells. Also Phytoene does not accumulate in large amounts in the cells treated with DPA. A new method for calculating the content of Cars in the complexes from the cells with inhibited Car synthesis including the number of empty Car's "pockets" has been used. Our results together with published data devoted to DPA action on the cell growth of purple bacteria revealed that Phytoene was not accumulated in the cells treated with DPA. We have concluded that (i) DPA completely inhibits or strongly reduces synthesis of the colored Cars in the cells of purple bacteria, (ii) Phytoene is the main one among the trace amounts of the other Cars in the case of significant inhibition of Car biosynthesis (80-90% or higher). The amount of the LH2 complexes presented in the membranes of Alc minutissimum was found to be little dependent on DPA. From DPA grown cultures it was possible to isolate Car-less both the LH1 (as LH1-RC complex) and the LH2 complexes. Electronic absorption properties of BChl's were very similar to those isolated from the control cells. It is shown by HPLC data that the 100 LH2 complexes from cells of Alc minutissimum, in which the synthesis of Car was depressed, contained ~9 Car molecules and 5 Phytoene molecules. Thus, only nine (with 1 Car molecule per a complex) or less (if more than one Car molecule per a complex) of the 100 LH2 complexes contain molecules of Cars. It means that 90 or more LH2 complexes from each 100 ones are assembled without any Cars. This is in strong contrast with the previous results obtained with purple non-sulfur bacterium Rhodobacter sphaeroides, where the amount of LH2 presented in the membrane was directly correlated to the amount of the carotenoids synthesized (H.P. Lang, C.N. Hunter, The relationship between carotenoid biosynthesis and the assembly of the light harvesting LH2 complex in Rhodobacter sphaeroides, Biochem. J. 298 (1994) 197-205). Our results show that although the presence of Car molecules is important for the stability of the LH2 complexes the overall native structure can be maintained without any Cars at least in the case of purple sulfur bacteria. PMID- 22245416 TI - Formamide in the cradle of life?: Comment on "Formamide and the origin of life" by R. Saladino, C. Crestini, S. Pino, G. Costanzo and E. Di Mauro. PMID- 22245417 TI - HnRNPL as a key factor in spermatogenesis: Lesson from functional proteomic studies of azoospermia patients with sertoli cell only syndrome. AB - Sertoli cell only syndrome (SCOS) is one of the main causes leading to the abnormal spermatogenesis. However, the mechanisms for abnormal spermatogenesis in SCOS are still unclear. Here, we analyzed the clinical testis samples of SCOS patients by two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF/TOF MS) to find the key factors contributing to SCOS. Thirteen differential proteins were identified in clinical testis samples between normal spermatogenesis group and SCOS group. Interestingly, in these differential proteins, Heterogeneous nuclear ribonucleoprotein L(HnRNPL) was suggested as a key regulator involved in apoptosis, death and growth of spermatogenic cells by String and Pubgene bioinformatic programs. Down-regulated HnRNPL in testis samples of SCOS patients was further confirmed by immunohistochemical staining and western blotting. Moreover, in vitro and in vivo experiments demonstrated that knockdown of HnRNPL led to inhibited proliferation, increased apoptosis of spermatogenic cell but decreased apoptosis of sertoli cells. Expression of carcinoembryonic antigen related cell adhesion molecule 1 in GC-1 cells or expression of inducible nitric oxide synthases in TM4 sertoli cells, was found to be regulated by HnRNPL. Our study first shows HnRNPL as a key factor involved in the spermatogenesis by functional proteomic studies of azoospermia patients with sertoli cell only syndrome. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22245418 TI - Differential protein profiling of synovial fluid from rheumatoid arthritis and osteoarthritis patients using LC-MALDI TOF/TOF. AB - The purpose of this study was to identify those proteins relatively more abundant in the synovial fluid (SF) of patients suffering from rheumatoid arthritis (RA) and osteoarthritis (OA) using high performance liquid chromatography coupled to mass spectrometry. 20 individual SF samples from each disease were pooled into two groups (RA and OA) to reduce the contribution of extreme individual values. Prior to the proteomic analysis, samples were immunodepleted from the top 20 most abundant plasma proteins, to enrich the lower-abundance protein fractions. Then, they were subjected to protein size fractioning and in-gel digestion, followed by reversed-phase peptide separation in a nano-LC system and subsequent peptide identification by MALDI-TOF/TOF. This strategy led to the identification of 136 different proteins in SF, which is the largest number of SF proteins described up to date by proteomics. A relative quantification of the proteins between RA and OA was carried out by spectral counting analysis. In RA, our results show a greater relative abundance of proteins related to complement activation, inflammation and the immune response, such as the major matrix metalloproteinases and several neutrophil-related proteins. In OA, we detected an increase in proteins involved in the formation and remodeling of the extracellular matrix (ECM), such as fibronectin, kininogen-1, cartilage acidic protein 1 and cartilage oligomeric matrix protein. The results obtained for MMP-1, BGH3, fibronectin and gelsolin were verified by immunoblotting analyses. Some of the novel proteins identified in this work might be relevant not only for increasing knowledge on the etiopathogenesis of RA and OA processes, but also as putative disease biomarkers, as their presence in SF is a prior step to their dilution in serum. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22245419 TI - Organ-specific proteomic analysis of drought-stressed soybean seedlings. AB - Changes in protein levels in drought-stressed soybean seedlings were analyzed using a proteomics approach. Three-day-old soybean seedlings were subjected to drought stress or treated with 10% polyethylene glycol (PEG) as osmotic stress. After treatment, the proteins were extracted from the leaf, hypocotyl, and root and separated using two-dimensional polyacrylamide gel electrophoresis. The root was the most drought-responsive organ, with the levels of 32, 13, and 12 proteins changing in response to drought stress, PEG treatment, and both, respectively. In the leaves of PEG-treated and drought-stressed seedlings, metabolism-related proteins increased and energy production- and protein synthesis-related proteins decreased. For 3 proteins present in all organs in drought-stressed plants, mRNA was differentially regulated: heat shock protein 70 and actin isoform B were upregulated, and methionine synthase was downregulated. mRNA expression patterns reflected those of protein levels, suggesting transcriptional regulation of these proteins. Western blot analysis confirmed the increase in ascorbate peroxidase in drought-stressed plants. The downregulation of mRNA and decreased protein levels of methionine synthase in the leaves, hypocotyl, and roots of drought-stressed plants, but not in other treatments, indicated that methionine synthase is a drought response protein. These results also suggest that the decreased methionine synthase in response to drought stress can impair the soybean seedling growth. PMID- 22245420 TI - Proteomic changes at 8 weeks after infection are associated with chronic liver pathology in experimental schistosomiasis. AB - Chronic Schistosoma mansoni infection can present as a moderate or severe disease, termed intestinal or hepatosplenic schistosomiasis, respectively. Similarly, either moderate splenomegaly or hypersplenomegaly syndrome develops in CBA/J mice by 20weeks of infection and is similar to intestinal or hepatosplenic schistosomiasis respectively. Using this mouse model and two-dimensional differential in gel electrophoresis, the liver proteomic signatures of uninfected mice and mice infected for 6, 8, 12, or 20weeks were compared, and significant protein spots identified using mass spectrometry. We found the greatest number of changes at 12weeks suggesting that this period represents the peak time of change. Pathway analysis identified specific proteins and pathways that correlated to the pathological changes indicative of severe disease, and these pathways were involved as early as 8weeks after infection. These findings provide insight into the development of severe liver pathology in schistosomiasis and may aid in developing biomarkers for hepatosplenic schistosomiasis. PMID- 22245421 TI - Chiari Malformation Type I, presenting as scapulothoracic pain: a case report. AB - Patients presenting with recalcitrant symptoms, which are resistant to a range of physical interventions over an extended period of time, need to be examined with care. A 'forensic' approach to the assessment of these patients, with a sensitive approach to the results of the test procedures is required to ensure the practitioner does not miss the more obscure causes. This case report presents a patient who was referred for a clinical assessment for long standing scapular pain, which had been labelled myofascial pain. Through a thorough approach to examination a number of flags appeared which suggested a need for further investigation. These investigations identified that the patient demonstrated a Chiari Malformation Type 1. On review 5 months following neurosurgical intervention her symptoms were significantly reduced. Chiari Malformations Type 1 are often diagnosed in adulthood when symptoms usually first appear. These symptoms may mimic those found with musculoskeletal conditions. Whilst we lack specific clinical tests for this condition, a thorough assessment should identify sufficient 'flags' for referral for further investigations. PMID- 22245422 TI - The association between pelvic floor muscle function and pelvic girdle pain--a matched case control 3D ultrasound study. AB - There is uncertainty regarding the association between the function of the pelvic floor muscles (PFM) and pelvic girdle pain (PGP), and whether exercises to strengthen the PFM should be recommended for patients with PGP. This one-to-one matched case-control study examined whether there is any difference in voluntary PFM function between women with and without clinically diagnosed PGP. PFM function was assessed by manometry and three-dimensional ultrasound. Images were saved anonymously and analyses were performed offline by one investigator. A special Cox regression model was used to fit a conditional logistic regression procedure for one-to-one matched case-control studies. Forty-nine pairs of women were successfully matched according to age and parity. The study showed no difference in voluntary PFM function measured by palpation, manometry or ultrasound. The size of the levator hiatus area, together with BMI, was significantly associated with PGP. Women with PGP had statistically significantly smaller levator hiatus areas and a tendency for higher vaginal resting pressure compared to the control group. A significantly smaller levator hiatus and a tendency for higher vaginal resting pressure may indicate increased activity of the PFM. Hence, no evidence was found to recommend strengthening exercises for the PFM in patients with PGP. It is important to note that in this study we examined only voluntary contractions and not an automatic response of the PFM to a functional activity. PMID- 22245423 TI - Crystal structures of the Arabidopsis thaliana abscisic acid receptor PYL10 and its complex with abscisic acid. AB - Abscisic acid (ABA) is one of the most essential phytohormones, and plays an important role in growth and development regulation, as well as in stress responses. The PYR/PYL/RCAR family (PYL for short)-comprised of 14 proteins in Arabidopsis-was recently identified as soluble ABA receptors that function in the perception and transduction of ABA signaling. In this work, the crystal structures of PYL10 were determined in the apo- and ABA-bound states, with respective resolutions of 3.0 and 2.7A. Surprisingly, a closed CL2 conformation was observed in the apo-PYL10 structure, which was different from a previously reported open CL2 conformation. A putative two-conformation dynamical equilibrium model was proposed to explain PYL10's constitutive binding to PP2Cs in the apo state and its increased PP2C binding ability in the ABA-bound state. PMID- 22245424 TI - FAM5C is a soluble osteoblast differentiation factor linking muscle to bone. AB - Muscle mass is related to higher bone mass and a reduction in fracture risk. However, the interactions between muscle tissues and bone metabolism are incompletely understood and there might be some humoral factors that are produced in muscle tissues and exhibit bone anabolic activity. We therefore investigated the role of FAM5C in osteoblast differentiation and the interactions between muscle and bone. A reduction of endogenous FAM5C by siRNA reduced the levels of osterix, alkaline phosphatase (ALP) and osteocalcin (OCN) mRNA as well as the levels of type 1 collagen and beta-catenin in mouse osteoblastic MC3T3-E1 cells and mouse calvarial osteoblasts, although FAM5C overexpression significantly antagonized the levels of osterix, ALP and OCN mRNA induced by bone morphogenetic protein-2 in C2C12 cells. The conditioned medium from FAM5C-overexpressed and suppressed C2C12 cells increased and decreased the levels of osterix, ALP and OCN mRNA in MC3T3-E1 cells, respectively. In conclusion, the present study is the first to show that FAM5C enhances osteoblast differentiation in differentiated osteoblasts, and that the effects of the conditioned medium from FAM5C-modulated myoblastic cells were positively correlated with the effects of FAM5C on osteoblast phenotype in osteoblasts. FAM5C might be an important humoral bone anabolic factor produced from muscle cells. PMID- 22245425 TI - Molecular interaction of the first 3 enzymes of the de novo pyrimidine biosynthetic pathway of Trypanosoma cruzi. AB - The first 3 reaction steps of the de novo pyrimidine biosynthetic pathway are catalyzed by carbamoyl-phosphate synthetase II (CPSII), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO), respectively. In eukaryotes, these enzymes are structurally classified into 2 types: (1) a CPSII-DHO-ATC fusion enzyme (CAD) found in animals, fungi, and amoebozoa, and (2) stand-alone enzymes found in plants and the protist groups. In the present study, we demonstrate direct intermolecular interactions between CPSII, ATC, and DHO of the parasitic protist Trypanosoma cruzi, which is the causative agent of Chagas disease. The 3 enzymes were expressed in a bacterial expression system and their interactions were examined. Immunoprecipitation using an antibody specific for each enzyme coupled with Western blotting-based detection using antibodies for the counterpart enzymes showed co-precipitation of all 3 enzymes. From an evolutionary viewpoint, the formation of a functional tri-enzyme complex may have preceded-and led to-gene fusion to produce the CAD protein. This is the first report to demonstrate the structural basis of these 3 enzymes as a model of CAD. Moreover, in conjunction with the essentiality of de novo pyrimidine biosynthesis in the parasite, our findings provide a rationale for new strategies for developing drugs for Chagas disease, which target the intermolecular interactions of these 3 enzymes. PMID- 22245426 TI - Evaluation of calcium depletion as a strategy for enhancement of mucosal absorption of macromolecules. AB - Extracellular calcium is crucial for functioning of the epithelial barrier. Compounds that bind calcium, reducing its extracellular levels, have therefore been investigated as mucosal absorption enhancers. However, the conditions under which calcium reduction sufficiently modulates the epithelial barrier to result in meaningful improvements in mucosal drug absorption are unclear. Present work investigated the settings in which calcium depletion leads to optimal epithelial barrier-modulating effects. Using Calu-3 and Caco-2 cell layers and inducing calcium depletion site-specifically (apically, basolaterally or on both sides) we demonstrate that apical calcium removal produces a modest effect on the tight junctions (the extent of the effect being dependent on the duration of apical calcium unavailability), whilst basolateral calcium exhaustion leads to a prominent effect on the epithelial barrier. However, using polyacrylic acid as an example, we show that polymeric calcium-binding agents proposed as mucosal absorption-enhancing excipients alter calcium levels exclusively on the apical side of the epithelium, which explains their modest effect on epithelial barrier modulation (also demonstrated in our work). Therefore the use of calcium depleting agents, especially those based on macromolecular polymers, is a relatively inefficacious strategy to promote mucosal absorption of macromolecules. PMID- 22245427 TI - Lenalidomide alone or lenalidomide plus dexamethasone significantly inhibit IgG and IgM in vitro... A possible explanation for their mechanism of action in treating multiple myeloma. AB - Lenalidomide (len) is an analog of thalidomide (thal), and both are used in the treatment of a diverse group of medical conditions. A common finding in this group is the detection of immunoglobulin in skin lesions, or high levels of immunoglobulin or myeloma protein in serum and urine. While their mechanism(s) of action is not known, the drugs are noted for their ability to modulate monocyte, lymphocyte, and natural killer cell functions; suppression of immunoglobulin synthesis could offer an explanation for their effectiveness in treating multiple myeloma (MM). Our objective was to determine if, on an equimolar basis, thal, len or dexamethasone (dex) could affect pokeweed (PWM)-induced synthesis of IgG, IgM and IL-2. When peripheral blood mononuclear cells were stimulated with PWM, len surpassed thal in suppressing IgM and IgG, and enhancing IL-2. Dex enhanced IgG, and suppressed IL-2. When the stimulated cells were treated with len (an effective promoter of IL-2 and suppressor of IgM and IgG) plus dex (an effective suppressor of IL-2 and enhancer of IgG), the net result was suppression of IgM and IgG. The synthesis of IgM and IgG by putative PWM-stimulated B cell blasts is significantly blocked by len. This suggest that the B-lymphocyte is a targeted cell for len, and that suppression of the synthesis of IgG and IgM could provide an explanation for the mechanism by which len effectively treats MM. PMID- 22245429 TI - Flt3 ligand enhances anti-tumor effects of antibody therapeutics. AB - Fms-like tyrosine kinase 3 ligand ([Flt3 ligand], FL) stimulates proliferation and development of a wide range of hematopoietic cells including hematopoietic stem cells and myeloid and lymphoid progenitor cells. FL also has been shown to have anti-tumor effects in a variety of in vivo tumor models. In this study, the effect of FL against tumor growth was investigated in the COLO-205 human colon tumor xenograft model. FL was delivered in vivo by the "hydrodynamics-based gene delivery of naked DNA" method. In this experimental setting, FL and/or the therapeutic antibody anti-carcinoembryonic antigen (CEA) monoclonal antibody was administered. FL alone or anti-CEA antibody alone induced significant growth inhibition; furthermore, FL plus antibody treatment produced synergistic anti tumor effects. This study is the first demonstration of a synergistic anti-tumor effect between FL and antibody therapeutics. PMID- 22245430 TI - Should we measure immunoglobulin levels in septic patients? PMID- 22245431 TI - Anti-leukemic effects of gallic acid on human leukemia K562 cells: downregulation of COX-2, inhibition of BCR/ABL kinase and NF-kappaB inactivation. AB - Gallic acid (GA) induces apoptosis in various cancer cell lines. In this study, we investigated the apoptotic activity induced by GA on chronic myeloid leukemia (CML) cell line-K562 and the underlying mechanism. GA reduced the viability of K562 cells in a dose and time dependent manner. GA led to G0/G1 phase arrest in K562 cells by promoting p21 and p27 and inhibiting the levels of cyclin D and cyclin E. Further studies indicated apoptosis with impaired mitochondrial function as a result of deranged Bcl-2/Bax ratio, leakage of cytochrome c and PARP cleavage along with DNA fragmentation and by up-regulating the expression of caspase-3. GA also activated the protein expressions of fatty acid synthase ligand and caspase-8. GA is more effective in imatinib resistant-K562 (IR-K562) cells (IC50 4 MUM) than on K562 cells (IC50 33 MUM). GA inhibited cyclooxygenase 2 (COX-2) in K562 as well as IR-K562 cells appears to be COX-2 involved in the suppression of growth. Interestingly, GA also inhibited BCR/ABL tyrosine kinase and NF-kappaB. In conclusion, GA induced apoptosis in K562 cells involves death receptor and mitochondrial-mediated pathways by inhibiting BCR/ABL kinase, NF kappaB activity and COX-2. PMID- 22245432 TI - The oculo-auriculo-fronto-nasal syndrome (OAFNS) - description of a rare and complex craniofacial deformity and its interdisciplinary management before school age. AB - Craniofacial clefts are certainly among the most challenging congenital malformations with respect to functional, aesthetic and psychosocial consequences. The aetiology is still under discussion, recent molecular genetic findings suggest defects in the ciliary function of neural crest cells during facial development. The severity of craniofacial clefting is known to be extremely variable. Different classifications have been proposed however nomenclature is not uniform. If vertical, median craniofacial clefting of fronto naso-maxillary structures is accompanied by auriculo-mandibular malformations the term oculo-auriculo-fronto-nasal syndrome (OAFNS) has been proposed. Extreme craniofacial abnormalities have to be expected in this rare disorder. Adequate correction is a surgical challenge and interventions have to be adapted individually to patient's needs with respect to general condition, age and growth. This case report describes both the underlying pathology as well as the interdisciplinary management of a female patient from birth to 6 years of age affected by this rare combination of vertical craniofacial clefting and bilateral auriculo-mandibular dysplasia. PMID- 22245433 TI - Glycosylation of human cyclooxygenase-2 (COX-2) decreases the efficacy of certain COX-2 inhibitors. AB - Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenase-2 (COX 2). COX-2 exists as two glycoforms, 72 and 74 kDa, the latter resulting from an additional glycosylation at Asn(580). In this study, Asn(580) was mutated, and the mutant and wild-type COX-2 genes were expressed in COS-1 cells to determine how glycosylation affects the inhibition of COX-2 activity by aspirin, flurbiprofen, ibuprofen, celecoxib, and etoricoxib. Results indicate that certain inhibitors were 2-5 times more effective at inhibiting COX-2 activity when the glycosylation site was eliminated, indicating that glycosylation of COX-2 at Asn(580) decreases the efficacy of some inhibitors. PMID- 22245434 TI - Are the eastern and western basins of the English Channel two separate ecosystems? AB - The English Channel is part of the "Greater North Sea" sub-region in the Marine Strategy Framework Directive. However, the Channel is characterized by hydrologic, oceanographic and biogeographic features that support its division into two main entities: the western basin and the eastern basin. This paper summarizes the Channel's main natural features and principal human activities to examine the similarities and differences between both basins. The differences between the basins support an ecosystem-based management approach at the combined basin scale, rather than the present approach of separating the France and UK sides. PMID- 22245435 TI - PCBs, PBDEs and organochlorine pesticides in crabs Hepatus pudibundus and Callinectes danae from Santos Bay, State of Sao Paulo, Brazil. AB - The occurrence of persistent organic pollutants (POPs) as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDE) in crabs Hepatus pudibundus and Callinectesdanae was assessed from two different places inside of the Santos Bay and Moela Island near one of the most economically important metropolitan areas in Southern Brazil. Among POPs analyzed, ?PCBs (222-923 ng g(-1)lipid weight) and ?DDTs (154-410 ng g(-1)lw) exhibited the highest concentrations in the crabs. ?HCHs ranged from 10.3 to 30.9 ng g(-1)lw and were found in all individuals. Other OCPs found in lower concentration was Mirex (7.6-41.6 ng g(-1)lw) and HCB (5.83-16.9 ng g(-1)lw). ?PBDEs (24.1 ng g(-1)lw) were only found in one male individual from the species C. danae collected near to the submarine sewage of Santos. Male crabs showed higher POP concentrations than female crabs for those two species. PMID- 22245436 TI - Spatial distribution and source apportionment of PAHs in surficial sediments of the Yangtze Estuary, China. AB - Spatial distribution and source apportionment of polycyclic aromatic hydrocarbons (PAHs) in the surface sediments of the Yangtze Estuary, especially the North Branch, have been fully investigated. PAH concentrations increased with the descending distance from the inner estuary to the adjacent sea, and varied significantly in various estuarine regions. Water currents (e.g., river runoff and ocean current) greatly affected the distribution pattern. In addition, ambient sewage and traffic also contributed to the PAH pollution in the estuary. In the adjacent sea, PAH values along the -20m isobath were higher than those along the -10m isobath due to the "marginal filter" phenomenon formed by different water currents. In most sites, PAHs had poor correlations with sediment size, but had positive correlations with total organic carbon. Based on the qualitative and quantitative analysis results, PAH sources were proved to be mainly from a mixture of petroleum combustion, biomass, and coal combustion. PMID- 22245437 TI - Rapid increase in copper concentrations in a new marina, San Diego Bay. AB - Concentrations of copper in water rose rapidly following the introduction of boats to a new marina in San Diego Bay. Two months after the marina reached half its capacity, a majority of water samples exceeded chronic and acute criteria for dissolved copper, and copper concentrations in several samples exceeded the highest concentrations observed in another marina that has been listed as an impaired water body. A box model suggested that a small fraction of the leached copper was sequestered in sediment. Copper concentrations in water entering the marina from the bay was more than half the chronic concentration limit, so only 50% of marina boat capacity could be accommodated without exceeding the chronic criterion more than 50% of the time. Copper concentrations in water may increase rapidly following boat introduction in small marinas, but could return to pre introduction levels by controlling boat numbers or reducing use of copper-based paints. PMID- 22245438 TI - Evaluation for the ecological quality status of coastal waters in East China Sea using fuzzy integrated assessment method. AB - This research presented an evaluation for the ecological quality status (EcoQS) of three semi-enclosed coastal areas using fuzzy integrated assessment method (FIAM). With this method, the hierarchy structure was clarified by an index system of 11 indicators selected from biotic elements and physicochemical elements, and the weight vector of index system was calculated with Delphi Analytic Hierarchy Process (AHP) procedure. Then, the FIAM was used to achieve an EcoQS assessment. As a result of assessment, most of the sampling stations demonstrated a clear gradient in EcoQS, ranging from high to poor status. Among the four statuses, high and good, owning a ratio of 55.9% and 26.5%, respectively, were two dominant statuses for three bays, especially for Sansha Bay and Luoyuan Bay. The assessment results were found consistent with the pressure information and parameters obtained at most stations. In addition, the sources of uncertainty in classification of EcoQS were also discussed. PMID- 22245439 TI - Adeno associated viral vector-mediated expression of somatostatin in rat hippocampus suppresses seizure development. AB - Somatostatin (SST) has been suggested to play an important role in maintaining hippocampal homeostasis by modulating excitatory neurotransmission. The putative anticonvulsant role for SST was tested in an electrical amygdala kindling model. SST was cloned into serotype 5 of the adeno-associated viral (AAV) vector and delivered bilaterally into the hippocampus of adult male Sprague Dawley rats that were subsequently electrically kindled. Behavioral severity and duration of kindled seizures was compared to uninjected and GFP-injected control rats. Results demonstrated that 70% of SST treated animals did not experience class IV or V seizures without affecting the threshold for individual stimulation-evoked seizures. This result was significantly different from control groups where 100% of animals reached class V seizures. No difference in the number of stimulations required to reach the first class I-III seizures was observed in the experimental cohort relative to age-matched controls. These preclinical results suggest a putative role for SST as an anticonvulsant therapeutic modality for epilepsy. PMID- 22245440 TI - The effects of exogenous CCK-8 on the acquisition and expression of morphine induced CPP. AB - Cholecystokinin octapeptide (CCK-8) is the most potent endogenous anti-opioid peptide and regulates a variety of physiological processes. In our previous study, we found that exogenous CCK-8 attenuated naloxone-induced withdrawal symptoms, but the possible regulative effects of CCK-8 on the rewarding effects of morphine were not examined. In the present study, we aimed to determine the exact effects of exogenous CCK-8 at various doses on the rewarding action of morphine by utilizing the unbiased conditioned place preference (CPP) paradigm. We therefore examined the effects of CCK-8 on the acquisition, expression and extinction of morphine-induced CPP and on locomotor activity. The results showed that CCK-8 (0.01-1MUg, i.c.v.), administered alone, induced neither CPP nor place aversion, but blocked the acquisition of CPP when administered with 10mg/kg morphine. The highest dose of CCK-8 (1MUg) administered before CPP testing increased CPP and, along with lower doses (0.1MUg), reduced its extinction. In addition, the highest dose (1MUg) of CCK-8 suppressed locomotor activity. Our study provides the first behavioral evidence for the inhibitory effects of exogenous CCK-8 on rewarding activity and reveals significant effects of exogenous CCK-8 on various stages of place preference and the development of opioid dependence. PMID- 22245441 TI - Nectarivory by the plant-tissue feeding predator Macrolophus pygmaeus Rambur (Heteroptera: Miridae): nutritional redundancy or nutritional benefit? AB - Most predators and parasitoids feed on plant-provided food (nectar, pollen) or engage in herbivory during at least part of their life stages. Plant feeding by these insects plays an important role in driving predator-herbivore dynamics. Thus, understanding the effects of plant feeding on omnivores could be an important element in improving biological control strategies. The mirid Macrolophus pygmaeus is an omnivorous heteropteran predator of whitefly and other pests. Unlike other predators that need to seek out accessible nectar to meet their carbohydrate requirements, mirid bugs can access the plant's carbohydrate resources by feeding directly on plant tissues. Leaf and stem feeding could be seen as a nutritional surrogate that allows mirids to become independent of nectar availability. However, to date feeding experiments have not yet considered nectar feeding by these mirid predators. In this study we demonstrate that M. pygmaeus survival is prolonged on broad bean plants featuring extrafloral nectar as compared to broad bean with extrafloral nectaries removed, irrespective of the presence of cattail pollen. Survival on extrafloral nectar was comparable to the survival by individuals kept on broad bean provided with eggs of Ephestia kuehniella as prey. Also, a greater proportion of mirid females laid eggs when extrafloral nectar was available as compared to those confined on nectariless plants without supplemental food. PMID- 22245442 TI - Is it possible to have impaired neurocognition but good social cognition in schizophrenia? AB - Social cognitive impairment in schizophrenia is common and associated with poor functional outcome. While correlations in the moderate range suggest that social cognition and neurocognition are separate but overlapping domains, less is known about whether intact neurocognition represents a "necessary but not sufficient" condition for intact social cognition, as has been suggested. In the present study we examined the following in a sample of 119 psychiatrically stable outpatients with schizophrenia: 1) correlations between multiple social cognitive measures and neurocognition, 2) the predictive value of neurocognitive domains in explaining social cognitive performance, and 3) the co-occurrence of social cognitive and neurocognitive impairment within participants. While 1/4 of participants showed intact overall neurocognition and impaired overall social cognition, only one participant had normal-range social cognition and impaired neurocognition. Results support the notion that normal range neurocognition is a necessary though not necessarily sufficient building block for good social cognitive performance. PMID- 22245443 TI - A second look: no effect of the COMT Val158Met polymorphism on conflict adaptation in youth with chromosome 22q11.2 deletion syndrome. PMID- 22245445 TI - Neurophysiological correlates of delinquent behaviour in adult subjects with ADHD. AB - The attention deficit/hyperactivity disorder (ADHD) shows an increased prevalence in arrested offenders compared to the normal population. The aim of the present study was to investigate whether ADHD symptoms are a major risk factor for criminal behaviour, or whether further deficits, mainly abnormalities in emotion processing, have to be considered as important additional factors that promote delinquency in the presence of ADHD symptomatology. Event related potentials (ERPs) of 13 non-delinquent and 13 delinquent subjects with ADHD and 13 controls were compared using a modified visual Go/Nogo continuous performance task (VCPT) and a newly developed version of the visual CPT that additionally requires emotional evaluation (ECPT). ERPs were analyzed regarding their topographies and Global Field Power (GFP). Offenders with ADHD differed from non-delinquent subjects with ADHD in the ERPs representing higher-order visual processing of objects and faces (N170) and facial affect (P200), and in late monitoring and evaluative functions (LPC) of behavioural response inhibition. Concerning neural activity thought to reflect the allocation of neural resources and cognitive processing capability (P300 Go), response inhibition (P300 Nogo), and attention/expectancy (CNV), deviances were observable in both ADHD groups and may thus be attributed to ADHD rather than to delinquency. In conclusion, ADHD symptomatology may be a risk factor for delinquency, since some neural information processing deficits found in ADHD seemed to be even more pronounced in offenders with ADHD. However, our results suggest additional risk factors consisting of deviant higher-order visual processing, especially of facial affect, as well as abnormalities in monitoring and evaluative functions of response inhibition. PMID- 22245444 TI - Differences between reported and actual restored caries lesion depths: results from The Dental PBRN. AB - OBJECTIVE: The objectives of this research were to (1) quantify the discordance between the caries lesion depth at which dentists restored initial lesions during a clinical study ("actual depth") and the lesion depth that they reported during a hypothetical clinical scenario ("reported depth"); (2) test the hypothesis that certain practitioner, practice, patient, and caries lesion characteristics are significantly associated with this discordance. METHODS: Practitioner investigators who perform restorative dentistry in their practices completed an enrollment questionnaire and participated in two consecutive studies on caries diagnosis and treatment. The first study was a survey asking about caries treatment. The second study collected data on restorations placed in routine clinical practice due to caries in patients over 19 years of age on occlusal surfaces only or proximal surfaces only. We report results on 2691 restorations placed by 205 dentists in 1930 patients with complete data. RESULTS: Discordance between actual depth and reported depth occurred in only about 2% of the restorations done due to proximal caries, but about 49% of the restorations done due to occlusal caries. Practice type, restorative material used and the diagnostic methods used were significantly associated with discordance. CONCLUSION: Dentists frequently restored occlusal caries at a shallower depth as compared to their reported depth, but the discordance was very small for proximal lesions. Discordance for occlusal caries was more common when radiographs were not taken or if a resin restoration was placed. PMID- 22245447 TI - What domains of the International Classification of Functioning, Disability and Health are covered by the most commonly used measurement instruments in traumatic brain injury research? AB - OBJECTIVE: To identify the most frequently used outcome measurement instruments reported in clinical studies on TBI and to provide a content comparison in the framework of the International Classification of Functioning, Disability and Health (ICF). PATIENTS AND METHODS: A systematic literature review of clinical studies in TBI was performed using Medline, EMBASE and PsychINFO. The items of the measurement instruments present in more than 20% of the studies were linked to the ICF language. RESULTS: 193 papers fulfilled the eligibility criteria. The frequency analysis identified six instruments: Functional Independence Measure (50%), Glasgow Outcome Scale (34%), Disability Rating Scale (32%), Wechsler Adult Intelligence Scale (29%), Trail Making Test (26%) and Community Integration Questionnaire (22%). The analysed instruments focus on different aspects of body functions (especially DRS, WAIS and TMT) and aspects of activities and participation in life (especially CIQ and FIM). Inter-researcher agreement for the ICF linking process was 0.83. CONCLUSIONS: Translating the items of different measurement instruments into the ICF language provides a practical tool to facilitate content comparisons among different outcome measures. The comparison can assist clinical researchers to integrate information acquired from different studies and different tools. PMID- 22245446 TI - Measuring and evaluating the role of ATP-sensitive K+ channels in cardiac muscle. AB - Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K(ATP) channel, but many of the techniques described are also used to study other ion channels. PMID- 22245448 TI - Risk factors for medical complication after spine surgery: a multivariate analysis of 1,591 patients. AB - BACKGROUND CONTEXT: Several studies have examined the occurrence of medical complication after spine surgery. However, many of these studies have been done using large national databases. Although these allow for analysis of thousands of patients, potentially influential covariates are not accounted for in these retrospective studies. Furthermore, the accuracy of these retrospective data collection in these databases has been called into question. PURPOSE: Using multivariate analysis on a prospectively collected data registry to determine significant risk factors for medical complication after spine surgery. STUDY DESIGN: Retrospective multivariate analysis of prospectively collected registry data. The registry is a prospectively collected database of all patients who underwent spine surgery in our two institutions from January 1, 2003 to December 31, 2004. METHODS: Extensive demographic and medical information were prospectively recorded as described previously by Mirza et al. Complications were defined in detail a priori, and they were prospectively recorded for at least 2 years after surgery. We analyzed risk factors for medical complication after spine surgery using univariate and multivariate analyses. RESULTS: We analyzed data from 1,591 patients who met out inclusion criteria. The cumulative incidences of complication after spine surgery per organ system are as follows: cardiac, 8.4%; pulmonary, 13%; gastrointestinal, 3.9%; neurological, 7.35%; hematological, 10.75%; and urological complications, 9.18%. The occurrence of cardiac or respiratory complication after spine surgery was significantly associated with death within 2 years (relative risk, 4.11 and 10.76, respectively). Surgical invasiveness and age were significant risk factors for complications in five of the six organ systems evaluated. Individual organ system specific elative risk values with 95% confidence intervals and p values are listed in Tables 3 and 4. CONCLUSIONS: Risk factors identified in this study can be beneficial to clinicians and patients alike when considering surgical treatment of the spine. Future analyses and models that predict the occurrence of medical complication after spine surgery may be of further benefit for surgical decision making. PMID- 22245449 TI - Is access to neighborhood green space associated with BMI among Egyptians? A multilevel study of Cairo neighborhoods. AB - Evidence of a link between green space and obesity has increased in the developed world, but few studies have been conducted in the developing world. Our study tests whether availability of neighborhood green space is associated with BMI among adults in Cairo, Egypt. Using data from the 2007 Cairo Urban Inequity Study, we conducted multilevel analyses and found no significant green space-BMI association, leading us to conclude that this intervention may not be as promising in this developing world context as it has been in some western urban contexts. Other aspects of the urban environment should be evaluated to better understand neighborhood variations in obesity in Cairo. PMID- 22245450 TI - [Recommendations of the Infectious Diseases Work Group (GTEI) of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) and the Infections in Critically Ill Patients Study Group (GEIPC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) for the diagnosis and treatment of influenza A/H1N1 in seriously ill adults admitted to the Intensive Care Unit]. AB - The diagnosis of influenza A/H1N1 is mainly clinical, particularly during peak or seasonal flu outbreaks. A diagnostic test should be performed in all patients with fever and flu symptoms that require hospitalization. The respiratory sample (nasal or pharyngeal exudate or deeper sample in intubated patients) should be obtained as soon as possible, with the immediate start of empirical antiviral treatment. Molecular methods based on nucleic acid amplification techniques (RT PCR) are the gold standard for the diagnosis of influenza A/H1N1. Immunochromatographic methods have low sensitivity; a negative result therefore does not rule out active infection. Classical culture is slow and has low sensitivity. Direct immunofluorescence offers a sensitivity of 90%, but requires a sample of high quality. Indirect methods for detecting antibodies are only of epidemiological interest. Patients with A/H1N1 flu may have relative leukopenia and elevated serum levels of LDH, CPK and CRP, but none of these variables are independently associated to the prognosis. However, plasma LDH> 1500 IU/L, and the presence of thrombocytopenia <150 x 10(9)/L, could define a patient population at risk of suffering serious complications. Antiviral administration (oseltamivir) should start early (<48 h from the onset of symptoms), with a dose of 75 mg every 12h, and with a duration of at least 7 days or until clinical improvement is observed. Early antiviral administration is associated to improved survival in critically ill patients. New antiviral drugs, especially those formulated for intravenous administration, may be the best choice in future epidemics. Patients with a high suspicion of influenza A/H1N1 infection must continue with antiviral treatment, regardless of the negative results of initial tests, unless an alternative diagnosis can be established or clinical criteria suggest a low probability of influenza. In patients with influenza A/H1N1 pneumonia, empirical antibiotic therapy should be provided due to the possibility of bacterial coinfection. A beta-lactam plus a macrolide should be administered as soon as possible. The microbiological findings and clinical or laboratory test variables may decide withdrawal or not of antibiotic treatment. Pneumococcal vaccination is recommended as a preventive measure in the population at risk of suffering severe complications. Although the use of moderate- or low-dose corticosteroids has been proposed for the treatment of influenza A/H1N1 pneumonia, the existing scientific evidence is not sufficient to recommend the use of corticosteroids in these patients. The treatment of acute respiratory distress syndrome in patients with influenza A/H1N1 must be based on the use of a protective ventilatory strategy (tidal volume <10 ml / kg and plateau pressure <35 mmHg) and positive end-expiratory pressure set to high patient lung mechanics, combined with the use of prone ventilation, muscle relaxation and recruitment maneuvers. Noninvasive mechanical ventilation cannot be considered a technique of choice in patients with acute respiratory distress syndrome, though it may be useful in experienced centers and in cases of respiratory failure associated with chronic obstructive pulmonary disease exacerbation or heart failure. Extracorporeal membrane oxygenation is a rescue technique in refractory acute respiratory distress syndrome due to influenza A/H1N1 infection. The scientific evidence is weak, however, and extracorporeal membrane oxygenation is not the technique of choice. Extracorporeal membrane oxygenation will be advisable if all other options have failed to improve oxygenation. The centralization of extracorporeal membrane oxygenation in referral hospitals is recommended. Clinical findings show 50-60% survival rates in patients treated with this technique. Cardiovascular complications of influenza A/H1N1 are common. Such problems may appear due to the deterioration of pre-existing cardiomyopathy, myocarditis, ischemic heart disease and right ventricular dysfunction. Early diagnosis and adequate monitoring allow the start of effective treatment, and in severe cases help decide the use of circulatory support systems. Influenza vaccination is recommended for all patients at risk. This indication in turn could be extended to all subjects over 6 months of age, unless contraindicated. Children should receive two doses (one per month). Immunocompromised patients and the population at risk should receive one dose and another dose annually. The frequency of adverse effects of the vaccine against A/H1N1 flu is similar to that of seasonal flu. Chemoprophylaxis must always be considered a supplement to vaccination, and is indicated in people at high risk of complications, as well in healthcare personnel who have been exposed. PMID- 22245451 TI - Hypotensive and vasorelaxing effects of the new NO-donor [Ru(terpy)(bdq)NO(+)](3+) in spontaneously hypertensive rats. AB - Drugs that release nitric oxide (NO) usually have limitations due to their harmful effects. Sodium nitroprusside (SNP) induces a rapid hypotension that leads to reflex tachycardia, which could be an undesirable effect in patients with heart disease, a common feature of hypertension. The nitrosyl ruthenium complex [Ru(terpy)(bdq)NO(+)](3+) (TERPY) is a NO donor that is less potent than SNP in denuded aortic rings. This study evaluated the hypotension and vasorelaxation induced by this NO donor in Wistar (W) and spontaneously hypertensive rats (SHR) and compared to the results obtained with SNP. Differently from the hypotension induced by SNP, the action of TERPY was slow, long lasting and it did not lead to reflex tachycardia in both groups. The hypotension induced by the NO-donors was more potent in SHR than in W. TERPY induced relaxation with similar efficacy to SNP, although its potency is lower in both strains. The relaxation induced by TERPY is similar in W and SHR, but SNP is more potent and efficient in SHR. The relaxation induced by TERPY is partially dependent on guanylate cyclase in SHR aorta. The NO released from the NO donors measured with DAF-2 DA by confocal microscopy shows that TERPY releases similar amounts of NO in W and SHR, while SNP releases more NO in SHR aortic rings. PMID- 22245452 TI - Cardiovascular effects and molecular targets of resveratrol. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol phytoalexin present in a variety of plant species and has been implicated to explain the health benefits of red wine. A wide range of health beneficial effects have been demonstrated for resveratrol in animal studies. In this review, we summarize the cardiovascular effects of resveratrol with emphasis on the molecular targets of the compound. In this regard, resveratrol stimulates endothelial production of nitric oxide, reduces oxidative stress, inhibits vascular inflammation and prevents platelet aggregation. In animal models of cardiovascular disease, resveratrol protects the heart from ischemia-reperfusion injury, reduces blood pressure and cardiac hypertrophy in hypertensive animals, and slows the progression of atherosclerosis. A number of direct and indirect target molecules mediating the aforementioned cardiovascular effects of resveratrol have been identified. These include, among others, the estrogen receptor alpha, the adenosine receptors, the cyclooxygenase 1, the histone/protein deacetylase sirtuin 1, the AMP-activated protein kinase, the Akt kinase, the nuclear factor E2-related factor-2, and NF-kappaB. Molecular mechanisms involved in the signal cascades are discussed. PMID- 22245453 TI - Genetics and arrhythmias: diagnostic and prognostic applications. AB - This review article discusses the genetic bases of cardiac arrest with a specific focus on cardiac channelopathies and right ventricular cardiomyopathy. We review the appropriate use of genetic testing in those patients suspected to have inherited cardiac arrhythmias, highlighting the importance of most genotype phenotype correlations for risk stratification. The article also presents the most recent views on diagnostic criteria and flowcharts for treatment of patients with inherited arrhythmogenic diseases. PMID- 22245454 TI - Role of lipids in the interaction of antimicrobial peptides with membranes. AB - Antimicrobial peptides (AMPs) take part in the immune system by mounting a first line of defense against pathogens. Recurrent structural and functional aspects are observed among peptides from different sources, particularly the net cationicity and amphipathicity. However, the membrane seems to be the key determinant of their action, either as the main target of the peptide action or by forming a barrier that must be crossed by peptides to target core metabolic pathways. More importantly, the specificity exhibited by antimicrobial peptides relies on the different lipid composition between pathogen and host cells, likely contributing to their spectrum of activity. Several mechanisms of action have been reported, which may involve membrane permeabilization through the formation of pores, membrane thinning or micellization in a detergent-like way. AMPs may also target intracellular components, such as DNA, enzymes and even organelles. More recently, these peptides have been shown to produce membrane perturbation by formation of specific lipid-peptide domains, lateral phase segregation of zwitterionic from anionic phospholipids and even the formation of non-lamellar lipid phases. To countermeasure their activity, some pathogens were successful in developing effective mechanisms of resistance to decrease their susceptibility to AMPs. The functional and integral knowledge of such interactions and the clarification of the complex interplay between molecular determinants of peptides, the pathogen versus host cells dichotomy and the specific microenvironment in which all these elements convene will contribute to an understanding of some elusive aspects of their action and to rationally design novel therapeutic agents to overcome the current antibiotic resistance issue. PMID- 22245455 TI - Doing Anger Differently: two controlled trials of percussion group psychotherapy for adolescent reactive aggression. AB - This study evaluates efficacy and effectiveness of 'Doing Anger Differently' (DAD), a group treatment for reactively aggressive 12-15 year old males. DAD uses percussion exercises to aid treatment. Study 1 compared a ten-week treatment with a waitlist control at pre, post and 6 month (treatment group only) follow-up. Study 2 replicated Study 1, but also followed up controls at 6 months. In study 1 (N = 54) the treatment resulted in lowered trait anger (Cohen's d = -1.3), aggression-reports (d = -1.0) and depression (d = -0.6), and increased self esteem (d = 0.6), all maintained at six months. In study 2 (N = 65), aggression reports fell to one fifth of pre-treatment levels at nine months follow-up (d = 1.2), with lowered trait anger (d = -0.4) and anger expression (d = -0.3) post treatment. PMID- 22245456 TI - Goal engagement and goal attainment in adolescents with and without visual impairment. AB - The present longitudinal study analyzed the effects of domain-specific goal engagement on the attainment of four developmental goals in 133 adolescents with visual impairment and in 449 sighted peers. Goal engagement predicted stronger progress in goal attainment with regard to getting access to a peer group, career choice and development of romantic relationships at the 1-year-follow-up. However, goal engagement at T(1) did not predict progress in the achievement of autonomy from ones' parents. Furthermore, we found an interaction effect between vision status and goal engagement on progress in career choice. Higher initial levels of goal engagement predicted stronger progress in goal attainment of sighted adolescents. No such effect was found in adolescents with visual impairment. It is concluded that effects of goal engagement vary by goal contents and contexts. PMID- 22245457 TI - Insulin resistance in the nervous system. AB - Metabolic syndrome is a cluster of cardiovascular risk factors including obesity, diabetes and dyslipidemia. Insulin resistance (IR) is at the core of metabolic syndrome. In adipose tissue and muscle, IR results in decreased insulin signaling, primarily affecting downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It was recently proposed that neurons can develop hyperinsulinemia-induced IR, which in turn results in injury to the peripheral and central nervous systems and is probably pathogenic in common neurological disorders such as diabetic neuropathy and Alzheimer's disease (AD). This review presents evidence indicating that, similarly to insulin-dependent metabolically active tissues such as fat and muscle, neurons also develop IR and thus cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury, subsequent dysfunction and disease states. PMID- 22245459 TI - Association between retinal nerve fiber layer thickness and abnormalities of vision in people with human immunodeficiency virus infection. AB - PURPOSE: To investigate relationships between contrast sensitivity (CS), color vision, and retinal nerve fiber layer (RNFL) among people with human immunodeficiency virus (HIV) infection; to evaluate the effect of time since diagnosis of HIV infection on RNFL thickness. DESIGN: Noninterventional cross sectional study. METHODS: We evaluated 102 eyes of 57 HIV-infected individuals without ocular opportunistic infections. Peripapillary RNFL thickness was determined with spectral-domain optical coherence tomography in 4 quadrants. CS was measured with the Pelli-Robson technique (expressed as logCS); color vision was measured with the Lanthony desaturated 15-hue technique (expressed as color confusion index [C-index], with higher scores indicating worse color vision). Correlations between values were assessed using Spearman correlation coefficients. RESULTS: Median RNFL thickness (average of 4 quadrants) was 102.9 MUm (range, 75.0-134.7 MUm). Median logCS was 1.90 (range, 1.25-1.95). Median C index was 1.58 (range, 0.96-4.07). Temporal RNFL thickness was correlated with logCS (r=0.295, P=.003) and C-index (r=-0.338, P=.0005). Time since diagnosis of HIV infection was shorter for those with thick average RNFL than for those with thin average RNFL (P=.18). CONCLUSIONS: Both worse CS and worse color vision are correlated with thinning of the temporal RNFL, with possible threshold effects. Increased prevalences of abnormal CS and abnormal color vision in this population are therefore likely attributable to neuroretinal compromise. This pattern of structural and functional losses may reflect preferential damage to small-caliber axons in the maculopapillary bundle, possibly associated with mitochondrial dysfunction, providing a potential disease mechanism for HIV-associated "neuroretinal disorder." PMID- 22245460 TI - Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. AB - PURPOSE: To investigate the potential influences that affect visual acuity (VA) outcome in a clinic-based cohort of age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) treatment for choroidal neovascularization. DESIGN: Prospective interventional case series. METHODS: Patients with subfoveal choroidal neovascularization (CNV) secondary to AMD were prospectively recruited. A detailed questionnaire was given to patients at time of enrollment, to collect information relating to demographics, history of visual symptoms, visual acuity (VA), and treatment scheduling. Delay from symptoms to treatment ("Treatment delay") was measured in terms of weeks and analyzed in tertiles. Information pertaining to treatment outcomes was collected over a 6-month period. RESULTS: One hundred eighty-five eyes of 185 patients were recruited into the study. Longer delay from first symptoms suggestive of CNV to first injection was a significant predictor (P=.015) of poorer treatment outcome, when controlling for age, sex, and baseline VA. Patients with a delay in treatment of 21 weeks or more compared to a delay of 7 weeks or less had an odds ratio of 2.62 (1.20, 5.68) for worsening vision after treatment. CONCLUSIONS: Patients experiencing a longer delay between their first symptoms of CNV and their first anti-VEGF treatment have a significantly lower chance of improving vision at 6 months following anti-VEGF therapy. It is critical that this information reach those at potential vision loss from AMD, in order that prompt treatment may be instituted, to maximize the benefits of anti-VEGF treatment. PMID- 22245458 TI - Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. AB - PURPOSE: To report 5-year treatment outcomes in the Tube Versus Trabeculectomy (TVT) Study. DESIGN: Multicenter randomized clinical trial. METHODS: SETTINGS: Seventeen clinical centers. STUDY POPULATION: Patients 18 to 85 years of age who had previous trabeculectomy and/or cataract extraction with intraocular lens implantation and uncontrolled glaucoma with intraocular pressure (IOP) >=18 mm Hg and <=40 mm Hg on maximum tolerated medical therapy. INTERVENTIONS: Tube shunt (350-mm(2) Baerveldt glaucoma implant) or trabeculectomy with mitomycin C ([MMC]; 0.4 mg/mL for 4 minutes). MAIN OUTCOME MEASURES: IOP, visual acuity, use of supplemental medical therapy, and failure (IOP >21 mm Hg or not reduced by 20%, IOP <=5 mm Hg, reoperation for glaucoma, or loss of light perception vision). RESULTS: A total of 212 eyes of 212 patients were enrolled, including 107 in the tube group and 105 in the trabeculectomy group. At 5 years, IOP (mean +/- SD) was 14.4 +/- 6.9 mm Hg in the tube group and 12.6 +/- 5.9 mm Hg in the trabeculectomy group (P = .12). The number of glaucoma medications (mean +/- SD) was 1.4 +/- 1.3 in the tube group and 1.2 +/- 1.5 in the trabeculectomy group (P = .23). The cumulative probability of failure during 5 years of follow-up was 29.8% in the tube group and 46.9% in the trabeculectomy group (P = .002; hazard ratio = 2.15; 95% confidence interval = 1.30 to 3.56). The rate of reoperation for glaucoma was 9% in the tube group and 29% in the trabeculectomy group (P = .025). CONCLUSIONS: Tube shunt surgery had a higher success rate compared to trabeculectomy with MMC during 5 years of follow-up in the TVT Study. Both procedures were associated with similar IOP reduction and use of supplemental medical therapy at 5 years. Additional glaucoma surgery was needed more frequently after trabeculectomy with MMC than tube shunt placement. PMID- 22245462 TI - Optimization of an implantable collamer lens sizing method using high-frequency ultrasound biomicroscopy. AB - PURPOSE: To develop and evaluate a new implantable collamer lens (ICL) sizing method that uses high-frequency ultrasound biomicroscopy (UBM). DESIGN: Interventional case series. METHODS: ICL were implanted in 47 eyes of 25 patients (8 male, 17 female, mean age 34.7+/-6.8 years). At 3 months after ICL surgery, the vault (distance between ICL and crystalline lens) was measured using anterior optical coherence tomography (OCT). Stepwise multiple regression analysis was performed in order to determine the optimal ICL size that will be expected to achieve a 0.5-mm vault, and the regression equation was calculated. Mean keratometric power, axial length, anterior chamber depth, sulcus-to-sulcus (STS) diameter, and distance between STS plane and crystalline lens were applied as candidates for explanatory variables. Subsequently, the equation was applied to a new group of patients (81 eyes of 43 patients, 20 male and 23 female, mean age 35.6+/-7.2 years) in order to decide the ICL size. Postoperative vault was evaluated at 3 months after surgery. Main outcome measures were mean postoperative vault and percentages of eyes that achieved moderate vault. RESULTS: The regression equation was determined using 3 explanatory variables: anterior chamber depth (ACD), STS diameter, and distance between STS plane and anterior crystalline lens surface (STSL). The mean vault error (postoperative vault-predicted vault) was -0.06+/-0.29 mm. Of the total number of eyes, 88.9% had a vault between 0.15 and 1.0 mm. None of the eyes had a low vault (<0.15 mm). Nine eyes (11.1%) had a high vault (>1.0 mm). CONCLUSION: A novel ICL sizing equation was developed and shown to be an effective method for calculation of the optimal ICL size in order to achieve an appropriate vault. PMID- 22245461 TI - Optical coherence tomography findings in autoimmune retinopathy. AB - PURPOSE: To report optical coherence tomography (OCT) features of patients with autoimmune retinopathy. DESIGN: Consecutive case series. METHOD: Eight patients who presented with unexplained loss of central vision, visual field defects, and/or photopsia were diagnosed with autoimmune retinopathy based on clinical features, electroretinogram (ERG) findings, and serum antiretinal antibody analysis. All patients underwent OCT testing of the macula and nerve fiber layer (NFL). RESULTS: Outer retinal abnormalities and/or decreased macular thickness on OCT were seen in all patients. Macular OCT showed reduced central macular and foveal thicknesses in 6 patients (mean thickness 143+/-30 MUm and 131+/-29 MUm respectively). In all but 1 patient, loss of the photoreceptor layer or disruption of the photoreceptor outer and inner segment junction was noted. Three patients showed only mild to moderate focal NFL loss. CONCLUSIONS: Retinal atrophy and reduced macular thickness on OCT are predominant features in patients with autoimmune retinopathy. OCT provides objective measures of retinal damage and may offer clues toward understanding the mechanism of visual dysfunction and the diagnosis of autoimmune retinopathy. PMID- 22245463 TI - The significance of cone outer segment tips as a prognostic factor in epiretinal membrane surgery. AB - PURPOSE: To evaluate the prognostic value of the cone outer segment tips (COST) and other features using spectral-domain optical coherence tomography (SD-OCT) in patients undergoing epiretinal membrane (ERM) surgery. DESIGN: Retrospective observational case series. METHODS: Fifty eyes of 49 patients that underwent vitrectomy for idiopathic ERM were studied. Best-corrected visual acuity (BCVA) and SD-OCT images were examined preoperatively and at 1 and 6 months postoperatively. The SD-OCT features evaluated included central foveal thickness (CFT) and the status and defect diameter of the external limiting membrane (ELM), the photoreceptor inner/outer segment (IS/OS) junction, and the COST line. The associations between SD-OCT parameters and BCVA were analyzed. RESULTS: There was no ELM disruption found, and thus the eyes were categorized into 3 groups: Group A, with a continuous IS/OS and COST line; Group B, with a continuous IS/OS but disrupted COST line; and Group C, with a disrupted IS/OS and COST line. At 6 months, Group A showed a significantly better BCVA than Group B (P<.005), and poorer BCVA was noted in Group C (P=.034). Defect diameters of IS/OS and COST line were also significantly correlated with BCVA postoperatively. The BCVA at 6 months was better in order of Group A, B, and C as assigned at baseline (P<.05) or 1 month (P<.001). There was no significant correlation between CFT and BCVA. CONCLUSIONS: The status of the COST line, in conjunction with the IS/OS junction, is a useful prognostic factor after ERM surgery. PMID- 22245466 TI - Purification and characterization of HSP-inducers from Eupatorium lindleyanum. AB - The expression of heat shock proteins (HSPs), particularly HSP70, provides resistance to stressors. We recently reported that ultraviolet (UV)-induced melanin production and skin damage were suppressed in transgenic mice expressing HSP70 and that an extract of Eupatorium lindleyanum induces the expression of HSP70 in cells. Here we report the purification of eupalinolide A and B (EA and EB) from E. lindleyanum, and describe their actions as HSP-inducers. EA and EB both induced the expression of HSP70 in cells at concentrations that did not significantly affect cell viability. Treatment of cells with EA or EB activated heat shock factor 1 (HSF1), while the artificial suppression of HSF1 expression diminished the EA- or EB-mediated induction of HSP70 expression. Furthermore, EB inhibited the interaction between HSF1 and HSP90, which is known to inhibit the activity of HSF1. These findings suggest that EA and EB induce the expression of HSP70 via the activation of HSF1 by inhibiting the interaction between HSF1 and HSP90. EA and EB both induced the expression of HSP70 synergistically with other stressors. Furthermore, pre-treatment of cells with EA or EB suppressed melanin production and stressor-induced apoptosis. These effects were suppressed by the artificial suppression of HSP70 expression. In vivo, the percutaneous administration of EB induced the expression of HSP70 and suppressed UVB radiation induced damage, inflammatory responses and melanin production in the skin. These results suggest that EA and EB could be beneficial for use in cosmetics and medicines as a consequence of their inhibitory action on UV-induced skin damage and melanin production. PMID- 22245467 TI - Medication adherence and fracture risk among patients on bisphosphonate therapy in a large United States health plan. AB - The association between bisphosphonate adherence in the first 12 months after therapy initiation and subsequent fracture risk was examined. Patients were identified from a large, commercially-insured population with integrated pharmacy and medical claims. Eligible patients were aged >=45 years, were new to osteoporosis therapy (no osteoporosis medication claims in prior year) with first (index) bisphosphonate claim between 1/1/2005 and 4/30/2008, and had continuous insurance coverage for >=12 months pre- and post-index. Patients with fracture claims <=12-months post-index were excluded. Adherence was assessed using the medication possession ratio (MPR) over 12-months post-index (i.e., sum of days' supply dispensed divided by 365 days). Patients with a MPR>0.8 were considered adherent. The follow-up period to assess incident fracture began at month 13. The analysis included 33,558 new bisphosphonate users with mean age (SD) 59.5 (9.3) years; 94.0% were female. Median MPR at 12 months was 0.61 for alendronate and risedronate; 0.58 for ibandronate. Proportionally more nonfracture patients (39.3%) had a MPR>0.8 compared with fracture patients (34.9%, p<0.001). In multivariate modeling of bisphosphonate users' experience, those with a MPR>0.8 had a 14% lower risk of subsequent fracture than those with MPR<0.5, after controlling for demographics, insurance type, select comorbidities, and other potential confounders (p=0.0459). In a large, commercially-insured population, suboptimal adherence with bisphosphonate treatment was associated with increased fracture risk even after controlling for potential confounders. PMID- 22245468 TI - Spectroscopic studies on the interaction between carbaryl and calf thymus DNA with the use of ethidium bromide as a fluorescence probe. AB - The interaction between carbaryl and calf thymus DNA (ctDNA) was investigated under simulated physiological conditions (Tris-HCl buffer of pH 7.4) using ethidium bromide (EB) dye as a probe by UV-vis absorption, fluorescence and circular dichroism (CD) spectroscopy, as well as DNA melting studies and viscosity measurements. It can be concluded that carbaryl molecules could intercalate into the base pairs of DNA as evidenced by hyperchromic effect of absorption spectra, decreases in iodide fluorescence quenching effect, induced CD spectral changes, and significant increases in melting temperature and relative viscosity of DNA. The binding constants and thermodynamic parameters of carbaryl with DNA were obtained by the fluorescence quenching method. Furthermore, a chemometrics approach, parallel factor analysis (PARAFAC), was applied to resolve the measured three-way synchronous fluorescence spectral data matrix of the competitive interaction between carbaryl and EB with DNA, and the results provided simultaneously the concentration profiles and corresponding pure spectra for three reaction components (carbaryl, EB and DNA-EB complex) of the kinetic system at equilibrium. This PARAFAC analysis demonstrated the intercalation of carbaryl to the DNA helix by substituting for EB in the DNA-EB complex. PMID- 22245469 TI - [Anti-neutrophil cytoplasmic antibodies: beyond vasculitis]. PMID- 22245470 TI - Comparison of haemocytic parameters among flat oyster Ostrea edulis stocks with different susceptibility to bonamiosis and the Pacific oyster Crassostrea gigas. AB - Farming of the flat oyster Ostrea edulis in Europe is severely constrained by the protozoan Bonamia ostreae. The introduction of the resistant species Crassostrea gigas has been a relief for the farmers, while the pilot programmes to select O. edulis strains resistant to bonamiosis performed in various countries can be seen as a promising strategy to minimise the effects of bonamiosis. However, the physiological bases of this differential susceptibility remain unknown. A search for an explanation of the intra and interspecific differences in oyster susceptibility to bonamiosis was accomplished by comparing some immune parameters among various O. edulis stocks and C. gigas. On December 2003, naive and Bonamia relatively resistant flat oysters from Ireland, Galician flat oysters and Pacific oysters C. gigas were deployed in a Galician area affected by bonamiosis; haemolymph samples were taken in February and May 2004. A new oyster deployment at the same place was carried out on June 2004 and haemolymph sampling was performed on April 2005. On November 2004, new sets of Irish flat oysters and C. gigas were deployed in Ireland and haemolymph sampling was performed in June 2005. Various haemocytic parameters were measured: total and differential haemocyte count, phagocytic ability, respiratory burst (superoxide anion [O(2)( )] and hydrogen peroxide [H(2)O(2)]) and nitric oxide [NO] production. The comparison of the parameters was carried out at 3 levels: (1) between O. edulis and C. gigas, (2) among O. edulis stocks with different susceptibility to bonamiosis, and (3) between Bonamia-infected and non infected O. edulis. In addition, haemocyte-B. ostreaein vitro encounters were performed to analyse interspecific differences in the haemocytic respiratory burst, using flow cytometry. Significant differences associated with total and differential haemocyte count, and respiratory burst between O. edulis and C. gigas were detected, which could be linked to differences in susceptibility to bonamiosis between both species. Additionally, significant changes in total and differential haemocyte count, and respiratory burst of O. edulis associated with B. ostreae infection were found. However, no consistent difference in any haemocyte parameter between the O. edulis stocks involved in the study was recorded. PMID- 22245471 TI - Susceptibility of two hymenopteran parasitoids of Agrilus planipennis (Coleoptera: Buprestidae) to the entomopathogenic fungus Beauveria bassiana (Ascomycota: Hypocreales). AB - Emerald ash borer (EAB), Agrilus planipennis Fairmaire, native to Asia, is killing ash trees (Fraxinus spp.) across 15 states and southeastern Canada. Integrated pest management using biological control is the only viable long-term approach for controlling the spread of EAB outside of host resistance. Three hymenopteran parasitoids, Spathius agrili Yang, Tetrastichus planipennisi Yang, and Oobius agrili Zhang and Huang were discovered attacking EAB in China and were approved for release in the United States in 2007. The objective of this study was to assess susceptibility of the larval parasitoid species S. agrili and T. planipennisi, relative to that of EAB, to Beauveria bassiana, an entomopathogenic fungus that infects and kills EAB adults when sprayed on ash bark or foliage. Adult EAB and parasitoids were exposed to B. bassiana inoculated ash twigs for 2 h and then monitored daily for death and signs of infection for up to 10 days. All EAB adults exposed to B. bassiana were fatally infected while mean survival for control EAB was 77%. Average survival in the treatment groups for T. planipennisi and S. agrili were 99% and 83%, respectively, indicating these parasitoids are relatively unaffected by exposure to B. bassiana. This research elucidates interactions between a fungal pathogen and two parasitoids of EAB, and provides data necessary to developing a successful multi-stage integrated management approach to control of EAB. PMID- 22245473 TI - Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches. AB - Nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection and prevalence in southern China and Southeast Asia. In addition to EBV, the development of NPC involves cumulative genetic and epigenetic changes influenced by predisposing genetic factors and environmental carcinogens. Over the past two decades, knowledge of genetic and epigenetic alterations of NPC has rapidly accumulated. Multiple chromosomal abnormalities (e.g. copy number changes on chromosomes 3p, 9p, 11q, 12p, and 14q), gene alterations (e.g. p16 deletion and LTBR amplification), and epigenetic changes (e.g. RASSF1A and TSLC1 methylation) have been identified by various genome-wide approaches, such as allelotyping, CGH, and microarray analysis. In this review, we will discuss the critical genetic events that contribute to the initiation and progression of NPC. Studies on the precancerous lesions and in vitro immortalized nasopharyngeal epithelial cell models provide important evidence for the involvement of genetic alterations and EBV infection in early development of this cancer. A hypothetical model describing the role of EBV latent infection and multiple genetic changes in NPC tumorigenesis is proposed. PMID- 22245474 TI - Multiple ST-segment elevations in anterior and inferior leads: an unusual electrocardiographic manifestation in acute pulmonary embolism. PMID- 22245472 TI - Monoclonal antibodies for the treatment of cancer. AB - Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism of action combined with target specificity underlies the capacity of antibodies to elicit anti-tumor responses while minimizing the frequency and magnitude of adverse events. This review will focus on mechanisms of action, clinical applications and putative mechanisms of resistance to monoclonal antibody therapy in the context of cancer. PMID- 22245475 TI - Pathophysiology of biventricular dysfunction during hemodialysis: emerging concepts. PMID- 22245476 TI - Myocardial infarction due to coronary thrombus formation in a postmenopausal woman with breast cancer after initiation of letrozol therapy. PMID- 22245477 TI - Interaction of smoking and metabolic syndrome on cardiovascular risk in a Chinese cohort. AB - BACKGROUND: The high prevalence of smoking and metabolic syndrome (MS) and increased incidence of cardiovascular disease (CVD) in China indicates that there may be an interaction between smoking and MS on cardiovascular risk. Therefore, we aimed to examine the independent and combined effects of smoking and MS on risk of CVD in a Chinese cohort. METHODS: We analyzed data from a population based prospective cohort of 3598 participants aged 35-74 years from Jiangsu China who were free of diabetes and CVD at enrollment and were followed for cardiovascular events (including myocardial infarction, ischemic stroke, hemorrhagic stroke, and cardiovascular mortality) until 31 August 2008. RESULTS: During 8 years (median 6.3 years) of follow-up, 82 participants developed CVD. After adjusting for age, sex, body mass index, alcohol consumption, family history of cardiovascular disease and MS, smoking significantly increased cardiovascular risk in a dose-response manner. After further adjustment for smoking status, the hazard ratio of CVD for participants with MS was 2.49 (95% confidence interval 1.59-3.90) compared with those without the syndrome. There was a statistically significant additive interaction between current smoking and MS on cardiovascular risk. The risk of CVD for current smokers with MS was 1.81 times as high as the sum of risks in participants with a single condition alone. CONCLUSIONS: Both cigarette smoking and MS are strong risk factors of CVD in the Chinese population. Moreover, this study further demonstrates an additive interaction of current smoking and MS on cardiovascular risk. PMID- 22245479 TI - Statins and coronary microvascular dysfunction in patients with acute ST segment elevation myocardial infarction. PMID- 22245478 TI - Effects of mineralocorticoid receptor antagonist spironolactone on cardiac sympathetic nerve activity and prognosis in patients with chronic heart failure. AB - BACKGROUND: Aldosterone prevents norepinephrine uptake and promotes structural remodeling of the heart. Spironolactone is well known to have an anti aldosteronergic effect, and this agent could improve cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF). On the other hand, we previously reported that the delta washout rate (WR) determined from serial (123)I-MIBG scintigraphic studies is the best currently available prognostic value in patients with CHF. METHODS: In total 208 patients with CHF (left ventricular ejection fraction [LVEF] <45%), but no cardiac events for at least 5 months, were identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and after 6 months of treatment. The patients were retrospectively divided into a spironolactone (n=82) and a non-spironolactone (n=126) group. RESULTS: The extents of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the spironolactone group were significantly better than those in the non spironolactone group. Of the 208 patients, 56 experienced fatal cardiac events during the study. The mean follow-up period was 4.45+/-1.82 years. On Kaplan Meier analysis, the rate freedom from cardiac death was 81.7% (67/82) in the spironolactone group and 67.5% (85/126) in the non-spironolactone group (P<0.05). Moreover, stepwise multivariate analyses showed spironolactone therapy to have the most independent and significant negative relationship with delta-WR, during the period from hospital discharge until 6 months after starting treatment, in patients with CHF (P<0.001). CONCLUSIONS: Spironolactone treatment improves CSNA and prevents LV remodeling in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of fatal cardiac events in CHF patients. PMID- 22245480 TI - Interaction between uric acid and endothelial dysfunction predicts new onset of diabetes in hypertensive patients. AB - BACKGROUND: Both uric acid and endothelial dysfunction are associated with new occurrence of type-2 diabetes but, at this moment, there is no evidence about a possible interaction between them. We tested, in untreated hypertensive patients, without clinical evidence of vascular damage, the hypothesis that serum uric acid and endothelial dysfunction may interact in predicting new diabetes. METHODS: In 500 uncomplicated hypertensive non diabetic (ADA criteria) patients we evaluated endothelial function, by strain-gauge plethysmography, and uric acid. RESULTS: During the follow-up (median 87.1 months), there were 54 new cases of diabetes (1.8%/year). On univariate analysis, incident diabetes was inversely related with ACh-stimulated FBF (HR=0.65, 95%CI=0.52-0.82; P<0.001) and directly with serum CRP (HR=1.22, 95%CI=1.09-1.37; P<0.001), HOMA-index (HR=1.20, 95%CI=1.05-1.37; P=0.007), fasting insulin (HR=1.05, 95%CI=1.01-1.09; P=0.006) and age (HR=1.03, 95%CI=1.00-1.05; P=0.014). At multiple regression analysis, the interaction between ACh-stimulated FBF and uric acid resulted statistically significant. Similar results were observed for the interaction between FBF and CRP. CONCLUSIONS: Our data clearly demonstrate that the coexistence of both hyperuricemia and reduced endothelium-dependent vasodilation increases the risk to develop new diabetes in hypertensive patients. In addition, mild-inflammation seems to be the mediator of the interaction between endothelial dysfunction and uric acid. PMID- 22245481 TI - Income poverty and cardiovascular disease. PMID- 22245482 TI - Implantable pneumatically actuated microsystem for renal pressure-mediated transfection in mice. AB - In vivo transfection is an important technique used in biological research and drug therapy development. Previously, we developed a renal pressure-mediated transfection method performed by pressing a kidney after an intravenous injection of naked nucleic acids. Although this is a useful method because of its safety and wide range of applications, an innovative approach for performing this method without repeatedly cutting open the abdomen is required. In this study, we developed an implantable microsystem fabricated by Micro-Electro-Mechanical Systems (MEMS) technologies for renal pressure-mediated transfection. The system consists of a polydimethylsiloxane pneumatic balloon actuator (PBA) used as an actuator to press the target kidney. The PBA of the implanted microsystem can be actuated without opening the abdomen by applying air pressure from outside the body to the pressure-supplying port via a needle. We successfully performed renal pressure-mediated transfection using the newly developed system when the implanted system was activated at 60kPa for 10s. This is the first report of an implantable MEMS-based microsystem that demonstrates in vivo transfection to a kidney using naked plasmid DNA. PMID- 22245483 TI - Injection Molding and its application to drug delivery. AB - Injection Molding (IM) consists in the injection, under high pressure conditions, of heat-induced softened materials into a mold cavity where they are shaped. The advantages the technique may offer in the development of drug products concern both production costs (no need for water or other solvents, continuous manufacturing, scalability, patentability) and technological/biopharmaceutical characteristics of the molded items (versatility of the design and composition, possibility of obtaining solid molecular dispersions/solutions of the active ingredient). In this article, process steps and formulation aspects relevant to IM are discussed, with emphasis on the issues and advantages connected with the transfer of this technique from the plastics industry to the production of conventional and controlled-release dosage forms. Moreover, its pharmaceutical applications thus far proposed in the primary literature, intended as either alternative manufacturing strategies for existing products or innovative systems with improved design and performance characteristics, are critically reviewed. PMID- 22245485 TI - [Hemolytic uremic syndrome with severe neurological involvement: how should it be managed?]. AB - INTRODUCTION: The management of diarrhea-associated hemolytic and uremic syndrome (D(+) HUS) with severe acute neurological involvement continues to be debated. We report on 2 cases and discuss the treatment. CASE REPORT 1: A 2.5-year-old girl presented with generalized seizures during gastroenteritis. Blood tests revealed features of HUS and a pyramidal syndrome was found on physical examination. Brain MRI, 24h after admission, showed lesions in the periventricular and subcortical area. She was started on peritoneal dialysis (PD) and daily plasma exchanges (PE) for 10 days. Her neurological condition improved quickly as well as the findings of the second brain MRI performed after PE. One year later she had no apparent neurological or renal sequelae. CASE REPORT 2: A 2.5-year-old boy presented with generalized seizures during gastroenteritis for 3 days, leading to a diagnosis of HUS. He also had a severe pyramidal syndrome with spastic tetraparesis and aphasia. Brain MRI, 48 h after admission, revealed severe bilateral and symmetric lesions involving the thalami, internal and external capsules, lenticular nuclei, and brainstem. He was started on PD and daily PE for 10 days. Brain MRI performed after PE was unchanged. Clinically, his neurological condition improved slowly with regression of spastic tetraparesis and progressive recovery of motor skills. Nine months later, his renal function is normal but he is still having intensive physiotherapy. DISCUSSION: Both children have received similar management including 10 PEs started within 48 h after the diagnosis of D(+) HUS with severe neurological involvement, but their neurological outcome appeared to be significantly different. There is no clear proof in the literature concerning the effects of PE in such patients, even when performed very early. Eculizumab, an antibody that inhibits complement factor 5a and the formation of the membrane attack complex, has recently been used in such cases and seems to provide a more specific therapeutic action. Control studies are needed to specify its use in this disease. PMID- 22245486 TI - [The healthcare project of the child with polyhandicap (multiple disabilities)]. PMID- 22245487 TI - Salmeterol improves fluid clearance from alveolar-capillary membrane in COPD patients: a pilot study. AB - The cardiovascular component associated with chronic obstructive pulmonary disease (COPD) plays a major role in disease prognosis, accounting for 25% of the deaths. Experimental and initial clinical data suggest that beta-adrenergic agonists accelerate fluid clearance from the alveolar airspace, with potentially positive effects on cardiogenic and noncardiogenic pulmonary oedema. This pilot study investigated the acute effects of the long-acting beta-2 agonist, salmeterol, on alveolar fluid clearance after rapid saline intravenous infusion by evaluating diffusive and mechanical lung properties. Ten COPD and 10 healthy subjects were treated with salmeterol or placebo 4 h before the patient's mechanical and diffusive lung properties were measured during four non consecutive days, just before and after a rapid saline infusion, or during a similar period without an infusion. RESULTS: In both COPD and healthy subjects, rapid saline infusion with placebo or salmeterol premedication lead to a significant decrease in diffusion capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1). Nonetheless, salmeterol pretreatment lead to a significantly reduced gas exchange impairment caused by saline infusion (-64% of DLCO reduction compared with placebo), whereas it did not affect changes in FEV1. In the control setting with no infusion, we found no significant change in either DLCO or mechanical properties of the lung. CONCLUSIONS: Salmeterol appears to provide a protective effect, not related to bronchodilation, against an acute alveolar fluid clearance challenge secondary to lung fluid overload in COPD patients. PMID- 22245488 TI - Methacholine delays pulmonary absorption of inhaled beta(2)-agonists due to competition for organic cation/carnitine transporters. AB - BACKGROUND: The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting beta(2)-agonist GW597901 with salbutamol and to determine the influence of an induced bronchoconstriction on the pharmacokinetics of the compounds using a human lung reperfusion model. METHODS: In an initial study with six lung perfusions the pharmacokinetic properties of the beta(2)-agonists were determined. We then investigated the influence of an induced bronchoconstriction on the pulmonary absorption in six lung lobes for each drug. Therefore, methacholine (MCh) challenge agent was nebulised prior to administration of the beta(2)-agonists. RESULTS: As expected, the extent of pulmonary absorption of salbutamol into the perfusate was more pronounced than for the more lipophilic GW597901. Although the observed differences were not statistically significant they were further supported by analysis of tissue concentrations. In contrast, we observed a statistically significant influence of the bronchoprovocation with MCh on the pulmonary absorption of both beta(2) agonists, but this effect was not limited to a successfully induced bronchoconstriction. A prominent decline of salbutamol distribution into perfusion fluid was also observed when the organic cation transporter substrate carnitine was nebulised prior to the bronchodilator. CONCLUSIONS: Nebulised methacholine had a significant influence on the pharmacokinetics of bronchodilators. Since we observed this effect independently of a successfully induced bronchoconstriction and also after nebulisation of carnitine we suggest a significant delay of pulmonary absorption of inhaled salbutamol and GW597901 due to competition for a cation/carnitine drug transporter, most likely OCTN2. PMID- 22245489 TI - Heterophil/lymphocyte ratios predict the magnitude of humoral immune response to a novel antigen in great tits (Parus major). AB - Animals display remarkable individual variation in their capacity to mount immune responses against novel antigens. According to the life-history theory, this variation is caused by the costs of immune responses to the hosts. We studied one of such potential costs, depletion of somatic resources in wintering wild-caught captive passerines, the great tits (Parus major) by immune challenging the birds with a novel antigen, killed Brucella abortus (BA) suspension. We found that despite mild temperature conditions in captivity and ad libitum availability of food, immune challenge depleted somatic resources (as indicated by a body mass loss) and elevated relative proportion of heterophils to lymphocytes (H/L ratio) in the peripheral blood of birds. However, body mass loss did not covary with an increase in H/L ratios between two sampling events, which indicates that these two markers of health state describe different aspects of individual physiological condition. Antibody titres were not associated with the extent of body mass loss during the development of immune response, which shows that the somatic cost of immune response was not proportional to the amount of antibody produced. Birds with high pre-immunisation H/L ratios mounted weaker antibody response, which is indicative of stress-induced suppression of humoral immune response and is consistent with the concept of an antagonistic cross-regulation between different components of the immune system. The latter finding suggests a novel diagnostic value of H/L ratios, which reinforces the utility of this simple haematological index for prediction of the outcomes of complicated immune processes. PMID- 22245490 TI - Effects of low salinity media on growth, condition, and gill ion transporter expression in juvenile Gulf killifish, Fundulus grandis. AB - The Gulf killifish, Fundulus grandis, is a euryhaline teleost which has important ecological roles in the brackish-water marshes of its native range as well as commercial value as live bait for saltwater anglers. Effects of osmoregulation on growth, survival, and body condition at 0.5, 5.0, 8.0 and 12.00/00 salinity were studied in F. grandis juveniles during a 12-week trial. Relative expression of genes encoding the ion transport proteins Na(+)/K(+)-ATPase (NKA), Na(+)/K(+)/2Cl(-) cotransporter(NKCC1), and cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel was analyzed. At 0.50/00, F. grandis showed depressed growth, body condition, and survival relative to higher salinities. NKA relative expression was elevated at 7 days post-transfer but decreased at later time points in fish held at 0.50/00 while other salinities produced no such increase. NKCC1, the isoform associated with expulsion of ions in saltwater, was downregulated from week 1 to week 3 at 0.50/00 while CFTR relative expression produced no significant results across time or salinity. Our results suggest that Gulf killifish have physiological difficulties with osmoregulation at a salinity of 0.50/00 and that this leads to reduced growth performance and survival while salinities in the 5.0-12.00/00 are adequate for normal function. PMID- 22245491 TI - Lentiviral vectors carrying enhancer elements of Hb9 promoter drive selective transgene expression in mouse spinal cord motor neurons. AB - Recombinant lentiviral vectors (rLVs) have emerged as versatile tools for gene delivery applications due to a number of favorable features, such as the possibility to maintain long-term transgene expression, the flexibility in the design of the expression cassettes and recent improvements in their biosafety profile. Since rLVs are able to infect multiple cell types including post-mitotic cells such as neurons and skeletal muscle cells, several studies have been exploring their application for the study and cure of neurodegenerative diseases. In particular, the introduction of rLVs carrying cell-type specific promoters could restrict the transgene expression either to neuronal or glial cells, thus helping to better dissect in vivo the role played by these cell populations in several neurodegenerative processes. In this study we developed rLVs carrying motor neuron specific regulatory sequences derived from the promoter of homeobox gene Hb9, and demonstrated that these constructs can represent a suitable platform for selective gene-targeting of murine spinal cord motor neurons, in vivo. This tool could be instrumental in the dissection of the molecular mechanisms involved in the selective degeneration of motor neurons occurring in Motor Neuron Diseases. PMID- 22245492 TI - Propagation of the prion phenomenon: beyond the seeding principle. AB - The deposition of misfolded proteins is the hallmark of the late-onset, rapidly progressive and devastating neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These diseases are caused by a gain of toxic properties associated with the propensity of otherwise soluble proteins to misfold. What governs the deposition of the disease-causing proteins in aged neurons is unclear, but recent evidence suggests that once misfolded, the diverse proteins associated with the neurodegenerative diseases can induce aggregation of their soluble counterpart, thereby sharing one of the defining properties of prions. In addition to the seeded polymerization, prions have the ability to replicate their aberrant conformation indefinitely and are transmissible. Are these properties also shared by diverse misfolded proteins? PMID- 22245493 TI - [Study of hospitalizations for pneumococcal pneumoniae in Centre region, 2004 2008]. AB - BACKGROUND: Streptococcus pneumoniae is a significant cause of morbidity mortality: leading agent of community-acquired pneumonia and the first cause of death due to infectious diseases in France. Vaccines are available for children and adults, avoiding serious complications. We studied hospitalizations for pneumococcal pneumonia in Centre region in 2004-2008, using the 2004-2008 national hospital discharges database and assessed vaccine coverage of a sample population. METHODS: Hospital discharges with diagnosis of pneumococcal pneumonia were selected, using the corresponding code (J13) in the French Diagnosis-Related Group coding system. We analysed hospitalization and patient data using linkage of the inpatient stays with their anonymous identification number. We analysed hospitalization and patient data: number and length of stay/patient, co-morbid factors and pneumococcal immunisation status. RESULTS: One thousand five hundred and forty-one hospitalisations were found for pneumococcal pneumonia in Centre Region, in 2004-2008. The time pattern showed an annual increase in hospital stays: winter hospitalisations were most frequent. The median age was 58 years, range: 2 months-106 years. The sex ratio M/F of the 1417 distinct inpatients was 1.43. The hospital impact was substantial, with prolonged length of stay (mean=9.9 days), frequent stays in intensive care unit (20%) and high death rate (6%). The vaccine coverage of the population with pneumococcal pneumonia was only 23%. CONCLUSION: Using the national hospital discharges database, this study presents a snapshot of pneumococcal pneumonia in one French region and demonstrates the local major clinical impact, as found in France. It shows that the hospital discharge database is a potential tool for epidemiology despite its possible bias. This type of study could be useful for organizing a regional vaccination campaing due to the better knowledge of the disease. PMID- 22245495 TI - Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. AB - Fibroblasts are responsible for producing the majority of collagen and other extracellular matrix (ECM) proteins in tissues. In the injured tissue, transforming growth factor-beta (TGF-beta)-activated fibroblasts or differentiated myofibroblasts synthesize excessive ECM proteins and play a pivotal role in the pathogenesis of fibrosis in heart, kidney and other organs. Recent studies suggest that fibroblast-like cells, derived from endothelial cells by endothelial-to-mesenchymal transition (EndMT), contribute to the pathogenesis of cardiac fibrosis. The molecular basis of EndMT, however, is poorly understood. Here, we investigated the molecular basis of EndMT in mouse cardiac endothelial cells (MCECs) in response to TGF-beta2. MCECs exposed to TGF-beta2 underwent EndMT as evidenced by morphologic changes, lack of acetylated-low density lipoprotein (Ac-LDL) uptake, and the presence of alpha-smooth muscle actin (alpha SMA) staining. Treatment with SB431542, a small molecule inhibitor of TGF-beta receptor I (TbetaRI) kinase, but not PD98059, a MEK inhibitor, completely blocked TGF-beta2-induced EndMT. The transcript and protein levels of alpha-SMA, Snail and beta-catenin as well as acetyltransferase p300 (ATp300) were elevated in EndMT derived fibroblast-like cells. Importantly, microRNA (miRNA) array data revealed that the expression levels of specific miRNAs, known to be dysregulated in different cardiovascular diseases, were altered during EndMT. The protein level of cellular p53, a bonafide target of miR-125b, was downregulated in EndMT derived fibroblast-like cells. Here, we report for the first time, the differential expression of miRNAs during cardiac EndMT. These results collectively suggest that TbetaRI serine-threonine kinase-induced TGF-beta signaling and microRNAs, the epigenetic regulator of gene expression at the posttranscriptional level, are involved in EndMT and promote profibrotic signaling in EndMT-derived fibroblast-like cells. Pharmacologic agents that restrict the progression of cardiac EndMT, a phenomenon that is found in adults only in the pathological conditions, in targeting specific miRNA may be helpful in preventing and treating cardiac fibrosis. PMID- 22245496 TI - RhoBTB3 interacts with the 5-HT7a receptor and inhibits its proteasomal degradation. AB - The 5-hydroxytryptamine (5-HT)7 receptor is the most recently identified serotonin receptor and is involved in a wide variety of central nervous system (CNS) functions, namely circadian rhythm, REM sleep, depression, thermoregulation, obsessive-compulsive disorder (OCD), anxiety, schizophrenia, epilepsy, nociception, migraine, sensation-seeking behavior, impulsivity, learning and memory. These numerous (patho)physiological processes of the CNS, in which the 5-HT7 receptor is involved, most likely reflect a diverse set of signaling pathways arising from this receptor. In order to reveal new interaction partners and possibly new signaling and/or trafficking pathways, we performed a yeast two-hybrid screening, using the C-terminal tail of the 5-HT7a receptor as bait and an adult-human brain cDNA library as prey. In this way we identified RhoBTB3 as a new interaction partner of the 5-HT7a receptor. By means of co immunoprecipitation we were able to confirm the interaction between full length 5 HT7a receptor and RhoBTB3 in HEK293T cells. Subsequent domain mapping of this interaction revealed that not only the C-terminal tail, but also the third intracellular loop of the 5-HT7a receptor is involved. In addition, immunofluorescence microscopy showed clear co-localization between the 5-HT7a receptor and RhoBTB3 at the plasma membrane and in the endoplasmic reticulum. Despite the fact that RhoBTB3 has been shown to interact with Cul3, which in turn interacts with the E3 ubiquitin ligase, Roc1, we show here that RhoBTB3 neither recruits Cul3/Roc1 to the 5-HT7a receptor nor does it mediate ubiquitination of this receptor. Instead, we demonstrate that RhoBTB3 strongly inhibits proteasomal degradation of the 5-HT7a receptor. PMID- 22245497 TI - Antimicrobial susceptibility of Streptococcus pneumoniae isolates from vaccinated and non-vaccinated patients with a clinically confirmed diagnosis of community acquired pneumonia in Belgium. AB - We assessed the in vitro susceptibility of Streptococcus pneumoniae isolates from patients with confirmed community-acquired pneumonia (CAP) to beta-lactams, macrolides and fluoroquinolones and the association of non-susceptibility and resistance with serotypes/serogroups (STs/SGs), patient's risk factors and vaccination status. Samples (blood or lower respiratory tract) were obtained in 2007-2009 from 249 patients (from seven hospitals in Belgium) with a clinical and radiological diagnosis of CAP [median age 61 years (11.6% aged <5 years); 85% without previous antibiotic therapy; 86% adults with level II Niederman's severity score]. MIC determination (EUCAST breakpoints) showed for: (i) amoxicillin, 6% non-susceptible; cefuroxime (oral), 6.8% resistant; (ii) macrolides: 24.9% erythromycin-resistant [93.5% erm(B)-positive] but 98.4% telithromycin-susceptible; and (iii) levofloxacin and moxifloxacin, all susceptible. Amongst SGs: ST14, all resistant to macrolides and most intermediate to beta-lactams; SG19 (>94% ST19A), 73.5% resistant to macrolides and 18-21% intermediate to beta-lactams; and SG6, 33% resistant to clarithromycin. Apparent vaccine failures: 3/17 for 7-valent vaccine (children; ST6B, 23F); 16/29 for 23 valent vaccine (adults ST3, 7F, 12F, 14, 19A, 22F, 23F, 33F). Isolates from nursing home residents, hospitalised patients and patients with non-respiratory co-morbidities showed increased MICs for amoxicillin, all beta-lactams, and beta lactams and macrolides, respectively. Regarding antibiotic susceptibilities: (i) amoxicillin is still useful for empirical therapy but with a high daily dose; (ii) cefuroxime axetil and macrolides (but not telithromycin) are inappropriate for empirical therapy; and (iii) moxifloxacin and levofloxacin are the next 'best empirical choice' (no resistant isolates) but levofloxacin will require 500 mg twice-daily dosing for effective coverage. PMID- 22245498 TI - Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes. AB - Metabotropic glutamate receptors (mGluRs) were previously shown to modulate several essential functions in glial cells, including cell proliferation, glutamate uptake, neurotrophic support, and inflammatory responses. As these receptors are regularly proposed as promising targets for the treatment of a wide range of neurological disorders, we herein examined the reciprocal modulation of glial mGluRs by inflammation. Such regulation of mGluRs was also studied in cultures from an experimental model of amyotrophic lateral sclerosis (ALS). Indeed, ALS is characterized by increased neuroinflammation, and glial cell cultures derived from the animal model (rat expressing hSOD1(G93A)) show enhanced glial reactivity. Within 72 h, the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) induced an increase in mGluR3 and a decrease in mGluR5 gene expression. A similar regulation of these receptors was observed in microglia 48 h after an initial 4-h exposure to lipopolysaccharide. In hSOD1(G93A)-derived glial cultures, the gene up-regulation of mGluR3 (but not the gene down-regulation of mGluR5) was found to be enhanced in both astrocytes and microglia. Together, these results indicate that an inflammatory environment triggers an opposite regulation in the gene expression of the two predominant mGluR subtypes found in glial cells, and that these regulations were particularly robust in hSOD1(G93A) glial cultures. As neuroinflammation commonly occurs in several nervous diseases, its influence on mGluR expression should be taken into account when considering these receptors as future drug targets. PMID- 22245500 TI - Single cell analysis of voltage-gated potassium channels that determines neuronal types of rat hypothalamic paraventricular nucleus neurons. AB - The hypothalamic paraventricular nucleus (PVN), a site for the integration of both the neuroendocrine and autonomic systems, has heterogeneous cell composition. These neurons are classified into type I and type II neurons based on their electrophysiological properties. In the present study, we investigated the molecular identification of voltage-gated K+ (Kv) channels, which determines a distinctive characteristic of type I PVN neurons, by means of single-cell reverse transcription-polymerase chain reaction (RT-PCR) along with slice patch clamp recordings. In order to determine the mRNA expression profiles, firstly, the PVN neurons of male rats were classified into type I and type II neurons, and then, single-cell RT-PCR and single-cell real-time RT-PCR analysis were performed using the identical cell. The single-cell RT-PCR analysis revealed that Kv1.2, Kv1.3, Kv1.4, Kv4.1, Kv4.2, and Kv4.3 were expressed both in type I and in type II neurons, and several Kv channels were co-expressed in a single PVN neuron. However, we found that the expression densities of Kv4.2 and Kv4.3 were significantly higher in type I neurons than in type II neurons. Taken together, several Kv channels encoding A-type K+ currents are present both in type I and in type II neurons, and among those, Kv4.2 and Kv4.3 are the major Kv subunits responsible for determining the distinct electrophysiological properties. Thus these 2 Kv subunits may play important roles in determining PVN cell types and regulating PVN neuronal excitability. This study further provides key molecular mechanisms for differentiating type I and type II PVN neurons. PMID- 22245499 TI - Response of limbic neurotensin systems to methamphetamine self-administration. AB - Methamphetamine (METH) abuse is personally and socially devastating. Although effects of METH on dopamine (DA) systems likely contribute to its highly addictive nature, no medications are approved to treat METH dependence. Thus, we and others have studied the METH-induced responses of neurotensin (NT) systems. NT is associated with inhibitory feedback action on DA projections, and NT levels are elevated in both the nucleus accumbens and dorsal striatum after noncontingent treatment with high doses of METH. In the present study, we used a METH self-administration (SA) model (linked to lever pressing) to demonstrate that substitution of an NT agonist for METH, while not significantly affecting motor activity, dramatically reduced lever pressing but was not self-administered per se. We also found that nucleus accumbens NT levels were elevated via a D1 mechanism after five sessions in rats self-administering METH (SAM), with a lesser effect in corresponding yoked rats. Extended (15 daily sessions) exposure to METH SA manifested similar NT responses; however, more detailed analyses revealed (i) 15 days of METH SA significantly elevated NT levels in the nucleus accumbens shell and dorsal striatum, but not the nucleus accumbens core, with a lesser effect in the corresponding yoked METH rats; (ii) the elevation of NT in both the nucleus accumbens shell and dorsal striatum significantly correlated with the total amount of METH received in the self-administering, but not the corresponding yoked METH rats; and (iii) an NT agonist blocked, but an NT antagonist did not alter, lever-pressing behavior on day 15 in SAM rats. After 5 days in SAM animals, NT levels were also elevated in the ventral tegmental area, but not frontal cortex of rats self-administering METH. PMID- 22245501 TI - Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance. AB - The nucleus accumbens shell (NAcS) has been implicated in controlling stress responses through corticotropin-releasing factor (CRF). In addition to studies indicating that CRF in the NAcS increases appetitive motivation, there is indirect evidence suggesting that NAcS CRF may also cause aversive responses and that these behaviors may be mediated through local dopamine (DA) and acetylcholine (ACh) systems. To provide a direct test of this hypothesis, we used male Sprague-Dawley rats with implanted cannulas aimed at the NAcS. Experiment 1 showed local CRF injection (10 or 50 ng/side) to increase immobility in the forced swim test and a CRF antagonist D-Phe-CRF ((12-41)) to attenuate this depressive-like behavior. In Experiment 2, injection of CRF (250 ng/side) also decreased the rats' preference for sucrose, while in Experiment 3, CRF (50 or 250 ng/side) induced anxiety-like behaviors in an elevated plus maze and open field. These same doses of CRF in Experiment 4 failed to alter the rats' locomotor activity, indicating that these behavioral changes were not caused by deficits in activity. In Experiment 5, results from in vivo microdialysis revealed that CRF in the NAcS markedly increased local extracellular ACh, while also producing a small increase in DA. These results show that NAcS CRF can generate a variety of aversive behaviors, including swim depression, anhedonia, and anxiety, in addition to approach behavior. They suggest that these behaviors may occur, in part, through enhanced activation of ACh and DA in the NAcS, respectively, supporting a role for this brain area in mediating the dual effects of stress. PMID- 22245502 TI - Naloxone in ultralow concentration restores endomorphin-1-evoked Ca2+ signaling in lipopolysaccharide pretreated astrocytes. AB - Long-term pain is a disabling condition that affects thousands of people. Pain may be sustained for a long time even after the physiological trigger has resolved. Possible mechanisms for this phenomenon include low-grade inflammation in the CNS. Astrocytes respond to inflammatory stimuli and may play an important role as modulators of the inflammatory response in the nervous system. This study aimed first to assess how astrocytes in a primary culture behave when exposed to the endogenous MU-opioid receptor agonist endomorphin-1 (EM-1), in a concentration-dependent manner, concerning intracellular Ca2+ responses. EM-1 stimulated the MU-opioid receptor from 10-15 M up to 10-4 M with increasing intensity, usually reflected as one peak at low concentrations and two peaks at higher concentrations. Naloxone, pertussis toxin (PTX), or the MU-opioid receptor antagonists CTOP did not totally block the EM-1-evoked Ca2+ responses. However, a combination of ultralow concentration naloxone (10-12 M) and PTX (100 ng/ml) totally blocked the EM-1-evoked Ca2+ responses. This suggests that ultralow (picomolar) concentrations of naloxone should block the MU-opioid receptor coupled G(s) protein, and that PTX should block the MU-opioid receptor coupled G(i/o) protein. The second aim was to investigate exposure of astrocytes with the inflammatory agent lipopolysaccharide (LPS). After 4 h of LPS incubation, the EM 1-evoked Ca2+ transients were attenuated, and after 24 h of LPS incubation, the EM-1-evoked Ca2+ transients were oscillated. To restore the EM-1-evoked Ca2+ transients, naloxone was assessed as a proposed anti-inflammatory substance. In ultralow picomolar concentration, naloxone demonstrated the ability to restore the Ca2+ transients. PMID- 22245504 TI - Hydrophobic cavity in C-terminus is essential for hTNF-alpha trimer conformation. AB - A variety of tumour necrosis factor alpha (TNF-alpha) derivatives have been bioengineered to improve antitumour activity and reduce toxicity. The expression of TNF-alpha in Escherichia coli usually yields a mixture of homotrimers and monomers; however, only the trimer shows antitumour activity. TNF-alphaD10, a bioengineered hTNF-alpha derivative, demonstrated 10-fold higher cytotoxicity against tumour cells compared to hTNF-alpha, but the trimer to monomer ratio was 58:42. In the present study, we investigated the structural differences between the trimer and the monomer of TNF-alphaD10. We found that the chemical shifts of the C-terminal Trp(114) in the trimer were significantly different from those in the monomer and that the replacement of Trp(114) with different amino acids remarkably reduced the trimer production. Further analysis of the publicly available X-ray crystallographic data for trimeric and monomeric hTNF-alpha revealed that the conformation of the U-shaped region formed by the fragment Cys(101)-Trp(114) was different between the two forms: a hydrophilic cavity in the monomer and a hydrophobic cavity in the trimer. These findings suggested the potential approaches of molecular and structural modification for future improvement of hTNF-alpha trimer production. PMID- 22245505 TI - Type 2 diabetes mellitus and chronic hepatitis C: which is worse? Results of a long-term retrospective cohort study. AB - BACKGROUND: The long-term outcome in patients with chronic hepatitis C and type 2 diabetes mellitus treated with interferon and ribavirin is unclear. We compared incidence of liver-related events and mortality rates between hepatitis C virus positive patients with or without diabetes mellitus, and the incidence of diabetes-related events between diabetic patients with and without hepatitis C. METHODS: Retrospective study of 309 patients with chronic hepatitis C. Incidence of liver-related events, diabetes-related events and mortality rates were assessed over a mean follow-up of 11.02+/-4.9 years. RESULTS: 50 (16%) chronic hepatitis C patients had diabetes mellitus. Diabetics showed a higher number of diabetes- and liver-related events than non-diabetics (10% vs 1.5%, p=0.006; 18% vs 5.7%, p=0.007, respectively) with a mortality of 14% vs 1.5% (p=0.0003). Baseline cirrhosis (p=0.002) and non-sustained virological response (p=0.01) were independent risk factors for liver events; diabetes mellitus (p=0.01) and hypertension (p=0.0017) were independent factors for diabetes-related events. CONCLUSIONS: In patients with chronic hepatitis C, comorbidity with diabetes mellitus was associated with a higher mortality rate and incidence of liver/diabetes-related events. Independent risk factors for liver-related events were the non-response to antiviral therapy and cirrhosis at baseline. PMID- 22245503 TI - Non-homogeneous stereological properties of the rat hippocampus from high resolution 3D serial reconstruction of thin histological sections. AB - Integrating hippocampal anatomy from neuronal dendrites to whole system may help elucidate its relation to function. Toward this aim, we digitally traced the cytoarchitectonic boundaries of the dentate gyrus (DG) and areas CA3/CA1 throughout their entire longitudinal extent from high-resolution images of thin cryostatic sections of adult rat brain. The 3D computational reconstruction identified all isotropic 16 MUm voxels with appropriate subregions and layers (http://krasnow1.gmu.edu/cn3/hippocampus3d). Overall, DG, CA3, and CA1 occupied comparable volumes (15.3, 12.2, and 18.8 mm(3), respectively), but displayed substantial rostrocaudal volumetric gradients: CA1 made up more than half of the posterior hippocampus, whereas CA3 and DG were more prominent in the anterior regions. The CA3/CA1 ratio increased from ~0.4 to ~1 septo-temporally because of a specific change in stratum radiatum volume. Next we virtually embedded 1.8 million neuronal morphologies stochastically resampled from 244 digital reconstructions, emulating the dense packing of granular and pyramidal layers, and appropriately orienting the principal dendritic axes relative to local curvature. The resulting neuropil occupancy reproduced recent electron microscopy data measured in a restricted location. Extension of this analysis across each layer and subregion over the whole hippocampus revealed highly non-homogeneous dendritic density. In CA1, dendritic occupancy was >60% higher temporally than septally (0.46 vs. 0.28, s.e.m. ~0.05). CA3 values varied both across subfields (from 0.35 in CA3b/CA3c to 0.50 in CA3a) and layers (0.48, 0.34, and 0.27 in oriens, radiatum, and lacunosum-moleculare, respectively). Dendritic occupancy was substantially lower in DG, especially in the supra-pyramidal blade (0.18). The computed probability of dendrodendritic collision significantly correlated with expression of the membrane repulsion signal Down syndrome cell adhesion molecule (DSCAM). These heterogeneous stereological properties reflect and complement the non-uniform molecular composition, circuit connectivity, and computational function of the hippocampus across its transverse, longitudinal, and laminar organization. PMID- 22245506 TI - Calcium-lowering medications in patients with primary hyperparathyroidism: intraoperative findings and postoperative hypocalcemia. AB - BACKGROUND: We analyzed how calcium-lowering medications (CLMs) influenced surgical findings in patients with primary hyperparathyroidism. METHODS: A retrospective review was conducted of 281 patients undergoing surgery for primary hyperparathyroidism. Logistic regression evaluated the relationship between CLM and surgical findings. A mixed-effects model determined the influence of CLMs on these curves. RESULTS: We found that CLM (P = .018) and a higher serum calcium level (P = .018) were variables making 4-gland hyperplasia less likely. Analysis of intraoperative parathyroid hormone (IOPTH) plots revealed that CLMs altered the kinetics (P = .043). However, the 2 groups did not differ in the number of measurements necessary for a 50% decrease in IOPTH levels. Multivariate logistic regression also revealed that patients taking more than one CLM had an increased association with postoperative hypocalcemia (P = .018). CONCLUSIONS: Although CLM contributed to differences in IOPTH curves, their use does not require changing standard IOPTH protocol but should alert the surgeon to the risk of postoperative hypocalcemia. PMID- 22245507 TI - Laparoscopic or open liver resection? Let systematic review decide it. AB - BACKGROUND: Laparoscopic liver resection is increasingly being used for the excision of benign and malignant hepatic lesions. The aim of this study was to perform meta-analysis on the compiled data from available observational studies. METHODS: All the studies comparing laparoscopic versus open liver resections were searched on the available databases. Data were analyzed using Review Manager software version 5.0 (The Cochrane Collaboration, Software Update, Oxford, UK). RESULTS: There was a total of 2,466 patients: 1,161 (47.1%) in the laparoscopic group and 1,305 (52.9%) in the open group. The laparoscopic group was associated with a reduced overall complication rate (odds ratio = .35; 95% confidence interval [CI], .28-.45; P < .001; heterogeneity (HG): P = .51), fewer positive resection margins for malignant tumor resections (odds ratio = .38; CI, .20-.76; P = .006; HG: P = .52) and a decrease in the number of patients requiring blood transfusion (odds ratio = .36; CI, .23-.74; P < .001; HG: P = .30). CONCLUSIONS: Laparoscopic liver resection showed a reduced overall morbidity rate and favorable and comparable outcomes when compared with the open group. However, there is still a need for randomized controlled trials to compare laparoscopic versus open hepatic resection in benign and malignant lesions. PMID- 22245508 TI - Circulating matrix metalloproteinases and their inhibitors in hypertension. AB - Growing experimental evidence indicates that matrix metalloproteinases (MMPs) are implicated in many cardiovascular diseases including hypertension and its chronic complications. It is now clear that MMPs have many more substrates other than components of the extracellular matrix. In fact, intracellular targets now include those associated with the cardiovascular system. Clinical studies have suggested that circulating MMPs may predict cardiovascular morbidity and mortality. It is highly probable that increased MMPs may predispose hypertensive patients to additional complications and clinical sequelae. In this article, we review the basic principles linking MMP activity with hypertension and summarize clinical studies examining two specific MMPs (MMP-2 and -9) in hypertension. We also discuss how antihypertensive drugs may affect MMPs and their endogenous inhibitors, i.e., tissue inhibitors of matrix metalloproteinases (TIMPs). Circulating MMPs may predict increased risk of developing cardiovascular complications associated with hypertension. As such, patients could benefit from early pharmacologic intervention including use of MMP inhibitors. PMID- 22245509 TI - PET/CT imaging in gynecologic malignancies: a critical overview of its clinical impact and our retrospective single center analysis. AB - Gynecologic cancers represent a major global healthcare problem since they are associated with a significant mortality and morbidity. Over the last decade, considerable efforts have been spent in the development and optimization of novel diagnostic modalities to achieve an early diagnosis, aid in choosing appropriate treatment, improving long term surveillance, with the ultimate goal of increasing survival of gynecologic cancer patients. A growing body of evidence defines PET/CT as one of the most powerful tools for tumor, nodal and metastasis (TNM) cancer staging both in pre-treatment and in post treatment follow-up settings. At any phase of cancer evaluation, detection of metastasis represents one of the most critical impediments to the cure of tumor; traditional diagnostic imaging modalities, such as computed tomography (CT), are frequently found to inadequately stage the tumor, based on subsequent outcomes. As a consequence, patients may undergo pointless surgery for disease that could be treated with local medical therapies. In the setting of restaging, the ability to describe primary lesion, lymph nodes, possible metastases to peritoneum, bone, liver, lungs and brain renders PET/CT a potential alternative for a series of tests, including bone scanning, MRI or ultrasound, diagnostic CT, lymph node surgical sampling, that need to be used in combination in order to obtain a level of clinical confidence. In this review, we describe, the theoretical advantage and prognostic implications of PET/CT in the management of gynecologic cancer patients. PMID- 22245510 TI - Borate complexes of x-ray iodinated contrast agents: characterization and sorption studies for their removal from aqueous media. AB - Iodinated contrast media (ICM) are persistent and ubiquitous water pollutants. Because of their high water solubility and biochemical stability, their phase separation and recovery from the aquatic environment is very difficult. Here, borate was chosen as a complexing agent of the two diagnostic aids iomeprol and iopamidol in order to provide them with a negative charge and to fix the resulting adducts on Dowex 1X4 ion exchangers. A systematic characterization study of the complex by means of capillary zone electrophoresis and 11B NMR revealed that iomeprol and iopamidol interact with borate anions in aqueous solutions giving a 1:1 single-charged adduct and that the association constant at 25 degrees C for both contrast agents is highest at pH 10.5. These findings allowed the proper calibration of experimental parameters for further batch adsorption-desorption trials, where the two ICM were shown to be almost completely removed from the water phase and released from the solid sorbents in mild conditions, enabling the recovery of functional resin. PMID- 22245511 TI - Background species effect on aqueous arsenic removal by nano zero-valent iron using fractional factorial design. AB - This study describes the removal of arsenic species in groundwater by nano zero valent iron process, including As(III) and As(V). Since the background species may inhibit or promote arsenic removal. The influence of several common ions such as phosphate (PO4(3-)), bicarbonate (HCO3-)), sulfate (SO4(2-)), calcium (Ca2+), chloride (Cl-), and humic acid (HA) were selected to evaluate their effects on arsenic removal. In particular, a 2(6-2) fractional factorial design (FFD) was employed to identify major or interacting factors, which affect arsenic removal in a significant way. As a result of FFD evaluation, PO4(3-) and HA play the role of inhibiting arsenic removal, while Ca2+ was observed to play the promoting one. As for HCO3- and Cl-, the former one inhibits As(III) removal, whereas the later one enhances its removal; on the other hand, As(V) removal was affected only slightly in the presence of HCO3- or Cl-. Hence, it was suggested that the arsenic removal by the nanoiron process can be improved through pretreatment of PO4(3-) and HA. In addition, for the groundwater with high hardness, the nanoiron process can be an advantageous option because of enhancing characteristics of Ca2+. PMID- 22245512 TI - Oxidative desulfurization of benzothiophene and thiophene with WOx/ZrO2 catalysts: effect of calcination temperature of catalysts. AB - Oxidative desulfurization (ODS) of model fuel containing benzothiophene (BT) or thiophene (Th) has been carried out with WO(x)/ZrO2 catalyst, which was calcined at various temperatures. Based on the conversion of BT in the model fuel, it can be shown that the optimum calcination temperature of WOx/ZrO2 catalyst is around 700 degrees C. The most active catalyst is composed of tetragonal zirconia (ZrO2) with well dispersed polyoxotungstate species and it is necessary to minimize the contents of the crystalline WO3 and monoclinic ZrO2 for a high BT conversion. The oxidation rate was interpreted with the first-order kinetics, and it demonstrated the importance of electron density since the kinetic constant for BT was higher than that for Th even though the BT is larger than Th in size. A WOx/ZrO2 catalyst, treated suitably, can be used as a reusable active catalyst in the ODS. PMID- 22245513 TI - Genomic- and protein-based approaches for connectin (titin) identification in the ascidian Ciona intestinalis. AB - Determining the complete primary structure of large proteins is difficult because of the large sequence size and low sequence homology among animals, as is the case with connectin (titin)-like proteins in invertebrate muscles. Conventionally, large proteins have been investigated using immuno-screenings and plaque hybridization screenings that require significant time and labor. Recently, however, the genomic sequences of various invertebrates have been determined, leading to changes in the strategies used to elucidate the complete primary structures of large proteins. In this paper, we describe our methods for determining the sequences of large proteins by elucidating the primary structure of connectin from the ascidian Ciona intestinalis as an example. We searched for genes that encode connectin-like proteins in the C. intestinalis genome using the BLAST search program. Subsequently, we identified some domains present in connectin and connectin-like proteins, such as immunoglobulin (Ig), fibronectin type 3 (Fn) and kinase domains in C. intestinalis using the SMART program and manual estimation. The existence of these domains and the unique sequences between each domain were confirmed using RT-PCR. We also examined the localization of mRNA using whole-mount in situ hybridization (WISH) and protein expression using SDS-PAGE. These analyses indicate that the domain structure and molecular weight of ascidian connectin are similar to those of vertebrate connectin and that ascidian connectin is also expressed in heart muscle, similarly to vertebrate connectin. The methods described in this study can be used to determine the primary structures of large proteins, such as novel connectin-like proteins in invertebrates. PMID- 22245514 TI - Spontaneous cooling and rewarming after cardiac arrest may not be therapeutic. PMID- 22245516 TI - A potential novel rule for therapeutic decision-making in the cardiocerebral resuscitation of patients with cardiac arrest on arrival. PMID- 22245517 TI - Emergency airway management: The need to refine - And redefine - The "state of the art". PMID- 22245518 TI - Prioritized sequencing of the second exon of MYO15A reveals a new mutation segregating in a Pakistani family with moderate to severe hearing loss. AB - Mutations in MYO15A are associated with deafness in humans, and shaker 2 mice also exhibit a hearing loss due to defects of unconventional myosin 15a. We ascertained a consanguineous Pakistani family with recessively inherited moderate to severe hearing loss, which putatively segregated with markers linked to the DFNB3 locus. Prioritized sequencing of the second exon of MYO15A from the DNA of all affected individuals of family revealed a duplication of Cytosine in a stretch of seven repetitive C nucleotides (c.1185dupC). This mutation results in a frameshift and incorporates a stop codon in the open reading frame of MYO15A (p.E396fsX431). The findings of less severe hearing loss in families with linkage to DFNB3 are only reported for some individuals with mutations in exon 2 of MYO15A, which are further supported by this study. Therefore, on basis of linkage data and the presence of a less severe hearing loss phenotype, sequencing of a single exon of MYO15A can efficiently identify the causative mutations in patients from these families. PMID- 22245519 TI - Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance. AB - We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. PMID- 22245520 TI - Adjuvant interferon therapy for patients at high risk for recurrent melanoma: an updated systematic review and practice guideline. AB - After complete resection of melanoma, some patients remain at high risk for recurrence. The efficacy of adjuvant systemic therapy has been inconsistent in randomised trials and remains controversial. An updated systematic review was conducted to identify new evidence on the role of adjuvant interferon therapy in patients with high-risk resected primary melanoma. Outcomes of interest included overall survival, disease-free survival (DFS), adverse effects and quality of life. MEDLINE, EMBASE, Cochrane Library and the proceedings of the American Society of Clinical Oncology were systematically searched to identify new randomised controlled trials, systematic reviews or meta-analyses. An updated meta-analysis of trials comparing high-dose interferon alpha with observation alone was conducted. The new data are presented in this review. Seven randomised controlled trials met the inclusion criteria: six trials of interferon alone and two trials of interferon plus chemotherapy. Two meta-analyses of adjuvant interferon alpha were also identified. Overall survival was not significantly different between adjuvant high-dose interferon and observation alone (hazard ratio 0.93; 95% confidence interval 0.78-1.12; P = 0.45). A meta-analysis of DFS showed a significant benefit for high-dose interferon over control (hazard ratio 0.77; 95% confidence interval 0.65-0.92; P = 0.004). One trial reported a significant DFS benefit for pegylated interferon over observation alone. Our updated literature review indicates that adjuvant interferon therapy does not confer a significant long-term overall survival benefit in patients with high risk resected primary melanoma; however, a significant DFS benefit for high-dose interferon or pegylated interferon treatment has been shown. An revised practice guideline was developed based on the systematic review. PMID- 22245521 TI - Peripheral and central alterations of pituitary adenylate cyclase activating polypeptide-like immunoreactivity in the rat in response to activation of the trigeminovascular system. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is present in the cranial arteries and trigeminal sensory neurons. We therefore examined the alterations in PACAP-like immunoreactivity (PACAP-LI) in a time-dependent manner in two rat models of trigeminovascular system (TS) activation. In one group chemical stimulation (CS) was performed with i.p. nitroglycerol (NTG), and in the other one the trigeminal ganglia (TRG) were subjected to electrical stimulation (ES). The two biologically active forms, PACAP-38 and PACAP-27, were determined by means of radioimmunoassay (RIA) and mass spectrometry (MS) in the plasma, the cerebrospinal fluid (CSF), the trigeminal nucleus caudalis (TNC), the spinal cord (SC) and the TRG. The tissue concentrations of PACAP-27 were 10 times lower than those of PACAP-38 in the TNC and SC, but about half in the TRG. PACAP-38, but not PACAP-27, was present in the plasma. Neither form could be identified in the CSF. PACAP-38-LI in the plasma, SC and TRG remained unchanged after CS, but it was increased significantly in the TNC 90 and 180 min after NTG injection. In response to ES of the TRG, the level of PACAP-38 in the plasma and the TNC was significantly elevated 90 and 180 min later, but not in the SC or the TRG. The alterations in the levels of PACAP-27 in the tissue homogenates in response to both forms of stimulation were identical to those of PACAP-38. The selective increases in both forms of PACAP in the TNC suggest its important role in the central sensitization involved in migraine-like headache. PMID- 22245522 TI - Evolutionary dynamics of collective action when individual fitness derives from group decisions taken in the past. AB - Many actions take some time to have an impact - their effects only appear at some point in the future. Such time lags turn out to be ubiquitous among living organisms. Here we study the impact of time lags in the evolutionary dynamics of cooperative collective action. We consider a population in which individuals interact via a N-Person Stag Hunt dilemma and must opt to cooperate or defect. In the absence of any delay, the replicator dynamics reveals the existence of regimes in which two internal fixed points appear simultaneously. We show that the presence of time delay in the fitness of individuals leads to a delayed replicator equation exhibiting new evolutionary profiles, each profile being separated by critical values of the delay that we determine explicitly. When we break the symmetry in the time lags, we show that, generally, defectors take more advantage from delay than cooperators. Finally, when we take into consideration, approximately, effects associated with the finite population size, we find that counter-intuitive evolutionary outcomes may occur, resulting from the interplay between delay and the basins of attraction in the neighborhood of the internal fixed-points, and which may lead to full cooperation in conditions under which the outcome would be Full Defection in infinite populations. PMID- 22245523 TI - [Native valve postoperative Klebsiella pneumoniae endocarditis]. PMID- 22245524 TI - Introduction to the special issue on coronary blood flow. PMID- 22245526 TI - Postnatal exposure to predator odor (TMT) enhances spatial learning in mice adulthood. AB - Adult behavioral and physiological responses are partly dependent on neonatal experiences. In several animal species, enriched/aprovished environments and stressful/appeasing events are crucial in the setting of adaptative behaviors. However, little is known about the effects of postnatal exposure to predator odor (as unconditioned fear-related stimulus) on spatial learning at adulthood. Thus, the aim of the present study was to investigate the effects of a postnatal exposure to 2,4,5-trimethylthiazoline (TMT, as a predator odor) on radial arm maze (RAM), Tolman maze (TM) and Morris water maze (MWM) in mice at adulthood. The results showed that a TMT group constituted by mice exposed postnatally during 3 weeks to TMT presented significantly better spatial learning achievements in adulthood compared to a water group, postnatally exposed to water only, as well as compared to a butanol group (butanol used as an odor without ecological significance) exposed postnatally to butanol during 3 weeks. PMID- 22245525 TI - Sub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments. AB - Sub-concussive brain injuries may result in neurophysiological changes, cumulative effects, and neurodegeneration. The current study investigated the effects of a mild lateral fluid percussion injury (0.50-0.99 atm) on rat behavior and neuropathology to address the need to better understand sub-concussive brain injury. Male Long-Evans rats received either a single mild lateral fluid percussion injury or a sham-injury, followed by either a short (24 h) or long (4 weeks) recovery period. After recovery, rats underwent extensive behavioral testing consisting of tasks for rodent cognition, anxiety- and depression-like behaviors, social behavior, and sensorimotor function. At the completion of behavioral testing rats were sacrificed and brains were examined immunohistochemically with markers for neuroinflammation and axonal injury. No significant group differences were found on behavioral and axonal injury measures. However, rats given one mild fluid percussion injury displayed an acute neuroinflammatory response, consisting of increased microglia/macrophages and reactive astrogliosis, at 4 days post-injury. Neuroinflammation is a mechanism with the potential to contribute to the cumulative and neurodegenerative effects of repeated sub-concussive injuries. The current findings are consistent with findings in humans experiencing a sub-concussive blow, and provide support for the use of mild lateral fluid percussion injury in the rat as a model of sub concussive brain injury. PMID- 22245527 TI - The influence of different Stop-signal response time estimation procedures on behavior-behavior and brain-behavior correlations. AB - The fundamental cognitive-control function of inhibitory control over motor behavior has been extensively investigated using the Stop-signal task. The critical behavioral parameter describing stopping efficacy is the Stop-signal response time (SSRT), and correlations with estimates of this parameter are commonly used to establish that other variables (e.g., other behavioral measures or brain activity measures) are closely related to inhibitory motor control. Recently, however, it has been argued that SSRT estimates can be strongly distorted if participants strategically slow down their responses over the course of the experiment, resulting in the SSRT no longer reliably representing response inhibition efficacy. Here, we performed new analyses on behavioral and functional data from an fMRI version of the Stop-signal task to gauge the consequences of using different SSRT estimation approaches that are differentially prone to the influence of strategic response slowing. The results indicate that the SSRT estimation approach can dramatically change behavior-behavior correlations. Specifically, a correlation between the SSRT and Go-trial accuracy that was highly significant with one estimation approach, virtually disappeared for the other. Additional analyses indeed supported that this effect was related to strategic response slowing. Concerning brain-behavior correlations, only the left anterior insula was found to be significantly correlated with the SSRT within the set of areas tested here. Interestingly, this brain-behavior correlation differed little for the different SSRT-estimation procedures. In sum, the current results highlight that different SSRT-estimation procedures can strongly influence the distribution of SSRT values across subjects, which in turn can ramify into correlational analyses with other parameters. PMID- 22245528 TI - The relationship between follicle development and progesterone receptor membrane component-1 expression in women undergoing in vitro fertilization. AB - OBJECTIVE: To determine the relationship between progesterone receptor membrane component-1 (PGRMC1) expression and the outcome of IVF treatment. DESIGN: A prospective study in which PGRMC1 messenger RNA (mRNA) levels, methylation status of the Pgrmc1 promoter, and the presence of point mutations within Pgrmc1 were obtained from granulosa (GC)/luteal cells of women undergoing controlled ovarian hyperstimulation (COH). SETTING: Fertility center/basic science laboratory. PATIENT(S): Eighty-five patients undergoing IVF treatment and 10 women who were undergoing COH for the purpose of oocyte donation were included in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The PGRMC1 measurements were correlated with clinical outcomes, such as number of follicles, number of retrieved oocytes, and ongoing pregnancy rates (PR). RESULT(S): The PGRMC1 mRNA levels within GC/luteal cells of 18% of IVF patients were >2.25-fold higher than those of oocyte donors. Individuals with elevated PGRMC1 mRNA levels had 30% fewer large follicles and fewer oocytes retrieved. The elevated PGRMC1 mRNA levels were associated with an increase in the methylation of Pgrmc1 promoter. CONCLUSION(S): In patients with elevated PGRMC1 mRNA levels, gonadotropin-induced follicle development is attenuated, although sufficient numbers of follicles develop to allow for ET and subsequent pregnancy. PMID- 22245529 TI - Agonist trigger: what is the best approach? Agonist trigger with aggressive luteal support. AB - Although gonadotropin-releasing hormone agonist (GnRHa) trigger is effective in the prevention of ovarian hyperstimulation syndrome, lower conception rates have been reported. Intensive luteal phase support is an effective approach to improve implantation rates in women with peak E(2) levels >= 4,000 pg/mL. However, patients with peak E(2) levels <4,000 pg/mL may require a dual trigger with GnRHa and 1,000 IU hCG and intensive luteal phase support to improve implantation rates. PMID- 22245530 TI - Sexuality after sigmoid vaginoplasty in patients with Mayer-Rokitansky-Kuster Hauser syndrome. AB - OBJECTIVE: To investigate the functional and sexual outcome of sigmoid vaginoplasty in patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Fifty-nine consecutive patients with MRKH syndrome. INTERVENTION(S): Forty-eight patients underwent sigmoid vaginoplasty, and 11 were treated using the Frank method of dilatation. MAIN OUTCOME MEASURE(S): Functional results and sexuality were evaluated with the use of two standardized questionnaires: the Female Sexual Function Index (FSFI) and the revised Female Sexual Distress Scale (FSDS-R). Questions were added to analyze depression, body image perception, and desire of motherhood. RESULT(S): Out of the 68% of patients who answered the questionnaire, 73% had regular sexual intercourse. The mean total FSFI score was 28 +/- 3.1 in the operated group and 30 +/- 5.3 in the group treated with the Frank method. Their mean FSDS-R scores were 21 +/- 12.1 and 18 +/- 13.8, respectively. CONCLUSION(S): Sigmoid vaginoplasty is an effective technique providing a nearly normal sexual function to patients with vaginal aplasia. Despite this, psychologic distress related to sexuality persists in most patients, demonstrating the need for a multidisciplinary support. PMID- 22245532 TI - Biological activities of ACL-I and physicochemical properties of ACL-II, lectins isolated from the marine sponge Axinella corrugata. AB - Lectin II from the marine sponge Axinella corrugata (ACL-II) was purified by affinity chromatography on rabbit erythrocytic stroma incorporated into a polyacrylamide gel, followed by gel filtration on Ultrogel AcA 44 column. Purified ACL-II is a lectin with an Mr of 80 kDa and 78 kDa, estimated by SDS PAGE and by FPLC on Superose 12 HR column, respectively. ACL-II mainly agglutinates native rabbit erythrocytes and this hemagglutinating activity is independent of Ca(2+), Mg(2+) and Mn(2+), but is inhibited by d-galactose, chitin and N-acetyl derivatives, with the exception of GalNAc. ACL-II is stable for up to 65 degrees C for 30 min, with a better stability at a pH range of 2 to 6. In contrast, ACL-I displays a strong mitogenic and cytotoxic effect. PMID- 22245533 TI - Novel applications of plant polyketide synthases. AB - The structurally and mechanistically simple type III polyketide synthases (PKSs) catalyze iterative condensations of CoA thioesters to produce a variety of polyketide scaffolds with remarkably diverse structures and biological activities. By exploiting the enzymes, we combined precursor-directed biosynthesis with nitrogen-containing substrates and structure-based enzyme engineering and generated unnatural, novel polyketide-alkaloid scaffolds with promising biological activities. The nucleophilic nitrogen atom and the engineered enzymes thus facilitated the formation of additional CC and CN bonds during the enzymatic transformations. The methodology will contribute to the further production of chemically and structurally divergent, unnatural natural products, as well as the rational design of novel biocatalysts with unprecedented catalytic functions. PMID- 22245531 TI - Developmental programming: prenatal testosterone excess disrupts anti-Mullerian hormone expression in preantral and antral follicles. AB - OBJECTIVE: To investigate the impact of prenatal T excess on the expression of key ovarian regulators implicated in follicular recruitment and persistence using a large animal model of polycystic ovarian syndrome (PCOS). DESIGN: Interventional, animal model study. SETTING: Academic research unit. ANIMAL(S): A total of 25 female fetuses, 14 prepubertal female, and 24 adult female Suffolk sheep. INTERVENTION(S): Prenatal T treatment. MAIN OUTCOME MEASURE(S): Immunohistochemical determination of expression of anti-Mullerian hormone (AMH), kit ligand, and growth differentiation factor 9 (GDF9) in fetal, prepubertal, and adult ovarian tissues. RESULT(S): Prenatal T treatment reduced the AMH protein expression in granulosa cells (GC) of preantral follicles and increased its expression in antral follicles compared with age-matched adult controls. These differences were not evident in prepubertal animals. Protein expression of GDF9 and kit ligand was not altered at any of the developmental time points studied. CONCLUSION(S): Prenatal T exposure is associated with changes in AMH expression in preantral and antral follicles in adult ovaries, similar to findings in women with PCOS. These findings indicate that abnormal folliculogenesis in PCOS may be at least in part mediated by changes in AMH expression. PMID- 22245534 TI - Spontaneous alternation and spatial learning in Dab1scm (scrambler) mutant mice. AB - Homozygous Dab1scm mutants with cell ectopias in cerebellar cortex, hippocampus, and neocortex were compared with non-ataxic heterozygous and wild-type controls in spontaneous alternation and Morris water maze tests. Although there were no group differences in alternation rates, wild-type and heterozygote groups alternated above chance levels, whereas homozygous Dab1scm mutants did not. In the Morris water maze, Dab1scm mutants were impaired in both hidden and visible platform subtests. The deficits in spontaneous alternation and water maze measures reproduce the phenotype previously described in Reln(rl-Orl) mutants, attributed to disturbance of the same molecular pathway involving reelin. PMID- 22245535 TI - Toxicity evaluation of diethylene glycol and its combined effects with produced waters of off-shore gas platforms in the Adriatic Sea (Italy): bioassays with marine/estuarine species. AB - Diethylene glycol (DEG) is commonly used to dehydrate natural gas in off-shore extraction plants and to prevent formation of gas hydrates. It may be released into the sea accidentally or in discharged produced waters (PWs). PWs samples from off-shore gas platforms in the Adriatic Sea (Italy) have been used in this study. The objectives of the study were: a) to evaluate the toxicity of DEG for marine organisms; b) to evaluate if a high DEG content in PWs may alter their toxicity; c) to verify whether the DEG threshold concentration established by the Italian legislation (3.5 g/l) for PWs discharged at sea is safe for marine environment. Ten different species (Vibrio fischeri, Phaeodactylum tricornutum, Dunaliella tertiolecta, Brachionus plicatilis, Artemia franciscana, Tigropus fulvus, Mytilus galloprovincialis, Crassostrea gigas, Tapes philippinarum and Dicentrarchus labrax) have been exposed to DEG; four of these species were also exposed to PWs in combination with DEG. The results showed that: a) DEG is not toxic at levels normally detected in Adriatic PWs; b) DEG in combination with PW showed mainly additive or synergistic effects; c) short-term bioassays showed that the DEG limit of 3.5 g/l could be acceptable. PMID- 22245537 TI - Modified Rose Bengal assay for surface hydrophobicity evaluation of cationic solid lipid nanoparticles (cSLN). AB - Surface hydrophobicity of nanocarriers influences protein binding and subsequently fate of nanoparticles in blood circulation. Therefore, characterization of surface hydrophobicity of nanocarriers provides important preclinical information. Here, a modified classical adsorption method for the needs of characterization of cationic solid lipid nanoparticles (cSLN) was developed. We have identified possible method limitations that should be considered when performing the analysis, i.e. the problems associated with particle separation from the dispersion and their own absorbance in visible spectrum. We propose two modified methods for performing the assay overcoming the stated limitations. We also discuss here evaluation by different approaches (calculation of binding constants or partitioning quotient) and their suitability for the prepared cSLN formulation. Overall, we confirmed that our modified adsorption method can provide useful information about surface properties of (cationic) SLN, however, performing and evaluation of the assay need special attention in order to obtain the desired results. PMID- 22245538 TI - Multivariate design for the evaluation of lipid and surfactant composition effect for optimisation of lipid nanoparticles. AB - Physicochemical properties of lipid nanoparticles (LN), such as size, size distribution and surface charge, have a major influence both, on in vitro stability and delivery of the incorporated drug in vivo. With the purpose of understanding how these properties are influenced by variations of LN composition (e.g. lipid and surfactant type and concentration) 2(2) factorial designs with centre point were applied for several types of lipids and surfactants in the present study. Tested factors and levels were the type and concentration of lipid (cetyl palmitate, Dynasan 114 and Witepsol E85) at the concentrations of 5%, 10% and 15%, in combination with type and concentration of surfactant (polysorbate 20, 40, 60 and 80 and poloxamer 188 and 407) at concentrations of 0.8%, 1.2% and 2.0%. Responses measured within the design space were the mean size and polydispersity index (photon correlation spectroscopy), content of microparticles (optical single particle sizing), macroscopic appearance, pH and zeta potential on the day of production, 1 and 2 years after production. Multivariate evaluation and modelling were performed starting with a principal component analysis (PCA) and followed by partial least square regression analysis (PLS) to assess both qualitative and quantitative influence of the investigated factors in the LN. Our study showed that both, lipid and surfactant concentration and the type of surfactant are crucial parameters for the particle size of the LN prepared by high pressure homogenisation (HPH). For LN stability during 2 years both, lipid and surfactant types and concentrations were identified as the most relevant parameters. Among the surfactants most suitable for producing LN with small sizes were the polysorbates and the lipid yielding best storage stability was cetyl palmitate. Furthermore, the models allowed the prediction of the mean size of LN that could be achieved with a certain lipid/surfactant combination and concentration. The obtained results are considered useful for future design of stable LN formulations without the need of extensive empirical testing of formulation parameters within the given HPH technology. PMID- 22245539 TI - Cytoprotective effect of nonsteroidal antiinflammatory drugs in rat brain slices subjected to reoxygenation after oxygen-glucose deprivation. AB - The aim of this study was to assess the possible neuroprotective effect of the main nonsteroidal antiinflammatory drugs (NSAIDs) in an experimental model of hypoxia-reoxygenation in rat brain slices. After reoxygenation the increase in lactate dehydrogenase (LDH) efflux was inhibited by nimesulide, celecoxib and meloxicam with an IC(50) in the 10(-6)M range, by flurbiprofen, ibuprofen and diclofenac in the 10(-5)M range, and by salicylic acid, indomethacin, acetylsalicylic acid and mefenamic acid the 10(-4)M range. The effect of other NSAIDs was seen with an IC(50) greater than 10(-3)M. A statistically significant linear correlation between the values of LDH efflux and prostaglandin E(2) was found for NSAIDs whose IC(50) of cytoprotection (LDH efflux) was below 10(-4)M. The concentration of interleukin 10 was increased with nimesulide, celecoxib, meloxicam, flurbiprofen, ibuprofen and diclofenac. Flurbiprofen and diclofenac significantly inhibited the production of lipid peroxides. The increase in brain nitrite levels was significantly reduced with celecoxib, flurbiprofen, diclofenac and salicylic acid. Concentrations of 3-nitrotyrosine were significantly reduced with celecoxib, flurbiprofen, ibuprofen, salicylic acid and ketorolac. In conclusion, NSAIDs with the greatest cytoprotective effect (nimesulide, celecoxib and meloxicam) may exert their effect mainly through the blockade of cyclooxygenase-2 (COX-2) activity. Other compounds with neuroprotective activity may complement their lower anti-COX-2 effect with a slight increase in interleukin 10 and reduced oxidative and nitrosative stress in our model of hypoxia-reoxygenation in rat brain slices. PMID- 22245536 TI - X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. AB - X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization. Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190 disease-causing mutations in the RS1 gene are known with most mutations occurring as non-synonymous changes in the discoidin domain. Cell expression studies have shown that disease-associated missense mutations in the discoidin domain cause severe protein misfolding and retention in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and mutations in regions flanking the discoidin domain cause defective disulphide linked subunit assembly, all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been generated and shown to display most of the characteristic features found in XLRS patients. Recombinant adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout mice result in long-term retinoschisin expression and rescue of retinal structure and function providing a 'proof of concept' that gene therapy may be an effective treatment for XLRS. PMID- 22245540 TI - Health effects for the population living near a cement plant: an epidemiological assessment. AB - Epidemiological studies have shown the association between the exposure to air pollution and several adverse health effects. To evaluate the possible acute health effects of air pollution due to the emissions of a cement plant in two small municipalities in Italy (Mazzano and Rezzato), a case-control study design was used. The risks of hospital admission for cardiovascular or respiratory diseases for increasing levels of exposure to cement plant emissions were estimated, separately for adults (age>34 years) and children (0-14 years). Odds ratios (OR) were estimated using unconditional regression models. Attributable risks were also calculated. Statistically significant risks were found mainly for respiratory diseases among children: OR 1.67 (95% CI 1.08-2.58) for the moderately exposed category (E1), OR 1.88 (95% CI 1.19-2.97) for the highly exposed category (E2), with an attributable risk of 38% of hospital admissions due to the exposure to cement plant exhausts. Adults had a weaker risk: OR 1.38 (95% CI 1.18-1.61) for group E1, OR 1.31 (95% CI 1.10-1.56) for group E2; the attributable risk was 23%. Risks were higher for females and for the age group 35 64. These results showed an association between the exposure to plant emissions and the risk of hospital admission for cardiovascular or respiratory causes; this association was particularly strong for children. PMID- 22245541 TI - Non-specific physical symptoms and electromagnetic field exposure in the general population: can we get more specific? A systematic review. AB - OBJECTIVE: A systematic review of observational studies was performed to address the strength of evidence for an association between actual and perceived exposure to electromagnetic fields (EMF) and non-specific physical symptoms (NSPS) in the general population. To gain more insight into the magnitude of a possible association, meta-analyses were conducted. METHODS: Literature databases Medline, Embase, SciSearch, PsychInfo, Psyndex and Biosis and additional bibliographic sources such as reference sections of key publications were searched for the detection of studies published between January 2000 and April 2011. RESULTS: Twenty-two studies met our inclusion criteria. Qualitative assessment of the epidemiological evidence showed either no association between symptoms and higher EMF exposure or contradictory results. To strengthen our conclusions, random effects meta-analyses were performed, which produced the following results for the association with actual EMF; for symptom severity: Headache odds ratio (OR)=1.65; 95% confidence interval (CI)=0.88-3.08, concentration problems OR=1.28; 95% CI=0.56-2.94, fatigue-related problems OR=1.15; 95% CI=0.59-2.27, dizziness-related problems OR=1.38; 95% CI=0.92-2.07. For symptom frequency: headache OR=1.01; 95% CI=0.66-1.53, fatigue OR=1.12; 95% CI=0.60-2.07 and sleep problems OR=1.18; 95% CI=0.80-1.74. Associations between perceived exposure and NSPS were more consistently observed but a meta-analysis was not performed due to considerable heterogeneity between the studies. CONCLUSIONS: This systematic review and meta-analysis finds no evidence for a direct association between frequency and severity of NSPS and higher levels of EMF exposure. An association with perceived exposure seems to exist, but evidence is still limited because of differences in conceptualization and assessment methods. PMID- 22245542 TI - Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor. AB - Homer proteins are associated with both dopaminergic and glutamatergic function. In addition, these proteins are implicated in many signal transduction pathways that are also putative targets of the mood stabilizers lithium and valproate (VPA). This study investigated the effect of in vivo chronic administration of therapeutically-relevant doses of lithium and VPA on the expression of the inducible (Homer1a and ania-3) and constitutive (Homer1b/c) isoforms of the Homer1 gene in rat brain, and of two other Homer-related genes: Inositol 1,4,5 trisphosphate receptor (IP3R) and Shank. Homer1b/c was significantly decreased in cortex by VPA, and in striatal and accumbal subregions by both lithium and VPA. Both mood stabilizers reduced Homer1b/c expression in the dorsolateral caudate putamen, while only VPA decreased gene expression in all other striatal subregions. Shank and IP3R were downregulated by both mood stabilizers in the cortex. Neither chronic lithium nor VPA affected Homer immediate-early genes. These results suggest that lithium and VPA similarly modulate the expression of structural postsynaptic genes with topographic specificity in cortical and subcortical regions. Thus, Homer may represent an additional molecular substrate for mood stabilizers, and a potential link with dopaminergic function. PMID- 22245543 TI - Effects of smoking history on selective attention in schizophrenia. AB - Smoking prevalence is highly elevated in schizophrenia compared to the general population and to other psychiatric populations. Evidence suggests that smoking may lead to improvements of schizophrenia-associated attention deficits; however, large-scale studies on this important issue are scarce. We examined whether sustained, selective, and executive attention processes are differentially modulated by long-term nicotine consumption in 104 schizophrenia patients and 104 carefully matched healthy controls. A significant interaction of 'smoking status' * 'diagnostic group' was obtained for the domain of selective attention. Smoking was significantly associated with a detrimental conflict effect in controls, while the opposite effect was revealed for schizophrenia patients. Likewise, a positive correlation between a cumulative measure of nicotine consumption and conflict effect in controls and a negative correlation in patients were found. These results provide evidence for specific directional effects of smoking on conflict processing that critically dissociate with diagnosis. The data supports the self-medication hypothesis of smoking in schizophrenia and suggests selective attention as a specific cognitive domain targeted by nicotine consumption. A potential mechanistic model explaining these findings is discussed. PMID- 22245544 TI - Evaluation of a Rapid Immunochromatographic Diagnostic Test for the detection of rabies from brain material of European mammals. AB - The surveillance of rabies relies on investigations conducted on dead suspected animals or animals showing clinical signs suggestive of rabies. An immunochromatographic method based on lateral flow principle has been evaluated against a collection of brain samples mainly of European mammals including bats. The performance of this new test has been compared to the conventional gold standard methods: the fluorescent Antibody Test (FAT) and the Rapid Tissue Culture Infection Test (RTCIT). This test enabled the detection of various rabies strains belonging to rabies species 1, 5, 6 and 7 and demonstrated an overall specificity of 100% and a sensitivity of more than 88% when compared to FAT and RTCIT. A total agreement between the Rapid Immunochromatographic Diagnostic Test and conventional technique results have been obtained for European bat samples. PMID- 22245546 TI - Dynamo: a flexible, user-friendly development tool for subtomogram averaging of cryo-EM data in high-performance computing environments. AB - Dynamo is a new software package for subtomogram averaging of cryo Electron Tomography (cryo-ET) data with three main goals: first, Dynamo allows user transparent adaptation to a variety of high-performance computing platforms such as GPUs or CPU clusters. Second, Dynamo implements user-friendliness through GUI interfaces and scripting resources. Third, Dynamo offers user-flexibility through a plugin API. Besides the alignment and averaging procedures, Dynamo includes native tools for visualization and analysis of results and data, as well as support for third party visualization software, such as Chimera UCSF or EMAN2. As a demonstration of these functionalities, we studied bacterial flagellar motors and showed automatically detected classes with absent and present C-rings. Subtomogram averaging is a common task in current cryo-ET pipelines, which requires extensive computational resources and follows a well-established workflow. However, due to the data diversity, many existing packages offer slight variations of the same algorithm to improve results. One of the main purposes behind Dynamo is to provide explicit tools to allow the user the insertion of custom designed procedures - or plugins - to replace or complement the native algorithms in the different steps of the processing pipeline for subtomogram averaging without the burden of handling parallelization. Custom scripts that implement new approaches devised by the user are integrated into the Dynamo data management system, so that they can be controlled by the GUI or the scripting capacities. Dynamo executables do not require licenses for third party commercial software. Sources, executables and documentation are freely distributed on http://www.dynamo-em.org. PMID- 22245545 TI - Salmon fibrin glue in rats: antibody studies. AB - Fibrin sealants and topical thrombin preparations are often used for haemostatic and sealing applications in clinical practice. Some of these preparations contain coagulation factors from bovine sources. To minimize the risk of infection and immunogenicity connected with mammalian blood products, proteins derived from the plasma of farmed Atlantic salmon have been considered as an alternative to these mammalian sources. The purpose of this study is to characterize the immunogenicity of salmon fibrin glue in an animal model focusing on crossreactivity of IgG antibodies to host endogenous counterparts. After two immunizations with salmon fibrin glue, rats developed antibodies of IgG and IgM type to both fibrin glue components. Weak crossreactivity to endogenous fibrinogen and thrombin was seen in a subset of rats after the second application of salmon proteins. Coagulation tests showed that salmon fibrin application has no effect on coagulation profiles in mammalian hosts, consistent with previous reports that found no evidence of significant crossreactivity with host proteins. These studies support the potential suitability of salmon fibrin glue for the development of preparations with clinical impact. Before human use can be considered, however, additional data about safety of this preparation in other animal models, including large animal studies, should be obtained. PMID- 22245547 TI - Nucleotide-dependent conformational changes in the N-Ethylmaleimide Sensitive Factor (NSF) and their potential role in SNARE complex disassembly. AB - Homohexameric, N-Ethylmaleimide Sensitive Factor (NSF) disassembles Soluble NSF Attachment Protein Receptor (SNARE) complexes after membrane fusion, an essential step in vesicular trafficking. NSF contains three domains (NSF-N, NSF-D1, and NSF D2), each contributing to activity. We combined electron microscopic (EM) analysis, analytical ultracentrifugation (AU) and functional mutagenesis to visualize NSF's ATPase cycle. 3D density maps show that NSF-D2 remains stable, whereas NSF-N undergoes large conformational changes. NSF-Ns splay out perpendicular to the ADP-bound hexamer and twist upwards upon ATP binding, producing a more compact structure. These conformations were confirmed by hydrodynamic, AU measurements: NSF-ATP sediments faster with a lower frictional ratio (f/f(0)). Hydrodynamic analyses of NSF mutants, with specific functional defects, define the structures underlying these conformational changes. Mapping mutations onto our 3D models allows interpretation of the domain movement and suggests a mechanism for NSF binding to and disassembly of SNARE complexes. PMID- 22245548 TI - Predominance of large VLDL particles in metabolic syndrome, detected by size exclusion liquid chromatography. AB - OBJECTIVE: To study size heterogeneity of triglyceride rich lipoproteins (TRL) in metabolic syndrome (MS). DESIGN AND METHODS: Thirty MS patients and 14 healthy subjects were included. In fasting serum we measured: lipid profile, free fatty acids (FFA) and adiponectin; TRL were isolated (d<1.006 g/mL) and analysis by size exclusion HPLC followed by UV detection was performed; each subfraction was expressed as percentage of total TRL. RESULTS: MS patients, even those with normal triglycerides, presented higher proportion of very large VLDL (90 nm diameter) and large VLDL (60 nm) and slightly lower of typical VLDL (37 nm) (p<0.04); increased FFA (p=0.04) and lower adiponectin (p=0.001). FFA correlated with large VLDL% (r=0.58; p=0.003), independently of insulin-resistance and waist. Furthermore, the lower the adiponectin, the greater the predominance of large VLDL (r=-0.40; p=0.04). CONCLUSION: MS was associated with large VLDL, described as more atherogenic beyond triglyceride levels. Size exclusion HPLC would represent a useful tool for assessing subfractions' lipoprotein profile. PMID- 22245549 TI - Association between serum total bilirubin level and leukoaraiosis in Korean adults. AB - OBJECTIVES: Leukoaraiosis is associated with cerebrovascular microangiopathy. Increasing evidence suggests that bilirubin is a potent cytoprotectant in the development of cardiovascular diseases. This study aimed to determine whether total bilirubin is related to leukoaraiosis. METHODS: We examined the relationship of total bilirubin with leukoaraiosis in 1005 Korean adults. The odds ratios for leukoaraiosis were calculated using multivariate logistic regression across serum total bilirubin tertiles. RESULTS: In comparison with the subjects in the reference group (total bilirubin: 15-26 MUmol/L), the odds ratio (95% CI) for leukoaraiosis in the 3rd tertile (total bilirubin <=10 MUmol/L) was 5.50 (1.24-24.40) in women after adjusting for confounding variables. However, this inverse association between serum total bilirubin and the prevalence of leukoaraiosis was not found in men after adjusting for the same co-variables. CONCLUSION: Total bilirubin level was inversely associated with leukoaraiosis regardless of classical cardiovascular risk factors in Korean women. PMID- 22245550 TI - Inherited factor V deficient neonate with galactosaemia. AB - OBJECTIVES: Reporting a case of inherited factor V deficiency and galactosemia. METHODS: A neonate was admitted with hematoma, jaundice, splenomegaly, diarrhea, anemia, abdominal ascites and bilateral cataracts that diagnosis of galactosaemia and factor V deficiency was established. RESULTS: Coinheritance of both coagulation disorder and metabolic disorder is very rare episode that was identified in a neonate. CONCLUSION: Our case indicates that in mild bleeding episodes of neonates that imitate of coagulation disorders should be considered promptly by pediatricians. PMID- 22245551 TI - A rapid method for capture and identification of immunogenic proteins in Bordetella pertussis enriched membranes fractions: a fast-track strategy applicable to other microorganisms. AB - Mass spectrometry (MS) coupled with 1-D and 2-D electrophoresis can be utilized to detect and identify immunogenic proteins, but these methods are laborious and time-consuming. We describe an alternative, simple, rapid gel-free strategy to identify multiple immunogenic proteins from Bordetella pertussis (Bp). It couples immunoprecipitation to nano liquid chromatography- tandem mass spectrometry (IP nLC-MS/MS) and is significantly both time- and labor-saving. We developed a gel free magnetic bead-based immunoprecipitation (IP) method using different NP 40/PBS concentrations in which solubilized proteins of Bp Tohama I membrane fractions were precipitated with polyclonal rabbit anti-Bp whole cell immune sera. Immune complexes were analyzed by MS and Scaffold analysis (>95% protein identification probability). Total immunoproteins identified were 50, 63 and 49 for 0.90%, 0.45% and 0.22% NP-40/PBS buffer concentrations respectively. Known Bp proteins identified included pertactin, serotype 2 fimbrial subunit and filamentous hemagglutinin. As proof of concept that this gel-free protein immunoprecipitation method enabled the capture of multiple immunogenic proteins, IP samples were also analyzed by SDS-PAGE and immunoblotting. Bypassing gels and subjecting immunoprecipitated proteins directly to MS is a simple and rapid antigen identification method with relatively high throughput. IP-nLC-MS/MS provides a novel alternative approach for current methods used for the identification of immunogenic proteins. PMID- 22245552 TI - Proteomic analysis of egg white proteins during the early phase of embryonic development. AB - Avian egg albumen participates in embryonic development by providing essential nutrients as well as antimicrobial protection. Although various biological functions of egg white proteins were suggested during embryogenesis, global changes of these proteins under incubation conditions remained uninvestigated. This study presents a proteomic analysis on the change of egg white proteins during the first week of embryonic development. By using 2-DE, together with MALDI-TOF MS/MS, thirty protein spots representing eight proteins were identified showing significant changes in abundance during incubation. An accelerating degradation of ovalbumin was observed in a wide range of molecular weight. In addition, four protein complexes were predicted according to the detected molecular weight increase. Among these speculated protein complexes, an ovalbumin spot coupled with RNA-binding protein was detected. The absence of these protein complexes before incubation, followed by the constant increase in abundance during incubation indicates conceivable pivotal roles in embryonic development. To better understand the function of the proteins identified in this study, discrepancies of egg white protein changes between fertilized and unfertilized chicken eggs were additionally demonstrated. These findings will provide insight into the embryogenesis process to improve our knowledge of egg white proteins in regulating and supporting early embryonic development. PMID- 22245553 TI - After genomics, what proteomics tools could help us understand the antimicrobial resistance of Escherichia coli? AB - Proteomic approaches have been considerably improved during the past decade and have been used to investigate the differences in protein expression profiles of cells grown under a broad spectrum of growth conditions and with different stress factors including antibiotics. In Europe, the most significant disease threat remains the presence of microorganisms that have become resistant to antimicrobials and so it is important that different scientific tools are combined to achieve the largest amount of knowledge in this area of expertise. The emergence and spread of the antibiotic-resistant Gram-negative pathogens, such as Escherichia coli, can lead to serious problem public health in humans. E. coli, a very well described prokaryote, has served as a model organism for several biological and biotechnological studies increasingly so since the completion of the E. coli genome-sequencing project. The purpose of this review is to present an overview of the different proteomic approaches to antimicrobial resistant E. coli that will be helpful to obtain a better knowledge of the antibiotic-resistant mechanism(s). This can also aid to understand the molecular determinants involved with pathogenesis, which is essential for the development of effective strategies to combat infection and to reveal new therapeutic targets. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22245554 TI - Proteome of a methicillin-resistant Staphylococcus aureus clinical strain of sequence type ST398. AB - Proteomics is a powerful tool to analyze the differences in gene expression of bacterial strains. Staphylococcus aureus has long been recognized as an important pathogen in human disease. In order to investigate this pathogen, the proteome of a clinical methicillin-resistant S. aureus (MRSA) strain of the sequence type ST398 was determined using 2-DE. Using 2-DE we obtained a total of 105 spots the MRSA strain. Furthermore in correlation with bioinformatic databases, they allowed accurate identification and characterization of proteins, resulting in 227 identified proteins. There were found proteins related to basic function of the cell, but also proteins related to virulence like catalase, specific of S. aureus species, and proteins related to antibiotic resistance. Proteins associated with antibiotic resistance or virulence factors are related to genomic databases. The most abundant classes identified involved glycolysis, energy production, one-carbon metabolism, and oxidation-reduction process, all of which reflect an active metabolism. These results highlight the importance of proteomics to deepen in the knowledge of protein expression of MRSA strain of the lineage ST398, microorganism with diverse and important resistance mechanisms. With this proteome map we have an essential tool for a better understanding of this pathogen and providing new data for protein databases. This article is part of a Special Issue entitled: Proteomics: The clinical link. PMID- 22245555 TI - Pain, body, and space: what do patients with complex regional pain syndrome really neglect? PMID- 22245556 TI - Modulation of GITR for cancer immunotherapy. AB - Modulation of co-inhibitory and co-stimulatory receptors of the immune system has become a promising new approach for immunotherapy of cancer. With the recent FDA approval of CTLA-4 blockade serving as an important proof of principal, many new targets are now being translated into the clinic. Preclinical research has demonstrated that targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR), a member of TNF receptor superfamily, by agonist antibodies or natural ligand, can serve as an effective anti-tumor therapy. In this review, we will cover this research and the rationale that has led to initiation of two phase 1 clinical trials targeting GITR as a new immunotherapeutic approach for cancer. PMID- 22245557 TI - The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated photothermal therapy. AB - Breast tumors contain a small population of tumor initiating stem-like cells, termed breast cancer stem cells (BCSCs). These cells, which are refractory to chemotherapy and radiotherapy, are thought to persist following treatment and drive tumor recurrence. We examined whether BCSCs are similarly resistant to hyperthermic therapy, and whether nanoparticles could be used to overcome this resistance. Using a model of triple-negative breast cancer stem cells, we show that BCSCs are markedly resistant to traditional hyperthermia and become enriched in the surviving cell population following treatment. In contrast, BCSCs are sensitive to nanotube-mediated thermal treatment and lose their long-term proliferative capacity after nanotube-mediated thermal therapy. Moreover, use of this therapy in vivo promotes complete tumor regression and long-term survival of mice bearing cancer stem cell-driven breast tumors. Mechanistically, nanotube thermal therapy promotes rapid membrane permeabilization and necrosis of BCSCs. These data suggest that nanotube-mediated thermal treatment can simultaneously eliminate both the differentiated cells that constitute the bulk of a tumor and the BCSCs that drive tumor growth and recurrence. PMID- 22245558 TI - Internalization of C60 fullerenes into cancer cells with accumulation in the nucleus via the nuclear pore complex. AB - A highly water-soluble, non-ionic, and non-cytotoxic fullerene malonodiserinolamide-derivatized fullerene C(60) (C(60)-ser) is under investigation as a potential nanovector to deliver biologic and cancer drugs across biological barriers. Using laser-scanning confocal microscopy and flow cytometry, we find that PF-633 fluorophore conjugated C(60)-ser nanoparticles (C(60)-serPF) are internalized within living cancer cells in association with serum proteins through multiple energy-dependent pathways, and escape endocytotic vesicles to eventually localize and accumulate in the nucleus of the cells through the nuclear pore complex. Furthermore, in a mouse model of liver cancer, the C(60)-serPF conjugate is detected in most tissues, permeating through the altered vasculature of the tumor and the tightly-regulated blood brain barrier while evading the reticulo-endothelial system. PMID- 22245560 TI - A meta-analysis of risk factors for post-traumatic stress disorder in children and adolescents. AB - Post-traumatic stress disorder (PTSD) is a complex and chronic disorder that causes substantial distress and interferes with social and educational functioning. Consequently, identifying the risk factors that make a child more likely to experience traumatic distress is of academic, clinical and social importance. This meta-analysis estimated the population effect sizes of 25 potential risk factors for PTSD in children and adolescents aged 6-18 years across 64 studies (N=32,238). Medium to large effect sizes were shown for many factors relating to subjective experience of the event and post-trauma variables (low social support, peri-trauma fear, perceived life threat, social withdrawal, comorbid psychological problem, poor family functioning, distraction, PTSD at time 1, and thought suppression); whereas pre-trauma variables and more objective measures of the assumed severity of the event generated small to medium effect sizes. This indicates that subjective peri-trauma factors and post-event factors are likely to have a major role in determining whether a child develops PTSD following exposure to a traumatic event. Such factors could potentially be assessed following a potentially traumatic event in order to screen for those most vulnerable to developing PTSD and target treatment efforts accordingly. The findings support the cognitive model of PTSD as a way of understanding its development and guiding interventions to reduce symptoms. PMID- 22245561 TI - Long lasting effects of early-life stress on glutamatergic/GABAergic circuitry in the rat hippocampus. AB - The objective of the present work was to study the effects of an early-life stress (maternal separation, MS) in the excitatory/inhibitory ratio as a potential factor contributing to the ageing process, and the purported normalizing effects of chronic treatment with the antidepressant venlafaxine. MS induced depressive-like behaviour in the Porsolt forced swimming test that was reversed by venlafaxine, and that persisted until senescence. Aged MS rats showed a downregulation of vesicular glutamate transporter 1 and 2 (VGlut1 and VGlut2) and GABA transporter (VGAT) and increased expression of excitatory amino acid transporter 2 (EAAT2) in the hippocampus. Aged rats showed decreased expression of glutamic acid decarboxylase 65 (GAD65), while the excitatory amino acid transporter 1 (EAAT1) was affected only by stress. Glutamate receptor subunits NR1 and NR2A and GluR4 were upregulated in stressed rats, and this effect was reversed by venlafaxine. NR2B, GluR1 and GluR2/3 were not affected by either stress or age. MS, both in young and aged rats, induced an increase in the circulating levels of corticosterone. Corticosterone induced an increase glutamate and a decrease in GABA release in hippocampal slices, which was reversed by venlafaxine. Chronic treatment with corticosterone recapitulated the main biochemical findings observed in MS. The different effects that chronic stress exerts in young and adult animals on expression of proteins responsible for glutamate/GABA cycling may explain the involvement of glucocorticoids in ageing-related diseases. Modulation of glutamate/GABA release may be a relevant component of the therapeutic action of antidepressants, such as venlafaxine. PMID- 22245559 TI - Tobacco and marijuana use among adolescents and young adults: a systematic review of their co-use. AB - Tobacco (TOB) and marijuana (MJ) are the most widely used drugs among adolescents and young adults. The literature on their co-use, however, has not been systematically reviewed. We identified 163 English language articles published from 1999 to 2009 examining TOB and MJ co-use, correlates or consequences of co use, or interventions for prevention or cessation of co-use with participants aging 13-25 years. Most studies (n=114, 70%) examined TOB and MJ co-use, and 85% of relationships studied indicated a significant association. Fifty-nine studies (36%) examined correlates or consequences of co-use. Factors consistently associated with increased likelihood of co-use, defined as significant associations in at least four studies, were African-American ethnicity, mental and physical health characteristics (e.g., high-intensity pleasure temperament), and school characteristics (e.g., good grades). The only consistent consequence of co-use was exacerbation of mental health symptoms. Few studies examined prevention (n=3) or cessation (n=2) interventions for TOB and MJ co-use, and the findings were stronger for prevention efforts. A sufficient literature base has documented that TOB and MJ use are strongly related in young people, yet few consistent correlates and consequences of co-use have been identified to inform intervention targets. PMID- 22245562 TI - Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP. AB - Donepezil is the current standard symptomatic treatment of mild-to-moderate Alzheimer's disease (AD) patients. It aims to compensate for the deficit in cholinergic neurotransmission by blocking acetylcholinesterase (AChE) and thus increases the concentration of extracellular acetylcholine. However, experience from clinical practice demonstrated that AChE inhibitors only have moderate treatment effects. As a potential new approach for memory enhancement, inhibition of specific phosphodiesterases (PDEs) has gained attention. Among those are PDE9A inhibitors which increase the levels of the second messenger cyclic guanosine monophosphate (cGMP) intracellularly. In order to gain more insight into the potential impact of extracellularly acting AChEs and intracellularly acting PDE9A inhibitors on synaptic plasticity, we analyzed the effects of the AChE inhibitor donepezil and the PDE9A inhibitor BAY 73-6691 on long-term potentiation (LTP) in rat hippocampal slices, a widely accepted cellular experimental model of memory formation. Generally, LTP can be differentiated into an early and a late form, being protein-synthesis independent and protein-synthesis dependent, respectively. Donepezil was found to increase early LTP, but did not affect late LTP. In contrast, BAY 73-6691 demonstrated enhancing effects on both early and late LTP and even transformed early into late LTP. Furthermore, it was shown that this transformation into late LTP was dependent on the NO-cGMP-PKG pathway. In conclusion, this study demonstrates that BAY 73-6691 exhibits a stronger effect in enhancing and prolonging LTP than donepezil suggesting that PDE9 inhibition might be more efficacious in enhancing learning and memory. PMID- 22245563 TI - Age at menarche and digit ratio (2D:4D): relationships with body dissatisfaction, drive for thinness, and bulimia symptoms in women. AB - This study examined the hypothesis that lower prenatal androgen exposure and earlier puberty are associated with more dysfunctional eating attitudes and behaviors. Relationships between both age at menarche (AAM) and 2D:4D (a marker of prenatal androgen exposure), and EDI-2-Body Dissatisfaction, EDI-2-Drive for Thinness, and EDI-2-Bulimia scores, were examined in women using correlations and regressions. Earlier menarche was associated with higher drive for thinness after controlling for BMI and negative affect, but only in women who were not exclusively heterosexual. Higher 2D:4D was associated with higher Bulimia and Body Dissatisfaction scores, but only in exclusively heterosexual women, and relationships disappeared when covariates were controlled. Later AAM and higher 2D:4D were unique predictors of higher Bulimia scores for exclusive heterosexuals when BMI was controlled. These findings suggest future research should examine sexual orientation as a mediator or moderator of prenatal and postnatal organizational hormonal effects on women's disordered eating attitudes and behaviors. PMID- 22245564 TI - Strain improvement of fungal insecticides for controlling insect pests and vector borne diseases. AB - Insect pathogenic fungi play an important natural role in controlling insect pests. However, few have been successfully commercialized due to low virulence and sensitivity to abiotic stresses that produce inconsistent results in field applications. These limitations are inherent in most naturally occurring biological control agents but development of recombinant DNA techniques has made it possible to significantly improve the insecticidal efficacy of fungi and their tolerance to adverse conditions, including UV. These advances have been achieved by combining new knowledge derived from basic studies of the molecular biology of these pathogens, technical developments that enable very precise regulation of gene expression, and genes encoding insecticidal proteins from other organisms, particularly spiders and scorpions. Recent coverage of genomes is helping determine the identity, origin, and evolution of traits needed for diverse lifestyles and host switching. In future, such knowledge combined with the precision and malleability of molecular techniques will allow design of multiple pathogens with different strategies and host ranges to be used for different ecosystems, and that will avoid the possibility of the host developing resistance. With increasing public concern over the continued use of synthetic chemical insecticides, these new types of biological insecticides offer a range of environmental-friendly options for cost-effective control of insect pests. PMID- 22245565 TI - Comparison of the mutagenicity of aristolochic acid I and aristolochic acid II in the gpt delta transgenic mouse kidney. AB - Aristolochic acid (AA) is known to be a potent mutagen and carcinogen. Aristolochic acid I (AAI) and aristolochic acid II (AAII), the two major components of AA, differ from each other by a single methoxy group. However, their individual mutagenic characteristics in vivo are unclear. In the present study, we compared their DNA adduct formation and mutagenicities in the gpt delta transgenic mouse kidney. The dA-AAI, dG-AAI, dA-AAII and dG-AAII were identified in the kidney two days after intragastric administration of AAI or AAII at 5mg/kg. The concentration of DNA adducts formed by AAII was approximately 2.5 fold higher than that formed by AAI (p<0.05). The mutant frequency induced by AAII was nearly two-fold higher than that induced by AAI (p<0.05) following administration of 5mg/kg AAI or AAII, five times per week for six weeks. Investigation of the mutation spectra showed no statistically significant difference between AAI- and AAII-treated mice (p>0.05). A:T to T:A transversion was the predominant type of mutation in both treated groups, the GC-associated mutation rates, however, differed between the AAI and AAII treatments. The in vivo metabolic pathways of AAI and AAII are different, and this may affect their mutagenicity. In the present study, we measured the levels of AAI and AAII in the kidney and plasma of gpt delta transgenic mice at multiple time points after a single intragastric dose of 1 or 5mg/kg of either component. Our results showed that the levels of AAII in both kidney and plasma were considerably higher than those of AAI (p<0.01). The present study indicated that AAII showed more carcinogenic risk than AAI in vivo, and this may be, at least partly, the result of its increased levels in kidney and plasma. PMID- 22245566 TI - Production of large numbers of plasmacytoid dendritic cells with functional activities from CD34(+) hematopoietic progenitor cells: use of interleukin-3. AB - Plasmacytoid dendritic cells (pDC), a subset of dendritic cells characterized by a rapid and massive type-I interferon secretion through the Toll-like receptor pathway in response to viral infection, play important roles in the pathogenesis of several diseases, such as chronic viral infections (e.g., hepatitis C virus, human immunodeficiency virus), autoimmunity (e.g., psoriasis, systemic lupus erythematosus), and cancer. As pDC represent a rare cell type in the peripheral blood, the goal of this study was to develop a new method to efficiently generate large numbers of cells from a limited number of CD34(+) cord blood progenitors to provide a tool to resolve important questions about how pDC mediate tolerance, autoimmunity, and cancer. Human CD34(+) hematopoietic progenitor cells isolated from cord blood were cultured with a combination of Flt3-ligand (Flt3L), thrombopoietin (TPO), and one of the following cytokine: interleukin (IL)-3, interferon-beta(IFN-beta), or prostaglandin E2(PGE(2)). Cells obtained in the different culture conditions were analyzed for their phenotype and functional characteristics. The addition of IL-3 cooperates with Flt3L and TPO in the induction of pDC from CD34(+) hematopoietic progenitor cells. Indeed, Flt3L/TPO alone or supplemented with prostaglandin E2 or interferon-beta produced smaller amounts of pDC from hematopoietic progenitor cells. In addition, pDC generated in Flt3L/TPO/IL-3 cultures exhibited morphological, immunohistochemical, and functional features of peripheral blood pDC. We showed that IL-3, in association with Flt3L and TPO, provides an advantageous tool for large-scale generation of pDC. This culture condition generated, starting from 2 * 10(5) CD34(+) cells, up to 2.6 * 10(6) pDC presenting features of blood pDC. PMID- 22245567 TI - Identification of a nuclear carbonic anhydrase in Caenorhabditis elegans. AB - BACKGROUND: Carbonic anhydrases (CA) catalyze the inter-conversion of CO(2) with HCO(3) and H(+), and are involved in a wide variety of physiologic processes such as anion transport, pH regulation, and water balance. In mammals there are sixteen members of the classical alpha-type CA family, while the simple genetic model organism Caenorhabditis elegans codes for six alphaCA isoforms (cah-1 through cah-6). METHODS: Fluorescent reporter constructs were used to analyze gene promoter usage, splice variation, and protein localization in transgenic worms. Catalytic activity of recombinant CA proteins was assessed using Hansson's histochemistry. CA's ability to regulate pH as a function of CO(2) and HCO(3) was measured using dynamic fluorescent imaging of genetically-targeted biosensors. RESULTS: Each of the six CA genes was found to be expressed in a distinct repertoire of cell types. Surprisingly, worms also expressed a catalytically active CA splice variant, cah-4a, in which an alternative first exon targeted the protein to the nucleus. Cah-4a expression was restricted mainly to the nervous system, where it was found in nearly all neurons, and recombinant CAH-4A protein could regulate pH in the nucleus. CONCLUSIONS: In addition to establishing C. elegans as a platform for studying alphaCA function, this is the first example of a nuclear-targeted alphaCA in any organism to date. GENERAL SIGNIFICANCE: A classical alphaCA isoform is targeted exclusively to the nucleus where its activity may impact nuclear physiologic and pathophysiologic responses. PMID- 22245568 TI - Recipient CTLA-4*CT60-AA genotype is a prognostic factor for acute graft-versus host disease in hematopoietic stem cell transplantation for thalassemia. AB - Polymorphisms of the cytotoxic T-lymphocyte antigen-4 gene (CTLA-4) have been associated with autoimmune diseases and it has recently been reported that donor genotypes correlate with the outcome of allogeneic hematopoietic stem cell transplantation in leukemia patients. With the aim of confirming this finding in thalassemia patients, we investigated the influence of genotype distribution of 3 CTLA-4 gene polymorphisms in 72 thalassemia patients and their unrelated donors. A significant association was observed for recipient CT60-AA genotype and onset of grade II-IV (63.2% vs 24.5%; p = 0.001) and grade III-IV (36.4% vs 7.6%; p = 0.005) acute graft-versus-host disease (aGVHD). The same association was observed for the 88-base-pair allele of the CTLA-4 (AT)n polymorphism, which was determined to be in complete linkage disequilibrium with the CT60 A allele. Multinomial Cox regression demonstrated that this association was independent of CT60 donor genotypes or other risk factors (p = 0.016; hazard ratio = 2.8). Our data confirm that the genetic variability in CTLA-4 is an important prognostic factor for aGVHD and suggest that some of the risk factors for this complication are generated by recipient cells that persist after the myeloablative conditioning regimen. PMID- 22245569 TI - Clinical study in Chinese patients with late-infantile form neuronal ceroid lipofuscinoses. AB - Clinical findings, pathological features and tripeptidyl peptidase 1 (TPP1) activity and genetic mutation analysis data of nine patients affected with the late-infantile form of neuronal ceroid lipofuscinoses (LINCL) in China are systematically reviewed with long-term follow-up. The patients were enrolled if curvilinear bodies were found on lymphocyte, skin or muscle specimens' examination, and/or reduction of tripeptidyl peptidase 1 (TPP1) activity were detected. CLN2 gene mutation were tested in five patients. The patients have onset age of 2-3.5 years, and most of them initially present partial seizure, and then progressed to deteriorated mental function, refractory myoclonic seizures, impaired vision, and ataxia with cerebellar atrophy. Discrete small vacuolated lymphocytes are found in 5-10% lymphocytes in 5 patients examined. Curvilinear bodies were found in vacuolated lymphocytes, in skin and muscle tissues. Tripeptidyl peptidase 1 (TPP1) activities are reduced in 5 patients with different CLN2 gene mutation. Detection of vacuolated lymphocytes may be a screen method for LINCL, ultrastructural examination of lymphocytes, combined with TPP1 activity assay, allowing for a definite and faster diagnosis and classification with minimal invasion. PMID- 22245570 TI - AgRP and POMC neurons are hypophysiotropic and coordinately regulate multiple endocrine axes in a larval teleost. AB - Plasticity in growth and reproductive behavior is found in many vertebrate species, but is common in male teleost fish. Typically, "bourgeois" males are considerably larger and defend breeding territories while "parasitic" variants are small and use opportunistic breeding strategies. The P locus mediates this phenotypic variation in Xiphophorus and encodes variant alleles of the melanocortin-4 receptor (MC4R). However, deletion of the MC4R has modest effects on somatic growth and reproduction in mammals, suggesting a fundamental difference in the neuroendocrine function of central melanocortin signaling in teleosts. Here we show in a teleost that the hypothalamic pro-opiomelanocortin and AgRP neurons are hypophysiotropic, projecting to the pituitary to coordinately regulate multiple pituitary hormones. Indeed, AgRP-mediated suppression of MC4R appears essential for early larval growth. This identifies the mechanism by which the central melanocortin system coordinately regulates growth and reproduction in teleosts and suggests it is an important anatomical substrate for evolutionary adaptation. PMID- 22245571 TI - Increased EETs participate in peripheral endothelial dysfunction of cirrhosis. AB - The hyperdynamic circulation of cirrhosis participates in the pathophysiology of portal hypertension. P450-dependent epoxyeicosatrienoic acids (EET) are potent vasodilators. We evaluated plasma levels of EETs in cirrhotic patients and the effect of epoxygenase and nitric oxide synthase (NOS) inhibition on skin blood flow, measured by laser Doppler flowmetry, in normal subjects and cirrhotic patients with and without ascites. Free plasma EETs were increased in cirrhotic patients compared to normal subjects, while the ratio between 8,9-, 11,12-, and 14-15-EET was the same. In cirrhotic patients without ascites, skin blood flow was significantly increased compared to normal subjects. In patients with ascites skin blood flow was significantly reduced compared to control subjects and patients without ascites. Inhibition of epoxygenase with miconazole and of NOS with L-NG-Nitroarginine methyl ester (L-NAME) decreased basal skin flow in normal subjects and in cirrhotic patients, the effect being higher in cirrhotic patients. Miconazole caused a further decrease in flow when administered with L NAME, both in normal subjects and in cirrhotic patients. In conclusion, EETs participate in the control of peripheral circulation of normal subjects and in the pathophysiology of peripheral vasodilatation of cirrhotic patients with ascites. PMID- 22245572 TI - MRI differentiation of pneumonia-like mucinous adenocarcinoma and infectious pneumonia. AB - OBJECTIVE: To evaluate the role of MRI water-sensitive sequences in the differential diagnosis between pneumonia-like mucinous adenocarcinoma and infectious pneumonia. SUBJECTS AND METHODS: Twenty-three patients with pneumonia like mucinous adenocarcinoma and 30 patients with infectious pneumonia underwent computed tomography (CT) and MRI. Two blinded and independent readers evaluated CT and MR images using a 3-level confidence scale in two separate sessions. Results were tested for statistical significance using the Fisher's exact test and the Cohen's k test. RESULTS: On CT, the two readers respectively made correct diagnoses of mucinous adenocarcinoma in 17 out of 23 cases (73.9%), and in 15 out of 23 cases (65.2%). A correct diagnosis of infectious pneumonia was made in 22 out of 30 cases (73.3%), and in 24 out of 30 cases (80.0%). On MRI, both readers made correct diagnoses of mucinous adenocarcinoma in 23 out of 23 (100%) cases, and of infectious pneumonia in 30 out of 30 (100%) cases. Fisher's exact test showed a significant difference in the diagnosis of mucinous adenocarcinoma between MRI and CT for both readers, P=0.01 for reader 1 and P=0.002 for reader 2, respectively. A good agreement (k=0.73) was found between the two readers on CT evaluation, whereas an almost perfect agreement (k=1.00) was found for MRI. CONCLUSIONS: MRI with "water-sensitive" sequences should be added in the diagnostic protocol of every patient with pulmonary consolidation suspected to be mucinous adenocarcinoma. PMID- 22245573 TI - Crosslinked chitosan nanoparticle formulations for delivery from pressurized metered dose inhalers. AB - Crosslinked chitosan nanoparticles, prepared using ionic gelation, have been successfully formulated into pressurized metered dose inhalers (pMDIs) with potential for deep lung delivery of therapeutic agents. Nanoparticles were prepared from crosslinked chitosan alone and incorporating PEG 600, PEG 1000 and PEG 5000 for dispersion in aerosol propellant, hydrofuoroalkane (HFA) 227. Spherical, smooth-surfaced, cationic particles of mean size less than 230 nm were produced. Nanoparticles were positively charged and non-aggregated at the pH of the airways. Crosslinked chitosan-PEG 1000 nanoparticles demonstrated greatest dispersibility and physical stability in HFA-227, whereas other formulations readily either creamed or sedimented. Following actuation from pMDIs, the fine particle fraction (FPF) for crosslinked chitosan-PEG 1000 nanoparticles, determined using a next generation impactor, was 34.0+/-1.4% with a mass median aerodynamic diameter of 4.92+/-0.3 MUm. The FPFs of crosslinked chitosan, crosslinked chitosan-PEG 600 and crosslinked chitosan-PEG 5000 nanoparticles were 5.7+/-0.9%, 11.8+/-2.7% and 17.0+/-2.1%, respectively. These results indicate that crosslinked chitosan-PEG 1000-based nanoparticles are promising candidates for delivering therapeutic agents, particularly biopharmaceuticals, using pMDIs. PMID- 22245574 TI - In vitro antifungal activities of longan (Dimocarpus longan Lour.) seed extract. AB - Longan, Dimocarpus longan Lour., contains polyphenolic compounds which exhibit several pharmacological properties. This study aims to evaluate antifungal activities of longan fruit extract in comparison to its active compounds. The results showed that longan seed exhibited antifungal activity against the opportunistic yeasts (Candida species and Cryptococcus neoformans). In contrast, longan pulp and whole fruit did not demonstrate any inhibitory effects. Ellagic acid showed the most potent antifungal activity followed by corilagin and gallic acid, respectively. Ellagic acid inhibited Candida parapsilosis and C. neoformans more effectively than Candida krusei and also some Candida albicans clinical strains. Baidam cultivar possessed higher antifungal activity (MIC=500-4000 MUg/ml) as it contained higher contents of ellagic acid and gallic acid than Edor (MIC=1000-8000 MUg/ml). For antibacterial activity, only corilagin and gallic acid possessed weak to moderate inhibitory effects against Staphylococcus aureus and Streptococcus mutans, respectively. Longan seed was then applied in the oral care products. Longan effervescent granule (5% extract) significantly reduced adhesion of C. albicans to acrylic strips. Mouthwash containing 0.5% extract exhibited good antifungal activity compared to a commercial product. These findings indicated that longan seed extract and its polyphenolic compounds can be used as an antifungal agent in oral care products for the treatment of opportunistic yeast infection. PMID- 22245575 TI - Engineering domain-swapped binding interfaces by mutually exclusive folding. AB - Domain swapping is a mechanism for forming protein dimers and oligomers with high specificity. It is distinct from other forms of oligomerization in that the binding interface is formed by reciprocal exchange of polypeptide segments. Swapping plays a physiological role in protein-protein recognition, and it can also potentially be exploited as a mechanism for controlled self-assembly. Here, we demonstrate that domain-swapped interfaces can be engineered by inserting one protein into a surface loop of another protein. The key to facilitating a domain swap is to destabilize the protein when it is monomeric but not when it is oligomeric. We achieve this condition by employing the "mutually exclusive folding" design to apply conformational stress to the monomeric state. Ubiquitin (Ub) is inserted into one of six surface loops of barnase (Bn). The 38-A amino-to carboxy-terminal distance of Ub stresses the Bn monomer, causing it to split at the point of insertion. The 2.2-A X-ray structure of one insertion variant reveals that strain is relieved by intermolecular folding with an identically unfolded Bn domain, resulting in a domain-swapped polymer. All six constructs oligomerize, suggesting that inserting Ub into each surface loop of Bn results in a similar domain-swapping event. Binding affinity can be tuned by varying the length of the peptide linkers used to join the two proteins, which modulates the extent of stress. Engineered, swapped proteins have the potential to be used to fabricate "smart" biomaterials, or as binding modules from which to assemble heterologous, multi-subunit protein complexes. PMID- 22245576 TI - Non-stressful death of 23S rRNA mutant G2061C defective in puromycin reaction. AB - Catalysis of peptide bond formation in the peptidyl transferase center is a major enzymatic activity of the ribosome. Mutations limiting peptidyl transferase activity are mostly lethal. However, cellular processes triggered by peptidyl transferase deficiency in the bacterial cell are largely unknown. Here we report a study of the lethal G2061C mutant of Escherichia coli 23S ribosomal RNA (rRNA). The G2061C mutation completely impaired the puromycin reaction and abolished formation of the active firefly luciferase in an in vitro translation system, while poly(U)- and short synthetic mRNA-directed peptidyl transferase reaction with aminoacylated tRNAs in vitro was seemingly unaffected. Study of the cellular proteome upon expression of the 23S rRNA gene carrying the G2061C mutation compared to cells expressing wild-type 23S rRNA gene revealed substantial differences. Most of the observed effects in the mutant were associated with reduced expression of stress response proteins and particularly proteins associated with the ppGpp-mediated stringent response. PMID- 22245577 TI - Complex spatial organization and flagellin composition of flagellar propeller from marine magnetotactic ovoid strain MO-1. AB - Marine magnetotactic ovoid bacterium MO-1 is capable of swimming along the geomagnetic field lines by means of its two sheathed flagellar bundles at a speed up to 300 MUm/s. In this study, by using electron microscopy, we showed that, in each bundle, six individual flagella were organized in hexagon with a seventh in the middle. We identified 12 flagellin paralogs and 2 putative flagellins in the genome of MO-1. Among them, 13 were tandemly located on an ~ 17-kb segment while the 14th was on a separated locus. Using reverse transcription PCR and quantitative PCR, we found that all the 14 flagellin or putative flagellin genes were transcribed and that 2 of them were more abundantly expressed than others. A nLC (nanoliquid chromatography)-ESI (electrospray ionization)-MS/MS (mass spectrometry/mass spectrometry) mass spectrometry analysis identified all the 12 flagellin proteins in three glycosylated polypeptide bands resolved by one dimensional denaturing polyacrylamide gel electrophoresis and 10 of them in 21 spots obtained by means of two-dimensional electrophoresis of flagellar extracts. Most spots contained more than one flagellin, and eight of the ten identified flagellins existed in multiple isoforms. Taken together, these results show unprecedented complexity in the spatial organization and flagellin composition of the flagellar propeller. Such architecture is observed only for ovoid-coccoid, bilophotrichously flagellated magnetotactic bacteria living in marine sediments, suggesting a species and environmental specificity. PMID- 22245578 TI - Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. AB - The amyloid precursor protein (APP) and its neurotoxic cleavage product Abeta are key players in the development of Alzheimer's disease and appear essential for neuronal development and cell homeostasis in mammals. Proteolytic processing of APP is influenced by metal ions, protein ligands and its oligomerization state. However, the structural basis and functional mechanism of APP regulation are hitherto largely unknown. Here we identified a metal-dependent molecular switch located within the E2 domain of APP containing four evolutionary highly conserved histidine residues. Three X-ray structures of the metal-bound molecule were solved at 2.6-2.0 A resolution. Using protein crystallographic and biochemical methods, we characterized this novel high-affinity binding site within the E2 domain that binds competitively to copper and zinc at physiological concentrations. Metal-specific coordination spheres induce large conformational changes and enforce distinct structural states, most likely regulating the physiological function of APP and its processing in Alzheimer's disease. PMID- 22245579 TI - Malleability of the folding mechanism of the outer membrane protein PagP: parallel pathways and the effect of membrane elasticity. AB - Understanding the interactions between membrane proteins and the lipid bilayer is key to increasing our ability to predict and tailor the folding mechanism, structure and stability of membrane proteins. Here, we have investigated the effects of changing the membrane composition and the relative concentrations of protein and lipid on the folding mechanism of the bacterial outer membrane protein PagP. The folding pathway, monitored by tryptophan fluorescence, was found to be characterized by a burst phase, representing PagP adsorption to the liposome surface, followed by a time course that reflects the folding and insertion of the protein into the membrane. In 1,2-dilauroyl-sn-glycero-3 phosphocholine (diC(12:0)PC) liposomes, the post-adsorption time course fits well to a single exponential at high lipid-to-protein ratios (LPRs), but at low LPRs, a second exponential phase with a slower folding rate constant is observed. Interrupted refolding assays demonstrated that the two exponential phases reflect the presence of parallel folding pathways. Partitioning between these pathways was found to be modulated by the elastic properties of the membrane. Folding into mixed 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine:diC(12:0)PC liposomes resulted in a decrease in PagP adsorption to the liposomes and a switch to the slower folding pathway. By contrast, inclusion of 1,2-dilauroyl-sn-glycero-3 phosphoserine into diC(12:0)PC liposomes resulted in a decrease in the folding rate of the fast pathway. The results highlight the effect of lipid composition in tailoring the folding mechanism of a membrane protein, revealing that membrane proteins have access to multiple, competing folding routes to a unique native structure. PMID- 22245580 TI - From dusk till dawn: one-plasmid systems for light-regulated gene expression. AB - Signaling photoreceptors mediate diverse organismal adaptations in response to light. As light-gated protein switches, signaling photoreceptors provide the basis for optogenetics, a term that refers to the control of organismal physiology and behavior by light. We establish as novel optogenetic tools the plasmids pDusk and pDawn, which employ blue-light photoreceptors to confer light repressed or light-induced gene expression in Escherichia coli with up to 460 fold induction upon illumination. Key features of these systems are low background activity, high dynamic range, spatial control on the 20-MUm scale, independence from exogenous factors, and ease of use. In optogenetic experiments, pDusk and pDawn can be used to specifically perturb individual nodes of signaling networks and interrogate their role. On the preparative scale, pDawn can induce by light the production of recombinant proteins and thus represents a cost effective and readily automated alternative to conventional induction systems. PMID- 22245582 TI - Autophagy regulation in macrophages and neutrophils. AB - Autophagy is a conserved proteolytic mechanism that degrades cytoplasmic material including cell organelles. Accumulating evidence exists that autophagy also plays a major role in immunity and inflammation. Specifically, it appears that autophagy protects against infections and inflammation. Here, we review recent work performed in macrophages and neutrophils, which both represent critical phagocytes in mammalians. PMID- 22245581 TI - Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia. AB - The Fragile X-associated disorders (FXDs) and Friedreich ataxia (FRDA) are genetic conditions resulting from expansion of a trinucleotide repeat in a region of the affected gene that is transcribed but not translated. In the case of the FXDs, pathology results from expansion of CGG*CCG-repeat tract in the 5' UTR of the FMR1 gene, while pathology in FRDA results from expansion of a GAA*TTC-repeat in intron 1 of the FXN gene. Expansion occurs during gametogenesis or early embryogenesis by a mechanism that is not well understood. Associated Expansion then produces disease pathology in various ways that are not completely understood either. In the case of the FXDs, alleles with 55-200 repeats express higher than normal levels of a transcript that is thought to be toxic, while alleles with >200 repeats are silenced. In addition, alleles with >200 repeats are associated with a cytogenetic abnormality known as a fragile site, which is apparent as a constriction or gap in the chromatin that is seen when cells are grown in presence of inhibitors of thymidylate synthase. FRDA alleles show a deficit of the FXN transcript. This review will address the role of repeat mediated chromatin changes in these aspects of FXD and FRDA disease pathology. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22245583 TI - Identification of new interacting partners of the shuttling protein ubinuclein (Ubn-1). AB - We have previously characterized ubinuclein (Ubn-1) as a NACos (Nuclear and Adherent junction Complex components) protein which interacts with viral or cellular transcription factors and the tight junction (TJ) protein ZO-1. The purpose of the present study was to get more insights on the binding partners of Ubn-1, notably those present in the epithelial junctions. Using an in vivo assay of fluorescent protein-complementation assay (PCA), we demonstrated that the N terminal domains of the Ubn-1 and ZO-1 proteins triggered a functional interaction inside the cell. Indeed, expression of both complementary fragments of venus fused to the N-terminal parts of Ubn-1 and ZO-1 was able to reconstitute a fluorescent venus protein. Furthermore, nuclear expression of the chimeric Ubn 1 triggered nuclear localization of the chimeric ZO-1. We could localize this interaction to the PDZ2 domain of ZO-1 using an in vitro pull-down assay. More precisely, a 184-amino acid region (from amino acids 39 to 223) at the N-terminal region of Ubn-1 was responsible for the interaction with the PDZ2 domain of ZO-1. Co-imunoprecipitation and confocal microscopy experiments also revealed the tight junction protein cingulin as a new interacting partner of Ubn-1. A proteomic approach based on mass spectrometry analysis (MS) was then undertaken to identify further binding partners of GST-Ubn-1 fusion protein in different subcellular fractions of human epithelial HT29 cells. LYRIC (Lysine-rich CEACAM1-associated protein) and RACK-1 (receptor for activated C-kinase) proteins were validated as bona fide interacting partners of Ubn-1. Altogether, these results suggest that Ubn-1 is a scaffold protein influencing protein subcellular localization and is involved in several processes such as cell-cell contact signalling or modulation of gene activity. PMID- 22245584 TI - Arl5b is a Golgi-localised small G protein involved in the regulation of retrograde transport. AB - Regulation of membrane transport is controlled by small G proteins, which include members of the Rab and Arf families. Whereas the role of the classic Arf family members are well characterized, many of the Arf-like proteins (Arls) remain poorly defined. Here we show that Arl5a and Arl5b are localised to the trans Golgi in mammalian cells, and furthermore have identified a role for Arl5b in the regulation of retrograde membrane transport from endosomes to the trans-Golgi network (TGN). The constitutively active Arl5b (Q70L)-GFP mutant was localised efficiently to the Golgi in HeLa cells whereas the dominant-negative Arl5b (T30N) GFP mutant was dispersed throughout the cytoplasm and resulted in perturbation of the Golgi apparatus. Stable HeLa cells expressing GFP-tagged Arl5b (Q70L) showed an increased rate of endosome-to-Golgi transport of the membrane cargo TGN38 compared with control HeLa cells. Depletion of Arl5b by RNAi resulted in an alteration in the intracellular distribution of mannose-6-phosphate receptor, and significantly reduced the endosome-to-TGN transport of the membrane cargo TGN38 and of Shiga toxin, but had no affect on the anterograde transport of the cargo E cadherin. Collectively these results suggest that Arl5b is a TGN-localised small G protein that plays a key role in regulating transport along the endosome-TGN pathway. PMID- 22245585 TI - Activation of CRHR2 exerts an inhibitory effect on the expression of collapsin response mediator protein 3 in hippocampal neurons. AB - Corticotropin-releasing hormone (CRH) family peptides as well as their receptors have been shown to exhibit various functions in hippocampus. However, effects of CRH receptors activation on collapsin response mediator protein 3 (CRMP3), the key protein for dendrite outgrowth and cell apoptosis, remain unclear. In the present study, we determined the effects of CRHR1 and CRHR2 on CRMP3 expression in cultured hippocampal neurons. CRH and urocortin II (UCNII) dose-dependently suppressed CRMP3 mRNA and protein expression. The inhibitory effect on CRMP3 expression was completely reversed by CRHR2 antagonist but not by CRHR1 antagonist. Investigations on the signaling pathways of UCNII showed that CRHR2 mediated UCNII-induced increase in phosphorylated phospholipase C (PLC)-beta3 expression. Blocking PLC activity with U73122 and PKC with Go6976 completely prevented UCNII-inhibited CRMP3 expression. Our results suggest that CRHR2 activation decrease CRMP3 expression in hippocampal neurons via a mechanism that is dependent on PLC/PKC signaling pathways. PMID- 22245586 TI - Effects of alarin on food intake, body weight and luteinizing hormone secretion in male mice. AB - Alarin is a member of the galanin family of neuropeptides that includes galanin and galanin-like peptide (GALP). Alarin is an alternate transcript of the GALP gene and is expressed in the brain and periphery. Recently, it was shown in male rats that alarin is an orexigenic peptide that also regulates reproductive hormone secretion. We hypothesized that alarin would also have similar central effects on feeding and luteinizing hormone (LH) secretion in mice as observed in rats. To test this hypothesis, we treated male mice with alarin intracerebroventricularly (i.c.v.) and measured its effects on food intake, body weight, body temperature, LH secretion, and Fos induction. We observed that i.c.v. injection of 1.0 nmol alarin significantly increased immediate food intake (p<0.01) from 30 to 120 min post-injection and relative body weight (p<0.05) after 24 h. Alarin had no effect on body temperature compared to controls. Alarin increased LH levels in male mice, an effect that was dependent on gonadotropin Releasing-Hormone (GnRH) signaling. Furthermore, alarin-stimulated Fos immunoreactivity was observed in diencephalic nuclei, including the hypothalamic dorsomedial nucleus and the bed nucleus of the stria terminalis. Our studies demonstrated that alarin, like other members of the galanin peptide family, is a neuromediator of food intake and reproductive hormone secretion in male mice. PMID- 22245587 TI - Postesophagectomy chylothorax: incidence, risk factors, and outcomes. AB - BACKGROUND: Chylothorax is a rare but potentially lethal complication of esophagectomy. This study evaluated the rate of postesophagectomy chylothorax, identified associated risk factors, and compared postoperative outcomes in patients with and without chylothorax. METHODS: We reviewed 892 consecutive patients who underwent esophagectomy (1997 to 2008). Preoperative, operative, and postoperative details, including adverse outcomes and mortality, were analyzed. RESULTS: Postesophagectomy chylothorax occurred in 34 patients (3.8%). Chylothorax was significantly associated with 30-day major complications (85% vs 46%; p<0.001), including an increased likelihood of sepsis (p=0.001), pneumonia (p=0.009), reintubation (p=0.002) or reoperation (p<0.001), and death (17.7% vs 3.9%, p<0.001). Median length of stay was 17 vs 8 days (p=0.005). Median time to chylothorax diagnosis was 5 days. Thoracic duct ligation was performed in 21 (62%) at a median 13 days after esophagectomy. Two patients required repeat duct ligation for persistent chylothorax. Squamous cell cancer histology (9 of 34; 26%) was an independent predictor of postoperative chylothorax (odds ratio, 4.18; 95% confidence interval, 1.39 to 12.6). Odds of chylothorax were 36 times greater with average daily chest tube output exceeding 400 mL in the first 6 postoperative days (odds ratio, 35.9; 95% confidence interval, 8.2 to 157.8). CONCLUSIONS: Postoperative chylothorax is associated with significant postoperative morbidity and mortality. Patients with squamous cell cancer may be at increased risk. In addition, average daily chest tube output exceeding 400 mL in the early postoperative period should prompt fluid analysis for chylothorax to facilitate early diagnosis and consideration of thoracic duct ligation. PMID- 22245589 TI - Global gene expression in channel catfish after vaccination with an attenuated Edwardsiella ictaluri. AB - To understand the global gene expression in channel catfish after immersion vaccination with an attenuated Edwardsiella ictaluri (AquaVac-ESCTM), microarray analysis of 65,182 UniGene transcripts was performed. With a filter of false discovery rate less than 0.05 and fold change greater than 2, a total of 52 unique transcripts were found to be upregulated in vaccinated fish at 48 h post vaccination, whereas a total of 129 were downregulated. The 52 upregulated transcripts represent genes with putative functions in the following seven major categories: (1) hypothetical (25%); (2) novel (23%); (3) immune response (17%); (4) signal transduction (15%); (5) cell structure (8%); (6) metabolism (4%); and (7) others (8%). The 129 downregulated transcripts represent genes with putative functions in the following ten major categories: (1) novel (25%); (2) immune response (23%); (3) hypothetical (12%); (4) metabolism (10%); (5) signal transduction (7%); (6) protein synthesis (6.2%); (7) cell structure (5%); (8) apoptosis (3%); (9) transcription/translation (2%); and (10) others (6%). Microarray analysis revealed that apolipoprotein A-I was upregulated the most (8.5 fold, P = 0.011) at 48 h post vaccination whereas a novel protein (accession no. CV995854) was downregulated the most (342 fold, P = 0.001). Differential regulation of several randomly selected transcripts in vaccinated fish was also validated by quantitative PCR. Our results suggest that these differentially regulated genes elicited by the vaccination might play important roles in the protection of channel catfish against E. ictaluri. PMID- 22245588 TI - The effect of mitral annuloplasty shape in ischemic mitral regurgitation: a finite element simulation. AB - BACKGROUND: Undersized mitral annuloplasty (MA) is the preferred surgical treatment for chronic ischemic mitral regurgitation. However, the preferred shape of undersized MA is unclear. METHODS: A previously described finite element model of the left ventricle with mitral valve based on magnetic resonance images of a sheep with chronic ischemic mitral regurgitation after posterolateral myocardial infarction was used. Saddle-shape (Edwards Physio II) and asymmetric (IMR ETlogix) MA rings were digitized and meshed. Virtual annuloplasty was performed using virtual sutures to attach the MA ring. Left ventricular diastole and systole were performed before and after virtual MA of each type. RESULTS: Both types of MA reduced the septolateral dimension of the mitral annulus and abolished mitral regurgitation. The asymmetric MA was associated with lower virtual suture force in the P2 region but higher force in P1 and P3 regions. Although both types of MA reduced fiber stress at the left ventricular base, fiber stress reduction after asymmetric MA was slightly greater. Neither type of MA affected fiber stress at the left ventricular equator or apex. Although both types of MA increased leaflet curvature and reduced leaflet stress, stress reduction with saddle-shape MA was slightly greater. Both MA types reduced stress on the mitral chordae. CONCLUSIONS: The effects of saddle-shape and asymmetric MA rings are similar. Finite element simulations are a powerful tool that may reduce the need for animal and clinical trials. PMID- 22245590 TI - Identification and characterization of a serine protease inhibitor (PtSerpin) in the swimming crab Portunus trituberculatus. AB - Serine protease inhibitors (Serpins) play a key role in diverse immune biological processes. A serine protease inhibitor (Serpin), namely PtSerpin, was identified from the haemocyte cDNA library of swimming crab Portunus trituberculatus. The full-length PtSerpin cDNA was 1593 bp, including an open reading frame (ORF) of 1227 bp encoding a polypeptide of 408 amino acids with estimated molecular mass of 45.048 kDa and theoretical isoelectric point of 7.23. Predicted tertiary structure of PtSerpin contained three beta-sheets and nine alpha-helices. Multiple sequence alignment revealed that deduced amino acid sequence of PtSerpin shared the highest similarity with serpin SPI from green mud crab Scylla paramamosain (SpSerpin). Phylogenetic analysis supported PtSerpin and SpSerpin were closely related to serpins from Penaeus monodon and Daphnia pulex while other decapods formed a separate group. Although the mRNA transcripts of PtSerpin could be detected in all the examined tissues, the higher levels were present in haemocytes and gills which are the major organs respond to pathogenic microorganism. After challenged by Vibrio alginolyticus, Micrococcus luteus and Pichia pastoris, the temporal expression of PtSerpin gene in haemocytes showed different activation times against bacteria and fungi within the experimental period of 72 h. These findings suggest that PtSerpin is involved in the antibacterial defense mechanism of P. trituberculatus crab. PMID- 22245591 TI - Quantification of the human lateral geniculate nucleus in vivo using MR imaging based on morphometry: volume loss with age. AB - BACKGROUND AND PURPOSE: Because it is a small subcortical structure, the precise measurement of the human LGN is still a technical challenge. In this article, we identify the LGN in vivo, measure its volume based on high-resolution MR imaging, and then relate its volume to subject age to evaluate the potential clinical application. MATERIALS AND METHODS: A semiautomatic LGN isolation method was developed on scans obtained with 1.5T MR imaging, which involves highlighting the surrounding landmarks, obtaining candidate LGN voxels with a region-growing algorithm, and isolating the LGN from the ventral diencephalon. The method was accessed with a test-retest reliability on the results from 55 healthy subjects at different ages. RESULTS: This method showed high test-retest within-subject reliability (ICC, 0.950 and 0.948 in left and right hemispheres, respectively) among 3 independent measurements in each subject. The unilateral volume was highly variable, ranging from 52 to 102 mm(3) in the left and 66 to 105 mm(3) in the right hemisphere, with significantly larger volumes on the right (86 mm(3)) than on the left (77 mm(3)). The combined bilateral volumes (controlled for ICV) significantly decreased in size with progressing age from 20 to 65 years (r = 0.512, P = .000). There was no sex difference in bilateral LGN volumes (male/female: 163.1 +/- 18.2/162.2 +/- 21.4 mm(3)). CONCLUSIONS: Using our new technique, we were able to reliably determine the human LGN volume in vivo, which was found to decline with age. The volumes obtained by our method corresponded well with previously reported postmortem values, so our method may be considered to be superior for investigating the pathology of LGN. PMID- 22245592 TI - Involvement of SIRT1 in hypoxic down-regulation of c-Myc and beta-catenin and hypoxic preconditioning effect of polyphenols. AB - SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis. In this study, we investigated the role of SIRT1 signaling in the hypoxic down regulations of c-Myc and beta-catenin and hypoxic preconditioning effect of the red wine polyphenols such as piceatannol, myricetin, quercetin and resveratrol. We found that the expression of SIRT1 was significantly increased in hypoxia exposed or hypoxic preconditioned HepG2 cells, which was closely associated with the up-regulation of HIF-1alpha and down-regulation of c-Myc and beta-catenin expression via deacetylation of these proteins. In addition, blockade of SIRT1 activation using siRNA or amurensin G, a new potent SIRT1 inhibitor, abolished hypoxia-induced HIF-1alpha expression but increased c-Myc and beta-catenin expression. SIRT1 was also found to stabilize HIF-1alpha protein and destabilize c-Myc, beta-catenin and PHD2 under hypoxia. We also found that myricetin, quercetin, piceatannol and resveratrol up-regulated HIF-1alpha and down-regulated c-Myc, PHD2 and beta-catenin expressions via SIRT1 activation, in a manner that mimics hypoxic preconditioning. This study provides new insights of the molecular mechanisms of hypoxic preconditioning and suggests that polyphenolic SIRT1 activators could be used to mimic hypoxic/ischemic preconditioning. PMID- 22245593 TI - 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells. AB - 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1), a 2-phenyl-1,8 naphthyridin-4-one (2-PN) derivative, was synthesized and evaluated as an effective antimitotic agent in our laboratory. However, the molecular mechanisms are uncertain. In this study, HKL-1 was demonstrated to induce multipolar spindles, sustain mitotic arrest and generate multinucleated cells, all of which indicate mitotic catastrophe, in human leukemia HL-60 cells. Western blotting showed that HKL-1 induces mitotic catastrophe in HL-60 cells through regulating mitotic phase-specific kinases (down-regulating CDK1, cyclin B1, CENP-E, and aurora B) and regulating the expression of Bcl-2 family proteins (down-regulating Bcl-2 and up-regulating Bax and Bak), followed by caspase-9/-3 cleavage. These findings suggest that HKL-1 appears to exert its cytotoxicity toward HL-60 cells in culture by inducing mitotic catastrophe. PMID- 22245594 TI - Elevated levels of plasma Big endothelin-1 and its relation to hypertension and skin lesions in individuals exposed to arsenic. AB - Chronic arsenic (As) exposure affects the endothelial system causing several diseases. Big endothelin-1 (Big ET-1), the biological precursor of endothelin-1 (ET-1) is a more accurate indicator of the degree of activation of the endothelial system. Effect of As exposure on the plasma Big ET-1 levels and its physiological implications have not yet been documented. We evaluated plasma Big ET-1 levels and their relation to hypertension and skin lesions in As exposed individuals in Bangladesh. A total of 304 study subjects from the As-endemic and non-endemic areas in Bangladesh were recruited for this study. As concentrations in water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The plasma Big ET-1 levels were measured using a one-step sandwich enzyme immunoassay kit. Significant increase in Big ET-1 levels were observed with the increasing concentrations of As in drinking water, hair and nails. Further, before and after adjusting with different covariates, plasma Big ET-1 levels were found to be significantly associated with the water, hair and nail As concentrations of the study subjects. Big ET-1 levels were also higher in the higher exposure groups compared to the lowest (reference) group. Interestingly, we observed that Big ET-1 levels were significantly higher in the hypertensive and skin lesion groups compared to the normotensive and without skin lesion counterpart, respectively of the study subjects in As-endemic areas. Thus, this study demonstrated a novel dose-response relationship between As exposure and plasma Big ET-1 levels indicating the possible involvement of plasma Big ET-1 levels in As-induced hypertension and skin lesions. PMID- 22245597 TI - To induce, or not to induce, that is the (still unanswered) question. PMID- 22245598 TI - The use of back-up units to enhance the safety of unrelated donor cord blood transplantation. AB - The inability to obtain additional stem cells is a disadvantage of unrelated donor cord blood transplantation (CBT). Moreover, in the event of problems with unit shipment, compromised unit quality, thaw mishaps, or graft failure, the time to secure a back-up graft could be unacceptable. Emergent shipment of 1 to 2 back up units that have been previously typed and reserved could overcome this limitation. However, the advantages of this approach are not established. Therefore, we present our use of back-up units over a 5.5-year period. Six of 121 CBT recipients (5%) required back-up unit infusion. Indications included shipment mishaps (n = 2), poor unit viability (n = 2), significant infusion reaction (n = 1), and graft failure (n = 1). Lack of back-up units would have caused transplantation delay or infusion of inferior-quality units. Five of the 6 patients achieved sustained donor engraftment. We demonstrate that back-up units are emergently required in a significant minority of patients, supporting the incorporation of at least 1 back-up unit in cord blood (CB) selection algorithms to enhance CBT safety. PMID- 22245599 TI - Predictive information processing in music cognition. A critical review. AB - Expectation and prediction constitute central mechanisms in the perception and cognition of music, which have been explored in theoretical and empirical accounts. We review the scope and limits of theoretical accounts of musical prediction with respect to feature-based and temporal prediction. While the concept of prediction is unproblematic for basic single-stream features such as melody, it is not straight-forward for polyphonic structures or higher-order features such as formal predictions. Behavioural results based on explicit and implicit (priming) paradigms provide evidence of priming in various domains that may reflect predictive behaviour. Computational learning models, including symbolic (fragment-based), probabilistic/graphical, or connectionist approaches, provide well-specified predictive models of specific features and feature combinations. While models match some experimental results, full-fledged music prediction cannot yet be modelled. Neuroscientific results regarding the early right-anterior negativity (ERAN) and mismatch negativity (MMN) reflect expectancy violations on different levels of processing complexity, and provide some neural evidence for different predictive mechanisms. At present, the combinations of neural and computational modelling methodologies are at early stages and require further research. PMID- 22245600 TI - High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-kappaB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol. AB - Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22(phox) and p47(phox) expression through JNK/NF-kappaB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-kappaB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF kappaB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy. PMID- 22245601 TI - A method for determining the number of documents needed for a gold standard corpus. AB - The unstructured narratives in medicine have been increasingly targeted for content extraction using the techniques of natural language processing (NLP). In most cases, these efforts are facilitated by creating a manually annotated set of narratives containing the ground truth; commonly referred to as a gold standard corpus. This corpus is used for modeling, fine-tuning, and testing NLP software as well as providing the basis for training in machine learning. Determining the number of annotated documents (size) for this corpus is important, but rarely described; rather, the factors of cost and time appear to dominate decision making about corpus size. In this report, a method is outlined to determine gold standard size based on the capture probabilities for the unique words within a target corpus. To demonstrate this method, a corpus of dictation letters from the Michigan Pain Consultant (MPC) clinics for pain management are described and analyzed. A well-formed working corpus of 10,000 dictations was first constructed to provide a representative subset of the total, with no more than one dictation letter per patient. Each dictation was divided into words and common words were removed. The Poisson function was used to determine probabilities of word capture within samples taken from the working corpus, and then integrated over word length to give a single capture probability as a function of sample size. For these MPC dictations, a sample size of 500 documents is predicted to give a capture probability of approximately 0.95. Continuing the demonstration of sample selection, a provisional gold standard corpus of 500 documents was selected and examined for its similarity to the MPC structured coding and demographic data available for each patient. It is shown that a representative sample, of justifiable size, can be selected for use as a gold standard. PMID- 22245602 TI - Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer. AB - Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis. PMID- 22245603 TI - A novel tick antigen shows high vaccine efficacy against the dog tick, Rhipicephalus sanguineus. AB - Ticks are acaridae ectoparasites that, while taking a blood meal, can transmit viruses, bacteria, protozoa and filarial nematodes, which cause a variety of human and animal illnesses. The use of chemical pesticides constitutes the primary measure for control of these ectoparasites. However, the intensive use of these chemicals has drawbacks such as the contamination of food, environmental pollution and development of resistance by ectoparasites. Vaccination is considered a promising alternative for controlling infestations by ectoparasites. Although emerging tick proteins have been identified recently, and have been proposed as potential targets for generating protective molecules, only a limited number of them have been evaluated in vaccine trials. More than 80 proteins are found in eukaryotic ribosomes. The protein P0 is essential for the assembly of the 60S ribosomal subunit. We have identified an immunogenic region of the ribosomal protein P0 from Rhipicephalus sp. ticks that is not very conserved compared to host P0. The efficacy of a 20 amino acid synthetic peptide from this sequence was assayed as a vaccine antigen against Rhipicephalus sanguineus infestations in an immunization and challenge experiment on rabbits. A remarkable diminution in the viability of newly molted nymphs from larvae fed on vaccinated rabbits was observed. The number of adults and the number of eggs hatching were significantly reduced, with an overall efficacy of 90%. Our results demonstrated that immunization with an immunogenic peptide of tick protein P0 greatly reduced survival of ticks, suggesting that it has promise as an effective tick control agent. PMID- 22245604 TI - Inactivated PCV2 one shot vaccine applied in 3-week-old piglets: improvement of production parameters and interaction with maternally derived immunity. AB - The present study describes the effects of a commercially available vaccine against Porcine circovirus type 2 (PCV2) on clinical, pathological and virological outcomes of 3-week-old piglets from two farms with a clinical history of postweaning multisystemic wasting syndrome (PMWS). The study was a controlled, double-blinded, parallel group (1:1) and randomized trial (with a negative control) involving a total of 1239 animals. The study period comprised from weaning age (time of vaccination or PBS inoculation) until the first shipment of pigs to the slaughterhouse. The vaccine product was able to reduce clinical signs, PCV2 viral load in sera and faeces, and overall mortality in nurseries and fattening units. Moreover, average daily gain was significantly higher in vaccinated versus non-vaccinated piglets during the trial period. On the other hand, it was shown that maternally derived antibodies interfered with the development of an active humoral immune response after PCV2 vaccination. PMID- 22245605 TI - The proportion of influenza vaccination in Ontario, Canada in 2007/2008 compared with other provinces. AB - In 2000, Ontario, Canada introduced a universal influenza immunization program (UIIP) to provide free vaccines to its residents, whose ages are six months or older. The current study sought to measure the effect of the UIIP on influenza vaccination uptake in Ontario compared with other provinces combined. Data from the 2007/2008 Canadian Community Health Survey (cycle 4.1) were used in the analyses. Logistic regression analyses were conducted to estimate the odds ratios for influenza vaccination 2007/2008 associated with province of residence (Ontario versus other provinces combined) and other factors including chronic disease status, age, gender, household income, smoking status, having a medical doctor, and self-perceived health status. Living in Ontario was positively associated with having an influenza vaccine during the 2007/2008 season [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.45-1.55]. Increased age (OR 6.13, 95% CI 5.77-6.51), a positive chronic disease status (OR 1.70, 95% CI 1.63-1.77) and having a regular medical doctor (OR 1.95, 95% CI 1.85-2.07) also demonstrated a positive relationship with influenza vaccination in 2007/2008. A stratified analysis by province of residence suggested that having a chronic disease, old age and high income had less impact on the likelihood of receiving a vaccine in Ontario than other provinces. The results of this study may help to inform the development of strategies to increase vaccination coverage in Canada. PMID- 22245606 TI - Influenza viruses and cross-reactivity in healthy adults: humoral and cellular immunity induced by seasonal 2007/2008 influenza vaccination against vaccine antigens and 2009 A(H1N1) pandemic influenza virus. AB - We analyzed humoral and cellular immune responses against vaccine antigens and the new A(H1N1) virus in healthy adults before and after immunization with the 2007/2008 commercially available trivalent subunit MF59-adjuvanted influenza vaccine during the Fall 2007, prior to the emergence of the new virus. Antibody titers were significantly boosted only against the three vaccine antigens. Seasonal vaccination boosted pre-existing cellular responses upon stimulation of peripheral blood mononuclear cells not only with the homologous three vaccine antigens, but also with the heterologous new 2009 A(H1N1) and with a highly conserved peptide present in the stalk region of hemagglutinin (HA). These results show that cross-reactive cell responses against the new virus were present before the circulation of the virus and were boosted by seasonal vaccination. The cross-reactivity of cellular responses might, at least in part, explain the low pathogenicity of the new pandemic virus. The finding of cellular immunity, that can be increased by seasonal vaccination, against the conserved HA peptide, underline the potential use, in human vaccines, of conserved peptides of the stalk region of HA characterized by broad immunogenicity in experimental systems. PMID- 22245607 TI - Immunogenicity and safety of LBVH0101, a new Haemophilus influenzae type b tetanus toxoid conjugate vaccine, compared with HiberixTM in Korean infants and children: a randomized trial. AB - BACKGROUND: The World Health Organization (WHO) recommends that all countries adopt Haemophilus influenzae type b (Hib) vaccine into routine child immunization programs to protect children from the significant burden of life-threatening pneumonia and meningitis. METHODS: In this blind, comparative, randomized, phase III Korean multicenter study, we assessed immunogenicity and safety following primary vaccination of a new H. influenzae type b tetanus toxoid conjugate vaccine, LBVH0101 (LG Life Sciences, Ltd., Seoul, Korea) compared with HiberixTM (GSK, Rixensart, Belgium) in Korean children at 2, 4 and 6 months of age followed by a booster vaccination at 12-15 months. Serum anti-PRP IgG concentration and bactericidal activity were determined. Local/systemic symptoms were assessed after vaccination. Serious adverse events were recorded throughout the study. RESULTS: A total of 185 infants were included in immunogenicity evaluations. After the second and third doses of LBVH0101, 90.32% and 100% of infants achieved an antibody level >=1 MUg/mL, respectively, compared with 78.26% and 96.74% of those who received HiberixTM. After the second vaccination, the geometric mean concentration (GMC) of LBVH0101 recipients was 7.34 MUg/mL and was higher than that of HiberixTM recipients (3.55 MUg/mL). After the third vaccination, the GMCs were 14.59 MUg/mL and 12.15 MUg/mL in the LBVH0101 and HiberixTM recipients, respectively. The booster dose produced higher antibody concentrations: 30.25 MUg/mL and 71.64 MUg/mL for LBVH0101 and HiberixTM recipients, respectively. Bactericidal capacity and antibody potency of anti-PRP IgG induced by LBVH0101 was 35.05 and 116.27 after the second and third vaccinations, respectively, compared with 53.76 and 79.64 for HiberixTM. Anti-PRP IgG seroprotection rate and GMC were similar post-primary immunization between the groups; both showed functional maturation and similar booster responses. LBVH0101 had comparable safety results as the control vaccine, HiberixTM, as most of the solicited adverse events and unsolicited adverse events upon LBVH0101 administration were mild in severity. No serious vaccination-related adverse reactions were observed. CONCLUSIONS: LBVH0101 showed a good immunogenicity and safety profile in infants and children. The two-dose infant-priming schedule with a booster dose may suffice for Hib immunization in Korean infants (Clinical trial registration numbers: NCT01019772 and NCT01251133). PMID- 22245608 TI - Role of DNA topology in uptake of polyplex molecules by dendritic cells. AB - Dendritic cells (DCs) are an attractive target for DNA vaccines as they are potent antigen presenting cells. This study demonstrated how non-viral gene delivery to DCs involving complexes of poly-l-lysine (PLL) and plasmid DNA (pDNA) (polyplexes) showed dependence on DNA vector topology. DNA topology is of importance from both production and regulatory viewpoints. In our previous study with CHO cells we demonstrated that polyplex uptake was dependent on DNA topology whereby complexes containing supercoiled (SC) pDNA were smaller, more resistant to nucleases and more effectively condensed by PLL than open circular (OC) and linear-pDNA complexes. In this study polyplex uptake in DCs was measured qualitatively and quantitatively by confocal microscopy along with gene expression studies and measurement of DC phenotype. PLL is known for its ability to condense DNA and serve as an effective gene delivery vehicle. Quantification studies revealed that by 1h following uptake 15% (+/-2.59% relative standard error [RSE]) of SC-pDNA polyplexes were identified to be associated (fluorescent co-localisation) with the nucleus, in comparison to no nuclear association identified for OC- and linear-pDNA complexes. By 48 h following uptake, 30% (+/ 1.82% RSE) of SC-pDNA complexes associated with the nucleus in comparison to 16% (+/-4.40% RSE) and 12% (+/-6.97% RSE) of OC- and linear-pDNA polyplexes respectively. Confocal microscopy images showed how DNA and PLL remained associated following uptake by dual labelling. Polyplex (containing 20 MUg pDNA) gene expression (plasmid encoded lacZ [beta-galactosidase] reporter gene) in DCs was greatest for SC-pDNA polyplexes at 14.12% unlike that of OC- (9.59%) and linear-pDNA (7.43%). DCs express cell surface markers which contribute towards antigen presentation. Polyplex gene expression did not alter DC phenotype through surface marker expression. This may be due to the pDNA dose employed (20MUg) as other studies have used doses as high as 200 MUg pDNA to induce DC phenotypic changes. Although no change in DC phenotype occurred, this could be advantageous in terms of biocompatibility. Collectively these results indicate that DNA topology is an important parameter for DC vector design, particularly pDNA in the SC conformation in regards to DNA vaccination studies. PMID- 22245609 TI - Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins. AB - The human aldo-keto reductase AKR1C2 converts 5alpha-dihydrotestosterone to the less active 3alpha-androstanediol and has a minor 20-ketosteroid reductase activity that metabolises progesterone to 20alpha-hydroxyprogesterone. AKR1C2 is expressed in different peripheral tissues, but its role in uterine diseases like endometriosis has not been studied in detail. Some progestins used for treatment of endometriosis inhibit AKR1C1 and AKR1C3, with unknown effects on AKR1C2. In this study we investigated expression of AKR1C2 in the model cell lines of peritoneal endometriosis, and examined the ability of recombinant AKR1C2 to metabolise progesterone and progestin dydrogesterone, as well as its potential inhibition by progestins. AKR1C2 is expressed in epithelial and stromal endometriotic cell lines at the mRNA level. The recombinant enzyme catalyses reduction of progesterone to 20alpha-hydroxyprogesterone with a 10-fold lower catalytic efficiency than the major 20-ketosteroid reductase, AKR1C1. AKR1C2 also metabolises progestin dydrogesterone to its 20alpha-dihydrodydrogesterone, with 8.6-fold higher catalytic efficiency than 5alpha-dihydrotestosterone. Among the progestins that are currently used for treatment of endometriosis, dydrogesterone, medroxyprogesterone acetate and 20alpha-dihydrodydrogesterone act as AKR1C2 inhibitors with low MUM K(i) values in vitro. Their potential in vivo effects should be further studied. PMID- 22245610 TI - Solid-state 17O NMR study of benzoic acid adsorption on metal oxide surfaces. AB - Solid-state (17)O NMR spectra of (17)O-labeled benzoic and anisic acids are reported and benzoic acid is used to probe the surface of metal oxides. Complexes formed when benzoic acid is dry mixed with mesoporous silica, and nonporous titania and alumina are characterized. Chemical reactions with silica are not observed. The nature of benzoic acid on silica is a function of the water content of the oxide. The acid disperses in the pores of the silica if the silica is in equilibrium with ambient laboratory humidity. The acid displays high mobility as evidenced by a liquid-like, Lorentzian resonance. Excess benzoic acid remains as the crystalline hydrogen-bonded dimer. Benzoic acid reacts with titania and alumina surfaces in equilibrium with laboratory air to form the corresponding titanium and aluminum benzoates. In both materials the oxygen of the (17)O labeled acid is bound to the metal, showing the reaction proceeds by bond formation between oxygen deficient metal sites and the oxygen of the carboxylic acid. (27)Al MAS NMR confirms this mechanism for the reaction on alumina. Dry mixing of benzoic acid with alumina rapidly quenches pentacoordinate aluminum sites, excellent evidence that these sites are confined to the surface of the alumina particles. PMID- 22245611 TI - ZmRFP1, the putative ortholog of SDIR1, encodes a RING-H2 E3 ubiquitin ligase and responds to drought stress in an ABA-dependent manner in maize. AB - Drought is one of the most important limiting factors in crop production. To identify genes required for the drought stress response in the cereal crop maize, a gene coding for RING-finger protein (ZmRFP1), which is highly responsive to PEG induced drought stress, was isolated by mRNA differential display and rapid amplification of cDNA ends. The ZmRFP1 encodes a protein of 280 amino acids and contains a single C(3)H(2)C(3)-type RING motif in its C-terminal region. ZmRFP1 is an ortholog of Arabidopsis SDIR1 (salt- and drought-induced RING finger 1) (66% identity to AtSDIR1).The recombinant ZmRFP1 protein purified from Escherichia coli exhibited an in vitro E3 ubiquitin ligase activity. Real-time PCR analysis indicates that the transcript levels of ZmRFP1 were higher in aerial tissues including stems, leaves, tassels and immature ears, and were markedly up regulated by drought stress, and exogenous ABA, but not by salt, heat and cold stresses. Transient expression of the green fluorescent protein (GFP)-ZmRFP1 fusion protein in onion cells revealed a plasma membrane localization of the protein. Further analysis of ZmRFP1 transcripts between an ABA-deficient transposon mutant viviparous14 (vp14) and its isogenic wild-type line W22 showed that ZmRFP1 transcript levels were induced significantly in the wild-type line under drought stress, but not in the mutant line VP14. These results indicate that ZmRFP1 responds to drought stress in an ABA-dependent way and is likely to function in the ubiquitin conjunction pathway. The ZmRFP1 might serve as a candidate gene in genetic improvement for drought tolerance engineering in cereal crop plants. PMID- 22245612 TI - Assessment of phylogenetic inter-relationships in the genus Cymbidium (Orchidaceae) based on internal transcribed spacer region of rDNA. AB - Sequence data obtained from nrITS region were used to assess phylogenetic inter relationships and infrageneric classification of ten Cymbidium species collected from north-east India. The final aligned data matrix of combined ITS 1, 5.8S and ITS 2 yielded 684 characters. The ITS 1 and ITS 2 regions showed variable sequence lengths and G+C content (%). The 5.8S region was found to be more conserved (98.71%) followed by ITS 1 (86.12%) and ITS 2 (69.40%). ITS 2 recorded highest percentage of parsimony informative sites (7.46%), high sequence divergence with indels (24.63%), high number of transitions and transversions. ITS sequence data determined the phylogeny of Asiatic Cymbidiums with high bootstrap values. All three proposed subgenera could be distinguished clearly by all four (MP, ML, NJ, and BI) phylogenetic methods. This study validates the utility of ITS rDNA region as a reliable indicator of phylogenetic relationships, especially ITS 2 as probable DNA barcode at higher levels and can serve as an additional approach for identification of broader range of plant taxa especially orchids. PMID- 22245613 TI - BsmI polymorphisms in vitamin D receptor gene are associated with diabetic nephropathy in type 2 diabetes in the Han Chinese population. AB - We investigated the relationship between BsmI/ApaI polymorphisms in vitamin D receptor gene and diabetic nephropathy in a Han Chinese population. PCR restriction fragment length polymorphism was used to test the genotype and allele frequency of BsmI and ApaI polymorphisms in 304 patients with type 2 diabetes mellitus (DM group) and 100 control individuals (ND group). The DM group was further divided into DN0 (no diabetic nephropathy), DN1 (diabetes with small amount of albuminuria), DN2 (diabetes with large amount of albuminuria), L/NDN (late-onset DN after 5 years/no DN over the whole follow-up period of 5 years) and EDN (early-onset diabetic nephropathy occurring within first year) subgroup. We found that (1) genotype and allele frequency of BsmI polymorphism had significant difference between DM and ND group; BB+Bb genotype and B allele frequency were significantly higher in DN2 group than in ND and DN0 group; the ApaI polymorphism and allele frequency did not show any difference between DM and ND group; (2) BsmI BB+Bb genotype and B allele frequency were significantly higher in EDN group than in L/NDN group; (3) among patients with nephropathy, albumin excretion rate (AER) in 24-hour urine was significantly higher in those with BB+Bb phenotype than in those with bb phenotype (P<0.01), (4) unconditional logistic regression analysis showed that BsmI BB+Bb genotype was not only correlated with type 2 diabetic nephropathy, but also correlated with early-onset type 2 diabetic nephropathy. We conclude that the allele B (BB or Bb genotype) in vitamin D receptor gene is correlated with large amount albuminuria in the Han Chinese population with type 2 diabetes, and is probably a risk factor for early onset diabetic nephropathy. PMID- 22245614 TI - Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern Chinese population. AB - Variants in the gene encoding transcription factor 7-like 2 (TCF7L2) are associated with type 2 diabetes mellitus (T2D) in several ethnic groups. Two intronic variants, rs290487 and rs11196218, were originally identified as T2D modifiers in Hong Kong Chinese and Taiwan Chinese populations, respectively. However, discrepancies were noted in subsequent replicated studies. In this study, an association of these two loci with T2D was investigated in a Harbin Chinese population. Whereas the two populations in the initial studies were southern Han Chinese, Harbin Chinese are from northeastern China. The SNPs rs290487 and rs11196218 were genotyped by ligase detection reactions in 700 T2D patients and 570 unrelated non-diabetic controls. Association analyses, which were carried out using the case-control sample set, yielded a significant association between rs290487 and T2D, with a trend opposite to that described in a previous report. Specifically, rs290487T was found to be significantly associated with disease susceptibility (p=0.039), and the allelic OR of rs290487T carriers was 1.184 (95% CI 1.008-1.391). There was no significant association between rs11196218 and T2D. Taken together, TCF7L2 may be an important susceptibility gene for T2D in some Chinese populations. The discrepancies in the allelic associations determined for northern vs. southern Chinese allude to the presence of genetic variation among the Han Chinese. PMID- 22245615 TI - Maternal serum insulin-like growth factor (IGF-I) and binding proteins IGFBP-1 and IGFBP-3 at 11-13 weeks' gestation in pregnancies delivering small for gestational age neonates. AB - OBJECTIVE: To investigate the possible value of maternal serum concentration of insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 at 11-13 weeks' gestation in the prediction of small-for-gestational age (SGA) neonates. STUDY DESIGN: Maternal serum concentrations of IGF-I, IGFBP-1 and IGFBP 3 at 11-13 weeks were measured in 60 cases that subsequently delivered SGA neonates in the absence of pre-eclampsia, and compared to 120 non-SGA controls. RESULTS: In the SGA group, compared to the non-SGA group, there was significantly lower median IGF-I (61.8, IQR 43.4-93.4 ng/mL vs 94.9, IQR 56.7-131.2 ng/mL, p=0.002) and IGFBP-1 (58.2, IGR 39.8-84.9 ng/mL vs 81.4, IGR 57.3-105.5 ng/mL, p=0.002) but not IGFBP-3 (54.5, IGR 45.6-61.5 ng/mL vs 55.4, IGR 47.4-64.9 ng/mL, p=0.402). However, after multiple regression analysis and adjustment for maternal characteristics, these biomarkers were not useful in predicting SGA. CONCLUSION: Maternal serum IGF-I, IGFBP-1 and IGFBP-3 at 11-13 weeks are unlikely to be useful biochemical markers for early prediction of SGA. PMID- 22245617 TI - Interactions of neurotransmitter systems during postnatal development of the rat hippocampal formation: effects of cisplatin. AB - The distribution of neuroimmunohistochemical markers for the serotoninergic, noradrenergic, glutamatergic and GABAergic systems (respectively, 5HT(2A)R, beta1AR, GluR 2/3 and GAD65/67) was determined in the hippocampal formation at stages PD11, PD17 and PD30 of postnatal development of untreated rats and cisplatin-treated rats after a single injection of the drug at 10days of life. In the different time points the neurons of the dentate gyrus and Cornu Ammonis progressively acquire mature morphological characteristics, and cell genesis, migration of interneurons and differentiation of mossy cells occur. Cisplatin induced decrease in immunoreactivity for most of the selected neurotransmitter markers, thereby altering the postnatal development of circuits in the hippocampal formation. Cisplatin also brought out clear evidence for an interaction between excitatory and inhibitory neurotransmitter markers during the postnatal maturation of cells and fiber projections containing GluR2/3 and GAD65, despite the fact that glutamatergic neurons and GABAergic interneurons are divergent in their source of genesis and in their mode of migration. In fact, GluR2/3 immunofluorescence was increased in the principal cells early, at PD11, possibly to reduce the calcium influx into the cell. Moreover, cisplatin might cause a loss of GABAergic interneurons early and reduction of fiber projections to hippocampal layers due to altered cell migration or to cell injury; late changes, particularly in GAD67 cell number in the dentate gyrus did not result in redistribution or recovery in treated rats. With the use of cisplatin it has been demonstrated here for the first time that the critical differentiation of dentate gyrus hilar beta1AR and GluR2/3 mossy cells takes place between PD11 and PD17. Changes in neurotransmitter marker immunopositivity occurred subsequently to cytoarchitectural changes in the dentate gyrus and Cornu Ammonis which were already evident one day after cisplatin injection, suggesting that degeneration and cell loss may have occurred. Cisplatin was found to be a useful tool for following CNS development and for understanding how hippocampal neuronal networks react to injury. Furthermore, cisplatin-induced neurotoxicity may be used to reveal useful information on the genesis, migration and distribution, and differentiation of distinct types of hippocampal neurons. PMID- 22245619 TI - Neuromuscular fatigue during dynamic maximal strength and hypertrophic resistance loadings. AB - The purpose of this study was to compare the acute neuromuscular fatigue during dynamic maximal strength and hypertrophic loadings, known to cause different adaptations underlying strength gain during training. Thirteen healthy, untrained males performed two leg press loadings, one week apart, consisting of 15 sets of 1 repetition maximum (MAX) and 5 sets of 10 repetition maximums (HYP). Concentric load and muscle activity, electromyography (EMG) amplitude and median frequency, was assessed throughout each set. Additionally, maximal bilateral isometric force and muscle activity was assessed pre-, mid-, and up to 30 min post-loading. Concentric load during MAX was decreased after set 10 (P<0.05), while the load was maintained throughout HYP. Both loadings caused large reductions in maximal isometric force (MAX=-30+/-6.4% vs. HYP=-48+/-9.7%, P<0.001). The decreased concentric and isometric strength during MAX loading was accompanied by reduced EMG amplitude (P<0.05). Conversely, hypertrophic loading caused decreased median frequency only during isometric contractions (P<0.01). During concentric contractions, EMG amplitude increased and median frequency decreased in HYP (P<0.01). Our results indicate reduced neural drive during MAX loading and more complex changes in muscle activity during HYP loading. PMID- 22245618 TI - The variable nature of cognitive control: a dual mechanisms framework. AB - A core component of cognitive control - the ability to regulate thoughts and actions in accordance with internally represented behavioral goals - might be its intrinsic variability. In this article, I describe the dual mechanisms of control (DMC) framework, which postulates that this variability might arise from qualitative distinctions in temporal dynamics between proactive and reactive modes of control. Proactive control reflects the sustained and anticipatory maintenance of goal-relevant information within lateral prefrontal cortex (PFC) to enable optimal cognitive performance, whereas reactive control reflects transient stimulus-driven goal reactivation that recruits lateral PFC (plus a wider brain network) based on interference demands or episodic associations. I summarize recent research that demonstrates how the DMC framework provides a coherent explanation of three sources of cognitive control variation - intra individual, inter-individual and between-groups - in terms of proactive versus reactive control biases. PMID- 22245620 TI - Effects of transcutaneous electrical nervous stimulation on electromyographic and kinesiographic activity of patients with temporomandibular disorders: a placebo controlled study. AB - The purpose of this study was to assess the effect of a single 60 min TENS application on sEMG and kinesiographic activity in TMD patients in remission, and to assess the sEMG and kinesiographic effect of TENS in placebo and untreated groups. Sixty female subjects, selected according to the inclusion/exclusion criteria, suffering from unilateral TMD in remission were assigned to one of the following group: Group TENS, that received a single session of 60 min of TENS; Group Placebo that received a single session of 60 min of sham TENS; Group Control, that received no treatment. Pre- and post-treatment differences in sEMG of TA, MM, SCM, and DA and interocclusal distance values within groups were tested using the Wilcoxon test. Differences in sEMG and kinesiographic data, among the three groups, were assessed by Kruskal-Wallis test. Significant differences were only observed in the TENS group, for masticatory muscles of both sides; one-way analysis of variance revealed that sEMG values of masticatory muscles of both sides in the TENS group were significantly reduced, in comparison with placebo and control groups. Kinesiographic results showed that the vertical component of the interocclusal distance was significantly increased after TENS only in the TENS group. TENS could be effective to reduce the sEMG activity of masticatory muscles and to improve the interocclusal distance of TMD patients in remission; the placebo effect seems not present in the TENS application. PMID- 22245616 TI - Advances in microRNA experimental approaches to study physiological regulation of gene products implicated in CNS disorders. AB - The central nervous system (CNS) is a remarkably complex organ system, requiring an equally complex network of molecular pathways controlling the multitude of diverse, cellular activities. Gene expression is a critical node at which regulatory control of molecular networks is implemented. As such, elucidating the various mechanisms employed in the physiological regulation of gene expression in the CNS is important both for establishing a reference for comparison to the diseased state and for expanding the set of validated drug targets available for disease intervention. MicroRNAs (miRNAs) are an abundant class of small RNA that mediates potent inhibitory effects on global gene expression. Recent advances have been made in methods employed to study the contribution of these miRNAs to gene expression. Here we review these latest advances and present a methodological workflow from the perspective of an investigator studying the physiological regulation of a gene of interest. We discuss methods for identifying putative miRNA target sites in a transcript of interest, strategies for validating predicted target sites, assays for detecting miRNA expression, and approaches for disrupting endogenous miRNA function. We consider both advantages and limitations, highlighting certain caveats that inform the suitability of a given method for a specific application. Through careful implementation of the appropriate methodologies discussed herein, we are optimistic that important discoveries related to miRNA participation in CNS physiology and dysfunction are on the horizon. PMID- 22245621 TI - Flexion relaxation of erector spinae response to spinal shrinkage. AB - The purpose of the study was to investigate the effect of spinal shrinkage on the characteristic of flexion relaxation phenomenon in erector spinae muscle. Twelve male university students volunteered for this study. The spinal shrinkage was created with a load of 20% body weight on shoulder in 10 min. Each performed three trials of lumbar flexion-extension with the cycle of 5s flexion and 5s extension in standing before and after shrinkage. Surface electromyography from right erector spinae muscle as well as trunk flexion performance was recorded synchronously in video camera. A one-way ANOVA with repeated measures was used to evaluate the effect of shrinkage. The results showed that there was a significant (p<0.001) stature change with mean magnitude of shrinkage 5.9 mm. The erector spinae was active through a significantly larger angle during flexion and began activity significantly earlier during extension after shrinkage. It was concluded that shrinkage caused by prolonged compressive loading will elicit the change of flexion relaxation characteristic, which may be closely related to low back disorder. PMID- 22245622 TI - Modeling erythroblastic islands: using a hybrid model to assess the function of central macrophage. AB - The production and regulation of red blood cells, erythropoiesis, occurs in the bone marrow where erythroid cells proliferate and differentiate within particular structures, called erythroblastic islands. A typical structure of these islands consists of a macrophage (white cell) surrounded by immature erythroid cells (progenitors), with more mature cells on the periphery of the island, ready to leave the bone marrow and enter the bloodstream. A hybrid model, coupling a continuous model (ordinary differential equations) describing intracellular regulation through competition of two key proteins, to a discrete spatial model describing cell-cell interactions, with growth factor diffusion in the medium described by a continuous model (partial differential equations), is proposed to investigate the role of the central macrophage in normal erythropoiesis. Intracellular competition of the two proteins leads the erythroid cell to either proliferation, differentiation, or death by apoptosis. This approach allows considering spatial aspects of erythropoiesis, involved for instance in the occurrence of cellular interactions or the access to external factors, as well as dynamics of intracellular and extracellular scales of this complex cellular process, accounting for stochasticity in cell cycle durations and orientation of the mitotic spindle. The analysis of the model shows a strong effect of the central macrophage on the stability of an erythroblastic island, when assuming the macrophage releases pro-survival cytokines. Even though it is not clear whether or not erythroblastic island stability must be required, investigation of the model concludes that stability improves responsiveness of the model, hence stressing out the potential relevance of the central macrophage in normal erythropoiesis. PMID- 22245623 TI - Reversed-phase HPLC/FD method for the quantitative analysis of the neurotoxin BMAA (beta-N-methylamino-L-alanine) in cyanobacteria. AB - A method has been developed and optimized in order to detect and quantify the non protein amino acid beta-N-methylamino-L-alanine(BMAA) in cyanobacteria. The novelty of the method is that we have used methanol instead of acetonitrile as the eluent. The method includes extraction with 0.1 M trichloroacetic acid (free BMAA) or protein hydrolysis with 6 M hydrochloric acid (total BMAA), derivatization with AQC (6-aminoquinolyl-N-hydroxysuccinimidyl carbamate) and reversed-phase high-performance liquid chromatography analysis with fluorescence detection (HPLC/FD). Detection limits ranged from 0.35 to 0.75 pg injected, while quantification limits ranged from 1.10 to 2.55 pg injected for total and free BMAA hydrolysis, respectively. The linear response range was up to 850 pmol in both methods, embracing three orders of magnitude. The method was successfully applied to a lyophilized estuarine species of Nostoc (LEGE 06077). All previous published methods for BMAA quantification, using HPLC/FD, have reported the usage of acetonitrile. This is the first report using methanol as the mobile phase. Although the elution strength differs with both solvents, the final method proved efficient for the quantification of BMAA in this complex sample. The method resulted effective, low-priced, and simple, being suitable for routine monitoring of BMAA in cyanobacteria. PMID- 22245624 TI - Turkish scorpion Buthacus macrocentrus: general characterization of the venom and description of Bu1, a potent mammalian Na+-channel alpha-toxin. AB - The venom of the scorpion Buthacus macrocentrus of Turkey was fractionated by high performance liquid chromatography (HPLC) and its mass finger print analysis was obtained by spectrometry. More than 70 different fractions were obtained, allowing the determination of the molecular masses of at least 60 peptides ranging between 648 and 44,336 Da. The venom is enriched with peptides containing molecular masses between 3200-4500 Da, and 6000-7500 Da. They very likely correspond to K+-channel and Na+-channel specific peptides, respectively, as expected from venoms of scorpions of the family Buthidae, already determined for other species. The major component obtained from HPLC was shown to be lethal to mice and was further purified and characterized. It contains 65 amino acid residues maintained closely packed by 4 disulfide bridges, and shows a molecular weight of 7263 Da. Additionally, a cDNA from the venomous glands of this scorpion was used in conjunction with sequence data from Edman degradation and mass spectrometry for cloning the gene that codes for Bu1 as we named this toxin. This gene codes for a 67 amino acid residues peptide, where the two last are eliminated post-translationally for production of an amidated C-terminal arginine. Its sequence is closely related to toxins from the species Leiurus quinquestriatus, as revealed by a phylogenetic tree analysis. Electrophysiological results conducted with Bu1 using patch-clamp techniques indicate that it modifies the Na+ currents, in a similar way as other well known alpha-scorpion toxins. These results support the conclusion that this species of scorpions is dangerous to humans, having an epidemiological interest for the country. PMID- 22245625 TI - Convergent evolution led ribosome inactivating proteins to interact with ribosomal stalk. AB - Ribosome-inactivating proteins (RIPs) inhibit protein synthesis by depurinating an adenine on the sarcin-ricin loop (SRL) of the large subunit ribosomal RNA. Several RIPs interact with the C-terminal end of ribosomal stalk P proteins, and this interaction is required for their full activity. In contrast, the activity of Pokeweed Antiviral Protein is not affected by blocking this stalk component. Here, we provide evidence from phylogenetic analyses and sequence alignments suggesting that the interaction with the C-terminal end of P proteins evolved independently in different RIPs by convergent evolution. PMID- 22245626 TI - Sublethal dietary effects of Microcystis on Sacramento splittail, Pogonichthys macrolepidotus. AB - The presence of the toxic cyanobacterium Microcystis in the upper San Francisco Estuary (SFE) since 1999 is a potential but to date an unquantified threat to the health and survival of aquatic organisms, such as fish and zooplankton. The microcystins (MCs) predominantly in the LR-form (MC-LR) contained in Microcystis is hepatotoxic and a potential threat to the fishery. This study was conducted to determine the effects of dietary exposure of the endemic Sacramento splittail, Pogonichthys macrolepidotus in SFE to Microcystis and its toxin, MC-LR. Juvenile splittail (12.59 +/- 0.7 g fish(-1)) were exposed to five diets for 28 d with MC LR obtained from: (1) Microcystis harvested from the SFE and (2) a synthetic purified form of MC-LR. Three of the test diets contained 3.55 (D5), 9.14 (D10) and 17.13 (D20)mg MC-LR kg(-1) from Microcystis. The other two diets contained either purified MC-LR at 3.89 mg MC-LR kg(-1) (D5R) or no MC-LR (D0). The RNA/DNA ratio of fish muscle was significantly lower for all treatments fed test diets containing MC-LR compared to the control diet D0, suggesting Microcystis adversely affected nutritional status. Protein phosphatase 2A expression in the fish from the D5, D10 and D20 treatments were inversely affected by increasing concentrations of MC-LR. Cytoplasmic inclusion bodies and single cell necrosis were more prevalent and greater in severity in the fish exposed to the diets D10 and D20 compared to fish from the D0 treatment and indicate severe liver toxicity in splittail exposed to MC-LR. The sublethal effects on splittail characterized by this study suggest cyanobacterial blooms have the potential to affect splittail nutritional status and health in SFE. PMID- 22245627 TI - The effects of Zn-contaminated diets on Daphnia magna reproduction may be related to Zn-induced changes of the dietary P content rather than to the dietary Zn content itself. AB - The effect of dietary zinc (Zn) exposure to Daphnia magna fed living algae remains unsure as existing experimental data exhibit considerable inconsistency. In this study, we examined if Zn-induced changes in nutritional quality (i.e., the molar carbon to phosphorus ratio (C:P) and concentrations of essential omega 3-poly-unsaturated fatty acids (omega3-PUFA)) may contribute to the reproductive effects of dietary Zn exposure to D. magna. We prepared 8 different algal diets differing in Zn content, C:P ratio and omega3-PUFA, by varying the culture conditions (i.e., exposure duration) and culture medium (i.e., Zn concentration and mineral composition). These diets were representative for the diets typically used in published dietary metal toxicity bioassays. The algal diets were offered to D. magna during a standard chronic bioassay, using reproduction as endpoint. A generalized linear model (GLM) was used to determine which algal characteristics significantly explained the observed variability in D. magna reproduction. The most parsimonious GLM resulting in the best prediction of the first brood size had the molar C:P ratio as the sole predictor. The 21-day reproduction was also predicted best by the molar C:P ratio, whereas the contribution of other variables (notably Zn and omega3-PUFA content of the diet) to enhanced predictability was only marginal. In addition, our GLM, which only uses C:P as a predictor, could accurately predict reproduction in an independent (previously published) chronic bioassay with dietary Zn and D. magna. Furthermore, this GLM also accurately predicted the observed effects of algal C:P ratio shifts on D. magna reproduction as reported in ecological literature. Our analysis highlights that the reproductive effects of dietary Zn exposure in D. magna, as observed in previous studies, are probably not caused by direct toxicity of Zn in the diet, but may rather be related to Zn-induced shifts of the dietary C:P ratio. Our study thus seems to resolve inconsistencies among results from different previous studies and has important implications for the experimental design of future dietary metal toxicity research. PMID- 22245628 TI - Synergy between prochloraz and esfenvalerate in Daphnia magna from acute and subchronic exposures in the laboratory and microcosms. AB - Azole fungicides can enhance the toxicity of pyrethroid insecticides on aquatic species. It is, however, unknown to what extend the synergy found under laboratory conditions for strongly sorbing compounds (Azole logK(ow): 3-4, pyrethroid logK(ow): 6-7) will also take place in the field. We therefore investigated the synergising potential of the fungicide prochloraz on the pyrethroid esfenvalerate on Daphnia magna in the laboratory and in situ in cages placed in outdoor aquatic microcosms treated with 0.17, 0.33 and 0.83 MUgL(-1) esfenvalerate with and without 90 MUg L(-1) prochloraz. We found that the 8-14 fold synergy observed after 2 and 7 days of exposure to mixtures in the microcosms was equivalent to or greater than the 3-7 fold synergy found in 2-day laboratory tests. Incubating new neonates in situ 7 and 14 days after pesticide addition gave EC(50) values of 0.012 +/- 0.001 and <0.005MUgesfenvalerateL(-1) in the mixture treatments, based on measured water column concentrations. The detection limit is more than ten-fold lower than the lowest esfenvalerate concentration observed to cause ecologically significant effects across seven long term mesocosms studies, hence, even on a longer time scale prochloraz apparently synergises the effect of esfenvalerate under field-like conditions in the microcosms. The results show that synergy found in the laboratory also takes place under field like conditions at quantitatively similar levels, and that it lasts for several weeks. More knowledge on the identification of potential synergists, their true bioavailability and the concentrations and time span within which they can cause synergy needs further study, before an overall evaluation of the occurrence and severity of synergy under field conditions can take place. PMID- 22245630 TI - Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study. AB - Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease. PMID- 22245629 TI - Murine ameloblasts are immunonegative for Tcirg1, the v-H-ATPase subunit essential for the osteoclast plasma proton pump. AB - Maturation stage ameloblasts of rodents express vacuolar type-H-ATPase in the ruffled border of their plasma membrane in contact with forming dental enamel, similar to osteoclasts that resorb bone. It has been proposed that in ameloblasts this v-H-ATPase acts as proton pump to acidify the enamel space, required to complete enamel mineralization. To examine whether this v-H-ATPase in mouse ameloblasts is a proton pump, we determined whether these cells express the lysosomal, T-cell, immune regulator 1 (Tcirg1, v-H-Atp6v(0)a(3)), which is an essential part of the plasma membrane proton pump that is present in osteoclasts. Mutation of this subunit in Tcirg1 null (or oc/oc) mice leads to severe osteopetrosis. No immunohistochemically detectable Tcirg1 was seen in mouse maturation stage ameloblasts. Strong positive staining in secretory and maturation stage ameloblasts however was found for another subunit of v-H-ATPase, subunit b, brain isoform (v-H-Atp6v(1)b(2)). Mouse osteoclasts and renal tubular epithelium stained strongly for both Tcirg1 and v-H-Atp6v(1)b(2). In Tcirg1 null mice osteoclasts and renal epithelium were negative for Tcirg1 but remained positive for v-H-Atp6v(1)b(2). The bone in these mutant mice was osteopetrotic, tooth eruption was inhibited or delayed, and teeth were often morphologically disfigured. However, enamel formation in these mutant mice was normal, ameloblasts structurally unaffected and the mineral content of enamel similar to that of wild type mice. We concluded that Tcirg1, which is essential for osteoclasts to pump protons into the bone, is not appreciably expressed in maturation stage mouse ameloblasts. Our data suggest that the reported v-H-ATPase in maturation stage ameloblasts is not the typical osteoclast-type plasma membrane associated proton pump which acidifies the extracellular space, but rather a v-H-ATPase potentially involved in intracellular acidification. PMID- 22245631 TI - Anatomical distribution of the degree of mineralization of bone tissue in human femoral neck: impact on biomechanical properties. AB - Osteoporotic hip fractures represent a major public health problem associated with high human and economic costs. The anatomical variation of the tissue mineral density (TMD) and of the elastic constants in femoral neck cortical bone specimens is an important determinant of bone fragility. The purpose of this study was to show that a Synchrotron radiation microcomputed tomography system coupled with a multiscale biomechanical model allows the determination of the 3-D anatomical dependence of TMD and of the elastic constants (i.e. the mechanical properties of an anisotropic material) in human femoral neck. Bone specimens from the inferior femoral neck were obtained from 18 patients undergoing standard hemiarthroplasty. The specimens were imaged using 3-D synchrotron micro-computed tomography with a voxel size of 10.13 MUm, leading to the determination of the anatomical distributions of porosity and TMD. The elastic properties of bone tissue were computed using a multiscale model. The model uses the experimental data obtained at the scale of several micrometers to estimate the components of the elastic tensor of bone at the scale of the organ. Statistical analysis (ANOVA) revealed a significant effect of the radial position on porosity and TMD and a significant effect of axial position on TMD only. Porosity was found to increase in the radial direction moving from the periosteum inwards (p<10(-5)). At any given distance from the periosteum, porosity does not vary noticeably along the bone axis. TMD was found to be significantly higher (p<10(-5)) in the periosteal region than in other bone locations and decreases from the periosteal to the endosteal region with an average slope of 10.05 g.cm(-3).m(-1), the decrease being faster in the porous part of the samples (average slope equal of 30.04 g.cm(-3).m(-1)) than in dense cortical bone. TMD was found to decrease from the distal to the proximal part of the femur neck (average slope of 6.5 g.cm( 3).m(-1)). Considering TMD variations in the radial direction induces weak changes of bone properties compared to constant TMD. TMD variations in the axial direction are responsible for a significant variation of elastic constants. These results demonstrate that the anatomical variations of TMD affect the bone elastic properties, which could be explained by the complex stress field in bone affecting bone remodeling. TMD spatial variations should be taken into account to properly describe the spatial heterogeneity of elastic coefficients of bone tissue at the organ scale. PMID- 22245633 TI - Phytotoxic activity in Flourensia campestris and isolation of (--)-hamanasic acid A as its active principle compound. AB - An aqueous extract from Flourensia campestris (Asteraceae) dry aerial parts showed strong inhibition on the germination and growth of Lactuca sativa. Based on bio-guided chromatographic fractionation of aq. extracts from dry and fresh leaves and spectroscopic means, (-)-hamanasic acid A (7-carboxy-8-hydroxy-1(2), 12(13)-dien-bisabolene (1)) was isolated as the most inhibitory active principle on germination (ECg(50)=2.9 mM) and on root (ECr(50)=1.5 mM)/shoot (ECs(50)=2.0 mM) growth. As measured by GC, and correlated with a simple designed 2D-TLC, compound 1 was distributed throughout the plant, with a remarkably high concentration (1.6%) in the leaves and the inflorescences. At least a quarter of the amount of 1 was found in aqueous extracts suggesting that leaching would be a key route for its release into the environment. By contrast, leaf essential oils (HD) between 0.5 and 1.5 MUl ml(-1) did not show herbicidal effects and 1 was not found in them (TLC) nor among volatiles (HS-SPME). Volatile compositions were assessed by GC-FID and GC-MS and led to the identification of 23 compounds (4 monoterpenes and 19 sesquiterpenes) with a wide seasonal (spring-summer%) variation, represented principally by bicyclo-germacrene (37-6%), spathulenol (4 32%), globulol (20-0%), beta-caryophyllene (15-6%), caryophyllene oxide (1-13%) and bicycloelemene (10-1%), respectively. The high amount of 1 in F. campestris together with its feasibility of being extracted with water suggest that (-) hamanasic acid A is an allelochemical in this species. Species-specific studies must be carried out to evaluate the potential of 1 as a natural herbicidal compound. PMID- 22245632 TI - The inhibition of lipopolysaccharide-induced macrophage inflammation by 4 compounds in Hypericum perforatum extract is partially dependent on the activation of SOCS3. AB - Our previous studies found that 4 compounds, namely pseudohypericin, amentoflavone, quercetin, and chlorogenic acid, in Hypericum perforatum ethanol extract synergistically inhibited lipopolysaccharide (LPS)-induced macrophage production of prostaglandin E2 (PGE2). Microarray studies led us to hypothesize that these compounds inhibited PGE2 production by activating suppressor of cytokine signaling 3 (SOCS3). In the current study, siRNA was used to knockdown expression of SOCS3 in RAW 264.7 macrophages and investigated the impact of H. perforatum extract and the 4 compounds on inflammatory mediators and cytokines. It was found that the SOCS3 knockdown significantly compromised the inhibition of PGE2 and nitric oxide (NO) by the 4 compounds, but not by the extract. The 4 compounds, but not the extract, decreased interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), while both lowered interleukine-1beta. SOCS3 knockdown further decreased IL-6 and TNF-alpha. Pseudohypericin was the major contributor to the PGE2 and NO inhibition in cells treated with the 4 compounds, and its activity was lost with the SOCS3 knockdown. Cyclooxygenase-2 (COX-2) and inducible NO synthase protein expression were not altered by the treatments, while COX-2 activity was decreased by the extract and the 4 compounds and increased by SOCS3 knockdown. In summary, it was demonstrated that the 4 compounds inhibited LPS-induced PGE2 and NO through SOCS3 activation. The reduction of PGE2 can be partially attributed to COX-2 enzyme activity, which was significantly elevated with SOCS3 knockdown. At the same time, these results also suggest that constituents in H. perforatum extract were alleviating LPS-induced macrophage response through SOCS3 independent mechanisms. PMID- 22245634 TI - Predicting the adaptive evolution of Thermoanaerobacterium saccharolyticum. AB - A fully evolved metabolic network can be described as a weighted sum of elementary modes where the usage probabilities of modes are distributed according to the Boltzmann distribution law (Srienc and Unrean, 2010). An organism presumably achieves the fully evolved state through adaptive changes in the kinetics of rate-controlling enzymes. Metabolic control analysis identifies reactions catalyzed by such enzymes. Comparison of the experimentally determined metabolic flux distributions of Thermoanaerobacterium saccharolyticum AS411 with the predicted flux distribution of a fully evolved metabolic network identified phosphoglucose isomerase (PGI) as the enzyme with the greatest flux control, the rate-controlling enzyme. The analysis predicts that an increased activity of PGI would enable the metabolic network to approach the fully evolved state and result in a faster specific growth rate. The prediction was confirmed by experimental results that showed an increased specific activity of PGI in a culture of strain AS411 that adaptively evolved over 280 generations. Sequencing of the gene confirmed the occurrence of a group of mutations clustered in the subunit binding domain of the dimeric enzyme. The results indicate that the evolutionary path is predictable as the strain AS411 adapted toward the fully evolved state by increasing the PGI activity. This experimental finding confirms that enzymes with predicted highest metabolic flux control are the targets of adaptive metabolic pathway evolution. PMID- 22245635 TI - Relationships between psychophysically acceptable and maximum voluntary hand force capacity in the context of underlying biomechanical limitations. AB - This research investigated if proportional relationships between psychophysically acceptable and maximum voluntary hand forces are dependent on the underlying biomechanical factor (i.e. whole body balance or joint strength) that limited the maximum voluntary hand force. Eighteen healthy males completed two unilateral maximal exertions followed by a 30 min psychophysical load-adjust protocol in each of nine pre-defined standing scenarios. Center of pressure (whole body balance) and joint moments (joint strength) were calculated to evaluate whether balance or joint strength was most likely limiting maximum voluntary hand force. The ratio of the psychophysically acceptable force to the maximal force was significantly different depending on the underlying biomechanical factor. Psychophysically acceptable hand forces were selected at 86.3 +/- 19.7% of the maximum voluntary hand force when limited by balance (pulling exertions), 67.5 +/ 15.2% when limited by joint strength (downward pressing) and 78 +/- 23% when the limitation was undefined in medial exertions. PMID- 22245636 TI - Measuring the risk of sustaining injury in sport a novel approach to aid the re design of personal protective equipment. AB - Despite the possibilities offered by new approaches in design and advances in materials and manufacturing methods, few items of Personal Protective Equipment (PPE) used in sport have seen significant change for many decades. A major reason for this is the tradition and conservative attitudes associated with many sports, although the absence of appropriate tools and techniques to assist the design and development process has also played a large part. The aim of this study was to develop the first stage of a method of identifying specific regions of the human anatomy that are at the greatest risk of sustaining injury during participation in sports in which the player is subjected to multiple ballistic impacts. It is proposed that the findings could be used to confirm future designs of sports PPE. Previous studies have identified the amount and the location of the protection provided by current commercially available products but, until now, no evidence has been reported to determine what protection is required based on an understanding of the likely impact and the anatomy of the athlete. Using the leg and cricket as examples of an anatomical feature and a sporting application respectively, the severity and probability of injury due to ball impacts typically observed in play are quantified, with respect to their location on the leg, to estimate the level of risk in that region. Results show that the level of risk is greatest in the shin regions of the front leg, suggesting that this region should be offered the greatest degree of protection, as is generally the case in commercially available leg guard designs. Conversely, however, the inner region of the mid shin of the back leg is at the lowest risk, suggesting that protection in this region might be substantially reduced, a feature which is certainly not included in current product; such a reduction may significantly enhance the ergonomic performance of the leg guard design. The findings of this preliminary study indicate that the method offers the potential to quantify the relative risk of sustaining injury, in a sports specific application, as a function of location on the body and is thus a potentially useful design tool for design engineers of sports PPE. Given the embryonic nature of this approach, however, a number of assumptions and additional considerations is presented which reveal that, whilst the technique offers additional design insight, further research is required before it should be applied to equipment design. PMID- 22245637 TI - FMRI group analysis combining effect estimates and their variances. AB - Conventional functional magnetic resonance imaging (FMRI) group analysis makes two key assumptions that are not always justified. First, the data from each subject is condensed into a single number per voxel, under the assumption that within-subject variance for the effect of interest is the same across all subjects or is negligible relative to the cross-subject variance. Second, it is assumed that all data values are drawn from the same Gaussian distribution with no outliers. We propose an approach that does not make such strong assumptions, and present a computationally efficient frequentist approach to FMRI group analysis, which we term mixed-effects multilevel analysis (MEMA), that incorporates both the variability across subjects and the precision estimate of each effect of interest from individual subject analyses. On average, the more accurate tests result in higher statistical power, especially when conventional variance assumptions do not hold, or in the presence of outliers. In addition, various heterogeneity measures are available with MEMA that may assist the investigator in further improving the modeling. Our method allows group effect t tests and comparisons among conditions and among groups. In addition, it has the capability to incorporate subject-specific covariates such as age, IQ, or behavioral data. Simulations were performed to illustrate power comparisons and the capability of controlling type I errors among various significance testing methods, and the results indicated that the testing statistic we adopted struck a good balance between power gain and type I error control. Our approach is instantiated in an open-source, freely distributed program that may be used on any dataset stored in the universal neuroimaging file transfer (NIfTI) format. To date, the main impediment for more accurate testing that incorporates both within and cross-subject variability has been the high computational cost. Our efficient implementation makes this approach practical. We recommend its use in lieu of the less accurate approach in the conventional group analysis. PMID- 22245639 TI - Spatial segregation of somato-sensory and pain activations in the human operculo insular cortex. AB - The role of operculo-insular region in the processing of somato-sensory inputs, painful or not, is now well established. However, available maps from previous literature show a substantial overlap of cortical areas activated by these stimuli, and the region referred to as the "secondary somatosensory area (SII)" is widely distributed in the parietal operculum. Differentiating SII from posterior insula cortex, which is anatomically contiguous, is not easy, explaining why the "operculo-insular" label has been introduced to describe activations by somatosensory stimuli in this cortical region. Based on the recent cyto-architectural parcellation of the human insular/SII cortices (Eickhoff et al., 2006, Kurth et al., 2010), the present study investigates with functional MRI (fMRI), whether these structural subdivisions could subserve distinct aspects of discriminative somato-sensory functions, including pain. Responses to five types of stimuli applied on the left hand of 25 healthy volunteers were considered: i) tactile stimuli; ii) passive movements; iii) innocuous cold stimuli; iv) non-noxious warm and v) heat pain. Our results show different patterns of activation depending on the type of somato-sensory stimulation. The posterior part of SII (OP1 area), contralateral to stimuli, was the only sub region activated by all type of stimuli and might therefore be considered as a common cortical target for different types of somato-sensory inputs. Proprioceptive stimulation by passive finger movements activated the posterior part of SII (OP1 sub-region) bilaterally and the contralateral median part of insula (PreCG and MSG). Innocuous cooling activated the contralateral posterior part of SII (OP1) and the dorsal posterior and median part of insula (OP2, PostCG). Pain stimuli induced the most widespread and intense activation that was bilateral in SII (OP1, OP4) and distributed to all sub-regions of contralateral insula (except OP2) and to the anterior part of the ipsilateral insula (PreCG, MSG, ASG). However, the posterior granular part of insula contralateral to stimulus (Ig area) and the anterior part of SII bilaterally (OP4) were specifically activated during pain stimulation. This raises the question whether these latter areas could be the anatomical substrate of the sensory discriminative processing of thermal pain. PMID- 22245638 TI - Distributed processing; distributed functions? AB - After more than twenty years busily mapping the human brain, what have we learned from neuroimaging? This review (coda) considers this question from the point of view of structure-function relationships and the two cornerstones of functional neuroimaging; functional segregation and integration. Despite remarkable advances and insights into the brain's functional architecture, the earliest and simplest challenge in human brain mapping remains unresolved: We do not have a principled way to map brain function onto its structure in a way that speaks directly to cognitive neuroscience. Having said this, there are distinct clues about how this might be done: First, there is a growing appreciation of the role of functional integration in the distributed nature of neuronal processing. Second, there is an emerging interest in data-driven cognitive ontologies, i.e., that are internally consistent with functional anatomy. We will focus this review on the growing momentum in the fields of functional connectivity and distributed brain responses and consider this in the light of meta-analyses that use very large data sets to disclose large-scale structure-function mappings in the human brain. PMID- 22245640 TI - Using manganese-enhanced MRI to understand BOLD. AB - The 1990s were designated "The Decade of the Brain" by U.S. Congress, perhaps in great anticipation of the impact that functional neuroimaging techniques would have on advancing our understanding of how the brain is functionally organized. While it is impossible to overestimate the impact of functional MRI in neuroscience, many aspects of the blood oxygenation level-dependent (BOLD) contrast remain poorly understood, in great part due to the complex relationship between neural activity and hemodynamic changes. To better understand such relationship, it is important to probe neural activity independently. Manganese enhanced MRI (MEMRI), when used to monitor neural activity, is a technique that uses the divalent manganese ion, Mn(2+), as a surrogate measure of calcium influx. A major advantage of using Mn(2+) as a functional marker is that the contrast obtained is directly related to the accumulation of the ion in excitable cells in an activity dependent manner. As such, the contrast in MEMRI is more directly related to neural activity then hemodynamic-based fMRI techniques. In the present work, the early conceptualization of MEMRI is reviewed, and the comparative experiments that have helped provide a better understanding of the spatial specificity of BOLD signal changes in the cortex is discussed. PMID- 22245641 TI - Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment. AB - Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimer's disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects. PMID- 22245642 TI - Perfusion MR imaging: evolution from initial development to functional studies. AB - A critical indicator of tissue viability and function is blood delivery to the capillary bed (referred to as perfusion or tissue/capillary blood flow), so the measurement of this process has been pursued by many MR scientists. Perfusion MRI is currently an effective tool to non-invasively quantify cerebral blood flow (CBF) and to easily obtain its relative change due to neural activity or other stimulus. This article describes the author's experiences in perfusion MRI over the past quarter-century, including initial development of the field, development of a flow-sensitive alternating inversion recovery (FAIR) MRI technique, development of a functional oxygen consumption MRI measurement approach, validation of the FAIR technique, characterization of perfusion changes induced by neural activity, and determination of arterial blood volume. PMID- 22245643 TI - Studying the freely-behaving brain with fMRI. AB - Given that the brain evolved to function in the real world then it seems reasonable to want to examine how it operates in that context. But of course the world is complex, as are the brain's responses to it, and MRI scanners are inherently restrictive environments. This combination of challenges makes the prospect of studying the freely-behaving brain with fMRI disconcerting to anyone sensible. When designing naturalistic fMRI experiments it is necessary to ensure that the thoughts or behaviours under scrutiny are not unduly perturbed or constrained by the imaging process, while still being amenable to experimental manipulation and control, and result in meaningful and interpretable data. This is difficult to achieve. Here, briefly, and in a highly subjective and selective manner, I consider: why we might want to deploy free-behaviour designs in an fMRI context, how to go about it, review some examples of it in action, and decide finally whether it is worth it (it is). PMID- 22245644 TI - The future of susceptibility contrast for assessment of anatomy and function. AB - The magnetic properties of tissues affect MR images and differences in magnetic susceptibility can be utilized to provide impressive image contrast. Specifically, phase images acquired with gradient echo MRI provide unique and superb contrast which reflects variations in the underlying tissue composition. There is great interest in extracting tissue susceptibility from image data since magnetic susceptibility is an intrinsic tissue property that reflects tissue composition much more closely than MRI phase. Still, this major tissue contrast mechanism is largely unexplored in magnetic resonance imaging because non conventional reconstruction and dipole deconvolution are required to quantitatively map tissue susceptibility properly. This short review summarizes the current state of susceptibility contrast and susceptibility mapping and aims to identify future directions. PMID- 22245645 TI - Amygdala response to smoking-cessation messages mediates the effects of serotonin transporter gene variation on quitting. AB - The amygdala is critically involved in detecting emotionally salient stimuli and in enhancing memory for emotional information. Growing evidence also suggests that the amygdala plays a crucial role in addiction, perhaps by strengthening associations between emotionally-charged drug cues and drug-seeking behavior. In the current study, by integrating functional MRI (fMRI), genetics, and outcome data from a large group of smokers who completed a smoking-cessation intervention and attempted to quit, we show that the amygdala also plays a role in quitting. Specifically, we demonstrate that the amygdala response to smoking-cessation messages in smokers trying to quit is a predictor of their post-intervention quitting outcome. We further show that the amygdala response is modulated by genetic variation in the serotonin transporter and mediates the impact of this genetic variation on quitting. These results point to a gene-brain-behavior pathway relevant to smoking cessation, and add to our understanding of the role of the amygdala in nicotine addiction. PMID- 22245646 TI - Neural basis of phonological processing in second language reading: an fMRI study of Chinese regularity effect. AB - The present study examined the neural basis of phonological processing in Chinese later acquired as a second language (L2). The regularity effect of Chinese was selected to elucidate the addressed phonological processing. We recruited a group of alphabetic language speakers who had been learning Chinese as L2 for at least one year, and a control group of native Chinese speakers. Participants from both groups exhibited a regularity effect in a pilot behavioral test. Neuroimaging results revealed that L2 learners exhibited stronger activation than native Chinese speakers in the right occipitotemporal region (i.e. right lingual gyrus and right fusiform gyrus). Moreover, L2 learners exhibited greater activations in the ventral aspects of the left inferior parietal lobule (LIPL) and the left inferior frontal gyrus (LIFG) for irregular character reading minus regular character reading. In contrast, native Chinese speakers exhibited more dorsal activations in the LIPL and LIFG. According to the "accommodation/assimilation" hypothesis of second language reading, the current findings suggest that native speakers of alphabetic languages utilized an accommodation pattern for the specific requirements of the visual form of Chinese characters, and an assimilation pattern for orthography-to-phonology transformation in Chinese reading. PMID- 22245647 TI - Maturation of task-induced brain activation and long range functional connectivity in adolescence revealed by multivariate pattern classification. AB - The present study uses multivariate pattern classification analysis to examine maturation in task-induced brain activation and in functional connectivity during adolescence. The multivariate approach allowed accurate discrimination of adolescent boys of respectively 13, 17 and 21years old based on brain activation during a gonogo task, whereas the univariate statistical analyses showed no or only very few, small age-related clusters. Developmental differences in task activation were spatially distributed throughout the brain, indicating differences in the responsiveness of a wide range of task-related and default mode regions. Moreover, these distributed age-distinctive patterns generalized from a simple gonogo task to a cognitively and motivationally very different gambling task, and vice versa. This suggests that functional brain maturation in adolescence is driven by common processes across cognitive tasks as opposed to task-specific processes. Although we confirmed previous reports of age-related differences in functional connectivity, particularly for long range connections (>60mm), these differences were not specific to brain regions that showed maturation of task-induced responsiveness. Together with the task-independency of brain activation maturation, this result suggests that brain connectivity changes in the course of adolescence affect brain functionality at a basic level. This basic change is manifest in a range of tasks, from the simplest gonogo task to a complex gambling task. PMID- 22245648 TI - The emergence of doing "nothing" as a viable paradigm design. AB - Resting state fMRI has become widely accepted as a viable technique for investigating functional connectivity of the human brain. I review from a personal perspective the events of the first 8-10 years after the initial report of resting state functional connectivity, focusing on the events that led to eventual acceptance of the method. During this time there were important studies, both in MRI and other modalities, that were critical to the eventual acceptance of the resting state as a viable research tool in fMRI. PMID- 22245649 TI - The role of susceptibility weighted imaging in functional MRI. AB - The development of functional brain magnetic resonance imaging (fMRI) has been a boon for neuroscientists and radiologists alike. It provides for fundamental information on brain function and better diagnostic tools to study disease. In this paper, we will review some of the early concepts in high resolution gradient echo imaging with a particular emphasis on susceptibility weighted imaging (SWI) and MR angiography (MRA). We begin with the history of our own experience in this area, followed by a discussion of the role of high resolution in studying the vasculature of the brain and how this relates to the BOLD (blood oxygenation level dependent) signal. We introduce the role of SWI and susceptibility mapping (SWIM) in fMRI and close with recommendations for future high resolution experiments. PMID- 22245650 TI - A review of the development of Vascular-Space-Occupancy (VASO) fMRI. AB - Vascular-Space-Occupancy (VASO) fMRI is a non-invasive technique to detect brain activation based on changes in Cerebral Blood Volume (CBV), as opposed to conventional BOLD fMRI, which is based on changes in blood oxygenation. This technique takes advantage of the T1 difference between blood and surrounding tissue, and uses an inversion recovery pulse sequence to null blood signal while maintaining part of the tissue signal. The VASO signal intensity can thus be considered proportional to 1-CBV. When neural activation causes CBV to increase, the VASO signal will show a decrease, allowing the detection of activated regions in the brain. Activation-induced changes in VASO signal, ?S/S, are in the order of -1%. Absolute quantification of ?CBV requires additional assumptions on baseline CBV and water contents of the parenchyma and blood. The first VASO experiment was conducted approximately 10 years ago. The original goal of nulling the blood signal was to isolate and measure extravascular BOLD effects, thus a long TE of 50 ms was used in the inversion recovery experiment. Instead of a positive signal change, a slight decrease in signal was observed, which became more pronounced when TE was shortened to 10 ms. These findings led to the hypothesis of a CBV signal mechanism and the development of VASO fMRI. Since its discovery, VASO has been validated by comparison with MION-CBV studies in animals and has been used in humans and animals to understand metabolic and hemodynamic changes during brain activation and physiologic challenges. With recent development of more sensitive VASO acquisitions, the availability of arterial based VASO sequences, and improvement in spatial coverage, this technique is finding its place in neuroscience and clinical studies. PMID- 22245652 TI - Suicide assistance for mentally disordered individuals in Switzerland and the state's positive obligation to facilitate dignified suicide: Haas C. Suisse, Cour europeenne des droits de l'homme, 1re section (20 janvier 2011) (Unreported). PMID- 22245651 TI - Development of orthogonal task designs in fMRI studies of higher cognition: the NIMH experience. AB - This paper chronicles one researcher's journey at the National Institute of Mental Health, exploring ways to understand the neural systems responsible for the cognitive sub-processes of working memory tasks. Both the opportunities and the pitfalls with applying the idea of cognitive subtraction to neuroimaging data were well-known from studies using positron emission tomography. We took advantage of the improved temporal resolution of fMRI with a delayed-recognition task and identified the time-courses of the different stages of the task (encoding, memory delay, and recognition test) as predictor variables in a multiple regression analysis. Because these signals were temporally independent, individual components of tasks could be contrasted with one another, rather than entire tasks, reducing the problem of violations of pure insertion in cognitive subtraction. This approach enabled us to draw more detailed conclusions about the neural systems of higher cognition and the organization of prefrontal cortex than had been possible before fMRI. Further enhancements and innovations over the last 20 years by a multitude of researchers across the field have greatly expanded this knowledge, but this approach called "orthogonal task design" has remained a fundamental component of many of these modern studies. PMID- 22245653 TI - A dignified approach to improving the patient experience: promoting privacy, dignity and respect through collaborative training. AB - Globally there is a plethora of literature surrounding patients' privacy, dignity and respect, consequently highlighting the need for healthcare professionals to ensure such basic human rights are upheld when delivering care. For qualified practitioners this is further emphasised through the professional bodies and their varying codes of practice. To ensure privacy, dignity and respect move from rhetoric to reality in professional practice many pre-registration programmes promote service user involvement. Evidence suggests that involving service users in the delivery of educational programmes by directly telling their own stories enhances patient centred care. However given a number of recent patient surveys and/or audits reporting the lack of privacy, dignity and respect in health and social care settings there seems to be a growing need to reaffirm practitioners' knowledge, skills and values once qualified and practising in healthcare organisations. This paper reports on a project in a UK NHS Mental health Trust where service users, in collaboration with Trust staff, planned and delivered a series of privacy and dignity workshops to healthcare practitioners with the aim of improving the patient experience. Although the project took place within a Mental Health Trust the issues of privacy, dignity and respect apply to all healthcare sectors. PMID- 22245654 TI - A new in vitro injury model of mouse neurons induced by mechanical scratching. AB - The mixed culture of neurons and glial cells has been widely used as a mechanical insult model for the study of neuron injury in vitro. However, a better model is desirable to eliminate the interference of glial cells during the study. Here we report a new model with exclusive cerebellar granule neurons (CGNs), which can be used for the study of in vitro neuron injury without involvement of glial cells. We found that after scratching insult, there was a decrease in both the survival rate and vitality of injured CGNs. Meanwhile, pathological changes were observed by electron microscopy. With this new model, we also tested the effects of neurotrophin-3 (NT-3) on neuroprotection. The result showed that the vitality of injured CGNs was enhanced by the administration of NT-3. These findings demonstrate that this new model is useful for investigation of the precise effect of mechanical damage on neurons excluding other factors, and to detect the neuroprotective effect of certain factors on mechanically injured neurons. PMID- 22245655 TI - CT-guided radiofrequency ablation after with transarterial chemoembolization in treating unresectable hepatocellular carcinoma with long overall survival improvement. AB - PURPOSE: To assess the time to disease progression (TTP), long-term survival benefit and safety of patients with unresectable hepatocellular carcinoma (HCC) treated with computed tomography (CT)-guided radiofrequency ablation (RFA) with transarterial chemoembolization chemoembolization (TACE). METHODS: This study was approved by the institutional review board. We reviewed the records of patients with intermediate and advanced HCC treated with CT-guided RFA with TACE between January 2000 and December 2009. Median TTP, overall survival (OS) and hepatic function were analyzed with the Kaplan-Meier method and log-rank tests. RESULTS: One hundred and twenty-two patients (112 men and 10 women, mean age 53 years, range 18-86 years) were included in the study. The median follow-up time was 42 months (range 6-89 months), TTP was 6.8 months, the median OS was 31 months, and the 1-, 3-, and 5-year OS were 88.5%, 41.0%, and 10.7%. The results of the univariate analysis revealed that intrahepatic lesion, AJCC stage, and Child-Pugh stage were predictors of OS (P<0.01). In the multivariate analysis, the AJCC stage system showed a statistically significant difference for prognosis. Procedure-related death was 0.21% (1/470) within 1 month, and a statistical difference was found between the TACE and RFA of liver decompensation and Child Pugh stage (P<0.05). CONCLUSIONS: The survival probabilities of OS increased with CT-guided RFA with TACE, as observed in randomized studies from Europe and Asia. The longest TTP was observed for the intermediate stage HCC. The procedures were well tolerated with acceptable minor and major complications in unresectable HCC patients. PMID- 22245656 TI - HSP90 inhibition: two-pronged exploitation of cancer dependencies. AB - The early clinical hypothesis for inhibiting HSP90 in cancers was based on the dependence of certain key client proteins in malignant cells--including a host of well-characterized oncoproteins--on the activity of HSP90 for their function and stability. The additional concept has been established that cancer cells have heightened dependence on the efficient maintenance of intracellular proteomic homeostasis, central components of which are HSP90 and other heat shock proteins. We evaluate the evidence that inhibiting HSP90 in cancer exploits both of these biological vulnerabilities very effectively, we review the current status of the discovery and development of HSP90 inhibitors and we identify routes to improve their clinical efficacy, based on emerging knowledge. PMID- 22245657 TI - Factors associated with preventive care practice among adults with diabetes. AB - Adherence to annual preventive care (foot, eye, and dental examinations) in this group of study participants with diabetes (n=253) was suboptimal. Participants were 2.6-5.8 times more likely to have a specific preventive care in the past 12 months if they were told to do so by a health care professional. PMID- 22245658 TI - Tamsulosin exposure is significantly increased by the CYP2D6*10/*10 genotype. PMID- 22245659 TI - [A new era for newborn screening in France?]. PMID- 22245660 TI - [Diagnostic investigations for an unexplained developmental disability]. AB - Developmental disability/mental retardation is a major public health problem and a common cause of consultation in pediatrics, neuropediatrics, and genetics. Etiologies of mental retardation are highly heterogeneous. Diagnostic strategies have been explored in a small number of consensus publications, essentially from English-speaking countries. In these publications, the utility of the conventional karyotype, fragile X screening, metabolic workup, and brain imaging were discussed. Recently, investigations in mental disabilities have been dramatically modified by molecular cytogenetics and the emergence of new metabolic pathologies. Based on the published experiments, the Reference centers for rare disease network "mental deficiencies with rare causes" elaborated an updated protocol for the investigation of nonsyndromal mental disability that takes into account recent innovations in genetics and genomics. Whenever local facilities make it possible, we recommend array CGH investigation as the first step or, when CGH is not available, a combination of classic karyotype with systematic screening of telomeric and interstitial rearrangements by MLPA, fragile X screening in both sexes, and a reorientation of metabolic screening toward certain diseases that have recently been described: congenital disorders of glycosylation (CDG), thyroid hormone carrier deficiency, and creatine metabolism deficiency. We recommend MRI imaging only if head size is abnormal, if neurological examination is abnormal, or regression occurs if walking is not achieved by 2 years, or if development is severely delayed. PMID- 22245661 TI - Intraspinal transplantation of neurogenin-expressing stem cells generates spinal cord neural progenitors. AB - Embryonic stem (ES) cells and their derivatives are an important resource for developing novel cellular therapies for disease. Controlling proliferation and lineage selection, however, are essential to circumvent the possibility of tumor formation and facilitate the safe translation of ES-based therapies to man. Expression of appropriate transcription factors is one approach to direct the differentiation of ES cells towards a specific lineage and stop proliferation. Neural differentiation can be initiated in ES cells by expression of Neurogenin1 (Ngn1). In this study we investigate the effects of controlled Ngn1 expression on mouse ES (mES) cell differentiation in vitro and following grafting into the rat spinal cord. In vitro, Ngn1 expression in mES cells leads to rapid and specific neural differentiation, and a concurrent decrease in proliferation. Similarly transplantation of Ngn1-expressing mES cells into the spinal cord lead to in situ differentiation and spinal precursor formation. These data demonstrate that Ngn1 expression in mES cells is sufficient to promote neural differentiation and inhibit proliferation, thus establishing an approach to safely graft ES cells into the spinal cord. PMID- 22245662 TI - Antiparkinsonian action of a selective group III mGlu receptor agonist is associated with reversal of subthalamonigral overactivity. AB - Activation of group III metabotropic glutamate (mGlu) receptors has been recently highlighted as a potential approach in the treatment of Parkinson's disease (PD). This study evaluates the antiparkinsonian action of systemic administration of the broad-spectrum agonist of group III mGlu receptors, 1-aminocyclopentane-1,3,4 tricarboxylic acid (ACPT-I), and investigates its site of action within the basal ganglia circuitry. Acute injection of ACPT-I reverses haloperidol-induced catalepsy, an index of akinesia in rodents. In a rat model of early PD based on partial bilateral nigrostriatal lesions, chronic (2weeks) administration of ACPT I is required to efficiently alleviate the akinetic deficit evidenced in a reaction time task. This treatment counteracts the post-lesional increases in the gene expression of cytochrome oxidase subunit I, a metabolic marker of neuronal activity, in the overall subthalamic nucleus and in the lateral motor part of the substantia nigra pars reticulata (SNr) but has no effect in the globus pallidus. Paradoxically, ACPT-I administration in sham animals impairs performance and induces overexpression of cytochrome oxidase subunit I mRNA in the lateral SNr, and has no effect in the subthalamic nucleus or globus pallidus. Altogether, our results provide new evidence for the antiparkinsonian efficiency of group III mGlu receptor agonism, point to the regulation of the overactive subthalamo nigral connection as a main site of action in an early stage of PD and underline the complex interplay between these receptors and the dopaminergic system to regulate basal ganglia function in control and PD conditions. PMID- 22245664 TI - Food and Chemical Toxicology, 2010, Association of phenylbutazone usage in horses bought for slaughter: a public health risk. PMID- 22245663 TI - NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia. AB - RATIONALE: There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently used pharmacological models of schizophrenia, recreate deficits in electrophysiological markers of disturbed brain circuits that are thought to underlie the illness. Furthermore, this study characterizes the specificity of these differences across the frequency spectrum so as to help identify the nature of selective circuit abnormalities that mediate each oscillatory response as relevant to schizophrenia. DESIGN: Mouse EEG was recorded during exposure to repeated auditory stimuli after injection of either vehicle or drug. The dose-response relationship for each electrophysiological measure was determined for ketamine and MK-801. Time-frequency analyses were performed to assess baseline, total, and evoked power and intertrial coherence (ITC) at low (5-10 Hz) and high (35-80 Hz) frequencies. RESULTS: High frequency evoked and total power was decreased by MK 801 and ketamine in a dose-dependent fashion. High frequency baseline power was increased by MK-801 and ketamine in a dose-dependent fashion. Similar to evoked power, high frequency inter-trial coherence was dose-dependently decreased by both drugs. Low frequency ITC was only decreased by ketamine. CONCLUSIONS: Both ketamine and MK-801 cause alterations in high-frequency baseline (noise), total (signal), and evoked (signal) power resulting in a loss of high frequency SNR that is thought to primarily reflect local circuit activity. These changes indicate an inappropriate increase in baseline activity, which can also be interpreted as non-task related activity. Ketamine induced a loss of intertrial coherence at low frequencies, indicating a loss of consistency in low-frequency circuit mechanisms. As a proportion of baseline power, both drugs had a relative shift from low to high frequencies, reflecting a change in the balance of brain activity from coordination of global regions to a pattern of discoordinated, autonomous local activity. These changes are consistent with a pattern of fragmented regional brain activity seen in schizophrenia. PMID- 22245665 TI - Body mass index increases risk for colorectal adenomas based on meta-analysis. AB - BACKGROUND & AIMS: There have been inconsistent results published about the relationship between excess body weight, expressed as increased body mass index (BMI), and risk of colorectal adenoma (CRA). We conducted a meta-analysis to explore this relationship. We focused on whether the relationship varied based on the sex of the study subjects, study design, features of the polyps, or potential confounders, including alcohol use, nonsteroidal anti-inflammatory drug use, smoking, and exercise. METHODS: We identified studies by performing a literature search of Medline, EMBASE, and ISI Web of Science through July 31, 2011, and by searching the reference lists of pertinent articles. We analyzed 36 independent studies, which included 29,860 incident cases of CRA. Summary relative risks with their 95% confidence intervals (CIs) were calculated with a random-effects model. Between-study heterogeneity was assessed using Cochran's Q statistic and I(2) analyses. RESULTS: Overall, a 5-unit increase in BMI (calculated as kg/m(2)) increased the risk for CRA (summary relative risk = 1.19; 95% CI: 1.13-1.26), although there was a high level of heterogeneity among studies (P(heterogeneity) < .001; I(2) = 76.8%). Subgroup analyses revealed that the increased risk of CRA in obese individuals was independent of race, geographic location, study design, sex, adenoma progression, and confounders. The association between increased BMI and risk for CRA was stronger for colon than rectal adenoma. CONCLUSIONS: Based on a meta-analysis, increased BMI increases the risk for colon but not rectal adenoma. Unlike colorectal cancer, there is no sex difference in the relationship between increased BMI and risk of CRA. PMID- 22245666 TI - Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. AB - BACKGROUND & AIMS: Endoscopic ultrasound-guided transmural gallbladder drainage (EUS-GBD) is an alternative to percutaneous transhepatic gallbladder drainage (PTGBD) for patients with acute, high-risk, or advanced-stage cholecystitis who do not respond to initial medical treatment and cannot undergo emergency cholecystectomy. However, the technical feasibility, efficacy, and safety of EUS GBD and PTGBD have not been compared. METHODS: Fifty-nine patients with acute cholecystitis, who did not respond to initial medical treatment and were unsuitable for an emergency cholecystectomy, were chosen randomly to undergo EUS GBD (n = 30) or PTGBD (n = 29). The technical feasibility, efficacy, and safety of EUS-GBD and PTGBD were compared. RESULTS: EUS-GBD and PTGBD showed similar technical (97% [29 of 30] vs 97% [28 of 29]; 95% 1-sided confidence interval lower limit, -7%; P = .001 for noninferiority margin of 15%) and clinical (100% [29 of 29] vs 96% [27 of 28]; 95% 1-sided confidence interval lower limit, -2%; P = .0001 for noninferiority margin of 15%) success rates, and similar rates of complications (7% [2 of 30] vs 3% [1 of 29]; P = .492 in the Fisher exact test) and conversions to open cholecystectomy (9% [2 of 23] vs 12% [3 of 26]; P = .999 in the Fisher exact test). The median post-procedure pain score was significantly lower after EUS-GBD than after PTGBD (1 vs 5; P < .001 in the Mann-Whitney U test). CONCLUSIONS: EUS-GBD is comparable with PTGBD in terms of the technical feasibility and efficacy; there were no statistical differences in the safety. EUS-GBD is a good alternative for high-risk patients with acute cholecystitis who cannot undergo an emergency cholecystectomy. PMID- 22245668 TI - Efficacy of different primaquine-based antimalarial regimens against Plasmodium falciparum gametocytemia. AB - This study compared the efficacy against Plasmodium falciparum gametocytes of four regimens: amodiaquine-sulfadoxine/pyrimethamine (AQ-SP) and mefloquine artesunate (MQ-AS), with and without primaquine (PQ) administered with the second dose of the schizonticide (AQ-SP; AQ-SP-PQ; MQ-AS; MQ-AS-PQ). Efficacy was determined by thick smear on days 1, 4 and 8 after the beginning of treatment. A total of 82 patients (19-23/group) were recruited. After AQ-SP administration, gametocytemia steadily increased until day 8. With AQ-SP-PQ, a marked decline in gametocytemia was detected on days 4 and 8. MQ-AS treatment resulted in reduced gametocytemia on days 4 and 8, and with MQ-AS-PQ it was reduced even further. None of the treatments cleared gametocytemia by day 8. Currently, artemisinin based combination therapies plus PQ are the recommended treatment option against falciparum malaria; however, further studies are required to optimize the use of PQ. Issues to be addressed include the optimal time of administration, treatment duration, optimal daily and total dose, and day of evaluation of the gametocytocidal effect. In falciparum malaria, the WHO recommends a maximum of 4days of treatment; consequently, an effective regimen must clear asexual parasites and symptoms within this time frame. The same criteria should be taken into account when evaluating the anti-gametocyte activity. PMID- 22245667 TI - Cigarette smoking increases risk of Barrett's esophagus: an analysis of the Barrett's and Esophageal Adenocarcinoma Consortium. AB - BACKGROUND & AIMS: Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett's esophagus. We investigated whether tobacco smoking and other factors increase risk for Barrett's esophagus. METHODS: We analyzed data from 5 case control studies included in the international Barrett's and Esophageal Adenocarcinoma Consortium. We compared data from subjects with Barrett's esophagus (n = 1059) with those from subjects with gastroesophageal reflux disease (gastroesophageal reflux disease controls, n = 1332), and population based controls (n = 1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for Barrett's esophagus. RESULTS: Subjects with Barrett's esophagus were significantly more likely to have ever smoked cigarettes than the population based controls (odds ratio [OR] = 1.67; 95% confidence interval [CI]: 1.04-2.67) or gastroesophageal reflux disease controls (OR = 1.61; 95% CI: 1.33-1.96). Increasing pack-years of smoking increased the risk for Barrett's esophagus. There was evidence of a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (95% CI: 0.25 0.52). CONCLUSIONS: Cigarette smoking is a risk factor for Barrett's esophagus. The association was strengthened with increased exposure to smoking until ~20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to development of Barrett's esophagus. PMID- 22245669 TI - Lentivirus-mediated silencing of I2PP2A through RNA interference attenuates trichloroethylene-induced cytotoxicity in human hepatic L-02 cells. AB - Trichloroethylene (TCE) is a common chemical pollutant that exists in air, soil, and drinking water. TCE exposure is known to cause severe hepatotoxicity; however, the mechanisms underlying TCE hepatotoxicity remain poorly understood. In a previous proteomics study, we found that TCE exposure up-regulated the expression of the inhibitor 2 of protein phosphatase 2A (I2PP2A), a potent and specific endogenous inhibitor of protein phosphatase (PP) 2A, in human hepatic L 02 cells. Here, we employed lentivirus-mediated RNA interference (RNAi) to knock down I2PP2A expression in L-02 cells and explored the potential role of I2PP2A in TCE-induced cytotoxicity. We found that TCE treatment of L-02 cells causes decreased cell viability, increased apoptosis and elevated I2PP2A mRNA and protein levels. TCE-treated L-02 cells were also found to have significantly reduced PP2A activity. Lentivirus-mediated I2PP2A knockdown partially prevented the decrease in viability and increased apoptosis induced by TCE treatment. Knockdown of I2PP2A in TCE-treated L-02 cells also suppressed the inhibition of PP2A activity and prevented caspase-3 activation. These data for the first time demonstrate that the up-regulation of I2PP2A could mediate, at least in part, TCE induced liver cell toxicity through the inhibition of PP2A activity and caspase-3 mediated pathway, and suggest that I2PP2A may play a crucial role in mediating TCE hepatotoxicity. PMID- 22245670 TI - Influx of extracellular calcium participates in rituximab-enhanced ionizing radiation-induced apoptosis in Raji cells. AB - We have previously shown that rituximab has a significant radiosensitizing effect on Raji cells in vitro. To investigate whether calcium signals participate in rituximab- and radiation-induced cell death in Raji cells, confocal laser scanning microscopy was used to detect kinetic changes in intracellular free calcium concentration ([Ca2+]i). Cell survival, the rates of apoptosis in Raji cells and the kinetics of gamma-H2AX foci induction and loss were also evaluated. X-irradiation of Raji cells induced an initial increase of [Ca2+]i in both the presence and absence of extracellular calcium, followed by a decrease in [Ca2+]i over time. Rituximab enhanced both the amplitude and the duration of intracellular calcium signals in the irradiated cells. EGTA significantly inhibited radiation- or radiation/rituximab combination treatment-induced apoptosis. However, the calcium chelators EGTA and BAPTA/AM conferred no survival advantage on the irradiated cells. Furthermore, although no significant difference was seen after 1h, the treatment of cells with a combination of irradiation and rituxiamb caused an increase of gamma-H2AX foci when compared with irradiated cells after 8h. Both EGTA and BAPTA/AM suppressed the number of gamma-H2AX foci induced by either radiation or radiation combined with rituximab. Our results suggest that rituximab increases the level of [Ca2+]i in irradiated Raji cells. The entry of calcium from the extracellular space plays an essential role in [Ca2+]i-dependent radiation-induced apoptosis in Raji cells. The calcium chelators inhibited the formation of gamma-H2AX foci, which are thought to prevent the activation of Ca2+/Mg(2+)-dependent endonucleases and subsequent DNA fragmentation. The calcium chelators most likely modulate only particular features of apoptosis and fail to change the fates of cells that are already committed to die. PMID- 22245671 TI - Hypomethylation mediated by decreased DNMTs involves in the activation of proto oncogene MPL in TK6 cells treated with hydroquinone. AB - Hydroquinone (HQ), one of the most important metabolites derived from benzene, is known to be associated with acute myelogenous leukemia (AML) risk, however, its carcinogenic mechanism remains unclear. In this study, the epigenetic mechanism of HQ exposure was investigated. We characterized the epigenomic response of TK6 cells to HQ exposure, and examined the mRNA expression of DNA methyltransferases (DNMTs) including DNMT1, DNMT3a and DNMT3b, methyl-CpG-binding domain protein 2 (MBD2) and six proto-oncogenes (MPL, RAF1, MYB, MYC, ERBB2 and BRAF). Compared to the control cells, HQ exposure (2.5, 5.0, 10.0 and 20.0 MUM for 48 h) resulted in the decrease of DNMTs and MBD2 expression, the global hypomethylation and increase of MPL at mRNA level. Meanwhile, most of these changes were in dose dependent manner. Moreover, inhibition of DNMTs induced by 5-aza-2'-deoxycytidine (5-AZA), an identified DNMT inhibitor, caused more induction of MPL expression at mRNA level compared to the HQ (10.0 MUM) pre-treated group. Furthermore, treatment of HQ potentially led to MPL itself hypomethylation (10.0 and 20.0 MUM reduced by 47% and 44%, respectively), further revealing that the activation of proto-oncogene MPL was related to hypomethylation in its DNA sequences. In conclusion, hypomethylation, including global and specific hypomethylation, might be involved in the activation of MPL, and the hypomethylation could be induced by decreased DNMTs in TK6 cells exposed to HQ. PMID- 22245672 TI - Biotransformation of geniposide by human intestinal microflora on cytotoxicity against HepG2 cells. AB - Intestinal microflora (IM) is able to produce toxic and carcinogenic metabolites and induce more potent cytotoxicity against cells than non-metabolites. This study was performed to investigate the cytotoxic responses of geniposide (GS) and its metabolite and to determine the role of metabolism by IM in GS-induced cytotoxicity. Genipin (GP), a GS metabolite, increased cytotoxic effects in cells, but GS did not. Following GS incubation with IM for metabolic activation, increased cytotoxicity was detected compared to GS. Western blot analysis revealed that the activated GS inhibited Bcl-2 expression with a subsequent increase in Bax expression. Likewise, GS activation by IM stimulated caspase-3 and the production of reactive oxygen species (ROS). In addition, activated GS induced apoptosis was confirmed by apoptosis and ROS assays; N-acetyl-l-cysteine (NAC) suppressed ROS production and apoptotic cell death. Activated GS induced sustained JNK phosphorylation. Moreover, activated GS-induced cell death was reversed by SP600125. Taken together, these findings suggest that human IM is able to metabolize GS into GP, and the related biological activities induce apoptosis through ROS/JNK signaling. PMID- 22245673 TI - Yeast ribosomal protein S3 possesses a beta-lyase activity on damaged DNA. AB - Yeast ribosomal protein S3 has multifunctional activities that are involved in both protein translation and DNA repair. Here, we report that yeast Rps3p cleaves variously damaged DNA that contains not only AP sites and pyrimidine dimers but also 7,8-hydro-8-oxoguanine. This study also revealed that Rps3p has a beta-lyase activity with a broad range of substrate specificity which cleaves phosphodiester bonds of UV or oxidatively damaged DNA substrates. Mutation analysis of the yeast Rps3 protein including introduction of domain deletions and residue replacements identified the residues Asp154 and Lys200 are important for the catalytic activity. In addition, the repair enzyme activity of yeast Rps3p was confirmed by complementation in xth, nfo Escherichia coli cells in which the DNA repair process is defective. PMID- 22245674 TI - Sorbitol dehydrogenase of Aspergillus niger, SdhA, is part of the oxido-reductive D-galactose pathway and essential for D-sorbitol catabolism. AB - In filamentous fungi D-galactose can be catabolised through the oxido-reductive and/or the Leloir pathway. In the oxido-reductive pathway D-galactose is converted to d-fructose in a series of steps where the last step is the oxidation of d-sorbitol by an NAD-dependent dehydrogenase. We identified a sorbitol dehydrogenase gene, sdhA (JGI53356), in Aspergillus niger encoding a medium chain dehydrogenase which is involved in D-galactose and D-sorbitol catabolism. The gene is upregulated in the presence of D-galactose, galactitol and D-sorbitol. An sdhA deletion strain showed reduced growth on galactitol and growth on D-sorbitol was completely abolished. The purified enzyme converted D-sorbitol to D-fructose with K(m) of 50+/-5 mM and v(max) of 80+/-10 U/mg. PMID- 22245675 TI - VapB as a regulator of osteoclastogenesis via modulation of PLCgamma2-Ca(2+)-NFAT signaling. AB - VapB has been shown to regulate calcium homeostasis in amyotrophic lateral sclerosis. Calcium signaling is also important in metabolic bone diseases, but the role of VapB in the generation of osteoclasts for bone resorption during osteoclastogenesis is not known. Therefore, we investigated the role of VapB in RANKL-induced osteoclast differentiation. Interestingly, VapB is induced during osteoclastogenesis, and regulates osteoclast differentiation by modulating NFATc1. The results also suggest that VapB regulates osteoclastogenesis via PLCgamma2-Ca(2+)-NFAT signaling. The involvement of PLCgamma2-Ca(2+)-NFAT signaling in VapB-regulated osteoclastogenesis was confirmed by a pharmacological study. Taken together, the results indicate that VapB positively regulates RANKL mediated osteoclastogenesis via PLCgamma2-Ca(2+)-NFAT signaling. PMID- 22245676 TI - Inflammatory changes in adipose tissue enhance expression of GPR84, a medium chain fatty acid receptor: TNFalpha enhances GPR84 expression in adipocytes. AB - In this study we aimed to identify the physiological roles of G protein-coupled receptor 84 (GPR84) in adipose tissue, together with medium-chain fatty acids (MCFAs), the specific ligands for GPR84. In mice, high-fat diet up-regulated GPR84 expression in fat pads. In 3T3-L1 adipocytes, co-culture with a macrophage cell line, RAW264, or TNFalpha remarkably enhanced GPR84 expression. In the presence of TNFalpha, MCFAs down-regulated adiponectin mRNA expression in 3T3-L1 adipocytes. Taken together, our results suggest that GPR84 emerges in adipocytes in response to TNFalpha from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity. PMID- 22245677 TI - Identification and characterization of an LCAT-like Arabidopsis thaliana gene encoding a novel phospholipase A. AB - A previously uncharacterized Arabidopsis lecithin:cholesterol acyltransferase (LCAT) family gene (At4g19860) was functionally expressed in yeast, where it was demonstrated to encode a novel cytosolic and calcium-independent phospholipase A with preferences for the sn-2 position. This enzyme shows optimal activity at pH 5.0, exhibits a headgroup specificity for phosphatidylcholine>phosphatidic acid>phosphatidylethanolamine>phosphatidylglycerol>phosphatidylserine and has an acyl chain specificity for oleoyl>linoleoyl>ricinoleoyl. The expression of AtLCAT PLA inhibited yeast cell growth and fatty acid accumulation. AtLCAT-PLA transcript in Arabidopsis was detected at high levels in roots and siliques. PMID- 22245678 TI - Exploring the mechanism of lipid transfer during biosynthesis of the acidic lipopeptide antibiotic CDA. AB - The non-ribosomally synthesized lipodepsipeptide CDA belongs to the group of acidic lipopeptide antibiotics, whose members feature a fatty acid side chain that strongly affects their antimicrobial activity. This study elucidates the N acylation of the N-terminal serine in the CDA peptide chain. This reaction is referred to as lipoinitiation and is shown to be catalyzed by the dissected starter C domain found at the N-terminus of Cda-PSI. The recombinantly produced C domain specifically interacts with 2,3-epoxyhexanoyl-S-ACP and catalyzes the transfer of the fatty acid moiety onto the amino group of PCP-bound serine with high selectivity for both carrier protein bound substrates at the donor and acceptor site. PMID- 22245679 TI - Anti-diabetic and anti-obesity agent sodium tungstate enhances GCN pathway activation through Glc7p inhibition. AB - Tungstate counteracts diabetes and obesity in animal models, but its molecular mechanisms remain elusive. Our Saccharomyces cerevisiae-based approach has found that tungstate alleviated the growth defect induced by nutrient stress and enhanced the activation of the GCN pathway. Tungstate relieved the sensitivity to starvation of a gcn2-507 yeast hypomorphic mutant, indicating that tungstate modulated the GCN pathway downstream of Gcn2p. Interestingly, tungstate inhibited Glc7p and PP1 phosphatase activity, both negative regulators of the GCN pathway in yeast and humans, respectively. Accordingly, overexpression of a dominant negative Glc7p mutant in yeast mimicked tungstate effects. Therefore tungstate alleviates nutrient stress in yeast by in vivo inhibition of Glc7p. These data uncover a potential role for tungstate in the treatment of PP1 and GCN related diseases. PMID- 22245680 TI - Influence of the intracellular GluN2 C-terminal domain on NMDA receptor function. AB - Excitatory neurotransmission mediated by N-methyl-d-aspartate receptors (NMDARs) is fundamental to learning and memory and, when impaired, causes certain neurological disorders. NMDARs are heterotetrameric complexes composed of two GluN1 [NR1] and two GluN2(A-D) [NR2(A-D)] subunits. The GluN2 subunit is responsible for subunit-specific channel activity and gating kinetics including activation (rise time), peak open probability (peak Po) and deactivation (decay time). The peak Po of recombinant NMDARs was recently described to be controlled by the extracellular GluN2 N-terminal domain (NTD). The cytoplasmic GluN2 C terminal domain (CTD) could also be involved, because the Po of synaptic NMDARs is reduced in mice expressing C-terminally truncated GluN2 subunits. Here, we examined the role of the GluN2 cytoplasmic tail for NMDAR channel activity and gating in HEK-293 cells. C-terminal truncation of GluN2A, GluN2B or GluN2C did not change the subunit-specific rise time but accelerated the decay time of glutamate-activated currents. Furthermore, the peak Po was reduced by about 50% for GluN2A and GluN2B but not for GluN2C. These results indicated that the CTD of GluN2 has a modulating role in NMDAR gating even in the absence of interacting synaptic proteins. Reduction of peak Po and deactivation kinetics following GluN2 C-terminal truncation were reversed by re-introducing a CTD from a different GluN2 subunit. Thus, the CTDs of GluN2 subunits behave as constitutive structural elements required for normal functioning of NMDARs but are not involved in determining the subunit-specific gating properties of NMDARs. PMID- 22245681 TI - Sex-specific disturbances of the glutamate/GABA balance in the hippocampus of adult rats subjected to adolescent cannabinoid exposure. AB - Adolescence is a period of active synaptic remodelling and plasticity and as such, a developmental phase of particular vulnerability to the effects of environmental insults. The endogenous cannabinoid system regulates central nervous system development and cannabinoid exposure during adolescence has been linked to several alterations to hippocampal-dependent processes such as cognition and emotion, which rely on intact glutamatergic and GABAergic systems. Here we show that K(+)-induced gamma-amino butyric acid (GABA) release increases in the CA1 hippocampal field of Wistar rats of both sexes that were treated chronically with the cannabinoid agonist CP 55,940 (CP55940) during adolescence. GABA(B) receptors levels also increased in cannabinoid-exposed rats. In addition, CP55940-treated females exhibit reduced GABA transporter gene expression (GAT-1), increased GABA(A) receptor expression, as well as decreased K(+)-induced glutamate release and NMDA receptor levels. CP55940 administration did not affect the glial (EAAT2) or neuronal (EAAT3) glutamate transporter gene expression in either males or females, and nor were any changes in the mGlu5 receptor protein levels observed. Taken together, these results show that while the exacerbated GABA release induced by early cannabinoid exposure may be compensated by an increment in GABA(B) receptors, which normally function as inhibitory autoreceptors, adolescent cannabinoid exposure in the females disturbs the normal balance between glutamate and GABA transmission. These observations may provide important insight into the neuronal basis of the well-documented alterations in cognitive and emotional processes induced by adolescent cannabinoid exposure. PMID- 22245682 TI - The effects of gamma irradiation on growth and expression of genes encoding DNA repair-related proteins in Lombardy poplar (Populus nigra var. italica). AB - In this study, to elucidate the mechanisms of adaptation and tolerance to ionizing radiation in woody plants, we investigated the various biological effects of gamma-rays on the Lombardy poplar (Populus nigra L. var. italica Du Roi). We detected abnormal leaf shape and color, fusion, distorted venation, shortened internode, fasciation and increased axillary shoots in gamma-irradiated poplar plants. Acute gamma-irradiation with a dose of 100Gy greatly reduced the height, stem diameter and biomass of poplar plantlets. After receiving doses of 200 and 300Gy, all the plantlets stopped growing, and then most of them withered after 4-10 weeks of gamma-irradiation. Comet assays showed that nuclear DNA in suspension-cultured poplar cells had been damaged by gamma-rays. To determine whether DNA repair-related proteins are involved in the response to gamma-rays in Lombardy poplars, we cloned the PnRAD51, PnLIG4, PnKU70, PnXRCC4, PnPCNA and PnOGG1 cDNAs and investigated their mRNA expression. The PnRAD51, PnLIG4, PnKU70, PnXRCC4 and PnPCNA mRNAs were increased by gamma-rays, but the PnOGG1 mRNA was decreased. Moreover, the expression of PnLIG4, PnKU70 and PnRAD51 was also up regulated by Zeocin known as a DNA cleavage agent. These observations suggest that the morphogenesis, growth and protective gene expression in Lombardy poplars are severely affected by the DNA damage and unknown cellular events caused by gamma-irradiation. PMID- 22245683 TI - Coated microneedle arrays for transcutaneous delivery of live virus vaccines. AB - Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8(+) T cell response in mice that was comparable to that obtained by needle-and syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices. PMID- 22245684 TI - Targeting the amyloid-beta antibody in the brain tissue of a mouse model of Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disease characterized pathologically by amyloid-beta (Abeta) aggregates in the brain. Notwithstanding many promising therapeutics that are under development, early diagnosis of Alzheimer's disease is limited. By targeting the Abeta aggregates, diagnosis can be improved and disease progression reduced. Molecular imaging using monoclonal antibodies to target specific isoforms of Abeta aggregates offer increased specificity in comparison to conventional imaging tracers; however, antibodies that are widely used in histology do not necessarily show similar binding in a dynamic in vivo environment. In this study, the diffusion and binding were studied of a classical monoclonal antibody, 6E10, in the brain of the TgCRND8 mouse model of AD. After intracranial injection of fluorescent 6E10, we observed broad and rapid labelling of Abeta deposits in the cortex and corpus callosum within 4h. Abeta plaques were detected up to 2.5mm away from the injection site in TgCRND8 mice and not in wild type mice at all, demonstrating specificity of binding. The apparent diffusivity and elimination constant of the anti-Abeta antibody were found to be independent of both the age of the animal and the accumulation of Abeta in the extracellular space, suggesting broad applicability of this targeting molecule. Mathematical modelling of the diffusion profiles of the anti-Abeta antibody in the brain parenchyma provides insights into the utility of antibodies as molecular imaging tools and targeted therapeutics. PMID- 22245685 TI - Biofunctional nanosystems based on dendritic polymers. AB - Among the various polymeric architectures, dendritic polymers have received a substantial scientific focus for their highly branched, multifunctional, and well defined structures. Dendritic scaffolds have found many applications for designing nanoscale drug/gene delivery carriers and constructing diagnostic and biosensor devices, and protein-resistant surfaces. A significant number of research groups across Europe share the common objective, yet in conspicuously individual ways, of utilizing such polymers for devising innovative biomedical tools and techniques. This review describes the European effort of finding the application of dendritic polymers as advanced generation therapeutics within the purview of nanomedicine. PMID- 22245686 TI - Non-glycosylated BMP-2 can induce ectopic bone formation at lower concentrations compared to glycosylated BMP-2. AB - Bone morphogenic protein-2 (BMP-2) is a well-known growth factor that can improve the biological performance of bone substitute materials. BMP-2 produced via bacterial expression systems are non-glycosylated (ng) whereas native and recombinant equivalents produced in mammalian cell expression systems are glycosylated (g) proteins. ngBMP-2 is less soluble, resulting in lower BMP-2 release from carriers as used as bone substitute materials. This seems promising for reducing the amount of included growth factor in bone substitute materials. Hence, it was hypothesized that ngBMP-2 would induce formation of the same amount of bone at an ectopic site at lower dosage as gBMP-2. To that end, gBMP-2 and ngBMP-2 were firstly in vitro comparatively evaluated for biological activity and release from a calcium phosphate (CaP) based bone substitute material. Thereafter, an ectopic implantation model in rats was used, in which gBMP-2 and ngBMP2 were loaded in various dosages (2-20 MUg/implant) on the CaP-based bone substitute material and implanted for 4 and 12 weeks. The results revealed that both the in vitro biological activity of and the in vitro release of ngBMP-2 are lower compared to gBMP2. Upon ectopic implantation, however, ngBMP-2 loaded implants induced more bone formation at lower concentrations from 4-weeks onward compared to gBMP-2 equivalents, indicating the value of ngBMP-2 as a potential alternative for mammalian produced recombinant BMP-2 for bone regenerative therapies. PMID- 22245687 TI - Towards tailored vaccine delivery: needs, challenges and perspectives. AB - The ideal vaccine is a simple and stable formulation which can be conveniently administered and provides life-long immunity against a given pathogen. The development of such a vaccine, which should trigger broad and strong B-cell and T cell responses against antigens of the pathogen in question, is highly dependent on tailored vaccine delivery approaches. This review addresses vaccine delivery in its broadest scope. We discuss the needs and challenges in the area of vaccine delivery, including restrictions posed by specific target populations, potentials of dedicated stable formulations and devices, and the use of adjuvants. Moreover, we address the current status and perspectives of vaccine delivery via several routes of administration, including non- or minimally invasive routes. Finally we suggest possible directions for future vaccine delivery research and development. PMID- 22245688 TI - Positron emission tomography evaluation of somatostatin receptor targeted 64Cu TATE-liposomes in a human neuroendocrine carcinoma mouse model. AB - Targeted therapeutic and diagnostic nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize over-expressed receptors or antigens on tumor cells have potential in the diagnosis and therapy of cancer. Somatostatin receptors (SSTRs) are over-expressed in a variety of cancers, particularly neuroendocrine tumors (NETs) and can be targeted with somatostatin peptide analogs such as octreotate (TATE). In the present study we investigate liposomes that target SSTR in a NET xenograft mouse model (NCI-H727) by use of TATE. TATE was covalently attached to the distal end of DSPE-PEG(2000) on PEGylated liposomes with an encapsulated positron emitter (64)Cu that can be utilized for positron emission tomography (PET) imaging. The biodistribution and pharmacokinetics of the (64)Cu-loaded PEGylated liposomes with and without TATE was investigated and their ability to image NETs was evaluated using PET. Additionally, the liposome accumulation and imaging capability was compared with free radiolabelled TATE peptide administered as (64)Cu-DOTA-TATE. The presence of TATE on the liposomes resulted in a significantly faster initial blood clearance in comparison to control-liposomes without TATE. PEGylated liposomes with or without TATE accumulated at significantly higher quantities in NETs (5.1+/-0.3 and 5.8+/-0.2 %ID/g, respectively) than the free peptide (64)Cu-DOTA-TATE (1.4+/ 0.3 %ID/g) 24 h post-injection. Importantly, (64)Cu-loaded PEGylated liposomes with TATE showed significantly higher tumor-to-muscle (T/M) ratio (12.7+/-1.0) than the control-liposomes without TATE (8.9+/-0.9) and the (64)Cu-DOTA-TATE free peptide (7.2+/-0.3). The higher T/M ratio of the PEGylated liposomes with TATE suggests some advantage of active targeting of NETs, although no absolute benefit in tumor accumulation over the non-targeted liposomes was observed. Collectively, these data showed that (64)Cu-loaded PEGylated liposomes with TATE conjugated to the surface could be promising new imaging agents for visualizing tumor tissue and especially NETs using PET. PMID- 22245689 TI - Carbon nanotubes-liposomes conjugate as a platform for drug delivery into cells. AB - Carbon nanotubes (CNT) are widely explored as carriers for drug delivery due to their facile transport through cellular membranes. However, the amount of loaded drug on a CNT is rather small. Liposomes, on the other hand, are employed as a carrier of a large amount of drug. The aim of this research is to develop a new drug delivery system, in which drug-loaded liposomes are covalently attached to CNT to form a CNT-liposomes conjugate (CLC). The advantage of this novel approach is the large amount of drug that can be delivered into cells by the CLC system, thus preventing potential adverse systemic effects of CNT when administered at high doses. This system is expected to provide versatile and controlled means for enhanced delivery of one or more agents stably associated with the liposomes. PMID- 22245690 TI - Strong association of common variants in the IGF2BP2 gene with type 2 diabetes in Lebanese Arabs. AB - OBJECTIVE: Several genome-wide association studies and replication analyses have identified common variation at the insulin-like binding protein 2 (IGF2BP2) gene to be associated with type 2 diabetes (T2DM). The aim of this study was to replicate in a Lebanese Arab population identified associations of IGF2BP2 variants rs4402960 and rs1470579 with T2DM. METHODS: This case-control study involved 544 T2DM patients and 606 control subjects. Genotyping was done by the allelic exclusion method. RESULTS: T allele of rs440960 (P=6.5 * 10(-6)) and C allele of rs1470579 (P=5.3 * 10(-4)) were significantly associated with T2DM; both SNPs were in strong LD (D'=0.83, r(2)=0.58). While both IGF2BP2 SNPs were significantly associated with T2DM under additive and recessive models, only rs4402960 remained significantly associated with T2DM under the dominant model. Taking the common rs4402960/rs1470579 GA haplotype as reference, multivariate analysis confirmed the positive association of TC (P=0.009; OR, 1.43; 95%CI, 1.09 1.87), and TA (P<0.001; OR=5.49; 95%CI=2.09-14.39) haplotypes with increased T2DM risk. These differences remained significant after applying the Bonferroni correction for multiple testing. CONCLUSION: We validate that IGF2BP2 susceptibility variants rs4402960 and rs1470579 associate with T2DM in Lebanese Arabs. PMID- 22245691 TI - Using Shiffman's political priority model for future diabetes advocacy. PMID- 22245692 TI - Impact of health professionals' contact frequency on response to a lifestyle intervention with individuals at high risk for diabetes. AB - AIM: To determine the independent effects of total and each health professional's frequency of contacts, on changes in anthropometric measures and physical capacity following a lifestyle intervention offered by a multi-disciplinary team in adults at high risk for type 2 diabetes. MATERIALS AND METHODS: A 12-month lifestyle intervention was performed in 48 adults with prediabetes. Participants were randomly assigned to either an individual counselling group (every six weeks)+an optional series of 25 group seminars (every week) or to the group seminars only. Physical activity level, energy intake, anthropometric measures, and physical capacity were assessed. RESULTS: Total frequency of contacts with any professional was associated with change in body weight, BMI and, waist circumference (all P <=.05). However, no frequency of contacts with a specific professional was associated with the studied outcomes, except for changes in physical capacity. The latest was significantly improved in participants who attended at least two group sessions with the kinesiologist (P=.02). DISCUSSION: To improve anthropometric measures, total contact frequency seems to be more important than contact frequency with any specific professionals. However, to improve physical capacity, meeting with a kinesiologist for two or more occasions, in group sessions, seems to be an effective strategy. PMID- 22245693 TI - Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells. AB - AIMS: To investigate the effect of metformin on the expression profiles of microRNAs in human pancreatic cancer cells. METHODS: MicroRNAs real-time PCR Array was applied to investigate differentially expressed miRNAs in Sw1990 cells treated with or without metformin. Stem-loop real time RT-PCR was used to confirm the results of the array assay in Sw1990 and Panc-1 cells. The effects of miR-26a on cell growth, apoptosis, invasion and migration abilities were respectively examined by CCK8 assay, Apoptosis assay, Matrigel invasion and migration assay. HMGA1 was proved to be a target of miR-26a by Luciferase reporter assay, Real time PCR and Western-blotting. RESULTS: Nine miRNAs were significantly up regulated in metformin treated cells. Metformin up-regulated the expression of miR-26a, miR-192 and let-7c in a dose-dependent manner. Forced expression of miR 26a significantly inhibited cell proliferation, invasion, migration and increased cell apoptosis, whereas knockdown of miR-26a obtained the opposite effect. Furthermore, we demonstrated that HMGA1, an oncogene, is a direct target of miR 26a. Nude mice xenograft models confirmed that metformin up-regulated the level of miR-26a and surpressed the expression of HMGA1 in vivo. CONCLUSION: These observations suggested that modulation of miRNA expression may be an important mechanism underlying the biological effects of metformin. PMID- 22245694 TI - An overview of the pharmacokinetics, efficacy and safety of liraglutide. AB - OBJECTIVE: Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists, are the latest addition to the range of available medications for the management of patients with type 2 diabetes. The GLP-1 analog liraglutide has been approved for use in Europe and the US for over a year and has undergone evaluation in several pharmacokinetic/pharmacodynamics studies and in an extensive phase 3 clinical program. The aim of this review is to assess the pharmacokinetics, efficacy and safety of the phase 3 data. METHODS: Data are presented from the pharmacokinetics/pharmacodynamics studies of liraglutide and from nine published phase 3 studies, including the six Liraglutide Effect and Action in Diabetes (LEAD) studies. RESULTS: Liraglutide is effective at improving indices of glycemic control, and has a good tolerability and safety profile. Beneficial effects on weight (mean reduction of 1-3.4 kg) and blood pressure (systolic blood pressure decreased by 2.1-6.7 mmHg) are also observed. CONCLUSION: Liraglutide is an effective and well tolerated option for the treatment of type 2 diabetes. PMID- 22245695 TI - Sex differences in the relationship between socioeconomic status and metabolic syndrome: the Korean National Health and Nutrition Examination Survey. AB - AIMS: To investigate sex differences in the relationship between socioeconomic status (SES) and the prevalence of metabolic syndrome (MetS) in Korean adults. METHODS: We examined the relationship between SES, as measured by household income or education level, and the prevalence of MetS in Korean adults who participated in the 2007-2008 Korean National Health Examination and Nutrition Survey (KNHANES). The adjusted odds ratios (ORs) for MetS were calculated using multivariate logistic regression analysis across household income and education level quartiles. RESULTS: We found significant differences between men and women in the association between SES and MetS, with a positive association for men and an inverse association for women. The adjusted OR and 95% confidence interval (95% CI) for MetS for the highest vs. lowest quartile of household income was 1.59 (1.15-2.20) in men. The adjusted ORs for MetS for the highest vs. lowest quartile of household income and education level were 0.54 (0.41-0.72) and 0.26 (0.17-0.38) in women, respectively. CONCLUSIONS: We found sex differences in the relationship between SES and the prevalence of MetS in Korea. These findings suggest that sex-specific public health interventions that consider SES are needed for the prevention and treatment of MetS. PMID- 22245696 TI - Modeling shear modulus distribution in magnetic resonance elastography with piecewise constant level sets. AB - Magnetic resonance elastography (MRE) is designed for imaging the mechanical properties of soft tissues. However, the interpretation of shear modulus distribution is often confusing and cumbersome. For reliable evaluation, a common practice is to specify the regions of interest and consider regional elasticity. Such an experience-dependent protocol is susceptible to intrapersonal and interpersonal variability. In this study we propose to remodel shear modulus distribution with piecewise constant level sets by referring to the corresponding magnitude image. Optimal segmentation and registration are achieved by a new hybrid level set model comprised of alternating global and local region competitions. Experimental results on the simulated MRE data sets show that the mean error of elasticity reconstruction is 11.33% for local frequency estimation and 18.87% for algebraic inversion of differential equation. Piecewise constant level set modeling is effective to improve the quality of shear modulus distribution, and facilitates MRE analysis and interpretation. PMID- 22245697 TI - Classification of breast mass lesions using model-based analysis of the characteristic kinetic curve derived from fuzzy c-means clustering. AB - The purpose of this study is to evaluate the diagnostic efficacy of the representative characteristic kinetic curve of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) extracted by fuzzy c-means (FCM) clustering for the discrimination of benign and malignant breast tumors using a novel computer aided diagnosis (CAD) system. About the research data set, DCE-MRIs of 132 solid breast masses with definite histopathologic diagnosis (63 benign and 69 malignant) were used in this study. At first, the tumor region was automatically segmented using the region growing method based on the integrated color map formed by the combination of kinetic and area under curve color map. Then, the FCM clustering was used to identify the time-signal curve with the larger initial enhancement inside the segmented region as the representative kinetic curve, and then the parameters of the Tofts pharmacokinetic model for the representative kinetic curve were compared with conventional curve analysis (maximal enhancement, time to peak, uptake rate and washout rate) for each mass. The results were analyzed with a receiver operating characteristic curve and Student's t test to evaluate the classification performance. Accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the combined model-based parameters of the extracted kinetic curve from FCM clustering were 86.36% (114/132), 85.51% (59/69), 87.30% (55/63), 88.06% (59/67) and 84.62% (55/65), better than those from a conventional curve analysis. The A(Z) value was 0.9154 for Tofts model-based parametric features, better than that for conventional curve analysis (0.8673), for discriminating malignant and benign lesions. In conclusion, model-based analysis of the characteristic kinetic curve of breast mass derived from FCM clustering provides effective lesion classification. This approach has potential in the development of a CAD system for DCE breast MRI. PMID- 22245698 TI - Anger, dissociation, and PTSD among male veterans entering into PTSD treatment. AB - Prior research suggests that dissociation and anger are risk factors for the development of posttraumatic stress disorder (PTSD). Research found that trauma survivors with higher levels of anger also report more severe PTSD overall. Studies also support a relationship between PTSD severity and dissociation. Only one prior study of sexual assault survivors by Feeny, Zoellner, and Foa (2000) examined the relationships among dissociation, anger, and PTSD. While Veterans have been found to report high levels of anger and dissociation, the relationship between these factors and PTSD has not been examined among Veterans. This paper examines the relationship among anger, dissociation, and PTSD in treatment seeking Veterans who presented for evaluation at the PTSD Clinic in the VA Ann Arbor Healthcare System during a four year period. Anger and dissociation predicted PTSD, hyperarousal, and avoidance/numbing severity while dissociation predicted intrusive severity. The implications of these results for clinical practice are discussed. PMID- 22245699 TI - Dimensional indicators of generalized anxiety disorder severity for DSM-V. AB - For DSM-V, simple dimensional measures of disorder severity will accompany diagnostic criteria. The current studies examine convergent validity and test retest reliability of two potential dimensional indicators of worry severity for generalized anxiety disorder (GAD): percent of the day worried and number of worry domains. In study 1, archival data from diagnostic interviews from a community sample of individuals diagnosed with one or more anxiety disorders (n = 233) were used to assess correlations between percent of the day worried and number of worry domains with other measures of worry severity (clinical severity rating (CSR), age of onset, number of comorbid disorders, Penn state worry questionnaire (PSWQ)) and DSM-IV criteria (excessiveness, uncontrollability and number of physical symptoms). Both measures were significantly correlated with CSR and number of comorbid disorders, and with all three DSM-IV criteria. In study 2, test-retest reliability of percent of the day worried and number of worry domains were compared to test-retest reliability of DSM-IV diagnostic criteria in a non-clinical sample of undergraduate students (n = 97) at a large west coast university. All measures had low test-retest reliability except percent of the day worried, which had moderate test-retest reliability. Findings suggest that these two indicators capture worry severity, and percent of the day worried may be the most reliable existing indicator. These measures may be useful as dimensional measures for DSM-V. PMID- 22245700 TI - Cost-effectiveness of child-focused and parent-focused interventions in a child anxiety prevention program. AB - In this study, the cost-effectiveness of three indicated anxiety prevention strategies was examined from a societal perspective. Children (aged 8-12) were recruited via primary schools, selecting children scoring as high-anxious on an anxiety screening questionnaire. Participating children and their parents were randomized to a child--a parent-focused, or non-intervention group. All groups completed a diagnostic interview and standardized cost-diaries at pretest, and 1- and 2-year follow-up. Incremental cost-effectiveness ratios per 'ADIS improved' child (based on diagnostic information) were calculated and cost-effectiveness acceptability curves and frontiers were plotted. The base-case and most secondary analyses showed it would be cost-effective to offer high-anxious children an intervention, and the parent-focused intervention to be the optimal strategy at lower monetary threshold values than the child-focused intervention and when parents were anxious. The child-focused intervention was dominant when analyses were performed from a healthcare perspective, for boys, and for children of grades 7-8 of primary school. PMID- 22245701 TI - Use of Wisteria floribunda agglutinin affinity chromatography in the structural analysis of the bovine lactoferrin N-linked glycosylation. AB - BACKGROUND: Over the years, the N-glycosylation of both human and bovine lactoferrin (LF) has been studied extensively, however not all aspects have been studied in as much detail. Typically, the bovine LF complex-type N-glycans include certain epitopes, not found in human LF N-glycans, i.e. Gal(alpha1 3)Gal(beta1-4)GlcNAc (alphaGal), GalNAc(beta1-4)GlcNAc (LacdiNAc), and N glycolylneuraminic acid (Neu5Gc). The combined presence of complex-type N glycans, with alphaGal, LacdiNAc, LacNAc [Gal(beta1-4)GlcNAc], Neu5Ac (N acetylneuraminic acid), and Neu5Gc epitopes, and oligomannose-type N-glycans complicates the high-throughput analysis of such N-glycoprofiles highly. METHODS: For the structural analysis of enzymatically released N-glycan pools, containing both LacNAc and LacdiNAc epitopes, a prefractionation protocol based on Wisteria floribunda agglutinin affinity chromatography was developed. The sub pools were analysed by MALDI-TOF-MS and HPLC-FD profiling, including sequential exoglycosidase treatments. RESULTS: This protocol separates the N-glycan pool into three sub pools, with (1) free of LacdiNAc epitopes, (2) containing LacdiNAc epitopes, partially shielded by sialic acid, and (3) containing LacdiNAc epitopes, without shielding by sialic acid. Structural analysis by MALDI-TOF-MS and HPLC-FD showed a complex pattern of oligomannose-, hybrid-, and complex-type di-antennary structures, both with, and without LacdiNAc, alphaGal and sialic acid. CONCLUSIONS: Applying the approach to bovine LF has led to a more detailed N-glycome pattern, including LacdiNAc, alphaGal, and Neu5Gc epitopes, than was shown in previous studies. GENERAL SIGNIFICANCE: Bovine milk proteins contain glycosylation patterns that are absent in human milk proteins; particularly, the LacdiNAc epitope is abundant. Analysis of bovine milk serum proteins is therefore excessively complicated. The presented sub fractionation protocol allows a thorough analysis of the full scope of bovine milk protein glycosylation. This article is part of a Special Issue entitled Glycoproteomics. PMID- 22245702 TI - Cardiac tissue slices with prolonged survival for in vitro drug safety screening. AB - INTRODUCTION: We have recently introduced the use of mammalian cardiac tissue slices for in vitro drug testing purposes. Here we show how this method can be applied for long-term studies in safety pharmacology. METHODS: In freshly prepared cardiac slices from guinea-pig or rat ventricle, extracellular field potentials (FP) and intracellular action potentials (AP) were recorded in response to electrical stimulation using the 4-channel heart slice screening system 'Synchroslice'. To assess viability of the slices on consecutive days after preparation, drug effects on FP/AP parameters, like duration and latency, were monitored. RESULTS: In the presence of the potassium channel blocker E4031 (1 MUM), FP and AP duration (FPD and APD) were significantly increased (FPD, 39.0%; APD, 28.1%) in guinea-pig ventricular slices. Similar changes were observed 24-28 h after slice preparation (FPD, 48.6%; APD, 25.4%). Furthermore, AP duration was reduced in the presence of the calcium channel blocker nifedipine (10 MUM) on the day of preparation (40.5%) and 24-28 h later (38.7%). In contrast, in the presence of the potassium channel blocker 4-aminopyridine (30 mM) AP duration was prolonged 4.95 and 4.19-fold, 2-8 h and 24-28 h after preparation, respectively. Finally, FP propagation was repeatedly slowed down by the gap junction blocker carbenoxolone (30 MUM), as revealed from FP onset latency increases observed on three consecutive days (2-8 h after preparation, 93.0%; 24-28 h, 76.8%, 48-56 h, 61.7%). DISCUSSION: Freshly isolated cardiac slices reproduced established physiological and pharmacological responses for more than 24 h after preparation. Thus, cardiac slices can be used for several days after preparation which makes them a robust model for electrophysiological studies. We propose that cardiac slices can become a versatile tool in heart research and risk assessment of drugs. PMID- 22245703 TI - [Structural magnetic resonance imaging in epilepsy]. AB - Magnetic resonance imaging is the main structural imaging in epilepsy. In patients with focal seizures, detection (and characterization) of a structural lesion consistent with electroclinical data allows therapeutic decisions without having to resort to other more expensive or invasive diagnostic procedures. The identification of some lesions may provide prognostic value, as in the case of Mesial Temporal Sclerosis (MTS) or may contribute to genetic counseling, as in the case of some Malformations of Cortical Development (MCD). The aim of this paper is to review the current state of structural MRI techniques, propose a basic protocol of epilepsy and mention the indications for structural MRI. Also, review the semiology of the main causes of epilepsy, with emphasis on MTS and MCD, by its highest frequency and by the special impact that MRI has shown in dealing with these entities. PMID- 22245704 TI - Metabolic effects of anti-angiogenic therapy in tumors. AB - Anti-angiogenic therapy has recently been added to the panel of cancer therapeutics, but predictive biomarkers of response are still not available. In animal models, anti-angiogenic therapy causes tumor starvation by increasing hypoxia and impairing nutrients supply. It is thus conceivable that angiogenesis inhibition causes remarkable metabolic perturbations in tumors, although they remain largely uncharted. We review here recent acquisitions about metabolic effects of angiogenesis blockade in tumors and discuss the possibility that some metabolic features of tumor cells - i.e. their dependency from glucose as primary energy substrate - might affect tumor responses to anti-VEGF treatment. PMID- 22245705 TI - Role of the tertiary and quaternary structure in the formation of bis-histidyl adducts in cold-adapted hemoglobins. AB - All tetrameric hemoglobins from Antarctic fish, including that from Trematomus bernacchii, HbTb form in the ferric state, promptly and distinctively from all the other tetrameric hemoglobins, a mixture of aquo-met at the alpha subunits and bis-histidyl adduct (hemichrome) at the beta subunits. The role of the tertiary and quaternary structure in the hemichrome formation is unknown. Here we report the cloning, expression, purification, spectroscopic and computational characterization of the beta-chain of HbTb (beta-HbTb). Similarly to the human beta-chains, beta-HbTb self-assembles to form the homotetramer beta(4)-HbTb; however, the latter quantitatively forms reversible ferric and ferrous bis histidyl adducts, which are only partially present in the human tetramer (beta(4) HbA). A molecular dynamics study of the isolated beta subunit of the two Hbs indicates that the ability to form hemichrome is an intrinsic feature of the chain; moreover, the greater propensity of beta-HbTb to form the bis-histidyl adduct is probably linked to the higher flexibility of the CD loop region. On the bases of these experimental and computational results on the isolated chain, the influence of the quaternary structure on the stability of the endogenous ferrous and ferric hexa-coordination is also discussed. PMID- 22245706 TI - Pattern formation in centrosome assembly. AB - A striking but poorly explained feature of cell division is the ability to assemble and maintain organelles not bounded by membranes, from freely diffusing components in the cytosol. This process is driven by information transfer across biological scales such that interactions at the molecular scale allow pattern formation at the scale of the organelle. One important example of such an organelle is the centrosome, which is the main microtubule organising centre in the cell. Centrosomes consist of two centrioles surrounded by a cloud of proteins termed the pericentriolar material (PCM). Profound structural and proteomic transitions occur in the centrosome during specific cell cycle stages, underlying events such as centrosome maturation during mitosis, in which the PCM increases in size and microtubule nucleating capacity. Here we use recent insights into the spatio-temporal behaviour of key regulators of centrosomal maturation, including Polo-like kinase 1, CDK5RAP2 and Aurora-A, to propose a model for the assembly and maintenance of the PCM through the mobility and local interactions of its constituent proteins. We argue that PCM structure emerges as a pattern from decentralised self-organisation through a reaction-diffusion mechanism, with or without an underlying template, rather than being assembled from a central structural template alone. Self-organisation of this kind may have broad implications for the maintenance of mitotic structures, which, like the centrosome, exist stably as supramolecular assemblies on the micron scale, based on molecular interactions at the nanometer scale. PMID- 22245708 TI - Effects of hemiretinal form deprivation on central refractive development and posterior eye shape in chicks. AB - We determined effects of hemiretinal form deprivation (i.e., form-depriving half of the retina) on central refractive development and posterior eye shape in chicks. Seventy-seven White Leghorn chicks were randomly assigned to receive superior (SRD, "Superior Retinal Deprivation" or inferior visual field deprivation, same principle applies for the following abbreviations, n=17), inferior (IRD, n=14), temporal (TRD, n=23) or nasal hemiretinal (NRD, n=23) form deprivation monocularly from day 5 to day 26. Central refractive errors, expressed as interocular difference in spherical equivalent (M), J0 and J45 astigmatic components, were measured using Hartinger refractometer at the beginning and weekly after treatment for 3weeks. At the end of the treatment period, eyes of a subset of birds were enucleated and eye shape profile was photographed along four different meridians. These digital images were later processed to extract axial length (AL), equatorial diameter (ED), and AL/ED. For comparison purposes, the eye shape profile was also acquired from a separate group of birds reared with monocular full-retinal form deprivation (FRD, n=10). The four hemiretinal form deprivations altered central ametropia and posterior eye shape to different degrees. The biggest contrast in M was found between SRD and IRD groups (mean+/-SE after 3weeks: SRD=-4.14+/-0.71 D vs. IRD=+1.24+/-0.36 D; p<0.05), whereas subtle differences in J0 and J45 components were found across the four treatment groups (both p?0.03). SRD group also showed significantly higher AL/ED ratio compared to IRD and NRD groups (0.76+/-0.05 vs. 0.74+/-0.07 and 0.75+/-0.04; both p?0.03). Furthermore, M was significantly correlated with AL/ED ratio in the treated eyes of hemiretinal treated chicks (r=-0.55, p<0.001). Our results suggest that mechanism regulating central ametropia can be influenced by selectively interrupting the visual experience at different parts of visual field. PMID- 22245707 TI - Marital status, education, and risk of acute myocardial infarction in Mainland China: the INTER-HEART study. AB - BACKGROUND: We investigated the effects of marital status and education on the risk of acute myocardial infarction (AMI) in a large-scale case-control study in China. METHODS: This study was part of the INTER-HEART China case-control study. The main outcome measure was first AMI. Incident cases of AMI and control patients with no past history of heart disease were recruited. Controls were matching by age (+/-5 years) and sex. Marital status was combined into 2 categories: single and not single. Education level was classified into 2 categories: 8 years or less and more than 8 years. RESULTS: From 1999 to 2002, we recruited 2909 cases and 2947 controls from 17 cities. After adjustment for age, sex, BMI, psychosocial factors, lifestyle, other factors, and mutually for other risk factors, the odds ratio (OR) for AMI associated with being single was 1.51 (95% confidence interval: 1.18-1.93) overall, 1.19 (0.84-1.68; P = 0.072) in men and 2.00 (1.39-2.86; P < 0.0001) in women. The interaction of sex and marital status was statistically significant (P = 0.045). Compared with a high education level, a low education level increased the risk of AMI (1.45, 1.26-1.67); the odds ratios in men and women were 1.29 (1.09-1.52) and 1.55 (1.16-2.08), respectively. Single women with a low education level had a high risk of AMI (2.95, 1.99-4.37). CONCLUSIONS: Being single was consistently associated with an increased risk for AMI, particularly in women. In addition, as compared with high education level, low education level was associated with a higher risk of AMI in both men and women. PMID- 22245709 TI - Microgenesis of surface completion in visual objects: evidence for filling-out. AB - Using metacontrast masking we examined the temporal dynamics of surface completion in object vision. By varying the stimulus onset asynchrony between the target object and the flanking mask(s), we obtained estimates of the time required for the entire surface contrast to fill out within the area delimited by the contours/edges of the target. The estimated speed of the filling-out process was 36.0 deg/s. Using existing estimates of cortical magnification, the computed filling-out speed in terms of cortical distance is .385 m/s, a value that approximates the estimated cortical filling-in speed and the speed of horizontal propagation in monkey V1. We discuss our results in relation to (1) prior findings of filling-in and filling-out phenomena, using surface completion in cortical space as the unifying principle, and (2) extant computational models of object vision. PMID- 22245710 TI - Motion adaptation does not depend on attention to the adaptor. AB - Prolonged inspection of moving stimuli causes stationary stimuli to appear moving in the opposite direction to the adapting stimulus (the Waterfall effect). It has been claimed that distracting the viewer's attention from the adapting stimulus by a secondary task reduces the strength of adaptation. However, the method used to show the effect of distraction (the duration of the aftereffect) is potentially susceptible to bias. The experiments reported here show no effect in genuinely naive subjects, or in experienced observers using a variety of cancellation procedures to measure the effect. PMID- 22245711 TI - Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. AB - OBJECTIVE: The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy. METHODS: A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fisher's exact test was used to calculate statistical differences. RESULTS: Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p=.002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p=.03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p=.02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p=.39), with 117 live births reported. CONCLUSION: Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts. PMID- 22245712 TI - A roadmap to membrane protein structures. PMID- 22245713 TI - Craving of prescription opioids in patients with chronic pain: a longitudinal outcomes trial. AB - Little is known about whether patients with chronic pain treated with opioids experience craving for their medications, whether contextual cues may influence craving, or if there is a relationship between craving and medication compliance. We hypothesized that craving for prescription opioids would be significantly correlated with the urge for more medication, preoccupation with the next dose, and current mood symptoms. We studied craving in 62 patients with chronic pain who were at low or high risk for opioid misuse, while they were enrolled in an RCT to improve prescription opioid medication compliance. Using electronic diaries, patients completed ratings of craving at monthly clinic visits and daily during a 14-day take-home period. Both groups consistently endorsed craving, whose levels were highly correlated (P < .001) with urge, preoccupation, and mood. The intervention to improve opioid compliance in the high-risk group was significantly associated with a rate of decrease in craving over time in comparison to a high-risk control group (P < .05). These findings indicate that craving is a potentially important psychological construct in pain patients prescribed opioids, regardless of their level of risk to misuse opioids. Targeting craving may be an important intervention to decrease misuse and improve prescription opioid compliance. PERSPECTIVE: Patients with noncancer pain can crave their prescription opioids, regardless of their risk for opioid misuse. We found craving to be highly correlated with the urge to take more medication, fluctuations in mood, and preoccupation with the next dose, and to diminish with a behavioral intervention to improve opioid compliance. PMID- 22245715 TI - Strategies and accomplishments of the Tinnitus Research Consortium. AB - The Tinnitus Research Consortium (TRC) is sponsored by a philanthropist who wants to accelerate progress in basic and clinical research on tinnitus. The TRC consists of 12 distinguished auditory scientists who began meeting in 1998 twice a year for brainstorming for new research approaches to tinnitus, developing requests for applications, judging the scientific merit of the applications received and reviewing the progress of funded projects. Through these efforts, common confounding variables in tinnitus research have been identified, and solutions to these problems have been suggested. TRC grants have been made up to $100,000.00 per year for three years. The sponsor had provided $600,000.00 per year; so two new grants could be made each year. The good news is that the sponsor's support has been increased by 50% for 2011 so that three grants have been awarded. Some of the landmark studies supported by the TRC over the last 14 years are reviewed as is the changing conceptualization of the pathogenesis of tinnitus and its management. The effect of strategies of the TRC on the applicants, grantees, scientific field, scientific societies and other funding agencies will be discussed. For example, when the TRC was initiated, sessions devoted to tinnitus research at national scientific meetings were rare. Through the efforts of the TRC, the American Tinnitus Association and the American Academy of Audiology, organizations such as the Association for Research in Otolaryngology and the Society for Neuroscience were encouraged to hold special sessions on tinnitus research. Now such organizations have well attended sessions on tinnitus research each year. The size of the TRC grants, large enough to support a substantial research project, has caused several other voluntary agencies to increase the size of their grants toward the TRC standard. The National Institute on Deafness and Other Communication Disorders and other institutes at the National Institutes of Health have devoted far more emphasis on tinnitus. By supporting sound research on tinnitus and recruiting world-class scientists to the field, the TRC has led in making tinnitus research respectable. PMID- 22245714 TI - Characteristics of detection thresholds and maximum comfortable loudness levels as a function of pulse rate in human cochlear implant users. AB - The ability of an implanted ear to integrate multiple pulses, as measured by the slopes of detection threshold level (T level) versus pulse rate functions, may reflect cochlear health in the cochlea, as suggested by previous animal studies (Kang et al., 2010; Pfingst et al., 2011). In the current study, we examined the slopes of T level versus pulse rate functions in human subjects with cochlear implants. Typically, T levels decrease as a function of pulse rate, consistent with a multipulse integration mechanism. The magnitudes of the slopes of the T level versus pulse rate functions obtained from the human subjects were comparable to those reported in the animal studies. The slopes varied across stimulation sites, but did not change systematically along the tonotopic axis. This suggests that the slopes are dependent on local conditions near the individual stimulation sites. The characteristics of these functions were also similar to those found in animals in that the slopes for higher pulse rates were steeper than those for the lower pulse rates, consistent with a combined effect of multipulse integration and cumulative partial depolarization mechanisms at rates above 1000 pps. The maximum comfortable loudness level (C level) versus pulse rate functions were also examined to determine the effect of level on the slopes. Slopes of C-level functions were shallower than those for the T-level functions and were not correlated with those of the T-level functions, so the mechanisms underlying these two functions are probably not identical. The slopes of the T- or C-level functions were not dependent on stimulus-current level. Based on these results, we suggest that slopes of T level versus pulse rate functions might be a useful measure for estimating nerve survival in the cochlea in regions close to the stimulation sites. PMID- 22245716 TI - Mitochondrial DNA haplogroups and incidence of lipodystrophy in HIV-infected patients on long-term antiretroviral therapy. AB - We investigated the rates of lipodystrophy events, according to mitochondrial DNA haplogroup, in 187 patients starting combination antiretroviral therapy and following it. Incidence rates of lipoatrophy and fat accumulation were 8.2 and 4.8 per 100 person-years of follow-up, respectively. In multivariable models, patients with haplogroup K were at higher risk of any lipodystrophy [adjusted relative risk (aRR) 4.02, P = 0.0009], lipoatrophy (competing-risk aRR 2.42, P = 0.09; cause-specific aRR 2.99, P = 0.031), and fat accumulation (competing-risk aRR, 2.63, P = 0.11; cause-specific aRR 5.27, P = 0.019) than those with haplogroup H. Mitochondrial haplogroups may explain part of the genetic predisposition to lipodystrophy during combination antiretroviral therapy. PMID- 22245717 TI - Serum levels of neutrophil gelatinase-associated lipocalin are associated with microalbuminuria in HIV-infected patients. PMID- 22245718 TI - Reverse transcriptase substitution at codons 208 and 228 among treatment experienced HIV-1 subtype-C-infected Indian patients is strongly associated with thymidine analogue mutations. PMID- 22245719 TI - Long chain polyunsaturated fatty acid synthesis in a marine vertebrate: ontogenetic and nutritional regulation of a fatty acyl desaturase with Delta4 activity. AB - Solea senegalensis is an unusual marine teleost as it has very low dietary requirement for long-chain polyunsaturated fatty acids (LC-PUFA) during early development. Aquaculture is rapidly becoming the main source of health-beneficial fish products for human consumption. This, associated with limited supply of LC PUFA-rich ingredients for fish feeds, render S. senegalensis a highly interesting species in which to study the LC-PUFA biosynthesis pathway. We have cloned and functionally characterized fatty acyl desaturase and elongase cDNAs corresponding to Delta4fad (with some Delta5 activity for the n-3 series) and elovl5 with the potential to catalyze docosahexaenoic acid (DHA) biosynthesis from eicosapentaenoic acid (EPA). Changes in expression of both transcripts were determined during embryonic and early larval development, and transcriptional regulation in response to higher or lower dietary n-3 LC-PUFA was assessed during larval and post-larval stages. There was a marked pattern of regulation during early ontogenesis, with both transcripts showing peak expression coinciding with the start of exogenous feeding. Although elovl5 transcripts were present in fertilized eggs, Delta4fad only appeared at hatching. However, eggs have high proportions of DHA (~20%) and high DHA/EPA ratio (~11) to meet the high demands for early embryonic development. The fatty acid profile of larvae after the start of exogenous feeding closely reflected dietary composition. Nonetheless, Delta4fad was significantly up-regulated in response to LC-PUFA-poor diets, which may suggest biological relevance of this pathway in reducing LC-PUFA dietary requirements in this species, compared to other marine teleosts. These results indicate that sole is capable of synthesizing DHA from EPA through a Sprecher independent pathway. PMID- 22245720 TI - Educational inequalities in blood pressure and cholesterol screening in nine European countries. AB - BACKGROUND: To perform the first European overview of educational inequalities in the use of blood pressure and cholesterol screening. METHODS: Data were obtained on the use of screening services according to educational level from nationally representative cross-sectional surveys in Belgium, Czech Republic, Denmark, Estonia, Finland, Hungary, Italy, Latvia and Lithuania. Screening rates were examined in the preceding 12 months and 5 years, for respondents 35+ years (45+ for women). ORs comparing low- to high-educated respondents were estimated using logistic regression controlling for age. RESULTS: Inequalities in cholesterol screening favouring higher socioeconomic groups were demonstrated with statistical significance among men in four countries, whereby men with higher education were more likely to receive screening, with 1.22 as the highest OR. Among women, a similar pattern was found. Inequalities in blood pressure screening were even smaller and less often statistically significant. Hungary was the only country with higher rates of both types of screening in the low-educated group. In other countries, pro-high inequalities were slightly increased after controlling for self-rated health. CONCLUSIONS: All European countries in this study had small educational inequalities in the utilisation of blood pressure and cholesterol screening. These inequalities are smaller than those previously observed in the USA. Further comparative studies need to distinguish between screening for preventive purposes and screening for treatment and control. PMID- 22245721 TI - Dangerous dads? Ecological and longitudinal analyses of paternity leave and risk for child injury. AB - BACKGROUND: In 1974, Sweden became the first country to permit fathers to take paid parental leave. Other countries are currently following suit issuing similar laws. While this reform supports the principles of the United Nations convention of the right for children to be with both parents and enshrines the ethos of gender equality, there has been little systematic examination of its potential impact on child health. Instead, there is uninformed debate that fathers may expose their children to greater risks of injury than mothers. In this Swedish national study, the authors therefore assess whether fathers' parental leave can be regarded as a more serious risk factor for child injuries than that of mothers. METHODS: Nationwide register-based ecological and longitudinal studies of hospitalisation due to injury (and intoxication) in early childhood, involving the Swedish population in 1973-2009 (ecological design), and children born in 1988 and 1989 (n=118 278) (longitudinal design). RESULTS: An increase in fathers' share of parental leave over time was parallelled by a downward trend in child injury rates (age 0-4 years). At the individual level, the crude incidence of child injury (age 0-2 years) was lower during paternity as compared with maternity leave. This association was, however, explained by parental socio demographic characteristics (multivariate HR 0.96, 95% CI 0.74 to 1.2). CONCLUSION: There is no support for the notion that paternity leave increases the risk of child injury. PMID- 22245722 TI - Paced reading in semantic dementia: word knowledge contributes to phoneme binding in rapid speech production. AB - Patients with semantic dementia (SD) show deficits in phoneme binding in immediate serial recall: when attempting to reproduce a sequence of words that they no longer fully understand, they show frequent migrations of phonemes between items (e.g., cap, frog recalled as "frap, cog"). This suggests that verbal short-term memory emerges directly from interactions between semantic and phonological systems, allowing semantic knowledge to make a critical contribution to the stability of phonological sequences. According to this standpoint, SD patients should show phoneme binding deficits in additional language tasks beyond standard assessments of verbal short-term memory: for example, these errors should emerge in paced reading, which also requires the rapid production of semantically degraded words in order. To test this hypothesis, we examined a cyclical paced reading task in three SD patients for the first time. Every patient showed deficits in phoneme binding: they were more vulnerable than a set of age-matched controls to phoneme competition effects following the repetition of a small set of words across several cycles. They also showed substantially elevated numbers of phoneme migration, substitution and omission errors, despite being able to read the individual words almost without error. These findings confirm that the semantic contribution to phoneme binding is disrupted in SD patients across tasks. In line with the view that verbal short-term memory emerges from interactions between basic phonological and semantic components, these effects occur both within classic short-term memory paradigms, such as immediate serial recall, and tasks without explicit memory demands, such as paced reading. PMID- 22245723 TI - Motivation and goal attainment. The role of compensatory beliefs. AB - It was recently proposed that one cognitive strategy people might employ to find a balance between fulfilling their immediate desires and adhering to their long term goals is to activate compensatory beliefs (CBs). CBs are convictions that the negative effects of a behavior can be compensated for by the positive effects of another behavior (e.g., "I can eat this piece of cake now because I will go to the gym tonight".). The purpose of the present research was to examine the motivational determinants and consequences of CBs in weight-loss dieting. It was proposed that autonomous motivation would lessen the activation of CBs. It was further proposed that activating CBs would decrease goal adherence, which, itself, would facilitate the attainment of one's dieting goals. Results of a prospective study using path analysis provided support for the model. PMID- 22245724 TI - Flaxseed dietary fiber supplements for suppression of appetite and food intake. AB - We conducted two single-blinded randomized crossover acute studies with 24 and 20 subjects, respectively, to compare (I) CONTROL vs. Flax drink; and (II) Flax drink vs. Flax tablets. The subjects were exposed to one of the treatments after an overnight fast, and rated appetite sensation for 120 min using visual analog scales (VAS). Hereafter they consumed an ad libitum early lunch to assess energy intake. The treatments were iso-caloric and iso-volumeric: CONTROL: 300 mL drink; Flax drink: CONTROL drink with addition flax fiber extract (2.5 g of soluble fibers); and Flax tablet: CONTROL drink with flax fiber tablets (2.5 g of soluble fibers). Flax drink increased sensation of satiety and fullness compared to CONTROL and a significant decrease in subsequent energy intake was observed after the Flax drink compared to CONTROL (2937 vs. 3214 kJ). Appetite ratings were similar for Flax tablets and Flax drink as they did not differ by more than 1-4%. Subsequent energy intake was similar after the two treatments (3370 vs. 3379 kJ). A small dose of flaxseed fiber significantly suppresses appetite and energy intake. Furthermore, flaxseed fibers administered as drinks or tablets produce similar responses. PMID- 22245725 TI - The color red reduces snack food and soft drink intake. AB - Based on evidence that the color red elicits avoidance motivation across contexts (Mehta & Zhu, 2009), two studies investigated the effect of the color red on snack food and soft drink consumption. In line with our hypothesis, participants drank less from a red labeled cup than from a blue labeled cup (Study 1), and ate less snack food from a red plate than from a blue or white plate (Study 2). The results suggest that red functions as a subtle stop signal that works outside of focused awareness and thereby reduces incidental food and drink intake. PMID- 22245726 TI - Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. AB - Tumor endothelial cells (TECs) are therapeutic targets in anti-angiogenic therapy. Contrary to the traditional assumption, TECs can be genetically abnormal and might also acquire drug resistance. In this study, mouse TECs and normal ECs were isolated to investigate the drug resistance of TECs and the mechanism by which it is acquired. TECs were more resistant to paclitaxel with the up regulation of multidrug resistance (MDR) 1 mRNA, which encodes the P glycoprotein, compared with normal ECs. Normal human microvascular ECs were cultured in tumor-conditioned medium (CM) and became more resistant to paclitaxel through MDR1 mRNA up-regulation and nuclear translocation of Y-box-binding protein 1, which is an MDR1 transcription factor. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Akt were activated in human microvascular ECs by tumor CM. We observed that tumor CM contained a significantly high level of VEGF. A VEGFR kinase inhibitor, Ki8751, and a phosphatidylinositol 3-kinase Akt inhibitor, LY294002, blocked tumor CM-induced MDR1 up-regulation. MDR1 up regulation, via the VEGF-VEGFR pathway in the tumor microenvironment, is one of the mechanisms of drug resistance acquired by TECs. We observed that VEGF secreted from tumors up-regulated MDR1 through the activation of VEGFR2 and Akt. This process is a novel mechanism of the acquisition of drug resistance by TECs in the tumor microenvironment. PMID- 22245727 TI - The nonreceptor-type tyrosine phosphatase PTPN13 is a tumor suppressor gene in non-small cell lung cancer. AB - The aim of the present work was to identify protein tyrosine phosphatases (PTPs) as novel, candidate tumor suppressor genes in lung cancer. Among the 38 PTPs in the human genome that show specificity for phosphotyrosine, we identified six PTPs by quantitative RT-PCR whose mRNA expression levels were significantly down regulated in lung cancer-derived cell lines (ie, PTPRE, PTPRF, PTPRU, PTPRK, PTPRD, and PTPN13). After validation in primary samples of non-small cell lung cancer (NSCLC), we selected PTPN13 for further studies. The results presented here demonstrate that PTPN13 is a candidate tumor suppressor gene that is frequently inactivated in NSCLC through the loss of either mRNA and protein expression (64/87, 73%) or somatic mutation (approximately 8%). Loss of PTPN13 expression was apparently due to the loss of one or both copies of the PTPN13 locus at 4q (approximately 26% double deletion and approximately 37% single deletion) but not to promoter methylation. Finally, the manipulation of PTPN13 expression in lung cancer cells (ie, NCI-H292, A549) demonstrated that PTPN13 negatively regulates anchorage-dependent and anchorage-independent growth in vitro and restrains tumorigenicity in vivo, possibly through the control of the tyrosine phosphorylation of both EGFR and HER2. In conclusion, the expression screening of PTPs in lung cancer reported here has identified PTPN13 as a novel candidate tumor suppressor in NSCLC whose loss increases signaling from epidermal growth factor receptor and HER2 tyrosine kinase receptors. PMID- 22245728 TI - Screening for offenders with an intellectual disability: the validity of the Learning Disability Screening Questionnaire. AB - The study assessed the validity of an intellectual disability screening tool, the Learning Disability Screening Questionnaire (LDSQ), in three forensic settings: a community intellectual disability forensic service; a forensic in-patient secure unit and a prison, using data for 94 individuals. A significant positive relationship was found between full scale IQ and LDSQ score, indicating convergent validity. Discriminative validity was indicated by, firstly, a significant difference in the LDSQ scores between those with and without an intellectual disability, with those with a diagnosis of intellectual disability, scoring significantly lower. Secondly, a ROC analysis indicated that the sensitivity and specificity of the LDSQ were both above 80%. The screening tool was found to have lower sensitivity in the forensic populations than was obtained in the original community standardisation sample, but had slightly higher specificity. Limitations and implications of the study are discussed. PMID- 22245729 TI - Family burden related to clinical and functional variables of people with intellectual disability with and without a mental disorder. AB - Few studies have been found that to assess the factors that explain higher levels of family burden in adults with intellectual disability (ID) and intellectual disability and mental disorders (ID-MD). The aims of this study were to assess family burden in people with ID and ID-MD and to determine which sociodemographic, clinical and functional disability variables account for family burden. The sample is composed of pairs of 203 participants with disability and their caregivers, of which 33.5% are caregivers of people with ID and 66.5% of ID MD. Assessments were performed using scales of clinical and functional disability as the following instruments: Weschler Adult Intelligence Scale-III (WAIS-III), Inventory for Client and Agency Planning (ICAP), Psychiatric Assessment Schedule for Adults with Development Disability (PAS-ADD checklist), Disability Assessment Schedule of the World Health Organization (WHO-DAS-II) and family burden (Subjective and Objective Family Burden Inventory - SOFBI/ECFOS-II). People with ID-MD presented higher levels of functional disability than those with ID only. Higher levels of family burden were related to higher functional disability in all the areas (p<0.006-0.001), lower intelligence quotient (p<0.001), diagnosis of ID-MD (p<0.001) and presence of organic, affective, psychotic and behavioral disorders (p<0.001). Stepwise multiple regression showed that behavioral problems, affective and psychotic disorder, disability in participation in society, disability in personal care and presence of ID-MD explained more than 61% of the variance in family burden. An integrated approach using effective multidimensional interventions is essential for both people with ID and ID-MD and their caregivers in order to reduce family burden. PMID- 22245730 TI - Medical expenditures attributable to cerebral palsy and intellectual disability among Medicaid-enrolled children. AB - This study estimated medical expenditures attributable to cerebral palsy (CP) among children enrolled in Medicaid, stratified by the presence of co-occurring intellectual disability (ID), relative to children without CP or ID. The MarketScan((r)) Medicaid Multi-State database was used to identify children with CP for 2003-2005 by using the International Classification of Diseases, Ninth Revision; Clinical Modification (ICD-9-CM) code 343.xx. Children with ID were identified for 2005 by using ICD-9-CM code 317.xx-319.xx. Children without CP or ID during the same period served as control subjects. Medical expenditures were estimated for case and control children for 2005. The difference between the average expenditures for children with and without CP was used as a proxy for attributable expenditures for the condition. The attributable expenditures of co occurring ID were calculated similarly as the difference in average expenditures among children with CP with and without ID. A total of 9927 children with CP were identified. Among them, 2022 (20.3%) children had co-occurring ID recorded in medical claims. Children with CP but without ID incurred medical expenditures that were $15,047 higher than those of control children without CP or ID. By contrast, children with CP and co-occurring ID incurred costs that were $41,664 higher, compared with control children, and $26,617 more than children with CP but without ID. Administrative data from a large, multistate database demonstrated high medical expenditures for publicly insured children with CP. Expenditures approximately tripled for children with CP and co-occurring ID. PMID- 22245731 TI - Patterns of participation and enjoyment in adolescents with Down syndrome. AB - This study aimed to determine participation and enjoyment in young people with Down syndrome (DS) in Taiwan and to assess how participation varies across gender, cognitive, and motor function variables. Using the Children's Assessment of Participation and Enjoyment, data on participation were collected from 997 adolescents with DS and their families. Findings indicated limited diversity and intensity of participation, with proportionately greater involvement in informal activities. Youth with better cognitive and motor functions participated more often in activities and reported higher enjoyment and social engagement with these. These findings provide a foundation for an improved understanding of activity participation of youth with DS. Service providers and families could provide and plan activities to ensure more satisfying and meaningful participation. PMID- 22245732 TI - Self-concept and physical self-concept in psychiatric children and adolescents. AB - Self-concept is a widely examined construct in the area of psychiatric disorders. This study compared the Physical Self-Description Questionnaire (PSDQ) scores of adolescents with psychiatric disorders (N=103) with the results of a matched group of non-clinical adolescents (N=103). Self-concept and Physical self-concept were lower in the clinical than in the non-clinical group. Girls (N=59) scored lower than boys (N=44) in both groups. In the different diagnostic groups specific domains were affected in line with symptomatology, which has implications for therapy. PMID- 22245733 TI - Gender and geographic differences in the prevalence of autism spectrum disorders in children: analysis of data from the national disability registry of Taiwan. AB - The prevalence of autism spectrum disorders (ASD) in the world has increased dramatically in the recent decades. However, data at the national level are limited, and geographic differences are seldom evaluated. According to the law, the local governments in Taiwan began to certify disabled residents and provide various services in 1980, and the central government maintains a registry of certified cases. The registry started to enroll cases of ASD in 1990, providing a unique opportunity for studying ASD at the national level. Because the government discourages the certification under 3 years of age, we limited our analyses to those who were at least 3 years old. Using the registry data from 2004 to 2010, we calculated the prevalence of ASD by age, gender, and geographic area and assessed the changes over time. From 2004 to 2010, the registered cases between 3 and 17 years old increased from 3995 to 8072 annually, and the prevalence generally increased every year in all age groups (p<0.01). In each year there were more boy cases than girl cases, and the prevalence rate ratio ranged from 5.64:1 to 6.06:1 (p<0.01 in all years), with an increasing trend over time (p<0.01). A higher prevalence was observed in the urban areas over the years, and the prevalence rate ratio ranged from 2.24:1 to 2.72:1 (p<0.01 in all years), with a decreasing trend over time (p<0.01). PMID- 22245734 TI - To what extent is mean EMG frequency during gait a reflection of functional muscle strength in children with cerebral palsy? AB - The aim of the current paper was to analyze the potential of the mean EMG frequency, recorded during 3D gait analysis (3DGA), for the evaluation of functional muscle strength in children with cerebral palsy (CP). As walking velocity is known to also influence EMG frequency, it was investigated to which extent the mean EMG frequency is a reflection of underlying muscle strength and/or the applied walking velocity. Surface EMG data of the lateral gastrocnemius (LGAS) and medial hamstrings (MEH) were collected during 3DGA. For each muscle, 20 CP children characterized by a weak and 20 characterized by a strong muscle (LGAS or MEH) were selected. A weak muscle was defined as a manual muscle testing score <3; a strong muscle was defined as a manual muscle testing score >=4. Patient selection was based on the following inclusion criteria: (a) predominantly spastic type of CP (3-15 years old), (b) either (near) normal muscle strength or muscle weakness in at least one of the studied lower limb muscles, (c) no lower limb Botulinum Toxin-A treatment within 6 months prior to the 3DGA, (d) no history of lower limb surgery, and (e) high-quality noise-free EMG-data. For each muscle, twenty age-related typically developing (TD) children were included as controls. In both muscles a consistent pattern of increasing mean EMG frequency with decreasing muscle strength was observed. This was significant in the LGAS (TD versus weak CP). Walking velocity also had a significant effect on mean EMG frequency in the LGAS. Furthermore, based on R(2) and partial correlations, it could be concluded that both walking velocity and muscle strength have an impact on EMG, but the contribution of muscle strength was always higher. These findings underscore the potential of the mean EMG frequency recorded during 3DGA, for the evaluation of functional muscle strength in children with CP. PMID- 22245735 TI - The role of a peri-urban forest on air quality improvement in the Mexico City megalopolis. AB - Air quality improvement by a forested, peri-urban national park was quantified by combining the Urban Forest Effects (UFORE) and the Weather Research and Forecasting coupled with Chemistry (WRF-Chem) models. We estimated the ecosystem level annual pollution removal function of the park's trees, shrub and grasses using pollution concentration data for carbon monoxide (CO), ozone (O(3)), and particulate matter less than 10 microns in diameter (PM(10)), modeled meteorological and pollution variables, and measured forest structure data. Ecosystem-level O(3) and CO removal and formation were also analyzed for a representative month. Total annual air quality improvement of the park's vegetation was approximately 0.02% for CO, 1% for O(3,) and 2% for PM(10), of the annual concentrations for these three pollutants. Results can be used to understand the air quality regulation ecosystem services of peri-urban forests and regional dynamics of air pollution emissions from major urban areas. PMID- 22245736 TI - Washing of waste prior to landfilling. AB - The main impact produced by landfills is represented by the release of leachate emissions. Waste washing treatment has been investigated to evaluate its efficiency in reducing the waste leaching fraction prior to landfilling. The results of laboratory-scale washing tests applied to several significant residues from integrated management of solid waste are presented in this study, specifically: non-recyclable plastics from source separation, mechanical biological treated municipal solid waste and a special waste, automotive shredded residues. Results obtained demonstrate that washing treatment contributes towards combating the environmental impacts of raw wastes. Accordingly, a leachate production model was applied, leading to the consideration that the concentrations of chemical oxygen demand (COD) and total Kjeldahl nitrogen (TKN), parameters of fundamental importance in the characterization of landfill leachate, from a landfill containing washed wastes, are comparable to those that would only be reached between 90 and 220years later in the presence of raw wastes. The findings obtained demonstrated that washing of waste may represent an effective means of reducing the leachable fraction resulting in a consequent decrease in landfill emissions. Further studies on pilot scale are needed to assess the potential for full-scale application of this treatment. PMID- 22245737 TI - Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. AB - The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid 'lock-and-key' binding underpinned the 1E6-HLA A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an 'aromatic-cap' over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity. PMID- 22245739 TI - Revealing the superfluid lambda transition in the universal thermodynamics of a unitary Fermi gas. AB - Fermi gases, collections of fermions such as neutrons and electrons, are found throughout nature, from solids to neutron stars. Interacting Fermi gases can form a superfluid or, for charged fermions, a superconductor. We have observed the superfluid phase transition in a strongly interacting Fermi gas by high-precision measurements of the local compressibility, density, and pressure. Our data completely determine the universal thermodynamics of these gases without any fit or external thermometer. The onset of superfluidity is observed in the compressibility, the chemical potential, the entropy, and the heat capacity, which displays a characteristic lambda-like feature at the critical temperature T(c)/T(F) = 0.167(13). The ground-state energy is 3/5xiN E(F) with xi = 0.376(4). Our measurements provide a benchmark for many-body theories of strongly interacting fermions. PMID- 22245738 TI - Innate response activator B cells protect against microbial sepsis. AB - Recognition and clearance of a bacterial infection are a fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern-recognition receptors, and produce granulocyte-macrophage colony-stimulating factor. Specific deletion of IRA B cell activity impairs bacterial clearance, elicits a cytokine storm, and precipitates septic shock. These observations enrich our understanding of innate immunity, position IRA B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases. PMID- 22245740 TI - Female leadership raises aspirations and educational attainment for girls: a policy experiment in India. AB - Exploiting a randomized natural experiment in India, we show that female leadership influences adolescent girls' career aspirations and educational attainment. A 1993 law reserved leadership positions for women in randomly selected village councils. Using 8453 surveys of adolescents aged 11 to 15 and their parents in 495 villages, we found that, relative to villages in which such positions were never reserved, the gender gap in aspirations closed by 20% in parents and 32% in adolescents in villages assigned a female leader for two election cycles. The gender gap in adolescent educational attainment was erased, and girls spent less time on household chores. We found no evidence of changes in young women's labor market opportunities, which suggests that the impact of women leaders primarily reflects a role model effect. PMID- 22245741 TI - High-latitude forcing of the South American summer monsoon during the Last Glacial. AB - The climate of the Last Glacial period (10,000 to 110,000 years ago) was characterized by rapid millennial-scale climate fluctuations termed Dansgaard/Oeschger (D/O) and Heinrich events. We present results from a speleothem-derived proxy of the South American summer monsoon (SASM) from 16,000 to 50,000 years ago that demonstrate the occurrence of D/O cycles and Heinrich events. This tropical Southern Hemisphere monsoon reconstruction illustrates an antiphase relationship to Northern Hemisphere monsoon intensity at the millennial scale. Our results also show an influence of Antarctic millennial-scale climate fluctuations on the SASM. This high-resolution, precisely dated, tropical precipitation record can be used to establish the timing of climate events in the high latitudes of the Northern and Southern Hemispheres. PMID- 22245742 TI - Ultrasound-guided evaluation of lung sliding for widespread use? PMID- 22245743 TI - Marked variation in newborn resuscitation practice: a national survey in the UK. AB - BACKGROUND: Although international newborn resuscitation guidance has been in force for some time, there are no UK data on current newborn resuscitation practices. OBJECTIVE: Establish delivery room (DR) resuscitation practices in the UK, and identify any differences between neonatal intensive care units (NICU), and other local neonatal services. METHODS: We conducted a structured two-stage survey of DR management, among UK neonatal units during 2009-2010 (n=192). Differences between NICU services (tertiary level) and other local neonatal services (non-tertiary) were analysed using Fisher's exact and Student's t-tests. RESULTS: There was an 89% response rate (n=171). More tertiary NICUs institute DR CPAP than non-tertiary units (43% vs. 16%, P=0.0001) though there was no significant difference in frequency of elective intubation and surfactant administration for preterm babies. More tertiary units commence DR resuscitation in air (62% vs. 29%, P<0.0001) and fewer in 100% oxygen (11% vs. 41%, P<0.0001). Resuscitation of preterm babies in particular, commences with air in 56% of tertiary units. Significantly more tertiary units use DR pulse oximeters (58% vs. 29%, P<0.01) and titrate oxygen based on saturations. Almost all services use occlusive wrapping to maintain temperature for preterm infants. CONCLUSIONS: In the UK, there are many areas of good evidence based DR practice. However, there is marked variation in management, including between units of different designation, suggesting a need to review practice to fulfil new resuscitation guidance, which will have training and resource implications. PMID- 22245744 TI - Laryngeal mask airway and newborn resuscitation. PMID- 22245747 TI - Molecular mechanisms of therapeutic hypothermia on neurological function in a swine model of cardiopulmonary resuscitation. AB - OBJECTIVE: To explore the molecular mechanisms by which mild hypothermia following resuscitation improves neurological function in a porcine model of cardiac arrest. METHODS: Thirty-three inbred Chinese Wuzhishan (WZS) minipigs were used. After 8 min of untreated ventricular fibrillation (VF), the surviving animals (n=29) were randomly divided into two groups including serum group (n=16) and molecular group (n=13). Serum group animals were used to measure porcine specific tumour necrosis factor-alpha (TNF-alpha), interleukin (IL-6, IL-10), matrix metalloproteinase (MMP9), Aquaporin-4 (AQP4), tissue inhibitor to metalloproteinase-1 (TIMP1), neuron-specific enolase (NSE) and S100B at 0.5 h, 6 h, 12 h, 24 h and 72h recovery by enzyme-linked immunosorbent assay (ELISA). Molecular group animals were used to measure cerebral cortex messenger RNA (mRNA) and protein expression of nuclear factor-kappaB (NF-kappaB), MMP9 and AQP4 by real-time (RT) quantitative polymerase chain reaction (PCR) and Western blotting at 24 h and 72 h recovery. Animals were further divided into either normothermia or hypothermia groups. Hypothermia (33 degrees C) was maintained for 12 h using an endovascular cooling device. Swine neurologic deficit scores (NDS) were used to evaluate neurological function at 24-h and 72-h recovery. RESULTS: Twenty-nine of the 33 (87.9%) animals were successfully resuscitated. The hypothermia group exhibited higher survival rates at 24 h (75%) and 72 h (62.5%) compared to the normothermia group (37.5% and 25%, respectively). Hypothermia markedly inhibited expression of NF-kappaB, TNF-alpha, MMP9 and NSE, and promoted expression of TIMP1 (P<0.01). The mean NDS at 24-h and 72-h recovery was 112.5 and 61, respectively, in the hypothermic group, and 230 and 207.5, respectively, in the normothermia group. CONCLUSION: Brain protection induced by hypothermia involves inhibition of inflammatory and brain edema pathways. PMID- 22245748 TI - Paediatric chest compressions, can we practice what we teach? PMID- 22245749 TI - Comment on 'Epidemiology and outcomes of poisoning-induced out-of-hospital cardiac arrest'. PMID- 22245750 TI - BML-111, a lipoxin receptor agonist, protects haemorrhagic shock-induced acute lung injury in rats. AB - OBJECTIVES: The main pathogenesis of acute lung injury induced by haemorrhagic shock is inflammation. BML-111, a lipoxinA(4)-receptor agonist, promotes acute inflammatory resolution. We sought to elucidate whether BML-111 protects haemorrhagic shock-induced acute lung injury in rats. METHODS: Thirty two adult male rats were randomized to sham group (sham), haemorrhagic shock/resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Haemorrhagic shock was induced by blood drawing, and then resuscitation was obtained by infusion of shed blood and two-fold volume saline. RESULTS: Histological findings, as well as assays of neutrophilic infiltration (myeloperoxidase activity, ICAM-1 expression), inflammatory cytokines and pro inflammatory factor (IkappaB-alpha and NF-kappaB p65) confirmed that haemorrhagic shock induced acute lung injury. BML-111 significantly mitigated acute lung injury induced by haemorrhagic shock. However, BOC-2, an antagonist of the lipoxinA(4)-receptor, partially reversed the protective effect of BML-111 on the haemorrhagic shock-induced the acute lung injury. CONCLUSION: BML-111 protects haemorrhagic shock-induced acute lung injury in rats. PMID- 22245751 TI - Analysis of post-exposure density growth in radiochromic film with respect to the radiation dose. AB - The post-exposure density growth (PEDG) is one of the characteristics of radiochromic film (RCF). In film dosimetry using RCF and a flatbed scanner, pixel values read out from the RCF are converted to dose (hereafter, film dose) by using a calibration curve. The aim of this study is to analyze the relationship between the pixel value read out from the RCF and the PEDG, and that between the film dose converted from the RCF and the PEDG. The film (GAFCHROMIC EBT) was irradiated with 10-MV X-rays in an ascending 11-dose-step arrangement. The pixel values of the irradiated EBT film were measured at arbitrary hours using an Epson flatbed scanner. In this study, the reference time was 24 h after irradiation, and all dose conversions from the pixel values read out from the EBT film were made using a calibration curve for 24 h after irradiation. For delivered doses of 33 and 348 cGy, the measured pixel values at 0.1 and 16 h after irradiation represented ranges of -9.6% to -0.7% and -3.9% to -0.3%, respectively, of the reference value. The relative changes between the pixel values read out from the EBT film at each elapsed time and that at the reference time decreased with increasing delivered dose. However, the difference range for all the film doses had a width of approximately -10% of the reference value at elapsed times from 0.1 to 16 h, and it showed no dependence on the delivered dose. PMID- 22245752 TI - Overproduction of anti-Tn antibody MLS128 single-chain Fv fragment in Escherichia coli cytoplasm using a novel pCold-PDI vector. AB - Overproduction of recombinant proteins in Escherichia coli is often hampered by their failure to fold correctly, leading to their accumulation within inclusion bodies. To overcome the problem, a variety of techniques aimed at soluble expression have been developed including low temperature expression and/or fusion of soluble tags and chaperones. However, a general protocol for bacterial expression of disulfide bond-containing proteins has hitherto not been established. Single chain Fv fragments (scFvs) are disulfide bond-containing proteins often difficult to express in soluble forms in E. coli. We here examine in detail the E. coli expression of a scFv originating from an anti-carbohydrate MLS128 antibody as a model system. We combine three techniques: (1) tagging scFv with thioredoxin, DsbC and protein disulfide isomerase (PDI), (2) expressing the proteins at low temperature using the pCold vector system, and (3) using Origami E. coli strains with mutations in the thioredoxin reductase and glutathione reductase genes. We observed a high expression level of soluble MLS128-scFv in the Origami strain only when PDI is used as a tag. The recombinant protein retains full binding activity towards synthetic carbohydrate antigens. The developed "pCold-PDI" vector has potential for overproduction of other scFvs and disulfide-containing proteins in the Origami strains. PMID- 22245753 TI - Gastroprotective effect of Senecio candicans DC on experimental ulcer models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senecio candicans DC (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris district, Tamil Nadu for which no scientific evidence exists. AIM OF THE STUDY: The present study was performed to evaluate the gastroprotective effects and acute oral toxicity of aqueous leaf extract of Senecio candicans (AESC) in experimental models. MATERIALS AND METHODS: The antiulcerogenic activity of AESC was performed in two different ulcer models viz., pylorus-ligated model and ethanol-induced model using Wistar albino rats. Acute toxicity study was also performed to get information on the admissible dose for treatment of ulcer. Preliminary phytochemical screening of AESC was performed to find the active principles present, which are thus responsible for the antiulcerogenic activity. DPPH assay was performed to confirm the antioxidant activity of AESC. RESULTS: The acute toxicity study did not show any mortality up to 2500mg/kg b.w. of AESC. Both the ulcer models showed gastroprotective effect comparable to that of the standard Omeprazole. The results of antioxidant enzymes, histopathology sections, ATPase and mucus content of gastric secretion showed that several mechanisms are involved in the gastroprotective effect. The preliminary phytochemical screening revealed the presence of alkaloids, flavonoids and steroids in AESC. The DPPH assay confirmed the antioxidant activity of AESC. CONCLUSION: The traditional consumption of AESC for the treatment of gastric ulcer is thus true, the antioxidant constituents present in the extract plays a major role in the gastroprotective activity, but since Senecio species are known for the presence of pyrrolizidine alkaloids, a detailed study in future is required to describe the safe dose for a prolonged period. PMID- 22245755 TI - Asymmetric organocatalytic formation of protected and unprotected tetroses under potentially prebiotic conditions. AB - Esters of proteinogenic amino acids efficiently catalyse the formation of erythrose and threose under potentially prebiotic conditions in the highest yields and enantioselectivities yet reported. Remarkably while esters of (L) proline yield (L)-tetroses, esters of (L)-leucine, (L)-alanine and (L)-valine generate (D)-tetroses, offering the potential to account for the link between natural (L)-amino acids and natural (D)-sugars. The effect of pH and NaCl on the yields and enantioselectivities was also investigated and was shown to be significant, with the optimal enantioselectivities occurring at pH 7. PMID- 22245754 TI - Potential antifertility agents from plants: a comprehensive review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicines are practiced worldwide for regulation fertility since ancient times. This review provides a comprehensive summary of medicinal flora inhabitating throughout the world regarding their traditional usage by various tribes/ethnic groups for fertility regulation in females. MATERIALS AND METHODS: Bibliographic investigation was carried out by analyzing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases from the last six decades. Plants/their parts/extracts traditionally used for abortion, contraception, emmenagogue and sterilization purposes have been considered as antifertility agents. Research status of selected potential plant species has been discussed. Further, compounds isolated from plants with attributed fertility regulating potentials are also classified into three categories: (a) phytoconstituents with anti-implantation activity, (b) phytoconstituents with abortifacient activity and (c) phytoconstituents with contraceptive activity. RESULTS: 577 plant species belonging to 122 families, traditionally used in fertility regulation in females, have been recorded, of which 298 plants have been mentioned as abortifacients (42%), 188 as contraceptives (31%), 149 as emmenagogues (24%), and 17 as sterilizers. Among 122 plant families, fabaceae constitutes 49.2%, asteraceae 40.98%, euphorbiaceae 19.7%, apiaceae 16.4%, poaceae 12.3%, labiateae 11.5%, and others in lesser proportion. Various plant parts used in fertility regulation include leaves (25%), roots (22%), fruits (15%), seeds (12%), stem/stem bark (37%), and flowers (4%). Some active compounds, isolated from about various plant species, have been reported to possess significant antifertility potential. CONCLUSION: This review clearly indicates that it is time to increase the number of experimental studies to find out novel potential chemical entities from such a vast array of unexploited plants having traditional role in fertility regulation. Also, the mechanisms of action by which plant extracts and their active compounds exert antifertility effects remain to be studied. PMID- 22245756 TI - Endoscopic repair of anterior or middle skull base cerebrospinal fluid leaks after tumour resection. AB - OBJECTIVES: This study analysed the factors influencing the risk of recurrence following endoscopic repair of CSF leaks of the anterior and middle skull base after endonasal skull base tumour resection. PATIENTS AND METHODS: A retrospective review was conducted on 17 patients operated between May 2007 and December 2010 by endonasal endoscopic resection of anterior or middle skull base tumour who presented an intraoperative CSF leak. Epidemiological data (body mass index [BMI], age, gender) and type of leak (site, size) were studied. RESULTS: CSF leaks involved the roof of the ethmoid sinus (one patient), cribriform plate (three), posterolateral wall of the sphenoid sinus (six) or the sella turcica (seven). The CSF leak recurrence rate after the first endoscopic procedure was 29.4% (5/17). Failures were not influenced by gender, age, BMI or size of the leak. All recurrences involved the sella turcica or the lateral wall of the sphenoid sinus. The success rate after a second endoscopic procedure was 88.2%. CONCLUSION: Endonasal endoscopic repair of anterior and middle skull base meningeal injuries after tumour resection is a minimally invasive and effective technique. The main challenge of this method consists of ensuring effective control of the postoperative defect after tumour resection in the sphenoidal region, as this region was the only potential risk factor for recurrence identified in this study. PMID- 22245757 TI - A novel molluscan sigma-like glutathione S-transferase from Manila clam, Ruditapes philippinarum: cloning, characterization and transcriptional profiling. AB - Glutathione S-transferases (GSTs) are versatile enzymes, act as primary intracellular detoxifiers and contribute to a broad range of physiological processes including cellular defense. In this study, a full-length cDNA representing a novel sigma-like GST was identified from Manila clam, Ruditapes philippinarum (RpGSTsigma). RpGSTsigma (884 bp) was found to possess an open reading frame of 609 bp. The encoded polypeptide (203 amino acids) had a predicted molecular mass of 23.21 kDa and an isoelectric point of 7.64. Sequence analysis revealed two conserved GST domain profiles in N- and C-termini. Alignment studies revealed that the identity between deduced peptides of RpGSTsigma and known GSTsigma members was relatively low (<35%), except a previously identified Manila clam GSTsigma isoform (87.2%). Phylogenetic analysis indicated that RpGSTsigma clustered together with molluscan GSTsigma homologs, which were closely related to insect GSTsigmas. The RpGSTsigma was subsequently cloned and expressed as recombinant protein, in order to characterize its biological activity. The recombinant RpGSTsigma exhibited characteristic glutathione conjugating catalytic activity toward 1-chloro-2,4-dinitrobenzene, 3,4-dichloronitrobenzene and ethacrynic acid. It had an optimal pH and temperature of 8.0 and 35 degrees C, respectively. Expression profiles under normal conditions and in response to lipopolysaccharide-, poly I:C- and Vibrio tapetis-challenges were also investigated. RpGSTsigma demonstrated a differential tissue distribution with robust transcription in gills of normal animals. We explored potential association of GSTsigma in cellular defense during bacterial infection and found that in challenged clams, RpGSTsigma gene was significantly induced in internal and external tissues, in conjunction with manganese- as well as copper-zinc superoxide dismutase (MnSOD and CuZnSOD) genes. Moreover, the induction was remarkably higher in hemocytes than in gill. Collectively, our findings suggested that RpGSTsigma could play a significant role in cellular defense against oxidative stress caused by bacteria, in conjunction with other antioxidant enzymes, such as SODs. PMID- 22245758 TI - Abnormal visual processing and increased seizure susceptibility result from developmental exposure to the biocide methylisothiazolinone. AB - Methylisothiazolinone (MIT) is a commonly used biocide known to be neurotoxic in vitro. Brief exposure of cortical neurons in culture to MIT results in increased neurodegeneration, whereas chronic exposure of developing neurons in culture to low concentrations of MIT has been shown to interfere with normal neurite outgrowth. However, the effects of chronic MIT exposure on the developing nervous system have not been tested in vivo. Here we expose Xenopus laevis tadpoles to sub-lethal concentrations of MIT during a critical period in neural development. We find that MIT exposure results in deficits in visually mediated avoidance behavior and increased susceptibility to seizures, as well electrophysiological abnormalities in optic tectal function, without any effects on overall morphology, gross anatomy of the visual projections, overall visual function, and swimming ability. These effects indicate that chronic exposure to low levels of MIT results in neural circuit-level deficits that result in abnormal neurological function without causing increased mortality or even gross anatomical defects. Our findings, combined with the fact that the long-term neurological impacts of environmental exposure to MIT have not been determined, suggest a need for a closer evaluation of the safety of MIT in commercial and industrial products. PMID- 22245759 TI - Impact of a national shortage of sterile ethanol on a home parenteral nutrition practice: a case series. AB - Catheter-related bloodstream infection (CRBSI) is a common and life-threatening infectious complication of home parenteral nutrition (PN). CRBSI is associated with hospital admissions, morbidity, mortality, loss of venous access, and healthcare costs. Ethanol has bactericidal and fungicidal properties, making it an ideal locking solution for preventing CRBSI. The authors report 6 patients with a recurrence of CRBSI when ethanol lock (ETL) was withheld due to a national shortage. This is the first known report of the ramifications of a national ethanol shortage on redevelopment of CRBSI in home PN patients with a history of CRBSIs. This series further supports the existing literature showing that ETL is a viable therapy for the prevention of CRBSIs, warranting prospective research. The impact of an ethanol shortage due to a sole-source manufacturer supports the need for the Food and Drug Administration to regulate pharmaceutical products to avoid shortages. PMID- 22245760 TI - Web-based teaching module improves success rates of postpyloric positioning of nasoenteric feeding tubes. AB - BACKGROUND: Bedside protocols improve success rates of postpyloric nasoenteric tube (NET) placement by nutrition teams and experienced individuals. However, many hospitals require novice practitioners to perform these procedures and often choose fluoroscopy, endoscopy, or newer alternative devices to achieve success. Little is known about the ability to train inexperienced practitioners or the effectiveness of the methods used to implement these protocols. Web-based learning is a potential tool to improve knowledge and procedural skills. The authors created a self-directed Web-based teaching module (WBTM) to educate and standardize placement of postpyloric NETs. METHODS: Forty-three first-, second-, or third-year residents or medical or physician assistant students took pretests for knowledge and confidence surveys, viewed the WBTM, placed NET at the bedside, then took a posttest and confidence survey while awaiting confirmation of tube position by abdominal radiograph. Success was acknowledged if the tip of the NET was beyond the pylorus. A retrospective chart review was used to determine a historical success rate, which was used as a control. RESULTS: Knowledge and confidence significantly improved. Overall success rate of postpyloric NET placement for all participants on first attempt was 74.4% vs 46.7% in the control (P = .005). Improvement occurred in all subgroups, including those with no prior experience, who were successful 70.4% of the time (P = .009). CONCLUSIONS: This WBTM is simple to implement, inexpensive, and resource efficient. The improvement in postpyloric NET placement, especially among novice practitioners, demonstrates the benefit and applicability of this method of standardized education. PMID- 22245761 TI - Prophylactic anticoagulation decreases catheter-related thrombosis and occlusion in children with home parenteral nutrition. AB - BACKGROUND: Home parenteral nutrition (PN) has improved the survival of children with intestinal failure. Important complications include catheter-related thrombosis, occlusion, and infection. This study evaluated the efficacy and safety of prophylactic anticoagulation in the prevention of these complications. METHODS: Medical records were retrospectively reviewed of all children (0-18 years) with PN between January 1994 and March 2007 in 1 tertiary center. After introduction of prophylactic low molecular weight heparin or vitamin K antagonists in March 2007, all patients were prospectively followed until March 2010. RESULTS: In sum, 14 patients did not receive prophylaxis; 13 switched from no prophylaxis to prophylaxis in March 2007; and 5 directly received prophylaxis. Median age of PN onset was 4 months (range, 0.1-202) in the nonprophylaxis group (n = 27) and 25 (range, 2-167) in the prophylaxis group (n = 18); 16 children received low molecular weight heparin and 2, vitamin K antagonists. Catheter related thrombosis developed in 9 patients with no prophylaxis (33%) and 1 with prophylaxis (6%) (P = .034). Cumulative 5-year thrombosis-free survival was 48% and 93% in the nonprophylaxis and prophylaxis groups, respectively (P = .047). Per 1,000 PN days, the nonprophylaxis and prophylaxis groups had 2.6 and 0.1 occlusions (P = .04) and 4.6 and 2.1 infections (P = .06), respectively. Cumulative infection-free survival after 3 years was 19% and 46% in the nonprophylaxis and prophylaxis groups, respectively (P = .03). Bleeding complications did not occur. CONCLUSION: Thromboprophylaxis significantly decreased catheter-related thrombosis and occlusion in children with PN without complications. PMID- 22245762 TI - Calcium chloride and sodium phosphate in neonatal parenteral nutrition containing TrophAmine: precipitation studies and aluminum content. AB - OBJECTIVES: The objectives were to determine concentrations of calcium chloride (CaCl) and sodium phosphate (NaPhos) that can be safely added to TrophAmine-based parenteral nutrition (PN) and to measure aluminum (Al) concentrations in PN solutions containing CaCl and NaPhos vs those containing calcium gluconate (CaGlu) and potassium phosphate (KPhos). METHODS: In study A, PN solutions containing varying amounts of TrophAmine, CaCl, and NaPhos were compounded and then evaluated visually for precipitation. In study B, Al concentrations were measured in PN solutions containing CaCl and NaPhos (S1), CaGlu and NaPhos (S2), or CaGlu and KPhos (S3). RESULTS: Study A showed that a maximum phosphorus concentration of 15 mmol/L could be added to a solution containing 12.5 mmol/L of calcium without evidence of precipitation when the amino acid (AA) concentration reached >=3 g/dL (3%). In study B, the mean (range) Al concentrations were S1 = 2.2 (1.9-2.4), S2 = 8.5 (7.8-9.3), and S3 = 11.7 (10.8-12.2) umol/L (means of 6.0, 22.9, and 31.5 micrograms/dL, respectively). CONCLUSIONS: The data can provide a guide for compounding neonatal PN solutions containing TrophAmine, CaCl, and NaPhos. More studies are needed to determine the long-term effects of substituting CaCl for CaGlu in PN solutions for neonates. Substituting CaCl and NaPhos for CaGlu and KPhos significantly decreases Al concentrations in PN and potential Al exposure of neonatal patients. PMID- 22245763 TI - Prevalence of vitamin D deficiency and response to oral vitamin D supplementation in patients receiving home parenteral nutrition. AB - The purpose of this study was to document vitamin D status in home parenteral nutrition (HPN) patients and determine if oral vitamin D supplementation has a substantial effect. METHODS: A retrospective chart review of eligible adults enrolled in the Southern Alberta Home Parenteral Nutrition program (n = 15) for a minimum of 6 months was conducted. Serum measurements of 25OHD were recorded and patients were categorized by vitamin D status as follows: sufficient; insufficient; deficient with respective levels of 25OHD >=75 nmol/L, 27.5-75 nmol/L, and <=27.5 nmol/L; and mixed. RESULTS: Five of 15 patients had insufficient vitamin D status throughout the study period; all had short bowel syndrome. Nine were in the mixed category; 1 was consistently sufficient, and no one was consistently deficient. Patient demographics were similar between the insufficient and mixed groups. There were no significant differences in health outcomes between the insufficient and mixed vitamin D status groups. The median (interquartile range) dose and duration of vitamin D3 supplementation for the insufficient group was 5000 IU/d (4,000-7,143) for 1,175 (1,145-1,578) total days compared to 3,000 IU/d (1,000-7,143) for 1,529 (111-1,980) days for the mixed group. CONCLUSIONS: Most patients receiving HPN had insufficient vitamin D status. When prescribed high doses of oral vitamin D, patients did not consistently achieve appropriate 25OHD levels. Alternate routes of vitamin D supplementation in patients receiving HPN should be considered. Large multicenter prospective studies are needed to best characterize the relationship between vitamin D dosing for HPN patients and vitamin D status. PMID- 22245764 TI - Immobilizing CC chemokine receptor 4's N-terminal extracellular tail on a capillary to study its potential ligands by capillary electrophoresis. AB - ML40 is the equivalent peptide derived from the N terminal of CCC4 (CC chemokine receptor 4), which plays a pivotal role in allergic inflammation. A new capillary electrophoresis method was developed to study the interactions between ML40 and its potential ligands in which ML40 was immobilized on the inner wall of capillary as the stationary phase based on the covalent linking technique. The interaction between S009, a known CCR4 antagonist, and the immobilized ML40 was studied to validate the bioactivity of ML40. The electropherogram of S009 showed that the peak height was reduced and the peak width was broadened in the ML40 immobilized capillary. Otherwise, 25 computer-aided design and drafting compounds were screened out using this method. Four compounds' peak widths were broadened and their peak heights were reduced, as with S009. Meanwhile, nonlinear chromatography was used to calculate the constants for the ligand-receptor complex formation. Furthermore, the tertiary amine compounds belonging to the chiral tertiary amines of the type NRR'R", which are optically inactive resulting from rapid pyramide inversion, were chiral separated by our protein immobilization method for the first time. In general, the methodology presented would be applicable to study compound-ML40 interactions as a reliable and robust screening method for CCR4 antagonist discovery. PMID- 22245765 TI - Primate model research for endometriosis. AB - Endometriosis is defined as the existence of endometrial tissue outside the uterine cavity, and it includes a chronic, inflammatory reaction associated with female infertility and pelvic pain. Endometriosis occurs in 7 to 10% of women. Although it has been studied for more than 50 years, the pathogenesis and development of endometriosis are still poorly understood. There is no curative therapy for endometriosis, which often recurs after surgical or medical treatment. There is a consensus that the adverse current of menstrual blood plays a crucial role in the development of endometriosis. This places a major limitation on research using rodent models of endometriosis, although these are still widely employed, because rodents do not menstruate and endometriosis does not occur spontaneously in these animals. In fact, menstruation and spontaneous endometriosis only occur in women and some non-human primates, making models that employ non-human primates the best animal models for research into the pathogenesis, pathophysiology, spontaneous onset, and treatment of endometriosis. This review assesses the effectiveness and potential of the non-human primate models of endometriosis. It also describes the current findings and theories on the pathogenesis of endometriosis that have been obtained by research using non human primates. PMID- 22245766 TI - Job stress strengthens the link between metabolic risk factors and renal dysfunction in adult men. AB - Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease. The metabolic risk factors obesity, hypertension, diabetes, and dyslipidemia are closely associated with renal dysfunction. As psychosocial stress affects these risk factors, here, we examined relationships between metabolic risk factors and renal function, and their association with job stress. The participants were 1,231 Japanese male office workers attending annual health examinations. The estimated glomerular filtration rate (eGFR) was determined using the equation recommended by the Japanese Society for Nephrology: eGFR (mL/min/1.73 m(2)) = 194 * age(-0.287) * Cr(-1.094). Job stress was measured using the Job Content Questionnaire based on the job demand-control model. The job strain index equaled the job demand scores divided by the job control scores. The participants were classified into four ordinal groups of job strain index, based on previous studies (i.e., <= 0.4 the lowest, 0.4-0.5 lower, 0.5-0.6 higher, or >= 0.6 the highest). A significant correlation was found between lowered eGFR and each of the metabolic risk factors waist circumference, systolic and diastolic blood pressure, and total cholesterol (p < 0.001). Furthermore, job stress had an interactive effect on the relationships between eGFR and systolic and diastolic blood pressure, and triglycerides, depending on the job strain index (highest vs. lowest) (p < 0.05). The highly stressed workers exhibited a close association of eGFR with metabolic risk factors like hypertension and dyslipidemia. Therefore, intensive management may be important for preventing the progression of renal dysfunction and cardiovascular complications in those experiencing stress. PMID- 22245767 TI - Prognostic implication of interdialytic fluid retention during the beginning period in incident hemodialysis patients. AB - Patient with end stage renal disease have characteristics in common with heart failure patients, and volume overload in heart failure is associated with poorer outcomes. Fluid removal during the hemodialysis (HD) is the cornerstone of volume management in this population. The objective of this study is to assess the long-term prognostic effect of interdialytic fluid retention (IDFR) and its relationship with cardiovascular (CV) events in incident HD patients who newly started dialysis. IDFR is defined as the difference between the predialysis weight and the weight at the end of the previous dialysis session, and it mainly reflects the consequence of salt and water intake between two consecutive dialysis sessions. We retrospectively reviewed the 172 patients who newly started and maintained HD over 6 months at Gachon University Gil Hospital between 1 January 2003 and 31 December 2008. The average data were collected for 3 months during the beginning period, including total IDFR and IDFR/dry weight (IDFR%), nutritional parameters, blood pressure, and other biochemical parameters. Patients were classified into 3 cohorts according to the tertile of IDFR%; low (T1; <= 3.21%), intermediate (T2; 3.21%-4.56%), and high (T3; >= 4.56%). The high IDFR% group showed higher prevalence of diabetes and better nutritional status. The adjusted odds ratio for CV events was 1.562 (95% confidence interval, 1.026-2.378) for high IDFR% group, compared with the low IDFR% group. In incident HD patients, greater IDFR% soon after HD initiation showed an independent association with higher risk for CV events. PMID- 22245768 TI - Organocatalytic enantioselective synthesis of 2,3-dihydropyridazines. AB - We have developed an efficient procedure for the easy and straightforward preparation of functionalized dihydropyridazines as highly enantiopure materials by reaction of pyruvaldehyde 2-tosyl hydrazone with a variety of alpha,beta unsaturated aldehydes using a chiral secondary amine as catalyst. The overall process consists of a cascade reaction involving an initial aza-Michael reaction, in which the stereocentre is installed, followed by an intramolecular aldol reaction/dehydration step. PMID- 22245769 TI - Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. AB - The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH(4)), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH(4). Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 +/- 1 yr, mean +/- SE) and eumenorrheic premenopausal (n = 9; 33 +/- 2 yr) women before and 3 h after the oral administration of BH(4). Subsequently, in postmenopausal women, vascular testing (before and after BH(4)) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH(4) administration increased carotid artery compliance (0.61 +/- 0.05 to 0.73 +/- 0.04 mm(2).mmHg( 1).10(-1) vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 +/- 0.05 to 0.78 +/- 0.06 mm(2).mmHg(-1).10(-1), P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH(4), possibly because estrogen increased BH(4) bioavailability. Carotid artery compliance and FMD increased with BH(4) in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH(4) may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone. PMID- 22245771 TI - Cardiac-specific genetic inhibition of nuclear factor-kappaB prevents right ventricular hypertrophy induced by monocrotaline. AB - Uncontrolled pulmonary arterial hypertension (PAH) results in right ventricular (RV) hypertrophy (RVH), progressive RV failure, and low cardiac output leading to increased morbidity and mortality (McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. J Am Coll Cardiol 53: 1573-1619, 2009). Although the exact figures of its prevalence are difficult to obtain because of the diversity of identifiable causes, it is estimated that the incidence of pulmonary hypertension is seven to nine cases per million persons in the general population and is most prevalent in the age group of 20-40, occurring more commonly in women than in men (ratio: 1.7 to 1; Rubin LJ. N Engl J Med 336: 111-117, 1997). PAH is characterized by dyspnea, chest pain, and syncope. Unfortunately, there is no cure for this disease and medical regimens are limited (Simon MA. Curr Opin Crit Care 16: 237-243, 2010). PAH leads to adverse remodeling that results in RVH, progressive right heart failure, low cardiac output, and ultimately death if left untreated (Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. J Am Coll Cardiol 43: 13S-24S, 2004; Humbert M, Sitbon O, Simonneau G. N Engl J Med 351: 1425-1436, 2004. LaRaia AV, Waxman AB. South Med J 100: 393-399, 2007). As there are no direct tools to assess the onset and progression of PAH and RVH, the disease is often detected in later stages marked by full-blown RVH, with the outcome predominantly determined by the level of increased afterload (D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Ann Intern Med 115: 343-349, 1991; Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Validation of a prognostic equation Circulation 89: 1733-1744, 1994). Various studies have been performed to assess the genetic, biochemical, and morphological components that contribute to PAH. Despite major advances in the understanding of the pathogenesis of PAH, the molecular mechanism(s) by which PAH promotes RVH and cardiac failure still remains elusive. Of all the mechanisms involved in the pathogenesis, inflammation and oxidative stress remain the core of the etiology of PAH that leads to development of RVH (Dorfmuller P, Perros F, Balabanian K, Humbert M. Eur Respir J 22: 358-363, 2003). PMID- 22245770 TI - Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy. AB - The hemolysis of red blood cells and muscle damage results in the release of the heme proteins myoglobin, hemoglobin, and free heme into the vasculature. The mechanisms of heme toxicity are not clear but may involve lipid peroxidation, which we hypothesized would result in mitochondrial damage in endothelial cells. To test this, we used bovine aortic endothelial cells (BAEC) in culture and exposed them to hemin. Hemin led to mitochondrial dysfunction, activation of autophagy, mitophagy, and, at high concentrations, apoptosis. To detect whether hemin induced lipid peroxidation and damaged proteins, we used derivatives of arachidonic acid tagged with biotin or Bodipy (Bt-AA, BD-AA). We found that in cells treated with hemin, Bt-AA was oxidized and formed adducts with proteins, which were inhibited by alpha-tocopherol. Hemin-dependent mitochondrial dysfunction was also attenuated by alpha-tocopherol. Protein thiol modification and carbonyl formation occurred on exposure and was not inhibited by alpha tocopherol. Supporting a protective role of autophagy, the inhibitor 3 methyladenine potentiated cell death. These data demonstrate that hemin mediates cytotoxicity through a mechanism which involves protein modification by oxidized lipids and other oxidants, decreased respiratory capacity, and a protective role for the autophagic process. Attenuation of lipid peroxidation may be able to preserve mitochondrial function in the endothelium and protect cells from heme dependent toxicity. PMID- 22245772 TI - New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling. AB - Pulmonary arterial hypertension (PAH) is a severe and progressive disease that usually culminates in right heart failure and death if left untreated. Although there have been substantial improvements in our understanding and significant advances in the management of this disease, there is a grim prognosis for patients in the advanced stages of PAH. A major cause of PAH is increased pulmonary vascular resistance, which results from sustained vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular stiffness. In addition to other signal transduction pathways, Ca(2+) signaling in pulmonary artery smooth muscle cells (PASMCs) plays a central role in the development and progression of PAH because of its involvement in both vasoconstriction, through its pivotal effect of PASMC contraction, and vascular remodeling, through its stimulatory effect on PASMC proliferation. Altered expression, function, and regulation of ion channels and transporters in PASMCs contribute to an increased cytosolic Ca(2+) concentration and enhanced Ca(2+) signaling in patients with PAH. This review will focus on the potential pathogenic role of Ca(2+) mobilization, regulation, and signaling in the development and progression of PAH. PMID- 22245773 TI - Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. AB - Endogenous cardiotonic steroids (CTS) raise blood pressure (BP) via vascular sodium calcium exchange (NCX1.3) and transient receptor-operated channels (TRPCs). Circulating CTS are superelevated in pregnancy-induced hypertension and preeclampsia. However, their significance in normal pregnancy, where BP is low, is paradoxical. Here we test the hypothesis that vascular resistance to endogenous ouabain (EO) develops in normal pregnancy and is mediated by reduced expression of NCX1.3 and TRPCs. We determined plasma and adrenal levels of EO and the impact of exogenous ouabain in pregnancy on arterial expression of Na(+) pumps, NCX1.3, TRPC3, and TRPC6 and BP. Pregnant (embryonic day 4) and nonpregnant rats received infusions of ouabain or vehicle. At 14-16 days, tissues and plasma were collected for blotting and EO assay by radioimmunoassay (RIA), liquid chromatography (LC)-RIA, and LC-multidimensional mass spectrometry (MS3). BP (-8 mmHg; P < 0.05) and NCX1.3 expression fell (aorta -60% and mesenteric artery -30%; P < 0.001) in pregnancy while TRPC expression was unchanged. Circulating EO increased (1.14 +/- 0.13 nM) vs. nonpregnant (0.6 +/- 0.08 nM; P < 0.05) and was confirmed by LC-MS3 and LC-RIA. LC-MS3 revealed two previously unknown isomers of EO; one increased ~90-fold in pregnancy. Adrenal EO but not isomers were increased in pregnancy. In nonpregnant rats, similar infusions of ouabain raised BP (+24 +/- 3 mmHg; P < 0.001). In ouabain-infused rats, impaired fetal and placental growth occurred with no BP increase. In summary, normal pregnancy is an ouabain-resistant state associated with low BP, elevated circulating levels of EO, two novel steroidal EO isomers, and increased adrenal mass and EO content. Ouabain raises BP only in nonpregnant animals. Vascular resistance to the chronic pressor activity of endogenous and exogenous ouabain is mediated by suppressed NCX1.3 and reduced sensitivity of events downstream of Ca(2+) entry. The mechanisms of EO resistance and the impaired fetal and placental growth due to elevated ouabain may be important in pregnancy-induced hypertension (PIH) and preeclampsia (PE). PMID- 22245774 TI - Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures. AB - Recent studies have indicated that inhibitors of the synthesis of 20 hydroxyeicosatetraenoic acid (20-HETE) may have direct neuroprotective actions since they reduce infarct volume after ischemia reperfusion in the brain without altering blood flow. To explore this possibility, the present study used organotypic hippocampal slice cultures subjected to oxygen-glucose deprivation (OGD) and reoxygenation to examine whether 20-HETE is released by organotypic hippocampal slices after OGD and whether it contributes to neuronal death through the generation of ROS and activation of caspase-3. The production of 20-HETE increased twofold after OGD and reoxygenation. Blockade of the synthesis of 20 HETE with N-hydroxy-N'-(4-butyl-2-methylphenol)formamidine (HET0016) or its actions with a 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, reduced cell death, as measured by the release of lactate dehydrogenase and propidium iodide uptake. Administration of a 20-HETE mimetic, 20-hydroxyeicosa 5(Z),14(Z)-dienoic acid (5,14-20-HEDE), had the opposite effect and increased injury after OGD. The death of neurons after OGD was associated with an increase in the production of ROS and activation of caspase-3. These effects were attenuated by HET0016 and potentiated after the administration of 5,14-20-HEDE. These findings indicate that the production of 20-HETE by hippocampal slices is increased after OGD and that inhibitors of the synthesis or actions of 20-HETE protect neurons from ischemic cell death. The protective effect of 20-HETE inhibitors is associated with a decrease in superoxide production and activation of caspase-3. PMID- 22245775 TI - The neurobiology of binge-like ethanol drinking: evidence from rodent models. AB - Binge alcohol (ethanol) drinking is a destructive pattern of ethanol consumption that may precipitate ethanol dependence-a chronic, debilitating, and prevalent health problem. While an abundance of research has focused on the neurochemical underpinnings of ethanol dependence, relatively little is known about the mechanisms underlying the heavy consumption characteristic of binge ethanol drinking. Recently, a simple preclinical model termed "drinking in the dark" (DID) was developed to examine binge-like ethanol consumption in a rodent population. This assay capitalizes on the predisposition of C57BL/6J mice to voluntarily consume substantial quantities of a high concentration (20% v/v) ethanol solution, resulting in pharmacologically relevant blood ethanol concentrations (BECs). This review provides a comprehensive overview of recent literature utilizing this model to investigate the neuromodulatory systems that may influence binge ethanol drinking. Studies examining the glutamatergic and opioidergic systems not only provide evidence for these systems in the modulation of binge-like ethanol consumption, but also suggest this preclinical model has predictive validity and may be an appropriate tool for screening novel pharmacological compounds aimed at treating binge ethanol drinking in the human population. Additionally, this review presents evidence for the involvement of the GABAergic, dopaminergic, nicotinic, and endocannabinoid systems in modulating binge-like ethanol consumption. Finally, recent evidence shows that corticotropin releasing factor (CRF), agouti-related protein (AgRP), neuropeptide Y (NPY), and ghrelin are also implicated as impacting this pattern of ethanol consumption. PMID- 22245776 TI - Crystal structure of JlpA, a surface-exposed lipoprotein adhesin of Campylobacter jejuni. AB - The Campylobacter jejuni JlpA protein is a surface-exposed lipoprotein that was discovered as an adhesin promoting interaction with host epithelium cells, an early critical step in the pathogenesis of C. jejuni disease. Increasing evidence ascertained that JlpA is antigenic, indicating a role of JlpA in immune response during the infectious process. Here, we report the crystal structure of JlpA at 2.7A resolution, revealing a catcher's mitt shaped unclosed half beta-barrel. Although the apparent architecture of JlpA is somewhat reminiscent of other bacterial lipoproteins such as LolB, the topology of JlpA is unique among the bacterial surface proteins reported to date and therefore JlpA represents a novel bacterial cell surface lipoprotein. The concave face of the structure results in an unusually large hydrophobic basin with a localized acidic pocket, suggesting a possibility that JlpA may accommodate multiple ligands. Therefore, the structure provides framework for determining the molecular function of JlpA and new strategies for the rational design of small molecule inhibitors efficiently targeting JlpA. PMID- 22245777 TI - Chemical mapping of mammalian cells by atom probe tomography. AB - In atom probe tomography (APT), a technique that has been used to determine 3D maps of ion compositions of metals and semiconductors at sub-nanometer resolutions, controlled emissions of ions can be induced from needle-shaped specimens in the vicinity of a strong electric field. Detection of these ions in the plane of a position sensitive detector provides two-dimensional compositional information while the sequence of ion arrival at the detector provides information in the third dimension. Here we explore the use of APT technology for imaging biological specimens. We demonstrate that it is possible to obtain 3D spatial distributions of cellular ions and metabolites from unstained, freeze dried mammalian cells. Multiple peaks were reliably obtained in the mass spectrum from tips with diameters of ~50 nm and heights of ~200 nm, with mass-to-charge ratios (m/z) ranging from 1 to 80. Peaks at m/z 12, 23, 28 and 39, corresponding to carbon, sodium, carbonyl and potassium ions respectively, showed distinct patterns of spatial distribution within the cell. Our studies establish that APT could become a powerful tool for mapping the sub-cellular distribution of atomic species, such as labeled metabolites, at 3D spatial resolutions as high as ~1 nm. PMID- 22245778 TI - Engineering human MEK-1 for structural studies: A case study of combinatorial domain hunting. AB - Structural biology studies typically require large quantities of pure, soluble protein. Currently the most widely-used method for obtaining such protein involves the use of bioinformatics and experimental methods to design constructs of the target, which are cloned and expressed. Recently an alternative approach has emerged, which involves random fragmentation of the gene of interest and screening for well-expressing fragments. Here we describe the application of one such fragmentation method, combinatorial domain hunting (CDH), to a target which historically was difficult to express, human MEK-1. We show how CDH was used to identify a fragment which covers the kinase domain of MEK-1 and which expresses and crystallizes significantly better than designed expression constructs, and we report the crystal structure of this fragment which explains some of its superior properties. Gene fragmentation methods, such as CDH, thus hold great promise for tackling difficult-to-express target proteins. PMID- 22245779 TI - An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. AB - Helminths induce potent T helper 2 (TH2)-type immune responses that can mediate worm expulsion, but the role of this response in controlling the acute tissue damage caused by migrating multicellular parasites through vital tissues remains uncertain. We used a helminth infection model in which parasitic nematode larvae migrate transiently through the lung, resulting in hemorrhage and inflammation. We found that IL-17 initially contributed to inflammation and lung damage, whereas subsequent IL-4 receptor (IL-4R) signaling reduced elevations in IL-17 mRNA levels, enhanced the expression of insulin-like growth factor 1 (IGF-1) and IL-10 and stimulated the development of M2 macrophages, all of which contributed to the rapid resolution of tissue damage. These studies indicate an essential role for TH2-type immune responses in mediating acute wound healing during helminth infection. PMID- 22245780 TI - Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids. AB - Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPbeta onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBPbeta to regulate expression of a subset of C/EBPbeta downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPbeta in mammary glands to control lipid secretion and pup survival. PMID- 22245781 TI - Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus. AB - Barrett's esophagus is an example of a pre-invasive state, for which current endoscopic surveillance methods to detect dysplasia are time consuming and inadequate. The prognosis of cancer arising in Barrett's esophagus is improved by early detection at the stage of mucosal carcinoma or high-grade dysplasia. Molecular imaging methods could revolutionize the detection of dysplasia, provided they permit a wide field of view and highlight abnormalities in real time. We show here that cell-surface glycans are altered in the progression from Barrett's esophagus to adenocarcinoma and lead to specific changes in lectin binding patterns. We chose wheat germ agglutinin as a candidate lectin with clinical potential. The binding of wheat germ agglutinin to human tissue was determined to be specific, and we validated this specific binding by successful endoscopic visualization of high-grade dysplastic lesions, which were not detectable by conventional endoscopy, with a high signal-to-background ratio of over 5. PMID- 22245782 TI - Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. AB - Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control. Hydrogen peroxide (H2O2) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H2O2 causes the formation of a disulfide bond between the two alpha subunits of protein kinase G I-alpha (PKGI-alpha), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-alpha oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S 'redox dead' version of PKGI-alpha. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H2O2 on resistance vessels and resulted in hypertension in vivo. PMID- 22245783 TI - Androgen receptor (AR) aberrations in castration-resistant prostate cancer. AB - Genetic aberrations affecting the androgen receptor (AR) are rare in untreated prostate cancers (PCs) but have been found in castration-resistant prostate cancers (CRPCs). Further, successful treatment with novel endocrine therapies indicates that CRPCs remain androgen-sensitive. Known AR aberrations include amplification of the AR gene leading to the overexpression of the receptor, point mutations of AR resulting in promiscuous ligand usage, and constitutively active AR splice variants. Gain, or amplification, of the AR gene is one of the most frequent genetic alterations observed in CRPCs. Up to 80% of CRPCs have been reported to carry an elevated AR gene copy number, and about 30% have a high level amplification of the gene. AR mutations are also commonly observed and have been found in approximately 10-30% of the CRPC treated with antiandrogens; however, the frequency and significance of AR splice variants is still unclear. Because AR aberrations are found almost exclusively in CRPC, these alterations must have been selected for during therapy. Interestingly, these aberrations lead to activation of the receptor, despite treatment-induced emergence of therapy resistant tumor clones. Therefore, future novel treatment strategies should focus on suppressing AR activity in CRPC. PMID- 22245785 TI - MICS-1 interacts with mitochondrial ATAD-3 and modulates lifespan in C. elegans. AB - Caenorhabditis elegans open reading frame T21C9.1 encodes an uncharacterized protein, which is here named MICS-1 (mitochondrial scaffolding protein-1). It is predicted to be the homolog of human outer mitochondrial membrane protein 25 (OMP25 or synaptojanin-2-binding protein), which is a PDZ domain containing protein with a putative role in cellular stress response pathways. Here, we provide evidence that MICS-1 is an interacting partner of mitochondrial protein ATAD-3 (homologue of human ATAD3), which is essential for C. elegans development. We demonstrate that mics-1(RNAi) animals or mics-1 mutants display enhanced longevity with an increased mean lifespan of up to 54% compared to control animals. Of note, also atad-3(RNAi) promoted longevity, although to a lesser extend (29% compared to controls). In addition, thermal stress of mics-1 mutants induced low reactive oxygen species (ROS) production, whereas atad-3(RNAi) animals were highly sensitive to this assay, displaying drastically increased ROS levels. Further studies revealed that MICS-1 and ATAD-3 associated longevity was partially dependent on the presence of DAF-16. However, for both conditions, we also found a DAF-16 independent extension of lifespan. Finally, we observed an additional lifespan extension in mics-1 mutants when subjected to atad-3(RNAi) whereas heat induced ROS production was even aggravated under this condition. This suggests (partially) independent effects of MICS-1 and ATAD-3 on lifespan and ROS production in vivo. PMID- 22245786 TI - Vascular effects of glycoprotein130 ligands--part II: biomarkers and therapeutic targets. AB - Glycoprotein130 (gp130) ligands are defined by the use of the common receptor subunit gp130 and comprise interleukin (IL)-6, oncostatin M (OSM), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), IL-27 and neuropoietin (NP). In part I of this review we addressed the pathophysiological functions of gp130 ligands with respect to the vascular wall. In part II of this review on the vascular effects of gp130 ligands we will discuss data about possible use of these molecules as biomarkers to predict development or progression of cardiovascular diseases. Furthermore, the possibility to modulate circulating levels of gp130 ligands or their tissue expression by specific antibodies, soluble gp130 protein, renin-angiotensin-aldosterone system (RASS) inhibitors, statins, agonists of peroxisome proliferator-activated receptors (PPAR), hormone replacement therapy, nonsteroidal anti-inflammatory drugs (NSAID) or lifestyle modulating strategies are presented. Recent knowledge about the application of recombinant cytokines from the gp130 cytokine family as therapeutic agents in obesity or atherosclerosis is also summarized. Thus the purpose of this review is to cover a possible usefulness of gp130 ligands as biomarkers and targets for therapy in cardiovascular pathologies. PMID- 22245787 TI - Time to positivity of blood cultures of different Candida species causing fungaemia. AB - This study investigated the time to positivity (TTP) for different species of Candida causing bloodstream infection and whether TTP can help differentiate fluconazole-resistant Candida glabrata and Candida krusei from other Candida species. We conducted this study at the National Taiwan University Hospital, a 2500-bed tertiary care medical centre in northern Taiwan. Patients with candidaemia were identified by central laboratory personnel from July 2010 to March 2011. TTP in each patient was determined using an automated blood culture instrument. Each patient was included only once at the time of detection of the first bloodstream infection. During the study period, a total of 329 sets of blood cultures positive for Candida were isolated from 176 patients. The mean TTP for all isolates causing candidaemia was 25.9+/-24.9 h. The TTP for C. glabrata was significantly longer than the TTP of the other species. In contrast, the TTP of C. tropicalis was significantly shorter than that of the other three species. The diagnostic sensitivity of TTP for C. glabrata isolates in patients with candidaemia was 93.9% (95% CI 0.798-0.993), the specificity was 66.4% (95% CI 0.581-0.741), the positive predictive value was 39.2% (95% CI 0.286-0.509), and the negative predictive value was 97.9% (95% CI 0.92-0.996) with a TTP cut-off value of >27.7 h. In conclusion, the different TTP values of different Candida species causing bloodstream infection may be helpful in differentiating C. glabrata from other Candida species. PMID- 22245788 TI - Bacillus cereus, an unusual cause of fulminant liver failure: diagnosis may prevent liver transplantation. AB - Bacillus cereus is a well-known cause of foodborne disease usually of benign course. Here, we present the case of a 15-year-old boy who developed reversible fulminant liver failure associated with rhabdomyolysis after pasta consumption. Suspecting B. cereus as the aetiological agent may prevent unnecessary liver transplantation. PMID- 22245789 TI - Evaluation of sclB gene variation in Streptococcus pyogenes (Lancefield group A Streptococcus) and potential for subtyping. AB - Variation of sclB gene sequences in group A Streptococcus (GAS) strains was evaluated for its potential use in subtyping the most common serotypes of Streptococcus pyogenes encountered in the UK. We sequenced a total of 188 strains, including randomly selected invasive GAS and outbreak-related strains. Variability was highest amongst M/emm 89 strains, whereas very little variation was observed amongst M/emm 1 and M/emm 28 GAS strains. Repeat patterns were identified in the collagen structure motif (CSM) of the M/emm 89 GAS strains. The sporadic strains were very diverse and encompassed most of the CSM patterns, whereas the outbreak-related strains were mainly clustered into two CSM groups. sclB gene cluster analysis distinguished outbreak strains from two different healthcare settings in the same geographical area. Sequence variations were assessed by the number of pentameric repeats (CAAAA) present at the 5' region of the sclB gene. The determination of sclB polymorphisms amongst GAS serotype M/emm 89 strains could be used as an important epidemiological marker to inform clinicians and outbreak control teams during outbreak investigations. PMID- 22245790 TI - Genetic diversity of Propionibacterium acnes strains isolated from human skin in Japan and comparison with their distribution in Europe. AB - Propionibacterium acnes, a commensal of human skin, is also an opportunistic pathogen of common acne and certain infectious diseases. However, it is still not obvious which strain is pathogenic for a certain infectious disease, and investigations to characterize pathogenic strains using molecular typing methods such as MLST using several housekeeping genes have been undertaken. However, to date, such analysis has focused mainly on strains isolated from Europeans, and it is unclear whether the clonal distribution in other parts of the world is similar. Here, we analysed 50 strains of P. acnes from healthy humans and patients with atopic dermatitis (AD) in Japan and utilized MLST of seven housekeeping genes to study their clonal patterns. The MLST successfully typed the strains into five types, IA, IB1, IB2, II and III. Strains that belonged to types IA, IB and II were common on the human skin of both populations (Europe and Japan), but this study demonstrated what we believe to be the first association of type III strains with human skin, existing on the skin of both the AD and non AD population. These results indicate the global existence of type III strains on human skin. PMID- 22245784 TI - Melatonin membrane receptors in peripheral tissues: distribution and functions. AB - Many of melatonin's actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORalpha/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORalpha/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes. PMID- 22245791 TI - Isolation of Streptococcus urinalis from a human blood culture. AB - Streptococcus urinalis was isolated from a blood culture of a 60-year-old man with a history of urethral stricture. This species has been recently described as a new member of the pyogenic subgroup of streptococci that cause urinary tract infections. PMID- 22245793 TI - Atrial fibrillation substrate: the "unknown species"-- from lone atrial fibrillation to fibrotic atrial cardiomyopathy. PMID- 22245792 TI - Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2. AB - BACKGROUND: Ranolazine (Ran) is known to inhibit multiple targets, including the late Na(+)current, the rapid delayed rectifying K(+)current, the L-type Ca(2+)current, and fatty acid metabolism. Functionally, Ran suppresses early afterdepolarization (EADs) and torsades de pointes (TdP) in drug-induced long QT type 2 (LQT2) presumably by decreasing intracellular [Na(+)](i) and Ca(2+)overload. However, simulations of EADs in LQT2 failed to predict their suppression by Ran. OBJECTIVE: To elucidate the mechanism(s) whereby Ran alters cardiac action potentials (APs) and cytosolic Ca(2+)transients and suppresses EADs and TdP in LQT2. METHODS: The known effects of Ran were included in simulations (Shannon and Mahajan models) of rabbit ventricular APs and Ca(2+)transients in control and LQT2 models and compared with experimental optical mapping data from Langendorff rabbit hearts treated with E4031 (0.5 MUM) to block the rapid delayed rectifying K(+)current. Direct effects of Ran on cardiac ryanodine receptors (RyR2) were investigated in single channels and changes in Ca(2+)-dependent high-affinity ryanodine binding. RESULTS: Ran (10 MUM) alone prolonged action potential durations (206 +/- 4.6 to 240 +/- 7.8 ms; P <0.05); E4031 prolonged action potential durations (204 +/- 6 to 546 +/- 35 ms; P <0.05) and elicited EADs and TdP that were suppressed by Ran (10 MUM; n = 7 of 7 hearts). Simulations (Shannon but not Mahajan model) closely reproduced experimental data except for EAD suppression by Ran. Ran reduced open probability (P(o)) of RyR2 (half maximal inhibitory concentration = 10 +/- 3 MUM; n = 7) in bilayers and shifted half maximal effective concentration for Ca(2+)-dependent ryanodine binding from 0.42 +/- 0.02 to 0.64 +/- 0.02 MUM with 30 MUM Ran. CONCLUSIONS: Ran reduces P(o) of RyR2, desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations, which represents a novel mechanism for its suppression of EADs and TdP. PMID- 22245794 TI - Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide. AB - BACKGROUND: The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear. OBJECTIVE: Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies. METHODS: Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 +/- 12 years). QRS, QT, and T(peak)-T(end) intervals were analyzed before and during rufinamide treatment. RESULTS: The mean QT interval shortened significantly following rufinamide administration (QT interval 349 +/- 23 ms vs 327 +/- 17 ms; corrected QT interval 402 +/- 22 ms vs 382 +/- 16 ms; P = .002). T(peak)-T(end) intervals were 79 +/- 17 ms before and 70 +/- 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 +/ 18 ms. During follow-up (3.04 +/- 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed. CONCLUSION: QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations notwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings. PMID- 22245796 TI - To the Editor--advice for "Proud flesh" post permanent pacemaker. PMID- 22245795 TI - Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. AB - BACKGROUND: Postpubertal women with inherited long QT syndrome type 2 (LQT2) are at increased risk for polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD), particularly during the postpartum period. OBJECTIVE: To investigate whether sex hormones directly modulate the arrhythmogenic risk in LQTS. METHODS: Prepubertal ovariectomized transgenic LQT2 rabbits were treated with estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX). RESULTS: During 8 weeks of treatment, major cardiac events-spontaneous pVT or SCD-occurred in 5 of the 7 EST rabbits and in 2 of the 9 OVX rabbits (P <.05); in contrast, no events occurred in 9 PROG rabbits and 6 DHT rabbits (P <.01 vs PROG; P <.05 vs DHT). Moreover, EST increased the incidence of pVT (P <.05 vs OVX), while PROG reduced premature ventricular contractions, bigeminy, couplets, triplets, and pVT (P <.01 vs OVX; P <.001 vs EST). In vivo electrocardiographic monitoring, in vivo electrophysiological studies, and ex vivo optical mapping studies revealed that EST promoted SCD by steepening the QT/RR slope (P <.05), by prolonging cardiac refractoriness (P <.05), and by altering the spatial pattern of action potential duration dispersion. Isoproterenol-induced Ca(2+) oscillations resulted in early afterdepolarizations in EST-treated hearts (4 of 4), while PROG prevented SCD by eliminating this early afterdepolarization formation in 4 of the 7 hearts (P = .058 vs EST; P <.05 vs OVX). Analyses of ion currents demonstrated that EST increased the density of I(Ca,L) as compared with OVX (P <.05) while PROG decreased it (P <.05). CONCLUSION: This study reveals the proarrhythmic effect of EST and the antiarrhythmic effect of PROG in LQT2 in vivo, outlining a new potential antiarrhythmic therapy for LQTS. PMID- 22245798 TI - Subclinical left ventricular dysfunction revealed by circumferential 2D strain imaging in patients with coronary artery disease and fragmented QRS complex. AB - BACKGROUND: Fragmented QRS (fQRS) complexes on a routine 12-lead electrocardiogram were associated with adverse cardiac events, including sudden death in patients with coronary artery disease (CAD). OBJECTIVE: To investigate the relationship between the fQRS complex and global and regional left ventricular (LV) functions in patients with CAD. METHODS: The study consisted of 176 patients (68 +/- 9 years; 145 [82%] men) with CAD with narrow QRS duration and preserved LV ejection fraction (>45%). All patients underwent detailed 2 dimensional speckle-tracking echocardiography to determine global and segmental (basal, middle, and apical) LV strains and strain rates and were prospectively followed-up in the outpatient clinic. RESULTS: Fifty-five patients (31%) had fQRS complexes. Global, middle, and apical LV longitudinal, radial, and circumferential strains and strain rates were significantly lower in the fQRS group than in the non-fQRS group (all P <.05). Multivariate logistic regression analysis revealed that the fQRS complex was associated with decreased global circumferential strain (odds ratio 1.19; 95% confidence interval 1.06-1.33; P = .003) and multivessel disease (odds ratio 3.69; 95% confidence interval 1.35 10.08; P = .011). Kaplan-Meier analysis revealed that event-free survival for cardiac events was significantly lower in the fQRS group than in the non-fQRS group (P = .036). CONCLUSIONS: Our results demonstrated that the fQRS complex in patients with CAD with preserved LV ejection fraction was associated with subclinical global and regional LV dysfunctions as detected by 2-dimensional speckle-tracking imaging, and the results also predicted adverse cardiac events. PMID- 22245799 TI - Quantum-dot-based biosensor for simultaneous detection of biomarker and therapeutic drug: first steps toward an assay for quantitative pharmacology. AB - Quantitative pharmacology (QP) is often used to study the recommended dose of a drug. Using colorectal cancer as a model, the relationship between exposure (cetuximab, C225, therapeutic drug of colorectal cancer) and the biomarker response (carcinoembryonic antigen, CEA, biomarker of colorectal cancer) is the core for the QP of C225. Thus, simultaneous detection of CEA and C225 is the first step towards an assay for the QP of C225. We developed a quantum dot (QD) based multi-analyte biosensor for the simultaneous determination of CEA and the corresponding therapeutic drug C225. The assay is based on the competition between a quantum-dots-labeled glycans and target glycans using lectins as the recognition element. The dual-analytic biosensor detected CEA and C225 in the range from 1 ng mL(-1) to 400 MUg mL(-1) by stripping voltammetry. The biosensor developed here for the simultaneous detection of the biomarkers and therapeutic drugs is expected to develop as a potential technique for quantitative pharmacology. PMID- 22245801 TI - Attempted suicide by self-immolation is a powerful predictive variable for survival of burn injuries. AB - Up to 9% of all burn victims in western countries are reported to have been caused by self-immolation with suicidal intent and usually involve extensive injuries. The authors sought to identify differences between suicide burn victims as opposed to those who sustained their injuries accidentally with regard to injury severity and mortality and determine the possible impact of suicide as a prognostic variable in the context of a scoring system such as the Abbreviated Burns Severity Index (ABSI). The data of all burns patients treated at the Specialist Burns Intensive Care Unit, University Hospital Zurich, between 1968 and 2008 were analyzed retrospectively. Of the 2813 patients included in the study, 191 were identified as attempted suicides, most commonly involving the use of accelerants. Thirty percent of all suicide victims had preexisting psychiatric diagnoses. Suicide victims presented with significantly more extensive burns (53.7%, +/-0.98 SEM vs 21.4 %, +/-0.36 SEM, P < .0001), had higher total ABSI scores (8.4, +/-0.23 SEM vs 6.6, +/-0.05 SEM, P < .0001), and had higher mortality rates (42.9% [83/191] vs 16.3% [426/2622]) than accident victims. Furthermore, logistic regression revealed suicide to be a significant predictor of mortality as inhalation injury (odds ratio 2.2, 95% confidence interval 1.4 3.5, P < .0003 and odds ratio 2.4, 95% confidence interval 1.4-4.0, P < .0009, respectively). The odds of dying from an attempted suicide are twice as high compared with those of accident patients in the same ABSI category, making suicide a powerful predictor of mortality. The authors therefore suggest including it as a fixed variable in scoring systems for estimating a patient's mortality after burn injuries such as the widely used ABSI. PMID- 22245800 TI - Effect of cigarette smoke exposure and structural modifications on the alpha-1 Antitrypsin interaction with caspases. AB - alpha-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke-induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL-deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation. PMID- 22245802 TI - Zinc supplementation in burn patients. AB - Micronutrient supplementation is a common practice throughout many burn centers across North America; however, uncertainty pertaining to dose, duration, and side effects of such supplements persists. The authors prospectively collected data from 23 hospitalized patients with burn sizes ranging from 10 to 93% TBSA. Each patient received a daily multivitamin and mineral supplement, 50 mg zinc (Zn) daily, and 500 mg vitamin C twice daily. Supplements were administered orally or enterally. Albumin, prealbumin, C-reactive protein, serum Zn, and serum copper were measured weekly during hospital admission until levels were within normal reference range. Our study concluded that 50 mg daily dose of Zn resulted in normal serum levels in 19 of 23 patients at discharge; 50 mg Zn supplementation did not interfere with serum copper levels; and Zn supplements, regardless of administration route, did not result in gastrointestinal side effects. PMID- 22245803 TI - Epidemiology of 1974 burn patients at a major burn center in Beijing: a nine-year study. AB - To date, little epidemiological data are available on burns in China. This study describes the characteristics of burn patients admitted to a major burn center in Beijing to show trends in admission and outcomes in burned patients to share information about the current state of care for burned patients in our burn center. A retrospective study on 1974 burn patients admitted to Jishuitan Hospital in Beijing was conducted during the 9-year period from 2000 to 2008, and data were collected on age, gender, TBSA, etiology, length of hospital stay, mortality, and inhalation injury. The male:female ratio of the burn population was 2.41:1 and did not differ significantly over the study period (P > .05). The mean age of admission was 36 +/- 16.3 years, and most patients were 30 to 39 years old (24.0%) or 20 to 29 years old (23.8%). The mean TBSA of burn was 14.7 +/- 3.4%, ranging from 1 to 100%, and the mean size/age did not change significantly over the course of the study (P > .05). The incidence in burn injury decreased over the study period (P < .05). The most common cause of burn was flame (67.9%) followed by electrical (16.1%) and scald (9.5%). The mean length of hospital stay was 33.2 +/- 3.5 days, extending from 1 to 413 days, and it did not differ significantly over the study period (P > .05). The mortality and inhalation injury rate were 2.8 and 6.9%, respectively. Annual mortality rate did not differ significantly over the study period (P > .05). This retrospective review of the specific epidemiological features of burn patients will provide important information for the development of proper control programs to reduce the incidence of burns and burn-related deaths. PMID- 22245804 TI - Multiple myeloma. PMID- 22245805 TI - Advantageous use of lenalidomide in multiple myeloma: discussion of three case studies. AB - PURPOSE OF REVIEW: Although multiple myeloma remains an essentially incurable disease, treatment options and patients' quality of life have improved over the last years with the introduction of more effective and less toxic agents. Therapy should be tailored to the clinical circumstance of each patient under consideration of factors such as patient age, comorbidities (e.g. history of renal failure, thromboembolism or neuropathy) and performance status. RECENT FINDINGS: This article presents three Portuguese clinical cases, illustrating the efficacy and good tolerability profile of lenalidomide in combination with dexamethasone, especially when used as second-line therapy. In particular, these cases illustrate the benefit of using such combinations in patients previously treated with thalidomide as well as patients with peripheral neuropathy or renal impairment. Finally, the last case highlights the importance of timely administration of effective thromboembolism prophylaxis in the presence of prothrombotic risk factors. SUMMARY: These cases are discussed in light of the current knowledge of achieving the best quality of life for the patients, while minimizing myeloma burden and improving existing organ damage due to either the presence of multiple myeloma or to previous therapies. PMID- 22245806 TI - Review of therapy for relapsed/refractory multiple myeloma: focus on lenalidomide. AB - PURPOSE OF REVIEW: Multiple myeloma is a malignant neoplasm of plasma cells, for which there is no known cure. This article examines the efficacy and tolerability of lenalidomide, a potent structural analogue of thalidomide, for second-line treatment of patients with relapsed multiple myeloma. RECENT FINDINGS: Lenalidomide, a thalidomide analogue, was designed to provide increased efficacy, while avoiding the adverse effects associated with thalidomide therapy. Studies assessing lenalidomide as second-line therapy for multiple myeloma have shown promising beneficial effects. Lenalidomide-dexamethasone is associated with significantly longer median time to disease progression and overall survival, as well as a significantly higher proportion of patients who respond to treatment compared with dexamethasone alone. Lenalidomide (with dexamethasone) was associated with a high rate of myelosuppression in clinical trials; neutropenia, infection, thrombocytopenia, and venous thromboembolism were common grade 3-4 adverse events. However, appropriate management of these adverse events maximizes the clinical benefit of lenalidomide. SUMMARY: Lenalidomide in combination with dexamethasone is approved by the US Food and Drug Administration and the European Medicines Agency for the second-line treatment of patients with multiple myeloma. Lenalidomide is recommended as a treatment option for patients with multiple myeloma in both United States and European treatment guidelines. PMID- 22245807 TI - Mitochondria-targeted antioxidant attenuates high glucose-induced P38 MAPK pathway activation in human neuroblastoma cells. AB - Excessive mitochondrial free radical production and the related mitogen-activated protein kinase P38 (P38 MAPK) activation are key regulators in the pathogenesis of high glucose-induced cell stress. Increasing evidence has emphasized the impact of hyperglycemia on neurons and the consequent neuronal stresses eventually resulting in neurodegeneration and neuronal death. In this study, we employed a novel mitochondria-targeted antioxidant, SS31 peptide, on high glucose insulted neuroblastoma cells (SH-SY5Y). Our results showed that high glucose promoted significantly increased P38 phosphorylation which was efficiently suppressed by the application of the SS31 peptide under the experimental conditions. The inhibition of high glucose-induced P38 activation by the SS31 peptide was associated with the impact of the SS31 peptide on attenuating high glucose-induced mitochondrial ROS (reactive oxygen species) elevation and mitochondrial membrane potential collapse. The addition of SS31 peptide significantly attenuated high-gluose-induced apoptosis. Therefore, our study suggests that elimination of high glucose-induced mitochondrial oxidative stress helps to rescue SH-SY5Y cells from high glucose-related P38 MAPK pathway disturbances, and the SS31 peptide has the potential to serve as a new treatment strategy against hyperglycemia-instigated neuronal perturbations. PMID- 22245808 TI - Controlling airborne cues to study small animal navigation. AB - Small animals such as nematodes and insects analyze airborne chemical cues to infer the direction of favorable and noxious locations. In these animals, the study of navigational behavior evoked by airborne cues has been limited by the difficulty of precisely controlling stimuli. We present a system that can be used to deliver gaseous stimuli in defined spatial and temporal patterns to freely moving small animals. We used this apparatus, in combination with machine-vision algorithms, to assess and quantify navigational decision making of Drosophila melanogaster larvae in response to ethyl acetate (a volatile attractant) and carbon dioxide (a gaseous repellant). PMID- 22245809 TI - Serial two-photon tomography for automated ex vivo mouse brain imaging. AB - Here we describe an automated method, named serial two-photon (STP) tomography, that achieves high-throughput fluorescence imaging of mouse brains by integrating two-photon microscopy and tissue sectioning. STP tomography generates high resolution datasets that are free of distortions and can be readily warped in three dimensions, for example, for comparing multiple anatomical tracings. This method opens the door to routine systematic studies of neuroanatomy in mouse models of human brain disorders. PMID- 22245811 TI - A microporous indium-organic framework with high capacity and selectivity for CO2 or organosulfurs. AB - Presented here is a multifunctional microporous indium-organic framework material with doubly linked MIL-88D structure, which exhibits high surface area, excellent CO(2)/N(2) adsorption selectivity, good hydrogen storage ability and notable desulfurization behavior. PMID- 22245810 TI - Generation of reactive oxygen species mediates butein-induced apoptosis in neuroblastoma cells. AB - Flavonoids exhibit chemopreventive and chemotherapeutic effects. Butein, a bioactive flavonoid isolated from numerous native plants, has been shown to induce apoptosis in human cancer cells. In the current study, the molecular mechanisms of butein action on cell proliferation and apoptosis of neuroblastoma cells were evaluated. Treatment with butein decreased the viability of Neuro-2A neuroblastoma cells in a dose- and time-dependent manner. The dose-dependent nature of butein-induced apoptosis was characterized by an increase in the sub-G1 phase population. Treatment with butein significantly increased intracellular reactive oxygen species (ROS)levels and reduced the Bcl-2/Bax ratio, triggering the cleavage of pro-caspase 3 and poly-(ADP-ribose) polymerase (PARP). Pre treatment with the antioxidant agent, N-acetyl cysteine (NAC), blocks butein induced ROS generation and cell death. NAC also recovers butein-induced apoptosis related protein alteration. In conclusion, butein-triggered neuroblastoma cells undergo apoptosis via generation of ROS, alteration of the Bcl-2/Bax ratio, and cleavage of pro-caspase 3 and PARP. Our results suggest that butein may serve as a potential therapeutic agent for the treatment of neuroblastoma. PMID- 22245812 TI - A graphene-amorphous FePO4 hollow nanosphere hybrid as a cathode material for lithium ion batteries. AB - Amorphous FePO(4) hollow nanospheres were directly grown on graphene for use as a cathode material in lithium ion batteries. This hybrid exhibits high rate capability and good cycle stability because of efficient Li(+) ion diffusion through the thin wall of the hollow nanospheres and fast electron transport through the graphene. PMID- 22245813 TI - Long-term functional results after radial nerve repair. AB - OBJECTIVE: This study aimed to evaluate the functional results of end-to-end repairs in radial nerve injuries. METHODS: The study included 18 (15 males, 3 females) patients who underwent middle level end-to-end radial nerve repair and who responded to our final follow-up call. Patients' average age was 30 (range: 16 to 43) years. The average time lapse between injury and repair was 25.1 days (range: 1 day to 13 months). Pinch and grip strength measurements were graded according to the modified Verga classification. The Highet classification was used for the evaluation of sensorial recovery. Functional outcome were assessed with the DASH-T score. Average follow-up time was 62.5 (range: 24 to 156) months. RESULTS: Motor function according to the Verga classification was excellent in 16 patients and poor in two. Pinch and grip power measurement comparison of the two sides in the 16 patients with excellent results showed a respective 24.1% and 14.3% decrease on the affected side. According to Highet's classification, sensorial evaluation was S4 in seven patients, S3+ in four, S3 in three, S2+ in one, S2 in one, and S1 in two patients. The average DASH-T score of patients with excellent results was 7.3. CONCLUSION: Radial nerve repairs, if done end-to-end using an appropriate technique, may lead to nearly full recovery in younger patients. PMID- 22245814 TI - The effect of excisional arthroplasty with palmaris longus tendon on carpal height ratio in Stage 3 Kienbock's disease. AB - OBJECTIVE: Treatment methods in Kienbock's disease remain controversial despite the long-term awareness of the disease by orthopedic surgeons. Currently, excisional arthroplasty with a palmaris longus tendon ball is one of the most frequently used treatment methods. The aim of this study was to evaluate the long term results of thirty-eight patients who had been treated with excisional arthroplasty and palmaris longus tendon ball, as well as the effect of this method on carpal height. METHODS: In this study, we retrospectively evaluated 38 patients (mean age: 30.4 years; range: 17-64 years) with Stage 3 Kienbock's disease who underwent excisional arthroplasty between 1978 and 2008. According to the Lichtman classification, 8 patients were classified as Stage 3a and 30 patients were classified as Stage 3b in Kienbock's disease. The mean duration of follow-up after surgery was 81.3 (range: 25 to 264) months. The outcomes were evaluated with joint range of motion, grip strength and functional assessment of Nakamura and radiographic changes in carpal height. RESULTS: According to the Nakamura's scoring system the results were excellent in 22 (57.9%) patients, good in 13 (34.2%) and moderate in 3 (7.9%). Comparison of pre and postoperative range of motion of the wrist revealed an average increase in wrist extension of 10 degrees (p<0.05), and an average decrease in ulnar deviation of 4 degrees (p<0.05) after the operation. No significant difference was observed when comparing other joint range of motion parameters. Dynamometric grip strength measurements revealed significant differences between the healthy and operated sides (67.6 kgf vs. 45.9 kgf, respectively; p<0.05). The decrease in the revised carpal height ratio were significant. CONCLUSION: According to patient satisfaction rate and clinical results, the outcome of excisional arthroplasty with palmaris longus tendon ball in Stage 3 Kienbock's disease is satisfactory. However, carpal height reduction and development of degenerative changes may be expected in long-term follow-up. PMID- 22245815 TI - Comparative evaluation of radiographic and functional outcomes in the surgical treatment of scaphoid non-unions. AB - OBJECTIVE: The aim of our study was to evaluate the correlation between the radiological signs of union and functional outcomes in patients with surgically treated scaphoid non-unions. METHODS: In our study, we evaluated 13 patients who underwent surgery at our clinic for complaints resulting from an unhealed scaphoid fracture. Of the scaphoid non-unions, 9 were on the scaphoid body and 4 were on the proximal pole. According to Slade's classification system, there were two Grade 4, eight Grade 5, and three Grade 6 fractures. The patients were all male with a mean age of 31, with 25 months of mean time between the onset of trauma and surgery. All fractures were treated through open reduction with autogenous bone grafting (cancellous in 4 cases; corticocancellous in 9 cases) and fixation with compression screws. Bone morphology and carpal alignment were assessed through radiography, using the scaphoid index and scapholunate angle measurements, respectively. Range of motion and grip strength measurements together with the modified Mayo wrist scores were used in the assessment of wrist functionality. RESULTS: Average duration of follow-up was 16 months. In 10 patients, radiological union was attained in a mean time of 12.4 weeks following the operation. There was a substantial improvement in grip strength and range of motion values after surgery. The preoperative mean modified Mayo wrist score of 41.5 improved to 79.2 postoperatively. Accordingly, 4 patients had perfect, 2 had good, 5 had fair and 2 had poor results. The surgical treatment allowed the preoperative mean scapholunate angle of 45.8 degrees and the preoperative mean scaphoid index of 0.69 to be reduced to 32 degrees and 0.6, respectively. The humpback deformity present in 11 patients before the surgery was restored in 10 patients by reconstruction of the scaphoid bone length. Abnormal carpal alignment was restored in 4 of these patients. No statistically significant correlation was found between the functional results and the surgically attained structural restorations and union process. CONCLUSION: The surgical treatment of scaphoid fracture non-unions can correct bone morphology and resolve alignment problems but might not be sufficient for the improvement of functional results. PMID- 22245816 TI - Deformity correction by Ilizarov distraction osteogenesis after distal radius physeal arrest. AB - OBJECTIVE: The aim of this study was to evaluate the results of osteotomy and distraction osteogenesis using Ilizarov circular external fixator to treat radial shortening and severe wrist deformity due to neglected post-traumatic distal radius physeal arrest. METHODS: The study retrospectively reviewed 4 patients (4 males; average age: 16 years; range: 14 to 19 years) who underwent osteotomy and distraction osteogenesis to treat radial shortening and severe wrist deformity due to neglected distal radius physeal arrest. Mean interval between trauma and surgical intervention was 8 (range: 4 to 12) years and mean follow-up time was 83 (range: 40 to 126) months. Patients were evaluated with radiographic measurements (shortening and lengthening ratio, radioulnar joint leveling, distal radioulnar joint congruency), objective functional measurements (grip and pinch strength, range of motion measurements [ROM]) and subjective functional measurements (Disabilities of the Arm, Shoulder and Hand [DASH] questionnaire and Mayo wrist score). Statistical analysis was made using the Mann-Whitney U non-parametric test. RESULTS: Radiographic measurements were obtained preoperatively and at the final follow-up. The mean shortening ratio of the radius was 14.6% (range: 9.3% to 18.7%) and mean lengthening ratio was 15.9% (range: 13.2% to 18.3%). Normal distal radioulnar joint leveling and distal radioulnar congruency resembling a joint was established in all but one patient with four millimeters of ulna plus deformity. According to the Mann-Whitney U non-parametric test, there was no statistical difference in grip and pinch power, ROM on flexion/extension, and ulnar/radial deviation axis between the operated and non-operated sides. There was statistically significant pronation/supination restriction between the operated and non-operated sides (p<0.04). Mean DASH score was 2.07 (range: 0.0 to 8.3) and the mean Mayo wrist score was 89 (range: 75 to 100) points. According to the Mayo wrist score, results were excellent in one patient, good in two patients, and satisfactory in one patient. CONCLUSION: The use of distal metaphyseal osteotomy and Ilizarov distraction osteogenesis is a viable treatment method for neglected physeal fractures of the distal radius as it establishes acceptable deformity correction and a functional wrist joint. PMID- 22245817 TI - Shoulder arthrodesis with plate fixation. AB - OBJECTIVE: The aim of this study was to evaluate the long-term outcome of shoulder arthrodesis with plate fixation and primary autogenous grafting in terms of pain, functional status and arthrodesis position. METHODS: The study included 8 patients (7 males and 1 female; mean age: 39.3 years; range: 22 to 68 years) who underwent arthrodesis with plate fixation and primary autogenous grafting. Mean follow-up period was 66.6 (range: 47 to 96) months. Five cases had traumatic brachial plexus palsy, 2 polio sequela and 1 sequela of an operated proximal humerus fracture due to a falling injury. One of the traumatic palsy cases was accompanied with a humerus shaft fracture. Arthrodesis was performed in all cases according to AO principles with plate fixation and primary autogenous grafting. Five of the paralytic patients also underwent Steindler flexorplasty. Follow-up assessments included monthly radiologic control for union, the visual analog scale (VAS) for pain and the Oxford shoulder score (OSS) for functional status. RESULTS: Radiological fusion was seen in all cases in an average of 16 (range: 12 to 18) weeks, and arthrodesis was stable at physical examination. The accompanying humerus shaft fracture was also fixed with plate. One patient with traumatic palsy experienced a humerus fracture distal to the arthrodesis plate at the 8th postoperative month. An additional traumatic palsy case had flexion deformity at the wrist in the second year of follow-up and a wrist arthrodesis with dorsal plate was performed. One patient (12.5%) had a donor site infection on the tenth day after surgery. The target positions of 30 degrees of abduction, 30 degrees of forward flexion, and 30 degrees of internal rotation were achieved with an average deviation of 7 degrees . Mean active abduction was 68.1 degrees (range: 55 degrees to 90 degrees ), flexion was 67.5 degrees (range: 60 degrees to 85 degrees ), and internal rotation was at the level of trochanter major. The mean OSS was 35.9 (range: 32 to 40), and the mean VAS score was 2.9 (range: 1 to 7). CONCLUSION: Our findings show that AO reconstruction plate and primary autogenous bone grafting is a safe and effective arthrodesis method that can also be used as a salvage procedure. PMID- 22245818 TI - Normal range of motion of hip and ankle in Indian population. AB - OBJECTIVE: Most studies that determine the range of motion of joints of the lower limbs study the Western population. The Asian population differs significantly, as daily activities demand different sitting positions. Our study aimed to establish the normal values of hip and ankle range of motion in various age groups in the Indian population and the effect of various functional positions of the hip on range of motion. METHODS: Three hundred and twenty-six Indian subjects, between the ages of 1 month to 75 years, were randomly selected for measurement of the range of motion of the hip and ankle joint. Exclusion criteria included history of injury or disease related to the lower extremities. Changes with age in the arc of joint motion were studied. The influence of various functional positions of the lower limb on the range of motion of the hip and the effect of weight-bearing on the ankle joint range of motion were also analyzed. RESULTS: Hip range of motion differed in various positions. Hip rotations were significantly greater when measured with the knee in flexion in both the sitting and prone positions than in the supine position. The arc of hip rotation was highest in the prone position. A significant increase in the arc of ankle dorsiflexion was found in a weight-bearing (squatting) position. Age related reduction in movement was found mainly in the rotations of the hip and dorsiflexion of the ankle. CONCLUSION: The data compiled in this study on the range of motion in the hip and ankle joint of the Indian population will be useful in the evaluation of patients with disorders of these joints, especially in the Indian and Asian population. PMID- 22245819 TI - Patelloplasty with patellar decompression to relieve anterior knee pain in total knee arthroplasty. AB - OBJECTIVE: Anterior knee pain continues to be an important problem following total knee arthroplasty (TKA). The aim of this study was to present the early results of patelloplasty with patellar decompression to relieve anterior knee pain in patients who undergo TKA. METHODS: We prospectively reviewed 49 knees from 46 patients (35 females, 11 males; mean age: 69.2 years; range: 54 to 82 years) who underwent TKA between January 2004 and December 2008. Decompression and patelloplasty were performed in patients in whom Grade 3 and 4 chondropathy was detected during operation according to the Outerbridge classification. All knees were rated according to the Knee Society Knee and Function Scores, before surgery and during the final follow-up. The patella score was evaluated according to a specific patellofemoral pain questionnaire used by Feller, and the mean knee range of motion was measured preoperatively and postoperatively. Additionally, a patient satisfaction questionnaire used by Levitsky was performed during the final follow-up exam. The mean follow-up period was 41.1 (range: 24 to 68) months. RESULTS: The mean preoperative and final follow-up knee scores were 48.6 +/- 8.8 and 87.70 +/- 9.3, and function scores were 48.4 +/- 10.4 and 81.4 +/- 12.6, respectively. The mean preoperative patellar score was 18.1 +/- 3.5, and the final follow-up patellar score was 25.7 +/- 2.8. The mean patellar scores were significantly greater in knees with Grade 3 chondropathy compared to Grade 4 chondropathy (26.47 +/- 2.38 and 24.29 +/- 3.19, respectively). Postoperative anterior knee pain was present in four knees (8.2%). The mean preoperative knee range of motion was 85.1 +/- 12.7, and the final follow-up knee range of motion was 117.0 +/- 9.8. Patients were "extremely" or "very" satisfied with 93.8% of their operative outcomes on their knees. CONCLUSION: Patellar decompression with patelloplasty in TKA is an option for the reduction of anterior knee pain, but there is a lack of significant evidence in the literature, demonstrating that this method is superior to patellar resurfacing and patellar retention. PMID- 22245820 TI - Early results of distal metatarsal osteotomy with K-wire fixation in the treatment of tailor's bunion. AB - OBJECTIVE: Tailor's bunion deformity is a lateral side bone and soft tissue prominence of the fifth metatarsal bone. The aim of our study was to assess the clinical and radiographic results of distal metatarsal osteotomies in patients with tailor's bunion deformity. METHODS: This study included 24 feet of 14 patients with tailor's bunion who were treated with distal metatarsal osteotomy of the 5th metatarsal between 2006 and 2009. The mean follow-up time was 24.45 (range: 12 to 47) months. Patients were evaluated clinically and radiographically, using the American Orthopaedic Foot and Ankle Society (AOFAS) scoring system with weight-bearing anteroposterior and lateral foot radiographs. RESULTS: Average AOFAS scores of the patients were 64.83 preoperatively and 91.62 at the final follow-up. Three patients had complications; avascular necrosis, delayed union, and superficial wound infection. CONCLUSION: Distal metatarsal osteotomy is a safe and easy treatment option for the painful tailor's bunion deformity and provides patient satisfaction rate of up to 96%. PMID- 22245821 TI - An effective treatment for hip instabilities: pelvic support osteotomy and femoral lengthening. AB - OBJECTIVE: In this study, we evaluated the effectiveness of pelvic support osteotomy treatment in hip instabilities due to various etiologies. METHODS: We retrospectively evaluated 21 hips of 20 patients that underwent pelvic support osteotomy between 2005 and 2007. Hip instability was caused by a neglected congenital dislocation of the hip in 12 of the patients (13 hips), by septic arthritis in 7 and by an unsuccessful total hip arthroplasty due to infection in the last patient. The mean age of the patients was 22.6 (range: 12 to 34) years. Osteotomy sites were fixed using monolateral external fixators in 11 patients, Ilizarov circular fixators in 8, and locking plates for both hips of the remaining patient. The mean follow-up period was 33.45 (range: 16 to 45) months. RESULTS: The mean Harris score increased from 48.3 preoperatively to 80.1 postoperatively. Preoperative mean limb length discrepancy was 53.3 mm and mean proximal migration was 42.9 mm. Residual limb length discrepancy was reduced to 16 mm after an average lengthening of 63.3. The preoperative Trendelenburg gait disappeared completely in 13 of 21 hips and was improved in 8 hips. Sixteen of the 20 patients (17 hips) expressed satisfaction with the operation. CONCLUSION: Pelvic support osteotomy is a good treatment option to overcome hip instability as it improves pain and equalizes limb length. PMID- 22245822 TI - Effects of vinblastine on microvascular anastomosis healing in diabetic rats. AB - OBJECTIVE: Diabetes mellitus and chemotherapy use are well-known factors that can affect success after microvascular repair. Although many studies have investigated each factor individually, no study exists on their combined effect. The aim of our study was to investigate the effects of preoperative vinblastine, a vinca alkaloid, on the healing of microvascular anastomosis in diabetic and non diabetic rats. METHODS: In this study, 144 Sprague Dawley rats were assigned randomly and equally into experimental or control groups. The experimental group consisted of 72 rats which were made diabetic by alloxan injections. Diabetes was confirmed by glycosuria (>2%) and elevated plasma glucose (>300 mg/100 ml) after three days of alloxan injections. The experimental group then received a single dose of intraperitoneal vinblastine. After applying the medication, the two main groups were divided into three subgroups. For each group, we performed end-to-end femoral artery anastomosis on Day 7, 14, and 21, respectively. We further divided each subgroup equally into three smaller groups to test patency and took biopsies at Day 7, 14 and 21, respectively. Histopathologic evaluation was carried out. RESULTS: The comparison of patency tests and pathologic examination indicated that there was no statistically significant difference between the two groups. CONCLUSION: The negative effects of diabetes and the administration of vinblastine did not significantly influence anastomosis healing. PMID- 22245823 TI - Biomechanical assessment of suture techniques used for tendon repair. AB - OBJECTIVE: The aim of this study was to assess different tendon suture techniques from the perspectives of both tensile strength and early active mobilization. METHODS: In this study, we implemented repairs on 40 flexor digitorum profundus (FDP) tendons, acquired from fresh frozen cadavers. The tendons were divided into 5 groups of 8 tendons each. We applied the 2-strand modified Kessler suture technique in the first group, the 4-strand Strickland suture technique in the second group, the 4-strand modified Kessler (without epitenon suture) suture technique in the third group, and the 4-strand modified Kessler (with epitenon sutures) suture technique in the fourth group. The remaining 8 intact tendons were set aside as the control group. The strength of the different tendon suture techniques were measured using the Instron((r)) device. RESULTS: The average tolerance strength of the first group was determined as 39.89 +/- 9.65 Newtons (N), the average tolerance strength of the second group was 39.64 +/- 9.14 N, the average tolerance strength of the third group was 50.29 +/- 11.24 N, the average tolerance strength of the fourth group was 54.47 +/- 6.83 N, and the average tolerance strength of the control group was 119 +/- 17.59 N. The tensile strength of the fourth group was significantly higher (p<0.05) than the first group, and the tensile strength of the third group was also significantly higher (p<0.05) than the first group. No significant difference was observed between the tensile strengths of the second and first groups (p>0.05). CONCLUSION: According to our findings, the tensile strength of 4-strand sutures, with or without epitenon sutures, are significantly higher than the tensile strength of 2-strand sutures. All suture techniques applied had sufficient tensile strength to promote early mobilization. PMID- 22245824 TI - Ray amputation for the treatment of macrodactyly in the foot: report of three cases. AB - Foot macrodactyly is a rare congenital anomaly which is characterized by an overgrowth of the soft tissue and bone of the toes. The aim of treatment is to obtain a cosmetic and functional foot. We present three cases of lesser toe macrodactyly on which we performed ray amputation. Postoperative cosmetic and functional results were good in three cases. Ray amputation is a possible surgical treatment that provides good cosmetic and functional results in severe lesser toe macrodactyly. PMID- 22245825 TI - Subcoracoid dislocation of the acromioclavicular joint. AB - Subcoracoid acromioclavicular dislocations are rarely seen injuries of the shoulder. We present a patient with multiple injuries and a subcoracoid acromioclavicular dislocation resulting from a falling injury. Physical examination revealed painful mechanical block at 90 degrees of abduction and swelling in the acromioclavicular region. Diagnosis was made with direct radiographs and computerized tomography. Treatment consisted of distal clavicular resection and coracoclavicular reconstruction with the transfer of the coracoacromial ligament over the clavicle. The patient had a pain-free shoulder after two years and was capable of performing daily activities despite the presence of coracoclavicular ossification. PMID- 22245826 TI - Proximal realignment surgery for unilateral chronic patella dislocation in Morquio syndrome: a case report. AB - Mucopolysaccharidosis IVA (MPS IVA: Morquio A syndrome) is a lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Patients with MPS IVA appear healthy at birth. Morquio-specific radiographic changes can be observed prior to clinical signs and symptoms. Patients are usually affected by a severe joint degeneration from the 2nd or 3rd decade. Hyperlaxity of the joints is prominent due to the excess of intermediate metabolites. We report a patient with inherited dwarfism, in which a proximal soft tissue realignment procedure was performed to treat chronic patellar dislocation. PMID- 22245830 TI - Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenemia, from ovarian and adrenal origin, and is characterized by insulin resistance (IR). Studies found that raising in vivo non-esterified fatty acid (NEFA) levels, which induces lipotoxicity, increases androgen levels and IR. The aim of this study was therefore to determine the effects of in vitro over exposure to NEFA on androgen synthesis in a bovine adrenocortical cell model. METHODS: Bovine fasciculata/reticularis cells were cultured for 2days in the absence or presence of ACTH (10nmol/L) or Forskolin (fsk, 10MUmol/L), alone or in combination with the saturated fatty acid (FA) palmitate (100MUmol/L). Steroid production was measured in medium and corrected for initial cell seeding count. CYP17 protein expression and ERK1/2 phosphorylation were assessed by Western blotting. RESULTS: Under unstimulated conditions, dehydroepiandrosterone (DHEA) levels were barely detected and no difference was observed after palmitate exposure, which was also the case for CYP17 expression and ERK1/2 phosphorylation. Under stimulation, palmitate exposure increased DHEA production by 38% and 69%, for ACTH and fsk, respectively, as compared to untreated conditions (Ps?0.05). In palmitate-treated vs untreated cells, fsk-stimulated ERK1/2 phosphorylation was reduced by 46% (P=0.0047), but stimulated CYP17 expression was not significantly affected. CONCLUSION: In a model of androgen producing cells, under stimulated conditions, overexposure to saturated FAs significantly increases androgen production and reduces MEK/ERK activation. Therefore, this study is the first to demonstrate that lipotoxicity can directly trigger androgen overproduction in vitro, in addition to its well-described impact on IR, which strongly supports a central role of lipotoxicity in PCOS pathophysiology. PMID- 22245833 TI - PAS kinase: integrating nutrient sensing with nutrient partitioning. AB - Recent data suggests that PAS kinase acts as a signal integrator to adjust metabolic behavior in response to nutrient conditions. Specifically, PAS kinase controls the partitioning of nutrient resources between the myriad of possible fates. In this capacity, PAS kinase elicits a pro-growth program, which includes both signaling and metabolic control, both in yeast and in mammals. We propose that, like other kinases possessing these properties-AMPK and TOR, PAS kinase might be target for therapy of diabetes, obesity and cancer. PMID- 22245831 TI - Selective destruction of abnormal proteins by ubiquitin-mediated protein quality control degradation. AB - Misfolded proteins are continuously produced in the cell and present an escalating detriment to cellular physiology if not managed effectively. As such, all organisms have evolved mechanisms to address misfolded proteins. One primary way eukaryotic cells handle the complication of misfolded proteins is by destroying them through the ubiquitin-proteasome system. To do this, eukaryotes possess specialized ubiquitin-protein ligases that have the capacity to recognize misfolded proteins over normally folded proteins. The strategies used by these Protein Quality Control (PQC) ligases to target the wide variety of misfolded proteins in the cell will likely be different than those used by ubiquitin protein ligases that function in regulated degradation to target normally folded proteins. In this review, we highlight what is known about how misfolded proteins are recognized by PQC ubiquitin-protein ligases. PMID- 22245834 TI - Laparoscopic robot-assisted pancreas transplantation: first world experience. AB - BACKGROUND: Surgical complications are a major disincentive to pancreas transplantation, despite the undisputed benefits of restored insulin independence. The da Vinci surgical system, a computer-assisted electromechanical device, provides the unique opportunity to test whether laparoscopy can reduce the morbidity of pancreas transplantation. METHODS: Pancreas transplantation was performed by robot-assisted laparoscopy in three patients. The first patient received a pancreas after kidney transplant, the second a simultaneous pancreas kidney transplantation, and the third a pancreas transplant alone. Operations were carried out through an 11-mm optic port, two 8-mm operative ports, and a 7 cm midline incision. The latter was used to introduce the grafts, enable vascular cross-clamping, and create exocrine drainage into the jejunum. RESULTS: The two solitary pancreas transplants required an operating time of 3 and 5 hr, respectively; the simultaneous pancreas kidney transplantation took 8 hr. Mean warm ischemia time of the pancreas graft was 34 min. All pancreatic transplants functioned immediately, and all recipients became insulin independent. The kidney graft, revascularized after 35 min of warm ischemia, also functioned immediately. No patient had complications during or after surgery. At the longer follow-up of 10, 8, and 6 months, respectively, all recipients are alive with normal graft function. CONCLUSIONS: We have shown the feasibility of laparoscopic robot assisted solitary pancreas and simultaneous pancreas and kidney transplantation. If the safety and feasibility of this procedure can be confirmed by larger series, laparoscopic robot-assisted pancreas transplantation could become a new option for diabetic patients needing beta-cell replacement. PMID- 22245832 TI - A new branch on the tree: next-generation sequencing in the study of cancer evolution. AB - Cancer is a disease caused by the accumulation of genetic alterations in association with successive waves of clonal expansion. Mapping of the human genome sequence, in conjunction with technical advances in the ability to sequence entire genomes, have provided new insight into the mutational spectra and genetic events associated with clonal evolution of cancer. Moving forward, a clearer understanding of those alterations that undergo positive and negative selection throughout carcinogenesis and leading to metastatic dissemination would provide a boon not only to our understanding of cancer evolution, but to the development of potential targets for therapeutic intervention as well. PMID- 22245835 TI - Batch and dynamic sorption of Ni(II) ions by activated carbon based on a native lignocellulosic precursor. AB - Vinal-derived Activated Carbon (VAC) developed by phosphoric acid activation of sawdust from Prosopis ruscifolia native wood was tested for the adsorption of Ni(II) ions from dilute solutions in both batch and dynamic modes, comparing it with a Commercial Activated Carbon (CAC). Batch experiments were performed to determine adsorption kinetics and equilibrium isotherms for both carbons. It was possible to remove near 6.55 mg Ni g(-1) VAC and 7.65 mg Ni g(-1) CAC after 5 h and 10 h contact time, respectively. A pseudo second order equation fitted well with the kinetics of the process, and Langmuir adsorption model was used to adjust the experimental results concerning the adsorption isotherm. The parameters obtained indicate a stronger interaction between sorbent and sorbate for VAC (K = 26.56 L mmol(-1)) than for CAC (K = 19.54 L mmol(-1)). Continuous experiments were performed in a fixed-bed column packed with the investigated carbons, evaluating the influence of operational parameters such as flow rate, bed height and feed concentration on the breakthrough curves obtained. The breakthrough occurred more slowly for low concentrations of the metal ion in the feed, low flow rates and high bed height. The breakthrough curves were properly represented by Hall's model for both carbon types. Regeneration of the vinal activated carbon in column was tested, obtaining the same breakthrough curve in a new cycle of use. Finally, vinal-derived activated carbon can effectively be used to treat wastewater having until 30 ppm Ni(II). PMID- 22245836 TI - Population data of 21 non-CODIS STR loci in Han population of northern China. AB - Allele frequencies and forensic statistics of 21 autosomal short tandem repeat loci (i.e., D6S474, D12ATA63, D22S1045, D10S1248, D1S1677, D11S4463, D1S1627, D3S4529, D2S441, D6S1017, D4S2408, D19S433, D17S1301, D1GATA113, D18S853, D20S482, D14S1434, D9S1122, D2S1776, D10S1435 and D5S2500) were estimated in Han population from northern China (n = 220). Significant deviation from Hardy Weinberg equilibrium was detected only for D22S1045. The observed heterozygosity, the expected heterozygosity, the discrimination power, the probability of paternity exclusion in trios, the probability of paternity exclusion in duos and the polymorphic information content ranged from 0.591 to 0.836, 0.594 to 0.830, 0.762 to 0.948, 0.341 to 0.659, 0.189 to 0.487 and 0.535 to 0.807, respectively. Triallelic patterns were observed at D19S433 and D10S1435. Mutations occurred at D22ATA63, D10S1248, D19S433 and D14S1434 loci with all single-step mutations. The expected mutation rates of these four loci are 0.0042 with 95% confidence interval [0.0001, 0.0232] in a total of 238 meioses. Our results show that these 21 non-CODIS STR loci are highly polymorphic and can be useful for human identification and kinship analysis in Northern Han population in China. PMID- 22245837 TI - Estimation of the time since death: post-mortem contractions of human skeletal muscles following mechanical stimulation (idiomuscular contraction). AB - The mechanically stimulated idiomuscular contraction of skeletal muscles is part of the widely used compound method for death time estimation and therefore represents an item of high relevance and practicability in forensic case work. However, data on the topic are scarce and inconsistent and the currently reported maximum time span for the occurrence of the phenomenon until 13 h post-mortem (hpm) is based on a single case report from the beginning of the twentieth century. Therefore, idiomuscular contraction following mechanical stimulation has been investigated in skeletal muscles of 270 cases with assured time of death at defined post-mortem time points between 7 and 15 hpm. Of all investigated cases, 45 (16.7%) showed a positive reaction with a preponderance of cases of sudden death. Our investigations confirmed the upper time limit of 13 hpm up until idiomuscular contraction could be stimulated. With every hour of the post-mortem interval, a 0.61-fold decrease of the phenomenon's occurrence was observed (95%CI, 0.52-0.72; p < 0.001). Furthermore, several parameters showed significant correlations with the likelihood of the phenomenon's occurrence, namely stimulation of upper arm as opposed to the thigh (p < 0.001), gender (p = 0.017), and BMI (p < 0.001). These findings for the first time give reliable evidence of a post-mortem time limit of mechanically stimulated idiomuscular contraction and therefore contribute to the future application of the method in forensic case work. PMID- 22245838 TI - Molecular characterization of three L-type lectin genes from channel catfish, Ictalurus punctatus and their responses to Edwardsiella ictaluri challenge. AB - L-type lectins have a leguminous lectin domain and can bind to high-mannose type oligosaccharides. In the secretory pathway, L-type lectins play crucial roles in selective protein trafficking, sorting and targeting. Three L-type lectins were cloned in the channel catfish, Ictalurus punctatus, the 53 kDa endoplasmic reticulum ER-Golgi intermediate compartment protein (ERGIC-53), the vesicular integral protein of 36 kDa (VIP36) and VIP36-like. Phylogenetic analysis indicated that the catfish genes are orthologous to their counterparts in other species. Southern blot analysis demonstrated that all three L-type lectin genes are likely single-copy genes in the catfish genome. Analysis of expression in healthy tissues using quantitative real time RT-PCR indicated that all three genes are expressed widely in all tested tissues, but with strong tissue preference of expression: ERGIC-53 was found to be abundantly expressed in the liver, VIP36 was found to be abundantly expressed in the head-kidney, whereas VIP36-like was found to be abundantly expressed in the brain. Upon infection with Edwardsiella ictaluri, expressions of the three genes all had significant up regulation in the head-kidney, but had distinct expression patterns: ERGIC-53 was gradually induced with the highest expression 7 days after challenge in the head kidney, but was down-regulated in the liver, spleen, and brain. VIP36 was highly induced in the head-kidney, and 3 days after challenge in the brain, but was not up-regulated in any other tissues or timepoints after challenge. Expression levels of the catfish VIP36-like gene appeared to also respond to infection, albeit with differing patterns among the tested tissues. Taken together, our results indicate that all three L-type lectin genes may be involved in the immune responses of catfish after infection with E. ictaluri. PMID- 22245839 TI - The effect of fucoidan from brown seaweed Sargassum wightii on WSSV resistance and immune activity in shrimp Penaeus monodon (Fab). AB - The polysaccharide-fucoidan was extracted from brown seaweed Sargassum wightii and characterized through FT-IR and (13)C &(1)H NMR analysis. The extracted fucoidan was supplemented with pellet diets at three different concentrations (0.1, 0.2 and 0.3%). The fucoidan supplemented diets were fed to Penaeus monodon for 45 days, then challenged with WSSV and the mortality percentage was recorded daily up to 21 days. During the challenge test, the control group showed 100% mortality within 10 days, but in the experimental groups, the mortality percentage (51-72% within 21 days) was decreased considerably (P < 0.05) with respect to the concentrations of fucoidan. The reduction in mortality percentage of experimental groups over control group was ranged from 50.81 to 68.06%. During challenge experiment, the immunological parameters such as THC, prophenoloxidase activity, respiratory burst activity, superoxide dismutase activity and phagocytic activity were measured before injection of WSSV (0 day) and after the injection of WSSV on 10th and 21st days, respectively. All the immunological parameters of experimental groups were significantly (P < 0.05) increased than control group. RT-PCR analysis confirmed the considerable reduction of WSSV DNA copy numbers with respect to the concentration of fucoidan. It was concluded that P. monodon fed with fucoidan of S. wightii supplemented diet had enhanced the innate immunity and increased resistance against WSSV infection. PMID- 22245840 TI - Effects of graded levels of dietary methionine hydroxy analogue on immune response and antioxidant status of immune organs in juvenile Jian carp (Cyprinus carpio var. Jian). AB - Immune response and antioxidant status of immune organs in juvenile Jian carp (Cyprinus carpio var. Jian) fed graded levels of methionine hydroxy analogue (MHA) (0, 5.1, 7.6, 10.2, 12.7, 15.3 g kg(-1) diet) for 60 days were investigated. Results indicated that head kidney index, spleen index, red and white blood cell counts significantly increased with increasing MHA levels up to a point (P < 0.05), whereupon decreased (P < 0.05). Glutathione reductase activity in head kidney and spleen, anti-hydroxy radical and glutathione-S transferase activities in spleen, catalase activity and GSH content in head kidney significantly increased by MHA supplement, while malondialdehyde content, anti-superoxide anion, superoxide dismutase, glutathione peroxidase activities in head kidney and spleen, protein carbonyl content and catalase activity in spleen, anti-hydroxy radical activity in head kidney significantly decreased by MHA supplement. However, protein carbonyl content and glutathione-S-transferase activity in head kidney, GSH content in spleen remained unaffected. After 60-day feeding trial, a challenge study was conducted by injection of Aeromonas hydrophila for 17 days. Results showed that survival rate, leukocytes phagocytic activity, lysozyme activity, acid phosphatase activity, total iron-binding capacity, haemagglutination titre, complement 3, 4 and immunoglobulin M contents significantly increased by optimal dietary MHA supplement (P < 0.05). These data suggested that MHA affected antioxidant status of immune organs and promoted immune response in juvenile Jian carp. PMID- 22245841 TI - In vitro and in vivo study of cucurbitacins-type triterpene glucoside from Citrullus colocynthis growing in Saudi Arabia against hepatocellular carcinoma. AB - Chromatographic investigation of fruits obtained from Citrullus colocynthis, growing in Saudi Arabia, led to isolation of two compounds; Cucurbitacin E glucoside (Cu E, 1), and Cucurbitacin I glucoside (Cu I, 2). The chemical structures of 1 and 2, were elucidated by spectroscopic analyses include; 1D ((1)H and (13)C) and 2D (COSY, HMQC and HMBC) NMR and ESI-MS spectroscopy. The in vitro cytotoxic activity against hepatoma cell line (HepG2) and mice-bearing tumor of Ehrlich's ascites carcinoma (EAC) of the compounds were estimated. Both compounds had potent inhibitory activity on HepG2 with IC(50) 3.5 and 2.8 nmol/mL, respectively. In addition to these activities, the in vivo study employing EAC, showed the capability of both compounds to prolong the survival time, life span and normalize the biochemical parameters of the infected mice with EAC. PMID- 22245842 TI - Risperidone interacts with serum albumin forming complex. AB - The aim of the work is to study the mechanisms of the interaction of risperidone with human and bovine serum albumins using the fluorescence quenching technique. Risperidone is an atypical antipsychotic drug used to treat many psychiatric disorders. We selectively excited the fluorescence of tryptophan residues with a 290 nm wavelength light, and observed quenching by titrating human and bovine serum albumin solutions with risperidone. Emission spectra were recorded in the range from 300 to 450 nm for each quencher addition. Stern-Volmer graphs were plotted and quenching constants were estimated. Results showed that the drug quenches the fluorescence of the human serum albumin by the formation of a complex risperidone-albumin. Association constants calculated from Stern-Volmer equation for low concentrations (lower than 1:10 ratio risperidone/albumin) were of 2.56 * 10(5)M(-1), at 25 degrees C, and 1.43 * 10(5)M(-1), at 37 degrees C. As the quenching intensity of bovine serum albumin, which contains two tryptophan residues, was found to be higher than that of human serum albumin, which contains only one tryptophan residue. Hence, we suggest that the primary binding site for risperidone in albumin should be located in sub domain IB. PMID- 22245843 TI - Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. AB - BACKGROUND & AIMS: Notch signaling mediates embryonic vascular development and normal vascular remodeling; Notch1 knockout mice develop nodular regenerative hyperplasia (NRH). The pathogenesis of NRH is unclear, but has been associated with vascular injury in the liver sinusoids in clinical studies. We investigated the role of Notch1 signaling in liver sinusoidal endothelial cells (LSECs). METHODS: We studied MxCre Notch1(lox/lox) mice (conditional knockout mice without tissue-specific disruption of Notch1); mice with hepatocyte-specific knockout were created by crossing Notch1(lox/lox) with AlbCre(+/-) mice. Portal vein pressure was measured; morphology of the hepatic vasculature was assessed by histologic and scanning electron microscopy analyses. We performed functional and expression analyses of isolated liver cells. RESULTS: MxCre-induced knockout of Notch1 led to NRH, in the absence of fibrosis, with a persistent increase in proliferation of LSECs. Notch1 deletion led to de-differentiation, vascular remodeling of the hepatic sinusoidal microvasculature, intussusceptive angiogenesis, and dysregulation of ephrinB2/EphB4 and endothelial tyrosine kinase. Time-course experiments revealed that vascular changes preceded node transformation. MxCre Notch1(lox/lox) mice had reduced endothelial fenestrae and developed portal hypertension and hepatic angiosarcoma over time. In contrast, mice with hepatocyte-specific disruption of Notch1 had a normal phenotype. CONCLUSIONS: Notch1 signaling is required for vascular homeostasis of hepatic sinusoids; it maintains quiescence and differentiation of LSECs in adult mice. Disruption of Notch1 signaling in LSECs leads to spontaneous formation of angiosarcoma, indicating its role as a tumor suppressor in the liver endothelium. PMID- 22245844 TI - Duodenal activation of cAMP-dependent protein kinase induces vagal afferent firing and lowers glucose production in rats. AB - BACKGROUND & AIMS: The duodenum senses nutrients to maintain energy and glucose homeostasis, but little is known about the signaling and neuronal mechanisms involved. We tested whether duodenal activation of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) is sufficient and necessary for cholecystokinin (CCK) signaling to trigger vagal afferent firing and regulate glucose production. METHODS: In rats, we selectively activated duodenal PKA and evaluated changes in glucose kinetics during the pancreatic (basal insulin) pancreatic clamps and vagal afferent firing. The requirement of duodenal PKA signaling in glucose regulation was evaluated by inhibiting duodenal activation of PKA in the presence of infusion of the intraduodenal PKA agonist (Sp-cAMPS) or CCK1 receptor agonist (CCK-8). We also assessed the involvement of a neuronal network and the metabolic impact of duodenal PKA activation in rats placed on high-fat diets. RESULTS: Intraduodenal infusion of Sp-cAMPS activated duodenal PKA and lowered glucose production, in association with increased vagal afferent firing in control rats. The metabolic and neuronal effects of duodenal Sp-cAMPS were negated by coinfusion with either the PKA inhibitor H89 or Rp-CAMPS. The metabolic effect was also negated by coinfusion with tetracaine, molecular and pharmacologic inhibition of NR1-containing N-methyl-d-aspartate (NMDA) receptors within the dorsal vagal complex, or hepatic vagotomy in rats. Inhibition of duodenal PKA blocked the ability of duodenal CCK-8 to reduce glucose production in control rats, whereas duodenal Sp-cAMPS bypassed duodenal CCK resistance and activated duodenal PKA and lowered glucose production in rats on high-fat diets. CONCLUSIONS: We identified a neural glucoregulatory function of duodenal PKA signaling. PMID- 22245845 TI - Increased reprogramming capacity of mouse liver progenitor cells, compared with differentiated liver cells, requires the BAF complex. AB - BACKGROUND & AIMS: Ectopic expression of certain transcription factors can reprogram somatic cells to a pluripotent state. Hematopoietic and muscle stem cells can be more efficiently reprogrammed than differentiated blood or muscle cells, yet similar findings have not been shown in other primary organ systems. Moreover, molecular characteristics of the cellular hierarchy of tissues that influence reprogramming capacities need to be delineated. We analyzed the effect of differentiation stage of freshly isolated, mouse liver cells on the reprogramming efficiency. METHODS: Liver progenitor cell (LPC)-enriched cell fractions were isolated from adult (6-8 wk) and fetal (embryonic day 14.5) livers of mice and reprogrammed to become induced pluripotent stem (iPS) cells. Different transcription factors were expressed in liver cells, and markers of pluripotency were examined, along with the ability of iPS cells to differentiate, in vitro and in vivo, into different germ layers. RESULTS: Fetal and adult LPCs had significantly greater reprogramming efficiency after transduction with 3 or 4 reprogramming factors. Transduction efficiency-corrected reprogramming rates of fetal LPCs were 275-fold higher, compared with unsorted fetal liver cells, when 3 reprogramming factors were transduced. The increased reprogramming efficiency of LPCs, compared with differentiated liver cells, occurred independently of proliferation rates, but was associated with endogenous expression of reprogramming factors (Klf4 and c-Myc) and BAF (Brg1/Brm associated factor) complex members Baf155 and Brg1, which mediate epigenetic changes during reprogramming. Knockdown of BAF complex members negated the increased reprogramming efficiency of LPCs, compared with non-LPCs. CONCLUSIONS: LPCs have intrinsic, cell proliferation-independent characteristics resulting in an increased reprogramming capacity compared to differentiated liver cells. PMID- 22245847 TI - Antiandrogenic activity of phthalate mixtures: validity of concentration addition. AB - Phthalates and bisphenol A have very widespread use leading to significant exposure of humans. They are suspected to interfere with the endocrine system, including the androgen, estrogen and the thyroid hormone system. Here we analyzed the antiandrogenic activity of six binary, and one ternary mixture of phthalates exhibiting complete antiandrogenic dose-response curves, and binary mixtures of phthalates and bisphenol A at equi-effective concentrations of EC(10), EC(25) and EC(50) in MDA-kb2 cells. Mixture activity followed the concentration addition (CA) model with a tendency to synergism at high and antagonism at low concentrations. Isoboles and the toxic unit approach (TUA) confirmed the additive to synergistic activity of the binary mixtures BBP+DBP, DBP+DEP and DEP+BPA at high concentrations. Both methods indicate a tendency to antagonism for the EC(10) mixtures BBP+DBP, BBP+DEP and DBP+DEP, and the EC(25) mixture of DBP+BPA. A ternary mixture revealed synergism at the EC(50), and weak antagonistic activity at the EC(25) level by the TUA. A mixture of five phthalates representing a human urine composition and reflecting exposure to corresponding parent compounds showed no antiandrogenic activity. Our study demonstrates that CA is an appropriate concept to account for mixture effects of antiandrogenic phthalates and bisphenol A. The interaction indicates a departure from additivity to antagonism at low concentrations, probably due to interaction with the androgen receptor and/or cofactors. This study emphasizes that a risk assessment of phthalates should account for mixture effects by applying the CA concept. PMID- 22245846 TI - Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. AB - BACKGROUND & AIMS: The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, noninvasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRIs). METHODS: We screened 225 asymptomatic adult HRIs at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. RESULTS: Ninety-two of 216 HRIs (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n = 5) by any of the imaging modalities. Fifty-one of the 84 HRIs with a cyst (60.7%) had multiple lesions, typically small (mean, 0.55 cm; range, 2-39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects younger than 50 years old, 34% of subjects 50-59 years old, and 53% of subjects 60-69 years old (P < .0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRIs, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRIs (82 intraductal papillary mucinous neoplasms and 3 pancreatic endocrine tumors). Three of 5 HRIs who underwent pancreatic resection had high-grade dysplasia in less than 3 cm intraductal papillary mucinous neoplasms and in multiple intraepithelial neoplasias. CONCLUSIONS: Screening of asymptomatic HRIs frequently detects small pancreatic cysts, including curable, noninvasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT. PMID- 22245849 TI - Current world literature. PMID- 22245848 TI - Apoptosis induction by silica nanoparticles mediated through reactive oxygen species in human liver cell line HepG2. AB - Silica nanoparticles are increasingly utilized in various applications including agriculture and medicine. In vivo studies have shown that liver is one of the primary target organ of silica nanoparticles. However, possible mechanisms of hepatotoxicity caused by silica nanoparticles still remain unclear. In this study, we explored the reactive oxygen species (ROS) mediated apoptosis induced by well-characterized 14nm silica nanoparticles in human liver cell line HepG2. Silica nanoparticles (25-200MUg/ml) induced a dose-dependent cytotoxicity in HepG2 cells. Silica nanoparticles were also found to induce oxidative stress in dose-dependent manner indicated by induction of ROS and lipid peroxidation and depletion of glutathione (GSH). Quantitative real-time PCR and immunoblotting results showed that both the mRNA and protein expressions of cell cycle checkpoint gene p53 and apoptotic genes (bax and caspase-3) were up-regulated while the anti-apoptotic gene bcl-2 was down-regulated in silica nanoparticles treated cells. Moreover, co-treatment of ROS scavenger vitamin C significantly attenuated the modulation of apoptotic markers along with the preservation of cell viability caused by silica nanoparticles. Our data demonstrated that silica nanoparticles induced apoptosis in human liver cells, which is ROS mediated and regulated through p53, bax/bcl-2 and caspase pathways. This study suggests that toxicity mechanisms of silica nanoparticles should be further investigated at in vivo level. PMID- 22245851 TI - Changes in T lymphocyte subsets and intracellular cytokines after transfer of chemically extracted acellular nerve allografts. AB - The aim of the present study was to observe the immune mechanism underlying the rejection of chemically extracted acellular nerve allografts for use in clinical applications. A total of 128 BALB/c mice were randomly divided into a negative contrast group (NC, 32 mice), a fresh autograft group (AG, 32 mice), a fresh allogeneic nerve group (FN, 32 mice) and a chemically extracted acellular allogeneic nerve group (CEN, 32 mice). Various types of nerve grafts were implanted into the thigh muscle of BALB/C mice in the corresponding groups. At 3, 7, 14 and 28 days post-operation, the mice (8 cases from each group) were sacrificed and their spleens were extracted. The spleens were ground into paste. The erythrocytes and other cells were lysed using distilled water and the T lymphocytes were collected. Monoclonal antibodies (CD3, CD4, CD8, CD25, IL-2, IFN gamma and TNF-alpha) were then added to the solution. The Facial Action Coding System was used to determine the positive rates of the cells combined with the monoclonal antibodies above. No significant statistical differences were observed between the CEN, NC and AG groups. However, some data of the FN group were significantly higher than those of the other groups at the corresponding time. No obvious immune rejections were observed among the chemically extracted acellular nerve allografts compared with fresh nerve autograft. PMID- 22245853 TI - Rapid consecutive three-component coupling-Fiesselmann synthesis of luminescent 2,4-disubstituted thiophenes and oligothiophenes. AB - (Hetero)aroyl chlorides, alkynes, and ethyl 2-mercapto acetate can be reacted in a consecutive three-component synthesis to give 2,4-disubstituted thiophene 5 carboxylates in good to excellent yields. In the sense of a pseudo-five-component reaction highly blue luminescent symmetrical terthiophenes and a quinquethiophene can be synthesized in excellent yield. PMID- 22245852 TI - Clinical, radiological, histological and retrieval findings of Activ-L and Mobidisc total disc replacements: a study of two patients. AB - INTRODUCTION: This study evaluates the short-term clinical outcome, radiological, histological and device retrieval findings of two patients with second generation lumbar total disc replacement (TDR). MATERIALS AND METHODS: The first patient had a single level L4-L5 Activ-L TDR, the second patient a L4-L5 Mobidisc and L5-S1 Activ-L TDR. The TDRs were implanted elsewhere and had implantation times between 1.3 and 2.8 years. RESULTS: Plain radiographs and CT-scanning showed slight subsidence of the Activ-L TDR in both patients and facet joint degeneration. The patients underwent revision surgery because of recurrent back and leg pain. After removal of the TDR and posterolateral fusion, the pain improved. Histological examination revealed large ultrahigh molecular weight polyethylene (UHMWPE) particles and giant cells in the retrieved tissue surrounding the Mobidisc. The particles in the tissue samples of the Activ-L TDR were smaller and contained in macrophages. Retrieval analysis of the UHMWPE cores revealed evidence of minor adhesive and abrasive wear with signs of impingement in both TDR designs. CONCLUSION: Although wear was unrelated to the reason for revision, this study demonstrates the presence of UHMWPE particles and inflammatory cells in second generation TDR. Long-term follow-up after TDR is indicated for monitoring wear and implant status. PMID- 22245854 TI - Characterization of ambient air quality during a rice straw burning episode. AB - Spatiotemporal characteristics and impact of ambient air-quality attributed to open burning of rice straw were analyzed and estimated with measured data. Two multivariate analytic methods, factor analysis and cluster analysis, were adopted to analyze the temporal and spatial impact on ambient air-quality during the rice straw burning episode. Temporal features of three scenarios were cited to compare the concentrations for ambient air-quality between the rice straw burning episode and non-episodes over two typical stations by factor analysis. Factor analysis demonstrated that the first rotational component, identified as being highly correlated to the open burning of rice straw, accounts for about 40% of the concentration variance for ambient air-quality. In typical air-quality stations, the average hourly incremental concentrations between the episode and non episodes were greater than 300 MUg m(-3) for PM(10), 1.0 ppm for CO and 35 ppb for NO(2) during the impact of rice straw burning. Factor analysis presented that the first rotated component was highly correlated with several primary pollutants (NO(2), NMHC, PM(10) and CO) during the rice straw burning episode, while every component was only highly correlated with a unique air pollutant during non episodes. The delineation isopleths indicated that factor analysis could serve as a better method than cluster analysis and provides cross-county cooperation for local governments located in the same separated district during the rice straw burning season. The results of factor analysis revealed that CO is the best index to demonstrate the impact of rice straw burning than the other six air pollutants measured during the episode. Backward trajectory analysis supplied a cause-effect relationship between measured stations and specific rice planted regions during the rice straw burning episode. PMID- 22245855 TI - Developing restoration planting mixes for active ski slopes: a multi-site reference community approach. AB - Downhill ski areas occupy large expanses of mountainous lands where restoration of ecosystem function is of increasing importance and interest. Establishing diverse native plant communities on ski runs should enhance sediment and water retention, wildlife habitat, biodiversity and aesthetics. Because ski slopes are managed for recreation, ski slope revegetation mixes must consist of low-stature or herbaceous plants that can tolerate typical environmental conditions on ski slopes (high elevation, disturbed soils, open, steep slopes). The most appropriate reference communities for selecting ski slope revegetation species are thus successional, or seral plant communities in similar environments (i.e., other ski slopes). Using results from a broad-scale reference community analysis, I evaluated plant communities naturally occurring on ski slopes from 21 active and abandoned ski areas throughout the northern Sierra Nevada to identify native plant species suitable for use in ski slope restoration. I constructed a baseline planting palette of regionally appropriate plant species (for restoration of either newly created or already existing ski runs) that is functionally diverse and is likely to succeed across a broad range of environments. I also identify a more comprehensive list of species for more specialized planting mixes based on site-specific goals and particular environmental settings. Establishing seral plant communities may be an appropriate restoration goal for many other types of managed lands, including roadsides, firebreaks and utility rights-of-way. This study describes an ecological (and potentially cost-effective) approach to developing restoration planting palettes for such managed lands. PMID- 22245856 TI - Airports offer unrealized potential for alternative energy production. AB - Scaling up for alternative energy such as solar, wind, and biofuel raises a number of environmental issues, notably changes in land use and adverse effects on wildlife. Airports offer one of the few land uses where reductions in wildlife abundance and habitat quality are necessary and socially acceptable, due to risk of wildlife collisions with aircraft. There are several uncertainties and limitations to establishing alternative energy production at airports, such as ensuring these facilities do not create wildlife attractants or other hazards. However, with careful planning, locating alternative energy projects at airports could help mitigate many of the challenges currently facing policy makers, developers, and conservationists. PMID- 22245857 TI - Assessment of water supply as an ecosystem service in a rural-urban watershed in southwestern Mexico City. AB - Studies from the ecosystem services perspective can provide a useful framework because they allow us to fully examine the benefits that humans obtain from socio ecological systems. Mexico City, the second largest city in the world, has faced severe problems related to water shortages, which have worsened due to increasing population. Demand for space has forced changes in land cover, including covering areas that are essential for groundwater recharge. The city has 880 km(2) of forest areas that are crucial for the water supply. The Magdalena River Watershed was chosen as a model because it is a well-preserved zone within Mexico City and it provides water for the population. The general aim of this study was to assess the ecosystem service of the water supply in the Magdalena River Watershed by determining its water balance (SWAT model) and the number of beneficiaries of the ecosystem services. The results showed that the watershed provides 18.4 hm(3) of water per year. Baseflow was dominant, with a contribution of 85%, while surface runoff only accounted for 15%. The zone provides drinking water to 78,476 inhabitants and could supply 153,203 potential beneficiaries. This work provides an example for understanding how ecosystem processes determine the provision of ecosystem services and benefits to the population in a rural-urban watershed in Mexico City. PMID- 22245859 TI - Ultrafast hot-carrier-dominated photocurrent in graphene. AB - The combination of its high electron mobility, broadband absorption and ultrafast luminescence make graphene attractive for optoelectronic and photonic applications, including transparent electrodes, mode-locked lasers and high-speed optical modulators. Photo-excited carriers that have not cooled to the temperature of the graphene lattice are known as hot carriers, and may limit device speed and energy efficiency. However, their roles in charge and energy transport are not fully understood. Here, we use time-resolved scanning photocurrent microscopy to demonstrate that hot carriers, rather than phonons, dominate energy transport across a tunable graphene p-n junction excited by ultrafast laser pulses. The photocurrent response time varies from 1.5 ps at room temperature to 4 ps at 20 K, implying a fundamental bandwidth of ~500 GHz (refs 12, 13, 21). Gate-dependent pump-probe measurements demonstrate that both thermoelectric and built-in electric field effects contribute to the photocurrent, with the contribution from each depending on the junction configuration. The photocurrent produced by a single pulsed laser also displays multiple polarity reversals as a function of carrier density, which is a possible signature of impact ionization. PMID- 22245858 TI - Effect of thymosin alpha-1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro. AB - Thymosin alpha 1 (Talpha1) has been shown to have beneficial effects on numerous immune system parameters, but little is known about the effects of Talpha1 on patients with gastric carcinoma. The objective of this study was to determine the effect of Talpha1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro, and to evaluate its efficacy as an immunoregulatory factor in patients with gastric carcinoma. We compared the effect of Talpha1 on the frequency of CD4+ and CD8+ T cells, especially the CD4+CD25+Foxp3+ Tregs in peripheral blood mononuclear cells (PBMCs) from gastric carcinoma patients (N = 35) and healthy donors (N = 22). We also analyzed the changes in the proliferation of PBMCs in response to treatment with Talpha1, and examined the production of Th1, Th2, and Th17 cytokines by PBMCs and tumor-infiltrating lymphocytes. The treatment of PBMCs from gastric cancer patients, with Talpha1 (50 ug/mL) alone increased the percentage of CD4+CD25+Foxp3+ (suppressive antitumor-specific Tregs) from 1.68 +/- 0.697 to 2.19 +/- 0.795% (P < 0.05). Our results indicate that Talpha1 increases the percentage of Tregs and IL-1beta, TNF alpha, and IL-6 in vitro. PMID- 22245860 TI - Electrophoretically induced aqueous flow through single-walled carbon nanotube membranes. AB - Electrophoresis, the motion of charged species through liquids and pores under the influence of an external electric field, has been the principle source of chemical pumping for numerous micro- and nanofluidic device platforms. Recent measurements of ion currents through single or few carbon nanotube channels have yielded values of ion mobility that range from close to the bulk mobility to values that are two to seven orders of magnitude higher than the bulk mobility. However, these experiments cannot directly measure ion flux. Experiments on membranes that contain a large number of nanotube pores allow the ion current and ion flux to be measured independently. Here, we report that the mobilities of ions within such membranes are approximately three times higher than the bulk mobility. Moreover, the induced electro-osmotic velocities are four orders of magnitude faster than those measured in conventional porous materials. We also show that a nanotube membrane can function as a rectifying diode due to ionic steric effects within the nanotubes. PMID- 22245861 TI - An ab initio mechanism for efficient population of triplet states in cytotoxic sulfur substituted DNA bases: the case of 6-thioguanine. AB - The deactivation mechanism of the cytotoxic 6-thioguanine, the 6-sulfur substituted analogue of the canonical DNA base, is unveiled by ab initio calculations. Oxygen-by-sulfur substitution leads to efficient population of triplet states-the first step for generating singlet oxygen-which is responsible for its cytotoxicity. PMID- 22245862 TI - Bacterial application increased the flow rate of CaCO3-clogged emitters of drip irrigation system. AB - CaCO(3) is one of the most common emitter clogging factors among chemical precipitates in drip irrigation systems. Continuous acid application as a classical approach to prevent CaCO(3) clogging can be tricky, expensive and hazardous for soil. In order to develop an environmentally friendly method to address the problem, two bacterial strains, one renowned as a PGPR and the other having extensive CaCO(3) dissolving capacity, were used in treatments of artificially clogged drip irrigation emitters. Results showed the flow rates of clogged emitters significantly increased in drip lines which were treated with bacterial suspensions but no increase was observed in control drip lines which were treated with sterile nutrient broth. Furthermore, scanning electron and florescence microscopies were used to examine residual CaCO(3) precipitates. Thus, in consideration of its extensively studied PGPR characteristics, microbial treatment with Bacillus subtilis OSU-142 was shown to be promising for field applications as a novel and environmentally friendly treatment for clogged emitters of drip irrigation systems. PMID- 22245863 TI - Pastoral wildfires in the Mediterranean: understanding their linkages to land cover patterns in managed landscapes. AB - The pastoral use of fire to regenerate rangelands is a major cause of wildfires in many Mediterranean countries. Despite producing important environmental impacts, this phenomenon has hardly ever been studied separately from other wildfire ignition causes. As extensive livestock breeding relies on the available pasture resources, we hypothesised that a higher rate of pastoral wildfire ignitions could be associated with land cover patterns, as these reflect the spatial arrangement of human activities in managed landscapes. To investigate these patterns, we studied landscape structure and the pastoral wildfires recorded between 1988 and 2000 in 24 Nature Park landscapes in Andalusia (Spain). The CORINE Land Cover map was reclassified according to five levels of grazing use and landscape metrics were calculated. Neural networks were developed to model the relationship between landscape metrics and pastoral wildfires, obtaining a set of significant variables which are discussed in the frame of land and livestock management in the region. We conclude that pastoral wildfire ignitions are more likely in landscapes where the pattern of being dominated by a matrix composed of several large patches of low to moderate grazing use, and having abundant small and elongated patches of higher grazing use, is more extreme. This pattern could be reflecting the persistence of numerous small livestock farms within an increasingly abandoned agrarian landscape. To prevent pastoral wildfires, land management could attempt to enlarge and merge those small patches of higher grazing use, reducing the amount of interface and their intermixture with the surrounding poorer pasture resources. PMID- 22245864 TI - The role of nutrients in the biodegradation of 2,4,6-trinitrotoluene in liquid and soil. AB - The widely used explosive 2,4,6-trinitrotoluene (TNT) has residues that are potentially explosive, toxic, and mutagenic. TNT and other explosives can be degraded by microorganisms; however, biostimulation is needed for process efficiency. To investigate the effectiveness of using biostimulation to degrade TNT, we added varying concentrations of a nutrient amendment consisting of inorganic salts, plant extracts, and molasses to soil and liquid media. For the inoculum we used a consortium of bacteria AM 06 that had exhibited the ability to degrade TNT and which had been previously isolated from explosives-contaminated soils. Phylogenetically, the clones clustered into seven different genera: Klebsiella, Raoultella, Serratia, Stenotrophomonas, Pseudoxanthomonas, Achromobacter and Pseudomonas. The addition of AM 06 consortium to a liquid environment along with 100% nutrient amendment decreased the amount of TNT (and its degradation products) by up to 90% after 14 days incubation. At the total amount of TNT was less than 100 mg/l, the concentration of TNT did not influence the amount of sugar consumed by the bacteria consortium. In soil media, the TNT degradation process was dependent on the concentration of nutrient amendment added. At higher initial concentrations of TNT (500 mg/kg), bioaugmentation (i.e., addition of bacteria inoculum) had a demonstrated effect, especially when nutrient concentrations of 50% and 100% were added to the soil. Findings of this study could further the understanding of the TNT biodegradation processes in water and soil and provide for optimization of the technological conditions for bioremediation. PMID- 22245865 TI - Role of average speed in N2O exhaust emissions as greenhouse gas in a huge urban zone (MVMZ): would we need a cold sun? AB - Nowadays, the drastic pollution problems, some of them related with greenhouse gas emissions, have promoted important attempts to face and diminish the global warming effects on the Mexico Valley Metropolitan Zone (MVMZ) as well as on the huge urban zones around the world. To reduce the exhaust gas emissions, many efforts have been carried out to reformulate fuels and design new catalytic converters; however, it is well known that other variables such as socio-economic and transport structure factors also play an important role around this problem. The present study analyzes the roles played by several commonly-used three-way catalytic converters (TWC) and the average traffic speed in the emission of N(2)O as greenhouse gas. According to this study, by increasing the average traffic flow and avoiding constant decelerations (frequent stops) during common trips, remarkable environmental and economic benefits could be obtained due to the diminution of N(2)O and other contaminant emissions such as ammonia (NH(3)) and even CO(2) with the concomitant reduced fossil fuel consumption. The actions mentioned above could be highly viable to diminish, in general, the global warming effects and contamination problems. PMID- 22245866 TI - Getting their voices heard: three cases of public participation in environmental protection in China. AB - By comparing three cases of environmental activism in China, our paper answers the following three questions about public participation in environment protection in China: (1) what are the drivers for public participation, (2) who are the agents leading the participation, and (3) do existing laws facilitate public participation? We find heightened public awareness of environmental degradation and increasing anxieties over health and property values drive people to fight for more political space to influence decisions that have an impact on the environment. Despite the promises one finds in the letter of Chinese laws, Chinese society lacks a meaningful institutional framework to allow public participation, even in the area of environmental protection. The Chinese government mainly passively responds to public demands on an ad hoc basis, with no institutional commitment for engaging the public on environmental issues. This is unfortunate, because public policies without adequate public input are doomed to be clouded by illegitimacy. PMID- 22245867 TI - Environmental analysis of Ribeiro wine from a timeline perspective: harvest year matters when reporting environmental impacts. AB - A series of Galician (NW Spain) wines, such as Rias Baixas and Ribeiro have acquired international renown in the past few years. In this particular study, viticulture, vinification and bottling and packaging in a winery of the Ribeiro appellation were studied from a life cycle assessment perspective, with the main objective of identifying the largest environmental impacts for four different years of production (2007-2010). The selected functional unit was a 750 mL bottle of Ribeiro white wine, packaged for distribution. Inventory data was gathered mainly through direct communication using questionnaires. Results showed considerable annual variability in environmental performance, stressing the importance of including timeline analysis in the wine sector. Therefore, environmental scaling was proposed for the assessed wine based on the individual environmental impacts for each harvest year. Furthermore, the main hot spots identified were compost and pesticide production and emissions, in the agricultural phase and bottle production and electricity consumption, in the subsequent stages of wine production, in most of the selected impact categories. Suggested improvement opportunities included shifts in the compost transportation policy, recovery of natural resources for vineyard infrastructure, the introduction of new packaging formats in the bottling process and the use of pesticides with lower toxicity potential. PMID- 22245868 TI - Fostering environmental champions: a process to build their capacity to drive change. AB - This paper describes a six-step process to build the leadership capacity of environmental champions. This process was developed during research involving champions in Australian water agencies. The process, like leadership, is sensitive to context. It includes gathering local information on the factors that assist particular types of champion to exert influence, and using this information to build customized capacity building tools, such as leadership development programs. The paper explains each step in the process and provides illustrative examples from research on water agency champions. Practical and theoretical implications are discussed, including the hypothesis that the process should be transferable to other work environments under certain circumstances. PMID- 22245870 TI - How deceased donor transplantation is impacting a decline in commercial transplantation-the Tamil Nadu experience. AB - India with a population of 1.2 billion has a renal transplantation rate of 3.25 per million population. The major cause of chronic kidney disease is hypertension and diabetes. The crude and age-adjusted incidence rates of end-stage renal disease are estimated to be 151 and 232 per million population, respectively, in India. There was a remarkable lack of knowledge in the public about deceased organ donation until a decade ago. However, the role played by the media and nongovernmental organizations in partnership with the government has emphasized and implemented deceased donor transplantation in certain states in India-to mention particularly, the Tamil Nadu model. In the last 2 years, deceased organ donation has reached 1.3 per million population in Tamil Nadu, thereby effectively eliminating commercial transplantation. There is no religious bar for organ donation. A central transplant coordinator appointed by the government oversees legitimate and transparent allocation of deceased organs both in the public and private facilities as per the transplant waiting list. This model also takes care of the poor sections of society by conducting donation and transplantation through government-run public facilities free of cost. In the last 2 years, deceased donor transplantation has been performed through this network procuring organs such as the heart, heart valves, lung, liver, kidneys, cornea, and skin. The infrastructural lack of immunological surveillance including donor-specific antibody monitoring, human leukocyte antigen typing, and panel reactive antibody except in a few tertiary care centers-prevents allocation according to the immunological status of the recipient. This private-public partnership promoting deceased donor transplantation has effectively eliminated commercialization in transplantation in the state of Tamil Nadu with a population of 72 million which is a model for other regions of South Asia and developing countries. PMID- 22245869 TI - Short hairpin RNA targeting Twist1 suppresses cell proliferation and improves chemosensitivity to cisplatin in HeLa human cervical cancer cells. AB - Development of multidrug resistance (MDR) remains a major hurdle to successful cancer chemotherapy and MDR1/P-gp overexpression is believed to be mainly responsible for MDR of tumor cells. Twist1, which is a highly conserved transcription factor that belongs to the family of basic helix-loop-helix proteins, has been shown to be a major regulator of the epithelial-mesenchymal transition (EMT), and therefore promotes carcinoma metastasis. Recently, a novel function of Twist1 was reported to confer radioresistance or chemoresistance in cervical cancer. However, mechanisms of such efficacy are not completely elucidated. In the present study, we firstly analyzed the relationship between Twist1 and MDR1/P-gp expression in human cervical cancer specimens and demonstrated a positive correlation between Twist1 and MDR1/P-gp expression in the same patient. Additionally, we provide the first evidence that silencing of Twist1 by RNAi downregulated MDR1/P-gp expression in HeLa cervical cancer cells, suppressed the cell proliferation, inhibited Rhodamine123 efflux activity of cells and sensitized cells to cisplatin treatment. Collectively, these findings suggest that Twist1-mediated modulation of MDR1/P-gp expression plays an important role in sensitization of cervical cancer cells to cisplatin, and also indicate a novel therapeutic strategy to overcome drug resistance through inactivation of Twist1 expression in cervical cancer. PMID- 22245871 TI - Everolimus as primary immunosuppression in kidney transplantation: experience in conversion from calcineurin inhibitors. AB - BACKGROUND: We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion. METHODS: Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival. RESULTS: Baseline creatinine clearance was 52.4+/-17.8 mL/min vs. 53.4+/-20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160-507) to 458 mg/day (interquartile range 238-892; P<0.001). Risk factors for development of proteinuria >=900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15-9.89), serum triglycerides >=150 mg/day (OR 4.35; 95% CI: 1.70-11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22-7.59), baseline proteinuria >=550 mg/day (OR 10.37; 95% CI: 3.99-26.99), and conversion >=3 years after transplant (OR 5.77; 95% CI: 1.89-17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria >=550 mg/day, the risk of developing proteinuria >=900 mg/day was 77.1% if they were converted after >=3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria >=550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion. CONCLUSIONS: Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria. PMID- 22245873 TI - Role of oncogenic pathways and KRAS/BRAF mutations in the behavior of colon adenocarcinoma in renal transplant patients. AB - BACKGROUND: The behavior and mechanisms of colorectal carcinoma in solid organ transplantation have not been well characterized. Our aim was to determine the clinical and molecular phenotypes of colorectal carcinoma in kidney transplant recipients and compare with those in the nonimmunosuppressed population. For the first time, we analyzed the impact of KRAS and BRAF mutations in kidney transplantation. METHODS: Kidney transplant recipients with colorectal carcinoma were diagnosed and followed up from 1992 to 2007. Twelve patients fulfilled inclusion criteria and were matched with the general population with colorectal cancer. To assess the possible mechanisms involved in the clinical behavior of colorectal carcinoma, we compared the tumoral expression by immunohistochemical analysis of molecule markers of mammalian target of rapamycin (mTOR) pathway, angiogenesis and proliferation, and the role of activating mutations in KRAS and BRAF genes. RESULTS: Colorectal carcinoma was more prevalent and exhibited a trend for worse prognosis in transplant patients. Although the mTOR pathway was activated in both populations, activation was lower in transplant patients because of relatively higher phosphatase and tensin homolog expression in the former. Angiogenesis was activated in colorectal carcinoma in both groups. KRAS mutations were found in transplant recipients treated with calcineurin inhibitors and with high expression of phosphatase and tensin homolog. CONCLUSION: The activation of oncogenic pathways could be responsible for the clinical behavior of posttransplant colorectal carcinoma. The mutation status of the KRAS gene is likely involved in mTOR pathway and to be a prognosis marker for colorectal cancer in kidney transplantation. PMID- 22245874 TI - Risk of transmission of H1N1 influenza by solid organ transplantation in the United Kingdom. AB - BACKGROUND: Concern that pandemic H1N1 swine influenza could be transmitted by solid organ transplantation led to the publication of guidance advising screening of donors, restriction of use of organs under certain conditions, and prophylaxis of recipients. We have reviewed the outcomes for cases of solid organ graft recipients from H1N1 influenza-positive donors in the United Kingdom up to May 2010. METHODS: The Organ Donation and Transplantation Directorate supplied a list of five known H1N1 influenza-positive donors, one of whom died from active H1N1 infection. Transplanting teams were contacted to gain information on clinical outcomes. RESULTS: Thirteen organs were grafted from the donors. None of the 13 recipients developed suspected or confirmed H1N1 influenza. There was variable use of antiviral chemoprophylaxis and screening of recipients for H1N1 influenza. CONCLUSIONS: No cases of transplant-related H1N1 influenza transmission were demonstrated in this series. It remains prudent that transplanting teams have a high index of suspicion for H1N1 influenza infection in donors and offer prophylaxis to and undertake active surveillance of recipients. PMID- 22245872 TI - A20-mediated modulation of inflammatory and immune responses in aortic allografts and development of transplant arteriosclerosis. AB - BACKGROUND: Transplant arteriosclerosis (TA) is the pathognomonic feature of chronic rejection, the primary cause of allograft failure. We have shown that the NF-kappaB inhibitory protein A20 exerts vasculoprotective effects in endothelial and smooth muscle cells (SMC), and hence is a candidate to prevent TA. We sought direct proof for this hypothesis. METHODS: Fully mismatched, C57BL/6 (H2) into BALB/c (H2), aorta to carotid allografts were preperfused with saline, recombinant A20 adenovirus (rAd.A20) or rAd.beta-galactosidase (beta-gal), implanted, harvested 4 weeks after transplantation, and analyzed by histology, immunohistochemistry, and immunofluorescence staining. We measured indoleamine 2,3-dioxygenase, interleukin-6, and transforming growth factor-beta mRNA and protein levels in nontransduced, and rAd.A20 or rAd.beta-gal-transduced human SMC cultures after cytokine treatment. RESULTS: Vascular overexpression of A20 significantly reduced TA lesions. This correlated with decreased graft inflammation and increased apoptosis of neointimal SMC. Paradoxically, T-cell infiltrates increased in A20-expressing allografts, including the immunoprivileged media, which related to A20 preventing indoleamine 2,3 dioxygenase upregulation in SMC. However, infiltrating T cells were predominantly T-regulatory cells (CD25+/Forkhead Box P3 [FoxP3+]). This agrees with A20 inhibiting interleukin-6 and promoting transforming growth factor-beta production by medial SMC and in SMC cultures exposed to cytokines, which favors differentiation of regulatory over pathogenic T cells. CONCLUSIONS: In summary, A20 prevents immune-mediated remodeling of vascular allografts, therefore reduces TA lesions by affecting apoptotic and inflammatory signals and modifying the local cytokine milieu to promote an immunoregulatory response within the vessel wall. This highlights a novel function for A20 in local immunosurveillance, which added to its vasculoprotective effects, supports its therapeutic promise in TA. PMID- 22245875 TI - Evaluation of native kidney recovery after simultaneous liver-kidney transplantation. AB - BACKGROUND: Debate continues about which liver transplantation candidates with impaired renal function should undergo liver transplant alone versus simultaneous liver-kidney transplantation (SLK). Identifying predictors of native kidney function recovery after SLK requires an accurate measure of the relative function of all three kidneys in patients with SLK. METHODS: The distance of a transplanted kidney from the renal scan camera can be substantially different from that of native kidneys. We developed a technique to correct attenuation of counts of all three kidneys based on their depth. RESULTS: In our series of 13 SLK recipients, attenuation correction increased the measured renal function of native kidneys by up to 40%, demonstrating the importance of this procedure for accurately measuring kidney function. Eight patients met the United Network for Organ Sharing (UNOS)-proposed criteria for receiving a SLK, but four of these still had significant native kidney function (>40% of total function) after transplant. Five patients did not meet the UNOS-proposed criteria for SLK, yet only one of these had native kidney function recovery. CONCLUSION: The criteria proposed by UNOS to determine that SLK is indicated, and thus that native kidney recovery is not expected, are not always accurate. Further study of factors associated with native kidney recovery after SLK is required. PMID- 22245876 TI - Minimal hepatic encephalopathy: follow-up 10 years after successful liver transplantation. AB - BACKGROUND: The long-term effect of liver transplantation (LT) on cognitive functions and the complete reversibility of minimal hepatic encephalopathy are poorly documented. Much evidence indicates that spatial attention improves starting from the immediate period after LT. However, at least in the first 2 years, some cognitive defects seem to persist to some degree, especially for supramodal nonverbal cognitive functions. The aim of this study is to investigate (i) whether the improvements observed in the perioperative period fluctuate or remain stable 10 years after LT and (ii) whether the functions that have been found defective also improve. METHODS: We called patients previously included in a prospective study (Mattarozzi et al., Arch Neurol 2004; 61: 242) for a further neuropsychological evaluation. We compared the cognitive evaluation after 7 to 10 years with previous data gathered 6 and 18 months after LT. RESULTS: The improvements obtained in the first 2 years after transplantation remain stable during the 7 to 10 years thereafter, especially for visuospatial attention, F(12,96) 1.70; P=0.04 and selective attention, F(6,66) 3.51; P=0.005. Furthermore, these findings also seem to suggest an improvement in supramodal cognitive functions, such as spatial planning intelligence, measured by the Elithorn Maze Test, F(3,33) 7.42; P=0.002. Verbal short-term memory, F(3,33) 3.69; P=0.038, and visuospatial short-term memory, F(6,64) 2.97; P=0.013, show a more fluctuating trend over time. CONCLUSIONS: Despite the risk of surgery, the neurotoxicity of immunosuppression therapy, and the effects of aging and related comorbidities, our data indicate that LT is able to significantly improve patients' cognitive functions in the long term. PMID- 22245877 TI - Improvement of urinary dysfunction after kidney transplantation by administration of the antimuscarinic agent--prospective randomized controlled study. AB - BACKGROUND: Bladder dysfunction after kidney transplantation (KTx) impairs the patients' quality of life. We examined the bladder function status perioperatively in patients undergoing KTx and performed a randomized prospective study to determine the efficacy of an antimuscarinic agent, solifenacin, in ameliorating the bladder dysfunction after KTx. METHODS: The subjects in this study were 33 patients who underwent KTx at our institution. The patients were divided into two groups: group 1 (n=18), composed of patients who were not treated with any antimuscarinic agent, and group 2 (n=15), composed of patients treated with an antimuscarinic agent. We investigated the actual bladder function status of these patients before and after KTx by the following two methods: (1) video water cystometry and (2) questionnaire study using the Overactive Bladder Symptom Score and King's Health Questionnaire. RESULTS: The cystometry study revealed a significantly greater increase of the maximum cystometric capacity in group 2 than in group 1 (173.0+/-60.7 mL in group 1 and 260.1+/-51.0 mL in group 2 [P=0.005]) after KTx. In the questionnaire surveys, the decreases in the scores for all domains were observed 6 weeks after KTx. The scores in group 2 tended to be lower than those in group 1. CONCLUSION: In all of our patients, the bladder dysfunction status improved dramatically after KTx. In addition, our results suggest that administration of the antimuscarinic agent, solifenacin, may contribute to improvement of the quality of life of patients undergoing KTx. PMID- 22245878 TI - Late antibody-mediated rejection after heart transplantation following the development of de novo donor-specific human leukocyte antigen antibody. AB - BACKGROUND: Antibody-mediated rejection (AMR) is an important problem after heart transplantation. Most cases seem to occur in sensitized recipients with preformed donor-specific human leukocyte antigen antibody (DSA) early after transplantation. Few data exist on AMR in patients who form de novo DSA. We describe the clinical features and treatment outcome for late AMR secondary to de novo DSA. METHODS: This was a retrospective, observational cohort study. All heart transplant patients treated for symptomatic AMR secondary to de novo DSA between November 2005 and August 2011. RESULTS: Fifteen patients were treated for AMR giving an incidence of 3.1 cases per 1000 person years and a prevalence of 1.4%. All had evidence of heart failure on presentation and de novo DSA at diagnosis. There was a spectrum of histologic and immunohistochemical findings. Despite treatment with immunepheresis, intravenous immunoglobulin, and rituximab, and in some cases total lymph node irradiation (n=3) and bortezomib (n=2), clinical outcomes were poor. DSA antibody levels, measured using Labscreen single antigen kits, were reduced by a mean of 76% with a median of 77% and a range of 35% to 99%, but were not eliminated. Forty-six percent had persistent cardiac allograft dysfunction. Mean and median survival was 1.3 and 0.8 years after diagnosis of AMR. Only 40% were alive at the end of the study period. CONCLUSION: Late cardiac AMR caused by de novo DSA was an uncommon but serious problem. Despite treatment consistent with current best practice, 46% of patients developed persistent cardiac dysfunction and their medium-term survival was poor. PMID- 22245880 TI - The global role of kidney transplantation. AB - World Kidney Day on March 8, 2012, provides a chance to reflect on the success of kidney transplantation as a therapy for end-stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost-effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end-stage kidney disease include the economic limitations which in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation, and vaccination. Even in high-income countries, the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical, and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental, and political environments. World Kidney Day is a call to deliver transplantation therapy to the 1 million people a year who have a right to benefit. PMID- 22245879 TI - Social deprivation, ethnicity, and uptake of living kidney donor transplantation in the United Kingdom. AB - BACKGROUND: Socioeconomic disparities and their contribution to the ethnic differences in living kidney donor transplantation have not been adequately studied. METHODS: A total of 12,282 patients aged 18 to 69 years starting renal replacement therapy (January 1, 1997, to December 31, 2004) in the United Kingdom were included. Logistic regression models were used to examine probability of living donor transplantation within 3 years of renal replacement therapy. The effect of area deprivation (Townsend index) was studied among whites only adjusted for patient characteristics and the effect of ethnic origin (South Asians and blacks compared with whites) was then examined among all patients adjusting for area deprivation. RESULTS: Among whites, increasing social deprivation was associated with lower odds of living donor transplantation. In the fully adjusted model, odds ratio (OR) for the most deprived quintile was 0.40 (95% confidence interval [CI] 0.33, 0.49; P trend<0.0001) compared with the least deprived. These gradients were more pronounced among centers performing more live donor transplants (P value for interaction <0.0001). South Asians and blacks had lower odds of living donor transplantation compared with whites, but there was an interaction with age (P<0.0001), so that this disparity was observed only in those younger than 50 years (blacks: OR, 0.31; 95% CI, 0.18, 0.54; South Asians: OR, 0.55; 95% CI, 0.34, 0.90; P value <0.0001). CONCLUSIONS: Socially deprived and younger ethnic minority patients have lower probability of living kidney donor transplantation. The extent to which these inequalities reflect modifiable societal healthcare system barriers and donor/recipient factors requires further study. PMID- 22245882 TI - Minimal effects of Darunavir on adipocyte differentiation and metabolism in 3T3 L1 cells. AB - Darunavir (DRV) has been confirmed to be an effective option for antiretroviral naive and experienced patients. It results in a more favorable lipid and glucose profile than other antiretrovirals. The objective of this study was to investigate the molecular mechanisms that could underline the lack of toxicity of DRV to metabolism and the better profile observed in HIV-infected patients in comparison with other drugs. The effects of DRV on adipogenesis were evaluated by oil red O staining after 8 days of induction of differentiation in 3T3-L1 cells, a very adequate and convenient cell culture model for investigation of adipose function. Several adipogenic genes (C/EBPalpha, PPARgamma, Pref-1, and AP2) were analyzed by real time-PCR. Fully differentiated adipocytes were also incubated with DRV for 24 h and glucose utilization and lactate and glycerol production were quantified by use of an autoanalyzer. No effects of DRV on murine adipocyte differentiation were observed. Significant decreases in lipolysis, glucose uptake, and lactate production were observed at the highest concentration used (50 MUM:) (p < 0.01-p < 0.001). However, DRV treatment did not modify the percentage of glucose transformed into lactate. Co-treatment with RTV did not induce any further effects on lipolysis and glucose metabolism. This study suggests that the decrease in lipolysis observed after DRV treatment could explain, at least in part, the lower plasma lipids observed in patients under DRV/r treatment in comparison with other drugs. The lack of effects of RTV co treatment on glucose and lipid metabolism emphasizes the safety of this treatment. PMID- 22245883 TI - Assembly of 1,2,3-benzenetricarboxylic acid and sliver(I) metal center to a novel 3D supramolecular framework: syntheses, structure and properties. AB - The reaction of AgNO3, pyrazine (pyz) and 1,2,3-benzenetricarboxylic acid (H3btc) leads to a new 3D supramolecular architecture, namely {[Ag(H2btc)(pyz)].(H2O)2}n (1), which has been characterized by IR spectroscopy, elemental analysis, thermogravimetry, photoluminescent and powder X-ray diffraction (PXRD). Compound 1 displays a 3D supramolecular network, which is built from cationic Ag-pyz chains and anionic [(H2btc)n.2H2O]- layers through the weak Ag?O interaction. Complex 1 exhibits photoluminesscence with an emission maximum at ca.391 nm upon excitation at ca. 241 nm. PMID- 22245884 TI - Development of electrochemiluminescent inhibition method for determination of gentian violet in aquatic water. AB - Gentian violet (GV) was found to quench the electrochemiluminescence (ECL) of the tris(2,2'-bipyridyl)ruthenium(II)/tris-n-propylamine (Ru(bpy)3(2+)-TPA) system at a glass carbon electrode (GCE). Based on the ECL signal changes, a simple and ultrasensitive detection method for GV in aquatic water was established. Under the optimized conditions, the quenched ECL intensity versus the logarithm of the concentration of GV was linear over a concentration range from 1.0*10(-10) to 5.0*10(-7) mol L(-1), and the limit of detection (LOD) was found to be 4.5*10( 12) mol L(-1) (S/N=3). The results obtained by the ECL system were better than other reported methods in literatures in terms of sensitivity or linear response range. The method was successfully applied to determine GV in aquatic water, and the relative standard deviations (RSDs) were found less than 6.3%, and the recoveries were obtained from 98.7 to 111.0%. Moreover, a possible mechanism of the quenching effect was primarily discussed based on UV-visible absorption spectra, cyclic voltammograms and IECL-E curves. PMID- 22245885 TI - Forster resonance energy transfer among a structural isomer of adenine and various Coumarins inside a nanosized reverse micelle. AB - In this article we have studied Forster Resonance Energy Transfer (FRET) using 2 aminopurine (2-AP), a structural isomer of adenine as donor and various Coumarins as acceptors inside AROSOL-OT (AOT)-water reverse micelles (RM) using steady state and time-resolved fluorescence spectroscopies. We have used three sets of FRET and all the pairs except 2-AP-Coumarin-480 exhibited quite efficient FRET. For the efficient pairs, overlap integral J(lambda) and Forster distance (R0) are of high values but the rate constant of energy transfer (kET) are quite low. The rate is gradually amplified with increase in water content for the 2-AP-Coumarin 440 pair while the reverse is observed for 2-AP-Coumarin-460. In future our FRET pair can be used in more modified and sophisticated confined media such as biomembranes of varying size, physical properties and chemical compositions etc. PMID- 22245886 TI - Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg negative patients treated with peginterferon alfa-2a. AB - BACKGROUND & AIMS: It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2log hepatitis B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. METHODS: HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N=85) and PegBeLiver study (N=75) were stratified according to the presence of any HBsAg decline and/or 2log HBV DNA decline at week 12. SR was defined as HBV DNA <2000IU/ml and normal alanine aminotransferase 24 weeks after treatment. RESULTS: The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies (p=0.001) and its negative predictive value [NPV] was 95% in the validation dataset harbouring genotypes A-D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2log HBV DNA decline at week 12 achieved an SR (NPV 100%). CONCLUSIONS: We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy. PMID- 22245887 TI - PPARalpha activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. AB - BACKGROUND & AIMS: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPARalpha activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl(4) cirrhotic rats. METHODS: Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25mg/kg/day, n=10) or its vehicle (n=12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (alpha-SMA) protein expression, cyclo oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB(2) production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers. RESULTS: CCl(4) cirrhotic rats treated with fenofibrate had a significantly lower PP (-29%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX 1 expression and TXB(2) production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed. CONCLUSIONS: PPARalpha activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis. PMID- 22245889 TI - Assessment of pathology reports on hilar cholangiocarcinoma: the results of a nationwide, multicenter survey performed by the AFC-HC-2009 study group. AB - BACKGROUND & AIMS: To assess the accuracy of pathology reports in patients operated on for hilar cholangiocarcinoma. METHODS: Pathology reports for 263 patients operated on in 22 tertiary hepatobiliary centers were reviewed. The report format, turnaround time, tissue specimens, intraoperative consultations, macroscopic and microscopic descriptions, and conclusions were assessed. RESULTS: Surgeons provided pathologists with pertinent clinical and imaging data in only 14% of cases and gave information on specimen orientation in only 24% of cases. The reports frequently failed to give information on prognostic histological factors: tumor differentiation (missing in 27% of cases), vascular invasion (45%), tumor thickness (99%), and infiltration of the bile duct surgical margins (4%). Distances between the tumor and the vessel margin, liver margin and the periductal soft tissue circumferential margin were not specified in 87%, 79%, and 89% of cases, respectively. Only 21% of the reports gave the pTNM stage in the conclusion section. A lack of information prevented retrospective pTNM staging in 48% of cases. Three percent of the reports had discrepancies in their conclusion section. CONCLUSIONS: Our French, nationwide study revealed that pathology reports on hilar cholangiocarcinoma frequently lack important information on the main prognostic histological factors and pTNM staging. We recommend the use of a standardized pathology report in this context. PMID- 22245888 TI - Understanding silibinin's modes of action against HCV using viral kinetic modeling. AB - BACKGROUND & AIMS: Legalon(r) SIL (SIL) is a chemically hydrophilized version of silibinin that has exhibited high antiviral effectiveness against hepatitis C virus (HCV). Its main mode of action (MOA) remains unclear, with contradicting in vitro studies supporting either suppression of entry and cell-to-cell spread or suppression of viral RNA synthesis as the main MOA. We sought to provide new insights into SIL's MOA in HCV genotype-1/4 patients receiving intravenous SIL monotherapy for 7 days via mathematical modeling. METHODS: Changes in HCV RNA in 25 patients receiving 10, 15, or 20mg/kg/day of SIL were analyzed and modeled using viral kinetic methods. RESULTS: In 15 patients, the virus declined in a biphasic manner, in which a sharp drop between days 0 and 2 was followed by a slower second phase of decline. In 10 patients, the initial decline was weaker and the virus declined in a single phase over the 7-day period. The blocking production effectiveness, epsilon, was dose-dependent with mean epsilon=0.49 and 0.89 in the 10 or 15 and 20mg/kg/day dosing groups, respectively (p=0.02). The effectiveness of blocking viral infection, eta, was estimated as 0.60 with no significant differences across dosing groups. For all patients, the mean rate of viral load decline measured between days 2 and 7 was high (0.3 log(10)IU/ml/day), i.e., 4-fold higher than typically observed during the 2nd phase of (pegylated) interferon-alpha+/-ribavirin treatment. CONCLUSIONS: Modeling HCV kinetics in vivo suggests that SIL may block both viral infection and viral production/release with its main dose-dependent effect being blocking viral production/release. PMID- 22245890 TI - The impact of organ dysfunction in cirrhosis: survival at a cost? AB - BACKGROUND & AIMS: The incidence of cirrhosis and subsequent development of organ dysfunction (OD) requiring intensive care unit (ICU) support is rising. Historically, critically ill cirrhotics are perceived as having poor prognosis and substantial cost of care. METHODS: The aim was to prospectively analyse resource utilisation and cost of a large cohort of patients (n=660) admitted to a Liver ICU from 2000 to 2007 with cirrhosis and OD. Child Pugh, MELD, SOFA, APACHE II, and organ support requirements were collected. The Therapeutic Intervention Scoring System (TISS) score, a validated tool for estimating cost in ICU, was calculated daily. Logistic regression was used to determine independent predictors of increased cost. RESULTS: Alcohol was the most common etiology (47%) and variceal bleeding (VB) the most common reason for admission (35%). Invasive ventilatory support was required in 74% of cases, vasopressors in 49%, and 50% required renal replacement therapy. Forty-nine per cent of non-transplanted patients survived to ICU discharge. Median TISS score and ICU cost per patient were 261 and ?14,139, respectively. VB patients had the highest survival rates (53% vs. 24%; p<0.001) and lower associated cost. A combination of VB (OR 0.48), need for ventilation (OR 2.81), low PO(2)/FiO(2) on admission (OR 0.97), and lactate (OR 0.93) improved cost prediction on multivariate analysis (AUROC 0.7; p<0.001) but organ failure scores per se were poor predictors of cost. CONCLUSIONS: Patients with cirrhosis and OD result in considerable resource expenditure but have acceptable hospital survival. Further health economic assessment and outcome prediction tools are required to appropriately target resource utilisation. PMID- 22245891 TI - Vandetanib in patients with inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled study. AB - BACKGROUND & AIMS: Inhibitors of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have shown anti-tumor activities in advanced hepatocellular carcinoma (HCC). The present study evaluated the efficacy and safety of vandetanib, an oral inhibitor of both VEGFR and EGFR, in patients with unresectable advanced HCC. METHODS: Eligible patients were randomized 1:1:1 to receive vandetanib 300mg/day, vandetanib 100mg/day, or placebo. Upon disease progression, all patients had the option to receive open label vandetanib 300mg/day. The primary objective was to evaluate tumor stabilization rate (complete response+partial response+stable disease ?4months). Secondary assessments included progression-free survival (PFS), overall survival (OS) and safety. Biomarker studies included circulating pro-angiogenic factors and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Sixty-seven patients were randomized to vandetanib 300mg (n=19), vandetanib 100mg (n=25) or placebo (n=23) groups. Twenty-nine patients entered open-label treatment. Vandetanib induced a significant increase in circulating VEGF and decrease in circulating VEGFR levels. In both vandetanib arms, tumor stabilization rate was not significantly different from placebo: 5.3% (vandetanib 300mg), 16.0% (vandetanib 100mg) and 8.7% (placebo). DCE-MRI did not detect significant vascular change after vandetanib treatment. Although trends of improved PFS and OS after vandetanib treatment were found, they were statistically insignificant. The most common adverse events were diarrhea and rash, whose incidence did not differ significantly between treatment groups. CONCLUSIONS: Vandetanib has limited clinical activity in HCC. The safety profile was consistent with previous studies. PMID- 22245893 TI - Focus. PMID- 22245892 TI - Structural and inflammatory heterogeneity in subcutaneous adipose tissue: relation with liver histopathology in morbid obesity. AB - BACKGROUND & AIMS: In addition to total body fat, the regional distribution and inflammatory status of enlarged adipose tissue are strongly associated with metabolic co-morbidities of obesity. We recently showed that the severity of histological liver lesions related to obesity increases with the amount of macrophage accumulation in visceral adipose tissue (VAT), while no association was found with the subcutaneous adipose tissue (SAT). In the abdominal region, SAT is anatomically divided into two layers, i.e. superficial (sSAT) and deep (dSAT). The aim of the present study was to test the hypothesis that these distinct compartments differentially contribute to hepatic alterations in obesity. METHODS: Biopsies of the liver, sSAT, dSAT, and VAT were collected in 45 subjects with morbid obesity (age 43.7+/-1.6 years; BMI 48.5+/-1.2kg/m(2)) during bariatric surgery. Large scale gene expression analysis was performed to identify the pathways that discriminate sSAT from dSAT. Adipose tissue macrophages were quantified by immunohistochemistry using HAM56 antibody in subjects scored for liver histopathology. RESULTS: An inflammatory gene pattern discriminates between sSAT and dSAT. dSAT displayed an intermediate level of macrophage accumulation between sSAT and VAT. The abundance of macrophages in dSAT, but not in sSAT, was significantly increased in patients with non-alcoholic steatohepatitis (NASH) and/or fibroinflammatory hepatic lesions. CONCLUSIONS: These data show distinct gene signature and macrophage abundance in the two compartments of SAT, with dSAT more closely related to VAT than to sSAT in terms of inflammation and relation with the severity of liver diseases in morbid obesity. PMID- 22245894 TI - Tumor progression-related transmembrane protein aspartate-beta-hydroxylase is a target for immunotherapy of hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-beta-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed in both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion. METHODS: Dendritic cells (DCs), expanded and isolated from the spleen, were incubated with a cytokine cocktail to optimize IL 12 secretion and co-stimulatory molecule expression, then subsequently loaded with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC tumor cells followed by subcutaneous inoculation with 5-10*10(5) ASPH loaded DCs using a prophylactic and therapeutic experimental approach. Tumor infiltrating lymphocytes (TILs) were characterized, and their role in producing anti-tumor effects determined. The immunogenicity of ASPH protein with respect to activating antigen specific CD4+ T cells derived from human peripheral blood mononuclear cells (PBMCs) was also explored. RESULTS: We found that immunotherapy with ASPH loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically. Ex-vivo re-stimulation experiments and in vivo depletion studies demonstrated that both CD4+ and CD8+ cells contributed to anti tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, we showed that ASPH stimulation led to significant development of antigen-specific CD4+ T-cells. CONCLUSIONS: Immunization with ASPH-loaded DCs has substantial anti tumor effects which could reduce the risk of HCC recurrence. PMID- 22245895 TI - Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. AB - BACKGROUND & AIMS: Data on the incidence and remission rates of non-alcoholic fatty liver disease (NAFLD) as well as predictive factors are scant. This study aims at evaluating NAFLD's epidemiology in prospective follow-up of individuals sampled from the general population. METHODS: Evaluation of metabolic parameters and ultrasonographic evidence of NAFLD was performed in 213 subjects, with no known liver disease or history of alcohol abuse. The evaluation was performed at baseline and after a 7-year period by identical protocols. RESULTS: Of the 147 patients who did not have NAFLD at baseline, 28 (19%) were found to have NAFLD at a 7-year follow-up. Baseline BMI, HOMA score, blood cholesterol, triglycerides, leptin levels, and weight gain (5.8+/-6.1 vs. 1.4+/-5.5kg, p<0.001) were significantly higher and adiponectin was lower among those who developed NAFLD at 7-year follow-up, compared with those who remained NAFLD-free. However, only weight gain and baseline HOMA were independent predictors for the development of NAFLD. Of the 66 patients who were found to have NAFLD at baseline, as many as 24 patients (36.4%) had no evidence of NAFLD at 7years. Weight loss of 2.7+/-5.0kg was significantly associated with NAFLD remission. Moreover, there was a 75% remission rate among NAFLD patients who lost 5% or more from their baseline weight. CONCLUSIONS: Among the general population, weight gain, and baseline insulin resistance are predictors for NAFLD incidence. One third of NAFLD patients may have remission of disease within a 7-year follow-up, mostly depending on modest weight reduction. PMID- 22245896 TI - Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. AB - BACKGROUND & AIMS: Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment. METHODS: Patients (n=602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle. RESULTS: Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively. CONCLUSIONS: These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy. PMID- 22245897 TI - High intrahepatic HHV-6 virus loads but neither CMV nor EBV are associated with decreased graft survival after diagnosis of graft hepatitis. AB - BACKGROUND & AIMS: In liver transplant recipients with graft hepatitis, the relevance of herpesviruses is not well defined. METHODS: Viral loads of CMV, EBV, and HHV-6 were determined in blood and liver biopsies of 170 liver transplant recipients with graft hepatitis by quantitative PCR. RESULTS: HHV-6-, CMV-, and EBV-DNA were detected in 58%, 14%, and 44% of the biopsies, respectively, with coinfections in 34%. High intrahepatic HHV-6 DNA levels (>75th percentile, 11.27 copies/1000 cells) and detection of HHV-6 DNAemia were significantly associated with decreased graft survival after diagnosis of graft hepatitis (p=0.014 and p=0.003, respectively, median follow-up was 23.8 months). Multivariate analysis confirmed high intrahepatic HHV-6 loads as an independent factor associated with reduced graft survival (adjusted hazard ratio 2.61, 95%confidence interval 1.16 5.87). Low concentrations of HHV6 DNA in the liver, indicating latent infection, did not influence graft survival. Neither CMV nor EBV (qualitative detection and high virus loads) nor acute rejection (according to the BANFF score) affected graft survival. However, patients had been treated for CMV reactivations and acute rejections in this retrospective study. High age and high bilirubin levels were the other independent factors associated with reduced graft survival (adjusted hazard ratio 3.56CI 1.52-8.34 and 3.23CI 1.50-6.96, respectively). CONCLUSIONS: High intrahepatic HHV-6-DNA levels are associated with decreased graft survival in liver transplant recipients with graft hepatitis. The significance of HHV-6 as potential etiology of graft hepatitis needs further evaluation. PMID- 22245899 TI - Histamine regulation of biliary proliferation. PMID- 22245898 TI - Development of the bile ducts: essentials for the clinical hepatologist. AB - Several cholangiopathies result from a perturbation of developmental processes. Most of these cholangiopathies are characterised by the persistence of biliary structures with foetal configuration. Developmental processes are also relevant in acquired liver diseases, as liver repair mechanisms exploit a range of autocrine and paracrine signals transiently expressed in embryonic life. We briefly review the ontogenesis of the intra- and extrahepatic biliary tree, highlighting the morphogens, growth factors, and transcription factors that regulate biliary development, and the relationships between developing bile ducts and other branching biliary structures. Then, we discuss the ontogenetic mechanisms involved in liver repair, and how these mechanisms are recapitulated in ductular reaction, a common reparative response to many forms of biliary and hepatocellular damage. Finally, we discuss the pathogenic aspects of the most important primary cholangiopathies related to altered biliary development, i.e. polycystic and fibropolycystic liver diseases, Alagille syndrome. PMID- 22245900 TI - Cost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the Italian Liver Cancer population. AB - BACKGROUND & AIMS: It was recently shown that semi-annual surveillance for hepatocellular carcinoma (HCC) in cirrhotic patients provides a prognostic advantage over the annual program; however, its cost-effectiveness (CE) in the general cirrhotic population still needs to be defined. METHODS: A Markov model was built to compare CE of these two strategies, considering literature results and treatment modalities of 918 cirrhotic patients from the Italian Liver Cancer (ITA.LI.CA) database. RESULTS: Results from the Markov model suggest that, compared to annual surveillance, semi-annual surveillance leads to a gain in quality-adjusted life expectancy, in an unselected cirrhotic population, of 1.35 quality-adjusted life-months (QALMs) over 10 years since surveillance start in compensated patients, and of 0.73 QALMs in decompensated patients. Semi-annual surveillance was more cost-effective in compensated than in decompensated cirrhosis, with an incremental CE ratio (ICER) of 1997 and 3814?/QALM, respectively. In compensated cirrhosis, semi-annual surveillance was more cost effective than the annual program when the annual HCC incidence was >=3.2% and the relative survival gain after cancer diagnosis was >=20% with respect to the annual program. In decompensated cirrhosis, semi-annual surveillance was cost effective in patients amenable to liver transplantation. In both groups, CE of semi-annual surveillance improved with the increase of annual incidence and the survival benefit obtainable with HCC treatment. CONCLUSIONS: Both surveillance strategies for HCC in cirrhotic patients can be recommended, according to the individual risk profile for HCC occurrence and the expected survival gain obtainable after tumor diagnosis and therapy. PMID- 22245901 TI - 4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration. AB - BACKGROUND & AIMS: Multidrug resistance-associated protein 2 (in humans, MRP2; in rodents, Mrp2) mediates biliary excretion of bilirubin glucuronides. Therefore, upregulation of MRP2/Mrp2 expression may improve hyperbilirubinemia. We investigated the effects of 4-phenylbutyrate (4PBA), a drug used to treat ornithine transcarbamylase deficiency (OTCD), on the cell surface expression and transport function of MRP2/Mrp2 and serum T-Bil concentration. METHODS: MRP2 expressing MDCKII (MRP2-MDCKII) cells and rats were studied to explore the change induced by 4PBA treatment in the cell surface expression and transport function of MRP2/Mrp2 and its underlying mechanism. Serum and liver specimens from OTCD patients were analyzed to examine the effect of 4PBA on hepatic MRP2 expression and serum T-Bil concentration in humans. RESULTS: In MRP2-MDCKII cells and the rat liver, 4PBA increased the cell surface expression and transport function of MRP2/Mrp2. In patients with OTCD, hepatic MRP2 expression increased and serum T Bil concentration decreased significantly after 4PBA treatment. In vitro studies designed to explore the mechanism underlying this drug action suggested that cell surface-resident MRP2/Mrp2 is degraded via ubiquitination-mediated targeting to the endosomal/lysosomal degradation pathway and that 4PBA inhibits the degradation of cell surface-resident MRP2/Mrp2 by reducing its susceptibility to ubiquitination. CONCLUSIONS: 4PBA activates MRP2/Mrp2 function through increased expression of MRP2/Mrp2 at the hepatocanalicular membrane by modulating its ubiquitination, and thereby decreases serum T-Bil concentration. 4PBA has thus therapeutic potential for improving hyperbilirubinemia. PMID- 22245902 TI - Renal failure and hyponatremia in patients with cirrhosis and skin and soft tissue infection. A retrospective study. AB - BACKGROUND & AIMS: Skin and soft tissue infection in cirrhosis is considered a non-severe infection, but specific information is lacking. This study aimed at assessing the characteristics, occurrence of renal failure, and outcome of cirrhotic patients with skin and soft tissue infection. METHODS: Ninety-two patients with cirrhosis and skin and soft tissue infection admitted to hospital within a 6-year period were retrospectively analyzed. A control group matched by severity of liver disease, admitted for reasons other than infection, was also studied. RESULTS: Resolution of the infection was achieved in 96% of patients. Twenty (21.7%) patients with skin and soft tissue infection developed renal failure, compared to only five patients (5.4%) of the control group (p=0.001). Renal failure was persistent despite infection resolution in 10 of the 20 patients vs. none of the control group. Renal failure was associated with poor prognosis. Hyponatremia developed in 40% and 25% of the infection and control group, respectively (p=0.028). Within a 3-month follow-up period, 25 patients (23%) with skin and soft tissue infection died or were transplanted compared to only four patients (4%) of the control group (p<0.001). Factors independently associated with mortality in the infection group were: site of acquisition of the infection and MELD-sodium score at diagnosis. CONCLUSIONS: Skin and soft tissue infection is a severe complication of cirrhosis with high frequency of renal failure and hyponatremia that may persist despite resolution of the infection. MELD-sodium score is useful to assess 3-month mortality in these patients. PMID- 22245903 TI - Clinical evidence for the regression of liver fibrosis. AB - Fibrosis is a common pathological process for the majority of liver diseases which in a significant minority of patients leads to end-stage cirrhosis and/or hepatocellular carcinoma. Data emerging from small rodent models of chronic liver disease have demonstrated that fibrotic extracellular matrix can be remodelled and near-normal hepatic architecture regenerated upon cessation of injury. Moreover, regression of liver fibrosis in these model systems can be stimulated with drugs that target the activities of fibrogenic hepatic stellate cells. These findings are exciting as they suggest that established fibrosis is susceptible to regression and possibly even reversion. Alongside these experimental studies is a growing body of clinical data that suggest regression of fibrosis may also occur in liver disease patients for whom an effective treatment is available for their underlying liver injury. This paper provides an up-to-date review of the currently available clinical data and also considers technical caveats that highlight the need for caution in establishing a new dogma that human liver fibrosis is reversible. PMID- 22245904 TI - Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. AB - OBJECTIVE: Studies on the epidemiology of primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) show variable outcome. We aimed at systematically reviewing the incidence and prevalence rates, as well as geographical distribution and temporal trends of PSC and PBC. DATA SOURCES: A systematic search of literature was performed in Medline and EMBASE (search last conducted January 10th, 2011). STUDY SELECTION: Population-based epidemiological studies reporting incidence and/or prevalence rates for PSC or PBC in a defined geographical area of at least 100,000 adult inhabitants were considered relevant. DATA EXTRACTION: Study area, study period, number of patients, number of inhabitants, incidence per 100,000 inhabitants per year, prevalence per 100,000 inhabitants, method of case-finding, method of case-ascertainment, male/female ratio and in case of PSC, occurrence of inflammatory bowel diseases (IBD) were extracted from retrieved articles. RESULTS: The literature search yielded 2286 abstracts of which 31 articles fulfilled all inclusion criteria. Studies varied in size from 10 to 770 patients in catchment areas from 100,312 to 19,230,000 inhabitants. The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and 0-16.2 per 100,000 inhabitants, respectively. PBC incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants; prevalence rates are increasing in time. CONCLUSIONS: Incidence and prevalence rates of both PSC and PBC vary widely and seem to be increasing. True population-based studies are scarce and therefore large population-based studies combining meticulous case finding and case-ascertainment strategies are necessary. PMID- 22245905 TI - Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: a subgroup analysis. AB - BACKGROUND & AIMS: Alpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: (a) correlation between AFP response and imaging response, and (b) ability of AFP, EASL, and WHO response to predict survival outcomes in patients with solitary HCC. METHODS: Six hundred and twenty-nine HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP >=200ng/ml, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as>50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel Byar methodologies. None of the patients received sorafenib. RESULTS: Three months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3%, and 93.3%, respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL, and AFP responders survived longer than non-responders (p=0.006, 0.0001, and <0.0001, respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (p <0.05). CONCLUSIONS: Response by AFP and EASL are predictors of survival outcome in patients with solitary HCC. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies (LRTs). PMID- 22245907 TI - Total joint replacement in adolescents: literature review and case examples. AB - PURPOSE OF REVIEW: The current review summarizes the recent studies of total knee and hip replacement outcomes in adolescent patients, as well as highlights current replacement strategies and bearing options. RECENT FINDINGS: The survival rates of total knee and hip replacements in adolescents are lower compared with those in the elderly adults. Adolescent patients almost inevitably require revision surgery in their lifetime. Cementless arthroplasty is a promising replacement strategy in adolescents because, theoretically, if bone ingrowth occurs, then implant survival should improve; further, if revision is required, the surgeon does not have the burden of removing cement. However, recent data suggest no difference in survival rates between cementless and cemented implants in the short-term. The advantages and disadvantages between various bearing surfaces in this population also remain controversial and survival data are limited. SUMMARY: Total knee and hip replacement, although rare in the adolescent population, is successful at alleviating pain and restoring mobility in end-stage arthritic disease in the short-term. Numerous replacement strategies and bearing options are currently available; however, there is currently no standard of care or implants specifically designed for the adolescent population. Long-term studies looking at the survival of the various prostheses is essential to determine the efficacy and safety in the adolescent population with different causes of end-stage arthritic disease. PMID- 22245906 TI - Microbial biodiversity in a Malaysian oil field and a systematic comparison with oil reservoirs worldwide. AB - Microbial diversity within formation water and oil from two compartments in Bokor oil reservoir from a Malaysian petroleum oil field was examined. A total of 1,056 16S rRNA gene clones were screened from each location by amplified ribosomal DNA restriction analysis. All samples were dominated by clones affiliated with Marinobacter, some novel Deferribacteraceae genera and various clones allied to the Methanococci. In addition, either Marinobacterium- or Pseudomonas-like operational taxonomic units were detected from either compartment. A systematic comparison with the existing pertinent studies was undertaken by analysing the microbial amplicons detected and the PCR primers used. The analyses demonstrated that bacterial communities were site specific, while Archaea co-occurred more frequently. Amplicons related to Marinobacter, Marinobacterium and Pseudomonas were detected in a number of the studies examined, suggesting they may be ubiquitous members in oil reservoirs. Further analysis of primers used in those studies suggested that most primer pairs had fairly broad but low matches across the bacterial and archaeal domains, while a minority had selective matches to certain taxa or low matches to all the microbial taxa tested. Thus, it indicated that primers may play an important role in determining which taxa would be detected. PMID- 22245908 TI - Novel genetic aspects of congenital anomalies of kidney and urinary tract. AB - PURPOSE OF REVIEW: Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most frequent organ malformations. They are a relevant cause of chronic renal failure in children. Apart from isolated forms of CAKUT, more than 500 syndromes have been described that are characterized by combined defects of the kidney and other organ systems. Familial aggregation of renal malformations in approximately 10% of patients suggests that genetic events might be involved. Modifying effects due to missense mutations in additional developmental genes seem to enhance the phenotypic variability in affected families. In these families, genetic counseling can be difficult. In contrast, in patients with defined autosomal dominant disease, genetic counseling is of high clinical relevance, also with respect to additional extrarenal symptoms. RECENT FINDINGS: Due to the development of numerous genetic knock-out mouse models, the identification of specific renal developmental genes and the application of novel sequencing techniques of the human genome, our understanding of kidney organogenesis has largely improved during very recent years. SUMMARY: This review will focus on important genetic factors that influence nephrogenesis and highlight important human disorders that are associated with anomalies of kidneys, proximal and distal urinary tract. PMID- 22245909 TI - Clinical implications of pharmacokinetics and pharmacodynamics of procedural sedation agents in children. AB - PURPOSE OF REVIEW: Procedural sedation has become the standard of care for managing pain and anxiety in children in the emergency department. RECENT FINDINGS: Numerous articles have been published on pediatric procedural sedation with, however, little in-depth discussion of the pharmacodynamics and pharmacokinetics of the sedation agents utilized. SUMMARY: We review the pharmacokinetics and pharmacodynamics of the pediatric procedural sedation pharmacopeia from a clinical perspective with emphasis on the practical implications for drug titration and dosing. PMID- 22245910 TI - Synthesis of beta-cyclodextrin conjugated superparamagnetic iron oxide nanoparticles for selective binding and detection of cholesterol crystals. AB - Water-soluble, beta-cyclodextrin conjugated superparamagnetic nanoparticles have been constructed. These particles showed selective binding to cholesterol crystals, which opens the door for the detection of cholesterol crystal-related diseases such as atherosclerosis by magnetic resonance imaging (MRI). PMID- 22245911 TI - Hydrogen sulfide attenuates cardiac hypertrophy and fibrosis induced by abdominal aortic coarctation in rats. AB - Hydrogen sulfide (H2S) has been recently found to be an endogenous signaling gasotransmitter. Cardiac hypertrophy often develops in the course of heart failure. It is unknown whether or not endogenous H2S protects cardiac hypertrophy. This study was conducted to examine the effects of H2S on cardiac hypertrophy and fibrosis induced by abdominal aortic coarctation and to explore its mechanisms. Male Sprague-Dawley rats were randomly divided into five groups: normal, sham, abdominal aortic coarctation (AAC), AAC treated with enalapril and AAC treated with H2S. One week after surgery, enalapril and sodium hydrosulfide (NaHS)-treated rats were fed for 28 consecutive days and sacrificed. After that, the left ventricle mass index (LVMI), cardiomyocyte size and areas, collagen volume fraction (CVF) of the rats were measured. In the AAC rats, the LVMI, the cardiomyocyte size and areas, and the CVF were all markedly increased while in the H2S groups they were significantly reduced. H2S decreased the levels of Ang II in the heart, but not in plasma. In addition, H2S also improved the expression of connexin 43 (Cx43). Our results suggest that H2S can significantly suppress cardiac hypertrophy and fibrosis induced by overloaded pressure, possibly by inhibiting the activity of intracardiac Ang-II and by modifying expression of Cx43. PMID- 22245912 TI - Global gene expression profiles in developing soybean seeds. AB - The gene expression profiles in soybean (Glycine max L.) seeds at 4 stages of development, namely, pod, 2-mm bean, 5-mm bean, and full-size bean, were examined by DNA microarray analysis. The total genes of each sample were classified into 4 clusters based on stage of development. Gene expression was strictly controlled by seed size, which coincides with the development stage. First, stage specific gene expression was examined. Many transcription factors were expressed in pod, 2 mm bean and 5-mm bean. In contrast, storage proteins were mainly expressed in full-size bean. Next, we extracted the genes that are differentially expressed genes (DEGs) that were extracted using the Rank products method of the Bioconductor software package. These DEGs were sorted into 8 groups using the hclust function according to gene expression patterns. Three of the groups across which the expression levels progressively increased included 100 genes, while 3 groups across which the levels decreased contained 47 genes. Storage proteins, seed-maturation proteins, some protease inhibitors, and the allergen Gly m Bd 28K were classified into the former groups. Lipoxygenase (LOX) family members were present in both the groups, indicating the multi-functionality with different expression patterns. PMID- 22245913 TI - Salicylic acid is a modulator of catalase isozymes in chickpea plants infected with Fusarium oxysporum f. sp. ciceri. AB - The relationship between salicylic acid level catalases isoforms chickpea cv. ICCV-10 infected with Fusarium oxysporum f. sp. ciceri was investigated. Pathogen treated chickpea plants showed high levels of SA compared with the control. Two isoforms of catalases in shoot extract (CAT-IS and CAT-IIS) and single isoform in root extract (CAT-R) were detected in chickpea. CAT-IS and CAT-R activities were inhibited in respective extracts treated with pathogen whereas, CAT-IIS activity was not inhibited. These isoforms were purified and their kinetic properties studied in the presence or absence of SA. The molecular mass determined by SDS PAGE of CAT-IS, CAT-IIS and CAT-R was found to be 97, 40 and 66 kDa respectively. Kinetic studies indicated that Km and V(max) of CAT-IS were 0.2 mM and 300 U/mg, 0.53 mM and 180 U/mg for CAT-IIS and 0.25 mM and 280 U/mg for CAT-R, respectively. CAT-IS and CAT-R were found to be more sensitive to SA and 50% of their activities were inhibited at 6 and 4 MUM respectively, whereas CAT-IIS was insensitive to SA up to 100 MUM. Quenching of the intrinsic tryptophan fluorescence of purified catalases were used to quantitate SA binding; the estimated K(d) value for CAT-IS, CAT-IIS and CAT-R found to be 2.3 MUM, 3.1 mM and 2.8 MUM respectively. SA is a modulator of catalase isozymes activity, supports its role in establishment of SAR in chickpea plants infected with the pathogen. PMID- 22245914 TI - Current trends in heparin use during arterial vascular interventional radiology. AB - PURPOSE: This study was designed to assess the current use of heparinized saline and bolus doses of heparin in non-neurological interventional radiology and to determine whether consensus could be reached to produce guidance for heparin use during arterial vascular intervention. METHODS: An interactive electronic questionnaire was distributed to members of the British Society of Interventional Radiology regarding their current practice in the use, dosage, and timing of heparin boluses and heparinized flushing solutions. RESULTS: A total of 108 completed questionnaires were received. More than 80% of respondents used heparinized saline with varying concentrations; the most prevalent was 1,000 IU/l (international units of heparin per liter) and 5,000 IU/l. Fifty-one percent of interventionalists use 3,000 IU as their standard bolus dose; however, the respondents were split regarding the timing of bolus dose with ~60% administering it after arterial access is obtained and 40% after crossing the lesion. There was no consensus on altering dose according to body weight, and only 4% monitored clotting parameters. CONCLUSIONS: There seems to be some coherence among practicing interventionalists regarding heparin administration. We hypothesize that heparinized saline should be used at a recognized standard concentration of 1,000 IU/l as a flushing concentration in all arterial vascular interventions and that 3,000 IU bolus is considered the standard dose for straightforward therapeutic procedures and 5000 IU for complex, crural, and endovascular aneurysm repair work. The bolus should be given after arterial access is obtained to allow time for optimal anticoagulation to be achieved by the time of active intervention and stenting. Further research into clotting abnormalities following such interventional procedures would be an interesting quantifiable follow-up to this initial survey of opinions and practice. PMID- 22245915 TI - Real-time observations on crystallization of gold nanorods into spiral or lamellar superlattices. AB - Real-time observations on gold nanorods evolving into spiral or lamellar superlattices are demonstrated. 2D critical nuclei and screw dislocations initiate the crystallization process. Kinetics of the superlattice growth is determined to be similar to that of classical crystal growth, where three basic modes are involved: spiral, layer-by-layer and dendritic. PMID- 22245916 TI - Clinical significance of miR-155 expression in breast cancer and effects of miR 155 ASO on cell viability and apoptosis. AB - Accumulating evidence shows that mircroRNAs (miRNAs) play a vital role in tumorigenesis. miR-155 is one of the most multifunctional miRNAs whose overexpression has been found to be associated with different types of cancer including breast cancer. To further determine the potential involvement of miR 155 in breast cancer, we evaluated the expression levels of miR-155 by real-time PCR and correlated the results with clinicopathological features. Matched non tumor and tumor tissues of 42 infiltrating ductal carcinomas and 3 infiltrating lobular carcinomas were analyzed for miR-155 expression by real-time PCR. Further, we used an antisense technique to inhibit miR-155 expression in vitro. WST-8 test was performed to evaluate cell viability and apoptosis assay was used to investigate the effect of the miR-155 antisense oligonucleotide (miR-155 ASO) on HS578T cell death. The expression levels of miR-155 were significantly higher in tumor tissues than the levels in matched non-tumor tissues (P<0.001). Up regulated miR-155 expression was associated with lymph node positivity (P=0.034), higher proliferation index (Ki-67 >10%) (P=0.019) and advanced breast cancer TNM clinical stage (P=0.002). Interestingly, we next found that miR-155 expression levels had close relations with ER status (P=0.041) and PR status (P=0.029). Transfection efficiency detected by flow cytometry was higher than 70%, the WST-8 test showed that viability of HS578T cells was greatly reduced after transfection with miR-155 ASO compared with the scramble (SCR) group or the liposome group. The Annexin V-FITC/PI assay also indicated that transfection with miR-155 ASO promoted apoptosis. PMID- 22245917 TI - Differences in metal concentration by particle size in house dust and soil. AB - The majority of particles that adhere to hands are <63 MUm in diameter yet risk assessments for soil remediation are typically based on soil samples sieved to <250 MUm. The objective of our study was to determine if there is a significant difference in metal concentration by particle size in both house dust and soil. We obtained indoor dust and yard soil samples from 10 houses in Tucson, Arizona. All samples were sieved to <63 MUm and 63 to <150 MUm and analyzed for 30 elements via ICP-MS following nitric acid digestion. We conducted t-tests of the log-transformed data to assess for significant differences that were adjusted with a Bonferroni correction to account for multiple comparisons. In house dust, significant differences in concentration were observed for Be, Al, and Mo between particles sizes, with a higher concentration observed in the smaller particle sizes. Significant differences were also determined for Mg, Ca, Cr, Co, Cu, Ge, Zr, Ag, Ba, and Pb concentration in yard soil samples, with the higher concentration observed in the smaller particles size for each element. The results of this exploratory study indicate that current risk assessment practices for soil remediation may under estimate non-dietary ingestion exposure. This is of particular concern for young children who are more vulnerable to this exposure route due to their high hand mouthing frequencies. Additional studies with a greater number of samples and wider geographic distribution with different climates and soil types should be completed to determine the most relevant sampling practices for risk assessment. PMID- 22245918 TI - Sound localization in noise by gerbils and humans. AB - Detection and localization of a target sound in the presence of concurrent, spatially distributed masking sounds is one of the most challenging tasks for the mammalian auditory system. Previous studies demonstrated that the ability to localize signals is decreased by interfering noise. In order to directly compare the behavioral performance in a signal processing task in noise between gerbils and humans in the free sound field, we quantified their localization ability for a low-frequency signal in the presence of six masking noise sources surrounding the subject. Thresholds were measured both for masking noises that were correlated or uncorrelated across the masking sources. Overall, the gerbils required a higher signal/noise ratio to detect the low-frequency signal than the humans; that is, the behavioral performance of the gerbils was considerably worse than that of the humans. Moreover, switching from maskers that were uncorrelated across the masking sources to correlated maskers resulted in more masking in gerbils but in a release from masking in humans. These results would suggest that the gerbil may not be a good animal model for binaural processing. However, simulations of the localization thresholds in a numerical model of binaural processing in gerbils and humans reveal that both the inferior overall performance in gerbils and the opposite effect of masker correlation on the detection thresholds can be attributed to the smaller head size and the wider peripheral auditory filters in gerbils. Thus, the current data indicate that the binaural processor itself (i.e., the evaluation of signals coming from the two ears) is equally sensitive in gerbils and humans. However, the physical limitations imposed by the small head prevent the gerbil from performing equally well in the current paradigm. PMID- 22245919 TI - The Danish national return-to-work program--aims, content, and design of the process and effect evaluation. AB - The Danish national return-to-work (RTW) program aims to improve the management of municipal sickness benefit in Denmark. A study is currently ongoing to evaluate the RTW program. The purpose of this article is to describe the study protocol. The program includes 21 municipalities encompassing approximately 19 500 working-age adults on long-term sickness absence, regardless of reason for sickness absence or employment status. It consists of three core elements: (i) establishment of multidisciplinary RTW teams, (ii) introduction of standardized workability assessments and sickness absence management procedures, and (iii) a comprehensive training course for the RTW teams. The effect evaluation is based on a parallel group randomized trial and a stratified cluster controlled trial and focuses on register-based primary outcomes - duration of sickness absence and RTW - and questionnaire-based secondary outcomes such as health and workability. The process evaluation utilizes questionnaires, interviews, and municipal data. The effect evaluation tests whether participants in the intervention have a (i) shorter duration of full-time sickness absence, (ii) longer time until recurrent long-term sickness absence, (iii) faster full RTW, (iv) more positive development in health, workability, pain, and sleep; it also tests whether the program is cost-effective. The process evaluation investigates: (i) whether the expected target population is reached; (ii) if the program is implemented as intended; (iii) how the beneficiaries, the RTW teams, and the external stakeholders experience the program; and (iv) whether contextual factors influenced the implementation. The program has the potential to contribute markedly to lowering human and economic costs and increasing labor force supply. First results will be available in 2013. The trial registrations are ISRCTN43004323, and ISRCTN51445682. PMID- 22245920 TI - Identification and validation of sex-linked SCAR markers in dioecious Hippophae rhamnoides L. (Elaeagnaceae). AB - The actinorhizal plant seabuckthorn (Hippophae rhamnoides L., Elaeagnaceae) is a wind pollinated dioecious crop. To distinguish male genotypes from female genotypes early in the vegetative growth phase, we have developed robust PCR based marker(s). DNA bulk samples from 20 male and 20 female plants each were screened with 60 RAPD primers. Two primers, OPA-04 and OPT-06 consistently amplified female-specific (FS) polymorphic fragments of 1,164 and 868 bp, respectively, that were absent in the male samples. DNA sequence of the two markers did not exhibit significant similarity to previously characterized sequences. A sequence-characterized amplified region marker HrX1 (JQ284019) and HrX2 (JQ284020) designed for the two fragments, continued to amplify the FS allele in 120 female plants but not in 100 male plants tested in the current study. Thus, HrX1 and HrX2 are FS markers that can determine the sex of seabuckthorn plants in an early stage and expedite cultivations for industrial applications. PMID- 22245921 TI - Neonatal resuscitation: in pursuit of evidence gaps in knowledge. AB - Guidelines for the techniques of resuscitating newly born infants have undergone major revisions over the past 25 years. The International Liaison Committee on Resuscitation (ILCOR) is committed to "periodically developing and publishing a consensus on resuscitation science" every five years with the most recent Consensus on Science and Treatment Recommendations (CoSTR) statement published in 2010. The CoSTR document is used as a basis for developing specific resuscitation guidelines felt to be appropriate for implementation in respective countries. A "gaps in knowledge" summary is created at the conclusion of a cycle. It is a goal that identification of these knowledge gaps will stimulate investigators to pursue more targeted studies to help close the gaps. The current document is based on the "gaps in knowledge" summary for neonatal resuscitation that was created at the conclusion of the 2005-2010 ILCOR cycle. PMID- 22245922 TI - Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study. AB - Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT. PMID- 22245923 TI - Highly efficient SO2 capture by dual functionalized ionic liquids through a combination of chemical and physical absorption. AB - Two kinds of dual functionalized ionic liquids with ether-functionalized cations and tetrazolate anions were designed, prepared, and used for SO(2) capture, which exhibit an extremely high SO(2) capacity and excellent reversibility through a combination of chemical and physical absorption. PMID- 22245924 TI - Lymph node metastasis from cancer of the esophagogastric junction, and determination of the appropriate nodal dissection. AB - PURPOSE: Both squamous cell carcinomas and adenocarcinomas can develop in the esophagogastric junction. To clarify the appropriate lymph node dissection range, lymph node metastases from cancers in the esophagogastric junction were investigated. METHODS: The nodal metastases were analyzed in 64 patients with squamous cell carcinoma and 129 with adenocarcinoma according to Siewert's classification, which is based on topographic anatomical criteria for adenocarcinoma. RESULTS: The squamous cell carcinomas located above the esophagocardial junction had more frequent metastasis to the lower and middle mediastinal lymph nodes in proportion to the depth of the tumor. Nodal metastasis was also often detected in the abdominal lymph nodes. In contrast, adenocarcinomas metastasized less frequently to the mediastinal lymph nodes, and the metastatic rates in the abdominal nodes were higher than those from squamous cell carcinoma. CONCLUSION: Esophagectomy with mediastinal and abdominal lymph node dissection is considered to be an appropriate approach for surgical resection of squamous cell carcinomas, whereas transhiatally extended gastrectomy with lower mediastinal and abdominal lymph node dissection is recommended for the treatment of adenocarcinomas. PMID- 22245926 TI - HIV: Tagged for destruction. PMID- 22245928 TI - Marine microbiology: SAR86: streamlined for success. PMID- 22245925 TI - The long-term outcomes of patients with hepatocellular carcinoma after living donor liver transplantation: a comparison of right and left lobe grafts. AB - PURPOSE: The feasibility of living donor liver transplantation (LDLT) using left lobe (LL) grafts has been demonstrated. However, the long-term outcome of the hepatocellular carcinoma (HCC) patients with LL grafts has not been elucidated. The aim of this study was to analyze the long-term outcomes after LDLT for HCC according to the graft type. METHODS: A retrospective analysis was performed evaluating the outcomes of LL graft recipients (n = 82) versus recipients of RL grafts (n = 46). The analysis endpoints were the overall and recurrence-free survival after LDLT. The demographics of both recipients and donors, and the tumor characteristics associated with the graft type were also analyzed. RESULTS: The graft volume (436 +/- 74 g), as well as the graft volume-standard liver volume rate (38.3 +/- 6.2%) of the LL graft group were significantly decreased as compared to those of the RL graft group (569 +/- 82 g, 46.3 +/- 6.7%; p < 0.01). The 1-, 3-, 5- and 7-year overall survival rates of the LL graft group were 88.2, 80.2, 75.7 and 72.4%, respectively, which were not significantly different compared to those of the RL graft group (95.4, 87.3, 87.3 and 87.3%). The recurrence-free survival rates of the LL graft group (89.1% at 1 year, 78.8% at 3 years, 75.8% at 5 years and 70.3% at 7 years) were similar to those of the RL graft group (88.6, 88.6, 88.6 and 88.6%). The mean peak postoperative total bilirubin levels and duration of hospital stay after surgery for the LL grafting donors were significantly decreased as compared to those of the RL grafting donors (p < 0.01). The rate of severe complications (over Clavien's IIIa) associated with LL graft procurement was 6.2%, which was lower than that in the RL graft group (15.6%). CONCLUSIONS: The long-term outcomes in the HCC patients with LL grafts were similar to those of patients receiving RL grafts, and the outcomes of the donors of LL grafts were more favorable. Therefore, LL grafts should be considered when selecting LDLT for HCC to ensure donor safety. PMID- 22245931 TI - Bacterial development: Racing to decide. PMID- 22245932 TI - Bacterial physiology: Environment shapes magnetic personality. PMID- 22245933 TI - Sequencing parasite populations. PMID- 22245934 TI - Behavior disorders in extremely preterm/extremely low birth weight children in kindergarten. AB - OBJECTIVE: To examine the prevalence of behavior disorders in a 2001-2003 birth cohort of extremely preterm/extremely low birth weight (EPT/ELBW, <28 weeks gestational age or <1000 g) children in kindergarten. METHOD: We compared 148 EPT/ELBW children with 111 term-born normal birth weight classmate controls on reports of psychiatric symptoms obtained from parent interview (Children's Interview for Psychiatric Syndromes-Parent Form [P-ChIPS]), parent and teacher ratings of behavior (Child Behavior Checklist, Teacher's Report Form, and Behavior Rating Inventory of Executive Function), and teacher ratings of social functioning (School Social Behavior Scales, second edition). Associations of behavior disorders with global cognitive ability and tests of executive function were also examined within the EPT/ELBW group. RESULTS: Rates of attention deficit/hyperactivity disorder combined on psychiatric interview were about twice as high for the EPT/ELBW group than for the normal birth weight group, odds ratio (95% confidence interval) = 2.50 (1.34, 4.68), p = .004. The EPT/ELBW group also had much higher rates of teacher-identified disorders in attention, behavior self regulation, and social functioning, with odds ratios (95% confidence intervals) ranging from 3.35 (1.64, 6.83) to 18.03 (4.12, 78.94), all p values <.01. Attention-deficit/hyperactivity disorder and impaired behavior self-regulation were associated with deficits on tests of executive function but not with global cognitive impairment. CONCLUSIONS: The findings document increased rates of disorders in attention, behavior self-regulation, and socialization in EPT/ELBW children and suggest that deficits on tests of executive function are associated with some of these disorders. Early identification and intervention for these disorders are needed to promote early adjustment to school and facilitate learning progress. PMID- 22245935 TI - Downregulation of Id1 by small interfering RNA in gastric cancer inhibits cell growth via the Akt pathway. AB - Inhibitor of differentiation or DNA binding (Id1) is a member of the helix-loop helix transcription factor family that is overexpressed in various types of cancer, including gastric carcinoma. Previous studies showed that Id1 is a prognostic marker in patients with gastric cancer. However, the role of Id1 in the proliferation of human gastric cancer cells has yet to be clarified. In the present study, we downregulated the Id1 gene in SGC-7901 gastric cancer cells by RNA interference, and we also constructed a recombinant plasmid-expressing Id1 to investigate its effects on the proliferation of SGC-7901 cells. Results showed that the downregulation of Id1 inhibited proliferation of SGC-7901 cells, while the upregulation of Id1 had no effect on SGC-7901 cell proliferation. The potential mechanism was also investigated. The changes of certain proteins associated with cell proliferation, apoptosis and the cell cycle were detected by western blotting. Furthermore, we demonstrated a positive correlation between Id1 and phospho-Akt expression in SGC-7901 cells. PMID- 22245936 TI - Generation of (nonafluoro-tert-butoxy)methyl ponytails for enhanced fluorous partition of aromatics and heterocycles. AB - The reaction of sodium perfluoro-tert-butoxide with benzylic carbon-bromide bond(s) leads to the formation of (nonafluoro-tert-butoxy)methyl ponytail(s), which can enhance the fluorous solubility and partition of aromatics and heterocycles. PMID- 22245937 TI - A biomonitor as a measure of an ecologically-significant fraction of metals in an industrialized harbour. AB - Biomonitors are commonly used to assess levels of bioavailable contaminants in the environment, however the relationships between biomonitor tissue concentrations and ecological effects are rarely assessed. The present study investigated metal contamination within a highly industrialised harbour and ecological effects on sessile invertebrates. The native oyster Saccostrea glomerata was deployed as a biomonitor across twenty-six sites to test for correlations between metal levels in their tissues and the recruitment of hard substrate invertebrates. Concentrations of lead and copper in oyster tissues were negatively correlated with densities of the dominant barnacle, Amphibalanus variegatus, and positively correlated with densities of the dominant polychaete, Hydroides elegans, and the two native encrusting bryozoans Celloporaria nodulosa and Arachnopusia unicornis. Results suggest that highly localised events drive contaminant availability and that these events pose a significant risk to fauna. Biomonitoring studies may be enhanced by running concurrent ecological surveys. PMID- 22245938 TI - Camptothecin nanocolloids based on N,N,N-trimethyl chitosan: efficient suppression of growth of multiple myeloma in a murine model. AB - Camptothecin (CPT) exhibits very strong antitumor effects by inhibiting the activity of DNA topoisomerase I, but its application is greatly limited due to its low solubility and the instability of the active lactone form. To overcome these shortcomings, in the present study, we prepared novel camptothecin nanocolloids based on N,N,N-trimethyl chitosan (CPT-TMC) to efficiently and safely administer CPT systemically. Herein, we investigated the antitumor activity of CPT-TMC against a murine Balb/c myeloma model. Our results showed that CPT-TMC more effectively inhibited tumor growth and prolonged survival time than CPT in vivo, but no statistical difference was observed in vitro between CPT TMC and CPT. These findings suggest that N,N,N-trimethyl chitosan could increase the stability and the antitumor effect of CPT and CPT-TMC is a potential approach for the effective treatment of multiple myeloma. PMID- 22245940 TI - Pigment analyses of a portrait and paint box of Turkish artist Feyhaman Duran (1886-1970): the EDXRF, FT-IR and micro Raman spectroscopic studies. AB - The samples obtained from nine different places of Ataturk portrait (oil on canvas, 86 cm*136 cm) by Feyhaman Duran (1886-1970), one of the famous Turkish painters of the 20th century, together with five pigment samples (two different white, two different yellow and blue), obtained as powders from artist's paint box, were analysed by EDXRF, FT-IR and micro-Raman spectroscopic methods, in order to characterise the pigments used by the artist. Informative Raman signals were not obtained from most of the samples of the portrait, due to huge fluorescence caused by the presence of impurities and organic materials in the samples, however the Raman spectrum of the sample from skin coloured part of the portrait and the pigment samples obtained from the paint box of the artist were found to be very informative to shed light on the determination of the pigments used. Analysis revealed the presences of chrome yellow (PbCrO4), strontium yellow (SrCrO4) and Cadmium yellow (CdS) as yellow, chromium oxides (Cr2O3 and Cr2O3.2H2O) as green, natural red ochre as red, brown ochre as brown and ivory black or bone black (C+Ca3(PO4)2) and manganese oxides (Mn2O3 and MnO2) as black pigments, in the composition of the Ataturk portrait. Lead white (2PbCO3.Pb(OH)2), calcite (CaCO3), barite (BaSO4), zinc white (ZnO) and titanium white (TiO2) were used as extenders to lighten the colours and/or as for ground level painting. Powder pigment samples, obtained from the paint box of artist, were found to be mixed pigments rather than pure ones. PMID- 22245939 TI - Conformational and vibrational studies of isomeric hydrogen cyanide tetramers by quantum chemical methods. AB - The results of structural studies and detailed harmonic and anharmonic vibrational analysis on two hydrogen cyanide (HCN) tetramers diaminomaleonitrile (DAMN) and diaminofumaronitrile (DAFN), which are important molecules for understanding the chemistry of interstellar space and nitrile rich environments, are being reported on the basis of density functional theory using second-order perturbation theory. Both the molecules are found to have C1 symmetry. While all the heavy atoms of DAMN lie in the same plane (maximum deviation 6 degrees ), the two nitrogen atoms in DAFN are out of plane by about 15 degrees . The two amino groups are tetrahedral and do not have significant bond angle anisotropy. Detailed conformational studies are reported on the two molecules and their possible rotational isomers are identified. Complete vibrational analysis based on harmonic and anharmonic frequencies, intensity of infrared and activity of Raman bands and potential energy distribution over the internal coordinates has been provided for the two molecules. Affect of hydrogen bonding on molecular geometry and frequencies of the NH stretch modes has been studied by calculations on the dimers of the two molecules. A close agreement has been observed between the experimental and calculated frequencies. Vibrational-rotational constants such as rotational constants in the ground vibrational state (A0, B0, C0) and the effective rotational constants (Ae, Be and Ce), including terms due to quartic centrifugal distortion constants, rotation-vibration coupling constants, Wilson and Nielsen's centrifugal distortion constants have been calculated using B3LYP and B97-1 functionals and 6-31G**, 6-311+G** and TZVP basis sets. PMID- 22245942 TI - Isolation and structural characterisation of okara polysaccharides. AB - Okara is a byproduct generated during tofu or soymilk production processes. Crude polysaccharide (yield 56.8%) was isolated by removing fat, protein and low molecular weight carbohydrates from initial okara. Crude okara polysaccharide was further divided into four soluble fractions and an insoluble residue fraction by extracting with 0.05 M EDTA + NH(4) oxalate, 0.05 M NaOH, 1 M NaOH and 4 M NaOH, with yields of 7.7%, 3.6%, 20.7%, 16.0% and 27.9%, respectively. Arabinose, galactose, galacturonic acid, xylose and glucose (only for the insoluble fraction) were the major constituent sugars. The primary sugar residues of okara polysaccharides were 1,4-linked beta-galactopyranose, 1,5- and 1,3-linked alpha arabinofuranose, 1,5-linked alpha-xylofuranose, 1,2-linked, 1,2,4-linked and terminal alpha-rhamnopyranose (or fucopyranose), and 1,4-linked beta glucopyranose (only for the insoluble fraction), indicating okara polysaccharides might contain galactan, arabinan, arabinogalactan, xylogalacturonan, rhamnogalacturonan, xylan, xyloglucan and cellulose. PMID- 22245941 TI - Comparison of polysaccharides from two species of Ganoderma. AB - Ganoderma lucidum and Ganoderma sinense, known as Lingzhi in Chinese, are commonly used Chinese medicines with excellent beneficial health effects. Triterpenes and polysaccharides are usually considered as their main active components. However, the content of triterpenes differs significantly between the two species of Ganoderma. To date, a careful comparison of polysaccharides from the two species of Ganoderma has not been performed. In this study, polysaccharides from fruiting bodies of two species of Lingzhi collected from different regions of China were analyzed and compared based on HPSEC-ELSD and HPSEC-MALLS-RI analyses, as well as enzymatic digestion and HPTLC of acid hydrolysates. The results indicated that both the HPSEC-ELSD profiles and the molecular weights of the polysaccharides were similar. Enzymatic digestion showed that polysaccharides from all samples of Lingzhi could be hydrolyzed by pectinase and dextranase. HPTLC profiles of their TFA hydrolysates colored with different reagents and their monosaccharides composition were also similar. PMID- 22245943 TI - Anti-bacterial treatment of polyethylene by cold plasma for medical purposes. AB - Polyethylene (PE) is one of the most widely used polymers in many industrial applications. Biomedical uses seem to be attractive, with increasing interest. However, PE it prone to infections and its additional surface treatment is indispensable. An increase in resistance to infections can be achieved by treating PE surfaces with substances containing antibacterial groups such as triclosan (5-Chloro-2-(2,4-dichlorophenoxy)phenol) and chlorhexidine (1,1' Hexamethylenebis[5-(4-chlorophenyl)biguanide]). This work has examined the impact of selected antibacterial substances immobilized on low-density polyethylene (LDPE) via polyacrylic acid (PAA) grafted on LDPE by low-temperature barrier discharge plasma. This LDPE surface treatment led to inhibition of Escherichia coli and Staphylococcus aureus adhesion; the first causes intestinal disease, peritonitis, mastitis, pneumonia, septicemia, the latter is the reason for wound and urinary tract infections. PMID- 22245945 TI - Traumatic rupture of diaphragm. PMID- 22245944 TI - High anxiety is a predisposing endophenotype for loss of control over cocaine, but not heroin, self-administration in rats. AB - RATIONALE: Although high anxiety is commonly associated with drug addiction, its causal role in this disorder is unclear. OBJECTIVES: In light of strong evidence for dissociable neural mechanisms underlying heroin and cocaine addiction, the present study investigated whether high anxiety predicts the propensity of rats to lose control over intravenous cocaine or heroin self-administration. METHODS: Sixty-four rats were assessed for anxiety in the elevated plus-maze, prior to extended access to intravenous cocaine or heroin self-administration. RESULTS: High-anxious rats, identified in the lower quartile of the population, showed a greater escalation of cocaine, but not heroin, self-administration compared with low-anxious rats selected in the upper quartile of the population. Anxiety scores were also positively correlated with the extent of escalation of cocaine self administration. CONCLUSIONS: The present data suggest that high anxiety predisposes rats to lose control over cocaine-but not heroin-intake. High anxiety may therefore be a vulnerability trait for the escalation of stimulant but not opiate self-administration. PMID- 22245946 TI - A new era of antithrombotic therapy in patients with atrial fibrillation. AB - Atrial fibrillation/flutter is the most common cardiac arrhythmia that can potentially result in stroke and death. For many years, aspirin and warfarin have been the cornerstone of stroke prevention among such patients. Although warfarin therapy has been advocated for patients with high likelihood of stroke, it requires close surveillance and monitoring, has a narrow therapeutic window and is quite often affected by medication interactions and diet. Thus, the need for a better and more consistent anticoagulant therapy was necessary and has been under development with various successes for many years. This article will review 3 new antithrombotic medications that may potentially become the mainstay for treatment of patients with atrial fibrillation in the near future. PMID- 22245947 TI - Hypobaric hypoxia preconditioning attenuates experimental heatstroke syndromes via preinduction of heat shock protein 70. AB - INTRODUCTION: Heatstroke has been defined as a form of hyperthermia associated with a systemic inflammatory response that leads to multiple organ dysfunction syndrome (MODS). It has also been documented that heat shock protein 70 (HSP70) preconditioning is able to induce thermotolerance. Here, the authors further investigated whether hypobaric hypoxia preconditioning (HHP) improved the MODS in heatstroke by up-regulation of HSP70. METHODS: Anesthetized rats were randomly assigned to (a) non-HHP + nonheated group, (b) non-HHP + heated group, (c) HHP + heated group and (d) HHP + HSP70 antibodies (Abs) + heated groups. All heated groups were exposed to heat stress (43 degrees C, 70 minutes) to induce heatstroke. For HHP, animals were exposed to 0.66 atmosphere absolute (18.3% O2) for 5 hours daily for consecutive 5 days per week for 2 weeks before the start of heat exposure. RESULTS: HHP significantly (i) attenuated hypotension, (ii) reduced plasma index of the toxic oxidizing radicals and the organ injury indicator, (iii) attenuated plasma systemic inflammatory response molecules, (iv) reduced an index of infiltration of polymorphonuclear neutrophils in the lung like myeloper-oxidase activity, (v) promoted plasma levels of an anti inflammatory cytokine, interleukin-10, (vi) promoted the survival time to fourfold compared with non-HHP group and (vii) promoted the overexpression of HSP70 in different organs (eg, the lung) during heatstroke. The beneficial effects of HHP could be significantly attenuated by HSP70 Ab preconditioning. CONCLUSION: Our results show that HHP protects rats from heat-induced MODS via up regulating HSP70. Thus, HHP could be a novel strategy for the prevention of heatstroke animals or patients before heat exposure. PMID- 22245949 TI - Epigenetic biomarkers in epithelial ovarian cancer. AB - Ovarian cancer is the most lethal gynecological malignancy and the 5th leading cause of cancer death in women. Women with ovarian cancer are typically diagnosed at late stage, when the cancer has spread into the peritoneal cavity and complete surgical removal is difficult. The 5-year survival time for patients diagnosed at this stage is 30%, in contrast to a 5-year survival of 90% for patients diagnosed at early stage. Cancer screening and early detection have the potential to greatly decrease the mortality and morbidity from cancer. The emerging field of epigenetics offers a valuable opportunity to identify cancer-specific DNA methylation changes that can be used in the clinic to improve early-stage diagnosis and better predict response in treated patients. To date, numerous DNA methylation aberrations have been identified in epithelial ovarian cancer; here we review some candidate genes and pathways with potential clinical utility as biomarkers for diagnosis and/or prognosis. It has become clear that even with the great promise of DNA methylation biomarkers in epithelial ovarian cancer, the identification of highly specific, sensitive and robust panels of markers and the standardization of analysis techniques are still required in order to improve detection, treatment and thus patient outcome. PMID- 22245948 TI - Protocadherin-10 is involved in angiogenesis and methylation correlated with multiple myeloma. AB - Protocadherin-10 (PCDH10) which is located at 4q28.3, is a member of the cadherin superfamily of cell adhesion molecules. PCDH10 is broadly expressed in normal adult, but nearly undetectable in multiple myeloma (MUMU) tissues and cell lines. Its promoter methylation was detected in virtually all the silenced or downregulated cell lines. The silencing of PCDH10 could be reversed by pharmacological demethylation, indicating a methylation-mediated mechanism. In the current study, we investigated 44 patients (23 females, 21 males), 77.27% (34/44) of whom presented high methylation of PCDH10. We found no associations between promoter hypermethylation and gender or age at the time of initial diagnosis. We also examined the role of PCDH10 as a mediator of MM cell proliferation, cell cycle progression, and its involvement in angiogenesis. Our results demonstrate that the PCDH10 gene is a target for epigenetic silencing in MM and provide a link between the dysregulation of angiogenesis and DNA methylation. PMID- 22245951 TI - Progression of cervical instabilities in patients with rheumatoid arthritis 5.7 years after their first lower limb arthroplasty. AB - We reviewed 101 rheumatoid arthritis (RA) patients who had undergone their first lower limb arthroplasty between 1990 and 2002. None of the patients had received immunosuppressant or biological drugs. Preoperative and follow-up cervical spine radiographs had been performed (more than 2 years after the arthroplasty). Cervical spine instabilities were found in 62 and 82 patients, and a posterior atlantodental interval (PADI) of <14 mm was present in 20 and 22 patients in the respective radiographs. The presence of cervical spine instabilities and PADI <14 mm were correlated with a higher modified Lansbury index (LI) both preoperatively and at final follow-up. Patients with no cervical spine instability throughout the follow-up had a lower average LI. Patients with atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS) had more joint arthroplasties at final follow-up compared with other patients. The percentage of patients with single and multiple cervical instabilities increased at final follow-up. The incidence of cervical spine instabilities in RA patients requiring a lower limb arthroplasty is extremely high, with progression of these instabilities after the procedure. There is a correlation between the severity of RA activity in peripheral joints and the severity of cervical spine instabilities. PMID- 22245950 TI - Pediatric eye injuries presenting to United States emergency departments: 2001 2007. AB - BACKGROUND: The epidemiology of pediatric eye injuries is not well-documented. This study describes the characteristics of non-fatal eye injuries in pediatric patients (<18 years of age) presenting to United States (US) emergency departments (EDs). METHODS: Retrospective cohort study utilizing the National Electronic Injury Surveillance System All Injury Program (NEISS-AIP) from 2001 to 2007 to perform a descriptive analysis of eye injury case information for patients <18 years of age, including demographic variables, locales, diagnoses, causes, and hospital disposition. RESULTS: In 2001-2007, an estimated 1,048,500 (95% confidence interval [CI] 878,198-1,218,801) ED visits for eye injury occurred among children less than 18 years of age, representing a rate of 14.31 per 1,000 children. Males accounted for 61.75% (CI 541,971-752,839) of visits. The rate of eye injury was highest in the 15-17 year old age group (18.74 per 1,000 children; CI 199,224-267,132). The most common diagnosis was contusion/abrasion (53.68%; CI 468,035-657,638). The most frequent cause of eye injury was being struck by or against an object (56.63%; CI 491,760-695,758). The majority of injuries occurred at home (65.84%; CI 382,443-588,416) and took place during the spring and summer (39.26%; CI 343,535-479,888). CONCLUSION: This study suggests that the risk for pediatric eye injuries is highest for adolescents 15 17 years of age and at home. Further research is needed to determine risk and protective factors associated with injuries in this age group and location to design appropriate prevention strategies. PMID- 22245952 TI - Good response to infliximab in a patient with deep vein thrombosis associated with Behcet disease. AB - Vascular involvement is a lethal complication in Behcet disease. It is often refractory to conventional therapy such as steroids and immunosuppressants in addition to anticoagulants. We describe here successful treatment with the anti tumor necrosis factor-alpha (anti-TNF-alpha) antibody, infliximab, in a patient with Behcet disease presenting with deep vein thrombosis. A 60-year-old man with Behcet disease complained of edema and pain in the lower extremities. Computed tomography revealed a thrombosis extending from the popliteal vein to the inferior vena cava at the level of the renal vein and which recurred despite combination therapy of steroid and immunosuppressants such as cyclosporine, azathioprine, and methotrexate. The patient was then administered infliximab (5 mg/kg) in weeks 0 and 2 and every 4 weeks thereafter. Clinical and laboratory findings improved after the infliximab therapy. Computed tomography of the abdomen and lower extremities showed a reduction of the thrombosis. No severe adverse events occurred during the clinical course. Although further studies are needed to confirm the efficacy and safety of its use, anti-TNF-alpha antibody may be worth considering as treatment for refractory venous thrombosis in patients with Behcet disease. PMID- 22245954 TI - The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients. AB - PURPOSE: The prodrug cyclophosphamide is metabolized by cytochrome P450(CYP)2B6 to the active metabolite, 4-hydroxycyclophosphamide (4-OH), and by CYP3A4/5 to toxic chloracetaldehyde and 2-dechloroethylcyclophosphamide (DCE). Since aprepitant is a moderate inhibitor of CYP3A4, the study was designed to determine whether its concurrent use alters the pharmacokinetics (PK) of cyclophosphamide. In addition, we sought to determine the effect of race and pharmacogenomics on cyclophosphamide PK. METHODS: Eighteen patients with localized breast cancer were randomized in this double-blinded cross-over study to receive aprepitant or placebo in addition to cyclophosphamide 600 mg/m(2) and doxorubicin 60 mg/m(2). Blood samples were collected for both PK analysis of cyclophosphamide and metabolites and pharmacogenomic analysis. Single nucleotide polymorphisms genotyped were CYP3A4*1B, CYP3A5*3, and CYP2B6*6. RESULTS: The geometric mean area under concentration-time curve (AUC(0-t) MUg/mL h) for cyclophosphamide was 282 following aprepitant and 230 following placebo (ratio 1.23; 90% CI 1.13, 1.33). 4-OH AUC(0-t) (MUg/mL h) was 6.80 following aprepitant and 6.96 following placebo (ratio 0.98; 90% CI 0.88, 1.08). DCE AUC(0-t) (MUg/mL h) was 6.76 following aprepitant and 9.37 following placebo (ratio 0.72; 90% CI 0.64, 0.81). Genotype analysis was confounded by race. Race was a significant predictor of DCE lnAUC(0-t) (P = 0.0169) as African Americans had approximately a 2-fold higher DCE AUC than Caucasians. CONCLUSIONS: Aprepitant altered the exposure of cyclophosphamide and DCE but not the active 4-OH metabolite, making it unlikely that aprepitant would change the clinical efficacy of cyclophosphamide. African Americans were also found to have altered PK compared with Caucasian patients. PMID- 22245953 TI - A three-dimensional microfluidic approach to scaling up microencapsulation of cells. AB - Current applications of the microencapsulation technique include the use of encapsulated islet cells to treat Type 1 diabetes, and encapsulated hepatocytes for providing temporary but adequate metabolic support to allow spontaneous liver regeneration, or as a bridge to liver transplantation for patients with chronic liver disease. Also, microcapsules can be used for controlled delivery of therapeutic drugs. The two most widely used devices for microencapsulation are the air-syringe pump droplet generator and the electrostatic bead generator, each of which is fitted with a single needle through which droplets of cells suspended in alginate solution are produced and cross-linked into microbeads. A major drawback in the design of these instruments is that they are incapable of producing sufficient numbers of microcapsules in a short-time period to permit mass production of encapsulated and viable cells for transplantation in large animals and humans. We present in this paper a microfluidic approach to scaling up cell and protein encapsulations. The microfluidic chip consists of a 3D air supply and multi-nozzle outlet for microcapsule generation. It has one alginate inlet and one compressed air intlet. The outlet has 8 nozzles, each having 380 micrometers inner diameter, which produce hydrogel microspheres ranging from 500 to 700 MUm in diameter. These nozzles are concentrically surrounded by air nozzles with 2 mm inner diameter. There are two tubes connected at the top to allow the air to escape as the alginate solution fills up the chamber. A variable flow pump 115 V is used to pump alginate solution and Tygon(r) tubing is used to connect in-house air supply to the air channel and peristaltic/syringe pump to the alginate chamber. A pressure regulator is used to control the flow rate of air. We have encapsulated islets and proteins with this high throughput device, which is expected to improve product quality control in microencapsulation of cells, and hence the outcome of their transplantation. PMID- 22245955 TI - Steroid receptor coactivator-3 differentially regulates the inflammatory response in peritoneal macrophages. AB - Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator that plays an important role in the regulation of cytokine mRNA translation. In the present study, SCR-3 gene knockout mice were used to study the effects of SCR-3 on the regulation of the inflammatory response in peritoneal macrophages induced by lipopolysaccharides (LPS). Peritoneal macrophages (PMs) of SRC-3-/- mice showed a decrease in the release of TNF-alpha, IL-1beta and IL-6, and an increase in the release of IL-10. Furthermore, results of RT-PCR also showed that levels of TNF-alpha, IL-1beta and IL-6 mRNA expression were significantly lower, while the level of IL-10 mRNA expression was higher in the SRC-3-/- mice, compared to those of wild-type mice, following treatment with LPS (p < 0.01). In addition, western blotting revealed that: i) the extent of reduction of the glucocorticoid receptor in PMs from SRC-3-/- mice was significantly lower than that in wild-type mice (p < 0.01); ii) the extent of increase of AP-1 in PMS from SRC-3-/- mice was significantly lower than that in wild-type mice (p < 0.01); iii) the extent of increase of NF-kappaB p65 in PMs from SRC-3-/- mice was significantly higher than that in wild-type mice (p < 0.01). Collectively, our studies revealed that SRC-3 may play a key role in the maintenance of innate immunity. Furthermore, absence of the SRC-3 protein may result in the partial loss of inflammation and phagocytosis barrier function, including suppression of LPS-induced transcriptional activity, release of TNF-alpha, IL-1beta and IL-6, and obstruction of the function of phagocytes and elimination of bacteria, as well as their production. PMID- 22245956 TI - GCMC investigation into adamantane-based aromatic frameworks with diamond-like structure as high-capacity hydrogen storage materials. AB - A new class of 3D adamantane-based aromatic framework (AAF) with diamond-like structure was computationally designed with the aid of density functional theory (DFT) calculation and molecular mechanics (MM) methods. The hydrogen storage capacities of these AAFs were studied by the method of grand canonical Monte Carlo (GCMC) simulations. The calculated pore sizes of three AAFs reveal that AAF 1 and AAF-2 belong to microporous materials, while AAF-3 is a member of mesoporous materials. The GCMC results reveal that at 77 K and 100 bar, AAF-3 exhibits the highest gravimetric hydrogen uptake of 29.50 wt%, while AAF-1 shows the highest volumetric hydrogen uptake of 63.04 g L(-1). In particular, the gravimetric hydrogen uptake of AAF-3 reaches the Department of Energy's target of 6 wt% at room temperature. The extraordinary performances of these new AAFs in hydrogen storage have made them enter the list of top hydrogen storage materials up to now. PMID- 22245957 TI - Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide. AB - OBJECTIVE AND DESIGN: To examine the effects of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2-inhibitor, JTP-74057, on inflammatory arthritis development, and compare its anti-arthritic effect with leflunomide. MATERIALS: Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models. TREATMENT: JTP-74057 was tested between 0.1-100 nM in in-vitro studies. JTP-74057 (0.01-0.3 mg/kg) and leflunomide (2-10 mg/kg) were administered orally in vivo. METHODS: PBMCs were stimulated with lipopolysaccharide. Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) was induced in Lewis rats or DBA1/J mice, respectively. RESULTS: JTP-74057 blocked tumor necrosis factor-alpha and interleukin-6 production from PBMCs. AIA and CIA development were suppressed almost completely by 0.1 mg/kg of JTP-74057 or 10 mg/kg of leflunomide. In the CIA, JTP-74057, but not leflunomide, suppressed collagen reactive T-cell proliferation ex vivo, whereas leflunomide, but not JTP-74057, suppressed anti-collagen antibody production. CONCLUSIONS: JTP-74057 exerts potent anti-arthritic effects with a different profile from leflunomide, suggesting that JTP-74057 may be useful as a new therapeutic reagent in the treatment of rheumatoid arthritis. PMID- 22245959 TI - Polyoxometalate-based inorganic-organic hybrid film structure with reversible electroswitchable fluorescence property. AB - A novel inorganic-organic hybrid film structure based on polyoxometalate and conventional organic dye has been fabricated, whose fluorescence can be reversibly switched using the electrochromic component to activate or suppress the related fluorescence quenching mechanism upon applying reduction or oxidation potentials of polyoxometalates. PMID- 22245958 TI - Diagnostic reproducibility of hydatidiform moles: ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis. AB - Distinction of hydatidiform moles (HMs) from nonmolar specimens (NMs) and subclassification of HMs as complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) are important for clinical practice and investigational studies; yet, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, and 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunostaining and genotyping. Cases were classified by 3 gynecologic pathologists on the basis of H&E slides (masked to p57 immunostaining and genotyping results) into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists) were determined. Genotyping results were used as the gold standard for assessing diagnostic performance. Sensitivity of a diagnosis of CHM ranged from 59% to 100% for individual pathologists and from 70% to 81% by consensus; specificity ranged from 91% to 96% for individuals and from 94% to 98% by consensus. Sensitivity of a diagnosis of PHM ranged from 56% to 93% for individual pathologists and from 70% to 78% by consensus; specificity ranged from 58% to 92% for individuals and from 74% to 85% by consensus. The percentage of correct classification of all cases by morphology ranged from 55% to 75% for individual pathologists and from 70% to 75% by consensus. The kappa values for interobserver agreement ranged from 0.59 to 0.73 (moderate to good) for a diagnosis of CHM, from 0.15 to 0.43 (poor to moderate) for PHM, and from 0.13 to 0.42 (poor to moderate) for NM. The kappa values for intraobserver agreement ranged from 0.44 to 0.67 (moderate to good). Addition of the p57 immunostain improved sensitivity of a diagnosis of CHM to a range of 93% to 96% for individual pathologists and 96% by consensus; specificity was improved from a range of 96% to 98% for individual pathologists and 96% by consensus; there was no substantial impact on diagnosis of PHMs and NMs. Interobserver agreement for interpretation of the p57 immunostain was 0.96 (almost perfect). Even with morphologic assessment by gynecologic pathologists and p57 immunohistochemistry, 20% to 30% of cases will be misclassified, and, in particular, distinction of PHMs and NMs will remain problematic. PMID- 22245960 TI - Rapid, sensitive, and multiplexed on-chip optical sensors for micro-gas chromatography. AB - We developed and characterized a rapid, sensitive and integrated optical vapor sensor array for micro-gas chromatography (MUGC) applications. The sensor is based on the Fabry-Perot (FP) interferometer formed by a micrometre-thin vapor sensitive polymer layer coated on a silicon wafer. The thickness and the refractive index of the polymer vary in response to the vapor analyte, resulting in a change in the reflected intensity of the laser impinged on the sensor. In our study, four different polymers were coated on four wells pre-etched on a silicon wafer to form a spatially separated sensor array. A CMOS imager was employed to simultaneously monitor the polymers' response, thus enabling multiplexed detection of a vapor analyte passing through the GC column. A sub second detection time was demonstrated. In addition, a sub-picogram detection limit was achieved, representing orders of magnitude improvement over the on-chip vapor sensors previously reported. PMID- 22245961 TI - Progressive primary sclerosing cholangitis requiring liver transplantation is associated with reduced need for colectomy in patients with ulcerative colitis. AB - BACKGROUND & AIMS: We investigated the association between the severity of primary sclerosing cholangitis (PSC) and clinical outcomes of patients with ulcerative colitis (UC) on the basis of need for colectomy. METHODS: We analyzed data from 167 patients with PSC and UC who were followed from 1985 to 2011. Patients with PSC and UC were divided into groups that received orthotopic liver transplantation (OLT) (n = 86) or did not (non-OLT, n = 81). Clinical and demographic variables were obtained, and patients were followed until they received OLT or the date of their last clinical visit. RESULTS: The OLT group had significantly more subjects with less severe symptoms of UC (59, 68.6%) than the non-OLT group (12, 14.8%; P < .001). The subjects in the OLT group had a median of 0 UC flares compared with 3 in the non-OLT group (P < .001); fewer subjects in the OLT group required use of azathioprine or mercaptopurine (1, 1.2%), compared with the non-OLT group (14, 17.3%; P = .006). More subjects in the non-OLT group required colectomies (61, 75.3%) than in the OLT group (23, 26.7%; P < .001). On the basis of Cox regression analysis, OLT for PSC independently reduces the need for colectomy (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.25-0.75; P = .003), as does a high Mayo risk score at diagnosis (HR, 0.52; 95% CI, 0.37 0.72; P < .001). Development of colon neoplasia increased the risk for colectomy (HR, 2.47; 95% CI, 1.63-3.75; P < .001). CONCLUSIONS: Severe progressive PSC that requires liver transplantation appears to reduce the disease activity of UC and the need for colectomy. PMID- 22245962 TI - Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs) have common metabolic risk factors. Despite reports from clinical studies, the association between NAFLD, cardiovascular disease, and cardiovascular mortality are not clear at the population level. METHODS: We analyzed data from the National Health and Nutrition Examination Survey III, conducted from 1988 to 1994, and compared hepatic ultrasound and mortality data. Participants were classified into those with NAFLD (moderate or severe hepatic steatosis, based on ultrasound analysis, without any evidence of other liver disease; n = 2492) and those without (absence of NAFLD or any other chronic liver diseases: controls). The prevalence of CVD was compared between subjects with and without NAFLD. Additional comparisons were made between NAFLD patients who had increased levels of liver enzymes and those who had normal levels. Independent predictors of CVD and cardiovascular mortality also were studied. RESULTS: During the follow-up period (median, 171 mo), 12.21% of the National Health and Nutrition Examination Survey III participants died; cardiovascular mortality was 3.76%. Regardless of whether levels of liver enzymes were increased or not, individuals with NAFLD were older, predominantly male, more likely to be Hispanic, and less likely to be African American than controls. They also had a higher prevalence of all components of metabolic syndrome and CVD. Regardless of levels of liver enzymes, NAFLD was associated independently with CVD, after adjusting for major demographic, clinical, and metabolic confounders (odds ratio, 1.23; 95% confidence interval, 1.04-1.44). The independent association of NAFLD with cardiovascular mortality was not statistically significant. CONCLUSIONS: NAFLD is associated independently with an increased risk of CVD. However, NAFLD did not increase cardiovascular mortality over a 14-year period. PMID- 22245963 TI - Erosive reflux disease increases risk for esophageal adenocarcinoma, compared with nonerosive reflux. AB - BACKGROUND & AIMS: Gastroesophageal reflux disease is a strong risk factor for esophageal adenocarcinoma, but it is not clear whether the mucosal inflammation that develops in patients with reflux disease promotes this cancer. We determined the development of adenocarcinoma among patients who underwent esophagogastroduodenoscopy and were found to have erosive (with esophagitis) or nonerosive (without esophagitis) reflux. METHODS: We performed a nationwide cohort study using data from 33,849 patients with reflux disease (52% men; median age, 59.3 y) from population-based Danish medical registries, from 1996 through 2008. The observed incidences of adenocarcinoma were compared with the expected incidence for the general population, standardized by age, sex, and calendar time. Absolute risks were estimated using Kaplan-Meier methods. RESULTS: In the study cohort, 26,194 of the patients (77%) had erosive reflux disease and 37 subsequently developed esophageal adenocarcinoma after a mean follow-up time of 7.4 years. Their absolute risk after 10 years was 0.24% (95% confidence interval [CI], 0.15%-0.32%). The incidence of cancer among patients with erosive reflux disease was significantly greater than that expected for the general population (standardized incidence ratio, 2.2; 95% CI, 1.6-3.0). In contrast, of the 7655 patients with nonerosive reflux disease, only 1 was diagnosed with esophageal adenocarcinoma after 4.5 years of follow-up evaluation (standardized incidence ratio, 0.3; 95% CI, 0.01-1.5). CONCLUSIONS: Erosive reflux disease, but not nonerosive disease, increased the risk of esophageal adenocarcinoma, based on analysis of population-based Danish medical registries. Inflammation therefore might be an important factor in the progression from reflux to esophageal adenocarcinoma. PMID- 22245964 TI - Endoscopic therapy is effective for patients with chronic pancreatitis. AB - BACKGROUND & AIMS: Endoscopic therapy (ET) frequently is used to treat patients with painful chronic pancreatitis (CP), but little is known about outcomes of patients for whom ET was not successful who then underwent surgery, or outcomes after ET compared with only medical treatment. We evaluated use and long-term effectiveness of ET in a well-defined cohort of patients with CP. METHODS: We analyzed data from 146 patients with CP who participated in the North American Pancreatitis Study 2 at the University of Pittsburgh Medical Center from 2000 to 2006; 71 (49%) patients received ET at the University of Pittsburgh Medical Center. Success of ET and surgery were defined by cessation of narcotic therapy and resolution of episodes of acute pancreatitis. Disease progression was followed up from its onset until January 1, 2011 (mean, 8.2 +/- 4.7 y). RESULTS: Patients who underwent ET had more symptoms (pain, recurrent pancreatitis) and had more complex pancreatic morphology (based on imaging) than patients who received medical therapy. ET had a high rate of technical success (60 of 71 cases; 85%); its rates of clinical success were 51% for 28 of 55 patients for whom follow-up data were available (mean time, 4.8 +/- 3.0 y) and 50% for 12 of 24 patients who underwent surgery after receiving ET. Patients who responded to ET were significantly older, had a shorter duration of disease before ET, had less constant pain, and required fewer daily narcotics than patients who did not respond to ET. Among the 36 symptomatic patients who received medical therapy and were followed up for a mean period of 5.7 +/- 4.1 years, 31% improved and 53% had no change in symptoms; of these, 21% underwent surgery. CONCLUSIONS: ET is clinically successful for 50% of patients with symptomatic CP. When ET is not successful, surgery has successful outcomes in 50% of patients. Symptoms resolve in 31% of symptomatic patients who receive only medical therapy. PMID- 22245965 TI - Structures of LeuT in bicelles define conformation and substrate binding in a membrane-like context. AB - Neurotransmitter sodium symporters (NSSs) catalyze the uptake of neurotransmitters into cells, terminating neurotransmission at chemical synapses. Consistent with the role of NSSs in the central nervous system, they are implicated in multiple diseases and disorders. LeuT, from Aquifex aeolicus, is a prokaryotic ortholog of the NSS family and has contributed to our understanding of the structure, mechanism and pharmacology of NSSs. At present, however, the functional state of LeuT in crystals grown in the presence of n-octyl-beta-D glucopyranoside (beta-OG) and the number of substrate binding sites are controversial issues. Here we present crystal structures of LeuT grown in DMPC CHAPSO bicelles and demonstrate that the conformations of LeuT-substrate complexes in lipid bicelles and in beta-OG detergent micelles are nearly identical. Furthermore, using crystals grown in bicelles and the substrate leucine or the substrate analog selenomethionine, we find only a single substrate molecule in the primary binding site. PMID- 22245966 TI - Newly folded substrates inside the molecular cage of the HtrA chaperone DegQ. AB - The HtrA protein family combines chaperone and protease activities and is essential for protein quality control in many organisms. Whereas the mechanisms underlying the proteolytic function of HtrA proteins are well characterized, their chaperone activity remains poorly understood. Here we describe cryo-EM structures of Escherichia coli DegQ in its 12- and 24-mer states in complex with model substrates, providing a structural model of HtrA chaperone action. Up to six lysozyme substrates bind inside the DegQ 12-mer cage and are visualized in a close-to-native state. An asymmetric reconstruction reveals the binding of a well ordered lysozyme to four DegQ protomers. DegQ PDZ domains are located adjacent to substrate density and their presence is required for chaperone activity. The substrate-interacting regions appear conserved in 12- and 24-mer cages, suggesting a common mechanism of chaperone function. PMID- 22245967 TI - The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. AB - The splicing-factor oncoprotein SRSF1 (also known as SF2/ASF or ASF/SF2) is upregulated in breast cancers. We investigated the ability of SRSF1 to transform human and mouse mammary epithelial cells in vivo and in vitro. SRSF1 overexpressing COMMA-1D cells formed tumors, following orthotopic transplantation to reconstitute the mammary gland. In three-dimensional (3D) culture, SRSF1 overexpressing MCF-10A cells formed larger acini than control cells, reflecting increased proliferation and delayed apoptosis during acinar morphogenesis. These effects required the first RNA-recognition motif and nuclear functions of SRSF1. SRSF1 overexpression promoted alternative splicing of BIM (also known as BCL2L11) and BIN1 to produce isoforms that lack pro-apoptotic functions and contribute to the phenotype. Finally, SRSF1 cooperated specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation, and these cooperating oncogenes are significantly coexpressed in human breast tumors. Thus, SRSF1 can promote breast cancer, and SRSF1 itself or its downstream effectors may be valuable targets for the development of therapeutics. PMID- 22245968 TI - Experimental conditions can obscure the second high-affinity site in LeuT. AB - Neurotransmitter:Na(+) symporters (NSSs), the targets of antidepressants and psychostimulants, recapture neurotransmitters from the synapse in a Na(+) dependent symport mechanism. The crystal structure of the NSS homolog LeuT from Aquifex aeolicus revealed one leucine substrate in an occluded, centrally located (S1) binding site next to two Na(+) ions. Computational studies combined with binding and flux experiments identified a second substrate (S2) site and a molecular mechanism of Na(+)-substrate symport that depends upon the allosteric interaction of substrate molecules in the two high-affinity sites. Here we show that the S2 site, which has not yet been identified by crystallographic approaches, can be blocked during preparation of detergent-solubilized LeuT, thereby obscuring its crucial role in Na(+)-coupled symport. This finding points to the need for caution in selecting experimental environments in which the properties and mechanistic features of membrane proteins can be delineated. PMID- 22245969 TI - Phosphorylation-dependent activity of the deubiquitinase DUBA. AB - Addition and removal of ubiquitin or ubiquitin chains to and from proteins is a tightly regulated process that contributes to cellular signaling and protein stability. Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. The crystal structure of the ubiquitin aldehyde adduct of active DUBA reveals a marked cooperation between phosphorylation and substrate binding. An intricate web of interactions involving the phosphate and the C-terminal tail of ubiquitin cause DUBA to fold around its substrate, revealing why phosphorylation is essential for deubiquitinase activity. Phosphoactivation of DUBA represents an unprecedented mode of protease regulation and a clear link between two major cellular signal transduction systems: phosphorylation and ubiquitin modification. PMID- 22245970 TI - Molecular basis for RNA polymerization by Qbeta replicase. AB - Core Qbeta replicase comprises the Qbeta virus-encoded RNA-dependent RNA polymerase (beta-subunit) and the host Escherichia coli translational elongation factors EF-Tu and EF-Ts. The functions of the host proteins in the viral replicase are not clear. Structural analyses of RNA polymerization by core Qbeta replicase reveal that at the initiation stage, the 3'-adenine of the template RNA provides a stable platform for de novo initiation. EF-Tu in Qbeta replicase forms a template exit channel with the beta-subunit. At the elongation stages, the C terminal region of the beta-subunit, assisted by EF-Tu, splits the temporarily double-stranded RNA between the template and nascent RNAs before translocation of the single-stranded template RNA into the exit channel. Therefore, EF-Tu in Qbeta replicase modulates RNA elongation processes in a distinct manner from its established function in protein synthesis. PMID- 22245971 TI - Immunomodulatory effects and improved prognosis of experimental autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment. AB - Experimental autoimmune encephalomyelitis (EAE) is a murine autoimmune disease used to study multiple sclerosis (MS), a human inflammatory demyelinating disease of the central nervous system. Genistein, an isoflavonoid phytoestrogenic compound found in soy, is known to reverse clinical signs of EAE. Although genistein has some potential in clinical application, it has some disadvantages related to its chemical structure, such as rapid in vivo metabolism and a fast decline in serum after oral administration. The present work investigates the treatment of EAE by using 7-O-tetradecanoyl-genistein (TDG), a more lipophilic analog of genistein obtained by esterification. The clinical course of EAE was investigated in C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG)(35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37RA. After 14 days of MOG immunization, mice were treated with TDG for seven days. Numbers of IL-17-producing cells and Foxp3 by CD4(+) T cells and CTLA-4 expression by CD3(+) T cells from brain were determined by flow cytometry. Levels of IL-6, IFN-gamma and IL-10 were evaluated by ELISA. Brain sections were stained by hematoxylin and eosin method. The data obtained indicate that TDG treatment ameliorates the clinical signs of EAE, which correlates with a decrease of IL-17-producing cells and an increase in Foxp3(+)CD4(+) cells in the brain. TDG is also shown to enhance IL-10 production and CTLA-4 expression and to reduce IFN-gamma and IL-6. Altogether, these findings suggest an immunomodulatory therapeutic role for TDG in EAE and multiple sclerosis. PMID- 22245972 TI - Altered miRNA expression patterns in Tff2 knock-out mice correlate with cellular pathways of neoplastic development and caloric metabolism. AB - The trefoil peptide family, consisting in mammals of three members namely TFF1, 2 and 3, plays a cytoprotective role in epithelial cells of various tissues, mainly in the digestive tract. Tff1, Tff2 or Tff3 knock-out mouse models developed various kinds of gastrointestinal impairment. microRNAs are known to be novel gene regulators. We aimed to investigate the physiological role of such miRNAs in Tff2 knock-out mice. Whole miRNome profiling and in silico analysis were performed for Tff2-KO and WT mice. Our latest data explored the role of miRNAs in the regulatory cascades and molecular processes of Tff2-/- mice. As much as 6% of the Tff2-KO mice miRNome was significantly dys-regulated. Further in silico analysis suggests that the respective dys-regulated part of the miRNome is involved in human pathological processes, including pancreatic, colorectal and basal cell cancer. Additionally, the dys-regulated miRNome targets pathways involved in carbohydrate metabolism and adipocytokine signaling. The latter links deficient caloric maintenance in Tff2 and previous observation in Tff3-KO mice with miRNAs. In summary, our proof-of-concept study indicates that miRNAs may play an important role in the regulatory processes of the trefoil peptide family, especially in the regulation of cancer-related cascades. PMID- 22245973 TI - Phase II trial of temsirolimus in patients with metastatic breast cancer. AB - Preclinical models suggested that activating mutations of the PIK3CA gene are associated with sensitivity to inhibitors of the mammalian target of rapamycin (mTOR). In breast cancers, PIK3CA mutations are associated with estrogen receptor (ER) positivity. We therefore performed an open-label single arm phase II study of the rapamycin analog, temsirolimus, at a dose of 25 mg weekly, in women with pretreated breast cancers that were positive for ER, PR, or HER2. Archived formalin-fixed paraffin embedded tumor was collected for immunohistochemical evaluation of components of the PI3K/Akt/mTOR pathway and PIK3CA mutation analysis. Thirty-one patients were enrolled. There were no major objective responses; however, three patients had stable disease for over 24 weeks. Twenty three tumor samples were available for mutational analysis. There were five tumors with PIK3CA mutations; no association was found between prolonged stable disease and PIK3CA mutation or any immunohistochemical marker. There was a trend toward improved progression free survival (PFS) for patients with positive nuclear staining for phospho-Akt308. One patient remains on study four and a half years after starting therapy; her tumor did not have a PIK3CA mutation. We conclude that single agent temsirolimus has minimal activity in a population of women with heavily pretreated breast cancer. We found no evidence that either absence of immunohistochemical staining for PTEN or mutations in the hotspot domains of PIK3CA in the primary tumor were associated with clinical benefit. PMID- 22245975 TI - The impact of general versus local anesthesia on early subclinical cognitive function following carotid endarterectomy evaluated using P3 event-related potentials. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is detected in 25% of patients undergoing carotid endarterectomy (CEA). The mechanism of POCD is poorly understood, but it is believed that general anesthesia (GA) itself may contribute significantly to POCD. The aim of our prospective study was to compare, with the aid of event-related potentials, the impact of general anesthesia (GA) and local anesthesia (LA) on POCD in patients undergoing CEA. METHODS: Sixty patients were included in this study and were divided into two groups: CEA was performed in 30 patients placed under GA (total intravenous anesthesia), herein the GA group, while 30 patients underwent CEA under LA (cervical plexus block), herein LA group. Cognitive outcome was assessed with the use of auditory event-related potentials (ERPs), P3 response. The measurements were taken before surgery (pre op) and on the first (1.post-op) and the sixth postoperative days (6.post-op). RESULTS: Preoperative cognitive functions did not differ significantly between the two groups. A significant decrease in P3 amplitude was found on the first postoperative day (1.post-op) in the GA group (p = 0.0005), but normalization of P3 amplitude was detected at the second postoperative measurement (6.post-op). The patients operated on under local anesthesia (LA group) showed stable P3 amplitudes in all three measurements. No significant changes in P3 latencies were observed in either group. There were no significant differences between the two groups regarding demographic characteristics, preoperative and postoperative clinical condition, percentage significance of carotid artery stenosis, duration of carotid cross-clamping or in the frequency of shunt use (zero frequency for both groups). CONCLUSIONS: Our study showed that general anesthesia, used for patients undergoing CEA, negatively influenced cognitive function during the immediate period after surgery (the first postoperative day). However, by the sixth postoperative day, this cognitive impairment was no longer being detected. POCD occurring shortly after carotid endarterectomy is the result of general anesthesia, which is probably an independent evoking factor in itself. The cognitive deficit recorded only during the immediate postoperative period, is not a negative effect of GA but merely a side-effect and thus GA should not be considered inferior to LA for use during CEA. PMID- 22245974 TI - Functional MRI techniques demonstrate early vascular changes in renal cell cancer patients treated with sunitinib: a pilot study. AB - OBJECTIVE: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. PATIENTS AND METHODS: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. RESULTS: DWI showed a significant increase in the apparent diffusion coefficient (*10(-6) s/mm(2)) from baseline (mean 1158, range 814-2003) to day 3 (mean 1306, range 1008-2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719-2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. CONCLUSIONS: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted. PMID- 22245976 TI - Validation of an Italian version of the functional index for hand osteoarthritis (FIHOA). AB - OBJECTIVES: To translate the functional index for hand osteoarthritis (FIHOA) into Italian and to evaluate its reliability and validity in Italian patients with hand osteoarthritis (HOA). METHODS: The original French FIHOA was translated into Italian according to the guidelines for cross-cultural adaptation and then administered to 72 outpatients with HOA, together with the visual analogue scale of pain (VAS), the Health Assessment Questionnaire (HAQ) and the Short Form Health Survey (SF-36). Test-retest reliability was verified by having all patients fill out the Italian version of FIHOA again 1 week later. Item-item analysis was performed. The Wilcoxon signed-rank test and Spearman's rank correlation coefficient were calculated to compare test and retest responses and to evaluate the degree of correlation. Internal consistency reliability was evaluated by Cronbach's alpha coefficient, and internal structure validity was appraised through factor analysis, also taking a varimax rotation into consideration. Construct validity was assessed by correlating FIHOA with other measures of functional impairment and pain using Spearman's rank correlation coefficient. RESULTS: Internal consistency was high (Cronbach's alpha = 0.87). Test-retest reliability showed a Spearman's rho of 0.942 (p < 0.001). A significant correlation (p < 0.001) between FIHOA, VAS and HAQ and a significant negative correlation between FIHOA and SF-36 subscales were observed. FIHOA was confirmed to be a non-unidimensional scale, but in addition to the total score of the index, three subtotals of item scores were considered to provide better evaluations of finger functionality (items 3, 6, 8 and 10), wrist functionality (items 2 and 7) and hand strength (items 4 and 5) in single individuals. CONCLUSIONS: The Italian version of FIHOA is a reliable and valid instrument for evaluating functional disability in Italian-speaking HOA patients. PMID- 22245977 TI - Thermocautery for inferior conjunctivochalasis. AB - PURPOSE: To describe a thermocautery technique to treat symptomatic inferior conjunctivochalasis. METHODS: Thirty-nine eyes of 23 patients with symptomatic inferior conjunctivochalasis were treated with thermocautery. The mean age of the patients was 78.6 +/- 5.4 years (+/-SD) with a range of 69-89 years. Patients with symptomatic inferior conjunctivochalasis were initially treated with topical medication, and the eyes that were unresponsive underwent a ligation test. We treated those eyes in which symptoms improved or disappeared during the ligation test. The redundant bulbar conjunctival tissue was grasped with smooth forceps and cauterized with the OPTEMP variable low temperature cauterizer until the redundant conjunctival tissue was gone. The mean follow-up period was 469.5 +/- 234.6 days (range, 101-823 days). RESULTS: After the thermocautery, the symptoms disappeared in 36 of 39 eyes (92.3%) and improved in the remaining 3 eyes (7.7%). The conjunctival laxity disappeared in 36 of 39 eyes (92.3%) and improved in 3 eyes (7.7%). There were no recurrences of the conjunctival laxity during the follow-up period. CONCLUSIONS: Thermocautery is a simple and effective treatment for symptomatic inferior conjunctivochalasis. PMID- 22245978 TI - Discrimination between coupling networks of glucopyranosides varying at a single stereocenter using two-dimensional vibrational correlation spectroscopy. AB - A combination of two-dimensional infrared (2DIR) correlation spectroscopy, linear absorption spectroscopy, and density functional theory quantum calculations was used to identify characteristic spectral features of two anomers of acetylated 2 azido-2-deoxy-D-glucopyranose. While the linear absorption spectra for the alpha and beta anomers were distinctive, a substantial difference between them was observed only in the spectral region below 1200 cm(-1). The infrared correlation spectra of the two anomers differed significantly, even in regions where their linear absorption spectra were similar. Very substantial differences were found for the N=N/C=O stretch mode region of the 2DIR correlation spectrum, indicating differences in the anharmonic coupling of the N=N stretching mode of the equatorially oriented N(3) group with the CO modes when the C(1) ester was either in the axial (alpha anomer) or equatorial (beta anomer) orientation. In addition, the energy transport patterns originating from the excited N=N stretching mode were found to be different for the two anomers; up to a 1.8-fold difference in the energy transport times was observed for the probed modes of the same type in the two anomers. The results demonstrate the capability of 2DIR and relaxation assisted 2DIR (RA 2DIR) spectroscopies to provide unique spectroscopic data specific to sugar anomers that vary at a single stereochemical center. These methods identify unique coupling networks within individual sugar stereochemical units and demonstrate the potential to identify a number of stereochemical differences among them. PMID- 22245979 TI - Investigation of a liposomal oxaliplatin drug formulation by capillary electrophoresis hyphenated to inductively coupled plasma mass spectrometry (CE ICP-MS). AB - A capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICP MS) method was developed for separation of the free oxaliplatin drug substance from liposome-entrapped oxaliplatin. Simultaneous determination of phosphorous and platinum opened the possibility to simultaneously monitor the liposomes (phospholipids) and platinum-based drug. In order to suppress the interferences, argon gas was used as a collision gas in ICP-MS. A detection limit of 29 ng/mL of platinum and a precision of 2.9% (for 10 MUg/mL of oxaliplatin standard) were obtained. Measurement of the total concentration of free and encapsulated oxaliplatin by CE-ICP-MS was compared with total determination by ICP-MS after microwave digestion and showed a good agreement. A liposomal formulation of oxaliplatin based on PEGylated liposomes was used as a model drug formulation. Studies of accelerated drug release induced by sonication and phospholipase A(2) catalyzed hydrolysis were performed. It was demonstrated that the CE-ICP-MS was an efficient in vitro characterization method in the development and quality assurance purposes of lipsome-based formulation of metallodrugs. PMID- 22245980 TI - Molecularly imprinted polymers as biomimetic catalysts. AB - The quest for synthetic biomimetic catalysts able to complement the activity of enzymes has attracted substantial research efforts, and the molecular imprinting approach is one of the attractive techniques that are currently being investigated. In the last 3 years, there has been considerable interest in studying in greater detail the parameters that control and influence the catalytic activity of imprinted polymers and applying molecular imprinting to a wider range of polymeric matrices. This article reports on some of the interesting examples available in the literature regarding the use of metal containing polymers, microgels and nanogels and thermoresponsive polymers. PMID- 22245981 TI - A method for increasing permeability in O2/N2 separation with mixed-matrix membranes made of water-stable MIL-101 and polysulfone. AB - Water-stable MIL-101 microcrystals adhere well to polysulfone (PSF) and yield a very robust mixed-matrix MIL-101-PSF membrane for the O(2)/N(2) separation with a selectivity of 5-6 and an unsurpassed O(2) permeability increase by a factor of four to above 6 barrer for MIL-101 loadings of 24%. PMID- 22245982 TI - High expression of Mfn1 promotes early development of bovine SCNT embryos: improvement of mitochondrial membrane potential and oxidative metabolism. AB - Mitofusin 1 (Mfn1) is the main mediator of mitochondrial fusion and homeostasis. To determine whether increased Mfn1 expression level could promote the fusion of heteroplasmic mitochondria and development of somatic cell nuclear transfer (SCNT) embryos. Embryos were constructed using bovine oocytes as recipient cytoplasm, and Holstein cow fetal fibroblasts with different expression levels of Mfn1 gene as donor nuclei. Mitochondrial membrane potential, ATP and H(2)O(2) generation, as well as the expression level of Mfn1 were detected in different development stages. The results showed that high level of Mfn1 expression significantly improved the embryo development rates by increasing ATP level and Deltapsim, while reducing H(2)O(2) generation. This study suggests that overexpression of Mfn1 could promote the early development of bovine SCNT embryos via improving oxidative phosphorylation. PMID- 22245983 TI - Usual energy intake mediates the relationship between food reinforcement and BMI. AB - The relative reinforcing value of food (RRV(food)) is positively associated with energy consumed and overweight status. One hypothesis relating these variables is that food reinforcement is related to BMI through usual energy intake. Using a sample of two hundred fifty-two adults of varying weight and BMI levels, results showed that usual energy intake mediated the relationship between RRV(food) and BMI (estimated indirect effect = 0.0027, bootstrapped 95% confidence intervals (CIs) 0.0002-0.0068, effect ratio = 0.34), controlling for age, sex, minority status, education, and reinforcing value of reading (RRV(reading)). Laboratory and usual energy intake were correlated (r = 0.24, P < 0.001), indicating that laboratory energy intake could provide an index of eating behavior in the natural environment. The mediational relationship observed suggests that increasing or decreasing food reinforcement could influence body weight by altering food consumption. Research is needed to develop methods of modifying RRV(food) to determine experimentally whether manipulating food reinforcement would result in changes in body weight. PMID- 22245984 TI - In situ electroporation of surface-bound siRNAs in microwell arrays. AB - Gene silencing using RNA interference (RNAi) has become a prominent biological tool for gene annotation, pathway analysis, and target discovery in mammalian cells. High-throughput screens conducted using whole-genome siRNA libraries have uncovered rich sets of new genes involved in a variety of biological processes and cellular models of disease. However, high-throughput RNAi screening is not yet a mainstream tool in life science research because current screening platforms are expensive and onerous. Miniaturizing the RNAi screening platform to reduce cost and increase throughput will enable its widespread use and harness its potential for rapid genome annotation. With this aim, we have combined semi conductor microfabrication and nanolitre dispensing techniques to develop miniaturized electroporation-ready microwell arrays loaded with siRNA molecules in which multiplexed gene knockdown can be achieved. Arrays of microwells are created using high-aspect ratio biocompatible photoresists on optically transparent and conductive Indium-Tin Oxide (ITO) substrates with integrated micro-electrodes to enable in situ electroporation. Non-contact inkjet microarraying allows precise dispensing of nanolitre volumes into the microwell structures. We have achieved parallel electroporation of multiple mammalian cells cultured in these microwell arrays and observed efficient knockdown of genes with surface-bound, printed siRNAs. Further integration of microfabrication and non contact nanolitre dispensing techniques described here may enable single substrate whole-genome siRNA screening in mammalian cells. PMID- 22245985 TI - Simvastatin reduces VCAM-1 expression in human umbilical vein endothelial cells exposed to lipopolysaccharide. AB - OBJECTIVE: Reducing the expression of endothelial cell adhesion molecules (ECAMs) is known to decrease inflammation-induced vascular complications. In this paper we looked at whether statins can reduce inflammation-induced ECAM expression after lipopolysaccharide (LPS) treatment in endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were pretreated with different concentrations of simvastatin, atorvastatin, and rosuvastatin and subsequently exposed to 5 MUg/ml LPS. Semi-quantitative RT-PCR analysis was used to measure the mRNA expression of ECAMs, including VCAM-1, ICAM-1, and E-selectin. RESULTS: VCAM-1 mRNA appeared to be the only target that was affected by the statins, with its expression being partially and almost completely reduced by simvastatin at 50 and 125 MUM concentrations, respectively, and only partially reduced by atorvastatin, but not reduced by rosuvastatin. VCAM-1 protein production was inhibited by simvastatin at concentrations from 5 to 125 MUM. Leukocyte endothelial cell adhesion assay revealed that simvastatin could inhibit the adhesion of labelled U937 cells to the HUVEC monolayer. CONCLUSIONS: This study showed that simvastatin reduces VCAM-1 expression in HUVECs exposed to LPS and decreases leukocyte-endothelial cell adhesion. PMID- 22245986 TI - Effect of mild hyperisulinemia on conduit vessel endothelial function: role of noradrenergic activation. AB - OBJECTIVE: The evidence that an exogenously induced modest hyperinsulinemia deteriorates conductance artery endothelial function - flow-mediated dilatation (FMD) - in healthy individuals is in contrast with in-vitro and in-vivo studies that consistently found that insulin facilitates both nitric oxide release and the endothelium-dependent dilatation. The aim of this study was to verify whether this effect is caused by the enhancement of insulin-induced adrenergic tone. METHOD: In 10 healthy male volunteers, endothelium-dependent (FMD) and endothelium-independent (glyceryl trinitrate, GTN) dilatation were evaluated by high-resolution ultrasound of the brachial artery, combined with a computerized edge detection system, at baseline (-60 and 0 min) and after 120 and 240 min during insulin infusion (INS study). In five participants, randomly selected from the initial group, the study was repeated during an isotonic saline (0.9% sodium chloride) intravenous infusion (SAL study). In an additional five participants, insulin infusion was preceded by an intravenous infusion of clonidine started 40 min before insulin and continued throughout the study (INS + CLN study). RESULTS: Plasma norepinephrine concentration increased in the INS study from 260 +/- 40 to 333 +/- 62 pg/ml (P < 0.05), whereas it remained stable throughout the INS + CLN study. In the INS study, no change in FMD was observed, whereas the response to GTN tended to decrease (P = 0.09). In the INS + CLN study, no significant changes in FMD response were observed, whereas GTN response was completely restored. CONCLUSION: Physiological hyperinsulinemia has no effect on endothelium-dependent vasodilatation in conduit vessels of healthy individuals, but it induces a slight decline in endothelium-independent vasodilatation, which is entirely explained by the insulin-induced noradrenergic activation. PMID- 22245987 TI - Facilitated defensive coping, silent ischaemia and ECG left-ventricular hypertrophy: the SABPA study. AB - BACKGROUND: Defensive active coping responses (being-in-control, acceptance of the stressor as reality) have been associated with vascular hyper-responsiveness in urban Africans. However, the association between active coping responses, blood pressure (BP), and ECG-derived left-ventricular hypertrophy (LVH) responses is unknown. OBJECTIVES AND METHODS: Associations between BP, silent ischaemia and ECG Cornell product LVH were assessed in 161 African and Caucasian men with active coping responses identified by the Amirkhan Coping Strategy Indicator. BP, ECG and silent ischaemia data were obtained from 24-h ambulatory monitoring. Beat to-beat BP was continuously recorded during stress testing and fasting resting blood samples obtained for biochemical analyses. RESULTS: Enhanced beta adrenergic central cardiac responses were evident in active coping Caucasians as opposed to a predomination of alpha-adrenergic vascular responses in active coping Africans. Active coping African men displayed higher 24-h BP and prevalence of silent ischaemia events compared to the Caucasian men. Regression analyses revealed that alpha-adrenergic responses were associated with silent ischaemic events, adjusted R 0.21 [beta 1.07, 95% confidence interval (CI) 0.29 1.85] and that ischaemic events predicted LVH in active coping Africans (adjusted R 0.12, beta 0.35, 95% CI 0.11-0.59). Receiver-operated characteristic (ROC) analyses indicated a defensive pathway cut point of 16 in Africans as opposed to 32 in Caucasians predicting silent ischaemia with sensitivity/specificity 100/96%. CONCLUSIONS: A defensive pathway revealed disturbed vascular function showing dissociation between behavioural and physiological beta-adrenergic active coping responses in Africans. Vascular responsiveness facilitated silent ischaemia events and structural LVH changes which potentially explain the increased risk for incident ischaemic stroke in black Africans. PMID- 22245988 TI - Estimation of central aortic systolic pressure from the second systolic peak of the peripheral upper limb pulse depends on central aortic pressure waveform morphology. AB - BACKGROUND: Direct identification of second systolic peaks of peripheral upper limb pulses (pSBP2) has been used to represent central systolic blood pressure (cSBP), but its accuracy at low SBP was questioned. OBJECTIVES: We investigated the relationship of pSBP2 with characteristics of central pressure waveforms. METHODS: High-fidelity central aortic and right brachial pressure waveforms were simultaneously recorded using a custom-made dual pressure sensor catheter in 78 patients (65.9 +/- 12.9 years) during catheterization for 285 measurements. RESULTS: Overall agreement between cSBP and pSBP2 was good (mean difference -0.9 +/- 4.8, r = 0.98), with a systematic bias at low SBP. We examined agreements of different waveform types according to the relationship of the second systolic peak of aortic pressure waveforms (cSBP2) to cSBP. Of type A (positive late systolic augmentation) and type B (zero augmentation) aortic pressure waveforms, in which cSBP = cSBP2, agreement between pSBP2 and cSBP was excellent (mean difference -0.4 +/- 4.1, r = 0.99). There were 40 type C aortic pressure waveforms (negative augmentation; cSBP > cSBP2) with cSBP 107.2 +/- 13.9 mmHg. Their cSBP2, compared with cSBP, showed closer agreement (mean difference -0.6 +/ 3.2 vs. -4.0 +/- 7.2 mmHg) and better correlation (r = 0.97 vs. 0.85, P = 0.03) with pSBP2. CONCLUSION: pSBP2 can be used with type A and B aortic pressure waveforms for estimation of cSBP. However, it should not be used with type C aortic pressure waveforms, typically at low SBP, because pSBP2 is closer to cSBP2 than cSBP. This explains why pSBP2 underestimates cSBP at low SBP. PMID- 22245989 TI - In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection. AB - Enterovirus 71(EV71) causes recurring outbreaks of hand, foot and mouth disease and encephalitis leading to complications or death in young children. More effective antiviral drugs are needed to prevent or reduce EV71-related disease and complications. However, there are no standard models currently in use to evaluate activity against EV71 infection both in vitro and in vivo. In this study, the activity of ribavirin and pleconaril against EV71 infection was evaluated in two models. An in vitro EV71 infection model was developed in RD cells, and an in vivo EV71 infection model was applied. Ribavirin and pleconaril effectively increased the viability of infected cells. Pleconaril reduced the morbidity and mortality of one-day-old infected mice, but ribavirin did not protect the infected mice. In all, the results demonstrated that infected cells and infected mice can be used to evaluate antiviral activity of ribavirin and pleconaril against EV71 infection in vitro and in vivo. PMID- 22245990 TI - Staging and imaging of small cell lung cancer. AB - Small cell lung cancer (SCLC) has been primarily classified as limited or extensive, with limited stage confined to the primary tumor and regional lymph nodes. In the future, the TNM staging system should be integrated into the classification of SCLC. The appropriate staging work-up for patients with SCLC has traditionally included contrast-enhanced computed tomography (CT) scans of the chest and abdomen, bone scan, and magnetic resonance imaging or CT scan of the brain. Recent data suggest that positron emission tomography can improve both staging accuracy and treatment planning in patients with SCLC. Treatment for limited-stage SCLC consists of chemotherapy plus radiotherapy, and such therapy can cure 20-25% of patients. Extensive-stage SCLC is incurable, but chemotherapy can improve quality of life and prolong life. PMID- 22245991 TI - Novel RS1 mutations associated with X-linked juvenile retinoschisis. AB - To identify mutations in the retinoschisin (RS1) gene in families with X-linked retinoschisis (XLRS). Twenty families with XLRS were enrolled in this study. All six coding exons and adjacent intronic regions of RS1 were amplified by polymerase chain reaction (PCR). The nucleotide sequences of the amplicons were determined by Sanger sequencing. Ten hemizygous mutations in RS1 were detected in patients from 14 of the 20 families. Four of the ten mutations were novel, including c:176G>A (p:Cys59Tyr) in exon 3, c:531T>G (p:Tyr177X), c:607C>G (p:Pro203Ala) and c:668G>A (p:Cys223Tyr) in exon 6. These four novel mutations were not present in 176 normal individuals. The remaining six were recurrent mutations, including c:214G>A (p:Glu72Lys), c:304C>T (p:Arg102Trp), c:436G>A (p:Glu146Lys), c:544C>T (p:Arg182Cys), c:599G>A (p:Arg200His) and c:644A>T (p:Glu215Val). Our study expanded the mutation spectrum of RS1 and enriches our understanding of the molecular basis of XLRS. PMID- 22245992 TI - Sir2 plays a key role in cell fate determination upon SAPK activation. AB - Although the benefit of sirtuin activation in age-related diseases is well characterized, the benefit of sirtuin activation in acute diseases has been elusive. Here we discuss that, at least in yeast, Sir2 activation prevents programmed cell death induced by the sustained activation of the stress activated protein kinase (SAPK) Hog1, the yeast homologue of the p38 SAPK. Sir2 prevents ROS formation and maximize cell survival upon SAPK activation. The conserved function of Sir2 in age-related diseases and the conserved role of SAPKs open the possibility of a novel role for sirtuins in cell fate determination in eukaryotic cells. PMID- 22245993 TI - Lipopolysaccharide and dose of nicotine determine the effects of nicotine on murine bone marrow-derived dendritic cells. AB - The reported effects of nicotine on dendritic cells (DCs) are controversial. To investigate the factors which determine the effects of nicotine on DCs, immature dendritic cells (imDCs) induced from murine bone marrow were treated with different doses of nicotine with or without lipopolysaccharides (LPS). The morphology and expression of the co-stimulatory molecules CD80, CD86, CD40 and CD54 were observed and determined by microscopy and flow cytometry, respectively. The results showed that, firstly, nicotine treatment promoted the development of DC precursors into imDCs with a semi-mature phenotype revealed by a higher expression of CD11c and more branched projections. Secondly, lower doses of nicotine (16.5 ng/ml), but not higher (200 ug/ml), up-regulated the expression of the co-stimulatory molecules CD80, CD40 and CD54 on imDCs. Co-administration of LPS and nicotine revealed differential effects on co-stimulatory molecule expression on imDCs. Thirdly and importantly, treatment with lower doses of nicotine (16.5 ng/ml) did not augment expression of the CD80, CD86, CD40 and CD54 molecules in mature DCs. Fourthly and interestingly, high doses of nicotine (more than 165 ug/ml) revealed pro-apoptotic activity but lower doses of nicotine (16.5 0.165 ng/ml) achieved an anti-apoptotic effect on imDCs. All data presented here indicate that the controversial effects of nicotine on DCs may be due to the LPS of the nicotinic environment and the dose of nicotine used. PMID- 22245994 TI - Arsenic trioxide induces cervical cancer apoptosis, but specifically targets human papillomavirus-infected cell populations. AB - OBJECTIVES: Human papillomavirus (HPV) is directly associated with the occurrence and development of cervical cancer. Targeting HPV infection has become the priority in treatment and prevention. Some treatment strategies have shown a limited therapeutic potential in suppressing and reversing the oncogenic effects of HPVs, but are compromised by the toxicity, immune suppression and the expense. Arsenic trioxide (As2O3) has shown therapeutic efficacy in the treatment of haematological and solid cancer and has been demonstrated to effectively induce apoptosis of HPV-infected cervical cancer cells in vitro. Here, we examined the effects and possible molecular pathway of As2O3-induced apoptosis in HPV-infected and noninfected cervical cancer cells. METHODS: As2O3 was added to HPV-infected cell lines HeLa and CaSki and the HPV-negative cell line C33A at concentrations from 1 to 10 umol/l. Cell proliferation rates were evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays after exposure. Expressions of tumour suppressor gene p53, activated caspase-3 and cell cycle distribution were evaluated in relation to HPV-E6 protein expression by confocal microscopy immunofluorescent staining and flow cytometry. RESULTS: As2O3 reduced cell populations by 16% in C33A but by 48-60% in HPV-infected cell lines CaSki and HeLa. The expression of HPV-E6 proteins was drastically down-regulated in a dose-dependent manner, whereas p53 and activated caspase-3 expressions increased in the HPV-infected cell lines. Flow cytometry demonstrated cell cycle arrest in S-G2/M phases, and increasing apoptotic bodies were seen in HPV-infected lines only. CONCLUSION: As2O3, at low concentrations, inhibited HPV-E6 protein expression, leading to up-regulated p53 levels, induced S to G2/M arrest and apoptosis. PMID- 22245995 TI - Use of talcum powder and endometrial cancer risk. AB - PURPOSE: Use of talcum powder in the perineal area has been associated with an increased risk of ovarian cancer, and a recent cohort study found a positive association with endometrial cancer. We sought to confirm this association using data from the Australian National Endometrial Cancer Study (ANECS). METHODS: ANECS was a population-based case-control study conducted from 2005 to 2007, in which 1,399 women with newly diagnosed histologically confirmed primary endometrial cancer and 740 control women provided risk factor information via telephone interview. Unconditional logistic regression was used to estimate odds ratios adjusting for potential confounders. RESULTS: We found no significant association between ever use of talc in the perineal area (OR 0.88, 95% CI: 0.68 1.14) or upper body area (OR 0.90, 95% CI: 0.71-1.14) and risk of endometrial cancer. The results were similar when stratified by subtype. Composite variables combining frequency and duration of talc use were also not significantly associated with risk (any perineal area use p = 0.07 and any upper body use p = 0.49). CONCLUSIONS: The absence of any increase in risk and the similarity of our results for talc use on the upper body and in the perineal area do not support the hypothesis that use of talc in the perineal area is associated with an increased risk of endometrial cancer. Our data do not confirm the positive association between perineal talc use and endometrial cancer observed in the only previous study. PMID- 22245996 TI - Lipopolysaccharide disrupts the directional persistence of alveolar myofibroblast migration through EGF receptor. AB - Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace size. Formation of alveoli involves a process known as secondary septation triggered by myofibroblasts. This study investigated the underlying mechanisms of altered lung morphogenesis in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS disrupted alveolar morphology and led to abnormal localization of myofibroblasts in the lung of newborn rats, mostly in primary septa with few in secondary septa. To identify potential mechanisms, in vitro experiments were carried out to observe the migration behavior of myofibroblasts. The migration speed of lung myofibroblasts increased with LPS treatment, whereas the directional persistence decreased. We found that LPS induced activation of EGFR and overexpression of its ligand, TGF-alpha in myofibroblasts. AG1478, an EGFR inhibitor, abrogated the enhanced locomotivity of myofibroblasts by LPS and also increased the directional persistence of myofibroblast migration. Myofibroblasts showed a high asymmetry of phospho-EGFR localization, which was absent after LPS treatment. Application of rhTGF-alpha to myofibroblasts decreased the directional persistence. Our findings indicated that asymmetry of phospho-EGFR localization in myofibroblasts was important for cell migration and its directional persistence. We speculate that LPS exposure disrupts the asymmetric localization of phospho-EGFR, leading to decreased stability of cell polarity and final abnormal location of myofibroblasts in vivo, which is critical to secondary septation and may contribute to the arrested alveolar development in BPD. PMID- 22245997 TI - Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension. AB - Autophagy is a process for cells to degrade proteins or entire organelles to maintain a balance in the synthesis, degradation, and subsequent recycling of cellular products. Increased reactive oxygen species formation is known to induce autophagy. We previously reported that increased NADPH oxidase (NOX) activity in pulmonary artery endothelial cells (PAEC) from fetal lambs with persistent pulmonary hypertension (PPHN) contributes to impaired angiogenesis in PPHN-PAEC compared with normal PAEC. We hypothesized that increased NOX activity in PPHN PAEC is associated with increased autophagy, which, in turn, contributes to impaired angiogenesis in PPHN-PAEC. In the present study, we detected increased autophagy in PPHN-PAEC as shown by increased ratio of the microtubule-associated protein 1 light chain (LC3)-II to LC3-I and increased percentage of green fluorescent protein-LC3 punctate positive cells. Inhibiting autophagy by 3 methyladenine, chloroquine, and beclin-1 knockdown in PPHN-PAEC has led to decreased autophagy and increased in vitro angiogenesis. Inhibition of autophagy also decreased the association between gp91(phox) and p47(phox), NOX activity, and superoxide generation. A nonspecific antioxidant N-acetylcysteine and a NOX inhibitor apocynin decreased autophagy in PPHN-PAEC. In conclusion, autophagy may contribute to impaired angiogenesis in PPHN-PAEC through increasing NOX activity. Our results suggest that, in PPHN-PAEC, a positive feedback relationship between autophagy and NOX activity may regulate angiogenesis. PMID- 22245998 TI - Activation of HGF/c-Met signaling by ultrafine carbon particles and its contribution to alveolar type II cell proliferation. AB - Hepatocyte growth factor (HGF) is a potent mitogen and motogen for various epithelial cells. The present study aimed to explore the role of HGF and c-Met receptor in ultrafine carbon particle-induced alveolar type II epithelial (type II) cell proliferation. ICR mice were intratracheally instilled with 100 MUg ultrafine carbon black (ufCB) and killed at 21, 48, and 72 days postexposure to examine type II cell proliferation, HGF release, and c-Met activation. In vivo and in vitro applications of neutralizing anti-HGF antibody were used to investigate the causal role of HGF in cell proliferation. The Met kinase inhibitor SU11274 and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 were used to delineate the involvement of c-Met/ERK1/2 in rat L2 pulmonary epithelial cell proliferation. The results demonstrated that in vivo exposure to 100 MUg ufCB caused increased HGF in bronchoalveolar lavage fluid, as well as increased HGF production, c-Met phosphorylation, and cell proliferation in type II cells. In vitro study revealed that ufCB caused a dose-dependent increase in HGF release, c-Met phosphorylation, and cell proliferation. Importantly, treatment with the neutralizing anti-HGF antibody significantly blocked ufCB-induced in vivo and in vitro type II cell proliferation. Moreover, SU11274 and PD98059 significantly reduced ufCB-increased L2 cell proliferation. Results from Western blotting demonstrated that SU11274 successfully suppressed ufCB-induced phosphorylation of c-Met and ERK1/2. In summary, the activation of HGF/c-Met signaling is a major pathway involved in ufCB-induced type II cell proliferation. PMID- 22245999 TI - TLR2 ligand engagement upregulates airway smooth muscle TNFalpha-induced cytokine production. AB - Airway inflammation and respiratory infections are important factors contributing to disease exacerbation in chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Airway smooth muscle (ASM) cells express Toll-like receptors (TLRs) and may be involved in the amplification of airway inflammatory responses during infectious exacerbations. We determined whether infectious stimuli (mimicked using Pam3CSK4, a synthetic bacterial lipopeptide that binds to TLR2/TLR1) further enhance ASM cell inflammatory responses to TNFalpha in vitro and the signaling pathways involved. Human ASM cells were pretreated for 1 h with Pam3CSK4 (1 MUg/ml) in the absence or presence of TNFalpha (10 ng/ml), and IL-6 and IL-8 release was measured after 24 h. As expected, stimulation with Pam3CSK4 or TNFalpha alone induced significant IL-6 and IL-8 release. Furthermore, Pam3CSK4 significantly increased TNFalpha-induced IL-6 and IL-8 mRNA expression and protein release and neutrophil chemotactic activity. The potentiating effect of Pam3CSK4 on TNFalpha-induced inflammatory responses was not due to enhanced TLR2 expression nor did it involve augmentation of NF-kappaB or MAPK signaling pathways. Rather, Pam3CSK4 induced cAMP response element (CRE) binding protein phosphorylation and induced CRE-mediated transcriptional regulation, suggesting that Pam3CSK4 and TNFalpha are acting in concert to enhance ASM cytokine secretion via parallel transcriptional pathways. Our findings suggest that ASM cells may be involved in the amplification of airway inflammatory responses during infectious exacerbations in chronic airway disease. PMID- 22246000 TI - Ciclesonide inhibits TNFalpha- and IL-1beta-induced monocyte chemotactic protein 1 (MCP-1/CCL2) secretion from human airway smooth muscle cells. AB - Monocyte chemotactic protein-1 (MCP-1) is a member of the CC family of cytokines. It has monocyte and lymphocyte chemotactic activity and stimulates histamine release from basophils. MCP-1 is implicated in the pathogenesis of inflammatory diseases, including asthma. The airway smooth muscle (ASM) layer is thickened in asthma, and the growth factors and cytokines secreted by ASM cells play a role in the inflammatory response of the bronchial wall. Glucocorticoids and beta(2) agonists are first-line drug treatments for asthma. Little is known about the effect of asthma treatments on MCP-1 production from human ASM cells. Here, we determined the effect of ciclesonide (a glucocorticoid) and formoterol (a beta(2) agonist) on MCP-1 production from human ASM cells. TNFalpha and IL-1beta induced MCP-1 secretion from human ASM cells. Formoterol had no effect on MCP-1 expression, while ciclesonide significantly inhibited IL-1beta- and TNFalpha induced MCP-1. Furthermore, ciclesonide inhibited IL-1beta- and TNFalpha-induced MCP-1 mRNA and IL-1beta- and TNFalpha-induced MCP-1 promoter and enhancer luciferase reporters. Western blots showed that ciclesonide had no effect on IkappaB degradation. Finally, ciclesonide inhibited an NF-kappaB luciferase reporter. Our data show that ciclesonide inhibits IL-1beta- and TNFalpha-induced MCP-1 production from human ASM cells via a transcriptional mechanism involving inhibition of NF-kappaB binding. PMID- 22246003 TI - [Obituary - HRH Prince Sultan bin Abdul-Aziz]. PMID- 22246002 TI - Abnormal platelet aggregation in idiopathic pulmonary arterial hypertension: role of nitric oxide. AB - Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease. Several processes are believed to lead to the fatal progressive pulmonary arterial narrowing seen in IPAH including vasoconstriction, cellular proliferation inflammation, vascular remodeling, abnormalities in the lung matrix, and in situ thrombosis. Nitric oxide (NO) produced by NO synthases (NOS) is a potent vasodilator and plays important roles in many other processes including platelet function. Reduced NO levels in patients with IPAH are known to contribute to the development of pulmonary hypertension and its complications. Platelet defects have been implied in IPAH, but original research supporting this hypothesis has been limited. Normal platelets are known to have NOS activity, but little is known about NOS expression and NO production by platelets in patients with IPAH. Here we characterized the phenotype of the platelets in IPAH and show a defect in their ability to be activated in vitro by thrombin receptor activating protein but not adenosine diphosphate. We also show that endothelial NOS (eNOS) levels in these platelets are reduced and demonstrate that NO is an important regulator of platelet function. Thus reduced levels of eNOS in platelets could impact their ability to regulate their own function appropriately. PMID- 22246001 TI - Pathophysiology of pulmonary hypertension in acute lung injury. AB - Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI. PMID- 22246005 TI - Significant beneficial effect of AT-1 receptor blockers (sartans) in stroke. AB - Hypertension is the most important controllable and modifiable risk factor for stroke. The relationship between blood pressure and stroke mortality is strong and linear. Angiotensin receptor blockers (sartans) are competitive pharmacological antagonists of angiotensin II receptors, and some of them are approved for use in the treatment of hypertension. These drugs also show anti inflammatory effects by reducing the cytokine levels. The anti-inflammatory effects of sartans play a role in reducing cerebral injury following stroke, and improve the outcome of stroke in terms of improving cognitive function. In humans, sartans are safe in hypertensive acute stroke patients and may offer advantages independent of blood pressure control. Sartans promote neovascularization and thereby provide long-term cerebro-protection in terms of vascular protection and enhancement of early angiogenic remodeling. In this review, the beneficial effects of sartans in the management of stroke are discussed, considering the results of experimental and clinical studies. PMID- 22246006 TI - Functional neurosurgery. The modulation of neural and mind circuits. AB - Different complex neuroanatomical and neurochemical circuits regulate a variety of neuronal behaviors and brain functions. Any disturbance in these circuits can generate functional disorders such as movement disorders, epilepsy, pain, memory disorders, and psychiatric disorders. Functional neurosurgery aims to restore these functions, either by removing or isolating the abnormally behaving neurons or by modulating the disturbed circuits. Neuromodulation is a fast-growing field, powered by the recent advances in neuroimaging and technology. Here, we discuss recent advances and new horizons in functional neurosurgery. PMID- 22246007 TI - Effects of sertraline on experimental mouse models of psychosis. AB - OBJECTIVE: To study the effects of sertraline on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior, and amphetamine or MK-801-induced locomotor activities in female Swiss albino mice weighing 30-35 g. METHODS: This study was performed in the Department of Pharmacology, Eskisehir Osmangazi University, Eskisehir, Turkey between April 2008 and January 2010. Catalepsy was induced by haloperidol (1 mg/kg intraperitoneally [ip]). Apomorphine (1.5 mg/kg subcutaneously [sc]) was used for studying climbing behavior, and d-amphetamine (30 mg/kg ip) or MK-801 (0.3 mg/kg ip) was used for testing locomotor activities. Eight animals were used in each group. Sertraline (10 mg/kg ip) was injected either acutely, or over 5 days of repeated treatment. RESULTS: Sertraline inhibited catalepsy and climbing behavior when it was used for 5 days in repeated doses, while it augmented amphetamine-induced locomotor activity. It reduced MK 801-induced stereotypic movements, but did not significantly affect amphetamine induced stereotypic movements when used in a single dose or repeated doses. CONCLUSION: These results suggest that sertraline, a selective serotonin reuptake inhibitor may be a beneficial adjuvant drug during psychosis therapy. PMID- 22246008 TI - Acute antidepressant and anxiolytic effects of simvastatin and its mechanisms in rats. AB - OBJECTIVE: The aim of this study is to investigate the antidepressant and anxiolytic effects of simvastatin in rats. METHODS: Sixty-four male adult (8-9 weeks old) Sprague-Dawley rats (200-250 g) were used. The forced swimming test and the elevated plus maze test were used for testing the antidepressant and anxiolytic effects. Eight groups were formed: control (saline), simvastatin 10, 30, and 50 mg/kg, amitriptyline 10 mg/kg, sertraline 5 mg/kg, simvastatin 30 mg/kg+amitriptyline 10 mg/kg, and simvastatin 30 mg/kg+sertraline 5mg/kg combinations. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Eskisehir Osmangazi University Medical School, Eskisehir, Turkey from March to May 2010. RESULTS: The immobility periods were significantly reduced by all doses of simvastatin. Simvastatin 10 and 30 mg/kg but not 50 mg/kg increased time spent in the open arm. A single dose of amitriptyline 10 mg/kg showed significant antidepressant and anxiolytic effects. Sertraline 5 mg/kg showed significant antidepressant, but not anxiolytic effects. There was no change in the antidepressant and anxiolytic effects of simvastatin when combined with amitriptyline. A potentialization in antidepressant effect, and a decrease in anxiolytic effect of simvastatin were observed in combinations of simvastatin and sertraline. CONCLUSION: Simvastatin presents significant antidepressant and anxiolytic effects in rats similar to selective serotonin reuptake inhibitors, and interactions between the effects of simvastatin on indoleamine 2,3-dioxygenase enzymes, N-methyl-D-aspartic acid receptor blockade, and dopaminergic functions possibly mediate its antidepressant and anxiolytic effects. PMID- 22246009 TI - Demographic pattern of carpal tunnel syndrome in western Saudi Arabia. AB - OBJECTIVE: To study the demographic characteristics of patients with carpal tunnel syndrome (CTS) in Saudi Arabia. METHODS: A retrospective collection of 135 cases with CTS, diagnosed clinically and electrophysiologically. The studied cases presented to the Orthopedic Clinic of King Abdulaziz University Hospital in Jeddah, Saudi Arabia, between January 1999, and December 2009. The demographic data (age, gender, and site of involvement) were collected from the medical records. RESULTS: The 135 cases comprised 112 females, and 23 males, with a male:female ratio of 1:4.9. The mean age was 45.5 years in women (range 17-74 years) and 48.5 years in males (range 20-77). The age related gender distribution of the subjects were the highest among the age group 45-54 years in both males (34.8%) and females (33.9%). The CTS occurred bilaterally in 74 cases (55%), and unilaterally in 61 cases (45%), with 41 cases affected on the right side and 20 the left side. CONCLUSION: The demographic pattern of CTS patients in the different provinces of Saudi Arabia is almost similar, and comparative to that reported in the western countries, with slightly higher male to female ratio among the Saudi patients. PMID- 22246010 TI - Autosomal recessive hereditary spastic paraplegia with thin corpus callosum among Saudis. AB - OBJECTIVE: To assess the mutational and clinical spectrum of spatacsin associated with autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC). METHODS: A retrospective study was carried out at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia from February 2008 until March 2011. Four unrelated Saudi Arabian families with ARHSP-TCC were studied, totaling 13 affected individuals. Clinical presentations included gait disturbance at variable ages (2-18 years), spastic paraplegia with mild to moderate cognitive impairment and evidence of peripheral neuropathy in 2 families. Brain MRI showed TCC accompanied by periventricular white matter changes and cortical atrophy. RESULTS: A genome wide scan demonstrated linkage to the SPG11 locus. Sequencing revealed 4 mutations. The first is an insertion/deletion (indel) consisting of a 3 base pair (bp) deletion and 23 bp insertion (L1268L fsX), the second is a one bp deletion (S1923R fsX), and the third and the fourth are nonsense mutations (Q341X and R651X). All mutations predict premature truncation of the spatacsin protein. CONCLUSION: We report 2 novel mutations in this gene, including an indel considerably larger than any other identified to date. The identification of these mutations further confirms the causative link between SPG11 and ARHSP-TCC in these families. PMID- 22246012 TI - Phrenic nerve CMAP amplitude, duration, and latency could predict respiratory failure in Guillain-Barre syndrome. AB - OBJECTIVE: To determine the frequency of phrenic nerve abnormalities in Guillain Barre syndrome (GBS), and evaluate the value of phrenic nerve conduction studies in predicting ventilation failure. METHODS: During a study period of one year between July 2008 and July 2009, 28 GBS patients referred to our tertiary university hospital (Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran) were enrolled in a case control study. Patients with predisposing factors for other polyneuropathies (diabetes mellitus, hypothyroidism, uremia, vitamin deficiency and toxicity) were excluded from the study. Phrenic nerve conduction was studied in the first week after the beginning of symptoms according to the procedure described by Preston and Shapiro. RESULTS: Diaphragmatic compound muscle action potential (CMAP) latencies, right diaphragmatic CMAP amplitude, and diaphragmatic CMAP duration were significantly different between GBS patients with respiratory failure and without respiratory failure. The CMAP duration was longer in GBS patients with respiratory failure than in the control group (p=0.018), and a CMAP duration of more than 9.6 is an alarm for impending respiratory failure in GBS patients. CONCLUSION: Not only phrenic nerve CMAP latency and amplitude, but also diaphragmatic CMAP duration could have predictive value for respiratory failure in GBS patients. PMID- 22246011 TI - Treatment with carotid angioplasty stent placement for post-stroke depression compared to antidepressants. AB - OBJECTIVE: To elucidate the differences between carotid angioplasty stent placement (CAS) and antidepressants on post-stroke depression (PSD) in high-grade carotid artery stenosis patients. METHODS: In this prospective, controlled study, 182 cerebral ischemia stroke patients with high-grade carotid artery stenosis who were admitted to the Southwest Hospital of the Third Military Medical University, Chongqing, China, between April 2004 and March 2009 were enrolled. Based on different treatments, the patients were assigned to 2 groups: the CAS group (n=104), and the selective serotonin reuptake inhibitors (SSRIs) group (n=78). All patients were tested using the Hamilton Depression Rating Scale (HDRS) and the National Institutes of Health Stroke Scale (NIHSS) before treatment, one, and 3 months after treatment. RESULTS: The NIHSS score of the CAS group was significantly decreased at one (p=0.007) and 3 months (p=0.006). At one month, the HDRS score of the CAS group was significantly lower than the SSRIs group (p=0.005), and there was no significant difference between these 2 groups at 3 months. CONCLUSION: The CAS relieved PSD and improved neurologic rehabilitation in high-grade carotid artery stenosis patients, and the therapeutic effect was superior to that of SSRIs after one month. PMID- 22246013 TI - Cerebral venous sinus thrombosis in Crohn's disease. The empty delta sign. AB - Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the gastrointestinal tract. There is a well-known risk of thrombosis in patients with IBD with an overall incidence of 1.3-7.5%. Cerebral venous sinus thrombosis (CVST) has been reported as an uncommon complication of IBD. It is suspected to be a consequence of genetic predisposition and the hypercoagulable state occurring during periods of increased activity. There are a few cases of Crohn's disease in the literature associated with CVST. Here, we describe a patient of Crohn's disease with thrombosis of the internal cerebral vein and sagittal sinus thrombosis in the intensive care unit of King Faisal Hospital, Makkah, Kingdom of Saudi Arabia. PMID- 22246014 TI - An uncommon cause of brachial plexus injury. AB - We report a case of left upper trunk neuropraxia following an uneventful case of lumbar spine fixation and fusion performed in the prone position. The cause of the injury was believed to be a very tight endotracheal tube tie in addition to the patient's head turned to one side; both caused a compression in the left supraclavicular region compressing the upper trunk of the brachial plexus. On literature review, there are limited reports of endotracheal tube tie causing upper trunk brachial plexus reported in the English literature. Attention and care needs to be exercised to avoid this largely preventable complication. PMID- 22246015 TI - Clinical and single-photon emission computed tomography study of pure akinesia with freezing of gait. AB - The clinical syndrome of pure akinesia (PA) is considered the third phenotype of progressive supranuclear palsy (PSP), and is characterized by freezing of gait and prominent speech disturbance without rigidity or tremor. It is frequently considered one of the dopamine resistant motor syndromes, and its pathophysiology remains unclear. We report a patient followed in the Department of Neurology of Razi Hospital, Tunisia, with PA with gait freezing (PAGF) with a frontal hypoperfusion on single photon emission CT and non-responsive dopa therapy. We discuss the clinical features of PAGF and efficiency of treatment options. PMID- 22246016 TI - Giant cerebral cavernoma. Case report with literature review. AB - Giant cerebral cavernoma is a rare malformation classified as a brain occult vascular lesion. We report a case of initially misdiagnosed giant cavernous angioma revealed by a spontaneous intracerebral hemorrhage. A 40-year-old woman was admitted with right hemiplegia and altered consciousness occurring 3 days prior to presentation. A non-contrast CT scan showed a left parietal gross hematoma, and she was immediately taken to the operating room for emergency surgery. However, the procedure was interrupted by massive bleeding, and therefore a vascular lesion was suspected. Magnetic resonance images suggested a giant cavernous malformation. Afterward, she underwent total removal of this lesion. The postoperative period was uneventful, and histopathological examination confirmed the diagnosis of cavernous angioma. Thus, the differential diagnosis of gross spontaneous intracerebral hematoma should include giant cavernous angioma. PMID- 22246017 TI - Frontal motor seizure following non-convulsive status epilepticus in ring chromosome 20 syndrome. AB - The ring chromosome 20 syndrome is a rare syndrome characterized by intractable epilepsy with particular electro clinical features including episodes of prolonged confusional state and nocturnal frontal lobe seizures. We report a 17 year-old girl who had intractable epilepsy with frontal seizure and prolonged confusional state secondary to non-convulsive status epilepticus. The diagnosis of ring chromosome 20 was suspected and confirmed by karyotype. The cytogenetic study of CHRNA4 and KCNQ2 genes did not detect deletion in the ring chromosome 20. During video-EEG recording, this girl presented a non-convulsive status epilepticus that lasted more than 20 minutes followed by typical frontal lobe seizure. This association was not previously described, and was probably caused by chromosomal instability. PMID- 22246018 TI - An adult patient with rubella encephalitis. PMID- 22246019 TI - Pseudomonas aeruginosa osteomyelitis of the cervical spine. PMID- 22246020 TI - Change of presynaptic vesicle cycling in the hippocampus after status convulsion. PMID- 22246022 TI - Zoster myelitis in sickle cell anemia. PMID- 22246021 TI - Evaluation of intracellular magnesium and calcium concentration in patients with migraine. PMID- 22246023 TI - Subclinical rhythmic electrographic discharges of adults (SREDA). PMID- 22246024 TI - Does blood flow restricted exercise result in prolonged torque decrements and muscle damage? PMID- 22246025 TI - One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults. AB - Several studies have shown that the prevalence of migraine and tension-type headache (TTH) varied between different geographical regions. Therefore, there is a need of a nationwide prevalence study for headache in our country, located between Asia and Europe. This nationwide study was designed to estimate the 1 year prevalence of migraine and TTH and analyse the clinical features, the impact as well as the demographic and socio-economic characteristics of the participant households in Turkey. We planned to investigate 6,000 representative households in 21 cities of Turkey; and a total of 5,323 households (response rate of 89%) aged between 18 and 65 years were examined for headache by 33 trained physicians at home on the basis of the diagnostic criteria of the second edition of the International Classification of Headache Disorders (ICHD-II). The electronically registered questionnaire was based on the headache features, the associated symptoms, demographic and socio-economic situation and history. Of 5,323 participants (48.8% women; mean age 35.9 +/- 12 years) 44.6% reported recurrent headaches during the last 1 year and 871 were diagnosed with migraine at a prevalence rate of 16.4% (8.5% in men and 24.6% in women), whereas only 270 were diagnosed with TTH at a prevalence rate of 5.1% (5.7% in men and 4.5% in women). The 1-year prevalence of probable migraine was 12.4% and probable TTH was 9.5% additionally. The rate of migraine with aura among migraineurs was 21.5%. The prevalence of migraine was highest among 35-40-year-old women while there were no differences in age groups among men and in TTH overall. More than 2/3 of migraineurs had ever consulted a physician whereas only 1/3 of patients with TTH had ever consulted a physician. For women, the migraine prevalence was higher among the ones with a lower income, while among men, it did not show any change by income. Migraine prevalence was lower in those with a lower educational status compared to those with a high educational status. Chronic daily headache was present in 3.3% and the prevalence of medication overuse headache was 2.1% in our population. There was an important impact of migraine with a monthly frequency of 5.9 +/- 6, and an attack duration of 35.1 +/- 72 h, but only 4.9% were on prophylactic treatment. The one-year prevalence of migraine estimated as 16.4% was similar or even higher than world-wide reported migraine prevalence figures and identical to a previous nation-wide study conducted in 1998, whereas the TTH prevalence was much lower using the same methodology with the ICHD-II criteria. PMID- 22246026 TI - Effect of CGRP and sumatriptan on the BOLD response in visual cortex. AB - To test the hypothesis that calcitonin gene-related peptide (CGRP) modulates brain activity, we investigated the effect of intravenous CGRP on brain activity in response to a visual stimulus. In addition, we examined if possible alteration in brain activity was reversed by the anti-migraine drug sumatriptan. Eighteen healthy volunteers were randomly allocated to receive CGRP infusion (1.5 MUg/min for 20 min) or placebo. In vivo activity in the visual cortex was recorded before, during and after infusion and after 6 mg subcutaneous sumatriptan by functional magnetic resonance imaging (3 T). 77% of the participants reported headache after CGRP. We found no changes in brain activity after CGRP (P = 0.12) or after placebo (P = 0.41). Sumatriptan did not affect brain activity after CGRP (P = 0.71) or after placebo (P = 0.98). Systemic CGRP or sumatriptan has no direct effects on the BOLD activity in visual cortex. This suggests that in healthy volunteers both CGRP and sumatriptan may exert their actions outside of the blood-brain barrier. PMID- 22246027 TI - The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation. AB - Community respiratory viruses are significant causes of morbidity and mortality in patients with leukemia and hematopoietic stem cell transplant (HSCT) recipients. Data on characteristics and outcomes of parainfluenza virus (PIV) infections in these patients are limited. We reviewed the records of patients with leukemia and HSCT recipients who developed PIV infections to determine the characteristics and outcomes of such infections. We identified 200 patients with PIV infections, including 80 (40%) patients with leukemia and 120 (60%) recipients of HSCT. At presentation, most patients (70%) had an upper respiratory tract infection and the remaining patients (30%) had pneumonia. Neutropenia, APACHE II score more than 15, and respiratory coinfections were independent predictors of progression to pneumonia on multivariate analysis. Overall mortality rate was 9% at 30 days after diagnosis and 17% among patients who had PIV pneumonia, with no significant difference between patients with leukemia and HSCT recipients (16% vs 17%). On multivariate analysis, independent predictors of death were relapsed or refractory underlying malignancy, APACHE II score more than 15, and high-dose steroid use. Patients with leukemia and HSCT are at risk for serious PIV infections, including PIV pneumonia, with a significant mortality rate. We identified multiple risk factors for progression to pneumonia and death. PMID- 22246028 TI - Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rgamma null mice is enhanced by transgenic expression of membrane-bound human SCF. AB - Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common gamma chain (IL2rg) gene, including NOD-scid IL2rgamma(null) (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of stem cell factor (SCF), which is critical for HSC engraftment, proliferation, and survival. We hypothesized that transgenic expression of human membrane-bound stem cell factor Tg(hu-mSCF)] would increase levels of human HSC engraftment in nonirradiated NSG mice and eliminate complications associated with irradiation. Surprisingly, detectable levels of human CD45(+) cell chimerism were observed after transplantation of cord blood derived human HSCs into nonirradiated adult as well as newborn NSG mice. However, transgenic expression of human mSCF enabled heightened levels of human hematopoietic cell chimerism in the absence of irradiation. Moreover, nonirradiated NSG-Tg(hu-mSCF) mice engrafted as newborns with human HSCs rejected human skin grafts from a histoincompatible donor, indicating the development of a functional human immune system. These data provide a new immunodeficient mouse model that does not require irradiation preconditioning for human HSC engraftment and immune system development. PMID- 22246029 TI - Glucose-6-phosphatase-beta, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality. AB - Glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) deficiency, also known as severe congenital neutropenia syndrome 4, is characterized not only by neutropenia but also by impaired neutrophil energy homeostasis and functionality. We now show the syndrome is also associated with macrophage dysfunction, with murine G6pc3(-/-) macrophages having impairments in their respiratory burst, chemotaxis, calcium flux, and phagocytic activities. Consistent with a glucose-6 phosphate (G6P) metabolism deficiency, G6pc3(-/-) macrophages also have a lower glucose uptake and lower levels of G6P, lactate, and ATP than wild-type macrophages. Furthermore, the expression of NADPH oxidase subunits and membrane translocation of p47(phox) are down-regulated, and G6pc3(-/-) macrophages exhibit repressed trafficking in vivo both during an inflammatory response and in pregnancy. During pregnancy, the absence of G6Pase-beta activity also leads to impaired energy homeostasis in the uterus and reduced fertility of G6pc3(-/-) mothers. Together these results show that immune deficiencies in this congenital neutropenia syndrome extend beyond neutrophil dysfunction. PMID- 22246030 TI - Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells. AB - Endothelial cells (ECs) express 2 members of the cadherin family, VE and N cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N cadherin leads to early fetal lethality suggesting that these cadherins play a nonredundant role in vascular development. We report here that VE-cadherin negatively controls junctional localization and expression of N-cadherin by limiting p120-catenin availability and reducing beta-catenin transcriptional activity. Using EC lines expressing either VE or N-cadherin we found that both cadherins inhibit cell proliferation and apoptosis. Both trigger the phosphatidylinositol-3-OH-kinase (PI3K)-AKT-Forkhead-box protein-O1 (FoxO1) pathway and reduce beta-catenin transcriptional activity. The extent of signaling correlates with the total level of cadherins regardless of the type of cadherin expressed. In contrast, basal and fibroblast growth factor (FGF)-induced cell motility is promoted by N-cadherin and strongly inhibited by VE-cadherin. This opposite effect is partly because of the ability of VE-cadherin to associate with FGF receptor and the density-enhanced phosphatase-1 (Dep-1) which, in turn, inhibits receptor signaling. We conclude that VE and N-cadherin have both additive and divergent effects on ECs. Differences in signaling are due, in part, to cadherin association with growth factor receptors and modulation of their downstream signaling. PMID- 22246032 TI - Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. AB - TLR ligands (TLR-Ls) represent novel vaccine adjuvants, but their immunologic effects in humans remain poorly defined in vivo. In the present study, we analyzed the innate responses stimulated by different TLR-Ls in rhesus macaques. MPL (TLR4-L), R-848 (TLR7/8-L), or cytosine-phosphate-guanine oligodeoxynucleotide (TLR9-L) induced a rapid and robust expansion of blood neutrophils, with a concomitant reduction in PBMCs. Furthermore, all TLR-Ls induced rapid (3-8 hours) expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L mobilized the CD14(+)CD16(+) and CD14(dim)CD16(++) monocytes, and only TLR7/8-L and TLR9-L induced activation of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs), production of IP-10 and type-I IFN, and expression of type-I IFN-related and chemokine genes in the blood. In the draining lymph nodes (LNs), consistent with the effects in blood, all TLR-Ls induced expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L expanded the activated CD14(+)CD16(+) cells. TLR4-L and TLR9-L differentially induced the expansion of mDCs and pDCs (1-3 days), but did not activate DCs. In contrast, TLR7/8-L did not induce DC expansion, but did activate mDCs. Finally, both TLR9-L and TLR7/8-L induced the expression of genes related to chemokines and type-I IFNs in LNs. Thus different TLR-Ls mediate distinct signatures of early innate responses both locally and systemically. PMID- 22246031 TI - Histone/protein deacetylases and T-cell immune responses. AB - Clinical and experimental studies show that inhibition of histone/protein deacetylases (HDAC) can have important anti-neoplastic effects through cytotoxic and proapoptotic mechanisms. There are also increasing data from nononcologic settings that HDAC inhibitors (HDACi) can exhibit useful anti-inflammatory effects in vitro and in vivo, unrelated to cytotoxicity or apoptosis. These effects can be cell-, tissue-, or context-dependent and can involve modulation of specific inflammatory signaling pathways as well as epigenetic mechanisms. We review recent advances in the understanding of how HDACi alter immune and inflammatory processes, with a particular focus on the effects of HDACi on T-cell biology, including the activation and functions of conventional T cells and the unique T-cell subset, composed of Foxp3(+) T-regulatory cells. Although studies are still needed to tease out details of the various biologic roles of individual HDAC isoforms and their corresponding selective inhibitors, the anti-inflammatory effects of HDACi are already promising and may lead to new therapeutic avenues in transplantation and autoimmune diseases. PMID- 22246033 TI - Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. AB - Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ~ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. PMID- 22246034 TI - A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event. PMID- 22246036 TI - How I treat heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia is a prothrombotic adverse drug effect induced by platelet-activating antibodies against multimolecular complexes of platelet factor 4 and heparin. Diagnosis rests on a clinical assessment of disease probability and laboratory testing. Management involves immediate discontinuation of heparin and initiation of an alternative anticoagulant. Because of the frequency of thrombocytopenia among heparinized patients, the limited specificity of widely available immunoassays, the limited availability of more specific functional assays, and clinicians' fears of missing a case of true disease, overtesting, overdiagnosis, and overtreatment have become common. As a result, a substantial number of thrombocytopenic patients are unnecessarily exposed to costly alternative anticoagulants and their attendant risk of bleeding. In this review, we describe not only our approach to the evaluation and management of patients with heparin-induced thrombocytopenia, but also the measures we use to minimize misdiagnosis and unnecessary treatment of patients without the disease. In addition, we propose areas of investigation for improvement of the diagnosis and management of this potentially fatal disorder. PMID- 22246035 TI - Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function. AB - HM1.24, an immunologic target for multiple myeloma (MM) cells, has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). In this study, we investigated in vitro and in vivo anti-MM activities of XmAb5592, a humanized anti-HM1.24 mAb with Fc-domain engineered to significantly enhance FcgammaR binding and associated immune effector functions. XmAb5592 increased antibody-dependent cellular cytotoxicity (ADCC) several fold relative to the anti HM1.24 IgG1 analog against both MM cell lines and primary patient myeloma cells. XmAb5592 also augmented antibody dependent cellular phagocytosis (ADCP) by macrophages. Natural killer (NK) cells became more activated by XmAb5592 than the IgG1 analog, evidenced by increased cell surface expression of granzyme B dependent CD107a and MM cell lysis, even in the presence of bone marrow stromal cells. XmAb5592 potently inhibited tumor growth in mice bearing human MM xenografts via FcgammaR-dependent mechanisms, and was significantly more effective than the IgG1 analog. Lenalidomide synergistically enhanced in vitro ADCC against MM cells and in vivo tumor inhibition induced by XmAb5592. A single dose of 20 mg/kg XmAb5592 effectively depleted both blood and bone marrow plasma cells in cynomolgus monkeys. These results support clinical development of XmAb5592, both as a monotherapy and in combination with lenalidomide, to improve patient outcome of MM. PMID- 22246037 TI - Demand-adapted regulation of early hematopoiesis in infection and inflammation. AB - During systemic infection and inflammation, immune effector cells are in high demand and are rapidly consumed at sites of need. Although adaptive immune cells have high proliferative potential, innate immune cells are mostly postmitotic and need to be replenished from bone marrow (BM) hematopoietic stem and progenitor cells. We here review how early hematopoiesis has been shaped to deliver efficient responses to increased need. On the basis of most recent findings, we develop an integrated view of how cytokines, chemokines, as well as conserved pathogen structures, are sensed, leading to divisional activation, proliferation, differentiation, and migration of hematopoietic stem and progenitor cells, all aimed at efficient contribution to immune responses and rapid reestablishment of hematopoietic homeostasis. We also outline how chronic inflammatory processes might impinge on hematopoiesis, potentially fostering hematopoietic stem cell diseases, and, how clinical benefit is and could be achieved by learning from nature. PMID- 22246038 TI - Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. AB - A strategy to produce sufficient anticoagulant properties with reduced risk of bleeding may be possible through inhibition of factor XI (FXI), a component of the intrinsic coagulation cascade. The objective of this work was to determine the safety profile of ISIS 416858, a 2'-methoxyethoxy (2'-MOE) antisense oligonucleotide inhibitor of FXI, with focus on assessment of bleeding risk. Cynomolgus monkeys administered ISIS 416858 (4, 8, 12, and 40 mg/kg/wk, subcutaneous) for up to 13 weeks produced a dose-dependent reduction in FXI (mRNA in liver and plasma activity) and a concomitant increase in activated partial thromboplastin time (APTT). ISIS 416858 (20 or 40 mg/kg/wk) reduced plasma FXI activity by 80% at 4 weeks of treatment that resulted in a 33% increase in APTT by 13 weeks with no effects on PT, platelets, or increased bleeding following partial tail amputation or gum and skin laceration. The dose-dependent presence of basophilic granules in multiple tissues in ISIS 416858-treated animals was an expected histologic change for a 2'-MOE antisense oligonucleotide, and no toxicity was attributed to hepatic FXI reduction. Basophilic granules reflect cellular drug uptake and subsequent visualization on hematoxylin staining. These results suggest that ISIS 416858 has an acceptable preclinical safety profile and is a promising clinical candidate to treat thrombotic disease. PMID- 22246039 TI - Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with "normal" FISH: correlations with clinicobiologic parameters. AB - It is unclear whether karyotype aberrations that occur in regions uncovered by the standard fluorescence in situ hybridization (FISH) panel have prognostic relevance in chronic lymphocytic leukemia (CLL). We evaluated the significance of karyotypic aberrations in a learning cohort (LC; n = 64) and a validation cohort (VC; n = 84) of patients with chronic lymphocytic leukemia with "normal" FISH. An abnormal karyotype was found in 21.5% and 35.7% of cases in the LC and VC, respectively, and was associated with a lower immunophenotypic score (P = .030 in the LC, P = .035 in the VC), advanced stage (P = .040 in the VC), and need for treatment (P = .002 in the LC, P = < .0001 in the VC). The abnormal karyotype correlated with shorter time to first treatment and shorter survival in both the LC and the VC, representing the strongest prognostic parameter. In patients with chronic lymphocytic leukemia with normal FISH, karyotypic aberrations by conventional cytogenetics with novel mitogens identify a subset of cases with adverse prognostic features. PMID- 22246040 TI - Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. AB - We examined the prevalence and prognostic relevance of bone marrow reticulin fibrosis in 526 patients with World Health Organization-defined polycythemia vera evaluated at the time of initial diagnosis. Seventy-four patients (14%) displayed mostly grade 1 reticulin fibrosis, with only 2 cases showing higher-grade fibrosis. Presenting clinical and laboratory characteristics, including JAK2V617F allele burden, between patients with and without fibrosis were similar for the most part, with the exception of a higher prevalence of palpable splenomegaly in patients with fibrosis (P < .01). Patients with fibrosis were less prone to experience thrombosis during their clinical course (1.1 vs 2.7 per 100 patient years; P = .03) and more prone to develop post-polycythemia vera myelofibrosis (2.2 vs 0.8 per 100 patient-years; P = .01). There was no significant difference between the 2 groups in terms of overall or leukemia-free survival. The present study clarifies the incidence, degree, and prognostic relevance of bone marrow fibrosis obtained at time of initial diagnosis of polycythemia vera. PMID- 22246041 TI - Nurse-led care for the management of side effects of pelvic radiotherapy: what does it achieve? AB - PURPOSE OF REVIEW: To describe what a nurse-led clinic can achieve, focusing on gastrointestinal side effects after pelvic radiotherapy. This article illustrates how a structured approach for management and treatment of late gastrointestinal symptoms after pelvic radiotherapy can be used as a model for other nurse-led clinics. RECENT FINDINGS: A large majority of cancer survivors treated for gynaecological, rectal and anal cancer suffer from physical symptoms from the bowels, the urinary bladder and the genitals. These long-term side effects lead to impairment of social functioning, sexual dysfunction and lowered quality of life. A structured model for the comprehensive management of cancer survivors can help care givers to offer patients treated with pelvic radiotherapy, methods that could help them to more fully restore physical health. SUMMARY: Nurses play an important role in the rehabilitation of cancer patients, improving patients' quality of life and psychosocial well being, and they are in the best position to provide continuity during the tailoring of rehabilitation care. PMID- 22246043 TI - Interventional management of cancer pain. AB - PURPOSE OF REVIEW: Interventional techniques were the mainstay for cancer pain management before the WHO ladder and opioids were freely available. The three step WHO ladder has its limitations, and cancer pain is often under treated. Advances in treatment options mean that cancer patients are living longer and pain interventions may have a role to play even early in the cancer diagnosis for better quality of analgesia. The role of high doses of opioids in pain management is also currently under scrutiny. RECENT FINDINGS: Recent advances in intrathecal analgesia, radiofrequency techniques, both in tumour ablation and neurotomies, are being widely used for palliation. Vertebroplasty techniques have been used not only for pain relief, but also for stabilization. Improved imaging and thoracoscopic techniques have made coeliac plexus and splanchnic blockade safer and more efficacious. There has been recent interest in percutaneous cordotomy with newer techniques using computed tomography/MRI and endoscopy guidance. Percutaneous electrical nerve stimulation and 8% capsaicin patches have been successfully used for managing neuropathic pain in cancer. SUMMARY: Interventions form an integral part in providing pain relief in complex cancer pains. Oncologists and palliative care physicians are to be educated on the usefulness and timing of interventions in the management of complex cancer pain. PMID- 22246042 TI - Visceral pain: the ins and outs, the ups and downs. AB - PURPOSE OF REVIEW: Visceral pain represents a major clinical problem, yet far less is known about its mechanisms compared with somatic pains, for example, from cutaneous and muscular structures. RECENT FINDINGS: In this review, we describe the neuroanatomical bases of visceral pain signalling in the peripheral and central nervous system, comparing to somatic pains and also the channels and receptors involved in these events. We include an overview of potential new targets in the context of mechanisms of visceral pain and hypersensitivity. SUMMARY: This review should inform on the recognition of what occurs in patients with visceral pain, why comorbidities are common and how analgesic treatments work. PMID- 22246044 TI - Screening, diversity and partial sequence comparison of vegetative insecticidal protein (vip3A) genes in the local isolates of Bacillus thuringiensis Berliner. AB - Characterization, direct sequencing of the PCR amplicon and phylogenetic relationship was done to discover a novel Vip protein genes of the Bt isolates, to improve the prospects for insect control, more Vip proteins should be sought out and researched to predict their insecticidal activity. Characterization was based on direct sequencing of PCR amplicon using primers specific to vip3A gene was presented here. 12 out of 18 isolates screened were positive for vip gene specific primers. Homology search for the partial sequences using BLAST showed that 11 isolates had high similarity to vip3Aa gene and only one fragment with vip3Ae gene (25-100% at nucleotide and amino acid level). Phylogenetic analysis showed that the gene sequences were responsible for geographic separation for divergence within vip genes, consistent with the evaluation of distinct bacterial population. Despite the geographical distances, strains harbouring vip genes have originated from common ancestors may significantly contribute to control resistant insect pests. Some strains have evolved to be quite distinct and others remain as members of closely related groups. The reported method is a powerful tool to find novel Vip3A proteins from large-scale Bt strains which is effective in terms of time and cost. Further the Vip proteins produced by different strains of B. thuringiensis are unique in terms of the sequence divergence and hence may also differ in their insecticidal activities. PMID- 22246045 TI - Profiling an electrospray plume by laser-induced fluorescence and Fraunhofer diffraction combined to mass spectrometry: influence of size and composition of droplets on charge-state distributions of electrosprayed proteins. AB - We investigated how physico-chemical properties of charged droplets are affected by the electrospray process, using simultaneous in situ measurements by laser induced fluorescence (LIF), Fraunhofer diffraction and mass spectrometry. For this purpose, we implemented a laser-induced-fluorescence profiling setup in conjunction with a fast, high-resolution particle sizing scheme on a modified Agilent Jet Stream electrospray source coupled to a single quadrupole mass analyser. The optical setup permits us to profile the solvent fractionation and the size of the droplets as they evaporate in an electrospray plume by measuring both the angular scattering pattern and emission spectra of a solvatochromic fluorescent dye. Mass spectra are recorded simultaneously. These mass spectrometry and optical spectroscopy investigations allow us to study the relation between the observed charge-state distributions of protein anions and physico-chemical properties of evaporating droplets in the spray plume. By mixing water with methanol, a refolding of cytochrome C is observed as the water percentage increases in the plume due to the preponderant evaporation of volatile methanol. PMID- 22246046 TI - Catalytic dephosphorylation of adenosine monophosphate (AMP) to form supramolecular nanofibers/hydrogels. AB - The use of enzyme to instruct the self-assembly of the nucleoside of adenosine in water provides a new class of molecular nanofibers/hydrogels as functional soft materials. PMID- 22246047 TI - Application of elemental bioimaging using laser ablation ICP-MS in forest pathology: distribution of elements in the bark of Picea sitchensis following wounding. AB - Element distribution in the bark of two 20-year-old clones of Picea sitchensis following wounding was studied using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Bark was sampled at 0, 3, and 43 days after wounding and analysed using a focused Nd:YAG laser (266 nm). Intensities of (13)C, (25)Mg, (27)Al, (31)P, (32)S, (39)K, (48)Ca, (55)Mn, (57)Fe, (63)Cu and (64)Zn were measured by ICP-MS to study elemental distribution across the bark samples during the wound repair process. A clear accumulation of Mg, P and K at the boundary zone between the lesion and healthy tissue was detected in the wounded samples and was more distinctive at 43 than at 3 days after treatment. This zone of accumulation mapped onto the position of formation of the ligno suberised boundary zone and differentiation of the wound periderm. These accumulations suggest major roles for Mg, P and K in the non-specific response of Sitka spruce both to wounding, possibly as co-factors to enzymes and energy utilisation. The LA-ICP-MS method developed in this work proved useful to study spatial element distribution across bark samples and has great potential for applications in other areas of plant pathology research. PMID- 22246049 TI - Shear bond strength and enamel fracture behavior of ceramic brackets Fascination(r) and Fascination(r)2. AB - OBJECTIVE: The purpose of this study was to compare the shear bond strength and incidence of enamel fractures of the ceramic brackets Fascination(r) and Fascination(r)2. MATERIALS AND METHODS: A total of 360 teeth (180 first upper bicuspids and 180 lower incisors) were stored in 96% ethanol, while 360 other teeth (180 first upper bicuspids and 180 lower incisors) were stored in 0.1% thymol. All 720 teeth were bonded one-half each with Fascination(r) and Fascination(r)2 brackets using three different adhesives and three different light curing units. The teeth were debonded with a debonding-device according to DIN EN ISO 10477 using a universal testing machine with a crosshead speed of 1 mm per minute. The enamel surface was then examined stereomicroscopically (10x and 40x magnification). The non-parametric Mann-Whitney U test was used, since the data were not normally distributed. RESULTS: The Fascination(r)2 brackets provided significantly lower shear bond strength than Fascination(r) brackets (p = 0.003). Fascination(r) brackets demonstrated significantly fewer, smaller enamel fractures than Fascination(r)2 brackets (p = 0.012). CONCLUSION: The lower shear bond strength of the Fascination(r)2 brackets is clinically acceptable, but our study's experimental design did not enable us to prove whether this is clinically associated with a lower risk of enamel fracture. PMID- 22246050 TI - Self-propelling surfactant droplets in chemically-confined microfluidics--cargo transport, drop-splitting and trajectory control. AB - We demonstrate the applicability of self-propulsion as a passive driving mechanism for droplets in chemically-confined microfluidics. The droplets can be used to transport considerably sized solid cargo particles. We implemented thermal actuation as a steering mechanism for the droplets at fluidic junctions. PMID- 22246048 TI - Impacted upper canines: examination and treatment proposal based on 3D versus 2D diagnosis. AB - AIM: The purpose of this diagnostic cross-over study was to evaluate whether three-dimensional (3D) diagnostics (cone-beam computed tomography, CBCT) was superior to two-dimensional (2D) diagnostics (panoramic X-ray, OPG) in patients with impacted upper canines for assessing their position and the probability of their alignment. MATERIALS AND METHODS: Panoramic X-rays, CBCTs, and study casts of 21 patients with a total of 29 impacted maxillary canines were analyzed. Patients with syndromes or tooth aplasias were excluded. A total of 26 dentists of various specialist disciplines rated different parameters, such as canine position and their probability of alignment as well as their relation to and resorption of adjacent teeth. 2D X-rays and study casts were rated first; then 3D images and casts were evaluated at least 2 weeks later. The actual level of displacement was defined by two trained examiners and labeled as the master finding, according to modified criteria established by Ericson and Kurol (1988). RESULTS: In 64% of all patients, canine position was assessed concordantly in 2D and 3D images. 2D assessments were in slight agreement (kappa = 0.374), while 3D ratings were in good agreement with the master findings (kappa = 0.714). Two thirds of the canines' apical regions were judged identifiable in 2D and 3D images; more than 1/4 of the canines' apices were not identifiable in 2D images, but were identifiable in 3D images. The diagnosis of lateral incisor root resorption in the CBCT agreed well with the master finding (kappa = 0.634), but examiners overlooked slight resorption in 20% of the patients. In 82% of the patients teeth, treatment suggestions (orthodontic alignment or surgical removal) were the same for 2D and 3D images. Canine inclination visible in the panoramic X rays was the most important factor influencing the treatment proposal. CONCLUSION: Small volume CBCT may be justified as a supplement to a routine panoramic X-ray in the following cases: when canine inclination in the panoramic X-ray exceeds 30 degrees , when root resorption of adjacent teeth is suspected, and/or when the canine apex is not clearly discernible in the panoramic X-ray, implying dilaceration of the canine root. We intend to validate the results of this study in a clinical trial. PMID- 22246052 TI - Hormone level and dopamine tells the value of food. PMID- 22246053 TI - The adsorption of quinizarin on boron-doped diamond. AB - The voltammetric response of the quinone species 'quinizarin' (QZ) and its electrocatalytic reduction of oxygen are studied at a boron doped diamond electrode (BDD). It is demonstrated that, contrary to the widespread belief that adsorption of organic molecules on BDD is minimal, not only does QZ readily adsorb to the electrodes surface but this adsorption is also influenced at low surface coverages by the pre-exposure of the electrode to organic solvents. Furthermore, the nature of this adsorbed QZ species is investigated and a potential dependent phase transition is observed. This is to the authors knowledge the first system to exhibit a phase transition of an adsorbed species on a boron doped diamond surface. At low scan rates the system is found to oscillate; these oscillations are ascribed to the presence of a 'negative differential resistance'. PMID- 22246054 TI - Passive and active contributions to generated force and retraction in heart valve tissue engineering. AB - In tissue engineered heart valves, cell-mediated stress development during culture results in leaflet retraction at time of implantation. This tissue retraction is partly active due to traction forces exerted by the cells and partly passive due to release of residual stress in the extracellular matrix and the cells. Within this study, we unraveled the passive and active contributions of cells and matrix to generated force and retraction in engineered heart valve tissues. Tissue engineered rectangular strips, fabricated from PGA/P4HB scaffolds and seeded with human myofibroblasts, were cultured for 4 weeks, after which the cellular contribution was changed at different levels. Elimination of the active cellular traction forces was achieved with Cytochalasin D and inhibition of the Rho-associated kinase pathway. Both active and passive cellular contributions were eliminated by lysation and/or decellularization of the tissue. Maximum cell activity was reached by increasing the fetal bovine serum concentration to 50%. The generated force decreased ~20% after elimination of the active cellular component, ~25% when the passive cellular component was removed as well and remained unaffected by increased serum concentrations. Passive retraction accounted for ~60% of total retraction, of which ~15% was residual stress in the matrix and ~45% was passive cell retraction. Cell traction forces accounted for the remainder ~40% of the retraction. Full activation of the cells increased retraction by ~45%. These results illustrate the importance of the cells in the process of tissue retraction, not only actively retracting the tissue, but also in a passive manner to a large extent. PMID- 22246055 TI - Val247Leu beta2-glycoprotein-I allelic variant is associated with antiphospholipid syndrome: systematic review and meta-analysis. AB - INTRODUCTION: Previous studies have suggested that the possession of the Val/Val genotype of the Val247Leu polymorphism of the beta(2)-glycoproteinI (beta(2)-GPI) gene may be associated with antiphospholipid syndrome (APS), and, among patients with APS, with the production of anti-beta(2)-GPI antibodies or the development of thrombosis. Given the controversial results reported, the aim of this work is to combine previous findings by means of a systematic review and a meta-analysis. METHODS: We retrieved studies analyzing the genotype of the above-mentioned polymorphism among patients with APS by means of electronic database search. A meta-analysis was conducted in a random effects model and calculations of odds ratio (OR) and confidence intervals (CI) were done. Sensitivity analysis and tests for heterogeneity of the results were performed. RESULTS: Eight previous studies analyzed the association of APS, anti-beta(2)-GPI antibodies and/or thrombosis with the Val247Leu polymorphism. After meta-analysis, patients with APS had a significantly higher prevalence of the Val/Val genotype of this genetic variant when compared with controls (OR=2.04; 95% CI: 1.12, 3.73; P=0.02). Among patients with APS, those with anti-beta(2)-GPI antibodies had a higher prevalence of this genotype (OR=1.73; 95% CI: 1.04, 2.87; P=0.03). No significant results were found for the presence of arterial or venous thrombosis. CONCLUSIONS: Val/Val genotype of beta(2)-GPI gene is associated with a significant excess risk to suffer from APS and, among patients with APS, to have anti-beta(2)-GPI antibodies. No definite conclusions can be made regarding the association of this polymorphism with thrombosis among APS patients. PMID- 22246056 TI - A certain amount of planning. PMID- 22246051 TI - The role of ATP-binding cassette transporters in bacterial pathogenicity. AB - The ATP-binding cassette transporter superfamily is present in all three domains of life. This ubiquitous class of integral membrane proteins have diverse biological functions, but their fundamental role involves the unidirectional translocation of compounds across cellular membranes in an ATP coupled process. The importance of this class of proteins in eukaryotic systems is well established as typified by their association with genetic diseases and roles in the multi-drug resistance of cancer. In stark contrast, the ABC transporters of prokaryotes have not been exhaustively investigated due to the sheer number of different roles and organisms in which they function. In this review, we examine the breadth of functions associated with microbial ABC transporters in the context of their contribution to bacterial pathogenicity and virulence. PMID- 22246058 TI - Evaluation and calibration of a binocular infrared pupillometer for measuring relative afferent pupillary defect. AB - BACKGROUND: Binocular infrared pupillometry allows an estimate of the relative afferent pupillary defect (RAPD), designated the pupillometric RAPD (pRAPD). We calibrated the pRAPD of a commercially available pupillometer against neutral density filters (NDFs) of known attenuation. The performance of the pupillometer using its own proprietary algorithm is assessed and compared to that of alternative algorithms. METHODS: The pRAPDs of 50 healthy volunteers were measured with each of 4 filters of known attenuation: 0.0, 0.3, 0.6, and 0.9 log units, positioned unilaterally in the light stimulus pathway. The filter values were plotted against the pupillometer output, and the slope and intercept were used to determine a calibration factor. Corrected pRAPD results were used to assess physiological ranges of pRAPD. The sensitivity and specificity to 0.3 log unit differences between increasing filter densities using receiver operator characteristic (ROC) curves. RESULTS: The calibrated physiological pRAPD ranged from 0 to 0.22 log units. The area under the ROC curve for detecting unilateral simulated pRAPD of 0.3 log units, the simulated disease progression from 0.3 to 0.6 log units, and a further progression from 0.6 to 0.9 log units by NDFs was 0.99 (95% confidence interval [CI], 0.95-1.00), 0.86 (95% CI, 0.78-0.92), and 0.79 (95% CI, 0.70-0.87), respectively. The optimum discrimination was for detecting a unilateral simulated pRAPD of 0.3 log units; sensitivity and specificity was 98% (95% CI, 88%-99%). CONCLUSION: The commercially available pupillometer detects the RAPD induced by the NDFs with high sensitivity and specificity. The results suggest that it is best for detecting unilateral early disease but potentially useful for assessing progression of disease. PMID- 22246059 TI - Cortical vision loss as a prominent feature of H1N1 encephalopathy. AB - A 20-year-old woman infected with the 2009 H1N1 strain of influenza A developed bilateral visual loss. Brain MRI showed restricted diffusion of the parietal and occipital lobes, and her spinal fluid did not contain inflammatory cells. This report describes an unusual case of H1N1 influenza A virus infection primarily affecting the posterior visual pathways. PMID- 22246057 TI - IL-33 regulates TNF-alpha dependent effects in synovial fibroblasts. AB - The recently described IL-33 acts as a pro-inflammatory cytokine, inducing the expression of multiple responses in the target cells. Although a nuclear localization of IL-33 has been described, its exact functional relevance is presently unknown. The present study was conducted to analyze the effects of IL 33 on the TNF-alpha induced synthesis of the pro-inflammatory mediators IL-6, IL 8, and monocyte chemotactic protein-1 (MCP-1) and the pro-destructive molecules matrix metalloproteinase-1 (MMP-1), MMP-3, and TIMP-1 of rheumatoid arthritis synovial fibroblast (RA-SFs) using RNA overexpression and silencing. TNF-alpha significantly induced IL-33 mRNA expression and protein synthesis in RA-SFs. TNF alpha-induced IL-33 protein expression was mediated via p38 signaling. Immunohistochemistry for IL-33 clearly showed that nuclear translocation of IL-33 was induced in TNF-alpha stimulated RA-SFs. IL-33 overexpression enhanced TNF alpha-induced pro-inflammatory and pro-destructive functions in RA-SFs. IL-33 silencing significantly downregulated TNF-alpha-induced pro-inflammatory functions, whereas TNF-alpha-induced pro-destructive functions were less influenced by IL-33 silencing. This study identifies IL-33 as a critical regulator/enhancer of TNF-alpha-induced functions in RA-SFs, pointing to a central role of this cytokine in the perpetuation of pro-inflammatory and pro destructive processes in rheumatoid arthritis (RA) and other inflammatory and degenerative diseases. PMID- 22246061 TI - Top-down search for color prevents voluntary directing of attention to informative singleton cues. AB - Visuo-spatial attention can be directed in a top-down controlled way to search for color targets and it can be captured by color contrasts, regardless of color identity. Here we tested whether participants can both search for a particular color target (e.g., red) and make use of a color-contrast cue that predicted the target's most likely position to direct their attention voluntarily. Our results show that this was impossible for the participants. Results support that top-down search for particular colors is incommensurate with directing attention to just any color contrast. The results are discussed in light of the current debates concerning the roles of color and color contrast for visuo-spatial attention. PMID- 22246060 TI - Nonconvulsive status epilepticus presenting as epileptic nystagmus in a patient with herpes encephalitis. AB - Epileptic nystagmus (EN) is characterized by rhythmic ocular oscillations or quick, repetitive eye movements secondary to seizure activity. The fast component of EN is known to be contralateral to the epileptogenic focus. There are few reports EN occurring patients in nonconvulsive status epilepticus (NCSE). We report such a patient in the setting of herpes encephalitis. PMID- 22246062 TI - Spatial reference in multiple object tracking. AB - Spatial reference in multiple object tracking is available from configurations of dynamic objects and static reference objects. In three experiments, we studied the use of spatial reference in tracking and in relocating targets after abrupt scene rotations. Observers tracked 1, 2, 3, 4, and 6 targets in 3D scenes, in which white balls moved on a square floor plane. The floor plane was either visible thus providing static spatial reference or it was invisible. Without scene rotations, the configuration of dynamic objects provided sufficient spatial reference and static spatial reference was not advantageous. In contrast, with abrupt scene rotations of 20 degrees , static spatial reference supported in relocating targets. A wireframe floor plane lacking local visual detail was as effective as a checkerboard. Individually colored geometric forms as static reference objects provided no additional benefit either, even if targets were centered on these forms at the abrupt scene rotation. Individualizing the dynamic objects themselves by color for a brief interval around the abrupt scene rotation, however, did improve performance. We conclude that attentional tracking of moving targets proceeds within dynamic configurations but detached from static local background. PMID- 22246063 TI - The effect of path length and display size on memory for spatial information. AB - In serial memory for spatial information, some studies showed that recall performance suffers when the distance between successive locations increases relatively to the size of the display in which they are presented (the path length effect; e.g., Parmentier et al., 2005) but not when distance is increased by enlarging the size of the display (e.g., Smyth & Scholey, 1994). In the present study, we examined the effect of varying the absolute and relative distance between to-be-remembered items on memory for spatial information. We manipulated path length using small (15") and large (64") screens within the same design. In two experiments, we showed that distance was disruptive mainly when it is varied relatively to a fixed reference frame, though increasing the size of the display also had a small deleterious effect on recall. The insertion of a retention interval did not influence these effects, suggesting that rehearsal plays a minor role in mediating the effects of distance on serial spatial memory. We discuss the potential role of perceptual organization in light of the pattern of results. PMID- 22246064 TI - Multicenter assessment of the reproducibility of volumetric radiofrequency-based intravascular ultrasound measurements in coronary lesions that were consecutively stented. AB - To assess in a multicenter design the between-center reproducibility of volumetric virtual histology intravascular ultrasound (VH-IVUS) measurements with a semi-automated, computer-assisted contour detection system in coronary lesions that were consecutively stented. To evaluate the reproducibility of volumetric VH IVUS measurements, experienced analysts of 4 European IVUS centers performed independent analyses (in total 8,052 cross-sectional analyses) to obtain volumetric data of 40 coronary segments (length 20.0 +/- 0.3 mm) from target lesions prior to percutaneous intervention that were performed in the setting of stable (65%) or unstable angina pectoris (35%). Geometric and compositional VH IVUS measurements were highly correlated for the different comparisons. Overall intraclass correlation for vessel, lumen, plaque volume and plaque burden was 0.99, 0.92, 0.96, and 0.83, respectively; for fibrous, fibro-lipidic, necrotic core and calcified volumes overall intraclass correlation was 0.96, 0.94, 0.98, and 0.99, respectively. Nevertheless, significant differences for both geometrical and compositional measurements were seen. Of the plaque components, fibrous tissue and necrotic core showed on average the highest measurement reproducibility. A central analysis for VH-IVUS multicenter studies of lesions prior to PCI should be pursued. Moreover, it may be problematical to pool VH-IVUS data of individual trials analyzed by independent centers. PMID- 22246065 TI - Evaluation of Brugada syndrome by cardiac magnetic resonance. AB - Brugada syndrome (BrS) has been originally considered to occur in structural normal hearts. However recent pathological and imaging data suggest that structural and functional changes may be present in this syndrome. This study was designed to elucidate whether any macroscopic heart abnormality is detectable in patients with BrS. For this purpose we used cardiac magnetic resonance (CMR). Twenty-nine patients displaying the BrS type-1 ECG pattern and 29 healthy controls underwent CMR (1.5 Tesla). Left (LV) and right ventricular (RV) dimensions, function and regional contractility were evaluated. Late-gadolinium enhancement (LGE) imaging was obtained in 24 patients. We found no difference between BrS patients and controls regarding LV and RV dimensions and ejection fraction. RV wall motion abnormalities (WMA) were detected in 19 patients (65.5%) and in 22 control subjects (75.9%). The majority of these WMA were attributable to areas of hypokinesia and found in the RV inferior wall. None of the patients showed LGE. No differences were detected between controls and the different subgroups of BrS patients according to symptoms, family history and spontaneous type-1 ECG pattern. BrS patients do not differ from normal subjects with regard to dimensions and global function of both LV and RV. BrS patients may show RV WMA, however similar changes are also present in healthy subjects and may therefore represent a physiological behaviour of RV. The lack of LGE further confirms the absence of myocardial structural damage. Our results indicate that BrS seems to occur in individuals with structurally and functionally normal heart. PMID- 22246066 TI - Reconstructing pedigrees: some identifiability questions for a recombination mutation model. AB - Pedigrees are directed acyclic graphs that represent ancestral relationships between individuals in a population. Based on a schematic recombination process, we describe two simple Markov models for sequences evolving on pedigrees--Model R (recombinations without mutations) and Model RM (recombinations with mutations). For these models, we ask an identifiability question: is it possible to construct a pedigree from the joint probability distribution of extant sequences? We present partial identifiability results for general pedigrees: we show that when the crossover probabilities are sufficiently small, certain spanning subgraph sequences can be counted from the joint distribution of extant sequences. We demonstrate how pedigrees that earlier seemed difficult to distinguish are distinguished by counting their spanning subgraph sequences. PMID- 22246067 TI - Correlation between hammerhead ribozyme-mediated eggshell protein gene cleavage and reproduction inhibition of Schistosoma japonicum. AB - Schistosoma japonicum (S. japonicum) is an extremely harmful pathogen, which infects humans and causes severe public health problems. To date, no effective therapeutic drugs for this pathogen are available. In this study, we designed and constructed three hammerhead ribozymes targeting the eggshell protein gene of S. japonicum (SjESG). The cleavage activities of these three ribozymes were determined using cleavage experiments. The in vitro cleavage results showed that among the three synthesized ribozymes (Rz1, Rz2 and Rz3), Rz1 and Rz3 cleaved their target RNAs effectively. However, Rz2 did not cleave its target RNA detectably. The putative therapeutic roles of these three ribozymes to inhibit the reproduction of S. japonicum in mice were studied in vivo. Compared with the negative controls, Rz1 and Rz3 treatments resulted in increased levels of IFN gamma but decreased levels of IL-4 in mice. Rz2 affected levels of IFN-gamma and IL-4 to degrees similar with those caused by the vector controls. In addition, Rz1 and Rz3 reduced the amounts of adult worms and eggs in the livers of mice more extensively than Rz2 and the vector controls. Altogether, these results suggest a correlation between the in vitro cleavage abilities of Rz1 and Rz3 and their roles in reproduction inhibition of S. japonicum. PMID- 22246068 TI - Hierarchical assembly of a homochiral triple concentric helical system in a novel 3D supramolecular metal-organic framework: synthesis, crystal structure, and SHG properties. AB - The hierarchical assembly of a homochiral triple concentric helical system in a novel 3D metal-organic framework with SHG activity has been observed. The result also provides a better understanding of host-guest chemistry and the process of water transport in biological systems. PMID- 22246069 TI - Optimized conditions for transgenesis of the ascidian Ciona using square wave electroporation. AB - The protochordate Ciona has recently become an important model organism for the study of developmental gene regulation, in part because transient transgenic embryos can be produced rapidly and reliably using electroporation. Published methods are currently for the use of electroporation devices delivering exponentially decaying pulses. However, some workers have advocated the use of square wave electroporation devices for eukaryotic transgenics. This paper presents results of experiments to find optimal conditions for the use of square wave electroporation in the ascidian Ciona. In the present analysis, a single pulse of 90 msec duration at 63-75 V/cm was found to give an optimal balance of a high proportion of cells transformed with the transgene, and a low level of abnormal development. Forty micrograms of DNA per electroporation is sufficient for effective visualization of reporter gene expression, although doses up to 100 MUg provide higher proportions of transformed cells. In side-by-side comparison with exponential pulse electroporation, square wave pulses give similar penetrance of transgene expression, along with lower proportions of embryos with abnormal development at higher amounts of input DNA. PMID- 22246070 TI - Replication of biosynthetic reactions enables efficient synthesis of A-factor, a gamma-butyrolactone autoinducer from Streptomyces griseus. AB - We report a concise synthesis of A-factor, the prototypical gamma-butyrolactone signalling compound of Streptomyces bacteria. In analogy to enzymatic reactions in A-factor biosynthesis, our synthesis features a tandem esterification Knoevenagel condensation yielding a 2-acyl butenolide and a surprising, chemoselective conjugate reduction of this alpha,beta-unsaturated carbonyl compound using sodium cyanoborohydride. PMID- 22246071 TI - Do monovalent mobile ions affect DNA's flexibility at high salt content? AB - Numerous theoretical and experimental studies disagree on the impact of surrounding mobile ions on DNA conformational flexibility at high salt content. Specifically, it is not clear how the DNA persistence length varies when concentration of monovalent mobile ions is increased beyond the physiological value of ~0.1 M. In the present Communication we address this biologically important issue computationally by means of molecular dynamics simulations. We utilize our recently developed chemically accurate coarse-grained model for the double-stranded DNA with explicit mobile ions. We find that in a range of moderate-to-high ionic concentrations, ~0.1-1 M, DNA persistence length drops noticeably by ~25%. Our results contradict some experimental works and the celebrated theory of Odijk, Skolnick and Fixman (Skolnick et al., Macromolecules, 1977, 10, 944), suggesting a negligible variation of DNA persistence length at these concentrations. On the other hand, our findings are in near quantitative agreement with a number of other theoretical and experimental studies. Combined with our recent work on elucidating the role of elastic and electrostatic effects in maintaining DNA shape, the results reported here may indicate that conceptually new understanding of DNA rigidity needs to be developed. PMID- 22246072 TI - [Professor Siewert and Professor Schumpelick retire. After influencing Der Chirurg for 25 years]. PMID- 22246074 TI - [Valid liability law in surgery. Principles of legal requirements and clinical benchmarks exemplified by visceral surgery]. AB - The spectacular increase in liability processes in the field of surgery and in particular in visceral surgery, necessitates an objectification of the conflict between surgical medical professionals and medico-legal institutions, firms of solicitors and courts. Out of court settlements assisted by expert opinion commissions of the Medical Council can avoid many legal conflicts. For improvement of the legal standpoint of a defendant medical professional an unambiguous, extensive and detailed documentation of medical examination findings, the indications for the planned operative intervention, extensive and detailed documentation on disclosure and informed consent of the patient for the planned operative intervention, an extensive, detailed careful and responsibly guided report of the operation as well as a systematic, orderly well-planned postoperative complication management are necessary to counter the accusation of an organizational failure of medical professionals and the accused hospital. The mutual building of confidence between surgical medical professionals and legal institutions is safeguarded by a comprehensive documentation and an unambiguous description and formulation of the medical discharge report on termination of inpatient treatment. PMID- 22246075 TI - [High frequency of hypocalcemia after total thyroidectomy. Are low preoperative vitamin D levels responsible?]. PMID- 22246076 TI - [Endoscopic and surgical resection of mucosal adenocarcinoma in Barrett's esophagus : Comparison at two high-volume centers]. PMID- 22246077 TI - [Ischemic preconditioning in major resection of the liver. No additional benefit from intermittent Pringle maneuver]. PMID- 22246078 TI - [Short-term radiotherapy and TME versus TMA alone for rectal cancer. Long-term data confirm previous knowledge]. PMID- 22246079 TI - [The 90th birthday of Professor Dr. med. h.c. Walther Weibetaauer]. PMID- 22246082 TI - [Intrathoracic injuries]. AB - Severe intrathoracic injuries are uncommon but immediately life-threatening. These injuries are mostly associated with polytrauma. After stabilization of polytraumatized patients imaging is a prerequisite for treatment and operation planning. The assessment warrants an interdisciplinary approach primarily between the specialties of anesthesia, trauma surgery and thoracic surgery and further specialties should be involved depending on the injury pattern. This article gives an overview about the current management of the most important intrathoracic injuries. PMID- 22246083 TI - Parathyroid carcinoma presenting as normocalcemic hyperparathyroidism. AB - Parathyroid carcinoma (PC) is a rare malignancy, with an indolent but progressive course. Long-term survival is largely dependent on the extent of the primary surgical resection. Hence, pre- or intraoperative suspicion of malignancy is of great importance. We describe the case of a 62-year-old woman with a 2-year history of asthenia and mental depression. Her past medical history was significant for osteoporosis. A diagnosis of primary normocalcemic hyperparathyroidism was established and the patient underwent surgery. PC was suspected intraoperatively because of the size and appearance of the parathyroid mass (a grayish, lobulated 3.5 cm mass). Thus, aggressive surgery (en bloc resection) was performed, along with bilateral neck exploration. Pathological examination of the specimens confirmed the suspicion of PC, demonstrating vascular invasion and extracapsular infiltration into adjacent soft tissue. Immunohistochemical staining revealed an elevated Ki-67 score (8.43%; cut-off value 5%). The mean area of silver-stained nucleolar organizer regions (AgNOR) was high (4.972 MUm(2)), indicating an elevated proliferation rate. Serum calcium and parathyroid hormone levels normalized postoperatively, and the patient's 5 year outcome was good. The present case provides evidence that parathyroid malignancy cannot be excluded a priori based on normocalcemic hyperparathyroidism, emphasizing the variability in clinical presentation. Moreover, Ki-67 expression and AgNOR analysis confirmed their additional value in complementing the histological evaluation of a parathyroid malignant mass. PMID- 22246084 TI - Effect of hyperlipidemia on femoral biomechanics and morphology in low-density lipoprotein receptor gene knockout mice. AB - The objective of this study was to evaluate the effect of hyperlipidemia on the biomechanical and morphological properties of the femur of low-density lipoprotein receptor gene knockout mice (LDLr-/-) mice. Ten wild-type mice (C57BL6) and 10 LDLr-/- mice generated on a C57BL6 background were used. Male 3 month-old animals were divided into four groups (n = 5): group W (wild type) and group L (LDLr-/-) receiving low-fat commercial ration, and group WH (wild type) and group LH (LDLr-/-) receiving a high-fat diet. After 60 days, blood samples were collected for laboratory analysis of calcium, triglycerides, and cholesterol. The femur was excised for mechanical testing and morphometric analysis. LDLr-/- mice receiving the high-fat diet presented more marked alterations in the mechanical and morphological properties of femoral cortical and trabecular bone. Changes in the plasma levels of calcium, triglycerides, cholesterol, and fractions were also more pronounced in this group. The present results demonstrate that hyperlipidemia causes alterations in the structure and mechanical properties of the femur of LDLr-/- mice. These effects were more pronounced when associated with a high-fat diet. PMID- 22246085 TI - A bioreactor for subjecting cultured cells to fast-rate intermittent hypoxia. AB - High frequency intermittent hypoxia is one of the most relevant injurious stimuli experienced by patients with obstructive sleep apnea (OSA). Given that the conventional setting for culturing cells under intermittent hypoxia conditions is limited by long equilibration times, we designed a simple bioreactor capable of effectively subjecting cultured cells to controlled high-frequency hypoxic/normoxic stimuli. The bioreactor's operation is based on exposing cells to a medium that is bubbled with the appropriate mixture of gases into two separate containers, and from there it is directed to the cell culture dish with the aid of two bidirectional peristaltic pumps. The device was tested on human alveolar epithelial cells (A549) and mouse melanoma cells (B16-F10), subjecting them to patterns of intermittent hypoxia (20s at 5% O(2) and 50s at 20% O(2)), which realistically mimic OSA of up to severe intensity as defined by the apnea hypopnea index. The proposed bioreactor can be easily and inexpensively assembled and is of practical use for investigating the effects of high-rate changes in oxygen concentration in the cell culture medium. PMID- 22246086 TI - Unrelated cord blood transplantation for newly diagnosed patients with severe acquired aplastic anemia using a reduced-intensity conditioning: high graft rejection, but good survival. AB - We report a single-center experience in treating 18 consecutive patients with severe aplastic anemia (SAA) who received unrelated cord blood transplantation (CBT). The median age was 17 years (range 5-61 years). Sixteen cases received a reduced-intensity regimen composed of CY (total dose 1200 mg/m(2)), rabbit antithymocyte globulin (ATG, total dose 30 mg/kg) and fludarabine (FLU, total dose 120 mg/m(2)). CYA and mycophenolate mofetil were used as GVHD prophylaxis. Two patients were not evaluable for engraftment because of early death on day +21 and +22. Only one of the sixteen cases achieved engraftment, but experienced secondary graft failure 3 months post transplantation. Fifteen patients experienced primary graft rejection, but all of them acquired autologous recovery. The 3-month and 6-month cumulative incidence of response was 56% and 81%, respectively. So far, 16 patients have survived for 330-1913 days (median, 750 days) after transplantation. The probability of OS at 2 years was 88.9%. Our data indicate that CBT for newly diagnosed SAA using no irradiation but FLU and ATG-based conditioning still seems to inevitably lead to the high risk of rejection, but may facilitate autologous recovery and improve survival with low risk of transplant-related mortality. PMID- 22246087 TI - Constrictive pericarditis and primary effusion lymphoma following allogeneic BMT for CML. PMID- 22246088 TI - Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs. AB - Recently, we demonstrated that reduced intensity conditioning (RIC) followed by partial T-cell-depleted SCT creates a platform for inducing the graft-versus myeloma effect by adjuvant immunotherapy. Here, we evaluated mHA-specific T-cell responses in a multiple myeloma (MM) patient who was treated with RIC-SCT followed by donor lymphocyte infusion (DLI) and subsequent recipient DC vaccination. We isolated a mHA-specific CTL clone with the capacity to target MM tumor cells from this patient experiencing long-term CR. This CTL clone recognizes an HLA-A3-restricted mHA and mediates killing of both primary MM cells and the MM-cell line U266, while BM-derived fibroblasts are not recognized. CTL specific T-cell receptor (TCR) transcripts could be detected by quantitative PCR analysis in both peripheral blood and BM during tumor remission. Interestingly, a strong increase of CTL-specific TCR transcripts at the BM tumor site was observed following DLI and recipient DC vaccination, while the TCR signal in peripheral blood decreased. These findings illustrate that the approach of partial T-cell depleted RIC-SCT followed by post-transplantation immunotherapy induces mHA specific T-cell responses targeting MM tumor cells. PMID- 22246089 TI - A reduced intensity conditioning regimen of fludarabine, cyclophosphamide, antithymocyte globulin, plus 2 Gy TBI facilitates successful hematopoietic cell engraftment in an adult with dyskeratosis congenita. PMID- 22246090 TI - Cervical spine injuries; an outcome analysis. AB - Cervical spine injury (CSI) in octogenarians continues to carry a high morbidity and mortality rate. The incidence of CSI among individuals who are below the age of 80 is declining, whereas the incidence of CSI for those 80 years and above is rising.The aim of the study was to evaluate outcomes of cervical spine injuries in octogenarians caused by different mechanisms: motor vehicle accidents, compared to a fall.Material and methods. The National Trauma Data Bank (NTDB) was queried for patients ages 80 and above, who sustained a cervical spine injury via motor vehicle collision and falls. Patient demographics, mechanism of injury, Glasgow Coma Score (GCS), injury severity score (ISS), days in Intensive Care Unit, Temperature on arrival, blood pressure on arrival, CT Scan of head results, complications, sex, and mortality.Results. Three-thousand three hundred seventy five patients, 80 years of age and older with CSI were included in the study; fifteen percent of these octogenarians with cervical spine injuries died. It was observed that patients in the motor vehicle accident (MVA) group have 1.737 (95% CI 1.407, 2.144 p-value < 0.0001) times the odds of dying, compared to those in the fall group. Patients over the age of 80 who were in a MVA have 1.209 (95% CI 0.941, 1.554 p-value = 0.1372) times the odds of having a positive head CT, compared with people over the age of 80 who experienced a fall. Patients involved in a motor vehicle accident with associated CSI were more likely to be a younger age, have a lower GCS on arrival, have a longer length of stay in the Intensive Care Unit, and a higher ISS (p<0.05).Conclusions. Cervical spine injury in octogenarians carries a high mortality regardless of mechanism. Elderly patients who suffer cervical spine injuries in motor vehicle accidents have a lower SBP, a higher ISS and are nearly twice as likely to die as those who were injured in a fall. PMID- 22246091 TI - Risk of permanent stoma after resection of rectal cancer depending on the distance between the tumour lower edge and anal verge. AB - The distance between the anal verge and lower edge of rectal cancer is one of the most important factors affecting the feasibility of sphincter-preserving resection.The aim of the study was to assess the risk of permanent stoma after resection of rectal tumour depending on the distance between the tumour and the anal verge.Material and methods. The retrospective analysis covered 884 patients after resection of rectal cancer. The distance between the anal verge and the lowest edge of the tumour was measured during endoscopic examination. Surgical technique was similar in all cases. For statistical analysis, the chi-square test and Fisher exact test were used.Results. The overall rate of sphincter-preserving procedures was 71.8%, 90.1% of which were anterior resections. The greatest differences between the rate of anterior resections were noted for the segment between the 4th and the 5th centimetres: 30.1% for 4 cm vs 66.7% for 5 cm, p = 0.005. Overall, in 328 patients (37.1%) surgical treatment resulted in a permanent stoma. The number included: 246 (75.0%) patients after abdominosacral resection, 44 (13.4%) patients after the Hartmann procedure, three (0.9%) patients after proctocolectomy, and 28 (8.5%) patients after anterior resection, with a permanent stoma as a result of anastomotic leak. The overall rate of anastomotic leak was 11.7%. Formation of a defunctioning stoma in patients with a low-lying (6 cm from the anal verge) tumour reduced the risk of symptomatic anastomotic leak: 6.3% vs 20.5%; p = 0.049.Conclusions. Anterior resection of tumours located 6 cm from the anal verge is feasible in 90%. Anastomotic leak that requires reoperation increases the risk of permanent colostomy. In selected cases, formation of a defunctioning stoma after resection of low-lying rectal cancer can reduce the risk of permanent colostomy. PMID- 22246092 TI - A prospective comparison of four methods of endovenous thermal ablation. AB - The aim of the study was to compare clinical and duplex Doppler results of treatment of varicose veins with four methods of endovenous thermal ablation (EVTA).Material and methods. The results of treatment of varicose veins with 980 nm laser (EVLA980) in 67 extremities, with a radiofrequency ablation (RFA) in 43 extremities, with 810 nm laser (EVLA810) in 46 extremities and with 1470 nm laser (EVLA1470) in 15 extremities were prospectively analyzed. The data on patients' demographics, weight, stage of the venous disease, type of anesthesia, duration of the procedure, linear energy density (LED) applied, intra- and postoperative complications were collected. Thromboprophylaxis was not routinely administered. The patients were followed clinically and with duplex Doppler for 12 (1-24) months.Results. Technical success was achieved in 99% of limbs. The procedure was carried out under local anesthesia in 140 (91%) of patients. In 17 patients bilateral procedure was performed. There were one gastroenemius muscle vein thrombosis and one protruding thrombus from sapheno-femoral junction in EVLA810. No other serious complications were observed. A median LED was higher in EVLA810 than in EVLA980 and EVLA1470, 86.8 (82-94), 59.2 (45.4-74.4) and 58.8 (53-67.7) J/cm, respectively (p<0.001), though only in EVLA980 was below the intended range. Recanalization rates were 7% after EVLA980, 2% after EVLA810 and 0% after RFA and EVLA1470, p=0.14. The vein shrinking was fastest after EVLA1470. Neither neovascularization nor formation of arteriovenous fistulas was observed. Permanent saphenous nerve paresthesia occurred in two patients after RFA.Conclusions. All methods of ambulatory EVTA are safe and effective once the adequate linear energy density is applied. PMID- 22246093 TI - Gastrointestinal bleeding in patients aged 85 years and older. AB - The aging of the population is associated with the increased risk of chronic diseases, and greater consumption of drugs used in their treatment, which may lead towards gastrointestinal bleeding.The aim of the study was to analyze the reasons, treatment results, complications and mortality connected with gastrointestinal bleeding in patients aged 85 years and older.Material and methods. The study comprised the retrospective analysis of 84 patients, aged between 85 and 97 years admitted to the Department of General Surgery with diagnosis of gastrointestinal bleeding, during the period between 2005 and 2010. The results were compared to a younger control group of 151 patients (mean age-53 years) with gastrointestinal bleeding, admitted to the department during the same period. Diagnosis was based on the history, physical examination, endoscopy, morphology and biochemical lab results. Analysis considered the therapeutic method used, treatment results, complications and hospital mortality. The endoscopic picture and risk of recurrent bleeding in patients with upper gastrointestinal hemorrhage was evaluated by means of the clinical Forrest scale. Results were subject to statistical analysis.Results. Most of the gastrointestinal bleeding cases considering patients aged 85 years and older concerned the upper gastrointestinal tract (41.67%). Thirty (35.71%) patients were on drugs affecting the coagulation system. On admission, the average hemoglobin concentration level in the elderly was comparable to results observed in case of the control group. Considering patients aged 85+, drugs affecting the coagulation system were used statistically more frequently, as compared to younger patients. Recurrence of bleeding was observed in 10 (11.9%) study group patients.Overall mortality due to gastrointestinal bleeding in elderly patients amounted to 20.24% and was statistically higher, as compared to the control group 7.2%.Conclusions. Treatment results in case of gastrointestinal bleeding in the elderly patients (above 85 years) are burdened with a higher mortality rate. Different diagnostic and therapeutic methods should be applied in case of elderly patients (above 85 years), in order to increase their chance of survival. The problem of aging is an epidemiological phenomenon and gastrointestinal bleeding will become an increasing problem, needing to be solved in everyday clinical practice. PMID- 22246094 TI - Effect of operative treatment on psychosocial problems of men with gynaecomastia. AB - Gynaecomastia is defined as a hyperplasia of the breast tissue in men, bilateral or unilateral, usually not associated with the presence of malignant lesions.The aim of the study was to explore the psychosocial problems of men with gynecomastia and the effect of operative breast reduction on these problems.Material and methods. The survey was conducted in a group of 47 men who were treated surgically for gynaecomastia in the Department of Plastic, Reconstructive and Aesthetic Surgery. The mean age of the respondents was 25.6+/ 3.5 years. For survey purposes, a questionnaire was developed with questions about the age of onset of gynaecomastia, coexisting disorders and medicines taken and also various aspects of the psychosocial life of the respondents. The questionnaire was completed by patients before surgery and at minimum 6 months after surgery.Results. The findings showed that in almost all patients gynaecomastia had caused emotional discomfort and limitation of everyday activity. In many patients, enlarged breasts caused difficulties in entering into social relationships. More than a half of the surveyed men admitted that their problems were ridiculed by others and they felt isolated. A comparison of the respondents' answers before and after the surgery showed statistically significant differences in all of the analysed questionnaire items.Conclusions. Gynaecomastia causes considerable emotional discomfort and limitation of everyday activity in young men, and that is why it constitutes a psychosocial problem. Surgical treatment of gynaecomastia significantly contributes to an increase in social activity and an improvement of social acceptance and emotional comfort, and thus significantly improves satisfaction from personal life in the men who underwent this intervention. PMID- 22246095 TI - A/G Polymorphism of the MMP-7 Gene Promoter Region in Colorectal Cancer. AB - In gastrointestinal malignancies increased expression of matrilysin - MMP-7 - is often observed. Its high level positively correlates with clinical stage of malignancy and is a negative prognostic factor. This suggests a possible relationship between functional polymorphisms of the MMP-7 gene and susceptibility to development of colorectal cancer and an aggressive course of the disease.The aim of the study was to assess the effects of A/G functional polymorphism at -181 site of the MMP-7 gene promoter region on development and progression of colorectal cancer.Material and methods. In total, 184 patients treated surgically for colorectal cancer at the Department of General and Colorectal Surgery of the Medical University in Lodz in the years 2006-2009 and a control group of 205 cancer-free individuals with a negative family history for malignancy have been investigated. Polymorphic variants of the MMP-7 gene promoter region have been analysed using the RFLP-PCR method.Results. A statistically significant difference in distribution of genotypes has been found between the investigated group and the control group, and the OR analysis confirmed a relationship between the A/G [1.67 (1.03-2.72); p= 0.038] and G/G [2.12 (1.34-3.38); p = 0.018] genotypes and an increased risk of colorectal cancer. The risk of lymph node involvement was more than twice higher for the G/G genotype (OR = 2.83 (1.18-6.79); P = 0.017). In addition, the analysis of genotype distribution in patients divided into groups according to the T parameter of the TNM classification revealed a relationship between the G/G genotype and advanced tumour infiltration. No relationship between the investigated A/G polymorphism and the presence of distant metastases has been found.Conclusions. Obtained results indicate a possible relationship between -181 A/G polymorphism of the MMP-7 gene and malignant transformation of colorectal epithelial cells and progression of colorectal cancer. This suggests applicability of this polymorphism as a predisposing factor for the disease and a prognostic factor, which in the future may be useful in the management algorithm for colorectal cancer. PMID- 22246096 TI - Neuroendocrine tumor in choledochal cyst--case report and review of literature. AB - The report presents a rare case of carcinoid tumor in a 17 year female who presented with epigastric pain of one week duration. She was diagnosed to have type I choledochal cyst on abdominal ultrasound and MRI. She underwent total excision of choledochal cyst with roux-en-Y hepaticojejunostomy. Histopathological examination revealed a neuroendocrine tumor within choledochal cyst which was immunoreactive for Chromogranin A. Patient is well at 6 months of follow up. These tumors are characteristically slow-growing, therefore awareness of its presence preoperatively can facilitate optimal management by performing surgical resection with negative margins which offers the best chance of long term survival. PMID- 22246097 TI - Enteral nutrition without the use of an endoscope in patients with severe acute pancreatitis. AB - One of the main elements of acute pancreatitis therapy is nutritional treatment, which should ensure the implementation of the patients' energetic needs, limit the exocrine activity of the pancreas, and maintain the gastrointestinal passage. The most important argument in favor of the above-mentioned is the fact that enteral nutrition in case of severe acute pancreatitis prevents infectious complications. The most effective method is enteral nutrition. The unavailability of bedside endoscopy, and thus the need to transport the patient in order to obtain access, considerably complicates the procedure. Literature data described various bedside techniques consisting in the blind introduction of the feeding tube, which are rarely used, despite the fact that they are cheaper and as effective as endoscopy. PMID- 22246098 TI - "There is no smoke without a fire"--surgical smoke and the risk connected with it. PMID- 22246099 TI - Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells. AB - Recent epidemiological studies have demonstrated that metformin lowers the risk of several types of cancer in diabetic patients. Matrix metalloproteinases (MMPs) play a crucial role in the degradation of the vascular basement membrane extracellular matrix proteins, thereby promoting endothelial cell invasion, migration and angiogenesis in the incidence and progression of tumors. The aim of this study was to investigate the effects of metformin on human umbilical vein endothelial cell (HUVEC) proliferation and migration, as well as on MMP-2 and MMP 9 expression. Cell proliferation was determined by cell counting and MTT colorimetric assays. Cell migration was assessed by the wound repair method. Quantitative real-time reverse transcription PCR was performed to quantify the mRNA expression of MMPs. Metformin at concentrations of 0.5-3.0 mM effectively reduced the number of endothelial cells by 5.5-55%, without being cytotoxic to the cells. Similarly, cell proliferation and migration were markedly inhibited by metformin. In addition, treatment with metformin demonstrated a strong (P<0.001) suppressive effect on the mRNA levels of MMP-2 and -9 in the endothelial cells. The inhibitory effects of metformin on endothelial cell number, migration, and MMP expression were reversed partially by compound C, which is an inhibitor of AMP-activated protein kinase (AMPK). The present study reports that metformin considerably inhibited the proliferation, migration, and MMP-2 and -9 expression of HUVECs, and the effect was partially AMPK-dependent. The obtained findings provide a molecular rationale, whereby metformin can exert anticancer effects. PMID- 22246100 TI - Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target. AB - Diverse stress stimuli induce long-lasting cognitive deficits, but the underlying molecular mechanisms are still incompletely understood. Here, we report three different stress models demonstrating that stress-inducible increases in microRNA 132 (miR-132) and consequent decreases in its acetylcholinesterase (AChE) target are causally involved. In a mild model of predator scent-induced anxiety, we demonstrate long-lasting hippocampal elevation of miR-132, accompanied by and associated with reduced AChE activity. Using lentiviral-mediated suppression of "synaptic" AChE-S mRNA, we quantified footshock stress-inducible changes in miR 132 and AChE and its corresponding cognitive damages. Stressed mice showed long lasting impairments in the Morris water maze. In contrast, pre-stress injected AChE-suppressing lentivirus, but not a control virus, reduced hippocampal levels of both miR-132 and AChE and maintained similar cognitive performance to that of naive, non-stressed mice. To dissociate between miR-132 and synaptic AChE-S as potential causes for stress-inducible cognitive deficits, we further used engineered TgR mice with enforced over-expression of the soluble "readthrough" AChE-R variant without the 3'-untranslated region binding site for miR-132. TgR mice displayed excess AChE-R in hippocampal neurons, enhanced c-fos labeling and correspondingly intensified reaction to the cholinergic agonist pilocarpine. They further showed excessive hippocampal expression of miR-132, accompanied by reduced host AChE-S mRNA and the GTPase activator p250GAP target of miR-132. At the behavioral level, TgR mice showed abnormal nocturnal locomotion patterns and serial maze mal-performance in spite of their reduced AChE-S levels. Our findings attribute stress-inducible cognitive impairments to cholinergic-mediated induction of miR-132 and consequently suppressed ACHE-S, opening venues for intercepting these miR-132-mediated damages. PMID- 22246102 TI - Cardiovascular pharmacotherapy can reduce mortality. PMID- 22246101 TI - Hypertension in the US Black population: risk factors, complications, and potential impact of central aortic pressure on effective treatment. AB - PURPOSE: The identification of specific factors that contribute to hypertension development and progression among blacks in the US is the focus of much ongoing research. The purpose of this paper is to review these factors and discuss how they present unique opportunities for improving the management of hypertension in this difficult-to-treat population. METHODS: We searched the published literature for articles discussing the risk factors for hypertension and cardiovascular disease in blacks; the target-organ damage and cardiovascular complications associated with hypertension in this difficult-to-treat population; and the role of central blood pressure in predicting cardiovascular events. RESULTS: The prevalence of hypertension is higher in blacks than in other race/ethnic groups, with environmental and genetic risk factors likely playing an important role. The cardiovascular and renal consequences of hypertension (eg, left ventricular hypertrophy and renal failure) are also greater in blacks relative to their white counterparts. Preliminary data suggest that central blood pressure may be higher in blacks than in whites and has the potential for greater prognostic capability relative to peripheral blood pressure. CONCLUSIONS: There is an urgent need to successfully control hypertension in the black population. Although data are limited in blacks, evidence suggests that central blood pressure warrants more continued assessment in future clinical studies. PMID- 22246103 TI - Antiproliferative effect of alpinetin in BxPC-3 pancreatic cancer cells. AB - Alpinetin is a novel plant flavonoid derived from Alpinia katsumadai Hayata, found to possess strong anticancer effects. However, the antitumor effect of alpinetin on pancreatic cancer cells and the detailed mechanism remain unclear. The aim of this study was to investigate alpinetin's beneficial effect on pancreatic cancer and the possible molecular mechanism involved. Pancreatic cancer cell lines were treated with alpinetin at various doses and for different times, and the effect of alpinetin on cell growth inhibition, apoptosis and the cell cycle was determined. The expression of Bcl-2, Bcl-xL, XIAP and Bax, the activity of caspases and the levels of cytochrome c released were measured. The results showed that alpinetin inhibited the viability of three pancreatic cancer cell lines and induced apoptosis of BxPC-3 cells in a dose- and time-dependent manner. This was accompanied by regulation of the expression of Bcl-2, Bcl-xL, Bax and XIAP. Furthermore, alpinetin treatment led to the release of cytochrome c and activation of caspases-3, -8 and -9 proteins. Taken together, our studies indicate that alpinetin inhibited the proliferation of pancreatic cancer cells possibly through the regulation of the Bcl-2 family and XIAP expression, release of cytochrome c and the activation of caspases. Alpinetin may serve as a potential agent for the development of pancreatic cancer cell therapies. PMID- 22246104 TI - Rapid changes in corticospinal excitability during force field adaptation of human walking. AB - Force field adaptation of locomotor muscle activity is one way of studying the ability of the motor control networks in the brain and spinal cord to adapt in a flexible way to changes in the environment. Here, we investigate whether the corticospinal tract is involved in this adaptation. We measured changes in motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in the tibialis anterior (TA) muscle before, during, and after subjects adapted to a force field applied to the ankle joint during treadmill walking. When the force field assisted dorsiflexion during the swing phase of the step cycle, subjects adapted by decreasing TA EMG activity. In contrast, when the force field resisted dorsiflexion, they increased TA EMG activity. After the force field was removed, normal EMG activity gradually returned over the next 5 min of walking. TA MEPs elicited in the early swing phase of the step cycle were smaller during adaptation to the assistive force field and larger during adaptation to the resistive force field. When elicited 5 min after the force field was removed, MEPs returned to their original values. The changes in TA MEPs were larger than what could be explained by changes in background TA EMG activity. These effects seemed specific to walking, as similar changes in TA MEP were not seen when seated subjects were tested during static dorsiflexion. These observations suggest that the corticospinal tract contributes to the adaptation of walking to an external force field. PMID- 22246105 TI - The bliss (not the problem) of motor abundance (not redundancy). AB - Motor control is an area of natural science exploring how the nervous system interacts with other body parts and the environment to produce purposeful, coordinated actions. A central problem of motor control-the problem of motor redundancy-was formulated by Nikolai Bernstein as the problem of elimination of redundant degrees-of-freedom. Traditionally, this problem has been addressed using optimization methods based on a variety of cost functions. This review draws attention to a body of recent findings suggesting that the problem has been formulated incorrectly. An alternative view has been suggested as the principle of abundance, which considers the apparently redundant degrees-of-freedom as useful and even vital for many aspects of motor behavior. Over the past 10 years, dozens of publications have provided support for this view based on the ideas of synergic control, computational apparatus of the uncontrolled manifold hypothesis, and the equilibrium-point (referent configuration) hypothesis. In particular, large amounts of "good variance"-variance in the space of elements that has no effect on the overall performance-have been documented across a variety of natural actions. "Good variance" helps an abundant system to deal with secondary tasks and unexpected perturbations; its amount shows adaptive modulation across a variety of conditions. These data support the view that there is no problem of motor redundancy; there is bliss of motor abundance. PMID- 22246106 TI - Interstrand cross-link of DNA by covalently linking a pair of abasic sites. AB - A pair of apurinic/apyrimidinic sites formed in DNA has been covalently connected with bis(aminooxy) derivatives. The efficacy of the interstrand cross-link is associated with the structural tethering of two aminooxy groups. The interstrand cross-link constructed stable DNA scaffolds for enzyme alignment. PMID- 22246107 TI - Plant expression, lyophilisation and storage of HBV medium and large surface antigens for a prototype oral vaccine formulation. AB - Current immunisation programmes against hepatitis B virus (HBV) increasingly often involve novel tri-component vaccines containing-together with the small (S HBsAg)-also medium and large surface antigens of HBV (M- and L-HBsAg). Plants producing all HBsAg proteins can be a source of components for a potential oral 'triple' anti-HBV vaccine. The objective of the presented research was to study the potential of M/L-HBsAg expression in leaf tissue and conditions of its processing for a prototype oral vaccine. Tobacco and lettuce carrying M- or L HBsAg genes and resistant to the herbicide glufosinate were engineered and integration of the transgenes was verified by PCR and Southern hybridizations. M- and L-HBsAg expression was confirmed by Western blot and assayed by ELISA at the level of micrograms per g of fresh weight. The antigens displayed a common S domain and characteristic domains preS2 and preS1 and were assembled into virus like particles (VLPs). Leaf tissues containing M- and L-HBsAg were lyophilised to produce a starting material of an orally administered vaccine formula. The antigens were distinctly sensitive to freeze-drying conditions and storage temperature, in the aspect of stability of S and preS domains and formation of multimeric particles. Efficiency of lyophilisation and storage depended also on the initial antigen content in plant tissue, yet M-HBsAg appeared to be approximately 1.5-2 times more stable than L-HBsAg. The results of the study provide indications concerning the preparation of two other constituents, next to S-HBsAg, for a plant-derived prototype oral tri-component vaccine against hepatitis B. PMID- 22246108 TI - Organocatalytic stereoselective synthesis of passifloricin A. AB - The enantioselective synthesis of passifloricin A has been achieved in high diastereomeric excess. The 1,3-polyol moiety was constructed by iterative proline catalyzed sequential alpha-aminoxylation and Horner-Wadsworth-Emmons (HWE) olefination of aldehydes while the synthesis of lactone moiety was achieved by ring-closing metathesis (RCM). PMID- 22246110 TI - Li self-diffusion in lithium niobate single crystals at low temperatures. AB - Li self-diffusion in Li(2)O-deficient LiNbO(3) single crystals is investigated in the temperature range between 423 and 773 K (150-500 degrees C) by secondary ion mass spectrometry. A thin layer of ion-beam sputtered isotope enriched (6)LiNbO(3) was used as a tracer source, which allows one to study pure isotope interdiffusion. The diffusivities can be described by the Arrhenius law with an activation enthalpy of (1.33 +/- 0.03) eV, which is in acceptable agreement with the migration energy of a single Li vacancy as determined by ab initio calculations given in the literature. Charge diffusivities as derived from impedance spectroscopy measurements on the same type of samples are identical to the tracer diffusivities within error limits. No indication of the formation of defect-complexes at low temperatures could be found in the diffusion behaviour. PMID- 22246109 TI - Social anxiety and cannabis use: an analysis from ecological momentary assessment. AB - Individuals with elevated social anxiety appear especially vulnerable to cannabis related problems, yet little is known about the antecedents of cannabis-related behaviors among this high-risk population. The present study used ecological momentary assessment (EMA) to examine the relations among social anxiety, cannabis craving, state anxiety, situational variables, and cannabis use in the natural environment during ad-lib cannabis use episodes. Participants were 49 current cannabis users. During the two-week EMA period, social anxiety significantly interacted with cannabis craving to predict cannabis use both cross sectionally and prospectively. Specifically, individuals with higher social anxiety and craving were most likely to use cannabis. There was a significant social anxiety x state anxiety x others' use interaction such that when others were using cannabis, those with elevations in both trait social anxiety and state anxiety were the most likely to use cannabis. PMID- 22246111 TI - Use of intercellular washing fluid to investigate the secreted proteome of the rice-Magnaporthe interaction. AB - Early interactions between invading penetration hyphae of the pathogenic fungus Magnaporthe oryzae and rice cells occur at the apoplast, the free diffusional space outside the plasma membrane of leaves. After initial colonization, intercellular hyphae are again in intimate contact with the rice apoplast. While several studies have looked at proteomics in rice-Magnaporthe interactions, none have focused on apoplast localized proteins. We adjusted a protocol for intercellular washing fluids (IWF) to rice leaves infected with Magnaporthe oryzae for proteomic analysis. In our IWF extract, we identified several proteins associated with compatible or incompatible pathogen interactions. Three DUF26 domain proteins were identified as changing in abundance 12 h after inoculation, confirming DUF26 domain-containing proteins are among early, pathogen stress responsive proteins induced by infection with Magnaporthe oryzae. A Magnaporthe cyclophilin, previously identified as a virulence factor was also identified in the intercellular washing fluid. PMID- 22246112 TI - Characterization of Aggregatibacter actinomycetemcomitans strains in periodontitis patients in Germany. AB - OBJECTIVES: Aggregatibacter actinomycetemcomitans strains of serotype b and with a deletion of 530 bp in the promoter region of the leukotoxin gene (JP2 clone) are known to be associated with severe periodontitis. Our study was aimed to detect virulence genes of A. actinomycetemcomitans strains obtained from patients living in four German cities with different proportions of immigrants. MATERIAL AND METHODS: Samples were obtained from severe periodontitis patients in Frankfurt, Hamburg, Leipzig, and Jena. Those being tested positive for A. actinomycetemcomitans were analyzed for serotypes, deletion in the promoter region of the leukotoxin gene, presence of cytolethal distending toxin encoding genes (cdtA, cdtB, and cdtC) and fibril gene1(flp-1). RESULTS: From all 99 A. actinomycetemcomitans-positive samples, the JP2 clone was found in two immigrants in Frankfurt. Seventy strains were tested positive for the cdtA, 52 for cdtB, and 92 for cdtC and flp-1 genes. Twenty-five strains belonged to serotype a, 22 to serotype b, 21 to serotype c, 31 to the others or could not be serotyped, respectively. The distribution of the serotypes differed between the cities. Further, differences regarding the serotypes were also significant between natives and immigrants. CONCLUSIONS: The JP2 clone is not spread within the Caucasian inhabitants in German cities. The serotypes distribution seems to be influenced by the numbers of immigrants in the cities. CLINICAL RELEVANCE: Patients originated from North Africa should be especially screened for the presence of the deletion in the ltx promoter region. PMID- 22246114 TI - Between adolescence and adulthood: rehabilitation research to improve services for youth and young adults. PMID- 22246113 TI - In vitro evaluation of the effect of post system and length on the fracture resistance of endodontically treated human anterior teeth. AB - OBJECTIVES: The aim of this study was to evaluate the effect of post system and length on the fracture resistance of endodontically treated human anterior teeth. MATERIAL AND METHOD: Seventy-five extracted human incisors were endodontically treated, out of which 60 were decoronated 2 mm above the cementoenamel junction and divided into two experimental groups based on the type of post system to be used: glass fiber post (GFP) and Ribbond fiber post groups (RFP). Endodontically treated human anterior teeth in which no post was placed served as control group. Each group was divided into two subgroups according to the length of post space: 5 and 10 mm and all the samples were restored with metal crowns. The fracture resistance was measured by applying loads at an angle of 130 degrees to the long axis of teeth in an Instron universal testing machine. RESULTS: The results revealed that GFP group at 10-mm post space length showed the significantly highest fracture resistance (740.2133 N) among all groups and subgroups. Decrease in post length resulted in the decrease in fracture resistance in GFP group (425.1867 N), whereas in group RFP 5-mm subgroup (299.6200 N) showed significantly higher fracture resistance than 10-mm subgroup (216.9300 N) but lesser than the control (437.8733 N) in both the subgroups. CONCLUSION: Glass fiber posts efficiently increase the fracture resistance of an endodontically treated tooth but the determination of optimal post length is also essential. CLINICAL RELEVANCE: The present investigation highlights the significance of using glass fiber posts in the restoration of endodontically treated teeth. Endodontically treated teeth restored with glass fiber posts showed increased fracture strength and favorable mode of fracture, and are therefore highly recommended to achieve better clinical outcomes. PMID- 22246115 TI - Supported employment outcomes for transition age youth and young adults. AB - TOPIC: Supported Employment (SE) can help transition age youth and young adults to obtain employment and develop meaningful careers and financial security. PURPOSE: The purpose of this analysis is to examine the role of SE in achieving employment outcomes for youth (ages 18-24) and young adults (ages 25-30), compared to outcomes for older adults. Given the importance of employment to the quality of life of young people in establishing work histories and starting careers, it is important to have a better understanding of what client and program characteristics result in better employment outcomes. SOURCES USED: Data are from the Employment Intervention Demonstration Program (EIDP), a multisite randomized controlled trial of SE among 1,272 individuals with psychiatric disabilities in 7 states. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Among all study participants, youth and young adults had significantly better outcomes in terms of any employment and competitive employment than older (>30 years) adults. However, in multivariable models of participants randomly assigned to SE, young adults had significantly better outcomes than youth or older adults. Other significant predictors of employment and competitive employment were future work expectations, not receiving Supplemental Security Income, and receipt of more hours of SE services. Characteristics of youth, young adults and SE programs that enhance employment are discussed in terms of policy and practice. PMID- 22246116 TI - Adapting services to engage young adults in ICCD clubhouses. AB - TOPIC: This article describes efforts to develop and offer supports for young adults within two clubhouse programs affiliated with the International Center for Clubhouse Development (ICCD). PURPOSE: In response to a need to address service gaps and create supports to engage young adults transitioning to the adult mental health system, the authors describe the background, development, and adaptations of services and supports for young adults within their respective clubhouse programs. The authors highlight details and challenges associated with program adaptation and success stories of transition aged youth actively engaged in their clubhouses. SOURCES USED: Published literature, personal observation, and member feedback. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These clubhouse programs share successful strategies used to engage young adults including outreach efforts led by young adults, developing supports and linkages with local educational institutions, addressing housing issues specific to young adults, and using current technologies that young adults find appealing. These strategies may prove useful to other service models that serve this population. Clubhouses affiliated with the ICCD show promise in expanding their approach and services to engage and support young adults. PMID- 22246117 TI - Does team-based planning "work" for adolescents? Findings from studies of wraparound. AB - OBJECTIVE: This article focuses on wraparound as an example of a team planning process, and uses data from several sources to reflect on questions about whether and under what conditions-collaborative teams are successful in engaging young people-and their caregivers-in planning. METHODS: We used data collected in three studies to address our research questions. The first data set comes from a study on wraparound service planning in Nevada. We examined data collected from 23 matched pairs of caregivers and youth at 6 months after wraparound planning began. Our second data set came from a national study of 41 local wraparound programs throughout the United States. Our analyses use data from 366 matched pairs of caregivers/youth. The third dataset comes from the pilot test of the Achieve My Plan! intervention. Data was gathered from eight teams before and after the intervention was implemented. RESULTS: Taken together, the findings suggest that teams' success in managing caregiver and adolescent perspectives simultaneously during care and treatment planning is more strongly related to the quality of the team process than to youth age. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Through attention to youth engagement, preparation, and tem process, it appears possible to increase meaningful youth participation in planning without sacrificing caregiver satisfaction with the team experience. PMID- 22246118 TI - Longitudinal transition outcomes of youth with emotional disturbances. AB - OBJECTIVE: Two perspectives are offered on the transition outcomes of youth with emotional disturbances (ED) using data from the National Longitudinal Transition Study (NLTS) and the National Longitudinal Transition Study-2 (NLTS2). The first perspective compares two cohorts of youth ages 18-21 who were out of high school up to 4 years in 1990 and 2005 on their rates of high school completion, postsecondary education enrollment, employment, independent living, and criminal justice system involvement. The second perspective provides similar information from the final wave of NLTS2 data collection (2009), when young adults were ages 21-25. METHODS: Using nationally representative interview and survey data, descriptive statistics are provided for outcomes at each time point. RESULTS: Significant increases over time are apparent in rates of high school completion, postsecondary education, and arrest, and there was a significant decline in employment. Analyses of young adults with ED in 2009 show that 82.5 percent had completed high school, and 53 percent had had some postsecondary education. Although 91.2 percent had been employed at some time since high school, 49.6 percent were employed when interviewed; 63.1 percent had lived independently, 60.5 percent had been arrested, and 44.2 percent had been on probation or parole. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Youth with emotional disturbances trail the general population in positive transition outcomes, and high rates of criminal justice system involvement suggest more effort is needed, including early intervening with response to intervention (RtI) strategies and self determination training, to help these young adults succeed after high school. PMID- 22246119 TI - Supporting the education goals of post-9/11 veterans with self-reported PTSD symptoms: a needs assessment. AB - PURPOSE: The influx of young adult veterans with mental health challenges from recent wars combined with newly expanded veteran education benefits has highlighted the need for a supported education service within the Veterans Administration. However, it is unknown how such a service should be designed to best respond to these needs. This study undertook a qualitative needs assessment for education supports among veterans with post-9/11 service with self-reported PTSD symptoms. METHODS: Focus groups were held with 31 veterans, 54% of whom were under age 30. Transcripts were analyzed and interpreted using a thematic approach and a Participatory Action Research team. RESULTS: Findings indicate a need for age relevant services that assist with: education planning and access, counseling for the G.I. Bill, accommodations for PTSD symptoms, community and family re integration, and outreach and support. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The veterans recommended that supported education be integrated with the delivery of mental health services, that services have varied intensity, and there be linkages between colleges and the Veterans Health Administration. PMID- 22246120 TI - Community participation as a predictor of recovery-oriented outcomes among emerging and mature adults with mental illnesses. AB - OBJECTIVE: The promotion of recovery and quality of life is a major focus of national and local mental health system transformation efforts. There has been simultaneous interest in enhancing community participation as a facilitator of recovery. This study examines the community participation experiences of emerging adults and mature adults with serious mental illnesses and the relationship between various types of participation and recovery, quality of life, and meaning of life. METHODS: Baseline data from the Consumer-Operated Service Program multisite study were utilized. The sample was recruited from traditional mental health services and consisted of 233 emerging adults and 1,594 mature adults. Ten areas of participation were examined: parenting, employment, volunteering, college student, group membership, civic engagement, peer support, friendships, intimate relationships, and engagement in religious/spiritual activities. RESULTS: Emerging and mature adults differed in developmentally appropriate ways. Emerging adults and those who participated more had higher scores on the recovery, quality of life and meaning of life measures. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The higher scores on the dependent variables may be explained by younger adults having greater hope and higher expectations that are typical for those at that stage of life and that living longer with a serious mental illness and being exposed longer to the mental health system may dampen hope. Participation in general, and specific areas of participation, were predictive of recovery-oriented outcomes. These results should inspire future developmentally-oriented research examining factors that facilitate recovery and provide direction to providers about participation areas that may be most beneficial in facilitating recovery. PMID- 22246121 TI - Participatory action research and young adults with psychiatric disabilities. AB - TOPIC: Participatory Action Research (PAR) methods are increasingly being used to include people with psychiatric disabilities in the research production process. PAR places a strong emphasis on collaboration between academic researchers and the disadvantaged community, along with strategies for overcoming barriers to collaboration. PURPOSE: The author describes key principles for engaging young adults with psychiatric disabilities as research associates in a participatory action research (PAR) project. SOURCES USED: Over the past decade, the author developed substantial knowledge by leading or co-leading five (5) funded PAR projects with young adults with psychiatric disabilities and has integrated this experience with an analysis of relevant publications. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The key components for achieving successful PAR with young adult researchers align well with the literature on PAR with adults with psychiatric disabilities. Specific adaptations for transition age youth researchers include mentorship from more experienced researchers and the availability of specialized vocational supports. PMID- 22246122 TI - Prevalence and impact of substance use among emerging adults with serious mental health conditions. AB - TOPIC: This critical review of the literature integrates findings across varied literatures and identifies areas for continued study on the prevalence, correlates, and impact of substance use (alcohol and illicit drugs) on social role functioning among emerging adults with serious mental health conditions. PURPOSE: This population is of interest because of high comorbidity rates between substance use and serious mental health conditions and the added difficulties posed by their co-occurrence during the transition to adulthood. This critical review presents the epidemiology of substance use in emerging adults with serious mental health conditions compared to emerging adults without these conditions, as well as what is known about predictors and consequences of substance use in this population. SOURCES USED: PsychINFO and PubMed along with relevant published literature. RESULTS: This review summarizes what is known about the impact of these co-occurring problems on the transition of emerging adults from school and training environments to adult work roles. Though this group presents with unique challenges, few programs have been developed to address their specific needs. This paper synthesizes what is known empirically about approaches with this population, discussing those that might be useful for emerging adults with comorbid serious mental health conditions and substance use problems, particularly in supporting their educational and vocational development. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Emerging adults with co-occurring serious mental health conditions and substance use problems are underserved by current mental health systems. Recommendations focus on how to promote mental health and social role functioning through comprehensive intervention programs that provide continuity of care through the transition to adulthood. PMID- 22246123 TI - Young adults with mental health conditions and social networking websites: seeking tools to build community. AB - OBJECTIVE: This study examined ways that young adults with mental illnesses (1) currently use social networking; and (2) how they would like to use a social networking site tailored for them. The authors examined differences between those with mental health conditions and those without. METHODS: An online survey was administered by the National Alliance on Mental Illness (NAMI) to 274 participants; of those, 207 reported being between 18 and 24 years old. The survey included questions about current social networking use, the key resources respondents believed young adults living with mental illness need, and the essential components that should be included in a social networking site specifically tailored to young adults living with mental illness. Pearson Chi square analyses examined the differences between those who reported having a mental illness and those who did not. RESULTS: Results indicate that almost all (94%) participants with mental illnesses currently use social networking sites. Individuals living with a mental illness are more likely than those not living with a mental illness to report engaging in various social networking activities that promote connectivity and making online friends. Individuals living with mental illnesses are also more likely to report wanting resources on independent living skills and overcoming social isolation available on a social networking site. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Young adults living with mental illnesses are currently using social networking sites and express high interest in a social networking site specifically tailored to their population with specific tools designed to decrease social isolation and help them live more independently. These results indicate that practitioners should themselves be aware of the different social networking sites frequented by their young adult clients, ask clients about their use of social networking, and encourage safe and responsible online behaviors. PMID- 22246124 TI - Transition experiences of mental health service users, parents, and professionals in the United Kingdom: a qualitative study. AB - OBJECTIVE: The aim of this study was to describe the experiences of child and adolescent mental health service (CAMHS) users, parents and professionals in relation to transition between CAMHS and adult mental health services (AMHS) in the United Kingdom. METHODS: Young people were sampled from an observational study population of people reaching the transition boundary between CAMHS and AMHS. We thematically analyzed qualitative interviews with service users, parents and clinicians. RESULTS: Eleven service users were interviewed and linked interviews were completed with parents (n=6), and responsible clinicians in CAMHS (n=3) and AMHS (n=6). Informal and gradual preparation, transfer planning meetings, periods of parallel care, and consistency in key-workers promoted positive experiences of transition. Transfers between AMHS, changes of key-worker and waiting lists were viewed negatively. Other life transitions, including changes in housing, pregnancy, physical illness, and the involvement of parents or other services were sometimes powerful extraneous influences on transition experiences. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The cumulative effect of multiple transitions is a complex and unsettling experience for many service users. Service user experiences are more likely to be positive if healthcare transition is a gradual process, tailored to the young person's needs and managed in the context of the other simultaneous practical, developmental and psychosocial transitions. Transfer planning meetings and parallel care were valued by all parties and should be standard practice at transition. CAMHS and AMHS need to work jointly to improve the transition process in these ways in order to enhance the outcomes for young people. PMID- 22246125 TI - Employment experiences of young Medicaid Buy-In participants with psychiatric disabilities. AB - OBJECTIVE: The Medicaid Buy-In (Buy-In) program allows people with disabilities to "buy into" Medicaid when their earnings or assets would typically make them ineligible. This program may be advantageous to youth with psychiatric disabilities by providing continuous health care coverage while they are employed. METHODS: State-submitted participant-level Buy-In enrollment data were linked with Social Security Administration data to identify the receipt of federal disability benefits, the primary disability used to determine eligibility, and annual earnings. We assessed the differences in employment outcomes between young participants (ages 18 to 30) with psychiatric disabilities versus young participants with other disabilities, including the likelihood of being employed, average earnings, and changes in earnings around the time of Buy In enrollment. RESULTS: Young Buy-In participants with psychiatric disabilities were just as likely to be employed as those with other disabling conditions, although their average earnings were slightly lower. Both groups were similarly likely to increase their earnings around the time of Buy-In enrollment, but among participants who had such increases, the amount of the increase was higher for those with psychiatric disabilities. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Young Buy-In participants with psychiatric disabilities achieve larger average increases in earnings around the time of enrollment in the program than those with other disabling conditions, though average earnings while employed are lower. This suggests that the coverage provided by Buy-In may be particularly beneficial for youth with psychiatric disabilities. Outreach to enroll these youth into the program may benefit this vulnerable group, who often lack other supports in the community. PMID- 22246126 TI - Social network analysis of child and adult interorganizational connections. AB - OBJECTIVE: Because most programs serve either children and their families or adults, a critical component of service and treatment continuity in mental health and related services for individuals transitioning into adulthood (ages 14-25) is coordination across programs on either side of the adult age divide. METHODS: This study was conducted in Clark County, Washington, a community that had received a Partnership for Youth Transition grant from the Federal Center for Mental Health Services. Social Network Analysis methodology was used to describe the strength and direction of each organization's relationship to other organizations in the transition network. Interviews were conducted before grant implementation (n=103) and again four years later (n=99). RESULTS: The findings of the study revealed significant changes in the nature of relationships between organizations over time. While the overall density of the transition service network remained stable, specific ways of connecting did change. Some activities became more decentralized while others became more inclusive as evidenced by the increase in size of the largest K-core. This was particularly true for the activity of "receiving referrals." These changes reflected more direct contact between child and adult serving organizations. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The two separate child and adult systems identified at baseline appeared more integrated by the end of the grant period. Having greater connectivity among all organizations regardless of ages served should benefit youth and young adults of transition age. This study provides further evidence that Social Network Analysis is a useful method for measuring change in service system integration over time. PMID- 22246127 TI - One size does not fit all. PMID- 22246128 TI - Fostering transitions to valued roles for youth: a training program. PMID- 22246129 TI - C-type lectin receptor-induced NF-kappaB activation in innate immune and inflammatory responses. AB - The C-type lectin receptors (CLRs) belong to a large family of proteins that contain a carbohydrate recognition domain (CRD) and calcium binding sites on their extracellular domains. Recent studies indicate that many CLRs, such as Dectin-1, Dectin-2 and Mincle, function as pattern recognition receptors (PRRs) recognizing carbohydrate ligands from infected microorganisms. Upon ligand binding, these CLRs induce multiple signal transduction cascades through their own immunoreceptor tyrosine-based activation motifs (ITAMs) or interacting with ITAM-containing adaptor proteins such as FcRgamma. Emerging evidence indicate that CLR-induced signaling cascades lead to the activation of nuclear factor kappaB (NF-kappaB) family of transcriptional factors through a Syk- and CARD9 dependent pathway(s). The activation of NF-kappaB plays a critical role in the induction of innate immune and inflammatory responses following microbial infection and tissue damages. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs, and how these CLRs activate NF-kappaB and contribute to innate immune and inflammatory responses. PMID- 22246130 TI - Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. AB - Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice-male (ACE2(-/y)) and female (ACE2(-/-))-and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(-/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes alpha-smooth muscle actin (alpha-SMA) and Transforming Growth Factor beta1. Compared with ACE2(-/y) exposed to BLM, ACE2(-/-) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS. PMID- 22246132 TI - Alcohol induced structural and dynamic changes in beta-lactoglobulin in aqueous solution: a neutron scattering study. AB - Structural and dynamic properties of beta-lactoglobulin (beta-LG) were revealed as a function of alcohol concentration in ethanol- and trifluoroethanol(TFE) water mixtures with circular dichroism (CD), small-angle neutron scattering (SANS) and quasi-elastic neutron scattering (QENS). The CD spectra showed that an increase in TFE concentration promotes the formation of the beta-sheet structure of beta-LG. The SANS-intensities were fitted using form factors for two attached spheres for the native and native-like states of the protein. At higher alcohol concentrations, where aggregation takes place, a form factor modelling diffusion limited colloidal aggregation (DLCA) was employed. The QENS-data were analyzed in terms of internal motions for all alcohol concentrations. While low concentrations of TFE (10% (v/v)) lead to an increase of the mean square amplitudes of vibrations and a retention of a native-like structure - but not to an increase of the characteristic radius of proton diffusion processes a. Addition of 20% (v/v) of TFE induces aggregation, going along with a further increase of . Further increase of TFE concentration to 30% (v/v) changes the nanoscale structure of the oligomeric nucleate, but induces no further significant changes in . The present study underlines the necessity of methods sensitive to the dynamics of a system to obtain a complete picture of a molecular process. PMID- 22246133 TI - Antigen-antibody interface properties: composition, residue interactions, and features of 53 non-redundant structures. AB - The structures of protein antigen-antibody (Ag-Ab) interfaces contain information about how Ab recognize Ag as well as how Ag are folded to present surfaces for Ag recognition. As such, the Ab surface holds information about Ag folding that resides with the Ab-Ag interface residues and how they interact. In order to gain insight into the nature of such interactions, a data set comprised of 53 non redundant 3D structures of Ag-Ab complexes was analyzed. We assessed the physical and biochemical features of the Ag-Ab interfaces and the degree to which favored interactions exist between amino acid residues on the corresponding interface surfaces. Amino acid compositional analysis of the interfaces confirmed the dominance of TYR in the Ab paratope-containing surface (PCS), with almost two fold greater abundance than any other residue. Additionally TYR had a much higher than expected presence in the PCS compared to the surface of the whole antibody (defined as the occurrence propensity), along with aromatics PHE, TRP, and to a lesser degree HIS and ILE. In the Ag epitope-containing surface (ECS), there were slightly increased occurrence propensities of TRP and TYR relative to the whole Ag surface, implying an increased significance over the compositionally most abundant LYS>ASN>GLU>ASP>ARG. This examination encompasses a large, diverse set of unique Ag-Ab crystal structures that help explain the biological range and specificity of Ag-Ab interactions. This analysis may also provide a measure of the significance of individual amino acid residues in phage display analysis of Ag binding. PMID- 22246134 TI - Ethanol-induced DNA damage and repair-related molecules in human intestinal epithelial Caco-2 cells. AB - The acute administration of ethanol to intestinal epithelial cells causes increased intestinal permeability and the translocation of endotoxins. The changes caused by ethanol in intestinal cells may be related to oxidative stress and DNA damage. However, DNA damage and repair-related molecules which act against stresses, including ethanol, have not been fully investigated in intestinal cells. Heat shock proteins (Hsps) are involved in the recovery and protection from cell damage and may be associated with DNA repair. Therefore, the aim of our study was to investigate cytotoxicity, DNA damage and the expression of DNA repair-related molecules, antioxidant proteins and Hsps in intestinal cells exposed to ethanol. Human intestinal Caco-2 cells were incubated with 1-8% ethanol for 1 h. Cell viability and DNA damage were determined using the MTT and comet assays, respectively. We measured DNA repair-related molecules, including DNA polymerase beta, apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref 1), growth arrest and DNA damage 45alpha (GADD45alpha) and proliferating cell nuclear antigen (PCNA), in Caco-2 cells using western blot analysis. We also measured glutathione peroxidase-1 (GPx-1), peroxiredoxin-1 (PRX-1), superoxide dismutase-2 (SOD-2), Hsp10, Hsp27, Hsp60, heat shock cognate (Hsc)70, Hsp70 and Hsp90. The viability of the Caco-2 cells exposed to ethanol decreased at concentrations >= 7% (P<0.05). The Olive tail moment, indicating DNA damage, increased dose dependently in >= 3% ethanol (P<0.05). Among the DNA repair proteins, the expression of PCNA and APE/Ref-1 increased significantly at 1% ethanol. Antioxidant enzymes, including GPx-1, PRX-1 and SOD-2, had an increased expression at 1% ethanol. Hsp10, Hsp27 and Hsp70 expression also increased significantly at 1% ethanol. In conclusion, the expression of DNA repair molecules, antioxidants and Hsps increased in intestinal Caco-2 cells exposed to low concentrations of ethanol. In particular, PCNA, APE/Ref-1, Hsp10, Hsp27 and Hsp70 were sensitive to low ethanol concentrations, indicating that they may be useful in evaluating the DNA repair and cytoprotective effects of the drug against stress in intestinal cells. PMID- 22246135 TI - Flavonoid baicalein modulates H2O2-induced mitogen-activated protein kinases activation and cell death in SK-N-MC cells. AB - It is believed that ROS-induced oxidative stress triggers numerous signaling pathways which are involved in neurodegenerative diseases, including Alzheimer's disease. To find the effective drugs for neurodegenerative diseases, the deep delve into molecular mechanisms underlie these diseases is necessary. In the current study, we investigated the effects of flavonoid baicalein on H(2)O(2) induced oxidative stress and cell death in SK-N-MC cells. Our results revealed that the treatment of SK-N-MC cells with H(2)O(2) led to a decrease in cell viability through phosphorylation and activation of extracellular signal regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs) pathways followed by increase in Bax/Bcl2 ratio and initiation of caspase-dependent apoptotic pathways. In addition, our results showed that the exposure of SK-N-MC cells to H(2)O(2) ended up in reduction of glutathione (GSH) levels of SK-N-MC cells via JNK/ERK-mediated down-regulation of gamma-glutamyl-cysteine synthetase (gamma GCS) expression. Our results demonstrated that flavonoid baicalein protected against H(2)O(2)-induced cell death by inhibition of JNK/ERK pathways activation and other key molecules in apoptotic pathways, including blockage of Bax and caspase-9 activation, induction of Bcl-2 expression and prevention of cell death. Baicalein supported intracellular defense mechanisms through maintaining GSH levels in SK-N-MC cells by the removal of inhibition effects of JNK/ERK pathways from gamma-GCS expression. In addition, baicalein attenuated lipid and protein peroxidation and intracellular reactive oxygen species in SK-N-MC cells. In accordance with these observations, baicalein can be a promising candidate in antioxidant therapy and designing of natural-based drug for ROS-induced neurodegenerative disorders. PMID- 22246137 TI - Effect of speech material on the benefit of temporal fine structure information in speech for young normal-hearing and older hearing-impaired participants. AB - OBJECTIVE: The purpose of this study was to investigate the influence of the type of speech material on the benefit obtained from temporal fine structure (TFS) information in speech for young normal-hearing (YNH) and older hearing-impaired (OHI) participants. DESIGN: The design was based on the work of . They measured the speech reception thresholds for a target talker in a background talker as a function of the frequency range over which TFS information was available. The signal was split into 32 channels, each with a bandwidth equal to the equivalent rectangular bandwidth of the "normal" auditory filter at the same center frequency. Above a cutoff (CO) channel, channels were vocoded and contained only temporal envelope information. Channels up to and including CO were not processed. Hopkins et al. found that, as CO was increased, speech reception thresholds decreased more for normal-hearing participants than for participants with cochlear hearing loss, suggesting that the latter were less able to use TFS information. We used the same design, but compared results when the target speech materials were open-set sentences, as used by Hopkins et al., and when they were more predictable sentences with a closed word set (Danish Dantale 2). RESULTS: With the open-set material, YNH listeners benefited more from TFS information than OHI listeners, replicating . For the YNH participants, the benefit of adding TFS was greater for the open-set material than for the closed-set material, while no difference in TFS benefit across speech materials was found for the OHI participants. CONCLUSIONS: The choice of speech material is important when assessing the benefit of TFS. Several factors may facilitate recognition in the absence of TFS cues, including small set size, predictable temporal structure of the target speech, and contextual effects. We speculate that TFS information is useful for reducing informational masking, by providing cues for the perceptual segregation of the target and background. When the target speech is highly predictable, informational masking may be minimal, rendering TFS cues unnecessary. PMID- 22246136 TI - Resveratrol, a polyphenol phytoalexin, protects cardiomyocytes against anoxia/reoxygenation injury via the TLR4/NF-kappaB signaling pathway. AB - Previous studies indicate resveratrol pretreatment can protect cardiomyocytes. However, it is largely unknown whether resveratrol protects cardiomyocytes when applied at reperfusion. The purpose of this study was to investigate whether resveratrol given at reoxygenation could protect cardiomyocytes under the anoxia/reoxygenation (A/R) condition and to examine the underlying mechanism. In this study, primary cultures of neonatal rat cardiomyocytes were randomly distributed into three groups: control group, A/R group (cultured cardiomyocytes were subjected to 3 h anoxia followed by 2 h reoxygenation), and the resveratrol group (cardiomyocytes were subjected to 3 h anoxia/2 h reoxygenation, and 5, 10 or 20 uM resveratrol was applied 5 min after reoxygenation). In order to evaluate cardiomyocyte damage, cell viability, lactate dehydrogenase (LDH) release, caspase-3 activity, and apoptosis were analyzed by the cell counting kit (CCK)-8 assay, colorimetric method and flow cytometry, respectively. The mRNA and protein expression of Toll-like receptor 4 (TLR4) were detected by quantitative real-time PCR and western blot analysis. Nuclear factor-kappaB (NF-kappaB) p65 protein and I-kappaBalpha protein levels were also examined by western blot analysis. The levels of proinflammatory cytokines in the culture medium were assessed by enzyme linked immunosorbent assay. We found that resveratrol prevented a reduction in cell viability, decreased the amount of LDH release, attenuated apoptotic cells and decreased caspase-3 activity induced by A/R in cardiomyocytes. Furthermore, resveratrol treatment significantly attenuated the TLR4 expression, inhibited NF kappaB activation and reduced the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta caused by A/R injury in the culture medium. Treatment with resveratrol shortly after the onset of reoxygenation improves cell survival and attenuates A/R-induced inflammatory response. This protection mechanism is possibly related to the TLR4/NF-kappaB signaling pathway. PMID- 22246138 TI - Relationships between electrically evoked potentials and loudness growth in bilateral cochlear implant users. AB - OBJECTIVES: The goals of this study were (1) to describe the relationship between electrically evoked compound action potential (ECAP) and electrically evoked auditory brainstem response (EABR) amplitude growth functions and loudness growth functions in bilateral cochlear implant (CI) users, and (2) to determine whether matching the stimulus levels in the two ears of bilateral CI users based on equal ECAP amplitude, EABR amplitude, or current level resulted in the smallest discrepancy in loudness rating across the two ears. DESIGN: Ten adult, bilateral CI users participated in this study. The stimulus used to elicit loudness judgments and generate ECAP and EABR growth functions was a train of biphasic current pulses (32 MUs/phase) presented at a rate of 23 pps. Loudness growth functions were obtained with a method of constant stimuli. ECAPs were measured using the implant telemetry system. EABR growth functions were recorded using surface electrodes and standard averaging techniques. Both ears of each subject were tested. For each ear, ECAP, EABR, and loudness functions were recorded using both an apical and basal stimulating electrode. Both the physiologic and psychophysical growth functions were fit using linear regression techniques. RESULTS: Comparison of the regression equations obtained for the two ears revealed that stimulus levels that yielded approximately equal ECAP amplitudes in the two ears were judged to differ in loudness, on average, by 20% for electrode 3 and 14% for electrode 13. Stimulation levels that evoked similar amplitude EABRs differed in loudness, on average, by 50% for electrode 3 and 13% for electrode 13. Matched stimulus current levels were judged to differ in loudness, on average, by 14% for electrode 3 and 16% for electrode 13. No significant differences in loudness discrepancy across ears derived from equal amplitude ECAP, EABR, or matched current levels were found. CONCLUSIONS: This study demonstrated that stimuli that evoke equal amplitude neural responses in both ears of a bilateral CI user or which are matched in current level cannot be assumed to be perceived as equally loud. No statistically significant differences in accuracy were found between ECAP, EABR, or matched current levels or between the basal and apical electrode in approximations of equal loudness. PMID- 22246139 TI - Effects of dynamic-range compression on the spatial attributes of sounds in normal-hearing listeners. AB - OBJECTIVES: Dynamic-range compression is routinely used in bilaterally fitted hearing devices. The objective of this study was to investigate how compression applied independently at each ear affects spatial perception in normal-hearing listeners and to relate the effects to changes in binaural cues caused by the compression for different types of sound. DESIGN: A semantic-differential method was used to measure the spatial attributes of sounds. Eleven normal-hearing participants responded to questions addressing certainty of location, diffuseness, movement, image splits, and externalization of sounds. Responses were given on seven-point scales between pairs of opposing terms. Stimuli included speech and a range of synthetic sounds with varying characteristics. Head-related transfer functions were used to simulate a source at an azimuth of 60 degrees or +60 degrees . Three processing conditions were compared: (1) an unprocessed reference condition; (2) fast-acting, wide-dynamic-range compression operating independently at each ear; and (3) imposition of a static bias in interaural level difference (ILD) equivalent to that generated by the compression under steady state conditions. All processing was applied in a high-frequency channel above 2 kHz. The three processing conditions were compared separately in two bandwidth conditions: a high-pass condition in which the high-frequency channel was presented to listeners in isolation and a full-bandwidth condition in which the high-frequency channel was recombined with the unprocessed low frequency channel. RESULTS: Hierarchical cluster analysis was used to group related questions based on similarity of participants' responses. This led to the calculation of composite scores for four spatial attributes: "diffuseness," "movement," "image split," and "externalization." Compared with the unprocessed condition, fast-acting compression significantly increased diffuseness, movement, and image-split scores and significantly reduced externalization scores. The effects of compression were greater when listeners heard the high-frequency channel in isolation than when it was recombined with the unprocessed low frequency channel. The effects were apparent only for sounds containing gradual onsets and offsets, including speech. Dynamic compression had a much more pronounced effect on the spatial attributes of sounds than imposition of a static bias in ILD. CONCLUSIONS: Fast-acting compression at high frequencies operating independently at each ear can adversely affect the spatial attributes of sounds in normal-hearing listeners by increasing diffuseness, increasing or giving rise to a sense of movement, causing images to split, and affecting the externalization of sounds. The effects are reduced, but not eliminated, when listeners have access to undisturbed low-frequency cues. Sounds containing gradual onsets and offsets, including speech, are most affected. The effects arise primarily as a result of relatively slow changes in ILD that are generated as the sound level at one or both ears crosses the compression threshold. The results may have implications for the use of compression in bilaterally fitted hearing devices, specifically in relation to spatial perception in dynamic situations. PMID- 22246144 TI - Gemini surfactant assisted synthesis of two-dimensional metal nanoparticles/graphene composites. AB - We demonstrate the synthesis of 2D metal nanoparticles (MNPs)/graphene nanocomposites using small cationic surfactants as stabilizers. 2D sandwich-like MNPs/graphene nanocomposites with a uniform distribution of MNPs can be achieved via a one-pot in situ growth and reduction protocol. PMID- 22246145 TI - Polymer-supported syntheses of thiophene-containing compounds using a new type of traceless linker. AB - A new type of traceless linker is described for use in polymer-supported (PS) syntheses of thiophene-containing compounds. It is based on the cleavage of PS aryl 2-thienyl ketones by a mixture of potassium t-butoxide and water (typical mol ratio 10:3) in an ethereal solvent. Cleavage occurs to give the soluble thiophene-containing product. The method is used to prepare a range of eight thiophene-containing compounds including a terthiophene and a dialkylquaterthiophene. PS unsymmetrical diaryl ketones incorporating, for example, ortho-methoxyphenyl or pyrrole moieties could also serve as traceless linkers. PMID- 22246146 TI - CT colonography without cathartic preparation: positive predictive value and patient experience in clinical practice. AB - OBJECTIVE: To determine the positive predictive value (PPV) for polyps >= 6 mm detected at CT colonography (CTC) performed without cathartic preparation, with low-dose iodine faecal tagging regimen and to evaluate patient experience. METHODS: 1920 average-risk patients underwent CTC without cathartic preparation. Faecal tagging was performed by diatrizoate meglumine and diatrizoate sodium at a total dose of 60 ml (22.2 g of iodine).The standard interpretation method was primary 3D with 2D problem solving. We calculated per-patient and per-polyp PPV in relation to size and morphology. All colonic segments were evaluated for image quality (faecal tagging, amount of liquid and solid residual faeces and luminal distension). Patients completed a questionnaire before and after CTC to assess preparation and examination experience. RESULTS: Per-polyp PPV for detected lesions of >= 6 mm, 6-9 mm, >= 10 mm and >= 30 mm were 94.3%, 93.1%, 94.7% and 98%, respectively. Per-polyp PPV, according to lesion morphology, was 94.6%, 97.3% and 85.1% for sessile, pedunculated and flat polyps, respectively. Per patient PPV was 92.8%. Preparation without frank cathartics was reported to cause minimal discomfort by 78.9% of patients. CONCLUSION: CTC without cathartic preparation and low-dose iodine faecal tagging may yield high PPVs for lesions >= 6 mm and is well accepted by patients. KEY POINTS: * Computed tomographic colonography (CTC) without cathartic preparation is well accepted by patients * Cathartic-free faecal tagging CTC yields high positive predictive values * CTC without cathartic preparation could improve uptake of colorectal cancer screening. PMID- 22246148 TI - Acceptability and preliminary feasibility of an internet/CD-ROM-based education and decision program for early-stage prostate cancer patients: randomized pilot study. AB - BACKGROUND: Prostate cancer is the most common cancer affecting men in the United States. Management options for localized disease exist, yet an evidence-based criterion standard for treatment still has to emerge. Although 5-year survival rates approach 98%, all treatment options carry the possibility for significant side effects, such as erectile dysfunction and urinary incontinence. It is therefore recommended that patients be actively involved in the treatment decision process. We have developed an Internet/CD-ROM-based multimedia Prostate Interactive Educational System (PIES) to enhance patients' treatment decision making. PIES virtually mirrors a health center to provide patients with information about prostate cancer and its treatment through an intuitive interface, using videos, animations, graphics, and texts. OBJECTIVES: (1) To examine the acceptability and feasibility of the PIES intervention and to report preliminary outcomes of the program in a pilot trial among patients with a new prostate cancer diagnosis, and (2) to explore the potential impact of tailoring PIES treatment information to participants' information-seeking styles on study outcomes. METHODS: Participants (n = 72) were patients with newly diagnosed localized prostate cancer who had not made a treatment decision. Patients were randomly assigned to 3 experimental conditions: (1) control condition (providing information through standard National Cancer Institute brochures; 26%), and PIES (2) with tailoring (43%) and (3) without tailoring to a patient's information seeking style (31%). Questionnaires were administrated before (t1) and immediately after the intervention (t2). Measurements include evaluation and acceptability of the PIES intervention, monitoring/blunting information-seeking style, psychological distress, and decision-related variables (eg, decisional confidence, feeling informed about prostate cancer and treatment, and treatment preference). RESULTS: The PIES program was well accepted by patients and did not interfere with the clinical routine. About 79% of eligible patients (72/91) completed the pre- and post-PIES intervention assessments. Patients in the PIES groups compared with those in the control condition were significantly more likely to report higher levels of confidence in their treatment choices, higher levels of helpfulness of the information they received in making a treatment decision, and that the information they received was emotionally reassuring. Patients in the PIES groups compared with those in the control condition were significantly less likely to need more information about treatment options, were less anxious about their treatment choices, and thought the information they received was clear (P < .05). Tailoring PIES information to information-seeking style was not related to decision-making variables. CONCLUSIONS: This pilot study confirms that the implementation of PIES within a clinical practice is feasible and acceptable to patients with a recent diagnosis of prostate cancer. PIES improved key decision-making process variables and reduced the emotional impact of a difficult medical decision. PMID- 22246149 TI - Pesticide exposure in honey bees results in increased levels of the gut pathogen Nosema. AB - Global pollinator declines have been attributed to habitat destruction, pesticide use, and climate change or some combination of these factors, and managed honey bees, Apis mellifera, are part of worldwide pollinator declines. Here we exposed honey bee colonies during three brood generations to sub-lethal doses of a widely used pesticide, imidacloprid, and then subsequently challenged newly emerged bees with the gut parasite, Nosema spp. The pesticide dosages used were below levels demonstrated to cause effects on longevity or foraging in adult honey bees. Nosema infections increased significantly in the bees from pesticide-treated hives when compared to bees from control hives demonstrating an indirect effect of pesticides on pathogen growth in honey bees. We clearly demonstrate an increase in pathogen growth within individual bees reared in colonies exposed to one of the most widely used pesticides worldwide, imidacloprid, at below levels considered harmful to bees. The finding that individual bees with undetectable levels of the target pesticide, after being reared in a sub-lethal pesticide environment within the colony, had higher Nosema is significant. Interactions between pesticides and pathogens could be a major contributor to increased mortality of honey bee colonies, including colony collapse disorder, and other pollinator declines worldwide. PMID- 22246150 TI - Eyelid nodule: a rare presentation of Langerhans cell histiocytosis. AB - Langerhans cell histiocytosis occurring as an isolated tumor of eyelid has rarely been reported. We report an unusual case of a 5-year-old boy who presented with a smooth nodular lesion over the right lower eyelid accompanied with hyperemia for a month. The biopsy and CD1a positivity confirmed it to be Langerhans cell histiocytosis. It was localized to the eyelid as no other organ was involved. Although Langerhans cell histiocytosis of the eyelid is exceptional, it must be included in the differential diagnosis of eyelid nodular lesions and the diagnostic and the subsequent management must be multidisciplinary. PMID- 22246151 TI - Osteochondroma with metaphyseal abnormalities after total body irradiation followed by stem cell transplantation. AB - The occurrence of osteochondroma after total body irradiation (TBI) followed by stem cell transplantation (SCT) in our institutions was described, and its clinical significance discussed. Of 305 cases treated with SCT using TBI conditioning from 1980 to 2001, 4 cases of osteochondroma were identified on clinical examination. Mean age at the time of TBI was 4.4 years (range, 1.6 to 8.0). One patient developed multiple osteochondromas. All 4 cases showed metaphyseal abnormalities, including sclerotic metaphyseal lesion, fraying, and longitudinal striation, in the area where osteochondromas occurred. Only 1 patient required resection of the tumor due to pain. Two cases had other skeletal abnormalities including slipped capital femoral epiphysis and valgus-knee deformity, which required surgical intervention to prevent or correct these deformities. Osteochondroma is one of the complications developing after TBI, possibly concurrently with the metaphyseal abnormalities as seen on radiographs. However, clinical problems arising from osteochondroma are minimal, and surgical intervention is necessary in limited cases. PMID- 22246147 TI - Molecular damage in cancer: an argument for mTOR-driven aging. AB - Despite common belief, accumulation of molecular damage does not play a key role in aging. Still, cancer (an age-related disease) is initiated by molecular damage. Cancer and aging share a lot in common including the activation of the TOR pathway. But the role of molecular damage distinguishes cancer and aging. Furthermore, an analysis of the role of both damage and aging in cancer argues against "a decline, caused by accumulation of molecular damage" as a cause of aging. I also discuss how random molecular damage, via rounds of multiplication and selection, brings about non-random hallmarks of cancer. PMID- 22246152 TI - Extraskeletal osteosarcoma of the breast in an adolescent girl. AB - Extraskeletal osteosarcoma (ESOS) is a rare malignancy, usually arising in older adults. We were unable to find reports of children or adolescents affected by an ESOS of the breast. Here, we present the case of a high-grade osteosarcoma arising in the breast of a 16-year-old girl. The tumor was treated with breast conserving resections and adjuvant multiagent chemotherapy, based on a regimen of doxorubicin, high-dose methotrexate, cisplatin, and ifosfamide. At last follow up, the patient was in first complete remission, 29 months after initial diagnosis. PMID- 22246153 TI - Sweet syndrome in an infant with chronic granulomatous disease. AB - Sweet syndrome is characterized by painful, erythematous cutaneous lesions containing neutrophilic infiltrates. Although more commonly seen in adults, Sweet syndrome has also been recognized in several pediatric cases. Two previous cases of pediatric Sweet syndrome and 1 adult case have been described in chronic granulomatous disease (CGD) patients. We report the case of an infant with known CGD who was presented with methicillin-sensitive Staphylococcus aureus lymphadenitis and subsequently developed Sweet syndrome. CGD patients are prone to several disorders of inflammation. This case illustrates that Sweet syndrome may be part of the spectrum of inflammatory conditions to which CGD patients are predisposed. PMID- 22246154 TI - Allogeneic cord hematopoietic stem cell transplantation in an infant with primary myelofibrosis. AB - Primary myelofibrosis (PMF) is rare in children. An allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for severe cases. Here, we report the case of a female infant with PMF treated with allogeneic HSCT using an unrelated cord blood unit. She had successful reversal of her disease, but experienced complications related to transplant. This is the seventh reported case of HSCT for PMF in children, and the second using umbilical cord blood. We conclude that cord HSCT is a useful curative treatment option in children with PMF, but that efforts must be taken to reduce complications. PMID- 22246155 TI - Premarital hemoglobinopathy screening in Kayseri: a city in Middle Anatolia region of Turkey. AB - OBJECTIVE: The aim of the present study was to report the frequency of beta thalassemia trait and other hemoglobinopathies in Kayseri province, which is located in Middle Anatolia of Turkey, as part of the premarital screening program. METHODS: The study included subjects admitted to Family Planning Center for premarital screening test between January 2009 and March 2010. Blood samples of the couples were obtained during admission to the marriage office. Complete blood counts and hemoglobin (Hb) variant analysis were performed with automatic counter and capillary electrophoresis. RESULTS: A total of 10,261 people were screened. The prevalence of patients with the beta-thalassemia trait was 1.71% (175/10261). Moreover, HbD Punjab and HbO Arab were the most common Hb variants after beta-thalassemia trait with the frequencies of 0.36% and 0.09%, respectively. Only 2 HbS were detected in 15 months of screening time. In 2 couples both partners were found to be carriers of beta-thalassemia trait, and both partners of 1 couple to be carrier of HbD. CONCLUSIONS: Kayseri is not a high-risk region according to Mediterranean parts of Turkey, but the city takes migrations apart from neighbor cities, migrations from East and South provinces because of its geographic and industrial situation. For that reason detecting carrier couples with premarital screening program is an effective way of controlling thalassemia major. PMID- 22246156 TI - Lung function before and after pediatric allogeneic hematopoietic stem cell transplantation: a predictive role for DLCOa/VA. AB - BACKGROUND: Pre-allogeneic hematopoietic stem cell transplantation (aHSCT) and post-aHSCT lung function of 41 eligible patients at Riley Hospital for Children were assessed to identify risk factors for post-aHSCT morbidity and mortality. OBSERVATIONS: One year post-aHSCT pulmonary function tests were significantly lower compared with baseline. These findings recovered at 2 years post-aHSCT. Refractory disease before aHSCT correlated with lower pulmonary function tests after aHSCT. Graft-versus-host disease was significantly associated with higher post-aHSCT residual volume. Importantly, low pre-aHSCT carbon monoxide diffusing capacity adjusted for hemoglobin and alveolar volume was predictive of death. CONCLUSIONS: Among survivors, lung function improves over time after pediatric aHSCT. Measurement of carbon monoxide diffusing capacity adjusted for hemoglobin and alveolar volume before pediatric aHSCT should be further investigated as a predictor of pulmonary dysfunction and mortality. PMID- 22246157 TI - Successful alternative treatment containing vindesine for acute lymphoblastic leukemia with Charcot-Marie-Tooth disease. AB - Peripheral neuropathy is a well-known side effect of vincristine (VCR), a microtubule inhibitor commonly used to treat malignancies. Severe neurological adverse events can occur in patients with Charcot-Marie-Tooth disease (CMT) treated with VCR. Vindesine is also a microtubule inhibitor, which, like VCR, is widely used to treat malignancies. The case of an 11-year-old female patient with CMT type 1A who developed severe peripheral neuropathy induced by VCR given for her acute lymphoblastic leukemia is reported. Alternative treatment containing vindesine instead of VCR led to a successful outcome without a relapse of leukemia or neurological worsening of CMT. PMID- 22246158 TI - RALLE pilot: response-guided therapy for marrow relapse in acute lymphoblastic leukemia in children. AB - Despite improved treatment results of childhood acute lymphoblastic leukemia (ALL), 20% to 30% have a relapse, and then the outcome is very poor. We studied 40 children with ALL marrow relapse piloting an ALL relapse protocol with well known drugs and drug combinations by using a concept of response-guided design. We also measured response in logarithmic fashion. Our primary end points were achievement of M1 marrow status, minimal residual disease status below 10, and second remission. The remission induction rate was 90% with 10% induction mortality. After the A blocks (dexamethasone, vincristine, idarubicin and pegylated L-asparaginase), 85% had M1 status, 39% had minimal residual disease <=1*10, and 66% had 2 to 3 log response. After B1 block (cyclo, VP-16) the figures were 92%, 58%, and 83%, respectively. Twenty-five of 40 patients received allogeneic stem cell transplantation. Three-year event-free survival of the whole cohort was 37%, and the relapse rate was 38%. Three-year event-free survival by risk group was 53% for late, 34% for early, and 21% for very early relapses. An ALL marrow relapse nonresponsive to steroids, vincristine, asparaginase, anthracyclines, and alkylating agents is uncommon, and these classic drugs can still be advocated for induction of ALL relapse. The problems lie in creating a consolidation capable of preventing particularly posttransplant relapses. PMID- 22246160 TI - A marked decrease in CD4-positive lymphocytes at the onset of hepatitis in a patient with hepatitis-associated aplastic anemia. AB - A 10-year-old Japanese boy developed acute hepatitis with high levels of serum Torque teno virus DNA and marked lymphocytopenia, especially CD4 T lymphocytopenia. Although the total lymphocyte counts rose as the patient recovered from hepatitis, this was largely because of a marked rise in CD8 cells. In contrast, CD4 cells recovered poorly, resulting in a further striking fall in the CD4/8 ratio. Two months later, the patient developed hepatitis-associated aplastic anemia. He was successfully treated with immunosuppressive therapy, which normalized the lymphocyte subset proportions. T-cell subsets analysis at the onset of hepatitis might be useful for predicting development of hepatitis associated aplastic anemia. PMID- 22246161 TI - Critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis in acute lymphoblastic leukemia. AB - We report a pediatric case of critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis during acute lymphoblastic leukemia therapy. A 15-year old boy developed B. cereus sepsis and multiple organ failure on the 19th day after initiation of chemotherapy, and multidisciplinary treatment was started. Treatment was effective and septic shock with multiple organ failure remitted. He was weaned from a respirator on day 23 after the onset of sepsis, but complete flaccid paralysis of the 4 extremities occurred. His compound muscle action potential and F-wave occurrence were reduced on a nerve conduction test. The number of motor units was markedly decreased, and the amplitude and duration of individual motor units were low and short, respectively, on electromyography. Cerebrospinal fluid was normal. On the basis of these findings, he was diagnosed with critical illness polyneuropathy/myopathy. He underwent intensive rehabilitation and recovered the ability to walk 3 months after onset. He was discharged 1 year after the initiation of chemotherapy, and remission has been maintained without inconvenience to daily living activities for 3 years since disease onset. PMID- 22246163 TI - Two-dimensional infrared spectroscopy of neat ice Ih. AB - The OH stretch line shape of ice Ih exhibits distinct peaks, the assignment of which remains controversial. We address this longstanding question using two dimensional infrared (2D IR) spectroscopy of the OH stretch of H(2)O and the OD stretch of D(2)O of ice Ih at T = 80 K. The isotropic response is dominated by a 2D line shape component which does not depend on the pump pulse frequency. The decay time of the component that does depend on the pump frequency is calculated using singular value decomposition (bi-exponential decay H(2)O: 30 fs, 490 fs; D(2)O: 40 fs, 690 fs). The anisotropic contribution exhibits on-diagonal peaks, which decay on a very fast timescale (H(2)O: 85 fs; D(2)O: 65 fs), with no corresponding anisotropic cross-peaks. Both isotropic and anisotropic results indicate that randomization of excited dipoles occurs with a very rapid rate, just like in neat liquid water. We conclude that the underlying mechanism relates to the complex interplay between exciton migration and exciton-phonon coupling. PMID- 22246162 TI - Effects and mechanism of downregulation of survivin expression by RNA interference on proliferation and apoptosis of lung cancer cells. AB - The survivin protein, a member of the inhibitors of apoptosis (IAP) family, has gained popularity as a therapeutic target for cancer due to its selective expression in tumor cells and its significant involvement in tumor cell viability. The aim of this study was to investigate the effect of the survivin small interfering RNA (siRNA) plasmid on survivin expression in the human lung cancer cell line, A549, and to observe its effects on apoptosis and proliferation of A549 cells. A549 human lung cancer cells were transfected with survivin targeting siRNA. The downregulation of survivin expression was determined by real time polymerase chain reaction and western blotting. The proliferation of A549 cells was determined by MTT assay. The apoptotic rate and cell cycle distribution were analyzed by flow cytometry (FCM). Caspase-9 activity was also detected to study the apoptosis of lung cancer cells induced by siRNA against survivin. The sequence-specific siRNA efficiently and specifically downregulated the expression of survivin at both the mRNA and protein levels. Downregulation of survivin expression dramatically suppressed the proliferation of A549 cells and arrested the cells at the G (1)/G (0) phase. Caspase-9 activity was significantly increased in A549 cells transfected with siRNA against survivin. In this study, we found that survivin-specific siRNA can efficiently suppress the expression of survivin, increase apoptosis and inhibit A549 cell proliferation. Our findings further indicate the possibility that the antitumor effects of survivin-siRNA are mediated through the activation of caspase-9. PMID- 22246164 TI - Primary biliary cirrhosis: bad genes, bad luck. PMID- 22246165 TI - Performance of a point-of-care device in determining prothrombin time in an anticoagulation clinic. AB - New portable devices for the measurement of the prothrombin time and the international normalized ratio (INR) from capillary blood samples have demonstrated to have good correlation with classic laboratory methods in multiple clinical settings. In this study, we evaluated the performance of the point-of care device CoaguChek XS (CoaguChek XS; Roche Diagnostics, Basel, Switzerland), comparing the INR results with the standard laboratory method (automatic coagulometer) in an outpatient anticoagulation clinic. Results were compared by linear regression and Bland-Altman plot. Two hundred paired results were collected from 170 patients in a period of 90 days. The main indications for anticoagulation were prophylaxis of venous thromboembolic events, atrial fibrillation and prosthetic heart valves. Mean INR results obtained with the portable device and with the standard laboratory method were 2.22 +/- 0.70 and 2.30 +/- 0.77, respectively. The proportion of patients with supratherapeutic INRs was 13.5%. The CoaguChek XS monitor tended to underestimate the INR on average by 0.08 U. The correlation coefficient (R) between the two methods was 0.91 (P < 0.0001). The CoaguChek XS device is suitable for INR monitoring in patients in outpatient oral anticoagulation clinics. PMID- 22246166 TI - Is routine blood cross-matching necessary in elective laparoscopic colorectal surgery? AB - BACKGROUND: Routine pre-operative cross-matching of two units of packed red cells (PRC) is current practice in most hospitals for patients undergoing elective laparoscopic colorectal surgery (LCS). AIMS: To determine the usage of PRC in patients undergoing elective LCS & its cost implications. METHODS: Retrospective analysis of 116 consecutive laparoscopic colorectal resections under the care of 2 consultant surgeons. RESULTS: Surgical procedures were anterior resection (31.9%; n = 37), right hemicolectomy (22.4%; n = 26), sigmoid colectomy (22.4%; n 26), subtotal colectomy (7.8%; n = 9), APR (4.3%; n = 5), panproctocolectomy (3.4%; n = 4), completion proctectomy (1.7%, n = 2), left hemicolectomy (0.9%, n = 1), total colectomy (0.9%; n = 1) & resection rectopexy (0.9%; n = 1). The median age was 65 years, 58% female. The median pre-operative haemoglobin was 131 g/L, median blood loss 100 ml and median post-operative haemoglobin 111.5 g/L. Eleven cases were converted. Three patients required perioperative blood transfusion, 2 of whom underwent open conversion. The cost of carrying out a group & save (G&S) in our hospital is L40.60 excluding laboratory staff labour cost. A 2 unit cross-match costs L294.60. There is potential for substantial cost savings with change of practice to G&S only. CONCLUSION: G&S is sufficient to allow safe & cost-effective operative practice in laparoscopic colorectal surgery. PMID- 22246167 TI - The effect of hydroxyapatite-hPRP, and coral-hPRP on bone healing in rabbits: radiological, biomechanical, macroscopic and histopathologic evaluation. AB - There is a continuing search for bone substitutes to avoid or minimize the need for autogenous bone grafts. Human platelet-rich plasma (hPRP) is used to stimulate bone formation in vivo. Hydroxyapatite, a crystalline phase of calcium phosphate found naturally in bone minerals, has shown tremendous promise as a graft material. Coral is an osteoconductive material used as a bone graft extender. This study examined the effect of human platelet-rich plasma in combination with hydroxyapatite and coral on osteogenesis in vivo using rabbit model bone healing. A critical size defect of 10 mm elongation was created in the radial diaphysis of 36 rabbit and either supplied with human platelet-rich plasma (12 rabbits), and in combination with hydroxyapatite (12 rabbits), or coral (12 rabbits). Radiographs of each forelimb were taken postoperatively on 1st day and then at the 2nd, 4th, 6th and 8th weeks post injury to evaluate bone defect healing. The operated radiuses were removed on the 56th postoperative day and were grossly and histopathologically evaluated. In addition, biomechanical test was conducted on the operated and normal forearms of another half of the rabbits in each group. This study demonstrated that high concentrations of xenogenic platelets lead to superior and faster bone formation in comparison with hydroxyapatite-hPRP and coral-hPRP. Hydroxyapatite-hPRP and coral-hPRP resulted to almost similar results in bone healing process at this stage. PMID- 22246169 TI - Calix[4]arene based 1,3,4-oxadiazole and thiadiazole derivatives: design, synthesis, and biological evaluation. AB - In the present investigation, we describe some novel calixarene based heterocyclic compounds (5a-5i) in which 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives have been coupled with 5,11,17,23-tetra-tert-butyl-25,27 bis(chlorocarbonyl-methoxy)-26,28-dihydroxy calix[4]arene. All the newly synthesized calixarene based heterocyclic compounds have been characterized by elemental analysis and various spectroscopic methods like FTIR, (1)H NMR, (13)C NMR, and FAB-MS. All the final scaffolds have been subjected to antioxidant activity, in vitro antimicrobial screening against two gram (+ve) bacteria (S. aureus, S. pyogenes), two gram (-ve) bacteria (E. coli, P. aeruginosa) and two fungal strains (C. albicans, A. clavatus) and also have been screened for their antitubercular activity against Mycobacterium tuberculosis H(37)Rv. PMID- 22246168 TI - Niacin protects against UVB radiation-induced apoptosis in cultured human skin keratinocytes. AB - Niacin and its related derivatives have been shown to have effects on cellular activities. However, the molecular mechanism of its reduced immunosuppressive effects and photoprotective effects remains unclear. In this study, we investigated the molecular mechanism of the photoprotective effect of niacin in ultraviolet (UV)-irradiated human skin keratinocytes (HaCaT cells). We found that niacin effectively suppressed the UV-induced cell death and cell apoptosis of HaCaT cells. Existing data have shown that AKT activation is involved in the cell survival process. Yet, the potential mechanism of niacin in protection against UV induced skin damage has thus far not fully been eluvidated. We observed that niacin pretreatment enhances UV induced activation of AKT (Ser473 phosphorylation) as well as that of the downstream signal mTOR (S6 and 4E-BP1 phosphorylation). The PI3K/AKT inhibitor, LY294002, and the mTOR inhibitor, rapamycin, largely neutralized the protective effects of niacin, suggesting that AKT and downstream signaling mTOR/S6 activation are necessary for the niacin induced protective effects against UV-induced cell death and cell apoptosis. Collectively, our data suggest that niacin may be utilized to prevent UV-induced skin damage and provide a novel mechanism of its photoprotective effects against the UV radiation of sunlight by modulating both AKT and downstream mTOR signaling pathways. PMID- 22246170 TI - An irreducible inguinal hernia in a girl. PMID- 22246172 TI - Unsymmetrical diarylethenes as molecular keypad locks with tunable photochromism and fluorescence via Cu2+ and CN- coordinations. AB - New unsymmetrical diarylethenes were synthesized and their photochromic and fluorescent properties are tailored by Cu(2+) and CN(-) coordinations. A novel molecular logic keypad lock is constructed based on the fluorescence emission changes by the inputs of UV/visible irradiation, Cu(2+) and CN(-). PMID- 22246171 TI - Is human cytomegalovirus a target in cancer therapy? AB - Human cytomegalovirus (HCMV) is a herpesvirus that is prevalent in the human population. HCMV has recently been implicated in different cancer forms where it may provide mechanisms for oncogenic transformation, oncomodulation and tumour cell immune evasion. Moreover, antiviral treatment against HCMV has been shown to inhibit tumour growth in preclinical models. Here we describe the possible involvement of HCMV in cancer and discuss the potential molecular impact expression of HCMV proteins have on tumour cells and the surrounding tumour microenvironment. PMID- 22246173 TI - Lung 18F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer (18)F-fluorodeoxyglucose (FDG). OBJECTIVES: The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. METHODS: PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. MEASUREMENTS AND MAIN RESULTS: Lung FDG increases 1 2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1alpha (HIF-1alpha), which underlies their glycolytic phenotype. CONCLUSIONS: HIF-1alpha-mediated Glut1 up regulation in proliferating vascular cells in PAH accounts for increased lung FDG PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature. PMID- 22246174 TI - Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. AB - RATIONALE: Acute lung injury (ALI) causes high mortality, but its molecular mechanisms and therapeutic options remain ill-defined. Gram-negative bacterial infections are the main cause of ALI, leading to lung neutrophil infiltration, permeability increases, deterioration of gas exchange, and lung damage. Platelets are activated during ALI, but insights into their mechanistic contribution to neutrophil accumulation in the lung are elusive. OBJECTIVES: To determine mechanisms of platelet-mediated neutrophil recruitment in ALI. METHODS: Interference with platelet-neutrophil interactions using antagonists to P selectin and glycoprotein IIb/IIIa or a small peptide antagonist disrupting platelet chemokine heteromer formation in mouse models of ALI. MEASUREMENTS AND MAIN RESULTS: In a murine model of LPS-induced ALI, we uncover important roles for neutrophils and platelets in permeability changes and subsequent lung damage. Furthermore, platelet depletion abrogated lung neutrophil infiltration, suggesting a sequential participation of platelets and neutrophils. Whereas antagonists to P-selectin and glycoprotein IIb/IIIa had no effects on LPS mediated ALI, antibodies to the platelet-derived chemokines CCL5 and CXCL4 strongly diminished neutrophil eflux and permeability changes. The two chemokines were found to form heteromers in human and murine ALI samples, positively correlating with leukocyte influx into the lung. Disruption of CCL5-CXCL4 heteromers in LPS-, acid-, and sepsis-induced ALI abolished lung edema, neutrophil infiltration, and tissue damage, thereby revealing a causal contribution. CONCLUSIONS: Taken together, our data identify a novel function of platelet-derived chemokine heteromers during ALI and demonstrate means for therapeutic interference. PMID- 22246175 TI - The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. AB - RATIONALE: Gene expression profiling of airway epithelial and inflammatory cells can be used to identify genes involved in environmental asthma. METHODS: Airway epithelia and inflammatory cells were obtained via bronchial brush and bronchoalveolar lavage (BAL) from 39 subjects comprising three phenotypic groups (nonatopic nonasthmatic, atopic nonasthmatic, and atopic asthmatic) 4 hours after instillation of LPS, house dust mite antigen, and saline in three distinct subsegmental bronchi. RNA transcript levels were assessed using whole genome microarrays. MEASUREMENTS AND MAIN RESULTS: Baseline (saline exposure) differences in gene expression were related to airflow obstruction in epithelial cells (C3, ALOX5AP, CCL18, and others), and to serum IgE (innate immune genes and focal adhesion pathway) and allergic-asthmatic phenotype (complement genes, histone deacetylases, and GATA1 transcription factor) in inflammatory cells. LPS stimulation resulted in pronounced transcriptional response across all subjects in both airway epithelia and BAL cells, with strong association to nuclear factor kappaB and IFN-inducible genes as well as signatures of other transcription factors (NRF2, C/EBP, and E2F1) and histone proteins. No distinct transcriptional profile to LPS was observed in the asthma and atopy phenotype. Finally, although no consistent expression changes were observed across all subjects in response to house dust mite antigen stimulation, we observed subtle differences in gene expression (e.g., GATA1 and GATA2) in BAL cells related to the asthma and atopy phenotype. CONCLUSIONS: Our results indicate that among individuals with allergic asthma, transcriptional changes in airway epithelia and inflammatory cells are influenced by phenotype as well as environmental exposures. PMID- 22246176 TI - Twenty-four-hour intensivist presence: a pilot study of effects on intensive care unit patients, families, doctors, and nurses. AB - RATIONALE: Around-the-clock intensivist presence in intensive care units (ICUs) has been promoted as necessary to optimize outcomes. Little data have addressed how it affects the multiple stakeholders in such care. OBJECTIVES: To assess effects of around-the-clock intensivist presence on intensivists, patients, families, housestaff, and nurses. METHODS: This 32-week, crossover pilot trial of two intensivist staffing models, performed in two Canadian ICUs, alternated 8 week blocks of two staffing models: the standard model, where one intensivist worked for 7 days, taking night call from home; and the shift work model, where one intensivist worked 7 day shifts, while other intensivists remained in the ICU at night. MEASUREMENTS AND MAIN RESULTS: Surveys scaled from 0-100 points assessed outcomes for 24 intensivists (primary outcome: burnout); 119 families (satisfaction); 74 nurses (satisfaction with collaboration and communications, role conflict); and 34 housestaff (autonomy, supervision, and learning opportunities). Outcomes for 501 patients included mortality, length of stay, and resource use. Intensivists doing shift work experienced less burnout (-6.9 points; P = 0.04). Adjusted hospital mortality (odds ratio, 1.22; P = 0.44), ICU length of stay (-6 h; P = 0.46), and family satisfaction (0.9 points; P = 0.79) did not differ between staffing models. Under shift work staffing, nurses reported more role conflict (9 points; P < 0.001), whereas nighttime housestaff reported less autonomy, more supervision, but no difference in learning opportunities. CONCLUSIONS: Shiftwork staffing was better for intensivists and most were receptive once they had experienced it. Although there were no evident negative outcomes for patients or families, further evaluation is needed to clarify how around-the-clock intensivist staffing influences the various stakeholders in ICU care, given power considerations in this study. Clinical trial registered with www.clinicaltrials.gov (NCT 01146691). PMID- 22246177 TI - Impact of anxiety and depression on chronic obstructive pulmonary disease exacerbation risk. AB - Chronic obstructive pulmonary disease (COPD) exacerbations contribute significantly to morbidity and mortality. COPD is also associated with high levels of psychological distress, which has been linked with higher exacerbation rates. At a recent American Thoracic Society conference symposium titled "Depression and Obstructive Lung Disease: State of the Science and Future Directions" held in 2010 in New Orleans, clinicians and researchers identified a number of important research priorities related to psychiatric comorbidities, including the need to better understand their impact on COPD outcomes, such as exacerbations. This article reviews the current literature and quantifies the prospective impact of anxiety and depression on exacerbation risk in patients with COPD. The limitations of the existing literature and the perspectives for future research are addressed. PMID- 22246178 TI - Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. AB - RATIONALE: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial. OBJECTIVES: To evaluate the association between statin use and ILD. METHODS: We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin induced fibrosis in mice and explored the mechanism behind these observations in vitro. MEASUREMENTS AND MAIN RESULTS: In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03 2.50; P = 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages isolated from Nlrp3(-/-) and Casp1(-/-) mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages. CONCLUSIONS: Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that statins may influence the susceptibility to, or progression of, ILD. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764). PMID- 22246179 TI - Mechanism of RNA synthesis initiation by the vesicular stomatitis virus polymerase. AB - The minimal RNA synthesis machinery of non-segmented negative-strand RNA viruses comprises a genomic RNA encased within a nucleocapsid protein (N-RNA), and associated with the RNA-dependent RNA polymerase (RdRP). The RdRP is contained within a viral large (L) protein, which associates with N-RNA through a phosphoprotein (P). Here, we define that vesicular stomatitis virus L initiates synthesis via a de-novo mechanism that does not require N or P, but depends on a high concentration of the first two nucleotides and specific template requirements. Purified L copies a template devoid of N, and P stimulates L initiation and processivity. Full processivity of the polymerase requires the template-associated N protein. This work provides new mechanistic insights into the workings of a minimal RNA synthesis machine shared by a broad group of important human, animal and plant pathogens, and defines a mechanism by which specific inhibitors of RNA synthesis function. PMID- 22246180 TI - Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre. AB - RNA-structural elements play key roles in pre-mRNA splicing catalysis; yet, the formation of catalytically competent RNA structures requires the assistance of spliceosomal proteins. We show that the S. cerevisiae Cwc2 protein functions prior to step 1 of splicing, and it is not required for the Prp2-mediated spliceosome remodelling that generates the catalytically active B complex, suggesting that Cwc2 plays a more sophisticated role in the generation of a functional catalytic centre. In active spliceosomes, Cwc2 contacts catalytically important RNA elements, including the U6 internal stem-loop (ISL), and regions of U6 and the pre-mRNA intron near the 5' splice site, placing Cwc2 at/near the spliceosome's catalytic centre. These interactions are evolutionarily conserved, as shown by studies with Cwc2's human counterpart RBM22, indicating that Cwc2/RBM22-RNA contacts are functionally important. We propose that Cwc2 induces an active conformation of the spliceosome's catalytic RNA elements. Thus, the function of RNA-RNA tertiary interactions within group II introns, namely to induce an active conformation of domain V, may be fulfilled by proteins that contact the functionally analogous U6-ISL, within the spliceosome. PMID- 22246181 TI - A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX. AB - The cellular response to p53 activation varies greatly in a stimulus- and cell type-specific manner. Dissecting the molecular mechanisms defining these cell fate choices will assist the development of effective p53-based cancer therapies and also illuminate fundamental processes by which gene networks control cellular behaviour. Using an experimental system wherein stimulus-specific p53 responses are elicited by non-genotoxic versus genotoxic agents, we discovered a novel mechanism that determines whether cells undergo proliferation arrest or cell death. Strikingly, we observe that key mediators of cell-cycle arrest (p21, 14-3 3sigma) and apoptosis (PUMA, BAX) are equally activated regardless of outcome. In fact, arresting cells display strong translocation of PUMA and BAX to the mitochondria, yet fail to release cytochrome C or activate caspases. Surprisingly, the key differential events in apoptotic cells are p53-dependent activation of the DR4 death receptor pathway, caspase 8-mediated cleavage of BID, and BID-dependent activation of poised BAX at the mitochondria. These results reveal a previously unappreciated role for DR4 and the extrinsic apoptotic pathway in cell fate choice following p53 activation. PMID- 22246182 TI - STIM1 is required for attenuation of PMCA-mediated Ca2+ clearance during T-cell activation. AB - T-cell activation involves a complex signalling cascade uniquely dependent on elevated cytosolic Ca(2+) levels. Further, the spatiotemporal characteristics of this Ca(2+) signal play a critical role in this process via selective activation of transcription factors. In T cells, store-operated Ca(2+) entry (SOCe) is the primary Ca(2+) influx pathway; however, cytosolic Ca(2+) concentration depends upon the balance between Ca(2+) influx and extrusion. The plasma membrane Ca(2+) ATPase (PMCA) has previously been identified as a critical player in Ca(2+) clearance in T cells. Here, we provide data revealing both functional and physical links between the activation of stromal interacting molecule 1 (STIM1) and PMCA-mediated Ca(2+) clearance. Due to the ubiquitous expression of both STIM1 and PMCA, these findings have wide-ranging implications for Ca(2+) signalling in multiple cell types. PMID- 22246183 TI - Axonal transcription factors signal retrogradely in lesioned peripheral nerve. AB - Retrograde axonal injury signalling stimulates cell body responses in lesioned peripheral neurons. The involvement of importins in retrograde transport suggests that transcription factors (TFs) might be directly involved in axonal injury signalling. Here, we show that multiple TFs are found in axons and associate with dynein in axoplasm from injured nerve. Biochemical and functional validation for one TF family establishes that axonal STAT3 is locally translated and activated upon injury, and is transported retrogradely with dynein and importin alpha5 to modulate survival of peripheral sensory neurons after injury. Hence, retrograde transport of TFs from axonal lesion sites provides a direct link between axon and nucleus. PMID- 22246184 TI - Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. AB - Microvesicles (MVs) released into the brain microenvironment are emerging as a novel way of cell-to-cell communication. We have recently shown that microglia, the immune cells of the brain, shed MVs upon activation but their possible role in microglia-to-neuron communication has never been explored. To investigate whether MVs affect neurotransmission, we analysed spontaneous release of glutamate in neurons exposed to MVs and found a dose-dependent increase in miniature excitatory postsynaptic current (mEPSC) frequency without changes in mEPSC amplitude. Paired-pulse recording analysis of evoked neurotransmission showed that MVs mainly act at the presynaptic site, by increasing release probability. In line with the enhancement of excitatory transmission in vitro, injection of MVs into the rat visual cortex caused an acute increase in the amplitude of field potentials evoked by visual stimuli. Stimulation of synaptic activity occurred via enhanced sphingolipid metabolism. Indeed, MVs promoted ceramide and sphingosine production in neurons, while the increase of excitatory transmission induced by MVs was prevented by pharmacological or genetic inhibition of sphingosine synthesis. These data identify microglia-derived MVs as a new mechanism by which microglia influence synaptic activity and highlight the involvement of neuronal sphingosine in this microglia-to-neuron signalling pathway. PMID- 22246185 TI - Rsk-mediated phosphorylation and 14-3-3E binding of Apaf-1 suppresses cytochrome c-induced apoptosis. AB - Many pro-apoptotic signals trigger mitochondrial cytochrome c release, leading to caspase activation and ultimate cellular breakdown. Cell survival pathways, including the mitogen-activated protein kinase (MAPK) cascade, promote cell viability by impeding mitochondrial cytochrome c release and by inhibiting subsequent caspase activation. Here, we describe a mechanism for the inhibition of cytochrome c-induced caspase activation by MAPK signalling, identifying a novel mode of apoptotic regulation exerted through Apaf-1 phosphorylation by the 90-kDa ribosomal S6 kinase (Rsk). Recruitment of 14-3-3E to phosphorylated Ser268 impedes the ability of cytochrome c to nucleate apoptosome formation and activate downstream caspases. High endogenous levels of Rsk in PC3 prostate cancer cells or Rsk activation in other cell types promoted 14-3-3E binding to Apaf-1 and rendered the cells insensitive to cytochrome c, suggesting a potential role for Rsk signalling in apoptotic resistance of prostate cancers and other cancers with elevated Rsk activity. Collectively, these results identify a novel locus of apoptosomal regulation wherein MAPK signalling promotes Rsk-catalysed Apaf-1 phosphorylation and consequent binding of 14-3-3E, resulting in decreased cellular responsiveness to cytochrome c. PMID- 22246186 TI - Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK mediated lamin B1 accumulation. AB - We report crosstalk between three senescence-inducing conditions, DNA damage response (DDR) defects, oxidative stress (OS) and nuclear shape alterations. The recessive autosomal genetic disorder Ataxia telangiectasia (A-T) is associated with DDR defects, endogenous OS and premature ageing. Here, we find frequent nuclear shape alterations in A-T cells, as well as accumulation of the key nuclear architecture component lamin B1. Lamin B1 overexpression is sufficient to induce nuclear shape alterations and senescence in wild-type cells, and normalizing lamin B1 levels in A-T cells reciprocally reduces both nuclear shape alterations and senescence. We further show that OS increases lamin B1 levels through p38 Mitogen Activated Protein kinase activation. Lamin B1 accumulation and nuclear shape alterations also occur during stress-induced senescence and oncogene-induced senescence (OIS), two canonical senescence situations. These data reveal lamin B1 as a general molecular mediator that controls OS-induced senescence, independent of established Ataxia Telangiectasia Mutated (ATM) roles in OIS. PMID- 22246188 TI - Fluoroquinolone-induced liver injury: three new cases and a review of the literature. AB - PURPOSE: Fluoroquinolones are popular and widely used in primary care and hospital settings. Premarketing studies showed a favourable side-effect profile. However, significant morbidity and the need for liver transplantation for acute liver failure have been reported. We reviewed the available data on liver damage linked to fluoroquinolones. METHODS: A systematic search of case reports on the MEDLINE database encompassing the years 2000-2011 was carried out. Additional references were found by a manual search of the retrieved paper. We also describe three new cases of hepatotoxicity attributable to fluoroquinolones seen at our Unit. RESULTS: Thirty-five cases were retrieved from MEDLINE (51.4% male). According to the RUCAM scale, liver injury was classified as hepatocellular (51.4%), cholestatic (28.6%) or mixed (20.0%). Older age (>= 65 years) was present in 42.8%. The time between initiation of treatment and hepatic injury ranged from 1 to 39 days (median 8 days). According to the RUCAM score, our cases were classified to be "highly probable" or "probable". Only one patient underwent liver biopsy, which showed the features of liver damage linked to drug exposure. Liver enzymes from all patients return to normal range within 4 weeks of withdrawal. Only one patient showed a renal failure, associated with liver injury, with a need for haemodialysis for 3 weeks. CONCLUSIONS: Fluoroquinolones are substantially safe antibiotics. Although fluoroquinolone-related hepatic injury occurs infrequently, its consequences can be severe. Patients should also be cautioned to avoid re-exposure to other members of the fluoroquinolone class. PMID- 22246189 TI - A retrospective analysis of ultralow anterior resection vs. abdomino-perineal resection for lower rectal cancer. AB - BACKGROUND/AIMS: The aim of this study was to compare the oncological outcome of ultralow anterior resection (ULAR) and abdominoperineal resection (APR) for lower rectal cancer. METHODOLOGY: Medical records of 276 patients with lower rectal cancer of whom 140 underwent ULAR and 136 underwent APR were included in a retrospective comparative study. Clinicopathological parameters, overall survival and tumor relapse and prognostic factors were analyzed retrospectively. RESULTS: There was no postoperative mortality in either group. Medical and surgical morbidity, especially pelvic abscess formation were similar in the two groups. The operation time was longer in the APR group (p<0.001). The hospital stay was shorter in the ULAR group (p=0.003). The 5 year overall and disease-free survival rates were 60.5% and 51.1%. There was no difference of overall and disease-free survival (p>0.05), between ULAR and APR surgery at 5 years. Patients who underwent ULAR showed more total recurrence (34.3% vs. 22.1%, p=0.031) and more local recurrence (20.7% vs. 8.8%, p=0.01) but showed no difference in distant recurrence (13.6% vs. 13.2%, p=0.92). CONCLUSIONS: Ultralow anterior resection and abdominoperineal resection have similar long-term outcome in lower rectal cancer. In tumor local relapse, APR is more effective than ULAR, but in distant metastasis, it not better than ULAR. PMID- 22246190 TI - Augmenter of liver regeneration may be a candidate for prognosis of HBV related acute-on-chronic liver failure as a regenerative marker. AB - BACKGROUND/AIMS: To search for a new regenerative marker to estimate the prognosis of acute-on-chronic liver failure (ACLF). METHODOLOGY: The CCl4 induced liver regeneration models were prepared and observed the change of ALR, hepatocyte growth factor (HGF), proliferation cell nuclear antigen (PCNA) and pathology. Meanwhile the sera of patients with HBV related liver disease were collected to examine the changes of ALR level and the prognosis of patients with ACLF was followed up. RESULTS: After CCl4 injection, serum ALR level rose firstly and then declined in the ensuing 12 hours to near-basal level (F=30.495, p<0.01). ALR level in the liver tissue showed an inverse pattern. The changes of PCNA, HGF and pathology showed a consistent trend with serum ALR level. Serum ALR level was higher in ACLF (n=20) and hepatocellular carcinoma (n=20) than in normal control (n=10) (2.68+/-1.95 vs. 0.74+/-0.31, p<0.01; 1.77+/-1.32 vs. 0.74+/-0.31, p=0.035). Serum ALR level of patients with ACLF was more significant in survival group (n=10) than in dead group (n=10) in early stage of disease (7.83+/-1.77 vs. 2.14+/-1.58, t=7.576, p<0.01). CONCLUSIONS: ALR level in serum may indicate hepatocyte proliferation or liver regeneration. High ALR level in serum in early stage of ACLF may mean a good prognosis. PMID- 22246191 TI - The effect of postoperative TACE on prognosis of HCC with microscopic venous invasion. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the clinical efficacy of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on hepatocellular carcinoma (HCC) with microscopic venous invasion. METHODOLOGY: Data from 76 patients with HCC who underwent hepatectomy with or without postoperative adjuvant TACE between July 2005 and August 2010 were retrospectively reviewed. Kaplan-Meier method was used to compare survival between the groups and prognostic factors were evaluated by Cox proportional hazard model. RESULTS: The 1-, 3- and 5-year disease- free survival rates were 76.3%, 44.5% and 31.8%, respectively, for the adjuvant TACE group (35 patients) and 60.1%, 39.3% and 21.5%, respectively, for the control group (41 patients). The 1-, 3- and 5-year overall survival rates were 88.6%, 67.2% and 42.3%, respectively, for the TACE group and 77.5%, 58.0% and 40.5%, respectively, for the control group. Although improving trends of both disease-free survival and overall survival were observed in adjuvant TACE group, there was no significant difference between the two groups (p>0.05). Cox regression analysis revealed that tumor size and differentiation were significant independent prognostic factors. CONCLUSIONS: Postoperative adjuvant TACE may improve 1, 3 and 5 year disease-free and overall survival rates of HCC patients with microscopic venous invasion but no statistical significance was found. It can be used as a preventative treatment but not a routine procedure for such patients. PMID- 22246192 TI - Thoracoscopic and laparoscopic esophagectomy with cervical manual anastomosis for esophageal cancer. AB - Evidence on the benefits of minimally invasive approach over traditional open procedure in gastrointestinal surgery is continuing to accumulate. This is also the case for esophageal surgery.Although laparoscopic esophageal surgery was initially reserved for benign pathology, the technical development, increasing experience with laparoscopic and thoracoscopic techniques and the theoretical advantages of minimally invasive surgery have widened the scope of minimally invasive approach to esophageal cancer. The surgical treatment of esophageal cancer often requires extensive procedures and is therefore, considered one of the most challenging and invasive procedure of gastrointestinal surgery. While transhiatal and transthoracic esophagectomy are common approaches for esophageal resection, data regarding the combined thoracoscopic and laparoscopic approach to esophagectomy are limited. The minimally invasive technique of esophagectomy to be described consists of three phases: thoracoscopic esophageal mobilization and mediastinal lymphadenectomy followed by laparoscopic gastric mobilization, abdominal lymphadenectomy and gastric conduit formation and finally retrieval of the resection specimen followed by an esophagogastric anastomosis via a left cervical incision. PMID- 22246193 TI - Plasma cell membrane localization of c-MET predicts longer survival in patients with malignant mesothelioma: a series of 157 cases from the MESOPATH Group. AB - INTRODUCTION: By regulating cell functions such as growth, survival, motility/migration, and invasion, the c-mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase/hepatocyte growth factor (HGF) axis accounts for a critical pathway in malignant pleural mesothelioma. METHODS: Overall survival correlations of c-MET and phospho-c-MET immunostainings were investigated in 157 malignant pleural mesothelioma patients for whom paraffin-embedded specimens were referred to our center for pathological diagnosis certification (MESOPATH French National group). Subcellular localization of the activated c-MET receptor after HGF stimulation was assessed in nontumorogenic cell lines. RESULTS: Positive c MET expression was found in 119 samples (75.8%), more frequently in the epithelioid subtype (p < 0.0001). Among those 119 positive c-MET specimens, 77 (64.7%) were also positive for phospho-c-MET. Both c-MET and phospho-c-MET scoring were independent of patient gender or age. Phospho-c-MET scoring or localization did not associate with survival. Conversely, patients with a c-MET immunohistochemical staining intensity higher than 1, but exclusively confined to plasma membrane, had a median overall survival of 25 months versus 13 months for all other patients. Only exclusive plasma membrane staining remained significantly associated with a worse prognosis in multivariate analysis (hazard ratio = 2.9, 95% confidence interval 1.0-8.2, p = 0.043). Using the HBEC3 immortalized epithelial cell lines treated with HGF, we showed the physiological relevance of phospho-c-MET nuclear translocation. CONCLUSIONS: Our results lighten that, disregarding the intracellular c-MET receptor traffic, only c-MET plasma membrane localization could be a relevant prognosis biomarker in malignant pleural mesothelioma. Whether patients with c-MET plasma membrane immunostaining could beneficiate from c-MET-targeted therapies remains to be established in prospective trials. PMID- 22246194 TI - Long-term excess mortality for survivors of non-small cell lung cancer in the Netherlands. AB - INTRODUCTION: Most patients diagnosed with non-small cell lung cancer (NSCLC) die within the first few years after diagnosis. However, only little is known about those who have survived these first years. We aimed to study conditional 5-year relative survival rates for NSCLC patients during long-term follow-up. METHODS: All 12,148 patients aged 45 to 74 years diagnosed with stage I-III NSCLC between 1989 and 2008 in the Netherlands were derived from the Netherlands Cancer Registry. Conditional 5-year relative survival was calculated for every additional year survived up to 15 years. RESULTS: Conditional 5-year relative survival rapidly improved with every year survived up to 4 to 5 years after diagnosis. However, a significant excess mortality of 20 to 40% remained. Conditional 5-year relative survival for those aged 45 to 59 years did not exceed 80% for survivors with stage I or II disease and remained just more than 70% for those with stage III disease. For those aged 60 to 74 years, these proportions were 70%, 65%, and 60%, respectively. CONCLUSIONS: A significant excess mortality remains in lung cancer after years which may be explained by excess risk of death due to smoking-related comorbidity in these patients. Caregivers should use this information for planning optimal cancer surveillance and informing cancer survivors about their actual prognosis. PMID- 22246195 TI - On the origin of reactivity of steam reforming of ethylene glycol on supported Ni catalysts. AB - This paper describes a strategy for producing hydrogen via steam reforming of ethylene glycol over supported nickel catalysts. Nickel plays a crucial role in conversion of ethylene glycol and production of hydrogen, while oxide supports affect product distribution of carbonaceous species. A plausible reaction pathway is proposed based on our results and the literature. PMID- 22246196 TI - Tanshinone IIA inhibits human breast cancer MDA-MB-231 cells by decreasing LC3 II, Erb-B2 and NF-kappaBp65. AB - The ability of tanshinone IIA (Tan-IIA) to inhibit the proliferation of human breast cancer cell lines in vitro and in vivo is well documented. However, the molecular mechanisms have not been fully elucidated. In the present study, MDA-MB 231 cells were treated with different concentrations of Tan-IIA for 48 h, followed by protein extraction for western blotting. For an in vivo study, MDA-MB 231 cells were implanted directly into female SCID mice which were divided randomly into three groups to be treated with vehicle, Tan-IIA (20 mg/kg) and Tan IIA (60 mg/kg) every other day orally, with treatment starting 4 weeks after inoculation with the MDA-MB-231 cells. The results showed that Tan-IIA inhibited the proliferation of MDA-MB-231 cells and decreased the protein expression of LC3 II and Erb-B2 in vitro. Treatment with Tan-IIA (20 or 60 mg/kg) for 90 days resulted in a reduction in tumor size and weight compared to the control group. The protein expression of NF-kappaBp65 was reduced, while caspase-3 was up regulated compared to the control group. These findings indicate that Tan-IIA inhibits tumor growth in a MDA-MB-231 xenograft animal model. One of the molecular mechanisms may be through a decrease in NF-kappaBp65 and an increase in caspase-3 expression. PMID- 22246197 TI - Negative electroretinograms in the pediatric and adult population. AB - Objective To assess the frequency of negative waveform electroretinograms (ERGs) in a tertiary referral center. Design Retrospective chart review. Participants All patients who had an ERG performed at the electrophysiology clinic at Emory University from January 1999 through March 2008 were included in the study. Methods Patients with b-wave amplitude <= a-wave amplitude during the dark adapted bright flash recording, in at least one eye, were identified as having a "negative ERG". Clinical information, such as age, gender, symptoms, best corrected visual acuity, and diagnoses were recorded for these patients when available. Results A total of 1,837 patients underwent ERG testing during the study period. Of those, 73 patients had a negative ERG, for a frequency of 4.0%. Within the adult (>= 18 years of age) and pediatric populations, the frequencies of a negative ERG were 2.5 and 7.2%, respectively. Among the 73 cases, negative ERGs were more common among male than female patients, 6.7% versus 1.8% (P < 0.0001). Negative ERGs were most common among male children and least common among female adults, 9.6% versus 1.1%, respectively, (P < 0.0001). Overall in this group of patients, the most common diagnoses associated with a negative ERG were congenital stationary night blindness (CSNB, n = 29) and X-linked retinoschisis (XLRS, n = 7). Conclusions The overall frequency of negative ERGs in this large retrospective review was 4.0%. Negative ERGs were most common among male children and least common among female adults. Despite the growing number of new diagnoses associated with negative ERGs, CSNB, and XLRS appear to be the most likely diagnoses for a pediatric patient who presents with a negative ERG. PMID- 22246198 TI - TASER electronic control devices and eye injuries. PMID- 22246199 TI - Time flies faster if a person has a high working-memory capacity. AB - Attention affects the perception of time, and the ability to control attention is reflected in measures of working-memory capacity. Individuals with low working memory capacity have more difficulty maintaining focus on a task than high capacity individuals, particularly when faced with contextual distracters. This experiment examined the effect of working-memory capacity on the perception of temporal duration while performing a cognitive task. We predicted that low capacity participants would be more likely to direct attention away from the cognitive task and towards the contextual distraction of time, and consequently perceive temporal duration more accurately, and perform the cognitive task less accurately, than high-capacity participants. The results showed that when performing both tasks simultaneously, low-capacity participants were less accurate than high-capacity participants on the cognitive task, but were more accurate on the timing task. High-capacity participants, conversely, were more accurate in the non-temporal cognitive task at the cost of monitoring duration. PMID- 22246200 TI - 5-Fluorouracil versus mitomycin C as adjuncts to conjunctival autograft in preventing pterygium recurrence. AB - To compare the efficacy of 5-fluorouracil (5-FU) with mitomycin C (MMC) in preventing pterygium recurrence when used as an adjuvant following pterygium excision with conjunctival autograft. Low-dose MMC combined with conjunctival autograft is an effective treatment for preventing recurrence following pterygium excision, but safety, cost, and availability limit its use in developing countries. There is a paucity of data on the efficacy of 5-FU when used in Africa as an adjuvant to conjunctival autograft following pterygium excision. This is a randomized controlled prospective trial using either 50 mg/ml 5-FU or 0.01% MMC. Eighty eyes of 80 subjects were studied. Forty-six subjects with a mean age 49.8 +/- 13.8 years were treated with 5-FU (USD 13.0 per unit), while 34 patients with a mean age 51.9 +/- 12.1 years were treated with MMC (USD 20.0 per unit). There was no significant difference in mean age between the two groups (p = 0.48). The ratio of male to female patients in both groups was similar at 0.92:1 for the 5 FU group and 1:1 for the MMC group (p = 0.85). Mean follow-up period was 35.2 +/- 29.1 weeks. Recurrence rate in the 5-FU group was 8.7% compared to 11.8% in the MMC group (recurrence risk ratio = 0.71, 95% CI 0.17-3.1, p = 0.7). One patient from the MMC-treated group had corneoscleral melting. Other complications were mild and not sight threatening. In the prevention of pterygium recurrence, 5-FU appears to compare favorably with low-dose MMC when used as an adjuvant following pterygium excision and conjunctival autograft. Further studies are required to assess the long-term effect of using 5-FU in such cases. PMID- 22246201 TI - Stereotactic radiosurgery for primary and metastatic sarcomas involving the spine. AB - The treatment for spinal sarcomas is difficult due to inadequate surgical margin and an inability to deliver high dose radiation. Advanced technology of stereotactic radiosurgery (SRS) enabled higher biological effective doses of radiation to be delivered to spinal sarcomas by hypofractionation method. The authors evaluated local control rate following SRS for primary and metastatic spinal sarcomas. Thirty-two spinal sarcomas (10 primary tumors, 22 metastatic tumors) in 27 patients were treated by SRS from November 2002 to September 2009. Patients were assessed for pain status, neurological status and radiological response by regular follow-up. Overall survival and local progression-free survival were calculated and prognostic factors were sought. Median tumor volume was 18.6 ml. Radiation doses to the tumor margins ranged from 16 to 45 Gy in one to three fractions, and the median single session equivalent dose was 21.8 Gy. Follow-up ranged from 4 to 68 months (median, 22 months). Overall median survival was 29 months and no related prognostic factors were identified. During follow up, pain was controlled in 89.3% (25/28) lesions at 6 months, in 68.2% (15/22) at 1 year, and in 61.5% (8/13) at 2 years. Tumor volume was found to be significantly related to post-SRS pain control rate. Radiological evaluation showed that local control was maintained in 96.7% (29/30) lesions at 6 months, in 78.3% (18/23) at 1 year, and in 76.9% (10/13) at 2 years. Radiation dose and tumor volume were found to be related to radiological control at 24 months following SRS. Nine cases developed recurrence between 2 and 33 months, median local progression-free survival was 23 months. Age was found to be predictive of local progression-free survival (P = 0.009). SRS proved to be an effective modality for the local control of primary and metastatic spinal sarcomas, and age was significantly related to local recurrence. PMID- 22246203 TI - Enhancing image analytic tools by fusing quantitative physiological values with image features. AB - Computer-aided diagnosis systems (CADs) can quantify the severity of diseases by analyzing a set of images and employing prior statistical models. In general, CADs have proven to be effective at providing quantitative measurements of the extent of a particular disease, thus helping physicians to better monitor the progression of cancer, infectious diseases, and other health conditions. Electronic Health Records frequently include a large amount of clinical data and medical history that can provide critical information about the underlying condition of a patient. We hypothesize that the fusion of image and clinical physiological features can be used to enhance the accuracy of automatic image classification models. In particular, this paper shows how image analytic tools can move beyond classical image interpretation models to broader systems where image and physiological measurements are fused and used to create more generic detection models. To test our hypothesis, a CAD system capable of quantifying the severity of patients with pulmonary fibrosis has been developed. Results show that CAD systems augmented with multimodal physiological values are more robust and accurate at determining the severity of the disease. PMID- 22246202 TI - Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells. AB - Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant, embryonal CNS tumors with a poor prognosis. Therapy relies on highly toxic chemotherapy and radiotherapy. To improve outcomes and decrease morbidity, more targeted therapy is required. Gene expression analysis revealed elevated expression of multiple kinases in ATRT tissues. Aurora Kinase A was one of the candidate kinases. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in ATRT cell lines. Our analysis revealed that inhibition of Aurora Kinase A induces cell death in ATRT cells and the small molecule inhibitor MLN 8237 sensitizes these cells to radiation. Furthermore, inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways. These data indicate that inhibition of Aurora Kinase A is a promising small molecule target for ATRT therapy. PMID- 22246204 TI - Computerized analysis of mammographic parenchymal patterns on a large clinical dataset of full-field digital mammograms: robustness study with two high-risk datasets. AB - The purpose of this study was to demonstrate the robustness of our prior computerized texture analysis method for breast cancer risk assessment, which was developed initially on a limited dataset of screen-film mammograms. This current study investigated the robustness by (1) evaluating on a large clinical dataset, (2) using full-field digital mammograms (FFDM) as opposed to screen-film mammography, and (3) incorporating analyses over two types of high-risk patient sets, as well as patients at low risk for breast cancer. The evaluation included the analyses on the parenchymal patterns of women at high risk of developing of breast cancer, including both BRCA1/2 gene mutation carriers and unilateral cancer patients, and of women at low risk of developing breast cancer. A total of 456 cases, including 53 women with BRCA1/2 gene mutations, 75 women with unilateral cancer, and 328 low-risk women, were retrospectively collected under an institutional review board approved protocol. Regions-of-interest (ROIs), were manually selected from the central breast region immediately behind the nipple. These ROIs were subsequently used in computerized feature extraction to characterize the mammographic parenchymal patterns in the images. Receiver operating characteristic analysis was used to assess the performance of the computerized texture features in the task of distinguishing between high-risk and low-risk subjects. In a round robin evaluation on the FFDM dataset with Bayesian artificial neural network analysis, AUC values of 0.82 (95% confidence interval [0.75, 0.88]) and 0.73 (95% confidence interval [0.67, 0.78]) were obtained between BRCA1/2 gene mutation carriers and low-risk women, and between unilateral cancer and low-risk women, respectively. These results from computerized texture analysis on digital mammograms demonstrated that high-risk and low-risk women have different mammographic parenchymal patterns. On this large clinical dataset, we validated our methods for quantitative analyses of mammographic patterns on FFDM, statistically demonstrating again that women at high risk tend to have dense breasts with coarse and low-contrast texture patterns. PMID- 22246206 TI - Unusual group migration and C(sp3)-H activation leading to stable metallacycles in the reactions of Cp*IrS2C2B10H10 and aryl azides. AB - The thermal or photochemical reactions of Cp*IrS(2)C(2)B(10)H(10) (1) and aryl azides lead to C-C coupling via C(sp(3))-H activation in 2 as well as the formation of C-S bonds and new-type SSN pincer ligands in 3-8 through ortho substituted electron-withdrawing group migration over an aryl ring. PMID- 22246205 TI - Microbial diversity and activity in hypersaline high Arctic spring channels. AB - Lost Hammer (LH) spring is a unique hypersaline, subzero, perennial high Arctic spring arising through thick permafrost. In the present study, the microbial and geochemical characteristics of the LH outflow channels, which remain unfrozen at >=-18 degrees C and are more aerobic/less reducing than the spring source were examined and compared to the previously characterized spring source environment. LH channel sediments contained greater microbial biomass (~100-fold) and greater microbial diversity reflected by the 16S rRNA clone libraries. Phylotypes related to methanogenesis, methanotrophy, sulfur reduction and oxidation were detected in the bacterial clone libraries while the archaeal community was dominated by phylotypes most closely related to THE ammonia-oxidizing Thaumarchaeota. The cumulative percent recovery of (14)C-acetate mineralization in channel sediment microcosms exceeded ~30% and ~10% at 5 and -5 degrees C, respectively, but sharply decreased at -10 degrees C (<=1%). Most bacterial isolates (Marinobacter, Planococcus, and Nesterenkonia spp.) were psychrotrophic, halotolerant, and capable of growth at -5 degrees C. Overall, the hypersaline, subzero LH spring channel has higher microbial diversity and activity than the source, and supports a variety of niches reflecting the more dynamic and heterogeneous channel environment. PMID- 22246207 TI - Contralateral suppression of transient-evoked otoacoustic emissions in children with sickle cell disease. AB - OBJECTIVES: In previous studies, otoacoustic emissions (OAEs) have been found to be larger in normal-hearing children with sickle cell disease (SCD). It was hypothesized that some dysfunction or reduction in the medial olivocochlear efferent suppression of outer hair cell activity was responsible for this phenomenon. To test this hypothesis, contralateral suppression of transient evoked otoacoustic emissions (TEOAEs) was examined in children with and without SCD. DESIGN: Thirteen African American school-aged normal-hearing children with homozygous SCD and 13 age- and gender-matched control children participated. TEOAEs were obtained bilaterally with 80 dB peSPL nonlinear click stimuli. To examine contralateral suppression, TEOAEs were obtained with 60 dB peSPL linear click stimuli with and without a contralateral 65 dB SPL white noise suppressor. RESULTS: Overall and half-octave band TEOAE levels were found to be larger in children with SCD relative to the normal control children (p < 0.05), consistent with previous reports of increased OAE levels. There was no significant difference (p > 0.05) in the absolute or proportional amount of TEOAE suppression as a function of group and ear. There were also no significant correlations or linear predictive relationships between TEOAE suppression and TEOAE level for either ear or group (p > 0.05). CONCLUSIONS: These findings do not support the notion that increased OAE levels in children with SCD are a consequence of abnormal medial olivocochlear system function as assessed with contralateral suppression of TEOAEs. PMID- 22246208 TI - Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients. AB - A major challenge in advanced-stage epithelial ovarian cancer (EOC) is prediction of chemoresistant relapse. Our aim was to identify a microRNA (miRNA) signature associated with early relapse in advanced-stage EOC patients. miRNA expression was assessed by microarray profiling in training (n = 55) and test (n = 30) sets selected on the basis of time to relapse (TTR), followed by internal quantitative reverse transcriptase-PCR validation on a set of 45 consecutive cases unselected for clinical response and external in silico validation on publicly available datasets. Thirty-two differentially expressed miRNAs in early vs. late relapsing patients were identified in the training set. In the test set, 8 of these, belonging to a cluster located on chrXq27.3, were down-modulated in early relapsing patients. Hierarchical clustering of the internal validation set according to chrXq27.3 miRNA expression associated low miRNA expression with shorter TTR (log-rank P=0.00074, HR 2.44). The cluster was an independent prognostic factor in both internal and external validation sets. Forced expression of chrXq27.3-cluster selected miRNAs in human EOC cellular models was associated to reduction of cell proliferation and increased sensitivity to cisplatin. The role of down-modulation of the chrXq27.3 miRNA cluster in early relapse of advanced-stage EOC patients and its association to a reduced sensitivity to chemotherapeutic treatments warrant further investigation. PMID- 22246210 TI - Grasshopper calling songs convey information about condition and health of males. AB - Females of the grasshopper Chorthippus biguttulus invest much more in the offspring than do males. As a consequence, females are the more selective sex and exert a sexual selection on males by responding to the songs of certain conspecific males while rejecting others. What kind of information about the sender may a female obtain from a male's song, in addition to its species identity? We searched for correlations between a series of song features and morphometric parameters of individual males. In addition, also the immunocompetence of males was assessed by implanting small pieces of nylon thread. We found significant, positive correlations between certain song characteristics and indicators of male size and immunocompetence. Thus, grasshopper females may--in principle--be able to judge a male's condition and health from the acoustic signals he produces. PMID- 22246209 TI - Soybean glyceollins mitigate inducible nitric oxide synthase and cyclooxygenase-2 expression levels via suppression of the NF-kappaB signaling pathway in RAW 264.7 cells. AB - Glyceollins, produced to induce disease resistance responses against specific species, such as an incompatible pathogen Phytophthora sojae in soybeans, have the potential to exhibit anti-inflammatory activity in RAW 264.7 cells. To investigate the anti-inflammatory effects of elicited glyceollins via a signaling pathway, we studied the glyceollin signaling pathway using several assays including RNA and protein expression levels. We found that soybean glyceollins significantly reduced LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production, as well as the expression of inducible NuOmicron synthase (iNOS) and cyclooxygenase-2 (COX-2) via the suppression of NF-kappaB activation. Glyceollins also inhibited the phosphorylation of IkappaBalpha kinase (IKK), the degradation of IkappaBalpha, and the formation of NF-kappaB-DNA binding complex in a dose dependent manner. Furthermore, they inhibited pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-18, but increased the generation of the anti-inflammatory cytokine IL-10. Collectively, the present data show that glyceollins elicit potential anti-inflammatory effects by suppressing the NF-kappaB signaling pathway in RAW 264.7 cells. PMID- 22246211 TI - Population pharmacokinetics of prophylactic cefoxitin in patients undergoing colorectal surgery. AB - PURPOSE: To elucidate whether a dose of 2 g cefoxitin as a prophylactic agent in patients undergoing elective colorectal surgery is able to maintain free drug concentrations above the minimum inhibitory concentration of the microorganisms involved in surgical site infection. METHODS: This was a prospective study involving 56 patients electively undergoing rectal or colon surgery. All plasma concentration-time data were analyzed simultaneously using the population approach to estimate population pharmacokinetic parameters and study the influence of the subjects' demographic characteristics, disease status, surgical procedure, and clinical laboratory values on the pharmacokinetic properties of cefoxitin. RESULTS: A one-compartment open model was chosen to describe plasma concentrations of cefoxitin. Since cefoxitin is eliminated almost entirely via the kidney, creatinine clearance was identified as a covariate of cefoxitin clearance. The relationship between total cefoxitin clearance (CL) and creatinine clearance (CL(CR)) was best described using a nonlinear model [CL = 11.5 * (CL(CR)/77)(0.52)]. The population apparent volume of distribution was 12 L. Computer simulations carried out to determine the probability to maintain free plasma concentrations above 8 mg/L (the concentration threshold for susceptible bacteria) 2 h after drug administration revealed that this probability decreased from 84% in patients with a CL(CR) of 40 mL/min to 28% in patients with a CL(CR) of 100 mL/min. CONCLUSIONS: To ensure cefoxitin target concentrations during surgery, we recommend that cefoxitin be administered every 1.5 h in patients with a CL(CR) >= 60 mL/min and every hour if the CL(CR) is >= 100 mL/min. Administration by continuous infusion preceded by a bolus injection should also be considered. PMID- 22246212 TI - Assessment of gastric emptying function after gastrectomy using a real-time 13C breath test. AB - BACKGROUND/AIMS: Effectiveness of gastric emptying after pylorus-preserving gastrectomy (PPG) remains unclear and a method for continuous assessment is needed. We assessed post-PPG gastric emptying with a continuous real-time 13C breath test (BreathID system, Oridion, Israel). METHODOLOGY: Gastric emptying function was assessed by 13C breath test in 12 post-PPG patients and 9 post distal gastrectomy (DG) patients. Continuous 13C-acetic acid breath test was performed using the BreathID system. Endoscopic study was also completed. RESULTS: Diarrhea was significantly less common in PPG than DG patients (p=0.021). No other questionnaire items and endoscopic findings showed a significant difference. In the 13C-acetic acid breath test, the gastric emptying coefficient (GEC) was significantly greater in PPG than DG patients (p=0.025). No other test parameters showed a significant difference. CONCLUSIONS: Emptying function in the remnant stomach was assessed successfully by the continuous 13C acetic acid breath test. A greater GEC suggested better gastric emptying in PPG patients. PMID- 22246213 TI - Laparoscopic assisted synchronous gastrectomy and colectomy with lymphadenectomy for double cancer in our experience. AB - Laparoscopic gastrointestinal surgery with lymphadenectomy is rarely performed for multiple gastrointestinal cancers. We report four patients undergoing laparoscopic surgery for synchronous cancer of the stomach and colon. Resection of each organ with lymphadenectomy was performed by each specialist and the region of the lymphadenectomy was determined according to the lesion of cancer and its depth. The selection of gastric anastomosis, whether intracorporeal or extracorporeal, depended on the resecting areas of the large bowel to allow a small incision. All four cases were male with the median age of 69 (range 59-77) years. The median number of trocars used were 6 (range 5-8) and median length of incision was 4.5 cm (range 4-4.5 cm). The median operative time and blood loss were 495.5 minutes (range 390-605) and 88 g (range 36-245), respectively. In all four cases, laparoscopic surgery with a lymphadenectomy on each region was successfully accomplished according to the respective progression stage. Anastomosis was completed with a small incision by using techniques and devices to provide a variation of anastomosis methods and incision positions. Laparoscopic surgery with lymphadenectomy was also undertaken for a patient with gastric remnant cancer and colorectal cancer. The median length of the postoperative hospital stay was 14.5 days (range 12-29). No complications were observed after the surgery. There was no case of recurrence during a median follow-up of 84.3 months (range 54.9-111.5). Laparoscopic surgery was feasible for patients with double cancer of the stomach and colon. PMID- 22246214 TI - Reversible addition-fragmentation chain transfer polymerization in microemulsion. AB - This tutorial review first details the uncontrolled microemulsion polymerization mechanism, and the RAFT polymerization mechanism to provide the necessary background for examining the RAFT microemulsion polymerization mechanism. The effect of the chain transfer agent per micelle ratio and the chain transfer agent aqueous solubility on the RAFT microemulsion polymerization kinetics, polymer molecular weight and polydispersity, and polymer nanoparticle size are discussed with a focus on oil-in-water microemulsions. Modeling of RAFT microemulsion polymerization kinetics and the resulting final polymer molecular weight are presented to assist with the analysis of observed experimental trends. Lastly, the current significance of RAFT microemulsion polymerization and the future directions are discussed. PMID- 22246215 TI - Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy. AB - The potential of EHT 6706, a novel tubulin-binding agent, was investigated in combination with ionizing radiation (IR) and with conventional cytotoxic chemotherapy agents. Cell proliferation, cell cycle, apoptosis and clonogenic assays were performed in five human cancer cell lines: H460 (non small cell lung carcinoma, NSCLC), HCT116 and HCT116 p53-/- (colorectal cancer), MDA-MB-231 (breast cancer), and MiaPaca2 cells (pancreatic cancer). The drug inhibited cell proliferation in all cell lines. This effect was associated with G2/M arrest and activation of apoptosis in a dose-dependent manner. The drug was then tested in combination with chemotherapy and IR in vitro. Effects on proliferation and clonogenic survival were analyzed. EHT 6706 treatment inhibited clonogenic survival synergistically with IR in H460 and MiaPaca2 cell lines. In the remaining cell lines, the effects of EHT 6706 and IR were additive. For H460 and MiaPaca2 cell lines, the highest effect was seen when cells were exposed for 20 h to EHT 6706 before being irradiated. EHT 6706 also exerted additive inhibition of proliferation when given in combination with conventional chemotherapy agents, such as oxaliplatin, cisplatin and gemcitabine in H460 and MiaPaca2 tumor cell lines. These data show that EHT 6706 could act synergistically with IR and additively with chemotherapy in tumor cell lines in vitro. This provides a good rationale to further assess EHT 6706 in combination protocols and confirm these effects in vivo. PMID- 22246216 TI - Clinical pilates versus general exercise for chronic low back pain: randomized trial. AB - PURPOSE: This single-assessor-blinded randomized controlled trial aimed to compare the efficacy of physiotherapy-delivered clinical Pilates and general exercise for chronic low back pain. METHODS: Eighty-seven community volunteers with low back pain for >=3 months and age 18-70 were randomized to either the Pilates (n = 44) or general exercise (n = 43) group. The primary outcome was pain/disability measured with the Quebec scale. Secondary outcomes included pain on a numeric rating scale, Patient-Specific Functional Scale, Pain Self-efficacy Questionnaire, quality of life, and global perceived effect of treatment. All participants attended 60-min exercise sessions twice weekly for 6 wk supervised by a physiotherapist and performed daily home exercises that were continued during the follow-up. Participants from the clinical Pilates group received an individualized direction-specific exercise program prescribed by the physiotherapist after a clinical examination. The general exercise group received a generic set of exercises that were multidirectional and nonspecific. Outcomes were assessed after 6 wk (primary time point) and at 12 and 24 wk. Differences in mean change were compared between groups using ANCOVA adjusted for baseline values of the outcome. RESULTS: Eighty-three participants (96%) completed the 6 wk intervention and 60 (69%) completed the 24-wk follow-up. At 6 wk, no difference was found between groups for change in the Quebec scale (3.5, 95% confidence interval = -7.3 to 0.3, P = 0.07); both groups showed significant improvements. Similar results were found at the 12- and 24-wk follow-up and for the secondary outcome measures. CONCLUSIONS: An individualized clinical Pilates program produced similar beneficial effects on self-reported disability, pain, function and health-related quality of life as a general exercise program in community volunteers with chronic low back pain. PMID- 22246217 TI - Physical activity increases bone mineral density in children with type 1 diabetes. AB - INTRODUCTION: Osteoporosis is a growing health problem in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to determine the effects of a 9-month weight-bearing physical activity program on bone mineral density (BMD) and bone biomarkers in T1DM compared with healthy children. METHODS: This was a randomized controlled trial including 27 diabetic and 32 healthy children (mean age = 10.5 +/- 2.5 yr). Both T1DM and healthy participants were randomized to either an exercise or a control group (i.e., four groups). At baseline and 9 months, total body (TB), lumbar spine (LS2-LS4), femoral neck, and greater trochanter areal BMD (aBMD) and serum bone biomarkers (osteocalcin, type 1 collagen cross-linking) were measured. The intervention consisted of two 90-min sessions per week of weight-bearing physical activity (ball games, jumping, rope skipping, and gymnastics). RESULTS: Baseline variables were similar among groups. At 9 months, changes in TB (T1DM = 0.035 +/- 0.022 g.cm(-2), healthy = 0.031 +/- 0.017 g.cm(-2)) and LS2-LS4 (T1DM = 0.046 +/- 0.038 g.cm(-2), healthy = 0.063 +/- 0.034 g.cm(-2)) aBMD were statistically significant in the intervention groups and of similar magnitude between T1DM and healthy subjects. The level of type 1 collagen cross-linking (T1DM = -0.12 +/- 0.32 ng.mL(-1), healthy = -0.36 +/- 0.11 ng.mL(-1)) decreased in the intervention groups but was not associated with TB aBMD changes. CONCLUSIONS: Regular weight-bearing physical activity (180 min.wk( 1), including ball games, jumping activities, and gymnastics) improves total and LS2-LS4 bone mineral accretion in children with T1DM, in a similar magnitude to healthy subjects. We conclude that children with T1DM should be encouraged to practice regular physical activity to enhance peak bone mass and prevent osteoporosis later in life. PMID- 22246219 TI - Motor unit survival in lifelong runners is muscle dependent. AB - A contributing factor to the loss of muscle mass and strength with adult aging is the reduction in the number of functioning motor units (MUs). Recently, we reported that lifelong competitive runners (master runners = ~66 yr) had greater numbers of MUs in a leg muscle (tibialis anterior) than age-matched recreationally active controls. This suggested that long-term exposure to high levels of physical activity may limit the loss of MU numbers with adult aging. However, it is unknown if this finding is the result of long-term activation of the specifically exercised motoneuron pool (i.e., tibialis anterior) or an overall systemic neuroprotective effect of high levels of physical activity. PURPOSE: The purpose was to estimate the number of functioning MUs (MUNEs) in the biceps brachii (an upper body muscle not directly loaded by running) of nine young (27 +/- 5 yr) and nine old (70 +/- 5 yr) men and nine lifelong competitive master runners (67 +/- 4 yr). METHODS: Decomposition-enhanced spike-triggered averaging was used to measure surface and intramuscular EMG signals during elbow flexion at 10% of maximum voluntary isometric contraction. RESULTS: Derived MUNEs were lower in the biceps brachii of runners (185 +/- 69 MUs) and old men (133 +/- 69 MUs) than the young (354 +/- 113 MUs), but the old and master runners were similar. CONCLUSIONS: Although there were no significant differences in MUNE between both older groups in the biceps brachii muscle, with the number of subjects tested here, we cannot eliminate the possibility of some whole-body neuroprotective effect. However, when compared with the remote biceps muscle, a greater influence on age-related spinal motoneuron survival was found in a chronically activated MN pool specific to the exercised muscle. PMID- 22246220 TI - Knee extensor fatigue threshold is related to whole-body VO2max. AB - PURPOSE: Above a given exercise intensity, rapid muscle fatigue will occur. We explored the possibility of assessing torque threshold for peripheral fatigue during single-legged repetitive isometric knee extensor exercise. We hypothesized this fatigue threshold to be related to the general aerobic fitness level and the so-called "critical torque" (CT) established with a recently validated 5-min all out test. METHODS: Seventeen healthy men (VO(2max) = 44.7-69.6 mL.kg(-1).min(-1)) performed six submaximal (20%-55% maximal voluntary contraction [MVC]) 5-min bouts of 60 repetitive contractions (3-s on, 2-s off). Torque was changed between bouts in steps of 5% MVC to estimate the highest intensity (fatigue threshold) at which average changes in rsEMG, EMG median power frequency, and tissue deoxygenation (near-infrared spectroscopy) of the three superficial knee extensor muscles were still <5%, signifying steady-state exercise with minimal peripheral fatigue. On another occasion, one bout was performed in an all-out manner with end-test torque representing CT. RESULTS: Fatigue threshold (40.0% +/- 8.1% MVC) was related (r(2) = 0.57, P < 0.05) to CT (53.1% +/- 10.0% MVC), but it was consistently lower (P < 0.05) and only fatigue threshold was significantly related to VO(2max) (r(2) = 0.68), and the first (r(2) = 0.45) and second (r(2) = 0.63) ventilatory threshold obtained during cycle ergometry. CONCLUSIONS: Performing submaximal bouts of knee extensor contractions, while monitoring EMG and deoxygenation, seems a feasible manner to estimate an aerobic capacity related exercise intensity of peripheral fatigue onset. This test may be used to evaluate changes in endurance capacity of single muscle groups, without the necessity for all-out testing, which could be problematic with frail subjects. PMID- 22246218 TI - Muscle protein synthesis response to exercise training in obese, older men and women. AB - INTRODUCTION: Physical activity and eating are two major physiological muscle growth stimuli. Although muscle protein turnover rates are not different in young and middle-aged men and women, we recently found that the basal rate of muscle protein synthesis is greater and the anabolic response to mixed-meal intake is blunted in 65- to 80-yr-old women compared with men of the same age. Whether older women are also resistant to the anabolic effect of exercise is not known. METHODS: We measured the rate of muscle protein synthesis (both during basal, postabsorptive conditions and during mixed-meal intake) before and after 3 months of exercise training in obese, 65- to 80-yr-old men and women. RESULTS: At the beginning of the study (before training) the basal, postabsorptive muscle protein fractional synthesis rate (FSR) was significantly greater in women than in men (0.064 +/- 0.006%.h(-1) vs 0.039 +/- 0.006%.h(-1), respectively, P < 0.01), whereas the meal-induced increase in the muscle protein FSR was greater in men than in women (P < 0.05). In men, exercise training approximately doubled the basal muscle protein FSR (P = 0.001) but had no effect on the meal-induced increase in muscle protein FSR (P = 0.78). In women, exercise training increased the muscle protein FSR by ~40% (P = 0.03) and also had no effect on the meal induced increase in muscle protein FSR (P = 0.51). CONCLUSIONS: These results suggest that there is significant sexual dimorphism not only in the basal, postabsorptive rate of muscle protein synthesis but also in the anabolic response to feeding and exercise training in obese, older adults. PMID- 22246221 TI - Extractive fermentation for enhanced production of thailandepsin A from Burkholderia thailandensis E264 using polyaromatic adsorbent resin Diaion HP-20. AB - Thailandepsin A is natural product of Burkholderia thailandensis E264 with potent histone deacetylase inhibitory activities and promising anticancer activities. The titer of thailandepsin A is very low (less than 10 mg/l) from limited empirical fermentation. To facilitate preclinical evaluations and potentially clinical development of thailandepsin A, systematic optimization and extractive fermentation of thailandepsin A from B. thailandensis E264 culture in flasks were investigated in this pilot study. The main fermentation parameters--28 degrees C, pH 7.0, inoculum ratio 1% (v/v), incubation duration 60 h, medium volume 26%, shaking speed 170 rpm, and chloroform as extracting solvent--were determined by single factor experiments. Polyaromatic adsorbent resin Diaion HP-20, when added at a concentration of 4% (w/v), was most effective to reduce feedback inhibition of thailandepsin A and to significantly increase the titer of target product. Central composite design was used to further optimize the fermentation medium for B. thailandensis E264. The optimized medium contains glucose 17.89 g/l, tryptone 34.98 g/l, potassium phosphate 24.84 g/l, and sodium citrate 0.01 g/l, which resulted in a large increase of the titer of thailandepsin A to 236.7 mg/l. Finally kinetic models based on the modified logistic and Luedeking-Piret equations were developed, delivering a good description of temporal variations of biomass, product, and substrate in the fermentation process, which could be used as references for developing large-scale fermentation. PMID- 22246222 TI - Cloning and characterization of two new thermostable and alkalitolerant alpha amylases from the Anoxybacillus species that produce high levels of maltose. AB - Two genes that encode alpha-amylases from two Anoxybacillus species were cloned and expressed in Escherichia coli. The genes are 1,518 bp long and encode 506 amino acids. Both sequences are 98% similar but are distinct from other well known alpha-amylases. Both of the recombinant enzymes, ASKA and ADTA, were purified using an alpha-CD-Sepharose column. They exhibited an optimum activity at 60 degrees C and pH 8. Both amylases were stable at pH 6-10. At 60 degrees C in the absence of Ca2+, negligible reduction in activity for up to 48 h was observed. The activity half-life at 65 degrees C was 48 and 3 h for ASKA and ADTA, respectively. In the presence of Ca2+ ions, both amylases were highly stable for at least 48 h and had less than a 10% decrease in activity at 70 degrees C. Both enzymes exhibited similar end-product profiles, and the predominant yield was maltose (69%) from starch hydrolysis. To the best of our knowledge, most alpha-amylases that produce high levels of maltose are active at an acidic to neutral pH. This is the first report of two thermostable, alkalitolerant recombinant alpha-amylases from Anoxybacillus that produce high levels of maltose and have an atypical protein sequence compared with known alpha amylases. PMID- 22246223 TI - Inhibitory effects of ethyl pyruvate administration on human gastric cancer growth via regulation of the HMGB1-RAGE and Akt pathways in vitro and in vivo. AB - The high mobility group box-B1 (HMGB1)-receptor for advanced glycation end products (RAGE) and the protein kinase B (Akt) pathways play a crucial role in tumorigenesis and development of many malignant tumors. Ethyl pyruvate (EP), a potent inhibitor of HMGB1 release, can exert antitumor effects on the growth of gastric cancer. Therefore, it is necessary to observe the effects of EP on gastric cancer growth in vitro and in vivo. Human gastric adenocarcinoma tissues of different grades (N=45) were collected. The expression of HMGB1 and RAGE was evaluated immunohistochemically in biopsy samples. After SGC-7901 gastric cancer cells were treated with EP, the expression of HMGB1, RAGE, Akt, phosphorylated Akt (p-Akt) and some transcription factors was identified and the effects of EP on cell proliferation, invasion, cell cycle distribution and apoptosis were assessed. A subcutaneous xenograft tumor model was established, validating the effects of EP on tumor growth in vivo. The expression of HMGB1 and RAGE was respectively observed in 73.3 and 68.9% of the gastric adenocarcinoma tissues. The frequency of positive expression increased with the ascending grade of the tumor malignancy. EP decreased the expression of HMGB1, RAGE, Akt, p-Akt, Ki-67 and matrix metallopeptidase-9 (MMP-9), and increased the expression of p53. Moreover, EP could inhibit tumor cell proliferation and invasion, induce cell cycle arrest and apoptosis and slow the growth of xenograft tumors. In conclusion, HMGB1 and RAGE were strongly expressed in gastric adenocarcinoma, and EP administration inhibited gastric cancer growth via regulation of the HMGB1 RAGE and Akt pathways. EP may play a critical role in the treatment of cancer in conjunction with other therapeutic agents. PMID- 22246224 TI - Dipeptide forms of glycine support mouse preimplantation embryo development in vitro and provide protection against high media osmolality. AB - PURPOSE: To examine potential benefits of dipeptide forms of amino acids for embryo culture by determining ability of dipeptide glycine forms to support embryo development, act as osmolytes, and reduce ammonia production. METHODS: Frozen thawed 1-cell mouse embryos were cultured in media with varying osmolality with glycine and dipeptide forms of glycine and development assessed. Ammonia levels were measured in various media. RESULTS: Dipeptide forms of glycine, alanyl- and glycyl-glycine, can support mouse embryo development in vitro. Additionally, dipeptide glycine can act as an organic osmolyte in developing embryos, permitting blastocyst formation in high osmolality media. Interestingly, as evidenced by decreased embryo development, dipeptides are not as efficient as osmolytes as their constituent individual amino acids. Dipeptide glycine produced less ammonia than glycine. CONCLUSION: Though dipeptides can provide osmoregulation in preimplantation embryos, efficacy may be lower than individual amino acids. The mechanism by which embryos transport and utilize dipeptide amino acids remains to be identified. PMID- 22246225 TI - Effects of DL-3-n-butylphthalide on vascular dementia and angiogenesis. AB - 3-n-Butylphthalide (NBP) is a compound extracted from Chinese celery and is used as an anti-hypertensive herbal medicine for treating stroke patients. The aim of this study is to demonstrate the effects and mechanisms of this compound through in vitro and in vivo experiments. Culture experiments were performed by adding hydrogen peroxide (H(2)O(2)) to SH-SY5Y cells. From the MTT assay result, enhanced cell survival was observed with DL-NBP treatment, regardless of whether they are added before, simultaneously with or after the addition of H(2)O(2). For the in vivo experiment, Spontaneously Hypertensive rats and Wistar Kyoto control rats with chronic cerebral ischemia, which were induced by bilateral transection of the common carotid arteries, were given DL-NBP. Their performances in the place navigation test and spatial probe test in the Morris Water Maze have significantly improved compared with the DL-NBP untreated animals, indicating an improvement in spatial learning and memory in the ischemic-animals. In addition, in the chick embryonic chorioallantoic membrane assay, angiogenesis was more vigorous under the effects of DL-NBP, together with increased expression of growth factors, VEGF, VEGF-receptor and bFGF. All these suggested that one of the mechanisms of DL-NBP might be ameliorating vascular dementia and promoting angiogenesis. PMID- 22246228 TI - Therapeutics against influenza. AB - Despite 75 years of research into prevention and treatment of influenza, the viruses that cause this disease continue to rank as some of the most important pathogens afflicting humans today. Progress in development of therapeutics for influenza has been slow for much of that time, but has accelerated in pace over the last two decades. Two classes of antiviral medications are used in humans at present, but each has limitations in scope and effectiveness of use. New strategies involving these licensed agents, including alternate forms of delivery and combination therapy with other drugs, are currently being explored. In addition, several novel antiviral compounds are in various clinical phases of development. Together with strategies designed to target the virus itself, new approaches to interrupt host-pathogen interactions or modulate detrimental aspects of the immune response have been proposed. Therapy for influenza will likely undergo substantial changes in the decades to come, evolving with our knowledge of pathogenesis as new approaches become viable and are validated clinically. PMID- 22246227 TI - Comparison of the immunoreactivity of Trx2/Prx3 redox system in the hippocampal CA1 region between the young and adult gerbil induced by transient cerebral ischemia. AB - In the present study, we compared the immunoreactivities and levels of Trx/prx redox system, thioredoxin 2 (Trx2), thioredoxin reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), as well as neuronal death in the hippocampal CA1 region between the adult and young gerbil after 5 min of transient cerebral ischemia. At 4 days post-ischemia, pyramidal neurons (about 90%) in the adult stratum pyramidale of the CA1 region showed "delayed neuronal death (DND)"; however, at this time point, few pyramidal neurons showed DND in the young stratum pyramidale. At 7 days post-ischemia, about 56% of pyramidal neurons showed DND in the young stratum pyramidale. The immunoreactivities of all the antioxidants in the young sham-group were similar to those in the adult sham-group. At 4 days post-ischemia, the immunoreactivity of TrxR2, not Trx2 and Prx3 in the adult ischemia-group was dramatically decreased in CA1 pyramidal neurons. At this time point, the immunoreactivities of all the antioxidants in the young ischemia-group were apparently increased compared to the adult ischemia-group. From 7 days pots ischemia, non-pyramidal cells showed the immunoreactivities of all the antioxidants in the ischemic CA1 region; however, in the young ischemia-groups, the immunoreactivities were much lower than those in the adult ischemia-groups. In brief, our results showed that the immunoreactivities of Trx2, TrxR2 and Prx3 were dramatically increased in CA1 pyramidal neurons of the young ischemia-groups at 4 days post-ischemia compared to those in the adult ischemia-groups induced by transient cerebral ischemia. PMID- 22246229 TI - Editorial. PMID- 22246226 TI - It's a lipid's world: bioactive lipid metabolism and signaling in neural stem cell differentiation. AB - Lipids are often considered membrane components whose function is to embed proteins into cell membranes. In the last two decades, studies on brain lipids have unequivocally demonstrated that many lipids have critical cell signaling functions; they are called "bioactive lipids". Pioneering work in Dr. Robert Ledeen's laboratory has shown that two bioactive brain sphingolipids, sphingomyelin and the ganglioside GM1 are major signaling lipids in the nuclear envelope. In addition to derivatives of the sphingolipid ceramide, the bioactive lipids discussed here belong to the classes of terpenoids and steroids, eicosanoids, and lysophospholipids. These lipids act mainly through two mechanisms: (1) direct interaction between the bioactive lipid and a specific protein binding partner such as a lipid receptor, protein kinase or phosphatase, ion exchanger, or other cell signaling protein; and (2) formation of lipid microdomains or rafts that regulate the activity of a group of raft-associated cell signaling proteins. In recent years, a third mechanism has emerged, which invokes lipid second messengers as a regulator for the energy and redox balance of differentiating neural stem cells (NSCs). Interestingly, developmental niches such as the stem cell niche for adult NSC differentiation may also be metabolic compartments that respond to a distinct combination of bioactive lipids. The biological function of these lipids as regulators of NSC differentiation will be reviewed and their application in stem cell therapy discussed. PMID- 22246230 TI - Commentary on: case report: The use of zero-balance ultrafiltration to correct acute metabolic acidosis after prolonged hypothermic circulatory arrest. PMID- 22246231 TI - Commentary on: Successful use of cardiopulmonary support for a transected bronchus. PMID- 22246232 TI - Commentary on: Long-term use of the Centrimag(R) ventricular assist system as a right ventricular assist system: a case report. PMID- 22246233 TI - Association of apolipoprotein E epsilon4 (ApoE epsilon4) homozygosity with psychiatric behavioral symptoms. AB - To examine the relationship between apolipoprotein E epsilon4 (ApoE epsilon4) and psychiatric symptoms, we compared epsilon4/epsilon4, epsilon3/epsilon3, and epsilon3/epsilon4 subjects. 659 outpatients with memory complaints underwent comprehensive neuropsychiatric assessment interview and neurological examination and ApoE genotyping: 98 were epsilon4/epsilon4. 18.4% (n = 18) epsilon4/epsilon4, 19.3% (n = 45) epsilon3/epsilon4, and 5.4% (n = 14) epsilon3/epsilon3 presented with symptoms of anxiety (p = 0.00001). epsilon4/epsilon4 patients with mild cognitive impairment (MCI; p < 0.0001) and those with Alzheimer's disease with late onset (p = 0.0175) were the most frequently affected. For anxiety, there were no gender dependent differences in the two homozygous groups, however, in the epsilon3/epsilon4 group, anxiety symptoms were evident in 7.3% (n = 8) of the male versus 30.1% (n = 37) of the female epsilon3/epsilon4 heterozygotes (p < 0.0001). Depression was found in 20.4% (n = 20) epsilon4/epsilon4 and 21.0% (n = 49) epsilon3/epsilon4 compared to 17.1% (n = 44) epsilon3/epsilon3 (p = 0.5181). Visual hallucinations were reported in 5.1% (n = 5) epsilon4/epsilon4 as opposed to 3.8% (n = 9) epsilon3/epsilon4 and 2.3% (n = 6) epsilon3/epsilon3 (p = 0.5278). We have seen a higher association of anxiety with the ApoE epsilon4 allele across all stages of disease and what may be a dosing effect in the early stage (MCI) for this ostensible risk, since we see a significantly higher frequency in the ApoE epsilon4 homozygotes when compared to the heterozygotes. PMID- 22246235 TI - Role of neurofilament light polypeptide in head and neck cancer chemoresistance. AB - Resistance to cisplatin-based chemotherapy is responsible for therapeutic failure of many common human cancers including cancer of head and neck (HNC). Mechanisms underlying cisplatin resistance remain unclear. In this study, we identified neurofilament light polypeptide (NEFL) as a novel hypermethylated gene associated with resistance to cisplatin-based chemotherapy in HNC. Analysis of 14 HNC cell lines revealed that downregulation of NEFL expression significantly correlated with increased resistance to cisplatin. Hypermethylation of NEFL promoter CpG islands was observed in cell lines as examined by bisulfite DNA sequencing and methylation-specific PCR (MSP) and tightly correlated with reduced NEFL mRNA and protein expression. Furthermore, in patient samples with HNC (n = 51) analyzed by quantitative MSP, NEFL promoter hypermethylation was associated with resistance to cisplatin-based chemotherapy [relative risk (RR), 3.045; 95% confidence interval (CI), 1.459-6.355; P = 0.007] and predicted diminished overall and disease-free survival for patients treated with cisplatin-based chemotherapy. Knockdown of NEFL by siRNA in the highly cisplatin-sensitive cell line PCI13 increased (P < 0.01) resistance to cisplatin. In cisplatin-resistant O11 and SCC25cp cells, restored expression of NEFL significantly increased sensitivity to the drug. Furthermore, NEFL physically associated with tuberous sclerosis complex 1 (TSC1), a known inhibitor of the mTOR pathway, and NEFL downregulation led to functional activation of mTOR pathway and consequentially conferred cisplatin resistance. This is the first study to show a role for NEFL in HNC chemoresistance. Our findings suggest that NEFL methylation is a novel mechanism for HNC chemoresistance and may represent a candidate biomarker predictive of chemotherapeutic response and survival in patients with HNC. PMID- 22246236 TI - Migfilin regulates esophageal cancer cell motility through promoting GSK-3beta mediated degradation of beta-catenin. AB - Migfilin, a protein component of focal adhesions, has been implicated in regulation of cell-extracellular matrix adhesion and motility but the underlying mechanisms are not fully elucidated. In this study, we have determined the functions of migfilin in esophageal cancer cells and the mechanisms involved. We show that the expression level of migfilin is negatively associated with clinical metastasis, and enforced expression of migfilin suppressed cell motility through decreased free beta-catenin level. Overexpression of migfilin resulted in destabilization of beta-catenin in concomitance with reduction of its transcriptional activity. Knockdown of migfilin by siRNA, transfection of a mutant beta-catenin at Ser37 which is a critical phosphorylation site of GSK 3beta, GSK-3beta inhibitor LiCl, or proteasome inhibitor MG132 reversed the migfilin-mediated beta-catenin degradation and transcription inhibition. Moreover, migfilin promoted beta-catenin degradation by reinforcing the association between beta-catenin and GSK-3beta. In addition, exogenously expressed beta-catenin partially restored migfilin-induced suppression of cell invasion. Collectively, these results suggest that the expression level of migfilin in ESCCs is inversely correlated with clinical metastasis status, and migfilin inhibits ESCC cell invasion at least in part through promoting degradation of beta-catenin. PMID- 22246238 TI - Well-defined (N-heterocyclic carbene)-Ag(I) complexes as catalysts for A3 reactions. AB - The use of well-defined (N-heterocyclic carbene)-Ag(I) complexes for the A(3) reaction allows for the coupling of unactivated aldehydes at room temperature and very short reaction times. PMID- 22246237 TI - Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts. AB - Treatment of base excision repair-proficient mouse fibroblasts with the DNA alkylating agent methyl methanesulfonate (MMS) and a small molecule inhibitor of PARP-1 results in a striking cell killing phenotype, as previously reported. Earlier studies showed that the mechanism of cell death is apoptosis and requires DNA replication, expression of PARP-1, and an intact S-phase checkpoint cell signaling system. It is proposed that activity-inhibited PARP-1 becomes immobilized at DNA repair intermediates, and that this blocks DNA repair and interferes with DNA replication, eventually promoting an S-phase checkpoint and G(2)-M block. Here we report studies designed to evaluate the prediction that inhibited PARP-1 remains DNA associated in cells undergoing repair of alkylation induced damage. Using chromatin immunoprecipitation with anti-PARP-1 antibody and qPCR for DNA quantification, a higher level of DNA was found associated with PARP 1 in cells treated with MMS plus PARP inhibitor than in cells without inhibitor treatment. These results have implications for explaining the extreme hypersensitivity phenotype after combination treatment with MMS and a PARP inhibitor. PMID- 22246240 TI - In situ monitoring of the DNA hybridization by attenuated total reflection surface-enhanced infrared absorption spectroscopy. AB - In situ monitoring of DNA hybridization kinetics is achieved via an attenuated total reflection surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS) technique using a sandwich assay structure. The synergistic enhancement effect gives this ATR-SEIRAS-based detection strategy promise to be a convenient and unique platform for bioanalysis. PMID- 22246239 TI - Diversity and function of the avian gut microbiota. AB - The intestinal microbiota have now been shown to largely affect host health through various functional roles in terms of nutrition, immunity, and other physiological systems. However, the majority of these studies have been carried out in mammalian hosts, which differ in their physiological traits from other taxa. For example, birds possess several unique life history traits, such as hatching from eggs, which may alter the interactions with and transmission of intestinal microbes compared to most mammals. This review covers the diversity of microbial taxa hosted by birds. It also discusses how avian microbial communities strongly influence nutrition, immune function, and processing of toxins in avian hosts, in manners similar to and different from mammalian systems. Finally, areas demanding further research are identified, along with descriptions of existing techniques that could be employed to answer these questions. PMID- 22246241 TI - Change in gene expression profiles of secreted frizzled-related proteins (SFRPs) by sodium butyrate in gastric cancers: induction of promoter demethylation and histone modification causing inhibition of Wnt signaling. AB - Activation of Wnt signaling without mutation of beta-catenin or APC occurs frequently in human gastric cancers. Secreted frizzled-related protein (SFRP), a negative modulator of the Wnt signaling pathway, are frequently inactivated in human gastric cancers. Inhibition of SFRP gene expression may account for the Wnt/beta-catenin activation in human gastric cancer. However, the molecular mechanisms of silencing of SFRP genes are not fully understood. Sodium butyrate, a histone deacetylase (HDAC) inhibitor, is known to exhibit anti-cancer effects partly through the differentiation of various cancer cells. In the present study, we investigated: i) the relationship between the silencing of SFRP genes and Wnt signaling; ii) the mechanism of sodium butyrate mediated epigenetic regulation of SFRPs expression in human gastric cancer. We observed that nuclear beta-catenin was significantly increased in gastric cancer tissues as compared to adjacent non cancerous tissues. Nuclear beta-catenin accumulation and SFRP promoter methylation in human gastric cancer cells were noted. Treatment with the DNA methyltransferase inhibitor, 5'-Aza-2-deoxycytidine (5'-Aza-dC) rapidly restored SFRPs expression. Sodium butyrate (NaB) induced demethylation and histone modification at the promoter region of SFRP1/2 restoring the SFRP expression in human gastric cancer cells. Analysis of general expression revealed that overexpression of SFRPs repressed Wnt target gene expression and induced changes in the proliferation and apoptosis related genes in human gastric cancer cells. These data suggest that aberrant epigenetic modification of SFRP genes is one of the major mechanisms by which Wnt signaling is activated in human gastric cancer cells and sodium butyrate may modulate the SFRP1/2 expression through histone modification and promoter demethylation causing anti-tumor effects. PMID- 22246242 TI - Education increases reserve against Alzheimer's disease--evidence from structural MRI analysis. AB - INTRODUCTION: The aim of this study was to determine whether years of schooling influences regional cortical thicknesses and volumes in Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls. METHODS: Using an automated image analysis pipeline, 33 regional cortical thickness and 15 regional volumes measures from MRI images were determined in 121 subjects with MCI, 121 patients with AD, and 113 controls from AddNeuroMed study. Correlations with years of schooling were determined and more highly and less highly educated subjects compared, controlling for intracranial volume, age, gender, country of origin, cognitive status, and multiple testing. RESULTS: After controlling for confounding factors and multiple testing, in the control group, subjects with more education had larger regional cortical thickness in transverse temporal cortex, insula, and isthmus of cingulate cortex than subjects with less education. However, in the AD group, the subjects with more education had smaller regional cortical thickness in temporal gyrus, inferior and superior parietal gyri, and lateral occipital cortex than the subjects with less education. No significant difference was found in the MCI group. CONCLUSION: Education may increase regional cortical thickness in healthy controls, leading to increased brain reserve, as well as helping AD patients to cope better with the effects of brain atrophy by increasing cognitive reserve. PMID- 22246243 TI - Can a gastrointestinal pathologist identify microsatellite instability in colorectal cancer with reproducibility and a high degree of specificity? AB - Clinical features usually initiate evaluation for Lynch Syndrome (LS) but some colorectal cancer (CRC) histopathology findings are compatible with high microsatellite instability (MSI-H) that also occurs in LS. This led to the suggestion that pathologists request MSI analysis, which is an expensive addition to routine histology. We aimed to see if a Gastrointestinal Pathologist could identify MSI-H features with reproducibility and high (95%) specificity (MSI-H 95%). Histopathology of all CRCs received during 2005 and 4 MSI-H controls were scored using 2 published methods, "MsScore" and "PathScore". MSI analysis was performed on CRCs scored by either method as probable MSI-H 95% and results compared. To examine reproducibility of histopathology, 100 coded slides, including 25 scored MSI-H 95% and 75 scored low, were re-examined to now identify those needing MSI analysis. Costs were evaluated for identifying MSI-H with or without scoring. All 227 CRCs were scored for possible MSI-H 95%; 24 had high scores and MSI analysis. DNA analysis proved 14 MSI-H, PathScore identified 13 (95%), MsPath identified 9 (64%), histopathology alone identified 7 (50%). Reproducibility for identifying histopathology characteristics of MSI-H at re examination, without scoring, was "moderate agreement" (Kappa statistic = 0.4615). Costs for identifying MSI-H by PathScore were the lowest, $436/identification. Conclusions; PathScore identified the most proven MSI-H CRCs at lowest cost and even an experienced gastrointestinal pathologist has difficulties identify MSI-H without scoring. So, scoring can be facilitated by a computerized evaluation form for routine CRC histology, prompting score computation and recommendation for MSI analysis with high specificity. PMID- 22246244 TI - Mismatch negativity of higher amplitude for melodic ascendance than descendance. AB - The auditory system prefers, presumably because of evolutionary adaptation, melodically upward over downward steps in sound frequency. The mismatch negativity (MMN) of event-related potentials (ERPs) to auditory oddball stimuli, an index of preattentive auditory change detection, is also augmented for the upward relative to the downward steps. We aimed to test whether this melodic MMN asymmetry shows specificity to the oddball stimuli. Auditory ERPs were recorded in adult humans during a visual task. In an oddball condition, a repeated 400 Hz tone was occasionally (P=0.01) replaced either by a 380 Hz or by a 420 Hz tone. In a same-rate condition, the tones of the three frequencies occurred at equal probabilities (P=0.33). In the oddball condition, frontally augmented ERPs of negative polarity (MMN) were found to be of higher amplitude for the 420 Hz tone than for the 380 Hz tone. In the same-rate condition, ERPs did not distinguish between the tones. The findings associate the melodic MMN asymmetry with the neural detection of oddball tones in particular. PMID- 22246245 TI - Continuous reactions in supercritical carbon dioxide: problems, solutions and possible ways forward. AB - This Tutorial Review focuses on supercritical carbon dioxide (scCO(2)), and discusses some of the problems that have frustrated its wide use on an industrial scale. It gives some recent examples where strategies have been developed to reduce the energy requirements, including sequential reactions and gas-expanded liquids. It then describes a number of cases where scCO(2) offers real chemical advantages over more conventional solvents, for example by controlled phase separation, tunable selectivity, oxidation and on-line analysis and self optimisation. Overall, this review indicates where scCO(2) could deliver value in the future. PMID- 22246246 TI - CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors. AB - Recurrent homozygous CBL-inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates SRC family kinases (SFK) and receptor tyrosine kinases (RTK). However, the most important SFK and RTK affected by these mutations, and hence, the most important therapeutic targets, have not been clearly characterized. We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation (GDM-1), heterozygous deletion (MOLM13) and wild-type (WT) CBL (THP1, U937). As expected with CBL loss, GDM-1 displayed high KIT expression and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity. Ectopic expression of WT CBL decreased GDM-1 proliferation but not cell lines with WT CBL. GDM-1, but not the other cell lines, was highly sensitive to growth inhibition by dasatinib (dual SFK and RTK inhibitor, LD50 50 nM); there was less or no selective inhibition of GDM-1 growth by sunitinib (RTK inhibitor), imatinib (ABL, KIT inhibitor), or PP2 (SFK inhibitor). Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM-1, including a number of proteins in the KIT and GM-CSF receptor pathways (for example, KIT Tyr721, STAT3 Tyr705). In conclusion, the promiscuous effects of CBL loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition. PMID- 22246247 TI - The mysterious cognitive abilities of bees: why models of visual processing need to consider experience and individual differences in animal performance. AB - Vision is one of the most important modalities for the remote perception of biologically important stimuli. Insects like honeybees and bumblebees use their colour and spatial vision to solve tasks, such as navigation, or to recognise rewarding flowers during foraging. Bee vision is one of the most intensively studied animal visual systems, and several models have been developed to describe its function. These models have largely assumed that bee vision is determined by mechanistic hard-wired circuits, with little or no consideration for behavioural plasticity or cognitive factors. However, recent work on both bee colour vision and spatial vision suggests that cognitive factors are indeed a very significant factor in determining what a bee sees. Individual bumblebees trade-off speed for accuracy, and will decide on which criteria to prioritise depending upon contextual information. With continued visual experience, honeybees can learn to use non-elemental processing, including configural mechanisms and rule learning, and can access top-down information to enhance learning of sophisticated, novel visual tasks. Honeybees can learn delayed-matching-to-sample tasks and the rules governing this decision making, and even transfer learned rules between different sensory modalities. Finally, bees can learn complex categorisation tasks and display numerical processing abilities for numbers up to and including four. Taken together, this evidence suggests that bees do have a capacity for sophisticated visual behaviours that fit a definition for cognition, and thus simple elemental models of bee vision need to take account of how a variety of factors may influence the type of results one may gain from animal behaviour experiments. PMID- 22246248 TI - Seeing near and seeing far; behavioural evidence for dual mechanisms of pattern vision in the honeybee (Apis mellifera). AB - Visual perception is a primary modality for interacting with complex environments. Recent work has shown that the brain and visual system of the honeybee is able, in some cases, to learn complex spatial relationships, while in other cases, bee vision is relatively rudimentary and based upon simple elemental type visual processing. In the present study, we test the ability of honeybees to learn 4-bar asymmetric patterns in a Y-maze with aversive-appetitive differential conditioning. In Experiment 1, a group of bees were trained at a small visual angle of 50 deg by constraining individuals to the decision chamber within the Y maze. Bees learned this task, and were able to solve the task even in the presence of background noise. However, these bees failed to solve the task when the stimuli were presented at a novel visual angle of 100 deg. In Experiment 2, a separate group of bees were trained to sets of 4-bar asymmetric patterns that excluded retinotopic matching and, in this case, bees learned the configural rule describing stimuli at a visual angle of approximately 50 deg, and this allowed the bees to solve the task when the stimuli were presented at a novel vision angle of 100 deg. This shows that the bee brain contains multiple mechanisms for pattern recognition, and what a bee sees is very dependent upon the specific experience that it receives. These multiple mechanisms would allow bees to interact with complex environments to solve tasks like recognising landmarks at variable distances or quickly discriminating between rewarding/non-rewarding flowers at reasonable constant visual angles. PMID- 22246249 TI - Flexural stiffness of feather shafts: geometry rules over material properties. AB - Flight feathers of birds interact with the flow field during flight. They bend and twist under aerodynamic loads. Two parameters are mainly responsible for flexibility in feathers: the elastic modulus (Young's modulus, E) of the material (keratin) and the geometry of the rachises, more precisely the second moment of area (I). Two independent methods were employed to determine Young's modulus of feather rachis keratin. Moreover, the second moment of area and the bending stiffness of feather shafts from fifth primaries of barn owls (Tyto alba) and pigeons (Columba livia) were calculated. These species of birds are of comparable body mass but differ in wing size and flight style. Whether their feather material (keratin) underwent an adaptation in stiffness was previously unknown. This study shows that no significant variation in Young's modulus between the two species exists. However, differences in Young's modulus between proximal and distal feather regions were found in both species. Cross-sections of pigeon rachises were particularly well developed and rich in structural elements, exemplified by dorsal ridges and a well-pronounced transversal septum. In contrast, cross-sections of barn owl rachises were less profiled but had a higher second moment of area. Consequently, the calculated bending stiffness (EI) was higher in barn owls as well. The results show that flexural stiffness is predominantly influenced by the geometry of the feathers rather than by local material properties. PMID- 22246250 TI - Wake structures behind a swimming robotic lamprey with a passively flexible tail. AB - A robotic lamprey, based on the silver lamprey, Ichthyomyzon unicuspis, was used to investigate the influence of passive tail flexibility on the wake structure and thrust production during anguilliform swimming. A programmable microcomputer actuated 11 servomotors that produce a traveling wave along the length of the lamprey body. The waveform was based on kinematic studies of living lamprey, and the shape of the tail was taken from a computer tomography scan of the silver lamprey. The tail was constructed of flexible PVC gel, and nylon inserts were used to change its degree of flexibility. Particle image velocimetry measurements using three different levels of passive flexibility show that the large-scale structure of the wake is dominated by the formation of two pairs of vortices per shedding cycle, as seen in the case of a tail that flexed actively according to a pre-defined kinematic pattern, and did not bend in response to fluid forces. When the tail is passively flexible, however, the large structures are composed of a number of smaller vortices, and the wake loses coherence as the degree of flexibility increases. Momentum balance calculations indicate that, at a given tailbeat frequency, increasing the tail flexibility yields less net force, but changing the cycle frequency to match the resonant frequency of the tail increases the force production. PMID- 22246251 TI - Brain activation pattern depends on the strategy chosen by zebra finches to solve an orientation task. AB - Zebra finches (Taeniopygia guttata) were trained to find food in one of four feeders on the floor of an aviary. This feeder was always in the same place during training and was additionally marked by a distinct pattern. In the test trial the distinctly patterned feeder was interchanged with one of the other feeders, so that the birds had to decide to use either the pattern or the original location for finding food. Half of the birds used one strategy and half used the other. According to the strategy applied, different brain areas were activated, as demonstrated by c-Fos immunohistochemistry. The hippocampus was activated when spatial cues were used, while in birds orienting using the pattern of the feeder, part of the collothalamic (tectofugal) visual system showed stronger activation. The visual wulst of the lemnothalamic (thalamofugal) visual system was activated with both strategies, indicating an involvement in both spatial and pattern-directed orientation. Because the experimental situation was the same for all zebra finches, the activation pattern was only dependent on the strategy that was voluntarily chosen by each of the birds. PMID- 22246252 TI - Time-varying motor control of autotomized leopard gecko tails: multiple inputs and behavioral modulation. AB - Autotomy (voluntary loss of an appendage) is common among diverse groups of vertebrates and invertebrates, and much attention has been given to ecological and developmental aspects of tail autotomy in lizards. Although most studies have focused on the ramifications for the lizard (behavior, biomechanics, energetics, etc.), the tail itself can exhibit interesting behaviors once segregated from the body. For example, recent work highlighted the ability of leopard gecko tails to jump and flip, in addition to being able to swing back and forth. Little is known, however, about the control mechanisms underlying these movements. Using electromyography, we examined the time-varying in vivo motor patterns at four sites (two proximal and two distal) in the tail of the leopard gecko, Eublepharis macularius, following autotomy. Using these data we tested the hypothesis that the disparity in movements results simply from overlapping pattern generators within the tail. We found that burst duration, but not cycle duration, of the rhythmic swings reached a plateau at approximately 150 s following autotomy. This is likely because of physiological changes related to muscle fatigue and ischemia. For flips and jumps, burst and cycle duration exhibited no regular pattern. The coefficient of variation in motor patterns was significantly greater for jumps and flips than for rhythmic swings. This supports the conclusion that the different tail behaviors do not stem from overlapping pattern generators, but that they rely upon independent neural circuits. The signal controlling jumps and flips may be modified by sensory information from the environment. Finally, we found that jumps and flips are initiated using relatively synchronous activity between the two sides of the tail. In contrast, alternating activation of the right and left sides of the tail result in rhythmic swings. The mechanism underlying this change in tail behavior is comparable to locomotor gait changes in vertebrates. PMID- 22246253 TI - The correlation between locomotor performance and hindlimb kinematics during burst locomotion in the Florida scrub lizard, Sceloporus woodi. AB - Burst locomotion is thought to be closely linked to an organism's ability to survive and reproduce. During the burst, animals start from a standstill and then rapidly accelerate to near-maximum running speeds. Many previous studies have described the functional predictors of maximum running speed; however, only recently has work emerged that describes the morphological, functional and biomechanical underpinnings of acceleration capacity. Herein we present data on the three-dimensional hindlimb kinematics during burst locomotion, and the relationship between burst locomotor kinematics and locomotor performance in a small terrestrial lizard (Sceloporus woodi). We focus only on stance phase joint angular kinematics. Sceloporus woodi exhibited considerable variation in hindlimb kinematics and performance across the first three strides of burst locomotion. Stride 1 was defined by larger joint angular excursions at the knee and ankle; by stride 3, the knee and ankle showed smaller joint angular excursions. The hip swept through similar arcs across all strides, with most of the motion caused by femoral retraction and rotation. Metatarsophalangeal (MTP) kinematics exhibited smaller maximum angles in stride 1 compared with strides 2 and 3. The significant correlations between angular kinematics and locomotor performance were different across the first three strides. For stride 1, MTP kinematics predicted final maximum running speed; this correlation is likely explained by a correlation between stride 1 MTP kinematics and stride 2 acceleration performance. For stride 3, several aspects of joint kinematics at each joint predicted maximum running speed. Overall, S. woodi exhibits markedly different kinematics, performance and kinematics-performance correlations across the first three strides. This finding suggests that future studies of burst locomotion and acceleration performance should perform analyses on a stride-by-stride basis and avoid combining data from different strides across the burst locomotor event. Finally, the kinematics performance correlations observed in S. woodi were quite different from those described for other species, suggesting that there is not a single kinematic pattern that is optimal for high burst performance. PMID- 22246254 TI - Worker division of labor and endocrine physiology are associated in the harvester ant, Pogonomyrmex californicus. AB - In Pogonomyrmex californicus harvester ants, an age-associated division of labor occurs in the worker caste, in which young workers perform in-nest tasks and older workers forage for food. Here, we tested whether this behavioral division is age based or age flexible, and whether it coincides with differential expression of systemic hormones with known roles in behavioral regulation. Whole body content of juvenile hormone (JH) and ecdysteroids was determined in workers from (1) age-typical colonies, in which a typical age structure is maintained and workers transition across behaviors naturally, and (2) single-cohort colonies, which are entirely composed of same-aged workers, facilitating the establishment of age-independent division of labor. Foragers from both colony types had higher JH and lower ecdysteroid content than workers performing in-nest tasks, suggesting that age is not the sole determinant of worker behavior. This association between hormone content and behavior of P. californicus workers is similar to that previously observed in founding queens of this species. Because these hormones are key regulators of development and reproductive behavior, our data are consistent with the reproductive ground plan hypothesis (RGPH), which posits that the reproductive regulatory mechanisms of solitary ancestors were co opted to regulate worker behavior. PMID- 22246255 TI - Phenotypic plasticity in response to dietary salt stress: Na+ and K+ transport by the gut of Drosophila melanogaster larvae. AB - Drosophila provides a useful model system for studies of the mechanisms involved in regulation of internal ion levels in response to variations in dietary salt load. This study assessed whether alterations in Na(+) and K(+) transport by the gut of larval D. melanogaster reared on salt-rich diets contribute to haemolymph ionoregulation. Na(+) and K(+) fluxes across the isolated guts of third instar larvae reared on control or salt-rich diets were measured using the scanning ion selective electrode technique (SIET). K(+) absorption across the anterior portion of the posterior midgut of larvae reared on diet in which the concentration of KCl was increased 0.4 mol l(-1) above that in the control diet was reduced eightfold relative to the same gut segment of larvae reared on the control diet. There was also an increase in the magnitude and extent of K(+) secretion across the posterior half of the posterior midgut. Na(+) was absorbed across the ileum of larvae reared on the control diet, but was secreted across the ileum of larvae reared on diet in which the concentration of NaCl was increased 0.4 mol l(-1) above that in the control diet. There was also a small reduction in the extent of Na(+) absorption across the middle midgut of larvae reared on the NaCl-rich diet. The results indicate considerable phenotypic plasticity with respect to K(+) and Na(+) transport by the gut epithelia of larval D. melanogaster. SIET measurements of K(+) and Na(+) fluxes along the length of the gut show that ion transport mechanisms of the gut are reconfigured during salt stress so that there are reductions in K(+) and Na(+) absorption and increases in K(+) and Na(+) secretion. Together with previously described changes in salt secretion by the Malpighian tubules, these changes contribute to haemolymph ionoregulation. PMID- 22246256 TI - Temperature gradients drive mechanical energy gradients in the flight muscle of Manduca sexta. AB - A temperature gradient throughout the dominant flight muscle (dorsolongitudinal muscle, DLM(1)) of the hawkmoth Manduca sexta, together with temperature dependent muscle contractile rates, demonstrates that significant spatial variation in power production is possible within a single muscle. Using in situ work-loop analyses under varying muscle temperatures and phases of activation, we show that regional differences in muscle temperature will induce a spatial gradient in the mechanical power output throughout the DLM(1). Indeed, we note that this power gradient spans from positive to negative values across the predicted temperature range. Warm ventral subunits produce positive power at their in vivo operating temperatures, and therefore act as motors. Concurrently, as muscle temperature decreases dorsally, the subunits produce approximately zero mechanical power output, acting as an elastic energy storage source, and negative power output, behaving as a damper. Adjusting the phase of activation further influences the temperature sensitivity of power output, significantly affecting the mechanical power output gradient that is expressed. Additionally, the separate subregions of the DLM(1) did not appear to employ significant physiological compensation for the temperature-induced differences in power output. Thus, although the components of a muscle are commonly thought to operate uniformly, a significant within-muscle temperature gradient has the potential to induce a mechanical power gradient, whereby subunits within a muscle operate with separate and distinct functional roles. PMID- 22246257 TI - Kinematics of quadrupedal locomotion in sugar gliders (Petaurus breviceps): effects of age and substrate size. AB - Arboreal mammals face unique challenges to locomotor stability. This is particularly true with respect to juveniles, who must navigate substrates similar to those traversed by adults, despite a reduced body size and neuromuscular immaturity. Kinematic differences exhibited by juveniles and adults on a given arboreal substrate could therefore be due to differences in body size relative to substrate size, to differences in neuromuscular development, or to both. We tested the effects of relative body size and age on quadrupedal kinematics in a small arboreal marsupial (the sugar glider, Petaurus breviceps; body mass range of our sample 33-97 g). Juvenile and adult P. breviceps were filmed moving across a flat board and three poles 2.5, 1.0 and 0.5 cm in diameter. Sugar gliders (regardless of age or relative speed) responded to relative decreases in substrate diameter with kinematic adjustments that promote stability; they increased duty factor, increased the average number of supporting limbs during a stride, increased relative stride length and decreased relative stride frequency. Limb phase increased when moving from the flat board to the poles, but not among poles. Compared with adults, juveniles (regardless of relative body size or speed) used lower limb phases, more pronounced limb flexion, and enhanced stability with higher duty factors and a higher average number of supporting limbs during a stride. We conclude that although substrate variation in an arboreal environment presents similar challenges to all individuals, regardless of age or absolute body size, neuromuscular immaturity confers unique problems to growing animals, requiring kinematic compensation. PMID- 22246258 TI - First evidence of epithelial transport in tardigrades: a comparative investigation of organic anion transport. AB - We investigated transport of the organic anion Chlorophenol Red (CPR) in the tardigrade Halobiotus crispae using a new method for quantifying non-fluorescent dyes. We compared the results acquired from the tardigrade with CPR transport data obtained from Malpighian tubules of the desert locust Schistocerca gregaria. CPR accumulated in the midgut lumen of H. crispae, indicating that organic anion transport takes place here. Our results show that CPR transport is inhibited by the mitochondrial un-coupler DNP (1 mmol l(-1); 81% reduction), the Na(+)/K(+) ATPase inhibitor ouabain (10 mmol l(-1); 21% reduction) and the vacuolar H(+) ATPase inhibitor bafilomycin (5 MUmol l(-1); 21% reduction), and by the organic anions PAH (10 mmol l(-1); 44% reduction) and probenecid (10 mmol l(-1); 61% reduction, concentration-dependent inhibition). Transport by locust Malpighian tubules exhibits a similar pharmacological profile, albeit with markedly higher concentrations of CPR being reached in S. gregaria. Immunolocalization of the Na(+)/K(+)-ATPase alpha-subunit in S. gregaria revealed that this transporter is abundantly expressed and localized to the basal cell membranes. Immunolocalization data could not be obtained from H. crispae. Our results indicate that organic anion secretion by the tardigrade midgut is transporter mediated with likely candidates for the basolateral entry step being members of the Oat and/or Oatp transporter families. From our results, we cautiously suggest that apical H(+) and possibly basal Na(+)/K(+) pumps provide the driving force for the transport; the exact coupling between electrochemical gradients generated by the pumps and transport of ions, as well as the nature of the apical exit step, are unknown. This study is, to our knowledge, the first to show active epithelial transport in tardigrades. PMID- 22246259 TI - Independence of net water flux from paracellular permeability in the intestine of Fundulus heteroclitus, a euryhaline teleost. AB - Paracellular permeability and absorptive water flux across the intestine of the euryhaline killifish were investigated using in vitro gut sac preparations from seawater- and freshwater-acclimated animals. The permeability of polyethylene glycol (PEG), a well-established paracellular probe, was measured using trace amounts of radiolabelled oligomers of three different molecular sizes (PEG-400, PEG-900 and PEG-4000) at various times after satiation feeding. All three PEG molecules were absorbed, with permeability declining as a linear function of increasing hydrodynamic radius. Response patterns were similar in seawater and freshwater preparations, though water absorption and PEG-900 permeability were greater in the latter. Despite up to 4-fold variations in absorptive water flux associated with feeding and fasting (highest at 1-3 h, lowest at 12-24 h and intermediate at 1-2 weeks post-feeding), there were no changes in PEG permeability for any size oligomer. When PEG permeability was measured in the opposite direction (i.e. serosal to mucosal) from net water flux, it was again unchanged. HgCl(2) (10(-3) mol l(-1)), a putative blocker of aquaporins, eliminated absorptive water flux yet increased PEG-4000 permeability by 6- to 8 fold in both freshwater and seawater preparations. Experimentally raising the serosal osmolality by addition of 300 mmol l(-1) mannitol increased the absorptive water flux rate 10-fold, but did not alter PEG permeability. Under these conditions, HgCl(2) reduced absorptive water flux by 60% and again increased PEG permeability by 6- to 8-fold in both freshwater and seawater preparations. Clearly, there was no influence of solvent drag on PEG movement. The putative paracellular blocker 2,4,6-triaminopyrimidine (TAP, 20 mmol l(-1)) had no effect on net water flux or PEG permeability. We conclude that PEG and water move by separate pathways; absorptive water transport probably occurs via a transcellular route in the intestine of Fundulus heteroclitus. PMID- 22246260 TI - Origin and mechanism of thermal insensitivity in mole hemoglobins: a test of the 'additional' chloride binding site hypothesis. AB - The structural and evolutionary origins underlying the effect of temperature on the O(2) binding properties of mammalian hemoglobins (Hbs) are poorly understood, despite their potential physiological importance. Previous work has shown that the O(2) affinities of the blood of the coast mole (Scapanus orarius) and the eastern mole (Scalopus aquaticus) are significantly less sensitive to temperature changes than that of the star-nosed mole (Condylura cristata). It was suggested that this difference may arise from the binding of 'additional' chloride ions within a cationic pocket between residues 8His, 76Lys and 77Asn on the beta-like delta-globin chains of coast and eastern mole Hbs. To test this hypothesis, we deduced the primary sequences of star-nosed mole and American shrew mole (Neurotrichus gibbsii) Hb, measured the sensitivity of these respiratory proteins to allosteric effector molecules and temperature, and calculated their overall oxygenation enthalpies (DeltaH'). Here we show that the variability in DeltaH' seen among mole Hbs cannot be attributed to differential Cl(-) binding at delta8, delta76 and delta77, as the Cl(-) sensitivity of mole Hbs is unaffected by amino acid changes at this site (i.e. the proposed 'additional' Cl- binding site is not operational in mole Hbs). Rather, we demonstrate that the numerically low DeltaH' of coast and eastern mole Hbs results from heightened proton binding relative to other mole Hbs. Comparative sequence analysis and molecular modelling moreover suggest that this attribute evolved in a common ancestor of these two fossorial lineages and arises from the development of a salt bridge between a pair of amino acid residues (delta125His and alpha34Glu/Asp) that are not present in other mole Hbs. PMID- 22246261 TI - The polarization compass dominates over idiothetic cues in path integration of desert ants. AB - Desert ants, Cataglyphis, use the sky's pattern of polarized light as a compass reference for navigation. However, they do not fully exploit the complexity of this pattern, rather - as proposed previously - they assess their walking direction by means of an approximate solution based on a simplified internal template. Approximate rules are error-prone. We therefore asked whether the ants use additional cues to improve the accuracy of directional decisions, and focused on 'idiothetic' cues, i.e. cues based on information from proprioceptors. We trained ants in a channel system that was covered with a polarization filter, providing only a single e-vector direction as a directional 'celestial' cue. Then we observed their homebound runs on a test field, allowing full view of the sky. In crucial experiments, the ants were exposed to a cue conflict, in which sky compass and idiothetic information disagreed, by training them in a straight channel that provided a change in e-vector direction. The results indicated that the polarization information completely dominates over idiothetic cues. Two path segments with different e-vector orientations are combined linearly to a summed home vector. Our data provide additional evidence that Cataglyphis uses a simplified internal template to derive directional information from the sky's polarization pattern. PMID- 22246262 TI - Sensory input from the osphradium modulates the response to memory-enhancing stressors in Lymnaea stagnalis. AB - In the freshwater environment species often rely on chemosensory information to modulate behavior. The pond snail, Lymnaea stagnalis, is a model species used to characterize the causal mechanisms of long-term memory (LTM) formation. Chemical stressors including crayfish kairomones and KCl enhance LTM formation (>=24 h) in Lymnaea; however, how these stressors are sensed and the mechanism by which they affect the electrophysiological properties of neurons necessary for memory formation are poorly understood. Here, we assessed whether the osphradium, a primary chemosensory organ in Lymnaea, modulates LTM enhancement. To test this we severed the osphradial nerve proximal to the osphradium, using sham-operated animals as controls, and assessed the behavioral and electrophysiological response to crayfish kairomones and KCl. We operantly conditioned aerial respiratory behavior in intact, sham and osphradially cut animals, and tested for enhanced memory formation after exposure to the chemical stressors. Sham-operated animals displayed the same memory enhancement as intact animals but snails with a severed osphradial nerve did not show LTM enhancement. Extracellular recordings made from the osphradial nerve demonstrate that these stressors evoked afferent sensory activity. Intracellular recordings from right pedal dorsal 1 (RPeD1), a neuron necessary for LTM formation, demonstrate that its electrophysiological activity is altered by input from the osphradium following exposure to crayfish kairomones or KCl in sham and intact animals but no response is seen in RPeD1 in osphradially cut animals. Therefore, sensory input from the osphradium is necessary for LTM enhancement following exposure to these chemical stressors. PMID- 22246263 TI - Glycogen synthase kinase-3: cryoprotection and glycogen metabolism in the freeze tolerant wood frog. AB - The terrestrial anuran Rana sylvatica tolerates extended periods of whole-body freezing during the winter. Freezing survival is facilitated by extensive glycogen hydrolysis and distribution of high concentrations of the cryoprotectant glucose into blood and all tissues. As glycogenesis is both an energy-expensive process and counter-productive to maintaining sustained high cryoprotectant levels, we proposed that glycogen synthase kinase-3 (GSK-3) would be activated when wood frogs froze and would phosphorylate its downstream substrates to inactivate glycogen synthesis. Western blot analysis determined that the amount of phosphorylated (inactive) GSK-3 decreased in all five tissues tested in 24 h frozen frogs compared with unfrozen controls. Total GSK-3 protein levels did not change, with the exception of heart GSK-3, indicating that post-translational modification was the primary regulatory mechanism for this kinase. Kinetic properties of skeletal muscle GSK-3 from control and frozen frogs displayed differential responses to a temperature change (22 versus 4 degrees C) and high glucose. For example, when assayed at 4 degrees C, the K(m) for the GSK-3 substrate peptide was ~44% lower for frozen frogs than the corresponding value in control frogs, indicating greater GSK-3 affinity for its substrates in the frozen state. This indicates that at temperatures similar to the environment encountered by frogs, GSK-3 in frozen frogs will phosphorylate its downstream targets more readily than in unfrozen controls. GSK-3 from skeletal muscle of control frogs was also allosterically regulated. AMP and phosphoenolpyruvate activated GSK-3 whereas inhibitors included glucose, glucose 6-phosphate, pyruvate, ATP, glutamate, glutamine, glycerol, NH(4)Cl, NaCl and KCl. The combination of phosphorylation and allosteric control argues for a regulatory role of GSK-3 in inactivating glycogenesis to preserve high glucose cryoprotectant levels throughout each freezing bout. PMID- 22246264 TI - Warmer is better: thermal sensitivity of both maximal and sustained power output in the iliotibialis muscle isolated from adult Xenopus tropicalis. AB - Environmental temperature varies temporally and spatially and may consequently affect organismal function in complex ways. Effects of temperature are often most pertinent on locomotor performance traits of ectothermic animals. Given the importance of locomotion to mobility and dispersion, variability in temperature may therefore affect the current and future distribution of species. Many previous studies have demonstrated that burst muscle performance changes with temperature. However, less is known about the effects of temperature on sustained skeletal muscle performance. The iliotibialis muscle was isolated from eight male Xenopus tropicalis individuals and subjected to in vitro isometric and work-loop studies at test temperatures of 15, 24, 30 and 32 degrees C. Work-loop power output (average power per cycle) was maximised at each temperature by altering stimulation and strain parameters. A series of 10 work loops was also delivered at each test temperature to quantify endurance performance. Warmer test temperatures tended to increase twitch stress (force normalised to muscle cross sectional area) and significantly increased tetanic stress. Increased temperature significantly reduced twitch and tetanus activation and relaxation times. Increased temperature also significantly increased both burst muscle power output (cycle average) and sustained (endurance) performance during work loop studies. The increase in burst power output between 15 and 24 degrees C yielded a high Q(10) value of 6.86. Recent studies have demonstrated that the negative effects of inorganic phosphate accumulation during prolonged skeletal muscle performance are reduced with increased temperature, possibly explaining the increases in endurance found with increased test temperature in the present study. PMID- 22246265 TI - Long-term memory and response generalization in mushroom body extrinsic neurons in the honeybee Apis mellifera. AB - Honeybees learn to associate an odor with sucrose reward under conditions that allow the monitoring of neural activity by imaging Ca(2+) transients in morphologically identified neurons. Here we report such recordings from mushroom body extrinsic neurons - which belong to a recurrent tract connecting the output of the mushroom body with its input, potentially providing inhibitory feedback - and other extrinsic neurons. The neurons' responses to the learned odor and two novel control odors were measured 24 h after learning. We found that calcium responses to the learned odor and an odor that was strongly generalized with it were enhanced compared with responses to a weakly generalized control. Thus, the physiological responses measured in these extrinsic neurons accurately reflect what is observed in behavior. We conclude that the recorded recurrent neurons feed information back to the mushroom body about the features of learned odor stimuli. Other extrinsic neurons may signal information about learned odors to different brain regions. PMID- 22246266 TI - Measurement of sensitive distortion-product otoacoustic emissions in insect tympanal organs. PMID- 22246267 TI - Could NICE guidance on the choice of blood pressure lowering drugs be simplified? PMID- 22246268 TI - Navigating the shoals in hypertension: discovery and guidance. PMID- 22246269 TI - NICE hypertension guideline 2011: evidence based evolution. PMID- 22246270 TI - Ugandan authorities deal with a mysterious ailment that leaves people nodding continuously. PMID- 22246271 TI - A reticulated eruption on the lower abdomen in a 17 year old girl. PMID- 22246272 TI - PFI scheme changes are inadequate, MPs say. PMID- 22246273 TI - Trusts will not be able to exclude drugs approved by NICE from formularies, says Lansley. PMID- 22246274 TI - Axing legal aid for clinical negligence claims will cost the NHS an extra 28.5m pound a year, says report. PMID- 22246275 TI - Merging hospitals may not have the intended benefits, suggests study. PMID- 22246276 TI - England's health secretary orders three new inquiries into safety of cosmetic surgery and devices. PMID- 22246277 TI - Building hygiene infrastructure is key to ending Haitian cholera epidemic, agree agencies. PMID- 22246278 TI - Tumor suppressor gene BLU is frequently downregulated by promoter hypermethylation in myelodysplastic syndrome. AB - PURPOSE: BLU methylation status was investigated in bone marrow mononuclear cells from newly diagnosed myelodysplastic syndrome (MDS) patients and patients who received 5-aza-2'-deoxycytidine (decitabine) treatment so as to determine the effect of BLU in the pathogenesis of MDS. METHODS: Methylation-specific polymerase chain reaction and bisulfite sequencing were used to evaluate the methylation status of the promoter region of the BLU gene. BLU expression was investigated by using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot analysis. RESULTS: Hypermethylation in the promoter region of BLU was detected in 34 of 79 (43%) newly diagnosed MDS patient samples and was significantly correlated with the loss of BLU mRNA and protein expression. There was a statistically significant difference in methylation frequency between the refractory anemia/refractory anemia with ringed sideroblasts/5q-syndrome (RA/RARS/5q-) group and the refractory anemia with excess blasts-1/-2 (RAEB-1/RAEB-2) group. A higher frequency of hypermethylation was observed in the intermediate-2/high-risk group compared to the low risk/intermediate-1-risk group. The demethylating agent decitabine could partly reverse hypermethylation and restore the expression of the BLU gene. CONCLUSION: BLU promoter hypermethylation frequently occurs in MDS cases, especially in higher risk MDS cases, and is significantly associated with the downregulated expression of BLU. BLU gene re-expression was induced in some MDS cases undergoing decitabine therapy. BLU may play a substantial role in the development and etiology of MDS. PMID- 22246279 TI - Racial disparities in treatment for pancreatic cancer and impact on survival: a population-based analysis. AB - PURPOSE: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related deaths in both men and women. Mortality from pancreatic cancer is higher amongst blacks compared to other races. We performed this analysis with the aim of examining racial disparity for receipt pancreatic cancer treatment and its association with survival. METHODS: Using the surveillance, epidemiology, and end results (SEER) database from 1988 to 2008, cases with locoregional pancreatic cancer were analysed. Kaplan-Meier survival curves were assessed to assess the survival amongst various races. Cox proportional hazard model was built to assess the impact of receipt of treatment on the racial disparity in survival. RESULTS: Of 16,282 cases with locoregional pancreatic cancer, 1,806 (11%) occurred in blacks. Median survival was 8-9 months with poorest survival in blacks. Blacks and Hispanics received radiation treatment less often compared to other races. On Cox regression logistic regression analysis, blacks had 20% poorer survival compared to whites. Treatment for pancreatic cancer explained only one-fourth of this poorer survival. CONCLUSION: Blacks have worst survival from locoregional pancreatic cancer. Receiving treatment for pancreatic cancer only explains 25% of the poorer survival amongst blacks, suggesting role of other factors. Studies are suggested to (a) identify barriers in receipt of treatment for pancreatic cancer amongst blacks and (b) to assess role of genetic and other factors to examine racial differences in survival. PMID- 22246280 TI - Are surrogate assumptions and use of diuretics associated with diagnosis and staging of acute kidney injury after cardiac surgery? AB - BACKGROUND AND OBJECTIVES: This study measured the association between the Acute Kidney Injury Network (AKIN) diagnostic and staging criteria and surrogates for baseline serum creatinine (SCr) and body weight, compared urine output (UO) with SCr criteria, and assessed the relationships between use of diuretics and calibration between criteria and prediction of outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective cohort study using prospective measurements of SCr, hourly UO, body weight, and drug administration records from 5701 patients admitted, after cardiac surgery, to a cardiac intensive care unit between 1995 and 2006. RESULTS: More patients (n=2424, 42.5%) met SCr diagnostic criteria with calculated SCr assuming a baseline estimated GFR of 75 ml/min per 1.73 m(2) than with known baseline SCr (n=1043, 18.3%). Fewer patients (n=484, 8.5%) met UO diagnostic criteria with assumed body weight (70 kg) than with known weight (n=624, 10.9%). Agreement between SCr and UO criteria was fair (kappa=0.28; 95% confidence interval 0.25-0.31). UO diagnostic criteria were specific (0.95; 0.94-0.95) but insensitive (0.36; 0.33-0.39) compared with SCr. Intravenous diuretics were associated with higher probability of falling below the UO diagnostic threshold compared with SCr, higher 30-day mortality (relative risk, 2.27; 1.08-4.76), and the need for renal support (4.35; 1.82 10.4) compared with no diuretics. CONCLUSIONS: Common surrogates for baseline estimated GFR and body weight were associated with misclassification of AKIN stage. UO criteria were insensitive compared with SCr. Intravenous diuretic use further reduced agreement and confounded association between AKIN stage and 30 day mortality or need for renal support. PMID- 22246281 TI - The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. AB - BACKGROUND AND OBJECTIVES: Fabry disease is a rare X-linked disease with multisystemic manifestations. This study investigated the effectiveness of long term enzyme replacement therapy with agalsidase alfa in Fabry nephropathy treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational study, data on patients receiving agalsidase alfa (0.2 mg/kg every other week) were extracted from the Fabry Outcome Survey, an international registry of patients with Fabry disease. Serum creatinine and estimated GFR (eGFR) at baseline and after >=5 years of treatment were assessed; 24-hour urinary protein excretion and BP measurements were also reviewed. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients with an eGFR <30 ml/min per 1.73 m(2) were excluded. RESULTS: Renal function was assessed in 208 patients (mean enzyme replacement therapy, 7.4 years; range, 5.0-11.2 years). Mean yearly change in eGFR was -2.2 ml/min per 1.73 m(2) in men and -0.7 ml/min per 1.73 m(2) in women (95% confidence limits, -2.8; -1.7 and -1.4; 0.0, respectively). Patients with 24-hour protein excretion >1 g/24 h had poorer renal function at baseline and follow-up compared with patients with protein excretion of 500-1000 mg/24 h or with proteinuria <500 mg/24 h. Renal function was worse in patients with baseline arterial hypertension, and there was a more rapid yearly decline compared with normotensive patients. CONCLUSIONS: This study suggests that long-term agalsidase alfa therapy is able to stabilize the rate of Fabry nephropathy progression in women and is associated with a mild to moderate decline of renal function in men. PMID- 22246282 TI - Baseline levels and trimestral variation of triiodothyronine and thyroxine and their association with mortality in maintenance hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Conflicting evidence exists with regard to the association of thyroid hormones and mortality in dialysis patients. This study assesses the association between basal and trimestral variation of thyroid stimulating hormone, triiodothyronine, and thyroxine and mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 210 prevalent hemodialysis patients, serum triiodothyronine, thyroxine, thyroid stimulating hormone, and interleukin-6 were measured 3 months apart. Cardiovascular and non-cardiovascular deaths were registered during follow-up. Based on fluctuations along tertiles of distribution, four trimestral patterns were defined for each thyroid hormone: persistently low, decrease, increase, and persistently high. The association of baseline levels and trimestral variation with mortality was investigated with Kaplan-Meier curves and Cox proportional hazard models. RESULTS: During follow up, 103 deaths occurred. Thyroid stimulating hormone levels did not associate with mortality. Patients with relatively low basal triiodothyronine concentrations had higher hazards of dying than patients with high levels. Longitudinally, patients with persistently low levels of triiodothyronine during the 3-month period had higher mortality hazards than those having persistently high levels. These associations were mainly attributable to cardiovascular related mortality. The association between thyroxine and mortality was not altered after adjustment for triiodothyronine. CONCLUSIONS: Hemodialysis patients with reduced triiodothyronine or thyroxine levels bear an increased mortality risk, especially due to cardiovascular causes. This was true when considering both baseline measurements and trimestral variation patterns. Our longitudinal design adds observational evidence supporting the hypothesis that the link may underlie a causal effect. PMID- 22246283 TI - (1-34) Parathyroid hormone infusion acutely lowers fibroblast growth factor 23 concentrations in adult volunteers. AB - BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Parathyroid hormone (PTH) infusion for 24 hours stimulated FGF23 secretion in healthy volunteers. The extent to which this was due to a direct stimulatory effect of PTH versus an indirect effect of increasing 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels was unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Changes in FGF23 in 26 adults undergoing 6 hour (1-34) PTH infusion were examined, focusing particularly on the effects of PTH on FGF23 in the early period of infusion before sustained increases in 1,25(OH)(2)D. RESULTS: FGF23 levels declined in parallel with serum phosphate during infusion (P<0.05 for both), with both analytes decreasing within the first hour and reaching their respective nadirs at 6 hours. These changes were observed despite no change in 1,25(OH)(2)D levels during the first hour and a significant increase in 1,25(OH)(2)D from baseline after 6 hours (P<0.001). There were no differences in these responses by race. However, modest racial differences in the phosphaturic response to (1-34) PTH were observed (P=0.04 for interaction), with a higher rate of increase in fractional phosphate excretion in blacks than in whites. CONCLUSIONS: During short-term (1-34) PTH infusion, FGF23 levels decreased in parallel with serum phosphate levels and despite significant increases in 1,25(OH)(2)D. When coupled with the results of prior longer-term infusion studies, these findings suggest that acute increases in PTH initially act to suppress FGF23 secretion, perhaps to mitigate urinary phosphate losses, before the stimulatory effect of 1,25(OH)(2)D on FGF23 eventually begins to predominate. PMID- 22246284 TI - Does allograft failure impact infection risk on peritoneal dialysis: a North American Pediatric Renal Trials and Collaborative Studies Study. AB - BACKGROUND AND OBJECTIVES: Several adult studies report that patients returning to peritoneal dialysis after allograft failure have increased infection-related morbidity. The impact of allograft failure on infection risk in children is uncertain. We compared peritonitis-free survival between pediatric peritoneal dialysis patients with prior allograft failure and those who were transplant naive. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied patients, 2-21 years of age, who initiated peritoneal dialysis from January 1, 1992, to December 31, 2007, in the North American Pediatric Renal Trials and Collaborative Studies registry. Demographic characteristics were compared between transplant naive and allograft failure patients using a chi-squared statistic. Peritonitis-free survival was compared between the two groups using Kaplan-Meier estimates. A Cox regression analysis was performed to adjust for covariates, which impact risk of peritonitis. RESULTS: Of 2829 patients on peritoneal dialysis, 445 had a prior history of allograft failure and 2384 did not (transplant naive). Demographic characteristics including age at dialysis initiation, race, primary renal disease, and era of dialysis initiation were significantly different between the two groups. Peritonitis-free survival was poorer for the allograft failure group. After covariate adjustment, allograft failure showed borderline significance as a factor predictive of peritonitis. CONCLUSIONS: Children initiating peritoneal dialysis after allograft failure may experience a slightly higher infection risk. PMID- 22246285 TI - Structural requirements of pyrimidine, thienopyridine and ureido thiophene carboxamide-based inhibitors of the checkpoint kinase 1: QSAR, docking, molecular dynamics analysis. AB - Our focus of current research is directed toward clarification of novel inhibitors (pyrazolo[1,5-a] pyrimidine (PP), thienopyridines (TP) and 2-ureido thiophene carboxamide (UTC) derivatives) targeting Checkpoint kinase 1 (CHK(1)), which is an oncology target of significant current interest. Our computational approaches include: (i) QSAR analysis was carried out on the computed steric/electrostatic/hydrophobic/hydrogen bond donor/hydrogen bond acceptor interactions with the pseudoreceptor surface, which yielded predictive models capable of explaining much of the variance of inhibitors. The resultant optimum QSAR/CoMFA models exhibited (N(training) = 51, N(test) = 16, R(cv) (2) = 0.47, R(pred) (2) = 0.7) for PP, (N(training) = 45, N(test) = 9, R(cv) (2) = 0.52, R(pred) (2) = 0.75) for TP and (N(training) = 58, N(test) = 15, R(cv) (2) = 0.67, R(pred) (2) = 0.88) for UTC. (ii) Molecular docking and molecular dynamics simulations experiments of the inhibitors into the binding site of CHK(1) aided the interpretation of the QSAR models and demonstrated the binding modes in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding interactions, which indicated that a set of critical residues (Cys87, Glu91, Glu85, Ser147, Asp148, Glu17, Leu84 and Asn135) played a key role in the drug target interactions. The obtained results in the present work will be fruitful for the design of new potent and selective inhibitors of CHK(1). PMID- 22246286 TI - Full-length structural model of RET3 and SEC21 in COPI: identification of binding sites on the appendage for accessory protein recruitment motifs. AB - COPI, a 600 kD heptameric complex (consisting of subunits alpha, beta, gamma, delta, epsilon, zeta, and beta') "coatomer," assembles non-clathrin-coated vesicles and is responsible for intra-Golgi and Golgi-to-ER protein trafficking. Here, we report the three-dimensional structures of the entire sequences of yeast Sec21 (gamma-COPI mammalian ortholog), yeast Ret3 (zeta-COPI mammalian ortholog), and the results of successive molecular dynamics investigations of the subunits and assembly based on a protein-protein docking experiment. The three-dimensional structures of the subunits in their complexes indicate the residues of the two subunits that impact on assembly, the conformations of Ret3 and Sec21, and their binding orientations in the complexed state. The structure of the appendage domain of Sec21, with its two subdomains--the platform and the beta-sandwich, was investigated to explore its capacity to bind to accessory protein recruitment motifs. Our study shows that a binding site on the platform is capable of binding the Eps15 DPF and epsin DPW2 peptides, whereas the second site on the platform and the site on the beta-sandwich subdomain were found to selectively bind to the amphiphysin FXDXF and epsin DPW1 peptides, respectively. Identifying the regions of both the platform and sandwich subdomains involved in binding each peptide motif clarifies the mechanism through which the appendage domain of Sec21 engages with the accessory proteins during the trafficking process of non-clathrin-coated vesicles. PMID- 22246287 TI - Probing the linear and nonlinear optical properties of nitrogen-substituted carbon nanotube. AB - In view of their intriguing structural and electrical properties, the linear and nonlinear optical (NLO) responses of six carbon nanotube (CNT) molecules substituted by nitrogen atoms at one end have been explored by using the CAM B3LYP method. Molecules 1, 2 and 3 were obtained by increasing the lengths of the CNTs, and 1-Li, 2-Li and 3-Li were constructed by doping one Li atom into the N substituted end of 1, 2 and 3 (mentioned above), respectively. Two effective approaches have been proposed to increase nonlinear optical properties(NLO): increasing the length of the CNT as well as doping one Li atom into the N substituted end. The results show that both the linear polarizabilities (alpha(0)) and nonlinear first hyperpolarizabilities (beta(tot)) values increase with increasing the lengths of the CNTs: 188 of 1 < 307 of 2 < 453 of 3 for alpha(0) and 477 of 1 < 2654 of 2 < 3906 au of 3 for beta(tot). Significantly, compared with the non-doped CNTs, the beta(tot) values are remarkably enhanced by doping one Li atom into the N-substituted end: 477 of 1 < 23258 of 1-Li, 2654 of 2 < 37244 of 2-Li, and 3906 of 3 < 72004 au of 3-Li. Moreover, the beta(vec) values show a similar trend to the beta(tot) values. Our results may be beneficial to experimentalists in exploring high-performance nonlinear optical materials based on CNT. PMID- 22246288 TI - Density functional studies on the endohedral complex of fullerene C70 with tetrahedrane (C4H4): C4H4@C70. AB - B3LYP/6-31G(d) hybrid HF/DFT calculations were carried out to determine the structural and electronic properties of the endohedral complex of a C(70) cage with tetrahedrane (C(4)H(4)). It was demonstrated that the formation of the complex is endothermic, with a destabilization energy of 72.56 kcal mol(-1). C(4)H(4) is seated in the center of the C(70) cage and exists in molecular form inside the fullerene. C(4)H(4) endohedral doping slightly perturbs the molecular orbitals of C(70). The calculated HOMO-LUMO gaps, the electron affinity (EA), and the ionization potential (IP) indicate that C(4)H(4)@C(70) is more chemically reactive than C(70). The IR active modes and harmonic vibrational frequencies of C(4)H(4)@ C(70) are also discussed. PMID- 22246290 TI - MR perfusion imaging by alternate slab width inversion recovery arterial spin labeling (AIRASL): a technique with higher signal-to-noise ratio at 3.0 T. AB - OBJECT: To propose a new arterial spin labeling (ASL) perfusion-imaging method (alternate slab width inversion recovery ASL: AIRASL) that takes advantage of the qualities of 3.0 T. MATERIALS AND METHODS: AIRASL utilizes alternate slab width IR pulses for labeling blood to obtain a higher signal-to-noise ratio (SNR). Numerical simulations were used to evaluate perfusion signals. In vivo studies were performed to show the feasibility of AIRASL on five healthy subjects. We performed a statistical analysis of the differences in perfusion SNR measurements between flow-sensitive alternating inversion recovery (FAIR) and AIRASL. RESULTS: In signal simulation, the signal obtained by AIRASL at 3.0 and 1.5 T was 1.14 and 0.85%, respectively, whereas the signal obtained by FAIR at 3.0 and 1.5 T was 0.57 and 0.47%, respectively. In an in vivo study, the SNR of FAIR (3.0 T) and FAIR (1.5 T) were 1.73 +/- 0.49 and 1.02 +/- 0.20, respectively, whereas the SNRs of AIRASL (3.0 T) and AIRASL (1.5 T) were 3.93 +/- 1.65 and 1.34 +/- 0.31, respectively. SNR in AIRASL at 3.0 T was significantly greater than that in FAIR at 3.0 T. CONCLUSION: The most significant potential advantage of AIRASL is its high SNR, which takes advantage of the qualities of 3.0 T. This sequence can be easily applied in the clinical setting and will enable ASL to become more relevant for clinical application. PMID- 22246289 TI - Repeatability of renal arterial spin labelling MRI in healthy subjects. AB - OBJECT: Arterial spin labelling (ASL) can be used to measure renal perfusion non invasively. The aim of this study was to determine the repeatability of this technique in healthy kidneys to vindicate its use in clinic. MATERIALS AND METHODS: Two groups of healthy volunteers were imaged two different days to assess intra- and inter-session repeatability. Oblique-coronal data volumes were acquired on a 1.5 T scanner with a dedicated abdominal 32-channel body phased array coil. ASL was performed using a multi-TI FAIR labelling scheme and 3D GRASE imaging module. Background suppression and respiratory triggering were used. T(1) maps of the kidney were acquired using the same sequence with background suppression disabled. RESULTS: For the group with multiple intra-session ASL measurements, the average cortical perfusion was 197 mL min(-1)100 g(-1) and average cortical T(1) was 1265 ms. For both perfusion and T(1) the variation shown by the within-subject standard deviation (SDws) (14.6 mL min(-1)100 g(-1) and 33.4 ms) and coefficient of variation (CVws) (7.52 and 2.69%, respectively) was small for all the analyses carried out. Bland-Altman plots were also used to visualise the variation between the same parameters collected from the different scanning sessions in both groups, and demonstrated good reproducibility. CONCLUSION: We have shown that in healthy volunteers, ASL parameters are repeatable over a short and long period. This supports the overall aim of using ASL in the clinic to assess longitudinal renal perfusion changes in patients. PMID- 22246291 TI - Leveraging physiological data from literature into a pharmacokinetic model to support informative clinical study design in pregnant women. AB - PURPOSE: Physiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy. METHODS: Changes in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models. RESULTS: The literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was successfully developed, with parameters expected with good precision (RSE < 36.4%). CONCLUSION: A literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable. PMID- 22246292 TI - Genetic and epigenetic mechanisms collaborate to control SERPINA3 expression and its association with placental diseases. AB - SERPINA3 (Serpin peptidase inhibitor clade A member 3), also known as a1 antichymotrypsin, is a serine protease inhibitor involved in a wide range of biological processes. Recently, it has been shown to be up-regulated in human placental diseases in association with a hypomethylation of the 5' region of the gene. In the present study, we show that the promoter of SERPINA3 is transcriptionally activated by three transcription factors (TFs) (SP1, MZF1 and ZBTB7B), the level of induction being dependent on the rs1884082 single nucleotide polymorphism (SNP) located inside the promoter, the T allele being consistently induced to a higher level than the G, with or without added TFs. When the promoter was methylated, the response to ZBTB7B was allele specific (the G allele was strongly induced, while the T allele was strongly down-regulated). We propose an adaptive model to explain the interest of such a regulation for placental function and homeostasis. Overexpression of SERPINA3 in JEG-3 cells, a trophoblast cell model, decreased cell adhesion to the extracellular matrix and to neighboring cells, but protects them from apoptosis, suggesting a way by which this factor could be deleterious at high doses. In addition, we show in different human populations that the T allele appears to predispose to Intra Uterine Growth Restriction (IUGR), while a G allele at a second SNP located in the second exon (rs4634) increases the risk of preeclampsia. Our results provide mechanistic views inside the involvement of SERPINA3 in placental diseases, through its regulation by a combination of epigenetic, genetic and TF-mediated regulations. PMID- 22246293 TI - Novel pharmacological chaperones that correct phenylketonuria in mice. AB - Phenylketonuria (PKU) is caused by inherited phenylalanine-hydroxylase (PAH) deficiency and, in many genotypes, it is associated with protein misfolding. The natural cofactor of PAH, tetrahydrobiopterin (BH(4)), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH(4) shows limited efficacy in some PKU genotypes and its chemical synthesis is very costly. Taking an integrated drug discovery approach which has not been applied to this target before, we identified alternative PCs for the treatment of PKU. Shape focused virtual screening of the National Cancer Institute's chemical library identified 84 candidate molecules with potential to bind to the active site of PAH. An in vitro evaluation of these yielded six compounds that restored the enzymatic activity of the unstable PAHV106A variant and increased its stability in cell-based assays against proteolytic degradation. During a 3-day treatment study, two compounds (benzylhydantoin and 6-amino-5-(benzylamino)-uracil) substantially improved the in vivo Phe oxidation and blood Phe concentrations of PKU mice (Pah(enu1)). Notably, benzylhydantoin was twice as effective as tetrahydrobiopterin. In conclusion, we identified two PCs with high in vivo efficacy that may be further developed into a more effective drug treatment of PKU. PMID- 22246295 TI - The good, the bad and the twisted: a survey of ligand geometry in protein crystal structures. AB - The protein databank now contains the structures of over 11,000 ligands bound to proteins. These structures are invaluable in applied areas such as structure based drug design, but are also the substrate for understanding the energetics of intermolecular interactions with proteins. Despite their obvious importance, the careful analysis of ligands bound to protein structures lags behind the analysis of the protein structures themselves. We present an analysis of the geometry of ligands bound to proteins and highlight the role of small molecule crystal structures in enabling molecular modellers to critically evaluate a ligand model's quality and investigate protein-induced strain. PMID- 22246297 TI - Performing artists, part 2. PMID- 22246294 TI - Sustained expression of PGC-1alpha in the rat nigrostriatal system selectively impairs dopaminergic function. AB - Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1alpha), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1alpha induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC 1alpha progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1alpha induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1alpha prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1alpha is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1alpha overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by alpha-synuclein overexpression. Overall, we find that lasting overexpression of PGC-1alpha leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1alpha in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1alpha activity. PMID- 22246296 TI - The errors of our ways: taking account of error in computer-aided drug design to build confidence intervals for our next 25 years. AB - The future of the advancement as well as the reputation of computer-aided drug design will be guided by a more thorough understanding of the domain of applicability of our methods and the errors and confidence intervals of their results. The implications of error in current force fields applied to drug design are given are given as an example. Even as our science advances and our hardware become increasingly more capable, our software will be perhaps the most important aspect in this realization. Some recommendations for the future are provided. Education of users is essential for proper use and interpretation of computational results in the future. PMID- 22246298 TI - Acupuncture in treatment of musculoskeletal disorders of orchestra musicians. AB - OBJECTIVE: Playing-related musculoskeletal disorders (PRMD) are common among musicians. Acupuncture is well established in Germany as a treatment for orthopedic conditions, but it is not commonly used in the treatment of PRMD yet. The authors examined the musicians' health literature and provide a brief overview about the background of acupuncture. Three case studies are presented to show possible benefits for the treatment of PRMD. PARTICIPANTS: 2456 medical doctors, members of the German research group for acupuncture. METHODS: We searched literature and Medline Database for publications about acupuncture, musicians' medicine and musculoskeletal disorders. Additionally we asked medical doctors, via a questionnaire, about the treatment of professional musicians as patients. Case studies are presented. RESULTS: No research was found to support the use oft acupuncture in PRMD. The survey study found that medical doctors are not satisfied with the quality of medical health care provided to musicians and regard specialist knowledge as being important. CONCLUSION: Evidence on the benefits of acupuncture for musculoskeletal disorders suggests that it could be of benefit as a complementary treatment of PRMD. We suggest performing clinical trials to demonstrate the value of standard treatment, acupuncture and complementary medicine for PRMD. PMID- 22246299 TI - Passion in the performing arts: clarifying active occupational participation. AB - Active participation in daily occupations is a vital part of everyday life, social participation and healthy life long human development; however, enablers of active participation are not well understood. Passion, a strong tendency towards an activity that a person finds meaningful and spends a lot of time doing, is a potential enabler. Accordingly, it is important to understand how an individual's passion for a specific occupation plays out across the occupational life course. OBJECTIVE: To explore the experience of passion across the life course of older adults involved in the performing arts. PARTICIPANTS: Seven older adults involved in, or retired from, the performing arts, who consider themselves passionate about their occupation. METHODS: A constructivist grounded theory approach was used to explore, through interviews with older adults, passion for performing arts across the life course. RESULTS: Emerging themes supported development of an initial theoretical framework explicating active participation and passion. It centers on passion as an enabler of occupational participation through different modes, and suggests barriers to that enablement process. CONCLUSIONS: Findings suggest that passion has an important role in continued active participation in an occupation; however, barriers, such as social and financial, can derail the pursuit of a passionate occupation. PMID- 22246300 TI - Influence of fitness and physical activity on cardiovascular reactivity to musical performance. AB - OBJECTIVE: The current study examines the relationships between physical activity and fitness and reactivity to a musical performance stressor (MPS). Numerous studies suggest that being fitter and more physically active has a beneficial effect on individuals' cardiovascular responses to laboratory-based mental challenges. The results are equivocal regarding the transfer of such benefits to real world contexts such as musical performance. PARTICIPANTS: Forty six advanced music students completed this assessment. METHOD: All participants completed a 20 min pre-performance assessment of heart rate (HR), HR variability (HRV) and blood pressure. Participants also completed baseline measures and a sub-maximal fitness assessment on a separate day. RESULTS: A positive association between fitness and HR pre-MPS was found. Fitness was also positively associated with root mean square SD RR(interval) before the MPS. Higher fitness was related to lower state anxiety post-MPS. CONCLUSIONS: Implications of the findings are discussed in relation to classical musicians' day-to-day work and performance. PMID- 22246301 TI - Special performing problems of female musicians: three case studies. AB - Female instrumentalists can encounter serious performing problems because of their physiology that is not regarded as being significant in medical terms, but which nevertheless may seriously hinder or even prevent them from playing their instruments. Music-related medical advice is based on fundamental medical procedures, and includes taking a detailed case history, instrumental biography and, above all, player observation. Three case studies from a medical information center for professional and lay musicians show the importance of gender-specific problems in female musicians: A pianist with "pseudo short-arm syndrome" due to circumference of the abdomen as a result of pregnancy; a violinist with pain in the shoulder girdle due to heavy mammae; and a young oboist with "pseudo breathing- problems" during menstruation. PMID- 22246302 TI - Page turning solutions for musicians: a survey. AB - Musicians have long been hampered by the challenge in turning sheet music while their hands are occupied playing an instrument. The sight of a human page turner assisting a pianist during a performance, for instance, is not uncommon. This need for a page turning solution is no less acute during practice sessions, which account for the vast majority of playing time. Despite widespread appreciation of the problem, there have been virtually no robust and affordable products to assist the musician. Recent progress in assistive technology and electronic reading devices offers promising solutions to this long-standing problem. The objective of this paper is to survey the technology landscape and assess the benefits and drawbacks of page turning solutions for musicians. A full range of mechanical and digital page turning products are reviewed. PMID- 22246303 TI - Musicians' social representations of health and illness: a qualitative case study about focal dystonia. AB - Musicians are artists who use the entire body when playing their instruments. Since over-practicing may lead to physical problems, musicians might encounter focal dystonia, a hand's motor disorder. The cause seems to be the brain's confusion between afferent and efferent information transfer provoking a disharmony with the instrument. Although focal dystonia may have serious consequences for a musician's career, it is unclear how musicians perceive this trouble. This case study describes two musicians with focal dystonia. Qualitative research was used to study their social representations of health and illness. The results show the central role of the hand during music playing, the passion for music and the understanding for focal dystonia as "brain panic". Therapists should account for those specific features inherent to this population in order to better help them in their quest for art through music. Giving a voice to musicians may improve their quality of care. PMID- 22246304 TI - Task specific focal hand dystonia: understanding the enigma and current concepts. AB - OBJECTIVE: The first step in approaching task specific focal hand dystonia (TSFHD) is recognition that it is a neurological disorder and not a deficiency in practice or technique. To eliminate the enigma, TSFHD needs to be a more familiar entity. That is the objective of this paper. METHOD: This is a state of the art review in concert with 3 decades of experience providing care for musicians written to act as a reference source. It is written as an introduction to TSFHD by reviewing history, etiology and current theories, presentation and characteristics, diagnosis and treatment. CONCLUSIONS: Information sources, both web-based and by consultation need to be accessible, reliable and comprehensive. Accurate diagnosis should include the diagnosis of concurrent impairments and the confirmation that the diagnosis of TSFHD is correct. Successful treatment is likely to be interdisciplinary. Successful approaches may include the administration of botulinum toxin but approaches should not be restricted to pharmaceuticals. Instrument modification, altering technique and sensory motor retraining are potential adjunctive approaches. A dichotomy exists between the therapeutic benefit achieved with treatment and the musician's need for optimum hand function. The final goal is successful return to playing at a level that meets the musician's needs. PMID- 22246305 TI - iDance. PMID- 22246307 TI - The effects of feedback on computer workstation posture habits. AB - Repetitive stress injuries (RSI) and musculoskeletal disorders in the United States and worldwide are increasing at an alarming rate due to the advent of ubiquitous computer usage. Factors that lead to computer-related musculoskeletal disorders (MSD) include inadequately designed workstations, poor posture, and lack of knowledge about proper ergonomics and use habits. Studies have documented the negative impact of improper posture and the MSD seen in students and office workers due to frequent computer usage. OBJECTIVE: Determine if the frequency (single vs. continuous reminder) and/or use of feedback affects posture at a computer workstation. PARTICIPANTS: Observations of posture habits were made in three local schools and one local company. Feedback effects were tested on the students (ages 10-15). METHODS: Real time feedback was given in two studies. In one study, instructions and a verbal reminder were given to students and in a second study, a prototype 'Posture Pad' was developed to provide continuous feedback to the user. RESULTS: Verbal reminders to sit correctly led to transient improvement of posture. Use of the 'Posture Pad' resulted in significant improvement in posture with subjects exhibiting correct posture 98 +/- 5% of the time. CONCLUSIONS: Real time feedback about how one is sitting is an effective mechanism for non-transient improvement of posture at computer workstations. PMID- 22246308 TI - Touch-screen tablet user configurations and case-supported tilt affect head and neck flexion angles. AB - OBJECTIVE: The aim of this study was to determine how head and neck postures vary when using two media tablet (slate) computers in four common user configurations. METHODS: Fifteen experienced media tablet users completed a set of simulated tasks with two media tablets in four typical user configurations. The four configurations were: on the lap and held with the user's hands, on the lap and in a case, on a table and in a case, and on a table and in a case set at a high angle for watching movies. An infra-red LED marker based motion analysis system measured head/neck postures. RESULTS: Head and neck flexion significantly varied across the four configurations and across the two tablets tested. Head and neck flexion angles during tablet use were greater, in general, than angles previously reported for desktop and notebook computing. Postural differences between tablets were driven by case designs, which provided significantly different tilt angles, while postural differences between configurations were driven by gaze and viewing angles. CONCLUSION: Head and neck posture during tablet computing can be improved by placing the tablet higher to avoid low gaze angles (i.e. on a table rather than on the lap) and through the use of a case that provides optimal viewing angles. PMID- 22246309 TI - Back pain among health care workers in Pennsylvania 2002-2006. AB - While back pain is common among health care workers in the United States, the epidemiology of back pain is unclear. OBJECTIVE: The purpose of this study was to estimate the incidence and trend of back pain from work-related injuries among health care workers. METHODS: Data from the Pennsylvania Work Injuries and Illnesses Reports from 2002 to 2006 were analyzed. RESULTS: Estimated back injuries account for 24.6% of all reported injuries in healthcare workers in Pennsylvania. From 2002 to 2006, there was a 22.5% increase in the incidence of reported back pain in this population. CONCLUSIONS: Due to a lack of detailed reports regarding the incidence of back pain among Pennsylvania healthcare workers, it is recommended that a survey of healthcare workers who perform patient handling be completed. PMID- 22246310 TI - Effect of backpack load carriage on cervical posture in primary schoolchildren. AB - OBJECTIVE: This study examined the effects of various backpack loads on elementary schoolchildren's posture and postural compensations as demonstrated by a change in forward head position. SUBJECTS: A convenience sample of 11 schoolchildren, aged 8-11 years participated. METHODS: Sagittal digital photographs were taken of each subject standing without a backpack, and then with the loaded backpack before and after walking 6 minutes (6MWT) at free walking speed. This was repeated over three consecutive weeks using backpacks containing randomly assigned weights of 10%, 15%, or 20% body weight of each respective subject. The craniovertebral angle (CVA) was measured using digitizing software, recorded and analyzed. RESULTS: Subjects demonstrated immediate and statistically significant changes in CVA, indicating increased forward head positions upon donning the backpacks containing 15% and 20% body weight. Following the 6MWT, the CVA demonstrated further statistically significant changes for all backpack loads indicating increased forward head postures. For the 15 & 20%BW conditions, more than 50% of the subjects reported discomfort after walking, with the neck as the primary location of reported pain. CONCLUSIONS: Backpack loads carried by schoolchildren should be limited to 10% body weight due to increased forward head positions and subjective complaints at 15% and 20% body weight loads. PMID- 22246311 TI - Narrative reflections on occupational transitions. PMID- 22246312 TI - Studies of the H-D exchange mechanism of malonganenone B. AB - Malonganenone B (1) exhibits an unusual H-D exchange of a formyl proton when in deuteric-NMR solvents. Synthetic and kinetic investigations were made to probe the mechanism of this exchange, which appears to occur via an uncommon and transient amine-amide NHC intermediate. PMID- 22246313 TI - Mapping of BnMs4 and BnRf to a common microsyntenic region of Arabidopsis thaliana chromosome 3 using intron polymorphism markers. AB - A recessive epistatic genic male sterile two-type line, 7365AB (Bnms3ms3ms4msRrfRf/BnMs3ms3ms4ms4RfRf), combined with the fertile interim maintainer 7365C (Bnms3ms3ms4ms4rfrf) is an effective pollination control system in hybrid rapeseed production. We report an effective strategy used to fine map BnMs4 and BnRf. The two genes were both defined to a common microsyntenic region with Arabidopsis chromosome 3 using intron polymorphism (IP) markers developed according to Arabidopsis genome information and published genome organization of the A genome. The near-isogenic lines 7365AC (Bnms3ms3ms4ms4Rfrf/Bnms3ms3ms4ms4rfrf) of BnRf and 736512AB (Bnms3ms3Ms4ms4RfRf/Bnms3ms3ms4ms4RfRf) of BnMs4 were constructed to screen developed markers and create genetic linkage maps. Nine polymorphic IP markers (P1-P9) were identified. Of these, P2, P3, P4, and P6 were linked to both BnMs4 and BnRf with genetic distances <0.6 cM. Three simple sequence repeat markers, SR2, SR3, and SR5, were also identified by using public information. Subsequently, all markers linked to the two genes were used to compare the micro collinearity of the regions flanking the two genes with Brassica rapa and Arabidopsis. The flanking regions showed rearrangements and inversion with fragments of different Arabidopsis chromosomes, but a high collinearity with B. rapa. This collinearity provided extremely valuable reference for map-based cloning in polyploid Brassica species. These IP markers could be exploited for comparative genomic studies within and between Brassica species, providing an economically feasible approach for molecular marker-assisted selection breeding, accelerating the process of gene cloning, and providing more direct evidence for the presence of multiple alleles between BnMs4 and BnRf. PMID- 22246315 TI - Single session removal of forgotten encrusted ureteral stents: combined endourological approach. PMID- 22246314 TI - The establishment of a standard and real patient kidney stone library utilizing Fourier transform-infrared spectroscopy with a diamond ATR accessory. AB - This investigation highlights the establishment of a real patient kidney stone library utilizing Fourier transform-infrared spectroscopy with a diamond attenuated total reflection accessory (FT-IR ATR) and the construction of a standard FT-IR ATR (sFTIRATR) library using OMNIC spectral math arithmetic operations for kidney stone analysis. This is necessary because reference spectra in commercial libraries provided with specialized software are usually complied using synthesized crystalline compounds which can exhibit changes in intensity, position and/or characteristic profile of reflectance bands when compared with authentic biological stone compositions. Currently, there is no published literature for the Republic of Ireland (RoI) on stone type and prevalence. The results obtained from the establishment of the real patient kidney stone library were a representative selection of kidney stones found in the population, and thereby provided an accurate picture of the present epidemiology of kidney stones in the RoI. The results of 188 patients were compared with those from our newly constructed sFTIRATR library and existing methods, namely wet chemical analysis, and FT-IR ATR utilizing an ATR algorithm and potassium bromide search libraries. We found that for the optimum quantitative analysis of kidney stone mixtures, FT IR ATR spectroscopy utilizing a standard FT-IR ATR library, supported by a real patient kidney stone library, applying library searching accurately provides the molecular and crystalline species of stone constituents present in an unknown kidney stone sample, providing some predicative value in diagnosing medical conditions. Our data suggest that the epidemiology for nephrolithiasis in the RoI is similar to other Western nations. PMID- 22246316 TI - Fluorescent conjugated block copolymer nanoparticles by controlled mixing. AB - Monitoring of the formation of stable fluorescent nanoparticles from controlled mixing of a THF solution of poly(fluorene ethynylene)-block-poly(ethylene glycol) in a microfluidic laminar flow crossjunction by spatially resolved fluorescence spectroscopy reveals the time scale of particle formation as well as incorporation of small molecule guests and the role of solvent mixing. PMID- 22246317 TI - Heat shock protein 90 is a promising target for effective growth inhibition of gastrointestinal neuroendocrine tumors. AB - Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is still unsatisfactory and innovative therapeutic approaches are urgently needed. Heat shock protein 90 (Hsp90) is overexpressed in a wide range of tumor types and is an emerging target for the treatment of cancer. However, the potential activity of Hsp90 inhibitors in GEP-NET has not yet been investigated. We studied the antineoplastic activity of the Hsp90 inhibitor IPI-504 on GEP-NET cells, and characterized its mechanism of action. In human insulinoma (CM) and pancreatic carcinoid (BON) cells IPI-504 induced a dose-dependent growth inhibition by almost 70%. The antiproliferative effect of IPI-504 correlated with a reduction in protein levels of the IGF-1 receptor. Additionally, several proteins of the PI3K/AKT/mTOR pathway, downstream of IGF-1 receptor activation in GEP-NETs, were downregulated as a consequence of Hsp90 inhibition. Combination treatment of IPI 504 with mTOR- or AKT-inhibitors led to additive antiproliferative effects. In addition, effects of IGF-1 receptor tyrosine kinase inhibition were strongly enhanced by IPI-504. Cancer gene expression profiling and FACS analysis revealed that IPI-504 antiproliferative effects were due to both induction of cell cycle arrest and apoptosis. A modified chick chorioallantoic membrane (CAM) assay confirmed the antineoplastic activity of IPI-504 in GEP-NETs in vivo. In conclusion, this study showed that Hsp90 inhibition may be an attractive target for innovative GEP-NET treatment alone or in combination with either IGF-1R or mTOR inhibitors. PMID- 22246318 TI - Exchange coupling and magnetic anisotropy of exchanged-biased quantum tunnelling single-molecule magnet Ni3Mn2 complexes using theoretical methods based on Density Functional Theory. AB - The magnetic properties of a new family of single-molecule magnet Ni(3)Mn(2) complexes were studied using theoretical methods based on Density Functional Theory (DFT). The first part of this study is devoted to analysing the exchange coupling constants, focusing on the intramolecular as well as the intermolecular interactions. The calculated intramolecular J values were in excellent agreement with the experimental data, which show that all the couplings are ferromagnetic, leading to an S = 7 ground state. The intermolecular interactions were investigated because the two complexes studied do not show tunnelling at zero magnetic field. Usually, this exchange-biased quantum tunnelling is attributed to the presence of intermolecular interactions calculated with the help of theoretical methods. The results indicate the presence of weak intermolecular antiferromagnetic couplings that cannot explain the ferromagnetic value found experimentally for one of the systems. In the second part, the goal is to analyse magnetic anisotropy through the calculation of the zero-field splitting parameters (D and E), using DFT methods including the spin-orbit effect. PMID- 22246319 TI - To be looked at as though air: civil attention matters. PMID- 22246320 TI - Welfare of farmed fish in present and future production systems. PMID- 22246321 TI - Effect of dietary Ergosan on growth performance, digestive enzymes, intestinal histology, hematological parameters and body composition of rainbow trout (Oncorhynchus mykiss). AB - Present study examined the effects of Ergosan on growth performance, digestive enzyme activities, hematological parameters and gastrointestinal structure of rainbow trout. Rainbow trout (mean weight 100-110 g) were fed basal diet (control) and diet treated with Aquavac Ergosan (5 g kg-1 of diet) for 50 days. Results of this study showed that Ergosan supplementation significantly increased weight gain (94.27 g vs. 65.04 g), specific growth rate (4.09 vs. 3.10) and feed intake (136.85 g vs. 111.22 g) and decreased feed conversion ratio (1.43 vs. 2.03) compared to control (P<0.05). Lipase activity and leukocyte and erythrocyte count also increased in juvenile fish fed Ergosan-treated diet compared to control (P<0.05). Light microscopy demonstrated that both groups of fish displayed normal morphology of proximal intestine and pyloric caeca. In Ergosan treated group, higher percentage of goblet cell was shown in proximal intestine and pyloric caeca. Present study suggests that Ergosan effectively promotes growth performance, lipase activity and gastrointestinal structure in rainbow trout. PMID- 22246322 TI - A novel sensor to map auxin response and distribution at high spatio-temporal resolution. AB - Auxin is a key plant morphogenetic signal but tools to analyse dynamically its distribution and signalling during development are still limited. Auxin perception directly triggers the degradation of Aux/IAA repressor proteins. Here we describe a novel Aux/IAA-based auxin signalling sensor termed DII-VENUS that was engineered in the model plant Arabidopsis thaliana. The VENUS fast maturing form of yellow fluorescent protein was fused in-frame to the Aux/IAA auxin interaction domain (termed domain II; DII) and expressed under a constitutive promoter. We initially show that DII-VENUS abundance is dependent on auxin, its TIR1/AFBs co-receptors and proteasome activities. Next, we demonstrate that DII VENUS provides a map of relative auxin distribution at cellular resolution in different tissues. DII-VENUS is also rapidly degraded in response to auxin and we used it to visualize dynamic changes in cellular auxin distribution successfully during two developmental responses, the root gravitropic response and lateral organ production at the shoot apex. Our results illustrate the value of developing response input sensors such as DII-VENUS to provide high-resolution spatio-temporal information about hormone distribution and response during plant growth and development. PMID- 22246323 TI - Multi-isotope imaging mass spectrometry reveals slow protein turnover in hair cell stereocilia. AB - Hair cells of the inner ear are not normally replaced during an animal's life, and must continually renew components of their various organelles. Among these are the stereocilia, each with a core of several hundred actin filaments that arise from their apical surfaces and that bear the mechanotransduction apparatus at their tips. Actin turnover in stereocilia has previously been studied by transfecting neonatal rat hair cells in culture with a beta-actin-GFP fusion, and evidence was found that actin is replaced, from the top down, in 2-3 days. Overexpression of the actin-binding protein espin causes elongation of stereocilia within 12-24 hours, also suggesting rapid regulation of stereocilia lengths. Similarly, the mechanosensory 'tip links' are replaced in 5-10 hours after cleavage in chicken and mammalian hair cells. In contrast, turnover in chick stereocilia in vivo is much slower. It might be that only certain components of stereocilia turn over quickly, that rapid turnover occurs only in neonatal animals, only in culture, or only in response to a challenge like breakage or actin overexpression. Here we quantify protein turnover by feeding animals with a (15)N-labelled precursor amino acid and using multi-isotope imaging mass spectrometry to measure appearance of new protein. Surprisingly, in adult frogs and mice and in neonatal mice, in vivo and in vitro, the stereocilia were remarkably stable, incorporating newly synthesized protein at <10% per day. Only stereocilia tips had rapid turnover and no treadmilling was observed. Other methods confirmed this: in hair cells expressing beta-actin-GFP we bleached fiducial lines across hair bundles, but they did not move in 6 days. When we stopped expression of beta- or gamma-actin with tamoxifen-inducible recombination, neither actin isoform left the stereocilia, except at the tips. Thus, rapid turnover in stereocilia occurs only at the tips and not by a treadmilling process. PMID- 22246325 TI - Preventing pandemics: The fight over flu. PMID- 22246324 TI - Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. AB - Autophagy defends the mammalian cytosol against bacterial infection. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin 8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol. PMID- 22246328 TI - Esomeprazole relieves upper gastrointestinal symptoms in high-risk and average risk NSAID users in daily clinical practice: results from an open-label study. AB - OBJECTIVE: To investigate whether esomeprazole can provide relief for nonsteroidal anti-inflammatory drug (NSAID)-associated upper gastrointestinal symptoms in patients at different gastrointestinal risk. METHODS: A multicentre, prospective, open-label study was conducted, wherein NSAID users visiting their general practitioner for upper gastrointestinal symptoms were asked to participate. Patients were treated with 20 mg esomeprazole and treatment effect was evaluated within 8 weeks. Response was defined as a maximum of 1 day per week with gastrointestinal symptoms during the last week of treatment. Partial response was defined as more than 50% improvement in the number of days per week with symptoms compared with baseline. Patients not meeting the above-mentioned criteria were classified as nonresponders. Patients who completely responded were compared with partial responders and nonresponders and were analysed according to their baseline gastrointestinal risk. RESULTS: A total of 1042 patients (mean age: 57 years; standard deviation: 15; 43% male) were analysed. Complete response, partial response and nonresponse were achieved in 57, 24 and 19% of the patients, respectively. Similar response was seen in average-risk and high-risk patients (58 and 56%; P=0.46) and in nonselective NSAID and selective cyclooxygenase-2 users (57 and 53%; P=0.32). CONCLUSION: Esomeprazole (20 mg) improved NSAID-associated upper gastrointestinal symptoms. Baseline gastrointestinal risk did not influence esomeprazole effectiveness. PMID- 22246326 TI - Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. AB - Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter, but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with submicrometre resolution. Here we apply MIMS to diverse organisms, including Drosophila, mice and humans. We test the 'immortal strand hypothesis', which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labelling mice with (15)N-thymidine from gestation until post-natal week 8, we find no (15)N label retention by dividing small intestinal crypt cells after a four-week chase. In adult mice administered (15)N-thymidine pulse-chase, we find that proliferating crypt cells dilute the (15)N label, consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of principle studies of lipid turnover in Drosophila and translation to the human haematopoietic system. These studies show that MIMS provides high-resolution quantification of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research. PMID- 22246327 TI - Promoter methylation of MGMT, MLH1 and RASSF1A tumor suppressor genes in head and neck squamous cell carcinoma: pharmacological genome demethylation reduces proliferation of head and neck squamous carcinoma cells. AB - Promoter hypermethylation of tumor suppressor genes (TSGs) is a common feature of primary cancer cells. However, to date the somatic epigenetic events that occur in head and neck squamous cell carcinoma (HNSCC) tumorigenesis have not been well defined. In the present study, we analyzed the promoter methylation status of the genes mutL homolog 1 (MLH1), Ras-association domain family member 1 (RASSF1A) and O-6-methylguanine-DNA methyltransferase (MGMT) in 23 HNSCC samples, three control tissues and one HNSCC cell line (UM-SCC 33) using methylation-specific PCR (MSP). The expression of the three proteins was quantified by semi-quantitative immunohistochemical analysis. The cell line was treated with the demethylating agent 5-azacytidine (5-Aza) and the methylation status after 5-Aza treatment was analyzed by MSP and DNA sequencing. Proliferation was determined by Alamar blue staining. We found that the MGMT promoter in 57% of the analyzed primary tumor samples and in the cell line was hypermethylated. The MLH promoter was found to be methylated in one out of 23 (4%) tumor samples while in the examined cell line the MLH promoter was unmethylated. The RASSF1A promoter showed methylation in 13% of the tumor samples and in the cell line. MGMT expression in the group of tumor samples with a hypermethylated promoter was statistically significantly lower compared to the group of tumors with no measured hypermethylation of the MGMT promoter. After treatment of the cell line with the demethylating agent 5-Aza no demethylation of the methylated MGMT and RASSF1A genes were determined by MSP. DNA sequencing verified the MSP results, however, increased numbers of unmethylated CpG islands in the promoter region of MGMT and RASSF1A were observed. Proliferation was significantly (p<0.05) reduced after treatment with 5 Aza. In summary, we have shown promoter hypermethylation of the tumor suppressor genes MGMT and RASSF1A in HNSCC, suggesting that this epigenetic inactivation of TSGs may play a role in the development of HNSCC. 5-Aza application resulted in partial demethylation of the MGMT and RASSF1A TSGs and reduced proliferation of the tumor cells suggesting further evaluation of 5-Aza for HNSCC treatment. PMID- 22246329 TI - The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease-induced liver injury: a study in the general population. AB - BACKGROUND AND AIM: Leptin and adiponectin have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). However, the usefulness of adipocytokines as a screening tool for nonalcoholic steatohepatitis (NASH) and fibrosis could not be evaluated in the general population due to the invasive nature of liver biopsy. The aim was to evaluate the association between adipocytokines and presumed liver injury in the general population using noninvasive biomarkers. METHODS: A cross-sectional study of 375 individuals, sampled from the National Health Survey was conducted. The exclusion criterion was any known secondary etiology for liver disease. Anthropometrics, serum leptin, adiponectin, insulin, lipids, and FibroMax were measured. RESULTS: Three hundred and thirty-eight individuals met the inclusion criteria and had valid FibroMax. Fibrosis diagnosed by the FibroTest was found in 25.7% of the patients, of whom 12.8% had significant fibrosis. Steatohepatitis was diagnosed by the NASH test in 0.9% and borderline NASH in 31.4% of the patients. Adiponectin was an independent negative correlate of borderline NASH [odds ratio (OR): 0.92; 95% confidence interval (CI): 0.86-0.98/1 ug/ml] together with high-density lipoprotein, and leptin was a positive correlate (OR: 1.03; CI: 1.01-1.06/1 ng/ml), together with abdominal obesity, serum triglycerides, and HbA1C. The OR for borderline NASH was 20.7 (CI: 7.5-57.5) when both high leptin (upper quartile) and suboptimal adiponectin were present, adjusting for age and sex. The FibroTest was not associated with leptin and adiponectin. The strongest predictors for fibrosis were age, sex, abdominal obesity, and insulin. CONCLUSION: Low adiponectin and high leptin and the combination of both have a strong independent association with presumed early-stage NASH. However, early stage fibrosis cannot be predicted by these adipocytokines. PMID- 22246330 TI - The use of antiendotoxin peptides in obstructive jaundice endotoxemia. AB - BACKGROUND: Two novel antiendotoxin peptides, P6 and C1, may reduce the inflammatory response. This study aimed to determine the effect of endotoxin on hepatic cytokine response and to assess P6 and C1-related attenuation of the proinflammatory response to endotoxemia, in experimental biliary obstruction. MATERIALS AND METHODS: 15 Male Wistar rats were randomized to one of three groups: bile duct ligation (BDL)+P6 (n=5), BDL+C1 (n=5), and BDL+no peptide (n=5). Rats were weighed and underwent BDL surgery on day 1. On day 8, the rats were reweighed and isolated hepatic perfusion was carried out. P6 or C1 peptide (10 MUmol/l) was preincubated with 300 ml of endotoxin-containing Krebs perfusate. After perfusion of 10 min with endotoxin-free perfusate, the livers were perfused for another 10 min with 300 ml of perfusate-containing endotoxin on its own or endotoxin plus peptide. This was followed by a further 100 min of perfusion with endotoxin-free perfusate. Effluent perfusate was collected at 20 min intervals for subsequent biochemical and cytokine analyses. RESULTS: Perfusion with endotoxin+P6 or endotoxin+C1 resulted in no significant difference in weight loss, or interleukin-6 response compared with perfusion with endotoxin alone. However, perfusion with endotoxin+P6 or endotoxin+C1 significantly reduced the tumor necrosis factor-alpha response to portal endotoxemia compared with perfusion with endotoxin alone. CONCLUSION: This study demonstrates that novel antiendotoxin peptides may attenuate the hepatic inflammatory response in portal endotoxemia. In obstructive jaundice, preoperative peptide administration may reduce endotoxin-related postoperative complications. PMID- 22246331 TI - Effect of prophylactic antibiotic drops on ocular microbiota and physiology during silicone hydrogel lens wear. AB - PURPOSE: Bacterial contamination of the contact lens surface has been demonstrated to cause corneal infiltrative events. A reduction in the rate of bacterially driven corneal infiltrative events associated with lens wear is one of the major goals of the contact lens industry. There is a concern over the potential of any antimicrobial strategy that there will be unwanted changes to the ocular microbiota or the development of resistance to the antimicrobial. The aim of this study was to investigate the effect of prophylactic topical antibiotic instillation during continuous wear of silicone hydrogel lenses on the normal ocular microbiota, the throat microbiota, and the ocular physiology. METHODS: Forty-two male subjects were dispensed with lotrafilcon A silicone hydrogel contact lenses for a 3-month, 30 night continuous wear, monthly replacement trial. Subjects were randomized into either tobramycin 0.3% (test) or saline (control) drop group. Two drops were instilled into each eye on waking and before sleep. At monthly visits, lenses were collected aseptically, and ocular and throat swabs were performed, followed by standard microbial recovery and identifications. Any corneal infiltrative event at scheduled or unscheduled visits was recorded. RESULTS: Numbers of microbes recovered from eye swabs from the tobramycin (test) group were significantly lower than the control (p = 0.01). Gram-positive cocci were recovered less frequently from the test group (p = 0.001). There were no significant differences in the numbers and types of microbes recovered from lens samples, or the contamination rate of the lenses between the two groups. There were no changes in the numbers of fungi or bacteria from throat swabs. There was no evidence of changes to resistance profile of microbes in the throat. More eye swabs from the test group (68.5%) were culture negative than swabs from control (46.5%; p = 0.002). The test group had less corneal staining superiorly (0.0 +/- 0.0 vs. 0.3 +/- 0.4; p = 0.025) but increased bulbar redness (2.2 +/- 0.5 vs. 1.5 +/- 0.4; p < 0.001) at the 3-month visit only, compared with control group. CONCLUSIONS: Overall, there appeared to be a minimal safety risk with 3-month's prophylactic antibiotic drop use during continuous wear of silicone hydrogel lenses. Clinically, antibiotic drop use induced a mild to moderate increase in bulbar redness by the 3-month time-point. Antibiotic use reduced microbiota on lids but did not affect the microbiota of the throat or change resistance to tobramycin. PMID- 22246332 TI - Madarosis as an indicator for malignancy in eyelid margin lesions. AB - PURPOSE: The purpose of this study was to determine the sensitivity of madarosis as an indicator for malignancy in eyelid lesions affecting the lid margin. METHODS: A retrospective medical record review was completed for patients who were diagnosed with lesions affecting the eyelid margin which were suspicious for malignancy. Suspicion was determined by considering an array of factors, including lesion characteristics, Fitzpatrick score, sun exposure history, and history of skin cancer. Presence of madarosis was assessed by clinical examination, and presence of malignancy was determined by biopsy. RESULTS: The association between madarosis and malignancy was statistically significant (p <= 0.001). Madarosis had a sensitivity of 0.643 and a specificity of 0.882 when used as a sole indicator for malignancy. The odds of malignancy were 13.4 times higher in the presence of madarosis. CONCLUSIONS: Madarosis is more common in malignant eyelid margin lesions than benign lesions. If madarosis is present, there is a 69.23% chance that the lesion is malignant. Therefore, biopsy of any suspicious lesion that demonstrates madarosis is recommended. However, many malignant eyelid margin lesions do not demonstrate madarosis, and so the sensitivity of madarosis as a sole indicator for malignancy is poor. In the absence of madarosis, it is important to consider other factors when determining malignant potential of eyelid lesions. PMID- 22246333 TI - Relation between upper and lower lids' meibomian gland morphology, tear film, and dry eye. AB - PURPOSE: To analyze relations between upper lid (UL) and lower lid (LL) meibomian gland (MG) morphology and tear film and the MG criteria ability to predict dry eye. METHODS: MG, lipid layer, and non-invasive break-up time (NIBUT) were evaluated of the OD of 20 randomly selected subjects (female = 10; median age = 44.5 years, interquartiles = 39.5 to 55 years). Subjects were grouped into nine Ocular Surface Disease Index (OSDI)- and 11 OSDI+ by the OSDI. Non-contact infrared meibography and image analysis were performed to evaluate MG loss, MG thickness, and MG bent angle. RESULTS: MG loss (Pearson correlation; r = 0.647, p = 0.003) and MG bent angle (r = 0.489, p = 0.027) were significantly correlated between lids, but MG thickness was not (r = -0.059, p = 0.413). MG loss was significantly (t-test; p = 0.048) less in the UL (median = 26.9%; LL = 32.3%), thicker in the LL (p < 0.001) and were more bent in the LL (p = 0.001). MG loss was significantly correlated to lipid-layer thickness (r < -0.597, p < 0.003) and NIBUT (r < -0.453, p < 0.030), whereas MG thickness and bent angle of the UL only were related to NIBUT (r < -0.563, p < 0.018). Combining MG loss of both lids (linear regression analysis) resulted in the best predictive ability of OSDI+/- (area under the receiver operative characteristic curve = 0.929, p = 0.001). CONCLUSIONS: MG scores between lids were significantly different but correlated. MG loss was significantly correlated to tear film characteristics including lipid layer thickness and stability. MG thickness and bent angle of the UL were related to NIBUT. The combination of both lids' MG loss showed best predictive ability of dry eye. PMID- 22246334 TI - Assessment of axial length measurements in mouse eyes. AB - PURPOSE: To compare measurements of murine ocular axial lengths (ALs) made with 780 nm partial coherence interferometry (PCI) and 1310 nm spectral domain-optical coherence tomography (SD-OCT). METHODS: AL was measured at postnatal day (P) 58 in C57BL/6J mice. Repeated AL measurements were taken using a custom-made 780 nm PCI and a commercial 1310 nm SD-OCT. Intra- and interuser variability was assessed along the central optical axis and 2-degree off-axes angles with the SD OCT. Data were collected and analyzed using Cronbach alpha (alpha), Bland-Altman coefficient of repeatability, agreement plots, and intraclass correlation coefficients (ICC). RESULTS: AL measurements agreed well between the two instruments (3.262 +/- 0.042 mm for PCI; 3.264 +/- 0.047 mm for SD-OCT; n = 20 eyes). The ICC for PCI compared with SD-OCT was 0.92, confirming high agreement between the two instruments. Intrauser ICC for the PCI and SD-OCT were 0.814 and 0.995, respectively. Similarly, interuser ICC for PCI and SD-OCT were 0.970 and 0.943, respectively. Using SD-OCT, a 2-degree misalignment of the eye along the horizontal meridian produced mean differences in AL of -0.002 +/- 0.017 mm relative to the centrally aligned images, whereas similar misalignment along the vertical meridian created 0.005 +/- 0.018 mm differences in AL measurements. CONCLUSIONS: AL measurements from the 780 nm PCI and 1310 nm SD-OCT correlate well. Multiple statistical indices indicate that both instruments have good precision and agreement for measuring murine ocular AL in vivo. Although the vertical meridian had the greater variability in AL in the small mouse eye; 2 degree off-axes differences were within the SD of centrally aligned AL. PMID- 22246335 TI - Neurodevelopmental functioning of infants with untreated single-suture craniosynostosis during early infancy. AB - PURPOSE: Single-suture craniosynostosis (SSC) is a congenital craniofacial disorder, in which premature fusion of one of the skull sutures restricts and distorts growth of the cranium and underlying brain. This disorder of prenatal onset occurs during a critical phase of rapid growth and development of the immature brain. Craniosynostosis carries a known risk of developmental impairment. The neurodevelopmental sequelae of SSC prior to treatment remains however incompletely understood. This study sought to determine the neurodevelopmental sequelae of untreated single-suture craniosynostosis during early infancy. METHODS: Fifty-six consecutive patients with unoperated SSC (sagittal, metopic and unicoronal) comprised the sample cohort. Patients were aged between 4 and 16 months (M = 8.9 months, SD = 2.9 months). Neurodevelopmental functioning was assessed with the mental (Mental Development Index) and motor (Psychomotor Development Index) scales of the Bayley Scales of Infant Development, second edition. RESULTS: Children with SSC displayed significantly lower mean mental (M = 97.7, SD = 6.7, p < 0.05) and motor (M = 87.7, SD = 13.0, p < 0.001) scores than normative population averages. The distribution of these scores also differed significantly from the normative distribution; an increased rate of significant motor developmental delay was found, and none of the children displayed accelerated development. Subgroup comparisons between the primary diagnostic subtypes in this sample revealed no significant differences in mental or motor skill functioning. CONCLUSIONS: Untreated SSC is associated with an increased incidence of developmental delay during early infancy, with motor skills appearing the most vulnerable to impairment during this developmental phase. PMID- 22246336 TI - Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system. AB - PURPOSE: The aim of this study is to elucidate the preventive effect of folic acid (FA) on teratogenic effects of valporic acid (VA) in early stage chick embryos on neural tube development. MATERIALS AND METHODS: One hundred and fifty specific pathogen-free (SPF) chick eggs were used to investigate the neurulation in five groups. Group A was the control group. Group B was injected 0.02 ml of saline (0.9% NaCl) and was used for sham group. VA (0.72 mg) in 0.02 ml saline was injected in Group C, and 0.342 mcg of FA in 0.02 ml NaCl were administered to the embryos in Group D. VA (0.72 mg) + 0.342 mcg of FA in 0.02 ml saline were administered simultaneously to the eggs in Group E. At the end of 72 h, all embryos were extracted from eggs and were fixed, and for histological analyses hematoxylin and eosine was used, for detection of apoptotic cells terminal deoxyribonucleotide transferase-mediated dUTP-X nick end labeling (TUNEL) was used and for distribution of P53, bcl-2 and caspase-3, caspase-6, caspase-8 and caspase-9 immunoperoxidase techniques were used. RESULTS: While there were no neural tube defects in the embryos of groups A, B and D, eight embryos died in group C and there were 12 embryos with retarded embryological development. In contrast to that, no death was observed in group E, but only eight embryos were detected with maldevelopmental delay stage. CONCLUSION: These results suggested that VA may induce apoptotic mechanisms but not through the p53 pathway. In addition, FA effectively prevents the teratogenic influence of VA on chick embryo at neurulation stages by stopping cascade of apoptosis before caspase 3 expression. PMID- 22246338 TI - Unusual dural substitute complications in pediatric patients. PMID- 22246337 TI - Biologic tumor behavior in pilocytic astrocytomas. AB - PURPOSE: The aim is to describe the behavior of pilocytic astrocytoma (PAs) and its effects on patient prognosis by using flow cytometric, immunohistochemical and cytogenetic methods. We also aim to find out whether there is any difference between differently localized tumors by the above mentioned analyses. METHODS: We studied DNA index, expression of p53, p16, pRb, MMAC/PTEN1, VEGF, MIB-1 index and chromosomal anomalies which can be detected by array comparative genomic hybridization (CGH) technique. We analyzed the association of the results of these studies with clinical prognosis and tumor localization. We included 53 patients (18 cerebellar, 20 chiasmatic/hypothalamic and 15 hemispheric). Samples were studied from paraffin embedded tumors. RESULTS: We found that PAs are mostly diploid and ploidy pattern does not affect the prognosis. The expression of p53, p16, pRb, MMAC/PTEN1 and VEGF was not significantly different between different localizations and could not predict the prognosis. Frequently seen copy number aberrations (CNAs) are: amplification in 1p36.33, 2p11.2, 9p11.2, 9q12, 16p11.2, 19q13.12-q13.2, Xp22.2-p21.3, Xp11.3-p11.22, Xq11.1-q12, Xq13.1, Xq21.1-q21.31, Xq22.3, Xq26.3 and homozygous deletion in 2p11.2, 8p23.1, 16p12.3. Among them, 2p11.2 amp, 9p11.2 amp and 1p36.21 hom del were correlated with prognosis. Moreover, we found a significant correlation between 16p11.2 amp and tumor localization. CONCLUSIONS: Differently localized PAs have different properties which make them behave with different biological aggressiveness. PAs demonstrate a significant amount of CNAs that can be detected by a high-resolution study. However, tumor suppressor genes p53, p16, pRb, MMAC/PTEN1 and expression patterns do not play a significant role in PAs. PMID- 22246339 TI - Treatment strategies for initially disseminated intracranial germinomas: experiences at a single institute. AB - PURPOSE: Initially disseminated intracranial germinomas (IDIGs) can be observed in pre-adult and adolescent brain tumor patients. However, the disease prognosis is undetermined, and the method of optimal treatment remains controversial. METHODS: From January 1990 to January 2011, data on 91 intracranial germinoma patients (<=20 years old) were gathered from the Pediatric Brain Tumor database at Taipei Veterans General Hospital. A total of seven patients with a median age of 17.0 years had IDIGs (lesion sites >2), including IDIGs in the ventricular system or the spinal column. Craniospinal irradiation (CSI) plus a primary or metastatic boost was the mainstay strategy for radiotherapy. Six out of a total of seven patients (85.7%) also received systemic chemotherapy (CHT) after radiotherapy. Survivals rates between IDIGs and patients without dissemination were estimated using the Kaplan-Meier method. RESULTS: The median follow-up time for all seven patients was 67.5 months (range, 10.3-142.3 months). None of the IDIG patients experienced a recurrence or mortality after the completion of treatment. The 5- and 10-year disease-free survival (DFS) between IDIG and non dissemination patients were 100%, 100%, 93.0% and 78.6%, respectively (p = 0.339). The 5- and 10-year overall survival (OS) between IDIGs and non dissemination cases were 100%, 100%, 93.7% and 89.4%, respectively (p = 0.473). CONCLUSIONS: IDIG patients did not show reduced survival compared to non dissemination patients if optimal radiotherapy and chemotherapy were used together. PMID- 22246340 TI - Wilhelm Fabricius von Hilden (Guilhelmus Fabricius Hildanus) 1560-1634: pioneer of early neurosurgery. AB - INTRODUCTION: Wilhelm Fabricius von Hilden, also known as Guilhelmus Fabricius Hildanus, became known as the father of German surgery. Hildanus had a strong interest in surgery of the adult and pediatric nervous systems and attempted to better understand the brain and its morphology. Moreover, as a surgeon, Hildanus performed many procedures that would be classified today as neurosurgery. These included treatment of empyema and depressed skull fractures. We highlight the life of Hildanus and his contributions to what would become the discipline of neurosurgery. CONCLUSIONS: In a broad view, Hildanus should be considered an early pioneer of this field of surgery. PMID- 22246342 TI - Sex and age differences in depression and baseline sport-related concussion neurocognitive performance and symptoms. AB - OBJECTIVE: To examine depression and baseline neurocognitive function and concussion symptoms in male and female high school and college athletes. DESIGN: Cross sectional. SETTING: Athletes completed testing at a designated computer laboratory at high schools and colleges. PARTICIPANTS: Participants included 1616 collegiate (n = 837) and high school (n = 779) athletes from 3 states participating in a variety of competitive sports. INTERVENTIONS: Participants completed the baseline Immediate Postconcussion Assessment and Cognitive Test (ImPACT), symptom inventory, and Beck Depression Inventory II (BDI-II). MAIN OUTCOME MEASURES: Between-group comparisons for depression groups on ImPACT composite scores (verbal and visual memory, reaction time, motor processing speed), total symptoms, and symptom cluster (sleep, cognitive, emotional, somatic/migraine) scores. Between-group comparisons for age and sex on BDI-II, ImPACT, total symptoms, and symptom cluster scores. RESULTS: The severe depression group scored worse on visual memory and reported more total, somatic/migraine, cognitive, emotional, and sleep symptoms than less depressed groups. High school athletes reported more somatic/migraine symptoms than collegiate athletes, whereas collegiate athletes reported more emotional and sleep symptoms than high school athletes. Women had higher verbal memory and reported more cognitive, emotional, and sleep symptom clusters compared with men. Women outperformed men on verbal memory, whereas collegiate athletes outperformed high school athletes on processing speed. CONCLUSIONS: Athletes with severe depression scored lower on visual memory than those with minimal depression. Athletes with severe depression report more concussion symptoms than athletes with minimal and moderate depression scores. Symptoms of depression should be included in baseline assessments to help disentangle depression from concussion symptoms. PMID- 22246341 TI - Prognostic implications of microRNA-100 and its functional roles in human epithelial ovarian cancer. AB - Dysregulation of microRNAs (miRNAs) has been found to be associated with a variety of diseases, including epithelial ovarian cancer (EOC). Recently, miR-100 was reported to be downregulated in human ovarian carcinoma, however, the clinical significance and functional roles of miR-100 expression in human EOC are unclear. TaqMan real-time quantitative RT-PCR assay was performed to detect the expression of miR-100 in 98 EOC tissues and 15 adjacent normal epithelial tissues. The relationship between miR-100 expression and clinicopathological factors in 98 EOC patients was statistically analyzed. The effect of miR-100 expression on patient survival was determined. Finally, the role of miR-100 in EOC cell growth and its possible mechanisms were analyzed with miR-100 precursor or inhibitor-transfected cells. We showed that the level of miR-100 was significantly lower in EOC tissues compared to adjacent normal tissues. Low miR 100 expression was found to be closely correlated with advanced FIGO stage, higher serum CA125 expression level and lymph node involvement. Also, low miR-100 expression was correlated with shorter overall survival of EOC patients, and multivariate analysis showed that the status of miR-100 expression was an independent predictor of overall survival in EOC. Additionally, miR-100 could affect the growth of EOC cells by post-transcriptionally regulating polo-like kinase 1 (PLK1) expression. Together, these results suggest that low miR-100 expression may be an independent poor prognostic factor and miR-100 can function as a tumor suppressor by targeting PLK1 in human EOCs. PMID- 22246343 TI - Hydration strategies of runners in the London Marathon. AB - OBJECTIVE: To explore the hydration strategies of marathon runners, their sources of information and knowledge about fluid intake in the marathon, and their understanding of exercise-associated hyponatremia (EAH). DESIGN: Anonymized questionnaire. SETTING: London Marathon. PARTICIPANTS: Marathon race participants. MAIN OUTCOME MEASURES: Responses regarding planned fluid consumption, volume to be consumed, volume of water and sports drink bottles, and the number of stations from which planning to take a drink. In addition, sources of information about appropriate drinking and understanding of hyponatremia. RESULTS: In total, 93.1% of the runners had read or been told about drinking fluids on marathon day and 95.8% of competitors had a plan regarding fluid intake. However, 12% planned to drink a volume large enough to put them at higher risk of EAH. Only 21.7% knew the volumes of water and sports drink bottles available on the course; 20.7% were planning to take a drink from all 24 water stations. Only 25.3% planned to drink according to thirst. Although 68.0% of the runners had heard of hyponatremia or low sodium levels, only 35.5% had a basic understanding of its cause and effects. CONCLUSIONS: Marathon runners lack knowledge about appropriate fluid intake to prevent hyponatremia on race day. Twelve percent reported drinking strategies that put them at risk of EAH. Effective educational interventions are still necessary to prevent overdrinking during marathons. PMID- 22246344 TI - Correlation between seminal oxidative stress biomarkers and antioxidants with sperm DNA damage in elite athletes and recreationally active men. AB - OBJECTIVE: To evaluate the seminal plasma 8-isoprostane, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), catalase, total antioxidant capacity (TAC), and levels of sperm DNA fragmentation in elite athletes and recreationally active men. DESIGN: Prospective design was used for this study. SETTING: The study was performed in the Exercise Physiology Laboratory of the Urmia University. PARTICIPANTS: Fifty-six elite athletes and 52 recreationally active men (18-28 years) participated in this study. INTERVENTION: All subjects had a semen sampling at baseline. MAIN OUTCOME MEASURES: Total antioxidant capacity and SOD activity were measured by colorimetric assay. Levels of ROS were measured by a chemiluminescence assay. Malondialdehyde levels were measured by thiobarbituric acid reactive substance assay. Catalase activity was measured by monitoring the initial rate of disappearance of hydrogen peroxide. Concentration of free 8-isoprostane was measured by enzyme immunoassay method. Sperm DNA fragmentation was evaluated with the terminal deoxynucleotidyl transferase-mediated fluorescein dUTP nick end-labeling assay. RESULTS: Recreationally active men have significantly higher levels of body fat, seminal SOD, TAC, and catalase and lower levels of V[Combining Dot Above]O2max, seminal ROS, MDA, and 8-isoprostane and subsequently lower rate of sperm DNA fragmentation when compared with elite athletes (P < 0.001). Significantly negative correlation was observed between sperm DNA fragmentation with body fat, seminal SOD, catalase, and TAC levels (P < 0.001). Significantly positive correlation was observed between sperm DNA fragmentation with V[Combining Dot Above]O2max, seminal 8-isoprostane, ROS, and MDA levels (P < 0.001). CONCLUSION: Spermatozoa from recreationally active men may be less susceptible to oxidative stress-induced DNA damage and hence infertility. PMID- 22246345 TI - Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge. AB - SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges. PMID- 22246346 TI - Programming human pluripotent stem cells into white and brown adipocytes. AB - The utility of human pluripotent stem cells is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into white or brown adipocytes. We found that inducible expression of PPARG2 alone or combined with CEBPB and/or PRDM16 in mesenchymal progenitor cells derived from pluripotent stem cells programmed their development towards a white or brown adipocyte cell fate with efficiencies of 85%-90%. These adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers and had mature functional properties such as lipid catabolism and insulin-responsiveness. When transplanted into mice, the programmed cells gave rise to ectopic fat pads with the morphological and functional characteristics of white or brown adipose tissue. These results indicate that the cells could be used to faithfully model human disease. PMID- 22246347 TI - N-heterocyclic carbene-mediated hydroacylation-Sonogashira/Heck/Suzuki coupling in a single pot: a new cascade reaction. AB - A dually NHC-catalyzed reaction cascade comprising an initial hydroacylation of an activated ketone and subsequent Sonogashira/Heck/Suzuki coupling in the same pot is reported. The reaction mechanism and scope of the methodology is presented. PMID- 22246348 TI - Blockade of irradiation-induced autophagosome formation impairs proliferation but does not enhance cell death in HCT-116 human colorectal carcinoma cells. AB - This work was undertaken to gain further information on the molecular mechanisms underlying autophagosome formation and its relation with tumor cell survival in response to radiation in colon cancer. A human colon cancer cell line, HCT-116, was examined with respect to cell survival after blockade of irradiation-induced autophagosome formation by pharmacological interference. Autophagosome formation was confirmed using a kinetic study with incorporated bovine serum albumin gold conjugate (BSA-Au) analyzed by electron microscopy and an autophagosome associated LC3B antibody measured by immunofluorescence and Western blotting. Annexin V/PI double staining was used to monitor cell death by apoptosis, and cell cycle profiles by flow cytometry. Ionizing radiation (IR) promoted autophagosome formation in the HCT-116 IR-surviving cells. Pharmacological interference showed that PI3K/Akt and Src were involved in early stages of autophagosome formation. IR alone decreased cell proliferation by arresting cells in the G2/M phase, and pharmacological interference of autophagosome formation decreased proliferation, but did not affect cell survival. Also, our data suggest that decreased proliferation caused by PI3K and Src inhibitors could be through S phase cell cycle delay. Our results clearly indicate that blockade of IR-induced autophagosome formation impairs proliferation but does not enhance cell death in colon cancer cells. PMID- 22246349 TI - [Axonal sprouting of somatostatin positive interneurons in the hippocampus in epileptic rats]. AB - OBJECTIVE: To investigate the axonal sprouting of somatostatin(SS) positive interneurons in temporal lobe epilepsy. METHODS: 6-8 week-old healthy male SD rats were divided randomly into an epileptic group (treated by lithium and pilocarpine intraperitoneal injection) and a control group (by lithium and normal sodium intraperitoneal injection). Each group was randomly divided into 5 subgroups at 1,7,15,30, amd 60 d after the injection. Immunohistochemistry method was used to detect the number changes of SS or neuronal nuclei (NeuN) positive neurons in different domains of the hippocampus at different time points in each group, and the coexpression of SS positive interneurons combined with NeuN was detected by double immunofluorescence to observe the dynamic changes and axonal sprouting of SS positive interneurons. RESULTS: The number of SS neurons in the experimental group exceeded that in the control group in the CA1 area at 60 d post-status epileptieus SE (P<0.01), and numerous SS positive fibers were seen throughout the layers of the CAl area at 60 d post-SE. NeuN positive neurons in the stratum oriens and stratum radiatum layers in the initiation site of the CA1 area were beyond normal at 60 d post-SE. The number of double labeled SS interneurons gradually rose at 15 d in stratum oriens of CA1, and even exceeded that of the controls in the stratum oriens and stratum radiatum layers of CA1 at 60 d. CONCLUSION: The numerous SS positive fibers throughout the layers of the CAl area at 60 d post-SE come from the increased interneurons in the stratum oriens and stratum radiatum layers of CA1 area. The pathological axonal sprouting may play an important role in the generation and compensation of temporal lobe epilepsy. PMID- 22246350 TI - [Molecular genetic research of a case of Bx subgroup]. AB - Serologic characters of Bx subtype were analyzed with standard Methods , PCR-SSP method was used for its genotype, and DNA sequences of 6 and 7 exons of ABO genes were analyzed by DNA sequencing. Serologically, the anti-B test was no or 1+, with anti-AB (1+ or 2+). The patient's auto antibodies were negative. PCR-SSP showed the patient was Bx02/O2. ABO genetic locus sequencing was 261delG in exon 6 and 297 was GG homozygous. The sample was a combination of blood group B and O2 because 297A> G, 526C> G, 657C> T, 703G> A, 796C> A, 803G> C, 905A> G, 930A> G shown by direct DNA sequencing and 803G> C, 905A> G shown by cloning DNA sequencing. The serological phenotype of the specimen was B and the genetic sequence was a combination of ABO*Bx.02.1.1 and ABO*O21.01.1.1. PMID- 22246351 TI - A clinical trial of xenotransplantation of neonatal pig islets for diabetic patients. AB - OBJECTIVE: To ascertain the safety and function of the transplantation of neonatal pig islets (NPIs) for diabetic patients. METHODS: NPIs were injected into the hepatic artery of 22 patients. After the transplantation, the patients were treated with a multiple drug immunosuppressive regimens. The first 14 patients were treated with cyclosporine (CsA), mycophenolate mofetil (MMF) and prednisolon, and porcine C-peptide was not monitored, the following 2 patients were given cyklosporin and MMF only, while the next 6 patients were given a quadruple drug regimen consisting of OKT3, takrolimus, sirolimus and prednisolon. The blood glucose levels,exogenous insulin requirement,HbA1c, porcine endogenous retrovirus (PERV) and liver function were assessed before and after NPI transplantation. The serum porcine C peptide were monitored in last 8 patients. RESULTS: The first 14 patients required less insulin and the HbA1c dropped after the transplantation. In the 2 subsequent patients, the metabolic parameters remained unchanged and monitor of porcine C-peptide was negative. Insulin requirements were reduced in all 6 patients, and HbA1c was normalized 3 months after the transplantation. Significant levels of porcine C-peptide were detected in the patient serum. Two of the patients were given a second injection of NPIs, and one of them became insulin independent for 7 d. No serious adverse events were noted after the transplantation. There was no evidence of PERV transmission. Six out of the 22 patients were followed up for 4-6 years after the NPIs injection, immunosuppressive treatment was stopped 1 year after the transplantation. The patients started to take insulin at the time of follow up. Four patients restricted the intake of sugar, while the other 2 did not. One patient had ketoacidosis twice and slight diabetic retinopathy, and another patient had ketoacidosis induced by acute gastroenteritis. The remaining 4 patients did not have any complications. Assays for PERV were again negative. CONCLUSION: Xenogenic islets can survive and function in the human body. No serious adverse events are noted. PMID- 22246352 TI - [Health safety of the offspring after orthotopic fetal ovarian allotransplantation in rats]. AB - OBJECTIVE: To investigate the health safety of the offspring delivered following natural pregnancy after orthotopic fetal ovarian allotransplantation in rats. METHODS: Any symptoms of spontaneous abortion during pregnancy and of any possible still birth and death of infant rats within 3 days after the delivery were observed and compared in 19 pregnant rats (the study group) after the orthotopic fetal ovarian allotransplantation and in another 10 pregnant rats (the control group). Forty offspring rats from each group were selected randomly. The mean weight at day 35 after the birth of offsprings was measured and compared. By routine G-banding technique, the karyotype was analyzed and the chromosomal number and structure were observed. RESULTS: There was no spontaneous abortion, still birth, or death in the infants within 3 days after the birth in both groups. The body weight of offsprings at 35 days in both groups was (93.80 +/- 4.93) g and (94.13 +/- 4.53) g, respectively. There was no significant difference between the 2 groups (P> 0.05). The karyotype analysis indicated that the karyotype from both offspring groups was 42, XX or 42, XY. No chromosome abnormality (abnormal chromosomal number or abnormal chromosomal structure) was observed in both groups. CONCLUSION: The health status of the offsprings of rats after orthotopic fetal ovarian allotransplantation is safe. PMID- 22246353 TI - [Effect of transfection of enhanced green fluorescent protein gene on neuron like differentiation of rat mesenchymal stem cells]. AB - OBJECTIVE: To determine the effect of transfection of enhanced green fluorescent protein (EGFP) on neuron-like differentiation of rat mesenchymal stem cells (rMSC) with plasmid vector. METHODS: In vitro cultured rMSC was transfected with plasmid vector containing EGFP, and its surface marker and differentiation neuron like cells were detected. Results There was no significant difference in the morphology and surface markers between the EGFP-rMSC and rMSC. The cell surface markers of EGFP-rMSC including expression of CD44(+),CD11b (-) and CD45(-) remained similar to those of rMSC. EGFP-rMSC presented the differentiated potential to neuron-like cells. There was no statistical difference in the positive ratio of neuron-like differentiation between the EGFP-rMSC and rMSC (P> 0.05). CONCLUSION: EGFP does not affect the neuron-like differentiation potential of rMSC, and can be used as the trace marker in the study of differentiation potential of rMSC. PMID- 22246354 TI - [Expression of EphA7 and MTDH and clinicopathological significance in the squamous cell cancer of the tongue]. AB - OBJECTIVE: To determine the expression levels of EphA7 and MTDH and detect their clinicopathological significance in the peritumoral normal tissues and the squamous cell cancer of the tongue. METHODS: Envision immunohistochemistry was used to assay the expression levels of EphA7 and MTDH in the conventional paraffin-embedded sections from specimens of squamous cell cancer (n=45) and peritumoral normal tissues (n=10). RESULTS: The positIVe rates of EphA7 and MTDH were significantly higher in the squamous cell cancer than those in the peritumoral normal tissues ( chi(2)(EphA7)=4.14; chi(2)(MTDH)= 5.25; P < 0.05). The positIVe rates of EphA7 and MTDH expression were significantly lower in the cases of histological grade I-II,clinical stage I-II, and no-metastasis of neck lymph node than those in the histological grade III-IV, clinical stage III-IV, and metastasis of neck lymph node (P <0.05 or P <0.01). CONCLUSION: The expression levels of EphA7 and/or MTDH might have important effect on the carcinogenesis and progression of tongue cancer. Overexpression of EphA7 and/or MTDH might have poor prognosis. PMID- 22246355 TI - [Treatment and classification of thoracic fracture accompanied with sternum fracture]. AB - OBJECTIVE: To determine the characteristics, classification, and treatment of thoracic fracture accompanied with sternum fracture. METHODS: Data of 32 patients with thoracic fractures accompanied with sternum fracture were reviewed. Patients information such as age, gender, cause of injury, site of sternum fracture, level and type of thoracic vertebral fracture, spinal cord injury and associated injuries was included in the analysis. Of the 32 patients, 13 had compressed fractures, 13 had fracture-dislocations, 5 had burst fracture and 1 had burst dislocation. Six patients had a complete lesion of the spinal cord, 13 sustained a neurologically incomplete injury, and the other 13 were neurologically intact. Ten patients were treated nonoperatively and the other 22 surgically. RESULTS: All patients were followed up for 10-103 months. Road traffic accidents and falling dominated among the causes. All patients were accompanied with other injuries. None of the 6 patients with a complete paralitic lesion regained any significant function. Of the 13 neurologically intact patients, 5 had local pain although 12 of them remained normal function. One patient showed tardive paralysis. Three of the 13 patients with incomplete paraplegia returned to normal, 5 regained some function and 5 did not recover. CONCLUSION: Thoracic fractures accompanied with sternum fracture are marked by violent force, severe fracture of the spine, severe injuries of the spinal cord, and high incidence of other injuries. The new classification method is more suitable to thoracic fractures accompanied with sternum fracture,and confirms the existence and clinical relevance of the 4th column of the thoracic spine and its role in providing spinal stability in patients with thoracic fracture. PMID- 22246356 TI - [Epigenetic mechanism of cardiac differentiation of stem cells]. AB - Epigenetics is a new branch of genetics which studies reversible and heritable changes of gene function that do not involve alterations in DNA sequence of nucleus. The epigenetic mechanism includes DNA methylation, post-translational histone modification, chromatin remodeling, microRNA regulation and so on. Some investigations have shown that epigenetic phenomena changes occur in the cardiac differentiation of stem cells. Drugs causing epigenetic modifications have been shown to induce the cardiac differentiation of stem cells. Epigenetics becomes a hot subject of research on the cardiac differentiation mechanism of stem cells providing new theories and Methods for stem cell application in developmental biology, genetics and regenerative medicine. PMID- 22246357 TI - Roles of toll-like receptors signaling in organ transplantation. AB - Organ transplantation is the gold standard of treatment for patients with end stage organ failure. However, transplant recipients must take immunosuppressive drugs lifelong to fight against rejection, which is inevitably caused by the recipient's immune system in response to transplanted foreign tissues. Despite advances in the prevention of acute rejection, it is still a significant and potentially devastating complication of solid organ transplantation. Moreover, chronic allograft dysfunction as a result of acute and chronic alloimmune mediated injury still develops in a majority of transplant recipients regardless of continuous immunosuppression. While host adaptive immune responses elicited by T lymphocytes are primarily responsible for allotransplant rejection, emerging evidence supports an important role of the innate immune system in the development of organ rejection. Innate immune recognition is initiated by a set of diverse receptors that belong to different protein families including the family of toll-like receptors (TLRs). TLR signaling is a highly specialized system that can identify a variety of microbial and endogenous mediators, and activate the innate immune system in response to danger. The discovery of TLRs over the past 10 years has started a new era in understanding the molecular events that initiate and regulate the inflammatory response following organ transplantation. They influence the adaptive immune reactions and contribute to ischemic reperfusion injury, acute and chronic allograft rejection, and tolerance induction. Their role as potential targets for therapeutic intervention has just begun to be appreciated. In this article, we summarize the structural and functional characteristics of TLRs and their ligands. We focus on the studies to define the roles of TLRs in ischemic reperfusion injury, allotransplant rejection, and immune regulation in both animal models and clinical transplantation. PMID- 22246358 TI - [siRNA-mediated tissue factor knockdown in porcine neonatal islet cell clusters in vitro]. AB - OBJECTIVE: To determine the genetic modification on neonatal porcine islet cell clusters (NICC) by small interfering RNA (siRNA)-mediated tissue factor (TF) knockdown in vitro. METHODS: Porcine NICC were transfected with 5 pairs of designed siRNA respectively or in different combinations with lipofectamine 2000. Transfected NICC were analyzed for TF gene by real-time PCR to select the siRNA which worked best. Meanwhile, the viability of NICC after the TF siRNA transfection was examined by FACS. The efficiency of TF gene and protein suppression was measured by real-time PCR and and FACS respectively. RESULTS: Real-time PCR and FACS showed that a 60% reduction in the TF gene expression and a 50% reduction in the protien level of TF on NICC were achieved by transfecting 3 pairs of selected siRNA. The siRNA transfection had no significant effect on the viability of NICC which was analyzed by FACS. CONCLUSION: The expression of TF on porcine NICC is efficiently suppressed by 3 pairs of designed siRNA in vitro. PMID- 22246359 TI - IL-17 in the early diagnosis of acute renal allograft rejection in mice. AB - OBJECTIVE: To investigate the expression of T helper (Th) 17 cells and the related interleukin 17 (IL-17) in acute renal allograft rejection in mice and its significance. METHODS: We established a mouse renal allograft model, in which mice were randomly divided into a renal isograft group and an acute renal allograft rejection group. Three and 7 d after the transplantation, the serum interferon (IFN)-gamma and IL-17 levels in the mice were determined by enzyme linked immunosorbent assay, the percentage of Th1 and Th17 cells in the total kidney-infiltrating lymphocytes was investigated by flow cytometry, and the transplanted kidney species were given routine pathological examination after fixation with 10% formalin. RESULTS: Compared with the isograft group, the allograft mice showed a significantly higher content of IL-17 (P<0.05) but not IFN-gamma in the serum 3 d after transplantation, and showed significantly higher serum IL-17 and IFN-gamma contents 7 d after transplantation (P<0.05). Also, compared with the isograft group, the allograft mice exhibited significantly higher percentage of Th1 and Th17 cells on both day 3 and day 7 (P<0.05). In the allograft group, the contents of serum IFN-gamma and IL-17 and the percentage of Th1 and Th17 cells were significantly higher on day 7 than on day 3 (P<0.05). Routine pathological examination indicated that, as time passed, the allograft mice showed gradually stronger rejection responses. CONCLUSION: Th17 cells might play an important role in the development of acute renal allograft rejection, and IL-17 can be used as an early indicator of acute rejection. PMID- 22246360 TI - Mouse model of orthotopic small bowel transplantation. AB - OBJECTIVE: To investigate the surgical procedures of orthotopic small bowel transplantation (SBT) model in mice to study the function and rejection of SBT. METHODS: We established a mouse SBT allograft model as follows: the donor portal vein was anastomosed end by side with the recipient inferior vena cava; the donor superior mesenteric artery with aorta patch was anastomosed end by side with recipient abdominal aorta. After an appropriate length of the recipient's small bowel was removed, the donor's small bowel and the recipient's small bowel were end-to-end anastomosed discontinuously. The mice were fasted for 4 d after the operation, free access to water and subcutaneously injection of 2 mL of 5% glucose saline twice daily. Operation success was regarded as survival for more than 5 d. There is no antibiotic and immunosuppressor. RESULTS: A total of 30 transplantations were done, the 5 d survival rate was 60% (18/30), and 12 died within 5 d. Among the dead recipients, 5 died of arterial anastomotic stenosis and anastomotic thrombosis, 2 of hemorrhagic shock caused by anastomotic bleeding, and the other 5 of intra-abdominal infection caused by postoperative intestinal fistula. The donors' operative time was (40 +/- 4.5) min, warm ischemia time was about 0.5 min, donor preparation time was about 3 min, and cold preservation time was (30 +/- 7.5) min. The recipients' operative time was (95 +/ 8.0) min, among which, the abdominal aorta and inferior vena cava clamping time was (38 +/- 3.5) min, the venous anastomotic time was (10 +/- 2.0) min and the arterial anastomotic time was (15 +/- 3.0) min. The mean intra-operative blood loss of the surviving recipient mice was about 0.2 mL. CONCLUSION: High quality vascular anastomosis, and rehydration of donors and recipients are crucial factors for improving the success rate of SBT. PMID- 22246361 TI - [Effect of methylation inhibitor on demethylation pattern of the PD-1 gene in promoter region and PD-1 expression in human T lymphocyte cell line]. AB - OBJECTIVE: To observe the demethylation effect of demethylation inhibitor 5 azacytidine (5-Zac) on programmed death receptor 1 (PD-1) in Molt-4 cells (T lymphocyte cell line) and to investigate the relationship between DNA demethylation and expression of PD-1. METHODS: Molt-4 cells were cultured in the medium containing different concentrations of 5-Zac(0, 5, 10 MUmol/L) for 72 h. According to the concentrations of 5-Zac, the Molt-4 cells were divided into a 0 MUmol/L 5-Zac group, a 5 MUmol/L 5-Zac group, and a 10 MUmol/L 5-Zac group. The expression of PD-1 in Molt-4 cells was detected by flow cytometry and the apoptosis rate was calculated. The mRNA transcription level of PD-1 was detected by real-time polymerase chain reaction; Molt-4 cell DNA in all groups were treated by sodium bisulfite. The PD-1 promoter fragment was amplified by PCR, the amplification fragments were transformed into E. coli., the positive clones were selected for equencing, and the methylation status of the fragments of PD-1 promoter was examined. RESULTS Seventy-two hours after the 5-Zac treatment, the expression rate of PD-1 in the Molt-4 cells in the 0 MUmol/L 5-Zac group, the 5 MUmol/L 5-Zac group, and the 10 MUmol/L 5-Zac group was (1.13 +/- 0.01)%, (18.96 +/- 1.87)%, and (63.09 +/- 6.25)% respectively, in a low concentration-dependent way. The PD-1 mRNA expression level was increased significantly with the 5-Zac treatment. Cells apoptosis showed that:compared with the 0 MUmol/L 5-Zac group, the apoptosid rate in the 5 MUmol/L 5-Zac group and 10 MUmol/L 5-Zac group was signficantly increased, which was (1.9 +/- 0.06)%, (8.89 +/- 1.36)%, and (24.50 +/- 3.68)% in the 0 MUmol/L 5-Zac group, the 5 MUmol/L 5-Zac group, and the 10 MUmol/L 5-Zac mol/L group respectively. The bisulfite genomic sequencing showed that the demethylation probability of CpG points on -601 bp and -553 bp was significantly increased in the 5-Zac treated cells compared with those untreated. CONCLUSION: 5-Zac can result in the increase of PD-1 expression in the human lymphoid cell series Molt-4 in vitro, and the apoptosis rate increases, which is related to PD-1 gene promoter demethylation. PMID- 22246362 TI - [MRI for brain structure and function in patients with first-episode panic disorder]. AB - OBJECTIVE: To determine the brain function and structure in patinets with first episode panic disorder (PD). METHODS: All subjects (24 PD patients and 24 healthy subjects) received MRI scan and emotional counting Stroop task during the functional magnetic resonance imaging. Blood oxygenation level dependent functional magnetic resonance imaging and voxel-based morphometric technology were used to detect the gray matter volume. RESULTS: Compared with the healthy controls, left thalamus, left medial frontal gyrus, left anterior cingulate gyrus, left inferior frontal gyrus, left insula (panic-related words vs. neutral words) lacked activation in PD patients, but the over-activation were found in right brain stem, right occipital lobe/lingual gyrus in PD patients. Compared with the healthy controls, the gray matter volume in the PD patients significantly decreased in the left superior temporal gyrus, right medial frontal gyrus, left medial occipital gyrus, dorsomedial nucleus of left thalamus and right anterior cingulate gyrus. There was no significantly increased gray matter volume in any brain area in PD patients. CONCLUSION: PD patients have selective attentional bias in processing threatening information due to the depression and weakening of the frontal cingulated gyrus. PMID- 22246363 TI - [Expression of RUNX3 in cervical carcinoma and its clinical significance]. AB - OBJECTIVE To explore the role of runt-related transcription factor 3(RUNX3) in the tumorgenesis and progression of cervical carcinoma. METHODS The immunohistochemical staining technique was used to detect the expression of RUNX3 protein in 25 cases of normal cervix, 34 intraepithelia neoplasia (CIN), and 48 cervical carcinomas. SYBR Green I chimeric fluorescence Real-time PCR was applied to detect the expression of RUNX3 mRNA in 10 cases of normal cervix, 24 CIN, and 30 cervical carcinomas. RESULTS The expressions of RUNX3 protein and mRNA in normal cervix, CINI,CINII-III, and cervical carcinoma tissues tended to be down regulated. There was significant difference among these groups (P<0.05). The expressions of RUNX3 protein and mRNA in the cervical carcinoma tissues were correlated with the histological differentiation, clinical stage, and lymphatic metastasis (P<0.05), but had no relationship with the age, high-risk human papillomavirus infection, and histological classification (P> 0.05). CONCLUSION RUNX3 may function as a tumor suppressor gene in the occurrence and progression of cervical carcinoma. PMID- 22246364 TI - [Prediction model of health workforce and beds in county hospitals of Hunan by multiple linear regression]. AB - OBJECTIVE: To construct prediction model for health workforce and hospital beds in county hospitals of Hunan by multiple linear regression. METHODS: We surveyed 16 counties in Hunan with stratified random sampling according to uniform questionnaires,and multiple linear regression analysis with 20 quotas selected by literature view was done. RESULTS: Independent variables in the multiple linear regression model on medical personnels in county hospitals included the counties' urban residents' income, crude death rate, medical beds, business occupancy, professional equipment value, the number of devices valued above 10 000 yuan, fixed assets, long-term debt, medical income, medical expenses, outpatient and emergency visits, hospital visits, actual available bed days, and utilization rate of hospital beds. Independent variables in the multiple linear regression model on county hospital beds included the the population of aged 65 and above in the counties, disposable income of urban residents, medical personnel of medical institutions in county area, business occupancy, the total value of professional equipment, fixed assets, long-term debt, medical income, medical expenses, outpatient and emergency visits, hospital visits, actual available bed days, utilization rate of hospital beds, and length of hospitalization. CONCLUSION: The prediction model shows good explanatory and fitting, and may be used for short- and mid-term forecasting. PMID- 22246365 TI - In silico analysis of ubiquitin/ubiquitin-like modifiers and their conjugating enzymes in Entamoeba species. AB - Covalent modification of proteins by ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) regulates many cellular functions in eukaryotes. These modifications are likely to be associated with pathogenesis, growth, and development of many protozoan parasites but molecular details about this pathway are unavailable for most protozoa. This study presents an analysis of the Ub pathway in three members of the Entamoeba species. Using bioinformatics tools we have identified all Ub and Ubl genes along with their corresponding activating, conjugating, and ligating enzymes (E1, E2s, and E3s) in three Entamoeba species, Entamoeba histolytica, Entamoeba dispar, and Entamoeba invadens. Phylogenetic trees were established for the identified E2s and RING finger E3s using maximum-likelihood method to infer the relationship among these proteins. In silico co-domain analysis of RING finger E3s implicates these proteins in a variety of functions. Several known and putative regulatory motifs were identified in the upstream regions of RING finger domain containing E3 genes. All E2 and E3 genes were analyzed in genomic context in E. histolytica and E. dispar. Most E2s and E3s were in syntenic positions in the two genomes. Association of these genes with transposable elements (TEs) was compared between E. histolytica and E. dispar. A closer association was found between RING finger E3s with TEs in E. histolytica. In summary, our analyses suggests that the complexity of the Ub pathway in Entamoeba species is close to that observed in higher eukaryotes. This study provides important data for further understanding the role of Ub pathway in the biology of these organisms. PMID- 22246366 TI - Rapid detection and differentiation of Clonorchis sinensis and Opisthorchis viverrini eggs in human fecal samples using a duplex real-time fluorescence resonance energy transfer PCR and melting curve analysis. AB - We developed a single step duplex real-time fluorescence resonance energy transfer (FRET) PCR merged with melting curve analysis for the fast detection and differentiation of Clonorchis sinensis and Opisthorchis viverrini eggs in human fecal samples. Two species of mitochondrial NADH dehydrogenase subunit 2 (nad2) DNA elements, the 165-bp nad2 product of C. sinensis and the 209-bp nad2 product of O. viverrini, were amplified by species-specific primers, and the fluorescence melting curve analyses were generated from hybrid of amplicons and two pairs of species-specific fluorophore-labeled probes. By their different fluorescence channels and melting temperatures, both C. sinensis and O. viverrini eggs in infected human fecal samples were detected and differentiated with high (100%) sensitivity and specificity. Detection limit was as little as a single C. sinensis egg and two O. viverrini eggs in 100 mg of fecal sample. The assay could distinguish the DNA of both parasites from the DNA of negative fecal samples and fecal samples with other parasitosis, as well as from the well-defined genomic DNA of human leukocytes and other parasites. It can reduce labor time of microscopic examination and is not prone to carry over contamination of agarose electrophoresis. Our duplex real-time FRET PCR method would be useful to determine the accurate range of endemic areas and/or to discover the co-endemic areas of two liver flukes, C. sinensis and O. viverrini, in Asia. This method also would be helpful for the differential diagnosis of the suspected cases of liver fluke infections among travelers who had visited the endemic countries of those parasites. PMID- 22246367 TI - Screening of 42 medicinal plants for in vivo anthelmintic activity against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus). AB - In the present study, methanol extracts of 42 traditional medicinal plants with potent anthelmintic activity against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus) were investigated. Cinnamomum cassia, Lindera aggregata, and Pseudolarix kaempferi exhibited 100% activity and were selected for further evaluation by applying five solvents (petroleum ether, chloroform, ethyl acetate, methanol, and water) for the extraction of the samples, followed by the in vivo bioassay. Among the extracts tested, water and methanol extracts of C. cassia showed the highest efficacies with EC(50) values of 13.2 and 12.3 mg L(-1), showing 100% efficacy against D. intermedius at 30.0 and 40.0 mg L(-1), followed by methanol extract of L. aggregata which demonstrated 100% efficacy at 60.0 mg L(-1) with EC(50) value of 17.1 mg L(-1) after 48 h of exposure. Methanol and ethyl acetate extract of P. kaempferi, which exhibited a 100% efficacy against D. intermedius at 60.0 and 50.0 mg L(-1), revealed similar activity with EC(50) values of 23.5 and 23.3 mg L(-1), respectively. Acute toxicity of these active extracts was investigated on goldfish for 48 h and the corresponding median lethal concentrations (LC(50)) of 56.9, 31.3, 88.7, 168.2, and 165.7 mg L( 1), respectively. These findings indicated that these extracts of the three plants can be developed as preferred natural antiparasitic agents for the treatment of D. intermedius. PMID- 22246368 TI - The complete mitochondrial genome of the rodent intra-arterial nematodes Angiostrongylus cantonensis and Angiostrongylus costaricensis. AB - The two rodent intra-arterial nematodes, Angiostrongylus cantonensis and Angiostrongylus costaricensis, can cause human ill-health. The present study aimed to characterize and compare the mitochondrial (mt) genomes of these two species, and clarify their phylogenetic relationship and the position in the phylum Nematoda. The complete mt genomes of A. cantonensis and A. costaricensis are 13,497 and 13,585 bp in length, respectively. Hence, they are the smallest in the class of Chromadorea characterized thus far. Like many nematode species in the class of Chromadorea, they encode 12 proteins, 22 transfer RNAs, and two ribosomal RNAs. All genes are located on the same strand. Nucleotide identity of the two mt genomes is 81.6%, ranging from 77.7% to 87.1% in individual gene pairs. Our mt genome-wide analysis identified three major gene arrangement patterns (II-1, II-2, and II-3) from 48 nematode mt genomes. Both patterns II-1 and II-2 are distinct from pattern II-3, which covers the Spirurida, supporting a closer relationship between Ascaridida and Strongylida rather than Spirurida. Thymine (T) was highly concentrated on coding strands in Chromadorea, but balanced between the two strands in Enoplea, probably due to the gene arrangement pattern. Interestingly, the gene arrangement pattern of mt genomes and phylogenetic analysis based on concatenated amino acids indicated a closer relationship between the order Ascaridida and Rhabditida rather than Spirurida as indicated in previous studies. These discrepancies call for new research, reassessing the position of the order of Ascaridida in the phylogenetic tree. Once consolidated, the findings are important for population genetic studies and target identification. PMID- 22246369 TI - Zoophilic feeding behaviour of phlebotomine sand flies in the endemic areas of cutaneous leishmaniasis of Sindh Province, Pakistan. AB - Leishmania (Leishmania) major has been identified as the major causative agent of cutaneous leishmaniasis in Sindh Province of southern Pakistan. To make a rational approach for understanding the pathogen transmission cycles, the sand fly species and their natural blood meals in the endemic areas were examined. Total DNA was individually extracted from sand flies collected in four villages in Sindh Province. PCR-RFLP (restriction fragment length polymorphism) and sequence analysis of the 18S ribosomal RNA gene revealed that female sand flies identified were Sergentomyia clydei/Sergentomyia ghesquierei/Sergentomyia magna (68.6%), Sergentomyia dubia (17.1%), Phlebotomus papatasi (7.4%), Phlebotomus alexandri-like sand flies (3.4%) and Sergentomyia dentata (3.4%). PCR amplification of leishmanial kinetoplast DNA did not result in positive signals, suggesting that all 175 tested female sand flies were not infected with leishmanial parasites or contained undetectable levels of leishmanial DNA. Amplification and sequencing of the vertebrate cytochrome b gene in 28 blood-fed sand flies revealed that P. papatasi fed on cattle and wild rat whereas P. alexandri-like specimens fed on human, cattle, goat and dog. Although Sergentomyia sand flies are generally known to feed on cold-blooded animals, S. clydei, S. dubia and S. ghesquierei preferred humans, cattle, goat, sheep, buffalo, dog, donkey, wild rat and Indian gerbil. The epidemiological significance of the zoophilic feeding on various host species by Phlebotomus and Sergentomyia sand flies in Pakistan is further required to study for better understanding the zoonotic transmission of sand-fly-borne pathogens and for appropriate management of the vectors. PMID- 22246370 TI - Spermiogenesis and spermatozoon ultrastructure of the paruterinid cestode Notopentorchis sp. (Cyclophyllidea). AB - Ultrastructural characters of the spermiogenesis and mature spermatozoon of Notopentorchis sp. (Cestoda, Cyclophyllidea, Paruterinidae), a parasite from Apus affinis (Aves, Apodiformes, Apodidae) from Gabon, are described by means of transmission electron microscopy. Cytochemical analysis for detection of glycogen was applied. Vestigial striated roots associated with the two centrioles are present in the zone of differentiation. The spermiogenesis is characterized by an external growth of free flagellum followed by a proximodistal fusion of the latter with cytoplasmic protrusion, thus, corresponding to the cestode spermiogenesis of the type III pattern described by Ba and Marchand (Mem. Mus. Natl. Hist. Nat. 166:87-95, 1995). In the final stage of spermiogenesis, a single crested body appears at the base of the forming spermatozoon. The mature spermatozoon of Notopentorchis sp. is filiform and tapering at both extremities. It consists of five regions differing in their ultrastructural characteristics. The anterior extremity of the mature spermatozoon is characterized by the presence of an apical cone and a single crested body. The cytoplasm contains one axoneme of 9 + "1" type of the trepaxonematan Platyhelminthes, a periaxonemal sheath, a layer of twisted cortical microtubules, transverse intracytoplasmic walls, and granules of glycogen. The nucleus is coiled in spiral around the axoneme. The posterior extremity of the spermatozoon is characterized by the presence of electron-dense material. This structural organization corresponds to the morphology of cestode spermatozoon of type VII as defined by Levron et al. (Biol Rev 85: 523-543, 2010). The comparison of the results with those of the two previous studies on paruterinids suggests that several characters of the spermiogenesis and the mature spermatozoon are invariable, i.e. the type III spermiogenesis and the presence of vestigial striated roots, a single crested body, a periaxonemal sheath, and intracytoplasmic walls. The main differences of the sperm cells among members of this family are the lack of dense granules (as in Triaenorhina rectangula) and the presence of electron-dense material in the posterior extremity of the spermatozoon (as in Notopentorchis sp.). PMID- 22246371 TI - Cryptosporidiosis: comparison of three diagnostic methods and effects of storage temperature on detectability of cryptosporidia in cattle faeces. AB - Three diagnostic methods (a modified Ziehl-Neelsen staining technique (MZN), a negative staining with carbol fuchsine (CF) and a commercial enzyme immunoassay (EIA) kit, ProSpecT(r) Cryptosporidium Microplate Assay (Remel, Lenexa, KS, USA)) for detection of Cryptosporidium oocysts in cattle faeces were compared regarding sensitivity and suitability under routine laboratory conditions, with particular emphasis on sample storage. In the 103 faecal samples examined, cryptosporidia infections were detected significantly more often by EIA (p<0.05; n=76) than by MZN (n=65) if ten random fields were evaluated microscopically, but not if the whole coverslip was scanned. In contrast, sensitivities of EIA and CF (n=69) did not differ significantly. Results were obtained very rapidly by CF. However, the hands-on time of CF is comparable to EIA, while MZN is more time consuming. EIA is more expensive than CF and MZN but easy to perform and to evaluate and does not need considerably experienced staff in contrast to CF and MZN. Moreover, 45 faecal samples stored for up to 27 days at different temperatures (+6 degrees C, +16 degrees C, +30 degrees C, +40 degrees C) were examined. The sensitivity of microscopic detection of oocysts in stained smears (CF, MZN) decreased in a temperature and time-dependent manner, while EIA results were not influenced by sample storage at any temperature. PMID- 22246372 TI - Preparation and structures of aryloxy- and alkoxy-Ti(IV) complexes and their evaluation in ethylene oligomerisation and polymerisation. AB - A range of aryloxy and alkoxy ligands, both monodenate and chelating, have been coordinated to Ti(IV) to yield complexes of the form [Ti(OAr)(2)Cl(2)], [Ti(RO^O)Cl(3)] and [Ti(RO^O)(2)Cl(2)] (R = aryl, alkyl). The complexes vary in their Lewis base solvation and/or aggregation state, as revealed by X-ray crystallography of selected examples. The complexes have been evaluated as catalysts for ethylene oligomerisation and polymerisation following activation with alkylaluminium reagents (AlEt(3), methylaluminoxane). While polyethylene is the major product, ethylene oligomers also result, ranging from dimers to higher oligomers. The results indicate a number of different active species are formed upon activation, with oligomers likely arising through a metallacyclic mechanism. The findings are discussed in the context of the commercial Alphabutol dimerisation system [Ti(OR)(4)], and the development of group 4 based ethylene trimerisation catalysts. PMID- 22246373 TI - Measures of health-related quality of life in diabetes-related foot disease: a systematic review. AB - AIMS/HYPOTHESIS: Patient-reported outcome measures (PROMs) are increasingly used as key performance indicators in chronic illness. We sought to review the value of these tools in assessing health-related quality of life (HRQOL) in patients with diabetes-related foot disease and identify the impact of each foot problem on life quality. METHODS: A systematic review of literature on HRQOL PROMs in diabetes-related foot disease was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The quality of eligible studies was evaluated within pre-existing criteria. RESULTS: 53 studies written between 1995 and 2010 met the inclusion criteria. A variety of HRQOL PROMs were used. Disease-specific tools were better than generic at quantifying temporal changes in life quality and showed greater sensitivity to ulcer/neuropathic severity. No studies have simultaneously evaluated disease specific tools. Generic and utility HRQOL PROMs are frequently used as secondary outcome measures in randomised trials and cost-utility analysis. HRQOL is depressed in diabetes, further impaired by the presence of foot disease. Ulcer healing is associated with improvements in HRQOL. Patients with active ulceration report poorer HRQOL than those whom have undergone successful minor lower extremity amputation (LEA) but there is a paucity of quality data on HRQOL outcomes for diabetes-related LEA. CONCLUSIONS/INTERPRETATION: No one PROM was identified as a 'gold standard' for assessing HRQOL in diabetes-related foot disease. Specific areas for further development include the most valid HRQOL PROM with disease-specific content; HRQOL outcomes in minor and major amputations and the role of HRQOL tools in routine clinical care. PMID- 22246374 TI - How the immunoassay transformed C-peptide from a duckling into a swan. AB - This edition of 'Then and now' re-examines Lise Heding's very highly cited paper 'Radioimmunological determination of human C-peptide in serum', which was published in Diabetologia in 1975. We show how this article and other related articles by Heding contributed to heightened respect for C-peptide (and transformation of Heding's research programme). Initially thought of as an inert discard, C-peptide in blood is now recognised as an excellent surrogate measure of insulin secretion under a wide range of conditions. The assay is especially valuable for acute ascertainment of the insulin secretory capabilities of patients with type 1 diabetes or of transplanted beta cells. The assay is also being used to monitor endogenous beta cell loss or in vivo expansion of beta cell mass over the long term. We conclude with two promising future applications: (1) measurements of C-peptide in blood (along with insulin, glucose, and HbA(1c)) at annual intervals as a potential approach to earlier diagnosis of diabetes; and (2) among many recent advances in recognising properties of C-peptide (including status as a candidate hormone), most promising is C-peptide as a possible therapy for diabetic neuropathy and nephropathy. PMID- 22246375 TI - Involvement of thioredoxin-interacting protein (TXNIP) in glucocorticoid-mediated beta cell death. AB - AIM/HYPOTHESIS: Glucocorticoid hormones (GCs) are widely used to treat a variety of inflammatory and immune diseases. However, their long-term administration is associated with adverse metabolic effects, including glucose intolerance and diabetes. Our objective was to elucidate the mechanisms by which GCs affect beta cell survival with a specific emphasis on the role of the thioredoxin-interacting protein (TXNIP) in beta cell apoptosis. METHODS: Human and mouse islets, together with MIN6 beta cells, were exposed to dexamethasone (Dex) and apoptosis was assessed by measuring the percentage of sub-G1 cells, the appearance of cleaved caspase-3 or by using a TUNEL assay. Dex-upregulated expression of Txnip mRNA was analysed by real-time PCR, and GC-modulated production and modification of proteins were determined by western blotting. RESULTS: We provide evidence that TXNIP, a negative regulator of the antioxidant thioredoxin (TRX), is strongly induced in beta cells by GCs and that its induction is dependent on p38 mitogen activated protein kinase (MAPK) activation. TXNIP downregulation by RNA interference, overexpression of the radical scavenger TRX1 or elevation of intracellular cAMP levels attenuated the Dex-mediated apoptosis. Dex-induced Txnip expression and beta cell apoptosis are mediated by the glucocorticoid receptor (GR), as the GR antagonist RU486 fully abolishes these effects. CONCLUSIONS/INTERPRETATION: Altogether, our data suggest TXNIP as a novel mediator of GC-induced apoptosis in beta cells and further contribute to our understanding of beta cell death pathways. PMID- 22246376 TI - Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes. AB - AIMS/HYPOTHESIS: The success of islet transplantation as a treatment for type 1 diabetes is currently hampered by post-transplantation loss of functional islets through adverse immune and non-immune reactions. We aimed to test whether early islet loss can be limited and transplant survival improved by the application of conformal nano-coating layers to islets. METHODS: Our novel coating protocol used alternate layers of phosphorylcholine-derived polysaccharides (chitosan or chondroitin-4-sulphate) and alginate as coating materials, with the binding based on electrostatic complexation. The in vitro function of encapsulated mouse islets was studied by analysing islet secretory function and cell viability. The in vivo function was evaluated using syngeneic and allogeneic transplantation in the streptozotocin-induced mouse model of diabetes. RESULTS: Nano-scale encapsulated islets retained appropriate islet secretory function in vitro and were less susceptible to complement- and cytokine-induced apoptosis than non-encapsulated control islets. In in vivo experiments using a syngeneic mouse transplantation model, no deleterious responses to the coatings were observed in host animals, and the encapsulated islet grafts were effective in reversing hyperglycaemia. Allo-transplantation of the nano-coated islets resulted in preserved islet function post-implantation in five of seven mice throughout the 1 month monitoring period. CONCLUSIONS/INTERPRETATION: Nano-scale encapsulation offers localised immune protection for implanted islets, and may be able to limit early allograft loss and extend survival of transplanted islets. This versatile coating scheme has the potential to be integrated with tolerance induction mechanisms, thereby achieving long-term success in islet transplantation. PMID- 22246377 TI - Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety. AB - AIMS/HYPOTHESIS: The aim of this study was to determine whether exenatide improves haemodynamic function in patients with type 2 diabetes with congestive heart failure (CHF). METHODS: The main eligibility criteria for inclusion were: male/female (18-80 years) with type 2 diabetes and CHF (ejection fraction <= 35%, and New York Heart Association functional class III or IV). Out of 237 patients screened, 20 male type 2 diabetic patients participated in this crossover trial design and were allocated (sequentially numbered) to i.v. infusions during two consecutive days with (1) exenatide (0.12 pmol/kg/min); and (2) placebo for 6 h followed by a washout period for 18 h, at Stockholm South Hospital, Sweden. Patients and researchers were blinded to the assignment. Cardiac haemodynamic variables were determined by right heart catheterisation. The primary endpoint was defined as an increase in cardiac index (CI) or a decrease in pulmonary capillary wedge pressure (PCWP) of >= 20%. Secondary endpoints were tolerability and safety of exenatide infusion. RESULTS: CI increased at 3 and 6 h by 0.4 +/- 0.1 (23%) and 0.33 +/- 0.1 (17%) l min(-1) m(-2), during exenatide infusion vs 0.02 +/- 0.1 (-1%) and -0.08 +/- 0.1 (-5%) l min(-1) m(-2) during placebo (p = 0.003); and heart rate (HR) increased at 1, 3 and 6 h by 8 +/- 3 (11%), 15 +/- 4 (21%) and 21 +/- 5 (29%) beats per min (bpm), during exenatide infusion vs -1 +/- 2 (-2%), 1 +/- 1 (2%) and 6 +/- 2 (8%) bpm, during placebo (p = 0.006); and PCWP decreased at 1, 3 and 6 h by -1.3 +/- 0.8 (-8%), -1.2 +/- 1 (-8%) and -2.2 +/- 0.9 (-15%) mmHg, during exenatide infusion vs 0.3 +/- 0.5 (2%), 1 +/- 0.6 (6%) and 1.4 +/- 0.7 (8%) mmHg, during placebo (p = 0.001). No serious adverse event was observed. Adverse events were reported in nine patients (six, nausea; two, increased HR; one, increased systolic blood pressure). CONCLUSIONS/INTERPRETATION: Infusion of exenatide in male type 2 diabetic patients with CHF increased the CI as a result of chronotropy, with concomitant favourable effects on PCWP and reasonable tolerability of the drug. The clinical implications of using exenatide in patients with CHF are still not clear and further studies are warranted. TRIAL REGISTRATION: www.isrctn.org/ISRCTN47533126 PMID- 22246378 TI - Effect of exercise training on insulin sensitivity, mitochondria and computed tomography muscle attenuation in overweight women with and without polycystic ovary syndrome. AB - AIMS/HYPOTHESIS: Polycystic ovary syndrome (PCOS) is an insulin resistant (IR) state. Increased skeletal muscle lipid content and impaired mitochondrial biogenesis have been implicated in the pathogenesis of IR. We investigated whether differences in these variables explain the IR of women affected by PCOS and whether improvements in IR with exercise are reflected by changes in these variables. METHODS: Sixteen PCOS and 13 non-PCOS overweight women were assessed, and eight PCOS and seven non-PCOS women were reassessed after 12 weeks of moderate and vigorous exercise training. Outcomes included insulin sensitivity (glucose infusion rate [GIR]), skeletal muscle gene expression and protein abundance, enzyme activity of selected mitochondrial components, and computed tomography (CT) attenuation-estimated muscle lipid. RESULTS: GIR was lower in women with PCOS versus those without (p = 0.01) and increased with exercise in both groups. Baseline CT muscle attenuation suggested a trend to less muscle lipid in PCOS, which increased with exercise training, with a difference in the change in muscle lipid (p = 0.01, age-corrected), compared with non-PCOS women. GIR correlated with PGC1A gene expression across the whole group; skeletal muscle expression of mitochondrial biogenesis markers was not different between groups at baseline, or after training. Neither lipid changes nor mitochondrial changes correlated with changes in GIR. CONCLUSIONS/INTERPRETATION: Differences in IR in women with and without PCOS were not explained by differences in skeletal muscle lipid or mitochondrial parameters. Improvements in IR with exercise were dissociated from mitochondrial parameters. CT muscle attenuation suggested a differential capacity of PCOS muscle to store lipid compared with non-PCOS. TRIAL REGISTRATION: Clinicaltrials.gov ISRCTN84763265. FUNDING: National Health & Medical Research Council (Grant number 606553), Monash University and The Jean Hailes Foundation. PMID- 22246379 TI - A step closer to making beta cells. PMID- 22246382 TI - A facial swelling with multiple discharging sinuses: a diagnostic conundrum. AB - BACKGROUND: Many disease processes can present with facial swelling and multiple discharging sinuses. A differential diagnosis would include actinomycosis, tuberculosis and osteomyelitis, but tinea barbae is a relatively uncommon presentation. CASE REPORT: The following case report describes a 48-year-old jockey who was diagnosed with tinea barbae. It chronicles the investigations that were performed to determine the offending pathogen and the difficulty in achieving a diagnosis. DISCUSSION: The investigations and the pathophysiology of dermatophytic infections and their management in a maxillofacial/oral medicine environment are discussed. PMID- 22246381 TI - Survey of sugar beet (Beta vulgaris L.) hAT transposons and MITE-like hATpin derivatives. AB - Genome-wide analyses of repetitive DNA suggest a significant impact particularly of transposable elements on genome size and evolution of virtually all eukaryotic organisms. In this study, we analyzed the abundance and diversity of the hAT transposon superfamily of the sugar beet (B. vulgaris) genome, using molecular, bioinformatic and cytogenetic approaches. We identified 81 transposase-coding sequences, three of which are part of structurally intact but nonfunctional hAT transposons (BvhAT), in a B. vulgaris BAC library as well as in whole genome sequencing-derived data sets. Additionally, 116 complete and 497 truncated non autonomous BvhAT derivatives lacking the transposase gene were in silico detected. The 116 complete derivatives were subdivided into four BvhATpin groups each characterized by a distinct terminal inverted repeat motif. Both BvhAT and BvhATpin transposons are specific for species of the genus Beta and closely related species, showing a localization on B. vulgaris chromosomes predominantely in euchromatic regions. The lack of any BvhAT transposase function together with the high degree of degeneration observed for the BvhAT and the BvhATpin genomic fraction contrasts with the abundance and activity of autonomous and non autonomous hAT transposons revealed in other plant species. This indicates a possible genus-specific structural and functional repression of the hAT transposon superfamily during Beta diversification and evolution. PMID- 22246380 TI - One-step immunopurification and lectinochemical characterization of the Duffy atypical chemokine receptor from human erythrocytes. AB - Duffy antigen/receptor for chemokines (DARC) is a glycosylated seven transmembrane protein acting as a blood group antigen, a chemokine binding protein and a receptor for Plasmodium vivax malaria parasite. It is present on erythrocytes and endothelial cells of postcapillary venules. The N-terminal extracellular domain of the Duffy glycoprotein carries Fy(a)/Fy(b) blood group antigens and Fy6 linear epitope recognized by monoclonal antibodies. Previously, we have shown that recombinant Duffy protein expressed in K562 cells has three N linked oligosaccharide chains, which are mainly of complex-type. Here we report a one-step purification method of Duffy protein from human erythrocytes. DARC was extracted from erythrocyte membranes in the presence of 1% n-dodecyl-beta-D maltoside (DDM) and 0.05% cholesteryl hemisuccinate (CHS) and purified by affinity chromatography using immobilized anti-Fy6 2C3 mouse monoclonal antibody. Duffy glycoprotein was eluted from the column with synthetic DFEDVWN peptide containing epitope for 2C3 monoclonal antibody. In this single-step immunoaffinity purification method we obtained highly purified DARC, which migrates in SDS-polyacrylamide gel as a major diffuse band corresponding to a molecular mass of 40-47 kDa. In ELISA purified Duffy glycoprotein binds anti Duffy antibodies recognizing epitopes located on distinct regions of the molecule. Results of circular dichroism measurement indicate that purified DARC has a high content of alpha-helical secondary structure typical for chemokine receptors. Analysis of DARC glycans performed by means of lectin blotting and glycosidase digestion suggests that native Duffy N-glycans are mostly triantennary complex-type, terminated with alpha2-3- and alpha2-6-linked sialic acid residues with bisecting GlcNAc and alpha1-6-linked fucose at the core. PMID- 22246383 TI - Auditory brainstem implants in NF2 patients: results and review of the literature. AB - OBJECTIVE: Neurofibromatosis Type 2 (NF2) patients have multiple central nervous system tumors and, specifically, bilateral vestibular schwannomas (VSs) causing bilateral deafness. If the cochlear nerve is not preserved during tumor removal, the only hearing rehabilitation in these patients could be via an auditory brainstem implant (ABI). STUDY DESIGN: Retrospective case study and literature review. SETTING: Tertiary referral cranial base center. PATIENTS: In 24 NF2 patients, 25 ABIs were placed in the lateral recess of the fourth ventricle after VS surgery via a translabyrinthine approach. RESULTS: In this series, a large range of results are observed: from open speech and use of the telephone to no ABI use, because of the poor sound identification ability. Of the 24 patients, 19 use their ABI on a daily basis, 4 are nonusers, and 1 died of NF2 progression. A multivariate analysis did not reveal a good predictor for ABI outcome. In literature, the results of ABI in NF2 are difficult to compare, and the overall outcome was poor compared with cochlear implantation results. CONCLUSION: Auditory brainstem implantation in NF2 patients directly after tumor removal is a safe procedure and the best means of hearing rehabilitation if the cochlear nerve is not preserved. The results in NF2 cases in the literature and these series are poor compared with cochlear implantation. If a cochlear implant is possible, it has the preference over an ABI, also in NF2. Nevertheless, the majority of the patients have benefit of the ABI during daily life particularly in combination with lip reading. PMID- 22246384 TI - Structural characterization and lipid composition of acquired cholesteatoma: a comparative study with normal skin. AB - HYPOTHESIS: The goal of this work is to characterize the morphology and lipid composition of acquired cholesteatoma. We hypothesize that constitutive lipid membranes are present in the cholesteatoma and resemble those found in human skin stratum corneum. METHODS: We performed a comparative noninvasive structural and lipid compositional study of acquired cholesteatoma and control human skin using multiphoton excitation fluorescence microscopy-related techniques and high performance thin-layer chromatography. RESULTS: The structural arrangement of the cholesteatoma is morphologically invariant along a depth of more than 200 MUm and resembles the stratum corneum of hyperorthokeratotic skin. Lipid compositional analyses of the cholesteatoma show the presence of all major lipid classes found in normal skin stratum corneum (ceramides, long chain fatty acids, and cholesterol). Consistent with this, evaluation of Nile red and LAURDAN generalized polarization function images of the cholesteatoma show intercellular regions similar to normal skin stratum corneum in terms of lipid membrane packing and local water content. CONCLUSION: The investigations show the presence of an extremely thickened stratum corneum within the cholesteatoma. The lipid composition and extracellular membranes similar to those of normal skin stratum corneum are present, indicating that a defensive/permeability barrier is present in the cholesteatoma. Finally, it is demonstrated that multiphoton excitation fluorescence microscopy is a suitable noninvasive tool for investigating the morphology and intrinsic physical properties of acquired cholesteatoma. PMID- 22246385 TI - Assessment of more than 1,000 implanted percutaneous bone conduction devices: skin reactions and implant survival. AB - OBJECTIVE: This study assesses soft tissue reactions and implant stability of 1,132 percutaneous titanium implants (970 patients) for bone conduction devices (BCDs). In addition, it examines BCD usage and comparisons between different patient groups. STUDY DESIGN: Retrospective survey. Mean follow-up time of 4.6 years. SETTING: Tertiary care referral center. PATIENTS: The surveyed cohort was divided into 3 different age groups (children, adults, and the elderly). In addition, 4 groups with variable loading times (i.e., the time between placement of the implant and loading the BCD sound processor) were identified as well as a subgroup of patients with mental retardation. MAIN OUTCOME MEASURES: Soft tissue reactions around the percutaneous implants as classified by the Holgers grading system, implant failure, and revision surgery rates. RESULTS: In 95.5% of the 7,415 observations of 1,132 implants, there were no adverse soft tissue reactions. Implant loss was 8.3%. Significantly more soft tissue reactions and implant failures were observed in children compared with adults and the elderly (p < 0.05). Implant survival was lower in patients with mental retardation compared with patients without mental retardation (p = 0.001). The loading time did not influence the occurrence of soft tissue reactions and implant survival rates. CONCLUSION: Children and patients with mental retardation are the most vulnerable to soft tissue reactions and implant losses. Additional and more frequent care needs to be given during outpatient consultations. Because loading as early as 3 to 5 weeks did not negatively affect skin reactions or implant survival, full BCD installation can occur earlier without risk. PMID- 22246386 TI - Predictive value of electrocochleography for determining hearing outcomes in Meniere's disease. AB - OBJECTIVE: To evaluate the clinical effectiveness of performing electrocochleography (ECoG) at the initial visit in predicting hearing outcomes. STUDY DESIGN: Retrospective study. SETTING: Tertiary hospital. PATIENTS: Ninety patients with unilateral, definite Meniere's disease. INTERVENTIONS: The summating potential (SP)/action potential (AP) ratio was obtained using ECoG at the initial visits. An SP/AP ratio greater than 0.34 was considered abnormal. MAIN OUTCOME MEASURES: Audiogram types, hearing fluctuations, hearing thresholds at the initial and last visits, hearing changes, caloric response, and treatment outcomes were analyzed in subjects with normal and abnormal ECoGs. Correlation analyses between the SP/AP ratio at the initial visit, hearing thresholds at each visit, and hearing changes were performed. RESULTS: The mean follow-up period was 22.6 months. Abnormal ECoGs were found in 50 (55.6%) of the 90 subjects. No significant differences regarding audiogram types, hearing fluctuations, caloric response, or treatment outcomes were observed between subjects with normal and abnormal ECoGs. Ipsilateral SP/AP ratios at the initial visit were correlated with both hearing thresholds at the initial (r = 0.347, p < 0.001) and last (r = 0.435, p < 0.001) visits. Furthermore, there was a significant correlation between SP/AP ratio and hearing change during follow-up (r = 0.280, p = 0.008). After stratification by initial hearing level, Stage 1 and 2 subjects (hearing threshold, 0-40 dB) with abnormal ECoGs at the initial visit showed a decrease in hearing over time compared with those with normal ECoGs (p = 0.008). CONCLUSION: A high SP/AP ratio at the initial visit may be used as a predictor of poor hearing outcomes in subjects with Meniere's disease, especially with initial hearing Stage 1 and 2. PMID- 22246387 TI - Treatment of macular edema due to branch retinal vein occlusion with single or multiple intravitreal injections of bevacizumab. AB - PURPOSE: We examined the predictive factors for final visual acuity (VA) with macular edema of branch retinal vein occlusion (BRVO) treated by intravitreal injection of bevacizumab (IVB) and examined the differences between patients without recurrent macular edema due to BRVO after a single IVB and patients treated with multiple IVB because of recurrent macular edema. METHODS: In this retrospective study, 37 eyes of 37 patients with BRVO were treated with IVB and followed up for more than 24 weeks. Eighteen eyes showed no recurrence of macular edema after a single IVB (single IVB group). The remaining 19 eyes showed recurrent macular edema and underwent multiple IVB (multiple IVB group). VA and morphologic parameters of optical coherence tomography were examined. RESULTS: Mean VA, central retinal thickness, and mean retinal thickness in a circular region of 1-mm diameter at the fovea improved significantly with IVB treatment in both groups. Final VA was correlated with baseline VA and integrity grade of the photoreceptor inner and outer segment (IS/OS) line beneath the fovea. CONCLUSION: Baseline VA and IS/OS line grade at 4 weeks may be predictive factors for final VA. PMID- 22246388 TI - Continuous flow metal-free oxidation of picolines using air. AB - The metal free, direct oxidation of 2-, 3-, and 4-picoline to the corresponding carboxylic acid using either oxygen or air has been developed under continuous flow conditions. Complete conversion for all three substrates was obtained at moderate temperatures and pressures within minutes. PMID- 22246389 TI - Metabolism of [6]-shogaol in mice and in cancer cells. AB - Ginger has received extensive attention because of its antioxidant, anti inflammatory, and antitumor activities. However, the metabolic fate of its major components is still unclear. In the present study, the metabolism of [6]-shogaol, one of the major active components in ginger, was examined for the first time in mice and in cancer cells. Thirteen metabolites were detected and identified, seven of which were purified from fecal samples collected from [6]-shogaol treated mice. Their structures were elucidated as 1-(4'-hydroxy-3'-methoxyphenyl) 4-decen-3-ol (M6), 5-methoxy-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M7), 3',4'-dihydroxyphenyl-decan-3-one (M8), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3 ol (M9), 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M10), 1-(4' hydroxy-3'-methoxyphenyl)-decan-3-one (M11), and 5-methylthio-1-(4'-hydroxy-3' methoxyphenyl)-decan-3-ol (M12) on the basis of detailed analysis of their (1)H, (13)C, and two-dimensional NMR data. The rest of the metabolites were identified as 5-cysteinyl-M6 (M1), 5-cysteinyl-[6]-shogaol (M2), 5-cysteinylglycinyl-M6 (M3), 5-N-acetylcysteinyl-M6 (M4), 5-N-acetylcysteinyl-[6]-shogaol (M5), and 5 glutathiol-[6]-shogaol (M13) by analysis of the MS(n) (n = 1-3) spectra and comparison to authentic standards. Among the metabolites, M1 through M5, M10, M12, and M13 were identified as the thiol conjugates of [6]-shogaol and its metabolite M6. M9 and M11 were identified as the major metabolites in four different cancer cell lines (HCT-116, HT-29, H-1299, and CL-13), and M13 was detected as a major metabolite in HCT-116 human colon cancer cells. We further showed that M9 and M11 are bioactive compounds that can inhibit cancer cell growth and induce apoptosis in human cancer cells. Our results suggest that 1) [6]-shogaol is extensively metabolized in these two models, 2) its metabolites are bioactive compounds, and 3) the mercapturic acid pathway is one of the major biotransformation pathways of [6]-shogaol. PMID- 22246391 TI - A judicial rashomon: on ageism and narrative justice. AB - How are old people treated in courts? How do judges construct old age? To what extent judicial decisions regarding older persons reflect ageist attitudes? Historically, these questions have received relatively little attention in gerontological literature. This Israeli case-study tries to add a new dimension to the growing literature in the field of jurisprudential gerontology, in a context that so far received little attention: narrative justice. More specifically, this study combines a narrative-justice theoretical approach, with a legal case-study methodology, in order to explore the relationships between judicial narratives and ageism. The narrative analysis presented in this case study exposes how in contrast to common perception, which views legal decisions as objective and unimaginative texts, reality is different. The judicial case studied in this article exemplify how in real life, judges often construct a socio-judicial narrative, embellished by personal bias and prejudices regarding old age. PMID- 22246390 TI - Urinary incontinence in children: botulinum toxin is a safe and effective treatment option. AB - PURPOSE: This study's aim was to assess the use of intravesical injection of botulinum neurotoxin type A (BoNT-A) as a treatment of overactive bladder (OAB) in children. METHODS: A 6-year retrospective study of children who received BoNT A for OAB was performed. Treatment outcome was classified as complete success (CS), partial success (PS) or treatment failure (TF). RESULTS: Of the 57 patients who received BoNT-A treatment for OAB, 35 were males. CS occurred in 74.2% of males and 54.5% of females. PS was achieved in 20% of males and 18.2% of females. TF occurred in 2.9% of males and 22.7% of females. Anticholinergics had previously been used and had been effective in 58.6% and 83.3% of males and females. Significant side effects to medications were experienced in 12 (41.4%) males and 4 (22.2%) females. Of these, BoNT-A achieved CS in seven (53.3%) males and two (50%) females and PS in three (25%) males and one (25%) female. BoNT-A was successful in seven (58.3%) males and two (66.7%) females where anticholinergics were ineffective. CONCLUSIONS: BoNT-A has a role in a carefully selected subgroup of children with overactive bladder symptoms including those with medication side effects and treatment compliance issues. It may have a role in patients who do not respond to conventional therapy. PMID- 22246392 TI - The effects of chronically increased intra-abdominal pressure on the rabbit diaphragm. AB - BACKGROUND: Diaphragmatic muscular remodeling is caused by various conditions and was mainly studied in pulmonary pathologies and chronic alterations of intra thoracic pressure. We investigate the effect of the chronically increased intra abdominal pressure (IAP) on the diaphragm by morphological and biochemical analysis. METHODS: Thirty rabbits were divided into control and study groups. IAP was increased in group B to 12 mmHg for 2 months. The left hemidiaphragm underwent morphological, while the right underwent biochemical analysis. RESULTS: In H&E, all fibers were normal. ATPase analysis demonstrated that type I fibers show no differences between groups. Type IotaIota(Alpha) were decreased (p = 0.016) while type IotaIota(Beta/X) fibers were increased (p = 0.025) in group B. Fibers with resistance to fatigue were decreased in group B (p = 0.024). In group B, biochemical activity for glutathione reductase (p = 0.004), glutathione peroxidase (p = 0.021), protein carbonylation (0.029), lipid peroxidation (p = 0.005), and balance of preoxidative-antioxidative factors (p = 0.006) was increased. CONCLUSIONS: Chronically increased IAP induces alterations to the rabbit diaphragm. Adaptation, equivalent to strenuous contraction, transforms the diaphragm to be functionally more efficient toward workload but makes it vulnerable against oxidative stress. PMID- 22246393 TI - Comparison of metabolic effects of surgical-induced massive weight loss in patients with long-term remission versus non-remission of type 2 diabetes. AB - BACKGROUND: The aim of this study was to evaluate the pathophysiological mechanisms underlying the non-remission of type 2 diabetes in Roux-en-Y gastric bypass (RYGB) patients. METHODS: A group of patients not in remission (NR) was formed (n = 13). A remission group (R) was composed of patients who had undergone normalization of fasting glycemia and A1c, without anti-diabetic drugs and matched for selected baseline characteristics (i.e., duration of disease, previous BMI, final BMI, fat distribution, and age; n = 15). A control group of lean subjects (n = 41) was formed. RESULTS: The NR group had higher uric acid (5.1 vs. 3.9 mg/dL), number of leukocytes (6,866.9 vs. 5,423.6), hs-CRP (0.27 vs. 0.12 mg/dL), MCP-1 (118.4 vs. 64.4 ng/mL), HOMA-IR, and AUC(glucose) but lower adiponectin (9.4 vs. 15.4 ng/mL), leptin (12.7 vs. 20.7 ng/mL), and AUC(GLP-1) in comparison to R group; the NR group also had lower leptin and higher adiponectin, HOMA-IR, AUC(glucose), AUC(C-peptide), AUC(glucagon), and AUC(GLP-1) than controls. The R group had lower MCP-1 and higher adiponectin compared to controls. Insulin sensitivity was significantly lower in the NR group than in the R and control groups. The insulin secretion index values were lower in the NR group than in the R and control groups. CONCLUSIONS: This study found greater insulin resistance, lower insulin secretion, persistent adiposopathy and chronic subclinical inflammation, and less robust incretin response in the NR group despite a similar level of weight loss. Persistently altered pathophysiological mechanisms can be related to the lack of remission of type 2 diabetes after RYGB. PMID- 22246394 TI - Is intake of vitamin D and calcium important for cardiovascular health in elderly obese patients? AB - There is compelling evidence that bariatric weight loss reduces cardiovascular complications; however, these still tend to be the most common cause of late death after surgical intervention. In a prospective cohort study, correlations of dietary nutrients with indexes of vascular health were sought, with emphasis on vitamin D and calcium. Clinically stable obese outpatient subjects (>60 years old, N = 44) were interviewed about dietary macro and micronutrients. Nutritional assessment targeted anthropometric and bioimpedance analysis (BIA), hematologic counts, lipid profile, glucose homeostasis, and inflammatory markers. Carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD), along with related vascular measurements, were documented, and results were correlated by uni- and multivariate analysis, corrected for known risk factors. IMT, FMD, and also brachial basal flow were positively influenced by vitamin D (P < 0.001). Calcium appeared beneficial for brachial basal flow only (P = 0.010). No association with IMT occurred, and a negative result for FMD was elicited. Also, vitamins A and B12 were advantageous for FMD, whereas iron was deleterious for IMT. Intake of many micronutrients including calcium and vitamin D did not meet recommendations. Vitamin D displayed a beneficial profile regarding vascular health, and more attention to this nutrient should be given, especially concerning obese patients with cardiometabolic risk. Calcium exhibited less straightforward results but deserves focus as well, along with antioxidant vitamin A as well as the B-complex which were mostly deficient in this experience. PMID- 22246396 TI - Bariatric surgery and diabetic retinopathy: a pilot analysis. PMID- 22246395 TI - An analysis of 1-3-year follow-up results of laparoscopic sleeve gastrectomy: an Indian perspective. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become very popular nowadays among bariatric surgeons because of its surgical simplicity and good postoperative results. We present our experience on LSG as a single stage primary bariatric procedure for morbid obesity and its 1-3-year follow-up results. METHODS: Between March 2008 and March 2011, a total of 110 patients underwent laparoscopic sleeve gastrectomy. Two patients were excluded from the study and thus the prospectively maintained data of 108 patients were retrospectively reviewed and outcomes were recorded. RESULTS: The mean patient age was 39.3 +/- 11.1 years, mean body mass index was 44.5 +/- 6.8, mean excess body weight was 54.1 +/- 16.3 kg, and the mean American Society of Anesthesiologists score was 3.1 +/- 0.57. The mean operative time for the LSG procedure was 64.8 +/- 10.6 min. The minimum follow-up duration was 6 months and maximum of 36 months. The mean postoperative percent excess body weight loss achieved was 67.5 +/- 13.0 at 1 year, 71.1 +/- 13.8 at 2 years, and 66.09 +/- 14.3 at 3 years. At the end of 3 years, there was 83.3% resolution in diabetes, 85.7% resolution in hypertension, and 85.71% resolution in dyslipidemia. There were no reports of postoperative hemorrhage, gastric leak, deep venous thrombosis, pulmonary embolism, delayed gastric tube stricture, and operative mortality. CONCLUSIONS: LSG is a safe and effective bariatric procedure with low perioperative complications. Before it is considered as a single stage primary procedure, a long-term prospective comparative study with other bariatric procedures is required. PMID- 22246397 TI - Cetuximab inhibits the growth of mucinous ovarian carcinoma tumor cells lacking KRAS gene mutations. AB - The purpose of this study was to explore the possibility of targeted molecular therapy with anti-epidermal growth factor receptor (anti-EGFR) antibody (cetuximab) for the treatment of mucinous ovarian carcinoma. We analyzed EGFR protein expression and KRAS gene mutations in 5 mucinous ovarian carcinoma cell lines RMUG-L, RMUG-S, MN-1, OMC-1 and MCAS and evaluated the in vitro and in vivo effects of cetuximab on each. EGFR expression was observed in all cell lines except for MN-1 cells, and a KRAS gene mutation at codon 12 was detected only in the MCAS cell line. Cetuximab inhibited RMUG-L and OMC-1 cell growth in vitro and completely blocked RMUG-L tumor growth in vivo. On the other hand, cetuximab did not affect MCAS cell growth in vitro and only partially reduced the MCAS tumor growth in vivo. These results suggest the possibility of targeted molecular therapy with cetuximab for mucinous ovarian carcinoma cells lacking a KRAS gene mutation. PMID- 22246399 TI - Millimeter wave treatment induces apoptosis via activation of the mitochondrial dependent pathway in human osteosarcoma cells. AB - Millimeter wave (MW) is an electromagnetic wave with a wavelength between 1 and 10 mm and a frequency of 30-300 GHz that causes multiple biological effects and has been used as a major component in physiotherapies for the clinical treatment of various types of diseases including cancers. However, the precise molecular mechanism of the anticancer activity of millimeter wave remains to be elucidated. In the present study, we investigated the cellular effects of the MW in the U-2OS human osteosarcoma cell line. Our results showed that MW induced cell morphological changes and reduced cell viability in a dose- and time-dependent manner suggesting that MW inhibited the growth of U-2OS cells as demonstrated. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. In addition, MW treatment caused loss of plasma membrane asymmetry, release of cytochrome c, collapse of mitochondrial membrane potential, activation of caspase 9 and -3, and increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Taken together, the results indicate that the U-2OS cell growth inhibitory activity of MW was due to mitochondrial-mediated apoptosis, which may partly explain the anticancer activity of millimeter wave treatment. PMID- 22246398 TI - Drug interaction and pharmacokinetic modeling of oxcarbazepine in korean patients with epilepsy. AB - OBJECTIVES: To determine first whether there was a clear relationship between concentrations of the active metabolite of oxcarbazepine (OXC), 10 hydroxycarbamazepine (OHC), and dose adjusted for weight, and second, whether the clearance of OHC was influenced by comedication with enzyme-inducing antiepileptic drugs (EIAED). METHODS: We analyzed 254 cases (patients 3-80 years of age) of OXC therapeutic drug monitoring, retrospectively. The cases were categorized into OXC monotherapy (n = 78), OXC in combination with EIAED (n = 73), and OXC in combination with non-EIAED (n = 103). The serum OHC concentrations of predose samples were measured by high-performance liquid chromatography. A population pharmacokinetic model was developed using NONMEM. RESULTS: The mean +/- SD serum concentration of OHC was 14.47 +/- 8.28 MUg/mL at a mean daily dose of 16.22 +/- 7.99 mg/kg. The serum concentration of OHC was correlated with the OXC dose per body weight (r = 0.6005; P < 0.0001). No association was found between OHC concentration and patient age, weight, sex, or seizure type. The concentration-to-dose ratio on OXC in combination with EIAED was significantly lower than that on OXC monotherapy (P = 0.002) or OXC in combination with non-EIAED (P < 0.0001). In population pharmacokinetic modeling, the apparent clearance of OHC was higher by 31.2% in combination with EIAED than in other groups. CONCLUSIONS: The serum concentration of OHC was statistically significantly correlated with the dose of OXC and negatively correlated with comedication of EIAED. Population pharmacokinetic analysis showed that the apparent clearance of OHC increased with comedication with EIAEDs. PMID- 22246400 TI - Evidence for dynamics in proteins as a mechanism for ligand dissociation. AB - Signal transduction, regulatory processes and pharmaceutical responses are highly dependent upon ligand residence times. Gaining insight into how physical factors influence residence times (1/k(off)) should enhance our ability to manipulate biological interactions. We report experiments that yield structural insight into k(off) involving a series of eight 2,4-diaminopyrimidine inhibitors of dihydrofolate reductase whose binding affinities vary by six orders of magnitude. NMR relaxation-dispersion experiments revealed a common set of residues near the binding site that undergo a concerted millisecond-timescale switching event to a previously unidentified conformation. The rate of switching from ground to excited conformations correlates exponentially with the binding affinity K(i) and k(off), suggesting that protein dynamics serves as a mechanical initiator of ligand dissociation within this series and potentially for other macromolecule ligand systems. Although the forward rate of conformational exchange, k(conf,forward), is faster than k(off), the use of the ligand series allowed for connections to be drawn between kinetic events on different timescales. PMID- 22246402 TI - [Ru(bpy)(3)](2+) as a reference in transient absorption spectroscopy: differential absorption coefficients for formation of the long-lived (3)MLCT excited state. AB - Transient absorption spectroscopy and other time-resolved methods are commonly used to study chemical reactions and biological processes induced by absorption of light. In order to scale the signal amplitude or to compare results obtained under different conditions, it is advisable to use a reference system, a standard of convenient and well-defined properties. Finding Tris(bipyridine)ruthenium(ii), [Ru(bpy)(3)](2+), a suitable candidate for a transient-absorption spectroscopy reference due to its favourable photochemical properties, we have determined accurate relative values of differential molar absorption coefficients (Deltaepsilon) for light-induced formation of the metal-to-ligand charge transfer (MLCT) excited triplet state at several relevant wavelengths (wavelengths of commercially available lasers) in the UV and visible regions. We have also attempted to determine the absolute value of Deltaepsilon close to the wavelength of maximum bleaching (~450 nm) and we propose to narrow down the interval of conceivable values for Deltaepsilon(450) from the broad range of published values (-0.88 * 10(4) M(-1)cm(-1) to -1.36 * 10(4) M(-1)cm(-1)) to -1.1 * 10(4) M(-1)cm( 1)+/- 15%. Having ourselves successfully applied [Ru(bpy)(3)](2+) as a standard in a recent time-resolved study of enzymatic DNA repair, we would like to encourage other scientists to use this convenient tool as a reference in their future spectroscopic studies on time scales from picoseconds to hundreds of nanoseconds. PMID- 22246401 TI - Chemical chaperones assist intracellular folding to buffer mutational variations. AB - Hidden genetic variations have the potential to lead to the evolution of new traits. Molecular chaperones, which assist protein folding, may conceal genetic variations in protein-coding regions. Here we investigate whether the chemical milieu of cells has the potential to alleviate intracellular protein folding, a possibility that could implicate osmolytes in concealing genetic variations. We found that the model osmolyte trimethylamine N-oxide (TMAO) can buffer mutations that impose kinetic traps in the folding pathways of two model proteins. Using this information, we rationally designed TMAO-dependent mutants in vivo, starting from a TMAO-independent protein. We show that different osmolytes buffer a unique spectrum of mutations. Consequently, the chemical milieu of cells may alter the folding pathways of unique mutant variants in polymorphic populations and lead to unanticipated spectra of genetic buffering. PMID- 22246403 TI - The N-terminally truncated p53 isoform Delta40p53 influences prognosis in mucinous ovarian cancer. AB - OBJECTIVE: The tumor suppressor p53 generates the N-terminally truncated isoforms Delta40p53 and Delta133p53 that possess the ability to modulate p53 function in vitro. The aim of the present study was to evaluate the clinical relevance of p53 isoforms in the main histological subtypes of ovarian cancer. METHODS: Delta40p53, Delta133p53, and full-length p53 (FLp53) expression was determined in 45 mucinous, 30 endometrioid, and 91 serous ovarian cancer specimens as well as 42 normal ovarian tissues using reverse transcriptase-quantitative polymerase chain reaction. In a subgroup of mucinous ovarian cancer cases, Delta40p53 expression was examined using Western blot analysis. A functional yeast-based assay and subsequent sequencing were performed to analyze the p53 mutational status. RESULTS: In endometrioid cancer specimens, Delta133p53 expression was significantly lower than in mucinous and serous cases (P = 0.016) or in normal tissues (P = 0.004). Mucinous cancer samples showed elevated Delta40p53 expression as compared with normal ovarian tissues (P = 0.003). In addition, high Delta40p53 expression constituted an independent prognostic marker for recurrence free but not for overall survival in patients with mucinous ovarian cancer (hazard ratio, 0.267; 95% confidence interval, 0.094-0.756 [P = 0.013]; hazard ratio, 0.453, 95% confidence interval, 0.193-1.064 [P = 0.069]). Western blot analysis confirmed the presence of p53beta and Delta40p53alpha in a subset of patients with mucinous ovarian cancer. Expression of p53 isoforms was not associated with p53 mutational status or clinicopathologic parameters. CONCLUSIONS: We show that expression of p53 isoforms differs in histological subtypes, thus supporting the hypothesis that histological subtypes represent distinct disease entities. In addition, we provide first evidence for a favorable role of Delta40p53 in patients with mucinous ovarian cancer. PMID- 22246404 TI - Accuracy of frozen-section diagnosis of ovarian mucinous tumors. AB - OBJECTIVE: The objective of the study was to evaluate the diagnostic accuracy of intraoperative frozen sections of ovarian mucinous tumors and to identify the features associated with an inaccurate diagnosis. METHODS: Cases of ovarian mucinous tumors (benign, low malignant potential [LMP] or borderline, primary malignant, and metastatic) diagnosed by frozen section or final histology were recruited. Frozen-section diagnoses were compared with the final histologic diagnoses. Possible variables associated with diagnostic discrepancy were analyzed. RESULTS: A comparison of the diagnoses was done in 195 cases (102 benign, 61 LMP, 18 primary malignant, and 14 metastatic). Diagnostic agreement was observed in 164 cases (84.1%) and discrepancy in 31 cases (15.9%). The sensitivity of frozen-section diagnosis was low in LMP (67.2%) and malignant tumors (55.6%). The specificity was the lowest in the benign category (78.5%). The positive predictive values of all categories were less than 90% (range, 83.3% 85.7%). Diagnostic discrepancy was associated with tumor size of greater than 13 cm (P = 0.019) and the number of frozen sections of 4 or more (P = 0.035). However, in a multivariate analysis, there was no independent predictor of diagnostic discrepancy. The number of frozen sections 4 or more was strongly associated with tumor size of greater than 13 cm (P = 0.004). CONCLUSIONS: The sensitivity of frozen-section diagnosis of LMP and malignant mucinous tumors was low. The inaccuracy of a frozen-section diagnosis of ovarian mucinous tumors may be related to a tumor size of greater than 13 cm. Increasing the number of intraoperative samples over 3 sections per case may not effectively increase the accuracy of frozen-section diagnosis in mucinous tumors. PMID- 22246405 TI - Bisprimer--a program for the design of primers for bisulfite-based genomic sequencing of both plant and Mammalian DNA samples. AB - Plants and animals differ in the sequence context of the methylated sites in DNA. Plants exhibit cytosine methylation in CG, CHG, and CHH sites, whereas CG methylation is the only form present in mammals (with an exception of the early embryonic development). This fact must be taken into account in the design of primers for bisulfite-based genomic sequencing because CHG and CHH sites can remain unmodified. Surprisingly, no user-friendly primer design program is publicly available that could be used to design primers in plants and to simultaneously check the properties of primers such as the potential for primer dimer formation. For studies concentrating on particular DNA loci, the correct design of primers is crucial. The program, called BisPrimer, includes 2 different subprograms for the primer design, the first one for mammals and the second one for angiosperm plants. Each subprogram is divided into 2 variants. The first variant serves to design primers that preferentially bind to the bisulfite modified primer-binding sites (C to U conversion). This type of primer preferentially amplifies the bisulfite-converted DNA strands. This feature can help to avoid problems connected with an incomplete bisulfite modification that can sometimes occur for technical reasons. The second variant is intended for the analysis of samples that are supposed to consist of a mixture of DNA molecules that have different levels of cytosine methylation (e.g., pollen DNA). In this case, the aim is to minimize the selection in favor of either less methylated or more methylated molecules. PMID- 22246406 TI - Recent progress in polymorphism-based population genetic inference. AB - The recent availability of whole-genome sequencing data affords tremendous power for statistical inference. With this, there has been great interest in the development of polymorphism-based approaches for the estimation of population genetic parameters. These approaches seek to estimate, for example, recently fixed or sweeping beneficial mutations, the rate of recurrent positive selection, the distribution of selection coefficients, and the demographic history of the population. Yet despite estimating similar parameters using similar data sets, results between methodologies are far from consistent. We here summarize the current state of the field, compare existing approaches, and attempt to reconcile emerging discrepancies. We also discuss the biases in selection estimators introduced by ignoring the demographic history of the population, discuss the biases in demographic estimators introduced by assuming neutrality, and highlight the important challenge to the field of achieving a true joint estimation procedure to circumvent these confounding effects. PMID- 22246407 TI - A comparison of strategies for selecting breeding pairs to maximize genetic diversity retention in managed populations. AB - Captive breeding programs aim to maintain populations that are demographically self-sustaining and genetically healthy. It has been well documented that the best way for managed breeding programs to retain gene diversity (GD) and limit inbreeding is to select breeding pairs that minimize a population's average kinship. We used a series of computer simulations to test 4 methods of minimizing average kinship across a variety of scenarios with varying generation lengths, mortality rates, reproductive rates, and rates of breeding pair success. "Static MK Selection" and "Dynamic MK Selection" are 2 methods for iteratively selecting genetically underrepresented individuals for breeding, whereas "Ranked MK Selection" and "Simultaneous MK Selection" are 2 methods for concurrently selecting the group of breeding individuals that produce offspring with the lowest average kinship. For populations with discrete generations (24 tested scenarios), we found that the Simultaneous and Ranked MK Selection methods were generally the best, nearly equivalent methods for selecting breeding pairs that retained GD and limited inbreeding. For populations with overlapping generations (198 tested scenarios), we found that Dynamic MK Selection was the most robust method for selecting breeding pairs. We used these results to provide guidelines for identifying which method of minimizing average kinship was most appropriate for various breeding program scenarios. PMID- 22246409 TI - Chloral hydrate sedation in radiology: retrospective audit of reduced dose. AB - BACKGROUND: Chloral hydrate (CH) is safe and effective for sedation of suitable children. OBJECTIVE: The purpose of this study was to assess whether adequate sedation is achieved with reduced CH doses. MATERIALS AND METHODS: We retrospectively recorded outpatient CH sedations over 1 year. We defined standard doses of CH as 50 mg/kg (infants) and 75 mg/kg (children >1 year). A reduced dose was defined as at least 20% lower than the standard dose. RESULTS: In total, 653 children received CH sedation (age, 1 month-3 years 10 months), 42% were given a reduced initial dose. Augmentation dose was required in 10.9% of all children, and in a higher proportion of children >1 year (15.7%) compared to infants (5.7%; P < 0.001). Sedation was successful in 96.7%, and more frequently successful in infants (98.3%) than children >1 year (95.3%; P = 0.03). A reduced initial dose had no negative effect on outcome (P = 0.19) or time to sedation. No significant complications were seen. CONCLUSION: We advocate sedation with reduced CH doses (40 mg/kg for infants; 60 mg/kg for children >1 year of age) for outpatient imaging procedures when the child is judged to be quiet or sleepy on arrival. PMID- 22246408 TI - Plasticity of the myelination genomic fabric. AB - This study aimed to quantify the influence of the astrocyte proximity on myelination genomic fabric (MYE) of oligodendrocytes, defined as the most interconnected and stably expressed gene web responsible for myelination. Such quantitation is important to evaluate whether astrocyte signaling may contribute to demyelination when impaired and remyelination when properly restored. For this, we compared changes in the gene expression profiles of immortalized precursor oligodendrocytes (Oli-neu), stimulated to differentiate by the proximity of nontouching astrocytes or treatment with db-cAMP. In a previous paper, we reported that the astrocyte proximity upregulated or turned-on a large number of myelination genes and substantially enriched the Ca(2+)-signaling and cytokine receptor regulatory networks of MYE in Oli-neu cells. Here, we introduce the "transcriptomic distance" to evaluate fabric remodeling and "pair-wise relevance" to identify the most influential gene pairs. Together with the prominence gene analysis used to select and rank the fabric genes, these novel analytical tools provide a comprehensively quantitative view of the physio/pathological transformations of the transcriptomic programs of myelinating cells. Applied to our data, the analyses revealed not only that the astrocyte neighborhood is a substantially more powerful regulator of myelination than the differentiating treatment but also the molecular mechanisms of the two differentiating paradigms are different. By inducing a profound remodeling of MYE and regulatory transcriptomic networks, the astrocyte-oligodendrocyte intercommunication may be considered as a major player in both pathophysiology and therapy of neurodegenerative diseases related to myelination. PMID- 22246410 TI - Increasing feasibility and patient comfort of MRI in children with juvenile idiopathic arthritis. AB - BACKGROUND: MRI is the most sensitive imaging modality in juvenile idiopathic arthritis (JIA), but has practical limitations. Optimizing the scanning protocol is, therefore, necessary to increase feasibility and patient comfort. OBJECTIVE: To determine the feasibility of bilateral non-contrast-enhanced open-bore MRI of knees and to assess the presence of literature-based MRI features in unsedated children with JIA. MATERIALS AND METHODS: Children were classified into two clinical subgroups: active arthritis (group 1; n = 29) and inactive disease (group 2; n = 18). MRI features were evaluated using a literature-based score, comprising synovial hypertrophy, cartilage lesions, bone erosions, bone marrow changes, infrapatellar fat pad heterogeneity, effusion, tendinopathy and popliteal lymphadenopathy. RESULTS: The MRI examination was successfully completed in all 47 children. No scan was excluded due to poor image quality. Synovial hypertrophy was more frequent in group 1 (36.2%), but was also seen in 19.4% of the knees in group 2. Infrapatellar fat pad heterogeneity was more prevalent in group 2 (86.1%; P = 0.008). Reproducibility of the score was good (Cohen kappa, 0.49-0.96). CONCLUSION: Bilateral non-contrast-enhanced open-bore knee MRI is feasible in the assessment of disease activity in unsedated children with JIA. Signs differing among children with active and inactive disease include infrapatellar fat pad heterogeneity and synovial hypertrophy. PMID- 22246411 TI - Deep sedation in pediatric imaging: efficacy and safety of intravenous chlorpromazine. AB - BACKGROUND: The quality of MRI and CT depends largely on immobility of the patient during the procedure, which is often difficult to achieve without sedation in children below the age of 6 years. OBJECTIVE: To assess the efficacy and safety of intravenous chlorpromazine sedation for repeated imaging in young children treated for cancer. MATERIALS AND METHODS: From July 2003 to January 2007, information on children younger than 6 years of age having MRI or CT was prospectively collected. Forty-five minutes before the scan, a 10-min infusion of chlorpromazine 0.5 mg/kg was administered and managed by non-anesthetic staff. Patient monitoring included continuous measurement of pulse, respiration, oxygen saturation and arterial blood pressure. Procedure-related parameters and adverse events were documented. Sedation was considered successful when the procedure was completed and at least 95% of images were usable. RESULTS: One-hundred-one procedures (82 MRI, 19 CT) were evaluated in 62 children, 3-74 months old. Adequate sedation was achieved in 96% of cases, with mean induction time, 22 min; mean duration of sleep, 72 min, and mean duration of procedure, 33 min. Mean time spent in the radiology unit was 104 min. Ninety-six percent of imaging procedures were successfully completed. No cardiac, respiratory, neurological or allergic complication occurred. CONCLUSION: Intravenous chlorpromazine is safe and effective for procedural sedation in young children with cancer undergoing MRI and CT. PMID- 22246413 TI - Percutaneous drainage of intra-abdominal abscess in children with perforated appendicitis. AB - BACKGROUND: Because the surgical management of perforated appendicitis remains controversial, percutaneous catheter drainage (PCD) has gained favor for managing periappendiceal abscess in hemodynamically stable children. OBJECTIVE: To determine the safety and effectiveness of PCD in children with perforated appendicitis and to identify any variables of prognostic value. MATERIALS & METHODS: We retrospectively evaluated clinical data and imaging features for 33 children undergoing PCD for periappendiceal abscess from October 2006 to February 2010. Those with preprocedural CT studies were assigned to one of three risk categories based on imaging features. RESULTS: Appendectomy was successfully postponed for all patients. Our technical success rate was 87.9%, with three recurrences (two requiring repeat drainage, one managed conservatively) and one possible complication (enterocutaneous fistula formation). Children with large and diffuse abscesses had a 50% rate of technical failure, which was significantly increased when compared to children with large but localized abscesses (P < 0.028). Extraluminal appendicolith, extraluminal gas, leukocytosis, ileus/obstruction and procedural variables were not reliable predictors of outcome. CONCLUSION: PCD can be effective for managing perforated appendicitis in children. Children with large and ill-defined abscess might be at increased risk for complication or recurrence. PMID- 22246414 TI - Are routine pelvic radiographs in major pediatric blunt trauma necessary? AB - BACKGROUND: Screening pelvic radiographs to rule out pelvic fractures are routinely used for the initial evaluation of pediatric blunt trauma. Recently, the utility of routine pelvic radiographs in certain subsets of patients with blunt trauma has been questioned. There is a growing amount of evidence that shows the clinical exam is reliable enough to obviate the need for routine screening pelvic radiographs in children. OBJECTIVE: To identify variables that help predict the presence or absence of pelvic fractures in pediatric blunt trauma. MATERIALS AND METHODS: We conducted a retrospective study from January 2005 to January 2010 using the trauma registry at a level 1 pediatric trauma center. We analyzed all level 1 and level 2 trauma victims, evaluating history, exam and mechanism of injury for association with the presence or absence of a pelvic fracture. RESULTS: Of 553 level 1 and 2 trauma patients who presented during the study period, 504 were included in the study. Most of these children, 486/504 (96.4%), showed no evidence of a pelvic fracture while 18/504 (3.6%) had a pelvic fracture. No factors were found to be predictive of a pelvic fracture. However, we developed a pelvic fracture screening tool that accurately rules out the presence of a pelvic fracture P = 0.008, NPV 99, sensitivity 96, 8.98 (1.52 52.8). This screening tool combines eight high-risk clinical findings (pelvic tenderness, laceration, ecchymosis, abrasion, GCS <14, positive urinalysis, abdominal pain/tenderness, femur fracture) and five high-risk mechanisms of injury (unrestrained motor vehicle collision [MVC], MVC with ejection, MVC rollover, auto vs. pedestrian, auto vs. bicycle). CONCLUSION: Pelvic fractures in pediatric major blunt trauma can reliably be ruled out by using our pelvic trauma screening tool. Although no findings accurately identified the presence of a pelvic fracture, the screening tool accurately identified the absence of a fracture, suggesting that pelvic radiographs are not warranted in this subset of patients. PMID- 22246415 TI - Simpson's paradox - aggregating and partitioning populations in health disparities of lung cancer patients. AB - It is well known that non-small cell lung cancer (NSCLC) is a heterogeneous group of diseases. Previous studies have demonstrated genetic variation among different ethnic groups in the epidermal growth factor receptor (EGFR) in NSCLC. Research by our group and others has recently shown a lower frequency of EGFR mutations in African Americans with NSCLC, as compared to their White counterparts. In this study, we use our original study data of EGFR pathway genetics in African American NSCLC as an example to illustrate that univariate analyses based on aggregation versus partition of data leads to contradictory results, in order to emphasize the importance of controlling statistical confounding. We further investigate analytic approaches in logistic regression for data with separation, as is the case in our example data set, and apply appropriate methods to identify predictors of EGFR mutation. Our simulation shows that with separated or nearly separated data, penalized maximum likelihood (PML) produces estimates with smallest bias and approximately maintains the nominal value with statistical power equal to or better than that from maximum likelihood and exact conditional likelihood methods. Application of the PML method in our example data set shows that race and EGFR-FISH are independently significant predictors of EGFR mutation. PMID- 22246416 TI - Gender-based violence and mental disorders in female college students. AB - PURPOSE: To assess the association between gender-based violence and DSM-IV Axis I disorders in female college students. METHODS: A stratified random sample of 1,043 college women (average age 22.2 years) participated in the study. We collected sociodemographic, socioeconomic and academic information as well as information on the participants' experience of gender-based violence victimization. The presence of mental disorders during the 12 months preceding the study was assessed by clinically trained interviewers applying the Structured Clinical Interview for DSM-IV Axis I disorders-Clinician Version (SCID-CV). RESULTS: 15.2% of the participants reported lifetime gender-based violence victimization. Almost two-thirds of the victims had suffered some Axis I disorder during the past year, a significantly larger proportion than among non-victims (OR = 3.72; 95% CI 2.61-5.30). Mood disorders and anxiety disorders were both significantly more common among victims than non-victims (OR = 4.26; 95% CI 2.81 6.46 and OR = 1.97; 95% CI 1.20-3.24, respectively). The most prevalent individual disorder among victims was major depressive disorder (26.41%). Among victims of purely psychological violence, the overall rate of Axis I disorder was similar to the rate among other victims (67 and 61%, respectively). CONCLUSIONS: Among female university students, the experience of physical or psychological gender-based violence is associated with mental disorder. These findings suggest the need for treatment and prevention interventions designed specifically for this population. PMID- 22246417 TI - Osteopoikilosis: what does the rheumatologist must know about it? AB - Osteopoikilosis (OPK) is a rare, benign, and asymptomatic bone dysplasia that is developed during childhood and persists throughout life. This condition is generally found incidentally on plain radiographies made by other reasons. The main differential diagnosis is osteoblastic metastasis. So, OPK must be in differential diagnosis when bone lesions are identified on plain radiograph to avoid alarming the patient with more serious disease and misdiagnosis. In this paper, we review the clinical manifestation, pathophysiology, diagnosis, and treatment of OPK. PMID- 22246418 TI - Managing cardiovascular risk in patients with chronic inflammatory diseases. AB - The role of traditional risk factors in the development of cardiovascular disease has been well studied. However, the relationship between chronic inflammatory conditions and cardiovascular risk has only recently been appreciated. Expression of numerous pro-inflammatory cytokines is common to the pathogenesis of both atherosclerosis and other chronic inflammatory diseases and may suggest that systemic inflammation independently contributes to elevated risk. This article examines the magnitude of cardiovascular risk in several of the most common chronic inflammatory diseases and summarizes currently available data to discern whether this risk is largely due to the presence of co-existing traditional risk factors for cardiovascular disease or the effect of increased systemic inflammation. Evidence is summarized to show which therapies may positively or negatively impact cardiovascular risk. Evidence is discussed in context of practical patient management tools, appropriate treatment based on risk, and treatment targets for high-risk patients. Overall, patients with chronic inflammatory diseases are at an often underestimated increase in cardiovascular risk and require individualized therapy and specific patient management strategies to address the disease process, cardiovascular risk factors, and comorbidities. PMID- 22246419 TI - Different clinical presentation of the hyperimmunoglobulin D syndrome (HIDS) (four cases from Turkey). AB - Hyperimmunoglobulin D syndrome (HIDS) is one of the autoinflammatory syndromes which are characterized by febrile attacks. Duration and frequency of the febrile attacks, as well as typical organ involvements vary greatly. Recently, it is possible to reach more reliable data by the possibilities that are opened up by molecular genetics in order to highlight the aetiopathogenesis of this group of diseases. Typical patients with HIDS have an onset of disease in the first year of life. Here, we report four Turkish HIDS cases; three of whom, the symptoms started at a later age. The diagnoses were made by relevant clinical symptoms along with MVK mutations detected by DNA sequencing method. As summarised in this article, HIDS could be presented with a broad spectrum of symptoms. Although most of the HIDS patients are reported from Europe and especially Dutch ancestry, case reports are presented from all over the world. For this reason, HIDS should be kept in mind for the differential diagnosis of periodic fever syndromes or before accepting an FMF patient as colchichine resistant. We suppose that the phenomenon of "later-onset HIDS" should shed light into unresolved clinical problems of patients with periodic fever. Especially in countries that FMF is more frequent such as Turkey, even though the symptoms start later than classic cases, HIDS should be kept in mind for differential diagnosis of periodic fever syndromes. PMID- 22246421 TI - Gold nanoparticles generated by thermolysis of "all-in-one" gold(I) carboxylate complexes. AB - Consecutive synthesis methodologies for the preparation of the gold(I) carboxylates [(Ph(3)P)AuO(2)CCH(2)(OCH(2)CH(2))(n)OCH(3)] (n = 0-6) (6a-g) are reported, whereby selective mono-alkylation of diols HO(CH(2)CH(2)O)(n)H (n = 0 6), Williamson ether synthesis and metal carboxylate (Ag, Au) formation are the key steps. Single crystal X-ray diffraction studies of 6a (n = 0) and 6b (n = 1) were carried out showing that the P-Au-O unit is essentially linear. These compounds were applied in the formation of gold nanoparticles (NP) by a thermally induced decomposition process and hence the addition of any further stabilizing and reducing reagents, respectively, is not required. The ethylene glycol functionalities, providing multiple donating capabilities, are able to stabilise the encapsulated gold colloids. The dependency of concentration, generation time and ethylene glycol chain lengths on the NP size and size distribution is discussed. Characterisation of the gold colloids was performed by TEM, UV/Vis spectroscopy and electron diffraction studies revealing that Au NP are formed with a size of 3.3 (+/-0.6) to 6.5 (+/-0.9) nm in p-xylene with a sharp size distribution. Additionally, a decomposition mechanism determined by TG-MS coupling experiments of the gold(i) precursors is reported showing that 1(st) decarboxylation occurs followed by the cleavage of the Au-PPh(3) bond and finally release of ethylene glycol fragments to give Au-NP and the appropriate organics. PMID- 22246420 TI - The effect of oral tolerance on the roles of small intestinal intraepithelial lymphocytes in murine colitis induced by dextran sodium sulfate. AB - BACKGROUNDS AND AIMS: There is increasing evidence that gut-derived intraepithelial lymphocytes have potent cytolytic and immunoregulatory functions, which they use to sustain epithelial integrity. The aims of this study were to investigate the roles of small intestinal intraepithelial lymphocytes (SI-IELs) in oral tolerance and dextran sodium sulfate (DSS)-induced colitis. METHODS: SI IELs or sorted gammadelta T cells from untreated, colitis, and colitis-extracted protein (CEP)-fed colitis mice were adoptively transferred to BALB/c mice; colitis was then induced with DSS. Cytokines were analyzed in sera from mice and culture supernatants. RESULTS: Transfer of SI-IELs or sorted gammadelta T cells from untreated and colitis mice all alleviated experimental colitis. Mice orally administered with five low doses of CEP showed less severe symptoms and histological injury. SI-IELs from CEP-fed colitis mice more significantly ameliorated colitis than those from control mice (weight, 94.1 +/- 2.5% vs. 89.8 +/- 2.6%, p < 0.05; disease activity index, 7.2 +/- 1.2 vs. 8.7 +/- 1.9, p < 0.05; histological scores, 22.1 +/- 2.8 vs. 25.7 +/- 2.1, p < 0.05, n = 8 per group); however, not did SI-gammadelta IELs from CEP-fed colitis mice. Alleviation of colitis was accompanied by an increase of TGF-beta1 secretion and no change of IFN-gamma in sera and culture supernatants. The level of serum TGF beta1 was negatively related to the severity of colitis. CONCLUSIONS: The protective effects of SI-IELs in DSS-induced colitis were partly accomplished by gammadelta T cells and could be mediated by TGF-beta but were not associated with IFN-gamma. Oral tolerance strengthens the suppressive effects of regulatory subsets in SI-IELs. PMID- 22246422 TI - Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking. AB - BACKGROUND: Cytochrome P4501A2 (CYP1A2) presents a high interindividual variability in its activity and also in its inducibility by smoking. Cytochrome P450 oxidoreductase (POR) is an electron transfer protein that catalyzes the activity of several cytochromes P450. We aimed to study the influence of POR genetic polymorphisms on CYP1A2 activity while smoking and after smoking cessation, as well as on CYP1A2 inducibility. METHODS: CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and in 113 of these smokers who were abstinent during a 4-week period. Participants were genotyped for POR rs17148944G>A, rs10239977C>T, rs3815455C>T, rs2286823G>A, rs2302429G>A, and rs1057868C>T (POR*28) polymorphisms. RESULTS: While smoking, none of the tested POR polymorphisms showed a significant influence on CYP1A2 activity. After smoking cessation, significantly higher CYP1A2 activity was found in POR rs2302429A carriers (P=0.038) and in carriers of rs17148944G-rs10239977C rs3815455T-rs2286823G-rs2302429A-rs1057868T haplotype (P=0.038), whereas carriers of POR rs2286823A (P=0.031) and of the rs17148944G-rs10239977C-rs3815455C rs2286823A-rs2302429G-rs1057868C haplotype (P=0.031) had decreased CYP1A2 activity. In the complete regression model, only POR rs2302429G>A showed a significant effect (P=0.017). No influence of POR genotypes or haplotypes was observed on the inducibility of CYP1A2. CONCLUSION: POR genetic polymorphisms influence CYP1A2 basal but not induced activity and do not seem to influence CYP1A2 inducibility. Future work is warranted to identify other clinical and genetic factors that may explain the variability in CYP1A2 activity and inducibility by smoking. PMID- 22246423 TI - Increased trefoil factor 3 levels in the serum of patients with three major histological subtypes of lung cancer. AB - Lung cancer is the most common cause of cancer-related deaths in the world. The trefoil factor (TFF) family is composed of three thermostable, and protease resistant proteins, named TFF1, TFF2 and TFF3. TFF protein levels have been found to be related to the development of various types of cancer. However, it is still unclear whether TFF proteins are differentially expressed in the serum of different histological subtypes of lung cancer compared to healthy individuals. In this study, we investigated the levels of TFF proteins in serum and lung tissues of 130 lung cancer patients (58 squamous cell lung carcinoma cases, 43 adenocarcinoma cases and 29 SCLC cases) and 60 healthy individuals. It was found that TFF1 and TFF2 have similar or slightly higher levels in these three subtypes of lung cancer compared to healthy individuals, while TFF3 levels were significantly higher in the examined lung cancer cases compared to healthy individuals. Immunoblot analyses of TFF1, TFF2 and TFF3 indicated that lung cancer tissues and lung cancer cell lines have a higher expression of the TFF3 protein, but not of TFF1 or TFF2 proteins, compared to tissues from healthy individuals or from the normal cell line. Quantitative RT-PCR analysis indicated higher levels of TFF3, but not TFF1 and TFF2, transcripts in lung cancer tissues or cell lines. These results show increased TFF3 levels in serum and lung tissues, suggesting that TFF3 may serve as a promising, easily detected biomarker of lung cancer. PMID- 22246424 TI - Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death. AB - The permeability transition pore (PTP) is a mitochondrial inner membrane channel involved in cell death. The inhibition of PTP opening has been proved to be an effective strategy to prevent cell death induced by oxidative stress. Several ubiquinone analogs are known to powerfully inhibit PTP opening with an effect depending on the studied cell line. Here, we have studied the effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)) and ubiquinone 10 (Ub(10)) on PTP regulation, H(2)O(2) production and cell viability in U937 cells. We found that Ub(0) induced both PTP opening and H(2)O(2) production. Ub(5) did not regulate PTP opening yet induced H(2)O(2) production. Ub(10) potently inhibited PTP opening yet induced H(2)O(2) production. Both Ub(0) and Ub(5) induced cell death, whereas Ub(10) was not toxic. Moreover, Ub(10) prevented tert-butyl hydroperoxide induced PTP opening and subsequent cell death. We conclude that PTP-inhibitor ubiquinone analogs are able to prevent PTP opening-induced cell death only if they are not toxic per se, which is the case when they have no or low pro-oxidant activity. PMID- 22246425 TI - NDRG2 is involved in the oncogenic properties of renal cell carcinoma and its loss is a novel independent poor prognostic factor after nephrectomy. AB - BACKGROUND: Although NDRG2 is a candidate tumor suppressor, its exact role in renal cell carcinoma (RCC) is not fully understood. We investigated the functional role of NDRG2 and its clinical relevance in RCC tumorigenesis. METHODS: NDRG2 expression and its clinical implications in clear cell RCC were evaluated. Biological function was assessed by a proliferation assay, anchorage independent growth assay, and wound healing and transwell migration assays in RCC cell lines overexpressing NDRG2 coupled with an investigation of the effects of NDRG2 expression on the epithelial-mesenchymal transition (EMT). RESULTS: NDRG2 was differentially expressed in patients with RCC. A loss of NDRG2 was significantly associated with a higher proportion of tumors >10 cm and a high nuclear grade. Furthermore, multivariate analyses indicated that a loss of NDRG2 was an independent poor prognostic factor for patient survival (recurrence-free survival, hazard ratio 7.901; disease-specific survival, hazard ratio 15.395; overall survival, hazard ratio 11.339; P < 0.001 for all parameters). NDRG2 expression inhibited the anchorage-independent growth and migration of RCC cells. NDRG2 expression also modulated the expression of EMT-related genes such as Snail, Slug, and SIP1, and it decreased EMT signaling in RCC cells. Finally, NDRG2 recovered E-cadherin expression in E-cadherin-negative RCC cells. CONCLUSIONS: These results indicate that a lack of NDRG2 is associated with oncogenic properties through the loss of its role as a tumor suppressor, and that NDRG2 is an independent poor prognostic factor predicting survival in clear cell RCC, suggesting that it can serve as a novel prognostic biomarker. PMID- 22246426 TI - Evaluation of the seventh edition of American Joint Committee on Cancer TNM staging system for gastric cancer: results from a Chinese monoinstitutional study. AB - BACKGROUND: To investigate the validity of the 7th edition of American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer with special attention paid to pT2/pT3, pN1/pN2, and pN3a/pN3b category. MATERIALS AND METHODS: Clinicopathologic data of 1998 patients underwent R0 surgery for histologically proven gastric cancers with >15 lymph nodes retrieved were retrospectively reviewed. RESULTS: Prognoses were significantly different between pT2 and pT3 categories, between pN1 and pN2 categories, or between pN3a and pN3b categories. Each stage in the 6th edition was divided into the 7th edition stage with different survival rates. Moreover, stage IIIA, IIIB, and IIIC in the 7th edition system was divided into the 6th edition stage with different survival rates. Prognoses for patients in 7th edition T4aN1M0/T3N2M0/T2N3aM0, T4bN0 1M0/T4aN2M0/T3N3aM0, and T4aN3aM0/T4bN2M0 were similar to that of patients in T1N3bM0, T2N3bM0, and T3N3bM0, respectively, but significantly better than that of patients in T2N3bM0, T3N3bM0, and T4aN3bM0, respectively. However, no significant difference could be observed among patients in T4bN3aM0, T4aN3bM0, T4bN3bM0, and stage IV. A revised TNM system was proposed, in which T1N3bM0 was incorporated into stage IIIA, T2N3bM0 into stage IIIB, T3N3bM0 into stage IIIC, T4bN3aM0/T4aN3bM0/T4bN3bM0 into stage IV. Further analyses revealed the revised TNM system had better homogeneity, discriminatory ability, and monotonicity of gradients than the 6th and the 7th edition system. CONCLUSIONS: It is reasonable to subclassify the 6th edition pT2 category and pN1 category into the 7th edition pT2/pT3 category and pN1/pN2 category, respectively. However, for better prognostic stratification, it might be more suitable for pN3a and pN3b categories to be considered individual determinants of the 7th edition TNM staging system. PMID- 22246427 TI - Clinical implication of elastography as a prognostic factor of papillary thyroid microcarcinoma. AB - BACKGROUND: A firm and hard thyroid nodule on palpation is known to be associated with an increased risk of thyroid malignancy. Elastography has been introduced to evaluate the tissue hardness objectively. We investigated the clinical implications of elastography as a prognostic factor in patients with papillary thyroid microcarcinoma. METHODS: Elastography images were classified according to Rago scores of 1-5. Malignancies with Rago scores of 4 or 5 were considered as "hard" and remaining malignancies as "soft." Clinicopathologic characteristics were compared between patients with hard or soft malignancies according to the extrathyroidal extension and central and lateral lymph node metastasis by using chi-square tests, Fisher's exact test, and independent t tests. Odds ratios with 95% confidence intervals were calculated for evaluating the factors for predicting extrathyroidal extension and central and lateral lymph node metastasis. RESULTS: A hard malignancy on the Rago score was significantly associated with pathologic extrathyroidal extension compared with a soft malignancy (P=0.001). The odds ratio of a hard malignancy on the Rago score for predicting extrathyroidal extension was 5.060 (95% confidence interval, 1.565 16.358). A hard malignancy on Rago scores was not associated with central or lateral lymph node metastasis. CONCLUSIONS: A hard malignancy on the Rago score of elastography was an independent factor for predicting pathologic extrathyroidal extension on pathology. PMID- 22246428 TI - Cu-catalyzed asymmetric [3+2] cycloaddition of alpha-iminoamides with activated olefins. AB - A variety of 2-amido pyrrolidines, including Weinreb-type amides, have been prepared with very high exo diastereoselectivity and enantioselectivitiy in the reaction of alpha-iminoamides with activated alkenes catalyzed by Cu(I)-Segphos ligands. PMID- 22246430 TI - Comparison of separations of fatty acids from fish products using a 30-m Supelcowax-10 and a 100-m SP-2560 column. AB - Commercial fish oils and foods containing fish may contain trans and/or isomerized fatty acids (FA) produced during processing or as part of prepared foods. The current American Oil Chemists' Society (AOCS) official method for marine oils (method Ce 1i-07) is based on separation by use of poly(ethylene glycol) (PEG) columns, for example Supelcowax-10 or equivalent, which do not resolve most unsaturated FA geometric isomers. Highly polar 100-m cyanopropyl siloxane (CPS) columns, for example SP-2560 and CP Sil 88 are recommended for separation of geometric FA isomers. Complementary separations were achieved by use of two different elution temperature programs with the same CPS column. This study is the first direct comparison of the separations achieved by use of 30-m Supelcowax-10 and 100-m SP-2560 columns for fatty acid methyl esters (FAME) prepared from the same fish oil and fish muscle sample. To simplify the identification of the FA in these fish samples, FA were fractionated on the basis of the number and type of double bonds by silver-ion solid-phase extraction (Ag+ SPE) before GC analysis. The results showed that a combination of the three GC separations was necessary to resolve and identify most of the unsaturated FA, FA isomers, and other components of fish products, for example phytanic and phytenic acids. Equivalent chain length (ECL) values of most FAME in fish were calculated from the separations achieved by use of both GC columns; the values obtained were shown to be consistent with previously reported values for the Supelcowax-10 column. ECL values were also calculated for the FA separated on the SP-2560 column. The calculated ECL values were equally valid under isothermal and temperature-programmed elution GC conditions, and were valuable for confirmation of the identity of several unsaturated FAME in the fish samples. When analyzing commercially prepared fish foods, deodorized marine oils, or foods fortified with marine oils it is strongly recommended that quantitative data acquired by use of PEG columns is complemented with data obtained from separations using highly polar CPS columns. PMID- 22246429 TI - Using the time-varying effect model (TVEM) to examine dynamic associations between negative affect and self confidence on smoking urges: differences between successful quitters and relapsers. AB - With technological advances, collection of intensive longitudinal data (ILD), such as ecological momentary assessments, becomes more widespread in prevention science. In ILD studies, researchers are often interested in the effects of time varying covariates (TVCs) on a time-varying outcome to discover correlates and triggers of target behaviors (e.g., how momentary changes in affect relate to momentary smoking urges). Traditional analytical methods, however, impose important constraints, assuming a constant effect of the TVC on the outcome. In the current paper, we describe a time-varying effect model (TVEM) and its applications to data collected as part of a smoking-cessation study. Differentiating between groups of short-term successful quitters (N = 207) and relapsers (N = 40), we examine the effects of momentary negative affect and abstinence self-efficacy on the intensity of smoking urges in each subgroup in the 2 weeks following a quit attempt. Successful quitters demonstrated a rapid reduction in smoking urges over time, a gradual decoupling of the association between negative affect and smoking urges, and a consistently strong negative effect of self-efficacy on smoking urges. In comparison, relapsers exhibited a high level of smoking urges throughout the post-quit period, a time-varying and, generally, weak effect of self-efficacy on smoking urges, and a gradual reduction in the strength of the association between negative affect and smoking urges. Implications of these findings are discussed. The TVEM is made available to applied prevention researchers through a SAS macro. PMID- 22246431 TI - Puerarin suppresses production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through regulating MAPK phosphorylation, O-GlcNAcylation and NF-kappaB translocation. AB - Microglial cells play a critical role in mediating central nervous system inflammatory processes. Activated microglial cells induced by proinflammatory factor, such as lipopolysaccharide (LPS), release many kinds of neurotoxic cytokines including reactive oxygen species (ROS) which contributes to the pathogenesis of neurodegenerative diseases. Puerarin, extracted from kudzu root, possesses the characteristic of neuroprotection, antioxidation and anticancer. In the present study, we observed that LPS induced over-production of nitric oxide (NO) and increased the level of intracellular ROS in N9 microglial cells, but it was inhibited by puerarin. Furthermore, treatment with puerarin on N9 cells suppressed the over-expression of inducible nitric oxide synthase (iNOS) induced by LPS which is implicated in intracellular O-linked beta-N-acetylglucosamine (O GlcNAc) level, phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) signaling pathway. We also observed that the enhanced phosphorylation of p38, JNK and ERK1/2 in N9 cells induced by LPS were inhibited by puerarin, otherwise the down-regulation of O-GlcNAcylation level of protein in N9 cell induced by LPS was up-regulated by pretreatment with puerarin. These results indicate that puerarin effectively inhibits microglia activation induced by LPS through inhibiting expression of iNOS, production of NO and ROS which was mediated via regulating O-GlcNAcylation, phosphorylation of MAPK and NF kappaB translocation. PMID- 22246432 TI - Food for folivores: nutritional explanations linking diets to population density. AB - Ecologists want to explain why populations of animals are not evenly distributed across landscapes and often turn to nutritional explanations. In seeking to link population attributes with food quality, they often contrast nutritionally positive traits, such as the concentration of nitrogen, against negative ones, such as fibre concentration, by using a ratio of these traits. This specific ratio has attracted attention because it sometimes correlates with the biomass of colobine primates across sites in Asia and Africa. Although empirically successful, we have identified problems with the ratio that may explain why it fails under some conditions to predict colobine biomass. First, available nitrogen, rather than total nitrogen, is nutritionally important, while the presence of tannins is the major factor reducing the availability of nitrogen in browse plant species. Second, tannin complexes inflate measures of fibre. Finally, simple ratios may be unsound statistically because they implicitly assume isometric relationships between variables. We used data on the chemical composition of plants from three continents to examine the relationships between the concentrations of nitrogen, available nitrogen, fibre and tannins in foliage and to evaluate the nitrogen to fibre ratio. Our results suggest that the ratio of the concentration of nitrogen to fibre in leaves does sometimes closely correlate with the concentration of available nitrogen. However, the ratio may give misleading results when leaves contain high concentrations of tannins. The concentration of available nitrogen, which incorporates measures of total nitrogen, dry matter digestibility and tannins, should give a better indication of the nutritional value of leaves for herbivorous mammals that can readily be extrapolated to habitats. PMID- 22246433 TI - Regulation of neuronal input transformations by tunable dendritic inhibition. AB - Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons. PMID- 22246434 TI - A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction. AB - NMDA receptors (NMDARs) are glutamate-gated ion channels that are present at most excitatory mammalian synapses. The four GluN2 subunits (GluN2A-D) contribute to four diheteromeric NMDAR subtypes that have divergent physiological and pathological roles. Channel properties that are fundamental to NMDAR function vary among subtypes. We investigated the amino acid residues responsible for variations in channel properties by creating and examining NMDARs containing mutant GluN2 subunits. We found that the NMDAR subtype specificity of three crucial channel properties, Mg(2+) block, selective permeability to Ca(2+) and single-channel conductance, were all controlled primarily by the residue at a single GluN2 site in the M3 transmembrane region. Mutant cycle analysis guided by molecular modeling revealed that a GluN2-GluN1 subunit interaction mediates the site's effects. We conclude that a single GluN2 subunit residue couples with the pore-forming loop of the GluN1 subunit to create naturally occurring variations in NMDAR properties that are critical to synaptic plasticity and learning. PMID- 22246435 TI - Preferential encoding of visual categories in parietal cortex compared with prefrontal cortex. AB - The ability to recognize the behavioral relevance, or category membership, of sensory stimuli is critical for interpreting the meaning of events in our environment. Neurophysiological studies of visual categorization have found categorical representations of stimuli in prefrontal cortex (PFC), an area that is closely associated with cognitive and executive functions. Recent studies have also identified neuronal category signals in parietal areas that are typically associated with visual-spatial processing. It has been proposed that category related signals in parietal cortex and other visual areas may result from 'top down' feedback from PFC. We directly compared neuronal activity in the lateral intraparietal (LIP) area and PFC in monkeys performing a visual motion categorization task. We found that LIP showed stronger, more reliable and shorter latency category signals than PFC. These findings suggest that LIP is strongly involved in visual categorization and argue against the idea that parietal category signals arise as a result of feedback from PFC during this task. PMID- 22246436 TI - Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. AB - Cortical plasticity is most evident during a critical period in early life, but the mechanisms that restrict plasticity after the critical period are poorly understood. We found that a developmental increase in the 4-sulfation/6-sulfation (4S/6S) ratio of chondroitin sulfate proteoglycans (CSPGs), which are components of the brain extracellular matrix, leads to the termination of the critical period for ocular dominance plasticity in the mouse visual cortex. Condensation of CSPGs into perineuronal nets that enwrapped synaptic contacts on parvalbumin expressing interneurons was prevented by cell-autonomous overexpression of chondroitin 6-sulfation, which maintains a low 4S/6S ratio. Furthermore, the increase in the 4S/6S ratio was required for the accumulation of Otx2, a homeoprotein that activates the development of parvalbumin-expressing interneurons, and for functional maturation of the electrophysiological properties of these cells. Our results indicate that the critical period for cortical plasticity is regulated by the 4S/6S ratio of CSPGs, which determines the maturation of parvalbumin-expressing interneurons. PMID- 22246437 TI - PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. AB - Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation has been widely studied, the control of PSD-95 cellular expression is not understood. We found that Psd-95 was controlled post-transcriptionally during neural development. Psd-95 was transcribed early in mouse embryonic brain, but most of its product transcripts were degraded. The polypyrimidine tract binding proteins PTBP1 and PTBP2 repressed Psd-95 (also known as Dlg4) exon 18 splicing, leading to premature translation termination and nonsense-mediated mRNA decay. The loss of first PTBP1 and then of PTBP2 during embryonic development allowed splicing of exon 18 and expression of PSD-95 late in neuronal maturation. Re-expression of PTBP1 or PTBP2 in differentiated neurons inhibited PSD-95 expression and impaired the development of glutamatergic synapses. Thus, expression of PSD-95 during early neural development is controlled at the RNA level by two PTB proteins whose sequential downregulation is necessary for synapse maturation. PMID- 22246439 TI - Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma. AB - The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2* daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma. PMID- 22246438 TI - A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors. AB - In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration. PMID- 22246440 TI - The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. AB - A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90alpha, Hsp90beta, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors. PMID- 22246441 TI - Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina. AB - BACKGROUND: Diverse pharmacological effects of anti-platelet thienopyridines due to individual differences in metabolism have been reported. However, an association between on-treatment platelet reactivity and adverse ischemic events after drug-eluting stent (DES) implantation in Japanese patients has not been fully elucidated. METHODS AND RESULTS: A total of 450 consecutive patients on dual anti-platelet therapy (aspirin and ticlopidine) with stable angina who underwent DES implantation were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation was measured before DES implantation using the screen filtration pressure method. The ADP concentration necessary for 50% aggregation was designated as the platelet aggregation threshold index (PATI). A composite primary endpoint of cardiac death, myocardial infarction, target lesion revascularization (TLR), and stent thrombosis occurring within 1 year after stenting, was evaluated. A PATI value <4.8 umol/L was defined as high on treatment reactivity to ADP. The composite primary endpoint occurred in 55 patients (12.2%) in the 1-year-period after DES implantation, and the prevalence was 19.0% and 5.1% in groups with high and low on-treatment reactivity to ADP, respectively, showing a significantly higher prevalence in the high reactivity group (P<0.001). The main event was TLR (18.1% vs. 5.1%, P<0.001). CONCLUSIONS: These data suggested that high on-treatment platelet reactivity to ADP and subsequent occurrence of adverse ischemic events (particularly TLR) were correlated in patients with stable angina who underwent DES implantation. PMID- 22246442 TI - Incorporation of a high potential quinone reveals that electron transfer in Photosystem I becomes highly asymmetric at low temperature. AB - Photosystem I (PS I) has two nearly identical branches of electron-transfer co factors. Based on point mutation studies, there is general agreement that both branches are active at ambient temperature but that the majority of electron transfer events occur in the A-branch. At low temperature, reversible electron transfer between P(700) and A(1A) occurs in the A-branch. However, it has been postulated that irreversible electron transfer from P(700) through A(1B) to the terminal iron-sulfur clusters F(A) and F(B) occurs via the B-branch. Thus, to study the directionality of electron transfer at low temperature, electron transfer to the iron-sulfur clusters must be blocked. Because the geometries of the donor-acceptor radical pairs formed by electron transfer in the A- and B branch differ, they have different spin-polarized EPR spectra and echo-modulation decay curves. Hence, time-resolved, multiple-frequency EPR spectroscopy, both in the direct-detection and pulse mode, can be used to probe the use of the two branches if electron transfer to the iron-sulfur clusters is blocked. Here, we use the PS I variant from the menB deletion mutant strain of Synechocyctis sp. PCC 6803, which is unable to synthesize phylloquinone, to incorporate 2,3 dichloro-1,4-naphthoquinone (Cl(2)NQ) into the A(1A) and A(1B) binding sites. The reduction midpoint potential of Cl(2)NQ is approximately 400 mV more positive than that of phylloquinone and is unable to transfer electrons to the iron-sulfur clusters. In contrast to previous studies, in which the iron-sulfur clusters were chemically reduced and/or point mutations were used to prevent electron transfer past the quinones, we find no evidence for radical-pair formation in the B branch. The implications of this result for the directionality of electron transfer in PS I are discussed. PMID- 22246443 TI - Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. AB - AIMS: The impact of some risk factors for stroke and bleeding, and the value of stroke and bleeding risk scores, in atrial fibrillation (AF), has been debated, as clinical trial cohorts have not adequately tested these. Our objective was to investigate risk factors for stroke and bleeding in AF, and application of the new CHA(2)DS(2)-VASc and HAS-BLED schemes for stroke and bleeding risk assessments, respectively. METHODS AND RESULTS: We used the Swedish Atrial Fibrillation cohort study, a nationwide cohort study of 182 678 subjects with a diagnosis of AF at any Swedish hospital between 1 July 2005 and 31 December 2008, who were prospectively followed for an average of 1.5 years (260 000 years at risk). With the use of the National Swedish Drug Registry, all patients who used an oral anticoagulant anytime during follow-up were identified. Most of the analyses were made on a subset of 90 490 patients who never used anticoagulants. Risk factors for stroke, the composite thromboembolism endpoint (stroke, TIA, or systemic embolism), and bleeding, and the performance of published stroke and bleeding risk stratification schemes were investigated. On multivariable analysis, significant associations were found between the following 'new' risk factors and thromboembolic events; peripheral artery disease [hazard ratio (HR) 1.22 (95% CI 1.12-1.32)], 'vascular disease' [HR 1.14 (1.06-1.23)], prior myocardial infarction [HR 1.09 (1.03-1.15)], and female gender [HR 1.17 (1.11 1.22)]. Previous embolic events, intracranial haemorrhage (ICH), hypertension, diabetes, and renal failure were other independent predictors of the composite thromboembolism endpoint, while thyroid disease (or hyperthyroidism) was not an independent stroke risk factor. C-statistics for the composite thromboembolic endpoint with the CHADS(2) and CHA(2)DS(2)-VASc schemes were 0.66 (0.65-0.66) and 0.67 (0.67-0.68), respectively. On multivariable analysis, age, prior ischaemic stroke or thromboembolism, prior major bleeding events, and hypertension were significant predictors of ICH and major bleeding. Heart failure, diabetes, renal failure, liver disease, anaemia or platelet/coagulation defect, alcohol abuse, and cancer were other significant predictors for major bleeding, but not ICH. The ability for predicting ICH and major bleeding with both bleeding risk schemes (HEMORR(2)HAGES, HAS-BLED) were similar, with c-statistics of ~0.6. CONCLUSION: Several independent risk factors (prior ICH, myocardial infarction, vascular disease, and renal failure) predict ischaemic stroke and/or the composite thromboembolism endpoint in AF, but thyroid disease (or hyperthyroidism) was not an independent risk factor for stroke. There is a better performance for CHA(2)DS(2)-VASc over CHADS(2) schemes for the composite thromboembolism endpoint. While both tested bleeding risk schemes have similar predictive value, the HAS-BLED score has the advantage of simplicity. PMID- 22246444 TI - Early percutaneous mitral commissurotomy vs. conventional management in asymptomatic moderate mitral stenosis. AB - AIMS: The optimal timing of percutaneous mitral commissurotomy (PMC) remains controversial in asymptomatic patients with moderate mitral stenosis (MS). We sought to compare the long-term outcomes of early preemptive PMC and a conventional treatment strategy. METHODS AND RESULTS: From 1997 to 2007, we prospectively enrolled 244 consecutive asymptomatic patients (191 women, age 51 +/- 11 years) with moderate rheumatic MS who were potential candidates for early PMC. The treatment groups were not randomly assigned and the choice of early PMC or conventional treatment for each patient was at the discretion of the attending physician. The primary endpoint was defined as the composite of cardiovascular mortality, cerebral infarction, systemic embolic events, and PMC-related complications. In the PMC group, there were no procedure-related deaths and mitral valve area was increased from 1.26 +/- 0.11 to 2.07 +/- 0.28 cm(2) immediately after PMC (P < 0.001). During a median follow-up of 8.3 years, there were 3 cardiovascular deaths and 5 cerebral infarctions in the PMC group (n= 106) compared with 16 cardiovascular deaths, 12 cerebral infarctions, and 7 systemic embolic events in the CONV group (n = 138). The estimated actuarial 11-year event free survival rate was 89 +/- 4% in the PMC group and 69 +/- 5% in the CONV group (P < 0.001) but not significantly different in those without atrial fibrillation and previous embolism (86 +/- 5% in the PMC group and 79 +/- 6% in the CONV group at 11 years, P = 0.28). For the 62 propensity score-matched pairs, the risk of cardiovascular endpoint was significantly lower in the PMC than in the CONV group (hazard ratio: 0.327; 95% CI: 0.112-0.954; P = 0.041). CONCLUSION: In asymptomatic patients with moderate MS and favourable valve morphology, the clinical benefits of early PMC may outweigh the risks associated with early intervention, but prospective randomized trials are required to confirm the efficacy of early PMC. PMID- 22246445 TI - Single-channel measurements of an N-acetylneuraminic acid-inducible outer membrane channel in Escherichia coli. AB - NanC is an Escherichia coli outer membrane protein involved in sialic acid (Neu5Ac, i.e., N-acetylneuraminic acid) uptake. Expression of the NanC gene is induced and controlled by Neu5Ac. The transport mechanism of Neu5Ac is not known. The structure of NanC was recently solved (PDB code: 2WJQ) and includes a unique arrangement of positively charged (basic) side chains consistent with a role in acidic sugar transport. However, initial functional measurements of NanC failed to find its role in the transport of sialic acids, perhaps because of the ionic conditions used in the experiments. We show here that the ionic conditions generally preferred for measuring the function of outer-membrane porins are not appropriate for NanC. Single channels of NanC at pH 7.0 have: (1) conductance 100 pS to 800 pS in 100 mM: KCl to 3 M: KCl), (2) anion over cation selectivity (V (reversal) = +16 mV in 250 mM: KCl || 1 M: KCl), and (3) two forms of voltage dependent gating (channel closures above +/- 200 mV). Single-channel conductance decreases by 50% when HEPES concentration is increased from 100 MUM: to 100 mM: in 250 mM: KCl at pH 7.4, consistent with the two HEPES binding sites observed in the crystal structure. Studying alternative buffers, we find that phosphate interferes with the channel conductance. Single-channel conductance decreases by 19% when phosphate concentration is increased from 0 mM: to 5 mM: in 250 mM: KCl at pH 8.0. Surprisingly, TRIS in the baths reacts with Ag|AgCl electrodes, producing artifacts even when the electrodes are on the far side of agar-KCl bridges. A suitable baseline solution for NanC is 250 mM: KCl adjusted to pH 7.0 without buffer. PMID- 22246446 TI - Consequences of subacute intratracheal exposure of rats to cadmium oxide nanoparticles: Electrophysiological and toxicological effects. AB - Cadmium (Cd) is a metal used in various industrial applications, thereby causing exposure to Cd-containing fumes. The submicron-sized particles in the fumes represent an extra risk due to their high mobility within the organism and high surface area. Toxicity of Cd on the liver, kidney and bones is well known, but there are less data on its neurotoxicity. Here, male Wistar rats were treated for 3 and 6 weeks by intratracheal instillation of cadmium oxide nanosuspension. The body weight gain in treated rats was significantly decreased, and in the rats treated with high dose (0.4 mg/kg Cd daily), there was a significant increase in the weight of lungs and thymus. In this group, the spectrum of spontaneous cortical electrical activity was shifted to higher frequencies, the latency of sensory-evoked potentials was lengthened, and the frequency following ability of the somatosensory evoked potential was impaired--even without detectable Cd deposition in the brain. The data support the role of the nano-sized Cd in the causation of nervous system damage and show the possibility of modeling human neurotoxic damage in rats. PMID- 22246447 TI - Treatment should be considered a competing risk when predicting natural conception in subfertile women. AB - BACKGROUND: Prediction of natural conception in subfertile couples can help to differentiate between couples who should have immediate treatment and couples who can aim for natural conception for some time. Natural conception rates are often estimated using standard techniques such as Kaplan-Meier or Cox proportional hazard models. These estimates can be biased by incorrect handling of data from women who start assisted reproductive technology therapy before the end of the follow-up period. This paper discusses the validity and the impact of the assumption of non-informative censoring as used in the Kaplan-Meier and Cox models. METHODS: In a cohort of 5360 subfertile couples with suspected tubal pathology, the probability of natural conception and the prognostic value of additional tests for tubal pathology were estimated using traditional methods and with a competing risks analysis. RESULTS: The estimated probability of natural conception within 3 years was almost 2-fold higher when assuming non-informative censoring compared with the competing risks model, 41 versus 22%. The prognostic value of tests was more conservative using the competing risks model than with the traditional methods, the fecundity rate ratio for Chlamydia antibody testing was 0.72 versus 0.67, for hysterosalpingography, 0.83 versus 0.71 and for diagnostic laparoscopy, 0.89 versus 0.74. CONCLUSIONS: Given the improbable validity of the non-informative censoring assumption, the predictions of natural conception and of the prognostic value of tests are likely to be overestimated by the traditional analytic methods. We suggest the use of competing risks models as an alternative, more conservative, form of analysis when predicting natural conception and evaluating prognostic fertility tests. PMID- 22246448 TI - Association between perfluorinated compounds and time to pregnancy in a prospective cohort of Danish couples attempting to conceive. AB - BACKGROUND: Perfluorinated chemicals (PFCs) have been widely used and have emerged as important food contaminants. A recent study on pregnant women suggested that PFC exposure was associated with a longer time to pregnancy (TTP). We examined the association between serum concentrations of PFCs in females and TTP in 222 Danish first-time pregnancy planners during the years 1992-1995. METHODS: The couples were enrolled in the study when discontinuing birth control and followed for six menstrual cycles or until a clinically recognized pregnancy occurred. Fecundability ratio (FR) was calculated using discrete-time survival models. In addition, odds ratio (OR) for TTP >6 cycles was calculated. RESULTS: OR for TTP >6 cycles for those with PFC concentrations above the median were 0.96 [95% confidence interval (CI): 0.54-1.64] for perfluorooctane sulfonic acid (PFOS), the major PFC, compared with those below the median. FRs for those with PFOS concentrations above the median were 1.05 (95% CI: 0.74-1.48) compared with those below the median. Other PFCs showed the same lack of association with TTP. The results were not affected by adjustment for covariates. PFOS and perfluorooctanoic acid concentrations were similar to those observed in a previous Danish study. CONCLUSIONS: These findings suggest that exposure to PFCs affects TTP only to a small extent, if at all. PMID- 22246449 TI - Endometrial receptivity defects during IVF cycles with and without letrozole. AB - BACKGROUND: Our aim was to study ways to improve IVF success rates in women with suspected endometrial receptivity defects. METHODS: We conducted a retrospective cohort study examining the effect of letrozole (aromatase inhibitor) on integrin expression as a marker of endometrial receptivity. We compared IVF outcomes in 97 infertile women who had undergone alphanubeta3 integrin assessment by immunohistochemistry in mid-luteal endometrial biopsies. Of 79 women undergoing standard IVF, 29 (36.7%) lacked normal integrin expression. Eighteen other women with low integrin were studied after receiving letrozole during early IVF stimulation. An independent set of alphanubeta3 integrin-negative patients (n = 15) who had undergone repeat endometrial biopsy for integrin testing while taking letrozole were re-evaluated. RESULTS: Clinical pregnancy and delivery rates were higher in women with normal alphanubeta3 integrin expression compared with those who were integrin negative [20/50 (40%) versus 4/29 (13.8%); P = 0.02 and 19/50 (38%) versus 2/29 (7%); P < 0.01, respectively]. In 18 women who received letrozole early in IVF, 11 conceived (61.1%; P < 0.001) compared with integrin negative patients who did not receive letrozole. In integrin-negative women who were rebiopsied on letrozole, 66.7% reverted to normal integrin expression. Positive endometrial aromatase immunostaining using a polyclonal antibody was a common finding in infertile patients compared with controls. CONCLUSIONS: Lack of endometrial alphanubeta3 integrin expression is associated with a poor prognosis for IVF that might be improved with letrozole co-treatment. Prospective studies are needed to confirm and extend these findings but the data suggest that aromatase expression may contribute to implantation failure in some women. PMID- 22246450 TI - Molecular characterization of corona radiata cells from patients with diminished ovarian reserve using microarray and microfluidic-based gene expression profiling. AB - BACKGROUND: Diminished ovarian reserve (DOR) is one of the causes of infertility in young women. In this prospective study, gene expression profiling (GEP) of corona radiata cells (CRC) was performed to identify genes deregulated in DOR patients. METHODS: Microarray-based GEP of CRC isolated from eight women undergoing IVF was performed to identify genes differentially expressed between patients with normal ovarian reserve and DOR patients. Microfluidic-based quantitative RT-PCR assays were used to validate selected transcripts on 40 independent patients. A principal component analysis was used to identify more homogeneous subgroups of DOR patients. In silico analyses focusing on cis regulation were performed to refine the interactions between patient's biological characteristics and their GEP. RESULTS: Forty-eight transcripts were differentially expressed, including CXXC finger protein 5 (CXXC5), forkhead box C1 (FOXC1) (down-regulated in DOR) as well as connective tissue growth factor (CTGF), follistatin-like 3 (FSTL3), prostaglandin-endoperoxide synthase 2 (PTGS2) and suppressor of cytokine signaling 2 (SOCS2) (up-regulated in DOR). According to these transcripts, two DOR patients' subgroups (DOR Gr1 and Gr2) were identified. In DOR Gr2 patients, C-terminal domain 2 (CITED2), CTGF, growth arrest-specific 1 (GAS1), insulin receptor substrate 2 (IRS2), PTGS2, SOCS2 and Versican (VCAN) were expressed at significantly higher levels and CXXC5, FOXC1, guanylate-binding protein 2 (GBP2) and zinc finger MIZ-domain containing 1 (ZMIZ1) at significantly lower levels. Higher baseline estradiol (E(2)) levels were observed in DOR Gr2 patients (P < 0.006). The in silico analyses suggested that all 11 genes differentially expressed between DOR Gr1 and DOR Gr2 subgroups could be transcriptional targets of estrogen. CONCLUSIONS: Despite small sample size limitations, 12 genes deregulated in the CRC of DOR patients were identified, which could be involved in DOR pathogenesis. A DOR patient's subgroup with high baseline E(2) levels and deregulated estrogen-responsive genes was also identified. PMID- 22246451 TI - Government distorted research on reforms to disability benefit, says campaign group. PMID- 22246452 TI - Portuguese health system is still too reliant on emergency care, finds review. PMID- 22246453 TI - Tipping point of too few carers for older people has been reached five years early, MPs hear. PMID- 22246454 TI - US hospital incident reporting systems do not capture most adverse events. PMID- 22246455 TI - GPs back withdrawal of health reform bill. PMID- 22246456 TI - Risk factors for post-polio syndrome among an Italian population: a case-control study. AB - Post-polio syndrome (PPS) is a clinical syndrome of new weakness, fatigue and musculoskeletal pain occurring in a variable proportion of polio survivors decades after acute disease. To date, several risk factors for PPS development have been reported, although the etiology of this disorder remains elusive. Using a case-control design, we aimed to assess risk indicators for PPS in a group of Italian polio survivors. Subjects with prior poliomyelitis attending the rehabilitation hospital of Malcesine, Italy, were the target population. Patients with PPS, diagnosed according to the European Federation of Neurological Societies criteria, served as cases, while patients not meeting diagnostic criteria for PPS were used as controls. All subjects were assessed through a structured questionnaire made of 82 questions and neurological examination. The association with investigated risk factors (sex, age at polio onset, age at onset of symptoms, extension and severity of polio, employment) was analyzed by the calculation of the odds ratio. A total of 161 out of 391 eligible patients met the adopted diagnostic criteria for PPS, giving a frequency of 41.2%. Symptoms most frequently complained by PPS patients were loss of muscle strength, loss of resistance, loss of muscle volume and generalized fatigue. Female gender, the presence of respiratory disturbance during the acute phase of polio and the use of orthoses and aids during the recovery and stabilization represented independent risk factors for PPS in the studied population. PMID- 22246457 TI - Trigeminal neuralgia and persistent trigeminal artery. AB - We report a case of trigeminal neuralgia caused by persistent trigeminal artery (PTA) associated with asymptomatic left temporal cavernoma. Our patient presented unstable blood hypertension and the pain of typical trigeminal neuralgia over the second and third divisions of the nerve in the right side of the face. The attacks were often precipitated during physical exertion. MRI and Angio-MRI revealed the persistent carotid basilar anastomosis and occasionally left parietal cavernoma. After drug treatment of blood hypertension, spontaneous recovery of neuralgia was observed and we planned surgical treatment of left temporal cavernoma. PMID- 22246458 TI - Systematic investigations on magneto-structural correlations of copper(II) coordination polymers based on organic ligands with mixed carboxylic and nitrogen based moieties. AB - Reaction of copper(II) tetrazolate-5-carboxylate with different neutral N-donor spacer ligands under hydrothermal conditions leads to the formation of five new coordination polymers, [Cu(tzc)(pyz)(0.5)(H(2)O)(2)](n).H(2)O (1), [Cu(tzc)(pyz)](n) (2), [Cu(tzc)(pym)(H(2)O)](n) (3), [Cu(tzc)(dpe)(0.5)(H(2)O)](n) (4) and [Cu(tzc)(azpy)(0.5)(H(2)O)](n) (5) (tzc = tetrazolate-5-carboxylate, pyz = pyrazine, pym = pyrimidine, dpe = 1,2-di(4 pyridyl)ethylene and azpy = 4,4'-azopyridine). All five structures were characterized by X-ray single-crystal measurements and bulk material can be prepared phase pure in high yields. The crystal structures of the hydrates 1, 3, 4 and 5 show dimeric [Cu(2)(N(tzc)-N(tzc))(2)] building units formed by MU(2) N1,O1:N2 bridging tzc ligands as the characteristic structural motif. These six membered entities in 1, 4 and 5 are connected by MU(2)-N,N' bridging N-donor ligands into 1D chains and in 3 into 2D layers. In the crystal structure of compound 2 adjacent Cu(II) cations are connected by MU(2)-N1,O1:N4,O2 bridging tzc ligands into chains, which are further connected by MU(2)-N,N' bridging pyz ligands forming 2D layers. Extensive hydrogen bonds in all compounds play an important role in the construction of their supramolecular networks. Investigations of their thermal properties reveal water release upon heating according to the formation of anhydrates before starting decomposing above 220 degrees C. Furthermore, the magnetic properties have been studied leading to consistent global antiferromagnetic exchange interactions with coupling constants of J = 3 +/- 1 cm(-1) and long-range antiferromagnetic ordering states at lower temperatures. PMID- 22246459 TI - Lp-PLA2: inflammatory biomarker of vascular risk in multiple sclerosis. AB - A member of the A2 phospholipase superfamily, the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), is involved in atherogenic processes. Lp-PLA2 mass and activity were measured by the enzyme-linked immunosorbent assay and by a colorimetric method, respectively, and compared among 63 multiple sclerosis (MS) patients and 47 age-matched healthy controls (HCs). Lp-PLA2 plasma levels were significantly higher in MS patients (236.7 +/- 10 ng/ml) compared to HCs (197.0 +/- 7 ng/ml) (p = 0.003), but LP-PLA2 activity did not differ between the two groups. Both Lp-PLA2 plasma mass and activity were higher in secondary progressive (mass 247.0 +/-15.5 ng/ml, p = 0.05; activity 156.1 +/-6 nmol/min/ml, p = 0.003) compared to relapsing-remitting MS patients (mass 227.0 +/- 16 ng/ml; activity 128.8 +/- 5 nmol/min/ml) and compared to HCs. Lp-PLA2 plasma activity was associated with measures of MS clinical disability. However, this association was attenuated after adjustment for the components of lipid profiles. PMID- 22246460 TI - Weaning from mechanical ventilation and sedation. AB - PURPOSE OF REVIEW: Guidelines for weaning from sedation and weaning from ventilator gained increasing interest in recent years. This includes patients with acute respiratory distress syndrome, as well as other mechanically ventilated patients. This review will give an overview of the current literature and practice guidelines in ventilator and sedation weaning. RECENT FINDINGS: Sedation and ventilator weaning are closely linked. Weaning protocols for both sedation and ventilator weaning should be implemented in daily routine. The essential element of such algorithm should be a daily spontaneous awakening trial and spontaneous breathing trial. Furthermore, regularly monitoring for deepness of sedation and delirium should be implemented. Too deep sedation, as well as prolonged delirium is associated with higher mortality. SUMMARY: The most important conclusion we come to from recent randomized controlled trials is that only using an integrative algorithm for sedation and ventilator weaning can improve survival of ICU patients. PMID- 22246461 TI - Towards ultraprotective mechanical ventilation. AB - PURPOSE OF REVIEW: To survey the causes of ventilator-induced lung injury focusing on its mechanical determinants, lung stress and strain. RECENT FINDINGS: Tidal volume per ideal body weight (tidal volume/IBW) and airway pressure (PAW) are poor surrogates of strain and stress, which are respectively defined as the ratio of volume variation to lung resting volume and transpulmonary pressure. In healthy lungs, ventilation becomes lethal with strain reaching total lung capacity (tidal volume/IBW around 30-40 ml/kg) and with its related stress (roughly 24 cmH2O). The striking discrepancy between experimental data and clinical scenarios (harm at tidal volume/IBW of 12 ml/kg) may be explained by lung dishomogeneity, locally generating 'stress risers' or 'pressure multipliers'. When mechanical ventilation becomes unsafe, as inferred from computed tomography-scan evaluation of dishomogeneity and stress/strain values, lung protective strategies can be maximized by further reducing tidal volume and increasing PAW (e.g. high frequency oscillatory ventilation). In alternative, artificial lungs may provide adequate gas exchange while reducing the load of mechanical ventilation. Recently, outcome benefit was shown with the use of this technique in H1N1 patients. SUMMARY: When lung protective strategy is considered unsafe, various techniques of extracorporeal respiratory support may be applied, which by decreasing the load of mechanical ventilation, allow partial to total lung rest. PMID- 22246462 TI - Ultrasound-guided peripheral nerve blockade of the upper extremity. AB - PURPOSE OF REVIEW: Is ultrasound guidance changing the practice of upper extremity regional anesthesia? This review will aim to describe the findings published in the literature during the previous 18 months. RECENT FINDINGS: In some approaches to brachial plexus blockade, local anesthetic volumes may be reduced without deterioration of analgesic effect. However, even 10 ml of local injected into the interscalene space may result in diaphragmatic paresis. High resolution ultrasonography has revealed anatomical variations of C5, C6 and C7 nerve roots in almost half of the patients examined, without negative block effectiveness. The addition of dexamethasone may prolong analgesia after single shot interscalene and supraclavicular blocks. Insertion of brachial plexus perineural catheters using ultrasound guidance can be successful and provides better postoperative analgesia than single-shot blocks for up to 24 h postoperatively. Infraclavicular catheters provide superior analgesia when compared with supraclavicular catheters. Multiple-site injections of local offer no advantage over a single-site injection during an infraclavicular block. Ultrasound guidance compared with neurostimulation may reduce patient discomfort during axillary blocks compared with neurostimulation. Intra-epineural injections are common during an interscalene blockade, but the incidence of neurological injury remains low. There is an ongoing debate on the effectiveness and safety of ultrasound-guided intra-epineurial injections. SUMMARY: Current literature suggests a reduction of the volume of local anesthetics used for ultrasound guided upper extremity blockades. Dexamethasone may prolong duration of brachial plexus blocks and more frequent use of perineural catheters is encouraged. Controversy over intra-epineurial injections exists and requires additional large scale studies. PMID- 22246463 TI - Community-based exercise program effectiveness and safety for cancer survivors. AB - PURPOSE: Clinical trials have demonstrated the benefits of exercise for cancer survivors. This investigation determined the effectiveness and safety of a disseminated community-based exercise program for cancer survivors who had completed treatment. METHODS: Personal trainers from regional YMCAs received training in cancer rehabilitation and supervised twice-a-week, 12-week group exercise sessions for survivors. At baseline and post-program, validated measures assessed patient-reported outcomes (PRO) and physiologic measurements. RESULTS: Data were collected from 221 survivors from 13 YMCA sites and 36 separate classes. All participants had data available at one time point, while matched baseline and post-program PRO and physiologic data were available for 85% (N = 187). Participants with matched data were largely female (82%), with mean age of 58 (range, 28-91 years). Time since diagnosis ranged from 1 to 48 (mean, 5.6 years), and mean time since last treatment was 3.0 (range, 1-33 years). Physiological improvements were significant in systolic (P < 0.001) and diastolic (P = 0.035) blood pressure, upper and lower body strength, the 6-min walk test (P = 0.004), and flexibility (P < 0.001). Participants reported improvements in overall health-related quality of life (P < 0.001), social support (P = 0.019), body pain (P = 0.016), fatigue (P < 0.001), insomnia (P < 0.001), and overall musculoskeletal symptoms (P = <0.001). Few injuries or lymphedema events occurred during classes. CONCLUSIONS: Community-based exercise groups for cancer survivors of mixed diagnoses and ages, who have completed active treatment, have physiologic and psychosocial benefits, and are safe. IMPLICATIONS FOR CANCER SURVIVORS: Survivors may expect significant benefit from participating in a community-based exercise program tailored to meet their individual needs as a survivor. PMID- 22246464 TI - Online oxygen measurements in ex vivo perfused muscle tissue in a porcine model using dynamic quenching methods. AB - INTRODUCTION: Transplantation of autologous free tissue flaps is the best applicable technique for treating large and complex tissue defects and still has one major failure criterion. Tissue--and in particular muscle tissue--is strongly sensitive to ischemia, thus after a critical period of oxygen depletion the risk of a partial or total flap loss is high. MATERIALS AND METHODS: For that reason a miniaturized ex vivo perfusion system has been developed, that supplies the tissue during operational delays. The purpose of this study was to determine the oxygenation levels during such a perfusion using different perfusates and therefore to objectify if a complementary oxygenation unit is required to improve perfusion quality. The oxygen levels of the tissue, as well of the perfusate, were measured by using minimal invasive optical oxygen sensors that are based on dynamic quenching. The ex vivo perfused tissue was the porcine rectus abdominis muscle. RESULTS: Results show, that during perfusion with heparinized crystalloid fluid (Jonosteril) and heparinized autologous whole blood, additional oxygenation of the perfusion reactor led to different ex vivo oxygen tissue saturations, which can be detected by dynamic quenching. CONCLUSION: Dynamic quenching methods are a promising and valuable technique to perform online oxygen measurements in ex vivo perfused muscle tissue in a porcine model. PMID- 22246466 TI - Organochlorine pesticide levels in Ensis siliqua (Linnaeus, 1758) from Ria de Vigo, Galicia (N.W. Spain): influence of season, condition index and lipid content. AB - Levels of organochlorine pesticides (OCPs), including SigmaDDTs, gamma-HCH, HCB, aldrin, isodrin, trans-nonachlor, heptachlor and dieldrin, were determined in the razor clam, Ensis siliqua, collected monthly from February 2003 to April 2004 from the Islas Cies in Ria de Vigo (Galicia, Spain). The sum of DDTs ranged from 2.17 to 26.9 ng g(-1) dry weight (dw). Principal component analysis showed seasonal trends in the levels of some OCPs (gamma-HCH and dieldrin). Pearson correlations (p < 0.05) were observed between OCP levels and the biometric parameters of condition index and body lipids. PMID- 22246465 TI - Demethylation restores SN38 sensitivity in cells with acquired resistance to SN38 derived from human cervical squamous cancer cells. AB - Using seven monoclonal SN38-resistant subclones established from ME180 human cervical squamous cell carcinoma cells, we examined the demethylation effects of 5-aza-2'-deoxycytidine (5-aza-CdR) on the SN38-sensitivity of the cells as well as the expression of death-associated protein kinase (DAPK) in the SN38-resistant cells. The DAPK expression levels were evaluated among parent ME180 cells, SN38 resistant ME180 cells and cisplatin-resistant ME180 cells by methylation-specific DAPK-PCR, quantitative RT-PCR and western blot analysis. The SN38-resistant cells co-treated with SN38 and 5-aza-CdR strongly exhibited enhanced SN38-sensitivities resembling those found in the parent cells. In the SN38-resistant subclones, no relationships were found between the restored SN38 sensitivity and hypermethylation of the DAPK promoter, DAPK mRNA expression, DAPK protein expression and induction of DAPK protein after 5-aza-CdR treatment, unlike the strong suppression of 5-aza-CdR-induced DAPK protein expression in the cisplatin resistant subclones. These findings indicate that reversibly methylated molecules, but not DAPK, may regulate SN38 resistance, and that demethylating agents can be strong sensitizing anticancer chemotherapeutic drugs for SN38 resistant cancers. PMID- 22246467 TI - Controllable three-component luminescence from a 1,8-naphthalimide/Eu(III) complex: white light emission from a single molecule. AB - A macrocycle-appended naphthalimide derivative and its Eu(III) complex show triple luminescence from isolated naphthalimide (blue), aggregated naphthalimide excimers (green) and Eu centres (red) with the balance being sensitive to the degree of aggregation, allowing white light emission to be obtained from a single molecule. PMID- 22246468 TI - Adapting space science methods for describing and planning research in simulation in healthcare: science traceability and Decadal Surveys. AB - Two recent conferences have reviewed the state of research on simulation in healthcare and considered future directions. They both point to the need for more comprehensive and robust studies on a variety of aspects of simulation. The next step for strategic planning about research on simulation in healthcare should be to implement two mechanisms already used in fields of space sciences. One is a Science Traceability Structure that formally delineate Themes, Goals, and Objectives for the field and links them to Programs, Projects, and Methods. The second is the Decadal Survey, a highly detailed research planning activity conducted every ten years by scientific experts in the relevant fields, working under the auspices of the National Research Council. Decadal Surveys have unique characteristics, especially their extensive engagement with the research community, and their recommendations have generally been highly influential with policy-makers and legislators. PMID- 22246469 TI - Effect of carrier gas properties on aerosol distribution in a CT-based human airway numerical model. AB - The effect of carrier gas properties on particle transport in the human lung is investigated numerically in an imaging based airway model. The airway model consists of multi-detector row computed tomography (MDCT)-based upper and intra thoracic central airways. The large-eddy simulation technique is adopted for simulation of transitional and turbulent flows. The image-registration-derived boundary condition is employed to match regional ventilation of the whole lung. Four different carrier gases of helium (He), a helium-oxygen mixture (He-O(2)), air, and a xenon-oxygen mixture (Xe-O(2)) are considered. A steady inspiratory flow rate of 342 mL/s is imposed at the mouthpiece inlet to mimic aerosol delivery on inspiration, resulting in the Reynolds number at the trachea of Re( t ) ~ 190, 460, 1300, and 2800 for the respective gases of He, He-O(2), air, and Xe O(2). Thus, the flow for the He case is laminar, transitional for He-O(2), and turbulent for air and Xe-O(2). The instantaneous and time-averaged flow fields and the laminar/transitional/turbulent characteristics resulting from the four gases are discussed. With increasing Re( t ), the high-speed jet formed at the glottal constriction is more dispersed around the peripheral region of the jet and its length becomes shorter. In the laminar flow the distribution of 2.5-MUm particles in the central airways depends on the particle release location at the mouthpiece inlet, whereas in the turbulent flow the particles are well mixed before reaching the first bifurcation and their distribution is strongly correlated with regional ventilation. PMID- 22246470 TI - Inhibition of migration and invasion of LNCaP human prostate carcinoma cells by cordycepin through inactivation of Akt. AB - Cordycepin (3'-deoxyadenosine), a major bioactive compound of Cordyceps militaris, has many pharmacological actions, such as anti-inflammatory and anticancer activities. In this study, the relationship between inhibition of cell motility and anti-invasive activity by cordycepin in LNCaP human prostate carcinoma cells was investigated. Within the concentration range that was not cytotoxic, cordycepin time-dependently inhibited cell motility and invasiveness of LNCaP cells. The inhibitory effects of cordycepin on cell invasiveness were associated with tightening of tight junctions (TJs), which was demonstrated by an increase in transepithelial electrical resistance (TER). Immunoblotting indicated that cordycepin decreases levels of claudin proteins, which are major components of TJs that play a key role in control and selectivity of paracellular transport. Furthermore, cordycepin inhibited the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9, and simultaneously increased levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/Akt pathway in LNCaP cells. These findings suggest that cordycepin inhibits the migration and invasion of LNCaP cells by downregulating the activity of TJs and MMPs, possibly in association with suppression of Akt activation. PMID- 22246471 TI - Choosing between good and better: optimal oviposition drives host plant selection when parents and offspring agree on best resources. AB - Insect preferences for particular plant species might be subjected to trade-offs among several selective forces. Here, we evaluated, through laboratory and field experiments, the feeding and ovipositing preferences of the polyphagous leafminer Liriomyza huidobrensis (Diptera: Agromyzidae) in relation to adult and offspring performance and enemy-free space. Female leafminers preferred laying their eggs on Vicia faba (Fabaceae) over Beta vulgaris var. cicla (Chenopodiaceae), in both laboratory and field choice experiments, although no oviposition preference was observed in no-choice tests. Females fed more often on B. v. var. cicla (no choice test) or showed no feeding preference (choice test), even when their realized fecundity was remarkably higher on V. faba. Offspring developed faster, tended to survive better, and attained bigger adult size on the preferred host plant. Also, a field experiment showed higher overall parasitism rates for leafminers developing on B. v. var. cicla, with a nonsignificant similar tendency in field surveys. According to these results, host plant selection by L. huidobrensis appears to be driven mainly by variation in host quality. Moreover, the consistent oviposition choices for the best host and the labile feeding preferences observed here, suggest that host plant selection might be driven by maximization of offspring fitness even without a conflict of interest between parents and offspring. Overall, these results highlight the complexity of decisions performed by phytophagous insects regarding their host plants, and the importance of simultaneous evaluation of the various driving forces involved, in order to unravel the adaptive significance of female choices. PMID- 22246473 TI - The coexistence of acorns with different maturation patterns explains acorn production variability in cork oak. AB - In dry areas such as Mediterranean ecosystems, fluctuations in seed production are typically explained by resource (water) availability. However, acorn production in cork oak (Quercus suber) populations shows a very low relationship to weather. Because cork oak trees produce acorns with different maturation patterns (annual and biennial), we hypothesized that acorn production in coexisting individuals with a different dominant acorn maturation type should respond differently to climatic factors and that disaggregating the trees according to their acorn-maturation pattern should provide a more proximal relation to weather factors. We assessed acorn production variability in fragmented cork oak populations of the eastern Iberian Peninsula by counting the total number of acorns in 155 trees during an 8-year period. An initial assessment of acorn production variability in relation to weather parameters yielded very low explained variance (7%). However, after the trees were grouped according to their dominant acorn maturation pattern, weather parameters were found to account for 44% of the variability in acorn crops, with trees with annual acorns exhibiting mast fruiting in years with reduced spring frost and shorter summer droughts and trees with biennial acorns showing the opposite pattern. Thus, conditions that negatively affect annual production could be beneficial for biennial production (and vice versa). The results highlight the importance of the resource-matching hypothesis for explaining acorn production in Quercus suber and suggest that different seed maturation types within a population may allow the species to deal with highly variable weather conditions. They also emphasize the importance of understanding acorn maturation patterns for interpreting masting cycles. PMID- 22246474 TI - Effect of topical dimethylarsinic acid on the expression of apoptosis-related proteins in mouse skin. AB - We investigated the effect of the topical application of dimethylarsinic acid (DMA) on skin thickness and the expression of several apoptosis-related proteins in skin. After administration of DMA during pregnancy, skin thickness and skin expression of Bcl-2, Bcl-3, Bad, Bid, and caspases-3, -6, -8, -9, and -12 were examined in dams and their offspring. DMA treatment caused significant increases in skin thickness (p < 0.05) and the expression of Bcl-2, Bad, and capase-12 in the skin of dams at the mRNA and protein levels (p < 0.01). However, maternal exposure to DMA did not significantly alter the expression of the studied apoptosis-related factors in the skin of the offspring. These findings indicate that DMA may induce skin apoptosis, in part, by modulating the expression of Bcl 2, Bad, and caspase-12 in maternal skin. Additionally, our results suggest that maternal exposure to DAM during pregnancy may not induce apoptosis in the skin of the offspring. PMID- 22246475 TI - Seasonal accumulations of some heavy metal in water, sediment and tissues of black-chinned tilapia Sarotherodon melanotheron from Bietri Bay in Ebrie Lagoon, Ivory Coast. AB - The seasonal accumulation of cadmium, copper, lead, mercury and zinc was determined in sediments, water, and black-chinned tilapia (Sarotherodon melanotheron; muscle, brain, kidney and liver tissues) collected monthly from Bietri Bay. The mean water concentration of metals (in mg L(-1)) ranged from 0.01 to 0.30 (mercury), 0.02-0.26 (cadmium), 2.40-4.80 (lead), 9.05-9.68 (copper), and 12.05-19.87 (zinc). The seasonal variations showed a significant difference in the levels of mercury, cadmium and lead among season. The highest mercury (0.30 +/- 0.02 MUg L(-1)), cadmium (0.26 +/- 0.02 mg L(-1)) and lead (4.80 +/- 1.03 mg L(-1)) levels were observed during dry season, while the lowest levels (0.21 +/- 0.01, 0.02 +/- 0.01 and 2.40 +/- 0.02 mg L(-1), respectively mercury, cadmium and lead) were measured during rainy season. The average cadmium (0.58 +/- 0.36 mg L( 1)), copper (42.15 +/- 19.40 mg L(-1)), lead (58.47 +/- 38.10 mg kg(-1)), mercury (0.79 +/- 0.47 MUg kg(-1)) and zinc (187.58 +/- 76.99 mg kg(-1)) concentrations determined in Bietri Bay sediments showed a similar trend as in water. The seasonal variations of mercury, cadmium and lead in tissues revealed that these metals were higher concentrated during dry and swelling seasons. The levels of zinc and copper followed by lead were higher in the tissues. The order of tissues metals concentrations was: kidney > liver > brain > muscle. PMID- 22246476 TI - Helical heterojunctions originating from helical inversion of conducting polymer nanofibers. AB - The helical sense of conducting polyaniline nanofibers was induced using chiral acid as dopant, which can be inversed through a copolymerization of aniline with N-methyl aniline. By delicately controlling the inversion driving force of steric hindrance, we successfully obtained "helical heterojunctions" composed of right- and left-handed helical structures in one helical nanofiber. PMID- 22246477 TI - Excited-state properties of chiral [4]helicene cations. AB - The photophysical properties of a series of helicene cations in various solvents have been investigated using stationary and time-resolved spectroscopy. These compounds fluoresce in the near infrared region with a quantum yield ranging between 2 and 20% and a lifetime between 1 and 12 ns, depending of the solvent. No clear solvent dependence could be recognized except for a decrease of fluorescence quantum yield and lifetime with increasing hydrogen-bond donating ability of the solvent. In water, the helicene cations undergo aggregation. This effect manifests itself by the presence of a slow fluorescence decay component, whose amplitude increases with dye concentration, and by a much slower decay of the polarization anisotropy in water compared to an organic solvent of similar viscosity. However, aggregation has essentially no effect on the stationary fluorescence spectrum, whereas relatively small changes can be seen in the absorption spectrum. Analysis of the dependence of aggregation on the dye concentration reveals that the aggregates are mostly dimers and that the aggregation constant is substantially larger for hetero- than homochiral dimers. PMID- 22246478 TI - Increasing fear of adverse effects drops intention to vaccinate after the introduction of prophylactic HPV vaccine. AB - PURPOSE: The purpose of this study was (1) to explore for socio-demographic factors that could potentially affect the intention of women to vaccinate themselves, their 13-year-old daughter and their 13-year-old son against HPV, and (2) to investigate the main reasons for declining vaccination. METHODS: A structured questionnaire was used in participants of the project (N = 5,249). Logistic regression analysis was applied in order to examine the correlation between vaccine acceptability and a list of potential predictors. In women declining vaccination, the reported reasons for decline were analyzed. RESULTS: Residence in rural areas and low to medium tiers of family income were the most constant factors in favor of intention to vaccinate. Receiving information from a healthcare professional was found to positively affect vaccine acceptability for the woman herself, but it did not affect her intention to vaccinate her daughter or her son. The acceptance rates decreased significantly after the vaccine became available, both for the women themselves and for their daughters or sons. During the same year, a shift was noted in the reason for declining vaccination; the self-perception of insufficient knowledge significantly decreased and the fear of adverse effects significantly increased in all three cases. CONCLUSION: Apart from demographic factors which may favor or disfavor vaccine acceptability, the intention to vaccinate decreased significantly and the proportion of women rejecting vaccination for safety concerns increased significantly after the introduction of the vaccine, coinciding with isolated cases of negative publicity and highlighting the potential of misinformation by the media. PMID- 22246479 TI - Does hormone replacement therapy have beneficial effects on renal functions in menopausal women? AB - BACKGROUND: The study was carried out to evaluate the possible effects of hormone replacement therapy (HRT) on renal functions in postmenopausal women. METHODS: A total of 85 postmenopausal women without a history of medical illness were enrolled in the study. They were divided into HRT users and control groups. After 30 weeks of HRT use, the changes in serum urea, creatinine, uric acid, urinary protein, urinary creatinine, urinary protein/creatinine ratio and glomerular filtration rate (GFR) (mL/min/1.73 m(2)) were evaluated. RESULTS: HRT was associated with statistically significant increases in glomerular filtration rate (p < 0.01), while serum urea, creatinine, uric acid, urinary protein, urinary creatinine and urinary protein/creatinine ratio did not change significantly in both groups. CONCLUSION: In our study, we suggested that usage of hormone replacement therapy appeared to affect renal functions in postmenopausal women. There were beneficial effects of HRT on GFR in our postmenopausal patients. HRT may have possible protective mechanisms for kidney against adverse effects of aging. PMID- 22246480 TI - Appropriate cut-off values of waist circumference to predict cardiovascular outcomes: 7-year follow-up in an Iranian population. AB - OBJECTIVE: Due to the lack of compelling evidence for waist circumference (WC) as a cardiovascular disease (CVD) risk factor in many ethnic groups, the need for local research has been expressed by international authorities. This study was undertaken to determine the optimal cut-off points of WC for predicting incident CVD and metabolic syndrome in an Iranian population. MATERIALS AND METHODS: A total of 6,504 participants from three areas in central Iran were followed over 7 years. Receiver operating characteristics (ROC) and area under the curve (AUC) were used to identify the maximum value of sensitivity and specificity combinations corresponding to the appropriate cut-off points of WC for the detection of the metabolic syndrome and CVD events. The optimal cut-off values were defined as the point at which the value of "sensitivity+specificity-1" reached the maximum value. Finally, Cox proportional hazard modeling was used to determine which cut-off point was better fit in the CVD risk prediction model. RESULTS: After 394,418 person-years of follow-up, 427 incident primary CVD events (233 men) were identified. Considering CVD, the optimum cut-off points were 99/103.5 cm (men/women) but these had a low sensitivity (AUC: 0.59, 95%CI 0.55 0.63 in both men and women). The second highest values for discriminating CVD were 93/97 cm that resulted in acceptable sensitivity. Regarding the metabolic syndrome, 92.6/97.8 cm were identified as optimum (AUC: 0.67, 95%CI 0.65-0.69 in men and 0.65, 95%CI 0.63-0.67 in women). The best cut-off values that fit in the Cox regression model were 90/97 cm. CONCLUSION: International recommended WC cut off values for the Middle East are not appropriate compared to the locally defined cut-off values in Iran. PMID- 22246481 TI - Arterial stiffness is associated with tissue Doppler atrial conduction times and P wave dispersion in hypertensive patients. AB - BACKGROUND: Arterial stiffness is strongly predictive for cardiovascular events in hypertensive individuals and it may increase the risk of stroke. This study was designed to evaluate the possible relationship between arterial stiffness and atrial electromechanical delay and P wave dispersion (PWD), as determinants of AF risk. MATERIALS AND METHODS: The study included 75 hypertensive patients and 45 healthy control subjects. Atrial electromechanical coupling (time interval from the onset of P wave on ECG to the beginning of A wave with tissue Doppler echocardiography [PA]), intraatrial and interatrial electromechanical delay (EMD) and PWD were measured. Stiffness index beta & PWV was measured to assess the arterial stiffness. RESULTS: The interatrial EMD and PWD were prolonged in hypertensive patients compared to controls (p<0.01 for both), There was increased arterial stiffness (PWV and stiffness index beta) in hypertensive patients compared to controls (6.43 +/- 1.73 vs. 4.8 +/- 1.6 m/sec & 4.9 +/- 2.8 vs. 2.63 +/- 1.2, p<0.01 for both). By multivariate analysis; PWV and Stiffness index beta were independently correlated with interatrial EMD (B +/- SE=0.42 +/- 1.87, B +/- SE=0.39 +/- 0.21 p<0.01 for both) and PWD (B +/- SE=0.37 +/- 1.93, p<0.01, B +/- SE=0.25 +/- 0.18, p<0.05 respectively). CONCLUSION: In hypertensive patients arterial stiffness indexes increased and showed a significant correlation with interatrial EMD and PWD independent of other variables. Further research is needed to determine whether interventions that reduce arterial stiffness will limit the growing incidence of AF. PMID- 22246482 TI - Elevated E/E' predicts cardiovascular events in hemodialysis patients with preserved systolic function. AB - OBJECTIVE: We conducted a cohort study to investigate whether diastolic function could predict cardiovascular (CV) events in 161 HD patients with preserved systolic function. MATERIALS AND METHODS: The ratio of early transmitral flow velocity to early mitral annular velocity (E/E') was measured by tissue Doppler imaging. Patients were stratified into two groups based on whether they experienced a CV event. RESULTS: During a 4-year follow-up period, 64 patients experienced a CV event. The E/E' values (15.18 +/- 5.78) in the CV-event group were significantly higher than in the group who had not experienced a CV event (12.32 +/- 4.23). Kaplan-Meier analysis indicated that the incidence of CV events was significantly higher in the group of patients whose E/E' was >15 than in the group whose E/E' was <= 15 (log-rank p=0.0016). Multivariate Cox proportional hazards regression analysis revealed the E/E' ratio to be a significant predictor of CV events in HD patients with preserved LV systolic function. CONCLUSION: The results of this study showed that elevated E/E' ratio in chronic HD patients predicts CV events better than other echocardiographic parameters. PMID- 22246483 TI - Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes -a cross-sectional study. AB - OBJECTIVE: Trends in diabetes and cardiovascular mortality rates are considerably different between women and men; this can be partially explained by differences in diabetes control. The aim of this cross-sectional study was to assess whether sex differences exist in effective control of cardiovascular risk factors among persons with type 2 diabetes treated at the Vuk Vrhovac University Clinic in 2008. MATERIALS AND METHODS: We performed a cross-sectional analysis including 8,775 patients who attended the clinic in 2008. Levels of HbA1c, systolic and diastolic blood pressure (SBP, DBP), LDL-cholesterol (LDL) and triglycerides (TG) were analyzed. Multiple adjusted odds-ratios were calculated for categories of cardiovascular risk factors considered not being in control (HbA1c >= 7%, SBP >= 130 mmHg, DBP >= 80 mmHg, LDL >= 2.5 mmol/L, TG >= 1.7 mmol/L). RESULTS: Women had higher levels of HbA1c (7.05 vs. 6.86%; p<0.001), despite the fact that a larger proportion of women were receiving insulin therapy than men (51.3% vs. 44%). Women also had higher mean values of SBP (144.7 vs. 141.9 mmHg; p<0.001) and LDL (2.92 vs. 2.84 mmol/L). There were no differences in DBP (86.1 vs. 86.0 mmHg; p=0.748) and only triglyceride levels were higher in men (2.04 vs. 1.94 mmol/L; p=0.003). In multi-adjusted logistic regression model female sex was associated with a higher odds ratio of having uncontrolled values of HbA1c (OR=1.21; 95%CI 1.11-1.32), SBP (OR=1.21; 95%CI 1.07-1.37) and LDL (OR=1.13; 95%CI 1.04-1.23). CONCLUSION: Women with diabetes have poorer control of main potentially modifiable cardiovascular risk factors than men. This could contribute to disparities in trends in cardiovascular mortality and it demands clinicians' and public health awareness. PMID- 22246484 TI - Cerebral microbleeds in patients with moyamoya-like vessels secondary to atherosclerosis. AB - OBJECTIVE: Hemorrhagic risk is unknown in patients with moyamoya-like vessels associated with atherosclerotic intracranial cerebral artery occlusion. This study was undertaken to investigate the association between moyamoya-like vessels and cerebral microbleeds (CMBs) in patients with atherosclerotic steno-occlusive disease. METHODS: The study population comprised 34 patients with steno-occlusive lesions in the intracranial cerebral artery caused by atherosclerosis. We evaluated the presence of moyamoya-like vessels at the base of the brain by cerebral angiography, and the presence of CMBs by T2*-weighted MRI. Patients were divided into 2 groups: those with and those without moyamoya-like vessels; clinical histories and the incidence of CMBs were compared between the groups. RESULTS: Sixteen patients had moyamoya-like vessels. Twelve of 16 patients with moyamoya-like vessels had a history of ischemic stroke or transient ischemic attack, whereas only 1 patient had a history of symptomatic cerebral hemorrhage. The incidence of CMBs did not differ between the 2 groups (31% vs. 28%, p=0.82). The location of CMBs varied and was not associated with the site of moyamoya-like vessels. CONCLUSION: CMBs were not associated with moyamoya-like vessels in patients with atherosclerotic cerebral artery occlusion. These patients may not have a high risk of cerebral hemorrhage. PMID- 22246485 TI - An adult patient with acute infection with hepatitis B virus genotype C that progressed to chronic infection. AB - In 2008, a 28-year-old woman consulted our hospital due to general fatigue. Her ALT level was within normal range but she was positive for hepatitis B surface antigen (HBsAg). Her ALT level was nearly within normal range thereafter and she was consistently positive for HBeAg. Later, it was proven that she was negative for HBsAg in 1999. She had been a sex worker in 2007-2008. Complete genome sequencing revealed that her HBV was genotype C. The present case may indicate that it is possible for acute infection with HBV genotype C to progress to chronic infection in adults. PMID- 22246486 TI - Long-term Taenia saginata infection successfully treated with meglumine/diatrizoate sodium. AB - A 46-year-old Japanese man visited our hospital for chronic abdominal pain, persistent diarrhea and discharge of proglottids for 7 years. He had been living in Lao People's Democratic Republic. Ileography using meglumine/diatrizoate sodium (Gastrografin) revealed a long tapeworm. A Taenia saginata including the scolex was excreted through the intestinal tract by the administration of total 780 ml of Gastrografin. Taeniasis is an important disease in the differential diagnosis of imported diseases in Japan. Parasite infection should be suspected in patients with chronic abdominal pain or persistent diarrhea regardless of the findings for small bowel obstruction when there is a history of overseas travel. PMID- 22246487 TI - Jejunal lipoma concealing intestinal adenocarcinoma: don't always regard CT imaging features like lipoma as benign or pseudomalignant features. AB - Lipomas are benign submucosal tumors composed of mature adipose tissue. Some authors have described patients with persistent abdominal pain who were misdiagnosed as intestinal adenocarcinoma and the diagnosis turned out to be a lipoma on histological examination. We discuss the case of a 57-year-old woman presenting with abdominal pain for 4 weeks. Intestinal adenocarcinoma was found by double-balloon enteroscopy (DBE), but at first only lipoma was found by CT scan. Therefore we want to emphasize that lipoma should not always be regarded as pseudomalignant features, sometimes lipoma conceals intestinal adenocarcinoma, and DBE may be a better way to discover malignancy. PMID- 22246488 TI - Unmasking of J waves during right coronary angiography in patients with spontaneous coronary spasms and ventricular fibrillation. AB - We encountered two consecutive cases with spontaneous ST elevation due to right coronary spasms and subsequent ventricular fibrillation (VF). Their 12-lead ECGs on anterior chest pain showed elevation of ST-segments in the inferior leads, but coronary angiography (CAG) revealed no significant stenosis. Both cases showed dramatically evolving J waves in the inferior leads during the right CAG, but it was not observed during angiography of the left CAG. Neither Brugada-type ECG nor long-QT was evident. In summary, J waves can be produced without ST-segment elevation, and contrast media-induced J waves might be related to the arrhythmogenesis of subsequent VF evoked by right coronary spasms. PMID- 22246489 TI - Central diabetes insipidus and hypothalamic type of hypopituitarism associated with atypical location of Rathke's cleft cyst. AB - A 68-year-old woman was admitted to determine the pathogenesis of weight loss and polyuria. Physical findings on admission showed BMI of 20.9, blood pressure of 147/69 mmHg, and that she had ciliac, axillar and pubic hair loss. Laboratory findings showed that plasma adrenocorticotropic hormone (ACTH) was 4.6 pg/mL with serum cortisol of 1.2 ug/dL. Serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) were markedly reduced. Serum growth hormone (GH) and insulin growth factor (IGF)-1 were 0.054 ng/mL and 25 ng/mL, respectively. Serum prolactin was as high as 85.6 ng/mL. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no response of ACTH and GH release to insulin-induced hypoglycemia and no response of LH and FSH release to clomiphene. Urine volume was more than 4,000 mL, with low urine osmolality of 134 mmol/kg. Plasma arginine vasopressin (AVP) was 0.8 pg/mL. There was no increase in urine osmolality and plasma AVP in response to 5% hypertonic saline load. Magnetic resonance imaging revealed Rathke's cleft cyst at the pituitary stalk level, but there was no abnormal finding in the hypothalamus. These findings indicate central diabetes insipidus and hypothalamic type of hypopituitarism, resulting from the atypical location of Rathke's cleft cyst. PMID- 22246490 TI - Pulmonary veno-occlusive disease following reduced-intensity allogeneic bone marrow transplantation for acute myeloid leukemia. AB - We report a case of pulmonary veno-occlusive disease (PVOD) following allogeneic bone marrow transplantation (BMT) for the treatment of acute myeloid leukemia (AML) from an HLA mismatched mother using a reduced-intensity conditioning (RIC) regimen including gemtuzumab ozogamicin. The patient was a 21-year-old male who complained of dyspnea with hypoxemia followed by loss of consciousness. The abnormalities in chest CT and echocardiography were compatible with a diagnosis of PVOD. Treatment with 1 mg/kg of oral prednisolone resolved dyspnea and hypoxemia within a few days, and chest CT abnormalities disappeared in a week. This report is the first to describe PVOD following RIC stem cell transplantation. PMID- 22246491 TI - Leukemic presentation of ALK-negative anaplastic large cell lymphoma in a patient with myelodysplastic syndrome. AB - A 50-year-old woman with a history of aplastic anemia developed cervical lymphadenopathy and atypical lymphocytosis. Atypical cells of lymph nodes were positive for CD3 and CD30 but negative for anaplastic lymphoma kinase (ALK). Bone marrow examination showed trilineage myelodysplasia. She was diagnosed with ALK negative anaplastic large cell lymphoma (ALCL) with leukemic transformation and myelodysplastic syndrome (MDS) which presumably developed from aplastic anemia. The lymphoma was resistant to intensive chemotherapies, ultimately leading to death. Leukemic presentation of ALK-negative ALCL as an initial manifestation is extremely rare, and the progression of the disease may be influenced by MDS through alteration of immune functions. PMID- 22246492 TI - Akinetic mutism caused by HIV-associated progressive multifocal leukoencephalopathy was successfully treated with mefloquine: a serial multimodal MRI Study. AB - We report a case of a patient with highly active anti-retroviral therapy resistant human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML). The patient showed an improvement in imaging findings and clinical symptoms after mefloquine was introduced as an additional treatment. Serial assessment of white matter lesions was conducted by proton magnetic resonance spectroscopy ((1)H-MRS) and diffusion-weighted imaging (DWI). As the clinical symptoms improved, the N-acetylaspartate/creatine ratio increased, the choline/creatine ratio decreased, and the elevated ADC value decreased. These concomitant changes suggested that (1)H-MRS and DWI were useful for the assessment of the therapeutic effect on PML. PMID- 22246493 TI - Culture-negative brain abscess with Streptococcus intermedius infection with diagnosis established by direct nucleotide sequence analysis of the 16s ribosomal RNA gene. AB - A 70-year-old woman developed a headache for a month followed by right upper limb weakness. CT scan and MRI showed multiple ring-enhancing lesions. An intracerebral aspiration of an abscess was performed, but culture results were negative. The nucleotide sequence analysis of the 16S rRNA gene from the specimens identified Streptococcus intermedius. Given this result, S. intermedius was cultured by enrichment culture, and its sensitivities to antibiotics were determined. The patient exhibited complete remission. Thus, 16S rRNA gene analysis was highly useful not only for pathogen identification with negative culture results but also for the appropriate selection of antibiotics. PMID- 22246494 TI - Chronic inflammatory demyelinating polyneuropathy due to the administration of pegylated interferon alpha-2b: a neuropathology case report. AB - We report a 35-year-old man who developed weakness in his extremities five months after pegylated interferon alpha (IFNalpha)-2b was administered. The serum tumor necrosis factor-alpha (TNFalpha) was elevated and nerve conduction studies revealed demyelination both in the distal and intermediate segments. The sural nerve pathology showed mild demyelinating process. The cessation of IFNalpha and administration of intravenous immunoglobulin improved both his clinical symptoms and the temporal dispersion in motor nerve conduction study. IFNalpha-induced CIDP is presumably a transient immunological condition that requires immunomodulatory therapy. The elevated serum TNFalpha may implicate the degree of downstream autoimmunity induced by IFNalpha. PMID- 22246495 TI - A hollenhorst plaque in cholesterol crystal embolism. PMID- 22246496 TI - Pulmonary arteriovenous communications in an elderly patient. PMID- 22246497 TI - Wegener granulomatosis-associated optic perineural hypertrophy and optic neuropathy. PMID- 22246498 TI - Expanded subarachnoid space of the optic nerve. PMID- 22246499 TI - Crowned dens syndrome. PMID- 22246500 TI - Isolated unilateral pulmonary artery agenesis. PMID- 22246501 TI - IgG4-related disease induced by localized pseudotumor. PMID- 22246502 TI - Genomic and metabolic prediction of complex heterotic traits in hybrid maize. AB - Maize is both an exciting model organism in plant genetics and also the most important crop worldwide for food, animal feed and bioenergy production. Recent genome-wide association and metabolic profiling studies aimed to resolve quantitative traits to their causal genetic loci and key metabolic regulators. Here we present a complementary approach that exploits large-scale genomic and metabolic information to predict complex, highly polygenic traits in hybrid testcrosses. We crossed 285 diverse Dent inbred lines from worldwide sources with two testers and predicted their combining abilities for seven biomass- and bioenergy-related traits using 56,110 SNPs and 130 metabolites. Whole-genome and metabolic prediction models were built by fitting effects for all SNPs or metabolites. Prediction accuracies ranged from 0.72 to 0.81 for SNPs and from 0.60 to 0.80 for metabolites, allowing a reliable screening of large collections of diverse inbred lines for their potential to create superior hybrids. PMID- 22246503 TI - CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. AB - Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction. PMID- 22246504 TI - PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. AB - Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family. PMID- 22246505 TI - Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior. AB - The breast cancer resistance protein, also known as ABCG2, is one of the most highly studied ATP-binding cassette (ABC) transporters because of its ability to confer multidrug resistance. The lack of information on the physiological role of ABCG2 in humans severely limits cancer chemotherapeutic approaches targeting this transporter. We report here that ABCG2 comprises the molecular basis of a new blood group system (Junior, Jr) and that individuals of the Jr(a-) blood type have inherited two null alleles of ABCG2. We identified five frameshift and three nonsense mutations in ABCG2. We also show that the prevalence of the Jr(a-) blood type in the Japanese and European Gypsy populations is related to the p.Gln126* and p.Arg236* protein alterations, respectively. The identification of ABCG2(-/-) (Jr(a-)) individuals who appear phenotypically normal is an essential step toward targeting ABCG2 in cancer and also in understanding the physiological and pharmacological roles of this promiscuous transporter in humans. PMID- 22246506 TI - ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. AB - The human ATP-binding cassette (ABC) transporter ABCB6 has been described as a mitochondrial porphyrin transporter essential for heme biosynthesis, but it is also suspected to contribute to anticancer drug resistance, as do other ABC transporters located at the plasma membrane. We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells, and we established that ABCB6 encodes a new blood group system (Langereis, Lan). Targeted sequencing of ABCB6 in 12 unrelated individuals of the Lan(-) blood type identified 10 different ABCB6 null mutations. This is the first report of deficient alleles of this human ABC transporter gene. Of note, Lan(-) (ABCB6(-/-)) individuals do not suffer any clinical consequences, although their deficiency in ABCB6 may place them at risk when determining drug dosage. PMID- 22246507 TI - ABCG2 null alleles define the Jr(a-) blood group phenotype. AB - The high-incidence erythrocyte blood group antigen Jr(a) has been known in transfusion medicine for over 40 years. To identify the gene encoding Jr(a), we performed SNP analysis of genomic DNA from six Jr(a-) individuals. All individuals shared a homozygous region of 397,000 bp at chromosome 4q22.1 that contained the gene ABCG2, and DNA sequence analysis showed that ABCG2 null alleles define the Jr(a-) phenotype. PMID- 22246508 TI - Whole-genome sequence of Schistosoma haematobium. AB - Schistosomiasis is a neglected tropical disease caused by blood flukes (genus Schistosoma; schistosomes) and affecting 200 million people worldwide. No vaccines are available, and treatment relies on one drug, praziquantel. Schistosoma haematobium has come into the spotlight as a major cause of urogenital disease, as an agent linked to bladder cancer and as a predisposing factor for HIV/AIDS. The parasite is transmitted to humans from freshwater snails. Worms dwell in blood vessels and release eggs that become embedded in the bladder wall to elicit chronic immune-mediated disease and induce squamous cell carcinoma. Here we sequenced the 385-Mb genome of S. haematobium using Illumina based technology at 74-fold coverage and compared it to sequences from related parasites. We included genome annotation based on function, gene ontology, networking and pathway mapping. This genome now provides an unprecedented resource for many fundamental research areas and shows great promise for the design of new disease interventions. PMID- 22246509 TI - Epidemiology of carbapenem resistant Klebsiella pneumoniae colonization in an intensive care unit. AB - Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged during recent years in several intensive care units. The objective of our study was to determine the incidence of CRKP and the risk factors associated with acquisition during intensive care unit (ICU) stay. This prospective cohort study was conducted between May 2007 and April 2008 in a medical-surgical ICU at a tertiary medical center. Rectal surveillance cultures were obtained from patients on admission and twice weekly. Of screened patients, 7.0% (21/299) were CRKP colonized on admission to the ICU. One hundred eighty (81%) patients were screened at least twice. Of these, 48 (27%) patients acquired CRKP during ICU stay. Of the 69 CRKP colonized patients (both imported and ICU acquired), 29% (20/69) were first identified by microbiologic cultures, while screening cultures identified 49 patients (71%). Of these, 23 (47%) subsequently developed clinical microbiological cultures. Independent risk factors for CRKP acquisition included recent surgery (OR 7.74; CI 3.42-17.45) and SOFA score on admission (OR 1.17; CI 1-1.22). In conclusion, active surveillance cultures detected a sizable proportion of CRKP colonized patients that were not identified by clinical cultures. Recent surgical procedures and patient severity were independently associated with CRKP acquisition. PMID- 22246510 TI - Diagnostic testing for Legionnaires' disease in the Netherlands between 2007 and 2009: a possible cause for the decline in reported Legionnaires' disease patients. AB - Legionnaires' disease (LD) is an acute pneumonia caused by the inhalation or aspiration of aerosols contaminated with the Legionella bacteria. In the Netherlands, around 300 LD cases per year were reported between 2000 and 2008, but in 2009, the number dropped to 251, which was the lowest number in the previous 5 years of surveillance. We investigated if this decrease could be explained by the number of performed Legionella diagnostic tests in this year. We analyzed the number of tests performed between 2007 and 2009 in three large microbiological laboratories in different geographical regions in the Netherlands. Our data showed that there was no decrease in the number of patients for whom a diagnostic test for Legionella was performed in this period. These results are not in line with our hypothesis that the decrease in reported Legionella pneumonia patients in 2009 would be due to a decrease in patients for whom a diagnostic test was performed. We conclude that it is more likely that other factors such as the influence of weather patterns might explain the sudden drop in reported Legionella pneumonia patients in 2009 compared to the previous years, and it would be interesting to investigate this for the period described. PMID- 22246511 TI - Correlates and contexts of US injection drug initiation among undocumented Mexican migrant men who were deported from the United States. AB - Preventing the onset of injection drug use is important in controlling the spread of HIV and other blood borne infections. Undocumented migrants in the United States face social, economic, and legal stressors that may contribute to substance abuse. Little is known about undocumented migrants' drug abuse trajectories including injection initiation. To examine the correlates and contexts of US injection initiation among undocumented migrants, we administered quantitative surveys (N = 309) and qualitative interviews (N = 23) on migration and drug abuse experiences to deported male injection drug users in Tijuana, Mexico. US injection initiation was independently associated with ever using drugs in Mexico pre-migration, younger age at first US migration, and US incarceration. Participants' qualitative interviews contextualized quantitative findings and demonstrated the significance of social contexts surrounding US injection initiation experiences. HIV prevention programs may prevent/delay US injection initiation by addressing socio-economic and migration-related stressors experienced by undocumented migrants. PMID- 22246512 TI - Aging, prospective memory, and health-related quality of life in HIV infection. AB - HIV infection and older age are each independently associated with lower health related quality of life (HRQoL) and deficits in prospective memory (PM), which is a distinct aspect of cognition involving the ability to "remember to remember" to do something at a future occasion. The present study investigated associations between PM and HRQoL in 72 older (>= 50 years) and 41 younger (<= 40 years) HIV infected adults. Self-reported PM complaints predicted HRQoL across the entire sample, but there was a significant interaction between performance-based PM and age group on HRQoL, such that lower time-based PM was associated with lower HRQoL only in the younger cohort. Within the younger group, time-based and self reported PM significantly predicted mental HRQoL independent of other risk factors (e.g. depression). These findings suggest that PM plays a unique role in HRQoL outcomes among younger persons living with HIV infection and support the examination of other age-related factors (e.g. effective use of compensatory strategies) that may regulate the adverse impact of PM on everyday functioning. PMID- 22246514 TI - Assessing HIV/AIDS stigma in south India: validation and abridgement of the Berger HIV Stigma scale. AB - HIV-related stigma has been associated with depression, poor adherence, and nondisclosure of HIV-positive status, all of which can lead to increased transmission of HIV and poorer health outcomes for HIV-infected individuals. The Berger HIV Stigma scale has been used in multiple settings but never adapted and validated in India, home to the world's second largest HIV-infected population. We assessed the reliability and validity of a Tamil translation of the original 40-item scale, and conducted confirmatory and exploratory factor analyses to assess cultural appropriateness and abbreviate the scale. Reliability and validity were high (alpha = 0.91; test-retest reliability ICC = 0.89). Exploratory and confirmatory factor analysis resulted in an abridged 25-item version of the scale that possessed better psychometric properties than the 40 item version. This culturally validated, abridged HIV-Stigma scale can be used in busy clinical settings to identify individuals in need of psychosocial support and assess post-intervention changes in stigma in Southern India. PMID- 22246513 TI - Association between use of specific drugs and antiretroviral adherence: findings from MACH 14. AB - To determine the association between individual substances of abuse and antiretroviral adherence, analyses require a large sample assessed using electronic data monitoring (EDM). In this analysis, EDM data from 1,636 participants in 12 US adherence-focused studies were analyzed to determine the associations between recent use of various substances and adherence during the preceding 4 weeks. In bivariate analyses comparing adherence among patients who had used a specific substance to those who had not, adherence was significantly lower among those who had recently used cocaine, other stimulants or heroin but not among those who had used cannabis or alcohol. In multivariate analyses controlling for sociodemographics, amount of alcohol use and recent use of any alcohol, cocaine, other stimulants and heroin each was significantly negatively associated with adherence. The significant associations of cocaine, other stimulants, heroin, and alcohol use with adherence suggest that these are important substances to target with adherence-focused interventions. PMID- 22246515 TI - A randomized controlled pilot study of an HIV risk-reduction intervention for sub Saharan African university students. AB - This pilot study used a randomized controlled trial to test the efficacy of an HIV risk-reduction intervention for university students in Eastern Cape Province, South Africa. Randomly selected second-year students were randomized to one of two interventions based on social cognitive theory and qualitative research: HIV risk-reduction, targeting sexual-risk behaviors; health-promotion control, targeting health behaviors unrelated to sexual risks. Participants completed behavioral assessments via audio computer-assisted self-interviewing pre intervention, 6, and 12 months post intervention, with 97.2% retained at 12-month follow-up. Averaged over the 2 follow-ups, HIV risk-reduction intervention participants reported less unprotected vaginal intercourse and more frequent condom use than control participants, with greater efficacy in non-South Africans than South Africans. Positive changes were also observed on theoretical mediators of condom use that the intervention targeted. Interventions based on social cognitive theory integrated with qualitative information from the population may reduce sexual risk behaviors among university students in sub-Saharan Africa. PMID- 22246517 TI - Correlates of anxiety in women living with HIV of reproductive age. AB - Prior investigations suggest that women living with HIV (WLWH) experience higher rates of anxiety compared to the general population. This study investigates correlates of anxiety among 361 WLWH of reproductive age in Ontario, Canada who completed a series of self-reported measures. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS-A). Thirty-seven percent of the sample had high anxiety (HADS-A >= 11). HIV-related stigma, reproductive health related worries, having experienced judgment from family and friends for trying to become pregnant and use of antiretrovirals were associated with high anxiety. Being in a romantic/sexual relationship, older age, and undetectable viral load were associated with low anxiety. Findings highlight the importance of HIV related stigma and having experienced judgment from family and friends for trying to become pregnant as important predictors of anxiety among WLWH of reproductive age. There is a need for appropriate management of anxiety and stigma for WLWH of childbearing age. PMID- 22246516 TI - No association found between traditional healer use and delayed antiretroviral initiation in rural Uganda. AB - Traditional healer and/or spiritual counselor (TH/SC) use has been associated with delays in HIV testing. We examined HIV-infected individuals in southwestern Uganda to test the hypothesis that TH/SC use was also associated with lower CD4 counts at antiretroviral therapy (ART) initiation. Approximately 450 individuals initiating ART through an HIV/AIDS clinic at the Mbarara University of Science and Technology (MUST) were recruited to participate. Patients were predominantly female, ranged in age from 18 to 75, and had a median CD4 count of 130. TH/SC use was not associated with lower CD4 cell count, but age and quality-of-life physical health summary score were associated with CD4 cell count at initiation while asset index was negatively associated with CD4 count at ART initiation. These findings suggest that TH/SC use does not delay initiation of ART. PMID- 22246518 TI - Application of molybdenum bis(imido) complexes in ethylene dimerisation catalysis. AB - In combination with EtAlCl(2) (Mo : Al = 1 : 15) the imido complexes [MoCl(2)(NR)(NR')(dme)] (R = R' = 2,6-Pr(i)(2)-C(6)H(3) (1); R = 2,6-Pr(i)(2) C(6)H(3), R' = Bu(t) (3); R = R' = Bu(t) (4); dme = 1,2-dimethoxyethane) and [Mo(NHBu(t))(2)(NR)(2)] (R = 2,6-Pr(i)(2)-C(6)H(3) (5); R = Bu(t) (6)) each show moderate TON, activity, and selectivity for the catalytic dimerisation of ethylene, which is influenced by the nature of the imido substituents. In contrast, the productivity of [MoCl(2)(NPh)(2)(dme)] (2) is low and polymerisation is favoured over dimerisation. Catalysis initiated by complexes 1 4 in combination with MeAlCl(2) (Mo : Al = 1 : 15) exhibits a significantly lower productivity. Reaction of complex 5 with EtAlCl(2) (2 equiv.) gives rise to a mixture of products, while addition of MeAlCl(2) affords [MoMe(2)(N-2,6-Pr(i)(2) C(6)H(3))(2)]. Treatment of 6 with RAlCl(2) (2 equiv.) (R = Me, Et) yields [Mo({MU-N-Bu(t)}AlCl(2))(2)] (7) in both cases. Imido derivatives 1 and 3 react with Me(3)Al and MeAlCl(2) to form the bimetallic complexes [MoMe(2)(N{R}AlMe(2){MU-Cl})(NR')] (R = R' = 2,6-Pr(i)(2)-C(6)H(3) (8); R = 2,6 Pr(i)(2)-C(6)H(3), R' = Bu(t) (10)) and [MoMe(2)(N{R}AlCl(2){MU-Cl})(NR')] (R = R' = 2,6-Pr(i)(2)-C(6)H(3) (9); R = 2,6-Pr(i)(2)-C(6)H(3), R' = Bu(t) (11)), respectively. Exposure of complex 8 to five equivalents of thf or PMe(3) affords the adducts [MoMe(2)(N-2,6-Pr(i)(2)-C(6)H(3))(2)(L)] (L = thf (12); L = PMe(3) (13)), while reaction with NEt(3) (5 equiv.) yields [MoMe(2)(N-2,6-Pr(i)(2) C(6)H(3))(2)]. The molecular structures of complexes 5, 9 and 11 have been determined. PMID- 22246519 TI - Chemical signals of elephant musth: temporal aspects of microbially-mediated modifications. AB - Mature male African (Loxodonta africana) and Asian (Elephas maximus) elephants exhibit periodic episodes of musth, a state in which serum androgens are elevated, food intake typically decreases, aggressiveness often increases, and breeding success is enhanced. Urine is a common source of chemical signals in a variety of mammals. Elephants in musth dribble urine almost continuously for lengthy periods, suggesting that the chemicals in their urine may reveal their physiological condition to conspecifics. We investigated the volatile urinary chemicals in captive male elephants using automated solid phase dynamic extraction (SPDE) and gas chromatography-mass spectrometry (GC-MS). We found higher levels of alkan-2-ones, alkan-2-ols, and some aromatic compounds in urine from males in musth than in urine from non-musth males or from females. Levels of ketones and alcohols increased as the urine aged, likely due to microbial metabolism of fatty acids. Protein-derived aromatic metabolites also increased in abundance after urination, likely due to microbial hydrolysis of hydrophilic conjugates. We suggest that microbes may play an important role in timed release of urinary semiochemicals during elephant musth. PMID- 22246520 TI - New synthesis--visual and chemical ornaments: what researchers of different signal modalities can learn from each other. PMID- 22246521 TI - Male-produced pheromone in the European woodwasp, Sirex noctilio. AB - A male-produced pheromone that attracts both males and females was identified for the European woodwasp, Sirex noctilio, a serious pest of pine trees. Males displayed excitatory behaviors when placed in groups, and were attracted to the odors from males that were 2-5-d-old, but not to odors from males that were 0-1-d old. An unsaturated short-chain alcohol, (Z)-3-decen-1-ol, was discovered in samples collected on SuperQ filters over groups of males and identified by using micro-derivatization reactions and gas chromatography coupled with mass spectrometry (GC-MS). The compound was not detected in volatile samples from females. Gas chromatography coupled electroantennographic detection (GC-EAD) of antennae from males exposed to male headspace odors produced strong antennal responses to the main peak of (Z)-3-decen-1-ol, as well as to an unknown minor component that had a similar retention time. Antennae from both males and females responded to synthetic (Z)-3-decen-1-ol. Several different synthetic candidates for the GC-EAD active minor components were selected based on GC-MS and GC-EAD responses to male headspace collections. These synthetic compounds were tested for antennal activity using GC-EAD, and those that produced strong responses were blended with the major component and tested for male attraction in the Y-tube olfactometer at different concentrations and ratios. Males tested in the Y-tube olfactometer were attracted to a synthetic blend of (Z)-3-decen-1-ol and (Z)-4 decen-1-ol at a ratio of 100:1. Whereas the addition of some suspected minor compounds reduced attraction, the addition of a third compound found in male emanations that produced strong male antennal responses, (E,E)-2,4-decadienal (at a ratio of 100:1:1), resulted in attraction of both males (Y-tube and wind tunnel) and females (wind tunnel). PMID- 22246522 TI - The absolute configuration of chrysomelidial: a widely distributed defensive component among oribotririid mites (Acari: Oribatida). AB - The absolute configuration of the iridoid monoterpene chrysomelidial from the oribatid mite, Austrotritia dentate Aoki, was elucidated by the GC-MS and GC comparisons with four synthetic stereoisomers of this well-known natural product. This identification was made possible by asymmetric synthesis of the known alcohol, (5S,8S)-chrysomelidiol. The GC retention time of diol derived from the natural oribatid dial agreed with that of the synthetic (5S,8S)-chrysomelidiol, confirming that the absolute configurations at C5 and C8 positions of the natural chrysomelidial are both S. Chrysomelidial was detected as a single or a major component in nine oribatid mites examined; thus, this compound is considered to be commonly distributed in Oribotririidae where it serves a defensive role. PMID- 22246523 TI - MicroRNA-34a affects the occurrence of laryngeal squamous cell carcinoma by targeting the antiapoptotic gene survivin. AB - Survivin has been shown to be an ideal target for cancer gene therapy because of its strong antiapoptotic effect. MicroRNA-34a (miR-34a) can function as a tumor suppressor in some cancers through negative regulation of gene expression. However, the relationship between miR-34a and survivin in larynx squamous cell carcinoma (LSCC) has not been explored. The abundance of survivin mRNA and miR 34a in LSCC tissues were measured using quantitative real-time polymerase chain reaction. Their expression levels were analyzed and correlated with tumor differentiation, lymphatic metastasis, clinical stages, and survival rates. MiR 34a mimic was transfected using liposomes to increase its level in LSCC cancer cell line, Hep-2. The effects of miR-34a on survivin protein expression were tested using western blot analysis. Cell cycle analyses were performed using flow cytometry. The results showed that transfection of miR-34a mimic significantly suppressed cell proliferation with decreased survivin protein expression, but did not affect mRNA expression level. The results from LSCC tissue samples showed that miR-34a was downregulated, while survivin expression was upregulated. The miR-34a levels were negatively correlated with histologic differentiation and were positively correlated with survival rate. MiR-34a significantly suppressed cell proliferation by arresting cells at G0/G1 phase in Hep-2 cells. These results indicated that miR-34a may affect the occurrence of LSCC by targeting survivin. PMID- 22246524 TI - N-acetyltransferase-2 gene polymorphisms and prostate cancer susceptibility in Latin American patients. AB - We investigated the role of N-acetyltransferases (NAT) in prostate cancer (PCa) susceptibility. NAT are polymorphic in the population and metabolize important carcinogenic products directly involved in the tumor initiation process. This prospective case-control study utilized the polymerase chain reaction-based restriction fragment length polymorphism method and comprised a cohort of consecutive 478 individuals: 126 men with prostate cancer; 101 men with benign prostatic hyperplasia (BPH); and a control health population of 177 female and 74 male blood donors from the same region. NAT2 slow or fast acetylators genotypes were determined by the combination of four variant alleles. Lifetime occupational history, dietary patterns, cigarette smoking and other anamnestic data were obtained by interviews. We were not able to find any correlation among smoking, dietary patterns, parameters of tumor aggressiveness or patient outcome and any NAT2 genotypes or phenotypes considered in separate or in different combinations. However, there was an association between NAT2T481C (OR=0.47; 95% CI=0.26-0.84; P=0.01) and NAT2A803G (OR=0.57; 95% CI=0.33-0.97; P=0.04) polymorphisms and PCa protection. Conversely, the presence of NAT2G857A genotype increased the risk of PCa more than 3 times (OR=3.57; 95% CI=1.39-9.15; P=0.005). Slow acetylator NAT2*7A and NAT2*6B genotypes occurred in 10.31% of PCa but in none of BPH patients (P=0.0007). The control health population confirmed the results and allowed the exclusion of possible biases caused by gender influence on genotype inheritance and by the inclusion of not diagnosed prostate diseases patients among the control individuals. We suggest that the investigation of germline polymorphisms of NAT2 gene may be useful in the assessment of Latin American patients at risk of BPH and PCa. PMID- 22246526 TI - Immunohistochemical detection of CD133 is associated with tumor regression grade after chemoradiotherapy in rectal cancer. AB - CD133 has been identified as a putative cancer stem cell (CSC) marker in various cancers including colorectal cancer. The relation between CD133 expression and biological characteristics of colorectal cancer remains to be clarified. Protein expression of CD133 was immunohistochemically evaluated in surgical specimens of 225 patients with colorectal cancer who were treated by surgery, as well as those of 78 patients with rectal cancer who received preoperative chemoradiotherapy (CRT) followed by curative resection. The correlation between CD133 expression and clinicopathological features, tumor recurrence and overall survival was analyzed in both populations. Among 225 colorectal cancers without CRT, 93 (41.3%) were positive for CD133 expression, which was enhanced in cases with advanced T stage and venous invasion. Moreover, CD133 was positive in 47 (60.3%) of 78 cases with CRT, which was significantly higher than the CD133-positive rate in non-CRT specimens (P=0.05). Expression of CD133 was independently correlated with the histological tumor regression grade (P<0.01). These results suggest that CD133 is not a distinctive colorectal CSC marker; expression of CD133 is suggested to be one of the key factors associated with resistance to CRT in colorectal cancer. PMID- 22246525 TI - High co-expression of vascular endothelial growth factor receptor-1 and Snail is associated with poor prognosis after curative resection of hepatocellular carcinoma. AB - VEGFR-1-mediated signaling promotes invasiveness by direct tumor activation in some cancers. However, VEGFR-1 expression and its relationship with clinical features and prognosis in HCC remained unclear. Overexpression of Snail is common in HCC and associated with poorer prognosis. Therefore, expression of VEGFR-1 and Snail was investigated in HCC cell lines and tissue specimens in our study, and special attention was paid to evaluating the role of VEGFR-1 expression in prognosis of HCC. Western blot and immunofluorescence were used to detect expression of VEGFR-1, Snail and MMP-9 in 4 HCC cell lines, respectively. Moreover, expression of these proteins was confirmed on the samples from 95 HCC patients who underwent curative resection using immunohistochemistry. ROC and survival analysis determined the predictive values of parameters and the association with survival. HCC cell lines with a higher VEGFR-1 expression were more invasive. Both VEGFR-1 and Snail expressions were significantly higher in HCC tissues than in non-cancerous tissues. High-expression VEGFR-1 and Snail, associated with adverse clinical features, were independent prognostic factors for RFS and OS (P=0.023 and P=0.044, respectively). Positive correlation was found between VEGFR-1 and Snail or MMP-9 (r=0.418 and r=0.232, respectively, P<0.05 for both) in cancerous tissues. The combination of VEGFR-1 and Snail gave a better power to predict patients' recurrence and death (P<0.001 for both). High VEGFR-1 expression, distinctively expressed in the cytomembrane of HCC cells, was associated with HCC progression and worse outcome. High co-expression of VEGFR-1 and Snail may be a novel prognostic marker for HCC, especially in recurrence. PMID- 22246527 TI - Characterization of a new ScbR-like gamma-butyrolactone binding regulator (SlbR) in Streptomyces coelicolor. AB - gamma-Butyrolactones in Streptomyces are well recognized as bacterial hormones, and they affect secondary metabolism of Streptomyces. gamma-Butyrolactone receptors are considered important regulatory proteins, and various gamma butyrolactone synthases and receptors have been reported in Streptomyces. Here, we characterized a new regulator, SCO0608, that interacted with SCB1 (gamma butyrolactone of Streptomyces coelicolor) and bound to the scbR/A and adpA promoters. The SCO0608 protein sequences are not similar to those of any known gamma-butyrolactone binding proteins in Streptomyces such as ScbR from S. coelicolor or ArpA from Streptomyces griseus. Interestingly, SCO0608 functions as a repressor of antibiotic biosynthesis and spore formation in R5 complex media. We showed the existence of another type of gamma-butyrolactone receptor in Streptomyces, and this SCO0608 was named ScbR-like gamma-butyrolactone binding regulator (SlbR) in S. coelicolor. PMID- 22246528 TI - Mercury-resistant rhizobial bacteria isolated from nodules of leguminous plants growing in high Hg-contaminated soils. AB - A survey of symbiotic bacteria from legumes grown in high mercury-contaminated soils (Almaden, Spain) was performed to produce a collection of rhizobia which could be well adapted to the environmental conditions of this region and be used for restoration practices. Nineteen Hg-tolerant rhizobia were isolated from nodules of 11 legume species (of the genera Medicago, Trifolium, Vicia, Lupinus, Phaseolus, and Retama) and characterized. Based on their growth on Hg supplemented media, the isolates were classified into three susceptibility groups. The minimum inhibitory concentrations (MICs) and the effective concentrations that produce 50% mortality identified the patterns of mercury tolerance and showed that 15 isolates were tolerant. The dynamics of cell growth during incubation with mercury showed that five isolates were unaffected by exposure to Hg concentrations under the MICs. Genetic analyses of the 16S rRNA gene assigned ten strains to Rhizobium leguminosarum, six to Ensifer medicae, two to Bradyrhizobium canariense, and one to Rhizobium radiobacter. Inoculation of host plants and analysis of the nodC genes revealed that most of them were symbiotically effective. Finally, three isolates were selected for bioremediation processes with restoration purposes on the basis of their levels of Hg tolerance, their response to high concentrations of this heavy metal, and their genetic affiliation and nodulation capacity. PMID- 22246529 TI - Evaluation of aroma active compounds in Tuber fruiting bodies by gas chromatography-olfactometry in combination with aroma reconstitution and omission test. AB - The aroma active compounds of three Tuber fruiting bodies (i.e., Tuber himalayense, Tuber indicum, and Tuber sinense) were firstly systematically evaluated by instrumental gas chromatography-olfactometry combining with quantitative analysis, aroma reconstitution, and omission tests. Twelve aroma active compounds were characterized by aroma extract dilution analysis, and 3 (methylthio) propanal, 3-methylbutanal, and 1-octen-3-ol with the highest flavor dilution (FD) factor (i.e., 1,024-2,048) were suggested as key contributors to the aroma. Odor activity value (OAV) was employed to determine the relative contribution of each compound to the aroma, and the compound with the highest FD factor also had the highest OAV (i.e., 10,234-242,951). Then, the synthetic blends of odorants (aroma reconstitution) were prepared with OAV larger than 15, and their aromas were very similar to the originals. Omission tests were carried out to verify the significance of 3-(methylthio) propanal, 1-octen-3-ol, and 3 methylbutanal as key compounds in the aroma of tested Tuber fruiting bodies. PMID- 22246530 TI - Modifying the product pattern of Clostridium acetobutylicum: physiological effects of disrupting the acetate and acetone formation pathways. AB - Clostridial acetone-butanol-ethanol (ABE) fermentation is a natural source for microbial n-butanol production and regained much interest in academia and industry in the past years. Due to the difficult genetic accessibility of Clostridium acetobutylicum and other solventogenic clostridia, successful metabolic engineering approaches are still rare. In this study, a set of five knock-out mutants with defects in the central fermentative metabolism were generated using the ClosTron technology, including the construction of targeted double knock-out mutants of C. acetobtuylicum ATCC 824. While disruption of the acetate biosynthetic pathway had no significant impact on the metabolite distribution, mutants with defects in the acetone pathway, including both acetoacetate decarboxylase (Adc)-negative and acetoacetyl-CoA:acyl-CoA transferase (CtfAB)-negative mutants, exhibited high amounts of acetate in the fermentation broth. Distinct butyrate increase and decrease patterns during the course of fermentations provided experimental evidence that butyrate, but not acetate, is re-assimilated via an Adc/CtfAB-independent pathway in C. acetobutylicum. Interestingly, combining the adc and ctfA mutations with a knock out of the phosphotransacetylase (Pta)-encoding gene, acetate production was drastically reduced, resulting in an increased flux towards butyrate. Except for the Pta-negative single mutant, all mutants exhibited a significantly reduced solvent production. PMID- 22246531 TI - RACK1 downregulation suppresses migration and proliferation of neuroblastoma cell lines. AB - Neuroblastoma is the most common extracranial solid tumor in childhood, whose molecular mechanism on clinically heterogeneous behavior is still unclear. Receptor for activated C-kinase 1 (RACK1) has been shown to be involved in the regulation of growth and migration in many types of cells. Two types of human neuroblastoma cell lines, SK-N-SH and SK-N-BE (2), were used to explore the role of RACK1 in neuroblastoma cell migration and proliferation. Cell migration and proliferation were detected by a transwell system and colorimetric bromodeoxyuridine (BrdU) ELISA, respectively. The expressions of RACK1, N-Myc, phospho-Src(Tyr416), phospho-Src(Tyr527), phospho-Akt, phospho-ERK1/2 and phospho p38 were analyzed by Western blotting. The expression of RACK1 was then repressed by target RNA interference (RNAi) in both types of neuroblastoma cells, and the expression of signaling molecules, migration and proliferation of cells was analyzed. Compared with SK-N-SH, the migration and proliferation of SK-N-BE(2) cells was remarkably higher which was accompanied by higher expression of RACK1 and phospho-Src(Tyr416). RACK1 RNAi repressed cell migration and proliferation, and decreased the expression of phospho-Src(Tyr416) in both cell lines. In summary, RACK1 was expressed in the neuroblastoma cells and positively regulated cell migration and proliferation probably via modulating the activation of Src on Tyr416 residue. PMID- 22246532 TI - Acoustofluidics 5: Building microfluidic acoustic resonators. AB - Acoustophoresis is getting more attention as an effective and gentle non-contact method of manipulating cells and particles in microfluidic systems. A key to a successful assembly of an acoustophoresis system is a proper design of the acoustic resonator where aspects of fabrication techniques, material choice, thickness matching of involved components, as well as strategies of actuation, all have to be considered. This tutorial covers some of the basics in designing and building microfluidic acoustic resonators and will hopefully be a comprehensive and advisory document to assist the interested reader in creating a successful acoustophoretic device. PMID- 22246533 TI - Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis. AB - The class VI intermediate filament protein, nestin is reported to be a progenitor cell marker in various tissues. In the present study, we analyzed the expression and roles of nestin in angiogenesis of pancreatic ductal adenocarcinomas, and determined whether nestin is a potential target for inhibiting tumor angiogenesis using a gene silencing strategy. Nestin expression was detected only in small vessels, whereas CD34, CD31 and factor VIII were also expressed in large-sized blood vessels in PDAC. The number of nestin-positive vessels was approximately 20% the number of CD34-positive vessels, and the average dimension of nestin positive vessels was approximately 75% that of CD34-positive vessels. The PCNA labeling indices of nestin-positive vessels were higher than those of CD34 positive vessels and nestin-negative vessels. Reducing nestin expression by use of siRNA targeting nestin transcripts inhibited growth of the vascular endothelial cell lines, but there was no difference in cell motility. In xenograft models, administration of siRNA targeting mouse-nestin suppressed subcutaneous human pancreatic cancer cell growth in nude mice. In conclusion, nestin was expressed in small proliferating blood vessels in pancreatic cancer tissues and may be a useful marker of angiogenesis in pancreatic ductal adenocarcinoma tissues. Furthermore, nestin is a potential novel therapeutic target in pancreatic cancers to inhibit tumor angiogenesis. PMID- 22246534 TI - Expression patterns of ADAMs in the developing chicken lens. AB - In the present study the expression patterns of ADAM (a disintegrin and metalloprotease) genes in the chicken developing lens were analyzed. Using in situ hybridization, we found that seven members of the ADAM family including ADAM9, ADAM10, ADAM12, ADAM13, ADAM17, ADAM22, and ADAM23 are expressed in the developing embryonic lens. From embryonic incubation day (E) 2 to E3, most of the ADAMs investigated here are expressed in the lens placode and lens vesicle. From E5 to E7, all seven ADAMs, but predominantly ADAM9 and ADAM10, are throughly expressed in the central epithelium, as well as in the proliferating lens epithelium and the equatorial lens epithelium. From E9 to E14, expression of ADAM9, ADAM10, and ADAM17 decreases moderately in these regions. ADAM12 and ADAM13 are weakly expressed in the central epithelium and the lens epithelium, and are not detectable from E14 onward. ADAM22 and ADAM23 are expressed in the central epithelium, the lens epithelium and the equatorial lens epithelium at E5 and decrease gradually afterwards in the same regions. At E16, only weak ADAM9, ADAM10 and ADAM17 signals are found in the anterior lens epithelium. The changing spatiotemporal expression of the seven ADAMs suggests a regulatory role for these molecules during chicken lens development. PMID- 22246535 TI - Use of focussed beam reflectance measurement (FBRM) for monitoring changes in biomass concentration. AB - The potential of focussed beam reflectance measurement (FBRM) as a tool to monitor changes in biomass concentration was investigated in a number of biological systems. The measurement technique was applied to two morphologically dissimilar plant cell suspension cultures, Morinda citrifolia and Centaurea calcitrapa, to a filamentous bacteria, Streptomyces natalensis, to high density cultures of Escherichia coli and to a murine Sp2/0 hybridoma suspension cell line, 3-2.19. In all cases, the biomass concentration proved to be correlated with total FBRM counts. The nature of the correlation varied between systems and was influenced by the concentration, nature, size and morphology of the particle under investigation. PMID- 22246536 TI - Magnetic field-based delivery of human CD133+ cells promotes functional recovery after rat spinal cord injury. AB - STUDY DESIGN: Experimental animal study of spinal cord injury (SCI), using a cell delivery system. OBJECTIVE: To investigate the therapeutic effects of transplantation of peripheral blood-derived CD133 cells, with a magnetic delivery system in a rat SCI model. SUMMARY OF BACKGROUND DATA: There are no reports on intrathecal transplantation of peripheral blood-derived CD133 cells, with a magnetic cell delivery system to treat SCI. METHODS: Magnetically isolated peripheral blood-derived CD133 cells were used as the cell source. Contusion SCI was induced by an Infinite Horizon impactor in athymic nude rats. CD133 cells or phosphate-buffered saline was administered via a lumbar puncture immediately after SCI, and a magnetic field was applied to rats for 30 minutes. Animals were analyzed at specific times after transplantation by several methods to examine cell tracking, functional recovery, and histological angiogenesis and neurogenesis. RESULTS: A combination of cell transplantation and application of a magnetic field at the site of injury caused significant functional recovery. Transplantation of the cells alone in the absence of the magnetic field showed no effect beyond that observed in control rats. CONCLUSION: The combination of intrathecal transplantation of CD133 cells and application of a magnetic field at the site of injury is a possible therapeutic strategy to treat rat SCI and may therefore find application in clinical settings. PMID- 22246537 TI - A case of symptomatic extra-foraminal lumbosacral stenosis ("far-out syndrome") diagnosed by diffusion tensor imaging. AB - STUDY DESIGN: Case report. OBJECTIVE: Diagnosis of symptomatic extra-foraminal lumbosacral stenosis using diffusion tensor imaging (DTI). SUMMARY OF BACKGROUND DATA: Conventional magnetic resonance imaging (MRI) has sometimes proved inadequate for evaluating symptomatic spinal nerve lesions. DTI has been developed to visualize anisotropy of nerve-fiber tracts to evaluate nerve degeneration. We report a case of nerve compression causing a far-out lesion diagnosed using DTI. METHODS: A 68-year-old patient presented with an 8-month history of severe right-sided sciatica. Computed tomography and MRI showed right L5-S1 foraminal stenosis and contact of the L5 transverse process and S1 ala without canal stenosis at the L4-L5 level. We evaluated the fractional anisotropy (FA) of the right L5 spinal nerve and compared it with bilateral L3-S1 spinal nerves to determine the L5 spinal nerve compression site. RESULTS: DTI revealed narrowing of the right L5 spinal nerve between the L5 transverse process and S1 ala. FA was significantly decreased in the right L5 spinal nerve between the L5 transverse process and S1 ala. There was no significant difference in the FA of spinal nerves between the right and left sides at L3, L4, or S1. The right L5 spinal nerve from the central spinal canal to the extra-foraminal lumbosacral lesion was exposed during surgery and found to be severely compressed by the L5 transverse process and S1 ala. Postoperatively, the patient's symptoms disappeared immediately. CONCLUSION: We used DTI to diagnose a symptomatic lesion as an extra-foraminal lumbosacral lesion caused by compression of the L5 spinal nerve at the foramina. Because DTI can quantitatively measure damage to nerve fibers, it may be advantageous for the diagnosis of far-out syndrome. PMID- 22246538 TI - Potential risk factors for new onset of back pain disability in Japanese workers: findings from the Japan epidemiological research of occupation-related back pain study. AB - STUDY DESIGN: Two-year, prospective cohort data from the Japan epidemiological research of occupation-related back pain study were used for this analysis. OBJECTIVE: To examine the association between a new onset of low back pain (LBP) with disability and potential risk factors among initially symptom-free Japanese workers. SUMMARY OF BACKGROUND DATA: Despite strong evidence that psychosocial issues may influence LBP onset among symptom-free persons, these and other LBP risk factors have not been well investigated in the Japanese workplace. METHODS: Of 5310 participants responding to a self-administered baseline questionnaire (response rate: 86.5%), 3194 (60.2%) completed both 1- and 2-year follow-up questionnaires. The baseline questionnaire assessed individual characteristics, ergonomic work demands, and work-related psychosocial factors. The outcome of interest was new-onset LBP with disability during the follow-up period. Incidence was calculated for the participants who reported no LBP during the past year at baseline. Logistic regression was used to explore risk factors associated with new-onset LBP with disability. RESULTS: Of 836 participants who were symptom-free during the preceding year, 33 (3.9%) reported LBP with disability during the 2 year follow-up. In univariate analyses, "history of LBP," "frequent lifting," "interpersonal stress at workplace," and "monotonous tasks" were all significant predictors of LBP incidence. All of these factors remained statistically significant or almost significant in the multivariate analysis adjusting for the other variables as well as age and sex: adjusted odds ratio (OR) and 95% confidence interval (95% CI) for history of LBP (OR: 3.25, 95% CI: 1.53-6.91), frequent lifting (OR: 3.77, 95% CI: 1.16-12.3), interpersonal stress at workplace (OR: 2.42, 95% CI: 1.08-5.43), and monotonous tasks (OR: 2.21, 95% CI: 0.99 4.94). CONCLUSION: Both ergonomic and work-related psychosocial factors may predict the development of LBP with disability among previously asymptomatic Japanese workers. Thus, workplace interventions aimed at reducing the incidence of LBP should focus on both ergonomic and psychosocial stress. PMID- 22246539 TI - Impact of lamina closure on long-term outcomes of open-door laminoplasty in patients with cervical myelopathy: minimum 5-year follow-up study. AB - STUDY DESIGN: A prospective follow-up study. OBJECTIVE: To elucidate the impact of lamina closure on long-term outcomes after open-door laminoplasty. SUMMARY OF BACKGROUND DATA: In a previous study, we did not find significant associations between lamina closure and short-term outcomes. METHODS.: Of the original cohort of 82 patients who underwent open-door laminoplasty, 69 were included in this study (52 men, 17 women; mean age, 60.9 yr; mean follow-up, 6.2 yr; 56 with spondylosis or disc herniation, 13 with ossification of posterior longitudinal ligament). Lamina closure was previously observed in 23 of these patients (closure group) but not in 46 (nonclosure group). The Japanese Orthopaedic Association (JOA) scores and Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire were recorded. RESULTS: The JOA score was 9.9 +/- 3.2 in the closure group and 11.2 +/- 2.3 in the nonclosure group before surgery (P = 0.1), 13.8 +/- 2.3 and 13.8 +/- 2.2 at 1.8 years (P = 0.99), and 13.6 +/- 2.2 and 14.2 +/- 2.7 at final follow-up (P = 0.29). The recovery rate of the JOA scores was 56.7 +/- 30.0% and 46.7 +/- 29.2% at 1.8 years (P = 0.22) and 51.0 +/- 32.5 and 57.6 +/- 31.1 at the final follow-up (P = 0.42). The subdomains assessed by the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire at follow-up were cervical spine function, 68.7 +/- 27.5 in the closure group and 67.7 +/- 30.0 in the nonclosure group (P = 0.93); upper extremity function, 78.6 +/- 24.3 and 87.6 +/- 15.4 (P = 0.40); lower extremity function, 69.9 +/- 26.0 and 73.9 +/- 22.5 (P = 0.68); bladder function, 74.6 +/- 22.6 and 84.9 +/- 29.2 (P = 0.18); and quality of life, 53.9 +/- 25.3 and 56.2 +/- 18.1 (P = 0.96). CONCLUSION: Lamina closure did not significantly impact the long-term surgical outcomes of laminoplasty for cervical myelopathy. Although not statistically significant, the recovery rate tended to decline in the closure group compared with the nonclosure group during the long-term follow-up period, and the utilization of a laminar retention device to prevent the laminar closure should be considered. PMID- 22246540 TI - Prevalence of mange among West African Dwarf sheep and goats and associated haematological and biochemical parameters. AB - This study was carried out to assess the prevalence of mange in sheep and goats in five local government areas (LGAs) of Ogun State in South Western Nigeria. A total of 4,973 sheep and 7,902 goats of West African Dwarf breeds were sampled of which only 4 (0.08%) of sheep and 42 (0.53%) of goats were confirmed positive for mange infestation. In all the LGAs sampled, Odeda LGA had the highest concentration of sheep (39%) and goats (51%) while Abeokuta South had the least percentage of sheep (1%) and goats (1%). All the mange-infested cases in sheep were recorded in just one LGA (Ewekoro) which constituted 0.24% of the population within the location. For goats, three out of five LGAs namely: Obafemi Owode, Ewekoro and Abeokuta North had prevalence of 1.46%, 0.53% and 0.72% respectively. There was no significant (P > 0.05) difference between non-infested and infested animals in terms of packed cell volume (31.79 +/- 0.87% vs. 31.41 +/- 1.13%), haemoglobin (10.51 +/- 0.21 g/100 ml vs. 10.28 +/- 0.37 g/100 ml) and red blood cells (8.71 +/- 0.29 * 10(12)/l vs. 9.40 +/- 0.37 * 10(12)/l). The infested group however showed significantly (P < 0.01) higher white blood cells count (7.60 +/- 0.22 * 10(9)/l) than the non-infested animals (6.81 +/- 0.17 * 10(9)/l). Neutrophil, eosinophil, basophil and monocyte as well as chloride were not significantly affected by the health status of the animals. There existed significant (P < 0.01) difference between non-infested and infested animals in terms of total protein (5.42 +/- 0.16 vs. 4.75 +/- 0.20 g/dl), sodium (137.98 +/- 1.53 vs. 128.92 +/- 1.92 mEq/l) and potassium (4.04 +/- 0.14 vs. 3.46 +/- 0.18 mEq/l). It can be concluded from this study that the prevalence of mange mite infestation varied with location and was generally low or absent in some of the LGAs considered. Goats were particularly more susceptible to mange infestation than sheep. More concerted effort is needed to control mange in order to avoid spread since it is a contagious disease. PMID- 22246541 TI - Voluntary intake and milk production in F1 Holstein * zebu cows in confinement. AB - The objective of this study was to evaluate the nutrient intake and milk production in Holstein * zebu (F1) cows in feedlot. Eighteen F1 cows were used, divided into three treatments; six were Holstein * Gir (HGI), six were Holstein * Guzerat (HGU), and another six were Holstein * Nelore (HNE), which had recently calved, distributed into simple, random samples, under the same feeding conditions of corn silage and concentrate with 20% crude protein. The three marker method was used (LIPE, titanium dioxide, and iADF) to estimate the individual intake and digestibility of the nutrients for the cows in group. The mathematical model used to establish the lactation curves was: Y = at(b)e(-ct) by Wood (Nature 216:164-165, 1967). The statistical analyses for the nutrient intake and digestibility, as well as parameters of metabolic efficiency, were performed using multiple linear regression (alpha = 5%). No effect (P > 0.05) of genetic group was observed for any of the variables studied. The intake and digestibility of the nutrients and the microbial nitrogen presented quadratic curves as a function of the lactation period (P < 0.05). The HGU cows exhibited an accumulated milk production of 4,946.81 kg at 305 days, whereas the HGI cows produced 4,821.78 kg. The HNE cows displayed inferior performance, with a production of 3,674.98 kg. It was concluded that, in confinement, F1 cows from different genetic groups do not exhibit different intake, digestibility, or metabolic efficiency. The HGU and HGI cows have greater cumulative production at 305 days. PMID- 22246542 TI - The occurrence of neurological symptoms in currently abstinent misusers of alcohol. AB - BACKGROUND: Significant neurological symptoms may be overlooked because of the traditional view that the non-Korsakoff's psychosis, middle aged alcoholic misuser is neurologically preserved. AIMS: In this study, we wanted to investigate the presence of neurological symptoms in individuals with misuse or dependence on alcohol who were abstinent for at least 1 month. METHOD: We used two scales from the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) to ascertain the presence of both neurological symptoms (HEA-2) and symptoms of general health concern (HEA-3) in 70 individuals who had a diagnosis of alcohol misuse or dependence, who were abstinent for greater than 1 month. RESULTS: Individuals reported significantly more neurological symptoms than general health difficulties (p < 0.001). We detected neurological symptoms, unlike general health difficulties in individuals who were abstinent from alcohol for 12 months. When we examined diagnostic subgroups, general health difficulties were most present in individuals with anxiety disorders; however, neurological difficulties were present across diagnostic groups. CONCLUSION: Neurological symptoms persist to a greater extent than general health concerns in individuals who previously were dependent or misused alcohol. PMID- 22246543 TI - Evaluation of novel urinary renal biomarkers with a cisplatin model of kidney injury: effects of collection period. AB - A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. To date, all evaluation studies have been made using 18 to 24 hour collection periods. However, shorter, more welfare friendly, urine collection periods are also used in industry. In this article, we quantify urinary biomarker concentration in serial paired sequential short and long urine collections from male rats administered varying concentrations of cisplatin. We calculate the rate of biomarker excretion in normal animals for both collection periods and the bias and correlation in urinary biomarker concentration between collection periods in dosed and control animals, and we estimate the level of agreement in biomarker concentration between both collection periods. We conclude that although there are minor differences in the concentration of some urinary biomarkers that are dependent upon the time and duration of collection, shorter collection protocols do not influence subsequent interpretation of normalized urinary biomarker data for most biomarkers. PMID- 22246544 TI - Strategies for patient profiling in articular cartilage repair of the knee: a prospective cohort of patients treated by one experienced cartilage surgeon. AB - PURPOSE: The purpose of this study was to report on the clinical outcome of a large heterogenic cartilage repair population treated with the profiling strategies of one experienced cartilage surgeon to provide evidence based tools for treatment selection in a clinical environment. METHODS: A total of 216 patients were identified in this prospective single-surgeon study. For the primary and secondary treatment of smaller defects, microfracture (MF) was used. Hyalograft C was used for first and second line larger defects, while carbon fiber rod and pad implantations were used as a salvage procedure. RESULTS: Three years after the initial procedure, the clinical improvement was excellent for MF and Hyalograft C (P < 0.001) and good for carbon-fiber procedures (P < 0.05). Hyalograft C patients with prior anterior cruciate ligament reconstruction had less clinical improvement (P < 0.05), while MF patients with prior cartilage repair were more likely to fail (Odds Ratio 20.5, P < 0.05). CONCLUSION: This is the first study that provides an assessment of the treatment strategies used by an experienced cartilage surgeon. A treatment algorithm for cartilage repair in a heterogenic population was created that based on the findings of this study could be implemented in a clinical environment. LEVEL OF EVIDENCE: Prospective clinical case series, Level IV. PMID- 22246545 TI - Radiographic landmarks for tunnel placement in reconstruction of the medial patellofemoral ligament. AB - PURPOSE: To verify the findings of previous studies in confirming radiographic landmarks for the femoral attachment of the medial patellofemoral ligament (MPFL), but also to define radiographic landmarks for the patellar attachment. Assess the effect of limb rotation upon these radiographic landmarks. METHODS: The medial patellofemoral ligament was identified in ten fresh-frozen human cadaveric knees. A headed pin was used to mark the centre of the femoral and patellar attachments. True lateral radiographs were performed followed by lateral radiographs in 10 degrees and 20 degrees of internal and external rotation. Posterior-anterior and proximal-distal position of the headed pin was evaluated. RESULTS: The femoral attachment averaged 3.8 +/- 5.0 mm anterior to the posterior femoral cortical line and 0.9 +/- 2.4 mm distal to the perpendicular line intersecting the posterior aspect of Blumensaat's line. The patellar attachment averaged 7.4 +/- 3.5 mm anterior to the posterior patellar cortical line, 5.4 +/- 2.6 mm distal to the perpendicular line intersecting the proximal margin of the patellar articular surface. There was a significant relationship between limb rotation and distance of femoral and patellar attachment from the posterior cortical line (P < 0.0001 and P < 0.0002 respectively). CONCLUSION: Radiographic landmarks for the femoral attachment of the MPFL identified in this study are comparable with other recent work. This study describes new radiographic landmarks for the patellar attachment of the MPFL and highlights that it is essential to acquire true lateral radiographs if these radiographic landmarks are to be interpreted accurately. PMID- 22246546 TI - Reliability of the dial test using a handheld inclinometer. AB - PURPOSE: The primary purpose of this study was to investigate the intra-tester and inter-tester reliability of the dial test using a handheld digital inclinometer. Additionally, we examined the responsiveness of the test, and side to-side differences for meaningful comparison. MATERIALS/METHODS: Twenty-four healthy subjects (22.5 +/- 2.8 years) participated in the study. The dial test was performed on both knees at 30 degrees and 90 degrees of knee flexion with the subject supine. While maintaining a neutral position of the ankle, an inclinometer was positioned parallel to the medial border of the foot to quantify external rotation of the tibia. Two examiners performed the dial test in a blinded manner. The minimal detectable change across repeated measures and side to-side difference was calculated. RESULTS: Intra-tester reliability for examiner 1 (E1) was 0.83 at 30 degrees knee flexion and 0.89 at 90 degrees knee flexion. Reliability values for examiner 2 (E2) were 0.86 at 30 degrees and 0.87 at 90 degrees knee flexion. Inter-tester reliability was 0.74 at 30 degrees and 0.83 at 90 degrees . The minimal detectable change (MDC) for E1 at 30 degrees was +/ 9.4 degrees and +/-7.4 degrees at 90 degrees . For E2, the MDC value was +/-9.1 degrees at 30 degrees and +/-8.3 degrees at 90 degrees . Ninety-five percent limits of agreement for side-to-side difference was 16.1 degrees and 11.3 degrees degrees for E1 at 30 degrees and 90 degrees and for E2 13.9 degrees at 30 degrees and 14.1 degrees at 90 degrees . CONCLUSIONS: This instrumented dial test using a handheld digital inclinometer to measure external rotation can be performed with acceptable reliability in the clinical setting. A difference of 10 degrees between two measurements on the same knee suggests that a meaningful change has occurred. For right to left comparison, differences greater than 15 degrees suggest clinical significance. LEVEL OF EVIDENCE: III. PMID- 22246547 TI - Objective measurement devices to assess static rotational knee laxity: focus on the Rotameter. AB - PURPOSE: The present article summarizes the development of a simple, objective, and non-invasive measurement device for tibiofemoral rotation to assess static rotational knee laxity. METHODS AND RESULTS: The device is based on the dial test with the patient lying prone and the knee flexed to 30 degrees . From measurements of 30 healthy participants, the device achieved high inter- and intra-observer reliability and showed a high correlation of the measured results with the contralateral knees of the participants. Measurements of the device were also performed in a human cadaver study and revealed highly correlated results when compared to the simultaneous measurements of a knee navigation system, which was used as an invasive standard method to assess tibial rotation. In human cadaver specimens, it was shown that a simulated tear of the posterolateral bundle as well as a complete ACL tear led to a significant increase in isolated tibiofemoral rotation compared to the intact ACL. A retrospective case series investigated the clinical results as well as knee laxity measurements after ACL surgery in vivo. Rotational, as well as anteroposterior (AP), knee laxity was objectively assessed in 52 patients at a mean postoperative follow-up of 27 months by comparing the measured results with the results of the contralateral unaffected knee in each patient. The clinical results were comparable to the results reported in the literature. Moreover, rotational laxity was successfully restored after ACL reconstruction, whereas AP laxity showed significant differences compared to the contralateral knees although they were defined as clinically successful according to the IKDC classification. CONCLUSIONS: A non invasive and objective knee rotational measurement device has been developed, which offers good potential for objective quality control in knee ligament injuries and their treatment. LEVEL OF EVIDENCE: Review article, Level IV. PMID- 22246548 TI - Influence of individual characteristics on static rotational knee laxity using the Rotameter. AB - PURPOSE: The purpose of this study was to evaluate the influence of individual characteristics on rotational knee laxity in healthy participants. Our second aim was to verify whether the contralateral knee of patients with a non-contact ACL injury presents greater rotational knee laxity than a healthy control group. METHODS: Sixty healthy participants and 23 patients having sustained a non contact ACL injury were tested with a new Rotameter prototype applying torques up to 10 Nm. Multiple linear regressions were performed to investigate the influence of gender, age, height and body mass on rotational knee laxity and to establish normative references for a set of variables related to rotational knee laxity. Multiple analyses of covariance were performed to compare the contralateral knee of ACL-injured patients and healthy participants. RESULTS: Being a women was associated with a significantly (P < 0.05) higher rotational knee laxity, and increased body mass was related to lower laxity results. In the multiple analyses of covariance, gender and body mass were also frequently associated with rotational knee laxity. When controlling for these variables, there were no differences in measurements between the contralateral leg of patients and healthy participants. CONCLUSION: In the present setting, gender and body mass significantly influenced rotational knee laxity. Furthermore, based on these preliminary results, patients with non-contact ACL injuries do not seem to have excessive rotational knee laxity. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 22246549 TI - Static rotational knee laxity in anterior cruciate ligament injuries. AB - PURPOSE: The purpose was to provide an overview of the non-invasive devices measuring static rotational knee laxity in order to formulate recommendations for the future. RESULTS: Early cadaver studies provided evidence that sectioning the anterior cruciate ligament (ACL) led to an increase of static rotational knee laxity of approximately 10-20% between full extension and 30 degrees of knee flexion. Sections of the menisci or of the peripheral structures induced a much higher increase in rotation. This supported the hypothesis that static rotation measurements might be useful for the diagnosis of ACL or associated injuries. In vivo evaluations with measurement devices are relatively new. Several articles were published during the last decade with many different devices and important differences were seen in absolute rotational knee laxity between them. This was due to the varying precision of the devices, the variability in patient positioning, the different methods of measurement, examination protocols and data analysis. As a consequence, comparison of the available results should be performed with caution. Nevertheless, it has been established that rotational knee laxity was greater in females as compared to males and that the inter subject variability was high. For this reason, it will probably be difficult to categorise injured patients preoperatively, and the interpretation of the results should probably be limited to side-to-side differences. CONCLUSION: Future studies will show whether rotational laxity measurements alone will be sufficient to provide clinically relevant data or if they should be combined to static sagittal laxity measurements. PMID- 22246550 TI - DNA microarrays on silicon surfaces through thiol-ene chemistry. AB - The potential of thiol-ene chemistry as a selective strategy to functionalize silicon materials for DNA microarraying is demonstrated and applied to discriminate genetic variations. PMID- 22246551 TI - Retrospective analysis of 76 immunocompetent patients with primary pulmonary cryptococcosis. AB - BACKGROUND: Pulmonary cryptococcosis typically occurs in immunocompromised patients, but it can also occur in immunocompetent patients. Our objective was to describe the clinical manifestations, diagnosis, and management of primary pulmonary cryptococcosis in immunocompetent patients. METHODS: We retrospectively reviewed the clinical data of 76 patients with primary pulmonary cryptococcosis who were admitted to our hospital from 1995 to 2010. RESULTS: Pulmonary cryptococcosis was pathologically proven in all patients. Mean patient age was 42.5 years and 55 patients (72%) were male. The major clinical manifestations were cough (47 pts, 62%), expectoration (29 pts, 38%), fever (16 pts, 21%), chest pain (15 pts, 20%), dyspnea (17 pts, 22%), and emaciation (10 pts, 13%). Eighteen patients (24%) were asymptomatic. Most patients were admitted due to shadows on chest X-rays. Lesions were more common in the lower lung (60 pts, 78.9%) than in the upper lung (25 pts, 32.9%). More lesions (28 pts, 37%) were characterized by patchy consolidations. Pulmonary cryptococcosis was confirmed histologically among all patients. Surgical removal of lesions or treatment with fluconazole and other antifungal agents for complete courses led to favorable outcomes for most patients. CONCLUSIONS: Primary pulmonary cryptococcosis was found mainly in immunocompetent patients aged <50 years without preexisting lung disease. Shadow on the chest X-ray is the predominant feature. Treatment with a complete course of fluconazole and/or other antifungal agents can achieve favorable outcome. PMID- 22246552 TI - Plasma N-terminal pro-brain natriuretic peptide: a prognostic marker in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are elevated in patients with secondary pulmonary hypertension and chronic lung disease with right ventricular overload. The aim of the present study was to investigate the use of plasma NT-proBNP levels as a prognostic marker of severe COPD with chronic respiratory failure and latent pulmonary hypertension. METHODS: Plasma NT-proBNP levels were measured in 61 patients with stable COPD. Plasma NT proBNP levels, pulmonary function, PaO(2), and PaCO(2) levels and systolic pulmonary artery pressure were compared according to COPD severity. In addition, we examined correlations between plasma NT-proBNP levels and pulmonary function, PaO(2), PaCO(2), and systolic pulmonary artery pressure. RESULTS: The levels of plasma NT-proBNP significantly increased in patients with stage IV and stage III COPD compared to individuals with stage II COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. The area under the receiver-operating characteristic curve of plasma NT-proBNP for severe to very severe COPD (FEV(1) <50%) was 0.707 (95% confidence interval [CI] 0.566 0.847, P=0.008). Plasma NT-proBNP levels significantly correlated with %FEV(1) (r= -0.557; P < 0.001), arterial blood gas parameters such as PaCO(2) (r = 0.476; P < 0.001) and PaO(2) (r = -0.347; P = 0.031), and systolic pulmonary artery pressure (r = 0.435; P = 0.001). CONCLUSIONS: Plasma NT-proBNP levels increased significantly with disease severity, progression of chronic respiratory failure, and secondary pulmonary hypertension in patients with stable COPD. These results suggest that plasma NT-proBNP can be a useful prognostic marker to monitor COPD progression and identify cases of secondary pulmonary hypertension in patients with stable COPD. PMID- 22246553 TI - Adipokines and systemic inflammation in weight-losing lung cancer patients. AB - BACKGROUND: Cancer cachexia is a devastating condition leading to loss of function and independence, decreased performance status, decreased quality of life, and poor prognosis. Adipokines play a role in a wide variety of physiological or pathological processes, including immunity and inflammation, in addition to having significant effects on metabolism and lipogenesis. The objective of the present study was to investigate the relationship of adipokines and systemic inflammation in weight-losing advanced-stage non-small-cell lung cancer (NSCLC) patients. METHODS: Sixty-three male NSCLC patients (stages III and IV) and 25 age- and sex-matched controls were included. NSCLC patients were further divided into subgroups as those with a>5% weight loss in last 6 months and those who did not. Serum leptin, adiponectin, and TNF-alpha concentrations were measured by ELISA using commercially available kits. RESULTS: The positive acute-phase reactants (APR) CRP, leukocyte, ferritin, thrombocyte, and fibrinogen were higher in the NSCLC group. Serum albumin level (which is a negative APR) was lower in the cancer group, whereas there was no difference in transferrin level between the groups. TNF-alpha and leptin concentrations were similar in the cancer group and the control group, whereas adiponectin was lower in the cancer group. There was a difference in thrombocyte and transferrin levels between patients with and without weight loss, whereas CRP, TNF-alpha, and adiponectin levels were similar. Leptin was lower in weight-losing cancer patients. However, there was no correlation between adipokines and markers of systemic inflammation. CONCLUSION: These results revealed a lack of association between adipokine levels and systemic inflammation with cancer cachexia. PMID- 22246555 TI - Improvement of knowledge, attitude and perception of healthcare workers about ADR, a pre- and post-clinical pharmacists' interventional study. AB - Purpose Healthcare workers have a main role in detection, assessment and spontaneous reporting of adverse drug reactions (ADRs), and improvement of their related knowledge, attitude and perception is essential. The goal of this study was evaluation of clinical pharmacists' interventions in improvement of knowledge, attitude and perception of healthcare workers about ADRs in a teaching referral hospital, Tehran, Iran. Method Changes in knowledge, attitude and perception of healthcare workers of Imam teaching hospital about ADRs were evaluated before and after clinical pharmacists' interventions including workshops, meetings and presentations. Results From the 100 participated subjects, 82 of them completed the study. 51% of the health workers have been aware of the Iranian Pharmacovigilance Center at the ministry of health before intervention and after that all the participants knew this centre. About awareness and detection of ADRs in patients, 69 (84.1%) healthcare workers recognised at least one, and following interventions, it was improved to 73 (89%). Only seven (8.5%) subjects have reported ADRs in before intervention phase that were increased significantly to 18 (22%) after intervention. Conclusion Clinical pharmacists' interventions were successful in improvement of healthcare workers' knowledge, attitude and perception about ADRs and spontaneous reporting in our hospital. PMID- 22246554 TI - Endobronchial valves in the management of broncho-pleural and alveolo-pleural fistulae. AB - Pneumothorax from bronchopleural or alveolo-pleural fistulae can be complicated by prolonged air leak (AL). This can occur in a variety of clinical settings. Examples include structural lung disease, such as bronchiectasis, and cavitary lung disorders. Prolonged AL is associated with prolonged hospital stay, atelectasis, pneumonia, and thromboembolic disease. Endobronchial valves (EBVs) have been recently introduced to manage such situations. The global experience in this novel therapeutic modality is still evolving. We report our preliminary experience with managing persistent AL treated successfully with EBVs and review the current literature on this subject. Our experience shows that EBVs are an effective tool for the management of prolonged AL from persistent bronchopleural or alveolo-pleural fistulae. It is a minimally invasive procedure recommended as an option, particularly in patients not fit for surgical repair. PMID- 22246556 TI - Ran and calcineurin can participate collaboratively in the regulation of spermatogenesis in scallop. AB - Calcineurin is a calcium/calmodulin-dependent protein phosphatase that plays important roles in the transduction of calcium signals in a variety of tissues. In addition, calcineurin has been implicated in the process of spermatogenesis. A novel calcineurin-binding protein, CaNBP75, has been identified in scallop testis. The C-terminal region of CaNBP75 is homologous to the C-terminal region of RanBP3, a Ran-binding domain-containing protein. A small G protein Ran has been involved in spermiogenesis by virtue of the fact that its localization in spermatids changes during spermiogenesis. The current study was performed to investigate the functions of Ran and CaNBP75 in the regulation of calcineurin in testis to further understand the basic functions of calcineurin during spermatogenesis. First, cloning and sequencing of a scallop Ran cDNA isolated from testis revealed that scallop Ran is well-conserved at the amino acid level. Secondly, direct binding of Ran to CaNBP75 was demonstrated in an in vitro pull down assay. Thirdly, analysis of the tissue distribution of Ran, CaNBP75, and calcineurin showed that these proteins are abundantly expressed in testis. Fourthly, comparison of the expression profiles of Ran and CaNBP75 with that of calcineurin in scallop testis during the maturation cycle revealed that Ran and CaNBP75 mRNA levels increase during meiosis and spermiogenesis, similar to calcineurin. Finally, co-immunoprecipitation analysis suggests that Ran, CaNBP75, and calcineurin interact in scallop testis during maturation. These results suggest that Ran, CaNBP75, and calcineurin may act in a coordinated manner to regulate spermatogenesis. PMID- 22246557 TI - [Epidemiology of cutaneous leishmaniasis in five villages of Dogon country, Mali]. AB - The epidemiology of the cutaneous leishmaniasis (CL) with Leishmania major is poorly documented in Mali. Following reports of CL in the tourist areas of the Dogon country (Bandiagara Escarpment), a joint French and Malian bio-clinical team conducted a field study from 16 to 27 January, 2010. The population of 5 villages has been examined by a dermato-infectiologist and cases were selected by visual inspection of skin lesions. Smears and biopsies (from the lesions) and venous blood were obtained from suspected cases of CL. Diagnosis was performed by light microscopy, in vitro cultures, serology and molecular biology. Fifty patients with skin lesions have been examined. Twenty-one have been suspected as CL. At least one sample was obtained from 18 patients. The lesions were predominantly old, more or less scarring and secondary infected. A skin smear was performed for 15 patients, a skin biopsy for 14 patients: smears and cultures were all negative. The PCR (Leishmania spp.) made on 14 biopsies was positive for 12 patients (86%). The low amount of amplified DNA obtained did not allow the sequencing and identification of the species of Leishmania. Western blot (WB) serology was positive in 11 cases out of 12 (92%). This investigation showed the presence of cutaneous leishmaniasis in Bandiagara. A further investigation is required during transmission period (September-October) to confirm the presence of Leishmania major epidemic in Dogon country. PMID- 22246558 TI - [Preliminary study of snake fauna in the Lama forest, South Benin]. AB - The following study aims at assessing the ophidian diversity of the Lama Forest, a classified area, situated in the South of Benin. One can distinguish three types of habitat according to the degree of human activity: the remaining dense forest at the centre, the intermediate plantation area, and finally the area around the edge which has been entirely subjected to human habitation. Each day for two weeks we have been working on various plots of study (by day), patrolled along transect routes (by night), and installed a trap in the central area. As a result, we were able to observe 32 snake specimens, 24 of which we captured. Nearly all were able to be identified, and have been classified into 13 genera and 17 species. PMID- 22246559 TI - [Ophidian envenomation in the region Souss-Massa-Draa in Morocco]. AB - The present study aims to determine the main characteristics of ophidian envenomation in the Souss-Massa-Draa region in Morocco. It consisted of a descriptive retrospective analysis of all snakebite cases recorded by the Moroccan Poison Control and Pharmacovigilance Center, from 1980 to 2008. According to reported data, this region is the most affected in Morocco with 479 cases, that is 27.6% (17 cases/year). The average age of victims was 26.07 +/- 18.28 years. The patients developed clinical signs (55%) dominated by disorders of the digestive system (35.5%), cardiovascular diseases (21.4%), and heart rhythm disorders (16.8%). The lethality and sequelae rates were 12% and 1.9%, respectively. PMID- 22246560 TI - [Post-malaria neurological syndrome complicating a Plasmodium falciparum malaria in Madagascar]. AB - Post-malaria neurological syndrome is a rare complication of malaria. Typically, it occurs in case of severe malaria. Here we report a case in a Malagasy patient presenting a non-severe Plasmodium falciparum malaria complicated by post-malaria neurological syndrome. The management of such a syndrome is radically different from non-severe malaria. No specific treatment is needed. PMID- 22246561 TI - Genetic testing integration panels (GTIPs): a novel approach for considering integration of direct-to-consumer and other new genetic tests into patient care. AB - There has been a dramatic increase in the number of genetic tests available but few tests have practice guidelines. In addition, many tests have become available outside of clinical settings through direct-to-consumer (DTC) companies and several offer tests not considered standard of care. To address several practical challenges associated with the rapid introduction of clinical and DTC genetic tests, we propose that genetic counselors and geneticists organize expert panels in their institutions to discuss the integration of new tests into patient care. We propose the establishment of Genetic Testing Integration Panels (GTIPs) to bring together local experts in medical genetics, genetic counseling, bioethics and law, health communication and clinical laboratory genetics. We describe key features of this approach and consider some of the potential advantages and limitations of using a GTIP to address the many clinical challenges raised by rapidly emerging clinical and DTC genetic tests. PMID- 22246563 TI - Determinants and consequences of child culture brokering in families from the former Soviet Union. AB - Child culture brokering occurs when immigrant children help their families navigate the new culture and language. The present study develops a model of the child culture broker role that situates it within the family and community economic and acculturative contexts of 328 families from the former Soviet Union. Path analysis was utilized to explore the relationships of community and family economic and cultural contexts with child culture brokering, child emotional distress, and family disagreements. All children reported some culture brokering for their parents. Less English proficient parents with lower status jobs, and living in areas with more Russian speaking families tended to utilize their children as brokers more often. Further, community economic conditions also predicted brokering indirectly, mediated by parent job social status. Brokering was related to child emotional distress and family disagreements. Further, culture brokering was a mediator of the impact of parent job social status on both child emotional distress and family disagreements. These results add to our understanding of the culture broker role and emphasize the utility of approaching research on it from an ecological perspective. PMID- 22246564 TI - 7 Tesla imaging of cerebral radiation necrosis after arteriovenous malformations treatment using amide proton transfer (APT) imaging. AB - Arteriovenous malformations (AVM) can be treated with stereotactic radiosurgery. An infrequent, but important complication of this treatment is radionecrosis, which can be detected by MRI. However, the imaging characteristics of necrosis are unspecific in conventional MRI. Here, we report a case of necrosis after radiotherapy of an AVM to illustrate the potential of 7 Tesla MRI including amide proton transfer (APT) for necrosis imaging. PMID- 22246562 TI - Carnosic acid inhibits the proliferation and migration capacity of human colorectal cancer cells. AB - Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. The objective of this study was to examine whether carnosic acid (CA), the main antioxidant compound of Rosmarinus officinalis L., would inhibit the cell viability of three CRC cell lines: Caco-2, HT29 and LoVo in a dose-dependent manner, with IC50 values in the range of 24-96 uM. CA induced cell death by apoptosis in Caco-2 line after 24 h of treatment and inhibited cell adhesion and migration, possibly by reducing the activity of secreted proteases such as urokinase plasminogen activator (uPA) and metalloproteinases (MMPs). These effects may be associated through a mechanism involving the inhibition of the COX 2 pathway, because we have determined that CA downregulates the expression of COX 2 in Caco-2 cells at both the mRNA and protein levels. Therefore, CA modulates different targets involved in the development of CRC. These findings indicate that carnosic acid may have anticancer activity and may be useful as a novel chemotherapeutic agent. PMID- 22246565 TI - Late temporal lobe necrosis after conventional radiotherapy for carcinoma of maxillary sinus. AB - Cerebral radiation necrosis is a serious late complication after conventional radiotherapy that can present with focal neurologic deficits or with more generalized signs and symptoms of increased intracranial pressure, depending on the location. The incidence and severity of radionecrosis are dose-volume dependent. We report a case of cerebral radiation necrosis 5 years after radiotherapy for a maxillary sinus carcinoma. PMID- 22246566 TI - First International Meeting of the Thematic Centre for Immune Modulatory Therapies for Autoimmunity and Cancer (IMTAC) 13-14 June 2011, Ljustero, Sweden. PMID- 22246567 TI - Sensitivity enhancement of remotely coupled NMR detectors using wirelessly powered parametric amplification. AB - A completely wireless detection coil with an integrated parametric amplifier has been constructed to provide local amplification and transmission of MR signals. The sample coil is one element of a parametric amplifier using a zero-bias diode that mixes the weak MR signal with a strong pump signal that is obtained from an inductively coupled external loop. The NMR sample coil develops current gain via reduction in the effective coil resistance. Higher gain can be obtained by adjusting the level of the pumping power closer to the oscillation threshold, but the gain is ultimately constrained by the bandwidth requirement of MRI experiments. A feasibility study here shows that on a NaCl/D(2) O phantom, (23) Na signals with 20 dB of gain can be readily obtained with a concomitant bandwidth of 144 kHz. This gain is high enough that the integrated coil with parametric amplifier, which is coupled inductively to external loops, can provide sensitivity approaching that of direct wire connection. PMID- 22246568 TI - Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus. AB - BACKGROUND: Sirolimus is a powerful immunosuppressive drug which is being used increasingly after liver transplantation because of its renal sparing and anti tumour effects. It has been associated with uncommon, but potentially fatal, interstitial pneumonitis. AIM: To determine the frequency and outcome of sirolimus-associated pneumonitis following liver transplantation. METHODS: Retrospective study in an adult liver transplant centre. RESULTS: We identified five patients with siromimus-associated pneumonitis, three of whom were transplanted at our centre. Between 1999 and 2008 a total of 522 liver transplants were performed, in our unit, and 45 patients were switched from calcineurin inhibitors to sirolimus. Three of these 45 patients subsequently developed pneumonitis (6.7%). The most common presenting symptoms were cough and dyspnea. The duration of use of sirolimus before diagnosis of pneumonitis varied between 4 and 16 months. Trough serum sirolimus levels were elevated in 3/5 patients with pneumonitis. Sirolimus was withdrawn in all five patients with complete resolution of symptoms and radiological findings. CONCLUSIONS: Pneumonitis is a relatively common side effect of sirolimus in liver transplant patients and can occur despite normal therapeutic blood levels. It is reversible on stopping the medication. Early recognition is important to prevent unnecessary investigations and prolonged morbidity. PMID- 22246570 TI - Downregulation of ferroportin 1 expression in hFOB1.19 osteoblasts by hepcidin. AB - The present study was designed to address the relationship between iron homeostasis and bone metabolism. Cultured hFOB 1.19 osteoblasts were incubated with selected concentrations of hepcidin (50, 100, and 200 nmol/L) for 20 h, harvested for extraction of total RNA and proteins, and the expression of ferroportin 1 was analyzed by RT-PCR and western blotting. The results showed the presence of ferroportin 1 expression in cultured hFOB 1.19 cells. Furthermore, the ferroportin 1 had a similar expression pattern in hFOB cells as in hepatocytes and enterocytes and was downregulated by hepcidin. Our data indicate that osteoblasts are target cells for hepcidin, suggest that hepcidin may have many more targets than previously recognized, and support the role of hepcidin in the development of osteoporosis. PMID- 22246569 TI - Genetic evidence for the vital function of Osterix in cementogenesis. AB - To date, attempts to regenerate a complete tooth, including the critical periodontal tissues associated with the tooth root, have not been successful. Controversy still exists regarding the origin of the cell source for cellular cementum (epithelial or mesenchymal). This disagreement may be partially due to a lack of understanding of the events leading to the initiation and development of the tooth roots and supportive tissues, such as the cementum. Osterix (OSX) is a transcriptional factor essential for osteogenesis, but its role in cementogenesis has not been addressed. In the present study, we first documented a close relationship between the temporal- and spatial-expression pattern of Osx and the formation of cellular cementum. We then generated 3.6-kilobase (kb) collagen type I (3.6-kb Col 1)-Osx transgenic mice, which displayed accelerated cementum formation versus wild-type (WT) controls. Importantly, the conditional deletion of Osx in the mesenchymal cells with two different Cre systems (the 2.3-kb Col 1 and an inducible CAG-Cre estrogen receptor [CreER]) led to a sharp reduction in cellular cementum formation (including the cementum mass and mineral deposition rate) and gene expression of dentin matrix protein 1 (DMP1) by cementocytes. However, the deletion of the Osx gene after cellular cementum formed did not alter the properties of the mature cementum as evaluated by backscattered scanning electron microscopy (SEM) and resin-casted SEM. Transient transfection of Osx in the cementoblasts in vitro significantly inhibited cell proliferation and increased cell differentiation and mineralization. Taken together, these data support: (1) the mesenchymal origin of cellular cementum (from periodontal ligament [PDL] progenitor cells); (2) the vital role of OSX in controlling the formation of cellular cementum; and (3) the limited remodeling of cellular cementum in adult mice. PMID- 22246571 TI - Expression of immunoglobulin-like transcript (ILT)2 and ILT3 in human gastric cancer and its clinical significance. AB - Immune inhibitory receptors play an important role in organ transplantation, autoimmune diseases and cancers. Immunoglobulin-like transcript (ILT)2 and ILT3 belong to the inhibitory receptors of the ILT family, which have been reported to regulate a broad range of cellular functions involved in the immune response. They contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are related to immune regulation. Although ILT receptors have been studied in dendritic cells (DCs), T cells, NK cells and other cell types, the expression and clinical significance of ILT2 and ILT3 in gastric cancer have yet to be elucidated. Here, the expression of ILT2 and ILT3 in gastric cancer cell lines and pathologic tissues, as well as their effects on the cytotoxicity of NK92MI against the gastric cancer cell lines MKNI with ILT2lowILT3low and HGC-27 with ILT2highILT3high were detected. The results suggest that ILT2 and ILT3 are expressed with diverse degrees in gastric cancer cells and tissues, and the expression of ILT2 is related with differentiation and size of tumors. Furthermore, the cytotoxic activity of NK92MI against the MKNI cell line was stronger than that against HGC-27. This study indicates that ILT2 and ILT3 play a key role in gastric cancer immune escape, and ILT2 may be a new target in the clinical diagnosis and treatment of gastric cancer. PMID- 22246572 TI - Diagnosing renal failure due to diethylene glycol in children in a resource constrained setting. AB - BACKGROUND: In 2008, several Nigerian children developed acute kidney injury (AKI) after ingesting teething syrup contaminated with diethylene glycol (DEG). Because there are limited diagnostic facilities in resource-constrained countries, this study investigated whether AKI associated with DEG could be identified by other means. METHODS: This was a multicenter study. Information was obtained from hospital records. Clinicopathological features of all children with AKI over a 6-month period were reviewed. RESULTS: Sixty (50.4%) of 119 children ingested "My pikin" teething syrup. Compared to children who had not ingested it, they were significantly (p < 0.05) younger (11.95 vs. 31 months), more were anuric (98.3 vs. 74.6%), hypertensive (84 vs. 52%), had severe metabolic acidosis (46.7 vs. 20.5%), and died (96.6 vs. 71.2%). They developed increasing metabolic acidosis and multiorgan dysfunction despite peritoneal dialysis. Late presentation, financial difficulties, inadequate facilities for toxicology, and hemodialysis complicated management. CONCLUSIONS: Identifying AKI associated with DEG is difficult. Detailed drug history, increasing metabolic acidosis, and multiorgan deterioration despite peritoneal dialysis should arouse suspicion. Simple diagnostic tests need to be developed and facilities for hemodialysis of infants and financial support provided. Recurrences can be prevented by creating awareness, improving manufacturing practices, field-testing of drugs, and international monitoring of pharmaceuticals imported for manufacture. PMID- 22246573 TI - Arynes in transition-metal-free multicomponent coupling reactions. PMID- 22246574 TI - Application of risk-rated profit model functions in estimation of economic values for indigenous chicken breeding. AB - The economic values for productive (egg number, average daily gain, live weight, and mature weight) and functional (fertility, hatchability, broodiness, survival rate, feed intake, and egg weight) traits were derived for three production systems utilizing indigenous chicken in Kenya. The production systems considered were free-range, semi-intensive, and intensive system and were evaluated based on fixed flock size and fixed feed resource production circumstances. A bio-economic model that combined potential performances, feeding strategies, optimum culling strategies, farmer's preferences and accounted for imperfect knowledge concerning risk attitude of farmers and economic dynamics was employed to derive risk-rated economic values. The economic values for all the traits were highest in free range system under the two production circumstances and decreased with level of intensification. The economic values for egg number, average daily gain, live weight, fertility, hatchability, and survival rate were positive while those for mature weight, broodiness, egg weight, and feed intake were negative. Generally, the economic values estimated under fixed feed resource production circumstances were higher than those derived under fixed flock size. The difference between economic values estimated using simple (traditional) and risk-rated profit model functions ranged from -47.26% to +67.11% indicating that inclusion of risks in estimation of economic values is important. The results of this study suggest that improvement targeting egg number, average daily gain, live weight, fertility, hatchability, and survival rate would have a positive impact on profitability of indigenous chicken production in Kenya. PMID- 22246575 TI - Urethral prolapse formation after urodynamic testing: a case report. AB - Urodynamic testing is a widely used modality for evaluation of lower urinary tract symptoms with minimal morbidity to the patient. We report a case of strangulated urethral prolapse in a 74-year-old female that occurred right after urodynamic evaluation. The urethral prolapse was managed conservatively and the patient fully recovered without the need for surgical intervention. PMID- 22246576 TI - Pelvic floor muscle training for urgency urinary incontinence in women: a systematic review. AB - The objective of this study is to evaluate the effectiveness of existing physiotherapy modalities for the treatment of urge urinary incontinence (UUI). A systematic review was performed for primary studies of physiotherapy techniques for UUI published in English between 1996 and August 2010 in major electronic databases. Only randomized clinical trials that reported outcomes separately for women with UUI were included. Outcomes assessed were reduction in UUI, urinary frequency, and nocturia. Data from 13 full-text trials including the modalities of pelvic floor muscles exercises with or without biofeedback, vaginal electrical stimulation, magnetic stimulation, and vaginal cones were analyzed. The methodologic quality of these trials was fair. Significant improvement in UUI was reported for all physiotherapy techniques except vaginal cone therapy. There are insufficient data to determine if pelvic physiotherapy improves urinary frequency or nocturia. Evidence suggests that physiotherapy techniques may be beneficial for the treatment of UUI. PMID- 22246577 TI - Levator hiatus dimensions and pelvic floor function in women with and without major defects of the pubovisceral muscle. AB - INTRODUCTION AND HYPOTHESIS: The aim of present study was to compare pelvic floor morphology and function in women with and without major defects of the pubovisceral muscle. METHODS: One hundred fifty-seven women with pelvic organ prolapse participated in this cross-sectional study. Participants answered a symptom questionnaire and underwent clinical and three- and four-dimensional transperineal ultrasound examination. Pelvic floor muscle maximum voluntary contraction (MVC), endurance, and resting vaginal pressure were registered with a vaginal balloon catheter. Offline analyses were performed for the presence of major pubovisceral muscle defects (PVMD) and hiatal dimensions. RESULTS: The levator hiatus dimensions at rest and contraction were significantly larger in women with than without major PVMD. Mean differences in levator hiatus area between women with and without major PVMD were: rest 1.9 cm(2) 95% confidence intervals (CI) 0.21-3.7, P = 0.028 and contraction 2.75 cm(2) 95% CI 1.0-4.5, P =0.002; and Valsalva maneuver mean difference was 0.82 cm(2) 95% CI 2.18-3.83, P = 0.543. Women with major PVMD had lower MVC and endurance measurements as compared with women without major PVMD, but the differences were not statistically significant. CONCLUSIONS: Women with major pubovisceral muscle defects have larger hiatal dimensions at rest and at contraction than women without PVMD. We were unable to prove the corresponding relationship for hiatal dimensions on Valsalva. PMID- 22246578 TI - Mosaic upd(7)mat in a patient with Silver-Russell syndrome. PMID- 22246579 TI - Study on the chaperone properties of conserved GTPases. AB - As a large family of hydrolases, GTPases are widespread in cells and play the very important biological function of hydrolyzing GTP into GDP and inorganic phosphate through binding with it. GTPases are involved in cell cycle regulation, protein synthesis, and protein transportation. Chaperones can facilitate the folding or refolding of nascent peptides and denatured proteins to their native states. However, chaperones do not occur in the native structures in which they can perform their normal biological functions. In the current study, the chaperone activity of the conserved GTPases of Escherichia coli is tested by the chemical denaturation and chaperone-assisted renaturation of citrate synthase and alpha-glucosidase. The effects of ribosomes and nucleotides on the chaperone activity are also examined. Our data indicate that these conserved GTPases have chaperone properties, and may be ancestral protein folding factors that have appeared before dedicated chaperones. PMID- 22246580 TI - Evaluating the suitability of essential genes as targets for antibiotic screening assays using proteomics. PMID- 22246582 TI - Formal reporting of second-opinion CT interpretation: experience and reimbursement in the emergency department setting. AB - The purpose of this study is to describe a system for formally reporting second opinion interpretations of CT imaging exams accompanying patients transferred emergently to a tertiary care center. Second-opinion interpretations of cross sectional imaging exams rendered in the emergency department setting over 6 months spanning 22 September 2009 to 22 March 2010 were reviewed and tallied by two radiologists and a research assistant, with a focus on professional fee reimbursement rates. A more in depth review was performed of those exams for which a clinical referral request form was available, detailing such information as the clinical history, content and source of available initial interpretation, and congruity of the initial interpretation with clinical data. Discrepancies between outside and second-opinion interpretations were also assessed. This quality assurance exercise was reviewed by our institutional review board, which waived formal informed consent. Formal second-opinion interpretation was rendered for 370 exams on 198 patients (mean age, 53.5 years; 45.1% female), received from 50 referring facilities. Head CT was the most common imaging exam referred for second opinion. Forty-one of 370 exams (11%) were submitted for self-pay, and 43 (12%) were written off as free care. The remaining 286 exams (77%) were submitted for reimbursement of the professional fee only. Ultimately, of the 286 exams submitted, 260 (91%) were reimbursed for professional fees, 199 (70%) on the initial submission. Of 29 health plans contracted with our facility, 22 ultimately approved all claims made. Three plans denied all claims submitted. The largest payer was Medicare, which reimbursed 88 of 90 submitted claims. Clinical intake forms were available for 184 exams on 107 patients (mean age, 52.7 years, 43.0% female). Trauma was the most common indication, or history, provided (55% of 184 exams, 40% of 107 patients). An outside report of some form was available for 112 of the 184 exams (61%), although only 18 were formal, signed radiology reports from the referring facility. Discrepancies between available outside reports and second-opinion interpretations were noted for 17 out of 112 exams. Need for reimaging was substantially curtailed, with only ten exams repeated within 24 h. A formal process for issuing second-opinion interpretations of cross sectional exams performed at outside institutions is feasible in the emergency department setting. In the majority of cases, reimbursement for full professional fees can be obtained. PMID- 22246581 TI - Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis. AB - OBJECTIVE: Single-nucleotide polymorphisms (SNPs) that alter immune function, inflammatory responses, and disease susceptibility have been identified in several genes encoding Toll-like receptors (TLRs). The TLR SNPs with the best evidence of an effect on immune function are those in TLR1 (1805GG), TLR2 (2258GA), and TLR5 (1174CT). This study was undertaken to assess the frequency and functional outcomes of these polymorphisms in patients with Lyme disease. METHODS: SNP frequencies and functional outcomes were assessed in 248 patients with Lyme disease. Cytokine and chemokine levels were determined using multiplex assays in the serum of patients with erythema migrans (EM), joint fluid of patients with Lyme arthritis, and supernatants of Borrelia burgdorferi-stimulated peripheral blood mononuclear cells (PBMCs) from patients with Lyme arthritis. RESULTS: The frequency of the TLR1-1805GG polymorphism was greater in patients with antibiotic-refractory arthritis compared with patients with EM or those with antibiotic-responsive arthritis. Early in the illness, patients with EM carrying 1805GG, primarily those infected with B burgdorferi 16S-23S ribosomal spacer RNA intergenic type 1 (RST1) strains, had higher serum levels of interferon-gamma (IFNgamma), CXCL9, and CXCL10 and had more severe infection than EM patients carrying the 1805TG/TT polymorphism. These inflammatory responses were amplified in patients with Lyme arthritis, and the highest responses were observed in patients with 1805GG in the antibiotic-refractory group who had been infected with RST1 strains. When PBMCs from patients with Lyme arthritis were stimulated with a B burgdorferi RST1 strain, the 1805GG group had a significantly larger fold increase in the levels of IFNgamma, CCL2, CXCL9, and CXCL10 compared to the 1805TG/TT group. In contrast, the TLR2 and TLR5 polymorphisms did not vary in frequency or function among the groups. CONCLUSION: The TLR1-1805GG polymorphism in B burgdorferi RST1-infected patients was associated with stronger Th1-like inflammatory responses, an environment that may set the stage for antibiotic refractory arthritis. PMID- 22246583 TI - Leukemia incidence in the Russian cohort of Chernobyl emergency workers. AB - Of all potentially radiogenic cancers, leukemia, a type of cancer of the blood, has the highest risk attributable to ionizing radiation. Despite this, the quantitative estimation of radiation risk of a leukemia demands studying very large exposed cohorts, because of the very low level of this disease in unexposed populations and because of the tendency for its radiation risk to decrease with time. At present, the Japanese cohort of atomic bomb survivors is still the primary source of data that allows analysis of radiation-induced leukemia and the underlying dose-response relationship. The second large cohort that would allow to study radiation-induced leukemia is comprised of individuals who were exposed due to the accident of the Chernobyl nuclear power plant in 1986. The objective of the present study was to estimate radiation risks of leukemia incidence among the Russian cohort of Chernobyl emergency workers, for different time periods after the accident. Twenty-five years after the Chernobyl accident and based on the results of the present study, one can conclude that the radiation risk of leukemia incidence derived from the Russian cohort of Chernobyl emergency workers is similar to that derived from the cohort of atomic bomb survivors: The time averaged excess relative risk per Gray (ERR Gy(-1)) equals 4.98 for the Russian cohort and 3.9 for the life span study (LSS) cohort; excess absolute risk decreases with time after exposure at an annual rate of 9% for the Russian cohort, and of 6.5% for the LSS cohort. Thus, the excess in risk of leukemia incidence in a population due to a single exposure is restricted in time after exposure by the period of about 15 years. PMID- 22246584 TI - Journal rubric. Haemophilic pseudotumour of the carotid artery. PMID- 22246585 TI - GBV-C: state of the art and future prospects. AB - The GB virus C is a common non-pathogenic virus, member of the Flaviviridae family with worldwide distribution. Favorable clinical course and reduced mortality among HIV-infected patients was demonstrated by several studies with patients co-infected with the GB virus C (GBV-C). This potential benefit of GBV-C has been demonstrated in the pre-HAART and post-HAART eras; however, this effect was not observed in all studies and the discrepancy may be due to changes during the course of HIV infection, characteristic of the cohort, and the degree of therapeutic response. The GBV-C has been found to decrease HIV replication in in vitro models, highlighting the interference of persistent GBV-C viremia. The mechanism of the beneficial effect of GBV-C appears to be mediated by changes in the cellular immune response, and elucidation of putative protective effects of GBV-C in HIV co-infection could potentially identify novel targets for anti-HIV agents. PMID- 22246586 TI - Natural history of human aberrant crypt foci and correlation with risk factors for colorectal cancer. AB - Although aberrant crypt foci (ACF) are estimated to have potential usefulness as a biomarker for colorectal carcinoma (CRC), this remains uncertain because the natural history of ACF has not been well-clarified. To determine the usefulness of ACF as a surrogate marker for CRC, it is necessary to understand the natural history of ACF. A total of 82 subjects who underwent total colonoscopy and whose ACF number was examined at least 2 times at Yokohama City University Hospital were enrolled. We retrospectively evaluated the changes in the ACF number at four different surveillance periods (6 months, 1 year, 2 years, 3 years) and in groups with and without colorectal neoplasms. Furthermore, we classified the subjects into an increased ACF group and a no change/decreased ACF group, and investigated the relationship between the changes in the ACF number and known risk factors for CRC. No significant differences were observed in the ACF number between the first and second observations in any surveillance period groups, and in the groups classified according to the presence or absence of colorectal neoplasms. There were no significant differences between the increased and no change/decreased ACF group in terms of gender, smoking habit, current alcohol consumption, age, BMI, HbA1c or serum triglyceride level (TG), whereas a significant difference between the groups was observed in the serum total cholesterol level (TC) (p=0.012). ACF are a reliable surrogate marker that are not affected by any risk factors for adenomas or CRC, except TC, and may therefore be considered as a useful marker in chemopreventive trials. PMID- 22246588 TI - Micromonospora haikouensis sp. nov., isolated from mangrove soil. AB - An actinomycete strain 232617(T) was isolated from a composite mangrove sediment sample collected in Haikou, China. Phylogenetic analysis of the 16S rRNA gene sequence of strain 232617(T) indicated the highest similarity with Micromonospora siamensis TT2-4(T) (99.05%), Micromonospora krabiensis A-2(T) (98.99%) and Micromonospora carbonacea DSM 43815(T) (98.91%). The gyrB gene sequence analysis also indicated that 232617(T) should be assigned to the genus Micromonospora. The cell wall contains meso-DAP and glycine. The major menaquinones were MK-10(H(4)) and MK-10(H(6)), with MK-9(H(4)) as minor components. The characteristic whole cell sugars are xylose, arabinose and glucose. The phospholipid profile comprises phosphatidylethanolamine, diphosphatidlglycerol and phosphatidylinositol mannoside. The DNA G+C content is 71.5 mol%. Furthermore, a combination of DNA DNA relatedness and some physiological and biochemical properties indicated that the novel strain could be readily distinguished from the closest related species. On the basis of these phenotypic and genotypic data, strain 232617(T) represents a novel species of the genus Micromonospora, for which the name Micromonospora haikouensis sp. nov. is proposed. The type strain is 232617(T) (= CCTCC AA 201112 (T) = DSM 45626 (T)). PMID- 22246589 TI - Saitoella coloradoensis sp. nov., a new species of the Ascomycota, subphylum Taphrinomycotina. AB - Saitoella coloradoensis sp. nov. (NRRL YB-2330, CBS 12360, type strain, MycoBank accession number 563858) is described. This new member of the phylum Ascomycota, subphylum Taphrinomycotina was isolated from insect frass occurring in an Engelmann spruce (Picea engelmannii) that was growing in Colorado, USA. Multigene sequence analysis showed that S. coloradoensis is distinct from Saitoella complicata, the only other known species of Saitoella. The two species may be separated phenotypically from growth reactions on D: -xylose, ribitol and methyl alpha-D: -glucoside. Asexual reproduction is by budding and both species produce thick-walled, spherical cells that appear morphologically similar to the ascogenous cells formed in plant host tissue by species of Protomyces and some species of Taphrina. The thick-walled cells did not form ascospores but did produce buds when placed on fresh growth media. PMID- 22246590 TI - Patellar resurfacing as a second stage procedure for persistent anterior knee pain after primary total knee arthroplasty. AB - PURPOSE: Knee pain after total knee arthroplasty may be caused by an unresurfaced patella. Secondary isolated resurfacing of the previously unresurfaced patella in total knee arthroplasty remains controversial. The aim of this retrospective study was to evaluate the outcome after patellar resurfacing as a second stage procedure. METHODS: The study included 22 patients (13 female/nine male) who underwent resurfacing of the patella with a mean follow-up of 61.8 +/- 39.2 months. The mean age of the patients was 60 +/- 9.7 years at the time of operation. The average period between total knee arthroplasty and patellar resurfacing was 26.3 +/- 15.2 months. The patient's subjective satisfaction was assessed by a custom-made questionnaire. RESULTS: The mean Knee Society Score improved significantly from 60.1 +/- 8.3 to 77.0 +/- 6.3 (p = 0.0063). The mean functional score also improved significantly from 42.7 +/- 2.3 to 60.2 +/- 3.9 (p = 0.001). Three patients (13.6%) needed further operative revision. CONCLUSIONS: Although clinical scores showed significant improvement some patients continued to have pain and remained dissatisfied without detecting a specific reason. Further studies are needed to better elucidate the benefit of patellar resurfacing as second stage procedure. PMID- 22246591 TI - The role of autologous chondrocyte implantation in the treatment of symptomatic chondromalacia patellae. AB - PURPOSE: Chondromalacia patella is a distinct clinical entity of abnormal softening of the articular cartilage of the patella, which results in chronic retropatellar pain. Its aetiology is still unclear but the process is thought to be a due to trauma to superficial chondrocytes resulting in a proteolytic enzymic breakdown of the matrix. Our aim was to assess the effectiveness of autologous chondrocyte implantation on patients with a proven symptomatic retropatellar lesion who had at least one failed conventional marrow-stimulating therapy. METHODS: We performed chondrocyte implantation on 48 patients: 25 received autologous chondrocyte implantation with a type I/III membrane (ACI-C) method (Geistlich Biomaterials, Wolhusen, Switzerland), and 23 received the Matrix assisted Chondrocyte Implantation (MACI) technique (Genzyme, Kastrup, Denmark). RESULTS: Over a mean follow-up period of 40.3 months, there was a statistically significant improvement in subjective pain scoring using the visual analogue scale (VAS) and objective functional scores using the Modified Cincinnati Rating System (MCS) in both groups. CONCLUSIONS: Chondromalacia patellae lesions responded well to chondrocyte implantation. Better results occurred with MACI than with ACI-C. Excellent and good results were achieved in 40% of ACI-C patients and 57% of MACI patients, but success of chondrocyte implantation was greater with medial/odd-facet lesions. Given that the MACI procedure is technically easier and less time consuming, we consider it to be useful for treating patients with symptomatic chondral defects secondary to chondromalacia patellae. PMID- 22246592 TI - Posterior mono-segmental fixation, combined with anterior debridement and strut graft, for treatment of the mono-segmental lumbar spine tuberculosis. AB - PURPOSE: A retrospective study was conducted to determine the beneficial effect of posterior mono-segmental fixation, combined with anterior debridement and strut graft for the treatment of mono-segmental lumbar spine tuberculosis. METHODS: From February 2002 to February 2008, a total of 34 cases with mono segmental lumbar spine tuberculosis were treated by posterior mono-segmental fixation, combined with anterior debridement and strut graft. The degree of damage to the patients' vertebral bodies was 1/3-2/3 height. Antituberculous therapy was performed both before and after surgery. RESULTS: None of the patients suffered from spinal cord, nerve, great vessel or organ damage, with all patients passing through the peri-operative period successfully. Graft union was observed four to six months after surgery, with a mean of five months. In addition, no fracture or prolapsed internal fixation was found. The Cobb's angle prior to and after surgery, and at the final follow-up were 22.70 +/- 9.8 degrees , 4.5 +/- 8.4 degrees and 5.30 +/- 7.10 degrees , respectively, with a mean correction of 18.20 +/- 5.8 degrees after surgery; however, 1.70 +/- 1.0 degrees loss was observed at the final follow-up. Four cases with neurological lesions recovered to 'E' grade. At the final follow-up, all patients could live and work normally. CONCLUSIONS: The results demonstrated that for cases with 1/3-2/3 height of vertebral body damaged in mono-segmental lumbar spine tuberculosis, treatment with posterior mono-segmental fixation, combined with anterior debridement and strut graft, can cure foci, rebuild spinal stability, reduce fused segments, and retain maximal function of the motion units. PMID- 22246593 TI - Effects of lowering dialysate sodium on carotid artery atherosclerosis and endothelial dysfunction in maintenance hemodialysis patients. AB - PURPOSE: Our aim in this study was to examine the effects of low-sodium dialysate on carotid artery atherosclerosis, endothelial dysfunction, and blood pressure (BP) in maintenance hemodialysis (HD) patients. METHODS: After baseline measurements were obtained, the dialysate sodium concentration was reduced from 140 to 137 mEq/L. Carotid artery intima-media thickness (CIMT) and flow-mediated dilatation (FMD%) were measured before and after 6 months of HD with low-sodium dialysate. Interdialytic weight gain (IDWG), pre- and post-dialysis BP, and dialysis-related symptoms were monitored during the study. RESULTS: Fifty-two patients were enrolled, and 41 patients completed the study. Twenty-one patients had hypertension and were receiving antihypertensive medications. The average number of antihypertensive drugs per patient was 1.9+/-0.8. There was no significant reduction in BP at the end of the study, but the average number of antihypertensive drugs was reduced to 1.2+/-0.4 (P<0.001). There were significant improvements in CIMT (P=0.003) and FMD (P<0.001) with low-sodium HD. The IDWG decreased significantly during the low-sodium dialysate treatment (P<0.001). However, hypotensive episodes and cramps were more frequent during the study period. CONCLUSIONS: Our study demonstrated that the lowering of dialysate sodium concentration reduced CIMT, improved FMD, and provided better control of IDWG and BP, but increased the incidence of dialysis-related symptoms. PMID- 22246594 TI - Quality of life and protein-energy wasting in kidney transplant recipients. AB - PURPOSE: Chronic kidney disease has profound effects on the health-related quality of life (HRQoL) of patients, with serious physiological, psychological and socio-economic implications. The co-occurrence of protein-energy wasting and inflammation in end-stage renal disease patients is associated with worse HRQoL and increased mortality. We designed this study to examine the relationship between nutritional and inflammatory status and HRQoL in kidney transplant recipients. METHODS: Data from 100 randomly selected kidney transplant patients were analyzed in a cross-sectional survey. Socio-demographic parameters, laboratory results, transplantation-related data, comorbidities, medication and malnutrition-inflammation score (MIS) (Kalantar Score) were tabulated at baseline. Patients completed the Kidney Disease Quality of Life-SF (KDQoL-SFTM) self-administered questionnaire. RESULTS: Mean age was 51 +/- 13 years, median (interquartile range, IQR) time since transplantation 66 (83) months, 57% were men, and 19% had diabetes. The median (IQR) MIS was 3 (3). The MIS significantly and negatively correlated with almost all HRQoL domains analyzed, and this association remained significant in multivariate linear regression analysis for the log-transformed scores on energy/fatigue (beta = -0.059 P < 0.001), bodily pain (beta = -0.056 P = 0.004), physical functioning (beta = -0.029, P = 0.022) and symptoms/problems (beta = -0.023 P = 0.005) domains after statistical correction for age, gender, eGFR, dialysis vintage, Charlson Comorbidity Index and occupational status. Additionally, cubic spline analyses revealed linearly increasing, "dose-response" relationship between almost all domains of KDQoL-SFTM and the MIS. CONCLUSIONS: Malnutrition-inflammation score is independently associated with different dimensions of HRQoL in kidney transplant recipients. PMID- 22246595 TI - Lymphangiogenesis and biological behavior in pancreatic carcinoma and other pancreatic tumors. AB - Lymphatic vessels in primary tumor tissue play an important role in lymphatic metastasis. Lymphatic metastasis of malignant neoplasms is significantly related to prognosis, influencing both recurrence and survival. The aim of this study was to investigate the correlation of intra-tumoral lymphatic vessel density (iLVD) and peri-tumoral lymphatic vessel density (pLVD) with biological behavior and prognostic parameters in pancreatic carcinoma (PC) and other pancreatic tumors. Lymphangiogenesis was examined using the D2-40 monoclonal antibody in 33 cases of PC, 7 neuroendocrine tumors of the pancreas (NETP), 7 solid pseudopapillary tumors of the pancreas (SPTP) and 3 cystadenomas of the pancreas (CP). Positively stained microvessels were counted at magnification x400 in dense lymphatic vascular foci (hotspots). The LVD of PC was compared to 3 other pancreatic tumors. The relationships among the LVD, the extent of differentiation, lymphatic invasion, lymph node metastasis and other clinicopathological parameters of PC were analyzed. There was no difference in the iLVD among PC, NETP, SPTP and CP. The pLVD of NETP was markedly higher than that of PC, SPTP and CP. The pLVD of PC was significantly higher than that of SPTP and CP, but there was no difference between SPTP and CP. The pLVD of PC was significantly associated with the extent of differentiation, lymphatic invasion and lymph node metastasis, whereas it was not associated with age, gender, tumor size, tumor location and peri-pancreatic invasion. The iLVD of PC was not correlated with these clinicopathological parameters. There was no difference in iLVD and no marked difference in pLVD among the pancreatic tumors. Detection of pLVD is of greater importance than detecting iLVD in these pancreatic tumors, as pLVD can be utilized for the prediction of lymph node metastasis, thus aiding in the evaluation of patient prognosis. PMID- 22246596 TI - Attachment styles in patients with lung cancer and their spouses: associations with patient and spouse adjustment. AB - PURPOSE: This study examined attachment styles in patients with lung cancer and their spouses and associations between attachment styles and patient and spouse adjustment. METHODS: One hundred twenty-seven patients with early stage lung cancer completed measures of attachment style, marital quality, self-efficacy, pain, depression, anxiety, and quality of life. Their spouses completed measures of attachment style, marital quality, self-efficacy, caregiver strain, and mood. RESULTS: Analyses indicated that, among patients, those high in either attachment anxiety or avoidance had significantly higher levels of anxiety and poorer social well-being. Attachment avoidance was also significantly associated with higher levels of depression and poorer marital quality and functional well-being. Spouse avoidant attachment was significantly associated with patient reports of increased pain and poorer functional well-being, and spouse anxious attachment was associated with poorer patient marital quality. Among spouses, those high in attachment avoidance reported significantly higher levels of caregiver strain, anger, depressed mood, and poorer marital quality; those high in attachment anxiety reported higher anxious mood. Dyads in which both partners were insecurely attached had significantly poorer adjustment compared to dyads in which both partners reported secure attachment. CONCLUSIONS: These preliminary findings raise the possibility that attachment styles of cancer patients and their spouses as individuals and as a dyad may be important factors affecting adjustment in multiple domains. PMID- 22246597 TI - Quality of end-of-life care for patients with metastatic non-small-cell lung cancer in general wards and palliative care units in Japan. AB - PURPOSE: Patients with lung cancer in Japan often receive aggressive care near the end of life and die in an acute care hospital. We describe the differences in end-of-life care for metastatic non-small-cell lung cancer (NSCLC) patients between general wards and a palliative care unit (PCU). METHODS: A retrospective analysis was conducted using data from patients who received at least second-line chemotherapy between 2002 and 2007 in a single institute. Among 72 eligible patients, we categorised patients into two groups, those who died in general wards (n = 57) and those who died in the PCU (n = 15), and examined end-of-life care including chemotherapy, do-not-resuscitate (DNR) decision making and treatment in the last 48 h of life. RESULTS: Mean number of days between the last chemotherapy and death was shorter in general wards than in the PCU (P = 0.019). Furthermore, 25% of patients in general wards received chemotherapy within the last 2 weeks of life. Rates of multiple hospitalisations in the last month of life appeared higher in general wards than in the PCU. Mean number of days between documentation of DNR and death was shorter in general wards than in the PCU (P = 0.0010). Patients in general wards received a greater volume of hydration than those in the PCU (P < 0.001). CONCLUSIONS: Patients with metastatic NSCLC in general wards receive inappropriate care near the end of life. Further studies are needed to develop interventions for making decisions regarding end-of-life care. PMID- 22246598 TI - The use of hyperbaric oxygen for treating delayed radiation injuries in gynecologic malignancies: a review of literature and report of radiation injury incidence. AB - PURPOSE: The purposes of this paper are to review the best evidence supporting the use of hyperbaric oxygen therapy (HBOT) in delayed radiation injuries in gynecologic malignancies and report the incidence of radiation injuries at two large medical centers in southeastern Wisconsin. METHODS: A literature search was performed on Google Scholar, PubMed, and Ovid for studies evaluating the use of HBOT radiation cystitis, proctitis, and necrosis. The studies were then reviewed for the highest quality evidence using American Academy of Neurology guidelines. To evaluate radiation injuries, cancer databases at Froedtert Memorial Lutheran Hospital (FMLH) and Aurora St. Luke's Hospital (ASLH) were accessed. RESULTS: Several studies support the use of HBOT in treating radiation cystitis, proctitis, and necrosis, with proctitis having the strongest evidence in its favor. The average annual incidence of radiation injury at FMLH was 13.8%. Patients with cervical cancer and vulvar cancer had rates of 23% each. The average annual incidence of radiation injury among gynecologic cancer patients at ASLH was 5.5%. CONCLUSIONS: There is level A evidence for using HBOT to treat radiation proctitis. There is level B evidence for using HBOT to treat radiation cystitis and necrosis. The incidence delayed radiation injuries can be as high as 23%. This has relevance in practice guidelines for the treatment of delayed radiation injuries in gynecologic malignancies. PMID- 22246599 TI - Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury. AB - The 70-kDa heat shock protein (Hsp70) is thought to protect the brain from a variety of insults. Although the mechanism has been largely limited to its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory pathways. Brain injury and ischemia are associated with an immune response that is largely innate. Hsp70 appears to suppress this response and lead to improved neurological outcome. However, most of this work has relied on the use of genetic mutant models or Hsp70 overexpression using gene transfer or heat stress, thus limiting its translational utility. A few compounds have been studied by various disciplines which, through their ability to inhibit Hsp90, can cause induction of Hsp70. The investigation of Hsp70-inducing pharmacological compounds has obvious clinical implications in terms of potential therapies to mitigate neuroinflammation and lead to neuroprotection from stroke or traumatic brain injury. This review will focus on the inflammation modulating properties of Hsp70, and the current literature surrounding the pharmacological induction in acute neurological injury models with comments on potential applications at the clinical level. PMID- 22246600 TI - Cultivar-specific kinetics of gene induction during downy mildew early infection in grapevine. AB - The oomycete pathogen Plasmopara viticola (Berk. et Curt.) Berl. et de Toni is the causing agent of the destructive downy mildew disease in grapevine. Despite the advances towards elucidation of grapevine resistance mechanisms to downy mildew, increased knowledge of the biological and genetic components of the pathosystem is important to design suitable breeding strategies. Previously, a cDNA microarray approach was used to compare two Vitis vinifera genotypes Regent and Trincadeira (resistant and susceptible to downy mildew, respectively) in field conditions. The same cDNA microarray chip was used to confirm field-based results and to compare both genotypes under greenhouse conditions at 0, 6, and 12 h post-inoculation with P. viticola. Results show that when comparing both cultivars after pathogen inoculation, there is a preferential modulation of several defense, signaling, and metabolism associated transcripts in Regent. Early transcriptional changes are discussed in terms of genetic background and resistance mechanism. This study is the first to directly compare resistant and susceptible cultivars responses as early as 6 hpi with P. viticola, providing several candidate genes potentially related to the expression of resistance traits. PMID- 22246601 TI - Self-reported recreational exercise combining regularity and impact is necessary to maximize bone mineral density in young adult women: a population-based study of 1,061 women 25 years of age. AB - Recreational physical activity in 25-year-old women in Sweden increases bone mineral density (BMD) in the trochanter by 5.5% when combining regularity and impact. Jogging and spinning were especially beneficial for hip BMD (6.4-8.5%). Women who enjoyed physical education in school maintained their higher activity level at age 25. INTRODUCTION: The aims of this study were to evaluate the effects of recreational exercise on BMD and describe how exercise patterns change with time in a normal population of young adult women. METHODS: In a population based study of 1,061 women, age 25 (+/-0.2), BMD was measured at total body (TB BMD), femoral neck (FN-BMD), trochanter (TR-BMD), and spine (LS-BMD). Self reported physical activity status was assessed by questionnaire. Regularity of exercise was expressed as recreational activity level (RAL) and impact load as peak strain score (PSS). A permutation (COMB-RP) was used to evaluate combined endurance and impacts on bone mass. RESULTS: More than half of the women reported exercising on a regular basis and the most common activities were running, strength training, aerobics, and spinning. Seventy percent participated in at least one activity during the year. Women with high RAL or PSS had higher BMD in the hip (2.6-3.5%) and spine (1.5-2.1%), with the greatest differences resulting from PSS (p < 0.001-0.02). Combined regularity and impact (high-COMB-RP) conferred the greatest gains in BMD (FN 4.7%, TR 5.5%, LS 3.1%; p < 0.001) despite concomitant lower body weight. Jogging and spinning were particularly beneficial for hip BMD (+6.4-8.5%). Women with high-COMB-RP scores enjoyed physical education in school more and maintained higher activity levels throughout compared to those with low scores. CONCLUSION: Self-reported recreational levels of physical activity positively influence BMD in young adult women but to maximize BMD gains, regular, high-impact exercise is required. Enjoyment of exercise contributes to regularity of exercising which has short- and long-term implications for bone health. PMID- 22246603 TI - Proteomic characterization of adipose tissue constituents, a necessary step for understanding adipose tissue complexity. AB - The original concept of adipose tissue as an inert storage depot for the excess of energy has evolved over the last years and it is now considered as one of the most important organs regulating body homeostasis. This conceptual change has been supported by the demonstration that adipose tissue serves as a major endocrine organ, producing a wide variety of bioactive molecules, collectively termed adipokines, with endocrine, paracrine and autocrine activities. Adipose tissue is indeed a complex organ wherein mature adipocytes coexist with the various cell types comprising the stromal-vascular fraction (SVF), including preadipocytes, adipose-derived stem cells, perivascular cells, and blood cells. It is known that not only mature adipocytes but also the components of SVF produce adipokines. Furthermore, adipokine production, proliferative and metabolic activities and response to regulatory signals (i.e. insulin, catecholamines) differ between the different fat depots, which have been proposed to underlie their distinct association to specific diseases. Herein, we discuss the recent proteomic studies on adipose tissue focused on the analysis of the separate cellular components and their secretory products, with the aim of identifying the basic features and the contribution of each component to different adipose tissue-associated pathologies. PMID- 22246602 TI - Hip fracture incidence is decreasing in the high incidence area of Oslo, Norway. AB - This study reports a significant decrease in age-adjusted incidence rates of hip fracture for women in Oslo, Norway, even compared with data from 1978/1979. Use of bisphosphonate may explain up to one third of the decline in the incidence. INTRODUCTION: The aims of the present study were to report the current incidence of hip fractures in Oslo and to estimate the influence of bisphosphonates on the current incidence. METHODS: Using the electronic diagnosis registers and lists from the operating theaters of the hospitals of Oslo, all patients with ICD-10 codes S72.0 and S72.1 (hip fracture) in 2007 were identified. Medical records of all identified patients were reviewed to verify the diagnosis. Age- and gender specific annual incidence rates were calculated using the population of Oslo on January 1, 2007 as the population at risk. Data on the use of bisphosphonates were obtained from official registers. RESULTS: A total number of 1,005 hip fractures, 712 (71%) in women, were included. The age-adjusted fracture rates per 10,000 for the age group >50 years were 82.0 for women and 39.1 for men in 2007, compared with 110.8 and 41.4 in 1996/1997, 116.5 and 42.9 in 1988/1989, and 97.5 and 34.5 in 1978/1979, respectively. It was estimated that the use of bisphosphonates may explain up to 13% of the decline in incidence in women aged 60-69 years and up to 34% in women aged 70-79 years. CONCLUSIONS: The incidence of hip fractures in women in Oslo has decreased significantly during the last decade and is now at a lower level than in 1978/1979. This reduction was not evident in men. The incidence of hip fractures in Oslo is, however, still the highest in the world. PMID- 22246604 TI - mTORC1 inhibition and ECM-cell adhesion-independent drug resistance via PI3K-AKT and PI3K-RAS-MAPK feedback loops. AB - Mammalian target of rapamycin (mTOR) serine threonine kinase is the enzyme that regulates cancer cell growth by altering nutrient supplies to cancer cells. The neuropeptide (proline-rich peptide 1 (PRP-1)), galarmin, produced by the brain neurosecretory cells is a mTOR kinase inhibitor with powerful 80% antiproliferative cytostatic effect in a high-grade chondosarcoma and other mesenchymal tumors. However, the negative feedback loop of phosphatidylinositol 3 kinase-Protein kinase B (PKB), PI3K-AKT and PI3K-rat sarcoma (RAS)-mitogen activated protein kinase (MAPK) activation is well documented for mTOR inhibitors. This study explored the involvement of those loops in drug resistance after the treatment with mTOR complex 1 (mTORC1) inhibitor, PRP-1. Multidrug resistance assay (MDR) demonstrated that this cytokine did not inhibit permeability glycoprotein-mediated MDR in chondrosarcoma. Phospho-MAPK array in human chondrosarcoma cell line treated with galarmin (10 MUg/ml,) showed a strong upregulation of phosphorylated glycogen synthase kinase 3beta (GSK3beta) via activation of PI3K-AKT and MAPK feedback loops. Such GSK3beta inactivation leads to beta-catenin accumulation that entails drug resistance. The ability of cells to metastasize is reflected in their capacity to adhere to extracellular matrix and endothelium. Laminin cell adhesion assay demonstrated that PRP-1 in the same concentrations that inhibit mTOR kinase inhibited JJ012 chondrosarcoma cell adhesion. The neuropeptide did not have any effect on the expression of total focal adhesion kinase and its phosphorylated form. Thus, it was not accompanied by total HAT downregulation and total HDAC upregulation. Combinatorial treatments of PRP-1 with MAPK and PI3K/AKT inhibitors most probably will lead to full cytotoxicity overcoming drug resistance. PMID- 22246605 TI - RKIP expression associated with gastric cancer cell invasion and metastasis. AB - The purpose of this study was to analyze Raf kinase inhibitor protein (RKIP) expression in gastric cancer tissue, its correlation with gastric cancer clinical pathology, and its role in gastric cancer invasion and metastasis in order to provide experimental evidence for the potential biological therapy of this disease. Both immunohistochemistry and western blot analyses were used to test for RKIP expression in 55 cases of gastric cancer tissue and the adjacent gastric mucous membrane tissue. The correlations of RKIP expression with the onset, development, and clinical pathology of gastric cancer were analyzed. After transiently transfecting the human gastric cancer cell line MKN45 with a eukaryotic expression vector containing the full length RKIP cDNA, the changes in MKN45 cell invasiveness and metastatic ability were studied. Immunohistochemistry and western blot results revealed that the quantity of RKIP protein expressed in the gastric cancer tissues was significantly lower than that of the adjacent normal gastric mucous membrane tissues (p < 0.05). The quantity of RKIP protein expression was reduced (p < 0.05) as the gastric cancer cells' differentiation decreased, the TNM stage increased, and the extent of invasion expanded. However, the expression of RKIP in the gastric cancer tissues was not associated with the patients' age or gender (p > 0.05). By overexpressing RKIP in the human gastric cancer cell line MKN45 and through the use of a Transwell invasion chamber, we determined that RKIP overexpression significantly reduced both the invasiveness and metastatic ability of MKN45 cells (p < 0.05). Low or absent RKIP expression may be associated with the onset and development of gastric cancer and its ability to invade and metastasize. PMID- 22246606 TI - Implementation of a coordinated and tailored return-to-work intervention for employees with mental health problems. AB - PURPOSE: Interventions to promote return to work (RTW) after sickness absence are often complex, involving numerous stakeholders and thus prone to implementation problems. To understand the outcomes of such interventions, researchers need to look beyond effectiveness data and incorporate systematic process evaluations. This article presents findings from a process evaluation of a coordinated and tailored RTW-intervention for employees with mental health problems. The purpose was to elucidate the implementation process and identify barriers for the feasibility and sustainability of the intervention. METHODS: The evaluation draws on comprehensive data from observations of and documents from the intervention, a two-waved survey among participants (n = 76), two group interviews with the intervention team, three group interviews with municipal social insurance officers (SIOs), and ten individual interviews with participants. RESULTS: We identified several barriers to the feasibility and sustainability of the intervention: (1) the inclusion criteria were perceived as too narrow by those responsible for recruitment (SIOs); (2) waiting lists occurred; (3) participants had more severe mental health problems than expected; (4) key stakeholders had divergent expectations of the timeframe for RTW; (5) the SIOs felt insufficiently informed about the intervention; (6) the global financial downturn resulted in many participants losing their job, which impeded workplace-based RTW-efforts. CONCLUSIONS: This study points out important pitfalls in implementing RTW interventions, pertaining to specification of the target population, consideration of contextual constraints, and ensuring cooperation between key stakeholders. Thorough assessment of local context and stakeholder needs and concerns is likely to improve the feasibility and sustainability of future RTW interventions. PMID- 22246607 TI - Facile access to transition-metal-carbonyl complexes with an amidinate-stabilized chlorosilylene ligand. AB - Three transition-metal-carbonyl complexes [V(L)(CO)(3)(Cp)] (1), [Co(L)(CO)(Cp)] (2), and [Co(L(2))(CO)(3)](+)[CoCO)(4)](-) (3), each containing stable N heterocyclic-chlorosilylene ligands (L; L=PhC(NtBu)(2)SiCl) were synthesized from [V(CO)(4)(Cp)], [Co(CO)(2)(Cp)], and Co(2)(CO)(8), respectively. Complexes 1-3 were characterized by NMR and IR spectroscopy, EI-MS spectrometry, and elemental analysis. The molecular structures of compounds 1-3 were determined by single crystal X-ray diffraction. PMID- 22246608 TI - Neoadjuvant clinical trials for the treatment of primary breast cancer: the experience of the German study groups. AB - The advantages of neoadjuvant chemotherapy are the ability to 1) increase the rate of breast conservation and improve operability, 2) to reduce mortality by recognizing resistance mechanisms early, and 3) to investigate the activity of new agents by assessing the pathological complete response rate as a surrogate marker for clinical efficacy. The German Breast Group (GBG) is a cooperative study group which focuses on neoadjuvant therapy for breast cancer. This group cooperates closely with the German Gynecological Oncology Working Group-Breast (AGO-B). Additionally, these two German study groups maintain close ties with other national and international study groups, such as the Breast International Group (BIG), Austrian Breast and Colorectal Cancer Study Group (ABCSG), Central European Cooperative Oncology Group (CECOG), International Cooperative Cancer Group (ICCG) and National Surgical Adjuvant Breast Project (NSABP). A series of clinical trials evaluating the role of neoadjuvant therapy in women with primary breast cancer have been designed, performed and published over the last 10 years. This article summarizes the results of the neoadjuvant trials that have been conducted by the German study groups, outlines ongoing clinical research projects, and discusses concepts for future clinical trials. PMID- 22246609 TI - Salivary gland cancers: biology and molecular targets for therapy. AB - Salivary gland carcinomas are a heterogeneous group of tumors with different biologic behavior. Given the lack of large randomized studies, there is no standard treatment for advanced and/or metastatic salivary gland tumors, and systemic therapy is empirically based. Tumor-specific recurrent chromosomal translocations and fusion oncogenes in aggressive head and neck malignancies have diagnostic, therapeutic, and prognostic implications. Pathognomonic fusion transcripts have been identified in subsets of mucoepidermoid carcinoma and adenoid cystic carcinoma. These translocations target 1) transcription factors involved in growth factor signaling and cell cycle regulation, 2) transcriptional co-activators, and 3) tyrosine kinase receptors. Prioritizing studies with a translational component to advance the molecular understanding of these cancers and molecular-targeted therapy clinical trials is critical. PMID- 22246610 TI - CVID enteropathy- a rare cause of chronic diarrhea in a child. AB - Common variable immunodeficiency (CVID) is a rare primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections especially in respiratory and gastrointestinal systems. The authors present here a case of CVID with uncommon gastrointestinal manifestation in the form of CVID enteropathy. Based upon the clinical presentation and histopatholic findings the patient was diagnosed as CVID enteropathy and treated with intravenous antibiotics and 3-4 wkly intravenous immunoglobulin infusion and he had responded poorly to gastrointestinal symptoms but the frequency of respiratory and skin infection reduced. CVID has heterogenous gastrointestinal manifestations; among them the CVID enteropathy is an uncommon presentation which responds poorly to the mainstay therapy of intravenous immunoglobulin infusion and represents a diagnostic as well as therapeutic challenge for treating physician. PMID- 22246611 TI - Kawasaki disease, what about seasonal variation? PMID- 22246612 TI - Perinatal tuberculosis associated hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis [HLH] is a reactive disorder characterized by generalised non-malignant histiocytic proliferation with prominent hemophagocytosis. It may be either primary [familial (FLH)] or secondary [infection or malignancy associated]. Organisms incriminated for infection associated hemophagocytic syndrome (IAHS) include viruses, bacteria, spirochetes, fungi and parasites. Reports of IAHS associated with tuberculosis in neonates are rare. The authors report a case of perinatal tuberculosis presenting as hemophagocytic lymphohistiocytosis. PMID- 22246613 TI - Monitoring of municipal waste generated in the city of Warsaw. AB - Waste management in the new EU member states is currently undergoing rapid development in order to comply with the European legislation. In Poland there is a lack of capacity of waste treatment installations for residual waste which amounts to 5.5 million tonnes year(-1). Detailed data on waste generation is needed to design new installations and ensure their efficient operation. This paper presents the results of the monitoring of municipal waste generation in Warsaw, being one of the largest agglomerations in the region. Detailed quantitative and qualitative results for both household and institutional waste are provided, as well as the technological properties of the household waste. The amount of municipal waste generated per capita amounted to 390 kg year(-1). The main fractions contributing to the mixed household waste were: biodegradable kitchen waste, packaging plastics, non-packaging paper and cardboard, packaging glass and packaging paper and cardboard. The coarse fraction (> 100 mm) constituted 40% of total household waste, of which the majority were recyclables. The lower heating value of residual waste was sufficient to allow mass incineration. Data on historical developments of household waste quantities and composition since the year 2000 along with their estimates until the year 2020 are provided and discussed. Current problems of municipal waste management in Warsaw along with the proposed future solutions are briefly outlined. PMID- 22246614 TI - A state-wide partnership to promote safe and supportive schools: the PBIS Maryland Initiative. AB - Schools continue to be an important context for preventive interventions targeting a range of behavioral and mental health problems. Yet competing demands on teachers and shifting priorities in response to federal legislation have posed some unique challenges to prevention researchers working in school settings. This paper summarizes an approach to prevention partnerships developed over a decade and centered on the three-tiered Positive Behavioral Interventions and Supports (PBIS) model. A state-wide initiative was formed and led through a partnership between the Maryland State Department of Education, Sheppard Pratt Health System, and Johns Hopkins University, which focused on implementing evidence-based practices and conducting prevention research in Maryland public schools. Drawing on a community-based participatory research framework for developing research partnerships, we highlight the importance of forming and sustaining authentic relationships to support school-based prevention research and implementation of evidence-based programs. We also discuss how these relationships have been used to disseminate PBIS and rigorously test its effectiveness. We describe some lessons learned from the partnership and identify potential areas for future research on the prevention partnership model. We conclude with a discussion of the implications for both researchers and community partners engaged in translational research in school settings. PMID- 22246615 TI - Effective intervention programming: improving maternal adjustment through parent education. AB - This study assessed the secondary effects of a parent training intervention program on maternal adjustment, with a focus on understanding ways in which program efficacy differed for participants as a function of whether or not their children had behavior problems. Mothers (N = 99) of toddlers (2-3 years of age) were randomly assigned to receive one of three levels of intervention: (1) informational booklet (2) booklet + face-to-face parent training sessions, or (3) booklet + web-based parent training sessions. Findings indicated that all levels of intervention were associated with increases in maternal well-being for participants with typically developing children. Mothers of toddlers with behavior problems, however, did not benefit from receiving only the booklet but significantly benefitted from receiving either the face-to-face or web-based interventions. Findings are discussed in terms of efficient and efficacious program dissemination and the resulting implications for public policy. PMID- 22246616 TI - Changing preferences for information and participation in the last phase of life: a longitudinal study among newly diagnosed advanced lung cancer patients. AB - PURPOSE: The objective is to explore changes over time in the information and participation preferences of newly diagnosed stage IIIb/IV non-small-cell lung cancer patients. METHODS: Patients were recruited by physicians in 13 hospitals and interviewed every 2 months until the fourth and every 4 months until the sixth interview. RESULTS: Sixty-seven patients were interviewed three times. Over a period of 4 months from diagnosis, half of patients changed their information preferences for palliative care and end-of-life decisions with a possible or certain life-shortening effect (ELDs, e.g., non-treatment decisions) in both directions, from not wanting to wanting the information, but also--and as much- from wanting to no longer wanting it. The latter were more likely to be in a better physical condition. Preferences for participation in medical decision making also changed: 50% to 78%, depending on the type of decision (general, treatment, transfer or ELD), changed their preference towards wanting more or less participation. Pain seemed to be a trigger for patients wanting more involvement, which contrasts with studies suggesting that patients who are more ill tend to give up more control. CONCLUSIONS: Doctors should regularly ask their advanced lung cancer patients how much information and participation they want because preferences do change in unexpected ways. PMID- 22246617 TI - Risk factors for malignant melanoma in white and non-white/non-African American populations: the multiethnic cohort. AB - It is unknown whether the established risk factors for malignant melanoma in whites influence malignant melanoma risk in non-whites. We examined the risk factors for melanoma among 39,325 whites and 101,229 non-whites/multiracials [Japanese American (47.5%), Latino American (34.8%), Native Hawaiian (2.1%), and multiracial (15.6%), excluding African Americans] in the Multiethnic Cohort study. With an average follow-up of 12.7 years, 581 invasive malignant melanoma (IMM) and 412 melanoma in situ (MIS) cases were identified, of which 107 IMM and 74 MIS were among non-whites/multiracials. The relative risks (RR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards models using days from cohort entry as the underlying time variable. Among non white/multiracial males, location of IMM tumors differed from those of white males (P < 0.001); and non-white/multiracial females were more likely to be diagnosed with later stage of disease (P < 0.001). After adjusting for potential confounders, age at cohort entry, male sex, higher education, and sunburn susceptibility phenotypes were associated with an increased risk of IMM in non whites/multiracials (P < 0.05). The risk estimates for age at cohort entry and lighter hair and eye color were greater in non-whites/multiracials than in whites (P(heterogeneity) = 0.062, 0.016, and 0.005, respectively). For MIS risk, RRs between whites and non-whites/multiracials also differed for study location and education (P(heterogeneity) <= 0.015). In conclusion, similar to whites, age at cohort entry, male sex, and susceptibility to sunburn phenotypes may be predictive of malignant melanoma risk in non-white populations excluding African Americans. PMID- 22246618 TI - Uterine serous carcinoma: increased familial risk for lynch-associated malignancies. AB - Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands' tumors had DNA MMR abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case control study. Pancreatic cancers were, however, significantly more common in relatives of patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06-5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers. PMID- 22246619 TI - Effect of 2-month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women. AB - There have been no controlled intervention studies to investigate the effects of green tea on circulating hormone levels, an established breast cancer risk factor. We conducted a double-blind, randomized, placebo-controlled intervention study to investigate the effect of the main green tea catechin, epigallocatechin gallate (EGCG), taken in a green tea extract, polyphenon E (PPE). Postmenopausal women (n = 103) were randomized into three arms: placebo, 400-mg EGCG as PPE, or 800-mg EGCG as PPE as capsules per day for 2 months. Urinary tea catechin and serum estrogen, androgen, lipid, glucose-related markers, adiponectin, and growth factor levels were measured at baseline and at the end of months 1 and 2 of intervention. On the basis of urinary tea catechin concentrations, compliance was excellent. Supplementation with PPE did not produce consistent patterns of changes in estradiol (E2), estrone (E1), or testosterone (T) levels. Low-density lipoprotein (LDL)-cholesterol decreased significantly in both PPE groups but was unchanged in the placebo group; the change in LDL-cholesterol differed between the placebo and PPE groups (P = 0.02). Glucose and insulin levels decreased nonsignificantly in the PPE groups but increased in the placebo group; statistically significant differences in changes in glucose (P = 0.008) and insulin (P = 0.01) were found. In summary, green tea (400- and 800-mg EGCG as PPE; ~5-10 cups) supplementation for 2 months had suggestive beneficial effects on LDL-cholesterol concentrations and glucose-related markers. PMID- 22246620 TI - Effects of energy restriction and wheel running on mammary carcinogenesis and host systemic factors in a rat model. AB - Limiting energy availability via diet or physical activity has health benefits; however, it is not known whether these interventions have similar effects on the development of cancer. Two questions were addressed as follows: (i) Does limiting energy availability by increasing physical activity have the same effect on mammary carcinogenesis as limiting caloric intake? and (ii) Are host systemic factors, implicated as risk biomarkers for breast cancer, similarly affected by these interventions? Female Sprague Dawley rats were injected with 50-mg 1-methyl 1-nitrosourea per kg body weight at 21 days of age and randomized to one of five groups (30 rats per group) as follows: (i) sham running wheel control; (ii) restricted fed to 85% of the sham control; (iii and iv) voluntary running in a motorized activity wheel (37 m/min) to a maximum of 3,500 m/d or 1,750 m/d; and (v) sedentary ad libitum fed control with no access to a running wheel. The three energetics interventions inhibited the carcinogenic response, reducing cancer incidence (P = 0.01), cancer multiplicity (P < 0.001), and cancer burden (P < 0.001) whereas prolonging cancer latency (P = 0.004) although differences among energetics interventions were not significant. Of the plasma biomarkers associated with the development of cancer, the energetics interventions reduced bioavailable insulin-like growth factor-1 (IGF-1), insulin, interleukin-6, serum amyloid protein, TNF-alpha, and leptin and increased IGF-binding protein 3 (IGFBP 3) and adiponectin. Plasma-fasting glucose, C-reactive protein, estradiol, and progesterone were unaffected. The plasma biomarkers of greatest value in predicting the carcinogenic response were adiponectin > IGF-1/IGFBP-3 > IGFBP-3 > leptin > IGF-1. PMID- 22246621 TI - Ruptured globe 20 years after radial and transverse keratotomy. AB - To report a case of corneal rupture due to blunt trauma occurring 20 years after radial keratotomy (RK) and transverse keratotomy. A 57-year-old woman sustained direct blunt trauma to her right eye. Ocular examination revealed a ruptured globe involving two of the eight RK incisions connected together across the visual axis with iris incarceration in the wound. The transverse keratotomy scars remained intact. The patient underwent primary corneal wound repair and iris repositioning. The postoperative period was uneventful. The patient had a visual acuity of counting fingers at 1 m and is awaiting penetrating keratoplasty. Traumatic rupture of RK incisions can still occur after 20 years. Patients having undergone RK many years before should be warned of a possible life-long risk of traumatic rupture. RK scars appear to be more vulnerable to rupture than astigmatic keratotomy scars. PMID- 22246622 TI - Glaucoma therapy escalation in eyes with pseudophakic corneal edema after penetrating keratoplasty and Descemet's stripping automated endothelial keratoplasty. AB - The purpose of this study was to determine and compare the prevalence of glaucoma therapy escalation (GTE) after penetrating keratoplasty (PKP) and Descemet's stripping automated endothelial keratoplasty (DSAEK) in eyes with a surgical indication of pseudophakic corneal edema. A retrospective review was conducted of the medical records of all patients who underwent PKP or DSAEK to treat pseudophakic corneal edema at a tertiary eye care center from January 1 2003 to December 31, 2006. Eyes that were treated with PKP from January 1, 2003 to December 31, 2004 and with DSAEK from January 1, 2005 to December 31, 2006 were included in the statistical analysis. Inclusion criteria included satisfactory preoperative control of intraocular pressure (IOP) and follow-up of at least 12 months. The main outcome measure was GTE, which was defined as a sustained requirement for escalation of topical medical therapy or the need to provide surgical intervention to maintain a satisfactory postoperative IOP. Among 54 eyes that met the inclusion criteria, GTE occurred in 7 (35.0%) of 20 eyes after PKP and in 14 (41.2%) of 34 eyes after DSAEK (P = 0.78) during a mean follow-up period of 27.6 and 28.6 months, respectively. Surgical escalation occurred in 2 (10.0%) eyes after PKP and 2 (5.9%) eyes after DSAEK (P = 0.62), and was associated with late-onset endothelial graft failure in all four eyes. Glaucoma therapy escalation is relatively common and occurs with comparable frequency in eyes with pseudophakic corneal edema after PKP and DSAEK. PMID- 22246623 TI - Cardiac MRI of the fetal heart using a novel triggering method: initial results in an animal model. AB - PURPOSE: To investigate MRI of the fetal heart by way of a novel triggering method with the use of an MR-compatible cardiotocography (CTG) in an animal model. MATERIALS AND METHODS: Fetal cardiac MRI was performed on four pregnant ewes on a 1.5 Tesla (T) MR system. A CTG was rendered MR compatible and its signal was used for the triggering of the fetal heart to perform cardiac cine MRI of the fetal heart with maternal free-breathing with cine steady-state free precession. The left ventricular volume and function were measured from the short axis (view). The image quality of anatomical structures was assessed. RESULTS: All cardiac valves and the foramen ovale could be visualized. Myocardial contraction was depicted in cine sequences. The average blood volume at the end systole was 1.7 mL (SD +/- 0.12). The average volume at the end diastole was 4.6 mL (+/- 0.4); thus the average stroke volumes of the left ventricle were 2.87 mL (+/- 0.31) with ejection fractions of 60.53% (+/- 4.17). CONCLUSION: The newly developed MR compatible CTG could be used as a tool for cardiac triggering method of the fetal heart. This novel device might help fetal cardiac MRI technology in the future. PMID- 22246624 TI - Single-cell network profiling of peripheral blood mononuclear cells from healthy donors reveals age- and race-associated differences in immune signaling pathway activation. AB - A greater understanding of the function of the human immune system at the single cell level in healthy individuals is critical for discerning aberrant cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-cell network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race associated variations in signaling responses in discrete cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics. PMID- 22246625 TI - Characterization of the promoter and the transcriptional regulation of the lipoxin A4 receptor (FPR2/ALX) gene in human monocytes and macrophages. AB - The lipoxin A4 receptor FPR2/ALX plays an important part in host defense and inflammation. The receptor binds structurally diverse agonistic ligands, which mainly regulate chemotaxis and activation of leukocytes. However, little is known about the promoter region of the FPR2/ALX gene and its transcriptional regulation in leukocytes. We identified two TATA-less promoter regions, separated by 224 bp, that drive the expression of FPR2/ALX in macrophages. Both promoter regions increased transcription in a reporter assay, and the basal transcription factors OCT1 and SP1 were shown to bind the first and the second promoter, respectively, and to transactivate transcription. Although monocytes expressed high levels of FPR2/ALX mRNA from the second promoter region, differentiation into macrophages abrogated FPR2/ALX expression. Stimulation of macrophages with a set of cytokines revealed that only IFN-gamma and LPS increased FPR2/ALX expression from the first promoter to levels similar to those detected in monocytes. The upregulation by IFN-gamma is in part mediated by the interaction of IFN regulatory factor 1 with an IFN-responsive sequence element transcription factor binding site located in the first promoter region of the FPR2/ALX gene. However, this upregulation on the mRNA level did not translate into FPR2/ALX protein expression in macrophages owing to reduced translation of the longer mRNA from the first promoter. In contrast, FPR2/ALX mRNA transcribed from the second promoter was translated into surface expression of FPR2/ALX in monocytes. These data support a model in which FPR2/ALX plays a role in chemotaxis and activation of monocytes; however, they also suggest that its function in resident tissue macrophages is limited. PMID- 22246626 TI - Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice. AB - We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 transgenic (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2-restricted CD8(+) T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells. Using an HHD model in which HLA-A2(neg) tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8(+) T cell repertoire, we now show that vaccines on the basis of tumor-associated blood vessel Ags (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2(neg)) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8(+) (but not CD4(+)) T cells, in a coordinate reduction of CD31(+) blood vessels in the tumor microenvironment, and in the "spreading" of CD8(+) T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or vascular endothelial cells flow-sorted from tumor tissue but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8(+), but not CD4(+), T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy. PMID- 22246627 TI - STAT1-independent control of a neurotropic measles virus challenge in primary neurons and infected mice. AB - Neurons are chiefly nonrenewable; thus, cytolytic immune strategies to clear or control neurotropic viral infections could have lasting neurologic consequences. IFN-gamma is a potent antiviral cytokine that is critical for noncytolytic clearance of multiple neurotropic viral infections, including measles virus (MV); however, the downstream pathways through which IFN-gamma functions in neurons have not been defined. Unlike most cell types studied to date in which IFN-gamma affects gene expression via rapid and robust activation of STAT1, basal STAT1 levels in primary hippocampal neurons are constitutively low, resulting in attenuated STAT1 activation and consequently slower kinetics of IFN-gamma-driven STAT1-dependent gene expression. Given this altered expression and activation of STAT1 in neurons, we sought to determine whether STAT1 was required for IFN-gamma mediated protection from infection in neurons. To do so, we evaluated the consequences of MV challenge of STAT1-deficient mice and primary hippocampal neurons explanted from these mice. Surprisingly, the absence of STAT1 did not restrict the ability of IFN-gamma to control viral infection either in vivo or ex vivo. Moreover, the canonical IFN-gamma-triggered STAT1 gene expression profile was not induced in STAT1-deficient neurons, suggesting that IFN-gamma regulates neuronal STAT1-independent pathways to control viral replication. PMID- 22246628 TI - IL-2 upregulates CD86 expression on human CD4(+) and CD8(+) T cells. AB - The glycoprotein CD86 is an important costimulatory molecule that has been shown to be predominantly expressed on APCs, such as dendritic cells, macrophages, and B cells. More recently, CD86 was also detected on T cells in specific pathological conditions. The mechanisms of how CD86 might be induced and its functional role in T cells are not well understood. In the present study, we showed that treatment with IL-2 markedly upregulated CD86, but not CD80, in human CD4(+) and CD8(+) T cells. This upregulation occurred in the absence of bystander cells, and isolated naive CD4(+) or CD8(+) T cells exhibited different time dependent CD86-expression patterns in response to IL-2. Upregulation of CD86 on activated T cells was reduced by Abs that block IL-2 and IL-2Ralpha (CD25), indicating a receptor-mediated mechanism. IL-2-dependent CD86 upregulation was blocked by pharmacological inhibitors of the NFAT and mammalian target of rapamycin pathways and was largely reduced by simultaneous exposure to IFN-alpha. Importantly, a marked increase in CD86 on T cells was also observed in vivo in IL 2-treated patients. In conclusion, IL-2 upregulates CD86 expression on human CD4(+) and CD8(+) T cells via a receptor-dependent mechanism that involves the NFAT and mammalian target of rapamycin pathways. PMID- 22246629 TI - Diverse functions of distal regulatory elements at the IFNG locus. AB - Previous studies have identified multiple conserved noncoding sequences (CNS) at the mouse Ifng locus sufficient for enhancer activity in cell-based assays. These studies do not directly address biology of the human IFNG locus in a genomic setting. IFNG enhancers may be functionally redundant or each may be functionally unique. We test the hypothesis that each IFNG enhancer has a unique necessary function using a bacterial artificial chromosome transgenic model. We find that CNS-30, CNS-4, and CNS+20 are required at distinct stages of Th1 differentiation, whereas CNS-16 has a repressive role in Th1 and Th2 cells. CNS+20 is required for IFN-gamma expression by memory Th1 cells and NKT cells. CNS-4 is required for IFN gamma expression by effector Th1 cells. In contrast, CNS-16, CNS-4, and CNS+20 are each partially required for human IFN-gamma expression by NK cells. Thus, IFNG CNS enhancers have redundant necessary functions in NK cells but unique necessary functions in Th cells. These results also demonstrate that distinct CNSs are required to transcribe IFNG at each stage of the Th1 differentiation pathway. PMID- 22246630 TI - Caspase-4 is required for activation of inflammasomes. AB - IL-1beta and IL-18 are crucial regulators of inflammation and immunity. Both cytokines are initially expressed as inactive precursors, which require processing by the protease caspase-1 for biological activity. Caspase-1 itself is activated in different innate immune complexes called inflammasomes. In addition, caspase-1 activity regulates unconventional protein secretion of many other proteins involved in inflammation and repair. Human caspase-4 is a poorly characterized member of the caspase family, which is supposed to be involved in endoplasmic reticulum stress-induced apoptosis. However, its gene is located on the same locus as the caspase-1 gene, which raises the possibility that caspase-4 plays a role in inflammation. In this study, we show that caspase-4 expression is required for UVB-induced activation of proIL-1beta and for unconventional protein secretion by skin-derived keratinocytes. These processes require expression of the nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 inflammasome, and caspase-4 physically interacts with its central molecule caspase-1. As the active site of caspase-4 is required for activation of caspase-1, the latter most likely represents a substrate of caspase-4. Caspase-4 expression is also essential for efficient nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 and for absent in melanoma 2 inflammasome-dependent proIL-1beta activation in macrophages. These results demonstrate an important role of caspase-4 in inflammation and innate immunity through activation of caspase-1. Therefore, caspase-4 represents a novel target for the treatment of (auto)inflammatory diseases. PMID- 22246631 TI - Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors. AB - Aging is associated with suboptimal CD8 T cell responses to viral infections. It is not clear whether these poor responses are due to environmental influences or quantitative and qualitative changes in the pool of responding CD8 T cells. Our studies demonstrated several deleterious age-related changes in the pool of Ag specific CD8 T cells that respond to infection. The majority of CD8 T cells from uninfected aged mice was CD44(Hi) and had increased expression of inhibitory receptors including PD1, LAG3, 2B4, and CD160. These aged CD44(Hi) CD8 T cells were transcriptionally similar to exhausted CD8 T cells found during chronic infections. In addition, the number of virus-specific precursors in aged mice prior to infection was decreased up to 10-fold, and many of these Ag-specific precursors had high expression of CD44 and PD1. Finally, TCR transgenic studies demonstrated that the CD44(Hi) Ag-specific CD8 T cells from unimmunized aged and young mice were qualitatively inferior compared with CD44(Lo) CD8 T cells from aged or young donors. Thus, a decrease in precursor frequency as well as qualitative changes of CD8 T cells during aging are directly related to impaired immunity. PMID- 22246632 TI - Decoupling the effects of surface chemistry and humidity on solid-state hydrolysis of aspirin in the presence of dicalcium phosphate dihydrate. AB - Atomic force microscopy (AFM) cantilevers were functionalized with particles of dicalcium phosphate dihydrate (DCP), and AFM, in force-displacement mode, was used to bring these probes into contact with aspirin (100) and (001) surfaces in order to investigate the effect of aspirin surface chemistry on the interaction between the two materials as a function of relative humidity (RH). The force of adhesion measurements showed a strong dependence on RH for the interactions between DCP and the aspirin (100) surface, with stronger interactions occurring at higher humudities. Relatively much weaker interactions were measured between DCP and the aspirin (001) surface under all RH conditions. Topographic imaging showed that contact between DCP and the aspirin (100) surface at high RH led to localised development of etch pits and, in some cases, growth normal to the surface. The methodology allows for the creation of a localised solid-solid interface between pharmaceutically relevant materials, providing a means of studying solid-state excipient-active ingredient decomposition reactions. PMID- 22246633 TI - Spinal interleukin-6 is an amplifier of arthritic pain in the rat. AB - OBJECTIVE: Significant joint pain is usually widespread beyond the affected joint, which results from the sensitization of nociceptive neurons in the central nervous system (central sensitization). This study was undertaken to explore whether the proinflammatory cytokine interleukin-6 (IL-6) in the joint induces central sensitization, whether joint inflammation causes the release of IL-6 from the spinal cord, and whether spinal IL-6 contributes to central sensitization. METHODS: In anesthetized rats, electrophysiologic recordings of spinal cord neurons with sensory input from the knee joint were made. Neuronal responses to mechanical stimulation of the rat knee and leg were monitored. IL-6 and soluble IL-6 receptor (sIL-6R) were applied to the knee joint or the spinal cord. Spinal release of IL-6 was measured by enzyme-linked immunosorbent assay. Soluble gp130, which neutralizes IL-6/sIL-6R, was spinally applied during the development of joint inflammation or during established inflammation. RESULTS: A single injection of IL-6/sIL-6R into the rat knee joint as well as application of IL 6/sIL-6R to the rat spinal cord significantly increased the responses of spinal neurons to mechanical stimulation of the knee and ankle joint, i.e., induced central sensitization. Application of soluble gp130 to the rat spinal cord attenuated this effect of IL-6. The development of knee inflammation in the rat caused spinal release of IL-6. Spinal application of soluble gp130 attenuated the development of inflammation-evoked central sensitization but did not reverse it. CONCLUSION: Our findings indicate that the generation of joint pain in the rat involves not only IL-6 in the joint but also IL-6 released from the spinal cord. Spinal IL-6 contributes to central sensitization and thus promotes the widespread hyperalgesia observed in the course of joint disease. PMID- 22246634 TI - Tipping points in the arctic: eyeballing or statistical significance? AB - Arctic ecosystems have experienced and are projected to experience continued large increases in temperature and declines in sea ice cover. It has been hypothesized that small changes in ecosystem drivers can fundamentally alter ecosystem functioning, and that this might be particularly pronounced for Arctic ecosystems. We present a suite of simple statistical analyses to identify changes in the statistical properties of data, emphasizing that changes in the standard error should be considered in addition to changes in mean properties. The methods are exemplified using sea ice extent, and suggest that the loss rate of sea ice accelerated by factor of ~5 in 1996, as reported in other studies, but increases in random fluctuations, as an early warning signal, were observed already in 1990. We recommend to employ the proposed methods more systematically for analyzing tipping points to document effects of climate change in the Arctic. PMID- 22246635 TI - The effects of hypoxia on sediment nitrogen cycling in the Baltic Sea. AB - Primary production in the eutrophic Baltic Sea is limited by nitrogen availability; hence denitrification (natural transformation of nitrate to gaseous N(2)) in the sediments is crucial in mitigating the effects of eutrophication. This study shows that dissimilatory nitrate reduction to ammonium (DNRA) process, where nitrogen is not removed but instead recycled in the system, dominates nitrate reduction in low oxygen conditions (O(2) <110 MUM), which have been persistent in the central Gulf of Finland during the past decade. The nitrogen removal rates measured in this study show that nitrogen removal has decreased in the Gulf of Finland compared to rates measured in mid-1990s and the decrease is most likely caused by the increased bottom water hypoxia. PMID- 22246636 TI - Electrospun hierarchical LiV3O8 nanofibers assembled from nanosheets with exposed {100} facets and their enhanced performance in aqueous lithium-ion batteries. AB - Hierarchical LiV(3)O(8) nanofibers, assembled from nanosheets that have exposed {100} facets, have been fabricated by using electrospinning combined with calcination. The formation mechanism of hierarchical nanofibers was investigated by X-ray diffraction and scanning electron microscopy. Poly(vinyl alcohol) (PVA) played a dual role in the formation of the nanofibers: besides acting as the template for forming the fibers, it effectively prevented the aggregation of LiV(3)O(8) nanoparticles, thereby allowing them to grow into small nanosheets with exposed {100} facets owing to the self-limitation property of LiV(3)O(8). This nanostructure is beneficial for the insertion/extraction of lithium ions. Meanwhile, the {100} facets have fewer and smaller channels, which may effectively alleviate proton co-intercalation into the electrode materials. Hence, the hierarchical LiV(3)O(8) nanofibers exhibit higher discharge capacities and better cycling stabilities as the anode electrode material for aqueous lithium-ion batteries than those reported previously. We demonstrate that these hierarchical nanofibers have promising potential applications in aqueous lithium ion batteries. PMID- 22246637 TI - Triggered gene expression in fed-vesicle microreactors with a multifunctional membrane. PMID- 22246638 TI - Unraveling the resistance of microbial biofilms: has proteomics been helpful? AB - Biofilms are surface-attached, matrix-encased, structured microbial communities which display phenotypic features that are dramatically different from those of their free-floating, or planktonic, counterparts. Biofilms seem to be the preferred mode of growth of microorganisms in nature, and at least 65% of all human infections are associated with biofilms. The most notable and clinically relevant property of biofilms is their greater resistance to antimicrobials compared with their planktonic counterparts. Although both bacterial and fungal biofilms display this phenotypic feature, the exact mechanisms underlying their increased drug resistance are yet to be determined. Advances in proteomics techniques during the past decade have facilitated in-depth analysis of the possible mechanisms underpinning increased drug resistance in biofilms. These studies have demonstrated the ability of proteomics techniques to unravel new targets for combating microbial biofilms. In this review, we discuss the putative drug resistance mechanisms of microbial biofilms that have been uncovered by proteomics and critically evaluate the possible contribution of the new knowledge to future development in the field. We also summarize strategic uses of novel proteomics technologies in studies related to drug resistance mechanisms of microbial biofilms. PMID- 22246639 TI - Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. AB - The TNF-R1 like receptor Fas is highly expressed on the plasma membrane of hepatocytes and plays an essential role in liver homeostasis. We recently showed that in collagen-cultured primary mouse hepatocytes, Fas stimulation triggers apoptosis via the so-called type I extrinsic signaling pathway. Central to this pathway is the direct caspase-8-mediated cleavage and activation of caspase-3 as compared to the type II pathway which first requires caspase-8-mediated Bid cleavage to trigger mitochondrial cytochrome c release for caspase-3 activation. Mathematical modeling can be used to understand complex signaling systems such as crosstalks and feedback or feedforward loops. A previously published model predicted a positive feedback loop between active caspases-3 and -8 in both type I and type II FasL signaling in lymphocytes and Hela cells, respectively. Here we experimentally tested this hypothesis in our hepatocytic type I Fas signaling pathway by using wild-type and XIAP-deficient primary hepatocytes and two recently characterized, selective caspase-3/-7 inhibitors (AB06 and AB13). Caspase-3/-7 activity assays and quantitative western blotting confirmed that fully processed, active p17 caspase-3 feeds back on caspase-8 by cleaving its partially processed p43 form into the fully processed p18 species. Our data do not discriminate if p18 positively or negatively influences FasL-induced apoptosis or is responsible for non-apoptotic aspects of FasL signaling. However, we found that caspase-3 also feeds back on Bid and degrades its own inhibitor XIAP, both events that may enhance caspase-3 activity and apoptosis. Thus, potent, selective caspase-3 inhibitors are useful tools to understand complex signaling circuitries in apoptosis. PMID- 22246640 TI - RETRACTED ARTICLE: Application of corn tassel for the removal of malachite green dye from aqueous solution. PMID- 22246641 TI - Aquatic photochemistry of paracetamol in the presence of dissolved organic chromophoric material and nitrate. AB - PURPOSE: This study contains some new findings connected to the photolysis of the drug paracetamol (hereinafter APAP) especially in light of estimating natural conditions, and it will offer information to better evaluate environmental problems connected with this widely used analgesic agent. Only a few studies, so far, have focussed on the photodegradation process of APAP in the natural environment, and the question about the role of the colored/chromophoric dissolved organic matter (CDOM) and nitrate (NO3-) as photoinductors is almost open. METHODS: APAP dissolved in freshwater and pure laboratory water in the presence and absence of CDOM and NO3- ions was irradiated using weak-energy photon energies simulating natural conditions. RESULTS: CDOM and NO3- as photoinductors produced only the slow phototransformation of APAP under weak energy radiation, and APAP seemed to be practically resistant to direct photolysis under weak radiant energies available in natural conditions. The estimated reaction efficiencies, in addition to half-lives, speak for that NO3- and CDOM do not act as quite independent photoinductors but their effect in conjunction (CDOM-NO3- -water) is stronger than the separate ones. The principal phototransformation intermediates of APAP were mono-hydroxy derivatives, depending on available photon energies formed via ortho- or meta-hydroxylation, possessing substantial power of resistance to further specific transformation reactions. CONCLUSIONS: The estimated half-life of the phototransformation of APAP in the natural aqueous environment and in the presence of suitable photoinductors will be about 30 days or more. PMID- 22246642 TI - Synthesis, properties and application research of atrazine Fe3O4@SiO2 magnetic molecularly imprinted polymer. AB - INTRODUCTION: Magnetic Fe3O4 nanoparticles were prepared by coprecipitation and then were coated with SiO2 on the surface. MATERIALS AND METHODS: Fe3O4@SiO2 composite microspheres were modified by KH570. Using molecular imprinting technology, atrazine magnetic molecularly imprinted polymer was prepared by using atrazine as template molecule, methacrylic acid as functional monomer and ethylene glycol dimethacrylate as cross-linkers. The morphology, composition and magnetic properties of magnetic nanoparticles were characterized. The recognition selectivity of polymer was studied for template molecule and simulation by UV spectrophotometry. The adsorption properties and selectivity ability were analyzed by Scatchard analysis. RESULTS: Scatchard linear regression analysis indicated that there are two binding sites of the target molecules. The magnetic molecularly imprinted polymer has been applied to the analysis of atrazine in real samples. CONCLUSION: The results show that: the recovery rates and the relative standard deviation were 94.0~98.7% and 2.1~4.0% in corn, the recovery rates and the relative standard deviation were 88.7~93.5% and 2.8~7.2% in water. PMID- 22246643 TI - A time-course study of immune response in Japanese flounder Paralichthys olivaceus exposed to heavy oil. AB - PURPOSE: The immunotoxicities of oil and its components on fish immunities have been investigated, but there is little literature on the recovery of the fish from the immune suppression. Therefore, the recovery of Japanese flounder Paralichthys olivaceus from an immunosuppressive effect due to heavy oil (HO) exposure was investigated in this study. METHODS: Fish were exposed to HO at a concentration of 0.385 g/L for 2 days, while control fish received no exposure. Seven fish were sampled at 0, 3, 7, and 14 days post-exposure. The respiratory rate was measured everyday as an indicator of the acute effect of HO exposure. Fish serum was collected and used for antibacterial activity assay against Edwardsiella tarda. Expression changes of respiratory and immune-related genes were evaluated by real-time PCR. RESULTS AND DISCUSSION: The respiratory rate was significantly increased in the HO-exposed group until 4 days post-exposure. A respiratory-related gene, beta-hemoglobin, was also significantly downregulated in the spleen both at 0 and 7 days post-exposure and kidney at 3 days post exposure in HO-exposed fish. Immunotoxicity, including suppression of antibacterial activities and downregulation of the IgM gene, was observed in HO exposed fish until 3 days post-exposure, but not after that time. From these results, we conclude that the fish likely return to normal status around 1 week. PMID- 22246644 TI - Predictors of outcome after surgery with disc prosthesis and rehabilitation in patients with chronic low back pain and degenerative disc: 2-year follow-up. AB - PURPOSE: A prospective study to evaluate whether certain baseline characteristics can predict outcome in patients treated with disc prosthesis or multidisciplinary rehabilitation. METHODS: Secondary analysis of 154 patients with chronic low back pain (LBP) for at least 1 year and degenerative discs originally recruited for a randomized trial. Outcome measures were Oswestry Disability Index (ODI) dichotomized to < or >=15 points improvement and whether subjects were working at 2-year follow-up. A multiple logistic regression analysis was used. RESULTS: In patients treated with disc prosthesis, long duration of LBP and high Fear Avoidance Beliefs for work (FABQ-W) predicted worse ODI outcome [odds ratio (OR) = 1.9, 95% confidence interval (CI) 1.2-3.2 and OR = 1.7, CI 1.2-2.4 for every 5 years or 5 points]. Modic type I or II predicted better ODI outcome (OR = 5.3, CI 1.1-25.3). In patients treated with rehabilitation, a high ODI, low emotional distress (HSCL-25), and no daily narcotics predicted better outcome for ODI (OR = 2.5, CI 1.4-4.5 for every 5 ODI points, OR = 2.1, CI 1.1-5.1 for every 0.5 HSCL points and OR = 23.6, CI 2.1-266.8 for no daily narcotics). Low FABQ-W and working at baseline predicted working at 2-year follow-up after both treatments (OR = 1.3, CI 1.0-1.5 for every 5 points and OR = 4.1, CI 1.2-13.2, respectively). CONCLUSIONS: Shorter duration of LBP, Modic type I or II changes and low FABQ-W were the best predictors of success after treatment with disc prosthesis, while high ODI, low distress and not using narcotics daily predicted better outcome of rehabilitation. Low FABQ-W and working predicted working at follow-up. PMID- 22246646 TI - ARFI-prepared MRgHIFU in liver: simultaneous mapping of ARFI-displacement and temperature elevation, using a fast GRE-EPI sequence. AB - MR acoustic radiation force imaging (ARFI) is an elegant adjunct to MR-guided high intensity focused ultrasound for treatment planning and optimization, permitting in situ assessment of the focusing and targeting quality. The thermal effect of high intensity focused ultrasound pulses associated with ARFI measurements is recommended to be monitored on line, in particular when the beam crosses highly absorbent structures or interfaces (e.g., bones or air-filled cavities). A dedicated MR sequence is proposed here, derived from a segmented gradient echo-echo planar imaging kernel by adding a bipolar motion encoding gradient with interleaved alternating polarities. Temporal resolution was reduced to 2.1 s, with in-plane spatial resolution of 1 mm. MR-ARFI measurements were executed during controlled animal breathing, with trans-costal successively steered foci, to investigate the spatial modulation of the focus intensity and the targeting offset. ARFI-induced tissue displacement measurements enabled the accurate localization, in vivo, of the high intensity focused ultrasound focal point in sheep liver, with simultaneous monitoring of the temperature elevation. ARFI-based precalibration of the focal point position was immediately followed by trans-costal MR-guided high intensity focused ultrasound ablation, monitored with a conventional proton resonance frequency shift MR thermometry sequence. The latter MR thermometry sequence had spatial resolution and geometrical distortion identical with the ARFI maps, hence no coregistration was required. PMID- 22246645 TI - The behavioral phenotype of Mowat-Wilson syndrome. AB - Mowat-Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of the ZEB2 gene. It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. The current study investigated the behavioral phenotype of MWS. Parents and carers of 61 individuals with MWS completed the Developmental Behavior Checklist. Data were compared with those for individuals selected from an epidemiological sample of people with ID from other causes. The behaviors associated with MWS included a high rate of oral behaviors, an increased rate of repetitive behaviors, and an under-reaction to pain. Other aspects of the MWS behavioral phenotype are suggestive of a happy affect and sociable demeanor. Despite this, those with MWS displayed similarly high levels of behavioral problems as those with intellectual disabilities from other causes, with over 30% showing clinically significant levels of behavioral or emotional disturbance. These findings have the potential to expand our knowledge of the role of the ZEB2 gene during neurodevelopment. Furthermore, they are a foundation for informing interventions and management options to enhance the independence and quality of life for persons with MWS. PMID- 22246647 TI - T2-weighted and diffusion-weighted MRI for discriminating benign from malignant focal liver lesions: diagnostic abilities of single versus combined interpretations. AB - PURPOSE: To compare the diagnostic accuracies of diffusion-weighted imaging (DWI), T2-weighted imaging (T2WI), and the combination of both sequences in discriminating benign from malignant focal liver lesions (FLLs). MATERIALS AND METHODS: In all, 166 patients with 269 FLLs (153 benign and 116 malignant) were retrospectively evaluated. Two abdominal readers visually assessed the DWI, T2WI, and the combined (DWI+T2WI) image sets in an independent and blinded manner. The diagnostic abilities of each image set in discriminating the benign from the malignant FLLs set were compared using a binary logistic regression model. Pathologic results, consensus reading, and follow-up imaging were used as the reference standard. RESULTS: The overall characterization accuracy in all lesions of the combined set (80.3%) was significantly higher than those of the T2WI set (68.8%) and DWI set (73.2%) (combined vs. T2WI, P < 0.001; combined vs. DWI, P = 0.001), while there was no significant difference between the T2WI and DWI sets (P = 0.058). All image sets were more accurate in the characterization of malignant FLLs than of benign FLLs (P < 0.001). CONCLUSION: T2WI and DWI are complementary in discriminating benign from malignant FLLs; their combination improves diagnostic confidence. PMID- 22246648 TI - Biomolecular chemistry of isopropyl fibrates. AB - Isopropyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid and isopropyl 2 (4-chlorophenoxy)-2-methylpropanoate, also known as fenofibrate and isopropyl (iPr) clofibrate, are hypolipidemic agents of the fibrate family. In a previously reported triclinic structure of fenofibrate (polymorph I), the methyl groups of the iPr moiety are located symmetrically about the carboxylate group. We report a new monoclinic form (polymorph II) of fenofibrate and a first structural description of iPr clofibrate, and in these the methyl groups are placed asymmetrically about the carboxylate group. In particular, the dihedral (torsion) angle between the hydrogen atom on the secondary C and the C atom of the carboxyl group makes a 2.74 degrees angle about the ester O...C bond in the symmetric fenofibrate structure of polymorph I, whereas the same dihedral angle is 45.94 degrees in polymorph II and -30.9 degrees in the crystal structure of iPr clofibrate. Gas-phase density functional theory (DFT) geometry minimizations of fenofibrate and iPr clofibrate result in lowest energy conformations for both molecules with a value of about +/-30 degrees for this same angle between the O?C-O-C plane and the C-H bond of the iPr group. A survey of crystal structures containing an iPr ester group reveals that the asymmetric conformation is predominant. Although the hydrogen atom on the secondary C atom of the iPr group is located at a comparable distance from the carbonyl oxygen in the symmetric and asymmetric fenofibrate (2.52 and 2.28 A) and the iPr clofibrate (2.36 A) structures, this hydrogen atom participates in a puckered five-membered ring arrangement in the latter two that is unlike the planar arrangement found in symmetric fenofibrate (polymorph I). Polar molecular surface area values indicate fenofibrate and iPr clofibrate are less able to act as acceptors of hydrogen bonds than their corresponding acid derivatives. Surface area calculations show that dynamic polar molecular surface area values of the iPr esters of the fibrates are lower than those of their acids, implying that the fibrates have better membrane permeability and a higher absorbability and hence are better prodrugs when these agents need to be orally administered. PMID- 22246650 TI - Ditopic receptors based on lower- and upper-rim substituted hexahomotrioxacalix[3]arenes: cation-controlled hydrogen bonding of anion. AB - Heteroditopic hexahomotrioxacalix[3]arene receptors that are capable of binding an anion and a cation simultaneously in a cooperative fashion were synthesized. The structure of one of the triamide derivatives was confirmed by single-crystal X-ray diffraction. The binding of alkali metals at the lower rim, and the binding of anions (chloride, bromide) at the upper rim, has been investigated by using (1)H NMR titration experiments. Alkali metal binding at the lower rim controls the calix cavity. Li(+)-ion binding to the lower rim can improve the binding ability of anions at the upper rim amide moiety by a factor of 15, thus suggesting a strong positive allosteric effect for anion recognition. However, when a Na(+) cation is bound to the ionophoric site on the lower rim, the calix cavity is changed from a "flattened cone" to a more-upright form, which is favored for intramolecular hydrogen bonding between the neighboring NH and C=O groups; this change can block the inclusion of anions onto the amide moiety at the upper rim, which strongly suggests a negative allosteric effect of Na(+)-ion binding, which controls the cooperative recognition system. PMID- 22246649 TI - Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint. AB - OBJECTIVE: Many forms of arthritis are accompanied by significant chronic joint pain. This study was undertaken to investigate whether there is significant sprouting of sensory and sympathetic nerve fibers in the painful arthritic knee joint and whether nerve growth factor (NGF) drives this pathologic reorganization. METHODS: A painful arthritic knee joint was produced by injection of Freund's complete adjuvant (CFA) into the knee joint of young adult mice. CFA injected mice were then treated systemically with vehicle or anti-NGF antibody. Pain behaviors were assessed, and at 28 days following the initial CFA injection, the knee joints were processed for immunohistochemistry analysis using antibodies against calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kd (NF200; sensory nerve fibers), growth-associated protein 43 (GAP-43; sprouted nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), CD31 (endothelial cells), or CD68 (monocyte/macrophages). RESULTS: In CFA-injected mice, there was a significant increase in the density of CD68+ macrophages, CD31+ blood vessels, and CGRP+, NF200+, GAP-43+, and TH+ nerve fibers in the synovium, as well as a significant increase in joint pain-related behaviors. None of these findings were observed in sham-injected mice. Administration of anti-NGF reduced these pain-related behaviors and the ectopic sprouting of nerve fibers, but had no significant effect on the increase in density of CD31+ blood vessels or CD68+ macrophages. CONCLUSION: These findings demonstrate that ectopic sprouting of sensory and sympathetic nerve fibers occurs in the painful arthritic joint and may be involved in the generation and maintenance of arthritic pain. PMID- 22246651 TI - Heterotopic spleen within the gastric wall mimicking a GIST: report of a case. PMID- 22246652 TI - Post-genomics of bone metabolic dysfunctions and neoplasias. AB - Post-genomic research on osteoblastic and osteoclastic cells, in contrast to that on many other cell types, has only been undertaken recently. Nevertheless, important information has been gained from these investigations on the mechanisms involved in osteoblast differentiation and on markers relevant for tissue regeneration and therapeutic validation of drugs, hormones and growth factors. These protein indicators may also have a diagnostic and prognostic value for bone dysfunctions and tumors. Some reviews have already focused on the application of transcriptomics and/or proteomics for exploring skeletal biology and related disorders. The main goal of the present review is to systematically summarize the most relevant post-genomic studies on various metabolic bone diseases (osteoporosis, Paget's disease and osteonecrosis), neoplasias (osteosarcoma) and metabolic conditions that indirectly affect bone tissue, such as alkaptonuria. PMID- 22246653 TI - Flexible optics: recent developments in molecular gels. PMID- 22246655 TI - Keyhole chemical exchange saturation transfer. AB - The keyhole technique, which involves the acquisition of dynamic data at low resolution in combination with a high-resolution reference, is developed for the purposes of chemical exchange saturation transfer (CEST) imaging, i.e., Keyhole CEST. Low-resolution data are acquired with saturation applied at different frequencies for Z-spectra, along with a high-resolution reference image taken without saturation. Three methods for high-resolution reconstruction of Keyhole CEST are evaluated using the values from quantitative high-resolution CEST maps. In addition, Keyhole CEST is applied for collection of data used for B(0) correction. The keyhole approach is evaluated for CEST contrast generation using exchanging protons in hydroxyl groups. First, the techniques are evaluated in vitro using samples of dextrose and chondroitin sulfate. Next, the work is extended in vivo to explore its applicability for gagCEST. Comparable quantitative gagCEST values are found using Keyhole CEST, provided the structure or region of interest is not limited by the low-resolution dataset. PMID- 22246654 TI - Treatment and outcomes for anxiety disorders among children and adolescents: a review of coping strategies and parental behaviors. AB - This article reviews the current literature on the treatment of anxiety disorders in children and adolescents and describes the factors that are essential to address in treatment. Coping deficits and parental behaviors are highlighted as factors that contribute to anxiety in youth. Interventions for anxious youth are described, with particular emphasis on cognitive-behavioral therapy for anxiety disorders. Finally, a review of the longitudinal course of anxiety and suggestions for future directions in treatment and research are provided. PMID- 22246656 TI - A faith-based prescription for the Surgeon General: challenges and recommendations. AB - This article summarizes how the Office of the Surgeon General can leverage faith based resources to fulfill its mission and that of the Surgeon General of the United States. Such resources, personal and institutional, have been utilized historically in health promotion and disease prevention efforts and are a valuable ally for public health, an alliance that continues under the Obama Administration. This paper outlines the history and mission of the Office; details the recent history of federal faith-based initiatives; and advocates an expanded alliance between the faith-based and public health sectors sensitive to legal and professional boundaries. PMID- 22246657 TI - Aggregation and pH-temperature phase behavior for aggregates of an IgG2 antibody. AB - Monomer unfolding and thermally accelerated aggregation kinetics to produce soluble oligomers or insoluble macroscopic aggregates were characterized as a function of pH for an IgG2 antibody using differential scanning calorimetry (DSC) and size-exclusion chromatography (SEC). Aggregate size was quantified via laser light scattering, and aggregate solubility via turbidity and visual inspection. Interestingly, nonnative oligomers were soluble at pH 5.5 above approximately 15 degrees C, but converted reversibly to visible/insoluble particles at lower temperatures. Lower pH values yielded only soluble aggregates, whereas higher pH resulted in insoluble aggregates, regardless of the solution temperature. Unlike the growing body of literature that supports the three-endotherm model of IgG1 unfolding in DSC, the results here also illustrate limitations of that model for other monoclonal antibodies. Comparison of DSC with monomer loss (via SEC) from samples during thermal scanning indicates that the least conformationally stable domain is not the most aggregation prone, and that a number of the domains remain intact within the constituent monomers of the resulting aggregates. This highlights continued challenges with predicting a priori which domain(s) or thermal transition(s) is(are) most relevant for product stability with respect to aggregation. PMID- 22246658 TI - Flexible and platinum-free dye-sensitized solar cells with conducting-polymer coated graphene counter electrodes. PMID- 22246659 TI - Dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2. AB - Fibrochondrogenesis is a severe, recessively inherited skeletal dysplasia shown to result from mutations in the gene encoding the proalpha1(XI) chain of type XI collagen, COL11A1. The first of two cases reported here was the affected offspring of first cousins and sequence analysis excluded mutations in COL11A1. Consequently, whole-genome SNP genotyping was performed to identify blocks of homozygosity, identical-by-descent, wherein the disease locus would reside. COL11A1 was not within a region of homozygosity, further excluding it as the disease locus, but the gene encoding the proalpha2(XI) chain of type XI collagen, COL11A2, was located within a large region of homozygosity. Sequence analysis identified homozygosity for a splice donor mutation in intron 18. Exon trapping demonstrated that the mutation resulted in skipping of exon 18 and predicted deletion of 18 amino acids from the triple helical domain of the protein. In the second case, heterozygosity for a de novo 9 bp deletion in exon 40 of COL11A2 was identified, indicating that there are autosomal dominant forms of fibrochondrogenesis. These findings thus demonstrate that fibrochondrogenesis can result from either recessively or dominantly inherited mutations in COL11A2. PMID- 22246660 TI - A culturally adapted telecommunication system to improve physical activity, diet quality, and medication adherence among hypertensive African-Americans: a randomized controlled trial. AB - BACKGROUND: Hypertension is more prevalent and clinically severe among African Americans than whites. Several health behaviors influence blood pressure (BP) control, but effective, accessible, culturally sensitive interventions that target multiple behaviors are lacking. PURPOSE: We evaluated a culturally adapted, automated telephone system to help hypertensive, urban African-American adults improve their adherence to their antihypertensive medication regimen and to evidence-based guidelines for dietary behavior and physical activity. METHODS: We randomized 337 hypertensive primary care patients to an 8-month automated, multi-behavior intervention or to an education-only control. Medication adherence, diet, physical activity, and BP were assessed at baseline and every 4 months for 1 year. Data were analyzed using longitudinal modeling. RESULTS: The intervention was associated with improvements in a measure of overall diet quality (+3.5 points, p < 0.03) and in energy expenditure (+80 kcal/day, p < 0.03). A decrease in systolic BP between groups was not statistically significant (-2.3 mmHg, p = 0.25). CONCLUSIONS: Given their convenience, scalability, and ability to deliver tailored messages, automated telecommunications systems can promote self-management of diet and energy balance in urban African-Americans. PMID- 22246662 TI - The Toll of a TLR1 polymorphism in lyme disease: a tale of mice and men. PMID- 22246661 TI - The rice Osmyb4 gene enhances tolerance to frost and improves germination under unfavourable conditions in transgenic barley plants. AB - The Osmyb4 rice gene, coding for a transcription factor, proved to be efficient against different abiotic stresses as a trans(cis)gene in several plant species, although the effectiveness was dependent on the host genomic background. Eight barley transgenic lines carrying the rice Osmyb4 gene under the control of the Arabidopsis cold inducible promoter cor15a were produced to test the efficiency of this gene in barley. After a preliminary test, the best performing lines were subjected to freezing at -11 degrees C and -12 degrees C. Frost tolerance was assessed measured the F(v)/F(m) parameter widely used to indicate the maximum quantum yield of photosystem II photochemistry in the dark adapted state. Three transgenic lines showed significantly increased tolerance. These selected lines were further studied under a complex stress applying cold and hypoxia at germinating stage. In these conditions the three selected transgenic lines outperformed the wild type barley in terms of germination vigour. The transgenic plants also showed a significant modification of their metabolism under cold/hypoxia conditions as demonstrated through the assessment of the activity of key enzymes involved in anoxic stress response. None of the transgenic lines showed dwarfism, just a slight retarded growth. These results provide evidence that the cold dependent expression of Osmyb4 can efficiently improved frost tolerance and germination vigour at low temperature without deleterious effect on plant growth. PMID- 22246663 TI - Proteomics and plant disease: advances in combating a major threat to the global food supply. AB - The study of plant disease and immunity is benefiting tremendously from proteomics. Parallel streams of research from model systems, from pathogens in vitro and from the relevant pathogen-crop interactions themselves have begun to reveal a model of how plants succumb to invading pathogens and how they defend themselves without the benefit of a circulating immune system. In this review, we discuss the contribution of proteomics to these advances, drawing mainly on examples from crop-fungus interactions, from Arabidopsis-bacteria interactions, from elicitor-based model systems and from pathogen studies, to highlight also the important contribution of non-crop systems to advancing crop protection. PMID- 22246664 TI - Protective effect of Melothria maderaspatana leaf fraction on electrolytes, catecholamines, endothelial nitric oxide synthase and endothelin-1 peptide in uninephrectomized deoxycorticosterone acetate-salt hypertensive rats. AB - This study was designed to investigate the protective effect of ethyl acetate fraction of Melothria maderaspatana (EAFM) leaf on electrolytes, catecholamines, endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) peptide in uninephrectomized deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Administration of DOCA-salt significantly increased the systolic and diastolic blood pressure and treatment with EAFM significantly lowered the blood pressure. In DOCA-salt rats, the levels of sodium and chloride increased significantly while potassium level decreased and administration of EAFM brought these parameters to normality. The levels of epinephrine and norepinephrine increased significantly in DOCA-salt rats and administration of EAFM significantly decreased these parameters to normality. DOCA-salt hypertensive rats exhibited significantly decreased L: -arginine and nitrite + nitrate levels and administration of EAFM brought these parameters to normality. DOA-salt hypertensive rats showed down-regulation of eNOS and up-regulation of ET-1 protein expressions in heart and kidney, and treatment with EAFM prevented down regulation of eNOS and significantly down-regulated the ET-1 protein expressions. In conclusion, EAFM provides good blood pressure control by enhancing potassium and decreasing sodium levels, decreasing levels of epinephrine and norepinephrine, and preventing down-regulation of eNOS and significantly down regulating ET-1 protein expression. PMID- 22246665 TI - Two new triterpenoid saponins from Caragana microphylla seeds. AB - Two new triterpenoid saponins, caraganins A and B (1 and 2), structurally characterized by a 22-oxo group, were isolated from the seeds of Caragana microphylla Lam., together with their n-butyl esters as artifacts (1a and 2a). Their structures and configurations were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. Compounds 1a and 2a exhibited potent antibacterial activity against Staphylococcus aureus and Bacillus subtilis with minimum inhibitory concentration values ranging from 3.125 to 6.25 MUg/ml. PMID- 22246666 TI - International round-robin study on the Ames fluctuation test. AB - An international round-robin study on the Ames fluctuation test [ISO 11350, 2012], a microplate version of the classic plate-incorporation method for the detection of mutagenicity in water, wastewater and chemicals was performed by 18 laboratories from seven countries. Such a round-robin study is a precondition for both the finalization of the ISO standardization process and a possible regulatory implementation in water legislation. The laboratories tested four water samples (spiked/nonspiked) and two chemical mixtures with and without supplementation of a S9-mix. Validity criteria (acceptable spontaneous and positive control-induced mutation counts) were fulfilled by 92-100%, depending on the test conditions. A two-step method for statistical evaluation of the test results is proposed and assessed in terms of specificity and sensitivity. The data were first subjected to powerful analysis of variance (ANOVA) after an arcsine-square-root transformation to detect significant differences between the test samples and the negative control (NC). A threshold (TH) value based on a pooled NC was then calculated to exclude false positive test results. Statistically, positive effects observed by the William's test were considered negative, if the mean of all replicates of a sample did not exceed the calculated TH. By making use of this approach, the overall test sensitivity was 100%, and the test specificity ranged from 80 to 100%. PMID- 22246667 TI - Does the amplatzer septal occluder device alter ventricular contraction pattern? A ventricular motion analysis by MR tagging. AB - PURPOSE: To assess by cardiovascular magnetic resonance (CMR) and CMR tagging if the Amplatzer Septal Occluder affects right ventricular (RV) and left ventricular (LV) motion pattern. MATERIALS AND METHODS: Sixteen consecutive patients with significant atrial septal defect (ASD) and nine consecutive patients with persistent foramen ovale (PFO) as controls were studied before and a median of 14 days after defect closure by an Amplatzer occluder. By CMR end-diastolic (EDV) and end-systolic (ESV) RV and LV volumes were determined. Aortic and pulmonary artery flow was measured for assessment of left-to-right shunt (Qp/Qs). By CMR tagging circumferential strain and radial shortening, maximal rotation and torsion were measured, RESULTS: In ASD patients RV-EDV and RV-ESV decreased (P < 0.05). LV-EDV and LV-ESV increased after ASD closure (P < 0.005). Qp/Qs dropped from 1.8 to 1.0 (P < 0.001). PFO patients showed no ventricular volume change after PFO closure. In ASD patients circumferential strain and radial shortening and maximal rotation of the RV decreased by ASD closure (P < 0.01). In LV only maximal rotation at the base and apex decreased significantly (P < 0.05). Torsion remained constant. In PFO patients no tagging parameter changed after defect closure. CONCLUSION: The Amplatzer occluder itself does not change the ventricular contraction pattern. All volume and myocardial deformation changes were caused by ventricular loading shifts. PMID- 22246668 TI - Fullerenes as neutral carbon-based Lewis acids. PMID- 22246669 TI - A kinetic model for vessel-encoded dynamic angiography with arterial spin labeling. AB - The ability to visualize blood flow in a vessel-selective manner is of importance in a range of cerebrovascular diseases. Conventional X-ray methods are invasive and carry risks to the patient. Recently, a noninvasive dynamic angiographic MRI based technique has been proposed using vessel-encoded pseudocontinuous arterial spin labeling, yielding vessel-selective angiograms of the four main brain feeding arteries. In this study, a novel kinetic model for the signal evolution in such acquisitions is derived and applied to healthy volunteers and to a patient with Moya-Moya disease. The model incorporates bolus dispersion, T(1) decay and radio frequency effects and is applicable to other angiographic methods based on continuous or pseudocontinuous arterial spin labeling. The model fits the data well in all subjects and yields parametric maps relating to blood volume, arrival time, and dispersion, changes to which may indicate disease. These maps are also used to generate synthesized images of blood inflow without bias from T(1) decay and radio frequency effects, greatly improving collateral vessel visibility in the patient with Moya-Moya disease. Relative volume flow rates in downstream vessels are also quantified, showing the relative importance of each feeding artery. This framework is likely to be of use in assessing collateral blood flow in patient groups. PMID- 22246671 TI - Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership. PMID- 22246670 TI - Oncogenicity of the developmental transcription factor Sox9. AB - SOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence, and collaborate with other oncogenes in neoplastic transformation. In primary mouse embryo fibroblasts and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whereas its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly, in colorectal cancer. PMID- 22246672 TI - Effect of soy flour addition and heat-processing method on nutritional quality and consumer acceptability of cassava complementary porridges. AB - BACKGROUND: The nutritional quality of cassava complementary porridge was improved through extrusion cooking and compositing with either defatted or full fat soy flour (65:35 w/w), and product acceptability by mothers with children of the target population was evaluated. RESULTS: The protein digestibility-corrected amino acid score (PDCAAS) of extrusion- and conventionally cooked composite porridges was within the recommendations for complementary foods. The kinetics of starch digestibility showed that all porridges had a rapid rate of starch digestibility, but the rate was lower when defatted soy flour was added and lowest when full fat soy flour was added. The formation of amylase-lipid complexes as shown by X-ray diffraction and differential scanning calorimetry can be attributed to the lower digestibility of extrusion-cooked porridge with full fat soy flour. If fed thrice per day, extrusion-cooked porridge with defatted or full fat soy flour would meet the energy, protein and available lysine requirements of a child aged 6-8 months receiving low or average nutrients from breast milk. All porridges were well received by Mozambican mothers who use cassava as a staple food. The mean scores for sensory liking of all porridges were 3 and above on a five-point hedonic scale. CONCLUSION: Extrusion-cooked cassava/soy flour porridges have good potential for use as high-energy/high protein complementary foods and have acceptable sensory properties. PMID- 22246673 TI - Novel CLDN14 mutations in Pakistani families with autosomal recessive non syndromic hearing loss. AB - Mutations in the CLDN14 gene are known to cause autosomal recessive (AR) non sydromic hearing loss (NSHL) at the DFNB29 locus on chromosome 21q22.13. As part of an ongoing study to localize and identify NSHL genes, the ARNSHL segregating in four Pakistani consanguineous families were mapped to the 21q22.13 region with either established or suggestive linkage. Given the known involvement of CLDN14 gene in NSHL, DNA samples from hearing-impaired members from the four families were sequenced to potentially identify causal variants within this gene. Three novel CLDN14 mutations, c.167G>A (p.Trp56*), c.242G>A (p.Arg81His), and c.694G>A (p.Gly232Arg), segregate with hearing loss (HL) in three of the families. The previously reported CLDN14 mutation c.254T>A (p.Val85Asp) was observed in the fourth family. None of the mutations were detected in 400 Pakistani control chromosomes and all were deemed damaging based on bioinformatics analyses. The non-sense mutation c.167G>A (p.Trp56*) is the first stop codon mutation in CLDN14 gene to be identified to cause NSHL. The c.242G>A (p.Arg81His) and c.694G>A (p.Gly232Arg) mutations were identified within the first extracellular loop and the carboxyl-tail of claudin-14, respectively, which highlights the importance of the extracellular domains and phosphorylation of cytoplasmic tail residues to claudin function within the inner ear. The HL due to novel CLDN14 mutations is prelingual, severe-to-profound with greater loss in the high frequencies. PMID- 22246674 TI - The virtual liver: a multidisciplinary, multilevel challenge for systems biology. AB - The liver is the central metabolic organ in human physiology, with functions that are fundamentally important to the detoxification of xenobiotics (drugs), the maintenance of homeostasis of numerous blood metabolites, and the production of mediators of the acute phase response. Liver toxicity, whether actual or implied is the reason for the failure of a significant proportion of many promising novel medicines that consequently never reach the market, and diseases such as atherosclerosis, diabetes, and fatty liver diseases, that are a major burden on current health resources, are directly linked to functional and structural disorders of the liver. This article presents the concepts and approaches underpinning one of the most exciting and ambitious modeling projects in the field of systems biology and systems medicine. This major multidisciplinary research program is aimed at developing a whole-organ model of the human liver, representing its central physiological functions under normal and pathological conditions The model will be composed of a larger battery of interconnected submodels representing liver anatomy and physiology, integrating processes across hierarchical levels in space, time, and structural organization. In this article, we outline the general architecture of the liver model and present first step taken to reach this ambitious goal. PMID- 22246675 TI - Estimating the prevalence of chronic hepatitis B virus infection--New York City, 2008. AB - Chronic hepatitis B virus (HBV) infection is a preventable cause of liver failure, cirrhosis, and liver cancer; estimated chronic HBV infection prevalence is 0.3-0.5% in the U.S.A. Prevalence in New York City (NYC) is likely higher because foreign-born persons, who represent 36% of NYC's population versus 11% nationwide, bear a disproportionate burden of chronic HBV infection. However, because no comprehensive, population-based survey of chronic HBV infection has been conducted in NYC, a reliable prevalence estimate is unavailable. We used two approaches to estimate chronic HBV infection prevalence in NYC: (1) a census based estimate, combining local and national prevalence data for specific populations, and (2) a surveillance-based estimate, using data from NYC's Department of Health and Mental Hygiene Hepatitis B Surveillance Registry and adjusting for out-migration and deaths. Results from both the census-based estimate and the surveillance-based estimate were similar, with an estimated prevalence of chronic HBV in NYC of 1.2%. This estimate is two to four times the estimated prevalence for the U.S.A. as a whole. According to the census-based estimate, >93% of all cases in NYC are among persons who are foreign-born, and approximately half of those are among persons born in China. These findings underscore the importance of local data for tailoring programmatic efforts to specific foreign-born populations in NYC. In particular, Chinese-language programs and health education materials are critical. Reliable estimates are important for policymakers in local jurisdictions to better understand their own population's needs and can help target primary care services, prevention materials, and education. PMID- 22246677 TI - Affinity-based proteomic profiling: problems and achievements. AB - Affinity chromatography becomes a more and more popular method used in proteomic studies for separation of various groups of proteins (subproteomes). The review highlights the role of affinity chromatography fractionation for proteomic profiling of the most of intensively studied groups of proteins including cyclic nucleotide-binding proteins, protein kinases (kinomes), phosphoproteins, glycoproteins, ubiquitinated proteins. Special attention is paid to the use of affinity chromatography for the characterization of small-molecule protein targets. The latter is especially important for the elucidation of direct protein targets of potential drug substances for evaluation of their possible side effects or additional pharmacological application. PMID- 22246678 TI - Context effects on tempo and pleasantness judgments for Beatles songs. AB - Context effects on tempo and pleasantness judgments of different tempos were demonstrated in three experiments using Beatles songs. In Experiments 1 and 2, we explored how listening to versions of the same song that were played at different tempos affected tempo and pleasantness ratings. In both experiments, contrast effects were found on judgments of tempo, with target tempos rated faster when context tempos were slow than when they were fast. In both experiments, we also showed that the peak of the pleasantness rating function shifted toward the values of the context tempos, reflecting disordinal context effects on pleasantness relationships. Familiarity with the songs did not moderate these effects, and shifts in tempo ratings did not correlate with shifts in most pleasant target tempos when context was manipulated within subjects. In Experiment 3, we examined how manipulations of context tempos for one song affected judgments of the same song as compared with judgments of other more or less similar songs. For tempo ratings, contrast effects transferred to ratings of a similar song, but for pleasantness ratings, assimilative shifts of ideals were found only for the same song and not for similar songs. This pattern of results was supportive of independent bases for the two context effects. PMID- 22246679 TI - Synthesis of uniform layered protonated titanate hierarchical spheres and their transformation to anatase TiO2 for lithium-ion batteries. AB - Layered protonated titanates (LPTs), a class of interesting inorganic layered materials, have been widely studied because of their many unique properties and their use as precursors to many important TiO(2)-based functional materials. In this work, we have developed a facile solvothermal method to synthesize hierarchical spheres (HSs) assembled from ultrathin LPT nanosheets. These LPT hierarchical spheres possess a porous structure with a large specific surface area and high stability. Importantly, the size and morphology of the LPT hierarchical spheres are easily tunable by varying the synthesis conditions. These LPT HSs can be easily converted to anatase TiO(2) HSs without significant structural alteration. Depending on the calcination atmosphere of air or N(2), pure anatase TiO(2) HSs or carbon-supported TiO(2) HSs, respectively, can be obtained. Remarkably, both types of TiO(2) HSs manifest excellent cyclability and rate capability when evaluated as anode materials for high-power lithium-ion batteries. PMID- 22246680 TI - Rapid access to chroman-3-ones through gold-catalyzed oxidation of propargyl aryl ethers. PMID- 22246681 TI - Ischemic extent as a biomarker for characterizing severity of coronary artery stenosis with blood oxygen-sensitive MRI. AB - PURPOSE: To investigate whether a statistical analysis of myocardial blood-oxygen level-dependent (mBOLD) signal intensities can lead to the identification and quantification of the ischemic area supplied by the culprit artery. MATERIALS AND METHODS: Cardiac BOLD images were acquired in a canine model (n = 9) with controllable LCX stenosis at rest and during adenosine infusion on a 1.5T clinical scanner. Statistical distributions of myocardial pixel-intensities derived from BOLD images were used to compute an area metric (ischemic extent, IE). True myocardial perfusion was estimated from microsphere analysis. IE was compared against a standard metric (segment-intensity-response, SIR). Additional animals (n = 3) were used to investigate the feasibility of the approach for identifying ischemic territories due to LAD stenosis from mBOLD images. RESULTS: Regression analyses showed that IE and myocardial flow ratio between rest and adenosine infusion (MFR) were exponentially related (R(2) > 0.70, P < 0.001, for end-systole and end-diastole), while SIR and MFR were linearly related to end systole (R(2) = 0.51, P < 0.04) and unrelated to end-diastole (R(2) ~ 0, P = 0.91). Receiver-operating-characteristic analysis that IE was superior to SIR for detecting critical stenosis (MFR <= 2) in end-systole and end-diastole. Feasibility studies on LAD narrowing demonstrated that the proposed approach could also identify oxygenation changes in the LAD territories. CONCLUSION: The proposed evaluation of cardiac BOLD magnetic resonance imaging (MRI) offers marked improvement in sensitivity and specificity for detecting critical coronary stenosis at 1.5T compared to the mean segmental intensity approach. Patient studies are now warranted to determine its clinical utility. PMID- 22246682 TI - CD4+ cell count and HIV load as predictors of size of anal warts over time in HIV infected women. AB - BACKGROUND: Little is known about the associations between CD4(+) cell counts, human immunodeficiency virus (HIV) load, and human papillomavirus "low-risk" types in noncancerous clinical outcomes. This study examined whether CD4(+) count and HIV load predict the size of the largest anal warts in 976 HIV-infected women in an ongoing cohort. METHODS: A linear mixed model was used to determine the association between size of anal wart and CD4(+) count and HIV load. RESULTS: The incidence of anal warts was 4.15 cases per 100 person-years (95% confidence interval [CI], 3.83-4.77) and 1.30 cases per 100 person-years (95% CI, 1.00-1.58) in HIV-infected and HIV-uninfected women, respectively. There appeared to be an inverse association between size of the largest anal warts and CD4(+) count at baseline; however, this was not statistically significant. There was no association between size of the largest anal warts and CD4(+) count or HIV load over time. CONCLUSIONS: There was no evidence for an association between size of the largest anal warts and CD4(+) count or HIV load over time. Further exploration on the role of immune response on the development of anal warts is warranted in a larger study. PMID- 22246683 TI - Conserved MHC class I-presented dengue virus epitopes identified by immunoproteomics analysis are targets for cross-serotype reactive T-cell response. AB - Dengue fever and dengue hemorrhagic fever are significant global public health problems, and understanding the overall immune response to infection will contribute to appropriate management of the disease and its potentially severe complications. Live attenuated and subunit vaccine candidates, which are under clinical evaluation, induce primarily an antibody response to the virus and minimal cross-reactive T-cell responses. Currently, there are no available tools to assess protective T-cell responses during infection or after vaccination. In this study, we utilize an immunoproteomics process to uncover novel HLA-A2 specific epitopes derived from dengue virus (DV)-infected cells. These epitopes are conserved, and we report that epitope-specific cytotoxic lymphocytes (CTLs) are cross-reactive against all 4 DV serotypes. These epitopes have potential as new informational and diagnostic tools to characterize T-cell immunity in DV infection and may serve as part of a universal vaccine candidate complementary to current vaccines in trial. PMID- 22246685 TI - Antimicrobial activity of food-compatible plant extracts and chitosan against naturally occurring micro-organisms in tomato juice. AB - BACKGROUND: Chitosan (AC) and five hydroalcoholic extracts from Lithospermum erythrorhizon (SE), Rheum palmatum (RE), Thymus vulgaris (AT), Lippia citriodora (PLX) and a mixture of Rosmarinus officinalis, Salvia lavandulifolia and Thymus mastichina (LA) were tested for antimicrobial activity against bacteria, yeasts and filamentous fungi using two broth dilution methods. The effects of adding single extracts on naturally occurring micro-organisms and sensory qualities of raw tomato juice were also evaluated. RESULTS: SE extract exhibited the strongest activity, with minimum inhibitory concentrations (MICs) of 100-400 ug mL-1 for Gram-positive and 1600-3200 ug mL-1 for Gram-negative bacteria. Enterobacter aerogenes showed the greatest susceptibility to AC (MIC 1600 ug mL-1). Lethal effects of extracts and AC were achieved at a minimum bactericidal concentration (MBC)/MIC ratio of 2 in 88% of assays. SE and RE extracts and AC also exhibited antifungal effect against yeasts, but they had no activity on filamentous fungi. Control and 100 mg L-1 SE-added tomato juices did not differ in acceptance, but this SE concentration was not effective in the control of microbial load throughout cold storage. CONCLUSION: Results confirm the antimicrobial potential of the plant extracts, but additional research is needed until the agents responsible for the activities have been determined in order to use them as natural constituents of multiple-barrier food preservation systems. PMID- 22246684 TI - CEST phase mapping using a length and offset varied saturation (LOVARS) scheme. AB - Chemical exchange saturation transfer MRI is a promising new technique for cellular and molecular imaging. This contrast allows the detection of tumors and ischemia without the use of gadolinium as well as the design of microenvironment sensitive probes that can be discriminated based on their exchange contrast properties and saturation frequency. Current acquisition schemes to detect and analyze this contrast suffer from sensitivity to spatial B0 inhomogeneity and low contrast-to-noise-ratio, which is an obstacle to widespread adoption of the technology. A new method to detect chemical exchange saturation transfer contrast is proposed here, termed "length and offset varied saturation" which acquires a set of images with the saturation parameters varied so as to modulate the exchange contrast. Either fast fourier transform or the general linear model can be employed to decompose the modulation patterns into separate sources of water signal loss. After transformation, a length and offset varied saturation phase map is generated, which is insensitive to B0 inhomogeneity. When collected on live mice bearing 9L gliosarcomas, and compared to the conventional asymmetry in the magnetization transfer ratio map using offset increment correction, the results show that length and offset varied saturation phase mapping obtains about three to four times contrast-to-noise-ratio and exhibits less B0 artifacts. PMID- 22246686 TI - Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation. AB - Aberrant methylation at different imprinted loci has been reported for several congenital imprinting disorders, that is, Silver-Russell syndrome (SRS), but the coincidental occurrence of aberrant methylation and uniparental disomy (UPD) has not yet been described. We report on a patient initially diagnosed with SRS carrying a segmental maternal UPD of chromosome 7 [upd(7q)mat]. By further screening the patient's DNA for methylation defects on other chromosomes we identified a hypomethylation of the paternally methylated DLK1/GTL2 locus in 14q32, an epigenotype typically associated with the upd(14)mat phenotype. Detailed clinical analysis confirmed the molecular finding in the patient indicating that the 14q32 epimutation was clinically preponderant. The parallel occurrence of upd(7q)mat and a DLK1/GTL2 hypomethylation in the same patient is a unique finding. Indeed, both disturbances might have occurred coincidentally, but it can also be hypothesized that the upd(7q)mat as the initial genomic mutation represents a trans-acting mutation causing an aberrant methylation in 14q32. PMID- 22246687 TI - Characterizing and identifying risk for falls in the LEAPS study: a randomized clinical trial of interventions to improve walking poststroke. AB - BACKGROUND AND PURPOSE: Better understanding of fall risk poststroke is required for developing screening and prevention programs. This study characterizes falls in the Locomotor Experience Applied Post-Stroke (LEAPS) randomized clinical trial, describes the impact of 2 walking recovery interventions on falls, and examines the value of clinical assessments for predicting falls. METHODS: Community-dwelling ambulatory stroke survivors enrolled in LEAPS were assessed 2 months poststroke. Falls were monitored until 12 months poststroke and participants were characterized as multiple or injurious (M/I); single, noninjurious; or nonfallers. Incidence and time to M/I falls were compared across interventions (home exercise and locomotor training initiated 2 months [early LTP] or 6 months [late-LTP] poststroke). Predictive value of 2-month clinical assessments for falls outcome was assessed. RESULTS: Among the 408 participants, 36.0% were M/I, 21.6% were single, noninjurious, and 42.4% were nonfallers. Most falls occurred at home in the first 3 months after assessment. Falls incidence was highest for those with severe walking impairment who received early-LTP (P=0.025). Berg Balance Scale score <= 42/56 was the single best predictor of M/I falls. CONCLUSIONS: As individuals with stroke improve in walking capacity, risk for M/I falls remains high. Individuals walking <0.4 m/s are at higher risk for M/I falls if they receive early-LTP training. Berg Balance Scale score at 2 months poststroke is useful for informing falls risk, but it cannot account for the multifactorial nature of the problem. Falls prevention in stroke will require multifactorial risk assessment and management provided concomitantly with exercise interventions to improve mobility. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243919. PMID- 22246688 TI - Critique of "Stenting versus aggressive medical therapy for intracranial arterial stenosis" by Chimowitz et al in the new England Journal of Medicine. AB - Symptomatic intracranial stenoses are an important cause of stroke and have a high risk of recurrent stroke with medical therapy. The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Arterial Stenosis (SAMMPRIS) trial unexpectedly showed a higher-than-expected rate of complications with intracranial stenting and a lower-than-expected recurrence rate with medical therapy. In this commentary, the authors review possible explanations for these findings and suggest future strategies for study. PMID- 22246689 TI - Letter by Coutinho et al regarding article, "Mortality of cerebral venous-sinus thrombosis in a large national sample". PMID- 22246690 TI - Is there a future for endovascular treatment of intracranial atherosclerotic disease after Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis (SAMMPRIS)? AB - The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis (SAMMPRIS) trial, a randomized clinical trial comparing aggressive medical management to stenting with aggressive medical management for symptomatic intracranial stenosis, was prematurely halted when a high rate of periprocedural events was found in the stent arm. The trial also demonstrated a high rate of stroke with medical management. This article explores possible reasons for these outcomes and discusses some weaknesses of the trial. Against this background endovascular therapy should continue to be explored in the treatment of this disease. PMID- 22246691 TI - Tracks of a non-main path traveler: 2011 Thomas Willis Lecture. AB - After an unconventional beginning in stroke research, I veered off the main path repeatedly to view problems from a different perspective. In this lecture summary, I would like to return to several points along the byways that led to research with some continuity. PMID- 22246692 TI - Transition to collateral flow after arterial occlusion predisposes to cerebral venous steal. AB - BACKGROUND AND PURPOSE: Stroke-related tissue pressure increase in the core and penumbra determines regional cerebral perfusion pressure (rCPP) defined as a difference between local inflow pressure and venous or tissue pressure, whichever is higher. We previously showed that venous pressure reduction below the pressure in the core causes blood flow diversion-cerebral venous steal. Now we investigated how transition to collateral circulation after complete arterial occlusion affects rCPP distribution. METHODS: We modified parallel Starling resistor model to simulate transition to collateral inflow after complete main stem occlusion. We decreased venous pressure from the arterial pressure to zero and investigated how arterial and venous pressure elevation augments rCPP. RESULTS: When core pressure exceeded venous, rCPP=inflow pressure in the core. Venous pressure decrease from arterial pressure to pressure in the core caused smaller inflow pressure to drop augmenting rCPP. Further drop of venous pressure decreased rCPP in the core but augmented rCPP in penumbra. After transition to collateral circulation, lowering venous pressure below pressure in the penumbra further decreased rCPP and collaterals themselves became a pathway for steal. Venous pressure level at which rCPP in the core becomes zero we termed the "point of no reflow." Transition from direct to collateral circulation resulted in decreased inflow pressure, decreased rCPP, and a shift of point of no reflow to higher venous loading values. Arterial pressure augmentation increased rCPP, but only after venous pressure exceeded point of no reflow. CONCLUSIONS: In the presence of tissue pressure gradients, transition to collateral flow predisposes to venous steal (collateral failure), which may be reversed by venous pressure augmentation. PMID- 22246693 TI - Factors associated with prehospital delays in the presentation of acute stroke in urban China. AB - BACKGROUND AND PURPOSE: Low rates of thrombolysis for ischemic stroke in China have mainly been attributed to delays in presentation to the hospital. This study aimed to evaluate factors associated with these delays. METHODS: Data were from a prospective, multicenter, hospital-based registry of patients with acute stroke (ChinaQUEST [Quality Evaluation of Stroke Care and Treatment]), which involved 62 hospitals across a variety of economic and geographic regions in China during 2006. Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation. RESULTS: Median time to hospital presentation was 15.0 hours for 6102 cases (interquartile range, 2.8-51.0 hours). A total of 1546 (25%) patients arrived within 3 hours and 2244 (37%) patients arrived within 6 hours after symptom onset. Factors that prolonged time to presentation were: visiting a local doctor before presenting at emergency (OR, 0.48; P<0.001), symptom onset at home (OR, 0.62; P<0.001), transfer to a large (Level III) hospital for management (OR, 0.70; P=0.04), and history of diabetes (OR, 0.78; P=0.01). In contrast, factors that accelerated presentation to the hospital were hemorrhagic stroke (OR, 2.25; P<0.001), history of atrial fibrillation (OR, 1.94; P<0.001), unconsciousness at presentation (OR, 1.91; P<0.001), transfer by ambulance (OR, 1.91; P<0.001), and history of coronary artery disease (OR, 1.20; P=0.04). CONCLUSIONS: Health promotion strategies to improve community awareness of early symptoms of stroke, establishment of an alert system to cater for patients likely to experience stroke at home, and wider availability and use of ambulance services are promising methods to help expedite presentation to hospital poststroke and thereby improve the management of stroke in China. PMID- 22246694 TI - A fibrocontractive mechanochemical model of dermal wound closure incorporating realistic growth factor kinetics. AB - Fibroblasts and their activated phenotype, myofibroblasts, are the primary cell types involved in the contraction associated with dermal wound healing. Recent experimental evidence indicates that the transformation from fibroblasts to myofibroblasts involves two distinct processes: The cells are stimulated to change phenotype by the combined actions of transforming growth factor beta (TGFbeta) and mechanical tension. This observation indicates a need for a detailed exploration of the effect of the strong interactions between the mechanical changes and growth factors in dermal wound healing. We review the experimental findings in detail and develop a model of dermal wound healing that incorporates these phenomena. Our model includes the interactions between TGFbeta and collagenase, providing a more biologically realistic form for the growth factor kinetics than those included in previous mechanochemical descriptions. A comparison is made between the model predictions and experimental data on human dermal wound healing and all the essential features are well matched. PMID- 22246695 TI - Asymmetric frontal brain activity and parental rejection predict altruistic behavior: moderation of oxytocin effects. AB - Asymmetric frontal brain activity has been widely implicated in reactions to emotional stimuli and is thought to reflect individual differences in approach withdrawal motivation. Here, we investigate whether asymmetric frontal activity, as a measure of approach-withdrawal motivation, also predicts charitable donations after a charity's (emotion-eliciting) promotional video showing a child in need is viewed, in a sample of 47 young adult women. In addition, we explore possibilities for mediation and moderation, by asymmetric frontal activity, of the effects of intranasally administered oxytocin and parental love withdrawal on charitable donations. Greater relative left frontal activity was related to larger donations. In addition, we found evidence of moderation: Low levels of parental love withdrawal predicted larger donations in the oxytocin condition for participants showing greater relative right frontal activity. We suggest that when approach motivation is high (reflected in greater relative left frontal activity), individuals are generally inclined to take action upon seeing someone in need and, thus, to donate money to actively help out. Only when approach motivation is low (reflected in less relative left/greater relative right activity) do empathic concerns affected by oxytocin and experiences of love withdrawal play an important part in deciding about donations. PMID- 22246696 TI - APRIL in systemic lupus erythematosus: essential or dispensable? Comment on the article by Jacob et al. PMID- 22246698 TI - Ratiometric fluorescence detection of pathogenic bacteria resistant to broad spectrum beta-lactam antibiotics. PMID- 22246697 TI - Reverse-engineering human regulatory networks. AB - The explosion of genomic, transcriptomic, proteomic, metabolomic, and other omics data is challenging the research community to develop rational models for their organization and interpretation to generate novel biological knowledge. The development and use of gene regulatory networks to mechanistically interpret this data is an important development in molecular biology, usually captured under the banner of systems biology. As a result, the repertoire of methods for the reconstruction of comprehensive and cell-context-specific maps of regulatory interactions, or interactomes, has also exploded in the past few years. In this review, we focus on Network Biology and more specifically on methods for reverse engineering transcriptional, post-transcriptional, and post-translational human interaction networks and show how their interrogation is starting to impact our understanding of cellular pathophysiology and one's ability to predict cellular phenotypes from genome-wide molecular observations. PMID- 22246699 TI - Mass spectrometry-based proteomics strategies for protease cleavage site identification. AB - Protease-catalyzed hydrolysis of peptide bonds is one of the most pivotal post translational modifications fulfilling manifold functions in the regulation of cellular processes. Therefore, dysregulation of proteolytic reactions plays a central role in many pathophysiological events. For this reason, understanding the molecular mechanisms in proteolytic reactions, in particular the knowledge of proteases involved in complex processes, expression levels and activity of protease and knowledge of the targeted substrates are an indispensable prerequisite for targeted drug development. The present review focuses on mass spectrometry-based proteomic methods for the analysis of protease cleavage sites, including the identification of the hydrolyzed bonds as well as of the surrounding sequence. Peptide- and protein-centric approaches and bioinformatic tools for experimental data interpretation will be presented and the major advantages and drawbacks of the different approaches will be addressed. The recent applications of these approaches for the analysis of biological function of different protease classes and potential future directions will be discussed. PMID- 22246700 TI - Impact of reimbursement schemes on quality of care: a European perspective. PMID- 22246701 TI - Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease: "Don't think twice, it's alright!". PMID- 22246702 TI - Lung endothelial Ca2+ and permeability response to platelet-activating factor is mediated by acid sphingomyelinase and transient receptor potential classical 6. AB - RATIONALE: Platelet-activating factor (PAF) increases lung vascular permeability within minutes by activation of acid sphingomyelinase (ASM) and a subsequent nitric oxide (NO)-inhibitable and Ca(2+)-dependent loss in barrier function. OBJECTIVES: To elucidate the molecular mechanisms underlying this response. METHODS: In isolated perfused rat and mouse lungs, endothelial Ca(2+) concentration ([Ca(2+)](i)) was quantified by real-time fluorescence imaging, and caveolae of endothelial cells were isolated and probed for Ca(2+) entry channels. Regulation of transient receptor potential classical (TRPC) 6-mediated currents in lung endothelial cells was assessed by patch clamp technique. MEASUREMENTS AND MAIN RESULTS: PAF increased lung weight gain and endothelial [Ca(2+)](i). This response was abrogated by inhibitors of ASM or in ASM-deficient mice, and replicated by lung perfusion with exogenous ASM or C2-ceramide. PAF increased the caveolar abundance of TRPC6 channels, which was similarly blocked by ASM inhibition. PAF-induced increases in lung endothelial [Ca(2+)](i), vascular filtration coefficient, and edema formation were attenuated by the TRPC inhibitor SKF96365 and in TRPC6-deficient mice, whereas direct activation of TRPC6 replicated the [Ca(2+)](i) and edema response to PAF. The exogenous NO donor PapaNONOate or the cyclic guanosine 3',5'-monophosphate analog 8Br-cGMP blocked the endothelial [Ca(2+)](i) and permeability response to PAF, in that they directly blocked TRPC6 channels without interfering with their PAF-induced recruitment to caveolae. CONCLUSIONS: The present findings outline a new signaling cascade in the induction of PAF-induced lung edema, in that stimulation of ASM causes recruitment of TRPC6 channels to caveolae, thus allowing for Ca(2+) influx and subsequent increases in endothelial permeability that are amplified in the absence of endothelial NO synthesis. PMID- 22246703 TI - Pulmonary hypertension as a risk factor for graft dysfunction, ultrasound-guided subclavian vein cannulation, and lebrikizumab for adult asthma. PMID- 22246704 TI - Mounier-Kuhn syndrome: imaging in recurrent pulmonary infections. PMID- 22246705 TI - Airway clearance in bronchiectasis: breaking the infection-inflammation cycle. PMID- 22246706 TI - Excess ventilation during exercise and prognosis in chronic heart failure. PMID- 22246708 TI - Regional lung strain and inflammation. PMID- 22246709 TI - ICU-acquired weakness: an extension of the effects of bed rest. PMID- 22246710 TI - Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center. PMID- 22246711 TI - Septic pulmonary embolism in a patient with defibrillator lead endocarditis. PMID- 22246712 TI - Seven-month pilot of an integrated, continuous evaluation, and quality improvement system for a state-based home-visiting program. AB - The objective of this study is to report the findings of a 7-month pilot for an integrated system evaluating a state-wide home visiting program. A cross sectional study design was used to determine baseline process and outcome measures for Tennessee's home visiting program which provides services to families, from pregnancy through 5-years-old. Baseline process measures included: time to initiate service after referral; frequency, duration and intensity of visits; completion of continuous assessment; and time from identification of a need to referral. The baseline outcome measures included: needs of eligible services (e.g. developmental screenings, WIC); prenatal care utilization; biological risks (prematurity; low birth weight); tobacco use and second-hand smoke exposure; and family planning utilization. During the pilot, 3,794 families were enrolled, representing 68% (+/- 1.5%) of incoming referrals. Enrollment dropped from 82% (90 days) to 69% (120 days); 52% of the families received a visit every month. Ninety percent of families had at least one full assessment after enrollment; 60% occurred within the first 60 days. Over 92% of outgoing referrals were made within 7 days. Immunization status (70%) is below the state level (80.8%). A quarter of the infants enrolled in the program are low birth weight and premature (state level 9.2%). Current tobacco use by the prenatal population is 16% compared to the state, 19.7%. The HUGS program serves high risk/high need clients and is consistent with other national home visiting models that have shown higher levels of attrition and lower levels of visits than intended by the model. PMID- 22246713 TI - Design and implementation of an integrated, continuous evaluation, and quality improvement system for a state-based home-visiting program. AB - To describe the design and implementation of an evaluation system to facilitate continuous quality improvement (CQI) and scientific evaluation in a statewide home visiting program, and to provide a summary of the system's progress in meeting intended outputs and short-term outcomes. Help Us Grow Successfully (HUGS) is a statewide home visiting program that provides services to at-risk pregnant/post-partum women, children (0-5 years), and their families. The program goals are to improve parenting skills and connect families to needed services and thus improve the health of the service population. The evaluation system is designed to: (1) integrate evaluation into daily workflow; (2) utilize standardized screening and evaluation tools; (3) facilitate a culture of CQI in program management; and, (4) facilitate scientifically rigorous evaluations. The review of the system's design and implementation occurred through a formative evaluation process (reach, dose, and fidelity). Data was collected through electronic and paper surveys, administrative data, and notes from management meetings, and medical chart review. In the design phase, four process and forty outcome measures were selected and are tracked using standardized screening and monitoring tools. During implementation, the reach and dose of training were adequate to successfully launch the evaluation/CQI system. All staff (n = 165) use the system for management of families; the supervisors (n = 18) use the system to track routine program activities. Data quality and availability is sufficient to support periodic program reviews at the region and state level. In the first 7 months, the HUGS evaluation system tracked 3,794 families (7,937 individuals). System use and acceptance is high. A successful implementation of a structured evaluation system with a strong CQI component is feasible in an existing, large statewide program. The evaluation/CQI system is an effective mechanism to drive modest change in management of the program. PMID- 22246714 TI - Long-term breastfeeding support: failing mothers in need. AB - This qualitative study analyzes mothers' reports of breastfeeding care experiences from pregnancy through infancy. Most research on medical support for breastfeeding examines a specific practice or intervention during an isolated phase of care. Little is know about how mothers experience breastfeeding education and support from the prenatal period through their child's first year. A convenience sample of 75 black and white WIC participants with infants was recruited at three Maryland WIC agencies. In-depth interviews covered mothers' comprehensive experiences of breastfeeding education and support from pregnancy through the interview date. Most mothers received education or support from a medical professional prenatally, at the hospital, or during the child's infancy, but most also reported receiving no education or support at one or more of these stages. Mothers often felt provided education and support was cursory and inadequate. Some mothers received misinformation or encountered practitioners who were hostile or indifferent to breastfeeding. Mothers were not given referrals to available resources, even after reporting breastfeeding challenges. Mothers received inconsistent messages regarding breastfeeding within and across institutions. Mothers need consistent, sustained information and support to develop and meet personal breastfeeding goals. Medical professionals should follow guidelines issued by their own organizations as well as those from the US Surgeon General, Healthy People 2020, and the Baby Friendly Hospital Initiative. Prenatal, postnatal, and pediatric care providers should coordinate to provide consistent messages and practices within and across sites of care. PMID- 22246715 TI - Estimation of intersubject variability of cerebral blood flow measurements using MRI and positron emission tomography. AB - PURPOSE: To investigate the within and between subject variability of quantitative cerebral blood flow (CBF) measurements in normal subjects using various MRI techniques and positron emission tomography (PET). MATERIALS AND METHODS: Repeated CBF measurements were performed in 17 healthy, young subjects using three different MRI techniques: arterial spin labeling (ASL), dynamic contrast enhanced T1 weighted perfusion MRI (DCE) and phase contrast mapping (PCM). All MRI measurements were performed within the same session. In 10 of the subjects repeated CBF measurements by (15) O labeled water PET had recently been performed. A mixed linear model was used to estimate between subject (CV(betw)) and within subject (CV(with)) coefficients of variation. RESULTS: Mean global CBF, CV(betw) and CV(with) using each of the four methods were for PCM 65.2 mL/100 g/min, 17.4% and 7.4%, for ASL 37.1 mL/100 g/min, 16.2% and 4.8%, for DCE 43.0 mL/100 g/min, 20.0%, 15.1% and for PET 41.9 mL/100 g/min, 16.5% and 11.9%, respectively. Only for DCE and PCM a significant positive correlation between measurements was demonstrated. CONCLUSION: These findings confirm large between subject variability in CBF measurements, but suggest also that in healthy subjects a subject-method interaction is a possible source of between subject variability and of method differences. PMID- 22246716 TI - Ligand-binding assays in the 21st Century laboratory: recommendations for an automated data interchange process. PMID- 22246717 TI - Reactions of beryllium halides in liquid ammonia: the tetraammineberyllium cation [Be(NH3)4]2+, its hydrolysis products, and the action of Be2+ as a fluoride-ion acceptor. AB - The first structural characterization of the text-book tetraammineberyllium(II) cation [Be(NH(3))(4)](2+), obtained in the compounds [Be(NH(3))(4)](2)Cl(4)?17NH(3) and [Be(NH(3))(4)]Cl(2), is reported. Through NMR spectroscopic and quantum chemical studies, its hydrolysis products in liquid ammonia were identified. These are the dinuclear [Be(2)(MU-OH)(NH(3))(6)](3+) and the cyclic [Be(2)(MU-OH)(2)(NH(3))(4)](2+) and [Be(3)(MU-OH)(3)(NH(3))(6)](3+) cations. The latter species was isolated as the compound [Be(3)(MU OH)(3)(NH(3))(6)]Cl(3)?7NH(3). NMR analysis of solutions of BeF(2) in liquid ammonia showed that the [BeF(2)(NH(3))(2)] molecule was the only dissolved species. It acts as a strong fluoride-ion acceptor and forms the [BeF(3)(NH(3))]( ) anion in the compound [N(2)H(7)][BeF(3)(NH(3))]. The compounds presented herein were characterized by single-crystal X-ray structure analysis, (9)Be, (17)O, and (19)F NMR, IR, and Raman spectroscopy, deuteration studies, and quantum chemical calculations. The extension of beryllium chemistry to the ammine system shows similarities but also decisive differences to the aquo system. PMID- 22246718 TI - Preoperative hydronephrosis: independent predictor for changes in renal function following nephroureterectomy. AB - OBJECTIVE: Partial or complete urinary obstruction caused by a tumor itself may affect renal function and the eligibility for perioperative cisplatin-based chemotherapy in patients with upper tract urothelial carcinoma. We investigated whether the status of preoperative hydronephrosis provides additional predictive information concerning changes in perioperative renal function. METHODS: A total of 155 patients who underwent nephroureterectomy for upper tract urothelial carcinoma from 1997 to 2010 were identified. The association between preoperative parameters including the grade of hydronephrosis and perioperative renal function was analyzed. RESULTS: Hydronephrosis was observed in 104 patients. The grade of hydronephrosis was 1, 2, 3 and 4 in 6 (3.9%), 25 (16.1%), 42 (27.1%) and 31 (20.0%) cases. Using a defined cut-off creatinine clearance value of >=50 ml/min indicating eligibility for cisplatin-based chemotherapy, only 94 patients (60.6%) were eligible in the neoadjuvant setting. Of these 94 patients, 30 (31.9%) were judged to be ineligible in the adjuvant setting. Multivariate analysis demonstrated that patient age >=70 years [P < 0.001, hazard ratio (HR) 27.9] and the absence of a higher grade hydronephrosis (P = 0.013, HR 7.40) were independent risk factors for predicting patients ineligible to receive adjuvant cisplatin-based chemotherapy. The proportion of patients ineligible to receive cisplatin-based chemotherapy changed from 40.9 to 88.6% following nephroureterectomy in patients aged >=70 years and those with no or a lower grade hydronephrosis. CONCLUSIONS: The status of hydronephrosis is an independent predictor of eligibility to receive adjuvant cisplatin-based chemotherapy. The information on preoperative hydronephrosis and patient age may assist in part of the decision-making when considering neoadjuvant cisplatin-based chemotherapy. PMID- 22246719 TI - Comparison and evaluation of molecular methods used for identification and discrimination of lactic acid bacteria. AB - BACKGROUND: Lactobacillus and Bifidobacterium strains are present in a great variety of habitats, including fermented products, probiotic concoctions and the human colon. Some species are so closely related that it is difficult to distinguish them by microbiological techniques. Nevertheless, discrimination of isolates is an important issue in respect of application, and molecular methods such as restriction fragment length polymorphism (RFLP), random amplification of polymorphic DNA (RAPD) or species-specific polymerase chain reaction (PCR) might help in resolving this problem. In this study, PCR, RFLP and sequencing were applied to identify lactobacilli and bifidobacteria originating from various sources and the DSMZ strain collection. RESULTS: The microbiological composition of foods was analysed by molecular methods. Using species-specific PCR primers, three restriction enzymes (AluI, HhaI and RsaI) and sequencing, three Bifidobacterium and six Lactobacillus reference strains could be distinguished and four additional lactobacilli of food origin were identified. CONCLUSION: A combination of three molecular methods resulted in successful discrimination of nine reference strains and four isolates of food origin. Since these methods are not always accurate owing to their high genetic homogeneity, it is advisable to use more than one method for the identification of L. casei and closely related species. PMID- 22246720 TI - Volumetric navigators for real-time motion correction in diffusion tensor imaging. AB - Prospective motion correction methods using an optical system, diffusion-weighted prospective acquisition correction, or a free induction decay navigator have recently been applied to correct for motion in diffusion tensor imaging. These methods have some limitations and drawbacks. This article describes a novel technique using a three-dimensional-echo planar imaging navigator, of which the contrast is independent of the b-value, to perform prospective motion correction in diffusion weighted images, without having to reacquire volumes during which motion occurred, unless motion exceeded some preset thresholds. Water phantom and human brain data were acquired using the standard and navigated diffusion sequences, and the mean and whole brain histogram of the fractional anisotropy and mean diffusivity were analyzed. Our results show that adding the navigator does not influence the diffusion sequence. With head motion, the whole brain histogram-fractional anisotropy shows a shift toward lower anisotropy with a significant decrease in both the mean fractional anisotropy and the fractional anisotropy histogram peak location (P<0.01), whereas the whole brain histogram mean diffusivity shows a shift toward higher diffusivity with a significant increase in the mean diffusivity (P<0.01), even after retrospective motion correction. These changes in the mean and the shape of the histograms are recovered substantially in the prospective motion corrected data acquired using the navigated sequence. PMID- 22246721 TI - Mucopolysaccharidosis type II in females and response to enzyme replacement therapy. AB - Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1-4 of IDS (minimal deletion range c.1 103_184del). The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype-phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both. PMID- 22246722 TI - Curium(III) borate shows coordination environments of both plutonium(III) and americium(III) borates. PMID- 22246723 TI - Representational pseudoneglect and reference points both influence geographic location estimates. AB - Our mental representation of the world is far from objective. For example, western Canadians estimate the locations of North American cities to be too far to the west. This bias could be due to a reference point effect, in which people estimate more space between places close to them than far from them, or to representational pseudoneglect, in which neurologically intact individuals favor the left side of space when asked to image a scene. We tested whether either or both of these biases influence the geographic world representations of neurologically intact young adults from Edmonton and Ottawa, which are in western and eastern Canada, respectively. Individuals were asked to locate North American cities on a two-dimensional grid. Both groups revealed effects of representational pseudoneglect in this novel paradigm, but they also each exhibited reference point effects. These results inform theories in both cognitive psychology and neuroscience. PMID- 22246724 TI - Action effects in saccade control. AB - According to the ideomotor principle, action preparation involves the activation of associations between actions and their effects. However, there is only sparse research on the role of action effects in saccade control. Here, participants responded to lateralized auditory stimuli with spatially compatible saccades toward peripheral targets (e.g., a rhombus in the left hemifield and a square in the right hemifield). Prior to the imperative auditory stimulus (e.g., a left tone), an irrelevant central visual stimulus was presented that was congruent (e.g., a rhombus), incongruent (e.g., a square), or unrelated (e.g., a circle) to the peripheral saccade target (i.e., the visual effect of the saccade). Saccade targets were present throughout a trial (Experiment 1) or appeared after saccade initiation (Experiment 2). Results showed shorter response times and fewer errors in congruent (vs. incongruent) conditions, suggesting that associations between oculomotor actions and their visual effects play an important role in saccade control. PMID- 22246725 TI - Postoperative adhesion prevention using a statin-containing cellulose film in an experimental model. AB - BACKGROUND: Intraperitoneal adhesions are a common problem in abdominal surgery. The aim of this study was to compare the effectiveness of Statofilm, a novel antiadhesive film based on cross-linked carboxymethylcellulose and atorvastatin, with that of sodium hyaluronate-carboxymethylcellulose (Seprafilm((r))) in the prevention of postoperative intraperitoneal adhesions in rats. METHODS: One hundred male Wistar rats underwent a laparotomy and adhesions were induced by caecal abrasion. The animals were allocated to five groups: a control group with no adhesion barrier, Seprafilm((r)) group, placebo group with a film containing carboxymethylcellulose without atorvastatin, and low- and high-dose groups with films containing carboxymethylcellulose and atorvastatin 0.125 and 1 mg per kg bodyweight respectively. Adhesions were classified by two independent surgeons 2 weeks after surgery. Caecal biopsies were obtained for histological evaluation of fibrosis, inflammation and vascular proliferation. RESULTS: All antiadhesive film groups (Seprafilm((r)), placebo, low-dose and high-dose) had statistically significant adhesion reduction compared with the control group (P < 0.001, P = 0.015, P < 0.001 and P < 0.001 respectively). The low-dose Statofilm was superior to Seprafilm((r)) in terms of adhesion prevention (P = 0.001). Adhesions were present in three-quarters of rats in the Seprafilm((r)) group, but only one quarter in the low-dose Statofilm group. CONCLUSION: The data suggest that the newly developed adhesion barrier Statofilm has better results than Seprafilm((r)) in preventing postoperative adhesions in rats. A low-dose atorvastatin-containing film, such as Statofilm, could be evaluated for future clinical application. PMID- 22246726 TI - Selenium enrichment on Cordyceps militaris link and analysis on its main active components. AB - To investigate the effects of selenium on the main active components of Cordyceps militaris fruit bodies, selenium-enriched cultivation of C. militaris and the main active components of the fruit bodies were studied. Superoxide dismutase (SOD) activity and contents of cordycepin, cordycepic acid, and organic selenium of fruit bodies were sodium selenite concentration dependent; contents of adenosine and cordycep polysaccharides were significantly enhanced by adding sodium selenite in the substrates, but not proportional to sodium selenite concentrations. In the cultivation of wheat substrate added with 18.0 ppm sodium selenite, SOD activity and contents of cordycepin, cordycepic acid, adenosine, cordycep polysaccharides, and total amino acids were enhanced by 121/145%, 124/74%, 325/520%, 130/284%, 121/145%, and 157/554%, respectively, compared to NS (non-selenium-cultivated) fruit bodies and wild Cordyceps sinensis; organic selenium contents of fruit bodies reached 6.49 mg/100 g. So selenium-enriched cultivation may be a potential way to produce more valuable medicinal food as a substitute for wild C. sinensis. PMID- 22246727 TI - Constitutive expression of Yarrowia lipolytica lipase LIP2 in Pichia pastoris using GAP as promoter. AB - A gene encoding Yarrowia lipolytica lipase LIP2 (YlLIP2) was cloned into a constitutive expression vector pGAPZalphaA and electrotransformed into the Pichia pastoris X-33 strain. The high-yield clones obtained by high copy and enzyme activity screening were chosen as the host strains for shaking flask and fermentor culture. The results showed that glucose was the optimum carbon source for YlLIP2 production, and the maximum hydrolytic activity of recombinant YlLIP2 reached 1,315 U/ml under the flask culture at 28 degrees C, pH 7.0, for 48 h. The fed-batch fermentation was carried out in 3- and 10-l bioreactors by continuously feeding glucose into the growing medium for achieving high cell density and YlLIP2 yields. The maximum hydrolytic activity of YlLIP2 and cell density obtained in the 3-l bioreactor were 10,300 U/ml and 116 g dry cell weight (DCW)/l, respectively. The peak hydrolytic activity of YlLIP2 and cell density were further improved in the 10-l fermentor where the values respectively attained were 13,500 U/ml and 120 g DCW/l. The total protein concentration in the supernatant reached 3.3 g/l and the cell viability remained approximately 99% after 80 h of culture. Furthermore, the recombinant YlLIP2 produced in P. pastoris pGAP and pAOX1 systems have similar content of sugar (about 12%) and biochemical characteristics. The above results suggest that the GAP promoter derived expression system of P. pastoris is effective for the expression of YlLIP2 by high cell density culture and is probably an alternative to the conventional AOX1 promoter expression system in large-scale production of industrial lipases. PMID- 22246728 TI - Keratinase production and biodegradation of whole chicken feather keratin by a newly isolated bacterium under submerged fermentation. AB - A new feather-degrading bacterium PKD 5 was isolated from feather dumping soil and identified as Bacillus weihenstephanensis based on morphological and physiochemical characteristics as well as 16S rRNA gene analysis. Extracellular keratinase was produced during submerged aerobic cultivation in a medium containing chicken feather as sole carbon and energy source and supplemented with salt solutions (NaCl 5.0, MgSO4 1.0, K2HPO4 1.0, (NH4)2SO4, 2.0 g/l). The optimal conditions for keratinase production include initial pH of 7.0, inoculum size of 2% (v/v), and cultivation at 40 degrees C. The maximum keratinase production and keratinolytic activity of PKD 5 was achieved after 7 days of fermentation under shaking condition (120 rpm). The enzyme has found application in developing cost effective feather by-products for feeds and fertilizers. The manuscript first time describes B. weihenstephanensis PKD 5-mediated keratinase production under submerged fermentation and whole chicken feather biodegradation. PMID- 22246729 TI - Strategies to overcome oxygen transfer limitations during hairy root cultivation of Azadiracta indica for enhanced azadirachtin production. AB - The vast untapped potential of hairy root cultures as a stable source of biologically active chemicals has focused the attention of scientific community toward its commercial exploitation. However, the major bottleneck remains its successful scale-up. Due to branching, the roots form an interlocked matrix that exhibits resistance to oxygen transfer. Thus, present work was undertaken to develop cultivation strategies like optimization of inlet gas composition (in terms of % (v/v) O(2) in air), air-flow rate and addition of oxygen vectors in the medium, to curb the oxygen transfer limitations during hairy root cultivation of Azadirachta indica for in vitro azadirachtin (a biopesticide) production. It was found that increasing the oxygen fraction in the inlet air (in the range, 20 100% (v/v) O(2) in air) increased the azadirachtin productivity by approximately threefold, to a maximum of 4.42 mg/L per day (at 100% (v/v) O(2) in air) with respect to 1.68 mg/L per day in control (air with no oxygen supplementation). Similarly, increasing the air-flow rate (in the range, 0.3-2 vvm) also increased the azadirachtin productivity to a maximum of 1.84 mg/L per day at 0.8 vvm of air flow rate. On the contrary, addition of oxygen vectors (in the range, 1-4% (v/v); hydrogen peroxide, toluene, Tween 80, kerosene, silicone oil, and n-hexadecane), decreased the azadirachtin productivity with respect to control (1.76 mg/L per day). PMID- 22246730 TI - Modelling growth and bacteriocin production by Pediococcus acidilactici PA003 as a function of temperature and pH value. AB - To investigate the effect of pH and temperature on the cell growth and bacteriocin production of Pediococcus acidilactici PA003, a lactic acid bacterium isolated from traditionally fermented cabbage, the kinetic behaviour of P. acidilactici PA003 was simulated in vitro during laboratory fermentations by making use of MRS broth. Firstly, primary models were developed for cell growth, glucose consumption, lactic acid and bacteriocin production for a given set of environmental conditions. Based on primary models, further study was undertaken to fit secondary models to describe the influence of temperature and pH on microbial behaviour. The models were validated successfully for all components. The results from the cell yield coefficient for lactic acid production reflected the homofermentative nature of P. acidilactici PA003. Both cell growth and bacteriocin production were very much influenced by changes in temperature and pH. The optimal condition for specific growth rate and biomass concentration was almost the same at pH 6.5 and 35 degrees C. At 35 degrees C and pH 6.1, the maximal bacteriocin activity was also achieved. The kinetic models provide useful tools for elucidating the mechanisms of temperature and pH on the kinetic behaviour of P. acidilactici PA003. The information obtained in this paper may be very useful for the selection of suitable starter cultures for a particular fermentation process and is a first step in the optimization of food fermentation processes and technology as well. PMID- 22246731 TI - Atropa belladonna hairy roots: orchestration of concurrent oxidation and reduction reactions for biotransformation of carbonyl compounds. AB - The biotransformation potential of a selected Atropa belladonna hairy root clone (AB-09) had been evaluated with regard to three different aromatic carbonyl compounds, i.e., 3,4,5-trimethoxybenzaldehyde (1), 3,4,5-trimethoxyacetophenone (2), and 3,4,5-trimethoxy benzoic acid (3). The results demonstrated for the first time the untapped potentials of the selected hairy root clone to perform simultaneous oxidation (34.49%) and reduction (32.68%) of 3,4,5-trimethoxy benzaldehyde (1) into 3,4,5-trimethoxy benzoic acid (3), and 3,4,5-trimethoxy benzyl alcohol (4), respectively, without any intermediate separation or addition of reagents. The same hairy root clone also demonstrated reduction (<5%) of a 3,4,5-trimethoxyacetophenone (2) into a secondary alcohol, i.e., 1-(3,4,5 trimethoxyphenyl) ethanol (5), while in the case of aromatic carboxylic acid substrate (3), no biotransformation could be obtained under the similar conditions. The current observations revealed oxidation and reduction of the formyl group of the aromatic ring, and only reduction of the carbonyl group of acetophenone through the specific hairy root clone. The concurrent oxidation and reduction reactions by the selected hairy root clone highlight the importance of this study, which, as per our observations, is the first of its kind relating the hairy root culture of A. belladonna. PMID- 22246732 TI - Genetically engineered epidermal growth factor conjugate crosses cell membrane. AB - Epidermal growth factor (EGF) is a well-known pleiotropic growth factor in mammal, and has been attempted to be used in many different fields. However, the application of EGF is limited because of its poor cell permeation. In order to increase membrane permeation ability of EGF, a genetically modified recombinant EGF (GST-TAT-EGF) was prepared through conjugation of EGF with two protein transduction domains, glutathione-S-transferase and TAT47-57. The results showed that the GST-TAT-EGF fusion protein exhibited higher ability in biomembrane penetration than that of the EGF alone. The results also implied that two different mechanisms (EGF receptor-mediated endocytosis and direct penetration) might be involved in GST-TAT-EGF transmembrane delivery. PMID- 22246733 TI - Design of biosolvents through hydroxyl functionalization of compounds with high dielectric constant. AB - We proposed basic principles for biosolvent design on the viewpoint of ionization. Two classes of biosolvents, based on cyclic carbonate moiety and amide moiety, were designed through hydroxyl functionalization of highly dielectric compound. The newly designed compounds, glycerol carbonate (GC) and N hydroxymethyl formamide (HOF), were synthesized for the development of soluble enzymatic systems and characterized by (13)C NMR and (1)H NMR. All the characterization data were consistent with the expected structures. Using conductance measurements, the pK (a) values of trichloroacetic acid in GC and HOF were determined as 0.80 and 0.85 at 25.0 degrees C, which was very close to that in water (pK (a) = 0.70), suggesting that the ionizing and dissociating abilities of GC and HOF are similar to those of water. The effects of various reaction parameters on activity and stability of Candida antarctica lipase B and lipase from Pseudomonas cepacia were investigated using the transesterification of ethyl butyrate with n-butanol as a model reaction. The activities of lipases in GC and HOF were comparable to those in water, indicating that the newly designed compounds were biocompactible. Biosolvent design is a promising and versatile method for developing new biosolvents. PMID- 22246734 TI - Multiscale models of thrombogenesis. AB - To restrict the loss of blood follow from the rupture of blood vessels, the human body rapidly forms a clot consisting of platelets and fibrin. However, to prevent pathological clotting within vessels as a result of vessel damage, the response must be regulated. Clots forming within vessels (thrombi) can restrict the flow of blood causing damage to tissues in the flow field. Additionally, fragments dissociating from the primary thrombus (emboli) may lodge and clog vessels in the brain (causing ischemic stroke) or lungs (resulting in pulmonary embolism). Pathologies related to the obstruction of blood flow through the vasculature are the major cause of mortality in the United States. Venous thromboembolic disease alone accounts for 900,000 hospitalizations and 300,000 deaths per year and the incidence will increase as the population ages (Wakefield et al. J Vasc Surg 2009, 49:1620-1623). Thus, understanding the interplay between the many processes involved in thrombus development is of significant biomedical value. In this article, we first review computational models of important subprocesses of hemostasis/thrombosis including coagulation reactions, platelet activation, and fibrin assembly, respectively. We then describe several multiscale models integrating these subprocesses to simulate temporal and spatial development of thrombi. The development of validated computational models and predictive simulations will enable one to explore how the variation of multiple hemostatic factors affects thrombotic risk providing an important new tool for thrombosis research. PMID- 22246735 TI - Biotherapeutic formulation factors affecting metal leachables from stainless steel studied by design of experiments. AB - Trace amounts of metals are inevitably present in biotherapeutic products. They can arise from various sources. The impact of common formulation factors such as protein concentration, antioxidant, metal chelator concentration and type, surfactant, pH, and contact time with stainless steel on metal leachables was investigated by a design of experiments approach. Three major metal leachables, iron, chromium, and nickel were monitored by inductively coupled plasma-mass spectrometry. It was observed that among all the tested factors, contact time, metal chelator concentration, and protein concentration were statistically significant factors with higher temperature resulting in higher levels of leached metals. Within a pH range of 5.5-6.5, solution pH played a minor role for chromium leaching at 25 degrees C. No statistically significant difference was observed due to type of chelator, presence of antioxidant, or surfactant. In order to optimize a biotherapeutic formulation to achieve a target drug product shelf life with acceptable quality, each formulation component must be evaluated for its impact. PMID- 22246736 TI - Fabrication of carvedilol nanosuspensions through the anti-solvent precipitation ultrasonication method for the improvement of dissolution rate and oral bioavailability. AB - The present study aims to prepare carvedilol (CAR) nanosuspensions using the anti solvent precipitation-ultrasonication technique to improve its dissolution rate and oral bioavailability. Alpha-tocopherol succinate (VES) was first used as a co stabilizer to enhance the stability of the nanosuspensions. The effects of the process parameters on particle size of the nanosuspensions were investigated. The optimal values of the precipitation temperature, power inputs, and the time length of ultrasonication were selected as 10 degrees C, 400 W, and 15 min, respectively. Response surface methodology based on central composite design was utilized to evaluate the formulation factors that affect the size of nanosuspensions, i.e., the concentration of CAR and VES in the organic solution, and the level of sodium dodecyl sulfate in the anti-solvent phase, respectively. The optimized formulation showed a mean size of 212 +/- 12 nm and a zeta potential of -42 +/- 3 mV. Scanning electron microscopy revealed that the nanosuspensions were flaky-shaped. Powder X-ray diffraction and differential scanning calorimetry analysis confirmed that the nanoparticles were in the amorphous state. Fourier transform infrared analysis demonstrated that the reaction between CAR and VES is probably due to hydrogen bonding. The nanosuspension was physically stable at 25 degrees C for 1 week, which allows it to be further processing such as drying. The dissolution rate of the nanosuspensions was markedly enhanced by reducing the size. The in vivo test demonstrated that the C(max) and AUC(0-36) values of nanosuspensions were approximately 3.3- and 2.9-fold greater than that of the commercial tablets, respectively. PMID- 22246737 TI - The current state of microbial proteomics: where we are and where we want to go. AB - Proteomics allows the assessment of cellular processes in an unprecedented scale by providing a comprehensive quantitative and qualitative overview of the protein content of a cell. Consequently, proteomics has been employed to investigate a multitude of bacterial processes ranging from the analysis of environmental communities, identification of virulence factors to the proteome-guided optimization of production strains. Proteomics has, in short, become an indispensable tool for the global analysis of bacterial physiology. Nonetheless, challenges exist, especially in the accurate prediction of phenotypic consequences based on any given proteome composition. In this review, we will give an overview of current highlights in the area of microbial proteomics, discuss some current challenges and present new developments that may help in overcoming them. PMID- 22246738 TI - It's the teachers. PMID- 22246743 TI - China. Tobacco scientist's election tars academy's image. PMID- 22246744 TI - Ground-based astronomy. Pleading poverty, NSF delays plans for giant telescope. PMID- 22246745 TI - Global change. A quick (partial) fix for an ailing atmosphere. PMID- 22246746 TI - Newsmaker interview: C. N. R. Rao. Top Indian chemist helps make the case for science windfall. Interview by Pallava Bagla. PMID- 22246747 TI - Archaeology. The peopling of the Aleutians. PMID- 22246748 TI - Materials Research Society's fall meeting and exhibit. New lease for leftover light. PMID- 22246749 TI - Materials Research Society's fall meeting and exhibit. Snapshots from the meeting. PMID- 22246750 TI - Materials Research Society's fall meeting and exhibit. Al bids to vie with Li in battery wars. PMID- 22246751 TI - Single-sex education: results one-sided. PMID- 22246752 TI - Single-sex education: positive effects. PMID- 22246753 TI - Single-sex education: unequal to segregation. PMID- 22246754 TI - Single-sex education: parameters too narrow. PMID- 22246757 TI - Comment on "Late Mousterian persistence near the Arctic Circle". AB - Slimak et al. (Reports, 13 May 2011, p. 841) reanalyzed the lithic assemblage from the northern site of Byzovaya (Russia) and concluded that it was Mousterian and produced by Neandertals. The previous interpretation of this assemblage as falling within Early Upper Paleolithic variability remains the most parsimonious explanation; pending additional fossil discoveries, there is no evidence supporting the occurrence of Neandertals at these high latitudes. PMID- 22246759 TI - Education. Better research needed on the impact of charter schools. PMID- 22246760 TI - Plant science. SWEET! The pathway is complete. PMID- 22246761 TI - Ecology. Biodiversity and ecosystem function. PMID- 22246762 TI - Astronomy. Gamma-ray binaries revealed. PMID- 22246763 TI - Materials science. A composite matter of alignment. PMID- 22246764 TI - Chemistry. An elusive intermediate gets caught. PMID- 22246765 TI - Cell biology. Sheddase gets guidance. PMID- 22246766 TI - Retrospective. Paul Mead Doty (1920-2011). PMID- 22246767 TI - Bubblegrams reveal the inner body of bacteriophage phiKZ. AB - Dense packing of macromolecules in cellular compartments and higher-order assemblies makes it difficult to pick out even quite large components in electron micrographs, despite nominally high resolution. Immunogold labeling and histochemical procedures offer ways to map certain components but are limited in their applicability. Here, we present a differential mapping procedure, based on the physical principle of protein's greater sensitivity to radiation damage compared with that of nucleic acid. PMID- 22246768 TI - Simultaneously mitigating near-term climate change and improving human health and food security. AB - Tropospheric ozone and black carbon (BC) contribute to both degraded air quality and global warming. We considered ~400 emission control measures to reduce these pollutants by using current technology and experience. We identified 14 measures targeting methane and BC emissions that reduce projected global mean warming ~0.5 degrees C by 2050. This strategy avoids 0.7 to 4.7 million annual premature deaths from outdoor air pollution and increases annual crop yields by 30 to 135 million metric tons due to ozone reductions in 2030 and beyond. Benefits of methane emissions reductions are valued at $700 to $5000 per metric ton, which is well above typical marginal abatement costs (less than $250). The selected controls target different sources and influence climate on shorter time scales than those of carbon dioxide-reduction measures. Implementing both substantially reduces the risks of crossing the 2 degrees C threshold. PMID- 22246770 TI - Universal signatures of fractionalized quantum critical points. AB - Ground states of certain materials can support exotic excitations with a charge equal to a fraction of the fundamental electron charge. The condensation of these fractionalized particles has been predicted to drive unusual quantum phase transitions. Through numerical and theoretical analysis of a physical model of interacting lattice bosons, we establish the existence of such an exotic critical point, called XY*. We measure a highly nonclassical critical exponent eta = 1.493 and construct a universal scaling function of winding number distributions that directly demonstrates the distinct topological sectors of an emergent Z(2) gauge field. The universal quantities used to establish this exotic transition can be used to detect other fractionalized quantum critical points in future model and material systems. PMID- 22246771 TI - Bistability in atomic-scale antiferromagnets. AB - Control of magnetism on the atomic scale is becoming essential as data storage devices are miniaturized. We show that antiferromagnetic nanostructures, composed of just a few Fe atoms on a surface, exhibit two magnetic states, the Neel states, that are stable for hours at low temperature. For the smallest structures, we observed transitions between Neel states due to quantum tunneling of magnetization. We sensed the magnetic states of the designed structures using spin-polarized tunneling and switched between them electrically with nanosecond speed. Tailoring the properties of neighboring antiferromagnetic nanostructures enables a low-temperature demonstration of dense nonvolatile storage of information. PMID- 22246772 TI - Composites reinforced in three dimensions by using low magnetic fields. AB - The orientation and distribution of reinforcing particles in artificial composites are key to enable effective reinforcement of the material in mechanically loaded directions, but remain poor if compared to the distinctive architectures present in natural structural composites such as teeth, bone, and seashells. We show that micrometer-sized reinforcing particles coated with minimal concentrations of superparamagnetic nanoparticles (0.01 to 1 volume percent) can be controlled by using ultralow magnetic fields (1 to 10 milliteslas) to produce synthetic composites with tuned three-dimensional orientation and distribution of reinforcements. A variety of structures can be achieved with this simple method, leading to composites with tailored local reinforcement, wear resistance, and shape memory effects. PMID- 22246769 TI - Periodic emission from the gamma-ray binary 1FGL J1018.6-5856. AB - Gamma-ray binaries are stellar systems containing a neutron star or black hole, with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that 1FGL J1018.6-5856 exhibits intensity and spectral modulation with a 16.6-day period. We identified a variable x-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an O6V((f)) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. 1FGL J1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy. PMID- 22246773 TI - Direct kinetic measurements of Criegee intermediate (CH2OO) formed by reaction of CH2I with O2. AB - Ozonolysis is a major tropospheric removal mechanism for unsaturated hydrocarbons and proceeds via "Criegee intermediates"--carbonyl oxides--that play a key role in tropospheric oxidation models. However, until recently no gas-phase Criegee intermediate had been observed, and indirect determinations of their reaction kinetics gave derived rate coefficients spanning orders of magnitude. Here, we report direct photoionization mass spectrometric detection of formaldehyde oxide (CH(2)OO) as a product of the reaction of CH(2)I with O(2). This reaction enabled direct laboratory determinations of CH(2)OO kinetics. Upper limits were extracted for reaction rate coefficients with NO and H(2)O. The CH(2)OO reactions with SO(2) and NO(2) proved unexpectedly rapid and imply a substantially greater role of carbonyl oxides in models of tropospheric sulfate and nitrate chemistry than previously assumed. PMID- 22246774 TI - Changes in wind pattern alter albatross distribution and life-history traits. AB - Westerly winds in the Southern Ocean have increased in intensity and moved poleward. Using long-term demographic and foraging records, we show that foraging range in wandering albatrosses has shifted poleward in conjunction with these changes in wind pattern, while their rates of travel and flight speeds have increased. Consequently, the duration of foraging trips has decreased, breeding success has improved, and birds have increased in mass by more than 1 kilogram. These positive consequences of climate change may be temporary if patterns of wind in the southern westerlies follow predicted climate change scenarios. This study stresses the importance of foraging performance as the key link between environmental changes and population processes. PMID- 22246775 TI - Plant species richness and ecosystem multifunctionality in global drylands. AB - Experiments suggest that biodiversity enhances the ability of ecosystems to maintain multiple functions, such as carbon storage, productivity, and the buildup of nutrient pools (multifunctionality). However, the relationship between biodiversity and multifunctionality has never been assessed globally in natural ecosystems. We report here on a global empirical study relating plant species richness and abiotic factors to multifunctionality in drylands, which collectively cover 41% of Earth's land surface and support over 38% of the human population. Multifunctionality was positively and significantly related to species richness. The best-fitting models accounted for over 55% of the variation in multifunctionality and always included species richness as a predictor variable. Our results suggest that the preservation of plant biodiversity is crucial to buffer negative effects of climate change and desertification in drylands. PMID- 22246776 TI - A DOC2 protein identified by mutational profiling is essential for apicomplexan parasite exocytosis. AB - Exocytosis is essential to the lytic cycle of apicomplexan parasites and required for the pathogenesis of toxoplasmosis and malaria. DOC2 proteins recruit the membrane fusion machinery required for exocytosis in a Ca(2+)-dependent fashion. Here, the phenotype of a Toxoplasma gondii conditional mutant impaired in host cell invasion and egress was pinpointed to a defect in secretion of the micronemes, an apicomplexan-specific organelle that contains adhesion proteins. Whole-genome sequencing identified the etiological point mutation in TgDOC2.1. A conditional allele of the orthologous gene engineered into Plasmodium falciparum was also defective in microneme secretion. However, the major effect was on invasion, suggesting that microneme secretion is dispensable for Plasmodium egress. PMID- 22246777 TI - Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. AB - The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFalpha-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the endoplasmic reticulum. The failure of TACE to exit the endoplasmic reticulum in the absence of iRhom2 prevents the furin-mediated maturation and trafficking of TACE to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target. PMID- 22246778 TI - iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. AB - Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor alpha (TNFalpha), which is shed from the plasma membrane after cleavage by the TNFalpha convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFalpha shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene targeted iRhom2-deficient mice showed reduced serum TNFalpha in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2 deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense. PMID- 22246779 TI - Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration. AB - Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. MU-Opioid receptor agonists exert a powerful but reversible depression at C fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca(2+)-dependent signaling and normalization of the phosphorylation state of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain. PMID- 22246780 TI - Association between exposure to secondhand smoke and sleep bruxism in children: a randomised control study. AB - BACKGROUND: Exposure to secondhand smoke (SHS) is a serious public health threat and represents a preventable cause of morbidity among children. Sleep bruxism is characterised by teeth grinding or clenching movements during sleep and may begin in adulthood as well as in childhood. OBJECTIVES: To investigate the association between SHS exposure and sleep bruxism in children. METHODS: Sleep bruxism was investigated in 498 children (mean age: 9.2+/-1.9). Family members were interviewed and asked whether they smoked in the presence of their children. Children were classified according to their exposure to SHS into heavily, moderately, lightly and occasionally exposed. Children with sleep bruxism and exposed to SHS were randomly divided into two groups: children in group 1 were not exposed to SHS for 6 months, whereas children in group 2 were. RESULTS: Thirty-one per cent of the children under investigation suffered from bruxism. Among them, 116 children (76%) were exposed to SHS. Exposed children showed a higher risk of sleep bruxism (p<0.05). After 6 months, sleep bruxism was found in 38% and in 90% of children, in the first and in the second group, respectively, this difference was statistically significant (p<0.05). In group 1, changes were statistically significant in those who were heavily and moderately exposed (p<0.05) but not in those lightly and occasionally exposed (p>0.05). In group 2, changes were not statistically significant (p>0.05). CONCLUSION: The findings showed that high and moderate exposure to SHS is associated with sleep bruxism in children. PMID- 22246781 TI - Who receives prescriptions for smoking cessation medications? An association rule mining analysis using a large primary care database. AB - AIMS: To use association rule mining methods to investigate prescribing of smoking cessation medication in the UK primary care and to identify the characteristics of numerically important groups of patients who typically do, or do not, receive cessation therapy. DESIGN: An association rule mining study using The Health Improvement Network Database. SETTINGS AND PARTICIPANTS: 282 433 patients aged 16 years and over from 419 UK general practices, who were registered with the practice throughout 2008 and recorded as a current smoker during that year. OUTCOME: Prescription for any type of smoking cessation medications in 2008 (nicotine replacement therapy, bupropion or varenicline). VARIABLES: Age, gender, lifestyle indicators and co-morbidity. RESULTS: Of the current smokers, 37 731 (13.4%) were given prescriptions for smoking cessation treatment during 2008. Prescriptions were particularly likely to be given to women, those aged 31-60 years, and people with diagnoses of chronic obstructive pulmonary disease and depression. On the contrary, of patients with dementia, with alcohol intake over recommended levels, atrial fibrillation or chronic kidney disease was extremely unlikely to be prescribed a smoking cessation medication. However, the largest group of patients who did not receive therapy was young and otherwise healthy individuals. CONCLUSIONS: This novel approach identified sizeable and easily definable groups of patients who are systematically failing to receive support for smoking cessation in primary care. Association rule mining can be used to identify key numerically important groups at high or low risk of receiving treatment and hence potentially to improve healthcare delivery. PMID- 22246783 TI - Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells. AB - High mobility group protein A2 (HMGA2) is an architectural transcription factor that plays an important role in development and progression of malignant neoplasias. Recently, some studies reported that HMGA2 is also implicated in epithelial-mesenchymal transitions (EMT) and cancer stem cells. But the underlying mechanisms of these conditions are poorly understood. Therefore, we established an EMT model of gastric carcinoma cells by overexpressing HMGA2 in vitro, then global mapping of HMGA2 potential transcription factor binding sites was identified by promoter microarray in these cells, and the date obtained from the microarrays were validated via chromatin immunoprecipitation-PCR (ChIP-PCR) and real-time PCR. HMGA2 potential target genes were classified in KEGG database and Gene Ontology (GO) analyses. To our knowledge, this is the first report on the genome-wide analysis of HMGA2 downstream direct targets, and these findings will be valuable in understanding the roles of HMGA2 in EMT. PMID- 22246782 TI - Applications of arterial spin labeled MRI in the brain. AB - Perfusion provides oxygen and nutrients to tissues and is closely tied to tissue function while disorders of perfusion are major sources of medical morbidity and mortality. It has been almost two decades since the use of arterial spin labeling (ASL) for noninvasive perfusion imaging was first reported. While initial ASL magnetic resonance imaging (MRI) studies focused primarily on technological development and validation, a number of robust ASL implementations have emerged, and ASL MRI is now also available commercially on several platforms. As a result, basic science and clinical applications of ASL MRI have begun to proliferate. Although ASL MRI can be carried out in any organ, most studies to date have focused on the brain. This review covers selected research and clinical applications of ASL MRI in the brain to illustrate its potential in both neuroscience research and clinical care. PMID- 22246784 TI - Antifungal activity of plant extracts against Colletotrichum lagenarium, the causal agent of anthracnose in cucumber. AB - BACKGROUND: Colletotrichum lagenarium is an important plant-pathogenic fungus that causes anthracnose of cucumber, a disease that is widespread under both greenhouse and field cultivation. To find a promising method for the control of this disease, extracts of eight plants from China were screened in the study presented here. RESULTS: The results showed that the extract of Cinnamomum camphora (L.) Presl had significantly greater inhibitory activity against C. lagenarium than the other seven plant extracts tested in vitro. At 5 days after inoculation in a potted seedling experiment, C. camphora extract demonstrated 95% control of C. lagenarium at a concentration of 16 mg mL-1, and the MIC50 was 2.596 mg mL-1. Microscopic observation showed that this extract had a significant impact on the morphology of the fungus, leading to shorter hyphae that were more branched; this observation was associated with the inhibition of mycelial growth. Stability assays revealed that the extract was relatively stable at 80 degrees C, under acidic conditions and when exposed to light and short periods of UV radiation. CONCLUSION: These results demonstrated that the extract from C. camphora could be used as a potent phytochemical fungicide. PMID- 22246785 TI - Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. AB - Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by developmental defects and tumorigenesis. The clinical manifestations of NBCCS have been reported in large epidemiological studies from the United States, the United Kingdom, and Australia, but not from an Asian country. We conducted a nationwide survey and identified 311 NBCCS patients in Japan. We investigated the detailed clinical manifestations of 157 patients ranging in age from 9 months to 77 years old (mean: 33.1 years). We then compared the frequency and age of onset for various tumors developed in Japanese NBCCS patients with patients from the three countries listed above in which NBCCS studies were previously conducted. Our most significant finding was the low frequency of basal cell carcinoma (BCC) in Japanese patients. Frequency of BCC in patients over 20 years of age was 51.4%, a much lower rate compared to the United States, Australia, and the United Kingdom (91%, 85%, and 73%, respectively). The mean age of BCC onset was 37.4 years of age, a much older age compared to the above-mentioned countries. These findings suggest that differences in ethnicity and/or environmental factors affect the incidence of BCC. Because the age of BCC onset is generally higher in Japanese NBCCS patients, careful skin examination over a prolonged period of time is warranted. PMID- 22246787 TI - A Kohonen neural network description of scoliosis fused regions and their corresponding Lenke classification. AB - PURPOSE: Surgical instrumentation for adolescent idiopathic scoliosis (AIS) is a complex procedure where selection of the appropriate curve segment to fuse, i.e., fusion region, is a challenging decision in scoliosis surgery. Currently, the Lenke classification model is used for fusion region evaluation and surgical planning. Retrospective evaluation of Lenke classification and fusion region results was performed. METHODS: Using a database of 1,776 surgically treated AIS cases, we investigated a topologically ordered self organizing Kohonen network, trained using Cobb angle measurements, to determine the relationship between the Lenke class and the fusion region selection. Specifically, the purpose was twofold (1) produce two spatially matched maps, one of Lenke classes and the other of fusion regions, and (2) associate these two maps to determine where the Lenke classes correlate with the fused spine regions. RESULTS: Topologically ordered maps obtained using a multi-center database of surgically treated AIS cases, show that the recommended fusion region agrees with the Lenke class except near boundaries between Lenke map classes. Overall agreement was 88%. CONCLUSION: The Lenke classification and fusion region agree in the majority of adolescent idiopathic scoliosis when reviewed retrospectively. The results indicate the need for spinal fixation instrumentation variation associated with the Lenke classification. PMID- 22246786 TI - Reconstruction of MRI data encoded by multiple nonbijective curvilinear magnetic fields. AB - Parallel imaging technique using localized gradients (PatLoc) uses the combination of surface gradient coils generating nonbijective curvilinear magnetic fields for spatial encoding. PatLoc imaging using one pair of multipolar spatial encoding magnetic fields (SEMs) has two major caveats: (1) The direct inversion of the encoding matrix requires exact determination of multiple locations which are ambiguously encoded by the SEMs. (2) Reconstructed images have a prominent loss of spatial resolution at the center of field-of-view using a symmetric coil array for signal detection. This study shows that a PatLoc system actually has a higher degree of freedom in spatial encoding to mitigate the two challenges mentioned above. Specifically, a PatLoc system can generate not only multipolar but also linear SEMs, which can be used to reduce the loss of spatial resolution at the field-of-view center. Here, we present an efficient and generalized image reconstruction method for PatLoc imaging using multiple SEMs without explicitly identifying the locations where SEM encoding is not unique. Reconstructions using simulations and empirical experimental data are compared with those using conventional linear gradients to demonstrate that the general combination of SEMs can improve image reconstructions. PMID- 22246788 TI - 100 picosecond diffraction catches structural transients of laser-pulse triggered switching in a spin-crossover crystal. AB - We study by 100 picosecond X-ray diffraction the photo-switching dynamics of single crystal of the orthorhombic polymorph of the spin-crossover complex [(TPA)Fe(TCC)]PF(6), in which TPA = tris(2-pyridyl methyl)amine, TCC(2-) = 3,4,5,6-Cl(4)-Catecholate(2-). In the frame of the emerging field of dynamical structural science, this is made possible by using optical pump/X-ray probe techniques, which allow following in real time structural reorganization at intra and intermolecular levels associated with the change of spin state in the crystal. We use here the time structure of the synchrotron radiation generating 100 picosecond X-ray pulses, coupled to 100 fs laser excitation. This study has revealed a rich variety of structural reorganizations, associated with the different steps of the dynamical process. Three consecutive regimes are evidenced in the time domain: 1) local molecular photo-switching with structural reorganization at constant volume, 2) volume relaxation with inhomogeneous distribution of local temperatures, 3) homogenization of the crystal in the transient state 100 us after laser excitation. These findings are fundamentally different from those of conventional diffraction studies of long-lived photoinduced high spin states. The time-resolution used here with picosecond X ray diffraction probes different physical quantities on their intrinsic time scale, shedding new light on the successive processes driving macroscopic switching in a functionalized material. These results pave the way for structural studies away from equilibrium and represent a first step toward femtosecond crystallography. PMID- 22246789 TI - Two iron catalysts are better than one: a general and convenient reduction of aromatic and aliphatic primary amides. PMID- 22246790 TI - N-acetylcysteine attenuates copper overload-induced oxidative injury in brain of rat. AB - Copper is an integral part of many important enzymes involved in a number of vital biological processes. Even though it is essential to life, at elevated tissue concentrations, copper can become toxic to cells. Recent studies have reported oxidative damage due to copper in various tissues. Considering the vulnerability of the brain to oxidative stress, this study was undertaken to explore possible beneficial antioxidant effects of N-acetylcysteine on oxidative stress induced by copper overload in brain tissue of rats. Thirty-two Wistar rats were equally divided into four groups. The first group was used as control. The second, third, and fourth groups were given 1 g/L copper in their drinking water for 1 month. At the end of this period, the group 2 rats were sacrificed. During the next 2 weeks, the rats in group 3 were injected intraperitoneally with physiological saline and those in group 4 with 20 mg/kg intraperitoneal injections of N-acetylcysteine. In group 2 the lipid peroxidation and nitric oxide levels were increased in the brain cortex while the activities of superoxide dismutase and catalase and the concentration of glutathione were decreased. In rats treated with N-acetylcysteine, lipid peroxidation decreased and the activities of antioxidant enzyme improved in the brain cortex. In conclusion, treatment with N-acetylcysteine modulated the antioxidant redox system and reduced brain oxidative stress induced by copper. PMID- 22246791 TI - Spectroscopic characterization of an oxovanadium(IV) complex of oxodiacetic acid and o-phenanthroline. Bioactivity on osteoblast-like cells in culture. AB - The oxovanadium(IV) complex of oxodiacetic acid (H(2)ODA) and o-phenanthroline of stoichiometry [VO(ODA)(ophen)].1.5H(2)O, which presents the interesting tridentate OOO coordination, was thoroughly characterized by infrared, Raman, and electronic spectroscopies. The biological activity of the complex on the cell proliferation was tested on osteoblast-like cells (MC3T3E1 osteoblastic mouse calvaria-derived cells and UMR106 rat osteosarcoma-derived cells) in culture. The complex caused inhibition of cellular proliferation in both osteoblast cell lines in culture, but the cytotoxicity was stronger in the normal (MC3T3E1) than in the tumoral (UMR106) osteoblasts. PMID- 22246792 TI - Effect of lanthanum on rooting of in vitro regenerated shoots of Saussurea involucrata Kar. et Kir. AB - In present study, the effect of lanthanum (La) on the rooting of regenerated shoots of Saussurea involucrata Kar. et Kir was analyzed. Rooting occurred from regenerated shoots inoculated on a medium supplemented with La, the plant rooting hormone indole-3-acetic acid (IAA), or both La and IAA together. The highest rooting efficiency (96%), root number/shoot (8.5), and root length (63 mm) were recorded in shoots cultured on medium containing 2.5 MUM IAA combined with 100 MUM La(3+). In order to elucidate the mechanism of rooting enhancement by La, we examined dynamic changes in antioxidant enzyme activities in plant tissue over time in culture. We found that the activities of peroxidase (POX) and superoxide dismutase (SOD) were significantly higher in plant tissue cultured in IAA plus La than in La or IAA alone. At the same time, the highest H(2)O(2) content was detected in plant tissue in the presence of 2.5 MUM IAA plus 100 MUM La(3+). In light of these data and previous results, we speculate that La enhanced IAA induced rooting by acting as a mild abiotic stress to stimulate POX and SOD activities in plant cells. Then, IAA reacted with oxygen and POX to form the ternary complex enzyme-IAA-O(2) that dissociated into IAA radicals and O(2)(-). Subsequently, IAA-induced O(2)(-) readily converted to hydroxyl radical (HO.) via SOD-catalyzed dismutation. Finally, cell wall loosening and cell elongation occurred as a consequence of HO-dependent scission of wall components, leading to root growth. The treatment of IAA combined with La resulted in the highest plantlet survival (80%) compared to single treatments with IAA or La alone. These data suggest that rare earth elements enhance root morphogenesis and the growth of S. involucrata. PMID- 22246793 TI - Epithelial-to-mesenchymal transition induced by Freund's adjuvant treatment in rat mesothelial cells: a morphological and immunocytochemical study. AB - Intraperitoneal injection of Freund's adjuvant induces acute peritonitis. By the time of the Freund's adjuvant treatment the flat, simple squamous epithelial cells became rounded, cuboidal shaped, many of them have lost their connection with the neighbouring cells and detached from the basement membrane. The macrophage markers' (ED1, OX43 and CD68) expression also increased in the mesothelial cells and more mesothelin and anti-ED1 double-labelled cells were found freely present close to the surface. The cytokeratin expression of the mesothelial cells has gradually decreased. At the 5th day of the inflammation practically there was no cytokeratin labelling present in the mesothelial cells and the mesothelin expression has significantly decreased. Parallel to this mesothelial cells started to express vimentin, a characteristic mesenchymal intermediate filament protein indicating that they gradually lost their epithelial character and gained mesenchymal phenotype. These results strongly suggest that under the effect of Freund's adjuvant treatment (inflammation) mesothelial cells can undergo epithelial-to-mesenchymal transition and differentiate into phagocytotic (macrophage-like) cells. Studying the caveolae/caveolin-1 on the plasma membrane of mesothelial cells we found that the Freund's adjuvant treatment has changed the cellular distribution of caveolin-1: as the inflammation progressed strong caveolin-1 labelling was found inside of the cytoplasm (in perinuclear localization) indicating that inflammation induced the caveolae internalization. These results indicate that caveolae/caveolin-1 might play important regulatory role in signal transduction leading to trasdifferentiation. PMID- 22246794 TI - The role of SPARC protein expression in the progress of gastric cancer. AB - We aimed to investigate the expression of SPARC (secreted protein, acidic and rich in cysteine) in gastric cancer and its relationship with tumor angiogenesis and cancer cells proliferation. Protein expression of SPARC, VEGF, CD34 and Ki-67 in 80 cases of gastric cancer and 30 cases of normal gastric tissue was evaluated by immunohistochemistry. CD34 staining was used as an indicator of microvessel density (MVD). Ki-67 labeling Index (LI) indicated cancer cells proliferation. Statistical analysis was used to investigate its relationship with clinical characteristics, tumor angiogenesis and cancer cells proliferation. SPARC expression was mainly in the stromal cells surrounding the gastric cancer cells, and was statistically significant differences between gastric cancer and normal gastric tissue (P < 0.05). Both the expression of SPARC and VEGF were related to differentiation degree, clinical stage, Lauren classification and lymph node metastasis (P < 0.05). Expression of SPARC was significantly negatively correlated with the expression of VEGF and MVD in gastric cancer tissues. Expression of SPARC was also negatively correlated with Ki-67-LI. Our findings suggest that both the expression of SPARC and VEGF are closed to tumor angiogenesis in gastric cancer, SPARC inhibited tumor angiogenesis but VEGF promoted tumor angiogenesis. SPARC also inhibited cells proliferation of gastric cancer. PMID- 22246796 TI - Modeling disability trajectories and mortality of the oldest-old in China. AB - This article uses a group-based modeling approach to jointly estimate disability and mortality trajectories over time based on data from the population aged 80 and older in China, and explores relations of demographic, socioeconomic, and early-life characteristics to membership in gender-specific trajectory groups. A three-group model best fits the data for both males and females. For most groups, predicted numbers of limitations in activities of daily living (ADLs) increase with age, but the pace is gradual in some cases and rapid in others. For each gender, the estimated mortality probability trajectories for the three groups follow a hierarchy that is related to the predicted ADL counts at age 80. Only a few characteristics predict trajectory-group membership. Prior nonagricultural occupation is associated with less favorable disability trajectories for both genders. For females, rural residence, a greater number of children ever born, and having a father who did not work in agriculture are associated with more favorable trajectories. For a small group of males who received education, disability is moderate but changes little with age. Findings may reflect heterogeneity of survival among the least advantaged, as well as a possible expansion of morbidity among a small advantaged group. PMID- 22246797 TI - Educational attainment and adult mortality in the United States: a systematic analysis of functional form. AB - A vast literature has documented the inverse association between educational attainment and U.S. adult mortality risk but given little attention to identifying the optimal functional form of the association. A theoretical explanation of the association hinges on our ability to describe it empirically. Using the 1979-1998 National Longitudinal Mortality Study for non-Hispanic white and black adults aged 25-100 years during the mortality follow-up period (N = 1,008,215), we evaluated 13 functional forms across race-gender-age subgroups to determine which form(s) best captured the association. Results revealed that the preferred functional form includes a linear decline in mortality risk from 0 to 11 years of education, followed by a step-change reduction in mortality risk upon attainment of a high school diploma, at which point mortality risk resumes a linear decline but with a steeper slope than that prior to a high school diploma. The findings provide important clues for theoretical development of explanatory mechanisms: an explanation for the selected functional form may require integrating a credentialist perspective to explain the step-change reduction in mortality risk upon attainment of a high school diploma, with a human capital perspective to explain the linear declines before and after a high school diploma. PMID- 22246798 TI - Employment patterns of less-skilled workers: links to children's behavior and academic progress. AB - Using data from five waves of the Women's Employment Survey (WES; 1997-2003), we examine the links between low-income mothers' employment patterns and the emotional behavior and academic progress of their children. We find robust and substantively important linkages between several different dimensions of mothers' employment experiences and child outcomes. The pattern of results is similar across empirical approaches-including ordinary least squares and child fixed effect models, with and without an extensive set of controls. Children exhibit fewer behavior problems when mothers work and experience job stability (relative to children whose mothers do not work). In contrast, maternal work accompanied by job instability is associated with significantly higher child behavior problems (relative to employment in a stable job). Children whose mothers work full-time and/or have fluctuating work schedules also exhibit significantly higher levels of behavior problems. However, full-time work has negative consequences for children only when it is in jobs that do not require cognitive skills. Such negative consequences are completely offset when this work experience is in jobs that require the cognitive skills that lead to higher wage growth prospects. Finally, fluctuating work schedules and full-time work in non-cognitively demanding jobs are each strongly associated with the probability that the child will repeat a grade or be placed in special education. PMID- 22246799 TI - Body composition and outcome in patients undergoing resection of colorectal liver metastases. AB - BACKGROUND: Recent evidence suggests that depletion of skeletal muscle mass (sarcopenia) and an increased amount of intra-abdominal fat (central obesity) influence cancer statistics. This study investigated the impact of sarcopenia and central obesity on survival in patients undergoing liver resection for colorectal liver metastases (CLM). METHODS: Diagnostic imaging from patients who had hepatic resection for CLM in one centre between 2001 and 2009, and who had assessable perioperative computed tomograms, was analysed retrospectively. Total cross sectional areas of skeletal muscle and intra-abdominal fat, and their influence on outcome, were analysed. RESULTS: Of the 196 patients included in the study, 38 (19.4 per cent) were classified as having sarcopenia. Five-year disease-free (15 per cent versus 28.5 per cent in patients without sarcopenia; P = 0.002) and overall (20 per cent versus 49.9 per cent respectively; P < 0.001) survival rates were lower for patients with sarcopenia at a median follow-up of 29 (range 1-97) months. Sarcopenia was an independent predictor of worse recurrence-free (hazard ratio (HR) 1.88, 95 per cent confidence interval 1.25 to 2.82; P = 0.002) and overall (HR 2.53, 1.60 to 4.01; P < 0.001) survival. Central obesity was associated with an increased risk of recurrence in men (P = 0.032), but not in women (P = 0.712). CONCLUSION: Sarcopenia has a negative impact on cancer outcomes following resection of CLM. PMID- 22246800 TI - The role of the Src family kinase Lyn in the immunomodulatory activities of cathelicidin peptide LL-37 on monocytic cells. AB - Cathelicidin LL-37 is a multifunctional, immunomodulatory and antimicrobial host defense peptide of the human immune system. Here, we identified the role of SFKs in mediating the chemokine induction activity of LL-37 in monocytic cells. LL-37 induced SFK phosphorylation; and chemical inhibitors of SFKs suppressed chemokine production in response to LL-37 stimulation. SFKs were required for the downstream activation of AKT, but Ca(2+)-flux and MAPK induction were SFK independent. Through systematic siRNA knockdown of SFK members, a requirement for Lyn in mediating LL-37 activity was identified. The involvement of Lyn in cathelicidin activities was further confirmed using Lyn-knockout mouse BMDMs. The role of SFKs and Lyn was also demonstrated in the activities of the synthetic cationic IDR peptides, developed as novel, immunomodulatory therapeutics. These findings elucidate the common molecular mechanisms mediating the chemokine induction activity of natural and synthetic cationic peptides in monocytic cells and identify SFKs as a potential target for modulating peptide responses. PMID- 22246801 TI - Resolving confusion of tongues in statistics and machine learning: a primer for biologists and bioinformaticians. AB - Bioinformatics is the field where computational methods from various domains have come together for analysis of biological data. Each domain has introduced its own specific jargon. However, in closely related domains, e.g. machine learning and statistics, concordant and discordant terminology occurs, the later can lead to confusion. This article aims to help solve the confusion of tongues arising from these two closely related domains, which are frequently used in bioinformatics. We provide a short summary of the most commonly applied machine learning and statistical approaches to data analysis in bioinformatics, i.e. classification and statistical hypothesis testing. We explain differences and similarities in common terminology used in various domains, such as precision, recall, sensitivity and true positive rate. This primer can serve as a guide to the terminology used in these fields. PMID- 22246802 TI - Hypocholesterolaemic and antioxidant activities of chickpea (Cicer arietinum L.) protein hydrolysates. AB - BACKGROUND: Some dietary proteins possess biological properties which make them potential ingredients of functional or health-promoting foods. Many of these properties are attributed to bioactive peptides that can be released by controlled hydrolysis using exogenous proteases. The aim of this work was to test the improvement of hypocholesterolaemic and antioxidant activities of chickpea protein isolate by means of hydrolysis with alcalase and flavourzyme. RESULTS: All hydrolysates tested exhibited better hypocholesterolaemic activity when compared with chickpea protein isolate. The highest cholesterol micellar solubility inhibition (50%) was found after 60 min of treatment with alcalase followed by 30 min of hydrolysis with flavourzyme. To test antioxidant activity of chickpea proteins three methods were used: beta-carotene bleaching method, reducing power and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging effect since antioxidant activity of protein hydrolysates may not be attributed to a single mechanism. Chickpea hydrolysates showed better antioxidant activity in all assays, especially reducing power and DPPH scavenging effect than chickpea protein isolate. CONCLUSION: The results of this study showed the good potential of chickpea protein hydrolysates as bioactive ingredients. The highest bioactive properties could be obtained by selecting the type of proteases and the hydrolysis time. PMID- 22246803 TI - Flexible transceiver array for ultrahigh field human MR imaging. AB - A flexible transceiver array, capable of multiple-purpose imaging applications in vivo at ultrahigh magnetic fields was designed, implemented and tested on a 7 T MR scanner. By alternately placing coil elements with primary and secondary harmonics, improved decoupling among coil elements was accomplished without requiring decoupling circuitry between resonant elements, which is commonly required in high-frequency transceiver arrays to achieve sufficient element isolation during radiofrequency excitation. This flexible array design is capable of maintaining the required decoupling among resonant elements in different array size and geometry and is scalable in coil size and number of resonant elements (i.e., number of channels), yielding improved filling factors for various body parts with different geometry and size. To investigate design feasibility, flexibility, and array performance, a multichannel, 16-element transceiver array was designed and constructed, and in vivo images of the human head, knee, and hand were acquired using a whole-body 7 T MR system. Seven Tesla parallel imaging with generalized autocalibrating partially parallel acquisitions (GRAPPA) performed using this flexible transceiver array was also presented. PMID- 22246804 TI - Instantaneous exposure to nuclear medicine staff involved in PET-CT imaging in developing countries: experience from a tertiary care centre in India. AB - PURPOSE: To assess the radiation exposure to nuclear medicine staff at a positron emission tomography-computed tomography (PET-CT) centre with high patient throughput. MATERIALS AND METHODS: This prospective study included 70 adult patients who underwent 18F-fluorodeoxyglucose (FDG) PET-CT for their clinical indications. The patients' actual injected FDG activity was calculated by subtracting the syringe activity (post-injection) from the loaded syringe activity (pre-injection). The instantaneous exposure to nuclear medicine staff involved in PET-CT imaging was measured. The instantaneous dose rate of the physicians was recorded during FDG injection and that of the technologist was recorded during the patient's positioning, respectively, at 1.0-m distance from the anterior chest using a calibrated portable gamma-ray survey meter. RESULTS: The average FDG activity injected in adult patients was 308.5 MBq (range 173.1 438.8 MBq). The instantaneous exposure to the nuclear medicine (NM) physician during the injection time was 31 MUSv/h (14-60 MUSv/h). The instantaneous exposure to the NM technologist during positioning was 18 (10-34) MUSv/h. With an average of 10 patients per day, the quarterly dose to physicians was 628 MUSv and to technologists 182 MUSv for 300 patients. The extrapolated annual dose was 2.5 mSv for physicians and 0.7 mSv for technologists, respectively. CONCLUSION: Instantaneous exposure of nuclear medicine staff involved in PET-CT imaging at a busy tertiary care centre is within permissible limits of the International Commission on Radiological Protection (ICRP-103) (total <100 mSv over 5 years and not >50 mSv in a single year) and atomic energy regulatory board (total <100 mSv over 5 years and not >30 mSv in a single year). PMID- 22246805 TI - Oral vitamin C supplementation and serum uric acid: comment on the article by Juraschek et al. PMID- 22246806 TI - Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. AB - Accumulation of saturated fatty acids in the liver can cause nonalcoholic fatty liver disease (NAFLD). This study investigated saturated fatty acid induction of endoplasmic reticulum (ER) stress and apoptosis in human liver cells and the underlying causal mechanism. Human liver L02 and HepG2 cell lines were exposed to the saturated fatty acid sodium palmitate. MTT assay was used for cell viability, flow cytometry and Hoechst 33258 staining for apoptosis, RT-PCR for mRNA expression, and Western blot for protein expression. Silence of PRK-like ER kinase (PERK) expression in liver cells was through transient transfection of PERK shRNA. Treatment of L02 and HepG2 cells with sodium palmitate reduced cell viability through induction of apoptosis. Sodium palmitate also induced ER stress in the cells, indicated by upregulation of PERK phosphorylation and expression of BiP, ATF4, and CHOP proteins. Sodium palmitate had little effect on activating XBP-1, a common target of the other two canonical sensors of ER stress, ATF6, and IRE1. Knockdown of PERK gene expression suppressed the PERK/ATF4/CHOP signaling pathway during sodium palmitate-induced ER stress and significantly inhibited sodium palmitate-induced apoptosis in L02 and HepG2 cells. Saturated fatty acid induced ER stress and apoptosis in these human liver cells were enacted through the PERK/ATF4/CHOP signaling pathway. Future study is warranted to investigate the role of these proteins in mediating saturated fatty acid-induced NAFLD in animal models. PMID- 22246807 TI - Heat shock transcription factor 1 inhibits H2O2-induced cardiomyocyte death through suppression of high-mobility group box 1. AB - Heat shock transcription factor 1 (HSF1), which has been identified as an endogenous cardioprotective factor, possesses considerable anti-inflammatory effects and the ability against oxidative stress. However, the mechanisms have not been fully characterized yet. In this study, we investigated the effects of HSF1-regulated HMGB1 on cardiomyocyte death. Cultured cardiomyocytes were transfected with empty vector or HSF1 plasmid before the exposure to H(2)O(2). Cell death was assessed by cell staining. Additionally, the levels of intracellular and extracellular HMGB1 as well as its subcellular location were detected, and the expression of heat shock proteins (HSP27 and HSP90) in the cardiomyocytes was also determined. Not only did H(2)O(2) significantly increase cell death, but also elevated the levels of intracellular and extracellular HMGB1 and induced its translocation, whereas, as expected, HSF1 overexpression effectively attenuated cell death. Furthermore, HSF1 inhibited the intracellular expression of HMGB1 at early stage of oxidative stress and subsequently, HSF1 did negatively regulate the extracellular levels and the translocation of HMGB1 at late stage. Besides, the expression of HSP27 and HSP90 was significantly increased. These results suggested HSF1-attenuated cardiomyocyte death via reducing intracellular and extracellular levels of HMGB1 as well as preventing its translocation, which was partially associated with HSP27 and HSP90 up regulated by HSF1 overexpression. PMID- 22246808 TI - The relation of serum 25-hydroxyvitamin-D levels with severity of obstructive sleep apnea and glucose metabolism abnormalities. AB - Obstructive sleep apnea (OSA) and 25-hydroxyvitamin-D3 (25-OH-D) deficiency are two separate disorders associating with obesity, inflammation, and impaired glucose metabolism. We aimed to investigate the vitamin D status of OSA patients regarding to potential links between lower vitamin D levels and abnormal glucose metabolism, which is one of the main adverse outcomes of OSA. Study group is composed of 190 non-diabetic subjects who were suspected of having OSA. Subjects undergone polysomnography and were grouped due to apnea-hypopnea indices (AHI) as controls (AHI < 5, n = 47), mild OSA (5 <= AHI < 15, n = 46), moderate OSA (15 <= AHI < 30, n = 47), and severe OSA (AHI >= 30, n = 50). Serum 25-OH-D, HbA1c, insulin levels were measured and 75-g oral glucose tolerance test was performed. Serum 25-OH-D level (ng/ml) of OSA patients were lower than control subjects (17.4 +/- 6.9 vs. 19.9 +/- 7.8), and decrement was parallel to severity of OSA; as 18.2 +/- 6.4 (5 <= AHI < 15), 17.5 +/- 7.4 (15 <= AHI < 30), and 16.3 +/- 6.9 (AHI > 30), respectively (P = 0.097, r = -0.13). However, severe female OSA patients had significantly lower 25-OH-D levels (11.55 ng/ml), while control males had the highest mean value (21.7 ng/ml) (P < 0.001). Frequency of insulin resistance (IR) was 48%, prediabetes 41%, diabetes 16% in OSA patients. Mean 25 OH-D level of insulin resistant subjects (HOMA-IR >= 2.7, n = 77, AHI = 35.5) was lower than non-insulin resistant subjects (HOMA-IR < 2.7, n = 113, AHI = 19.8) as 16.18 +/- 7.81 versus 19.2 +/- 6.6, respectively (P = 0.004). 25-OH-D level of 91 non-diabetic subjects (n = 91, AHI = 19.7) was 19.5 +/- 7.4, prediabetics (n = 75, AHI = 28.7) was 17.45 +/- 6.9, and diabetics (n = 24, AHI = 46.3) was 13.8 +/ 5.3 (P = 0.02). We showed that subjects with more severe OSA indices (AHI >= 15) tended to present lower vitamin D levels correlated to increased prevalence of IR, prediabetes, and diabetes. Vitamin D deficiency may play a role and/or worsen OSA's adverse outcomes on glucose metabolism. OSA patients may be considered for supplementation treatment which was shown to ameliorate abnormal glucose metabolism and inflammation. PMID- 22246809 TI - Serum AMH concentration as a marker evaluating gonadal function in boys operated on for unilateral cryptorchidism between 1st and 4th year of life-why patients with inguinal hernia served as controls. PMID- 22246810 TI - Age at first anal sex and HIV/STI vulnerability among gay men in Australia. AB - OBJECTIVES: To determine whether there is a link between age at first anal intercourse (AFAI) and gay men's HIV/sexually transmissible infection (STI) vulnerability, including tendencies to engage in higher risk sexual behaviour. METHODS: A nationwide cross-sectional survey was conducted online involving 845 Australian gay men born between 1944 and 1993. RESULTS: Median AFAI fell from 35 years for men born between 1944 and 1953 to 18 years for men born between 1984 and 1993. Of those who reported having had anal intercourse (N=822), HIV-positive men were found to be significantly younger on average when they first had anal intercourse compared with HIV-negative men (18.5 vs. 21.3 years, p<0.001). Men with a history of other STIs were also significantly younger. Engaging in higher risk sexual behaviour is a likely factor, with AFAI generally younger among men who reported >10 sexual partners in the past year (p<0.001) and who engaged in group sex (p<0.001), receptive anal intercourse (p=0.008) or were drug or alcohol affected (p=0.06) during their most recent sexual encounter. CONCLUSIONS: There appears to be a strong link between AFAI and infection with HIV/STIs, as well as tendencies to engage in higher risk sexual behaviour. While further research is needed to understand this link, these findings highlight a need for sexuality education aimed at gay-identified youth to ensure their sexual debut does not lead to poorer sexual health outcomes. PMID- 22246813 TI - Comparison of visceral adipose tissue quantification on water suppressed and nonwater-suppressed MRI at 3.0 Tesla. AB - PURPOSE: To systematically evaluate and compare the performance of water saturated and nonwater-saturated T1-weighted 3.0 T magnetic resonance imaging (MRI) in the application of visceral adipose tissue (VAT) quantification. MATERIALS AND METHODS: Forty-five patients underwent abdomen MRI using two different sequences at 3.0 T: 1) a traditional T1-weighted gradient echo sequence, and 2) the same sequence with water presaturation to enhance fat and nonfat contrast. VAT amounts from both water-saturated and nonwater-saturated images were quantified with a manual thresholding technique and an automated segmentation method to study quantification variability and consistency of the two imaging techniques. RESULTS: Nonwater-saturated MRI had significantly larger coefficient of variation than water-saturated MRI in the imaging reproducibility study based on 112 slices from seven subjects (11.4% vs. 2.5%, P < 0.0001). VAT volumes measured from the nonwater-saturation MRI sequence had significantly higher variability than those from water-saturation images even when using a manual quantification method based on images from 38 subjects (1.76% vs. 1.08%, P < 0.001). In addition, the VAT volume amounts from nonwater-saturation images and water-saturated images quantified with the automatic and manual quantification methods were statistically consistent. CONCLUSION: Water-saturated MRI sequences at 3.0 T for VAT quantification improve reproducibility and decrease variability compared with nonwater saturated sequences, especially with the use of automatic quantification methods. PMID- 22246814 TI - Synthesis of tetrasubstituted furans by palladium-catalyzed decarboxylative [3+2] cyclization of propargyl beta-keto esters. PMID- 22246815 TI - The analysis of binary longitudinal data with time-dependent covariates. AB - We consider longitudinal studies with binary outcomes that are measured repeatedly on subjects over time. The goal of our analysis was to fit a logistic model that relates the expected value of the outcomes with explanatory variables that are measured on each subject. However, additional care must be taken to adjust for the association between the repeated measurements on each subject. We propose a new maximum likelihood method for covariates that may be fixed or time varying. We also implement and make comparisons with two other approaches: generalized estimating equations, which may be more robust to misspecification of the true correlation structure, and alternating logistic regression, which models association via odds ratios that are subject to less restrictive constraints than are correlations. The proposed estimation procedure will yield consistent and asymptotically normal estimates of the regression and correlation parameters if the correlation on consecutive measurements on a subject is correctly specified. Simulations demonstrate that our approach can yield improved efficiency in estimation of the regression parameter; for equally spaced and complete data, the gains in efficiency were greatest for the parameter associated with a time-by group interaction term and for stronger values of the correlation. For unequally spaced data and with dropout according to a missing-at-random mechanism, MARK1ML with correctly specified consecutive correlations yielded substantial improvements in terms of both bias and efficiency. We present an analysis to demonstrate application of the methods we consider. We also offer an R function for easy implementation of our approach. PMID- 22246816 TI - Effectively training pediatric residents to deliver diagnoses of Down syndrome. AB - Physicians and parents report a need for pediatricians to have additional training in delivering a diagnosis of Down syndrome (DS). This study tested a web based tutorial to assess its effectiveness in improving physicians' perceived comfort with both ambiguous and more medically factual situations as they deliver diagnoses of DS. Based on this web tutorial that integrated prenatal and postnatal information into virtual patient scenarios, the study assessed pediatrics residents' knowledge and comfort in delivering a diagnosis of DS pre and postnatally. A separate survey, given at the same time, asked for residents' perception of their need for this training. Ninety-one volunteer residents from 10 pediatric training programs across the country participated. The tutorial yielded significant improvement in knowledge and a significant decrease in perceived level of discomfort in both ambiguous situations and more medically certain contexts related to a DS diagnosis. In addition, across all pediatric resident groups (by year, gender, and performance on the knowledge test and the comfort scale), residents strongly agreed that this type of training was beneficial for themselves, other residents, practicing physicians, and other medical professionals. This study suggests that web-based, interactive, multi media training may be an effective tool for improving resident physician comfort with both ambiguous and more medically certain situations in delivering a diagnosis of DS to families. PMID- 22246817 TI - Bleeding risk assessment and management in atrial fibrillation patients. PMID- 22246820 TI - The methylproteome and the intracellular methylation network. AB - Since its discovery more than 50 years ago, post-translational modification (PTM) of proteins via methylation has grown in prominence, its involvement having been recognised in a number of central processes in the cell. Of these, the best characterised is its role in the epigenetic code. However, there is increasing evidence that its role extends far beyond this and we propose that it is a key regulator in interactome dynamics. In this review, we focus on the role of methylation in regulating protein-protein interactions and illustrate, by providing a broad-scale summary of our current knowledge of methylation and its impact on systems biology, how this can ultimately affect interactome dynamics. We describe the variety of analytical techniques available for the study of the methylproteome, comment on their advantages and limitations, and consider how these tools can help elucidate how methylation regulates the dynamics of the interactome. The insights gained from methyltransferase-substrate networks will be summarised and the ability of protein methylation to facilitate or block protein-protein interactions as well as their interplay with other post translational modifications, in particular phosphorylation, is highlighted. Finally, the importance of methylation in pathology-associated protein interaction networks will be discussed using examples involving human diseases and the p53 protein. PMID- 22246821 TI - Viral load and epidemiological profile of patients infected by pandemic influenza a (H1N1) 2009 and seasonal influenza a virus in Southern Brazil. AB - Correlation between virologic profile and clinical features of patients infected by influenza virus provides important information for epidemiological control and clinical management of future disease outbreaks. Samples from patients in Southern Brazil, from June to December 2009, were examined and the viral load was correlated with epidemiological data. All samples were analyzed by qRT-PCR for detection of the 2009-pandemic Influenza A (H1N1). Relative viral loads were assessed based on the 2(-DeltaCT) method and epidemiological data were obtained for each patient, following ethical policies. A total of 933 samples were positive for pH1N1 (2009) influenza; 172 were positive for seasonal influenza A; 13 were undetermined; 1992 samples were negative for influenza A. Combined molecular and epidemiological data were available for 38 seasonal and 198 pandemic samples. The median viral load was higher in pandemic than in seasonal influenza samples; in patients infected with pH1N1 (2009), viral load associated positively with chills, myalgia and rhinorrhea, and negatively with dyspnea, but no association was observed with other symptoms, nor with clinical conditions such as pregnancy, smoking, immunodepression and co-morbidities. Regarding patients infected with seasonal influenza, viral loads did not show statistically significant association with any of the symptoms. This is the first study in Brazil that examines epidemiological and molecular data from the 2009 influenza pandemic. The results may serve as a basis for developing strategies to control human-to-human infection and viral dissemination, and for implementing effective measures and public health policies against future novel disease outbreaks. PMID- 22246822 TI - Case report: Increased viral receptor expression associated with high viral load and severe pneumonia in a young patient infected with 2009 H1N1 influenza a with no pre-existing conditions. AB - A case of unusually high severity of influenza pneumonia leading to acute respiratory distress syndrome and death was investigated. This was a previously a healthy 28-year-old man with no underlying conditions, admitted to a hospital during the first wave of influenza pandemic in Thailand in July 2009. He had experienced high fever and influenza-like illness for 5 days before coming to the hospital. He developed acute respiratory distress syndrome and expired on day 7 after admission. In comparison to three other cases of influenza pneumonia in the same outbreak with known risk factors for severe influenza, such as pregnancy and diabetes mellitus, a much higher viral load was detected in the lungs of this patient despite antiviral treatment. In agreement with the high viral load, the lung specimens from this patient, but not the other three patients, showed a high expression of alpha-2,6-linked sialic acid by lectin staining. The gene responsible for the synthesis of this sialic acid was also found to be upregulated. The data indicated overexpression of the viral receptor as a potential mechanism for severe disease in some patients. PMID- 22246823 TI - Genetic diversity of HA1 domain of hemagglutinin gene of pandemic influenza H1N1pdm09 viruses in New Delhi, India. AB - Genetic analysis of pandemic 2009 influenza A (H1N1; H1N1pdm09) virus was undertaken to understand virus evolution during 2009 and 2010 in India. Surveillance of influenza viruses from July 2009 to December 2010 revealed major peaks of circulating H1N1pdm09 viruses in August-September and December-January 2009 and then in August-September 2010. To understand the diversity of the H1N1pdm09 virus, selected specimens (n = 23) from 2009 or 2010 were characterized by nucleotide sequence determination of the HA1 subunit of the HA gene. Phylogenetic analysis revealed that 22 clustered with clade 7 viruses characterized by S203T mutations, whereas one virus from 2010 fell within clade 6. None of the viruses from either 2009 or 2010 formed a monophyletic group, suggesting a continuum of independent introduction of circulating viral strains. Amino acid analysis revealed minor amino acid changes in the antigenic or receptor-binding domains. Importantly, we observed mutations that were also present in 1918 pandemic virus, which includes S183P in 4 and S185T mutation in 3 of 13 viruses analyzed from 2010, while none of the 2009 viruses carried these mutations. Whether antibody-mediated pressure is imposing such changes remains to be determined. Continued genetic surveillance is warranted to monitor pathogenicity as the virus evolves to acquire new features. PMID- 22246824 TI - An in-house HIV genotyping assay for the detection of drug resistance mutations in Southeast Asian patients infected with HIV-1. AB - Genotyping for HIV drug resistance is costly and beyond the means for many Southeast Asian patients, who are self-funded. This prompted the development of a more cost-effective, in-house assay for an ethnically diverse, Southeast Asian population at the National University Hospital in Singapore, using Sanger-based sequencing. Plasma samples from 20 treatment-failure patients with a broad spectrum of HIV drug resistance mutations were used to validate this assay clinically. Blinded testing gave concordant results for 7/7 (100%) protease drug resistance-related mutations, including one major and six minor mutations, and 111/116 (95.7%) reverse-transcriptase (RT) drug resistance-related mutations, including 65 nucleoside RT inhibitors (NRTI) and 46 non-nucleoside RT inhibitors (NNRTI) mutations. There were five discordant results, involving three NRTI- and two NNRTI-resistance-associated mutations. Highly conserved primers designed to have a wide coverage of the HIV pol gene (covering the entire protease and 395 codons of the RT region) enabled efficient multi-ethnic population-based genotyping. Reagents for this in-house test cost around 60% less than those for commercially available assays (SGD150 vs. SGD350 per sample). In addition, this assay also identified mutations located within the C-terminal domain (codons 312 560) of RT that are beyond the reach of most published and commercial GRTs. Currently, most research on C-terminal drug-resistance-related mutations has been conducted on HIV subtype B infections. Therefore this assay enables further study of these C-terminal mutations in Southeast Asian populations, where there is a high prevalence of CRF01_AE and other non-subtype B HIV infections. PMID- 22246825 TI - Discordance in HIV-1 co-receptor use prediction by different genotypic algorithms and phenotype assay: intermediate profile in relation to concordant predictions. AB - Concordant and discordant genotypic predictions of HIV-1 co-receptor tropism were analyzed. V3 region was sequenced from plasma samples of patients screened for R5 tropism by the Trofile(r) assay, before CCR5 antagonist prescription. Ten tools including geno2pheno, PSSM, an "11/25" and "net charge" rule, and other published algorithms were used. Patients were grouped according to concordance or discordance between tools and Trofile(r) result. Trofile(r) tropism reports from 50 patient samples were R5 in 38 and Dual/Mixed (DM) in 12. Prediction with the genotypic tools were concordant for 23 R5 samples, and discordant for the 15 other ones. From Trofile(r) DM strains were concordant in 6 and discordant in 6. V3 sequences were not clearly distinct between R5 and DM strains, except a greater diversity in the later. Discordances were found with any tool or combination of them, so that no one can be proposed as better than the others. Predictive values of each algorithm were similar and rather good (efficacy ranged from 74% to 84%), but the rate of non-confirmed prediction is greater when compelling the results of all tools with each individual sample. The mean of quantitative values obtained with one tool when another tool give the opposite prediction were different from those obtained when all tools agree with that prediction. The two discordant groups were often not distinguishable from each other. These results suggest that viruses giving discordant prediction with bioinformatic tools could be functionally distinct and/or in a different evolutionary state compared to those with concordant prediction. PMID- 22246826 TI - Characterization of hepatitis B virus genome variability in Iranian patients with chronic infection, a nationwide study. AB - Hepatitis B virus (HBV) isolates from Iranian patients around the country were characterized. Eighty-one complete genomes from HBV isolates were sequenced and analyzed. The studied population was grouped into three categories including inactive carriers, patients with chronic hepatitis, and patients with liver cirrhosis. Molecular and phylogenetic analyses revealed that Iranian patients were infected with HBV genotype D and subgenotype D1. The most common subtype was ayw2, followed by ayw3 and ayw4. Several deletions and insertions that had no correlation with disease outcome were observed in the HBV genomes. The most frequent mutation in the major hydrophilic region (MHR) of HBV surface antigen (HBsAg) was sP120S. Almost half of the patients studied carried precore (PC) mutant variants and one-third of the studied population was infected with variants carrying basal core promoter (BCP) mutations. PC and BCP mutations were observed in older patients, especially in those with chronic liver disease. Sixty seven patients (82.7%) were HBeAg negative, and the prevalence of precore mutant isolates (G1896A) was higher in this group than in HBeAg-positive patients. Lamivudine drug resistance mutations were detected after 1 year of treatment in about 30% of lamivudine-treated patients. In conclusion, these results demonstrate that HBV subgenotype D1 is the only subgenotype circulating in Iran, and there is no evidence of any exotic genotype in the region. The HBV PC (G1896A) mutation may play an important role in the clinical outcome of the disease by increasing the risk of progressive liver disease among Iranian patients infected with HBV. PMID- 22246827 TI - Antiviral efficacy of combination therapy with entecavir and adefovir for entecavir/lamivudine-resistant hepatitis B virus with or without adefovir resistance. AB - There is little clinical information on the management of hepatitis B virus (HBV) that is resistant to multiple drugs including entecavir (ETV). The present retrospective cohort study assessed the antiviral efficacy of ETV/adefovir dipivoxil (ADV) combination therapy for ETV-resistant HBV with prior lamivudine (LAM) resistance, and either with or without previous ADV resistance. The cumulative probability of achieving a virological response (undetectable serum HBV DNA) was compared by Kaplan-Meier analysis and the Breslow method. Seventeen patients with ETV-resistant HBV who were treated with ETV/ADV combination therapy for at least 6 months at a tertiary care center, were included; seven had dual resistance to ETV and LAM [ADV-r(-) group] and 10 had triple resistance to ETV, LAM, and ADV [ADV-r(+) group]. The median follow-up period was 9 months (range, 6 23). A virological response was noted in seven patients after a median of 3 months (range, 3-12) of treatment; five in the ADV-r(-) group and two in the ADV r(+) group. The cumulative probability of a virological response was significantly higher in the ADV-r(-) group than in the ADV-r(+) group (6 months cumulative probability, 57.1% vs. 11.1%). In conclusion, ETV/ADV combination therapy led to virological responses in five of seven patients with resistance to ETV and LAM, but a significantly poorer response in patients with prior ADV resistance than in those without prior ADV resistance. Therefore, ETV/ADV combination therapy could be a useful therapeutic option for ETV- and LAM resistant HBV without prior ADV resistance. PMID- 22246828 TI - Quantitation of hepatitis C virus RNA in peripheral blood mononuclear cells in HCV-monoinfection and HIV/HCV-coinfection. AB - Peripheral blood mononuclear cells (PBMCs) represent an extrahepatic hepatitis C virus (HCV) reservoir, the significance of which is unclear due to limited studies and varying test methodologies. In this study, a commercial viral load assay for measuring cell-associated PBMC HCV RNA was evaluated. HCV RNA was extracted from PBMCs, sorted CD14+, and CD19+ cells and corresponding plasma samples using the Abbott m2000 and Real-Time HCV assay. Test performance and influence of HIV seropositivity on plasma and PBMC HCV RNA were studied. Among 51 patients, 67 and 62 unique patient samples had detectable plasma and PBMC HCV viral load, respectively. The median PBMC viral load was 535 IU/1 M cells (range 29-5,190). CD19+ cells had significantly higher viral load than CD14+ cells (median log(10) HCV viral load 2.63 vs. 1.50 IU/ml; P< 0.001). Stability of PBMC viral load over time was demonstrated in untreated patients; all patients with an undetectable plasma HCV viral load after HCV treatment also demonstrated undetectable PBMC viral load. Repeated testing in nine samples yielded consistent PBMC viral load, differing by only 1.3-fold (range 1.0-1.7-fold). Among samples with detectable plasma HCV RNA, the correlation between PBMC and plasma viral load was moderate (r = 0.66) and was greater among HCV mono-infected compared to HIV/HCV co-infected subjects (r = 0.80 vs. 0.52). Measurement of cell-associated PBMC HCV RNA using a commercial assay demonstrated promising test characteristics. Differences in PBMC HCV viral load based on HIV-coinfection status and the significance of greater copy number in B-cells requires further study. PMID- 22246829 TI - Prevalence of hepatitis C virus genotype 1a in Japan and correlation of mutations in the NS5A region and single-nucleotide polymorphism of interleukin-28B with the response to combination therapy with pegylated-interferon-alpha 2b and ribavirin. AB - Hepatitis C virus (HCV) genotype 1a is rare in Japanese patients and the clinical characteristics of this genotype remain unclear. The interferon (IFN) sensitivity determining region (ISDR) and single-nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) among patients with HCV genotype 1b are associated with IFN response, but associations among patients with genotype 1a are largely unknown. This study investigated the clinical characteristics of genotype 1a and examined whether genomic heterogeneity of the ISDR and SNPs of IL28B among patients with HCV genotype 1a affects response to combination therapy with pegylated-IFN-alpha2b and ribavirin. Subjects comprised 977 patients infected with HCV genotype 1, including 574 men and 412 women (mean age, 55.2 +/- 10.6 years). HCV was genotyped by direct sequencing of the 5'-untranslated region and/or core regions and confirmed by direct sequencing of the NS5A region. HCV genotypes 1a (n = 32) and 1b (n = 945) were detected. Twenty-three (71.9%) of the 32 patients with genotype 1a were patients with hemophilia who had received imported clotting factors. Prevalence of genotype 1a after excluding patients with hemophilia was thus 0.9%. Of the 23 patients with genotype 1a who completed IFN therapy, 11 (47.8%) were defined as achieving sustained virological response. Factors related to sustained virological response by univariate analysis were IL28B and ISDR. In conclusion, HCV genotype 1a is rare in Japan. The presence of IL28B genotype TT, and more than two mutations, in the ISDR are associated with a good response to IFN therapy in patients with HCV genotype 1a. PMID- 22246830 TI - Development of a hepatitis delta virus antibody assay for study of the prevalence of HDV among individuals infected with hepatitis B virus in China. AB - Co-infection with hepatitis delta virus (HDV) and hepatitis B virus (HBV) has been shown to be associated with a more severe form of acute and chronic hepatitis. Cloning and expression of recombinant HDV antigen (rHDAg) in Escherichiacoli are described. Using purified rHDAg, a cost-effective indirect anti-HDV enzyme-linked immunosorbent assay (ELISA) kit was developed. Direct comparison of 15 known HDV-positive sera and 15 HDV-negative sera showed concordance agreement between the new assay kit and the Abbott Murex Anti-Delta (total) kit. In addition, 1,486 hepatitis B surface antigen (HBsAg) positive blood samples collected from various areas of China were tested using this indirect anti-HDV ELISA. It was found that 1.2% (95% CI: 0.7-1.9%) of the samples were anti-HDAg positive. It is suggested that the prevalence of HDV and HBV co infection in China is relatively low. PMID- 22246831 TI - Confirmation of the low clinical effect of human herpesvirus-6 and -7 infections after renal transplantation. AB - Human herpesvirus-6 and -7 (HHV-6 and HHV-7) may lead to pathological manifestations in renal transplant recipients. The aim of this study was to investigate beta-herpesvirus infections in 50 adult kidney transplant recipients after transplantation to examine the effect, interactions, and pathogenic consequences of infection and the effect of immunosuppressive regimens and Human cytomegalovirus (HCMV) prophylaxis with VACV. Beta-herpesviruses loads in the blood of 50 adult kidney transplant recipients over a 6-month period after transplantation and 198 blood donors were determined using polymerase chain reaction. The rate of HHV-6 detection in peripheral mononuclear cells (PBMCs) was higher in patients with end-stage renal disease and during the post transplantation follow-up than in healthy subjects (33% and 68% vs. 12%, respectively). The detection rate of HHV-7 in PBMCs was similar between patients, both before grafting and during the follow-up for transplant recipients (69% and 88%, respectively), and healthy subjects (78%), and correlated with the number of lymphocytes. HCMV in plasma was detected only in patients during the post transplant period (24%). VACV prophylaxis had no negative effect on the replication of HHV-6 or HHV-7, and univariate analyses demonstrated associations between HHV-6 infection and acute graft rejection [Odds ratio (OR) = 2.94, 95% confidence interval (CI), 1.05-8.2, P = 0.04], and between HHV-7 infection and cholestasis [OR = 2.61 (95% CI, 1.08-6.3), P = 0.03]. Immunosuppressive regimens had no effect on beta-herpesviruses infections. This study revealed the differing behavior of HCMV, HHV-6, and HHV-7 in kidney transplant recipients, and confirmed the association of HHV-6 with graft rejection. PMID- 22246833 TI - Genetic diversity of Chikungunya virus, India 2006-2010: evolutionary dynamics and serotype analyses. AB - The genetic diversity of Chikungunya virus (CHIKV) causing recurring outbreaks in India since 2006 was studied. The 2006 epidemic was caused by a virus strain of the East, Central and South African (ECSA) genotype with 226A in the E1 glycoprotein. The variant strain with E1-A226V mutation caused outbreaks since 2007 in the state of Kerala where Aedes albopictus is the abundant mosquito vector. Molecular epidemiology data since 2007 is scarce from other regions of the country. RT-PCR, sequencing and phylogenetic analyses of CHIKV isolates from the 2009 to 2010 epidemics in the States of Tamil Nadu and Andhra Pradesh placed them in a separate clade within the ECSA lineage. The isolates of the study had 226A in the E1 glycoprotein. The isolates had a novel E1-K211E mutation that was under significant positive selection. E1-211E is highly conserved in the Asian genotype of the virus circulated by Aedes aegypti. Unique mutations in E2 glycoprotein were identified. The two sub-lineages of ECSA genotype circulating in India parallel the abundance of Ae. albopictus and Ae. aegypti. Novel mutations in the envelope glycoproteins suggest adaptive evolution of the virus to local vector abundance. Cross neutralization of the virus isolates from recurring Indian epidemics indicated that no distinct serotypes had evolved. The study has provided insights into the origin, distribution and evolutionary adaptation of the virus to local vector abundance in the region that has reportedly, the highest incidence of CHIKV infection in the world. PMID- 22246832 TI - Case report: benefits of quantitative polymerase chain reaction in the clinical management of herpes simplex virus 1 infection with prominent hepatitis and unusual secondary progression. AB - Herpes simplex virus (HSV) infection is rarely considered in the differential diagnosis of severe acute hepatitis and disseminated infection in immunocompetent adults. A case of disseminated HSV-1 infection in an 82-year-old woman initially presenting with neurological problems, signs of meningitis and prominent hepatitis was investigated. Initial diagnosis, monitoring, and follow-up were based on the application of molecular methods to cerebrospinal fluid, serum, and liver tissue samples from this patient. Following an initial full recovery, the patient presented delayed intracerebral haemorrhage and diffuse arthralgia. This atypical case, with delayed secondary progression, highlights the wide range of clinical features of HSV infection and the benefits of monitoring viral load by quantitative real-time polymerase chain reaction (PCR) during patient management. PMID- 22246834 TI - Lack of genetic diversity in Crimean-Congo hemorrhagic fever viruses in Turkey: assessment of present and future patterns of disease. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonosis which is common in Africa, Asia, Eastern Europe, and the Balkan Peninsula. CCHF has been reported in Turkey with high frequency since 2002. The aim of the present study was to investigate the genetic diversity and genetic relationship between CCHF virus (CCHFV) isolates derived from infected patients over a 2-year period (2009 and 2010) in several provinces of Turkey. Serum samples (n = 48) were selected from CCHFV RNA positive patients and subjected to sequence analysis of the gene regions encoding the S (48 samples) and M (14 samples) segments. The nucleotide sequence alignments showed that the nucleic acid relatedness of CCHFV isolates ranged from 95.7% to 100% and from 93.7% to 100% for S and M segments, respectively. Phylogenetic analysis of both segment sequences revealed that CCHFV isolates circulating in Turkey belonged to the European lineage I and were closely related to the viruses found in the Eastern European-Russian and Balkan Peninsula. The M gene segment-based phylogenetic analysis suggested that 2/14 CCHFV isolates (KYSR3159/09 and YZGT714/10) had additional genetic variations. The results of the present study confirmed that the CCHFV isolates present in Turkey associated with human disease had high genetic homology in S segment, but some variability in the M segment of the RNA. PMID- 22246835 TI - Detection of active human cytomegalovirus by the promyelocytic leukemia body assay in cultures of PBMCs from patients undergoing hematopoietic stem cell transplantation. AB - A novel detection system was established previously for cells infected with the human cytomegalovirus (HCMV) in vitro that utilizes the unique IE1-dependent nuclear dispersion of promyelocytic leukemia (PML) bodies early in the HCMV replication cycle. This assay system, designated "the PML assay," makes use of the GFP-PML-expressing cell line SE/15, and allows real-time monitoring of infected cells by fluorescence microscopy without any staining procedures. A rapid and quantitative drug susceptibility testing was developed for low-titer clinical isolates propagated in fibroblasts in vitro. The present study sought to exploit the PML assay for evaluating in vivo status of HCMV without virus isolation. Progeny viruses were detected directly from peripheral blood mononuclear cells (PBMCs) infected in vivo obtained from hematopoietic stem cell transplantation recipients. The overall positivity of the PML assay tended to correlate with the levels of genomic DNA. Direct phenotypic susceptibility testing detected one ganciclovir (GCV)-resistant case among 19 samples, which was confirmed further by genomic and plaque reduction assays. However, in another patient with the sequence-proven mutant confirmed by sequencing, the progeny viruses exhibiting GCV-resistance were not detected. Studies on the isolated virus from the latter patient suggested the possibility that replication efficiency may differ between PBMCs and lesions infected in vivo, which may hamper the detection of GCV-resistant viruses by the PML assay, at least in this case. Taken together, the PML assay is sufficiently sensitive to monitor replication-competent HCMV directly from PBMCs infected in vivo, and provides a novel tool for comparing the characteristics of HCMV strains infected in vivo. PMID- 22246836 TI - Transient ischemic attack associated with acute cytomegalovirus infection. AB - Acute cytomegalovirus (CMV) infection is associated with thromboembolism. However, cerebrovascular ischemic events have not been reported in relation to acute CMV infection. A patient with a transient ischemic attack and acute CMV infection is described. Transient appearance of anti-phospholipid antibodies suggests a causal relationship between the two. Physicians should be alert to symptoms and signs of acute CMV infection in patients with idiopathic cerebrovascular ischemic events. PMID- 22246837 TI - Nonstructural protein NS1 immunodominant epitope detected specifically in dengue virus infected material by a SELDI-TOF/MS based assay. AB - Dengue virus (DV) infection is the most common mosquito-born viral disease of public health significance. Though most patients only suffer from flu-like symptoms, a small group of patients experiences more severe forms of the disease. The viral nonstructural protein 1 (NS1), a secreted protein correlating with viremia, is a key element used for dengue diagnosis with potential implications in severe dengue prognosis. Capture-ELISAs for the early detection of the NS1 protein in the sera during the acute febrile stage are commonly used in routine by diagnostic laboratories. In this study, the detection of NS1 protein in DV infected material was assessed by an alternative method combining a single NS1 directed monoclonal antibody and the SELDI-TOF/MS technology. According to the epitope mapping, the antibodies used are mainly directed against an immuno dominant peptide located on the C-terminal part of the protein. The NS1 SELDI-TOF assay is specific, has a sensitivity level close to capture-ELISAs and is potentially useful for a coupled serotyping/detection assay or for the detection of subtle post-translational modifications on the protein. PMID- 22246838 TI - Epidemiology of dengue infections in Kassala, Eastern Sudan. AB - Eighty-one (71.7%) out of 113 patients had confirmed dengue infection (using ELISA IgM serology) at Kassala, Eastern Sudan during the period of August through November 2010. According to the WHO criteria, dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) were observed in 30.9, 58, and 11.1% of these patients, respectively. The mean age of these 81 patients was 25.5 years. Male:female ratio was 1.8:1. Various symptoms including fever (100%), headache (75.3%), vomiting (55.6%), nausea (53.1%), and backache (30.9%) were observed among these patients. Thrombocytopenia (<100/10(9) platelets/L), and leucopenia (WBC count <4,000 * 10(9) cells/L) and hemoconcentration (hematocrit >45) were reported in 86.4, 69.1, and 67.9% of the patients, respectively. High alanine aminotransferase (ALT, >65 U/L) and aspartate aminotransferase (AST >37 U/L) were seen in 9.9 and 14.8% of the patients, respectively. There were five (6.1%) deaths, three of them had DHF and the other two patients had DSS. PMID- 22246839 TI - EBV lytic infection enhances transformation of B-lymphocytes infected with EBV in the presence of T-lymphocytes. AB - Epstein-Barr virus (EBV) establishes lifelong latency in B-lymphocytes following infection. Although in immune-competent individuals EBV remains in a quiescent state, in immunodeficient individuals, such as those with AIDS or transplant recipients, B-lymphocytes infected with EBV proliferate to give rise to lymphoproliferative diseases. Similarly, in vitro, EBV transforms human B lymphocytes into indefinitely growing lymphoblastoid cell lines (LCLs) in the absence of cytotoxic T-lymphocytes. Although LCLs harbor the entire EBV genome as an episome, in most cells the virus remains in a latent state expressing a fraction of EBV genes, and lytic infection occurs spontaneously but only in a small percentage of cells. Here, we report that lytic infection contributes to EBV-induced lymphoproliferation by a paracrine mechanism. An EBV immediate-early protein, BZLF1, induces IL-13, thus facilitating the proliferation of EBV transformed B-lymphocytes in the presence of T-lymphocytes. These data suggest that lytic gene products could contribute to virus-induced oncogenesis by a paracrine mechanism. PMID- 22246840 TI - Human metapneumovirus-associated hospital admissions over five consecutive epidemic seasons: evidence for alternating circulation of different genotypes. AB - Human metapneumovirus (hMPV) is a pathogen of the respiratory tract with a worldwide distribution. The purpose of this study was to identify hMPV as the cause of acute respiratory diseases in children admitted at Spedali Civili, a public hospital in Brescia, Italy. Eight hundred forty-six nasopharyngeal aspirate samples negative for the presence of other common respiratory viruses were tested for the presence of hMPV RNA by reverse transcription-polymerase chain reaction. Of the 846 samples, 79 (9.3%) were positive for hMPV. Polymerase chain reaction products, obtained by amplification of the partial nucleotide sequence of gene F, were sequenced and compared with sequences deposited in GenBank. All four hMPV subtypes were identified, including the proposed subtype A2 sublineages "A" and "B". In successive epidemic seasons, large outbreaks of hMPV alternated with small outbreaks in a biannual pattern. This local study provides further evidence that hMPV infection should be considered as a reason for hospital admission for acute respiratory disease in children. PMID- 22246841 TI - Increase of GII.2 norovirus infections during the 2009-2010 season in Osaka City, Japan. AB - During the 2009-2010 season, a significant numerical increase of genotype GII.2 norovirus (NoV)-associated outbreaks was observed in Osaka City, Japan. The most common genotype in that season was GII.2 (44.6%), followed by GII.4 (39.2%). Mostly, GII.2 strains were associated with outbreaks in children and with person to-person contact. The National Infectious Disease Surveillance Center reported that GII.2 NoV infections were widespread in Japan in that season. Comparative phylogenetic analysis of RNA-dependent RNA polymerase (RdRp) and capsid sequences revealed that this GII.2 epidemic resulted from two genetic strains. The first, GII.2p2 strains, had an identical genotype in the RdRp and capsid genes. GII.2p2 strains in the 2009-2010 season were a different genetic cluster from the strains of spring 2004, the previous epidemic of GII.2 NoV, but showed no unique amino acid change. The second, GII.2 chimera virus (GII.2p16), had GII.16 RdRp and GII.2 capsid genotypes, suggesting prior recombination at the junction of ORF1 and ORF2. GII.2p16 strains had four significant amino acid changes in the P2 subdomain, suggesting antigenic changes. Before the 2009-2010 season, GII.2 chimera viruses had been observed only sporadically. This spreading of GII.2p16 strains in the 2009-2010 season might be the first epidemic of GII.2 chimera virus. This study revealed that the NoV epidemic in the 2009-2010 season differed considerably from the prior season, when GII.4 was predominant. Furthermore, GII.2 strains persisted in human populations by drastic recombination and gradual accumulation of mutations, indicating a prevalent pattern of non-GII.4 genotypes with genetic evolution. PMID- 22246842 TI - The 40-80 nt region in the 5'-NCR of genome is a critical target for inactivating poliovirus by chlorine dioxide. AB - Chemical disinfection is the most common method used to inactivate viruses from drinking water throughout the world. In this study, cell culture, ELISA, RT-PCR, and spot hybridization were employed to investigate the mechanism underlying chlorine dioxide (ClO(2) )-induced inactivation of Poliovirus type 1 (PV1), which was also confirmed by recombinant viral genome RNA infection models. The results suggested that ClO(2) inactivated PV1 primarily by disrupting the 5'-non-coding region (5'-NCR) of the PV1 genome. Further study revealed that ClO(2) degraded specifically the 40-80 nucleotides (nt) region in the 5'-NCR. Recombinant viral genome RNA infection models confirmed that PV1 RNA lacking this 40-80 nt region was not infectious. This study not only elucidated the mechanism of PV1 inactivation by ClO(2), but also defined the critical genetic target for the disinfectant to inactivate Poliovirus. This study also provides a strategy by which rapid, accurate, and molecular methods based on sensitive genetic targets may be established for evaluating the effects of disinfectants on viruses. PMID- 22246843 TI - High detection frequency and viral loads of human rhinovirus species A to C in fecal samples; diagnostic and clinical implications. AB - Human rhinoviruses (HRVs) can be divided into three species; HRV-A to HRV-C. Up to 148 different HRV (sero)types have been identified to date. Because of sequence similarity between 5'-NCR of HRVs and enteroviruses (EVs), it is problematic to design EV-specific RT-PCR assays. The aims of this study were to assess the rate of false-detection of different rhinoviruses by EV RT-PCR, and to evaluate the diagnostic and clinical significance of such cross-reactivity. In vitro RNA transcripts of HRV A-C created from cDNA templates were quantified spectrophotometrically. Six hundred twenty-one stool samples screened as part of routine diagnostic for EV, 17 EV-positive stool samples referred for typing, 288 stool samples submitted for gastroenteritis investigations, and 1,500 CSF samples were included in the study. EV-specific RT-PCR detected RNA transcripts of HRV A1b, HRV-B14, and HRV-Crpat18 but with 10-1,000 reduced sensitivity compared to EV transcripts. Screening fecal samples by EV RT-PCR identified 13 positive samples identified subsequently as rhinoviruses; a further 26 HRV-positive samples were identified by nested HRV RT-PCR. All individuals were hospitalized and presented mostly with diarrhea. A total of 26 HRV types were identified (HRV A: 46%; HRV-B: 13%; HRV-C: 41%). Results confirm that EV-specific RT-PCR can detect HRVs, and at a practical level, identify potential problems of interpretation if fecal samples are used for surrogate screening in cases of suspected viral meningitis. High detection frequencies (10%) and viral loads in stool samples provide evidence for enteric replication of HRV, and its association with enteric disease requires further etiological studies. PMID- 22246844 TI - Single treatment with ethanol hand rub is ineffective against human rhinovirus- hand washing with soap and water removes the virus efficiently. AB - Ethanol-containing hand rubs are used frequently as a substitute for hand washing with water and soap. However, not all viruses are inactivated by a short term rubbing with alcohol. The capacity of a single round of instructed and controlled hand cleaning with water and soap or ethanol-containing hand rub, respectively, was tested for removal of human rhinovirus administered onto the skin of healthy volunteers on the back of the hands. Hand washing with soap and water appeared to be much more efficient for removing rhinoviruses from skin than rubbing hands with an ethanol-containing disinfectant. After washing with soap and water the virus was detected in 3/9 (33.3%) test persons from the left hand and 1/9 (11.1%) cases from the right hand, whereas the virus was detected invariably by real-time RT-PCR from both hands after cleaning with alcohol hand rub (P-value <0.01). Both substances evaluated clinically were also tested in vitro for virucidal efficacy against Human rhinovirus2 (HRV2) using a standardized assay. Both tested substances were poor within the contact time used in the hand-cleaning test. In conclusion, thorough and conventional hand washing with water and soap can clean efficiently hands contaminated with the virus responsible for an extensive share of common cold episodes. PMID- 22246845 TI - Rubella immune status among immigrant and nonimmigrant women in Spain. AB - A cross-sectional study of seroprevalence of rubella antibodies was carried out in all immigrant pregnant women (1,627) from February 2006 to June 2010. For each immigrant woman one Spanish pregnant woman was recruited. The seroprevalence of IgG antibodies against rubella in immigrant women was 92% (95% confidence interval [CI]: 90.4-93.3), and in native women was 97.7% (95%CI: 96.7-98.4) (P < 0.001). Immunity against was lowest among women from Latin America (odds ratio [OR]: 0.17), followed by women from Asia (OR: 0.20), Sub-Saharan Africa (OR: 0.27) and Northern Africa (OR: 0.37). Female immigrants from developing countries should be targeted for immunization to reduce the risk of congenital rubella. PMID- 22246846 TI - Systematic review of outcomes after intersphincteric resection for low rectal cancer. AB - BACKGROUND: For a select group of patients proctectomy with intersphincteric resection (ISR) for low rectal cancer may be a viable alternative to abdominoperineal resection, with good oncological outcomes while preserving sphincter function. The purpose of this systematic review was to evaluate the current evidence regarding oncological outcomes, morbidity and mortality, and functional outcomes after ISR for low rectal cancer. METHODS: A systematic review of the literature was undertaken to evaluate evidence regarding oncological outcomes, morbidity and mortality after ISR for low rectal cancer. Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The review included all original articles reporting outcomes after ISR, published in English, from January 1950 to March 2011. RESULTS: Eighty-four studies were identified. After applying inclusion and exclusion criteria, 14 studies involving 1289 patients were included (mean age 59.5 years, 67.0 per cent men). R0 resection was achieved by ISR in 97.0 per cent. The operative mortality rate was 0.8 per cent and the cumulative morbidity rate 25.8 per cent. Median follow-up was 56 (range 1-227) months. The mean local recurrence rate was 6.7 (range 0-23) per cent. Mean 5-year overall and disease-free survival rates were 86.3 and 78.6 per cent respectively. Functional outcome was reported in eight studies; among these, the mean number of bowel motions in a 24-h period was 2.7. CONCLUSION: Oncological outcomes after ISR for low rectal cancer are acceptable, with diverse, often imperfect functional results. These data will aid the clinician when counselling patients considering an ISR for management of low rectal cancer. PMID- 22246848 TI - Schizophrenia genes: on the matter of their convergence. AB - Schizophrenia is a common mental disorder, affecting 0.5-1% of the population. The mode of inheritance is complex and non-Mendelian with a high heritability of ca. 65-80%. Given this complexity, until most recently it was difficult to identify disease genes. But fortunately this has changed. Due to new technologies the last few years have brought highest interest in human genetics of complex diseases. The knowledge resulting from the availability of the complete sequence of the human genome, the systematic identification of single nucleotide polymorphisms (SNPs) throughout the genome, and the development of parallel genotyping technology (microarrays) established the conditions that brought about the current successful time in our ability to probe the genome for identifying disease genes. All these studies showed up new avenues for the biology of common complex diseases and yielded a multitude of genes showing strong association with complex diseases. PMID- 22246847 TI - Molecular simulation of rapid translocation of cholesterol, diacylglycerol, and ceramide in model raft and nonraft membranes. AB - The translocation of lipids across membranes (flip-flop) is an important biological process. Slow exchange on a physiological timescale allows the creation of asymmetric distributions of lipids across cellular membranes. The location of lipids and their rate of exchange have important biological consequences, especially for lipids involved in cellular signaling. We investigated the translocation of cholesterol, ceramide, and diacylglycerol in two model bilayers using molecular dynamics simulations. We estimate half times for flip-flop for cholesterol, diacylglycerol, and ceramide of 20 MUs, 30 MUs, and 10 ms in a POPC bilayer, compared with approximately 30 min, 30 ms, and 30 s in a model raft bilayer (1:1:1 PSM, POPC, and cholesterol). Cholesterol has a large (54 kJ/mol) free energy of exchange between the POPC and raft bilayer, and therefore, it strongly prefers the more ordered and rigid raft bilayer over the more liquid POPC bilayer. Ceramide and diacylglycerol have relatively small free energies of exchange, suggesting nearly equal preference for both bilayers. This unexpected result may have implications for ceramide and diacylglycerol signaling and membrane localization. PMID- 22246849 TI - Insulin sensitivity modifies the relationship between thyroid function and lipid profile in euthyroid type 1 diabetic patients. AB - It has been suggested that association between hypothyroidism with dyslipidemia might be present already at the stage of normal thyroid function through altered insulin sensitivity. We analyzed the role of insulin sensitivity as a mediator of thyroid-induced lipid changes in euthyroid type 1 diabetic patients. Study included 304 patients with type 1 diabetes and normal thyroid function. Insulin sensitivity was measured with estimated glucose disposal rate calculated using the equation: eGDR = 24.31 - (12.22 * WHR) - (3.29 * HT) - (0.57 * HbA1c); WHR = waist-to-hip ratio, HT = hypertension. TSH, FT4, FT3, and serum lipids were measured. Correlations and multiple linear regressions analysis were performed to identify relationships between thyroid status and serum lipid parameters after stratifying patients in quartiles of eGDR. After adjustment for age, sex, BMI, duration of diabetes and insulin dose TSH, FT3, and FT4 was not significantly associated with serum lipids in all patients, independently of level of insulin sensitivity. However, after stratifying patients for the degree of insulin sensitivity in subjects in the lowest quartile of insulin sensitivity TSH was independently associated with LDL cholesterol (beta = 0.210, p = 0.02). The independent relation of eGDR with TSH and LDL cholesterol suggests that the influence of thyroid function on lipid metabolism might extend into euthyroid range through altered insulin sensitivity. PMID- 22246851 TI - Urinary endogenous steroids and their relationships with BMD and body composition in healthy young males. PMID- 22246850 TI - The relationship between high-sensitivity C-reactive protein and ApoB, ApoB/ApoA1 ratio in general population of China. AB - Inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) is considered as a major predictor of cardiovascular events. Apolipoprotein B (ApoB) directly reflects the number of plasma atherogenic lipoproteins, and may play a major role in vascular inflammation. We aimed to assess whether an association between ApoB and hsCRP exists and, furthermore, to examine whether ApoB is more predictive of the inflammatory status than other cardiovascular risk factors. This was a cross sectional study, with 511 apparently healthy adult subjects enrolled. Waist circumference (WC), body mass index (BMI), and blood pressure (BP) were measured. Plasma glucose levels, hsCRP, lipid profile, and insulin were collected after 10 14 h fasting. From the lowest to the highest quartile of hsCRP, the values for BMI, WC, BP, HOMA-IR, insulin, glucose level, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), ApoB and the ApoB/apolipoprotein A1 (ApoA1) ratio were increased as the hsCRP level increased (P < 0.01), and high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels declined as hsCRP level increased (P < 0.0001). Pearson's correlation analysis demonstrated that hsCRP correlated with all variables (P < 0.01), except for total cholesterol (TC) (P = 0.154) and LDL-C (P = 0.087). According to forward stepwise regression analysis with hsCRP as the dependent variable, WC was the only variable entered the regression model. ApoB level correlated with hsCRP level but was not the major determinant of hsCRP. WC was stronger than other cardiovascular risk factors in the associations with hsCRP. Abdominal obesity rather than atherogenic dyslipidemia was the primary cause of chronic inflammatory status. PMID- 22246852 TI - The psychotropic self/imaginary: subjectivity and psychopharmaceutical use among heroin users with co-occurring mental illness. AB - Many people diagnosed with mental illnesses struggle with illicit drug addiction. These individuals are often treated with psychiatric medications, yet little is known about how they experience this treatment. Research on the subjective experience of psychiatric medication use highlights the complex, contradictory, and ambiguous feelings often associated with this treatment. However, for those with mental illness and addiction, this experience is complicated by the need to manage both psychiatric medication and illicit drug use. Using ethnographic data from a study of heroin use in Northeast Ohio, we explore this experience by expanding the pharmaceutical self/imaginary (Jenkins, Pharmaceutical Self: The Global Shaping of Experience in an Age of Psychopharmacology, School for Advanced Research Press, Santa Fe, NM, 2010b) to include psychopharmaceuticals and illicit drugs, what we call the psychotropic self/imaginary. Through this lens we explore the ways participants interpret and manage their psychotropic drug use in relation to sociocultural, institutional, and political-economic contexts. This analysis reveals how participants seek desired effects of legally prescribed and illicit drugs to treat mental illness, manage heroin addiction, and maintain a perceived "normal" self. Participants manage their drug use using active strategies, such as selective use of psychiatric medications, in the context of structural constraints, such as restricted access to mental health care, and cultural contexts that blur distinctions between "good" medicines and "bad" drugs. PMID- 22246853 TI - Associated malformations among infants with anophthalmia and microphthalmia. AB - BACKGROUND: Infants with anophthalmia and microphthalmia frequently have other associated congenital anomalies. The reported frequency and types of associated malformations vary among different studies. METHODS: The purpose of this investigation was to assess the frequency and types of associated malformations among infants with anophthalmia and microphthalmia in a geographically well defined population from 1979 to 2004 of 346,831 consecutive births. RESULTS: Of the 87 infants with anophthalmia and microphthalmia born during this period (prevalence at birth, 2.5 per 10,000), 90% had associated malformations. Infants with associated malformation were divided into recognizable conditions (22 infants [25%] with chromosomal and 15 infants [17%] with nonchromosomal conditions), and nonrecognizable conditions (41 infants [47%] with multiple malformations). Trisomies 13 and 18 were the most frequent chromosomal abnormalities. Amniotic bands sequence, CHARGE syndrome, Meckel-Gruber syndrome, and VACTERL association were most often present in recognizable nonchromosomal conditions. Malformations in the musculoskeletal, cardiovascular, and central nervous systems were the most common other anomalies in infants with multiple malformations and nonrecognizable conditions. CONCLUSIONS: The frequency of associated malformations in infants with anophthalmia or microphthalmia emphasizes the need for a thorough investigation of these infants. Routine screening for other malformations-especially musculoskeletal, cardiac, and central nervous system anomalies-may need to be considered in infants with anophthalmia or microphthalmia, and referral of these infants for genetics evaluation and counseling seems warranted. PMID- 22246854 TI - Accumulation of pro-cancer cytokines in the plasma fraction of stored packed red cells. AB - INTRODUCTION: Perioperative blood transfusion has been linked to decreased survival in pancreatic cancer; however, the exact causal mechanism has not been elucidated. Allogeneic transfusions are known to expose patients to foreign cells and lipid mediators. We hypothesize that stored packed red cells (pRBCs) contain pro-cancer cytokines that augment tumor progression. We analyzed the plasma fraction of stored pRBCs for pro-cancer cytokines and evaluated the affect of both storage time and leukocyte reduction on these mediators. METHODS: ChemiarrayTM analysis for pro-cancer cytokines was performed on the acellular plasma fraction of stored leukocyte-reduced (LR) and non-leukocyte-reduced (NLR) pRBCs at day 1 (D.1-fresh) and day 42 (D.42-outdate) of storage. Elevated expression of monocyte chemotactic protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), angiogenin, tumor necrosis factor alpha (TNF-alpha), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) was found. Specific enzyme-linked immunosorbent assay was performed for each of these factors in LR and NLR blood at D.1, day 28, and D.42. Data were analyzed by ANOVA. A p value <= 0.05 was considered significant; N >= 4 per group. Migration assays were performed using inhibitors of EGF (gefitinib) and PDGF (imatinib) on murine pancreatic adenocarcinoma cells (Pan02) exposed to D.1 and D.42 LR and NLR plasma. Proliferation assays were performed on Pan02 cells to test the inhibition of PDGF. RESULTS: MCP-1 levels increased with storage time in LR blood, 86.3 +/- 6.3 pg/ml at D.1 vs. 121.2 +/- 6.1 pg/ml at D.42 (p = 0.007), and NLR blood, 78.2 +/- 7.3 pg/ml at D.1 vs. 647.8 +/- 220.7 pg/ml at D.42 (p = 0.02). RANTES levels are lower in LR compared to NLR stored blood, 3.0 +/- 1.9 vs. 15.8 +/- 0.7 pg/ml at D.42 (p < 0.001), but similar in D.1 blood, 13.8 +/- 1.8 pg/ml in LR vs. 12.0 +/- 1.6 pg/ml in NLR. Angiogenin levels were different between LR and NLR blood, 0 pg/ml (undetectable) vs. 44.2 +/- 3.7 pg/ml (p < 0.001). Storage time did not affect concentration. TNF-alpha levels were not different between LR and NLR blood, and there was no storage time effect on concentration. EGF and PDGF levels increased with storage time in NLR blood only, 216.4 +/- 3.8 pg/ml at D.1 vs. 1,436.4 +/- 238.6 pg/ml at D.42 for EGF (p = 0.001), and 61.6 +/- 6.0 pg/ml at D.1 vs. 76.5 +/- 1.7 pg/ml at D.42 (p = 0.003) for PDGF. Inhibition of EGF reduced migration in Pan02 cells treated with D.42 NLR blood, 245.9 +/- 11.2 vs. 164.6 +/- 10.6 cells/hpf (p < 0.001). Inhibition of PDGF had no effect on Pan02 migration and reduced cell proliferation in cells treated with D.42 NLR, 181.1 +/- 1.5% over control vs. 157.5 +/- 2.1% (p < 0.001). CONCLUSION: Pro-cancer cytokines that can augment tumor progression were identified in pRBCs. Some of these factors are present in fresh blood. The soluble factors identified herein may represent possible therapeutic targets to offset negative effects of transfusion. These data stress the need for efforts in cancer patients to reduce transfusion requirements if needed. PMID- 22246855 TI - Expression of matrix metalloproteinase-7 is an unfavorable prognostic factor in intrahepatic cholangiocarcinoma. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (IHCC) is a highly malignant neoplasm, but the prognostic factors of IHCC are not yet fully understood. The matrix metalloproteinases (MMPs) are known to be related to tumor viability. The aim of this study was to evaluate the prognostic significance of clinicopathological and immunohistochemical characteristics of resected IHCC. PATIENTS AND METHODS: From 1996 to 2006, we surgically treated 35 patients with IHCC. Clinicopathological and immunohistochemical characteristics, including expression of MMPs, vascular endothelial growth factor, and epidermal growth factor receptor in the resected specimens, were investigated, and overall survival rates were evaluated with regard to the characteristics using univariate and multivariate analyses. RESULTS: Univariate analysis revealed the significant prognostic factors to be preoperative serum CEA and CA19-9, intraoperative transfusion, tumor size, surgical margin, lymph node metastasis, invasion of portal and hepatic vein, intrahepatic metastasis, UICC stage, and expression of MMP-7. Subsequent multivariate analysis indicated that MMP-7 was an independent prognostic factor (hazard ratio (HR), 4.698; 95% confidence interval (CI), 0.057 0.866; P = 0.03) along with intrahepatic metastasis (HR, 5.694; 95% CI, 0.029 0.706; P = 0.017). CONCLUSION: MMP-7 expression is associated with a poor prognosis in patients with resected IHCC. PMID- 22246856 TI - Real-time PCR-based analysis of BRAF V600E mutation in low and intermediate grade lymphomas confirms frequent occurrence in hairy cell leukaemia. AB - Hairy cell leukaemia (HCL) is a rare type of B-cell non-Hodgkin lymphoma (B-NHL), which is not known to be associated with any characteristic recurrent karyotypic abnormality. A recent study that used massively parallel whole exome sequencing identified an activating V600E mutation in BRAF, which appeared specific for HCL. Here, we confirm the specificity of BRAF V600E for HCL among low and intermediate grade B-NHL and describe a real-time polymerase chain reaction method for detecting this mutation in cases with low tumour burden. The V600E mutation does not appear to be associated with microsatellite instability, unlike the case in colorectal cancer. Thus, in conjunction with prior data, our results suggest incorporation of BRAF V600E mutation analysis in the diagnostic workup of HCL cases. Additionally, targeting the Ras-Raf-Mek-Erk-Map kinase pathway should be investigated as a potential therapeutic strategy for patients with this disease. PMID- 22246857 TI - Comparison of two ultrashort echo time sequences for the quantification of T1 within phantom and human Achilles tendon at 3 T. AB - Ultrashort echo time (UTE) techniques enable direct imaging of musculoskeletal tissues with short T2 allowing measurement of T1 relaxation times. This article presents comparison of optimized 3D variable flip angle UTE (VFA-UTE) and 2D saturation recovery UTE (SR-UTE) sequences to quantify T1 in agar phantoms and human Achilles tendon. Achilles tendon T1 values for asymptomatic volunteers were compared to Achilles tendon T1 values calculated from patients with clinical diagnoses of spondyloarthritis (SpA) and Achilles tendinopathy using an optimized VFA-UTE sequence. T1 values from phantom data for VFA- and SR-UTE compare well against calculated T1 values from an assumed gold standard inversion recovery spin echo sequence. Mean T1 values in asymptomatic Achilles tendon were found to be 725+/-42 ms and 698+/-54 ms for SR- and VFA-UTE, respectively. The patient group mean T1 value for Achilles tendon was found to be 957+/-173 ms (P<0.05) using an optimized VFA-UTE sequence with pulse repetition time of 6 ms and flip angles 4, 19, and 24 degrees , taking a total 9 min acquisition time. The VFA-UTE technique appears clinically feasible for quantifying T1 in Achilles tendon. T1 measurements offer potential for detecting changes in Achilles tendon due to SpA without need for intravenous contrast agents. PMID- 22246858 TI - Risk factors for Raynaud's phenomenon in the workforce. AB - OBJECTIVE: To assess the prevalence of and risk factors for Raynaud's phenomenon (RP) in a French working population characterized by various levels of exposure to work-related constraints. METHODS: The study population comprised 3,710 workers (2,161 men and 1,549 women) who were followed up by 83 occupational physicians and were representative of the region's workforce. RP, as diagnosed by a questionnaire and a standardized interview, was defined as the occurrence of at least occasional attacks of finger blanching triggered by exposure to environmental cold during the previous 12 months. Personal factors and work exposure were assessed by self-administered questionnaires. The associations between RP and personal and occupational factors were analyzed using logistic regression modeling. RESULTS: A total of 87 cases of RP (56 women and 31 men) were diagnosed. The population-based annual prevalence rates of RP were 3.6% (95% confidence interval [95% CI] 2.7-4.5%) for women and 1.4% (95% CI 0.9-1.9%) for men. Women had a higher risk of RP (odds ratio [OR] 2.1 [95% CI 1.3-3.4]) and the risk decreased continuously with body mass index (OR for 1-kg/m(2) increment 0.87 [95% CI 0.81-0.94]). The risk of RP increased consistently but moderately with age after 35 years (ORs ranging from 2.0 [95% CI 1.1-3.8] to 2.9 [95% CI 1.6 5.2]). Among the work-related factors studied, RP was associated with an exposure to a cold environment or objects (OR 2.2 [95% CI 1.0-4.6]), a high repetitiveness of a task (OR 1.7 [95% CI 1.0-2.7]), a high psychological demand at work (OR 1.7 [95% CI 1.0-2.7]), and low support from supervisors (OR 2.4 [95% CI 1.5-3.8]). CONCLUSION: Personal and work-related factors were associated with RP, with a clear difference between the sexes. Work-related psychosocial stressors played a significant role independently of biomechanical and environmental exposure. PMID- 22246859 TI - Anthropometric charts for infants with trisomies 21, 18, or 13 born between 22 weeks gestation and term: the VON charts. AB - Data on birth weight for gestational age (GA) are not well described for infants with trisomy 21 (T21), trisomy 18 (T18), or trisomy 13 (T13). We report on anthropometric charts of infants with these conditions using data from the Vermont Oxford Network (VON). Data from a total of 5,147 infants with T21 aged 22 41 weeks, 1,053 infants with T18 aged 22-41 weeks, and 613 infants with T13 aged 22-40 weeks were used to create birth weight for GA charts. Head circumference for GA charts were created for infants with T21 only. Combined-sex charts were generated for infants with T18 or T13 while sex-specific charts were generated for infants with T21. Smoothed centiles were created using LmsChartMaker Pro 2.3. Among the three examined groups, infants with T18 were the most likely to be growth restricted while infants with T21 were the least likely to be growth restricted. The new charts for infants with T21 were also compared to the Lubchenco and Fenton charts and both show frequent misclassification of infants with T21 as small or large for GA. The new charts should prove to be useful, especially for infants with T21, to assist in medical management and guide nutrition care decisions. PMID- 22246860 TI - Hypercapnia: a nonpermissive environment for the lung. AB - Patients with severe acute and chronic lung diseases develop derangements in gas exchange that may result in increased levels of CO(2) (hypercapnia), the effects of which on human health are incompletely understood. It has been proposed that hypercapnia may have beneficial effects in patients with acute lung injury, and the concepts of "permissive" and even "therapeutic" hypercapnia have emerged. However, recent work suggests that CO(2) can act as a signaling molecule via pH independent mechanisms, resulting in deleterious effects in the lung. Here we review recent research on how elevated CO(2) is sensed by cells in the lung and the potential harmful effects of hypercapnia on epithelial and endothelial barrier, lung edema clearance, innate immunity, and host defense. In view of these findings, we raise concerns about the potentially deleterious effects hypercapnia may have in patients with acute and chronic lung diseases. PMID- 22246861 TI - Resistin-like molecule-alpha regulates IL-13-induced chemokine production but not allergen-induced airway responses. AB - Resistin-like molecule alpha (Relm-alpha) is one of the most up-regulated gene products in allergen- and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-alpha was shown to exert an anti inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-alpha production, and the role of Relm-alpha after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-alpha was secreted into the airway lumen, dependent on both the IL-13 receptor-alpha1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene targeted mice demonstrate that Relm-alpha was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-alpha in the lungs. The differential regulation of Relm-alpha expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm alpha in acute experimental models of allergen-associated Th2 immune responses. PMID- 22246862 TI - Prenatal nicotine exposure alters lung function and airway geometry through alpha7 nicotinic receptors. AB - Maternal smoking during pregnancy has been associated with adverse effects on respiratory health. Whereas the epidemiologic link is incontrovertible, the mechanisms responsible for this association are still poorly understood. Although cigarette smoke has many toxic constituents, nicotine, the major addictive component in cigarette smoke, may play a more significant role than previously realized. The objectives of this study were to determine whether exposure to nicotine prenatally leads to alterations in pulmonary function and airway geometry in offspring, and whether alpha7 nicotinic acetylcholine receptors (nAChRs) mediate these effects. In a murine model of in utero nicotine exposure, pulmonary function, airway size and number, methacholine response, and collagen deposition were examined. Exposure periods included Gestation Days 7-21, Gestation Day 14 to Postnatal Day 7, and Postnatal Days 3-15. Prenatal nicotine exposure decreases forced expiratory flows in offspring through alpha7 nAChR mediated signals, and the critical period of nicotine exposure was between Prenatal Day 14 and Postnatal Day 7. These physiologic changes were associated with increased airway length and decreased diameter. In addition, adult mice exposed to prenatal nicotine exhibit an increased response to methacholine challenge, even in the absence of allergic sensitization. Collagen expression was increased between adjacent airways and vessels, which was absent in alpha7 nAChR knockout mice. These observations provide a unified mechanism of how maternal smoking during pregnancy may lead to lifelong alterations in offspring pulmonary function and increased risk of asthma, and suggest potential targets to counteract those effects. PMID- 22246863 TI - Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-alpha compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD. PMID- 22246864 TI - Spiruchostatin A inhibits proliferation and differentiation of fibroblasts from patients with pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. Spiruchostatin A (SpA) is a histone deacetylase inhibitor (HDI) with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit (myo)fibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that SpA inhibits the proliferation and differentiation of IPF fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with IPF or from normal control subjects, using two-dimensional or three-dimensional culture models. The effect of SpA on fibroproliferation in serum-containing medium +/- transforming growth factor (TGF)-beta(1) was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor p21(waf1), and the myofibroblast markers alpha-smooth muscle actin (alpha-SMA) and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. SpA inhibited the proliferation of IPF or normal fibroblasts in a time-dependent and concentration-dependent manner (concentration required to achieve 50% inhibition = 3.8 +/- 0.4 nM versus 7.8 +/- 0.2 nM, respectively; P < 0.05), with little cytotoxicity. Western blot analyses revealed that SpA caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. SpA also increased p21(waf1) expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-beta(1) induced myofibroblast differentiation associated with increased expression of alpha-SMA, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by SpA. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for IPF. PMID- 22246866 TI - Measuring changes in muscle stiffness after eccentric exercise using elastography. AB - Muscle stiffness has been reported to increase following eccentric muscle exercise, but to date only indirect methods have been used to measure it. This study aimed to use Magnetic Resonance Elastography (MRE), a noninvasive imaging technique, to assess the time-course of passive elasticity changes in the medial gastrocnemius and soleus muscles before and after a bout of eccentric exercise. Shear storage modulus (G') and loss modulus (G'') measurements were made in eight healthy subjects for both muscles in vivo before, one hour after, 48 hours after and 1 week after eccentric exercise. The results show a 21% increase in medial gastrocnemius storage modulus following eccentric exercise with a peak occurring ~48 hours after exercise (before exercise 1.15 +/- 0.23 kPa, 48 hours after 1.38 +/- 0.27 kPa). No significant changes in soleus muscle storage modulus were measured for the exercise protocol used in this study, and no significant changes in loss modulus were observed. This study provides the first direct measurements in skeletal muscle before and after eccentric exercise damage and suggests that MRE can be used to detect the time course of changes to muscle properties. PMID- 22246867 TI - Nipple reconstruction with banked costal cartilage after vertical-type skin sparing mastectomy and deep inferior epigastric artery perforator flap. AB - We recently used skin-sparing mastectomy (SSM), the deep inferior epigastric artery perforator (DIEP) flap, and delayed nipple reconstruction with banked costal cartilage. Eight patients who underwent these reconstructions between 2008 and 2010 were reviewed. SSM was performed by vertical-type incision. We transferred the DIEP flap using an internal thoracic vessel and banked costal cartilage into an abdominal wound. Three to 6 months later, we removed the cartilage and cut it into a cylindrical shape. We fixed the cartilage on the dermal base of a modified C-V flap. No flap necrosis or exposure of cartilage was seen and the scar was acceptable in all cases. At a mean follow-up of 12.6 months, 59% of the nipple projection was maintained in comparison to immediately postoperatively. Our new concept is the combination of SSM, DIEP, and banked cartilage, and furthermore putting the cartilage on a dermal base. With support from the dermis, a large, complicated cartilage form is unnecessary. PMID- 22246865 TI - Profiling protease activities by dynamic proteomics workflows. AB - Proteases play prominent roles in many physiological processes and the pathogenesis of various diseases, which makes them interesting drug targets. To fully understand the functional role of proteases in these processes, it is necessary to characterize the target specificity of the enzymes, identify endogenous substrates and cleavage products as well as protease activators and inhibitors. The complexity of these proteolytic networks presents a considerable analytic challenge. To comprehensively characterize these systems, quantitative methods that capture the spatial and temporal distributions of the network members are needed. Recently, activity-based workflows have come to the forefront to tackle the dynamic aspects of proteolytic processing networks in vitro, ex vivo and in vivo. In this review, we will discuss how mass spectrometry-based approaches can be used to gain new insights into protease biology by determining substrate specificities, profiling the activity-states of proteases, monitoring proteolysis in vivo, measuring reaction kinetics and defining in vitro and in vivo proteolytic events. In addition, examples of future aspects of protease research that go beyond mass spectrometry-based applications are given. PMID- 22246868 TI - UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia. AB - Recent findings highlight a pathologic and functional convergence in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) at the level of protein recycling and disposal. Genes linked to rare cases of familial ALS and ALS-FTD, like UBQLN2, OPTN, SQSTM1/p62, and VCP, may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Interactions between these genes need to be further explored to understand their common molecular pathways. Future efforts should be directed toward generation and characterization of in vivo models to dissect the pathogenic mechanisms of ALS and ALS-FTD and the role of protein degradation pathways, both centrally, at the cell body, and peripherally, at the level of the synapse. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences in ALS and ALS-FTD and, possibly, other neurodegenerative diseases as well. PMID- 22246869 TI - Knee extensor strength exhibits potential to predict function in sporadic inclusion-body myositis. AB - INTRODUCTION: In this study we address the challenging issue of potential use of muscle strength to predict function in clinical trials. This has immediate relevance to translational studies that attempt to improve quadriceps strength in sporadic inclusion-body myositis (sIBM). METHODS: Maximum voluntary isometric contraction testing as a measure of muscle strength and a battery of functional outcomes were tested in 85 ambulatory subjects with sIBM. RESULTS: Marked quadriceps weakness was noted in all patients. Strength was correlated with distance walked at 2 and 6 minutes. Additional correlations were found with time to get up from a chair, climb stairs, and step up on curbs. CONCLUSIONS: Quadriceps (knee extensor) strength correlated with performance in this large cohort of sIBM subjects, which demonstrated its potential to predict function in this disease. These data provide initial support for use of muscle strength as a surrogate for function, although validation in a clinical trial is required. PMID- 22246870 TI - Discrimination of spinal and bulbar muscular atrophy from amyotrophic lateral sclerosis using sensory nerve action potentials. AB - INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are motor neuron diseases. Sensory impairment is sometimes observed, and electrophysiological involvement has been described in the sensory nerves of SBMA patients. We hypothesized that a sensory nerve conduction study (NCS) could be used to discriminate SBMA from ALS. METHODS: We compared the results from NCSs in a total of 120 SBMA cases confirmed by genetic analysis, 188 ALS cases, and 50 normal subjects. RESULTS: Sensory nerve action potential (SNAP) amplitudes of the SBMA group were significantly lower than in the ALS and control groups. In addition, receiver-operating characteristic curve analysis for SNAP amplitude showed that a cut-off value of 13.8 MUV for median, 10.7 MUV for ulnar, and 9.9 MUV for sural nerve best discriminated SBMA from ALS. CONCLUSIONS: The specific decrease of SNAP amplitude in SBMA provides another useful tool for the differential diagnosis of motor neuron diseases. PMID- 22246871 TI - Fasciculation potentials in amyotrophic lateral sclerosis and the diagnostic yield of the Awaji algorithm. AB - INTRODUCTION: The role of fasciculation potentials (FPs) in the diagnosis of amyotrophic lateral sclerosis (ALS) has been underrated. The Awaji algorithm has restored the value of FPs. Our aim was to test the diagnostic yield of the Awaji algorithm, with consideration of FPs. METHODS: Subjects consisted of 139 consecutive ALS patients retrospectively enrolled over 5 years. At presentation we evaluated the diagnostic categories using the revised El Escorial Criteria (R EEC) and the Awaji algorithm. RESULTS: The percentage of patients classified as confirmed ALS, clinically probable (laboratory-supported), or higher was 43% using the R-EEC and 37% using the Awaji algorithm. Thirteen patients with upper motor neuron signs only in one body region showed a decrease in their category using the Awaji algorithm. FPs were observed in 89% of ALS patients and were frequent in proximal muscles. CONCLUSION: The sensitivity of the Awaji algorithm is lower than that of the R-EEC. PMID- 22246872 TI - Carpal tunnel syndrome: Clinical, electrophysiological, and ultrasonographic ratio after surgery. AB - INTRODUCTION: The aim of this study was to improve our understanding of the pathophysiology of carpal tunnel syndrome (CTS) and to highlight the ultrasonographic cross-sectional area (CSA) ratio as a tool for assessing outcomes by investigating postoperative changes. METHODS: Twenty-four individuals with CTS were evaluated using the Boston questionnaire, nerve conduction studies, and ultrasound, preoperatively and at 3 weeks and 3 months postoperatively. RESULTS: Improved symptom scores, decreased CSA, and decreased CSA ratio were observed in the first 3 weeks, but functional improvement was also observed after 3 weeks postoperatively. The ratios between the CSA at the sites of enlargement and unaffected areas correlated significantly with the Padua classification, although the coefficient was not superior to the coefficient of CSA at the maximal swelling site. CONCLUSIONS: Symptoms improved more rapidly than function after surgery. Measurement of the ultrasonographic CSA ratio may provide clinicians with a useful assessment tool after surgery. PMID- 22246873 TI - Necrotizing myopathy: clinicoserologic associations. AB - INTRODUCTION: Necrotizing myopathy (NM) is distinguished from idiopathic inflammatory myositis (IIM) by dominance of myofiber necrosis, lack of mononuclear inflammatory infiltrates, and presence of antibodies to signal recognition particle (SRP). METHODS: The clinical features of 64 cases of NM were determined. Measurement of autoantibodies was undertaken on stored sera from 23 patients with NM. The incidence of malignancy was determined from the South Australian Cancer Registry. RESULTS: NM patients showed male predominance (61%), more frequent myalgias, and higher creatine kinase (CK) levels compared with IIM patients. Patients with NM had a high incidence of systemic lupus erythematosus (SLE) (21%), hypertension (11 of 17, 65%), and diabetes mellitus (3 of 13, 23%). No patient had antibodies to SRP. NM patients showed no altered risk for malignancy compared with the South Australian population (P = 0.86). CONCLUSIONS: NM is associated with SLE, hypertension, and diabetes mellitus. Comprehensive assessment of cardiovascular risk is indicated in NM, which raises the possibility of targeted interventions. PMID- 22246874 TI - Clinical utility of sensory nerve conduction of medial femoral cutaneous nerve. AB - INTRODUCTION: In this investigation we report on the clinical utility of sensory nerve conduction studies of the medial femoral cutaneous (MFC) nerve. METHODS: Sensory nerve conduction of the MFC nerve was assessed in 22 patients for whom this test was considered clinically necessary. RESULTS: MFC nerve conduction was abnormal in 4 cases of MFC neuropathy. The most common cause was iatrogenic in 14 femoral neuropathy cases. MFC nerve conduction showed absent or low-amplitude sensory nerve action potential (SNAP) in 13 cases, with femoral motor nerve conduction abnormal in 5 cases. In 2 cases with acute lumbar plexopathy, the MFC SNAP was absent unilaterally. MFC nerve conduction was normal in 1 case with diabetic lumbar radiculopathy and in another case with postpolio syndrome. CONCLUSION: Assessment of MFC nerve conduction is extremely useful in the diagnosis of femoral neuropathy, medial femoral cutaneous neuropathy, and lumbar plexopathy. PMID- 22246875 TI - Impaired expression of insulin-like growth factor-1 system in skeletal muscle of amyotrophic lateral sclerosis patients. AB - INTRODUCTION: Adult muscle fibers are a source of growth factors, including insulin-like growth factor-1 (IGF-1). These factors influence neuronal survival, axonal growth, and maintenance of synaptic connections. METHODS: We investigated the components of the IGF system in skeletal muscle samples obtained from 17 sporadic amyotrophic lateral sclerosis patients (sALS) and 29 control subjects (17 with normal muscle and 12 with denervated muscle unrelated to ALS). RESULTS: The muscle expression of IGF-1 and IGF-binding proteins 3, 4, and 5 (IGF-BP3, -4, and -5, respectively), assessed by immunohistochemistry, was differently decreased in sALS compared with both control groups; conversely, IGF-1 receptor beta subunit (IGF-1Rbeta) was significantly increased. Western blot analysis confirmed the severe reduction of IGF-1, IGF-BP3, and -BP5 with the increment of IGF-1Rbeta in sALS. CONCLUSION: In this study we describe the abnormal expression of the IGF-1 system in skeletal muscle of sALS patients that could participate in motor neuron degeneration and should be taken into account when developing treatments with IGF-1. PMID- 22246876 TI - Ocular and generalized myasthenia gravis induced by human acetylcholine receptor gamma subunit immunization. AB - INTRODUCTION: HLA-DQ8 transgenic mice develop ocular myasthenia gravis (oMG), which then progresses to generalized MG (gMG) when immunized with the human acetylcholine receptor (H-AChR) alpha subunit. Because the fetal AChR gamma subunit is expressed in adult extraocular muscles, we anticipated that gamma subunit immunization would generate an immune response to mouse AChR and induce MG in mice. RESULTS: H-AChR gamma subunit immunization in HLA-DQ8 mice induced an autoimmune response to mouse AChR and led to the destruction of AChR in the neuromuscular junction (NMJ) by anti-AChR antibody and complement activation, and it triggered upregulation of AChR gene transcription. CONCLUSION: Our findings indicate that oMG may be induced by immunity to the AChR gamma subunit. PMID- 22246877 TI - Effective zone of botulinum toxin a injections in hallux claw toe syndrome: an anatomical study. AB - INTRODUCTION: The aim of this study was to determine the anatomical location of the motor points of the flexor hallucis longus (FHL) and brevis (FHB) muscles for an effective motor point block. METHODS: Twenty cadavers were used for this study. For the FHL, we identified the line between the medial and lateral epicondyle of the femur and the line joining the prominent point on the surface of the medial malleolus of the tibia and the lateral malleolus of the fibula. For the FHB, we identified the line between the middle-lowest point of the great toe and the middle-lowest point of the sole of the foot. RESULTS: The dense area of the motor points was located at 40-70% for the FHL and 50-70% for the FHB. CONCLUSION: An injection area of 50-60% on the reference line for the FHL and FHB is suggested. PMID- 22246878 TI - High-frequency sonography of the volar digital nerves of the hand. AB - INTRODUCTION: The purpose of this study is to describe our technique for high frequency sonography of the volar digital nerves and to define the course, caliber, and morphology of normal volar digital nerves. METHODS: The volar digital nerves of 10 volunteers were imaged in the long axis using a linear ultrasound transducer. Height, weight, glove size, and hand dominance were recorded. Each radial and ulnar nerve was divided into four segments. Segment thickness and depth were measured. A mixed model analysis for repeated measures was utilized (alpha = 0.05). RESULTS: The average nerve thickness (NT) was 1.1 mm (+/- 0.01 SE), and the average nerve depth (ND) was 2.8 mm (+/- 0.04 SE). Neither NT nor ND demonstrated any significant correlation with height, age, weight, body mass index, or glove size. Nerves ranged in thickness from 0.7 to 1.5 mm and in depth from 0.7 to 6.8 mm. CONCLUSION: High-frequency sonography permits high resolution imaging of the volar digital nerves. PMID- 22246879 TI - Sonographic assessment of suture artifact obscuring visualization of the digital nerve. AB - INTRODUCTION: The purpose of this study was to grade the severity of sonographic artifact produced by four suture materials and to determine whether these artifacts affect visualization of a digital nerve. METHODS: A needle was placed into a pig foot to mimic a normal volar digital nerve. Incisions superficial to the needle were closed with different suture types, specifically nylon (N), chromic (C), vicryl (V), and prolene (P). Sonographic images were obtained using a high-frequency transducer. Twenty radiology residents and attending physicians graded the severity of artifact and nerve obscuration. Two image types were shown: one suture type per image and a composite image of each suture type, adjacent to one another. RESULTS: Severity of nerve obscuration was as follows: composite image: P = N = V > C; individual images: P > N > V > C. Severity of artifact was: composite image: V = N > P > C; individual image: P > N > V > C. CONCLUSION: Although all sutures produced artifact, only C produced mild artifact, which did not significantly obscure visualization of the nerve model. PMID- 22246880 TI - Chronic nerve compression alters Schwann cell myelin architecture in a murine model. AB - INTRODUCTION: Myelinating Schwann cells compartmentalize their outermost layer to form actin-rich channels known as Cajal bands. Herein we investigate changes in Schwann cell architecture and cytoplasmic morphology in a novel mouse model of carpal tunnel syndrome. METHODS: Chronic nerve compression (CNC) injury was created in wild-type and slow-Wallerian degeneration (Wld(S) ) mice. Over 12 weeks, nerves were electrodiagnostically assessed, and Schwann cell morphology was thoroughly evaluated. RESULTS: A decline in nerve conduction velocity and increase in g-ratio is observed without early axonal damage. Schwann cells display shortened internodal lengths and severely disrupted Cajal bands. Quite surprisingly, the latter is reconstituted without improvements to nerve conduction velocity. CONCLUSIONS: Chronic entrapment injuries like carpal tunnel syndrome are primarily mediated by the Schwann cell response, where decreases in internodal length and myelin thickness disrupt the efficiency of impulse propagation. Restitution of Cajal bands is not sufficient for remyelination after CNC injury. PMID- 22246882 TI - Gender differences in contractile and passive properties of mdx extensor digitorum longus muscle. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe, muscle-wasting disease caused by mutations in the dystrophin gene. The mdx mouse is the first and perhaps the most commonly used animal model for study of DMD. Both male and female mdx mice are used. However, it is not completely clear whether gender influences contraction and the passive mechanical properties of mdx skeletal muscle. METHODS: We compared isometric tetanic forces and passive forces of the extensor digitorum longus muscle between male and female mdx mice. RESULTS: At age 6 months, female mdx mice showed better-preserved specific tetanic force. Interestingly, at 20 months of age, female mdx muscle appeared stiffer. CONCLUSIONS: Our results suggest that gender may profoundly influence physiological measurement outcomes in mdx mice. PMID- 22246881 TI - Differences in capillary architecture, hemodynamics, and angiogenic factors in rat slow and fast plantarflexor muscles. AB - INTRODUCTION: The capillary architecture in skeletal muscles is unique in that it has anastomoses that interconnect individual capillaries. METHODS: We used new techniques to measure velocity of red blood cells (V(RBC) ) in both capillaries and anastomoses in situ. The volume of capillaries/anastomoses was determined, and the levels of several angiogenic regulators were compared between the soleus and the superficial gastrocnemius (LG(sup) ). RESULTS: The V(RBC) in both capillaries and anastomoses was slower in soleus than in LG(sup) . The numbers of capillaries and anastomoses were higher, diameter of capillaries smaller, and tortuosity greater in soleus than in LG(sup) . Consequently, the capillary/anastomoses volume was larger in soleus than in LG(sup) . Furthermore, several angiogenic regulators (HIF-1alpha, VEGF, Flt-1, KDR, angiopoietin-1 and 2, and Tie-2) were higher in soleus than in LG(sup) . CONCLUSION: The differences in microvascular architecture, V(RBC) , and levels of angiogenic regulators between soleus and LG(sup) reflect the greater oxygen demands of the highly active soleus muscle. PMID- 22246883 TI - Reliability of a simple method for determining muscle fiber conduction velocity. AB - INTRODUCTION: This study evaluated the reliability of muscle fiber conduction velocity (MFCV) measurement. METHODS: Forty healthy, young participants performed isometric dorsiflexion of the foot on 3 non-consecutive days. The reliability of force, root-mean-square (RMS) amplitude of the surface electromyographic (sEMG) signal, and MFCV were evaluated using the intraclass correlational analysis of variance technique. RESULTS: The means across test days for all measures exhibited slight changes (<5%) and were considered stable. All measures exhibited remarkable consistency within subjects as indicated by high intraclass correlation coefficients (0.83-0.98). CONCLUSIONS: The procedures resulted in highly reliable MFCV values, and included: (1) electric identification of motor points prior to electrode placement; (2) twitch identification of muscle fiber orientation to guide initial electrode placement; (3) rotation of electrodes clockwise or counter-clockwise to maximize the similarity and delay of compound muscle action potentials across all detection surfaces; and (4) minimization of synergistic activity during voluntary contractions. PMID- 22246886 TI - Concentric needle jitter in stimulated frontalis in 20 healthy subjects. AB - Normative data for jitter parameters using a disposable concentric needle have been presented in a few studies. Jitter, expressed as the mean consecutive difference (MCD), was measured in the frontalis muscle in 20 subjects by percutaneous bar stimulation of the temporal nerve branch. The mean MCD for individual studies (20) and for all potentials (600) were 16.05 +/- 2.73 MUs and 16.05 +/- 5.96 MUs, respectively. The suggested limit for mean MCD is 22 MUs and for outliers is 28 MUs. PMID- 22246884 TI - p38gamma activity is required for maintenance of slow skeletal muscle size. AB - INTRODUCTION: p38gamma kinase is highly enriched in skeletal muscle and is implicated in myotube formation. However, the activation status of p38gamma in muscle is unclear. METHODS: p38gamma activity in slow and fast adult mouse skeletal muscle tissue was examined, as was the impact of p38gamma deficiency on muscle development and gene expression. RESULTS: p38gamma is preferentially activated in slow muscle, but it is inactive in fast muscle types. Furthermore, the loss of p38gamma in mice led to decreased muscle mass associated with a smaller myofiber diameter in slow muscle, but there was no impact on fast muscle in either mass or myofiber diameter. Finally, p38gamma-deficient muscle showed selective changes in genes related to muscle growth in slow muscle fibers. CONCLUSION: This study provides evidence that p38gamma is selectively activated in slow skeletal muscle and is involved in the normal growth and development of a subset of skeletal muscle. PMID- 22246885 TI - The novel TrkB receptor agonist 7,8-dihydroxyflavone enhances neuromuscular transmission. AB - Neurotrophin signaling at the neuromuscular junction modulates cholinergic transmission and enhances neuromuscular transmission via the tropomyosin-related kinase receptor subtype B (TrkB).A novel flavonoid, 7,8-dihydroxyflavone (7,8 DHF), selectively activates TrkB receptors. Using TrkB(F616A) mice that are susceptible to specific inhibition of TrkB activity by 1NMPP1, we show that neuromuscular transmission is enhanced by 7,8-DHF (?32%) via activation of TrkB in diaphragm muscle. The small molecule 7,8-DHF may constitute a novel therapy to improve neuromuscular function. PMID- 22246888 TI - SOX10 mutation with peripheral amyelination and developmental disturbance of axons. AB - In this study we describe a case of a term infant with the neurological variant of Waardenburg syndrome type 4 (i.e., PCWH = peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, as defined in OMIM #609136) due to a novel heterozygous base exchange (c.671C>G) in exon 4 of SOX10. Magnetic resonance imaging suggested central myelin deficiency with cerebral and cerebellar hypoplasia. Hirschsprung disease was confirmed by rectal biopsy. Sural nerve biopsy revealed hypoplasia due to amyelination (with the exception of a single, small myelinated fiber) and severe reduction in the number of axons. PMID- 22246887 TI - Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype. AB - We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia. PMID- 22246889 TI - Granulomatous myositis associated with brucellosis: a case report and literature review. AB - Brucellosis, a multisystem infectious disorder, continues to be a serious public health problem in some parts of the world. Neurobrucellosis constitutes about 4% of all brucellosis cases. Brucellosis-associated myositis is extremely rare, and there is only 1 reported case in the English literature. We report a 16-year-old boy with subacute, fluctuating, progressive muscle pain, with tenderness, swelling, and diffuse, asymmetric weakness. He also had significantly elevated serum Brucella titers and a muscle biopsy showed inflammatory granulomatous myositis. We review the literature on myositis associated with brucellosis. PMID- 22246890 TI - Chorea-acanthocytosis presenting as motor neuron disease. AB - INTRODUCTION: Chorea-acanthocytosis (ChAc) is a rare autosomal recessive disease characterized by involuntary movements, seizures, cognitive changes, myopathy, and axonal neuropathy. METHODS: We report a patient who presented with gait impairment and dysarthria. Clinical and neurophysiological assessment disclosed upper and lower motor neuron signs suggestive of motor neuron disease (MND). RESULTS: Later observation of involuntary movements prompted further investigation. Acanthocytes were identified, and the patient's chorein level was low. Genetic studies identified a novel double heterozygous mutation of the chorein gene involving an exon-stop mutation associated with another mutation that can affect the normal splicing of the RNA. CONCLUSIONS: We speculate that this genetic mutation could cause the atypical presentation. ChAc should be included in the differential diagnosis of atypical MND. PMID- 22246891 TI - An unusual cause of thenar hypertrophy and carpal tunnel syndrome. PMID- 22246892 TI - Pure monomelic sensory neuronopathy associated with anti-yo antibodies. PMID- 22246893 TI - An autopsy case of a dysferlinopathy patient with cardiac involvement. PMID- 22246894 TI - Ultrasound in the diagnosis and treatment of posterior interosseous nerve entrapment: a case report. PMID- 22246895 TI - How common is misdiagnosis in late-onset Pompe disease? PMID- 22246900 TI - Prognosis for primary retroperitoneal sarcoma survivors: a conditional survival analysis. AB - BACKGROUND: The AJCC staging system and post-operative nomograms use patient and tumor characteristics to provide prognostic estimates after resection of retroperitoneal sarcoma (RPS). While these variables help to predict survival at the time of diagnosis and resection, the applicability of these prognostic factors to survivors of RPS remains unknown. We hypothesized that the variables evaluated in the current staging system and post-operative nomograms would have limited ability to predict conditional survival in patients surgically treated for RPS. METHODS: A retrospective study was conducted using National Cancer Institute-sponsored tumor registries. We identified 1,199 patients who underwent surgical resection for non-metastatic RPS from 1988 to 2007. Conditional survival was defined as time-specific estimates conditioned on living a certain number of years post-diagnosis. Cox proportional hazards regression was used to assess the impact of various factors on sarcoma-specific survival (SSS) at baseline and up to 5 years after diagnosis. RESULTS: Older age, male gender, histologic subtype, and high tumor grade predicted worse SSS at the time of diagnosis. After 1 year of survival, older age, male gender, and histologic subtype were no longer significant predictors of conditional survival. Only high grade tumors remained a significant predictor of worse prognosis after 5 years of survival (HR 1.95). CONCLUSIONS: This population-based study demonstrates that the factors which are predictive of survival at baseline lose significance after one year of survival. Conditional survival estimates allow clinicians to provide survivors with more meaningful prognostic estimates that may impact surveillance schedules and streamline adjuvant therapy decisions and design of future clinical trials. PMID- 22246901 TI - Blood oxygenation level-dependent (BOLD) MRI of human skeletal muscle at 1.5 and 3 T. AB - PURPOSE: To evaluate the dependence of skeletal muscle blood oxygenation level dependent (BOLD) effect and time course characteristics on magnetic field strength in healthy volunteers using an ischemia/reactive hyperemia paradigm. MATERIALS AND METHODS: Two consecutive skeletal muscle BOLD magnetic resonance imaging (MRI) measurements in eight healthy volunteers were performed on 1.5 T and 3.0 T whole-body MRI scanners. For both measurements a fat-saturated multi shot multiecho gradient-echo EPI sequence was applied. Temporary vascular occlusion was induced by suprasystolic cuff compression of the thigh. T2 time courses were obtained from two different calf muscles and characterized by typical curve parameters. Ischemia- and hyperemia-induced changes in R2 (DeltaR2) were calculated for both muscles in each volunteer at the two field strengths. RESULTS: Skeletal muscle BOLD changes are dependent on magnetic field strength as the ratio DeltaR2(3.0 T)/DeltaR2(1.5 T) was found to range between 1.6 and 2.2. Regarding time course characteristics, significantly higher relative T2 changes were found in both muscles at 3.0 T. CONCLUSION: The present study shows an approximately linear field strength dependence of DeltaR2 in the skeletal muscle in response to ischemia and reactive hyperemia. Using higher magnetic fields is advisable for future BOLD imaging studies of peripheral limb pathologies. PMID- 22246902 TI - Tumor suppressor function of PGP9.5 is associated with epigenetic regulation in prostate cancer--novel predictor of biochemical recurrence after radical surgery. AB - BACKGROUND: The expression level of protein G product 9.5 (PGP9.5) is downregulated because of promoter CpG hypermethylation in several tumors. We speculated that impaired regulation of PGP9.5 through epigenetic pathways is associated with the pathogenesis of prostate cancer. METHODS: CpG methylation of the PGP9.5 gene was analyzed in cultured prostate cancer cell lines, 226 localized prostate cancer samples from radical prostatectomy cases, and 80 benign prostate hyperplasia (BPH) tissues. RESULTS: Following 5-aza-2'-deoxycytidune treatment, increased PGP9.5 mRNA transcript expression was found in the LNCaP and PC3 cell lines. With bisulfite DNA sequencing, partial methylation of the PGP9.5 promoter was shown in LNCaP whereas complete methylation was found in PC3 cells. After transfection of PGP9.5 siRNA, cell viability was significantly accelerated in LNCaP but not in PC3 cells as compared with control siRNA transfection. Promoter methylation of PGP9.5 was extremely low in only one of 80 BPH tissues, whereas it was found in 37 of 226 prostate cancer tissues. Expression of the mRNA transcript of PGP9.5 was significantly lower in methylation (+) than methylation (-) prostate cancer tissues. Multivariate analysis of biochemical recurrence (BCR) after an radical prostatectomy revealed pT category and PGP9.5 methylation as prognostically relevant. Further stratification with the pT category in addition to methylation status identified a stepwise reduction of BCR-free probability. CONCLUSION: This is the first clinical and comprehensive study of inactivation of the PGP9.5 gene via epigenetic pathways in primary prostate cancer. IMPACT: CpG methylation of PGP9.5 in primary prostate cancer might become useful as a molecular marker for early clinical prediction of BCR after radical prostatectomy. PMID- 22246903 TI - Health literacy and discharge instruction adherence. PMID- 22246905 TI - Prognostic and predictive markers in hematologic neoplasms. A review. PMID- 22246904 TI - Craniofacial features resembling frontonasal dysplasia with a tubulonodular interhemispheric lipoma in the adult 3H1 tuft mouse. AB - Intracranial lipomas are rare, but 45% of them occur along the midline cisterns between the hemispheres and are often associated with corpus callosum hypoplasia and craniofacial defects. They are difficult to detect as they are generally asymptomatic and visible by MRI or by postmortem examination. The exact cause of these interhemispheric lipomas is not known, but they arise from a developmental defect resulting in the maldifferentiation of mesenchymal cells into mesodermal derivatives that are not normally present. We have identified a new mouse mutant called tuft, exhibiting a forebrain, intracranial lipoma with midline craniofacial defects resembling frontonasal dysplasia (FND) that arose spontaneously in our wild-type 3H1 colony. The tuft trait seems to be transmitted in recessive fashion, but approximately 80% less frequent than the expected Mendelian 25%, due to either incomplete penetrance or prenatal lethality. MRI and histologic analysis revealed that the intracranial lipoma occurred between the hemispheres and often protruded through the sagittal suture. We also observed a lesion at the lamina terminalis (LT) that may indicate improper closure of the anterior neuropore. We have mapped the tuft trait to within an 18 cM region on mouse chromosome 10 by microsatellite linkage analysis and identified several candidate genes involved with craniofacial development and cellular differentiation of adipose tissue. Tuft is the only known mouse model for midline craniofacial defects with an intracranial lipoma. Identifying the gene(s) and mutation(s) causing this early developmental defect will help us understand the pathogenesis of FND and related craniofacial disorders. PMID- 22246906 TI - Serous neoplasms of the pancreas constitute a continuous spectrum of morphological patterns rather than distinct clinico-pathological variants. A study of 40 cases. AB - Serous neoplasms (SN) of the pancreas account for 1-2% of all pancreatic tumours. Six morphological variants of SN were previously recognized: serous microcystic (cyst)adenoma, serous macrocystic (cyst)adenoma, von Hippel-Lindau-associated serous cystic neoplasm, solid serous adenoma/neoplasm, mixed serous neuroendocrine neoplasm and serous cystadenocarcinoma. It was recently postulated that SN shows a continuous spectrum of morphological patterns rather than distinct clinico-pathological subtypes. To address this issue, we performed a detailed review of 40 SN cases diagnosed at our institution between 1989 and 2011. We found 11 cases of serous microcystic (cyst)adenoma, 5 cases of serous macrocystic (cyst)adenoma, and a single case of von Hippel-Lindau-associated serous cystic neoplasm. Apart from that, we found 20 cases of SN which showed features of both microcystic and macrocystic (cyst)adenomas, 2 cases of small 'incipient' SN and a single case of a mixed microcystic and solid adenoma. In conclusion, we showed that 'borderline' lesions among SNs truly exist and are not rare. The reason for such a wide diversity of morphological patterns of SN remains unknown. PMID- 22246907 TI - Association between hepatic angiogenesis and serum adipokine profile in non-obese chronic hepatitis C patients. AB - It is unclear whether angiogenesis merely represents a homeostatic mechanism aimed at ensuring an adequate oxygen supply or one that exerts an additional pathogenic role leading to liver damage in chronic hepatitis. Chronic hepatitis C (CHC) patients present a proangiogenic profile of angiogenic markers. Adipokines not only regulate adipose tissue and glucose metabolism, but also influence inflammation, fibrogenic process and production of proangiogenic factors. On the basis of this evidence we aimed to assess the number of new blood vessels in lobules and portal tracts in the liver and evaluate the relationship between angiogenesis intensity and serum adipokine concentrations in CHC. Our study showed a positive association between serum vaspin and angiogenesis intensity in portal tracts and lobules in CHC patients (r = 0.41, p = 0.04; r = 0.46, p = 0.03; respectively). Serum visfatin was found to be negatively related to angiogenesis in portal tracts and lobules but only in females (r = -0.76, p = 0.03; r= -0.95, p < 0.001; respectively). In conclusion, the role of some adipokines in liver angiogenesis seems to be different in females than in males. Serum vaspin concentration seems to reflect intensity of liver angiogenesis in CHC. Further studies are necessary to better determine the role of adipokines in new blood vessel formation in CHC. PMID- 22246908 TI - The routine immunohistochemical evaluation in Paget disease of the nipple. AB - Paget disease (PD) of the nipple with coexisting intraductal (DCIS) and invasive carcinoma of the breast comprises 0.6-1.8% of all malignant epithelial neoplasms of this organ. Unlike invasive ductal carcinoma, there are many controversies concerning histological features of PD and the significance of the immunohistochemical characteristics of this neoplasm, which limits the optimal treatment protocols. Therefore, we decided to verify the immunohistochemical markers of PD basing on the retrospective analysis of postoperative material from 69 patients treated surgically. Microscopic examination revealed partial (7 cases) or total (62 cases) replacement of the squamous epithelium of the nipple with nests of atypical glandular cells spreading in an area ranging from 0.2 to 2.5 cm. DCIS coexisting with the PD lesions was present in all examined patients, and infiltrating carcinoma occurred in 31 (44.9%) patients. Both intraepidermal and DCIS components presented c-erbB2 overexpression. Positive estrogen and progesterone receptor staining was observed only in 7 (10.1%) and 2 (2.7%) tumours, respectively. Ki-67 proliferation index of PD cells ranged from 10% to 30%, whereas in DCIS it varied from 4% to 20%. The value of Ki-67 index exceeding 25% in the intraepidermal component of PD was associated with worse overall survival rate. PMID- 22246909 TI - Immunohistochemical investigation of selected endothelial markers in pulmonary epithelioid haemangioendothelioma. AB - Epithelioid haemangioendothelioma (EH) is a very rare neoplasm. It is assumed that these tumours derive from vascular endothelial cells. The aim of the study was to identify the immunohistochemical profile of tumour cells in lung EH. The unique material consisting of eight cases of lung EH was collected and examined by immunohistochemistry with three antibodies: CD-31, CD105, both marking vascular endothelial cells, and D2-40, marking lymphatic endothelial cells. In all cases, the cytoplasm of tumour cells showed widespread expression of CD-31. Reaction with CD-105 antibody gave a positive result mainly in the cytoplasm of tumour cells located at the periphery of tumours, especially in highly cellular neoplasms containing spindle cells. Reaction with D2-40 antibody in most cases was negative. The presence of a few capillary vessels with positive endothelial cells was revealed in two cases at the periphery of the tumour. Only in one case of a highly cellular tumour did a small portion of spindle cells show a positive reaction to D2-40. The above studies confirmed the origin of EH mainly from vascular endothelial cells. Medications inhibiting vascular endothelial growth factors can be considered as a treatment option for multifocal EH that does not qualify for surgical intervention. PMID- 22246910 TI - Cytokeratin 8 and 18 tissue expression in gallbladder mucosa of patients with cholelithiasis. AB - Cytokeratins (CKs) 8 and 18 are normally expressed in simple epithelia. This unique pair of CKs is believed to be involved in hepatic diseases and many human cancers. Little is known about the role of tissue expression of both CKs in patients with cholelithiasis (CH). The aim of the study was to analyse tissue expression of CK8 and 18 in the specimens of gallbladder mucosa in 35 young (up to 25 years of age) and 20 older patients (approximately 50 years of age) with CH. An immunocytochemical ABC method and the spatial visualization technique were conducted. Our study demonstrated significantly lower amounts of both CKs in young patients, as compared to older patients. The higher cellular expression of CK8 in older patients was linked to acute clinical course vs. chronic ones. Tissue expression of neither CK correlated with inflammatory activity (grading) of the gallbladder mucosa. A positive correlation between reciprocal expressions of the two CKs may confirm a cytoprotective role of the two proteins in both groups of patients with symptomatic CH. Significantly higher expression of CK18 than that of CK8 in younger patients suggests a different role of CK8 and 18 in lithogenesis in this group. PMID- 22246911 TI - Clinico-morphological parameters affecting survival of patients with advanced cervical cancer. AB - The aim of the study was to investigate the prognostic significance of selected clinico-morphological parameters including Ki-67 antigen expression and microvessel density. The data of 122 patients with squamous cell carcinoma, FIGO stages IB-IIIB and treated with radiochemotherapy and brachytherapy were studied. Significant prognostic factors for disease-free survival in univariate analysis were the FIGO stage and the presence of atypical mitoses in carcinoma cells. Multivariate Cox analysis confirmed prognostic significance of the FIGO stage and Ki-67 expression with regard to disease-free survival. With regard to overall survival, the most important prognostic factor was Ki-67 antigen expression. The data concerning the pretreatment status of these parameters may be helpful in clinical practice. PMID- 22246912 TI - Concentration of cadmium, nickel and aluminium in female breast cancer. AB - AIMS: The aim of this study was to investigate the cadmium (Cd), nickel (Ni) and aluminium (Al) concentrations in female breast cancer and normal tissue. MATERIALS AND METHODS: The concentration of metals in 16 non-cancerous breast tissues and 67 breast cancer samples was measured by flame atomic absorption spectrometry. RESULTS: In the case of normal breast tissue the concentrations were 0.61 +/- 0.24 MUg Cd/g dry tissue, 1.84 +/- 0.67 MUg Ni/g dry tissue, and 3.63 +/- 1.00 MUg Al/g dry tissue, whereas in breast cancer concentrations of metals were 0.76 +/- 0.38 MUg/g dry tissue, 2.26 +/- 0.79 MUg/g dry tissue, and 4.40 +/- 1.82 MUg/g dry tissue, respectively. The concentration of Cd and Al in normal breast tissue was significantly lower than in breast cancer. In the case of Ni concentration, we did not observe statistically significant differences between normal and cancerous tissue. There were no significant differences in concentration of studied metals, in breast cancer, in the context of age, menopausal status, and cancer histological grading. CONCLUSION: The data obtained show higher concentration of cadmium and aluminium and support a possible relationship between those metals and breast cancer. PMID- 22246913 TI - Vanadium compounds affect growth and morphology of human rhabdomyosarcoma cell line. AB - Rhabdomyosarcoma (RMS) cells were incubated with four vanadium compounds: cations BMOV and vanadyl sulphate, and anions ortho- and metavanadate. Growth inhibition of RMS cells in the culture was determined by two staining methods: with N hexamethylpararosaniline (crystal violet = CV) or bromide 3-(4,5-dimethylthiazol 2)-2,5-diphenyltetrazolium (MTT). After 48 h incubation with 10-40 MUM for NaVO3 or 20-40 MUM for the other three vanadium salts, the results were statistically significantly lower (0.001 < p < 0.01) as compared to the controls (without vanadium in the medium). A vanadium concentration higher than 40 MUM resulted in cell destruction or death in all cells. A comparison with our previously obtained results showed the greatest sensitivity of rat hepatoma H 35-19 cells in comparison to four human cancer cell lines (A549, DU145, HTB, RMS). Investigations of human cancer cells demonstrated that the highest resistance to orthovanadate was characteristic of RMS (c.40 MUM) and HTB (c. 20 MUM). Electron microscopic examination showed pleomorphic nuclei with visible amounts of heterochromatin and large nucleoli, characteristic of RMS cells. Cells at various stages of differentiation were observed. PMID- 22246914 TI - Exogenous lipoid pneumonia (oil granulomas of the lung). AB - The authors observed three cases of exogenous lipid pneumonia clinically suspected of lung carcinoma. Histological examination of material after thoracotomy gave the possibility of correct diagnosis. The lesions in lungs were characteristic granulomas around lipid material and with surrounding advanced fibrosis. PMID- 22246915 TI - Interdigitating dendritic cell sarcoma of lymph node mimicking granuloma: a case report and review of the literature. AB - Interdigitating dendritic cell sarcoma (IDCS), is an extremely rare neoplasm. We report a case of a 77-year-old man presented with gradual lymph nodes enlargement in inguina, neck and axilla for 6 months. Biopsy revealed that part of the lymph node was replaced by several large granuloma-like nodules composed of mild atypical tumor cells, resembling epithelioid cells. Mitotic figures were hardly found. Immunohistochemistry showed that tumor cells were positive for S-100, CD68 and CD45. Ki-67 labeling index was 5%. To the best of our knowledge, this is the first case of IDCS showing granuloma-like growth pattern with mild atypical tumor cells. PMID- 22246916 TI - Low grade malignant peripheral nerve sheath tumor with mesenchymal differentiation: a case report. AB - Malignant peripheral nerve sheath tumor (MPNST) is an uncommon neoplasm. Rarely, MPNST may display focal mesenchymal differentiation and this is more frequently encountered in high than low grade lesions. Here we present an example of a low grade MPNST with osteoid, cartilaginous and probably smooth muscle components occurring in the subtemporal fossa of a 26-year-old male patient with no associated neurofibromatosis type 1. The tumor exhibited diffuse S-100 protein expression, whereas immunostainings for epithelial membrane antigen and smooth muscle actin were positive in a portion of neoplastic cells. PMID- 22246917 TI - DANTE-prepared pulse trains: a novel approach to motion-sensitized and motion suppressed quantitative magnetic resonance imaging. AB - Delay alternating with nutation for tailored excitation (DANTE) pulse trains are well appreciated as frequency-selective excitation methods in Fourier transform NMR and for spatial tagging in MRI. In this study, nonselective DANTE pulse trains are used in combination with gradient pulses and short repetition times as motion-sensitive preparation modules. We show that while the longitudinal magnetization of static tissue is mostly preserved, flowing spins are largely (or fully) attenuated as they fail to establish transverse steady state due to a spoiling effect caused by flow along the applied gradient. The attenuation of flowing spins is effectively insensitive to spin velocity (above a low threshold) and can be approximately quantified with a simple T1 longitudinal magnetization decay model. The relevant analytical equations for moving spins and static spins during DANTE module application are derived for both transient and steady state epochs. The equations are validated by comparing analytical solutions and numerical Bloch equation simulations against experimental observations in phantoms and in vivo. Based on this contrast mechanism, the application of the DANTE preparation to black blood vessel imaging is proposed. A simple demonstration of DANTE black blood imaging modules shows that it provides excellent blood signal suppression and static tissue signal preservation. PMID- 22246919 TI - A de novo interstitial deletion of 2p23.3-24.3 in a boy presenting with intellectual disability, overgrowth, dysmorphic features, skeletal myopathy, dilated cardiomyopathy. AB - Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations. PMID- 22246918 TI - Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump. AB - Z-Guggulsterone is a major ingredient in the Indian traditional hypolipidemic remedy guggul. A study in mice has established that its hypolipidemic effect involves the farnesoid X receptor (FXR), presumably by acting as an antagonist of this receptor. It is generally assumed that the antagonism leads to induction of cytochrome P450 7A1 (CYP7A1), the rate-limiting enzyme converting free cholesterol to bile acids. In this study, we tested whether Z-guggulsterone indeed induces human CYP7A1. In addition, the expression of cholesteryl ester hydrolase CES1 and bile salt export pump (BSEP) was monitored. Contrary to the general assumption, Z-guggulsterone did not induce CYP7A1. Instead, this phytosterol significantly induced CES1 and BSEP through transactivation. Z Guggulsterone underwent metabolism by CYP3A4, and the metabolites greatly increased the induction potency on BSEP but not on CES1. BSEP induction favors cholesterol elimination, whereas CES1 involves both elimination and retention (probably when excessively induced). Interestingly, clinical trials reported the hypolipidemic response rates from 18% to 80% and showed that higher dosages actually increased VLDL cholesterol. Our findings predict that better hypolipidemic outcomes likely occur in individuals who have a relatively higher capacity of metabolizing Z-guggulsterone with moderate CES1 induction, a scenario possibly achieved by lowering the dosing regimens. PMID- 22246920 TI - Pheochromocytoma and Paraganglioma: progress on all fronts. PMID- 22246921 TI - Pathological findings of thyroid nodules after percutaneous laser ablation : a series of 22 cases with cyto-histological correlation. AB - Ultrasound (US)-guided percutaneous laser ablation (LA) of benign thyroid nodules may be a potential alternative to surgery in patients with compressive symptoms, at high surgical risk, or in patients who refuse to undergo surgery. We evaluated the morphological effects of LA procedure on 22 patients and compared the cytological findings before and after LA with the histological features on surgical specimens. Twenty-two (4.9%; 19 women, three men, mean age 53.2 years) out of 452 patients treated with LA for benign thyroid nodules in our Hospital underwent surgery after LA procedure, either because nodule regrowth (treatment failure, n = 17) or indeterminate cytology (Thy3) after LA (n = 5). Morphological findings varied according to the time between LA and surgical intervention. Within 2 months, the area was occasionally cavitated and filled in with dark amorphous material. The inflammatory response was abundant and composed of neutrophils, lymphocytes, and macrophages. After 18 months or more since LA, the expected laser-induced histologic changes in thyroid morphology consisted of a well-defined area surrounded by a fibrous capsule and filled in by amorphous material. No significant pathologic features were found in the thyroid tissue adjacent to the treated area. Histological evaluation of thyroid tissues after LA shows that thermal damage is restricted to the ablated area, with no involvement of the nearby parenchyma. Our long-term histopathological findings indicate that LA treatment of benign thyroid nodules is safe, and patients undergoing LA may also be followed up by fine needle aspiration. PMID- 22246922 TI - Combinatorial peptide ligand libraries for the analysis of low-expression proteins: Validation for normal urine and definition of a first protein MAP. AB - In this review, we report the evolution on experimental conditions for the analysis of normal urine based on combinatorial peptide ligand library (CPLL) treatment and successive 2-DE and 2-DE/MS analysis. The main topics are (i) definition of the urine sample requirements, (ii) optimization of the urine/ligand ratio, (iii) essay conditions, (iv) en bloc elution. Overall, normal urine protein composition as studied by 2-DE includes over 2600 spots. Relevant data on inter and intraessay reproducibility obtained by the analysis of different normal urines repeated several times are also here presented. We found a 73% reproducibility upon analysis of the same sample and 68% correspondence of protein composition among different normal urine samples. Based on the above results, we are completing the characterization with LC-MS of 249 spots. The composition of normal urine proteins after CPLLs is finally shown with the indication of those spots which are currently under identification. This map will be completed in a near future; in the meantime this would represent the basic reference sample for newly developed studies on human diseases. PMID- 22246923 TI - Individual estimated sensitivity and workload for manual screening of SurePath gynecologic cytology. AB - Data correlating individual screening sensitivity in gynecologic cytology and workload is limited. We compared the estimated sensitivity of manual screening of SurePath slides with individual workload. Estimated sensitivity determined by rapid prescreening was correlated with total workload in a laboratory performing manual screening of SurePath preparations for a 1 year period. There were 12 CTs with a total daily workload ranging from 8-35 slides. The mean estimated sensitivity for SurePath was 97.0% (range 91-100%). The mean estimated sensitivity for the lowest half workload (8-23 slides/day) was significantly higher than that for the highest half workload (23-35 slides/day) (98.3 versus 95.7%, P <= 0.001). The highest workload that achieved 100% estimated sensitivity was 30 slides/day. For manual screening of SurePath slides, individual estimated sensitivity is correlated with workload even at relatively low daily workloads. PMID- 22246924 TI - Rinse fluid and imprint smear cytology of bronchial biopsies in diagnosis of lung tumors. AB - The usefulness of rinse fluid and imprint smear cytology of the bronchial biopsy has been studied in diagnosis of lung cancer. However, scarce data is available regarding rinse fluid cytology of biopsy. The aim of this study was to evaluate these cytologic techniques for their diagnostic accuracy. Bronchial biopsy was taken in 52 patients clinically/radiologically suspected to have lung carcinoma. Imprint smears of the biopsy were prepared, following which it was put in balanced saline solution to collect rinse fluid of biopsy before transferring it to formalin for fixation. Cytological diagnosis from imprint and rinse fluid smears was compared with histopathological diagnosis. Malignancy was detected in 45 cases of 52 patients on histopathology. Positive result was given by rinse fluid cytology in 34 (65.4%) cases while diagnostic accuracy was 78.8%. The imprint smears were positive for malignancy in 44 (84.6%) cases with diagnostic accuracy of 98.08%. There were no false-positive results, but one case was incorrectly typed by both the techniques. Imprint smear cytology has a better diagnostic accuracy and efficacy over rinse fluid while the two cytologic techniques can be used in combination routinely with biopsy to provide an early and reliable diagnosis in lung cancer. PMID- 22246925 TI - Intraoperative squash cytology of central nervous system lesions: a single center study of 326 cases. AB - Cytology has been shown to be of great value in intraoperative consultations of central nervous system (CNS) pathology. Intraoperative smear cytology provides a rapid and reliable intraoperative diagnosis and guidance to the neurosurgeon during surgical resection and lesion targeting. It also helps the surgeon to monitor and modify the approach at surgery. The current study was undertaken to assess the accuracy and utility of intraoperative consultations for cytomorphological diagnosis by smear technique and correlate with histopathological diagnosis. A retrospective study of 326 cases of CNS intraoperative consultations was performed. Smears were prepared from the biopsy samples sent in isotonic saline for immediate processing and stained by the Haematoxylin and Eosin method. The cytomorphological features were noted and correlated with final histopathological diagnosis. Concordance between the intraoperative diagnosis and the final diagnosis was seen in 83.7% of cases. We demonstrated >95% accuracy for glioblastomas and >89% accuracy for meningiomas and schwannomas. A reduction of diagnostic accuracy was seen in oligodendrogliomas (60%) and anaplastic oligodendrogliomas (57.2%). Smear technique is a fairly accurate, relatively safe, rapid, simple, easily reproducible, and cost effective tool to diagnose brain tumors. Smear cytology is of great value in intraoperative consultation of CNS pathology. PMID- 22246926 TI - Spectrum of male breast lesions diagnosed by fine needle aspiration cytology: a 5 year experience at a tertiary care rural hospital in central India. AB - This study examines the spectrum of lesions in the male breast at a tertiary care rural hospital in central India and explores the role of Fine Needle Aspiration Cytology (FNAC) in the diagnosis of these lesions. Male breast lesions formed 5.89% (119 cases) of the 2017 breast lesions which were sent for FNA in the cytology section over a period of 5 years (January 2005-December 2009). Of these, biopsy had been performed only on 37 (31.1%) patients. Benign lesions comprised 102 (85.7%) cases, malignant lesions comprised 14 (11.8%) cases and inflammation/abscess was found in 3 (2.5%) cases. Gynecomastia was the commonest benign lesion in 86 (84.3%) cases. The cytologic features of gynecomastia included mild to moderate cellularity, cohesive sheets of bland cells, bipolar bare nuclei. Mild nuclear atypia was found in 19 cases. The cytologic features of malignancy comprised of dyshesive groups of ductular cells with moderate to severe degree of nuclear atypia and absence of bare nuclei. Histology was done in 37 cases and diagnostic accuracy of FNAC for gynecomastia was 100% and for malignancy 85.7%. This study showed that FNAC is a reliable tool for diagnosing male breast lesions. We conclude that FNAC should be performed as a standard procedure in the clinical evaluation of male breast masses. Many unnecessary surgical biopsies for histopathologic diagnosis can thus be avoided. PMID- 22246927 TI - Diagnostic accuracy and safety of fine-needle aspiration biopsy of the parapharyngeal space. AB - Fine-needle aspiration (FNA) biopsy of the parapharyngeal space (PPS) is a diagnostic challenge and sampling is often done without image guidance, often trans-orally. Primary PPS tumors are rare, and there is a broad differential diagnosis. The accuracy of PPS FNA, in particular without CT-guidance and using liquid-based cytology (LBC), has not been well studied. Pathology records from our institution (a 1,100 bed Canadian academic tertiary care centre) were searched to identify all patients who underwent PPS FNA from September 1991 to August 2009. The FNA diagnosis was compared to the gold standard of subsequent histopathology or long-term clinical follow-up. Of 36 FNAs, 3 employed image guidance. Eleven (31%) FNAs were nondiagnostic. In the 25 diagnostic FNAs, there was sensitivity 89%, specificity 94%, PPV 89%, NPV 94%, and accuracy 92% for the diagnosis of positive or negative for malignancy. A correct specific diagnosis was made in 9/25 (36%) cases. The nondiagnostic rate was significantly higher (P < 0.025) in FNAs prepared as conventional smears (9/17 = 53%) versus LBC (2/19 = 11%). A specific diagnosis was made significantly more often (P < 0.05) with LBC (8/19 = 43%) versus conventional smear (1/17 = 5.9%). One minor complication from FNA occurred. In conclusion, PPS FNA is safe and accurate for the diagnosis of malignancy. The rate of reporting a specific diagnosis is low. Nondiagnostic FNAs are common. There are more specific diagnoses and fewer nondiagnostic tests with LBC than with conventional smears. Improved specimen quality with LBC is likely a factor. PMID- 22246928 TI - Utility of the Thin Prep Imaging System(r) in the detection of squamous intraepithelial abnormalities on retrospective evaluation: can we trust the imager? AB - Prospective studies analyzing the ThinPrep Imaging System (TIS) have demonstrated a significant decrease in screening time and detection rates comparable or better than manual screening. We retrospectively analyzed the accuracy of the TIS in detecting cervical abnormalities. Our study included all new HSIL diagnoses in 2007 with previous negative (NIL) pap tests screened with TIS. The original 22 fields of view (FOV) were reviewed by 2 blinded screeners followed by manual screening of all slides. Any ASC-US or above was considered "abnormal." Of a total of 111,080 pap tests performed in 2007, 180 were reported as HSIL. Of these, 45 cases had a previous NIL pap diagnosed within the last year, screened with TIS. Following re-examination of the NIL pap, 31 diagnoses remained unchanged and 9 were reclassified as abnormal on the basis of cells present within the original FOV. When manually reviewed, all nine cases were confirmed as abnormal. Four cases were reclassified as abnormal on the basis of the manual screen (abnormal cells absent in the FOV). The sensitivity of TIS for the detection of abnormality was 99.95% (false-negative rate FNR: 0.05%) and the sensitivity for detection of HSIL was 99.07% (FNR: 0.92%). When analyzing the cytotechnologist interpretation of the FOV, the sensitivity for detection of abnormality and HSIL was 99.89% (FNR: 0.1%), and 99.53% (FNR: 0.4%), respectively. On retrospective analysis based on newly diagnosed HSIL cases, the sensitivity of TIS was comparable to that of manual screening with a slightly decreased rate of false negatives. PMID- 22246929 TI - Endobronchial ultrasound-guided transbronchial needle aspirate (EBUS-TBNA): a proposal for on-site adequacy criteria. AB - This is a retrospective study of 48 patients who underwent EBUS-TBNA procedure between the periods January 2008 to September 2009 at Long Island Jewish Medical Center. The study was undertaken with the following objectives: First, to define practical and useful on-site adequacy criteria for EBUS-TBNA samples; Second, to understand the diagnostic pitfalls associated with accurate interpretation of EBUS-TBNA samples. EBUS-TBNA procedure was able to diagnose 24/48 (50%) patients with malignancy, 1/48 (2%) suspicious for malignancy, 9/48 (19%) with granulomatous process, and 9/48 (19%) negative for disease. Only five cases (10%) could not be diagnosed with this procedure. Based on our experience, any smear with presence of > 5 low power fields (*100) with >= 100 lymphocytes in each and containing < 2 groups of bronchial cells/low power field (*100) can be considered adequate for evaluation. Also, the presence of germinal center fragments renders a smear adequate for evaluation, irrespective of the above mentioned criteria. Adequacy criteria are to be applied only to the smears not showing any identifiable pathology such as malignancy or granuloma. An understanding of diagnostic pitfalls associated with accurate interpretation of EBUS-TBNA samples is essential to avoid false-positive and false-negative diagnosis. To conclude, an effective communication between the clinician and cytologist, an algorithmic approach to diagnosis, and the on-site adequacy criteria proposed in this study can markedly improve the diagnostic yield of the procedure. PMID- 22246930 TI - The diagnostic utility of CK5/6 and p63 in fine-needle aspiration of the breast lesions diagnosed as proliferative fibrocystic lesion. AB - Fine-needle aspiration (FNA) biopsy (FNAB) in the preoperative assessment of breast lesions has shown diagnostic limitations with false-positive and false negative diagnoses. We investigated the diagnostic value of cytokeratin 5/6 (CK5/6) and p63 in a series of breast FNABs, diagnosed as proliferative breast lesions with or without atypia, to see whether these ancillary studies enhance the ability to make an accurate diagnosis by FNAB. Sixty-four breast FNABs were retrieved between January 2000 and December 2005 and included in the study as follows: 29/64 (45%) cases as proliferative with atypia and 35/64 (55%) without atypia. We also included 10 cases of fibroadenoma. All cases had histological follow-up available for correlation. Immunostaining for CK5/6 and p63 was performed on the cell block material in all cases. The percentage of staining cells in the specimen was graded as 0 (0-10%), 1 (11-25%), 2 (26-50%), and 3 (>50%). There were 9/29 (31%) cases in the atypical group that were found to be malignant on resection, compared with 6/35 (17%) in the cases without atypia. In histologically proven malignant cases, CK5/6 was negative in 11/15 (73%) or showed 1+ stain in 2/15 (13%) cases. In benign breast lesions, CK5/6 stained more than 25% of cell proliferation in 44/49 (90%). p63 showed characteristic staining for single naked bipolar nuclei in the background of the specimen (not appreciated by CK5/6) in all fibroadenoma cases. In conclusion, CK5/6 may enhance the ability to differentiate between benign and malignant epithelial proliferations in breast FNABs. In fibroepithelial lesions, p63 may be more useful than CK5/6. PMID- 22246931 TI - Breast carcinoma with osteoclast-like giant cells diagnosed by fine-needle aspiration cytology. PMID- 22246932 TI - Fractal dimension of chromatin texture of squamous intraepithelial lesions of cervix. AB - The aim of this study was to explore the role of fractal dimension (FD) of chromatin texture in routinely stained Papanicolaou's smears and to distinguish the different grades of cervical intraepithelial lesions and normal cervical cells. We selected 14 each cases of normal, low grade cervical intra epithelial lesions (LSIL), and high-grade cervical intra epithelial lesions (HSIL) of Papanicolaou's stained cervical smears. Fractal dimension of the pseudo three dimensional grey image of the nuclear chromatin was measured in 140 nuclei of each group. Mean FD of the normal cases, LSIL cases, and HSIL cases were 2.4225 +/- 0.06410, 2.5159 +/- 0.03291, and 2.5905 +/- 0.06840, respectively. ANOVA test showed significant differences of mean FD in all these three groups (P < 0.000). Fractal dimension of the chromatin texture is easy to perform and can be done in routinely stained Papanicolaou's smear. It is reproducible and gives valuable information about the chromatin texture of the nucleus. In future, this promising variable can be incorporated along with other image morphometric features for accurate classification of dysplastic cells in cervical smear. PMID- 22246933 TI - Chordoid glioma in suprasellar location with extension into the third ventricle: smear preparation morphology of a rare tumor. AB - We report a rare case of recurrent chordoid glioma in suprasellar region with extension into the third ventricle diagnosed peroperatively. On MRI, a brilliantly contrast enhancing lesion in the suprasellar region extending superiorly into the third ventricle and measuring 2.5 * 3 * 3.5 cm was identified. Patient had a previous history of subtotal removal of the tumor 8 months back and had received 56 Gy of postoperative radiotherapy. On smear preparation the tumor was composed of cells arranged in chords and rows in a myxoid background with sprinkling of lymphocytes. The individual cells were polygonal with moderate amount of faintly eosinophilic cytoplasm with cytoplasmic vacoules in few cells. The nuclei showed fine chromatin with small prominent nucleoli. Paraffin sections confirmed the diagnosis and on immunohistochemistry the tumor cells showed strong positivity for GFAP and focal weak positivity for EMA with low MIB-1 labeling index (<1%). To the best of our knowledge this is the first documented case of chordoid glioma described on crush cytology. PMID- 22246934 TI - Endometriosis of sigmoid colon mimicking malignant tumor diagnosed by intraoperative imprint cytology. AB - A case of endometriosis of the sigmoid colon on imprint cytology from an intraoperative biopsy is discussed. Cytologic specimens showed sheets or tubular epithelial clusters and stromal fragments. The epithelial cell nuclei were small and round to ovoid with finely granular chromatin and inconspicuous nucleoli. The background showed a few scattered spindle-type stromal cells without pigment laden histiocytes. A definitive diagnosis of endometriosis can be based on cytology, provided that the cytologic findings are interpreted in the appropriate clinical context. PMID- 22246935 TI - Urothelial carcinoma involving vaginal specimens from patients with neobladder: a potential pitfall in diagnostic cytopathology. AB - Most vaginal neoplasms represent metastasis from the cervix, endometrium, colon and ovary and distinction from a primary lesion does not pose a diagnostic problem. Recently, it has been recognized that women with urothelial carcinoma (UC) who have undergone radical cystectomy with orthotopic neobladder reconstruction are at risk for recurrence in the lower gynecologic tract. Our objective is to describe the cytologic features of cases with confirmed UC in the vagina in this clinical setting. Four vaginal specimens from patients with prior radical cystectomy and orthotopic neobladder reconstruction with histologically confirmed UC were evaluated. The vaginal specimens consisted of Thinprep(r) and Papanicolaou-stained slides. Cytomorphologic parameters including cellular arrangement, cell size and shape, cytoplasm, and nuclear features were evaluated and compared with a corresponding surgical biopsy. All four cases were highly cellular with abundant neoplastic cells arranged singly and in loose three dimensional clusters with overlapping nuclei. The neoplastic cells were large and polygonal with well-defined cell borders, high nuclear to cytoplasmic ratio, and granular basophilic cytoplasm. The chromatin was coarse with small nucleoli. Scattered keratinized single cells with atypical hyperchromatic nuclei were observed in each case. In summary, UC involving the vagina can share many morphologic features with primary squamous cell carcinomas at this site, including focal keratinization. Abundant three dimensional clusters of neoplastic cells and a previous history of orthotopic neobladder reconstruction are helpful cytomorphologic and clinical features supporting a diagnosis of UC involving the vagina and may prevent unnecessary work-up for a new primary lesion. PMID- 22246936 TI - Fine-needle aspiration diagnosis of metastatic urothelial carcinoma: a review. AB - Urothelial carcinoma (UC) is the most common malignant neoplasm of the urinary tract. Metastases of UC are most common in the regional lymph nodes, lungs, liver, bone, and adrenal glands. Fine-needle aspiration cytology diagnosis of such metastases can be difficult, particularly in the setting of incomplete clinical history or when multiple primary neoplasms may be present. This review focuses on the cytologic features helpful in differentiating UC from its potential mimics, as well as ancillary studies that may be helpful in the distinction. PMID- 22246937 TI - Cytomorphology of male breast lesions: diagnostic pitfalls and clinical implications. AB - Because lesions of the male breast have been exceeded in number by those of the female breast, marginal attention was given to these lesions in the past. Fortunately, this has changed over the years leading to an increased awareness about male breast cancer. Although male breast cancer constitutes only about 1% of all diagnosed breast cancer cases, an increased mortality is seen in this patient population. This is probably caused by late diagnosis as a consequence of low level of concern about breast cancer among male patients. However, the vast majority of lesions of the male breast are benign, gynecomastia being the number one cause of unilateral or bilateral breast mass. Since it is important to avoid unnecessary surgical treatment without missing malignancy, accurate diagnostic tools are necessary in order to triage these patients. Fine-needle aspiration biopsy has demonstrated excellent accuracy in the diagnosis and management of breast lesions in female patients. In addition, several authors have proven the value of this technique in the evaluation of lesions of the male breast. Fine needle aspiration biopsy permits accurate diagnosis in many lesions arising in the male breast. It also allows gathering cytological material that can be used for ancillary studies which enhances the diagnostic value of this technique. PMID- 22246938 TI - Cytology of chordoid glioma of the third ventricle. PMID- 22246939 TI - Image cytometry of insular carcinoma. AB - To study the morphometric features of insular carcinoma (IC) of thyroid and follicular carcinoma (FC) in fine needle aspiration cytology (FNAC) smear to evaluate the role of the morphometric features to distinguish these two groups. We performed image morphometry in Hematoxyline and Eosin stained FNAC smears of eight each histopathology proven cases of IC and FC of thyroid. Nuclear area, diameter, perimeter, and standard deviation of nuclear area (SDNA) of these two groups were studied and compared. Nuclear area, diameter, perimeter, and SDNA of IC and FC were 30.43 MU(2) , 7.31 MU, 23.01 MU, 8.81 and 38.43 MU(2) , 7.66 MU, 25.63 MU, 10.83, respectively. Student's t-test analysis did not show any significant difference (P > 0.05) in these two groups. Nuclear morphometry data indicate that the nuclear size and shape of IC and FC are essentially similar and it is not possible to differentiate these two entities with the help of image morphometric data. PMID- 22246940 TI - Validation of diffusion tensor MRI in the central nervous system using light microscopy: quantitative comparison of fiber properties. AB - Diffusion tensor imaging (DTI) provides an indirect measure of tissue structure on a microscopic scale. To date, DTI is the only imaging method that provides such information in vivo, and has proven to be a valuable tool in both research and clinical settings. In this study, we investigated the relationship between white matter structure and diffusion parameters measured by DTI. We used micrographs from light microscopy of fixed, myelin-stained brain sections as a gold standard for direct comparison with data from DTI. Relationships between microscopic tissue properties observed with light microscopy (fiber orientation, density and coherence) and fiber properties observed by DTI (tensor orientation, diffusivities and fractional anisotropy) were investigated. Agreement between the major eigenvector of the tensor and myelinated fibers was excellent in voxels with high fiber coherence. In addition, increased fiber spread was strongly associated with increased radial diffusivity (p = 6 * 10(-6)) and decreased fractional anisotropy (p = 5 * 10(-8)), and was weakly associated with decreased axial diffusivity (p = 0.07). Increased fiber density was associated with increased fractional anisotropy (p = 0.03), and weakly associated with decreased radial diffusivity (p < 0.06), but not with axial diffusivity (p = 0.97). The mean diffusivity was largely independent of fiber spread (p = 0.24) and fiber density (p = 0.34). PMID- 22246941 TI - Gene cloning, expression and functional characterization of a proliferation inducing ligand (APRIL) from hedgehog (Erinaceus europaeus). AB - Here we describe the identification of the hedgehog Erinaceus europaeus homologue of a proliferation-inducing ligand (APRIL) of the TNF family (designated heAPRIL). Hedgehog APRIL contains two cysteine residues (Cys(196) and Cys(211)), a furin protease cleavage site and a conserved putative N-glycosylation site (Asn(124)). Real-time quantitative PCR (qPCR) analysis revealed that heAPRIL could be detected in various tissues. MTT assays and flow cytometric analysis revealed that Nus-hesAPRIL and hesAPRIL could promote the survival/proliferation of splenic B cells. Laser scanning confocal microscopy analysis showed GFP hesAPRIL could successfully bind to the APRIL receptors of lymphocytes. PMID- 22246942 TI - Explaining racial differences in prostate cancer mortality. AB - BACKGROUND: In the United States, black males have an annual death rate from prostate cancer that is 2.4 times that of white males. The reasons for this are poorly understood. METHODS: Using the Surveillance, Epidemiology, and End Results Medicare database, 77,038 black and white males aged >65 years were identified with a first primary diagnosis of prostate cancer between 1995 and 2005, as well as 49,769 controls. The racial gap in mortality was decomposed to differential incidence and stage-specific prostate cancer mortality. The importance of various clinical and socioeconomic factors to each of these components was then examined. RESULTS: The estimated mortality gap for prostate cancer-specific mortality was 1320 more cases per 100,000 males among black than white men. This gap was due to higher prostate cancer incidence among black males (76%) and higher stage specific mortality once diagnosed (24%). Differences in prostate-specific antigen testing, comorbidities, and income explained 29% of the difference in metastatic cancer incidence but none of the racial gap for local/regional incidence. Conditional on diagnosis, tumor characteristics explained 50% of the racial gap, comorbidities an additional 4%, choice of treatment and physician 17%, and socioeconomic factors 15%. Overall, approximately 25% of the racial gap in mortality and 86% of the gap in mortality conditional on diagnosis could be explained. CONCLUSIONS: More frequent prostate-specific antigen testing for black and low-income males could potentially reduce the prostate cancer mortality gap through earlier diagnosis of tumors that otherwise may become metastatic. More aggressive treatment of prostate cancer, especially in poor communities, might also reduce the gap. PMID- 22246943 TI - Short-term effects of brimonidine/timolol and dorzolamide/timolol on ocular perfusion pressure and blood flow in glaucoma. AB - INTRODUCTION: To examine the comparative short-term effects of brimonidine/timolol and dorzolamide/timolol on ocular perfusion pressure and retrobulbar blood flow in patients with primary open angle glaucoma (OAG). METHODS: In a prospective, randomized, double-blind, crossover study, intraocular pressure (IOP), blood pressure (BP), ocular perfusion pressure (OPP), and retrobulbar hemodynamics were assessed in 15 patients with OAG (mean age 68.1 years, eight women) with well controlled IOP. IOP was measured by Goldman applanation tonometery and color Doppler imaging was utilized to assess the retrobulbar blood vessels before and 1 month after treatment with topical brimonidine/timolol and dorzolamide/timolol. Statistical analysis was performed by Friedman two-way analysis of variance by ranks and post-hoc Wilcoxon signed rank test for multiple comparisons with Holm's sequential Bonferroni procedure. P values <0.05 were considered statistically significant. RESULTS: The Friedman test and subsequent post-hoc analysis indicated that IOP, BP, OPP, and retrobulbar blood flow velocities did not significantly differ between brimonidine/timolol and dorzolamide/timolol after 1-month treatment administration in patients with OAG and well controlled IOP. CONCLUSION: In this cohort of patients with OAG, short-term treatment with brimonidine/timolol and dorzolamide/timolol results in similar effects on OPP and retrobulbar blood flow velocities. PMID- 22246944 TI - Fixed-dose combination antidiabetic therapy: real-world factors associated with prescribing choices and relationship with patient satisfaction and compliance. AB - INTRODUCTION: Compliance with antidiabetic therapy has the potential to impact on the risk for complications by an effect on glycemic control. Fixed-dose combinations (FDCs) offer a simplified dosing regimen that may improve patient compliance. We undertook a retrospective database analysis to understand the real world association between FDCs, treatment practices, glycated hemoglobin (HbA(1c)) levels, and patient perspectives in type 2 diabetes. METHODS: Data were drawn from the Adelphi Diabetes Disease Specific Programme (DSP), a multicenter, patient recordbased market research study of primary care physicians and diabetologists/endocrinologists in Europe. The study is based on physician interviews, completion of detailed patient record forms by physicians, and a self completion questionnaire by patients. Regression analyses were used to identify factors associated with (1) physician-reported dipeptidyl peptidase-4 inhibitor (DPP-4)/metformin FDC prescribing in dual or triple therapy regimens; (2) HbA1c of patients prescribed a DPP-4 FDC alone versus free-form DPP-4 plus metformin dual therapy regimens; and (3) differences between patients prescribed any oral antidiabetic therapy (OAD) FDC therapy (alone or in combination with one other OAD) versus those prescribed dual or triple OAD free-form combination therapy. RESULTS: Physician-reported data were available for 5891 patients (mean age 61.5 years, 43% female, mean duration since diagnosis 5.7 years). Factors associated with DPP-4 FDC usage included physicians' reason for choice being "improves patient compliance." The relative mean % HbA(1c) level associated with being on a DPP-4 FDC rather than free-form independent of the physician perception of patient compliance was 0.25 lower (CI -0.40 to -0.09). When physician-perceived patient compliance was described as "fairly compliant" rather than "poorly compliant" or "not at all compliant," the relative mean % HbA1c level was 0.42 lower (CI -0.67 to -0.18). Similarly, being perceived as "fully compliant" rather than "fairly compliant" was associated with a relative mean % HbA(1c) level that was 0.17 lower (CI -0.31 to -0.02). A significant predictor for the current regimen being any FDC (alone or in combination with one other OAD) regimen was patients' satisfaction with treatment (odds ratio 1.32; 95% CI 1.10 to 1.58; P=0.003). CONCLUSIONS: These results suggest that DPP-4 FDC prescribing is considered to be a positive prescribing choice to improve compliance and that choice is associated with improved glycemic control. From the patient's perspective, the decision to prescribe an FDC is associated with improved satisfaction with treatment. PMID- 22246945 TI - Atrial fibrillation and risk. PMID- 22246946 TI - Can we predict outcomes in atrial fibrillation? AB - Atrial fibrillation (AF) is the most common arrhythmia encountered by generalists and cardiologists alike. Much of the attendant morbidity from AF arises from systemic embolic complications which are effectively reduced with utilization of anti-platelet and/or anticoagulant therapy. The systemic embolic complications of AF and the medical therapy to attenuate these risks are very well established. Through the course of this review, we aim to highlight the complex relationship between AF and other, "non-embolic" outcomes. The presence of AF has been demonstrated to be associated with a 1.5 to 2-fold increase in mortality across numerous observational cohorts. Still further, AF frequently coexists with heart failure, whether as a causative factor or a consequence of underlying structural heart disease or neurohumoral derangement, where its presence is associated with worse clinical outcomes. Whether AF is an independent risk factor for acute coronary syndromes (ACS) remains controversial, though its occurrence in patients with ACS has been shown to be associated with adverse outcomes both in observational cohorts as well as clinical trial populations. Individuals with AF have a 1.5 to 3-fold increase in the rate of hospitalization and are at elevated risk for other arrhythmic disorders including both bradyarrhythmias as well as tachyarrhythmias. AF leads to considerable morbidity and mortality for patients and exacts a tremendous financial toll on the healthcare system-estimated to range from $6.0 to $26.0 billion. Given the current demographic transition in developed countries, the prevalence of AF will continue to increase and the need for refined approaches to risk stratification and pharmacotherapeutic interventions to attenuate the burden on patients will only become more important. PMID- 22246947 TI - Atrial fibrillation and vascular disease--a bad combination. AB - This article provides an overview of (i) the risk of stroke associated with vascular disease (acute coronary syndromes and peripheral artery disease) in patients with atrial fibrillation, (ii) the frequent coexistence of vascular disease in patients with atrial fibrillation and, (iii) the cardiovascular risk associated with the coexisting of the two diseases. The literature on this topic is relatively sparse, and we discuss results from both clinical trials and observational studies. There is a clear indication of an increased stroke risk associated with vascular disease in patients with atrial fibrillation. Indeed, patients with atrial fibrillation often had coexisting vascular disease (around 18%), and the combination of the two diseases substantially increases the risk of future cardiovascular events. The increased risk associated with peripheral artery disease in atrial fibrillation is even more pronounced. Patients with atrial fibrillation and stable vascular disease should be treated with oral anticoagulation only, although when these patients present with acute coronary syndrome and/or undergo coronary stenting, concomitant treatment with antiplatelet drugs is indicated. To guide antithrombotic management in patients with atrial fibrillation, several stroke and bleeding risk prediction schemes have been developed. PMID- 22246948 TI - Can we predict stroke in atrial fibrillation? AB - Stroke prevention with appropriate thromboprophylaxis still remains central to the management of atrial fibrillation (AF). Nonetheless, stroke risk in AF is not homogeneous, but despite stroke risk in AF being a continuum, prior stroke risk stratification schema have been used to 'artificially' categorise patients into low, moderate and high risk stroke strata, so that the patients at highest risk can be identified for warfarin therapy. Data from recent large cohort studies show that by being more inclusive, rather than exclusive, of common stroke risk factors in the assessment of the risk for stroke and thromboembolism in AF patients, we can be so much better in assessing stroke risk, and in optimising thromboprophylaxis with the resultant reduction in stroke and mortality. Thus, there has been a recent paradigm shift towards getting better at identifying the 'truly low risk' patients with AF who do not even need antithrombotic therapy, whilst those with one or more stroke risk factors can be treated with oral anticoagulation, whether as well-controlled warfarin or one or the new oral anticoagulant drugs. The new European guidelines on AF have evolved to deemphasise the artificial low/moderate/high risk strata (as they were not very predictive of thromboembolism, anyway) and stressed a risk factor based approach (within the CHA(2) DS(2)-VASc score) given that stroke risk is a continuum. Those categorised as 'low risk' using the CHA(2) DS(2)-VASc score are 'truly low risk' for thromboembolism, and the CHA(2) DS(2)-VASc score performs as good as-and possibly better--than the CHADS(2) score in predicting those at 'high risk'. Indeed, those patients with a CHA(2) DS(2)-VASc score = 0 are 'truly low risk' so that no antithrombotic therapy is preferred, whilst in those with a CHA(2) DS(2) VASc score of 1 or more, oral anticoagulation is recommended or preferred. Given that guidelines should be applicable for >80% of the time, for >80% of the patients, this stroke risk assessment approach covers the majority of the patients we commonly seen in everyday clinical practice, and considers the common stroke risk factors seen in these patients. The European guidelines also do stress that antithrombotic therapy is necessary in all patients with AF unless they are age <65 years and truly low risk. Indeed, some patients with 'female gender' only as a single risk factor (but still CHA(2) DS(2)-VASc score of 1, due to gender) do not need anticoagulation, especially if they fulfil the criterion of "age <65 and lone AF, and very low risk". In the European and Canadian guidelines, bleeding risk assessment is also emphasised, and the simple validated HAS-BLED score is recommended. A HAS-BLED score of >= 3 represents a sufficiently high risk such that caution and/or regular review of a patient is needed. It also makes the clinician think of correctable common bleeding risk factors, and the availability of such a score allows an informed assessment of bleeding risk in AF patients, when antithrombotic therapy is being initiated. PMID- 22246949 TI - Benefit-risk assessment of current antiarrhythmic drug therapy of atrial fibrillation. AB - Over the last decade, several rhythm-versus rate-control trails in patients with atrial fibrillation (AF) have failed to demonstrate benefit of the rhythm control strategy with respect to mortality and morbidity. This had let to the guideline recommendation that antiarrhythmic drug therapy should be considered predominantly for symptomatic improvement of patients. Recent trails and meta analyses have demonstrated that amiodarone is the most antiarrhythmic drug currently available. However, its use has been associated with many adverse effects. Currently, dronedarone is the only available antiarrhythmic drug which has shown a reduction in cardiovascular hospitalizations in medium-risk AF patients. However, the drug was associated with increased mortality in patients with recently decompensated heart failure. Hence, antiarrhythmic drug therapy has to be evaluated in patients with AF on an individual patients basis. PMID- 22246951 TI - Can we predict the occurrence of atrial fibrillation? AB - Atrial fibrillation (AF) is a complex disease with increasing prevalence in an aging population and longer survival with cardiovascular diseases. Whereas most clinical efforts have been aimed at predicting risk of AF sequelae such as stroke and heart failure, little is known on primary prevention. AF risk assessment is complicated by the existence of distinct subtypes of AF, such as lone AF or postoperative AF, in contrast to common AF in the elderly. Due to its often intermittent nature, diagnosing AF can be a challenge. Risk prediction becomes reasonable when specific interventions arise. Due to our limited understanding of AF pathophysiology and substantial lack of specific preventive strategies in the population, modification of the general cardiovascular risk profile has largely remained the only option. Initial attempts at combining established risk factors for AF such as age, sex, hypertension, body mass index, electrocardiographic characteristics, and cardiovascular disease in a risk-prediction instrument have produced a robust algorithm. However, known risk factors only explain a fraction of the population-attributable risk of AF, and the search for novel risk indicators is ongoing. More efficient monitoring for electrocardiographic precursors of AF and the field of genomics are evolving areas of AF risk factor research. A better understanding of the underlying substrate of AF will provide targets for prevention. In the future, clinical trials will be needed to establish risk categories, interventions, and their efficacy. Despite a relevant public-health impact, knowledge on risk prediction and primary prevention of AF is still limited today. There are no conflicts of interest to disclose. PMID- 22246952 TI - Accuracy of MR elastography and anatomic MR imaging features in the diagnosis of severe hepatic fibrosis and cirrhosis. AB - PURPOSE: To compare the diagnostic accuracy of magnetic resonance imaging elastography (MRE) and anatomic MRI features in the diagnosis of severe hepatic fibrosis and cirrhosis. MATERIALS AND METHODS: Three readers independently assessed presence of morphological changes associated with hepatic fibrosis in 72 patients with liver biopsy including: caudate to right lobe ratios, nodularity, portal venous hypertension (PVH) stigmata, posterior hepatic notch, expanded gallbladder fossa, and right hepatic vein caliber. Three readers measured shear stiffness values using quantitative shear stiffness maps (elastograms). Sensitivity, specificity, and diagnostic accuracy of stiffness values and each morphological feature were calculated. Interreader agreement was summarized using weighted kappa statistics. Intraclass correlation coefficient was used to assess interreader reproducibility of stiffness measurements. Binary logistic regression was used to assess interreader variability for dichotomized stiffness values and each morphological feature. RESULTS: Using 5.9 kPa as a cutoff for differentiating F3-F4 from F0-2 stages, overall sensitivity, specificity, and diagnostic accuracy for MRE were 85.4%, 88.4%, and 87%, respectively. Overall interreader agreement for stiffness values was substantial, with an insignificant difference (P = 0.74) in the frequency of differentiating F3-4 from F0-2 fibrosis. Only hepatic nodularity and PVH stigmata showed moderately high overall accuracy of 69.4% and 72.2%. Interreader agreement was substantial only for PVH stigmata, moderate for C/R m, deep notch, and expanded gallbladder fossa. Only posterior hepatic notch (P = 0.82) showed no significant difference in reader rating. CONCLUSION: MRE is a noninvasive, accurate, and reproducible technique compared with conventional features of detecting severe hepatic fibrosis. PMID- 22246954 TI - Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. AB - We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected. PMID- 22246955 TI - Using SILAC and quantitative proteomics to investigate the interactions between viral and host proteomes. AB - Viruses continue to pose some of the greatest threats to human and animal health, and food security worldwide. Therefore, new approaches are required to increase our understanding of virus-host cell interactions and subsequently design more effective therapeutic countermeasures. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture (SILAC), coupled to LC-MS/MS and bioinformatic analysis, is providing an excellent resource for studying host cell proteomes and can readily be applied for the study of virus infection. Here, we review this approach and discuss how virus-host cell interactions can best be studied, what is realistically feasible, and the potential limitations. For example, sub-cellular fractionation can reduce sample complexity for LC-MS/MS, increase data return and provide information regarding protein trafficking between different cellular compartments. The key to successful quantitative proteomics combines good experimental design and appropriate sample preparation with statistical analysis and validation of the MS data through the use of independent techniques and functional analysis. The annotation of the human genome and the increasing availability of biological reagents such as antibodies, provide the optimum parameters for studying viruses that infect humans, in human cell lines. SILAC-based quantitative proteomics can also be used to study the interactome of viral proteins with the host cell. Coupling proteomic studies with global transcriptomic and RNA depletion experiments will provide great insights into the complexity of the infection process, and potentially reveal new antiviral targets. PMID- 22246956 TI - B1 mapping with selective pulses. AB - Knowledge of B1+ distribution is crucial for many applications, such as quantitative MRI. A novel method has been developed to improve the accuracy of the conventionally applied double-angle method for B1+ mapping. It solves the remaining issues raised by the use of selective pulses for slice selection to accelerate the acquisition process. A general approach for reconstructing B1+ maps is presented first. It takes B1+-induced slice profile distortions over off resonance frequencies into account. It is then shown how the ratio between the prescribed flip angles can be adjusted to reach a compromise between the level of noise propagated onto B1+ maps and the width of the range in which the field can be mapped. Lastly, several solutions are proposed for reducing the B1+-dependent pollution of regions distal to the image slice which participates significantly in the inaccuracy of B1+ mapping. These methods were experimentally tested by comparison with gold standard B1+ maps obtained on a phantom using a non selective and thus much slower technique. As they are independent and lead to significant improvements, these solutions can be combined to achieve high precision and fast B1+ mapping using spin-echo DAM. PMID- 22246958 TI - Setting up an off-site emergency mortuary facility (EMF) to deal with a DVI incident: disaster victim management (DVM). AB - Forensic mortuaries in all Australian jurisdictions are dealing with increasing workloads, with routine cases regularly occupying greater than 50%, and often as much as 85%, of existing cold room body storage capacity, particularly over long weekends and during seasonal increases in respiratory infections. Hence the need to deal with a sudden influx of deceased persons or multiple body parts in a mass fatality incident would overwhelm most Australian forensic mortuaries, thereby requiring other means of body storage and processing. Exercise "Construct" was a joint South Australian Police (SAPol) and Forensic Science South Australia exercise designed to practice the establishment and construction of an emergency mortuary facility (EMF) to deal with a mass fatality incident and the subsequent disaster victim identification process. The aims of the exercise were to test preparedness, activation and construction processes relative to the establishment of an EMF. The exercise provided the opportunity to identify gaps in the capacity to successfully complete the tasks within the allotted time frames. The exercise reinforced the need to have a comprehensive and clearly documented process which must include a current list of suppliers who can deliver goods and services in a timely manner. The aim of this paper is to report on the exercise findings and share the experience with other jurisdictions. It will also provide other jurisdictions with the opportunity to consider whether the South Australian model will be useful to them in improving their own response when confronted with a mass fatality incident that may overwhelm existing local mortuary capacities and capabilities. PMID- 22246957 TI - Postmortem tandem mass spectrometry profiling for detection of infection in unexpected infant death. AB - Numerous hypotheses have been suggested to explain the cause of sudden unexpected infant death, including infection. As part of the autopsy, routine ancillary investigations are performed, including blood/bile tandem mass spectrometry (TMS) primarily for detection of metabolic disease. The aim of this study was to evaluate and assess TMS derived acylcarnitine profiles to determine whether infectious deaths were associated with characteristic profiles. As part of a retrospective study including >2,500 pediatric autopsies at a single specialist centre over a 14 year period, acylcarnitine profiles were reviewed. Using multiple linear regression, standardised residuals were prepared and findings compared between different cause of death groups, including unexplained, focal infection, microbiological infection and accidental injuries. 415 blood samples from SUDI autopsies were identified. Statistically significant differences in TMS profiles were identified between those dying of infection and the unexplained SUDI group, including changes in free carnitine, short chain acylcarnitines and octanoylcarnitine. Cases with microbiological infection diagnosed only from postmortem cultures did not show any significant difference from the unexplained group. Postmortem TMS profiling identifies SUDI deaths which are associated with histological evidence of infection, and an acylcarnitine profile suggesting perturbation of oxidative metabolism. Such findings raise the possibility that more comprehensive TMS profiling may offer additional diagnostic clues beyond screening for metabolic disorders, and may contribute to determination of mode of death. PMID- 22246959 TI - A generic hierarchical screening method for the analysis of microscale refolds using an automated robotic platform. AB - The refolding of protein derived from inclusion bodies is often characterized by low yields of active protein. The optimization of the refolding step is achieved empirically and consequently is time-consuming slowing process development. An automated robotic platform has been used to develop a dilution refold process screening platform upon which a hierarchical set of assays rapidly determine optimal refolding conditions at the microscale. This hierarchy allows the simplest, cheapest, and most generic high-throughput assays to first screen for a smaller subset of potentially high-yielding conditions to take forward for analysis by slower, more expensive, or protein specific assays, thus saving resources whilst maximizing information output. An absorbance assay was used to initially screen out aggregating conditions, followed by an intrinsic fluorescence assay of the soluble protein to identify the presence of native-like tertiary structure, which was then confirmed by an activity assay. Results show that fluorescence can be used in conjunction with absorbance to eliminate low yielding conditions, leaving a significantly reduced set of conditions from which the highest yielding ones can then be identified with slower and often more costly activity or RP-HPLC assays, thus reducing bottlenecks in high-throughput analysis. The microwell-based automated process sequence with generic hierarchical assays was also used to study and minimize the effect on redox potential or misfolding, of oxygenation due to agitation, before demonstrating that the platform can be used to rapidly collect data and evaluate different refolding conditions to speed up the acquisition of process development data in a resource efficient manner. PMID- 22246960 TI - Intra-abdominal cryptococcosis by Cryptococcus gattii: case report and review. AB - Although abdominal cryptococcomas and visceral cryptococcal lymphadenitis as part of disseminated fungal infection have been reported mostly in HIV-infected patients, localized intra-abdominal involvement due to Cryptococcus gattii has not been previously described in non-HIV-infected patients. In general, a smaller proportion of cryptococcosis is caused by C. gattii. We report here on a type II diabetic HIV-negative patient who presented with a localized intra-abdominal cryptococcal mass due to C. gattii. In addition, we review the general aspects of intra-abdominal and gastrointestinal involvement by Cryptococcus neoformans in the literature and discuss the importance of identifying the C. neoformans varieties and C. gattii in routine laboratories. PMID- 22246961 TI - Susceptibilities of Candida albicans mouth isolates to antifungal agents, essentials oils and mouth rinses. AB - Forty Candida albicans strains isolated from patient's mouth with fixed orthodontic appliances were analyzed to their susceptibilities to antifungal agents, mouth rinses and essential oils. Susceptibility to fluconazole, econazole, miconazole and ketoconazole, amphotericin B and nystatin was assessed by the disk diffusion (DD) method based on the Clinical and Laboratory Standards Institute M44-A protocol, and by Etest (fluconazole and amphotericin B). The susceptibilities to mouth rinses and essential oils were also determined by the DD technique. All isolates tested were susceptible (S) to amphotericin B, nystatin and fluconazole. The overall concordance between the DD and the Etest was 100% for amphotericin and fluconazole. One isolate was resistant to econazole (2.5%) and the other to ketoconazole (2.5%). Econazole and ketoconazole had the highest percentages of susceptible dose dependent (SDD), 55 and 95%, respectively. Regarding to the susceptibility isolates profile, seven phenotypes were detected, and the 3 more represented (90% of the isolates) of them were SDD to one, two or three azoles. The study of mouth rinses showed a high variability of efficacy against C. albicans. The results showed that the isolates susceptibility to essential oils differed (P < 0.05). The profile activity was: cinnamon > laurel > mint > eucalyptus > rosemary > lemon > myrrh > tangerine. The main finding was that the susceptibility to cinnamon and laurel varied among the three more representative antifungal phenotypes (P < 0.05). The susceptibility of econazole-SDD isolates to cinnamon and lemon was higher than those of the econazole-S yeasts (P < 0.05). In contrast, econazole-SDD isolates were less affected by laurel than econazole-S counterparts (P < 0.05). PMID- 22246962 TI - Connectivity of thalamo-cortical pathway in rat brain: combined diffusion spectrum imaging and functional MRI at 11.7 T. AB - Fiber tracking in combination with functional MRI has recently attracted strong interest, as it may help to elucidate the structural basis for functional connectivities and may be selective in the determination of the fiber bundles responsible for a particular circuit. Diffusion spectrum imaging provides a more complex analysis of fiber circuits than the commonly used diffusion tensor imaging approach, also allowing the discrimination of crossing fibers in the brain. For the understanding of pathophysiological alterations during brain lesion and recovery, such studies need to be extended to small-animal models. In this article, we present the first study combining functional MRI with high resolution diffusion spectrum imaging in vivo. We have chosen the well characterized electrical forepaw stimulation paradigm in the rat to examine the thalamo-cortical pathway. Using the functionally activated areas in both thalamus and somatosensory cortex as seed and target regions for fiber tracking, we are able to characterize the fibers responsible for this stimulation pathway. Moreover, we show that the selection of the thalamic nucleus and primary somatosensory cortex on the basis of anatomical description results in a larger fiber bundle, probably encompassing connectivities between the thalamus and other areas of the somatosensory cortex, such as the hindpaw and large barrel field cortex. PMID- 22246963 TI - The effectiveness of a new generation of computerized drug alerts in reducing the risk of injury from drug side effects: a cluster randomized trial. AB - CONTEXT: Computerized drug alerts for psychotropic drugs are expected to reduce fall-related injuries in older adults. However, physicians over-ride most alerts because they believe the benefit of the drugs exceeds the risk. OBJECTIVE: To determine whether computerized prescribing decision support with patient-specific risk estimates would increase physician response to psychotropic drug alerts and reduce injury risk in older people. DESIGN: Cluster randomized controlled trial of 81 family physicians and 5628 of their patients aged 65 and older who were prescribed psychotropic medication. INTERVENTION: Intervention physicians received information about patient-specific risk of injury computed at the time of each visit using statistical models of non-modifiable risk factors and psychotropic drug doses. Risk thermometers presented changes in absolute and relative risk with each change in drug treatment. Control physicians received commercial drug alerts. MAIN OUTCOME MEASURES: Injury risk at the end of follow up based on psychotropic drug doses and non-modifiable risk factors. Electronic health records and provincial insurance administrative data were used to measure outcomes. RESULTS: Mean patient age was 75.2 years. Baseline risk of injury was 3.94 per 100 patients per year. Intermediate-acting benzodiazepines (56.2%) were the most common psychotropic drug. Intervention physicians reviewed therapy in 83.3% of visits and modified therapy in 24.6%. The intervention reduced the risk of injury by 1.7 injuries per 1000 patients (95% CI 0.2/1000 to 3.2/1000; p=0.02). The effect of the intervention was greater for patients with higher baseline risks of injury (p<0.03). CONCLUSION: Patient-specific risk estimates provide an effective method of reducing the risk of injury for high-risk older people. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier: NCT00818285. PMID- 22246964 TI - Compression of an anomalous single coronary artery from pulmonary artery by banding. AB - This report describes a case with double outlet right ventricle and doubly committed ventricular septal defect associated with congenital diaphragmatic hernia. The patient underwent pulmonary artery banding and clipping of patent ductus arteriosus after repair of the diaphragmatic hernia. At 6 months, cardiac catheterization revealed anomalous origin of a single coronary artery from the pulmonary artery of the proximal banding. Although ischaemic symptoms had not been observed, the banding had resulted in compression of the coronary ostium. An emergency Rastelli procedure with Damus-Kaye-Stansel anastomosis was successfully performed. PMID- 22246965 TI - Oesophagectomy performed by trainees is as safe as that performed by consultants. PMID- 22246966 TI - Improving results for coronary artery bypass graft surgery in the elderly. AB - OBJECTIVES: The proportion of elderly patients undergoing isolated coronary artery bypass grafting (CABG) surgery has steadily increased. We have evaluated temporal trends in hospital outcomes of patients who were 75 years and older undergoing CABG (1990-2010) at our institution. METHODS: Data were collected prospectively for 3483 consecutive patients who were 75 years and older (median 78 years; range 75-94) undergoing isolated CABG at our institution over three time cohorts: 1990-96 (n = 817), 1997-2003 (n = 1534) and 2004-10 (n = 1132). RESULTS: Overall mortality declined from 6.0% (49/817) in the earliest era (1990 96) to 1.9% (22/1132) in the most recent era (2003-10; P < 0.001). Mortality in low-risk patients (elective, primary surgery with the ejection fraction >40%) was 5.9% (13/220), 0.8% (4/514) and 0% (0/411) in the first, second and third eras, respectively (P < 0.001). Despite the overall increase in comorbidities in our elderly patients, the prevalences of certain risk factors such as poor LV function, urgency of surgery and reoperation have all declined with time. The independent risk factors for mortality in our population were congestive heart failure, left main disease, earlier year of operation, reoperation, preoperative myocardial infarction, cardiopulmonary bypass time, emergent/urgent surgery and peripheral vascular disease. Of these, earlier year of operation (OR: 3.0; 95% CI: 1.8-5.2) was the most significant predictor. Also, age >80 did not predict mortality. CONCLUSIONS: The principle finding from this analysis is a contemporary low operative mortality for CABG in an elderly patient cohort. Risk of death is particularly low in a low-risk subset of elderly patients with reasonable LV function undergoing elective, primary CABG. PMID- 22246967 TI - Incomplete revascularization: appropriate and inappropriate. PMID- 22246969 TI - Single versus multiple primary melanomas: old questions and new answers. AB - BACKGROUND: In patients with multiple primary melanomas (MPM), mean tumor thickness tends to decrease from the first melanoma to the second melanoma, and prognosis may be improved compared with the prognosis for patients who have a single primary melanoma (SPM). In this study, the authors compared the clinicopathologic features of patients with MPM and SPM to better characterize the differences between these 2 groups and to determine whether or not there is an inherent difference in tumor aggression. METHODS: In total, 788 patients with melanoma who were enrolled prospectively in the Interdisciplinary Melanoma Cooperative Group database from 2002 to 2008 were studied. Patients with SPM and with MPM were compared with regard to clinical and primary melanoma characteristics. RESULTS: Of 788 patients with melanoma, 61 patients (7.7%) had 2 or more primary melanomas. The incidence of developing a second primary melanoma 1 year and 5 years after initial melanoma diagnosis was 4.1% and 8.7%, respectively, and most of the risk accumulated within the first year. The incidence of MPM was greater in patients aged >=60 years than in those aged <=60 years. The absence or presence of mitosis and other tumor characteristics did not differ significantly between patients with SPM and patients with MPM (P = .61). CONCLUSIONS: No difference was observed in the presence or absence of mitoses, a marker of tumor proliferation, in SPM and MPM. Because it has been demonstrated that the presence of mitosis is a powerful prognostic marker, the current findings suggested that the tumors behave similarly in patients with SPM and patients with MPM. The authors concluded that differences in tumor thickness and prognosis between SPM and MPM more likely are caused by factors other than tumor biology, such as increased surveillance. PMID- 22246968 TI - SPECT and PET to optimize cardiac stem cell therapy. PMID- 22246971 TI - Improving quality of arterial spin labeling MR imaging at 3 Tesla with a 32 channel coil and parallel imaging. AB - PURPOSE: To compare 12-channel and 32-channel phased-array coils and to determine the optimal parallel imaging (PI) technique and factor for brain perfusion imaging using Pulsed Arterial Spin labeling (PASL) at 3 Tesla (T). MATERIALS AND METHODS: Twenty-seven healthy volunteers underwent 10 different PASL perfusion PICORE Q2TIPS scans at 3T using 12-channel and 32-channel coils without PI and with GRAPPA or mSENSE using factor 2. PI with factor 3 and 4 were used only with the 32-channel coil. Visual quality was assessed using four parameters. Quantitative analyses were performed using temporal noise, contrast-to-noise and signal-to-noise ratios (CNR, SNR). RESULTS: Compared with 12-channel acquisition, the scores for 32-channel acquisition were significantly higher for overall visual quality, lower for noise and higher for SNR and CNR. With the 32-channel coil, artifact compromise achieved the best score with PI factor 2. Noise increased, SNR and CNR decreased with PI factor. However mSENSE 2 scores were not always significantly different from acquisition without PI. CONCLUSION: For PASL at 3T, the 32-channel coil at 3T provided better quality than the 12-channel coil. With the 32-channel coil, mSENSE 2 seemed to offer the best compromise for decreasing artifacts without significantly reducing SNR, CNR. PMID- 22246970 TI - Carotid artery stenting in clinical practice: does sex matter? Results from the carotid artery stenting registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK). AB - BACKGROUND: Carotid artery stenting (CAS) is increasingly used for treatment of severe carotid artery stenosis, but only few procedural risk factors for complications of CAS are clearly defined yet. A possible impact of the patient's gender on the outcome of patients undergoing CAS has not been investigated properly and only little information about this topic is available so far. METHODS: We analysed data of the German prospective, multicenter CAS Registry of the Arbeitsgemeinschaft leitende kardiologische Krankenhausarzte. RESULTS: From July 1996 to May 2009 5130 patients underwent CAS at 35 German hospitals and were enrolled into the prospective ALKK CAS Registry. Therefrom 1443 (28.1%) patients were female. There was no significant time-related difference in the proportion of women undergoing CAS over the years. Women undergoing CAS were significantly older than men (73 years vs. 70 years, p < 0.01) and had a longer in hospital stay in comparison to men (p < 0.01). The majority of patients treated with CAS was between 60 and 80 years of age (~73%). No significant differences between women and men could be found regarding in-hospital events like death (0.5% vs. 0.5%, p = 0.99), major or minor stroke (1.7% vs. 1.6%, p = 0.97; 1.0% vs. 1.6%, p = 0.12), TIA (2.8% vs. 2.6%, p = 0.64), amaurosis fugax (0.3% vs. 0.5%, p = 0.25) , intracranial bleeding (0.5% vs. 0.3%, p = 0.43), myocardial infarction (0.1% vs. 0.0%, p = 0.48) or all non-fatal strokes and all death (3.0% vs. 3.4%, p = 0.47). 30 day event rates did not show gender related differences in the combined endpoint of the outcome of patients undergoing CAS, as well (? n = 31/882 [3.5%] vs. ? n = 109/2273 [4.8%], p = 0.12). CONCLUSION: Our results do not suggest any gender-related differences in success rates and complications in CAS. In clinical practice approximately 30% of patients treated with CAS are women. The institutions and people who participated in the ALKK CAS Registry are listed in Zahn et al.16 The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 22246972 TI - The noncompliant patient: a Kantian and Levinasian response. AB - When a patient fails to follow the advice or prescription of a physician, she is termed to be "noncompliant" by the medical community. The medical community's response to and understanding of patient noncompliance fails to acknowledge noncompliance as either a relational failure between physician and patient or as a patient choice. I offer an analysis of Immanuel Kant and Emmanuel Levinas that refocuses the issue of noncompliance by examining the physician role, the doctor patient relationship, and the nature of responsibility. PMID- 22246973 TI - Responsibly managing uncertainties in clinical ethics. AB - It is well-recognized that uncertainty is an endemic feature and limitation of clinical judgment and practice that cannot be eliminated in many cases. Among the tasks of clinical ethics is the responsible management of uncertainties, first articulated in E. Haavi Morreim's very nice concept of the "moral management of medical uncertainty." The papers in the 2012 Clinical Ethics issue of the Journal provide philosophically innovative and clinically applicable accounts of the varieties of uncertainty in clinical medicine and therefore in clinical ethics: epistemic uncertainty, metaphysical uncertainty, and relational uncertainty. PMID- 22246974 TI - Enhanced electroporation in plant tissues via low frequency pulsed electric fields: influence of cytoplasmic streaming. AB - Pulsed electric fields (PEF) are known to be effective at permeabilizing plant tissues. Prior research has demonstrated that lower pulse frequencies induce higher rates of permeabilization, but the underlying reason for this response is unclear. Intriguingly, recent microscopic observations with onion tissues have also revealed a correlation between PEF frequency and the subsequent speed of intracellular convective motion, i.e., cytoplasmic streaming. In this paper, we investigate the effect of cytoplasmic streaming on the efficacy of plant tissue permeabilization via PEF. Onion tissue samples were treated with Cytochalasin B, a known inhibitor of cytoplasmic streaming, and changes in cellular integrity and viability were measured over a wide range of frequencies and field strengths. We find that at low frequencies (f < 1 Hz), the absence of cytoplasmic streaming results in a 19% decrease in the conductivity disintegration index compared with control samples. Qualitatively, similar results were observed using a microscopic cell viability assay. The results suggest that at low frequencies convection plays a statistically significant role in distributing more conductive fluid throughout the tissue, making subsequent pulses more efficacious. The key practical implication is that PEF pretreatment at low frequency can increase the rate of tissue permeabilization in dehydration or extraction processes, and that the treatment will be most effective when cytoplasmic streaming is most active, i.e., with freshly prepared plant tissues. PMID- 22246975 TI - Spatially resolved extended phase graphs: modeling and design of multipulse sequences with parallel transmission. AB - A spatially resolved extended phase graph (SR-EPG) framework is proposed for prediction of echo amplitudes in the presence of spatially variable radio frequency (RF) fields. The method may be used to examine any regularly repeating pulse sequence and provides a design framework for parallel transmission (PTx) systems; in this work signal homogeneity in static pseudo-steady state (SPSS) turbo spin echo (TSE) imaging was investigated. Building on SR-EPG calculations with PTx, a dynamic RF-shimming approach is proposed in which, RF pulse amplitudes and phases are optimized on a per channel and per pulse basis to yield the desired signal response for all echoes. Results show significant improvements over "static" RF shimming (in which the relative amplitude/phase of the PTx channels are fixed for all pulses). SPSS-TSE imaging using dynamic RF shimming resulted in excellent image quality, both in phantoms and in vivo, and confirmed SR-EPG predictions. PMID- 22246976 TI - Electron transfer dissociation mass spectrometry in proteomics. AB - Mass spectrometry has rapidly evolved to become the platform of choice for proteomic analysis. While CID remains the major fragmentation method for peptide sequencing, electron transfer dissociation (ETD) is emerging as a complementary method for the characterization of peptides and post-translational modifications (PTMs). Here, we review the evolution of ETD and some of its newer applications including characterization of PTMs, non-tryptic peptides and intact proteins. We will also discuss some of the unique features of ETD such as its complementarity with CID and the use of alternating CID/ETD along with issues pertaining to analysis of ETD data. The potential of ETD for applications such as multiple reaction monitoring and proteogenomics in the future will also be discussed. PMID- 22246978 TI - Abnormal WT1 expression in human fetuses with bilateral renal agenesis and cardiac malformations. AB - BACKGROUND: Bilateral renal agenesis has multiple etiologies. Animal models have provided useful information on possible causes of this condition, but its etiology in humans is less clear. We recently described autopsy findings of two human fetuses with bilateral renal agenesis and abnormal expression of WT1 (Wilms tumor 1) in liver mesothelium. METHODS: We have identified 14 additional fetuses with bilateral renal agenesis from autopsies performed in our institution over the past 10 years and subjected archival liver biopsy specimens from these cases to immunohistochemistry for WT1, as well as alpha-smooth muscle actin (alpha-SMA) and desmin to assess liver mesenchymal abnormalities. RESULTS: Six of seven fetuses with combined bilateral renal agenesis and cardiac anomalies showed abnormalities of WT1 expression in liver mesothelial cells, which was not seen in other fetuses with bilateral renal agenesis. Except in one case, the fetuses with renal agenesis and cardiac defects also showed liver mesenchymal anomalies (assessed by increased alpha-SMA expression), which was not present in other renal agenesis fetuses. CONCLUSIONS: WT1 is widely expressed in mesothelial cells during development, and we hypothesized that some of the defects are caused by abnormal function of mesenchyme derived from mesothelial cells, similar to the mesothelium-derived defects proposed in animal models. The methods we used are available to many laboratories and can be applied to archival paraffin tissue blocks. We suggest that future similar studies could help to expand the understanding of renal agenesis in humans and could help to subclassify this condition. This would be useful in patient management and counseling. PMID- 22246977 TI - Accidental intoxication with 60 mg intrathecal baclofen: survived. AB - BACKGROUND: Intrathecal baclofen (ITB) is an effective and well-tolerated treatment for patients with severe spasticity. Intoxications are rare and usually iatrogenic, with reported intrathecal boluses varying between 0.050 and 30 mg. METHODS: We here report the case of a 47-year-old woman with severe spastic paraplegia due to multiple sclerosis who, during a routine filling procedure, accidentally received a bolus of 60 mg ITB because of injection into the side port instead of the reservoir of her ITB pump (Archimedes((r)), Codman, Germany). RESULTS: After a short period of dizziness, she lost consciousness and stopped breathing. She was immediately intubated, mechanically ventilated, and admitted to the intensive care unit. As specific treatment, she received cerebrospinal fluid drainage through a newly implanted lumbar catheter. A series of generalized and complex partial seizures were treated with levetiracetam and lacosamide. Acute autonomic dysfunction with episodic arterial hypo- and hypertensions was controlled by catecholamines and clonidine, respectively. Recurrent hyperthermia, however, responded neither to drugs nor to physical treatment. After 3 weeks, the patient was discharged without any relevant new neurologic signs or symptoms. CONCLUSIONS: This case demonstrates that even excessive doses of ITB can let the patients survive without sequelae if treated promptly and offensively. A pertinent problem during detoxification is the question of when to restart ITB to avoid drug withdrawal. PMID- 22246979 TI - Assessment of the dentin-pulp complex response to caries by ADC mapping. AB - The prognostic potential of apparent diffusion coefficient (ADC) mapping was studied as complemented by high-resolution 3D T(1)-weighted MRI in the assessment of dentin-pulp complex response to caries. Twenty-six extracted human teeth, with or without caries lesions of different grades in accord with the International Caries Detection and Assessment System (ICDAS), were analyzed by high-resolution MRI at 2.35 T. A signal rise in demineralized hard dental tissues in high resolution T(1)-weighted MR images enabled assessment of the demineralization depth over the whole range of ICDAS scores. ADC maps of the teeth were calculated from corresponding diffusion-weighted images of four different b values: 0, 132, 317, 635 s/mm(2). These maps enabled reliable differentiation between intact (ADC > 1.0.10(-9) m(2)/s) and affected (ADC < 1.0.10(-9) m(2)/s) regions of dental pulp. Linear regression analyses of demineralization depth in relation to ICDAS score and then also to average ADC of dental pulp showed that a demineralization depth increase of one millimeter corresponds to an ICDAS score increase of 1.2 and an average ADC decrease of 0.07.10(-9) m(2)/s. Results of the study indicate that the average ADC value of dental pulp could be used as a potential marker to assess tissue response to caries comparable to that of ICDAS scoring. PMID- 22246980 TI - Detection and localization of prostate cancer with the targeted biopsy strategy based on ADC map: a prospective large-scale cohort study. AB - PURPOSE: To investigate the usefulness of targeted biopsy strategy based on apparent diffusion coefficient (ADC) maps in the detection and localization of prostate cancer. MATERIALS AND METHODS: Institutional review board approval and informed consent from all participants were obtained. This study included 1448 consecutive patients suspected of having prostate cancer based on PSA level, who were divided into two groups: Group A included 890 patients with low-ADC lesions who underwent targeted and systematic biopsies; Group B included 558 patients with no low-ADC lesions who underwent only systematic biopsies. The cancer detection rates (CDR) of each group, positive predictive value (PPV), and negative predictive value (NPV) of ADC maps were calculated. RESULTS: The CDR was 70.1% for Group A, higher than those for overall patients (48.1%) and for Group B (13.1%) with significant difference (P < 0.001). In the serum, PSA range from 4 to 20 ng/mL, the CDR was higher for the Group A than for the Group B and overall patients with significant differences. PPV and NPV of MR findings were 70.1% and 86.9%, respectively. Especially, the PPV of the MR findings for the anterior portion was as high as 90.1%. Among the false negatives of MR findings, Gleason score proved 6 or smaller in 79.5%, and positive core number was merely one or two in 80.8%. CONCLUSION: The targeted biopsy strategy based on ADC maps can be useful in the detection and localization of prostate cancer with high PPV. PMID- 22246981 TI - Topical steroids implicated in postoperative infection following ablative laser resurfacing. PMID- 22246982 TI - An in vivo histopathological comparison of single and double pulsed modes of a fractionated CO(2) laser. AB - INTRODUCTION: Studies examining the histopathological changes that occur in human skin following fractional laser treatment have been performed mainly in animals or abdominal tissue prior to abdominoplasty. This study looks at the effect of double pulse fractional CO(2) laser compared to single pulse treatments to assess differences in tissue injury in the face and abdomen. METHODS: Twelve healthy subjects randomized into two groups, had two 1 cm(2) areas (infraumbilical and forehead) treated with the fractional CO(2) laser (Deep Fx, Lumenis). Settings used were 15 mJ double pulse, and 30 mJ single pulse, 300 Hz, 10% density and compared to the historic control of 15 patients treated at 15 mJ single pulse [Bailey et al. (2011), Lasers Surg Med 43: 99-107]. Treated sites were biopsied and analyzed with H&E and TUNEL staining to measure width and depth of the microthermal zones (MTZ) of ablation. RESULTS: When comparing 15 mJ double pulse to single pulse there were significant differences both in depth (abdominal skin, P = 0.002 and facial skin, P = 0.001) and width (facial skin, P = 0.0002) of MTZ. When comparing double pulsing at 15 mJ with single pulsing at 30 mJ there were significant differences between MTZ depths in the abdomen (P < 0.01) but not in either the MTZ depth (P = 0.69) or the width in the face (P = 0.502). DISCUSSION: This study demonstrates the differences between histopathological laser injury patterns in the face compared to the abdomen when single pulsing is used. It also demonstrates that double pulsing at 15 mJ is statistically similar to single pulsing at 30 mJ in the face. We think this could have ramifications for clinical practice where by double pulsing at lower energies may result in better clinical outcomes than increasing energies or using multiple passes at single pulse. Clinical studies needs to be performed to investigate this further. PMID- 22246983 TI - Diagnostic efficacy of backscattering intensity measurements in optical coherence tomography of cervical intraepithelial dysplasia. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the diagnostic efficacy of backscattering intensity measurements in optical coherence tomography in identifying different grades of cervical intraepithelial dysplasia. STUDY DESIGN/MATERIALS AND METHODS: OCT images were taken from 153 unsuspicious and suspicious areas of 30 fresh conisation and hysterectomy specimens, evaluated by two blinded investigators using a six-grade classification (normal, inflammation, CIN1, CIN2, CIN3, squamous carcinoma) and later compared to the corresponding histology. Differences between judgments based on either the histology or the OCT images were investigated employing Correspondence Analysis (CA). Further, we explored the extent as to which backscattering intensity profiles of OCT images contained the essential information required for a reliable and valid diagnosis, using Linear Discriminant Analysis (LDA). RESULTS: The CA of histology- and OCT based judgments suggests that the diagnostic process may be characterized in terms of two stochastically independent underlying ("latent") variables, the first of them reflecting the definiteness with which CIN classes are identified, the second reflecting a bias towards diagnosing inflammation on the side of the OCT-based judgments. This finding is supported by the results of LDAs, where histology and OCT categorizations differ in particular with respect to the positions of inflammation and CIN1. Possibly, a second canonical variable has to be assumed accounting for the evaluation of carcinoma. CONCLUSIONS: The systematic differences between histology-based and OCT-based diagnoses suggest that the use of available information is influenced by perceptual and/or cognitive biases. Apart from this it seems that the profiles appear to provide a remarkably large amount of information determining the main course of the diagnostic process. PMID- 22246984 TI - Combined two-photon luminescence microscopy and OCT for macrophage detection in the hypercholesterolemic rabbit aorta using plasmonic gold nanorose. AB - BACKGROUND AND OBJECTIVES: The macrophage is an important early cellular marker related to risk of future rupture of atherosclerotic plaques. Two-channel two photon luminescence (TPL) microscopy combined with optical coherence tomography (OCT) was used to detect, and further characterize the distribution of aorta based macrophages using plasmonic gold nanorose as an imaging contrast agent. STUDY DESIGN/MATERIALS AND METHODS: Nanorose uptake by macrophages was identified by TPL microscopy in macrophage cell culture. Ex vivo aorta segments (8 * 8 * 2 mm(3) ) rich in macrophages from a rabbit model of aorta inflammation were imaged by TPL microscopy in combination with OCT. Aorta histological sections (5 um in thickness) were also imaged by TPL microscopy. RESULTS: Merged two-channel TPL images showed the lateral and depth distribution of nanorose-loaded macrophages (confirmed by RAM-11 stain) and other aorta components (e.g., elastin fiber and lipid droplet), suggesting that nanorose-loaded macrophages are diffusively distributed and mostly detected superficially within 20 um from the luminal surface of the aorta. Moreover, OCT images depicted detailed surface structure of the diseased aorta. CONCLUSIONS: Results suggest that TPL microscopy combined with OCT can simultaneously reveal macrophage distribution with respect to aorta surface structure, which has the potential to detect vulnerable plaques and monitor plaque-based macrophages overtime during cardiovascular interventions. PMID- 22246985 TI - The effect of photodynamic therapy on tumor cell expression of major histocompatibility complex (MHC) class I and MHC class I-related molecules. AB - BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is FDA-approved anti-cancer modality for elimination of early disease and palliation in advanced disease. PDT efficacy depends in part on elicitation of a tumor-specific immune response that is dependent on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The cytolytic potential of CTLs and NK cells is mediated by the ability of these cells to recognize major histocompatibility complex (MHC) class I and MHC class I related molecules. The MHC class I-related molecules MICA and MICB are induced by oxidative stress and have been reported to activate NK cells and co-stimulate CD8(+) T cells. The purpose of this study was to examine the effect of PDT on tumor cell expression of MHC classes I and II-related molecules in vivo and in vitro. STUDY DESIGN/MATERIALS AND METHODS: Human colon carcinoma Colo205 cells and murine CT26 tumors were treated with 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH)-PDT at various doses. MHC classes I and I-related molecule expression following treatment of Colo205 cells was temporally examined by flow cytometry using antibodies specific for components of MHC class I molecules and by quantitative PCR using specific primers. Expression of MHC class I-related molecules following HPPH-based PDT (HPPH-PDT) of murine tumors was monitored using a chimeric NKG2D receptor. RESULTS: In vitro HPPH-PDT significantly induces MICA in Colo205 cells, but had no effect on MHC class I molecule expression. PDT also induced expression of NKG2D ligands (NKG2DL) following in vivo HPPH-PDT of a murine tumor. Induction of MICA corresponded to increased NK killing of PDT-treated tumor cells. CONCLUSIONS: PDT induction of MICA on human tumor cells and increased expression of NKG2DL by murine tumors following PDT may play a role in PDT induction of anti-tumor immunity. This conclusion is supported by our results demonstrating that tumor cells have increased sensitivity to NK cell lysis following PDT. PMID- 22246986 TI - Enhancement of photodynamic antitumor effect with pro-oxidant ascorbate. AB - BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a treatment modality that utilizes photosensitizers activated by light to induce cell death via the formation of singlet oxygen and other free radicals. Although this method has its advantages for tumor treatment, it cannot be well performed for involving so many therapeutic parameters during use. Tumor recurrence is common due to insufficient treatment. Therefore, a supplemental or complemental treatment is necessary for PDT. STUDY DESIGN/MATERIALS AND METHODS: L-ascorbate, commonly known as vitamin C, is an essential nutrient for humans. It is also a well-established pro-oxidant in the presence of certain transition metal ions. In our experiments, ascorbate was administered to tumor-bearing mice by intraperitoneal injection (i.p.) for 10 days after they were treated with PDT. We hypothesize that this supplement may improve the therapeutic outcome by as a result of the reactions between ascrobate and the metal ions induced by PDT. RESULTS: The results demonstrate that PDT can cause Fe and Cu ions to be released from their protein complexes. The reactions between the ions and ascorbate resulted in a post-PDT surge in reactive oxygen species (ROS) as demonstrated in vitro with chemiluminescence detection. This ultimately leads to enhanced tumor cell death and, thus, an improved treatment outcome. CONCLUSION: Based on the results that PDT induces metal ion release and ascorbate reacts with the metal ions producing subsequent ROS, an internal related, complementary and strengthened tumor treatment is established by combination of both PDT and ascorbate, as a low-toxicity and effective method. PMID- 22246987 TI - The enhanced anti-cancer effect of hexenyl ester of 5-aminolaevulinic acid photodynamic therapy in adriamycin-resistant compared to non-resistant breast cancer cells. AB - BACKGROUND AND OBJECTIVE: 5-Aminolaevulinic acid (ALA) and its derivatives act as precursors of the photosensitizer protoporphyrin IX (PpIX). In this study, we compared cytotoxic effects of photodynamic therapy (PDT) with the hexenyl ester of ALA (ALA-hx) between MCF-7 human breast cancer cells and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. MATERIALS AND METHODS: Cell viability and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT), flow cytometry assays. Chick chorioallantoic membrane (CAM) assays were applied to assess in vivo effect of ALA-hx PDT. Molecular analyses using Western blots and minimal reporter constructs containing the antioxidant response element (ARE) region were performed to reveal mechanistic basis for the differential PDT sensitivity of MCF-7 and MCF-7/ADR cells. RESULTS: In MCF-7/ADR cells, PDT with ALA-hx more efficiently produced reactive oxygen species (ROS) and suppressed cell viability compared to MCF-7 cells. Cell death induced by ALA-hx PDT in MCF 7/ADR cells was mainly due to apoptosis. CAM assays confirmed that the apoptotic activity of PDT in MCF-7/ADR cells was significantly higher than that in control MCF-7 cells. We also found that MCF-7/ADR cells produced lower levels of glutathione (GSH), a major antioxidant, than control MCF-7 cells. Expression of Nrf2-dependent anti-oxidant genes including gamma-glutamylcysteine ligase, heme oxygenase-1, and quinone oxidoreductase were down-regulated in MCF-7/ADR cells, and Nrf2 overexpression partially decreased the susceptibility of ALA-hx PDT in MCF-7/ADR cells. Moreover, PpIX synthesis and expression levels of protoporphyrinogen oxidase (PPO) and coproporphyrinogen oxidase (CPO) were much higher in MCF-7/ADR cells than MCF-7 cells. CONCLUSIONS: ALA-hx PDT more potently produced intracellular ROS in MCF-7/ADR cells, which might be due to down regulation of Nrf2-mediated anti-oxidant gene transcription and up-regulation of PpIX synthesis via the induction of CPO and PPO. These findings suggest that ALA hx PDT may be usable as a therapeutic alternative for adriamycin-resistant breast cancer. PMID- 22246989 TI - Periconceptional folic acid use: still room to improve. AB - BACKGROUND: Folic acid use before and during pregnancy prevents neural tube defects. Since 1995, six surveys have been carried out among pregnant women to measure their knowledge and use of folic acid. The results of the most recent survey in 2009 will be discussed and compared with earlier surveys. METHODS: Pregnant women in the Northern Netherlands were asked to fill out a questionnaire when visiting their midwife or gynecologist. RESULTS: Of the 515 participating women, 87.0% knew of folic acid before they became pregnant. Of all respondents, 51.6% reported to have used folic acid during the entire recommended period. Multivariate analysis showed that planned pregnancy (odds ratio [OR], 7.1; 95% confidence interval [CI], 2.4-20.7), smoking (OR, 0.2; 95% CI, 0.1-0.7), folic acid use during a former pregnancy (OR, 22.6; 95% CI, 5.5-92.8) and the number of previous children (per child OR, 0.5; 95% CI, 0.3-0.9) were predicting factors for the recommended use of folic acid; 89.9% of women were sufficiently knowledgeable to start to use folic acid before pregnancy. CONCLUSIONS: The knowledge about folic acid has declined over recent years, and the use during the recommended period did not improve since the survey of 2005. Based on this survey, there is still room for improvement in the knowledge and actual use of folic acid before pregnancy. Attention to these aspects should focus on younger, low-educated women and should include information about family planning and contraceptives. PMID- 22246990 TI - Expert consensus report on remote monitoring of implantable devices: the Dutch experience. PMID- 22246988 TI - N-myc downstream regulated gene 1 modulates Wnt-beta-catenin signalling and pleiotropically suppresses metastasis. AB - Wnt signalling has pivotal roles in tumour progression and metastasis; however, the exact molecular mechanism of Wnt signalling in the metastatic process is as yet poorly defined. Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG-/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients. Collectively, we have identified NDRG1 as a novel negative master regulator of Wnt signalling during the metastatic progression, which opens an opportunity to define a potential therapeutic target for metastatic disease. PMID- 22246991 TI - On the fluid-tissue contrast behavior of high-resolution steady-state sequences. AB - In general, MR image contrast is expected to be resolution independent, but a pronounced loss of contrast is observed between fluids and tissues with contemporary musculoskeletal protocols (typical inplane resolution << 1 mm) using nonbalanced steady-state free precession, such as double echo steady state. For nonbalanced steady-state free precession, diffusion sensitivity increases with increasing spoiler moments which increase with decreasing voxel size, suggesting diffusion damping as the major cause for the observed contrast variation. This is confirmed by simulations and measurements indicating that for fluids, diffusion effects become apparent already for resolutions Deltax < 1 mm, whereas tissues typically require Deltax < 200 MUm. Gradient spoiling, however, is generically not minimized but frequently applied along the readout direction. For anisotropic steady-state free precession scans, the loss of contrast between fluids and tissues from diffusion can thus be minimized by simply moving the spoiler gradients to the lowest resolution direction. PMID- 22246992 TI - HtrA2/Omi is involved in 6-OHDA-induced endoplasmic reticulum stress in SH-SY5Y cells. AB - Endoplasmic reticulum (ER) stress has been shown to be associated with the pathogenesis of neurodegenerative disorders including Parkinson's disease (PD). HtrA2/Omi, from its participation in protein quality control, is involved in ER stress. However, little is known about the relationship between HtrA2/Omi and ER stress in PD. Here, we explored the association of HtrA2/Omi and ER stress in a cell model of PD and found that the expression level of HtrA2/Omi decreased with ER stress induction in 6-OHDA-treated SH-SY5Y cells. Furthermore, silencing endogenous expression of HtrA2/Omi with siRNA resulted in aggregated ER stress and cell death. Taken together, our results show that HtrA2/Omi may exert a protective function in 6-OHDA-induced cell death by regulating ER stress-related proteins. This research offers some clues as why mutations in HtrA2/Omi lead to higher susceptibility in some PD patients. PMID- 22246993 TI - Dynamic expression of adenylate kinase 2 in the hippocampus of pilocarpine model rats. AB - Studies have shown that adenylate kinase 2 (AK2) is released from the mitochondrial inner membrane space during neuronal apoptosis, which plays an important role in temporal lobe epilepsy (TLE). We investigated the expression of AK2 in the hippocampus of a pilocarpine model rats. Using reverse transcription polymerase chain reaction and immunohistochemistry, AK2 mRNA and immune-positive cells were investigated during the entire epileptic process in pilocarpine induced rat model of TLE. AK2 mRNA level was increased in rat hippocampus during different phases of the epileptogenesis, and reached a peak at 72 h. At 72 h time point, AK2 mRNA level was more than threefold comparing with the control. AK2 positive cells were observed in all regions of the hippocampus in model rats, but not in brain tissues of controls. The mean percentage of AK2-positive cells was increased as early as 6 h following seizure and reached a peak at 72 h. The pattern of AK2 expression over time was similar to that observed during neuronal apoptosis as detected with TUNEL staining. These results suggest that AK2 participates in the pathophysiological process of TLE and may be a marker for neuronal apoptosis induced by pathological injury in TLE. PMID- 22246994 TI - FOXJ2 expression in rat spinal cord after injury and its role in inflammation. AB - Foxj2 (forkhead box J2), a novel member of the forkhead/HNF3 family, binds DNA with a dual sequence specificity. It may play a role in maintenance and survival of developing and adult neurons. However, its expression and function in the central nervous system lesion are still unclear. In this study, we performed a spinal cord injury (SCI) model in adult Sprague-Dawley rats and investigated the dynamic changes of Foxj2 expression in the spinal cord. Western blot analysis revealed that Foxj2 was present in normal spinal cord. It gradually increased, reached a peak at day 5 after SCI, and then declined during the following days. Double immunofluorescence staining revealed wide expression of Foxj2, which is detected in neurons and astrocytes. After injury, Foxj2 expression was increased predominantly in astrocytes, which highly expressed proliferating cell nuclear antigen, a marker for proliferating cells. And knockdown of Foxj2 in cultured primary astrocytes by siRNA showed that Foxj2 played an important role in lipopolysaccharide-induced inflammatory responses. These results suggested that Foxj2 may be involved in the pathophysiology of SCI, and further research is needed to have a good understanding of its function and mechanism. PMID- 22246995 TI - Combination of vascular endothelial and fibroblast growth factor 2 for induction of neurogenesis and angiogenesis after traumatic brain injury. AB - Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) are potent mitogens for endogenous neural stem cells (eNSC) and also induce angiogenesis. We infused the individual factors or their combination into the lateral ventricles of mice for 7 days after traumatic brain injury (TBI) in order to evaluate the effects on functional outcome and on eNSC proliferation and differentiation. The results show that VEGF induced a significant increment in the number of proliferating eNSC in the subventricular zone and in the perilesion cortex and that combination of FGF2 and VEGF did not augment the effects of VEGF alone. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia while only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF, FGF2, or their combination as compared to vehicle. Injury size was significantly reduced only in mice treated with VEGF suggesting additional neuroprotective effects for VEGF. Combination therapy did not have an additive effect on outcome or neuronal differentiation. In conclusion, FGF2-VEGF combination does not augment neurogenesis and angiogenesis or reduce lesion volumes after TBI compared with individual factors. This may suggest the existence of a ceiling effect for brain regeneration. PMID- 22246996 TI - Probing protein stability and proteolytic resistance by loop scanning: a comprehensive mutational analysis. AB - Improvement in protein thermostability was often found to be associated with increase in its proteolytic resistance as revealed by comparative studies of homologous proteins from extremophiles or mutational studies. Structural elements of protein responsible for this association are not firmly established although loops are implicated indirectly due to their structural role in protein stability. To get a better insight, a detailed study of protein wide mutants and their influence on stability and proteolytic resistance would be helpful. To generate such a data set, a model protein, Bacillus subtilis lipase was subjected to loop scanning site-saturation mutagenesis on 86 positions spanning all loops including termini. Upon screening of ~16,000 clones, 17 single mutants with improved thermostability were identified with increment in apparent melting temperature (Tm(app) ) by 1-6 degrees C resulting in an increase in free energy of unfolding (DeltaG(unf) ) by 0.04-1.16 kcal/mol. Proteolytic resistance of all single mutants upon incubation with nonspecific protease, Subtilisin A, was determined. Upon comparison, post-proteolysis residual activities as well as kinetics of proteolysis of mutants showed excellent correlation with DeltaG(unf) , (r > 0.9), suggesting that proteolysis was strongly correlated with the global stability of this protein. This significant correlation in this set, with least possible sequence changes (single aa substitution), while covering >60% of protein surface strongly argues for the covariance of these two variables. Compared to studies from extremophiles, with large sequence heterogeneity, the observed correlation in such a narrow sequence space (DeltaDeltaG(unf) = 1.57 kcal-1) justifies the robustness of this relation. PMID- 22246997 TI - The role of recalibration response shift in explaining bodily pain in cancer patients undergoing invasive surgery: an empirical investigation of the Sprangers and Schwartz model. AB - OBJECTIVE: This study aims to explain bodily pain using the Sprangers and Schwartz theoretical model (1999) on quality of life (QL) and response shift in its entirety. Response shift refers to the phenomenon that the meaning of a person's self-evaluation changes over time. In this model, response shift mediates effects of changes in health status (catalysts), stable characteristics of the person (antecedents), and coping mechanisms (mechanisms) on QL. METHODS: Cancer patients (202) were assessed prior to and 3 months following surgery. Measures were for catalysts: type of operation and possibility of tumor resection; for antecedents: age, duration of pain, optimism, and rigidity; for mechanisms: post-traumatic growth, social comparisons, social support, denial, and acceptance; and for QL: bodily pain; for response shift: the pretest-minus thentest bodily pain score, further referred to as recalibration response shift. Structural equation modeling and sequential regression analyses were used. RESULTS: The final model reached close fit (RMSEA = 0.03; 90% CI = 0.000-0.071; chi2 (18) = 21.13; p = 0.27). Significant effects were found for catalysts on mechanisms, antecedents on mechanisms, mechanisms on response shift, and response shift on bodily pain. Four extra model effects had to be permitted. Using sequential regression analysis, recalibration response shift added 4.4% to the total amount of 29.8% explained variance of bodily pain. CONCLUSIONS: Many effects as hypothesized by the model were found. Recalibration response shift had a unique albeit small contribution to the explanation of bodily pain. PMID- 22246998 TI - Osteogenic and chondrogenic potential of biomembrane cells from the PMMA segmental defect rat model. AB - A layer of cells (the "biomembrane") has been identified in large segmental defects between bone and surgically placed methacrylate spacers or antibiotic impregnated cement beads. We hypothesize that this contains a pluripotent stem cell population with potential valuable applications in orthopedic tissue engineering. Objectives using biomembranes harvested from rat segmental defects were to: (1) Culture biomembrane cells in specialized media to direct progenitor cells along bone or cartilage cell differentiation lineages; (2) evaluate harvested biomembranes for mesenchymal stem cell markers, and (3) define relevant gene expression patterns in harvested biomembranes using microarray analysis. Culture in osteogenic media produced mineralized nodules; culture in chondrogenic media produced masses containing chondroitin sulfate/sulfated proteoglycans. Molecular analysis of biomembrane cells versus control periosteum showed significant upregulation of key genes functioning in mesenchymal stem cell differentiation, development, maintenance, and proliferation. Results identified significant upregulation of WNT receptor signaling pathway genes and significant upregulation of BMP signaling pathway genes. Findings confirm that the biomembrane has a pluripotent stem cell population. The ability to heal large bone defects is clinically challenging, and novel tissue engineering uses of the biomembrane hold great promise in treating non-unions, open fractures with large bone loss and/or infections, and defects associated with tumor resection. PMID- 22246999 TI - Validation of an ex vivo human cervical tissue model for optical imaging studies. AB - OBJECTIVE: To establish and validate an ex vivo human cervical tissue model for optical coherence tomography (OCT) studies with special emphasis on investigating time dependent structural changes of the epithelium. METHODS: Four hundred OCT images were taken from 80 unsuspicious and suspicious areas of 18 fresh conisation specimens immediately after resection (0 hour) and 1, 2, 3, and 4 hours, referred to as waiting times in the following, postoperatively and compared to the corresponding histology. For each 2D-OCT-image, a 1D-intensity profile was generated. The profiles were analyzed with respect to systematic differences which may result from different waiting times, employing discriminant analysis (DA). RESULTS: The different waiting times do not appear to imply significant differences among the corresponding OCT-images as represented by the intensity profiles. CONCLUSION: We conclude that the proposed cervical tissue model appears to be applicable for ex vivo OCT studies. PMID- 22247000 TI - Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome. AB - Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, which is characterized by cleft palate and severe defects of the skin, is an autosomal dominant disorder caused by mutations in the gene encoding transcription factor p63. Here, we report the generation of a knock-in mouse model for AEC syndrome (p63(+/L514F) ) that recapitulates the human disorder. The AEC mutation exerts a selective dominant-negative function on wild-type p63 by affecting progenitor cell expansion during ectodermal development leading to a defective epidermal stem cell compartment. These phenotypes are associated with impairment of fibroblast growth factor (FGF) signalling resulting from reduced expression of Fgfr2 and Fgfr3, direct p63 target genes. In parallel, a defective stem cell compartment is observed in humans affected by AEC syndrome and in Fgfr2b(-/-) mice. Restoring Fgfr2b expression in p63(+/L514F) epithelial cells by treatment with FGF7 reactivates downstream mitogen-activated protein kinase signalling and cell proliferation. These findings establish a functional link between FGF signalling and p63 in the expansion of epithelial progenitor cells and provide mechanistic insights into the pathogenesis of AEC syndrome. PMID- 22247001 TI - ACE I/D, ACTN3 R577X, PPARD T294C and PPARGC1A Gly482Ser polymorphisms and physical fitness in Taiwanese late adolescent girls. AB - Physical performance of youth is influenced by various factors, including body composition, biological maturity status, level of habitual physical activity, and muscular strength. Muscular strength has been largely attributed to genetic effects. To exclude possible confounding effects from various acquired factors, this study examined the relationships between polymorphisms of the angiotensin converting enzyme (ACE), alpha-actinin-3 (ACTN3), peroxisome proliferator activated receptor delta (PPARD), and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A) genes and performance as measured by six fitness tests (handgrip strength of dominant hand, 30- and 60-s sit-ups, standing long jump, 60-m dash, and 800-m run) in 170 sedentary adolescent girls with the adjustment of anthropometric characteristics. We found that subjects with the ACE DD genotype were significantly heavier than those with I allele, while those with the ACTN3 RR genotype had higher fat-free mass percentage (FFM%) than those with the XX genotype. In addition, those with the PPARD TT genotype were significantly taller, heavier, and had a greater FFM than those with the CC genotype. Subjects with the ACE DD, ACTN3 RR and PPARD TC genotype had better performance in handgrip strength, 30- and 60-s sit-up tests, and standing long jump, respectively, when individual gene was analyzed independently after adjusting anthropometric characteristics. In the gene combination analysis, subjects with ACE DD, ACTN3 RR and PPARD TT genotype had significantly greater performance in handgrip strength. Overall, the results indicate that the genes studied have a modest influence on individual performance as assessed by specific fitness and strength tests in female late adolescents. PMID- 22247002 TI - Matted nodes: poor prognostic marker in oropharyngeal squamous cell carcinoma independent of HPV and EGFR status. AB - BACKGROUND: Despite better prognosis, there is a group of oropharyngeal squamous cell carcinoma (SCC) human papillomavirus (HPV)+ patients who experience treatment failure and succumb to distant metastasis. METHODS: Seventy-eight previously untreated patients nested in a concurrent chemoradiation protocol were reviewed to correlate patterns of local-regional tumor extent to distant metastasis. Biomarker assessment was: HPV in situ hybridization and epidermal growth factor receptor (EGFR) immunointensity. RESULTS: The 3-year disease specific survival (DSS) for patients presenting with and without matted nodes was 69% and 94%, respectively (p = .003). Matted nodes were a poor prognostic factor independent of T classification, HPV, EGFR, and smoking status. For patients who were HPV+, 7 of 11 died of distant metastasis and 6 of 7 with distant metastasis had matted nodes. CONCLUSION: Matted nodes are a novel marker of poor prognosis in oropharyngeal SCC independent of established prognostic factors. Matted nodes may identify patients at risk for the development of distant metastasis who could benefit from systemic therapy, whereas patients without matted nodes may be candidates for de-escalation of therapy. PMID- 22247003 TI - Zebrafish cadherin-11 participates in retinal differentiation and retinotectal axon projection during visual system development. AB - BACKGROUND: Cadherins orchestrate tissue morphogenesis by controlling cell adhesion, migration and differentiation. Various cadherin family members are expressed in the retina and other neural tissues during embryogenesis, regulating development of these tissues. Cadherin-11 (Cdh11) is expressed in mesenchymal, bone, epithelial, neural and other tissues, and this cadherin was shown to control cell migration and differentiation in neural crest, tumor and bone cells. Our previous studies characterized Cdh11 expression and function in zebrafish. RESULTS: Here, we report effects of Cdh11 loss-of-function on visual system development using morpholino oligonucleotide knockdown methods. Cdh11 is expressed in the retina and lens during retinal differentiation. Cdh11 loss-of function produced defects in retinal differentiation and lens development. Cdh11 loss-of-function also reduced retinotectal axon projection and organization, consistent with known Cdh11 function in cell migration. CONCLUSION: Cdh11 expression in the developing visual system and Cdh11 loss-of-function phenotype illustrates the critical role for differential cadherin activity in visual system differentiation and organization. PMID- 22247004 TI - Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates. AB - Four nonvolatile nerve agent surrogates, 4-nitrophenyl ethyl dimethylphosphoramidate (NEDPA, a tabun surrogate), 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate), and two sarin surrogates, phthalimidyl isopropyl methylphosphonate (PIMP) and 4-nitrophenyl isopropyl methylphosphonate (NIMP), were synthesized and tested as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. These surrogates were designed to phosphorylate cholinesterases with the same moiety as their respective nerve agents, making them highly relevant for the study of cholinesterase reactivators. Surrogates were characterized by liquid chromatography-mass spectrometry and nuclear magnetic resonance. NEMP, PIMP, and NIMP were potent inhibitors of rat brain, skeletal muscle, diaphragm, and serum AChE as well as human erythrocyte AChE and serum BuChE in vitro. PIMP was determined to degrade quickly in aqueous solution, making it useful for in vitro assays only, and NEDPA was not a potent inhibitor of AChE or BuChE in vitro; therefore, these two surrogates were not tested in subsequent in vivo studies. Sublethal dosages (yielding about 80% brain AChE inhibition) were determined for both the stable sarin surrogate, NIMP (0.325 mg/kg ip), and the VX surrogate, NEMP (0.4 mg/kg ip), in adult male rats. Time course studies indicated the time to peak brain AChE inhibition for both NIMP and NEMP to be 1 h postexposure. Both surrogates yielded severe cholinergic signs. These dosages did not require the addition of atropine to prevent lethality, and the rate of AChE aging was slow, making these surrogates useful for reactivation studies both in vitro and in vivo. The surrogates synthesized in this study are potent yet safer to test than nerve agents and are useful tools for initial screening of nerve agent oxime therapeutics. PMID- 22247005 TI - Efficacy assessment of various anticholinergic agents against topical sarin induced miosis and visual impairment in rats. AB - Eye exposure to the organophosphorus (OP) irreversible acetylcholinesterase inhibitor sarin results in long-term miosis and reduction in visual function. Anticholinergic drugs, such as atropine or homatropine, which are used topically in order to counter these effects may produce mydriasis and partial cycloplegia, which may worsen visual performance. This study was aimed to test the efficacy of short-acting anticholinergic drugs against sarin-induced miosis and visual impairment, which will minimally insult vision. Long-Evans rats, exposed topically to various sarin doses from 0 to 10 MUg, showed a dose-dependent miosis, which returned to pre-exposure levels within 24-48 h. Tropicamide treatment rapidly widened the miotic effect to a different extent depending on time following treatment and dosage given. Cyclopentolate, however, showed a delayed response that finally widened the pupils in a dose-dependent manner. Atropine treatment showed a rapid widening of the pinpoint pupils exceeding baseline level finally causing mydriasis. Light reflex test showed that the contraction ability of the iris following atropine treatment was impaired, as opposed to the use of tropicamide which facilitated the iris contraction, similar to control. Finally, tropicamide and atropine treatments ameliorated the visual impairment, as opposed to cyclopentolate, which worsened visual performance. Considering that tropicamide treatment against sarin exposure did not cause mydriasis nor did it impair the iris contraction flexibility as a response to light, the use of this drug should be taken into consideration as a first-choice topical treatment against OP intoxication. PMID- 22247006 TI - DNA double-strand breaks and DNA recombination in benzene metabolite-induced genotoxicity. AB - In utero exposure to environmental carcinogens, including the ubiquitous pollutant benzene, may cause DNA damage in the fetus, leading to an increased risk for the development of childhood cancer. Benzene metabolite-induced DNA double-strand breaks (DSBs) may undergo erroneous repair, leading to chromosomal aberrations including chromosomal inversions and translocations. In this study, fetal murine hematopoietic cells from pZK1 transgenic mice were exposed to p benzoquinone (BQ), a toxic metabolite of benzene, and assessed for DNA recombination, DNA damage including DNA DSBs as measured by gamma-H2A.X foci and oxidative DNA damage, and reactive oxygen species (ROS) production. The pZK1 transgenic mouse model contains a DNA construct allowing for the detection of intrachromosomal recombination events. Using this model, a significant increase in recombination was observed following exposure to BQ (25 and 50MUM) at various time points. Additionally, increased gamma-H2A.X foci were observed following exposure to 25MUM BQ for 30 min, 45 min, and 1 h, whereas this exposure did not significantly increase oxidative DNA damage. Pretreatment with 400 U/ml polyethylene glycol-conjugated-catalase attenuated increases in DNA recombination as compared with treatment with BQ alone. An increase in ROS production (30 min and 1 h), as measured by dichlorodihydrofluorescein diacetate fluorescence, was also observed following exposure to 25MUM BQ. These studies indicate that BQ is able to induce DNA damage and recombination in fetal liver cells and that ROS may be important in the mechanism of toxicity. PMID- 22247007 TI - Early in vivo MR spectroscopy findings in organophosphate-induced brain damage potential biomarkers for short-term survival. AB - Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and 1H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P < 0.05). On spectroscopy, N-acetyl aspartate (NAA)/creatine and NAA/choline levels significantly decreased 3 h postintoxication (>20% decrease, P < 0.005), and 3 h lactate peak was evident in all intoxicated animals. On the 8th day, although very little T2 changes were evident, NAA/creatine and choline/creatine were significantly decreased (>15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival. PMID- 22247008 TI - Effects of shock waves on oxidative stress and some trace element levels of rat liver and diaphragm muscles. AB - This study was designed to investigate whether the short-term extracorporeal shockwave lithotripsy (ESWL) exposure to kidney produces an oxidative stress and a change in some trace element levels in liver and diaphragm muscles of rats. Twelve male Wistar albino rats were divided randomly into two groups, each consisting of six rats. The animals in the first group did not receive any treatment and served as control group. The right-side kidneys of animals in group 2 were treated with two-thousand 18 kV shock waves while anesthetized with 50 mg kg(-1) ketamine. The localization of the right kidney was achieved after contrast medium injection through a tail vein under fluoroscopy control. The animals were killed 72 h after the ESWL treatment, and liver and diaphragm muscles were harvested for the determination of tissue oxidative stress and trace element levels. Although the malondialdehyde level increased, superoxide dismutase and glutathione peroxidase enzyme activities decreased in the livers and diaphragm muscles of ESWL-treated rats. Although glutathione level increased in liver, it decreased in diaphragm muscles of ESWL-treated animals. Fe, Mg and Mn levels decreased, and Cu and Pb levels increased in the livers of ESWL-treated animals. Fe and Cu levels increased, and Mg, Pb, Mn and Zn levels decreased in the diaphragm muscles of ESWL-treated animals. It also causes a decrease or increase in many mineral levels in liver and diaphragm muscles, which is an undesirable condition for the normal physiological function of tissues. PMID- 22247009 TI - Nanocrystalline hydroxyapatite facilitates bone apposition to polymethylmethacrylate: histological investigation using a sheep model. AB - Polymethylmethacrylate (PMMA) is the most commonly used bone void filler for vertebral augmentation in osteoporotic fracture. It provides mechanical stability and immediate pain relief; however, PMMA is not osteointegrated and is separated from the surrounding bone tissue by a thin fibrous layer. The aim of this study was to investigate the effect of nanocrystalline hydroxyapatite (HA) on osteointegration of PMMA in a sheep model. A composite material, consisting of PMMA and nanocrystalline HA (70:30, v/v), was implanted in one distal femur, with pure PMMA in the other femur as a control. Three and 6 months after implantation, the distal femora were histologically investigated. All composite implants exhibited a tight junction to the surrounding bone tissue, with minimal bone ingrowth into the outer surface of the implant. In comparison, with use of the control implants, we observed an overall bone resorption around pure PMMA, with fibrous connective tissue encapsulating the implant. These results suggest that nanocrystalline HA enables osteointegration of PMMA in bone tissue, which might alter the biomechanical characteristics of the osteoporotic vertebral body after augmentation. PMID- 22247012 TI - Preoperative prediction of papillary thyroid carcinoma prognosis with the assistance of computerized morphometry of cytology samples obtained by fine needle aspiration: preliminary report. AB - BACKGROUND: The purpose of this study was to analyze the relationship between cytologic features, clinical features, and recurrence of papillary thyroid cancer (PTC). We hoped to predict prognosis preoperatively. METHODS: We retrospectively studied cytologic features by using computerized morphometry and clinical data of 118 patients with usual-type PTC without initial metastasis, including 34 patients with cancer recurrence in 10 years after surgery and 84 patients who did not have recurrence for more than 10 years after surgery. Another 24 patients were recruited for validation. RESULTS: Multivariate logistic analysis indicated that nucleus-to-cell ratio, variation of nuclear area, tumor size, and patient age were significantly related to recurrence. Cox regression analysis showed that hazard ratios were 3.34, 1.53, 1.77, and 2.6, respectively. CONCLUSION: Cytologic features of PTC analyzed with computerized morphometry significantly correlated with recurrence. It helped to predict prognosis preoperatively and may be helpful for planning further treatment. PMID- 22247010 TI - Tumour growth inhibition and anti-metastatic activity of a mutated furin resistant Semaphorin 3E isoform. AB - Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61 Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading. PMID- 22247011 TI - N-methyl N-nitrosourea induced functional and structural alterations in mice brain-role of curcumin. AB - Curcumin is being widely used both as an herbal drug and a food additive in Asian countries. However, its prophylactic potential in containing certain brain disorders is yet to be fully explored. The present study was conceived with an idea that curcumin may prove to be effective in ameliorating N-methyl N nitrosourea (MNU)-induced adverse effects in cerebrum and cerebellum of mice. Male laca mice received either intravenous MNU treatment at a dose of 10 mg/kg body weight in sterile double distilled water, curcumin alone 60 mg/kg body weight in drinking water via oral gavage, or combined MNU and curcumin treatment on alternate days for a total duration of 2 months. MNU treatment resulted in significant alteration in neurobehavior, reactive oxygen species, lipid profile and histoarchitecture which showed appreciable signs of improvements upon curcumin supplementation. Therefore, the study concludes that prophylactic treatment with curcumin shall prove to be effective in containing MNU-induced neurotoxicity. PMID- 22247013 TI - The novel function of OCT4B isoform-265 in genotoxic stress. AB - OCT4 is a key transcription factor in maintaining the pluripotency and self renewal of embryonic stem cells (ESCs). Human OCT4 gene can generate three mRNA isoforms (OCT4A, OCT4B, and OCT4B1) by alternative splicing and four protein isoforms (OCT4A, OCT4B-265, OCT4B-190, and OCT4B-164) by alternative splicing or alternative translation initiation. OCT4A is a transcription factor responsible for the stemness of ESCs, while the function of OCT4B protein isoforms is still not clear. We have previously reported that OCT4B-190 functioned in cell stress response. Here, we present another product of OCT4 gene, OCT4B-265, which is upregulated under genotoxic stress in stem cells, and it may function in stress response through p53 signaling pathway. This work gives an insight into the novel function of OCT4B protein isoforms and helps us to understand the complex expression patterns and biological functions of OCT4 gene. PMID- 22247014 TI - Factor mediated gene priming in pluripotent stem cells sets the stage for lineage specification. AB - Priming of lineage-specific genes in pluripotent embryonic stem cells facilitates rapid and coordinated activation of transcriptional programmes during differentiation. There is growing evidence that pluripotency factors play key roles in priming tissue-specific genes and in the earliest stages of lineage commitment. As differentiation progresses, pluripotency factors are replaced at some primed genes by related lineage-specific factors that bind to the same sequences and maintain epigenetic priming until the gene is activated. Polycomb and trithorax group proteins bind many genes in pluripotent cells generating bivalent domains that contain both active and repressive histone modifications. The properties of polycomb proteins suggest that they act as gatekeepers, helping to maintain silencing in pluripotent stem cells while establishing a chromatin environment that is permissive for priming by sequence-specific factors. The overall effect of factor-mediated priming is to initiate the input of information required for cell differentiation before the first lineage choices have been made. PMID- 22247015 TI - A history of cranial radiotherapy is associated with a higher visceral to subcutaneous fat ratio in men with pituitary insufficiency. AB - OBJECTIVE: Endocrine deficiencies, like GH and estrogen deficiencies, are likely candidates to explain increased visceral to subcutaneous fat ratio in patients with pituitary insufficiency. However, recent reports pointed to cranial radiotherapy (CRT) as an additional determinant of an unfavorable fat distribution. Therefore, we determined the effect of CRT on abdominal fat distribution in men with treated pituitary insufficiency. DESIGN: Cross-sectional study. METHODS: Thirty-five consecutive male subjects (16 men with and 19 men without CRT aged 62+/-12 and 56+/-14 years respectively, P=0.175) visiting our Endocrine Outpatient Clinic for pituitary insufficiency were invited to participate in this study. A standardized single-slice abdominal CT scan at the level of fourth lumbar vertebra was performed to determine visceral fat area, subcutaneous fat area, and visceral to subcutaneous fat ratio. In addition, we assessed body mass index, total fat percentage with bioelectrical impedance analysis, resting energy expenditure with indirect calorimetry, calorie intake using a diary, and serum hormone concentrations. RESULTS: Subjects with CRT had a smaller subcutaneous fat area (225.1 (71.1-480.7) vs 269.0 (133.2-59.9) cm(2), P=0.022) and a higher visceral to subcutaneous fat ratio (0.79 (0.39-1.55) vs 0.63 (0.23-0.88), P=0.001) than subjects without CRT. Both the groups were comparable for body mass index, waist-hip ratio, resting energy expenditure, and calorie intake. Importantly, serum hormone concentrations were similar. CONCLUSION: In men treated for pituitary insufficiency, previous CRT is associated with a higher visceral to subcutaneous fat ratio. PMID- 22247016 TI - The natural history of macroprolactinaemia. AB - OBJECTIVE: Macroprolactinaemia is a condition in which serum prolactin (PRL) consists mainly of large molecular weight PRL (macroPRL). The aim of this study was to examine the natural history of macroprolactinaemia. DESIGN AND PARTICIPANTS: Six hundred and fifty-four hospital workers participated in this study, including 27 subjects with macroprolactinaemia and 627 controls. MacroPRL and serum PRL concentrations were evaluated over a 4-year period. The ratio of macroPRL was examined by the polyethylene glycol (PEG) method and gel filtration chromatography. IgG-bound PRL and anti-PRL autoantibodies were examined by protein G and (125)I-PRL binding studies respectively. RESULTS: Over the 4 years of the study, all 27 macroprolactinaemic subjects had persistent macroprolactinaemia without the development of raised free PRL, while none of the 627 controls developed macroprolactinaemia. The ratios of PEG-precipitable PRL and IgG-bound PRL did not significantly change, but (125)I-PRL binding ratios significantly increased. As a whole, total and free serum PRL concentrations did not significantly change in subjects with macroprolactinaemia over the 4-year period. However, hyperprolactinaemia developed in five of the 18 macroprolactinaemic subjects who were initially normoprolactinaemic along with an increase in anti-PRL autoantibody titres. One of the remaining nine macroprolactinaemic subjects who were initially hyperprolactinaemic showed a decrease in serum PRL concentrations, which occurred concomitantly with a decrease in the anti-PRL autoantibody titre. CONCLUSIONS: Macroprolactinaemia may develop before middle age and is likely a chronic condition leading to hyperprolactinaemia. PMID- 22247017 TI - PTHrP-associated hypercalcemia of pregnancy resolved after delivery: a case report. AB - A 35-year-old oriental woman, who was 32 weeks pregnant, was hospitalized with suspected preeclampsia. Subsequently, she developed stupor and lethargia. Biochemical assessment showed severe hypercalcemia (21 mg/dl) with undetectable parathyroid hormone (PTH) and markedly elevated PTH-related peptide (PTHrP) levels (26 pmol/l, normal values <1.1 pmol/l). The patient was treated with i.v. fluid administration, which resulted in an unsatisfactory reduction in serum calcium. Therefore, a cesarean section was performed to deliver the baby. Serum calcium levels promptly normalized after delivery with undetectable PTHrP levels. She delivered a healthy infant only presenting with transient mild jaundice and slightly prolonged QT interval with serum calcium level of 7.8-8.4 mg/dl (corrected for albumin levels). In the subsequent days, the patient developed a transient 'hungry bone' syndrome (calcium 6.7 mg/dl, phosphorous 2.1 mg/dl, and PTH 100.4 pg/ml). In conclusion, this pregnant patient presented with PTHrP associated hypercalcemia, presumably of placental origin. Delivery resulted in prompt reduction of serum calcium levels and a transient 'hungry bone' syndrome. PMID- 22247018 TI - Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation. AB - OBJECTIVE: Mutations in the selenocysteine insertion sequence binding protein 2 gene (SECISBP2 also known as SBP2) lead to a multisystemic disorder. Our objectives are to examine the clinical manifestations of the present patient and evaluate the effects of GH and triiodothyronine (T(3)) for longitudinal bone growth and maturation. METHODS: A Japanese boy presented with unusual thyroid function tests (normal or slightly elevated TSH, low-normal or slightly decreased free T(3) (FT(3)), and elevated free thyroxine (FT(4))), short stature without GH deficiency, and delayed bone maturation. The entire coding region of the patient's SBP2 was analyzed. GH treatment was initiated when the patient was 4 years old, and combination therapy with GH plus T(3) was started when the patient was 10 years old. We monitored the patient's height and bone age until he was 11 years old. RESULTS: The patient showed typical symptoms of SBP2 deficiency, and novel compound heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X). Six years of GH monotherapy improved the patient's height s.d. from -3.4 to -1.7 without accelerating bone maturation, whereas 6 months of T(3) treatment combined with GH almost normalized the thyroid function tests and improved both longitudinal bone growth and maturation. CONCLUSIONS: In the growth plate, GH may compensate for decreased local T(3) effects on longitudinal bone growth; however, GH does not appear to compensate for the effects of T(3) on bone maturation. We believe that the present case has important implications for understanding the mechanism of thyroid hormone and GH on longitudinal bone growth and maturation. PMID- 22247019 TI - A large-scale replication study for the association of rs17039192 in HIF-2alpha with knee osteoarthritis. AB - Osteoarthritis (OA) is a common disease with a genetic component for its etiology. Recently, a genetic association of a single nucleotide polymorphism (SNP), rs17039192 in HIF-2alpha with knee OA has been reported in a Japanese population; however, controversy exits for its replication and a role of HIF 2alpha in OA. This study aimed to evaluate the association of the SNP by a large scale replication study. A total of 8,457 subjects (3,129 OA cases and 5,328 controls) from seven independent cohorts from six countries (Japan, China, Taiwan, Korea, Greece, and Australia) were recruited and genotyped. The association of rs17039192 with knee OA was evaluated by meta-analyses. The association of the HIF-2alpha SNP was not replicated in any of the populations. Contrary to the previous report, the odds ratios (ORs) of the risk allele frequency were all less than 1. A combined analysis for the seven populations also showed no replication of the association (OR = 0.91, 95% confidence interval = 0.81-1.03). Our large-scale meta-analysis showed that the association of rs17039192 in HIF-2alpha with knee OA is negative. The significance of HIF-2alpha in human OA (idiopathic OA as a common disease) should be further evaluated carefully. PMID- 22247020 TI - Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. AB - BACKGROUND: The envelope (env) protein of the human endogenous retrovirus type K (HERV-K) family is commonly expressed on the surface of breast cancer cells. We assessed whether HERV-K env is a potential target for antibody-based immunotherapy of breast cancer. METHODS: We examined the expression of HERV-K env protein in various malignant (MDA-MB-231, MCF-7, SKBR3, MDA-MB-453, T47D, and ZR 75-1) and nonmalignant (MCF-10A and MCF-10AT) human breast cell lines by immunoblot, enzyme-linked immunosorbent assay, immunofluorescence staining, and flow cytometry. Anti-HERV-K env monoclonal antibodies (mAbs; 6H5, 4D1, 4E11, 6E11, and 4E6) were used to target expression of HERV-K, and antitumor effects were assessed by quantifying growth and apoptosis of breast cancer cells in vitro, and tumor growth in vivo in mice (n = 5 per group) bearing xenograft tumors. The mechanisms responsible for 6H5 mAb-mediated effects were investigated by microarray assays, flow cytometry, immunoblot, and immunofluorescence staining. The expression of HERV-K env protein was assessed in primary breast tumors (n = 223) by immunohistochemistry. All statistical tests were two-sided. RESULTS: The expression of HERV-K env protein in malignant breast cancer cell lines was substantially higher than nonmalignant breast cells. Anti-HERV-K specific mAbs inhibited growth and induced apoptosis of breast cancer cells in vitro. Mice treated with 6H5 mAb showed statistically significantly reduced growth of xenograft tumors compared with mice treated with control immunoglobulin (control [mIgG] vs 6H5 mAb, for tumors originating from MDA-MB-231 cells, mean size = 1448.33 vs 475.44 mm(3); difference = 972.89 mm(3), 95% CI = 470.17 to 1475.61 mm(3); P < .001). Several proteins involved in the apoptotic signaling pathways were overexpressed in vitro in 6H5 mAb-treated malignant breast cells compared with mIgG-treated control. HERV-K expression was detected in 148 (66%) of 223 primary breast tumors, and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors (43% vs 23%, P = .003). CONCLUSION: Monoclonal antibodies against HERV-K env protein show potential as novel immunotherapeutic agents for breast cancer therapy. PMID- 22247021 TI - Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. AB - BACKGROUND: Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. METHODS: We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two sided. RESULTS: Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. CONCLUSIONS: Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor. PMID- 22247022 TI - Predictive value of symptoms for ovarian cancer: comparison of symptoms reported by questionnaire, interview, and general practitioner notes. AB - BACKGROUND: Because of the poor survival outcomes associated with advanced ovarian cancer, early detection strategies are needed. Although several symptom indices have been described, their relationship with the potential lead time has been poorly documented. METHODS: Women aged 50-79 years who had newly diagnosed ovarian cancer (n = 194) and control subjects (n = 268) who attended ovarian cancer screening clinics were included in the analysis. Symptoms and their onset dates were obtained from three sources: a questionnaire (191 case patients and 268 control subjects), telephone interview (111 case patients and 125 control subjects), and general practitioner (GP) notes (171 case patients and 227 control subjects). Data from questionnaires and GP notes were used to derive two new symptom indices (Index 1 and Index 2). Sensitivity and specificity for these new indices and the previously reported Goff index were calculated for the periods of 0-11 and 3-14 months before diagnosis for all three data sources. RESULTS: For each data source and period, the two new symptom indices derived from questionnaire and GP notes were similar both qualitatively (symptoms included) and quantitatively (sensitivity and specificity) to the Goff index. When symptoms that started within 3 months before diagnosis were excluded, sensitivity was decreased for all indices and all data sources (eg, for telephone interviews, sensitivity for the period 0-11 vs 3-14 months before diagnosis: for Index 1 = 91.0% vs 69.4%, difference = 21.6%, 95% confidence interval [CI] = 13.6% to 29.7%; for Index 2 = 91.0% vs 60.4%, difference = 30.6%, 95% CI = 21.7% to 39.6%; and for the Goff index = 75.7% vs 51.4%, difference = 24.3%, 95% CI = 16.0% to 32.7%). Also, the specificity of all indices was consistently decreased for telephone interviews compared with questionnaires and GP notes (eg, 1 - specificity for the period of 3-14 months before diagnosis for telephone interviews vs questionnaires: for Index 1 = 19.2% vs 10.4%, difference = 8.8%, 95% CI = 1.0% to 16.6%; for Index 2 = 14.4% vs 6.7%, difference = 7.7%, 95% CI = 0.9% to 14.5%; and for the Goff Index = 7.2% vs 1.5%, difference = 5.7%, 95% CI = 0.9% to 10.5%). CONCLUSIONS: Previous estimates of index performance have been overly optimistic because they did not take into account the time required to make a diagnosis on the basis of testing in response to symptoms. In addition, the specificity of a symptom index is lower when based on a telephone interview vs questionnaire or GP notes. Thus, the clinical utility of a symptom index depends on precisely how it is used and how index-positive women are managed. PMID- 22247023 TI - Finding ovarian cancer. PMID- 22247024 TI - Chemical shift-based water/fat separation in the presence of susceptibility induced fat resonance shift. AB - Chemical shift-based water/fat separation methods have been emerging due to the growing clinical need for fat quantification in different body organs. Accurate quantification of proton-density fat fraction requires the assessment of many confounding factors, including the need of modeling the presence of multiple peaks in the fat spectrum. Most recent quantitative chemical shift-based water/fat separation approaches rely on a multipeak fat spectrum with precalibrated peak locations and precalibrated or self-calibrated peak relative amplitudes. However, water/fat susceptibility differences can induce fat spectrum resonance shifts depending on the shape and orientation of the fatty inclusions. The effect is of particular interest in the skeletal muscle due to the anisotropic arrangement of extracellular lipids. In this work, the effect of susceptibility-induced fat resonance shift on the fat fraction is characterized in a conventional complex-based chemical shift-based water/fat separation approach that does not model the susceptibility-induced fat resonance shift. A novel algorithm is then proposed to quantify the resonance shift in a complex based chemical shift-based water/fat separation approach that considers the fat resonance shift in the signal model, aiming to extract information about the orientation/geometry of lipids. The technique is validated in a phantom and preliminary in vivo results are shown in the calf musculature of healthy and diabetic subjects. PMID- 22247026 TI - Neglected markers: altered serum proteome in murine models of disease. AB - More than a decade ago our groups pioneered the analysis of serum proteins of laboratory animals with up-to-date proteomic techniques. We were, and still are, convinced that conforming animal procedures to the minimally invasive approaches typical of clinical biochemistry focuses attention on the actual conditions under which any finding arrived at on animal models of disease may eventually be applied to human patients for screening/diagnosis. We are also convinced that, besides the proteins present in trace level as a result of tissue leakage during disorders affecting specific peripheral organs, changes in the concentration of some of the major serum proteins as part of an acute-phase response may be taken as biological end-points during a number of experimental procedures. When reviewing literature data about proteomic investigations on plasma or serum of mice, we realized that not much work has been done in the direction we favor. In addition, we noticed that sometimes information about serum proteome has been coarsely treated and in a few cases even misunderstood/misused. In the following, we present current findings on serum/plasma proteome of the laboratory mouse not only under control conditions and during an experimentally induced acute-phase reaction, but also in a number of models of disease, mainly related to cancer and to metabolic disorders. PMID- 22247025 TI - Brainstem origins of glutamatergic innervation of the rat hypothalamic paraventricular nucleus. AB - Multiple lines of evidence document a role for glutamatergic input to the hypothalamic paraventricular nucleus (PVH) in stress-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. However, the neuroanatomical origins of the glutamatergic input have yet to be definitively determined. We have previously shown that vesicular glutamate transporter 2 (VGLUT2) is the predominant VGLUT isoform expressed in the basal forebrain and brainstem, including PVH-projecting regions, and that the PVH is preferentially innervated by VGLUT2-immunoreactive terminals/boutons. The present study employed a dual labeling approach, combining immunolabeling for a retrograde tract tracer, Fluoro Gold (FG), with in situ hybridization for VGLUT2 mRNA, to map the brainstem and caudal forebrain distribution of glutamatergic PVH-projecting neurons. The present report presents evidence for substantial dual labeling in the periaqueductal gray, caudal portions of the zona incerta and subparafascicular nucleus, and the lateral parabrachial nucleus. The current data also suggest that relatively few PVH-projecting neurons in ascending raphe nuclei, nucleus of the solitary tract, or ventrolateral medulla are VGLUT2 positive. The data reveal multiple brainstem origins of glutamatergic input to PVH that are positioned to play a role in transducing a diverse range of stressful stimuli. PMID- 22247027 TI - Synthesis, in vitro cytotoxicity, and interaction with DNA of platinum(II) complexes with N-monocycloalkyl derivatives of 1R,2R-diaminocyclohexane as carrier ligands. AB - A series of platinum(II) complexes with N-monocyclopentyl/cyclohexyl derivatives of 1R,2R-diaminocyclohexane as carrier ligands and dicarboxylate anions as leaving groups were synthesized and characterized. All complexes were characterized by elemental analysis, IR, (1)H NMR, and (13)C NMR spectroscopy, as well as ESIMS. The in vitro antiproliferative activities were tested by MTT assay against four human cancer cell lines; breast carcinoma (MCF-7) and colon cancer (HCT-116) cells were particularly sensitive, especially to complexes 1f (IC(50) =9.81 and 1.49 MUM) and 2f (IC(50) =4.59 and 0.36 MUM). Flow cytometry indicated that representative compounds exert cytotoxicity toward MCF-7 and HCT-116 cells through induction of apoptosis and blockage of cell-cycle progression in the S phase, similar to cisplatin. The interaction between the platinum(II) complexes and pET22b plasmid DNA was observed by agarose gel electrophoresis, revealing that complex 2f has the capacity to distort plasmid DNA in a manner distinct from that of oxaliplatin. PMID- 22247028 TI - [Genetic polymorphisms as new predictive factors for successful treatment of chronic hepatitis C]. AB - Currently, the gold standard for the treatment of chronic hepatitis C is combination therapy with pegylated interferon alpha and ribavirin. Despite advances in treatment modalities, only 50 % of patients achieve sustained virological response. Therefore, determination of predictive factors related to response to therapy is very important. In 2009, three independent studies concerning genome-wide association identified several single nucleotide polymorphisms near the IL-28 gene, associated with virological response. Hence, it appears that genetic polymorphism may become important predictive factors. All patients beginning therapy, will probably be tested for the presence of these polymorphisms, allowing individualized treatment options for every patient. PMID- 22247029 TI - [Role of PCR detection and quantification of herpes viruses in bronchoalveolar lavage of immunocompromised patients]. AB - Herpes virus infections represent common complications associated with respiratory tract involvement which may result in pneumonia development in immunocompromised patients. The analysis of bronchoalveolar lavage (BAL) fluid obtained from the lower respiratory tract may contribute to detection of aetiological agents of the disease. The routine use of quantitative molecular methods enables the discrimination between acute infection and viral reactivation with asymptomatic virus shedding. The aim of this review is to evaluate the contribution of BAL viral load monitoring in high-risk patients and to determine the cut-off of viral load leading to progression to herpes virus pneumonia. PMID- 22247030 TI - [Prevalence and risk factors of hepatitis C in Roma people in Brno]. AB - BACKGROUND: Assessment of hepatitis C prevalence in a representative sample of Roma people in the town of Brno and determination of the main risk factors of this disease. MATERIAL AND METHODS: A 27-item questionnaire was prepared for this project. The questions were focused on basic demographic data and risk factors significant for possible transmission of hepatitis C virus (HCV) infection. RESULTS: Data from 415 respondents were obtained. As the questionnaires were collected, anti-HCV antibodies in capillary blood were detected. In case of anti HCV positivity, HCV RNA was detected by polymerase chain reaction in venous blood. The main results are as follows: (1) the employment rate in the Roma population living in Brno is very low (14.3 %), (2) almost 86 % of the respondents had only primary education, (3) the prevalence of HCV infection was 4.3 %, i.e. many times higher than in the general Czech population (0.2 % in 2001), (4) intravenous drug use and former imprisonment were the significant parameters associated with HCV infection, (5) heroin abuse prevailed over pervitin (methamphetamine) abuse especially in unemployed men under 20 years of age, and (6) heroin abuse was associated with higher risk of HCV infection than pervitin abuse. CONCLUSIONS: Hepatitis C is much more frequent in Brno Roma people than in general Czech population, mainly due to more frequent drug abuse in this ethnic minority. PMID- 22247031 TI - [A study of patients with Clostridium difficile infection hospitalized at Brno Clinic of Infectious Diseases in 2007-2010]. AB - BACKGROUND: To describe a set of patients hospitalized at the Clinic of Infectious Diseases of the University Hospital Brno with Clostridium difficile infection (CDI), to interpret clinical and epidemiological data, and to determine the risk factors for the disease and its complications. MATERIAL AND METHODS: A retrospective study of 284 patients with confirmed diagnosis of Clostridium difficile infection hospitalized between 1 January 2007 and 31 December 2010. Epidemiological, clinical and laboratory data were collected from their clinical documentation. RESULTS: Of the 284 patients with a mean age of 73.2 years, 38.0 % were men. Risk factors for developing CDI include the use of antibiotics in the previous 8 weeks (89.1 % of patients), age over 65 years (77.6 %), hospitalization in the previous 4 weeks (65.5 %), and the use of proton pump inhibitors (41.9 %). Recurrence was noted in 89 (31.3 %) cases. Sixty-six (23.2 %) patients required intensive care and 50 (14.6 %) patients died during their hospitalization. Isolates of C. difficile from the stool of 4 patients were sent for ribotyping and identified as ribotype 176. CONCLUSIONS: The CDI rates at the clinic KICH have increased in the recent years. The rise is consistent with the global trends. The study confirmed the disease risk factors reported in the literature. The disease is associated with a high percentage of relapses and complications. PMID- 22247032 TI - [First experiences with faecal bacteriotherapy in the treatment of relapsing pseudomembranous colitis due to Clostridium difficile]. AB - BACKGROUND: The aim was to prove the effectiveness and safety of faecal bacteriotherapy in the treatment of relapsing pseudomembranous colitis due to Clostridium difficile in clinical practice. METHODS: The protocol of faecal bacteriotherapy was adopted from foreign authors (Bakken JS, Aas J, MacConnachie AA). After six months, the success rate was not satisfying and the method was modified so that 40-50 g of stool were administered instead of 20-30 g. RESULTS: A total of 77.8 % of patients included in the study were successfully treated. The study achieved results comparable with foreign literature where the lowest success rate is about 80 %. Neither complications nor death were noticed (0 % mortality rate). CONCLUSIONS: Faecal bacteriotherapy is a safe and simple method capable of curing chronically relapsing forms of pseudomembranous colitis. PMID- 22247033 TI - Inhibition of endogenous CO by ZnPP protects against stress-induced gastric lesion in adult male albino rats. AB - Carbon monoxide (CO) has been found to be produced in every living cell in a biochemical reaction catalyzed by heme-oxygenase (HO) enzyme which degrades heme into biliverdin, CO, and iron. Endogenous CO is not a waste product, but acts as a chemical messenger mediating and modulating many intracellular biochemical reactions that regulate physiological functions. This study was designed to investigate the effect of inhibition of endogenous CO production by zinc protoporphyrin (ZnPP), an HO inhibitor, on the gastric secretion and ulceration induced by cold-restraint stress (CRS) in adult male albino rats. Rats were pylorically ligated and divided randomly into the following groups (six rats each): control, ZnPP treated (50 MUmol/kg/day, s.c. for 10 days), CRS, and stressed ZnPP treated groups. Blood samples were collected from the retro-orbital sinus of anesthetized rats for determination of CO concentration. We found that ZnPP pretreatment significantly decreased HO-1 level, CO level, and volume of gastric juice as compared to the control non-stressed rats. In the present study, ZnPP pretreatment proved to be protective against development of ulcerative lesions in CRS model as evidenced by reduction of the ulcer index, and this could be mediated through reduction of free and total acidity of gastric secretion and decreased lipid peroxidation but with significantly decreased gastric protective nitric oxide and prostaglandin E(2) levels. In conclusion and according to our results, the protective effect of ZnPP on CRS-induced gastric ulcers despite of inhibition of endogenous CO could be attributed to the presence of zinc which is known to have a protective anti-ulcer effect. PMID- 22247034 TI - N-Methyl-2-pyridone-5-carboxamide is 1-methylnicotinamide metabolite of low cyclooxygenase-dependent vasodilating activity. AB - 1-Methylnicotinamide (MNA) is a primary metabolite of nicotinamide recently proven to cause systemic increase in PGI(2) plasma levels in an unknown mechanism. Our present study was aimed at verifying whether the increased production of PGI(2), a vasodilating prostanoid, in response to MNA, its metabolite N-methyl-2-pyridone-5-carboxamide (Met2PY), and nicotinamide may be reproduced under in vitro conditions. Since prostacyclin is a vasodilating prostanoid, we also performed the functional tests in the ex vivo model of coronary vascular bed perfusion to evaluate the vasoactive properties of those compounds. We did not observe any significant effect of the tested drugs on either PGI(2) or PGE(2) secretion in our in vitro model. Nicotinamide at the concentrations of 10 and 100 MUmol/l and 100 MUmol/l Met2PY slightly but significantly increased coronary flow in rat heart. These increases, however, remained very low when compared to that induced by the reference compound, bradykinin (100 nmol/l). Perfusion of rat hearts with Met2PY in the presence of 50 MUmol/l indomethacin resulted in decreased coronary flow, which proves that the effect is cyclooxygenase dependent. We conclude that MNA metabolites should be more carefully addressed in reference to pro-prostacyclin activity and that systemic mechanism of MNA-induced PGI(2) production needs further clarification. PMID- 22247035 TI - Graphene oxide nanoparticles as a nonbleaching optical probe for two-photon luminescence imaging and cell therapy. PMID- 22247036 TI - Cyclooxygenase-2 expression and clinical parameters in laryngeal squamous cell carcinoma, vocal fold nodule, and laryngeal atypical hyperplasia. AB - BACKGROUND: The diagnostic role of cyclooxygenase-2 (COX-2) expression in laryngeal atypical hyperplasia, vocal fold nodule, and laryngeal squamous cell carcinoma was examined. METHODS: Specimens obtained from patients diagnosed with vocal fold nodule (n = 35), atypical hyperplasia (n = 35), laryngeal squamous cell carcinoma (n = 35), and clinical parameters were evaluated retrospectively. RESULTS: Although no staining was observed in patients with vocal fold nodules, staining was noted in laryngeal atypical hyperplasia and squamous cell carcinoma. The percentage of COX-2 staining was the highest in the carcinoma group. CONCLUSION: It was determined that COX-2 staining was significantly associated with laryngeal squamous cell carcinoma. It should be noted that overexpression of COX-2, a potentially important factor in the evolution of carcinogenesis in precancerous lesions, might be an indicator of the development of carcinoma. PMID- 22247037 TI - Mechanism of FGF23 processing in fibrous dysplasia. AB - Fibroblast growth factor-23 (FGF23) is a phosphate- and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 + iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G protein G(s) alpha that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G(s) alpha mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. PMID- 22247038 TI - Serum cartilage metabolites as biomarkers of degenerative lumbar scoliosis. AB - Several biomarkers have been used to evaluate osteoarthritis of the limb joints. Here we evaluated the use of serum cartilage metabolites as biomarkers for degenerative lumbar scoliosis (DLS). Fifty-two DLS patients with Cobb angle > 10 degrees were compared with 19 control patients. Serum levels of hyaluronic acid (HA), keratan sulfate (KS), cartilage oligomeric matrix protein (COMP), collagen type II cleavage (C2C), and procollagen type II C-propeptide (CPII) were measured. Serum levels of KS (DLS 1.20 +/- 0.44 ug/ml vs. control 0.98 +/- 0.33 ug/ml), CPII (DLS 1905.1 +/- 948.2 ng/ml vs. control 1223.6 +/- 884.4 ng/ml), and C2C (DLS 219.1 +/- 59.2 ng/ml vs. control 177.7 +/- 71.7 ng/ml) were significantly higher in DLS. There were no significant differences in the levels of HA or COMP. There was a significant positive correlation between the Cobb angle and CPII in DLS. This is the first study to evaluate the cartilage biomarkers in DLS. The results suggest DLS patients have higher levels of type II collagen synthesis and degradation, indicated by elevated serum CPII and C2C, respectively. As type II collagen is a major component of collagens in the nucleus pulposus and facet joint cartilages, its enhanced turnover may be related to the development and progression of DLS. PMID- 22247039 TI - Red algal parasites: models for a life history evolution that leaves photosynthesis behind again and again. AB - Many of the most virulent and problematic eukaryotic pathogens have evolved from photosynthetic ancestors, such as apicomplexans, which are responsible for a wide range of diseases including malaria and toxoplasmosis. The primary barrier to understanding the early stages of evolution of these parasites has been the difficulty in finding parasites with closely related free-living lineages with which to make comparisons. Parasites found throughout the florideophyte red algal lineage, however, provide a unique and powerful model to investigate the genetic origins of a parasitic lifestyle. This is because they share a recent common ancestor with an extant free-living red algal species and parasitism has independently arisen over 100 times within this group. Here, we synthesize the relevant hypotheses with respect to how these parasites have proliferated. We also place red algal research in the context of recent developments in understanding the genome evolution of other eukaryotic photosynthesizers turned parasites. PMID- 22247040 TI - Amygdala afferents monosynaptically innervate corticospinal neurons in rat medial prefrontal cortex. AB - The amygdala provides the medial prefrontal cortex (mPFC; areas 25, 32, and 24b) with salient emotional information. This study investigated the synaptic connectivity of identified amygdalocortical boutons (ACBs; labeled anterogradely following injections of Phaseolus vulgaris leucoagglutinin into the basolateral nucleus of the amygdala), with the dendritic processes of identified layer 5 corticospinal neurons in the rat mPFC. The corticospinal (CS) neurons in the mPFC had been retrogradely labeled with rhodamine fluorescent latex microspheres and subsequently intracellularly filled with biotinylated lucifer yellow to visualize their basal and apical dendrites. Two main classes of mPFC CS neurons were identified. Type 1 cells had apical dendrites bearing numerous dendritic spines with radiate basal dendritic arbors. Type 2 cells possessed apical dendrites with greatly reduced spine densities and a broad range of basal dendritic tree morphologies. Identified ACBs made asymmetric synaptic junctions with labeled dendritic spines and the labeled apical and basal dendritic shafts of identified CS neurons. On average, eight ACBs were closely associated with the labeled basal dendritic arbors of type 1 CS neurons and five ACBs with type 2 CS basal dendrites. The mean Scholl distance of ACBs from CS somata (for both types 1 and 2 cells) was 66 MUm-coinciding with a region containing the highest length density of CS neuron basal dendrites. These results indicate that neurons in the BLA can monosynaptically influence CS neurons in the mPFC that project to autonomic regions of the thoracic spinal cord and probably to other additional subcortical target regions, such as the lateral hypothalamus. PMID- 22247041 TI - Mosaic tetrasomy 5p resulting from an isochromosome 5p marker chromosome: case report and review of literature. AB - We report on the fifth case, and oldest reported patient, of an individual affected with mosaic tetrasomy 5p resulting from an isochromosome 5p [i(5)(p10)] marker chromosome. A syndrome of mosaic tetrasomy 5p is defined, and includes the following features seen in the reported cases: developmental delay, seizures, ventriculomegaly (other brain anomalies), small stature/growth delay and mosaic pigmentary skin changes. Other findings include various dysmorphic facial features as well as hand and foot anomalies. This syndrome is likely more common than suggested in the literature, as the clinical presentation can be variable, and the chromosome anomaly is unlikely to be found on routine karyotype of peripheral blood lymphocytes. The i(5)(p10) marker chromosome is found only as a mosaic anomaly, with levels ranging from 0% to 10% in cultured lymphocytes to 12 85% in cultured skin fibroblasts. Microarray analysis performed on unstimulated lymphocytes from the patient in this report did not detect any evidence of the chromosome abnormality, indicating that this methodology may not be useful as a diagnostic tool in this disorder. Diagnosis of the mosaic tetrasomy 5p syndrome will rely on good clinical assessment, and appropriate cytogenetic studies, including analysis of skin fibroblasts. A child with unexplained developmental delay, seizures, hypotonia, and ventriculomegaly with or without dysmorphic features should be assessed carefully for pigmentary changes of the skin. If a diagnosis of mosaic 5p tetrasomy is suspected, karyotype of cultured fibroblasts in addition to routine cytogenetic analysis, to look for this marker chromosome is warranted. PMID- 22247042 TI - How advancement in biological network analysis methods empowers proteomics. AB - Proteomics provides important information--that may not be inferable from indirect sources such as RNA or DNA--on key players in biological systems or disease states. However, it suffers from coverage and consistency problems. The advent of network-based analysis methods can help in overcoming these problems but requires careful application and interpretation. This review considers briefly current trends in proteomics technologies and understanding the causes of critical issues that need to be addressed--i.e., incomplete data coverage and inter-sample inconsistency. On the coverage issue, we argue that holistic analysis based on biological networks provides a suitable background on which more robust models and interpretations can be built upon; and we introduce some recently developed approaches. On consistency, group-based approaches based on identified clusters, as well as on properly integrated pathway databases, are particularly useful. Despite that protein interactions and pathway networks are still largely incomplete, given proper quality checks, applications and reasonably sized data sets, they yield valuable insights that greatly complement data generated from quantitative proteomics. PMID- 22247043 TI - A synthetic C34 trimer of HIV-1 gp41 shows significant increase in inhibition potency. PMID- 22247044 TI - Strength of association for incident diabetes risk factors according to diabetes case definitions: the Atherosclerosis Risk in Communities Study. AB - Prospective epidemiologic studies have characterized major risk factors for incident diabetes by a variety of diabetes case definitions. Whether different definitions alter the association of diabetes with risk factors is largely unknown. Using 1987-1998 data from the ongoing Atherosclerosis Risk in Communities (ARIC) Study, the authors assessed the relation of traditional risk factors with 3 different diabetes case definitions and 4 fasting glucose categories. They compared the study protocol case definition with 2 nested case definitions, self-reported diabetes and a multiple-evidence definition. Significant differences in risk factor associations by case definition and by screening cutpoints were observed. Specifically, the magnitude of the association between the risk factors (baseline metabolic syndrome, fasting glucose, blood pressure, body mass index, and serum insulin) and incident diabetes differed by case definition. Associations with these risk factors were weaker with a case definition based on self-report compared with other definitions. These results illustrate the potential limitations of case definitions that rely solely on self report or those that incorporate measured glucose values to ascertain undiagnosed cases. Although the ability to identify risk factors of diabetes was consistent for the case definitions studied, tests of novel risk factors may result in different estimates of effect sizes depending on the definition used. PMID- 22247045 TI - Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions. AB - As with other instrumental variable (IV) analyses, Mendelian randomization (MR) studies rest on strong assumptions. These assumptions are not routinely systematically evaluated in MR applications, although such evaluation could add to the credibility of MR analyses. In this article, the authors present several methods that are useful for evaluating the validity of an MR study. They apply these methods to a recent MR study that used fat mass and obesity-associated (FTO) genotype as an IV to estimate the effect of obesity on mental disorder. These approaches to evaluating assumptions for valid IV analyses are not fail safe, in that there are situations where the approaches might either fail to identify a biased IV or inappropriately suggest that a valid IV is biased. Therefore, the authors describe the assumptions upon which the IV assessments rely. The methods they describe are relevant to any IV analysis, regardless of whether it is based on a genetic IV or other possible sources of exogenous variation. Methods that assess the IV assumptions are generally not conclusive, but routinely applying such methods is nonetheless likely to improve the scientific contributions of MR studies. PMID- 22247046 TI - Passive cigarette smoke exposure during various periods of life, genetic variants, and breast cancer risk among never smokers. AB - The association between passive cigarette smoke exposure and breast cancer risk is inconclusive and may be modified by genotype. The authors investigated lifetime passive cigarette smoke exposures, 36 variants in 12 carcinogen metabolizing genes, and breast cancer risk among Ontario, Canada, women who had never smoked (2003-2004). DNA (saliva) was available for 920 breast cancer cases and 960 controls. Detailed information about passive smoke exposure was collected for multiple age periods (childhood, teenage years, and adulthood) and environments (home, work, and social). Adjusted odds ratios and 95% confidence intervals were estimated by multivariable logistic regression, and statistical interactions were assessed using the likelihood ratio test. Among postmenopausal women, most associations between passive smoke and breast cancer risk were null, whereas among premenopausal women, nonsignificant positive associations were observed. Significant interactions were observed between certain types of passive smoke exposure and genetic variants in CYP2E1, NAT2, and UGT1A7. While these interactions were statistically significant, the magnitudes of the effect estimates were not consistent or easily interpretable, suggesting that they were perhaps due to chance. Although the results of this study were largely null, it is possible that premenopausal women exposed to passive smoke or carrying certain genetic variants may be at higher risk of breast cancer. PMID- 22247047 TI - Anti-Mullerian hormone: a potential new tool in epidemiologic studies of female fecundability. AB - The objective of the present commentary is to suggest that epidemiologists explore the use of anti-Mullerian hormone (AMH) as a new measurement tool in fecundability studies. The authors briefly summarize the advantages and limitations of the 3 current approaches to studies of fecundability. All 3 approaches involve the collection of time-to-pregnancy or attempt-time data, and most are limited to participants who plan their pregnancies. AMH is produced by ovarian follicles during their early growth stages and is measured clinically to assess ovarian reserve (the number of remaining oocytes). Unlike time to pregnancy, serum AMH level can be assessed regardless of pregnancy-attempt status. Measurements are not significantly affected by phase of the menstrual cycle, oral contraceptive use, or early pregnancy. The authors suggest that AMH measurement can be a valuable addition to traditionally designed fecundability studies. In addition, this hormone should be investigated as an independent measure of fecundability in studies that focus on exposures hypothesized to target the ovary. PMID- 22247048 TI - Influenza and community-acquired pneumonia interactions: the impact of order and time of infection on population patterns. AB - Discoveries made during the 1918 influenza A pandemic and reports of severe disease associated with coinfection during the 2009 hemagglutinin type 1 and neuraminidase type 1 (commonly known as H1N1 or swine flu) pandemic have renewed interest in the role of coinfection in disease pathogenesis. The authors assessed how various timings of coinfection with influenza virus and pneumonia-causing bacteria could affect the severity of illness at multiple levels of interaction, including the biologic and population levels. Animal studies most strongly support a single pathway of coinfection with influenza inoculation occurring approximately 7 days before inoculation with Streptococcus pneumoniae, but less examined pathways of infection also may be important for human disease. The authors discussed the implications of each pathway for disease prevention and what they would expect to see at the population level if there were sufficient data available. Lastly, the authors identified crucial gaps in the study of timing of coinfection and proposed related research questions. PMID- 22247050 TI - Water-silicone separated volumetric MR acquisition for rapid assessment of breast implants. AB - PURPOSE: To develop a robust T(2) -weighted volumetric imaging technique with uniform water-silicone separation and simultaneous fat suppression for rapid assessment of breast implants in a single acquisition. MATERIALS AND METHODS: A three-dimensional (3D) fast spin echo sequence that uses variable refocusing flip angles was combined with a three-point chemical-shift technique (IDEAL) and short tau inversion recovery (STIR). Phase shifts of -pi/6, +pi/2, and +7pi/6 between water and silicone were used for IDEAL processing. For comparison, two dimensional images using 2D-FSE-IDEAL with STIR were also acquired in axial, coronal, and sagittal orientations. RESULTS: Near-isotropic (true spatial resolution-0.9 * 1.3 * 2.0 mm(3) ) volumetric breast images with uniform water silicone separation and simultaneous fat suppression were acquired successfully in clinically feasible scan times (7:00-10:00 min). The 2D images were acquired with the same in-plane resolution (0.9 * 1.3 mm(2) ), but the slice thickness was increased to 6 mm with a slice gap of 1 mm for complete coverage of the implants in a reasonable scan time, which varied between 18:00 and 22:30 min. CONCLUSION: The single volumetric acquisition with uniform water and silicone separation enables images to be reformatted into any orientation. This allows comprehensive assessment of breast implant integrity in less than 10 min of total examination time. PMID- 22247049 TI - Smoking and risk of incident psoriasis among women and men in the United States: a combined analysis. AB - The authors evaluated the association between smoking and the incidence of psoriasis among 185,836 participants from a cohort of older women (the Nurses' Health Study, 1996-2008), a cohort of younger women (the Nurses' Health Study II, 1991-2005), and a cohort of men (Health Professionals' Follow-up Study, 1986 2006). Information on smoking was collected biennially during follow-up. The authors identified a total of 2,410 participants with incident psoriasis. Compared with never smokers, past smokers had a relative risk of incident psoriasis of 1.39 (95% confidence interval (CI): 1.27, 1.52) and current smokers had a relative risk of 1.94 (95% CI: 1.64, 2.28). For current smokers who smoked 1-14 cigarettes/day, the relative risk was 1.81 (95% CI: 1.38, 2.36); for those who smoked 15-24 cigarettes/day, the relative risk was 2.04 (95% CI: 1.68, 2.47); and for those who smoked 25 or more cigarettes/day, the relative risk was 2.29 (95% CI: 1.74, 3.01). There was a trend toward an increased risk of psoriasis with increasing pack-years or duration of smoking (P(trend) < 0.0001). The risk was highest among smokers who had 65 or more pack-years of smoking (relative risk = 2.72, 95% CI: 2.05, 3.60) and among those with a smoking duration of 30 or more years (relative risk = 1.99, 95% CI: 1.75, 2.25). The authors observed a graded reduction of risk with an increase in time since smoking cessation (P(trend) <0.0001). In this study, smoking was found to be an independent risk factor for psoriasis in both women and men. Psoriasis risk was particularly augmented for heavy smokers and persons with longer durations of smoking. PMID- 22247051 TI - Variation of the glycosylation pattern in MUC1 glycopeptide BSA vaccines and its influence on the immune response. PMID- 22247052 TI - Searching for Eve: basal metazoans and the evolution of multicellular complexity. PMID- 22247053 TI - Ascending gustatory pathways to the telencephalon in goldfish. AB - Ascending pathways to the telencephalon from the secondary gustatory nucleus (SGN), preglomerular tertiary gustatory nucleus (pTGN), and medial preglomerular nucleus (PGm) were examined by tract-tracing experiments in goldfish Carassius auratus. Tracer injections to the SGN suggest the presence of direct ascending pathways to the supracommissural and the dorsal parts of the ventral telencephalic area, and the medial part of the dorsal telencephalic area (Dm), restricted to its ventral region. The SGN experiments also suggest projections to the pTGN and PGm, and several neuronal types in the primary gustatory centers were newly found to give rise to ascending fibers to the SGN. Injections to the pTGN suggest reciprocal connections of the nucleus with the dorsal region of the Dm (dDm). Injections to the PGm resulted in labeled cells in the dorsal part of the SGN, the secondary general visceral nucleus, and the posterior part of the dorsal telencephalic area, suggesting that this preglomerular nucleus receives gustatory, general visceral, and olfactory inputs. Fibers labeled from the PGm terminated in the central part of the dorsal telencephalic area and the dDm; the latter region contained many labeled somata. The terminal zone of PGm fibers in the dDm is located laterally adjacent to that from the pTGN. Injection experiments to the pTGN and PGm also suggest connections of these nuclei with the inferior lobar nuclei and torus lateralis. Based on the results of the present as well as recent studies, an updated map is provided that shows by and large distinct sensory representation within the goldfish dorsal telencephalic area. PMID- 22247054 TI - Revascularization of carotid artery stenosis - a brief update on current evidence. AB - Major and long-awaited trials comparing carotid endarterectomy (CEA) with carotid stenting (CAS) were published in recent years. Both, ICSS and CREST, documented a higher rate of periprocedural stroke and death in CAS, in particular in elderly patients, thereby confirming the results of prior trials and meta-analyses. In CREST, the composite endpoint included myocardial infarction (MI), which led to statistical equipoise between the treatment arms due to a higher rate of MI with CEA. However, whether MI is a relevant endpoint in trials for stroke prevention remains debatable. The stroke preventive benefit seems equally sustained after CEA and CAS, although the significance of restenoses, whose frequency is twice as high after CAS compared to CEA, is unclear in the long range. Emergent CEA in patients with clinically unstable carotid stenosis is associated with a very high complication risk, but the optimal treatment strategy for these patients remains to be elucidated. Recent evidence indicates a very low stroke risk of asymptomatic stenoses with intensive medical treatment, rendering revascularization almost unnecessary. The detection of microembolic signals on transcranial Doppler and rapid stenosis progression by duplex sonography might help to identify patients with higher stroke risk in whom revascularization is warranted. PMID- 22247055 TI - Duration of anticoagulation after venous thrombosis. AB - Venous thromboembolism (VTE) is a multicausal disease which tends to recur. Recurrence can be prevented by anticoagulant treatment albeit at the cost of bleeding. Deciding on the optimal duration of anticoagulation is based on balancing the risk of recurrence and of bleeding in case anticoagulation is continued. Patients with VTE provoked by a transient risk factor have a low risk of recurrence and stopping anticoagulation after 3 months is recommended because the risk of bleeding likely outweighs the risk of recurrence. In patients with unprovoked VTE recurrence is high and indefinite anticoagulation should be considered. However, the majority of these patients will not suffer recurrence but thus far safe identification of low or high patients risk is not possible. Despite considerable advances in the identification of new risk factors for (recurrent) VTE, predicting the risk of recurrence in an individual patient remains a challenge. Measuring D-Dimer as a global coagulation markers and the use of prediction models that integrate clinical characteristics and laboratory markers are the most promising approaches to improve risk assessment and to optimize the duration of anticoagulation. New oral anticoagulants have been studied for treatment of patients with VTE. However, more data on the bleeding risk during extended thromboprophylaxis are needed to decide which patients may indeed benefit from these novel agents. PMID- 22247056 TI - Qualitative and quantitative assessment of nailfold capillaries by capillaroscopy in healthy volunteers. AB - BACKGROUND: Nailfold capillaroscopy (NVC) is a diagnostic tool particularly useful in the differential diagnosis of rheumatic and connective tissue diseases. Although successfully applied since many years, little is known about prevalence and distribution of NVC changes in healthy individuals. PROBANDS AND METHODS: NVC was performed in 120 individuals (57 men and 63 women; age 18 to 70 years) randomly selected according to predefined age and sex strata. Diseases associated with NVC changes were excluded. The nailfolds of eight fingers were assessed according to standardized procedures. A scoring system was developed based on the distribution of the number of morphologically deviating capillaries, microhaemorrhages, and capillary density. RESULTS: Only 18 individuals (15 %) had no deviation in morphology, haemorrhages, or capillary density on any finger. Overall 67 % had morphological changes, 48 % had microhaemorrhages, and 40 % of volunteers below 40 years of age and 18 % above age 40 had less than 8 capillaries/mm. Among morphological changes tortous (43 %), ramified (47 %), and bushy capillaries (27 %) were the most frequently altered capillary types. A semiquantitative scoring system was developed in such a way that a score above 1 indicates an extreme position (above the 90th percentile) in the distribution of scores among healthy individuals. CONCLUSIONS: Altered capillaries occur frequently among healthy individuals and should be interpreted as normal unless a suspicious increase in their frequency is determined by reference to the scoring system. Megacapillaries and diffuse loss of capillaries were not found and seem to be of specific diagnostic value. PMID- 22247057 TI - Clinical application and technique of 64-slice spiral CT subtraction angiography in head and neck. AB - BACKGROUND: To discuss the technique of 64-slice spiral CT subtraction angiography (64-SCTSA) in head and neck, and evaluate its clinical application. PATIENTS AND METHODS: 84 patients suspected of head-neck vascular diseases were examined with 64-SCTSA. The examination techniques, image quality and clinical application were retrospectively analyzed, and the diagnoses of 64-SCTSA were compared with those of surgery or DSA. RESULTS: Eighty-four subjects were successfully examined with 64-SCTSA, whose scanning and imaging parameters are effective. Image quality was excellent in 51 cases (60.7 %), good in 29 (34.5 %) and acceptable in 4 (4.8 %). In the 84 subjects, 79 cases were found abnormal in blood vessel (58 in head and 21 in neck), of which 57 were confirmed by surgical operation or digital subtraction angiography (DSA). CONCLUSIONS: 64-SCTSA is a feasible technique with satisfactory image quality and has the advantages of showing the lesions of vasculature without shelter from bone. It can improve the diagnostic accuracy in head-neck vascular diseases. PMID- 22247058 TI - Reduction of small infrarenal abdominal aortic aneurysm expansion rate by statins. AB - BACKGROUND: To evaluate the effect of statins on the annual expansion rate (ER) of small infrarenal abdominal aortic aneurysms (AAA). PATIENTS AND METHODS: All patients under regular surveillance for small AAA between January 2000 and September 2007, in the Department of Angiology, Lausanne University Hospital, were included. Inclusion criteria were baseline abdominal aortic diameter between 25 and 55 mm, at least two measurements of AAA diameter and a minimum follow up of 6 months. Patients with Marfan disease, infectious or inflammatory AAA, and patients with prior AAA repair were excluded. The influence of statin use and other factors on ER were examined by bivariate and multivariate analysis. RESULTS: Among 589 patients who underwent an abdominal aorta evaluation, 94 patients (89 % men, mean age 69.1 years) were finally included in the analysis. Baseline AAA size was 39.9 +/- 7.7 mm (mean+/-SE) and 48.7 +/- 8.4 mm at end of follow-up. Patients had a regular aneurysm size assessment during 38.5 +/- 27.7 months. Mean ER was 3.59 mm/y (+/- 2.81). The 50 patients who were treated with statin during the study period had a lower ER compared to the 44 controls (2.91 vs 4.37 mm/year, p = 0.01). CONCLUSIONS: This study confirms the considerable individual variations in the AAA expansion rate, and emphasizes the need for regular aortic diameter assessments. In this study, patients treated with statin demonstrate a significant decrease in the ER compared to controls. This finding need to be evaluated in prospective interventional studies powered to demonstrate the potential benefit of statin treatment. PMID- 22247059 TI - Erythromelalgia: Incidence and clinical experience in a single centre in Sweden. AB - BACKGROUND: Erythromelalgia (EM) incidence has not been well studied and there are only two studies published on this subject as far as we know. The aims are to study the incidence of this rare condition in the south of Sweden, to report the clinical experience from a single centre including characterisation of comorbidity and to report on prognosis. PATIENTS AND METHODS: Retrospective study of a population-based analysis of data from the southernmost part of Sweden corresponding to the median age of the patients (Statistics Sweden). The diagnosis of EM is based on the medical record reflecting the triad of redness, burning pain and increased temperature of the feet or hands or both. We evaluated the presence or absence of EM triad by recording the history, physical examination, laboratory analysis, cold provocation test and laser Doppler imaging, and by searching for any confounding disease in cases of suspected EM. RESULTS: During a 10.5 year period we clinically identified 27 patients with EM. Median age was 49 [IQR (34 - 68)] years, 19 (70 %) were women. The mean delay from the onset of the symptoms to the time of diagnosis was 4.5 (SD +/- 3.9) years. Gender and age adjusted incidence of EM for our region was calculated to be 0.36 per 100 000 persons per year. Three patients developed intraabdominal cancer during the follow up, but there was no mortality directed related to EM. CONCLUSIONS: The overall population-based incidence of erythromelalgia was 0.36 per 100 000 which is identical with a previous report in a Scandinavian population. PMID- 22247060 TI - Mid-term outcome after endovascular therapy in the superficial femoral and popliteal artery using long stents. AB - BACKGROUND: Peripheral artery disease (PAD) affecting the femoropopliteal artery is treated by endovascular interventions [2, 5, 13] increasingly. Aim of the study was to evaluate mid-term efficacy and patency of long stents in the superficial femoral and popliteal artery. PATIENTS AND METHODS: Between September 2006 and September 2007 103 patients received 128 stents for endovascular treatment of femoropopliteal vascular stenosis or occlusion. Clinical and hemodynamic parameters were collected. Risk factors, popliteal involvement and TASC classification, were documented and evaluated. RESULTS: Immediate outcome was satisfactory with a technical success rate of 100 %. After a mean follow-up period of 21 months, primary patency was 83.6 %. Potential risk factor analysis for restenosis and fracture demonstrated hypertension to have borderline significance (P = 0.06). In normotensive patients no restenosis occurred. Further pre-conditions, e.g. smoking, metabolic syndrome, age, gender and previous intervention did not show any influence on restenosis or stent fracture. TASC C and D lesion had similar patency rates compared to TASC A and B lesions. Most of the restenoses (13 out of 16) were observed within the first six months of follow up. Six stent fracture were observed (4.7 %). CONCLUSIONS: Long stents had convincing results after endovascular treatment of the femoropopliteal PAD. The used stent was an efficacious endovascular tool for long athersclerotic lesions in the superficial femoral and popliteal artery. Fracture rate was low with an incidence of 4.7 %. Most restenoses occurred within the first six months so that careful follow-up would be necessary. PMID- 22247061 TI - Primary splenic angiosarcoma. AB - Primary angiosarcoma of the spleen is a very rare but very aggressive soft tissue sarcoma due to early dissemination. The outcome of this disease is typically dismal with a mean survival of one to two years. However, our here presented case remained uncommonly symptom-free for nine years after splenectomy alone at the early phase of the disease. PMID- 22247062 TI - Unusual abdominal aneurysms in a patient after kidney transplantation treated by endovascular technique. AB - While abdominal aortic aneurysms are quite common, visceral aneurysms are a seldomly diagnosed vascular pathology. Aneurysms of renal arteries, abdominal aorta and iliac arteries seem to be very rare. We present a patient after renal transplantation with aneurysms of both stumps of the renal arteries, abdominal aortic aneurysm and aneurysms of common iliac arteries. Because of the symptomatic course, the patient required urgent treatment. A successful endovascular procedure was performed. Follow-up imaging did not reveal any complications. PMID- 22247063 TI - Incidental diagnosis of idiopathic gonadal vein thrombosis. AB - Gonadal vein thrombosis is a rare but well recognized entity which predominantly occurs in the post partum period. It is also associated with gynecological malignancies, cesarean deliveries, abortions, hypercoagulability and pelvic inflammatory disease. Prompt diagnosis and treatment is warranted to avoid serious complications. We report the rare case of idiopathic, unprovoked gonadal vein thrombosis. PMID- 22247065 TI - Negative effects of ADAMTS-7 and ADAMTS-12 on endplate cartilage differentiation. AB - The roles of ADAMTS-7 and ADAMTS-12 in disc degeneration have not been previously examined. The purpose of this study was to examine the expression of ADAMTS-7 and ADAMTS-12 in the endplate cells isolated from patients with degenerative disc disease and to see whether they are associated with the pathological change of endplate. Sixty-four degenerated lumbar endplate specimens were obtained from the patients with degenerative disc disease categorized as type Modic I or II in magnetic resonance imaging (MRI) and 12 nondegenerative specimens as control (vertebra burst fracture patients without degenerative change in MRI) during surgical procedures. The expression of ADAMTS-7 and ADAMTS-12 was examined by real-time PCR and Western blotting. A statistically significant increase in mRNA expression of ADAMTS-7 and ADAMTS-12 was observed in the endplate cells in degenerative discs compared with nondegenerative discs. The corresponding protein levels of ADAMTS-7 and ADAMTS-12 had the same expression patterns. Moreover, ADAMTS-7 and ADAMTS-12 down-regulated the expression of Col II, Sox9, and Col X the marker genes for chondrogenesis. Our results indicate that ADAMTS-7 and ADAMTS-12 appear to be potent negative regulators of endplate cartilage development. PMID- 22247066 TI - Search for a gene responsible for Floating-Harbor syndrome on chromosome 12q15q21.1. AB - Floating-Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7 Mb de novo 12q15-q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array-CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high-throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15-q21.1 microdeletions argue in favor of the phenocopy hypothesis. PMID- 22247068 TI - Mesoporous silicon nitride for reversible CO2 capture. PMID- 22247070 TI - Fracture healing in protease-activated receptor-2 deficient mice. AB - Protease-activated receptor-2 (PAR-2) provides an important link between extracellular proteases and the cellular initiation of inflammatory responses. The effect of PAR-2 on fracture healing is unknown. This study investigates the in vivo effect of PAR-2 deletion on fracture healing by assessing differences between wild-type (PAR-2(+/+)) and knock-out (PAR-2(-/-)) mice. Unilateral mid shaft femur fractures were created in 34 PAR-2(+/+) and 28 PAR-2(-/-) mice after intramedullary fixation. Histologic assessments were made at 1, 2, and 4 weeks post-fracture (wpf), and radiographic (plain radiographs, micro-computed tomography (uCT)) and biomechanical (torsion testing) assessments were made at 7 and 10 wpf. Both the fractured and un-fractured contralateral femur specimens were evaluated. Polar moment of inertia (pMOI), tissue mineral density (TMD), bone volume fraction (BV/TV) were determined from uCT images, and callus diameter was determined from plain radiographs. Statistically significant differences in callus morphology as assessed by uCT were found between PAR-2(-/-) and PAR-2(+/+) mice at both 7 and 10 wpf. However, no significant histologic, plain radiographic, or biomechanical differences were found between the genotypes. The loss of PAR-2 was found to alter callus morphology as assessed by uCT but was not found to otherwise effect fracture healing in young mice. PMID- 22247067 TI - Secreted proteins as a fundamental source for biomarker discovery. AB - The proteins secreted by various cells (the secretomes) are a potential rich source of biomarkers as they reflect various states of the cells at real time and at given conditions. To have accessible, sufficient and reliable protein markers is desirable as they mark various stages of disease development and their presence/absence can be used for diagnosis, prognosis, risk stratification and therapeutic monitoring. As direct analysis of blood/plasma, a common and noninvasive patient screening method, can be difficult for candidate protein biomarker identification, the alternative/complementary approaches are required, one of them is the analysis of secretomes in cell conditioned media in vitro. As the proteins secreted by cells as a response to various stimuli are most likely secreted into blood/plasma, the identification and pre-selection of candidate protein biomarkers from cell secretomes with subsequent validation of their presence at higher levels in serum/plasma is a promising approach. In this review, we discuss the proteins secreted by three progenitor cell types (smooth muscle, endothelial and cardiac progenitor cells) and two adult cell types (neonatal rat ventrical myocytes and smooth muscle cells) which can be relevant to cardiovascular research and which have been recently published in the literature. We found, at least for secretome studies included in this review, that secretomes of progenitor and adult cells overlap by 48% but the secretomes are very distinct among progenitor cell themselves as well as between adult cells. In addition, we compared secreted proteins to protein identifications listed in the Human Plasma PeptideAtlas and in two reports with cardiovascular related proteins and we performed the extensive literature search to find if any of these secreted proteins were identified in a biomarker study. As expected, many proteins have been identified as biomarkers in cancer but 18 proteins (out of 62) have been tested as biomarkers in cardiovascular diseases as well. PMID- 22247069 TI - Hepatoma-derived growth factor regulates breast cancer cell invasion by modulating epithelial--mesenchymal transition. AB - Hepatoma-derived growth factor (HDGF) participates in tumourigenesis but its role in breast cancer is unclear. We set out to elucidate the expression profile and function of HDGF during breast carcinogenesis. Immunoblot and immunohistochemical studies revealed elevated HDGF expression in human breast cancer cell lines and tissues. Nuclear HDGF labelling index was positively correlated with tumour grade, stage and proliferation index, but negatively correlated with survival rate in breast cancer patients. HDGF over-expression was associated with lymph node metastasis and represented an independent prognostic factor for tumour recurrence. Gene transfer studies were performed to elucidate the influence of cellular HDGF level on the malignant behaviour and epithelial-mesenchymal transition (EMT) of breast cancer cells. Adenovirus-mediated HDGF over-expression stimulated the invasiveness and colony formation of MCF-7 cells. Moreover, HDGF over-expression promoted breast cancer cell EMT by E-cadherin down-regulation and vimentin up-regulation. Conversely, HDGF knockdown by RNA interference in MDA-MB 231 cells attenuated the malignant behaviour and elicited EMT reversal by enhancing E-cadherin expression while depleting vimentin expression. Because HDGF is a secreted protein, we evaluated the cellular function of recombinant HDGF and found that exogenously supplied HDGF enhanced the invasiveness of breast cancer cells by down-regulating E-cadherin and up-regulating vimentin at transcriptional and translational levels. In contrast, blockade of HDGF secretion with an HDGF antibody inhibited the malignant behaviours and EMT. Finally, exogenous HDGF partially reversed benzyl isothiocyanate (BITC)-induced EMT suppression. HDGF over-expression may exert a prognostic role for tumour metastasis and recurrence in breast cancer by modulating EMT. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 22247071 TI - c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104. AB - Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic proteins 2 (BMP2). Mitogen-activated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other kinase of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first showed that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then showed that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain of-function, such as enforced expression of a constitutively active JNK1 (CA JNK1). Most importantly, we showed that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type (WT) Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation. PMID- 22247072 TI - Time course study on the effects of iodinated contrast medium on intrarenal water transport function using diffusion-weighted MRI. AB - PURPOSE: To assess the effects of intravenous-injected iodinated contrast medium (CM) on intrarenal water diffusion using noninvasive diffusion-weighted MRI (DW MRI). MATERIALS AND METHODS: Ten New Zealand White rabbits were randomized to receive a 6 mL/kg body weight intravenous injection of clinically used iopamidol 370 (n = 7) or an equivalent amount of 0.9% physiological saline (n = 3). A sequential DW-MRI was performed to estimate the intrarenal apparent diffusion coefficient (ADC) at 24 h before and 1 h, 24 h, 48 h, and 72 h after administration. RESULTS: Iopamidol produced a progressive ADC reduction in inner stripes of the renal outer medulla (IS) by 13.92% (P = 0.05) at 1 h, 17.52% (P = 0.02) at 24 h, 20.23% (P = 0.01) at 48 h and 16.31% (P = 0.04) at 72 h after injection. Cortical ADC was decreased by 14.14% (P = 0.01) at 48 h and 14.12% (P = 0.01) at 72 h after injection. Iopamidol produced slight decrease of ADCs in outer stripes of the outer medulla (OS) and inner medulla (IM) of kidney but without statistical difference. In control group, no significant ADC changes was observed in each anatomic compartment due to saline injection (P > 0.05). CONCLUSION: As demonstrated by DW-MRI, intravenous iopamidol injection resulted in a successive reduction of intrarenal water diffusion, particularly in IS of kidney. This MR technique may be used as a noninvasive tool to perform a time course study of the pathogenesis associated with contrast-induced nephropathy (CIN). PMID- 22247073 TI - Conversion of cysteine into dehydroalanine enables access to synthetic histones bearing diverse post-translational modifications. PMID- 22247074 TI - A missed oesophageal foreign body. PMID- 22247075 TI - Rapid diagnosis of ectopic pregnancy. PMID- 22247076 TI - Vomiting after head injury: a reminder of traumatic pneumocephalus. PMID- 22247077 TI - To label or not to label: applications of quantitative proteomics in neuroscience research. AB - Proteomics has provided researchers with a sophisticated toolbox of labeling based and label-free quantitative methods. These are now being applied in neuroscience research where they have already contributed to the elucidation of fundamental mechanisms and the discovery of candidate biomarkers. In this review, we evaluate and compare labeling-based and label-free quantitative proteomic techniques for applications in neuroscience research. We discuss the considerations required for the analysis of brain and central nervous system specimens, the experimental design of quantitative proteomic workflows as well as the feasibility, advantages, and disadvantages of the available techniques for neuroscience-oriented questions. Furthermore, we assess the use of labeled standards as internal controls for comparative studies in humans and review applications of labeling-based and label-free mass spectrometry approaches in relevant model organisms and human subjects. Providing a comprehensive guide of feasible and meaningful quantitative proteomic methodologies for neuroscience research is crucial not only for overcoming current limitations but also for gaining useful insights into brain function and translating proteomics from bench to bedside. PMID- 22247078 TI - Whorled hairless nevus of the scalp, linear hyperpigmentation, and telangiectatic nevi of the lower limbs: a novel variant of the "phacomatosis complex". AB - The term "phacomatosis" refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded. PMID- 22247079 TI - Molecular structure and electronic state of the dibenzo[a,e]pentalene anion radical. PMID- 22247080 TI - Parallel excitation for B-field insensitive fat-saturation preparation. AB - Multichannel transmission has the potential to improve many aspects of MRI through a new paradigm in excitation. In this study, multichannel transmission is used to address the effects that variations in B(0) homogeneity have on fat saturation preparation through the use of the frequency, phase, and amplitude degrees of freedom afforded by independent transmission channels. B(1) homogeneity is intrinsically included via use of coil sensitivities in calculations. A new method, parallel excitation for B-field insensitive fat saturation preparation, can achieve fat saturation in 89% of voxels with M(z) <= 0.1 in the presence of +/- 4 ppm B(0) variation, where traditional CHESS methods achieve only 40% in the same conditions. While there has been much progress to apply multichannel transmission at high field strengths, particular focus is given here to application of these methods at 1.5 T. PMID- 22247081 TI - Evaluation of lymph node metastases: comparison of gadofluorine M-enhanced MRI and diffusion-weighted MRI in a rabbit VX2 rectal cancer model. AB - PURPOSE: To compare the diagnostic performance of a diffusion-weighted imaging (DWI) dataset and a gadofluorine M-enhanced imaging dataset for identifying lymph node (LN) metastases in a rabbit rectal cancer model. MATERIALS AND METHODS: VX2 carcinomas were injected into the rectum of 26 rabbits. Four weeks later, T2 weighted imaging (T2WI), pre-T1WI, DWI, and post-T1WI were performed. Two radiologists independently reviewed the DWI set (T2WI, pre-T1WI, DWI) and the gadofluorine M set (T2WI, pre- and post-T1WI) and recorded their confidence scores for LN metastasis on a per-LN basis. Receiver operating characteristic (ROC) analysis was performed to compare the area under the ROC curve (A(z) ) of the two imaging sets. Histopathologic results were used as the reference standard. RESULTS: The A(z) and sensitivity of the gadofluorine M set were comparable to those of the DWI set (A(z) , for reader 1, 0.849, 0.829, P = 0.571; for reader 2, 0.923, 0.876, P = 0.212; sensitivity, for reader 1, 97%, 97%; for reader 2, 97%, 92%, P = 0.304). The specificity of the former was greater than that of the latter (for reader 1, 65%, 53%, P = 0.0003; for reader 2, 81%, 68%, P = 0.01). CONCLUSION: Gadofluorine M-enhanced images provided greater specificity than DWI for identifying LN metastases, whereas the A(z) and sensitivity of the former were comparable to those of the latter. PMID- 22247082 TI - Increased physical activity is associated with enhanced development of peak bone mass in men: a five-year longitudinal study. AB - Data supporting physical activity guidelines to optimize bone development in men is sparse. Peak bone mass is believed to be important for the risk of osteoporosis later in life. The objective of this study was to determine if an increased amount of physical activity over a 5-year period was associated with increased bone mineral content (BMC), areal (aBMD) and volumetric (vBMD) bone mineral density, and a favorable development of cortical bone size in young adult men. The original 1068 young men, initially enrolled in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study, were invited to participate in the longitudinal study, and a total of 833 men (78%), 24.1 +/- 0.6 years of age, were included in the 5-year follow-up. A standardized self-administered questionnaire was used to collect information about patterns of physical activity at both the baseline and 5-year follow-up visits. BMC and aBMD were measured using dual energy X-ray absorptiometry, whereas vBMD and bone geometry were measured by peripheral quantitative computed tomography. Increased physical activity between the baseline and follow-up visits was associated with a favorable development in BMC of the total body, and aBMD of the lumbar spine and total hip (p < 0.001), as well as with development of a larger cortex (cortical cross sectional area), and a denser trabecular bone of the tibia (p < 0.001). In conclusion, increased physical activity was related to an advantageous development of aBMD, trabecular vBMD and cortical bone size, indicating that exercise is important in optimizing peak bone mass in young men. PMID- 22247083 TI - A highly porous and robust (3,3,4)-connected metal-organic framework assembled with a 90 degrees bridging-angle embedded octacarboxylate ligand. PMID- 22247084 TI - Dissecting cell death with proteomic scalpels. AB - Programmed cell deaths (PCD), including apoptosis, autophagy and programmed necrosis, are genetically determined, complex processes in multi-cellular organisms. Problems with the regulation of PCD have been implicated in a number of diseases including myocardial infarction, cancer and autoimmune disease. As a result, the investigation on PCD regulation has stirred considerable interest. In the past decades, many PCD-involved proteins had been identified as being modulated by post-translational mechanisms, including post-translational modification, protein-protein interactions and protein cleavage, which fall precisely within the range of proteomic analysis. Contemporary quantitative proteomics, interactomics, PTMomics, degradomics, chemical proteomics and pharmacoproteomics have been quickly applied in the field of PCD research, and possess the potential to be the driving forces of the field. This review attempts to highlight some of the major achievements in the application of proteomics in PCD research to trigger further thinking and application. PMID- 22247086 TI - Early intervention in psychosis: evidence, evidence gaps, criticism, and confusion. PMID- 22247087 TI - The truth, and nothing but the truth, about early intervention in psychosis. PMID- 22247088 TI - In it together: physical health and well-being for people with mental illness. PMID- 22247089 TI - Psychiatrists and termination of pregnancy: clinical, legal and ethical aspects. AB - OBJECTIVE: To provide practical guidance for psychiatrists asked to conduct an assessment of a woman requesting a termination of pregnancy. METHOD: The law relevant to termination of pregnancy in each of the Australian states and territories and in New Zealand was synthesised and reviewed, as was the available literature around the key roles for the psychiatrist in these settings. RESULTS: Little is known about the rates of and reasons for terminations in Australasia. The 'lawfulness' of termination varies between jurisdictions and might require a consideration of the woman's mental health. When psychiatrists are asked to assist, their roles can be divided into: assessment and management of the woman's mental health, assessment of the woman's capacity to consent to the termination, assessment of the impact of having a termination or not having a termination upon the woman's mental health, assistance in determining the lawfulness of the proposed termination and, finally, support of the obstetric team providing terminations. CONCLUSIONS: The psychiatric assessment of a woman requesting a termination of pregnancy requires an understanding of the ethical issues, the relevant law and a clinical framework within which the psychiatrist can delineate his or her various roles. PMID- 22247090 TI - Australian youth still have limited awareness of headspace: results from a national survey. AB - OBJECTIVES: The aim of this paper is to assess Australian young people's awareness of mental health services available for their age group. Of particular interest was awareness of headspace, which was created in 2006 to provide youth oriented mental health services, and has expanded to 30 centres nationally in 5 years. METHOD: In 2011, a telephone interview was conducted with a national sample of 3021 Australians aged between 15 and 25 years. Participants were asked questions about awareness of mental health organizations, where they would seek help for themselves and how they would assist a peer with a mental health problem. RESULTS: There were very low frequencies of spontaneous mentions of headspace as a mental health organization, or as a service where respondents would seek help for themselves or refer a peer to. However, when prompted, about half of respondents recognized headspace as a mental health organization. Living within a headspace service area predicted better recognition of headspace. However, past-year psychological distress was unrelated to recognition of headspace as a mental health organization. CONCLUSIONS: In order to reach them more effectively, young people need to be aware of youth-oriented services that are available to them and their peers. Awareness campaigns need to be targeted to the subgroups of young people who have the greatest need for headspace services, namely those with recent mental health problems. PMID- 22247091 TI - Childhood trauma increases the risk of post-traumatic stress disorder in response to first-episode psychosis. AB - OBJECTIVE: To investigate the relationship between childhood trauma, post traumatic stress symptoms due to the experience of childhood trauma, and post traumatic stress symptoms due to the experience of psychosis. METHOD: The current study assessed childhood trauma and post-traumatic stress disorder (PTSD) symptoms as a result of both childhood trauma and psychosis using the Impact of Events Scale - Revised, in a group of 36 people with first-episode psychosis. RESULTS: Reported rates of clinical level post-psychotic PTSD symptoms, childhood trauma and childhood trauma-related clinical level PTSD symptoms were 47% (95% CI 31-64%), 64% (95% CI 48-80%) and 39% (95% CI 23-55%), respectively. Reporting childhood trauma increased the risk of developing post-psychosis PTSD 27-fold (95% CI 2.96-253.80, p = 0.01). Having childhood trauma-related PTSD increased the risk of developing post-psychosis PTSD 20-fold (95% CI 3.38-123.25, p = 0.01). These risks were not explained by illness factors such as duration of untreated psychosis, age of onset or severity of psychotic symptoms. Those without post-psychotic PTSD symptoms at clinical levels were unlikely to report childhood trauma (6%; 95% CI 3-8%). CONCLUSIONS: These results suggest the cognitive, social and biological consequences of childhood trauma can prevent effective recovery from the trauma of acute first-episode psychosis resulting in post-psychotic PTSD. Treatment strategies for post-psychotic PTSD must address childhood trauma and related PTSD. PMID- 22247092 TI - Risk assessment of self- and other-directed aggression in adolescent psychiatric inpatient units. AB - OBJECTIVE: To examine the predictive validity of unstructured clinical risk assessment and associated risk factors for aggression in predicting self- and other-directed aggression in the first 4 weeks of admission for patients admitted to an Australian adolescent psychiatric inpatient facility. METHOD: A retrospective review of patient records was conducted at the Marian Drummond Adolescent Unit during late 2009 for the period of September 2006 to July 2009. Information collected included admission risk assessment ratings, aggressive incident reports, patient diagnoses, sex and history of aggression and self harming behaviour. RESULTS: A total of 193 adolescents (aged 13-18 years old) were included in retrospective analyses. The hypothesis that unstructured clinical risk assessment would be predictive of self- and other-directed aggression was partially supported. High risk assessment scores were predictive of engagement in other-directed aggression. A history of physical aggression was also found to be predictive of engagement in other-directed aggression; however, it was not as predictive as the risk assessment rating. High risk assessment scores were not predictive of self-directed aggression. A history of engaging in one or more acts of self-harm or suicide was the most predictive of engagement in self-directed aggression during inpatient stay. Female sex also predicted engagement in self-directed aggression. CONCLUSIONS: Based on professional expertise, prior experience and intuition, clinicians are relatively good predictors of other-directed aggression in adolescent inpatient units; however, they are less successful at predicting self-directed aggression in this population. It is possible that, unlike other-directed aggression, self-harming behaviour is heavily dependent on environmental factors and that admission to the inpatient unit removes these triggers from the individual's environment. PMID- 22247093 TI - The Self-Efficacy Questionnaire for Depressed Adolescents: a measure to predict the course of depression in depressed youth. AB - OBJECTIVE: Self-efficacy can be conceptualised as a person's perception of their own ability to produce a desired outcome. Low self-efficacy has been reported to be a mediating variable in developing depression. The Self-Efficacy Questionnaire for Depressed Adolescents (SEQ-DA) is a 12-item inventory, designed to measure self-perceived ability of the young person to cope with depressive symptoms. This paper presents further information on the psychometric properties of the SEQ-DA in a clinical sample of depressed adolescents. METHOD: The SEQ-DA was administered to a clinical sample of 130 adolescents with a depressive disorder at baseline, at the end of 3 months of therapy and 6 months following therapy. A diagnosis of depression was made using the Schedule for Affective Disorders and Schizophrenia for School Aged Children. The ability of the SEQ-DA to identify those adolescents who had a diagnosis of major depressive disorder at baseline, following treatment and at 6-month follow-up was evaluated. Receiver operating characteristic (ROC) analysis of the SEQ-DA in this clinical sample of depressed adolescents was undertaken to establish cut-off scores of the SEQ-DA. RESULTS: The SEQ-DA score at baseline of < 36 and following treatment of < 43 were predictive of a depressive disorder. CONCLUSIONS: The SEQ-DA is a very simple self-report measure that can be used to predict which adolescents treated for depression are likely to remain depressed, thus prompting more intensive treatment and follow-up. PMID- 22247094 TI - The contribution of BDNF and 5-HTT polymorphisms and early life stress to the heterogeneity of major depressive disorder: a preliminary study. AB - OBJECTIVE: Two reported genetic polymorphisms related to the production of brain derived neurotrophic factor (BNDF) and reuptake by the serotonin transporter (5 HTT) appear to contribute to depression in combination with stressful life events. The aim of the current study was to investigate the contribution of early life stress (ELS), BDNF (Val versus Met alleles) and 5-HTT polymorphisms (L versus S alleles) to melancholic (n = 65) and non-melancholic depression (n = 59). METHODS: A mediation approach ((G * G) * E mediation model) was employed to confirm the indirect effects of ELS on the relationship between 5-HTTPLR * BDNF polymorphism combinations and depression subtype. A series of binary logistic regressions were then conducted to determine whether genotype, ELS, and their interaction were able to predict depression subtype. RESULTS: Key findings indicated that BDNF and 5-HTT polymorphisms in combination with ELS contributed to the development of non-melancholic depression. An interaction between BDNF and ELS increased the risk of non-melancholia by 3.327, whereas the interaction between 5-HTT and ELS increased risk by 2.406. CONCLUSION: The results support a role for genetic factors in the development of non-melancholia. The lack of findings in melancholia indicates that other mechanisms may underlie the subtype. Alternatively, null findings may reflect a Type II error associated with a small sample size. Future studies should consider further examination of differential gene-environment interactions for melancholia versus non-melancholia. PMID- 22247095 TI - 'Prodromal' diagnosis of psychosis: Ethical problems in research and clinical practice. PMID- 22247096 TI - 'Prodromal' research and clinical services: the imperative for shared decision making. PMID- 22247097 TI - Risk assessment for aggression in child inpatient mental health units. PMID- 22247098 TI - John Cade (1912-1980). PMID- 22247099 TI - Alopecia areata associated with haloperidol decanoate long-acting injection. PMID- 22247100 TI - Wernicke's encephalopathy confirmed via brain MRI in cancer patient. PMID- 22247101 TI - Amphetamine psychosis and eye autoenucleation. PMID- 22247102 TI - Intolerable fever: a previously unreported side-effect of quetiapine. PMID- 22247104 TI - Detection and classification of contrast-enhancing masses by a fully automatic computer-assisted diagnosis system for breast MRI. AB - PURPOSE: To evaluate a fully automatic computer-assisted diagnosis (CAD) method for breast magnetic resonance imaging (MRI), which considered dynamic as well as morphologic parameters and linked those to descriptions laid down in the Breast Imaging Reporting and Data System (BI-RADS) MRI atlas. MATERIALS AND METHODS: MR images of 108 patients with 141 histologically proven mass-like lesions (88 malignant, 53 benign) were included. The CAD system automatically performed the following processing steps: 3D nonrigid motion correction, detection of lesions by a segmentation algorithm, extraction of multiple dynamic and morphologic parameters, and classification of lesions. As one final result, the lesions were categorized by defining their probability of malignancy; this so-called morpho dynamic index (MDI) ranged from 0%-100%. The results of the CAD system were correlated with histopathologic findings. RESULTS: The CAD system had a high detection rate of the histologically proven lesions, missing only two malignancies of invasive multifocal carcinomas and four benign lesions (three fibroadenomas, one atypical ductal hyperplasia). The 86 detected malignant lesions showed a mean MDI of 86.1% (+/- 15.4%); the mean MDI of the 49 coded benign lesions was 41.8% (+/- 22.0%; P < 0.001). Based on receiver-operating characteristic analysis, the diagnostic accuracy of the CAD system was 93.5%. Using an appropriate cutoff value (MDI 50%), sensitivity was 96.5% combined with specificity of 75.5%. CONCLUSION: The fully automatic CAD technique seems to reliably distinguish between benign and malignant mass-like breast tumors. Observer-independent CAD may be a promising additional tool for the interpretation of breast MRI in the clinical routine. PMID- 22247105 TI - A co-crystal composed of the paramagnetic endohedral metallofullerene La@C82 and a nickel porphyrin with high electron mobility. PMID- 22247106 TI - The Spanish SF-36 in Peru: factor structure, construct validity, and internal consistency. AB - This study assessed the psychometric properties of the SF-36 questionnaire in a sample of 4344 Peruvian people aged 15 to 64 years. Internal consistency reliability was estimated using Cronbach's alpha coefficient, construct validity by known-groups comparison defined with respect to key sociodemographic characteristics, and factor structure by confirmatory factor analysis (CFA) at item level. Cronbach's alpha coefficient for the full questionnaire was 0.82 and ranged between 0.66 and 0.92 by scales. The 8 scales discriminated well between sexes, age, and socioeconomic groups. CFA showed that a model with 8 first-order factors and 2 second-order factors (namely, physical and mental health) was a feasible representation of the SF-36 factor structure and had better fit to data than alternative factor structures. The SF-36 showed appropriate psychometric properties regarding internal consistency, construct validity, and factor structure when tested in Peru. Future studies should focus on testing other psychometric properties of the SF-36, such as convergent and discriminant validity, test-retest reliability, and sensitivity to change. PMID- 22247108 TI - Prevalence of musculoskeletal disorders and physiological stress among adult, male potato cultivators of West Bengal, India. AB - A total of 70 male potato cultivators were selected randomly from the villages of West Bengal, India, to evaluate musculoskeletal disorder (MSD), thermal stress, and physiological stress and were compared with 70 controls from the urban sector of West Bengal. Modified Nordic questionnaire studies and a posture analysis were performed in for the male potato cultivators by the Rapid Entire Body Assessment method. Most of the participants suffered discomfort at different parts of the body, especially in the lower back, knee, ankle, and feet regions. Potato cultivators suffered maximum discomfort during spading, planting seeds, weeding, picking crops, and sprinkling water. Therefore, it can be concluded that prolonged work activity, high repetitiveness, and remaining constantly in an awkward posture for a prolonged period of time may lead to MSDs. This study also revealed that a significant physiological load is exerted on the potato cultivators, as shown by increased heart rates. PMID- 22247107 TI - Association between vision impairment and health among a national cohort of 87,134 Thai adults. AB - To date, more than 300 million people worldwide live with low vision and blindness, imposing social and economic burdens on individuals and families. This study analyzes a cohort of 87 134 Thai adults, reporting odds ratios (ORs) and calculating population attributable fractions (PAFs). PAF estimates the proportion of the disease or condition that would not occur if no one in the population had the risk factor. Approximately 28% and 8% reported having refractive errors and vision impairment not correctable by visual aids. Both types of vision impairment were positively associated with poor self-assessed health (adjusted ORs = 1.23 to 2.03) and poor psychological health (adjusted ORs = 1.13 to 1.63). PAFs show that refractive errors explain 6.1% of poor self assessed health, 3.5% of poor psychological health, and 2.2% of falls in the last year. PAFs for vision impairment not correctable by visual aids explain 7.5%, 4.7%, and 3.1%, respectively. Incorporating early detection and prevention of vision impairment at the primary health care level will contribute to promoting the health of Thais. PMID- 22247109 TI - Fiber fermentability effects on energy and macronutrient digestibility, fecal traits, postprandial metabolite responses, and colon histology of overweight cats. AB - Considering the different potential benefits of divergent fiber ingredients, the effect of 3 fiber sources on energy and macronutrient digestibility, fermentation product formation, postprandial metabolite responses, and colon histology of overweight cats (Felis catus) fed kibble diets was compared. Twenty-four healthy adult cats were assigned in a complete randomized block design to 2 groups of 12 animals, and 3 animals from each group were fed 1 of 4 of the following kibble diets: control (CO; 11.5% dietary fiber), beet pulp (BP; 26% dietary fiber), wheat bran (WB; 24% dietary fiber), and sugarcane fiber (SF; 28% dietary fiber). Digestibility was measured by the total collection of feces. After 16 d of diet adaptation and an overnight period without food, blood glucose, cholesterol, and triglyceride postprandial responses were evaluated for 16 h after continued exposure to food. On d 20, colon biopsies of the cats were collected under general anesthesia. Fiber addition reduced food energy and nutrient digestibility. Of all the fiber sources, SF had the least dietary fiber digestibility (P < 0.05), causing the largest reduction of dietary energy digestibility (P < 0.05). The greater fermentability of BP resulted in reduced fecal DM and pH, greater fecal production [g/(cat * d); as-is], and greater fecal concentration of acetate, propionate, and lactate (P < 0.05). For most fecal variables, WB was intermediate between BP and SF, and SF was similar to the control diet except for an increased fecal DM and firmer feces production for the SF diet (P < 0.05). Postprandial evaluations indicated reduced mean glucose concentration and area under the glucose curve in cats fed the SF diet (P < 0.05). Colon mucosa thickness, crypt area, lamina propria area, goblet cell area, crypt mean size, and crypt in bifurcation did not vary among the diets. According to the fiber solubility and fermentation rates, fiber sources can induce different physiological responses in cats, reduce energy digestibility, and favor glucose metabolism (SF), or improve gut health (BP). PMID- 22247110 TI - Growth and Development Symposium: Endotoxin, inflammation, and intestinal function in livestock. AB - Endotoxin, also referred to as lipopolysaccharide (LPS), can stimulate localized or systemic inflammation via the activation of pattern recognition receptors. Additionally, endotoxin and inflammation can regulate intestinal epithelial function by altering integrity, nutrient transport, and utilization. The gastrointestinal tract is a large reservoir of both gram-positive and gram negative bacteria, of which the gram-negative bacteria serve as a source of endotoxin. Luminal endotoxin can enter circulation via two routes: 1) nonspecific paracellular transport through epithelial cell tight junctions, and 2) transcellular transport through lipid raft membrane domains involving receptor mediated endocytosis. Paracellular transport of endotoxin occurs through dissociation of tight junction protein complexes resulting in reduced intestinal barrier integrity, which can be a result of enteric disease, inflammation, or environmental and metabolic stress. Transcellular transport, via specialized membrane regions rich in glycolipids, sphingolipids, cholesterol, and saturated fatty acids, is a result of raft recruitment of endotoxin-related signaling proteins leading to endotoxin signaling and endocytosis. Both transport routes and sensitivity to endotoxin may be altered by diet and environmental and metabolic stresses. Intestinal-derived endotoxin and inflammation result in suppressed appetite, activation of the immune system, and partitioning of energy and nutrients away from growth toward supporting the immune system requirements. In livestock, this leads to the suppression of growth, particularly suppression of lean tissue accretion. In this paper, we summarize the evidence that intestinal transport of endotoxin and the subsequent inflammation leads to decrease in the production performance of agricultural animals and we present an overview of endotoxin detoxification mechanisms in livestock. PMID- 22247111 TI - Genetic parameters for androstenone, skatole, indole, and human nose scores as measures of boar taint and their relationship with finishing traits. AB - The purpose of this study was to evaluate measures of boar (Sus scrofa) taint as potential selection criteria to reduce boar taint so that castration of piglets will become unnecessary. Therefore, genetic parameters of boar taint measures and their genetic correlations with finishing traits were estimated. In particular, the usefulness of a human panel assessing boar taint (human nose score) was compared with chemical assessment of boar taint compounds, androstenone, skatole, and indole. Heritability estimates for androstenone, skatole, and indole were 0.54, 0.41, and 0.33, respectively. The heritability for the human nose score using multiple panelists was 0.12, and ranged from 0.12 to 0.19 for individual panelists. Genetic correlations between scores of panelists were generally high up to unity. The genetic correlations between human nose scores and the boar taint compounds ranged from 0.64 to 0.999. The boar taint compounds and human nose scores had low or favorable genetic correlations with finishing traits. Selection index estimates indicated that the effectiveness of a breeding program based on human nose scores can be comparable to a breeding program based on the boar taint compounds themselves. Human nose scores can thus be used as a cheap and fast alternative for the costly determination of boar taint compounds, needed in breeding pigs without boar taint. PMID- 22247112 TI - Linear reaction norm models for genetic merit prediction of Angus cattle under genotype by environment interaction. AB - The objectives of this work were to assess alternative linear reaction norm (RN) models for genetic evaluation of Angus cattle in Brazil. That is, we investigated the interaction between genotypes and continuous descriptors of the environmental variation to examine evidence of genotype by environment interaction (G*E) in post-weaning BW gain (PWG) and to compare the environmental sensitivity of national and imported Angus sires. Data were collected by the Brazilian Angus Improvement Program from 1974 to 2005 and consisted of 63,098 records and a pedigree file with 95,896 animals. Six models were implemented using Bayesian inference and compared using the Deviance Information Criterion (DIC). The simplest model was M(1), a traditional animal model, which showed the largest DIC and hence the poorest fit when compared with the 4 alternative RN specifications accounting for G*E. In M(2), a 2-step procedure was implemented using the contemporary group posterior means of M(1) as the environmental gradient, ranging from -92.6 to +265.5 kg. Moreover, the benefits of jointly estimating all parameters in a 1-step approach were demonstrated by M(3). Additionally, we extended M(3) to allow for residual heteroskedasticity using an exponential function (M(4)) and the best fitting (smallest DIC) environmental classification model (M(5)) specification. Finally, M(6) added just heteroskedastic residual variance to M(1). Heritabilities were less at harsh environments and increased with the improvement of production conditions for all RN models. Rank correlations among genetic merit predictions obtained by M(1) and by the best fitting RN models M(3) (homoskedastic) and M(5) (heteroskedastic) at different environmental levels ranged from 0.79 and 0.81, suggesting biological importance of G*E in Brazilian Angus PWG. These results suggest that selection progress could be optimized by adopting environment-specific genetic merit predictions. The PWG environmental sensitivity of imported North American origin bulls (0.046 +/- 0.009) was significantly larger (P < 0.05) than that of local sires (0.012 +/ 0.013). Moreover, PWG of progeny of imported sires exceeded that of native sires in medium and superior production levels. On the other hand, Angus cattle locally selected in Brazil tended to be more robust to environmental changes and hence be more suitable when production environments for potential progeny is uncertain. PMID- 22247113 TI - The effect of 7, 8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of tall larkspur (Delphinium spp.) in cattle. AB - Delphinium spp. contain numerous norditerpenoid alkaloids which are structurally delineated as 7, 8-methylenedioxylycoctonine (MDL) and N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids. The toxicity of many tall larkspur species has been primarily attributed to their increased concentration of MSAL type alkaloids, such as methyllycaconitine (MLA), which are typically 20 times more toxic than MDL-type alkaloids. However, the less toxic MDL-type alkaloids are often more abundant than MSAL-type alkaloids in most Delphinium barbeyi and Delphinium occidentale populations. Previous research demonstrated that MDL-type alkaloids increase the acute toxicity of MSAL-type alkaloids. In this study, we examined the role of MDL-type alkaloids on the overall toxicity of tall larkspur plants to cattle while controlling for the exact dose of MSAL-type alkaloids. Cattle were dosed with plant material from 2 different populations of tall larkspur containing either almost exclusively MDL- or MSAL-type alkaloids. These 2 plant populations were combined to create mixtures with ratios of 0.3:1, 1:1, 5:1, and 10:1 MDL- to MSAL-type alkaloids. The dose that elicited similar clinical signs of poisoning in mice and cattle was determined for each mixture on the basis of the MSAL-type alkaloid content. As the ratio of MDL- to MSAL-type alkaloids increased, the amount of MSAL-type alkaloids required to elicit clinical signs decreased. These results indicate that the less toxic MDL-type alkaloids in tall larkspur exacerbate the toxicity of the MSAL-type alkaloids. Consequently, both the amount of MSAL-type alkaloids and the amount of total alkaloids should be fully characterized to determine more accurately the relative toxicity of tall larkspur plant material. PMID- 22247114 TI - Evaluation of tropically adapted straightbred and crossbred cattle: postweaning gain and feed efficiency when finished in a temperate climate. AB - Beef cows in the subtropical USA must be adapted to the stressors of the environment, typically supplied by using Brahman (Br) breeding. Calves produced in the region, however, are usually grown and finished in more temperate regions, and have a perceived reputation for poor ADG and feed efficiency during finishing. Compromised fertility and carcass quality often associated with the Br have increased interest in tropically adapted Bos taurus breed types. The objective of this study was to evaluate 3 breeds [An = Angus (Bos taurus, temperate); Br (B. indicus, tropical); and Ro = Romosinuano (B. taurus, tropical)] and all possible crosses during various segments of post-weaning growth, and for feed efficiency during the finishing phase. Steer calves (n = 473) born over 3 yr were weaned in late September, backgrounded for at least 21 d (BKG), shipped 2,025 km to El Reno, OK, in October, fed a preconditioning diet for 28 d (RCV), grazed wheat (Triticum aestivum L.) pasture from November to May (WHT), finished on a conventional feedlot diet (FIN), and serially harvested after approximately 95, 125, and 150 d on feed. Body weight and ADG during each segment were tested using a mixed model that included calf age at weaning, year (Y), breed of sire (SB), breed of dam (DB), and interactions. In addition, winter treatment (continuous wheat or reduced grazing of wheat with supplement) was included for the wheat and feedlot phases. Sire within SB * SB [and pen (barn * year) for feedlot phase] were considered random. The SB * DB interaction was significant for all traits (P < 0.01) except exit velocity taken at weaning and ADG during FIN, but both traits were affected by 3-way interactions with Y or harvest group. Tropically-adapted purebred steers had greater (P < 0.01) ADG than AnAn through weaning and BKG in FL but the reverse was true during the RCV and WHT segments. Similar, but less pronounced results were noted for F(1) steers with 100% tropical influence compared with those with only 50%. Heterosis was numerically greater for most traits for An * Br (11 to 64%) compared with An * Ro and Br * Ro (3 to 42%), which were similar. In a subset of the steers (n = 261), G:F was not influenced by level of tropical breeding, but tropically adapted steers were more efficient (P < 0.05) by residual feed intake. No heterosis was evident. These data show that in temperate zones, winter is the period when productivity of tropically adapted cattle is compromised. PMID- 22247115 TI - The effect of microbial-nutrient interaction on the immune system of young chicks after early probiotic and organic acid administration. AB - The combined effects of probiotics (Lactobacillus acidophilus, Lactobacillus casei, Streptococcus faecium, and Saccharomyces cerevisiae) and organic acids (sorbic and citric acid) on intestinal morphology and expression of immune related genes were investigated. One-day-old chicks were randomly assigned to 1 of 3 groups: birds not receiving probiotic or organic acids (control; T1), or birds receiving an oral combination (1 g/L in water) of 10(8) CFU/g of each of the aforementioned probiotics and organic acids (1% sorbic acid and 0.2% citric acid) for 7 (T2) or 14 d (T3). Each group was divided into 5 replicate pens of 20 birds each, and 5 birds from each group (1 from each pen) were killed on d 11 and 22. Intestinal sections were collected for histological assessment, and reverse transcriptase-PCR analysis was used to assess defensin and cathelicidins expression. Quantitative real-time PCR was used to assess toll-like receptors (TLR) and cytokine expression. Duodenal villus height was greater in T2 and T3 at d 11 (P <= 0.036) and 22 (P <= 0.015) compared with T1. At d 11, duodenal goblet cell/unit area was less in T3, whereas it was greater in T2 compared with T1 in the jejunum (P = 0.009). Ileal goblet cell/unit area was greater in T3 at d 22 compared with T1 (P < 0.001). Avian beta-defensin-3 was expressed in all tissues except the bursa of T3 birds at d 11, and TLR-2 was down regulated in the cecal tonsil of birds in T2 and T3 at d 11 compared with T1 (P = 0.020 and 0.003, respectively). Expression of IL-12p35 in the ileum at d 11 was down regulated in T2 and T3 compared with T1 (P = 0.030 and 0.012, respectively). Reduced expression of INF-gamma was observed in the ileum in T3 compared with T1 at d 11 (P = 0.047). Ileal IL-6 and IL-10 and cecal tonsil interferon-gamma (INF-gamma) expressions were greater T2 at d 22 (P <= 0.047) than T1. In conclusion, supplementation of combined probiotics and organic acids resulted in inconsistent gut morphology associated responses, and avian beta-defensins and cathelicidins expression were not associated with combined probiotics and organic acids supplementation. Birds supplemented with combined probiotics and organic acids for 7 d showing similar responses in TLR-2, IL-12p35, and IFN-gamma compared with those supplemented for 14 d indicates that shorter periods of supplementation might be enough to elicit beneficial responses. PMID- 22247116 TI - Effect of castration technique on beef calf performance, feed efficiency, and inflammatory response. AB - The objective of this experiment was to examine the effect of castration technique on daily feed intake (DFI), daily water intake (DWI), growth performance, residual feed intake (RFI), and inflammatory response in weaned beef calves. Seventy-five beef calves (214 +/- 3.2 kg; 200 +/- 26 d of age) were housed in a GrowSafe 4000 feed intake facility 7 d post weaning (15 calves/pen). Calves were offered a total mixed ration (TDN = 67.3% and CP = 12.2%, DM = 89%) for ad libitum consumption. On d 0, calves were assigned to 1 of 5 treatments (n = 15 calves/treatment): 1) steers castrated surgically pre-weaning (52 d of age; CON); 2) intact bulls (BULL); 3) bulls castrated by the Callicrate Bander on d 0 (No-Bull Enterprises LLC.; BAN); 4) bulls castrated by the Henderson Castrating Tool on d 0 (Stone Mfg & Supply Co.; HEN); and 5) bulls castrated surgically utilizing an emasculator on d 0 (SUR). Average daily gain, DFI, and DWI were recorded over 84 d. Blood was collected from a sub-sample of calves (n = 45) on d 0, 2, 6, 9, 12, and 15 relative to castration. Castration decreased (P = 0.06) ADG for castrates compared with CON from d 0 to 14 but not d 0 to 84. Daily feed intake and DWI were similar (P > 0.10) among treatments during d 0 to 84. Gain:feed was not affected by castration technique; however, RFI tended (P = 0.09) to be negative for CON and BULL compared with castrates on d 0 to 14 but not d 0 to 84. Acute phase protein analyses indicated that surgical castration (SUR or HEN) elicited a short-term inflammatory response in calves, whereas calves castrated with BAN elicited a delayed response. Calves castrated pre weaning had improved d 0 to 14 ADG, feed intake, and inflammation response compared with calves castrated at weaning. Banding elicited a delayed negative response in ADG, DWI, and inflammation. In weaned calves, castration method did not affect performance, DFI, DWI, or inflammatory response during the 84-d trial. PMID- 22247117 TI - A herd management survey on culling guidelines and actual culling practices in three herd groups based on reproductive productivity in Japanese commercial swine herds. AB - The objective of the present study was to investigate culling guidelines for gilts and sows in Japanese commercial herds and to compare differences between culling guidelines and actual culling practices in different herd productivity groups. A questionnaire survey was undertaken to obtain information on culling guidelines in 115 commercial swine herds that participated in the PigCHAMP data share program. The questionnaire included questions on guideline values for culling intervals and the number of conception failure occurrences that would trigger a culling decision to be made. Ninety-two of the 115 herds (80.0%) returned appropriate data for the study and were included in the present study. In addition to questionnaire data, culling data regarding the actual culling intervals and number of reservices for gilts and sows culled during 2007 to 2008 were also obtained for the same herds from a PigCHAMP database. Culled gilts and sows were divided into 4 female groups on the basis of the stages of their reproductive life when they were culled: unmated gilts, mated gilts, unmated sows, and mated sows. Culling intervals in unmated gilts and sows were defined as the number of days from birth or weaning to culling, respectively, whereas in mated gilts and sows culling intervals were the number of days from last service to culling. Three herd productivity groups were formed on the basis of the upper and lower 25th percentiles of pigs weaned mated female(-1).yr(-1):high ,intermediate- or low-performing herds. For unmated gilts and sows actual culling intervals were 15 d shorter than the guideline culling intervals in the surveyed data submitted by producers (P < 0.05). This shorter actual culling period for unmated gilts and sows did not vary significantly between herd productivity groups in any parity. However, for mated gilts and sows the actual culling intervals were at least 30 d longer than the guideline culling intervals (P < 0.05). Guideline and actual culling intervals for mated gilts and sows were at least 10 d shorter in high-performing herds than in low-performing herds (P < 0.05). High-performing herds had lower proportions of sows culled after the second reservice than intermediate- or low-performing herds in parity groups 0 to 5 (P < 0.05). In conclusion, culling guidelines for mated sows differed between herd productivity groups, and culling guidelines for mated gilts and sows were not strictly followed in any herd group in the commercial herds. PMID- 22247118 TI - Bovine acute-phase response after different doses of corticotropin-releasing hormone challenge. AB - The objective was to compare the acute-phase response of steers receiving different doses of bovine corticotropin-releasing hormone (CRH). Fourteen weaned Angus steers (BW = 191 +/- 2.1 kg, age = 167 +/- 4.7 d) fitted with an indwelling jugular catheter and a rectal temperature (RT) monitoring device were assigned to receive 1 of 3 treatments (intravenous infusion): 1) 0.1 MUg of CRH/kg of BW (CRH1; n = 5), 2) 0.5 MUg of CRH/kg of BW (CRH5; n = 5), and 3) 10 mL of saline (0.9%; n = 4). Blood samples were collected via catheters, relative to treatment infusion (0 h), hourly from -2 to 0 h and 4 to 8 h and every 30 min from 0 to 4 h. Rectal temperatures were recorded every 30 min from -2 to 8 h. Blood samples were also collected via jugular venipuncture and rectal temperatures assessed using a digital thermometer every 6 h from 12 to 72 h and every 24 h from 96 to 168 h. All plasma samples collected during the study were analyzed for concentrations of haptoglobin. All plasma samples collected from -2 to 8 h were analyzed for cortisol concentrations. Serum samples collected hourly from -2 to 8 h were analyzed for concentrations of NEFA, IL-6, tumor necrosis factor (TNF) alpha, and interferon-gamma. Cortisol peaked at 0.5 h for CRH1 steers but returned to baseline concentrations at 1 h relative to infusion (time effect; P < 0.01). In CRH5 steers, cortisol peaked at 0.5 h and returned to baseline concentrations 3.5 h relative to infusion (time effect; P < 0.01). Cortisol concentrations did not change after treatment infusion for saline steers (time effect; P = 0.42). In CRH1 steers, NEFA concentrations peaked 5 h after treatment infusion (time effect; P = 0.01). Conversely, serum NEFA concentrations did not change for CRH5 and saline steers after treatment infusion (time effect; P > 0.37). Mean serum TNF-alpha concentrations in CRH1 steers after treatment infusion were greater compared with saline (P = 0.02), tended to be greater (P = 0.08) compared with CRH5, and were similar (P = 0.40) between CRH5 and saline steers. Mean RT in CRH1 steers after treatment infusion were greater (P < 0.04) compared with saline and CRH5 and similar (P = 0.50) between CRH5 and saline steers. Haptoglobin increased and peaked 72 h after treatment infusion for CRH1 steers (time effect; P = 0.01) but did not change for CRH5 and saline steers (time effect; P > 0.45). In conclusion, the bovine acute-phase response stimulated by CRH infusion is dependent on the CRH dose and the subsequent response in circulating cortisol. PMID- 22247119 TI - Associations between the distance traveled from sale barns to commercial feedlots in the United States and overall performance, risk of respiratory disease, and cumulative mortality in feeder cattle during 1997 to 2009. AB - Most beef cattle are transported at least once during their lives, and this potentially stressful practice may affect subsequent health and performance. Limited research is available quantifying the effects of transport on feedlot performance and health, and particularly the risk of bovine respiratory disease complex (BRD), which is the most common disease of weaned calves after arrival to the feedlot. The objective of this retrospective study was to determine potential associations between distance traveled (DTV) during transportation with health (cumulative BRD morbidity and mortality of all causes) and performance (ADG and HCW) parameters in cattle cohorts (n = 14,601) that arrived to 21 U.S. commercial feedlots from 1997 to 2009. Multivariable mixed-effects negative binomial and linear regression models were employed to determine associations between health and performance outcomes with DTV and other cohort-level demographic variables. Cattle were transported a median of 552 km from origin to feedlot with a mean (+/ SEM) of 698 +/- 4.4 km. The mean (+/-SEM) cumulative BRD morbidity was 4.9% +/- 0.01% (median = 1.1%; range: 0 to 100%) whereas the mean (+/-SEM) cumulative mortality due to all causes was 1.3% +/- 0.01% (median = 0.8%; range: 0 to 28.7%). Distance traveled was significantly associated (P < 0.05) with BRD morbidity, overall mortality, HCW and ADG, and its effects were modified by demographic characteristics (i.e., cohort region of origin, mean arrival BW, gender, and the season of the year) of the cohort. Knowledge of the distance traveled during transportation could allow a more precise prediction of cattle feedlot health and performance. PMID- 22247120 TI - Effects of body weight loss during transit from sale barns to commercial feedlots on health and performance in feeder cattle cohorts arriving to feedlots from 2000 to 2008. AB - Body weight loss during transport or shrink (SHK) is a common occurrence in feeder cattle that results from a physiological, complex process. Previous studies have assessed the effects of environmental and dietary stressors on transport-associated BW loss; however, data on associations between shrink and subsequent health and performance parameters in feeder cattle are limited. Operational data from 13 U.S. commercial feedlots (n = 16,590 cattle cohorts) were used to quantify how SHK was associated with bovine respiratory disease (BRD) morbidity and overall mortality risks, HCW and ADG in feeder cattle cohorts arriving to feedlots during 2000 to 2008. Multivariable mixed-effects negative binomial and linear regression models were employed to determine these associations while accounting for other cohort-level demographic variables. The median SHK among the study cohorts was 3.0% with a mean (+/- SEM) of 2.4 +/- 0.02%. The mean (+/- SEM) cumulative BRD morbidity was 10.0% +/- 0.09% (median = 5.8%; range 0 to 100%) and the mean (+/- SEM) overall cumulative mortality was 1.3% +/- 0.01% (median = 0.9%; range: 0 to 25.6%). The mean and median number of days on feed of cohorts experiencing initial BRD cases was 143 and 150 d (range = 23 to 288 d). The effects of SHK were significantly (P < 0.05) associated with BRD morbidity, overall mortality, HCW and ADG, and these effects were significantly (P < 0.05) modified by gender, season and mean arrival BW of the cohort. Combining data on BW loss during transport with cohort demographics could allow a more precise prediction of health and performance of feedlot cattle. PMID- 22247121 TI - Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study. AB - BACKGROUND: Little is known about how chronic conditions other than prematurity, heart disease, and Down syndrome affect the risk and severity of hospitalization for respiratory syncytial virus (RSV). We assess the risk and severity of RSV hospitalization in children with chronic conditions in this register-based, population-based cohort study. METHODS: Data on RSV tests, maternal smoking, siblings, single parenthood, mode of delivery, gestational age at birth, major surgery, asthma diagnosis, chronic conditions, and hospitalization and discharge dates were obtained from the Danish RSV database, the National Patient and Birth Registries, and the Civil Registration System. STATISTICS: Cox regression models were used to estimate incidence rate ratios (IRRs) for RSV hospitalization between groups stratified by sex and date of birth. Duration of RSV hospitalization was analyzed in a linear regression and reported as geometric mean ratios. RESULTS: A total of 391 983 children aged 0-23 months were included in the analysis. A total of 10,616 (2.7%) had a diagnosis for chronic disease. IRRs (95% confidence intervals) for RSV hospitalization in children with any congenital or acquired chronic condition were 2.18 (2.01-2.36) and 2.25 (1.94 2.61), respectively. Several new risk factors for RSV hospitalization, including malformations, interstitial lung disease, neuromuscular disease, liver disease, chromosomal abnormalities, congenital immunodeficiencies, and inborn errors of metabolism, were identified. Duration of RSV hospitalization was increased in many chronic conditions. CONCLUSIONS: Chronic disease per se is an important risk factor for RSV hospitalization. PMID- 22247122 TI - Antibiotic treatment against methicillin-resistant Staphylococcus aureus hospital and ventilator-acquired pneumonia: a step forward but the battle continues. PMID- 22247123 TI - Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. AB - BACKGROUND: Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. METHODS: This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. RESULTS: Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5% 21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). CONCLUSIONS: For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar. PMID- 22247124 TI - Variation in inbreeding depression and plasticity across native and non-native field environments. AB - BACKGROUND AND AIMS: Since the early 1990s, research on genetic variation of phenotypic plasticity has expanded and empirical research has emphasized the role of the environment on the expression of inbreeding depression. An emerging question is how these two evolutionary ecology mechanisms interact in novel environments. Interest in this area has grown with the need to understand the establishment of populations in response to climate change, and to human-assisted transport to novel environments. METHODS: We compare performance in the field of outcrossed (O) and inbred lines (S1, S2) from 20 maternal families from each of two native populations of Mimulus guttatus. The experiment was planted in California in each population's home site, in the other populations's home site, in a novel site within the native range of M. guttatus, and in a novel site within the non-native range in North America. The experiment included nearly 6500 individuals. Survival, sexual reproduction and above-ground biomass were examined in order to evaluate inbreeding depression, and stem diameter and plant height were examined in order to evaluate phenotypic plasticity. KEY RESULTS: Across all field sites, approx. 36 % of plants survived to flowering. Inbreeding depression differed among sites and outcrossed offspring generally outperformed selfed offspring. However, in the native-novel site, self-progeny performed better or equally well as outcross progeny. Significant phenotypic plasticity and genetic variation in plasticity was detected in the two architectural traits measured. The absolute value of plasticity showed the most marked difference between home and non-native novel site or non-native-novel site. Evidence was detected for an interaction between inbreeding and plasticity for stem diameter. CONCLUSIONS: The results demonstrate that during initial population establishment, both inbreeding depression and phenotypic plasticity vary among field sites, and may be an important response to environments outside a species' currently occupied range. However, the interaction between inbreeding and plasticity may be limited and environment-dependent. PMID- 22247125 TI - Seedling traits, plasticity and local differentiation as strategies of invasive species of Impatiens in central Europe. AB - BACKGROUND AND AIMS: Invasiveness of some alien plants is associated with their traits, plastic responses to environmental conditions and interpopulation differentiation. To obtain insights into the role of these processes in contributing to variation in performance, we compared congeneric species of Impatiens (Balsaminaceae) with different origin and invasion status that occur in central Europe. METHODS: Native I. noli-tangere and three alien species (highly invasive I. glandulifera, less invasive I. parviflora and potentially invasive I. capensis) were studied and their responses to simulated canopy shading and different nutrient and moisture levels were determined in terms of survival and seedling traits. KEY RESULTS AND CONCLUSIONS: Impatiens glandulifera produced high biomass in all the treatments and the control, exhibiting the 'Jack-and master' strategy that makes it a strong competitor from germination onwards. The results suggest that plasticity and differentiation occurred in all the species tested and that along the continuum from plasticity to differentiation, the species at the plasticity end is the better invader. The most invasive species I. glandulifera appears to be highly plastic, whereas the other two less invasive species, I. parviflora and I. capensis, exhibited lower plasticity but rather strong population differentiation. The invasive Impatiens species were taller and exhibited higher plasticity and differentiation than native I. noli-tangere. This suggests that even within one genus, the relative importance of the phenomena contributing to invasiveness appears to be species' specific. PMID- 22247127 TI - Identification of the haloarchaeal phasin (PhaP) that functions in polyhydroxyalkanoate accumulation and granule formation in Haloferax mediterranei. AB - The polyhydroxyalkanoate (PHA) granule-associated proteins (PGAPs) are important for PHA synthesis and granule formation, but currently little is known about the haloarchaeal PGAPs. This study focused on the identification and functional analysis of the PGAPs in the haloarchaeon Haloferax mediterranei. These PGAPs were visualized with two-dimensional gel electrophoresis (2-DE) and identified by matrix-assisted laser desorption ionization-tandem time of flight mass spectrometry (MALDI-TOF/TOF MS). The most abundant protein on the granules was identified as a hypothetical protein, designated PhaP. A genome-wide analysis revealed that the phaP gene is located upstream of the previously identified phaEC genes. Through an integrative approach of gene knockout/complementation and fermentation analyses, we demonstrated that this PhaP is involved in PHA accumulation. The DeltaphaP mutant was defective in both PHA biosynthesis and cell growth compared to the wild-type strain. Additionally, transmission electron microscopy results indicated that the number of PHA granules in the DeltaphaP mutant cells was significantly lower, and in most of the DeltaphaP cells only a single large granule was observed. These results demonstrated that the H. mediterranei PhaP was the predominant structure protein (phasin) on the PHA granules involved in PHA accumulation and granule formation. In addition, BLASTp and phylogenetic results indicate that this type of PhaP is exclusively conserved in haloarchaea, implying that it is a representative of the haloarchaeal type PHA phasin. PMID- 22247126 TI - Influence of anaerobiosis and low temperature on Bacillus cereus growth, metabolism, and membrane properties. AB - The impact of simultaneous anaerobiosis and low temperature on growth parameters, metabolism, and membrane properties of Bacillus cereus ATCC 14579 was studied. No growth was observed under anaerobiosis at 12 degrees C. In bioreactors, growth rates and biomass production were drastically reduced by simultaneous anaerobiosis and low temperature (15 degrees C). The two conditions had a synergistic effect on biomass reduction. In anaerobic cultures, fermentative metabolism was modified by low temperature, with a marked reduction in ethanol production leading to a lower ability to produce NAD(+). Anaerobiosis reduced unsaturated fatty acids at both low optimal temperatures. In addition, simultaneous anaerobiosis and low temperatures markedly reduced levels of branched-chain fatty acids compared to all other conditions (accounting for 33% of total fatty acids against more 71% for low-temperature aerobiosis, optimal temperature aerobiosis, and optimal-temperature anaerobiosis). This corresponded to high-melting-temperature lipids and to low-fluidity membranes, as indicated by differential scanning calorimetry, 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence anisotropy, and infrared spectroscopy. This is in contrast to requirements for cold adaptation. A link between modification in the synthesis of metabolites of fermentative metabolism and the reduction of branched-chain fatty acids at low temperature under anaerobiosis, through a modification of the oxidizing capacity, is assumed. This link may partly explain the impact of low temperature and anaerobiosis on membrane properties and growth performance. PMID- 22247128 TI - Wide distribution of closely related, antibiotic-producing Arthrobacter strains throughout the Arctic Ocean. AB - We isolated 16 antibiotic-producing bacterial strains throughout the central Arctic Ocean, including seven Arthrobacter spp. with almost identical 16S rRNA gene sequences. These strains were numerically rare, as revealed using 454 pyrosequencing libraries. Arthrobacter spp. produced arthrobacilins A to C under different culture conditions, but other, unidentified compounds likely contributed to their antibiotic activity. PMID- 22247129 TI - Identification and characterization of psychrotolerant sporeformers associated with fluid milk production and processing. AB - Psychrotolerant spore-forming bacteria represent a major challenge to the goal of extending the shelf life of pasteurized dairy products. The objective of this study was to identify prominent phylogenetic groups of dairy-associated aerobic sporeformers and to characterize representative isolates for phenotypes relevant to growth in milk. Analysis of sequence data for a 632-nucleotide fragment of rpoB showed that 1,288 dairy-associated isolates (obtained from raw and pasteurized milk and from dairy farm environments) clustered into two major divisions representing (i) the genus Paenibacillus (737 isolates, including the species Paenibacillus odorifer, Paenibacillus graminis, and Paenibacillus amylolyticus sensu lato) and (ii) Bacillus (n = 467) (e.g., Bacillus licheniformis sensu lato, Bacillus pumilus, Bacillus weihenstephanensis) and genera formerly classified as Bacillus (n = 84) (e.g., Viridibacillus spp.). When isolates representing the most common rpoB allelic types (ATs) were tested for growth in skim milk broth at 6 degrees C, 6/9 Paenibacillus isolates, but only 2/8 isolates representing Bacillus subtypes, grew >5 log CFU/ml over 21 days. In addition, 38/40 Paenibacillus isolates but only 3/47 Bacillus isolates tested were positive for beta-galactosidase activity (including some isolates representing Bacillus licheniformis sensu lato, a common dairy-associated clade). Our study confirms that Paenibacillus spp. are the predominant psychrotolerant sporeformers in fluid milk and provides 16S rRNA gene and rpoB subtype data and phenotypic characteristics facilitating the identification of aerobic spore forming spoilage organisms of concern. These data will be critical for the development of detection methods and control strategies that will reduce the introduction of psychrotolerant sporeformers and extend the shelf life of dairy products. PMID- 22247130 TI - Development of a modified gentamicin resistance cassette for genetic manipulation of the oral spirochete Treponema denticola. AB - Herein, we report that a modified gentamicin cassette and a PCR-based method can be used for targeted mutagenesis of the oral spirochete Treponema denticola. This approach minimizes polar effects and spontaneous antibiotic resistance. Therefore, it can serve as a reliable tool for genetic manipulation of T. denticola. PMID- 22247131 TI - Culture-independent approaches for studying viruses from hypersaline environments. AB - Hypersaline close-to-saturation environments harbor an extremely high concentration of virus-like particles, but the number of haloviruses isolated so far is still very low. Haloviruses can be directly studied from natural samples by using different culture-independent techniques that include transmission electron microscopy, pulsed-field gel electrophoresis, and different metagenomic approaches. Here, we review the findings of these studies, with a main focus on the metagenomic approaches. The analysis of bulk viral nucleic acids directly retrieved from the environment allows estimations of viral diversity, activity, and dynamics and tentative host assignment. Results point to a diverse and active viral community in constant interplay with its hosts and to a "hypersalineness" quality common to viral assemblages present in hypersaline environments that are thousands of kilometers away from each other. PMID- 22247132 TI - Wide variation in antibiotic resistance proteins identified by functional metagenomic screening of a soil DNA library. AB - Most genes for antibiotic resistance present in soil microbes remain unexplored because most environmental microbes cannot be cultured. Only recently has the identification of these genes become feasible through the use of culture independent methods. We screened a soil metagenomic DNA library in an Escherichia coli host for genes that can confer resistance to kanamycin, gentamicin, rifampin, trimethoprim, chloramphenicol, or tetracycline. The screen revealed 41 genes that encode novel protein variants of eight protein families, including aminoglycoside acetyltransferases, rifampin ADP-ribosyltransferases, dihydrofolate reductases, and transporters. Several proteins of the same protein family deviate considerably from each other yet confer comparable resistance. For example, five dihydrofolate reductases sharing at most 44% amino acid sequence identity in pairwise comparisons were equivalent in conferring trimethoprim resistance. We identified variants of aminoglycoside acetyltransferases and transporters that differ in the specificity of the drugs for which they confer resistance. We also found wide variation in protein structure. Two forms of rifampin ADP-ribosyltransferases, one twice the size of the other, were similarly effective at conferring rifampin resistance, although the short form was expressed at a much lower level. Functional metagenomic screening provides insight into the large variability in antibiotic resistance protein sequences, revealing divergent variants that preserve protein function. PMID- 22247133 TI - Response of fatty acid synthesis genes to the binding of human salivary amylase by Streptococcus gordonii. AB - Streptococcus gordonii, an important primary colonizer of dental plaque biofilm, specifically binds to salivary amylase via the surface-associated amylase-binding protein A (AbpA). We hypothesized that a function of amylase binding to S. gordonii may be to modulate the expression of chromosomal genes, which could influence bacterial survival and persistence in the oral cavity. Gene expression profiling by microarray analysis was performed to detect genes in S. gordonii strain CH1 that were differentially expressed in response to the binding of purified human salivary amylase versus exposure to purified heat-denatured amylase. Selected genes found to be differentially expressed were validated by quantitative reverse transcription-PCR (qRT-PCR). Five genes from the fatty acid synthesis (FAS) cluster were highly (10- to 35-fold) upregulated in S. gordonii CH1 cells treated with native amylase relative to those treated with denatured amylase. An abpA-deficient strain of S. gordonii exposed to amylase failed to show a response in FAS gene expression similar to that observed in the parental strain. Predicted phenotypic effects of amylase binding to S. gordonii strain CH1 (associated with increased expression of FAS genes, leading to changes in fatty acid synthesis) were noted; these included increased bacterial growth, survival at low pH, and resistance to triclosan. These changes were not observed in the amylase-exposed abpA-deficient strain, suggesting a role for AbpA in the amylase induced phenotype. These results provide evidence that the binding of salivary amylase elicits a differential gene response in S. gordonii, resulting in a phenotypic adjustment that is potentially advantageous for bacterial survival in the oral environment. PMID- 22247134 TI - Evidence of two functionally distinct ornithine decarboxylation systems in lactic acid bacteria. AB - Biogenic amines are low-molecular-weight organic bases whose presence in food can result in health problems. The biosynthesis of biogenic amines in fermented foods mostly proceeds through amino acid decarboxylation carried out by lactic acid bacteria (LAB), but not all systems leading to biogenic amine production by LAB have been thoroughly characterized. Here, putative ornithine decarboxylation pathways consisting of a putative ornithine decarboxylase and an amino acid transporter were identified in LAB by strain collection screening and database searches. The decarboxylases were produced in heterologous hosts and purified and characterized in vitro, whereas transporters were heterologously expressed in Lactococcus lactis and functionally characterized in vivo. Amino acid decarboxylation by whole cells of the original hosts was determined as well. We concluded that two distinct types of ornithine decarboxylation systems exist in LAB. One is composed of an ornithine decarboxylase coupled to an ornithine/putrescine transmembrane exchanger. Their combined activities results in the extracellular release of putrescine. This typical amino acid decarboxylation system is present in only a few LAB strains and may contribute to metabolic energy production and/or pH homeostasis. The second system is widespread among LAB. It is composed of a decarboxylase active on ornithine and l 2,4-diaminobutyric acid (DABA) and a transporter that mediates unidirectional transport of ornithine into the cytoplasm. Diamines that result from this second system are retained within the cytosol. PMID- 22247135 TI - Biodiversity in Oscypek, a traditional Polish cheese, determined by culture dependent and -independent approaches. AB - Oscypek is a traditional Polish scalded-smoked cheese, with a protected designation-of-origin (PDO) status, manufactured from raw sheep's milk without starter cultures in the Tatra Mountains region of Poland. This study was undertaken in order to gain insight into the microbiota that develops and evolves during the manufacture and ripening stages of Oscypek. To this end, we made use of both culturing and the culture-independent methods of PCR followed by denaturing gradient gel electrophoresis (PCR-DGGE) and pyrosequencing of 16S rRNA gene amplicons. The culture-dependent technique and PCR-DGGE fingerprinting detected the predominant microorganisms in traditional Oscypek, whereas the next generation sequencing technique (454 pyrosequencing) revealed greater bacterial diversity. Besides members of the most abundant bacterial genera in dairy products, e.g., Lactococcus, Lactobacillus, Leuconostoc, Streptococcus, and Enterococcus, identified by all three methods, other, subdominant bacteria belonging to the families Bifidobacteriaceae and Moraxellaceae (mostly Enhydrobacter), as well as various minor bacteria, were identified by pyrosequencing. The presence of bifidobacterial sequences in a cheese system is reported for the first time. In addition to bacteria, a great diversity of yeast species was demonstrated in Oscypek by the PCR-DGGE method. Culturing methods enabled the determination of a number of viable microorganisms from different microbial groups and their isolation for potential future applications in specific cheese starter cultures. PMID- 22247136 TI - Development and validation of a predictive model for the growth of Vibrio vulnificus in postharvest shellstock oysters. AB - Postharvest growth of Vibrio vulnificus in oysters can increase risk of human infection. Unfortunately, limited information is available regarding V. vulnificus growth and survival patterns over a wide range of storage temperatures in oysters harvested from different estuaries and in different oyster species. In this study, we developed a predictive model for V. vulnificus growth in Eastern oysters (Crassostrea virginica) harvested from Chesapeake Bay, MD, over a temperature range of 5 to 30 degrees C and then validated the model against V. vulnificus growth rates (GRs) in Eastern and Asian oysters (Crassostrea ariakensis) harvested from Mobile Bay, AL, and Chesapeake Bay, VA, respectively. In the model development studies, V. vulnificus was slowly inactivated at 5 and 10 degrees C with average GRs of -0.0045 and -0.0043 log most probable number (MPN)/h, respectively. Estimated average growth rates at 15, 20, 25, and 30 degrees C were 0.022, 0.042, 0.087, and 0.093 log MPN/h, respectively. With respect to Eastern oysters, bias (B(f)) and accuracy (A(f)) factors for model dependent and -independent data were 1.02 and 1.25 and 1.67 and 1.98, respectively. For Asian oysters, B(f) and A(f) were 0.29 and 3.40. Residual variations in growth rate about the fitted model were not explained by season, region, water temperature, or salinity at harvest. Growth rate estimates for Chesapeake Bay and Mobile Bay oysters stored at 25 and 30 degrees C showed relatively high variability and were lower than Food and Agricultural Organization (FAO)/WHO V. vulnificus quantitative risk assessment model predictions. The model provides an improved tool for designing and implementing food safety plans that minimize the risk associated with V. vulnificus in oysters. PMID- 22247137 TI - Hyperthermophilic Thermotoga species differ with respect to specific carbohydrate transporters and glycoside hydrolases. AB - Four hyperthermophilic members of the bacterial genus Thermotoga (T. maritima, T. neapolitana, T. petrophila, and Thermotoga sp. strain RQ2) share a core genome of 1,470 open reading frames (ORFs), or about 75% of their genomes. Nonetheless, each species exhibited certain distinguishing features during growth on simple and complex carbohydrates that correlated with genomic inventories of specific ABC sugar transporters and glycoside hydrolases. These differences were consistent with transcriptomic analysis based on a multispecies cDNA microarray. Growth on a mixture of six pentoses and hexoses showed no significant utilization of galactose or mannose by any of the four species. T. maritima and T. neapolitana exhibited similar monosaccharide utilization profiles, with a strong preference for glucose and xylose over fructose and arabinose. Thermotoga sp. strain RQ2 also used glucose and xylose, but was the only species to utilize fructose to any extent, consistent with a phosphotransferase system (PTS) specific for this sugar encoded in its genome. T. petrophila used glucose to a significantly lesser extent than the other species. In fact, the XylR regulon was triggered by growth on glucose for T. petrophila, which was attributed to the absence of a glucose transporter (XylE2F2K2), otherwise present in the other Thermotoga species. This suggested that T. petrophila acquires glucose through the XylE1F1K1 transporter, which primarily serves to transport xylose in the other three Thermotoga species. The results here show that subtle differences exist among the hyperthermophilic Thermotogales with respect to carbohydrate utilization, which supports their designation as separate species. PMID- 22247138 TI - Prevalence, characterization, and antimicrobial resistance of Listeria monocytogenes isolates from bovine hides and carcasses. AB - Listeria monocytogenes isolates from bovine hides and carcasses (n = 812) were mainly of serogroup 1/2a. All strains were positive for internalin genes. Several isolates were resistant to oxacillin (72.2%) or clindamycin (37.0%). These findings indicate that L. monocytogenes of beef origin can be considered a public health concern. PMID- 22247139 TI - Fine-tuned transcriptional regulation of malate operons in Enterococcus faecalis. AB - In Enterococcus faecalis, the mae locus is constituted by two putative divergent operons, maePE and maeKR. The first operon encodes a putative H(+)/malate symporter (MaeP) and a malic enzyme (MaeE) previously shown to be essential for malate utilization in this bacterium. The maeKR operon encodes two putative proteins with significant similarity to two-component systems involved in sensing malate and activating its assimilation in bacteria. Our transcriptional and genetic assays showed that maePE and maeKR are induced in response to malate by the response regulator MaeR. In addition, we observed that both operons were partially repressed in the presence of glucose. Accordingly, the cometabolism of this sugar and malate was detected. The binding of the complex formed by CcpA and its corepressor P-Ser-HPr to a cre site located in the mae region was demonstrated in vitro and explains the carbon catabolite repression (CCR) observed for the maePE operon. However, our results also provide evidence for a CcpA-independent CCR mechanism regulating the expression of both operons. Finally, a biomass increment of 40 or 75% was observed compared to the biomass of cells grown only on glucose or malate, respectively. Cells cometabolizing both carbon sources exhibit a higher rate of glucose consumption and a lower rate of malate utilization. The growth improvement achieved by E. faecalis during glucose malate cometabolism might explain why this microorganism employs different regulatory systems to tightly control the assimilation of both carbon sources. PMID- 22247140 TI - The 60-kilodalton protein encoded by orf2 in the cry19A operon of Bacillus thuringiensis subsp. jegathesan functions like a C-terminal crystallization domain. AB - The cry19A operon of Bacillus thuringiensis subsp. jegathesan encodes two proteins, mosquitocidal Cry19A (ORF1; 75 kDa) and an ORF2 (60 kDa) of unknown function. Expression of the cry19A operon in an acrystalliferous strain of B. thuringiensis (4Q7) yielded one small crystal per cell, whereas no crystals were produced when cry19A or orf2 was expressed alone. To determine the function of the ORF2 protein, different combinations of Cry19A, ORF2, and the N- or C terminal half of Cry1C were synthesized in strain 4Q7. Stable crystalline inclusions of these fusion proteins similar in shape to those in the strain harboring the wild-type operon were observed in sporulating cells. Comparative analysis showed that ORF2 shares considerable amino acid sequence identity with the C-terminal region of large Cry proteins. Together, these results suggest that ORF2 assists in synthesis and crystallization of Cry19A by functioning like the C terminal domain characteristic of Cry protein in the 130-kDa mass range. In addition, to determine whether overexpression of the cry19A operon stabilized its shape and increased Cry19A yield, it was expressed under the control of the strong chimeric cyt1A-p/STAB-SD promoter. Interestingly, in contrast to the expression seen with the native promoter, overexpression of the operon yielded uniform bipyramidal crystals that were 4-fold larger on average than the wild type crystal. In bioassays using the 4th instar larvae of Culex quinquefasciatus, the strain producing the larger Cry19A crystal showed moderate larvicidal activity that was 4-fold (95% lethal concentration [LC(95)] = 1.9 MUg/ml) more toxic than the activity produced in the strain harboring the wild-type operon (LC(95) = 8.2 MUg/ml). PMID- 22247141 TI - Membrane lipid peroxidation in copper alloy-mediated contact killing of Escherichia coli. AB - Copper alloy surfaces are passive antimicrobial sanitizing agents that kill bacteria, fungi, and some viruses. Studies of the mechanism of contact killing in Escherichia coli implicate the membrane as the target, yet the specific component and underlying biochemistry remain unknown. This study explores the hypothesis that nonenzymatic peroxidation of membrane phospholipids is responsible for copper alloy-mediated surface killing. Lipid peroxidation was monitored with the thiobarbituric acid-reactive substances (TBARS) assay. Survival, TBARS levels, and DNA degradation were followed in cells exposed to copper alloy surfaces containing 60 to 99.90% copper or in medium containing CuSO(4). In all cases, TBARS levels increased with copper exposure levels. Cells exposed to the highest copper content alloys, C11000 and C24000, exhibited novel characteristics. TBARS increased immediately at a very rapid rate but peaked at about 30 min. This peak was associated with the period of most rapid killing, loss in membrane integrity, and DNA degradation. DNA degradation is not the primary cause of copper-mediated surface killing. Cells exposed to the 60% copper alloy for 60 min had fully intact genomic DNA but no viable cells. In a fabR mutant strain with increased levels of unsaturated fatty acids, sensitivity to copper alloy surface-mediated killing increased, TBARS levels peaked earlier, and genomic DNA degradation occurred sooner than in the isogenic parental strain. Taken together, these results suggest that copper alloy surface-mediated killing of E. coli is triggered by nonenzymatic oxidative damage of membrane phospholipids that ultimately results in the loss of membrane integrity and cell death. PMID- 22247142 TI - Occurrence and persistence of bacterial pathogens and indicator organisms in beach sand along the California coast. AB - This report documents the presence of fecal indicators and bacterial pathogens in sand at 53 California marine beaches using both culture-dependent and independent (PCR and quantitative PCR [QPCR]) methods. Fecal indicator bacteria were widespread in California beach sand, with Escherichia coli and enterococci detected at 68% and 94% of the beaches surveyed, respectively. Somatic coliphages and a Bacteroidales human-specific fecal marker were detected at 43% and 13% of the beaches, respectively. Dry sand samples from almost 30% of the beaches contained at least one of the following pathogens: Salmonella spp., Campylobacter spp., Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA), which were detected at 15%, 13%, 14%, and 3% of tested beaches, respectively. Fecal indicators and pathogens were poorly correlated to one another and to land cover. Sands were dry at the time of collection, and those with relatively high moisture tended to have higher concentrations or a more frequent occurrence of both indicators and pathogens. Using culture-dependent assays, fecal indicators decayed faster than pathogens in microcosm experiments using unaltered beach sand seeded with sewage and assessed by culture-dependent assays. The following order of persistence was observed (listed from most to least persistent): Campylobacter > Salmonella > somatic coliphages > enterococci > E. coli > F(+) phages. In contrast, pathogens decayed faster than fecal indicators in culture-independent assays: enterococci > Bacteroidales human specific marker > Salmonella > Campylobacter. Microcosm experiments demonstrated that both indicators and pathogens were mobilized by wetting with seawater. Decay rates measured by QPCR were lower than those measured with culture-dependent methods. Enterococcal persistence and possible growth were observed for wetted microcosms relative to unwetted controls. PMID- 22247143 TI - Detection of Coxiella burnetii DNA on small-ruminant farms during a Q fever outbreak in the Netherlands. AB - During large Q fever outbreaks in the Netherlands between 2007 and 2010, dairy goat farms were implicated as the primary source of human Q fever. The transmission of Coxiella burnetii to humans is thought to occur primarily via aerosols, although available data on C. burnetii in aerosols and other environmental matrices are limited. During the outbreak of 2009, 19 dairy goat farms and one dairy sheep farm were selected nationwide to investigate the presence of C. burnetii DNA in vaginal swabs, manure, surface area swabs, milk unit filters, and aerosols. Four of these farms had a positive status during the Coxiella burnetii bulk milk monitoring program in 2009 and additionally reported abortion waves in 2008 or 2009. Eleven farms were reported as having positive bulk milk only, and five selected (control) farms had a bulk milk-negative status in 2009 and no reported Q fever history. Screening by quantitative PCR (qPCR) revealed that on farms with a history of abortions related to C. burnetii and, to a lesser extent, on farms positive by bulk milk monitoring, generally higher proportions of positive samples and higher levels of C. burnetii DNA within positive samples were observed than on the control farms. The relatively high levels of C. burnetii DNA in surface area swabs and aerosols sampled in stables of bulk milk-positive farms, including farms with a Q fever-related abortion history, support the hypothesis that these farms can pose a risk for the transmission of C. burnetii to humans. PMID- 22247144 TI - Conserved mechanisms of Mycobacterium marinum pathogenesis within the environmental amoeba Acanthamoeba castellanii. AB - Mycobacterium marinum is a waterborne mycobacterial pathogen. Due to their common niche, protozoa likely represent natural hosts for M. marinum. We demonstrate that the ESX-1 secretion system is required for M. marinum pathogenesis and that M. marinum utilizes actin-based motility in amoebae. Therefore, at least two virulence pathways used by M. marinum in macrophages are conserved during M. marinum infection of amoebae. PMID- 22247145 TI - Generation of a monoclonal antibody against Mycoplasma spp. following accidental contamination during production of a monoclonal antibody against Lawsonia intracellularis. AB - This report describes Mycoplasma contamination of Lawsonia intracellularis cultures that led to the unintended acquisition of a monoclonal antibody against Mycoplasma spp. during the attempted generation of a monoclonal antibody against L. intracellularis. PMID- 22247146 TI - Human-associated extended-spectrum beta-lactamase in the Antarctic. AB - Escherichia coli bacteria with extended-spectrum beta-lactamase (ESBL) type CTX-M resistance were isolated from water samples collected close to research stations in Antarctica. The isolates had bla(CTX-M-1) and bla(CTX-M-15) genotypes and sequence types (ST) indicative of a human-associated origin. This is the first record of ESBL-producing enterobacteria from Antarctica. PMID- 22247148 TI - Candida zemplinina can reduce acetic acid produced by Saccharomyces cerevisiae in sweet wine fermentations. AB - In this study we investigated the possibility of using Candida zemplinina, as a partner of Saccharomyces cerevisiae, in mixed fermentations of must with a high sugar content, in order to reduce its acetic acid production. Thirty-five C. zemplinina strains, which were isolated from different geographic regions, were molecularly characterized, and their fermentation performances were determined. Five genetically different strains were selected for mixed fermentations with S. cerevisiae. Two types of inoculation were carried out: coinoculation and sequential inoculation. A balance between the two species was generally observed for the first 6 days, after which the levels of C. zemplinina started to decrease. Relevant differences were observed concerning the consumption of sugars, the ethanol and glycerol content, and acetic acid production, depending on which strain was used and which type of inoculation was performed. Sequential inoculation led to the reduction of about half of the acetic acid content compared to the pure S. cerevisiae fermentation, but the ethanol and glycerol amounts were also low. A coinoculation with selected combinations of S. cerevisiae and C. zemplinina resulted in a decrease of ~0.3 g of acetic acid/liter, while maintaining high ethanol and glycerol levels. This study demonstrates that mixed S. cerevisiae and C. zemplinina fermentation could be applied in sweet wine fermentation to reduce the production of acetic acid, connected to the S. cerevisiae osmotic stress response. PMID- 22247147 TI - FSL J1-208, a virulent uncommon phylogenetic lineage IV Listeria monocytogenes strain with a small chromosome size and a putative virulence plasmid carrying internalin-like genes. AB - The bacterial genus Listeria contains both saprotrophic and facultative pathogenic species. A small genome size has been suggested to be associated with the loss of pathogenic potential of L. welshimeri and L. seeligeri. In this paper we present data on the genome of L. monocytogenes strain FSL J1-208, a representative of phylogenetic lineage IV. Although this strain was isolated from a clinical case in a caprine host and has no decreased invasiveness in human intestinal epithelial cells, our analyses show that this strain has one of the smallest Listeria chromosomes reported to date (2.78 Mb). The chromosome contains 2,772 protein-coding genes, including well-characterized virulence-associated genes, such as inlA, inlB, and inlC and the full prfA gene cluster. The small genome size is mainly caused by the absence of prophages in the genome of L. monocytogenes FSL J1-208, and further analyses showed that the total size of prophage-related regions is highly correlated to chromosome size in the genus Listeria. L. monocytogenes FSL J1-208 carries a unique type of plasmid of approximately 80 kbp that does not carry genes annotated as being involved in resistance to antibiotics or heavy metals. The accessory genes in this plasmid belong to the internalin family, a family of virulence-associated proteins, and therefore this is the first report of a potential virulence plasmid in the genus Listeria. PMID- 22247149 TI - Design of chimeric levansucrases with improved transglycosylation activity. AB - Fructansucrases (FSs), including levansucrases and inulosucrases, are enzymes that synthesize fructose polymers from sucrose by the direct transfer of the fructosyl moiety to a growing polymer chain. These enzymes, particularly the single domain fructansucrases, also possess an important hydrolytic activity, which may account for as much as 70 to 80% of substrate conversion, depending on reaction conditions. Here, we report the construction of four chimeric levansucrases from SacB, a single domain levansucrase produced by Bacillus subtilis. Based on observations derived from the effect of domain deletion in both multidomain fructansucrases and glucansucrases, we attached different extensions to SacB. These extensions included the transitional domain and complete C-terminal domain of Leuconostoc citreum inulosucrase (IslA), Leuconostoc mesenteroides levansucrase (LevC), and a L. mesenteroides glucansucrase (DsrP). It was found that in some cases the hydrolytic activity was reduced to less than 10% of substrate conversion; however, all of the constructs were as stable as SacB. This shift in enzyme specificity was observed even when the SacB catalytic domain was extended only with the transitional region found in multidomain FSs. Specific kinetic analysis revealed that this change in specificity of the SacB chimeric constructs was derived from a 5-fold increase in the transfructosylation k(cat) and not from a reduction of the hydrolytic k(cat), which remained constant. PMID- 22247150 TI - Characterization of airborne bacteria at an underground subway station. AB - The reliable detection of airborne biological threat agents depends on several factors, including the performance criteria of the detector and its operational environment. One step in improving the detector's performance is to increase our knowledge of the biological aerosol background in potential operational environments. Subway stations are enclosed public environments, which may be regarded as potential targets for incidents involving biological threat agents. In this study, the airborne bacterial community at a subway station in Norway was characterized (concentration level, diversity, and virulence- and survival associated properties). In addition, a SASS 3100 high-volume air sampler and a matrix-assisted laser desorption ionization-time of flight mass spectrometry based isolate screening procedure was used for these studies. The daytime level of airborne bacteria at the station was higher than the nighttime and outdoor levels, and the relative bacterial spore number was higher in outdoor air than at the station. The bacterial content, particle concentration, and size distribution were stable within each environment throughout the study (May to September 2010). The majority of the airborne bacteria belonged to the genera Bacillus, Micrococcus, and Staphylococcus, but a total of 37 different genera were identified in the air. These results suggest that anthropogenic sources are major contributors to airborne bacteria at subway stations and that such airborne communities could harbor virulence- and survival-associated properties of potential relevance for biological detection and surveillance, as well as for public health. Our findings also contribute to the development of realistic testing and evaluation schemes for biological detection/surveillance systems by providing information that can be used to mimic real-life operational airborne environments in controlled aerosol test chambers. PMID- 22247151 TI - Fulminant cryptosporidiosis after near-drowning: a human Cryptosporidium parvum strain implicated in invasive gastrointestinal adenocarcinoma and cholangiocarcinoma in an experimental model. AB - In the present work, we report the characterization of a Cryptosporidium parvum strain isolated from a patient who nearly drowned in the Deule River (Lille, France) after being discharged from the hospital where he had undergone allogeneic stem cell transplantation. After being rescued and readmitted to the hospital, he developed fulminant cryptosporidiosis. The strain isolated from the patient's stools was identified as C. parvum II2A15G2R1 (subtype linked to zoonotic exposure) and inoculated into SCID mice. In this host, this virulent C. parvum isolate induced not only severe infection but also invasive gastrointestinal and biliary adenocarcinoma. The observation of adenocarcinomas that progressed through all layers of the digestive tract to the subserosa and spread via blood vessels confirmed the invasive nature of the neoplastic process. These results indicate for the first time that a human-derived C. parvum isolate is able to induce digestive cancer. This study is of special interest considering the exposure of a large number of humans and animals to this waterborne protozoan, which is highly tumorigenic when inoculated in a rodent model. PMID- 22247152 TI - Transcriptional responses of Escherichia coli K-12 and O157:H7 associated with lettuce leaves. AB - An increasing number of outbreaks of gastroenteritis recently caused by Escherichia coli O157:H7 have been linked to the consumption of leafy green vegetables. Although it is known that E. coli survives and grows in the phyllosphere of lettuce plants, the molecular mechanisms by which this bacterium associates with plants are largely unknown. The goal of this study was to identify E. coli genes relevant to its interaction, survival, or attachment to lettuce leaf surfaces, comparing E. coli K-12, a model system, and E. coli O157:H7, a pathogen associated with a large number of outbreaks. Using microarrays, we found that upon interaction with intact leaves, 10.1% and 8.7% of the 3,798 shared genes were differentially expressed in K-12 and O157:H7, respectively, whereas 3.1% changed transcript levels in both. The largest group of genes downregulated consisted of those involved in energy metabolism, including tnaA (33-fold change), encoding a tryptophanase that converts tryptophan into indole. Genes involved in biofilm modulation (bhsA and ybiM) and curli production (csgA and csgB) were significantly upregulated in E. coli K-12 and O157:H7. Both csgA and bhsA (ycfR) mutants were impaired in the long-term colonization of the leaf surface, but only csgA mutants had diminished ability in short-term attachment experiments. Our data suggested that the interaction of E. coli K-12 and O157:H7 with undamaged lettuce leaves likely is initiated via attachment to the leaf surface using curli fibers, a downward shift in their metabolism, and the suppression of biofilm formation. PMID- 22247153 TI - Marked genomic diversity of norovirus genogroup I strains in a waterborne outbreak. AB - Marked norovirus (NoV) diversity was detected in patient samples from a large community outbreak of gastroenteritis with waterborne epidemiology affecting approximately 2,400 people. NoV was detected in 33 of 50 patient samples examined by group-specific real-time reverse transcription-PCR. NoV genotype I (GI) strains predominated in 31 patients, with mixed GI infections occurring in 5 of these patients. Sequence analysis of RNA-dependent polymerase-N/S capsid-coding regions (~900 nucleotides in length) confirmed the dominance of the GI strains (n = 36). Strains of NoV GI.4 (n = 21) and GI.7 (n = 9) were identified, but six strains required full capsid amino acid analyses (530 to 550 amino acids) based on control sequencing of cloned amplicons before the virus genotype could be determined. Three strains were assigned to a new NoV GI genotype, proposed as GI.9, based on capsid amino acid analyses showing 26% dissimilarity from the established genotypes GI.1 to GI.8. Three other strains grouped in a sub-branch of GI.3 with 13 to 15% amino acid dissimilarity to GI.3 GenBank reference strains. Phylogenetic analysis (2.1 kb) of 10 representative strains confirmed these genotype clusters. Strains of NoV GII.4 (n = 1), NoV GII.6 (n = 2), sapovirus GII.2 (n = 1), rotavirus (n = 3), adenovirus (n = 1), and Campylobacter spp. (n = 2) were detected as single infections or as mixtures with NoV GI. Marked NoV GI diversity detected in patients was consistent with epidemiologic evidence of waterborne NoV infections, suggesting human fecal contamination of the water supply. Recognition of NoV diversity in a cluster of patients provided a useful warning marker of waterborne contamination in the Lilla Edet outbreak. PMID- 22247155 TI - Comparison of the prevalences and antimicrobial resistances of Escherichia coli isolates from different retail meats in the United States, 2002 to 2008. AB - Escherichia coli isolates were recovered from the National Antimicrobial Resistance Monitoring System retail meat program and examined for antimicrobial susceptibility. Retail meat samples (n = 11,921) from four U.S. states collected during 2002 to 2008, consisting of 2,988 chicken breast, 2,942 ground turkey, 2,991 ground beef, and 3,000 pork chop samples, were analyzed. A total of 8,286 E. coli isolates were recovered. The greatest numbers of samples contaminated with the organism were chicken (83.5%) and turkey (82.0%), followed by beef (68.9%) and pork (44.0%). Resistance was most common to tetracycline (50.3%), followed by streptomycin (34.6%), sulfamethoxazole-sulfisoxazole (31.6%), ampicillin (22.5%), gentamicin (18.6%), kanamycin (8.4%), amoxicillin-clavulanic acid (6.4%), and cefoxitin (5.2%). Less than 5% of the isolates had resistance to trimethoprim, ceftriaxone, ceftiofur, nalidixic acid, chloramphenicol, and ciprofloxacin. All isolates were susceptible to amikacin. Compared to beef and pork isolates, the poultry meat isolates had a greater percentage of resistance to all tested drugs, with the exception of chloramphenicol, to which pork isolates had the most resistance. More than half of the turkey isolates (56%) were resistant to multidrugs (>=3 classes) compared to 38.9% of chicken, 17.3% of pork, and 9.3% of beef isolates. The bla(CMY) gene was present in all ceftriaxone and ceftiofur-resistant isolates. The cmlA, flo, and catI genes were present in 45%, 43%, and 40% of chloramphenicol-resistant isolates, respectively. Most nalidixic acid-resistant isolates (98.5%) had a gyrA mutation in S83 or D87 or both, whereas only 6.7% had a parC mutation in either S80 or E84. The results showed that E. coli was commonly present in the retail meats, and antimicrobial resistance profiles differed according to the animal origin of the isolates. PMID- 22247154 TI - Contribution of surface beta-glucan polysaccharide to physicochemical and immunomodulatory properties of Propionibacterium freudenreichii. AB - Propionibacterium freudenreichii is a bacterial species found in Swiss-type cheeses and is also considered for its health properties. The main claimed effect is the bifidogenic property. Some strains were shown recently to display other interesting probiotic potentialities such as anti-inflammatory properties. About 30% of strains were shown to produce a surface exopolysaccharide (EPS) composed of (1->3,1->2)-beta-D-glucan due to a single gene named gtfF. We hypothesized that functional properties of P. freudenreichii strains, including their anti inflammatory properties, could be linked to the presence of beta-glucan. To evaluate this hypothesis, gtfF genes of three beta-glucan-producing strains were disrupted. These knockout (KO) mutants were complemented with a plasmid harboring gtfF (KO-C mutants). The absence of beta-glucan in KO mutants was verified by immunological detection and transmission electron microscopy. We observed by atomic force microscopy that the absence of beta-glucan in the KO mutant dramatically changed the cell's topography. The capacity to adhere to polystyrene surface was increased for the KO mutants compared to wild-type (WT) strains. Anti inflammatory properties of WT strains and mutants were analyzed by stimulation of human peripheral blood mononuclear cells (PBMCs). A significant increase of the anti-inflammatory interleukin-10 cytokine production by PBMCs was measured in the KO mutants compared to WT strains. For one strain, the role of beta-glucan in mice gut persistence was assessed, and no significant difference was observed between the WT strain and its KO mutant. Thus, beta-glucan appears to partly hide the anti-inflammatory properties of P. freudenreichii; which is an important result for the selection of probiotic strains. PMID- 22247156 TI - Use of high hydrostatic pressure to inactivate Escherichia coli O157:H7 and Salmonella enterica internalized within and adhered to preharvest contaminated green onions. AB - Green onions grown in soil and hydroponic medium contaminated with Escherichia coli O157:H7 and Salmonella were found to take up the pathogens in their roots, bulbs, stems, and leaves. Pressure treatment at 400 to 500 MPa for 2 min at 20 to 40 degrees C eliminated both pathogens that were internalized within green onions during plant growth. PMID- 22247157 TI - Phenotypic switching in Pseudomonas brassicacearum involves GacS- and GacA dependent Rsm small RNAs. AB - The plant-beneficial bacterium Pseudomonas brassicacearum forms phenotypic variants in vitro as well as in planta during root colonization under natural conditions. Transcriptome analysis of typical phenotypic variants using microarrays containing coding as well as noncoding DNA fragments showed differential expression of several genes relevant to secondary metabolism and of the small RNA (sRNA) genes rsmX, rsmY, and rsmZ. Naturally occurring mutations in the gacS-gacA system accounted for phenotypic switching, which was characterized by downregulation of antifungal secondary metabolites (2,4-diacetylphloroglucinol and cyanide), indoleacetate, exoenzymes (lipase and protease), and three different N-acyl-homoserine lactone molecules. Moreover, in addition to abrogating these biocontrol traits, gacS and gacA mutations resulted in reduced expression of the type VI secretion machinery, alginate biosynthesis, and biofilm formation. In a gacA mutant, the expression of rsmX was completely abolished, unlike that of rsmY and rsmZ. Overexpression of any of the three sRNAs in the gacA mutant overruled the pleiotropic changes and restored the wild-type phenotypes, suggesting functional redundancy of these sRNAs. In conclusion, our data show that phenotypic switching in P. brassicacearum results from mutations in the gacS-gacA system. PMID- 22247158 TI - A novel restriction-modification system is responsible for temperature-dependent phage resistance in Listeria monocytogenes ECII. AB - Listeria monocytogenes epidemic clone II (ECII) strains are unusual in being completely resistant to phage when grown at low temperatures (<=30 degrees C). In the current study we constructed and characterized a mariner-based mutant (J46C) of the ECII strain H7550-Cd(S) that lacked temperature-dependent resistance to phage. The transposon was localized in LMOh7858_2753 (open reading frame [ORF] 2753), a member of a 12-ORF genomic island unique to ECII strains. ORF 2753 and ORF 2754 exhibited homologies to restriction endonucleases and methyltransferases associated with type II restriction-modification (RM) systems. In silico-based predictions of the recognition site for this putative RM system were supported by resistance of DNA from ECII strains to digestion by BfuI, a type II restriction enzyme specific for GTATCC (N6/5). Similarly to J46C, a mutant harboring an in frame deletion of ORF 2753 was susceptible to phage regardless of temperature of growth (25 degrees C or 37 degrees C). Genetic complementation restored phage resistance in 25 degrees C-grown cells of ORF 2753 mutants. Reverse transcription (RT) and quantitative real-time PCR data suggested enhanced transcription of ORF 2753 at low temperatures (<=25 degrees C) compared to 37 degrees C. In contrast, available transcriptional data suggested that the putative methyltransferase (ORF 2754) was constitutively expressed at all tested temperatures (4 to 37 degrees C). Thus, temperature-dependent resistance of L. monocytogenes ECII to phage is mediated by temperature-dependent expression of the restriction endonuclease associated with a novel RM system (LmoH7) unique to this epidemic clone. PMID- 22247159 TI - Orally administered thermostable N-acyl homoserine lactonase from Bacillus sp. strain AI96 attenuates Aeromonas hydrophila infection in zebrafish. AB - N-Acylated homoserine lactone (AHL) lactonases are capable of degrading signal molecules involved in bacterial quorum sensing and therefore represent a new approach to control bacterial infection. Here a gene responsible for the AHL lactonase activity of Bacillus sp. strain AI96, 753 bp in length, was cloned and then expressed in Escherichia coli. The deduced amino acid sequence of Bacillus sp. AI96 AiiA (AiiA(AI96)) is most similar to those of other Bacillus sp. AHL lactonases (~80% sequence identity) and was consequently categorized as a member of the metallo-beta-lactamase superfamily. AiiA(AI96) maintains ~100% of its activity at 10 degrees C to 40 degrees C at pH 8.0, and it is very stable at 70 degrees C at pH 8.0 for at least 1 h; no other Bacillus AHL lactonase has been found to be stable under these conditions. AiiA(AI96) resists digestion by proteases and carp intestinal juice, and it has broad-spectrum substrate specificity. The supplementation of AiiA(AI96) into fish feed by oral administration significantly attenuated Aeromonas hydrophila infection in zebrafish. This is the first report of the oral administration of an AHL lactonase for the efficient control of A. hydrophila. PMID- 22247160 TI - Association of pandemic Vibrio parahaemolyticus O3:K6 present in the coastal environment of Northwest Mexico with cases of recurrent diarrhea between 2004 and 2010. AB - In 2004, more than 1,230 cases of gastroenteritis due to pandemic O3:K6 strains of Vibrio parahaemolyticus were reported in southern Sinaloa, a state in Northwestern Mexico. Recurrent sporadic cases arose from 2004 to 2010, spreading from the south to the north. In the present study, Vibrio parahaemolyticus was detected in both environmental samples and clinical cases along the Pacific coast of Sinaloa during 2004 to 2010. An evaluation was made of the serotypes, distribution of virulence genes, and presence of pandemic O3:K6 strains. A total of 144 strains were isolated from environmental samples (from sediment, seawater, and shrimp), and 154 clinical strains were isolated. A total of 10 O serogroups and 30 serovars were identified in the strains. Environmental strains (n = 144) belonged to 10 O serogroups and 28 serovars, while clinical strains (n = 154) belonged to 8 O serogroups and 14 serovars. Ten serovars were shared by both environmental and clinical strains. Among 144 environmental isolates, 4.1% (6/144) belonged to the pandemic clone, with 83.3% containing the orf8 gene and with O3:K6 accounting for 67%. On the other hand, pathogenic strains (tdh and/or trh) accounted for 52% (75/144) of the environmental isolates. Interestingly, among 154 clinical isolates, 80.5% (124/154) were pandemic strains, with O3:K6 (tdh, toxRS(new), and orf8) representing the predominant serovar (99.2%, 123/124). Overall, our results indicate that in spite of a high serodiversity and prevalence of pathogenic Vibrio parahaemolyticus in the environment, the pandemic strain O3:K6 caused >79% of reported cases between 2004 and 2010 in Sinaloa, Mexico. PMID- 22247161 TI - Relationship between yield components and partial resistance to Lecanicillium fungicola in the button mushroom, Agaricus bisporus, assessed by quantitative trait locus mapping. AB - Dry bubble, caused by Lecanicillium fungicola, is one of the most detrimental diseases affecting button mushroom cultivation. In a previous study, we demonstrated that breeding for resistance to this pathogen is quite challenging due to its quantitative inheritance. A second-generation hybrid progeny derived from an intervarietal cross between a wild strain and a commercial cultivar was characterized for L. fungicola resistance under artificial inoculation in three independent experiments. Analysis of quantitative trait loci (QTL) was used to determine the locations, numbers, and effects of genomic regions associated with dry-bubble resistance. Four traits related to resistance were analyzed. Two to four QTL were detected per trait, depending on the experiment. Two genomic regions, on linkage group X (LGX) and LGVIII, were consistently detected in the three experiments. The genomic region on LGX was detected for three of the four variables studied. The total phenotypic variance accounted for by all QTL ranged from 19.3% to 42.1% over all traits in all experiments. For most of the QTL, the favorable allele for resistance came from the wild parent, but for some QTL, the allele that contributed to a higher level of resistance was carried by the cultivar. Comparative mapping with QTL for yield-related traits revealed five colocations between resistance and yield component loci, suggesting that the resistance results from both genetic factors and fitness expression. The consequences for mushroom breeding programs are discussed. PMID- 22247162 TI - Seasonal and successional influences on bacterial community composition exceed that of protozoan grazing in river biofilms. AB - The effects of protozoa (heterotrophic flagellates and ciliates) on the morphology and community composition of bacterial biofilms were tested under natural background conditions by applying size fractionation in a river bypass system. Confocal laser scanning microscopy (CLSM) was used to monitor the morphological structure of the biofilm, and fingerprinting methods (single stranded conformation polymorphism [SSCP] and denaturing gradient gel electrophoresis [DGGE]) were utilized to assess changes in bacterial community composition. Season and internal population dynamics had a greater influence on the bacterial biofilm than the presence of protozoa. Within this general framework, bacterial area coverage and microcolony abundance were nevertheless enhanced by the presence of ciliates (but not by the presence of flagellates). We also found that the richness of bacterial operational taxonomic units was much higher in planktonic founder communities than in the ones establishing the biofilm. Within the first 2 h of colonization of an empty substrate by bacteria, the presence of flagellates additionally altered their biofilm community composition. As the biofilms matured, the number of bacterial operational taxonomic units increased when flagellates were present in high abundances. The additional presence of ciliates tended to at first reduce (days 2 to 7) and later increase (days 14 to 29) bacterial operational taxonomic unit richness. Altogether, the response of the bacterial community to protozoan grazing pressure was small compared to that reported in planktonic studies, but our findings contradict the assumption of a general grazing resistance of bacterial biofilms toward protozoa. PMID- 22247163 TI - Site-specific recombination strategies for engineering actinomycete genomes. AB - The feasibility of using technologies based on site-specific recombination in actinomycetes was shown several years ago. Despite their huge potential, these technologies mostly have been used for simple marker removal from a chromosome. In this paper, we present different site-specific recombination strategies for genome engineering in several actinomycetes belonging to the genera Streptomyces, Micromonospora, and Saccharothrix. Two different systems based on Cre/loxP and Dre/rox have been utilized for numerous applications. The activity of the Cre recombinase on the heterospecific loxLE and loxRE sites was similar to its activity on wild-type loxP sites. Moreover, an apramycin resistance marker flanked by the loxLERE sites was eliminated from the Streptomyces coelicolor M145 genome at a surprisingly high frequency (80%) compared to other bacteria. A synthetic gene encoding the Dre recombinase was constructed and successfully expressed in actinomycetes. We developed a marker-free expression method based on the combination of phage integration systems and site-specific recombinases. The Cre recombinase has been used in the deletion of huge genomic regions, including the phenalinolactone, monensin, and lipomycin biosynthetic gene clusters from Streptomyces sp. strain Tu6071, Streptomyces cinnamonensis A519, and Streptomyces aureofaciens Tu117, respectively. Finally, we also demonstrated the site-specific integration of plasmid and cosmid DNA into the chromosome of actinomycetes catalyzed by the Cre recombinase. We anticipate that the strategies presented here will be used extensively to study the genetics of actinomycetes. PMID- 22247164 TI - The composition of Camembert cheese-ripening cultures modulates both mycelial growth and appearance. AB - The fungal microbiota of bloomy-rind cheeses, such as Camembert, forms a complex ecosystem that has not been well studied, and its monitoring during the ripening period remains a challenge. One limitation of enumerating yeasts and molds on traditional agar media is that hyphae are multicellular structures, and colonies on a petri dish rarely develop from single cells. In addition, fungi tend to rapidly invade agar surfaces, covering small yeast colonies and resulting in an underestimation of their number. In this study, we developed a real-time quantitative PCR (qPCR) method using TaqMan probes to quantify a mixed fungal community containing the most common dairy yeasts and molds: Penicillium camemberti, Geotrichum candidum, Debaryomyces hansenii, and Kluyveromyces lactis on soft-cheese model curds (SCMC). The qPCR method was optimized and validated on pure cultures and used to evaluate the growth dynamics of a ripening culture containing P. camemberti, G. candidum, and K. lactis on the surface of the SCMC during a 31-day ripening period. The results showed that P. camemberti and G. candidum quickly dominated the ecosystem, while K. lactis remained less abundant. When added to this ecosystem, D. hansenii completely inhibited the growth of K. lactis in addition to reducing the growth of the other fungi. This result was confirmed by the decrease in the mycelium biomass on SCMC. This study compares culture-dependent and qPCR methods to successfully quantify complex fungal microbiota on a model curd simulating Camembert-type cheese. PMID- 22247165 TI - SulE, a sulfonylurea herbicide de-esterification esterase from Hansschlegelia zhihuaiae S113. AB - De-esterification is an important degradation or detoxification mechanism of sulfonylurea herbicide in microbes and plants. However, the biochemical and molecular mechanisms of sulfonylurea herbicide de-esterification are still unknown. In this study, a novel esterase gene, sulE, responsible for sulfonylurea herbicide de-esterification, was cloned from Hansschlegelia zhihuaiae S113. The gene contained an open reading frame of 1,194 bp, and a putative signal peptide at the N terminal was identified with a predicted cleavage site between Ala37 and Glu38, resulting in a 361-residue mature protein. SulE minus the signal peptide was synthesized in Escherichia coli BL21 and purified to homogeneity. SulE catalyzed the de-esterification of a variety of sulfonylurea herbicides that gave rise to the corresponding herbicidally inactive parent acid and exhibited the highest catalytic efficiency toward thifensulfuron-methyl. SulE was a dimer without the requirement of a cofactor. The activity of the enzyme was completely inhibited by Ag(+), Cd(2+), Zn(2+), methamidophos, and sodium dodecyl sulfate. A sulE-disrupted mutant strain, DeltasulE, was constructed by insertion mutation. DeltasulE lost the de-esterification ability and was more sensitive to the herbicides than the wild type of strain S113, suggesting that sulE played a vital role in the sulfonylurea herbicide resistance of the strain. The transfer of sulE into Saccharomyces cerevisiae BY4741 conferred on it the ability to de-esterify sulfonylurea herbicides and increased its resistance to the herbicides. This study has provided an excellent candidate for the mechanistic study of sulfonylurea herbicide metabolism and detoxification through de-esterification, construction of sulfonylurea herbicide-resistant transgenic crops, and bioremediation of sulfonylurea herbicide-contaminated environments. PMID- 22247166 TI - Criteria for selection of surrogates used to study the fate and control of pathogens in the environment. AB - This article defines the term surrogate as an organism, particle, or substance used to study the fate of a pathogen in a specific environment. Pathogenic organisms, nonpathogenic organisms, and innocuous particles have been used as surrogates for a variety of purposes, including studies on survival and transport as well as for method development and as "indicators" of certain conditions. This article develops a qualitative surrogate attribute prioritization process and allows investigators to select a surrogate by systematically detailing the experimental process and prioritizing attributes. The results are described through the use of case studies of various laboratories that have used this process. This article also discusses the history of surrogate and microbial indicator use and outlines the method by which surrogates can be used when conducting a quantitative microbial risk assessment. The ultimate goal of selecting a sufficiently representative surrogate is to improve public health through a health-based risk assessment framework. Under- or overestimating the resistance, inactivation, or movement may negatively impact risk assessments that, in turn, will impact health assessments and estimated safety levels. Reducing uncertainty in a risk assessment is one of the objectives of using surrogates and the ultimate motive for any experiment investigating potential exposure of a pathogen. PMID- 22247167 TI - Thermal inactivation of infectious pancreatic necrosis virus in a peptone-salt medium mimicking the water-soluble phase of hydrolyzed fish by-products. AB - Infectious pancreatic necrosis virus (IPNV) (serotype Sp) was exposed to temperatures between 60 and 90 degrees C in a medium mimicking the water-soluble phase of hydrolyzed fish by-products. D values ranged from 290 to 0.5 min, and the z value was approximately 9.8 degrees C. Addition of formic acid to create a pH 4 medium did not enhance heat inactivation. Predicted inactivation effects at different temperature-time combinations are provided. PMID- 22247169 TI - Swimming behavior of selected species of Archaea. AB - The swimming behavior of Bacteria has been studied extensively, at least for some species like Escherichia coli. In contrast, almost no data have been published for Archaea on this topic. In a systematic study we asked how the archaeal model organisms Halobacterium salinarum, Methanococcus voltae, Methanococcus maripaludis, Methanocaldococcus jannaschii, Methanocaldococcus villosus, Pyrococcus furiosus, and Sulfolobus acidocaldarius swim and which swimming behavior they exhibit. The two Euryarchaeota M. jannaschii and M. villosus were found to be, by far, the fastest organisms reported up to now, if speed is measured in bodies per second (bps). Their swimming speeds, at close to 400 and 500 bps, are much higher than the speed of the bacterium E. coli or of a very fast animal, like the cheetah, each with a speed of ca. 20 bps. In addition, we observed that two different swimming modes are used by some Archaea. They either swim very rapidly, in a more or less straight line, or they exhibit a slower kind of zigzag swimming behavior if cells are in close proximity to the surface of the glass capillary used for observation. We argue that such a "relocate-and-seek" behavior enables the organisms to stay in their natural habitat. PMID- 22247168 TI - Unexpected stability of Bacteroidetes and Firmicutes communities in laboratory biogas reactors fed with different defined substrates. AB - In the present study, bacterial communities in 200-liter biogas reactors containing liquid manure consecutively fed with casein, starch, and cream were investigated over a period of up to 33 days. A 16S rRNA gene clone library identified Bacteroidetes and Firmicutes as the most abundant bacterial groups in the starting material, at 58.9% and 30.1% of sequences, respectively. The community development of both groups was monitored by real-time PCR and single strand conformation polymorphism (SSCP) analysis. The Firmicutes and Bacteroidetes communities were unexpectedly stable and hardly influenced by batch feeding events. The continuous feeding of starch led to community shifts that nevertheless contributed to a stable reactor performance. A longer starving period and a change in the pH value resulted in further community shifts within the Bacteroidetes but did not influence the Firmicutes. Predominant DNA bands from SSCP gels were cloned and sequenced. Sequences related to Peptococcaceae, Cytophagales, and Petrimonas sulfuriphila were found in all samples from all experiments. Real-time PCR demonstrated the abundance of members of the phylum Bacteroidetes and also reflected changes in gene copy numbers in conjunction with a changing pH value and acetate accumulation. PMID- 22247170 TI - Extensive manipulation of caseicins A and B highlights the tolerance of these antimicrobial peptides to change. AB - Caseicins A and B are low-molecular-weight antimicrobial peptides which are released by proteolytic digestion of sodium caseinate. Caseicin A (IKHQGLPQE) is a nine-amino-acid cationic peptide, and caseicin B (VLNENLLR) is a neutral eight amino-acid peptide; both have previously been shown to exhibit antibacterial activity against a number of pathogens, including Cronobacter sakazakii. Previously, four variants of each caseicin which differed subtly from their natural counterparts were generated by peptide synthesis. Antimicrobial activity assays revealed that the importance of a number of the residues within the peptides was dependent on the strain being targeted. In this study, this engineering-based approach was expanded through the creation of a larger collection of 26 peptides which are altered in a variety of ways. The investigation highlights the generally greater tolerance of caseicin B to change, the fact that changes have a more detrimental impact on anti-Gram-negative activity, and the surprising number of variants which exhibit enhanced activity against Staphylococcus aureus. PMID- 22247171 TI - Effects of UV-B radiation on the structural and physiological diversity of bacterioneuston and bacterioplankton. AB - The effects of UV radiation (UVR) on estuarine bacterioneuston and bacterioplankton were assessed in microcosm experiments. Bacterial abundance and DNA synthesis were more affected in bacterioplankton. Protein synthesis was more inhibited in bacterioneuston. Community analysis indicated that UVR has the potential to select resistant bacteria (e.g., Gammaproteobacteria), particularly abundant in bacterioneuston. PMID- 22247172 TI - Characterization of the proteomic profiles of the brown tide alga Aureoumbra lagunensis under phosphate- and nitrogen-limiting conditions and of its phosphate limitation-specific protein with alkaline phosphatase activity. AB - The persistent bloom of the brown tide alga Aureoumbra lagunensis has been reported in coastal embayments along southern Texas, but the molecular mechanisms that sustain such algal bloom are unknown. We compared the proteome and physiological parameters of A. lagunensis grown in phosphate (P)-depleted, P- and nitrogen (N)-depleted, and nutrient-replete cultures. For the proteomic analysis, samples from three conditions were subjected to two-dimensional electrophoresis and tandem mass spectrometry analysis. Because of the paucity of genomic resources in this species, a de novo cross-species protein search was used to identify the differentially expressed proteins, which revealed their involvement in several key biological processes, such as chlorophyll synthesis, antioxidative protection, and protein degradation, suggesting that A. lagunensis may adopt intracellular nutrient compensation, extracellular organic nutrient regeneration, and damage protection to thrive in P-depleted environments. A highly abundant P limitation-specific protein, tentatively identified as a putative alkaline phosphatase, was further characterized by enzyme activity assay on nondenaturing gel and confocal microscopy, which confirmed that this protein has alkaline phosphatase activity, is a cytoplasmic protein, and is closely associated with the cell membrane. The abundance, location, and functional expression of this alkaline phosphatase all indicate the importance of organic P utilization for A. lagunensis under P limitation and the possible role of this alkaline phosphatase in regenerating phosphate from extra- or intracellular organic phosphorus. PMID- 22247173 TI - Characterization of the ELPhiS prophage from Salmonella enterica serovar Enteritidis strain LK5. AB - Phages are a primary driving force behind the evolution of bacterial pathogens by transferring a variety of virulence genes into their hosts. Similar to other bacterial genomes, the Salmonella enterica serovar Enteritidis LK5 genome contains several regions that are homologous to phages. Although genomic analysis demonstrated the presence of prophages, it was unable to confirm which phage elements within the genome were viable. Genetic markers were used to tag one of the prophages in the genome to allow monitoring of phage induction. Commonly used laboratory strains of Salmonella were resistant to phage infection, and therefore a rapid screen was developed to identify susceptible hosts. This approach showed that a genetically tagged prophage, ELPhiS (Enteritidis lysogenic phage S), was capable of infecting Salmonella serovars that are diverse in host range and virulence and has the potential to laterally transfer genes between these serovars via lysogenic conversion. The rapid screen approach is adaptable to any system with a large collection of isolates and may be used to test the viability of prophages found by sequencing the genomes of various bacterial pathogens. PMID- 22247174 TI - Identification of the herboxidiene biosynthetic gene cluster in Streptomyces chromofuscus ATCC 49982. AB - The 53-kb biosynthetic gene cluster for the novel anticholesterol natural product herboxidiene was identified in Streptomyces chromofuscus ATCC 49982 by genome sequencing and gene inactivation. In addition to herboxidiene, a biosynthetic intermediate, 18-deoxy-herboxidiene, was also isolated from the fermentation broth of S. chromofuscus ATCC 49982 as a minor metabolite. PMID- 22247175 TI - Characterization of the SpaCBA pilus fibers in the probiotic Lactobacillus rhamnosus GG. AB - Lactobacillus rhamnosus GG is a human intestinal isolate that has been studied intensively because of its probiotic properties. We have previously shown that L. rhamnosus GG produces proteinaceous pili that earlier had been observed only in Gram-positive pathogens (M. Kankainen et al., Proc. Natl. Acad. Sci. U. S. A. 106:17193-17198, 2009). These pili were found to be encoded by the spaCBA gene cluster, and the pilus-associated SpaC pilin was shown to confer on the cells a mucus-binding ability. In addition to the spaCBA cluster, another putative pilus cluster, spaFED, was predicted from the L. rhamnosus GG genome sequence. Herein, we show that only SpaCBA pili are produced by L. rhamnosus, and we describe a detailed analysis of cell wall-associated and affinity-purified SpaCBA pili by Western blotting and immunogold electron microscopy. Our results indicate that SpaCBA pili are heterotrimeric protrusions with a SpaA subunit as the shaft forming major pilin. Only a few SpaB subunits could be observed in pilus fibers. Instead, SpaB pilins were found at pilus bases, as assessed by immunogold double labeling of thin sections of cells, suggesting that SpaB is involved in the termination of pilus assembly. The SpaC adhesin was present along the whole pilus length at numbers nearly equaling those of SpaA. The relative amount and uniform distribution of SpaC within pili not only makes it possible to exert both long distance and intimate contact with host tissue but also provides mucus-binding strength, which explains the prolonged intestinal residency times observed for L. rhamnosus GG compared to that of nonpiliated lactobacilli. PMID- 22247176 TI - Short-read sequencing for genomic analysis of the brown rot fungus Fibroporia radiculosa. AB - The feasibility of short-read sequencing for genomic analysis was demonstrated for Fibroporia radiculosa, a copper-tolerant fungus that causes brown rot decay of wood. The effect of read quality on genomic assembly was assessed by filtering Illumina GAIIx reads from a single run of a paired-end library (75-nucleotide read length and 300-bp fragment size) at three different stringency levels and then assembling each data set with Velvet. A simple approach was devised to determine which filter stringency was "best." Venn diagrams identified the regions containing reads that were used in an assembly but were of a low-enough quality to be removed by a filter. By plotting base quality histograms of reads in this region, we judged whether a filter was too stringent or not stringent enough. Our best assembly had a genome size of 33.6 Mb, an N50 of 65.8 kb for a k mer of 51, and a maximum contig length of 347 kb. Using GeneMark, 9,262 genes were predicted. TargetP and SignalP analyses showed that among the 1,213 genes with secreted products, 986 had motifs for signal peptides and 227 had motifs for signal anchors. Blast2GO analysis provided functional annotation for 5,407 genes. We identified 29 genes with putative roles in copper tolerance and 73 genes for lignocellulose degradation. A search for homologs of these 102 genes showed that F. radiculosa exhibited more similarity to Postia placenta than Serpula lacrymans. Notable differences were found, however, and their involvements in copper tolerance and wood decay are discussed. PMID- 22247177 TI - External ecological niche for Candida albicans within reducing, oxygen-limited zones of wetlands. AB - Candida albicans within the human host is well studied; however, identifying environmental reservoirs of pathogens is epidemiologically valuable for disease management. Oxygen-limited, carbohydrate-rich zones of wetlands, to which sewage borne C. albicans is often exposed, are characteristically similar to the gastrointestinal reservoir. Consequently, using quantitative real-time PCR (qRT PCR) and gas chromatography-mass spectrometry (GC-MS), we demonstrated that oxygen-limited zones in polluted wetlands may act as potential reservoirs of C. albicans. PMID- 22247179 TI - Asbestos fibre burden in the lungs of patients with mesothelioma who lived near asbestos-cement factories. AB - BACKGROUND: Epidemics of malignant mesothelioma are occurring among inhabitants of Casale Monferrato and Bari never employed in the local asbestos-cement (AC) factories. The mesothelioma risk increased with proximity of residence to both plants. OBJECTIVES: To provide information on the intensity of environmental asbestos exposure, in the general population living around these factories, through the evaluation of the lung fibre burden in mesothelioma patients. METHODS: We analysed by a scanning electron microscope equipped with X-ray microanalysis wet (formalin-fixed) lung tissue samples from eight mesothelioma patients who lived in Casale Monferrato or Bari and underwent surgery. Their occupational and residential history was obtained during face-to-face interviews. Semi-quantitative and quantitative indices of cumulative environmental exposure to asbestos were computed, based on residential distance from the AC plants and duration of stay. RESULTS: The lung fibre burden ranged from 110 000 to 4 300 000 fibres per gram of dry lung (f/g) and was >1 000 000 f/g in three subjects. In four cases, only amphibole fibres were detected. Environmental exposures had ceased at least 10 years before samples were taken. No patient had other definite or probable asbestos exposures. A linear relationship was observed between the lung fibre burden and all three indices of environmental cumulative exposure to asbestos. CONCLUSIONS: Environmental exposure to a mixture of asbestos fibres may lead to a high lung fibre burden of amphiboles years after exposure cessation. The epidemiological evidence of an increased mesothelioma risk for the general population of Casale Monferrato and Bari, associated with asbestos contamination of the living environment, is corroborated. PMID- 22247180 TI - Open-access community child health clinics: the everyday experience of parents and child health nurses. AB - In Australia, Community Child Health Services (CCHS) is the primary health care service which seeks to strengthen and support families, prevent illness and manage risks. Several nursing models of care exist within CCHS, and limited research has investigated which is the best way to provide child health surveillance and parenting support during the early years. This study qualitatively explored the everyday lived experience of parents and child health nurses involved with an open-access (appointment-free, parent-led) group child health surveillance clinic. Findings showed that participants considered the open access clinic provided a helpful and supportive way of delivering child health surveillance and parental support to families with infants aged 0-18 months, without identified risk factors. The perspectives of multiple parents, nurses and other health workers found it effective, flexible and parent-directed, which may be in contrast to some traditional individual appointment child health surveillance methods. PMID- 22247178 TI - Biochemical and mutational analyses of a multidomain cellulase/mannanase from Caldicellulosiruptor bescii. AB - Thermophilic cellulases and hemicellulases are of significant interest to the biofuel industry due to their perceived advantages over their mesophilic counterparts. We describe here biochemical and mutational analyses of Caldicellulosiruptor bescii Cel9B/Man5A (CbCel9B/Man5A), a highly thermophilic enzyme. As one of the highly secreted proteins of C. bescii, the enzyme is likely to be critical to nutrient acquisition by the bacterium. CbCel9B/Man5A is a modular protein composed of three carbohydrate-binding modules flanked at the N terminus and the C terminus by a glycoside hydrolase family 9 (GH9) module and a GH5 module, respectively. Based on truncational analysis of the polypeptide, the cellulase and mannanase activities within CbCel9B/Man5A were assigned to the N- and C-terminal modules, respectively. CbCel9B/Man5A and its truncational mutants, in general, exhibited a pH optimum of ~5.5 and a temperature optimum of 85 degrees C. However, at this temperature, thermostability was very low. After 24 h of incubation at 75 degrees C, the wild-type protein maintained 43% activity, whereas a truncated mutant, TM1, maintained 75% activity. The catalytic efficiency with phosphoric acid swollen cellulose as a substrate for the wild type protein was 7.2 s(-1) ml/mg, and deleting the GH5 module led to a mutant (TM1) with a 2-fold increase in this kinetic parameter. Deletion of the GH9 module also increased the apparent k(cat) of the truncated mutant TM5 on several mannan-based substrates; however, a concomitant increase in the K(m) led to a decrease in the catalytic efficiencies on all substrates. These observations lead us to postulate that the two catalytic activities are coupled in the polypeptide. PMID- 22247182 TI - Evaluation of therapy services with the Measure of Processes of Care (MPOC-20): the perspectives of Icelandic parents of children with physical disability. AB - The aim of this population-based study was to examine how parents of Icelandic children with physical disability view the services of physical, occupational, and speech therapists and how family centered those services are. A secondary aim was to compare the differences of parental perceptions of therapy services based on age, residence, and disabilities. Parents of 88 (46%) children aged 2-18 answered the Measure of Processes of Care-20 (MPOC-20), and six parents participated in a focus group interview. Descriptive data were used to explore central tendency and variability, and comparisons were made using analysis of variance. Overall, the parents found the therapy services respectful, supportive, and coordinated; they felt enabled in their parent role and worked mostly in partnership with the professionals. Nevertheless, parents perceived they received insufficient information from therapists. Parents reported a wish for more cooperation, teamwork, and a key worker. Findings indicate that the MPOC is reliable and easy to use within the Icelandic context. PMID- 22247181 TI - Struggling to do what is right for the child: pediatric life-support decisions among physicians and nurses in France and Quebec. AB - This study examined (a) how physicians and nurses in France and Quebec make decisions about life-sustaining therapies (LSTs) for critically ill children and (b) corresponding ethical challenges. A focus groups design was used. A total of 21 physicians and 24 nurses participated (plus 9 physicians and 13 nurses from a prior secondary analysis). Principal differences related to roles: French participants regarded physicians as responsible for LST decisions, whereas Quebec participants recognized parents as formal decision-makers. Physicians stated they welcomed nurses' input but found they often did not participate, while nurses said they wanted to contribute but felt excluded. The LST limitations were based on conditions resulting in long-term consequences, irreversibility, continued deterioration, inability to engage in relationships and loss of autonomy. Ethical challenges related to: the fear of making errors in the face of uncertainty; struggling with patient/family consequences of one's actions; questioning the parental role and dealing with relational difficulties between physicians and nurses. PMID- 22247183 TI - Parental beliefs about behaviour problems of their asthmatic children and interventions to support parenting. AB - The aim of this study was to explore parents' attributions for their children's behaviour and their beliefs about treatment efficacy, and to investigate the specific topics and strategies parents believe would be most beneficial in a parenting intervention. A survey of 165 parents and qualitative interviews with 13 parents were conducted, assessing child behaviour, parental attributions and intervention characteristics. The findings indicated that parents were confident in their ability to manage the challenges of asthma, and in general, believed that five key asthma treatment recommendations were at least moderately helpful in managing their child's asthma. Many parents believed that asthma medications were related to behavioural difficulties including hyperactivity, disruptiveness, and disobedience. Nearly half of the parents were concerned about how to best manage their child's asthma, and a number of themes were identified as important intervention elements. The implications of these findings for intervention development are discussed. PMID- 22247184 TI - Children's regard for nurses and nursing: a mosaic of children's views on community nursing. AB - In the past decade there has been both an increase in the number of children who receive nursing care in their communities rather than in hospitals, and an increasing willingness to listen to children. This qualitative study used Clark's Mosaic approach to elicit children's views of community children's nursing. Twenty-one children took part in total, with seven children making up a core group who participated in a number of activities for over a year. A non-core group of 14 children were observed receiving care from six community children's nurses. The children had diverse medical conditions, were aged from 11 months to 17 years old and came from diverse social, ethnic and cultural backgrounds. Some children expressed a positive regard for nurses and nursing. Some children a negative regard, others were ambiguous. From these data it is proposed that there is a continuum of regard for nurses. How children regarded nurses did not seem to be related to the nurse's actions, but to the child's understanding of their illness and their involvement in care. Further study is required to clarify the concept and should focus on what effect children's regard for nurses and nursing has on health outcomes. PMID- 22247185 TI - Extremes, uncertainty, and responsibility across boundaries: facets and challenges of the experience of transition to complex, pediatric home care. AB - The availability of complex, pediatric home care (CPHC) allows ventilator dependent children to live at home not hospital. The process of transition from hospital to home encompasses the morphing of responsibilities from uniquely hospital based to CPHC based. This study promoted contextualized understanding of transition using in-depth case-study methodology. A total of 26 adults were interviewed for their roles and responsibilities in transition; they represented members of the family, hospital team, home team, and government programs. Interview analyses revealed four major facets of transition, each accompanied by a significant challenge. Transition (a) was a continuous shift in responsibility challenged by precarious human resources, (b) was peppered with losses producing uncertainty and grief, (c) was focused on crossing jurisdictions in the face of polarization around knowledge, and (d) was heavily reliant on mothers leading to expectations of maternal extraordinariness. The overarching conceptualization emerged that transition entailed extremes and uncertainty in the bridging of boundaries. PMID- 22247188 TI - Overlooked areas need attention for sound evaluation of DNA strand inheritance patterns in Drosophila male germline stem cells. PMID- 22247190 TI - Septins at a glance. PMID- 22247193 TI - Advisory group to develop model for surveillance. PMID- 22247192 TI - The epigenetic H3S10 phosphorylation mark is required for counteracting heterochromatic spreading and gene silencing in Drosophila melanogaster. AB - The JIL-1 kinase localizes specifically to euchromatin interband regions of polytene chromosomes and is the kinase responsible for histone H3S10 phosphorylation at interphase. Genetic interaction assays with strong JIL-1 hypomorphic loss-of-function alleles have demonstrated that the JIL-1 protein can counterbalance the effect of the major heterochromatin components on position effect variegation (PEV) and gene silencing. However, it is unclear whether this was a causative effect of the epigenetic H3S10 phosphorylation mark, or whether the effect of the JIL-1 protein on PEV was in fact caused by other functions or structural features of the protein. By transgenically expressing various truncated versions of JIL-1, with or without kinase activity, and assessing their effect on PEV and heterochromatic spreading, we show that the gross perturbation of polytene chromosome morphology observed in JIL-1 null mutants is unrelated to gene silencing in PEV and is likely to occur as a result of faulty polytene chromosome alignment and/or organization, separate from epigenetic regulation of chromatin structure. Furthermore, the findings provide evidence that the epigenetic H3S10 phosphorylation mark itself is necessary for preventing the observed heterochromatic spreading independently of any structural contributions from the JIL-1 protein. PMID- 22247194 TI - Vigilance urged as new virus emerges in livestock. PMID- 22247195 TI - Nottingham student scoops Connect top honours. PMID- 22247196 TI - Revised proposals for dog breeding legislation in Wales. PMID- 22247191 TI - GLUT4 exocytosis. AB - GLUT4 is an insulin-regulated glucose transporter that is responsible for insulin regulated glucose uptake into fat and muscle cells. In the absence of insulin, GLUT4 is mainly found in intracellular vesicles referred to as GLUT4 storage vesicles (GSVs). Here, we summarise evidence for the existence of these specific vesicles, how they are sequestered inside the cell and how they undergo exocytosis in the presence of insulin. In response to insulin stimulation, GSVs fuse with the plasma membrane in a rapid burst and in the continued presence of insulin GLUT4 molecules are internalised and recycled back to the plasma membrane in vesicles that are distinct from GSVs and probably of endosomal origin. In this Commentary we discuss evidence that this delivery process is tightly regulated and involves numerous molecules. Key components include the actin cytoskeleton, myosin motors, several Rab GTPases, the exocyst, SNARE proteins and SNARE regulators. Each step in this process is carefully orchestrated in a sequential and coupled manner and we are beginning to dissect key nodes within this network that determine vesicle-membrane fusion in response to insulin. This regulatory process clearly involves the Ser/Thr kinase AKT and the exquisite manner in which this single metabolic process is regulated makes it a likely target for lesions that might contribute to metabolic disease. PMID- 22247197 TI - Privy Council dismisses appeal. PMID- 22247198 TI - New online community to promote responsible pet ownership. PMID- 22247201 TI - Investigating antimicrobial resistance in people and animals. PMID- 22247203 TI - BVA Council calls for more transparency on RCVS governance review. PMID- 22247204 TI - Maintaining health in foals: the role of colostrum constituents. PMID- 22247205 TI - Schmallenberg virus: a novel viral disease in northern Europe. PMID- 22247206 TI - Human and veterinary general practice. PMID- 22247207 TI - Donating medicines to welfare projects. PMID- 22247208 TI - Suspected anthelmintic resistance to macrocyclic lactones in lambs in the UK. PMID- 22247209 TI - Leptospirosis and embryo recovery rate in mares. PMID- 22247210 TI - Toxopsis calypsus gen. nov., sp. nov. (Cyanobacteria, Nostocales) from cave 'Francthi', Peloponnese, Greece: a morphological and molecular evaluation. AB - Representatives of a new cyanobacterial genus, Toxopsis Lamprinou & Pantazidou gen. nov., were found in fresh material from Cave 'Francthi' (Peloponnese, Greece) and isolated in cultures. Ecological data relating to the environmental parameters of the sampling sites are provided, such as the photosynthetically active radiation (PAR), temperature and relative humidity. Morphological characteristics and the life cycle of the type species Toxopsis calypsus Lamprinou & Pantazidou sp. nov. were studied using light microscopy and scanning and transmission microscopy. Molecular analysis based on the 16S rRNA gene sequence was also conducted. Toxopsis calypsus sp. nov. is a false-branched nostocalean cyanobacterium with both isopolar and heteropolar filaments bearing mono-pored and bi-pored heterocysts, and also hormogonia and akinetes. Isopolar filaments adhere by the centre to the substrate and are found mainly in fresh material and in young cultures; heteropolar filaments bearing a basic mono-pore heterocyst are dominant in aged (more than one-year-old) cultures. According to the revised taxonomic classification system of Komarek & Anagnostidis (1989) [Komarek, J. & Anagnostidis, K. (1989). Algol Stud, 56, 247-345] based mainly on morphological data, the new genus described here shares morphological characters with both nostocalean families Scytonemataceae and Microchaetaceae, showing similarities in particular to Scytonematopsis contorta [Vaccarino, M. A. & Johansen, J. R. (2011). Fottea 11, 149-161], Microchaetaceae. Molecular data from the 16S rRNA sequence determined in this paper showed that Toxopsis calypsus sp. nov. is more related to the family Microchaetaceae, and the five phylotypes analysed by PCR showed that the closest nostocalean relatives are Tolypothrix distorta SAG 93.79 (GenBank accession no. GQ287651) and Coleodesmium sp. ANT.L52B.5 (AY493596) with 95-96% and 96% similarity, respectively. In contrast, the five phylotypes showed a distant similarity to Scytonematopsis contorta (<91%). The phenotypic and genetic traits strongly supported the classification of the five phylotypes as a new taxon for which the name Toxopsis calypsus Lamprinou & Pantazidou gen. nov., sp. nov. is proposed. PMID- 22247211 TI - Kistimonas scapharcae sp. nov., isolated from a dead ark clam (Scapharca broughtonii), and emended description of the genus Kistimonas. AB - A Gram-negative, motile, facultatively anaerobic rod, designated A36(T), was isolated from a dead ark clam found on the south coast of Korea. The isolate was catalase- and oxidase-negative. 16S rRNA gene sequence analysis indicated that strain A36(T) was most closely related to Kistimonas asteriae KMD 001(T), with which it shared 98.2% 16S rRNA gene sequence similarity. Strain A36(T) grew optimally at 30-37 degrees C, with 1% (w/v) NaCl and at pH 8.0. The major respiratory quinone was ubiquinone-9 (Q-9). The major polar lipids were phosphatidylserine, phosphoethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The major fatty acids were summed feature 3 (comprising C(16:1)omega7c and/or iso-C(15) 2-OH) and C(16:0). The genomic DNA G+C content was 47.3 mol%. DNA-DNA relatedness between the isolate and K. asteriae JCM 15607(T) was <25 +/- 3%. Strain A36(T) represents a novel species of the genus Kistimonas, for which the name Kistimonas scapharcae sp. nov. is proposed. The type strain is A36(T) ( = KACC 16204(T) = JCM 17805(T)). An emended description of the genus Kistimonas is also provided. PMID- 22247212 TI - Kaistia defluvii sp. nov., isolated from river sediment. AB - A Gram-stain-negative, aerobic, non-motile, rod- and coccus-shaped bacterium, designated strain B6-12(T), was isolated from sediment collected from the River Geumho in South Korea. In comparative 16S rRNA gene sequence analysis, the novel strain appeared to be affiliated with the class Alphaproteobacteria and to be most closely related to Kaistia adipata KCTC 12095(T), Kaistia dalseonensis DSM 18800(T), Kaistia geumhonensis DSM 18799(T), Kaistia granuli KCTC 12575(T), Kaistia soli KACC 12605(T) and Kaistia terrae KACC 12910(T), with sequence similarities of 96.2-99.1%. The predominant ubiquinone in the isolate was Q-10, major fatty acids were C(18:0), C(18:1)omega7c and C(19:0)omega8c cyclo, and genomic DNA G+C content was 63.0 mol%. Based on the phylogenetic and chemotaxonomic evidence and the results of DNA-DNA hybridizations, strain B6 12(T) represents a novel species in the genus Kaistia, for which the name Kaistia defluvii sp. nov. is proposed. The type strain is B6-12(T) ( = KCTC 23766(T) = JCM 18034(T)). PMID- 22247213 TI - Acinetobacter indicus sp. nov., isolated from a hexachlorocyclohexane dump site. AB - The taxonomic position of a Gram-negative, non-motile, oxidase negative and catalase positive strain, A648(T), isolated from a hexachlorocyclohexane (HCH) dump site located in Lucknow, India, was ascertained by using a polyphasic approach. A comparative analysis of a partial sequence of the rpoB gene and the 16S rRNA gene sequence revealed that strain A648(T) belonged to the genus Acinetobacter. DNA-DNA relatedness values between strain A648(T) and other closely related members (16S rRNA gene sequence similarity greater than 97%), namely Acinetobacter radioresistens DSM 6976(T), A. venetianus ATCC 31012(T), A. baumannii LMG 1041(T), A. parvus LMG 21765(T) A. junii LMG 998(T) and A. soli JCM 15062(T), were found to be less than 8%. The major cellular fatty acids of strain A648(T) were 18:1omega9c (19.6%), summed feature 3 (15.9%), 16:0 (10.6%) and 12:0 (6.4%). The DNA G+C content was 40.4 mol%. The polar lipid profile of strain A648(T) indicated the presence of diphosphatidylglycerol, phosphatidylethanolamine, followed by phosphatidylglycerol and phosphatidylcholine. The predominant polyamine of strain A648(T) was 1,3 diaminopropane and moderate amounts of putrescine, spermidine and spermine were also detected. The respiratory quinone consisted of ubiquinone with nine isoprene units (Q-9). On the basis of DNA-DNA hybridization, phenotypic characteristics and chemotaxonomic and phylogenetic comparisons with other members of the genus Acinetobacter, strain A648(T) is found to be a novel species of the genus Acinetobacter, for which the name Acinetobacter indicus sp. nov. is proposed. The type strain is A648(T) ( = DSM 25388(T) = CCM 7832(T)). PMID- 22247214 TI - Flavobacterium rakeshii sp. nov., isolated from marine sediment, and emended description of Flavobacterium beibuense Fu et al. 2011. AB - A Gram-negative, non-motile bacterial strain that formed straight rods and straw yellow colonies, designated FCS-5(T), was isolated from a marine sediment from the Arabian Sea. The isolate exhibited most of the phenotypic properties expected for a member of the genus Flavobacterium. The major fatty acids were iso-C(15:0), iso-C(17:0) 3-OH, C(17:1)omega9c and summed feature 3 (comprising iso-C(15:0) 2 OH and/or C(16:1)omega7c). The only isoprenoid quinone was MK-6. The only polyamine was homospermidine and the major polar lipid was phosphatidylethanolamine. The G+C content of the genomic DNA was 32.4 mol%. According to 16S rRNA gene sequence analysis, strain FCS-5(T) belonged to the genus Flavobacterium and exhibited 99.3% 16S rRNA gene sequence similarity with Flavobacterium beibuense F44-8(T) and 90.9-94.6% sequence similarity with other members of the genus Flavobacterium. The results of physiological and biochemical tests allowed the discrimination of the isolate from its phylogenetic relatives. Strain FCS-5(T) is a representative of a novel species of the genus Flavobacterium, for which the name Flavobacterium rakeshii sp. nov. is proposed. The type strain is FCS-5(T) ( = MTCC 10967(T) = JCM 17928(T)). An emended description of F. beibuense is also proposed. PMID- 22247215 TI - Halomonas ramblicola sp. nov., a moderately halophilic bacterium from Rambla Salada, a Mediterranean hypersaline rambla. AB - A moderately halophilic bacterium (strain RS-16(T)) was isolated from saline soil in Rambla Salada, a Mediterranean hypersaline rambla in Murcia, south-east Spain. Cells of strain RS-16(T) were Gram-negative rods, oxidase-negative and motile by peritrichous flagella. Strain RS-16(T) required NaCl for growth, and grew between 1% and 30% (w/v) NaCl (optimum, 5-7.5%), at temperatures of between 4 degrees C and 41 degrees C (optimum, 32-37 degrees C), and at pH values of between 5 and 10 (optimum, pH 7). Strain RS-16(T) was chemo-organotrophic and its metabolism was respiratory with oxygen and nitrate as terminal electron acceptors. It produced acids from d-glucose and myo-inositol, accumulated poly-beta hydroxyalkanoate granules and produced cream colonies on MY 7.5% (w/v). The DNA G+C content of strain RS-16(T) was 56.2 mol%. A comparison of 16S rRNA gene sequences confirmed the relationship of strain RS-16(T) to species of the genus Halomonas. The most phylogenetically related species was Halomonas cerina SP4(T) (97.4%16S rRNA gene sequence similarity). In DNA-DNA hybridization assays strain RS-16(T) showed DNA-DNA relatedness values of 62.7 +/- 3.09%, 64.5 +/- 1.97% and 64.7 +/- 1.74% to Halomonas cerina CECT 7282(T), Halomonas cerina CECT 7284 and Halomonas cerina CECT 7283, respectively. The major fatty acids of strain RS 16(T) were C(18:1)omega7c and C(16:0), and the predominant respiratory lipoquinone was ubiquinone, with nine isoprene units (Q-9). On the basis of these data, strain RS-16(T) is considered to represent a novel species of the genus Halomonas, for which the name Halomonas ramblicola sp. nov. is proposed. The type strain is RS-16(T) ( = CECT 7896(T) = LMG 26647(T)). PMID- 22247216 TI - Sphingomonas laterariae sp. nov., isolated from a hexachlorocyclohexane contaminated dump site. AB - A Gram-staining-negative, non-motile, cream-coloured and rod-shaped bacterium, designated strain LNB2(T), was isolated from a hexachlorocyclohexane-contaminated dump site in the village of Ummari, in northern India. The taxonomic position of the novel strain was investigated by using a polyphasic approach. In a phylogenetic analysis based on 16S rRNA gene sequences, strain LNB2(T) appeared to be most closely related to Sphingomonas haloaromaticamans A175(T) (98.0% sequence similarity) and Sphingomonas histidinilytica UM2(T) (97.3%). In DNA-DNA hybridizations, the levels of DNA-DNA relatedness between the novel strain and S. haloaromaticamans A175(T) and S. histidinilytica UM2(T) were found to be low (8.6% and 5.6%, respectively). The genomic DNA G+C content of strain LNB2(T) was 61.0 mol%. The novel strain's predominant fatty acids were summed feature 8 (C(18:1)omega7c and/or C(18:1)omega6c), C(16:0), summed feature 3 (C(16:1)omega7c and/or C(16:1)omega6c), C(14:0) 2-OH, C(17:1)omega6c and 11-methyl C(18:1)omega7c. The major ubiquinone was Q-10, the predominant polyamine was homospermidine, and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, sphingoglycolipid, phosphatidylethanolamine and phosphatidyldimethylethanolamine. Based on the phylogenetic, biochemical and chemotaxonomic evidence and the results of the DNA DNA hybridizations, strain LNB2(T) represents a novel species of the genus Sphingomonas, for which the name Sphingomonas laterariae sp. nov. is proposed. The type strain is LNB2(T) ( = MTCC 10873(T) = CCM 7880(T) = DSM 25432(T)). PMID- 22247217 TI - 'Candidatus Phytoplasma convolvuli', a new phytoplasma taxon associated with bindweed yellows in four European countries. AB - Plants of Convolvulus arvensis exhibiting symptoms of undersized leaves, shoot proliferation and yellowing, collectively defined as bindweed yellows, were sampled in different regions of Europe and assessed for phytoplasma infection by PCR amplification using phytoplasma universal rRNA operon primer pairs. Positive results were obtained for all diseased plants. RFLP analysis of amplicons comprising the16S rRNA gene alone or the16S rRNA gene and 16-23S intergenic spacer region indicated that the detected phytoplasmas were distinguishable from all other previously described rRNA gene sequences. Analysis of 16S rRNA gene sequences derived from seven selected phytoplasma strains (BY-S57/11, BY-S62/11, BY-I1015, BY-I1016, BY-BH1, BY-BH2 and BY-G) showed that they were nearly identical (99.9-100% gene sequence similarity) but shared less than 97.5% similarity with comparable sequences of other phytoplasmas. Thus, BY phytoplasmas represent a new taxon whose closest relatives are stolbur phytoplasma strains and 'Candidatus Phytoplasma fragariae' with which they share 97.2% and 97.1% 16S rRNA gene sequence similarity, respectively. Phylogenetic analysis of 16S rRNA gene sequences confirmed that bindweed yellows phytoplasma strains collectively represent a distinct lineage within the phytoplasma clade and share a common ancestor with previously published or proposed 'Candidatus Phytoplasma' taxa within a major branch including aster yellows and stolbur phytoplasmas. On the basis of unique 16S rRNA gene sequences and biological properties that include a single host plant species and a geographical distribution limited to parts of Europe, the bindweed yellows (BY) phytoplasmas represent a coherent but discrete taxon, 'Candidatus Phytoplasma convolvuli', with strain BY-S57/11 (GenBank accession no. JN833705) as the reference strain. PMID- 22247219 TI - Factors in nonadherence to quitline services: smoker characteristics explain little. AB - BACKGROUND: Quitlines offer evidence-based, multisession coaching support for smoking cessation in the 50 U.S. states, Canada, and several other countries. Smokers who enroll in quitline services have, ipso facto, shown readiness to attempt to quit, but noncompletion of coaching services appears widespread and has not been widely investigated. The current study explored the magnitude and correlates of quitline service abandonment. METHOD: A state's quitline intake, coaching, and nicotine patch/gum utilization data were obtained for smokers who enrolled during the period July 2007 to June 2008 (n = 20,882). Analyses examined demographic, socioeconomic status, nicotine dependence-related, and nicotine replacement therapy--utilization factors associated with completion of only one coaching session (of five offered). RESULTS: Almost half of enrollees (47.8%) completed only one session. All significant predictors together explained less than 4% of variance; not being sent nicotine replacement therapy was most strongly correlated with completion of only one session. A framework is proposed for directing research toward reducing quitline service nonadherence. CONCLUSIONS: Premature user abandonment of coaching calls is widespread within a quitline. Further research should determine the extent of the problem in national quitline systems, increase knowledge of mediators of nonadherence, and develop strategies for increasing coaching completion. PMID- 22247220 TI - Avoidance denial versus optimistic denial in reaction to the threat of future cardiovascular disease. AB - Two distinctly different denial-based threat orientations (avoidance denial and optimistic denial) were examined using a message about the future risk of cardiovascular disease (CVD) for young adults. Participants (N = 101) completed measures of denial-based dispositional threat orientations, current eating, comparative risk, and objective risk for CVD. They then read a high-threat message about CVD and rated their reactions of threat, denial, and worry. One month later, eating patterns in the past month were assessed. Both types of dispositional denial processes were associated with more self-distancing denial, but showed distinctly different, sometimes opposite, patterns of relationships with perceptions of threat, worry, and optimistic self-risk for CVD. In addition, the two denial-based processes were driven by different factors. The implications of these two denial-based threat orientations for the development of theory on denial and health messages, as well as the design of messages to change behavior, are discussed. PMID- 22247221 TI - The mask-onset delay paradigm and the availability of central and peripheral visual information during scene viewing. AB - We employed a variant of the mask-onset delay paradigm in order to limit the availability of visual information in central and peripheral vision within individual fixations during scene viewing. Subjects viewed full-color scene photos with instructions to search for a target object (Experiment 1) or to study them for a later memory test (Experiment 2). After a fixed interval following the onset of each eye fixation (50-100 ms), the scene was scrambled either in the central visual field or over the entire display. The intact scene was presented when the subject made an eye movement. Our results reconcile different sets of findings from prior research regarding the masking of central and peripheral visual information at different intervals following fixation onset. In particular, we found that when the entire display was scrambled, both search and memory performance were impaired even at relatively long mask-onset intervals. In contrast, when central vision was scrambled, there were subtle impairments that depended on the viewing task. In the 50-ms mask-onset interval, subjects were selectively impaired at identifying, but not in locating, the search target (Experiment 1), while memory performance (Experiment 2) was unaffected in this condition, and hence, the reliance on central and peripheral visual information depends partly on the viewing task. PMID- 22247222 TI - "Non-retinotopic processing" in Ternus motion displays modeled by spatiotemporal filters. AB - Recently, M. Boi, H. Ogmen, J. Krummenacher, T. U. Otto, & M. H. Herzog (2009) reported a fascinating visual effect, where the direction of apparent motion was disambiguated by cues along the path of apparent motion, the Ternus-Pikler group motion, even though no actual movement occurs in this stimulus. They referred to their study as a "litmus test" to distinguish "non-retinotopic" (motion-based) from "retinotopic" (retina-based) image processing. We adapted the test to one with simple grating stimuli that could be more readily modeled and replicated their psychophysical results quantitatively with this stimulus. We then modeled our experiments in 3D (x, y, t) Fourier space and demonstrated that the observed perceptual effects are readily accounted for by integration of information within a detector that is oriented in space and time, in a similar way to previous explanations of other motion illusions. This demonstration brings the study of Boi et al. into the more general context of perception of moving objects. PMID- 22247223 TI - Offenders' crime narratives as revealed by the Narrative Roles Questionnaire. AB - The study of narrative processes as part of the immediate factors that shape criminal action is limited by the lack of a methodology for differentiating the narrative themes that characterise specific crime events. The current study explores how the roles offenders see themselves as playing during an offence encapsulate their underlying crime narratives and thus provide the basis for a quantitative methodology. To test this possibility, a 33-item Narrative Roles Questionnaire (NRQ) was developed from intensive interviews with offenders about their experience of committing a recent offence. A multidimensional analysis of the NRQ completed by 71 convicted offenders revealed life narrative themes similar to those identified in fiction by Frye and with noncriminals by McAdams, labelled The Professional, Victim, Hero, and Revenger offence roles. The NRQ thus is a first step in opening up the possibility of empirical studies of the narrative aetiological perspective in criminology. PMID- 22247224 TI - Evaluation of the effects of the bonding agent on acid-etched human enamel demineralization: in situ study. AB - This in situ study evaluated the influence of the bonding agent on demineralization of acid-etched human enamel. Enamel blocks obtained from 20 human molars (four blocks per tooth) were divided into five groups. For the control groups, healthy control (HC, no treatment) and acid-etched control (EC, etching with 35 per cent phosphoric acid for 20 seconds), the specimens were obtained by sectioning in half, one block from each tooth. For the experimental groups, experimental etched group (EE), experimental ConciseTM group (CE), and experimental TransbondTM group (TE), all specimens were etched with 35 per cent phosphoric acid for 20 seconds (EE) and treated with ConciseTM enamel bond (CE) and TransbondTM XT primer (TE). Specimens from the experimental groups were fixed at intra-oral appliances wore by 10 volunteers and exposed to oral environment. After 28 days, the specimens were sectioned in the mesial-distal direction and the enamel cross-sectional Knoop hardness number (KHN, 50 g, 15 seconds) was measured at the cervical and occlusal regions at 25, 50, and 75 MUm from the enamel surfaces. Data were analysed by analysis of variance (ANOVA) and Tukey honestly significantly different test for multiple comparisons (alpha = 0.05). Enamel KHN (P < 0.05) was recovered only in the Concise-treated group (CE; P < 0.05). When considering depth measurements, KHN results were 25 > 50 > 75 MUm (P < 0.05). None of the groups exposed to the intra-oral environment for 28 days have recovered completely the enamel microhardness, but the order of improvement was better in the CE group than the TE group, the latter being only slightly better than the EE group. PMID- 22247225 TI - Screening for salivary levels of deoxypyridinoline and bone-specific alkaline phosphatase during orthodontic tooth movement: a pilot study. AB - Deoxypyridinoline (DPD) and bone-specific alkaline phosphatase (BAP) have been regarded as systemic determinants of bone remodelling. Owing this fact, this study aimed to determine whether the variations in the salivary concentration of these two biomarkers as detected through a longitudinal follow-up with four consecutive visits may be linked with the different phases of orthodontic tooth movement (OTM). Twenty-two healthy subjects who required fixed appliance therapy not involving tooth extractions/surgical procedures were selected. Unstimulated whole saliva samples were collected from each patient prior to fitting the orthodontic appliances and 24-48 hours, 2 weeks, and 5 weeks after the activation. Salivary DPD and BAP concentrations were determined by enzyme-linked immunosorbent assay. The data were analysed using non-parametric statistics. There were no statistically significant differences in salivary levels of biomarkers regarding demographic and clinical parameters. Overall, although DPD values revealed an increasing nature after force application and BAP values showed a descending trend, only the former showed statistically significant changes over time. Furthermore, p ost hoc comparisons for DPD salivary levels revealed significant differences between every paired sampling times, except for the pair baseline test/24-48 hours test. Synchronously, a moderate positive significant correlation between both salivary biomarkers was observed at 2 weeks test. The findings indicate that although salivary levels of DPD and BAP may act as indicators of increased bone remodelling, it appears that DPD dominates the earlier phases of OTM, whereas BAP might serve as indicator of bone formation as soon as the tooth movement stops. PMID- 22247226 TI - Sulfatide inhibits alpha-galactosylceramide presentation by dendritic cells. AB - Sulfatide-reactive type II NKT cells, the so-called non-invariant NKT (non-iNKT) cells, have been shown to counteract invariant NKT (iNKT) cell activity. However, the effects of sulfatide on activation of iNKT cells by alpha-galactocylceramide (alphaGC) in the context of CD1d have not been studied in detail. Therefore, we studied the blocking effect of sulfatide on alphaGC-induced iNKT cell activation by dendritic cells (DCs). Even in the absence of non-iNKT cells, sulfatide inhibited alphaGC-mediated iNKT cell activation by reducing alphaGC/CD1d complex formations in a dose-dependent manner. This was also confirmed in a cell-free setting using immobilized CD1d-Ig. Moreover, simultaneous injection of alphaGC with sulfatide decreased alphaGC/CD1d complex formations on DCs, accompanied by the reduced CD40L-up-regulation and IFN-gamma production by iNKT cells and IL 12p70 production by DCs. However, sulfatide by itself did not interfere with the presentation of MHC class II-mediated antigen presentation to specific T cells. These results demonstrate that sulfatide competes with alphaGC to be loaded onto CD1d along the endocytic pathway in DCs, thereby inhibiting the iNKT cell response. PMID- 22247227 TI - Mandatory evacuation of residents during the Fukushima nuclear disaster: an ethical analysis. AB - BACKGROUND: The Japan earthquake and tsunami of 11 March 2011 severely damaged the Fukushima Daiichi nuclear plant. After learning of the radiation leak, the Japanese government issued an evacuation directive for residents within 20 km of the plant a day after the earthquake. Approximately 1 month later, this area was designated a 'high alert zone' and effectively sealed-off. The purpose of this report is to examine these measures from an ethical perspective, and consider what lessons can be drawn from this experience. METHODS: Analytic discussion. RESULTS: We examine the measures from an ethical perspective and argue that if the government's aim was to avoid health risks posed by radiation exposure, then ordering compulsory expulsion of all residents cannot be ethically justified. We assert that the government may not have ordered the mandatory evacuation solely based on health risks, but rather to maintain public order. CONCLUSION: Careful scrutiny of the case revealed that this public health intervention involved an objective completely unrelated to public health, and that disguising these policies using the reasonable and acceptable purpose of public health made it easier to justify undue restriction of individual liberty. PMID- 22247228 TI - Decreased paraoxonase 1 (PON1) lactonase activity in hemodialyzed and renal transplanted patients. A novel cardiovascular biomarker in end-stage renal disease. AB - BACKGROUND: Human paraoxonase-1 (PON1) has also been described as a lactonase. Decreased PON1 lactonase activity was found to be a predictor of cardiovascular disease. Homocysteine thiolactonase activity may prevent proteins from homocysteinylation and is thought to be a protective factor against the progression of atherosclerosis. Previous studies have demonstrated decreased PON1 paraoxonase activity in hemodialyzed (HD) and renal transplant (TRX) patients; however, lactonase activity has not been investigated. We aimed to determine the paraoxonase and lactonase activities and to clarify the relationship between lactonase activity and a set of cardiovascular risk factors, such as homocysteine, cystatin C and asymmetric dimethylarginine (ADMA) levels, in HD and TRX patients and in healthy controls. METHODS: One hundred and eight HD and 78 TRX patients and 63 healthy controls were involved in the study. Paraoxonase and lactonase activities (paraoxon and gamma-thiobutyrolactone as substrates) were measured spectrophotometrically. ADMA level was determined with sandwich enzyme linked immunosorbent assay. RESULTS: Both HD and TRX patients had significantly lower lactonase activities compared to the control group (P<0.05). Significantly lower paraoxonase activities were found in HD patients compared to the TRX group (P<0.05). Significant negative correlation was found between lactonase activity and ADMA level in the whole study population (P<0.001), while paraoxonase and lactonase activities showed significant positive correlation (P<0.001). Multiple regression analysis identified paraoxonase activity and homocysteine level as independent predictors of lactonase activity. CONCLUSION: Lactonase activity is a potential new predictor of cardiovascular risk in renal failure. Measurement of lactonase activity is recommended in future studies on HD and TRX patients. PMID- 22247229 TI - The regulatory/cytotoxic infiltrating T cells in early renal surveillance biopsies predicts acute rejection and survival. AB - BACKGROUND: To analyze the immune phenotype of T-lymphocyte infiltrations in surveillance renal biopsies with stable renal function early post-transplantation (median time 40 days, range from 18 to 85 days). METHODS: One hundred and twenty five surveillance biopsies with interstitial T-lymphocyte infiltration between non-atrophic tubules in the cortex (14 with subclinical rejection, 32 with borderline change and 79 with only interstitial T-lymphocyte infiltration but no obvious pathological abnormalities according to Banff criteria) were enrolled. All cases were classified into two groups: regulatory phenotype (RP) group, which was dominated by FOXP3-positive T lymphocytes in surveillance biopsies, and cytotoxic phenotype (CP) group, which was dominated by Granzyme B-positive T lymphocytes. RESULTS: The RP group includes 83.2% (104/125) cases, none of which developed acute rejection during nearly 5 years of follow-up. The CP group includes 16.8% (21/125) cases, all of which developed biopsy-proven acute rejection or clinical diagnostic acute rejection within 1 year after biopsy. Glomerular filtration rate and cumulative graft survival time were superior in the RP group than in the CP group (P<0.001). CONCLUSION: Analyzing the immunophenotype of graft-infiltrating T cells in renal surveillance biopsies during early post-transplantation could predict acute rejection and survival. PMID- 22247231 TI - Prognostic impact of renal arterial resistance index upon renal allograft survival: the time point matters. AB - BACKGROUND: The renal arterial resistance index (RI) is reported to be a significant predictive parameter for renal allograft failure or death. The influence of the time point after renal transplantation on its predictive power has not been sufficiently evaluated. We performed a retrospective analysis of RI and its power to predict renal allograft failure or death with special emphasis on the time point of RI measurement. METHODS: The present analysis is based on ultrasonographically recorded intrarenal arterial RI measurements, routinely obtained in our outpatient department, over a period of 13 years. Altogether, 88 patients with an RI measurement 0-3, 3-6 and 12-18 months after transplantation were included and retrospectively stratified into two groups according to the RI: those with an index >0.75 and those with an index of <=0.75. RESULTS: Twenty patients (23%) reached the combined end point, i.e. allograft failure with a return to dialysis or death. The RI measured early after transplantation (0-3 and 3-6 months) did not predict the end point, whereas the RI obtained between 12 and 18 months showed a significant predictive value for renal transplant failure or death in a univariate approach [Wald test, P = 0.0013, hazard ratio (HR) 4.787, 95% confidence interval (CI) 1.846-12.411]. At 12-18 months after transplantation, 14% (12 patients) of the study population had an RI >0.75. Seven (58%) of these patients reached the end point versus 13 of 76 patients (17%) with an RI <=0.75. In a multivariate Cox model, the RI measured between 12 and 18 months after transplantation exhibited the highest hazard ratio (HR 6.191, 95% CI 2.288-16.756, P = 0.0003) for transplant failure or death. CONCLUSION: In our hands, the RI obtained during the first 6 months after transplantation failed to predict renal allograft failure or death, whereas the RI measured 12-18 months after transplantation appeared useful to predict long-term allograft outcomes. PMID- 22247232 TI - Pharmacotherapy to improve outcomes in vascular access surgery: a review of current treatment strategies. AB - BACKGROUND: Renal failure is a major cause of morbidity in western Europe, with rising prevalence. Vascular access complications are the leading cause of morbidity among patients on haemodialysis. Considering the health care burden of vascular access failure, there is limited research dedicated to the topic. METHODS: Randomised control trials of medications aimed at improving vascular access patency were identified using a medline search between January 1950 and January 2011. RESULTS: Thirteen randomised trials were identified, investigating antiplatelets, anticoagulants and fish oil in preserving vascular access patency. Outcomes are presented and reviewed in conjunction with the underlying pathophysiological mechanisms of failure of vascular access. DISCUSSION: Vascular access failure is a complex process. Most clinical trials so far have involved medications primarily aimed at preventing thrombosis. Other contributing pathways such as neointimal hyperplasia have not been investigated clinically. Improved outcomes may be seen by linking future therapies to these pathways. PMID- 22247230 TI - Metabolic syndrome and the risk of calcium stones. AB - BACKGROUND: The metabolic syndrome (MS) is associated with increased prevalence of kidney stones, yet the specific stone type remains largely unknown. This study was conducted to assess whether risk factors associated with calcium nephrolithiasis increase with individual characteristics of the MS. METHODS: A retrospective analysis was performed in 109 non-stone-forming subjects and 128 recurrent calcium stone formers from Dallas, Texas. A separate analysis was performed in 140 recurrent calcium stone formers from Bern, Switzerland. Demographic, anthropometric, serum and urinary profiles were measured. RESULTS: In non-stone formers from Dallas, urinary calcium (3.6 +/- 1.8 to 6.0 +/- 2.9 mmol/day, P = 0.0003 for trend, zero to four features) increased with increasing features of the MS. This change was attendant with a significant rise in supersaturation index (SI) of calcium oxalate (CaOx) (2.76 +/- 1.21 to 4.45 +/- 1.65, P < 0.0001; zero to four features). In calcium stone formers from Dallas, urinary calcium marginally increased (5.2 +/- 2.3 to 7.0 +/- 4.0 mmol/day, P = 0.09; zero to four features), while urinary oxalate (356 +/- 141 to 504 +/- 203 MUmol/day, P = 0.001; zero to four features) and SI CaOx (4.46 +/- 1.80 to 6.16 +/- 3.71, P = 0.009; zero to four features) significantly increased with features of the MS. However, when adjusted for confounding variables such as total volume, age, gender, urine sodium and urine sulfate, urinary calcium and SI CaOx showed no significant changes in stone formers yet remained significant in non-stone formers. In a separate cohort from Bern, Switzerland urinary calcium (6.9 +/- 3.6 versus 7.0 +/- 3.2, P = 0.8) and SI CaOx (3.37 +/- 1.98 versus 4.04 +/- 2.78, P = 0.5) did not differ between subjects with and without the MS. CONCLUSIONS: In non stone formers, the risk of CaOx stone formation increases with the number of features of the MS. However, in stone-forming subjects, the propensity for CaOx precipitation is much higher but is not independently associated with increasing features of the MS. PMID- 22247233 TI - Losartan prevents the development of the pro-inflammatory monocytes CD14+CD16+ in haemodialysis patients. AB - BACKGROUND: The principal cause of mortality in haemodialysis (HD) patients is cardiovascular disease, which is linked to chronic inflammation. Recent studies have demonstrated that angiotensin II receptor AT1 antagonists have anti inflammatory properties. In this study, we evaluated the effect of losartan on CD14+CD16+ monocytes in HD patients. In addition, we developed an in vitro model to study the mechanisms by which losartan modulates these cells. METHODS: We divided 18 HD patients into two groups, based on anti-hypertensive treatment: 9 patients were treated with losartan (losartan group) and 9 received other anti hypertensive drugs that did not affect the renin-angiotensin axis (no-losartan group). Losartan was withdrawn in five patients from the losartan group for 2 months. Ten healthy subjects were included as controls. Invitro, we studied the differentiation of monocytes from healthy donors on stimulation with interleukin (IL)-10, IL-4 and granulocyte monocytes colony-stimulating factor with or without losartan in the culture medium. RESULTS: In patients who were taking losartan, the percentage of monocytes that expressed CD14+CD16+ was lower compared with patients in the no-losartan group. The percentage of CD14+CD16+ was similar in the losartan group and healthy subjects. When losartan was withdrawn from five patients in the losartan group, the percentage of CD14+CD16+ monocytes increased compared with before withdrawal. In vitro, when we added losartan to the culture medium, CD14++CD16- monocytes failed to differentiate into CD14+CD16+ cells. CONCLUSION: Losartan acts as an immunomodulator that prevents the development of CD14+CD16+ pro-inflammatory monocytes in HD patients. PMID- 22247218 TI - Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry. AB - OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma 70 antibodies. PMID- 22247234 TI - Commentary: The decreasing age of puberty--as much a psychosocial as biological problem? PMID- 22247235 TI - Pericallosal artery aneurysm treatment using Y-configuration stent-assisted coil embolization: a report of four cases. AB - BACKGROUND: Pericallosal artery aneurysms at the bifurcation represent a special endovascular technical challenge given their distal location, commonly wide-neck morphology, small parent vessel diameter and potentially high recurrence rate after coiling given the bifurcation location. Y-configuration stent-assisted coil embolization techniques have been reported for the treatment of wide-neck aneurysms located at other vascular bifurcations and only rarely with A2 bifurcation aneurysms. METHODS: A neurointerventional database was reviewed for identification of all cases of A2 bifurcation aneurysms that were treated with Y stent configuration. The authors report clinical, technical and outcome data on four patients with pericallosal aneurysms who were treated with a Y-configuration stent-assisted coil embolization technique. RESULTS: A Y-configuration stent placement in the anterior cerebral artery/A2 bifurcation was successfully achieved in all four patients without significant technical difficulties. One patient presented with a previously ruptured and partially treated aneurysm and three patients with incidentally found aneurysms. All four patients had a Y configuration stent placement in one setting. The Y-configuration allowed for complete occlusion of all four aneurysms with no recurrence or arterial occlusion on mean angiographic follow-up of 13.5 months (6-28). CONCLUSION: Treating wide neck pericallosal artery aneurysms at the bifurcation with Y-configuration stent placement is feasible and effective. This technique may be considered as a therapeutic option for wide-neck aneurysms that pose a difficult technical challenge. PMID- 22247237 TI - Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of pelargonic acid (nonanoic acid) and nonanoate esters. AB - Pelargonic acid and its esters function as skin-conditioning agents in cosmetics. Molecular weight (mw) and octanol-water partition coefficient data suggest that dermal penetration is possible. The biohandling of branched-chain fatty acids is not the same as for straight-chain fatty acids, but the differences are not significant to the conclusion that they all are readily metabolized to nontoxic moieties. Limited data suggested that the penetration of other ingredients may be enhanced if these ingredients are present in the same formulation. These ingredients are not significant oral or dermal toxicants in animal studies. They are not reproductive/developmental toxicants or genotoxic/carcinogenic in animal studies. The available data suggested that product formulations containing these ingredients would be nonirritating and nonsensitizing to human skin, but formulators were cautioned to consider the penetration enhancement potential. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that these ingredients are safe in the present practices of use and concentration. PMID- 22247236 TI - Safety assessment of cyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, and cycloheptasiloxane. AB - Cyclomethicone (mixture) and the specific chain length cyclic siloxanes (n = 4-7) reviewed in this safety assessment are cyclic dimethyl polysiloxane compounds. These ingredients have the skin/hair conditioning agent function in common. Minimal percutaneous absorption was associated with these ingredients and the available data do not suggest skin irritation or sensitization potential. Also, it is not likely that dermal exposure to these ingredients from cosmetics would cause significant systemic exposure. The Cosmetic Ingredient Review Expert Panel concluded that these ingredients are safe in the present practices of use and concentration. PMID- 22247238 TI - Safety assessment of xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes as used in cosmetics. AB - Xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes used in cosmetics as surfactants, hydrotropes, were reviewed in this safety assessment. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to these ingredients. The panel concluded that xylene sulfonic acid and alkyl aryl sulfonate hydrotropes are safe as cosmetic ingredients in the present practices of use and concentrations as described in this safety assessment, when formulated to be nonirritating. PMID- 22247239 TI - Research on return to work in European Union countries. AB - BACKGROUND: Research on return to work (RTW) is increasing. It is important to benefit from studies originating from different countries since certain factors influencing the RTW process are specific to each country. AIMS: To compare RTW research in Europe with the USA and to describe research on RTW in Europe. METHODS: Medline was scanned with specific search strings to identify studies concerning RTW in Europe, in the USA and in the rest of the world. Characteristics of the European studies were analyzed with two specific tools for bibliometrics research. RESULTS: Four thousand five hundred and twenty-five studies were identified (1100, 1005 and 2420 coming from Europe, the USA and the rest of the world, respectively). The European countries producing the greatest number of research papers standardized for population of that country were Sweden, the Netherlands, Finland and Denmark. Sweden was 5.7 times more prolific than the USA. Specialties covered by the European publications included occupational medicine (the subject of 66% of the articles), neurology (36%), environment and public health (32%), physical medicine and rehabilitation (26%) and rheumatology (24%). CONCLUSIONS: There is a worldwide trend upwards in the number of publications on RTW. Europe recently overtook the USA in the number of publications per head of population, although there were large differences in publication rates among the European countries. The publications of European researchers on RTW are spread over a wide variety of journals, making access to this research difficult. PMID- 22247240 TI - Third location decompression for individual augmentees after a military deployment. AB - BACKGROUND: Third location decompression (TLD) refers to the initial process, undertaken by military personnel at the end of an operational deployment, whereby adjustment from military operations commences. TLD has been shown to be useful for personnel in formed units (FU). AIMS: To examine the subjective utility of TLD for personnel deployed as individual augmentees (IAs) by comparing their experience with FU personnel. METHODS: One hundred and twenty-nine IAs and 121 FU personnel completed a short survey at the end of the decompression period asking about operational exposures, perceived usefulness, stigma, concerns about readjustment and post-traumatic stress symptoms (PTSS). RESULTS: The strongest predictor of perceived utility was the desire to participate prior to arrival at the facility. FU personnel were more likely to want to participate in TLD than IAs (60% versus 30%); however, on completion, IAs reported high usefulness ratings with 78% of IAs and 84% of FU personnel finding it useful or a little useful. More FU personnel reported substantial PTSS, reporting that high numbers of PTSS were associated with finding the briefings that dealt with traumatic stress useful. Personnel reporting substantial operational exposures also reported greater levels of PTSS. CONCLUSIONS: IAs found TLD to be as useful as FU personnel; therefore, exclusion from the TLD process is not warranted. Military commanders should consider restricting TLD to both IA and FU personnel deemed to be at increased risk of a difficult adjustment due to greater operational exposure. Our data suggest that smaller numbers of IA personnel would fall into this group. PMID- 22247241 TI - A cluster of four cases of meningococcal disease in a single nuclear family. AB - A cluster of four confirmed cases of meningococcal disease was seen in the same nuclear family across a 15-week period. The cases were three siblings and a parent and all recovered well. The first case was confirmed by meningococcal PCR only but the subsequent three cases were due to indistinguishable strains of serogroup B (B:NT:P1.19-1,15-11). Contact tracing was initially undertaken and reviewed in detail after each subsequent case. Antibiotic prophylaxis was administered to close family contacts on three separate occasions, including switching of antibiotic agents, with good compliance. Subsequent investigation of the family has not revealed any obvious immunological problem and no further significant infections have been recognised. A cluster of meningococcal disease of this nature and timescale is highly unusual. Details of the cluster, investigation and implications for health protection practice are discussed. PMID- 22247242 TI - Pulse oximetry as a screening test for congenital heart defects in newborn infants: a cost-effectiveness analysis. AB - OBJECTIVE: To undertake a cost-effectiveness analysis that compares pulse oximetry as an adjunct to clinical examination with clinical examination alone in newborn screening for congenital heart defects (CHDs). DESIGN: Model-based economic evaluation using accuracy and cost data from a primary study supplemented from published sources taking an NHS perspective. SETTING: Six large maternity units in the UK. PATIENTS: 20 055 newborn infants prior to discharge from hospital. INTERVENTION: Pulse oximetry as an adjunct to clinical examination. MAIN OUTCOME MEASURE: Cost effectiveness based on incremental cost per timely diagnosis. RESULTS: Pulse oximetry as an adjunct to clinical examination is twice as costly but provides a timely diagnosis to almost 30 additional cases of CHD per 100 000 live births compared with a modelled strategy of clinical examination alone. The incremental cost-effectiveness ratio for this strategy compared with clinical examination alone is approximately L24 000 per case of timely diagnosis in a population in which antenatal screening for CHDs already exists. The probabilistic sensitivity analysis suggests that at a willingness-to-pay (WTP) threshold of L100 000, the probability of 'pulse oximetry as an adjunct to clinical examination' being cost effective is more than 90%. Such a WTP threshold is plausible if a newborn with timely diagnosis of a CHD gained just five quality-adjusted life years, even when treatment costs are taken into consideration. CONCLUSION: Pulse oximetry as an adjunct to current routine practice of clinical examination alone is likely to be considered a cost effective strategy in the light of currently accepted thresholds. PMID- 22247243 TI - Lyme meningitis, the major cause of childhood meningitis in an endemic area: a population based study. AB - OBJECTIVE: To evaluate the epidemiology of infectious meningitis in children in a Lyme borreliosis (LB) endemic area, and to study how clinical and laboratory characteristics may distinguish between different types of childhood meningitis. DESIGN: Retrospective, population based study. SETTING: A paediatric department serving all children (62 000) in a costal LB endemic region of southwestern Norway. PATIENTS: All children with cerebrospinal fluid pleocytosis aged 3 months to 14 years. MAIN OUTCOME MEASURES: Epidemiological, clinical and laboratory characteristics of different types of childhood meningitis. RESULTS: Infectious meningitis was diagnosed in 211 children (annual incidence 38/100 000). Lyme meningitis (LM) was identified in 142 children (67%), non-Lyme aseptic meningitis in 46 children (22%) and bacterial meningitis in 23 children (11%). Age, month of admission and clinical and laboratory characteristics differed between the groups. An aetiological agent was found in 89% of children. The positive predictive value for having LM if the child had facial nerve palsy or head and/or neck stiffness (meningism) as the only symptom was 97% for both variables. Symptoms of cerebral involvement or signs of systemic inflammation were rare in children with LM compared to children non-Lyme aseptic meningitis. CONCLUSION: LM was diagnosed in two-thirds of children with infectious meningitis in this LB endemic area. Distinct clinical characteristics distinguished the majority of children with LM from children with non-Lyme aseptic meningitis and bacterial meningitis. PMID- 22247244 TI - Role of the 2-week urgent referral pathway in childhood cancer. AB - OBJECTIVE: To evaluate the role of the urgent 2-week referral pathway in facilitating the early diagnosis of childhood cancer. DESIGN: Retrospective case notes review of all children referred via the pathway and all children diagnosed as having cancer via other means over a period of 31/2 years (January 2007-July 2010). SETTING: District general hospital with a shared care oncology service. PATIENTS: 82 children aged 0-15 years. OUTCOME MEASURES: Outcomes for children referred via the 2-week urgent referral pathway, including diagnosis, need for further investigations and need for further specialist input. RESULTS: 35 children were referred via the 2-week urgent referral pathway with suspected cancer. Only one of these children had a malignancy. 49% of children required no further investigations and 43% were discharged after the first appointment with no follow-up thought necessary. Over the same time period, 47 children were diagnosed as having cancer via other means. CONCLUSION: The pickup rate of cancer among children referred via the 2-week urgent referral pathway is extremely low and the vast majority of cancer is diagnosed via different routes. PMID- 22247245 TI - A proposed new international convention supporting the rights of pregnant women and girls and their newborn infants. AB - For a multitude of eminently modifiable reasons, death rates for pregnant women and girls and their newborn infants in poorly resourced countries remain unacceptably high. The concomitant high morbidity rates compound the situation. The rights of these vulnerable individuals are incompletely protected by existing United Nations human rights conventions, which many countries have failed to implement. The authors propose a novel approach grounded on both human rights and robust evidence-based clinical guidelines to create a 'human rights convention specifically for pregnant women and girls and their newborn infants'. The approach targets the 'right to health' of these large, vulnerable and neglected populations. The proposed convention is designed so that it can be monitored, audited and evaluated objectively. It should also foster a sense of national ownership and accountability as it is designed to be relevant to local situations and to be incorporated into local clinical governance systems. It may be of particular value to those countries that are not yet on target to meet the Millennium Development Goals (MDGs), especially MDGs 4 and 5, which target child and maternal mortality, respectively. To foster a sense of international responsibility, two additional initiatives are integral to its philosophy: the promotion of twinning between well and poorly resourced regions and a raising of awareness of how some well-resourced countries can damage the health of mothers and babies, for example, through the recruitment of health workers trained by national governments and taken from the public health system. PMID- 22247246 TI - Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions. AB - OBJECTIVE: To describe prevalence, prenatal diagnosis and epidemiological data on oesophageal atresia from 23 well-defined European regions and compare the prevalence between these regions. DESIGN: Population-based study using data from a large European database for surveillance of congenital anomalies (EUROCAT) for two decades (1987-2006). SETTINGS: Twenty-three participating registries based on multiple sources of information including information about live births, fetal deaths with gestational age >=20 weeks and terminations of pregnancy. PATIENTS: 1222 cases of oesophageal atresia in a population of 5 019 804 births. RESULTS: The overall prevalence was 2.43 cases per 10 000 births (95% CI 2.30 to 2.57). There were regional differences in prevalence ranging from 1.27 to 4.55. Prenatal detection rates varied by registry from >50% of cases to <10% of cases. A total of 546 cases (44.7%) had an isolated oesophageal anomaly, 386 (31.6%) were multiple malformed and 290 (23.7%) had an association or a syndrome. There were 1084 live born cases (88.7%), 43 cases were fetal deaths and 95 cases were terminations of pregnancy. One-week survival for live births was 86.9% and 99.2% if the gestational age was >=38 weeks and isolated oesophageal atresia was present. Males accounted for 57.3% of all cases and 38.5% of live born cases were born with gestational age <37 weeks. CONCLUSION: There were regional differences in prevalence of oesophageal atresia in Europe. Half of all cases had associated anomalies. Prenatal detection rate increased from 26% to 36.5% over the two decades. Survival in infants with isolated oesophageal atresia born at term is high. PMID- 22247247 TI - Intestinal failure-associated liver disease in hospitalised children. AB - OBJECTIVE AND AIM: Liver disease is a potentially life-threatening complication of intravenous/parenteral nutrition (PN). Our aim was to determine the incidence, aetiology and outcome of intestinal failure-associated liver disease (IFALD) in hospitalised children treated with long-term PN (>27 days). METHODS: Over 4 years all long-term intestinal failure (IF) patients were reviewed for the possible predisposing factors of age, diagnosis, PN lipid, sepsis, length of PN treatment and length of hospitalisation. Outcome measures were IFALD incidence, severity and prognosis. RESULTS: Of 60/279 (22%) children aged 0-18 years who developed IFALD, 13 (5%) progressed to type 3/end stage disease. IFALD was associated with younger age (p=0.03), longer treatment (p<0.001), longer hospitalisation (p=0.01), surgical diagnosis (p=0.005) and prematurity (p=0.03). IFALD was not associated with sepsis. Intestinal surgery was associated with IFALD independently of age (p=0.03). Survival was 86%, with three deaths attributed to IFALD (1% of all cases), all of which were surgical. CONCLUSION: IFALD incidence was lower than previously reported in paediatric patients, with surgical neonates at greatest risk. PMID- 22247248 TI - VvBOR1, the grapevine ortholog of AtBOR1, encodes an efflux boron transporter that is differentially expressed throughout reproductive development of Vitis vinifera L. AB - Boron (B) is an essential micronutrient for normal development of roots, shoots and reproductive tissues in plants. Due to its role in the structure of rhamnogalacturonan II, a polysaccharide required for pollen tube growth, B deficiency has been associated with the occurrence of parthenocarpic seedless grapes in some varieties of Vitis vinifera L. Despite that, it is unclear how B is mobilized and accumulated in reproductive tissues. Here we describe the characterization of an efflux B transporter, VvBOR1, homolog to AtBOR1, which is involved in B xylem loading in Arabidopsis thaliana roots. VvBOR1-green fluorescent protein (GFP) fusion protein expressed in A. thaliana localizes in the proximal plasma membrane domain in root pericycle cells, and VvBOR1 overexpression restores the wild-type phenotype in A. thaliana bor1-3 mutant plants exposed to B deficiency. Complementation of a mutant yeast strain indicates that VvBOR1 corresponds to a B efflux transporter. Transcriptional analyses during grapevine reproductive development show that the VvBOR1 gene is preferentially expressed in flowers at anthesis and a direct correlation between the expression pattern and B content in grapes was established, suggesting the involvement of this transporter in B accumulation in grapevine berries. PMID- 22247249 TI - CRYPTIC PRECOCIOUS/MED12 is a novel flowering regulator with multiple target steps in Arabidopsis. AB - The proper timing of flowering is of crucial importance for reproductive success of plants. Regulation of flowering is orchestrated by inputs from both environmental and endogenous signals such as daylength, light quality, temperature and hormones, and key flowering regulators construct several parallel and interactive genetic pathways. This integrative regulatory network has been proposed to create robustness as well as plasticity of the regulation. Although knowledge of key genes and their regulation has been accumulated, there still remains much to learn about how they are organized into an integrative regulatory network. Here, we have analyzed the CRYPTIC PRECOCIOUS (CRP) gene for the Arabidopsis counterpart of the MED12 subunit of the Mediator. A novel dominant mutant, crp-1D, which causes up-regulation of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), FRUITFULL (FUL) and APETALA1 (AP1) expression in a FLOWERING LOCUS T (FT)-dependent manner, was identified in an enhancer screen of the early flowering phenotype of 35S::FT. Genetic and molecular analysis of both crp-1D and crp loss-of-function alleles showed that MED12/CRP is required not only for proper regulation of SOC1, FUL and AP1, but also for up-regulation of FT, TWIN SISTER OF FT (TSF) and FD, and down-regulation of FLOWERING LOCUS C (FLC). These observations suggest that MED12/CRP is a novel flowering regulator with multiple regulatory target steps both upstream and downstream of the key flowering regulators including FT florigen. Our work, taken together with recent studies of other Mediator subunit genes, supports an emerging view that the Mediator plays multiple roles in the regulation of flowering. PMID- 22247250 TI - Acetylesterase-mediated deacetylation of pectin impairs cell elongation, pollen germination, and plant reproduction. AB - Pectin is a major component of the primary cell wall of higher plants. Some galacturonyl residues in the backbone of pectinaceous polysaccharides are often O acetylated at the C-2 or C-3 position, and the resulting acetylesters change dynamically during the growth and development of plants. The processes involve both enzymatic acetylation and deacetylation. Through genomic sequence analysis, we identified a pectin acetylesterase (PAE1) from black cottonwood (Populus trichocarpa). Recombinant Pt PAE1 exhibited preferential activity in releasing the acetate moiety from sugar beet (Beta vulgaris) and potato (Solanum tuberosum) pectin in vitro. Overexpressing Pt PAE1 in tobacco (Nicotiana tabacum) decreased the level of acetyl esters of pectin but not of xylan. Deacetylation engendered differential changes in the composition and/or structure of cell wall polysaccharides that subsequently impaired the cellular elongation of floral styles and filaments, the germination of pollen grains, and the growth of pollen tubes. Consequently, plants overexpressing PAE1 exhibited severe male sterility. Furthermore, in contrast to the conventional view, PAE1-mediated deacetylation substantially lowered the digestibility of pectin. Our data suggest that pectin acetylesterase functions as an important structural regulator in planta by modulating the precise status of pectin acetylation to affect the remodeling and physiochemical properties of the cell wall's polysaccharides, thereby affecting cell extensibility. PMID- 22247251 TI - The apoplastic oxidative burst peroxidase in Arabidopsis is a major component of pattern-triggered immunity. AB - In plants, reactive oxygen species (ROS) associated with the response to pathogen attack are generated by NADPH oxidases or apoplastic peroxidases. Antisense expression of a heterologous French bean (Phaseolus vulgaris) peroxidase (FBP1) cDNA in Arabidopsis thaliana was previously shown to diminish the expression of two Arabidopsis peroxidases (peroxidase 33 [PRX33] and PRX34), block the oxidative burst in response to a fungal elicitor, and cause enhanced susceptibility to a broad range of fungal and bacterial pathogens. Here we show that mature leaves of T-DNA insertion lines with diminished expression of PRX33 and PRX34 exhibit reduced ROS and callose deposition in response to microbe associated molecular patterns (MAMPs), including the synthetic peptides Flg22 and Elf26 corresponding to bacterial flagellin and elongation factor Tu, respectively. PRX33 and PRX34 knockdown lines also exhibited diminished activation of Flg22-activated genes after Flg22 treatment. These MAMP-activated genes were also downregulated in unchallenged leaves of the peroxidase knockdown lines, suggesting that a low level of apoplastic ROS production may be required to preprime basal resistance. Finally, the PRX33 knockdown line is more susceptible to Pseudomonas syringae than wild-type plants. In aggregate, these data demonstrate that the peroxidase-dependent oxidative burst plays an important role in Arabidopsis basal resistance mediated by the recognition of MAMPs. PMID- 22247252 TI - The rice pentatricopeptide repeat protein RF5 restores fertility in Hong-Lian cytoplasmic male-sterile lines via a complex with the glycine-rich protein GRP162. AB - The cytoplasmic male sterility (CMS) phenotype in plants can be reversed by the action of nuclear-encoded fertility restorer (Rf) genes. The molecular mechanism involved in Rf gene-mediated processing of CMS-associated transcripts is unclear, as are the identities of other proteins that may be involved in the CMS-Rf interaction. In this study, we cloned the restorer gene Rf5 for Hong-Lian CMS in rice and studied its fertility restoration mechanism with respect to the processing of the CMS-associated transcript atp6-orfH79. RF5, a pentatricopeptide repeat (PPR) protein, was unable to bind to this CMS-associated transcript; however, a partner protein of RF5 (GRP162, a Gly-rich protein encoding 162 amino acids) was identified to bind to atp6-orfH79. GRP162 was found to physically interact with RF5 and to bind to atp6-orfH79 via an RNA recognition motif. Furthermore, we found that RF5 and GRP162 are both components of a restoration of fertility complex (RFC) that is 400 to 500 kD in size and can cleave CMS associated transcripts in vitro. Evidence that a PPR protein interacts directly with a Gly-rich protein to form a subunit of the RFC provides a new perspective on the molecular mechanisms underlying fertility restoration. PMID- 22247254 TI - Dynamic immune cell accumulation during flow-induced atherogenesis in mouse carotid artery: an expanded flow cytometry method. AB - OBJECTIVE: Inflammation plays a central role in atherosclerosis. However, the detailed changes in the composition and quantity of leukocytes in the arterial wall during atherogenesis are not fully understood in part because of the lack of suitable methods and animal models. METHODS AND RESULTS: We developed a 10 fluorochrome, 13-parameter flow cytometry method to quantitate 7 major leukocyte subsets in a single digested arterial wall sample. Apolipoprotein E-deficient mice underwent left carotid artery (LCA) partial ligation and were fed a high-fat diet for 4 to 28 days. Monocyte/macrophages, dendritic cells, granulocytes, natural killer cells, and CD4 T cells significantly infiltrated the LCA as early as 4 days. Monocyte/macrophages and dendritic cells decreased between 7 and 14 days, whereas T-cell numbers remained steady. Leukocyte numbers peaked at 7 days, preceding atheroma formation at 14 days. B cells entered LCA by 14 days. Control right carotid and sham-ligated LCAs showed no significant infiltrates. Polymerase chain reaction and ELISA arrays showed that expression of proinflammatory cytokines and chemokines peaked at 7 and 14 days postligation, respectively. CONCLUSION: This is the first quantitative description of leukocyte number and composition over the life span of murine atherosclerosis. These results show that disturbed flow induces rapid and dynamic leukocyte accumulation in the arterial wall during the initiation and progression of atherosclerosis. PMID- 22247253 TI - Suppression of Arabidopsis ARGONAUTE1-mediated slicing, transgene-induced RNA silencing, and DNA methylation by distinct domains of the Cucumber mosaic virus 2b protein. AB - Unique among the known plant and animal viral suppressors of RNA silencing, the 2b protein interacts directly with both small interfering RNA (siRNA) and ARGONAUTE1 (AGO1) and AGO4 proteins and is targeted to the nucleolus. However, it is largely unknown which regions of the 111-residue 2b protein determine these biochemical properties and how they contribute to its diverse silencing suppressor activities. Here, we identified a functional nucleolar localization signal encoded within the 61-amino acid N-terminal double-stranded RNA (dsRNA) binding domain (dsRBD) that exhibited high affinity for short and long dsRNA. However, physical interaction of 2b with AGOs required an essential 33-residue region C-terminal to the dsRBD and was sufficient to inhibit the in vitro AGO1 Slicer activity independently of its dsRNA binding activities. Furthermore, the direct 2b-AGO interaction was not essential for the 2b suppression of posttranscriptional gene silencing (PTGS) and RNA-directed DNA methylation (RdDM) in vivo. Lastly, we found that the 2b-AGO interactions in vivo also required the nucleolar targeting of 2b and had the potential to redistribute both the 2b and AGO proteins in nucleus. These findings together suggest that 2b may suppress PTGS and RdDM in vivo by binding and sequestering siRNA and the long dsRNA precursor in a process that is facilitated by its interactions with AGOs in the nucleolus. PMID- 22247255 TI - Pro-inflammatory role of microrna-200 in vascular smooth muscle cells from diabetic mice. AB - OBJECTIVE: Vascular smooth muscle cells (VSMC) from type 2 diabetic db/db mice exhibit enhanced proinflammatory responses implicated in accelerated vascular complications. We examined the role of microRNA(miR)-200 family members and their target Zeb1, an E-box binding transcriptional repressor, in these events. METHODS AND RESULTS: The expression levels of miR-200b, miR-200c, and miR-429 were increased, although protein levels of Zeb1 were decreased in VSMC and aortas from db/db mice relative to control db/+ mice. Transfection of miR-200 mimics into VSMC downregulated Zeb1 by targeting its 3'-UTR, upregulated the inflammatory genes cyclooxygenase-2 and monocyte chemoattractant protein-1, and promoted monocyte binding in db/+VSMC. In contrast, miR-200 inhibitors reversed the enhanced monocyte binding of db/dbVSMC. Zeb1 gene silencing with siRNAs also increased these proinflammatory responses in db/+VSMC confirming negative regulatory role of Zeb1. Both miR-200 mimics and Zeb1 siRNAs increased cyclooxygenase-2 promoter transcriptional activity. Chromatin immunoprecipitation showed that Zeb1 occupancy at inflammatory gene promoters was reduced in VSMC from type 2 diabetic db/db mice. Furthermore, Zeb1 knockdown increased miR-200 levels demonstrating a feedback regulatory loop. CONCLUSION: Disruption of the reciprocal negative regulatory loop between miR-200 and Zeb1 under diabetic conditions enhances proinflammatory responses of VSMC implicated in vascular complications. PMID- 22247256 TI - Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia. AB - OBJECTIVE: Mutations of the ANGPTL3 gene have been associated with a novel form of primary hypobetalipoproteinemia, the combined hypolipidemia (cHLP), characterized by low total cholesterol and low HDL-cholesterol levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in 2 large cohorts of 913 among American and Italian subjects with primary hypobetalipoproteinemia (total cholesterol<5th percentile). METHODS AND RESULTS: The combined hypolipidemia cut-offs were chosen according to total cholesterol and HDL-cholesterol levels reported in the ANGPTL3 kindred described to date: total cholesterol levels, <2nd percentile and HDL-cholesterol, levels<2nd decile. Seventy-eight subjects with combined hypolipidemia were analyzed for ANGPTL3 and APOB genes. We identified nonsense and/or missense mutations in ANGPTL3 gene in 8 subjects; no mutations of the APOB gene were found. Mutated ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3 negative subjects, although ANGPTL3 heterozygotes did not differ from ANGPTL3 negative subjects. CONCLUSION: These results demonstrated that in a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%, whereas mutations of APOB gene are absent. PMID- 22247257 TI - Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells. AB - OBJECTIVE: Phospholipase A2, group 7 (Pla2g7) is an important mediator in cardiovascular development and diseases because of its divergent physiological and pathological functions in inflammation and oxidative stress. However, little is known about the functional role of Pla2g7 in smooth muscle cell (SMC) differentiation from stem cells. METHODS AND RESULTS: In the present study, embryonic stem cells were cultivated on collagen IV-coated plates to allow SMC differentiation. Pla2g7 gene expression and activity were upregulated significantly following 4 to 14 days of cell differentiation and colocalized with SMC differentiation markers in the differentiated SMCs. Knockdown of Pla2g7 resulted in downregulation of smooth muscle-specific markers in vitro and impairment of SMC differentiation in vivo, whereas enforced expression of Pla2g7 enhanced SMC differentiation and increased reactive oxygen species generation. Importantly, enforced expression of Pla2g7 significantly increased the binding of serum response factor to SMC differentiation gene promoters, resulting in SMC differentiation, which was abolished by free radical scavenger and flavoprotein inhibitor of NADPH oxidase but not hydrogen peroxide inhibitor. Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene. CONCLUSION: Our findings demonstrated that Pla2g7 plays a crucial physiological role in SMC differentiation from stem cells, and the fine interactions between Nrf3 and Pla2g7 are essential for SMC differentiation. PMID- 22247259 TI - CD36 ectodomain phosphorylation blocks thrombospondin-1 binding: structure function relationships and regulation by protein kinase C. AB - OBJECTIVE: CD36 phosphorylation on its extracellular domain inhibits binding of thrombospondin-1. The mechanisms of cellular CD36 ectodomain phosphorylation and whether it can be regulated in cells are not known. We determined structure function relationships of CD36 phosphorylation related to thrombospondin-1 peptide binding in vitro and explored mechanisms regulating phosphorylation by protein kinase C (PKC) in melanoma cells. METHODS AND RESULTS: Phosphorylation of CD36 peptide on Thr92 by PKCalpha suppressed binding of thrombospondin-1 peptides in vitro, and the level of inhibition correlated with the level of phosphorylation. Basal phosphorylation levels of CD36 in vivo in platelets, endothelial cells, and melanoma cells were assessed by immunoprecipitation and immunoblot and were found to be very low. Treatment of CD36-transfected melanoma cells with phorbol 12-myristate 13-acetate (PMA), a PKC activator, induced substantial CD36 phosphorylation and decreased ligand-mediated recruitment of Src family proteins to CD36. PMA treatment did not induce detectable extracellular or cell surface-associated kinase activity, and both cycloheximide and brefeldin A blocked CD36 phosphorylation. CONCLUSION: New protein synthesis and trafficking through the Golgi are required for PMA-induced CD36 phosphorylation, suggesting that phosphorylation probably occurs intracellularly. These studies suggest a novel in vivo pathway for CD36 phosphorylation that modulates cellular affinity for thrombospondin-related proteins to blunt vascular cell signaling. PMID- 22247258 TI - EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis. AB - OBJECTIVE: Endothelial cell activation results in altered cell-cell interactions with adjacent endothelial cells and with infiltrating leukocytes. Eph receptors and their ephrin ligands regulate cell-cell interactions during tissue remodeling, and multiple proinflammatory mediators induce endothelial EphA receptor and ephrinA ligand expression. Therefore, we sought to elucidate the role of EphA receptors and ephrinA ligands in endothelial cell activation and atherosclerosis. METHODS AND RESULTS: Quantitative reverse transcription polymerase chain reaction screening for EphA/ephrinA expression in atherosclerosis-prone macrovascular endothelium identified EphA2, EphA4, and ephrinA1 as the dominant isoforms. Endothelial activation with oxidized low density lipoprotein and proinflammatory cytokines induced EphA2 and ephrinA1 expression and sustained EphA2 activation, whereas EphA4 expression was unaffected. Atherosclerotic plaques from mice and humans showed enhanced EphA2 and ephrinA1 expression colocalizing in the endothelial cell layer. EphA2 activation with recombinant Fc-ephrinA1 induced proinflammatory gene expression (eg vascular cell adhesion molecule-1, E-selectin) and stimulated monocyte adhesion, whereas inhibiting EphA2 (small interfering RNA, pharmacological inhibitors) abrogated both ephrinA1-induced and oxidized low-density lipoprotein induced vascular cell adhesion molecule-1 expression. CONCLUSION: The current data suggest that enhanced EphA2 signaling during endothelial cell activation perpetuates proinflammatory gene expression. Coupled with EphA2 expression in mouse and human atherosclerotic plaques, these data implicate EphA2 as a novel proinflammatory mediator and potential regulator of atherosclerotic plaque development. PMID- 22247261 TI - Different tests for a difference: how do we do research? PMID- 22247260 TI - Fractalkine: a survivor's guide: chemokines as antiapoptotic mediators. AB - Chemokines are a family of low-molecular-weight proteins essential to the directed migration of cells under homeostatic and pathological conditions. Fractalkine (CX3CL1) is an unusual chemokine that can act as either a soluble or membrane-bound mediator and signals through the G protein-coupled chemokine receptor CX3CR1, expressed on monocytes, natural killer cells, T cells, and smooth muscle cells. Accumulating evidence suggests that fractalkine, in addition to its role in chemotaxis and adhesion of leukocytes, supports the survival of multiple cell types during homeostasis and inflammation. This review presents the evidence obtained from several disease models implying an antiapoptotic function for fractalkine and shows how this is relevant to the pathology of atherosclerosis and other vascular diseases. We discuss whether the key role of fractalkine, unlike other chemokines, is the promotion of cell survival and whether this has implications for vascular disease. PMID- 22247262 TI - Glycinergic neurons process images. PMID- 22247263 TI - Bioinformatics for personal genome interpretation. AB - An international consortium released the first draft sequence of the human genome 10 years ago. Although the analysis of this data has suggested the genetic underpinnings of many diseases, we have not yet been able to fully quantify the relationship between genotype and phenotype. Thus, a major current effort of the scientific community focuses on evaluating individual predispositions to specific phenotypic traits given their genetic backgrounds. Many resources aim to identify and annotate the specific genes responsible for the observed phenotypes. Some of these use intra-species genetic variability as a means for better understanding this relationship. In addition, several online resources are now dedicated to collecting single nucleotide variants and other types of variants, and annotating their functional effects and associations with phenotypic traits. This information has enabled researchers to develop bioinformatics tools to analyze the rapidly increasing amount of newly extracted variation data and to predict the effect of uncharacterized variants. In this work, we review the most important developments in the field--the databases and bioinformatics tools that will be of utmost importance in our concerted effort to interpret the human variome. PMID- 22247264 TI - The Ustilago maydis Nit2 homolog regulates nitrogen utilization and is required for efficient induction of filamentous growth. AB - Nitrogen catabolite repression (NCR) is a regulatory strategy found in microorganisms that restricts the utilization of complex and unfavored nitrogen sources in the presence of favored nitrogen sources. In fungi, this concept has been best studied in yeasts and filamentous ascomycetes, where the GATA transcription factors Gln3p and Gat1p (in yeasts) and Nit2/AreA (in ascomycetes) constitute the main positive regulators of NCR. The reason why functional Nit2 homologs of some phytopathogenic fungi are required for full virulence in their hosts has remained elusive. We have identified the Nit2 homolog in the basidiomycetous phytopathogen Ustilago maydis and show that it is a major, but not the exclusive, positive regulator of nitrogen utilization. By transcriptome analysis of sporidia grown on artificial media devoid of favored nitrogen sources, we show that only a subset of nitrogen-responsive genes are regulated by Nit2, including the Gal4-like transcription factor Ton1 (a target of Nit2). Ustilagic acid biosynthesis is not under the control of Nit2, while nitrogen starvation-induced filamentous growth is largely dependent on functional Nit2. nit2 deletion mutants show the delayed initiation of filamentous growth on maize leaves and exhibit strongly compromised virulence, demonstrating that Nit2 is required to efficiently initiate the pathogenicity program of U. maydis. PMID- 22247265 TI - The septin AspB in Aspergillus nidulans forms bars and filaments and plays roles in growth emergence and conidiation. AB - In yeast, septins form rings at the mother-bud neck and function as diffusion barriers. In animals, septins form filaments that can colocalize with other cytoskeletal elements. In the filamentous fungus Aspergillus nidulans there are five septin genes, aspA (an ortholog of Saccharomyces cerevisiae CDC11), aspB (an ortholog of S. cerevisiae CDC3), aspC (an ortholog of S. cerevisiae CDC12), aspD (an ortholog of S. cerevisiae CDC10), and aspE (found only in filamentous fungi). The aspB gene was previously reported to be the most highly expressed Aspergillus nidulans septin and to be essential. Using improved gene targeting techniques, we found that deletion of aspB is not lethal but results in delayed septation, increased emergence of germ tubes and branches, and greatly reduced conidiation. We also found that AspB-green fluorescent protein (GFP) localizes as rings and collars at septa, branches, and emerging layers of the conidiophore and as bars and filaments in conidia and hyphae. Bars are found in dormant and isotropically expanding conidia and in subapical nongrowing regions of hyphae and display fast movements. Filaments form as the germ tube emerges, localize to hyphal and branch tips, and display slower movements. All visible AspB-GFP structures are retained in DeltaaspD and lost in DeltaaspA and DeltaaspC strains. Interestingly, in the DeltaaspE mutant, AspB-GFP rings, bars, and filaments are visible in early growth, but AspB-GFP rods and filaments disappear after septum formation. AspE orthologs are only found in filamentous fungi, suggesting that this class of septins might be required for stability of septin bars and filaments in highly polar cells. PMID- 22247266 TI - The Giardia median body protein is a ventral disc protein that is critical for maintaining a domed disc conformation during attachment. AB - Giardia has unique microtubule structures, including the ventral disc, the primary organelle of attachment to the host, and the median body, a structure of undefined function. During attachment, the ventral disc has a domed conformation and enables Giardia to attach to the host intestinal epithelia within seconds. The mechanism of attachment via the ventral disc and the overall structure, function, and assembly of the ventral disc are not well understood. Our recent proteomic analysis of the ventral disc indicated that the median body protein (MBP), previously reported to localize exclusively to the median body, was primarily localized to the ventral disc. Using high-resolution light and electron microscopy, we confirm that the median body protein localizes primarily to the overlap zone of the ventral disc. The MBP also occasionally localized to the median body during prophase. To define the contribution of MBP to the ventral disc structure, we depleted MBP using an anti-MBP morpholino. We found that the ventral disc was no longer able to form properly and that the disc structure often had an aberrant nondomed or flattened horseshoe conformation. The ability of attached anti-MBP morpholino-treated trophozoites to withstand shear forces and normal forces was significantly decreased. Most notably, the plasma membrane contacts with the surface, including those of the bare area, were defective after the anti-MBP knockdown. To our knowledge, this is the first ventral disc protein whose depletion directly alters ventral disc structure, confirming that the domed ventral disc conformation is important for robust attachment. PMID- 22247267 TI - Trehalose 6-phosphate is required for the onset of leaf senescence associated with high carbon availability. AB - Trehalose 6-phosphate (T6P) is an important regulator of plant metabolism and development. T6P content increases when carbon availability is high, and in young growing tissue, T6P inhibits the activity of Snf1-related protein kinase (SnRK1). Here, strong accumulation of T6P was found in senescing leaves of Arabidopsis (Arabidopsis thaliana), in parallel with a rise in sugar contents. To determine the role of T6P in senescence, T6P content was altered by expressing the bacterial T6P synthase gene, otsA (to increase T6P), or the T6P phosphatase gene, otsB (to decrease T6P). In otsB-expressing plants, T6P accumulated less strongly during senescence than in wild-type plants, while otsA-expressing plants contained more T6P throughout. Mature otsB-expressing plants showed a similar phenotype as described for plants overexpressing the SnRK1 gene, KIN10, including reduced anthocyanin accumulation and delayed senescence. This was confirmed by quantitative reverse transcription-polymerase chain reaction analysis of senescence-associated genes and genes involved in anthocyanin synthesis. To analyze if the senescence phenotype was due to decreased sugar sensitivity, the response to sugars was determined. In combination with low nitrogen supply, metabolizable sugars (glucose, fructose, or sucrose) induced senescence in wild type and otsA-expressing plants but to a smaller extent in otsB-expressing plants. The sugar analog 3-O-methyl glucose, on the other hand, did not induce senescence in any of the lines. Transfer of plants to and from glucose-containing medium suggested that glucose determines senescence during late development but that the effects of T6P on senescence are established by the sugar response of young plants. PMID- 22247268 TI - A comprehensive dataset of genes with a loss-of-function mutant phenotype in Arabidopsis. AB - Despite the widespread use of Arabidopsis (Arabidopsis thaliana) as a model plant, a curated dataset of Arabidopsis genes with mutant phenotypes remains to be established. A preliminary list published nine years ago in Plant Physiology is outdated, and genome-wide phenotype information remains difficult to obtain. We describe here a comprehensive dataset of 2,400 genes with a loss-of-function mutant phenotype in Arabidopsis. Phenotype descriptions were gathered primarily from manual curation of the scientific literature. Genes were placed into prioritized groups (essential, morphological, cellular-biochemical, and conditional) based on the documented phenotypes of putative knockout alleles. Phenotype classes (e.g. vegetative, reproductive, and timing, for the morphological group) and subsets (e.g. flowering time, senescence, circadian rhythms, and miscellaneous, for the timing class) were also established. Gene identities were classified as confirmed (through molecular complementation or multiple alleles) or not confirmed. Relationships between mutant phenotype and protein function, genetic redundancy, protein connectivity, and subcellular protein localization were explored. A complementary dataset of 401 genes that exhibit a mutant phenotype only when disrupted in combination with a putative paralog was also compiled. The importance of these genes in confirming functional redundancy and enhancing the value of single gene datasets is discussed. With further input and curation from the Arabidopsis community, these datasets should help to address a variety of important biological questions, provide a foundation for exploring the relationship between genotype and phenotype in angiosperms, enhance the utility of Arabidopsis as a reference plant, and facilitate comparative studies with model genetic organisms. PMID- 22247269 TI - The developmental trajectory of leaflet morphology in wild tomato species. AB - Leaves between species vary in their size, serration, complexity, and shape. However, phylogeny is not the only predictor of leaf morphology. The shape of a leaf is the result of intricate developmental processes, including heteroblastic progression (changes in leaf size and shape at different nodes) and the developmental stage of an organ. The leaflets that arise from complex leaves are additionally modified by their positioning along the proximal-distal axis of a leaf and whether they fall on the left or right side of leaves. Even further, leaves are environmentally responsive, and their final shape is influenced by environmental inputs. Here, we comprehensively describe differences in leaflet shape between wild tomato (Solanum section Lycopersicon) species using a principal component analysis on elliptical Fourier descriptors arising from >11,000 sampled leaflets. We leverage differences in developmental rate to approximate a developmental series, which allows us to resolve the confounding differences in intrinsic leaflet form and developmental stage along positions of the heteroblastic leaf series and proximal-distal axis of leaves. We find that the resulting developmental trajectory of organs at different positions along these axes are useful for describing the changes in leaflet shape that occur during the shade avoidance response in tomato. We argue that it is the developmental trajectory, the changes in shape that occur over developmental time in organs reiterated at multiple positions, that is the relevant phenotype for discerning differences between populations and species, and to understand the underlying developmental processes that change during evolution. PMID- 22247270 TI - CYP701A8: a rice ent-kaurene oxidase paralog diverted to more specialized diterpenoid metabolism. AB - All higher plants contain an ent-kaurene oxidase (KO), as such a cytochrome P450 (CYP) 701 family member is required for gibberellin (GA) phytohormone biosynthesis. While gene expansion and functional diversification of GA biosynthesis-derived diterpene synthases into more specialized metabolism has been demonstrated, no functionally divergent KO/CYP701 homologs have been previously identified. Rice (Oryza sativa) contains five CYP701A subfamily members in its genome, despite the fact that only one (OsKO2/CYP701A6) is required for GA biosynthesis. Here we demonstrate that one of the other rice CYP701A subfamily members, OsKOL4/CYP701A8, does not catalyze the prototypical conversion of the ent-kaurene C4alpha-methyl to a carboxylic acid, but instead carries out hydroxylation at the nearby C3alpha position in a number of related diterpenes. In particular, under conditions where OsKO2 catalyzes the expected conversion of ent-kaurene to ent-kaurenoic acid required for GA biosynthesis, OsKOL4 instead efficiently reacts with ent-sandaracopimaradiene and ent cassadiene to produce the corresponding C3alpha-hydroxylated diterpenoids. These compounds are expected intermediates in biosynthesis of the oryzalexin and phytocassane families of rice antifungal phytoalexins, respectively, and can be detected in rice plants under the appropriate conditions. Thus, it appears that OsKOL4 plays a role in the more specialized diterpenoid metabolism of rice, and our results provide evidence for divergence of a KO/CYP701 family member from GA biosynthesis. This further expands the range of enzymes recruited from the ancestral GA primary pathway to the more complex and specialized labdane-related diterpenoid metabolic network found in rice. PMID- 22247273 TI - Closed-loop cardiac pacing vs. conventional dual-chamber pacing with specialized sensing and pacing algorithms for syncope prevention in patients with refractory vasovagal syncope: results of a long-term follow-up. AB - AIMS: Closed-loop stimulation (CLS) pacing has shown greater efficacy in preventing the recurrence of vasovagal syncope (VVS) in patients with a cardioinhibitory response to head-up tilt test (HUTT) compared with conventional pacing. Moreover, there is no conclusive evidence to support the superiority of CLS over the conventional algorithms for syncope prevention. This study retrospectively evaluated the effectiveness of CLS pacing compared with dual chamber pacing with conventional specialized sensing and pacing algorithms for syncope prevention in the prevention of syncope recurrence in patients with refractory VVS and a cardioinhibitory response to HUTT during a long-term follow up. METHODS AND RESULTS: Forty-one patients (44% male, 53 +/- 16 years) with recurrent, refractory VVS (26% with trauma) and a cardioinhibitory response to HUTT who had undergone pacemaker implantation were included in the analysis. Twenty-five patients received a dual-chamber CLS pacemaker (CLS group) and 16 patients received a dual-chamber pacemaker with conventional algorithms for syncope prevention (conventional pacing group): 9 patients with Medtronic rate drop response algorithm and 7 patients with Guidant-Boston Scientific sudden brady response algorithm. During the follow-up (mean 4.4 +/- 3.0 years, interquartile range 2.2-7.4 years) one patient (4%) in the CLS group and six (38%) in the conventional pacing group had syncope recurrences (P= 0.016). The Kaplan-Meier actuarial estimate of first recurrence of syncope after 8 years was 4% in the CLS group and 40% in the conventional pacing group (P= 0.010). CONCLUSIONS: The results of this retrospective analysis show that, in order to prevent a recurrence of VVS in patients with a cardioinhibitory response to HUTT, dual-chamber CLS pacing was more effective than dual-chamber pacing with conventional algorithms for syncope prevention in preventing bradycardia-related syncope. PMID- 22247271 TI - Plant defense mechanisms are activated during biotrophic and necrotrophic development of Colletotricum graminicola in maize. AB - Hemibiotrophic plant pathogens first establish a biotrophic interaction with the host plant and later switch to a destructive necrotrophic lifestyle. Studies of biotrophic pathogens have shown that they actively suppress plant defenses after an initial microbe-associated molecular pattern-triggered activation. In contrast, studies of the hemibiotrophs suggest that they do not suppress plant defenses during the biotrophic phase, indicating that while there are similarities between the biotrophic phase of hemibiotrophs and biotrophic pathogens, the two lifestyles are not analogous. We performed transcriptomic, histological, and biochemical studies of the early events during the infection of maize (Zea mays) with Colletotrichum graminicola, a model pathosystem for the study of hemibiotrophy. Time-course experiments revealed that mRNAs of several defense-related genes, reactive oxygen species, and antimicrobial compounds all begin to accumulate early in the infection process and continue to accumulate during the biotrophic stage. We also discovered the production of maize-derived vesicular bodies containing hydrogen peroxide targeting the fungal hyphae. We describe the fungal respiratory burst during host infection, paralleled by superoxide ion production in specific fungal cells during the transition from biotrophy to a necrotrophic lifestyle. We also identified several novel putative fungal effectors and studied their expression during anthracnose development in maize. Our results demonstrate a strong induction of defense mechanisms occurring in maize cells during C. graminicola infection, even during the biotrophic development of the pathogen. We hypothesize that the switch to necrotrophic growth enables the fungus to evade the effects of the plant immune system and allows for full fungal pathogenicity. PMID- 22247272 TI - Transcriptional regulation of Arabidopsis MIR168a and argonaute1 homeostasis in abscisic acid and abiotic stress responses. AB - The accumulation of a number of small RNAs in plants is affected by abscisic acid (ABA) and abiotic stresses, but the underlying mechanisms are poorly understood. The miR168-mediated feedback regulatory loop regulates ARGONAUTE1 (AGO1) homeostasis, which is crucial for gene expression modulation and plant development. Here, we reveal a transcriptional regulatory mechanism by which MIR168 controls AGO1 homeostasis during ABA treatment and abiotic stress responses in Arabidopsis (Arabidopsis thaliana). Plants overexpressing MIR168a and the AGO1 loss-of-function mutant ago1-27 display ABA hypersensitivity and drought tolerance, while the mir168a-2 mutant shows ABA hyposensitivity and drought hypersensitivity. Both the precursor and mature miR168 were induced under ABA and several abiotic stress treatments, but no obvious decrease for the target of miR168, AGO1, was shown under the same conditions. However, promoter activity analysis indicated that AGO1 transcription activity was increased under ABA and drought treatments, suggesting that transcriptional elevation of MIR168a is required for maintaining a stable AGO1 transcript level during the stress response. Furthermore, we showed both in vitro and in vivo that the transcription of MIR168a is directly regulated by four abscisic acid-responsive element (ABRE) binding factors, which bind to the ABRE cis-element within the MIR168a promoter. This ABRE motif is also found in the promoter of MIR168a homologs in diverse plant species. Our findings suggest that transcriptional regulation of miR168 and posttranscriptional control of AGO1 homeostasis may play an important and conserved role in stress response and signal transduction in plants. PMID- 22247274 TI - Differences in encapsulating lead tissue in patients who underwent transvenous lead removal. AB - AIM: The aim of our study was to characterize specific tissue reaction of encapsulating lead tissue in patients who underwent transvenous lead removal and evaluate condition of the outer leads' insulation. METHODS AND RESULTS: Fifty-six leads (27 atrial, 24 ventricular, 5 implantable cardioverter-defibrillators) were removed from 31 patients (mean age 70 years). Indications for removal were chronic pocket infection (CPI) (9 patients ), infective endocarditis (IE) (6), and non-infective indications (NI) (16). Leads with their surrounding tissue were fixed in paraformaldehyde. Tissues were embedded in paraffin wax, stained with haematoxylin-eosin, and examined histologically. The outer leads' insulations were examined in stereomicroscope. The mean lead age encapsulated by connective tissue sheath was 89, whereas encapsulated by granulation tissue was 47.34 months (P= 0.03). Calcification was present in 13 patients. Haemosiderine was observed only in patients with severe abrasion with perforation in the pocket (P= 0.04). Vasculogenesis was present in one (6%) with NI, five (56%) with CPI, and three (50%) with IE (P= 0.02) and was associated with elevated white blood cells (WBC) (P= 0.04). Eosinophilia was associated with elevated WBC (P= 0.04). The most frequently observed are third level of degradation (severe with perforation) in the intracardiac part of the silicone leads. Insulation damage due to environmental stress cracking concerned all leads with polyurethane overlay. CONCLUSIONS: Granulation in encapsulating tissue was present in patients with younger leads. Vasculogenesis was observed more often in IE and CPI patients, which might indirectly indicate thickness of the sheath. Eosinophila may indicate allergic component of inflammation. Insulation damage frequently concerned the intracardiac part. PMID- 22247275 TI - Roundup 2.0: enabling comparative genomics for over 1800 genomes. AB - Roundup is an online database of gene orthologs for over 1800 genomes, including 226 Eukaryota, 1447 Bacteria, 113 Archaea and 21 Viruses. Orthologs are inferred using the Reciprocal Smallest Distance algorithm. Users may query Roundup for single-linkage clusters of orthologous genes based on any group of genomes. Annotated query results may be viewed in a variety of ways including as clusters of orthologs and as phylogenetic profiles. Genomic results may be downloaded in formats suitable for functional as well as phylogenetic analysis, including the recent OrthoXML standard. In addition, gene IDs can be retrieved using FASTA sequence search. All source code and orthologs are freely available. AVAILABILITY: http://roundup.hms.harvard.edu. PMID- 22247276 TI - BOCTOPUS: improved topology prediction of transmembrane beta barrel proteins. AB - MOTIVATION: Transmembrane beta barrel proteins (TMBs) are found in the outer membrane of Gram-negative bacteria, chloroplast and mitochondria. They play a major role in the translocation machinery, pore formation, membrane anchoring and ion exchange. TMBs are also promising targets for antimicrobial drugs and vaccines. Given the difficulty in membrane protein structure determination, computational methods to identify TMBs and predict the topology of TMBs are important. RESULTS: Here, we present BOCTOPUS; an improved method for the topology prediction of TMBs by employing a combination of support vector machines (SVMs) and Hidden Markov Models (HMMs). The SVMs and HMMs account for local and global residue preferences, respectively. Based on a 10-fold cross-validation test, BOCTOPUS performs better than all existing methods, reaching a Q3 accuracy of 87%. Further, BOCTOPUS predicted the correct number of strands for 83% proteins in the dataset. BOCTOPUS might also help in reliable identification of TMBs by using it as an additional filter to methods specialized in this task. AVAILABILITY: BOCTOPUS is freely available as a web server at: http://boctopus.cbr.su.se/. The datasets used for training and evaluations are also available from this site. PMID- 22247277 TI - Mining and evaluation of molecular relationships in literature. AB - MOTIVATION: Specific information on newly discovered proteins is often difficult to find in literature. Particularly if only sequences and no common names of proteins or genes are available, preceding sequence similarity searches can be crucial for the process of information collection. In drug research, it is important to know whether a small molecule targets only one specific protein or whether similar or homologous proteins are also influenced that may account for possible side effects. RESULTS: prolific (protein-literature investigation for interacting compounds) provides a one-step solution to investigate available information on given protein names, sequences, similar proteins or sequences on the gene level. Co-occurrences of UniProtKB/Swiss-Prot proteins and PubChem compounds in all PubMed abstracts are retrievable. Concise 'heat-maps' and tables display frequencies of co-occurrences. They provide links to processed literature with highlighted found protein and compound synonyms. Evaluation with manually curated drug-protein relationships showed that up to 69% could be discovered by automatic text-processing. Examples are presented to demonstrate the capabilities of prolific. AVAILABILITY: The web-application is available at http://prolific.pharmaceutical-bioinformatics.de and a web service at http://www.pharmaceutical-bioinformatics.de/prolific/soap/prolific.wsdl. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22247278 TI - nEASE: a method for gene ontology subclassification of high-throughput gene expression data. AB - High-throughput technologies can identify genes whose expression profiles correlate with specific phenotypes; however, placing these genes into a biological context remains challenging. To help address this issue, we developed nested Expression Analysis Systematic Explorer (nEASE). nEASE complements traditional gene ontology enrichment approaches by determining statistically enriched gene ontology subterms within a list of genes based on co-annotation. Here, we overview an open-source software version of the nEASE algorithm. nEASE can be used either stand-alone or as part of a pathway discovery pipeline. AVAILABILITY: nEASE is implemented within the Multiple Experiment Viewer software package available at http://www.tm4.org/mev. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22247279 TI - Robust rank aggregation for gene list integration and meta-analysis. AB - MOTIVATION: The continued progress in developing technological platforms, availability of many published experimental datasets, as well as different statistical methods to analyze those data have allowed approaching the same research question using various methods simultaneously. To get the best out of all these alternatives, we need to integrate their results in an unbiased manner. Prioritized gene lists are a common result presentation method in genomic data analysis applications. Thus, the rank aggregation methods can become a useful and general solution for the integration task. RESULTS: Standard rank aggregation methods are often ill-suited for biological settings where the gene lists are inherently noisy. As a remedy, we propose a novel robust rank aggregation (RRA) method. Our method detects genes that are ranked consistently better than expected under null hypothesis of uncorrelated inputs and assigns a significance score for each gene. The underlying probabilistic model makes the algorithm parameter free and robust to outliers, noise and errors. Significance scores also provide a rigorous way to keep only the statistically relevant genes in the final list. These properties make our approach robust and compelling for many settings. AVAILABILITY: All the methods are implemented as a GNU R package RobustRankAggreg, freely available at the Comprehensive R Archive Network http://cran.r-project.org/. PMID- 22247280 TI - Estimation of pairwise sequence similarity of mammalian enhancers with word neighbourhood counts. AB - MOTIVATION: The identity of cells and tissues is to a large degree governed by transcriptional regulation. A major part is accomplished by the combinatorial binding of transcription factors at regulatory sequences, such as enhancers. Even though binding of transcription factors is sequence-specific, estimating the sequence similarity of two functionally similar enhancers is very difficult. However, a similarity measure for regulatory sequences is crucial to detect and understand functional similarities between two enhancers and will facilitate large-scale analyses like clustering, prediction and classification of genome wide datasets. RESULTS: We present the standardized alignment-free sequence similarity measure N2, a flexible framework that is defined for word neighbourhoods. We explore the usefulness of adding reverse complement words as well as words including mismatches into the neighbourhood. On simulated enhancer sequences as well as functional enhancers in mouse development, N2 is shown to outperform previous alignment-free measures. N2 is flexible, faster than competing methods and less susceptible to single sequence noise and the occurrence of repetitive sequences. Experiments on the mouse enhancers reveal that enhancers active in different tissues can be separated by pairwise comparison using N2. CONCLUSION: N2 represents an improvement over previous alignment-free similarity measures without compromising speed, which makes it a good candidate for large-scale sequence comparison of regulatory sequences. AVAILABILITY: The software is part of the open-source C++ library SeqAn (www.seqan.de) and a compiled version can be downloaded at http://www.seqan.de/projects/alf.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22247281 TI - Application of canonical correlation analysis for identifying viral integration preferences. AB - MOTIVATION: Gene therapy aims at using viral vectors for attaching helpful genetic code to target genes. Therefore, it is of great importance to develop methods that can discover significant patterns around viral integration sites. Canonical correlation analysis is an unsupervised statistical tool that is used to describe the relations between two related views of the same semantic object, which fits well for identifying such salient patterns. RESULTS: Proposed method is demonstrated on a sequence dataset obtained from a study on HIV-1 preferred integration regions. The subsequences on the left and right sides of the integration points are given to the method as the two views, and statistically significant relations are found between sequence-driven features derived from these two views, which suggest that the viral preference must be the factor responsible for this correlation. We found that there are significant correlations at x=5 indicating a palindromic behavior surrounding the viral integration site, which complies with the previously reported results. AVAILABILITY: Developed software tool is available at http://ce.istanbul.edu.tr/bioinformatics/hiv1/. PMID- 22247282 TI - Evidence that angiotensin-(1-7) is an intermediate of gonadotrophin-induced oocyte maturation in the rat preovulatory follicle. AB - Several studies have shown the presence of components of the renin-angiotensin system in mammalian ovaries and their involvement in ovarian physiology. We have previously shown the presence of angiotensin-(1-7) [Ang-(1-7)], an important biologically active component of the renin-angiotensin system, and its receptor, Mas, in rat, rabbit and human ovaries. We have also shown the involvement of Ang (1-7) in the rabbit ovulatory process in vitro. In the present study, we observed that Ang-(1-7) stimulated the resumption of meiosis in oocytes of rat preovulatory follicles, reaching more than 30% of oocytes with germinal vesicle breakdown. The specific antagonist of the Mas receptor, A-779, inhibited the germinal vesicle breakdown induced by Ang-(1-7) and reduced the oocyte maturation stimulated by luteinizing hormone (LH). Immunohistochemistry showed that LH increased both Ang-(1-7) and angiotensin-converting enzyme 2 (ACE2) staining in preovulatory follicles. The effect of gonadotrophins on mRNA expression of Mas and ACE2 in ovaries of immature equine chorionic gonadotrophin-primed rats was analysed by real-time PCR after 6 h of human chorionic gonadotrophin (hCG) injection, which exhibits LH-like effects. After hCG treatment, ACE2 mRNA expression was higher in the ovaries of treated rats than in the ovaries of control rats, whereas Mas mRNA levels were unchanged. A-779 changed the steroidogenesis stimulated by LH. An increased testosterone concentration and decreased progesterone levels were measured in the follicle medium. In conclusion, our results suggest that LH upregulates the ACE2-Ang-(1-7)-Mas axis and that Ang-(1-7) promotes meiotic resumption, possibly as a gonadotrophin intermediate. PMID- 22247283 TI - Different patterns of pulmonary vascular disease induced by type 1 diabetes and moderate hypoxia in rats. AB - Although type 1 and type 2 diabetes are strongly associated with systemic cardiovascular morbidity, the relationship with pulmonary vascular disease had been almost disregarded until recent epidemiological data revealed that diabetes might be a risk factor for pulmonary hypertension. Recent experimental studies suggest that diabetes induces changes in lung function insufficient to elevate pulmonary pressure. The aim of this study was to assess the effects of diabetes on the sensitivity to other risk factors for pulmonary hypertension. We therefore analysed the effects of the combination of diabetes with exposure to moderate hypoxia on classical markers of pulmonary hypertension. Control (saline-treated) and diabetic (70 mg kg(-1) streptozotocin-treated) male Wistar-Kyoto rats were followed for 4 weeks and exposed to normoxia or moderate normobaric hypoxia (14%) for another 2 weeks. Hypoxia, but not diabetes, strongly reduced voltage-gated potassium currents, whereas diabetes, but not hypoxia, induced pulmonary artery endothelial dysfunction. Both factors independently induced pulmonary vascular remodelling and downregulated the lung bone morphogenetic protein receptor type 2. However, diabetes, but not hypoxia, induced pulmonary infiltration of macrophages, which was markedly increased when both factors were combined. Diabetes plus hypoxia induced a modest increase in diastolic and mean pulmonary artery pressure and right ventricular weight, while each of the two factors alone had no significant effect. The pattern of changes in markers of pulmonary hypertension was different for moderate hypoxia and diabetes, with no synergic effect except for macrophage recruitment, and the combination of both factors was required to induce a moderate elevation in pulmonary arterial pressure. PMID- 22247284 TI - Neural regulation of inflammation: no neural connection from the vagus to splenic sympathetic neurons. AB - The 'inflammatory reflex' acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7-9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue-labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic-projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity. PMID- 22247285 TI - A new lacrimal bypass tube fixation method to prevent tube displacement in conjunctivodacryocystorhinostomy (CDCR). AB - AIMS: To evaluate the efficacy of a new lacrimal bypass tube fixation technique to the conjunctiva and caruncle, preventing postoperative displacement of the tube in conjunctivodacryocystorhinostomies (CDCRs). METHODS: The authors conducted 52 CDCR procedures by a new tube fixation technique using a 6-0 prolene suture encircling the tube neck (encircling group). The suture was not removed during the follow-up period. Over the same period, the authors carried out 51 CDCRs with tube fixation using a 5-0 vicryl suture with the purse string procedure (purse string group) and 71 conventional CDCRs with tube fixation to the skin using a 6-0 nylon suture (control group). Postoperative complications, including dislodgement and tube length problems, were recorded. The three groups were statistically compared. RESULTS: Among the 52 cases using the new fixation technique, tube malpositions, including extrusions, had developed in only four cases (7.7%) at 12 months after the operation. In the purse string and control groups, the same complications developed in 11 (21.6%) and 22 cases (31.0%), respectively. A statistically significant difference between these groups was detected (p=0.008). Other complications, such as conjunctival granulomas and tube obstruction, developed postoperatively in four cases (8.0%) in the encircling group, and this did not differ significantly from that in the other groups (p=0.193). CONCLUSIONS: The authors believe that this encircling fixation procedure can help in CDCRs for maintaining the location and orientation of the tube during the early postoperative period. PMID- 22247286 TI - Negotiating refusal in primary care consultations: a qualitative study. AB - BACKGROUND: How GPs negotiate patient requests is vital to their gatekeeper role but also a source of potential conflict, practitioner stress and patient dissatisfaction. Difficulties may arise when demands of shared decision-making conflict with resource allocation, which may be exacerbated by new commissioning arrangements, with GPs responsible for available services. OBJECTIVES: To explore GPs' accounts of negotiating refusal of patient requests and their negotiation strategies. METHODS: A qualitative design was employed with two focus groups of GPs and GP registrars followed by 20 semi-structured interviews. Participants were sampled by gender, experience, training/non-training, principal versus salaried or locum. Thematic content analysis proceeded in parallel with interviews and further sampling. The setting was GP practices within an English urban primary care trust. RESULTS: Sickness certification, antibiotics and benzodiazepines were cited most frequently as problematic patient requests. GP trainees reported more conflict within interactions than experienced GPs. Negotiation strategies, such as blaming distant third parties such as the primary care organization, were designed to prevent conflict and preserve the doctor patient relationship. GPs reported patients' expectations being strongly influenced by previous encounters with other health care professionals. CONCLUSIONS: The findings reiterate the prominence of the doctor-patient relationship in GPs' accounts. GPs' relationships with colleagues and the wider National Health Service (NHS) are particular of relevance in light of provisions in the Health and Social Care Bill for clinical commissioning consortia. The ability of GPs to offset blame for rationing decisions to third parties will be undermined if the same GPs commission services. PMID- 22247287 TI - Jaundice in primary care: a cohort study of adults aged >45 years using electronic medical records. AB - BACKGROUND: Jaundice is a rare but important symptom of malignant and benign conditions. When patients present in primary care, understanding the relative likelihood of different disease processes can help GPs to investigate and refer patients appropriately. OBJECTIVE: To identify and quantify the various causes of jaundice in adults presenting in primary care. DESIGN: Historical cohort study using electronic primary care records. SETTING: UK General Practice Research Database. METHODS: Participants (186 814 men and women) aged >45 years with clinical events recorded in primary care records between 1 January 2005 and 31 December 2007. Data were searched for episodes of jaundice and explanatory diagnoses identified within the subsequent 12 months. If no diagnosis was found, the patient's preceding medical record was searched for relevant chronic diseases. RESULTS: From the full cohort, 277 patients had at least one record of jaundice between 1 January 2005 and 31 December 2006. Ninety-two (33%) were found to have bile duct stones; 74 (27%) had an explanatory cancer [pancreatic cancer 34 (12%), cholangiocarcinoma 13 (5%) and other diagnosed primary malignancy 27 (10%)]. Liver disease attributed to excess alcohol explained 26 (9%) and other diagnoses were identified in 24 (9%). Sixty-one (22%) had no diagnosis related to jaundice recorded. CONCLUSION: Although the most common cause of jaundice is bile duct stones, cancers are present in over a quarter of patients with jaundice in this study, demonstrating the importance of urgent investigation into the underlying cause. PMID- 22247288 TI - Isoprenoid biosynthesis is required for miRNA function and affects membrane association of ARGONAUTE 1 in Arabidopsis. AB - Plant and metazoan microRNAs (miRNAs) guide ARGONAUTE (AGO) protein complexes to regulate expression of complementary RNAs via base pairing. In the plant Arabidopsis thaliana, the main miRNA effector is AGO1, but few other factors required for miRNA activity are known. Here, we isolate the genes defined by the previously described miRNA action deficient (mad) mutants, mad3 and mad4. Both genes encode enzymes involved in isoprenoid biosynthesis. MAD3 encodes 3-hydroxy 3-methylglutaryl CoA reductase (HMG1), which functions in the initial C(5) building block biogenesis that precedes isoprenoid metabolism. HMG1 is a key regulatory enzyme that controls the amounts of isoprenoid end products. MAD4 encodes sterol C-8 isomerase (HYDRA1) that acts downstream in dedicated sterol biosynthesis. Using yeast complementation assays and in planta application of lovastatin, a competitive inhibitor of HMG1, we show that defects in HMG1 catalytic activity are sufficient to inhibit miRNA activity. Many isoprenoid derivatives are indispensable structural and signaling components, and especially sterols are essential membrane constituents. Accordingly, we provide evidence that AGO1 is a peripheral membrane protein. Moreover, specific hypomorphic mutant alleles of AGO1 display compromised membrane association and AGO1-membrane interaction is reduced upon knockdown of HMG1/MAD3. These results suggest a possible basis for the requirement of isoprenoid biosynthesis for the activity of plant miRNAs, and unravel mechanistic features shared with their metazoan counterparts. PMID- 22247289 TI - Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction. AB - For subunit vaccines, adjuvants play a key role in shaping immunological memory. Nanoparticle (NP) delivery systems for antigens and/or molecular danger signals are promising adjuvants capable of promoting both cellular and humoral immune responses, but in most cases the mechanisms of action of these materials are poorly understood. Here, we studied the immune response elicited by NPs composed of multilamellar "stapled" lipid vesicles carrying a recombinant Plasmodium vivax circumsporozoite antigen, VMP001, both entrapped in the aqueous core and anchored to the lipid bilayer surfaces. Immunization with these particles and monophosphoryl lipid A (MPLA), a US Food and Drug Administration-approved immunostimulatory agonist for Toll-like receptor-4, promoted high-titer, high avidity antibody responses against VMP001, lasting more than 1 y in mice at 10 fold lower doses than conventional adjuvants. Compared to soluble VMP001 mixed with MPLA, VMP001-NPs promoted broader humoral responses, targeting multiple epitopes of the protein and a more balanced Th1/Th2 cytokine profile from antigen specific T cells. To begin to understand the underlying mechanisms, we examined components of the B-cell response and found that NPs promoted robust germinal center (GC) formation at low doses of antigen where no GC induction occurred with soluble protein immunization, and that GCs nucleated near depots of NPs accumulating in the draining lymph nodes over time. In parallel, NP vaccination enhanced the expansion of antigen-specific follicular helper T cells (T(fh)), compared to vaccinations with soluble VMP001 or alum. Thus, NP vaccines may be a promising strategy to enhance the durability, breadth, and potency of humoral immunity by enhancing key elements of the B-cell response. PMID- 22247290 TI - Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. AB - Malaria, caused by Plasmodium sp, results in almost one million deaths and over 200 million new infections annually. The World Health Organization has recommended that artemisinin-based combination therapies be used for treatment of malaria. Artemisinin is a sesquiterpene lactone isolated from the plant Artemisia annua. However, the supply and price of artemisinin fluctuate greatly, and an alternative production method would be valuable to increase availability. We describe progress toward the goal of developing a supply of semisynthetic artemisinin based on production of the artemisinin precursor amorpha-4,11-diene by fermentation from engineered Saccharomyces cerevisiae, and its chemical conversion to dihydroartemisinic acid, which can be subsequently converted to artemisinin. Previous efforts to produce artemisinin precursors used S. cerevisiae S288C overexpressing selected genes of the mevalonate pathway [Ro et al. (2006) Nature 440:940-943]. We have now overexpressed every enzyme of the mevalonate pathway to ERG20 in S. cerevisiae CEN.PK2, and compared production to CEN.PK2 engineered identically to the previously engineered S288C strain. Overexpressing every enzyme of the mevalonate pathway doubled artemisinic acid production, however, amorpha-4,11-diene production was 10-fold higher than artemisinic acid. We therefore focused on amorpha-4,11-diene production. Development of fermentation processes for the reengineered CEN.PK2 amorpha-4,11 diene strain led to production of > 40 g/L product. A chemical process was developed to convert amorpha-4,11-diene to dihydroartemisinic acid, which could subsequently be converted to artemisinin. The strains and procedures described represent a complete process for production of semisynthetic artemisinin. PMID- 22247293 TI - Gut bacteria and brain function: the challenges of a growing field. PMID- 22247292 TI - Alternative reading frame selection mediated by a tRNA-like domain of an internal ribosome entry site. AB - The dicistrovirus intergenic region internal ribosome entry site (IRES) utilizes a unique mechanism, involving P-site tRNA mimicry, to directly assemble 80S ribosomes and initiate translation at a specific non-AUG codon in the ribosomal A site. A subgroup of dicistrovirus genomes contains an additional stem-loop 5' adjacent to the IRES and a short open reading frame (ORFx) that overlaps the viral structural polyprotein ORF (ORF2) in the +1 reading frame. Using mass spectrometry and extensive mutagenesis, we show that, besides directing ORF2 translation, the Israeli acute paralysis dicistrovirus IRES also directs ORFx translation. The latter is mediated by a UG base pair adjacent to the P-site tRNA mimicking domain. An ORFx peptide was detected in virus-infected honey bees by multiple reaction monitoring mass spectrometry. Finally, the 5' stem-loop increases IRES activity and may couple translation of the two major ORFs of the virus. This study reveals a novel viral strategy in which a tRNA-like IRES directs precise, initiator Met-tRNA-independent translation of two overlapping ORFs. PMID- 22247294 TI - Targeting the microbiota-gut-brain axis to modulate behavior: which bacterial strain will translate best to humans? PMID- 22247295 TI - Airway injury during high-level exercise. AB - Airway epithelial cells act as a physical barrier against environmental toxins and injury, and modulate inflammation and the immune response. As such, maintenance of their integrity is critical. Evidence is accumulating to suggest that exercise can cause injury to the airway epithelium. This seems the case particularly for competitive athletes performing high-level exercise, or when exercise takes place in extreme environmental conditions such as in cold dry air or in polluted air. Dehydration of the small airways and increased forces exerted on to the airway surface during severe hyperpnoea are thought to be key factors in determining the occurrence of injury of the airway epithelium. The injury repair process of the airway epithelium may contribute to the development of the bronchial hyper-responsiveness that is documented in many elite athletes. PMID- 22247296 TI - Treatment of proximal metatarsal V fractures in athletes and non-athletes. PMID- 22247297 TI - Assessment and prevention of exercise-induced bronchoconstriction. AB - The assessment of exercise-induced bronchoconstriction (EIB) in athletes requires the measurement of forced expiratory volume in 1 s (FEV(1)) before and after vigorous exercise or a surrogate of exercise such as eucapnic voluntary hyperpnoea (EVH) of dry air or mannitol dry powder. Exercise testing in a laboratory has a low sensitivity to identify EIB, and exercise testing in the field can be a challenge in itself particularly in cold weather athletes. The EVH test requires the subject to ventilate dry air containing ~5% CO(2) for 6 min through a low-resistance circuit at a rate higher than that usually achieved on maximum exercise. A >=10% reduction in FEV(1) is a positive response to exercise and EVH and, when sustained, is usually associated with release of inflammatory mediators of broncho constriction. Another surrogate, mannitol dry powder, given by inhalation in progressively increasing doses, is used to mimic the dehydrating stimulus of exercise hyperpnoea. A positive mannitol test is a 15% fall in FEV(1) at <=635 mg and reveals potential for EIB. Mannitol has a high specificity for identifying a clinical diagnosis of asthma. Once a diagnosis of EIB is established, the athlete needs to know how to avoid EIB. Being treated daily with an inhaled corticosteroid to reduce airway inflammation, inhaling a beta(2) agonist or a cromone immediately before exercise, or taking a leukotriene antagonist several hours before exercise, all inhibit or prevent EIB. Other strategies include warming up prior to exercise and reducing respiratory water and heat loss by using face masks or nasal breathing. PMID- 22247298 TI - Therapeutic ultrasound is not clinically beneficial for acute ankle sprains. PMID- 22247299 TI - Airway dysfunction in swimmers. AB - Elite competitive swimmers are particularly affected by airway disorders that are probably related to regular and intense training sessions in a chlorinated environment. Upper and lower airway respiratory symptoms, rhinitis, airway hyper responsiveness, and exercise-induced bronchoconstriction are highly prevalent in these athletes, but their influence on athletic performance is still unclear. The authors reviewed the main upper and lower respiratory ailments observed in competitive swimmers who train in indoor swimming pools, their pathophysiology, clinical significance and possible effects on performance. Issues regarding the screening of these disorders, their management and preventive measures are addressed. PMID- 22247300 TI - Rapid and reproducible surveillance for ventilator-associated pneumonia. AB - BACKGROUND: The complexity and subjectivity of ventilator-associated pneumonia (VAP) surveillance limit its value in assessing and comparing quality of care for ventilated patients. A simpler, more quantitative VAP definition may increase utility. METHODS: We streamlined the Centers for Disease Control and Prevention definition of VAP to increase objectivity and efficiency. Qualitative criteria were replaced with quantitative criteria, and changes in ventilator settings were used to screen patients for worsening oxygenation. We retrospectively compared surveillance time, reproducibility, and outcomes for streamlined versus conventional surveillance among medical and surgical patients on mechanical ventilation in 3 university hospitals. RESULTS: Application of the streamlined definition was faster (mean 3.5 minutes vs 39.0 minutes per patient) and more objective (interrater reliability kappa 0.79 vs 0.45) than the conventional definition. On multivariate analysis, the streamlined definition predicted increases in ventilator days (6.5 days [95% CI, 4.1-10.0] vs 6.4 days [95% CI, 4.7-8.6]), intensive care days (5.6 days [95% CI, 3.2-8.9] vs 6.2 days [95% CI, 4.6-8.2]), and hospital mortality (odds ratio [OR] 0.84 [95% CI, 0.31-2.29] vs OR 0.69 [95% CI, 0.30-1.55]) as effectively as conventional surveillance. The conventional definition was a marginally superior predictor of increased hospital days (5.2 days [95% CI, 3.4-7.6] vs 2.1 days [95% CI, -0.5-5.6]). CONCLUSIONS: A streamlined version of the VAP definition was faster, more objective, and predicted patients' outcomes almost as effectively as the conventional definition. VAP surveillance using the streamlined method may facilitate more objective and efficient quality assessment for ventilated patients. PMID- 22247301 TI - Improving surveillance definitions for ventilator-associated pneumonia in an era of public reporting and performance measurement. PMID- 22247304 TI - Gingivostomatitis with fever and rash. Measles. PMID- 22247305 TI - Therapy-resistant opsoclonus-myoclonus syndrome secondary to HIV-1 infection. PMID- 22247303 TI - Human cytomegalovirus infant infection adversely affects growth and development in maternally HIV-exposed and unexposed infants in Zambia. AB - BACKGROUND: Human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) coinfections have been shown to increase infant morbidity, mortality, and AIDS progression. In HIV-endemic regions, maternal HIV-exposed but HIV-uninfected infants, which is the majority of children affected by HIV, also show poor growth and increased morbidity. Although nutrition has been examined, the effects of HCMV infection have not been evaluated. We studied the effects of HCMV infection on the growth, development, and health of maternally HIV-exposed and unexposed infants in Zambia. METHODS: Infants were examined in a cohort recruited to a trial of micronutrient-fortified complementary foods. HIV-infected mothers and infants had received perinatal antiretroviral therapy to prevent mother-to-child HIV transmission. Growth, development, and morbidity were analyzed by linear regression analyses in relation to maternal HIV exposure and HCMV infection, as screened by sera DNA for viremia at 6 months of age and by antibody for infection at 18 months. RESULTS: All HCMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants (standard deviation [z]-score difference: -0.44 [95% confidence interval {CI}, -.72 to -.17]; P = .002). In HIV exposed infants, those who were HCMV positive compared with those who were negative, also had reduced head size (mean z-score difference: -0.72 [95% CI, 1.23 to -.22]; P = .01) and lower psychomotor development (Bayley test score difference: -4.1 [95% CI, -7.8 to -.5]; P = .03). HIV-exposed, HCMV-viremic infants were more commonly referred for hospital treatment than HCMV-negative infants. The effects of HCMV were unaffected by micronutrient fortification. CONCLUSION: HCMV affects child growth, development, and morbidity of African infants, particularly in those maternally exposed to HIV. HCMV is therefore a risk factor for child health in this region. PMID- 22247307 TI - Outbreak of invasive aspergillosis after major heart surgery caused by spores in the air of the intensive care unit. AB - BACKGROUND: Outbreaks of invasive aspergillosis (IA) are believed to be caused by airborne Aspergillus conidia. Few studies have established a correlation between high levels of Aspergillus fumigatus conidia and the appearance of new cases of IA or have demonstrated matching genotypes between clinical isolates and those from the environment. METHODS: We detected an outbreak of IA (December 2006 through April 2008) in the major heart surgery intensive care unit (MHS-ICU) of our institution. Our local surveillance program consists of monthly environmental air sampling in operating rooms and ICUs for quantitative and qualitative identification of filamentous fungi. During the study period, we obtained 508 environmental samples from 3 different periods: 6 months before the outbreak, during it, and 6 months after it. Available environmental and clinical strains were genotyped according to the short tandem repeats assay. RESULTS: Seven patients developed proven or probable IA (5 with lung infection, 1 with mediastinitis, and 1 with lung infection and mediastinitis). A. fumigatus was involved in 6 cases. The underlying conditions of the patients were heart transplantation (n = 3), corticosteroid-dependent conditions (n = 2), and diabetes mellitus (n = 2). The mortality rate was 85.7%. Before and after the outbreak (+/-6 months), the median airborne A. fumigatus conidia levels were 0 colony-forming units (CFUs) per cubic meter, and no cases of IA occurred during these periods. However, during the outbreak period, the occurrence of the 6 cases of IA caused by A. fumigatus was linked to peaks of abnormally high A. fumigatus airborne conidia levels (175, 50, 25, 20, 160, and 400 CFUs/m(3)) in the MHS-ICU, whereas counts in the air of both operating rooms remained negative. Matches between A. fumigatus genotypes collected from the air of the MHS-ICU and from representative clinical samples were found in 3 of the 6 patients. The outbreak abated when high-efficiency particulate air filters were installed in the affected areas. CONCLUSIONS: Our study revealed that abnormally high levels of airborne A. fumigatus conidia correlated with new cases of IA, even in patients who were not severely immunocompromised. The demonstration of matches between air and clinical genotypes reinforces the role of environmental air in the acquisition of IA during the period following MHS. Environmental monitoring of Aspergillus spores in the air of postoperative units is mandatory, even when these units receive nonimmunocompromised patients undergoing major surgery. PMID- 22247316 TI - Hospital consultants and workplace based assessments: how foundation doctors view these educational interactions? AB - AIM: To determine how foundation year 2 (F2) doctors view the input of hospital consultants into their workplace based assessments (WPBAs). STUDY DESIGN: F2 doctors in Northern Ireland participated in an electronic survey to evaluate their experiences of foundation programme WPBAs. The opportunity to participate was available to all F2 doctors. The survey was performed using questions displayed electronically and the responses were collated using Turning Point technology. Two weeks later a focus group was convened to assess the issues raised by the electronic survey. RESULTS: Consultant input into foundation doctor's WPBAs was an infrequent occurrence. The F2 doctors expressed a clear view that they valued consultant input, when this occurred. The WPBAs gave the foundation doctors an opportunity to have a one to one learning opportunity with their supervising consultants. However, many of the WPBAs were completed by other doctors in training, in the grades immediately above the foundation doctors. It was suggested that friendship could influence these assessments. CONCLUSIONS: Completion of foundation doctors' assessments by hospital consultants is viewed as a low priority. These assessments are being completed to a large extent by fellow doctors in training. The learning opportunities are consequently less educationally productive. F2 doctors want more opportunities for valued consultant interaction with timely feedback. Suggestions are proposed to improve WPBA implementation. The present WPBA process lacks integrity and a change in approach is urgently required. PMID- 22247317 TI - Junior doctors' reflections on patient safety. AB - AIM: To determine whether foundation year 1 (FY1) doctors reflect upon patient safety incidents (PSIs) within their portfolios and the potential value of such reflections for quality of care. METHODS: A cross-sectional retrospective review of every 'reflective practice' portfolio entry made by all FY1 doctors within an Acute Teaching Hospital Trust was conducted in February 2010. Entries were reviewed by two independent blinded researchers to determine whether they related to a PSI that is, any unintended or unexpected incident that could have or did lead to patient harm. For all entries rated positive by both reviewers, a content analysis approach was used to code PSI into incident type, contributing factors and patient outcome according to validated frameworks developed by the National Patient Safety Agency. RESULTS: 139 reflective practice entries were completed by 30 trainees (15 men, 15 women, mean age 24 years). Of the 139 entries, 49% reflected on a PSI. Of these, 22% were due to errors in clinical assessment; 22% were due to delayed access to care; 18% were due to infrastructure/staffing deficiencies; and 16% were due to medication errors. The most common contributing factors were team/social factors (23%), patient factors (22%), communication and task factors (both 17%). The majority of PSIs led to no harm. Six entries described PSIs resulting in patient death, the majority of which were attributable to diagnostic errors. CONCLUSIONS: FY1 doctors commonly reflect on PSIs within their professional portfolios. Such critical reflection can encourage learning but may also promote patient safety and the quality of healthcare across all medical specialties. PMID- 22247318 TI - A fresh face and a new chapter. PMID- 22247319 TI - Lame cats: masters of disguise. PMID- 22247320 TI - Orthopedic examination in the cat: clinical tips for ruling in/out common musculoskeletal disease. AB - PATIENT GROUP: The majority of cats will develop radiographic evidence of degenerative joint disease by the time they are 12 years of age, and many will suffer from a decline in quality of life associated with undiagnosed and untreated orthopedic disease. PRACTICAL RELEVANCE: A focused, efficient orthopedic examination, including gait observation and palpation (awake and under sedation), supplemented with appropriate history, is key in ruling in, or out, clinically important musculoskeletal disease. Identifying problems assists in both developing a diagnostic plan and monitoring response to treatment. CLINICAL CHALLENGES: Many clinicians feel uncomfortable in their ability to reliably perform an orthopedic examination in the cat, and diagnosis and evaluation of response to treatment in cats with orthopedic disease can be challenging. Hands on training in feline orthopedic examination is limited in many veterinary curricula. Additional constraints may include failure to obtain important information in the history that indicates feline orthopedic disease, lack of appropriate facilities in which to conduct a complete orthopedic examination, and inability to obtain the most important information during the time available to conduct the examination. These problems can create gaps in the practitioner's ability to provide excellent care for a large proportion of the feline population. GOALS: The above challenges can mostly be overcome with advanced planning and with consideration of the unique behavioral aspects related to feline handling. As discussed in this review, the aim of the initial orthopedic examination is to localize the problem to a specific limb, ideally to a region or joint of the limb, which can further direct diagnostics such as radiography or arthrocentesis. This should provide a basis for follow-up and assessment of whether treatment strategies are effective. PMID- 22247321 TI - Musculoskeletal imaging in the cat: what's normal? What's abnormal? AB - PRACTICAL RELEVANCE: Despite the increasing availability of ultrasonography, computed tomography and magnetic resonance imaging (MRI), radiography remains the primary imaging modality for the assessment of feline musculoskeletal disease in practice. In many respects, having a more feline-focused approach to radiography will reward the clinician with better quality images and, hence, a greater likelihood of a correct diagnosis. CLINICAL CHALLENGES: Correct interpretation of radiographic films requires familiarity with some of the unique aspects of normal feline skeletal anatomy. For optimal patient management, the clinician also needs an appreciation of the distinct advantages of advanced imaging modalities in certain circumstances, in particular for head trauma patients. EQUIPMENT: When considering what equipment is most suitable for musculoskeletal imaging, the small size of our feline patients means that image resolution is of primary importance. Choosing an x-ray system (film-screen or digital) that offers more detail, and selecting ultrasound probes of a higher frequency than would be used on larger canine patients, will go some way to improving the diagnostic yield of any feline imaging study. If there is the option of referral for MRI, and a choice between high-field and low-field MRI systems for the feline patient, a high-field system will always provide more detail. AUDIENCE: This review, drawing on the author's experience and established imaging and anatomical principles, aims to assist general veterinary practitioners in their approach to feline musculoskeletal imaging. It provides an overview of the imaging choices and techniques for different regions of the body, and gives examples of normal anatomy that is peculiar to the cat. PMID- 22247322 TI - Hips, elbows and stifles: common joint diseases in the cat. AB - PRACTICAL RELEVANCE: Cats commonly present with joint disease and trauma. A methodical approach to diagnostics and treatment can aid the clinician in the management of these cases. CLINICAL CHALLENGES: Cats with joint disease may present with a vague history owing to their independent nature, and gait assessment is often challenging when compared with the dog. Knowledge of feline specific anatomy is important to avoid over- or misinterpretation of physical examination or imaging findings. AUDIENCE: This review of feline joint disease focuses on the more common, non-traumatic conditions of the hip, stifle and elbow. It aims to provide first opinion clinicians with a guide to decision making that will assist them in achieving a diagnosis and formulating a management strategy. EVIDENCE BASE: There is an extensive body of original articles and textbooks in the published literature relating to aspects of feline joint disease. This article combines information from key companion animal and feline-specific references together with the author's clinical experience to provide a practical overview of joint disease, and highlight important differences between cats and dogs in terms of presentation and treatment. PMID- 22247323 TI - Musculoskeletal oddities in the cat: an overview of some curious causes of lameness. AB - PRACTICAL RELEVANCE: Cats, both young and old, can suffer a variety of weird and wonderful musculoskeletal conditions that are a cause of lameness. These include developmental, metabolic and nutritional bone diseases, ectopic mineralisation disorders, conditions that cause lameness or exercise intolerance and primarily or secondarily affect muscle, and lastly pad conditions. CLINICAL CHALLENGES: These conditions are mostly rare and can be challenging to diagnose. The aim of this review is to bring these conditions to the attention of practitioners so that, if they are encountered, further research around the topic can be undertaken. Radiographic changes and diagnostic tests that can be used to try to confirm diagnoses are described. EVIDENCE BASE: These unusual causes of lameness are the subject of multiple single case reports or small case series, many of which are relatively old. The evidence presented here is drawn from these articles. However, it is not possible within the scope of this review to discuss all the conditions in as much detail as they may warrant, or to make reference to every article relating to them. PMID- 22247324 TI - Musculoskeletal neoplasia: an important differential for lumps or lameness in the cat. AB - PRACTICAL RELEVANCE: Musculoskeletal neoplasia is an uncommon but Important differential diagnosis for cats presenting with lameness, pain or swellings associated with bones and/or soft tissues. The most common tumours of soft tissue origin are the sarcomas (in particular feline injection site sarcomas [FISSs]); the most common bone tumour of the cat is osteosarcoma (OSA). CLINICAL CHALLENGES: FISSs present a clinical challenge in terms of their local invasiveness, difficulty in obtaining complete surgical excision and high risk of local recurrence. Axial and extraskeletal OSAs pose similar challenges, whereas appendicular OSA is usually easy to remove via limb amputation and can, therefore, carry a good prognosis in many cases. PATIENT GROUP: Cats of any age, gender or breed may be affected, although bone tumours predominantly affect middle- to old-aged cats. GLOBAL IMPORTANCE: Vaccination of cats is of global importance in preventing feline diseases; hence, any possible significant consequences of vaccination such as neoplasia, even of a low incidence, are of huge concern to cat owners and veterinarians alike. EVIDENCE BASE: This review is based on current literature relating to pathogenesis, pathology, presentation, diagnosis, staging, treatment and prognosis. It aims to summarise feline musculoskeletal neoplasia for clinicians in general practice. PMID- 22247325 TI - Complex and open fractures: a straightforward approach to management in the cat. AB - CLINICAL CHALLENGES: Cats often present with traumatic injuries of the limbs, including complex and open fractures, frequently as a result of road traffic accidents. On initial assessment, complex and open fractures may appear to require expertise beyond the experience of the general practitioner and, in some cases, referral to a specialist may be indicated or amputation should be considered. PRACTICAL RELEVANCE: Many cases, however, can be managed using straightforward principles. This review describes a logical and practical approach to treating such injuries. It discusses general principles of fracture management, highlights the treatment of open fractures, and describes the use of external skeletal fixation for stabilisation of both open and complex fractures. EQUIPMENT: Most fractures can be stabilised using equipment and expertise available in general practice if the basic principles of fracture fixation are understood and rigorously applied. EVIDENCE BASE: Many textbooks and journal articles have been published on the management of fractures in companion animals, presenting case studies, case series and original biomechanical research. The simple strategy for managing complex injuries that is provided in this review is based on the published literature and the author's clinical experience. PMID- 22247326 TI - Osteoarthritis in the cat: 1. how common is it and how easy to recognise? AB - PRACTICAL RELEVANCE: Osteoarthritis (OA) is very common, particularly in older cats, but its clinical significance has largely gone unrecognised until recently. As in other species, OA is often painful and appropriate treatment is required to improve the animal's quality of life. Most cases appear to be primary or idiopathic. It is important for the clinician to actively seek these cases in the practice population. CLINICAL CHALLENGES: The recognition of chronic arthritic pain is a major challenge since most cats will not exhibit lameness. The main features of feline OA are changes in behaviour and lifestyle, which develop gradually and which owners tend to interpret as simply being the effects of old age. A meaningful physical orthopaedic examination can be difficult to achieve. A lack of familiarity with feline joint radiographs, and the fact that major cartilage pathology can be present in the absence of any bony change, mean that radiographic identification of OA in the cat can also be problematic. CLIENT QUESTIONNAIRE: The recognition of chronic arthritic pain in the cat is based on owner questionnaires designed to elicit information about changes in mobility, activity levels, grooming habits and general demeanour. EVIDENCE BASE: Several publications now report on the significance of behavioural and lifestyle changes as indicators of chronic arthritic pain in the cat. However, there is not as yet a fully validated owner-based questionnaire for recognising chronic pain in the cat. Furthermore, the aetiopathogenesis of feline OA still requires detailed investigation. Such studies are likely to make a major contribution to comparative rheumatology, since feline OA, more so than the canine disease, shows many similarities with human OA. PMID- 22247327 TI - Osteoarthritis in the cat: 2. how should it be managed and treated? AB - PRACTICAL RELEVANCE: Osteoarthritis (OA) is very common in the cat and in many cases is associated with significant long-term pain, which limits mobility and activity, and severely compromises the animal's quality of life. CLINICAL CHALLENGES: The treatment of chronic arthritic pain is a major challenge and many analgesic drugs used in other species are not licensed, not available or not tested for use in the cat. Many older cats with painful OA have some degree of chronic kidney disease (CKD) and many clinicians are reluctant to use non steroidal anti-inflammatory drugs (NSAIDs) in these animals because of the potential for nephrotoxicity. EVIDENCE BASE: There are several publications that show that meloxicam is an effective NSAID for the cat and can be used long-term. It is easy to administer and there is published evidence that meloxicam can actually slow the progression of CKD in this species. Many other drugs are used to treat chronic pain in the cat but there is no documented evidence of their efficacy in OA. Unlike the dog, there is limited evidence for the effectiveness of omega-3 fatty acid-rich diets in managing feline OA and further work is required. There is no published data as yet for the usefulness or otherwise of nutraceuticals (glucosamine and chondroitin) in managing feline OA; studies in the authors' clinic suggest some pain-relieving effect. Research into environmental enrichment as a way of improving quality of life in cats with painful OA is lacking, but it is an approach worth using where possible. Modifications to the environment (eg, provision of comfortable bedding and ramps) are also important. PMID- 22247328 TI - Neurological lameness in the cat: common causes and clinical approach. AB - PRACTICAL RELEVANCE: Neurological causes of lameness are infrequently seen in cats but they are an important consideration when an obvious orthopaedic cause cannot be identified. Monoparetic cats are also frequently presented for veterinary investigation with the main complaint being lameness. CLINICAL CHALLENGES: Neurological causes of lameness may be difficult to determine without access to advanced imaging modalities, electrodiagnostics or cerebrospinal fluid analysis. AUDIENCE: This review, aimed at all veterinarians who treat cats, sets out to describe the specific approach to cats with lameness that cannot be attributed to an orthopaedic cause. It describes the diagnosis and management of the most common neurological conditions responsible for lameness or monoparesis in cats. PMID- 22247331 TI - Intestinal microbiota determine severity of myocardial infarction in rats. AB - Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls. Vancomycin altered the abundance of intestinal bacteria and fungi, measured by 16S and 18S ribosomal DNA quantity. Pretreatment with leptin (0.12 MUg/kg i.v.) 24 h before ischemia/reperfusion abolished cardioprotection produced by vancomycin treatment. Dahl S rats fed the commercially available probiotic product Goodbelly, which contains the leptin-suppressing bacteria Lactobacillus plantarum 299v, also resulted in decreased circulating leptin levels by 41%, smaller myocardial infarcts (29% reduction), and greater recovery of postischemic mechanical function (23%). Pretreatment with leptin (0.12 MUg/kg i.v.) abolished cardioprotection produced by Goodbelly. This proof-of-concept study is the first to identify a mechanistic link between changes in intestinal microbiota and myocardial infarction and demonstrates that a probiotic supplement can reduce myocardial infarct size. PMID- 22247332 TI - Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. AB - Autophagy is a lysosome-mediated catabolic process that allows cells to degrade unwanted cytoplasmic constituents and to recycle nutrients. Autophagy is also involved in innate and adaptive immune responses, playing a key role in interactions against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. Over recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmunity. Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by autoimmune responses against self-antigens generated by dying cells. Genome-wide association studies have linked several single-nucleotide polymorphisms (SNPs) in the autophagy-related gene Atg5 to SLE susceptibility. Loss of Atg5-dependent effects, including clearance of dying cells and cell antigen presentation, might contribute to the autoimmunity and inflammation associated with SLE. Moreover, activation of the mammalian target of rapamycin (mTOR), a key player in the autophagy regulation, has recently been demonstrated in SLE, confirming an altered autophagy pathway in this disease. In the present review, we summarize the autophagy mechanisms, their molecular regulation, and their relevance in immunity and autoimmunity. The potential of targeting autophagy pathway in SLE, by developing innovative therapeutic approaches, has finally been discussed. PMID- 22247330 TI - Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens. AB - Influenza virus encodes only 11 viral proteins but replicates in a broad range of avian and mammalian species by exploiting host cell functions. Genome-wide RNA interference (RNAi) has proven to be a powerful tool for identifying the host molecules that participate in each step of virus replication. Meta-analysis of findings from genome-wide RNAi screens has shown influenza virus to be dependent on functional nodes in host cell pathways, requiring a wide variety of molecules and cellular proteins for replication. Because rapid evolution of the influenza A viruses persistently complicates the effectiveness of vaccines and therapeutics, a further understanding of the complex host cell pathways coopted by influenza virus for replication may provide new targets and strategies for antiviral therapy. RNAi genome screening technologies together with bioinformatics can provide the ability to rapidly identify specific host factors involved in resistance and susceptibility to influenza virus, allowing for novel disease intervention strategies. PMID- 22247333 TI - Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells. AB - Asthma is a chronic inflammatory disease that is associated with airway remodeling, including hyperplasia of airway epithelial cells and airway smooth muscle cells, and goblet cell differentiation. We wished to address the potential role of histamine, a key biogenic amine involved in allergic reactions, in airway remodeling through the epidermal growth factor receptor (EGFR) pathway. Here, we demonstrate that histamine releases 2 EGFR ligands, amphiregulin and heparin binding epidermal growth factor-like growth factor (HB-EGF), from airway epithelial cells. Amphiregulin and HB-EGF were expressed in airway epithelium of patients with asthma. Histamine up-regulated their mRNA expression (amphiregulin 3.2-fold, P<0.001; HB-EGF 2.3-fold, P<0.05) and triggered their release (amphiregulin EC(50) 0.50 MUM, 31.2 +/- 2.7 pg/ml with 10 MUM histamine, P<0.01; HB-EGF EC(50) 0.54 MUM, 78.5 +/- 1.8 pg/ml with 10 MUM histamine, P<0.001) compared to vehicle control (amphiregulin 19.3 +/- 0.9 pg/ml; HB-EGF 60.2 +/- 1.0 pg/ml), in airway epithelial cells. Histamine increased EGFR phosphorylation (2.1 fold by Western blot analysis) and induced goblet cell differentiation (CLCA1 up regulation by real-time qPCR) in normal human bronchial epithelial (NHBE) cells. Moreover, amphiregulin and HB-EGF caused proliferation and migration of both NHBE cells and human airway smooth muscle cells. These results suggest that histamine may induce airway remodeling via the epithelial-derived EGFR ligands amphiregulin and HB-EGF. PMID- 22247334 TI - Interaction of MxiG with the cytosolic complex of the type III secretion system controls Shigella virulence. AB - Gram-negative bacteria use the type 3 secretion system (T3SS) to colonize host cells. T3SSs are ring-shaped macromolecular complexes specific for the transport of effector molecules into host cells. It was recently suggested that a cytosolic ring-shaped protein complex delivers effector molecules to the T3SS. However, how transport of effector proteins is regulated is not known. Here, we report the high-resolution X-ray crystal structure of the whole cytosolic domain of MxiG (MxiG(1-126)), a major component of the inner T3SS rings in Shigella flexneri. MxiG(1-126) folds as an FHA domain, which specifically binds phosphorylated threonines. Indeed, MxiG(1-126) binds to Spa33, a cytoplasmic-ring component of Shigella, as revealed in pulldown studies. Surface plasmon resonance analysis showed specific interaction of MxiG with a Spa33 peptide only if phosphorylated. In total, 24 copies of the MxiG(1-126) crystal structure were fitted into the cryo-EM map of the Shigella T3SS. The phosphoprotein binding site of each MxiG molecule faces the channel of the T3SS, allowing interaction with cytosolic binding partners. Secretion assays and host cell invasion studies of complemented Shigella knockout cells indicated that the phosphoprotein binding of MxiG is essential for bacterial virulence. Our findings suggest that MxiG is involved in T3SS regulation. PMID- 22247335 TI - Factors influencing adherence to ART: new insights from a center providing free ART under the national program in Delhi, India. AB - BACKGROUND: Adherence to therapy is central to the success of antiretroviral treatment (ART). With the availability of free ART under the national program in India, cost of ART is no longer the primary determinant of adherence. This study evaluated the adherence and factors influencing it among patients receiving free ART in a public health ART center in India. METHODS: The adherence and its influences among 250 HIV-positive patients on first line ART for at least 3 months from the ART Center of Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India were analyzed. The adherence was assessed by patients' self report using the adult AIDS Clinical Trial Group (ACTG) questionnaire and counter checked with pharmacy records. The association of various parameters affecting adherence levels was analyzed by using SPSS package and Epiinfo software. RESULTS: Of the 250 patients, 242 (96.8%) had optimum adherence (>95%) and 8 (3.2%) were "non-adherent." CD4 counts (P = 0.05), high level of belief among patients, patients' knowledge about importance of adherence (P = 0.04), and sound mental health were positively influencing adherence. The main barriers to adherence were poor mental health and negative psychological states in the patients (0.001). The presence of adverse reactions to ART also resulted in poorer adherence. CONCLUSIONS: The modifiable factors most strongly associated with good adherence rates were higher current CD4 counts, patients' beliefs in ART, and positive mental health. These factors can be targeted by simple, practical interventions to improve and maintain high adherence levels. PMID- 22247336 TI - Preferences for rapid point-of-care HIV testing in primary care. AB - Although the identification of individuals infected with HIV is an important element of treatment and prevention programs, many people living with HIV are unaware of their status. Thus, individuals are unable to benefit from treatment, and preventable HIV transmission continues to occur. Rapid point-of-care testing for HIV has been found to be preferred by patients in some contexts. However, few studies have examined preferences in primary care populations. This study investigates HIV testing preferences within an urban primary care clinic. Employing a cross-sectional design, data were collected on demographic characteristics, HIV risk factors, and testing history and preferences of participants. A total of 81% of participants stated that they would prefer rapid testing to standard testing, a finding that is consistent across demographic variables and risk factors examined. Increased availability of this modality may decrease barriers to HIV testing, with positive implications both for clinical management of HIV infection and prevention of HIV transmission. PMID- 22247337 TI - Immunologic effectiveness of maraviroc- and raltegravir-containing regimens (R+M+) versus raltegravir-based regimens that do not include maraviroc (R+M-). AB - OBJECTIVE: To compare the immunologic effectiveness of raltegravir-maraviroc (R+M+)-based regimens with raltegravir-based regimens that do not include maraviroc (R+M-) in treatment-experienced patients in clinical practice. METHODS: We conducted a retrospective study of treatment-experienced HIV-infected adults receiving either R+M+- or R+M--based therapy. Longitudinal CD4 counts were analyzed using a linear mixed model. RESULTS: One hundred and fifty-six patients were included in the analysis, of whom 32 were receiving R+M+ and 124 R+M-. Mean baseline CD4 counts in patients on R+M+ and R+M- were 463.8 and 442.3 cells/mm(3), respectively (P = .67). In multivariable mixed models, a baseline viral load >=50 copies/mL was significantly associated with CD4 change during follow-up (P < .0001). No difference between R+M+ and R+M- was observed during follow-up (P = .81). CONCLUSION: CD4 cell recovery was similar among patients receiving either R+M+- or R+M--based therapy during a 24-month period of follow up. PMID- 22247338 TI - Vitamin D insufficiency and deficiency among HIV-1-infected patients in a tropical setting. AB - Vitamin D plays role in bone health and the regulation of the immune system. A cross-sectional study of serum 25-hydroxyvitamin D (25[OH]D) levels was conducted among HIV-1-infected Thai patients to determine the prevalence and associated factors of low vitamin D levels (25[OH]D <30 ng/mL) in tropical setting. 25 Hydroxyvitamin D was measured by liquid chromatography/tandem mass spectrometry. Of 178 patients, 58% received antiretroviral therapy at median (interquartile range [IQR]) duration of 7.4 (5.9-8.5) years. The prevalence of 25(OH)D deficiency (<20 ng/mL) and insufficiency (20-29.9 ng/mL) was 26.8% and 44.9%, respectively. Multivariate analysis showed that receiving efavirenz (EFV) was significantly associated with low vitamin D status (odds ratio = 3.60; 95% confidence interval, 1.06-12.15, P <.05). The mean (+/-standard deviation) level of 25(OH)D in patients receiving and not receiving EFV was 22.9 (6.6) and 28.6 (10.7) ng/mL, respectively, (P <.05). Low vitamin D status is common and needs to be assessed among HIV-infected patients including tropical residents especially when EFV is used. PMID- 22247339 TI - Nephron-specific expression of components of the renin-angiotensin-aldosterone system in the mouse kidney. AB - INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) plays an integral role in the regulation of blood pressure, electrolyte and fluid homeostasis in mammals. The capability of the different nephron segments to form components of the RAAS is only partially known. This study therefore aimed to characterize the nephron-specific expression of RAAS components within the mouse kidney. MATERIALS AND METHODS: Defined nephron segments of adult C57B/16 mice were microdissected after collagenase digestion. The gene expression of renin, angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II receptors 1a (AT1a), 1b (AT1b), and 2 (AT2) was assessed by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Renin mRNA was present in glomeruli, in proximal tubules, in distal convoluted tubules (DCT) and cortical collecting ducts (CCD). AGT mRNA was found in proximal tubules, descending thin limb of Henle's loop (dTL) and in the medullary part of the thick ascending limb (mTAL). ACE mRNA was not detectable in microdissected mouse nephron segments. AT1a, AT1b and AT2 mRNA was detected in glomeruli and proximal convoluted tubules. CONCLUSIONS: Our data demonstrate a nephron-specific distribution of RAAS components. All components of the local RAAS - except ACE - are present in proximal convoluted tubules, emphasizing their involvement in sodium and water handling. PMID- 22247340 TI - A case of lupus erythematosus profundus with multiple arc-shaped erythematous plaques on the scalp and a review of the literature. AB - A 26-year-old Japanese female presented to us with a 2-year history of multiple arc-shaped erythematous lesions on her scalp and the right side of her forehead. Histopathological examination of two of the lesions showed lobular and septal panniculitis with deposits of IgG in the basement membrane zone. We diagnosed the case as lupus erythematosus profundus, and successfully treated her with 20 mg/day prednisolone. To our knowledge, there has been only one previously reported case of lupus erythematosus profundus with annular-shaped erythematous lesions and six cases with linear configuration. PMID- 22247341 TI - Expression and significance of leukocyte membrane cofactor protein transcript in systemic lupus erythematosus. AB - Membrane cofactor protein (MCP) is a complement regulatory protein ubiquitously expressed on most nucleated cells. Since MCP protects autologous cells from complement-mediated injury, it is suggested to have a protective role against the self-tissue damage in inflammatory conditions such as systemic lupus erythematosus (SLE). However, the relevance of MCP in human SLE is not well explored. To assess the significance of MCP in SLE, we studied expression of leukocyte MCP transcript in 60 healthy individuals (controls) and 60 patients with SLE and correlated that with the levels of circulating immune complex (CIC), C3, C3d and SLEDAI scores. The levels of leukocyte MCP transcript were significantly higher (p < 0.001) in patients with SLE than the controls. Furthermore, MCP transcript levels exhibited significant positive correlations with SLEDAI scores and CIC level and a negative correlation with C3d level in patients. Twelve patients were followed-up until remission. The levels of MCP transcripts decreased significantly during remission as compared with the state of active disease. These findings suggest that in SLE, the expression of leukocyte MCP at the mRNA level is closely related to disease activity. A protective role of MCP in response to increased disease burden may be speculated. The follow-up study suggested MCP as a potential disease marker. PMID- 22247342 TI - Involvement of the femoropopliteal arteries in giant cell arteritis: clinical and color duplex sonography. AB - OBJECTIVE: To determine the extent and clinical significance of giant cell arteritis (GCA) of the femoropopliteal arteries. METHODS: This was a retrospective clinical color duplex sonography (CDS) study; 60 of 112 consecutive patients with the diagnosis of GCA underwent complete clinical examination of the lower extremities including the vasculature, systolic ankle pressure measurement, and CDS scans of the femoropopliteal arteries within 1 year after diagnosis of GCA. Circumferential, hypoechogenic, homogenous wall thickening was regarded as a hallmark of femoropopliteal GCA. RESULTS: GCA of femoropopliteal arteries was present in 32 (53.3%) of 60 patients. In general, femoropopliteal GCA developed bilaterally (100%) and 14 patients (23.3%) had significant lower extremity artery obstructions secondary to vasculitis, all leading to symptomatic lower extremity ischemia, with development of critical leg ischemia in 4 patients. Compared with subjects without lower extremity vasculitis, patients with femoropopliteal involvement had a significant time delay until diagnosis (mean 23.9 vs 11.1 weeks; p = 0.03) and a higher frequency of concomitant vasculitis of the arm arteries (74.2% vs 42.9%; p = 0.02). CONCLUSION: Femoropopliteal artery involvement appears to be a clinically relevant manifestation of GCA, frequently leading to symptomatic lower extremity ischemia. CDS of the femoropopliteal arteries is a noninvasive diagnostic tool for detection of lower extremity vasculitis in GCA. PMID- 22247343 TI - Adverse events during longterm low-dose glucocorticoid treatment of polymyalgia rheumatica: a retrospective study. AB - OBJECTIVE: To assess the occurrence of adverse events in a cohort of patients with polymyalgia rheumatica (PMR), treated with low-dose glucocorticoids (GC). METHODS: This was a retrospective study by review of medical records. RESULTS: We identified 222 patients who had a mean duration of followup of 60 +/- 22 months and a mean duration of GC therapy of 46 +/- 22 months. We found that 95 patients (43%) had at least 1 adverse event after a mean duration of GC therapy of 31 +/- 22 months and a mean cumulative dose of 3.4 +/- 2.4 g. In particular, 55 developed osteoporosis, 31 had fragility fractures; 27 developed arterial hypertension; 11 diabetes mellitus; 9 acute myocardial infarction; 3 stroke; and 2 peripheral arterial disease. Univariate analysis showed that the duration of GC treatment was significantly associated with osteoporosis (p < 0.0001), fragility fractures (p < 0.0001), arterial hypertension (p < 0.005), and acute myocardial infarction (p < 0.05). Cumulative GC dose was significantly associated with osteoporosis (p < 0.0001), fragility fractures (p < 0.0001), and arterial hypertension (p < 0.01). The adverse events occurred more frequently after 2 years of treatment. Multivariate analysis showed that GC duration was significantly associated with osteoporosis (adjusted OR 1.02, 95% CI 1.02-1.05) and arterial hypertension (adjusted OR 1.03, 95% CI 1.01-1.06); GC cumulative dose was significantly associated with fragility fractures (adjusted OR 1.4, 95% CI 1.03-1.8). CONCLUSION: Longterm, low-dose GC treatment of PMR is associated with serious adverse events such as osteoporosis, fractures, and arterial hypertension; these adverse events occur mostly after 2 years of treatment. PMID- 22247345 TI - Familial autoimmunity in systemic sclerosis -- results of a French-based case control family study. AB - OBJECTIVE: To assess the prevalence of autoimmune diseases in first-degree relatives of patients with systemic sclerosis (SSc), and to compare those results with control families in order to identify patterns of autoimmune diseases in relatives. METHODS: A retrospective case-control postal questionnaire survey was performed in France to recruit patients with SSc belonging to an association of patients with SSc and unrelated age-matched and sex-matched controls. Each participant was asked to self-report on the existence of autoimmune diseases in their first-degree relatives. The prevalence of autoimmune diseases in the families of patients with SSc was compared with the corresponding prevalence in the families of controls. RESULTS: A total of 121 families out of 373 (32.4%) with a member having SSc reported at least 1 autoimmune disease in 1 or more first-degree relatives. The most frequent autoimmune diseases in SSc families when adjusted for family size were autoimmune thyroid disease (AITD; 4.9%), rheumatoid arthritis (4.1%), psoriasis (3.9%), and type 1 diabetes mellitus (2.9%). Compared with control families, AITD and connective tissue diseases (SSc, systemic lupus erythematosus, or Sjogren's syndrome) were more likely to occur in families with SSc (p = 0.01 and p = 0.01, respectively), with OR of 3.20 (95% CI 1.25-8.18) and 5.20 (95% CI 1.22-21.8). In contrast, inflammatory bowel disease was less likely to occur within families with SSc (p = 0.02, OR 0.29, 95% CI 0.11 0.80). In addition, the coexistence of more than 1 autoimmune disease in the index SSc case was associated with familial aggregation of autoimmune diseases. CONCLUSION: Our results show that autoimmune diseases cluster within families of patients with SSc. This supports the notion that these diseases might arise on a shared genetic basis underlying several autoimmune phenotypes. PMID- 22247344 TI - Interferon-gamma contributes to HLA-B27-associated unfolded protein response in spondyloarthropathies. AB - OBJECTIVE: HLA-B27 positivity strongly influences the susceptibility to and phenotype of spondyloarthropathies (SpA). This study was designed to screen factors that activate the promoter of HLA-B27 in U937 cells, and to assess whether these promoter-activating factors induce the unfolded protein response (UPR) in HLA-B27-expressing cells. METHODS: Cytometric Bead Array, flow cytometry, and real-time polymerase chain reaction were used to detect the expression of cytokines and UPR-associated proteins in peripheral blood and synovial fluid of patients with SpA. The HLA-B27 promotor transfectant was incubated separately with cytokines and Toll-like receptor ligands. After interferon-gamma (IFN-gamma) stimulation, expressions of GRP78, CHOP, and XBP-1 were tested in HLA-B27-expressing U937 cells and peripheral blood mononuclear cell (PBMC) of patients with ankylosing spondylitis (AS). (Clinical trial registration no. ChiCTR-OCC-11001565) RESULTS: Expressions of GRP78, CHOP, and XBP-1 in monocytes/macrophages of SpA peripheral blood and synovial fluid were higher than those in healthy controls and patients with osteoarthritis (OA) (p < 0.05). Tumor necrosis factor-alpha (TNF-alpha) and IFN-alpha, IFN-beta, and IFN gamma were found to have activated the HLA-B27 promoter in the U937 cell line (p < 0.05). Following stimulation with IFN-gamma, the expressions of GRP78, CHOP and XBP-1 in HLA-B27-transfected U937 cells and PBMC of HLA-B27-positive AS patients were more intense than those in A2-U937 cells, HLA-B27-negative AS patients, or healthy controls (p < 0.05). CONCLUSION: Expressions of GRP78, CHOP, and XBP-1 were higher in monocytes/macrophages of patients with SpA than those in both OA patients and healthy controls, suggesting that UPR may participate in the pathogenesis of SpA. TNF-alpha and IFN-alpha, IFN-beta, and IFN-gamma significantly activated HLA-B27 promoter in the U937 cell line, and IFN-gamma, the strongest activating factor, may induce the UPR in HLA-B27-expressing cells. PMID- 22247346 TI - Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes -- possible pathogenic role in osteoarthritis. AB - OBJECTIVE: Degradative enzymes, such as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinases (MMP), play key roles in development of osteoarthritis (OA). We investigated if crosstalk between subchondral bone osteoblasts (SBO) and articular cartilage chondrocytes (ACC) in OA alters the expression and regulation of ADAMTS5, ADAMTS4, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-13, and also tested the possible involvement of mitogen activated protein kinase (MAPK) signaling pathway during this process. METHODS: ACC and SBO were isolated from normal and OA patients. An in vitro coculture model was developed to study the regulation of ADAMTS and MMP under normal and OA joint crosstalk conditions. The MAPK-ERK inhibitor PD98059 was applied to delineate the involvement of specific pathways during this interaction process. RESULTS: Indirect coculture of OA SBO with normal ACC resulted in significantly increased expression of ADAMTS5, ADAMTS4, MMP-2, MMP-3, and MMP-9 in ACC, whereas coculture of OA ACC led to increased MMP-1 and MMP-2 expression in normal SBO. Upregulation of ADAMTS and MMP under these conditions was correlated with activation of the MAPK-ERK1/2 signaling pathway, and addition of the MAPK-ERK inhibitor PD98059 reversed the overexpression of ADAMTS and MMP in cocultures. CONCLUSION: These results add to the evidence that in human OA, altered bidirectional signals between SBO and ACC significantly influence the critical features of both cartilage and bone by producing abnormal levels of ADAMTS and MMP. We have demonstrated for the first time that this altered crosstalk was mediated by the phosphorylation of MAPK-ERK1/2 signaling pathway. PMID- 22247347 TI - Agreement with guidelines from a large database for management of systemic sclerosis: results from the Canadian Scleroderma Research Group. AB - OBJECTIVE: We determined congruence with published guidelines from the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trials and Research group, for systemic sclerosis (SSc) investigations and treatment practices within the Canadian Scleroderma Research Group (CSRG). METHODS: Investigations and medication use for SSc complications were obtained from records of patients with SSc in the CSRG to determine adherence to guidelines for patients enrolled before and after the guidelines were published. RESULTS: The CSRG database of 1253 patients had 992 patients with SSc enrolled before publication of the guidelines and 261 after. For pulmonary arterial hypertension (PAH) treatment, there were no differences in use before and after the guidelines, yet annual echocardiograms for PAH screening were done in 95% of patients enrolled before the guidelines and in only 86% of those enrolled after (p <0.0001), and fewer followup echocardiograms were done 1 year later in the latter group (88% vs 59%). No differences were found for the frequency of PAH-specific treatment; 60% had ever used calcium channel blockers for Raynaud's phenomenon, with no differences in the groups before and after the guidelines. But the use of phosphodiesterase type 5 inhibitors (which does not have guidelines) was increased in the after guidelines group. Proton pump inhibitors were used in > 80% with gastroesophageal reflux disease before and after the guidelines. One-quarter with gastrointestinal symptoms were taking prokinetic drugs. For those with past SSc renal crisis, use of angiotensin-converting enzyme inhibitors was not different before and after the guidelines. For early diffuse SSc < 2 years, ever-use of methotrexate was similar (one-quarter of each group); and for symptomatic interstitial lung disease, 19% had ever used cyclophosphamide before the guidelines and 9% after (p = nonsignificant). CSRG practices were generally comparable to recently published guidelines; however, use of iloprost and bosentan was low for digital ulcers because these drugs are not approved for use in Canada. CONCLUSION: There did not seem to be an increase in adherence to recommendations once the guidelines were published. For many guidelines, 25% to 40% of patients who would qualify received the recommended treatment. PMID- 22247348 TI - Evaluation of circulating endothelial and platelet microparticles in men with ankylosing spondylitis. AB - OBJECTIVE: To evaluate the profiles of endothelial microparticles (EMP) and platelet microparticles (PMP) in men with ankylosing spondylitis (AS) and healthy subjects. We also aimed to determine whether microparticles (MP) correlate with disease activity, function, and spinal mobility indices. METHODS: There were 82 men with AS and 53 healthy controls. Subjects with a history of chronic diseases including coronary artery disease, hypertension, diabetes mellitus, and dyslipidemia were excluded. MP were stained with monoclonal antibodies against platelets and endothelial cells and quantified using flow cytometry. MP that were positive for both CD42a+/CD31+ and total CD42a+ were identified as PMP; and MP consisting of CD42a-/CD31+ and total CD144+ were considered EMP. RESULTS: EMP and PMP were similar between the patient and control groups (p > 0.05). Comparison of patients with AS in the active disease state (BASDAI >= 4) and in the inactive state showed that EMP and PMP were not different between the groups (p > 0.05). Correlation analysis revealed no correlation with Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, or Bath Ankylosing Spondylitis Metrology Index. C-reactive protein was significantly correlated with PMP and CD42a-/CD31+ EMP (p < 0.05). Comparison of patients with AS treated with anti-tumor necrosis factor (anti-TNF) drugs, subjects treated conventionally, and healthy controls revealed that PMP and CD42a-/CD31+ EMP were significantly downregulated in patients receiving biological agents. CONCLUSION: Circulating EMP and PMP, known to be indicators and mediators of vascular injury, were not significantly altered in men with AS who did not have classical cardiovascular risk factors. Significantly downregulated MP in patients receiving biological agents suggested that anti-TNF treatment may have a beneficial effect on vascular function in AS. PMID- 22247349 TI - Blood pressure and vascular dysfunction underlie elevated cerebral blood flow in systemic lupus erythematosus. AB - OBJECTIVE: In previous studies cerebral blood flow (CBF) was found to be altered in patients with systemic lupus erythematosus (SLE) compared to controls. We investigated the relationships between CBF and clinical data from subjects with SLE with the aim of determining the pathologic factors underlying altered CBF in SLE. METHODS: A total of 42 SLE subjects and 19 age- and sex-matched healthy control subjects were studied. Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) was used to measure CBF. Patients and controls underwent complete clinical and laboratory evaluations in close proximity with their MRI studies. RESULTS: A higher CBF was present in the SLE group and was independently associated in statistical models with higher systolic blood pressure (SBP; p < 0.01). The intensity of the relationships (slope of curve) between CBF and mean arterial blood pressure, diastolic blood pressure, or blood levels of tissue plasminogen activator in the SLE group was significantly blunted relative to the control group. CONCLUSION: These findings are consistent with an underlying cerebral hyperperfusion in SLE induced by elevated but nonhypertensive levels of SBP. The factors underlying this relationship may be functional and/or structural (atherosclerotic, thrombotic, thromboembolic, or vasculitic) cerebrovascular disease. PMID- 22247350 TI - Orthopedic surgery among patients with rheumatoid arthritis 1980-2007: a population-based study focused on surgery rates, sex, and mortality. AB - OBJECTIVE: To describe current trends in arthritis-related joint surgery among a population-based cohort of patients with rheumatoid arthritis (RA) and to examine the influence of joint surgery on mortality. METHODS: A retrospective medical record review was performed of all orthopedic surgeries following diagnosis in cases of adult-onset RA in Olmsted County, Minnesota, USA, in 1980-2007. Surgeries included primary total joint arthroplasty, joint reconstructive procedures (JRP), soft tissue procedures (STP), and revision arthroplasty. Cumulative incidence of surgery was estimated using Kaplan-Meier methods. Time trends, sex differences, and mortality were examined using Cox models with time dependent covariates for surgery. RESULTS: A total of 189 of 813 patients underwent at least 1 surgical procedure involving joints during followup. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3% compared to 19.5% for the 1995-2007 cohort (p = 0.08). The greatest reduction was in STP, which decreased from 12.1% in 1980-94 to 6.0% in 1995-2007 at 10 years after RA incidence (p = 0.012). Women had more surgery (cumulative incidence 26.6% at 10 years for women; 20.4% for men; p = 0.049), as did obese patients. JRP were significantly associated with mortality (hazard ratio 2.6; 95% CI 1.8, 3.9; p < 0.001) compared to patients not requiring JRP. CONCLUSION: The rates of joint surgery continue to decrease for patients more recently diagnosed with RA. JRP is associated with increased mortality. These findings may reflect improved treatments for RA as well as continued higher disease burden among some patients. PMID- 22247351 TI - IgG glycosylation changes and MBL2 polymorphisms: associations with markers of systemic inflammation and joint destruction in rheumatoid arthritis. AB - OBJECTIVE: To examine whether IgG glycosylation changes and MBL2 genotypes are associated with systemic inflammation and joint destruction in rheumatoid arthritis (RA). METHODS: IgG N-glycan content was determined from serum in 118 patients with RA by high-throughput glycan analysis using normal-phase high pressure liquid chromatography. MBL2 extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) were determined. Systemic inflammation was assessed by serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Joint destruction was assessed by total Sharp score (TSS) and alloplastic surgery records. RESULTS: IgG hypogalactosylation was significantly correlated to IL-6 (Spearman's rho = 0.32, p < 0.001), CRP (Spearman's rho = 0.31, p < 0.001), TSS (Spearman's rho = 0.25, p = 0.01), and alloplastic replacement of joints (Spearman's rho = 0.18, p = 0.05). In multivariate analysis including age, CRP, anticitrullinated protein antibodies (ACPA), and other confounders, IgG hypogalactosylation was significantly associated with TSS (p = 0.014) and alloplastic joint replacement (OR 76.5, p = 0.041) in patients homozygous for the high expression MBL2 genotype YA/YA, but not in carriers of lower expression genotypes. CONCLUSION: Decreased galactosylation of IgG correlated to markers of inflammation, i.e., IL-6 and CRP. Only in patients homozygous for high expression of the MBL2 genotype YA/YA was IgG hypogalactosylation associated with markers of joint destruction. Our results suggest that inflammation-associated decreased galactosylation of IgG combined with high expression MBL2 genotypes are involved in the pathophysiology of RA. PMID- 22247352 TI - Optimization of autologous stem cell transplantation for systemic sclerosis -- a single-center longterm experience in 26 patients with severe organ manifestations. AB - OBJECTIVE: Autologous stem cell transplantation (aSCT) for systemic sclerosis (SSc) has been shown to be effective in recent reports. This aggressive approach and the disease itself are associated with a high mortality. We report our experiences in 26 consecutive patients. METHODS: Between 1997 and 2009, 26 patients were scheduled for aSCT. Our standard transplant regimen consists of cyclophosphamide (CYC) and granulocyte colony-stimulating factor (GCSF) for mobilization and CYC plus antithymocyte globulin for conditioning before the retransfusion of CD34 selected stem cells. The major outcome variable was the response to treatment [reduction of modified Rodnan skin score (mRSS) by 25%] at Month 6. Secondary endpoints were the transplant-related mortality and the progression-free survival. RESULTS: Significant skin and lung function improvement of the mRSS was achieved in 78.3% of patients at Month 6. The overall response rate was 91%, as some patients improved even after Month 6. Three patients died between mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was considered treatment-related (i.e., GCSF or CYC toxicity). Depending on definitions, transplant-related mortality was 4% and treatment-related mortality 11%. Seven patients experienced a relapse during the 4.4 years of followup. The progression-free survival was 74%. Four patients died during followup and the most frequent causes of death were pulmonary and cardiac complications of SSc. CONCLUSION: aSCT led to significant improvement in most patients with SSc. The procedure requires further optimization; hence we are modifying our screening and treatment strategy. To minimize infectious complications, CYC for mobilization and GCSF were reduced. We intensified our screening for cardiac involvement and modified our conditioning regimen in case of cardiac involvement. PMID- 22247353 TI - Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. AB - OBJECTIVE: Warfarin is recommended in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and idiopathic PAH (IPAH) to improve survival. There is no evidence to support this in SSc-PAH and the evidence in IPAH is conflicting. We evaluated the ability of warfarin to improve survival using 2 large SSc-PAH and IPAH cohorts. METHODS: The effect of warfarin on all-cause mortality was evaluated. Bayesian propensity scores (PS) were used to adjust for baseline differences between patients exposed and not exposed to warfarin, and to assemble a matched cohort. Bayesian Cox proportional hazards models were constructed using informative priors based on international PAH expert elicitation. RESULTS: Review of 1138 charts identified 275 patients with SSc-PAH (n = 78; 28% treated with warfarin) and 155 patients with IPAH (n = 91; 59% treated with warfarin). Baseline differences in PAH severity and medications were resolved using PS matching. In the matched cohort of 98 patients with SSc-PAH (49 treated with warfarin), the posterior median hazard ratio (HR) was 1.06 [95% credible interval (CrI) 0.70, 1.63]. In the matched cohort of 66 patients with IPAH (33 treated with warfarin), the posterior median HR was 1.07 (95% CrI 0.57, 1.98). The probability that warfarin improves median survival by 6 months or more is 23.5% in SSc-PAH and 27.7% in IPAH. Conversely, there is a > 70% probability that warfarin provides no significant benefit or is harmful. CONCLUSION: There is a low probability that warfarin improves survival in SSc-PAH and IPAH. Given the availability of other PAH therapies with demonstrable benefits, there is little reason to use warfarin to improve survival for these patients. PMID- 22247354 TI - Safety and efficacy of various dosages of ocrelizumab in Japanese patients with rheumatoid arthritis with an inadequate response to methotrexate therapy: a placebo-controlled double-blind parallel-group study. AB - OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab (OCR) in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). METHODS: RA patients with an inadequate response to MTX 6-8 mg/week received an infusion of 50, 200, or 500 mg OCR or placebo on Days 1 and 15 and were observed for 24 weeks. The double-blind period was prematurely terminated because of a possible risk for serious infection from OCR. RESULTS: A total of 152 patients were randomized into the study. The incidence of infection was 37.7% (43/114) in the OCR groups combined, compared to 18.9% (7/37) in the placebo group. Serious infections occurred in 7 patients in the OCR groups combined; there were no serious infections in the placebo group. Among the serious infections, Pneumocystis jirovecii pneumonia occurred in 2 patients in the OCR 200 mg group. The American College of Rheumatology 20% response rates at Week 24 (the primary endpoint) of the OCR 50, 200, and 500 mg groups were 54.1% (p = 0.0080), 55.6% (p = 0.0056), and 47.2% (p = 0.044), respectively, all significantly higher than that of the placebo group (25.0%). CONCLUSION: These results suggest inappropriate benefit-risk balance of OCR in this patient population. Because rituximab is not approved for treatment of RA in Japan, it will be necessary to investigate safety and efficacy of other anti-B cell therapies in Japanese patients with RA. (ClinicalTrials.gov NCT00779220). PMID- 22247355 TI - Prevalence of monoclonal gammopathy among patients with psoriatic arthritis. AB - OBJECTIVE: The occurrence of monoclonal gammopathy is common in chronic inflammatory disorders such as chronic infections and autoimmune disorders. There is limited information about the prevalence of monoclonal gammopathy in psoriatic arthritis (PsA). We investigated the prevalence, type, and associated features of monoclonal gammopathy in patients with PsA. METHODS: We performed a cross sectional analysis of patients followed from 2008 to 2011 at the University of Toronto PsA clinic. The presence of monoclonal gammopathy was defined as the occurrence of a discrete band in the gammaglobulin region on at least 2 separate serum protein electrophoresis tests performed 6 months apart. Comparisons between patients with and those without monoclonal gammopathy were performed using t tests for continuous variables and chi-square tests for categorical variables. RESULTS: Of the 361 patients with PsA, 35 (9.7%) had evidence of monoclonal gammopathy in at least 2 separate blood tests. Seven (24%) of the 29 patients who were tested for Bence Jones protein were found to be positive. One patient was diagnosed as having multiple myeloma. Patients with monoclonal gammopathy were older (p = 0.001), had a longer duration of psoriasis (p = 0.02) and PsA (p = 0.006), were less likely to use disease-modifying antirheumatic drugs (p = 0.05), and had higher sedimentation rate (p = 0.01) and lower hemoglobin levels (p = 0.02). Patients with monoclonal gammopathy also trended toward having more active disease, with a higher active joint count (p = 0.07). CONCLUSION: Monoclonal gammopathy occurs in patients with PsA more commonly than in the general population. Its prevalence is associated with measures of disease activity and duration. PMID- 22247356 TI - Morbidity, mortality, and organ damage in patients with antiphospholipid syndrome. AB - OBJECTIVE: To describe morbidity, organ damage, mortality, and cause of death in patients with antiphospholipid syndrome (APS). METHODS: Descriptive analysis of 135 patients. Patients were clustered according to initial event: arterial thrombosis including stroke (AT; n = 46), venous thrombosis including pulmonary emboli (VT; n = 53), or pregnancy morbidity (PM; n = 36). Disease progression according to initial event and prevalence of organ damage was observed. RESULTS: APS occurs among young individuals (mean age 33.3 +/- 11.9 yrs). One-third of the patients have APS secondary to systemic lupus erythematosus (SLE) or SLE-like disease. A broad spectrum of clinical manifestations mark the disease onset even before diagnosis. The pattern of initial presentation is preserved with regard to second event; VT is followed by VT (84%), AT is followed by AT (95%), and PM is followed by PM (88.9%). The highest morbidity is attributed to neurologic damage. PM is more likely to be followed by a second event, yet is associated with less organ damage than AT and VT. After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died, with Systemic Lupus International Collaborating Clinics score associated with increased mortality (HR 1.31, 95% CI 1.07-1.60, p = 0.01, per 1-unit increase); hematological malignancies occurred in 2 patients after a cumulative followup of 1020 person-years. Coexistent SLE adds significant damage in patients with APS. CONCLUSION: APS is a disease of young individuals, who experience increased morbidity. Neurologic damage is the most common cause of morbidity. AT at presentation as well as coexistent SLE are associated with poor outcome. PMID- 22247357 TI - Methotrexate and corticosteroids in the treatment of localized scleroderma: a standardized prospective longitudinal single-center study. AB - OBJECTIVE: To evaluate the effectiveness of a uniform single-center treatment protocol composed of high-dose methotrexate (MTX) and oral corticosteroids in a pediatric localized scleroderma (LS) cohort. METHODS: Thirty-six patients with LS were recruited. Patients with active disease, defined as erythematous lesions and/or new lesions, or expansion of existing lesions, were started on oral prednisone 2 mg/kg/day (maximum 60 mg/day) and subcutaneous (SC) MTX at 1 mg/kg/week (maximum 25 mg/week). Prednisone was tapered and kept at 0.25 mg/kg/day for 12 months. MTX SC was continued for 24 months, and then switched to oral administration to complete 36 months of therapy. Modified LS Skin Severity Index (mLoSSI) and the physician global assessment of disease activity (PGA-A) were used as outcome measures. RESULTS: Twenty-five patients with LS were female with a median age at onset of 7.86 years [interquartile range (IQR) 4.63-11.91]. Median disease duration from onset until start of this treatment regimen was 19.2 months (IQR 8.96-35.35). Median duration of followup was 36.40 months (IQR 29.39 45.36). All patients demonstrated significant improvement in mLoSSI at median 1.77 months (IQR 0.76-2.37, 95% CI 1.54, 2.01). PGA-A followed the same trend. No significant adverse reactions or flares were observed during therapy. CONCLUSION: This single-center LS treatment protocol was effective and well tolerated. Clinical outcome in LS is affected by dose and route of administration of immunosuppressive regimens. Daily tapering dose of corticosteroids and parenteral MTX were effective in controlling LS activity without significant adverse reaction. This regimen should be considered as one of the therapies for LS clinical trials. PMID- 22247358 TI - Utility of interferon-alpha as a biomarker in central neuropsychiatric involvement in systemic lupus erythematosus. AB - OBJECTIVE: To assess the utility of interferon-alpha (IFN-alpha) in serum and cerebrospinal fluid (CSF) as a biomarker of disease activity in central neuropsychiatric systemic lupus erythematosus (cNPSLE). METHODS: Serum and CSF samples were drawn at hospitalization in 34 patients with cNPSLE, 16 surgical SLE, 4 primary neuropsychiatric conditions, and 25 with nonautoimmune conditions, except in 44 non-NPSLE patients in whom only serum was studied. Six months later, serum/CSF and serum samples were taken in 20 cNPSLE and 35 non-NPSLE patients, respectively. SLE activity was assessed at hospitalization, and 6 months later in cNPSLE and non-NPSLE patients. IFN-alpha was detected by Luminex technology. RESULTS: The mean +/- SD age of patients with cNPSLE was 31.4 +/- 12.2 years, which was similar across the study groups (p = 0.46). Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores among cNPSLE, non NPSLE, and SLE-surgical patients were 15.3 +/- 8.2, 12.4 +/- 8.2, and 3.8 +/- 1.5, respectively. IFN-alpha levels in serum were higher in cNPSLE than in nonautoimmune patients (p = 0.02), but were similar to non-NPSLE and SLE-surgical groups. In CSF samples, IFN-alpha levels were higher in cNPSLE than in nonautoimmune patients (p = 0.03), and were nonsignificantly higher than in SLE surgical and primary neuropsychiatric patients. Six months later, serum levels of IFN-alpha did not vary from baseline values despite a significant decrease in SLEDAI-2K score in cNPSLE and non-NPSLE patients. IFN-alpha levels in the CSF of patients with cNPSLE also remained stable. Among specific cNPSLE syndromes, CSF IFN-alpha levels were significantly higher among patients with acute confusional syndrome. CONCLUSION: IFN-alpha does not seem to represent a useful biomarker of cNPSLE syndromes; its utility in specific cNPSLE manifestations merits further investigation. PMID- 22247360 TI - Remission in early rheumatoid arthritis: predicting treatment response. AB - OBJECTIVE: Optimizing therapeutic strategies to induce remission requires an understanding of the initial features predicting remission. Currently no suitable model exists. We aim to develop a remission score using predictors of remission in early rheumatoid arthritis (RA). METHODS: We used a dataset from a UK randomized controlled trial that evaluated intensive treatment with conventional combination therapy, to develop a predictive model for 24-month remission. We studied 378 patients in the trial who received 24 months' treatment. Our model was validated using data from a UK observational cohort (Early RA Network, ERAN). A group of 194 patients was followed for 24 months. Remission was defined as 28 joint Disease Activity Score < 2.6. Logistic regression models were used to estimate the associations between remission and potential baseline predictors. RESULTS: Multivariate logistic regression analyses showed age, sex, and tender joint count (TJC) were independently associated with 24-month remission. The multivariate remission score developed using the trial data correctly classified 80% of patients. These findings were replicated using ERAN. The remission score has high specificity (98%) but low sensitivity (13%). Combining data from the trial and ERAN, we also developed a simplified remission score that showed that younger men with a TJC of 5 or lower were most likely to achieve 24-month remission. Remission was least likely in older women with high TJC. Rheumatoid factor, rheumatoid nodules, and radiographic damage did not predict remission. CONCLUSION: Remission can be predicted using a score based on age, sex, and TJC. The score is relevant in clinical trial and routine practice settings. PMID- 22247359 TI - Propylthiouracil-induced antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis versus primary ANCA-associated renal vasculitis: a comparative study. AB - OBJECTIVE: Renal involvement is frequently present in primary antineutrophil cytoplasmic antibody-associated small-vessel vasculitis (AAV) as well as propylthiouracil (PTU)-induced AAV. We analyzed the characteristics of patients with PTU-induced AAV with renal involvement and investigated the differences of the 2 diseases. METHODS: Thirty-six patients with PTU-induced AAV, diagnosed from 1997 to 2010, were enrolled for study. Their data were compared with those of 174 patients with primary AAV diagnosed at the same time. Renal involvement was present in all patients. RESULTS: There was a prominent proportion of young women with PTU-induced AAV (p < 0.01). They had lower levels of proteinuria and serum creatinine and higher estimated glomerular filtration rate (p < 0.01, p < 0.01, and p < 0.01, respectively). Clinical immunological abnormalities were less severe in patients with PTU-induced AAV. Patients with PTU-induced AAV had less organ involvement and lower Birmingham Vasculitis Assessment Score than patients with primary AAV (p < 0.01). Renal biopsies showed a lower proportion of glomeruli with crescents (p < 0.01). Interstitial inflammation was less severe in patients with PTU-induced AAV (p < 0.05). Similarly, interstitial fibrosis and tubular atrophy were less severe in patients with PTU-induced AAV (p < 0.01, p < 0.05, respectively). Renal survival and total survival were better in patients with PTU-associated vasculitis (p < 0.05, p = 0.01). CONCLUSION: Clinical and histopathological abnormalities were less severe in patients with PTU-induced AAV and most of them had a good prognosis. PMID- 22247361 TI - Predictors of early minimal disease activity in patients with psoriatic arthritis treated with tumor necrosis factor-alpha blockers. AB - OBJECTIVE: To identify predictors of early minimal disease activity in patients with psoriatic arthritis (PsA) receiving tumor necrosis factor-alpha (TNF-alpha) antagonists. METHODS: In total 146 consecutive patients with PsA eligible for anti-TNF-alpha therapy were enrolled. At baseline (T0) information about age, sex, PsA subset, disease duration, comorbidities, and treatments was collected. All subjects were tested for metabolic syndrome (MetS) and/or liver steatosis. A clinical and laboratory evaluation was performed at T0 and at 3 months (T3). Changes in all these variables were compared in subjects achieving minimal disease activity (MDA) and those who did not. RESULTS: Among 146 PsA subjects, 10 discontinued therapy before 3-month followup because of adverse events; thus 136 concluded the study. All clinical outcome measures changed significantly from T0 to T3. Erythrocyte sedimentation rate showed a significant reduction (p < 0.001). C-reactive protein (CRP), serum cholesterol, and triglycerides showed no significant variation (p > 0.05). The prevalence of MetS and liver steatosis showed no significant differences between subjects achieving MDA and those who did not (p = 0.347 and 0.053, respectively). Patients achieving MDA at T3 were younger than those not achieving MDA (p = 0.001). A lower baseline tender joint count (p = 0.001), swollen joint count (p = 0.013), Bath Ankylosing Spondylitis Disease Activity Index (p = 0.021), and Ritchie index (p = 0.006) were found in subjects achieving MDA. Age (OR 0.896, p = 0.003) and Bath Ankylosing Spondylitis Functional Index (BASFI) (OR 0.479, p = 0.007) inversely predicted, whereas CRP (OR 1.78, p = 0.018) directly predicted, achievement of MDA at T3. CONCLUSION: In patients with PsA, age, CRP, and BASFI at the beginning of treatment were found to be reliable predictors of MDA after 3 months of TNF-alpha blocker therapy. PMID- 22247362 TI - Mortality profile related to systemic lupus erythematosus: a multiple cause-of death analysis. AB - OBJECTIVE: To analyze the mortality profile related to systemic lupus erythematosus (SLE) in the state of Sao Paulo, Brazil. METHODS: For the 1985-2007 period, we analyzed all death certificates (n = 4815) on which SLE was listed as an underlying (n = 3133) or non-underlying (n = 1682) cause of death. We evaluated sex, age, and the causes of death, comparing the first and last 5 years of the period, as well as determining the observed/expected death ratio (O/E ratio). RESULTS: For SLE as an underlying cause, the mean age at death was 35.77 years (SD 15.12) and the main non-underlying causes of death were renal failure, circulatory system diseases, pneumonia, and septicemia. Over the period, the proportional mention of infectious causes and circulatory system diseases increased, whereas renal diseases decreased. For SLE as a non-underlying cause of death, the most common underlying causes of death were circulatory, respiratory, genitourinary, and digestive system diseases, and certain infections. The overall death O/E ratio was > 1 for renal failure, tuberculosis, septicemia, pneumonia, and digestive system diseases, as well as for circulatory system diseases at < 50 years of age, particularly acute myocardial infarct. CONCLUSION: Unlike in developed countries, renal failure and infectious diseases are still the most frequent causes of death. The increase in SLE deaths associated with infection, especially pneumonia and septicemia, is worrisome. The judicious use of immunosuppressive therapy together with vigorous treatment of cardiovascular comorbidities is crucial to the successful management of SLE and to improving survival of patients with SLE. PMID- 22247363 TI - Identification of the clinical features distinguishing psoriatic arthritis and fibromyalgia. AB - OBJECTIVE: To identify the clinical features that can help to distinguish between psoriatic arthritis (PsA) and fibromyalgia (FM). METHODS: Our cross-sectional study was carried out in 10 Italian rheumatology centers between January and September 2009, and enrolled all consecutive patients with PsA and FM who agreed to participate. Standard clinical and laboratory data for PsA and FM were collected from all patients. Records were made of somatic symptoms, response to nonsteroidal antiinflammatory drugs (NSAID), self-evaluated pain, general health, disability, and responses to the Fibromyalgia Impact Questionnaire. Data were statistically analyzed by univariate and multivariate analyses, and receiver operating characteristic curves. The analysis concentrated on the clinical features shared by the 2 conditions. RESULTS: Two hundred sixty-six patients with PsA (mean age 51.7 yrs; disease duration 10.2 yrs) and 120 patients with FM (mean age 50.2 yrs; disease duration 5.6 yrs) were evaluated. Univariate analysis showed that patients with FM had higher mean tender point and enthesitis scores, more somatic symptoms, and responded less to NSAID. Multivariate analysis showed that the presence of >= 6 FM-associated symptoms and >= 8 tender points was the best predictor of FM. CONCLUSION: The shared clinical features of PsA and FM that had the greatest discriminating power for FM were the number of FM-associated symptoms and tender point count. PMID- 22247364 TI - Assessment of preclinical atherosclerosis in patients with ankylosing spondylitis. AB - OBJECTIVE: Epidemiological studies recently confirmed the increased risk of vascular morbidity and mortality during ankylosing spondylitis (AS). Increase of intima-media thickness (IMT) of the common carotid artery is a useful and noninvasive marker of preclinical atherosclerosis. The aim of our study was to compare IMT in patients with AS with matched controls and to determine risk factors of atherosclerosis related to AS. METHODS: We performed a prospective study of 60 consecutive patients meeting modified New York criteria for AS, compared to 60 controls matched for age and sex. Disease-specific measures were determined. Measurement of IMT was performed by the same radiologist using the same machine and probe in right and left common carotid arteries, and the average of the 2 measurements was considered. RESULTS: In total 48 male and 12 female patients were recruited, and 60 corresponding controls; mean age was 36 +/- 11 years. We found significantly increased IMT in the AS group (0.51 +/- 0.12 mm) compared with controls (0.39 +/- 0.09 mm; p = 0.001). After adjustment for confounding factors, increased IMT was still present (p = 0.003). Age at onset of AS (p = 0.001), Bath AS Disease Activity Index (p = 0.002), AS Disease Activity Score (ASDAS) erythrocyte sedimentation rate (ESR; p = 0.047), ASDAS C-reactive protein (CRP; p = 0.012), Bath AS Functional Index (p = 0.008), global spine visual analog scale for pain (p = 0.000), Schober index (p = 0.039), Bath AS Metrology Index (p = 0.028), modified Stoke Ankylosing Spondylitis Spine Score (p = 0.035), and high ESR (p = 0.001) and CRP (p = 0.000) were correlated with high IMT in patients with AS. Otherwise, status of arthritis (p = 0.442), enthesitis (p = 0.482), and HLA-B27 (p = 0.528) seemed to have no effect on IMT. CONCLUSION: AS is associated with an increased risk of atherosclerosis independent of traditional risk factors. Disease activity, functional and mobility limitations, structural damage, and inflammation are the most incriminated risk factors. PMID- 22247365 TI - Effectiveness of teriparatide in postmenopausal women with osteoporosis and glucocorticoid use: 3-year results from the EFOS study. AB - OBJECTIVE: To describe clinical fracture rates, back pain, and health-related quality of life (HRQOL) in postmenopausal women with osteoporosis who are receiving glucocorticoids (GC), during a 36-month study of teriparatide treatment for up to 18 months, with an additional 18-month followup period when patients were receiving other osteoporosis medications. METHODS: A prospective, multinational, observational study. Data for clinical fractures, back pain (by visual analog scale; VAS) and HRQOL (by EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month segments and analyzed using logistic regression with repeated measures. Changes from baseline in back pain VAS and EQ VAS were analyzed. RESULTS: Of 1581 enrolled women with followup data, 294 (18.6%) had antecedents of GC use. Of these, 49 (16.7%) patients sustained a total of 69 fractures during the 36-month study period. Adjusted odds of fracture were significantly decreased during the last year of followup compared with the first 6 months of teriparatide treatment: an 81% decrease in the 24 to < 30-month period (p < 0.05), and an 89% decrease in the 30 to < 36-month period (p < 0.05). There were significant reductions in back pain and improvements in HRQOL in both groups of GC users and nonusers. CONCLUSION: Postmenopausal women with severe osteoporosis receiving GC, who were treated with teriparatide for up to 18 months, showed a reduced incidence of clinical fractures during the third year while receiving sequential osteoporosis treatments compared with the first 6 months, together with reduced back pain and improved HRQOL. Our results should be interpreted in the context of an uncontrolled observational study in a routine clinical setting. PMID- 22247366 TI - The influence of individual joint impairment on functional disability in rheumatoid arthritis using a large observational database of Japanese patients. AB - OBJECTIVE: To clarify the influence of individual joint impairment on functional capacity through a retrospective study with a 3-year interval, using a large cohort of Japanese patients with rheumatoid arthritis (RA). METHODS: Subjects included 3457 patients with RA who participated in a large observational cohort study in both April 2004 and April 2007; 43 joints were assessed and classified into 10 joint areas. Impairment of each joint area was scored based on the presence of swelling or tenderness: score 0 (no swelling or tenderness in either joint), score 1 (swelling or tenderness in a unilateral joint), and score 2 (swelling or tenderness in bilateral joints). Score change was defined as the difference between scores from 2004 and 2007. The Japanese validated version of the Health Assessment Questionnaire is the J-HAQ; DeltaJ-HAQ score was determined by subtracting J-HAQ score in 2007 from that in 2004. The relationship between score change and DeltaJ-HAQ score, and the effect of joint impairment on DeltaJ HAQ score were assessed. RESULTS: Major joint areas that contributed to DeltaJ HAQ score included the wrist (31%), shoulder (21%), knee (13%), and ankle (10%). The shoulder, wrist, knee, and ankle in the worsening group were associated with a J-HAQ score increase of 0.13 to 0.18 compared to the improvement group. CONCLUSION: Our study demonstrated that impairment of the shoulder, wrist, knee, and ankle significantly affects functional capacity in patients with RA. Care of these joints is suggested to be especially important for better functional outcomes. PMID- 22247367 TI - Serum levels of galectin-3: possible association with fibrosis, aberrant angiogenesis, and immune activation in patients with systemic sclerosis. AB - OBJECTIVE: Galectin-3 is a multifunctional protein implicated in a variety of biological processes including fibrosis, angiogenesis, and immune activation, all of which are associated with the development of systemic sclerosis (SSc). We investigated the clinical significance of serum galectin-3 levels in SSc. METHODS: Serum galectin-3 levels were determined by a specific ELISA in 58 patients with SSc and 19 healthy controls. RESULTS: Serum galectin-3 levels were significantly lower in patients with diffuse cutaneous SSc (dcSSc) than in controls (3.29 +/- 3.27 ng/ml vs 4.91 +/- 2.67 ng/ml, respectively; p < 0.05), while being comparable between limited cutaneous SSc (3.70 +/- 2.39 ng/ml) and healthy controls. In dcSSc, serum galectin-3 levels significantly correlated with total skin score (r = 0.45, p < 0.05). Serum galectin-3 levels were significantly decreased in early dcSSc (disease duration < 1 year; 1.64 +/- 1.74 ng/ml; p < 0.05), but not in mid-stage dcSSc (1 to 6 years; 3.22 +/- 3.16 ng/ml) or late stage dcSSc (> 6 years; 4.86 +/- 4.10 ng/ml), compared with controls. Serum galectin-3 levels were higher in SSc patients with both digital ulcers (DU) and elevated right ventricular systolic pressure (RVSP) than in those without each symptom (DU: 5.44 +/- 3.74 ng/ml vs 2.99 +/- 2.36 ng/ml, p < 0.05; elevated RVSP: 4.44 +/- 3.14 ng/ml vs 2.82 +/- 2.64 ng/ml, p < 0.05). CONCLUSION: Galectin-3 may be related to the developmental process of skin sclerosis in dcSSc and of DU and pulmonary vascular involvements in total SSc. PMID- 22247368 TI - Occurrence, diagnosis, and strain typing of Mycobacterium avium subspecies paratuberculosis infection in Rocky Mountain bighorn sheep (Ovis canadensis canadensis) in southwestern Alberta. AB - The role that wildlife may play in the transmission of Mycobacterium avium subspecies paratuberculosis (Map), the causative agent of Johne's disease (JD), and the potential consequences of infection in these populations are being given increasing consideration. A yearling male Rocky Mountain bighorn sheep (Ovis canadensis canadensis) from southwestern Alberta, Canada, was found infected with Map in August 2009. Clinical signs of emaciation and diarrhea and histologic findings of diffuse granulomatous enteritis of the distal ileum, lymphadenitis of the mesenteric lymph nodes, and lymphangitis of the ileum were similar to previously described cases of JD in bighorn sheep. Infection with Map was confirmed by bacterial isolation through fecal culture, acid-fast staining, and polymerase chain reaction (PCR) of IS900. The Map1506 gene was sequenced, and the isolate was identified as a Cattle (Type II) strain. In a follow-up herd-level survey, three of 44 fecal samples (7%) from individual bighorn sheep from the same herd as the index case were PCR-positive and identified as Type II Map strains. Twenty-five samples from a distant bighorn population were negative. Additional strain typing of the isolates from the index case and the positive fecal samples was done by sequencing three discriminatory short sequence repeat (SSR) regions. All four SSR profiles differed from one another, suggesting multiple introductions or a long-existing circulation of Map within this bighorn population. Detailed molecular analyses are essential for understanding and managing diseases at the wildlife-livestock interface. PMID- 22247370 TI - Seasonal hematology and serum chemistry of wild beluga whales (Delphinapterus leucas) in Bristol Bay, Alaska, USA. AB - We collected blood from 18 beluga whales (Delphinapterus leucas), live-captured in Bristol Bay, Alaska, USA, in May and September 2008, to establish baseline hematologic and serum chemistry values and to determine whether there were significant differences in hematologic values by sex, season, size/age, or time during the capture period. Whole blood was collected within an average of 19 min (range=11-30 min) after the net was set for capture, and for eight animals, blood collection was repeated in a later season after between 80-100 min; all blood was processed within 12 hr. Mean hematocrit, chloride, creatinine, total protein, albumin, and alkaline phosphatase were significantly lower in May than they were in September, whereas mean corpuscular hemoglobin concentration, monocytes, phosphorous, magnesium, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltranspeptidase, and creatinine kinase were significantly higher. Mean total protein, white blood cell count, neutrophils, and lymphocytes were significantly higher early in the capture period than they were later. No significant differences in blood analyte values were noted between males and females. Using overall body length as a proxy for age, larger (older) belugas had lower white blood cell, lymphocyte, and eosinophil counts as well as lower sodium, potassium, and calcium levels but higher creatinine levels than smaller belugas. These data provide values for hematology and serum chemistry for comparisons with other wild belugas. PMID- 22247369 TI - Serum antibodies to whole-cell and recombinant antigens of Borrelia burgdorferi in cottontail rabbits. AB - Archived serum samples, from 95 eastern cottontail rabbits (Sylvilagus floridanus) captured in New York, New York, USA and Millbrook, New York, USA, during 1985-86, were analyzed in solid-phase enzyme-linked immunosorbent assays (ELISA) for total and class-specific immunoglobulin (Ig) M antibodies to whole cell or recombinant antigens of Borrelia burgdorferi sensu stricto. Using a polyvalent conjugate, rabbit sera contained antibodies to whole-cell and recombinant antigens (protein [p]35, p37, or VlsE) during different seasons, but there was no reactivity to outer surface protein (Osp)A or OspB. Seventy-six of the 102 sera (75%) analyzed were reactive with one or more of the antigens; 61 of the positive samples (80%) reacted to whole-cell antigens, followed by results for the p35 (58%, 44/76), VlsE (43%, 33/76), and p37 (29%, 22/ 76) antigens. Fifty-eight sera (76%) contained antibodies to the VlsE or p35 antigens with or without reactivity to whole-cell antigens. High antibody titers (>=1:2,560) recorded for 52 sera indicate robust antibody production. In analyses for IgM antibodies in an ELISA containing whole-cell antigens, there were 30 positive sera; titers ranged from 1:160 to 1:640. There was minimal cross-reactivity when rabbit antisera to Treponema pallidum or four serovars of Leptospira interrogans were screened against B. burgdorferi antigens. Based on more-specific results, VlsE and p35 antigens appear to be useful markers for detecting possible B. burgdorferi infections. PMID- 22247371 TI - Serosurveillance for foot-and-mouth disease in Mongolian gazelles (Procapra gutturosa) and livestock on the Eastern Steppe of Mongolia. AB - Foot-and-mouth disease (FMD) is a highly contagious, viral disease that affects most ruminant and porcine species, and periodic outbreaks on Mongolia's Eastern Steppe affect Mongolian gazelles (Procapra gutturosa) and livestock. During 2005 08, we collected sera from 36 and 57 calf and adult gazelles, respectively, and from adult domestic animals sympatric with the gazelles, including 138 sheep (Ovis aries), 140 goats (Capra aegagrus hircus), 139 Bactrian camels (Camelus bactrianus), and 138 cattle (Bos taurus). Our goal was to determine whether the prevalence of the antibody to foot-and-mouth disease virus (FMDV) in gazelles declined relative to previous estimates in the absence of FMD outbreaks. Overall, 2.0% (95% CI 0.7-3.3%, n=555) of the four livestock species were antibody positive for nonstructural proteins of FMDV (FMDV-NS), whereas 30.3% (95% CI 26.5 34.1%, n=555) had antibodies for structural proteins (i.e., vaccination-derived antibodies). Seven of 57 free-ranging gazelle calves (7.5%, 95%CI 1.6-12.4%) were FMDV-NS positive. None of 36 adult gazelles sampled in 2008 were antibody positive for exposure to FMDV, indicating a significant decline (chi(2)=18.99; P<0.001; df=1) in antibody prevalence among gazelles from the same area during a livestock outbreak in 2001. The episodic nature of FMD outbreaks on the Eastern Steppe, Mongolia, with evidence of FMDV exposure in gazelles only during or following concurrent outbreaks in livestock, suggests that FMDV may spill over into the gazelle population during livestock outbreaks and that successful control of FMD on the Eastern Steppe requires a focus on control in livestock populations through vaccination. PMID- 22247372 TI - Health evaluation of Galapagos Hawks (Buteo galapagoensis) on Santiago Island, Galapagos. AB - Galapagos Hawks (Buteo galapagoensis), the only endemic, diurnal raptor species in Galapagos, are currently distributed on eight Galapagos Islands having been extirpated from three of the human-inhabited islands. In January 2009, we performed health assessments of 89 Galapagos Hawks on Santiago Island, Galapagos. Four of the 89 Galapagos Hawks (4%) evaluated had physical abnormalities. Blood parameters did not differ between males and females, except for aspartate transaminase values, which were significantly higher in females than males. No Galapagos Hawks tested positive for antibodies to avian encephalitis virus, Marek virus, and paramyxovirus-1 or to haemosporidian antigen. Chlamydophila psittaci antigen was detected in 2 of 86 Galapagos Hawks (2%), with 24 of 43 Galapagos Hawks (56%) antibody-positive for avian adenovirus-1 and 1 of 48 Galapagos Hawks (2%) antibody positive for Toxoplasma gondii. There were no significant differences in infectious disease results based on sex. This study contributes to the understanding of the health status of the Galapagos Hawk and to the establishment of baseline information for the species. PMID- 22247373 TI - Morbillivirus infection in live stranded, injured, trapped, and captive cetaceans in southeastern Queensland and northern New South Wales, Australia. AB - We report serologic evidence of cetacean morbillivirus (CMV) infection in five of eight cetacean species found live stranded, injured, or trapped along the coast of southeastern Queensland and northern New South Wales, Australia between December 2005 and January 2011. Antibody to CMV was detected in 13 of 27 (48%) wild cetaceans sampled. Antibody prevalence was significantly higher in clinically diseased (69%) compared to nondiseased (18%) animals (P=0.018). There was high antibody prevalence (83%, n=6) in melon-headed whales (Peponocephala electra). Two of 13 (15%) captive cetaceans sampled between November 2005 and January 2011 had CMV antibodies and, as infection was unlikely to have occurred while in captivity, CMV infection appears to have been present in Australian wild cetaceans since at least 1985. These results indicate that morbillivirus infection is occurring without widespread cetacean mortality in this region. However, as the deaths of two immature Australian offshore bottlenose dolphins (Tursiops truncatus) were attributed to CMV infection, morbillivirus infection should be included in the differential diagnosis of disease in cetaceans in Australia. Captive cetacean populations may be prone to significant mortality as a result of CMV introduction, so strict quarantine procedures should be enforced when injured or stranded cetaceans are hospitalized and rehabilitated at Australian zoos and marine parks. PMID- 22247374 TI - Carriage of antibiotic-resistant enteric bacteria varies among sites in Galapagos reptiles. AB - Increased overlap between humans and wildlife populations has increased the risk for novel disease emergence. Detecting contacts with a high risk for transmission of pathogens requires the identification of dependable measures of microbial exchange. We evaluated antibiotic resistance as a molecular marker for the intensity of human-wildlife microbial connectivity in the Galapagos Islands. We isolated Escherichia coli and Salmonella enterica from the feces of land iguanas (Conolophus sp.), marine iguanas (Amblyrhynchus cristatus), giant tortoises (Geochelone nigra), and seawater, and tested these bacteria with the use of the disk diffusion method for resistance to 10 antibiotics. Antibiotic-resistant bacteria were found in reptile feces from two tourism sites (Isla Plaza Sur and La Galapaguera on Isla San Cristobal) and from seawater close to a public use beach near Puerto Baquerizo Moreno on Isla San Cristobal. No resistance was detected at two protected beaches on more isolated islands (El Miedo on Isla Santa Fe and Cape Douglas on Isla Fernandina) and at a coastal tourism site (La Loberia on Isla San Cristobal). Eighteen E. coli isolates from three locations, all sites relatively proximate to a port town, were resistant to ampicillin, doxycycline, tetracycline, and trimethoprin/sulfamethoxazole. In contrast, only five S. enterica isolates showed a mild decrease in susceptibility to doxycycline and tetracycline from these same sites (i.e., an intermediate resistance phenotype), but no clinical resistance was detected in this bacterial species. These findings suggest that reptiles living in closer proximity to humans potentially have higher exposure to bacteria of human origin; however, it is not clear from this study to what extent this potential exposure translates to ongoing exchange of bacterial strains or genetic traits. Resistance patterns and bacterial exchange in this system warrant further investigation to understand better how human associations influence disease risk in endemic Galapagos wildlife. PMID- 22247375 TI - Prevalence of antibodies to canine parvovirus and distemper virus in wolves in the Canadian Rocky Mountains. AB - Wild carnivores are often exposed to diseases via contact with peridomestic host species that travel through the wildland-urban interfaces. To determine the antibody prevalences and relationships to human activity for two common canid pathogens, we sampled 99 wolves (Canis lupus) from 2000 to 2008 for antibodies to canine parvovirus (CPV) and canine distemper virus (CDV) in Banff and Jasper National Parks and surrounding areas of the Canadian Rockies. This population was the source for wolves reintroduced into the Northern Rockies of the US. Of 99 wolves sampled, 94 had detectable antibody to CPV (95%), 24 were antibody positive for CDV (24%), and 24 had antibodies to both pathogens (24%). We tested whether antibody prevalences for CPV and CDV were higher closer to human activity (roads, town sites, First Nation reserves) and as a function of sex and age class. Wolves >=2 yr old were more likely to be have antibodies to CPV. For CDV, male wolves, wolves >=2 yr, and those closer to First Nation reserves were more likely to have antibodies. Overall, however, we found minimal support for human influence on antibody prevalence for CDV and CPV. The similarity between our antibody prevalence results and results from recent studies in Yellowstone National Park suggests that at least in the case of CDV, and perhaps CPV, these could be important pathogens with potential effects on wolf populations. PMID- 22247376 TI - Mandibular osteomyelitis in red deer (Cervus elaphus hispanicus) and fallow deer (Dama dama): occurrence and associated factors in free-living populations in southern Spain. AB - The prevalence of mandibular osteomyelitis, which results in a condition called lumpy jaw, and factors associated with its occurrence were investigated in syntopic free-living populations of red deer (Cervus elaphus hispanicus) and fallow deer (Dama dama) in Spain. The study material consisted of 3,586 mandibles from 2,548 red deer and 1,038 fallow deer shot during sport hunting, herd management culls, and programs for population control between 1988 and 1997 (period 1) and 2002 and 2009 (period 2) in eastern Sierra Morena, southern Spain. Disease prevalence ranged from 0.36% to 10.91% among age groups. Older animals were significantly more likely to be affected than younger ones. Red deer stags had higher prevalence than other groups. There was a significantly higher prevalence in period 1, probably associated with differences in climatic and population conditions. High population densities of female red deer contributed significantly to occurrence of disease. Intensive herd management and poor environmental conditions were considered risk factors that increased susceptibility to disease. The study of this affliction could be useful for monitoring general herd welfare and ecologic changes in Mediterranean ecosystems. PMID- 22247377 TI - Porcine reproductive and respiratory syndrome virus and porcine circovirus type 2 infections in wild boar (Sus scrofa) in southwestern Germany. AB - Samples were collected from 203 wild boars (Sus scrofa) hunted in Baden Wurtemburg, Germany from November-January 2008 and 2009. Samples from the lung and tonsil were analyzed by quantitative polymerase chain reaction (qPCR) for porcine reproductive and respiratory syndrome virus (PRRSV) type 1 (European type) and type 2 (American type). A qPCR to detect porcine circovirus type 2 (PCV2)-specific genome was performed on tissue homogenates including lung, tonsils, and inguinal lymph nodes. Serum samples were tested for antibodies against PRRSV and PCV2 by enzyme-linked immunosorbent assay (ELISA). No PRRSV was detected in any of the 203 samples and one sample had detectable antibodies against PRRSV. We detected PCV2 in organ materials from 103 wild boars with a prevalence of 50.7%. The number of wild boars positive for PCV2 by PCR varied according to the population density of wild boars among woodlands. More positive samples were detected in woodlands with a high density of wild boars. We found no correlation between the number of PCV2-positive wild boars and the density of domestic pigs in the surrounding area. The number of wild boars positive for antibodies against PCV2 by the INGEZIM Circovirus IgG/IgM test kit was low (53 sera positive for IgG- and three sera positive for IgM-antibodies) in comparison to the higher positive results from the INGEZIM CIRCO IgG test kit (102 positive and 12 inconclusive results). PMID- 22247378 TI - Patterns of mortality in free-ranging California Condors (Gymnogyps californianus). AB - We document causes of death in free-ranging California Condors (Gymnogyps californianus) from the inception of the reintroduction program in 1992 through December 2009 to identify current and historic mortality factors that might interfere with establishment of self-sustaining populations in the wild. A total of 135 deaths occurred from October 1992 (the first post-release death) through December 2009, from a maximum population-at-risk of 352 birds, for a cumulative crude mortality rate of 38%. A definitive cause of death was determined for 76 of the 98 submitted cases, 70% (53/76) of which were attributed to anthropogenic causes. Trash ingestion was the most important mortality factor in nestlings (proportional mortality rate [PMR] 73%; 8/11), while lead toxicosis was the most important factor in juveniles (PMR 26%; 13/50) and adults (PMR 67%; 10/15). These results demonstrate that the leading causes of death at all California Condor release sites are anthropogenic. The mortality factors thought to be important in the decline of the historic California Condor population, particularly lead poisoning, remain the most important documented mortality factors today. Without effective mitigation, these factors can be expected to have the same effects on the sustainability of the wild populations as they have in the past. PMID- 22247379 TI - Septicemic salmonellosis caused by Salmonella Hessarek in wintering and migrating Song Thrushes (Turdus philomelos) in Spain. AB - We investigated two mortality events in wintering and migrating Song Thrushes (Turdus philomelos) in Catalonia, northeastern Spain in 2009 and 2010. Both episodes occurred in late February to mid-March during the spring migration. Salmonellosis produced by the serotype Salmonella enterica subsp. enterica serotype Hessarek (S. Hessarek) was identified as the cause of death in both episodes. Poor body condition, marked splenomegaly, and microscopic disseminated intravascular coagulation with numerous intravascular and tissular bacteria were the most consistent findings. Macro-restriction profiling by pulsed-field gel electrophoresis (PFGE) using XbaI was performed for epidemiologic typing of the S. Hessarek isolates. Two clusters were discernible, that are possibly related, with a similarity of 82.8%. Analysis comparing pectoral muscle and subcutaneous fat scores from the Song Thrushes that died from S. Hessarek with those from healthy Song Thrushes from nearby areas during 2009 and 2010 suggest that poor body condition was associated with the S. Hessarek infection. PMID- 22247380 TI - Chemical immobilization of raccoons (Procyon lotor) with ketamine-medetomidine mixture and reversal with atipamezole. AB - Safe and reliable capture techniques for wild animals are important for ecologic studies and management operations. We assessed the efficiency of ketamine medetomidine (K:M) injection and reversal with atipamezole. We anesthetized 67 raccoons (Procyon lotor; 34 males, 33 females) 103 times (individuals captured between one and five times) from April 2009-October 2010 in Mont-Orford Provincial Park, Quebec, Canada. We administered a 1:1 mixture by volume of ketamine and medetomidine by intramuscular injection. Mean (+/-SD) induction times for males and females were 6.1+/-2.8 and 6.6+/-3.7 min, respectively. Mean induction time was 2 min longer for juveniles than for adults (7.8+/-3.9 and 5.8+/-2.9 min, respectively) and longer in autumn than in spring for adults (7.7+/-3.8 and 5.4+/-2.9 min, respectively). Recovery time after administration of atipamezole was 9.6+/-3.8 and 8.4+/-4.4 min for males and females, respectively. Recovery time was longer in spring than in autumn (10.2+/-4 and 7.4+/-3.8 min, respectively) for adults. Induction time increased by 166% after five captures of the same individual. Immobilization did not affect body mass, adult survival, or female reproductive success. We suggest the K:M mixture used is a safe and reliable method for anesthetizing raccoons in field conditions. PMID- 22247381 TI - Prevalence of antibodies to selected viral pathogens in wild boars (Sus scrofa) in Croatia in 2005-06 and 2009-10. AB - We determined prevalence of antibody to selected viral pathogens important for domestic pigs and livestock in 556 wild boar (Sus scrofa) sera collected during 2005-06 and 2009-10 in four counties in Croatia. These counties account for an important part of the Croatian commercial pig production and have a high density of wild boars. Samples were tested for antibodies to porcine parvovirus (PPV), Aujeszky's disease virus (ADV), porcine circovirus type 2 (PCV2), swine influenza virus, porcine respiratory and reproductive syndrome virus (PRRSV), porcine respiratory coronavirus (PRCV), transmissible gastroenteritis virus, and swine vesicular disease virus (SVDV). Antibodies to all of the infectious pathogens except SVDV were detected. There was a statistically significant difference in prevalence between the two periods for PPV, ADV, PCV2, PRRSV, and PRCV, with a higher prevalence of PPV and ADV in the 2009-10 period (P<0.05). During the same period, the prevalence of PCV2, PRRSV, and PRCV was lower (P<0.05). Our results provide information on the current disease exposure and health status of wild boars in Croatia and suggest that wild boars may act as a reservoir for several pathogens and a source of infection for domestic pigs and other livestock as well as humans, especially for ADV. PMID- 22247382 TI - Seasonal variation and age-related correlates of Buggy Creek virus (Togaviridae) infection in nestling house sparrows. AB - Wild birds are rarely found with active arbovirus infections, and relatively little is known about the patterns of viremia they exhibit under field conditions or how infection varies with date, bird age, or other factors that potentially affect transmission dynamics. Buggy Creek virus (BCRV; Togaviridae, Alphavirus) is an arbovirus associated with colonially nesting Cliff Swallows (Petrochelidon pyrrhonota) and transmitted by its vector, the hematophagous swallow bug (Oeciacus vicarius), an ectoparasite of the Cliff Swallow. Introduced House Sparrows (Passer domesticus) that have occupied swallow nests at colony sites in peridomestic settings are also exposed to BCRV when fed upon by swallow bugs. We used data from 882 nestling House Sparrows in western Nebraska from 2006 to 2008 to examine seasonal variation and age-related correlates of virus infection in the field. Over 17% of nestling House Sparrows had active infections. Prevalence was higher in 2007 than in 2008 when birds from all colony sites were analyzed, but there was no significant difference between years for sites sampled in both seasons. Buggy Creek virus prevalence was similar in early and late summer, with a peak in midsummer, coinciding with the greatest swallow bug abundance. Nestlings 10 days of age and younger were most commonly infected, and the likelihood of BCRV infection declined for older nestlings. Average viremia titers also declined with age (but did not vary with date) and were high enough at all nestling ages to likely infect blood-feeding arthropods (swallow bugs). Length of viremia for nestlings in the field was >=4 days, in agreement with an earlier study of BCRV. Nestling birds offer many advantages for field studies of arbovirus amplification and transmission. PMID- 22247383 TI - Impact of Puumala virus infection on maturation and survival in bank voles: a capture-mark-recapture analysis. AB - Many zoonotic diseases are caused by rodent-borne viruses. Major fluctuations in the transmission of these viruses have been related to large changes in reservoir host population numbers due to external factors. However, the impact of the pathogen itself on the demography of its reservoir host is often overlooked. We investigated the impact of Puumala virus (PUUV) on survival and reproductive maturation probability of its reservoir host, the bank vole (Myodes glareolus). Three years (2004-06) of data from nine independent sites in southern Belgium were collected and analyzed with a capture-mark-recapture (CMR) method that includes statistical correction for the variation in capture probability of voles. A multistate model based on four states of reproductive activity and PUUV immunoglobulin G (IgG) antibody status was used to estimate survival and probability of transition from one reproductive or infection state to another. Although survival estimates for reproductively active voles were similar between infected and noninfected individuals, PUUV infection in reproductively inactive voles decreased mean monthly survival by 14%. PUUV infection was associated with a threefold increase in the probability of reproductive maturation in bank voles. Moreover, the probability of PUUV IgG seroconversion was three times higher for reproductively active voles compared to reproductively inactive voles. Our model indicates that PUUV infection may alter bank vole population dynamics by affecting both survival and maturation in its host. Additional studies, using CMR methodology with shorter time intervals between trapping sessions and possibly a longer duration, are needed to confirm these findings. PMID- 22247384 TI - Comparing ONRAB(r) AND RABORAL V-RG(r) oral rabies vaccine field performance in raccoons and striped skunks, New Brunswick, Canada, and Maine, USA. AB - Control of rabies in mesocarnivore reservoirs through oral rabies vaccination (ORV) requires an effective vaccine bait. Oral rabies vaccine performance in the field may be affected by a variety of factors, including vaccine bait density and distribution pattern, habitat, target species population density, and the availability of competing foods. A field study in which these covariates were restricted as much as possible was conducted along the international border of the state of Maine (ME), USA, and the province of New Brunswick (NB), Canada, to compare the performance of two oral rabies vaccines in raccoons (Procyon lotor) and striped skunks (Mephitis mephitis). RABORAL V-RG((r)) (vaccinia-rabies glycoprotein recombinant oral vaccine in fishmeal-coated sachet) or ONRAB((r)) (adenovirus-rabies glycoprotein recombinant oral vaccine in Ultralite bait matrix) were distributed in ME and NB, respectively, by fixed-wing aircraft at a density of 75 baits/km(2) along parallel flight lines spaced 1.0 km apart. Sera were collected from live-trapped raccoons and skunks 5-7 wk post-ORV and assayed to determine antibody prevalence in each area. Duplicate serum samples were provided blind to two different laboratories for analyses by rabies virus serum neutralization assays (at both laboratories) and a competitive enzyme-linked immunosorbent assay (at one laboratory). There was no significant difference in the proportion of antibody-positive animals determined by the three serologic methods, nor was there a significant difference between ONRAB and RABORAL V-RG in the proportion of antibody-positive striped skunks observed post-ORV. In contrast, the proportion of antibody-positive raccoons was significantly higher in the ONRAB- versus the RABORAL V-RG-baited areas (74% vs. 30%; chi(2)=89.977, df=5, P<0.0001). These data support that ONRAB may serve as an effective tool for raccoon rabies control. PMID- 22247385 TI - Survival of bighorn sheep (Ovis canadensis) commingled with domestic sheep (Ovis aries) in the absence of Mycoplasma ovipneumoniae. AB - To test the hypothesis that Mycoplasma ovipneumoniae is an important agent of the bighorn sheep (Ovis canadensis) pneumonia that has previously inevitably followed experimental commingling with domestic sheep (Ovis aries), we commingled M. ovipneumoniae-free domestic and bighorn sheep (n=4 each). One bighorn sheep died with acute pneumonia 90 days after commingling, but the other three remained healthy for >100 days. This unprecedented survival rate is significantly different (P=0.002) from that of previous bighorn-domestic sheep contact studies but similar to (P>0.05) bighorn sheep survival following commingling with other ungulates. The absence of epizootic respiratory disease in this experiment supports the hypothesized role of M. ovipneumoniae as a key pathogen of epizootic pneumonia in bighorn sheep commingled with domestic sheep. PMID- 22247386 TI - Field immobilization of Molina's hog-nosed skunk (Conepatus chinga) using ketamine and xylazine. AB - We injected 27 adult Molina's hog-nosed skunks (Conepatus chinga) intramuscularly by hand with ketamine hydrochloride (KH) and xylazine hydrochloride (XH) in the Pampas grassland of Argentina. Skunks were immobilized with a mean (+/-SD) dosage of 24.9+/-6.5 mg/kg KH and 1.9+/-0.6 mg/kg XH. The mean effective dosages of KH (27.6 mg/kg) and XH (1.7 mg/kg) were higher and lower, respectively, than those reported in skunks previously. Mean induction and recovery time were 5.3+/-1.9 min and 47.7+/-18.5 min, respectively. Hypothermia was the only problem detected in field immobilization and occurred in winter but did not appear to be associated with to drug doses. We conclude that KH/XH is a safe immobilizing drug combination for Molina's hog-nosed skunk. PMID- 22247387 TI - Blood collection from the facial (maxillary)/musculo-cutaneous vein in true frogs (family Ranidae). AB - Collection of blood from amphibians, as in other classes of vertebrate animals, is essential to evaluate parameters of health, diagnose hemoparasitism, identify viral and bacterial pathogens, and measure antibodies. Various methods of blood collection have been described for amphibians. Most can be cumbersome (venipucture of femoral vein, ventral abdominal vein or lingual venus plexus) or result in pain or deleterious health consequences (cardiac puncture and toe clipping). We describe an easy and practical technique to collect blood from frogs and toads that can be used in multiple species and is minimally invasive. The technique consists of puncturing either the facial or, less commonly, the musculo-cutaneous vein and collecting the blood with a capillary tube. These veins run dorsal and parallel to the maxillary bone and can be accessed by quick insertion and withdrawal of a needle through the skin between the upper jawline and the rostral or caudal side of the tympanum. The needle should be of 27 or 30 gauge for anurans weighing more or less than 25 g, respectively. Although the technique has been used by some amphibian researchers for years, it is little known by others and has never been fully described in a peer-reviewed publication. PMID- 22247388 TI - Mustelid herpesvirus-2, a novel herpes infection in northern sea otters (Enhydra lutris kenyoni). AB - Oral ulcerations and plaques with epithelial eosinophilic intranuclear inclusions were observed in northern sea otters (Enhydra lutris kenyoni) that died or were admitted for rehabilitation after the 1989 Exxon Valdez oil spill (EVOS) in Alaska, USA. Transmission electron microscopy demonstrated the presence of herpesviral virions. Additionally, a serologic study from 2004 to 2005 found a high prevalence of exposure to a herpesvirus in live-captured otters. Tissues from 29 otters after the EVOS and nasal swabs from 83 live-captured otters in the Kodiak Archipelago were tested for herpesviral DNA. Analysis identified a novel herpesvirus in the gamma subfamily, most closely related to Mustelid herpesvirus 1 from badgers. Results indicated that this herpesvirus is associated with ulcerative lesions but is also commonly found in secretions of healthy northern sea otters. PMID- 22247390 TI - Frequency of deposition and location of Baylisascaris procyonis eggs in raccoon feces. AB - Baylisascaris procyonis is a large ascarid nematode found in the small intestine of raccoons (Procyon lotor). Infection with larvae of B. procyonis can produce visceral, ocular, and neural larval migrans in humans. Infected raccoons can shed millions of eggs a day in their feces. However, it is unknown whether eggs are consistently shed or whether eggs occur at irregular intervals by the population of female nematodes within a host. We trapped, infected, and collected daily fecal samples from 11 raccoons maintained in captivity. Eggs from B. procyonis were obtained from anterior, central, and posterior sections of raccoon feces, isolated by flotation, and quantified under 100* magnification. Naturally infected raccoons were collected and used as a comparison with the experimentally infected group. All raccoons in the experimental group (n=11) became infected with B. procyonis after consuming one infected mouse. Additionally, differential egg deposition rates were observed among individual raccoons from the experimental and naturally infected groups. Mean number of eggs per gram of feces (means+/-SE) was 16,563+/-4,321, which was less than previously reported for the species. However, no differences (F(2,30)=0.84, P=0.45) were noted in mean number of eggs per gram of feces among fecal sections. Wildlife biologists, veterinarians, health officials, and researchers of B. procyonis should collect daily fecal samples for a minimum of 3 days before identifying a raccoon as negative for B. procyonis infection. However, it does not matter where within the fecal matter the sample is obtained. PMID- 22247389 TI - Serosurvey of free-ranging Amur tigers in the Russian Far East. AB - Wild Amur tigers (Panthera tigris altaica, n=44) from the Russian Far East were tested for antibodies to feline leukemia virus, feline corona virus (FCoV), feline immunodeficiency virus, feline parvovirus (FPV), canine distemper virus (CDV), Toxoplasma gondii, and Bartonella henselae. Antibodies to FCoV, CDV, FPV, and T. gondii were detected in 43, 15, 68, and 42% of tigers, respectively. No differences were detected in antibody prevalence estimates between tigers captured as part of a research program and those captured to mitigate human-tiger conflicts. Domestic dogs (Canis familiaris) were tested as a potential source for CDV; 16% were vaccinated against CDV and 58% of unvaccinated dogs were antibody positive for CDV. A high percentage of tigers were exposed to potential pathogens that could affect the survival of this species. We recommend continued monitoring of wild tigers throughout Asia, development of standardized sampling and postmortem examination procedures, and additional research to better understand potential domestic and wild animal sources for these pathogens. PMID- 22247391 TI - Avian influenza viruses in wild land birds in northern Vietnam. AB - Given a paucity of data on the occurrence of avian influenza viruses (AIVs) in wild passerines and other small terrestrial species in Southeast Asia and the importance of highly pathogenic Asian-strain H5N1 outbreaks in humans and domestic poultry in these areas, we focused on surveillance for influenza A viral nucleic acids and antibodies for AIVs in wild-caught birds in northern Vietnam. Four of 197 serum samples collected in 2007 from Black-crested Bulbul (Pycnonotus melanicterus), Crow-billed Drongo (Dicrurus annectans), Buff-breasted Babbler (Pellorneum tickelli), and Black-browed Fulvetta (Alcippe grotei) were antibody positive for the H5 subtype. Fourteen of 193 samples collected in 2008 were positive for the influenza A viral M gene by real-time reverse transcriptase polymerase chain reaction. These included samples from 10 Japanese White-eyes (Zosterops japonicus), two Puff-throated Bulbuls (Alophoixus pallidus), one White tailed Robin (Cinclidium leucurum), and one Striped Tit-babbler (Macronous gularis). Almost all positive samples were from bird species that forage in flocks, including Japanese White-eyes with an unusually high prevalence of 14.9%. We collected samples from birds from three habitat types but detected no strong pattern in prevalence. Our results suggest that attention should be given to terrestrial species, particularly flocking passerines, in AIV surveillance and monitoring programs. PMID- 22247392 TI - Coxiella burnetii infection of marine mammals in the Pacific Northwest, 1997 2010. AB - Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii. Humans are commonly exposed via inhalation of aerosolized bacteria derived from the waste products of domesticated sheep and goats, and particularly from products generated during parturition. However, many other species can be infected with C. burnetii, and the host range and full zoonotic potential of C. burnetii is unknown. Two cases of C. burnetii infection in marine mammal placenta have been reported, but it is not known if this infection is common in marine mammals. To address this issue, placenta samples were collected from Pacific harbor seals (Phoca vitulina richardsi), harbor porpoises (Phocoena phocoena), and Steller sea lions (Eumetopias jubatus). Coxiella burnetii was detected by polymerase chain reaction (PCR) in the placentas of Pacific harbor seals (17/27), harbor porpoises (2/6), and Steller sea lions (1/2) collected in the Pacific Northwest. A serosurvey of 215 Pacific harbor seals sampled in inland and outer coastal areas of the Pacific Northwest showed that 34.0% (73/215) had antibodies against either Phase 1 or Phase 2 C. burnetii. These results suggest that C. burnetii infection is common among marine mammals in this region. PMID- 22247393 TI - Histopathology confirms white-nose syndrome in bats in Europe. AB - White-nose syndrome, associated with the fungal skin infection geomycosis, caused regional population collapse in bats in North America. Our results, based on histopathology, show the presence of white-nose syndrome in Europe. Dermatohistopathology on two bats (Myotis myotis) found dead in March 2010 with geomycosis in the Czech Republic had characteristics resembling Geomyces destructans infection in bats confirmed with white-nose syndrome in US hibernacula. In addition, a live M. myotis, biopsied for histopathology during hibernation in April 2011, had typical fungal infection with cupping erosion and invasion of muzzle skin diagnostic for white-nose syndrome and conidiospores identical to G. destructans that were genetically confirmed as G. destructans. PMID- 22247394 TI - Hematology, plasma chemistry, and bacteriology of wild Tundra Swans (Cygnus columbianus) in Alaska. AB - Blood and cloacal swabs were collected from 100 (66 female, 34 male) wild Tundra Swans (Cygnus columbianus) molting in northwestern Alaska, USA, 25-28 July 2008, to establish hematologic and serum chemistry reference values and to isolate enteric Salmonella spp. and Escherichia coli O157:H7. Plasma biochemistry and hematology values did not vary significantly by sex or age. Tundra swans had high levels of creatine kinase, lactate dehydrogenase, amylase, and alkaline phosphatase compared with some other avian species (values were up to 7 times greater), possibly indicating capture myopathy. However, concentrations were much lower (up to 8 times lower) than in other waterfowl exposed to similar or more intensive capture methods. White blood cell count and hematocrit values were similar to other waterfowl species, and enteric Salmonella spp. and E. coli O157:H7 were not present among birds sampled. Our data provide the first biochemical, hematologic, and bacteriologic reference values for wild Tundra Swans. PMID- 22247395 TI - Acute lead toxicosis via ingestion of spent ammunition in a free-ranging cougar (Puma concolor). AB - Lead toxicity has long been documented and acknowledged as a significant health issue of water birds and avian scavengers. However, few instances of toxic effects to higher mammalian carnivores have been documented. Here we present an acute case of lead toxicity in a free-ranging cougar (Puma concolor) in Oregon. PMID- 22247396 TI - A serologic survey for Coxiella burnetii in semi-wild ungulates in the Emirate of Dubai, United Arab Emirates. AB - Q fever, a highly infectious zoonotic disease caused by Coxiella burnetii, has not been officially reported in the United Arab Emirates (UAE). This first serosurvey of a large group of semi-free-ranging animals in the UAE indicates that a wide range of ungulates have been exposed C. burnettii in the region. PMID- 22247397 TI - Screening for Trichinella britovi infection in red fox (Vulpes vulpes) and wild boar (Sus scrofa) in southeastern France. AB - From 2006 to 2009 we screened 108 red foxes (Vulpes vulpes) and 894 wild boars (Sus scrofa) in Haut-Var, France for Trichinella britovi infection. Prevalences were 2.7 and 0% respectively. The fox may be considered a predictive sentinel for Trichinella in the Haut-Var ecosystem. PMID- 22247398 TI - Detection of a second novel gammaherpesvirus in a free-ranging koala (Phascolarctos cinereus). AB - A second novel gammaherpesvirus was detected in a free-ranging koala (Phascolarctos cinereus) shown previously to be infected with phascolarctid herpesvirus 1. Analysis of the DNA polymerase gene showed that the virus was genetically distinct from all known gammaherpesviruses. This is the first reported dual gammaherpesvirus infection in an Australian marsupial. PMID- 22247399 TI - Orbivirus infections in collared peccaries (Tayassu tajacu) in southeastern Brazil. AB - We surveyed 49 free-living collared peccaries (Pecari tajacu) in Brazil for antibodies against bluetongue virus (BTV) and porcine circovirus 2 (PCV2). Antibodies against BTV were detected in 19/49 (39%) samples. All samples were negative for PCV2. The importance of antibodies to BTV in collared peccaries remains to be determined. PMID- 22247400 TI - Dipylidium caninum (Cyclophyllidea, Dipylidiidae) in a wild carnivore from Brazil. AB - We report Dipylidium caninum for the first time in a wild carnivore in Brazil, the crab-eating fox (Cerdocyon thous). Presence of the cestode could be the consequence of anthropogenic expansion into natural habitats of this host, as this parasite has only previously been reported in domestic hosts in Brazil. PMID- 22247401 TI - Herpes-like virus infection in Yangtze finless porpoise (Neophocaena phocaenoides): pathology, ultrastructure and molecular analysis. AB - A moribund juvenile Yangtze finless porpoise (Neophocaena phocaenoides) with skin lesions and ulceration was found in Dongting Lake, China. Pathologic examination, electron microscopy, and polymerase chain reaction of liver tissue revealed widely distributed necrotic lesions, sinusoidal dilatation, congestion and herpes like virus particles. PMID- 22247403 TI - Hippotherapy--an intervention to habilitate balance deficits in children with movement disorders: a clinical trial. AB - BACKGROUND: Clinical observations have suggested that hippotherapy may be an effective strategy for habilitating balance deficits in children with movement disorders. However, there is limited research to support this notion. OBJECTIVE: The purposes of this study were to assess the effectiveness of hippotherapy for the management of postural instability in children with mild to moderate balance problems and to determine whether there is a correlation between balance and function. DESIGN: A repeated-measures design for a cohort of children with documented balance deficits was used. METHODS: Sixteen children (9 boys and 7 girls) who were 5 to 16 years of age and had documented balance problems participated in this study. Intervention consisted of 45-minute hippotherapy sessions twice per week for 6 weeks. Two baseline assessments and 1 postintervention assessment of balance, as measured with the Pediatric Balance Scale (PBS), and of function, as measured with the Activities Scale for Kids Performance (ASKp), were performed. RESULTS: With the Friedman analysis of variance, the PBS and the ASKp were found to be statistically significant across all measurements (P<.0001 for both measures). Post hoc analysis revealed a statistical difference between baseline and postintervention measures (P<=.017). This degree of difference resulted in large effect sizes for PBS (d=1.59) and ASKp (d=1.51) scores after hippotherapy. A Spearman rho correlation of .700 indicated a statistical association between PBS and ASKp postintervention scores (P=.003). There was no correlation between the change in PBS scores and the change in ASKp scores (r(s)=.13, P>.05). LIMITATIONS: Lack of a control group and the short duration between baseline assessments are study limitations. CONCLUSIONS: The findings suggest that hippotherapy may be a viable strategy for reducing balance deficits and improving the performance of daily life skills in children with mild to moderate balance problems. PMID- 22247404 TI - Lyme disease as an underlying cause of supraspinatus tendinopathy in an overhead athlete. AB - BACKGROUND AND PURPOSE: Supraspinatus tendinopathy is a common cause of shoulder pain seen in overhead athletes, but there appear to be no published cases that present Lyme disease as the underlying cause of tendinopathy. Lyme disease is diagnosed primarily by clinical signs and symptoms and then supported by laboratory tests, including enzyme-linked immunosorbant assay (ELISA) and Western blot testing. This case demonstrates the importance of a physical therapist's input and clinical role in reaching the correct diagnosis in an athlete with Lyme disease who had a diagnosis of rotator cuff impingement and tendinitis. CASE DESCRIPTION: A 34-year-old male tennis player was seen for physical therapy for right shoulder impingement and tendinitis diagnosed by an orthopedic surgeon. He was unable to participate in sporting activities due to impairments in strength and pain. Initial examination revealed distal supraspinatus impingement and tendinopathy. OUTCOMES: The patient was not progressing with commonly accepted interventions and began to have "arthritis-like" shoulder pain in the uninvolved left shoulder. Suspicious of an underlying condition, the physical therapist informed the physician of the patient's updated status and referred the patient to the physician to discuss the current symptoms in therapy. After testing, the patient was diagnosed with chronic Lyme disease and underwent antibiotic therapy. DISCUSSION: Many active patients spend time in the outdoors, increasing their risk of exposure to a vector for Borrelia burgdorferi. Physical therapists spend a larger portion of time with patients than other health care professionals and due to this extended contact and musculoskeletal knowledge are able to recognize atypical musculoskeletal disorders or musculoskeletal manifestations of unusual pathologies, including Lyme disease. PMID- 22247405 TI - Direct access: factors that affect physical therapist practice in the state of Ohio. AB - BACKGROUND: Direct access to physical therapist services is permitted by law in the majority of states and across all practice settings. Ohio enacted such legislation in 2004; however, it was unknown how direct access had affected actual clinical practice. OBJECTIVES: The purpose of this study was to describe physical therapist and physical therapist practice environment factors that affect direct access practice. DESIGN: A 2-phase, mixed-method descriptive study was conducted. METHODS: In the first phase, focus group interviews with 32 purposively selected physical therapists were completed, which resulted in 8 themes for an electronically distributed questionnaire. In the second phase, survey questionnaires were distributed to physical therapists with an e-mail address on file with the Ohio licensing board. An adjusted return rate of 23% was achieved. Data were analyzed for descriptive statistics. A constant comparative method assessed open-ended questions for common themes and patterns. RESULTS: Thirty-one percent of the respondents reported using direct access in physical therapist practice; however, 80% reported they would practice direct access if provided the opportunity. Physical therapists who practiced direct access were more likely to be in practice 6 years or more and hold advanced degrees beyond the entry level, were American Physical Therapy Association members, and had supportive management and organizational practice policies. The direct access physical therapist practice was generally a locally owned suburban private practice or a school-based clinic that saw approximately 6% to 10% of its patients by direct access. The majority of patients treated were adults with musculoskeletal or neuromuscular impairments. LIMITATIONS: Nonresponse from e mail may be associated with sample frame bias. CONCLUSIONS: Implementation of a direct access physical therapist practice model is evident in Ohio. Factors related to reimbursement and organizational policy appear to impede the process. PMID- 22247406 TI - Efficacy of a hip flexion assist orthosis in adults with hemiparesis after stroke. AB - BACKGROUND: During gait, the hip flexors generate 40% of the total power. Nevertheless, no device has been tested extensively for clinical purposes to cope with weakness in the hip flexors in patients with stroke. OBJECTIVE: The purpose of this study was to assess the efficacy and safety of a newly developed hip flexion assist orthosis in adult patients with hemiparesis after stroke. DESIGN: The study used a prospective, randomized, before-after trial design. The inclusion criteria were hemiparesis resulting from stroke (onset >=8 weeks); ability to walk, even if with assistance; and hip flexion weakness (Medical Research Council Scale score <=4). METHODS: The main outcome measures were the 10 Meter Walk Test and the Six-Minute Walk Test. Patients also were evaluated with the Trunk Control Test, the Functional Ambulation Categories, the Motricity Index, and hip flexor strength on the Medical Research Council Scale. Sixty-two survivors of stroke were tested in random order with and without the orthosis. Any adverse event associated with its use was recorded. RESULTS: Both the Six Minute Walk Test and the 10-Meter Walk Test scores improved with the use of the orthosis. A significant negative correlation was found for improvement between scores on the 2 main outcome measures with the orthosis and the Functional Ambulation Categories scores. The improvement in Six-Minute Walk Test scores with the orthosis was related inversely to hip flexor strength. CONCLUSIONS: The data showed that the use of a hip flexion assist orthosis can improve gait in patients with poststroke hemiparesis, particularly those with more severe walking impairment. PMID- 22247407 TI - Efficacy of directional preference management for low back pain: a systematic review. AB - BACKGROUND: Providing specific treatment based on symptom response for people with low back pain (LBP) and a directional preference (DP) is a widely used treatment approach. The efficacy of treatment using the principles of directional preference management (DPM) for LBP is unclear. OBJECTIVE: The purpose of this study was to determine the efficacy of treatment using the principles of DPM for people with LBP and a DP. METHODS: Computer databases were searched for randomized controlled trials (RCTs) published in English up to January 2010. Only RCTs investigating DPM for people with LBP and a DP were included. Outcomes for pain, back specific function, and work participation were extracted. RESULTS: Six RCTs were included in this review. Five were considered high quality. Clinical heterogeneity of the included trials prevented meta-analysis. GRADE quality assessment revealed mixed results; however, moderate evidence was identified that DPM was significantly more effective than a number of comparison treatments for pain, function, and work participation at short-term, intermediate-term, and long term follow-ups. No trials found that DPM was significantly less effective than comparison treatments. CONCLUSIONS: Although this systematic review showed mixed results, some evidence was found supporting the effectiveness of DPM when applied to participants with a DP, particularly at short-term and intermediate-term follow-ups. Further high-quality RCTs are warranted to evaluate the effect of DPM applied to people with LBP and a DP. PMID- 22247408 TI - An in vitro comparison of two silver-containing antimicrobial wound dressings . AB - Preclinical studies have shown that release of silver by different wound dressings varies. The purpose of this in vitro study was to compare the antimicrobial activity of silver alginate (SA) and silver carboxymethylcellulose (SCM) dressings. An- timicrobial activity was tested using nine bacterial strains with log10 reduction and corrected zone of inhibition (CZOI) as- says. Antimicrobial effect was visualized using confocal microscopy (CLSM). Log10 reduction was comparable between both dressings for Staphylococcus aureus NCIMB 9518, Candida albicans ATCC 90028, Finegoldia magna NCTC 11804T, and Pseudomonas aeruginosa NCTC 10662. Log10 reduction was higher for SCM than SA dressing exposed Escherichia coli (P = 0.035) and P. aeruginosa ATCC 15692 (P = 0.032), and lower for SCM than SA dressing-exposed Streptococcus pyogenes (P = 0.007), Peptoniphilus asaccharolyticus (P = 0.045), and S. aureus NCTC 8325 (P = 0.012). Both dressings were equivalent against four strains (5 to 8 days' activity) in the CZOI assay. SA dressing silver activity lasted >24 hours longer than SCM activity when exposed to C. albicans (9 days' activity), E. coli (7 days' activity), F. magna (5 days' activity), and P. asaccharolyticus (5 days' activity), whereas the SMC exhibited greater persistence against S. pyogenes (13 days' activity). CLSM showed complete kill of S. aureus after 20 hours for both dressings. The results of this study confirm the broad-spectrum, in vitro activity of some dressings containing ionic silver. The in vitro antimicrobial efficacy of both wound dressings was comparable, but clinical studies comparing the efficacy and effectiveness of silver-containing dressings to nonionic silver containing dressings are needed. PMID- 22247409 TI - Caring for the patient with a fecal or urinary diversion in palliative and hospice settings: a literature review. AB - The number of people requiring palliative or hospice care who have a fecal or urinary diversion is increasing, but the literature about the number of persons with a stoma receiving end-of-life care, or research to help guide that care, is very limited. A broader review of the literature and clinical experience indicate that several progressive changes will affect the ability of persons with a stoma to provide self-care, including motor, sensor, vision, and cognitive deficits. It is important for the wound ostomy continence nurse (WOCN) to anticipate these changes and take steps to address them. The lat- ter may include simplifying the equipment or accessories used and identifying and teaching caregivers how to manage the stoma or empty a continent diversion or neobladder. A thorough assessment and stoma care adjustment also are needed when peristomal complications such as a change in the abdominal plane, mucocutaneous separation, or caput medusa are observed. Medication absorption and its effect on fluid and electrolyte balances must be considered at all times, especially in persons with an ileostomy, and the elimination side effects of commonly used medications in the palliative and hospice care environment must be monitored and addressed. The Advanced Practice WOCN with knowledge about end-of-life care can help prevent complications and improve patient quality of life. Research is needed to increase understanding about the scope of these problems and best practices to address them and to understand the experience of patients with a stoma at end-of-life. PMID- 22247410 TI - Postnatally diagnosed neonatal lupus. PMID- 22247412 TI - Postnatally acquired cytomegalovirus infection in preterm infants: a prospective study on risk factors and cranial ultrasound findings. AB - OBJECTIVE: To study risk factors and cranial ultrasound (cUS) findings in a large cohort of preterm infants, admitted to a neonatal intensive care unit and diagnosed with postnatally acquired cytomegalovirus (CMV) infection. STUDY DESIGN: This prospective, observational study was performed from April 2007 until June 2009 among 315 infants born <32 weeks of gestation. Postnatal CMV infection was diagnosed by CMV PCR on urine collected at term-equivalent age. In CMV positive infants, congenital infection was excluded. The authors compared the clinical and demographic data, feeding pattern and cUS results of infected and non-infected patients. Logistic regression analysis was performed. RESULTS: In 39 of 315 infants, the diagnosis of postnatal CMV infection has been made. The majority of CMV-infected infants (33/39.85%) did not develop any symptoms of CMV infection. The most important, independent risk factors of postnatal CMV infection were non-native Dutch maternal origin (OR 9.6 (95% CI 4.3 to 21.5)) and breast milk (OR 13.2 (95% CI 1.7 to 104.5)). The risk of infection significantly increased in infants with lower gestational age (GA) (OR 0.7 (95% CI 0.5 to 0.9)). Lenticulostriate vasculopathy (LSV) was significantly more often present in infants with CMV infection (OR 4.1 (95% CI 1.9 to 8.8)). CONCLUSIONS: Postnatal CMV infection is an asymptomatic infection among preterm infants. Infants with lower GA are at greatest risk of postnatal CMV infection, especially when fed with fresh breast milk from their non-native Dutch mother. LSV not present at birth but confirmed at term-equivalent age can suggest a postnatal CMV infection. PMID- 22247413 TI - Geographical disparities of infant mortality in rural China. AB - OBJECTIVE: The purpose of the study was to investigate the trends and causes of regional disparities of infant mortality rate (IMR) in rural China from 1996 to 2008. DESIGN: A population-based, longitudinal study. SETTING: The national child mortality surveillance network. POPULATION: Population of the 79 surveillance counties. MAIN OUTCOME MEASURE: IMR, leading causes of infant death and the RR of IMR. RESULTS: The IMR in coastal, inland and remote regions declined by 72.4%, 62.9% and 58.2%, respectively, from 1996 to 2008. Compared with the coastal region, the RR of IMR were 1.7 (95% CI 1.6 to 1.9), 1.9 (95% CI 1.7 to 2.0) and 1.8 (95% CI 1.6 to 2.0) for inland region and 2.6 (95% CI 2.4 to 2.7), 3.2 (95% CI 3.0 to 3.5) and 3.1 (95% CI 2.7 to 3.4) for the remote region during 1996 2000, 2001-2005 and 2006-2008, respectively. The regional disparities existed for both male and female IMRs. The postneonatal mortality showed the highest regional disparities. Pneumonia, birth asphyxia, prematurity/low birth weight, injuries and diarrhoea were the main contributors to the regional disparities. There were significantly more infants who did not seek healthcare services before death in the remote region relative to the inland and coastal regions. CONCLUSION: The results indicated persistent existence of regional disparities in IMR in rural China. It is worth noting that regional disparities in IMR increased in the remote and coastal regions during 2001-2005 in rural China. These disparities remained unchanged during 2006-2008. The results indicate that strategies to reduce mortality caused by pneumonia, birth asphyxia and diarrhoea are keys to reducing IMR. PMID- 22247414 TI - Fetiform sacrococcygeal teratoma. PMID- 22247415 TI - Trends in the incidence of retinopathy of prematurity in Lothian, south-east Scotland, from 1990 to 2009. PMID- 22247416 TI - Visible thyroid ectopia. PMID- 22247417 TI - Prevention of preterm births: are we looking in the wrong place? The case for primary prevention. PMID- 22247418 TI - Workload and costs associated with providing a neonatal surgery service. AB - AIM: To identify the workload related to provision of a neonatal surgical service in a UK neonatal network in order to inform local and national service commissioning. METHOD: Data relating to neonatal surgical admissions to a level 3 perinatal centre serving a network with 36,000 births per year collected prospectively over a 5-year period were analysed to identify annual activity. Daily dependency was assessed prospectively over a 6-month period and service costs calculated using existing local tariffs. Admissions from outside the network were excluded from analysis, and allowance was made for refused network admissions. RESULTS: On average 140 admissions required 2137 cot-days per year. At 80% occupancy, the service requires seven neonatal cots suggesting that there is a national requirement for one neonatal surgical cot per 5000 births. Intensive care, high care (HC) and special care accounted for 37%, 46% and 17% of cot-days, respectively. This equates to an annual service cost of L2m, about L250,000 per 5000 births. CONCLUSIONS: This assessment of the facilities and costs required to provide a neonatal surgical service in a level 3 perinatal centre in the UK may be used to inform network and national commissioning. PMID- 22247419 TI - Treatment experience, burden, and unmet needs (TRIBUNE) in multiple sclerosis: the costs and utilities of MS patients in Canada. AB - BACKGROUND: Multiple sclerosis (MS) is the most common neurological disease among young adults in Canada, but few studies to date have measured the burden imposed by MS on Canadian society. OBJECTIVES: To estimate the costs and quality of life of MS patients in Canada, while focusing on the burden of relapses and increasing disease severity. METHODS: MS patients in Canada (N=241) completed a web-based questionnaire which captured information on demographics, disease characteristics, severity (Expanded Disability Status Scale [EDSS]), comorbidities, relapses, as well as resource consumption and quality of life associated with MS. RESULTS: Most patients (74%) reported treatment with disease modifying therapies (DMTs). 54% of patients with the relapsing-remitting form of the disease with an EDSS score <= 5 had experienced at least one relapse in the past year. The mean cost per patient per year increased with worsening disability, and was estimated at Can $30,836 for patients with mild disability (EDSS score 0-3), Can $46,622 for patients with moderate disability (EDSS 4-6.5), and Can $77,981 for patients with severe disability due to MS (EDSS score 7-9). The excess costs of relapsing-remitting MS patients with EDSS score <= 5 that could be attributable to relapse(s) were estimated at Can $10,512. More severe disease and experiencing a relapse were also associated with poorer quality of life of MS patients. CONCLUSIONS: Costs of MS patients are higher today than shown in previous studies. Disease progression and relapses are associated with increased economic and quality of life burden. Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and may help to reduce the societal burden of MS. PMID- 22247421 TI - Effectiveness of personalized and interactive health risk calculators: a randomized trial. AB - BACKGROUND: Risk calculators are popular websites that provide individualized disease risk assessments to the public. Little is known about their effect on risk perceptions and health behavior. OBJECTIVE: This study sought to test whether risk calculator features-namely, personalized estimates of one's disease risk and feedback about the effects of risk-mitigating behaviors-improve risk perceptions and motivate healthy behavior. DESIGN: A web-based experimental study using simple randomization was conducted to compare the effects of 3 prediabetes risk communication websites. Setting The study was conducted in the context of ongoing health promotion activities sponsored by a university's human resources office. Patients Participants were adult university employees. Intervention The control website presented nonindividualized risk information. The personalized noninteractive website presented individualized risk calculations. The personalized interactive website presented individualized risk calculations and feedback about the effects of hypothetical risk-mitigating behaviors. Measurements Pre- and postintervention risk perceptions were measured in absolute and relative terms. Health behavior was measured by assessing participant interest in follow-up preventive health services. RESULTS: On average, risk perceptions decreased by 2%. There was no general effect of personalization or interactivity in aligning subjective risk perceptions with objective risk calculations or in increasing healthy behaviors. However, participants who previously overestimated their risk reduced their perceptions by 16%. This was a significantly larger change than the 2% increase by participants who underestimated their risk. Limitations Results may not generalize to different populations, different diseases, or longer-term outcomes. CONCLUSIONS: Compared to nonpersonalized information, individualized risk calculators had little positive effect on prediabetes risk perception accuracy or health behavior. Risk perception accuracy was improved in people who receive relatively "good news" about risk rather than "bad news." PMID- 22247420 TI - Impact of literacy and numeracy on motivation for behavior change after diabetes genetic risk testing. AB - BACKGROUND: Type 2 diabetes genetic risk testing might motivate at-risk patients to adopt diabetes prevention behaviors. However, the influence of literacy and numeracy on patient response to diabetes genetic risk is unknown. OBJECTIVE: The authors investigated the association of health literacy, genetic literacy, and health numeracy with patient responses to diabetes genetic risk. DESIGN: and Measurements Overweight patients at high phenotypic risk for type 2 diabetes were recruited for a clinical trial of diabetes genetic risk testing. At baseline, participants predicted how their motivation for lifestyle modification to prevent diabetes might change in response to hypothetical scenarios of receiving "high" and "low" genetic risk results. Responses were analyzed according to participants' health literacy, genetic literacy, and health numeracy. RESULTS: Two-thirds (67%) of participants (n = 175) reported very high motivation to prevent diabetes. Despite high health literacy (92% at high school level), many participants had limited health numeracy (30%) and genetic literacy (38%). Almost all (98%) reported that high-risk genetic results would increase their motivation for lifestyle modification. In contrast, response to low-risk genetic results varied. Higher levels of health literacy (P = 0.04), genetic literacy (P = 0.02), and health numeracy (P = 0.02) were associated with an anticipated decrease in motivation for lifestyle modification in response to low-risk results. CONCLUSIONS: While patients reported that high-risk genetic results would motivate them to adopt healthy lifestyle changes, response to low-risk results varied by patient numeracy and literacy. However, anticipated responses may not correlate with true behavior change. If future research justifies the clinical use of genetic testing to motivate behavior change, it may be important to assess how patient characteristics modify that motivational effect. PMID- 22247422 TI - How much should we pay for a new HIV diagnosis? A mathematical model of HIV screening in US clinical settings. AB - OBJECTIVE: To develop a model to assist clinical setting decision makers in determining how much they can spend on human immunodeficiency virus (HIV) screening and still be cost-effective. DESIGN: The authors developed a simple mathematical model relating the program cost per new HIV diagnosis to the cost per HIV infection averted and the cost per quality-adjusted life year (QALY) saved by screening. They estimated outcomes based on behavioral changes associated with awareness of HIV infection and applied the model to US sexually transmitted disease clinics. METHODS: The authors based the cost per new HIV diagnosis (2009 US dollars) on the costs of testing and the proportion of persons who tested positive. Infections averted were calculated from the reduction in annual transmission rates between persons aware and unaware of their infections. The authors defined program costs from the sexually transmitted disease clinic perspective and treatment costs and QALYs saved from the societal perspective. They undertook numerous sensitivity analyses to determine the robustness of the base case results. RESULTS: In the base case, the cost per new HIV diagnosis was $2528, the cost per infection averted was $40,516, and the cost per QALY saved was less than zero, or cost-saving. Given the model inputs, the cost per new diagnosis could increase to $22,909 to reach the cost-saving threshold and to $63,053 for the cost-effectiveness threshold. All sensitivity analyses showed that the cost-effectiveness results were consistent for extensive variation in the values of model inputs. CONCLUSIONS: HIV screening in a clinical setting is cost-effective for a wide range of testing costs, variations in positivity rates, reductions in HIV transmissions, and variation in the receipt of test results. PMID- 22247423 TI - Perceptions of shared decision making and decision aids among rural primary care clinicians. AB - BACKGROUND: Shared decision making (SDM) and decision aids (DAs) increase patients' involvement in health care decisions and enhance satisfaction with their choices. Studies of SDM and DAs have primarily occurred in academic centers and large health systems, but most primary care is delivered in smaller practices, and over 20% of Americans live in rural areas, where poverty, disease prevalence, and limited access to care may increase the need for SDM and DAs. OBJECTIVE: To explore perceptions and practices of rural primary care clinicians regarding SDM and DAs. DESIGN: Cross-sectional survey. Setting and Participants Primary care clinicians affiliated with the Oregon Rural Practice-based Research Network. RESULTS: Surveys were returned by 181 of 231 eligible participants (78%); 174 could be analyzed. Two-thirds of participants were physicians, 84% practiced family medicine, and 55% were male. Sixty-five percent of respondents were unfamiliar with the term shared decision making, but following definition, 97% reported that they found the approach useful for conditions with multiple treatment options. Over 90% of clinicians perceived helping patients make decisions regarding chronic pain and health behavior change as moderate/hard in difficulty. Although 69% of respondents preferred that patients play an equal role in making decisions, they estimate that this happens only 35% of the time. Time was reported as the largest barrier to engaging in SDM (63%). Respondents were receptive to using DAs to facilitate SDM in print- (95%) or web-based formats (72%), and topic preference varied by clinician specialty and decision difficulty. CONCLUSIONS: Rural clinicians recognized the value of SDM and were receptive to using DAs in multiple formats. Integration of DAs to facilitate SDM in routine patient care may require addressing practice operation and reimbursement. PMID- 22247424 TI - A shortcut to mean-based time tradeoff tariffs for the EQ-5D? AB - BACKGROUND: EQ-5D valuation studies are usually performed using the time tradeoff (TTO) method, which is costly and time consuming. We focused on 2 properties that particularly characterize TTO: the initial choice task categorizing health states as better than death (BTD), worse than death (WTD), or equal to death (ETD), and unwillingness to trade (UTT) lifetime to improve health. The aim of this study was to estimate the value of the information to be gained from continuing the conventional TTO tasks beyond the initial question and the extent to which mean based EQ-5D tariff values could be predicted through a simplified method of categorizing health states into BTD, WTD, ETD, and UTT. METHODS: We used data from the UK EQ-5D valuation study (n = 2997). We designed an abbreviated system with only 4 values (collapsed TTO [cTTO]) based on the 4 response categories and assigned values as follows: WTD = -.5, ETD = 0, BTD = .5, and UTT = 1. Based on the mean cTTO scores for the valued health states, we created a regression-based cTTO tariff, which was compared with the conventional (full) TTO tariff (fTTO) by regressing 1) the fTTO means on cTTO means and 2) the fTTO tariff on the cTTO tariff. RESULTS: WTD values were unrelated to health state severity. Correlation between the means of fTTO and means of cTTO was >.999, and tariff values from fTTO correlated with tariff values from cTTO at r > .999. CONCLUSIONS: Once respondents have classified health states as UTT, BTD, ETD, or WTD, the TTO procedure adds little further information to the tariff values. The WTD task fails to discriminate between good and bad health states. TTO valuation could likely be simplified using cTTO. PMID- 22247425 TI - Clinical use of meconium fatty acid ethyl esters for identifying children at risk for alcohol-related disabilities: the first reported case. AB - Fatty acid ethyl esters (FAEEs) in meconium are validated biomarkers of heavy fetal alcohol exposure that may potentially be used clinically for identifying children at risk for alcohol-related disabilities. However, until now, FAEEs have been largely used anonymously in epidemiological studies, and by child protection authorities in need for verification of heavy alcohol use in pregnancy. Here we describe the first case of a neonate identified as part of a research study on a pilot neonatal screening program for prenatal alcohol exposure. The neonate's meconium tested high for FAEEs (52 nmol/g; positive cut-off >= 2 nmol/g), which prompted active follow-up of the infant's development, identifying early neurocognitive problems and allowing initiation of a remedial program. PMID- 22247427 TI - Alcohol-induced behavioural problems in fetal alcohol spectrum disorders versus confounding behavioural problems. AB - Prenatal alcohol exposure is strongly associated with disruptive behaviour in childhood and antisocial behaviour later in life. There are numerous confounding risk factors in the lives of alcohol-abusing mothers that may contribute to the behaviour problems seen in their children, rather than direct brain injury by alcohol. In fact, many of these additional environmental and genetic risk factors for childhood behaviour problems co-occur with prenatal alcohol exposure and affect the same child, creating a confluence of risk. As a result, one cannot with any certainty attribute behaviour problems in an individual child to prenatal alcohol exposure. This has important clinical and legal implications. PMID- 22247428 TI - Dynamic evolution of telomeric sequences in the green algal order Chlamydomonadales. AB - Telomeres, which form the protective ends of eukaryotic chromosomes, are a ubiquitous and conserved structure of eukaryotic genomes but the basic structural unit of most telomeres, a repeated minisatellite motif with the general consensus sequence T(n)A(m)G(o), may vary between eukaryotic groups. Previous studies on several species of green algae revealed that this group exhibits at least two types of telomeric sequences, a presumably ancestral type shared with land plants (Arabidopsis type, TTTAGGG) and conserved in, for example, Ostreococcus and Chlorella species, and a novel type (Chlamydomonas type, TTTTAGGG) identified in Chlamydomonas reinhardtii. We have employed several methodical approaches to survey the diversity of telomeric sequences in a phylogenetically wide array of green algal species, focusing on the order Chlamydomonadales. Our results support the view that the Arabidopsis-type telomeric sequence is ancestral for green algae and has been conserved in most lineages, including Mamiellophyceae, Chlorodendrophyceae, Trebouxiophyceae, Sphaeropleales, and most Chlamydomonadales. However, within the Chlamydomonadales, at least two independent evolutionary changes to the Chlamydomonas type occurred, specifically in a subgroup of the Reinhardtinia clade (including C. reinhardtii and Volvox carteri) and in the Chloromonadinia clade. Furthermore, a complex structure of telomeric repeats, including a mix of the ancestral Arabidopsis-type motifs and derived motifs identical to the human-type telomeric repeats (TTAGGG), was found in the chlamydomonadalean clades Dunaliellinia and Stephanosphaeria. Our results indicate that telomere evolution in green algae, particularly in the order Chlamydomonadales, is far more dynamic and complex than thought before. General implications of our findings for the mode of telomere evolution are discussed. PMID- 22247429 TI - Recent acceleration of plastid sequence and structural evolution coincides with extreme mitochondrial divergence in the angiosperm genus Silene. AB - The angiosperm genus Silene exhibits some of the most extreme and rapid divergence ever identified in mitochondrial genome architecture and nucleotide substitution rates. These patterns have been considered mitochondrial specific based on the absence of correlated changes in the small number of available nuclear and plastid gene sequences. To better assess the relationship between mitochondrial and plastid evolution, we sequenced the plastid genomes from four Silene species with fully sequenced mitochondrial genomes. We found that two species with fast-evolving mitochondrial genomes, S. noctiflora and S. conica, also exhibit accelerated rates of sequence and structural evolution in their plastid genomes. The nature of these changes, however, is markedly different from those in the mitochondrial genome. For example, in contrast to the mitochondrial pattern, which appears to be genome wide and mutationally driven, the plastid substitution rate accelerations are restricted to a subset of genes and preferentially affect nonsynonymous sites, indicating that altered selection pressures are acting on specific plastid-encoded functions in these species. Indeed, some plastid genes in S. noctiflora and S. conica show strong evidence of positive selection. In contrast, two species with more slowly evolving mitochondrial genomes, S. latifolia and S. vulgaris, have correspondingly low rates of nucleotide substitution in plastid genes as well as a plastid genome structure that has remained essentially unchanged since the origin of angiosperms. These results raise the possibility that common evolutionary forces could be shaping the extreme but distinct patterns of divergence in both organelle genomes within this genus. PMID- 22247430 TI - The TAGteam motif facilitates binding of 21 sequence-specific transcription factors in the Drosophila embryo. AB - Highly overlapping patterns of genome-wide binding of many distinct transcription factors have been observed in worms, insects, and mammals, but the origins and consequences of this overlapping binding remain unclear. While analyzing chromatin immunoprecipitation data sets from 21 sequence-specific transcription factors active in the Drosophila embryo, we found that binding of all factors exhibits a dose-dependent relationship with "TAGteam" sequence motifs bound by the zinc finger protein Vielfaltig, also known as Zelda, a recently discovered activator of the zygotic genome. TAGteam motifs are present and well conserved in highly bound regions, and are associated with transcription factor binding even in the absence of canonical recognition motifs for these factors. Furthermore, levels of binding in promoters and enhancers of zygotically transcribed genes are correlated with RNA polymerase II occupancy and gene expression levels. Our results suggest that Vielfaltig acts as a master regulator of early development by facilitating the genome-wide establishment of overlapping patterns of binding of diverse transcription factors that drive global gene expression. PMID- 22247440 TI - Meeting the challenges of an emerging pathogen: the Henry Schueler 41&9 Foundation International Forum on Mucormycosis. AB - Invasive mucormycosis comprises a group of uncommon but emerging life-threatening pulmonary, sinal, rhinocerebral, and disseminated infections, which cause debilitating morbidity and severe mortality in our most vulnerable pediatric and adult immunocompromised patients. While important advances are being achieved in understanding the epidemiology, molecular taxonomy, pathogenesis, pharmacology, host defenses, and microbiology of these infections, there are critical needs for improving these approaches for diagnosis, treatment, and prevention. This supplement is dedicated to the memory and courage of Hank Schueler, who fought valiantly against this infection. It provides a comprehensive resource for current approaches to management of this infection and also reviews the key advances against invasive mucormycosis. PMID- 22247431 TI - Translation of two evidence-based programs for training families to improve care of persons with dementia. AB - The need for evidence-based non-pharmacological community programs to improve care of older adults with dementia is self-evident, considering the sheer numbers of affected individuals; the emotional, physical, and financial toll on affected individuals and their caregivers; the impact on our health care system; and the growing availability of evidence regarding the potential for psychosocial interventions to enhance care and decrease costs. To address this need, the Administration on Aging has begun funding translation of evidence-based programs into community settings. Two programs, Reducing Disability in Alzheimer's Disease and STAR-Community Consultants (STAR-C), were selected by the Ohio Department of Aging (in collaboration with the Alzheimer's Association Chapters in Ohio) and the Oregon Department of Health Services (in partnership with Area Agencies on Aging and the Oregon Chapter of the Alzheimer's Association) to be implemented by their staff. Both programs are designed to improve care, enhance life quality, and reduce behavioral problems of persons with dementia and have demonstrated efficacy via randomized controlled trials. This article addresses the developmental and ongoing challenges encountered in the translation of these programs to inform other community-based organizations considering the translation of evidence-based programs and to assist researchers in making their work more germane to their community colleagues. PMID- 22247441 TI - Pathogenesis of mucormycosis. AB - Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat mucormycosis are urgently needed. Understanding the pathogenesis of mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified. PMID- 22247442 TI - Epidemiology and clinical manifestations of mucormycosis. AB - Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited. Based on anatomic localization, mucormycosis can be classified as one of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. The underlying conditions can influence clinical presentation and outcome. This review describes the emerging epidemiology and the clinical manifestations of mucormycosis. PMID- 22247444 TI - Healthcare-associated mucormycosis. AB - Mucormycosis is a severe emerging invasive fungal infection that occurs as a consequence of environmental exposure. We exhaustively reviewed all the cases of mucormycosis (European Organisation for Research and Treatment of Cancer/Mycoses Study Group 2008 criteria) attributed to healthcare procedures that occurred between 1970 and 2008. A total of 169 cases were studied (29% children, 61% male). Major underlying diseases were solid organ transplantation (24%), diabetes mellitus (22%), and severe prematurity (21%). Skin was the most common localization (57%), followed by gastrointestinal tract (15%). Culture results were available in 75% (92% positive), and results of histological examination were positive in 95%. Rhizopus was the most frequent genus (43%). Infection portal of entry included surgery and presence of medical devices such as catheters or adhesive tape. Outbreaks and clusters were related to adhesive bandages (19 cases), wooden tongue depressors (n = 5), ostomy bags (n = 2), water circuitry damage (n = 2), and adjacent building construction (n = 5). Thorough investigations are mandatory to identify healthcare-associated mucormycosis, notably in neonatology, hematological, and transplantation units. PMID- 22247445 TI - Into the winter whiteness. AB - A father recounts a transformative journey of love, loss, and learning as his son developed and eventually died of a fungal infection that occurred during a period of immunocompromise after a bone marrow transplantation to treat hypodiploid leukemia. He then thanks the many physicians, researchers, family members, and friends who came together to memorialize his son and create knowledge, hope, and wisdom, so that others will not have to suffer a similar journey. PMID- 22247446 TI - Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis). AB - Early diagnosis of invasive mucormycosis is important for timely therapeutic intervention, improved survival, and reduced morbidity. Given the importance of an accurate and rapid diagnosis of invasive mucormycosis to guide the timely initiation of amphotericin B and possible surgical intervention, a coordinated multidisciplinary approach of clinical assessment, diagnostic imaging, and laboratory assessment is necessary. Laboratory assessment for mucormycosis includes the conventional methods of direct examination and culture of tissue, respiratory secretions, bronchoalveolar lavage fluid, and other fluids. However, because conventional diagnostic tools are limited in their sensitivity, advanced molecular amplification systems, antigen detection assays, proteomic profiles, and metabolite detection may complement existing approaches to improve the rate of early diagnosis of invasive mucormycosis. PMID- 22247447 TI - Host defenses against zygomycetes. AB - Mucormycosis is a devastating disease and can occur in patients with a variety of risk factors, the most important of which are immunosuppression, anatomic barrier breakdown, iron overload, and hyperglycemia/acidosis. Similarly to what occurs with Aspergillus, the host stimulates an innate immune response against the challenging sporangiospores and invading hyphae of Zygomycetes. This article discusses the host defense to different Zygomycetes, its augmentation, and its subsequent impact on the outcome of mucormycosis. PMID- 22247448 TI - How does antifungal pharmacology differ for mucormycosis versus aspergillosis? AB - Over the last decade, advances in diagnostic systems and the introduction of new antifungal agents have significantly improved outcomes in immunocompromised patients who develop invasive aspergillosis. However, mortality rates remain relatively unchanged for less common, but highly aggressive, mold infections such as mucormycosis. Recent genome sequencing of Rhizopus oryzae revealed evidence of a whole-genome duplication event during the evolution of this pathogen. Consequently, R. oryzae has a 2- to 10-fold enrichment in gene families associated with ergosterol and cell wall biosynthesis, cell growth, iron uptake, and known fungal virulence factors compared with sequenced Aspergillus fumigatus strains. This genetic plasticity may explain the remarkable capability of this pathogen for rapid growth in hostile environments, such as the inflammatory milieu, as well as its relative resistance to multiple antifungal classes. Herein, we examine how pharmacological aspects of treating mucormycosis may differ from those of the more commonly encountered invasive aspergillosis. PMID- 22247443 TI - A global analysis of mucormycosis in France: the RetroZygo Study (2005-2007). AB - BACKGROUND: Mucormycosis is a deadly invasive fungal infection whose characteristics are only partially understood. METHODS: Data on mucormycosis obtained in France between 2005 and 2007 from 2 notification systems were merged. The 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group definition criteria were applied and risk factors for death were analyzed by hazard ratios (HRs) calculated from the Cox proportional hazards regression model. RESULTS: A total of 101 cases (60 proven, 41 probable), mostly in men (58%) >50 years (mean age, 50.7 +/- 19.9) were recorded. Hematological malignancies represented 50% (median time for occurrence, 8.8 months after disease onset), diabetes 23%, and trauma 18% of cases. Sites of infection were lungs (28%; 79% in hematology patients), rhinocerebral (25%; 64% in diabetic patients), skin (20%), and disseminated (18%). Median time between first symptoms and diagnosis was 2 weeks. The main fungal species were Rhizopus oryzae (32%) and Lichtheimia species (29%). In cases where the causative species was identified, R. oryzae was present in 85% of rhinocerebral forms compared with only 17% of nonrhinocerebral forms (P < .001). Treatment consisted of surgery in 59% and antifungals in 87% of cases (liposomal amphotericin B in 61%). Ninety-day survival was 56%; it was reduced in cases of dissemination compared with rhinocerebral (HR, 5.38 [2.0-14.1]; P < .001), pulmonary (HR, 2.2 [1.0-4.7]; P = .04), or skin localization (HR, 5.73 [1.9-17.5]; P = .002); survival was reduced in cases of hematological malignancies compared with diabetes mellitus (HR, 2.3 [1.0-5.2]; P < .05) or trauma (HR, 6.9 [1.6-28.6], P = .008) and if >=2 underlying conditions (HR, 5.9 [1.8-19.0]; P = .004). Mucormycosis localization remained the only independent factor associated with survival. CONCLUSIONS: This 3-year study performed in one country shows the diverse clinical presentation of mucormycosis with a high prevalence of primary skin infection following trauma and a prognosis significantly influenced by localization. PMID- 22247449 TI - Combination therapy for mucormycosis: why, what, and how? AB - The high mortality rate of mucormycosis with currently available monotherapy, particularly in hematology patients, has stimulated interest in studying novel combinations of antifungal agents to determine whether superior outcomes might be achieved. Combination lipid polyene-echinocandin therapy is the most promising of such regimens based on safety profile, the availability of parenteral formulations of echinocandins, their synergy in murine models of mucormycosis, and observational clinical data that are concordant. Other options include combination lipid polyene plus deferasirox or posaconazole therapy. Definitive, randomized, placebo-controlled phase III clinical trials are needed to determine whether combination therapy with any of these options is superior to monotherapy. Until such studies are conducted, clinicians will continue to be placed in the unacceptable position of not knowing if and when to administer combination therapy. Such a state of confusion may lead to undertreatment if combination therapy is indeed superior but is not used and, conversely, may lead to unacceptable toxicity and cost to patients if combination therapy is not superior but is used. It is critical that sponsors step forward with funding to conduct these clinical trials to determine whether outcomes from these devastating infections can be improved. PMID- 22247450 TI - Future directions in mucormycosis research. AB - Mucormycosis has emerged as an important opportunistic infection, especially in severely immunosuppressed hosts. The evolving epidemiology, immunopathogenesis, molecular virulence studies, early diagnosis, and pitfalls in designing clinical studies of mucormycosis are discussed in this article. PMID- 22247451 TI - Taxonomy of fungi causing mucormycosis and entomophthoramycosis (zygomycosis) and nomenclature of the disease: molecular mycologic perspectives. AB - Molecular phylogenetic analysis confirmed the phylum Zygomycota to be polyphyletic, and the taxa conventionally classified in Zygomycota are now distributed among the new phylum Glomeromycota and 4 subphyla incertae sedis (uncertain placement). Because the nomenclature of the disease zygomycosis was based on the phylum Zygomycota (Zygomycetes) in which the etiologic agents had been classified, the new classification profoundly affects the name of the disease. Zygomycosis was originally described as a convenient and inclusive name for 2 clinicopathologically different diseases, mucormycosis caused by members of Mucorales and entomophthoramycosis caused by species in the order Entomophthorales of Zygomycota. Without revision of original definition, the name "zygomycosis," however, has more often been used as a synonym only for mucormycosis. This article reviews the progress and changes in taxonomy and nomenclature of Zygomycota and the disease zygomycosis. The article also reiterates the reasons why the classic names "mucormycosis" and "entomophthoramycosis" are more appropriate than "zygomycosis." PMID- 22247452 TI - Type 1 diabetes affects topoisomerase I activity and GlcNAcylation in rat organs: kidney, liver and pancreas. AB - Chronic hyperglycemia leads to the development of diabetes-induced organ complications, through changes in gene expression and protein function. We previously showed that in cell lines, topoisomerase I (topo I) is modified by O GlcNAcylation, which affects its DNA relaxation activity. Since topo I participates in gene expression processes, we assumed that high glucose levels will affect its regulation and activity. Here we examined the effect of hyperglycemia on the regulation, GlcNAcylation and activity of topo I, in various internal rat organs that were subjected to diabetes-induced complications. Type 1 diabetes was induced in female rats by Streptozotocin injection. Topo I activity in nuclear protein extracts derived from diabetic and nondiabetic rat organs and topo I mRNA level were examined. Topo I and O-linked beta-N-acetylglucosamine (O GlcNAc) transferase proteins and their O-GlcNAcylation were determined by western blot and immunoprecipitation assays. We show that topo I activity and enzyme protein level decreased in various tissues derived from the diabetic animals, whereas the enzyme mRNA level was not altered. Topo I protein was modified in vivo by O-GlcNAc, and O-GlcNAc transferase was coprecipitated with topo I protein, suggesting a possible interaction between both enzymes. This study demonstrates, for the first time, that topo I activity is regulated by high glucose levels, as a result of the diabetic state and is modified in vivo by O GlcNAcylation, suggesting that topo I, an essential enzyme for gene expression, is involved in cellular processes which may lead to the pathogenesis of diabetic complications. PMID- 22247453 TI - Mobilizing homeless youth for HIV prevention: a social network analysis of the acceptability of a face-to-face and online social networking intervention. AB - The objective of the study is to use social network analysis to examine the acceptability of a youth-led, hybrid face-to-face and online social networking HIV prevention program for homeless youth.Seven peer leaders (PLs) engaged face to-face homeless youth (F2F) in the creation of digital media projects (e.g. You Tube videos). PL and F2F recruited online youth (OY) to participate in MySpace and Facebook communities where digital media was disseminated and discussed. The resulting social networks were assessed with respect to size, growth, density, relative centrality of positions and homophily of ties. Seven PL, 53 F2F and 103 OY created two large networks. After the first 50 F2F youth participated, online networks entered a rapid growth phase. OY were among the most central youth in these networks. Younger aged persons and females were disproportionately connected to like youth. The program appears highly acceptable to homeless youth. Social network analysis revealed which PL were the most critical to the program and which types of participants (younger youth and females) may require additional outreach efforts in the future. PMID- 22247454 TI - Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34+ cells in NOD-SCID mice with acute ischemia-reperfusion injury. AB - PURPOSE: To determine long-term safety of intravitreal administration of good manufacturing practice (GMP)-grade human bone-marrow-derived CD34(+) cells in NOD SCID (nonobese diabetic-severe combined immunodeficiency) mice with acute retinal ischemia-reperfusion injury, a model for retinal vasculopathy. METHOD: Acute ischemia-reperfusion injury was induced in the right eye of adult NOD-SCID mice (n = 23) by transient elevation of intraocular pressure. Seven days later, 12 injured eyes and 5 normal contralateral eyes were injected each intravitreally with 5 * 10(4) CD34(+) cells isolated under GMP conditions from a healthy human donor bone marrow using an immunomagnetic cell isolation system. The remaining 11 injured eyes were not treated and served as controls. Mice were euthanized 1 day, 4 months, and 8 months later. Both eyes were enucleated and examined by immunohistochemical analysis and hematoxylin and eosin staining. Among mice followed for 8 months, electroretinography (ERG) was performed on both eyes before euthanization. All major organs were examined grossly and histologically after serial sectioning. RESULTS: Immunohistochemical staining 4 months after injection showed detectable CD34(+) cells in the retinal vasculature. ERG at 8 months after CD34(+) cell injection showed signals that were similar in untreated eyes. Histology of the enucleated eyes injected with CD34(+) cells showed no intraocular tumor or abnormal tissue growth after 8 months. Histologic analysis of all major organs showed no abnormal proliferation of human cells. CONCLUSIONS: Intravitreal administration of GMP-grade human bone-marrow-derived CD34(+) cells appears to be well tolerated long-term in eyes with acute retinal ischemic injury. A clinical trial will start to further explore this therapy. PMID- 22247455 TI - The association between glaucoma prevalence and supplementation with the oxidants calcium and iron. AB - PURPOSE: To investigate the relationship between supplementary consumption of the oxidants calcium and iron and the prevalence of glaucoma. METHODS: This cross sectional study included 3833 participants in the National Health and Nutrition Examination Survey (NHANES) for 2007 and 2008, >= 40 years of age, who reported a presence or absence of glaucoma. Participants were interviewed regarding the use of dietary supplements and antacids during the preceding 30-day period. Data pertaining to the supplementary intake of calcium and iron was aggregated and divided into quintiles. Information regarding the presence or absence of glaucoma and demographics, comorbidities, and health-related behavior was obtained via interview. RESULTS: Participants who consumed >= 800 mg/d of supplementary calcium or >= 18 mg/d of supplementary iron had significantly higher odds of having been diagnosed with glaucoma than did those who had not consumed supplementary calcium or iron, after adjustment for potential confounders (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.25-4.76 for calcium; OR 3.80, 95% CI 1.79-8.06 for iron). Concurrent consumption of both calcium and iron above these levels was associated with still greater odds of having been diagnosed with glaucoma (OR 7.24, 95% CI 2.42-21.62). A clear dose-response relationship between quintiles of supplementary calcium or iron intake and glaucoma prevalence was not found. CONCLUSIONS: These results suggest that there may be a threshold intake of iron and calcium above which there is an increased risk of development of glaucoma. Prospective longitudinal studies are needed, to assess whether oxidant intake is a risk factor for development and progression of glaucoma. PMID- 22247456 TI - Relevance of complement factor H-related 1 (CFHR1) genotypes in age-related macular degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) has a strong genetic component with a major locus at 1q31, including the complement factor H (CFH) gene. Detailed analyses of this locus have demonstrated the existence of one SNP haplotype block, carrying the CFH 402His allele, which confers increased risk for AMD, and two protective SNP haplotypes, one of them carrying a deletion of the CFHR1 and CFHR3 genes (DeltaCFHR3-CFHR1). The purpose of these studies was to evaluate the contribution of newly described CFHR1 alleles to the association of the 1q31 locus with AMD. METHODS: Two hundred fifty-nine patients and 191 age matched controls of Spanish origin were included in a transversal case-control study using multivariate logistic regression analysis and ROC (receiver operating characteristic) statistics to generate and test models predictive of the development of AMD. RESULTS: This study showed for the first time that a particular CFHR1 allotype, CFHR1*A, is strongly associated with AMD (odds ratio, 2.08; 95% confidence interval, 1.59-2.73; P<0.0001) and illustrate a peculiar genotype-phenotype correlation between the CFHR1 alleles and different diseases that may have important implications for understanding the pathophysiology of AMD. It also shows that CFHR1*A is in strong linkage disequilibrium with the CFH 402His allele, which provides additional candidate variants within the major risk haplotype at 1q31, promoting its association with AMD. Further, using the Spanish population as a model, the results showed that analysis of the CFHR1 genotypes provide sufficient information to delineate the individual risk of developing AMD. CONCLUSIONS: The results support a relevant role of CFHR1 in the pathogenesis of AMD. PMID- 22247457 TI - Diffusion tensor imaging correlates of visual impairment in multiple sclerosis and chronic optic neuritis. AB - PURPOSE: To compare white matter (WM) injuries associated with vision loss in multiple sclerosis (MS) and optic neuritis (ON). METHODS: Twenty-three patients with clinically definite relapsing-remitting MS and chronic unilateral ON and 14 neurologically healthy volunteers were monocularly tested with Sloan 100%, 2.5%, and 1.25% contrast visual acuity charts. Primary visual pathway and whole-brain WM injury were assessed with optical coherence tomography (OCT) and diffusion tensor imaging (DTI). OCT and DTI correlates of high- and low-contrast visual impairment were identified using correlation analyses. RESULTS: The MS patients displayed significantly reduced retinal nerve fiber layer (RNFL) thickness and altered optic nerve and radiation DTI measures compared with the controls. In the patients, 2.5% and 1.25% contrast letter acuity in the unaffected eye correlated significantly and independently with optic nerve and optic radiation DTI measures. Visual acuity in affected eyes did not correlate with optic nerve or optic radiation DTI measures, but did correlate with DTI measures in prefrontal and temporal brain regions that were shown to connect structurally to visual cortices. CONCLUSIONS: In unaffected eyes, visual impairment was associated with WM injury in the visual pathway. In contrast, irrecoverable visual impairment after ON was associated with injury to frontal WM, which potentially impairs the capacity for remapping visual processing. PMID- 22247459 TI - Myofibroblast differentiation modulates keratocyte crystallin protein expression, concentration, and cellular light scattering. AB - PURPOSE: The purpose of this study was to determine whether myofibroblast differentiation altered keratocyte crystallin protein concentration and increased cellular light scattering. METHODS: Serum-free cultured rabbit corneal keratocytes and TGFbeta (5 ng/mL) induced myofibroblasts were harvested and counted and protein/RNA extracted. Expression of myofibroblast and keratocyte markers was determined by real-time PCR and Western blot analysis. The cell volume of calcein AM-loaded keratocytes and myofibroblasts was determined by using nonlinear optical microscopy. Cellular light scattering of transformed myofibroblasts expressing human keratocyte crystallins was measured by reflectance confocal microscopy. RESULTS: Differentiated myofibroblasts showed a significant decrease in RNA levels for the keratocyte markers ALDH1A1, lumican, and keratocan and a significant increase in the myofibroblast marker alpha-smooth muscle actin. Volumetric and protein measurements showed that myofibroblast differentiation significantly increased cytoplasmic volume (293%; P < 0.001) and water-soluble and -insoluble protein content per cell (respectively, 442% and 431%; P < 0.002) compared to keratocytes. Western blot analysis showed that the level of ALDH1A1 protein per cell was similar between myofibroblasts and keratocytes, but was substantially reduced as a percentage of total water-soluble protein. Light scattering measurements showed that induced expression of corneal crystallins significantly decreased light scattering. CONCLUSIONS: These data suggest that myofibroblast differentiation leads to a marked increase in cell volume and dilution of corneal crystallins associated with an increase in cellular light scattering. PMID- 22247458 TI - Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials. AB - PURPOSE: To measure macular visual function in patients with unstable fixation, to define the photoreceptor source of this function, and to estimate its test retest repeatability as a prerequisite to clinical trials. METHODS: Patients (n = 38) with ABCA4-associated retinal degeneration (RD) or with retinitis pigmentosa (RP) were studied with retina-tracking microperimetry along the foveo-papillary profile between the fovea and the optic nerve head, and point-by-point test retest repeatability was estimated. A subset with foveal fixation was also studied with dark-adapted projection perimetry using monochromatic blue and red stimuli along the horizontal meridian. RESULTS: Macular function in ABCA4-RD patients transitioned from lower sensitivity at the parafovea to higher sensitivity in the perifovea. RP patients had the inverse pattern. Red-on-red microperimetric sensitivities successfully avoided ceiling effects and were highly correlated with absolute sensitivities. Point-by-point test-retest limits (95% confidence intervals) were +/-4.2 dB; repeatability was not related to mean sensitivity, eccentricity from the fovea, age, fixation location, or instability. Repeatability was also not related to the local slope of sensitivity and was unchanged in the parapapillary retina. CONCLUSIONS: Microperimetry allows reliable testing of macular function in RD patients without foveal fixation in longitudinal studies evaluating natural disease progression or efficacy of therapeutic trials. A single estimate of test-retest repeatability can be used to determine significant changes in visual function at individual retinal loci within diseased regions that are homogeneous and those that are heterogeneous and also in transition zones at high risk for disease progression. PMID- 22247460 TI - Relationships among multifocal electroretinogram amplitude, visual field sensitivity, and SD-OCT receptor layer thicknesses in patients with retinitis pigmentosa. AB - PURPOSE: To compare local functional measures, the multifocal electroretinogram (mfERG) and visual field sensitivity, with a local structural measure, spectral domain (SD) optical coherence tomography (OCT), of receptor damage in patients with retinitis pigmentosa (RP). METHODS: MfERGs, visual fields, and SD-OCT scans were obtained from 10 patients with RP, ranging in age from 23 to 59 years. Average amplitudes, average linear sensitivities, and average layer thicknesses were measured from within the central 3 degrees and from three concentric annuli located between 3 degrees and 8 degrees , 8 degrees and 15 degrees , and 15 degrees and 24 degrees . A computer program aided manual segmentation and calculated OCT thickness in the scans. RESULTS: Within each patient with RP, mfERG amplitude for each circle/annulus was highly correlated with corresponding layer thicknesses in the outer retina (r = 0.88 to 0.99), but not at all correlated with thickness of the inner nuclear layer or total retina. Across all ring eccentricities, relative mfERG amplitude and relative visual field sensitivity were correlated with relative SD-OCT outer retinal thickness. CONCLUSIONS: In patients with RP, preserved cone photoreceptor function measured by mfERG amplitude and visual field sensitivity correlate well with the remaining thickness of the photoreceptor layer. All three measures show comparable relative loss beyond 3 degrees eccentricity. In the fovea, SD-OCT outer retina thickness showed less relative loss than either mfERG or visual field sensitivity. PMID- 22247461 TI - Asymmetry in hemifield macular thickness as an early indicator of glaucomatous change. AB - PURPOSE: To investigate whether asymmetry in hemifield macular thickness can serve as an early indicator of glaucomatous structural damage using spectral domain optical coherence tomography. METHODS: Five zones in the macular thickness map were defined. Each zone included reciprocal areas in the superior and inferior hemifield. Differences in average retinal thickness (DRT) between corresponding regional pairs were measured in each of the five zones in 50 healthy eyes. An abnormality was defined as the DRT value lying outside the 95% confidence intervals. An eye was considered to yield an "abnormal macular hemifield test" (MHT) if abnormality was evident in any zone. The sensitivity and specificity for glaucoma detection of MHT and average circumpapillary retinal nerve fiber layer (cRNFL) classification were determined. RESULTS: A total of 114 healthy, 103 glaucoma-suspect, and 74 glaucomatous eyes were included. Overall, 5.8%, 36.9%, 88.4%, and 77.4% of the eyes of the healthy, glaucoma-suspect (GS), early glaucoma (EG), and advanced glaucoma (AG) groups yielded abnormal MHT results, respectively. In EG eyes, the sensitivity of an abnormal MHT result was significantly greater than that of abnormal average cRNFL classification (P=0.008). In the GS and AG groups, the sensitivity did not significantly differ between an abnormal MHT result and an average cRNFL classification (P=0.880, 0.180). Compared with sectoral cRNFL thickness measurements, MHT showed a similar level of diagnostic performance. Specificity was not different between an abnormal MHT result and an average cRNFL classification (P=0.687). CONCLUSIONS: Evaluation of asymmetry in hemifield macular thickness may serve as an assessment tool in the early diagnosis of glaucoma. PMID- 22247463 TI - Retinal blood flow in healthy young subjects. AB - PURPOSE: To characterize total retinal blood flow in a group of healthy subjects. METHODS: Included in this study were 64 healthy volunteers. Retinal venous diameters were measured using a dynamic vessel analyzer. Retinal blood velocities were measured using bidirectional laser Doppler velocimetry. All vessels with a diameter of >60 MUm entering the optic nerve head were measured. Total retinal blood flow was measured by summing up all data from the individually measured vessels. In a subgroup of 10 healthy subjects measurements were also taken from the arterioles, and results obtained for total retinal blood flow as measured both from retinal venules and from retinal arterioles were compared. RESULTS: Total retinal blood flow was 44.0 +/- 13.3 MUL/min. Retinal blood flow was highest in the temporal inferior quadrant, followed by the temporal superior quadrant, the nasal inferior quadrant, and the nasal superior quadrant (P < 0.001 each). In all quadrants retinal blood velocities were linearly correlated to vessel diameters. Retinal blood flow as measured in retinal venules (42.1 +/- 13.0 MUL/min) and in retinal arterioles (43.3 +/- 12.1 MUL/min) was similar (P = 0.16). CONCLUSIONS: The present study provides reference values for total retinal blood flow in 64 healthy subjects. The interindividual variability in retinal blood flow is high, making it unlikely that individual diagnostics can be based on measurements of retinal blood flow. Total retinal blood flow, however, may be important in risk stratification, which needs to be proven in future studies. PMID- 22247462 TI - Progressive loss of retinal ganglion cell function is hindered with IOP-lowering treatment in early glaucoma. AB - PURPOSE: To investigate progressive changes of retinal ganglion cell (RGC) function in glaucoma suspects before and after IOP-lowering treatment. METHODS: The authors retrospectively analyzed pattern electroretinograms (PERG) recorded twice a year in 32 glaucoma suspects over at least 6 years. Fifteen patients (28 eyes in the study group) received IOP-lowering treatment at intermediate points during the follow-up, thereby generating a break point between the untreated period and the treated period. Seventeen patients (31 eyes in the control group) were not treated; a break point in the follow-up period was randomly assigned. To assess the effect of treatment, linear regression slopes of PERG amplitude were calculated for periods before and after the break point, and compared both within and between groups. Linear mixed models applied to raw PERG amplitudes recorded over the entire follow-up period were also calculated. RESULTS: Before the break point, slopes had a similar negative trend in both groups, whereas after the break point the slope became shallower in the treated group (P = 0.002). The linear mixed model revealed an interaction between groups, period relative to break point, and segment duration (P = 0.001). Both analyses agreed that after the break point, the rate of PERG amplitude decline slowed in treated eyes by 0.013-0.019 MUV/year compared with the untreated eyes. Mean IOPs measured before and after break point were similar in control eyes (14.8 +/- 3.20 vs. 14.8 +/- 3.14 mm Hg) but different in treated eyes (16.84 +/- 3.96 vs. 14.8 +/- 3.24 mm Hg; P < 0.001). CONCLUSIONS: Progressive loss of RGC function in early glaucoma may be alleviated after IOP lowering, as measured by PERG. PMID- 22247464 TI - Aqueous humor suppression of dendritic cell function helps maintain immune regulation in the eye during human uveitis. AB - PURPOSE: Noninfectious uveitis is characterized by a dysregulated inflammatory or immune response in the eye. It is unclear whether this represents a failure of immune privilege or an overwhelming inflammatory drive that has exceeded the capacity of regulatory mechanisms that are still functioning. The authors investigated immune regulation in the human eye during intraocular inflammation (uveitis) and its impact on dendritic cell (DC) function and subsequent T-cell responses. METHODS: Myeloid DCs were isolated from the aqueous humor (AqH) and peripheral blood of patients with active uveitis and characterized by flow cytometry. The effect of uveitis AqH was interrogated in an in vitro model of peripheral blood monocyte-derived DCs from healthy controls. RESULTS: Myeloid DCs isolated from uveitic AqH were characterized by elevated major histocompatibility complex classes I and II (MHC I/II), but reduced CD86 compared with matched peripheral blood DCs. Exposure of peripheral blood monocyte-derived DCs from healthy controls to the inflammatory AqH supernatant recapitulated this phenotype. Despite interferon gamma (IFNgamma)-dependent upregulation of MHC I, inflammatory AqH was overall suppressive to DC function, with reduced CD86 expression and diminished T-cell responses. This suppressive effect was equal to or greater than that induced by noninflammatory AqH, but was glucocorticoid independent (in contrast to noninflammatory AqH). CONCLUSIONS: These data indicate that the ocular microenvironment continues to regulate DC function during uveitis, despite IFNgamma-driven upregulation of MHC expression, supporting the hypothesis that immune regulation within the eye is maintained during inflammation. PMID- 22247465 TI - Effects of antioxidant components of AREDS vitamins and zinc ions on endothelial cell activation: implications for macular degeneration. AB - PURPOSE: To investigate whether the benefit of Age-Related Eye Disease Study (AREDS) formula multivitamins and zinc in the progression of age-related macular degeneration (AMD) may occur through inhibiting inflammatory events in the choroid. METHODS: Mouse C166 endothelial cells (ECs) and, for some experiments, human retinal pigment epithelium (RPE)-choroid organ cultures were treated with AREDS multivitamin solution (MVS) or ZnCl(2). The cytotoxicity of MVS was evaluated using a lactate dehydrogenase colorimetric assay. Cell motility was assessed using a scratch assay. Macrophage adhesion to EC monolayers or ICAM-1 protein was determined after MVS and zinc treatment and with or without lipopolysaccharide (LPS). Quantitative reverse transcription PCR and Western blot analysis were used to determine the effects of MVS on the expression of proinflammatory molecules in treated and untreated cells. RESULTS: AREDS MVS and zinc did not affect C166 EC viability until the 56th hour after treatment. Scratch assays showed partial inhibition of MVS and zinc on EC migration. In cell adhesion assays, MVS and zinc decreased the number of macrophages bound to EC and to ICAM-1 protein. Quantitative PCR showed that LPS increased the expression of ICAM-1 in both C166 and human RPE-choroid cultures, which was partially offset by MVS and zinc. MVS and zinc also mitigated LPS-induced ICAM-1 protein expression on Western blot analysis. CONCLUSIONS: Treatment with AREDS MVS and zinc may affect both angiogenesis and endothelial-macrophage interactions. These results suggest that AREDS vitamins and zinc ions may slow the progression of AMD, in part through the attenuation of EC activation. PMID- 22247466 TI - Long-term rescue of rat retinal ganglion cells and visual function by AAV mediated BDNF expression after acute elevation of intraocular pressure. AB - PURPOSE: To evaluate the ability of increased expression of brain-derived neurotrophic factor (BDNF) using adenoassociated viral (AAV) vector to prevent the loss of rat retinal ganglion cells (RGCs) and visual function after acute elevation of intraocular pressure (IOP). METHODS: AAV vectors (expressing BDNF or GFP) were injected into the vitreous 6 hours after a transient IOP elevation to 130 mm Hg for 45 minutes. Protective effects were evaluated by counting RGCs retrogradely labeled with fluorogold (FG) from the superior colliculus, measuring the amplitude and the latency of the P1 component of the visual evoked potential (VEP), and observing the visual acuity and contrast sensitivity in awake and behaving animals. RESULTS: RGC numbers decreased continuously to 9 weeks after the elevation of IOP. FG-positive RGC loss was significantly decreased in the retinas treated with AAV-BDNF at 3, 6, and 9 weeks after the insult, with corresponding improvements in VEP parameters. Supplementing BDNF protein once to compensate for the slow onset of AAV-mediated gene expression rescued a larger number of RGCs and the parameters of the VEP. Visual acuity and contrast sensitivity were significantly improved in all treated groups, with the largest improvement in the combined-therapy group, and were maintained for up to 70 weeks. The authors further demonstrated that BDNF rescued the RGCs by activating TrkB receptors through both autocrine and paracrine mechanisms. CONCLUSIONS: AAV mediated BDNF expression in the rat retina achieved a sustained rescue of RGCs and visual function after an acute elevation of IOP. PMID- 22247467 TI - Improved corneal wound healing through modulation of gap junction communication using connexin43-specific antisense oligodeoxynucleotides. AB - PURPOSE: Gap junctions play a major role in corneal wound healing. This study used reproducible models of corneal wound healing to evaluate the effect of a gap junction channel modulator, connexin43 (Cx43) antisense oligodeoxynucleotides (AsODN), on corneal healing dynamics. METHODS: A mechanical scrape wound model was used to evaluate Cx43 AsODN penetration and initial wound reepithelialization 12 hours postsurgery. Thereafter, detailed analyses of corneal edema, inflammation, and healing were performed in an excimer laser surface ablation model. In vivo confocal microscopy determined clinical parameters (edema, haze) and cellular changes (stromal hypercellularity, reepithelialization), whereas histology and immunohistochemistry were used to quantify stromal edema, inflammation, and reepithelialization. RESULTS: Cx43 AsODN penetrated through the hydrophilic stroma where the epithelium had been removed and accumulated in the basal epithelium close to the wound edge. Twelve hours after scrape wounding, Cx43 AsODN-treated eyes showed a significant reduction in wound area compared with the vehicle alone (1.59+/-0.37 and 2.29+/-0.58 mm2, respectively, P<0.01). After excimer laser ablation, stromal edema and inflammation were reduced, with endothelial structures being clearly visible, and reepithelialization rates were again increased in Cx43 AsODN-treated eyes. Histologic analysis confirmed reduced edema in the central wound site and at the periphery of treated corneas (P<0.05), whereas immunohistochemistry showed lower Cx43 levels (P<0.05), reduced myofibroblast activation, and improved epithelial basal lamina deposition in antisense-treated wounds (P<0.01). CONCLUSIONS: Application of Cx43 AsODN to the cornea reduces stromal edema and inflammation, promoting faster wound closure and a more uniform repair of the epithelial basal lamina after laser ablation. PMID- 22247468 TI - Slug is upregulated during wound healing and regulates cellular phenotypes in corneal epithelial cells. AB - PURPOSE: The involvement of the epithelial mesenchymal transition (EMT) in the process of corneal wound healing remains largely unclear. The purpose of the present study was to gain insight into Slug expression and corneal wound healing. METHODS: Slug expression during wound healing in the murine cornea was evaluated using fluorescence staining in vivo. Slug or Snail was stably introduced into human corneal epithelial cells (HCECs). These stable transfectants were evaluated for the induction of the EMT, cellular growth, migration activity, and expression changes in differentiation-related molecules. RESULTS: Slug, but not Snail, was clearly expressed in the nuclei of corneal epithelial cells in basal lesion of the corneal epithelium during wound healing in vivo. The overexpression of Slug or Snail induced an EMT-like cellular morphology and cadherin switching in HCECs, indicating that these transcription factors were able to mediate the typical EMT in HCECs. The overexpression of Slug or Snail suppressed cellular proliferation but enhanced the migration activity. Furthermore, ABCG2, TP63, and keratin 19, which are known as stemness-related molecules, were downregulated in these transfectants. CONCLUSIONS: It was found that Slug is upregulated during corneal wound healing in vivo. The overexpression of Slug mediated a change in the cellular phenotype affecting proliferation, migration, and expression levels of differentiation-related molecules. This is the first evidence that Slug is regulated during the process of corneal wound healing in the corneal epithelium in vivo, providing a novel insight into the EMT and Slug expression in corneal wound healing. PMID- 22247469 TI - CNGA3 deficiency affects cone synaptic terminal structure and function and leads to secondary rod dysfunction and degeneration. AB - PURPOSE: To investigate rod function and survival after cone dysfunction and degeneration in a mouse model of cone cyclic nucleotide-gated (CNG) channel deficiency. METHODS: Rod function and survival in mice with cone CNG channel subunit CNGA3 deficiency (CNGA3-/- mice) were evaluated by electroretinographic (ERG), morphometric, and Western blot analyses. The arrangement, integrity, and ultrastructure of photoreceptor terminals were investigated by immunohistochemistry and electron microscopy. RESULTS: The authors found loss of cone function and cone death accompanied by impairment of rods and rod-driven signaling in CNGA3-/- mice. Scotopic ERG b-wave amplitudes were reduced by 15% at 1 month, 30% at 6 months, and 40% at 9 months and older, while scotopic a-wave amplitudes were decreased by 20% at 9 months, compared with ERGs of age-matched wild-type mice. Outer nuclear layer thickness in CNGA3-/- retina was reduced by 15% at 12 months compared with age-matched wild-type controls. This was accompanied by a 30%-40% reduction in expression of rod-specific proteins, including rhodopsin, rod transducin alpha-subunit, and glutamic acid-rich protein (GARP). Cone terminals in the CNGA3-/- retina showed a progressive loss of neurochemical and ultrastructural integrity. Abnormalities were observed as early as 1 month. Disorganized rod terminal ultrastructure was noted by 12 months. CONCLUSIONS: These findings demonstrate secondary rod impairment and degeneration after cone degeneration in mice with cone CNG channel deficiency. Loss of cone phototransduction accompanies the compromised integrity of cone terminals. With time, rod synaptic structure, function, and viability also become compromised. PMID- 22247470 TI - Myeloid suppressor cells induced by retinal pigment epithelial cells inhibit autoreactive T-cell responses that lead to experimental autoimmune uveitis. AB - PURPOSE: To test whether retinal pigment epithelial (RPE) cells are able to induce myeloid-derived suppressor cell (MDSC) differentiation from bone marrow (BM) progenitors. METHODS: BM cells were cocultured with or without RPE cells in the presence of GM-CSF and IL-4. Numbers of resultant MDSCs were assessed by flow cytometry after 6 days of incubation. The ability of the RPE cell-induced MDSCs to inhibit T cells was evaluated by a CFSE-based T-cell proliferation assay. To explore the mechanism by which RPE cells induce MDSC differentiation, PD-L1 deficient RPE cells and blocking antibodies against TGF-beta, CTLA-2alpha, and IL 6 were used. RPE cell-induced MDSCs were adoptively transferred into mice immunized with interphotoreceptor retinoid-binding protein in complete Freund's adjuvant to test their efficacy in suppressing autoreactive T-cell responses in experimental autoimmune uveitis (EAU). RESULTS: RPE cells induced the differentiation of MDSCs. These RPE cell-induced MDSCs significantly inhibited T cell proliferation in a dose-dependent manner. PD-L1-deficient RPE cells induced MDSC differentiation as efficiently as wild-type RPE cells, and neutralizing TGF beta or CTLA-2alpha did not alter the numbers of induced MDSCs. However, blocking IL-6 reduced the efficacy of RPE cell-induced MDSC differentiation. Finally, adoptive transfer of RPE cell-induced MDSCs suppressed IRBP-specific T-cell responses that led to EAU. CONCLUSIONS: RPE cells induce the differentiation of MDSCs from bone marrow progenitors. Both cell surface molecules and soluble factors are important in inducing MDSC differentiation. PD-L1, TGF-beta, and CTLA 2alpha were not measurably involved in RPE cell-induced MDSC differentiation, whereas IL-6 was important in the process. The induction of MDSCs could be another mechanism by which RPE cells control immune reactions in the retina, and RPE cell-induced MDSCs should be further investigated as a potential approach to therapy for autoimmune posterior uveitis. PMID- 22247472 TI - Establishing levels of indications for cataract surgery: combining clinical and questionnaire data into a measure of cataract impact. AB - PURPOSE: To develop a model for establishing indications for cataract surgery that incorporates clinical and questionnaire data on a single linear scale using Rasch analysis. METHODS: In this prospective study, 293 preoperative cataract surgery patients (mean age, 72.8+/-10 years; age range, 33-98 years; 174 female, 119 male; 49% with ocular comorbidity) completed two questionnaires, and visual acuity was measured in each eye. A cataract impact model was developed using Rasch analysis incorporating questionnaire scores and visual acuity. Participants were ranked from 1 to 293 based on the order in which they presented (first in first out [FIFO]) and then were ranked based on the cataract impact model. The main outcome measure was the number of participants moving 49 (16.7% change) rank positions, which represented a likelihood to change priority category. RESULTS: The cataract impact model was unidimensional (fit statistics within 0.66-1.68) and had adequate precision (person separation of 2.58), and the components were well targeted to the population (0.05 logits between the mean item difficulty and person ability). Two hundred twenty-seven (77.5%) patients moved by at least 49 rank positions. CONCLUSIONS: It is possible to combine clinical and questionnaire data and rank patients on a single linear scale. This approach modifies the ranking that occurs with the FIFO model and can be used for prioritizing patients for surgical intervention. More sophisticated models incorporating more clinical information may provide a better measure of the cataract impact latent trait. PMID- 22247471 TI - Meckelin is necessary for photoreceptor intraciliary transport and outer segment morphogenesis. AB - PURPOSE: Cilia, complex structures found ubiquitously in most vertebrate cells, serve a variety of functions ranging from cell and fluid movement, cell signaling, tissue homeostasis, to sensory perception. Meckelin is a component of ciliary and cell membranes and is encoded by Tmem67 (Mks3). In this study, the retinal morphology and ciliary function in a mouse model for Meckel Syndrome Type 3 (MKS3) throughout the course of photoreceptor development was examined. METHODS: To study the effects of a disruption in the Mks3 gene on the retina, the authors introduced a functional allele of Pde6b into B6C3Fe a/a-bpck/J mice and evaluated their retinas by ophthalmoscopic, histologic, and ultrastructural examination. In addition, immunofluorescence microscopy was used to assess protein trafficking through the connecting cilium and to examine the localization of ciliary and synaptic proteins in Tmem67(bpck) mice and controls. RESULTS: Photoreceptors degenerate early and rapidly in bpck/bpck mutant mice. In addition, phototransduction proteins, such as rhodopsin, arrestin, and transducin, are mislocalized. Ultrastructural examination of photoreceptors reveal morphologically intact connecting cilia but dysmorphic and misoriented outer segment (OS) discs, at the earliest time point examined. CONCLUSIONS: These findings underscore the important role for meckelin in intraciliary transport of phototransduction molecules and their effects on subsequent OS morphogenesis and maintenance. PMID- 22247474 TI - Repeatability and reproducibility of subfoveal choroidal thickness in normal eyes of Japanese using different SD-OCT devices. AB - PURPOSE: To compare subfoveal choroidal thickness (SCT) measurements of three different commercially available spectral-domain optical coherence tomography instruments with healthy eyes of Japanese. METHODS: A prospective, cross sectional study was performed at a single institution. SCT of the right eye of 43 normal subjects was measured using three different SD-OCTs: Heidelberg Spectralis OCT (Spectralis), Cirrus HD-OCT (Cirrus), and Topcon 3D OCT-1000 Mark II (Topcon). Two separate measurements were performed for the same eye with a maximum by a single examiner. SCT was defined as the distance from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction. After manual segmentation, measurements were made using calipers equipped on each machine by masked raters. Intraclass, interrater, and intermachine agreements were assessed. RESULTS: Forty-three subjects (mean age, 30.5 years) were enrolled. Of 43 eyes, the SCT of 39 eyes (90.7%) could be measured using each machine. Intraclass correlation coefficients (95% confidence intervals) were 0.976 (0.954-9.987), 0.958 (0.919-0.978), and 0.939 (0.895-0.971) with Spectralis, Cirrus, and Topcon, respectively. Interrater correlation coefficients (95% confident interval) were 0.944 (0.893 to 0.971), 0.956 (0.831 to 0.983), and 0.924 (0.825 to 0.964) with Spectralis, Cirrus, and Topcon, respectively. The average SCT was 272.6, 272.8, and 269.2 MUm with Spectralis, Cirrus, and Topcon, respectively. The intermachine correlation coefficient was significantly high among the machines (P<0.001, Spearman), 0.97 (Spectralis-Cirrus), 0.96 (Cirrus Topcon), and 0.98 (Topcon-Cirrus). Bland-Altman plot analysis showed no typical trend among the machines. CONCLUSIONS: SCT measurements obtained with three different SD-OCTs were highly correlated and could be used interchangeably. (http://upload.umin.ac.jp number, UMIN000005287.). PMID- 22247473 TI - Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models. AB - PURPOSE: Understanding the effect of genes on progression to different stages of age-related macular degeneration (AMD) may suggest stage-specific therapeutic targets and more precise prediction of the development of this disease. METHODS: Progression events and time to each stage of AMD were derived from the longitudinal data of 2560 subjects without advanced AMD. SNPs in 12 AMD risk loci were genotyped. A multistate Markov model for progression from normal to intermediate drusen, then to large drusen, and eventually to neovascular disease (NV) or geographic atrophy (GA) was applied to estimate stage-specific hazard ratios for each SNP. The effects of these genetic factors were also estimated by a multivariate multistate Markov model adjusted for baseline age, sex, smoking, body mass index (BMI), education, antioxidant treatment, and the status of AMD in the fellow eye. RESULTS: Controlling for demographic and behavioral factors and other SNPs, the TT genotype of rs10468017 in LIPC was associated with decreased risk of progression from large drusen to NV (HR = 0.57, P = 0.04) and tended to reduce the risk of progression from normal to intermediate drusen (HR = 0.72, P = 0.07). The SNP rs1883025 (T allele) in ABCA1 was associated with decreased risk of progression from normal to intermediate drusen (HR per allele = 0.82 per allele, P = 9.7 * 10(-3)) and from intermediate drusen to large drusen (HR per allele = 0.77, P = 5.2 * 10(-3)). The genes CFH, C3, CFB, and ARMS2/HTRA1 were associated with progression from intermediate drusen to large drusen and from large drusen to GA or NV. CONCLUSIONS: Genes in different pathways influence progression to different stages of AMD. PMID- 22247475 TI - Substratum stiffness and latrunculin B regulate matrix gene and protein expression in human trabecular meshwork cells. AB - PURPOSE: To determine the impact of substratum stiffness and latrunculin-B (Lat B), on the expression of several matrix proteins that are associated with glaucoma. METHODS: Human trabecular meshwork (HTM) cells were cultured on hydrogels possessing stiffness values mimicking those found in normal (5 kPa) and glaucomatous meshworks (75 kPa), or tissue culture polystyrene (TCP; >1 GPa). Cells were treated with 2.0 MUM Lat-B in dimethyl sulfoxide (DMSO) or DMSO alone. RT-PCR was used to determine the impact of substratum stiffness and/or Lat-B treatment on the expression of secreted protein, acidic, cysteine rich (SPARC), myocilin, angiopoietin-like factor (ANGPTL)-7, and transglutaminase (TGM)-2. Immunofluorescence was used to assess changes in protein expression. RESULTS: SPARC and myocilin mRNA expression were dramatically increased on the 75 kPa hydrogels and decreased on the 5 kPa hydrogels in comparison to TCP. In contrast, ANGPTL-7 mRNA and TGM-2 mRNA was decreased on the 75 kPa and 5 kPa hydrogels, respectively, in comparison with TCP. Treatment with Lat-B dramatically downregulated both SPARC and myocilin on 75 kPa hydrogels. In contrast, cells grown on TCP produced greater or similar amounts of SPARC and myocilin mRNA after Lat-B treatment. SPARC and myocilin protein expression paralleled changes in mRNA expression. CONCLUSIONS: Substratum stiffness impacts HTM matrix gene and protein expression and modulates the impact of Lat-B treatment on the expression of these matrix proteins. Integrating the use of biologically relevant substratum stiffness in the conduction of in vitro experiments gives important insights into HTM cell response to drugs that may more accurately predict responses observed in vivo. PMID- 22247476 TI - Progression of keratoconus by longitudinal assessment with corneal topography. AB - PURPOSE: To investigate the longitudinal changes in corneal topographic indices over time in patients with mild keratoconus (KC) and to determine predictive factors for the increase in corneal curvature. METHODS: The authors retrospectively reviewed the data of 94 eyes of patients with mild KC who had undergone computerized videokeratography (Orbscan IIz; Bausch & Lomb Surgical, Rochester, NY) at least twice at an interval of >=1 year. Patients with an increase of >=1.50 diopters (D) in the central keratometry (K) were placed in the progression group, and the others were placed in the nonprogression group. In each group, the quantitative topographic parameters were compared and tested as predictive factors for KC progression. Additionally, corneal astigmatic changes were evaluated by means of vector analysis. RESULTS: In total, 94 eyes of 85 patients were included. Twenty-five of 94 (26.5%) eyes showed progression of the central K >=1.50 D; progression took 3.5 years on average. Median time to progression by Kaplan-Meier analysis was 12 years. Significant predictors for KC progression were as follows: highest point on the anterior elevation from the anterior best-fit sphere (BFS), >=0.04 mm; irregularity index at 3 mm, >=6.5 D; irregularity index at 5 mm, >=6.0 D; thinnest pachymetry, <350 MUm at baseline examination; yearly change rate of anterior BFS, >=0.1 D/y; central K, >=0.1 D/y; simulated K in maximum, >=0.15 D/y; simulated K in minimum, >=0.2 D/y; and anterior chamber depth, >=0.0 mm/y. The dominant with-the-rule pattern of astigmatism at the baseline examination was changed to an oblique pattern of astigmatism at the last examination. CONCLUSIONS: Mild KC tended to be progressive in approximately 25% of patients, and progression lasted 3.5 years on average. Longitudinal changes in the corneal topography quantitative indices can be used as predictors of KC progression. PMID- 22247477 TI - Characterization of autoreactive and bystander IL-17+ T cells induced in immunized C57BL/6 mice. AB - PURPOSE: To characterize antigen-specific and bystander IL-17+ T cells induced in immunized mice. METHODS: C57BL/6 (B6) mice were immunized with the uveitogenic peptide IRBP1-20 in either incomplete (IFA) or complete (CFA) Freund's adjuvant. In vivo-primed T cells were stimulated with syngeneic APCs, with or without the immunizing peptide, under polarizing conditions. Activated T cells were analyzed for expression and production of IL-17. RESULTS: B6 mice immunized with the uveitogenic peptide IRBP1-20 generated two types of IL-17+ T cell: one specific for the immunizing autoantigen (IRBP-Th17) and a much more abundant type (bystander-Th17) that is not reactive with the immunizing antigen. The bystander Th17 can be demonstrated when in vivo-primed T cells are cultured in Th17 polarizing conditions in the absence of antigen stimulation. Increased expansion of both types of Th17 cells was seen in mice immunized with IRBP1-20/CFA, but not with IRBP1-20/IFA. Both T-cell types produced IL-17, IL-22, and IFN-gamma, but only bystander Th17 cells produced IL-10. Addition to culture medium of IL-6 and TGF-beta1 caused more activation of bystander-Th17 T cells than IRBP-Th17 cells. When adoptively transferred into syngeneic naive mice, the bystander-Th17 cells neutralized the pathogenic activity of the IRBP-Th17 cells. CONCLUSIONS: A procedure commonly used to induce autoimmune disease promotes two functionally antagonistic types of IL-17+ T cells, and the pathogenic type is restricted to the population that specifically responds to the immunizing autoantigen. Molecular components of the CFA, rather than the immunizing peptide, promote the generation of both types of IL-17+ T cells. PMID- 22247478 TI - Prevalence and risk factors of epiretinal membrane in Asian Indians. AB - PURPOSE: To describe the prevalence of epiretinal membrane (ERM) and its risk factors in an Indian population and compare the findings with other populations. METHODS: The Singapore Indian Eye Study is a population-based survey of 3400 Asian Indians aged between 40 and 80 years. A comprehensive ophthalmic examination, standardized interviews, and laboratory blood tests were performed. Digital retinal fundus photographs were assessed for the presence of ERM following the definitions used in the Blue Mountains Eye Study (BMES). ERM was classified into a less severe form termed "cellophane macular reflex" (CMR) and a more severe form termed "preretinal macular fibrosis" (PMF) and also as primary and secondary (if it was associated with retinal pathology or cataract surgery). RESULTS: A total of 3328 persons (mean age 57.8 +/- [SD] 10.1 years, and 50.2% male) provided data in this study. The age-standardized prevalence of ERM was 7.6% (95% confidence interval [CI], 6.8-8.6), CMR 4.1% (95% CI, 3.5-4.9), and PMF 3.5% (95% CI, 2.9-4.2). Older age (odds ratio [OR], 1.09; 95% CI, 1.07-1.11, per year increase), increasing myopic refraction (OR, 1.14; 95% CI, 1.07-1.22, per diopter decrease), and narrower retinal arteriolar diameter (OR, 1.02; 95% CI, 1.00-1.03, per MUm decrease) were significantly associated with primary ERM. CONCLUSIONS: The age-standardized prevalence of ERM in the Indian population in Singapore was 7.6%. This is similar to Malays in Singapore (8.0%) and higher than the prevalence in whites in Australia (4.7%). Significant factors associated with primary ERM were older age, myopia, and narrower retinal arteriolar diameter. PMID- 22247479 TI - Growth factor regulation of corneal keratocyte mechanical phenotypes in 3-D collagen matrices. AB - PURPOSE: To assess how wound healing cytokines and the extracellular matrix (ECM) environment regulate the keratocyte mechanical phenotype. METHODS: Rabbit corneal keratocytes were plated within standard bovine or rat tail type I collagen matrices (2.5 mg/mL), compressed collagen matrices (approximately 100 mg/mL), or on collagen-coated dishes and cultured for up to 7 days in serum-free media, platelet derived growth factor BB (PDGF BB), insulin-like growth factor (IGF), TGFbeta1, TGFbeta2, or FGF2. F-actin, alpha-smooth muscle actin (alpha-SMA) and collagen fibrils were imaged using confocal microscopy. Cell morphology, local matrix reorganization, and global matrix contraction were quantified digitally. RESULTS: IGF and PDGF BB stimulated elongation of keratocytes and extension of dendritic processes within 3-D matrices, without inducing stress fiber formation or collagen reorganization. In contrast, treatment with TGFbeta1 and TGFbeta2 increased keratocyte contractility, as indicated by stress fiber formation and matrix compaction and alignment. This transformation was enhanced at higher cell densities within standard 3-D matrices, in which alpha-SMA was incorporated into stress fibers. In contrast, alpha-SMA was expressed within compressed 3-D matrices even at low cell density. FGF2 did not produce significant cytoskeletal or matrix reorganization in standard 3-D matrices; however, stress fibers were consistently expressed within compressed collagen matrices and on rigid two dimensional substrates. Inhibiting Rho kinase blocked both TGFbeta- and FGF2 induced stress fiber formation. CONCLUSIONS: Keratocytes cultured in IGF or PDGF BB maintain a quiescent mechanical phenotype over a range of matrix environments. In contrast, the mechanical phenotypes induced by FGF and TGFbeta vary in response to the structural and/or mechanical properties of the ECM. PMID- 22247480 TI - Altered systemic hemodynamic and baroreflex response to angiotensin II in postural tachycardia syndrome. AB - BACKGROUND: Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls. METHODS AND RESULTS: Following a 3-day sodium-controlled diet, we infused Ang II (3 ng/kg per minute) for 1 hour in patients with POTS (n=15) and healthy controls (n=13) in the supine position. All study subjects were women with normal BP. Ages were similar for patients with POTS and controls (mean+/-SEM, 30+/-2 versus 26+/-1 years; P=0.11). We measured the changes from baseline mean arterial pressure, renal plasma flow, plasma renin activity, aldosterone, urine sodium, and baroreflex sensitivity in both groups. In response to Ang II infusion, patients with POTS had a blunted increase compared with controls in mean arterial pressure (10+/-1 versus 14+/-1 mm Hg, P=0.01) and diastolic BP (9+/-1 versus 13+/-1 mm Hg, P=0.01) but not systolic BP (13+/-2 versus 15+/-2 mm Hg, P=0.40). Renal plasma flow decreased similarly with Ang II infusion in patients with POTS versus controls (-166+/-20 versus -181+/-17 mL/min per 1.73 kg/m(2), P=0.58). Postinfusion, the decrease in plasma renin activity (-0.9+/-0.2 versus -0.6+/-0.2 ng/mL per hour, P=0.43) and the increase in aldosterone (17+/-1 versus 15+/-2 pg/mL, P=0.34) were similar in both groups. The decrease in urine sodium excretion was similar in patients with POTS and controls (-49+/-12 versus -60+/ 16 mEq/g creatinine, P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in patients with POTS compared with controls (10.1+/-1.2 versus 16.8+/-1.5 ms/mm Hg, P=0.003), and it was further reduced with Ang II infusion. CONCLUSIONS: Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962949. PMID- 22247481 TI - Incidence and long-term follow-up of silent cerebral lesions after pulmonary vein isolation using a remote robotic navigation system as compared with manual ablation. AB - BACKGROUND: The incidence of silent cerebral lesions (SCL) after atrial fibrillation (AF) ablation is highly variable, depending on the technology used. Recently, an increased risk for SCL has been described for a novel, nonirrigated ablation tool using multielectrode phased radiofrequency (PVAC). The aim of this prospective study was to evaluate the incidence and long-term follow-up of SCL in patients undergoing robotically assisted pulmonary vein isolation (RA-PVI) as compared with manual PVI. METHODS AND RESULTS: Circumferential PVI using irrigated radiofrequency current was performed on 70 patients (41 patients with paroxysmal AF, 59%). Fifty patients underwent RA-PVI and 20 patients underwent a manual approach. Cerebral MRI was performed the day before and the day after the ablation procedure; follow-up MRI was performed on 9 of 12 (75%) patients after a follow-up period of 21 months. SCLs were found in 12 of 70 (17%) patients in this study; the incidence of SCLs was similar in patients undergoing RA-PVI as compared with manually ablated patients (n=9, 18% versus n=3, 15%; probability value=1.0). In 1 patient undergoing manual PVI (1%), an SCL with asymptomatic subarachnoid hemorrhage was detected; the bleeding completely resolved within 1 month. Transient ischemic attack occurred in 1 (1%) patient 2 days after manual PVI. After a median follow-up period of 21 months, no residual SCLs were detected. CONCLUSIONS: The incidence of SCL using the robotic navigation system was 18% in this study. Incidence and size of SCL appears to be similar after RA PVI as compared with manual PVI. Repeat MRI showed no residual SCLs at long-term follow-up. PMID- 22247482 TI - A connexin40 mutation associated with a malignant variant of progressive familial heart block type I. AB - BACKGROUND: Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation. METHODS AND RESULTS: We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2+/-1.7 nS, n=14; Cx40-Q58L, 0.56+/-0.34 nS, n=14; P<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ~50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques. CONCLUSIONS: Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system. PMID- 22247484 TI - Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor hearts. AB - BACKGROUND: A change in allocation algorithm in July 2006 allowed broader regional sharing of donor hearts in the United States (US). We assessed if the allocation change has been associated with a decline in wait list mortality in the US. METHODS AND RESULTS: We compared baseline characteristics and outcomes in patients >=18 years old listed for a primary heart transplant in the US before (July 1, 2004-July 11, 2006, Era1) and after (July 12, 2006-June 30, 2009, Era 2) the change in allocation algorithm. Of 11 864 patients in the study, 4503 were listed during Era 1 and 7361 during Era 2. Patients listed during Era 2 were more likely to be listed status 1A, have an implantable cardioverter-defibrillator, and supported on a continuous flow assist device (P<0.001 for distribution. Patients listed in Era 2 were at a 17% lower risk of dying on the wait list or becoming too sick to transplant (adjusted hazard ratio, 0.83, 95% CI 0.75, 0.93). Transplant recipients in Era 2 were more likely to be transplanted as status 1A (37% versus 48%, respectively, P<0.001). Post-transplant in-hospital mortality (6.3% versus 5.4%; adjusted odds ratio, 0.86 for Era 2, 95% CI 0.79, 1.06) and 1 year survival were similar. CONCLUSIONS: The risk of death on the wait list or becoming too sick to transplant has decreased by 17% in the US since the allocation algorithm allowing broader regional sharing was implemented in 2006. The shift in hearts to sicker candidates has not resulted in higher in-hospital or first year post-transplant mortality. PMID- 22247483 TI - Acculturation and outcomes among patients with heart failure. AB - BACKGROUND: Acculturation to US society among minority patients may-beyond race and ethnicity alone-influence health outcomes beyond race and ethnicity alone. In particular, those who are foreign-born and who do not speak English as their primary language may have greater challenges interacting with the health care system and thus be at greater risk for adverse outcomes. METHODS AND RESULTS: We studied patients hospitalized with a principal discharge diagnosis of heart failure between January 2000 and December 2007 in an integrated delivery system that cares for minority patients. Individuals were defined as having low acculturation if their primary language was not English and their country of birth was outside of the United States. Multivariable logistic regression and Cox proportional hazards regression were used to determine the independent risk of 30 day rehospitalization and 1-year mortality, respectively. Candidate adjustment variables included demographics (age, sex, race/ethnicity), coexisting illnesses, laboratory values, left ventricular systolic function, and characteristics of the index admission. Of 1268 patients, 30% (n=379) were black, 39% (n=498) were Hispanic, and 27% (n=348) were white. Eighteen percent (n=228) had low acculturation. After adjustment, low acculturation was associated with a higher risk of readmission at 30 days (odds ratio, 1.70; 95% confidence interval, 1.07 2.68) but not 1-year all-cause mortality (hazard ratio, 0.69; 95% confidence interval, 0.42-1.14). CONCLUSIONS: Patients with heart failure who are foreign born and do not speak English as their primary language have a greater risk of rehospitalization, independent of clinical factors and race/ethnicity. Future studies should evaluate whether culturally concordant interventions focusing on such patients may improve outcomes for this patient population. PMID- 22247485 TI - Bmp signaling exerts opposite effects on cardiac differentiation. AB - RATIONALE: The importance for Bmp signaling during embryonic stem cell differentiation into myocardial cells has been recognized. The question when and where Bmp signaling in vivo regulates myocardial differentiation has remained largely unanswered. OBJECTIVE: To identify when and where Bmp signaling regulates cardiogenic differentiation. METHODS AND RESULTS: Here we have observed that in zebrafish embryos, Bmp signaling is active in cardiac progenitor cells prior to their differentiation into cardiomyocytes. Bmp signaling is continuously required during somitogenesis within the anterior lateral plate mesoderm to induce myocardial differentiation. Surprisingly, Bmp signaling is actively repressed in differentiating myocardial cells. We identified the inhibitory Smad6a, which is expressed in the cardiac tissue, to be required to inhibit Bmp signaling and thereby promote expansion of the ventricular myocardium. CONCLUSION: Bmp signaling exerts opposing effects on myocardial differentiation in the embryo by promoting as well as inhibiting cardiac growth. PMID- 22247486 TI - EphA2/Ephrin-A1 signaling complexes restrict corneal epithelial cell migration. AB - PURPOSE: Eph/ephrin signaling proteins are present in the corneal epithelium, where their function remains unknown. The authors examined the role of the EphA2 receptor and ephrin-A1 ligand in human corneal epithelial cell migration. METHODS: Immunohistochemical analysis of EphA2 and ephrin-A1 in healthy and diabetic corneas was performed in concert with linear scratch wound healing studies in primary and telomerase-immortalized human corneal epithelial cells. Corneal epithelial cells were exposed to a soluble ephrin-A1-Fc peptide mimetic that targets EphA2 to trigger receptor phosphorylation and subsequent downregulation. Genetic modulation of EphA2 and ephrin-A1 levels was combined with manipulation of Erk1/2 or Akt signaling during wound healing. RESULTS: EphA2 was immunolocalized to human corneal epithelial cells in vivo and in vitro. Ephrin-A1 ligand targeting of EphA2 restricted the ability of corneal epithelial cells to seal linear scratch wounds in a manner that was associated with a transient reduction in Erk1/2 and Akt activation state. Ephrin-A1-Fc treatment delayed wound healing independently of Mek-Erk1/2 signaling but was no longer capable of restricting migration after pharmacologic blockade of the PI3K-Akt pathway. Interestingly, ephrin-A1 immunoreactivity was increased in the corneal epithelia of diabetic individuals, mice maintained on a high-fat diet, or cultured corneal epithelial cells exposed to high glucose, which exhibit impaired Akt signaling and slower wound healing responses. CONCLUSIONS: EphA2 attenuates corneal epithelial cell migration when stimulated by ephrin-A1 ligand in a manner that involves the suppression of Akt. Elevated levels of ephrin-A1 may contribute to diabetic keratopathies by persistently engaging EphA2 and prohibiting Akt dependent corneal epithelial repair processes. PMID- 22247487 TI - Generation of an inbred miniature pig model of retinitis pigmentosa. AB - PURPOSE: The Pro23His (P23H) rhodopsin (RHO) mutation underlies the most common form of human autosomal dominant retinitis pigmentosa (adRP). The objective of this investigation was to establish a transgenic miniature swine model of RP using the human P23H RHO gene. METHODS: Somatic cell nuclear transfer (SCNT) was used to create transgenic miniature pigs that expressed the human P23H RHO mutation. From these experiments, six transgenic founders were identified whose retinal function was studied with full-field electroretinography (ffERG) from 3 months through 2 years. Progeny from one founder were generated and genotyped to determine transgene inheritance pattern. Retinal mRNA was isolated, and the ratio of P23H to wild-type pig RHO was measured. RESULTS: A single transgene integration site was observed for five of the six founders. All founders had abnormal scotopic and photopic ffERGs after 3 months. The severity of the ffERG phenotype was grouped into moderately and severely affected groups. Offspring of one founder inherited the transgene as an autosomal dominant mutation. mRNA analyses demonstrated that approximately 80% of total RHO was mutant P23H. CONCLUSIONS: Expression of the human RHO P23H transgene in the retina creates a miniature swine model with an inheritance pattern and retinal function that mimics adRP. This large-animal model can serve as a novel tool for the study of the pathogenesis and therapeutic intervention in the most common form of adRP. PMID- 22247488 TI - Increased IL-7 expression in Vogt-Koyanagi-Harada disease. AB - PURPOSE: IL-7/IL-7R has been found to be involved in the pathogenesis of several autoimmune diseases. This study was designed to investigate the potential role of IL-7/IL-7R in the pathogenesis of Vogt Koyanagi-Harada (VKH), an organ-specific autoimmune disease. METHODS: IL-7 was measured with an enzyme-linked immunosorbent assay (ELISA) in serum obtained from patients with active or inactive VKH and from healthy individuals. The expression of IL-7R was measured by flow cytometry (FCM). Cell proliferation was determined after exposure of peripheral blood mononuclear cells (PBMCs) and CD4(+) T cells to recombinant IL 7. The levels of IL-17 and IFN-gamma levels were detected by ELISA after these cells were cocultured with recombinant IL-7. The influence of recombinant IL-7 on the expansion of Th1 and Th17 cells was evaluated by using FCM. RESULTS: IL-7 was significantly increased in the serum of patients with active VKH compared with those with inactive VKH (P < 0.001) and normal controls (P < 0.001). However, there was no difference between VKH patients and normal controls in the expression of IL-7Ralpha on CD4(+) T cells. Recombinant IL-7 induced significant cell proliferation and secretion of IL-17 and IFN-gamma by PBMCs and CD4(+) T cells. It furthermore promoted the expansion of both Th1 and Th17 cells. CONCLUSIONS: The findings suggest that IL-7 is involved in the pathogenesis of VKH disease. PMID- 22247491 TI - Emergence of metallo-beta-lactamases GIM-1 and VIM in multidrug-resistant Pseudomonas aeruginosa in North Rhine-Westphalia, Germany. PMID- 22247490 TI - Role of CTCF in EGF-induced migration of immortalized human corneal epithelial cells. AB - PURPOSE: EGF-induced activation of the epigenetic CCCTC binding factor (CTCF) plays an important role in corneal epithelial cell proliferation by suppressing the Pax6 gene. The present study focused on further understanding the role of CTCF in mediating EGF-induced migration of immortalized human corneal epithelial cells. METHODS: CTCF activities in human corneal epithelial cells immortalized by telomerase (HTCE cells) and SV-40 (HCE cells) transformation were suppressed and enhanced by CTCF mRNA knockdown and by overexpressing CTCF cDNA, respectively. EGF-induced cell migration was evaluated by linear scratch wound healing, a cell migration assay, and live cell motility GFP-tracking with a fluorescence microscope. Immunochemical analysis was performed for detecting focal adhesion changes in EGF-induced and CTCF activity-altered cells. RESULTS: EGF-induced wound closure and cell migration rates of human corneal epithelial cells were significantly suppressed and enhanced by CTCF mRNA knockdown and by overexpression of CTCF, respectively. CTCF mRNA knockdown also markedly suppressed cell motility, determined by using a live-cell-tracking system in GFP tag-expressed HTCE cells. Finally, alterations of EGF-stimulated focal adhesion were observed in CTCF knockdown HTCE cells by immunostaining of F-actin and vinculin in cytoskeleton reorganization. CONCLUSIONS: CTCF, an epigenetic regulator and transcription factor, involves EGF-induced increases in cell motility and migration. CTCF plays an essential role in growth factor-regulated human corneal epithelial cell wound healing. PMID- 22247492 TI - Metabolic syndrome in adolescence: can it be predicted from natal and parental profile? The Prediction of Metabolic Syndrome in Adolescence (PREMA) study. AB - BACKGROUND: There are well-established predisposing factors for the development of metabolic syndrome (MetS) in childhood or adolescence, but no specific risk profile has been identified as yet. The Prediction of Metabolic Syndrome in Adolescence (PREMA) study was conducted (1) to construct a classification score that could detect children at high risk for MetS in adolescence and (2) to test its predictive accuracy. METHODS AND RESULTS: In the derivation cohort (1270 children), data from natal and parental profile and from initial laboratory assessment at 6 to 8 years of age were used to detect independent predictors of MetS at 13 to 15 years of age according to the International Diabetes Federation definition. In the validation cohort (1091 adolescents), the discriminatory capacity of the derived prediction score was tested on an independent adolescent population. MetS was diagnosed in 105 adolescents in the derivation phase (8%), whereas birth weight <10th percentile (odds ratio, 6.02; 95% confidence interval, 2.53-10.12, P<0.001), birth head circumference <10th percentile (odds ratio, 4.15; 95% confidence interval, 2.04-7.14, P<0.001), and parental overweight or obesity (in at least 1 parent; odds ratio, 3.22; 95% confidence interval, 1.30 5.29, P<0.01) were independently associated with diagnosis of MetS in adolescence. Among adolescents in the validation cohort (86 [8%] with MetS), the presence of all these 3 predictors predicted MetS with a sensitivity of 91% and a specificity of 98%. CONCLUSIONS: The coexistence of low birth weight, small head circumference, and parental history of overweight or obesity may be useful for detection of children at risk of developing MetS in adolescence. PMID- 22247493 TI - White matter protection in congenital heart surgery. AB - BACKGROUND: Neurodevelopmental delays in motor skills and white matter (WM) injury have been documented in congenital heart disease and after pediatric cardiac surgery. The lack of a suitable animal model has hampered our understanding of the cellular mechanisms underlying WM injury in these patients. Our aim is to identify an optimal surgical strategy for WM protection to reduce neurological injury in congenital heart disease patients. METHODS AND RESULTS: We developed a porcine cardiopulmonary bypass model that displays area-dependent WM maturation. In this model, WM injury was identified after cardiopulmonary bypass induced ischemia-reperfusion injury. The degree of injury was inversely correlated with the maturation stage, which indicates maturation-dependent vulnerability of WM. Within different oligodendrocyte developmental stages, we show selective vulnerability of O4+ preoligodendrocytes, whereas oligodendrocyte progenitor cells were resistant to insults. This indicates that immature WM is vulnerable to cardiopulmonary bypass-induced injury but has an intrinsic potential for recovery mediated by endogenous oligodendrocyte progenitor cells. Oligodendrocyte progenitor cell number decreased with age, which suggests that earlier repair allows successful WM development. Oligodendrocyte progenitor cell proliferation was observed within a few days after cardiopulmonary bypass-induced ischemia-reperfusion injury; however, by 4 weeks, arrested oligodendrocyte maturation and delayed myelination were detected. Logistic model confirmed that maintenance of higher oxygenation and reduction of inflammation were effective in minimizing the risk of injury at immature stages of WM development. CONCLUSIONS: Primary repair in neonates and young infants potentially provides successful WM development in congenital heart disease patients. Cardiac surgery during this susceptible period should avoid ischemia-reperfusion injury and minimize inflammation to prevent long-term WM-related neurological impairment. PMID- 22247494 TI - Gremlin plays a key role in the pathogenesis of pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated. METHODS AND RESULTS: Expression of 2 BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs, and gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension in a distribution suggesting endothelial localization. CONCLUSIONS: These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension. PMID- 22247489 TI - Associations among visual acuity and vision- and health-related quality of life among patients in the multicenter uveitis steroid treatment trial. AB - PURPOSE: To evaluate the associations between visual acuity and self-reported visual function; visual acuity and health-related quality of life (QoL) metrics; a summary measure of self-reported visual function and health-related QoL; and individual domains of self-reported visual function and health-related QoL in patients with uveitis. METHODS: Best-corrected visual acuity, vision-related functioning as assessed by the NEI VFQ-25, and health-related QoL as assessed by the SF-36 and EuroQoL EQ-5D questionnaires were obtained at enrollment in a clinical trial of uveitis treatments. Multivariate regression and Spearman correlations were used to evaluate associations between visual acuity, vision related function, and health-related QoL. RESULTS: Among the 255 patients, median visual acuity in the better-seeing eyes was 20/25, the vision-related function score indicated impairment (median, 60), and health-related QoL scores were within the normal population range. Better visual acuity was predictive of higher visual function scores (P <= 0.001), a higher SF-36 physical component score, and a higher EQ-5D health utility score (P < 0.001). The vision-specific function score was predictive of all general health-related QoL (P < 0.001). The correlations between visual function score and general quality of life measures were moderate (rho = 0.29-0.52). CONCLUSIONS: The vision-related function score correlated positively with visual acuity and moderately positively with general QoL measures. Cost-utility analyses relying on changes in generic healthy utility measures will be more likely to detect changes when there are clinically meaningful changes in vision-related function, rather than when there are only changes in visual acuity. (ClinicalTrials.gov number, NCT00132691.). PMID- 22247496 TI - Targeting proteasomal protein degradation in cancer-letter. PMID- 22247495 TI - Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival. AB - PURPOSE: Human papillomavirus (HPV) is linked with a subset of head and neck squamous cell carcinomas (HNSCC). HPV-positive HNSCCs show a better prognosis than HPV-negative HNSCCs, which may be explained by sensitivity of the HPV positive HNSCCs to ionizing radiation (IR). Although the molecular mechanism behind sensitivity to IR in HPV-positive HNSCCs is unresolved, DNA damage response (DDR) might be a significant determinant of IR sensitivity. An important player in the DDR, SMG-1 (suppressor with morphogenetic effect on genitalia), is a potential tumor suppressor and may therefore be deregulated in cancer. No studies have yet been conducted linking defects in SMG-1 expression with cancer. We investigated whether deregulation of SMG-1 could be responsible for defects in the DDR in oropharyngeal HNSCC. EXPERIMENTAL DESIGN: Expression and promoter methylation status of SMG-1 were investigated in HNSCCs. To identify a functional link between HPV infection and SMG-1, we transfected the HPV-negative cells with an E6/E7 expression construct. SMG-1 short hairpin RNAs were expressed in HPV negative cells to estimate survival upon IR. RESULTS: Forced E6/E7 expression in HPV-negative cells resulted in SMG-1 promoter hypermethylation and decreased SMG 1 expression. Due to promoter hypermethylation, HPV-positive HNSCC cells and tumors express SMG-1 at lower levels than HPV-negative SCCs. Depletion of SMG-1 in HPV-negative HNSCC cells resulted in increased radiation sensitivity, whereas SMG-1 overexpression protected HPV-positive tumor cells from irradiation. CONCLUSIONS: Levels of SMG-1 expression negatively correlated with HPV status in cancer cell lines and tumors. Diminished SMG-1 expression may contribute to the enhanced response to therapy exhibited by HPV-positive HNSCCs. PMID- 22247498 TI - Vitamin D and multiple sclerosis: an interaction between genes and environment. PMID- 22247499 TI - Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood. AB - BACKGROUND: Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation. METHODS: We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides. RESULTS: We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls. CONCLUSIONS: Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6. PMID- 22247500 TI - Accuracy of 6 routine 25-hydroxyvitamin D assays: influence of vitamin D binding protein concentration. AB - BACKGROUND: Recent recognition of its broad pathophysiological importance has triggered an increased interest in 25-hydroxyvitamin D [25(OH)D]. By consequence, throughput in 25(OH)D testing has become an issue for clinical laboratories, and several automated assays for measurement of 25(OH)D are now available. The aim of this study was to test the accuracy and robustness of these assays by comparing their results to those of an isotope dilution/online solid-phase extraction liquid chromatography/tandem mass spectrometry (ID-XLC-MS/MS) method. We put specific focus on the influence of vitamin D-binding protein (DBP) by using samples with various concentrations of DBP. METHODS: We used 5 automated assays (Architect, Centaur, iSYS, Liaison, and Elecsys), 1 RIA (Diasorin) preceded by extraction, and an ID-XLC-MS/MS method to measure 25(OH)D concentrations in plasma samples of 51 healthy individuals, 52 pregnant women, 50 hemodialysis patients, and 50 intensive care patients. Using ELISA, we also measured DBP concentrations in these samples. RESULTS: Most of the examined 25(OH)D assays showed significant deviations in 25(OH)D concentrations from those of the ID-XLC MS/MS method. As expected, DBP concentrations were higher in samples of pregnant women and lower in samples of IC patients compared to healthy controls. In 4 of the 5 fully automated 25(OH)D assays, we observed an inverse relationship between DBP concentrations and deviations from the ID-XLC-MS/MS results. CONCLUSIONS: 25(OH)D measurements performed with most immunoassays suffer from inaccuracies that are DBP concentration dependent. Therefore, when interpreting results of 25(OH)D measurements, careful consideration of the measurement method is necessary. PMID- 22247501 TI - Functional plasticity induced by mirror training: the mirror as the element connecting both hands to one hemisphere. AB - BACKGROUND: Mirror therapy (MT) is a promising therapeutic approach in stroke patients with severe hand paresis. OBJECTIVE: The ipsilateral (contralesional) primary sensorimotor cortex (SMC) and the mirror neuron system have been suggested to play decisive roles in the MT network. The present study investigated its underlying neural plasticity. METHODS: Two groups of healthy participants (n = 13 in each group) performed standardized fine motor tasks moving pegs and marbles (20 min/d for 4 days) with their right hand with either a mirror (mirror training group, MG) or a nonreflective board (control training group, CG) positioned orthogonally in front of them. The number of items moved by each hand was tested after each training session. Functional MRI (fMRI) was acquired before and after the training procedure to investigate the mirror training (MTr)-specific network by the analysis of the factors Time and Group. RESULTS: The hand performance test of the trained right hand did not differ between the 2 groups. The untrained left hand improved significantly more in the MG compared with the CG. fMRI analysis of action observation and imitation of grasping tasks demonstrated MTr-specific activation changes within the right dorsal and left ventral premotor cortex as well as in the left SMC (SMC(left)). Analysis of functional and effective connectivity showed a MTr-specific increase of functional coupling between each premotor region and the left supplementary motor area, which in turn showed an increased functional interaction with the ipsilateral SMC(left). CONCLUSIONS: MTr remodels the motor system by functionally connecting hand movement to the ipsilateral SMC. On a system level, it leads to interference of the neural circuit related to motor programming and observation of the trained hand with the illusionary movement of the untrained hand. PMID- 22247502 TI - Reduced upper limb sensation impairs mental chronometry for motor imagery after stroke: clinical and electrophysiological findings. AB - BACKGROUND: Motor imagery (MI) is increasingly recognized as a treatment option after stroke, but not all stroke patients are able to perform MI. OBJECTIVE: To examine if severe somatosensory deficits would affect MI ability. METHODS: The Box and Block Test (BBT) was used to evaluate mental chronometry as 1 component of MI. Two groups of stroke patients and an age-matched healthy control group (CG) were studied. Patient group 1 (n = 10, PG1) had a severe somatosensory impairment on the affected side and PG2 (n = 10) had pure motor strokes. All subjects first performed the BBT in a mental and in a real version. The time needed to move 15 blocks from 1 side of the box to the other was measured. To compare the groups independently of their performance level, a (real performance- MI)/(real performance) ratio was calculated. Corticospinal excitability was measured by transcranial magnetic stimulation at rest and while the subjects performed an imagined pinch grip. RESULTS: The CG performed the BBT faster than both patient groups, and PG1 was slower than PG2. MI ability was impaired in PG1 but only for the affected hand. Transcranial magnetic stimulation data showed an abnormally low MI-induced corticospinal excitability increase for the affected hand in PG1, but not in PG2. CONCLUSIONS: Severe somatosensory deficits impaired mental chronometry. A controlled study is necessary to clarify if these patients benefit at all from MI as an additional treatment. PMID- 22247503 TI - CtsR regulation in mcsAB-deficient Gram-positive bacteria. AB - CtsR is an important repressor that modulates the transcription of class III stress genes in Gram-positive bacteria. In Bacillus subtilis, a model Gram positive organism, the DNA binding activity of CtsR is regulated by McsAB mediated phosphorylation of the protein where phosphorylated CtsR is a substrate for degradation by the ClpCP complex. Surprisingly, the mcsAB genes are absent from many Gram-positive bacteria, including streptococci; therefore, how CtsR activity is modulated in those bacteria remains unknown. Here we show that the posttranslational modulation of CtsR activity is different in Streptococcus mutans, a dental pathogen. We observed that of all of the Clp-related proteins, only ClpL is involved in the degradation of CtsR. Neither ClpP nor ClpC had any effect on the degradation of CtsR. We also found that phosphorylation of CtsR on a conserved arginine residue within the winged helix-turn-helix domain is necessary for modulation of the repressor activity of CtsR, as demonstrated by both in vitro and in vivo assays. We speculate that CtsR is regulated posttranslationally by a different mechanism in S. mutans and possibly in other streptococci. PMID- 22247504 TI - Evolutionary link between the mycobacterial plasmid pAL5000 replication protein RepB and the extracytoplasmic function family of sigma factors. AB - Mycobacterial plasmid pAL5000 represents a family of plasmids found mostly in the Actinobacteria. It replicates using two plasmid-encoded proteins, RepA and RepB. While BLAST searches indicate that RepA is a replicase family protein, the evolutionary connection of RepB cannot be established, as no significant homologous partner (E < 10(-3)) outside the RepB family can be identified. To obtain insight into the structure-function and evolutionary connections of RepB, an investigation was undertaken using homology modeling, phylogenetic, and mutational analysis methods. The results indicate that although they are synthesized from the same operon, the phylogenetic affinities of RepA and RepB differ. Thus, the operon may have evolved through random breaking and joining events. Homology modeling predicted the presence of a three-helical helix-turn helix domain characteristic of region 4 of extracytoplasmic function (ECF) sigma factors in the C-terminal region of RepB. At the N-terminal region, there is a helical stretch, which may be distantly related to region 3 of sigma factors. Mutational analysis identified two arginines indispensable for RepB activity, one each located within the C- and N-terminal conserved regions. Apart from analyzing the domain organization of the protein, the significance of the presence of a highly conserved A/T-rich element within the RepB binding site was investigated. Mutational analysis revealed that although this motif does not bind RepB, its integrity is important for efficient DNA-protein interactions and replication to occur. The present investigation unravels the possibility that RepB-like proteins and their binding sites represent ancient DNA-protein interaction modules. PMID- 22247506 TI - Further unraveling the regulatory twist by elucidating metabolic coinducer mediated CbbR-cbbI promoter interactions in Rhodopseudomonas palustris CGA010. AB - The cbb(I) region of Rhodopseudomonas palustris (Rp. palustris) contains the cbbLS genes encoding form I ribulose-1,5-bisphosphate (RuBP) carboxylase oxygenase (RubisCO) along with a divergently transcribed regulator gene, cbbR. Juxtaposed between cbbR and cbbLS are the cbbRRS genes, encoding an unusual three protein two-component (CbbRRS) system that modulates the ability of CbbR to influence cbbLS expression. The nature of the metabolic signals that Rp. palustris CbbR perceives to regulate cbbLS transcription is not known. Thus, in this study, the CbbR binding region was first mapped within the cbbLS promoter by the use of gel mobility shift assays and DNase I footprinting. In addition, potential metabolic coinducers (metabolites) were tested for their ability to alter the cbbLS promoter binding properties of CbbR. Gel mobility shift assays and surface plasmon resonance analyses together indicated that biosynthetic intermediates such as RuBP, ATP, fructose 1,6-bisphosphate, and NADPH enhanced DNA binding by CbbR. These coinducers did not yield identical CbbR-dependent DNase I footprints, indicating that the coinducers caused significant changes in DNA structure. These in vitro studies suggest that cellular signals such as fluctuating metabolite concentrations are perceived by and transduced to the cbbLS promoter via the master regulator CbbR. PMID- 22247505 TI - Characterization of Escherichia coli dinJ-yafQ toxin-antitoxin system using insights from mutagenesis data. AB - Escherichia coli dinJ-yafQ operon codes for a functional toxin-antitoxin (TA) system. YafQ toxin is an RNase which, upon overproduction, specifically inhibits the translation process by cleaving cellular mRNA at specific sequences. DinJ is an antitoxin and counteracts YafQ-mediated toxicity by forming a strong protein complex. In the present study we used site-directed mutagenesis of YafQ to determine the amino acids important for its catalytic activity. His50Ala, His63Ala, Asp67Ala, Trp68Ala, Trp68Phe, Arg83Ala, His87Ala, and Phe91Ala substitutions of the predicted active-site residues of YafQ abolished mRNA cleavage in vivo, whereas Asp61Ala and Phe91Tyr mutations inhibited YafQ RNase activity only moderately. We show that YafQ, upon overexpression, cleaved mRNAs preferably 5' to A between the second and third nucleotides in the codon in vivo. YafQ also showed RNase activity against mRNA, tRNA, and 5S rRNA molecules in vitro, albeit with no strong specificity. The endoribonuclease activity of YafQ was inhibited in the complex with DinJ antitoxin in vitro. DinJ-YafQ protein complex and DinJ antitoxin alone selectively bind to one of the two palindromic sequences present in the intergenic region upstream of the dinJ-yafQ operon, suggesting the autoregulation mode of this TA system. PMID- 22247507 TI - The O-methyltransferase SrsB catalyzes the decarboxylative methylation of alkylresorcylic acid during phenolic lipid biosynthesis by Streptomyces griseus. AB - Streptomyces griseus contains the srs operon, which is required for phenolic lipid biosynthesis. The operon consists of srsA, srsB, and srsC, which encode a type III polyketide synthase, an O-methyltransferase, and a flavoprotein hydroxylase, respectively. We previously reported that the recombinant SrsA protein synthesized 3-(13'-methyltetradecyl)-4-methylresorcinol, using iso-C(16) fatty acyl-coenzyme A (CoA) as a starter substrate and malonyl-CoA and methylmalonyl-CoA as extender substrates. An in vitro SrsA reaction using [(13)C(3)]malonyl-CoA confirmed that the order of extender substrate condensation was methylmalonyl-CoA, followed by two extensions with malonyl-CoA. Furthermore, SrsA was revealed to produce an alkylresorcylic acid as its direct product rather than an alkylresorcinol. The functional SrsB protein was produced in the membrane fraction in Streptomyces lividans and used for the in vitro SrsB reaction. When the SrsA reaction was coupled, SrsB produced alkylresorcinol methyl ether in the presence of S-adenosyl-l-methionine (SAM). SrsB was incapable of catalyzing the O methylation of alkylresorcinol, indicating that alkylresorcylic acid was the substrate of SrsB and that SrsB catalyzed the conversion of alkylresorcylic acid to alkylresorcinol methyl ether, namely, by both the O-methylation of the hydroxyl group (C-6) and the decarboxylation of the neighboring carboxyl group (C 1). O-methylated alkylresorcylic acid was not detected in the in vitro SrsAB reaction, although it was presumably stable, indicating that O-methylation did not precede decarboxylation. We therefore postulated that O-methylation was coupled with decarboxylation and proposed that SrsB catalyzed the feasible SAM dependent decarboxylative methylation of alkylresorcylic acid. To the best of our knowledge, this is the first report of a methyltransferase that catalyzes decarboxylative methylation. PMID- 22247508 TI - AMP-forming acetyl coenzyme A synthetase in the outermost membrane of the hyperthermophilic crenarchaeon Ignicoccus hospitalis. AB - Ignicoccus hospitalis, a hyperthermophilic, chemolithoautotrophic crenarchaeon was found to possess a new CO(2) fixation pathway, the dicarboxylate/4 hydroxybutyrate cycle. The primary acceptor molecule for this pathway is acetyl coenzyme A (acetyl-CoA), which is regenerated in the cycle via the characteristic intermediate 4-hydroxybutyrate. In the presence of acetate, acetyl-CoA can alternatively be formed in a one-step mechanism via an AMP-forming acetyl-CoA synthetase (ACS). This enzyme was identified after membrane preparation by two dimensional native PAGE/SDS-PAGE, followed by matrix-assisted laser desorption ionization-time of flight tandem mass spectrometry and N-terminal sequencing. The ACS of I. hospitalis exhibits a molecular mass of ~690 kDa with a monomeric molecular mass of 77 kDa. Activity tests on isolated membranes and bioinformatic analyses indicated that the ACS is a constitutive membrane-associated (but not an integral) protein complex. Unexpectedly, immunolabeling on cells of I. hospitalis and other described Ignicoccus species revealed that the ACS is localized at the outermost membrane. This perfectly coincides with recent results that the ATP synthase and the H(2):sulfur oxidoreductase complexes are also located in the outermost membrane of I. hospitalis. These results imply that the intermembrane compartment of I. hospitalis is not only the site of ATP synthesis but may also be involved in the primary steps of CO(2) fixation. PMID- 22247509 TI - Outer membrane targeting, ultrastructure, and single molecule localization of the enteropathogenic Escherichia coli type IV pilus secretin BfpB. AB - Type IV pili (T4P) are filamentous surface appendages required for tissue adherence, motility, aggregation, and transformation in a wide array of bacteria and archaea. The bundle-forming pilus (BFP) of enteropathogenic Escherichia coli (EPEC) is a prototypical T4P and confirmed virulence factor. T4P fibers are assembled by a complex biogenesis machine that extrudes pili through an outer membrane (OM) pore formed by the secretin protein. Secretins constitute a superfamily of proteins that assemble into multimers and support the transport of macromolecules by four evolutionarily ancient secretion systems: T4P, type II secretion, type III secretion, and phage assembly. Here, we determine that the lipoprotein transport pathway is not required for targeting the BfpB secretin protein of the EPEC T4P to the OM and describe the ultrastructure of the single particle averaged structures of the assembled complex by transmission electron microscopy. Furthermore, we use photoactivated localization microscopy to determine the distribution of single BfpB molecules fused to photoactivated mCherry. In contrast to findings in other T4P systems, we found that BFP components predominantly have an uneven distribution through the cell envelope and are only found at one or both poles in a minority of cells. In addition, we report that concurrent mutation of both the T4bP secretin and the retraction ATPase can result in viable cells and found that these cells display paradoxically low levels of cell envelope stress response activity. These results imply that secretins can direct their own targeting, have complex distributions and provide feedback information on the state of pilus biogenesis. PMID- 22247510 TI - Mutations at several loci cause increased expression of ribonucleotide reductase in Escherichia coli. AB - Production of deoxyribonucleotides for DNA synthesis is an essential and tightly regulated process. The class Ia ribonucleotide reductase (RNR), the product of the nrdAB genes, is required for aerobic growth of Escherichia coli. In catalyzing the reduction of ribonucleotides, two of the cysteines of RNR become oxidized, forming a disulfide bond. To regenerate active RNR, the cell uses thioredoxins and glutaredoxins to reduce the disulfide bond. Strains that lack thioredoxins 1 and 2 and glutaredoxin 1 do not grow because RNR remains in its oxidized, inactive form. However, suppressor mutations that lead to RNR overproduction allow glutaredoxin 3 to reduce sufficient RNR for growth of these mutant strains. We previously described suppressor mutations in the dnaA and dnaN genes that had such effects. Here we report the isolation of new mutations that lead to increased levels of RNR. These include mutations that were not known to influence production of RNR previously, such as a mutation in the hda gene and insertions in the nrdAB promoter region of insertion elements IS1 and IS5. Bioinformatic analysis raises the possibility that IS element insertion in this region represents an adaptive mechanism in nrdAB regulation in E. coli and closely related species. We also characterize mutations altering different amino acids in DnaA and DnaN from those isolated before. PMID- 22247511 TI - Structure, diversity, and mobility of the Salmonella pathogenicity island 7 family of integrative and conjugative elements within Enterobacteriaceae. AB - Integrative and conjugative elements (ICEs) are self-mobile genetic elements found in the genomes of some bacteria. These elements may confer a fitness advantage upon their host bacteria through the cargo genes that they carry. Salmonella pathogenicity island 7 (SPI-7), found within some pathogenic strains of Salmonella enterica, possesses features indicative of an ICE and carries genes implicated in virulence. We aimed to identify and fully analyze ICEs related to SPI-7 within the genus Salmonella and other Enterobacteriaceae. We report the sequence of two novel SPI-7-like elements, found within strains of Salmonella bongori, which share 97% nucleotide identity over conserved regions with SPI-7 and with each other. Although SPI-7 within Salmonella enterica serovar Typhi appears to be fixed within the chromosome, we present evidence that these novel elements are capable of excision and self-mobility. Phylogenetic analyses show that these Salmonella mobile elements share an ancestor which existed approximately 3.6 to 15.8 million years ago. Additionally, we identified more distantly related ICEs, with distinct cargo regions, within other strains of Salmonella as well as within Citrobacter, Erwinia, Escherichia, Photorhabdus, and Yersinia species. In total, we report on a collection of 17 SPI-7 related ICEs within enterobacterial species, of which six are novel. Using comparative and mutational studies, we have defined a core of 27 genes essential for conjugation. We present a growing family of SPI-7-related ICEs whose mobility, abundance, and cargo variability indicate that these elements may have had a large impact on the evolution of the Enterobacteriaceae. PMID- 22247512 TI - J-Western forms of Helicobacter pylori cagA constitute a distinct phylogenetic group with a widespread geographic distribution. AB - Chronic infection with Helicobacter pylori strains expressing the bacterial oncoprotein CagA confers an increased risk of gastric cancer. While much is known about the ancestry and molecular evolution of Western, East Asian, and Amerindian cagA sequences, relatively little is understood about a fourth group, known as "J Western," which has been detected mainly in strains from Okinawa, Japan. We show here that J-Western cagA sequences have a more widespread global distribution than previously recognized, occur in strains with multiple different ancestral origins (based on multilocus sequence typing [MLST] analysis), and did not arise recently. As shown by comparisons of Western and J-Western forms of CagA, there are 45 fixed or nearly fixed amino acid differences, and J-Western forms contain a unique 4-amino-acid insertion. The mean nucleotide diversity of synonymous sites (pi(s)) is slightly lower in the J-Western group than in the Western and East Asian groups (0.066, 0.086, and 0.083, respectively), which suggests that the three groups have comparable, but not equivalent, effective population sizes. The reduced pi(s) of the J-Western group is attributable to ancestral recombination events within the 5' region of cagA. Population genetic analyses suggest that within the cagA region encoding EPIYA motifs, the East Asian group underwent a marked reduction in effective population size compared to the Western and J-Western groups, in association with positive selection. Finally, we show that J-Western cagA sequences are found mainly in strains producing m2 forms of the secreted VacA toxin and propose that these functionally interacting proteins coevolved to optimize the gastric colonization capacity of H. pylori. PMID- 22247514 TI - Transoral robotic glossectomy for the treatment of obstructive sleep apnea hypopnea syndrome. AB - OBJECTIVE: In previous reports of transoral robotic surgery (TORS) for the treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS), patients underwent routine tracheotomy. We aim to assess the feasibility of performing robotically assisted partial glossectomy without tracheotomy and to assess efficacy by comparing OSAHS outcomes with those of established techniques. STUDY DESIGN: Historical cohort study with planned data collection. SETTING: Tertiary care center. SUBJECTS AND METHODS: Forty consecutive patients underwent TORS for OSAHS between October 2010 and June 2011 and were followed up with regard to complications, morbidity, and subjective and objective outcomes. Data from 27 of these patients who underwent concomitant z-palatoplasty with 6-month follow-up were compared with those of 2 matched cohorts of patients, who underwent either radiofrequency (radiofrequency base-of-tongue reduction [RFBOT]) or coblation (submucosal minimally invasive lingual excision [SMILE]) reduction of the tongue base and z-palatoplasty. RESULTS: No major bleeding or airway complications were observed. Postoperative pain and length of admission were similar between groups. All groups saw Epworth score and snore score improvement. Patients undergoing robot-assisted surgery took longer than their SMILE and RFBOT counterparts to tolerate normal diet and longer than RFBOT patients to resume normal activity. Apnea hypopnea index (AHI) reduction averaged 60.5% +/- 24.9% for TORS versus 37.0% +/- 51.6% (P = .042) and 32.0% +/- 43.3% (P = .012) for SMILE and RFBOT, respectively. Only the robotic group achieved statistically significant improvement in minimum oxygen saturation. Surgical cure rate for TORS (66.7%) was significant compared with RFBOT (20.8%, P = .001) but not compared with SMILE (45.5%, P = .135). CONCLUSION: Robotically assisted partial glossectomy feasibly can be performed without the need for tracheotomy. This technique resulted in greater AHI reduction but increased morbidity compared with the other techniques studied. PMID- 22247513 TI - Nitric oxide stress resistance in Porphyromonas gingivalis is mediated by a putative hydroxylamine reductase. AB - Porphyromonas gingivalis, the causative agent of adult periodontitis, must maintain nitric oxide (NO) homeostasis and surmount nitric oxide stress from host immune responses or other oral bacteria to survive in the periodontal pocket. To determine the involvement of a putative hydroxylamine reductase (PG0893) and a putative nitrite reductase-related protein (PG2213) in P. gingivalis W83 NO stress resistance, genes encoding those proteins were inactivated by allelic exchange mutagenesis. The isogenic mutants P. gingivalis FLL455 (PG0893ermF) and FLL456 (PG2213ermF) were black pigmented and showed growth rates and gingipain and hemolytic activities similar to those of the wild-type strain. P. gingivalis FLL455 was more sensitive to NO than the wild type. Complementation of P. gingivalis FLL455 with the wild-type gene restored the level of NO sensitivity to a level similar to that of the parent strain. P. gingivalis FLL455 and FLL456 showed sensitivity to oxidative stress similar to that of the wild-type strain. DNA microarray analysis showed that PG0893 and PG2213 were upregulated 1.4- and 2 fold, respectively, in cells exposed to NO. In addition, 178 genes were upregulated and 201 genes downregulated more than 2-fold. The majority of these modulated genes were hypothetical or of unknown function. PG1181, predicted to encode a transcriptional regulator, was upregulated 76-fold. Transcriptome in silico analysis of the microarray data showed major metabolomic variations in key pathways. Collectively, these findings indicate that PG0893 and several other genes may play an important role in P. gingivalis NO stress resistance. PMID- 22247515 TI - Postural control in older patients with benign paroxysmal positional vertigo. AB - OBJECTIVE: To evaluate the effectiveness of a canalith-repositioning procedure in postural control of older patients with idiopathic benign paroxysmal positional vertigo (BPPV). STUDY DESIGN: Prospective clinical trial. SETTING: A tertiary referral center. METHODS: A 9-month follow-up survey with a prospective design was conducted among 33 older patients with BPPV. Patients underwent static posturography (Balance Rehabilitation Unit [BRU]) and were administered the Dizziness Handicap Inventory (DHI) before and after the maneuver. After the treatment, they were compared with 33 healthy older subjects. The posturography parameters were the limit of stability (LOS), the center of body-pressure area (COP), and the velocity of oscillation (VOS) under conditions of visual, somatosensory, and visual-vestibular conflict. RESULTS: One canalith repositioning procedure relieved most patients' complaints (54.5%), and 100% were relieved with 1 to 3 maneuvers. Total DHI score and all subscales improved after treatment (P < .01). The LOS values pretreatment (mean [SD] 134.27 [55.32] cm(2)) and posttreatment (181.03 [47.79] cm(2)) were significantly different (P < .01). Comparative analysis of COP values showed a relevant statistical difference in 8 of 10 postmaneuver conditions (P < .01). The postmaneuver VOS showed a significant difference under 7 conflict conditions. There were no differences between the healthy older subjects and treated patients for all VOS values under all conditions and for COP values under 9 conditions. CONCLUSION: The canalith repositioning procedure promotes remission of symptoms, an increase in LOS, and improvement in postural control under conditions of somatosensory and visual conflict and visual-vestibular interaction. PMID- 22247516 TI - The beauty of TLR agonists for CTCL. PMID- 22247517 TI - Aurora: a new direction for a new dawn. PMID- 22247518 TI - Bad to the bone. PMID- 22247519 TI - FIXing factor VIII inhibitors. PMID- 22247520 TI - Relaxin' with endothelial progenitor cells. PMID- 22247521 TI - Complete genome sequence of a Dengue virus serotype 4 strain isolated in Roraima, Brazil. AB - Dengue is the most important arboviral disease worldwide. We report the complete genome sequence of a dengue virus serotype 4, genotype II strain isolated in 2010 from a patient with classical dengue fever in Boa Vista, Roraima, Brazil. PMID- 22247523 TI - A revision of the organ radiation doses from 2-fluoro-2-deoxy-D-glucose with reference to tumour presence. AB - Absorbed radiation doses to major human organs after intravenous bolus administration of 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) were reviewed. Absorbed doses were calculated using the medical internal radiation dose (MIRD) formalism from experimental activity-time curves. Thirty patients (22 with macroscopic lung tumour and 8 without observable disease) were investigated using a state-of-the art combined positron emission tomography/computer tomography system (Siemens Biograph 64). Each patient underwent a series of 10 consecutive whole-body PET scans during the first 60-min post-FDG administration. Differences were observed between organ radiation doses in this work and those reported in International Commission for Radiation Protection 106 (21 % in effective dose). The presence of tumour did not affect the FDG biodistribution. Large inter-individual variations in organ-absorbed doses were observed. This in combination with the lack of a model for bladder voiding suitable for all patients suggests the need for a more precise estimate of normal-organ radiation doses. This will be beneficial in optimising FDG administration in clinical routine. PMID- 22247522 TI - Genome sequence of a highly prevalent porcine partetravirus in Mainland China. AB - Partetravirus is a novel defined genus of animal parvoviruses. Here, we first report the genome sequence of porcine partetravirus strain JSNJ62, which is highly prevalent in mainland China. It will help in understanding the epidemiology and molecular characteristics of the porcine partetravirus. PMID- 22247524 TI - Dexamethasone suppression test: development of a method for simultaneous determination of cortisol and dexamethasone in human plasma by liquid chromatography/tandem mass spectrometry. AB - BACKGROUND: Dexamethasone is a synthetic glucocorticoid and is analogous to cortisol. It is used in the low-dose overnight dexamethasone suppression test (LDODST) to diagnose hypercortisolism in patients suspected to be suffering from Cushing's syndrome (CS). Measuring plasma dexamethasone in conjunction with measuring the amount of cortisol following the LDODST may allow clinicians to improve the diagnosis of CS. METHODS: Plasma samples were cleaned up by solid phase extraction before analysis. Liquid chromatographic separation was carried out under reversed-phase conditions prior to detection by tandem mass spectrometry. The analytes were determined in the presence of deuterated internal standards cortisol-d4 and dexamethasone-d4. RESULTS: Limit of quantitation (LOQ) was 1.89 nmol/L for dexamethasone and <0.02 MUmol/L for cortisol. Recoveries of both analytes ranged from 80.2% to 114.4%. Intra- and interassay coefficients of variation were <15%. The concentration of dexamethasone and cortisol was determined in 62 patients after performing LDODST. Dexamethasone concentrations ranged from 3.0 to 21.5 nmol/L (median 7.4 nmol/L) for 57 of these samples. For five patients the concentration was 0.22 MUmol/L). CONCLUSIONS: A method for the simultaneous measurement of dexamethasone and cortisol in human plasma by liquid chromatography/tandem mass spectrometry has been developed and validated. The method is suitable for controlling the compliance to the LDODST and for determining the cortisol plasma concentration after the test. The interpretation of LDODSTs was improved by the simultaneous determination of both analytes. PMID- 22247525 TI - Draft genome sequence of the virulent strain 01-B526 of the fish pathogen Aeromonas salmonicida. AB - Aeromonas salmonicida is an important fish pathogen, mainly of salmonids. This bacterium causes a disease named furunculosis, which is particularly detrimental for the aquaculture industry. Here, we present the draft genome sequence of A. salmonicida 01-B526, a strain isolated from a brook trout that is more virulent than A. salmonicida reference strain A449, for which a genome sequence is available. PMID- 22247527 TI - Genome sequence of Lactobacillus rhamnosus ATCC 8530. AB - Lactobacillus rhamnosus is found in the human gastrointestinal tract and is important for probiotics. We became interested in L. rhamnosus isolate ATCC 8530 in relation to beer spoilage and hops resistance. We report here the genome sequence of this isolate, along with a brief comparison to other available L. rhamnosus genome sequences. PMID- 22247528 TI - Complete genome sequence of strain 1860, a crenarchaeon of the genus Pyrobaculum able to grow with various electron acceptors. AB - Strain 1860, a novel member of the genus Pyrobaculum, is a hyperthermophilic organotrophic crenarchaeon growing anaerobically with various electron acceptors. The complete genome sequence reveals genes for several membrane-bound oxidoreductases, the Embden-Meyerhof and Entner-Doudoroff pathways for glucose metabolism, the tricarboxylic acid cycle, the glyoxylate cycle, and the dicarboxylate/4-hydroxybutyrate cycle. PMID- 22247530 TI - Complete genome sequence of Leuconostoc mesenteroides subsp. mesenteroides strain J18, isolated from kimchi. AB - Leuconostoc mesenteroides subsp. mesenteroides is one of the most predominant lactic acid bacterial groups during kimchi fermentation. Here, we report the complete genome sequence of L. mesenteroides subsp. mesenteroides J18, which was isolated from kimchi. The genome of the strain consists of a 1,896,561-bp chromosome and five plasmids. PMID- 22247529 TI - Draft genome sequence of Pantoea ananatis B1-9, a nonpathogenic plant growth promoting bacterium. AB - Pantoea ananatis B1-9 is an endophytic Gram-negative rhizobacterium that was isolated for its ability to promote plant growth and improve crop yield in the field. Here we report the draft genome sequence of P. ananatis B1-9. Comparison of this sequence to the sequenced genome of a plant-pathogenic P. ananatis strain, LMG20103, indicated that the pathogenesis-related genes were absent, but a subset of gene functions that may be related to its plant growth promotion were present. PMID- 22247531 TI - Genome sequence of strain HIMB30, a novel member of the marine Gammaproteobacteria. AB - Strain HIMB30 was isolated from coastal Hawaii seawater by extinction culturing in seawater-based oligotrophic medium. It is a phylogenetically unique member of the class Gammaproteobacteria that is only distantly related to its closest cultured relatives. Here we present the genome sequence of strain HIMB30, including genes for proteorhodopsin-based phototrophy and the Calvin-Benson Bassham cycle. PMID- 22247526 TI - Draft genome sequences of the Pseudomonas fluorescens biocontrol strains Wayne1R and Wood1R. AB - Pseudomonas fluorescens strains Wayne1R and Wood1R have proven capacities to improve plant health. Here we report the draft genome sequences and automatic annotations of both strains. Genome comparisons reveal similarities with P. fluorescens strain Pf-5, reveal the novelty of Wood1R, and indicate some genes that may be related to biocontrol. PMID- 22247533 TI - Draft genome sequence of plant growth-promoting rhizobium Mesorhizobium amorphae, isolated from zinc-lead mine tailings. AB - Here, we describe the draft genome sequence of Mesorhizobium amorphae strain CCNWGS0123, isolated from nodules of Robinia pseudoacacia growing on zinc-lead mine tailings. A large number of metal(loid) resistance genes, as well as genes reported to promote plant growth, were identified, presenting a great future potential for aiding phytoremediation in metal(loid)-contaminated soil. PMID- 22247532 TI - Draft genome sequences of the biocontrol bacterium Mitsuaria sp. strain H24L5A. AB - Mitsuaria sp. strain H24L5A is a plant-associated bacterium with proven capacities to suppress plant pathogens. Here, we report the draft genome sequences and automatic annotation of H24L5A. Comparative genomic analysis indicates H24L5A's similarity to the Leptothrix and Methylibium species, as well as several genes potentially contributing to its biocontrol activities. PMID- 22247534 TI - Genome sequence of Corynebacterium casei UCMA 3821, isolated from a smear-ripened cheese. AB - Corynebacterium casei is one of the most prevalent species present on the surfaces of smear-ripened cheeses, where it contributes to the production of the desired organoleptic properties. Here, we report the draft genome sequence of Corynebacterium casei UCMA 3821 to provide insights into its physiology. PMID- 22247535 TI - Genome sequence of Edwardsiella ictaluri 93-146, a strain associated with a natural channel catfish outbreak of enteric septicemia of catfish. AB - Edwardsiella ictaluri is the cause of extensive mortalities and economic losses to the channel catfish industry of the southeast United States. Here we report the complete genome of Edwardsiella ictaluri 93-146. Whole-genome sequence analysis of E. ictaluri provides a tool for understanding the genomic regions specific to the species and the Edwardsiella genus. PMID- 22247536 TI - Genome sequence of Corynebacterium glutamicum ATCC 14067, which provides insight into amino acid biosynthesis in coryneform bacteria. AB - We report the genome sequence of Corynebacterium glutamicum ATCC 14067 (once named Brevibacterium flavum), which is useful for taxonomy research and further molecular breeding in amino acid production. Preliminary comparison with those of the reported coryneform strains revealed some notable differences that might be related to the difficulties in molecular manipulation. PMID- 22247537 TI - Complete genome sequence of Salmonella enterica serovar pullorum RKS5078. AB - Salmonella enterica serovar Pullorum is a chicken-adapted pathogen, causing pullorum disease. Its strict host adaptation has been suspected to result in gene decay. To validate this hypothesis and identify the decayed genes, we sequenced the complete genome of S. Pullorum RKS5078. We found 263 pseudogenes in this strain and conducted functional analyses of the decayed genes. PMID- 22247538 TI - Skype: a tool for functional assessment in orthopaedic research. AB - Skype is a free program which enables PC users to make video calls to other users with Internet access. We carried out a prospective review of all acromioclavicular joint hook plates for lateral-third clavicle fractures over a five-year period. Functional assessment with Oxford and Constant shoulder scores were carried out using Skype and compared to outpatient review using the Bland Altman method. Of 36 patients (mean age 36 years), 33 had a computer with a video camera, all 33 had Internet access and 22 were already users of Skype. In total 29 patients were happy to take part in Skype assessment (83%). In comparison with outpatient review, there was a mean difference in the Oxford score of -0.48 (95% confidence interval -0.84, -0.12); the mean difference for the Constant score was -0.68 (95% confidence interval -1.08, -0.29). These differences were not clinically significant, confirming that Skype can be used as an alternative to goniometry in this clinical setting. A survey showed that 93% of 29 patients surveyed preferred the use of Skype for follow-up, mainly due to the convenience and cost-saving involved. The study demonstrates the potential for this new technique in providing patients with more options for follow-up. PMID- 22247539 TI - At issue: Cochrane, early intervention, and mental health reform: analysis, paralysis, or evidence-informed progress? AB - Among the noncommunicable diseases, mental ill-health represents the major threat to social and economic progress because it impacts so powerfully on the most critical decades of life. Consequently, mental health reform is increasingly recognized as an urgent priority worldwide. This brings into sharp focus the role of evidence, and more specifically the Cochrane paradigm, in influencing decisions about health system reform. Cochrane clearly still has great value, especially in evidence-based medicine, where the focus is the evaluation of individual treatments. However, it cannot be allowed to be a dominant influence in evidence-based health care (EBHC) policy decisions for health system reform, unless it is modernized or complemented. Health services reform should definitely be as evidence-based as possible; however, the jury should consider its verdict on key reform proposals based on the balance of probabilities and informed by the best "available" evidence from all sources, not only randomized clinical trials, which in many domains may be never be feasible. This is particularly the case when reform is urgent, and the status quo has manifestly failed. So on the one hand, the evidence-based paradigm must not be misused to stifle or paralyze urgent reform. Alternatively, there is a real risk that, if we do not improve the sophistication of EBHC, the whole paradigm will be sidelined and reform will remain reactive, impulsive, and desultory. The recent Cochrane review on early intervention in psychosis provides an opportunity to consider these issues and their wider significance. PMID- 22247541 TI - Development of a novel method for analyzing collagen O-glycosylations by hydrazide chemistry. AB - In recent years, glycopeptide purification by hydrazide chemistry has become popular in structural studies of glycoconjugates; however, applications of this method have been almost completely restricted to analysis of the N-glycoproteome. Here we report a novel method for analyzing O-glycosylations unique to collagen, which are attached to hydroxylysine and include galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine. We established a hydrazide chemistry-based glycopeptide purification method using (1) galactose oxidase to introduce an aldehyde into glycopeptides and (2) formic acid with heating to elute the bound glycopeptides by cleaving the hydrazone bond. This method allows not only identification of O-glycosylation sites in collagen but also concurrent discrimination of two types of carbohydrate substitutions. In bovine type I and type II collagens, galactosyl-hydroxylysine /glucosyl-galactosyl-hydroxylysine containing peptides were specifically detected on subsequent comprehensive liquid chromatography (LC)/MS analysis, and many O-glycosylation sites, including unreported ones, were identified. The position of glycosylated hydroxylysine, which is determined by our unambiguous and simple method, could provide insight into the physiological role of the modifications. PMID- 22247542 TI - DHHC protein S-acyltransferases use similar ping-pong kinetic mechanisms but display different acyl-CoA specificities. AB - DHHC proteins catalyze the reversible S-acylation of proteins at cysteine residues, a modification important for regulating protein localization, stability, and activity. However, little is known about the kinetic mechanism of DHHC proteins. A high-performance liquid chromatography (HPLC), fluorescent peptide-based assay for protein S-acylation activity was developed to characterize mammalian DHHC2 and DHHC3. Time courses and substrate saturation curves allowed the determination of V(max) and K(m) values for both the peptide N myristoylated-GCG and palmitoyl-coenzyme A. DHHC proteins acylate themselves upon incubation with palmitoyl-CoA, which is hypothesized to reflect a transient acyl enzyme transfer intermediate. Single turnover assays with DHHC2 and DHHC3 demonstrated that a radiolabeled acyl group on the enzyme transferred to the protein substrate, consistent with a two-step ping-pong mechanism. Enzyme autoacylation and acyltransfer to substrate displayed the same acyl-CoA specificities, further supporting a two-step mechanism. Interestingly, DHHC2 efficiently transferred acyl chains 14 carbons and longer, whereas DHHC3 activity was greatly reduced by acyl-CoAs with chain lengths longer than 16 carbons. The rate and extent of autoacylation of DHHC3, as well as the rate of acyl chain transfer to protein substrate, were reduced with stearoyl-CoA when compared with palmitoyl-CoA. This is the first observation of lipid substrate specificity among DHHC proteins and may account for the differential S-acylation of proteins observed in cells. PMID- 22247543 TI - Battles with iron: manganese in oxidative stress protection. AB - The redox-active metal manganese plays a key role in cellular adaptation to oxidative stress. As a cofactor for manganese superoxide dismutase or through formation of non-proteinaceous manganese antioxidants, this metal can combat oxidative damage without deleterious side effects of Fenton chemistry. In either case, the antioxidant properties of manganese are vulnerable to iron. Cellular pools of iron can outcompete manganese for binding to manganese superoxide dismutase, and through Fenton chemistry, iron may counteract the benefits of non proteinaceous manganese antioxidants. In this minireview, we highlight ways in which cells maximize the efficacy of manganese as an antioxidant in the midst of pro-oxidant iron. PMID- 22247544 TI - Mapping structural determinants within third intracellular loop that direct signaling specificity of type 1 corticotropin-releasing hormone receptor. AB - The type 1 corticotropin-releasing hormone receptor (CRH-R1) influences biological responses important for adaptation to stressful stimuli, through activation of multiple downstream effectors. The structural motifs within CRH-R1 that mediate G protein activation and signaling selectivity are unknown. The aim of this study was to gain insights about important structural determinants within the third intracellular loop (IC3) of the human CRH-R1alpha important for cAMP and ERK1/2 pathways activation and selectivity. We investigated the role of the juxtamembrane regions of IC3 by mutating amino acid cassettes or specific residues to alanine. Although simultaneous tandem alanine mutations of both juxtamembrane regions Arg(292)-Met(295) and Lys(311)-Lys(314) reduced ligand binding and impaired signaling, all other mutant receptors retained high affinity binding, indistinguishable from wild-type receptor. Agonist-activated receptors with tandem mutations at the proximal or distal terminal segments enhanced activation of adenylyl cyclase by 50-75% and diminished activation of inositol trisphosphate and ERK1/2 by 60-80%. Single Ala mutations identified Arg(292), Lys(297), Arg(310), Lys(311), and Lys(314) as important residues for the enhanced activation of adenylyl cyclase, partly due to reduced inhibition of adenylyl cyclase activity by pertussis toxin-sensitive G proteins. In contrast, mutation of Arg(299) reduced receptor signaling activity and cAMP response. Basic as well as aliphatic amino acids within both juxtamembrane regions were identified as important for ERK1/2 phosphorylation through activation of pertussis toxin sensitive G proteins as well as G(q) proteins. These data uncovered unexpected roles for key amino acids within the highly conserved hydrophobic N- and C terminal microdomains of IC3 in the coordination of CRH-R1 signaling activity. PMID- 22247545 TI - NEU1 sialidase expressed in human airway epithelia regulates epidermal growth factor receptor (EGFR) and MUC1 protein signaling. AB - Epithelial cells (ECs) lining the airways provide a protective barrier between the external environment and the internal host milieu. These same airway epithelia express receptors that respond to danger signals and initiate repair programs. Because the sialylation state of a receptor can influence its function and is dictated in part by sialidase activity, we asked whether airway epithelia express catalytically active sialidase(s). Human primary small airway and A549 ECs expressed NEU1 sialidase at the mRNA and protein levels, and NEU1 accounted for >70% of EC sialidase activity. Blotting with Maackia amurensis and peanut agglutinin lectins established epidermal growth factor receptor (EGFR) and MUC1 as in vivo substrates for NEU1. NEU1 associated with EGFR and MUC1, and NEU1-EGFR association was regulated by EGF stimulation. NEU1 overexpression diminished EGF stimulated EGFR Tyr-1068 autophosphorylation by up to 44% but enhanced MUC1 dependent Pseudomonas aeruginosa adhesion by 1.6-1.7-fold and flagellin stimulated ERK1/2 activation by 1.7-1.9-fold. In contrast, NEU1 depletion increased EGFR activation (1.5-fold) and diminished MUC1-mediated bacterial adhesion (38-56%) and signaling (73%). These data indicate for the first time that human airway epithelia express catalytically active NEU1 sialidase that regulates EGFR- and MUC1-dependent signaling and bacterial adhesion. NEU1 catalytic activity may offer an additional level of regulation over the airway epithelial response to ligands, pathogens, and injurious stimuli. PMID- 22247546 TI - O-antigen and core carbohydrate of Vibrio fischeri lipopolysaccharide: composition and analysis of their role in Euprymna scolopes light organ colonization. AB - Vibrio fischeri exists in a symbiotic relationship with the Hawaiian bobtail squid, Euprymna scolopes, where the squid provides a home for the bacteria, and the bacteria in turn provide camouflage that helps protect the squid from night time predators. Like other gram-negative organisms, V. fischeri expresses lipopolysaccharide (LPS) on its cell surface. The structure of the O-antigen and the core components of the LPS and their possible role in colonization of the squid have not previously been determined. In these studies, an O-antigen ligase mutant, waaL, was utilized to determine the structures of these LPS components and their roles in colonization of the squid. WaaL ligates the O-antigen to the core of the LPS; thus, LPS from waaL mutants lacks O-antigen. Our results show that the V. fischeri waaL mutant has a motility defect, is significantly delayed in colonization, and is unable to compete with the wild-type strain in co colonization assays. Comparative analyses of the LPS from the wild-type and waaL strains showed that the V. fischeri LPS has a single O-antigen repeat composed of yersiniose, 8-epi-legionaminic acid, and N-acetylfucosamine. In addition, the LPS from the waaL strain showed that the core structure consists of L-glycero-D-manno heptose, D-glycero-D-manno-heptose, glucose, 3-deoxy-D-manno-octulosonic acid, N acetylgalactosamine, 8-epi-legionaminic acid, phosphate, and phosphoethanolamine. These studies indicate that the unusual V. fischeri O-antigen sugars play a role in the early phases of bacterial colonization of the squid. PMID- 22247547 TI - Membrane estrogen signaling enhances tumorigenesis and metastatic potential of breast cancer cells via estrogen receptor-alpha36 (ERalpha36). AB - Protein kinase C (PKC) signaling can be activated rapidly by 17beta-estradiol (E(2)) via nontraditional signaling in ERalpha-positive MCF7 and ERalpha-negative HCC38 breast cancer cells and is associated with tumorigenicity. Additionally, E(2) has been shown to elicit anti-apoptotic effects in cancer cells counteracting pro-apoptotic effects of chemotherapeutics. Supporting evidence suggests the existence of a membrane-associated ER that differs from the traditional receptors, ERalpha and ERbeta. Our aim was to identify the ER responsible for rapid PKC activation and to evaluate downstream effects, such as proliferation, apoptosis, and metastasis. RT-PCR, Western blot, and immunofluorescence were used to determine the presence of ER splice variants in multiple cell lines. E(2) effects on PKC activity were measured with and without ER-blocking antibodies. Cell proliferation was determined by [(3)H]thymidine incorporation, and cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide, (MTT) whereas apoptosis was determined by DNA fragmentation and TUNEL. Quantitative RT-PCR and sandwich ELISA were used to determine the effects on metastatic factors. The role of membrane-dependent signaling in cancer cell invasiveness was examined using an in vitro assay. The results indicate the presence of an ERalpha splice variant, ERalpha36, in ERalpha positive MCF7 and ERalpha-negative HCC38 breast cancer cells, which localized to plasma membranes and rapidly activated PKC in response to E(2), leading to deleterious effects such as enhancement of proliferation, protection against apoptosis, and enhancement of metastatic factors. These findings propose ERalpha36 as a novel target for the development of therapies that can prevent progression of breast cancer in the primary tumor as well as during metastasis. PMID- 22247548 TI - Five decades with glutathione and the GSTome. AB - Uncle Folke inspired me to become a biochemist by demonstrating electrophoresis experiments on butterfly hemolymph in his kitchen. Glutathione became the subject for my undergraduate project in 1964 and has remained a focal point in my research owing to its multifarious roles in the cell. Since the 1960s, the multiple forms of glutathione transferase (GST), the GSTome, were isolated and characterized, some of which were discovered in our laboratory. Products of oxidative processes were found to be natural GST substrates. Examples of toxic compounds against which particular GSTs provide protection include 4 hydroxynonenal and ortho-quinones, with possible links to the etiology of Alzheimer and Parkinson diseases and other degenerative conditions. The role of thioltransferase and glutathione reductase in the cellular reduction of disulfides and other oxidized forms of thiols was clarified. Glyoxalase I catalyzes still another glutathione-dependent detoxication reaction. The unusual steady-state kinetics of this zinc-containing enzyme initiated model discrimination by regression analysis. Functional properties of the enzymes have been altered by stochastic mutations based on DNA shuffling and rationally tailored by structure-based redesign. We found it useful to represent promiscuous enzymes by vectors or points in multidimensional substrate-activity space and visualize them by multivariate analysis. Adopting the concept "molecular quasi species," we describe clusters of functionally related enzyme variants that may emerge in natural as well as directed evolution. PMID- 22247549 TI - Ubiquitination of human leukocyte antigen (HLA)-DM by different membrane associated RING-CH (MARCH) protein family E3 ligases targets different endocytic pathways. AB - HLA-DM plays an essential role in the peptide loading of classical class II molecules and is present both at the cell surface and in late endosomal peptide loading compartments. Trafficking of DM within antigen-presenting cells is complex and is, in part, controlled by a tyrosine-based targeting signal present in the cytoplasmic tail of DMbeta. Here, we show that DM also undergoes post translational modification through ubiquitination of a single lysine residue present in the cytoplasmic tail of the alpha chain, DMalpha. Ubiquitination of DM by MARCH1 and MARCH9 induced loss of DM molecules from the cell surface by a mechanism that cumulatively involved both direct attachment of ubiquitin chains to DMalpha and a functional tyrosine-based signal on DMbeta. In contrast, MARCH8 induced loss of surface DM was entirely dependent upon the tyrosine signal on DMbeta. In the absence of this tyrosine residue, levels of DM remained unchanged irrespective of whether DMalpha was ubiquitinated by MARCH8. The influence of MARCH8 was indirect and may have resulted from modification of components of the endocytic machinery by ubiquitination. PMID- 22247550 TI - Pliable DNA conformation of response elements bound to transcription factor p63. AB - We show that changes in the nucleotide sequence alter the DNA conformation in the crystal structures of p63 DNA-binding domain (p63DBD) bound to its response element. The conformation of a 22-bp canonical response element containing an AT spacer between the two half-sites is unaltered compared with that containing a TA spacer, exhibiting superhelical trajectory. In contrast, a GC spacers abolishes the DNA superhelical trajectory and exhibits less bent DNA, suggesting that increased GC content accompanies increased double helix rigidity. A 19-bp DNA, representing an AT-rich response element with overlapping half-sites, maintains superhelical trajectory and reveals two interacting p63DBD dimers crossing one another at 120 degrees . p63DBD binding assays to response elements of increasing length complement the structural studies. We propose that DNA deformation may affect promoter activity, that the ability of p63DBD to bind to superhelical DNA suggests that it is capable of binding to nucleosomes, and that overlapping response elements may provide a mechanism to distinguish between p63 and p53 promoters. PMID- 22247551 TI - Structural insight into recognition of methylated histone tails by retinoblastoma binding protein 1. AB - Retinoblastoma-binding protein 1 (RBBP1), also named AT-rich interaction domain containing 4A (ARID4A), is a tumor and leukemia suppressor involved in epigenetic regulation in leukemia and Prader-Willi/Angelman syndromes. Although the involvement in epigenetic regulation is proposed to involve its chromobarrel and/or Tudor domains because of their potential binding to methylated histone tails, the structures of these domains and their interactions with methylated histone tails are still uncharacterized. In this work, we first found that RBBP1 contains five domains by bioinformatics analysis. Three of the five domains, i.e. chromobarrel, Tudor, and PWWP domains, are Royal Family domains, which potentially bind to methylated histone tails. We further purified these domains and characterized their interaction with methylated histone tails by NMR titration experiments. Among the three Royal Family domains, only the chromobarrel domain could recognize trimethylated H4K20 (with an affinity of ~3 mm), as well as recognizing trimethylated H3K9, H3K27, and H3K36 (with lower affinities). The affinity could be further enhanced up to 15-fold by the presence of DNA. The structure of the chromobarrel domain of RBBP1 determined by NMR spectroscopy has an aromatic cage. Mutagenesis analysis identified four aromatic residues of the cage as the key residues for methylated lysine recognition. Our studies indicate that the chromobarrel domain of RBBP1 is responsible for recognizing methylated histone tails in chromatin remodeling and epigenetic regulation, which presents a significant advance in our understanding of the mechanism and relationship between RBBP1-related gene suppression and epigenetic regulation. PMID- 22247552 TI - Key role of two terminal domains in the bidirectional polymerization of FtsA protein. AB - The effect of two different truncations involving either the 1C domain or the simultaneous absence of the S12-13 beta-strands of the FtsA protein from Streptococcus pneumoniae, located at opposite terminal sides in the molecular structure, suggests that they are essential for ATP-dependent polymerization. These two truncated proteins are not able to polymerize themselves but can be incorporated to some extent into the FtsA(+) polymers during the assembling process. Consequently, they block the growth of the FtsA(+) polymers and slow down the polymerization rate. The combined action of the two truncated proteins produces an additive effect on the inhibition of FtsA(+) polymerization, indicating that each truncation affects a different interaction site within the FtsA molecule. PMID- 22247553 TI - Fibronectin induces endothelial cell migration through beta1 integrin and Src dependent phosphorylation of fibroblast growth factor receptor-1 at tyrosines 653/654 and 766. AB - The extracellular matrix microenvironment regulates cell phenotype and function. One mechanism by which this is achieved is the transactivation of receptor tyrosine kinases by specific matrix molecules. Here, we demonstrate that the provisional matrix protein, fibronectin (FN), activates fibroblast growth factor (FGF) receptor-1 (FGFR1) independent of FGF ligand in liver endothelial cells. FN activation of FGFR1 requires beta1 integrin, as evidenced by neutralizing antibody and siRNA-based studies. Complementary genetic and pharmacologic approaches identify that the non-receptor tyrosine kinase Src is required for FN transactivation of FGFR1. Whereas FGF ligand-induced phosphorylation of FGFR1 preferentially activates ERK, FN-induced phosphorylation of FGFR1 preferentially activates AKT, indicating differential downstream signaling of FGFR1 in response to alternate stimuli. Mutation analysis of known tyrosine residues of FGFR1 reveals that tyrosine 653/654 and 766 residues are required for FN-FGFR1 activation of AKT and chemotaxis. Thus, our study mechanistically dissects a new signaling pathway by which FN achieves endothelial cell chemotaxis, demonstrates how differential phosphorylation profiles of FGFR1 can achieve alternate downstream signals, and, more broadly, highlights the diversity of mechanisms by which the extracellular matrix microenvironment regulates cell behavior through transactivation of receptor tyrosine kinases. PMID- 22247554 TI - Characterizing phospholamban to sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) protein binding interactions in human cardiac sarcoplasmic reticulum vesicles using chemical cross-linking. AB - Chemical cross-linking was used to study protein binding interactions between native phospholamban (PLB) and SERCA2a in sarcoplasmic reticulum (SR) vesicles prepared from normal and failed human hearts. Lys(27) of PLB was cross-linked to the Ca(2+) pump at the cytoplasmic extension of M4 (at or near Lys(328)) with the homobifunctional cross-linker, disuccinimidyl glutarate (7.7 A). Cross-linking was augmented by ATP but abolished by Ca(2+) or thapsigargin, confirming in native SR vesicles that PLB binds preferentially to E2 (low Ca(2+) affinity conformation of the Ca(2+)-ATPase) stabilized by ATP. To assess the functional effects of PLB binding on SERCA2a activity, the anti-PLB antibody, 2D12, was used to disrupt the physical interactions between PLB and SERCA2a in SR vesicles. We observed a tight correlation between 2D12-induced inhibition of PLB cross-linking to SERCA2a and 2D12 stimulation of Ca(2+)-ATPase activity and Ca(2+) transport. The results suggest that the inhibitory effect of PLB on Ca(2+)-ATPase activity in SR vesicles results from mutually exclusive binding of PLB and Ca(2+) to the Ca(2+) pump, requiring PLB dissociation for catalytic activation. Importantly, the same result was obtained with SR vesicles prepared from normal and failed human hearts; therefore, we conclude that PLB binding interactions with the Ca(2+) pump are largely unchanged in failing myocardium. PMID- 22247555 TI - Determinants of Formin Homology 1 (FH1) domain function in actin filament elongation by formins. AB - Formin-mediated elongation of actin filaments proceeds via association of Formin Homology 2 (FH2) domain dimers with the barbed end of the filament, allowing subunit addition while remaining processively attached to the end. The flexible Formin Homology 1 (FH1) domain, located directly N-terminal to the FH2 domain, contains one or more stretches of polyproline that bind the actin-binding protein profilin. Diffusion of FH1 domains brings associated profilin-actin complexes into contact with the FH2-bound barbed end of the filament, thereby enabling direct transfer of actin. We investigated how the organization of the FH1 domain of budding yeast formin Bni1p determines the rates of profilin-actin transfer onto the end of the filament. Each FH1 domain transfers actin to the barbed end independently of the other and structural evidence suggests a preference for actin delivery from each FH1 domain to the closest long-pitch helix of the filament. The transfer reaction is diffusion-limited and influenced by the affinities of the FH1 polyproline tracks for profilin. Position-specific sequence variations optimize the efficiency of FH1-stimulated polymerization by binding profilin weakly near the FH2 domain and binding profilin more strongly farther away. FH1 domains of many other formins follow this organizational trend. This particular sequence architecture may optimize the efficiency of FH1-stimulated elongation. PMID- 22247556 TI - High throughput engineering to revitalize a vestigial electron transfer pathway in bacterial photosynthetic reaction centers. AB - Photosynthetic reaction centers convert light energy into chemical energy in a series of transmembrane electron transfer reactions, each with near 100% yield. The structures of reaction centers reveal two symmetry-related branches of cofactors (denoted A and B) that are functionally asymmetric; purple bacterial reaction centers use the A pathway exclusively. Previously, site-specific mutagenesis has yielded reaction centers capable of transmembrane charge separation solely via the B branch cofactors, but the best overall electron transfer yields are still low. In an attempt to better realize the architectural and energetic factors that underlie the directionality and yields of electron transfer, sites within the protein-cofactor complex were targeted in a directed molecular evolution strategy that implements streamlined mutagenesis and high throughput spectroscopic screening. The polycistronic approach enables efficient construction and expression of a large number of variants of a heteroligomeric complex that has two intimately regulated subunits with high sequence similarity, common features of many prokaryotic and eukaryotic transmembrane protein assemblies. The strategy has succeeded in the discovery of several mutant reaction centers with increased efficiency of the B pathway; they carry multiple substitutions that have not been explored or linked using traditional approaches. This work expands our understanding of the structure-function relationships that dictate the efficiency of biological energy-conversion reactions, concepts that will aid the design of bio-inspired assemblies capable of both efficient charge separation and charge stabilization. PMID- 22247557 TI - Regulation of insulin signaling and glucose transporter 4 (GLUT4) exocytosis by phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, skeletal muscle, and kidney enriched inositol polyphosphate phosphatase (SKIP). AB - The glucose transporter 4 (GLUT4) is responsible for glucose uptake in the skeletal muscle. Insulin-induced translocation of GLUT4 to the plasma membrane requires phosphatidylinositol 3-kinase activation-mediated generation of phosphatidylinositol 3,4,5-trisphosphate PIP(3) and subsequent activation of Akt. Previous studies suggested that skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) has negative effects on the regulation of insulin signaling in the skeletal muscle cells. Here, we compared its effects on insulin signaling by selective inhibition of SKIP, SHIP2, and phosphatase and tensin homologue on chromosome 10 (PTEN) by short interfering RNA in the C2C12 myoblast cells. Suppression of SKIP significantly increased the insulin stimulated phosphatidylinositol 3,4,5-trisphosphate levels and Akt phosphorylation. Furthermore, silencing of SKIP, but not of PTEN, increased the insulin-dependent recruitment of GLUT4 vesicles to the plasma membrane. Taken together, these results imply that SKIP negatively regulates insulin signaling and glucose uptake by inhibiting GLUT4 docking and/or fusion to the plasma membrane. PMID- 22247558 TI - Role of Cdc14 in timing the end of cell division: Cdc14 phosphatases preferentially dephosphorylate a subset of cyclin-dependent kinase (Cdk) sites containing phosphoserine. PMID- 22247559 TI - Regulation of the catalytic domain of protein phosphatase 1 by the terminal region of protein phosphatase 2B. AB - C-terminal regions of the protein phosphatases PP1 and PP2B were seldom studied. C-terminal 24 amino acids of PP1 was deleted, its enzymatic activity increased 3 fold while its stability declined. When the truncated PP1 was fused with the terminal (residues 483-511) of PP2B, both its enzymatic activity and its stability remained low. This indicates that the termini of PP2B and PP1 have inhibitory effect on the catalytic domain of PP1. PP1-(1-306) and PP1wt differ in their activation by metal ions, showing that the sites interacting with metal ions are not located in its C-terminus; while metal ions activated notably to PP1/PP2B chimera. In addition, the sensitivity results of PP1-(1-306) to the inhibitors, TM and NCTD, proved that these two inhibitors also did not bind to the C-terminus. However, the IC(50)s of PP1/PP2B chimera were higher than for PP1 (1-306), indicating that the C-terminal region interferes interactions with these inhibitors to some extent. Although 483-511 segment of PP2B was not the functional domain, it played important role in interaction with metal ions and inhibitors. It further indicates although PP1 and PP2B have high sequence identity, their non-conserved termini have different roles. PMID- 22247560 TI - The OsGEN-L protein from Oryza sativa possesses Holliday junction resolvase activity as well as 5'-flap endonuclease activity. AB - OsGEN-L has a 5'-flap endonuclease activity and plays an essential role in rice microspore development. The Class 4 RAD2/XPG family nucleases, including OsGEN-L, were recently found to have resolving activity for the Holliday junction (HJ), the intermediate of DNA strand recombination. In this study, we performed a detailed characterization of OsGEN-L, as a structure-specific endonuclease. Highly purified OsGEN-L was prepared as the full-length protein for in vitro endonuclease assays using various structured DNAs, and the 5'-flap endonuclease activity, which is stimulated in a PCNA-dependent manner, was demonstrated. In addition, the in vitro HJ resolving activity of OsGEN-L represents the first such activity originating from plant cells. OsGEN-L cleaved HJ at symmetrically related sites of the branch point. However, the two branched strands seemed to be cleaved individually, and not cooperatively, by each OsGEN-L monomer protein. The substrate specificity suggests that OsGEN-L functions in multiple processes of DNA metabolism in rice cells. PMID- 22247561 TI - Hydroxylation mediates chromatin demethylation. AB - Methylation of DNA and histones in chromatin has been implicated in numerous biological processes. For many years, methylation has been recognized as static and stable modification, as compared with other covalent modifications of chromatin. Recently, however, several mechanisms have been demonstrated to be involved in demethylation of chromatin, suggesting that chromatin methylation is more dynamically regulated. One chemical reaction that mediates demethylation of both DNA and histones is hydroxylation, catalysed by Fe(II) and alpha ketoglutarate (KG)-dependent hydroxylase/dioxygenase. Given that methylation of chromatin is an important epigenetic mark involved in fundamental biological processes such as cell fate determination, understanding how chromatin methylation is dynamically regulated has implications for human diseases and regenerative medicine. PMID- 22247562 TI - Membrane-induced alteration of the secondary structure in the SWAP-70 pleckstrin homology domain. AB - Differences in the conformation of the pleckstrin homology (PH) domain of switch associated protein-70 (SWAP-70) in solution and at the lipid bilayer membrane surface were examined using CD, fluorescence and NMR spectroscopy. Intracellular relocalization of SWAP-70 from the cytoplasm to the plasma membrane and then to the nucleus is associated with its cellular functions. The PH domain of SWAP-70 contains a phosphoinositide-binding site and a nuclear localization signal, which localize SWAP-70 to the plasma membrane and nucleus, respectively. CD and fluorescence spectra showed that a significant conformational alteration involving formation of disordered structure occurs when the PH domain binds to D myo-phosphatidylinositol 3,4,5-trisphosphate or D-myo-phosphatidylinositol 4,5 bisphosphate embedded in lipid bilayer vesicles. NMR spectra indicate that Ala and Trp residues located in the C-terminal alpha-helix of the PH domain undergo conformational alterations to form a disordered structure at the vesicle surface. These conformational alterations were not induced by association with inositol 1,3,4,5-tetrakisphosphate in solution or coexistence of phosphatidylcholine vesicles. Interaction with the plane of the lipid bilayer via association with the phosphoinositides is required for the unfolding of the C-terminal alpha-helix of the PH domain. The unwinding of the C-terminal alpha-helix could regulate the functions of SWAP-70 at the plasma membrane surface. PMID- 22247563 TI - T/NK cell type chronic active Epstein-Barr virus disease in adults: an underlying condition for Epstein-Barr virus-associated T/NK-cell lymphoma. AB - A chronic infectious mononucleosis-like illness caused by Epstein-Barr virus (EBV) is called 'chronic active EBV disease', which is defined as an EBV associated lymphoproliferative disease. This lymphoproliferative disease is rare and predominantly occurs in Japanese children. Between 1998 and 2010, seven adult onset cases (aged 20-45 years, median 39 years) were identified, which initially presented with inflammatory diseases, including hepatitis, interstitial pneumonitis, uveitis, nephritis and hypersensitivity to mosquito bites. They showed an EBV viral load in the peripheral blood and evidence of EBV infection of T or natural killer (NK) cells. Five cases (71.4%) developed EBV-positive T/NK cell lymphoma/leukaemia at a median of 5 years (range 1-7 years) after the diagnosis. Although l-asparaginase-containing chemotherapy was effective for the lymphomas, only allogeneic haematopoietic cell transplantation eradicated EBV infected cells. This observation indicates that persistent EBV infection of T or NK cells defines a distinct disease entity, which provides an underlying condition for EBV-positive T/NK-cell lymphoma/leukaemia. PMID- 22247564 TI - An Ecological Perspective on the Media and Youth Development. AB - From an ecological perspective, daily activities are both a cause and a consequence of youth development. Research on youth activities directs attention to the processes through which daily activities may have an impact on youth, including: (a) providing chances to learn and practice skills; (b) serving as a forum for identity development; (c) affording opportunities to build social ties; (d) connecting youth to social institutions; and (e) keeping youth from engaging in other kinds of activities. Youth's daily activities, in turn, both influence and are influenced by the multi-layered ecology within which their lives are embedded, an ecology that ranges from the proximal contexts of everyday life (e.g., family, peer group) to the larger political, economic, legal and cultural contexts of the larger society. The paper concludes with consideration of methodological issues and directions for research on the media and youth development. PMID- 22247566 TI - Microparticle trapping in an ultrasonic Bessel beam. AB - This paper describes an acoustic trap consisting of a multi-foci Fresnel lens on 127 MUm thick lead zirconate titanate sheet. The multi-foci Fresnel lens was designed to have similar working mechanism to an Axicon lens and generates an acoustic Bessel beam, and has negative axial radiation force capable of trapping one or more microparticle(s). The fabricated acoustic tweezers trapped lipid particles ranging in diameter from 50 to 200 MUm and microspheres ranging in diameter from 70 to 90 MUm at a distance of 2 to 5 mm from the tweezers without any contact between the transducer and microparticles. PMID- 22247565 TI - Heritable choice of colony size in cliff swallows: does experience trump genetics in older birds? AB - The variation in breeding-colony size seen in populations of most colonial birds may reflect heritable choices made by individuals who are phenotypically specialized for particular social environments. Although a few studies have reported evidence for genetically based choice of group sizes in birds, we know relatively little about the extent to which animals potentially rely on experience versus innate preferences in deciding with how many conspecifics to settle at different times of their lives. We conducted a cross-fostering experiment in 1997-1998 on cliff swallows (Petrochelidon pyrrhonota) in southwestern Nebraska, USA, in which some individuals were reared in colonies different in size from those in which they were born. Breeding-colony sizes chosen by this cohort of birds were monitored by mark-recapture throughout their lives. A multistate mark-recapture analysis revealed that birds in their first breeding year chose colony sizes similar to those of their birth, regardless of their rearing environment, confirming a previous analysis. Beyond the first breeding year, however, cliff swallows' colony choice was less dependent on where they were born. Birds born in small colonies and reared in large colonies showed evidence of a delayed rearing effect, with these birds overwhelmingly choosing large colonies in later years. Heritabilities suggested strong genetic effects on first-year colony choice but not in later years. Cliff swallows' genetically based colony-size preferences their first year could be a way to ensure matching of their phenotype to an appropriate social environment as yearlings. In later years, familiarity with particular colony sites and available information on site quality may override innate group-size preferences when birds choose colonies. PMID- 22247567 TI - Study on characteristic parameters influencing laser-induced damage threshold of KH(2)PO(4) crystal surface machined by single point diamond turning. AB - It has fundamental meaning to find the elements influencing the laser-induced damage threshold (LIDT) of KH(2)PO(4) (KDP) crystal and to provide suitable characterization parameters for these factors in order to improve the LIDT of KDP. Using single-point diamond turning (SPDT) to process the KDP crystal, the machined surface quality has important effects on its LIDT. However, there are still not suitable characteristic parameters of surface quality of KDP to correspond with the LIDT nowadays. In this paper, guided by the Fourier model theory, we study deeply the relationship between the relevant characteristic parameters of surface topography of KDP crystal and the experimental LIDT. Research results indicate that the waviness rather than the roughness is the leading topography element on the KDP surface machined by the SPDT method when the LIDT is considered and the amplitude of micro-waviness has greater influence on the light intensity inside the KDP crystal within the scope of dangerous frequencies between (180 MUm)(-1) and (90 MUm)(-1); with suitable testing equipment, the characteristic parameters of waviness amplitude, such as the arithmetical mean deviation of three-dimensional profile S(a) or root mean square deviation of three-dimensional contour S(q), are able to be considered as suitable parameters to reflect the optical quality of the machined surface in order to judge approximately the LIDT of the KDP surface and guide the machining course. PMID- 22247568 TI - Buffer standards for the physiological pH of the zwitterionic compound of 3-(N morpholino)propanesulfonic acid (MOPS) from T = (278.15 to 328.15) K. AB - This paper reports the pH values of five NaCl-free buffer solutions and eleven buffer compositions containing NaCl at I = 0.16 mol.kg(-1). Conventional pa(H) values are reported for sixteen buffer solutions with and without NaCl salt. The operational pH values have been calculated for five buffer solutions and are recommended as pH standards at T = (298.15 and 310.15) K after correcting the liquid junction potentials. For buffer solutions with the composition m(1) = 0.04 mol.kg(-1), m(2) = 0.08 mol.kg(-1), m(3) = 0.08 mol.kg(-1) at I = 0.16 mol.kg( 1), the pH at 310.15 K is 7.269, which is close to 7.407, the pH of blood serum. It is recommended as a pH standard for biological specimens. PMID- 22247569 TI - Emotional Relationships in Mothers and Infants: Culture-Common and Community Specific Characteristics of Dyads from Rural and Metropolitan Settings in Argentina, Italy, and the United States. AB - This study uses country and regional contrasts to examine culture-common and community-specific variation in mother-infant emotional relationships. Altogether, 220 Argentine, Italian, and U.S. American mothers and their daughters and sons, living in rural and metropolitan settings, were observed at home at infant age 5 months. Both variable- and person-centered perspectives of dyadic emotional relationships were analyzed. Supporting the notion that adequate emotional relationships are a critical and culture-common characteristic of human infant development, across all samples most dyads scored in the adaptive range in terms of emotional relationships. Giving evidence of community-specific characteristics, Italian mothers were more sensitive, and Italian infants more responsive, than Argentine and U.S. mothers and infants; in addition, rural mothers were more intrusive than metropolitan mothers, and rural dyads more likely than expected to be classified as mid-range in emotional relationships and less likely to be classified as high in emotional relationships. Adaptive emotional relationships appear to be a culture-common characteristic of mother infant dyads near the beginning of life, but this relational construct is moderated by community-specific (country and regional) context. PMID- 22247570 TI - An Aristotelian Approach to Cognitive Enhancement. PMID- 22247571 TI - Synthesis and Characterization of Amphiphilic Cyclic Diblock Copolypeptoids from N-Heterocyclic Carbene-Mediated Zwitterionic Polymerization of N-Substituted N carboxyanhydride. AB - N-Heterocyclic carbene (NHC)-mediated ring-opening polymerization of N-decylN carboxylanhydride monomer (De-NCA) has been shown to occur in a controlled manner, yielding cyclic poly(N-decyl-glycine)s (c-PNDGs) with polymer molecular weights (MW) between 4.8 and 31 kg.mol(-1) and narrow molecular weight distributions (PDI < 1.15). The reaction exhibits pseudo-first order kinetics with respect to monomer concentration. The polymer MW increases linearly with conversion, consistent with a living polymerization. ESI MS and SEC analysesconfirm the cyclic architectures of the forming polymers. DSC and WAXS studies reveal that the c-PNDG homopolymers are highly crystalline with two prominent first order transitions at 72-79 degrees C (T(m,1)) and 166-177 degrees C (T(m,2)), which have been attributed to the side chain and main chain melting respectively. A series of amphiphilic cyclic diblock copolypeptoids [i.e.,poly(N methyl-glycine)-b-poly(N-decyl-glycine) (c-PNMG-b-PNDG)] with variable molecular weight and composition was synthesized by sequential NHC-mediated polymerization of the corresponding N-methyl N-carboxyanhydride (Me-NCA) and De-NCA monomers. (1)H NMR analysis reveals that adjusting the initial monomer to NHC molar ratio can readily control the block copolymer chain length and composition. Time-lapsed light scattering and cryogenic transmission electron microscopy (cryo-TEM) analysis of c-PNDG-b-PNMG samples revealed that the amphiphilic cyclic block copolypeptoids self-assemble into spherical micelles that reorganize into micron long cylindrical micelles with uniform diameter in room temperature methanol over the course of several days. An identical morphological transition has also been noted for the linear analogs, which occurs more rapidly than for the cyclic copolypeptoids. We tentatively attribute this difference to the different crystallization kinetics of the solvophobic block (i.e., PNDG) in the cyclic and linear block copolypeptoids. PMID- 22247572 TI - The conserved global regulator VeA is necessary for symptom production and mycotoxin synthesis in maize seedlings by Fusarium verticillioides. AB - The veA or velvet gene is necessary for biosynthesis of mycotoxins and other secondary metabolites in Aspergillus species. In addition, veA has also been demonstrated to be necessary for normal seed colonization in Aspergillus flavus and Aspergillus parasiticus. The present study shows that veA homologues are broadly distributed in fungi, particularly in Ascomycetes. The Fusarium verticillioides veA orthologue, FvVE1, is also required for the synthesis of several secondary metabolites, including fumonisin and fusarins. This study also shows that maize plants grown from seeds inoculated with FvVE1 deletion mutants did not show disease symptoms, while plants grown from seeds inoculated with the F. verticillioides wildtype and complementation strains clearly showed disease symptoms under the same experimental conditions. In this latter case, the presence of lesions coincided with accumulation of fumonisins in the plant tissues, and only these plant tissues had elevated levels of sphingoid bases and their 1-phosphate derivatives, indicating inhibition of ceramide synthase and disruption of sphingolipid metabolism. The results strongly suggest that FvVE1 is necessary for pathogenicity by F. verticillioides against maize seedlings. The conservation of veA homologues among ascomycetes suggests that veA could play a pivotal role in regulating secondary metabolism and associated pathogenicity in other fungi. PMID- 22247573 TI - (+)-Sorangicin A: evolution of a viable synthetic strategy. AB - An effective, asymmetric total synthesis of the antibiotic (+)-sorangicin A (1) has been achieved. Central to this venture was the development of first and second generation syntheses of the signature dioxabicyclo[3.2.1]octane core, the first featuring chemo- and stereoselective epoxide ring openings facilitated by a Co(2)(CO)(6)-alkyne complex, the second involving a KHMDS-promoted epoxide ring formation/opening cascade. Additional highlights include effective construction of the dihydro- and tetrahydropyran ring systems, respectively via a stereoselective conjugate addition/alpha-oxygenation protocol and a thioketalization/hydrostannane reduction sequence. Late-stage achievements entailed two Julia-Kocienski olefinations to unite three advanced fragments with high E-stereoselectivity, followed by a modified Stille protocol to introduce the Z,Z,E trienoate moiety, thereby completing the carbon skeleton. Mukaiyama macrolactonization, followed by carefully orchestrated Lewis and protic acid promoted deprotections that suppressed isomerization and/or destruction of the sensitive (Z,Z,E)-trienoate linkage completed the first, and to date only, total synthesis of (+)-sorangicin A (1). PMID- 22247574 TI - Function Oriented Synthesis: Preparation and Initial Biological Evaluation of New A-Ring-Modified Bryologs. AB - The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7 to 2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function. PMID- 22247575 TI - Studies on the synthesis of amidoximes from nitroalkanes. AB - The reaction of primary nitroalkanes with magnesium or lithium amides provides a convenient, one-step synthesis of substituted amidoximes. PMID- 22247576 TI - Palladium-catalyzed direct arylation of pyridine N-oxide with 2 bromoacetanilides. Synthesis of benzisoxazolo[2,3-a]pyridinium tetrafluoroborates. AB - The synthesis of a variety of novel benzisoxazolo[2,3-a]pyridinium tetrafluoroborates is described. These compounds are conveniently prepared from pyridine N-oxide via a microwave-promoted palladium-catalyzed direct arylation of pyridine N-oxide with 2-bromoacetanilides to give 2-(2-acetamidoaryl)pyridine N oxides, followed by hydrolysis, diazotization and intramolecular displacement of nitrogen which affords the target benzisoxazolo[2,3-a]pyridinium tetrafluoroborates. PMID- 22247577 TI - Education for Humanity. PMID- 22247578 TI - Mathematics: The Basis for Quantitative Knowledge. PMID- 22247579 TI - Human Annulus Fibrosus Dynamic Tensile Modulus Increases with Degeneration. AB - The annulus fibrosus (AF) of the intervertebral disc experiences cyclic tensile loading in vivo at various states of mechanical equilibrium. Disc degeneration is associated with alterations in the biochemical composition of the AF including decreased water content, decreased proteoglycan concentration, and increased collagen deposition that affect mechanical function of the AF in compression and shear. Such changes may also affect the dynamic viscoelastic properties of the AF and thus alter the disc's ability to dissipate energy under physiologic loading. The objectives of this study were to quantify the dynamic viscoelastic properties of human AF in circumferential tension and to determine the effect of degeneration on these properties. Nondegenerated and degenerated human AF tensile samples were tested in uniaxial tension over a spectrum of loading frequencies spanning 0.01Hz to 2Hz at several states of equilibrium strain to determine the dynamic viscoelastic properties (dynamic modulus, phase angle) using a linear viscoelastic model. The AF dynamic modulus increased at higher equilibrium strain levels. The AF behaved more elastically at higher frequencies with a decreased phase angle. Degeneration resulted in a higher dynamic modulus at all strain levels but had no effect on phase angle. The findings from this study elucidate the effect of degeneration on the dynamic viscoelastic properties of human AF and lend insight into the mechanical role of the AF in cyclic loading conditions. PMID- 22247581 TI - Estimating Effectiveness of the Control of Violence and Socioeconomic Development in Colombia: An Application of Dynamic Data Envelopment Analysis and Data Panel Approach. AB - This paper develops an index to evaluate the level of effectiveness of the control of violence based on the data envelopment analysis approach. The index is used to examine the grade of effectiveness of the control of violence at the level of Colombian departments between 1993 and 2007. Comparing the results across Colombian departments, we find that the majority of departments show improvement in their scores of effectiveness. A second stage of the regression model reveals that departments with a higher gross domestic product and higher education and employment are more effective in the control of violence, whereas departments with higher political violence, unemployment rates, unsatisfied basic needs, a displaced population, and hectares cultivated with coca show lower effectiveness in the control of violence. All these findings are of particular interest in the formulation and development of policies against violence, taking into account that organised forms of violence, such as drug trafficking, impede the adequate effectiveness of its control. Moreover, violence decreases social investments, generating alterations in social services that produce long-run deterioration in faith in the government's ability to govern, which should become an incentive to further violence. PMID- 22247580 TI - Stepping Down and Stepping In: Youth's Perspectives on Making the Transition from Residential Treatment to Treatment Foster Care. AB - Older youth preparing to emancipate from the foster care system are often served in residential treatment settings where they have limited opportunities to practice skills for independent living in a community setting. Stepping these youth down to less restrictive environments such as treatment foster care is a growing trend, especially for youth with mental health issues. Yet, few studies have explored the youth's perspective on making this transition. This study utilized qualitative interviews with youths who were participating in a treatment foster care intervention study (n=8) to gain their perspectives on the process of transitioning from residential care. Youths were interviewed right before they exited residential care and two months after placement in the new foster home. Youths reported hopes for gaining family in the new home as well as fears of placement disruption. Findings point to the need to enlist youths in discussion and problem solving about difficulties they anticipate in the new home and expectations for their relationship with the new foster parents. In addition, the struggles described after two months in the home point to the need for youths to build specific skills to better manage ongoing relationships with foster parents and for foster parent training on how to help build these skills. PMID- 22247582 TI - Factor Structure and Psychometric Properties of the Work-Family Balance Scale in an Urban Chinese Sample. AB - The purpose of this study was to explore the factor structure of the Work-Family Balance Scale (WFBS) and examine its reliability and validity in use in the urban Chinese population. The scale was validated using a sample of 605 urban Chinese residents from 7 cities. Exploratory factor analysis identified two factors: work family conflict and work-family enrichment. The WFBS showed adequate reliability and concurrent validity. The WFBS is a reliable and valid instrument to measure work-family balance for Chinese working parents. However, further examination of the scale is needed. PMID- 22247583 TI - Positive Youth Development, Life Satisfaction and Problem Behaviour Among Chinese Adolescents in Hong Kong: A Replication. AB - The purpose of this replication study was to examine the relationships among life satisfaction, positive youth development and problem behaviour. The respondents were 7,151 Chinese Secondary 2 (Grade 8) students (3,707 boys and 3,014 girls) recruited from 44 schools in Hong Kong. Validated assessment tools measuring positive youth development, life satisfaction and problem behaviour were used. As predicted, positive youth development was positively correlated with life satisfaction, and positive youth development and life satisfaction were negatively correlated with adolescent problem behaviour. Based on a series of structural equation models, the present findings replicated the previous findings that adolescents with a higher level of positive youth development were more satisfied with life and had lesser problem behaviour, with higher level of life satisfaction and lower level of problem behaviour mutually influencing each other. These replicated findings provide a further advance in the literature on positive youth development, particularly in the Chinese context. Implications for future research and intervention were discussed. PMID- 22247584 TI - Individual- and Neighbourhood-Level Indicators of Subjective Well-Being in a Small and Poor Eastern Cape Township: The Effect of Health, Social Capital, Marital Status, and Income. AB - Our study used multilevel regression analysis to identify individual- and neighbourhood-level factors that determine individual-level subjective well-being in Rhini, a deprived suburb of Grahamstown in the Eastern Cape province of South Africa. The Townsend index and Gini coefficient were used to investigate whether contextual neighbourhood-level differences in socioeconomic status determined individual-level subjective well-being. Crime experience, health status, social capital, and demographic variables were assessed at the individual level. The indicators of subjective well-being were estimated with a two-level random intercepts and fixed slopes model. Social capital, health and marital status (all p < .001), followed by income level (p < .01) and the Townsend score (p < .05) were significantly related to individual-level subjective well-being outcomes. Our findings showed that individual-level subjective well-being is influenced by neighbourhood-level socioeconomic status as measured by the Townsend deprivation score. Individuals reported higher levels of subjective well-being in less deprived neighbourhoods. Here we wish to highlight the role of context for subjective well-being, and to suggest that subjective well-being outcomes may also be defined in ecological terms. We hope the findings are useful for implementing programs and interventions designed to achieve greater subjective well-being for people living in deprived areas. PMID- 22247585 TI - Geological control of floristic composition in Amazonian forests. AB - AIM: Conservation and land-use planning require accurate maps of patterns in species composition and an understanding of the factors that control them. Substantial doubt exists, however, about the existence and determinants of large area floristic divisions in Amazonia. Here we ask whether Amazonian forests are partitioned into broad-scale floristic units on the basis of geological formations and their edaphic properties. LOCATION: Western and central Amazonia. METHODS: We used Landsat imagery and Shuttle Radar Topography Mission (SRTM) digital elevation data to identify a possible floristic and geological discontinuity of over 300 km in northern Peru. We then used plant inventories and soil sampling to document changes in species composition and soil properties across this boundary. Data were obtained from 138 sites distributed along more than 450 km of road and river. On the basis of our findings, we used broad-scale Landsat and SRTM mosaics to identify similar patterns across western and central Amazonia. RESULTS: The discontinuity identified in Landsat and SRTM data corresponded to a 15-fold change in soil cation concentrations and an almost total change in plant species composition. This discontinuity appears to be caused by the widespread removal of cation-poor surface sediments by river incision to expose cation-rich sediments beneath. Examination of broad-scale Landsat and SRTM mosaics indicated that equivalent processes have generated a north-south discontinuity of over 1500 km in western Brazil. Due to similarities with our study area, we suggest that this discontinuity represents a chemical and ecological limit between western and central Amazonia. MAIN CONCLUSIONS: Our findings suggest that Amazonian forests are partitioned into large-area units on the basis of geological formations and their edaphic properties. The evolution of these units through geological time may provide a general mechanism for biotic diversification in Amazonia. These compositional units, moreover, may correspond to broad-scale functional units. The existence of large-area compositional and functional units would suggest that protected-area, carbon sequestration, and other land-use strategies in Amazonia be implemented on a region-by-region basis. The methods described here can be used to map these patterns, and thus enable effective conservation and management of Amazonian forests. PMID- 22247586 TI - Robust thermoregulatory overcompensation, rather than tolerance, develops with serial administrations of 70% nitrous oxide to rats. AB - Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug's pharmacological effect, the individual's autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature (T(c)), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N(2)O)-induced hypothermia would exhibit different patterns of tolerance development across N(2)O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N(2)O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups (n=10 each/group) that received: 1) twelve 90-min exposures to 70% N(2)O using a classical conditioning procedure, 2) twelve 90-min exposures to 70% N(2)O using a random control procedure for conditioning, or 3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and T(c) (via telemetry) were simultaneously quantified during N(2)O and control gas administrations. Initially insensitive rats rapidly acquired (3(rd) administration) a significant allostatic hyperthermic phenotype during N(2)O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N(2)O inhalation in the 4(th) and 5(th) sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11(th) and 12th N(2)O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N(2)O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N(2)O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production. PMID- 22247587 TI - Information content of female copulation calls in wild long-tailed macaques (Macaca fascicularis). AB - Primates are unusual in that many females display sexual signals, such as sex skin swellings/colorations and copulation calls, without any sex role reversal. The adaptive function of these signals remains largely unclear, although it has been suggested that they provide males with information on female reproductive status. For sex skin swellings, there is increasing evidence that they represent a graded signal indicating the probability of ovulation. Data on the functional significance of copulation calls are much scarcer. To clarify the information content of such calls, we recorded copulation calls in wild long-tailed macaques (Macaca fascicularis) and analysed the structure of these calls during the ovarian cycle. Specifically, we correlated selected call parameters with the female oestrogen to progestogen ratio (obtained from faecal samples), which are known to be elevated during the female's fertile phase. In addition, we ran a general linear mixed model for these call parameters, testing factors (cycle phase, occurrence/absence of ejaculation, male dominance status, occurrence/absence of mate guarding) which potentially influence female copulation calls in primates. Our results show that copulation calls of female long-tailed macaques signal mating outcome and rank of the mating partner, but not female reproductive status. They also show for the first time on primates that copulation calls can convey information on whether a female is mate guarded or not. We suspect that the function of these calls is manipulation of male mating and mate-guarding behaviour and that in this way the degree of sperm competition and ultimately male reproductive success is influenced. PMID- 22247588 TI - Benefits and Challenges of Conducting Psychotherapy by Telephone. AB - Telephone-delivered psychotherapy has increased utility as a method of service delivery in the current world, where a number of barriers, including economic hardships and limited access to care, may prevent people from receiving the treatment they need. This method of service provision is practical and has the potential to reach large numbers of underserved people in a cost-effective manner. The aim of this paper is to review the state-of-the-art of telephone delivered psychotherapy and to identify improvements and possible solutions to challenges. Results of randomized controlled trials indicate high client acceptance and positive outcomes with this method of delivering psychotherapy. Nonetheless, psychotherapists wishing to deliver psychotherapy by telephone face a number of challenges, including a lack of control over the environment, potential compromises of privacy and confidentiality, developing therapeutic alliance without face-to-face contact, ethical and legal issues in providing psychotherapy by telephone, handling crisis situations at a distance, and psychotherapist adjustment to conducting psychotherapy in an alternative manner. There remains a need for further research, including direct comparisons of face to-face psychotherapy with telephone-delivered psychotherapy and feasibility of telephone delivery of psychotherapies other than cognitive behavioral therapy. PMID- 22247589 TI - The Role of Non-Actuality Implicatures in Processing Elided Constituents. AB - When an elided constituent and its antecedent do not match syntactically, the presence of a word implying the non-actuality of the state of affairs described in the antecedent seems to improve the example (This information should be released but Gorbachev didn't. vs This information was released but Gorbachev didn't.) We model this effect in terms of Non-Actuality Implicatures (NAIs) conveyed by non-epistemic modals like should and other words such as want to and be eager to that imply non-actuality. We report three studies. A rating and interpretation study showed that such implicatures are drawn and that they improve the acceptability of mismatch ellipsis examples. An interpretation study showed that adding a NAI trigger to ambiguous examples increases the likelihood of choosing an antecedent from the NAI clause. An eye movement study shows that a NAI trigger also speeds online reading of the ellipsis clause. By introducing alternatives (the desired state of affairs vs. the actual state of affairs), the NAI trigger introduces a potential Question Under Discussion (QUD). Processing an ellipsis clause is easier, the processor is more confident of its analysis, when the ellipsis clause comments on the QUD. PMID- 22247590 TI - The Shape Bias is Affected by Differing Similarity Among Objects. AB - Previous research has demonstrated that visual properties of objects can affect shape-based categorization in a novel-name extension task; however, we still do not know how a relationship between visual properties of objects affects judgments in a novel-name extension task. We examined effects of increased visual similarity among the target and test objects in a shape bias task in young children and adults. Experiment 1 assessed college students with sets of objects whose similarity between target and test objects was either low or high similarity. Adults preferred shape when the similarity among objects was minimized. Experiment 2 tested 24- month-olds in their use of the shape bias using the Intermodal Preferential Looking Paradigm. Children showed a shape bias only with items whose similarity to each other was low. These findings suggest that the visual properties of objects affect shape bias performance. PMID- 22247591 TI - Pointing Disrupts Preschoolers' Ability to Discriminate Between Knowledgeable and Ignorant Informants. AB - By 4 years of age, children have been reinforced repeatedly for searching where they see someone point. In two studies, we asked whether this history of reinforcement could interfere with young children's ability to discriminate between a knowledgeable and an ignorant informant. Children watched as one informant hid a sticker while another turned around, and then both informants indicated where they though the sticker was, either by pointing or by using a less practiced means of reference. Children failed to discriminate between the two informants when they pointed, but they chose the location indicated by the knowledgeable informant when the informants used a cue other than pointing. Pointing can disrupt as basic an understanding as the link between seeing and knowing. PMID- 22247592 TI - Amphiphilic Interpenetrating Networks for the Delivery of Hydrophobic, Low Molecular Weight Therapeutic Agents. AB - To investigate the delivery of hydrophobic therapeutic agents, a novel class of interpenetrating networks (IPNs) were synthesized and composed of two networks: methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and poly(n-butyl acrylate) (PBA). The hydrophilic P(MAA-g-EG) networks are pH responsive hydrogels capable of triggered release of an encapsulated therapeutic agent, such as a low molecular weight drug or a protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). PBA is a hydrophobic homopolymer that can affect the IPN swelling behavior, the therapeutic agent loading efficiencies in IPNs, and solute release profiles from IPNs. In dynamic swelling conditions, IPNs had greater swelling ratios than P(MAA-g-EG), but in equilibrium swelling conditions the IPN swelling ratio decreased with increasing PBA content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 21 - 44%. Release studies from neat P(MAA-g-EG) and the ensuing IPNs indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophilicity of the carriers used in these studies. PMID- 22247593 TI - Extension of the GLYCAM06 Biomolecular Force Field to Lipids, Lipid Bilayers and Glycolipids. AB - GLYCAM06 is a generalisable biomolecular force field that is extendible to diverse molecular classes in the spirit of a small-molecule force field. Here we report parameters for lipids, lipid bilayers and glycolipids for use with GLYCAM06. Only three lipid-specific atom types have been introduced, in keeping with the general philosophy of transferable parameter development. Bond stretching, angle bending, and torsional force constants were derived by fitting to quantum mechanical data for a collection of minimal molecular fragments and related small molecules. Partial atomic charges were computed by fitting to ensemble-averaged quantum-computed molecular electrostatic potentials.In addition to reproducing quantum mechanical internal rotational energies and experimental valence geometries for an array of small molecules, condensed-phase simulations employing the new parameters are shown to reproduce the bulk physical properties of a DMPC lipid bilayer. The new parameters allow for molecular dynamics simulations of complex systems containing lipids, lipid bilayers, glycolipids, and carbohydrates, using an internally consistent force field. By combining the AMBER parameters for proteins with the GLYCAM06 parameters, it is also possible to simulate protein-lipid complexes and proteins in biologically relevant membrane-like environments. PMID- 22247594 TI - As a researcher engaging in the field of oxidative stress. PMID- 22247595 TI - Fukushima Daiichi Nuclear Power Plant accident: facts, environmental contamination, possible biological effects, and countermeasures. AB - On March 11, 2011, an earthquake led to major problems at the Fukushima Daiichi Nuclear Power Plant. A 14-m high tsunami triggered by the earthquake disabled all AC power to Units 1, 2, and 3 of the Power Plant, and carried off fuel tanks for emergency diesel generators. Despite many efforts, cooling systems did not work and hydrogen explosions damaged the facilities, releasing a large amount of radioactive material into the environment. In this review, we describe the environmental impact of the nuclear accident, and the fundamental biological effects, acute and late, of the radiation. Possible medical countermeasures to radiation exposure are also discussed. PMID- 22247596 TI - Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme. AB - NADPH oxidase is a superoxide (O(2) (*-))-generating enzyme first identified in phagocytes, essential for their bactericidal activities. Later, in non phagocytes, production of O(2) (*-) was also demonstrated in an NADPH-dependent manner. In the last decade, several non-phagocyte-type NADPH oxidases have been identified. The catalytic subunit of these oxidases, NOX, constitutes the NOX family. There are five homologs in the family, NOX1 to NOX5, and two related enzymes, DUOX1 and DUOX2. Transgenic or gene-disrupted mice of the NOX family have also been established. NOX/DUOX proteins possess distinct features in the dependency on other components for their enzymatic activities, tissue distributions, and physiological functions. This review summarized the characteristics of the NOX family proteins, especially focused on their functions clarified through studies using gene-modified mice. PMID- 22247598 TI - Roles of oxidative stress in stomach disorders. AB - The stomach is a sensitive digestive organ that is susceptible and exposed to exogenous pathogens from the diet. In response to such pathogens, the stomach induces oxidative stress, which might be related to the development of gastric organic disorders such as gastritis, gastric ulcers, and gastric cancer, as well as functional disorders such as functional dyspepsia. In particular, the bacterium Helicobacter pylori plays a major role in eliciting and confronting oxidative stress in the stomach. The present paper summarizes the pathogenesis of oxidative stress in the stomach during the development of various stomach diseases. PMID- 22247599 TI - Temperature-dependent free radical reaction in water. AB - Temperature-dependent free radical reactions were investigated using nitroxyl radicals as redox probes. Reactions of two types of nitroxyl radicals, TEMPOL (4 hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl) and carbamoyl-PROXYL (3-carbamoyl 2,2,5,5-tetramethylpyrrolidine-N-oxyl), were tested in this paper. Heating a solution containing a nitroxyl radical and a reduced form of glutathione (GSH) caused temperature-dependent decay of electron paramagnetic resonance (EPR) signal of the nitroxyl radical. Heating a solution of the corresponding hydroxylamine form of the nitroxyl radical showed EPR signal recovery. The GSH dependent reduction of nitroxyl radicals at 70 degrees C was suppressed by antioxidants, spin trapping agents, and/or bubbling N(2) gas, although heating carbamoyl-PROXYL with GSH showed temporarily enhanced signal decay by bubbling N(2) gas. Since SOD could restrict the GSH-dependent EPR signal decay of TEMPOL, O(2) (*-) is related with this reaction. O(2) (*-) was probably generated from dissolved oxygen in the reaction mixture. Oxidation of the hydroxylamines at 70 degrees C was also suppressed by bubbling N(2) gas. Heating a solution of spin trapping agent, DMPO (5,5-dimethyl-1-pyrroline-N-oxide) showed a temperature dependent increase of the EPR signal of the hydroxyl radical adduct of DMPO. Synthesis of hydroxyl radical adduct of DMPO at 70 degrees C was suppressed by antioxidants and/or bubbling N(2) gas. The results suggested that heating an aqueous solution containing oxygen can generate O(2) (*-). PMID- 22247597 TI - Thioredoxin binding protein (TBP)-2/Txnip and alpha-arrestin proteins in cancer and diabetes mellitus. AB - Thioredoxin binding protein -2/ thioredoxin interacting protein is an alpha arrestin protein that has attracted much attention as a multifunctional regulator. Thioredoxin binding protein -2 expression is downregulated in tumor cells and the level of thioredoxin binding protein is correlated with clinical stage of cancer. Mice with mutations or knockout of the thioredoxin binding protein -2 gene are much more susceptible to carcinogenesis than wild-type mice, indicating a role for thioredoxin binding protein -2 in cancer suppression. Studies have also revealed roles for thioredoxin binding protein -2 in metabolic control. Enhancement of thioredoxin binding protein -2 expression causes impairment of insulin sensitivity and glucose-induced insulin secretion, and beta cell apoptosis. These changes are important characteristics of type 2 diabetes mellitus. Thioredoxin binding protein -2 regulates transcription of metabolic regulating genes. Thioredoxin binding protein -2-like inducible membrane protein/ arrestin domain containing 3 regulates endocytosis of receptors such as the beta(2)-adrenergic receptor. The alpha-arrestin family possesses PPXY motifs and may function as an adaptor/scaffold for NEDD family ubiquitin ligases. Elucidation of the molecular mechanisms of alpha-arrestin proteins would provide a new pharmacological basis for developing approaches against cancer and type 2 diabetes mellitus. PMID- 22247600 TI - Detection of N-(hexanoyl)lysine in the tropomyosin 1 protein in N-methyl-N'-nitro N-nitrosoguanidine-induced rat gastric cancer cells. AB - N(epsilon)-(Hexanoyl)lysine, formed by the reaction of lysine with n-6 lipid hydroperoxide, is a lipid peroxidation marker during the initial stage of oxidative stress. The aim of the present study is to indentify N(epsilon) (hexanoyl)lysine-modified proteins in neoplastic transformed gastric mucosal cells by N-methyl-N'-nitro-N-nitrosoguanidine, and to compare the levels of these proteins between gastric mucosal cells and normal gastric cells. Much greater fluorescence of 2-[6-(4'-hydroxy)phenoxyl-3H-xanthen-3-on-9-yl]benzoic acid, an index of the intracellular levels of reactive oxygen species, was observed for gastric mucosal cells compared to normal gastric cells. N(epsilon) (Hexanoyl)lysine-modified proteins were detected by SDS-PAGE or two-dimensional electrophoresis and Western blotting using anti-N(epsilon)-(hexanoyl)lysine polyclonal antibody, and a protein band of between 30-40 kDa was clearly increased in gastric mucosal cells compared to normal gastric cells. Two N(epsilon)-(hexanoyl)lysine-modified protein spots in gastric mucosal cells were identified as the tropomyosin 1 protein by mass spectrometry using a MASCOT search. The existence of N(epsilon)-(hexanoyl)lysine modification in tropomyosin 1 was confirmed by Western blotting of SDS-PAGE-separated or two-dimensional electrophoresis-separated proteins as well as by the immunoprecipitation with anti-tropomyosin 1 antibody. These data indicate that N(epsilon)-(hexanoyl)lysine modification of tropomyosin 1 may be related to neoplastic transformation by N methyl-N'-nitro-N-nitrosoguanidine in gastric epithelial cells. PMID- 22247602 TI - Butyrate enhancement of inteleukin-1beta production via activation of oxidative stress pathways in lipopolysaccharide-stimulated THP-1 cells. AB - In inflammatory bowel diseases, interleukin-1beta production is accelerated. Butyrate, a short chain fatty acid, plays an important role in inflammatory bowel diseases. We investigated the effect of butyrate on interleukin-1beta production in macrophage and elucidated its underlying mechanism. We stimulated THP-1 cells, a human premonocytic cell line, by lipopolysaccharide alone and by butyrate with lipopolysaccharide. Butyrate with lipopolysaccharide increased interleukin-1beta production more than lipopolysaccharide alone. Butyrate with lipopolysaccharide increased caspase-1 activity more than lipopolysaccharide alone. As for the phosphorylation pathway, PD98059 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor) decreased caspase-1 activity and interleukin-1beta production to approximately 50% of the controls. Pertussis toxin (G protein-coupled signal transduction pathway inhibitor) also reduced interleukin-1beta production to approximately 50%. Butyrate with lipopolysaccharide increased reactive oxygen species levels more than lipopolysaccharide alone. The addition of N-acetyl L-cysteine reduced reactive oxygen species levels to a level similar to that of lipopolysaccharide alone. Butyrate with lipopolysaccharide increased nitric oxide production more than lipopolysaccharide alone, and the addition of N-acetyl L-cysteine reduced the elevated amount of nitric oxide. In conclusions, butyrate enhances interleukin 1beta production by activating caspase-1, via reactive oxygen species, the phosphorylation of MAPK, and G protein mediated pathways in lipopolysaccharide stimulated THP-1 cells. PMID- 22247601 TI - Okanin, a chalcone found in the genus Bidens, and 3-penten-2-one inhibit inducible nitric oxide synthase expression via heme oxygenase-1 induction in RAW264.7 macrophages activated with lipopolysaccharide. AB - Excess production of nitric oxide by activated macrophages via inducible nitric oxide synthase leads to the development of various inflammatory diseases. Heme oxygenase-1 expression via activation of nuclear factor-erythroid 2-related factor 2 inhibits nitric oxide production and inducible nitric oxide synthase expression in activated macrophages. Okanin is one of the most abundant chalcones found in the genus Bidens (Asteraceae) that is used as various folk medications in Korea and China for treating inflammation. Here, we found that okanin (possessing the alpha-beta unsaturated carbonyl group) induced heme oxygenase-1 expression via nuclear factor-erythroid 2-related factor 2 activation in RAW264.7 macrophages. 3-Penten-2-one, of which structure, as in okanin, possesses the alpha-beta unsaturated carbonyl group, also induced nuclear factor-erythroid 2 related factor 2-dependent heme oxygenase-1 expression, while both 2-pentanone (lacking a double bond) and 2-pentene (lacking a carbonyl group) were virtually inactive. In lipopolysaccharide-activated RAW264.7 macrophages, both okanin and 3 penten-2-one inhibited nitric oxide production and inducible nitric oxide synthase expression via heme oxygenase-1 expression. Collectively, our findings suggest that by virtue of its alpha-beta unsaturated carbonyl functional group, okanin can inhibit nitric oxide production and inducible nitric oxide synthase expression via nuclear factor-erythroid 2-related factor 2-dependent heme oxygenase-1 expression in lipopolysaccharide-activated macrophages. PMID- 22247603 TI - Effect of branched-chain amino acid supplementation on the oxidized/reduced state of plasma albumin in rats with chronic liver disease. AB - We examined whether continuous supplementation with branched-chain amino acids phosphorylates ribosomal protein S6, a downstream effector of mammalian target of rapamycin, and improves hypoalbuminemia of rats with chronic liver disease. Sprague-Dawley rats were fed a casein diet (control group) or a branched-chain amino acid-supplemented casein diet (branched-chain amino acid group) for 11 weeks with repeated injections of carbon tetrachloride. Throughout this experimental period, no significant difference in plasma albumin concentration was seen between groups. The percentage of reduced albumin within total plasma albumin gradually decreased in both control and branched-chain amino acid groups. After 11 weeks with supplementation, phosphorylation of ribosomal protein S6 was significantly increased in the liver of rats in the branched-chain amino acid group compared with the control group. Furthermore, the percentage of reduced albumin within total albumin was significantly higher in the branched-chain amino acid group than in the control group. These results indicate that continuous supplementation with branched-chain amino acids in rats with chronic liver disease induces phosphorylation of hepatic ribosomal protein S6 and attenuates decreases in the percentage of reduced albumin, although levels of plasma albumin are not increased. PMID- 22247604 TI - Supplementation with probiotics modifies gut flora and attenuates liver fat accumulation in rat nonalcoholic fatty liver disease model. AB - This study aimed to evaluate the relationship between gut probiotic flora and nonalcoholic fatty liver disease in a diet-induced rat model, and to compare the effects of two different probiotic strains on nonalcoholic fatty liver disease. Forty male Sprague-Dawley rats were randomized into 4 groups for 12 weeks: control (standard rat chow), model (fat-rich diet), Lactobacillus (fat-rich diet plus Lactobacillus acidophilus), and Bifidobacterium (fat-rich diet plus Bifidobacterium longum) groups. Probiotics were provided to rats in drinking water (10(10)/ml). Gut bifidobacteria and lactobacilli were obviously lower at weeks 8 and 10, respectively, in the model group compared with the control group. Supplementation with Bifidobacterium significantly attenuated hepatic fat accumulation (0.10 +/- 0.03 g/g liver tissue) compared with the model group (0.16 +/- 0.03 g/g liver tissue). However, there was no improvement in intestinal permeability in either the Lactobacillus or the Bifidobacterium group compared with the model group. In all 40 rats, the hepatic total lipid content was negatively correlated with gut Lactobacillus (r = -0.623, p = 0.004) and Bifidobacterium (r = -0.591, p = 0.008). Oral supplementation with probiotics attenuates hepatic fat accumulation. Further, Bifidobacterium longum is superior in terms of attenuating liver fat accumulation than is Lactobacillus acidophilus. PMID- 22247605 TI - Exogenously-added copper/zinc superoxide dismutase rescues damage of endothelial cells from lethal irradiation. AB - The vascular endothelium is important for the early and late effects observed in lethally irradiated tissue and organs. We examined the effects of exogenously added superoxide dismutase on cell survival and angiogenesis in lethally irradiated human primary umbilical vein endothelial cells. Cell survival was significantly improved in superoxide dismutase-treated cells; the addition of superoxide dismutase to cells after irradiation was also effective for increased survival, as it was before irradiation. Moreover, treatment of cells with superoxide dismutase enhanced the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases 1 and 2 in human primary umbilical vein endothelial cells. The addition of superoxide dismutase to cells after irradiation attenuated the reduction of angiogenesis by irradiation, and inhibition of the mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases signaling pathway abrogated the rescue effect of superoxide dismutase. Our results suggest that superoxide dismutase rescues human primary umbilical vein endothelial cells from endothelial dysfunction caused by irradiation via a pathway requiring activation of mitogen-activated protein/extracellular signal regulated kinase/extracellular signal regulated kinases 1 and 2. PMID- 22247606 TI - Inhibition of endothelial- and neuronal-type, but not inducible-type, nitric oxide synthase by the oxidized cholesterol metabolite secosterol aldehyde: Implications for vascular and neurodegenerative diseases. AB - The cholesterol ozonolysis products secosterol-A and its aldolization product secosterol-B were recently detected in human atherosclerotic tissues and brain specimens, and have been postulated to play pivotal roles in the pathogenesis of atherosclerosis and neurodegenerative diseases. We examined several oxidized cholesterol metabolites including secosterol-A, secosterol-B, 25 hydroxycholesterol, 5beta,6beta-epoxycholesterol and 7-ketocholesterol for their effects on the activities of three nitric oxide synthases. In contrast to other oxidized metabolites, secosterol-A was found to be a potent inhibitor against the neuronal- and endothelial-type, but not the inducible-type nitric oxide synthase, with IC(50) values of 22 +/- 1 and 50 +/- 5 uM, respectively. The calmodulin binding regions of the neuronal- and endothelial-nitric oxide synthases contain lysine residues which are not present in the inducible-type nitric oxide synthase. Secosterol-A modifies proteins through the formation of a Schiff base with the lysine epsilon-amino group. It is possible that secosterol-A modifies lysine residues of constitutive nitric oxide synthases, leading to the inhibition of enzymatic activities. As nitric oxide is a critical signaling molecule in vascular function and in long-term potentiation, its reduced production through inhibition of constitutive nitric oxide synthases by secosterol-A may contribute to the development of atherosclerosis and memory impairment in particular neurodegenerative diseases. PMID- 22247608 TI - Research audit. PMID- 22247607 TI - Asian ethnicity is associated with a higher trunk/periphery fat ratio in women and adolescent girls. AB - OBJECTIVE: Ethnic differences in body fat mass and distribution may develop in childhood and contribute to the elevated obesity-related disease risk among Asians. We evaluated adiposity measures of adult women and their adolescent daughters of predominantly Japanese and Caucasian ethnicity using Dual Energy X ray Absorptiometry (DXA). METHODS: We obtained DXA whole body scans for 101 mothers aged >=30 years and 112 daughters aged 10-16 years who were classified as Asian, Part-Asian, Mixed-Other, and Caucasian. As a measure of central adiposity, we calculated the trunk/periphery fat ratio (TPFR). General linear models were applied to evaluate differences in adiposity measures by ethnic category. RESULTS: In mothers, TPFR was significantly higher (p(trend)=0.01) in Asians and Part-Asians (1.38+/-0.42 for and 1.32+/-0.51) than in Mixed-Others and Caucasians (1.18+/-0.27 and 1.09+/-0.21). Daughters showed a similar trend (p(trend) =0.001) with respective values of 1.09+/-0.18, 0.97+/-0.17, 0.99+/-0.16, and 0.87+/-0.11. Among mothers, gynoid fat mass and periphery fat mass were significantly lower in Asians than Caucasians, whereas none of the regional DXA adiposity measures in girls differed by ethnicity. CONCLUSIONS: These results confirm previous reports of greater central adiposity in women of Asian ancestry and indicate that ethnic differences in adiposity are already present in adolescence. PMID- 22247609 TI - A novel in vitro angiogenesis model based on a microfluidic device. AB - Angiogenesis is very important for many physiological and pathological processes. However, the molecular mechanisms of angiogenesis are unclear. To elucidate the molecular mechanisms of angiogenesis and to develop treatments for "angiogenesis- dependent" diseases, it is essential to establish a suitable in vitro angiogenesis model. In this study, we created a novel in vitro angiogenesis model based on a microfluidic device. Our model provides an in vivo-like microenvironment for endothelial cells (ECs) cultures and monitors the response of ECs to changes in their microenvironment in real time. To evaluate the potential of this microfluidic device for researching angiogenesis, the effects of pro-angiogenic factors on ECs proliferation, migration and tube-like structure formation were investigated. Our results showed the proliferation rate of ECs in 3D matrix was significantly promoted by the pro-angiogenic factors (with an increase of 59.12%). With the stimulation of pro-angiogenic factors gradients, ECs directionally migrated into the Matrigel from low concentrations to high concentrations and consequently formed multi-cell chords and tube-like structures. These results suggest that the device can provide a suitable platform for elucidating the mechanisms of angiogenesis and for screening pro-angiogenic or anti-angiogenic drugs for "angiogenesis-dependent" diseases. PMID- 22247610 TI - Does Clinical Inertia Vary According to Provider Type? AB - Despite the well established risks of persistently elevated blood pressure, as well as the benefits of controlling such elevations, hypertension remains underdiagnosed and undertreated. These VA researchers compared the rates of antihypertensive medication intensification between resident physicians, midlevel practitioners, and attending physicians. PMID- 22247611 TI - Erratum: corrigendum. AB - [This corrects the article on p. 495 in vol. 7, PMID: 21931491.]. PMID- 22247612 TI - Pregnancy is associated with psychiatric symptoms in a low-income countryside community of Brazil. AB - BACKGROUND: Psychiatric symptoms during pregnancy induce an increase in morbidity and also in the mortality levels among women and children. However, the real association between pregnancy and psychiatric disorders and the peculiarities of the phenomenology of symptoms in underprivileged countryside communities remain uncertain. OBJECTIVE: To verify the association between psychiatric disorder, symptoms, and pregnancy among women from a low-income countryside community and to determine the specific cutoff points for major depression diagnosis according to Beck Depression Inventory for the different trimesters of pregnancy in this population. METHODS: Ninety-four pregnant women and 38 healthy women from the Conceicao do Mato Dentro health service, a rural low-income community in Brazil, participated in the present study. Psychiatric examination included a structured clinical interview for psychiatric disorders according to Mini International Neuropsychiatric Interview and psychometric scales such as the Yale-Brown Obsessive Scale, the Beck Depression Inventory, and the Hamilton Anxiety Scale. The cutoff points for Beck Depression Inventory were determined through the application of receiver operating characteristic curves considering the diagnosis of major depression according to Mini International Neuropsychiatric Interview. RESULTS: The pregnant women had a higher frequency of psychiatric disorders and depression and anxiety symptoms. All cutoff points of Beck Depression Inventory were equal or higher than 12 with high sensitivity and specificity. Although the modified cutoff was selected based on both high sensitivity and high specificity, they were lower than when the cutoff was applied to nonpregnant women. CONCLUSION: Pregnancy was associated with the occurrence of psychiatric disorders and depressive and anxiety symptoms. In comparison to the literature, the present results indicate that there are different cutoff points in the Beck Depression Inventory for pregnant women from different cultures and in different pregnancy trimesters. PMID- 22247613 TI - Association between obstructive sleep apnea (OSA) and depression and the effect of continuous positive airway pressure (CPAP) treatment. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a relatively common disorder which has a negative impact on the psychological well-being of affected individuals. OBJECTIVE: To assess the association between OSA and depression as well as the effect of treatment with continuous positive airway pressure (CPAP). METHODS: A total of 37 newly diagnosed individuals with OSA underwent an overnight polysomnography and were assessed using the Epworth Sleepiness Scale (ESS), the Hamilton Depression Rating Scale (HDRS), and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Patients were assessed before and after 2 months of CPAP use. RESULTS: Of the 37 patients included in the study, 21 (56.7%) had clinically relevant depression as indicated by a score >10 on the HDRS and eleven patients (29.7%) met the diagnostic criteria for a major depressive episode using the Structured Clinical Interview. Scores on the HDRS were correlated with the Apnea Hypoxia Index, ESS scores, and oxygen saturation. Patients showed a significant reduction in depressive symptoms and improvement in ESS scores after CPAP treatment. CONCLUSION: Patients with OSA should be screened carefully for depressive disorders. CPAP should be tried first before starting other treatment modalities for depression. PMID- 22247614 TI - Rapid improvement of depressive symptoms in suicide attempters following treatment with milnacipran and tricyclic antidepressants - a case series. AB - Suicide is a serious social problem in many countries, including Japan. The majority of people who commit suicide suffer from depression. Suicide attempt patients suffering from serious physical injuries are initially treated in hospital emergency departments. The present post hoc analysis examined data from patients admitted to an emergency hospital for treatment of physical injuries, resulting from a suicide attempt, and initial psychiatric treatment for depression and prevention of future suicide attempts. The effects on depressive symptoms were studied in two groups of patients using the 17-item Hamilton depression scale (HAMD). One group (n = 6) had received intravenous tricyclic antidepressants (TCA) (amitriptyline or clomipramine) while the other group (n = 7) had been treated orally with milnacipran, a serotonin and norepinephrine reuptake inhibitor antidepressant. Prior to treatment the four highest scoring items on the HAMD scale were the same in both groups namely, item 1 (depressed mood), item 3 (suicidality), item 7 (interest in work and activities), and item 10 (psychic anxiety). After 1 week of treatment, mean global HAMD scores were significantly reduced in both groups. Treatment resulted in a significant reduction of five HAMD items in the TCA group, whereas in the milnacipran group 12 HAMD items were significantly reduced. Suicidality (item 3) was significantly improved by 1 week treatment with milnacipran, but not by TCAs. Milnacipran rapidly improved a wide range of depressive symptoms, including suicidality within the first week. The improvement with milnacipran would appear to be, at least, equivalent to that achieved with TCAs, possibly affecting a wider range of symptoms. Since milnacipran has been shown in comparative studies to be better tolerated than TCAs, this antidepressant offers an interesting option for the treatment of suicidal patients in an emergency setting. PMID- 22247615 TI - The occurrence of adverse drug reactions reported for attention deficit hyperactivity disorder (ADHD) medications in the pediatric population: a qualitative review of empirical studies. AB - BACKGROUND: To review empirical studies of adverse drug reactions (ADRs) reported to be associated with the use of medications generally licensed for treatment of attention deficit hyperactivity disorder (ADHD) symptoms in the pediatric population. METHODS: PubMed, Embase, and PsycINFO((r)) databases were searched from origin until June 2011. Studies reporting ADRs from amphetamine derivates, atomoxetine, methylphenidate, and modafinil in children from birth to age 17 were included. Information about ADR reporting rates, age and gender of the child, type, and seriousness of ADRs, setting, study design, ADR assessors, authors, and funding sources were extracted. RESULTS: The review identified 43 studies reporting ADRs associated with medicines for treatment of ADHD in clinical studies covering approximately 7000 children, the majority of 6- to 12-year-old boys, and particularly in the United States of America (USA). The most frequently reported ADRs were decrease in appetite, gastrointestinal pain, and headache. There were wide variations in reported ADR occurrence between studies of similar design, setting, included population, and type of medication. Reported ADRs were primarily assessed by the children/their parents, and very few ADRs were rated as being serious. A large number of children dropped out of studies due to serious ADRs, and therefore, the actual number of serious ADRs from use of psychostimulants is probably higher. A large number of studies were conducted by the same groups of authors and sponsored by the pharmaceutical companies manufacturing the respective medications. CONCLUSION: Reported ADRs from use of psychostimulants in children were found in clinical trials of short duration. Since ADHD medications are prescribed for long-term treatment, there is a need for long-term safety studies. The pharmaceutical companies should make all information about ADRs reported for these medications accessible to the public, and further studies are needed on the impact of the link between researchers and the manufacturers of the respective products. PMID- 22247616 TI - Attention deficits in Japanese multiple sclerosis patients with minor brain lesion loads. AB - BACKGROUND: To investigate whether Japanese multiple sclerosis (MS) patients with minor brain lesion loads have attention deficits and brain atrophy, and to correlate their circumstance. METHOD: Twenty-one Japanese patients with relapsing remitting MS were included in this study. Attention deficits were evaluated using Clinical Assessment for Attention (CAT) standardized according to age groups. Lesion load in the brain was assessed by tallying the total volume of plaques visible on brain magnetic resonance imaging (MRI). The width of the third ventricle and the bicaudate ratio were measured. RESULTS: The completion time for the visual cancellation tasks and/or the reaction times for the continuous performance test were prolonged in 14 patients (66.7%). The accuracy of responses was preserved throughout the CAT. Deviation from the normal value was not exaggerated based on the increasing difficulty of the task. The total volume of plaques on brain MRI was small. The width of the third ventricle was significantly increased in patients with MS when compared to controls, but was not correlated with the low performance on the CAT. CONCLUSIONS: Japanese MS patients with minor brain lesion loads frequently had attention deficits characterized by slowness of automatic information processing, but controlled processing that requires working memory demands was spared. PMID- 22247617 TI - Mobilizing male opinion leaders' support for family planning to improve maternal health: a theory-based qualitative study from Pakistan. AB - PURPOSE: Pakistan is a patriarchal society in which male opinion leaders play an important role in determining health-seeking behaviors pertaining to family planning (FP) among their respective communities. This research focuses on cataloguing the perceptions of opinion leaders (clergymen, health professionals, and social workers) about the barriers for using services and practical solutions for promoting FP in the slums of Karachi, Pakistan. MATERIALS AND METHODS: A qualitative study using an open-ended, semistructured interview schedule with hypothetical scenarios and in-depth interviews with a purposive sample of 45 opinion leaders (25 mosque imams/clergymen, 12 nonallopathic health professionals, and eight social workers/activists) was conducted in 2006-2007 in Karachi, Pakistan. Transcripts were coded thematically utilizing NVivo by using an adapted constant comparison analysis process as described by Strauss and Corbin. RESULTS: Seven key themes were derived from the in-depth interviews. Five themes provide insight into the opinion leaders' perceptions of barriers to FP and modern contraception methods. Among the barriers religious taboos and cultural pressures were particularly note-worthy. Two themes offered opportunities for more effective development and implementation of FP programs. CONCLUSION: It is evident from the study that opinion leaders in the community and the clergy lack the understanding of the importance of birth spacing. However, because they have a great deal of influence on the community at large, it is imperative to interact with them to build their capacity in order to propagate the messages of FP and improve maternal health and reproductive health in general. PMID- 22247618 TI - Lack of information and access to advanced treatment for Parkinson's disease patients. AB - BACKGROUND: Parkinson's disease (PD) patients' own knowledge and experience and access to information, in relation to advanced treatment methods, are very limited. The aim of this study was to map out PD patients' perception about various advanced treatment methods, their availability and regional differences in medical care, and to investigate patients' experience of their medication and quality of life. METHODS: A survey was sent to 4886 PD patients of the Swedish Parkinson's Disease Association covering demography, the patient's illness, current treatment, received information about advanced treatment alternatives, and health status. Advanced PD was considered as patients diagnosed >5 years ago, using PD medication >5 times/day, and experiencing motor complications >2 hours/day. RESULTS: In total, 3327/4886 persons (68%) responded (57% men) of which 1300 (39%) were classified as having advanced PD. Mean age was 71 years with a median disease duration of 8 years. The treating physician was a neurologist (86%) but varied between counties (96% to 52%) and was most frequent in urban areas. Doctor appointments were 1.7 times/year with regional variation (2.1 to 1.1). Three out of four patients had heard of advanced treatment options and were interested, but were denied treatment. Only a small proportion of patients were informed of these by their physician. Nine percent were satisfied with their medication (including 4% of advanced patients). One third of patients experienced their general health as poor or very poor. CONCLUSION: The majority of Swedish PD patients are treated by neurologists. Annual numbers of doctors' appointments were low in an international context and can partly be explained by the shortage of neurologists and other trained specialists. Doctors only provided a small proportion of patients with advanced therapy information, despite patients' interest. Hence, improvement is warranted regarding doctor appointments, information about various advanced treatment options, and their availability. PMID- 22247620 TI - Australian perspective regarding recommendations for physical activity and exercise rehabilitation in pulmonary arterial hypertension. AB - AIM: To determine the opinion of health care professionals within Australia, regarding acceptable levels of exertion and symptoms, and referral for exercise rehabilitation in patients with pulmonary arterial hypertension (PAH). METHOD: In 2010, 76 health care professionals at a specialist pulmonary hypertension meeting in Australia were surveyed using a self-administered questionnaire. The questionnaire included case studies of patients with PAH in World Health Organization (WHO) functional classes II-IV. For each case study, respondents were asked to report their opinion regarding the acceptable level of exertion and symptoms during daily activities, and whether they would refer the patient for exercise rehabilitation. Three additional questions asked about advice in relation to four specific physical activities. RESULTS: The response rate was 70% (n = 53). Overall, 58% of respondents recommended patients undertake daily activities 'as tolerated'. There was no consensus regarding acceptable levels of breathlessness or fatigue, but the majority of respondents considered patients should have no chest pain (73%) and no more than mild light-headedness (92%) during daily activities. Overall, 63% of respondents would have referred patients for exercise rehabilitation. There was little difference in opinion regarding the acceptable level of exertion or symptoms, or referral for exercise rehabilitation, according to functional class. However, the patients' functional class did influence the advice given regarding the specific physical activities. CONCLUSION: In 2010, there were inconsistencies between individual health care professionals within Australia regarding appropriate levels of physical exertion and acceptable symptoms during daily activities. Almost two-thirds of the respondents reported they would refer patients for exercise rehabilitation. PMID- 22247619 TI - Current surgical status of thyroid diseases. AB - Thyroid nodules are a common clinical problem for surgeons. The clinical importance of nodules is the need to exclude thyroid cancer, which occurs in 5% 15% of patients. If fine needle aspiration cytology is positive, or suspicious for malignancy, surgery is recommended. During the past decade, with the tendency to develop smaller incisions, an endoscopic approach has been applied to thyroid surgery, called minimally invasive video-assisted thyroidectomy. This approach was immediately followed by other minimally invasive or scarless neck techniques, such as the breast approach, axillary-breast approach, and robot-assisted method. All these techniques follow the same principles of surgery and oncology. This review presents the current surgical management of the thyroid gland, including the surgical techniques and compares them by describing benefits and drawbacks of each one. PMID- 22247621 TI - Tolerability of NGX-4010, a capsaicin 8% patch for peripheral neuropathic pain. AB - BACKGROUND/PURPOSE: NGX-4010 (QUTENZA(TM); NeurogesX Inc, San Mateo, CA), a capsaicin 8% dermal patch, is licensed in the European Union for the treatment of peripheral neuropathic pain (PNP) in nondiabetic adults and in the United States for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN). While NGX-4010 treatment is associated with a low risk of systemic adverse events, patch application-related pain is common and may be managed with local cooling and/or oral analgesics. This article characterizes the tolerability of NGX-4010 and will help to guide any pain management. METHODS: This integrated analysis of tolerability data collected from the NGX-4010 clinical study program included 1696 patients with PNP. Patch application-related pain on the treatment day was captured as Numeric Pain Rating Scale (NPRS) "pain now" scores while "average pain for the past 24 hours" NPRS scores were analyzed for 7 days following treatment. Other tolerability assessments included the percentage of patients completing >=90% of the intended treatment duration and patients using medication for patch application-related pain. RESULTS: The mean maximum change in "pain now" NPRS scores from pretreatment levels during and after patch application was 2.6 for all patients. This pain was transient and resolved following patch removal. Mean "average pain for the past 24 hours" NPRS scores returned to baseline by the evening of the treatment day for patients with PHN, and the evening of day 2 for patients with human immunodeficiency virus associated distal sensory polyneuropathy or painful diabetic neuropathy. Repeated NGX-4010 applications did not affect the intensity of patch application-related pain. Almost all patients (>=98%) completed >=90% of the full treatment duration, regardless of the number of treatments received. CONCLUSION: Transient patch application-related pain with NGX-4010 can be managed with local cooling and/or oral analgesics in nearly all cases. Patient adherence to the full intended treatment duration indicated that patch application-related pain was not a barrier to NGX-4010 use. PMID- 22247622 TI - Somatosensory test responses in children with growing pains. AB - PURPOSE: To further the understanding of growing pains (GP), in particular, the nature of this pain disorder. METHODS: This study included 33 children aged 5-12 years who met criteria for GP (cases) and 29 children without GP of similar age and sex (controls). Nineteen controls were siblings of cases. GP was diagnosed by standard consensus questionnaires. A questionnaire addressed characteristics of the pain and family history of GP. Evidence for peripheral neuropathic disorder was tested by somatosensory testing and provocation tests of peripheral nerves. Somatosensory testing by a blinded researcher involved threshold determination and/or response magnitude to nonpainful stimuli including touch, dynamic brush, cold, vibration, and deep pressure applied to limb and abdominal sites. RESULTS: Distributional, temporal, and quality characteristics of the pain were in accordance with published descriptions. There was no indication of primary musculoskeletal disorder. No evidence was found that GP is a peripheral neuropathic pain syndrome. There were minor but statistically significantly increased responses to cutaneous cold, vibration, and to deep pressure stimuli in cases compared to controls, evident in a wider distribution than the symptomatic lower limbs. CONCLUSION: GP is a regional pain syndrome with evidence in this study of mild widespread disorder of somatosensory processing. PMID- 22247623 TI - fMRI in patients with lumbar disc disease: a paradigm to study patients over time. AB - Low back pain is a common human ailment. It is estimated that over 70% of the population will experience low back pain that will require medication and/or medical attention. There are many causes for low back pain, one being herniation of the discs of the lumbar spine. Treatment options are very limited. Why patients develop chronic pain especially when there is no known organic cause or when the offending painful stimulus has been removed remains poorly understood. Functional magnetic resonance imaging (fMRI) is a technique that allows researchers to image which regions of the brain that are activated during motor, cognitive, and sensory experiences. Using fMRI to study pain has revealed new information about how the brain responds to painful stimuli and what regions of the brain are activated during pain. However, many of the paradigms used do not replicate the subject's pain or use painful stimuli in volunteers without pain. Also, following patients from their acute phase of pain to the chronic phase with serial fMRI has not been performed. In this study we developed a paradigm that would allow studying patients with low back pain and leg pain including lumbar radiculopathy to better mimic a clinical pain syndrome and to have a method of following patients with this type of pain over time. PMID- 22247624 TI - Communication gaps between physicians and patients with postherpetic neuralgia: results from a national study on practice patterns. AB - BACKGROUND: The purpose of this study was to identify differences in perceptions of care regarding postherpetic neuralgia, including communication patterns between patients and physicians and levels of satisfaction with therapies and care. METHODS: A survey was developed for physicians (neurologists, internists, and family physicians) and patients with postherpetic neuralgia in order to determine their perspectives on its management. RESULTS: A total of 142 eligible patient respondents were included in the study, and responses were compared with those of 150 primary care physicians and 76 neurologist respondents. Few patients and physicians indicated satisfaction with the currently available treatments for postherpetic neuralgia. While nearly all physicians responded that they discuss the cause of postherpetic neuralgia with a patient, one in four patients indicated that their physician did not discuss the cause. Similarly, one in four patients were not aware of the duration of postherpetic neuralgia, the treatment side effects, or what to expect from treatment. Patients may be less likely to discuss treatment side effects and quality of life issues than physicians perceive. CONCLUSION: Physicians and patients have similar perceptions regarding treatment options for postherpetic neuralgia; however, certain gaps in communication were evident, which may be attributable to physician knowledge and communication skills with patients. Strategies to improve issues of expected outcomes and side effects of treatment may be useful to physicians. PMID- 22247625 TI - Implications and reflections on the 2010 Supreme Court ruling on Canada's AHR Act. AB - In December, 2010, Canada's 6 year old Assisted Human Reproduction Act was successfully challenged in the Supreme Court of Canada. There may be important implications for public health and the evolution of reproductive technologies in this country. PMID- 22247626 TI - Non-fistulous urinary leakage among women attending a Nigerian family planning clinic. AB - Urinary leakage is an important gynecological challenge, which has a substantial impact on quality of life. The aim of this study was to determine the prevalence and types of non-fistulous urinary leakage among women attending the family planning clinic of the University of Ilorin teaching hospital, Ilorin, Nigeria. The study was a cross-sectional study carried out between January 3 and April 25 2009. One hundred and two women experienced urinary leakage out of 333 women interviewed, giving a prevalence rate of 30.6%. Stress incontinence was the most common urinary leakage (prevalence rate 12.0%). This is followed by urge incontinence (10.8%), urinary incontinence (4.8%), and overflow incontinence (3.0%). None of the women afflicted sought medical help. Conclusively, this study has demonstrated that non-fistulous urinary leakage is a common problem among women of reproductive age in this environment. PMID- 22247627 TI - Effect of educational intervention using the Internet on quantitative ultrasound parameters in prevention of osteoporosis: a randomized controlled trial in young Japanese women. AB - BACKGROUND: The objective of this study was to determine whether or not educational intervention using the Internet, to prevent osteoporosis, is able to increase bone strength in young women. METHODS: Subjects were 253 healthy female university and junior college students aged 18-25 years. After initial measurements of bone stiffness index, a bone formation marker, and a bone absorption marker, the minimization method was used to allocate the subjects to an intervention group (n = 126) or a control group (n = 127) according to whether the measurements were above or below average. Subjects in the intervention group were instructed to perform osteoporosis prevention activities, ie, jump on the spot as high as possible ten times per day and increase calcium intake by 300 mg per day to a total of 800 mg or more per day on average. In addition, they were instructed to report the implementation status of the recommended measures via email. The researcher sent out information on osteoporosis and preventive behaviors to the subjects five times via email. RESULTS: A total of 182 subjects, comprising 87 (69.0%) in the intervention group and 95 (74.8%) in the control group, underwent remeasurement 6 months later. Of the subjects in the intervention group, 54 (42.9%) reported their daily additional calcium intake amount and number of jumps via email. The mean amount of additional calcium taken was 216.3 +/- 85.9 mg per day, and mean number of jumps performed was 6.4 +/- 4.2 per day. Subjects in the intervention group were further divided into an implementation group (n = 54), consisting of subjects who sent in reports and a nonimplementation group (n = 72) who did not. No significant difference was found among the groups for rate of change in bone stiffness index and speed of sound, but there was a significant difference for broadband ultrasound attenuation (BUA) (P = 0.017). Sheffe's multiple comparison test was performed using baseline body weight and BUA values as covariates, and revealed that the rate of decrease in bone strength in the control group was larger than that in the implementation group (P = 0.049). CONCLUSION: Health education for preventing osteoporosis via Internet email was performed over 6 months for women aged 18 to 25 and a comparison was performed between the intervention group and control group. The intervention consisted of high jumps on the spot (ten times a day), which reduced the drop in BUA, and thus indicates robustness of the trabecular structure. This suggests that a longer intervention period may maintain or improve bone strength. PMID- 22247628 TI - Seroprevalence of cytomegalovirus antibodies amongst normal pregnant women in Nigeria. AB - OBJECTIVE: Cytomegalovirus (CMV), a ubiquitous virus belonging to the herpes family, is known to be transmitted frequently to developing fetuses in pregnancy. In an immunocompromised state like pregnancy, primary infection through blood transfusion or reactivation of a latent CMV infection can cause severe illness. The study was carried out to determine the seroprevalence of the immunoglobulin G (IgG) antibody to cytomegalovirus amongst pregnant women in correlation with previous exposure to blood transfusion. METHODS: A cross sectional study was carried out amongst 179 HIV negative pregnant women attending the antenatal clinic of Lagos State University Teaching Hospital (LASUTH), Ikeja, Nigeria. Five mL of blood was collected and stored in a plain bottle, centrifuged on the same day and the serum stored at -20 degrees C. All samples were screened for anti-CMV IgG antibodies using the enzyme linked immunosorbent assay (ELISA). Consenting participants were instructed to fill a semi-structured questionnaire to obtain demographic and other related information. Statistical analysis of the results was done using Pearson's chi squared test for analytical assessment. RESULTS: A total of 97.2% of the pregnant women recruited for this study were anti-CMV IgG positive. Out of the 179 recruited for the study 174 responded to the question on previous history of blood transfusion, 14.9% of the respondents (26 of 174) had a previous history of blood transfusion and all tested positive to the anti-CMVIgG antibody. However, past history of blood transfusion and educational level were found to be insignificant to the risk of acquiring CMV infection. CONCLUSION: The seroprevalence of the CMV antibody amongst pregnant women in this environment is high in relation to findings in other developing countries. There is the need to assess anti-CMV immunoglobulin M antibodies in pregnant women, which is a determinant of active infection. PMID- 22247629 TI - Dynamics of IUD use in Vietnam: implications for family planning services at primary health care level. AB - This study describes the dynamics of intrauterine device (IUD) use in Vietnam and implications for family planning services. A retrospective study was conducted among women who received IUD services in 2006-2009 at six commune health stations in three provinces. Women were interviewed about IUD use and switching behaviors. Of 1316 participants, 12.1% had discontinued IUD use at 12 months after insertion, 19.4% at 24 months, and 26.9% at 36 months. The highest rates of discontinuation were among older women and farmers/manual workers. Among 434 women who had an IUD removed, 49% cited health concerns as the main reason. Following removal, 70% switched to another contraceptive method (n = 306); of these, 15% switched to withdrawal, and 12% waited >2 months before adopting a new method. Dissatisfaction with IUD services was associated with high rates of discontinuation. Early discontinuation, delays in adopting new methods, and switching to withdrawal may contribute to unintended pregnancy among commune health station users in Vietnam. PMID- 22247630 TI - CT radiation dose optimization and estimation: an update for radiologists. AB - In keeping with the increasing utilization of CT examinations, the greater concern about radiation hazards from examinations has been addressed. In this regard, CT radiation dose optimization has been given a great deal of attention by radiologists, referring physicians, technologists, and physicists. Dose-saving strategies are continuously evolving in terms of imaging techniques as well as dose management. Consequently, regular updates of this issue are necessary especially for radiologists who play a pivotal role in this activity. This review article will provide an update on how we can optimize CT dose in order to maximize the benefit-to-risk ratio of this clinically useful diagnostic imaging method. PMID- 22247631 TI - Dynamic CT perfusion imaging for the detection of crossed cerebellar diaschisis in acute ischemic stroke. AB - OBJECTIVE: Although the detection of crossed cerebellar diaschisis (CCD) by means of different imaging modalities is well described, little is known about its diagnosis by computed tomography perfusion (CTP) imaging. We investigated the detection rate of CCD by CTP imaging and the factors related to CCD on CTP images in patients with acute ischemic stroke. MATERIALS AND METHODS: CT perfusion maps of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) obtained from 81 consecutive patients affected by an acute ischemic stroke were retrospectively reviewed. Whole-brain perfusion maps were obtained with a multichannel CT scanner using the toggling-table technique. The criteria for CCD was a unilateral supratentorial ischemic lesion and an accompanying decrease in perfusion of the contralateral cerebellar hemisphere on the basis of CTP maps by visual inspection without a set threshold. Maps were quantitatively analyzed in CCD positive cases. RESULTS: The criteria for CCD were fulfilled in 25 of the 81 cases (31%). Detection rates per CTP map were as follows: MTT (31%) > TTP (21%) > CBF (9%) > CBV (6%). Supratentorial ischemic volume, degree of perfusion reduction, and infratentorial asymmetry index correlated strongly (R, 0.555-0.870) and significantly (p < 0.05) with each other in CCD-positive cases. CONCLUSION: It is possible to detect CCD on all four of the CTP-based maps. Of these maps, MTT is most sensitive in detecting CCD. Our data indicate that CTP imaging is a valid tool for the diagnosis of CCD in patients affected by an acute hemispheric stroke. PMID- 22247632 TI - High-definition computed tomography for coronary artery stent imaging: a phantom study. AB - OBJECTIVE: To assess the performance of a high-definition CT (HDCT) for imaging small caliber coronary stents (<= 3 mm) by comparing different scan modes of a conventional 64-row standard-definition CT (SDCT). MATERIALS AND METHODS: A cardiac phantom with twelve stents (2.5 mm and 3.0 mm in diameter) was scanned by HDCT and SDCT. The scan modes were retrospective electrocardiography (ECG)-gated helical and prospective ECG-triggered axial with tube voltages of 120 kVp and 100 kVp, respectively. The inner stent diameters (ISD) and the in-stent attenuation value (AV(in-stent)) and the in-vessel extra-stent attenuation value (AV(in vessel)) were measured by two observers. The artificial lumen narrowing (ALN = [ISD - ISD(measured)]/ISD) and artificial attenuation increase between in-stent and in-vessel (AAI = AV(in-stent) - AV(in-vessel)) were calculated. All data was analyzed by intraclass correlation and ANOVA-test. RESULTS: The correlation coefficient of ISD, AV(in-vessel) and AV(in-stent) between the two observers was good. The ALNs of HDCT were statistically lower than that of SDCT (30 +/- 5.7% versus 35 +/- 5.4%, p < 0.05). HDCT had statistically lower AAI values than SDCT (15.7 +/- 81.4 HU versus 71.4 +/- 90.5 HU, p < 0.05). The prospective axial dataset demonstrated smaller ALN than the retrospective helical dataset on both HDCT and SDCT (p < 0.05). Additionally, there were no differences in ALN between the 120 kVp and 100 kVp tube voltages on HDCT (p = 0.05). CONCLUSION: High definition CT helps improve measurement accuracy for imaging coronary stents compared to SDCT. HDCT with 100 kVp and the prospective ECG-triggered axial technique, with a lower radiation dose than 120 kVp application, may be advantageous in evaluating coronary stents with smaller calibers (<= 3 mm). PMID- 22247633 TI - Coronary vasospastic angina: assessment by multidetector CT coronary angiography. AB - OBJECTIVE: We aimed to describe the imaging findings of multidetector CT coronary angiography (MDCTA) in cases of vasospastic angina (VA) and to determine the accuracy of MDCTA in the identification of VA as compared with invasive coronary angiography with an ergonovine provocation test (CAG with an EG test). MATERIALS AND METHODS: Fifty-three patients with clinically suspected VA were enrolled in this study. Two radiologists analyzed the stenosis degree, presence or absence of plaque, plaque composition, and a remodeling index of the related-segment in CAG with an EG test, which were used as a gold standard. We evaluated the diagnostic performances of MDCTA by comparing the MDCTA findings with those of CAG with an EG test. RESULTS: Among the 25 patients with positive CAG with an EG test, all 12 patients with significant stenosis showed no definite plaque with the negative arterial remodeling. Of the six patients with insignificant stenosis, three (50%) had non-calcified plaque (NCP), two (33%) had mixed plaque, and one (17%) had calcified plaque. When the criteria for significant stenosis with negative remodeling but no definite evidence of plaque as a characteristic finding of MDCTA were used, results showed sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) of 48%, 100%, 100%, and 68%, respectively. CONCLUSION: Significant stenosis with negative remodeling, but no definite evidence of plaque, is the characteristic finding on MDCTA of VA. Cardiac MDCTA shows good diagnostic performance with high specificity and PPV as compared with CAG with an EG test. PMID- 22247635 TI - MR imaging of the spine at 3.0T with T2-weighted IDEAL fast recovery fast spin echo technique. AB - OBJECTIVE: To compare the iterative decomposition of water and fat with echo asymmetry and the least-squares estimation (IDEAL) method with a fat-saturated T2 weighted (T2W) fast recovery fast spin-echo (FRFSE) imaging of the spine. MATERIALS AND METHODS: Images acquired at 3.0 Tesla (T) in 35 patients with different spine lesions using fat-saturated T2W FRFSE imaging were compared with T2W IDEAL FRFSE images. Signal-to-noise ratio (SNR)-efficiencies measurements were made in the vertebral bodies and spinal cord in the mid-sagittal plane or nearest to the mid-sagittal plane. Images were scored with the consensus of two experienced radiologists on a four-point grading scale for fat suppression and overall image quality. Statistical analysis of SNR-efficiency, fat suppression and image quality scores was performed with a paired Student's t test and Wilcoxon's signed rank test. RESULTS: Signal-to-noise ratio-efficiency for both vertebral body and spinal cord was higher with T2W IDEAL FRFSE imaging (p < 0.05) than with T2W FRFSE imaging. T2W IDEAL FRFSE demonstrated superior fat suppression (p < 0.01) and image quality (p < 0.01) compared to fat-saturated T2W FRFSE. CONCLUSION: As compared with fat-saturated T2W FRFSE, IDEAL can provide a higher image quality, higher SNR-efficiency, and consistent, robust and uniform fat suppression. T2W IDEAL FRFSE is a promising technique for MR imaging of the spine at 3.0T. PMID- 22247634 TI - Percutaneous radiofrequency ablation with multiple electrodes for medium-sized hepatocellular carcinomas. AB - OBJECTIVE: To prospectively evaluate the safety and short-term therapeutic efficacy of switching monopolar radiofrequency ablation (RFA) with multiple electrodes to treat medium-sized (3.1-5.0 cm), hepatocellular carcinomas (HCC). MATERIALS AND METHODS: In this prospective study, 30 patients with single medium sized HCCs (mean, 3.5 cm; range, 3.1-4.4 cm) were enrolled. The patients were treated under ultrasonographic guidance by percutaneous switching monopolar RFA with a multichannel RF generator and two or three internally cooled electrodes. Contrast-enhanced CT scans were obtained immediately after RFA, and the diameters and volume of the ablation zones were then measured. Follow-up CT scans were performed at the first month after ablation and every three months thereafter. Technical effectiveness, local progression and remote recurrence of HCCs were determined. RESULTS: There were no major immediate or periprocedural complications. However, there was one bile duct stricture during the follow-up period. Technical effectiveness was achieved in 29 of 30 patients (97%). The total ablation time of the procedures was 25.4 +/- 8.9 minutes. The mean ablation volume was 73.8 +/- 56.4 cm(3) and the minimum diameter was 4.1 +/- 7.3 cm. During the follow-up period (mean, 12.5 months), local tumor progression occurred in three of 29 patients (10%) with technical effectiveness, while new HCCs were detected in six of 29 patients (21%). CONCLUSION: Switching monopolar RFA with multiple electrodes in order to achieve a sufficient ablation volume is safe and efficient. This method also showed relatively successful therapeutic effectiveness on short-term follow up for the treatment of medium-sized HCCs. PMID- 22247637 TI - A retrospective review on feasibility and safety of a new pneumatic compression device for femoral arteriotomy hemostasis. AB - OBJECTIVE: To report our initial experience on the technical feasibility and safety for hemostasis of a new pneumatic compression device in patients undergoing femoral arteriotomy. MATERIALS AND METHODS: This study included 40 consecutive patients in whom hemostasis after transfemoral catheterization was readered by using a pneumatic compression device consisting of an inflatable bulb containing main body and four pieces of supplementary tape. Medical records were retrospectively reviewed for outcomes and complications of hemostasis. Technical success was defined as achieving immediate hemostasis 10 minutes after applying the device over the arteriotomy sites, and clinical success was defined as the ability to ambulate after 4 hours of bed rest without any complications. RESULTS: Technical and clinical success was achieved in 38 (95%) and 37 (93%) patients, respectively. In two patients, hemostasis was achieved after conversion to manual compression. One patient required sand bag placement after removal of the device to control minimal oozing of blood. No patients had late complications. CONCLUSION: The new pneumatic compression device provides effective and safe hemostasis after transfemoral catheterization in selected patient populations. PMID- 22247636 TI - Right gastric venous drainage: angiographic analysis in 100 patients. AB - OBJECTIVE: To evaluate the pattern of right gastric venous drainage by use of digital subtraction angiography. MATERIALS AND METHODS: A series of 100 consecutive patients who underwent right gastric arteriography during transcatheter arterial chemoembolization for hepatocellular carcinoma were included in this study. Angiographic findings were retrospectively analyzed with respect to the presence or absence of the right and aberrant gastric veins, multiplicity of draining veins, aberrant right gastric venous drainage sites, and the termination pattern of aberrant right gastric veins (ARGVs). We also compared the relative size of the right and left gastric veins. RESULTS: A total of 49 patients collectively had 66 ARGVs. The common drainage sites for the ARGVs included the hepatic segment IV (n = 35) and segment I (n = 15). The termination pattern of ARGV could be classified into 4 different types. The most common type was termination as a superficial parenchymal blush formation in small areas without demonstrable portal branches. A statistically significant difference was found for the dominancy of the right gastric vein in gastric venous drainage between the two groups with or without ARGV (p < 0.05, Fisher's exact test). In the group of patients without ARGV (n = 51), the right gastric vein was equal to (n = 9) or larger than (n = 17) the left gastric vein in 26 patients (26 of 51, 51%). CONCLUSION: The incidence of ARGV is higher than expected with four distinct types in its termination pattern. The right gastric vein may play a dominant role in gastric venous drainage. PMID- 22247638 TI - Dual-design expandable colorectal stent for a malignant colorectal obstruction: preliminary prospective study using new 20-mm diameter stents. AB - OBJECTIVE: To evaluate the safety and effectiveness of a 20-mm diameter dual design expandable colorectal stent for malignant colorectal obstruction. MATERIALS AND METHODS: The study series included 34 patients with malignant colorectal obstruction who underwent implantation of a 20-mm dual-design expandable colorectal stent in our department between March 2009 and June 2010. The 20-mm dual-design expandable colorectal stent was placed by using a 3.8-mm delivery system that had 28-mm diameter proximal and distal ends. Among the 34 patients, stent placement for palliation was performed in 20 patients, while stent placement for bridge to surgery was performed in 14 patients. RESULTS: A 97% (33 of 34) success rate was achieved for the stent placement. The perforation rate in the bridge to surgery group was 7% (1 of 14), compared to 0% (0 of 19) in palliative group. Migration occurred in one of 33 patients (3%) at 30 days after stent placement. CONCLUSION: The placement of a 20-mm diameter dual-design stent appears to be clinically safe and effective for the management of colorectal obstruction, with low perforation and migration rates. PMID- 22247639 TI - Selective embolization for post-endoscopic sphincterotomy bleeding: technical aspects and clinical efficacy. AB - OBJECTIVE: The objective of this study was to evaluate the technical aspects and clinical efficacy of selective embolization for post-endoscopic sphincterotomy bleeding. MATERIALS AND METHODS: We reviewed the records of 10 patients (3%; M:F = 6:4; mean age, 63.3 years) that underwent selective embolization for post endoscopic sphincterotomy bleeding among 344 patients who received arteriography for nonvariceal upper gastrointestinal bleeding from 2000 to 2009. We analyzed the endoscopic procedure, onset of bleeding, underlying clinical condition, angiographic findings, interventional procedure, and outcomes in these patients. RESULTS: Among the 12 bleeding branches, primary success of hemostasis was achieved in 10 bleeding branches (83%). Secondary success occurred in two additional bleeding branches (100%) after repeated embolization. In 10 patients, post-endoscopic sphincterotomy bleedings were detected during the endoscopic procedure (n = 2, 20%) or later (n = 8, 80%), and the delay was from one to eight days (mean, 2.9 days; +/- 2.3). Coagulopathy was observed in three patients. Eight patients had a single bleeding branch, whereas two patients had two branches. On the selective arteriography, bleeding branches originated from the posterior pancreaticoduodenal artery (n = 8, 67%) and anterior pancreaticoduodenal artery (n = 4, 33%), respectively. Superselection was achieved in four branches and the embolization was performed with n-butyl cyanoacrylate. The eight branches were embolized by combined use of coil, n-butyl cyanoacrylate, or Gelfoam. After the last embolization, there was no rebleeding or complication related to embolization. CONCLUSION: Selective embolization is technically feasible and an effective procedure for post-endoscopic sphincterotomy bleeding. In addition, the posterior pancreaticoduodenal artery is the main origin of the causative vessels of post-endoscopic sphincterotomy bleeding. PMID- 22247641 TI - Aggressive angiomyxoma: an unusual presentation. AB - Aggressive angiomyxoma is an uncommon mesenchymal myxoid tumor that is characterized by slow growth and frequent local recurrence. It is currently regarded as a nonmetastasizing tumor. We describe a case of recurrent aggressive angiomyxoma with invasion into the veins including the inferior vena cava and the right atrium and with pulmonary metastases. Our case, together with those unusual cases documented in previous reports, may lead to a reappraisal of the nature of aggressive angiomyxoma. PMID- 22247640 TI - Diffusion-weighted imaging of a prostate cancer xenograft model seen on a 7 Tesla animal MR scanner: comparison of ADC values and pathologic findings. AB - OBJECTIVE: To assess the relationship between apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance (MR) imaging and pathologic measures of a tumor using a prostate cancer xenograft model. MATERIALS AND METHODS: Eighteen athymic nude mice with 36 PC-3-induced tumors were sacrificed to obtain specimens immediately after MR imaging in order to compare the findings on MR images with those seen on pathological specimens. Using a high-field small animal MR scanner, T1- and T2-weighted imaging and DW MR imaging was performed. Tumors were then processed for Hematoxylin and Eosin staining to evaluate tumor cellularity, intratumoral necrosis and immunostaining using antibodies directed against CD31 and vascular endothelial growth factor (VEGF) to determine the levels of microvessel density (MVD). Mean ADC values that were measured on the solid portion within each tumor were compared with tumor volume, cellularity, degree of necrosis, VEGF expression, and MVD in the corresponding section of the pathological specimen. RESULTS: Mean ADC values of the solid portion within the PC-3-induced high-grade tumors were significantly correlated with the degree of intratumoral necrosis (r = 0.63, p < 0.0001) and MVD (r = -0.44, p = 0.008) on pathologic slides. The ADC values were not significantly correlated with tumor cellularity, VEGF expression, or tumor volume in high-grade prostate cancer tissues. CONCLUSION: In the xenografted prostate cancer model, the ADC values of the solid portion of the tumors are significantly correlated with tumor necrosis and MVD of the pathologic specimens. The ADC values may be utilized as surrogate markers for the noninvasive assessment of tumor necrosis and MVD in high-grade prostate cancer. PMID- 22247642 TI - Pancreatic islet cell amyloidosis manifesting as a large pancreas. AB - A 39-year-old female patient presented to our hospital with epigastric pain lasting for two months. Laboratory results showed impaired glucose tolerance. Ultrasonography of the patient showed a hypoechoic, diffusely enlarged pancreas. CT revealed a large pancreas, with multiple calcifications. On MRI, a diffusely enlarged pancreas was seen hypointense on both T1- and T2-weighted images with heterogeneous enhancement after gadolinium administration. A biopsy of the pancreas revealed primary amyloidosis of islet cells. Decreased signal on T1 weighted images without inflammation findings on CT and MRI were clues for the diagnosis. PMID- 22247643 TI - Occult interpositional rotator cuff - an extremely rare case of traumatic rotator cuff tear. AB - Traumatic interposition of a rotator cuff tendon in the glenohumeral joint without recognizable glenohumeral dislocation is an unusual complication after shoulder trauma. Here we report the clinical and imaging presentations of a 17 year-old man with trapped rotator cuff tendons in the glenohumeral joint after a bicycle accident. The possible trauma mechanism is also discussed. PMID- 22247644 TI - Coronary to bronchial artery fistula causing massive hemoptysis in patients with longstanding pulmonary tuberculosis. AB - We report on three cases of longstanding pulmonary tuberculosis patients with coronary to bronchial artery fistula (CBF) who presented with recurrent massive hemoptysis. The first and second patients died because of decreased functional pulmonary volume plus massive hemoptysis and cannulation failure of CBF due to hypovolemic vasospasm, respectively. When recurrent hemoptysis occurs despite successful embolization treatment, CBF should be considered as a potential bleeding source. Moreover, a coronary angiography should be performed, especially in patients with longstanding cardiopulmonary disease such as pulmonary tuberculosis. PMID- 22247645 TI - Atypical developmental venous anomaly associated with single arteriovenous fistula and intracerebral hemorrhage: a case demonstrated by superselective angiography. AB - We present a case of developmental venous anomaly associated with arteriovenous fistula supplied by a single arterial feeder adjacent to a large acute intracerebral hemorrhage. The arteriovenous fistula was successfully obliterated by superselective embolization while completely preserving the developmental venous anomaly. Two similar cases, including superselective angiographic findings, have been reported in the literature; however, we describe herein superselective angiographic findings in more detail and demonstrate the arteriovenous shunt more clearly than the previous reports. In addition, a literature review was performed to discuss the association of a developmental venous anomaly with vascular lesions. PMID- 22247646 TI - Giant high-flow type pulmonary arteriovenous malformation: coil embolization with flow control by balloon occlusion and an anchored detachable coil. AB - Pulmonary arteriovenous malformations (PAVMs) are often treated by pushable fibered or non-fibered microcoils, using an anchor or scaffold technique or with an Amplatzer plug through a guiding sheath. When performing percutaneous transcatheter microcoil embolization, there is a risk of coil migration, particularly with high-flow type PAVMs. The authors report on a unique treatment in a patient with a giant high-flow PAVM whose nidus had a maximum diameter of 6 cm. A detachable coil, not detached from a delivery wire (an anchored detachable coil), was first placed in the feeding artery under flow control by balloon occlusion, and then multiple microcoils were packed proximally to the anchored detachable coil. After confirming the stability of the microcoils during a gradual deflation of the balloon, we finally released the first detachable coil. The nidus was reduced in size to 15 mm at one year postoperatively. PMID- 22247647 TI - RE: endovascular treatment of congenital intrahepatic portosystemic shunts with Amplatzer plugs. PMID- 22247648 TI - The receptive-expressive gap in the vocabulary of young second-language learners: Robustness and possible mechanisms. AB - Adults and children learning a second language show difficulty accessing expressive vocabulary that appears accessible receptively in their first language (L1). We call this discrepancy the receptive-expressive gap. Kindergarten Spanish (L1) - English (L2) sequential bilinguals were given standardized tests of receptive and expressive vocabulary in both Spanish and English. We found a small receptive-expressive gap in English but a large receptive-expressive gap in Spanish. We categorized children as having had high or low levels of English exposure based on demographic variables and found that the receptive-expressive gap persisted across both levels of English exposure. Regression analyses revealed that variables predicting both receptive and expressive vocabulary scores failed to predict the receptive-expressive gap. The results suggest that the onset of the receptive-expressive gap in L1 must have been abrupt. We discuss possible mechanisms underlying the phenomenon. PMID- 22247649 TI - ELECTRON DETACHMENT DISSOCIATION AND INFRARED MULTIPHOTON DISSOCIATION OF HEPARIN TETRASACCHARIDES. AB - Heparin glycosaminoglycans (GAGs) present the most difficult glycoform for analytical characterization due to high levels of sulfation and structural heterogeneity. Recent contamination of the clinical heparin supply and subsequent fatalities has highlighted the need for sensitive methodologies of analysis. In the last decade, tandem mass spectrometry has been increasingly applied for the analysis of GAGs, but developments in the characterization of highly sulfated compounds have been minimal due to the low number of cross-ring cleavages generated by threshold ion activation by collisional induced dissociation (CID). In the current work, electron detachment dissociation (EDD) and infrared multiphoton dissociation (IRMPD) are applied to a series of heparin tetrasaccharides. With both activation methods, abundant glycosidic and cross ring cleavages are observed. The concept of Ionized Sulfate Criteria (ISC) is presented as a succinct method for describing the charge state, degree of ionization and sodium/proton exchange in the precursor ion. These factors contribute to the propensity for useful fragmentation during MS/MS measurements. Precursors with ISC values of 0 are studied here, and shown to yield adequate structural information from ion activation by EDD or IRMPD. PMID- 22247650 TI - Characterization of protonated phospholipids as fragile ions in quadrupole ion trap mass spectrometry. AB - Some ions exhibit "ion fragility" in quadrupole ion trap mass spectrometry (QIT MS) during mass analysis with resonance ejection. In many cases, different ions generated from the same compound exhibit different degrees of ion fragility, with some ions (e.g., the [M+H](+) ion) stable and other ions (e.g., the [M+Na](+) ion) fragile. The ion fragility for quadrupole ion trap (QIT) mass spectrometry (MS) for protonated and sodiated ions of three phospholipids, 1,2-dipalmitoyl-sn glycero-3-phosphocholine, PC (16:0/16:0), 1,2-dipalmitoyl-sn-glycero-3 phophoethanolamine, PE (16:0/16:0), and N-palmitoyl-D-erythro sphingosylphosphorylcholine, SM (d18:1/16:0), was determined using three previously developed experiments: 1) the peak width using a slow scan speed, 2) the width of the isolation window for efficient isolation, and 3) the energy required for collision-induced dissociation. In addition, ion fragility studies were designed and performed to explore a correlation between ion fragility in QIT mass analysis and ion fragility during transport between the ion source and the ion trap. These experiments were: 1) evaluating the amount of thermal-induced dissociation as a function of heated capillary temperature, and 2) determining the extent of fragmentation occurring with increasing tube lens voltage. All phospholipid species studied exhibited greater ion fragility as protonated species in ion trap mass analysis than as sodiated species. In addition, the protonated species of both SM (d18:0/16:0) and PC (16:0/16:0) exhibited greater tendencies to fragment at higher heated capillary temperatures and high tube lens voltages, whereas the PE (16:0/16:0) ions did not appear to exhibit fragility during ion transport. PMID- 22247651 TI - Overview of stabilizing ligands for biocompatible quantum dot nanocrystals. AB - Luminescent colloidal quantum dots (QDs) possess numerous advantages as fluorophores in biological applications. However, a principal challenge is how to retain the desirable optical properties of quantum dots in aqueous media while maintaining biocompatibility. Because QD photophysical properties are directly related to surface states, it is critical to control the surface chemistry that renders QDs biocompatible while maintaining electronic passivation. For more than a decade, investigators have used diverse strategies for altering the QD surface. This review summarizes the most successful approaches for preparing biocompatible QDs using various chemical ligands. PMID- 22247652 TI - Earthworm (Eisenia andrei) avoidance of soils treated with cypermethrin. AB - The pyrethroid insecticide cypermethrin is used for agricultural and public health campaigns. Its residues may contaminate soils and the beneficial soil organisms, like the earthworms, that may ingest the contaminated soil particles. Due to its ecological relevance, earthworms Eisenia andrei/fetida have been used in different ecotoxicological tests. The avoidance of soils treated with cypermethrin by compost worms Eisenia andrei was studied here as a bioindicator of the influence of treatment dosage and the pesticide formulation in three different agricultural soils indicated by the Brazilian environmental authorities for ecotoxicological tests. This earthworms' behavior was studied here as a first attempt to propose the test for regulation purposes. The two-compartment test systems, where the earthworms were placed for a two-day exposure period, contained samples of untreated soil alone or together with soil treated with technical grade or wettable powder formulation of cypermethrin. After 48 h, there was no mortality, but the avoidance was clear because all earthworms were found in the untreated section of each type of soil (p < 0.05). No differences were found by the Fisher's exact test (p <= 1.000) for each soil and treatment, demonstrating that the different soil characteristics, the cypermethrin concentrations and formulation, as well as the smaller amounts of soil and earthworms did not influence the avoidance behavior of the earthworms to cypermethrin. The number and range of treatments used in this study do not allow a detailed recommendation of the conditions applied here, but to the best of our knowledge, this is the first reported attempt to identify the avoidance of pesticide treated tropical soils by earthworms. PMID- 22247653 TI - Serological thymidine kinase 1 is a biomarker for early detection of tumours--a health screening study on 35,365 people, using a sensitive chemiluminescent dot blot assay. AB - Serological thymidine kinase 1 (STK1) is a reliable proliferation marker for prognosis, monitoring tumour therapy, and relapse. Here we investigated the use of STK1 in health screening for early detection of pre-malignant and malignant diseases. The investigation was based on 35,365 participants in four independent health screening studies in China between 2005-2011. All participants were clinically examined. The concentration of STK1 was determined by a sensitive chemiluminescent dot blot ECL assay. The ROCvalue of the STK1 assay was 0.96. At a cut-off STK1 value of 2.0 pM, the likelihood (+) value was 236.5, and the sensitivity and the specificity were 0.78 and 0.99, respectively. The relative number of city-dwelling people with elevated STK1 values (>=2.0 pM) was 0.8% (198/26,484), while the corresponding value for the group of oil-field workers was 5.8% (514/8,355). The latter group expressed significantly higher frequency of refractory anaemia, fatty liver, and obesity, compared to the city dwellers, but no cases of breast hyperplasia or prostate hyperplasia. Furthermore, people working in oil drilling/oil transportation showed higher STK1 values and higher frequency of pre-malignancies and benign diseases than people working in the oil field administration. In the STK1 elevated group of the city-dwelling people, a statistically significantly higher number of people were found to have malignancies, pre-malignancies of all types, moderate/severe type of hyperplasia of breast or prostate, or refractory anaemia, or to be at high risk for hepatitis B, compared to people with normal STK1 values (<2.0 pM). No malignancies were found in the normal STK1 group. In the elevated STK1 group 85.4% showed diseases linked to a higher risk for pre-/early cancerous progression, compared to 52.4% of those with normal STK1 values. Among participants with elevated STK1 values, 8.8% developed new malignancies or progress in their pre-malignancies within 5 to 72 months, compared to 0.2% among people with normal STK1 values. People who showed elevated STK1 values were at about three to five times higher risk to develop malignancies compared to a calculated risk based on a cancer incidence rate of 0.2-0.3%. We conclude that serological TK1 protein concentration is a reliable marker for risk assessment of pre/early cancerous progression. PMID- 22247654 TI - Luminescence sensors applied to water analysis of organic pollutants--an update. AB - The development of chemical sensors for environmental analysis based on fluorescence, phosphorescence and chemiluminescence signals continues to be a dynamic topic within the sensor field. This review covers the fundamentals of this type of sensors, and an update on recent works devoted to quantifying organic pollutants in environmental waters, focusing on advances since about 2005. Among the wide variety of these contaminants, special attention has been paid polycyclic aromatic hydrocarbons, pesticides, explosives and emerging organic pollutants. The potential of coupling optical sensors with multivariate calibration methods in order to improve the selectivity is also discussed. PMID- 22247655 TI - Magnetic field measurements based on Terfenol coated photonic crystal fibers. AB - A magnetic field sensor based on the integration of a high birefringence photonic crystal fiber and a composite material made of Terfenol particles and an epoxy resin is proposed. An in-fiber modal interferometer is assembled by evenly exciting both eigenemodes of the HiBi fiber. Changes in the cavity length as well as the effective refractive index are induced by exposing the sensor head to magnetic fields. The magnetic field sensor has a sensitivity of 0.006 (nm/mT) over a range from 0 to 300 mT with a resolution about +/-1 mT. A fiber Bragg grating magnetic field sensor is also fabricated and employed to characterize the response of Terfenol composite to the magnetic field. PMID- 22247656 TI - A zinc oxide nanorod ammonia microsensor integrated with a readout circuit on-a chip. AB - A zinc oxide nanorod ammonia microsensor integrated with a readout circuit on-a chip fabricated using the commercial 0.35 MUm complementary metal oxide semiconductor (CMOS) process was investigated. The structure of the ammonia sensor is composed of a sensitive film and polysilicon electrodes. The ammonia sensor requires a post-process to etch the sacrificial layer, and to coat the sensitive film on the polysilicon electrodes. The sensitive film that is prepared by a hydrothermal method is made of zinc oxide. The sensor resistance changes when the sensitive film adsorbs or desorbs ammonia gas. The readout circuit is used to convert the sensor resistance into the voltage output. Experiments show that the ammonia sensor has a sensitivity of about 1.5 mV/ppm at room temperature. PMID- 22247657 TI - A New MANET wormhole detection algorithm based on traversal time and hop count analysis. AB - As demand increases for ubiquitous network facilities, infrastructure-less and self-configuring systems like Mobile Ad hoc Networks (MANET) are gaining popularity. MANET routing security however, is one of the most significant challenges to wide scale adoption, with wormhole attacks being an especially severe MANET routing threat. This is because wormholes are able to disrupt a major component of network traffic, while concomitantly being extremely difficult to detect. This paper introduces a new wormhole detection paradigm based upon Traversal Time and Hop Count Analysis (TTHCA), which in comparison to existing algorithms, consistently affords superior detection performance, allied with low false positive rates for all wormhole variants. Simulation results confirm that the TTHCA model exhibits robust wormhole route detection in various network scenarios, while incurring only a small network overhead. This feature makes TTHCA an attractive choice for MANET environments which generally comprise devices, such as wireless sensors, which possess a limited processing capability. PMID- 22247658 TI - Gaussian multiscale aggregation applied to segmentation in hand biometrics. AB - This paper presents an image segmentation algorithm based on Gaussian multiscale aggregation oriented to hand biometric applications. The method is able to isolate the hand from a wide variety of background textures such as carpets, fabric, glass, grass, soil or stones. The evaluation was carried out by using a publicly available synthetic database with 408,000 hand images in different backgrounds, comparing the performance in terms of accuracy and computational cost to two competitive segmentation methods existing in literature, namely Lossy Data Compression (LDC) and Normalized Cuts (NCuts). The results highlight that the proposed method outperforms current competitive segmentation methods with regard to computational cost, time performance, accuracy and memory usage. PMID- 22247659 TI - Earthworms and soil pollutants. AB - Although the toxicity of metal contaminated soils has been assessed with various bioassays, more information is needed about the biochemical responses, which may help to elucidate the mechanisms involved in metal toxicity. We previously reported that the earthworm, Eisenia fetida, accumulates cadmium in its seminal vesicles. The bio-accumulative ability of earthworms is well known, and thus the earthworm could be a useful living organism for the bio-monitoring of soil pollution. In this short review, we describe recent studies concerning the relationship between earthworms and soil pollutants, and discuss the possibility of using the earthworm as a bio-monitoring organism for soil pollution. PMID- 22247660 TI - Design and implementation of a biomimetic turtle hydrofoil for an autonomous underwater vehicle. AB - This paper presents the design and implementation of a turtle hydrofoil for an Autonomous Underwater Vehicle (AUV). The final design of the AUV must have navigation performance like a turtle, which has also been the biomimetic inspiration for the design of the hydrofoil and propulsion system. The hydrofoil design is based on a National Advisory Committee for Aeronautics (NACA) 0014 hydrodynamic profile. During the design stage, four different propulsion systems were compared in terms of propulsion path, compactness, sealing and required power. The final implementation is based on a ball-and-socket mechanism because it is very compact and provides three degrees of freedom (DoF) to the hydrofoil with very few restrictions on the propulsion path. The propulsion obtained with the final implementation of the hydrofoil has been empirically evaluated in a water channel comparing different motion strategies. The results obtained have confirmed that the proposed turtle hydrofoil controlled with a mechanism with three DoF generates can be used in the future implementation of the planned AUV. PMID- 22247661 TI - Modeling the behavior of an underwater acoustic relative positioning system based on complementary set of sequences. AB - The great variability usually found in underwater media makes modeling a challenging task, but helpful for better understanding or predicting the performance of future deployed systems. In this work, an underwater acoustic propagation model is presented. This model obtains the multipath structure by means of the ray tracing technique. Using this model, the behavior of a relative positioning system is presented. One of the main advantages of relative positioning systems is that only the distances between all the buoys are needed to obtain their positions. In order to obtain the distances, the propagation times of acoustic signals coded by Complementary Set of Sequences (CSS) are used. In this case, the arrival instants are obtained by means of correlation processes. The distances are then used to obtain the position of the buoys by means of the Multidimensional Scaling Technique (MDS). As an early example of an application using this relative positioning system, a tracking of the position of the buoys at different times is performed. With this tracking, the surface current of a particular region could be studied. The performance of the system is evaluated in terms of the distance from the real position to the estimated one. PMID- 22247662 TI - Design, fabrication and levitation experiments of a micromachined electrostatically suspended six-axis accelerometer. AB - A micromachined electrostatically suspended six-axis accelerometer, with a square plate as proof mass housed by a top stator and bottom stator, is presented. The device structure and related techniques concerning its operating principles, such as calculation of capacitances and electrostatic forces/moments, detection and levitation control of the proof mass, acceleration measurement, and structural parameters design, are described. Hybrid MEMS manufacturing techniques, including surface micromachining fabrication of thin film electrodes and interconnections, integration fabrication of thick nickel structures about 500 MUm using UV-LIGA by successful removal of SU-8 photoresist mold, DRIE of silicon proof mass in thickness of 450 MUm, microassembly and solder bonding, were employed to fabricate this prototype microdevice. A levitation experiment system for the fabricated microaccelerometer chip is introduced, and levitation results show that fast initial levitation within 10 ms and stable full suspension of the proof mass have been successfully demonstrated. PMID- 22247663 TI - Design of sensor data processing steps in an air pollution monitoring system. AB - Environmental monitoring is required to understand the effects of various kinds of phenomena such as a flood, a typhoon, or a forest fire. To detect the environmental conditions in remote places, monitoring applications employ the sensor networks to detect conditions, context models to understand phenomena, and computing technology to process the large volumes of data. In this paper, we present an air pollution monitoring system to provide alarm messages about potentially dangerous areas with sensor data analysis. We design the data analysis steps to understand the detected air pollution regions and levels. The analyzed data is used to track the pollution and to give an alarm. This implemented monitoring system is used to mitigate the damages caused by air pollution. PMID- 22247664 TI - The new pelagic Operational Observatory of the Catalan Sea (OOCS) for the multisensor coordinated measurement of atmospheric and oceanographic conditions. AB - The new pelagic Operational Observatory of the Catalan Sea (OOCS) for the coordinated multisensor measurement of atmospheric and oceanographic conditions has been recently installed (2009) in the Catalan Sea (41 degrees 39'N, 2 degrees 54'E; Western Mediterranean) and continuously operated (with minor maintenance gaps) until today. This multiparametric platform is moored at 192 m depth, 9.3 km off Blanes harbour (Girona, Spain). It is composed of a buoy holding atmospheric sensors and a set of oceanographic sensors measuring the water conditions over the upper 100 m depth. The station is located close to the head of the Blanes submarine canyon where an important multispecies pelagic and demersal fishery gives the station ecological and economic relevance. The OOCS provides important records on atmospheric and oceanographic conditions, the latter through the measurement of hydrological and biogeochemical parameters, at depths with a time resolution never attained before for this area of the Mediterranean. Twenty four moored sensors and probes operating in a coordinated fashion provide important data on Essential Ocean Variables (EOVs; UNESCO) such as temperature, salinity, pressure, dissolved oxygen, chlorophyll fluorescence, and turbidity. In comparison with other pelagic observatories presently operating in other world areas, OOCS also measures photosynthetic available radiation (PAR) from above the sea surface and at different depths in the upper 50 m. Data are recorded each 30 min and transmitted in real-time to a ground station via GPRS. This time series is published and automatically updated at the frequency of data collection on the official OOCS website (http://www.ceab.csic.es/~oceans). Under development are embedded automated routines for the in situ data treatment and assimilation into numerical models, in order to provide a reliable local marine processing forecast. In this work, our goal is to detail the OOCS multisensor architecture in relation to the coordinated capability for the remote, continuous and prolonged monitoring of atmospheric and oceanographic conditions, including data communication and storage. Accordingly, time series of measurements for a number of biological parameters will be presented for the summer months of 2011. Marine hindcast outputs from the numerical models implemented for simulating the conditions over the study area are shown. The strong changes of atmospheric conditions recorded in the last years over the area have altered the marine conditions of living organisms, but the dimension of the impact remains unclear. The OOCS multisensor coordinated monitoring has been specifically designed to address this issue, thus contributing to better understand the present environmental fluctuations and to provide a sound basis for a more accurate marine forecast system. PMID- 22247665 TI - Modeling and analysis of an energy-efficient mobility management scheme in IP based wireless networks. AB - An energy-efficient mobility management scheme in IP-based wireless networks is proposed to reduce the battery power consumption of mobile hosts (MHs). The proposed scheme manages seven MH states, including transmitting, receiving, attention/cell-connected, attention/paging area(PA)-connected, idle, off/attached, and detached states, to efficiently manage battery power, radio resources, and network load. We derive the stationary probabilities and steady state probabilities of the seven MH states for the proposed scheme in IP-based wireless networks in compact form. The effects of various input parameters on MH steady state probabilities and power consumption are investigated in the proposed scheme compared to the conventional scheme. Network costs such as cell updates, PA updates, binding-lifetime-based registrations, and paging messages are analyzed in the proposed and conventional schemes. The optimal values of PA size and registration interval are derived to minimize the network cost of the proposed scheme. The combined network and power costs are investigated for the proposed and conventional schemes. The results provide guidelines to select the proper system parameters in IP-based wireless networks. PMID- 22247666 TI - Protein binding detection using on-chip silicon gratings. AB - We demonstrate a silicon gratings-based biosensor to detect functionalized protein binding on its surface. The designed silicon gratings have sensitivities up to 197 nm/RIU in detecting refractive index change and 1.61 nm per nanometer of thickness change of bio-material on the surface of silicon gratings. Functionalizing proteins on gratings surface by eliminating unspecific binding makes this device more selective and efficient. Streptavidin at a concentration of 0.016 MUmol/mL was functionalized on silicon substrate and biotin of 12 MUmol/mL concentration was used as a target molecule in our detection experiments. Normal transmission measurements of gratings are made in air at different stages of immobilization, bare silicon grating, after attaching streptavidin and after trapping biotin. Total shifts in resonant peak wavelength of ~15 nm in normal transmission were observed after immobilizing biotin with ~7 nm of shift in resonant peak wavelength after functionalizing streptavidin to silicon substrate. PMID- 22247667 TI - On the biomimetic design of agile-robot legs. AB - The development of functional legged robots has encountered its limits in human made actuation technology. This paper describes research on the biomimetic design of legs for agile quadrupeds. A biomimetic leg concept that extracts key principles from horse legs which are responsible for the agile and powerful locomotion of these animals is presented. The proposed biomimetic leg model defines the effective leg length, leg kinematics, limb mass distribution, actuator power, and elastic energy recovery as determinants of agile locomotion, and values for these five key elements are given. The transfer of the extracted principles to technological instantiations is analyzed in detail, considering the availability of current materials, structures and actuators. A real leg prototype has been developed following the biomimetic leg concept proposed. The actuation system is based on the hybrid use of series elasticity and magneto-rheological dampers which provides variable compliance for natural motion. From the experimental evaluation of this prototype, conclusions on the current technological barriers to achieve real functional legged robots to walk dynamically in agile locomotion are presented. PMID- 22247668 TI - Time-resolved fluorescence immunoassay for C-reactive protein using colloidal semiconducting nanoparticles. AB - Besides the typical short-lived fluorescence with decay times in the nanosecond range, colloidal II/VI semiconductor nanoparticles dispersed in buffer also possess a long-lived fluorescence component with decay times in the microsecond range. Here, the signal intensity of the long-lived luminescence at microsecond range is shown to increase 1,000-fold for CdTe nanoparticles in PBS buffer. This long-lived fluorescence can be conveniently employed for time-gated fluorescence detection, which allows for improved signal-to-noise ratio and thus the use of low concentrations of nanoparticles. The detection principle is demonstrated with a time-resolved fluorescence immunoassay for the detection of C-reactive protein (CRP) using CdSe-ZnS nanoparticles and green light excitation. PMID- 22247669 TI - A hierarchical communication architecture for oceanic surveillance applications. AB - The interest in monitoring applications using underwater sensor networks has been growing in recent years. The severe communication restrictions imposed by underwater channels make that efficient monitoring be a challenging task. Though a lot of research has been conducted on underwater sensor networks, there are only few concrete applications to a real-world case study. In this work, hence, we propose a general three tier architecture leveraging low cost wireless technologies for acoustic communications between underwater sensors and standard technologies, Zigbee and Wireless Fidelity (WiFi), for water surface communications. We have selected a suitable Medium Access Control (MAC) layer, after making a comparison with some common MAC protocols. Thus the performance of the overall system in terms of Signals Discarding Rate (SDR), signalling delay at the surface gateway as well as the percentage of true detection have been evaluated by simulation, pointing out good results which give evidence in applicability's favour. PMID- 22247670 TI - Finger vein recognition using local line binary pattern. AB - In this paper, a personal verification method using finger vein is presented. Finger vein can be considered more secured compared to other hands based biometric traits such as fingerprint and palm print because the features are inside the human body. In the proposed method, a new texture descriptor called local line binary pattern (LLBP) is utilized as feature extraction technique. The neighbourhood shape in LLBP is a straight line, unlike in local binary pattern (LBP) which is a square shape. Experimental results show that the proposed method using LLBP has better performance than the previous methods using LBP and local derivative pattern (LDP). PMID- 22247671 TI - Improving social odometry robot networks with distributed reputation systems for collaborative purposes. AB - The improvement of odometry systems in collaborative robotics remains an important challenge for several applications. Social odometry is a social technique which confers the robots the possibility to learn from the others. This paper analyzes social odometry and proposes and follows a methodology to improve its behavior based on cooperative reputation systems. We also provide a reference implementation that allows us to compare the performance of the proposed solution in highly dynamic environments with the performance of standard social odometry techniques. Simulation results quantitatively show the benefits of this collaborative approach that allows us to achieve better performances than social odometry. PMID- 22247672 TI - Use of Earth's magnetic field for mitigating gyroscope errors regardless of magnetic perturbation. AB - Most portable systems like smart-phones are equipped with low cost consumer grade sensors, making them useful as Pedestrian Navigation Systems (PNS). Measurements of these sensors are severely contaminated by errors caused due to instrumentation and environmental issues rendering the unaided navigation solution with these sensors of limited use. The overall navigation error budget associated with pedestrian navigation can be categorized into position/displacement errors and attitude/orientation errors. Most of the research is conducted for tackling and reducing the displacement errors, which either utilize Pedestrian Dead Reckoning (PDR) or special constraints like Zero velocity UPdaTes (ZUPT) and Zero Angular Rate Updates (ZARU). This article targets the orientation/attitude errors encountered in pedestrian navigation and develops a novel sensor fusion technique to utilize the Earth's magnetic field, even perturbed, for attitude and rate gyroscope error estimation in pedestrian navigation environments where it is assumed that Global Navigation Satellite System (GNSS) navigation is denied. As the Earth's magnetic field undergoes severe degradations in pedestrian navigation environments, a novel Quasi-Static magnetic Field (QSF) based attitude and angular rate error estimation technique is developed to effectively use magnetic measurements in highly perturbed environments. The QSF scheme is then used for generating the desired measurements for the proposed Extended Kalman Filter (EKF) based attitude estimator. Results indicate that the QSF measurements are capable of effectively estimating attitude and gyroscope errors, reducing the overall navigation error budget by over 80% in urban canyon environment. PMID- 22247673 TI - On mobility management in multi-sink sensor networks for geocasting of queries. AB - In order to efficiently deal with location dependent messages in multi-sink wireless sensor networks (WSNs), it is key that the network informs sinks what geographical area is covered by which sink. The sinks are then able to efficiently route messages which are only valid in particular regions of the deployment. In our previous work (see the 5th and 6th cited documents), we proposed a combined coverage area reporting and geographical routing protocol for location dependent messages, for example, queries that are injected by sinks. In this paper, we study the case where we have static sinks and mobile sensor nodes in the network. To provide up-to-date coverage areas to sinks, we focus on handling node mobility in the network. We discuss what is a better method for updating the routing structure (i.e., routing trees and coverage areas) to handle mobility efficiently: periodic global updates initiated from sinks or local updates triggered by mobile sensors. Simulation results show that local updating perform very well in terms of query delivery ratio. Local updating has a better scalability to increasing network size. It is also more energy efficient than our previously proposed approach, where global updating in networks have medium mobility rate and speed. PMID- 22247674 TI - An approach to improve the quality of infrared images of vein-patterns. AB - This study develops an approach to improve the quality of infrared (IR) images of vein-patterns, which usually have noise, low contrast, low brightness and small objects of interest, thus requiring preprocessing to improve their quality. The main characteristics of the proposed approach are that no prior knowledge about the IR image is necessary and no parameters must be preset. Two main goals are sought: impulse noise reduction and adaptive contrast enhancement technologies. In our study, a fast median-based filter (FMBF) is developed as a noise reduction method. It is based on an IR imaging mechanism to detect the noisy pixels and on a modified median-based filter to remove the noisy pixels in IR images. FMBF has the advantage of a low computation load. In addition, FMBF can retain reasonably good edges and texture information when the size of the filter window increases. The most important advantage is that the peak signal-to-noise ratio (PSNR) caused by FMBF is higher than the PSNR caused by the median filter. A hybrid cumulative histogram equalization (HCHE) is proposed for adaptive contrast enhancement. HCHE can automatically generate a hybrid cumulative histogram (HCH) based on two different pieces of information about the image histogram. HCHE can improve the enhancement effect on hot objects rather than background. The experimental results are addressed and demonstrate that the proposed approach is feasible for use as an effective and adaptive process for enhancing the quality of IR vein pattern images. PMID- 22247675 TI - Ultrasonic array for obstacle detection based on CDMA with Kasami codes. AB - This paper raises the design of an ultrasonic array for obstacle detection based on Phased Array (PA) techniques, which steers the acoustic beam through the environment by electronics rather than mechanical means. The transmission of every element in the array has been encoded, according to Code Division for Multiple Access (CDMA), which allows multiple beams to be transmitted simultaneously. All these features together enable a parallel scanning system which does not only improve the image rate but also achieves longer inspection distances in comparison with conventional PA techniques. PMID- 22247676 TI - Development of a 3D parallel mechanism robot arm with three vertical-axial pneumatic actuators combined with a stereo vision system. AB - This study aimed to develop a novel 3D parallel mechanism robot driven by three vertical-axial pneumatic actuators with a stereo vision system for path tracking control. The mechanical system and the control system are the primary novel parts for developing a 3D parallel mechanism robot. In the mechanical system, a 3D parallel mechanism robot contains three serial chains, a fixed base, a movable platform and a pneumatic servo system. The parallel mechanism are designed and analyzed first for realizing a 3D motion in the X-Y-Z coordinate system of the robot's end-effector. The inverse kinematics and the forward kinematics of the parallel mechanism robot are investigated by using the Denavit-Hartenberg notation (D-H notation) coordinate system. The pneumatic actuators in the three vertical motion axes are modeled. In the control system, the Fourier series-based adaptive sliding-mode controller with H(infinity) tracking performance is used to design the path tracking controllers of the three vertical servo pneumatic actuators for realizing 3D path tracking control of the end-effector. Three optical linear scales are used to measure the position of the three pneumatic actuators. The 3D position of the end-effector is then calculated from the measuring position of the three pneumatic actuators by means of the kinematics. However, the calculated 3D position of the end-effector cannot consider the manufacturing and assembly tolerance of the joints and the parallel mechanism so that errors between the actual position and the calculated 3D position of the end effector exist. In order to improve this situation, sensor collaboration is developed in this paper. A stereo vision system is used to collaborate with the three position sensors of the pneumatic actuators. The stereo vision system combining two CCD serves to measure the actual 3D position of the end-effector and calibrate the error between the actual and the calculated 3D position of the end-effector. Furthermore, to verify the feasibility of the proposed parallel mechanism robot driven by three vertical pneumatic servo actuators, a full-scale test rig of the proposed parallel mechanism pneumatic robot is set up. Thus, simulations and experiments for different complex 3D motion profiles of the robot end-effector can be successfully achieved. The desired, the actual and the calculated 3D position of the end-effector can be compared in the complex 3D motion control. PMID- 22247677 TI - Design of a lightweight, cost effective thimble-like sensor for haptic applications based on contact force sensors. AB - This paper describes the design and calibration of a thimble that measures the forces applied by a user during manipulation of virtual and real objects. Haptic devices benefit from force measurement capabilities at their end-point. However, the heavy weight and cost of force sensors prevent their widespread incorporation in these applications. The design of a lightweight, user-adaptable, and cost effective thimble with four contact force sensors is described in this paper. The sensors are calibrated before being placed in the thimble to provide normal and tangential forces. Normal forces are exerted directly by the fingertip and thus can be properly measured. Tangential forces are estimated by sensors strategically placed in the thimble sides. Two applications are provided in order to facilitate an evaluation of sensorized thimble performance. These applications focus on: (i) force signal edge detection, which determines task segmentation of virtual object manipulation, and (ii) the development of complex object manipulation models, wherein the mechanical features of a real object are obtained and these features are then reproduced for training by means of virtual object manipulation. PMID- 22247679 TI - An integrated testbed for cooperative perception with heterogeneous mobile and static sensors. AB - Cooperation among devices with different sensing, computing and communication capabilities provides interesting possibilities in a growing number of problems and applications including domotics (domestic robotics), environmental monitoring or intelligent cities, among others. Despite the increasing interest in academic and industrial communities, experimental tools for evaluation and comparison of cooperative algorithms for such heterogeneous technologies are still very scarce. This paper presents a remote testbed with mobile robots and Wireless Sensor Networks (WSN) equipped with a set of low-cost off-the-shelf sensors, commonly used in cooperative perception research and applications, that present high degree of heterogeneity in their technology, sensed magnitudes, features, output bandwidth, interfaces and power consumption, among others. Its open and modular architecture allows tight integration and interoperability between mobile robots and WSN through a bidirectional protocol that enables full interaction. Moreover, the integration of standard tools and interfaces increases usability, allowing an easy extension to new hardware and software components and the reuse of code. Different levels of decentralization are considered, supporting from totally distributed to centralized approaches. Developed for the EU-funded Cooperating Objects Network of Excellence (CONET) and currently available at the School of Engineering of Seville (Spain), the testbed provides full remote control through the Internet. Numerous experiments have been performed, some of which are described in the paper. PMID- 22247678 TI - Contrastive analysis of the Raman spectra of polychlorinated benzene: hexachlorobenzene and benzene. AB - Detection of persistent pollutants such as polychlorinated benzene in environment in trace amounts is challenging, but important. It is more difficult to distinguish homologues and isomers of organic pollutantd when present in trace amounts because of their similar physical and chemical properties. In this work we simulate the Raman spectra of hexachlorobenzene and benzene, and figure out the vibration mode of each main peak. The effect on the Raman spectrum of changing substituents from H to Cl is analyzed to reveal the relations between the Raman spectra of homologues and isomers of polychlorinated benzene, which should be helpful for distinguishing one kind of polychlorinated benzene from its homologues and isomers by surface enhanced Raman scattering. PMID- 22247680 TI - Heterogeneous collaborative sensor network for electrical management of an automated house with PV energy. AB - In this paper we present a heterogeneous collaborative sensor network for electrical management in the residential sector. Improving demand-side management is very important in distributed energy generation applications. Sensing and control are the foundations of the "Smart Grid" which is the future of large scale energy management. The system presented in this paper has been developed on a self-sufficient solar house called "MagicBox" equipped with grid connection, PV generation, lead-acid batteries, controllable appliances and smart metering. Therefore, there is a large number of energy variables to be monitored that allow us to precisely manage the energy performance of the house by means of collaborative sensors. The experimental results, performed on a real house, demonstrate the feasibility of the proposed collaborative system to reduce the consumption of electrical power and to increase energy efficiency. PMID- 22247681 TI - ATLAS: a traffic load aware sensor MAC design for collaborative body area sensor networks. AB - In collaborative body sensor networks, namely wireless body area networks (WBANs), each of the physical sensor applications is used to collaboratively monitor the health status of the human body. The applications of WBANs comprise diverse and dynamic traffic loads such as very low-rate periodic monitoring (i.e., observation) data and high-rate traffic including event-triggered bursts. Therefore, in designing a medium access control (MAC) protocol for WBANs, energy conservation should be the primary concern during low-traffic periods, whereas a balance between satisfying high-throughput demand and efficient energy usage is necessary during high-traffic times. In this paper, we design a traffic load aware innovative MAC solution for WBANs, called ATLAS. The design exploits the superframe structure of the IEEE 802.15.4 standard, and it adaptively uses the contention access period (CAP), contention free period (CFP) and inactive period (IP) of the superframe based on estimated traffic load, by applying a dynamic "wh" (whenever which is required) approach. Unlike earlier work, the proposed MAC design includes load estimation for network load-status awareness and a multi-hop communication pattern in order to prevent energy loss associated with long range transmission. Finally, ATLAS is evaluated through extensive simulations in ns-2 and the results demonstrate the effectiveness of the protocol. PMID- 22247682 TI - Towards smart homes using low level sensory data. AB - Ubiquitous Life Care (u-Life care) is receiving attention because it provides high quality and low cost care services. To provide spontaneous and robust healthcare services, knowledge of a patient's real-time daily life activities is required. Context information with real-time daily life activities can help to provide better services and to improve healthcare delivery. The performance and accuracy of existing life care systems is not reliable, even with a limited number of services. This paper presents a Human Activity Recognition Engine (HARE) that monitors human health as well as activities using heterogeneous sensor technology and processes these activities intelligently on a Cloud platform for providing improved care at low cost. We focus on activity recognition using video-based, wearable sensor-based, and location-based activity recognition engines and then use intelligent processing to analyze the context of the activities performed. The experimental results of all the components showed good accuracy against existing techniques. The system is deployed on Cloud for Alzheimer's disease patients (as a case study) with four activity recognition engines to identify low level activity from the raw data captured by sensors. These are then manipulated using ontology to infer higher level activities and make decisions about a patient's activity using patient profile information and customized rules. PMID- 22247683 TI - Dynamic sensing performance of a point-wise fiber Bragg grating displacement measurement system integrated in an active structural control system. AB - In this work, a fiber Bragg grating (FBG) sensing system which can measure the transient response of out-of-plane point-wise displacement responses is set up on a smart cantilever beam and the feasibility of its use as a feedback sensor in an active structural control system is studied experimentally. An FBG filter is employed in the proposed fiber sensing system to dynamically demodulate the responses obtained by the FBG displacement sensor with high sensitivity. For comparison, a laser Doppler vibrometer (LDV) is utilized simultaneously to verify displacement detection ability of the FBG sensing system. An optical full-field measurement technique called amplitude-fluctuation electronic speckle pattern interferometry (AF-ESPI) is used to provide full-field vibration mode shapes and resonant frequencies. To verify the dynamic demodulation performance of the FBG filter, a traditional FBG strain sensor calibrated with a strain gauge is first employed to measure the dynamic strain of impact-induced vibrations. Then, system identification of the smart cantilever beam is performed by FBG strain and displacement sensors. Finally, by employing a velocity feedback control algorithm, the feasibility of integrating the proposed FBG displacement sensing system in a collocated feedback system is investigated and excellent dynamic feedback performance is demonstrated. In conclusion, our experiments show that the FBG sensor is capable of performing dynamic displacement feedback and/or strain measurements with high sensitivity and resolution. PMID- 22247684 TI - Development of a multisensor-based bio-botanic robot and its implementation using a self-designed embedded board. AB - This paper presents the design concept of a bio-botanic robot which demonstrates its behavior based on plant growth. Besides, it can reflect the different phases of plant growth depending on the proportional amounts of light, temperature and water. The mechanism design is made up of a processed aluminum base, spring, polydimethylsiloxane (PDMS) and actuator to constitute the plant base and plant body. The control system consists of two micro-controllers and a self-designed embedded development board where the main controller transmits the values of the environmental sensing module within the embedded board to a sub-controller. The sub-controller determines the growth stage, growth height, and time and transmits its decision value to the main controller. Finally, based on the data transmitted by the sub-controller, the main controller controls the growth phase of the bio botanic robot using a servo motor and leaf actuator. The research result not only helps children realize the variation of plant growth but also is entertainment educational through its demonstration of the growth process of the bio-botanic robot in a short time. PMID- 22247685 TI - Pressure-sensitive paint: effect of substrate. AB - There are numerous ways in which pressure-sensitive paint can be applied to a surface. The choice of substrate and application method can greatly affect the results obtained. The current study examines the different methods of applying pressure-sensitive paint to a surface. One polymer-based and two porous substrates (anodized aluminum and thin-layer chromatography plates) are investigated and compared for luminescent output, pressure sensitivity, temperature sensitivity and photodegradation. Two luminophores [tris Bathophenanthroline Ruthenium(II) Perchlorate and Platinum-tetrakis (pentafluorophenyl) Porphyrin] will also be compared in all three of the substrates. The results show the applicability of the different substrates and luminophores to different testing environments. PMID- 22247686 TI - CdTe and CdSe quantum dots cytotoxicity: a comparative study on microorganisms. AB - Quantum dots (QDs) are colloidal semiconductor nanocrystals of a few nanometers in diameter, being their size and shape controlled during the synthesis. They are synthesized from atoms of group II-VI or III-V of the periodic table, such as cadmium telluride (CdTe) or cadmium selenium (CdSe) forming nanoparticles with fluorescent characteristics superior to current fluorophores. The excellent optical characteristics of quantum dots make them applied widely in the field of life sciences. Cellular uptake of QDs, location and translocation as well as any biological consequence, such as cytotoxicity, stimulated a lot of scientific research in this area. Several studies pointed to the cytotoxic effect against micoorganisms. In this mini-review, we overviewed the synthesis and optical properties of QDs, and its advantages and bioapplications in the studies about microorganisms such as protozoa, bacteria, fungi and virus. PMID- 22247687 TI - Amperometric immunosensor based on a protein A/deposited gold nanocrystals modified electrode for carbofuran detection. AB - In this paper, an amperometric immunosensor modified with protein A/deposited gold nanocrystals (DpAu) was developed for the ultrasensitive detection of carbofuran residues. First, DpAu were electrodeposited onto the Au electrode surface to absorb protein A (PA) and improve the electrode conductivity. Then PA was dropped onto the surface of DpAu film, used for binding antibody Fc fragments. Next, anti-carbofuran monoclonal antibody was immobilized on the PA modified electrode. Finally, bovine serum albumin (BSA) was employed to block the possible remaining active sites avoiding any nonspecific adsorption. The fabrication procedure of the immunosensor was characterized by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV), respectively. With the excellent electroconductivity of DpAu and the PA's oriented immobilization of antibodies, a highly efficient immuno-reaction and detection sensitivity could be achieved. The influences of the electrodeposition time of DpAu, pH of the detection solution and incubation time on the current response of the fabricated immunosensor were investigated. Under optimized conditions, the current response was proportional to the concentration of carbofuran which ranged from 1 to 100 ng/mL and 100 ng/mL to 100 MUg/mL. The detection limit was 0.1924 ng/mL. The proposed carbofuran immnuosensor exhibited high specificity, reproducibility, stability and regeneration performance, which may open a new door for ultrasensitive detection of carbofuran residues in vegetables and fruits. PMID- 22247688 TI - The need and potential of biosensors to detect dioxins and dioxin-like polychlorinated biphenyls along the milk, eggs and meat food chain. AB - Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are hazardous toxic, ubiquitous and persistent chemical compounds, which can enter the food chain and accumulate up to higher trophic levels. Their determination requires sophisticated methods, expensive facilities and instruments, well-trained personnel and expensive chemical reagents. Ideally, real-time monitoring using rapid detection methods should be applied to detect possible contamination along the food chain in order to prevent human exposure. Sensor technology may be promising in this respect. This review gives the state of the art for detecting possible contamination with dioxins and DL-PCBs along the food chain of animal source foods. The main detection methods applied (i.e., high resolution gas chromatography combined with high resolution mass-spectrometry (HRGC/HRMS) and the chemical activated luciferase gene expression method (CALUX bioassay)), each have their limitations. Biosensors for detecting dioxins and related compounds, although still under development, show potential to overcome these limitations. Immunosensors and biomimetic-based biosensors potentially offer increased selectivity and sensitivity for dioxin and DL-PCB detection, while whole cell based biosensors present interpretable biological results. The main shortcoming of current biosensors, however, is their detection level: this may be insufficient as limits for dioxins and DL-PCBs for food and feedstuffs are in pg per gram level. In addition, these contaminants are normally present in fat, a difficult matrix for biosensor detection. Therefore, simple and efficient extraction and clean-up procedures are required which may enable biosensors to detect dioxins and DL-PCBs contamination along the food chain. PMID- 22247689 TI - A cost effective block framing scheme for underwater communication. AB - In this paper, the Selective Multiple Acknowledgement (SMA) method, based on Multiple Acknowledgement (MA), is proposed to efficiently reduce the amount of data transmission by redesigning the transmission frame structure and taking into consideration underwater transmission characteristics. The method is suited to integrated underwater system models, as the proposed method can handle the same amount of data in a much more compact frame structure without any appreciable loss of reliability. Herein, the performance of the proposed SMA method was analyzed and compared to those of the conventional Automatic Repeat-reQuest (ARQ), Block Acknowledgement (BA), block response, and MA methods. The efficiency of the underwater sensor network, which forms a large cluster and mostly contains uplink data, is expected to be improved by the proposed method. PMID- 22247691 TI - Low cost sensors based on SPR in a plastic optical fiber for biosensor implementation. AB - This paper reports the fabrication and testing of two configurations of optical sensor systems based on Surface Plasmon Resonance (SPR) at the interface of a liquid sample and sandwiched structures realized starting from the exposed core of a Plastic Optical Fiber (POF). The proposed geometries have proven to be suitable for measuring the refractive indexes of liquids whose refractive index falls around 1.35. Furthermore, the proposed sensing head, being low cost and relatively easy to realize, may be very attractive for biosensor implementation. PMID- 22247692 TI - Force to rebalance control of HRG and suppression of its errors on the basis of FPGA. AB - A novel design of force to rebalance control for a hemispherical resonator gyro (HRG) based on FPGA is demonstrated in this paper. The proposed design takes advantage of the automatic gain control loop and phase lock loop configuration in the drive mode while making full use of the quadrature control loop and rebalance control loop in controlling the oscillating dynamics in the sense mode. First, the math model of HRG with inhomogeneous damping and frequency split is theoretically analyzed. In addition, the major drift mechanisms in the HRG are described and the methods that can suppress the gyro drift are mentioned. Based on the math model and drift mechanisms suppression method, four control loops are employed to realize the manipulation of the HRG by using a FPGA circuit. The reference-phase loop and amplitude control loop are used to maintain the vibration of primary mode at its natural frequency with constant amplitude. The frequency split is readily eliminated by the quadrature loop with a DC voltage feedback from the quadrature component of the node. The secondary mode response to the angle rate input is nullified by the rebalance control loop. In order to validate the effect of the digital control of HRG, experiments are carried out with a turntable. The experimental results show that the design is suitable for the control of HRG which has good linearity scale factor and bias stability. PMID- 22247690 TI - Semiconductor quantum dots for biomedicial applications. AB - Semiconductor quantum dots (QDs) are nanometre-scale crystals, which have unique photophysical properties, such as size-dependent optical properties, high fluorescence quantum yields, and excellent stability against photobleaching. These properties enable QDs as the promising optical labels for the biological applications, such as multiplexed analysis of immunocomplexes or DNA hybridization processes, cell sorting and tracing, in vivo imaging and diagnostics in biomedicine. Meanwhile, QDs can be used as labels for the electrochemical detection of DNA or proteins. This article reviews the synthesis and toxicity of QDs and their optical and electrochemical bioanalytical applications. Especially the application of QDs in biomedicine such as delivering, cell targeting and imaging for cancer research, and in vivo photodynamic therapy (PDT) of cancer are briefly discussed. PMID- 22247693 TI - Electromagnetic imaging methods for nondestructive evaluation applications. AB - Electromagnetic nondestructive tests are important and widely used within the field of nondestructive evaluation (NDE). The recent advances in sensing technology, hardware and software development dedicated to imaging and image processing, and material sciences have greatly expanded the application fields, sophisticated the systems design and made the potential of electromagnetic NDE imaging seemingly unlimited. This review provides a comprehensive summary of research works on electromagnetic imaging methods for NDE applications, followed by the summary and discussions on future directions. PMID- 22247694 TI - Surface acoustic wave (SAW) vibration sensors. AB - In the paper a feasibility study on the use of surface acoustic wave (SAW) vibration sensors for electronic warning systems is presented. The system is assembled from concatenated SAW vibration sensors based on a SAW delay line manufactured on a surface of a piezoelectric plate. Vibrations of the plate are transformed into electric signals that allow identification of the sensor and localization of a threat. The theoretical study of sensor vibrations leads us to the simple isotropic model with one degree of freedom. This model allowed an explicit description of the sensor plate movement and identification of the vibrating sensor. Analysis of frequency response of the ST-cut quartz sensor plate and a damping speed of its impulse response has been conducted. The analysis above was the basis to determine the ranges of parameters for vibrating plates to be useful in electronic warning systems. Generally, operation of electronic warning systems with SAW vibration sensors is based on the analysis of signal phase changes at the working frequency of delay line after being transmitted via two circuits of concatenated four-terminal networks. Frequencies of phase changes are equal to resonance frequencies of vibrating plates of sensors. The amplitude of these phase changes is proportional to the amplitude of vibrations of a sensor plate. Both pieces of information may be sent and recorded jointly by a simple electrical unit. PMID- 22247695 TI - A query result merging scheme for providing energy efficiency in underwater sensor networks. AB - Underwater sensor networks are emerging as a promising distributed data management system for various applications in underwater environments, despite their limited accessibility and restricted energy capacity. With the aid of recent developments in ubiquitous data computing, an increasing number of users are expected to overcome low accessibility by applying queries to underwater sensor networks. However, when multiple users send queries to an underwater sensor network in a disorganized manner, it may incur lethal energy waste and problematic network traffic. The current query management mechanisms cannot effectively deal with this matter due to their limited applicability and unrealistic assumptions. In this paper, a novel query management scheme involving query result merging is proposed for underwater sensor networks. The mechanism is based on a relational database model and is adjusted to the practical restrictions affecting underwater communication environments. Network simulations will prove that the scheme becomes more efficient with a greater number of queries and a smaller period range. PMID- 22247696 TI - Characterization of a low-cost optical flow sensor when using an external laser as a direct illumination source. AB - In this paper, a low cost optical flow sensor is combined with an external laser device to measure surface displacements and mechanical oscillations. The measurement system is based on applying coherent light to a diffuser surface and using an optical flow sensor to analyze the reflected and transferred light to estimate the displacement of the surface or the laser spot. This work is focused on the characterization of this measurement system, which can have the optical flow sensor placed at different angles and distances from the diffuser surface. The results have shown that the displacement of the diffuser surface is badly estimated when the optical mouse sensor is placed in front of the diffuser surface (angular orientation >150 degrees ) while the highest sensitivity is obtained when the sensor is located behind the diffuser surface and on the axis of the laser source (angular orientation 0 degrees ). In this case, the coefficient of determination of the measured displacement, R(2), was very high (>0.99) with a relative error of less than 1.29%. Increasing the distance between the surface and the sensor also increased the sensitivity which increases linearly, R(2) = 0.99. Finally, this measurement setup was proposed to measure very low frequency mechanical oscillations applied to the laser device, up to 0.01 Hz in this work. The results have shown that increasing the distance between the surface and the optical flow sensor also increases the sensitivity and the measurement range. PMID- 22247697 TI - Advances in SAW gas sensors based on the condensate-adsorption effect. AB - A surface-acoustic-wave (SAW) gas sensor with a low detection limit and fast response for volatile organic compounds (VOCs) based on the condensate-adsorption effect detection is developed. In this sensor a gas chromatography (GC) column acts as the separator element and a dual-resonator oscillator acts as the detector element. Regarding the surface effective permittivity method, the response mechanism analysis, which relates the condensate-adsorption effect, is performed, leading to the sensor performance prediction prior to fabrication. New designs of SAW resonators, which act as feedback of the oscillator, are devised in order to decrease the insertion loss and to achieve single-mode control, resulting in superior frequency stability of the oscillator. Based on the new phase modulation approach, excellent short-term frequency stability (+/-3 Hz/s) is achieved with the SAW oscillator by using the 500 MHz dual-port resonator as feedback element. In a sensor experiment investigating formaldehyde detection, the implemented SAW gas sensor exhibits an excellent threshold detection limit as low as 0.38 pg. PMID- 22247698 TI - Robust and cooperative image-based visual servoing system using a redundant architecture. AB - The reliability and robustness of image-based visual servoing systems is still unsolved by the moment. In order to address this issue, a redundant and cooperative 2D visual servoing system based on the information provided by two cameras in eye-in-hand/eye-to-hand configurations is proposed. Its control law has been defined to assure that the whole system is stable if each subsystem is stable and to allow avoiding typical problems of image-based visual servoing systems like task singularities, features extraction errors, disappearance of image features, local minima, etc. Experimental results with an industrial robot manipulator based on Schunk modular motors to demonstrate the stability, performance and robustness of the proposed system are presented. PMID- 22247699 TI - Contamination of runoff water at Gdansk Airport (Poland) by polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs). AB - Airport runoff can contain high concentrations of various pollutants, in particular polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), the environmental levels of which have to be monitored. Airport runoff water samples, collected at the Gdansk-Rebiechowo Airport from 2008 to 2009, were analysed for PAHs and PCBs by gas chromatography. The aromatic fractions were separated by liquid-liquid extraction and analysed by GC/MS. Total PAH concentrations were 295-6,758 ng/L in 2008 and 180-1,924 ng/L in 2009, while total PCB levels in 2008 ranged from 0.14 to 0.44 MUg/L and in 2009 from 0.06 to 0.23 MUg/L. The PAH and PCB compositions in airport runoff waters were examined over a range of spatial and temporal scales to determine distributions, trends and possible sources. This pollution is mainly pyrolytic and related to anthropogenic activity. There were significant differences between the samples collected in the two seasons. An understanding of the magnitude of contamination due to airport runoff water is important for the effective management of airport infrastructure. PMID- 22247700 TI - Merlin-deficient human tumors show loss of contact inhibition and activation of Wnt/beta-catenin signaling linked to the PDGFR/Src and Rac/PAK pathways. AB - Neurofibromatosis type 2 (NF2) is an inherited predisposition cancer syndrome characterized by the development of multiple benign tumors in the nervous system including schwannomas, meningiomas, and ependymomas. Using a disease model comprising primary human schwannoma cells, we previously demonstrated that adherens junctions (AJs) are impaired in schwannoma cells because of a ubiquitous, upregulated Rac activity. However, the mechanism by which loss of contact inhibition leads to proliferation remains obscure in merlin-deficient tumors. In this study, we show that proliferative Wnt/beta-catenin signaling is elevated as active beta-catenin (dephosphorylated at serine 37 and threoine 41) localizes to the nucleus and the Wnt targets genes c-myc and cyclin D1 are upregulated in confluent human schwannoma cells. We demonstrate that Rac effector p21-activated kinase 2 (PAK2) is essential for the activation of Wnt/beta-catenin signaling because depletion of PAK2 suppressed active beta-catenin, c-myc, and cyclin D1. Most importantly, the link between the loss of the AJ complex and the increased proliferation in human schwannoma cells is connected by Src and platelet-derived growth factor receptor-induced tyrosine 654 phosphorylation on beta-catenin and associated with degradation of N-cadherin. We also demonstrate that active merlin maintains beta-catenin and N-cadherin complex at the plasma membrane through direct regulation. Finally, we demonstrate that phosphorylation of tyrosine 654 is critical for the increased proliferation in human schwannoma cells because overexpression of a Y654F mutant beta-catenin reduces hyperproliferation of schwannoma cells. We suggest a model that these pathways are coordinated and relevant for proliferation in merlin-deficient tumors. PMID- 22247701 TI - Pairwise long-range compensation for strongly ionic systems. AB - We propose a pairwise compensation method for long-range electrostatics, as an alternative to traditional infinite lattice sums. The approach represents the third generation in a series beginning with the shifted potential corresponding to counterions surrounding a cutoff sphere. That simple charge compensation scheme resulted in pairwise potentials that are continuous at the cutoff, but forces that are not. A second-generation approach modified both the potential and the force such that both are continuous at the cutoff. Here we introduce another layer of softening such that the derivative of the force is also continuous at the cutoff. In strongly ionic liquids, this extension removes structural artifacts associated with the earlier pairwise compensation schemes, and provides results that compare well with Ewald sums. PMID- 22247702 TI - IDSite: An accurate approach to predict P450-mediated drug metabolism. AB - Accurate prediction of drug metabolism is crucial for drug design. Since a large majority of drugs metabolism involves P450 enzymes, we herein describe a computational approach, IDSite, to predict P450-mediated drug metabolism. To model induced-fit effects, IDSite samples the conformational space with flexible docking in Glide followed by two refinement stages using the Protein Local Optimization Program (PLOP). Sites of metabolism (SOMs) are predicted according to a physical-based score that evaluates the potential of atoms to react with the catalytic iron center. As a preliminary test, we present in this paper the prediction of hydroxylation and O-dealkylation sites mediated by CYP2D6 using two different models: a physical-based simulation model, and a modification of this model in which a small number of parameters are fit to a training set. Without fitting any parameters to experimental data, the Physical IDSite scoring recovers 83% of the experimental observations for 56 compounds with a very low false positive rate. With only 4 fitted parameters, the Fitted IDSite was trained with the subset of 36 compounds and successfully applied to the other 20 compounds, recovering 94% of the experimental observations with high sensitivity and specificity for both sets. PMID- 22247703 TI - Buffer standards for the physiological pH of N,N-bis(2-hydroxyethyl)-2 aminoethanesulfonic acid (BES) from (278.15 to 328.15) K. AB - This paper reports the results for the pH of six buffer solutions free of chloride ion with compositions: (a) BES (0.03 mol.kg(-1)) + NaBES (0.09 mol.kg( 1)); (b) BES (0.02 mol.kg(-1)) + NaBES (0.04 mol.kg(-1)); (c) BES (0.04 mol.kg( 1)) + NaBES (0.08 mol.kg(-1)); (d) BES (0.04 mol.kg(-1)) + NaBES (0.04 mol.kg( 1)) (e) BES (0.05 mol.kg(-1)) + NaBES (0.05 mol.kg(-1)); and (f) (0.06 mol.kg( 1)) + NaBES (0.06 mol.kg(-1)). The remaining eight buffer solutions (g) to (n) have saline media of the ionic strength I = 0.16 mol.kg(-1), matching closely to that of the physiological sample. Conventional pa(H) values, designated as pH(s), for all six buffer solutions (a) - (f) without the chloride ion and eight buffer solutions with the chloride ion (g) - (n) at I = 0.16 mol.kg(-1) from (278.15 K to 328.15) K have been calculated. The operational pH values for five buffer solutions at T = 298.15 K and T = 310.15 K have been determined based on the difference in the values of the liquid junction potentials between the blood phosphate standard and the experimental buffer solutions. Five of these buffers are recommended as secondary standards for the physiological pH range 7.5 to 8.5. PMID- 22247705 TI - Phase II Study of S-1 Plus Either Irinotecan or Docetaxel for Non-small Cell Lung Cancer Patients Treated with More Than Three Lines of Treatment. AB - PURPOSE: This study was designed to evaluate the efficacy of a combination treatment of S-1 plus either irinotecan or docetaxel for advanced/metastatic non small cell lung cancer (NSCLC) patients who have already failed 3 or more lines of treatment. MATERIALS AND METHODS: This was a prospective single center phase II study. The eligible patients received S-1 40 mg/m(2) twice a day orally on days 1 though 14 combined with irinotecan 150 mg/m(2)on D1 only or docetaxel 35 mg/m(2) on D1 and D8. The treatment was repeated every 3 weeks until disease progression, unacceptable toxicity, or patient refusal. The choice between the two regimens was made at the discretion of the treating physician. RESULTS: A total of 14 patients participated in the study. There were 3 patients with squamous cell carcinoma, 9 with adenocarcinoma, and 2 with NSCLC, NOS. Eight of the patients were male. There were 8 patients with an Eastern Cooperative Oncology Group (ECOG) of 1, and 6 patients with an ECOG of 2. All the patients had already been treated with platinum-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitor therapy. Out of the 14 patients, 10 received irinotecan and S-1 and the other 4 received docetaxel and S-1. Twelve patients had also received pemetrexed. Disappointingly, there were no response from 2 patients with a stable disease, and therefore, as per the protocol, we stopped the study early. With a median follow-up time of 49 months, the median survival time was 5.6 months (95% confidence interval, 4.3 to 6.9 months). CONCLUSION: S-1 containing doublets did not show activity in this population as a salvage treatment and further investigation cannot be recommended. PMID- 22247704 TI - Systems biology approaches to decoding the genome of liver cancer. AB - Molecular classification of cancers has been significantly improved patient outcomes through the implementation of treatment protocols tailored to the abnormalities present in each patient's cancer cells. Breast cancer represents the poster child with marked improvements in outcome occurring due to the implementation of targeted therapies for estrogen receptor or human epidermal growth factor receptor-2 positive breast cancers. Important subtypes with characteristic molecular features as potential therapeutic targets are likely to exist for all tumor lineages including hepatocellular carcinoma (HCC) but have yet to be discovered and validated as targets. Because each tumor accumulates hundreds or thousands of genomic and epigenetic alterations of critical genes, it is challenging to identify and validate candidate tumor aberrations as therapeutic targets or biomarkers that predict prognosis or response to therapy. Therefore, there is an urgent need to devise new experimental and analytical strategies to overcome this problem. Systems biology approaches integrating multiple data sets and technologies analyzing patient tissues holds great promise for the identification of novel therapeutic targets and linked predictive biomarkers allowing implementation of personalized medicine for HCC patients. PMID- 22247706 TI - Gemcitabine Plus Platinum Combination Chemotherapy for Elderly Patients with Advanced Non-small Cell Lung Cancer: A Retrospective Analysis. AB - PURPOSE: This study aimed to analyze the efficacy and toxicity of gemcitabine plus platinum chemotherapy for patients aged 70 years or older with advanced non small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed the records of stage IIIB, IV NSCLC patients or surgically inoperable stage II, IIIA NSCLC patients who were aged 70 years or older when treated with gemcitabine (1,250 mg/m(2)) plus cisplatin (75 mg/m(2)) or carboplatin (AUC5) chemotherapy from 2001 to 2010 at Seoul St. Mary's Hospital, Uijeongbu St. Mary's Hospital and St. Vincent's Hospital. Gemcitabine was administered on days 1 and 8, and cisplatin or carboplatin was administered on day 1. Treatments were repeated every 3 weeks for a maximum of 4 cycles. RESULTS: The median age of the 62 patients was 73.5 years (range, 70 to 84 years). Forty-one (66%) patients exhibited comorbidity. The mean number of treatment cycles was 3.9. The compared average relative dose intensity of gemcitabine plus platinum chemotherapy was 84.8%. The median progression-free survival and overall survival (OS) were 5.0 months and 9.4 months, respectively. Reduced Eastern Cooperative Oncology Group (ECOG) performance status (none vs. >=1) and weight loss (<5% vs. >=5%) after treatment were found to have a significant effect on OS (p=0.01). CONCLUSION: Gemcitabine plus platinum chemotherapy is an effective treatment option with an acceptable level of toxicity in patients aged 70 years or older with good performance status in advanced NSCLC. PMID- 22247707 TI - A Phase II Study of Modified FOLFOX4 for Colorectal Cancer Patients with Peritoneal Carcinomatosis. AB - PURPOSE: Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is common and is the second most common cause of death. Clinical studies regarding chemotherapy for CRC with PC have been classically rather limited in scope. We evaluated the efficacy of modified oxaliplatin, leucovorin, and fluorouracil (m-FOLFOX4) regimen for PC of CRC origin. MATERIALS AND METHODS: CRC patients with PC were treated with cycles of oxaliplatin at 85 mg/m(2) on day 1, leucovorin 20 mg/m(2) followed by 5-fluorouracil (5-FU) via a 400 mg/m(2) bolus and a 22 hours continuous infusion of 600 mg/m(2) 5-FU on days 1-2 at 2-week intervals. RESULTS: Forty patients participated in this study. Median age was 55 years. Thirty-two patients (80.0%) received previous operation, and 60.0% of PC occurred synchronously. Thirty-five patients (87.5%) were assessable and exhibited measurable lesions. Two patients (5.7%) demonstrated complete response and five patients (14.3%) showed partial response. The median time to progression was 4.4 months (95% confidence interval, 2.5 to 6.3 months), the median overall survival time was 21.5 months (95% confidence interval, 17.2 to 25.7 months). There was no treatment related death. Presence of liver metastasis (p=0.022), performance status (p=0.039), and carcinoembryonic antigen level (p=0.016) were related to the time to progression. Patients with low carcinoembryonic antigen level (37.2 months vs. 15.6 months, p=0.001) or good performance status (22.5 months vs. 6.8 months, p=0.040) showed better overall survival. CONCLUSION: The m-FOLFOX4 regimen was determined to be effective for CRC patients with PC. PMID- 22247708 TI - Adjuvant Effect of IV Clodronate on the Delay of Bone Metastasis in High-Risk Prostate Cancer Patients: A Prospective Study. AB - PURPOSE: High-risk prostate cancer patients undergoing treatment often experience biochemical recurrence. The use of bisphosphonates as an adjuvant treatment delays skeletal events, yet whether or not bisphosphonates also delay metastastic development remains to be determined. MATERIALS AND METHODS: A total of 140 high risk prostate cancer patients who were undergoing definitive treatment and who had clinically organ-confined disease and who suffered from biochemical recurrence were administered intravenous (IV) clodronate. The patients were treated with a radical retropubic prostatectomy (RP) or curative radiotherapy (RTx). Upon androgen deprivation therapy initiation, tri-monthly IV clodronate was added to the treatment to prevent bone demineralization. Twenty-six out of 60 operated cases and 45 out of 80 irradiated cases received bisphosphonate. The length of time until the first bone metastasis was recorded and analyzed. RESULTS: No statistical difference was found for the type of primary treatment (RP or RTx) on the time to the first bone metastasis (95% confidence interval [CI], 0.40 to 2.43; p=0.98). However, there was a clear advantage favoring the group that received bisphosphonate (p<0.001). The addition of bisphosphonate delayed the appearance of the first bone metastasis by seven-fold (95% CI, 3.1 to 15.4; p<0.001). CONCLUSION: Treatment with tri-monthly IV clodronate delayed the time to the first bone metastasis in high-risk prostate cancer patients who were experiencing an increase in the prostate specific antigen level after definitive treatment. PMID- 22247709 TI - Prognostic factors of second and third line chemotherapy using 5-fu with platinum, irinotecan, and taxane for advanced gastric cancer. AB - PURPOSE: The aims of this study are to find out whether the sequence of chemotherapeutic regimens including second- and third-line taxane and irinotecan influences the survival of patients with unresectable gastric carcinoma and to identify clinical characteristics of patients with improved response. MATERIALS AND METHODS: Fifty gastric carcinoma patients who were treated by third-line sequential chemotherapy between November 2004 and July 2010 were enrolled in this study. Their overall survival (OS) and time to progression (TTP) were set up as primary and secondary end points. For the sequence of chemotherapy regimen, two arms were used. Arm A was defined as 5-fluorouracil (5-FU)+cisplatin (FP) or folinic acid, 5-FU and oxaliplati (FOLFOX), followed by folinic acid, 5-FU and irinotecan (FOLFIRI), and paclitaxel or docetaxel plus 5-FU, with or without epirubicin. Arm B was defined as FP or FOLFOX, followed by paclitaxel or docetaxel plus 5-FU, and FOLFIRI. RESULTS: The median OS of all patients was 16.0 months (95% confidence interval, 13.6 to 18.3 months), which is longer than historical control of patients who did not receive third-line chemotherapy. The sequence of second and third-line regimen, including irinotecan and taxane, did not present significant difference in OS or TTP after failure of 5-FU with platinum chemotherapy. In survival analysis of patients' clinicopathologic characteristics, poor prognosis was shown in patients with poorly differentiated histologic features, elevated serum carcinoembryonic level, and shorter TTP of first line chemotherapy. CONCLUSION: It is possible for patients to respond differently to chemotherapy due to differences in clinical features and underlying gene expression profiles. Development of individualized chemotherapy regimens based on gene expression profiles is warranted. PMID- 22247710 TI - Clinical outcome of gastric cancer patients with bone marrow metastases. AB - PURPOSE: The prognosis of gastric cancer patients with bone marrow metastases is extremely poor. The current study was conducted to evaluate the clinical outcomes of advanced gastric cancer patients with bone marrow metastases. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 26 advanced gastric cancer patients with bone marrow metastases who were treated at Soonchunhyang University Hospital between September 1986 and February 2009. RESULTS: The median age was 46 years (range, 24 to 61 years). All patients had poorly differentiated adenocarcinoma, including 17 signet ring cell carcinomas. The majority of the patients had thrombocytopenia, anemia, and elevated lactate dehydrogenase levels. Sixteen patients (61.5%) received palliative chemotherapy (median, 4 cycles; range, 1 to 13 cycles). The median overall survival after detection of bone marrow metastases for the cohort of patients was 37 days (95% confidence interval, 12.5 to 61.5 days). The median overall survival after detection of bone marrow involvement was 11 days in the best supportive care group (range, 2 to 34 days) and 121 days (range, 3 to 383 days) in the palliative chemotherapy group (p<0.001). The causes of death were tumor progression (11 patients, 45%), brain hemorrhage (6 patients, 25%), infection (5 patients, 21%), and disseminated intravascular coagulation (1 patient, 4%). There were no chemotherapy-related deaths. CONCLUSION: Palliative chemotherapy could be considered in advanced gastric cancer patients with bone marrow metastases as a treatment option. PMID- 22247711 TI - Expression of BamHI-A Rightward Transcripts in Epstein-Barr Virus-Associated Gastric Cancers. AB - PURPOSE: About 10% of all gastric cancers (GCs) are Epstein-Barr virus (EBV) associated. However, the oncogene of EBV in gastric carcinogenesis has not yet been established. In the present study, we investigated the virus-derived transcripts in the EBV-infected GC cell line to explore the viral oncogene of EBV positive GCs. MATERIALS AND METHODS: We used the SNU719 cell line, a naturally derived EBV-infected GC cell line. The individual expressed sequence tags from the cDNA libraries of SNU719 were searched against the mRNA subset extracted from the GenBank data base. Sequence reaction was carried out for the EBV-associated clones. Reverse transcription-polymerase chain reaction was performed after cells were partitioned into nuclear and cytoplasmic fractions. RESULTS: Using bioinformatic tools, we selected 13 EBV-associated clones from cDNA libraries of SNU719. By sequencing analysis, we revealed that they were all associated with RPMS1, one of the BamHI-A rightward transcripts (BART) of EBV. Some BART cDNAs such as RPMS1 and A73 are known to be translated into protein in vitro, and have been shown to have some biochemical functions relevant to tumorigenesis. But, presently, the BART transcripts were expressed only in the nucleus and not in the cytoplasm, arguing against their role as messenger RNAs. Some other BART transcripts expressed in GCs (BARF0, CST, vIL, BARF1, BLLF1, and BcLF1) were also extensively detected in the nucleus. CONCLUSION: BART transcripts are the predominant viral transcripts expressed in EBV-associated GCs, and they are located only in the nucleus. Therefore, it seems less likely that BART transcripts produce functional proteins to play a role in carcinogenesis of EBV associated GCs. PMID- 22247712 TI - Cyclosporine in Relapsed Subcutaneous Panniculitis-like T-Cell Lymphoma after Autologous Hematopoietic Stem Cell Transplantation. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare T-cell lymphoma characterized by involvement of the subcutaneous tissue of neoplastic T lymphocytes. SPTCL with hemophagocytic syndrome (HPS) is associated with an aggressive clinical course and treatment of SPTCL with HPS is not well established. Cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy is not successful in most patients suffering from SPTCL with HPS. The role of high dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT) remains controversial. We report a case of relapsed SPTCL after CHOP chemotherapy and salvage chemotherapy followed by autologous HSCT, which had rapid improvement within weeks after cyclosporine and prednisolone. Immunosuppressive therapy may be an important and successful treatment option in SPTCL patients, even though they may have clinically aggressive disease. PMID- 22247713 TI - Fatal Ifosfamide-induced metabolic encephalopathy in patients with recurrent epithelial ovarian cancer: report of two cases. AB - Central nervous system (CNS) toxicity has been reported in approximately 10-30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Although methylene blue can be used to treat ifosfamide-induced neurotoxicity, including encephalopathy, its mechanism of action remains poorly defined. We describe here two patients with recurrent epithelial ovarian cancer who experienced fatal encephalopathy following ifosfamide/mesna treatment. PMID- 22247714 TI - Diethyl 2-(triphenyl-meth-yl)malonate. AB - In the title compound, C(26)H(26)O(4), steric crowding of the Ph(3)C- group with the -CH(CO(2)Et)(2) unit leads to a long C-C bond [1.585 (2) A]. One of the two ethyl groups is disordered over two sites in a 60:40 ratio. PMID- 22247715 TI - (1-Naphthyl-imino-meth-yl)ferrocene. AB - In the title mol-ecule, [Fe(C(5)H(5))(C(16)H(12)N)], the cyclo-penta-dienyl rings are approximately eclipsed and the inter-planar angle is 0.8 (7) degrees . The Fe atom is slightly closer to the substituted cyclo-penta-dienyl ring, with an Fe?centroid distance of 1.639 (2) A, compared with 1.645 (2) A for the unsubstituted ring. The C=N double bond is essentially coplanar with the substituted cyclo-penta-dienyl ring with a deviation of 10.3 (1) degrees . The angle formed by the C=N double bond and the naphthal-ene ring system is 47.1 (1) degrees . The C-N=C-C torsion angle is 177.32 (5) degrees . PMID- 22247716 TI - Dichlorido[2-(3,5-dimethyl-1H-pyrazol-1-yl-kappaN)ethanamine-kappaN]zinc(II). AB - The amine title complex, [ZnCl(2)(C(7)H(13)N(3))], resulted from imine hydrolysis in a Schiff base compound. The Zn metal atom has a distorted tetra-hedral geometry with the most significant deviation identified in the magnitude of the N Zn-N angle. This deviation stems from the participation of the Zn and N atoms in a six-membered metallocyclic ring. The latter is in an approximate screw-boat conformation. Two strong N-H?Cl hydrogen bonds link the mol-ecules into ribbons propagating along the b-axis direction. The ribbons contain two second-order hydrogen-bonded motifs: a chain and a ring. The chain described by the graph set notation C(2) (2)(6) is formed by one hydrogen bond going in the forward direction (donor to acceptor) and the other in the backward direction (acceptor to donor). In the ring motif R(2) (2)(8), both hydrogen bonds propagate in the forward direction. PMID- 22247717 TI - 1-(Benz-yloxy)naphthalene. AB - In the title compound, C(17)H(14)O, the dihedral angle between the naphthyl ring system and the benzyl group is 83.22 (4) degrees . Both of these moieties are planar, with mean deviations from their least-squares planes, defined by the naphthyl ring C atoms and the O atom, and the phenyl ring C atoms and the benzyl alpha-C atom, of 0.0176 (1) and 0.0024 (13) A, respectively. The crystal structure is stabilized by C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.7817 (10) A]. PMID- 22247718 TI - threo-Diethyl 2-ethyl-2-hy-droxy-3-(4-methyl-benzene-sulfonamido)-succinate. AB - The asymmetric unit of the title compound, C(17)H(25)NO(7)S, contains two independent mol-ecules, which are enanti-omers forming a hydrogen-bonded dimer associated with two R(2) (2)(7) patterns. In each mol-ecule, one ethyl group from the two available ethyl ester functional groups is disordered. In one mol-ecule, the ethyl group of the ester function from an alpha-carb-oxy-lic acid is positionally disordered over two sets of sites with occupancies of 0.66:0.34. In the second mol-ecule, it is the ethyl group in the gamma-ester function that is disordered over two sets of sites with occupancies of 0.58:0.42. PMID- 22247719 TI - Cross-stream diffusion under pressure-driven flow in microchannels with arbitrary aspect ratios: a phase diagram study using a three-dimensional analytical model. AB - This article presents a three-dimensional analytical model to investigate cross stream diffusion transport in rectangular microchannels with arbitrary aspect ratios under pressure-driven flow. The Fourier series solution to the three dimensional convection-diffusion equation is obtained using a double integral transformation method and associated eigensystem calculation. A phase diagram derived from the dimensional analysis is presented to thoroughly interrogate the characteristics in various transport regimes and examine the validity of the model. The analytical model is verified against both experimental and numerical models in terms of the concentration profile, diffusion scaling law, and mixing efficiency with excellent agreement (with <0.5% relative error). Quantitative comparison against other prior analytical models in extensive parameter space is also performed, which demonstrates that the present model accommodates much broader transport regimes with significantly enhanced applicability. PMID- 22247720 TI - Effects of eicosapentaenoic acid and vitamin C on glycemic indices, blood pressure, and serum lipids in type 2 diabetic Iranian males. AB - BACKGROUND: Eicosapentaenoic acid (EPA) is the principal omega-3 fatty acids in marine oils. Fasting blood sugar (FBS), HbA1c and some of the plasma lipids and lipoproteins has been negatively related to the intake of omega-3 fatty acids and ascorbic acid, in some studies. Therefore, the purpose of this study was to assess the effects of EPA and/or vitamin C on glycemic indices, blood pressure, and plasma lipids in type 2 diabetic Iranian males. METHODS: Sixty five men with type 2 diabetes were enrolled into the study between April 2 and June 27, 2008. Venous blood samples were obtained from all participants after 10 hours of fasting, at the baseline and after the intervention. Subjects received 500 mg EPA and/or 200 mg vitamin C and/or placebo depending on their groups. For eight weeks, 15 participants received EPA supplements with vitamin C (group 1), 16 took EPA supplements and vitamin C placebo (group 2), 17 took EPA placebo and vitamin C (group 3), and 17 received EPA placebo and vitamin C placebo (group 4), daily. RESULTS: There were significant decreases in FBS, HbA1C, LDL-C and TG in groups 1, 2, 3 and 4 (p < 0.01), but significant decreases in TC were shown only in groups 1, 2 and 3 (p < 0.01). There was a significant increase in HDL-C in all groups (p < 0.01). CONCLUSIONS: In summary, it is concluded that, eight weeks of taking EPA + vitamin C supplementation improved the plasma levels of cardiovascular markers but didn't reduce BP. PMID- 22247721 TI - The impact of obesity on hypertension and diabetes control following healthy Lifestyle Intervention Program in a developing country setting. AB - BACKGROUND: The aim of this study was to evaluate the impact of obesity and overweight on diabetes mellitus (DM) and hypertension (HTN) control in a healthy lifestyle intervention program in Iran. METHODS: Within the framework of the Isfahan Healthy Heart Program (IHHP), a community trial that was conducted to prevent and control cardiovascular disease and its risk factors, two intervention counties (Isfahan and Najafabad) and one reference county (Arak) were selected. Demographic information, medical history, anti-diabetic and anti-hypertensive medications use were asked by trained interviewers in addition to physical examination and laboratory tests for 12514 adults aged more than 19 years in 2001 and were repeated for 9572 adults in 2007. RESULTS: In women, the frequency of HTN control change significantly neither in normal weight nor in those with high body mass index (BMI), waist circumference (WC) or waist to hip ratio (WHR). In men, the frequency of HTN control was only significant among those with high WHR, whereas the interaction between changes in intervention compared to reference area from 2001 to 2007 was significant in men with normal or high WC or WHR. In intervention area, the number of women with high BMI who controlled their DM increased significantly from 2001 to 2007 (p = 0.008), however, this figure decreased in men. In reference area, obesity indices had no significant association with DM control. The percentage of diabetic subjects with high WC who controlled their DM decreased non-significantly in intervention area compared to reference area in 2007. A non-significant increase in controlled DM among men and women with high WHR was observed between intervention and reference areas. CONCLUSIONS: Our lifestyle interventions did not show any improving effect on HTN or DM control among obese subjects based on different obesity indices. Other lifestyle intervention strategies are suggested. PMID- 22247722 TI - Attenuation of the pressor response to direct laryngoscopy and tracheal Intubation: oral clonidine vs. oral gabapentin premedication. AB - BACKGROUND: We carried out this study to compare the efficacy of oral gabapentin and clonidine premedication for controlling the pressor responses to laryngoscopy and tracheal intubation. METHODS: In this double-blind clinical trial, ninety-six patients were randomly allocated to one of three groups according to the agents to be used before the induction of anaesthesia: Group P (n = 32) received oral placebo, Group G (n = 32) received 800 mg of gabapentin, and Group C (n = 32) received 0.3 mg of clonidine 90 minutes prior to surgery. Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), heart rate (HR) and rate pressure product (RPP) were measured at baseline (3 min before induction), just before laryngoscopy, and postintubation (at 1, 3, 5, 10 and 15 min after starting laryngoscopy). Statistical analysis of data was done with repeated measure ANOVA and chi-square test. RESULTS: HR and RPP significantly decreased in Group G and Group C at 5, 10, and 15 minutes after tracheal intubation compared with those just before laryngoscopy (p < 0.05). No significant difference was noted between Group G and Group C considering these variables. SAP, DAP, MAP and RPP at 1, 3, 5, 10, and 15 minutes after intubation were significantly lower in Group G compared with Group P (p < 0.05). There was no significant difference between Group C and Group P in this regard. CONCLUSIONS: The present study demonstrated that premedication with oral gabapentin 800 mg or clonidine 0.3 mg similarly blunted the hyperdynamic response after laryngoscopy and intubation. PMID- 22247723 TI - Effects of adenoidectomy on markers of endothelial function and inflammation in normal-weight and overweight prepubescent children with sleep apnea. AB - BACKGROUND: This trial study aimed to assess the effects of adenoidectomy on the markers of endothelial function and inflammation in normal-weight and overweight prepubescent children with obstructive sleep apnea (OSA). METHODS: This trial study was conducted in Isfahan, Iran in 2009. The study population was comprised of 90 prepubescent children (45 normal-weight and 45 overweight children), aged between 4-10 years old, who volunteered for adenoidectomy and had OSA documented by validated questionnaire. The assessment included filling questionnaire, physical examination, and laboratory tests; it was conducted before the surgery and was repeated two weeks and six months after the surgery. RESULTS: Out of the 90 children evaluated, 83 completed the 2-week evaluation and 72 patients continued with the study for the 6-month follow up. Markers of endothelial function, i.e., serum adhesion molecules including endothelial leukocyte adhesion molecule (E-selectin), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1), and the markers of inflammation, i.e., interleukin-6, and high-sensitive C-reactive protein (hsCRP) decreased significantly in both normal-weight and overweight children after both two weeks and six months. After six months, the total and LDL-cholesterol showed a significant decrease in the overweight children. CONCLUSIONS: The findings of the study demonstrated that irrespective of the weight status, children with OSA had increased levels of the endothelial function and inflammation markers, which improved after OSA treatment by adenoidectomy. This might be a form of confirmatory evidence on the onset of atherogenesis from the early stages of the life, and the role of inflammation in the process. The reversibility of endothelial dysfunction after improvement of OSA underscores the importance of primordial and primary prevention of chronic diseases from the early stages of the life. PMID- 22247724 TI - Effect of cisatracurium versus atracurium on intraocular pressure in patients undergoing tracheal intubation for general anesthesia. AB - BACKGROUND: Increase in intraocular pressure (IOP) following tracheal intubation during general anesthesia can be troublesome. We compared the influence of two muscle relaxants, cisatracurium and atracurium, on IOP in patients undergoing general anesthesia. METHODS: This randomized, double-blind, comparative trial was conducted on 90 candidates for elective non-ophthalmic surgery under general anesthesia. Patients were 18 to 60 years old with the American Society of Anesthesiologists (ASA) class of I or II. Anesthesia was induced with fentanyl (1.5 mg/kg) and sodium thiopental (5 mg/kg). Patients received atracurium (0.5 mg/kg) or cisatracurium (0.15 mg/kg) two minutes prior to tracheal intubation. IOP, systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR) were measured at baseline (before medication), after medication (before intubation), and 2, 5, and 10 minutes after intubation. RESULTS: In both groups IOP decreased after administration of muscle relaxants (-3.3 +/- 3.6 mmHg), then increased 2 minutes after intubation (5.5 +/- 4.4 mmHg), but decreased 5 (-3.3 +/- 3.3 mmHg) and 10 (-0.5 +/- 2.6 mmHg) minutes after intubation. IOP and SBP were significantly higher in the atracurium compared with the cisatracurium group after 2 (p < 0.001 and 0.002, respectively), 5 (p < 0.001 and 0.012, respectively), and 10 (p = 0.02 and 0.048, respectively) minutes after intubation. CONCLUSIONS: Compared with atracurium, administration of cisatracurium can better prevent the increase of IOP following tracheal intubation in general anesthesia. The observed difference might be related to different effects on hemodynamic variables. Application of these results in patients under ophthalmic surgery is warranted. PMID- 22247725 TI - Celiac disease in type-I diabetes mellitus: coexisting phenomenon. AB - BACKGROUND: This study aimed to determine the prevalence of celiac disease in type I diabetic patients and to compare the symptoms and complications of celiac in patients with diabetes and celiac with patients with diabetes only. METHODS: A total of 241 type I diabetic patients age >= 18 who needed insulin intake were recruited from diabetic patients attending the Diabetic Research Center in Kermanshah, Iran. Sample was screened for celiac disease by drawing 5cc blood for complete blood count (CBC), and anti-endomysial antibody test (AEA). Patients then were classified based on immunofluorescent method for the presence of AEA. Those with AEA positive underwent biopsy. The biopsy tissues were classified based on Marsh classification. RESULTS: Twenty one patients tested positive for celiac disease based on AEA test (8.7%) and 20 (8.3%) tested positive based on the biopsy. Prevalence of celiac among diabetic patients in comparison to normal population was 8.3% vs. 0.6%; and 70% were in the stages III and IV. Weight loss was significantly more prevalent among the celiac patients, who were 4 times more likely to lose weight. Other parameters such as anemia, mucocutaneous and cutaneous hemorrhage, milk intolerance, related oral aphthous, diarrhea and steatorrhea, alopecia, dermatitis herpetiform and alopecia were higher in celiac patients but not high enough to be statistically significant. CONCLUSIONS: There is a need to improve screening identification and treatment of celiac among all diabetic patients type I, especially in cases with uncontrolled diabetic or weight loss. PMID- 22247726 TI - Helicobacter pylori serum antibody titers in patients with cerebral non cardioembolic ischemic stroke. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection has been associated with atherosclerosis of coronary arteries but there is lack of data regarding possible association between chronic H. Pylori infection and cerebral non-cardioembolic ischemia. We evaluated H. pylori serum antibody titers in patients with cerebral non-cardioembolic ischemic stroke. METHODS: This was a cross-sectional study carried out in Alzahra hospital, Isfahan, Iran. 96 patients with ischemic stroke were enrolled in this study. Control group were selected from healthy blood donors. IgG and IgA antibodies to H. pylori were detected using a rapid enzyme linked immunosorbent assay. Quantitative variables and categorical variables were compared using t student and chi-square tests. RESULTS: There were 21 cases of hypertension and 5 cases of diabetes mellitus among patients. Patients and controls were similar regarding serum IgA and IgG titers as well as positivity. There were 13 and 15 cases of positive IgA and 44 and 39 cases of positive IgG among patients and controls, respectively. Also, there were 7 and 9 cases of both positive IgA and IgG in patients and controls, respectively. No differences were found between the two groups in IgA or IgG titers or positivity (p > 0.05). CONCLUSIONS: Patients with stroke were not different regarding either H. Pylori IgA or IgG positivity or the antibody titers. Comparing genetic typing of H. pylori in patients with or without stroke and diagnosis of H. pylori with more specific and sensitive tests such as stool antigen test are recommended. PMID- 22247727 TI - Impact of pharmaceutical care on quality of life in patients with type 2 diabetes mellitus. AB - BACKGROUND: Diabetes mellitus has become an international healthcare crisis that requires new approaches to prevent and treat it. The objective of this study was to evaluate the impact of pharmaceutical care on quality of life (QOL) in patients with type 2 diabetes mellitus. METHODS: A prospective study on impact of pharmaceutical care on QOL in patients with type 2 diabetes mellitus was conducted in a private tertiary care teaching hospital in South India for a period of 8 months. Study was done on 120 eligible patients with type 2 diabetes mellitus enrolled randomly in the intervention group (with pharmaceutical care teachings) or the control (without drug related educations). The intervention group patients received pharmaceutical care through diabetes education, medication counseling, instructions on lifestyle that needed modifications (necessary for better drug function) and dietary regulations regarding their prescribed drugs, whereas the control group patients were deprived of any pharmaceutical care till the end of the study. The "Audit of Diabetes Dependent Quality of Life" standard questionnaire was used to assess the relevant parameters (including: Fasting Blood Glucose, HbA1c, Body Mass Index) and to evaluate the impact of the pharmaceutical care on the subjects. Data were analyzed using t-student test. RESULTS: The intervention group showed an improvement in the quality of life score from -2.156 +/- 0.12 at the baseline to 1.41 +/- 0.13 at the final interview (p < 0.01). The average HbA1c values decreased from 8.44 +/- 0.29% to 6.73 +/- 0.21% (p < 0.01). There was a significant decrease in the fasting blood glucose from 195.57 +/- 10.10 mg/dl to 107.25 +/- 3.70 mg/dl between the baseline and the final interview in the intervention group (p < 0.01). The findings in the diabetes treatment satisfaction score also changed in a similar pattern. CONCLUSIONS: The pharmaceutical care program was effective in improving the clinical outcome and the patients' QOL with type 2 diabetes mellitus. PMID- 22247728 TI - Visual acuity in an Iranian cohort of patients with type 2 diabetes: the role of nephropathy and ischemic heart disease. AB - BACKGROUND: The aim of this study was to investigate the risk factors of low vision in type 2 diabetic patients and the prevalence of ischemic heart diseases and nephropathy for different visual acuities. METHODS: In this cross-sectional study, data from 738 type 2 diabetic patients including evidences for nephropathy and ischemic heart disease, demographic characteristics, blood pressure and body mass index were collected, and then patients were divided into 3 groups based on their best corrected visual acuity in the better-seeing eye. Analysis of variance was used to compare basic characteristics according to different levels of visual acuity. RESULTS: The prevalence of blindness and low vision was 5.5% and 13.3% respectively, and as age, duration of diabetes, systolic blood pressure and body mass index increased, the visual acuity decreased. The prevalence of hypertension and obesity in patients with visual disabilities was significantly higher than in patients with not impaired visions (p = 0.008 and p = 0.02, respectively). We also found that with greater decline in visual acuity, the prevalence of neph ropathy and ischemic heart diseases increased. CONCLUSIONS: The factors related to retinopathy play a role in affecting the degree of visual impairment in diabetic patients. Therefore, controlling risk factors can be useful in decreasing impairment of vision and blindness. PMID- 22247729 TI - Evaluation of damage index and its association with risk factors in patients with systemic lupus erythematosus. AB - BACKGROUND: This study aimed to determine the value of damage index in patients with systemic lupus erythematosus (SLE) and the association between damage index and disease severity, flare up numbers, disease duration, and antiphospholipid antibodies. METHODS: Eighty patients with systemic lupus erythematosus were included. The damage was measured using the SLICC (Systemic Lupus International Collaborating Clinics)/ACR damage index (SDI). The disease flare was defined by the increase in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). The disease severity surrogates were the presence of class III/IV glomerulonephritis, the presence of severe central nervous system (CNS) involvement, and cyclophosphamide administration. Analysis was performed by independent Student-t and chi-square tests via SPSS(16) software. RESULTS: There were significant association between the damage accrual and the disease severity, flare-up, and antiphospholipid antibodies (p = 0.001, p = 0.004, and p = 0.05, respectively). CONCLUSIONS: The disease severity, frequency of flares, and positive antiphospholipid antibodies are associated with damage accrual in patients with systemic lupus erythematosus. PMID- 22247730 TI - Effect of hydrochlorothiazide on reducing recurrent abdominal pain in girls with idiopathic hypercalciuria. AB - BACKGROUND: This study assessed the possible effect of hydrochlorothiazide (HCT) on soothing recurrent abdominal pain (RAP). METHODS: A hundred girls with RAP and IH were randomly assigned into two groups of experiment (treated with hydrochlorothiazide 1mg/kg/day) and control and all patients were followed for 3 months. RESULTS: In the experiment group, the mean of painful attacks in the first, second and third month were 0.38, 0.4 and 0.26, respectively which were far less than their counterparts in the control group. CONCLUSIONS: Single daily dose of HCT is a safe and effective therapeutic option in the treatment of RAP in children with IH. PMID- 22247731 TI - Folate and vitamin B12 status in schizophrenic patients. AB - BACKGROUND: This study aimed to determine red blood cell (RBC) and serum folate and vitamin B12 levels as well as their intake in schizophrenic patients. METHODS: The folate and cobalamin status of 60 schizophrenic patients (15-55 years) was compared to 60 matched healthy controls using Radio Isotope Dilution Assay (RIDA). RESULTS: Serum and RBC folate in schizophrenic patients was significantly lower than the control group. Mean serum cobalamin levels in the schizophrenic group were higher than controls. CONCLUSIONS: This study showed that folate deficiency is common in schizophrenic patients; therefore, it is important to pay attention to folate levels in these patients. PMID- 22247732 TI - Takayasu arteritis presenting as sudden onset vision loss simulates multiple sclerosis: a case report. AB - Neurological manifestation may complicate Takayasu arteritis (TA). A 23-year-old girl with sudden onset of vision loss was admitted to hospital. Her brain MRI showed abnormal T2-signal hyperintensity and visual evoked potential revealed prolonged P100 latency. Consequently, optic neuritis was diagnosed. A review on history of dizziness, falling, and weak pulses of upper extremities led to more investigation. Angiography revealed a total occlusion of right and left carotids, left vertebral arteries, aneurismal dilatation of innominate artery and critical stenosis of right vertebral artery. Following diagnosis of TA, stenting of right vertebral artery was done, but she passed away because of subarachnoid hemorrhage. PMID- 22247733 TI - Huge simultaneous trichobezoars causing gastric and small-bowel obstruction. AB - Bezoars are concretions of foreign materials that impair gastrointestinal motility or cause intestinal obstruction in the stomach, small intestine or bowel of humans or animals. There are many types of them such as phyto, lacto and trichobezoars. Although bezoars are not rare, multiple giant bezoars which totally fill the stomach lumen and have extension to the small intestine (Rapunzel syndrome) are very rare. This is a case report of a young girl who had a history of trichophagia and presented with partial gastric and intestinal obstructive signs. The patient was healthy, and her physical exam was almost normal and the only positive thing in her past medical history was trichophagia from several years ago. She had a big trapped bobble in her stomach and several air-fluid levels in abdominal radiograph and was investigated with endoscopy which confirmed the diagnosis of a huge gastric trichobezoar. PMID- 22247734 TI - Folie a deux and delusional disorder by proxy in a family. AB - This report presents a 52-year-old woman who was admitted to nephrology ward with hypernatremia. She shared a persecutory delusion of poisoning with her 22-year old daughter and did not feed her 8-year-old son due to her delusion. PMID- 22247736 TI - Cancer Behavior: An Optimal Control Approach. AB - With special attention to cancer, this essay explains how Optimal Control Theory, mainly used in Economics, can be applied to the analysis of biological behaviors, and illustrates the ability of this mathematical branch to describe biological phenomena and biological interrelationships. Two examples are provided to show the capability and versatility of this powerful mathematical approach in the study of biological questions. The first describes a process of organogenesis, and the second the development of tumors. PMID- 22247735 TI - Developmental Endophenotypes: Indexing Genetic Risk for Substance Abuse with the P300 Brain Event-Related Potential. AB - Although substance use disorders are heritable, their complexity has made identifying genes underlying their development challenging. Endophenotypes, biologically informed quantitative measures that index genetic risk for a disorder, are being recognized for their potential to assist the search for disorder relevant genes. After outlining criteria for an endophenotype that includes developmental considerations, we review how the brain P300 response serves as an index of genetic risk for substance abuse and related externalizing disorders. The P300 response is highly heritable and associated broadly with characteristics of externalizing disorder, including childhood disruptive disorders, antisociality, and precocious expression of deviant behavior. This association appears to be mediated by shared genetic influences. Prospective studies confirm that reduced P300 amplitude present in youth prior to significant exposure to addictive substances is associated with the subsequent development of substance use disorders. Despite pronounced change in mean level over the course of development, P300 amplitude shows strong rank order stability with repeated assessment through young adulthood. In addition, P300 developmental trajectories based on multiple assessments show very high heritability and may be especially informative as measures of genetic risk. Collectively, these findings provide strong support that P300 amplitude and its change through development reflect genetic vulnerability to substance abuse and related externalizing psychopathology. PMID- 22247737 TI - How Work-Family Research Can Finally Have an Impact in Organizations. AB - Although work-family research has mushroomed over the past several decades, an implementation gap persists in putting work-family research into practice. Because of this, work-family researchers have not made a significant impact in improving the lives of employees relative to the amount of research that has been conducted. The goal of this article is to clarify areas where implementation gaps between work-family research and practice are prevalent, discuss the importance of reducing these gaps, and make the case that both better and different research should be conducted. We recommend several alternative but complementary actions for the work-family researcher: (a) work with organizations to study their policy and practice implementation efforts, (b) focus on the impact of rapid technological advances that are blurring work-family boundaries, (c) conduct research to empower the individual to self-manage the work-family interface, and (d) engage in advocacy and collaborative policy research to change institutional contexts and break down silos. Increased partnerships between industrial organizational (I-O) psychology practitioners and researchers from many industries and disciplines could break down silos that we see as limiting development of the field. PMID- 22247738 TI - Innovative Ideas on How Work-Family Research Can Have More Impact. AB - The commentaries on our focal article agreed with its main premise that work family research should follow new strategies to improve its practical impact, and made suggestions clustering into three main themes. The first theme built on our suggestion to improve the research focus, terminology, and framing of work-family research. These essays offered additional ideas such as decoupling work-family from work-life research, and examining contextual factors more deeply. The second theme focused on how to better apply the findings from work family research. These commentaries provided social change approaches for making work-family issues more central to key stakeholders and to organizations. The third theme focused on broadening our scope to the societal level. These editorials advocated tactics supporting the development of basic rights of work-life balance within and across nations. PMID- 22247739 TI - Maintaining Superior Follow-Up Rates in a Longitudinal Study: Experiences from the College Life Study. AB - Longitudinal studies are often considered to be a gold standard for research, but the operational management of such studies is not often discussed in detail; this paper describes strategies used to track and maintain high levels of participation in a longitudinal study involving annual personal interviews with a cohort of 1,253 undergraduates (first-time, first-year students at time of enrollment) at a large public mid-Atlantic university. PMID- 22247740 TI - Endothelial Cell Membrane Sensitivity to Shear Stress is Lipid Domain Dependent. AB - Blood flow-associated shear stress causes physiological and pathophysiological biochemical processes in endothelial cells that may be initiated by alterations in plasma membrane lipid domains characterized as liquid-ordered (l(o)), such as rafts or caveolae, or liquid-disordered (l(d)). To test for domain-dependent shear sensitivity, we used time-correlated single photon counting instrumentation to assess the photophysics and dynamics of the domain-selective lipid analogues DiI-C(12) and DiI-C(18) in endothelial cells subjected to physiological fluid shear stress. Under static conditions, DiI-C(12) fluorescence lifetime was less than DiI-C(18) lifetime and the diffusion coefficient of DiI-C(12) was greater than the DiI-C(18) diffusion coefficient, confirming that DiI-C(12) probes l(d), a more fluid membrane environment, and DiI-C(18) probes the l(o) phase. Domains probed by DiI-C(12) exhibited an early (10 s) and transient decrease of fluorescence lifetime after the onset of shear while domains probed by DiI-C(18) exhibited a delayed decrease of fluorescence lifetime that was sustained for the 2 min the cells were subjected to flow. The diffusion coefficient of DiI-C(18) increased after shear imposition, while that of DiI-C(12) remained constant. Determination of the number of molecules (N) in the control volume suggested that DiI-C(12)-labeled domains increased in N immediately after step-shear, while N for DiI-C(18)-stained membrane transiently decreased. These results demonstrate that membrane microdomains are differentially sensitive to fluid shear stress. PMID- 22247741 TI - Synergistic Regulation of Angiogenic Sprouting by Biochemical Factors and Wall Shear Stress. AB - The process of sprouting angiogenesis involves activating endothelial cells in a quiescent monolayer of an existing vessel to degrade and migrate into the underlying matrix to form new blood vessels. While the roles of biochemical factors in angiogenic sprouting have been well characterized, the roles of fluid forces have received much less attention. This review summarizes results that support a role for wall shear stress in post-capillary venules as a mechanical factor capable of synergizing with biochemical factors to stimulate pro angiogenic signaling in endothelial cells and promote sprout formation. PMID- 22247742 TI - Focal Adhesion Induction at the Tip of a Functionalized Nanoelectrode. AB - Cells dynamically interact with their physical micro-environment through the assembly of nascent focal contacts and focal adhesions. The dynamics and mechanics of these contact points are controlled by transmembrane integrins and an array of intracellular adaptor proteins. In order to study the mechanics and dynamics of focal adhesion assembly, we have developed a technique for the timed induction of a nascent focal adhesion. Bovine aortic endothelial cells were approached at the apical surface by a nanoelectrode whose position was controlled with a resolution of 10s of nanometers using changes in electrode current to monitor distance from the cell surface. Since this probe was functionalized with fibronectin, a focal contact formed at the contact location. Nascent focal adhesion assembly was confirmed using time-lapse confocal fluorescent images of red fluorescent protein (RFP) - tagged talin, an adapter protein that binds to activated integrins. Binding to the cell was verified by noting a lack of change of electrode current upon retraction of the electrode. This study demonstrates that functionalized nanoelectrodes can enable precisely-timed induction and 3-D mechanical manipulation of focal adhesions and the assay of the detailed molecular kinetics of their assembly. PMID- 22247743 TI - Gut microbiota is not modified by Randomized, Double-blind, Placebo-controlled Trial of VSL#3 in Diarrhea-predominant Irritable Bowel Syndrome. AB - Irritable Bowel Syndrome (IBS) is a common condition that negatively impacts the quality of life for many individuals. The exact etiology of this disorder is largely unknown; however, emerging studies suggest that the gut microbiota is a contributing factor. Several clinical trials show that probiotics, such as VSL#3, can have a favorable effect on IBS. This double-blind, randomized placebo controlled study has been conducted in diarrhea-predominant IBS subjects in order to investigate the effect of VSL#3 on the fecal microbiota. The bacterial composition of the fecal microbiota was investigated using high-throughput microarray technology to detect 16S RNA. Twenty four subjects were randomized to receive VSL#3 or placebo for 8 weeks. IBS symptoms were monitored using GSRS and quality of life questionnaires. A favorable change in Satiety subscale was noted in the VSL #3 groups. However, the consumption of the probiotic did not change the gut microbiota. There were no adverse events or any safety concerns encountered during this study. To summarize, the use of VSL#3 in this pilot study was safe and showed improvement in specific GSRS-IBS scores in diarrhea predominant IBS subjects. The gut microbiota was not affected by VSL#3 consumption suggesting that the mechanism of action is not directly linked to the microbiota. PMID- 22247745 TI - Ethics and Nanopharmacy: Value Sensitive Design of New Drugs. AB - Although applications are being developed and have reached the market, nanopharmacy to date is generally still conceived as an emerging technology. Its concept is ill-defined. Nanopharmacy can also be construed as a converging technology, which combines features of multiple technologies, ranging from nanotechnology to medicine and ICT. It is still debated whether its features give rise to new ethical issues or that issues associated with nanopharma are merely an extension of existing issues in the underlying fields. We argue here that, regardless of the alleged newness of the ethical issues involved, developments occasioned by technological advances affect the roles played by stakeholders in the field of nanopharmacy to such an extent that this calls for a different approach to responsible innovation in this field. Specific features associated with nanopharmacy itself and features introduced to the associated converging technologies- bring about a shift in the roles of stakeholders that call for a different approach to responsibility. We suggest that Value Sensitive Design is a suitable framework to involve stakeholders in addressing moral issues responsibly at an early stage of development of new nanopharmaceuticals. PMID- 22247746 TI - Moral Arguments in the Debate over Nanotechnologies: Are We Talking Past Each Other? AB - How are we to understand the fact that the philosophical debate over nanotechnologies has been reduced to a clash of seemingly preprogrammed arguments and counterarguments that paralyzes all rational discussion of the ultimate ethical question of social acceptability in matters of nanotechnological development? With this issue as its starting point, the study reported on here, intended to further comprehension of the issues rather than provide a cause-and effect explanation, seeks to achieve a rational grasp of what is being said through the appeals made to this or that principle in the range of arguments put forward in publications on the subject. We present the results of the study's analyses in two parts. In the first, we lay out the seven categories of argument that emerged from an analysis of the literature: the arguments based on nature, dignity, the good life, utility, equity, autonomy, and rights. In the second part, we present the background moral stances that support each category of argument. Identifying the different categories of argument and the moral stance that underlies each category will enable a better grasp of the reasons for the multiplicity of the arguments that figure in discussions of the acceptability of nanotechnologies and will ultimately contribute to overcoming the tendency towards talking past each other that all too often disfigures the exchange. Clarifying the implications of the moral arguments deployed in the debate over nanotechnologies may make it possible to reduce the confusion observable in these exchanges and contribute to a better grasp of the reasons for their current unproductiveness. PMID- 22247747 TI - The Social and Ethical Acceptability of NBICs for Purposes of Human Enhancement: Why Does the Debate Remain Mired in Impasse? AB - The emergence and development of convergent technologies for the purpose of improving human performance, including nanotechnology, biotechnology, information sciences, and cognitive science (NBICs), open up new horizons in the debates and moral arguments that must be engaged by philosophers who hope to take seriously the question of the ethical and social acceptability of these technologies. This article advances an analysis of the factors that contribute to confusion and discord on the topic, in order to help in understanding why arguments that form a part of the debate between transhumanism and humanism result in a philosophical and ethical impasse: 1. The lack of clarity that emerges from the fact that any given argument deployed (arguments based on nature and human nature, dignity, the good life) can serve as the basis for both the positive and the negative evaluation of NBICs. 2. The impossibility of providing these arguments with foundations that will enable others to deem them acceptable. 3. The difficulty of applying these same arguments to a specific situation. 4. The ineffectiveness of moral argument in a democratic society. The present effort at communication about the difficulties of the argumentation process is intended as a necessary first step towards developing an interdisciplinary response to those difficulties. PMID- 22247748 TI - Is Technology Good for Us? A Eudaimonic Meta-Model for Evaluating the Contributive Capability of Technologies for a Good Life. AB - The title refers to the question addressed in this paper, namely, to what degree if any technology, including nanotechnologies, in the form of products and processes, is capable of contributing to a good life. To answer that question, the paper will develop a meta-normative model whose primary purpose is to determine the essential conditions that any normative theory of the Good Life and Technology (T-GLAT) must adequately address in order to be able to account for, explain and evaluate the Contributive Capability of Technology for a Good Life (CCT-GL). By CCT-GL understand the capability of any technological product or process in its design and/or its use to contribute in some way, if any, to the good life of individuals and society at large. In this paper, the all-embracing term "technology" will be used to refer to both the products and processes of different technologies. PMID- 22247749 TI - GPR30 FORMS AN INTEGRAL PART OF E2-PROTECTIVE PATHWAY IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. AB - A major focus of our laboratory has been an in-depth evaluation as to how estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). An important issue regarding their therapeutic application has been the undesirable estrogenic side effects thought to be mediated primarily through 17beta-estradiol (E2) binding to intracellular estrogen receptor alpha (ERalpha). With the discovery and characterization of GPR30 as the putative membrane estrogen receptor, we sought to study whether signaling through GPR30 was sufficient to mediate protection against EAE without engagement of ERalpha. Treatment of EAE in WT mice with G-1, a selective GPR30 agonist, retained estradiol's ability to protect against clinical and histological EAE without estrogenic side effects. G-1 treatment deviated cytokine profiles and enhanced suppressive activity of CD4(+)Foxp3(+) Treg cells through a GPR30- and programmed death 1 (PD-1)-dependent mechanism. This novel finding was indicative of the protective effect of GPR30 activation in EAE and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in MS. However, future studies are needed to elucidate cross-signaling and evaluate possible additive effects of combined signaling through both GPR30 and ER-alpha. Deciphering the possible mechanism of involvement of GPR30 in estrogen-mediated protection against EAE may result in lowering treatment doses of E2 and GPR30 agonists that could minimize risks and maximize immunoregulation and therapeutic effects in MS. Alternatively, one might envision using E2 derivatives with reduced estrogenic activity alone or in combination with GPR30 agonists as therapies for both male and female MS patients. PMID- 22247750 TI - Association of community antibiotic consumption with clinically active trachoma in rural Ethiopia. AB - Community antibiotic utilization and its relationship with trachoma has been poorly characterized in areas with endemic trachoma. A survey of all drug dispensing facilities in an area of rural Ethiopia was conducted. Antibiotic use was calculated using both retrospective and prospective methodology, and expressed as defined daily doses (DDDs). Overall antibiotic consumption estimates ranged from 2.91 to 3.07 DDDs per 1000 person days. Macrolide antibiotics accounted for 0.01 to 0.02 DDDs per 1000 person days. Each additional DDD of antibiotic use per 1000 person days was associated with a 15.0% (95% CI -19.7 to 10.3) decrease in the prevalence of clinically active trachoma among children under 10 years of age after adjusting for age, gender, altitude and the distance to nearest town. Increased background community antibiotic use may therefore be an aspect of socioeconomic development that can partially explain why trachoma prevalence has decreased in some areas in the absence of a trachoma program. The low volume of macrolide consumption in this area suggests that selection for nasopharyngeal pneumococcal macrolide resistance after mass azithromycin treatments likely has little clinical significance. PMID- 22247744 TI - Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. AB - Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies. PMID- 22247752 TI - A Bayesian Semiparametric Temporally-Stratified Proportional Hazards Model with Spatial Frailties. AB - Incorporating temporal and spatial variation could potentially enhance information gathered from survival data. This paper proposes a Bayesian semiparametric model for capturing spatio-temporal heterogeneity within the proportional hazards framework. The spatial correlation is introduced in the form of county-level frailties. The temporal effect is introduced by considering the stratification of the proportional hazards model, where the time-dependent hazards are indirectly modeled using a probability model for related probability distributions. With this aim, an autoregressive dependent tailfree process is introduced. The full Kullback-Leibler support of the proposed process is provided. The approach is illustrated using simulated and data from the Surveillance Epidemiology and End Results database of the National Cancer Institute on patients in Iowa diagnosed with breast cancer. PMID- 22247751 TI - White matter development in adolescence: the influence of puberty and implications for affective disorders. AB - There have been rapid advances in understanding a broad range of changes in brain structure and function during adolescence, and a growing interest in identifying which of these neurodevelopmental changes are directly linked with pubertal maturation-at least in part because of their potential to provide insights into the numerous emotional and behavioral health problems that emerge during this developmental period. This review focuses on what is known about the influence of puberty on white matter development in adolescence.We focus on white matter because of its role in providing the structural architectural organization of the brain and as a structural correlate of communication within complex neural systems. We begin with a review of studies that report sex differences or sex by age interactions in white matter development as these findings can provide, although indirectly,information relevant to puberty-related changes. Studies are also critically reviewed based on methodological procedures used to assess pubertal maturation and relations with white matter changes. Findings are discussed in light of their implications for the development of neural systems underlying the regulation of emotion and behavior and how alterations in the development of these systems may mediate risk for affective disorders in vulnerable adolescents. PMID- 22247753 TI - COMT val158met polymorphism and neural pain processing. AB - A functional polymorphism (val158met) of the gene coding for Catechol-O methyltransferase (COM) has been demonstrated to be related to processing of emotional stimuli. Also, this polymorphism has been found to be associated with pain regulation in healthy subjects. Therefore, we investigated a possible influence of this polymorphism on pain processing in healthy persons as well as in subjects with markedly reduced pain sensitivity in the context of Borderline Personality Disorder (BPD). Fifty females (25 patients with BPD and 25 healthy control participants) were included in this study. Genotype had a significant- though moderate--effect on pain sensitivity, but only in healthies. The number of val alleles was correlated with the BOLD response in several pain-processing brain regions, including dorsolateral prefrontal cortex, posterior parietal cortex, lateral globus pallidus, anterior and posterior insula. Within the subgroup of healthy participants, the number of val alleles was positively correlated with the BOLD response in posterior parietal, posterior cingulate, and dorsolateral prefrontal cortex. BPD patients revealed a positive correlation between the number of val alleles and BOLD signal in anterior and posterior insula. Thus, our data show that the val158met polymorphism in the COMT gene contributes significantly to inter-individual differences in neural pain processing: in healthy people, this polymorphism was more related to cognitive aspects of pain processing, whereas BPD patients with reduced pain sensitivity showed an association with activity in brain regions related to affective pain processing. PMID- 22247754 TI - Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias. AB - OBJECTIVES: To identify genetic factors that would be predictive of individuals who require an implantable cardioverter-defibrillator (ICD), we conducted a genome-wide association study among individuals with an ICD who experienced a life-threatening arrhythmia (LTA; cases) vs. those who did not over at least a 3 year period (controls). BACKGROUND: Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors may help identify who is most at risk. METHODS: Patients with an ICD and extended follow-up were recruited from 34 clinical sites with the goal of oversampling those who had experienced LTA, with a cumulative 607 cases and 297 controls included in the analysis. A total of 1,006 Caucasian patients were enrolled during a time period of 13 months. Arrhythmia status of 904 patients could be confirmed and their genomic data were included in the analysis. In this cohort, there were 704 males, 200 females, and the average age was 73.3 years. We genotyped DNA samples using the Illumina Human660 W Genotyping BeadChip and tested for association between genotype at common variants and the phenotype of having an LTA. RESULTS AND CONCLUSIONS: We did not find any associations reaching genome-wide significance, with the strongest association at chromosome 13, rs11856574 at P = 5*10-6. Loci previously implicated in phenotypes such as QT interval (measure of the time between the start of the Q wave and the end of the T wave as measured by electrocardiogram) were not found to be significantly associated with having an LTA. Although powered to detect such associations, we did not find common genetic variants of large effect associated with having a LTA in those of European descent. This indicates that common gene variants cannot be used at this time to guide ICD risk-stratification. TRIAL REGISTRATION: ClinicalTrials.gov NCT00664807. PMID- 22247755 TI - The vividness of happiness in dynamic facial displays of emotion. AB - Rapid identification of facial expressions can profoundly affect social interactions, yet most research to date has focused on static rather than dynamic expressions. In four experiments, we show that when a non-expressive face becomes expressive, happiness is detected more rapidly anger. When the change occurs peripheral to the focus of attention, however, dynamic anger is better detected when it appears in the left visual field (LVF), whereas dynamic happiness is better detected in the right visual field (RVF), consistent with hemispheric differences in the processing of approach- and avoidance-relevant stimuli. The central advantage for happiness is nevertheless the more robust effect, persisting even when information of either high or low spatial frequency is eliminated. Indeed, a survey of past research on the visual search for emotional expressions finds better support for a happiness detection advantage, and the explanation may lie in the coevolution of the signal and the receiver. PMID- 22247757 TI - Attitudes and acceptance of oral and parenteral HIV preexposure prophylaxis among potential user groups: a multinational study. AB - BACKGROUND: The use of antiviral medications by HIV negative people to prevent acquisition of HIV or pre-exposure prophylaxis (PrEP) has shown promising results in recent trials. To understand the potential impact of PrEP for HIV prevention, in addition to efficacy data, we need to understand both the acceptability of PrEP among members of potential user groups and the factors likely to determine uptake. METHODS AND FINDINGS: Surveys of willingness to use PrEP products were conducted with 1,790 members of potential user groups (FSWs, MSM, IDUs, SDCs and young women) in seven countries: Peru, Ukraine, India, Kenya, Botswana, Uganda and South Africa. Analyses of variance were used to assess levels of acceptance across different user groups and countries. Conjoint analysis was used to examine the attitudes and preferences towards hypothetical and known attributes of PrEP programs and medications. Overall, members of potential user groups were willing to consider taking PrEP (61% reported that they would definitely use PrEP). Current results demonstrate that key user groups in different countries perceived PrEP as giving them new possibilities in their lives and would consider using it as soon as it becomes available. These results were maintained when subjects were reminded of potential side effects, the need to combine condom use with PrEP, and for regular HIV testing. Across populations, route of administration was considered the most important attribute of the presented alternatives. CONCLUSIONS: Despite multiple conceivable barriers, there was a general willingness to adopt PrEP in key populations, which suggests that if efficacious and affordable, it could be a useful tool in HIV prevention. There would be a willingness to experience inconvenience and expense at the levels included in the survey. The results suggest that delivery in a long lasting injection would be a good target in drug development. PMID- 22247756 TI - Transcriptional profiling of human familial longevity indicates a role for ASF1A and IL7R. AB - The Leiden Longevity Study consists of families that express extended survival across generations, decreased morbidity in middle-age, and beneficial metabolic profiles. To identify which pathways drive this complex phenotype of familial longevity and healthy aging, we performed a genome-wide gene expression study within this cohort to screen for mRNAs whose expression changes with age and associates with longevity. We first compared gene expression profiles from whole blood samples between 50 nonagenarians and 50 middle-aged controls, resulting in identification of 2,953 probes that associated with age. Next, we determined which of these probes associated with longevity by comparing the offspring of the nonagenarians (50 subjects) and the middle-aged controls. The expression of 360 probes was found to change differentially with age in members of the long-lived families. In a RT-qPCR replication experiment utilizing 312 controls, 332 offspring and 79 nonagenarians, we confirmed a nonagenarian specific expression profile for 21 genes out of 25 tested. Since only some of the offspring will have inherited the beneficial longevity profile from their long-lived parents, the contrast between offspring and controls is expected to be weak. Despite this dilution of the longevity effects, reduced expression levels of two genes, ASF1A and IL7R, involved in maintenance of chromatin structure and the immune system, associated with familial longevity already in middle-age. The size of this association increased when controls were compared to a subfraction of the offspring that had the highest probability to age healthily and become long-lived according to beneficial metabolic parameters. In conclusion, an "aging-signature" formed of 21 genes was identified, of which reduced expression of ASF1A and IL7R marked familial longevity already in middle-age. This indicates that expression changes of genes involved in metabolism, epigenetic control and immune function occur as a function of age, and some of these, like ASF1A and IL7R, represent early features of familial longevity and healthy ageing. PMID- 22247759 TI - Sex, war, and disease: the role of parasite infection on weapon development and mating success in a horned beetle (Gnatocerus cornutus). AB - While parasites and immunity are widely believed to play important roles in the evolution of male ornaments, their potential influence on systems where male weaponry is the object of sexual selection is poorly understood. We experimentally infect larval broad-horned flour beetles with a tapeworm and study the consequent effects on: 1) adult male morphology 2) male-male contests for mating opportunities, and 3) induction of the innate immune system. We find that infection significantly reduces adult male size in ways that are expected to reduce mating opportunities in nature. The sum of our morphological, competition, and immunological data indicate that during a life history stage where no new resources are acquired, males allocate their finite resources in a way that increases future mating potential. PMID- 22247758 TI - Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. AB - Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3) antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener's granulomatosis). Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rgamma-/- mice. Matched chimera mice were treated with human IgG from patients with: anti PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17%) more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury. PMID- 22247760 TI - Resemblance of symptoms for major depression assessed at interview versus from hospital record review. AB - BACKGROUND: Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies. PRINCIPAL FINDINGS: We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors were identified for twelve symptoms from medical records and the same four factors emerged from analysis of structured interviews. Factor congruencies were high but the correlation of factors between interviews and records were modest (i.e. +0.2 to +0.4). CONCLUSIONS: Structured interviews and medical records are highly concordant for age of onset, and the number and length of episodes, but agree more modestly for individual symptoms and symptom factors. The modesty of these correlations probably arises from multiple factors including i) inconsistency in the definition of the worst episode, ii) inaccuracies in self-report and iii) difficulties in coding medical records where symptoms were recorded solely for clinical purposes. PMID- 22247761 TI - Gender inequity norms are associated with increased male-perpetrated rape and sexual risks for HIV infection in Botswana and Swaziland. AB - BACKGROUND: There is limited empirical research on the underlying gender inequity norms shaping gender-based violence, power, and HIV risks in sub-Saharan Africa, or how risk pathways may differ for men and women. This study is among the first to directly evaluate the adherence to gender inequity norms and epidemiological relationships with violence and sexual risks for HIV infection. METHODS: Data were derived from population-based cross-sectional samples recruited through two stage probability sampling from the 5 highest HIV prevalence districts in Botswana and all districts in Swaziland (2004-5). Based on evidence of established risk factors for HIV infection, we aimed 1) to estimate the mean adherence to gender inequity norms for both men and women; and 2) to model the independent effects of higher adherence to gender inequity norms on a) male sexual dominance (male-controlled sexual decision making and rape (forced sex)); b) sexual risk practices (multiple/concurrent sex partners, transactional sex, unprotected sex with non-primary partner, intergenerational sex). FINDINGS: A total of 2049 individuals were included, n = 1255 from Botswana and n = 796 from Swaziland. In separate multivariate logistic regression analyses, higher gender inequity norms scores remained independently associated with increased male controlled sexual decision making power (AORmen = 1.90, 95%CI:1.09-2.35; AORwomen = 2.05, 95%CI:1.32-2.49), perpetration of rape (AORmen = 2.19 95%CI:1.22-3.51), unprotected sex with a non-primary partner (AORmen = 1.90, 95%CI:1.14-2.31), intergenerational sex (AORwomen = 1.36, 95%CI:1.08-1.79), and multiple/concurrent sex partners (AORmen = 1.42, 95%CI:1.10-1.93). INTERPRETATION: These findings support the critical evidence-based need for gender-transformative HIV prevention efforts including legislation of women's rights in two of the most HIV affected countries in the world. PMID- 22247762 TI - Characterization of the rabbit neonatal Fc receptor (FcRn) and analyzing the immunophenotype of the transgenic rabbits that overexpresses FcRn. AB - The neonatal Fc receptor (FcRn) regulates IgG and albumin homeostasis, mediates maternal IgG transport, takes an active role in phagocytosis, and delivers antigen for presentation. We have previously shown that overexpression of FcRn in transgenic mice significantly improves the humoral immune response. Because rabbits are an important source of polyclonal and monoclonal antibodies, adaptation of our FcRn overexpression technology in this species would bring significant advantages. We cloned the full length cDNA of the rabbit FcRn alpha chain and found that it is similar to its orthologous analyzed so far. The rabbit FcRn - IgG contact residues are highly conserved, and based on this we predicted pH dependent interaction, which we confirmed by analyzing the pH dependent binding of FcRn to rabbit IgG using yolk sac lysates of rabbit fetuses by Western blot. Using immunohistochemistry, we detected strong FcRn staining in the endodermal cells of the rabbit yolk sac membrane, while the placental trophoblast cells and amnion showed no FcRn staining. Then, using BAC transgenesis we generated transgenic rabbits carrying and overexpressing a 110 kb rabbit genomic fragment encoding the FcRn. These transgenic rabbits--having one extra copy of the FcRn when hemizygous and two extra copies when homozygous--showed improved IgG protection and an augmented humoral immune response when immunized with a variety of different antigens. Our results in these transgenic rabbits demonstrate an increased immune response, similar to what we described in mice, indicating that FcRn overexpression brings significant advantages for the production of polyclonal and monoclonal antibodies. PMID- 22247763 TI - Disease progression in MRL/lpr lupus-prone mice is reduced by NCS 613, a specific cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor. AB - Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFalpha secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC50= 1.4 nM) than the other subtypes (PDE4A, IC50= 44 nM; PDE4B, IC50= 48 nM; and PDE4D, IC50= 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (K(i) = 148 nM) in comparison to rolipram (K(i) = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFalpha secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease. PMID- 22247764 TI - Intense or spatially heterogeneous predation can select against prey dispersal. AB - Dispersal theory generally predicts kin competition, inbreeding, and temporal variation in habitat quality should select for dispersal, whereas spatial variation in habitat quality should select against dispersal. The effect of predation on the evolution of dispersal is currently not well-known: because predation can be variable in both space and time, it is not clear whether or when predation will promote dispersal within prey. Moreover, the evolution of prey dispersal affects strongly the encounter rate of predator and prey individuals, which greatly determines the ecological dynamics, and in turn changes the selection pressures for prey dispersal, in an eco-evolutionary feedback loop. When taken all together the effect of predation on prey dispersal is rather difficult to predict. We analyze a spatially explicit, individual-based predator prey model and its mathematical approximation to investigate the evolution of prey dispersal. Competition and predation depend on local, rather than landscape scale densities, and the spatial pattern of predation corresponds well to that of predators using restricted home ranges (e.g. central-place foragers). Analyses show the balance between the level of competition and predation pressure an individual is expected to experience determines whether prey should disperse or stay close to their parents and siblings, and more predation selects for less prey dispersal. Predators with smaller home ranges also select for less prey dispersal; more prey dispersal is favoured if predators have large home ranges, are very mobile, and/or are evenly distributed across the landscape. PMID- 22247765 TI - Echinoderms have bilateral tendencies. AB - Echinoderms take many forms of symmetry. Pentameral symmetry is the major form and the other forms are derived from it. However, the ancestors of echinoderms, which originated from Cambrian period, were believed to be bilaterians. Echinoderm larvae are bilateral during their early development. During embryonic development of starfish and sea urchins, the position and the developmental sequence of each arm are fixed, implying an auxological anterior/posterior axis. Starfish also possess the Hox gene cluster, which controls symmetrical development. Overall, echinoderms are thought to have a bilateral developmental mechanism and process. In this article, we focused on adult starfish behaviors to corroborate its bilateral tendency. We weighed their central disk and each arm to measure the position of the center of gravity. We then studied their turning-over behavior, crawling behavior and fleeing behavior statistically to obtain the center of frequency of each behavior. By joining the center of gravity and each center of frequency, we obtained three behavioral symmetric planes. These behavioral bilateral tendencies might be related to the A/P axis during the embryonic development of the starfish. It is very likely that the adult starfish is, to some extent, bilaterian because it displays some bilateral propensity and has a definite behavioral symmetric plane. The remainder of bilateral symmetry may have benefited echinoderms during their evolution from the Cambrian period to the present. PMID- 22247766 TI - Two lysines in the forkhead domain of foxp3 are key to T regulatory cell function. AB - BACKGROUND: The forkhead box transcription factor, Foxp3, is master regulator of the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. The carboxyl-terminal forkhead (FKH) domain is required for the nuclear localization and DNA binding of Foxp3. We assessed how individual FKH lysines contribute to the functions of Foxp3 in Treg cells. METHODOLOGY/PRINCIPAL FINDINGS: We found that mutation of FKH lysines at position 382 (K17) and at position 393 (K18) impaired Foxp3 DNA binding and inhibited Treg suppressive function in vivo and in vitro. These lysine mutations did not affect the level of expression of Foxp3 but inhibited IL-2 promoter remodeling and had important and differing effects on Treg-associated gene expression. CONCLUSIONS/SIGNIFICANCE: These data point to complex effects of post translational modifications at individual lysines within the Foxp3 FKH domain that affect Treg function. Modulation of these events using small molecule inhibitors may allow regulation of Foxp3+ Treg function clinically. PMID- 22247767 TI - Comparing the prognostic accuracy for all-cause mortality of frailty instruments: a multicentre 1-year follow-up in hospitalized older patients. AB - BACKGROUND: Frailty is a dynamic age-related condition of increased vulnerability characterized by declines across multiple physiologic systems and associated with an increased risk of death. We compared the predictive accuracy for one-month and one-year all-cause mortality of four frailty instruments in a large population of hospitalized older patients in a prospective multicentre cohort study. METHODS AND FINDINGS: On 2033 hospitalized patients aged >= 65 years from twenty Italian geriatric units, we calculated the frailty indexes derived from the Study of Osteoporotic Fractures (FI-SOF), based on the cumulative deficits model (FI-CD), based on a comprehensive geriatric assessment (FI-CGA), and the Multidimensional Prognostic Index (MPI). The overall mortality rates were 8.6% after one-month and 24.9% after one-year follow-up. All frailty instruments were significantly associated with one-month and one-year all-cause mortality. The areas under the receiver operating characteristic (ROC) curves estimated from age- and sex adjusted logistic regression models, accounting for clustering due to centre effect, showed that the MPI had a significant higher discriminatory accuracy than FI-SOF, FI-CD, and FI-CGA after one month (areas under the ROC curves: FI-SOF = 0.685 vs. FI-CD = 0.738 vs. FI-CGA = 0.724 vs. MPI = 0.765, p<0.0001) and one year of follow-up (areas under the ROC curves: FI-SOF = 0.694 vs. FI-CD = 0.729 vs. FI-CGA = 0.727 vs. MPI = 0.750, p<0.0001). The MPI showed a significant higher discriminatory power for predicting one-year mortality also in hospitalized older patients without functional limitations, without cognitive impairment, malnourished, with increased comorbidity, and with a high number of drugs. CONCLUSIONS: All frailty instruments were significantly associated with short- and long-term all-cause mortality, but MPI demonstrated a significant higher predictive power than other frailty instruments in hospitalized older patients. PMID- 22247768 TI - Association of differentiation state of CD4+ T cells and disease progression in HIV-1 perinatally infected children. AB - BACKGROUND: In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied. METHODOLOGY/PRINCIPAL FINDINGS: We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%>=25%) compared to those with severe immune suppression (LTS-SS; CD4%<=15%). Subjects in the LTS-NS group had significantly higher frequencies of naive (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) CD4+ T cells compared to LTS-SS subjects (p = 0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells compared to slow progressing subjects (p<0.0001). CONCLUSIONS/SIGNIFICANCE: Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ T(EMRA) (CCR7 CD45RA+) cells. PMID- 22247769 TI - Factor Xa generation by computational modeling: an additional discriminator to thrombin generation evaluation. AB - Factor (f)Xa is a critical enzyme in blood coagulation that is responsible for the initiation and propagation of thrombin generation. Previously we have shown that analysis of computationally generated thrombin profiles is a tool to investigate hemostasis in various populations. In this study, we evaluate the potential of computationally derived time courses of fXa generation as another approach for investigating thrombotic risk. Utilizing the case (n = 473) and control (n = 426) population from the Leiden Thrombophilia Study and each individual's plasma protein factor composition for fII, fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor, tissue factor-initiated total active fXa generation was assessed using a mathematical model. FXa generation was evaluated by the area under the curve (AUC), the maximum rate (MaxR) and level (MaxL) and the time to reach these, TMaxR and TMaxL, respectively. FXa generation was analyzed in the entire populations and in defined subgroups (by sex, age, body mass index, oral contraceptive use). The maximum rates and levels of fXa generation occur over a 10- to 12- fold range in both cases and controls. This variation is larger than that observed with thrombin (3-6 fold) in the same population. The greatest risk association was obtained using either MaxR or MaxL of fXa generation; with an ~2.2 fold increased risk for individuals exceeding the 90(th) percentile. This risk was similar to that of thrombin generation(MaxR OR 2.6). Grouping defined by oral contraceptive (OC) use in the control population showed the biggest differences in fXa generation; a >60% increase in the MaxR upon OC use. FXa generation can distinguish between a subset of individuals characterized by overlapping thrombin generation profiles. Analysis of fXa generation is a phenotypic characteristic which may prove to be a more sensitive discriminator than thrombin generation among all individuals. PMID- 22247770 TI - Blue news update: BODIPY-GTP binds to the blue-light receptor YtvA while GTP does not. AB - Light is an important environmental factor for almost all organisms. It is mainly used as an energy source but it is also a key factor for the regulation of multiple cellular functions. Light as the extracellular stimulus is thereby converted into an intracellular signal by photoreceptors that act as signal transducers. The blue-light receptor YtvA, a bacterial counterpart of plant phototropins, is involved in the stress response of Bacillus subtilis. The mechanism behind its activation, however, remains unknown. It was suggested based on fluorescence spectroscopic studies that YtvA function involves GTP binding and that this interaction is altered by absorption of light. We have investigated this interaction by several biophysical methods and show here using fluorescence spectroscopy, ITC titrations, and three NMR spectroscopic assays that while YtvA interacts with BODIPY-GTP as a fluorescent GTP analogue originally used for the detection of GTP binding, it does not bind GTP. PMID- 22247772 TI - The significance of African lions for the financial viability of trophy hunting and the maintenance of wild land. AB - Recent studies indicate that trophy hunting is impacting negatively on some lion populations, notably in Tanzania. In 2004 there was a proposal to list lions on CITES Appendix I and in 2011 animal-welfare groups petitioned the United States government to list lions as endangered under their Endangered Species Act. Such listings would likely curtail the trophy hunting of lions by limiting the import of lion trophies. Concurrent efforts are underway to encourage the European Union to ban lion trophy imports. We assessed the significance of lions to the financial viability of trophy hunting across five countries to help determine the financial impact and advisability of the proposed trade restrictions. Lion hunts attract the highest mean prices (US$24,000-US$71,000) of all trophy species. Lions generate 5-17% of gross trophy hunting income on national levels, the proportional significance highest in Mozambique, Tanzania, and Zambia. If lion hunting was effectively precluded, trophy hunting could potentially become financially unviable across at least 59,538 km(2) that could result in a concomitant loss of habitat. However, the loss of lion hunting could have other potentially broader negative impacts including reduction of competitiveness of wildlife-based land uses relative to ecologically unfavourable alternatives. Restrictions on lion hunting may also reduce tolerance for the species among communities where local people benefit from trophy hunting, and may reduce funds available for anti-poaching. If lion off-takes were reduced to recommended maximums (0.5/1000 km(2)), the loss of viability and reduction in profitability would be much lower than if lion hunting was stopped altogether (7,005 km(2)). We recommend that interventions focus on reducing off-takes to sustainable levels, implementing age-based regulations and improving governance of trophy hunting. Such measures could ensure sustainability, while retaining incentives for the conservation of lions and their habitat from hunting. PMID- 22247771 TI - Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample. AB - Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01*10-6) and of the nearby intergenic SNP, rs1033772, (p = 6.59*10-6) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required. PMID- 22247773 TI - Social features of online networks: the strength of intermediary ties in online social media. AB - An increasing fraction of today's social interactions occur using online social media as communication channels. Recent worldwide events, such as social movements in Spain or revolts in the Middle East, highlight their capacity to boost people's coordination. Online networks display in general a rich internal structure where users can choose among different types and intensity of interactions. Despite this, there are still open questions regarding the social value of online interactions. For example, the existence of users with millions of online friends sheds doubts on the relevance of these relations. In this work, we focus on Twitter, one of the most popular online social networks, and find that the network formed by the basic type of connections is organized in groups. The activity of the users conforms to the landscape determined by such groups. Furthermore, Twitter's distinction between different types of interactions allows us to establish a parallelism between online and offline social networks: personal interactions are more likely to occur on internal links to the groups (the weakness of strong ties); events transmitting new information go preferentially through links connecting different groups (the strength of weak ties) or even more through links connecting to users belonging to several groups that act as brokers (the strength of intermediary ties). PMID- 22247774 TI - Assessment of variation in bacterial composition among microhabitats in a mangrove environment using DGGE fingerprints and barcoded pyrosequencing. AB - Here, we use DGGE fingerprinting and barcoded pyrosequencing data, at six cut-off levels (85-100%), of all bacteria, Alphaproteobacteria and Betaproteobacteria to assess composition in the rhizosphere of nursery plants and nursery-raised transplants, native plants and bulk sediment in a mangrove habitat. When comparing compositional data based on DGGE fingerprinting and barcoded pyrosequencing at different cut-off levels, all revealed highly significant differences in composition among microhabitats. Procrustes superimposition revealed that ordination results using cut-off levels from 85-100% and DGGE fingerprint data were highly congruent with the standard 97% cut-off level. The various approaches revealed a primary gradient in composition from nursery to mangrove samples. The affinity between the nursery and transplants was greatest when using Betaproteobacteria followed by Alphaproteobacteria data. There was a distinct secondary gradient in composition from transplants to bulk sediment with native plants intermediate, which was most prevalent using all bacteria at intermediate cut-off levels (92-97%). Our results show that PCR-DGGE provides a robust and cost effective exploratory approach and is effective in distinguishing among a priori defined groups. PMID- 22247775 TI - A new hammer to crack an old nut: interspecific competitive resource capture by plants is regulated by nutrient supply, not climate. AB - Although rarely acknowledged, our understanding of how competition is modulated by environmental drivers is severely hampered by our dependence on indirect measurements of outcomes, rather than the process of competition. To overcome this, we made direct measurements of plant competition for soil nitrogen (N). Using isotope pool-dilution, we examined the interactive effects of soil resource limitation and climatic severity between two common grassland species. Pool dilution estimates the uptake of total N over a defined time period, rather than simply the uptake of 15N label, as used in most other tracer experiments. Competitive uptake of N was determined by its available form (NO3- or NH4+). Soil N availability had a greater effect than the climatic conditions (location) under which plants grew. The results did not entirely support either of the main current theories relating the role of competition to environmental conditions. We found no evidence for Tilman's theory that competition for soil nutrients is stronger at low, compared with high nutrient levels and partial support for Grime's theory that competition for soil nutrients is greater under potentially more productive conditions. These results provide novel insights by demonstrating the dynamic nature of plant resource competition. PMID- 22247776 TI - A high resolution genetic map anchoring scaffolds of the sequenced watermelon genome. AB - As part of our ongoing efforts to sequence and map the watermelon (Citrullus spp.) genome, we have constructed a high density genetic linkage map. The map positioned 234 watermelon genome sequence scaffolds (an average size of 1.41 Mb) that cover about 330 Mb and account for 93.5% of the 353 Mb of the assembled genomic sequences of the elite Chinese watermelon line 97103 (Citrullus lanatus var. lanatus). The genetic map was constructed using an F(8) population of 103 recombinant inbred lines (RILs). The RILs are derived from a cross between the line 97103 and the United States Plant Introduction (PI) 296341-FR (C. lanatus var. citroides) that contains resistance to fusarium wilt (races 0, 1, and 2). The genetic map consists of eleven linkage groups that include 698 simple sequence repeat (SSR), 219 insertion-deletion (InDel) and 36 structure variation (SV) markers and spans ~800 cM with a mean marker interval of 0.8 cM. Using fluorescent in situ hybridization (FISH) with 11 BACs that produced chromosome specifc signals, we have depicted watermelon chromosomes that correspond to the eleven linkage groups constructed in this study. The high resolution genetic map developed here should be a useful platform for the assembly of the watermelon genome, for the development of sequence-based markers used in breeding programs, and for the identification of genes associated with important agricultural traits. PMID- 22247777 TI - Potential key bases of ribosomal RNA to kingdom-specific spectra of antibiotic susceptibility and the possible archaeal origin of eukaryotes. AB - In support of the hypothesis of the endosymbiotic origin of eukaryotes, much evidence has been found to support the idea that some organelles of eukaryotic cells originated from bacterial ancestors. Less attention has been paid to the identity of the host cell, although some biochemical and molecular genetic properties shared by archaea and eukaryotes have been documented. Through comparing 507 taxa of 16S-18S rDNA and 347 taxa of 23S-28S rDNA, we found that archaea and eukaryotes share twenty-six nucleotides signatures in ribosomal DNA. These signatures exist in all living eukaryotic organisms, whether protist, green plant, fungus, or animal. This evidence explicitly supports the archaeal origin of eukaryotes. In the ribosomal RNA, besides A2058 in Escherichia coli vs. G2400 in Saccharomyces cerevisiae, there still exist other twenties of sites, in which the bases are kingdom-specific. Some of these sites concentrate in the peptidyl transferase centre (PTC) of the 23S-28S rRNA. The results suggest potential key sites to explain the kingdom-specific spectra of drug resistance of ribosomes. PMID- 22247779 TI - Positivity of the English language. AB - Over the last million years, human language has emerged and evolved as a fundamental instrument of social communication and semiotic representation. People use language in part to convey emotional information, leading to the central and contingent questions: (1) What is the emotional spectrum of natural language? and (2) Are natural languages neutrally, positively, or negatively biased? Here, we report that the human-perceived positivity of over 10,000 of the most frequently used English words exhibits a clear positive bias. More deeply, we characterize and quantify distributions of word positivity for four large and distinct corpora, demonstrating that their form is broadly invariant with respect to frequency of word use. PMID- 22247778 TI - Characterization of the endothelial cell cytoskeleton following HLA class I ligation. AB - BACKGROUND: Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood. METHODOLOGY AND PRINCIPAL FINDINGS: The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin. CONCLUSIONS/SIGNIFICANCE: Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types as a method for uncovering novel regulators of cytoskeleton changes. PMID- 22247780 TI - Balanced biochemical reactions: a new approach to unify chemical and biochemical thermodynamics. AB - A novel procedure is presented which, by balancing elements and electric charge of biochemical reactions which occur at constant pH and pMg, allows assessing the thermodynamics properties of reaction Delta(r)G'0, Delta(r)H'0, Delta(r)S'0 and the change in binding of hydrogen and magnesium ions of these reactions. This procedure of general applicability avoids the complex calculations required by the use of the Legendre transformed thermodynamic properties of formation Delta(f)G'0, Delta(f)H'0 and Delta(f)S'0 hitherto considered an obligatory prerequisite to deal with the thermodynamics of biochemical reactions. As a consequence, the term "conditional" is proposed in substitution of "Legendre transformed" to indicate these thermodynamics properties. It is also shown that the thermodynamic potential G is fully adequate to give a criterion of spontaneous chemical change for all biochemical reactions and then that the use of the Legendre transformed G' is unnecessary. The procedure proposed can be applied to any biochemical reaction, making possible to re-unify the two worlds of chemical and biochemical thermodynamics, which so far have been treated separately. PMID- 22247781 TI - Trypanosoma cruzi gene expression in response to gamma radiation. AB - Trypanosoma cruzi is an organism highly resistant to ionizing radiation. Following a dose of 500 Gy of gamma radiation, the fragmented genomic DNA is gradually reconstructed and the pattern of chromosomal bands is restored in less than 48 hours. Cell growth arrests after irradiation but, while DNA is completely fragmented, RNA maintains its integrity. In this work we compared the transcriptional profiles of irradiated and non-irradiated epimastigotes at different time points after irradiation using microarray. In total, 273 genes were differentially expressed; from these, 160 were up-regulated and 113 down regulated. We found that genes with predicted functions are the most prevalent in the down-regulated gene category. Translation and protein metabolic processes, as well as generation of precursor of metabolites and energy pathways were affected. In contrast, the up-regulated category was mainly composed of obsolete sequences (which included some genes of the kinetoplast DNA), genes coding for hypothetical proteins, and Retrotransposon Hot Spot genes. Finally, the tyrosyl-DNA phosphodiesterase 1, a gene involved in double-strand DNA break repair process, was up-regulated. Our study demonstrated the peculiar response to ionizing radiation, raising questions about how this organism changes its gene expression to manage such a harmful stress. PMID- 22247782 TI - The organisation of Ebola virus reveals a capacity for extensive, modular polyploidy. AB - BACKGROUND: Filoviruses, including Ebola virus, are unusual in being filamentous animal viruses. Structural data on the arrangement, stoichiometry and organisation of the component molecules of filoviruses has until now been lacking, partially due to the need to work under level 4 biological containment. The present study provides unique insights into the structure of this deadly pathogen. METHODOLOGY AND PRINCIPAL FINDINGS: We have investigated the structure of Ebola virus using a combination of cryo-electron microscopy, cryo-electron tomography, sub-tomogram averaging, and single particle image processing. Here we report the three-dimensional structure and architecture of Ebola virus and establish that multiple copies of the RNA genome can be packaged to produce polyploid virus particles, through an extreme degree of length polymorphism. We show that the helical Ebola virus inner nucleocapsid containing RNA and nucleoprotein is stabilized by an outer layer of VP24-VP35 bridges. Elucidation of the structure of the membrane-associated glycoprotein in its native state indicates that the putative receptor-binding site is occluded within the molecule, while a major neutralizing epitope is exposed on its surface proximal to the viral envelope. The matrix protein VP40 forms a regular lattice within the envelope, although its contacts with the nucleocapsid are irregular. CONCLUSIONS: The results of this study demonstrate a modular organization in Ebola virus that accommodates a well-ordered, symmetrical nucleocapsid within a flexible, tubular membrane envelope. PMID- 22247783 TI - A new method for inferring hidden markov models from noisy time sequences. AB - We present a new method for inferring hidden Markov models from noisy time sequences without the necessity of assuming a model architecture, thus allowing for the detection of degenerate states. This is based on the statistical prediction techniques developed by Crutchfield et al. and generates so called causal state models, equivalent in structure to hidden Markov models. The new method is applicable to any continuous data which clusters around discrete values and exhibits multiple transitions between these values such as tethered particle motion data or Fluorescence Resonance Energy Transfer (FRET) spectra. The algorithms developed have been shown to perform well on simulated data, demonstrating the ability to recover the model used to generate the data under high noise, sparse data conditions and the ability to infer the existence of degenerate states. They have also been applied to new experimental FRET data of Holliday Junction dynamics, extracting the expected two state model and providing values for the transition rates in good agreement with previous results and with results obtained using existing maximum likelihood based methods. The method differs markedly from previous Markov-model reconstructions in being able to uncover truly hidden states. PMID- 22247784 TI - Genetically-engineered pig-to-baboon liver xenotransplantation: histopathology of xenografts and native organs. AB - Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (alpha1,3-galactosyltransferase gene knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptable immunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h post-transplantation. Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4-7 days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs were also examined. The WT pig liver underwent hyperacute rejection. After genetically-engineered pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4-7 days due to repeated spontaneous bleeding in the liver and native organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmed by confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role. PMID- 22247785 TI - Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease. AB - Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease. PMID- 22247786 TI - Integrated dataset of screening hits against multiple neglected disease pathogens. AB - New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach. PMID- 22247787 TI - A manganese-porphyrin complex decomposes H(2)O(2), inhibits apoptosis, and acts as a radiation mitigator in vivo. AB - Ionizing radiation triggers mitochondrial overproduction of H(2)O(2) with concomitant induction of intrinsic apoptosis, whereby clearance of H(2)O(2) upon overexpression of mitochondrial catalase increases radioresistance in vitro and in vivo. As an alternative to gene therapy, we tested the potential of Mn((III)) porphyrin complexes to clear mitochondrial H(2)O(2). We report that triphenyl [(2E)-2-[4-[(1Z,4Z,9Z,15Z)-10,15,20-tris(4-aminophenyl)-21,23-dihydroporphyrin-5 yl]phenyl]iminoethyl]phosphonium-Mn((III)) compartmentalizes preferentially into mitochondria of mouse embryonic cells, reacts with H(2)O(2), impedes gamma-ray induced mitochondrial apoptosis, and increases the survival of mice exposed to whole body irradiation with gamma-rays. PMID- 22247788 TI - Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. AB - The receptor tyrosine kinase AXL has emerged in recent years as an potential oncology target due to its over expression in several types of cancers coupled with its ability to promote tumor growth and metastasis. In order to identify small molecule inhibitors of AXL, we built a homology model of its catalytic domain to virtually screen and identify scaffolds displaying an affinity for AXL. Further computational and structure-based design resulted in the synthesis of a series of 2,4,5-trisubstitued pyrimidines which demonstrated potent inhibition of AXL in vitro (IC(50) 19 nM) and strongly inhibited the growth of several pancreatic cell lines. PMID- 22247789 TI - 10'-Fluorovinblastine and 10'-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids. AB - A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10' fluorovinblastine and 10'-fluorovincristine. In addition to defining a pronounced and unanticipated substituent effect on the biomimetic coupling, fluorine substitution at C10', which minimally alters the natural products, was found to uniquely enhance the activity 8-fold against both sensitive (IC(50) = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC(50) = 80 nM, HCT166/VM46). As depicted in the X-ray structure of vinblastine bound to tubulin, this site resides at one end of the upper portion of the T-shaped conformation of the tubulin-bound molecule, suggesting the 10'-fluorine substituent makes critical contacts with the protein at a hydrophobic site uniquely sensitive to steric interactions. PMID- 22247790 TI - Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors. AB - Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif. Optimization of the representative 6c through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., 9c) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties. PMID- 22247791 TI - Identification of Simple Compounds with Microtubule-Binding Activity That Inhibit Cancer Cell Growth with High Potency. AB - We analyzed more than 1 million small molecules with the goal of finding simple synthetic compounds that potently inhibit cancer cell growth. We identified three such compounds with unknown mechanisms of action. Subsequent studies revealed that all three of these small molecules target microtubules. These three scaffolds can serve as templates for developing new microtubule-targeted agents, overcoming the limits of existing microtubule-inhibiting drugs derived from complex natural products. PMID- 22247792 TI - Total Synthesis (+)-7-Bromotrypargine and Unnatural Analogs: Biological Evaluation Uncovers Activity at CNS Targets of Therapeutic Relevance. AB - The first total synthesis of (+)-7-bromotrypargine, a beta-carboline alkaloid from Ancornia sp. is reported. The synthesis proceeds in 9 steps, 8 steps longest linear sequence, in 36.9% overall yield. Biological characterization found that (+)-7-bromotrypargine is an H(3) antagonist, and a selective inhibitor of DAT and NET, without inhibiting SERT. Moreover, unlike electron rich congeners, (+)-7 bromotrypargine is not cytotoxic, and thus represents an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries for the synthesis of unnatural analogs. PMID- 22247793 TI - Synthesis and evaluation of dimeric derivatives of 5-HT(2A) receptor (5-HT(2A)R) antagonist M-100907. AB - It is now well accepted that at least some serotonin receptors exist in dimeric and oligmeric forms. The linking of receptor ligands has been shown to have potential in the development of selective agonists and antagonists for traditionally refractive receptors. Here we report the development of a dimeric version of the known 5-HT(2A)R antagonist, M-100907. Derivatives of M-100907 were synthesized to determine an appropriate site for the linker connection. Then, homodimers with polyether linkers of different lengths were functionally tested in a bioassay to determine the optimal linker length. Attachment at the catechol of M-100907 with linkers between 12 and 18 atoms in length proved to be optimal. PMID- 22247794 TI - Discovery and functional study of a novel crustacean tachykinin neuropeptide. AB - Tachykinin-related peptide (TRP) refers to a large and structurally diverse family of neuropeptides found in vertebrate and invertebrate nervous systems. These peptides have various important physiological functions, from regulating stress in mammals to exciting the pyloric (food filtering) rhythm in the stomatogastric nervous system (STNS) of decapod crustaceans. Here, a novel TRP, which we named CalsTRP (Callinectes sapidus TRP), YPSGFLGMRamide (m/z 1026.52), was identified and de novo sequenced using a multifaceted mass spectrometry-based platform in both the central nervous system (CNS) and STNS of C. sapidus. We also found, using isotopic formaldehyde labeling, that CalsTRP in the C. sapidus brain and commissural ganglion (CoG) was up-regulated after food-intake, suggesting that TRPs in the CNS and STNS are involved in regulating feeding in Callinectes. Using imaging mass spectrometry, we determined that the previously identified CabTRP Ia (APSGFLGMRamide) and CalsTRP were co-localized in the C. sapidus brain. Lastly, our electrophysiological studies show that bath-applied CalsTRP and CabTRP Ia each activates the pyloric and gastric mill rhythms in C. sapidus, as shown previously for pyloric rhythm activation by CabTRP Ia in the crab Cancer borealis. In summary, the newly identified CalsTRP joins CabTRP Ia as a TRP family member in the decapod crustacean nervous system, whose actions include regulating feeding behavior. PMID- 22247795 TI - Sexual Health Information Seeking Online Among Runaway and Homeless Youth. AB - Research shows runaway and homeless youth are reluctant to seek help from traditional health providers. The Internet can be useful in engaging this population and meeting their needs for sexual health information, including information about HIV and other sexually transmitted infections (STIs). Using a sample of homeless youth living in Los Angeles, California in June 2009, this study assesses the frequency with which runaway and homeless youth seek sexual health information via the Internet, and assesses which youth are more likely to engage in seeking health information from online sources. Drawing from Andersen's (1968) health behavior model and Pescosolido's (1992) network episode model, we develop and refine a model for seeking online sexual health information among homeless youth. Rather than testing the predicative strength of a given model, our aim is to identify and explore conceptually driven correlates that may shed light on the characteristics associated with these help seeking behaviors among homeless youth. Analyses using multivariate logistic regression models reveal that among the sample of youth, females and gay males most frequently seek sexual health information online. We demonstrate the structure of social network ties (e.g., connection with parents) and the content of interactions (e.g., e-mail forwards of health information) across ties are critical correlates of online sexual health information seeking. Results show a continued connection with parents via the Internet is significantly associated with youth seeking HIV or STI information. Similarly for content of interactions, more youth who were sent health information online also reported seeking HIV information and HIV-testing information. We discuss implications for intervention and practice, focusing on how the Internet may be used for dissemination of sexual health information and as a resource for social workers to link transient, runaway, and homeless youth to care. PMID- 22247797 TI - Recent advances in the biomarkers for epithelial ovarian cancer. PMID- 22247796 TI - Mental state decoding abilities in young adults with borderline personality disorder traits. AB - Previous studies have demonstrated that patients with borderline personality disorder (BPD) tend to misattribute malevolence to benign social stimuli, including facial expressions. Yet, facial emotion recognition studies examining those with BPD have yielded mixed results, with some studies showing impaired accuracy and others demonstrating enhanced accuracy in the recognition of emotions or mental states. The current study examined the ability to decode mental states from photographs of just the eye region of faces in a nonclinical sample of young adults who exhibited BPD traits (high BPD) compared with those who did not (low BPD). Group differences in mental state decoding ability depended on the valence of the stimuli. The high-BPD group performed better for negative stimuli compared with the low-BPD group, but did not perform significantly different from the low-BPD group for stimuli of neutral or positive valence. The high-BPD group also demonstrated a response bias for attributing negative mental states to facial stimuli. In addition, findings suggested that the group difference in accuracy for negative stimuli could not be explained by response bias, because the group difference in response bias for negative stimuli did not reach significance. These findings suggest that BPD traits may be associated with enhanced ability to detect negative emotions and a bias for attributing negative emotions to nonnegative social stimuli. PMID- 22247798 TI - Combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro. AB - OBJECTIVE: The aim of the study was to investigate whether lithium chloride and medroxyprogesterone acetate can potentiate the cytotoxicity of imatinib mesylate in human endometrial cancer in vitro and the effect of midkine in these therapies. METHODS: Imatinib mesylate (50 uM), lithium chloride (100 uM), medroxyprogesterone acetate (200 uM) and their combination were applied to monolayer and three dimensional cultures of human Ishikawa endometrial cancer for 72 hours. The cell proliferation index, apoptotic index, caspase-3 and midkine levels, cell cycle distributions in monolayer cultures and cell ultrastructure in spheroid cultures were evaluated. Results were statistically analyzed using the Student's t-test. RESULTS: All drug applications inhibited cell proliferation (p<0.05), however the combination were the effective groups for 72 hours (p<0.05). Interestingly, although the loss of efficiency was seen higly seen every 24 hours at single applications, the inhibition rates of the combination groups were almost same for 72 hours. In concordance with these results, the apoptotic index, caspase-3 levels (p<0.05), cell morphology and ultrastructure damages were much higher in the combination groups. Imatinib mesylate induced S phase arrest, however other groups induced G0+G1-phase arrest at 24 hours and all groups induced G0+G1 arrest at 72 hours (p<0.05). Imatinib mesylate and imatinib mesylate with medroxyprogesterone acetate induced highest decrease in midkine levels, respectively (p<0.05). CONCLUSION: The present study showed that the combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro and the inhibition of midkine involved in their mechanism of action against endometrium defense. PMID- 22247799 TI - Synchronous gynecologic malignancy and preliminary results of Lynch syndrome. AB - OBJECTIVE: Lynch syndrome is a hereditary cancer syndrome that increases the risks of colorectal and gynecologic malignancies such as endometrial and ovarian cancer. Studies have shown that mutations in mismatch repair genes (MSH2, MSH6, and MLH1) are associated with Lynch syndrome. The aim of our study was to estimate the value of MSH2, MSH6, and MLH1 immunohistochemistry based on family history in a Korean sample. METHODS: Thirty six women with synchronous gynecologic tumors of endometrial and ovarian cancer were identified among patients being treated at our institution. Among them, 32 patients had tumor blocks (total 62 slides) available for analysis. According to a diagnostic algorithm, we performed immunohistochemistry analyses. Staining was scored based on intensity and proportion (negative or 0: intensity undetectable or minimal, proportion <5%; weak or 1+: intensity mild, proportion 5-30%; strong or 2+: intensity moderate to marked, proportion 30-99%). RESULTS: Among 32 eligible patients, 9 (28%) had a family history of cancer. Six patients (19%) were negative for MLH1; among them, four (4/6) were negative at both sites. Nine patients (28%) were negative for MSH2 or MSH6 at both sites or negative for both MSH2 and MSH6. Among these three patients showed negative staining for both sites. The three patients showing negative staining for MLH1, MSH2, and MSH6 at both sites with family history were considered to be the screening positive groups of Lynch syndrome. CONCLUSION: In this study, the frequency of Lynch syndrome associated immunohistochemical staining (MLH1, MSH2, and MSH6) group was estimated as 9% (3/32) among Korean women with synchronous gynecologic tumors. PMID- 22247800 TI - Survival outcome of women with synchronous cancers of endometrium and ovary: a 10 year retrospective cohort study. AB - OBJECTIVE: Synchronous occurrence of endometrial and ovarian tumors is uncommon, and they affect less than 10% of women with endometrial or ovarian cancers. The aim of this study is to describe the epidemiological and clinical factors; and survival outcomes of women with these cancers. METHODS: This is a retrospective cohort study in a large tertiary institution in Singapore. The sample consists of women with endometrial and epithelial ovarian cancers followed up over a period of 10 years from 2000 to 2009. The epidemiological and clinical factors include age at diagnosis, histology types, grade and stage of disease. RESULTS: A total of 75 patients with synchronous ovarian and endometrial cancers were identified. However, only 46 patients met the inclusion criteria. The median follow-up was 74 months. The incidence rate for synchronous cancer is 8.7% of all epithelial ovarian cancers and 4.9% of all endometrial cancers diagnosed over this time frame. Mean age at diagnosis was 47.3 years old. The most common presenting symptom was abnormal uterine bleeding (36.9%) and 73.9% had endometrioid histology for both endometrial and ovarian cancers. The majority of the women (78%) presented were at early stages of 1 and 2. There were 6 (13.6%) cases of recurrence and the 5 year cumulative survival rate was at 84%. CONCLUSION: In our cohort, we found that majority of women afflicted with synchronous cancer of the endometrium and ovary were younger at age of diagnosis, had early stage of cancer and good survival. PMID- 22247801 TI - Evaluation of ovarian cancer biomarkers HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass. AB - OBJECTIVE: Women presenting with a large or complex ovarian cyst are referred to extensive surgical staging to ensure the correct diagnosis and treatment of a possible epithelial ovarian cancer. We hypothesized that measurement of the biomarkers HE4 and CA-125 preoperatively would improve the assignment of these patients to the correct level of care. METHODS: Patients diagnosed with a cystic ovarian mass and scheduled for an operation at our center of excellence for ovarian cancer surgery from 2001 to 2010 were prospectively included (n=394) and plasma was collected consecutively. Cut-off for HE4 was calculated at 75% specificity (85 pM and 71.8 pM for post and premenopausal women). For CA-125, 35 U/mL cut-off was used. The study population included women with malignant (n=114), borderline (n=45), and benign (n=215) ovarian tumors. RESULTS: Receiver operator characteristic (ROC) area under the curve (AUC) in the benign versus malignant cohorts was 86.8% for CA-125 and 84.4% for HE4. Negative predictive value was 91.7% when at least one of the biomarkers was positive, with only early stage epithelial ovarian cancer showing false negative results. Sensitivity at set specificity (75%) was 87% for risk of ovarian malignancy algorithm (ROMA) in the postmenopausal cohort (cut-off point, 26.0%) and 81% in the premenopausal cohort (cut-off point, 17.3%). ROC AUC in the benign versus stage I epithelial ovarian cancer was only 72% for HE4 and 76% for CA-125. CONCLUSION: In our study, population HE4 did not outperform CA-125. Based on our data a prospective trial with patients already diagnosed with an ovarian cyst may be conducted. PMID- 22247803 TI - Thoracic metastasis in advanced ovarian cancer: comparison between computed tomography and video-assisted thoracic surgery. AB - OBJECTIVE: To determine which computed tomography (CT) imaging features predict pleural malignancy in patients with advanced epithelial ovarian carcinoma (EOC) using video-assisted thoracic surgery (VATS), pathology, and cytology findings as the reference standard. METHODS: This retrospective study included 44 patients with International Federation of Obstetrics and Gynecology (FIGO) stage III or IV primary or recurrent EOC who had chest CT <=30 days before VATS. Two radiologists independently reviewed the CT studies and recorded the presence and size of pleural effusions and of ascites; pleural nodules, thickening, enhancement, subdiaphragmatic tumour deposits and supradiaphragmatic, mediastinal, hilar, and retroperitoneal adenopathy; and peritoneal seeding. VATS, pathology, and cytology findings constituted the reference standard. RESULTS: In 26/44 (59%) patients, pleural biopsies were malignant. Only the size of left-sided pleural effusion (reader 1: rho=-0.39, p=0.01; reader 2: rho=-0.37, p=0.01) and presence of ascites (reader 1: rho=-0.33, p=0.03; reader 2: rho=-0.35, p=0.03) were significantly associated with solid pleural metastasis. Pleural fluid cytology was malignant in 26/35 (74%) patients. Only the presence (p=0.03 for both readers) and size (reader 1: rho=0.34, p=0.04; reader 2: rho=0.33, p=0.06) of right-sided pleural effusion were associated with malignant pleural effusion. Interobserver agreement was substantial (kappa=0.78) for effusion size and moderate (kappa=0.46) for presence of solid pleural disease. No other CT features were associated with malignancy at biopsy or cytology. CONCLUSION: In patients with advanced EOC, ascites and left-sided pleural effusion size were associated with solid pleural metastasis, while the presence and size of right-sided effusion were associated with malignant pleural effusion. No other CT features evaluated were associated with pleural malignancy. PMID- 22247802 TI - Total laparoscopic hysterectomy versus da Vinci robotic hysterectomy: is using the robot beneficial? AB - OBJECTIVE: To compare the outcomes of total laparoscopic to robotic approach for hysterectomy and all indicated procedures after controlling for surgeon and other confounding factors. METHODS: Retrospective chart review of all consecutive cases of total laparoscopic and da Vinci robotic hysterectomies between August 2007 and July 2009 by two gynecologic oncology surgeons. Our primary outcome measure was operative procedure time. Secondary measures included complications, conversion to laparotomy, estimated blood loss and length of hospital stay. A mixed model with a random intercept was applied to control for surgeon and other confounders. Wilcoxon rank-sum, chi-square and Fisher's exact tests were used for the statistical analysis. RESULTS: The 124 patients included in the study consisted of 77 total laparoscopic hysterectomies and 47 robotic hysterectomies. Both groups had similar baseline characteristics, indications for surgery and additional procedures performed. The difference between the mean operative procedure time for the total laparoscopic hysterectomy group (111.4 minutes) and the robotic hysterectomy group (150.8 minutes) was statistically significant (p=0.0001) despite the fact that the specimens obtained in the total laparoscopic hysterectomy group were significantly larger (125 g vs. 94 g, p=0.002). The robotic hysterectomy group had statistically less estimated blood loss than the total laparoscopic hysterectomy group (131.5 mL vs. 207.7 mL, p=0.0105) however no patients required a blood transfusion in either group. Both groups had a comparable rate of conversion to laparotomy, intraoperative complications, and length of hospital stay. CONCLUSION: Total laparoscopic hysterectomy can be performed safely and in less operative time compared to robotic hysterectomy when performed by trained surgeons. PMID- 22247804 TI - Prediction of a high-risk group based on postoperative nadir CA-125 levels in patients with advanced epithelial ovarian cancer. AB - OBJECTIVE: We aimed to determine the ideal cut-off of nadir serum CA-125 level for prediction of progression free survival. METHODS: Among 267 patients who achieved complete remission after chemotherapy, the correlation between nadir CA 125 and progression free survival were compared among the subgroups classified according to the distribution of CA-125. The diagnostic odds ratio and area under the receiver operator characteristics curve were compared at various cut-off points. RESULTS: The nadir CA-125 levels did not have prognostic value under 12 U/mL (to 75 percentile). In contrast, they were significantly correlated with progression free survival only when the CA-125 level was greater than 12, which was 75 percentile (p=0.034). In predicting progression free survival <6 and 12 months, the cut-off value of 18 (90 percentile) showed superior diagnostic performance over 10 or 12 U/mL. Compared with patients who showed nadir levels between 0 and 12 U/mL (0 to 75 percentile), those with nadir >18 U/mL showed a hazard ratio of 2.85 (95% confidence interval, 1.70 to 4.76; p<0.001); patients with nadir levels between 18 and 12 U/mL showed a the hazard ratio of 1.68 (95% confidence interval, 1.11 to 2.56; p=0.015) compared with those whose nadir levels were under 12 U/mL. CONCLUSION: The predictive power of the traditional cut-off of 10 U/mL to classify a risk group or to identify high risk patients was unsatisfactory. The optimal diagnostic performance was observed at the cut-off of 18 U/mL and this can be proposed to dichotomize cut-off values to predict outcomes among individual patients. PMID- 22247806 TI - A mediastinal germ cell tumor mimicking an ectopic pregnancy. AB - The objective is to report the case of a 36 year-old female with a primary mediastinal germ cell tumor mimicking an ectopic pregnancy. The patient under birth control pill presented, at seven weeks of amenorrhea, a beta-human chorionic gonadotropin (beta-hCG) level of 850 UI and uterine vacuity with left lateral uterine heterogeneous mass but no bleeding and no pain. She received left adnexectomy, uterine curettage and further treatment by methotrexate because of persistent high beta-hCG markers. Computed tomography scan finally permitted to discover a voluminous anterior mediastinal tumor. We may recommend investigating patients with a simple chest X-ray that present with persistent increased beta hCG despite efficient ectopic pregnancy treatment. PMID- 22247807 TI - Long-term recurrence-free survival in a patient with stage IVB uterine carcinosarcoma. AB - Uterine carcinosarcomas are rare and highly aggressive tumors with a poor prognosis. Due to early metastasis and disease progression, it is known to be far more aggressive than matched grade 3 endometroid endometrial carcinomas. Five year survival for stage IV is reported to be 10% and overall survival for stage IVB is expected to be very poor. The authors report one case after experiencing long-term survival (over 5 years) for stage IVB carcinosarcoma of uterus. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed to 56 year old patient for uterine myoma. On pathology report, uterine carcinosarcoma was diagnosed and image studies were performed. With the impression of stage IVB uterine carcinosarcoma, 6 cycles of chemotherapy (ifosfamide and cisplatin) was conducted as adjuvant. Up to recently (over 5 years), she maintains good performance scale without evidence of tumor recurrence or disease progression. PMID- 22247805 TI - Diffusion-weighted MR imaging in gynecologic cancers. AB - Diffusion-weighted imaging (DWI) reflects changes in proton mobility caused by pathological alterations of tissue cellularity, cellular membrane integrity, extracellular space perfusion, and fluid viscosity. Functional imaging is becoming increasingly important in the evaluation of cancer patients because of the limitations of morphologic imaging. DWI is being applied to the detection and characterization of tumors and the evaluation of treatment response in patients with cancer. The advantages of DWI include its cost-effectiveness and brevity of execution, its complete noninvasiveness, its lack of ionizing radiation, and the fact that it does not require injection of contrast material, thus enabling its use in patients with renal dysfunction. In this article, we describe the clinical application of DWI to gynecological disorders and its diagnostic efficacy therein. PMID- 22247808 TI - Paratubal serous borderline tumor. AB - Although paratubal cysts are well-characterized incidental findings, paratubal serous borderline tumors are very rare, with only one case report in the literature. We describe here a 27-year-old, nulliparous, married woman with a paratubal serous borderline tumor. The patient presented with a huge pelvic mass accompanied by flank pain and underwent paratubal cystectomy and fertility sparing surgical staging procedures. Thirteen months after surgery, she delivered a healthy baby at term. She is well, without evidence of disease, 20 months after surgery. Because paratubal serous borderline tumors are very rare, their optimal management must be extrapolated from their ovarian counterparts. PMID- 22247809 TI - The role of neoadjuvant chemotherapy in ovarian cancer patients with extensive tumor burden. PMID- 22247810 TI - Brain Neoplasm and the Potential Impact on Self-Identity. AB - Cancers of the brain can cause alterations in a person's neurocognitive abilities, and in some patients can even challenge their concept of self and self identity. Cancer treatment may offer some hope for longer survival, but residual neurocognitive alterations generally remain. Individualized care for these patients should include information related to anticipated effects of their disease or treatments affecting their perception or expression of self. At present, the concepts of self and self-identity are largely unexplored in neuro oncology, but we will discuss this clinical population in order to highlight the need for further clinical evaluation of these phenomena among patients with brain neoplasm. Finally, we will briefly note the need for a clinical tool to assess self and self-identity changes in brain tumor patients. PMID- 22247812 TI - The christmas effect on psychopathology. AB - Urban legend suggests that psychopathology tends to increase around the holidays, including Christmas. To explore this issue, we undertook a literature search of the PsycINFO and PubMed databases for empirical studies relating to this phenomenon. According to our findings, the general mood of individuals may worsen and the number of alcohol-related fatalities may increase around the Christmas holiday; however, overall utilization patterns by psychiatric patients in emergency rooms and in inpatient wards is lower as is the prevalence of self-harm behavior and suicide attempts/completions. Following the Christmas holiday, there appears to be a rebound phenomena with these latter behaviors-a concerning pattern that is relevant for both psychiatrists and primary care clinicians. PMID- 22247813 TI - Should psychiatrists self disclose? AB - The extent to which psychiatrists disclose personal information about their feelings, their pasts, and themselves to their patients has always been an important ethical and clinical question. In the past, psychiatrists tended to believe they should not self disclose personal information to their patients, mainly to help patients by exploring their transference. More recent work has suggested that self disclosing by the psychiatrist may benefit some patients and cause harm to other patients. This article presents the author's present understanding of some of the core pros and cons of self disclosing by the psychiatrist, as well as some specific contexts in which self disclosure is indicated or should be avoided. PMID- 22247811 TI - Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease. AB - Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease. PMID- 22247814 TI - Pain during transcranial magnetic stimulation in youth. AB - Pain or discomfort at the site of stimulation is a common side effect of transcranial magnetic stimulation. Relevant physiology and predisposing factors have not been adequately described. Literature regarding work with minors is even more limited. The authors present two cases from a child and adolescent neurophysiology transcranial magnetic stimulation protocol and one case from a therapeutic study of repetitive transcranial magnetic stimulation in adolescents with treatment-resistant major depressive disorder. Relevant literature is reviewed. Potential subjects, parents, and study teams should be well aware of this potential side effect in child and adolescent populations. Subjects with anxiety disorders may be prone to pain during these procedures. Further work could assist in identifying predisposed individuals, refining the informed consent process, and implementing procedures to minimize discomfort. PMID- 22247815 TI - Early detection of illicit drug use in teenagers. AB - The illicit use of drugs, including alcohol, by teenagers has been extensively studied and documented. It is not uncommon for teenagers to be involved in illicit drug use before exhibiting signs and symptoms of drug use. Unsuspecting parents may be unaware of drug use in their children. The authors' objective in this article is to review the literature on illicit drug use in teenagers and highlight the risk factors for teen involvement. The authors also review the warning signs that a teen is using illicit drugs. The aim of this article is to assist parents and healthcare workers involved in substance use intervention programs to be more aware of these risk factors and warning signs in order to adopt early screening and intervention measures. PMID- 22247816 TI - Opsoclonus myoclonus. AB - Opsoclonus myoclonus is a rare autoimmune condition characterized by cerebellar degeneration. It occurs most often as a paraneoplastic syndrome when a cancer remote to the brain induces cerebellar dysfunction that is unrelated to metastases. Half of all cases occur in children with a neuroblastoma. Most adults with opsoclonus myoclonus have neoplastic, infectious, metabolic, or idiopathic etiologies. Signs of cerebellar dysfunction noted at presentation include opsoclonus, myoclonus and ataxia, hence the name "dancing eyes, dancing feet syndrome." Opsoclonus is characterized by rapid, involuntary eye movements that are dysrhythmic and uncoordinated.Neuronal damage is induced by antibodies usually related to the primary pathology. Treatment targets the etiology and also employs steroids, plasmapheresis, immunosuppressive agents, or other anti inflammatory therapies. Children with opsoclonus myoclonus resulting from a neuroblastoma often retain neurological sequelae. Adult cases of opsoclonus myoclonus with idiopathic or infectious etiologies have a more favorable prognosis than those with neoplastic origins. PMID- 22247817 TI - Nonphysician providers and liability exposure to supervising psychiatrists. PMID- 22247818 TI - A Fast Exact k-Nearest Neighbors Algorithm for High Dimensional Search Using k Means Clustering and Triangle Inequality. AB - The k-nearest neighbors (k-NN) algorithm is a widely used machine learning method that finds nearest neighbors of a test object in a feature space. We present a new exact k-NN algorithm called kMkNN (k-Means for k-Nearest Neighbors) that uses the k-means clustering and the triangle inequality to accelerate the searching for nearest neighbors in a high dimensional space. The kMkNN algorithm has two stages. In the buildup stage, instead of using complex tree structures such as metric trees, kd-trees, or ball-tree, kMkNN uses a simple k-means clustering method to preprocess the training dataset. In the searching stage, given a query object, kMkNN finds nearest training objects starting from the nearest cluster to the query object and uses the triangle inequality to reduce the distance calculations. Experiments show that the performance of kMkNN is surprisingly good compared to the traditional k-NN algorithm and tree-based k-NN algorithms such as kd-trees and ball-trees. On a collection of 20 datasets with up to 10(6) records and 10(4) dimensions, kMkNN shows a 2-to 80-fold reduction of distance calculations and a 2- to 60-fold speedup over the traditional k-NN algorithm for 16 datasets. Furthermore, kMkNN performs significant better than a kd-tree based k-NN algorithm for all datasets and performs better than a ball-tree based k-NN algorithm for most datasets. The results show that kMkNN is effective for searching nearest neighbors in high dimensional spaces. PMID- 22247819 TI - Workforce Capacity for Reducing Rural Disparities in Public Mental Health Services for Adults with Severe Mental Illness. PMID- 22247820 TI - The Impact of Magnesium Sulfate Therapy on Angiogenic Factors in Preeclampsia. AB - OBJECTIVE: The objective was to evaluate whether intravenous magnesium sulfate (magnesium) alters levels of angiogenic factors in women with preeclampsia. STUDY DESIGN: This was a prospective cohort study comparing women with preeclampsia treated with magnesium for seizure prophylaxis to those who were not. Serum levels of angiogenic factors, soluble fms-like tyrosine kinase 1, soluble endoglin and placental growth factor, were measured at the time of diagnosis and approximately 24 hours later. Secondary analysis compared women receiving magnesium for preeclampsia to women receiving magnesium for preterm labor. Analysis of covariance was used to compare levels at 24 hours, adjusting for levels at enrollment and potential confounders. RESULTS: Angiogenic factor levels did not differ between preeclampsia groups with and without magnesium or between preeclampsia and preterm labor groups treated with magnesium (all P > 0.05). CONCLUSION: Magnesium likely decreases seizure risk in preeclampsia by a mechanism other than altering angiogenic factor levels. PMID- 22247821 TI - Role of cytokines in altitude-associated preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is more common at high than low altitude and contributes to the altitude-related decline in birth weight. Since inflammatory markers are implicated in PE, we asked if such markers differed in PE vs. normotensive pregnant (NORM) women residing at high altitude (3600-4100 m), and were related to uterine artery blood flow (UA BF) or fetal growth. METHODS: Subjects were 33 Andean pregnant residents of Bolivia, comprising six with early onset PE (<= 34 wk), 12 with late-onset PE (> 34 wk), and 15 gestational-age matched NORM. Maternal pro- and anti-inflammatory cytokines were measured using a multiplex bead-based assay and UA BF by Doppler ultrasound. RESULTS: PE compared to NORM women had higher levels of the pro-inflammatory cytokines IL-6 and IL-8 as well as higher levels of the anti-inflammatory cytokine IL-1ra, but only IL-6 levels were higher when gestational age was controlled. Women with early- vs. late-onset PE had higher TNFalpha levels, and higher IL-6 was negatively correlated with birth weight in all women at <= 34 wk. We suggest that pro inflammatory factors influence both the timing and severity of PE at high altitude. PMID- 22247822 TI - Serendipity in anticancer drug discovery. AB - It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%) were discovered following an incident in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. The therapeutic field that has benefited the most from serendipity are central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind. PMID- 22247823 TI - Challenges in the differential diagnosis of hypercalcemia: A case of hypercalcemia with normal PTH level. AB - The hypercalcemias are a common and heterogeneous group of disorders, ranging from the occasional detection of a high level of serum calcium to a life-treating condition. In a patient presenting with hypercalcemia, a differential diagnosis can be established easily by measuring serum calcium and parathyroid hormone (PTH) concentrations. We describe the case of an 83-year-old man presenting with a severe symptomatic hypercalcemia with high-normal PTH level due to the coexistence of primary hyperparathyroidism and malignancy-associated hypercalcemia. The presence of two conditions producing hypercalcemia was revealed only during in-hospital stay and after the administration of an intravenous bisphosphonate, when the PTH concentration increased rapidly after bisphosphonate treatment with a decrease in serum calcium. The occurrence of two conditions producing hypercalcemia is a rare event in the literature, and should be considered in the presence of an abnormally high serum calcium level associated with normal or high-normal PTH, in order to establish a correct diagnosis and appropriate interventions. PMID- 22247824 TI - Optimal combination of radiofrequency ablation with chemoradiotherapy for locally advanced pancreatic cancer. AB - Problems have been reported in the treatment of pancreatic cancer with radiofrequency ablation (RFA), such as the friability of the organ itself. This report presents possible solutions to such problems. Although our patient suffered from locally advanced unresectable pancreatic cancer, she remained well at 18 mo after RFA with no evidence of recurrence. To ameliorate the side effects of RFA, after a palliative bypass procedure, the subject was treated with combined radiotherapy and chemotherapy. After this regimen had been administered, a contrast-enhanced computed tomography scan confirmed that RFA is a viable approach to the treatment of pancreatic cancer as the chemoradiotherapy had resulted in marked tumor shrinkage and pancreatic fibrosis; i.e., sufficient tumor ablation was achieved without serious RFA-related complications, such as pancreatitis or pancreatic fistulae. The present case suggests that RFA combined with preceding chemoradiotherapy is safe and effective for the palliative treatment of locally advanced pancreatic cancer. PMID- 22247825 TI - Trouble shooting during bioanalytical estimation of drug and metabolites using lc ms/ms: a review. AB - Bioanalysis frequently involves the measurement of very low analyte concentrations in complex and potentially variable matrices. An initial attempt has been made to apply a risk management tool to the bioanalytical method development like selection of spiked plasma volume, selection of internal standard to minimize processing error, selection of medium and extraction procedure, setting of mobile phase and pH, determination of chromatographic conditions etc. and to minimize instrumental error like; ion suppression and matrix effect. PMID- 22247826 TI - The facts about penicillin allergy: a review. AB - Hypersensitivity reactions are the major problem in the use of penicillins. True penicillin allergy is rare with the estimated frequency of anaphylaxis at 1-5 per 10 000 cases of penicillin therapy. Hypersensitivity is however, its most important adverse reaction resulting in nausea, vomiting, pruritus, urticaria, wheezing, laryngeal oedema and ultimately, cardiovascular collapse. Identification of patients who erroneously carry beta-lactam allergy leads to improved utilization of antibiotics and slows the spread of multiple drug resistant bacteria. Cross-reactivity between penicillin and second and third generation cephalosporin is low and may be lower than the cross-reactivity between penicillin and unrelated antibiotics. PMID- 22247827 TI - Case report and clinical databased research study on malaria. AB - Malaria is endemic in Gujarat and the adjoining areas like many other parts of the India. Depending upon the environmental conditions different species of malarial parasite are found in different areas. The present study was planned to see the pattern of malarial infection diagnosed at B.J. Desai Trust Hospital, Kheda, Gujarat METHODS: Giemsa stained thick and thin blood films of indoor and outdoor febrile patients sent to the laboratory of B.J. Desai Trust Hospital, Kheda, Gujarat with a suspicion of malaria, were examined. Thick film was examined for the diagnosis of malaria while thin films were seen to know the species. RESULTS: Out of 1994 patients screened, 145 (7.2%) were found infected. Plasmodium vivax was seen in the majority (72.47.2%). Plasmodium falciparum was the second common species detected in 24.1 % cases. Mixed infection was seen in 3.44% cases while Plasmodium malariae and ovale was not seen in any patient. CONCLUSION: Plasmodium vivax was the commonest type of malaria diagnosed at Kheda District in Gujarat, during 2008- 2009. PMID- 22247828 TI - In vivo rodent micronucleus assay of gmelina arborea roxb (gambhari) extract. AB - Gmelina arborea Roxb (family Verbenaceae) commonly known as 'Gambhari' tree, the various parts of the plants are widely used in diarrhoea, anti-pyretic, thirst, anemia, leprosy, ulcers, consumption, strangury, vaginal discharges. We tested the genotoxic potential of G. arborea in bone marrow cells obtained from Swiss albino mice using micronuclei formation as the toxicological endpoints. Aqueous extract of G. arborea (AEGA) was tested at the dose of 286 & 667 mg/kg body weight (b. w.). Cyclophosphamide (CPZ) 25 mg/kg b. w. was used as positive control in micronucleus test. The AEGA significantly increased the % micronucleated polychrometics at doses of 286mg/kg and 667mg/kg, after 24, 48 72h time interval. And also decreased the PCE/NCE ratio after 24, 48 and 72 h as compared to solvent control group. In this study, we investigated the effect of G. arborea on mammalian bone marrow cells using micronuclei formation to assess the genotoxicity of the herb. PMID- 22247829 TI - Antipsychotic activity of aqueous ethanolic extract of tinospora cordifolia in amphetamine challenged mice model. AB - Tinospora cordifolia is reported to have CNS active principle and is used for the treatment of various neurological disorders. Hence, the effect of aqueous ethanolic extract of Tinospora cordifolia was investigated for its putative antipsychotic activity using amphetamine challenged mice model. Haloperidol (1 mg/kg i.p.) was administered acutely to mice as standard drug. Control animals received vehicle (10% DMSO). The in vivo receptor binding studies were carried out to correlate the antipsychotic activity of the extract with its capacity to bind to the DAD2 receptor. The results in SLA showed that the hydro alcoholic extract of the stems of Tinospora cordifolia at a dose level of 250 mg/kg and 500 mg/kg showed no significant antipsychotic activity in amphetamine induced hyperactivity in mice when compared to standard. Extract alone treated group at a dos level of 250 mg/kg and 500 mg/kg showed a decreased in locomotor activity when compared to the control. The plant extract increased the DAD(2) receptor binding in a dose dependent manner in treated mice compared to the control group. PMID- 22247830 TI - Assessment of anti-nociceptive efficacy of costus speciosus rhizome in swiss albino mice. AB - Present study attempts to evaluate the anti-nociceptive activity of the aqueous and ethanol extracts of Costus speciosus rhizome (CPA and CPE) in Swiss albino mice. The maceration extracts were evaluated for anti-nociceptive activity by acetic acid-induced writhing and tail flick method in mice. The anti-nociceptive screening revealed significant peripheral anti-nociceptive actions of both extracts against acetic acid induced writhing in mice. Aqueous extract (CPA) significantly inhibited writhes at the dose of 75 and 150 mg/kg body weight, while ethanol extract (CPE) produced significant protection at the dose of 150 mg/kg body weight. However, in tail flick method only the ethanol extract (CPE) showed significant central analgesic action, while aqueous extract was totally ineffective. The present investigation demonstrates that the rhizome extracts of C. speciosus exhibited significant anti-nociceptive effects in Swiss albino mice. PMID- 22247831 TI - Antidiarrhoeal activity of leaf extract of celosia argentea in experimentally induced diarrhoea in rats. AB - In order to scientifically apprise some of the anecdotal, folkloric, ethno medical uses of celosia argentea, the present study was undertaken to examine the antidiarrhoeal properties of alcoholic extract of leaves of Celosia argentea on diarrhoea by using different experimental models. Anti-diarrhoeal effect was evaluated by castor oil induced diarrhoea, charcoal meal test and PGE(2) induced diarrhoea. Loperamide (2 mg/kg) and atropine (0.1mg/kg) were used as standard drugs. Extract was used in 100 and 200 mg/kg dose. It produced dose related anti diarrhoeal effect. Results suggest that it may act centrally and may inhibit the PGE(2) to give anti-diarrhoeal effects. Result of charcoal meal test also suggests its anti-muscarinic activity. PMID- 22247832 TI - In-vitro characterization of gastroretentive microballoons prepared by the emulsion solvent diffusion method. AB - Microballoons floatable on JPXIII No.1 solution were developed as a dosage form capable of floating in the stomach. Microballoons were prepared by the emulsion solvent diffusion method using enteric acrylic and other polymers with drug in a mixture of dichloromethane and ethanol. It was found that preparation temperature determined the formation of cavity inside the microsphere and the surface smoothness, determining the floatability and the drug release rate of the microballoons. The correlation between the buoyancy of microballoons and their physical properties, e.g. apparent density and roundness of microballoons were elucidated. The drug loading efficiency of microballoons was also determined. The optimum loading amount of metformin in the microballoons was found to impart ideal floatable properties to the microballoons. By fitting the data into zero order, first order and Highuchi model it was concluded that the release followed zero order release. PMID- 22247833 TI - Leaves extract of murraya koenigii linn for anti-inflammatory and analgesic activity in animal models. AB - This work has been done for the investigation of the anti-inflammatory and analgesic activity of methanol extract of dried leaves of Murraya koenigii Linn by oral administration at dose of 100, 200 and 400 mg/kg body weight, to healthy animals. Extract was studied for its anti-inflammatory activity by using carrageenan-induced hind paw edema in albino rats and the mean increase in paw volume and % inhibition in paw volume were measured plethysmometrically at different time intervals after carrageenan (1% w/v) injection. Extract was also evaluated for analgesic activity using Eddy's hot plate method and formalin induced paw licking method in albino rats. The methanol extract showed significant (P < 0.001) reduction in the carrageenan-induced paw edema and analgesic activity evidenced by increase in the reaction time by eddy's hot plate method and percentage increase in pain in formalin test. The methanol extract showed anti-inflammatory and analgesic effect in dose dependent manner when compared with the control and standard drug, diclofenac sodium (10mg/kg, p.o). These inhibitions were statistically significant (P < 0.05). Thus our investigation suggests a potential benefit of Murraya koenigii in treating conditions associated with inflammatory pain. PMID- 22247834 TI - A novel method for quantitative determination of aceclofenac in bulk drug and tablets using sodium salicylate as a hydrotropic solubilizing agent. AB - In titrimetric analysis costlier organic solvents are more often employed to solubilize the poorly water-soluble drugs. Volatility and pollution are drawbacks of such solvents. Various techniques are employed to enhance the aqueous solubility of poorly water-soluble drugs. Hydrotropic solubilization phenomenon has been widely used to enhance the aqueous solubility of large number of poorly water-soluble drugs. Aqueous solubility of aceclofenac bulk drug [a poorly water soluble NSAID] was enhanced to a great extent i.e., 400 folds with 2.5 M sodium salicylate. The primary objective of the present investigation was to employ this hydrotropic solution to extract the drug from its dosage forms, precluding the use of costlier organic solvents. The proposed method of analysis is new, simple, accurate, environmentally friendly and reproducible. Statistical data proved the accuracy, reproducibility and the precision of the proposed method. The results of titrimetric analysis by use of hydrotropy compared very well with the results of Pharmacopoeial method. PMID- 22247835 TI - Preliminary investigation on antipyretic activity of cuscuta reflexa in rats. AB - In present study, the antipyretic activity of aqueous and ethanol extracts from Cuscuta reflexa Roxb. (Cuscutaceae) was evaluated using Brewer's yeast induced pyrexia in rats. Both the extracts at 200 and 400 mg/kg body weight dose significantly (p < 0.05) reduced the increased rectal temperature. The extracts started reducing the elevated rectal temperature after 3 h of treatment in a dose related manner. At the dose of 400 mg/kg body weight the aqueous and ethanol extract reduced 79 % and 83.8 % respectively of the elevated rectal temperature as compared to reference drug paracetamol (96.5 %) after 6 h of treatment. It was therefore concluded that both the extracts of C. reflexa demonstrated antipyretic activity, the ethanol extract was found to be slightly potent than the aqueous extract. PMID- 22247836 TI - Design and evaluation of a metronidazole central core matrix tablet. AB - In this paper, a study of different concentration of HPMC K 15 M exerts influence on the drug release process from a new controlled drug delivery system has been realized in order to obtain a constant release rate during a prolonged period of time, for a programmed drug release. The drug release profiles obtained for the different batches have shown an interesting relationship between the particle size of the channeling agent used and the length of different operational periods. PMID- 22247837 TI - From the Editor's Desk. PMID- 22247838 TI - Clinical aspects of acute post-operative pain management & its assessment. AB - Management of postoperative pain relieve suffering and leads to earlier mobilization, shortened hospital stay, reduced hospital costs, and increased patient satisfaction. An effective postoperative management is not a standardized regime rather is tailored to the needs of the individual patient, taking into account medical, psychological, and physical condition; age; level of fear or anxiety; surgical procedure; personal preference; and response to therapeutic agents given. The major goal in the management of postoperative pain is to minimize the dose of medications to lessen side effects & provide adequate analgesia. Postoperative pain is still under managed due to obstacles in implementation of Acute Pain Services due to insufficient education, fear of complications associated with available analgesic drugs, poor pain assessment and inadequate staff. This review reflects the clinical aspects of postoperative pain & its assessment & management with an emphasis on research for new analgesic molecules & delivery system. PMID- 22247839 TI - Various types and management of breast cancer: an overview. AB - Now days, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women. Since last two decades, researches related to the breast cancer has lead to extraordinary progress in our understanding of the disease, resulting in more efficient and less toxic treatments. Increased public awareness and improved screening have led to earlier diagnosis at stages amenable to complete surgical resection and curative therapies. Consequently, survival rates for breast cancer have improved significantly, particularly in younger women. This article addresses the types, causes, clinical symptoms and various approach both non- drug (such as surgery and radiation) and drug treatment (including chemotherapy, gene therapy etc.) of breast cancer. PMID- 22247840 TI - Need for harmonization of labeling of medical devices: a review. AB - Medical device labeling is any information associated with a device targeted to the patient or lay caregiver. It is intended to help assure that the device is used safely and effectively. Medical device labeling is supplied in many formats, for example, as patient brochures, patient leaflets, user manuals, and videotapes. The European commission has discussed a series of agreements with third countries, Australia, New Zealand, USA, Canada, Japan and Eastern European countries wishing to join the EU, concerning the mutual acceptance of inspection bodies, proof of conformity in connection with medical devices. Device labeling is exceedingly difficult for manufacturers for many reasons like regulations from government bodies to ensure compliance, increased competent authority surveillance, increased audits and language requirements. PMID- 22247841 TI - Novel drug delivery systems: desired feat for tuberculosis. AB - Tuberculosis has claimed its victims throughout much of known human history and is currently the most devastating human bacterial disease. The ability to infect human population on a global scale, combined with the widespread emergence of multi-drug resistant strains, has led to the placement of Mycobacterium tuberculosis on the National Institute of Allergy and Infectious Diseases (NIAID) list of Biodefence and Emerging Infectious Disease Threats Agents. The resurgence of interest in tuberculosis (TB) has stemmed because of increased evidences from developed countries. Contrary to expectations, no country has reached the phase of elimination and in no subsection of society TB has been completely eliminated. A deeper understanding of the process will assist in the identification of the host and mycobacterial efforts involved and provide targets for therapeutic strategies against tuberculosis. The article presents a view on pathogenesis of tuberculosis and its diverse manifestations, host defense evasion, mechanisms of microbial persistence, emergence of Multiple Drug Resistance and Extensive Drug Resistance, conventional therapy used and the possible novel systems which are under extensive investigation as drug carriers for improving the cytosolic concentration of the anti-tubercular agents. PMID- 22247842 TI - Various techniques for the evaluation of anti arthritic activity in animal models. AB - Arthritis is an auto immune disorder characterized by pain, swelling and stiffness. Its prevalence depends upon age. It occurs more frequently in women than in men. It is an inflammation of synovial joint due to immuno mediated response. All anti inflammatory drugs are not anti arthritic because it does not suppress T-cell and B-cell mediated response. Epidemiological studies overall show a female to male ratio of about 3:1. There are many class of anti-arthritic drugs are available like NSAIDS, Monoclonal anti-bodies, uricosuric agents, gold compounds, anti-cytokinine immunosuppressant like glucocorticoids, etc. But this all class of drugs is responsible for symptomatic relief. To evaluate the drug which actually prevent cause of arthritic or act during various step of arthritis there is requirement of evaluative model which produce arthritis in (vial same that produce in humans. Animal models of arthritis are used to study pathogenesis of disease and to evaluate potential anti-arthritic drugs for clinical use. Therefore morphological similarities to human disease and capacity of the model to predict efficacy in humans are important criteria in model selection. PMID- 22247843 TI - Hptlc method development and validation of trandolapril in bulk and pharmaceutical dosage forms. AB - A simple, precise, accurate and rapid high performance thin layer chromatographic method has been developed and completely validated for the estimation of trandolapril in bulk and pharmaceutical dosage forms. Quantification of trandolapril was carried out with percolated silica gel 60F(254) as stationary phase using mobile phase consisting of Chloroform: Methanol: Acetic acid (8:1.5:0.5 v/ v/ v) and scanned in Absorbancei Reflectance mode at 212 nm using Camag TLC scanner 3 with WinCAT software. The R(f) value of trandolapril was found to be 0.54 (+/-0.03). The proposed method has permitted the quantification of trandolapril over the linearity range of 25-150 ng/spot and its percentage recovery was found to 99.7%. The intraday and inter day precision were found to be 1.26% and 1.4%, respectively. The limit of detection and the limit of quantification were found to be 18 ng/ spot and 54 ng/ spot, respectively. The proposed method can be successfully applied for the estimation of drug content of different marketed formulations simultaneously on a single plate and provides a faster and cost effective quality control tool for routine analysis of trandolapril as bulk drug and in tablet dosage forms. PMID- 22247844 TI - Formulation of furosemide solid dispersion with micro crystalline cellulose for achieve rapid dissolution. AB - Furosemide, a weekly acidic, loop diuretic drug indicated for treatment of edema and hypertension having high permeability through stomach. It is practically insoluble in gastric fluid (0.006 mg/ mL) and having highly permeability through stomach but due to its solubility limitation it can't enter into systemic circulation. It was logically decided to design experiment, so as to achieve the set objectives. Attempt was made to prepare solid dispersion of furosemide with Poly ethylene glycol (PEG) 6000 containing microcrystalline cellulose (MCC) as adsorbent which would dissolve completely in less than 30 minutes (target selected by considering minimum gastric empting time). Microcrystalline cellulose converted sticky dispersion in to free flow powder hence increase surface area which responsible for dissolution improvement. Factorial design was applied to optimize formulation. Amount of poly ethylene glycol 6000 and microcrystalline cellulose were selected as an Independent variable while angle of repose and T(100%) were selected as dependent variable. Attempts for dissolution rate of furosemide improve bioavailability and consequently dose reduction would possible. PMID- 22247845 TI - A simple and rapid method for simultaneous estimation of glycyrrhetinic Acid and piperine by hptlc in a herbomineral formulation. AB - Many of the traditional herbal formulations contain extracts of Piper longum and Glycyrrhiza glabra, piperine and glycyrrhetinic acid respectively, being active constituents of these two herbs. An attempt has been made to develop a simple, precise, rapid, and cost-effective high-performance thin-layer chromatographic (HPTLC) method for simultaneous estimation of these in a herbomineral formulation (Efiplus((r)) Capsules). Precoated silica gel 60 F(254) plates with toluene-ethyl acetate-glacial acetic acid 12.5:7.5:0.5, as mobile phase were used in chromatographic determinations. The plates were scanned and the compounds were quantified at their wavelengths of maximum absorption of 260 and 331 nm for glycyrrhetinic acid and piperine respectively. The respective R(F), values of glycyrrhetinic acid and piperine were 0.51 and 0.55. Under these experimental conditions linearity was observed between 0.8-2.6 MUg/ spot for glycyrrhetinic acid and between 10-50 ng/ spot for piperine and average recovery was 96.25% for glycyrrhetinic acid and 98.55% for piperine. PMID- 22247846 TI - Formulation and evaluation of s-(-)-amlodipine besylate and nebivolol hydrochloride tablets. AB - The objective of the present study was to develop a tablet formulation of S-(-) amlodipine besylate chiral separation drug and nebivolol hydrochloride for better management of hypertension, while reducing or avoiding undesirable adverse effects, which are often associated with administration of a racemic mixture of amlodipine. The composition containing the optically pure S-(-)- isomer of amlodipine 2.5 mg has calcium channel blocking activity and, nebivolol hydrochloride 5 mg has beta-receptor blocking activity.The study was also carried out to design a suitable dissolution medium for S-(-) - amlodipine besylate and nebivolol hydrochloride. Amlodipine besylate and nebivolol hydrochloride had maximum solubility in pH 1.2 and thus pH 1.2 was selected as the most suitable media for S-(-) - amlodipine besylate and nebivolol hydrochloride dissolution studies. The RSD below 2% indicated insignificant batch-to-batch variation. The accelerated stability study of the optimized formulation was performed as the ICH guidelines. The results indicated no change in optical rotation of S-(-) - amlodipine besylate. Hence, combination of two drugs can be formulated into the tablet by wet granulation technique having satisfactory release profile. PMID- 22247847 TI - Antimicrobial resistance of bacterial agents of the upper respiratory tract in South Indian population. AB - The study was aimed at determining bacterial agents of the upper respiratory tract and the susceptibility patterns of isolates to antibiotics. The throat swab samples from 250 patients suspected of upper respiratory tract infection (URTI) were obtained from the General Medicine outpatient department of a Rural Health Centre of Rajah Muthiah Medical College and Hospital (RMMC and H), Annamalai University, Chidambaram, Tamilnadu, India and inoculated in the culture medium. The bacterial infection was confirmed only in 228 patients. The organisms isolated on medium were identified by their cultural, morphological and biochemical characteristics. Staphylocccus aureus was identified as the most prevalent bacterial isolate (45.61%) followed by beta hemolytic streptococci (22.51%). Thirty four strains (14.91%) were identified as Klebsiella penumoniae, 19 (8.33%) as Pseudomonas aeruginosa and the rest belonged to a hemolytic streptococci, Escherichia coli and Haemophitus influenzae. All Staphylococcus spp, were resistant to penicillin., ampicillin and co-trimoxazole. All the isolates were resistant to at least one antibiotic. The overall resistance rates were generally low for gentaruicin, cefixine and ceftazidime respectively. PMID- 22247848 TI - Pharmacognostic evaluation of toona ciliata bark. AB - Pharmacognostic standardizations of powdered and anatomical sections of the Toona ciliata bark was carried out to determine its macro- and microscopical characters and also some of its quantitative standards. Externally bark are Grey to reddish brown in colour when it is dry, 200 mm in length, 20 to 60 mm in width and 2 to 3 mm in thickness outer surface brown coloured, strong odour, bitter taste, rough and hard, double quill and curved curvature. The transverse section (T. S.) revealed the presences of periderm, cortex, Sclerides, mednllary rays and phloem fiber. Physico-chemical evaluation includes ash values, extractive values and moisture content. These findings will be useful towards establishing pharmacognostic standards on identification, purity, quality and classification of the plant, which is gaining relevance in plant drug research. PMID- 22247849 TI - Development, characterization and solubility study of solid dispersions of azithromycin dihydrate by solvent evaporation method. AB - Azithromycin Dihydrate (Poorly water soluble drug), when prepared as solid dispersion showed improved solubility and dissolution. So the main purpose of this investigation was to increase the solubility and dissolution rate of Azithromycin Dihydrate by the preparation of its solid dispersion with urea using solvent evaporation method. Physical mixtures and solid dispersions of Azithromycin Dihydrate were prepared by using urea as water-soluble carrier in various proportions (1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 by weight), by employing solvent evaporation method. The drug release profile was studied and it was found that the dissolution rate and the dissolution parameters of the drug from the physical mixture as well as solid dispersion were higher than those of the intact drug. FT- IR spectra revealed no chemical incompatibility between drug and urea. Drug-polymer interactions were investigated using differential scanning calorimetry (DSC) and Powder X-Ray Diffraction (PXRD). PMID- 22247850 TI - Hypolipidemic activity of haritaki (terminalia chebula) in atherogenic diet induced hyperlipidemic rats. AB - Haritaki (Terminalia chebula) family Combretaceae is an important plant used traditionally for medicinal purposes. It is component of the classic Ayurvedic combination called "Triphala". Hyperlipidemia was induced by treated orally with atherogemc diet. In atherogenic diet induced hyperlipidemic model, the rats receiving treatment with Haritaki showed significant reduction in total cholesterol, triglycerides, total protein and elevation of high density lipoprotein cholesterol. Haritaki was found to possess significant hypolipidemic activity. The results also suggest that Haritaki at 1.05 and 2.10 mg/kg b.wt. concentrations are an excellent lipid-lowering agent. PMID- 22247851 TI - Antimicrobial evaluation of novel substituted pyrimidinopyrazoles and pyrimidinotriazoles. AB - Some novel substituted pyramidinopyrazoles and pyrimidinotriazoles have been synthesized by using 6-anisyl-5-cyan-2-hydrazine-3-N-methyl-3, 4 dihydropyrimidine-4-one as the starting material. Structures of these compounds have been established by IR, (1)H NMR, Mass and elemental analysis data and have been evaluated for their antimicrobial activity. Significant antimi.crobial activity was observed for some members of these series. PMID- 22247852 TI - In vitro cytotoxicity study of agave americana, strychnos nuxvomica and areca catechu extracts using mcf-7 cell line. AB - Research is focusing on the search for new types of natural chemotherapeutic agent that is plant based medicines which are proving to be excellent sources of new compounds. In present research study, an attempt was made to prove cytotoxicity activity of various parts of medicinal plants such as Agave americana, Strychnos nuxvomica and Areca catechu using MCF-7 and Vero cell line. Various parts of the medicinal plants were extracted by soxhlet apparatus using solvents likes methanol and water. By trypan blue dye exclusion method, Viability of MCF-7 and Vero cell lines were 85.50 and 81.13%, respectively. IC(50) value of methanol extract of Agave americana leaves and aqueous extract of Areca catechu fruits were found to be 545.9 & 826.1 MUg/ml by SRB assay and 775.1 & 1461pg/ml by MTT assay, respectively, against MCF-7 cell line. From cytotoxicity study data by SRB and MTT assay, it revealed that methanol extract of Agave americana and aqueous extract of Areca catechu are potent cytotoxic. PMID- 22247853 TI - Studies on some physicochemical properties of leucaena leucocephala bark gum. AB - Gum exudates from Leucaena Leucocephala (Family: Fabaceae) plants grown all over India were investigated for its physicochemical properties such as pH, swelling capacity and viscosities at different temperatures using standard methods. Leucaena Leucocephala bark gum appeared to be colorless to reddish brown translucent tears. 5 % w/v mucilage has pH of 7.5 at 28 degrees C. The gum is slightly soluble in water and practically insoluble in ethanol, acetone and chloroform. It swells to about 5 times its original weight in water. A 5 %w/ v mucilage concentration gave a viscosity value which was unaffected at temperature ranges (28-40 degrees C). At concentrations of 2 and 5 %w/v, the gum exhibited pseudo plastic flow pattern while at 10 %w/v concentration the flow behaviour was thixotropic. The results indicate that the swelling ability of Leucaena Leucocephala (LL) bark gum may provide potentials for its use as a disintegrant in tablet formulation, as a hydro gel in modified release dosage forms and the rheological flow properties may also provide potentials for its use as suspending and emulsifying agents owing to its pseudo plastic and thixotropic flow patterns. PMID- 22247854 TI - Evaluation of antioxidant potential of pyrazolone derivatives. AB - In this article the antioxidant property of pyrazolones derivatives (PYZ1 to PYZ10) are reported. It was assessed by estimation of Malonaldehyde (MDA) and 4 Hydroxyl-2-noneal (4-HNE) as lipid peroxidation markers in myocardial ischemic reperfusion injury. The inhibition of lipid peroxidation was compared with the standard ascorbic acid. Among synthesized derivatives PYZ2, PYZ3, PYZ7, PYZ8, PYZ9, and PYZ10 were found to have potent antioxidant effect against MDA marker. In case of 4-HNE, PYZ4, PYZ5, PYZ6, PYZ7, PYZ8, PYZ9 and PYZ10 were found to have effective antioxidant activity and the rest of the compounds are moderately active. Comparatively PYZ7, PYZ8, PYZ9 and PYZ10 are having effective role to control both MDA and 4-HNE generation. All the experimental data were statistically significant at p< 0.05 level. Interestingly, beyond its NSAID property, this study explores the protective role of pyrazolone derivatives in ischemic heart injury. PMID- 22247855 TI - A preliminary study on the in vitro antioxidant activity of the stems of opuntia vulgaris. AB - The in vitro antioxidant activity of stems of Opuntia vulgaris Mill had been investigated by estimating degree of non-enzymatic haemoglobin glycosylation measured colorimetrically at 520 urn. It was found that benzene and chloroform extract of O. vulgaris had better antioxidant activity than petroleum ether, ethyl acetate, ethanol and aqueous extract. The antioxidant activity of the extracts was concentration dependent and comparable to that of D-alpha- tocopherol (vitamin E) and ascorbic acid (vitamin C), standard antioxidant compounds used. PMID- 22247856 TI - From the Editor's desk. PMID- 22247857 TI - From the Editor's desk. PMID- 22247858 TI - Therapeutic and cosmeceutical potential of ethosomes: An overview. AB - The main disadvantage of transdermal drug delivery is the poor penetration of most compounds into the human skin. The main barrier of the skin is located within its uppermost layer, the stratum corneum (SC). Several approaches have been developed to weaken this skin barrier. One of the approaches for increasing the skin penetration of drugs and many cosmetic chemicals is the use of vesicular systems, such as, liposomes and ethosomes. Ethosomes are phospholipid-based elastic nanovesicles containing a high content of ethanol (20-45%). Ethanol is known as an efficient permeation enhancer and has been added in the vesicular systems to prepare elastic nanovesicles. It can interact with the polar head group region of the lipid molecules, resulting in the reduction of the melting point of the stratum corneum lipid, thereby increasing lipid fluidity and cell membrane permeability. The high flexibility of vesicular membranes from the added ethanol permits the elastic vesicles to squeeze themselves through the pores, which are much smaller than their diameters. Ethosomal systems are much more efficient in delivering substances to the skin in the terms of quantity and depth, than either conventional liposomes or hydroalcoholic solutions. The scope of this small review is to introduce the novel concept of ethosomes and to describe some approaches and mechanisms of stimulating topical and transdermal products with ethosomes. PMID- 22247859 TI - Microsponges: A novel strategy for drug delivery system. AB - Microsponges are polymeric delivery systems composed of porous microspheres. They are tiny sponge-like spherical particles with a large porous surface. Moreover, they may enhance stability, reduce side effects and modify drug release favorably. Microsponge technology has many favorable characteristics, which make it a versatile drug delivery vehicle. Microsponge Systems are based on microscopic, polymer-based microspheres that can suspend or entrap a wide variety of substances, and can then be incorporated into a formulated product such as a gel, cream, liquid or powder. The outer surface is typically porous, allowing a sustained flow of substances out of the sphere. Microsponges are porous, polymeric microspheres that are used mostly for topical use and have recently been used for oral administration. Microsponges are designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects, and modify drug release. PMID- 22247860 TI - Ocular inserts - Advancement in therapy of eye diseases. AB - The ocular insert represents a significant advancement in the therapy of eye disease. Ocular inserts are defined as sterile, thin, multilayered, drug impregnated, solid or semisolid consistency devices placed into the cul-de-sac or conjuctival sac, whose size and shape are especially designed for ophthalmic application. They are composed of a polymeric support that may or may not contain a drug. The drug can later be incorporated as dispersion or a solution in the polymeric support. They offer several advantages as increased ocular residence and sustained release of medication into the eye. The insert includes a body portion sized to position within a lachrymal canaliculus of the eyelid. The inserts are classified according to their solubility as insoluble, soluble, or bioerodible inserts. The release of drug from the insert depends upon the diffusion, osmosis, and bioerosion of the drug, and this article is an attempt to present a brief about this newer drug delivery system. PMID- 22247861 TI - Male hypogonadism: Symptoms and treatment. AB - Male hypogonadism is a condition in which the body does not produce enough of the testosterone hormone; the hormone that plays a key role in masculine growth and development during puberty. There is a clear need to increase the awareness of hypogonadism throughout the medical profession, especially in primary care physicians who are usually the first port of call for the patient. Hypogonadism can significantly reduce the quality of life and has resulted in the loss of livelihood and separation of couples, leading to divorce. It is also important for doctors to recognize that testosterone is not just a sex hormone. There is an important research being published to demonstrate that testosterone may have key actions on metabolism, on the vasculature, and on brain function, in addition to its well-known effects on bone and body composition. This article has been used as an introduction for the need to develop sensitive and reliable assays for sex hormones and for symptoms and treatment of hypogonadism. PMID- 22247862 TI - Recent trends in the impurity profile of pharmaceuticals. AB - Various regulatory authorities such as the International Conference on Harmonization (ICH), the United States Food and Drug administration (FDA), and the Canadian Drug and Health Agency (CDHA) are emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical Ingredients (APIs). The various sources of impurity in pharmaceutical products are - reagents, heavy metals, ligands, catalysts, other materials like filter aids, charcoal, and the like, degraded end products obtained during ? after manufacturing of bulk drugs from hydrolysis, photolytic cleavage, oxidative degradation, decarboxylation, enantiomeric impurity, and so on. The different pharmacopoeias such as the British Pharmacopoeia, United State Pharmacopoeia, and Indian Pharmacopoeia are slowly incorporating limits to allowable levels of impurities present in APIs or formulations. Various methods are used to isolate and characterize impurities in pharmaceuticals, such as, capillary electrophoresis, electron paramagnetic resonance, gas-liquid chromatography, gravimetric analysis, high performance liquid chromatography, solid-phase extraction methods, liquid-liquid extraction method, Ultraviolet Spectrometry, infrared spectroscopy, supercritical fluid extraction column chromatography, mass spectrometry, Nuclear magnetic resonance (NMR) spectroscopy, and RAMAN spectroscopy. Among all hyphenated techniques, the most exploited techniques for impurity profiling of drugs are Liquid Chromatography (LC)-Mass Spectroscopy (MS), LC-NMR, LC-NMR-MS, GC-MS, and LC-MS. This reveals the need and scope of impurity profiling of drugs in pharmaceutical research. PMID- 22247863 TI - A comprehensive review on Nymphaea stellata: A traditionally used bitter. AB - Nymphaea stellata Willd. (Syn. Nymphaea nouchali Burman f.) (Nymphaeaceae) is an important and well-known medicinal plant, widely used in the Ayurveda and Siddha systems of medicines for the treatment of diabetes, inflammation, liver disorders, urinary disorders, menorrhagia, blenorrhagia, menstruation problem, as an aphrodisiac, and as a bitter tonic. There seems to be an agreement between the traditional use and experimental observations, such as, hepatoprotective, anti inflammatory, and particularly antidiabetic activity. Nymphayol, a steroid isolated from the flowers has been scientifically proved to be responsible for the traditionally claimed antidiabetic activity; it reverses the damaged endocrine tissue and stimulates secretion of insulin in the beta-cells. However, taking into account the magnitude of its traditional uses, the studies conducted are still negligible. This review is an attempt to provide the pharmaceutical prospective of Nymphaea stellata. PMID- 22247864 TI - Synthesis and anti-microbial screening of novel schiff bases of 3-amino-2-methyl quinazolin 4-(3H)-one. AB - In the present study, novel Schiff bases were synthesized by condensation of 3 amino-2-methyl quinazolin-4-(3H)-ones with different aromatic aldehydes. The 3 amino-2-methyl quinazolin-4-(3H)-one was synthesized from anthranilic acid via the 2-methyl benzoxazin-4-one. The chemical structures of the synthesized compounds were confirmed by means of Infrared (IR), (1)H-NMR, (13)C-NMR, Mass spectral, and Elemental analysis. These compounds were screened for anti bacterial (Staphylococcus aureus ATCC 9144, Staphylococcus epidermidis ATCC 155, Micrococcus luteus ATCC 4698, Bacillus cereus ATCC 11778, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 2853, and Klebsiella pneumoniae ATCC 11298)) and anti-fungal (Aspergillus niger ATCC 9029 and Aspergillus fumigatus ATCC 46645) activities, using the paper disk diffusion technique. The minimum inhibitory concentrations (MIC) of the compounds were also determined by the agar streak dilution method. Most of the synthesized compounds exhibited significant anti-bacterial and anti-fungal activities. Among the synthesized compounds, 3-(4 hydroxy benzylideneamino)-2-methyl quinazolin-4(3H)-one 4g and 4c was found to exhibit the highest anti-bacterial activity and 3-(4-hydroxy-3-methoxy benzylideneamino)-2-methyl quinazolin-4(3H)-one 4k exhibited the highest anti fungal activity. PMID- 22247865 TI - Development, characterization and solubility study of solid dispersions of Cefuroxime Axetil by the solvent evaporation method. AB - Cefuroxime Axetil (Poorly water soluble drug), when prepared as solid dispersion showed improved solubility and dissolution. Therefore, the main purpose of this investigation was to increase the solubility and dissolution rate of Cefuroxime Axetil by the preparation of its solid dispersion with urea, using the solvent evaporation method. Physical mixtures and solid dispersions of Cefuroxime Axetil were prepared by using urea as a water-soluble carrier in various proportions (1:1, 1:2, 1:3, 1:4, 1:5, 1:6, and 1:7 by weight), by employing the solvent evaporation method. The drug release profile was studied and it was found that the dissolution rate and the dissolution parameters of the drug from the physical mixture as well as solid dispersion were higher than those of the intact drug. The Fourier Transform Infrared (FTIR) spectra revealed no chemical incompatibility between the drug and urea. Drug-polymer interactions were investigated using differential scanning calorimetry (DSC) and Powder X-Ray Diffraction (PXRD). PMID- 22247866 TI - Assessment of the antidiabetic potential of Cassia grandis using an in vivo model. AB - The aqueous and ethanolic extracts of C. grandis (Family: Leguminosae) were evaluated for antidiabetic activity by a glucose tolerance test, in normal rats and alloxan-induced diabetic rats. The aqueous and ethanolic extracts showed that they significantly lowered the blood glucose levels to normal in the glucose tolerance test. In alloxan-induced diabetic rats the maximum reduction in blood glucose was observed after three hours, at a dose level of 150 mg/kg of body weight. The percentage of protection given by the aqueous and ethanolic extracts was 32.72 and 46.42%, respectively. In the long-term treatment of alloxan-induced diabetic rats, the degree of protection was determined by measuring the blood glucose, cholesterol, and triglycerides on the tenth day. Both the extracts showed a significant antidiabetic activity comparable to that of glibenclamide. These results showed that the Cassia grandis possessed significant antidiabetic activity. PMID- 22247867 TI - Design and development of hydrogel nanoparticles for mercaptopurine. AB - Hydrogel nanoparticles have gained attention in recent years as they demonstrate the features and characters of hydrogels and nanoparticles at the same time. In the present study chitosan and carrageenan have been used, as hydrogel nanoparticles of mercaptopurine are developed using natural, biodegradable, and biocompatible polymers like chitosan and carrageenan. As these polymers are hydrophilic in nature, the particles will have a long life span in systemic circulation. Hydrogel nanoparticles with mercaptopurine is form an antileukemia drug by the counter polymer gelation method. Fourier-Transform Infrared (FT-IR) studies have shown a compatibility of polymers with the drug. The diameter of hydrogel nanoparticles was about 370 - 800 nm with a positive zeta potential of 26 - 30 mV. The hydrogel nanoparticles were almost spherical in shape, as revealed by scanning electron microscopy (SEM). Drug loading varied from 9 to 17%. Mercaptopurine released from the nanoparticles at the end of the twenty fourth hour was about 69.48 - 76.52% at pH 7.4. The drug release from the formulation was following zero order kinetics, which was evident from the release kinetic studies and the mechanism of drug release was anomalous diffusion, which indicated that the drug release was controlled by more than one process. PMID- 22247868 TI - Evaluation of Spinacia oleracea L. leaves mucilage as an innovative suspending agent. AB - The present study was undertaken to evaluate the mucilage isolated from Spinacia oleracea L. leaves, commonly named spinach (family: Amaranthaceae) as an innovative suspending agent. Zinc oxide suspensions (20% w/v) were prepared using the mucilage of S. oleracea L. leaves as a suspending agent, and it was evaluated for its stability by using parameters like, sedimentation profile, degree of flocculation, and redispersibility. The effect of the tested mucilage on the suspension was compared with various commonly used suspending agents, such as, tragacanth, bentonite, and sodium carboxymethyl cellulose (NaCMC) at concentrations of 0.5, 1.0, and 2.0% w/v. The results obtained indicated that the mucilage of S. oleracea L. leaves could be used as a suspending agent, and the performance was found to be superior to both tragacanth and bentonite. PMID- 22247869 TI - Synthesis, characterization, and analgesic activity of novel schiff base of isatin derivatives. AB - In the present study, a series of novel Schiff bases of isatin [5a-5l] were synthesized by condensation of imesatin with different aromatic aldehydes. The imesatins were synthesized by the reaction of isatin with p-phenylenediamine. The chemical structures of the synthesized compounds were confirmed by means of Infrared (IR), Mass spectroscopy, and Elemental analysis. These compounds were screened for the analgesic activity by the tail-immersion method at a dose of 200 mg/kg body weight. Among the tested compounds 3-(4-(4-hydroxy-3 methoxylbenzylideneamino) phenylimino) indoline-2-one (5i) exhibited better analgesic activity when compared to standard pentazocine. From the above mentioned results it may be concluded that compounds containing electron-donating groups exhibit better analgesic activity than the electron-withdrawing groups. PMID- 22247870 TI - Spectrophotometric methods for the determination of letrozole in bulk and pharmaceutical dosage forms. AB - Ultraviolet (UV), first derivative, second derivative, and AUC-spectrophotometric methods for the determination of letrozole in pharmaceutical formulations have been developed. For UV-spectrophotometry, the standard solutions were measured at 240.0 nm. The linearity ranges were found to be 0.25-20.0 MUgml(-1) in methanol and the regression equation was A=1.20*10(-1)C+2.22*10(-2)(r(2)=0.9994). For the first derivative spectrophotometry, the response (dA/dlambda) of standard solutions was measured at 224.0 nm. The calibration curve was constructed by plotting dA/dlambda values against concentrations 0.25-20.0 MUgml(-1), of letrozole. The regression equation of the linear calibration graph was calculated as D(1)=3.89*10(-3)C+1.85*10(-4)(r(2)=0.9987). For the second derivative spectrophotometry, the response (d(2)A/dlambda(2)) of standard solutions was measured at 241.0 nm. The calibration curve was constructed by plotting d(2)A/dlambda(2) values against concentrations 0.5-20.0 MUgml(-1) of letrozole standards in methanol. The regression equation of the linear calibration graph was calculated as D(2)=-1.59*10(-3)C-4.66*10(-4)(r(2)=0.9985). The AUC spectrophotometric method was based on the calculation of Area under Curve (AUC), for analysis of letrozole in the wavelength range of 235.0-245.0 nm. The calibration curve was constructed by plotting AUC values against concentrations 0.25-20.0 MUgml(-1), of letrozole. The regression equation of the linear calibration graph was calculated as AUC=1.132C+0.2153 (r(2)=0.9994). The methods were validated by following the analytical performance parameters suggested by the International Conference on Harmonization (ICH). All validation parameters were within the acceptable range. The developed methods were successfully applied to estimate the amount of letrozole in pharmaceutical formulations. PMID- 22247871 TI - Determination of pregabalin in human plasma by electrospray ionisation tandem mass spectroscopy. AB - A rapid, precise, specific, and accurate Electrospray Ionisation Tandem Mass Spectrometry (ESI-MS / MS) method has been developed and subsequently validated, for the determination of pregabalin (PB) in human plasma. Gabapentin (GB) was used as the internal standard. PB and GB were extracted from the plasma using a combination of deproteinization, using 0.1% formic acid and liquid-liquid extraction, using methylene chloride. PB and GB were separated using the Hypurity advance column (50 mm * 4.6 mm, 5 MUm) and mobile phase, consisting of methanol : 0.1% formic acid (80:20 v / v). PB was determined by using ESI-MS / MS in positive ion mode, with the help of the API 2000 spectrophotometer, operated in a multiple reaction monitoring mode. The parent-to-product ion combination of m / z 160.2->55.1 and 172.2->95.0 was used to quantify PB and GB, respectively. The assay was validated in the concentration range of 99.79 - 4019.90 ng / mL for PB. The limit of quantification (LOQ) was identifiable and reproducible at 99.79 ng / mL. The method has been successfully applied to study the pharmacokinetics of PB in healthy male volunteers. PMID- 22247872 TI - Practice of rational drug uses in a rural area of 24 pgs(s) in West Bengal. AB - Rational drug use is a function of prescription practices having medical, social, and economic implications. A household level cross-sectional study was undertaken to determine the prescribing practices and extent of rational therapy in the rural area of 24 pgs (s) South district. Following multistage stratified random sampling, 250 households were selected for the study from 24 pgs South, West Bengal, India. Medical care received by morbid persons was noted as per prescription details, wherever available. The results indicate that of the total of 485 morbid episodes, 302 were treated at some healthcare facility and prescriptions were available for 137 (45.36%) only. Injection use was seen in 9.49% of the prescriptions. In all, 29.20% prescriptions contained at least one antibiotic. This observation was more or less the same among the private and public practitioners (34%). The average number of drugs found was 3.153 per prescription. Overall 63.51% prescriptions were found to be irrational. The prescribing practices and use of drugs have been found to be truly unsatisfactory. PMID- 22247873 TI - The miracle of IVF. PMID- 22247874 TI - 'Journal of advanced pharmaceutical technology & research'. PMID- 22247875 TI - Anticounterfeit packaging technologies. AB - Packaging is the coordinated system that encloses and protects the dosage form. Counterfeit drugs are the major cause of morbidity, mortality, and failure of public interest in the healthcare system. High price and well-known brands make the pharma market most vulnerable, which accounts for top priority cardiovascular, obesity, and antihyperlipidemic drugs and drugs like sildenafil. Packaging includes overt and covert technologies like barcodes, holograms, sealing tapes, and radio frequency identification devices to preserve the integrity of the pharmaceutical product. But till date all the available techniques are synthetic and although provide considerable protection against counterfeiting, have certain limitations which can be overcome by the application of natural approaches and utilization of the principles of nanotechnology. PMID- 22247876 TI - Niosome: A future of targeted drug delivery systems. AB - Over the past several years, treatment of infectious diseases and immunisation has undergone a revolutionary shift. With the advancement of biotechnology and genetic engineering, not only a large number of disease-specific biological have been developed, but also emphasis has been made to effectively deliver these biologicals. Niosomes are vesicles composed of non-ionic surfactants, which are biodegradable, relatively nontoxic, more stable and inexpensive, an alternative to liposomes. This article reviews the current deepening and widening of interest of niosomes in many scientific disciplines and, particularly its application in medicine. This article also presents an overview of the techniques of preparation of niosome, types of niosomes, characterisation and their applications. PMID- 22247877 TI - Mucoadhesive drug delivery system: An overview. AB - Mucoadhesive drug delivery systems interact with the mucus layer covering the mucosal epithelial surface, and mucin molecules and increase the residence time of the dosage form at the site of absorption. The drugs which have local action or those which have maximum absorption in gastrointestinal tract (GIT) require increased duration of stay in GIT. Thus, mucoadhesive dosage forms are advantageous in increasing the drug plasma concentrations and also therapeutic activity. In this regard, this review covers the areas of mechanisms and theories of mucoadhesion, factors influencing the mucoadhesive devices and also various mucoadhesive dosage forms. PMID- 22247878 TI - Comparative pharmacognostical investigation on four ethanobotanicals traditionally used as Shankhpushpi in India. AB - People in Indian region often apply Shankhpushpi and other Sanskrit-based common name to Evolvulus alsinoides, Convolvulus pluricaulis, Canscora decussata, and Clitorea ternatea. These are pre-European names that are applied to a medicinal plant. Before the establishment of British rule, like the other books, ayurvedic treatises were also hand written. This might be one of the reasons due to which ayurveda could not stand parallel to the western medicine and an ambiguity is reflected in the interpretation of names and description of drugs found in the books like Charaka Samhita and Sushruta Samhita. The most widespread application of Shankhpushpi is for mental problems, but they have been considered for an array of other human maladies. The present investigation deals with the comparative pharmacognostical evaluation of four ethanobotanicals of Shankhpushpi. A comparative morphoanatomy of the root, stem, and leaves has been studied with the aim to aid pharmacognostic and taxonomic species identification. Various physicochemical, morphological, histological parameters, comparative high performance thin-layer chromatography (HPTLC), and comparative high-performance liquid chromatography (HPLC), chromatogram of methanolic extract presented in this communication may serve the purpose of standard parameters to establish the authenticity of commercialized varieties and can possibly help to differentiate the drug from the other species. All the parameters were studied according to the WHO and pharmacopoeial guidelines. PMID- 22247879 TI - Synthesis and biological evaluation of formazan derivatives. AB - The formazan derivatives (FM1-FM5) were synthesized by the reaction of benzaldehyde phenylhydrazone with substituted aromatic and hetero aromatic amines. The structures of the synthesized compounds were then elucidated using UV, IR, (1)H NMR and mass spectral data. The synthesized derivatives were screened for anticonvulsant, antibacterial and antiviral activities. All the compounds showed remarkable antibacterial activity at 250 MUg/ml, but FM4 and FM3 did not show any inhibition on Staphylococcus aureus and Vibriocholera, respectively. All the compounds showed significant anticonvulsant effect at 100 mg/kg p.o. and the experimental data were statistically significant at P<0.001 level. But none of the compounds was effective against Japanese encephalitis virus. PMID- 22247880 TI - Synthesis and antimalarial evaluation of some 4-quinazolinone derivatives based on febrifugine. AB - A series of 2-substituted and 2,3-substituted quinazolin -4(3H)-one derivatives were designed and synthesized based on the structure of febrifugine. The structures of the new compounds were confirmed by spectral analysis. The in vivo biological activity test results indicated that those compounds exhibited antimalarial activities against Plasmodium berghei in mice, at a dose of 5 mg/kg. Compared to Chloroquine and Artemisinin, these compounds have the advantages of shorter synthetic routes and consequently are highly cost effective in nature. PMID- 22247881 TI - Detachment and recovery index: A new parameter measuring powder compressibility. AB - This investigation introduces a simple and reliable approach to measure the compressibility of some direct compression excipients in tablet systems made from compressible components. The claim made here is that: the total reduction, DeltaL(T), in the thickness of a tablet batch due to compression at a confined machine settings is the integral sum of small reductions generated by the compressible components in the batch. The reduction value, DeltaL(E), generated by a single or a blend of excipients in a batch could be calculated and was found to correlate to its concentration, C, by the relation: DeltaL(E) = A(E).C(x). The constants AE and x concern the reduction tendency, RT, of the excipient particles due to compression, and detachment and recovery index (DRI), respectively. Some physicomechanical parameters characterizing the compression behavior of an excipient in a tablet batch could be determined and were found to be functions of the determine DRI of the excipient in the batch. PMID- 22247882 TI - Analgesic and antipyretic activities of Momordica charantia Linn. fruits. AB - Plant Momordica charantia Linn. belongs to family Cucurbitaceae. It is known as bitter gourd in English and karela in Hindi. Earlier claims show that the plant is used in stomachic ailments as a carminative tonic; as an antipyretic and antidiabetic agent; and in rheumatoid arthritis and gout. The fruit has been claimed to contain charantin, steroidal saponin, momordium, carbohydrates, mineral matters, ascorbic acid, alkaloids, glucosides, etc. The ethanolic extract of the fruit showed the presence of alkaloids, tannins, glycosides, steroids, proteins, and carbohydrates. The present study was carried out using acetic acid induced writhing and tail-immersion tests in mice, while yeast-induced pyrexia in rats. The ethanolic extracts (250 and 500 mg/kg, po.) showed an analgesic and antipyretic effect, which was significantly higher than that in the control rats. The observed pharmacological activities provide the scientific basis to support traditional claims as well as explore some new and promising leads. PMID- 22247883 TI - Antibacterial activity of Croton roxburghii Balak. against the enteric pathogens. AB - In this study, the antibacterial activity of crude (aqueous and alcoholic) extracts of the bark and leaf of Croton roxburghii Balak. (Euphorbiaceae) was tested against enteric pathogens causing urinary tract infection (UTI) using the agar cup method, minimum inhibitory concentration (MIC), time kill kinetics and synergy study. The ethanol extract exhibited a significant and broad spectrum of inhibition as compared to the aqueous extract of both the bark and leaf. The highest antibacterial activity was observed against Staphylococcus aureus followed by enteropathogenic and enterotoxigenic Escherichia coli. The diameter of inhibition zones varied from 10 to 18 mm for both aqueous and alcoholic extracts. The MIC value ranged from 356 to 625 MUg/ml. This could justify the traditional use of this plant in dysentery and other infections. PMID- 22247884 TI - Pharmacogenetics: The future medicine. PMID- 22247885 TI - Journal of advanced pharmaceutical technology and research. PMID- 22247886 TI - Current scenario in the field of pharmacy. PMID- 22247887 TI - Biological activities and medicinal properties of Cajanus cajan (L) Millsp. AB - Cajanus cajan (L) Millsp. (Sanskrit: Adhaki, Hindi: Arhar, English: Pigeon pea, Bengali: Tur) (family: Fabaceae) is the most important grain legume crop of rain fed agriculture in semi-arid tropics. It is both a food crop and a cover/forage crop with high levels of proteins and important amino acids like methionine, lysine and tryptophan. During the last few decades extensive studies have been carried out regarding the chemistry of C. cajan and considerable progress has been achieved regarding its biological activities and medicinal applications. This review article gives an overview on the biological activities of the compounds isolated, pharmacological actions and clinical studies of C. cajan extracts apart from its general details. PMID- 22247888 TI - A review on mucoadhesive polymer used in nasal drug delivery system. AB - This update review is on mucoadhesive polymers used in nasal dosage forms. The nasal mucosa provides a potentially good route for systemic drug delivery. One of the most important features of the nasal route is that it avoids first-pass hepatic metabolism, thereby reducing metabolism. The application of mucoadhesive polymers in nasal drug delivery systems has gained to promote dosage form residence time in the nasal cavity as well as improving intimacy of contact with absorptive membranes of the biological system. The various new technology uses in development of nasal drug delivery dosage forms are discussed. The various dosage forms are vesicular carriers (liposome, noisome), nanostructured particles, prodrugs, in situ gelling system with special attention to in vivo studies. PMID- 22247889 TI - Fast disintegrating tablets: Opportunity in drug delivery system. AB - Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Oral drug delivery remains the preferred route for administration of various drugs. Recent developments in the technology have prompted scientists to develop FDTs with improved patient compliance and convenience. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. The popularity and usefulness of the formulation resulted in development of several FDT technologies. FDTs are solid unit dosage forms, which disintegrate or dissolve rapidly in the mouth without chewing and water. FDTs or orally disintegrating tablets provide an advantage particularly for pediatric and geriatric populations who have difficulty in swallowing conventional tablets and capsules. This review describes various formulations and technologies developed to achieve fast dissolution/dispersion of tablets in the oral cavity. In particular, this review describes in detail FDT technologies based on lyophilization, molding, sublimation, and compaction, as well as approaches to enhancing the FDT properties, such as spray drying and use of disintegrants. In addition, taste masking technologies, experimental measurements of disintegration times, and dissolution are also discussed. PMID- 22247891 TI - Phytochemical investigation and diuretic activity of Cyclea peltata leaf extracts. AB - Ayurvedic system of medicine is well known for treating renal problems. A vast number of medicinal plants mentioned in Ayurvedic system of medicine are known to possess diuretic properties. Present study reports the preliminary phytochemical investigation of petroleum ether and ethanolic extracts of Cyclea peltata and their diuretic activity. Preliminary phytochemical screening reveals the presence of phytosterols and alkaloids as major phytoconstituents in petroleum ether extract. The ethanolic extract showed the presence of alkaloids, flavonoids, tannins, diterpenes and saponins. Pharmacological investigation revealed that ethanolic extract of C. peltata leaves possessed significant diuretic activity in a given dose of 200 and 300 mg/kg body weight (Diuretic action 1.7 and 2.6, respectively). Where as petroleum ether extract has shown moderate diuresis at a dose of 300 mg/kg body weight (Diuretic action 1.1). The present study justifies the use of C. peltata in the Ayurvedic system of medicine as a diuretic drug. PMID- 22247890 TI - The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARalpha, PPARgamma, and PPARbeta/delta. Activation of PPAR-alpha reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-gamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-beta/delta enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. The present review critically analyzes the protective and detrimental effect of PPAR agonists in dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. PMID- 22247892 TI - Development and evaluation of aceclofenac-loaded mucoadhesive microcapsules. AB - Microencapsulation is an accepted process used to achieve controlled release and drug targeting for many years. Mucoadhesion has been a topic of interest in the design of drug delivery systems to prolong its intestinal residence time. Mucoadhesion facilitates the intimate contact of the dosage form with the underlying absorption surface for improved bioavailability of drugs. Aceclofenac is a newer nonsteroidal anti-inflammatory drug (NSAID) having short biological half-life of 4-4.3 h, and therefore a sustained release medication is required to get prolonged effect and to reduce fluctuations in drug plasma concentration levels. Aceclofenac microcapsules were prepared employing sodium alginate as the coat material in combination with some mucoadhesive polymers such as (hydroxypropyl methyl cellulose) HPMC, (sodium carboxymethyl cellulose) Sod. CMC, Carbopol and methyl cellulose (MC) (drug:SA:polymer at ratios 2:2:1, 2:3:1 and 2:4:1), following orifice-ionic gelation technique. Infrared (IR) spectroscopy, differential scanning calorimetry and X-ray diffraction studies proved the compositions were compatible, without any interaction between the drug and excipients. The prepared microcapsules were evaluated for various physical and release parameters. The resulted microcapsules were found to be discrete and spherical in scanning electron microscopy studies and free flowing in rheological studies. The size of microcapsules was found to be around 757.44 +/- 5.201 MUm to 814.46 +/- 6.586 MUm. The microencapsulation efficiency was found to be higher in HPMC than in Carbopol > MC > Sod. CMC containing formulations, but the swelling index was found to be higher in Sod. CMC formulations. The microcapsules with HPMC exhibited good mucoadhesive property in the in vitro wash-off test. In vitro drug release studies of aceclofenac microcapsules were carried out up to 24 h and they followed zero-order release kinetics with Super Case II mechanism. The drug release from the microcapsules was sustained over a prolonged period with greater retardation in drug:SA:HPMC (2:4:1) containing microcapsules and this proved to be the best formulation. PMID- 22247893 TI - Neuropharmacological properties of Mikania scandens (L.) Willd. (Asteraceae). AB - Mikania scandens (L.) Willd. (Asteraceae), known as climbing hemp weed in English, is a herbaceous climbing vine grown as a weed throughout the plains of the Indian subcontinent. The present study evaluated some neuropharmacological properties of hydroalcoholic extract of aerial parts from M. scandens (HAMS) in experimental animal models. HAMS (at 250 and 500 mg/kg body weight, i.p.) was evaluated for central antinociceptive activity by tail flick method. Locomotor depressant activity was measured by means of an actophotometer. Skeletal muscle relaxant effect was evaluated by using rotarod apparatus and sedative potentiating property by phenobarbitone-induced sleep potentiation study. The results of the present study revealed significant (P<0.001) and dose-dependent central antinociceptive, locomotor depressant, muscle relaxant, and sedative potentiating effects of HAMS, demonstrating its depressant action on the central nervous system (CNS). From the present study, it can be concluded that the aerial parts of M. scandens possessed prominent depressant action on the CNS, as manifested by the important neuropharmacological properties in mice. PMID- 22247894 TI - Antioxidant potential of hydro-methanolic extract of seed of Caesalpinia bonduc: An in vitro study. AB - It is well known that the over production of reactive oxygen species is harmful for living organisms and it damages major cellular constituents such as DNA, protein, and lipid. At present, searching of new plant sources having free radical scavenging activity is an important field of research in phytomedicine as natural products are safe and relatively low cost. In this respect, attention has been focused to evaluate the antioxidant potential of hydro-methanolic extract of seed of Caesalpinia bonduc (Caesalpenacae) using different in vitro models. To evaluate the antioxidant activity, extract was examined on 2, 2-diphenyl-1 picrylhydrazyl radical scavenging effect, scavenging of hydrogen peroxide, hydroxyl radical scavenging potential, and anti-lipid peroxidation activity by biochemical methods. Total phenol and flavonoids contents in the said extract were measured biochemically as per standard methods. Results were compared with butylated hydroxyl toluene and alpha-tocopherol. Results indicated that hydro methanolic extract has strong scavenging activity on 2, 2-diphenyl-1 picrylhydrazyl radical with IC(50) value 157.4 MUg/ml, hydroxyl radical with IC(50) value 61.9 MUg/ml and hydrogen peroxide with IC(50) value 64.32 MUg/ml. Hydro-methanolic extract also showed notable inhibition in lipid peroxidation having IC(50) value 58.87 MUg/ml. Phytochemical study focused that the extract is rich in phenolic compounds (24.66 mg gallic acid equivalent/g dried extract) and flavonoids (136.65 mg quercetin equivalent/g dried extract). Findings of the experiment indicated that the hydro-methanolic extract of seed of Caesalpinia bonduc is a source of natural antioxidants. PMID- 22247895 TI - Formulation and evaluation of fast dissolving tablets of cinnarizine using superdisintegrant blends and subliming material. AB - The aim of this investigation was to develop fast dissolving tablet of cinnarizine. A combination of super disintegrants, i.e., sodium starch glycolate (SSG) and crosscarmellose sodium (CCS) were used along with camphor as a subliming material. An optimized concentration of camphor was added to aid the porosity of the tablet. A 3(2) full factorial design was applied to investigate the combined effect of two formulation variables: Amount of SSG and CCS. Infrared (IR) spectroscopy was performed to identify the physicochemical interaction between drug and polymer. IR spectroscopy showed that there is no interaction of drug with polymer. In the present study, direct compression was used to prepare the tablets. The powder mixtures were compressed into tablet using flat face multi punch tablet machine. Camphor was sublimed from the tablet by exposing the tablet to vacuum drier at 60 degrees C for 12 hours. All the formulations were evaluated for their characteristics such as average weight, hardness, wetting time, friability, content uniformity, dispersion time (DT), and dissolution rate. An optimized tablet formulation (F 9) was found to have good hardness of 3.30 +/- 0.10 kg/cm(2), wetting time of 42.33 +/- 4.04 seconds, DT of 34.67 +/- 1.53 seconds, and cumulative drug release of not less than 99% in 16 minutes. PMID- 22247896 TI - Obesity and metabolic syndrome in Korea. AB - In Korea, a person with a body mass index (BMI) >=25 kg/m(2) is considered obese, and a person with a BMI >=30 kg/m(2) is classified as severely obese. Central obesity is defined as a waist circumference >=90 cm for Korean men and >=85 cm for Korean women. Recent epidemiologic data show that the prevalence of severe obesity and metabolic syndrome is steadily increasing. These epidemics increased morbidity and mortality of type 2 diabetes, cardiovascular diseases, and obesity related cancers such as breast, colorectal, and other cancers in Korea. Decreased physical activity, increased fat and alcohol consumption, heavy smoking, and stress/depressed mood are the primary modifiable life-style risk factors for Koreans. Recently, public health interventions to encourage life-style changes have shown promising results in reducing the prevalence of severe obesity and metabolic syndrome. PMID- 22247897 TI - Costs of diabetes mellitus in Korea. AB - Outcome research focusing on the economics of the medical field began in the mid 1990s and has included studies about costs, cost effectiveness, and policies. According to the American Diabetes Association, the total estimated cost of diabetes in 2007 was $174 billion. The economic burden of patients with diabetes in Canada is expected to be about $12.2 billion in 2010. Recent Korean studies have analyzed the expenses associated with type 2 diabetes for patients in selected general hospitals. Type 2 diabetic patients without complications cost approximately 1,184,563 won (the equivalent of US $1,184) per patient for healthcare annually. In contrast, patients with microvascular disease due to diabetic complications cost up to 4.7 times that amount, and patients with macrovascular disease incur up to 10.7 times the annual costs for patients without diabetic complications. Diabetic complications ultimately impact the quality of life for patients and patient mortality, and are associated with higher direct medical expenses for patients. To avoid increased medical costs, appropriate management techniques must be implemented to ensure timely care for patients with diabetes. PMID- 22247898 TI - Epidemiology of micro- and macrovascular complications of type 2 diabetes in Korea. AB - The prevalence of diabetes in Korea has increased six- to sevenfold over the past 40 years with its complications becoming major causes of morbidity and mortality. The rate of death among patients with diabetes is about twice as high as that among persons without diabetes and the most common cause of death is cardiovascular disease (30.6%). Despite the seriousness of diabetic complications, 30 to 70% of patients receive inadequate care, and only 40% of treated diabetic patients achieve the optimal control with HbA1c level <7% in Korea. In 2006, over 30 to 40% of patients with diabetes have microvascular complications and around 10% of them have macrovascular complications from our national data. Despite there are some debates about intensive glycemic control resulting in the deterioration of macrovascular complication, multifactorial treatment approaches including proper glycemic control are important to prevent diabetic complications. There have been needs for finding proper biomarkers for predicting diabetic complications properly but we still need more longitudinal studies to find this correlation with causal relationship. In this article, we wanted to review the recent status of micro- and macrovascular complications of type 2 diabetes in Korea from integration of many epidemiologic studies. PMID- 22247899 TI - Low density lipoprotein cholesterol target goal attainment rate in korean patients with diabetes. PMID- 22247900 TI - Effect on Glycemic, Blood Pressure, and Lipid Control according to Education Types. AB - BACKGROUND: Diabetes self-management education and reinforcement are important for effective management of the disease. We investigated the effectiveness of interactive small-group education on glycemic, blood pressure, and lipid levels. METHODS: For this study, 207 type 2 diabetes patients with suboptimal glycemic control (HbA1c levels >6.5%) were enrolled. The conventional education group received an existing education program from April to November in 2006, and the interactive education group received a new small-group education program from December 2006 to July 2007. The two groups were comparatively analyzed for changes in blood sugar, glycated hemoglobin, lipid, and blood pressure at baseline, 3, 6, and 12 months and the proportion of patients achieving target goals at 12 months. RESULTS: After 12 months of follow-up, HbA1c levels in the interactive education group were significantly lower than in the conventional education group (6.7% vs. 6.4%, P<0.001). Fasting and 2 hour postprandial glucose concentrations, total cholesterol, and low density lipoprotein cholesterol were significantly lower in the interactive education group than in the conventional education group. The proportion of patients that achieved target goals was significantly higher in the interactive education group. CONCLUSION: The small group educational method improved and re-established the existing group educational method. This finding suggests that the importance of education appears to be related to the method by which it is received rather than the education itself. Thus, the use of small-group educational methods to supplement existing educational methods established for diverse age levels should be considered in the future. PMID- 22247901 TI - The Relationship between Diabetes Mellitus and Health-Related Quality of Life in Korean Adults: The Fourth Korea National Health and Nutrition Examination Survey (2007-2009). AB - BACKGROUND: Diabetes is a major health problem in Korea. However, interest in the quality of life in patients with diabetes is low. We examined the effects of diabetes on health-related quality of life (HRQoL) and compared it with HRQoL in the general Korean population using the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) (2007-2009). METHODS: Using KNHANES IV data, we compared EuroQol (EQ)-5D and EQ-visual analogue scale (VAS) scores after adjusting for sociodemographic and psychosocial factors as well as for comorbidities (hypertension, heart disease, stroke, arthritis, and chronic renal disease). Logistic regressions were used to explore determinants for the lowest quintile HRQoL scales in the diabetes group. RESULTS: The mean age of the 14,441 enrolled subjects (6,129 men and 8,312 women) was 52.5+/-14.5 years. The mean EQ 5D and EQ-VAS scores were significantly lower in the diabetes group (EQ-5D. 0.87; EQ-VAS, 71.94) than in the non-diabetes group (EQ-5D, 0.94; EQ-VAS, 77.40) (P<0.001). Self-reported depressive symptom had a significant effect on lowering the EQ-VAS (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.1 to 2.6) in the diabetes group. Stress level had a significant effect in lowering both the EQ 5D (OR, 2.0; 95% CI, 1.3 to 2.9) and the EQ-VAS (OR, 1.9; 95% CI, 1.3 to 2.9). HbA1c, diabetes duration, and treatment modalities had no significant effect on lowering HRQoL. CONCLUSION: Diabetes was clearly associated with impaired HRQoL compared with the non-diabetic population regardless of comorbidities. Therapeutic approaches should focus much more on the subjective perception of health in patients with diabetes. PMID- 22247902 TI - The Relationship among Homocysteine, Bilirubin, and Diabetic Retinopathy. AB - BACKGROUND: Diabetic retinopathy is a common microvascular complication of diabetes mellitus (DM) and the leading cause of blindness in adults. Homocysteine, a risk factor with toxic effects on vascular endothelial cells, and bilirubin, a protectant with antioxidant and anti-inflammatory properties on the vasculature, have been reported to be linked to vaso-occlusive disorders. Therefore, the author of the present study investigated the association between the levels of plasma homocysteine and serum total bilirubin and the incidence of diabetic retinopathy as a chronic microvascular complication in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 102 patients with T2DM who visited our hospital from January 2009 to January 2010 were assessed. RESULTS: Of the 102 patients, the prevalence of diabetic retinopathy was 67 cases (65.7%) according to clinical ophthalmic examination. The duration of DM (P<0.001), age (P=0.003), fasting blood glucose (P=0.045) and urine albumin-creatinine ratio (P=0.015) in univariate analysis and plasma homocysteine level (P=0.038), duration of DM (P=0.001), and total bilirubin level (P=0.012) in multiple logistic regression analysis were statistically significantly associated with the incidence of diabetic retinopathy. CONCLUSION: The present study indicates that homocysteine and bilirubin may be useful biomarkers for increased risk of diabetic retinopathy since retinopathy in patients with T2DM was linked to higher plasma homocysteine level and decreased serum total bilirubin level. PMID- 22247903 TI - Serum cystatin C reflects the progress of albuminuria. AB - BACKGROUND: Research on the relationship between urinary albumin excretion and serum cystatin C in diabetes is restricted to cross-sectional studies. In this study, we investigated how well serial measurements of serum cystatin C level reflect changes in the urinary albumin excretion rate. METHODS: We enrolled and retrospectively collected data on 1,058 participants with type 2 diabetes who were older than 18 years and who had more than 3 years of follow-up with serial measurements of albuminuria and serum cystatin C at an outpatient clinic. RESULTS: With the use of a linear mixed model, we found that the albuminuria level for each patient over time corresponded with the annual change in serum cystatin C-based estimated glomerular filtration rate (cysC-eGFR) but did not correspond with the creatinine-based eGFR calculated by the modification of diet in renal disease formula (MDRD-eGFR). The discrepancy in the direction of the trend was smaller with cysC-eGFR than with MDRD-eGFR. CONCLUSION: Serum cystatin C level reflects the trend in albuminuria level more accurately than serum creatinine level in Korean type 2 diabetes mellitus patients. PMID- 22247904 TI - Associations between Fatness, Fitness, IGF and IMT among Obese Korean Male Adolescents. AB - BACKGROUND: The purpose of this study was to investigate the association between obesity, fitness levels and cardiovascular (CVD) risk factors, and to identify the correlation between of insulin-like growth factor (IGF)-1, IGF binding protein-3 (IGFBP-3), and carotid intima media thickness (IMT) in Korean adolescents. METHODS: A total of 225 high school males with a mean age of 16.96+/ 0.23 years participated in this study, and their fatness and fitness levels, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), blood lipids, IGF-1, IGFBP-3, and IMT were measured. RESULTS: The results showed that total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), fasting insulin, HOMA-IR, IGF-1, and IGFBP-3 levels were significantly higher in the most obese group than in the other two groups (tertiles). Muscular and cardiopulmonary fitness were negatively associated with weight, body mass index (BMI), fat mass, body fat, waist circumference (WC), fasting insulin, HOMA-IR, and IMT. IGF-1 and IGFBP-3 levels were correlated with WC, hip circumference (HC), fasting glucose, TG, HDL-C, fasting insulin, and HOMA-IR. IMT levels were significantly associated with weight, BMI, muscle mass, fat mass, percent body fat, WC, HC, systolic blood pressure, diastolic blood pressure and high-sensitivity C-reactive protein. CONCLUSION: There was a significant association between increased obesity and decreased fitness and HOMA-IR, IGF, and IMT among adolescents. PMID- 22247905 TI - Cardiovascular Risk Assessment with Vascular Function, Carotid Atherosclerosis and the UKPDS Risk Engine in Korean Patients with Newly Diagnosed Type 2 Diabetes. AB - BACKGROUND: Patients with type 2 diabetes have an increased risk of cardiovascular disease. Few studies have evaluated the cardiovascular disease (CVD) risk simultaneously using the United Kingdom Prospective Diabetes Study (UKPDS) risk engine and non-invasive vascular tests in patients with newly diagnosed type 2 diabetes. METHODS: Participants (n=380; aged 20 to 81 years) with newly diagnosed type 2 diabetes were free of clinical evidence of CVD. The 10-year coronary heart disease (CHD) and stroke risks were calculated for each patient using the UKPDS risk engine. Carotid intima media thickness (CIMT), flow mediated dilation (FMD), pulse wave velocity (PWV) and augmentation index (AI) were measured. The correlations between the UKPDS risk engine and the non invasive vascular tests were assessed using partial correlation analysis, after adjusting for age, and multiple regression analysis. RESULTS: The mean 10-year CHD and 10-year stroke risks were 14.92+/-11.53% and 4.03+/-3.95%, respectively. The 10-year CHD risk correlated with CIMT (P<0.001), FMD (P=0.017), and PWV (P=0.35) after adjusting for age. The 10-year stroke risk correlated only with the mean CIMT (P<0.001) after adjusting for age. FMD correlated with age (P<0.01) and systolic blood pressure (P=0.09). CIMT correlated with age (P<0.01), HbA1c (P=0.05), and gender (P<0.01). CONCLUSION: The CVD risk is increased at the onset of type 2 diabetes. CIMT, FMD, and PWV along with the UKPDS risk engine should be considered to evaluate cardiovascular disease risk in patients with newly diagnosed type 2 diabetes. PMID- 22247907 TI - Letter: the prevalence of peripheral arterial disease in korean patients with type 2 diabetes mellitus attending a university hospital (diabetes metab j 2011;35:543-50). PMID- 22247906 TI - Low Density Lipoprotein Cholesterol Target Goal Attainment Rate and Physician Perceptions about Target Goal Achievement in Korean Patients with Diabetes. AB - BACKGROUND: This study aims to investigate the discrepancy between clinicians' perceptions and actual achievement rates of low density lipoprotein cholesterol (LDL-C) in Korean patients with diabetes according to updated American Diabetes Association (ADA)/American College of Cardiology Foundation (ACC) recommendations. METHODS: This is a multi-center, retrospective, non interventional, observational study. Diabetic patients aged 18 years or older were eligible if they had been diagnosed with hypercholesterolemia or were receiving a lipid-lowering therapy between May 2010 and August 2010. The information was obtained by reviewing medical records and using a self-completed questionnaire to examine physician perceptions. RESULTS: A total of 2,591 subjects who satisfied the inclusion criteria were enrolled. Highest-risk and high-risk patients accounted for 61.9% and 38.1% of the patients, respectively. Although most (96.3%) underwent a statin monotherapy or a statin-based combination therapy, just 47.4% of patients attained the LDL-C target. However, the physicians' perceptions on target achievement rate (70.6%) were different from the actual results (47.4%). Many patients (65.3%) remained on the starting doses of statins, despite evidence of poor achievement of lipid goals. CONCLUSION: Only less than half of patients with diabetes attained the LDL-C goal. The surveys showed that poor physician performance might be due to the lack of recognition on ADA/ACC consensus causing a low LDL-C target attainment rate. Therefore, changes in doctor perception are needed to attain target LDL-C level and reduce cardiovascular risk in Korean patients with diabetes. PMID- 22247909 TI - Erratum: Author's Name Correction. AB - [This corrects the article on p. 431 in vol. 35, PMID: 22111032.]. PMID- 22247908 TI - Response: Association between Diabetic Polyneuropathy and Chronic Complications in Type 2 Diabetic Patients (Diabetes Metab J 2011;35:390-6). PMID- 22247910 TI - Erratum: ACKNOWLEDGMENTS. AB - [This corrects the article on p. 504 in vol. 35, PMID: 22111042.]. PMID- 22247911 TI - Erratum: Author's Name Correction. AB - [This corrects the article on p. 166 in vol. 35, PMID: 21738899.]. PMID- 22247912 TI - The role of visfatin in diabetic nephropathy. AB - As a result of the energy overload in obesity, insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together comprise the metabolic syndrome. Although the kidney becomes a victim of hyperglycemia in diabetes mellitus, recent work has shown that the abnormalities of lipid and glucose metabolism in the kidney are similarly important to those in adipose tissue. Interestingly, obesity triggers the release of adipokines such as leptin, resistin, and visfatin, and these can then be associated with the progression of diabetic nephropathy and other vascular complications. These adipokines, which are also synthesized in the kidney, appear to have an important role in renal injury associated with insulin resistance. Our studies found that visfatin is not only a surrogate marker of systemic inflammation in type 2 diabetic patients but is also up-regulated in diabetic kidney through the uptake of glucose into renal cells, which leads to the activation of the intracellular insulin signaling pathway and pro-inflammatory mechanisms. However, we also observed a beneficial effect of visfatin administration to type 2 diabetic mice. Visfatin injection improved diabetic nephropathy in vivo, in contrast to our previous in vitro study of cultured renal mesangial cells. These results suggest the possibility of multiple cross-talk between adipose tissue and kidney in the metabolic syndrome, particularly in diabetic nephropathy. Further study should be undertaken to understand the role of adipose tissue and kidney as major organs in the metabolic syndrome. PMID- 22247913 TI - Time point expression of apoptosis regulatory proteins in a photochemically induced focal cerebral ischemic rat brain. AB - Apoptosis after global or focal cerebral ischemia plays a crucial role in mediating cell death. In this study, we observed the time point expression of physiologic events involving apoptosis regulatory proteins after photochemically induced focal cerebral ischemia in Sprague-Dawley rats. Protein expression was evaluated at days 1, 3, and 7 by Western blot. Bcl-2, Bax, caspase-3, and phosphorylated Akt (pAkt) activity markedly increased in the ischemic hemisphere in a time-dependent manner, not affected. The expression of Bcl-2, Bax, and caspase-3 was dramatically changed around day 3, whereas changes in pAkt expression occurred at day 1. Differential elevation of these apoptosis regulatory proteins at various time points indicates that different modes of cell death occur in photochemically-induced focal cerebral ischemia in a rat brain. PMID- 22247914 TI - Clinical progress of epilepsy in children with tuberous sclerosis: prognostic factors for seizure outcome. AB - The incidence and outcome of epilepsy in tuberous sclerosis (TS) patients have not yet been thoroughly investigated. The aim of this study was to evaluate the clinical features and prognosis of epileptic seizures associated with TS. The medical records of 29 patients who satisfied the diagnostic criteria for TS and were followed up for at least 2 years at the Department of Pediatrics, Chonnam National University Hospital (CNUH), between January 2000 and December 2010 were reviewed. Onset age of seizure, initial electroencephalography (EEG) findings, and efficacy of treatment were evaluated. Brain imaging studies were reanalyzed to determine the number of cortical tubers and subependymal nodules present. A total of 26 (89.6%) cases presented with seizures. In the seizure-controlled group (n=9, 34.6%), the mean number of cortical tubers was 4.5 (range, 0-16) and the mean number of subependymal nodules was 6.2 (range, 0-14). Initial EEG identified epileptiform discharges in 4 (44.5%) of these cases. In the seizure sustained group (n=17, 58.6%), 10 patients had initial seizures before 1 year of age. In this group, the mean number of cortical tubers was 6.0 (range, 0-20) and the mean number of subependymal nodules was 6.0 (range, 1-11). A total of 15 (88.2%) had epileptiform discharges on their initial EEGs. In three patients who did not show any seizures during the observation period, the mean number of cortical tubers was 1.3 (range, 0-2), and the mean number of subependymal nodules was 4.6 (range, 0-13). Medical intractability of epilepsy in conjunction with TS did not correlate with age at onset of seizure, the number of cortical tubers, or subependymal nodules, but was associated with initial EEG findings. PMID- 22247915 TI - Effects of cyclic nucleotide-gated channels in vestibular nuclear neurons. AB - This study was designed to investigate the effects an 8-Br-cGMP on the neuronal activity of rat vestibular nuclear cells. Sprague-Dawley rats aged 14 to 16 days were decapitated under ether anesthesia. After treatment with pronase and thermolysin, the dissociated vestibular nuclear cells were transferred into a chamber on an inverted microscope. Spontaneous action potentials and potassium currents were recorded by standard patch-clamp techniques under current and voltage-clamp modes. Twelve vestibular nuclear cells revealed excitatory responses to 1-5 uM of 8-Br-cGMP, and 3 neurons did not respond to 8-Br-cGMP. Whole potassium currents of vestibular nuclear cells were decreased by 8-Br-cGMP (n=12). After calcium-dependent potassium currents were blocked by tetraethylammonium, the potassium currents were not decreased by 8-Br-cGMP. These experimental results suggest that 8-Br-cGMP changes the neuronal activity of vestibular nuclear cells by blocking the calcium-dependent potassium currents that underlie the afterhyperpolarization. PMID- 22247916 TI - Evaluation of metabolic syndrome in patients with chronic low back pain: using the fourth Korea national health and nutrition examination survey data. AB - The aim of this study was to investigate the frequency of the metabolic syndrome in patients with chronic lower back pain in Korea and to evaluate the differences in clinical characteristics in chronic lower back pain patients with and without metabolic syndrome. This was a cross-sectional study using data from the fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) 2008. The sample consisted of 1085 participants with chronic lower back pain. The diagnosis of metabolic syndrome was made according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the Korean Society for the Study of Obesity. The prevalence of metabolic syndrome among chronic lower back pain patients was 36.2% (30.2% male, 38.6% female). According to our results, female sex, advanced age, and high BMI were risk factors for metabolic syndrome. These results from a representative sample show that metabolic syndrome is common in chronic lower back pain patients in Korea. Clinicians managing chronic lower back pain should consider the risk factors for metabolic syndrome. PMID- 22247917 TI - Complications Following Outside-in and Inside-out Transobturator-Tape Procedures with Concomitant Gynecologic Operations. AB - This study was undertaken to compare the complications of outside-in transobturator tape procedures (TOT) and inside-out transobturator tape procedures (TVT-O) with concomitant gynecologic surgery for the treatment of female stress urinary incontinence (SUI). A retrospective review of 206 consecutive patients who underwent either TOT or TVT-O with concomitant gynecologic operations between March 2008 and February 2011 was conducted. The incidence of perioperative complications was compared. For statistical analysis, chi-squared tests were used. There were no reports of intraoperative complications such as vaginal injury or bladder perforation. Postoperative complications were noted in 23 procedures (11.2%). These included 6 cases of urinary retention (2.9%), 2 cases of vulva hematoma (1.0%), 7 cases of urinary tract infection (3.4%), 4 cases of de novo urgency (2.9%), and 4 cases of vaginal erosion (2.9%). There were no significant differences in complication rates between the two groups. Our results suggest that inside-out and outside-in procedures are simple and safe techniques that may have a low rate of complications when used with a concomitant gynecologic operation. PMID- 22247918 TI - Incomplete distal renal tubular acidosis with nephrocalcinosis. AB - We report the case of a female patient with incomplete distal renal tubular acidosis with nephrocalcinosis. She was admitted to the hospital because of acute pyelonephritis. Imaging studies showed dual medullary nephrocalcinosis. Subsequent evaluations revealed hypokalemia, hypocalcemia, hypercalciuria, and hypocitraturia with normal acid-base status. A modified tubular acidification test with NH4Cl confirmed a defect of urine acidification, which is compatible with incomplete distal tubular acidosis. We treated our patient with potassium citrate, which corrects hypokalemia and prevents further deposition of calcium salts. PMID- 22247919 TI - Hemophagocytic Lymphohistiocytosis (HLH) Associated with Plasmodium vivax Infection: Case Report and Review of the Literature. AB - Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, and pathologic findings of hemophagocytosis in the bone marrow and other tissues. HLH may be familial or associated with different types of infections, autoimmune disorders, or malignancies. Infection-associated HLH has been reported in various viral, bacterial, fungal, and parasitic infections, and case reports of parasitic infections implicated in HLH include rare cases from Plasmodium vivax infection, which occasionally affects both military personnel and civilians in Korea. We describe an unusual case of HLH resulting from Plasmodium vivax infection and review the literature. This case suggests that clinical suspicion of HLH is important when P. vivax infection is accompanied by cytopenias. Administration of antimalarial drugs may prevent irreversible end organ damage resulting from P. vivax-associated HLH. PMID- 22247920 TI - Cause of chest pain in a patient with previous myocardial infarction: look outside the heart for extracardiac mass. AB - We report a case of thymic carcinoma that was initially detected by echocardiography in an 80-year-old male who visited the emergency room for chest pain and had a history of myocardial infarction and percutaneous coronary intervention. Transthoracic echocardiography showed a huge extracardiac mass that was located in the anterior mediastinum and was diagnosed as a thymic carcinoma by biopsy. PMID- 22247921 TI - A case of urine leakage: an unusual complication after renal biopsy. AB - Renal biopsy is a crucial method in the diagnosis and treatment of acute renal failure of unknown origin, nephrotic syndrome, suspicious interstitial nephritis, and glomerulonephritis as a possible cause of hematuria or proteinuria. Complications occur in 2% to 8% of patients after percutaneous renal biopsy. Complications include gross hematuria, perirenal hematoma, arteriovenous fistula, aneurysm, injury of other organs, and urine leakage. Urine leakage as a complication after kidney biopsy is rare. We experienced a case of urine leakage into the intra-abdominal cavity after renal biopsy. PMID- 22247922 TI - A case of portal vein thrombosis by protein C and s deficiency completely recanalized by anticoagulation therapy. AB - Portal vein thrombosis (PVT) is a rare form of venous thrombosis that affects the hepatic portal vein flow, which can lead to portal hypertension. Treatment of PVT includes anticoagulants, thrombolysis, insertion of shunts, bypass surgery, and liver transplantation. Single anticoagulation therapy is not regarded as a curative treatment but can be associated with a reduction in new thrombotic episodes. We experienced a case of acute total occlusion of PVT provoked by protein C and S deficiency syndrome. PVT was completely recanalized with oral anticoagulant therapy following low molecular weight heparin therapy. PMID- 22247923 TI - Biopsychosocial pain model crippled? PMID- 22247924 TI - Topical review: cluster headache and sleep-related breathing disorders. AB - This article reviews the existing literature of the common anatomic and physiologic aspects of cluster headache and sleep-related breathing disorders to point out evidence suggesting potential therapies beneficial for both maladies. A search of PubMed, as well as relevant textbooks, was conducted using the terms cluster, headache, sleep, apnea, pain, and chronobiology to find any previously published work that may connect the two disorders. Relevant references in the literature were also investigated. As a group, cluster headache patients tend to have a higher incidence of sleep-related breathing disorders as compared to the noncluster headache population. While commonalities in anatomy and physiology exist, robust evidence linking the two disorders is currently lacking. Many people are unaware that they suffer with a sleep-related breathing disorder. The high incidence of these two disorders occurring together should prompt the clinician who treats cluster headache patients to be acutely aware that a yet undiagnosed sleep disorder may also be present. PMID- 22247925 TI - Effectiveness of low-level laser therapy in temporomandibular disorders: a systematic review and meta-analysis. AB - AIM: To assess the scientific evidence on the efficacy of low-level laser therapy (LLLT) in the treatment of temporomandibular disorders (TMD). METHODS: The databases of PubMed, Science Direct, Cochrane Clinical Trials Register, and PEDro were manually and electronically searched up to February 2010. Two independent reviewers screened, extracted, and assessed the quality of the publications. A meta-analysis- was performed to quantify the pooled effect of LLLT on pain and function in patients with chronic TMD. RESULTS: The literature search identified 323 papers without overlap between selected databases, but after the two-phase study selection, only six randomized clinical trials (RCT) were included in the systematic review. The primary outcome of interest was the change in pain from baseline to endpoint. The pooled effect of LLLT on pain, measured through a visual analog scale with a mean difference of 7.77 mm (95% confidence interval [CI]: -2.49 to 18.02), was not statistically significant from placebo. Change from baseline to endpoint of secondary outcomes was 4.04 mm (95% CI 3.06 to 5.02) for mandibular maximum vertical opening; 1.64 mm (95% CI 0.10 to 3.17) for right lateral excursion and 1.90 mm (95% CI: -4.08 to 7.88) for left lateral excursion. CONCLUSION: Currently, there is no evidence to support the effectiveness of LLLT in the treatment of TMD. PMID- 22247926 TI - Global self-rating of oral health, concerns about oral health, and history of jaw injury related to temporomandibular joint symptoms in Korean adults. AB - AIMS: To examine the association between temporomandibular joint (TMJ) symptoms and the global self-rating of oral health, concerns about oral health, and a history of jaw injury or third molar extraction in a representative Korean population. METHODS: From the Korean National Oral Health Survey 2006, 4,546 adults aged 18 years and older were included in the analysis. The dependent variable was TMJ symptoms. The independent variables were the global self-rating of oral health, concerns about oral health, and a history of jaw injury or third molar extraction. The demographic information (age and gender), socioeconomic status (education level, monthly household income, vocation, and residence), and behavioral factors (recent dental visit and smoking) were evaluated as confounders. Multivariate linear and logistic regression analyses were applied. RESULTS: The overall prevalence of TMJ symptoms in Koreans was 15.3%. The younger, more educated, middle class, those employed in office and sales, and those who resided in city areas had more TMJ symptoms. The TMJ symptoms were significantly associated with the global self-rating of oral health, concerns about oral health, and history of jaw injury. No significant association was found between the TMJ symptoms and a history of a third molar extraction. The global self-rating of oral health, concerns about oral health, and history of jaw injury had a dose-effect relationship with the severity of TMJ symptoms. Age and gender modified the effect of the global self-rating of oral health, concerns about oral health, and the history of jaw injury on TMJ symptoms. CONCLUSION: The global self-rating of oral health, concerns about oral health, and a history of jaw injury might be associated with TMJ symptoms. PMID- 22247927 TI - Gender modifies effect of perceived stress on orofacial pain symptoms: National Survey of Adult Oral Health. AB - AIMS: To determine in a representative sample of the Australian adult population the relationship between age, gender, and two components of perceived stress (distress and control) and to investigate whether the relationship of perceived stress and temporomandibular disorder (TMD)-related orofacial pain symptoms was modified by gender or age. METHODS: Data were from the National Survey of Adult Oral Health conducted in Australia in 2004-2006 and were collected from 3,954 adults aged 18 to 91 years. TMD-related orofacial pain symptoms were evaluated using seven validated screening questions. Perceived stress was measured with the 14-item Perceived Stress Scale and was investigated to empirically test its two theoretical components (distress and sense of control), using principal components analysis. RESULTS: Prevalence of TMD-related orofacial pain symptoms was 10.1% in the Australian adult population. Prevalence was higher in females than in males, inversely related to age, and positively related to distress and current cigarette smoking. Principal component analysis confirmed the theoretical presence of two factors labeled here as distress and control. An inverse relationship of age and distress was more pronounced in females than in males (P value for interaction = .005). In the adjusted binary logistic regression model, age, smoking, and distress remained positively associated with symptoms. A sense of control was protective against TMD-related orofacial pain symptoms, but only for males (P value for interaction = .040). CONCLUSION: The higher prevalence of TMD-related orofacial pain symptoms in females was better explained by their lower perception of control than from a greater perception of distress. PMID- 22247928 TI - Efficacy of topical 1% lidocaine in the symptomatic treatment of pain associated with oral mucosal trauma or minor oral aphthous ulcer: a randomized, double blind, placebo-controlled, parallel-group, single-dose study. AB - AIMS: To determine the efficacy in pain reduction of a topical 1% lidocaine compared to a placebo cream in patients with oral mucosal lesions due to trauma or minor oral aphthous ulcer. METHODS: The design was a double-blind, randomized, placebo-controlled, six-center trial on 59 patients. Pain intensity and relief were measured using a 100-mm visual analog scale (VAS). One-tailed Student t test and ANOVA analyses were used for statistical analyses. RESULTS: Independent of the pain origin (oral mucosal trauma or minor oral aphthous ulcer), the application of the 1% lidocaine cream led to a mean reduction in VAS pain intensity of 29.4 mm +/- 17.0, which was significantly greater than the decrease obtained with the placebo cream. Analysis showed a statistically significant efficacy of the 1% lidocaine cream (P = .0003). Its efficacy was not related to the type of lesion, and no adverse drug reaction, either local or systemic, was reported by any of the patients. CONCLUSION: A significant reduction in pain intensity occurred after application of 1% lidocaine cream and was significantly greater than that with the placebo cream. Taking into account the study's limitations, this product seems safe to use. PMID- 22247929 TI - Profiling of patients presenting with posttraumatic neuropathy of the trigeminal nerve. AB - AIMS: To describe the cause, clinical signs, and symptoms of patients presenting to a tertiary care center with iatrogenic lesions to the mandibular branches of the trigeminal nerve. METHODS: Pain history, pain scores using the visual analog scale, and mechanosensory testing results were recorded from 93 patients with iatrogenic lingual nerve injuries (LNI) and 90 patients with iatrogenic inferior alveolar nerve injuries (IANI). Results were analyzed using the SPSS statistical software. Chi-square tests were applied for nonparametric testing of frequencies, where P ? .05 indicated statistical significance. Appropriate correlations were also carried out between certain data sets. RESULTS: Significantly more females were referred than males (P < .05). Overall, third molar surgery (TMS) caused 73% of LNI, followed by local anesthesia (LA) (17%). More diverse procedures caused IANI, including TMS (60%), LA (19%), implants (18%), and endodontics (8%). Approximately 70% of patients presented with neuropathic pain coincident with anesthesia and/or paresthesia. Neuropathy was demonstrable in all patients with varying degrees of loss of mechanosensory function, paresthesia, dysesthesia, allodynia, and hyperalgesia. Functionally, IANI and LNI patients mostly had problems with speech and eating, where speech was affected amongst significantly more patients with LNI (P < .001). Sleep, brushing teeth, and drinking were significantly more problematic for IANI patients (P < .05, P < .001, and P < .0001, respectively). CONCLUSION: Neuropathic pain, as well as anesthesia, frequently occurs following iatrogenic trigeminal nerve injury similar to other posttraumatic sensory nerve injuries. This must be acknowledged by clinicians as a relatively common problem and informed consent appropriately formulated for patients at risk of trigeminal nerve injuries in relation to dentistry requires revision. PMID- 22247931 TI - Antihyperalgesic effects of clomipramine and tramadol in a model of posttraumatic trigeminal neuropathic pain in mice. AB - AIMS: To develop a behavioral model in mice that is capable of mimicking some distinctive symptoms of human posttraumatic trigeminal neuropathic pain such as spontaneous pain, cold allodynia, and chemical/inflammatory hyperalgesia, and to use this model to investigate the antinociceptive effects of clomipramine and tramadol, two drugs used for the treatment of neuropathic pain. METHODS: A partial tight ligature of the right infraorbital nerve by an intraoral access or a sham procedure was performed. Fourteen days later, mice were subcutaneously injected with saline or drugs and the spontaneous nociceptive behavior, as well as the responses to topical acetone and to formalin or capsaicin injected into the ipsilateral vibrissal pad, were assessed. Data were analyzed by ANOVA. RESULTS: Neuropathic mice exhibited an increased spontaneous rubbing/scratching of the ipsilateral vibrissal pad, together with enhanced responses to cooling (acetone) and the chemical irritants (formalin, capsaicin). Clomipramine and tramadol produced an antihyperalgesic effect on most of these nociceptive responses, but tramadol was ineffective on capsaicin-induced hyperalgesia. CONCLUSION: Nociceptive responses in this neuropathic pain model in mice exhibited a pattern consistent with the pain described by posttraumatic trigeminal neuropathic patients. The selective antihyperalgesic effect obtained with two commonly used drugs for treating neuropathic pain confirms the validity of this preclinical model. PMID- 22247932 TI - Conditioned pain modulation evoked by different intensities of mechanical stimuli applied to the craniofacial region in healthy men and women. AB - AIMS: To investigate systematically whether conditioned pain modulation (CPM) evoked by tonic mechanical stimuli applied to the craniofacial region is intensity-, assessment site-, and gender-dependent. METHODS: Twenty healthy men and 20 women participated in four sessions. Tonic painful mechanical stimulation was applied to pericranial muscles by a mechanical headband pressure device. The pressures applied to four probes were adjusted via pain feedback from a 0 to 10 electronic visual analog scale (VAS) to generate different pain levels (VAS0, VAS1, VAS3, or VAS5) for 10 minutes. Pressure pain thresholds (PPTs) and pressure pain tolerance thresholds (PPTols) were assessed from right masseter muscle and left forearm by pressure algometry before, during, immediately after, 10 minutes after, and 20 minutes after the conditioning stimulus (CS). Data were analyzed with multilevel ANOVAs. RESULTS: PPT values normalized to baseline recordings were not dependent on gender or assessment site, but dependent on intensity (P < .001) and time (P < .001). The most painful CS (VAS5) was associated with the highest PPT increases (32.6% +/- 3.3%, mean value for the two assessment sites and two genders) during CS compared to all other intensities of CS (P < .001). PPTol values normalized to baseline recordings were also not dependent on gender or assessment site, but dependent on intensity (P < .001) and time (P < .001). The most painful CS (VAS5) was associated with higher PPTol increases (11.2% +/- 2.8%, mean value for the two assessment sites and two genders) during CS (P < .001). CONCLUSION: CPM evoked by mechanical stimulation of the craniofacial region is intensity-dependent but not assessment site- or gender-dependent. PMID- 22247933 TI - Findings of research misconduct. PMID- 22247934 TI - [Behavioral pharmacology and psychopharmacology]. PMID- 22247930 TI - Magnetic resonance imaging of the temporomandibular joint disc: feasibility of novel quantitative magnetic resonance evaluation using histologic and biomechanical reference standards. AB - AIMS: To use the ultrashort time-to-echo magnetic resonance imaging (UTE MRI) technique to quantify short T2* properties (obtained through gradient echo) of a disc from the human temporomandibular joint (TMJ) and to corroborate regional T2* values with biomechanical properties and histologic appearance of the discal tissues. METHODS: A cadaveric human TMJ was sliced sagittally and imaged by conventional and UTE MRI techniques. The slices were then subjected to either biomechanical indentation testing or histologic evaluation, and linear regression was used for comparison to T2* maps obtained from UTE MRI data. Feasibility of in vivo UTE MRI was assessed in two human volunteers. RESULTS: The UTE MRI technique of the specimens provided images of the TMJ disc with greater signal-to-noise ratio (~3 fold) and contrast against surrounding tissues than conventional techniques. Higher T2* values correlated with lower indentation stiffness (softer) and less collagen organization as indicated by polarized light microscopy. T2* values were also obtained from the volunteers. CONCLUSION: UTE MRI facilitates quantitative characterization of TMJ discs, which may reflect structural and functional properties related to TMJ dysfunction. PMID- 22247935 TI - [Future of cochlear implants: a new approach to cochlear implants, low stress, and preservation of residual hearing acuity]. PMID- 22247936 TI - Characterization of bupivacaine-loaded formulations based on liquid crystalline phases and microemulsions: the effect of lipid composition. AB - This report details the structural characterization and the in vitro drug-release properties of different local anesthetic bupivacaine (BUP)-loaded inverted-type liquid crystalline phases and microemulsions. The effects of variations in the lipid composition and/or BUP concentration on the self-assembled nanostructures were investigated in the presence of the commercial distilled glycerol monooleate Myverol 18-99K (GMO) and medium-chain triglycerides (MCT). Synchrotron small angle X-ray scattering (SAXS) and rotating dialysis cell model were used to characterize the BUP formulations and to investigate the in vitro BUP release profiles, respectively. The evaluation of SAXS data for the BUP-loaded GMO/MCT formulations indicates the structural transition of inverted-type bicontinuous cubic phase of the symmetry Pn3m -> inverted-type hexagonal (H(2)) phase -> inverted-type microemulsion (L(2)) with increasing MCT content (0-40 wt %). In the absence of MCT, the solubilization of BUP induces the transition of Pn3m -> H(2) at pH 7.4; whereas a transition of Pn3m -> (Pn3m + H(2)) is detected as the hydration is achieved at pH 6.0. To mimic the drug release and transport from in situ formed self-assembled systems after subcutaneous administration, the release experiments were performed by injecting low viscous stimulus-responsive precursors to a buffer in the dialysis cell leaving the surface area between the self-assembled system and the release medium variable. Our results suggest that the pH-dependent variations in the lipidic partition coefficient, K(l/w), between the liquid crystalline nanostructures and the surrounding buffer solution are significantly affecting BUP release rates. Thus, a first step toward understanding of the drug-release mechanism of this drug-delivery class has been undertaken tackling the influence of drug ionization as well as the type of the self-assembled nanostructure and its release kinetics under pharmaceutically relevant conditions. PMID- 22247937 TI - Plasmonic-enhanced molecular fluorescence within isolated bowtie nano-apertures. AB - We report experimental behaviors of polarization-dependent, plasmonic-enhanced molecular fluorescence within isolated bowtie nano-apertures (BNAs) milled in aluminum films. BNAs provide efficient control of the fluorescent count rate per molecule and the decay lifetime of the molecules and provide an effective detection volume at the nanometer scale by tuning either the excitation light polarization or the BNA size. Interestingly, large BNAs (>300 nm) present high plasmonic-enhanced fluorescence efficiency and can simultaneously confine the detection volume below the subdiffraction limit. Numerical simulations were performed that agreed qualitatively with the experimental results. The BNAs have potential applications, especially for single-molecule biological analysis. PMID- 22247939 TI - Equilibrium adsorption of polycyclic aromatic hydrocarbons from water onto activated carbon. PMID- 22247940 TI - Sedimentological reconstruction of the recent pattern of mercury pollution in the Niagara River. PMID- 22247941 TI - Molecular weight distribution of dissolved organic carbon and dissolved organic halogen in advanced treated wastewaters. PMID- 22247942 TI - Development of a general kinetic model for biodegradation and its application to chlorophenols and related compounds. PMID- 22247943 TI - Methyl parathion and EPN washoff from cotton plants by simulated rainfall. PMID- 22247944 TI - GC/MS and MS/MS studies of diesel exhaust mutagenicity and emissions from chemically-defined fuels. PMID- 22247945 TI - Fate and metabolism of isopropylphenyl diphenyl phosphate in freshwater sediments. PMID- 22247946 TI - Three-parameter equation describing the uptake of organic compounds by fish. PMID- 22247947 TI - Environmental fate of combustion-generated polychlorinated dioxins and furans. PMID- 22247949 TI - Generator column determination of octanol/water partition coefficients for selected polychlorinated biphenyl congeners. PMID- 22247948 TI - Reduction and dissolution of manganese(III) and manganese(IV) oxides by organics. 1. Reaction with hydroquinone. PMID- 22247950 TI - Photooxidation of methyl sulfide, ethyl sulfide, and methanethiol. PMID- 22247951 TI - High-resolution PCB analysis: synthesis and chromatographic properties of all 209 PCB congeners. PMID- 22247952 TI - Field evaluation of a cost-effective screening procedure for polynuclear aromatic pollutants in ambient air samples. PMID- 22247953 TI - Emission of organic air pollutants from shale oil wastewaters. PMID- 22247955 TI - Recognition memory deficits in mild cognitive impairment. AB - There is no agreement on the pattern of recognition memory deficits characteristic of patients diagnosed with mild cognitive impairment (MCI). Whereas lower performance in recollection is the hallmark of MCI, there is a strong controversy about possible deficits in familiarity estimates when using recognition memory tasks. The aim of this research is to shed light on the pattern of responding in recollection and familiarity in MCI. Five groups of participants were tested. The main participant samples were those formed by two MCI groups differing in age and an Alzheimer's disease group (AD), which were compared with two control groups. Whereas one of the control groups served to assess the performance of the MCI and AD people, the other one, composed of young healthy participants, served the purpose of evaluating the adequacy of the experimental tasks used in the evaluation of the different components of recognition memory. We used an associative recognition task as a direct index of recollection and a choice task on a pair of stimuli, one of which was perceptually similar to those studied in the associative recognition phase, as an index of familiarity. Our results indicate that recollection decreases with age and neurological status, and familiarity remains stable in the elderly control sample but it is deficient in MCI. This research shows that a unique encoding situation generated deficits in recollective and familiarity mechanisms in mild cognitive impaired individuals, providing evidence for the existence of deficits in both retrieval processes in recognition memory in a MCI stage. PMID- 22247956 TI - A novel class of highly potent irreversible hepatitis C virus NS5B polymerase inhibitors. AB - Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 MUM.h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation. PMID- 22247957 TI - Errorless learning in cognitive rehabilitation: a critical review. AB - Cognitive rehabilitation research is increasingly exploring errorless learning interventions, which prioritise the avoidance of errors during treatment. The errorless learning approach was originally developed for patients with severe anterograde amnesia, who were deemed to be at particular risk for error learning. Errorless learning has since been investigated in other memory-impaired populations (e.g., Alzheimer's disease) and acquired aphasia. In typical errorless training, target information is presented to the participant for study or immediate reproduction, a method that prevents participants from attempting to retrieve target information from long-term memory (i.e., retrieval practice). However, assuring error elimination by preventing difficult (and error permitting) retrieval practice is a potential major drawback of the errorless approach. This review begins with discussion of research in the psychology of learning and memory that demonstrates the importance of difficult (and potentially errorful) retrieval practice for robust learning and prolonged performance gains. We then review treatment research comparing errorless and errorful methods in amnesia and aphasia, where only the latter provides (difficult) retrieval practice opportunities. In each clinical domain we find the advantage of the errorless approach is limited and may be offset by the therapeutic potential of retrieval practice. Gaps in current knowledge are identified that preclude strong conclusions regarding a preference for errorless treatments over methods that prioritise difficult retrieval practice. We offer recommendations for future research aimed at a strong test of errorless learning treatments, which involves direct comparison with methods where retrieval practice effects are maximised for long-term gains. PMID- 22247958 TI - Feasible etiology of vanishing testis regarding disturbance of testicular development: histopathological and immunohistochemical evaluation of testicular nubbins. AB - OBJECTIVES: To identify the causes of vanishing testis besides vascular events secondary to testicular torsion. METHODS: A total of 102 boys with vanishing testis were treated in our hospital from 1984 to 2011. Of these cases, 91 testicular nubbins were excised. Immunohistochemical analysis of testicular nubbins was carried out using anti-Wilms tumor 1 antibody, which is a stable marker of Sertoli cells. Reverse transcription polymerase chain reaction was also carried out using Wilms tumor 1-specific primers. RESULTS: Most testicular nubbins were associated with inguinal lesion (51 patients, 56.0%). Light microscopy showed that 11 patients (12.5%) had seminiferous tubules (with germ cells in three patients [3.4%]), and 77 patients lacked seminiferous tubules, some of which had calcification (26 patients, 29.5%), and/or deposition of hemosiderin (21 patients, 23.9%). Immunohistochemical analysis showed Wilms tumor 1 expression not only in the Sertoli cells of the seminiferous tubules in the seminiferous tubule-positive patients, but also in the interstitium of testicular nubbins in the seminiferous tubule-negative patients. Reverse transcription polymerase chain reaction showed Wilms tumor 1 messenger ribonucleic acid expression in the testicular nubbins of both seminiferous tubule-positive and tubule-negative patients. CONCLUSIONS: The presence of Wilms tumor 1-positive cells in the interstitium of vanishing testis lacking seminiferous tubules suggests that the disturbance of testicular development after Sertoli cell differentiation and during testicular tubule formation might be involved in the etiology of vanishing testis. PMID- 22247959 TI - Matrix metalloproteinase (MMP-2 and MMP-9) and steroid receptor expressions in feline mammary tumors. AB - We evaluated the presence of estrogen (ER) and progesterone (PR) receptors, and matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) enzymes in 18 feline mammary tubulopapillary carcinomas. Immunohistochemistry was performed to localize ER, PR, MMP-2 and MMP-9 in situ. Western blotting and zymographic analyses also were performed to investigate the presence and activities of MMP-2 and MMP-9 enzymes in fresh tissue homogenates. ER immune expression was detected in five samples (27.7%) and PR was positive in sixteen (88.8%) samples. Diffuse cytoplasmic staining of MMP-2 and MMP-9 in neoplastic mammary epithelial cells, stromal fibroblasts and inflammatory cell was evident. MMP-2 and MMP-9 staining was observed also in metastasizing neoplastic cells within lymphatic vessels. MMP-2 and MMP-9 enzymes and their activities in fresh tumor homogenates were demonstrated by zymography. Comparison of MMP-9 gelatinolytic bands from tumor samples and controls revealed a statistically significant difference. We demonstrated elevated MMP-9 and MMP-2 levels in tumor samples by Western blotting; analysis of protein bands revealed 1.9-to-3 fold increase in MMP-9 in tumor samples and the difference was statistically significant. Our results suggest that the expression of MMP-9 can be an important indicator for tumor progression and the possible metastatic nature of feline tubulopapillary carcinomas. PMID- 22247960 TI - It's time for gene therapy to get disruptive! PMID- 22247961 TI - The European hospital exemption clause-new option for gene therapy? AB - Gene-therapy medicinal products are currently applied to patients enrolled in authorized clinical trials to demonstrate safety and efficacy. Given a positive outcome, marketing authorization can subsequently be achieved via the centralized procedure coordinated by the European Medicines Agency. With Regulation (EC) No. 1394/2007 in force, advanced therapy medicinal products, including gene- and cell therapy products, can be excepted from the obligation of obtaining a marketing authorization via the centralized procedure under specific conditions (so-called "hospital exemption"). This hospital exemption allows the application of gene therapy medicinal products prepared on a non-routine basis for an individual patient and used under the exclusive professional responsibility of a medical practitioner. Here, we explain the requirements to be fulfilled in order to fall under this exemption, the implementation of this regulation into the German national legislation, and its impact on gene-therapy product development in the future. PMID- 22247962 TI - Gene therapy briefs. PMID- 22247964 TI - Linkage of cardiac gene expression profiles and ETS2 with lifespan variability in rats. AB - Longevity variability is a common feature of aging in mammals, but the mechanisms responsible for this remain largely unknown. Using microarray datasets coupled with prediction analysis of microarrays (PAM), we identified a set of 252 cardiac transcripts predictive of relative lifespan in Wistar and Fisher 344 rats. Prediction analysis of microarrays 'tests' of rat heart transcriptomes from a third longer lived Fisher * Norway Brown rat strain validated the predictive value of this gene subset. The expression patterns of these genes were highly conserved, and corresponding promoter regions were employed to identify common cis-elements and trans-activating factors implicated in their control. Specifically, four transcription factors (Max, Ets2, Erg, and Msx2) present in heart displayed longevity-dependent, strain-independent changes in abundance, but only ETS2 had an expression profile that directly correlated with the relative lifespan gene set. In heart, ETS2 was prevalent in cardiomyocytes (CMs) and showed a high degree of myocyte-to-myocyte variability predominantly in adult rat hearts prior to the exponential increase in the rate of mortality. Exclusively in this group, elevated ETS2 significantly overlapped with TUNEL staining in heart myocytes. In response to sympathetic stimuli, ETS2 is also up-regulated, and functionally, adenovirus-mediated over-expression of ETS2 promotes apoptosis inducing factor-mediated, caspase-independent programmed necrosis exclusively in CMs that can be fully inhibited by the PARP-1 inhibitor DPQ. We conclude that variations in ETS2 abundance in hearts of adult rodents and the associated loss of CMs contribute at least partially, to the longevity variability observed during normal aging of rats through activation of programmed necrosis. PMID- 22247965 TI - Changing insurance company claims handling processes improves some outcomes for people injured in road traffic crashes. AB - BACKGROUND: Regaining good health and returning to work are important for people injured in road traffic crashes and for society. The handling of claims by insurance companies may play an important role in the rate at which health recovers and return to work is actually attained. METHODS: A novel approach towards claims handling for people injured in road traffic accidents was compared to the standard approach. The setting was a large insurance company (NRMA Insurance) in the state of New South Wales, Australia. The new approach involved communicating effectively with injured people, early intervention, screening for adverse prognostic factors and focusing on early return to work and usual activities. Demographic and injury data, health outcomes, return to work and usual activities were collected at baseline and 7 months post-injury. RESULTS: Significant differences were found 7 months post-injury on 'caseness' of depression (p = 0.04), perceived health limitation on activities (p = 0.03), and self-reported return to usual activities (p = 0.01) with the intervention group scoring better. Baseline general health was a significant predictor for general health at 7 months (OR 11.6, 95% CI 2.7-49.4) and for return to usual activities (OR 4.6, 95% CI 2.3-9.3). CONCLUSION: We found a few positive effects on health from a new claims handling method by a large insurance company. It may be most effective to target people who report low general health and low expectations for their health recovery when they file their claim. PMID- 22247966 TI - Rapid circulatory clearances and half-lives of plasma free metanephrines. PMID- 22247967 TI - Molecular profiling of patient-derived breast cancer xenografts. AB - INTRODUCTION: Identification of new therapeutic agents for breast cancer (BC) requires preclinical models that reproduce the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and gene expression profiles of human BC xenografts and the corresponding patient tumors. METHODS: Eighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. Molecular characterization of patient tumors and xenografts was performed by DNA copy number analysis and gene expression analysis using Affymetrix Microarrays. RESULTS: Comparison analysis showed that 14/18 pairs of tumors shared more than 56% of copy number alterations (CNA). Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together, confirming the similarity between tumor pairs. Analysis of recurrent CNA changes between patient tumors and xenografts showed losses in 176 chromosomal regions and gains in 202 chromosomal regions. Gene expression profile analysis showed that less than 5% of genes had recurrent variations between patient tumors and their respective xenografts; these genes largely corresponded to human stromal compartment genes. Finally, analysis of different passages of the same tumor showed that sequential mouse-to-mouse tumor grafts did not affect genomic rearrangements or gene expression profiles, suggesting genetic stability of these models over time. CONCLUSIONS: This panel of human BC xenografts maintains the overall genomic and gene expression profile of the corresponding patient tumors and remains stable throughout sequential in vivo generations. The observed genomic profile and gene expression differences appear to be due to the loss of human stromal genes. These xenografts, therefore, represent a validated model for preclinical investigation of new therapeutic agents. PMID- 22247968 TI - Vitamin D and diabetes in Koreans: analyses based on the Fourth Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2009. AB - AIMS: A causal relationship between vitamin D deficiency and the incidence of diabetes mellitus has been suggested, but little research has been conducted on the Korean population. METHODS: We analysed the glucose tolerance status and serum 25-hydroxyvitamin D concentrations in 12263 subjects >19 years old who were registered for the Korea National Health and Nutrition Examination Survey, 2008 2009. RESULTS: Various demographic variables such as gender, age, season, resident area, physical activity, smoking, alcohol, marital status, education and occupation were associated with serum 25-hydroxyvitamin D concentrations. After adjusting for these variables as confounders, 25-hydroxyvitamin D concentrations in subjects with diabetes were significantly lower than those in subjects with normal glucose tolerance and those with impaired fasting glucose (P=0.005). Compared with the >= 75 nmol/l subgroup of serum 25-hydroxyvitamin D concentration, the odds ratios and 95% confidence intervals for diabetes mellitus were 1.206 (95%CI 0.948-1.534) in the 50- to 74-nmol/l subgroup, 1.339 (1.051 1.707) in the 25-to 49-nmol/l subgroup and 1.759 (1.267-2.443) in the <25-nmol/l subgroup. Compared with the serum >= 75-nmol/l 25-hydroxyvitamin D subgroup, serum insulin and homeostasis model assessment 2%B, a marker of insulin secretory capacity, were significantly higher, and homeostasis model assessment 2%S, a marker of insulin sensitivity, was significantly lower in the <25- and 25- to 49 nmol/l serum 25-hydroxyvitamin D subgroups than those in the other subgroups (P<0.001). CONCLUSIONS: The findings suggest that vitamin D deficiency, possibly involving altered insulin sensitivity, is associated with an increased risk for diabetes mellitus in the Korean population. PMID- 22247969 TI - Outcomes of inborn and transported extremely premature very-low-birthweight infants in Hawai'i. AB - BACKGROUND: Delivery of premature infants outside tertiary care centers is not always preventable. The aim of this study was to compare rates of survival and common morbidities in extremely premature babies transported to a level III facility versus those born at the level III center. METHODS: Retrospective chart review was performed on all neonates born at <= 28 weeks of gestation with birthweight <= 1500 g who were admitted to the Newborn Intensive Care Unit at Kapi'olani Medical Center for Women and Children (KMCWC) between 1 January 2000 and 31 December 2005. Infants were divided into two groups, those born at KMCWC (Inborn) and those born at level I institutions and subsequently transported (Transport) to KMCWC. RESULTS: A total of 394 neonates met the study criteria; 349 were inborn while 45 were transported. Survival rates were identical for both groups. However, the Transport group survivors displayed a significantly longer mean length of stay and higher rate of severe retinopathy of prematurity than those in the Inborn group (P <= 0.01). CONCLUSION: Identical rates of survival in both groups suggest that community medical professionals are providing satisfactory care to stabilize critical neonates without reducing their chances of survival. However, increased length of stay and higher rate of retinopathy of prematurity in the Transport group suggest that differences in medical management during the first few hours of life may adversely affect outcomes. PMID- 22247970 TI - Alternative mRNA processing increases the complexity of microRNA-based gene regulation in Arabidopsis. AB - MicroRNAs (miRNAs) represent an important class of sequence-specific, trans acting endogenous small RNA molecules that modulate gene expression at the post transcriptional level. They function by binding to partial complementary cis regulatory sites (miRNA binding sites) in their target mRNAs. Based on two recent observations from plant genome studies, namely that alternative splicing is a common phenomenon and that miRNA regulates a significant proportion of the transcriptome, we hypothesize that there may be a mechanism for gene regulation that involves both processes. In the present study, we performed a systemic search in the model plant Arabidopsis thaliana using annotated gene models as well as publically available high-throughput RNA sequencing data with a total of 570 million reads. Of the 354 high-confidence miRNA binding sites identified in Arabidopsis, at least 44 (12.4%) were affected by alternative splicing such that mRNA isoforms of the same miRNA target gene differ in the sequences encoding the miRNA binding sites. By simulation, we found that the frequency of alternative splicing at miRNA binding sites is significantly higher than at other regions. Comparative and functional analyses further indicated that the alternative splicing events are important for target gene expression and miRNA action. Together our results show that alternative splicing of miRNA binding sites is a plausible mechanism for attenuating miRNA-mediated gene regulation. PMID- 22247971 TI - Marathon of eponyms: 23 Wegener granulomatosis. AB - The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology and oral, oral and maxillofacial radiology and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognized relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarizes data about Wegener granulomatosis. PMID- 22247972 TI - Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats. AB - OBJECTIVE: Radiation-induced skin injury remains a serious concern for radiation therapy. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant and anti-apoptotic properties. However, the role of HO-1 in radiation-induced skin damage remains unclear. This study aims to elucidate the effects of HO-1 on radiation-induced skin injury in rats. METHODS: A control adenovirus (Ad-EGFP) and a recombinant adenovirus (Ad HO1-EGFP) were constructed. Rats were irradiated to the buttock skin with a single dose of 45 Gy followed by a subcutaneous injection of PBS, 5 * 109 genomic copies of Ad-EGFP or Ad-HO1-EGFP (n = 8). After treatment, the skin MDA concentration, SOD activity and apoptosis were measured. The expression of antioxidant and pro-apoptotic genes was determined by RT-PCR and real-time PCR. Skin reactions were measured at regular intervals using the semi-quantitative skin injury score. RESULTS: Subcutaneous injection of Ad-HO1-EGFP infected both epidermal and dermal cells and could spread to the surrounding regions. Radiation exposure upregulated the transcription of the antioxidant enzyme genes, including SOD-1, GPx2 and endogenous HO-1. HO-1 overexpression decreased lipid peroxidation and inhibited the induction of ROS scavenging proteins. Moreover, HO-1 exerted an anti-apoptotic effect by suppressing FAS and FASL expression. Subcutaneous injection of Ad-HO1-EGFP demonstrated significant improvement in radiation induced skin injury. CONCLUSIONS: The present study provides evidences for the protective role of HO-1 in alleviating radiation-induced skin damage in rats, which is helpful for the development of therapy for radiation-induced skin injury. PMID- 22247973 TI - Novel extraction technique to remove a penile constriction device. AB - INTRODUCTION: Penile strangulation can be a challenging clinical situation and usually requires prompt treatment. The clinician should be aware of the various techniques to remove such devices. AIM: The aim of this article was to describe a new noninvasive technique, the "pseudo-pulley" method, to remove a penile constriction device. METHODS: During an episode of medication-induced hypersexuality, a 63-year-old man presented to the emergency department with a cast iron locking nut of a vehicle towbar lodged at the base of the patient's penis. RESULTS: The utilization of the "pseudo-pulley" method to remove the constriction device negated the need for more invasive measures. We outline a step-by-step description on this new technique. The patient's recovery was complete and uneventful. CONCLUSION: The current case report describes a noninvasive technique for removing a penile constriction device that does not rely on specialized equipment and industrial drills that can cause iatrogenic injury. PMID- 22247975 TI - Dilemmas in the reliable estimation of the in-vitro cell viability in magnetic nanoparticle engineering: which tests and what protocols? AB - Magnetic nanoparticles [MNPs] made from iron oxides have many applications in biomedicine. Full understanding of the interactions between MNPs and mammalian cells is a critical issue for their applications. In this study, MNPs were coated with poly(ethylenimine) [MNP-PEI] and poly(ethylene glycol) [MNP-PEI-PEG] to provide a subtle difference in their surface charge and their cytotoxicity which were analysed by three standard cell viability assays: 3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium [MTS], CellTiter Blue and CellTiter-Glo (Promega, Southampton, UK) in SH-SY5Y and RAW 264.7 cells The data were validated by traditional trypan blue exclusion. In comparison to trypan blue manual counting, the MTS and Titer-Blue assays appeared to have consistently overestimated the viability. The Titer-Glo also experienced a small overestimation. We hypothesise that interactions were occurring between the assay systems and the nanoparticles, resulting in incorrect cell viability evaluation. To further understand the cytotoxic effect of the nanoparticles on these cells, reactive oxygen species production, lipid peroxidation and cell membrane integrity were investigated. After pegylation, the MNP-PEI-PEG possessed a lower positive surface charge and exhibited much improved biocompatibility compared to MNP-PEI, as demonstrated not only by a higher cell viability, but also by a markedly reduced oxidative stress and cell membrane damage. These findings highlight the importance of assay selection and of dissection of different cellular responses in in-vitro characterisation of nanostructures. PMID- 22247976 TI - From the horse's mouth: perceptions of the management of the 2007 equine influenza outbreak in Australia. AB - In August 2007, Australia experienced its first-ever outbreak of equine influenza, a highly infectious respiratory disease of horses. Although the outbreak spread over a large geographic area, it was eradicated within 5 months following a substantial disease control effort led by federal and state animal health authorities. Despite its timely control, this large-scale outbreak caused severe impacts on horse owners and industry participants. This study aimed to describe the perceptions of horse owners and managers, impacted by outbreak control measures, regarding the state government's animal health authority outbreak management. Participants were interviewed face-to-face. Factors associated with ordinal ratings of perception ('well managed', 'adequately managed' and 'poorly managed') were identified using ordinal logistic regression. Factors significantly associated with a reduced likelihood of 'well-managed' outbreak response ratings, adjusted for age and gender, were being involved in horse competitions/sporting events (OR = 0.48; 95% CI: 0.25-0.91), managing a horse stud (OR = 0.09; 95% CI: 0.03-0.28) and believing that another outbreak of equine influenza was highly likely in the next 5 years (OR = 0.29; 95% CI: 0.12 0.68). Possible reasons for these ratings were further investigated using content analyses. Outbreak communications and government efficiency/support were mentioned most frequently as both strengths (30% and 28%, respectively) and weaknesses (40% and 30%, respectively) of the outbreak management. To promote manager-government rapport and future compliance with disease control regulations, we recommend that outbreak communications and outbreak information systems be reviewed. PMID- 22247977 TI - Self-generation amplifies the errorless learning effect in healthy older adults when transfer appropriate processing conditions are met. AB - Errorless learning improves memory for older adults by providing individuals with correct information from the onset, thereby minimizing the misleading influence of errors. Our previous research demonstrated that self-generation enhanced the errorless learning effect among older adults in cued recall when encoding encouraged processing of cue-target relationships, suggesting that transfer appropriate processing is necessary for this interactive effect ( Lubinsky, Rich, & Anderson, 2009 , Journal of the International Neuropsychological Society, 15, 704). The current study further tests this notion by investigating whether the interaction of errorless learning and self-generated learning is observed in free recall when study conditions foster encoding of inter-item associations. Healthy older adult participants studied related or unrelated words (manipulated between subjects) under four within-subjects learning conditions representing the crossing of errorless/errorful learning and self-generated/experimenter-provided information. As predicted, self-generation enhanced the errorless learning advantage in free recall for related word lists but not unrelated word lists. The results are discussed in relation to the transfer appropriate processing view of generation effects. PMID- 22247978 TI - Substrate reduction therapy with miglustat for type 1 Gaucher disease: a retrospective analysis from a single institution. AB - INTRODUCTION: Gaucher disease (GD) is an infrequent progressive multisystem lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme, glucocerebrosidase. A retrospective, single-center analysis of the clinical experience concerning the use of miglustat (N-butyldeoxynojirimycin), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease (GD1) was conducted to evaluate the efficacy, adverse events (AE), and outcome of miglustat therapy. PATIENTS AND METHODS: Six adult Caucasian patients with GD1 (two women and four men), aged 21-81 years (median age 59 years), were treated with miglustat between October 2005 and April 2011. All but one patient (83%) carried at least one allele with c.1226A>G (N370S) mutation in the GBA1 gene. RESULTS: Weight loss, diarrhea, poor appetite, and tremor were frequently reported AE by the patients. All of them experienced at least 2 AE, and three patients (50%) experienced at least 4 AE. Only two out of six patients (33%) have used miglustat longer than 12 months, of which only one used it longer than 15 months. CONCLUSIONS: The major obstacle to successful miglustat therapy in GD1 was the high proportion of patients discontinuing their treatment due to the AE and the worsened quality of life. Further efforts are needed to improve tolerability of miglustat and, in consequence, compliance of patients treated with this orphan drug. PMID- 22247980 TI - Determination of the atomic weight of 28Si-enriched silicon for a revised estimate of the Avogadro constant. AB - The much anticipated overhaul of the International System of Units (SI) will result in new definitions of base units in terms of fundamental constants. However, redefinition of the kilogram in terms of the Planck constant (h) cannot proceed without consistency between the Avogadro and Planck constants, which are both related through the Rydberg constant. In this work, an independent assessment of the atomic weight of silicon in a highly enriched (28)Si crystal supplied by the International Avogadro Coordination (IAC) was performed. This recent analytical approach, based on dissolution with NaOH and its isotopic characterization by multicollector inductively coupled plasma mass spectrometry, is critically evaluated. The resultant atomic weight A(r)(Si) = 27.976 968 39(24)(k=1) differs significantly from the most recent value of A(r)(Si) = 27.976 970 27(23)(k=1). Using the results generated herein for A(r)(Si) along with other IAC measurement results for mass, volume, and the lattice spacing, the estimate of the Avogadro constant becomes N(A) = 6.022 140 40(19) * 10(23) mol(-1). PMID- 22247979 TI - A case of hypoglycemic hemiparesis and literature review. AB - An 89-year-old man with diabetes treated with metformin 500 mg/day and glimepiride 4 mg/day was hospitalized because of hypoglycemic right hemiparesis and dysarthria (casual glucose value 1.8 mmol/L), which resolved quickly following administration of 40 mL of 40% dextrose. Hemiparesis is a rare symptom (4.2%) of hypoglycemia. There are about 200 case reports of hypoglycemic hemiparesis. The average glucose level at which hemiparesis developed was 1.8 mmol/L. Right-sided hemiparesis predominated (R 66%; L 34%). On imaging studies, abnormal findings were frequently observed in the internal capsule or splenium of the corpus callosum. The mechanism of hemiparesis is not fully understood. The existence of cases in which hypoglycemia cannot be distinguished from stroke on imaging studies suggests the importance of measurement of the blood glucose level when the symptoms of stroke are first recognized. PMID- 22247981 TI - Decreasing cues for a dynamic list of noun and verb naming targets: a case-series aphasia therapy study. AB - Errorless learning has had positive reports across both clinical and non-clinical domains. Within aphasia therapy studies, decreasing cue methods have been proposed as the optimal combination of low error and high effort. This study aimed to evaluate a modification to the decreasing cue method in which the set size of target nouns and verbs for training was extended dependent on participant progress in naming therapy. Four participants with word retrieval symptoms as part of their aphasia took part in a case-series study in which a decreasing cue hierarchy was applied to a dynamic list of noun and verb targets. An assessment probe at the start of each session determined how many new items were to be taken on in therapy, dependent on participant responsiveness to that point. All participants made significant improvements in naming accuracy for treated items from baseline and compared to control items. Two participants continued to take on new items which reflected consistent trajectories of improving naming accuracy, while two participants reached saturation points at which the frequency of errors in naming accuracy limited their set sizes. The varying trajectories of the participants were evaluated in relation to their baseline language and cognitive skills. Clinical implications from the findings and themes for further research were also considered. PMID- 22247984 TI - Letters - california redoubles its efforts - mulford-carrell act highlights. PMID- 22247983 TI - Editorial - Society sometimes speaks with cautious tongue. PMID- 22247985 TI - Environmental currents. PMID- 22247987 TI - The impact of water quallity standards. PMID- 22247986 TI - FWPCA, An Agency with a Mission. PMID- 22247989 TI - Tastes and odors in water supplies. PMID- 22247988 TI - Waste management, a rapidly growing market. PMID- 22247990 TI - Quote...Technological change, a national necessity. PMID- 22247991 TI - A river can be made to help itself. PMID- 22247993 TI - Determination of calcium in natural water by atomic absorption spectrophotometry. PMID- 22247992 TI - Stabilization and determination of traces of silver in waters. PMID- 22247994 TI - Geochemistry of Tertiary and Cretaceous age oil-bearing formation waters. PMID- 22247995 TI - Odorous compounds in natural waters. Some sulfur compounds associated with blue green algae. PMID- 22247996 TI - Nitrate and other water pollutants under fields and feedlots. PMID- 22247997 TI - Atrazine losses from fallow land caused by runoff and erosion. PMID- 22247998 TI - Determination of radiostrontium in food and other environmental samples. PMID- 22247999 TI - Ammonia in auto exhaust. PMID- 22248001 TI - New products digest. PMID- 22248000 TI - Bookshelf - public policy on pesticides modified by economic factors. PMID- 22248002 TI - New literature digest. PMID- 22248003 TI - Preparation and deproteinization of garlic polysaccharide. AB - Preparation and deproteinization methods of polysaccharide from garlic (Allium sativum L.) were studied. The crude polysaccharide was prepared by the method of hot water extraction. The percentages of deproteinization and polysaccharide loss were compared as indexes using the hydrochloric acid (HCl) method, trichloroacetic acid method, NaCl method and CaCl(2) method, respectively. The infrared spectra analysis and content analysis showed that the HCl method exhibited the highest percentage of deproteinization, and a little higher percentage of polysaccharide loss than the other three methods. The CaCl(2) method exceeded NaCl method in deproteinization. PMID- 22248004 TI - Psychological distress does not compromise outcome in spinal surgery. AB - SUMMARY OF BACKGROUND DATA: Physical outcomes following surgery for degenerative spine disease have been well studied whereas the importance of psychological factors has only recently been acknowledged. Previous studies suggest that pre operative psychological distress predicts poor outcome from spinal surgery. In the drive to identify patients who will not benefit, these patients risk being denied surgery. STUDY DESIGN: This is a prospective series from a spinal surgical register. AIM: The study examines the relationship between the physical symptoms, pre-operative psychological distress and outcome following surgery. METHODS: The Short Form 36 (SF36) Health Survey Questionnaire and the Hospital Anxiety and Depression Scale (HADS) were administered to patients undergoing elective surgery for degenerative spine disease pre-operatively and at 3 and 12 months post operatively. Levels of physical disability (SF-36 physical functioning (SF36PF) and bodily pain (SF36BP) scores) and psychological distress (HADS-anxiety and HADS-depression scores) before and after surgery were compared. RESULTS: A total of 302 patients were included (169 men, 133 women, mean age 55 years). Pre operatively patients had worse physical scores than age-matched controls (SF36PF normative mean (S.D.) 80.97 (12.69) vs. pre-op 33.31 (24.7) P < 0.05). Of the 302 patients, 117 (39%) had significant anxiety or depression. Increased levels of anxiety or depression pre-operatively correlated with worse physical (SF-36PF and SF-36BP) scores pre-operatively (Spearman's r P < 0.05). Levels of anxiety and depression were reduced post-operatively and physical outcomes improved post operatively. Physical function remained worse in those groups who had high levels of anxiety and depression pre-operatively but when matched for pre-operative physical function, psychological distress did not have any additional effect on outcome. CONCLUSIONS: Poor physical function pre-operatively correlates with psychological distress. Both physical and psychological symptoms improve after surgery. Physical outcome after surgery is strongly influenced by pre-operative physical functioning but not independently by psychological distress. Anxious and depressed patients should continue to be offered surgery if clinically indicated. PMID- 22248005 TI - Palladium-catalyzed oxidative Heck coupling reaction for direct synthesis of 4 arylcoumarins using coumarins and arylboronic acids. AB - An efficient protocol for the direct synthesis of 4-arylcoumarins via palladium catalyzed oxidative Heck coupling reaction of coumarins and arylboronic acids was developed. 4-Arylcoumarins were obtained in moderate to excellent yields, and the reaction also showed tolerance toward functional groups such as hydro, methoxy, diethylamino, nitro, and chloro groups. PMID- 22248009 TI - Surfactant adsorption onto interfaces: measuring the surface excess in time. AB - We propose a direct method to measure the equilibrium and dynamic surface properties of surfactant solutions with very low critical micellar concentrations (CMC) using a pendant drop tensiometer. We studied solutions of the nonionic surfactant hexaethylene glycol monododecyl ether (C(12)E(6)) and of the ionic surfactant hexadecyl trimethyl ammonium bromide (CTAB) with concentrated sodium bromide (NaBr). The variation of the surface tension as a function of surface concentration is obtained easily without the need for complex models and compares well with the result obtained using the Gibbs adsorption equation. The time dependent surface concentration of each surfactant was also measured, and the adsorption process was found to be diffusion-controlled. The diffusion coefficients of the two surfactants can be extracted from the data and were found in very good agreement with literature values, further validating the method. PMID- 22248010 TI - Use of the CogState Brief Battery in the assessment of Alzheimer's disease related cognitive impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. AB - The aim of this study was to validate the CogState Brief Battery, which assesses psychomotor, attentional, working memory, and visual learning functions, in healthy older people and in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. In healthy older adults, weak relationships between demographic variables (e.g., education, depression) and cognitive performance were observed. In AD and MCI groups, the magnitude of impairment was greatest for tasks of working memory and memory, with a negative influence of apolipoprotein E epsilon4 status on learning but not working memory. These results suggest that the CogState Brief Battery can be used to screen for AD-related cognitive changes. PMID- 22248012 TI - Pigment epithelium-derived factor increases in type 2 diabetes after treatment with metformin. AB - OBJECTIVE: Pigment epithelium-derived factor (PEDF) has anti-angiogenic, immunomodulatory and anti-inflammatory properties. In addition to the significant role it plays in reducing diabetic complications, PEDF is now used in the treatment of certain cancers. It possibly plays a role in insulin resistance cases, too. However, whether metformin treatment has any significant effects on PEDF levels is not known. In this study, we investigated the regulation of PEDF in type 2 diabetes in relation to fat mass and insulin resistance before and after the use of metformin for treatment. DESIGN: Prospective cohort study. SUBJECTS: Thirty-six patients with newly diagnosed type 2 diabetes and 33 healthy individuals. MEASUREMENTS: Baseline weight, waist circumference (WC), fasting (FPG) and postprandial (PPPG) glucose, insulin, HbA1c, HOMA, PEDF and total/truncal fat mass were determined both in the diabetic and control subjects. Procedures were repeated in the diabetic group after a 6-month metformin treatment. RESULTS: Baseline FPG, PPPG, HbA1c, HOMA, weight, WC and truncal fat mass were higher in patients with diabetes whereas PEDF levels were found to be comparable with the controls. We completed the study with 31 of the 36 patients with diabetes we had selected for the study. We observed a decrease in the weight, WC, FPG, PPPG, HOMA, total and truncal fat mass of the patients while there was a significant rise in the PEDF levels (P = 0.002) after the metformin treatment. On the other hand, no significant correlation was observed between the change in PEDF levels and the clinical and laboratory findings. CONCLUSION: Our study is the first to identify a metformin-related increase in PEDF levels in diabetes. The increase observed in PEDF levels after the metformin treatment does not seem to be related to the changes in insulin resistance, fat mass or glycemic control. Hence, our results suggest that further investigation is necessary to determine the direct effects of metformin on PEDF gene and protein expression in vitro. PMID- 22248011 TI - Undergraduate student drinking and related harms at an Australian university: web based survey of a large random sample. AB - BACKGROUND: There is considerable interest in university student hazardous drinking among the media and policy makers. However there have been no population based studies in Australia to date. We sought to estimate the prevalence and correlates of hazardous drinking and secondhand effects among undergraduates at a Western Australian university. METHOD: We invited 13,000 randomly selected undergraduate students from a commuter university in Australia to participate in an online survey of university drinking. Responses were received from 7,237 students (56%), who served as participants in this study. RESULTS: Ninety percent had consumed alcohol in the last 12 months and 34% met criteria for hazardous drinking (AUDIT score >= 8 and greater than 6 standard drinks in one sitting in the previous month). Men and Australian/New Zealand residents had significantly increased odds (OR: 2.1; 95% CI: 1.9-2.3; OR: 5.2; 95% CI: 4.4-6.2) of being categorised as dependent (AUDIT score 20 or over) than women and non-residents. In the previous 4 weeks, 13% of students had been insulted or humiliated and 6% had been pushed, hit or otherwise assaulted by others who were drinking. One percent of respondents had experienced sexual assault in this time period. CONCLUSIONS: Half of men and over a third of women were drinking at hazardous levels and a relatively large proportion of students were negatively affected by their own and other students' drinking. There is a need for intervention to reduce hazardous drinking early in university participation. TRIAL REGISTRATION: ACTRN12608000104358. PMID- 22248013 TI - A review of surgical techniques for impending distal erosion and intraoperative penile implant complications: part 2 of a three-part review series on penile prosthetic surgery. AB - INTRODUCTION: More than half of intraoperative complications occur during dilatation of the corpora cavernosa, a critical step in the placement of any type of penile prosthesis, which can be especially difficult in a patient with corporal fibrosis. A late manifestation of cylinder placement can be impending erosion with lateral extrusion or medial deviation (into the urethra) of the distal tips. There are many different approaches to try and fix these surgical issues. AIM: The review article evaluates the many different surgical techniques prosthetic surgeons use in the management of intraoperative complications and lateral extrusion. METHODS: A review of the literature was preformed with published results being evaluated to try to help guide the management of intraoperative complications and impending distal erosion. There is a special focus on dilation of the corpora cavernosa. MAIN OUTCOMES MEASURES: The article reviews and evaluates the outcomes of the landmark papers in the management of intraoperative complications and impending distal erosion. RESULTS: Intraoperative complications of penile implant placement can be distressing for the prosthetic surgeon, but with proper recognition, most of these complications can be navigated with excellent postoperative results. CONCLUSIONS: This review article summarizes many of the techniques, outcomes, and new developments in the complicated field of penile prosthetic surgery to help guide the implanting surgeon. PMID- 22248015 TI - Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention? AB - BACKGROUND: Alzheimer's disease has become a growing socio-economical concern in developing countries where increased life expectancy is leading to large aged populations. While curing Alzheimer's disease or stopping its progression does not appear within reach in a foreseeable future, new therapies capable of delaying the pathogenesis would represent major breakthroughs. PRESENTATION OF THE HYPOTHESIS: The growing number of medical benefits of cannabinoids, such as their ability to regulate age-related processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of AD. TESTING THE HYPOTHESIS: To test this hypothesis, epidemiological studies on long term, chronic cannabinoid users could enlighten us on the potential benefits of these compounds in normal and pathological ageing processes. Systematic pharmacological (and thus more mechanistic) investigations using animal models of Alzheimer's disease that have been developed would also allow a thorough investigation of the benefits of cannabinoid pharmacotherapy in the pathogenesis of Alzheimer's disease. IMPLICATIONS OF THE HYPOTHESIS: The chronic administration of non-selective cannabinoids may delay the onset of cognitive deficits in AD patients; this will dramatically reduce the socio economic burden of AD and improve the quality of life of the patients and their families. PMID- 22248016 TI - Prompt before the choice is made: effects of a stair-climbing intervention in university buildings. AB - OBJECTIVES: Recent interventions report positive results following a multi component campaign to increase stair climbing. This study investigated the effectiveness of volitional and motivational components of a stair-climbing intervention in the workplace. Design. Interrupted time-series design. METHODS: Ascending stair/lift choices, coded by gender, were observed between 08:00-10:00 and 14:15-16:15 on weekdays, in four university buildings (n = 14,138; 46% female). Baseline observations (stage 1; 5 days) preceded a motivational intervention, that is, a poster positioned inside the lift(s), that was positioned in each building (stage 2; 5 days). Next a volitional intervention, that is, point-of-choice prompt, supplemented the motivational one (stage 3; 8 days). Logistic regression analysis of stair/lift choices included the independent variables of intervention components, gender, time of day, building height, number of lifts, and pedestrian traffic. RESULTS: There was no significant change in stair climbing when the motivational component was positioned alone (Odds Ratio [OR] = 0.93, 95% Confidence Interval [CI] = 0.85 1.02, p = .123). In contrast, stair climbing increased significantly when the volitional component, that is, the point-of-choice prompt, was added (OR = 1.23, 95% CI = 1.14-1.32, p < .001). During both stages, building height, number of lifts, time of day, and pedestrian traffic were all associated with stair climbing. No significant gender effects were seen. CONCLUSIONS: A motivational component positioned alone, inside the lift(s) did not increase stair climbing. When a volitional component was added, that is, point-of-choice prompt positioned at the time and place where individuals choose their method of ascent, stair climbing increased significantly. Visibility of a prompt at the time behavioural choice is made appears necessary to change actual behaviour. PMID- 22248017 TI - Andropausal symptoms in men with Type 2 diabetes. AB - AIMS: Serum androgen concentration is reported to be low in patients with Type 2 diabetes. There have been no studies comparing andropausal symptoms such as sleep disturbance, depression, erectile dysfunction and lower urinary tract symptoms simultaneously between men with Type 2 diabetes and subjects without diabetes. METHODS: We compared andropausal symptom scores such as the Pittsburgh Sleep Quality Index, the Self-Rating Depression Scale, the International Index of Erectile Function and the International Prostate Symptom Score in 296 men with Type 2 diabetes and in 267 subjects without diabetes. Furthermore, we evaluated relationships of andropausal symptom scores to various anthropometric factors and compared andropausal symptom scores according to diabetic complications in men with Type 2 diabetes. RESULTS: Andropausal symptom scores such as the Pittsburgh Sleep Quality Index, the Self-Rating Depression Scale, the International Index of Erectile Function and the International Prostate Symptom Score were 4.2 +/- 2.6 vs. 5.0 +/- 3.3, P<0.01 by unpaired Student's t-test, 34.8 +/- 8.2 vs. 38.4 +/- 9.3, P<0.0001, 11.5 +/- 6.4 vs. 9.9 +/- 6.9, P<0.01 and 7.3 +/- 6.7 vs. 9.0 +/- 7.1, P<0.01 in subjects without diabetes and in patients with diabetes, respectively. The Pittsburgh Sleep Quality Index was higher in patients with neuropathy than without. The Self-Rating Depression Scale was higher in patients with advanced retinopathy. The International Index of Erectile Function was lower in patients with advanced retinopathy and nephropathy. The International Index of Erectile Function was lower and the International Prostate Symptom Score was higher in patients with cardiovascular disease than without. CONCLUSIONS: Our data demonstrated that men with Type 2 diabetes have higher prevalence of andropausal symptoms, especially those with diabetic complications. PMID- 22248018 TI - Increased incidence of aberrant DNA methylation within diverse imprinted gene loci outside of IGF2/H19 in Silver-Russell syndrome. AB - Almost half of the patients with Silver-Russell syndrome (SRS) are affected by DNA hypomethylation of the Imprinting Center Region 1 (ICR1) at the IGF2/H19 locus on 11p15. We searched genome-wide for additional aberrant DNA methylation in such SRS patients that could account for the clinical variability of the disorder. For this purpose, 18 children with SRS (11 with ICR1 hypomethylation) and 9 children small for gestational age (SGA), serving as controls, were recruited. Genomic DNA from whole blood was subjected to microarray analysis with the HumanMethylation27 BeadChip. This array allows investigating 27,500 CpG sites mostly located in the promoter regions of 14,000 genes. Data were validated by the methylation-specific multiplex ligation-dependent probe amplification (MS MLPA) technique for the 11p15 region. SRS patients with ICR1 hypomethylation were significantly more frequently affected by DNA hypo- and hypermethylation of CpG sites from diverse imprinted loci than the SGA controls (p = 0.0048). There was no recurrent specific methylation defect outside of IGF2/H19. These findings suggest as causative in SRS a defective mechanism necessary for establishment or maintenance of imprinting marks, which affects imprinted loci in general with low specificity and the IGF2/H19 locus with high specificity, implying the existence of some structural peculiarities at the IGF2/H19 locus. PMID- 22248020 TI - A strand specific high resolution normalization method for chip-sequencing data employing multiple experimental control measurements. AB - BACKGROUND: High-throughput sequencing is becoming the standard tool for investigating protein-DNA interactions or epigenetic modifications. However, the data generated will always contain noise due to e.g. repetitive regions or non specific antibody interactions. The noise will appear in the form of a background distribution of reads that must be taken into account in the downstream analysis, for example when detecting enriched regions (peak-calling). Several reported peak callers can take experimental measurements of background tag distribution into account when analysing a data set. Unfortunately, the background is only used to adjust peak calling and not as a pre-processing step that aims at discerning the signal from the background noise. A normalization procedure that extracts the signal of interest would be of universal use when investigating genomic patterns. RESULTS: We formulated such a normalization method based on linear regression and made a proof-of-concept implementation in R and C++. It was tested on simulated as well as on publicly available ChIP-seq data on binding sites for two transcription factors, MAX and FOXA1 and two control samples, Input and IgG. We applied three different peak-callers to (i) raw (un-normalized) data using statistical background models and (ii) raw data with control samples as background and (iii) normalized data without additional control samples as background. The fraction of called regions containing the expected transcription factor binding motif was largest for the normalized data and evaluation with qPCR data for FOXA1 suggested higher sensitivity and specificity using normalized data over raw data with experimental background. CONCLUSIONS: The proposed method can handle several control samples allowing for correction of multiple sources of bias simultaneously. Our evaluation on both synthetic and experimental data suggests that the method is successful in removing background noise. PMID- 22248019 TI - Clinical utility of biomarkers of endothelial activation in sepsis--a systematic review. AB - INTRODUCTION: A strong biologic rationale exists for targeting markers of endothelial cell (EC) activation as clinically informative biomarkers to improve diagnosis, prognostic evaluation or risk-stratification of patients with sepsis. METHODS: The objective was to review the literature on the use of markers of EC activation as prognostic biomarkers in sepsis. MEDLINE was searched for publications using the keyword 'sepsis' and any of the identified endothelial derived biomarkers in any searchable field. All clinical studies evaluating markers reflecting activation of ECs were included. Studies evaluating other exogenous mediators of EC dysfunction and studies of patients with malaria and febrile neutropenia were excluded. RESULTS: Sixty-one studies were identified that fulfilled the inclusion criteria. Overall, published studies report positive correlations between multiple EC-derived molecules and the diagnosis of sepsis, supporting the critical role of EC activation in sepsis. Multiple studies also reported positive associations for mortality and severity of illness, although these results were less consistent than for the presence of sepsis. Very few studies, however, reported thresholds or receiver operating characteristics that would establish these molecules as clinically-relevant biomarkers in sepsis. CONCLUSIONS: Multiple endothelial-derived molecules are positively correlated with the presence of sepsis in humans, and variably correlated to other clinically-important outcomes. The clinical utility of these biomarkers is limited by a lack of assay standardization, unknown receiver operating characteristics and lack of validation. Additional large-scale prospective clinical trials will be required to determine the clinical utility of biomarkers of endothelial activation in the management of patients with sepsis. PMID- 22248021 TI - Direct detection of DNA conformation in hybridization processes. AB - DNA hybridization studies at surfaces normally rely on the detection of mass changes as a result of the addition of the complementary strand. In this work we propose a mass-independent sensing principle based on the quantitative monitoring of the conformation of the immobilized single-strand probe and of the final hybridized product. This is demonstrated by using a label-free acoustic technique, the quartz crystal microbalance (QCM-D), and oligonucleotides of specific sequences which, upon hybridization, result in DNAs of various shapes and sizes. Measurements of the acoustic ratio DeltaD/DeltaF in combination with a "discrete molecule binding" approach are used to confirm the formation of straight hybridized DNA molecules of specific lengths (21, 75, and 110 base pairs); acoustic results are also used to distinguish between single- and double stranded molecules as well as between same-mass hybridized products with different shapes, i.e., straight or "Y-shaped". Issues such as the effect of mono and divalent cations to hybridization and the mechanism of the process (nucleation, kinetics) when it happens on a surface are carefully considered. Finally, this new sensing principle is applied to single-nucleotide polymorphism detection: a DNA hairpin probe hybridized to the p53 target gene gave products of distinct geometrical features depending on the presence or absence of the SNP, both readily distinguishable. Our results suggest that DNA conformation probing with acoustic wave sensors is a much more improved detection method over the popular mass-related, on/off techniques offering higher flexibility in the design of solid-phase hybridization assays. PMID- 22248022 TI - Metabolic, hormonal and stress-related molecular changes in post-mortem pituitary glands from schizophrenia subjects. AB - OBJECTIVES: To identify a molecular profile for schizophrenia using post-mortem pituitaries from schizophrenia and control subjects. METHODS: Molecular profiling analysis of pituitaries from schizophrenia (n = 14) and control (n = 15) subjects was carried out using a combination of liquid chromatography tandem mass spectrometry (LC-MS(E)), multiplex analyte profiling (MAP), two-dimensional difference gel electrophoresis (2D-DIGE) and Western blot analysis. RESULTS: This led to identification of differentially expressed molecules in schizophrenia patients including hypothalamic-pituitary-adrenal axis-associated constituents such as cortisol, pro-adrenocorticotropic hormone, arginine vasopressin precursor, agouti-related protein, growth hormone, prolactin and secretagogin, as well as molecules associated with lipid transport and metabolism such as apolipoproteins A1, A2, C3 and H. Altered levels of secretagogin in serum from a cohort of living first onset schizophrenia patients were also detected, suggesting disease association and illustrating the potential for translating some components of this molecular profile to serum-based assays. CONCLUSIONS: Future studies on the molecules identified here may lead to new insights into schizophrenia pathophysiology and pave the way for translation of novel diagnostics for use in a clinical setting. PMID- 22248023 TI - Posterior musculofascial plate reconstruction promotes early restoration of continence and prevents severe incontinence in patients undergoing laparoscopic radical prostatectomy. AB - The objective of the present study was to assess the efficacy of posterior reconstruction of Denonvilliers' musculofascial plate for restoring urinary continence after laparoscopic radical prostatectomy. A total of 48 consecutive patients who underwent laparoscopic radical prostatectomy were retrospectively reviewed. Of them, 23 underwent laparoscopic radical prostatectomy without posterior reconstruction of Denonvilliers' musculofascial plate (group 1) and 25 underwent laparoscopic radical prostatectomy with posterior reconstruction of Denonvilliers' musculofascial plate (group 2). Patients' demographics were analyzed and continence rates between the two groups at 1, 3, 6 and 12 months after surgery were compared. Patients in group 2 had significantly larger prostates than in group 1. There were no significant differences between the two groups in terms of the other patient characteristics. The urinary continence rates were significantly higher in group 2 than in group 1 at 1, 3 and 12 months after surgery, and the rates of severe incontinence were significantly lower in group 2 at all time-points considered. These findings suggest that posterior reconstruction of Denonvilliers' musculofascial plate helps in restoring early continence and decreasing severe incontinence in patients undergoing laparoscopic radical prostatectomy. PMID- 22248024 TI - Monitoring of African swine fever in the wild boar population of the most recent endemic area of Spain. AB - Wild boars are natural hosts for African swine fever (ASF). The ASF virus (ASFV) can persist for long periods in the environment, such as in ticks and contaminated products, which may be sources of infection for wild boar populations. African swine fever was eradicated in domestic pig populations in Spain in 1995, after 35 years of significant effort. To determine whether ASFV can persist in wild boar hosts after it has been eradicated from domestic pigs and to study the role of wild boar in helping ASFV persist in the environment, we checked for the presence of ASFV in wild boars in Donana National Park, one of the largest natural habitats of wild boar in Spain and one of the last areas where ASF was endemic prior its eradication. Samples from 158 animals collected between 2006 and 2010 were analysed using serological and nucleic acid-based diagnostic techniques recommended by the World Organization for Animal Health (OIE). None of the samples was found to be positive. These results confirm the absence of disease in wildlife in what was once one of the areas most affected by ASF in Spain, and they suggest that wild boars play a limited role in ASFV persistence. These results confirm that ASFV cannot persist in isolated wild boar populations for long periods of time without the interaction of other factors such as re-infection by contact with domestic pigs or by feeding on contaminated swill. PMID- 22248025 TI - Functional disruption of the pentatricopeptide protein SLG1 affects mitochondrial RNA editing, plant development, and responses to abiotic stresses in Arabidopsis. AB - Land plants contain a large family of genes that encode for pentatricopeptide (PPR) proteins. To date, few of these PPR proteins have been functionally characterized. In this study, we have analyzed an Arabidopsis mutant, slg1, which exhibits slow growth and delayed development. In addition, slg1 shows an enhanced response to ABA and increased tolerance to drought stress. The SLG1 gene encodes a PPR protein that is localized in mitochondria. In the slg1 mutant, RNA editing in a single site of the mitochondrial transcript nad3 is abolished. nad3 is a subunit of complex I of the electron transport chain in mitochondria. As a consequence, the NADH dehydrogenase activity of complex I in slg1 is strongly impaired and production of ATP is reduced. When responding to ABA treatment, slg1 accumulates more H(2) O(2) in its guard cells than the wild type. The slg1 mutant also has an increased expression of genes involved in the alternative respiratory pathway, which may compensate for the disrupted function of complex I and help scavenge the excess accumulation of H(2) O(2). Our functional characterization of the slg1 mutant revealed a putative link between mitochondrial RNA editing and plant responses to abiotic stress. PMID- 22248026 TI - What you say matters: exploring visual-verbal interactions in visual working memory. AB - The aim of this study was to explore whether the content of a simple concurrent verbal load task determines the extent of its interference on memory for coloured shapes. The task consisted of remembering four visual items while repeating aloud a pair of words that varied in terms of imageability and relatedness to the task set. At test, a cue appeared that was either the colour or the shape of one of the previously seen objects, with participants required to select the object's other feature from a visual array. During encoding and retention, there were four verbal load conditions: (a) a related, shape-colour pair (from outside the experimental set, i.e., "pink square"); (b) a pair of unrelated but visually imageable, concrete, words (i.e., "big elephant"); (c) a pair of unrelated and abstract words (i.e., "critical event"); and (d) no verbal load. Results showed differential effects of these verbal load conditions. In particular, imageable words (concrete and related conditions) interfered to a greater degree than abstract words. Possible implications for how visual working memory interacts with verbal memory and long-term memory are discussed. PMID- 22248028 TI - Down-regulation of survivin and hypoxia-inducible factor-1 alpha by beta-elemene enhances the radiosensitivity of lung adenocarcinoma xenograft. AB - Elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane) is a naturally occurring compound that can be isolated from the traditional Chinese medicinal herb Curcuma wenyujin. beta-elemene, its active component, has recently been demonstrated to enhance the radiosensitivity of human cancer cell lines in vitro and of one animal tumor in vivo. The underlying mechanism, however, is still unclear. In this study, we demonstrated for the first time that beta-elemene significantly improves the radiosensitivity of A549 lung adenocarcinoma xenograft in vivo as measured by tumor regrowth delay experiments. Our results showed that beta elemene, at 45 mg/kg, significantly inhibited radiation-induced expression of survivin and hypoxia-inducible factor (HIF)-1 alpha proteins. Because HIF-1 alpha is known to regulate survivin transcription and acts as upstream regulator of survivin, it is possible that beta-elemene regulates the transcription of survivin through HIF-1 alpha. Our study suggests that beta-elemene is a promising drug to enhance tumor radioresponse, and survivin and HIF-1 alpha are novel targets of beta-elemene. PMID- 22248031 TI - Bioactive compounds with effects on inflammation markers in humans. AB - Obesity and other chronic diseases are accompanied by adipose tissue, liver, pancreas, muscle and brain low-grade chronic inflammation. Indeed, the obese condition and metabolic syndrome are characterized by an increased expression of inflammatory cytokines and infiltration of immune cells in adipocytes. The inflammatory response promotes the activation of transcriptional factors and pro inflammatory cytokines, which can lead to an unresolved inflammatory response associated with an inhibition of insulin signalling and high risk for cardiovascular events. Epidemiological and intervention studies have been carried out to find out dietary patterns, foods and bioactive compounds with protective anti-inflammatory actions. The most studied compounds are polyphenols, especially isoflavone and anthocyanin, but quercertin, catechin and resveratrol have also been investigated. Furthermore, some studies have reported the effects of milk peptides, plant sterol and stanol, l-carnitine and alpha-lipoic acid on inflammatory processes. This review aimed to collect and discuss those relevant studies reported in the scientific literature following a systematic scientific search about the effect of such bioactive compounds on inflammation in humans. PMID- 22248032 TI - Two new compounds from marine-derived fungus Penicillium sp. F11. AB - Two new compounds, penicillone A (1) and penicillactam (2), were isolated together with 17 known compounds from a marine-derived fungus Penicillium sp. F11. The structures of the new compounds as well as a firstly literatural reported known compound (3) were assigned by spectroscopic methods including 1D/2D NMR and MS analysis techniques. Their cytotoxicities against HT1080, Cne2, and Bel7402 cell lines were also evaluated. PMID- 22248033 TI - A systematic review of randomized controlled trials on the theraputic effect of intravenous sodium valproate in status epilepticus. AB - We performed this systematic review to determine whether intravenous sodium valproate was more effective or safer than other drugs in patients with status epilepticus (SE). A literature search was performed using Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). From 544 articles screened, 5 were identified as randomized controlled trials and were included for data extraction. The main outcomes were SE controlled and risk of seizure continuation. The meta-analysis was performed with the Random-effect model. The quality of the included studies was evaluated by GRADE (Grading of Recommendations Assessment, Development, and Evaluation). There was no significant statistics in SE controlled between intravenous sodium valproate and phenytoin. Compared with diazepam, sodium valproate had a statistically significant lower risk of time interval for control of refractory SE (RSE) after having drugs; however, there was no statistically significant difference in SE controlled within 30 min between the two groups. There was no statistically significant difference in cessation from status between intravenous sodium valproate and levetiracetam. Intravenous sodium valprate was as effective as intravenous phenytoin for SE controlled and risk of seizure continuation. PMID- 22248034 TI - Neuroprotection by nicotine against colchicine-induced apoptosis is mediated by PI3-kinase--Akt pathways. AB - Although nicotine is known to protect against beta-amyloid (Abeta)-induced neurotoxicity, the effect of nicotine on colchicine-induced neurotoxicity remains unknown. Colchicine is a microtubule-interfering agent and is able to induce neural apoptosis. Here we investigated whether nicotine exhibits similar neuroprotective effects and the mechanism against colchicine-induced neurotoxicity of the primarily cultured cortical neurons. In this study, we investigated the effect of nicotine on the protection of neurons against colchicine damage and evaluated the associated intracellular signaling pathways. Nicotine-induced protection was blocked by an alpha7 nicotinic acetylcholine receptors (nAChRs) antagonist and a phosphatidylinositol 3-kinase (PI3K) inhibitor. These results suggest that the neuroprotective effects of nicotine are mediated by the alpha7 nAChRs and PI3K-Akt signaling pathway. In addition, we reveal that blockade of p38 and JNK (c-Jun N-terminal kinase) signaling increased Akt signaling, thus enhancing the survival of cell treatment with colchicine. On the other hand, inhibition of constitutively active Akt enhanced p38 or JNK signaling phosphorylation. These data suggested that crosstalk between PI3K Akt and p38 or JNK signaling pathways contributed to nicotine against colchicine induced cytotoxicity. PMID- 22248035 TI - Oxidative damage is ameliorated by curcumin treatment in brain and sciatic nerve of diabetic rats. AB - To date, there have not been enough studies about the effects of curcumin against oxidative stress on sciatic nerves caused by streptozotocin (STZ) in diabetic rats. Therefore, this study was undertaken to determine whether curcumin, by virtue of its antioxidant properties, could affect the oxidant/antioxidant balance in the sciatic nerve and brain tissues of streptozotocin (STZ)-induced diabetic rats. A total of 28 rats were randomly divided into four groups of seven rats each: normal controls, only curcumin treated, diabetic controls, and diabetics treated with curcumin. Biomarkers-malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and NO levels-for oxidative stress in the brain and sciatic nerve tissues of the rats were measured. We found a significant increase in MDA, NO, TOS, and OSI, along with a reduction in TAS levels in the brains and sciatic nerves of the STZ induced diabetic rats (for both parameters p < 0.05). The MDA, TOS, OSI, and NO levels in these tissues were significantly reduced in the curcumin-treated diabetic group compared to the untreated diabetic group. In conclusion, the results of this study suggested that curcumin exhibits neuroprotective effects against oxidative damage in the brain and sciatic tissues of diabetic rats. PMID- 22248036 TI - MRI findings of neurological complications in hand-foot-mouth disease by enterovirus 71 infection. AB - OBJECTIVE: To explore the imaging characterization of neurological complications associated with the enterovirus 71 (EV71) epidemics. METHODS: Thirty-five cases of hand-foot-mouth disease with neurological complications during the recent EV71 outbreaks in Hainan Province, China, from May 2008 to September 2010 were collected. All patients were performed MRI scan. The clinical data and MRI appearance were analyzed. RESULTS: Acute flaccid paralysis associated with EV71 infected hand-foot-mouth diseases was seen in seven cases. The typical MRI appearance was linear long T2 signal intensity in the posterior part of spinal cord. Symmetrical, well-defined hyperintensity lesions in the spinal cord were seen in T2-weighted transverse images. Obvious enhancements of the ventral horns and root were seen in the contrast-enhanced axial T1-weighted image. In 21 cases of pontine encephalitis, long T1 and long T2 signal intensity was seen in the posterior portions of the medulla oblongata, midbrain, and pons. It is nonspecific MRI appearance in seven cases of aseptic meningitis (AM), but subdural effusion, meningeal enhancement, and hydrocephalus can be indirect sign of AM. CONCLUSION: MRI is an effective modality to investigate neurological complications associated with the EV71 epidemics. Involvements of posterior portions of the medulla oblongata and pons, and bilateral anterior horns of spinal cord are characteristic findings. PMID- 22248037 TI - Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy. AB - OBJECTIVE: To validate the American Thyroid Association (ATA) initial risk of recurrence scheme and the Memorial Sloan Kettering Cancer Center (MSKCC) response to therapy re-stratification approach in a large cohort of patients with differentiated thyroid cancer (DTC) treated outside of the United States. DESIGN: Retrospective chart review. PATIENTS: Five hundred and six patients with DTC followed for a median of 10 years after total thyroidectomy and RAI remnant ablation at a major cancer centre in Brazil. MEASUREMENTS: Final clinical outcomes were assessed based on American Joint Cancer Committee (AJCC)/Union Internationale Contre le Cancer (UICC) staging, ATA risk stratification and response to therapy assessment (excellent, acceptable, biochemical incomplete and structural incomplete). RESULTS: The AJCC/UICC staging system did not adequately stratify patients with regard to the risk of recurrence/persistent disease. However, the ATA system demonstrated a 13% risk of recurrent/persistent disease in low-risk patients, 36% in intermediate risk patients, and 68% in high-risk patients. Furthermore, an excellent response to therapy decreased the risk of recurrent/persistent disease to 1.4%. At the time of final follow-up, 34% of the biochemical incomplete response patients had been re-classified as having no evidence of disease (NED) without having received any additional therapy beyond continue levothyroxine suppression. Conversely, even after additional therapies, only 9% of the patients with an incomplete structural response were eventually re classified as NED. CONCLUSIONS: These data validate the ATA risk classification as an excellent initial predictor of recurrent/persistent disease and confirm the clinical utility of the MSKCC dynamic risk assessment system in a cohort of patients evaluated and treated outside the United States. PMID- 22248038 TI - Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study. AB - INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is the most common form of female sexual dysfunction and is characterized by low sexual desire that causes distress. AIM: The aim of this study was to assess the efficacy and safety of flibanserin, a postsynaptic 5-HT(1A) agonist/5-HT(2A) antagonist, in premenopausal women with HSDD. METHODS: North American premenopausal women with HSDD were randomized to 24 weeks' treatment with placebo (N = 295), flibanserin 50 mg (N = 295), or flibanserin 100 mg (N = 290), once daily at bedtime. MAIN OUTCOME MEASURES: Coprimary endpoints were change from baseline to study end in number of satisfying sexual events (SSE) and sexual desire score measured daily using an electronic diary (eDiary). Secondary endpoints included change from baseline to study end in female sexual function index (FSFI) desire domain and total scores, female sexual distress scale-revised (FSDS-R) Item 13 and total scores, and patient's global impression of improvement. RESULTS: Flibanserin 50 mg and 100 mg led to increases in SSE (P < 0.05 and P < 0.01 vs. placebo, respectively). There was a numerical trend toward improvement in eDiary desire score on flibanserin 100 mg, but statistical significance was not reached (P = 0.07 vs. placebo). FSFI desire domain and total scores increased with both flibanserin regimens (P < 0.05). FSDS-R total and Item 13 scores decreased with flibanserin 100 mg (P < 0.001), indicating reduced sexual distress. More women receiving flibanserin 50 mg and 100 mg considered their HSDD to have improved than women receiving placebo (39.6% and 50.0% vs. 30.3%, respectively) (P < 0.05). CONCLUSION: In premenopausal women with HSDD, flibanserin 50 mg and 100 mg once daily at bedtime were well tolerated and associated with statistically significant improvements in SSE, sexual desire (FSFI desire domain score but not eDiary desire score) and overall sexual function, and reduction of sexual distress, vs. placebo. PMID- 22248039 TI - IFN-gamma signaling in the central nervous system controls the course of experimental autoimmune encephalomyelitis independently of the localization and composition of inflammatory foci. AB - BACKGROUND: Murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFNgamma) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFNgamma signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive. METHODS: We induced EAE in IFNgamma-/- mice and bone marrow chimeric mice in which IFNgammaR is not expressed in the CNS but is intact in the periphery (IFNgammaRCNSKO) and vice versa (IFNgammaRperiKO). Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration. RESULTS: Incidence and severity of atypical EAE were more pronounced in IFNgammaRCNSKO as compared to IFNgammaRperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFNgammaRCNSKO mice were only minimally infiltrated, while the same areas of IFNgammaRperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFNgammaRperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFNgammaRCNSKO. Immunohistochemical analysis of the CNS of IFNgamma-/- and IFNgammaR chimeric mice revealed that IFNgamma protective actions are exerted through microglial STAT1. CONCLUSIONS: Alterations in distribution and composition of CNS inflammatory foci are not sufficient for the onset of atypical EAE. IFNgamma dictates the course of neuroinflammatory disorders mainly through actions exerted within the CNS. This study provides strong evidence that link microglial STAT1 inactivation to vestibular dysfunction. PMID- 22248040 TI - Evaluation of postural balance in postmenopausal women and its relationship with bone mineral density--a cross sectional study. AB - BACKGROUND: Low bone mineral density (BMD) and falls are common problems encountered in the postmenopausal women. The purpose was to evaluate the association between postural balance and BMD in postmenopausal women and its relation to risk for falls. METHODS: In this cross-sectional study, 225 women in amenorrhea > 12 months and age >= 45 years were included and divided, according to BMD, in T-score values > -2.0 SD (n = 140) and <= -2 SD (n = 85). Those with neurological or musculoskeletal disorders, history of vestibulopathies, uncorrected visual deficit or drug use that could affect balance were excluded. History of falls (last 24 months), clinical and anthropometric characteristics were evaluated. Postural balance was assessed by stabilometry (force platform). For statistical analysis were used Wilcoxon's Test, Chi-Square Test and logistic regression method for fall risk (Odds Ratio-OR). RESULTS: Patients with BMD > 2.0 SD were younger, with shorter time since menopause, and showed higher BMI as compared to those with low BMD (<= -2 SD) (p < 0.05). It was observed that 57.8% of the participants reported fall episodes without significant difference distribution between the groups (p = 0.055). No differences were found from the comparison between the groups (p > 0.05) for stabilometric parameters. Risk for falls increased with age (OR 1.07; CI 95% 1.01-1.13), current smoking (OR 2.19; CI 95% 1.22-3.21) and corrected visual deficit (OR 9.06; CI 95% 1.14-4.09). In contrast, hormone therapy (HT) use was significantly associated with reduced risk for falls (OR 0.48; CI 95% 0.26-0.88). CONCLUSIONS: In postmenopausal women, BMD did not show association with postural balance or risk for falls. Age, smoking and corrected visual deficit were clinical indicators of risk for falls whereas HT use showed to be a protective factor. PMID- 22248041 TI - Clusters of leprosy transmission and of late diagnosis in a highly endemic area in Brazil: focus on different spatial analysis approaches. AB - OBJECTIVE: The Brazilian National Hansen's Disease Control Program recently identified clusters with high disease transmission. Herein, we present different spatial analytical approaches to define highly vulnerable areas in one of these clusters. METHOD: The study area included 373 municipalities in the four Brazilian states Maranhao, Para, Tocantins and Piaui. Spatial analysis was based on municipalities as the observation unit, considering the following disease indicators: (i) rate of new cases/100,000 population, (ii) rate of cases <15 years/100,000 population, (iii) new cases with grade-2 disability/100,000 population and (iv) proportion of new cases with grade-2 disabilities. We performed descriptive spatial analysis, local empirical Bayesian analysis and spatial scan statistic. RESULTS: A total of 254 (68.0%) municipalities were classified as hyperendemic (mean annual detection rates >40 cases/100,000 inhabitants). There was a concentration of municipalities with higher detection rates in Para and in the center of Maranhao. Spatial scan statistic identified 23 likely clusters of new leprosy case detection rates, most of them localized in these two states. These clusters included only 32% of the total population, but 55.4% of new leprosy cases. We also identified 16 significant clusters for the detection rate <15 years and 11 likely clusters of new cases with grade-2. Several clusters of new cases with grade-2/population overlap with those of new cases detection and detection of children <15 years of age. The proportion of new cases with grade-2 did not reveal any significant clusters. CONCLUSIONS: Several municipality clusters for high leprosy transmission and late diagnosis were identified in an endemic area using different statistical approaches. Spatial scan statistic is adequate to validate and confirm high-risk leprosy areas for transmission and late diagnosis, identified using descriptive spatial analysis and using local empirical Bayesian method. National and State leprosy control programs urgently need to intensify control actions in these highly vulnerable municipalities. PMID- 22248042 TI - Pathophysiological role of inflammatory molecules in paediatric ischaemic brain injury. AB - Ischaemic stroke is one of the major causes of death and lifelong disability also in the paediatric population. Strong scientific effort has been put to clarify the pathophysiology of this disease in adults. However, only few studies have been performed in children. Preliminary results indicate that pathophysiological processes might differently affect the poststroke neuronal injury in neonates as compared to children. During the neural development, selective molecular mechanisms might be differently triggered by an ischaemic insult, thus potentially resulting in defined postischaemic clinical outcomes. Basic research studies in neonatal animal models of cerebral ischaemia have recently shown a potential role of soluble inflammatory molecules (such as cytokines, chemokines and oxidants) as pivotal players of neuronal injury in both perinatal and childhood ischaemic stroke. Although larger clinical trials are still needed to confirm these preliminary results, the potential benefits of selective treatments targeting inflammation in perinatal asphyxia encephalopathy might represent a promising investigation field in the near future. In this review, we will update evidence on the pathophysiological role of soluble inflammatory mediators in neonatal and childhood ischaemic stroke. Recent evidence on potential anti inflammatory treatments to improve paediatric stroke prognosis will be discussed. PMID- 22248043 TI - The risk of overall mortality in patients with Type 2 diabetes receiving different combinations of sulfonylureas and metformin: a retrospective analysis. AB - AIMS: Sulfonylureas have been shown to increase mortality when used in combination with metformin. This may not be a class effect of sulfonylureas, but rather secondary to differences in properties inherent to the individual sulfonylureas (hypoglycaemic risk, sulfonylurea receptor selectivity and effects on myocardial ischemic preconditioning). The purpose of this study was to assess the risk of overall mortality in patients with Type 2 diabetes treated with different combinations of sulfonylureas and metformin. METHODS: A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record system to identify 7320 patients with Type 2 diabetes (3768 initiators of glyburide (glibenclamide) and metformin, 2277 initiators of glipizide and metformin and 1275 initiators of glimepiride and metformin), >= 18 years of age and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality by documentation in the electronic health record and Social Security Death Index. Multivariable Cox models with propensity analysis were used to compare cohorts. RESULTS: No statistically significant difference in overall mortality risk was observed among the different combinations of sulfonylureas and metformin: glimepiride and metformin vs. glipizide and metformin (HR 1.03; 95% CI 0.89-1.20), glimepiride and metformin vs. glyburide (glibenclamide) and metformin (HR 1.08; 95% CI 0.90-1.30), or with glipizide and metformin vs. glyburide (glibenclamide) and metformin (HR 1.05; 95% CI 0.95-1.15). CONCLUSIONS: Our results did not identify an increased mortality risk among the different combinations of sulfonylureas and metformin, suggesting that overall mortality is not substantially influenced by the choice of sulfonylurea. PMID- 22248044 TI - Influence of respiratory rate and end-expiratory pressure variation on cyclic alveolar recruitment in an experimental lung injury model. AB - INTRODUCTION: Cyclic alveolar recruitment/derecruitment (R/D) is an important mechanism of ventilator-associated lung injury. In experimental models this process can be measured with high temporal resolution by detection of respiratory dependent oscillations of the paO2 (DeltapaO2). A previous study showed that end expiratory collapse can be prevented by an increased respiratory rate in saline lavaged rabbits. The current study compares the effects of increased positive end expiratory pressure (PEEP) versus an individually titrated respiratory rate (RRind) on intra-tidal amplitude of Delta paO2 and on average paO2 in saline lavaged pigs. METHODS: Acute lung injury was induced by bronchoalveolar lavage in 16 anaesthetized pigs. R/D was induced and measured by a fast-responding intra aortic probe measuring paO2. Ventilatory interventions (RRind (n=8) versus extrinsic PEEP (n=8)) were applied for 30 minutes to reduce Delta paO2. Haemodynamics, spirometry and Delta paO2 were monitored and the Ventilation/Perfusion distributions were assessed by multiple inert gas elimination. The main endpoints average and Delta paO2 following the interventions were analysed by Mann-Whitney-U-Test and Bonferroni's correction. The secondary parameters were tested in an explorative manner. RESULTS: Both interventions reduced Delta paO2. In the RRind group, DeltapaO2 was significantly smaller (P<0.001). The average paO2 continuously decreased following RRind and was significantly higher in the PEEP group (P<0.001). A sustained difference of the ventilation/perfusion distribution and shunt fractions confirms these findings. The RRind application required less vasopressor administration. CONCLUSIONS: Different recruitment kinetics were found compared to previous small animal models and these differences were primarily determined by kinetics of end expiratory collapse. In this porcine model, respiratory rate and increased PEEP were both effective in reducing the amplitude of paO2 oscillations. In contrast to a recent study in a small animal model, however, increased respiratory rate did not maintain end-expiratory recruitment and ultimately resulted in reduced average paO2 and increased shunt fraction. PMID- 22248047 TI - Determination of everolimus in blood samples from kidney and liver transplant recipients using the sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA) on the Architect-i1000(r) system. AB - BACKGROUND: There is significant immunoassay cross-reactivity between everolimus and sirolimus, and their routine determination using a common method may reduce the reagent costs. METHODS: In 122 blood samples from kidney (n = 30) and liver (n = 92) transplant recipients, everolimus concentrations were determined using the Abbott IMx(r) microparticle enzyme immunoassay (MEIA) as previously described, and the Abbott sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA) on the Architect-i1000(r) system. RESULTS: A high correlation coefficient (r = 0.981, p < 0.001) and a linear regression MEIA = 0.73CMIA + 0.55, with an acceptable standard error of the estimate (ma68 = 0.32 ng/mL), were obtained, indicating the transferability of the results produced by both immunoassays. CONCLUSIONS: The newly-developed sirolimus CMIA assay on the Architect(r) platform may be a valid alternative to other immunoassays for the routine therapeutic monitoring of everolimus. PMID- 22248045 TI - Meningeal defects alter the tangential migration of cortical interneurons in Foxc1hith/hith mice. AB - BACKGROUND: Tangential migration presents the primary mode of migration of cortical interneurons translocating into the cerebral cortex from subpallial domains. This migration takes place in multiple streams with the most superficial one located in the cortical marginal zone. While a number of forebrain-expressed molecules regulating this process have emerged, it remains unclear to what extent structures outside the brain, like the forebrain meninges, are involved. RESULTS: We studied a unique Foxc1 hypomorph mouse model (Foxc1hith/hith) with meningeal defects and impaired tangential migration of cortical interneurons. We identified a territorial correlation between meningeal defects and disruption of interneuron migration along the adjacent marginal zone in these animals, suggesting that impaired meningeal integrity might be the primary cause for the observed migration defects. Moreover, we postulate that the meningeal factor regulating tangential migration that is affected in homozygote mutants is the chemokine Cxcl12. In addition, by using chromatin immunoprecipitation analysis, we provide evidence that the Cxcl12 gene is a direct transcriptional target of Foxc1 in the meninges. Further, we observe migration defects of a lesser degree in Cajal Retzius cells migrating within the cortical marginal zone, indicating a less important role for Cxcl12 in their migration. Finally, the developmental migration defects observed in Foxc1hith/hith mutants do not lead to obvious differences in interneuron distribution in the adult if compared to control animals. CONCLUSIONS: Our results suggest a critical role for the forebrain meninges to promote during development the tangential migration of cortical interneurons along the cortical marginal zone and Cxcl12 as the factor responsible for this property. PMID- 22248048 TI - Large molecular size EDTA-resistant complexes containing S100A12, ERAC, in serum during inflammatory conditions. AB - The pro-inflammatory, leukocyte-derived S100A12 protein occurs as calcium dependent oligomers in serum, while EDTA plasma from the majority of healthy individuals contains only monomers. Addition of 5 mM EDTA to serum leads to a rapid dissociation of the oligomers in most samples. However, using gel permeation chromatography, we have found that sera from some patients and seemingly healthy individuals contain molecular complexes in the 400-1000 kDa range reacting with anti-S100A12 even in the presence of EDTA; for these we introduce the name ERAC (EDTA Resistant S100A12 Complexes). Based upon monoclonal antibodies and the lateral flow principle, we have developed a quantitative rapid ERAC test giving results within 10 minutes. The highest prevalence of ERAC positivity was found in sera from patients with concomitant rheumatoid arthritis and coronary heart disease. The structure of ERAC is not yet known. Further studies are needed to analyse the mechanism behind the appearance of ERAC and the possible association with inflammatory-related diseases. PMID- 22248049 TI - Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta amyloid levels and improves cognitive performance in Tg APP 2576 mice. AB - BACKGROUND: Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. METHODS: We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG) uptake by positron emission tomography (PET). RESULTS: Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-alpha mRNA expression found in the AD model. Increased cortical beta-amyloid (Abeta) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Abeta transport across choroid plexus cells in vitro. CONCLUSIONS: In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Abeta clearance. PMID- 22248050 TI - Lipid-bound apolipoproteins in tyrosyl radical-oxidized HDL stabilize ABCA1 like lipid-free apolipoprotein A-I. AB - BACKGROUND: ATP-binding cassette transporter A1 (ABCA1) mediates the lipidation of exchangeable apolipoproteins, the rate-limiting step in the formation of high density lipoproteins (HDL). We previously demonstrated that HDL oxidized ex vivo by peroxidase-generated tyrosyl radical (tyrosylated HDL, tyrHDL) increases the availability of cellular cholesterol for efflux and reduces the development of atherosclerosis when administered to apolipoprotein E-deficient mice as compared to treatment with control HDL. RESULTS: In the current study we determined that tyrHDL requires functional ABCA1 for this enhanced activity. Like lipid-free apolipoprotein A-I (apoA-I), tyrHDL increases total and cell surface ABCA1, inhibits calpain-dependent and -independent proteolysis of ABCA1, and can be bound by cell surface ABCA1 in human skin fibroblasts. Additionally, tyrHDL apoproteins are susceptible to digestion by enteropeptidase like lipid-free apoA I, but unlike lipid-bound apoA-I on HDL, which is resistant to proteolysis. CONCLUSIONS: These results provide the first evidence that lipid-bound apolipoproteins on the surface of spherical HDL particles can behave like lipid free apoA-I to increase ABCA1 protein levels and activity. PMID- 22248051 TI - Preface: special issue on yin yang 1 and oncogenesis. PMID- 22248054 TI - Oncogenic potential of yin yang 1 mediated through control of imprinted genes. AB - The transcription factor Yin Yang (YY) 1 is one of the most evolutionarily well conserved DNA binding proteins that is ubiquitously expressed among different tissue types. YY1 functions as a critical regulator for a diverse set of genes, making its role in the cancerous environment elusive. Recent studies have demonstrated that clusters of YY1 binding sites are overrepresented in imprinted gene loci. These clustered binding sites may function as a molecular rheostat with respect to YY1 protein levels. YY1 levels were documented to be altered in various tumor tissues in conjunction with the transcriptional levels of the imprinted genes it regulates. This review highlights the unexplored mechanism through which fluctuations in YY1 protein levels alter the transcriptional status of imprinted genes containing clustered YY1 binding sites, which potentially could affect cancer development and/or progression. PMID- 22248055 TI - The novel role of Yin Yang 1 in the regulation of epithelial to mesenchymal transition in cancer via the dysregulated NF-kappaB/Snail/YY1/RKIP/PTEN Circuitry. AB - The majority of cancers develop genetic and molecular strategies to resist conventional cytotoxic therapies as well as escape from the host's immune surveillance. These events lead to tumor persistence and spread through activation of the epithelial to mesenchymal transition (EMT) program and metastasis. Expression profiling analysis has revealed various tumor metastasis inducing and metastasis-suppressing genes that regulate the metastatic process and maintain the microenvironment of the tumor cells. EMT in cancer entails the molecular reprogramming and phenotypic changes that characterize the conversion of immobile cancer epithelial cells to motile mesenchymal cells. A hallmark of EMT is the loss of E-cadherin, the epithelial homotypic adhesion molecule, and gain of mesenchymal markers such as vimentin and fibronectin. The molecular mechanisms underlying the initiation of EMT consist, in part, in the constitutive activation of survival signaling pathways such as the nuclear factor (NF)-kappaB pathway. The NF-kappaB pathway has been implicated directly in the regulation of EMT and indirectly through the transcription and expression of several gene products that participate in the EMT cascade, such as Snail, the metastasis inducer and E-cadherin suppressor transcription factor. In turn, Snail represses the metastasis-suppressor gene product Raf-kinase inhibitor protein (RKIP) that inhibits both the Raf-1/MEK/ERK and NF-kappaB survival pathways implicated in EMT. Consequently, tumor cells normally exhibit a dysregulated NF kappaB/Snail/RKIP circuitry that is intimately involved in the initiation of EMT and maintenance of drug resistance. Additional deregulated gene products in this circuit, such as the metastasis-suppressor phosphatase and tensin homologue (PTEN; repressed by Snail) and the putative-metastasis inducer Yin Yang (YY) 1 (target of NF-kappaB) also have been associated in the regulation of EMT. We recently have investigated the direct role of YY1 in the regulation of EMT. This review discusses the molecular regulation of EMT in cancer cells through the activity of the dysregulated NF-kappaB/Snail/ YY1/PTEN/RKIP circuitry. In addition, we propose YY1 as a potential novel prognostic biomarker for EMT and a therapeutic target for both the prevention of metastasis and the reversal of resistance. PMID- 22248052 TI - Mechanisms of Yin Yang 1 in oncogenesis: the importance of indirect effects. AB - Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that performs numerous functions including transcriptional regulation, cell growth control, apoptosis, large-scale chromosomal dynamics, and X-chromosome inactivation. YY1 clearly is able to control cell functions, including proliferation, by acting as a transcription factor either to activate or repress specific genes. Based on its ability to regulate cell growth control genes, it has been argued that YY1 can function as an oncogene that initiates oncogenesis. Although this is an attractive hypothesis, no reports indicate that YY1 can acutely transform cells in culture or form tumors within animals when overexpressed. Thus, it remains unclear whether YY1 is a "classic" oncogene. However, YY1 controls many diverse cell functions, and these functions may provide clues to its role in oncogenesis. We propose that in many cases YY1 may function in oncogenesis and disease progression through "indirect" effects by virtue of its role in either recruiting Polycomb group proteins to DNA, regulating mutator protein accumulation, controlling large-scale chromosomal dynamics or genomic integrity. Disruption of these functions may causally initiate cancer or may contribute to disease progression. Targeting YY1 functions provides possible avenues for clinical intervention. PMID- 22248056 TI - Transcription regulator Yin-yang 1: from silence to cancer. AB - Yin Yang (YY) 1 represents the epitome of what is considered to be a "Swiss army knife" transcription factor and regulator. YY1 is a ubiquitous and multifunctional zinc-finger transcription factor member of the Polycomb group protein family, a group of homeobox gene receptors that can act as activators or repressors of transcriptional activity. Furthermore, YY1 can act as a redox sensor, adaptor molecule, and chromatin structure and function regulator. YYl's characteristic function as transcriptional activator and repressor relies on its C2H2 (x4) zinc-finger structural DNA-binding motifs tangled with 2 specific regulatory domains. This structural conformation will render the activity of YY1 susceptible to changes in cellular redox status. YY1 also has been shown to undergo chromatin remodeling via interactions with histone acetyl transferase and histone deacetylase complexes. Both groups modify histones, resulting in altered chromatin structure. Herein, we will discuss the multiple roles and mechanisms of YY1 in the regulation of gene expression, its genetic factor functions, epigenetic regulatory activity, and its role as a redox sensor in the context of malignant neoplastic diseases. PMID- 22248057 TI - Yin Yang 2: the great unknown within the Yin Yang 1 regulatory network. AB - The fundamental biological relevance of the transcription factor Yin Yang 1 (YY1) has been studied and described intensively in hundreds of publications. To date, however, only limited data of its structural and functional homologue YY2 are available. Especially, the impact of Yin Yang 2 (YY2) in the regulatory network of YY1 is almost unexplored. This article summarizes all critical aspects that are (or will be) relevant for a better understanding of YY1- and/or YY2-mediated cellular control mechanisms. PMID- 22248053 TI - The oncogenic role of Yin Yang 1. AB - Yin Yang 1 (YY1) is a transcription factor with diverse and complex biological functions. YY1 either activates or represses gene transcription, depending on the stimuli received by the cells and its association with other cellular factors. Since its discovery, a biological role for YY1 in tumor development and progression has been suggested because of its regulatory activities toward multiple cancer-related proteins and signaling pathways and its overexpression in most cancers. In this review, we primarily focus on YY1 studies in cancer research, including the regulation of YY1 as a transcription factor, its activities independent of its DNA binding ability, the functions of its associated proteins, and mechanisms regulating YY1 expression and activities. We also discuss the correlation of YY1 expression with clinical outcomes of cancer patients and its target potential in cancer therapy. Although there is not a complete consensus about the role of YY1 in cancers based on its activities of regulating oncogene and tumor suppressor expression, most of the currently available evidence supports a proliferative or oncogenic role of YY1 in tumorigenesis. PMID- 22248058 TI - Yin Yang 1 in human cancer. AB - The transcription factor Yin Yang (YY) 1 controls many divergent cellular processes, including cell proliferation and apoptosis. These are key to cancer development, as a consequence of which its expression has been studied in an increasingly wide range of human cancers, including lymphoma, breast, prostate, colon, ovarian, cervical, and brain cancers, osteosarcoma, rhabdomyosarcoma, and leukemia. It is a regulatory transcription factor for a wide range of genes, including genes involved in control of the cell cycle and apoptosis, and it can act either to upregulate or downregulate downstream gene expression, depending on the cellular environment, cofactors, and the gene targeted. Its expression has been associated with development of a malignant phenotype in some human cancers; tumor progression, including metastasis; and survival. However, as data on its prognostic significance has become available for more human cancers, its role in tumor progression has become controversial; there is conflicting data on its association with outcome, with some studies showing a favorable and others an unfavorable association. This is probably because of the many different roles YY1 plays in control of proliferation and apoptosis, one or the other of which may be more prominent in any given tumor. These studies are reviewed to give an overview of the increasingly recognized importance of YY1 in human tumorigenesis. PMID- 22248059 TI - Overexpression of Yin Yang 1 in the pathogenesis of human hematopoietic malignancies. AB - The transcription factor Yin Yang (YY) 1 has been reported to be overexpressed in several tumor types and plays a role in both the progression of the disease as well as the maintenance of tumor cell resistance to cell death by cytotoxic drugs. YY1 also has been reported to be a prognostic factor for several cancers and was proposed to be a therapeutic target. The expression, function, and role of YY1 in the pathogenesis of hematologic malignancies are summarized briefly herein. Data are represented for B non-Hodgkin lymphoma, AIDS-related lymphoma, multiple myeloma, and children's acute lymphocytic leukemia. PMID- 22248060 TI - On chip droplet characterization: a practical, high-sensitivity measurement of droplet impedance in digital microfluidics. AB - We demonstrate a new approach to impedance measurement on digital microfluidics chips for the purpose of simple, sensitive, and accurate volume and liquid composition measurement. Adding only a single series resistor to existing AC droplet actuation circuits, the platform is simple to implement and has negligible effect on actuation voltage. To accurately measure the complex voltage across the resistor (and hence current through the device and droplet), the designed system is based on software-implemented lock-in amplification detection of the voltage drop across the resistor which filters out noise, enabling high resolution and low-limit signal recovery. We observe picoliter sensitivity with linear correlation of voltage to volume extending to the microliter volumes that can be handled by digital microfluidic devices. Due to the minimal hardware, the system is robust and measurements are highly repeatable. The detection technique provides both phase and magnitude information of the real-time current flowing through the droplet for a full impedance measurement. The sensitivity and resolution of this platform enables it to distinguish between various liquids which, as demonstrated in this paper, could potentially be extended to quantify solute concentrations, liquid mixtures, and presence of analytes. PMID- 22248062 TI - High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): a phase I trial. AB - BACKGROUND: Consensus is that patients with locally advanced rectal cancer (LARC) should receive long-term chemoradiotherapy (CRT) before surgery. With the intent to offer the patients intensified concomitant chemotherapy (CT) to improve outcome and to assess tolerability and toxicity of oxaliplatin (Ox) a phase I trial of high dose pelvic radiotherapy (RT), fixed dose of oral UFT/l-leucovorin and increasing doses of weekly Ox were performed. METHODS: Pelvic RT with 48.6 Gy/27 fractions was given to the primary tumour and the regional lymph nodes and a concurrent boost of 5.4 Gy/27 fractions with a final boost of 6 Gy/3 fractions was given to the gross tumour volume (GTV) (60 Gy/30 fractions). Concurrent with RT patients received a daily dose of UFT 300 mg/m(2) plus fixed dose l-leucovorin 22.5 mg 5/7 days and increasing weekly doses of Ox with 10 mg/m(2)/week from a start dose of 30 mg/m(2)/week to a maximum of 60 mg/m(2)/week. In addition, before and after CRT the patients received one course of TEGAFOX (UFT 300 mg/m(2) with l/leucovorin 22.5 mg Days 1-14 and Ox 130 mg/m(2) given on Day 1). Surgery was planned at least six weeks after the completion of the CRT. RESULTS: From May 2005 to March 2009, 18 patients with LARC (16 primary, two recurrent) were included in this phase I trial. Toxicity was low with only 5-17% grade 3-4 toxicity. Fifteen patients (83%) were operated (14 R0 resection and 1 R1 resection) after completion of CRT. Five (33%) patients had a pathological complete response (ypCR). When ypCR was combined with yp few residual cells, the rate was 60%. Thirteen patients are still alive December 2011. CONCLUSION: Preoperative high-dose RT and concomitant UFT with increasing doses of Ox up to 60 mg/m(2)/week was feasible with low toxicity, high ypCR rates and promising OS in patients with non-resectable LARC. PMID- 22248063 TI - Testicular cancer risk according to county of birth and county of diagnosis in Norway, 1958-2007. AB - BACKGROUND: The etiology of testicular germ cell cancer (TGCC) is still poorly understood, but biological and epidemiological evidence suggest that TGCC originates early in life. The aim of the present study was to analyze heterogeneity in TGCC risk within Norway, comparing county of birth to county of diagnosis, in order to assess the relative contribution of risk factors acting early and later in life. A further aim was to present the Norwegian TGCC incidence rates (1958-2007). MATERIAL AND METHODS: All TGCC cases (n = 7130) reported to the Cancer Registry of Norway, 1958-2007, were analyzed by county of diagnosis in 10-year intervals. The relative risk of TGCC based on county of birth, was estimated by Poisson regression analysis of all new TGCC cases (n = 1943), based on the mother's county of residence at the time of the son's birth, 1967-2007, obtained by linkage between the Cancer Registry and the Medical Birth Registry of Norway. RESULTS: Between the first (1958-67) and last (1998-2007) 10 year period, the average incidence rate more than tripled from 3.3 to 10.5 per 100 000 person-years (world adjusted), respectively. The average incidence rate during 1968-2007 was highest in the county of Rogaland (8.6) and lowest in Hedmark (5.3), the ratio between them being 1.6. The relative risk of TGCC based on county of birth (1967-2007) varied between 1.43 (More og Romsdal) and 0.95 (Buskerud), giving a ratio of 1.5. CONCLUSIONS: The ratio between the relative risk in the highest and lowest county was basically similar when comparing counties of birth with counties of diagnosis. Thus, our data do not shed light on the relative contribution of risk factors acting early versus later in life. The incidence rate of TGCC in Norway is among the highest in the world, and the increase in incidence rate does not seem to level off. PMID- 22248064 TI - Does VMAT for treatment of NSCLC patients increase the risk of pneumonitis compared to IMRT ? - a planning study. AB - BACKGROUND: Volumetric modulated arc therapy (VMAT) for treatment of non-small cell lung cancer (NSCLC) patients potentially changes the risk of radiation induced pneumonitis (RP) compared to intensity modulated radiation therapy (IMRT) if the dose to the healthy lung is changed significantly. In this study, clinical IMRT plans were used as starting point for VMAT optimization and differences in risk estimates of RP between the two plan types were evaluated. MATERIAL AND METHODS: Fifteen NSCLC patients prescribed 66 Gy in 2 Gy fractions were planned with IMRT and subsequently with single arc VMAT. Dose metrics were evaluated for target and lung together with population averaged dose volume histograms. The risk of RP was calculated using normal tissue complication probability (NTCP) models. Finally, applicability of the plans was tested through delivery on an Elekta accelerator. RESULTS: When changing from IMRT to VMAT only modest differences were observed in the dose to the lung and target volume. On average, fractions of lung irradiated to doses between 18 Gy and 48 Gy were statistically significant reduced using VMAT compared to IMRT. For the fraction of lung receiving more than 20 Gy the reduction was 1.2% percentage points: (range -0.6 2.6%). The evaluated toxicity were smaller with VMAT compared to IMRT, however only modest differences were observed in the NTCP values. The plans were delivered without any problems. The average beam on time with VMAT was 83 s. This was a reduction of 141 s (ranging from 37 s to 216 s) compared to IMRT. CONCLUSIONS: Using IMRT as reference for the VMAT optimization it was possible to implement VMAT in the clinic with no increase in estimated risk of RP. Thus, toxicity is not expected to be a hindrance to using VMAT and will profit from the shorter delivery time with VMAT compared to IMRT. PMID- 22248065 TI - Cardiac differentiation of human pluripotent stem cells. AB - Due to the extremely limited proliferative capacity of adult cardiomyocytes, human embryonic (pluripotent) stem cell derived cardiomyocytes (hESC-CMs) are currently almost the only reliable source of human heart cells which are suited to large-scale production. These cells have the potential for wide-scale application in drug discovery, heart disease research and cell-based heart repair. Embryonic atrial-, ventricular- and nodal-like cardiomyocytes can be obtained from differentiated human embryonic stem cells (hESCs). In recent years, several highly efficient cardiac differentiation protocols have been developed. Significant progress has also been made on understanding cardiac subtype specification, which is the key to reducing the heterogeneity of hESC-CMs, a major obstacle to the utilization of these cells in medical research and future cell-based replacement therapies. Herein we review recent progress in cardiac differentiation of hESCs and cardiac subtype specification, and discuss potential applications in drug screening and cell-based heart regeneration. PMID- 22248066 TI - Interoceptive and exteroceptive attention have opposite effects on subsequent somatosensory perceptual decision making. AB - Evidence suggests that interoceptive and exteroceptive attention might have different perceptual effects. However, the effects of these different types of body-focused attention have never been directly compared. The current research investigated how interoceptive and exteroceptive attention affect subsequent performance on the somatic signal detection task (SSDT). In Experiment 1, 37 participants completed the SSDT under usual testing conditions and after performing an interoceptive heartbeat perception task. This task led to a more liberal response criterion, leading to increased touch reports in the presence and absence of a target vibration. This finding is consistent with suggestions that attending internally contributes to physical symptom reporting in patients with medically unexplained symptoms (MUS). In Experiment 2, 40 participants completed the SSDT before and after an exteroceptive grating orientation task. This task led to a more stringent response criterion, leading to decreased touch reports in the presence and absence of the target, possibly via a reduction in sensory noise. This work demonstrates that internal and external body-focused attention can have opposite effects on subsequent somatic perceptual decision making and suggests that attentional training could be useful for patients reporting MUS. PMID- 22248067 TI - Two new N-acetyldopamine tetrapolymers from periostracum Cicadae. AB - Two new N-acetyldopamine tetrapolymers, cicadamide A (1) and cicadamide B (2), were isolated from periostracum Cicadae, and their structures were elucidated as 3-acetylamino-7-(3"-acetylamino-7"-(N-acetyl-2'''-aminoethyl)-1",4"-benzodioxan 2"-yl)-2-(2'-(3"",4""-dihydroxyphenyl)-3'-acetylamino-1',4'-benzodioxan-7'-yl) 1,4-benzodioxane (1) and 3-acetylamino-7-(3"-acetylamino-6"-(N-acetyl-2''' aminoethyl)-1",4"-benzodioxan-2"-yl)-2-(2'-(3"",4""-dihydroxyphenyl)-3' acetylamino-1',4'-benzodioxan-7'-yl)-1,4-benzodioxane (2), by the combined analysis of 1D NMR and 2D NMR, and mass spectrometry. Pharmacological investigation on two compounds obtained in this study showed that part of them had anti-inflammatory activities. PMID- 22248068 TI - Editorial comment to correlates for nocturia: a review of epidemiological studies. PMID- 22248070 TI - Submicrosecond time resolution atomic force microscopy for probing nanoscale dynamics. AB - We propose, simulate, and experimentally validate a new mechanical detection method to analyze atomic force microscopy (AFM) cantilever motion that enables noncontact discrimination of transient events with ~100 ns temporal resolution without the need for custom AFM probes, specialized instrumentation, or expensive add-on hardware. As an example application, we use the method to screen thermally annealed poly(3-hexylthiophene):phenyl-C(61)-butyric acid methyl ester photovoltaic devices under realistic testing conditions over a technologically relevant performance window. We show that variations in device efficiency and nanoscale transient charging behavior are correlated, thereby linking local dynamics with device behavior. We anticipate that this method will find application in scanning probe experiments of dynamic local mechanical, electronic, magnetic, and biophysical phenomena. PMID- 22248071 TI - Creation and validation of a ligation-independent cloning (LIC) retroviral vector for stable gene transduction in mammalian cells. AB - BACKGROUND: Cloning vectors capable of retroviral transduction have enabled stable gene overexpression in numerous mitotic cell lines. However, the relatively small number of feasible restriction enzyme sequences in their cloning sites can hinder successful generation of overexpression constructs if these sequences are also present in the target cDNA insert. RESULTS: Utilizing ligation independent cloning (LIC) technology, we have modified the highly efficient retroviral transduction vector, pBABE, to eliminate reliance on restriction enzymes for cloning. Instead, the modified plasmid, pBLIC, utilizes random 12/13 base overhangs generated by T4 DNA polymerase 3' exonuclease activity. PCR-based introduction of the complementary sequence into any cDNA of interest enables universal cloning into pBLIC. Here we describe creation of the pBLIC plasmid, and demonstrate successful cloning and protein overexpression from three different cDNAs, Bax, catalase, and p53 through transduction into the human prostate cancer cell line, LNCaP or the human lung cancer line, H358. CONCLUSIONS: Our results show that pBLIC vector retains the high transduction efficiency of the original pBABE while eliminating the requirement for checking individual cDNA inserts for internal restriction sites. Thus it comprises an effective retroviral cloning system for laboratory-scale stable gene overexpression or for high-throughput applications such as creation of retroviral cDNA libraries. To our knowledge, pBLIC is the first LIC vector for retroviral transduction-mediated stable gene expression in mammalian cells. PMID- 22248072 TI - Expression of the proliferation marker Ki-67 associates with tumour staging and clinical outcome in differentiated thyroid carcinomas. AB - OBJECTIVE: Although the prognosis of differentiated thyroid carcinoma (DTC) is excellent, with 10-year survival rates of about 90%, about one-third of patients experiences recurrent disease. We aimed to identify novel histological prognostic factors to optimize treatment and follow-up of patients at risks. DESIGN: Retrospective analysis of patients diagnosed from January 1990 to March 2004. SUBJECTS: A total of 93 patients diagnosed with DTC of which 67 with papillary and 26 with follicular histology. MEASUREMENTS: Analysis of immunohistochemical expression of somatostatin receptor (sst) subtypes 1-5, glucose transporter-1 (GLUT-1), receptor tyrosine kinase c-KIT, oestrogen and progesterone receptors, and proliferation marker Ki-67 and correlation with the patients' clinical outcome. RESULTS: DTC showed immunohistochemical expression of GLUT-1, C-KIT and progesterone receptor in a high percentage of cases (range: 57-80%). In contrast, the oestrogen receptor as well as the sst subtypes 1-5 was less frequently detected (range: 15-29%). Mean staining of the proliferation marker Ki-67 was 6% positive cells (range 0-20%). Ki-67 expression was significantly associated with tumour staging (rho = 0.2076, P = 0.0459), whereas the other histopathological markers were not associated with gender, age, tumour entity, or tumour classification. Tumour staging and expression of Ki-67, oestrogen receptor and sst2, but of none of the other histopathological factors, independently predicted the clinical outcome 5 years after definitive treatment (P < 0.0001, P < 0.0001, P = 0.0004 and P = 0.0206, respectively). CONCLUSIONS: In patients with DTC, Ki 67 expression associates with tumour staging and clinical outcome. PMID- 22248074 TI - Sexual function questionnaire: further refinement and validation. AB - INTRODUCTION: The Sexual Function Questionnaire (SFQ) is a self-report outcome measure of female sexual function. It has recently been refined to create a 28 item version (SFQ28) including the addition of a new arousal-cognitive domain. AIM: This study aimed to validate the SFQ28 in female sexual arousal disorder (FSAD) and hypoactive sexual desire disorder (HSDD) populations and to develop a screening cut-score for the arousal-cognitive domain. METHODS: Women with FSAD (n=222) and HSDD (n=114) and 303 women without female sexual dysfunction (FSD) completed the SFQ28, the Female Sexual Distress Scale (FSDS), and the Sexual Quality of Life-Female (SQOL-F) at a clinic visit. Retests were performed within FSD groups only (FSAD: n=92, HSDD: n=183), using postal questionnaires 7-14 days later. The optimal cut-score for the arousal-cognitive domain was based on diagnostic tests of sensitivity and specificity from a receiver operating characteristic curve. MAIN OUTCOME MEASURES: Psychometric analyses. RESULTS: The factor analysis confirmed the domain structure of the SFQ28. The SFQ28 demonstrated excellent internal consistency, test retest reliability and known groups validity, and good convergent validity with the FSDS and SQOL-F for all domains except pain. The sensitivity/specificity analysis determined a screening cut-score of 5 for the arousal-cognitive domain. CONCLUSION: Given the replication of the psychometric data and the cut-scores for each domain, the SFQ28 is a robust measure that can be used in women with either FSAD or HSDD. PMID- 22248073 TI - Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. AB - This study describes the effects of long-chain fatty acids on inflammatory signaling in cultured astrocytes. Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFalpha and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. Inhibitor studies revealed that pharmacologic inhibition of p38 or p42/44 MAPK pathways prevents the pro-inflammatory effects of palmitic acid, whereas JNK and PI3K inhibition does not affect cytokine release. Depletion of microglia from primary astrocyte cultures using the lysosomotropic agent l-leucine methyl ester revealed that the ability of palmitic acid to trigger cytokine release is not dependent on the presence of microglia. Finally, data show that the essential omega-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro. These data thus raise the possibility that high levels of circulating saturated fatty acids could cause reactive gliosis and brain inflammation in vivo, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome. PMID- 22248075 TI - Phenolic compounds, carotenoids, anthocyanins, and antioxidant capacity of colored maize (Zea mays L.) kernels. AB - In this study, the contents of total phenolics, flavonoids, anthocyanins, beta carotene, and lutein as well as free, conjugated, and insoluble bound phenolic acids were determined in whole kernels of 10 different colored maize genotypes. In addition, the antioxidant activity was evaluated as radical scavenging activity with ABTS (2,2-azino-bis/3-ethil-benothiazoline-6-sulfonic acid) and DPPH (2,2-diphenyl-1-picrylhydrazyl) reagents. Generally, considerable differences in phytochemical contents and antioxidant capacity were observed between the genotypes. The beta-carotene and lutein contents ranged from 0 to 2.42 mg/kg d.m. and from 0 to 13.89 mg/kg d.m., respectively, whereas the total anthocyanin contents of anthocyanin-rich colored maize genotypes ranged from 2.50 to 696.07 mg CGE/kg d.m. (cyanidin 3-glucoside equivalent) with cyanidin 3 glucoside (Cy-3-Glu) as the most dominant form. The light blue ZPP-2 selfed maize genotype has a higher content of total phenolics, flavonoids, and ferulic acid as compared to other tested maize and the highest ABTS radical scavenging activity. PMID- 22248076 TI - Faecal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae among humans in Java, Indonesia, in 2001-2002. AB - OBJECTIVE: To characterise commensal Escherichia coli and other Enterobacteriaceae with reduced susceptibility to cefotaxime that were collected in a large survey carried out among 3995 patients and healthy persons in two urban regions on Java, Indonesia, in 2001-2002. METHODS: The putative extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae were analysed using double-disk synergy tests, isoelectric focusing, PCR assays, DNA sequencing, and pulsed-field gel electrophoresis (PFGE). RESULTS: On the day of discharge after five or more days of hospitalisation, at least 95 of 999 (9.5%) patients carried ESBL-positive Enterobacteriaceae as dominant faecal flora. Six patients were simultaneously colonised with E. coli and Klebsiella pneumoniae isolates with ESBL activity. On admission, only 6 of 998 (0.6%) patients were colonised. Faecal carriage of ESBL-producing Enterobacteriaceae among healthy persons or persons visiting a public health centre was not detected. The 107 ESBL-positive strains included 68 E. coli, 35 K. pneumoniae, and four other Enterobacteriaceae. bla(CTX M-15) was the most prevalent ESBL in both E. coli (47.1%) and K. pneumoniae (45.7%), but the E. coli O25b-ST131 clone was virtually absent. Other ESBL types found were: SHV-2, -2a, -5, -12, CTX-M-3, -9, -14, and TEM-19. PFGE revealed extensive genetic diversity among the isolates. CONCLUSIONS: In 2001-2002, faecal carriage of ESBL-producing Enterobacteriaceae as dominant flora in Indonesia was almost exclusively hospital-associated. The presence of various bla(ESBL) genes and the extensive genetic diversity among isolates argue against a single/dominant strain outbreak. PMID- 22248077 TI - ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. AB - BACKGROUND: Premature ovarian failure (POF) is a complex and heterogeneous disorder that is influenced by multiple genetic components. Numerous candidate gene studies designed to identify POF susceptibility loci have been published, but most positive findings have not been confirmed in follow up studies. We sought to determine if sequence variants previously associated with age at natural menopause (AANM) or early menopause (EM) contribute as well to genetic susceptibility to POF. METHODS: Our study was performed on 371 unrelated idiopathic women with POF and 800 women controls, all Chinese Han. Thirty six SNPs from previous genome-wide association studies (GWAS) responsible for AANM or EM and 3 additional SNPs in ESR1, and 2 additional SNPs in PTHB1 were tested using the Sequenom MassARRAY iPLEX platform for genotyping. RESULTS: Three SNPs - rs2278493 in HK3, rs2234693 in ESR1 and rs12611091 in BRSK1 - showed nominally significant association with POF. Thus, a plausible relationship could exist between ESR1, BRSK1, HK3 and POF. CONCLUSIONS: This largest association study undertaken to determine correlation between POF and AANM/EM revealed three significant SNPs (rs2278493, rs2234693, and rs12611091). All are associated with not only AAWM and EM but also POF. Insights into shared genetic susceptibility between POF and AANM/EM will provide novel entry points for unraveling genetic mechanism involved in ovarian reserve and oocyte aging processes. PMID- 22248078 TI - Regional differences in the prevalence of known Type 2 diabetes mellitus in 45-74 years old individuals: results from six population-based studies in Germany (DIAB CORE Consortium). AB - AIM: In Germany, regional data on the prevalence of Type 2 diabetes mellitus are lacking for health-care planning and detection of risk factors associated with this disease. We analysed regional variations in the prevalence of Type 2 diabetes and treatment with antidiabetic agents. METHODS: Data of subjects aged 45-74 years from five regional population-based studies and one nationwide study conducted between 1997 and 2006 were analysed. Information on self-reported diabetes, treatment, and diagnosis of diabetes were compared. Type 2 diabetes prevalence estimates (95% confidence interval) from regional studies were directly standardized to the German population (31 December 2007). RESULTS: Of the 11,688 participants of the regional studies, 1008 had known Type 2 diabetes, corresponding to a prevalence of 8.6% (8.1-9.1%). For the nationwide study, a prevalence of 8.2% (7.3-9.2%) was estimated. Prevalence was higher in men (9.7%; 8.9-10.4%) than in women (7.6%; 6.9-8.3%). The regional standardized prevalence was highest in the east with 12.0% (10.3-13.7%) and lowest in the south with 5.8% (4.9-6.7%). Among persons with Type 2 diabetes, treatment with oral antidiabetic agents was more frequently reported in the south (56.9%) and less in the northeast (46.0%), whereas treatment with insulin alone was more frequently reported in the northeast (21.6%) than in the south (16.4%). CONCLUSION: The prevalence of known Type 2 diabetes showed a southwest-to-northeast gradient within Germany, which is in accord with regional differences in the distribution of risk factors for Type 2 diabetes. Furthermore, the treatment with antidiabetic agents showed regional differences. PMID- 22248079 TI - The cyclin L homolog MOS12 and the MOS4-associated complex are required for the proper splicing of plant resistance genes. AB - Plant resistance (R) proteins protect cells from infections through recognizing effector molecules produced by pathogens and initiating downstream defense cascades. To mount proper immune responses, the expression of R genes has to be tightly controlled transcriptionally and post-transcriptionally. Intriguingly, alternative splicing of the R genes of the nucleotide binding leucine-rich repeat (NB-LRR) type was observed in different plant species, but its regulatory mechanism remains elusive. Here, we report the positional cloning and functional analysis of modifier of snc1,12 (mos12-1), a partial loss-of-function mutant that can suppress the constitutive defense responses conferred by the gain-of-function R gene mutant suppressor of npr1-1 constitutive 1 (snc1). MOS12 encodes an arginine-rich protein that is homologous to human cyclin L. A null allele of mos12-2 is lethal, suggesting it has a vital role in plant growth and development. MOS12 localizes to the nucleus, and the mos12-1 mutation results in altered splicing patterns of SNC1 and RPS4, indicating that MOS12 is required for the proper splicing of target R genes. MOS12 co-immunoprecipitates with MOS4, indicating that MOS12 associates with the MOS4-associated complex (MAC). Accordingly, splicing patterns of SNC1 and RPS4 are changed in most MAC core mutants. Our study highlights the contribution of MOS12 and the MAC in the alternative splicing of R genes, providing regulatory details on how alternative splicing is used to fine-tune R gene expression in plant immunity. PMID- 22248080 TI - Ethyl pyruvate reduces liver injury at early phase but impairs regeneration at late phase in acetaminophen overdose. AB - INTRODUCTION: Inflammation may critically affect mechanisms of liver injury in acetaminophen (APAP) hepatotoxicity. Kupffer cells (KC) play important roles in inflammation, and KC depletion confers protection at early time points after APAP treatment but can lead to more severe injury at a later time point. It is possible that some inflammatory factors might contribute to liver damage at an early injurious phase but facilitate liver regeneration at a late time point. Therefore, we tested this hypothesis by using ethyl pyruvate (EP), an anti inflammatory agent, to treat APAP overdose for 24-48 hours. METHODS: C57BL/6 male mice were intraperitoneally injected with a single dose of APAP (350 mg/kg dissolved in 1 mL sterile saline). Following 2 hours of APAP challenge, the mice were given 0.5 mL EP (40 mg/kg) or saline treatment every 8 hours for a total of 24 or 48 hours. RESULTS: Twenty-four hours after APAP challenge, compared to the saline-treated group, EP treatment significantly lowered serum transaminases (ALT/AST) and reduced liver injury seen in histopathology; however, at the 48 hour time point, compared to the saline therapy, EP therapy impaired hepatocyte regeneration and increased serum AST; this late detrimental effect was associated with reduced serum TNF-alpha concentration and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration. CONCLUSIONS: Inflammation likely contributes to liver damage at an early injurious phase but improves hepatocyte regeneration at a late time point, and prolonged anti inflammation therapy at a late phase is not beneficial. PMID- 22248081 TI - Directional biases and resource-dependence in dispersal generate spatial patterning in a consumer-producer model. AB - Directional dispersal plays a large role in shaping ecological processes in diverse systems such as rivers, coastlines and vegetation communities. We describe an instability driven by directional dispersal in a spatially explicit consumer-producer model where spatial patterns emerge in the absence of external environmental variation. Dispersal of the consumer has both undirected and directed components that are functions of producer biomass. We demonstrate that directional dispersal is required for the instability, while undirected diffusive dispersal sets a lower bound to the spatial scale of emerging patterns. Furthermore, instability requires indirect feedbacks affecting consumer per capita dispersal rates, and not activator-inhibitor dynamics affecting production and mortality as is described in previous theory. This novel and less-restrictive mechanism for generating spatial patterns can arise over realistic parameter values, which we explore using an empirically inspired model and data on stream macroinvertebrates. PMID- 22248082 TI - Quantification and accurate normalisation of small RNAs through new custom RT qPCR arrays demonstrates Salmonella-induced microRNAs in human monocytes. AB - BACKGROUND: Small interfering and non-coding RNAs regulate gene expression across all kingdoms of life. MicroRNAs constitute an important group of metazoan small RNAs regulating development but also disease. Accordingly, in functional genomics microRNA expression analysis sheds more and more light on the dynamic regulation of gene expression in various cellular processes. RESULTS: We have developed custom RT-qPCR arrays allowing for accurate quantification of 31 small RNAs in triplicate using a 96 well format. In parallel, we provide accurate normalisation of microRNA expression data based on the quantification of 5 reference snRNAs. We have successfully employed such arrays to study microRNA regulation during human monocyte differentiation as well as Salmonella infection. Besides well-known protagonists such as miR-146 or miR-155, we identified the up-regulation of miR 21, miR-222, miR-23b, miR-24, miR-27a as well as miR-29 upon monocyte differentiation or infection, respectively. CONCLUSIONS: The provided protocol for RT-qPCR arrays enables straight-forward microRNA expression analysis. It is fully automatable, compliant with the MIQE guidelines and can be completed in only 1 day. The application of these arrays revealed microRNAs that may mediate monocyte host defence mechanisms by regulating the TGF-beta signalling upon Salmonella infection. The introduced arrays are furthermore suited for customised quantification of any class of small non-coding RNAs as exemplified by snRNAs and thus provide a versatile tool for ubiquitous applications. PMID- 22248085 TI - Opportunities for sensitive plasma proteome analysis. AB - Despite great interest, investments, and efforts, the ongoing search for plasma protein biomarkers for disease so far has come up surprisingly empty-handed. Although discovery programs have revealed large numbers of biomarker candidates, the clinical utility has been validated for only a very small number of these. While this disappointing state of affairs may suggest that plasma protein biomarkers have little more to offer for diagnostics, we take the perspective that experimental conditions might not have been optimal and that analyses will be required that offer far greater sensitivity than currently available, in terms of numbers of molecules needed for unambiguous detection. Accordingly, techniques are needed to search deep and wide for protein biomarker candidates. The requirements and feasibility of such assays will be discussed. PMID- 22248083 TI - Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS challenge. AB - BACKGROUND: There is ample evidence that psychological stress adversely affects many diseases. Recent evidence has shown that intense stressors can increase inflammation within the brain, a known mediator of many diseases. However, long term outcomes of chronic psychological stressors that elicit a neuroinflammatory response remain unknown. METHODS: To address this, we have modified previously described models of rat/mouse predatory stress (PS) to increase the intensity of the interaction. We postulated that these modifications would enhance the predator-prey experience and increase neuroinflammation and behavioral dysfunction in prey animals. In addition, another group of mice were subjected to a modified version of chronic unpredictable stress (CUS), an often-used model of chronic stress that utilizes a combination of stressors that include physical, psychological, chemical, and other. The CUS model has been shown to exacerbate a number of inflammatory-related diseases via an unknown mechanism. Using these two models we sought to determine: 1) whether chronic PS or CUS modulated the inflammatory response as a proposed mechanism by which behavioral deficits might be mediated, and 2) whether chronic exposure to a pure psychological stressor (PS) leads to deficits similar to those produced by a CUS model containing psychological and physical stressors. Finally, to determine whether acute PS has neuroinflammatory consequences, adult mice were examined at various time-points after PS for changes in inflammation. RESULTS: Adolescent mice subjected to chronic PS had increased basal expression of inflammation within the midbrain. CUS and chronic PS mice also had an impaired inflammatory response to a subsequent lipopolysaccharide challenge and PS mice displayed increased anxiety- and depressive-like behaviors following chronic stress. Finally, adult mice subjected to acute predatory stress had increased gene expression of inflammatory factors. CONCLUSION: Our results demonstrate that predatory stress, an ethologically relevant stressor, can elicit changes in neuroinflammation and behavior. The predatory stress model may be useful in elucidating mechanisms by which psychological stress modulates diseases with an inflammatory component. PMID- 22248086 TI - Enhanced apoptosis-inducing function of MDA-7/IL-24 RGD mutant via the increased adhesion to tumor cells. AB - Melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) has shown potent tumor cell apoptosis inducing capacity in multiple cancers. However, the apoptosis induction capacity of mda-7/IL-24 was low and directly correlated with the adhesion to tumor cells.Cell adhesion molecule integrin alpha(v)beta(3) expressed on the surface of several types of solid tumor cells, and they bind to arginine-glycine-aspartic acid (RGD) which enhanced the adhesion to tumor cells. This rout was exploited to construct a tumor-targeting gene RGD-IL-24 which can express RGD-MDA-7/IL-24 protein that includes the cell adhesive sequence (164)Arg (165)Gly-(166)Asp (A Glycine residue was inserted into the recombinant MDA-7/IL 24 between Arg164 and Asp165 to form a RGD motif). We successfully got the MDA 7/IL-24 mutant by overlapping polymerase chain reaction (PCR) and evaluated its therapeutic efficacy for tumor cell lines MCF-7, HeLa, HepG2, and normal human lung fibroblast (NHLF) line. And we found that the expression of pCDNA3.1/RGD-IL 24 was same to the expression of pCDNA3.1/IL-24. The RGD-IL-24 enhanced the apoptosis-inducing function in tumor cells, but not in normal cells. In tumor cell lines, the apoptosis-inducing activities of RGD-IL-24 was significantly higher than IL-24 detecting by MTT assay, Annexin V, and Hoechst 33258 analysis. Further, pCDNA3.1/RGD-IL-24 showed a significant increase in the ratio of pro apoptotic (bax) to anti-apoptotic (bcl-2) proteins in tumor cell lines, but not in NHLF cell line. Together, these results suggest that RGD-IL-24 can enhance the apoptosis of tumor cells and may provide a promising drug in tumor therapy. PMID- 22248087 TI - Single-photon emission and quantum characterization of zinc oxide defects. AB - Room temperature single-photon emission and quantum characterization is reported for isolated defects in zinc oxide. The defects are observed in thin films of both in-house synthesized and commercial zinc oxide nanoparticles. Emission spectra in the red and infrared, second-order photon correlation functions, lifetime measurements, and photon count rates are presented. Both two- and three state emitters are identified. Sub-band gap absorption and red emission suggest these defects are the zinc vacancy. These results identify a new source of single photons in a readily available wide band gap semiconductor material which has exceptional electrical, optical, and biocompatibility properties. PMID- 22248088 TI - Three new compounds from Dictamnus dasycarpus. AB - Phytochemical investigation of the ethyl acetate extracts from root barks of Dictamnus dasycarpus led to the isolation of three new compounds, named as dasycarpusenester A (1), dasycarpusester B (2), dasycarpusacid (3). Their structures were elucidated as (2S)-4-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl)-2 hydroxypent-3-enoic acid methyl ester (1), (2R)-4-(2,2-dimethyl-5 oxotetrahydrofuran-3-yl)-2-hydroxypent-3-anoic acid methyl ester (2), and (2S)-4 (2,2-dimethyl-5-oxotetrahydrofuran-3-yl)-2-hydroxypent-3-anoic acid (3), respectively, on the basis of modern spectroscopic methods and chemical analysis. PMID- 22248089 TI - A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases. AB - BACKGROUND: To investigate the utility of stereotactic body radiotherapy (SBRT) in the treatment of painful renal cell carcinoma (RCC) bone metastases, and for a possible dose effect on time to symptom relief. MATERIAL AND METHODS: Eighteen patients with 24 painful osseous lesions from metastatic RCC were treated with SBRT. The most common treatment regimens were 24 Gy in 3 fractions and 40 Gy in 5 fractions. The times from treatment to first reported pain relief and time to symptom recurrence were evaluated. Median follow-up was 38 weeks (1-156 weeks). RESULTS: Seventy-eight percent of all patients had pain relief. Patients treated with a BED > 85 Gy achieved faster and more durable pain relief compared to those treated with a BED < 85 Gy. There was decrease in time to pain relief after a change in treatment regimen to 8 Gy * 5 fractions (BED = 86). There was only one patient with grade 1 skin toxicity. No neurological or other toxicity was observed. CONCLUSIONS: SBRT can safely and effectively treat painful RCC bony metastases. There appears to be a relationship between radiation dose and time to stable pain relief. PMID- 22248090 TI - The association between family health status and child injury in a sample of African children. PMID- 22248091 TI - Synergistic inhibitory effect of nicotine plus oral contraceptive on mitochondrial complex-IV is mediated by estrogen receptor-beta in female rats. AB - Chronic nicotine and oral contraceptive (NOC) exposure caused significant loss of hippocampal membrane-bound estrogen receptor-beta (ER-beta) in female rats compared with exposure to nicotine alone. Mitochondrial ER-beta regulates estrogen-mediated mitochondrial structure and function; therefore, investigating the impact of NOC on mitochondrial ER-beta and its function could help delineate the harmful synergism between nicotine and OC. In this study, we tested the hypothesis that NOC-induced loss of mitochondrial ER-beta alters the oxidative phosphorylation system protein levels and mitochondrial respiratory function. This hypothesis was tested in hippocampal mitochondria isolated from female rats exposed to saline, nicotine, OC or NOC for 16 days. NOC decreased the mitochondrial ER-beta protein levels and reduced oxygen consumption and complex IV (CIV) activity by 34% and 26% compared with saline- or nicotine-administered groups, respectively. We also observed significantly low protein levels of all mitochondrial-encoded CIV subunits after NOC as compared with the nicotine or saline groups. Similarly, the silencing of ER-beta reduced the phosphorylation of cyclic-AMP response element binding protein, and also reduced levels of CIV mitochondrial-encoded subunits after estrogen stimulation. Overall, these results suggest that mitochondrial ER-beta loss is responsible for mitochondrial malfunction after NOC. PMID- 22248094 TI - Ripening attributes of new passion fruit line featuring seasonal non-climacteric behavior. AB - The passion fruit hybrid cultivar 'Passion Dream' (PD) produces two cycles of fruiting per year, in the summer and winter. Self-hybridization of PD created various lines, including 'Ripens during Summer' (RS), which lacks the ability to abscise during winter, suggesting a seasonal nonclimacteric behavior. The two lines were characterized by several quality traits: PD produced high ethylene levels in both seasons; RS produced significantly less ethylene during summer and almost none during winter. The ratio of total soluble solids to titratable acidity (TSS/TA), and aroma volatiles production, as determined by solid-phase microextraction/gas chromatograph-mass spectrometer (SPME/GC-MS) techniques, and taste indices were highest in PD summer fruits and lowest in RS winter fruits. Peel color in PD was affected by environmental and storage temperatures, whereas RS fruits always showed a strong purple color. The present findings suggest that ethylene production levels in passion fruit greatly influence various ripening processes, including acid degradation, increased TSS/TA ratio, accumulation of aroma volatiles, and tastiness. PMID- 22248095 TI - Categorical perception effects for facial identity in robustly represented familiar and self-faces: the role of configural and featural information. AB - Categorical perception of robustly represented faces (self, friend) and unfamiliar faces is investigated, and the relative roles of configural and featural information are examined. Participants performed identification and discrimination tasks on morph series containing the self-face and a friend's face (self-Friend 1), two friends' faces (Friend 2-Friend 3), and two unfamiliar faces (Unfamiliar 1-Unfamiliar 2), presented in upright and inverted orientations. For upright faces, categorical perception effects were observed for both familiar morph series but not for the unfamiliar morph series, suggesting that robust representation is a requirement for categorical perception in facial identity. For inverted faces, categorical perception was observed for the self-Friend 1 morph series only. This suggests that categorical perception is tied to configural processing for familiar non-self-faces, but can be observed for self faces during featural processing-consistent with evidence that self-face representations contain strong configural and featural components. Finally, categorical perception is not enhanced by the presence of the self-face relative to other familiar faces when upright, but shows a trend of being enhanced for self-faces when inverted, adding to the debate on the ways in which robustly represented faces can elicit categorical perception. PMID- 22248092 TI - The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury. AB - Heparin and low molecular weight heparins have been demonstrated to reduce myocardial ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhagic and thrombotic complications. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility of producing heparin-like compounds with low anticoagulant activity and strong anti inflammatory effects. Using a rat model of regional myocardial I/R, we investigated the effects of an epimerized N-,O-sulphated K5 polysaccharide derivative, K5-N,OSepi, on infarct size and histological signs of myocardial injury caused by 30 min. ligature of the left anterior descending coronary artery followed by 1 or 24 h reperfusion. K5-N,OSepi (0.1-1 mg/kg given i.v. 15 min. before reperfusion) significantly reduced the extent of myocardial damage in a dose-dependent manner. Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by K5-N,OSepi. In left ventricular samples, I/R induced mast cell degranulation and a robust increase in lipid peroxidation, free radical-induced DNA damage and calcium overload. Markers of neutrophil infiltration and activation were also induced by I/R in rat hearts, specifically myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, prostaglandin-E(2) and tumour-necrosis-factor-alpha production. The robust increase in oxidative stress and inflammatory markers was blunted by K5 N,OSepi, in a dose-dependent manner, with maximum at 1 mg/kg. Furthermore, K5 N,OSepi administration attenuated the increase in caspase 3 activity, Bid and Bax activation and ameliorated the decrease in expression of Bcl-2 within the ischaemic myocardium. In conclusion, we demonstrate that the cardioprotective effect of the non-anticoagulant K5 derivative K5-N,OSepi is secondary to a combination of anti-apoptotic and anti-inflammatory effects. PMID- 22248097 TI - CNGA3 is expressed in inner ear hair cells and binds to an intracellular C terminus domain of EMILIN1. AB - The molecular characteristics of CNG (cyclic nucleotide-gated) channels in auditory/vestibular hair cells are largely unknown, unlike those of CNG mediating sensory transduction in vision and olfaction. In the present study we report the full-length sequence for three CNGA3 variants in a hair cell preparation from the trout saccule with high identity to CNGA3 in olfactory receptor neurons/cone photoreceptors. A custom antibody targeting the N-terminal sequence immunolocalized CNGA3 to the stereocilia and subcuticular plate region of saccular hair cells. The cytoplasmic C-terminus of CNGA3 was found by yeast two hybrid analysis to bind the C-terminus of EMILIN1 (elastin microfibril interface located protein 1) in both the vestibular hair cell model and rat organ of Corti. Specific binding between CNGA3 and EMILIN1 was confirmed with surface plasmon resonance analysis, predicting dependence on Ca2+ with Kd=1.6*10-6 M for trout hair cell proteins and Kd=2.7*10-7 M for organ of Corti proteins at 68 MUM Ca2+. Pull-down assays indicated that the binding to organ of Corti CNGA3 was attributable to the EMILIN1 intracellular sequence that follows a predicted transmembrane domain in the C-terminus. Saccular hair cells also express the transcript for PDE6C (phosphodiesterase 6C), which in cone photoreceptors regulates the degradation of cGMP used to gate CNGA3 in phototransduction. Taken together, the evidence supports the existence in saccular hair cells of a molecular pathway linking CNGA3, its binding partner EMILIN1 (and beta1 integrin) and cGMP-specific PDE6C, which is potentially replicated in cochlear outer hair cells, given stereociliary immunolocalizations of CNGA3, EMILIN1 and PDE6C. PMID- 22248096 TI - Analysis of tanshinone IIA induced cellular apoptosis in leukemia cells by genome wide expression profiling. AB - BACKGROUND: Tanshinone IIA (Tan IIA) is a diterpene quinone extracted from the root of Salvia miltiorrhiza, a Chinese traditional herb. Although previous studies have reported the anti-tumor effects of Tan IIA on various human cancer cells, the underlying mechanisms are not clear. The current study was undertaken to investigate the molecular mechanisms of Tan IIA's apoptotic effects on leukemia cells in vitro. METHODS: The cytotoxicity of Tan IIA on different types of leukemia cell lines was evaluated by the 3-[4,5-dimethylthiazol-2,5]-diphenyl tetrazolium bromide (MTT) assay on cells treated without or with Tan IIA at different concentrations for different time periods. Cellular apoptosis progression with and without Tan IIA treatment was analyzed by Annexin V and Caspase 3 assays. Gene expression profiling was used to identify the genes regulated after Tan IIA treatment and those differentially expressed among the five cell lines. Confirmation of these expression regulations was carried out using real-time quantitative PCR and ELISA. The antagonizing effect of a PXR inhibitor L-SFN on Tan IIA treatment was tested using Colony Forming Unit Assay. RESULTS: Our results revealed that Tan IIA had different cytotoxic activities on five types of leukemia cells, with the highest toxicity on U-937 cells. Tan IIA inhibited the growth of U-937 cells in a time- and dose-dependent manner. Annexin V and Caspase-3 assays showed that Tan IIA induced apoptosis in U-937 cells. Using gene expression profiling, 366 genes were found to be significantly regulated after Tan IIA treatment and differentially expressed among the five cell lines. Among these genes, CCL2 was highly expressed in untreated U-937 cells and down-regulated significantly after Tan IIA treatment in a dose-dependent manner. RT-qPCR analyses validated the expression regulation of 80% of genes. Addition of L-sulforaphane (L-SFN), an inhibitor of Pregnane*receptor (PXR) significantly attenuated Tan IIA's effects using colony forming assays. CONCLUSIONS: Tan IIA has significant growth inhibition effects on U-937 cells through the induction of apoptosis. And Tan IIA-induced apoptosis might result from the activation of PXR, which suppresses the activity of NF-kappaB and lead to the down-regulation of CCL2 expression. PMID- 22248098 TI - A scoping exercise of favourable characteristics of professionals working in teenage and young adult cancer care: 'thinking outside of the box'. AB - A scoping exercise to define the preferred competencies of professionals involved in teenage and young adult (TYA) cancer care. Data were generated during two workshops with health professionals. In groups, they ranked skills, knowledge and attitudes, previously identified through a literature search, onto a diamond template. Data were also used from an education day with TYA professionals, who generated lists of key skills, knowledge and attitudes. Individually, professionals then selected the top five areas of competence to care for young people with cancer. The workshops generated three diamonds, which exhibited agreement of 13 principle skills, knowledge and attitudes. The top two being: 'expertise in treating paediatric and adult cancers' and 'understanding cancer'. The data from the education day suggested communication, technical knowledge and teamwork as being core role features for professionals who care for young people with cancer. Integration of both datasets; one derived inductively, the other deductively provides a comprehensive outline of core skills health professionals require to be proficient in young people's cancer care. These results will form the basis of future discussion around workforce strategies and inform a Delphi survey. PMID- 22248099 TI - Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. AB - BACKGROUND: We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings. RESULTS: In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU beta-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU beta-chain were significantly enriched in AD patients (OR(MH) = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region. CONCLUSIONS: We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the beta-chain domain and CLU protein functioning remains unclear and requires further studies. PMID- 22248100 TI - Ascona 2011: Proceedings of the HRM working group conference-introduction for the proceedings of the Ascona conference on advances in clinical investigation of esophageal dysmotility and reflux disease. PMID- 22248101 TI - High resolution manometry: the Ray Clouse legacy. PMID- 22248102 TI - Technical aspects of clinical high-resolution manometry studies. AB - BACKGROUND: A number of commercial and research systems are available for making high-resolution manometry recordings. purpose: In this document, we review the standard equipment, patient preparation and routine protocol for high-resolution manometry. The major differences between HRM systems lie in the method of signal transduction, with solid-state catheter systems recording form intraluminal transducers and water perfusion systems recording pressures from external transducers via a perfused silicone catheter. The variations in recording systems result in different mechanical and electrical characteristics which dictate different techniques for setting up and using equipment. These issues are relevant in terms of costs and day to day management, but have little clinical significance. After the equipment is prepared for a manometric study, the esophagus is intubated transnasally with the manometric catheter and the catheter is positioned so that the UES and LES/diaphragm are visualized on the recording screen. The subject then undergoes 10 5 ml water swallows in the supine position. Manometric data may be integrated with other data streams such as multichannel impedance or images from fluoroscopy to increase the power of the technique in difficult cases. PMID- 22248103 TI - Evaluation of the esophagogastric junction using high resolution manometry and esophageal pressure topography. AB - BACKGROUND: The assessment of the esophagogastric junction (EGJ) is the most challenging aspect of clinical esophageal manometry. Although conventional manometric systems can be optimized toward interrogating specific aspects of the EGJ, they are too limited in recording channels and/or fidelity for a comprehensive assessment. The technological advantages inherent in high resolution manometry (HRM) with esophageal pressure topography (EPT) analysis substantially change this equation providing a technology sufficiently robust to dynamically record the contractile activity within the EGJ with both good fidelity and good spatial resolution. PURPOSE: This review is an update on our understanding of the application of HRM and EPT to the analysis of EGJ function. With respect to sphincter relaxation, the integrated relaxation pressure (IRP) has proven to be a robust metric in differentiating intact from impaired EGJ relaxation. In the process, it revealed that impaired EGJ relaxation could occur not only in the setting of achalasia but also with other causes of EGJ outflow obstruction including hiatus hernia. The morphological description of the EGJ by EPT has also revealed not only a spectrum of abnormality ranging from an intact sphincter to overt herniation, but also the surprise finding of spontaneous conversion among sphincter configurations, emphasizing its dynamic nature. With respect to barrier function, preliminary data have refocused on the crural diaphragm as a key-differentiating feature between preserved and compromised function. Finally, although the accomplishments summarized above are substantial, much work remains to fully exploit the potential of EPT in the clinical characterization of the EGJ. PMID- 22248104 TI - Evaluation of esophageal contractile propagation using esophageal pressure topography. AB - BACKGROUND: High-resolution manometry and esophageal pressure topography have enhanced our ability to analyze esophageal motor disturbances by improving the detail and accuracy of measurements of peristaltic activity.This has been extremely helpful in the evaluation of disorders of rapid propagation as the technique is able to define important time points and physiologic landmarks that are crucial in defining peristaltic velocity and latency intervals. PURPOSE: The goal of the current review will be to assess how esophageal pressure topography has impacted our ability to define important phenotypes of rapid propagation. Additionally, this review will also be utilized to complement the description of the Chicago Classification of Esophageal Motor Disorders, which is presented in this supplement issue. PMID- 22248105 TI - Achalasia and esophago-gastric junction outflow obstruction: focus on the subtypes. AB - BACKGROUND: The choice between pneumatic dilation and surgical myotomy is mainly determined by the preference and expertise of the treating physician. Ideally, however, treatment should be personalized to provide the optimal clinical outcome. The introduction of high resolution manometry has not only improved the specificity to diagnose achalasia, but also identified three different manometric subclasses. PURPOSE: To review, the data suggesting differences in clinical response to treatment depending on the manometric profile. PMID- 22248106 TI - Esophageal hypertensive peristaltic disorders. AB - BACKGROUND: Esophageal motility abnormalities include a series of manometric findings that differ to a significant degree from findings in normal, asymptomatic volunteers. METHODS: Current review summarizes conventional and high resolution esophageal manometry criteria used to define and characterize esophageal hypertensive motility abnormalities. KEY RESULTS: In the conventional esophageal manometry classification scheme hypertensive esophageal motility abnormalities include nutcracker esophagus (average distal contraction amplitude >180 mmHg), hypertensive lower esophageal sphincter (average resting LES pressure >45 mmHg) and poorly relaxing lower esophageal sphincter (average LES residual pressure >8 mmHg). The new, high resolution esophageal manometry scheme includes in the group of hypertensive peristaltic disorders hypertensive peristalsis ("nutcracker esophagus": mean DCI >5000 mmHg*sec*cm) and hypercontractile esophagus ("jackhammer esophagus": at least one contraction with DCI > 8,000 mmHg*sec*cm) and defines a separate group for disorders with impaired esophageal gastric junction relaxation (mean integrated residual (LES) pressure >15 mmHg). CONCLUSIONS & INFERENCES: Hypertensive motility disorders represent a heterogeneous condition subdivided into hypercontractile esophagus and hypertensive peristalsis. Further studies are required to determine the clinical relevance of this new classification. PMID- 22248107 TI - Weak and absent peristalsis. AB - BACKGROUND: Weak and absent esophageal peristalsis are frequently encountered esophageal motility disorders, which may be associated with dysphagia and which may contribute to gastroesophageal reflux disease. Recently, rapid developments in the diagnostic armamentarium have taken place, in particular, in high resolution manometry with or without concurrent intraluminal impedance monitoring. PURPOSE: This article aims to review the current insights in the terminology, pathology, pathophysiology, clinical manifestations, diagnostic work up,and management of weak and absent peristalsis. PMID- 22248108 TI - Future directions in esophageal motility and function - new technology and methodology. AB - BACKGROUND: Symptom based diagnosis is not reliable in patients with swallowing problems, heartburn, and other dyspeptic complaints. The aim of investigation is to provide clinically relevant measurements of gastrointestinal structure and function that explain the cause of symptoms, identify pathology, and guide effective management. Current practice rarely meets these ideals. PURPOSE: This review considers recent advances in technology such as high-resolution manometry (HRM) with esophageal pressure topography (EPT), HRM with impedance, high frequency ultrasound, and endoscopic functional luminal impedance planimetry (Endo-FLIP) that provide new opportunities to identify the pathophysiologic basis of esophageal symptoms and disease. As experience with these new devices increases researchers are developing new methodologies that maximize their utility in clinical practice. For example, application of HRM to assess motility and function during and after a test meal can identify the causes of swallowing problems, reflux and other postprandial symptoms and intra-operative application of Endo-FLIP may help surgeons perform antireflux surgery. These examples illustrate the potential of physiologic measurement to direct rational and effective clinical management for individual patients. PMID- 22248109 TI - Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. AB - BACKGROUND: The Chicago Classification of esophageal motility was developed to facilitate the interpretation of clinical high resolution esophageal pressure topography (EPT) studies, concurrent with the widespread adoption of this technology into clinical practice. The Chicago Classification has been an evolutionary process, molded first by published evidence pertinent to the clinical interpretation of high resolution manometry (HRM) studies and secondarily by group experience when suitable evidence is lacking. PURPOSE: This publication summarizes the state of our knowledge as of the most recent meeting of the International High Resolution Manometry Working Group in Ascona, Switzerland in April 2011. The prior iteration of the Chicago Classification was updated through a process of literature analysis and discussion. The major changes in this document from the prior iteration are largely attributable to research studies published since the prior iteration, in many cases research conducted in response to prior deliberations of the International High Resolution Manometry Working Group. The classification now includes criteria for subtyping achalasia, EGJ outflow obstruction, motility disorders not observed in normal subjects (Distal esophageal spasm, Hypercontractile esophagus, and Absent peristalsis), and statistically defined peristaltic abnormalities (Weak peristalsis, Frequent failed peristalsis, Rapid contractions with normal latency, and Hypertensive peristalsis). The Chicago Classification is an algorithmic scheme for diagnosis of esophageal motility disorders from clinical EPT studies. Moving forward, we anticipate continuing this process with increased emphasis placed on natural history studies and outcome data based on the classification. PMID- 22248110 TI - Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation? a systematic review and meta-analysis. AB - INTRODUCTION: Premature ejaculation (PE) is a highly prevalent and complex syndrome that remains poorly defined and inadequately characterized. Pharmacotherapy represents the current basis of lifelong PE treatment. AIM: The goal of this study was to assess the role of phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of patients with PE without associated erectile dysfunction (ED). MAIN OUTCOME MEASURE: The posttreatment intravaginal ejaculatory latency time was used as the primary end point of efficacy. METHODS: A systematic review of the literature was performed by electronically searching the MedLine database for peer-reviewed articles regarding the mechanism of action and the clinical trials of PDE5 in the management of PE. A meta-analysis of these clinical studies was performed to pool the efficacy. RESULTS: Twenty-nine articles that examined the supposed mechanisms of action and 14 articles that reported data from clinical studies were reviewed. The PDE5 may exert their influence by increasing the levels of nitric oxide both centrally (reducing sympathetic drive) and peripherally (leading to smooth-muscle dilatation of the seminal tract). These drugs may also induce peripheral analgesia to prolong the duration of the erection, increase confidence, improve the perception of ejaculatory control and overall sexual satisfaction, and decrease the postorgasmic refractory time for achieving a second erection after ejaculation. Concerning the efficacy, the meta-analysis shows an overall positive effect for the use of PDE5 as monotherapy or as components of a combination regimen in the treatment of PE. The major limitations of the published literature included poor study design, the absence of solid methodology, which was characterized by the lack of a unique PE definition, and the lack of appropriate endpoints for outcome evaluation of a placebo control arm and of Institutional Review Board approval. CONCLUSION: There is inadequate, partial basic, and clinical evidence to support the use of PDE5 for the treatment of PE. PMID- 22248112 TI - How do genetic correlations affect species range shifts in a changing environment? AB - Species may be able to respond to changing environments by a combination of adaptation and migration. We study how adaptation affects range shifts when it involves multiple quantitative traits evolving in response to local selection pressures and gene flow. All traits develop clines shifting in space, some of which may be in a direction opposite to univariate predictions, and the species tracks its environmental optimum with a constant lag. We provide analytical expressions for the local density and average trait values. A species can sustain faster environmental shifts, develop a wider range and greater local adaptation when spatial environmental variation is low (generating low migration load) and multitrait adaptive potential is high. These conditions are favoured when nonlinear (stabilising) selection is weak in the phenotypic direction of the change in optimum, and genetic variation is high in the phenotypic direction of the selection gradient. PMID- 22248113 TI - Retraction: The absence of MyD88 has no effect on the induction of alternatively activated macrophage during Fasciola hepatica infection. PMID- 22248111 TI - HIV infection and HERV expression: a review. AB - The human genome contains multiple copies of retrovirus genomes known as endogenous retroviruses (ERVs) that have entered the germ-line at some point in evolution. Several of these proviruses have retained (partial) coding capacity, so that a number of viral proteins or even virus particles are expressed under various conditions. Human ERVs (HERVs) belong to the beta-, gamma-, or spuma- retrovirus groups. Endogenous delta- and lenti- viruses are notably absent in humans, although endogenous lentivirus genomes have been found in lower primates. Exogenous retroviruses that currently form a health threat to humans intriguingly belong to those absent groups. The best studied of the two infectious human retroviruses is the lentivirus human immunodeficiency virus (HIV) which has an overwhelming influence on its host by infecting cells of the immune system. One HIV-induced change is the induction of HERV transcription, often leading to induced HERV protein expression. This review will discuss the potential HIV-HERV interactions.Several studies have suggested that HERV proteins are unlikely to complement defective HIV virions, nor is HIV able to package HERV transcripts, probably due to low levels of sequence similarity. It is unclear whether the expression of HERVs has a negative, neutral, or positive influence on HIV-AIDS disease progression. A positive effect was recently reported by the specific expression of HERVs in chronically HIV-infected patients, which results in the presentation of HERV-derived peptides to CD8+ T-cells. These cytotoxic T-cells were not tolerant to HERV peptides, as would be expected for self-antigens, and consequently lysed the HIV-infected, HERV-presenting cells. This novel mechanism could control HIV replication and result in a low plasma viral load. The possibility of developing a vaccination strategy based on these HERV peptides will be discussed. PMID- 22248114 TI - The impact of gender and physical environment on the handwashing behaviour of university students in Ghana. AB - OBJECTIVES: To establish levels of handwashing after defecation among students at the University of Cape Coast in Ghana, and to test hypotheses that gender and washroom environment affect handwashing behaviour. METHODS: Data on students' handwashing behaviour after defecation were collected by structured observations in washrooms. Eight hundred and six observations were made (360 female students and 446 males) in 56 washrooms over 496 observation periods. Observers recorded gender, duration of handwashing, use of soap, and physical characteristics of the washroom (cleanliness, availability of soap, tap flow and presence of handwashing posters). RESULTS: Fewer than half the students observed washed their hands or bathed after defecation. Of these, only two-thirds washed both hands and a minority (20%) used soap; only 16 students (all men) washed their hands for the recommended 15 s or longer. Female students were more likely to wash their hands at all, and were more likely to wash both hands, than males. Cleanliness of the washroom was strongly associated with improved handwashing behaviour for both women and men, as was tap flow quality for female students. CONCLUSIONS: Handwashing behaviour is generally poor among UCC students, mirroring results from North American Universities. The findings underline the plasticity of handwashing behaviour among this population, and highlight the need for ensuring that the physical environment in washrooms on university campuses is conducive to handwashing. PMID- 22248115 TI - Alcohol-associated risks for young adults with Type 1 diabetes: a narrative review. AB - AIM: To undertake a narrative review of the impact and pattern of alcohol consumption in young adults with Type 1 diabetes. METHODS: DATA SOURCES: MEDLINE, EMBASE, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of the European Association for the Study of Diabetes, the American Diabetes Association and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, UK Clinical Research Network, scrutiny of bibliographies of retrieved papers and contact with experts in the field. INCLUSION CRITERIA: relevant studies of any design of alcohol consumption and young adults with Type 1 diabetes (age 14-25 years) were included. The key outcomes were the quantity, pattern and impact of alcohol consumption, the effect on diabetes control and the effect of interventions to minimize the risks of alcohol for this population. RESULTS: Six articles and two conference abstracts met the inclusion criteria. There were six cross-sectional studies, one qualitative study and one within subjects design study. Quality of studies was variable. Alcohol use amongst young adults with Type 1 diabetes was reported to be common and potentially harmful. There was a paucity of evidence on interventions to minimize the risks of alcohol in this target group. CONCLUSIONS: Research is required to understand the social context of alcohol consumption in this population with a view to developing appropriate interventions to minimize the risks associated with its use. PMID- 22248116 TI - Erectile dysfunction in testicular cancer patients treated with chemotherapy. AB - Information on male potency in testicular cancer (TC) patients treated with chemotherapy is insufficient. We aimed to assess the levels of depression and anxiety symptoms, sexual function and gonodotrophins. Participants (n = 27) were identified and recruited from the genitourinary services of two medical centres, one in Inonu University and the other in the Firat University. All patients are TC patients treated with chemotherapy after unilateral orchiectomy. Participants completed follow-up assessments after the completion of the chemotherapy regimen. Serum luteinising hormone, follicle-stimulating hormone and testosterone levels were determined after blood samples had been taken in the morning after an overnight fast. International Index of Erectile Function (IIEF-15) was also used to evaluate erectile dysfunction (ED) score. Beck Depression and Beck Anxiety Scale were used to assess psychological symptoms. The findings indicated that men treated with chemotherapy had significantly different IIEF-15 and Beck Anxiety scores compared with men who did not receive chemotherapy. But no statistically significant difference was determined in the serum gonodotrophin levels and depression score between the two groups. It is concluded that patients with TC undergoing chemotherapy have greater risk than normal men for ED, independently of the gonodotrophin's level. PMID- 22248120 TI - 'Legal highs'--novel and emerging psychoactive drugs: a chemical overview for the toxicologist. AB - INTRODUCTION: 'Legal highs' are psychoactive chemicals which are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. METHODS: A survey of the internet was used to identify websites that are marketing 'legal highs' in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl tryptamine. RESULTS: 'Legal highs' from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. CONCLUSIONS: 'Legal highs' are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with 'legal highs' is needed. PMID- 22248121 TI - 2010 pediatric fatality review of the National Poison Center database: results and recommendations. PMID- 22248122 TI - Zygomatic implants/fixture: a systematic review. AB - Patients with moderate to severe atrophy challenge the surgeon to discover alternative ways to use existing bone or resort to augmenting the patient with autogenous or alloplastic bone materials. Many procedures have been suggested for these atrophied maxillae before implant placement, which include Le Fort I maxillary downfracture, onlay bone grafts and maxillary sinus graft procedures. A zygomatic implant can be an effective device for rehabilitation of the severely resorbed maxilla. If zygomatic implants are used, onlay bone grafting or sinus augmentation would likely not be necessary. The purpose of this article is to review the developments that have taken place in zygomatic implant treatment over years, including anatomic information for installing the zygomatic implants, implant placement techniques, stabilization, and prosthodontic procedures. PMID- 22248124 TI - Safety incentive and penalty provisions in Indian construction projects and their impact on safety performance. AB - Safety incentive and penalty (I/P) provisions in construction contracts are one of the most common forms of I/P. Contradictory opinions on the effectiveness of these provisions have been expressed in the literature. Statistics on safety provisions were collected from 32 construction projects, which include both types of contracts - those with safety I/P provisions and those without them. Although inclusion of safety I/P provisions in contracts helps in improving the overall safety performance in construction projects, further scope for improvement still exists. Literature review and structured personal interviews, coupled with a survey based on preliminary questionnaire, revealed that successful formulation and implementation of such provisions are dependent on 25 attributes which need the attention of both clients and contractors. A questionnaire-based survey was conducted to evaluate these attributes. The six factors extracted by carrying out factor analysis are: incentive distribution method, proper labour training, special attention to risky situations, role of safety committee and sub contractors, specialised works and safety equipments, and right form of I/P. If taken care of, these attributes have the potential to improve the safety performance in construction projects. The results would be useful to clients and contractors in implementing the safety I/P provisions and thereby improving safety performance. PMID- 22248125 TI - Interlaboratory comparison of PCR-based identification of Candida and Aspergillus DNA in spiked blood samples. AB - Despite PCR per se being a powerful and sensitive technique, regarding the detection of fungi in patients' blood, no consensus for a standardised PCR protocol yet exists. To complement other ongoing or accomplished studies which tackle this problem, the German Reference Center for Systemic Mycoses conducted an interlaboratory comparison starting with blood samples spiked with fungal cell elements. Altogether, six laboratories using in-house PCR-protocols from Germany and Austria participated in the trial. Blood samples were spiked with vital cells of Candida albicans or Aspergillus fumigatus. Candida was used in the yeast form, whereas Aspergillus cells were either spiked as conidia or as very young germlings, also known as smoo cells. Spiked blood samples contained between 10 and 10 000 cells ml(-1). Depending on the techniques used for fungal cell disruption and DNA-amplification, detection quality was variable between laboratories, but also differed within single laboratories in different trials particularly for samples spiked with less than 100 cells ml(-1). Altogether, at least regarding the detection of A. fumigatus, two of six laboratories showed constant reliable test results also with low fungal cell number spiked samples. Protocols used by these labs do not differ substantially from others. However, as particularities, one protocol included a conventional phenol chloroform extraction during the DNA preparation process and the other included a real time PCR-protocol based on FRET probes. Other laboratory comparisons on the basis of clinical samples should follow to further evaluate the procedures. The difficulties and problems of such trials in general are discussed. PMID- 22248126 TI - A secondary metabolite amberin from Amberboa ramosa. AB - Amberin (1), a new sesquiterpene lactone, has been isolated from the ethyl acetate soluble fraction of Amberboa ramosa together with apigenin (2), jaseocidine (3), crysoeriol (4), and 3beta, 8alpha-dihydroxy-11alpha-methyl 1alphaH, 5alphaH, 6betaH, 7alphaH, 11betaH-guai-10(14), 4 (15)-dien-6, 12-olide (5). The structures of the isolated compounds have been elucidated by 1D and 2D NMR spectroscopy. PMID- 22248127 TI - Metabolic dynamics during autumn cold acclimation within and among populations of Sitka spruce (Picea sitchensis). AB - * Autumnal cold acclimation in conifers is a complex process, the timing and extent of which vary widely along latitudinal gradients for many tree species and reflect local adaptation to climate. Although previous studies have detailed some aspects of the metabolic remodelling that accompanies cold acclimation in conifers, little is known about global metabolic dynamics, or how these changes vary among phenotypically divergent populations. * Using untargeted GC-MS metabolite profiling, we monitored metabolic dynamics during autumnal cold acclimation in three populations of Sitka spruce from the southern, central, and northern portions of the species range, which differ in both the timing and extent of cold acclimation. * Latitudinal variation was evident in the nature, intensity, and timing of metabolic events. Early development of strong freezing tolerance in the northern population was associated with a transient accumulation of amino acids. By late autumn, metabolic profiles were highly similar between the northern and central populations, whereas profiles for the southern population were relatively distinct. * Our results provide insight into the metabolic architecture of latitudinal adaptive variation in autumn acclimation and show that different mechanisms are the basis of early October cold hardiness and autumn-acclimated cold hardiness. PMID- 22248128 TI - MyD88 provides a protective role in long-term radiation-induced lung injury. AB - PURPOSE: The role of innate immune regulators is investigated in injury sustained from irradiation as in the clinic for cancer treatment or from a nuclear incident. The protective benefits of flagellin signaling through Toll-like receptors (TLR) in an irradiation setting warrant study of a key intracellular adaptor of TLR signaling, namely Myeloid differentiation primary response factor 88 (MyD88). The role of MyD88 in regulating innate immunity and Nuclear factor kappa-B (NF-kappaB)-activated responses targets this critical factor for influencing injury and recovery as well as maintaining immune homeostasis. MATERIALS AND METHODS: To examine the role of MyD88, we examined immune cells and factors during acute pneumonitic and fibrotic phases in Myd88-deficient animals receiving thoracic gamma (gamma)-irradiation. RESULTS: We found that MyD88 supports survival from radiation-induced injury through the regulation of inflammatory factors that aid in recovery from irradiation. The absence of MyD88 resulted in unresolved pulmonary infiltrate and enhanced collagen deposition plus elevated type 2 helper T cell (Th2) cytokines in long-term survivors of irradiation. CONCLUSIONS: These results based only on a gene deletion model suggest that alterations of MyD88-dependent inflammatory processes impact chronic lung injury. Therefore, MyD88 may contribute to attenuating long-term radiation induced lung injury and protecting against fibrosis. PMID- 22248129 TI - What can we learn from the failure of yet another 'miracle cure' for addiction? PMID- 22248131 TI - Dopamine is not dopamine. PMID- 22248132 TI - Addiction as aberrant learning-evidence from Parkinson's disease. PMID- 22248133 TI - Compulsive use of dopamine replacement therapy in Parkinson's disease: insights into the neurobiology of addiction. PMID- 22248134 TI - Compulsive use of dopamine replacement therapy among Parkinson's disease patients: if it looks like a duck, swims like a duck and quacks like a duck... PMID- 22248135 TI - Stimulating debate in the field of addiction. PMID- 22248136 TI - Top priorities for alcohol regulators in the United States: protecting public health or the alcohol industry? AB - AIMS: This paper describes alcohol industry involvement in the 2010 annual conference proceedings of the National Conference of State Liquor Administrators (NCSLA) in the United States. DESIGN: The author attended the conference, observed conference attendees and panelists and identified key themes in the panel sessions. SETTING: The NCSLA Annual Meeting took place 20-24 June 2010 in New Orleans, Louisiana. PARTICIPANTS: NCSLA meeting attendees and panelists were professionals from state alcohol control systems; federal government agencies; and companies representing the alcohol industry. MEASUREMENTS: The total number of conference attendees and participants were counted as well as the number of attendees and participants from regulator, industry and public health sectors. FINDINGS: More than two-thirds (72.2%) of the 187 conference attendees were from alcohol producers, importers, wholesalers, retailers or their attorneys. Nearly two-thirds (65.0%) of the 40 panelists were from the alcohol industry. The author of this paper was the only attendee, and the only panelist, representing public health policy. CONCLUSIONS: The National Conference of State Liquor Administrators in the United States is dominated by the global companies that produce, import, distribute and sell alcohol, highlighting a lack of public health considerations within the Association's liquor control agenda [corrected]. PMID- 22248137 TI - Commentary on Baker et al. (2012): Assessing dependence-are specific criteria for nicotine enough or do we need to consider its forms of administration? PMID- 22248138 TI - Psychosocial therapeutic interventions for volatile substance use: a systematic review. AB - AIMS: Volatile substance use (VSU) is associated with a range of adverse outcomes, including cognitive impairment and death. It occurs disproportionately within young and marginalized populations. A previous international systematic review of VSU treatment identified no relevant studies. This paper reports on a systematic review of a range of study types concerning psychosocial interventions for VSU. METHODS: Search parameters were developed using the Population, Intervention, Professionals, Outcomes, Health care setting and Contexts (PIPOH) tool with input from an expert committee. Included were randomized controlled trials (RCTs), comparative studies with or without concurrent controls, case series studies and grey literature, published in English during 1980-2010. RESULTS: The initial search identified 2344 references. After two screening phases, 23 studies of VSU therapeutic interventions remained. Of these, 19 concerned psychosocial interventions, which we discuss as: case management; counselling; recreation and engagement programmes; and residential treatment. Studies were conducted in Australia, Canada, the United States, United Kingdom and Brazil. No RCTs were identified and studies were generally of low evidentiary levels. CONCLUSIONS: Even when a range of study types are included, clear conclusions for volatile substance use psychological treatment are not supported, but three intervention types merit further examination: family therapy, activity based programmes and Indigenous-led residential approaches. Future volatile substance use research could be enhanced by developing and validating outcome measurement tools. Robust multi-site studies are also required. PMID- 22248139 TI - Commentary on Kelly et al. (2012): Multiple mediation-many mechanisms signal more questions. PMID- 22248140 TI - Commentary on Mehta et al. (2012): Natural history of injecting drug use. PMID- 22248141 TI - Commentary on Ling et al. (2012): The PROMETATM treatment does not reduce methamphetamine use. PMID- 22248142 TI - Concurrent use of tobacco and khat: added burden on chronic disease epidemic. PMID- 22248143 TI - 100 years ago in addiction science. PMID- 22248144 TI - Quinolinic acid, the inescapable neurotoxin. AB - Over the last two decades, evidence for the involvement of quinolinic acid (QUIN) in neuroinflammatory diseases has been exponentially increasing. Within the brain, QUIN is produced and released by infiltrating macrophages and activated microglia, the very cells that are prominent during neuroinflammation. QUIN acts as an agonist of the N-methyl-D-aspartate receptor and as such is considered to be a brain endogenous excitotoxin. Since the discovery of the excitotoxic activity of QUIN in the early 1980s, several other cytotoxic mechanisms have been identified. We know today that QUIN acts as a neurotoxin, gliotoxin, proinflammatory mediator, pro-oxidant molecule and can alter the integrity and cohesion of the blood-brain barrier. This paper aims to review some of the most recent findings about the effects of QUIN and its mode of action. PMID- 22248146 TI - Clonidine extended-release in attention-deficit hyperactivity disorder: profile report. PMID- 22248147 TI - Hard and glossy-colored films composed of micropatterned organic dots and electrodeposited honeycomb-shaped nickel walls. AB - This paper proposes a novel approach for the preparation of colored films with a metallic luster and high hardness. The colored organic films were patterned as microdots by photolithography, and then honeycomb-shaped Ni walls were electrodeposited between the micropatterning. The organic/inorganic composite films showed the hardest grade in a pencil hardness test and high durability in wear resistance tests because the honeycomb-shaped Ni walls protected the colored organic dots. PMID- 22248145 TI - Cranberry proanthocyanidins inhibit the adherence properties of Candida albicans and cytokine secretion by oral epithelial cells. AB - BACKGROUND: Oral candidiasis is a common fungal disease mainly caused by Candida albicans. The aim of this study was to investigate the effects of A-type cranberry proanthocyanidins (AC-PACs) on pathogenic properties of C. albicans as well as on the inflammatory response of oral epithelial cells induced by this oral pathogen. METHODS: Microplate dilution assays were performed to determine the effect of AC-PACs on C. albicans growth as well as biofilm formation stained with crystal violet. Adhesion of FITC-labeled C. albicans to oral epithelial cells and to acrylic resin disks was monitored by fluorometry. The effects of AC PACs on C. albicans-induced cytokine secretion, nuclear factor-kappa B (NF kappaB) p65 activation and kinase phosphorylation in oral epithelial cells were determined by immunological assays. RESULTS: Although AC-PACs did not affect growth of C. albicans, it prevented biofilm formation and reduced adherence of C. albicans to oral epithelial cells and saliva-coated acrylic resin discs. In addition, AC-PACs significantly decreased the secretion of IL-8 and IL-6 by oral epithelial cells stimulated with C. albicans. This anti-inflammatory effect was associated with reduced activation of NF-kappaB p65 and phosphorylation of specific signal intracellular kinases. CONCLUSION: AC-PACs by affecting the adherence properties of C. albicans and attenuating the inflammatory response induced by this pathogen represent potential novel therapeutic agents for the prevention/treatment of oral candidiasis. PMID- 22248148 TI - Phlorotannins from brown algae (Fucus vesiculosus) inhibited the formation of advanced glycation endproducts by scavenging reactive carbonyls. AB - Accumulation of advanced glycation end products (AGEs) in vivo is associated with aging, diabetes, Alzheimer's disease, renal failure, etc. The objective of this study was to investigate the inhibitory effects of brown algae Fucus vesiculosus phlorotannins on the formation of AGEs. F. vesiculosus phlorotannins were extracted using 70% acetone. The resultant extract was fractionated into dichloromethane, ethyl acetate, butanol, and water fractions. The ethyl acetate fraction was further fractionated into four subfractions (Ethyl-F1 to -F4) using a Sephadex LH-20 column. F. vesiculosus acetone extract or fractions significantly inhibited the formation of AGEs mediated by glucose and methylglyoxal in a concentration-dependent manner. The concentrations of F. vesiculosus extracts required to inhibit 50% of albumin glycation (EC(50)) in the bovine serum albumin (BSA)-methylglyoxal assay were lower than those of aminoguanidine (a drug candidate for diabetic complication), except for F. vesiculosus acetone extract and dichloromethane fraction. In the BSA-glucose assay, F. vesiculosus extracts inhibited BSA glycation more than or as effectively as aminoguanidine, except for Ethyl-F3 and -F4. The ethyl acetate fraction and its four subfractions scavenged more than 50% of methylglyoxal in two hours. The hypothesis whether F. vesiculosus phlorotannins scavenged reactive carbonyls by forming adducts was tested. Phloroglucinol, the constituent unit of phlorotannins, reacted with glyoxal and methylglyoxal. Five phloroglucinol carbonyl adducts were detected and tentatively identified using HPLC-ESI-MS(n). PMID- 22248149 TI - Biochemical identification of the OsMKK6-OsMPK3 signalling pathway for chilling stress tolerance in rice. AB - MAPK (mitogen-activated protein kinase) pathways have been implicated in stress signalling in plants. In the present study, we performed yeast two-hybrid screening to identify partner MAPKs for OsMKK (Oryza sativa MAPK kinase) 6, a rice MAPK kinase, and revealed specific interactions of OsMKK6 with OsMPK3 and OsMPK6. OsMPK3 and OsMPK6 each co-immunoprecipitated OsMKK6, and both were directly phosphorylated by OsMKK6 in vitro. An MBP (myelin basic protein) kinase assay of the immunoprecipitation complex indicated that OsMPK3 and OsMPK6 were activated in response to a moderately low temperature (12 degrees C), but not a severely low temperature (4 degrees C) in rice seedlings. A constitutively active form of OsMKK6, OsMKK6DD, showed elevated phosphorylation activity against OsMPK3 and OsMPK6 in vitro. OsMPK3, but not OsMPK6, was constitutively activated in transgenic plants overexpressing OsMKK6DD, indicating that OsMPK3 is an in vivo target of OsMKK6. Enhanced chilling tolerance was observed in the transgenic plants overexpressing OsMKK6DD. Taken together, our data suggest that OsMKK6 and OsMPK3 constitute a moderately low-temperature signalling pathway and regulate cold stress tolerance in rice. PMID- 22248150 TI - Regional spread pattern predicts survival in patients with sporadic amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: Sporadic amyotrophic lateral sclerosis (sALS) is a disease with a focal clinical onset and contiguous spread. We examined patterns of disease spread following symptoms onset in sALS and whether the pattern of spread predicted survival. METHODS: Review of medical records (2003-2009) at London Ontario and Buenos Aires clinic cohorts retrieved 318 patients with sporadic sALS. According to patient self-report, we determined eight spread patterns: rostro-caudal, caudo-rostral, crossed, circular, superior interposed, middle interposed, inferior interposed and isolated. The variables studied were as follows: age, gender, sALS phenotypes, time from onset to diagnosis and time and direction of the spreading to the first region. Survival from symptoms onset was analysed by Kaplan-Meier, Tarone-Ware and Cox proportional hazards methods. RESULTS: The direction of first spread was horizontal in 33%, rostral to caudal in 32% and caudal to rostral in 21%, whereas spread to remote regions was observed in 14% of patients. Survival curves and 3- and 5-year survival rates favoured patients with an isolated and caudo-rostral pattern of spread compared to patients progressing to distant regions without involvement in the intervening region, or 'superior and inferior interposed patterns' (Tarone-Ware P = 0.001, chi(2) = 0.002 and chi(2) = 0.006, respectively). Factors affecting survival were gender, time to diagnosis, flail arm phenotype and age at diagnosis. CONCLUSIONS: We have provided evidence that not all spread in ALS is contiguous and that the nature of symptom progression influences survival. Patients with sALS with 'interposed patterns' had a worse prognosis, whereas patients with caudo-rostral pattern fared better than the rest. PMID- 22248151 TI - Tracking antioxidant properties and color changes in low-sugar bilberry jam as effect of processing, storage and pectin concentration. AB - BACKGROUND: Recently, an increased interest in the identification of valuable possibilities for preserving the antioxidant properties of products obtained by thermal processing of fruits rich in bioactive compounds can be noticed. In this regard, an extensive analysis is necessary in terms of thermal processed products behavior in relation to various factors. The purpose of the present study was to assess the effect which processing and storage at 20 degrees C has on the antioxidant properties and color quality of low-sugar bilberry jam with different low-methoxyl pectin (LMP) concentrations. RESULTS: For all measured parameters, it should be noted that thermal processing induced significant alterations reported to the values registered for fresh fruit. Most important losses due to thermal processing were recorded for total monomeric anthocyanins (TMA) (81-84%), followed by L-ascorbic acid (L-AsAc) content (53-58%), total phenolics (TP) content (42-51%) and FRAP (ferric reducing antioxidant power) values (36-47%). Moreover, depreciation of the investigated compounds occurred during storage at 20 degrees C. Jam storage for 7 months resulted in severe losses in TMA content in the range 58-72% from the value recorded one day after processing. This coincided with marked increases in polymeric color percent of these products after 7 months of storage. Also, bilberry jam storage for 7 months resulted in a decrease in L-AsAc content of 40-53% from the value recorded one day after processing, 41-57% in TP content and 33-46% from the value recorded one day after processing for FRAP values. By decreasing of LMP concentration in the jam recipe from 1 to 0.3% there has been an increase in losses of investigated compounds. CONCLUSION: Overall, the results indicated that bilberry jams can also represent a good source of antioxidant compounds, although compared to the fruit, important losses seem to occur. Practical application of this work is that this kind of information will be very useful in optimizing the jam processing technology and storage conditions, in order to improve the quality of these products. PMID- 22248152 TI - Senescence and age-specific trade-offs between reproduction and survival in female Asian elephants. AB - Although studies on laboratory species and natural populations of vertebrates have shown reproduction to impair later performance, little is known of the age specific associations between reproduction and survival, and how such findings apply to the ageing of large, long-lived species. Herein we develop a framework to examine population-level patterns of reproduction and survival across lifespan in long-lived organisms, and decompose those changes into individual-level effects, and the effects of age-specific trade-offs between fitness components. We apply this to an extensive longitudinal dataset on female semi-captive Asian timber elephants (Elephas maximus) and report the first evidence of age-specific fitness declines that are driven by age-specific associations between fitness components in a long-lived mammal. Associations between reproduction and survival are positive in early life, but negative in later life with up to 71% of later life survival declines associated with investing in the production of offspring within this population of this critically endangered species. PMID- 22248153 TI - A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction. AB - INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors have become standard treatment for erectile dysfunction (ED). AIM: To prospectively evaluate the safety and efficacy of avanafil, a novel PDE5 inhibitor, in men with mild to severe ED. METHODS: In this multicenter, double-blind, Phase 3 trial, 646 subjects were randomized to receive avanafil (50 mg, 100 mg, 200 mg) or placebo throughout a 12-week treatment period. Subjects were instructed to take study drug 30 minutes prior to initiation of sexual activity. At least a 12-hour separation time between doses was required; no restrictions were placed on food or alcohol intake. MAIN OUTCOME MEASURES: Improvement in erectile function (EF) was measured by Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3) and by the EF domain of the International Index of Erectile Function (IIEF) questionnaire. RESULTS: Mean change in percentage of successful sexual attempts (SEP2 and SEP3) and IIEF-EF domain score significantly favored all doses of avanafil over placebo (P <= 0.001). Secondary analyses demonstrated achievement of successful intercourse by subjects within 15 minutes of dosing. Of the 300 sexual attempts made during this interval, 64% to 71% were successful in avanafil treated subjects compared with 27% in placebo-treated subjects. Successful intercourse was also demonstrated >6 hours post dosing, with 59% to 83% of the 80 sexual attempts successful in avanafil-treated subjects compared with 25% of placebo-treated subjects. The most commonly reported adverse events in subjects taking avanafil included headache, flushing, and nasal congestion; there were no drug-related serious adverse events. CONCLUSION: Following 12 weeks of avanafil treatment without food or alcohol restrictions, significant improvements in sexual function were observed with all 3 doses of avanafil compared with placebo. Successful intercourse was observed as early as 15 minutes and >6 hours after dosing in some subjects. Avanafil was generally well tolerated for the treatment of ED. PMID- 22248154 TI - Audit of insulin detemir in pregnancy: a retrospective case series. PMID- 22248156 TI - Characterization of the expression of macrophage inflammatory protein-1alpha (MIP 1alpha) and C-C chemokine receptor 5 (CCR5) after kainic acid-induced status epilepticus (SE) in juvenile rats. AB - AIMS: To identify the potential role of macrophage inflammatory protein-1alpha (MIP-1alpha) with its C-C chemokine receptor 5 (CCR5) in epileptogenic brain injury, we examined their expression in juvenile rat hippocampus and explored the potential link between MIP-1alpha, CCR5 and neuropathological alterations after status epilepticus (SE) induced by intracerebroventricular (i.c.v.) kainic acid (KA) injection. METHODS: Based on the determination of the development of spontaneous seizures initiated by SE in developing rat brain, we firstly examined hippocampal neurone damage through Nissl and Fluoro-Jade B staining, and evaluated microglial reaction during the early phase following KA-induced SE in 21-day-old rats. MIP-1alpha and CCR5 protein were quantified by ELISA and Western blot respectively following mRNA by real-time PCR. We also mapped MIP-1alpha and CCR5 expression in the hippocampus by immunohistochemistry and identified their cellular sources using double-labelling immunofluorescence. RESULTS: In juvenile rats, KA caused characteristic neurone damage in the hippocampal subfields, with accompanying microglial accumulation. In parallel with mRNA expression, MIP 1alpha protein in hippocampus was transiently increased after KA treatment, and peaked from 16 to 72 h. Double-labelling immunofluorescence revealed that MIP 1alpha was localized to microglia. Up-regulated CCR5 remained prominent at 24 and 72 h and was mainly localized to activated microglia. Further immunohistochemistry revealed that MIP-1alpha and CCR5 expression were closely consistent with microglial accumulation in corresponding hippocampal subfields undergoing degenerative changes. CONCLUSIONS: Our data indicated that MIP-1alpha as a regulator, linking with the CCR5 receptor, may be involved within the early stages of the epileptogenic process following SE by i.c.v. KA injection. PMID- 22248157 TI - Micrurus snake venoms activate human complement system and generate anaphylatoxins. AB - BACKGROUND: The genus Micrurus, coral snakes (Serpentes, Elapidae), comprises more than 120 species and subspecies distributed from the south United States to the south of South America. Micrurus snake bites can cause death by muscle paralysis and further respiratory arrest within a few hours after envenomation. Clinical observations show mainly neurotoxic symptoms, although other biological activities have also been experimentally observed, including cardiotoxicity, hemolysis, edema and myotoxicity. RESULTS: In the present study we have investigated the action of venoms from seven species of snakes from the genus Micrurus on the complement system in in vitro studies. Several of the Micrurus species could consume the classical and/or the lectin pathways, but not the alternative pathway, and C3a, C4a and C5a were generated in sera treated with the venoms as result of this complement activation. Micrurus venoms were also able to directly cleave the alpha chain of the component C3, but not of the C4, which was inhibited by 1,10 Phenanthroline, suggesting the presence of a C3alpha chain specific metalloprotease in Micrurus spp venoms. Furthermore, complement activation was in part associated with the cleavage of C1-Inhibitor by protease(s) present in the venoms, which disrupts complement activation control. CONCLUSION: Micrurus venoms can activate the complement system, generating a significant amount of anaphylatoxins, which may assist due to their vasodilatory effects, to enhance the spreading of other venom components during the envenomation process. PMID- 22248160 TI - Design and evaluation of a low-cost instrumented glove for hand function assessment. AB - BACKGROUND: The evaluation of hand function impairment following a neurological disorder (stroke and cervical spinal cord injury) requires sensitive, reliable and clinically meaningful assessment tools. Clinical performance measures of hand function mainly focus on the accomplishment of activities of daily living (ADL), typically rather complex tasks assessed by a gross ordinal rating; while the motor performance (i.e. kinematics) is less detailed. The goal of this study was to develop a low-cost instrumented glove to capture details in grasping, feasible for the assessment of hand function in clinical practice and rehabilitation settings. METHODS: Different sensor types were tested for output signal stability over time by measuring the signal drift of their step responses. A system that converted sensor output voltages into angles based on pre-measured curves was implemented. Furthermore, the voltage supply of each sensor signal conditioning circuit was increased to enhance the sensor resolution. The repeatability of finger bending trajectories, recorded during the performance of three ADL-based tasks, was established using the intraclass correlation coefficient (ICC). Moreover, the accuracy of the glove was evaluated by determining the agreement between angles measured with the embedded sensors and angles measured by traditional goniometry. In addition, the feasibility of the glove was tested in four patients with a pathological hand function caused by a cervical spinal cord injury (cSCI). RESULTS: A sensor type that displayed a stable output signal over time was identified, and a high sensor resolution of 0.5 degrees was obtained. The evaluation of the glove's reliability yielded high ICC values (0.84 to 0.92) with an accuracy error of about +/- 5 degrees . Feasibility testing revealed that the glove was sensitive to distinguish different levels of hand function impairment in cSCI patients. CONCLUSIONS: The device satisfied the desired system requirements in terms of low cost, stable sensor signal over time, full finger flexion range of motion tracking and capability to monitor all three joints of one finger. The developed rapid calibration system for easy use (high feasibility) and excellent psychometric properties (i.e. reliability and validity) qualify the device for the assessment of hand function in clinical practice and rehabilitation settings. PMID- 22248162 TI - The role of selected metalloproteinases in cheiroarthropathy in children with type 1 diabetes - a pilotage study. AB - BACKGROUND: Metalloproteinases of the external matrix play an important role in ethiopatogenesis of diabetic complications especially in microangiopathy and also in fibrosing processes with occurrence the cheiroarthropathy, but clinical data are insufficient. AIMS: The aim of the study was to assess the influence of metalloproteinases such as gelatinase A (MMP2) and gelatinase B (MMP9), and their tissue inhibitors (TIMP2, TIMP9) in ethiopathogenesis of cheiroatrhopathy in children with diabetes type 1. MATERIALS AND METHODS: Forty one children were observed in average age of 14.98 years (+/-3.03 years), with the average duration of diabetes 6.78 years (+/-3.21 years), and with average HbA1c within all diabetes duration time 7.1% (6.47-7.5%). In all patients, the occurrence of cheiroarthropathy was checked, and concentration of metalloproteinase's and their inhibitors in serum were measured using ELISA method. Probe was divided into two groups because of presence of cheiroarthropathy. The comparing analysis of these two groups was conducted, and the correlation between metalloproteinase's concentration and their tissue inhibitors with selected parameters was done. RESULTS: When comparing group with cheiroarthropathy (n = 19) with the group without cheiroarthropathy (n = 22), the statistically significant elevated levels of metalloproteinase's were proved such as: MMP2 - 202 ng/ml (193-207) vs. 138 ng/ml (130-158), p < 0.001; MMP9 - 462 ng/ml (426-505) vs. 288 ng/ml (251-313), 0.001; TIMP2 - 182 ng/ml (177-190) vs. 104 ng/ml (88-165), p < 0.001); TIMP9 - 85 ng/ml (68-95) vs. 55 ng/ml (50-60), p < 0.001. There was no correlation between occurrence of cheiroarthropathy and age of the diabetes onset, duration of diabetes, grade of metabolic compensation, insulin dosages, weight and height. CONCLUSION: In children with long-term diabetes, although relatively metabolic compensation, the cheiroarthropathy has been occurred accompanying by elevated concentrations of metalloproteinase's and their tissue inhibitors. The presence of cheiroarthropathy could be treated as a simple test to identification the patients endangered to develop chronic vascular complication. PMID- 22248163 TI - The effect of adding tobramycin to Simplex P cement on femoral stem micromotion as measured by radiostereometric analysis: a 2-year randomized controlled trial. AB - BACKGROUND: Previous in vitro research on addition of antibiotics to bone cement has found no statistically significant deterioration in mechanical properties. However, no clinical studies have compared the performance of tobramycin-laden bone cement with that of standard bone cement (Simplex P). PATIENTS AND METHODS: 23 patients (25 hips) were randomized to receive an Exeter (Stryker Orthopaedics) femoral stem cemented with either Simplex P (standard) or Simplex T (tobramycin laden) cement. There were 2 years of follow-up, with scheduled radiostereometric (RSA) examinations. RESULTS: All stems migrated distally and showed some degree of retroversion. No clinically significant differences in stem subsidence or retroversion were found between the Simplex T and Simplex P cement groups after 2 years. Overall subsidence was less than in previous studies, probably due to a postponed initial post-surgical examination. Rates of subsidence in both cement groups were consistent with those from previous studies of Exeter stems. INTERPRETATION: Subsidence of the femoral stem after 2 years was similar in the Simplex T (tobramycin-laden) and Simplex P (standard) groups. PMID- 22248164 TI - Association between venous thromboembolism and plasma levels of both soluble fibrin and plasminogen-activator inhibitor 1 in 170 patients undergoing total hip arthroplasty. AB - BACKGROUND AND PURPOSE: Markers of coagulation and fibrinolysis, such as soluble fibrin (SF), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), have been developed in order to determine thrombotic tendency. We investigated whether these markers could be used to diagnose venous thromboembolism (VTE) in the early phase after primary total hip arthroplasty (THA). METHODS: This prospective study involved 2 groups: an intermittent pneumatic compression (IPC) group (67 patients who underwent IPC only as prophylaxis for VTE) and a fondaparinux (FPX) group (103 patients who received IPC and FPX postoperatively). Plasma levels of SF and PAI-1 were measured on postoperative day 1. To diagnose postoperative VTE, multi detector row computed tomography (MDCT) and duplex ultrasonography (US) were performed on postoperative day 7. RESULTS: VTE was detected postoperatively in 17 cases in the IPC group (25%) and in 8 cases in the FPX group (6%). In the IPC group, plasma levels of SF and PAI-1 were higher in patients with VTE (p < 0.01) than in those without VTE. On the other hand, in the FPX group there were no differences in the levels of SF or PAI-1 measured before administration of FPX on postoperative day 1. The diagnostic criterion of an increase in SF or PAI-1 above the cutoff level (19.8 ug/mL and 53.5 ng/mL, respectively) provided a sensitivity of 100% and a specificity of 67% in the IPC group. In addition, when this criterion was applied to FPX patients, 7 of the 8 patients with VTE met the criterion, and there was a negative agreement rate of 48/49. INTERPRETATION: Screening using the cutoff levels of SF and PAI-1 may be useful and shows high sensitivity in predicting postoperative VTE in the early phase after THA. PMID- 22248165 TI - A new algorithm for hip fracture surgery. Reoperation rate reduced from 18 % to 12 % in 2,000 consecutive patients followed for 1 year. AB - BACKGROUND AND PURPOSE: Treatment of hip fracture patients is controversial. We implemented a new operative and supervision algorithm (the Hvidovre algorithm) for surgical treatment of all hip fractures, primarily based on own previously published results. METHODS: 2,000 consecutive patients over 50 years of age who were admitted and operated on because of a hip fracture were prospectively included. 1,000 of these patients were included after implementation of the algorithm. Demographic parameters, hospital treatment, and reoperations within the first postoperative year were assessed from patient records. RESULTS: 931 of 1,000 operative procedures were performed according to the algorithm, as compared to only 726 of 1,000 prior to its introduction (p < 0.001). After implementation of the algorithm, junior registrars still performed half of the operations, but unsupervised procedures declined from 192 of 1,000 to 105 of 1,000 (p < 0.001). The rate of reoperations declined from 18% to 12% (p < 0.001 in a multiple Cox regression analysis), with a decline of 24% to 18% for intracapsular fractures and a decline of 13% to 7% for extracapsular fractures. The proportion of bed days caused by reoperations was reduced from 24% of total hospitalization before the algorithm was introduced to 18% after it was introduced. INTERPRETATION: It is possible to implement an algorithm for treatment of all hip fracture patients in a large teaching hospital. In our case, the Hvidovre algorithm both raised the rate of supervision and reduced the rate of reoperations. The reduced reoperation rate saved many hospital bed-days. PMID- 22248166 TI - Obesity in total hip arthroplasty-does it really matter? PMID- 22248168 TI - Results of 189 wrist replacements. PMID- 22248167 TI - Value of routine blood tests for prediction of mortality risk in hip fracture patients. AB - BACKGROUND: There is a 5- to 8-fold increased risk of mortality during the first 3 months after a hip fracture. Several risk factors are known. We studied the predictive value (for mortality) of routine blood tests taken on admission. METHODS: 792 hip fracture patients were included prospectively; blood tests were taken on admission. Follow-up data on mortality were obtained from the civil registration system. Patients were divided into 2 groups based on whether they had survived at least 90 days after the hip fracture. To estimate which laboratory tests could be used to predict outcome, we used receiver operation characteristic (ROC) curves. RESULTS: 3-month mortality could be predicted with 69% accuracy from the level of plasma creatinine in standard admission blood tests. The mortality in patients with elevated levels of creatinine was almost 3 fold that of the patients with normal creatinine. Mortality was also associated with age, low blood hemoglobin, high plasma potassium, and low plasma albumin levels. INTERPRETATION: Our findings could be of use in identifying patients who might benefit from increased attention perioperatively. PMID- 22248169 TI - Operative and nonoperative treatment of clavicle fractures in adults. AB - BACKGROUND AND PURPOSE: Traditionally, clavicle fractures have been treated nonoperatively. However, many recent studies have concentrated on the results of operative treatment. We assessed and compared the outcomes of operative and nonoperative treatment for acute clavicle fractures in adults. METHODS: We performed a systematic search of the medical literature from 1966 until the end of March 2011. We included randomized controlled trials and controlled clinical trials comparing operative and nonoperative treatment and studies comparing different operative and nonoperative treatments. We required that there should be at least 30 adult patients and a follow-up of at least 6 months in each individual trial. We used the GRADE method to assess the quality of evidence. RESULTS: 6 randomized controlled trials (n = 631) and 7 controlled clinical trials (n = 559) were included. There was moderate-quality evidence (i.e. of grade B) (1) that surgery has considerable effectiveness on better function and less disability at short follow-up, (2) of similar risk of relatively mild complications after operative or nonoperative treatment, (3) that delayed union and nonunion were more common in patients who were treated nonoperatively than in those treated operatively, and (4) that the osteosynthesis method had no effect on the incidence of delayed union or nonunion. Only 1 controlled clinical trial was found on lateral clavicle fractures with very limited (grade D) evidence. INTERPRETATION: Patients treated operatively have slightly better function and less disability than those treated nonoperatively at short follow-up, but then the effectiveness diminishes and is weak at 6 months. The different operative techniques may not differ in effectiveness or in adverse effects, but the evidence is very limited or conflicting. Surgery could be considered for active patients who require recovery to the previous level of activity in the shortest possible time. PMID- 22248170 TI - Transient expression of myofibroblast-like cells in rat rib fracture callus. AB - BACKGROUND AND PURPOSE: We have previously shown that early fracture callus of rat rib has viscoelastic and contractile properties resembling those of smooth muscle. The cells responsible for this contractility have been hypothesized to be myofibroblast-like in nature. In soft-tissue healing, force generated by contraction of myofibroblasts promotes healing. Accordingly, we tried to identify myofibroblast-like cells in early fibrous callus. ANIMALS AND METHODS: Calluses from rat rib fractures were removed 7, 14, and 21 days after fracture and unfractured ribs acted as controls. All tissues were analyzed using qPCR and immunohistochemistry. We analyzed expression of smooth muscle- and myofibroblast associated genes and proteins including alpha smooth muscle actin (alphaSMA), non muscle myosin, fibronectin extra domain A variant (EDA-fibronectin), OB-cadherin, connexin-43, basic calponin (h1CaP), and h-caldesmon. RESULTS: In calluses at 7 days post-fracture, there were statistically significant increases in expression of alphaSMA mRNA (2.5 fold), h1CaP mRNA (2.1 fold), EDA-fibronectin mRNA (14 fold), and connexin-43 mRNA (1.8 fold) compared to unfractured ribs, and by 21 days post-fracture mRNA expression in calluses had decreased to levels approaching those in unfractured rib. Immunohistochemistry of 7 day fibrous callus localized calponin, EDA-fibronectin and co-immunolabeling of OB-cadherin and alphaSMA (thus confirming a myofibroblastic phenotype) within various cell populations. INTERPRETATION: This study provides further evidence that early rat rib callus is not only smooth muscle-like in nature but also contains a notable population of cells that have a distinct myofibroblastic phenotype. The presence of these cells indicates that in vivo contraction of early callus is a mechanism that may occur in fractures so as to facilitate healing, as it does in soft tissue wound repair. PMID- 22248171 TI - Time-dependent improvement in functional outcome following Oxford medial unicompartmental knee arthroplasty. A prospective longitudinal multicenter study involving 96 patients. AB - BACKGROUND AND PURPOSE: 10-year survival rates after unicompartmental knee replacement (UKR) have been up to 97% in single-center studies, but they have been as low as 80% in studies from arthroplasty registers. Few studies have evaluated short-term functional outcome and its improvement with time. We determined the time course of functional outcome as evaluated by the knee injury and osteoarthritis outcome score (KOOS) over the first 2 years after Oxford medial UKR. PATIENTS AND METHODS: In a prospective multicenter study, we included 99 unselected knees (96 patients, mean age 65 (51-80) years, 57 women) operated with Oxford medial UKR at 3 hospitals in the southeast of Norway between November 2003 and October 2006. Data were collected by independent investigators preoperatively and at 6 weeks, 3 months, 6 months, 1 year, and 2 years postoperatively. KOOS and range of motion (ROM) were determined at all follow ups. RESULTS: Mean KOOS values for pain and activities of daily living were improved already after 6 weeks, and increased between each time point up to 2 years postoperatively. However, no statistically significant improvements were seen after 6 months. Mean active and passive ROM gradually improved up to 2 years after UKR, and were then better than before surgery. INTERPRETATION: Most of the expected improvements in pain and function after UKR are achieved within 6 months of surgery. Only minimal improvement can be expected beyond this time. PMID- 22248172 TI - No adverse effects of submelt-annealed highly crosslinked polyethylene in cemented cups: an RSA study of 8 patients 10 yaers after surgery. AB - BACKGROUND AND PURPOSE: Highly crosslinked polyethylene (PE) is in standard use worldwide. Differences in the crosslinking procedure may affect the clinical performance. Experimenatal data from retrieved cups have shown free radicals and excessive wear of annealed highly crosslinked PE. We have previously reported low wear and good clinical performance after 6 years with this implant, and now report on the 10-year results. PATIENTS AND METHODS: In 8 patients, we measured wear of annealed highly crosslinked PE prospectively with radiostereometry after 10 years. Activity was assessed by UCLA activity score and a specifically designed activity score. Conventional radiographs were evaluated for osteolysis and clinical outcome by the Harris hip score (HHS). RESULTS: The mean (95% CI) proximal head penetration for highly crosslinked PE after 10 years was 0.07 ( 0.015 to 0.153) mm, and the 3D wear was 0.2 (0.026 to 0.36) mm. Without creep, proximal head penetration was 0.02 (-0.026 to 0.066) mm and for 3D penetration was 0.016 (-0.47 to 0.08) mm. This represents an annual proximal wear of less than 2 um. All cups were clinically and radiographically stable but showed a tendency of increased rotation after 5 years. INTERPRETATION: Wear for annealed highly crosslinked PE is extremely low up to 10 years. Free radicals do not affect mechanical performance or lead to clinically adverse effects. Creep stops after the first 6 months after implantation. Highly crosslinked PE is a true competitor of hard-on-hard bearings. PMID- 22248173 TI - A new aristolactam-type alkaloid from the roots of Aristolochia fangchi. AB - Phytochemical investigation of 85% ethanol extracts from the roots of Aristolochia fangchi yielded a new aristolactam derivative named 6-methoxyl aristolactam I N-beta-glucoside (1), together with four known compounds, aristolactam IVa (2), aristolactam I-beta-D-glucoside (3), aristolactam I (4), and aristolactam-N-beta-D-glucoside (5). Their structures were elucidated by spectral analysis. The cytotoxicity of the isolated compounds was also determined. PMID- 22248176 TI - Effects of substituents on synthetic analogs of chlorophylls. Part 3: The distinctive impact of auxochromes at the 7- versus 3-positions. AB - Assessing the effects of substituents on the spectra of chlorophylls is essential for gaining a deep understanding of photosynthetic processes. Chlorophyll a and b differ solely in the nature of the 7-substituent (methyl versus formyl), whereas chlorophyll a and d differ solely in the 3-substituent (vinyl versus formyl), yet have distinct long-wavelength absorption maxima: 665 (a) 646 (b) and 692 nm (d). Herein, the spectra, singlet excited-state decay characteristics, and results from DFT calculations are examined for synthetic chlorins and 13(1)-oxophorbines that contain ethynyl, acetyl, formyl and other groups at the 3-, 7- and/or 13 positions. Substituent effects on the absorption spectra are well accounted for using Gouterman's four-orbital model. Key findings are that (1) the dramatic difference in auxochromic effects of a given substituent at the 7- versus 3- or 13-positions primarily derives from relative effects on the LUMO+1 and LUMO; (2) formyl at the 7- or 8-position effectively "porphyrinizes" the chlorin and (3) the substituent effect increases in the order of vinyl < ethynyl < acetyl < formyl. Thus, the spectral properties are governed by an intricate interplay of electronic effects of substituents at particular sites on the four frontier MOs of the chlorin macrocycle. PMID- 22248179 TI - In vitro activity of extract and fractions of natural cocoa powder on Plasmodium falciparum. AB - Several flavonoids isolated from certain plants have demonstrated antiplasmodial activity, after their initial indigenous use in malaria treatment. Cocoa has been found to be a rich food source of flavonoids in comparison with many common foods and beverages. The aim of this work was to investigate the in vitro activity of natural cocoa powder on the growth of Plasmodium falciparum. Prepared crude methanol extract was partitioned successively with petroleum ether, ethyl acetate, chloroform, and butanol. Total flavonoid concentration in the crude methanol extract and fractions was measured by the AlCl(3) colorimetric assay. Direct inhibitory activity of the natural cocoa powder was assessed by culturing extract and fractions with P. falciparum in vitro. Greater antiplasmodial activity was observed in nonpolar solvent fractions (chloroform, ethyl acetate, and petroleum ether) compared with polar solvents. The chloroform fraction was most active, with mean+/-SEM 50% and 90% inhibition concentrations of 48.3+/-0.9 and 417+/-7.8 MUg/mL, respectively. The study showed a weak association between total flavonoid concentration and antiplasmodial activity. Early trophozoite (ring-stage) synchronized cultures treated with the chloroform fraction of natural cocoa powder showed a decline in growth. Further reduction in parasitemia was also observed for other erythrocytic stages. These results suggest that natural cocoa powder has measurable direct in vitro inhibitory effect on P. falciparum and support the anecdotal reports of its ability to prevent malaria as a result of regular intake as a beverage. PMID- 22248178 TI - Consumption of rice bran increases mucosal immunoglobulin A concentrations and numbers of intestinal Lactobacillus spp. AB - Gut-associated lymphoid tissue maintains mucosal homeostasis by combating pathogens and inducing a state of hyporesponsiveness to food antigens and commensal bacteria. Dietary modulation of the intestinal immune environment represents a novel approach for enhancing protective responses against pathogens and inflammatory diseases. Dietary rice bran consists of bioactive components with disease-fighting properties. Therefore, we conducted a study to determine the effects of whole dietary rice bran intake on mucosal immune responses and beneficial gut microbes. Mice were fed a 10% rice bran diet for 28 days. Serum and fecal samples were collected throughout the study to assess total immunoglobulin A (IgA) concentrations. Tissue samples were collected for cellular immune phenotype analysis, and concentrations of native gut Lactobacillus spp. were enumerated in the fecal samples. We found that dietary rice bran induced an increase in total IgA locally and systemically. In addition, B lymphocytes in the Peyer's patches of mice fed rice bran displayed increased surface IgA expression compared with lymphocytes from control mice. Antigen-presenting cells were also influenced by rice bran, with a significant increase in myeloid dendritic cells residing in the lamina propria and mesenteric lymph nodes. Increased colonization of native Lactobacillus was observed in rice bran-fed mice compared with control mice. These findings suggest that rice bran-induced microbial changes may contribute to enhanced mucosal IgA responses, and we conclude that increased rice bran consumption represents a promising dietary intervention to modulate mucosal immunity for protection against enteric infections and induction of beneficial gut bacteria. PMID- 22248180 TI - Inhibition of nuclear transcription factor-kappaB and activation of peroxisome proliferator-activated receptors in HepG2 cells by cucurbitane-type triterpene glycosides from Momordica charantia. AB - Momordica charantia is used to treat various diseases, including inflammatory conditions. Previous reports indicated that the extract of this plant inhibits activation of nuclear transcription factor-kappaB (NF-kappaB) but activates peroxisome proliferator-activated receptor (PPAR). Additionally, cucurbitane-type triterpene glycosides are the main bioactive components of the fruit of M. charantia. Therefore, we investigated the anti-inflammatory activity of 17 cucurbitane-type triterpene glycosides (1-17) isolated from this plant. Their inhibition of NF-kappaB and activation of PPAR activities in HepG2 cells were measured using luciferase reporter and PPAR subtype transactivation assays. Compounds 6 and 8 were found to inhibit NF-kappaB activation stimulated by tumor necrosis factor-alpha (TNFalpha) in a dose-dependent manner. With 50% inhibition concentration (IC(50)) values of 0.4 MUM, compounds 6 and 8 were more potent inhibitors than the positive control, sulfasalazine (IC(50)=0.9 MUM). Compounds 4, 6, and 8 also inhibited TNFalpha-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 mRNA. However, only compound 13 significantly increased PPARgamma transactivation. PMID- 22248181 TI - Facilitative governance: transforming global health through complexity theory. AB - Any initiative to coordinate actions, plans, or initiatives to improve the interaction between global health stakeholders finds itself feeding into a vastly complex global system. By utilising complexity theory as part of a new scientific paradigm, complex adaptive behaviour can emerge to create coherence. A suggested global health convention facilitating incremental regime development could be a way to create good governance processes. Minimum specifications could provide wide space for innovation and encourage shared action. Such specifications would be both a product of, and a facilitator for, future generative relationships. The potential empowerment of individuals as a result of this has the potential to transform global health by creating an arena for continual cooperation, interaction and mutual dependence among global stakeholders. PMID- 22248182 TI - MgO-doped tantalum coating on Ti: microstructural study and biocompatibility evaluation. AB - Pure and MgO incorporated Ta coatings were prepared on Cp-Ti substrate using laser engineered net shaping (LENS), which resulted in diffuse coating-substrate interface. MgO was found along the Ta grain boundaries in the Ta matrix that increased the coating hardness from 185 +/- 2.7 HV to 794 +/- 93 HV. In vitro biocompatibility study showed excellent early cellular attachment and later stage proliferation in MgO incorporated coatings. The results indicated that although Ta coatings had higher biocompatibility than Ti, it could further be improved by incorporating MgO in the coating, while simultaneously improving the mechanical properties. PMID- 22248183 TI - Does individual learning styles influence the choice to use a web-based ECG learning programme in a blended learning setting? AB - BACKGROUND: The compressed curriculum in modern knowledge-intensive medicine demands useful tools to achieve approved learning aims in a limited space of time. Web-based learning can be used in different ways to enhance learning. Little is however known regarding its optimal utilisation. Our aim was to investigate if the individual learning styles of medical students influence the choice to use a web-based ECG learning programme in a blended learning setting. METHODS: The programme, with three types of modules (learning content, self assessment questions and interactive ECG interpretation training), was offered on a voluntary basis during a face to face ECG learning course for undergraduate medical students. The Index of Learning Styles (ILS) and a general questionnaire including questions about computer and Internet usage, preferred future speciality and prior experience of E-learning were used to explore different factors related to the choice of using the programme or not. RESULTS: 93 (76%) out of 123 students answered the ILS instrument and 91 the general questionnaire. 55 students (59%) were defined as users of the web-based ECG-interpretation programme. Cronbach's alpha was analysed with coefficients above 0.7 in all of the four dimensions of ILS. There were no significant differences with regard to learning styles, as assessed by ILS, between the user and non-user groups; Active/Reflective; Visual/Verbal; Sensing/Intuitive; and Sequential/Global (p = 0.56-0.96). Neither did gender, prior experience of E-learning or preference for future speciality differ between groups. CONCLUSION: Among medical students, neither learning styles according to ILS, nor a number of other characteristics seem to influence the choice to use a web-based ECG programme. This finding was consistent also when the usage of the different modules in the programme were considered. Thus, the findings suggest that web-based learning may attract a broad variety of medical students. PMID- 22248184 TI - The rising prevalence of prescription opioid injection and its association with hepatitis C incidence among street-drug users. AB - AIMS: To examine trends in prescription opioid (PO) injection and to assess its association with hepatitis C virus (HCV) seroconversion among injection drug users (IDUs). DESIGN: Prospective cohort study. SETTING: Montreal, Canada. PARTICIPANTS: HCV-negative IDUs at baseline, reporting injection in the past month. MEASUREMENTS: Semi-annual visits included HCV antibody testing and an interview-administered questionnaire assessing risk behaviours. HCV incidence rate was calculated using the person-time method. Time-updated Cox regression models were conducted to examine predictors of HCV incidence. FINDINGS: The proportion of IDUs reporting PO injection increased from 21% to 75% between 2004 and 2009 (P < 0.001). Of the 246 participants (81.6% male; mean age 34.5 years; mean follow-up time 23 months), 83 seroconverted to HCV [incidence rate: 17.9 per 100 person-years; 95% confidence interval (CI) 14.3, 22.1]. Compared to non-PO injectors, PO injectors were more likely to become infected [adjusted hazard ratio (AHR): 1.87; 95%CI:1.16, 3.03]. An effect modification was also found: PO injectors who did not inject heroin were more likely to become infected (AHR: 2.88; 95%CI: 1.52, 5.45) whereas no association was found for participants using both drugs (AHR: 1.19; 95% CI: 0.61, 2.30). Other independent predictors of HCV incidence were: cocaine injection, recent incarceration and >30 injections per month. CONCLUSIONS: Prescription opioid injectors who do not inject heroin are at greater risk for HCV seroconversion than are those injecting both heroin and prescription opioids. Important differences in age, behaviour and social context suggest a need for targeted outreach strategies to this population. PMID- 22248185 TI - Lipocalin-type prostaglandin D synthase protects against oxidative stress-induced neuronal cell death. AB - L-PGDS [lipocalin-type PGD (prostaglandin D) synthase] is a dual-functional protein, acting as a PGD2-producing enzyme and a lipid transporter. L-PGDS is a member of the lipocalin superfamily and can bind a wide variety of lipophilic molecules. In the present study we demonstrate the protective effect of L-PGDS on H2O2-induced apoptosis in neuroblastoma cell line SH-SY5Y. L-PGDS expression was increased in H2O2-treated neuronal cells, and the L-PGDS level was highly associated with H2O2-induced apoptosis, indicating that L-PGDS protected the neuronal cells against H2O2-mediated cell death. A cell viability assay revealed that L-PGDS protected against H2O2-induced cell death in a concentration dependent manner. Furthermore, the titration of free thiols in H2O2-treated L PGDS revealed that H2O2 reacted with the thiol of Cys65 of L-PGDS. The MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight)-MS spectrum of H2O2 treated L-PGDS showed a 32 Da increase in the mass relative to that of the untreated protein, showing that the thiol was oxidized to sulfinic acid. The binding affinities of oxidized L-PGDS for lipophilic molecules were comparable with those of untreated L-PGDS. Taken together, these results demonstrate that L PGDS protected against neuronal cell death by scavenging reactive oxygen species without losing its ligand-binding function. The novel function of L-PGDS could be useful for the suppression of oxidative stress-mediated neurodegenerative diseases. PMID- 22248186 TI - Treatment options for primary hyperhidrosis. PMID- 22248187 TI - Surgical therapy for multiple sclerosis tremor: a 12-year follow-up study. AB - BACKGROUND AND PURPOSE: Severe multiple sclerosis (MS) tremor causes disability poorly responsive to medication. Deep brain stimulation (DBS) or thalamotomy can suppress tremor, but long-term outcomes are unclear. METHODS: Nine patients with MS tremor underwent disability measures at baseline and 12 months post-surgery (six thalamotomy, three DBS) in 1997-1998 (previously reported, Matsumoto et al., Neurology 2001;57:1876-82). We report the prospective 12-year follow-up of this cohort for tremor, disability, and death. RESULTS: Surgery was initially successful in all. Tremor recurred in all patients within median 3 months, although two DBS patients were tremor-free for 5 years. Median tremor-free survival (tremor-free time/survival time) was 4.3%. At 12-year follow-up, four survivors (two thalamotomy, two DBS) (Expanded Disability Status Scale scores 8 8.5) were severely disabled. Five patients were dead (four thalamotomy, one DBS) median 5.8 years post-operative. CONCLUSIONS: Surgery benefit for severe tremor was overall short-lived (median 3 months), with long-term poor prognosis. Although two DBS patients had sustained 5-year tremor-suppression, the observed progressive disability and death in this cohort bear importance for long-term success in future MS tremor surgery trials. PMID- 22248190 TI - Biogenesis and functions of model integral outer membrane proteins: Escherichia coli OmpA and Pseudomonas aeruginosa OprF. PMID- 22248191 TI - The HIV-1 epidemic in Bolivia is dominated by subtype B and CRF12_BF "family" strains. AB - BACKGROUND: Molecular epidemiological studies of HIV-1 in South America have revealed the occurrence of subtypes B, F1 and BF1 recombinants. Even so, little information concerning the HIV-1 molecular epidemiology in Bolivia is available. In this study we performed phylogenetic analyses from samples collected in Bolivia at two different points in time over a 10 year span. We analyzed these samples to estimate the trends in the HIV subtype and recombinant forms over time. MATERIALS AND METHODS: Fifty one HIV-1 positive samples were collected in Bolivia over two distinct periods (1996 and 2005). These samples were genetically characterized based on partial pol protease/reverse transcriptase (pr/rt) and env regions. Alignment and neighbor-joining (NJ) phylogenetic analyses were established from partial env (n = 37) and all pol sequences using Mega 4. The remaining 14 env sequences from 1996 were previously characterized based on HMA env (Heteroduplex mobility assay). The Simplot v.3.5.1 program was used to verify intragenic recombination, and SplitsTree 4.0 was employed to confirm the phylogenetic relationship of the BF1 recombinant samples. RESULTS: Phylogenetic analysis of both env and pol regions confirmed the predominance of "pure" subtype B (72.5%) samples circulating in Bolivia and revealed a high prevalence of BF1 genotypes (27.5%). Eleven out of 14 BF1 recombinants displayed a mosaic structure identical or similar to that described for the CRF12_BF variant, one sample was classified as CRF17_BF, and two others were F1pol/Benv. No "pure" HIV-1 subtype F1 or B" variant of subtype B was detected in the present study. Of note, samples characterized as CRF12_BF-related were depicted only in 2005. CONCLUSION: HIV-1 genetic diversity in Bolivia is mostly driven by subtype B followed by BF1 recombinant strains from the CRF12_BF "family". No significant temporal changes were detected between the mid-1990s and the mid-2000s for subtype B (76.2% vs 70.0%) or BF1 recombinant (23.8% vs 30.0%) samples from Bolivia. PMID- 22248193 TI - Japanese case of Budd-Chiari syndrome due to hepatic vein thrombosis successfully treated with liver transplantation. AB - A 22-year-old Japanese woman was found to have severe esophageal varices and then suffered from hepatic encephalopathy. She was diagnosed with Budd-Chiari syndrome (BCS) due to hepatic vein (HV) thrombosis accompanied by portal vein thrombosis without inferior vena cava (IVC) obstruction. Latent myeloproliferative neoplasm (MPN) lacking the JAK2-V617F mutation was considered to be the underlying disease. Liver transplantation was strikingly effective for treating the clinical symptoms attributable to portal hypertension. Although thrombosis of the internal jugular vein occurred due to thrombocythemia, which manifested after transplantation despite anticoagulation therapy with warfarin, the thrombus immediately disappeared with the addition of aspirin. Neither thrombosis nor BCS has recurred in more than 4 years since the amelioration of the last thrombotic event, and post-transplant immunosuppression with tacrolimus has not accelerated the progression of MPN. In Japan, IVC obstruction, which was a predominant type of BCS, is suggested to have decreased in incidence with recent improvements in hygiene. The precise diagnosis of BCS and causative underlying diseases should be made with attention to the current trend of the disease spectrum, which fluctuates with environmental sanitation levels. Because the stepwise strategy, including liver transplantation, has been proven effective for patients with pure HV obstruction in Western countries, this strategy should also be validated for utilization in Japan and in developing countries where HV obstruction potentially predominates. PMID- 22248188 TI - Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells. AB - BACKGROUND: The association between Helicobacter pylori infection and upper gastrointestinal disease is well established. However, only a small fraction of H. pylori carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. H. pylori Outer Membrane Phospholipase A (OMPLA) has been suggested to play a role in the virulence of this bacterium. The aim of this study was to profile the most significant cellular pathways and biological processes affected in gastric epithelial cells during 24 h of H. pylori exposure, and to study the inflammatory response to OMPLA+ and OMPLA- H. pylori variants. RESULTS: Interleukin-8 was the most significantly up-regulated gene and appears to play a paramount role in the epithelial cell response to H. pylori infection and in the pathological processes leading to gastric disease. MAPK and NF-kappaB cellular pathways were powerfully activated, but did not seem to explain the impressive IL-8 response. There was marked up-regulation of TP53BP2, whose corresponding protein ASPP2 may interact with H. pylori CagA and cause marked p53 suppression of apoptosis. Other regulators of apoptosis also showed abberant regulation. We also identified up-regulation of several oncogenes and down-regulation of tumor suppressor genes as early as during the first 24 h of infection. H. pylori OMPLA phase variation did not seem to influence the inflammatory epithelial cell gene response in this experiment. CONCLUSION: In whole genome analysis of the epithelial response to H. pylori exposure, IL-8 demonstrated the most marked up-regulation, and was involved in many of the most important cellular response processes to the infection. There was dysregulation of apoptosis, tumor suppressor genes and oncogenes as early as in the first 24 h of H. pylori infection, which may represent early signs of gastric tumorigenesis. OMPLA+/- did not affect the acute inflammatory response to H. pylori. PMID- 22248195 TI - Overview of regular dialysis treatment in Japan (as of 31 December 2009). AB - A nationwide statistical survey of 4196 dialysis facilities was conducted at the end of 2009, and 4133 facilities (98.5%) responded. The number of patients undergoing dialysis at the end of 2009 was determined to be 290 661, an increase of 7240 patients (2.6%) compared with that of 2008. The number of dialysis patients per million at the end of 2009 was 2279.5. The crude death rate of dialysis patients from the end of 2008 to the end of 2009 was 9.6%. The mean age of the new patients introduced into dialysis was 67.3 years old and the mean age of the entire dialysis patient population was 65.8 years old. Primary diseases such as diabetic nephropathy and chronic glomerulonephritis for new dialysis patients, showed a percentage of 44.5% and 21.9%, respectively. Based on the facilities surveyed, 84.2% of the facilities that responded to the questionnaire satisfied the microbiological quality standard for dialysis fluids for the Japanese Society for Dialysis Therapy (JSDT), with an endotoxin concentration of less than 0.05 EU/mL in the dialysis fluid. Similarly, 98.2% of the facilities surveyed satisfied another standard of the society of a bacterial count of less than 100 cfu/mL in the dialysis fluid. The facility survey indicated that the number of patients who were treated by blood purification by both peritoneal dialysis and extracorporeal circulation, such as hemodialysis, was 1720. Among the total number of patients, 24.8% were satisfied with the management target recommended in the treatment guidelines for secondary hyperparathyroidism. These standards are set by the JSDT, based on the three parameters, i.e. serum calcium concentration, serum phosphorus concentration, and serum intact parathyroid hormone concentration. According to the questionnaire, 9.8% of the patients were considered to have a complication of dementia. PMID- 22248196 TI - Ideal timing and predialysis nephrology care duration for dialysis initiation: from analysis of Japanese dialysis initiation survey. AB - Previous studies have suggested that early initiation of dialysis therapy was not superior in terms of patient survival. In this study, we analyzed the effects of renal function at the start of renal replacement therapy (RRT), duration of nephrology care, and comorbidity on 12-month survival of end-stage renal disease (ESRD) patients. The subjects in this study were 9695 new ESRD patients who started RRT in 2007. The average age of the subjects was 67.5 years, 64.1% of the subjects were male, and 42.9% had diabetes. During the 12-month period after the start of RRT, 1546 patients died, and 35 patients received renal transplantation. Average estimated glomerular filtration rate (eGFR) at the initiation of dialysis was 6.52 +/- 4.20 mL/min/1.73 m(2) . By unadjusted logistic analysis, one-year Odds Ratio (OR) of mortality in patients with eGFR more than 4-6 mL/min/1.73 m(2) was increased with increased eGFR at dialysis initiation, but the OR was identical among the groups with eGFR less than 4 mL/min/1.73 m(2) . After adjustment for age, gender, underlying renal diseases, and other clinical characteristics at dialysis initiation, OR was identical among the groups with eGFR less than 8 mL/min/1.73 m(2) . Furthermore, an OR increment was observed in eGFR less than 4 mL/min/1.73 m(2) group. In terms of the duration of nephrology care before dialysis initiation, 6 months or longer of nephrology care significantly decreased the OR of mortality after adjustment of covariance. Not only patients with sufficient residual renal function at the initiation of dialysis, but also patients with very low eGFR at the initiation of dialysis showed poor survival. PMID- 22248197 TI - Use of Japanese Society for Dialysis Therapy dialysis tables to compare the local and national incidence of dialysis. AB - The Japanese Society for Dialysis Therapy generates many tables of data on dialysis patients in their annual reports. These tables, derived from over 37 000 patients who started dialysis in 2008, allow comparison of the local incidence of new dialysis patients with the national incidence by estimating a standardized incidence ratio and confidence interval. Since this method adjusts for age and gender, it may be useful to evaluate local strategies for managing chronic kidney disease, including the response to campaigns and local quality assurance. Furthermore, the end-stage renal disease population of other countries can also be directly compared by this method. That is, the age- and gender-adjusted incidence of dialysis can be calculated for another country and compared with the national data for Japan. This might be one step toward improving local care and preventing the progression of chronic kidney disease. PMID- 22248198 TI - Protein oxidative stress and dyslipidemia in dialysis patients. AB - Our aim was to investigate and determine the associations between oxidative stress (OS), dyslipidemia and inflammation in patients treated with continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) using observational cross-sectional study. Twenty patients in CAPD and 48 in HD for at least 8 weeks and aged >=18 years were included in the study. Individuals with malignant or acute inflammatory disease were excluded. A control group of 17 healthy individuals was also recruited. The biochemical parameter evaluations were analyzed using colorimetric kits for albumin, serum glucose, total cholesterol (TC) and lipid fractions. To determine the inflammatory status, CRP, IL-6 and TNF alpha were analyzed by automated chemiluminescence kits. Plasma advanced oxidation protein products (AOPP) were determined by spectrophotometry. Mean AOPP levels were significantly higher for the HD group compared to the control, and there was no difference in AOPP concentrations between the control and CAPD groups. Dialysis patients had levels of inflammatory parameters higher than controls, and showed a high prevalence of patients with dyslipidemia, especially in CAPD. In the HD group, AOPP was positively correlated with triglycerides (TG) and inversely associated with HDL. Also the HD group was observed to have negative associations between TNF-alpha and HDL, LDL and TC. In the CAPD group, CRP was inversely correlated with HDL. Hemodialysis patients had increased protein OS and associations of inflammation and dyslipidemia were also observed in these dialysis groups. A more detailed characterization of the relations between oxidative stress and other more traditional risk factors has therapeutic importance, since cardiovascular diseases are the leading cause of death among dialysis patients. PMID- 22248199 TI - Effects of renin-angiotensin-aldosterone system blockade on chlorhexidine gluconate-induced sclerosing encapsulated peritonitis in rats. AB - Sclerosing encapsulated peritonitis (SEP) is a rare complication of long term peritoneal dialysis. Renin-angiotensin-aldosterone system (RAAS) may play a role in the development of peritoneal fibrosis in CAPD patients. We aimed to evaluate the effect of aliskiren, valsartan, and aliskiren + valsartan therapy on SEP. The study included 30 Wistar albino rats which were divided into five groups: I (Control) SF solution i.p.; II (CG group) chlorhexidine gluconate i.p.; III aliskiren oral plus CG i.p.; IV valsartan oral plus CG i.p.; and V aliskiren oral, valsartan oral and CG i.p. On the twenty-first day, all of the rats were sacrificed. All of the groups were analyzed in terms of peritoneal thickness, degree of inflammation, vasculopathy, neovascularization and fibrosis. Also, the parietal peritoneal tissue samples were evaluated for matrix metalloproteinase 2 (MMP-2) using the ELISA method. Peritoneal thickness and fibrosis scores were lower in the valsartan group compared to the CG group (P < 0.05). Peritoneal fibrosis scores were lower in the aliskiren group compared to CG group (P < 0.05) but no difference was observed between the peritoneal thickness scores of the two groups (P > 0.05). Tissue MMP-2 levels were significantly higher in the CG group compared other groups (P < 0.05). There were no statistically significant differences between the aliskiren, valsartan and aliskiren + valsartan groups according to the tissue MMP-2 levels. Due to the antifibrotic properties of valsartan, it is thought to be a possible choice to prevent SEP development. We found no positive impact of aliskiren or aliskiren + valsartan combination compared to valsartan alone. PMID- 22248200 TI - Regional citrate anticoagulation in predilution continuous venovenous hemofiltration using prismocitrate 10/2 solution. AB - Regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) is associated with a longer filter life and fewer bleeding events. Complexity of the regimen is the major hurdle preventing widespread application. This study describes a simple predilution continuous venovenous hemofiltration (CVVH) protocol utilizing a commercially prepared replacement solution containing citrate (Prismocitrate 10/2). Ten patients with acute renal failure were evaluated. The Prismaflex system was used for predilution CVVH, with Prismocitrate 10/2 running at 2500 mL/h as the main predilution replacement. An 8.4% sodium bicarbonate solution was infused at 50 mL/h in the first 2 h followed by 30 mL/h; 10% calcium gluconate was given to achieve an ionized calcium (iCa) level of 1-1.2 mmol/L. The circuit was run for 72 h unless there was filter clotting, transportation was required, or the patient did not require further CRRT. Total treatment duration was 504.5 h. The post-dilution equivalent ultrafiltration rate was 32.9 mL/kg/h (interquartile range [IQR] 31.6-38.2) and the median circuit life was 50.3 h (IQR 25.5-72.0). None of the circuit was changed due to circuit clotting. The median systemic iCa was 0.98 mmol/L (IQR 0.91-1.08). The total calcium-to-iCa ratio was 2.33 (IQR 2.21-2.45). None of the patients developed hypernatremia (Na >= 150 mmol/L) or citrate toxicity (total Ca to-iCa ratio > 2.5 plus increasing metabolic acidosis), and metabolic alkalosis (pH >= 7.5) occurred in one patient. This simple RCA CVVH protocol using commercially-prepared solution could be a feasible, relatively safe, and effective alternative to the conventional regimen for patients with a body weight up to 80 kg. PMID- 22248201 TI - Impact of the Fukushima Daiichi Nuclear Power Plant accident on hemodialysis facilities: an evaluation of radioactive contaminants in water used for hemodialysis. AB - Following the crisis at the Fukushima Daiichi Nuclear Power Plant caused by the 2011 Tohoku earthquake and tsunami, radioactive substances ((131) I, (134) Cs, (137) Cs) were detected in tap water throughout eastern Japan. There is now concern that internal exposure to radioactive substances in the dialysate could pose a danger to hemodialysis patients. Radioactive substances were measured in three hemodialysis facilities before and after purification of tap water for use in hemodialysis. Radioactive iodine was detected at levels between 13 and 15 Bq/kg in tap water from the three facilities, but was not detected by reverse osmosis membrane at any of the facilities. We confirmed that the amount of radioactive substances in dialysate fell below the limit of detection (7-8 Bq/kg) by reverse osmosis membrane. It is now necessary to clarify the maximum safe level of radiation in dialysate for chronic hemodialysis patients. PMID- 22248202 TI - Cryofiltration in the treatment of cryoglobulinemia and HLA antibody-incompatible transplantation. AB - Cryofiltration is a technique in which plasma is separated from blood and chilled, leading to the formation of "cryogel", a composite of heparin, fibronectin, fibrinogen, immunoglobulins, and other proteins. This is retained by further filtration and plasma is returned to the patient. There may be a role for cryofiltration in the treatment of cryoglobulinemia or where the application of other forms of plasmapheresis or immunoadsorption is limited. Five patients received six courses of cryofiltration. Two patients had cryoglobulinemia and three were treated before HLA antibody-incompatible renal transplantation. The treatment was associated with few adverse effects, and it was possible to treat up to 120 mL/kg plasma per session. There was a good clinical response in four patients. One patient was switched back to double filtration plasmapheresis (DFPP) because cryofiltration seemed to remove HLA antibodies less effectively, but the other two transplants have excellent function. In the cryoglobulinemia patients there was excellent clearance of cryoglobulins during each treatment (mean decrease of 78.2 (SD 14.1)% per treatment). Compared with DFPP, fewer immunoglobulins were removed and the mean percentage reductions in immunoglobulin G per treatment were 36.0 (4.0)% for cryoglobulinemia and 59.2 (2.5)% for DFPP (P < 0.01), with respective mean plasma volumes of 64.2 (10.3) and 71.1 (6.8) mL/kg treated. Cryofiltration offers a treatment choice in patients with cryoglobulinemia and in those who may not be able to tolerate high-volume DFPP. The technique used in the patients described here was less effective than DFPP; however, use of an alternative fractionator and treatment of higher plasma volumes may enhance the efficiency of cryofiltration. PMID- 22248203 TI - Retrospective review of 25 cases of thrombotic thrombocytopenic purpura in Pakistan. AB - Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological abnormalities, and renal dysfunction. Because of the rarity of TTP, no comprehensive data is available in the Pakistani population. The present study aimed to review the therapeutic interventions, relapses and mortality rate in patients with TTP treated at a tertiary care hospital in Pakistan. This was a retrospective review of patients treated over a period of more than nine years (2001-2010). Medical charts were retrieved using the ICD coding system version 9 and each file was reviewed by the principal author for clinical and laboratory details, along with the therapy utilized and the outcome. Twenty-five patients were diagnosed with TTP, including nine males (36%) and 16 females (64%) with a median age of 30 +/- 18.4 years for all patients. Idiopathic TTP was seen in 17 patients (68%) and secondary causes were identified in eight (32%). Patients were treated with plasma exchange once the diagnosis of TTP was established. Only neurological and renal involvement at the time of presentation emerged as important indicators in determining the outcome and response to treatment. Most of our patients tolerated plasmapheresis very well; however, delay in starting plasmapheresis due to late presentation was a major hurdle in our set up. PMID- 22248204 TI - Intima-media thickness is associated with non-traditional risk factors and ischemic heart disease in hemodialysis patients. PMID- 22248205 TI - An unusual left-sided tunneled catheter in a hemodialysis patient. PMID- 22248206 TI - Ecchymosis and purpura associated with an arteriovenous fistula. PMID- 22248211 TI - Anomalous left coronary artery from the pulmonary artery presenting with aborted sudden death in an octogenarian: a case report. AB - INTRODUCTION: We report a rare coronary anomaly presenting with aborted sudden death in an octogenarian. An anomalous left coronary artery from the pulmonary artery is a rare coronary anomaly which usually presents in the first year of life. Survival into adulthood and the elderly years is extremely rare. CASE PRESENTATION: An 85-year-old Caucasian woman was brought to our hospital following cardiopulmonary arrest. After prolonged resuscitation and stabilization of our patient, further evaluation revealed an anomalous left coronary artery from pulmonary artery syndrome. She was discharged on medication. CONCLUSION: An anomalous left coronary artery from the pulmonary artery can present in elderly and even octogenarian patients. Careful history, physical examination and an appropriate invasive study are needed to confirm the diagnosis. PMID- 22248210 TI - Temporal stability and representational distinctiveness: key functions of orthographic working memory. AB - A primary goal of working memory research has been to understand the mechanisms that permit working memory systems to effectively maintain the identity and order of the elements held in memory for sufficient time as to allow for their selection and transfer to subsequent processing stages. Based on the performance of two individuals with acquired dysgraphia affecting orthographic working memory (WM; the graphemic buffer), we present evidence of two distinct and dissociable functions of orthographic WM. One function is responsible for maintaining the temporal stability of letters held in orthographic WM, while the other is responsible for maintaining their representational distinctiveness. The failure to maintain temporal stability and representational distinctiveness gives rise, respectively, to decay and interference effects that manifest themselves in distinctive error patterns, including distinct serial position effects. The findings we report have implications beyond our understanding of orthographic WM, as the need to maintain temporal stability and representational distinctiveness in WM is common across cognitive domains. PMID- 22248212 TI - The light-activated proton pump Bop I of the archaeon Haloquadratum walsbyi. AB - We have isolated and characterized the light-driven proton pump Bop I from the ultrathin square archaeon Haloquadratum walsbyi, the most abundant component of the dense microbial community inhabiting hypersaline environments. The disruption of cells by hypo-osmotic shock yielded Bop I retinal protein highly enriched membranes, which contain one main 27 kDa protein band together with a high content of the carotenoid bacterioruberin. Light-induced pH changes were observed in suspensions of Bop I retinal protein-enriched membranes under sustained illumination. Solubilization of H. walsbyi cells with Triton X-100, followed by phenyl-Sepharose chromatography, resulted in isolation of two purified Bop I retinal protein bands; mass spectrometry analysis revealed that the Bop I was present as only protein in both the bands. The study of light/dark adaptations, M decay kinetics, responses to titration with alkali in the dark and endogenous lipid compositions of the two Bop I retinal protein bands showed functional differences that could be attributed to different protein aggregation states. Proton-pumping activity of Bop I during the photocycle was observed in liposomes constituted of archaeal lipids. Similarities and differences of Bop I with other archaeal proton-pumping retinal proteins will be discussed. PMID- 22248215 TI - Two new oleanane-type pentacyclic triterpenoid saponins from the husks of Xanthoceras sorbifolia Bunge. AB - Two new triterpenoid saponins (1, 2) and a known saponin (3) were isolated from the husks of Xanthoceras sorbifolia Bunge., and their structures were elucidated as 3-O-beta-D-glucopyranosyl(1 -> 6)-[angeloyl(1 -> 2)]-beta-D-glucopyranosyl-28 O-alpha-L-rhamnopyranosyl(1 -> 2)-[beta-D-glucopyranosyl(1 -> 6)]-beta-D glucopyranosyl-21beta,22alpha-dihydroxyl-olean-12-ene (1), 3-O-beta-D glucopyranosyl-28-O-[beta-D-glucopyranosyl(1 -> 2)]-beta-D-glucopyranosyl 21beta,22alpha-dihydroxyl-olean-12-ene (2), and 3-O-beta-D-glucopyranosyl-28-O [alpha-L-rhamnopyranosyl(1 -> 2)]-beta-D-glucopyranosyl-21beta,22alpha-dihydroxyl olean-12-ene (3), on the basis of the spectral analysis of NMR and chemical methods. Cytotoxic assay indicated that none of them showed obvious inhibitory effect on the proliferation of two human tumor cell lines. PMID- 22248217 TI - Tooth and periodontal clinical attachment loss are associated with hyperglycemia in patients with diabetes. AB - BACKGROUND: Periodontal disease has been associated with diabetes, but there is still controversy on the relationship between periodontal clinical parameters and glycemic control. The purpose of this study is to assess the relationship between blood glucose levels and clinical parameters of periodontal disease in individuals with diabetes. METHODS: A total of 65 individuals with diabetes and 81 individuals without diabetes were included in the study. A full-mouth periodontal examination and preprandial fasting glycemia values were recorded for each individual. Glycosylated hemoglobin was only measured in patients with diabetes. A comparative analysis between groups (Mann-Whitney U test) and a correlation analysis between glycemia and periodontal parameters were performed (Spearman test). RESULTS: Patients without diabetes presented more teeth than individuals with diabetes (P <0.05). Patients with diabetes with periodontitis displayed loss of periodontal clinical attachment compared to patients without diabetes, but the highest value was observed in patients with periodontitis that reported a smoking habit. Furthermore, patients with diabetes with periodontitis presented higher glycemia and glycated hemoglobin values in contrast to patients with gingivitis. Patients with diabetes with hyperglycemia had a higher risk to develop periodontitis (odds ratio = 2.24; 95% confidence interval = 1.02 to 4.93). A positive correlation was observed between glycemia and clinical attachment loss (AL), whereas a negative correlation between glycemia and the number of teeth present was found (P <0.05). CONCLUSIONS: Tooth and periodontal AL were increased by hyperglycemia in individuals with diabetes. This study contributes additional evidence that diabetes could aggravate periodontal disease and affect the systemic health of individuals. PMID- 22248218 TI - Effect of priming in subpopulations of peripheral neutrophils from patients with chronic periodontitis. AB - BACKGROUND: Patients with periodontal disease are reported to generate more reactive oxygen species (ROS) than matched controls, suggesting increased inflammatory defense activity. The purpose of this study is to determine whether there are subpopulations of peripheral neutrophils in patients with chronic periodontitis (CP) that generate different levels of intracellular ROS when primed with tumor necrosis factor-alpha (TNF-alpha) or the chemokine interleukin 8 (IL-8, CXCL8) compared to controls. METHODS: Venous blood was collected from 13 patients with CP despite careful maintenance over 2 to 8 years and from 13 healthy age- and sex-matched controls. Neutrophils were separated from whole blood over a Percoll gradient and then activated via the Fcgamma receptor with opsonized Staphylococcus aureus after priming with TNF-alpha or IL-8. The samples were analyzed by flow cytometry using the fluorescent probe dihydrorhodamine 123. Generation of ROS was measured as the intensity of fluorescence (IFL). RESULTS: Two subpopulations were found in both patients and controls: one with low and one with high generation of IFL. The subpopulation with high generation of IFL in patients with CP was more responsive to IL-8 (P <0.05) than the same subpopulation in healthy controls. No other differences in generation of ROS or priming effects were found between patients with CP and controls. Generation of ROS was dependent on nicotinamide adenine dinucleotide phosphate oxidase, and the intracellular ROS was primarily the oxygen anion. CONCLUSION: Patients with CP had a subpopulation of peripheral neutrophils that were more responsive to IL-8 priming than controls. PMID- 22248219 TI - Fusobacterium nucleatum biofilm induces epithelial migration in an organotypic model of dento-gingival junction. AB - BACKGROUND: Effects of Fusobacterium nucleatum (F. nucleatum) biofilm on epithelial cell proliferation, apoptotic cell death, and basement membrane constituent collagen IV production were examined in an organotypic dento epithelial (OD-E) model. METHODS: The OD-E model was constructed by seeding keratinocytes on fibroblast-containing collagen gels and by placing tooth pieces on top. A 3-day-old biofilm either a laboratory strain (American Type Culture Collection [ATCC] 25586) or a clinical strain (Anaerobe Helsinki Negative [AHN] 9508) of F. nucleatum was placed on the top of the model. The coculture was incubated <=24 hours. The expression and localization of Ki-67, caspase-3, and collagen IV were examined by immunohistochemistry. RESULTS: Hematoxylin and eosin staining showed epithelial migration and lateral sprouting into the connective tissue matrix in F. nucleatum OD-E cocultures. The proliferation pattern of the in vitro dento-epithelial junction was changed. In controls without bacterial challenge, the Ki-67 expression was abundant in the cells attached to the tooth, whereas in F. nucleatum biofilm-treated cultures, the Ki-67-expressing cells were more often in the connective tissue-facing side of the epithelium. An apoptotic marker caspase-3 was expressed in controls and in F. nucleatum laboratory strain ATCC cocultures throughout the epithelium, in contrast to cultures treated with F. nucleatum clinical strain AHN, in which caspase-3 was absent. Collagen IV stainings were negative in both controls and F. nucleatum cocultures. CONCLUSION: F. nucleatum biofilm coculture with OD-E model causes lateral sprouting of the epithelium with an altered epithelial proliferation pattern, resembling the histologic changes seen in vivo in the early pathogenesis of periodontal disease. PMID- 22248220 TI - Association between periodontitis and chronic obstructive pulmonary disease in a Chinese population. AB - BACKGROUND: A relationship between periodontitis and chronic respiratory disease has been suggested by recent studies. The aim of this study is to explore the association between periodontitis and chronic obstructive pulmonary disease (COPD) in a Chinese population. METHODS: We conducted a case-control study of 581 COPD cases and 438 non-COPD controls. Lung function examination, a 6-minute walk test, and the British Medical Research Council questionnaire were performed. Periodontal clinical examination index included probing depth (PD), attachment loss (AL), bleeding index (BI), plaque index (PI), and alveolar bone loss. A validated index for predicting COPD prognosis, the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index, was also calculated. RESULTS: Participants with more severe COPD were more likely to have severe periodontal disease. PD, AL, PI, alveolar bone loss, and the number of teeth were significantly associated with all stages of COPD (all P <0.001). When compared to controls (BODE = 0), participants with higher BODE scores had significantly higher AL (P <0.001), BI (P = 0.027), PI (P <0.001), alveolar bone loss (P <0.001), and the number of teeth (P <0.001). PI appeared to be the main periodontal health-related factor for COPD, with an odds ratio (OR) = 9.01 (95% CI = 3.98 to 20.4) in the entire study population OR = 8.28 (95% CI = 2.36 to 29.0), OR = 5.89 (95% CI = 2.64 to 13.1), and OR = 2.46 (95% CI = 1.47 to 4.10) for current, smokers, and non-smokers, respectively. CONCLUSION: Our study found a strong association between periodontitis and COPD, and PI seemed to be a major periodontal factor for predicting COPD among Chinese adults. PMID- 22248221 TI - The gingival crevicular fluid levels of interleukin-11 and interleukin-17 in patients with aggressive periodontitis. AB - BACKGROUND: The balance (ratio) of anti-inflammatory and proinflammatory cytokines is thought to play an important role in the pathogenesis of chronic periodontitis. Moreover, the imbalance of anti-inflammatory/proinflammatory cytokines may modulate disease progression in aggressive periodontitis (AgP). This study aims to investigate the levels of interleukin (IL)-11 and IL-17 and their ratio in gingival crevicular fluid (GCF) in patients with AgP. METHODS: This study included 20 patients with generalized AgP (GAgP) and 18 healthy controls (HC). For each patient, the values of clinical parameters, such as gingival index, plaque index, probing depth, and clinical attachment level, were recorded. Levels of IL-11 and IL-17 in GCF samples were evaluated using enzyme linked immunosorbent assay. The values of clinical parameters, cytokine levels, and the ratios of cytokines were evaluated. RESULTS: The values of all the clinical parameters were significantly higher in the GAgP group than in the HC group (P < 0.001). The total amount and concentration of IL-11 and the concentration of the IL-17 and IL-11/IL-17 ratio were significantly lower in the GAgP group than in the HC group (P < 0.001). The total amount of IL-17 was not significantly different between the groups (P = 0.317). CONCLUSIONS: The IL-11/IL 17 ratio was decreased in the GAgP group because of the decreased IL-11 levels. The IL-11/IL-17 axis and the link between IL-17 and neutrophil function disorders in AgP should be investigated to clarify the role of the IL-11/IL-17 axis and its balance and imbalance in the pathogenesis of AgP. PMID- 22248222 TI - Enamel matrix derivative in intrabony defects: prognostic parameters of clinical and radiographic treatment outcomes. AB - BACKGROUND: The purpose of this retrospective case series study is to identify possible preoperative parameters that could predict postoperative probing depth (PD), clinical attachment level (CAL) gain, or radiographic defect resolution in intrabony defects treated with enamel matrix derivative (EMD). METHODS: Sixty-one chronic periodontitis patients, each contributing a 2- or 3-wall intrabony defect treated with EMD, were included. Clinical parameters recorded included the following: PD; CAL; gingival margin position; supracrestal soft tissue (SST); surgical distances of cemento-enamel junction (CEJ) to bone crest (CEJ-BC), CEJ to base of the defect (CEJ-BD), and BC to BD (BC-BD); and depth of 2- and 3-wall components. Radiographic parameters recorded included the following: CEJ-BC, CEJ BD, BC-BD distances, and radiographic defect angle. Postoperative assessments were performed at 12 months. RESULTS: The probability of postoperative PD >4 mm increased 1.6-fold (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.2 to 2.3) with each 1-mm baseline PD increase. Baseline PD and surgical CEJ-BD were statistically significant predictors of CAL gain; the greater the baseline PD (OR = 0.5; 95% CI = 0.3 to 0.8) and bone loss (OR = 0.6; 95% CI = 0.3 to 0.9), the less likely that postoperative CAL gain was <=3 mm. Smoking and SST were significantly associated with defect resolution; failure to achieve >=65% defect resolution was six-fold greater for smokers (OR = 6.5; 95% CI = 1.7 to 24.5) and almost double (OR = 1.7; 95% CI = 1.1 to 2.8) for each millimeter of SST increase. CONCLUSION: In EMD-treated intrabony defects, baseline PD predicts both CAL gain and postoperative PD. Smoking and SST are predictors of defect resolution. PMID- 22248223 TI - Efficacy of local drug delivery of 0.5% clarithromycin gel as an adjunct to non surgical periodontal therapy in the treatment of current smokers with chronic periodontitis: a randomized controlled clinical trial. AB - BACKGROUND: The relationship between cigarette smoking and periodontal disease has been examined extensively. Local delivery of antimicrobials into periodontal pockets improves periodontal health. The present study is designed to investigate the adjunctive effects of subgingivally delivered 0.5% clarithromycin (CLM) as an adjunct to scaling and root planing for treating chronic periodontitis in smokers. METHODS: Sixty-one patients were randomized and categorized into two treatment groups: group 1, in which 31 individuals received scaling and root planing plus 0.5% CLM, and group 2, in which 30 individuals received scaling and root planing plus placebo gel. Clinical parameters were recorded at baseline and at 1, 3, and 6 months; they included plaque index (PI), modified sulcus bleeding index (mSBI), gingival index (GI), probing depth (PD), and clinical attachment level (CAL). The mean concentration of 0.5% CLM in gingival crevicular fluid (GCF) was estimated by reverse-phase high-performance liquid chromatography. RESULTS: Both therapies resulted in significant improvements. At the end of 6 months, the mean GI, PI, mSBI, PD, and CAL for the CLM group were 1.06 +/- 0.28, 2.82 +/- 0.64, 1.36 +/- 0.24, 4.64 +/- 0.63, and 4.90 +/- 0.46, respectively, versus 1.38 +/- 0.41, 3.22 +/- 0.57, 1.44 +/- 0.27, 6.07 +/- 0.88, and 5.69 +/- 0.46, respectively, for the placebo group. Using an individual-based analysis, individuals in group 1 showed enhanced clinical outcome (P <0.05) over a period of 6 months compared with those in group 2. CLM was detected in GCF until a period of 7 weeks after the local drug delivery. CONCLUSION: Although both treatment strategies seemed to benefit the individuals, the adjunctive use of 0.5% CLM as a controlled drug delivery system enhanced the clinical outcome. PMID- 22248224 TI - Gingival crevicular fluid and plasma acute-phase cytokine levels in different periodontal diseases. AB - BACKGROUND: The aim of the present study is to investigate gingival crevicular fluid (GCF) and plasma acute-phase cytokines, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-11 (IL-11), oncostatin M (OSM), and leukemia inhibitory factor (LIF) levels in patients with different periodontal diseases. METHODS: Eighty individuals were included in this study; 20 with chronic periodontitis (CP), 20 with generalized aggressive periodontitis (GAgP), 20 with gingivitis, and 20 classified as healthy (H). Probing depth, clinical attachment level, plaque index, and papilla bleeding index were recorded. Plasma and GCF IL 1beta, IL-6, IL-11, OSM, and LIF levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: CP and GAgP groups had significantly higher GCF IL 1beta, IL-6, and IL-11 levels when compared with the H group (P <0.05). Conversely, GCF LIF levels of the CP and GAgP groups were lower than those of the H group (P <0.05). GCF OSM levels did not differ significantly among study groups. Plasma levels of all the cytokines studied were not significantly different among the study groups. CONCLUSIONS: Based on the present data, elevated IL-1beta, IL-6, and IL-11 GCF levels, but not plasma levels, are suggested as reliable inflammatory biomarkers in periodontal diseases. Decreased LIF levels in diseased groups might reflect the possible beneficial effects of LIF in the modulation of inflammatory response in gingiva. PMID- 22248225 TI - AAP president's address. PMID- 22248226 TI - Periodontal status and metabolic syndrome in middle-aged Japanese. AB - BACKGROUND: Metabolic syndrome (MetS) increases the risk of various lifestyle related diseases. Although some studies have reported a significant relationship between periodontal status and MetS, little information exists about the nature of the relationship between periodontal health status and MetS. METHODS: Comprehensive health examinations of 6,421 Japanese individuals (aged 34 to 77 years) were performed. Five components (obesity, high blood pressure, low high density lipoprotein cholesterol, hypertriglyceridemia, and high plasma glucose) of MetS were evaluated, and individuals with >=3 positive components were defined as having MetS. The periodontal parameters were periodontal probing depth (PD) and clinical attachment level (CAL), and each parameter was divided into three categories (none/mild: <=3 mm; moderate: 4 to 5 mm; and severe: >=6 mm). RESULTS: When PD and CAL were analyzed separately in multivariate models, both parameters were significantly associated with MetS. In a multivariate logistic regression analysis using a combination of PD and CAL as an independent variable, individuals with severe PD and severe CAL or with moderate PD and moderate CAL had significantly higher odds ratios for MetS, but severe CAL without severe PD was not significantly associated with MetS. CONCLUSION: The results of this study suggest that periodontal status, particularly in individuals suspected to have untreated periodontal infection indicated by >=4 mm PD, is significantly associated with MetS. PMID- 22248227 TI - Obituary: Richard Chace, DDS. PMID- 22248229 TI - Mesenchymal stromal cells for tissue-engineered tissue and organ replacements. AB - Mesenchymal stromal cells (MSCs), a rare heterogeneous subset of pluripotent stromal cells that can be easily isolated from different adult tissues, in vitro expanded and differentiated into multiple lineages, are immune privileged and, more important, display immunomodulatory capacities. Because of this, they are the preferred cell source in tissue-engineered replacements, not only in autogeneic conditions, where they do not evoke any immune response, but especially in the setting of allogeneic organ and tissue replacements. However, more preclinical and clinical studies are requested to completely understand MSC's immune biology and possible clinical applications. We herein review the immunogenicity and immunomodulatory properties of MSCs, their possible mechanisms and potential clinical use for tissue-engineered organ and tissue replacement. PMID- 22248230 TI - Enhancement of visible-light photocatalysis by coupling with narrow-band-gap semiconductor: a case study on Bi2S3/Bi2WO6. AB - To overcome the drawback of low photocatalytic efficiency brought by electron hole recombination and narrow photoresponse range, we designed a novel Bi(2)S(3)/Bi(2)WO(6) composite photocatalyst. The composite possesses a wide photoabsorption until 800 nm, which occupies nearly the whole range of the visible light. Compared with bare Bi(2)WO(6), the Bi(2)S(3)/Bi(2)WO(6) composite exhibits significantly enhanced photocatalytic activity for phenol degradation under visible light irradiation. On the basis of the calculated energy band positions, the mechanism of enhanced photocatalytic activity was proposed. The present study provides a new strategy to design composite materials with enhanced photocatalytic performance. PMID- 22248231 TI - Involving patients in HTA activities at local level: a study protocol based on the collaboration between researchers and knowledge users. AB - BACKGROUND: The literature recognizes a need for greater patient involvement in health technology assessment (HTA), but few studies have been reported, especially at the local level. Following the decentralisation of HTA in Quebec, Canada, the last few years have seen the creation of HTA units in many Quebec university hospital centres. These units represent a unique opportunity for increased patient involvement in HTA at the local level. Our project will engage patients in an assessment being carried out by a local HTA team to assess alternatives to isolation and restraint for hospitalized or institutionalized adults. Our objectives are to: 1) validate a reference framework for exploring the relevance and applicability of various models of patient involvement in HTA, 2) implement strategies that involve patients (including close relatives and representatives) at different stages of the HTA process, 3) evaluate intervention processes, and 4) explore the impact of these interventions on a) the applicability and acceptability of recommendations arising from the assessment, b) patient satisfaction, and c) the sustainability of this approach in HTA. METHODS: For Objective 1, we will conduct individual interviews with various stakeholders affected by the use of alternatives to isolation and restraint for hospitalized or institutionalized adults. For Objective 2, we will implement three specific strategies for patient involvement in HTA: a) direct participation in the HTA process, b) consultation of patients or their close relatives through data collection, and c) patient involvement in the dissemination of HTA results. For Objectives 3 and 4, we will evaluate the intervention processes and the impact of patient involvement strategies on the recommendations arising from the HTA and the understanding of the ethical and social implications of the HTA. DISCUSSION: This project is likely to influence future HTA practices because it directly targets knowledge users' need for strategies that increase patient involvement in HTA. By documenting the processes and outcomes of these involvement strategies, the project will contribute to the knowledge base related to patient involvement in HTA. PMID- 22248232 TI - Year in review 2011: asthma, chronic obstructive pulmonary disease and airway biology. PMID- 22248233 TI - The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a. AB - Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8 hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin/IGF-1 (insulin like growth factor-1) signalling] kinase Akt/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to IIS is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases. PMID- 22248234 TI - Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents. AB - Adolescent smoking remains a public health problem. Despite concerns regarding adolescent nicotine dependence, few well-designed smoking cessation studies have been conducted with teen smokers. This is particularly true regarding pharmacologic treatments for nicotine dependence. Currently, pharmacologic aids are not recommended for treating adolescent nicotine dependence, as efficacy has not been shown in this population. This review includes studies that have examined the efficacy of pharmacotherapy for smoking abstinence and/or reduction in cigarette consumption among adolescent smokers who want to quit smoking, laboratory-based adolescent studies that have examined the efficacy of these medications in reducing cravings and/or withdrawal symptoms, and/or studies that have assessed the tolerability of medications for smoking cessation in adolescent smokers. It provides information on the pharmacologic action of each medication, the efficacy of each medication for adolescent smoking cessation, the tolerability of each medication based on reported adverse events, and compliance with the medication protocols. Thirteen relevant articles were identified and included in the review. Nicotine patch (NP), nicotine gum, nicotine nasal spray, bupropion, and varenicline have been studied in adolescent smokers. The adverse events reported in the studies on pharmacology for adolescent smoking suggest that the side effect profiles for nicotine replacement therapy, bupropion, and varenicline are similar to those reported in adult studies. There is some evidence of efficacy of NP and bupropion at the end of treatment (efficacy of varenicline has not been assessed), but none of the medications included in this review were efficacious in promoting long-term smoking cessation among adolescent smokers. It is noted that many of the study protocols did not follow the recommended dose or length of pharmacotherapy for adults, rendering it difficult to determine the true efficacy of medication for adolescent smoking cessation. Future efficacy studies are warranted before recommending pharmacotherapy for adolescent smoking cessation. PMID- 22248235 TI - Clinical and radiological differences in posterior reversible encephalopathy syndrome between patients with preeclampsia-eclampsia and other predisposing diseases. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a serious maternal complication in pregnancy, but data on the clinicoradiological differences to other etiologies of PRES are scarce. In this study, we aimed to investigate the clinical and imaging characteristics of PRES in preeclampsia eclampsia patients compared with other predisposing diseases in a large cohort. METHODS: We retrospectively reviewed the radiological report data bases between January 1999 and August 2010 for patients with PRES. Patients fulfilling the criteria for PRES after detailed investigation of clinical charts and imaging studies were separated into patients with eclampsia-preeclampsia and other predisposing causes. Various imaging features at onset of symptoms and on follow up as well as clinical and paraclinical data were analyzed. RESULTS: A total of 24 patients with preeclampsia-eclampsia associated PRES and 72 patients with PRES of other predisposing causes were included into the study. In preeclampsia eclampsia patients, headaches were significantly more frequent as initial PRES related symptom (P < 0.001), whereas altered mental state was significantly less frequent (P = 0.001). Thalamus, midbrain, and pons affection was significantly less frequent in preeclampsia-eclampsia associated PRES (P = 0.01). Preeclampsia eclampsia patients had significantly less severe edema, less cytotoxic edema, hemorrhage and contrast enhancement, while more frequent complete resolution of edema and less frequent residual structural lesions were seen on follow-up imaging. CONCLUSION: In our PRES cohort, we found major clinicoradiological differences between preeclampsia-eclampsia and other predisposing causes pointing toward a less severe course of disease in preeclampsia-eclampsia. PMID- 22248236 TI - Diverse heterocyclic scaffolds as allosteric inhibitors of AKT. AB - Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model. PMID- 22248238 TI - The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo. AB - INTRODUCTION: Nowadays the 'redox hypothesis' is based on the fact that thiol/disulfide couples such as glutathione (GSH/GSSG), cysteine (Cys/CySS) and thioredoxin ((Trx-(SH)2/Trx-SS)) are functionally organized in redox circuits controlled by glutathione pools, thioredoxins and other control nodes, and they are not in equilibrium relative to each other. Although ROS can be important intermediates of cellular signaling pathways, disturbances in the normal cellular redox can result in widespread damage to several cell components. Moreover, oxidative stress has been linked to a variety of age-related diseases. In recent years, oxidative stress has also been identified to contribute to drug-induced liver, heart, renal and brain toxicity. AREAS COVERED: This review provides an overview of current in vitro and in vivo methods that can be deployed throughout the drug discovery process. In addition, animal models and noninvasive biomarkers are described. EXPERT OPINION: Reducing post-market drug withdrawals is essential for all pharmaceutical companies in a time of increased patient welfare and tight budgets. Predictive screens positioned early in the drug discovery process will help to reduce such liabilities. Although new and more efficient assays and models are being developed, the hunt for biomarkers and noninvasive techniques is still in progress. PMID- 22248237 TI - The double-stranded break-forming activity of plant SPO11s and a novel rice SPO11 revealed by a Drosophila bioassay. AB - BACKGROUND: SPO11 is a key protein for promoting meiotic recombination, by generating chromatin locus- and timing-specific DNA double-strand breaks (DSBs). The DSB activity of SPO11 was shown by genetic analyses, but whether SPO11 exerts DSB-forming activity by itself is still an unanswered question. DSB formation by SPO11 has not been detected by biochemical means, probably because of a lack of proper protein-folding, posttranslational modifications, and/or specific SPO11 interacting proteins required for this activity. In addition, plants have multiple SPO11-homologues. RESULTS: To determine whether SPO11 can cleave DNA by itself, and to identify which plant SPO11 homologue cleaves DNA, we developed a Drosophila bioassay system that detects the DSB signals generated by a plant SPO11 homologue expressed ectopically. We cytologically and genetically demonstrated the DSB activities of Arabidopsis AtSPO11-1 and AtSPO11-2, which are required for meiosis, in the absence of other plant proteins. Using this bioassay, we further found that a novel SPO11-homologue, OsSPO11D, which has no counterpart in Arabidopsis, displays prominent DSB-forming activity. Quantitative analyses of the rice SPO11 transcripts revealed the specific increase in OsSPO11D mRNA in the anthers containing meiotic pollen mother cells. CONCLUSIONS: The Drosophila bioassay system successfully demonstrated that some plant SPO11 orthologues have intrinsic DSB activities. Furthermore, we identified a novel SPO11 homologue, OsSPO11D, with robust DSB activity and a possible meiotic function. PMID- 22248239 TI - Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. AB - The oxidative pathway for the metabolism of tryptophan along the kynurenine pathway generates quinolinic acid, an agonist at N-methyl-D-aspartate receptors, as well as kynurenic acid which is an antagonist at glutamate and nicotinic receptors. The pathway has become recognized as a key player in the mechanisms of neuronal damage and neurodegenerative disorders. As a result, manipulation of the pathway, so that the balance between the levels of components of the pathway can be modified, has become an attractive target for the development of pharmacological agents with the potential to treat those disorders. This review summarizes some of the relevant background information on the pathway itself before identifying some of the chemical strategies for its modification, with examples of their successful application in animal models of infection, stroke, traumatic brain damage, cerebral malaria and cerebral trypanosomiasis. PMID- 22248240 TI - Epidemiologic parameters and evaluation of control measure for 2009 novel influenza a (H1N1) in Xiamen, Fujian Province, China. AB - BACKGROUND: Containment of influenza A H1N1 virus spread was implemented successfully in Xiamen, with large-scale inoculation to reduce morbidity. To identify beneficial elements and to guide decision-making in epidemic containment, we analyzed the epidemiologic parameters and evaluated the control measures. METHOD: We determined various parameters from laboratory-confirmed cases, including incubation period, duration of illness and reproductive number (R0), and evaluated the control measures. RESULTS: There were 1414 cases with dates of onset between June 14, 2009 and March 22, 2010. The incidence was 56.79/100,000, and mortality was 0.12/100,000. The incidence during the community epidemic phase was 6.23 times higher than in the containment phase. A total of 296,888 subjects were inoculated with domestic influenza H1N1 virus cleavage vaccine. An epidemic curve showed that vaccination in students cut the peak incidence of illness significantly. Men (relative risk (RR) = 1.30, 95% confidence interval (CI): 1.17-1.45) and persons aged 0-14 years were at greater risk of infection. The incidence increased with younger age (chi2 = 950.675, p = infinity). Morbidity was lower in urban than in rural areas (RR = 0.56, 95%CI: 0.50-0.62). The median incubation time was 2 days, median duration of symptoms was 7 days, and the within-school reproductive number was 1.35. CONCLUSION: Our analysis indicated that the characteristics of this novel influenza virus were similar to those of seasonal influenza. The principle of "interception of imported cases" applied at Xiamen ports, and vaccination of students effectively limited the spread of the influenza pandemic and reduced the epidemic peak. PMID- 22248242 TI - Antiplasmodial activity of steroidal chalcones: evaluation of their effect on hemozoin synthesis and the new permeation pathway of Plasmodium falciparum infected erythrocyte membrane. AB - Chalcone derivatives on an estradiol framework were evaluated for their ability to inhibit the growth and development of the malaria parasite Plasmodium falciparum. Out of twelve steroidal chalcones and one indanone derivative studied, three were found to have 50% growth inhibitory concentration less than 5MUm and minimum inhibitory concentration for parasite development from ring to schizont stage as <=20MUm with best activity for gallic acid-based chalcone derivative 1 as 2.07 and 10MUm, respectively. Two of the active derivatives 1 and 10 did not exhibit cytotoxicity against vero cells as evident by the good selectivity ratio. Study of structure-activity relationship indicated that increasing substitution in the benzoyl ring-enhanced antiplasmodial activity. Hemozoin synthesis of the parasite remained unaffected by these derivatives. These derivatives were also investigated for their effect on parasite-induced new permeation pathway in the erythrocyte membrane by sorbitol-induced hemolysis, and four derivatives 1, 2, 9, and 10 exhibited significant inhibition (>70%) at 20MUm concentration. A positive correlation was also observed among the antiplasmodial activity and inhibition of new permeation pathway. These observations suggest that steroidal chalcones with selective activity for the parasite may be considered as antimalarial leads for further optimization and preclinical study. PMID- 22248243 TI - Propagule pressure determines recruitment from a commercial shipping pier. AB - Artificial structures associated with shipping and boating activities provide habitats for a diverse suite of non-indigenous marine species. Little is known about the proportion of invader success in nearby waters that is attributable to these structures. Areas close to piles, wharves and piers are likely to be exposed to increasing levels of propagule pressure, enhancing the recruitment of non-indigenous species. Recruitment of non-indigenous and native marine biofouling taxa were evaluated at different distances from a large commercial shipping pier. Since artificial structures also represent a desirable habitat for fish, how predation on marine invertebrates influences the establishment of non indigenous and native species was also evaluated. The colonisation of several non indigenous marine species declined rapidly with distance from the structure. Little evidence was found to suggest that predators have much influence on the colonisation success of marine sessile invertebrate species, non-indigenous or otherwise. It is suggested that propagule pressure, not predation, more strongly predicts establishment success in these biofouling assemblages. PMID- 22248244 TI - Increased serum levels of high-mobility group box 1 (HMGB1) in primary Sjogren's syndrome. AB - OBJECTIVE: To determine serum levels of high-mobility group box 1 (HMGB1) in patients with primary Sjogren's syndrome (pSS) as compared to healthy volunteers and patients with sicca symptoms, and to determine whether serum HMGB1 levels are correlated with disease activity in pSS. METHODS: Serum HMGB1 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 101 patients with pSS, 13 patients with sicca symptoms, and 40 healthy volunteers. Clinical and laboratory variables were also analysed and serum HMGB1 levels were correlated with the Sjogren's Syndrome Disease Activity Index (SSDAI). RESULTS: The serum levels of HMGB1 were significantly increased in pSS patients as compared to patients with sicca symptoms and healthy controls (p = 0.04 and p = 0.01, respectively). In the subgroups of patients with anti-SSA autoantibodies, the serum levels of HMGB1 were significantly higher than those in the subgroup of pSS patients who were anti-SSA negative and in healthy controls and patients with sicca symptoms (p < 0.001, p < 0.001, and p = 0.004, respectively). There was no significant correlation between serum HMGB1 levels (in pSS patients with anti-SSA autoantibodies) and SSDAI score (r = 0.03, p = 0.83). Patients with active disease had higher HMGB1 levels than patients with low disease activity (p = 0.04), but HMGB1 levels did not correlate with the SSDAI. CONCLUSION: Serum HMGB1 levels are increased in pSS patients and more specifically in patients with SSA autoantibodies. There was, however, no correlation of HMGB1 with the SSDAI. PMID- 22248246 TI - Impaired perception of harmonic complexity in congenital amusia: a case study. AB - This study investigates whether congenital amusia (an inability to perceive music from birth) also impairs the perception of musical qualities that do not rely on fine-grained pitch discrimination. We established that G.G. (64-year-old male, age-typical hearing) met the criteria of congenital amusia and demonstrated music specific deficits (e.g., language processing, intonation, prosody, fine-grained pitch processing, pitch discrimination, identification of discrepant tones and direction of pitch for tones in a series, pitch discrimination within scale segments, predictability of tone sequences, recognition versus knowing memory for melodies, and short-term memory for melodies). Next, we conducted tests of tonal fusion, harmonic complexity, and affect perception: recognizing timbre, assessing consonance and dissonance, and recognizing musical affect from harmony. G.G. displayed relatively unimpaired perception and production of environmental sounds, prosody, and emotion conveyed by speech compared with impaired fine grained pitch perception, tonal sequence discrimination, and melody recognition. Importantly, G.G. could not perform tests of tonal fusion that do not rely on pitch discrimination: He could not distinguish concurrent notes, timbre, consonance/dissonance, simultaneous notes, and musical affect. Results indicate at least three distinct problems-one with pitch discrimination, one with harmonic simultaneity, and one with musical affect-and each has distinct consequences for music perception. PMID- 22248248 TI - Changes in cinnamyl alcohol dehydrogenase activities from sugarcane cultivars inoculated with Sporisorium scitamineum sporidia. AB - This study describes a method for determining cinnamyl alcohol dehydrogenase activity in sugarcane stems using reverse phase (RP) high-performance liquid chromatography to elucidate their possible lignin origin. Activity is assayed using the reverse mode, the oxidation of hydroxycinnamyl alcohols into hydroxycinnamyl aldehydes. Appearance of the reaction products, coniferaldehyde and sinapaldehyde is determined by measuring absorbance at 340 and 345 nm, respectively. Disappearance of substrates, coniferyl alcohol and sinapyl alcohol is measured at 263 and 273 nm, respectively. Isocratic elution with acetonitrile:acetic acid through an RP Mediterranea sea C18 column is performed. As case examples, we have examined two different cultivars of sugarcane; My 5514 is resistant to smut, whereas B 42231 is susceptible to the pathogen. Inoculation of sugarcane stems elicits lignification and produces significant increases of coniferyl alcohol dehydrogenase (CAD) and sinapyl alcohol dehydrogenase (SAD). Production of lignin increases about 29% in the resistant cultivar and only 13% in the susceptible cultivar after inoculation compared to uninoculated plants. Our results show that the resistance of My 5514 to smut is likely derived, at least in part, to a marked increase of lignin concentration by the activation of CAD and SAD. PMID- 22248249 TI - Complement fixing donor-specific antibodies and allograft loss. PMID- 22248250 TI - Should we retransplant a patient who is non-adherent? A literature review and critical reflection. AB - The majority of transplant centers around the world face an ethical debate whether to retransplant a young non-adherent patient. Non-adherence to lifelong immunosuppressants presents a significant risk for graft loss, yet rates remain consistently high. Despite a number of these patients presenting for retransplantation, there is little evidence to guide professionals in their decision-making. This paper aims to provide such guidance, by systematically reviewing the existing outcome data for retransplantation in patients who are known to be non-adherent to their immunosuppressants. This review searched for original papers that addressed retransplantation of a solid organ and included quantitative data on adherence or graft function. Only one original research paper was found to meet the inclusion criteria. This paper is reviewed, and details of the protocol to determine eligibility for retransplantation are summarized. The findings are discussed within the ethical context that transplant professionals work within, and the arguments for and against retransplantation are considered. The need for effective integration of adherence management into routine practice is highlighted, with an emphasis on reliable measurement of adherence throughout the patient's life. Examples of good practice are discussed, favoring prevention over cure. PMID- 22248251 TI - Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients. AB - Polyoma BKVN is a significant cause of allograft dysfunction and loss in renal transplant recipients. Reduction in immunosuppression is accepted as first-line therapy to decrease viral load and prevent allograft injury and dysfunction. We report our experience with persistent BKV after reduction in immunosuppression followed by successful clearance of BKV in three pediatric renal transplant recipients and histological resolution of BKVN in a fourth patient following therapy with IVIG. Once BKV was detected, immunosuppression was reduced and BKV was monitored until clearance was achieved. All four patients were given IVIG in a dose of 2 g/kg. Allograft function remained stable in all patients. Early routine screening for BKV allows early intervention to prevent the development of BKVN and permanent allograft damage. While immunosuppression reduction is a logical first-line therapy, second-line therapy is not well established. IVIG seems to be an effective treatment for persistent BKV after reduction in immunosuppression and for BKVN and can therefore be considered as a therapeutic option in these patients. PMID- 22248252 TI - Year in review 2011: acute lung injury, interstitial lung diseases, physiology, sleep and lung cancer. PMID- 22248253 TI - Controlled fabrication of core-shell TiO2/C and TiC/C nanofibers on Ti foils and their field-emission properties. AB - Core-shell TiO(2)/C and TiC/C nanofibers are fabricated in situ on Ti and Al ion implanted Ti substrates by a thermochemical reaction in acetone and the growth mechanism is described. Implantation of Al into Ti leads to in situ growth of TiC/C in lieu of TiO(2)/C nanofibers. This is because Al has a higher affinity to oxygen than Ti and Ti reacts preferentially with C to form TiC. The Ti foil serves as both the Ti source and substrate for the core-shell TiO(2)/C and TiC/C NFs to ensure strong bonding and small contact resistance between the Ti substrate and the core-shell field emitters. The core-shell TiC/C and TiO(2)/C nanofibers have similar morphology and structure, but the TiC/C nanofibers possess better field emission properties with a turn on field (E(to)) of 2.2 V/MUm compared to an E(to) of 3.2 V/MUm measured from the TiO(2)/C nanofibers. The enhanced field-emission property of the TiC/C nanofibers is attributed to the high electrical and thermal conductivity of the TiC inner core, which provides a more effective electron transfer pathway between the cathode and C shell emitters. PMID- 22248255 TI - Ovarian germ cell tumors with rhabdomyosarcomatous components and later development of growing teratoma syndrome: a case report. AB - INTRODUCTION: Development of a sarcomatous component in a germ cell tumor is an uncommon phenomenon. Most cases reported have a grim prognosis. Growing teratoma syndrome is also an uncommon phenomenon and occurs in approximately 2% to 7% of non seminomatous germ cell tumors and should be treated surgically. CASE PRESENTATION: We report the case of a 12-year-old Asian girl with an ovarian mixed germ cell tumor containing a rhabdomyosarcomatous component. She was treated with a germ cell tumor chemotherapy regimen and rhabdomyosarcoma-specific chemotherapy. Towards the end of her treatment, she developed a retroperitoneal mass that was increasing in size. It was completely resected, revealing a mature teratoma, consistent with growing teratoma syndrome. She is still in complete remission approximately three years after presentation. CONCLUSION: The presence of rhabdomyosarcoma in a germ cell tumor should be treated by a combined chemotherapy regimen (for germ cell tumor and rhabdomyosarcoma). In addition, development of a mass during or after therapy with normal serum markers should raise the possibility of growing teratoma syndrome that should be treated surgically. PMID- 22248256 TI - A perspective of end-of-life care education in undergraduate medical and nursing students in Buenos Aires, Argentina. AB - BACKGROUND: The goals of this study were to evaluate: (1) the experiences and attitudes after exposure to dying patients in undergraduate medicine and nursing students with lack of training in end-of-life care issues; (2) whether or not exposure to terminally ill patients (TIPs) influences attitudes in students who had no training in end-of-life care; (3) students wishes regarding their future care of TIPs; and (4) if medicine and nursing students are indeed interested in receiving training in end-of-life care. MATERIALS AND METHODS: A survey was administered to students in the first and last year in schools of medicine and nursing, comprising seven universities in the city of Buenos Aires, Argentina, and surrounding areas. Data were collected during the 2005 to 2010 time period. Data from 730 students were analyzed. DISCUSSION AND CONCLUSION: We found that nursing and medical undergraduate students at nursing and medicine schools in the city of Buenos Aires and surrounding areas: (a) come in direct contact with TIPs and perceive their suffering; and (b) have a highly positive attitude toward these patients, even though some of them referred to that relationship as arduous and in some cases they tended to avoid emotional involvement because they did not feel well trained. We also found that (c) this wish for avoidance was increased in final-year medical and nursing students who had been exposed to a higher number of TIPs; and (d) students unanimously manifested the opinion that the teaching about caring of TIPs should be included in the curricula and they would be well disposed to receive it. For all these reasons, we consider that the teaching of caregiving to TIPs in the academic degree programs of nursing and medicine should not be presented as a marginal issue. PMID- 22248257 TI - Clinical outcomes and health-related quality of life after thoracoscopic talc pleurodesis. AB - OBJECTIVES: Thoracoscopic pleurodesis is a safe and effective method of palliative care for patients suffering from malignant pleural effusion. Health related quality of life (QOL) is an important factor in palliative therapy; however, we are not aware of any studies that have examined the QOL of patients following thoracoscopic pleurodesis. METHODS: A total of 123 patients underwent thoracoscopic pleurodesis between January 2006 and February 2009. A total of 45 patients agreed to take part at the QOL assessment and were enrolled in our prospective study. In addition to clinical outcome, the patients' QOL data were assessed prior to thoracoscopic pleurodesis and for 12 months after surgery using the European Organization for Research and Treatment of Cancer (EORTC) QLQ C-30 questionnaire. We compared the patients' QOL scores at each time point with their preoperative scores and analyzed these data relative to the scores of a healthy age-matched population. RESULTS: Due to the advanced clinical status of the patients in our study, the overall median survival time was 7.5 months versus 10.2 months for patients' QOL data. Following discharge from the hospital, most functional scales (with exception of emotional function, p=0.035) did not significantly differ from preoperative scores. Throughout the study period, patients experienced statistically and clinically significant improvements in functional scales. Global health values increased after surgery throughout the entire study period. There was a clear decline in dyspnea upon discharge, followed by a continuous remote increase throughout the subsequent months. QOL of the study population remained lower than that of the healthy cohort. CONCLUSIONS: Our data are consistent with clinical findings that pleurodesis decreases respiratory symptoms, but does not alleviate impairments in the patient's general condition. PMID- 22248258 TI - Effect of all-trans-retinoic acid on the expression of primordial germ cell differentiation-associated genes in mESC-derived EBs. AB - atRA (all-trans-retinoic acid) is known to induce the differentiation of mESCs (mouse embryonic stem cells) into PGCs (primordial germ cells) in vitro. However, it is not clear as to what changes occur in PGC differentiation-associated genes or what mechanisms are involved when EBs (embryoid bodies) derived from mESCs are induced by atRA. EBs derived from mESCs were treated with 1, 2 or 5 MUM atRA for 16 h, 2 days or 5 days. Real-time PCR and Western blot analysis were performed to detect the relative levels of PGC differentiation-associated genes (Lin28, Blimp1, Stra8 and Mvh) and the corresponding proteins respectively. Immunofluorescence was used to detect the protein location and distribution in EBs. The expression characteristics of genes could be divided into three categories: rapidly reached the peak value in 16 h and then decreased (Stra8, Lin28), initially low and then increased to reach the peak value in 5 days (Mvh) and relatively unchanged (Blimp1). A low level of Lin28 was expressed in EBs treated with atRA for 2 days or 5 days. The variation in the level of Lin28 mRNA did not influence the change in the level of Blimp1 mRNA. The changes in Stra8/Lin28 were consistent with the corresponding changes in the levels of their respective mRNAs, but the changes for Mvh/Blimp1 were not consistent with the corresponding changes in the levels of their respective mRNAs. Blimp1 expression may be independent of the effect of atRA on PGC differentiation. atRA may promote the start of a period in which there is a low level of Lin28 expression during PGC differentiation. PMID- 22248259 TI - FTO and obesity: a problem for a billion people. AB - It is an inescapable fact that obesity results from consuming more energy than you burn. The interesting question, however, is why some people eat more than others? Recent genetic analyses have revealed that variations in the fat mass and obesity-associated (FTO) gene are robustly associated with obesity and increased food intake. This association is replicable across different age groups in multiple populations and attention is now turned to studying the complex biology of FTO. PMID- 22248260 TI - Platelet hyperaggregability in high-fat fed rats: a role for intraplatelet reactive-oxygen species production. AB - BACKGROUND: Adiposity greatly increases the risk of atherothrombotic events, a pathological condition where a chronic state of oxidative stress is reported to play a major role. This study aimed to investigate the involvement of (NO) soluble guanylyl cyclase (sGC) signaling pathway in the platelet dysfunction from high fat-fed (HFF) rats. METHODS: Male Wistar rats were fed for 10 weeks with standard chow (SCD) or high-fat diet (HFD). ADP (10 MUM)- and thrombin (100 mU/ml)-induced washed platelet aggregation were evaluated. Measurement of intracellular levels of ROS levels was carried out using flow cytometry. Cyclic GMP levels were evaluated using ELISA kits. RESULTS: High-fat fed rats exhibited significant increases in body weight, epididymal fat, fasting glucose levels and glucose intolerance compared with SCD group. Platelet aggregation induced by ADP (n = 8) and thrombin from HFD rats (n = 8) were significantly greater (P < 0.05) compared with SCD group. Platelet activation with ADP increased by 54% the intraplatelet ROS production in HFD group, as measured by flow cytometry (n = 6). N-acetylcysteine (NAC; 1 mM) and PEG-catalase (1000 U/ml) fully prevented the increased ROS production and platelet hyperaggregability in HFD group. The NO donors sodium nitroprusside (SNP; 10 MUM) and SNAP (10 MUM), as well as the NO independent soluble guanylyl cyclase stimulator BAY 41-2272 (10 MUM) inhibited the platelet aggregation in HFD group with lower efficacy (P < 0.05) compared with SCD group. The cGMP levels in response to these agents were also markedly lower in HFD group (P < 0.05). The prostacyclin analogue iloprost (1 MUM) reduced platelet aggregation in HFD and SCD rats in a similar fashion (n = 4). CONCLUSIONS: Metabolic abnormalities as consequence of HFD cause platelet hyperaggregability involving enhanced intraplatelet ROS production and decreased NO bioavailability that appear to be accompanied by potential defects in the prosthetic haem group of soluble guanylyl cyclase. PMID- 22248261 TI - Duodenal levodopa/carbidopa infusion therapy in patients with advanced Parkinson's disease leads to improvement in caregivers' stress and burden. AB - BACKGROUND: Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson's disease (PD). However, the impact of DLI on caregivers' stress and burden has not been reported. METHODS: We evaluated prospectively open-label seven advanced PD patients (65.7 +/- 9.6 years, 71.4% men) treated with DLI. Schwab & England Activities of Daily Living Scale (ADLS), 39-item Parkinson's disease QoL Questionnaire Summary Index score (PDQ-39SI), Zarit Caregiver Burden Interview (ZCBI), and Caregiver Strain Index (CSI) were used. Comparisons were made between scores obtained at baseline and those at a mean follow-up of 31.4 +/- 7.9 months (range, 23-42). RESULTS: In patients, mean +/- SD ADLS was increased from 50 +/- 8.2 to 80 +/- 11.6 (P = 0.014), and mean +/- SD PDQ-39SI was decreased from 53.7 +/- 11.9 to 33.6 +/- 12.8 (P = 0.018). In caregivers, ZCBI decreased from 43 +/- 13.3 to 20.7 +/- 12.1 (P = 0.018) and CSI from 6.3 +/- 2.5 to 1.6 +/- 0.9 (P = 0.018). At baseline, 57.1% of caregivers reported moderate to severe burden (ZCBI 41-88) compared to 28.6% at the end of the follow-up (P = 0.015); at that time, no caregiver reported high level of stress (CSI >= 7) compared to 57.1% at baseline (P = 0.046). There were significant correlations between ZCBI and CSI improvement (r = 0.813, P = 0.026), ZCBI and PDQ-39SI (r = 0.875, P = 0.01), and ZCBI and ADLS (r = 0.813, P = 0.026). CONCLUSIONS: Duodenal levodopa infusion related clinical improvement in patients with advanced PD leads to substantial reductions in caregivers' stress and burden. PMID- 22248264 TI - Longitudinal pharmacometabonomics for predicting patient responses to therapy: drug metabolism, toxicity and efficacy. AB - Pharmacometabonomics describes the use of metabolic profiling of biofluids, tissues and tissue extracts to predict, prior to dosing, the beneficial and adverse effects of an intervention such as drug administration. The approach not only is analogous to pharmacogenomics but also is sensitive to environmental factors such as the gut microbiome. Recent applications of pharmacometabonomics are presented and the extension to the use of longitudinal sampling is introduced. Clinical and other human applications of pharmacometabonomics are highlighted and possible future clinical applications of pharmacometabonomics and longitudinal pharmacometabonomics are discussed. These include clinical trials of new drugs either at the first-into-man stage or later in Phase II and III trials, and assessment of individual patients or groups of patients for particular therapies (personalised and stratified medicine approaches). Since metabonomics approaches are sensitive to both the host genome effects and the gut microbiome, pharmacometabonomics has particular utility for studying the host-microbiome interactions and for assessing new therapies that target the gut bacteria. Since the microbiome also has implications for nutrition and drug pharmacokinetics, such metabolic profiling approaches are likely to of use in such studies. It is anticipated that as metabonomics analytical and statistical technologies continue to develop, more applications will be realised and these should find use in real clinical situations, even monitoring patients in real time. PMID- 22248262 TI - Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity. AB - The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K(i)(app) <= 10 nM and GI(50) ~ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies. PMID- 22248265 TI - Standardization of pluripotent stem cell cultures for toxicity testing. AB - INTRODUCTION: Pluripotent stem cell (PSC) lines offer a unique opportunity to derive various human cell types that can be exploited for human safety assessments in vitro and as such contribute to modern mechanistically oriented toxicity testing. AREAS COVERED: This article reviews the two major types of PSC cultures that are currently most promising for toxicological applications: human embryonic stem cell lines and human induced PSC lines. Through the review, the article explains how these cell types will improve the current safety evaluations of chemicals and will allow a more efficient selection of drug candidates. Additionally, the article discusses the important issues of maintaining PSCs as well as their differentiation efficiency. EXPERT OPINION: The demonstration of the reliability and relevance of in vitro toxicity tests for a given purpose is mandatory for their use in regulatory toxicity testing. Given the peculiar nature of PSCs, a high level of standardization of undifferentiated cell cultures as well as of the differentiation process is required in order to ensure the establishment of robust test systems. It is, therefore, of pivotal importance to define and internationally agree on crucial parameters to judge the quality of the cellular models before enrolling them for toxicity testing. PMID- 22248266 TI - In silico models for drug-induced liver injury--current status. AB - INTRODUCTION: Drug-induced liver injury (DILI) is one of the most important reasons for drug attrition at both pre-approval and post-approval stages. Therefore, it is crucial to develop methods that will detect potential hepatotoxicity among drug candidates as early and quickly as possible. However, the complexity of hepatotoxicity endpoint makes it very difficult to predict. In addition, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data, which are the key to any modelling approach. AREAS COVERED: This review explores the current status of existing in silico models predicting hepatotoxicity. Over the past decade, attempts have been made to compile hepatotoxicity data and develop in silico models, which can be used as a first-line screening of drug candidates for further testing. EXPERT OPINION: Most of the predictive methods discussed in this review are based on the structural properties of chemicals and do not take into account genetic and environmental factors; therefore, their predictions are still uncertain. To improve the predictability of in silico models for DILI, it is essential to better understand its mechanisms as well as to develop sensitive toxicogenomics biomarkers, which show relatively good differentiation between hepatotoxins and non-hepatotoxins. PMID- 22248267 TI - Monoclonal antibodies: what are the pharmacokinetic and pharmacodynamic considerations for drug development? AB - INTRODUCTION: The number of monoclonal antibodies available for clinical use and under development has dramatically increased in the last 10 years. Understanding their pharmacokinetics and pharmacodynamics is essential for selecting the right clinical candidate, correct dose and regimen for a target indication. AREAS COVERED: This article reviews the existing literature and knowledge of monoclonal antibodies. Specifically, the authors discuss monoclonal antibodies with respect to their pharmacokinetics (including absorption, distribution and elimination) and their pharmacodynamics. The authors also look at the pharmacokinetic/pharmacodynamic relationship, scaling from preclinical to clinical studies and selection of the first-in-human dose. EXPERT OPINION: Monoclonal antibodies have complex pharmacokinetic and pharmacodynamic characteristics that are dependent on several factors. Therefore, it is important to improve our understanding of the pharmacokinetics and pharmacodynamics of monoclonal antibodies from a basic research standpoint. It is also equally important to apply mechanistic pharmacokinetic/pharmacodynamic models to interpret the experimental results and facilitate efforts to predict the safety and efficacy of monoclonal antibodies. PMID- 22248268 TI - Time trends in cervical cancer epidemiology in the Slovak Republic: reflection on the non-implementation of screening with international comparisons. AB - Cervical cancer is a serious public health problem with high geographical variations in incidence, mainly due to historical patterns of risk factors and the influence of screening activities. To reduce both cervical cancer incidence and mortality is the primary objective of organized screening and annual reports of high quality utilising accepted interventional measures. Currently, the time trends in overall incidence and mortality from cervical cancer in the Slovak Republic are implacable. The high incidence values of this condition that have stabilized long term without any signs of a significant decrease rank us among the "developing countries" in Europe. Moreover, the continuing low accessibility of vaccinations for the population lowers the potential effect of an improvement in the incidence of pre-malignant lesions of cervical cancer. Without a basic analysis of the cervical cancer epidemiological data it is not possible to discover the causes of this unfavorable situation and thus condition changes at the level of screening and early diagnostics.Following this, we aimed to analyse the incidence and mortality of cervical cancer over the period 1968-2006 and to point out the necessity for the early introduction of interventional measures in accordance with organized screening in the Slovak Republic.There was recorded a stabilized trend in incidence with an estimated average annual change 0.008/100.000 (95% CI = -0.048 to 0,032, p =0.689) and a moderately increasing trend in mortality with average annual increase 0.049/100,000 (95% CI = 0.033 to 0.065, p < 0.0001). In 2003-2006, the cumulative risk of disease (0-74 years) averaged 1.5 %, the cumulative risk of death reached 0.5%. The analyses of clinical stages during the period 1978-2003 showed that the number of cases in clinical stage I increased, the stage II rate declined, and the numbers of cases in stages III and IV were still high with, moreover, a rising tendency. In comparison with other European countries these trends are unfavorable and our results have confirmed the necessity of an immediate introduction of organized screening in the SR. PMID- 22248269 TI - Postoperative radiochemotherapy with weekly cisplatin in patients with head and neck cancer single-institution outcome analysis. AB - The objective of this study was to evaluate the feasibility, toxicity and efficacy of postoperative radiochemotherapy with weekly cisplatin in locoregionally advanced or high risk head and neck cancer in a single institutional setting. Patients with head and neck cancer of stage III/IV or patients with insufficient margins of resection were included in the study. Radiotherapy consisted of 70 Gy/ 7 weeks/ 35 fraction after R1/2 resection and 60 64 Gy/ 6-6,5 weeks/ 30-32 fraction after R0 resection, respectively. All patients received concurrent cisplatin 40 mg/m2 weekly. Between 7/2002 and 12/2008, 100 consecutive patients [WHO <= 2, male to female ratio 84/16, median age 54 years] were treated. Tumors of the oropharynx were the most frequent (49%) and stage IV was predominant (86%). 96% patients received the full radiation treatment as planned, median total tumor dose was 66 Gy. Omission of weekly cisplatin had been occurring frequently, the most frequent reason for its early cessation were hematological toxicities (34%). Grade 3/4 mucosal toxicity developed in 32%. No death was observed during the treatment. The late toxicities were acceptable, predominantly subcutaneous fibrosis and xerostomia in most of the cases. We recorded six cases of osteonecrosis. Two and half year overall survival, locoregional control, time to progression and disease free survival were 64%, 88%, 79% and 59%, respectively. Postoperative radiochemotherapy with weekly cisplatin is toxic, but tolerable and highly effective in terms of locoregional control and survival. Multivariete analysis revealed that the only prognostic factor for survival was primary surgery at the University centre. PMID- 22248270 TI - Immunohistochemical analysis of the mTOR pathway in intrahepatic cholangiocarcinoma. AB - The aim of the study was to evaluate the expression of activated mammalian rapamycin (mTOR) and its downstream effectors, phosphorylated p70 ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), in intrahepatic cholangiocarcinomas (ICC), in order to strengthen the rationale for targeted therapy using mTOR inhibitors in patients with ICC. p-mTOR (Ser 2448), p-4EBP1 (Thr 70) and p-p70S6K (Thr 389) were detected in 77 primary ICC tumors by immunohistochemistry. High levels of p-mTOR, p-4EBP1 and p-p70S6K expression were defined in 48.1% (37/77), 50.6% (39/77) and 51.9% (40/77) of all tumors, respectively. No significant correlation was observed between mTOR pathway proteins overexpression with clinicopathological characteristics and patient's prognosis, except that high p-p70S6K expression correlated with the poorly differentiated subtype, and high expression of p-4EBP1 predicted poor prognosis in ICC patients and retained an independent prognostic factor in multivariate analysis. In conclusion, our results showed high prevalence of activation of mTOR pathway in ICC tumors, suggesting that a high proportion of ICC patients might benefit from mTOR pathway targeted therapies. In addition, p 4EBP1 phosphorylation at Thr 70 could be a useful prognostic biomarker for ICC patients. PMID- 22248271 TI - Effects of pantoprazole as a HIF-1alpha inhibitor on human gastric adenocarcinoma sgc-7901 cells. AB - Previously, it has been demonstrated that HIF-1alpha has close connection with malignant tumor progression, aggressive behavior and prognosis. In addition, proton pump inhibitors (PPIs) have been reported to selectively induce tumor cell apoptosis, thus exerting its anticancer effects. In vitro and in vivo our study revealed that pantoprazole (PPZ) inhibited tumor cells proliferation, induced apoptosis and decreased the expression of HIF-1alpha protein. In summary, PPZ could suppress tumor growth acting as a HIF-1alpha protein inhibitor. PMID- 22248272 TI - Diagnostic performance of des-gamma-carboxy prothrombin (DCP) for hepatocellular carcinoma: a bivariate meta-analysis. AB - Serum markers are needed to be developed to specifically diagnose Hepatocellular carcinoma (HCC). Des-gamma-carboxy prothrombin (DCP) is a promising tool with limited expense and widely accessibility, but the reported results have been controversial. In order to review the performance of DCP for the diagnosis of HCC, the meta-analysis was performed. After a systematic review of relevant studies, the sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR, respectively) were pooled using a bivariate meta-analysis. Potential between-study heterogeneity was explored by meta-regression model. The post-test probability and the likelihood ratio scattergram to evaluate clinical usefulness were calculated. Based on literature review of 20 publications, the overall sensitivity, specificity, PLR and NLR of DCP for the detection of HCC were 67% (95%CI, 58%-74%), 92% (95%CI, 88%-94%), 7.9 (95%CI, 5.6-11.2) and 0.36 (95%CI, 0.29-0.46), respectively. The area under the bivariate summary receiving operating characteristics curve was 0.89 (95%CI, 0.85-0.92). Significant heterogeneity was present. In conclusion, the major role of DCP is the moderate confirmation of HCC. More prospective studies of DCP are needed in future. PMID- 22248273 TI - Lung adenocarcinoma and squamous cell carcinoma in association with genetic polymorphisms of GSTs in Slovak population. AB - Slovak Republic belongs to the countries with high incidence of lung cancer. Gene polymorphisms of the glutathione S-transferases (GSTs) may play a role in individual lung cancer susceptibility. In presented case-control study we investigate the incidence of polymorphism of GSTT1, GSTM1, GSTP1 genes and their combinations as possible predictive factors for identification of individuals with increased risk of formation and development of adenocarcinoma (AC) and squamous cell carcinoma (SCC) of lung in Slovak population. The study was conducted on 520 individuals consisting of 118 patients with adenocarcinoma, 112 patients with squamous cell carcinoma and 290 control individuals. GSTT1, GSTM1, GSTP1 gene polymorphisms were assayed by standard PCR and PCR-RFLP technique. The results of this study indicate that the GSTT1null-genotype and combination GSTT1 null and Ile/Val or Val/Val are associated with increased risk of lung adenocarcinoma. A significant association with 2.13 - fold increased risk was observed between lung adenocarcinoma and GSTT1 null genotype (95% CI = 1.29 - 3.51; p= 0.004). Also it was proved 2.83 times statistically higher risk for development of this histological type of lung cancer (95% CI = 1.34 - 6.01; P= 0.005) in combination of GSTT1null and Ile/Val or Val/Val genotypes. GSTT1, GSTM1, GSTP1 polymorphism did not show any significant association with SCC. Our study suggests that genetic make-up in metabolizing genes may increase susceptibility towards lung cancer development. PMID- 22248274 TI - Monitoring of methylation changes in 9p21 region in patients with myelodysplastic syndromes and acute myeloid leukemia. AB - Epigenetic de novo methylation of CpG islands is an important event in malignant transformation. Two genes are frequently methylated: cyclin-dependent kinase inhibitor 2B (CDKN2B) and cyclin-dependent kinase inhibitor 2A (CDKN2A). In our study methylation of these genes was studied in 63 patients with myelodysplastic syndromes (MDS), 2 with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and 13 with acute myeloid leukemia (AML). Five patients were monitored during 5 azacytidine treatment. Twenty-six healthy donors were tested in a control group. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method with all associated techniques was used for detection. Aberrant methylation was present in the CDKN2A gene in 38% and in the CDKN2B gene in 77% of the patients in MDS group. The level of methylation was higher in the group of AML patients - 77% in CDKN2A gene and 100% in CDKN2B gene. In MDS patients, an aberrant methylation was associated with a tendency to disease progression towards more advanced forms according to the World Health Organization (WHO) classification and the International Prognostic Scoring System (IPSS). Significant differences in methylation level were observed between early and advanced forms of MDS in CDKN2B gene (P value < 0.05) but not for CDKN2A gene. The trend of methylation in patients treated with azacitidine was analyzed in CDKN2B gene and correlated with the course of the disease. Increased methylation was connected with disease progression. We concluded that the methylation level of CDKN2B gene might be used as a marker of leukemic transformation in MDS. Our study indicates the role of hypermethylation as an important event in the progression of MDS to AML. PMID- 22248275 TI - The significance of portal vein embolization in the treatment of colorectal liver metastases. AB - The first aim of the present paper was to evaluate hypertrophy of liver parenchyma after portal vein embolization in patients after systemic chemotherapy for colorectal carcinoma metastases and planned extensive liver resections. The second aim was to study whether hypertrophy of the liver parenchyma remnant after could influence the postoperative course large liver resections in long-term chemotherapy within complex therapy of colorectal carcinoma.The prospective study comprised of 43 patients with colorectal hepatic metastases in whom liver resections of 4-5 segments were planned (Table 1). All patients underwent complex therapy of colorectal carcinoma, including chemotherapy consisting of 6-12 therapeutic cycles. Time interval between chemotherapy and liver resection was 2 24 months (mean interval of 8 months). Twenty patients whose presumed liver parenchyma remnant was less than 40% of total liver volume were indicated for portal vein embolization (mean liver parenchyma remnant of 29%). This was always embolization of the right portal branch. Twenty-three patients were primarily indicated to liver resection. RESULTS: Hypertrophy of the left liver lobe occurred in all 20 patients. After portal vein embolization, the volume of left liver increased on average from 476 ml (282-754) to 584 ml (380-892) (P < 0.05). Mean hypertrophy of left liver lobe after portal vein embolization was 28.5%. The measured parenchyma remnant after tumor resection increased from 29% up to 38% by hypertrophy. Mean values of ALT and AST in the postoperative period were significantly different in the groups in this study. The values of alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GMT) were lower in patients after portal vein embolization (P < 0.05). Significant differences were in postoperative level of serum bilirubin, bilirubin levels in patients after portal vein embolization were 2-3 times lower than in the group of patients after immediate surgery (P < 0.05). he values of prothrombin time were also significantly lower in patients who underwent surgery without previous portal vein embolization (P < 0.05). PMID- 22248276 TI - Pretransplant serum ferritin level may be a predictive marker for outcomes in patients having undergone allogeneic hematopoietic stem cell transplantation. AB - Iron overload increases the risk of infections, veno-occlusive disease and hepatic dysfunction in post-transplant period. Our objective was to investigate the association of pre-transplant ferritin levels with complications and survival after allogeneic hematopoietic stem cell transplantation (alloHSCT).We retrospectively analysed 84 patients' data who had undergone allogeneic HSCT into two groups: patients with a serum ferritin level >= 1000 ng/ml, and patients with <1000 ng/ml at the time of HSCT.Cox-regression analysis showed that pre transplant serum ferritin levels were significantly higher in patients who had at least one infectious event compared with those who had no any infectious event in the post-transplant 100 days (p<0.023). Overall survival (OS) and disease-free survival (DFS) rates were significantly higher in patients with a time-to-tx interval 12 months (p=0.002 and p=0.008 respectively). A higher risk of death was observed in high-ferritin group (hazard ratio=2.27, CI:1.01-5.09, p=0.023 for OS and hazard ratio=2.49, CI:1.12-5.53 p=0.039 for DFS). No significant effect on OS and DFS among groups was observed for variables conditioning regimen, gender and diagnosis. Acute GVHD was more common in patients with a ferritin level >= 1000 ng /mL, but this was not statistically significant (p>0.05). There was no statistical significance in both groups (ferritin >= 1000 ng /mL and ferritin <1000 ng/mL) for relapse rates (p>0.05). Platelet and neutrophil engaftment day was not found statistically significant compared with both groups (p=0.273 and p=0.882, respectively). Pre-transplant ferritin levels may predict poor outcomes in patients who had undergone allogeneic hematopoietic stem cell transplantation. PMID- 22248278 TI - Fiber-optic bronchoscope and detection of lung cancer: a five year study. AB - White light bronchoscopy [WLB] has been used for identification and localization of intra-epithelial pre-neoplastic and neoplastic lesions within the bronchus. Aim of the study was to evaluate the uses of WLB to detect and localize the precancerous and cancerous lesions, and in addition to analyze morphologic presentation, and association to histological type and the variation between genders.A total of 4983 patients were examined by WLB from 2004 to 2009 in a local tertiary teaching hospital. The following parameters were collected: morphological presentation, biopsy sites, histology. The patients' records of age, sex, smoking status, blood-gas, X-RAY/CT, CBC, ECG, PT, and APTT were obtained for analysis. Differences between the patients groups were analyzed using Chi square test.1489 patients who had hyperplasia or neoplasic lesions were further confirmed as having lung cancer pathologically. Lung cancer was more commonly found in the right lung (51.58% vs 42.82%). The upper lobe was more frequently found to have lesions (44.17% vs 22.42%) than the lower lobe. Male patients with squamous cell carcinoma showed more commonly upper lobe involvement, while left main bronchus was more commonly involved in female patients. Adenocarcinoma was mostly involved in lesions of the upper lobe. Proliferative type was found in 80.15% of squamous cell carcinoma cases and in 76.16 % of small cell carcinoma cases.Fiberoptic bronchoscopy is an effective method for the detection of preinvasive neoplasic lesions. The morphological presentation is associated to histological type. There is variation in presentation and histology of cancerous lung lesion between the genders. PMID- 22248277 TI - Evaluation of alpha-methylacyl-CoA racemase, metallothionein and prostate specific antigen as prostate cancer prognostic markers. AB - Current diagnostic techniques are inefficient in distinguishing latent and low risk forms of prostate cancer from high-risk forms. The present study is focused on determination of putative tumor markers of aggressive high-grade forms of prostate cancer. Potential markers were determined in blood sera of 133 patients (82 cases and 51 controls) and in cell lines (Gleason score 9-derived 22Rv1 and normal tissue derived PNT1A) on mRNA and protein levels. Alpha-methylacyl-CoA racemase (AMACR), metallothionein classes 1A and 2A (MT1A and MT2A) were determined and compared to prostate specific antigen (PSA) levels. On mRNA level, significantly increased expression of MT2A (2.4-fold), PSA (2.6-fold) and AMACR (8.4-fold) and insignificantly (1.9-fold) elevated MT1A in 22Rv1 compared to non tumor PNT1A were determined. On protein level, significant enhancement of free PSA and total PSA in tumor cell line was evident. AMACR protein was 1.5-fold elevated in tumor line (below the level of significance). Contrary to mRNA, significantly (p = 0.01) reduced level of MT protein in tumor lines was determined. In the case of serum level, significantly enhanced MT level (4.5 fold) in patients' sera was found. No significant changes were observed in the case of AMACR. These findings indicate possible alternative role of MT to PSA prostate cancer marker. In addition, level of AMACR is distinctly higher in the Gleason score 9 in serum of patients and MT shows a descending trend in relation to Gleason score. PMID- 22248279 TI - Overexpression of potassium channel ether a go-go in human osteosarcoma. AB - Human ether a go-go (hEAG) potassium channels are primarily expressed in brain but also frequently overexpressed in solid tumors, which could indicate their potential value for cancer diagnosis and therapy. hEAG1, one member of the hEAG subfamily, has been shown to play a role in neoplastic process. Here we report the expression of hEAG1 in human osteosarcoma detected by a new polyclonal antibody. The full-length hEAG1 cDNA was cloned from human osteosarcoma cell line MG63 by RT-PCR and expressed in Escherichia coli as His tagged protein. The 6His hEAG1F protein was purified by nickel agarose and used as the antigen to immunize rabbits following standard protocols. The obtained antiserum could detect hEAG1 exogenously expressed in HEK 293 cells. Furthermore, the polyclonal antibody was used to evaluate hEAG1 expression in 42 human osteosarcoma specimens and 19 osteochondromas specimens by immunohistochemistry. hEAG1 was expressed in 71.4% (30/42) osteosarcoma, and 15.8% (3/19) osteochondromas. Moreover, statistical analysis revealed that hEAG1 expression was not dependent on age, sex, site, histology, grade and type in the osteosarcoma specimens. Our data provide evidence that hEAG1 is overexpressed in human osteosarcoma and the hEAG1 polyclonal antibody offers a good tool for further characterization of the oncogenic function of hEAG1 in osteosarcoma. PMID- 22248280 TI - Cigarette smoking extract causes hypermethylation and inactivation of WWOX gene in T-24 human bladder cancer cells. AB - Genomic, epigenetic and expression alterations of WW domain containing oxidoreductase (WWOX) have been implicated in multiple tumor types. The current study was designed to examine the expression of WWOX in tumor tissues of human bladder transitional cell carcinoma (BTCC) and the influence of cigarette smoke extract (CSE) on WWOX expression and methylation status in T-24 bladder cancer cells. WWOX protein expression was evaluated by immunohistochemistry staining in a series of tumor samples from 78 patients with BTCC and 26 normal bladder tissues. The expression level and methylation status of WWOX in CSE-treated cells were examined by using quantitative Real-Time RT-PCR and methylation specific PCR, respectively. The expression levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were also detected. We found that WWOX expression was absent or reduced in 79.5% (62/78) of BTCC tissues, but only in 19.2% (5/26) of normal bladder tissues. Loss of WWOX expression was correlated with tumor grade (P=0.019) and cigarette smoking (P=0.031), but was not associated with age, gender, tumor size and tumor number. Hypermethylation of WWOX promoter and exon 1 was specifically induced by CSE with a kinetics concurrent to the suppression of WWOX mRNA in T-24 cells. Furthermore, CSE treatment induced a significant time-dependent increase in the level of DNMT1, but has no effects on DNMT3A and DNMT3B. Taken together, these novel findings suggest that hypermethylation of WWOX induced by cigarette smoking may represent one underlying mechanism for the loss expression of WWOX in bladder cancer. PMID- 22248281 TI - Immunohistochemical analysis of gastrin-releasing peptide receptor (GRPR) and possible regulation by estrogen receptor betacx in human prostate carcinoma. AB - Gastrin-releasing peptide (GRP) belongs to the family of bombesin-like peptides. GRP was demonstrated to stimulate the proliferation and invasiveness of androgen independent prostate carcinoma. GRP mediates its action through the membrane bound receptor, GRP receptor (GRPR), which is characterized by a high-affinity binding for both GRP and bombesin. In human prostate cancer tissue, GRPR mRNA was reported to be detectable in more than 90% but its immunolocalizaition has not been reported. Therefore, in this study we immunolocalized GRPR in 51 human prostate cancer cases and correlated the findings with several clinicopathological parameters in order to better understand the function and regulation of GRPR in human prostate cancer. GRPR was immnolocalized in carcinoma cells and their values were significantly associated with Gleason score and immunoreactivity of estrogen receptor betacx (ERbetacx) that is one of splicing variants of ligand dependent transcription factor, ERbeta, and considered to be prognostic factor of prostate cancer patients. The amounts of GRPR and ERbetacx mRNA in three prostate cancer cell lines PC-3, DU-145 and LNCaP evaluated by quantitative RT-PCR (qPCR) analysis were also significantly correlated. In addition, we established stable transformants of prostate carcinoma cell line PC 3 introduced with ERbetacx, and confirmed that GRPR mRNA was induced in ERbetacx over-expressing PC-3 cells by qPCR analysis. These results also suggest that ERbetacx contributes to prostate cancer development possibly through mediating GRPR expression in carcinoma cells. PMID- 22248282 TI - Docetaxel and Cisplatin Plus Fluorouracil compared with Modified Docetaxel, Cisplatin, and 5-Fluorouracil as first-line therapy for advanced gastric cancer: a retrospective analysis of single institution. AB - Gastric cancer is the second most common among cancer-related deaths in the world. Systemic chemotherapy for patients with gastric cancer has limited impact on overall survival. We performed a retrospective analysis of the efficacy and side effects of Docetaxel and Cisplatin Plus Fluorouracil (DCF) versus Modified Dose Docetaxel, Cisplatin, and 5-Fluorouracil (mDCF) in the metastatic gastric cancer with first-line chemotherapy treated patients. Retrospectively were reviewed 107 locally advanced or metastatic gastric cancer patients who were treated DCF or mDCF as first-line treatment from June 2007 to August 2011 in Dicle University Hospital, Department of Medical Oncology.The DCF protocol included 75 mg/m2 docetaxel and cisplatin on day 1 and 750 mg/m2/day 5-FU infusion for 5 days, repeated every 3 weeks. The mDCF protocol included 60 mg/m2 docetaxel and cisplatin on day 1 and 600 mg/m2 5-Fluorouracil continuous infusion per day on days 1-5, every 3 weeks.Patients were treated using DCF arm 85 (M: 56, F: 29), the mDCF arm 22 (M: 13, F: 9) After treatment toxicities were: Grade III IV neutropenia (48.2% vs 13.6% p=0.003), anemia (21.2% vs 4.5% p=0.06), nausea (44.7% vs 13.6% p=0.008) and vomiting (31.8% vs 4.5%, p=0.01) was higher in the DCF arm. Other toxicities profile was similar in both groups (p>0.05). The rate of response was similar in both arm. Among patients with the DCF and mDCF arm rate complete response (10.3% vs 6.7%, p>0.05), partial response (35.3% vs 40.0%, p>0.05), stable disease (32.4% vs 33.3%, p>0.05), progressive disease (22.1% vs 20.0%, p>0.05) and overall response (45.6% vs 46.7%, p>0.05) did not have a statistically difference (p>0.05). Progression-free survival (PFS) and overall survival (OS) were more favorable in the DCF arm than mDCF arm, but the difference was not significant statistically (9.9 vs 8.6, 7.4 vs 6.5 p>0.05)In conclusion, the response rate, median PFS and median OS are similar in both arms, while the mDCF regimen are more favorable than the DCF for toxicity profile regimen in advanced gastric cancer patients who were undergoing first-line palliative treatment. Therefore, a prospective and larger clinical trials are needed. PMID- 22248283 TI - Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes. AB - Insulin signaling through insulin receptor (IR) and insulin receptor substrate-1 (IRS1) is important for insulin control of target cells. We have previously demonstrated a rapid and simultaneous overshoot behavior in the phosphorylation dynamics of IR and IRS1 in human adipocytes. Herein, we demonstrate that in murine adipocytes a similar overshoot behavior is not simultaneous for IR and IRS1. The peak of IRS1 phosphorylation, which is a direct consequence of the phosphorylation and the activation of IR, occurs earlier than the peak of IR phosphorylation. We used a conclusive modeling framework to unravel the mechanisms behind this counter-intuitive order of phosphorylation. Through a number of rejections, we demonstrate that two fundamentally different mechanisms may create the reversed order of peaks: (i) two pools of phosphorylated IR, where a large pool of internalized IR peaks late, but phosphorylation of IRS1 is governed by a small plasma membrane-localized pool of IR with an early peak, or (ii) inhibition of the IR-catalyzed phosphorylation of IRS1 by negative feedback. Although (i) may explain the reversed order, this two-pool hypothesis alone requires extensive internalization of IR, which is not supported by experimental data. However, with the additional assumption of limiting concentrations of IRS1, (i) can explain all data. Also, (ii) can explain all available data. Our findings illustrate how modeling can potentiate reasoning, to help draw nontrivial conclusions regarding competing mechanisms in signaling networks. Our work also reveals new differences between human and murine insulin signaling. PMID- 22248285 TI - Characterization of 3'-untranslated region of the mouse GDNF gene. AB - BACKGROUND: Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for many cell types, and its expression is widespread both within and outside of the nervous system. The regulation of GDNF expression has been extensively investigated but is not fully understood. RESULTS: Using a luciferase reporter assay, we identified the role of the 3'-untranslated region (3'-UTR) of the mouse GDNF gene in the regulation of gene expression. We focused on a well conserved A- and T-rich region (approximately 200 bp in length), which is located approximately 1000 bp downstream of the stop codon in exon 4 of the gene and contains three typical AU-rich elements (AREs), AUUUA. Interestingly, these AREs are well conserved in several GDNF genes. By testing reporter constructs containing various regions and lengths of the 3'-UTR fused to the end of the luciferase gene, we demonstrated that the ARE-induced decrease in luciferase activity correlates with the attenuation of the mRNA stability. Furthermore, we found that several regions around the AREs in the 3'-UTR suppressed the luciferase activity. Moreover, the expression level of the GDNF protein was negligible in C6 glioma cells transfected with the ARE-containing GDNF expression vector. CONCLUSIONS: Our study is the first characterization of the possible role of AREs and other suppressive regions in the 3'-UTR in regulating the amounts of GDNF mRNA in C6 cells. PMID- 22248286 TI - Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism. AB - AIM: Warfarin is a clinical anticoagulant that requires periodic monitoring because it is associated with adverse outcomes. Personalized medicine, which is based on pharmacogenetics, holds great promise in solving these types of problems. It aims to provide the tools and knowledge to tailor drug therapy to an individual patient, with the potential of increasing safety and efficacy of medications. MATERIALS & METHODS: In the present study we analyzed genotypes of 14 SNPs for seven genes using DNA from 297 Han Chinese venous thromboembolism patients treated with warfarin. RESULTS: Multiple regression analyses revealed that CYP2C9 genotype (p = 0.001), VKORC1 genotype (p < 0.001), age (p < 0.01) and weight (p < 0.001) were all associated with warfarin dose requirements, which can explain 37.4% of the variability of warfarin dose among Han Chinese patients. Meanwhile, in the validation cohort, the predicted warfarin daily dose was calculated using the best model with a 64.5% predicted dose being acceptable (-1 mg/day <=Deltawarfarin dose <=1 mg/day). CONCLUSION: We developed a pharmacogenetic dose algorithm for warfarin treatment that uses genotypes from two genes (VKORC1 and CYP2C9) and clinical variables to predict therapeutic maintenance doses in Chinese patients with venous thromboembolism. The validity of the dosing algorithm was confirmed in a cohort of venous thromboembolism patients on warfarin therapy. PMID- 22248284 TI - IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice. AB - BACKGROUND: Antibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis. RESULTS: The gamma3 genotype (+/+ vs. +/- vs. -/-) did not appear to significantly affect serum titers of IgG auto-antibodies specific for double-stranded DNA (dsDNA) or alpha-actinin. However, while substantial serum titers of IgG3 auto-antibodies specific for double-stranded DNA (dsDNA) or alpha-actinin were seen in gamma3 +/+ mice, somewhat lower serum titers of these IgG3 auto-antibodies were found in gamma3 +/- mice, and gamma3 -/- mice exhibited baseline concentrations of these auto-antibodies. Analysis of immunoglobulins eluted from snap-frozen kidneys obtained from mice of all three gamma3 genotypes at ~18 weeks of age revealed much higher quantities of IgG in the kidneys from gamma3 +/+ than gamma3 -/- mice, and most IgG eluted from +/+ mice was IgG3. The serum creatinine levels in gamma3 +/+ mice substantially exceeded those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lpr mice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85% of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis. CONCLUSIONS: The available evidence suggests that IgG3 deficiency partially protects MRL/lpr mice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the progression to glomerulosclerosis. PMID- 22248288 TI - Understanding the physical interactions in the FGF21/FGFR/beta-Klotho complex: structural requirements and implications in FGF21 signaling. AB - The endocrine fibroblast growth factor 21 (FGF21) requires both fibroblast growth factor receptor (FGFR) and beta-Klotho for signaling. In this study, we sought to understand the inter-molecular physical interactions in the FGF21/FGFR/beta Klotho complex by deleting key regions in FGFR1c or FGF21. Deletion of the D1 and the D1-D2 linker (the D1/linker region) from FGFR1c led to beta-Klotho independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region-deficient FGFR1c. Consistent with this, the extracellular portion of FGFR1c lacking the D1/linker region blocked FGF21 action in a reporter assay, presumably by binding to and sequestering FGF21 from acting on cell surface receptor complex. In addition, the D1/linker region-deficient FGFR1c had enhanced interaction with beta-Klotho. Further, we demonstrated that deletion of the D1/linker region enhanced the formation of the FGF21/beta-Klotho/FGFR1c ternary complex in both Biacore and asymmetrical flow field flow fractionation studies. Finally, we found that the N terminus of FGF21 is involved in the interaction with FGFR1c and FGF21/beta Klotho/FGFR1c ternary complex formation. Taken together, our data suggest that the D1/linker region regulates both the FGF21/FGFR1c and FGFR1c/beta-Klotho interaction, and a direct interaction of FGF21 with FGFR1c may be an important step in receptor-mediated FGF21 signaling. PMID- 22248290 TI - A coupled biventricular finite element and lumped-parameter circulatory system model of heart failure. AB - Numerical modelling of the cardiovascular system is becoming an important tool for assessing the influence of heart disease and treatment therapies. In the current study, we present an approach for modelling the interaction between the heart and the circulatory system. This was accomplished by creating animal specific biventricular finite element (FE) models, which characterise the mechanical response of the heart, and by coupling them to a lumped-parameter model that represents the systemic and pulmonic circulatory system. In order to minimise computation time, the coupling was enforced in a weak (one-way) manner, where the ventricular pressure-volume relationships were generated by the FE models and then passed into the circulatory system model to ensure volume conservation and physiological pressure changes. The models were first validated by tuning the parameters, such that the output of the models matched experimentally measured pressures and volumes. Then the models were used to examine cardiac function and the myofibre stress in a healthy canine heart and a canine heart with dilated cardiomyopathy. The results showed good agreement with experimental measurements. The stress in the case of cardiomyopathy was found to increase significantly, while the pump function was decreased, compared to the healthy case. The total runtime of the simulations is lesser than that of many fully coupled models presented in the literature. This will allow for a much quicker evaluation of possible treatment strategies for combating the effects of heart failure, especially in optimisation schemes that require numerous FE simulations. PMID- 22248291 TI - Analysis of repeated high-intensity running performance in professional soccer. AB - The aims of this study were twofold: (1) to characterize repeated high-intensity movement activity profiles of a professional soccer team in official match-play; and (2) to inform and verify the construct validity of tests commonly used to determine repeated-sprint ability in soccer by investigating the relationship between the results from a test of repeated-sprint ability and repeated high intensity performance in competition. High-intensity running performance (movement at velocities >19.8 km . h(-1) for a minimum of 1 s duration) was measured in 20 players using computerized time-motion analysis. Performance in 80 French League 1 matches was analysed. In addition, 12 of the 20 players performed a repeated-sprint test on a non-motorized treadmill consisting of six consecutive 6 s sprints separated by 20 s passive recovery intervals. In all players, most consecutive high-intensity actions in competition were performed after recovery durations >=61 s, recovery activity separating these efforts was generally active in nature with the major part of this spent walking, and players performed 1.1 +/ 1.1 repeated high-intensity bouts (a minimum of three consecutive high-intensity bouts with a mean recovery time <=20 s separating efforts) per game. Players reporting lowest performance decrements in the repeated-sprint ability test performed more high-intensity actions interspersed by short recovery times (<=20 s, P < 0.01 and <=30 s, P < 0.05) compared with those with higher decrements. Across positional roles, central-midfielders performed more high-intensity actions separated by short recovery times (<=20 s) and spent a larger proportion of time running at higher intensities during recovery periods, while fullbacks performed the most repeated high-intensity bouts (statistical differences across positional roles from P < 0.05 to P < 0.001). These findings have implications for repeated high-intensity testing and physical conditioning regimens. PMID- 22248292 TI - Mitochondrial electron transport chain deficiency, cardiomyopathy, and long-term cardiac transplant outcome. AB - Organ transplantation in multisystemic mitochondrial cytopathies is usually not performed because of perceived untoward complications. We report three patients with demonstrated oxidative phosphorylation defects and dilated cardiomyopathy who underwent cardiac transplant. All three patients tolerated immunosuppression medications and have had an excellent long-term outcome. Our results suggest that with proper patient selection in this population, cardiac transplantation is feasible and can have good outcomes. PMID- 22248293 TI - The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats. AB - Masculinization is programmed by androgen exposure during a masculinization programming window (MPW). Deficiency in MPW androgen action results in reduced size of all reproductive organs and anogenital distance (AGD) and reproductive disorders. Although timing of MPW closing has been defined, what determines 'opening' and 'closing' of the MPW remains unknown. To test whether initiation of testosterone production/action defines the opening of the window, we first demonstrated that androgen receptor mRNA and protein are expressed prior to the MPW, and then investigated whether masculinization could be advanced or enhanced by treating pregnant rats with either 1 or 10 mg/kg/day dihydrotestosterone (DHT) prior to (early window, EW; e11.5-e14.5) or during the MPW (e15.5-e18.5), and then evaluating offspring in foetal life (e18.5, e21.5), early puberty (day 25) or adulthood (~day 75). DHT treatment did not affect pregnancy duration, birth, litter or pup size. DHT exposure in either time window did not advance foetal male development (Wolffian duct coiling) and had no effect on AGD, testis, penis and ventral prostate (VP) size at any age when measured; there was a tendency towards smaller penis size. In contrast, exposure of females to 10 mg DHT in either time window induced varying degrees of masculinization, including stabilization of the Wolffian duct and increased AGD (e21.5, Pnd25), VP formation, more male-like phallus structure, absence of nipples and vaginal opening and, in some adult females, gross fluid distension of the uterus (hydrometrocolpos); these effects were generally more pronounced after exposure in the MPW than in the EW. In conclusion, exposure of the male rat foetus to additional androgens prior to or during the MPW does not advance or enhance any measured parameter of reproductive development. Therefore, androgen availability plays no role in determining timing of the MPW. Susceptibility of the female reproductive system to androgens may precede the MPW. PMID- 22248296 TI - Superior mesenteric artery syndrome following initiation of cisplatin-containing chemotherapy: a case report. AB - INTRODUCTION: Superior mesenteric artery syndrome is a rare cause of upper intestinal obstruction resulting from compression of the duodenum by the superior mesenteric artery and abdominal aorta. CASE PRESENTATION: We describe a case of superior mesenteric artery syndrome in a 61-year-old Japanese man with non-small cell lung cancer who had been treated with cisplatin-containing chemotherapy and had lost 7 kg in weight. The diagnosis was confirmed by the typical findings of abdominal computed tomography showing distended stomach resulting from compression of the third portion of the duodenum and reduction of an aortomesenteric distance and aortomesenteric angle. CONCLUSIONS: This case highlights the importance of considering the possibility of superior mesenteric artery syndrome in patients treated with chemotherapy, especially those presenting with a low body mass index and showing weight loss during chemotherapy. PMID- 22248294 TI - Year in review 2011: respiratory infections, tuberculosis, pleural diseases, bronchoscopic intervention and imaging. PMID- 22248297 TI - Antiwear performance and mechanism of an oil-miscible ionic liquid as a lubricant additive. AB - An ionic liquid (IL) trihexyltetradecylphosphonium bis(2-ethylhexyl) phosphate has been investigated as a potential antiwear lubricant additive. Unlike most other ILs that have very low solubility in nonpolar fluids, this IL is fully miscible with various hydrocarbon oils. In addition, it is thermally stable up to 347 degrees C, showed no corrosive attack to cast iron in an ambient environment, and has excellent wettability on solid surfaces (e.g., contact angle on cast iron <8 degrees ). Most importantly, this phosphonium-based IL has demonstrated effective antiscuffing and antiwear characteristics when blended with lubricating oils. For example, a 5 wt % addition into a synthetic base oil eliminated the scuffing failure experienced in neat oil and, as a result, reduced the friction coefficient by 60% and the wear rate by 3 orders of magnitude. A synergistic effect on wear protection was observed with the current antiwear additive when added into a fully formulated engine oil. Nanostructure examination and composition analysis revealed a tribo-boundary film and subsurface plastic deformation zone for the metallic surface lubricated by the IL-containing lubricants. This protective boundary film is believed to be responsible for the IL's antiscuffing and antiwear functionality. PMID- 22248298 TI - Glutamine and glutathione at ICU admission in relation to outcome. AB - Glutamine depletion is demonstrated to be an independent predictor of hospital mortality in ICU (intensive care unit) patients. Today glutamine supplementation is recommended to ICU patients on parenteral nutrition. In addition to glutamine, glutathione may be a limiting factor in ICU patients with MOF (multiple organ failure). To study the prevalence of glutamine and glutathione depletion an observational study was performed. The results were analysed in relation to mortality and the conventional predictors of mortality outcome, APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). Consecutive patients admitted to the ICU at Karolinska University Hospital Huddinge were studied. Patient admission scoring of APACHE II and SOFA were registered as well as mortality up to 6 months. Plasma glutamine concentration and whole blood glutathione status at admittance were analysed. The admission plasma glutamine concentrations were totally independent of the conventional risk scoring at admittance, and a subnormal concentration was an independent predictor of mortality. In addition, glutathione redox status was also an independent mortality predictor, but here a normal ratio was the risk factor. In both cases the mortality risk was mainly confined to the post-ICU period. A low plasma concentration of glutamine at ICU admission is an independent risk factor for post-ICU mortality. The possible benefit of extending glutamine supplementation post-ICU should be evaluated prospectively. PMID- 22248299 TI - Diabetes and its ocular complications: awareness among adults aged 40 years and older in Timor-Leste. AB - PURPOSE: The aim was to assess awareness of diabetes mellitus and its ocular complications among Timorese aged 40 years and older. METHODS: An interview-based questionnaire was administered to a subset of five urban and five rural clusters of 45 people aged 40 years and older as part of a population-based cross sectional survey. RESULTS: The participation rate was 96.2 per cent and data were analysed for 413 respondents. Correct nomination of at least one symptom, risk factor, prevention or treatment of diabetes was made by 6.1 per cent of participants. When explicitly asked, 6.8 per cent thought that diabetes caused problems with the body and 3.6 per cent thought diabetes caused eye problems. CONCLUSION: There is little awareness of diabetes and its ocular complications in Timor-Leste. Given the predicted urbanisation and economic development in the coming decades, as other health challenges are addressed and resources become available, consideration of diabetes might be prudent. Improving knowledge among the population will be an important component of any strategy developed. PMID- 22248300 TI - Is there a future for neuroprotective agents in acute ischaemic stroke? PMID- 22248301 TI - Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. AB - Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM. PMID- 22248302 TI - From the first selective non-peptide AT(2) receptor agonist to structurally related antagonists. AB - A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K(i) ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models. PMID- 22248303 TI - Immobilization-stabilization of proteins on nanofibrillated cellulose derivatives and their bioactive film formation. AB - In a number of different applications for enzymes and specific binding proteins a key technology is the immobilization of these proteins to different types of supports. In this work we describe a concept for protein immobilization that is based on nanofibrillated cellulose (NFC). NFC is a form of cellulose where fibers have been disintegrated into fibrils that are only a few nanometers in diameter and have a very large aspect ratio. Proteins were conjugated through three different strategies using amine, epoxy, and carboxylic acid functionalized NFC. The conjugation chemistries were chosen according to the reactive groups on the NFC derivatives; epoxy amination, heterobifunctional modification of amino groups, and EDC/s-NHS activation of carboxylic acid groups. The conjugation reactions were performed in solution and immobilization was performed by spin coating the protein-NCF conjugates. The structure of NFC was shown to be advantageous for both protein performance and stability. The use of NFC allows all covalent chemistry to be performed in solution, while the immobilization is achieved by a simple spin coating or spreading of the protein-NFC conjugates on a support. This allows more scalable methods and better control of conditions compared to the traditional methods that depend on surface reactions. PMID- 22248304 TI - An amperometric biosensor for fish freshness detection from xanthine oxidase immobilized in polypyrrole-polyvinylsulphonate film. AB - A new amperometric biosensor was developed for determining hypoxanthine in fish meat. Xanthine oxidase with pyrrole and polyvinylsulphonate was immobilized on the surface of a platinum electrode by electropolymerization. The determination of xanthine-hypoxanthine was performed by means of oxidation of uric acid liberated during the enzyme reaction on the surface of the enzyme electrode at + 0.30V (SCE). The effects of pH, substrate concentration, and temperature on the response of the xanthine-hypoxanthine biosensor were investigated. The linear working range of the enzyme electrode was 1.0 * 10(-7) -1.0 * 10(-3) M of the hypoxanthine concentration, and the detection limit was 1.0 * 10(-7)M. The apparent K(m(app)) and I(max) of the immobilized xanthine oxidase were found to be 0.0154 mM and 1.203 MUA/mM, respectively. The best pH and temperature value for xanthine oxidase were selected as 7.75 and 25 degrees C, respectively. The sensor was used for the determination of hypoxhantine in fish meat. Results show that the fish degraded very rapidly after seven days and the hypoxanthine amount was found to increase over days of storage. PMID- 22248305 TI - Pharmacokinetics of alteplase in the treatment of ischaemic stroke. AB - INTRODUCTION: Alteplase is the only approved drug for thrombolysis in acute ischaemic stroke (AIS) after its initial use in acute myocardial infarction (AMI). Its role in functional recovery is time-dependent while its major adverse effect, intracranial haemorrhage, is dose-dependent. These underline the importance of the pharmacokinetics of alteplase to its clinical use. AREAS COVERED: The authors discuss the pharmacology of alteplase with a major focus on its pharmacokinetics based on literature obtained from the OVID electronic database and other institutional resources. EXPERT OPINION: The pharmacokinetic profile of alteplase is almost entirely derived from studies in AMI. Differences in the pathophysiology of AMI and AIS mean it cannot be assumed that the pharmacokinetics of alteplase is similar in these two populations. During AMI, cardiac function and, hence, hepatic perfusion and clearance of alteplase may be impaired. The relatively older population in AIS may have impaired metabolic clearance which may increase plasma concentrations. The concurrent use of medications such as nitrates in the management of elevated blood pressure during AIS thrombolysis is also associated with reduced plasma concentrations of alteplase. Again, differences in clot size and type between AMI and AIS and between subtypes of AIS may influence response to alteplase. There is an inherently higher risk of intracranial haemorrhage in AIS compared to AMI emanating from cerebral infarction and BBB disruption. Accordingly, stroke specific pharmacokinetics of alteplase and its relationship to efficacy and safety outcomes are required. PMID- 22248306 TI - Preclinical in vivo ADME studies in drug development: a critical review. AB - INTRODUCTION: The last two decades have brought many fundamental changes to the drug development process. One such change is the importance of preclinical pharmacokinetics, which has become an essential part of early drug discovery. Furthermore, bioanalytical methods have become more sensitive and the identification and quantitation of metabolites can now be carried out on limited amount of biological material. There has also been a change in regulatory expectations, which are now particularly focused on the safety of human metabolites. AREAS COVERED: The focus of this paper is on some 'traditional' in vivo ADME studies: excretion balance, metabolic profile and WBA in the toxicological species. These studies, performed with radiolabeled material, have a long history: and are a regular presence in submission dossiers. This paper reviews their value in the perspective of the contemporary drug development process. EXPERT OPINION: These experiments may sometimes still be relevant to explain toxicological findings or for other special purposes but should not be considered required pieces of the registration dossiers. An appropriate investigation of samples coming from safety evaluation and human Phase I studies and the knowledge generated during the lead optimization phase provide, in most instances, all the DMPK information needed to take decisions in the drug development process. PMID- 22248307 TI - Mechanisms of cyst formation in metastatic lymph nodes of head and neck squamous cell carcinoma. AB - Cystic change in metastatic lymph nodes occurs in certain types of tumors and mostly in squamous cell carcinoma of the head and neck. In the majority of cases, psuedocystic change is the mechanism of cyst formation. However, sometimes a true cyst cavity is formed. This occurrence is unexplained and some theories are introduced to explain it. In this paper, related articles and introduced concepts are reviewed and the best conclusions of present hypotheses are provided. Cystic SCC in cervical lymph node is now considered as a typical presentation of metastatic SCC arising in the oro/nasopharynx. True cystic cavities have eosinophilic fluid content and present active transport mechanism across the epithelium; Cytokeratin7 is also expressed in the lining of these cysts, which is an accepted marker of ductal differentiation. These are all strong evidences that show salivary gland type cells are present among tumor cells. In fact, some squamous cell carcinomas, especially those arising in Waldeyer's ring, originate from minor salivary glands. The other probability is that these tumors are cancers of transitional type and arise from transformed keratinocytes, which have intrinsic property for cyst formation. These malignant cells in lymph nodes, rather than primary sites, found the opportunity to express their parental property. PMID- 22248308 TI - Filial ethics and judgments of filial behaviour in Taiwan and the United States. AB - Parent-child relationships are fundamental human relationships in which specific norms govern proper parent-child interactions. Such norms, or filial ethics, have been observed in different cultures, including in the United States and Taiwan, but important differences may exist in how filial practices are viewed across cultures. From a traditional view of power as domination over others, if filial relationships are viewed to reflect power differentials between parents and children, actors who follow filial ethics should be viewed as less powerful than actors who do not follow filial ethics for maintaining or enhancing positive parent-child relationships. Alternatively, power can be conceptualized as the ability to meet one's needs (e.g., for communal care and trust), and actors who follow filial ethics should be viewed as more powerful and trustworthy than actors who do not follow filial ethics because they have the ability to maintain or enhance positive parent-child relationships. Based on a power-trust model, we compared American and Taiwanese perceptions of actors in an experiment using vignettes describing filial behaviours. We conducted a path analysis with a sample of 112 American and 74 Taiwanese participants to test the proposed relations. Results showed that both Taiwanese and Americans rated actors more favourably (i.e., as more powerful and trustworthy) when actors behaved according to filial ethics than when they did not. Some cross-cultural differences were also observed: Taiwanese attributed trust-traits to actors who performed filial practices to a larger degree than did Americans. We discuss implications for the implicit nature of filial relationships and conceptualization of power cross culturally. PMID- 22248309 TI - Implications of intra-limb variability on asymmetry analyses. AB - The aim of this study was to investigate the effect of intra-limb variability on the calculation of asymmetry with the purpose of informing future analyses. Asymmetry has previously been quantified for discrete kinematic and kinetic variables; however, intra-limb variability has not been routinely included in these analyses. Synchronized lower-limb kinematic and kinetic data were collected from eight trained athletes (age 22 +/- 5 years, mass 74.0 +/- 8.7 kg, stature 1.79 +/- 0.07 m) during maximal velocity sprint running. Asymmetry was quantified using a modified version of the symmetry angle for selected kinematic and kinetic variables. Significant differences (P < 0.05) between left and right values for each variable were calculated to indicate intra-limb variability relative to between-limb differences. Significant asymmetry was present in only 39% of kinematic variables and 23% of kinetic variables analysed. Large kinetic asymmetry values (>90%) were calculated for some athletes that were not significant, due to large intra-limb variability. Variables that displayed significant asymmetry were athlete-specific. Findings highlight the potential for misleading results if intra-limb variability is not included in asymmetry analyses. The exclusion of asymmetry scores for variables not displaying significant asymmetry will be useful when calculating overall asymmetry for different participants and could be applied to future running gait analyses. PMID- 22248310 TI - The efficacy of maggot debridement therapy--a review of comparative clinical trials. AB - Over the last decade, maggot debridement therapy (MDT) has been recognized by many clinicians as a potential adjunct to conventional therapy, and many patients with non healing, chronic ulcers have been treated. Numerous case reports and case series have described the successful use of MDT in a variety of ulcers. However, comparative clinical trials and in particular randomized controlled trials investigating the efficacy of MDT are sparse. A systematic search in the literature showed three randomized clinical trials and five non randomized studies evaluating the efficacy of sterile Lucilia sericata applied on ulcers with various aetiologies. Of these, seven studies had debridement and/or healing as an outcome variable. When evaluating maggots as debriding agents, the studies report MDT as being significantly more effective than hydrogel or a mixture of conventional therapy modalities, including hydrocolloid, hydrogel and saline moistened gauze. However, the design of the studies was suboptimal, with important differences in the use of other therapies, such as compression, that may influence both debridement and healing between the compared groups, as well as inappropriately short follow-up times. The quality of the studies therefore makes it difficult to conclude that MDT shortens healing time. The poor quality of the data used for evaluating the efficacy of MDT highlights the need for more and better designed investigations. PMID- 22248312 TI - Special observation and older persons with dementia/delirium: a disappointing literature review. AB - BACKGROUND: In gerontological practice, special observation is a known nursing activity across different settings. The group that possibly are most effected by this intervention are older persons with dementia and/or delirium. The research literature about special observations in the mental health field is small, more disappointingly there appears to be little published literature about special observations in regard to older persons with dementia and/or delirium. AIMS: The aims of this study are to (i) establish the state of current published research on special observations in regard to older persons with dementia and/or delirium and (ii) make recommendations for research and practice. DESIGN AND METHOD: A literature review. RESULTS: Most literature pertains to adult mental health practice and services. Themes were generated and discussed in relation to gerontological practice. CONCLUSION: This review has established there is variance in the usage of the terms 'special observation' and 'constant observation'. It concludes that there is no published research on special or constant observations in relation to older people with dementia/delirium or the purpose of this activity. There is therefore a clear need to establish a research base in the topic. IMPLICATIONS FOR PRACTICE: Given the limited evidence, practitioners and managers need to be cautious when writing and implementing policies about special observation. However, until gerontological research is improved, research from mental health nursing will need to be drawn on with caution and the purpose of special observation determined locally. To be of therapeutic value and to be cost effective, special observation should be seen as a skilled nursing intervention and not a passive 'watching' or 'sitter' activity. PMID- 22248311 TI - Defects in leaf carbohydrate metabolism compromise acclimation to high light and lead to a high chlorophyll fluorescence phenotype in Arabidopsis thaliana. AB - BACKGROUND: We have studied the impact of carbohydrate-starvation on the acclimation response to high light using Arabidopsis thaliana double mutants strongly impaired in the day- and night path of photoassimilate export from the chloroplast. A complete knock-out mutant of the triose phosphate/phosphate translocator (TPT; tpt-2 mutant) was crossed to mutants defective in (i) starch biosynthesis (adg1-1, pgm1 and pgi1-1; knock-outs of ADP-glucose pyrophosphorylase, plastidial phosphoglucomutase and phosphoglucose isomerase) or (ii) starch mobilization (sex1-3, knock-out of glucan water dikinase) as well as in (iii) maltose export from the chloroplast (mex1-2). RESULTS: All double mutants were viable and indistinguishable from the wild type when grown under low light conditions, but--except for sex1-3/tpt-2--developed a high chlorophyll fluorescence (HCF) phenotype and growth retardation when grown in high light. Immunoblots of thylakoid proteins, Blue-Native gel electrophoresis and chlorophyll fluorescence emission analyses at 77 Kelvin with the adg1-1/tpt-2 double mutant revealed that HCF was linked to a specific decrease in plastome encoded core proteins of both photosystems (with the exception of the PSII component cytochrome b559), whereas nuclear-encoded antennae (LHCs) accumulated normally, but were predominantly not attached to their photosystems. Uncoupled antennae are the major cause for HCF of dark-adapted plants. Feeding of sucrose or glucose to high light-grown adg1-1/tpt-2 plants rescued the HCF- and growth phenotypes. Elevated sugar levels induce the expression of the glucose-6 phosphate/phosphate translocator2 (GPT2), which in principle could compensate for the deficiency in the TPT. A triple mutant with an additional defect in GPT2 (adg1-1/tpt-2/gpt2-1) exhibited an identical rescue of the HCF- and growth phenotype in response to sugar feeding as the adg1-1/tpt-2 double mutant, indicating that this rescue is independent from the sugar-triggered induction of GPT2. CONCLUSIONS: We propose that cytosolic carbohydrate availability modulates acclimation to high light in A. thaliana. It is conceivable that the strong relationship between the chloroplast and nucleus with respect to a co-ordinated expression of photosynthesis genes is modified in carbohydrate-starved plants. Hence carbohydrates may be considered as a novel component involved in chloroplast-to-nucleus retrograde signaling, an aspect that will be addressed in future studies. PMID- 22248314 TI - Indicators of self-rated health in the Canadian population with diabetes. AB - AIMS: Self-rated health is a widely used measure of general health assessing risk factors and poor health outcomes in health surveys and clinical settings. The characteristics of self-rated health may be different in populations with specific chronic conditions, such as populations with diabetes. This study investigates the characteristics of self-rated health in a Canadian community sample of people with diabetes. METHODS: Self-rated health was obtained from 1837 adults with Type 2 diabetes participating in the Montreal Diabetes Health and Well-Being Study. Global disability and depression were assessed using the World Health Organization Disability Assessment Schedule II and the Patient Health Questionnaire, respectively. Logistic regressions studied the association between self-rated health and depression, disability, diabetes-related characteristics, socio-demographic factors, social support and lifestyle-related behaviours in both men and women. RESULTS: Participants' answers were dichotomized into excellent/very good/ good (78%) and fair/poor (22%) self-rated health. Both depression (men: odds ratio 1.9, 95% CI 1.4-2.6; women: odds ratio 1.5, 95% CI 1.2-1.9) and disability (men: odds ratio 1.7, 95% CI 1.4-1.9; women: odds ratio 1.7, 95% CI 1.5-1.9) were associated with fair/poor self-rated health. The associations remained unchanged even after controlling for diabetes characteristics. After controlling for confounding variables, chronic conditions were associated with fair/poor self-rated health in both men and women. Obesity was associated with fair/poor self-rated health in women only, while lifestyle behaviours such as being physically active and alcohol consumption were associated with good/very good/excellent self-rated health in men. CONCLUSIONS: In men and women, depression and disability are important factors that are associated with self-rated health in a large sample of individuals with Type 2 diabetes. PMID- 22248316 TI - Recurrent subacute visual loss presenting in a 52-year-old Caucasian woman with chronic relapsing inflammatory optic neuropathy: a case report. AB - INTRODUCTION: Chronic relapsing inflammatory optic neuropathy is a recently described form of recurrent isolated subacute optic neuropathy. The condition is highly responsive to systemic steroid treatment and prone to relapse on steroid withdrawal. A complete work up for demyelination, autoimmune disease and sarcoidosis must be made before considering chronic relapsing inflammatory optic neuropathy. CASE PRESENTATION: We describe the case of a 52-year-old Caucasian woman who presented with isolated subacute optic neuropathy. There was no evidence of demyelination, autoimmunity or sarcoidosis. There was an abrupt and prompt response to systemic corticosteroids and a relapse of the condition on steroid withdrawal. CONCLUSIONS: Chronic relapsing inflammatory optic neuropathy requires careful consideration and differentiation from demyelinating optic neuritis and ischemic optic neuropathy since the treatment is different and the outcome without treatment is likely to be poor. The importance of identifying these patients has considerable clinical implications as the condition is highly responsive to steroids. PMID- 22248317 TI - Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism. AB - Patients with congenital hypogonadotropic hypogonadism (HH) may have reduced peak bone mass in early adulthood, and increased risk for osteoporosis despite long term hormonal replacement therapy (HRT). To investigate the relationship between HRT history and measures of bone health in patients with HH, we recruited 33 subjects (24 men, nine women; mean age 39.8 years, range: 24.0-69.1) with congenital HH (Kallmann syndrome or normosmic HH). They underwent clinical examination, were interviewed and medical charts were reviewed. Twenty-six subjects underwent dual-energy X-ray absorptiometry for evaluation of BMD of lumbar spine, hip, femoral neck and whole body; body composition and vertebral morphology were evaluated in 22 and 23 subjects, respectively. Circulating PINP, ICTP and sex hormone levels were measured. HRT history clearly associated to bone health: BMDs of lumbar spine, femoral neck, hip and whole body were lower in subjects (n = 9) who had had long (>=5 years) treatment pauses or low dose testosterone (T) treatment as compared to subjects without such history (n = 17; all p-values < 0.05). In addition, fat mass and body mass index (BMI) were significantly higher in men with deficient treatment history (median fat mass: 37.5 vs. 23.1%, p = 0.005; BMI: 32.6 vs. 25.2 kg/m(2), p < 0.05). Serum PINP correlated with ICTP (r(s) = 0.61; p < 0.005) in men, but these markers correlated neither with circulating T, nor with serum estradiol levels in women. In conclusion, patients with congenital HH require life-long follow-up to avoid inadequate HRT, long treatment pauses and further morbidity. PMID- 22248318 TI - Genotypes and serotype distribution of macrolide resistant invasive and non invasive Streptococcus pneumoniae isolates from Lebanon. AB - BACKGROUND: This study determined macrolide resistance genotypes in clinical isolates of Streptococcus pneumoniae from multiple medical centers in Lebanon and assessed the serotype distribution in relation to these mechanism(s) of resistance and the source of isolate recovery. METHODS: Forty four macrolide resistant and 21 macrolide susceptible S. pneumoniae clinical isolates were tested for antimicrobial susceptibility according to CLSI guidelines (2008) and underwent molecular characterization. Serotyping of these isolates was performed by Multiplex PCR-based serotype deduction using CDC protocols. PCR amplification of macrolide resistant erm (encoding methylase) and mef (encoding macrolide efflux pump protein) genes was carried out. RESULTS: Among 44 isolates resistant to erythromycin, 35 were resistant to penicillin and 18 to ceftriaxone. Examination of 44 macrolide resistant isolates by PCR showed that 16 isolates harbored the erm(B) gene, 8 isolates harbored the mef gene, and 14 isolates harbored both the erm(B) and mef genes. There was no amplification by PCR of the erm(B) or mef genes in 6 isolates. Seven different capsular serotypes 2, 9V/9A,12F, 14,19A, 19F, and 23, were detected by multiplex PCR serotype deduction in 35 of 44 macrolide resistant isolates, with 19F being the most prevalent serotype. With the exception of serotype 2, all serotypes were invasive. Isolates belonging to the invasive serotypes 14 and 19F harbored both erm(B) and mef genes. Nine of the 44 macrolide resistant isolates were non-serotypable by our protocols. CONCLUSION: Macrolide resistance in S. pneumoniae in Lebanon is mainly through target site modification but is also mediated through efflux pumps, with serotype 19F having dual resistance and being the most prevalent and invasive. PMID- 22248319 TI - Huntington's disease: advocacy driving science. AB - My mother, Leonore, was diagnosed with Huntington's disease (HD) in 1968 at age 53. I was 23, my sister Alice 26, and our father, Milton Wexler, 60 years old. The same year, our father created the Hereditary Disease Foundation (HDF), dedicated to finding treatments and cures for HD. HD is an autosomal dominant, neurodegenerative disorder. Alice and I each have a 50% chance of inheriting and dying from the disorder. Over the past 43 years, we have been proud to change the face of science. Through Milton Wexler Interdisciplinary Workshops, judicious funding, and focusing on innovation and creativity, the HDF is an integral partner in key discoveries. The HDF recruited and supported >100 scientists worldwide who worked together as the Huntington's Disease Collaborative Research Group in a successful ten-year search for the HD gene. We found a DNA marker for the HD gene in 1983-the first marker to be found when the chromosomal location was unknown. We isolated the HD gene itself a decade later. These breakthroughs helped launch the Human Genome Project. We supported creating the first mouse model of HD and many other model systems. Currently, we focus on gene silencing, among other approaches, to create new treatments and cures. PMID- 22248322 TI - Familial and acquired hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an uncontrolled and ineffective immune response, triggered in most cases by infectious agents, leads to severe hyperinflammation. Familial forms of HLH (FHL), which are increasingly found also in adolescents and adults, are due to genetic defects leading to impaired function of natural killer cells and cytotoxic T cells. These mutations occur either in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes, which induce apoptosis upon entering (infected) target cells. Additionally, perforin is important for the downregulation of the immune response. Acquired forms of HLH are encountered in association with (usually) viral infections, autoinflammatory/autoimmune diseases, malignant diseases, and acquired immune deficiency states (e.g., after organ transplantation). Treatment of HLH includes immune-suppressive and immune-modulatory agents, cytostatic drugs, and biological response modifiers. For patients with FHL, stem cell transplantation is indicated and can be curative. PMID- 22248320 TI - Human genome sequencing in health and disease. AB - Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges. PMID- 22248321 TI - Immunogenetics of spontaneous control of HIV. AB - Host genetic variation is presently estimated to account for about one-fourth of the observed differences in control of HIV across infected individuals. Genome wide association studies have confirmed that polymorphism within the HLA class I locus is the primary host genetic contributor to determining outcome after infection. Here we progress beyond the genetic associations alone to consider the functional explanations for these correlations. In this process, the complex and multidimensional effects of HLA molecules in viral disease become apparent. PMID- 22248323 TI - Carotid stenting versus endarterectomy. AB - Since the landmark NASCET and ECST trials demonstrated the superiority of carotid endarterectomy over medical therapy in the prevention of stroke for patients with symptomatic carotid artery stenosis, surgical intervention as a part of secondary prevention of stroke has become widespread. However, the newer technology of carotid artery angioplasty and stenting challenges this mode of intervention, promising the benefits of a procedure under local anesthesia and potentially avoiding the surgical complications of cranial nerve palsy and hematoma. Pooled evidence from randomized controlled trials of endarterectomy versus stenting shows a higher rate of stroke or death in the stenting groups-but this finding is mitigated to an extent by the lower incidence of myocardial infarction and cranial nerve palsy in patients undergoing stenting. At present, carotid endarterectomy combined with optimal drug therapy remains the standard of care for symptomatic 70%-99% stenosis of the internal carotid artery, but stenting might be an option in younger patients and in those not suitable for endarterectomy. PMID- 22248324 TI - Mitral valve prolapse. AB - Mitral valve prolapse is defined as abnormal bulging of the mitral valve leaflets into the left atrium during ventricular systole. Mitral valve prolapse is a common condition that is a risk factor for mitral regurgitation, congestive heart failure, arrhythmia, and endocarditis. Myxomatous degeneration is the most common cause of mitral prolapse in the United States and Europe, and progression of myxomatous mitral prolapse is the most common cause of mitral regurgitation that requires surgical treatment. Myxomatous degeneration appears to have genetic etiology. The genetics of myxomatous degeneration is complex and not fully worked out; it appears to be heterogeneous with multi-gene, multi-chromosomal autosomal dominance with incomplete penetrance. The molecular disorder of myxomatous degeneration appears to consist of a connective tissue disorder with altered extracellular matrix status and involves the action of matrix metalloproteinase, cysteine endoproteases, and tenomodulin. Treatment of mitral prolapse with regurgitation is complex, and the technological advances that are currently in development will be challenging and controversial. PMID- 22248327 TI - Traumatic brain injury and its neuropsychiatric sequelae in war veterans. AB - The post-September 11, 2001 wars in and around Afghanistan and Iraq have increased awareness of traumatic brain injury (TBI), particularly blast-induced mild TBI. This article provides an overview of TBI and its neuropsychiatric sequelae in U.S. war veterans who participated in the current operations in and around Afghanistan and Iraq, with particular emphasis on blast-related mild TBI. Psychiatric disorders, particularly posttraumatic stress disorder, pain, and sensory impairments are prevalent in war veterans with TBI. Research is needed to more definitively characterize the epidemiology of TBI-related functional difficulties, the effects of blasts compared with other mechanisms of injury, recovery trajectories, and treatment outcomes in this population. PMID- 22248326 TI - Role of endoplasmic reticulum stress in metabolic disease and other disorders. AB - Perturbations in the normal functions of the endoplasmic reticulum (ER) trigger a signaling network that coordinates adaptive and apoptotic responses. There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer. With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress. PMID- 22248325 TI - Aquaporins in clinical medicine. AB - The aquaporins are a family of membrane water channels, some of which also transport glycerol. They are involved in a wide range of physiological functions (including water/salt homeostasis, exocrine fluid secretion, and epidermal hydration) and human diseases (including glaucoma, cancer, epilepsy, and obesity). At the cellular level, aquaporin-mediated osmotic water transport across cell plasma membranes facilitates transepithelial fluid transport, cell migration, and neuroexcitation; aquaporin-mediated glycerol transport regulates cell proliferation, adipocyte metabolism, and epidermal water retention. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and congenital cataracts. The neuroinflammatory demyelinating disease neuromyelitis optica is marked by pathogenic autoantibodies against astrocyte water channel aquaporin-4. There remain broad opportunities for the development of aquaporin-based diagnostics and therapeutics. Disease-relevant aquaporin polymorphisms are beginning to be explored. There is great promise in the development of small-molecule aquaporin modulators for therapy of some types of refractory edema, brain swelling, neuroinflammation, glaucoma, epilepsy, cancer, pain, and obesity. PMID- 22248328 TI - Magnetic resonance imaging abnormalities in children with epilepsy. AB - BACKGROUND AND PURPOSE: The aim of this study is to analyze the proportional distribution of epilepsy and epileptic syndromes in children and to describe the magnetic resonance imaging (MRI) abnormalities found in these patients. METHODS: Data from 457 children aged 1 month to 15 years at the time of diagnosis of epilepsy were recorded. A routine MRI has been requested in all patients with epilepsy at diagnosis according to a standardized pediatric seizure protocol. Abnormalities on MRI were classified as either significant or non-significant (standardized scoring system). International League Against Epilepsy criteria were used for diagnoses. RESULTS: The prevalence of significant MRI abnormalities was 21.9% (in infants 42.3%, in childhood 18.2%, and in adolescents 15.9%). The most common abnormalities included white-matter lesions (27.6%), volume loss (19.6%), gray-matter lesions (19.6%), and ventricular enlargement (12%). CONCLUSIONS: The use of MRI and a reliable standardized scoring system at diagnosis of epilepsy in children identified a high rate of significant abnormalities findings. This may have important implications for practice guidelines in this population. PMID- 22248329 TI - Association of exposure to environmental tobacco smoke in childhood with chronic obstructive pulmonary disease and respiratory symptoms in adults. AB - BACKGROUND AND OBJECTIVE: Exposure to environmental tobacco smoke (ETS) is associated with impaired lung function in childhood, which in turn, is associated with chronic obstructive pulmonary disease (COPD) in adulthood. However, little is known regarding the direct association between childhood exposure to ETS and the development of COPD. The main objective of the present study was to examine the associations between childhood ETS exposure and adult COPD and respiratory symptoms. METHODS: Patients with COPD (n = 433) and control subjects (n = 325) participated in the Bergen COPD Cohort Study during 2006-2009. Participants performed spirometry and answered extensive questionnaires. The risk factors for COPD, morning cough, cough with phlegm, chronic cough and dyspnoea were examined using logistic regression analysis. Analyses were stratified by gender. RESULTS: The prevalence of childhood exposure to ETS was 61%. After adjustment, women who were exposed to ETS during childhood had a higher risk of COPD than those who were not exposed: odds ratio 1.9, 95% confidence interval 1.0, 3.7. Other important predictors for COPD and respiratory symptoms among women were occupational dust exposure (COPD), family history of COPD (COPD, all symptoms), current exposure to ETS in the home (morning cough) and education (COPD, dyspnoea). ETS exposure during childhood was associated with respiratory symptoms among males (odds ratios 1.5-1.7). Risk factors for COPD among men were occupational dust exposure, family history of COPD and level of education. Occupational dust exposure and family history of COPD also predicted dyspnoea among males. CONCLUSIONS: Exposure to ETS during childhood was associated with COPD and respiratory symptoms in adulthood. Although active smoking is still the most important risk factor for COPD, reduction of childhood ETS exposure could contribute to the prevention of COPD and respiratory symptoms. PMID- 22248330 TI - Effect of Ramadan fasting in tropical summer months on ocular refractive and biometric characteristics. AB - BACKGROUND: Islamic Ramadan is the month of fasting, in which intake of food and drink is restricted from sunrise until sunset. The objective of the present study was to find out the effect of altered eating habits during Ramadan fasting on ocular refractive and biometric properties. METHODS: In this prospective case series, 40 eyes of 22 healthy volunteers with a mean age of 60.55 +/- 12.20 years were enrolled. Patients with any systemic disorder and eyes with pathology or previous surgery were excluded. One month before Ramadan (at 8.00 am), during Ramadan fasting (at 8.00 am and 4.00 pm) and one month later during the non fasting period (at 8.00 am), ocular refractive and biometric characteristics were measured using an autokeratorefractometer (Auto-Kerato-Refractometer KR-8900; Topcon Co, Tokyo, Japan) and contact ultrasonic biometry (Nidek Echoscan US 800; Nidek Co, Tokyo, Japan). RESULTS: Anterior chamber depth was significantly increased during fasting compared with baseline measurements and returned to baseline one month after Ramadan (3.22 +/- 0.07 mm and 4.33 +/- 0.17 mm for non fasting and fasting, respectively; p < 0.001). The anterior chamber depth measurements were significantly larger at 8.00 am during fasting compared with 4.00 pm (p = 0.01). Axial length was significantly decreased during fasting and returned to baseline one month after Ramadan (23.09 +/- 0.14 mm and 22.65 +/- 0.18 mm, for non-fasting and fasting, respectively; p < 0.001). Intraocular lens power calculations were significantly increased during fasting and returned to baseline one month after Ramadan (SRK-T formula: 21.46 +/- 0.27 D and 22.92 +/- 0.46 D, for non-fasting and fasting, respectively; p < 0.001). There were no significant differences in spherical equivalent, corneal astigmatism, mean keratometry and flatter and steeper corneal radii of curvature between time intervals. CONCLUSIONS: Ramadan fasting is associated with statistically significant alterations in anterior chamber depth and axial length that result in both statistically and clinically significant changes in intraocular lens power calculations. Therefore, relying on measurements taken during this month might lead to refractive errors after cataract surgery. PMID- 22248332 TI - Linkages to care for newly diagnosed individuals who test HIV positive in nonprimary care settings. AB - Linkage services are an increasingly important component of the continuum of care for people living with HIV, particularly for individuals diagnosed in nonprimary care settings who are less likely than those identified in primary care settings to have a usual source of care. This study examines successful models used by hospital emergency departments, health department outpatient clinics, and other nonprimary care providers for testing, linking, and engaging newly diagnosed HIV positive racial and ethnic minorities into medical care. Based on studies of five mature linkage-to-care (LTC) programs implemented in geographically and institutionally diverse settings, we identify five key characteristics that make them viable. Effective linkage programs are low cost, intensive, time limited, unique, and flexible. We also identify four core components of successful LTC protocols: directly employed linkage workers, active referral to medical care, person-centered linkage case management, and cultural and linguistic concordance. Finally, we develop a set of operational strategies to help providers address barriers at all levels of the health care system to help promote the effective linkage of newly diagnosed patients to care. We organize the strategies around four key areas: adherence to LTC protocols, selection of linkage workers, execution of linkage programs, and sustainability of linkage programs. The findings presented in this study provide a practical and operational guide for developing and implementing policies and procedures for linking newly diagnosed individuals who test HIV positive in nonprimary care settings into ongoing care for HIV infection. PMID- 22248331 TI - Development and pilot testing of a standardized training program for a patient mentoring intervention to increase adherence to outpatient HIV care. AB - Although peer interventionists have been successful in medication treatment adherence interventions, their role in complex behavior-change approaches to promote entry and reentry into HIV care requires further investigation. The current study sought to describe and test the feasibility of a standardized peer mentor training program used for MAPPS (Mentor Approach for Promoting Patient Self-Care), a study designed to increase engagement and attendance at HIV outpatient visits among high-risk HIV inpatients using HIV-positive peer interventionists to deliver a comprehensive behavioral change intervention. Development of MAPPS and its corresponding training program included collaborations with mentors from a standing outpatient mentor program. The final training program included (1) a half-day workshop; (2) practice role-plays; and (3) formal, standardized patient role-plays, using trained actors with "real time" video observation (and ratings from trainers). Mentor training occurred over a 6-week period and required demonstration of adherence and skill, as rated by MAPPS trainers. Although time intensive, ultimate certification of mentors suggested the program was both feasible and effective. Survey data indicated mentors thought highly of the training program, while objective rating data from trainers indicated mentors were able to understand and display standards associated with intervention fidelity. Data from the MAPPS training program provide preliminary evidence that peer mentors can be trained to levels necessary to ensure intervention fidelity, even within moderately complex behavioral-change interventions. Although additional research is needed due to limitations of the current study (e.g., limited generalizability due to sample size and limited breadth of clinical training opportunities), data from the current trial suggest that training programs such as MAPPS appear both feasible and effective. PMID- 22248334 TI - HIV symptom distress and anxiety sensitivity in relation to panic, social anxiety, and depression symptoms among HIV-positive adults. AB - Although past work has documented relations between HIV/AIDS and negative affective symptoms and disorders, empirical work has only just begun to address explanatory processes that may underlie these associations. The current investigation sought to test the main and interactive effects of HIV symptom distress and anxiety sensitivity in relation to symptoms of panic disorder (PD), social anxiety disorder (SA), and depression among people with HIV/AIDS. Participants were 164 adults with HIV/AIDS (17.1% women; mean age, 48.40) recruited from AIDS service organizations (ASOs) in Vermont/New Hampshire and New York City. The sample identified as 40.9% white/Caucasian, 31.1% black, 22.0% Hispanic, and 6.1% mixed/other; with more than half (56.7%) reporting an annual income less than or equal to $10,000. Both men and women reported unprotected sex with men as the primary route of HIV transmission (64.4% and 50%, respectively). HIV symptom distress and anxiety sensitivity (AS) were significantly positively related to PD, SA, and depression symptoms. As predicted, there was a significant interaction between HIV symptom distress and anxiety sensitivity in terms of PD and SA symptoms, but not depressive symptoms. Results suggest that anxiety sensitivity and HIV symptom distress are clinically relevant factors to consider in terms of anxiety and depression among people living with HIV/AIDS. It may be important to evaluate these factors among patients with HIV/AIDS to identify individuals who may be at a particularly high risk for anxiety and depression problems. Limitations included recruitment from ASOs, cross-sectional self-report data, and lack of a clinical diagnostic assessment. PMID- 22248333 TI - Behavioral and serologic survey of men who have sex with men in Beijing, China: implication for HIV intervention. AB - We assessed HIV prevalence and associated behaviors and risk factors among men who have sex with men (MSM) in Beijing, China. Five hundred MSM were recruited for a biological and behavioral survey using respondent-driven sampling (RDS) in 2009. Serologic specimens were tested for markers of HIV and syphilis infection. A computer-assisted personal interview (CAPI) administered questionnaire gathered information including demographic characteristics, sexual behaviors, HIV testing, and social norms concerning condom use. The adjusted HIV prevalence was 8.0%, syphilis 22.0%. HIV testing and disclosure was low; only 39.3% had HIV tested in the past 12 months, 49.7% knew their own HIV status and 22.8% knew their last male partner's HIV status. HIV infection was associated with syphilis, ever having sex with a woman, not knowing the HIV status of the most recent male partner, and never buying condoms in the past 12 months. Stronger endorsement of positive social norms around condom use strongly and predicted lower prevalence of HIV infection. Compared to surveys of similar design in the recent past, HIV continues to spread rapidly among Beijing's MSM. Our results identify points of intervention that, if addressed in time, may still alter the course of the epidemic including the promotion of HIV testing and partner disclosure, syphilis control and particularly changing social norms around condom use. PMID- 22248336 TI - Validity of a point-of-care based on heterophile antibody detection for the diagnosis of infectious mononucleosis in primary care. AB - OBJECTIVE: To evaluate the validity of a point-of-care test to diagnose infectious mononucleosis (IM) compared with Epstein-Barr virus (EBV) specific serology. METHODS: Patients over 14 years with sore throat and four Centor criteria--tonsillar exudate, fever, lymph glands tenderness and absence of cough- and negative pharyngeal testing for group A beta-haemolytic streptococcal antigen were consecutively recruited. All patients underwent pharyngotonsillar swab for microbiological culture, the rapid OSOM MonoTest for the diagnosis of IM in whole blood, the Paul-Bunnell test and complete blood analysis with serology for EBV and cytomegalovirus the day after the visit and at 15 days. Sensitivity and specificity were determined. RESULTS: We included 145 patients with a mean age of 24 +/- 6.8 years. Of these, serology was determined in 129 subjects, with IM being diagnosed in 14 (10.9%). Both the MonoTest and the Paul-Bunnell test were positive in 13 patients with IM (92.9%) with no patient without disease being positive for either test--sensitivity of 92.9% (95% CI: 64.2-99.6%) and specificity of 100% (95% CI: 96-100%). The culture showed streptococcus A infection in 1 case (0.7%) and streptococcus C in 62 cases (42.8%). A total of 78 patients presented past infection by EBV (60.5%). CONCLUSIONS: Only one out of 10 patients with sore throat, four Centor criteria and negative rapid test for streptococcal infection presents IM. Despite the MonoTest presenting optimum sensitivity and specificity, it was found to have the same validity as the Paul Bunnell test, with serological study continuing to be necessary for precise diagnosis of IM. PMID- 22248337 TI - A critical review of modern and emerging absorbent dressings used to treat exuding wounds. AB - Wound management has progressed significantly over the last five decades. This emanates from a greater understanding of wound healing, technological progression and improved clinical and scientific research. There are currently a plethora of absorbent dressings on the wound care market which claim to have the ability to manage exudates whilst encouraging healing. However, it is becoming clear, from analysing randomised controlled trials, that some of these absorbent dressings are not meeting their expectations when applied in a clinical setting. Many clinicians now feel that there should be more focus, not only on a dressing's ability to manage exudate efficiently, but on a dressing's ability to proactively encourage healing and thus exudate reduction will ensue. This paper proposes to critically review modern and emerging absorbent wound care dressings used to manage exuding wounds and discuses some advances in this area. PMID- 22248341 TI - The use of ELISAs for monitoring exposure of pig herds to Brachyspira hyodysenteriae. AB - BACKGROUND: Swine dysentery (SD), a mucohaemorrhagic diarrhoeal disease of pigs, results from infection of the large intestine with the spirochaete Brachyspira hyodysenteriae. ELISA systems using whole spirochaete cells (WC) and the B. hyodysenteriae outer membrane lipoprotein Bhlp29.7 previously have been established as potential diagnostic tools for SD. However, their true value in identifying infected herds remains unclear. The present study aimed to compare the performance of whole-cell and Bhlp29.7 based ELISAs in detecting specific immunoglobulin class IgG and IgM to B. hyodysenteriae in growing pigs, and additionally evaluated whether meat juice could serve as a source of specific antibodies. RESULTS: Levels of circulating IgG and IgM reacting with WC spirochaete preparations and recombinant Bhlp29.7 peaked 4-6 weeks post-infection in the experimentally challenged pigs, and remained elevated in the present study. In a cohort of pigs on an infected farm levels of antibody directed against both antigens showed a progressive increase with time. However, other than for the level of IgG against WC antigen, a significant increase in antibody levels also was observed in a cohort of pigs on a non-infected farm. In addition, assays using meat juice had 100% specificity and equivalent sensitivity to those based on serum, and likewise the best performance was achieved using the WC IgG ELISA. CONCLUSIONS: IgG ELISAs using either WC or Bhlp29.7 as plate-coating antigens were shown to be useful for monitoring the dynamics of B. hyodysenteriae infection in grower pigs. Of the two antigens, the WC preparation tended to give better discrimination between pigs from infected and non-infected farms. Testing of meat juice was shown to have potential for identifying infected herds. PMID- 22248339 TI - Ceramide synthases at the centre of sphingolipid metabolism and biology. AB - Sphingolipid metabolism in metazoan cells consists of a complex interconnected web of numerous enzymes, metabolites and modes of regulation. At the centre of sphingolipid metabolism reside CerSs (ceramide synthases), a group of enzymes that catalyse the formation of ceramides from sphingoid base and acyl-CoA substrates. From a metabolic perspective, these enzymes occupy a unique niche in that they simultaneously regulate de novo sphingolipid synthesis and the recycling of free sphingosine produced from the degradation of pre-formed sphingolipids (salvage pathway). Six mammalian CerSs (CerS1-CerS6) have been identified. Unique characteristics have been described for each of these enzymes, but perhaps the most notable is the ability of individual CerS isoforms to produce ceramides with characteristic acyl-chain distributions. Through this control of acyl-chain length and perhaps in a compartment-specific manner, CerSs appear to regulate multiple aspects of sphingolipid-mediated cell and organismal biology. In the present review, we discuss the function of CerSs as critical regulators of sphingolipid metabolism, highlight their unique characteristics and explore the emerging roles of CerSs in regulating programmed cell death, cancer and many other aspects of biology. PMID- 22248342 TI - Music preferences and personality among Japanese university students. AB - Little research has been conducted outside of the European-North American cultural area concerning the personality-based determinants of musical genre preferences The present research investigated the personality profiles and general music genre preferences of 268 Japanese college students. Six dimensions and 24 facets of personality, and 12 music genres, were assessed. Results indicated that, consistent with much previous research, openness (to experience) and particularly the facet of "aesthetic appreciation" were associated with a preference for "reflective" music (jazz, classical, opera, gospel, enka), while one extraversion facet (sociability) was associated with the preference for pop music. Other personality dimensions were less consistently associated with musical preferences, pointing to cultural differences and the need to assess both personality and music genres at more specific levels. PMID- 22248343 TI - Pharmacokinetic evaluation of axitinib. AB - INTRODUCTION: The role of angiogenic inhibitors is clearly established in the treatment of diverse malignancies. The field of antiangiogenesis is expanding rapidly, with an increasing number of agents currently approved by the FDA. Axitinib is a vascular endothelial growth factor receptor (VEGFR)-specific inhibitor currently being developed for the treatment of various malignancies. The pharmacokinetic (PK) properties of axitinib may provide a selective treatment effect while minimizing adverse reactions and enhancing safety. It is paramount that health-care providers understand the properties and nuances of each agent inclusive of PK variability in the patient population as well as current safety and tolerability data. AREAS COVERED: This article provides a comprehensive and critical review of the PK properties of axitinib as they relate to safety and tolerability, as well as potential pharmacodynamic and efficacy parameters. EXPERT OPINION: Axitinib is a unique VEGFR tyrosine kinase inhibitor (TKI), which acts through greater receptor specificity compared with many other VEGFR TKIs. An understanding of axitinib's PK characteristics and common adverse events may allow for a tailored dosing approach in patients with cancer, in an attempt to maximize efficacy while minimizing toxicity. PMID- 22248344 TI - Incretin based therapies: do they hold their promise? PMID- 22248338 TI - Glycogen and its metabolism: some new developments and old themes. AB - Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease. PMID- 22248346 TI - MWCNTs/P(St-co-GMA) composite nanofibers of engineered interface chemistry for epoxy matrix nanocomposites. AB - Strengthened nanofiber-reinforced epoxy matrix composites are demonstrated by engineering composite electrospun fibers of multi-walled carbon nanotubes (MWCNTs) and reactive P(St-co-GMA). MWCNTs are incorporated into surface modified, reactive P(St-co-GMA) nanofibers by electrospinning; functionalization of these MWCNT/P(St-co-GMA) composite nanofibers with epoxide moieties facilitates bonding at the interface of the cross-linked fibers and the epoxy matrix, effectively reinforcing and toughening the epoxy resin. Rheological properties are determined and thermodynamic stabilization is demonstrated for MWCNTs in the P(St-co-GMA)-DMF polymer solution. Homogeneity and uniformity of the fiber formation within the electrospun mats are achieved at polymer concentration of 30 wt %. Results show that the MWCNT fraction decreases the polymer solution viscosity, yielding a narrower fiber diameter. The fiber diameter drops from an average of 630 nm to 460 nm, as the MWCNTs wt fraction (1, 1.5, and 2%) is increased. The electrospun nanofibers of the MWCNTs/P(St-co-GMA) composite are also embedded into an epoxy resin to investigate their reinforcing abilities. A significant increase in the mechanical response is observed, up to >20% in flexural modulus, when compared to neat epoxy, despite a very low composite fiber weight fraction (at about 0.2% by a single-layer fibrous mat). The increase is attributed to the combined effect of the two factors the inherent strength of the well-dispersed MWCNTs and the surface chemistry of the electrospun fibers that have been modified with epoxide to enable cross-linking between the polymer matrix and the nanofibers. PMID- 22248345 TI - Contribution of phosphates and adenine to the potency of adenophostins at the IP3 receptor: synthesis of all possible bisphosphates of adenophostin A. AB - Although adenophostin A (AdA), the most potent agonist of d-myo-inositol 1,4,5 trisphosphate receptors (IP(3)R), is thought to mimic IP(3), the relative roles of the different phosphate groups and the adenosine motif have not been established. We synthesized all three possible bisphosphate analogues of AdA and glucose 3,4-bisphosphate (7, AdA lacking the 2'-AMP). 2'-Dephospho-AdA (6) was prepared via a novel regioselective dephosphorylation strategy. Assessment of the abilities of these bisphosphates to stimulate intracellular Ca(2+) release using recombinant rat type 1 IP(3)R (IP(3)R1) revealed that 6, a mimic of Ins(4,5)P(2), is only 4-fold less potent than IP(3), while 7 is some 400-fold weaker and even 3"-dephospho-AdA (5) is measurably active, despite missing one of the vicinal bisphosphate groups normally thought to be crucial for IP(3)-like activity. Compound 6 is the most potent bisphosphate yet discovered with activity at IP(3)R. Thus, adenosine has a direct role independent of the 2'-phosphate group in contributing toward the potency of adenophostins, the vicinal bisphosphate motif is not essential for activity at the IP(3)R, as always thought, and it is possible to design potent agonists with just two of the three phosphates. A model with a possible adenine-R504 interaction supports the activity of 5 and 6 and also allows a reappraisal of the unexpected activity previously reported for the AdA regioisomer 2"-phospho-3"-dephospho-AdA 40. PMID- 22248347 TI - Myoid hamartoma of the breast that proved difficult to diagnose: a case report. AB - Myoid hamartomas of the breast are extremely rare breast lesions, with a poorly understood pathogenesis. We describe the case of a 38-year-old premenopausal woman who presenting with a mass in the left breast. Mammography revealed an oval mass that was partly indistinct, and ultrasonography showed a hypoechoic mass with a slightly irregular margin. Bilateral breast dynamic magnetic resonance imaging was performed for a more detailed evaluation. The images showed rapid initial enhancement and a microlobulated margin. Because the suspicion of malignancy was strong at that time, core needle biopsy was performed. Histologically, the tumor was identified as fibroadenoma. A case of myoid hamartoma of the breast that proved difficult to diagnose is reported, and discussed with reference to the literature. PMID- 22248348 TI - Epilepsy associated with glutamic acid decarboxylase antibody (GADA). PMID- 22248349 TI - Haemoglobin A1c cut-off point to identify a high risk group of future diabetes: results from the Omiya MA Cohort Study. AB - AIMS: Using the HbA(1c) level to define diabetes has several advantages and these advantages also apply to define a high-risk group. However, the risk of diabetes increases as HbA(1c) increases and a certain degree of arbitrariness in the cut off for the high risk group is unavoidable. The aim of this study was to determine the HbA(1c) cut-off for defining a high-risk group that corresponds to the fasting plasma glucose cut-off by comparing the risk of diabetes against the fasting plasma glucose and HbA(1c) levels in the Japanese population. METHODS: A retrospective cohort study was conducted using data from annual health examinations performed in Omiya city. A total of 11,271 subjects between the ages of 40 and 79 years without diabetes at baseline were followed for up to 7 years. According to the new diagnostic criteria, diabetes was defined as an fasting plasma glucose level >= 7 mmol/l or an HbA(1c) level >= 48 mmol/mol (>= 6.5%) or a self-report. The HbA(1c) cut-off corresponding to the fasting plasma glucose cut-off was determined using the incidence, hazard ratio, and a receiver operating characteristic analysis. RESULTS: Eight hundred and sixty subjects developed diabetes. The incidence, hazard ratio, and receiver operating characteristic analysis all indicated that an HbA(1c) cut-off of 39 mmol/mol (5.7%) corresponded to an fasting plasma glucose level of 5.6 mmol/l. CONCLUSIONS: Our results suggested that the HbA(1c) cut-off for high-risk of diabetes should be 39 mmol/mol (5.7%), consistent with the American Diabetes Association recommendation. Further research is needed to determine whether our results are applicable to other populations. PMID- 22248350 TI - Gene therapy for Fanconi anemia: one step closer to the clinic. PMID- 22248351 TI - Spectral Karyotyping for identification of constitutional chromosomal abnormalities at a national reference laboratory. AB - Spectral karyotyping is a diagnostic tool that allows visualization of chromosomes in different colors using the FISH technology and a spectral imaging system. To assess the value of spectral karyotyping analysis for identifying constitutional supernumerary marker chromosomes or derivative chromosomes at a national reference laboratory, we reviewed the results of 179 consecutive clinical samples (31 prenatal and 148 postnatal) submitted for spectral karyotyping. Over 90% of the cases were requested to identify either small supernumerary marker chromosomes (sSMCs) or chromosomal exchange material detected by G-banded chromosome analysis. We also reviewed clinical indications of those cases with marker chromosomes in which chromosomal origin was identified by spectral karyotyping. Our results showed that spectral karyotyping identified the chromosomal origin of marker chromosomes or the source of derivative chromosomal material in 158 (88%) of the 179 clinical cases; the identification rate was slightly higher for postnatal (89%) compared to prenatal (84%) cases. Cases in which the origin could not be identified had either a small marker chromosome present at a very low level of mosaicism (< 10%), or contained very little euchromatic material. Supplemental FISH analysis confirmed the spectral karyotyping results in all 158 cases. Clinical indications for prenatal cases were mainly for marker identification after amniocentesis. For postnatal cases, the primary indications were developmental delay and multiple congenital anomalies (MCA). The most frequently encountered markers were of chromosome 15 origin for satellited chromosomes, and chromosomes 2 and 16 for non-satellited chromosomes. We were able to obtain pertinent clinical information for 47% (41/88) of cases with an identified abnormal chromosome. We conclude that spectral karyotyping is sufficiently reliable for use and provides a valuable diagnostic tool for establishing the origin of supernumerary marker chromosomes or derivative chromosomal material that cannot be identified with standard cytogenetic techniques. PMID- 22248352 TI - Effects of budesonide/formoterol combination therapy versus budesonide alone on airway dimensions in asthma. AB - BACKGROUND AND OBJECTIVE: Combination therapy with inhaled corticosteroids and long-acting beta(2)-agonists results in improved asthma symptom control compared with the use of inhaled corticosteroids alone. However, the effects of combination therapy on structural changes and inflammation of the airways are still unknown. The aim of this study was to compare the effects of budesonide/formoterol with those of budesonide alone on airway dimensions and inflammation in individuals with asthma. METHODS: Fifty asthmatic patients were randomized to treatment with budesonide/formoterol (200/6 ug, two inhalations bd) or budesonide (200 ug, two inhalations bd) for 24 weeks. Airway dimensions were assessed using a validated computed tomography technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/Osquare root BSA, and luminal area (Ai)/BSA at the right apical segmental bronchus, were measured. The percentage of eosinophils in induced sputum, pulmonary function, and Asthma Quality of Life Questionnaires (AQLQ) were also evaluated. RESULTS: There were significantly greater decreases in WA/BSA (P < 0.05), WA% (P < 0.001) and wall thickness/square root BSA (P < 0.05), and increases in Ai/BSA (P < 0.05), in subjects treated with budesonide/formoterol compared with those treated with budesonide. The reduction in sputum eosinophils and increase in per cent of predicted forced expiratory volume in 1 s (FEV(1) %) were greater for subjects treated with budesonide/formoterol compared with those treated with budesonide alone. In the budesonide/formoterol group, the changes in WA% were significantly correlated with changes in sputum eosinophils and FEV(1%) (r = 0.84 and r = 0.64, respectively). There were improvements in the AQLQ scores after treatment with budesonide/formoterol. CONCLUSIONS: Budesonide/formoterol combination therapy is more effective than budesonide alone for reducing airway wall thickness and inflammation in individuals with asthma. PMID- 22248353 TI - Endothelial cells and magnesium: implications in atherosclerosis. AB - There is no doubt that the functional and structural integrity of the endothelium is critical in maintaining vascular homoeostasis and in preventing atherosclerosis. In the light of epidemiological and experimental studies, magnesium deficiency is emerging as an inducer of endothelial dysfunction. In particular, data on the effects of low extracellular magnesium on cultured endothelial cells reinforce the idea that correcting magnesium homoeostasis might be a helpful and inexpensive intervention to prevent and treat endothelial dysfunction and, consequently, atherosclerosis. PMID- 22248354 TI - Effect of statins therapy prior to percutaneous coronary intervention. AB - BACKGROUND: Many previous studies have demonstrated that statins pre-treatment before percutaneous coronary intervention (PCI) reduced myocardial infarction (MI) in statin-naive patients with both stable angina and acute coronary syndrome. However, clinical benefit of statins is controversial as some studies have shown different results. METHODS: A search of MEDLINE, EMBASE using the term statins AND PCI, statins AND percutaneous coronary intervention. The review was limited to articles published in English between January 1990 and July 2011. RESULTS: Most trials noted that statins pretreatment before PCI in patients are associated with risk reduction of periprocedural myocardial infarction (PMI) and major adverse cardiovascular events (MACE). The mechanisms underlying this protective action of statins possibly attribute to the pleiotropic effects. However, controversial results were also reported in some trials that early use of statins before PCI did not influence occurrence of PMI or long-term clinical outcomes. CONCLUSION: Statins therapy among PCI patients seems to be associated with a significant mortality advantage at early and long-term follow-up. However, currently early statins use before intervention still cannot serve as a routine strategy of treatment. Further large-scale randomized studies are critically required to demonstrate the importance of early treatment with statins in pre PCI. PMID- 22248355 TI - Do stakeholders in wound care prefer evidence-based wound care products? A survey in the Netherlands. AB - For several wound products compelling evidence is available on their effectiveness, for example, from systematic reviews. The process of buying, prescribing and applying wound materials involve many stakeholders, who may not be aware of this evidence, although this is essential for uniform and optimum treatment choice. In this survey, we determined the general awareness and use of evidence, based on (Cochrane) systematic reviews, for wound products in open wounds and burns among wound care stakeholders, including doctors, nurses, buyers, pharmacologists and manufacturers. We included 262 stakeholders. Doctors preferred conventional antiseptics (e.g. iodine), while specialised nurses and manufacturers favoured popular products (e.g. silver). Most stakeholders considered silver-containing products as evidence-based effective antiseptics. These were mostly used by specialised nurses (47/57; 82%), although only few of them (9/55; 16%) thought using silver is evidence-based. For burns, silver sulfadiazine and hydrofibre were most popular. The majority of professionals considered using silver sulfadiazine to be evidence-based, which contradicts scientific results. Awareness and use of the Cochrane Library was lower among nurses than among doctors (P < 0.001). Two thirds of the manufacturers were unaware of, or never used, the Cochrane Library. Available compelling evidence in wound care is not equally internalised by stakeholders, which is required to ensure evidence-based decision making. PMID- 22248356 TI - A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. AB - Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small molecule inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with electric dipoles. PMID- 22248357 TI - Does gratitude always work? Ambivalence over emotional expression inhibits the beneficial effect of gratitude on well-being. AB - The psychological benefit of gratitude has been well demonstrated in previous studies. However, when we examined these studies closely, we found that the moderators were rarely investigated, suggesting that further work is needed to explore the boundaries of gratitude In this regard, the authors have proposed that ambivalence over emotional expression might be a potential moderator that would inhibit the beneficial effect of gratitude on well-being. Two studies were conducted to examine our hypothesis. Study 1 consisted of 353 Taiwanese college students who completed the Gratitude Questionnaire-Taiwan version (GQ-T), Ambivalence over Emotional Expression Questionnaire (AEQ), and one question about subjective happiness. We found that ambivalence over emotional expression significantly moderated the effect of gratitude on happiness. To validate our findings in Study 1, 233 Taiwanese college students were recruited for Study 2, and they completed the GQ-T, AEQ, subjective happiness short-form UCLA loneliness scale, as well as the Center for Epidemiological Studies Depression Scale (CES D). Both studies demonstrated that ambivalence over emotional expression moderated the relationship between gratitude and well-being indexes. Simply stated, the authors found that across the two independent samples, among students who are high in ambivalence over emotional expression, the beneficial effect of gratitude on subjective happiness was inhibited. However, the moderating pattern for loneliness and depression was contrary to our expectations, indicating that high ambivalence over emotional expression does not inhibit gratitude. Possible explanations and implications for social relationships and emotional expression are discussed. PMID- 22248360 TI - Alcohol use in the first three years of bereavement: a national representative survey. AB - BACKGROUND: Earlier results concerning alcohol consumption of bereaved persons are contradictory. The aim of the present study was to analyze the relationship between bereavement and alcohol consumption accounting for time and gender differences on a nationally representative sample from Hungary ("Hungarostudy Epidemiological Panel Survey", N = 4457) METHODS: Drinking characteristics of mourning persons (alcohol consumption, dependence symptoms, and harmful consequences of alcohol use) in the first three years of grief were examined among persons between 18-75 years using the Alcohol Use Disorders Identification Test (AUDIT). RESULTS: Men bereaved for one year scored higher on two dimensions of AUDIT (dependence symptoms and harmful alcohol use), while men bereaved for two years scored higher on all three dimensions of AUDIT compared to the non bereaved. The rate of men clinically at-risk concerning alcohol consumption among the non-bereaved is 12.9%, and among men bereaved for one year is 18.4% (a non significant difference), while 29.8% (p < 0.001, OR = 2,781) among men bereaved for two years. However, men bereaved for three years did not differ from the non bereaved in their drinking habits. In case of bereaved women, again no difference was found with respect to alcohol use compared to the non-bereaved. CONCLUSION: Among bereaved men, the risk of alcohol related problems tends to be higher, which can be shown both among men bereaved for one year as well as men bereaved for two years. Considering the higher morbidity and mortality rates of bereaved men, alcohol consumption might play a mediator role. These facts draw attention to the importance of prevention, early recognition, and effective therapy of hazardous drinking in bereaved men. PMID- 22248361 TI - Design of barbiturate-nitrate hybrids that inhibit MMP-9 activity and secretion. AB - We describe a new type of barbiturate-based matrix metalloproteinase (MMP) inhibitor incorporating a nitric oxide (NO) donor/mimetic group (series 1). The compounds were designed to inhibit MMP at enzyme level and to attenuate MMP-9 secretion arising from inflammatory signaling. To detect effects related to the nitrate, we prepared and studied an analogous series of barbiturate C5-alkyl alcohols that were unable to release NO (series 2). Both series inhibited recombinant human MMP-2/9 activity with nanomolar potency. Series 1 consistently inhibited the secretion of MMP-9 from TNFalpha/IL1beta stimulated Caco-2 cells at 10 MUM, which could be attributed to NO related effects because the non-nitrate panel did not affect enzyme levels. Several compounds from series 1 (10 MUM) inhibited tumor cell invasion but none from the non-nitrate panel did. The work shows that MMP-inhibitory barbiturates are suitable scaffolds for hybrid design, targeting additional facets of MMP pathophysiology, with potential to improve risk-benefit ratios. PMID- 22248362 TI - Molecular dynamics simulation studies of the interactions between ionic liquids and amino acids in aqueous solution. AB - Although the understanding of the influence of ionic liquids (ILs) on the solubility behavior of biomolecules in aqueous solutions is relevant for the design and optimization of novel biotechnological processes, the underlying molecular-level mechanisms are not yet consensual or clearly elucidated. In order to contribute to the understanding of the molecular interactions established between amino acids and ILs in aqueous media, classical molecular dynamics (MD) simulations were performed for aqueous solutions of five amino acids with different structural characteristics (glycine, alanine, valine, isoleucine, and glutamic acid) in the presence of 1-butyl-3-methylimidazolium bis(trifluoromethyl)sulfonyl imide. The results from MD simulations enable to relate the properties of the amino acids, namely their hydrophobicity, to the type and strength of their interactions with ILs in aqueous solutions and provide an explanation for the direction and magnitude of the solubility phenomena observed in [IL + amino acid + water] systems by a mechanism governed by a balance between competitive interactions of the IL cation, IL anion, and water with the amino acids. PMID- 22248363 TI - Skin swabbing as a new efficient DNA sampling technique in amphibians, and 14 new microsatellite markers in the alpine newt (Ichthyosaura alpestris). AB - This study introduces a novel DNA sampling method in amphibians using skin swabs. We assessed the relevancy of skin swabs relevancy for genetic studies by amplifying a set of 17 microsatellite markers in the alpine newt Ichthyosaura alpestris, including 14 new polymorphic loci, and a set of 11 microsatellite markers in Hyla arborea, from DNA collected with buccal swabs (the standard swab method), dorsal skin swabs and ventral skin swabs. We tested for quality and quantity of collected DNA with each method by comparing electrophoresis migration patterns. The consistency between genotypes obtained from skin swabs and buccal swabs was assessed. Dorsal swabs performed better than ventral swabs in both species, possibly due to differences in skin structure. Skin swabbing proved to be a useful alternative to buccal swabbing for small or vulnerable animals: by drastically limiting handling, this method may improve the trade-off between the scientific value of collected data, individual welfare and species conservation. In addition, the 14 new polymorphic microsatellites for the alpine newt will increase the power of genetic studies in this species. In four populations from France (n=19-25), the number of alleles per locus varied from 2 to 16 and expected heterozygosities ranged from 0.04 to 0.91. Presence of null alleles was detected in two markers and two pairs displayed gametic disequilibrium. No locus appeared to be sex-linked. PMID- 22248364 TI - Isolated granulocytic sarcoma of the pancreas: a tricky diagnostic for primary pancreatic extramedullary acute myeloid leukemia. AB - We report two clinical cases of primary granulocytic sarcoma of the pancreas that were diagnosed on the surgical specimen. Atypical clinical and morphological presentations may have lead to pretherapeutic biopsies of the pancreatic mass in order to indicate primary chemotherapy. Literature review of this rare clinical presentation may help physicians to anticipate diagnostic and therapeutic strategies. PMID- 22248365 TI - Correlation of circulating dehydroepiandrosterone with activated protein C generation and carotid intima-media thickness in male patients with type 2 diabetes. AB - AIMS: Dehydroepiandrosterone exerts a protective effect against cardiovascular diseases. However, the relationship of dehydroepiandrosterone with the anticoagulant factor activated protein C, generated by the thrombin thrombomodulin complex on vascular endothelial cells, remains unknown. This study aimed at studying the relationship between dehydroepiandrosterone and activated protein C generation in patients with Type 2 diabetes. METHODS: Sixty-two male patients with Type 2 diabetes were enrolled in this study. Data obtained from 40 healthy male subjects were used as controls. The plasma levels of dehydroepiandrosterone, the activated protein C-protein C inhibitor complex, high sensitivity C-reactive protein and monocyte chemoattractant protein-1 were measured by enzyme immunoassays. Carotid intima-media thickness was measured by ultrasonography. RESULTS: The plasma levels of dehydroepiandrosterone (5.15 +/- 2.81 vs. 3.76 +/- 2.16 ng/ml; P < 0.005) and the activated protein C-protein C inhibitor complex (1.90 +/- 1.07 vs. 1.02 +/- 0.51 ng/ml; P < 0.001) were significantly lower in patients with diabetes than in normal subjects. Univariate analysis showed a significant correlation of the plasma level of dehydroepiandrosterone with that of the activated protein C-protein C inhibitor complex (r = 0.48, P < 0.001), high-sensitivity C-reactive protein (r = -0.30, P < 0.05) and with the mean intima-media thickness (r = -0.28, P < 0.05) in patients with diabetes. Stepwise multiple regression analysis showed that the plasma level of dehydroepiandrosterone is significantly correlated with the plasma levels of the activated protein C-protein C inhibitor complex (F = 18.06) and high-sensitivity C-reactive protein (F = 4.94). There was no correlation between the plasma levels of dehydroepiandrosterone and monocyte chemoattractant protein-1. CONCLUSIONS: These results suggest that lower circulating levels of dehydroepiandrosterone are associated with decreased activated protein C generation and higher intima-media thickness in patients with Type 2 diabetes. PMID- 22248366 TI - Treatment for Helicobacter pylori infection and risk of Parkinson's disease in Denmark. AB - BACKGROUND AND PURPOSE: It has been speculated that gastrointestinal infection with Helicobacter pylori (HP) contributes to the development of Parkinson's disease (PD). We used nationwide Danish registers to investigate this hypothesis. METHODS: We identified 4484 patients with a first time PD diagnosis between 2001 and 2008 from the Danish National Patient Register (DNPR) and 22, 416 population controls from the Danish Civil Registration System (CRS). Information on drug use was obtained from the National Prescription Registry (NPR). We used logistic regression to compute odds ratios (OR) for the association between treatment for HP and risk of PD. RESULTS: Prescriptions for HP-eradication drugs and proton pump inhibitors (PPI) 5 or more years prior to the diagnosis of PD were associated with a 45% and 23% increase in PD risk, respectively. Hospitalizations and outpatient visits for gastritis and peptic/duodenal ulcers, however, were not associated with PD. CONCLUSIONS: Our population-based study suggests that chronic HP infections and/or gastritis contribute to PD or that these are PD related pathologies that precede motor symptoms. PMID- 22248367 TI - Negative regulation-resistant p53 variant enhances oncolytic adenoviral gene therapy. AB - Intact p53 function is essential for responsiveness to cancer therapy. However, p53 activity is attenuated by the proto-oncoprotein Mdm2, the adenovirus protein E1B 55kD, and the p53 C-terminal domain. To confer resistance to Mdm2, E1B 55kD, and C-terminal negative regulation, we generated a p53 variant (p53VPDelta30) by deleting the N-terminal and C-terminal regions of wild-type p53 and inserting the transcriptional activation domain of herpes simplex virus VP16 protein. The oncolytic adenovirus vector Ad-mDelta19 expressing p53VPDelta30 (Ad mDelta19/p53VPDelta30) showed greater cytotoxicity than Ad-mDelta19 expressing wild-type p53 or other p53 variants in human cancer cell lines. We found that Ad mDelta19/p53VPDelta30 induced apoptosis through accumulation of p53VPDelta30, regardless of endogenous p53 and Mdm2 status. Moreover, Ad-mDelta19/p53VPDelta30 showed a greater antitumor effect and increased survival rates of mice with U343 brain cancer xenografts that expressed wild-type p53 and high Mdm2 levels. To our knowledge, this is the first study reporting a p53 variant modified at the N terminus and C terminus that shows resistance to degradation by Mdm2 and E1B 55kD, as well as negative regulation by the p53 C terminus, without decreased trans-activation activity. Taken together, these results indicate that Ad mDelta19/p53VPDelta30 shows potential for improving p53-mediated cancer gene therapy. PMID- 22248368 TI - Interleukin-13/-4-induced oxidative stress contributes to death of hippocampal neurons in abeta1-42-treated hippocampus in vivo. AB - AIMS: The present study examined whether Abeta(1-42) can induce endogenous expression of interleukin-13 (IL-13) or (IL-4) within activated microglia in the rat hippocampus in vivo. We further investigated whether these cytokines mediate ROS/RNS generation through activation of NADPH oxidase and/or inducible nitric oxide synthase (iNOS), and thus contribute to the degeneration of hippocampal neurons in vivo. RESULTS: Here, we show that IL-13 and IL-4, endogenously expressed in Abeta(1-42)-activated microglia in hippocampus in vivo, contribute to degeneration of hippocampal neurons in vivo. Neutralization of IL-13 and IL-4 protected hippocampal neurons in vivo against neurotoxicity by inhibiting activation of microglial NADPH oxidase and iNOS, resulting in attenuation of ROS generation and oxidative damage of protein, lipid and DNA. INNOVATION: To our knowledge, this is the first study to demonstrate the possible involvement of endogenously expressed IL-13 and/or IL-4 in activated microglia after Abeta(1-42) injection in the degeneration of hippocampal neurons in vivo. The current findings suggest that the deleterious effects of microglia-derived endogenous IL 13 and/or IL-4 are involved in oxidative stress-mediated neurodegenerative diseases, such as AD. CONCLUSION: We carefully hypothesize that IL-13 and IL-4, well-known as anti-inflammatory cytokines might serve as neurotoxic mediators by enhancing microglia-derived oxidative stress in Abeta(1-42)-treated hippocampus in vivo. PMID- 22248369 TI - Quantification of the physical properties of keloid and hypertrophic scars using the Vesmeter novel sensing device. AB - There is still no objective method or reliable device to measure and assess the physical properties of keloid and hypertrophic scars. Using the Vesmeter, we measured the physical properties of keloid and hypertrophic scars, and investigated how their physical properties changed during the process of clinical follow-up. We followed up 11 patients with keloid (n = 6) and hypertrophic (n = 5) scars for 4 months, and measured their physical properties three times over a 2-month period using the Vesmeter. Measurements included hardness, elasticity, penetration depth, relaxation time, viscosity and viscoelastic ratio. All physical properties were measured simultaneously while an indenter was pressed onto the lesion and digitalise the measured data by analysing the wave forms of the lesion's surface behaviour. Data collection was repeated three times for each measurement point, and the average of these three values was used. Overall hardness and viscosity decreased in nine patients, whereas penetration depth increased in nine. Relaxation time decreased in nine patients and elasticity increased in six. Vesmeter was considered to be an objective, convenient and comparatively reliable measuring device for the quantification of the physical properties of keloid and hypertrophic scars. PMID- 22248370 TI - Beneficial impact of prolonged dual antiplatelet therapy after drug-eluting stent implantation. AB - BACKGROUND: Twelve-month dual antiplatelet therapy (DAT) with aspirin and clopidogrel after drug-eluting stent (DES) implantation is routinely recommended. It is unclear if prolonged (>12-month) DAT is also favorable. We compared the outcome of patients discontinuing DAT 12 months after off-label DES implantation versus those with DAT for >12 months. METHODS: Baseline, treatment, and outcome data of patients undergoing off-label DES implantation and free from events 11.5 months after index procedure were retrospectively retrieved. Those discontinuing DAT between 11.5 and 12.5 months (12-month DAT group) were compared to those discontinuing DAT after 12.5 months (>12-month DAT group). The primary end-point was the long-term (>24-month) rate of major adverse cerebro-cardiovascular events (MACCE). RESULTS: Two hundred seventy-two patients met study inclusion criteria: 133 (48.9%) in the 12-month DAT group and 139 (51.1%) in the >12-month DAT group (who were on DAT for an average of 24 months). After an average of 36 months after DES implantation, 14 patients (5.1%) developed MACCE, with 6 (3.5%) cardiac deaths, 7 (2.2%) myocardial infarctions, no stroke, and 5 (1.8%) repeat revascularizations. The >12-month DAT group had a significantly lower risk of MACCE (1 [0.7%] vs. 13 [9.8%] in the 12-month DAT group, P < 0.001) and myocardial infarction (0 vs. 7 [5.3%], P = 0.006), with such differences confirmed at multivariable propensity-adjusted analyses. No significant differences in terms of minor or major bleedings occurred. CONCLUSIONS: In this retrospective registry, patients with off-label DES implantation receiving prolonged (>12 months) DAT presented with lower rates of MACCE and myocardial infarction. PMID- 22248371 TI - ToxR of Vibrio cholerae affects biofilm, rugosity and survival with Acanthamoeba castellanii. AB - BACKGROUND: Vibrio cholerae causes the diarrheal disease cholera and utilizes different survival strategies in aquatic environments. V. cholerae can survive as free-living or in association with zooplankton and can build biofilm and rugose colonies. The bacterium expresses cholera toxin (CT) and toxin-coregulated pilus (TCP) as the main virulence factors. These factors are co-regulated by a transcriptional regulator ToxR, which modulates expression of outer membrane proteins (OmpU) and (OmpT). The aims of this study were to disclose the role of ToxR in expression of OmpU and OmpT, biofilm and rugose colony formation as well as in association with the free-living amoeba Acanthamoeba castellanii at different temperatures. RESULTS: The toxR mutant V. cholerae produced OmpT, significant biofilm and rugose colonies compared to the wild type that produced OmpU, decreased biofilm and did not form rugoes colonies at 30 degrees C. Interestingly, neither the wild type nor toxR mutant strain could form rugose colonies in association with the amoebae. However, during the association with the amoebae it was observed that A. castellanii enhanced survival of V. cholerae wild type compared to toxR mutant strain at 37 degrees C. CONCLUSIONS: ToxR does seem to play some regulatory role in the OmpT/OmpU expression shift, the changes in biofilm, rugosity and survival with A. castellanii, suggesting a new role for this regulatory protein in the environments. PMID- 22248372 TI - Single and inappropriate shock delivered out of tachycardia: device dysfunction? PMID- 22248373 TI - Predicting scores for left ventricular dysfunction in Duchenne muscular dystrophy. AB - BACKGROUND: The aim of this study was to predict left ventricular (LV) dysfunction and the timing to perform echocardiography in patients with Duchenne muscular dystrophy (DMD). We developed a scoring system using clinical parameters and examined its efficacy. It is indispensable to utilize echocardiogram for evaluating myocardial damage of DMD patients, but there is no established guideline for determining the clinical conditions which require echocardiographic examination. METHODS: We retrospectively analyzed 86 patients with DMD who were treated in Kobe University Hospital from 2007 to 2009. The multiple logistic regression analysis on routine clinical data was performed to identify parameters that can find abnormal LV contraction, and to develop a weighted scoring system. Echocardiogram was performed as the gold standard for detecting LV dysfunction. RESULTS: Four parameters were associated with abnormal LV contraction: (i) brain natriuretic peptide (BNP); (ii) creatine kinase; (iii) scoliosis; and (iv) body surface area. When BNP was used as the only predictor to evaluate LV systolic dysfunction, sensitivity and specificity were 36.4% and 92.1%, respectively. In contrast, abnormal LV contraction was detected in high accuracy (sensitivity: 95.5%; specificity: 68.3%) when we used a two-step scoring system in which BNP was combined with the other three factors, raising the sensitivity compared to using BNP levels as the single parameter (P= 0.008). CONCLUSION: Our scoring system detects the early heart dysfunction of DMD patients, especially when BNP level is not elevated. This system is useful to determine the timing for echocardiographic examination and consulting cardiologists. PMID- 22248375 TI - Aging, imagery, and the bizarreness effect. AB - This study examined the bizarre imagery effect in young and older adults, under incidental and intentional conditions. Intentionality was manipulated across experiments, with participants receiving an incidental free recall test in Experiment 1 and an intentional test in Experiment 2. This study also examined the relation between working memory resources and the bizarreness effect. In Experiment 1 young and older adults were presented with common and bizarre sentences; they later received an incidental recall test. There were no age differences in sensitivity to the bizarreness effect in Experiment 1 when ANOVAs were used to analyze the data. However, when the bizarreness effect was examined in terms of effect size, there was evidence that younger adults produced larger bizarreness effect sizes than younger adults. Experiment 2 further explored age differences in sensitivity to the bizarreness effect by presenting young and older adults with bizarre and common sentences under intentional learning conditions. Experiment 2 failed to yield age differences as a function of item type (bizarre vs. common). In addition, Experiment 2 failed to yield significant evidence that the bizarreness effect is modulated by working memory resources. The results of this study are most consistent with the distinctiveness account of the bizarreness effect. PMID- 22248376 TI - Contributions of frontal and medial temporal lobe functioning to the errorless learning advantage. AB - Among individuals with episodic memory impairments, trial-and-error learning is less successful than when errors are avoided. This "errorless learning advantage" has been replicated numerous times, but its neurocognitive mechanism is uncertain, with existing evidence pointing to both medial temporal lobe (MTL) and frontal lobe (FL) involvement. To test the relative contribution of MTL and FL functioning to the errorless learning advantage, 51 healthy older adults were pre experimentally assigned to one of four groups based on their neuropsychological test performance: Low MTL-Low FL, Low MTL-High FL, High MTL-Low FL, High MTL-High FL. Participants learned two word lists under errorless learning conditions, and two word lists under errorful learning conditions, and memory was tested via free recall, cued recall, and source recognition. Performance on all three tests was better for those with High relative to Low MTL functioning. An errorless learning advantage was found in free and cued recall, in cued recall marginally more so for those with Low than High MTL functioning. Participants with Low MTL functioning were also more likely to misclassify learning errors as target words. Overall, these results are consistent with a MTL locus of the errorless learning advantage. The results are discussed in terms of the multi-componential nature of neuropsychological tests and the impact of demographic and mood variables on cognitive functioning. PMID- 22248379 TI - Analysis of YM-216391 biosynthetic gene cluster and improvement of the cyclopeptide production in a heterologous host. AB - YM-216391, an antitumor natural product, represents a new class of cyclic peptides containing a polyoxazole-thiazole moiety. Herein we describe its gene cluster encoding the biosynthetic paradigm featuring a ribosomally synthesizing precursor peptide followed by a series of novel posttranslational modifications, which include (i) cleavage of both N-terminal leader peptide and C-terminal extension peptide and cyclization in a head-to-tail fashion, (ii) conversion of an L-Ile to D-allo-Ile, and (iii) beta-hydroxylation of Phe by a P450 monooxygenase followed by further heterocyclization and oxidation to form a phenyloxazole moiety. The cluster was heterologously expressed in Streptomyces lividans to bypass difficult genetic manipulation. Deletion of the ymR3 gene, encoding a putative transcriptional regulator, increased the YM-216391 yield about 20-fold higher than the original yields for the heterologous expression of wild-type cluster, which set the stage for further combinatorial biosynthesis. PMID- 22248380 TI - Highly penetrant melanoma in a zebrafish model is independent of ErbB3b signaling. PMID- 22248382 TI - Stabilization of mid-sized silicon nanoparticles by functionalization with acrylic acid. AB - We present an enhanced method to form stable dispersions of medium-sized silicon nanoparticles for solar cell applications by thermally induced grafting of acrylic acid to the nanoparticle surface. In order to confirm their covalent attachment on the silicon nanoparticles and to assess the quality of the functionalization, X-ray photoelectron spectroscopy and diffuse reflectance infrared Fourier spectroscopy measurements were carried out. The stability of the dispersion was elucidated by dynamic light scattering and Zeta-potential measurements, showing no sign of degradation for months. PMID- 22248381 TI - Proteomic study of the mucin granulae in an intestinal goblet cell model. AB - Goblet cells specialize in producing and secreting mucus with its main component, mucins. An inducible goblet-like cell line was used for the purification of the mucus vesicles stored in these cells by density gradient ultracentrifugation, and their proteome was analyzed by nanoLC-MS and MS/MS. Although the density of these vesicles coincides with others, it was possible to reveal a number of proteins that after immunolocalization on colon tissue and functional analyses were likely to be linked to the MUC2 vesicles. Most of the proteins were associated with the vesicle membrane or their outer surface. The ATP6AP2, previously suggested to be associated with vesicular proton pumps, was colocalized with MUC2 without other V ATPase proteins and, thus, probably has roles in mucin vesicle function yet to be discovered. FAM62B, known to be a calcium-sensitive protein involved in vesicle fusion, also colocalized with the MUC2 vesicles and is probably involved in unknown ways in the later events of the MUC2 vesicles and their secretion. PMID- 22248383 TI - Substrate limitation for methanogenesis in hypersaline environments. AB - Motivated by the increasingly abundant evidence for hypersaline environments on Mars and reports of methane in its atmosphere, we examined methanogenesis in hypersaline ponds in Baja California Sur, Mexico, and in northern California, USA. Methane-rich bubbles trapped within or below gypsum/halite crusts have delta13C values near -400/00. Methane with these relatively high isotopic values would typically be considered thermogenic; however, incubations of crust samples resulted in the biological production of methane with similar isotopic composition. A series of measurements aimed at understanding the isotopic composition of methane in hypersaline systems was therefore undertaken. Methane production rates, as well as the concentrations and isotopic composition of the particulate organic carbon (POC), were measured. Methane production was highest from microbial communities living within gypsum crusts, whereas POC content at gypsum/halite sites was low, generally less than 1% of the total mass. The isotopic composition of the POC ranged from -260/00 to -100/00. To determine the substrates used by the methanogens, 13C-labeled methylamines, methanol, acetate, and bicarbonate were added to individual incubation vials, and the methane produced was monitored for 13C content. The main substrates used by the methanogens were the noncompetitive substrates, the methylamines, and methanol. When unlabeled trimethylamine (TMA) was added to incubating gypsum/halite crusts in increasing concentrations, the isotopic composition of the methane produced became progressively lower; the lowest methane delta13C values occurred when the most TMA was added (1000 MUM final concentration). This decrease in the isotopic composition of the methane produced with increasing TMA concentrations, along with the high in situ methane delta13C values, suggests that the methanogens within the crusts are operating at low substrate concentrations. It appears that substrate limitation is decreasing isotopic fractionation during methanogenesis, which results in these abnormally high biogenic methane delta13C values. PMID- 22248384 TI - Bacterial growth at the high concentrations of magnesium sulfate found in martian soils. AB - The martian surface environment exhibits extremes of salinity, temperature, desiccation, and radiation that would make it difficult for terrestrial microbes to survive. Recent evidence suggests that martian soils contain high concentrations of MgSO4 minerals. Through warming of the soils, meltwater derived from subterranean ice-rich regolith may exist for an extended period of time and thus allow the propagation of terrestrial microbes and create significant bioburden at the near surface of Mars. The current report demonstrates that halotolerant bacteria from the Great Salt Plains (GSP) of Oklahoma are capable of growing at high concentrations of MgSO4 in the form of 2 M solutions of epsomite. The epsotolerance of isolates in the GSP bacterial collection was determined, with 35% growing at 2 M MgSO4. There was a complex physiological response to mixtures of MgSO4 and NaCl coupled with other environmental stressors. Growth also was measured at 1 M concentrations of other magnesium and sulfate salts. The complex responses may be partially explained by the pattern of chaotropicity observed for high-salt solutions as measured by agar gelation temperature. Select isolates could grow at the high salt concentrations and low temperatures found on Mars. Survival during repetitive freeze-thaw or drying-rewetting cycles was used as other measures of potential success on the martian surface. Our results indicate that terrestrial microbes might survive under the high-salt, low temperature, anaerobic conditions on Mars and present significant potential for forward contamination. Stringent planetary protection requirements are needed for future life-detection missions to Mars. PMID- 22248385 TI - Delivering stepped care: an analysis of implementation in routine practice. AB - BACKGROUND: In the United Kingdom, clinical guidelines recommend that services for depression and anxiety should be structured around a stepped care model, where patients receive treatment at different 'steps,' with the intensity of treatment (i.e., the amount and type) increasing at each step if they fail to benefit at previous steps. There are very limited data available on the implementation of this model, particularly on the intensity of psychological treatment at each step. Our objective was to describe patient pathways through stepped care services and the impact of this on patient flow and management. METHODS: We recorded service design features of four National Health Service sites implementing stepped care (e.g., the types of treatments available and their links with other treatments), together with the actual treatments received by individual patients and their transitions between different treatment steps. We computed the proportions of patients accessing, receiving, and transiting between the various steps and mapped these proportions visually to illustrate patient movement. RESULTS: We collected throughput data on 7,698 patients referred. Patient pathways were highly complex and very variable within and between sites. The ratio of low (e.g., self-help) to high-intensity (e.g., cognitive behaviour therapy) treatments delivered varied between sites from 22:1, through 2.1:1, 1.4:1 to 0.5:1. The numbers of patients allocated directly to high intensity treatment varied from 3% to 45%. Rates of stepping up from low intensity treatment to high-intensity treatment were less than 10%. CONCLUSIONS: When services attempt to implement the recommendation for stepped care in the National Institute for Health and Clinical Excellence guidelines, there were significant differences in implementation and consequent high levels of variation in patient pathways. Evaluations driven by the principles of implementation science (such as targeted planning, defined implementation strategies, and clear activity specification around service organisation) are required to improve evidence on the most effective, efficient, and acceptable stepped care systems. PMID- 22248386 TI - Minimum infusion rate and hemodynamic effects of propofol, propofol-lidocaine and propofol-lidocaine-ketamine in dogs. AB - OBJECTIVE: To evaluate the effects of a constant rate infusion (CRI) of lidocaine alone or in combination with ketamine on the minimum infusion rate (MIR) of propofol in dogs and to compare the hemodynamic effects produced by propofol, propofol-lidocaine or propofol-lidocaine-ketamine anesthesia. STUDY DESIGN: Prospective, randomized cross-over experimental design. ANIMALS: Fourteen adult mixed-breed dogs weighing 15.8 +/- 3.5 kg. METHODS: Eight dogs were anesthetized on different occasions to determine the MIR of propofol alone and propofol in combination with lidocaine (loading dose [LD] 1.5 mg kg(-1), CRI 0.25 mg kg(-1) minute(-1)) or lidocaine (LD 1.5 mg kg(-1), CRI 0.25 mg kg(-1) minute(-1)) and ketamine (LD 1 mg kg(-1), CRI 0.1 mg kg(-1) minute(-1)). In six other dogs, the hemodynamic effects and bispectral index (BIS) were investigated. Each animal received each treatment (propofol, propofol-lidocaine or propofol-lidocaine ketamine) on the basis of the MIR of propofol determined in the first set of experiments. RESULTS: Mean +/- SD MIR of propofol was 0.51 +/- 0.08 mg kg(-1) minute(-1). Lidocaine-ketamine significantly decreased the MIR of propofol to 0.31 +/- 0.07 mg kg(-1) minute(-1) (37 +/- 18% reduction), although lidocaine alone did not (0.42 +/- 0.08 mg kg(-1) minute(-1), 18 +/- 7% reduction). Hemodynamic effects were similar in all treatments. Compared with the conscious state, in all treatments, heart rate, cardiac index, mean arterial blood pressure, stroke index and oxygen delivery index decreased significantly, whereas systemic vascular resistance index increased. Stroke index was lower in dogs treated with propofol-lidocaine-ketamine at 30 minutes compared with propofol alone. The BIS was lower during anesthesia with propofol-lidocaine-ketamine compared to propofol alone. CONCLUSIONS AND CLINICAL RELEVANCE: Lidocaine ketamine, but not lidocaine alone, reduced the MIR of propofol in dogs. Neither lidocaine nor lidocaine in combination with ketamine attenuated cardiovascular depression produced by a continuous rate infusion of propofol. PMID- 22248387 TI - Material attrition and bone micromorphology after conventional and ultrasonic implant site preparation. AB - OBJECTIVES: Little is known about the recently introduced ultrasonic implant site preparation. The purpose of this study was to compare material attrition and micromorphological changes after ultrasonic and conventional implant site preparations. MATERIAL AND METHODS: Implant site preparations were performed on fresh bovine ribs using one conventional (Straumann, Freiburg, Germany) and two ultrasonic (Piezosurgery; Mectron Medical Technology, Carasco, Italy and Variosurg; NSK, Tochigi, Japan) systems with sufficient saline irrigation. Sections were examined by environmental scanning electron microscopy (ESEM). Energy-dispersive X-ray spectroscopy (EDX) was performed to evaluate the metal attrition within the bone and the irrigation fluid. RESULTS ESEM: After conventional osteotomy, partially destroyed trabecular structures of the cancellous bone that were loaded with debris were observed, whereas after ultrasonic implant site preparations, the anatomic structures were preserved. EDX: None of the implant site preparation methods resulted in metal deposits in the adjacent bone structures. However, within the irrigation liquid, there was significantly higher metal attrition with ultrasonic osteotomy (P < 0.0001 and P < 0.0001 for Mectron and NSK, respectively). Whereas for Straumann system used, 15.5% of the SEM/EDX findings were drill-origin metals, this percentage increased to 37.3% and 37.9% with the application of Mectron and NSK, respectively. CONCLUSIONS: Ultrasonic implant site preparation is associated with the preservation of bone microarchitecture and with the increased attrition of metal particles. Therefore, copious irrigation seems to be even more essential for ultrasonic implant site preparation than for the conventional method. PMID- 22248388 TI - Gender, women's work and ergonomics. PMID- 22248389 TI - Gender and ergonomics: a case study on the 'non-formal' work of women nurses. AB - Women's work activities are often characterised by 'non-formal actions' (such as giving support). Gender differences in ergonomics may be due to this peculiarity. We applied the method of organisational congruencies (MOC) to ascertain the 'non formal' work portion of nurses employed in three hospital units (haematology, emergency room and general medicine) during the three work shifts in a major University Hospital in Rome, Italy. We recorded a total of 802 technical actions performed by nine nurses in 72 h of work. Twenty-six percent of the actions in direct patient's care were communicative actions (mainly giving psychological support) while providing physical care. These 'double actions' are often not considered to be a formal part of the job by hospital management. In our case study, the 'non-formal' work of nurses (psychological support) is mainly represented by double actions while taking physical care of the patients. The dual task paradigm in gender oriented research is discussed in terms of its implications in prevention in occupational health. PRACTITIONER SUMMARY: The main purpose of the study was to assess all the formal and non-formal activities of women in the nursing work setting. Offering psychological support to patients is often not considered to be a formal part of the job. Our case study found that nurses receive no explicit guidelines on this activity and no time is assigned to perform it. In measuring the burden of providing psychological support to patients, we found that this is often done while nurses are performing tasks of physical care for the patients (double actions). The article discusses the significance of non-formal psychological work load of women nurses through double actions from the ergonomic point view. PMID- 22248390 TI - Gender analysis of musculoskeletal disorders and emotional exhaustion: interactive effects from physical and psychosocial work exposures and engagement in domestic work. AB - The objective of this study was to assess the relationships between physical and psychosocial work exposures, engagement in domestic work and work-home imbalance in relation to symptoms of musculoskeletal disorders and emotional exhaustion in white- and blue-collar men and women. Three thousand employees from 21 companies were asked to answer a questionnaire on family structure, household and child care tasks, work exposure, work-home imbalance and symptoms of neck/shoulder disorders, low back disorders and emotional exhaustion. Women reported more musculoskeletal disorders and engagement in domestic work. Adverse at-work exposures were highest in blue-collar women. High engagement in domestic work was not separately associated with symptoms but paid work exposure factors were associated. High engagement in domestic work interacted with adverse work exposure and increased risk estimates for low back disorders and emotional exhaustion. Reported work-home imbalance was associated with neck/shoulder disorders in women and with emotional exhaustion in both women and men. PRACTITIONER SUMMARY: The current article adds to earlier research by showing that high engagement in domestic work is not separately associated with increased symptoms, but interacts with psychosocial work exposure variables to produce emotional exhaustion in both women and men and low back disorders in women. PMID- 22248392 TI - Targeted treatment of invasive fungal infections accelerates healing of foot wounds in patients with Type 2 diabetes. AB - AIM: To test the hypothesis that fluconazole plus standard care is superior to the standard care for diabetic foot wounds infected with deep-seated fungal infections. METHODS: We carried out a randomized, controlled, open-label, parallel-arm study in 75 patients with both fungal and bacterial infections in deep tissues of diabetic foot wounds. Thirty-seven patients (control group) were given standard care (surgical debridement + culture-specific antibiotics + offloading + glycaemic control) and 38 patients (treatment group) were given fluconazole 150 mg daily plus standard care. Wound surface area was measured every 2 weeks until the endpoints (complete epithelialization or skin grafting) were met. RESULTS: By week 4, the mean wound surface area reduced to 27.3 from 111.5 cm(2) in the treatment group, as opposed to 67.1 from 87.3 cm(2) in the control group. Subsequently, the mean wound surface areas were remarkably smaller in the treatment group compared with the control group, and statistically significant differences (P <= 0.05) in mean wound surface area were observed between the treatment group and the control group at week 6. However, no statistically significant (P <= 0.47) difference in complete healing was observed between the treatment group and the control group, 20 vs. 24. The mean wound healing time for the treatment group was 7.3 weeks, whereas for the control group it was 11.3 weeks (P <= 0.022). Similarly, the probability of wound healing in the treatment group was 50 vs. 20% in the control group at week 10. CONCLUSIONS: Fluconazole plus standard care was superior to standard care alone in accelerating wound reduction among patients with diabetes with deep-seated fungal infections in diabetic foot wounds. Those in the treatment group who did heal, healed more quickly (P <= 0.022), but overall healing was not different. PMID- 22248391 TI - Aberrant cyclization affords a C-6 modified cyclic adenosine 5'-diphosphoribose analogue with biological activity in Jurkat T cells. AB - Two nicotinamide adenine dinucleotide (NAD(+)) analogues modified at the 6 position of the purine ring were synthesized, and their substrate properties toward Aplysia californica ADP-ribosyl cyclase were investigated. 6-N-Methyl NAD(+) (6-N-methyl nicotinamide adenosine 5'-dinucleotide 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5'-diphosphoribose, 11), whereas 6-thio NHD(+) (nicotinamide 6-mercaptopurine 5'-dinucleotide, 17) generates a cyclic dinucleotide. Surprisingly, NMR correlation spectra confirm this compound to be the N1 cyclic product 6-thio N1-cIDPR (6-thio cyclic inosine 5'-diphosphoribose, 3), although the corresponding 6-oxo analogue is well-known to cyclize at N7. In Jurkat T cells, unlike the parent cyclic inosine 5'-diphosphoribose N1-cIDPR 2, 6 thio N1-cIDPR antagonizes both cADPR- and N1-cIDPR-induced Ca(2+) release but possesses weak agonist activity at higher concentration. 3 is thus identified as the first C-6 modified cADPR (cyclic adenosine 5'-diphosphoribose) analogue antagonist; it represents the first example of a fluorescent N1-cyclized cADPR analogue and is a new pharmacological tool for intervention in the cADPR pathway of cellular signaling. PMID- 22248393 TI - Long-term preservation of cardiac structure and function after adeno-associated virus serotype 9-mediated microdystrophin gene transfer in mdx mice. AB - Dystrophin plays an important role in muscle contraction, linking the intracellular cytoskeleton to the extracellular matrix. Mutations of the dystrophin gene leading to a complete loss of the protein cause Duchenne muscular dystrophy (DMD), frequently associated with severe cardiomyopathy. Early clinical trials in DMD using gene transfer to skeletal muscle are underway, but gene transfer to dystrophic cardiac muscle has not yet been tested in humans. The aim of this study was to develop an optimized protocol for cardiac gene therapy in the mouse model of dystrophin deficiency (mdx), using a cardiac promoter for expression of a microdystrophin (MUDys) transgene packaged into an adeno associated virus serotype 9 vector (AAV9). In this study adult mdx mice were intravenously injected with 1*10(12) genomic particles of AAV9 vectors carrying a cDNA encoding MUDys under the control of either a ubiquitously active cytomegalovirus (CMV) promoter or a cardiac-specific CMV-enhanced myosin light chain (MLC0.26) promoter. After 10 months, both AAV9 vectors led to sustained MUDys expression in cardiac muscle, but the MLC promoter conferred about 4-fold higher protein levels. AAV9-CMV-MLC0.26-MUDys resulted in significant protection of cardiac morphology and function as assessed by histopathology, echocardiography, and left ventricular catheterization. In conclusion, we established an AAV9-mediated gene transfer approach for efficient and specific long-term MUDys expression in the hearts of mdx mice, resulting in a sustained therapeutic effect. Thus, this approach might be a basis for further translation into a treatment strategy for DMD-associated cardiomyopathy. PMID- 22248396 TI - Editorial. Potable reuse standards. PMID- 22248394 TI - Androgen deprivation therapy in prostate cancer: focusing on sexual side effects. AB - INTRODUCTION: Androgen deprivation therapy (ADT) is the cornerstone in the treatment of advanced and metastatic prostate cancer (PC). However, recent publications suggest that ADT may increase cardiovascular (CV) problems (morbidity and mortality), most probably because androgens regulate fat distribution, insulin sensitivity, and lipid metabolism. AIM: The aim of the present review is to analyze different modalities of ADT, emphasizing advantages and possible related adverse sexual events. METHOD: A systematic search of published evidence was performed using Medline (from 1969 to September 2011). MAIN OUTCOME MEASURE: The most important studies regarding the relationship among testosterone, PC, and the role of ADT were reviewed. RESULTS: There is unequivocal evidence that reducing androgen signaling to the hypogonadal range can reduce PC growth and patient symptoms; however, androgen dependency of prostate growth is evident only in the hypogonadal condition but not in the eugonadal state (the "saturation hypothesis"). There is clear evidence that ADT improves disease-free and overall survival only under two conditions: (i) in combination with primary radiation for locally advanced or high-risk diseases and (ii) as an adjuvant therapy for positive lymph node diseases after prostatectomy. On the other hand, it should be recognized that ADT can adversely affect not only traditional CV risk factor (including serum lipoproteins, insulin sensitivity, and obesity) but also sexual life, being associated with reduced libido and erectile, ejaculatory, and orgasmic disorders. CONCLUSIONS: Physicians should weigh the risk/benefit ratio before prescribing ADT. PMID- 22248398 TI - Outlook. PMID- 22248397 TI - Currents. PMID- 22248399 TI - Regulatory Alert: EPA "policy" for testing toxics. PMID- 22248400 TI - Pollutant effects on stone monuments. PMID- 22248402 TI - Trace metals in contaminated waters. PMID- 22248401 TI - Aircraft and air pollution. PMID- 22248404 TI - ES Literature. PMID- 22248403 TI - ES Products. PMID- 22248405 TI - ES Books. PMID- 22248407 TI - Correction-coal tar coatings of storage tanks, a source of contamination of the portable water supply. PMID- 22248406 TI - Reduction of sulfur dioxide emissions from a sulfuric acid plant by means of feed modulation. PMID- 22248408 TI - Evaluation of the chloroisocyanurate hydrolysis constants. PMID- 22248409 TI - Approach to forecasting daily maximum ozone levels in St. Louis. PMID- 22248410 TI - Gas-flow model to determine methane production at sanitary landfills. PMID- 22248411 TI - Runoff losses of atrazine and terbutryn from unlimed and limed soil. PMID- 22248412 TI - Chlorophyll-phosphorus relations in individual lakes. Their importance to lake restoration strategies. PMID- 22248413 TI - Particle collection in cyclones at high temperature and high pressure. PMID- 22248414 TI - A drop impact sampler. PMID- 22248415 TI - Preparative isolation of aquatic humic substances. PMID- 22248416 TI - Impact of fossil fuel combustion on the sediments of Lake Michigan. PMID- 22248417 TI - Sensitive integrated and time-resolved aerosol measurement by means of light transmission changes of metal-coated Nuclepore filters (filter-fotometer). PMID- 22248418 TI - Model of trace-metal partitioning in marine sediments. PMID- 22248419 TI - Reply to Correspondence. Acoustic Particle Counting and/or Sizing Device. PMID- 22248420 TI - Correspondence. Acoustice Particle Counting and/or Sizing Device. PMID- 22248421 TI - Timing of injury in utero causing respiratory inhibition after crying. AB - BACKGROUND: The aim of this study was to clarify the timing of injuries in utero that cause respiratory inhibition after crying (RIAC). We evaluated infants with cranial ultrasound abnormalities diagnosed during hospitalization. METHODS: We retrospectively examined the medical records of preterm infants who were treated in the neonatal intensive care unit at Nara Prefectural Hospital in Nara, Japan from January 2006 through December 2010. Inclusion criterion was gestational age less than 34 weeks. We evaluated the perinatal factors and cranial ultrasound abnormalities associated with RIAC, feeding hypoxemia, and prolonged apnea. We also evaluated the timing of appearance of cranial ultrasound abnormalities. RESULTS: A total of 125 infants were examined. Mean gestational age was 30.6 +/- 2.4 weeks and mean birthweight was 1465 +/- 454 g. The numbers of infants who showed RIAC, feeding hypoxemia, and prolonged apnea were 44, 48, and 63, respectively. Among 91 infants who showed cranial ultrasound abnormalities, 67 had increased echogenicity in the ganglionic eminence (GE). There was a significant correlation between increased echogenicity and RIAC (P < 0.001). Of the infants who showed increased echogenicity in the GE, 19 had this finding during the course of hospitalization. In these 19 infants, however, gestational age of those with RIAC was less than 31 weeks. CONCLUSION: We speculate that the timing of intrauterine injury resulting in RIAC in infants is less than 31 gestational weeks. PMID- 22248422 TI - Medial temporal lobe is vulnerable to vascular risk factors in men: a population based study. AB - BACKGROUND AND PURPOSE: Vascular risk factors (VRFs) are known to cause cerebral microvascular disease, but evidence supporting an effect of VRFs on regional brain atrophy is mixed. We investigate whether an aggregation of VRFs is associated with volume of hippocampus and entorhinal cortex in elderly people living in the community. METHODS: This cross-sectional study consists of 523 participants (age >=60 years, 59.3% women) of the SNAC-K Study in central Stockholm, Sweden, who were free of clinical stroke and cognitive impairment. We collected data on VRFs through interviews, clinical examination and inpatient register system. Hippocampal and entorhinal cortex volume was manually measured on magnetic resonance images. Data were analysed with general linear regression models controlling for demographics and total intracranial volume. RESULTS: In men, high total cholesterol and diabetes were significantly or marginally associated with smaller hippocampus and entorhinal cortex; when current smoking, binge alcohol drinking, high cholesterol and diabetes were aggregated, an increasing number of VRFs were significantly associated with decreasing volume of hippocampus and entorhinal cortex (P for linear trend <0.01). In women, none of individual VRFs or their aggregation was significantly associated with the volume of these brain regions, except former smoking that was significantly associated with a larger volume of these regions. CONCLUSIONS: Aggregation of VRFs is associated with reduced hippocampal and entorhinal cortex volume in apparently healthy elderly men, but not in women. This implies that in men, the medial temporal lobe is vulnerable to cardiovascular risk factors. PMID- 22248423 TI - Can we treat ulcerative colitis with nutritional supplements? PMID- 22248425 TI - Development and assessment of the constipation-related disability scale. PMID- 22248426 TI - Visceral adiposity index and exercise in non-alcoholic fatty liver disease. PMID- 22248428 TI - Intrabiliary rapamycin may slow progression of primary sclerosing cholangitis. PMID- 22248429 TI - Brain training in older adults: evidence of transfer to memory span performance and pseudo-Matthew effects. AB - In this study the effects of 'brain training' using the Nintendo DS Brain Training program were examined in two groups of older adults; the cognitive performance of an experimental group (n = 21) who were asked to use the Nintendo DS regularly over a 6-week period was compared with the control group (n = 20). Groups were matched on age (mean age = 74 years), education, computer experience, daily activities (time spent reading or watching television), and initial scores of Wechsler Adult Intelligence Scale. Analyses revealed that improvements were primarily in the Digit Span Test, specifically Digits Backwards. Although the Brain Training package appeared to have some efficacy, other factors such as perceived quality of life and perceived cognitive functioning were at least equally important in determining training outcomes. The implications of these findings for cognitive training are discussed. PMID- 22248430 TI - Surface labeling of enveloped viruses assisted by host cells. AB - Labeling of virus opens new pathways for the understanding of viruses themselves and facilitates the utilization of viruses in modern biology, medicine, and materials. Based on the characteristic that viruses hijack their host cellular machineries to survive and reproduce themselves, a host-cell-assisted strategy is proposed to label enveloped viruses. By simply feeding Vero cells with commercial 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(cap biotinyl) (sodium salt) (Biotin-Cap-PE), we obtained biotinylated Vero cells whose membrane systems were modified with biotin. Subsequently, pseudorabies viruses (PrV) were cultivated in the biotinylated Vero cells, and the PrV progenies were spontaneously labeled with Biotin-Cap-PE during viral natural assembly process. Since the viral natural assembly process was employed for the labeling, potential threats of genetic engineering and difficulties in keeping viral natural bioactivity were avoided. Importantly, this labeling strategy for enveloped virus greatly reduces the technical complexity and allows researchers from different backgrounds to apply it for their specified demands. PMID- 22248432 TI - Mesoporous carbon/zirconia composites: a potential route to chemically functionalized electrically-conductive mesoporous materials. AB - Mesoporous nanocomposite materials in which nanoscale zirconia (ZrO(2)) particles are embedded in the carbon skeleton of a templated mesoporous carbon matrix were prepared, and the embedded zirconia sites were used to accomplish chemical functionalization of the interior surfaces of mesopores. These nanocomposite materials offer a unique combination of high porosity (e.g., ~84% void space), electrical conductivity, and surface tailorability. The ZrO(2)/carbon nanocomposites were characterized by thermogravimetric analysis, nitrogen adsorption porosimetry, helium pychnometry, powder X-ray diffraction, Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy. Comparison was made with templated mesoporous carbon samples prepared without addition of ZrO(2). Treatment of the nanocomposites with phenylphosphonic acid was undertaken and shown to result in robust binding of the phosphonic acid to the surface of ZrO(2) particles. Incorporation of nanoscale ZrO(2) surfaces in the mesoporous composite skeleton offers unique promise as a means for anchoring organophosphonates inside of pores through formation of robust covalent Zr-O-P bonds. PMID- 22248434 TI - Attitudes toward obese persons and controllability beliefs: clarifying previously reported data. PMID- 22248433 TI - International Sleeve Gastrectomy Expert Panel Consensus Statement: best practice guidelines based on experience of >12,000 cases. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an emerging surgical approach, but 1 that has seen a surge in popularity because of its perceived technical simplicity, feasibility, and good outcomes. An international expert panel was convened in Coral Gables, Florida on March 25 and 26, 2011, with the purpose of providing best practice guidelines through consensus regarding the performance of LSG. The panel comprised 24 centers and represented 11 countries, spanning all major regions of the world and all 6 populated continents, with a collective experience of >12,000 cases. It was thought prudent to hold an expert consensus meeting of some of the surgeons across the globe who have performed the largest volume of cases to discuss and provide consensus on the indications, contraindications, and procedural aspects of LSG. The panel undertook this consensus effort to help the surgical community improve the efficacy, lower the complication rates, and move toward adoption of standardized techniques and measures. The meeting took place at on-site meeting facilities, Biltmore Hotel, Coral Gables, Florida. METHODS: Expert panelists were invited to participate according to their publications, knowledge and experience, and identification as surgeons who had performed >500 cases. The topics for consensus encompassed patient selection, contraindications, surgical technique, and the prevention and management of complications. The responses were calculated and defined as achieving consensus (>=70% agreement) or no consensus (<70% agreement). RESULTS: Full consensus was obtained for the essential aspects of the indications and contraindications, surgical technique, management, and prevention of complications. Consensus was achieved for 69 key questions. CONCLUSION: The present consensus report represents the best practice guidelines for the performance of LSG, with recommendations in the 3 aforementioned areas. This report and its findings support a first effort toward the standardization of techniques and adoption of working recommendations formulated according to expert experience. PMID- 22248436 TI - Directed R-group combination graph: a methodology to uncover structure-activity relationship patterns in a series of analogues. AB - A graphical method is introduced to study details of structure-activity relationships (SARs) in analogue series that further extends conventional analysis of analogues using R-group tables or related approaches and that provides additional and more differentiated SAR information. The newly designed graph structure represents entire series of analogues in a consistent manner, regardless of their size and complexity of substitution patterns. The approach is specifically tailored toward a systematic exploration and intuitive interpretation of SAR features involving different R-groups and their combinations. Analogues and their potency information are systematically organized on the basis of R-group combinations that are present in a series. This organization scheme results in graph components that represent well-defined SAR patterns. Analysis of these patterns provides an immediate access to critical substitution sites and R-group combinations, favorable and unfavorable R-groups, or nonadditive potency effects of multisite substitutions. Furthermore, the data structure makes it possible to design new analogues by combining favorable R group combinations derived from different compounds. PMID- 22248435 TI - Taeniasis and cysticercosis due to Taenia solium in Japan. AB - Taenia solium is a zoonotic cestode that causes taeniasis and cysticercosis in humans. The parasite is traditionally found in developing countries where undercooked pork is consumed under poor sanitary conditions and/or as part of traditional food cultures. However, the recent increase in international tourism and immigration is spreading the disease into non-endemic developed countries such as the United States. Although there has been concern that the number of cysticercosis cases is increasing in Japan, the current situation is not clear. This is largely because taeniasis and cysticercosis are not notifiable conditions in Japan and because there have been no comprehensive reviews of T. solium infections in Japan conducted in the last 15 years. Herein, we provide an overview of the status of T. solium infection in Japan over the past 35 years and point out the potential risks to Japanese society. PMID- 22248438 TI - Reviewing the somatic genetics of melanoma: from current to future analytical approaches. AB - Metastatic melanoma has traditionally been difficult to treat, and although molecularly based targeted therapies have shown promising results, they have yet to show consistent improvements in overall survival rates. Thus, identifying the key mutation events underlying the etiology of metastatic melanoma will no doubt lead to the improvement of existing therapeutic approaches and the development of new treatment strategies. Significant advances toward understanding the complexity of the melanoma genome have recently been achieved using next generation sequencing (NGS) technologies. However, identifying those mutations driving tumorigenesis will continue to be a challenge for researchers, in part because of the high rates of mutation compared to other cancers. This article will review the catalog of mutations identified in melanoma through a variety of approaches, including the use of unbiased exome and whole-genome NGS platforms, as well discuss complementary strategies for identifying driver mutations. The promise of personalized medicine afforded by better understanding these mutation events should provide impetus for increased activity and rapid advances in this field. PMID- 22248437 TI - Cancer immunotherapy. AB - The remarkable specificity of the immune system through antigen recognition has long attracted investigators to the possibility of immune-based therapy for cancer. Previous cancer immunotherapeutics had been restricted to non-specific immunomodulatory agents, such as the cytokines IL-2 or IFN-alpha. However, the molecular definition of cancer-associated antigens introduced the possibility of specific vaccines and adoptive T cell approaches aiming to target the tumor cells more specifically. The recent introduction of total exome sequencing has enabled the identification of patient tumor-specific epitopes generated through somatic point mutations, raising the possibility of targeting tumor antigens in individual patients which are even more tumor-specific. Transcriptional profiling and immunohistochemistry analyses have revealed a subset of patients with a pre existing T cell-inflamed tumor microenvironment. This phenotype may be predictive of clinical outcome to immunotherapies and offers the possibility of a predictive biomarker. Further analysis of these tumors has identified a set of defined immune suppressive factors which themselves are being targeted with new immunotherapeutics, already with interesting early phase clinical trial results. Understanding not only the expression of tumor antigens but also the dynamic between a growing tumor and the host immune response is thus generating a rich set of opportunities for the specific immunotherapy of cancer. PMID- 22248439 TI - Genetic polymorphism M235T of angiotensinogen: effects on endothelial function and arterial stiffness in hypertensives. PMID- 22248441 TI - High reliability transformation of the wheat pathogen Bipolaris sorokiniana using Agrobacterium tumefaciens. AB - Bipolaris sorokiniana, the causal agent of spot blotch of wheat, significantly reduces grain yield worldwide. In order to study pathogenic mechanisms of the fungus, conditions for efficient transformation using Agrobacterium-mediated transformation were investigated. To study different stages of hyphal fusion and pathogenic mechanisms of the fungus, two fluorescence markers viz. the red fluorescent protein (DsRed-Express) and the green fluorescent protein (EGFP1) were constitutively expressed. Southern hybridizations confirmed the presence of T-DNA in all hygromycin B or geneticin resistant transformants, and also showed random and single copy integration. Fluorescence microscopy suggested the high level expression of both DsRed and EGFP fluorescent proteins in spores and mycelia. The results signify that DsRed and EGFP can be used as efficient reporter gene for monitoring B. sorokiniana hyphal fusion as well as colonization in the host tissues. This work will be useful to develop methodologies for understanding the mechanisms of Bipolaris-wheat interaction and functional genomics of B. sorokiniana for various applications including insertional mutagenesis, targeted disruption of specific genes, ectopic complementation of loss-of-function strains and over-expression. PMID- 22248442 TI - Hormonal organization and activation: evolutionary implications and questions. AB - Comparative endocrinology is a fascinating field of science in part because it addresses both ultimate and proximate causation. Research on sexual dimorphism and sexual differentiation has excellent potential for this kind of integration. Vertebrate comparative endocrinologists have made many important discoveries about the role of genes and sex steroid hormones in the organization and activation of sexually differentiated behavior, brain function, anatomy and physiology. In addition to taxonomically general principles and conserved features, there is also striking diversity in sexual differentiation processes. Much of the evolutionary basis of this diversity (its phylogenetic history and adaptive functions) is not well understood. A set of questions is raised to illustrate this point, with an emphasis on mechanisms of sexual dimorphism in body size and ornamentation, sexual differentiation of avian behavior, particularly in Japanese quail and zebra finches, and the puzzle of the phylogenetic distribution of vertebrate sex determining mechanisms. Applying a comparative approach grounded in established phylogenies and concepts from evolutionary developmental biology such as developmental modules holds promise for generating and testing new hypotheses and eventually answering some of these questions. PMID- 22248440 TI - Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration. AB - Methylphenidate (MPD) is a psychostimulant that enhances dopaminergic neurotransmission in the central nervous system by using mechanisms similar to cocaine and amphetamine. The mode of action of brain circuitry responsible for an animal's neuronal response to MPD is not fully understood. The nucleus accumbens (NAc) has been implicated in regulating the rewarding effects of psychostimulants. The present study used permanently implanted microelectrodes to investigate the acute and chronic effects of MPD on the firing rates of NAc neuronal units in freely behaving rats. On experimental day 1 (ED1), following a saline injection (control), a 30 min baseline neuronal recording was obtained immediately followed by a 2.5 mg/kg i.p. MPD injection and subsequent 60 min neuronal recording. Daily 2.5 mg/kg MPD injections were given on ED2 through ED6 followed by 3 washout days (ED7 to ED9). On ED10, neuronal recordings were resumed from the same animal after a saline and MPD (rechallenge) injection exactly as obtained on ED1. Sixty-seven NAc neuronal units exhibited similar wave shape, form and amplitude on ED1 and ED10 and their firing rates were used for analysis. MPD administration on ED1 elicited firing rate increases and decreases in 54% of NAc units when compared to their baselines. Six consecutive MPD administrations altered the neuronal baseline firing rates of 85% of NAc units. MPD rechallenge on ED10 elicited significant changes in 63% of NAc units. These alterations in firing rates are hypothesized to be through mechanisms that include D1 and D2-like DA receptor induced cellular adaptation and homeostatic adaptations/deregulation caused by acute and chronic MPD administration. PMID- 22248443 TI - The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis. AB - Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in the mammalian pituitary gland is well documented its functional significance remains obscure. Studies on the pars intermedia of the pituitary of the amphibian Xenopus laevis have shown that BDNF is produced by the neuroendocrine melanotrope cells, its expression is physiologically regulated, and the melanotrope cells themselves express receptors for the neurotrophin. The neurotrophin has been shown to act as an autocrine factor on the melanotrope to promote cell growth and regulate gene expression. In doing so BDNF supports the physiological function of the cell to produce and release alpha-melanophore-stimulating hormone for the purpose of adjusting the animal's skin color to that of its background. PMID- 22248444 TI - Thyroid hormone-dependent development in Xenopus laevis: a sensitive screen of thyroid hormone signaling disruption by municipal wastewater treatment plant effluent. AB - Because thyroid hormones (THs) are conserved modulators of development and physiology, identification of compounds adversely affecting TH signaling is critical to human and wildlife health. Anurans are an established model for studying disruption of TH signaling because metamorphosis is dependent upon the thyroid system. In order to strengthen this model and identify new gene transcript biomarkers for TH disruption, we performed DNA microarray analysis of Xenopus laevis tadpole tail transcriptomes following treatment with triiodothyronine (T(3)). Comparison of these results with previous studies in frogs and mammals identified 36 gene transcripts that were TH-sensitive across clades. We then tested molecular biomarkers for sensitivity to disruption by exposure to wastewater effluent (WWE). X. laevis tadpoles, exposed to WWE from embryo through metamorphosis, exhibited an increased developmental rate compared to controls. Cultured tadpole tails showed dramatic increases in levels of four TH-sensitive gene transcripts (thyroid hormone receptor beta (TRbeta), deiodinase type II (DIO2), and corticotropin releasing hormone binding protein (CRHBP), fibroblast activation protein alpha (FAPalpha)) when exposed to T(3) and WWE extracts. TRbeta, DIO2, and CRHBP were identified as TH sensitive in other studies, while FAPalpha mRNA transcripts were highly TH sensitive in our array. The results validate the array and demonstrate TH-disrupting activity by WWE. Our findings demonstrate the usefulness of cross-clade analysis for identification of gene transcripts that provide sensitivity to endocrine disruption. Further, the results suggest that development is disrupted by exposure to complex mixes of compounds found in WWE possibly through interference with TH signaling. PMID- 22248445 TI - Effects of carprofen, meloxicam and deracoxib on platelet function in dogs. AB - OBJECTIVE: To determine effects of anti-inflammatory doses of COX-2 selective NSAIDs carprofen, meloxicam, and deracoxib on platelet function in dogs and urine 11-dehydro-thromboxane B2. STUDY DESIGN: Randomized, blocked, crossover design with a 14-day washout period. ANIMALS: Healthy intact female Walker Hounds aged 1 6 years and weighing 20.5-24.2 kg. METHODS: Dogs were given NSAIDs for 7 days at recommended doses: carprofen (2.2 mg kg(-1), PO, every 12 hours), carprofen (4.4 mg kg(-1), PO, every 24 hours), meloxicam (0.2 mg kg(-1), PO, on the 1st day then 0.1 mg kg(-1), PO, every 24 hours), and deracoxib (2 mg kg(-1), PO, every 24 hours). Collagen/epinephrine and collagen/ADP PFA-100 cartridges were used to evaluate platelet function before and during and every other day after administration of each drug. Urine 11-dehydro-thromboxane B(2) was also measured before and during administration of each drug. RESULTS: All NSAIDs significantly prolonged PFA-100 closure times when measured with collagen/epinephrine cartridges, but not with collagen/ADP cartridges. The average duration from drug cessation until return of closure times (collagen/epinephrine cartridges) to baseline values was 11.6, 10.6, 11 and 10.6 days for carprofen (2.2 mg kg(-1) every 12 hours), carprofen (4.4 mg kg(-1) every 24 hours), meloxicam and deracoxib, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of some COX-2 selective NSAIDs causes detectable alterations in platelet function in dogs. As in humans, PFA-100 collagen/ADP cartridges do not reliably detect COX mediated platelet dysfunction in dogs. Individual assessment of platelet function is advised when administering these drugs prior to surgery, particularly in the presence of other risk factors for bleeding. PMID- 22248446 TI - Different efficiencies of attentional orienting in different wandering minds. AB - This study examined the relations between properties of attentional networks and Mind Wandering (MW) across individuals. For the attentional networks, we measured three components of attention, known as alerting, orienting, and executive control, using the Attention Network Test (ANT). To investigate MW, we measured thought probes embedded in the Sustained Attention to Response Task (SART). Moreover, four performance characteristics of the SART were calculated as behavioral indices of MW. Three of them showed significant associations with probed MW. Most research regarding MW focused on its relation to executive functions, while the present study revealed that MW, as indexed by self-reports and RT variability, was negatively correlated with orienting, specifically the exogenous orienting system. Furthermore, there was a positive association between RT variability and executive control. Our results suggest that individuals with higher tendency of MW are less sensitive to irrelevant external stimuli, supporting the decoupling hypothesis of MW. PMID- 22248447 TI - The dehaloperoxidase paradox. AB - The dual functions of the dehaloperoxidase-hemoglobin of Amphitrite ornata leads to a paradox. Peroxidase and hemoglobin functions require ferric and ferrous resting states, respectively. Assuming that hemoglobin function is the dominant function, the starting point for peroxidase activation would be the oxyferrous state. Activation of that state leads to the ferryl intermediate, followed by one electron oxidation of the substrate, which results in the ferric state. Since no exogenous reductant is known, there is no return to the ferrous form or hemoglobin function. The observation that an internal binding site for 4 bromophenol leads to inhibition leads to a further paradox that the enzyme would be inhibited immediately upon activation under ambient conditions in benthic ecosystems where the inhibitor, 4-bromophenol is present in greater concentration than the substrate, 2,4,6-tribromophenol. In this review, we explore the unresolved aspects of the reaction scheme that leads to the apparent paradox. Recent data showing activation of the oxyferrous state, an extremely high reduction potential and exogenous reduction by the 2,6-dibromoquinone product present a potential resolution of the paradox. These aspects are discussed in the context of control of reactivity radical pathways and reactivity by the motion of the distal histidine, H55, which in turn is coupled to the binding of substrate and inhibitor. PMID- 22248448 TI - Water. PMID- 22248449 TI - Real-space processing of helical filaments in SPARX. AB - We present a major revision of the iterative helical real-space refinement (IHRSR) procedure and its implementation in the SPARX single particle image processing environment. We built on over a decade of experience with IHRSR helical structure determination and we took advantage of the flexible SPARX infrastructure to arrive at an implementation that offers ease of use, flexibility in designing helical structure determination strategy, and high computational efficiency. We introduced the 3D projection matching code which now is able to work with non-cubic volumes, the geometry better suited for long helical filaments, we enhanced procedures for establishing helical symmetry parameters, and we parallelized the code using distributed memory paradigm. Additional features include a graphical user interface that facilitates entering and editing of parameters controlling the structure determination strategy of the program. In addition, we present a novel approach to detect and evaluate structural heterogeneity due to conformer mixtures that takes advantage of helical structure redundancy. PMID- 22248450 TI - Computational separation of conformational heterogeneity using cryo-electron tomography and 3D sub-volume averaging. AB - We have previously used cryo-electron tomography combined with sub-volume averaging and classification to obtain 3D structures of macromolecular assemblies in cases where a single dominant species was present, and applied these methods to the analysis of a variety of trimeric HIV-1 and SIV envelope glycoproteins (Env). Here, we extend these studies by demonstrating automated, iterative, missing wedge-corrected 3D image alignment and classification methods to distinguish multiple conformations that are present simultaneously. We present a method for measuring the spatial distribution of the vector elements representing distinct conformational states of Env. We identify data processing strategies that allow clear separation of the previously characterized closed and open conformations, as well as unliganded and antibody-liganded states of Env when they are present in mixtures. We show that identifying and removing spikes with the lowest signal-to-noise ratios improves the overall accuracy of alignment between individual Env sub-volumes, and that alignment accuracy, in turn, determines the success of image classification in assessing conformational heterogeneity in heterogeneous mixtures. We validate these procedures for computational separation by successfully separating and reconstructing distinct 3D structures for unliganded and antibody-liganded as well as open and closed conformations of Env present simultaneously in mixtures. PMID- 22248451 TI - Hydrogen-bond network and pH sensitivity in transthyretin: Neutron crystal structure of human transthyretin. AB - Transthyretin (TTR) is a tetrameric protein associated with human amyloidosis. In vitro, the formation of amyloid fibrils by TTR is known to be promoted by low pH. Here we show the neutron structure of TTR, focusing on the hydrogen bonds, protonation states and pH sensitivities. A large crystal was prepared at pD 7.4 for neutron protein crystallography. Neutron diffraction studies were conducted using the IBARAKI Biological Crystal Diffractometer with the time-of-flight method. The neutron structure solved at 2.0A resolution revealed the protonation states of His88 and the detailed hydrogen-bond network depending on the protonation states of His88. This hydrogen-bond network is composed of Thr75, Trp79, His88, Ser112, Pro113, Thr118-B and four water molecules, and is involved in both monomer-monomer and dimer-dimer interactions, suggesting that the double protonation of His88 by acidification breaks the hydrogen-bond network and causes the destabilization of the TTR tetramer. In addition, the comparison with X-ray structure at pH 4.0 indicated that the protonation occurred to Asp74, His88 and Glu89 at pH 4.0. Our neutron model provides insights into the molecular stability of TTR related to the hydrogen-bond network, the pH sensitivity and the CH...O weak hydrogen bond. PMID- 22248452 TI - Three-dimensional structure of the shell plate assembly of the chiton Tonicella marmorea and its biomechanical consequences. AB - This study investigates the three-dimensional structure of the eight plate exoskeletal (shell) assembly of the chiton Tonicella marmorea. X-ray micro computed tomography and 3D printing elucidate the mechanism of conformational change from a passive (slightly curved, attached to surface) to a defensive (rolled, detached from surface) state of the plate assembly. The passive and defensive conformations exhibited differences in longitudinal curvature index (0.43 vs. 0.70), average plate-to-plate overlap (~62% vs. ~48%), cross-sectional overlap heterogeneity (60-82.5% vs. 0-90%, fourth plate), and plate-to-plate separation distance (100% increase in normalized separation distance between plates 4 and 5), respectively. The plate-to-plate interconnections consist of two rigid plates joined by a compliant, actuating muscle, analogous to a geometrically structured shear lap joint. This work provides an understanding of how T. marmorea achieves the balance between mobility and protection. In the passive state, the morphometry of the plates and plate-to-plate interconnections results in an approximately continuous curvature and constant armor thickness, resulting in limited mobility but maximum protection. In the defensive state, the underlying soft tissues gain protection and the chiton gains mobility through tidal flow, but regions of vulnerability open dorsally, due to the increase in plate-to-plate separation and decrease in plate-to-plate overlap. Lastly, experiments using optical and scanning electron microscopy, mercury porosimetry, and Fourier-transform infrared spectroscopy explore the microstructure and spatial distribution of the six layers within the intermediate plates, the role of multilayering in resisting predatory attacks, and the detection of chitin as a major component of the intra-plate organic matrix and girdle. PMID- 22248453 TI - Structural and dynamical analysis of an engineered FhuA channel protein embedded into a lipid bilayer or a detergent belt. AB - Engineered channel proteins are promising nano-components with applications in nanodelivery and nanoreactors technology. Because few of the engineered channel proteins have been crystallized, solution studies based on Neutron Scattering, Circular Dichroism and NMR play a major role. Consequently, the understanding of membrane proteins dynamics in water/detergent solutions or when embedded in a lipid membrane, can clarify how the environment affects protein behavior. In this study, molecular dynamics simulations of the FhuA Escherichia coli outer membrane channel protein and its engineered FhuA Delta1-159 variant have been performed in two different environments: a DNPC (1,2-dinervonyl-sn-glycero-3-phosphocholine) lipid bilayer and a water/OES (N-octyl-2-hydroxyethyl sulfoxide) detergent solution. Furthermore the FhuA Delta1-159 variant has been simulated in the open and closed states, the last induced by the presence of six 3-(2-pyridyldithio) propionic-acid in the channel inner core. Differences in protein structural and dynamical behavior between the two environments have been found. Considering the FhuA protein characterized by an elliptical-cylindrical symmetry: (a) neither variations on the secondary structure nor axial deformation have been observed in any of the systems; (b) the ellipticity of the channel section (open state) and its fluctuations are enhanced in presence of water/OES, while diminished or suppressed in the DNPC bilayer; (c) the insertion of hydrophobic pyridyl groups into the FhuA Delta1-159 channel (closed state) induces a higher ellipticity in water/OES solution, while shifting to a circular section in the DNPC membrane; (d) the cork domain represented by the first 159 amino acids does not play a major role for protein stability. PMID- 22248454 TI - Removing high contrast artifacts via digital inpainting in cryo-electron tomography: an application of compressed sensing. AB - To cope with poor quality in cryo-electron tomography images, electron-dense markers, such as colloidal goldbeads, are often used to assist image registration and analysis algorithms. However, these markers can create artifacts that occlude a specimen due to their high contrast, which can also cause failure of some image processing algorithms. One way of reducing these artifacts is to replace high contrast objects with pixel densities that blend into the surroundings in the projection domain before volume reconstruction. In this paper, we propose digital inpainting via compressed sensing (CS) as a new method to achieve this goal. We show that cryo-ET projections are sparse in the discrete cosine transform (DCT) domain, and, by finding the sparsest DCT domain decompositions given uncorrupted pixels, we can fill in the missing pixel values that are occluded by high contrast objects without discontinuities. Our method reduces visual artifacts both in projections and in tomograms better than conventional algorithms, such as polynomial interpolation and random noise inpainting. PMID- 22248455 TI - Structure, glass transition temperature and spectroscopic properties of 10Li2O xP2O5-(89-x)TeO2-1CuO (5<=x<=25 mol%) glass system. AB - X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), energy dispersive X-ray spectrometry (EDS), differential scanning calorimetry (DSC), infrared (IR), Raman, electron paramagnetic resonance (EPR) and optical absorption studies on 10Li2O-xP2O5-(89-x)TeO2-1CuO glasses (where x=5, 10, 15, 20 and 25 mol%) have been carried out. The amorphous nature of the glasses was confirmed using XRD and FESEM measurements. The glass transition temperature (Tg) of glass samples have been estimated from DSC traces and found that the Tg increases with increasing P2O5 content. Both the IR and Raman studies have been showed that the present glass system consists of [TeO3], [TeO4], [PO3] and [PO4] units. The spin-Hamiltonian parameters such as g?, g?, and A? have been determined from EPR spectra and it was found that the Cu2+ ion is present in tetragonal distorted octahedral site with [Formula: see text] as the ground state. Bonding parameters and bonding symmetry of Cu2+ ions have been calculated by correlating EPR and optical data and were found to be composition dependent. PMID- 22248456 TI - Structural, vibrational, electronic, NMR and reactivity analyses of 2-amino-4H chromene-3-carbonitrile (ACC) by ab initio HF and DFT calculations. AB - This study represents an integrated approach towards understanding the vibrational, electronic, NMR, reactivity and structural aspects of 2-amino-4H chromene-3-carbonitrile (ACC). A detailed interpretation of the FT IR, UV and NMR spectra were reported. Theoretical calculations were performed by ab initio HF and density functional theory (DFT)/B3LYP method using 6-311++G(d,p) basis sets. The electronic properties was also studied and the most prominent transition corresponds to pi->pi*. The lower frontier orbital energy gap and high dipole moment illustrates the high reactivity of the title molecule. The NMR results indicated that the observed chemical shifts depend not only on the structure of the molecule being studied, but also on the solvent used. ACC exhibited good nonlinear optical activity and was much greater than that of urea. Molecular electrostatic potential (MEP) results predicted that the enaminonitrile fragment of ACC to be the most reactive site for both electrophilic and nucleophilic attack. In addition, the thermodynamic properties of the compound were calculated at different temperatures and corresponding relations between the properties and temperature were also studied. PMID- 22248458 TI - Current concepts on pathogenesis and biology of metastatic osteosarcoma tumors. AB - Osteosarcoma (OS) remains the most common malignancy among orthopaedic neoplasms. Despite advanced surgical techniques and attempts to use second-line chemotherapy, 5 year overall survival in OS patients is still reported to be as low as 60-70%. Progression to metastatic disease is the main cause of treatment failures. Broadening current knowledge on the pathogenesis and biology of metastatic OS tumors is a key element in improving treatment results, i.e. identifying potential therapeutic targets. Recent studies have brought new concepts into this field. This paper outlines the most important issues which may influence treatment methods in the near future. In a few sections, we discuss (1) a model of OS dissemination with special regard to proteins mediating the lysis of the extracellular matrix; (2) the mechanisms protecting circulating OS cells from programmed death; (3) the relationship between angiogenesis, its pathogenesis, and OS metastatic potential; (4) the role of cytokines in OS progression and site-specific metastasis formation; (5) an example of treatment resistance mechanism - the P glycoprotein efflux pump; and, finally, we theorize on (6) whether cancer stem cells may play a role in OS progression. PMID- 22248457 TI - Multiple processes underlie benzodiazepine-mediated increases in the consumption of accepted and avoided stimuli. AB - Hyperphagia is a reported side effect of anxiolytic benzodiazepines such as chlordiazepoxide (CDP). Prior research has focused primarily on the ingestive responses to sweet or solid foods. We examined CDP effects on licking for normally accepted and avoided taste solutions across a range of concentrations. The effect of CDP (10 mg/kg) versus saline on the licking patterns of water restricted rats for water and 3 concentrations of sucrose, saccharin, NaCl, monosodium glutamate (MSG), citric acid, and quinine (Q-HCl) solutions was evaluated during 1 h tests. CDP increased meal size for all tastants except citric acid. Analysis of licking microstructure revealed 3 dissociable effects of CDP. CDP affected oromotor coordination as indicated by a uniform increase in the modal interlick interval for all stimuli. CDP increased meal size as indicated by shorter pauses during consumption of water, MSG, and weaker saccharin concentrations, and by fewer long interlick intervals (250-2000 ms) for normally avoided tastants. CDP also increased meal size by increasing burst size, burst duration, and the initial rate of licking for most solutions, suggesting increased hedonic taste evaluation. CDP did not affect variables associated with postingestive feedback such as meal duration or number of bursts, and the results also suggest that CDP did not enhance the perceived taste intensity. We hypothesize that the reduction of pause duration is consistent with an increased motivation to sample the stimulus that synergizes with changes in taste-mediated responsiveness to some but not all stimuli to yield increases in the consumption of both normally accepted and avoided taste stimuli. PMID- 22248459 TI - Fingertip injuries in children treated in Department of Pediatric Surgery and Oncology in the years 2008-2010. AB - BACKGROUND: Fingertip injuries are the most common hand injuries in children seeking medical advice at trauma care centres. Most cases are treated conservatively and hospitalisation is not necessary. However, surgery under general anaesthesia is often required on account of severity of the injuries and the patients' young age. The aim of the paper is to discuss a series of patients treated in the Department of Paediatric Surgery and Oncology between 2008 and 2010, and present the problems associated with surgical care in fingertip injuries in children. MATERIAL AND METHODS: A total of 76 children were treated in the Department of Pediatric Surgery and Oncology between 2008 and 2010 because of fingertip injuries. This group is estimated to represent approx. 10% of all patients admitted to the Emergency Unit. Fingertip injuries were treated with situation sutures, V-Y-plasty, suturing back the amputated fingertip and by suturing into thenar skin. Data were extracted from medical files and presented as percentages. RESULTS: There were 50 boys in the group of 76 children (65.79%). Mean age was 7 years. Most of the patients were children aged 1 to 5 years (36 patients, 47.37%). In 45 children (59%), the right hand was injured. Injury to fingers responsible for the pincer grasp occurred in 29 children (38.16%). CONCLUSIONS: Fingertip injuries are among the most common injuries in children and preservation of the hand's motor abilities depends on thorough surgical care. Most children with fingertip injuries are treated in Emergency Units and only 10% of patients need surgery under general anaesthesia after hospital admission. A number of surgical techniques can be used in the management of fingertip injuries in children. These techniques represent adaptations of methods used in adults. A model for the evaluation of severity and management of fingertip injuries in children should be established. PMID- 22248460 TI - Immediate and long-term effects of selected physiotherapy methods in patients with carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome is a serious therapeutic problem and it considerably impairs the patients' quality of life. Despite many studies, the effectiveness of conservative treatment is still debatable. This study aimed to evaluate the immediate and long-term effects of conservative treatment involving ultrasound therapy combined with massage and kinesiotherapy for carpal tunnel syndrome. MATERIAL AND METHODS: A total of 61 patients with carpal tunnel syndrome were assessed with regard to such symptoms as pain, numbness, tingling sensation, morning stiffness, and self-care difficulties. We used provocation tests and investigated sensory impairments, autonomic disturbances, and Luthy's sign. Conduction in the median nerve fibres was assessed during a nerve conduction study. We performed computer-aided measurement of the hand joint range of motion and global grip strength. The tests were conducted before and on completion of a rehabilitation programme. The hands were re-examined one year later. The treatment involved ultrasound therapy, massage, and kinesiotherapy. RESULTS: The treatment outcomes confirmed the effectiveness of the therapeutic programme. Significant improvements concerning the majority of the symptoms were observed between the first and second examination as well for the entire follow up period. We observed significant improvement in the quality of sensation, the hand range of motion and muscle strength. CONCLUSIONS: Ultrasound therapy combined with massage and kinesiotherapy brings the expected, long-term effects in patients with carpal tunnel syndrome. PMID- 22248461 TI - The treatment of intertrochanteric fractures of the femur with Endovis nail. AB - BACKGROUND: The incidence of fractures in the trochanteric area has risen with the increasing numbers of elderly persons with osteoporosis. The imperative goals of treatment are early mobilization by means of stable fixation using as minimally invasive a procedure as possible. Nowadays, there is an increasing interest in intramedullary nailing, especially for unstable intertrochanteric fractures. The aim of the present paper is to assess the efficacy of closed intramedullary osteosynthesis with the Endovis(r) proximal femoral nail in the treatment of peritrochanteric fractures to solve the problems associated with the use of intramedullary fixation devices. MATERIAL AND METHODS: The authors describe their experience with 87 stable and unstable proximal extra-capsular femoral fractures treated with the Endovis femoral nail from July 2007 to March 2009. The results were evaluated clinically, functionally and radiographically during the 1st, 3th, 6th and 12th months post-op. Pre-injury activity and functional levels were recorded using the modified Harris hip score and V.A.S. score. RESULTS: Postoperative radiographs showed a near-anatomical fracture reduction in 85% of patients. Three were the cases of cut-out, one case of valgus and two cases of shortening of the operated leg (<1 cm). The Harris Hip Score increased between the thirtieth and ninetieth postoperative day, accompanied by a significant decrease in pain symptoms and functional limitation. CONCLUSION: 1. The application of an intramedullary nail provides primary stability of the fracture. 2. The Endovis nail constitutes a powerful synthesis for stable and unstable fractures of the trochanteric region, in which is difficult to reconstruct appropriate continuity between the medial and posterior cortical layers. 3.The good mechanical stability of the nail allows rapid mobilization and early functional recovery. 4. The presence of an additional anti-rotational screw and the free sliding mechanism of the lag screw may increase rotational stability of cervico-cephalic fragments and decrease overload on the femoral head. PMID- 22248462 TI - Selected cases of arthroscopic treatment of popliteal cyst with associated intra articular knee disorders primary report. AB - INTRODUCTION: The goal of the reported study was an evaluation of results, obtained in the treatment of knee joints with intraarticular pathologies, concomitant with cysts in the popliteal fossa. We hypothesized that removal of popliteal cyst and associated pathology will provide improvement in function, pain of operated knee and patient satisfaction. MATERIAL AND METHODS: There were 10 patients involved in the study (6 male and 4 female) at the age ranging from 6 to 53 years, with a symptomatic popliteal cyst. The follow-up period varied from 6 to 20 months. RESULTS: In all patients intraarticular pathologies were concomitant with popliteal cyst and included: ACL lesion, medial meniscal tear, synovitis, chondral lesion, chondromatosis and synovial plica syndrome. In 50% of the patients, a valvular mechanism was visualised and eliminated during operation. On the average, the Lysholm score was 45.9 before operation and 86.1 at last follow-up. Based on the Visual Analogue Scale patients evaluated their knee joints, on the average 8.2 at before and 3.3 after the operation. According our own scales all but one patient had functional improvement of operated knee, felt better about the knee than before operation and would recommend the treatment to friends and family. Also according to Rauschning and Lindgren classification all but one patient had improvement. No long-term complications were found in any of the operated patients. CONCLUSIONS: Elimination of intraarticular pathologies coexisting with popliteal cyst provides significant improvement of knee function, pain and patient satisfaction. PMID- 22248463 TI - Evaluation of anterior stability of knee joint following arthroscopic ACL reconstruction with patellar ligament. AB - BACKGROUND: The aim of the study was to investigate and assess anterior stability of the knee joint before and during 12-month rehabilitation after arthroscopic reconstruction of the anterior cruciate ligament with the central third of the patellar ligament and stabilization with interference screws (Kenneth-Jones method) and to analyse the effectiveness of the surgery and rehabilitation by patient self-assessment of pain and crepitation in the patello-femoral joint. MATERIAL AND METHODS: The study involved a group of 46 patients after arthroscopic ACL reconstruction with the patellar ligament performed in 2005 and 2006. All patients underwent examinations of anterior stability of the knee joint using a KT-1000/S arthrometer. Stability measurements were performed on both knees on the day before surgery, and at 3, 6 and 12 months after the operation. Additionally, the patients subjectively evaluated post-operative pain and crepitation in the patello-femoral joint at 3, 6 and 12 months. RESULTS: Knee stability after ACL reconstruction according to the Mazurkiewicz scale using a KT 1000 arthrometer was rated as good and excellent, while the patients subjectively assessed the treatment process in terms of pain and crepitation in the patello femoral joint at 12 months after the operation as excellent (10.8%), good (74%), and satisfactory (15.2%). CONCLUSIONS: Arthroscopic ACL reconstruction with the central third of the patellar ligament and stabilization with interference screws fully restored the lost stability of the knee, but the possibility of pain and crepitations in the patello-femoral joint needs to be taken into account. In the course of rehabilitation, it is natural that an ACL graft may extend as a result of remodeling and the impact of rehabilitation being administered. PMID- 22248464 TI - Weight-height ratios and parameters of body posture in 7-9-year-olds with particular posture types. AB - BACKGROUND: Small and relatively balanced anteroposterior curvatures and symmetric positioning of the shoulders, scapulae, waist triangles, anterior superior iliac spines, knees and feet are the elements of a good posture. The aim of our study was to determine which somatic features and parameters of spinal curvatures in the sagittal plane show statistically significant differences among children with particular types of body posture. MATERIAL AND METHODS: The study was carried out in selected primary schools of the Subcarpathian and Silesian regions. We examined a total of 563 randomly selected first- to third-graders whose parents had submitted written informed consent. The study group included 278 boys (49.38%) and 285 girls (50.62%). Twenty-four parameters describing the body posture were determined in every participant using the photogrammetric method. RESULTS: Gender-independent parameters helpful in differentiating postural types comprise the compensation indicator, inclination angle of the superior thoracic spine, C7-PL length (length of kyphosis), and inclination angle of the thoracolumbar spine. CONCLUSIONS: The inclination angle of the lumbosacral spine, total curvature length, position of the apex of lordosis relative to S1, and S1-PL length (length of lordosis), appeared to be the least helpful in differentiating among postural types. PMID- 22248465 TI - A case study in bilateral radial head fractures in apparently trivial trauma: a subtle diagnosis. AB - Radial head and neck fractures are common in young to middle age adults and are seen in nearly 20 % of acute elbow injuries in this age group. These are usually associated with high energy traumas like falls from height, road traffic accidents and sports injuries. Unilateral radial head fractures are relatively common and may be associated with other concomitant injuries. Bilateral radial head fractures are rare and are mostly seen in situations when the patient has a fall on outstretched, supinated hands or a direct fall on the elbow. These injuries can be easily missed by the attending physician if the symptoms are more severe on one side, thus neglecting the other. The treatment of these fractures may be conservative or operative, depending upon the degree of head comminution, the percentage of articular surface involved, presence of loose intra-articular fragments and angulation between the radial neck and proximal shaft. We present a case series of three patients with bilateral type 1 radial head fractures (one case having type 3 on one side) managed with brief immobilization followed by active physiotherapy and full, uneventful recovery. The emphasis in these cases is the need for a high index of suspicion in the diagnosis of multiple injuries, no matter how 'trivial' the mechanism of injury and, unless the history of the mode of trauma is highly suggestive, such injuries can be missed easily and cause long term problems for the patient. PMID- 22248466 TI - Reconstruction of chronic patellar tendon rupture with semitendinosus tendon: case report. AB - Chronic patellar tendon rupture is a rare injury whose treatment poses technical difficulties. Surgical repair is mandatory to restore the extensor mechanism of the knee. Many different surgical methods of patellar tendon reconstruction have been described. We present the case of a 48-year-old male patient who sustained patellar tendon rupture 8 months before surgery. A semitendinosus tendon graft and the modified Ecker technique were used for the reconstruction of the patellar tendon. Full extension was achieved alongside high patient satisfaction. However, the patient required prolonged intensive rehabilitation. PMID- 22248467 TI - Prostheses and orthoses in the collections of the Auschwitz-Birkenau State Museum. AB - The authors described 424 orthopaedic appliances left by the prisoners of the Nazi Concentration Camp in Oswiecim. A collection of prostheses and orthoses, which is currently a part of the Auschwitz-Birkenau State Museum's exhibition, is extraordinary as it illustrates the fate of innocent, crippled people, who were incarcerated and murdered. Another point of value of the collection is its technical aspect, as it provides a clear picture of construction of prostheses and orthoses at the beginning of the 20th century. PMID- 22248468 TI - A fully implantable rodent neural stimulator. AB - The ability to electrically stimulate neural and other excitable tissues in behaving experimental animals is invaluable for both the development of neural prostheses and basic neurological research. We developed a fully implantable neural stimulator that is able to deliver two channels of intra-cochlear electrical stimulation in the rat. It is powered via a novel omni-directional inductive link and includes an on-board microcontroller with integrated radio link, programmable current sources and switching circuitry to generate charge balanced biphasic stimulation. We tested the implant in vivo and were able to elicit both neural and behavioural responses. The implants continued to function for up to five months in vivo. While targeted to cochlear stimulation, with appropriate electrode arrays the stimulator is well suited to stimulating other neurons within the peripheral or central nervous systems. Moreover, it includes significant on-board data acquisition and processing capabilities, which could potentially make it a useful platform for telemetry applications, where there is a need to chronically monitor physiological variables in unrestrained animals. PMID- 22248469 TI - TGFBI promoter hypermethylation correlating with paclitaxel chemoresistance in ovarian cancer. AB - The purpose of this study is to determine the methylation status of Transforming growth factor-beta-inducible gene-h3 (TGFBI) and its correlation with paclitaxel chemoresistance in ovarian cancer. The methylation status of TGFBI was examined in ovarian cancer and control groups by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). The TGFBI expression and cell viability were compared by Quantitative Real-Time PCR, Western Blotting and MTT assay before and after demethylating agent 5-aza-2'-deoxycytidine (5-aza-dc) treatment in 6 cell lines (SKOV3, SKOV3/TR, SKOV3/DDP, A2780, 2780/TR, OVCAR8). In our results, TGFBI methylation was detected in 29/40 (72.5%) of ovarian cancer and 1/10 (10%) of benign ovarian tumors. No methylation was detected in normal ovarian tissues (P < 0.001). No statistical correlation between RUNX3 methylation and clinicopathological characteristics was observed. A significant correlation between TGFBI methylation and loss of TGFBI mRNA expression was found (P < 0.001). The methylation level of TGFBI was significantly higher in paclitaxel resistant cell lines (SKOV3/TR and 2780/TR) than that in the sensitive pairs (P < 0.001). After 5-aza-dc treatment, the relative expression of TGFBI mRNA and protein increased significantly in SKOV3/TR and A2780/TR cells. However, no statistical differences of relative TGFBI mRNA expression and protein were found in other cells (all P > 0.05), which showed that re-expression of TGFBI could reverse paclitaxel chemoresistance. Our results show that TGFBI is frequently methylated and associated with paclitaxel-resistance in ovarian cancer. TGFBI might be a potential therapeutic target for the enhancement of responses to chemotherapy in ovarian cancer patients. PMID- 22248470 TI - Hormonally active doses of isoflavone aglycones promote mammary and endometrial carcinogenesis and alter the molecular tumor environment in Donryu rats. AB - Our research is focused on modifying effects of an isoflavone aglycones (IAs) rich extract at a hormonally active dose of 150 mg/kg body weight/day on mammary and endometrial carcinogenesis in female Donryu rats. IA administered for 2 weeks in a phytoestrogen-low diet exerted estrogenic activity and induced cell proliferation in the uterus of ovariectomized rats. Furthermore, administration for 4 weeks resulted in elevation of cell proliferation in the mammary glands of 7,12-dimethylbenz[a]anthracene (DMBA)-treated animals. Forty weeks of postpubertal administration of IA to 5-week-old rats after initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) caused significant increase of incidence and multiplicity of mammary adenocarcinoma, multiplicities of endometrial atypical hyperplasia, adenomatous polyps, and an increased trend of uterine adenocarcinomas. Liquid chromatography with tandem mass spectrometry and immunohistochemical analyses revealed significant elevation of tumorigenesis-related proteins such as S100 calcium binding protein A8, kininogen 1, and annexins 1 and 2 in mammary adenocarcinomas and cadherin EGF LAG seven-pass G-type receptor 2, DEAD box polypeptide 1, and cysteine- and glycine-rich protein 1 in uterine proliferative lesions of IA treated animals. Those changes are likely to be related to modulation of estrogen receptor (ER), AP1, nuclear factor-kappa B, and actin signaling pathways. Our results indicate that the postpubertal exposure of Donryu rats to IA at an estrogenic dose results in promotion of mammary and uterine carcinogenesis induced by DMBA and ENNG, which might be related to the activation of ER dependent signaling and alteration of the molecular tumor environment in the mammary gland and endometrium. PMID- 22248471 TI - Editorial comment: Left ureteral replacement with appendix in pediatric renal transplantation. PMID- 22248472 TI - Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. AB - The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2 directed therapies to treat resistant tumors or deter relapse. PMID- 22248474 TI - Simulation study on discrete charge effects of SiNW biosensors according to bound target position using a 3D TCAD simulator. AB - We introduce a simulation method for the biosensor environment which treats the semiconductor and the electrolyte region together, using the well-established semiconductor 3D TCAD simulator tool. Using this simulation method, we conduct electrostatic simulations of SiNW biosensors with a more realistic target charge model where the target is described as a charged cube, randomly located across the nanowire surface, and analyze the Coulomb effect on the SiNW FET according to the position and distribution of the target charges. The simulation results show the considerable variation in the SiNW current according to the bound target positions, and also the dependence of conductance modulation on the polarity of target charges. This simulation method and the results can be utilized for analysis of the properties and behavior of the biosensor device, such as the sensing limit or the sensing resolution. PMID- 22248473 TI - The relationship of thioredoxin-1 and cisplatin resistance: its impact on ROS and oxidative metabolism in lung cancer cells. AB - Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatin-resistant tumors have higher reactive oxygen species (ROS) levels and can be exploited for targeted therapy. Here, we show that increased secretion of the antioxidant thioredoxin-1 (TRX1) resulted in lowered intracellular TRX1 and contributed to higher ROS in cisplatin-resistant tumors in vivo and in vitro. By reconstituting TRX1 protein in cisplatin-resistant cells, we increased sensitivity to cisplatin but decreased sensitivity to elesclomol (ROS inducer). Conversely, decreased TRX1 protein in parental cells reduced the sensitivity to cisplatin but increased sensitivity to elesclomol. Cisplatin resistant cells had increased endogenous oxygen consumption and mitochondrial activity but decreased lactic acid production. They also exhibited higher levels of argininosuccinate synthetase (ASS) and fumarase mRNA, which contributed to oxidative metabolism (OXMET) when compared with parental cells. Restoring intracellular TRX1 protein in cisplatin-resistant cells resulted in lowering ASS and fumarase mRNAs, which in turn sensitized them to arginine deprivation. Interestingly, cisplatin-resistant cells also had significantly higher basal levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Overexpressing TRX1 lowered ACC and FAS proteins expressions in cisplatin resistant cells. Chemical inhibition and short interfering RNA of ACC resulted in significant cell death in cisplatin-resistant compared with parental cells. Conversely, TRX1 overexpressed cisplatin-resistant cells resisted 5 (tetradecyloxy)-2-furoic acid (TOFA)-induced death. Collectively, lowering TRX1 expression through increased secretion leads cisplatin-resistant cells to higher ROS production and increased dependency on OXMET. These changes raise an intriguing therapeutic potential for future therapy in cisplatin-resistant lung cancer. PMID- 22248475 TI - Photoactive memory by a Si-nanowire field-effect transistor. AB - A photoactive memory is implemented on a n-type and p-type double-gate silicon nanowire (Si-NW) field-effect transistor (FET) through the grafting of solution processable [6,6]-phenyl-C(61)-butyric acid methyl ester (PCBM) in nanogaps. Despite integration with organic material, superior FET characteristics are observed. Lowered operation voltage is achieved through the use of an optical source and an efficient photon-absorbing structure. Due to the naturally separated gate structure for PCBM embedment, moreover, memory performances stemming from a photoactive property are notably improved by biasing asymmetric voltage to the separated gates, which are individually controlled. The development of photoactive Si-NW FET based on CMOS process can pave the way of optoelectronic applications with more degree of freedom in terms of overall device design. PMID- 22248476 TI - Syncope and Raynaud's disease. AB - OBJECTIVE: To investigate an association between syncope and Raynaud's disease (RD), its clinical features, and the effect of treatment with nifedipine. DESIGN: One-year prospective study of new outpatients after 3 initial clinical observations. SETTING: Neurology clinics at Chelsea and Westminster, Royal Free, Barnet, and Edgware Hospitals. PATIENTS: Ten women and 1 man. The group had a mean (SD) age of 33 (17) years. Mean (SD) follow-up was 24 (36) months. INTERVENTION: Treatment with nifedipine. OUTCOME MEASURES: Observed vs expected frequency of syncope in RD, temporal relation between syncope and Raynaud's phenomenon, clinical features, and response to nifedipine treatment. RESULTS: Eight additional patients with syncope and RD were identified from 603 new patients (1.3%); we had expected only 1 patient to be identified with syncope and RD (P=.003). A chance association between RD and migraine with recurrent syncope was unlikely (P=.01). The prevalence of RD in patients with syncope with migraine was higher than expected (P=.03), but that of migraine in patients with RD was not (P=.2). All 11 patients had 5 or more syncopal episodes for a median of 2 years (range, 0.1-62 years). Three patients had previous diagnoses of nonepileptic attacks. Syncope was preceded by or contemporaneous with Raynaud's phenomenon in 10 patients (P=.02). Nine patients had migraine; headache was contemporaneous with syncope in 4 patients as expected by chance (P=1.0). In all patients, syncope was preceded by brainstem or vertebrobasilar symptoms, and it ceased after treatment with nifedipine. Raynaud's disease and migraine improved less. CONCLUSIONS: The association of syncope to RD was unrelated to chance or migraine. The temporal relation between syncope and Raynaud's phenomenon but not headache was statistically significant. Treatment with nifedipine stopped recurrent syncope in all patients. Syncope related to RD may result from brainstem ischemia. Unexplained recurrent syncope should prompt screening for RD. PMID- 22248477 TI - Brainstem infarct due to traumatic basilar artery entrapment caused by longitudinal clival fracture. PMID- 22248478 TI - Novel FUS deletion in a patient with juvenile amyotrophic lateral sclerosis. AB - BACKGROUND: Juvenile amyotrophic lateral sclerosis (JALS) refers to a form of amyotrophic lateral sclerosis (ALS) in which a progressive upper and lower motor neuron degeneration begins before 25 years of age. It is generally associated with slow disease progression. During the past decade, a number of genes have been reported to cause JALS. Mutations in the ALSIN gene cause JALS type 2 (ALS2) as well as juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. Mutations in the SETX gene can also sometimes lead to JALS. Conversely, mutations in SOD1, TARDBP, and FUS typically cause pure ALS, with adult onset between 46 and 56 years of age and usually rapid progression over 3 to 5 years. Recently, a few mutations in FUS have been associated with juvenile onset of ALS characterized by a very rapid progression. OBJECTIVE: To investigate the genetics of a patient with juvenile-onset ALS. DESIGN AND PATIENT: We sequenced all the coding exons of SOD1, TARDBP, and FUS in a 19-year-old patient experiencing rapid degeneration of upper and lower motor neurons. RESULTS: A novel 1-base pair deletion was detected in exon 14 of the FUS gene, leading to a frameshift and the integration of 33 new amino acids. The variant p.R495QfsX527 is located in the highly conserved, extreme C terminal of the FUS protein, where most of the mutations in FUS have been identified. The variant was also identified in the unaffected 47-year-old mother of the patient, who remains asymptomatic. CONCLUSIONS: Our finding, along with other research, further confirms that FUS mutations can lead to an early-onset malignant form of ALS. In addition, our data lend additional support to the notion that disruption of the conserved C terminal of FUS is critical for developing ALS. PMID- 22248479 TI - Modified Stranski-Krastanov growth in Ge/Si heterostructures via nanostenciled pulsed laser deposition. AB - The combination of nanostenciling with pulsed laser deposition (PLD) provides a flexible, fast approach for patterning the growth of Ge on Si. Within each stencilled site, the morphological evolution of the Ge structures with deposition follows a modified Stranski-Krastanov (SK) growth mode. By systematically varying the PLD parameters (laser repetition rate and number of pulses) on two different substrate orientations (111 and 100), we have observed corresponding changes in growth morphology, strain and elemental composition using scanning electron microscopy, atomic force microscopy and MU-Raman spectroscopy. The growth behaviour is well predicted within a classical SK scheme, although the Si(100) growth exhibits significant relaxation and ripening with increasing coverage. Other novel aspects of the growth include the increased thickness of the wetting layer and the kinetic control of Si/Ge intermixing via the PLD repetition rate. PMID- 22248480 TI - Diagnosis of osteoporosis from dental panoramic radiographs using the support vector machine method in a computer-aided system. AB - BACKGROUND: Early diagnosis of osteoporosis can potentially decrease the risk of fractures and improve the quality of life. Detection of thin inferior cortices of the mandible on dental panoramic radiographs could be useful for identifying postmenopausal women with low bone mineral density (BMD) or osteoporosis. The aim of our study was to assess the diagnostic efficacy of using kernel-based support vector machine (SVM) learning regarding the cortical width of the mandible on dental panoramic radiographs to identify postmenopausal women with low BMD. METHODS: We employed our newly adopted SVM method for continuous measurement of the cortical width of the mandible on dental panoramic radiographs to identify women with low BMD or osteoporosis. The original X-ray image was enhanced, cortical boundaries were determined, distances among the upper and lower boundaries were evaluated and discrimination was performed by a radial basis function. We evaluated the diagnostic efficacy of this newly developed method for identifying women with low BMD (BMD T-score of -1.0 or less) at the lumbar spine and femoral neck in 100 postmenopausal women (>=50 years old) with no previous diagnosis of osteoporosis. Sixty women were used for system training, and 40 were used in testing. RESULTS: The sensitivity and specificity using RBF kernel-SVM method for identifying women with low BMD were 90.9% [95% confidence interval (CI), 85.3-96.5] and 83.8% (95% CI, 76.6-91.0), respectively at the lumbar spine and 90.0% (95% CI, 84.1-95.9) and 69.1% (95% CI, 60.1-78.6), respectively at the femoral neck. The sensitivity and specificity for identifying women with low BMD at either the lumbar spine or femoral neck were 90.6% (95% CI, 92.0-100) and 80.9% (95% CI, 71.0-86.9), respectively. CONCLUSION: Our results suggest that the newly developed system with the SVM method would be useful for identifying postmenopausal women with low skeletal BMD. PMID- 22248481 TI - Transgenic overexpression of tartrate-resistant acid phosphatase is associated with induction of osteoblast gene expression and increased cortical bone mineral content and density. AB - Bone remodeling is a central event in the maintenance of skeletal tissue, and involves cycles of resorption followed by the formation of bone tissue. The activity of osteoclasts and osteoblasts during these cycles is tightly regulated by systemic and local factors coupling the action of these cells. Tartrate resistant acid phosphatase (TRAP) is predominantly expressed in bone by osteoclasts but has also been detected in osteoblasts and osteocytes. Moreover, TRAP can stimulate the differentiation of mesenchymal lineage cells, i.e. progenitors of osteoblasts and adipocytes. In order to further explore the effects of TRAP on bone turnover, the structural and molecular phenotypes of osteoclasts and osteoblasts were assessed in TRAP-overexpressing transgenic mice. Transgenic mice of both sexes display increased cortical bone mineral content and density, which cannot be accounted for by decreased bone resorption since osteoclast numbers and resorptive activity do not differ from wild-type mice. Examination of the osteoblast phenotype revealed that markers of bone formation, i.e. procollagen type I N-terminal propeptides, and osteoblast lineage markers as well as the TRAP 1B mRNA transcript are increased in TRAP-overexpressing mice. Expression of the osteoclast-selective TRAP 1C mRNA is not increased in TRAP transgenic mice. Elevated expression of TRAP mRNA and protein were detected in osteoblasts, osteocytes and in the bone matrix of TRAP transgenic mice, suggesting that TRAP overexpression in osteoblast lineage cells is associated with increased cortical bone mineral content and density. The data presented here support the hypothesis that TRAP overexpression in the osteoblastic cell lineage stimulates the differentiation and/or activation of these cells. PMID- 22248482 TI - Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome. PMID- 22248483 TI - Dense codes at high speeds: varying stimulus properties to improve visual speller performance. AB - This paper investigates the effect of varying different stimulus properties on performance of the visual speller. Each of the different stimulus properties has been tested in previous literature and has a known effect on visual speller performance. This paper investigates whether a combination of these types of stimuli can lead to a greater improvement. It describes an experiment aimed at answering the following questions. (i) Does visual speller performance suffer from high stimulus rates? (ii) Does an increase in stimulus rate lead to a lower training time for an online visual speller? (iii) What aspect of the difference in the event related potential to a flash or a flip stimulus causes the increase in accuracy. (iv) Can an error-correcting (dense) stimulus code overcome the reduction in performance associated with decreasing target-to-target intervals? We found that higher stimulus rates can improve the visual speller performance and can lead to less time required to train the system. We also found that a proper stimulus code can overcome the stronger response to rows and columns, but cannot greatly improve speller performance. PMID- 22248484 TI - Super-resolution imaging reveals a difference between SERS and luminescence centroids. AB - Super-resolution optical imaging of Rhodamine 6G surface-enhanced Raman scattering (SERS) and silver luminescence from colloidal silver aggregates are measured with sub-5 nm resolution and found to originate from distinct spatial locations on the nanoparticle surface. Using correlated scanning electron microscopy, the spatial origins of the two signals are mapped onto the nanoparticle structure, revealing that, while both types of emission are plasmon mediated, SERS is a highly local effect, probing only a single junction in a nanoparticle aggregate, whereas luminescence probes all collective plasmon modes within the nanostructure. Calculations using the discrete-dipole approximation to calculate the weighted centroid position of both the |E|(2)/|E(inc)|(2) and |E|(4)/|E(inc)|(4) electromagnetic fields were compared to the super-resolution centroid positions of the SERS and luminescence data and found to agree with the proposed plasmon dependence of the two emission signals. These results are significant to the field of SERS because they allow us to assign the exact nanoparticle junction responsible for single-molecule SERS emission in higher order aggregates and also provide insight into how SERS is coupled into the plasmon modes of the underlying nanostructure, which is important for developing new theoretical models to describe SERS emission. PMID- 22248485 TI - A unique solid-solid transformation of silver nanoparticles on reactive ion etching-processed silicon. AB - Processes that combine nanoparticle suspensions with micromechanical or microelectronics platforms can reveal new phenomena unique to nanoscale objects. We report that silver nanoparticles react with silicon wafers that have been patterned by reactive ion etching (RIE) in SF(6)/O(2) plasma. This reaction results in the localized deposition of silver on the patterns. Through the modification of the reaction conditions, the reaction mechanism was explored. Redeposition of the sputtered RIE products is suggested as the key to this transformation. The new silver deposition process was utilized to localize the growth of gold nanoparticles and silicon nanowires on the vertical sidewalls of patterns in silicon, demonstrating a simple route to the fabrication of overhanging nanoscale objects. PMID- 22248486 TI - Effects of ethnicity and vitamin D supplementation on vitamin D status and changes in bone mineral content in infants. AB - BACKGROUND: To evaluate the effects on serum 25(OH)D and bone mineralization of supplementation of breast-fed Hispanic and non-Hispanic Caucasian infants with vitamin D in infants in Houston, Texas. METHODS: We measured cord serum 25(OH)D levels, bone mineral content (BMC), bone mineral density (BMD) and their changes over 3 months of life with 400 IU/day of vitamin D3 supplementation. RESULTS: Cord serum 25(OH)D was significantly lower in Hispanic than non-Hispanic Caucasian infants (16.4 +/- 6.5 ng/mL, n = 27, vs 22.3 +/- 9.4 n = 22, p = 0.013). Among 38 infants who completed a 3 month vitamin D supplementation intervention, provision of 400 IU/day of vitamin D increased final 25(OH)D to a higher level in non-Hispanic Caucasian compared to Hispanic infants. There was no significant relationship between cord serum 25(OH)D and BMC or BMD in the first week of life (n = 49) or after 3 months of vitamin D supplementation. CONCLUSION: Low cord 25(OH)D levels are seen in Hispanic infants, but their functional significance is uncertain related to bone health in a southern US setting. Daily vitamin D intake of 400 IU during the first months of life appears adequate to increase serum 25(OH)D and support BMC increases despite low initial 25(OH)D levels in some infants. TRIAL REGISTRATION: ClincalTrials.gov NCT00697294. PMID- 22248487 TI - Precise control of the number of walls formed during carbon nanotube growth using chemical vapor deposition. AB - We demonstrate a one-step approach for selecting the number of walls formed during carbon nanotube (CNT) growth by catalytic decomposition of CH(4) over Fe Mo/MgO catalysts. Scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), thermal gravimetric analysis (TGA) and Raman spectroscopy analyses indicate that high purity single-walled, double walled and triple-walled carbon nanotubes can be synthesized by tuning the Fe:Mo atomic ratio of catalysts. The results reveal that the concentration of Mo in the catalyst plays an important role in the size of catalyst particles and in the deposition rate of carbon atoms during CNT growth. Thus, the wall numbers of CNTs can be controlled precisely. PMID- 22248489 TI - Structural basis of high-affinity nuclear localization signal interactions with importin-alpha. AB - Classical nuclear localization signals (cNLSs), comprising one (monopartite cNLSs) or two clusters of basic residues connected by a 10-12 residue linker (bipartite cNLSs), are recognized by the nuclear import factor importin-alpha. The cNLSs bind along a concave groove on importin-alpha; however, specificity determinants of cNLSs remain poorly understood. We present a structural and interaction analysis study of importin-alpha binding to both designed and naturally occurring high-affinity cNLS-like sequences; the peptide inhibitors Bimax1 and Bimax2, and cNLS peptides of cap-binding protein 80. Our data suggest that cNLSs and cNLS-like sequences can achieve high affinity through maximizing interactions at the importin-alpha minor site, and by taking advantage of multiple linker region interactions. Our study defines an extended set of binding cavities on the importin-alpha surface, and also expands on recent observations that longer linker sequences are allowed, and that long-range electrostatic complementarity can contribute to cNLS-binding affinity. Altogether, our study explains the molecular and structural basis of the results of a number of recent studies, including systematic mutagenesis and peptide library approaches, and provides an improved level of understanding on the specificity determinants of a cNLS. Our results have implications for identifying cNLSs in novel proteins. PMID- 22248491 TI - Effect of preeclampsia serum on human uterine spiral artery smooth muscle cell apoptosis in a coculture model with cytotrophoblasts. AB - BACKGROUND/AIMS: To investigate cytotrophoblast (CTB) invasive ability and human uterine spiral artery smooth muscle cell (HUSASMC) apoptosis in a coculture model with serum from preeclamptic pregnancies. METHODS: Transwell migration assay was used to detect the invasive ability of CTBs. Cocultured CTBs and HUSASMCs were incubated with normal or preeclamptic serum for 24 h. Monocultures of CTBs and HUSASMCs were treated identically to the cocultures and served as controls. HUSASMC viability and apoptosis rates were determined by MTT and annexin V-FITC assays. The expressions of Fas ligand (FasL) mRNA in CTBs and Fas mRNA in HUSASMCs were detected by RT-PCR. The expression of the Fas protein in HUSASMCs was detected by Western blotting. RESULTS: In a model of CTBs cocultured with HUSASMCs, preeclamptic serum effectively decreased the invasive ability and FasL mRNA expression of the CTBs. Preeclampsia serum also increased HUSASMC viability, decreased their apoptotic rate, and decreased the expression of Fas mRNA and protein. CONCLUSION: The abnormal invasive ability of CTBs and decreased expression of the Fas/FasL system may be directly involved in the defective remodeling of the uterine spiral arteries during preeclampsia. Furthermore, the decrease in HUSASMC apoptosis may be related to the abnormal expression of Fas/FasL. PMID- 22248490 TI - Prevalence of cardiovascular disease and risk factors in a rural district of Beijing, China: a population-based survey of 58,308 residents. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of global disease burden. Although stroke was thought to be more prevalent than coronary heart disease (CHD) in Chinese, the epidemic pattern might have been changed in some rural areas nowadays. This study was to estimate up-to-date prevalence of CVD and its risk factors in rural communities of Fangshan District, Beijing, China. METHODS: A cross-sectional population survey was carried out by stratified cluster sampling. A total of 58,308 rural residents aged over 40 years were surveyed by face-to-face interview and physical examination during 2008 and 2010. The standardized prevalence was calculated according to adult sample data of China's 5th Population Census in 2000, and the adjusted prevalence odds ratio (POR) was calculated for the association of CHD/stroke with its cardiovascular risk factors in multivariate logistic regression models. RESULTS: Age- and sex standardized prevalence was 5.6% for CHD (5.2% in males and 5.9% in females), higher than the counterpart of 3.7% (4.7% in males and 2.6% in females) for stroke. Compared with previous studies, higher prevalence of 7.7%, 47.2%, 53.3% in males and 8.2%, 44.8%, 60.7% in females for diabetes, hypertension and overweight/obesity were presented accordingly. Moreover, adjusted POR (95% confidence interval) of diabetes, obesity, stage 1 and stage 2 hypertension for CHD as 2.51 (2.29 to 2.75), 1.53 (1.38 to 1.70), 1.13 (1.02 to 1.26) and 1.35 (1.20 to 1.52), and for stroke as 2.24 (1.98 to 2.52), 1.25 (1.09 to 1.44), 1.44 (1.25 to 1.66) and 1.70 (1.46 to 1.98) were shown respectively in the multivariate logistic regression models. CONCLUSIONS: High prevalence of CVD and probably changed epidemic pattern in rural communities of Beijing, together with the prevalent cardiovascular risk factors and population aging, might cause public health challenges in rural Chinese population. PMID- 22248492 TI - Phase-dependent electron transport through a quantum wire on a surface. AB - Electron transport through a quantum wire in the presence of external periodic energy-level modulations with different on-site phases is studied within the time evolution operator method for a tight-binding Hamiltonian. It is found that in the presence of spatial symmetry of the system and no source-drain and static gate voltages the pumping current can be generated. Moreover, for a wire which is tunnel-coupled to the underlying substrate, the current flowing through an unbiased wire does not fade away but increases with the wire-surface coupling. For randomly chosen phases at every wire site two regimes of the phase-averaged current are found which are related to small and high wire density of states. PMID- 22248493 TI - Cooperative dual-activity targeted nanomedicine for specific and effective prostate cancer therapy. AB - A key issue in cancer therapy is how to enhance the tumor-targeting efficacy of chemotherapeutic agents. In this study, we developed a cooperative dual-targeted delivery platform for paclitaxel (PTX) that has potential application as a powerful prostate cancer treatment. The nanomedicine was prepared by first conjugating PTX to nontoxic high-magnetization nanocarriers which can be actively guided and targeted by an external magnet. Next, the surface was functionalized with carboxylated o-(2-aminoethyl)polyethyleneglycol (NH(2)-EPEG-COOH) to enable uptake by the reticuloendothelial system. Antiprostate-specific membrane antigen antibodies (APSMAs) were then conjugated onto the carrier to recognize the extracellular domain of the prostate-cancer specific membrane antigen (PSMA), thus binding to cancer cells as a secondary active targeting mechanism. We found a significant enhancement of PTX concentration at the tumor site by nearly 20 fold. In addition, the drug half-life was prolonged more than 4.1-fold (from 24 to 99 h) at 37 degrees C. Low-dose (4.5 mg/kg) injection of the dual-targeted therapeutic nanomedicine in the presence of magnetic targeting significantly prolonged the median survival of nude mice from 35 to 58 days compared to mice that received a high dose (6 mg/kg) of free PTX. This report demonstrates the potential utility of targeted nanomedicine in the clinical treatment of cancer. PMID- 22248494 TI - Swimming's prevention of ovariectomy-induced obesity through activation of skeletal-muscle PPARalpha. AB - Ovariectomy leads to weight gain primarily in the form of adipose tissue in rodents. The authors investigated whether swimming improves ovariectomy-induced obesity through activation of peroxisome proliferator-activated receptor alpha (PPARalpha) in the skeletal muscle of female ovariectomized (OVX) mice, an animal model of postmenopausal women. Female mice were randomly divided into 3 groups (n=8/group): a sedentary sham-operated group, a sedentary OVX group, and a swim trained OVX group. After mice were subjected to swim training or kept sedentary for 6 wk, the authors studied the effects of swimming on not only bodyweight gain, white adipose tissue (WAT) mass, adipocyte size, and skeletal-muscle lipid accumulation but also the expression of skeletal-muscle PPARalpha target genes. Sedentary OVX mice had significantly higher body weight and WAT than sedentary sham mice. However, swim training reduced body-weight gain, WAT mass, and adipocyte size of OVX mice. Swim-trained OVX mice had significantly lower levels of serum triglycerides and total cholesterol than sedentary OVX mice. Lipid accumulation in skeletal muscle was also markedly decreased by swimming. Concomitantly, swim training significantly increased mRNA levels of skeletal muscle PPARalpha and its target enzymes, as well as uncoupling protein 3 (UCP3) responsible for fatty-acid oxidation. These results suggest that swimming can effectively prevent weight gain, adiposity, adipocyte hypertrophy, and lipid disorders caused by ovariectomy, in part through the activation of PPARalpha and UCP3, in the skeletal muscle of female mice and may contribute to the alleviation of metabolic syndrome, including obesity, hyperlipidemia, and Type 2 diabetes in postmenopausal women. PMID- 22248495 TI - Effects of fed- versus fasted-state aerobic training during Ramadan on body composition and some metabolic parameters in physically active men. AB - The aim of this study was to evaluate the effects of aerobic training in a fasted versus a fed state during Ramadan on body composition and metabolic parameters in physically active men. Nineteen men were allocated to 2 groups: 10 practicing aerobic training in a fasted state (FAST) and 9 training in an acutely fed state (FED) during Ramadan. All subjects visited the laboratory for a total of 4 sessions on the following occasions: 3 days before Ramadan (Bef-R), the 15th day of Ramadan; the 29th day of Ramadan (End-R), and 21 days after Ramadan. During each session, subjects underwent anthropometric measurement, completed a dietary questionnaire, and provided fasting blood and urine samples. Body weight decreased in FAST and FED by 1.9% (p<.001) and 2.6% (p=.046), respectively. Body fat percentage decreased only in FAST by 6.2% (p=.016). FAST experienced an increase in the following parameters from Bef-R to End-R: urine specific gravity (0.64%, p=.012), urea (8.7%, p<.001), creatinine (7.5%, p<.001), uric acid (12.7%, p<.001), sodium (1.9%, p=.003), chloride (2.6%, p<.001), and high-density lipoprotein cholesterol (27.3%, p<.001). Of these parameters, only creatinine increased (5.8%, p=.004) in FED. Creatinine clearance values of FAST decreased by 8.9% (p<.001) and by 7.6% in FED (p=.01) from Bef-R to End-R. The authors conclude that aerobic training in a fasted state lowers body weight and body fat percentage. In contrast, fed aerobic training decreases only body weight. In addition, Ramadan fasting induced change in some metabolic parameters in FAST, but these changes were absent in FED. PMID- 22248496 TI - Energy intakes of ultraendurance cyclists during competition, an observational study. AB - Endurance events>10 hr are becoming increasingly popular but provide numerous physiological challenges, several of which can be attenuated with optimal nutritional intakes. Previous studies in ultraendurance races have reported large energy deficits during events. The authors therefore aimed to assess nutritional intakes in relation to performance among ultraendurance cyclists. This observational study included 18 cyclists in a 384-km cycle race. At race registration each cyclist's support crew was provided with a food diary for their cyclist. On completion of the race, cyclists were asked to recall their race food and drink intakes. All food and fluids were analyzed using a computer software package. Mean (SD) time to complete the race was 16 hr 21 min (2 hr 2 min). Mean (SD) energy intake was 18.7 (8.6) MJ, compared with an estimated energy requirement for the race of 25.5 (7.4) MJ. There was a significant negative relationship between energy intake and time taken to complete the race (p=.023, r2=-.283). Mean (SD) carbohydrate, fat, and protein intakes were 52 (27), 15.84 (56.43), and 2.94 (7.25) g/hr, respectively. Only carbohydrate (p=.015, r2=-.563) and fat intake (p=.037, r2=-.494) were associated with time taken to complete the race. This study demonstrates the difficulties in meeting the high energy demands of ultraendurance cycling. The relationship between energy intake and performance suggests that reducing the energy deficit may be advantageous. Given the high carbohydrate intakes of these athletes, increasing energy intake from fat should be investigated as a means of decreasing energy deficits. PMID- 22248497 TI - A comparative analysis between the effects of galactose and glucose supplementation on endurance performance. AB - PURPOSE: To determine beneficial effects of short-term galactose (GAL) supplementation over a 50:50 glucose-maltodextrin (GLUC) equivalent on self-paced endurance cycling performance. METHODS: On 2 separate occasions, subjects performed a 100-km self-paced time trial (randomized and balanced order). This was interspersed with four 1-km and four 4-km maximal efforts reflecting the physical requirements of racing. Before each trial 38+/-3 g of GAL or GLUC was ingested in a 6% concentrate fluid form 1 hr preexercise and then during exercise at a rate of 37+/-3 g/hr. Performance variables were recorded for all 1- and 4-km efforts, all interspersed intervals, and the total 100-km distance. Noninvasive indicators of work intensity (heart rate [HR] and rating of perceived exertion) were also recorded. RESULTS: Times taken to complete the 100-km performance trial were 8,298+/-502 and 8,509+/-578 s (p=.132), with mean power outputs of 271+/-37 and 256+/-45 W (p=.200), for GAL and GLUC, respectively. Mean HR did not differ (GAL 157+/-7 and GLUC 157+/-7 beats/min, p=.886). A main effect of carbohydrate (CHO) type on time to complete 4-km efforts occurred, with no CHO Type*Effort Order interaction observed. No main effect of CHO type or interaction of CHO Type*Sequential Order occurred for 1-km efforts. CONCLUSION: A 6% GAL drink does not enhance performance time during a self-paced cycling performance trial in highly trained endurance cyclists compared with a formula typically used by endurance athletes but may improve the ability to produce intermediate self-paced efforts. PMID- 22248498 TI - Dietary supplementation practices in Canadian high-performance athletes. AB - Dietary supplementation is a common practice in athletes with a desire to enhance performance, training, exercise recovery, and health. Supplementation habits of elite athletes in western Canada have been documented, but research is lacking on supplement use by athletes across Canada. The purpose of this descriptive study was to evaluate the dietary supplementation practices and perspectives of high performance Canadian athletes affiliated with each of the country's eight Canadian Sport Centres. Dietitians administered a validated survey to 440 athletes (63% women, 37% men; M=19.99+/-5.20 yr) representing 34 sports who predominantly trained>=16 hr/wk, most competing in "power" based sports. Within the previous 6 months, 87% declared having taken>=3 dietary supplements, with sports drinks, multivitamin and mineral preparations, carbohydrate sports bars, protein powder, and meal-replacement products the most prevalent supplements reported. Primary sources of information on supplementation, supplementation justification, and preferred means of supplementation education were identified. Fifty-nine percent reported awareness of current World Anti-Doping Agency legislation, and 83% subjectively believed they were in compliance with such anti doping regulations. It was concluded that supplementation rates are not declining in Canada, current advisors on supplementation for this athletic population are not credible, and sports medicine physicians and dietitians need to consider proactive strategies to improve their influence on supplementation practices in these elite athletes. PMID- 22248499 TI - Carbohydrate-electrolyte drink ingestion and skill performance during and after 2 hr of indoor tennis match play. AB - Twenty-two tennis players were individually studied on 2 occasions. They performed a prematch skill test, a 2-hr tennis match against an equally ranked opponent, and a postmatch skill test. A carbohydrate-electrolyte (CHO-E; Lucozade Sport) or flavor-matched placebo-electrolyte (PL) beverage was administered in a double-blind fashion. During the trials, heart-rate and movement intensity were monitored, and the match was recorded for performance analysis. There were no differences in skill-test scores pre- to postmatch or between trials (154+/-38 pre- and 160+/-35 postmatch on PL, 155+/-36 pre- and 165+/-33 postmatch on CHO E). CHO-E ingestion elevated blood glucose concentration throughout the match, and participants reported feeling more energetic (general activation) and more tense (high activation) 1 hr into the match than at baseline (p<.05). Participants in the CHO-E trial spent more time in moderate-intensity activity and less time in low-intensity activity than on PL. Performance analysis revealed that CHO-E ingestion increased overall serve success (M+/-SD, 68%+/-7% for CHO-E vs. 66%+/-7% for PL; p<.05) and success of first serves (65%+/-9% for CHO-E, 61%+/-7% for PL; p<.01) and serves to the advantage side (70%+/-9% for CHO-E, 66%+/-7% for PL; p<.05). Return success was greater during the second set of the match (p<.05) in the CHO-E trial. Differences in serve and return success were not associated with blood glucose response to CHO or player ability. PMID- 22248500 TI - Effect of sprint interval exercise on postexercise metabolism and blood pressure in adolescents. AB - The current study examined the effect of sprint interval exercise on postexercise oxygen consumption, respiratory-exchange ratio (RER), substrate oxidation, and blood pressure in adolescents. Participants were 10 normal-weight healthy youth (7 female), age 15-18 years. After overnight fasts, each participant undertook 2 trials in a random balanced order: (a) two 30-s bouts of sprint interval exercise on a cycle ergometer and (b) rested in the laboratory for an equivalent period. Time-matched measurements of oxygen consumption, RER, and blood pressure were made 90 min into recovery, and substrate oxidation were calculated over the time period. Total postexercise oxygen uptake was significantly higher in the exercise than control trial over the 90 min (mean [SD]: control 20.0 [6.0] L, exercise 24.8 [9.8] L; p=.030). After exercise, RER was elevated above control but then fell rapidly and was lower than control 30-60 min postexercise, and fat oxidation was significantly higher in the exercise than control trial 45-60 min postexercise. However, total fat oxidation did not differ between trials (control 4.5 [2.5] g, exercise 5.4 [2.7] g; p=.247). Post hoc tests revealed that systolic blood pressure was significantly lower than in control at 90 min postexercise (control 104 [10] mm Hg, exercise 99 [10] mm Hg; p<.05). These data indicate that acute sprint interval exercise leads to short-term increases in oxygen uptake and reduced blood pressure in youth. The authors suggest that health outcomes in response to sprint interval training be examined in children. PMID- 22248501 TI - The effects of 8 weeks of endurance running on hepcidin concentrations, inflammatory parameters, and iron status in female runners. AB - Exercise-associated iron deficiency is a common disorder in endurance athletes. The authors investigated the effects of long-term endurance exercise on hepcidin concentrations, inflammatory parameters, and iron status in moderately trained female long-distance runners. Eighteen runners were assigned to either an interval- or a continuous-training exercise group. The physical training consisted of two 3-week progressive overload periods, each followed by a week's recovery, and concluded with a 10- or 21-km competitive run. Samples were taken 6 times during the 8-wk training program, first at baseline (BPre), then after the first and second 3-wk training loads (TPost1, TPost2), after each recovery week (Recovery1 and Recovery2), and poststudy (BPost). Soluble transferrin receptor (sTfR) concentrations were increased in Recovery2 and BPost compared with BPre (p=.02), hemoglobin decreased in TPost1 and TPost2 (p<.001), and red blood cells decreased in TPost2 (p=.01). Hepcidin decreased with time in TPost1 and in BPost compared with BPre (p<.001) and increased in TPost2 compared with TPost1 (p<.001). No differences over time were found for high-sensitivity C-reactive protein. The main findings of the current study indicate that serum hepcidin and sTfR were affected after 8 weeks of endurance running in women. No positive relation was found with inflammation. PMID- 22248503 TI - Plasmonic electromagnetically induced transparency in metallic nanoparticle quantum dot hybrid systems. AB - We study the variation of the energy absorption rate in a hybrid semiconductor quantum dot-metallic nanoparticle system doped in a photonic crystal. The quantum dot is taken as a three-level V-configuration system and is driven by two applied fields (probe and control). We consider that one of the excitonic resonance frequencies is near to the plasmonic resonance frequency of the metallic nanoparticle, and is driven by the probe field. The other excitonic resonance frequency is far from both the plasmonic resonance frequency and the photonic bandgap edge, and is driven by the control field. In the absence of the photonic crystal we found that the system supports three excitonic-induced transparencies in the energy absorption spectrum of the metallic nanoparticle. We show that the photonic crystal allows us to manipulate the frequencies of such excitonic induced transparencies and the amplitude of the energy absorption rate. PMID- 22248502 TI - Nitrate supplementation's improvement of 10-km time-trial performance in trained cyclists. AB - Six days of dietary nitrate supplementation in the form of beetroot juice (~0.5 L/d) has been reported to reduce pulmonary oxygen uptake (VO2) during submaximal exercise and increase tolerance of high-intensity work rates, suggesting that nitrate can be a potent ergogenic aid. Limited data are available regarding the effect of nitrate ingestion on athletic performance, and no study has investigated the potential ergogenic effects of a small-volume, concentrated dose of beetroot juice. The authors tested the hypothesis that 6 d of nitrate ingestion would improve time-trial performance in trained cyclists. Using a double-blind, repeated-measures crossover design, 12 male cyclists (31+/-3 yr, VO2peak=58+/-2 ml.kg-1.min-1, maximal power [Wmax]=342+/-10 W) ingested 140 ml/d of concentrated beetroot (~8 mmol/d nitrate) juice (BEET) or a placebo (nitrate depleted beetroot juice; PLAC) for 6 d, separated by a 14-d washout. After supplementation on Day 6, subjects performed 60 min of submaximal cycling (2*30 min at 45% and 65% Wmax, respectively), followed by a 10-km time trial. Time trial performance (953+/-18 vs. 965+/-18 s, p<.005) and power output (294+/-12 vs. 288+/-12 W, p<.05) improved after BEET compared with PLAC supplementation. Submaximal VO2 was lower after BEET (45% Wmax=1.92+/-0.06 vs. 2.02+/-0.09 L/min, 65% Wmax 2.94+/-0.12 vs. 3.11+/-0.12 L/min) than with PLAC (main effect, p<.05). Whole-body fuel selection and plasma lactate, glucose, and insulin concentrations did not differ between treatments. Six days of nitrate supplementation reduced VO2 during submaximal exercise and improved time-trial performance in trained cyclists. PMID- 22248504 TI - Control of optical bandgap energy and optical absorption coefficient by geometric parameters in sub-10 nm silicon-nanodisc array structure. AB - A sub-10 nm, high-density, periodic silicon-nanodisc (Si-ND) array has been fabricated using a new top-down process, which involves a 2D array bio-template etching mask made of Listeria-Dps with a 4.5 nm diameter iron oxide core and damage-free neutral-beam etching (Si-ND diameter: 6.4 nm). An Si-ND array with an SiO(2) matrix demonstrated more controllable optical bandgap energy due to the fine tunability of the Si-ND thickness and diameter. Unlike the case of shrinking Si-ND thickness, the case of shrinking Si-ND diameter simultaneously increased the optical absorption coefficient and the optical bandgap energy. The optical absorption coefficient became higher due to the decrease in the center-to-center distance of NDs to enhance wavefunction coupling. This means that our 6 nm diameter Si-ND structure can satisfy the strict requirements of optical bandgap energy control and high absorption coefficient for achieving realistic Si quantum dot solar cells. PMID- 22248505 TI - Prolonged survival with imatinib mesylate combined with chemotherapy and allogeneic stem cell transplantation in de novo Ph+ acute myeloid leukemia. AB - BACKGROUND: De novo Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) is a rare disease with a poor prognosis. Imatinib mesylate (IM) is the standard treatment for Ph+ chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia; however, its role in Ph+ AML has not been extensively investigated. METHODS: Two patients aged of 46 and 19 years were diagnosed with de novo Ph+ AML according to the WHO Classification of Myeloid Neoplasms (2002) and the French American-British (FAB) classification systems (1989). Cytogenetic analysis confirmed the presence of t(9;22). Standard RT-PCR was used to detect expression of the BCR-ABL1 fusion gene. Minimal residual disease was monitored by RQ-PCR for the BCR-ABL1/ABL ratio. Both patients received initial IM therapy combined with daunorubicin-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) and IM maintenance treatment after allo-HSCT. RESULTS: Both patients achieved long-term disease-free survival with complete hematologic response, complete molecular response, and complete cytogenetic response for 44 and 48 months, respectively. CONCLUSIONS: Our cases indicate that IM combined with daunorubicin-based chemotherapy followed by allo-HSCT and IM maintenance treatment is associated with a favorable outcome for de novo Ph+ AML, especially when IM is used in an early phase of AML. PMID- 22248507 TI - Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery. AB - PURPOSE: To evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms (XRCC1, TP53, MSH2, MSH3, XPD), oxidative stress response (GSTP1, GSTA1, eNOS, SOD2) and fibroblast proliferation (TGFbeta1) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy. MATERIAL AND METHODS: Skin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery. Genotyping was conducted by PCR-RFLP analysis and real time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. RESULTS: In the multivariate analysis, nominally significant associations, before multiple testing corrections, were found between XRCC1 T-77C (T carriers vs. CC, OR: 2.240, 95% CI: 1.015-4.941, P=0.046), eNOS G894T polymorphisms (TT vs. G carriers, OR: 2.473, 95% CI: 1.220-5.012, P=0.012), breast diameter (OR: 1.138, 95% CI: 1.001-1.293, P=0.048), boost dose-fractionation (3 Gy vs. no boost, OR: 4.902, 95% CI: 1.458-16.483, P=0.010) and >= grade 2 acute radiation skin toxicity in breast cancer patients. CONCLUSIONS: As our exploratory study suggests that XRCC1 T-77C and eNOS G874T may confer an increased risk of acute skin reactions to radiotherapy in breast cancer patients, further confirmatory studies are warranted to determine the clinical significance. PMID- 22248506 TI - Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma. AB - PURPOSE: To investigate threshold dose (TD) of focal liver reaction (FLR) following stereotactic body radiotherapy (SBRT) for patients with hepatocellular carcinoma (HCC) and liver cirrhosis. MATERIALS AND METHODS: In consecutive 50 patients receiving SBRT for small HCC, 38 patients receiving SBRT and follow up >6 months, FLR on follow-up CT had been previously studied. Patients with good concordance between FLR and highly irradiated area were eligible. Dose volume histogram (DVH) was used to identify TDs for FLR. Clinical factors were analyzed for correlation with TDs. RESULTS: Of 24 eligible patients, 23 had Child-Pugh score A and 1 scored B. Presence of FLR peaked at a median of 6 (range; 3-12) months. The median and 95% confidential intervals of TDs of pre-contrast and portal-venous phase CT were 32.4 Gy (30.3-35.4) and 34.4 Gy (31.9-36.0), respectively. Each median coefficient representing the concordance was 74.9% (range; 55.8-98.0%) and 80.5% (range; 70.8-92.4%), respectively. No clinical factors significantly correlated with the TDs. CONCLUSION: We proposed 30 Gy/5 fractions as TD of FLRs following SBRT for patients with HCC and liver cirrhosis. This TD will enable us to predict injured liver volume and to avoid complication beforehand from toxicity. Further pathological and clinical studies, in addition to more practical and precise data of DVH, are needed to clarify the significance of FLRs. PMID- 22248508 TI - Stereotactic body radiation therapy in the treatment of multiple primary lung cancers. AB - BACKGROUND AND PURPOSE: Patients with multiple primary lung cancers (MPLC) present a therapeutic dilemma, particularly when they are at high risk for surgical resection. We evaluated the role of stereotactic body radiation therapy (SBRT) in the treatment of MPLC. MATERIALS AND METHODS: A prospective thoracic SBRT registry was explored for patients with either synchronous or metachronous MPLC treated with SBRT for one or both of their tumors. Sixty-three patients were identified and clinical data were analyzed. RESULTS: Fifteen patients had synchronous lesions and 48 patients had metachronous lesions. Seventy-six lesions were treated with SBRT. Median follow-up was 24 months for living patients. Median progression-free survival (PFS) and overall survival (OS) for the entire cohort was 15.5 and 20 months, respectively. Patients with metachronous MPLC had a significantly higher 2 year PFS (53.3% vs. 0%, p=0.0466) compared to patients with synchronous MPLC. Likewise, 2 year OS was also superior for patients with metachronous versus synchronous MPLC (68.1% vs. 27.5%, p=0.0014). Six tumors (7.9%) recurred within the radiation field. There were no grade >=3 toxicities. CONCLUSIONS: SBRT for patients with MPLC appears to be a safe and effective local treatment alternative to surgery, particularly for medically inoperable patients. Patients with metachronous MPLC have encouraging survival rates, and thus local therapy appears justified. However, patients with synchronous MPLC have poor OS and PFS despite having excellent local control, and thus the utility of local therapy in this population requires further study. PMID- 22248509 TI - Impact of nephrotic edema of the lower limbs on obstructive sleep apnea: gathering a unifying concept for the pathogenetic role of nocturnal rostral fluid shift. AB - BACKGROUND: Nocturnal rostral fluid shift has been suggested to be a risk factor for obstructive sleep apnea (OSA) in healthy subjects after lower body positive pressurization. It remains unclear whether this may apply to subjects with nephrotic lower limb edema and, if so, whether disease remission may reverse the accompanying OSA. METHODS: Patients who presented with steroid-responsive primary nephrotic syndrome with lower limb edema as the predominant presenting clinical feature were recruited. They underwent one overnight polysomnography (PSG) before treatment and a repeat testing after achieving remission of the nephrotic edema. RESULTS: Among 23 consecutive nephrotic subjects, 11 (48%) had polysomnographic evidence of sleep apnea [apnea-hypopnea index (AHI)>=5] upon presentation. After steroid-based treatment, there was remission of proteinuria associated with complete disappearance of lower limb edema, significant reduction of body mass index, waist, hip and calf circumferences and total body water mainly in the extracellular compartment. Repeat PSG, performed 8.1+/-2.6 months later, showed that the overall (N=23) respiratory disturbance index (RDI) and AHI fell from 17.3+/-5.0 to 8.7+/-2.5 (P<0.05) and from 16.3+/-5.1 to 7.8+/-2.3 (P=0.057), respectively. Among the 11 subjects with sleep apnea detected at baseline, their AHI and RDI fell from 33.4+/-7.8 to 15.0+/-3.7 (P<0.05) and from 34.8+/-7.6 to 16.5+/-4.0 (P<0.05), respectively. There was also concomitant improvement in sleep efficiency, mean nocturnal oxygen saturation, shorter duration during sleep with oxygen saturation<95 and <90% and reduced desaturation index. There was also subjective improvement in self-reported daytime sleepiness. CONCLUSIONS: Nephrotic lower limb edema is associated with disturbed respiratory breathing and increased propensity to OSA, which was reversed upon remission of the nephrosis. This gathers a unifying concept for the role of nocturnal rostral fluid shift in the pathogenesis of OSA. PMID- 22248510 TI - HIV-associated kidney glomerular diseases: changes with time and HAART. AB - BACKGROUND: Treatment and co-morbidities of human immunodeficiency virus (HIV) infected individuals have changed dramatically in the last 20 years with a potential impact on renal complications. Our objective was to assess the change in distribution of the glomerular diseases in HIV patients. METHODS: We retrospectively analysed demographic, clinical, laboratory and renal histopathological data of 88 HIV-infected patients presenting with a biopsy proven glomerular disease between 1995 and 2007. RESULTS: In our study including 66% Black patients, HIV-associated nephropathy (HIVAN) was observed in 26 cases, classic focal segmental glomerulosclerosis (FSGS) in 23 cases, immune complex glomerulonephritis in 20 cases and other glomerulopathies in 19 patients. HIVAN decreased over time, while FSGS emerged as the most common cause of glomerular diseases (46.9%) in HIV-infected individuals undergoing kidney biopsy in the last 2004-07 period. Patients with HIVAN were usually Black (97%), with CD4 <200/mL (P = 0.01) and glomerular filtration rate <30 mL/min/1.73 m(2) (P < 0.01). Compared to HIVAN, patients with classic FSGS were less often Black (P < 0.01), have been infected for longer (P = 0.03), were more often co-infected with hepatitis C virus (P = 0.05), showed more often cardiovascular (CV) risk factors (P < 0.01), had less often CD4 <200/mL (P = 0.01), lower HIV viral load (P = 0.01) and tended to be older (P = 0.06). CONCLUSIONS: Classic FSGS associated with metabolic and CV risk factors has overcome HIVAN in HIV-infected patients. Compared with other glomerulopathies, HIVAN remains strongly associated with severe renal failure, Black origin and CD4 lower than 200/mL at presentation. PMID- 22248511 TI - Warming up to ischemia. PMID- 22248512 TI - Management of the high urogenital sinus--risk of overexposure? PMID- 22248513 TI - Early adoption of new devices: flying on untested wings. PMID- 22248514 TI - National trends in the use of partial nephrectomy: a rising tide that has not lifted all boats. AB - PURPOSE: Treatment of organ confined renal masses with partial nephrectomy has durable oncologic outcomes comparable to radical nephrectomy. Partial nephrectomy is associated with lower risk of chronic kidney disease and in some series with better overall survival. We report a contemporary analysis on national trends of partial nephrectomy use to determine partial nephrectomy use over time, and whether nontumor related factors such as structural attributes of the treating institution or patient characteristics are associated with the underuse of partial nephrectomy. MATERIALS AND METHODS: We performed an analysis of the NIS (National Inpatient Sample), which contains 20% of all United States inpatient hospitalizations. We included patients who underwent radical or partial nephrectomy for a renal mass between 2002 and 2008. Survey weights were applied to obtain national estimates of nephrectomy use and to evaluate nonclinical predictors of partial nephrectomy. RESULTS: A total of 46,396 patients were included in the study for a weighted sample of 226,493. There was an increase in partial nephrectomy use from 15.3% in 2002 to 24.7% in 2008 (p <0.001). On multivariate analysis hospital attributes (urban teaching status, nephrectomy volume, geographic region) and patient socioeconomic status (higher income ZIP code and private/HMO payer) were independent predictors of partial nephrectomy use. CONCLUSIONS: Since 2002 the national use of partial nephrectomy for the management of renal masses has increased. However, the adoption of partial nephrectomy at smaller, rural and nonacademic hospitals lags behind that of larger hospitals, urban/teaching hospitals and higher volume centers. A lower rate of partial nephrectomy use among patients without private insurance and those living in lower income ZIP code areas highlights the underuse of partial nephrectomy as a quality of care concern. PMID- 22248515 TI - Focal therapy will become standard treatment for localized prostate cancer: con. PMID- 22248516 TI - Impact of distance to a urologist on early diagnosis of prostate cancer among black and white patients. AB - PURPOSE: We examined whether an increased distance to a urologist is associated with a delayed diagnosis of prostate cancer among black and white patients, as manifested by higher risk disease at diagnosis. MATERIALS AND METHODS: North Carolina Central Cancer Registry data were linked to Medicare claims for patients with incident prostate cancer diagnosed in 2004 to 2005. Straight-line distances were calculated from the patient home to the nearest urologist. Race stratified multivariate ordinal logistic regression was used to examine the association between distance to a urologist and prostate cancer risk group (low, intermediate, high or very high/metastasis) at diagnosis for black and white patients while accounting for age, comorbidity, marital status and diagnosis year. An overall model was then used to examine the distance * race interaction effect. RESULTS: Included in analysis were 1,720 white and 531 black men. In the overall cohort the high risk cancer rate increased monotonically with distance to a urologist, including 40% for 0 to 10, 45% for 11 to 20 and 57% for greater than 20 miles. Correspondingly the low risk cancer rate decreased with longer distance. On race stratified multivariate analysis longer distance was associated with higher risk prostate cancer for white and black patients (p = 0.04 and <0.01, respectively) but the effect was larger in the latter group. The distance * race interaction term was significant in the overall model (p = 0.03). CONCLUSIONS: Longer distance to a urologist may disproportionally impact black patients. Decreasing modifiable barriers to health care access, such as distance to care, may decrease racial disparities in prostate cancer. PMID- 22248518 TI - Editorial comment. PMID- 22248519 TI - Zero ischemia anatomical partial nephrectomy: a novel approach. AB - PURPOSE: We present a novel concept of zero ischemia anatomical robotic and laparoscopic partial nephrectomy. MATERIALS AND METHODS: Our technique primarily involves anatomical vascular microdissection and preemptive control of tumor specific, tertiary or higher order renal arterial branch(es) using neurosurgical aneurysm micro-bulldog clamps. In 58 consecutive patients the majority (70%) had anatomically complex tumors including central (67%), hilar (26%), completely intrarenal (23%), pT1b (18%) and solitary kidney (7%). Data were prospectively collected and analyzed from an institutional review board approved database. RESULTS: Of 58 cases undergoing zero ischemia robotic (15) or laparoscopic (43) partial nephrectomy, 57 (98%) were completed without hilar clamping. Mean tumor size was 3.2 cm, mean +/- SD R.E.N.A.L. score 7.0 +/- 1.9, C-index 2.9 +/- 2.4, operative time 4.4 hours, blood loss 206 cc and hospital stay 3.9 days. There were no intraoperative complications. Postoperative complications (22.8%) were low grade (Clavien grade 1 to 2) in 19.3% and high grade (Clavien grade 3 to 5) in 3.5%. All patients had negative cancer surgical margins (100%). Mean absolute and percent change in preoperative vs 4-month postoperative serum creatinine (0.2 mg/dl, 18%), estimated glomerular filtration rate (-11.4 ml/minute/1.73 m(2), 13%), and ipsilateral kidney function on radionuclide scanning at 6 months (-10%) correlated with mean percent kidney excised intraoperatively (18%). Although 21% of patients received a perioperative blood transfusion, no patient had acute or delayed renal hemorrhage, or lost a kidney. CONCLUSIONS: The concept of zero ischemia robotic and laparoscopic partial nephrectomy is presented. This anatomical vascular microdissection of the artery first and then tumor allows even complex tumors to be excised without hilar clamping. Global surgical renal ischemia is unnecessary for the majority of patients undergoing robotic and laparoscopic partial nephrectomy at our institution. PMID- 22248520 TI - Potential years of life lost due to urogenital cancer in the United States: trends from 1972 to 2006 based on data from the SEER database. AB - PURPOSE: Urogenital cancer is a major health problem in the United States. We assessed potential years of life lost secondary to genitourinary cancer in the United States from 1972 to 2006 using the SEER (Surveillance, Epidemiology and End Results) database. We report trends in potential years of life lost during the same period. MATERIALS AND METHODS: Potential years of life lost were calculated to assess premature mortality trends for ureter, bladder, kidney and renal pelvis, penis, testis and prostate cancers. Calculations were based on SEER cancer mortality data. Potential years of life lost up to and including age 75 years were calculated by and across genders in 5-year increments between 1972 and 2006. RESULTS: A total of 7,733,235 potential years of life were lost in men and women. In each gender the greatest potential loss was for kidney and renal pelvis cancer related mortality. In each gender no improvement in the potential loss due to ureteral and bladder cancer related mortality was observed during 3 decades. In males the greatest decrease in potential years of life lost was for testicular cancer, followed by prostate cancer. CONCLUSIONS: There has been an increasing trend in potential years of life lost related to urogenital cancer during the last 35 years for males and females. This trend is mainly due to an increase in kidney cancer. The continued increase in potential years of life lost due to renal cancer and the lack of a decrease in the loss in those with bladder cancer should alert urologists and health care policy makers to deficient areas that most need to be addressed. PMID- 22248521 TI - Long-term impact of arsenic in drinking water on bladder cancer health care and mortality rates 20 years after end of exposure. AB - PURPOSE: In this study we assessed bladder cancer health care and mortality trends in recent decades in a well studied arsenic exposed area in Northern Chile. MATERIALS AND METHODS: Arsenic levels in the affected region were obtained for the last 60 years, and correlated with bladder cancer hospital discharge and mortality rates in recent decades. RESULTS: Bladder cancer hospital discharge rates were significantly higher in the affected region (peak RR 3.6, 95% CI 3.0 4.7). Mortality rates for bladder cancer showed a trend of increase during the period analyzed, reaching peak mortality rates of 28.4 per 100,000 for men and 18.7 per 100,000 for women in the last 10 years. Poisson regression models showed an increased mortality risk in the studied region compared to the rest of the country until the present for men (IRR 5.3, 95% CI 4.8-5.8) and women (IRR 7.8, 95% CI 7.0-8.7). Mean age at cancer specific death was significantly lower in the exposed region (69.6 years, 95% CI 68.4-70.7 vs 73.7 years, 95% CI 73.3-74.2, p <0.01). CONCLUSIONS: Exposure to arsenic is related to a significant need for bladder cancer health care and to high mortality rates even 20 years after having controlled arsenic levels in drinking water. Affected individuals should be aware of the significant impact of this ecological factor. Further research is required to identify strategies for the management of bladder cancer in arsenic exposed populations. PMID- 22248522 TI - Prognostic value of extranodal extension and other lymph node parameters in patients with upper tract urothelial carcinoma. AB - PURPOSE: We assessed the prognostic value of extranodal extension and other lymph node parameters in a large multicenter cohort of patients with lymph node metastasis after radical nephroureterectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of 222 patients with lymph node metastasis treated with radical nephroureterectomy for upper tract urothelial carcinoma without neoadjuvant therapy. Each lymph node metastasis was microscopically evaluated for extranodal extension. RESULTS: A median of 4 lymph nodes (IQR 8) was removed. Two lymph nodes (IQR 2) were positive. Lymph node density was 51.3% (IQR 71.7%). Overall 110 patients (49.5%) had extranodal extension, which was associated with more advanced pT stage (p = 0.026). On multivariable analysis extranodal extension was associated with disease recurrence (p = 0.01) and cancer specific mortality (p = 0.013). When stratified by a 30% cutoff, lymph node density was associated with disease recurrence and cancer specific mortality on univariable but not multivariable analysis (p = 0.048 and 0.049, respectively). Adding extranodal extension to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p <0.001). Adding extranodal extension to a multivariable model including age, pT stage and tumor architecture improved predictive accuracy for cancer specific mortality from 70.6% to 74.4% (p <0.001). CONCLUSIONS: Extranodal extension is a powerful predictor of clinical outcomes in patients with upper tract urothelial carcinoma with lymph node metastasis. While other lymph node parameters seem to have limited clinical value, extranodal extension could help risk stratify patients with upper tract urothelial carcinoma and lymph node metastasis for better counseling and clinical trial design. PMID- 22248523 TI - Editorial comment. PMID- 22248524 TI - Can we better predict and treat urinary incontinence after prostatectomy? PMID- 22248525 TI - Synthesis and characterization of an aggrecan mimic. AB - Aggrecan (AGG) is a large, aggregating proteoglycan present throughout the body, but predominantly found in articular cartilage. The principle features of AGG, its hyaluronan (HA) binding domain and its abundance of covalently attached glycosaminoglycans (GAGs), make it an essential component of the functional ability of articular cartilage. Current tissue engineering constructs have attempted to stimulate AGG production, but have been unable to produce adequate amounts of mature AGG, and hence have suffered a mismatch in mechanical properties. To address these deficiencies, an AGG mimic was synthesized to match AGG functional properties and provide greater control within tissue engineering constructs. Chondroitin sulfate was functionalized with HA-specific binding peptides to replicate both the GAG presence and HA-binding ability of AGG, respectively. Upon characterization and testing, the mimic was able to effectively bind to HA, increase the compressive strength of cartilage extracellular matrix-based constructs, and protect the other extracellular matrix (ECM) components from degradation, replicating the important functions of AGG. In particular, the mimic produced a 78% increase in compressive strength of the ECM based constructs, and was able to significantly reduce the degradation of both HA and collagen. The initial characterization of the newly synthesized AGG mimic demonstrates its potential in tissue engineering constructs, and provides an essential basis for more explorative studies of the AGG mimic's abilities as an AGG substitute and beyond. PMID- 22248526 TI - Effect of Si and Fe doping on calcium phosphate glass fibre reinforced polycaprolactone bone analogous composites. AB - Reinforcing biodegradable polymers with phosphate-based glass fibres (PGF) is of interest for bone repair and regeneration. In addition to increasing the mechanical properties, PGF can also release bioinorganics, as they are water soluble, a property that may be controllably translated into a fully degradable composite. Herein, the effect of Si and Fe on the solubility of calcium containing phosphate-based glasses (PG) in the system (50P(2)O(5)-40CaO-(10 x)SiO(2)-xFe(2)O(3), where x=0, 5 and 10 mol.%) were investigated. On replacing SiO(2) with Fe(2)O(3), there was an increase in the glass transition temperature and density of the PG, suggesting greater crosslinking of the phosphate chains. This significantly reduced the dissolution rates of degradation and ion release. Two PG formulations, 50P(2)O(5)-40CaO-10Fe(2)O(3) (Fe10) and 50P(2)O(5)-40CaO 5Fe(2)O(3)-5SiO(2) (Fe5Si5), were melt drawn into fibres and randomly incorporated into polycaprolactone (PCL). Initially, the flexural strength and modulus significantly increased with PGF incorporation. In deionized water, PCL Fe(5)Si(5) displayed a significantly greater weight loss and ion release compared with PCL-Fe10. In simulated body fluid, brushite was formed only on the surface of PCL-Fe(5)Si(5). Dynamic mechanical analysis in phosphate buffered saline (PBS) at 37 degrees C revealed that the PCL-Fe10 storage modulus (E') was unchanged up to day 7, whereas the onset of PCL-Fe(5)Si(5)E' decrease occurred at day 4. At longer-term ageing in PBS, PCL-Fe(5)Si(5) flexural strength and modulus decreased significantly. MC3T3-E1 preosteoblasts seeded onto PCL-PGF grew up to day 7 in culture. PGF can be used to control the properties of biodegradable composites for potential application as bone fracture fixation devices. PMID- 22248527 TI - A multiplex PCR for the simultaneous detection of species of filarioids infesting dogs. AB - The present study reports the applicability of a multiplex PCR for the simultaneous detection and differentiation of common filarioids infecting dogs, i.e., Dirofilaria immitis, Dirofilaria repens, Acanthocheilonema reconditum and Cercopithifilaria sp. Amplicons of different sizes (i.e., 170 bp, 480 bp, 590 bp and 300 bp, respectively) of regions within the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene were amplified on a single-step multiplex PCR using a mix of species-specific forward primers coupled with a single reverse primer. Experiments were carried out by amplifying genomic DNA extracted from blood or skin samples test-positive for microfilariae (mff). The number of mff present in each blood sample was quantified (from 800 to 25,000 mff/ml for A. reconditum and D. repens, respectively) and mixed blood samples were tested for the simultaneous detection of DNA from these mff. Specific amplicons for blood-circulating mff of A. reconditum, D. immitis and D. repens and for those whose adults are localized in skin (i.e., A. reconditum and Cercopithifilaria sp.) were simultaneously detected on agarose gel up to a dilution of 250 mff/ml for D. repens. The specific identity of the amplicons was confirmed by sequencing. The multiplex PCR assay reported herein represents a new tool for the molecular detection and differentiation of canine filarioids in blood and skin samples. PMID- 22248530 TI - Population-based analysis of inpatient vascular procedures and predicting future workload and implications for training. AB - OBJECTIVE: The purpose of this study was to analyze the trend in inpatient vascular procedures in the United States over the past decade and predict the future demand for vascular surgeons. METHODS: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample was queried to determine the weighted national estimates of inpatient vascular procedures performed on adult patients (age >= 18) between 1997 and 2008. Using population estimates from the United States Census Bureau, the per capita rates of inpatient procedures were calculated for age-specific groups (18-64 years, 65-84 years, and >= 85 years). The change in per capita rates over the past decade along with population forecasts were used to predict future workload. RESULTS: There was a net increase of 22% from 971,046 inpatient vascular procedures for all adults in 1997 to 1,188,332 in 2008. During the same time period, the adult population increased by 16% from 198 to 230 million. The age-stratified per capita rates of all vascular procedures were +21% for age 18 to 64; -4% for age 65 to 84; and +18% for age >= 85. This resulted in a net increase of 5% (490 to 515 procedures per 100,000 capita) in the per capita rate for all adults. Based on the assumption that trends in age-specific rates remain constant, there is a predicted inpatient workload increase (compared to 2008) of 18% by 2015, 34% by 2020, and 72% by 2030. The vascular workload is predicted to more than double by the year 2040. CONCLUSIONS: Despite a conservative approach of using a population-based analysis of only inpatient procedures, there is a dramatic increase in the predicted vascular workload for the future. The vascular surgery training process will need to adapt to ensure an adequate number of fellowship-trained vascular surgeons is available to provide quality vascular care in the future. PMID- 22248531 TI - Common genetic variation modulating cardiac ECG parameters and susceptibility to sudden cardiac death. AB - Sudden cardiac death (SCD) is a prevalent cause of death in Western societies. Genome-wide association studies (GWAS) conducted over the last few years have uncovered common genetic variants modulating risk of SCD. Furthermore, GWAS studies uncovered several loci impacting on heart rate and ECG indices of conduction and repolarization, as measures of cardiac electrophysiological function and likely intermediate phenotypes of SCD risk. We here review these recent developments and their implications for the identification of novel molecular pathways underlying normal electrophysiological function and susceptibility to SCD. PMID- 22248528 TI - Malaria in South Asia: prevalence and control. AB - The "Malaria Evolution in South Asia" (MESA) program project is an International Center of Excellence for Malaria Research (ICEMR) sponsored by the US National Institutes of Health. This US-India collaborative program will study the origin of genetic diversity of malaria parasites and their selection on the Indian subcontinent. This knowledge should contribute to a better understanding of unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and Plasmodium vivax infections. In this first of two reviews, we highlight malaria prevalence in India. In particular, we draw attention to variations in distribution of different human-parasites and different vectors, variation in drug resistance traits, and multiple forms of clinical presentations. Uneven malaria severity in India is often attributed to large discrepancies in health care accessibility as well as human migrations within the country and across neighboring borders. Poor access to health care goes hand in hand with poor reporting from some of the same areas, combining to possibly distort disease prevalence and death from malaria in some parts of India. Corrections are underway in the form of increased resources for disease control, greater engagement of village-level health workers for early diagnosis and treatment, and possibly new public-private partnerships activities accompanying traditional national malaria control programs in the most severely affected areas. A second accompanying review raises the possibility that, beyond uneven health care, evolutionary pressures may alter malaria parasites in ways that contribute to severe disease in India, particularly in the NE corridor of India bordering Myanmar Narayanasamy et al., 2012. PMID- 22248532 TI - Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease. AB - Studies of human diseased aortic valves have demonstrated increased expression of genetic markers of valve progenitors and osteogenic differentiation associated with pathogenesis. Three potential mouse models of valve disease were examined for cellular pathology, morphology, and induction of valvulogenic, chondrogenic, and osteogenic markers. Osteogenesis imperfecta murine (Oim) mice, with a mutation in Col1a2, have distal leaflet thickening and increased proteoglycan composition characteristic of myxomatous valve disease. Periostin null mice also exhibit dysregulation of the ECM with thickening in the aortic midvalve region, but do not have an overall increase in valve leaflet surface area. Klotho null mice are a model for premature aging and exhibit calcific nodules in the aortic valve hinge-region, but do not exhibit leaflet thickening, ECM disorganization, or inflammation. Oim/oim mice have increased expression of valve progenitor markers Twist1, Col2a1, Mmp13, Sox9 and Hapln1, in addition to increased Col10a1 and Asporin expression, consistent with increased proteoglycan composition. Periostin null aortic valves exhibit relatively normal gene expression with slightly increased expression of Mmp13 and Hapln1. In contrast, Klotho null aortic valves have increased expression of Runx2, consistent with the calcified phenotype, in addition to increased expression of Sox9, Col10a1, and osteopontin. Together these studies demonstrate that oim/oim mice exhibit histological and molecular characteristics of myxomatous valve disease and Klotho null mice are a new model for calcific aortic valve disease. PMID- 22248533 TI - Mitochondrial thioredoxin-2 from Manila clam (Ruditapes philippinarum) is a potent antioxidant enzyme involved in antibacterial response. AB - Thioredoxin (TRx) is a ubiquitous protein involved in the regulation of multiple biological processes. The TRx-2 isoform is exclusively expressed in mitochondria, where it contributes to mitochondrial redox state maintenance. In the present study, a novel thioredoxin-2 gene was identified in the Manila clam, Ruditapes philippinarum. The full-length sequence of RpTRx-2 (1561 bp) consists of a 498 bp coding region encoding a 166 amino acid protein. The N-terminal region of RpTRx-2 harbors a mitochondrial localization signal (56 amino acids), while the C terminal portion contains the characteristic (89)WCGPC(93) catalytic active site. Phylogenetic analysis revealed that RpTRx-2 is closest to its ortholog from abalone. The broad distribution pattern of RpTRx-2 mRNA in healthy animal tissues implicates a generally significant function in normal clam physiology. The transcription level of RpTRx-2, however, is highest in hemocytes. Lipopolysaccharide and Vibrio tapetis bacterium caused up-regulation of the RpTrx 2 transcript levels in gill and hemocytes. Interestingly, clam manganese superoxide dismutase (MnSOD) mRNA levels in hemocytes elicited a corresponding response to these immune challenges. RpTRx-2 was recombinantly expressed in Escherichia coli BL21 (DE3) and used in insulin disulfide reduction assay as well as metal-catalyzed oxidation assay to elucidate its antioxidant property by reducing substrate and protecting super-coiled DNA from oxidative damage through free radical scavenging, respectively. Collectively, our data indicated that RpTRx-2, a mitochondrial TRx-2 family member, is an antioxidant enzyme that may be involved in antibacterial defense of clams. PMID- 22248535 TI - A diagnostic dilemma: dystrophic calcified nodule of the testicle in a patient with no other symptoms - case report and review of the literature. AB - Dystrophic calcified nodule of the testicle represents an exceptional lesion with an unknown etiology and controversial diagnostic approach. There are very few reports in the literature that have examined this feature. Here, we report the fourth case of dystrophic testis nodule, identified in a 46-year-old man who presented the urologist with a palpable mass on his left testicle and no other symptoms. Histopathological findings were discussed and pooled with those of all previously published series. We believe that this description is particularly innovative because of the absence of symptoms and testicular pain associated with the lesion, and interesting as an attempt to determine the recognition of this rare entity. PMID- 22248534 TI - Cytotoxic, cytoprotective and antioxidant effects of isolated phenolic compounds from fresh ginger. AB - Twenty-nine phenolic compounds were isolated from the root bark of fresh (Yunnan) ginger and their structures fully characterized. Selected compounds were divided into structural categories and twelve compounds subjected to in-vitro assays including DPPH radical scavenging, xanthine-oxidase inhibition, monoamine oxidase inhibition, rat-brain homogenate lipid peroxidation, and rat pheochromocytoma PC12 cell and primary liver cell viability to determine their antioxidant and cytoprotective properties. Isolated compounds were also tested against nine human tumor cell lines to characterize anticancer potency. Several diarylheptanoids and epoxidic diarylheptanoids were effective DPPH radical scavengers and moderately effective at inhibiting xanthine oxidase. An enone-dione analog of 6-shogaol (compound 2) was isolated and identified to be most effective at protecting PC12 cells from H2O2-induced damage. Almost all tested compounds inhibited lipid peroxidation. Three compounds, 6-shogaol, 10-gingerol and an enone diarylheptanoid analog of curcumin (compound 6) were identified to be cytotoxic in cell lines tested, with KB and HL60 cells most susceptible to 6-shogaol and the curcumin analog with IC50<10 MUM. QSAR analysis revealed cytotoxicity was related to compound lipophilicity and chemical reactivity. In conclusion, we observed distinct compounds in fresh ginger to have biological activities relevant in diseases associated with reactive oxygen species. PMID- 22248537 TI - Predictive information processing in the brain: the neural perspective. PMID- 22248536 TI - Perceptual load, voluntary attention, and aging: an event-related potential study. AB - The locus of attentional selection is known to vary with perceptual load (Lavie et al., 2004). Under voluntary attention, perceptual load modulates selective visual processing at an early cortical stage, as reflected in the posterior P1 and N1 components of the event-related potentials (ERPs). Adult aging also affects both behavioral and ERP signs of attentional selection. However, it is not known whether perceptual load modulates this relationship. Accordingly, in the present study ERPs were recorded in a voluntary attention task. Young and old participants were asked to discriminate the direction of a target line embedded within a display of four lines that appeared in the left or right visual field. Participants responded faster and more accurately to valid relative to invalid trials and to low-load relative to high-load condition. Older participants responded more slowly and with lower accuracy than young participants in all conditions. The amplitudes of the posterior contralateral P1 and N1 components in valid trials were larger than that in invalid trials in all conditions. N1 amplitude was larger under the high load condition than that in the low load condition. Moreover, in the high perceptual load condition, the old group had a larger N1 than the young group at contralateral sites. The findings suggest that under voluntary attention, perceptual load and aging modulates attentional selection at an early but not the earliest stage, during the N1 (120-200ms) time range. Increased N1 amplitude in older adults may reflect increased demands on target discrimination in high perceptual load. PMID- 22248538 TI - Did adaptive and directed mutation evolve to accelerate stress-induced evolutionary change? PMID- 22248540 TI - Fitness effects of mutations in bacteria. AB - Mutation is the primary source of variation in any organism. Without it, natural selection cannot operate and organisms cannot adapt to novel environments. Mutation is also generally a source of defect: many mutations are not neutral but cause fitness decreases in the organisms where they arise. In bacteria, another important source of variation is horizontal gene transfer. This source of variation can also cause beneficial or deleterious effects. Determining the distribution of fitness effects of mutations in different environments and genetic backgrounds is an active research field. In bacteria, knowledge of these distributions is key for understanding important traits. For example, for determining the dynamics of microorganisms with a high genomic mutation rate (mutators), and for understanding the evolution of antibiotic resistance, and the emergence of pathogenic traits. All of these characteristics are extremely relevant for human health both at the individual and population levels. Experimental evolution has been a valuable tool to address these questions. Here, we review some of the important findings of mutation effects in bacteria revealed through laboratory experiments. PMID- 22248539 TI - What limits the efficiency of double-strand break-dependent stress-induced mutation in Escherichia coli? AB - Stress-induced mutation is a collection of molecular mechanisms in bacterial, yeast and human cells that promote mutagenesis specifically when cells are maladapted to their environment, i.e. when they are stressed. Here, we review one molecular mechanism: double-strand break (DSB)-dependent stress-induced mutagenesis described in starving Escherichia coli. In it, the otherwise high fidelity process of DSB repair by homologous recombination is switched to an error-prone mode under the control of the RpoS general stress response, which licenses the use of error-prone DNA polymerase, DinB, in DSB repair. This mechanism requires DSB repair proteins, RpoS, the SOS response and DinB. This pathway underlies half of spontaneous chromosomal frameshift and base substitution mutations in starving E. coli [Proc Natl Acad Sci USA 2011;108:13659 13664], yet appeared less efficient in chromosomal than F' plasmid-borne genes. Here, we demonstrate and quantify DSB-dependent stress-induced reversion of a chromosomal lac allele with DSBs supplied by I-SceI double-strand endonuclease. I SceI-induced reversion of this allele was previously studied in an F'. We compare the efficiencies of mutagenesis in the two locations. When we account for contributions of an F'-borne extra dinB gene, strain background differences, and bypass considerations of rates of spontaneous DNA breakage by providing I-SceI cuts, the chromosome is still ~100 times less active than F. We suggest that availability of a homologous partner molecule for recombinational break repair may be limiting. That partner could be a duplicated chromosomal segment or sister chromosome. PMID- 22248541 TI - Stress-induced modulators of repeat instability and genome evolution. AB - Evolution hinges on the ability of organisms to adapt to their environment. A key regulator of adaptability is mutation rate, which must be balanced to maintain genome fidelity while permitting sufficient plasticity to cope with environmental changes. Multiple mechanisms govern an organism's mutation rate. Constitutive mechanisms include mutator alleles that drive global, permanent increases in mutation rates, but these changes are confined to the subpopulation that carries the mutator allele. Other mechanisms focus mutagenesis in time and space to improve the chances that adaptive mutations can spread through the population. For example, environmental stress can induce mechanisms that transiently relax the fidelity of DNA repair to bring about a temporary increase in mutation rates during times when an organism experiences a reduced fitness for its surroundings, as has been demonstrated for double-strand break repair in Escherichia coli. Still, other mechanisms control the spatial distribution of mutations by directing changes to especially mutable sequences in the genome. In eukaryotic cells, for example, the stress-sensitive chaperone Hsp90 can regulate the length of trinucleotide repeats to fine-tune gene function and can regulate the mobility of transposable elements to enable larger functional changes. Here, we review the regulation of mutation rate, with special emphasis on the roles of tandem repeats and environmental stress in genome evolution. PMID- 22248542 TI - Transcriptional de-repression and Mfd are mutagenic in stressed Bacillus subtilis cells. AB - In recent years, it has been proposed that conflicts between transcription and active chromosomal replication engender genome instability events. Furthermore, transcription elongation factors have been reported to prevent conflicts between transcription and replication and avoid genome instability. Here, we examined transcriptional de-repression as a genetic diversity-producing agent and showed, through the use of physiological and genetic means, that transcriptional de represssion of a leuC defective allele leads to accumulation of Leu(+) mutations. We also showed, by using riboswitches that activate transcription in conditions of tyrosine or methionine starvation, that the effect of transcriptional de repression of the leuC construct on the accumulation of Leu(+) mutations was independent of selection. We examined the role of Mfd, a transcription elongation factor involved in DNA repair, in this process and showed that proficiency of this factor promotes mutagenic events. These results are in stark contrast to previous reports in Escherichia coli, which showed that Mfd prevents replication fork collapses. Because our assays place cells under non-growing conditions, by starving them for two amino acids, we surmised that the Mfd mutagenic process associated with transcriptional de-repression does not result from conflicts with chromosomal replication. These results raise the interesting concept that transcription elongation factors may serve two functions in cells. In growing conditions, these factors prevent the generation of mutations, while in stress or non-growing conditions they mediate the production of genetic diversity. PMID- 22248543 TI - Transposon-mediated adaptive and directed mutations and their potential evolutionary benefits. AB - Transposons, mobile genetic elements that can hop from one chromosomal location to another, are known to be both beneficial and deleterious to the cell that bears them. Their value in accelerating evolutionary adaptation is well recognized. We herein summarize published research dealing with these elements and then move on to review our own research efforts which focus on a small transposon that can induce mutations under the control of host factors in a process that phenotypically and mechanistically conforms to the definition of 'directed mutation'. Directed mutations occur at higher frequencies when they are beneficial, being induced by the stress condition that they relieve. Here, we review evidence for transposon-mediated directed mutation in Escherichia coli. Deletion mutants in the crp gene can not grow on glycerol (Glp(-)); however, these cells mutate specifically to efficient glycerol utilization (Glp(+)) at rates that are greatly enhanced by the presence of glycerol or the loss of the glycerol repressor (GlpR). These rates are greatly depressed by glucose or by glpR overexpression. Of the four tandem GlpR-binding sites (O1-O4) in the control region of the glpFK operon, O4 (downstream) specifically controls glpFK expression while O1 (upstream) controls mutation rate. Mutation is due to insertion of the small transposon IS5 into a specific site just upstream of the glpFK promoter. Mutational control by the glycerol regulon repressor GlpR is independent of the selection and assay procedures, and IS5 insertion into other gene activation sites is unaffected by the presence of glycerol or the loss of GlpR. The results establish the principle of transposon-mediated directed mutation, identify a protein responsible for its regulation, and define essential aspects of the mechanism. PMID- 22248544 TI - Specific and nonspecific host adaptation during arboviral experimental evolution. AB - During the past decade or so, there has been a substantial body of work to dissect arboviral evolution and to develop models of adaptation during host switching. Regardless of what species serve as host or vectors, and of the geographic distribution and the mechanisms of replication, arboviruses tend to have slow evolutionary rates in nature. The hypothesis that this is the result of replication in the disparate environments provided by host and vector did not receive solid experimental support in any of the many viral species tested. Instead, it seems that from the virus's point of view, either the two environments are sufficiently similar or one of the environments so dominates viral evolution that there is tolerance for suboptimal adaptation to the other environment. Replication in alternating environments has an unexpected cost in that there is decreased genetic variance that translates into a compromised adaptability for bypassed environments. Arboviruses under strong and continuous positive selection may have unusual patterns of genomic changes, with few or no mutations accumulated in the consensus sequence or with dN/dS values typically consistent with random drift in DNA-based organisms. PMID- 22248545 TI - The role of the indirect tunneling processes and asymmetry in couplings in orbital Kondo transport through double quantum dots. AB - A system of two quantum dots attached to external electrodes is considered theoretically in the orbital Kondo regime. In general, the double dot system is coupled via both Coulomb interaction and direct hopping. Moreover, the indirect hopping processes between the dots (through the leads) are also taken into account. To investigate the system's electronic properties we apply the slave boson mean field (SBMF) technique. With the help of the SBMF approach the local density of states for both dots and the transmission (as well as linear and differential conductance) is calculated. We show that Dicke- and Fano-like line shapes may emerge in the transport characteristics of the double dot system. Moreover, we observed that these modified Kondo resonances are very susceptible to the change of the indirect coupling's strength. We have also shown that the Kondo temperature becomes suppressed with increasing asymmetry in the dot-lead couplings when there is no indirect coupling. Moreover, when the indirect coupling is turned on the Kondo temperature becomes suppressed. By allowing a relative sign of the nondiagonal elements of the coupling matrix with left and right electrodes, we extend our investigations to become more generic. Finally, we have also included the level renormalization effects due to indirect tunneling, which are mostly neglected. PMID- 22248546 TI - The challenge of performing aerobic exercise in tropical environments: applied knowledge and perspectives. AB - The tropical climate is unique in that the seasons are dominated by the movement of the tropical rain belt, resulting in dry and wet seasons rather than the four season pattern of changes in temperature and day length seen in other parts of the world. More than 33% of the world population lives in the humid tropics, which are characterized by consistently high monthly temperatures and rainfall that exceeds evapotranspiration for most days of the year. Both the 2014 Football World Cup (in Brazil) and the 2016 Olympic Games (in Rio de Janeiro) will take place in this climate. This review focuses on the effects of the tropical environment on human exercise performance, with a special emphasis on prolonged aerobic exercise, such as swimming, cycling, and running. Some of the data were collected in Guadeloupe, the French West Indies Island where all the French teams will be training for the 2016 Olympic Games. We will first fully define the tropical climate and its effects on performance in these sports. Then we will discuss the types of adaptation that help to enhance performance in this climate, as well as the issues concerning the prescription of adequate training loads. We will conclude with some perspectives for future research. PMID- 22248551 TI - Physical characteristics, physiological attributes, and on-field performances of soccer goalkeepers. AB - The soccer goalkeeper (GK) is required to perform strenuous actions during practice sessions and actual games. One of the objectives of those professionals who work with GKs is to obtain relevant information on physical characteristics and physiological attributes of GKs, and to use it effectively when planning training programs for them. This article has three purposes: (a) to review a series of studies (n = 23) on physical characteristics, physiological attributes, and on-field performances of soccer GKs; (b) to outline a number of methodological limitations and research concerns associated with these studies; and (c) to suggest several practical recommendations for soccer coaches who work with GKs. Four main findings emerged from our review: (a) professional adult GKs usually are over 180 cm tall and have a body mass of over 77 kg; (b) studies on agility and speed produced mixed results, with some showing similar values between GKs and field players and others showing reduced performance in GKs; (c) GKs usually have higher vertical jump values when compared with players playing the various field positions; (d) GKs cover approximately 5.5 km during a game, mostly by walking and jogging. Four methodological limitations and research concerns associated with the reviewed studies were discussed, among them the lack of a longitudinal approach and the lack of on-field performance studies. Three practical recommendations are made for coaches, one of which is that coaches should adopt a careful approach when selecting testing protocols and devices for the assessment of GKs' physiological attributes. PMID- 22248553 TI - Validity of a reactive agility test for Australian football. AB - PURPOSE: To study the validity of a video-based reactive agility test in Australian footballers. METHODS: 15 higher performance, 15 lower performance, and 12 nonfootballers completed a light-based reactive agility test (LRAT), a video based reactive agility test (VRAT), and a planned test (PLAN). RESULTS: With skill groups pooled, agility time in PLAN (1346 +/- 66 ms) was significantly faster (P = .001) than both reactive tests (VRAT = 1550 +/- 102 ms; LRAT = 1572 +/- 97 ms). In addition, decision time was significantly faster (P = .001; d = 0.8) in LRAT (278 +/- 36 ms) than VRAT (311 +/- 47 ms). The correlation in agility time between the two reactive tests (r = .75) was higher than between the planned and reactive tests (r = .41-.68). Higher performance players had faster agility and movement times on VRAT (agility, 130 +/- 24 ms, d = 1.27, P = .004; movement, 69 +/- 73 ms, d = 0.88, P = .1) and LRAT (agility, 95 +/- 86 ms, d = 0.99, P = .08; movement, 79 +/- 74 ms; d = 0.9; P = .08) than the nonfootballers. In addition, higher (55 +/- 39 ms, d = 0.87, P = .05) and lower (40 +/- 57 ms, d = 0.74, P = .18) performance groups exhibited somewhat faster agility time than nonfootballers on PLAN. Furthermore, higher performance players were somewhat faster than lower performance for agility time on the VRAT (63 +/- 85 ms, d = 0.82, P = .16) and decision time on the LRAT (20 +/- 39 ms, d = 0.66, P = .21), but there was little difference in PLAN agility time between these groups (15 +/- 150 ms, d = 0.24, P = .8). CONCLUSIONS: Differences in decision-making speed indicate that the sport-specific nature of the VRAT is not duplicated by a light based stimulus. In addition, the VRAT is somewhat better able to discriminate different groups of Australian footballers than the LRAT. Collectively, this indicates that a video-based test is a more valid assessment tool for examining agility in Australian footballers. PMID- 22248554 TI - Comparison of physiological responses and performance between mountain bicycles with differing suspension systems. AB - PURPOSE: This study compared the metabolic and performance effects of riding front-only suspension (FS) and front-and-rear suspension (FRS) mountain bicycles on an off-road course that simulated competitive cross-country race conditions (>105 min in duration, with ~70% of time spent riding uphill). METHODS: Seven competitive mountain bikers (73.8 +/- 7.6 kg; 61.0 +/- 4.3 mL.kg-1.min-1) completed two randomized FS and FRS trials. Bikes were similar, excluding rear wheel suspension on the FRS, which increased bike weight by ~2 kg. Each trial consisted of four laps of rugged 8 km trail with 154 m of elevation gain per lap. The first three laps were performed at ~70% of VO2max; VO2, HR, and RPE were collected during the first and third laps. The final lap was performed as a maximal time-trial effort. RESULTS: During the first and third laps, VO2, HR, and RPE were similar between FS and FRS. However, FS was significantly faster than FRS during the ascending segment of the course (17.6 +/- 2.9 vs 18.9 +/- 3.4 min, P = .035), despite similar VO2 (P = .651). Although not statistically significant, FRS tended to be faster than FS during the descending portion of the course (8.1 +/- 2.0 vs 9.1 +/- 2.1, P = .067) at similar VO2. Performance during the final time-trial lap was significantly faster for FS than FRS (24.9 +/- 3.9 min, 27.5 +/- 4.9 min, P = .008). CONCLUSION: FS was faster than FRS over a course that simulated competitive cross-country race conditions. The faster times were likely the result of improved cycling economy during ascending, which were at least partially influenced by the lighter weight of the FS. PMID- 22248558 TI - Photophysics of resonantly and non-resonantly excited erbium doped Ge nanowires. AB - We have fabricated Er doped germanium nanowires of different diameters by pulsed laser deposition and chemical methods. Er induced photoluminescence emission due to the intra-4f (4)I(13/2)->(4)I(15/2) transition of Er energy levels at 1.53 um has been achieved at room temperature using both resonant (980 nm) and non resonant (325 nm) excitation of Er ions. The observed 1.53 um photoluminescence signal upon non-resonant 325 nm excitation is attributed to the Ge related oxygen deficiency centers surrounding the Ge core. For direct excitation, the infrared photoluminescence characteristics have been studied as a function of Er concentration, photon flux, and diameter of the nanowires. The Er related emission signal is found to be enhanced with increase in Er concentration, pump flux of 980 nm, and the nanowire diameter. The time resolved characteristics of the Er induced emission peak have been studied as a function of the pump flux as well as the diameter of the Ge nanowires. PMID- 22248559 TI - The thermal conductivity of embedded nano-aluminum nitride-doped multi-walled carbon nanotubes in epoxy composites containing micro-aluminum nitride particles. AB - Amino-functionalized nano-aluminum nitride (nano-AlN) particles were doped onto the surfaces of chlorinated multi-walled carbon nanotubes (MWCNTs) to act as fillers in thermally conducting composites. These synthesized materials were embedded in epoxy resin. Then, the untreated micro-aluminum nitride (micro-AlN) particles were added to this resin, whereby the composites filled with nano-AlN doped MWCNTs (0, 0.5, 1, 1.5, 2 wt%) and micro-AlN (25.2, 44.1, 57.4 vol%) were fabricated. As a result, the thermal diffusivity and conductivity of all composites continuously improved with increasing nano-AlN-doped MWCNT content and micro-AlN filler loading. The thermal conductivity reached its maximum, which was 31.27 times that of the epoxy alone, when 2 wt% nano-AlN-doped MWCNTs and 57.4 vol% micro-AlN were added to the epoxy resin. This result is due to the high aspect ratio of the MWCNTs and the surface polarity of the doped nano-AlN and micro-AlN particles, resulting in the improved thermal properties of the epoxy composite. PMID- 22248560 TI - Long-term health-related quality of life in survivors of head and neck cancer. AB - OBJECTIVE: To examine health-related quality of life (HRQOL) reported by 5-year head and neck cancer survivors and factors that predicted these long-term scores. DESIGN: Prospective, observational outcomes study. SETTING: Tertiary care institution. PATIENTS: A total of 337 patients diagnosed as having head and neck carcinoma between January 1995 and December 2004, who enrolled in the Outcomes Assessment Project and survived at least 5 years. INTERVENTIONS: While participating in the longitudinal Outcomes Assessment Project, patients filled out surveys measuring HRQOL at numerous points in time. MAIN OUTCOME MEASURES: Outcomes included 5-year scores in eating, speech, aesthetics, social disruption, physical and mental health, depressive symptoms, and overall quality of life (QOL). In addition to analyzing patients' 5-year HRQOL outcomes, multivariate analyses were performed to determine which patient, clinical, treatment, and 1 year HRQOL factors independently predicted these 5-year outcomes. RESULTS: Overall, the cohort's long-term general health was similar to that to age-matched norms from the general population. But over 50% of these survivors had problems eating, 28.5% reported depressive symptoms, and 17.3% reported substantial pain. At long-term follow-up, 13.6% continued to smoke, and 38.9% used alcohol. Multivariate analyses demonstrated that 1-year pain and diet were the strongest independent predictors of 5-year HRQOL outcomes. CONCLUSIONS: Eating problems due to poor oropharyngeal functioning and persistent pain are the most prevalent problems that these survivors face. Early interventions addressing eating issues, swallowing problems, and pain management will be a crucial component in improving this patient population's long-term QOL, especially in those who are functioning poorly 1 year after diagnosis. PMID- 22248561 TI - Sequential bilateral cochlear implantation in children: quality of life. AB - OBJECTIVE: To assess the effect of sequential bilateral cochlear implantation in children on their quality of life (QoL). DESIGN: Prospective cohort-control study. SETTING: Tertiary academic referral center. PATIENTS: Thirty children with prelingual deafness underwent sequential bilateral cochlear implantation (mean age at first implant, 1.8 years; mean age at second implant, 5.3 years). Nine children with a unilateral cochlear implant were also included in the study. All children had prelingual deafness, had good implant performance, and had no benefit from a contralateral conventional hearing aid. The groups were matched on duration of unilateral implant use, chronological age, and degree of bilateral hearing loss. INTERVENTION: Sequential bilateral cochlear implantation. MAIN OUTCOME MEASURES: Quality of life was assessed before surgery of the second implant and after 12 and 24 months of bilateral implant use. In the children with a unilateral cochlear implant, QoL was assessed over time and was compared with the study group after 12 and 24 months. Six questionnaires were used to measure QoL: overall health status using a visual analog scale; the Health Utilities Index Mark 3 (HUI3); the Pediatric Quality of Life Inventory (PedsQL); the Glasgow Children's Benefit Inventory (GCBI); the Speech, Spatial, and Qualities of Hearing Scale (SSQ); and the Nijmegen Cochlear Implant Questionnaire (NCIQ). RESULTS: Results showed no significant gain in generic QoL measures associated with sequential bilateral cochlear implantation (P > .05). The nonsignificant effect yielded on the HUI3 could be attributed to the ceiling effect and the lack of resolution in the hearing domain obtained in cochlear implant recipients. The gain in QoL of +0.04 may, therefore, be underestimated. In contrast, the 3 disease-specific questionnaires showed a significant improvement in QoL (P < .05). Results also showed that, unlike the children with a unilateral implant, QoL measures continued to improve with longer durations of bilateral implant use. Within the study group, the age at second implantation had no influence on the gain in QoL (P > .05). CONCLUSION: Sequential bilateral cochlear implantation in children is associated with an improvement in QoL, although this is predominantly reflected in the disease-related aspects of QoL and not necessarily in generic QoL. PMID- 22248562 TI - Disinfection of flexible fiberoptic laryngoscopes after in vitro contamination with Staphylococcus aureus and Candida albicans. AB - OBJECTIVE: To determine the efficacy of various cleaning and disinfective methods in reducing bacterial and fungal load on flexible fiberoptic laryngoscopes (FFLs). DESIGN: In vitro model. SUBJECTS: Flexible fiberoptic laryngoscopes contaminated with Staphylococcus aureus and Candida albicans. INTERVENTIONS: Contamination with S aureus and C albicans was separately induced on FFLs, which were then disinfected with different protocols: 20-, 15-, 10-, and 5-minute soaks in ortho-phthalaldehyde (Cidex OPA; Johnson & Johnson) with or without presoaking in an enzymatic soap solution for 5 minutes; an isolated 5-minute soak in an enzymatic soap solution; a 30-second wipe with antibacterial soap and water; a 30 second wipe with isopropyl alcohol; a 30-second wipe with antibacterial soap, followed by a 30-second scrub with isopropyl alcohol; and a 30-second wipe with germicidal cloth, all accompanied by previous rinsing with 30 seconds of running tap water. RESULTS: All protocols except the isolated 5-minute soak in enzymatic soap solution were successful in completely disinfecting the FFLs after experimental contamination with S aureus or C albicans. CONCLUSION: Various different cleaning methods appeared to properly disinfect FFLs after inoculation with S aureus and C albicans in an in vitro model. PMID- 22248563 TI - Membranoproliferative glomerulonephritis and mixed cryoglobulinemia after hepatitis C virus infection secondary to glomerular NS3 viral antigen deposits. AB - BACKGROUND: We report on 3 cases of membranoproliferative glomerulonephritis associated with mixed cryoglobulin in patients with hepatitis C virus (HCV) antibodies but a negative blood viral load. These cases explore the pathogenesis of the renal disease. METHODS: We searched for occult HCV infection in peripheral blood mononuclear cells, cryoprecipitate, bone marrow cells, and glomeruli using ultrasensitive PCR assays and immunohistochemistry. We also looked for infraclinical B cell lymphoma by computed tomodensitometry, bone marrow aspiration and biopsy, and lymphocyte typing. RESULTS: By PCR assays, we did not evidence occult hepatitis C infection in peripheral blood mononuclear cells, bone marrow cells, or cryoprecipitates. In the only patient with available kidney specimen, we evidenced HCV-NS3 antigen in glomeruli. HCV-associated lymphoma was excluded, but mild polyclonal B lymphocytosis was present in the 3 patients. Remission occurred spontaneously in 1 patient, and in another patient it occurred after rituximab treatment. The third patient was lost to follow-up. CONCLUSIONS: In patients with hepatitis C-negative viral load, membranoproliferative glomerulonephritis could be induced by the persistence of HCV antigen in the kidney but not in hematopoietic cells. Nonlymphomatous B cell proliferation may also be induced by chronic viral stimulation. PMID- 22248565 TI - Place of birth in England: still a contentious issue? PMID- 22248564 TI - Design of a Web-based individual coping and alcohol-intervention program (web ICAIP) for children of parents with alcohol problems: study protocol for a randomized controlled trial. AB - BACKGROUND: It has been estimated that approximately 20% of all Swedish children grow up with parents having alcohol problems, which may result in negative outcomes among these children. Therefore, most Swedish municipalities provide resources for support, but at the same time figures reveal that not even 2% receive support, mainly due to difficulties in identifying and recruiting these children into support programs. Delivering intervention programs to children and adolescents via the Internet seems a promising strategy, but to date, the number of web-based interventions aimed at this target group is very scarce. We have therefore developed a novel internet-delivered therapist assisted self-management intervention called the web-ICAIP (Individual Coping and Alcohol Intervention Program) for adolescents having parents with alcohol problems. The purpose of the program is to strengthen adolescents' coping behavior, improve their mental health, and postponing the onset or decreasing risky alcohol consumption. This paper describes the web-ICAIP and the design of a randomized controlled trial (RCT) to measure the efficacy of this intervention. METHODS/DESIGN: The RCT will include at least 183 adolescents (15-19 year old) who will be randomly allocated to two conditions where one group has access to the web-ICAIP and the other is a waiting list control group. Participants will be recruited from websites containing information and facts for adolescents about alcohol and other drugs. Possible participants will be screened using the short version of the Children of Alcoholics Screening Test (CAST-6). The assessment consists of a baseline and two follow-up measurements taking place after two and six months, respectively. The primary outcomes include the Center for Epidemiological Studies Depression Scale (CES-DC), a coping behavior scale, and also the short version of the Alcohol Use Disorders Identification Test (AUDIT-C). Additional outcomes include the "Ladder of life" which measures overall life satisfaction and questions concerning program adherence. DISCUSSION: There is an urgent need for developing and evaluating web-based intervention programs which target children having parents with alcohol problems. This study will therefore make an important contribution to this novel field of research. TRIAL REGISTRATION: ISRCTN41545712. PMID- 22248566 TI - Functional gait asymmetry of unilateral transfemoral amputees. AB - The aim of prosthetic devices is to mimic the function of biological systems. Numerous investigations have demonstrated significant asymmetries in unilateral amputee gait. The underlying interactions of prosthetic and intact leg are not widely discussed, so far. To get more insight into the functionality of asymmetries, we investigated temporal and kinetic parameters of walking transfemoral amputees wearing the computerized C-Leg and the non-computerized 3R80. Experiments were conducted on an instrumented treadmill at four different walking speeds (0.5, 0.8, 1.1, 1.4m/s) measuring vertical and horizontal ground reaction forces. Single support, double support and contact times, vertical and horizontal impulses as well as their asymmetry factors were calculated. Gait patterns were similar for both prosthetic knee joints, manifesting in (i) reduced stance times of the prosthetic leg, (ii) prolonged load transfer during double support from intact to prosthetic leg at lower speeds, (iii) reduced vertical and horizontal impulses of the prosthetic leg, (iv) net accelerating horizontal impulses during contact of the prosthetic leg, (v) missing impacts at touch-down of the prosthetic leg. Our results suggest that deficits of the prosthetic leg like missing active knee extension and ankle push-off are compensated by the intact leg. The altered touch-down configuration for the prosthetic leg enables it to provide forward propulsion while load bearing is largely shifted to the intact leg. PMID- 22248568 TI - Does a temperate ungulate that breeds in summer exhibit rut-induced hypophagia? Analysis of time budgets of male takin (Budorcas taxicolor) in Sichuan, China. AB - Mammals maximize fitness by optimizing time and energy allocation between reproduction and survival. Describing time budgets is a way to understand a species' constraints in energy allocation. We describe a time budget for male takin (Budorcas taxicolor) in Tangjiahe Nature Reserve, China, to better understand rut-induced hypophagia, which is frequently observed in temperate ungulates that breed in autumn or in winter. Observations generally occurred at two elevations (1200-1600m and 2600-3200m), using 20-min focal animal scan sampling from 2007 to 2009. Feeding behaviors accounted for the majority in takin's time budget (61.1%) during daylight hours, relative to the other observed behaviors, such as rest (14.1%), alert behavior (10.2%) and locomotion (6.8%). We found a negative correlation between feeding behavior and rutting behavior during the rutting season. A ratio of feeding time to resting time increased from pre rut to rut, while resting behavior did not change significantly across seasons. These results suggest the "energy saving" hypothesis could explain reduced foraging in male takin during the rut, but aspects of the species biology suggest that hypotheses for rut-induced hypophagia developed for other temperate ungulates do not apply to takin. We suggest that the unusual summer rutting season of takin releases males from the energy constraints encountered by temperate ungulates that breed in the autumn and has other benefits for offspring survival. Further research should be conducted on ungulates that exhibit rut during the summer and tropical ungulates that might not experience limited food availability following the mating season to improve our understanding on rut induced hypophagia. PMID- 22248567 TI - A chimeric antibody to L1 cell adhesion molecule shows therapeutic effect in an intrahepatic cholangiocarcinoma model. AB - Intrahepatic cholangiocarcinoma (ICC), a malignant tumor derived from the intrahepatic bile duct epithelium, has a poor prognosis and is refractory to conventional chemotherapy and radiation therapy. Thus, there is an urgent need to develop new effective therapeutic strategies for this disease. We previously found that L1 cell adhesion molecule (L1CAM) plays an important role in tumor progression of ICC, and we generated a murine mAb, A10-A3 (IgG1), that binds to the Ig1 domain of L1CAM. In the present study, we further characterized A10-A3, constructed a chimeric A10-A3 antibody (cA10-A3) containing the constant regions of human IgG1, and evaluated the therapeutic potential in a human ICC xenograft nude mice model. The affinities (KD) of A10-A3 and cA10-A3 for soluble L1CAM were 1.8 nM and 1.9 nM, respectively, as determined by competition ELISA. A10-A3 inhibited L1CAM homophilic binding and was slowly internalized into the tumor cells, but it did not significantly inhibit proliferation of ICC cells in vitro. cA10-A3 mediated antibody- dependent cell-mediated cytotoxicity in vitro and displayed anti-tumor activity in the ICC animal model. These results suggest that the humanized A10-A3 antibody may have potential as an anticancer agent for the treatment of ICC. PMID- 22248569 TI - Fear-like behavioral responses in mice in different odorant environments: Trigeminal versus olfactory mediation under low doses. AB - Odors can have repulsive effects on rodents based on two complementary adaptive behaviors: the avoidance of predator odors (potentially dangerous) and the avoidance of trigeminal stimulants (potentially noxious). The present study aimed to compare the behavioral effects on mice of odors according to their trigeminal properties and ecological significance. We used three different odors: 2,4,5 trimethylthiazoline (TMT: a fox feces odor frequently used to elicit fear-induced behaviors), toluene (a strong stimulant of the trigeminal system) and phenyl ethyl alcohol (PEA: a selective stimulant of the olfactory system). First, we checked preference and avoidance behaviors in mice with and without anosmia towards these odors to ensure their olfactory/trigeminal properties. Secondly, we used a standard test (open-field and elevated plus-maze) to assess the behaviors of mice when exposed to these odors. The results show that the anosmic and control mice both avoided TMT and toluene odors. In the open-field and the elevated plus-maze, mice exhibited "anxious" behaviors when exposed to TMT. Conversely, exposure to PEA induced "anxiolytic" effects confirmed by low blood corticosterone levels resulting from completion of the elevated plus-maze. Compared with TMT exposure, toluene exposure induced moderate "anxious" effects. PMID- 22248570 TI - Distress of mice induces approach behavior but has an aversive property for conspecifics. AB - In the first experiment, approach/avoidance behavior of mice to a restrained cage mate was examined. The mice explored the restrained mates but they did not stay longer at the restrained mates in comparison to free moving mates. Conditioned Place Preference (CPP) training in the presence of a restrained mate did not result in preference or aversion to the compartment associated with the restrained mates. A second experiment used formalin injection to a hind paw of a cage mate, instead of restraint. Mice stayed longer at the cage mate injected with the formalin in comparison to intact mates. However, CPP with formalin injected mates caused conditioned aversion to the compartment associated with the formalin-injected mate. Thus, distress in mice induced short-term approach behavior in conspecifics but also had an aversive property. PMID- 22248571 TI - Persistent current and Drude weight for the one-dimensional Hubbard model from current lattice density functional theory. AB - The Bethe ansatz local density approximation (LDA) to lattice density functional theory (LDFT) for the one-dimensional repulsive Hubbard model is extended to current-LDFT (CLDFT). The transport properties of mesoscopic Hubbard rings threaded by a magnetic flux are then systematically investigated by this scheme. In particular we present calculations of ground state energies, persistent currents and Drude weights for both a repulsive homogeneous and a single impurity Hubbard model. Our results for the ground state energies in the metallic phase compare favorably well with those obtained with numerically accurate many-body techniques. Also the dependence of the persistent currents on the Coulomb and the impurity interaction strength, and on the ring size are all well captured by LDA CLDFT. Our study demonstrates the value of CLDFT in describing the transport properties of one-dimensional correlated electron systems. As its computational overheads are rather modest, we propose this method as a tool for studying problems where both disorder and interaction are present. PMID- 22248572 TI - The BOLD post-stimulus undershoot, one of the most debated issues in fMRI. AB - This paper provides a brief overview of how we got involved in fMRI work and of our efforts to elucidate the mechanisms underlying BOLD signal changes. The phenomenon discussed here in particular is the post-stimulus undershoot (PSU), the interpretation of which has captivated many fMRI scientists and is still under debate to date. This controversy is caused both by the convoluted physiological origin of the BOLD effect, which allows many possible explanations, and the lack of comprehensive data in the early years. BOLD effects reflect changes in cerebral blood flow (CBF), volume (CBV), metabolic rate of oxygen (CMRO(2)), and hematocrit fraction (Hct). However, the size of such effects is modulated by vascular origin such as intravascular, extravascular, macro and microvascular, venular and capillary, the relative contributions of which depend not only on the spatial resolution of the measurements, but also on stimulus duration, on magnetic field strength and on whether spin echo (SE) or gradient echo (GRE) detection is used. The two most dominant explanations of the PSU have been delayed vascular compliance (first venular, later arteriolar, and recently capillary) and sustained increases in CMRO(2), while post-activation reduction in CBF is a distant third. MRI has the capability to independently measure CBF and arteriolar, venous, and total CBV contributions in humans and animals, which has been of great assistance in improving the understanding of BOLD phenomena. Using currently available MRI and optical data, we conclude that the predominant PSU origin is a sustained increase in CMRO(2). However, some contributions from delayed vascular compliance are likely, and small CBF undershoot contributions that are difficult to detect with current arterial spin labeling technology can also not be excluded. The relative contribution of these different processes, which are not mutually exclusive and can act together, is likely to vary with stimulus duration and type. PMID- 22248574 TI - Human auditory cortex is sensitive to the perceived clarity of speech. AB - Feedback connections among auditory cortical regions may play an important functional role in processing naturalistic speech, which is typically considered a problem solved through serial feed-forward processing stages. Here, we used fMRI to investigate whether activity within primary auditory cortex (PAC) is sensitive to the perceived clarity of degraded sentences. A region-of-interest analysis using probabilistic cytoarchitectonic maps of PAC revealed a modulation of activity, in the most primary-like subregion (area Te1.0), related to the intelligibility of naturalistic speech stimuli that cannot be driven by stimulus differences. Importantly, this effect was unique to those conditions accompanied by a perceptual increase in clarity. Connectivity analyses suggested sources of input to PAC are higher-order temporal, frontal and motor regions. These findings are incompatible with feed-forward models of speech perception, and suggest that this problem belongs amongst modern perceptual frameworks in which the brain actively predicts sensory input, rather than just passively receiving it. PMID- 22248575 TI - Intracortical recordings and fMRI: an attempt to study operational modules and networks simultaneously. AB - The brain can be envisaged as a complex adaptive system. It is characterized by a very high structural complexity and by massive connectivity, both of which change and evolve in response to experience. Information related to sensors and effectors is processed in both a parallel and a hierarchical fashion; the connectivity between different hierarchical levels is bidirectional, and its effectiveness is continuously controlled by specific associational and neuromodulatory centers. When questions are addressed at the level of a distributed, large-scale whole system such as that underlying perception and cognition, it is not clear what should be considered as an elementary operational unit because the behavior of integral, aggregate systems is always emergent and most often remains unpredicted by the behaviors of single cells. To localize and comprehend the neural mechanisms underlying our perceptual or cognitive capacities, concurrent studies of microcircuits, of local and long-range interconnectivity between small assemblies, and of the synergistic activity of larger neuronal populations are called for. In other words, multimodal methodologies that include invasive neuroscientific methods as well as global neuroimaging techniques are required, such as the various functional aspects of magnetic resonance imaging. These facts were the driving force behind the decision to begin animal-MRI in my lab. The wonderful idea of the editors of NeuroImage to publish a Special Issue commemorating 20years of functional fMRI provides me with the opportunity of sharing not only our first moments of frustration with the readers, but also our successful results. PMID- 22248573 TI - FreeSurfer. AB - FreeSurfer is a suite of tools for the analysis of neuroimaging data that provides an array of algorithms to quantify the functional, connectional and structural properties of the human brain. It has evolved from a package primarily aimed at generating surface representations of the cerebral cortex into one that automatically creates models of most macroscopically visible structures in the human brain given any reasonable T1-weighted input image. It is freely available, runs on a wide variety of hardware and software platforms, and is open source. PMID- 22248576 TI - A short history of causal modeling of fMRI data. AB - Twenty years ago, the discovery of the blood oxygen level dependent (BOLD) contrast and invention of functional magnetic resonance imaging (MRI) not only allowed for enhanced analyses of regional brain activity, but also laid the foundation for novel approaches to studying effective connectivity, which is essential for mechanistically interpretable accounts of neuronal systems. Dynamic causal modeling (DCM) and Granger causality (G-causality) modeling have since become the most frequently used techniques for inferring effective connectivity from fMRI data. In this paper, we provide a short historical overview of these approaches, describing milestones of their development from our subjective perspectives. PMID- 22248577 TI - Task by stimulus interactions in brain responses during Chinese character processing. AB - In the visual word recognition literature, it is well understood that various stimulus effects interact with behavioral task. For example, effects of word frequency are exaggerated and effects of spelling-to-sound regularity are reduced in the lexical decision task, relative to reading aloud. Neuroimaging studies of reading often examine effects of task and stimulus properties on brain activity independently, but potential interactions between task demands and stimulus effects have not been extensively explored. To address this issue, we conducted lexical decision and symbol detection tasks using stimuli that varied parametrically in their word-likeness, and tested for task by stimulus class interactions. Interactions were found throughout the reading system, such that stimulus selectivity was observed during the lexical decision task, but not during the symbol detection task. Further, the pattern of stimulus selectivity was directly related to task difficulty, so that the strongest brain activity was observed to the most word-like stimuli that required "no" responses, whereas brain activity to words, which elicit rapid and accurate "yes" responses were relatively weak. This is in line with models that argue for task-dependent specialization of brain regions, and contrasts with the notion of task independent stimulus selectivity in the reading system. PMID- 22248578 TI - Which "neural activity" do you mean? fMRI, MEG, oscillations and neurotransmitters. AB - Over the last 20 years, BOLD-FMRI has proved itself to be a powerful and versatile tool for the study of the neural substrate underpinning many of our cognitive and perceptual functions. However, exactly how it is coupled to the underlying neurophysiology, and how this coupling varies across the brain, across tasks and across individuals is still unclear. The story is further complicated by the fact that within the same cortical region, multiple evoked and induced oscillatory effects may be modulated during task execution, supporting different cognitive roles, and any or all of these may have metabolic demands that then drive the BOLD response. In this paper I shall concentrate on one experimental approach to shedding light on this problem i.e. the execution of the same experimental tasks using MEG and fMRI in order to reveal which electrophysiological responses best match the BOLD response spatially, temporally and functionally. The results demonstrate a rich and complex story that does not fit with a simplistic view of BOLD reflecting "neural activity" and suggests that we could consider the coupling between BOLD and the various parameters of neural function as an ill-posed inverse problem. Finally, I describe recent work linking individual variability in both cortical oscillations and the BOLD-fMRI response to variability in endogenous GABA concentration. PMID- 22248579 TI - The future of FMRI connectivity. AB - "FMRI connectivity" encompasses many areas of research, including resting-state networks, biophysical modelling of task-FMRI data and bottom-up simulation of multiple individual neurons interacting with each other. In this brief paper I discuss several outstanding areas that I believe will see exciting developments in the next few years, in particular concentrating on how I think the currently separate approaches will increasingly need to take advantage of each others' respective complementarities. PMID- 22248580 TI - Brain templates and atlases. AB - The core concept within the field of brain mapping is the use of a standardized, or "stereotaxic", 3D coordinate frame for data analysis and reporting of findings from neuroimaging experiments. This simple construct allows brain researchers to combine data from many subjects such that group-averaged signals, be they structural or functional, can be detected above the background noise that would swamp subtle signals from any single subject. Where the signal is robust enough to be detected in individuals, it allows for the exploration of inter-individual variance in the location of that signal. From a larger perspective, it provides a powerful medium for comparison and/or combination of brain mapping findings from different imaging modalities and laboratories around the world. Finally, it provides a framework for the creation of large-scale neuroimaging databases or "atlases" that capture the population mean and variance in anatomical or physiological metrics as a function of age or disease. However, while the above benefits are not in question at first order, there are a number of conceptual and practical challenges that introduce second-order incompatibilities among experimental data. Stereotaxic mapping requires two basic components: (i) the specification of the 3D stereotaxic coordinate space, and (ii) a mapping function that transforms a 3D brain image from "native" space, i.e. the coordinate frame of the scanner at data acquisition, to that stereotaxic space. The first component is usually expressed by the choice of a representative 3D MR image that serves as target "template" or atlas. The native image is re-sampled from native to stereotaxic space under the mapping function that may have few or many degrees of freedom, depending upon the experimental design. The optimal choice of atlas template and mapping function depend upon considerations of age, gender, hemispheric asymmetry, anatomical correspondence, spatial normalization methodology and disease-specificity. Accounting, or not, for these various factors in defining stereotaxic space has created the specter of an ever expanding set of atlases, customized for a particular experiment, that are mutually incompatible. These difficulties continue to plague the brain mapping field. This review article summarizes the evolution of stereotaxic space in term of the basic principles and associated conceptual challenges, the creation of population atlases and the future trends that can be expected in atlas evolution. PMID- 22248581 TI - The time-course and spatial distribution of brain activity associated with sentence processing. AB - Sentence comprehension involves a host of highly interrelated processes, including syntactic parsing, semantic composition, and pragmatic inferencing. In neuroimaging, a primary paradigm for examining the brain bases of sentence processing has been to compare brain activity elicited by sentences versus unstructured lists of words. These studies commonly find an effect of increased activity for sentences in the anterior temporal lobes (aTL). Together with neuropsychological data, these findings have motivated the hypothesis that the aTL is engaged in sentence level combinatorics. Combinatoric processing during language comprehension, however, occurs within tens and hundreds of milliseconds, i.e., at a time-scale much faster than the temporal resolution of hemodynamic measures. Here, we examined the time-course of sentence-level processing using magnetoencephalography (MEG) to better understand the temporal profile of activation in this common paradigm and to test a key prediction of the combinatoric hypothesis: because sentences are interpreted incrementally, word-by word, activity associated with basic linguistic combinatorics should be time locked to word-presentation. Our results reveal increased anterior temporal activity for sentences compared to word lists beginning approximately 250 ms after word onset. We also observed increased activation in a network of other brain areas, extending across posterior temporal, inferior frontal, and ventral medial areas. These findings confirm a key prediction of the combinatoric hypothesis for the aTL and further elucidate the spatio-temporal characteristics of sentence-level computations in the brain. PMID- 22248584 TI - Twist is a new prognostic marker for renal survival in patients with chronic kidney disease. AB - BACKGROUND/AIMS: Our previous studies indicate that Twist plays important roles in hypoxia-induced tubular epithelial-mesenchymal transition and the development of kidney fibrosis in cellular and animal models. However, the expression and clinical significance of Twist in patients with chronic kidney disease are not clear. METHODS: We analyzed the degree of expression and localization of Twist in renal biopsies from a wide variety of hypoxic kidney diseases and correlated their immunostaining scores with clinical and histologic parameters. In particular, we also retrospectively analyzed whether the degree of expression of Twist in the renal interstitium was correlated with renal survival. RESULTS: Activated Twist was strongly expressed in tubular epithelial cell nuclei from the kidneys of patients with chronic kidney diseases, while little positive staining for Twist was found in the renal tubules of normal kidneys (p = 0.001). Twist protein in the tubulointerstitium was inversely correlated with estimated glomerular filtration rate (eGFR; r = -0.468, p = 0.029) and positively correlated with serum creatinine (r = 0.44, p = 0.045) and the percentage of tubulointerstitial fibrosis (r = 0.551, p = 0.000). Moreover, a high level of Twist was correlated with activation of HIF-1alpha expression and E-cadherin repression across all disease groups (p = 0.000, p = 0.000, respectively). By multivariate analysis, the experimental data show that the factors influencing renal survival were eGFR [relative risk (RR) 4.39 (95%CI 1.342, 14.393), p = 0.014] and the degree of expression of Twist [RR 3.43 (95% CI 1.098, 10.684), p = 0.034]. CONCLUSIONS: Our results raise the possibility that Twist activation is a common mechanism in the pathophysiology of a wide range of chronic hypoxic renal diseases and that Twist staining in renal biopsy specimens might provide a valuable histologic index of progression. PMID- 22248582 TI - Morphine decreases bacterial phagocytosis by inhibiting actin polymerization through cAMP-, Rac-1-, and p38 MAPK-dependent mechanisms. AB - Morphine increases the susceptibility to opportunistic infection by attenuating bacterial clearance through inhibition of Fcgamma receptor (FcgR)-mediated phagocytosis. Mechanisms by which morphine inhibits this process remain to be investigated. Actin polymerization is essential for FcgR-mediated internalization; therefore, disruption of the signaling mechanisms involved in this process is detrimental to the phagocytic ability of macrophages. To our knowledge, this study is the first to propose the modulation of actin polymerization and upstream signaling effectors [cAMP, Rac1-GTP, and p38 mitogen activated protein kinase (MAPK)] as key mechanisms by which morphine leads to inhibition of pathogen clearance. Our results indicate that long-term morphine treatment in vitro and in vivo, through activation of the MU-opioid receptor, leads to an increase in intracellular cAMP, activation of protein kinase A, and inhibition of Rac1-GTPase and p38 MAPK, thereby attenuating actin polymerization and reducing membrane ruffling. Furthermore, because of long-term morphine treatment, FcgR-mediated internalization of opsonized dextran beads is also reduced. Morphine's inhibition of Rac1-GTPase activation is abolished in J774 macrophages transfected with constitutively active pcDNA3-EGFP-Rac1-Q61L plasmid. Dibutyryl-cAMP inhibits, whereas H89 restores, activation of Rac-GTPase and abolishes morphine's inhibitory effect, implicating cAMP as the key effector in morphine's modulation of actin polymerization. These findings indicate that long term morphine treatment, by increasing intracellular cAMP and activating protein kinase A, leads to inhibition of Rac1-GTPase and p38 MAPK, causing attenuation of actin polymerization, FcgR-mediated phagocytosis, and decreased bacterial clearance. PMID- 22248583 TI - beta1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses. AB - How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which beta1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of beta1 integrin was reduced to 35% of control levels, but function remained normal at baseline. With aortic constriction, the knockout mice survived but had a blunted hypertrophic response. Integrin knockout myocytes, in contrast to controls, showed reduced integrin-linked kinase expression both at baseline and after hemodynamic stress; focal adhesion kinase expression was reduced after stress. Alterations in multiple signaling pathways were detected in the integrin knockout group after acute and chronic hemodynamic stress. Most remarkably, when we challenged the knockout mice with short-term loading, the robust responses of several kinases (extracellular signal-regulated kinase 1/2, p38, and Akt) evident in control mice were essentially abolished in the knockout mice. We also found that reduction of myocyte beta1 integrin expression modified adrenergic-mediated signaling through extracellular signal regulated kinase, p38, and Akt. Reduction of beta1 integrin expression in the mature cardiac myocyte leads to a varied response compared with when this protein is reduced during either the embryonic or perinatal period. These results show that beta1 integrin expression is required for proper mechanotransductive and adrenergic responses of the adult heart. PMID- 22248585 TI - Streptococcal IdeS and its impact on immune response and inflammation. AB - Survival of the important bacterial pathogen Streptococcus pyogenes relies on its ability to circumvent the antimicrobial actions of innate and specific immune responses and to modulate the inflammatory responses induced during the course of an infection. Inflammatory processes play key roles during streptococcal pathogenesis and streptococcal infections are accompanied by an intense inflammatory state. As an exclusively human pathogen, S. pyogenes has adapted to the various countermeasures employed by its host to fight bacterial infections, in particular to interfere with the effector functions of immunoglobulin G (IgG). For this purpose, S. pyogenes has evolved an IgG-specific endopeptidase, IdeS, which is highly specific for the lower hinge region of IgG. This review summarizes the current knowledge about this intriguing enzyme as well as its role in inflammation and in the attenuation of human immune responses towards streptococcal infection. PMID- 22248586 TI - Automated nanomanipulation for nanodevice construction. AB - Nanowire field-effect transistors (nano-FETs) are nanodevices capable of highly sensitive, label-free sensing of molecules. However, significant variations in sensitivity across devices can result from poor control over device parameters, such as nanowire diameter and the number of electrode-bridging nanowires. This paper presents a fabrication approach that uses wafer-scale nanowire contact printing for throughput and uses automated nanomanipulation for precision control of nanowire number and diameter. The process requires only one photolithography mask. Using nanowire contact printing and post-processing (i.e. nanomanipulation inside a scanning electron microscope), we are able to produce devices all with a single-nanowire and similar diameters at a speed of ~1 min/device with a success rate of 95% (n = 500). This technology represents a seamless integration of wafer scale microfabrication and automated nanorobotic manipulation for producing nano FET sensors with consistent response across devices. PMID- 22248587 TI - Oligomeric intermediates in amyloid formation: structure determination and mechanisms of toxicity. AB - Oligomeric intermediates are non-fibrillar polypeptide assemblies that occur during amyloid fibril formation and that are thought to underlie the aetiology of amyloid diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Focusing primarily on the oligomeric states formed from Alzheimer's disease beta-amyloid (Abeta) peptide, this review will make references to other polypeptide systems, highlighting common principles or sequence-specific differences. The covered topics include the structural properties and polymorphism of oligomers, the biophysical mechanism of peptide self-assembly and its role for pathogenicity in amyloid disease. Oligomer dependent toxicity mechanisms will be explained along with recently emerging possibilities of interference. PMID- 22248588 TI - Unperturbing a non-helically perturbed bacterial flagellar filament: Salmonella typhimurium SJW23. AB - Salmonella typhimurium SJW23 has a right-handed, non-helically perturbed filament of serotype gt with a unique surface pattern. Non-helical perturbations involve symmetry reduction along the five-start helical lines resulting in layer lines of fractional Bessel orders and a consequent seam. The flagellin gene, fliC(23), which we sequenced, differs from the sequence of the canonic, plain SJW1655 flagellin, fliC(1655). We modified discrete components of fliC(23) in order to localize, in the expressed filament, the submolecular site responsible for the non-helical perturbation. These modifications include (i) deleting the outermost domain D3(23), (ii) replacing D3(23) with D3(1655), (iii) substituting a hydrophilic alpha-helix at the interface between the neighboring domains D1 and D2 with a hydrophobic one from fliC(1655), and (iv) substituting a serine/glycine pair in the loop connecting the modified alpha-helix to its neighbor; these modifications were made in the presence and absence of D3(23). We used S. typhimurium SJW1655 both as a reference and as a source for 'spare parts'. The symmetry of the constructs was assessed from the power spectra through changes in the layer lines at a height of 1/105 and 1/35 A(-1), unique to the non-helical perturbation. Deleting D3(23), either alone or in combination with various substitutions, or replacing it with D3(1655) transforms the non-helically perturbed filament into a plain one as judged by the disappearance of the typical layer lines from the power spectra. We conclude that the non-helical perturbation is a product of unique interactions in the D3(23) density shell. Whereas other minor structural changes may occur at the filaments interior, they are all helically symmetric. PMID- 22248589 TI - Roles of extracellular chaperones in amyloidosis. AB - Extracellular protein misfolding and aggregation underlie many of the most serious amyloidoses including Alzheimer's disease, spongiform encephalopathies and type II diabetes. Despite this, protein homeostasis (proteostasis) research has largely focussed on characterising systems that function to monitor protein conformation and concentration within cells. We are now starting to identify elements of corresponding systems, including an expanding family of secreted chaperones, which exist in the extracellular space. Like their intracellular counterparts, extracellular chaperones are likely to play a central role in systems that maintain proteostasis; however, the precise details of how they participate are only just emerging. It is proposed that extracellular chaperones patrol biological fluids for misfolded proteins and facilitate their clearance via endocytic receptors. Importantly, many amyloidoses are associated with dysfunction in rates of protein clearance. This is consistent with a model in which disruption to, or overwhelming of, the systems responsible for extracellular proteostasis results in the accumulation of pathological protein aggregates and disease. Further characterisation of mechanisms that maintain extracellular proteostasis will shed light on why many serious diseases occur and provide us with much needed strategies to combat them. PMID- 22248590 TI - Synbiotics and probiotics in the critically ill after the PROPATRIA trial. AB - PURPOSE OF REVIEW: Recent clinical trials have furthered our understanding of the role of probiotic and synbiotic therapy across a variety of diverse diseases including antibiotic-associated diarrhea, Clostridium difficile associated diarrhea, acute pancreatitis, ventilator-associated pneumonia, and sepsis among others. Although each of these conditions has implications for critically ill patients, relatively few studies have specifically studied this vulnerable population. RECENT FINDINGS: One recent clinical trial studying probiotics in severe pancreatitis (the PROPATRIA trial) found an unexpected increase in mortality in probiotic-treated patients. These results stimulated an immediate, extensive, and badly overdue discussion focused on the need for improved safety monitoring during the execution of all clinical trials using probiotics. However, issues with the design, execution, and analysis of PROPATRIA ultimately created more questions than it answered. SUMMARY: Regardless of technical issues with the study, the increased mortality seen with probiotics cannot be ignored. As a result, various regulatory agencies have clarified their stance on the safety of probiotic research and the legacy of PROPATRIA is increasingly stringent regulation of this fledgling niche. PMID- 22248591 TI - Update on lipids and mitochondrial function: impact of dietary n-3 polyunsaturated fatty acids. AB - PURPOSE OF REVIEW: Recent evidence has linked n-3 polyunsaturated fatty acid (PUFA) supplementation with dramatic alterations of mitochondrial phospholipid membranes and favorable changes in mitochondrial function. In the present review, we examine the novel effects of n-3 PUFA on mitochondria, with an emphasis on cardiac mitochondrial phospholipids. RECENT FINDINGS: There is growing evidence that dietary n-3 PUFA, particularly docosahexaenoic acid (DHA), has profound effects on mitochondrial membrane phospholipid composition and mitochondrial function. Supplementation with n-3 PUFA increases membrane phospholipid DHA and depletes arachidonic acid, and can increase cardiolipin, a tetra-acyl phospholipid that is unique to mitochondrial and essential for optimal mitochondrial function. Recent studies show that supplementation with DHA decreases propensity for cardiac mitochondria to undergo permeability transition, a catastrophic event often leading to cell death. This finding provides a potential mechanism for the cardioprotective effect of DHA. Interestingly, other n-3 PUFAs that modify membrane composition to a lesser extent have substantially less of an effect on mitochondria and do not appear to directly protect the heart. SUMMARY: Current data support a role for n-3 PUFA supplementation, particularly DHA, on mitochondria that are strongly associated with changes in mitochondrial phospholipid composition. PMID- 22248592 TI - CD36 and taste of fat. AB - PURPOSE OF REVIEW: This review explores the recent literature on the role of CD36 in the taste of fat, eating behavior and obesity risk in rodents and humans. RECENT FINDINGS: During the last decade, evidence was accumulated supporting the existence of a taste of fat responsible for the spontaneous preference for lipid rich foods. Surprisingly, the multifunctional membrane-associated protein CD36 appears to play a significant role in this system in rodents. Recently, another plausible gustatory lipid sensor, the GPR120, was also identified in mice, revealing that the mechanism involved in oral fat detection is more complex than initially expected. Interestingly, lingual CD36 and GPR120 display a differential regulation during a meal suggesting complementary functions. CD36 and GPR120 have also been identified in human taste buds. Implication of lingual CD36 in the chemoreception of fat in foods and consequences on eating behavior and obesity risk is actively studied in various species. SUMMARY: Recent studies suggest that lingual CD36 is involved in the attraction for fatty foods in rodents. The fact that it is also expressed in taste buds in humans raises the possibility of a universal function as gustatory lipid sensor able to affect eating behavior. PMID- 22248593 TI - Overexpression of a modified protein from amaranth seed in Escherichia coli and effect of environmental conditions on the protein expression. AB - Amaranth seeds are considered as an excellent complementary source of food protein due to their balanced amino acid composition. Amarantin acidic subunit has the potential as a functional and nutraceutical protein, and it is structurally a good candidate for modification. The aim of this work was to improve its functionality, then the primary structure was modified into the third variable region of 11S globulins, by inserting antihypertensive peptides: four Val-Tyr in tandem and Arg-Ile-Pro-Pro in the C-terminal region. Modified protein was expressed in Escherichia coli Origami (DE3) and was purified. The culture conditions, including the culture media, temperature, agitation speed and air flow were tested in order to obtain an increased expression levels of the modified protein. A 2(3) factorial design was used for evaluate the effect of environmental conditions on modified protein production. The results indicated that the yield of modified protein could be increased by up 3-fold in bioreactor as compared with flask. In addition, the temperature, the agitation speed and the oxygen were significant factors on the expression of the antihypertensive protein. The maximum production was 99 mg protein-L(-1). The hydrolyzed protein showed a high inhibitory activity of the angiotensin converting enzyme (IC50=0.047 mg mL(-1)). PMID- 22248594 TI - Enhancement of the enantioselectivity of carboxylesterase A by structure-based mutagenesis. AB - Previously studied Bacillus subtilis carboxylesterases (CesA and CesB) have potential for the kinetic resolution of racemic esters of 1,2-O isopropylideneglycerol (IPG). CesA exhibits high activity but low enantioselectivity towards IPG-butyrate and IPG-caprylate, while the more enantioselective CesB does not process IPG-butyrate and exhibits several-fold lower activity than CesA towards IPG-caprylate. A sequence and structure comparison allowed us to identify active site residues that may cause the difference in (enantio)selectivities of CesA and CesB towards these IPG esters. This structure-based approach led to the identification of two active site residues in CesA (F166 and F182), as promising candidates for mutagenesis in order to enhance its enantioselectivity. Mutagenesis of positions 166 and 182 in CesA yielded novel variants with enhanced enantioselectivity and without significant loss of catalytic activity. For IPG-butyrate, a CesA double mutant F166V/F182C (ER=13) was generated showing a ~13-fold increased enantioselectivity as compared to wild-type CesA (E=1). For IPG-caprylate, we designed a CesA double mutant F166V/F182Y (ER=9) displaying a ~5-fold increased enantioselectivity as compared to the wild-type enzyme (ER=2). These findings, combined with the results of molecular docking experiments, demonstrate the importance of residues at positions 166 and 182 for the enantioselectivity of CesA, and may contribute to the development of efficient biocatalysts. PMID- 22248595 TI - Validation of the Prague C & M criteria for the endoscopic grading of Barrett's esophagus by gastroenterology trainees: a multicenter study. AB - BACKGROUND: The Prague C & M criteria, developed for the endoscopic grading of Barrett's esophagus (BE), (C = circumferential length, M = maximal length) were previously validated among a panel of 29 expert endoscopists with a special interest in BE. Its performance among gastroenterology trainees is unknown. OBJECTIVE: To test interobserver agreement among gastroenterology trainees for the Prague C & M criteria, identification of the gastroesophageal junction (GEJ) and the diaphragmatic hiatus. DESIGN: A prospective study. SETTING: Two tertiary referral centers. PATIENTS AND INTERVENTIONS: Standardized endoscopic videos were used. MAIN OUTCOME MEASUREMENTS: Interobserver agreement. RESULTS: Eighteen high quality videos (normal esophagus, short and long lengths of BE, equally distributed) were independently evaluated by 18 gastroenterology trainees (year 1, n = 5; year 2, n = 6; year 3, n = 7) after administration of a formal teaching module by an expert endoscopist. Overall intraclass correlation coefficients for assessment of the C and M extent of the endoscopic BE segment above the GEJ were 0.94 (95% CI, 0.89-0.98) and 0.96 (95% CI, 0.94-0.98), respectively. The overall intraclass correlation coefficients for GEJ and diaphragmatic hiatus location recognition were 0.92 (0.86-0.96) and 0.90 (0.82-0.95), respectively. The year of training did not affect interobserver agreement. LIMITATIONS: The use of videos for endoscopic evaluation. CONCLUSION: After standardized teaching, the Prague C & M criteria have high overall validity among gastroenterology trainees irrespective of the level of training for endoscopic evaluation of visualized BE lengths as well as key endoscopic landmarks. PMID- 22248596 TI - Ain't nothing like the real thing? Simulators in endoscopy training. PMID- 22248597 TI - Nonvariceal upper GI bleeding: it's not just about peptic ulcers. PMID- 22248598 TI - Endoscopic intrapyloric injection of botulinum toxin A in the treatment of children with gastroparesis: a retrospective, open-label study. AB - BACKGROUND: Botulinum toxin A has been used in children to treat spastic disorders and recently for GI conditions. Open-label studies in adults with gastroparesis have reported an improvement in symptoms and gastric emptying after endoscopic intrapyloric botulinum injections (IPBIs), although placebo-controlled trials have shown conflicting results. Only a single case report of IPBI is available in children. OBJECTIVE: To determine the long-term clinical outcomes and predictive factors for IPBI response in children with gastroparesis refractory to medical therapy. DESIGN: Retrospective review. SETTING: Single tertiary care center. PATIENTS: Children with refractory gastroparesis symptoms undergoing IPBIs. INTERVENTIONS: IPBIs. MAIN OUTCOME MEASUREMENTS: Clinical improvement and predictive factors for response. RESULTS: A total of 70 injections were given to 47 patients (mean age 9.98 +/- 6.5 years; 23 female patients) with follow-up in 45 patients. IPBI failed in 15 patients and was successful in 30 patients. The median duration of response to the first IPBI was 3.0 months (95% CI, 1.2-4.8). A total of 29 patients received a single IPBI, and 18 received multiple IPBIs. Older age and vomiting predicted response to initial IPBI, and male sex predicted response to repeat IPBI. Only 1 patient reported exacerbation of vomiting after IPBI resolving within a week. LIMITATIONS: The open-label and retrospective nature of the study. CONCLUSION: IPBI is safe and may be effective in the management of children with symptoms of gastroparesis. Subgroups identifying who responded to the first IPBI include older patients and those presenting with vomiting, whereas male patients responded better to repeat IPBIs. PMID- 22248599 TI - High yield of same-session EUS-guided liver biopsy by 19-gauge FNA needle in patients undergoing EUS to exclude biliary obstruction. AB - BACKGROUND: EUS-guided liver biopsy by Trucut yields variable specimen adequacy at high cost, limiting its utility. A modified EUS-guided technique with reliable adequacy could be a viable alternative to standard techniques in cost-effective clinical settings. OBJECTIVE: To describe our experience with EUS-guided liver biopsy by 19-gauge FNA, non-Trucut, needle in a cost-effective setting: patients with abnormal liver test results of unclear etiology referred for EUS to exclude biliary obstruction in whom an unrevealing EUS would have prompted a next-step liver biopsy by the referring physician. DESIGN: Prospective case series. SETTING: Tertiary-care teaching hospital. PATIENTS: Consecutive patients with abnormal liver tests referred for EUS. INTERVENTIONS: EUS-guided liver biopsy by 19-gauge FNA needle (non-Trucut). MAIN OUTCOME MEASUREMENTS: Diagnostic yield, specimen adequacy, and complications. An adequate specimen was defined as a length of 15 mm or longer and 6 or more complete portal tracts (CPTs). RESULTS: Between July 2008 and July 2011, 22 of 31 consecutive patients meeting inclusion criteria underwent unrevealing EUS with same-session EUS-guided liver biopsy by 19-gauge FNA needle. A median of 2 FNA passes (range 1-3) yielded a median specimen length of 36.9 mm (range 2-184.6 mm) with a median of 9 CPTs (range 1-73 CPTs). EUS-guided liver biopsies yielded a histologic diagnosis and adequate specimens in 20 of 22 patients (91%). Expanded experience led to improved specimen adequacy. There were no complications. LIMITATION: Small study size. CONCLUSIONS: EUS-guided liver biopsy by using a 19-gauge FNA needle appears to be feasible and safe and provides excellent diagnostic yield and specimen adequacy. PMID- 22248600 TI - EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis. AB - BACKGROUND: Preoperative diagnosis of solid pancreatic lesions remains challenging despite advancement in imaging technologies. EUS has the benefit of being a minimally invasive, well-tolerated procedure, although results are operator-dependent. The addition of FNA (EUS-guided FNA) provides samples for cytopathologic analysis, a major advantage over other imaging techniques. OBJECTIVE: To determine the diagnostic accuracy of EUS-FNA for pancreatic cancer. DESIGN: This is a meta-analysis of published studies assessing the diagnostic capability of EUS-FNA. Relevant studies were identified via MEDLINE and were included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. MAIN OUTCOME MEASUREMENTS: Data from selected studies were analyzed by using test accuracy meta-analysis software, providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. Cytology results were classified as inadequate, benign, atypical, suspicious, or malignant. Predefined subgroup analysis was performed. RESULTS: Thirty-three studies published between 1997 and 2009 were included, with a total number of 4984 patients. The pooled sensitivity for malignant cytology was 85% (95% confidence interval [CI], 84-86), and pooled specificity was 98% (95% CI, 0.97-0.99). If atypical and suspicious cytology results were included to determine true neoplasms, the sensitivity increased to 91% (95% CI, 90-92); however, the specificity was reduced to 94% (95% CI, 93-96). The diagnostic accuracy of EUS-FNA was enhanced in prospective, multicenter studies. LIMITATION: Publication bias was not a significant determinant of pooled accuracy. CONCLUSION: This meta-analysis demonstrates that EUS-FNA is a highly accurate diagnostic test for solid neoplasms of the pancreas and should be considered when algorithms for investigating solid pancreatic lesions are being planned. PMID- 22248601 TI - EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study. AB - BACKGROUND: TNFeradeBiologic (AdGVEGR.TNF.11D) is a replication-deficient adenoviral vector that expresses tumor necrosis factor-alpha (TNF-alpha) under the control of the Egr-1 promoter, which is inducible by chemotherapy and radiation. OBJECTIVE: This study was conducted to determine the maximal tolerated dose of TNFeradeBiologic with standard chemoradiotherapy and preliminary activity and safety of the combination in the treatment of locally advanced pancreatic cancer (LAPC). DESIGN: TNFeradeBiologic was injected into locally advanced pancreatic carcinomas by using EUS or percutaneous administration once a week for 5 weeks together with 50.4 Gy radiation and 5-fluorouracil (5-FU) 200 mg/m(2) daily over 5.5 weeks. Dose levels from 4 * 10(9) to 1 * 10(12) particle units (PU) were studied. SETTING: Multicentered, academic institutions. PATIENTS: Fifty patients with LAPC were treated. INTERVENTIONS: Doses of TNFerade Biologic were administered to patients. MAIN OUTCOME MEASUREMENTS: Toleration of TNFerade Biologic was measured through toxicity and tumor response, by using the criteria of the Response Evaluation Criteria in Solid Tumors and the World Health Organization, and was reviewed by a central radiology facility. Overall survival and progression-free survival were also measured. RESULTS: Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3 patients at the 1 * 10(12) PU dose, making 4 * 10(11) PU the maximum tolerated dose. One complete response, 3 partial responses, and 12 patients with stable disease were noted. Seven patients eventually went to surgery, 6 had clear margins, and 3 survived >24 months. LIMITATIONS: This is a Phase 1/2 non-randomized study. CONCLUSIONS: Intratumoral delivery of TNFerade Biologic by EUS with fine-needle viral injection or percutaneously, combined with chemoradiation, shows promise in the treatment of LAPC. There appeared to be better clinical outcome at the maximal tolerated dose than at lower doses. The dose of 4 *10(11) PU TNFerade Biologic was generally well tolerated, with encouraging indications of activity, and will be tested in the randomized phase of this study. Delivery of TNFerade Biologic did not interfere with subsequent surgical resection. PMID- 22248602 TI - Diagnostic accuracy of conventional and cholangioscopy-guided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study. AB - BACKGROUND: The diagnostic accuracy of cholangioscopy-guided sampling has not been rigorously evaluated. OBJECTIVE: To prospectively evaluate the accuracy of cholangioscopy-guided mini-forceps sampling and compare it with standard cytology brushings and forceps biopsies for the tissue diagnosis of indeterminate biliary lesions. DESIGN: Prospective, long-term follow-up, paired design cohort study. SETTING: Tertiary center. PATIENTS: Patients undergoing cholangioscopy for the evaluation of indeterminate biliary lesions. INTERVENTIONS: Each patient underwent triple sampling with cholangioscopy-guided mini-forceps, cytology brushing, and standard forceps. MAIN OUTCOME MEASUREMENTS: Diagnostic accuracy of each sampling method compared with the patient final status (cancer vs no cancer). RESULTS: A total of 26 patients (17 cancer positive/9 cancer negative) were enrolled. The mean follow-up in the patients with no cancer was 21.78 (SD +/ 6.78) months. The procedure was technically successful in all cases (100%). Sample quality was adequate in 25 of 26 (96.2%) of the cytology brushings, in 26 of 26 (100%) of the standard forceps biopsies, and in 25 of 26 (96.2%) of the mini-forceps biopsies. The sensitivity, accuracy, and negative predictive values were 5.9%, 38.5%, and 36% for standard cytology brushings; 29.4%, 53.8%, and 42.8% for standard forceps biopsies; and 76.5%, 84.6%, and 69.2% for mini-forceps biopsies, respectively. When comparing the 3 methods of sampling, mini-forceps biopsy provided significantly better sensitivity and overall accuracy compared with standard cytology brushing (P < .0001) and standard forceps biopsy (P = .0215). LIMITATIONS: Potential for selection bias. CONCLUSIONS: Cholangioscopy guided biopsies of indeterminate biliary lesions have significantly higher accuracy compared with ERCP-guided cytology brushings and standard forceps biopsies, but negative findings on mini-forceps biopsy cannot rule out malignancy with a high degree of certainty. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01227382.). PMID- 22248603 TI - Comparison of EUS-guided rendezvous and precut papillotomy techniques for biliary access (with videos). AB - BACKGROUND: Precut papillotomy after failed bile duct cannulation is associated with an increased risk of pancreatitis. EUS-guided rendezvous drainage is a novel alternative technique, but there are no data comparing this approach with precut papillotomy. OBJECTIVE: To evaluate the safety and efficacy of EUS-guided rendezvous drainage of the bile duct and compare its outcome with that of precut papillotomy. DESIGN: Retrospective study. SETTING: Tertiary care referral center. PATIENTS: Consecutive patients with distal bile duct obstruction, in whom selective cannulation of the bile duct at ERCP failed after 5 attempts with a guidewire and sphincterotome, underwent an EUS-guided rendezvous procedure. The outcomes were compared with those in a historical cohort of patients who underwent precut papillotomy. INTERVENTIONS: Patients in whom selective cannulation failed underwent EUS-guided rendezvous drainage by use of the short wire technique or precut papillotomy by use of the Erlangen papillotome. At EUS, after the extrahepatic bile duct was punctured with a 19-gauge needle, a hydrophilic angled-tip guidewire 260 cm long was passed in an antegrade manner across the papilla into the duodenum. The echoendoscope was then exchanged for a duodenoscope, which was introduced alongside the EUS-placed guidewire. The transpapillary guidewire was retrieved through its biopsy channel, and accessories were passed over the wire to perform the requisite endotherapy. MAIN OUTCOME MEASURES: Comparison of the rates of technical success and complications between patients treated by the EUS-guided rendezvous and those treated by precut papillotomy techniques. Treatment success was defined as completion of the requisite endotherapy in one treatment session. RESULTS: Treatment success was significantly higher for the EUS-guided rendezvous (57/58 patients) than for those undergoing precut papillotomy technique (130/144 patients) (98.3% vs 90.3%; P = .03). There was no significant difference in the rate of procedural complications between the EUS and precut papillotomy techniques (3.4% vs 6.9%, P = .27). LIMITATIONS: Retrospective nonrandomized study design; highly selective patient cohort. CONCLUSIONS: In this study, the EUS-guided rendezvous technique was found to be superior to precut papillotomy for single-session biliary access. Prospective randomized trials are needed to confirm these preliminary but promising findings. PMID- 22248604 TI - EUS-guided biliary rendezvous: EUS to the rescue. PMID- 22248606 TI - The ins and outs of diverticular bleeding. PMID- 22248605 TI - A multicenter, prospective, randomized study of selective bile duct cannulation performed by multiple endoscopists: the BIDMEN study. AB - BACKGROUND: Wire-guided cannulation (WGC) with a sphincterotome (S) for selective bile duct cannulation (SBDC) has been reported to have a higher success rate and lower incidence of post-ERCP pancreatitis (PEP) than conventional methods in some randomized, controlled trials (RCTs) that were both single center and limited to only a few endoscopists. OBJECTIVE: To estimate the difference in SBDC according to the method and catheter used in a multicenter and multiendoscopist study. DESIGN: A prospective, multicenter RCT with a 2 * 2 factorial design. SETTING: Fifteen referral endoscopy units. PATIENTS: In total, 400 consecutive patients with naive papillae who were candidates for ERCP were enrolled and randomized. INTERVENTIONS: Patients were assigned to 4 groups according to combined catheter (S or catheter [C]) and method (with/without guidewire [GW]). MAIN OUTCOME MEASUREMENTS: Success rate of SBDC performed in 10 minutes, SBDC time, fluoroscopy time, and incidence of complications. RESULTS: There was no significant difference in the SBDC success rate between the groups with and without GW, between C and S, or among the 4 groups (C+GW, C, S+GW, S). WGC had a tendency to significantly shorten cannulation and fluoroscopy times only in approximately 70% of patients in this study in whom SBDC was achieved in 10 minutes or less (P = .036 and .00004, respectively). All 4 groups resulted in similar outcomes in PEP (4%, 5.9%, 2%, and 2.1%, respectively). LIMITATIONS: Non double-blind study. CONCLUSIONS: WGC appears to significantly shorten cannulation and fluoroscopy times. However, neither the method nor type of catheter used resulted in significant differences in either SBDC success rate or incidence of PEP in this RCT. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002572.). PMID- 22248607 TI - Unsedated colonoscopy: an option for some but not for all. AB - BACKGROUND: The increasing request for colonoscopy in clinical practice, coupled with the lack of time, has led to a renewed interest in unsedated procedures. OBJECTIVE: To evaluate the acceptability of unsedated colonoscopy and to characterize the subset of patients more likely to undergo and complete the procedure without sedation and/or analgesia. DESIGN: Prospective, population study. SETTING: Nonacademic community hospital, 6-month observation period. PATIENTS: Adult outpatients referred for colonoscopy were offered unsedated procedure, with the possibility of on-demand sedation. INTERVENTIONS: Demographics, clinical features, and endoscopy outcomes were recorded. Data were analyzed by stepwise logistic regression analysis, and odds ratio (OR) and 95% confidence interval (CI) are given for significant variables. MAIN OUTCOME MEASUREMENTS: Unsedated colonoscopy acceptance rate. Factors significantly associated with acceptance and completion of unsedated procedures. RESULTS: The acceptance rate for unsedated colonoscopy was 56.2% of 964 consecutive evaluated patients. The cecal intubation rate in unsedated patients was 81.6% and increased to 97.3% with the option of on-demand sedation. At multivariate analysis, factors significantly associated with the acceptance were no previous colonoscopy (OR 1.52; 95% CI, 1.10-2.11), absent/low level of anxiety (OR 3.82; 95% CI, 2.71 5.38), and no concern about the examination (OR 1.80; 95% CI, 1.17-2.77). Fear of procedure-related pain was inversely associated with acceptance (OR 0.28; 95% CI, 0.17-0.35). Factors associated to drug-free colonoscopy completion were absence of preprocedure anxiety (OR 1.87; 95% CI, 1.08-3.21) and male sex (OR 3.59; 95% CI, 2.13-6.05). LIMITATIONS: Single-center study. CONCLUSION: The acceptance rate of unsedated colonoscopy is clinically relevant, and the procedure can be completed without sedation in the majority of patients. Subject-related factors may help to identify patients willing to undergo and potentially complete unsedated procedures. PMID- 22248608 TI - In vivo histologic imaging of the muscularis propria and myenteric neurons with probe-based confocal laser endomicroscopy in porcine models (with videos). AB - BACKGROUND: The submucosal tunneling technique enables us to endoscopically access deeper tissue layers. Use of probe-based confocal laser endomicroscopy (pCLE) provides optical histologic imaging on the site. OBJECTIVE: To determine the technical feasibility of ex vivo and in vivo pCLE imaging of the muscularis propria and myenteric neurons by using submucosal endoscopy with a mucosal flap safety valve (SEMF). DESIGN: Acute porcine model study. SETTING: Animal laboratory. INTERVENTION: Two ex vivo and 6 in vivo porcine models were used. A submucosal space was created with SEMF, and a neuronal molecular probe was topically applied onto the muscularis. Confocal imaging of the stained muscularis was performed by using pCLE. The selected sites were sampled, and the histopathology of the sites was analyzed. MAIN OUTCOME MEASUREMENTS: The two main outcome measures were the procedural success rate of submucosal access and the correlation between pCLE and histologic images. RESULTS: Submucosal access to the pCLE study site was successful in all attempts (100%; 17/17 sites). The muscularis propria was visualized with pCLE in the ex vivo and in vivo porcine models in 83.3% of sites (20/24), and the neuron-like cells were identified in 41.7% of sites (10/24). LIMITATIONS: Animal experiment. CONCLUSION: The muscularis propria and myenteric neurons could be selectively visualized with pCLE in vivo. PMID- 22248609 TI - An endoscopic wireless gastrostimulator (with video). AB - BACKGROUND: Gastric electric stimulation (GES) at a high-frequency, low-energy setting is an option for treating refractory gastroparesis. The currently available commercial stimulator, the Enterra neurostimulator (Medtronic Inc, Minneapolis, MN), however, requires surgical implantation and is powered by a nonrechargeable battery. OBJECTIVE: To develop and test a miniature wireless GES device for endoscopic implantation in an experimental model. DESIGN: In-vivo gastric signals were recorded and measured in a nonsurvival swine model (n = 2; 110-lb animals). INTERVENTION: An endoscopically placed, wireless GES device was inserted into the stomach through an overtube; the two GES electrodes were endoscopically attached to the gastric mucosa and secured with endoclips to permit stimulation. MAIN OUTCOME MEASUREMENTS: Stable electrogastrogram measures were observed during GES stimulation. RESULTS: Electrogastrogram recordings demonstrated that gastric slow waves became more regular and of constant amplitudes when stomach tissues were stimulated, in comparison with no stimulation. The frequency-to-amplitude ratio also changed significantly with stimulation. LIMITATION: Nonsurvival pig studies. CONCLUSION: Gastric electric stimulation is feasible by our endoscopically implanted, wireless GES device. PMID- 22248610 TI - Gastric involvement by mantle cell lymphoma observed by magnified endoscopy with narrow-band imaging. PMID- 22248611 TI - Unusual presentation of MALT lymphoma as diffuse gastric erythema. PMID- 22248612 TI - Weck clip migration into the rectum. PMID- 22248613 TI - Use of a forward-viewing echoendoscope for evaluation of GI submucosal lesions. PMID- 22248614 TI - Early additional endoscopic submucosal dissection in patients with positive lateral resection margins after initial endoscopic submucosal dissection for early gastric cancer. PMID- 22248615 TI - Duodenal bulb nodularity: an endoscopic sign of cow's milk protein allergy in infants? PMID- 22248616 TI - A gigantic ectopic pancreatic lesion in the upper body of the stomach. PMID- 22248617 TI - Direct percutaneous endoscopic jejunostomy tube placement using double-balloon enteroscopy. PMID- 22248618 TI - Eradication of Pseudomonas aeruginosa by early antibiotic treatment has been one of the major advances in the last decade for subjects with CF. Introduction. PMID- 22248619 TI - Nuclear export as a key arbiter of "mRNA identity" in eukaryotes. AB - Over the past decade, various studies have indicated that most of the eukaryotic genome is transcribed at some level. The pervasiveness of transcription might seem surprising when one considers that only a quarter of the human genome comprises genes (including exons and introns) and less than 2% codes for protein. This conundrum is partially explained by the unique evolutionary pressures that are imposed on species with small population sizes, such as eukaryotes. These conditions promote the expansion of introns and non-functional intergenic DNA, and the accumulation of cryptic transcriptional start sites. As a result, the eukaryotic gene expression machinery must effectively evaluate whether or not a transcript has all the hallmarks of a protein-coding mRNA. If a transcript contains these features, then positive feedback loops are activated to further stimulate its transcription, processing, nuclear export and ultimately, translation. However if a transcript lacks features associated with "mRNA identity", then the RNA is degraded and/or used to inhibit further transcription and translation of the gene. Here we discuss how mRNA identity is assessed by the nuclear export machinery in order to extract meaningful information from the eukaryotic genome. In the process, we provide an explanation of why certain sequences that are enriched in protein-coding genes, such as the signal sequence coding region, promote mRNA nuclear export in vertebrates. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. PMID- 22248621 TI - Sex differences in stroke incidence and survival in Hong Kong, 2000-2007. AB - BACKGROUND: Few studies have examined the impact of sex across different age groups and over time on chronic diseases in Asia. The objective of this study was to explore the effect of sex across different age groups and over time on stroke incidence and 30-day case fatality in Hong Kong. METHODS: Over 90% first hospitalizations for stroke in Hong Kong (from 2000 to 2007) were identified from the Clinical Management System of the Hospital Authority. Age-specific rate ratios (RRs; women to men) for incidence of first hospitalization and the 30-day case fatality were estimated based on Poisson regression models after adjustment for year of hospitalization. RESULTS: Women below the age of 85 years had a lower incidence of first hospitalization than men, and the effect size varied with age [35-44 years: RR = 0.56, 95% confidence interval (CI) = 0.49-0.64; 45-54 years: 0.65, 0.53-0.79; 55-64 years: 0.58, 0.48-0.71; 65-74 years: 0.71, 0.58-0.85; 75 84 years: 0.83, 0.68-1.00)]. Women aged >=85 years had a stroke incidence similar to men, but the adjusted 30-day case fatality was significantly higher than that of men aged >=85 years (RR = 1.14, 95% CI = 1.05-1.23). CONCLUSIONS: Lower rates of incidence were observed in women than men aged 35-84 years in Hong Kong but short-term case fatality is greater in women aged >=85 years. PMID- 22248620 TI - Regulated pre-mRNA splicing: the ghostwriter of the eukaryotic genome. AB - Intron removal is at the heart of mRNA synthesis. It is mediated by one of the cell's largest complexes, the spliceosome. Yet, the fundamental chemistry involved is simple. In this review we will address how the spliceosome acts in diverse ways to optimize gene expression in order to meet the cell's needs. This is done largely by regulating the splicing of key transcripts encoding products that control gene expression pathways. This widespread role is evident even in the yeast Saccharomyces cerevisiae, where many introns appear to have been lost; yet how this control is being achieved is known only in a few cases. Here we explore the relevant examples and posit hypotheses whereby regulated splicing fine-tunes gene expression pathways to maintain cell homeostasis. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. PMID- 22248622 TI - Prevalence of Shiga toxin-producing Escherichia coli in food products of animal origin as determined by molecular methods. AB - In this study we report on the prevalence and distribution of Shiga toxin producing Escherichia coli (STEC) in food products of animal origin, collected in the Piedmont region of Italy, as determined by a combination of quantitative PCR (qPCR) protocols, applied directly to the samples, and of culture-dependent isolation and subsequent molecular identification and characterization of isolates. The qPCR protocols were developed and optimized in this study and targeted the rpoB gene (as a marker for total E. coli) and the stx1, stx2 and eaeA genes (as markers for potentially virulent E.coli). They were then used to test for STEC in 101 food samples, before and after enrichment. A STEC prevalence of 42% (21/50) for dairy products and 70% (36/51) for meat products was obtained. A total of 54 STEC isolates were recovered from dairy and meat samples, resulting in a prevalence of 36% and 27% in dairy and meat products, respectively, by the culture method. A large number of strains carried the stx2 gene (39 out of the 54 STEC strains) compared to strains that carried stx1 (30 out of 54); only 11 out of 54 strains contained the eaeA gene, while 14 strains contained both stx1 and stx2. Eight of the 54 isolates belonged to the O157 serogroup, and none belonged to serogroups O26, O145, O111 or O103. Strains isolated from meat products were diverse, as determined by Enterobacterial repetitive intergenic consensus-PCR (ERIC), while those isolated from dairy products were more similar and grouped together by cluster analysis. The results of the qPCR approach showed a high prevalence of STEC in dairy and meat based products, mainly fermented, indicating a possible safety risk for these types of food commodities. PMID- 22248623 TI - Mechanical properties of Bi(x)Sb(2-x)Te3 nanostructured thermoelectric material. AB - Research on thermoelectric (TE) materials has been focused on their transport properties in order to maximize their overall performance. Mechanical properties, which are crucial for system reliability, are often overlooked. The recent development of a new class of high-performance, low-dimension thermoelectric materials calls for a better understanding of their mechanical behavior to achieve the desired system reliability. In the present study we investigate the mechanical behavior of nanostructure bulk TE material p-type Bi(x)Sb(2-x)Te(3) by means of nanoindentation and 3D finite element analysis. The Young's modulus of the material was estimated by the Oliver-Pharr (OP) method and by means of numerically assisted nanoindentation analysis yielding comparable values about 40 GPa. Enhanced hardness and yield strength can be predicted for this nanostructured material. Microstructure is studied and correlation with mechanical properties is discussed. PMID- 22248624 TI - Coexisting role of fasting or feeding and dietary lipids in the control of gene expression of enzymes involved in the synthesis of saturated, monounsaturated and polyunsaturated fatty acids. AB - In the liver, maintaining lipid homeostasis is regulated by physiological and exogenous factors. These lipids are synthesized by Fasn, elongases and desaturases. Interactions in an organism among these factors are quite complex and, to date, relatively little is known about them. The aim of this study was to evaluate the coexisting role of physiological (insulin, fasting and feeding) and exogenous (dietary lipids) factors in the control of gene expression of Fasn, elongases and desaturases via Srebf-1c in liver from rats. Gene expression of encoding enzymes for fatty acid synthesis and fatty acid composition was evaluated in liver from rats in fasting and feeding (at 30, 60, 90 and 120 min after feeding) when food intake (adequate or high-lipid diet) was synchronized to a restricted period of 7h. Fasn, Scd and Fads2 were induced during 120 min after initial feeding in both dietary groups. This induction may be activated in part by insulin via Srebf-1c. Also, we showed for the first time that Elovl7 may be regulated by insulin and dietary lipids. The failure to synthesize saturated and monounsaturated fatty acids is consistent with a downregulation of Fasn and Scd, respectively, by dietary lipids. A higher content of LC-PUFAs was observed due to a high expression of Elovl2 and Elovl5, although Fads2 was suppressed by dietary lipids. Therefore, elongases may have a mechanism that is Srebf-1c-independent. This study suggests that a high-lipid diet triggers, during 120 min after initial feeding, a tight coordination among de novo lipogenesis, elongation, and desaturation and may not always be regulated by Srebf-1c. Finally, upregulation by feeding (insulin) of Fasn, Scd, Fads2 and Srebf-1c is insufficient to compensate for the inhibitory effect of dietary lipids. PMID- 22248625 TI - Prenatal diagnosis of a fetus with a de novo trisomy 12p by array-comparative genomic hybridization (array-CGH). AB - Trisomy 12p syndrome is a rare chromosomal abnormality, which presents with facial dysmorphism, moderate to severe psychomotor retardation and generalized hypotonia. Here we present the prenatal sonographic findings investigated of a fetus in prenatal diagnosis with a de novo trisomy of 12p identified by array comparative genomic hybridization (aCGH). PMID- 22248626 TI - Isolation and molecular characterisation of flavonoid 3'-hydroxylase and flavonoid 3', 5'-hydroxylase genes from a traditional Chinese medicinal plant, Epimedium sagittatum. AB - The epimedii herb, a traditional Chinese medicinal plant, has significant pharmacological effects on human health. The bioactive components in the herb (Epimedium sagittatum (Sieb. et Zucc.) Maxim) are mainly prenylated flavonol glycosides, which are end-products of the flavonoid biosynthetic pathway. This has not been clearly elucidated until recently. The genes encoding flavonoid 3' hydroxylase (F3'H) and flavonoid 3', 5'-hydroxylase (F3'5'H) involved in the flavonoid biosynthetic pathway, designated as EsF3'H and EsF3'5'H, were isolated from E. sagittatum using a homology-based cloning method and deposited in the GenBank databases (GenBank ID: HM011054 and HM011055), respectively. EsF3'H and EsF3'5'H proteins shared high homology with other plant-specific flavonoid hydroxylases and were clustered into the CYP75B and CYP75A group, respectively. In addition, four conserved cytochrome P450-featured motifs were found in the amino acid sequences of both genes. Transcription levels of both genes were detected in all tissues tested and were high in most of the pigmented tissues. Moreover, the expression levels of both EsF3'H and EsF3'5'H correlated positively with the anthocyanin accumulation pattern in leaves from E. sagittatum. The cloning and molecular characterisation of EsF3'H and EsF3'5'H genes will accelerate progress in the study of the flavonoid biosynthetic pathway to elucidate the molecular mechanisms of the biosynthesis of the bioactive components in E. sagittatum. PMID- 22248627 TI - Characterization of suramin binding sites on the human group IIA secreted phospholipase A2 by site-directed mutagenesis and molecular dynamics simulation. AB - Suramin is a polysulphonated naphthylurea with inhibitory activity against the human secreted group IIA phospholipase A(2) (hsPLA2GIIA), and we have investigated suramin binding to recombinant hsPLA2GIIA using site-directed mutagenesis and molecular dynamics (MD) simulations. The changes in suramin binding affinity of 13 cationic residue mutants of the hsPLA2GIIA was strongly correlated with alterations in the inhibition of membrane damaging activity of the protein. Suramin binding to hsPLA2GIIA was also studied by MD simulations, which demonstrated that altered intermolecular potential energy of the suramin/mutant complexes was a reliable indicator of affinity change. Although residues in the C-terminal region play a major role in the stabilization of the hsPLA2GIIA/suramin complex, attractive and repulsive hydrophobic and electrostatic interactions with residues throughout the protein together with the adoption of a bent suramin conformation, all contribute to the stability of the complex. Analysis of the hsPLA2GIIA/suramin interactions allows the prediction of the properties of suramin analogues with improved binding and higher affinities which may be candidates for novel phospholipase A(2) inhibitors. PMID- 22248628 TI - An advanced multi-orbital impurity solver for dynamical mean field theory based on the equation of motion approach. AB - We propose an improved fast multi-orbital impurity solver for the dynamical mean field theory based on equations of motion (EOM) for Green's functions and a decoupling scheme. In this scheme the inter-orbital Coulomb interactions are treated fully self-consistently, and involve the inter-orbital fluctuations. As an example of the use of the derived multi-orbital impurity solver, the two orbital Hubbard model is studied for various cases. Comparisons are made between numerical results obtained with our EOM scheme and those obtained with quantum Monte Carlo and numerical renormalization group methods. The comparison shows a good agreement, but also reveals a dissimilarity of the behaviors of the densities of states which is caused by inter-site inter-orbital hopping effects and on-site inter-orbital fluctuation effects, thus corroborating the assertion of the value of the EOM method for the study of multi-orbital strongly correlated systems. PMID- 22248629 TI - Intracranial stenting as monotherapy in subarachnoid hemorrhage and sickle cell disease. AB - INTRODUCTION: Although there have been a few reports of coiling intracranial aneurysms in patients with sickle cell disease (SCD), there are no reports of intracranial stent placement in this patient population. A patient in whom stent placement was utilized as monotherapy to treat a blister-like aneurysm is described and the implications of SCD and endovascular treatment are discussed. CASE REPORT: A 37-year-old man with SCD presented with diffuse subarachnoid hemorrhage. Angiography confirmed a 2 mm irregular aneurysm on the posterior cerebral artery which was treated with an oversized Neuroform 3 stent that was placed across the aneurysm neck by the senior author (KRB). Follow-up CT angiography showed no residual aneurysmal filling. The patient was discharged home in a stable condition, and he continues to do well 4 weeks following the procedure with no recurrence of the aneurysm. DISCUSSION: This report reviews hypercoagulability in SCD and the treatment options for intracranial aneurysms in patients with SCD. Additionally, the reported case suggests that intracranial stent placement may be a viable option for treating complex intracranial aneurysms in SCD patients. PMID- 22248630 TI - Onyx embolization of an extensive mandibular arteriovenous malformation via a dual lumen balloon catheter: a technical case report. AB - SUMMARY: The first known use of Onyx delivered via a dual lumen balloon catheter is reported. A mandibular arteriovenous malformation was successfully embolized with Onyx via an Ascent balloon catheter. CASE PRESENTATION: A teenage girl presented with facial deformity and episodes of oral bleeding. Angiogram showed an extensive left mandibular arteriovenous malformation with ectatic intraosseous venous pouches. A dual lumen Ascent balloon catheter was placed in the inferior alveolar artery. With balloon inflation, Onyx was injected transarterially with excellent penetration into the venous puches. There was closure of over 80% of the lesion with reduction in arteriovenous shunting. CONCLUSION: Onyx embolization via a dual lumen balloon catheter allows for great penetration without the necessity of the long plug creation process for the usual 'plug and push technique' or the use of detachable tip microcatheters. The technique is limited by the deliverability of the balloon catheter, and is safest in the external carotid circulation. PMID- 22248631 TI - A unified strategy for landing and docking using spherical flow divergence. AB - We present a new visual control input from optical flow divergence enabling the design of novel, unified control laws for docking and landing. While divergence based time-to-contact estimation is well understood, the use of divergence in visual control currently assumes knowledge of surface orientation, and/or egomotion. There exists no directly observable visual cue capable of supporting approaches to surfaces of arbitrary orientation under general motion. Central to our measure is the use of the maximum flow field divergence on the view sphere (max-div). We prove kinematic properties governing the location of max-div, and show that max-div provides a temporal measure of proximity. From this, we contribute novel control laws for regulating both approach velocity and angle of approach toward planar surfaces of arbitrary orientation, without structure-from motion recovery. The strategy is tested in simulation, over real image sequences and in closed-loop control of docking/landing maneuvers on a mobile platform. PMID- 22248632 TI - Minimum-distortion isometric shape correspondence using EM algorithm. AB - We present a purely isometric method that establishes 3D correspondence between two (nearly) isometric shapes. Our method evenly samples high-curvature vertices from the given mesh representations, and then seeks an injective mapping from one vertex set to the other that minimizes the isometric distortion. We formulate the problem of shape correspondence as combinatorial optimization over the domain of all possible mappings, which then reduces in a probabilistic setting to a log likelihood maximization problem that we solve via the Expectation-Maximization (EM) algorithm. The EM algorithm is initialized in the spectral domain by transforming the sampled vertices via classical Multidimensional Scaling (MDS). Minimization of the isometric distortion, and hence maximization of the log likelihood function, is then achieved in the original 3D euclidean space, for each iteration of the EM algorithm, in two steps: by first using bipartite perfect matching, and then a greedy optimization algorithm. The optimal mapping obtained at convergence can be one-to-one or many-to-one upon choice. We demonstrate the performance of our method on various isometric (or nearly isometric) pairs of shapes for some of which the ground-truth correspondence is available. PMID- 22248633 TI - Measuring the objectness of image windows. AB - We present a generic objectness measure, quantifying how likely it is for an image window to contain an object of any class. We explicitly train it to distinguish objects with a well-defined boundary in space, such as cows and telephones, from amorphous background elements, such as grass and road. The measure combines in a Bayesian framework several image cues measuring characteristics of objects, such as appearing different from their surroundings and having a closed boundary. These include an innovative cue to measure the closed boundary characteristic. In experiments on the challenging PASCAL VOC 07 dataset, we show this new cue to outperform a state-of-the-art saliency measure, and the combined objectness measure to perform better than any cue alone. We also compare to interest point operators, a HOG detector, and three recent works aiming at automatic object segmentation. Finally, we present two applications of objectness. In the first, we sample a small numberof windows according to their objectness probability and give an algorithm to employ them as location priors for modern class-specific object detectors. As we show experimentally, this greatly reduces the number of windows evaluated by the expensive class-specific model. In the second application, we use objectness as a complementary score in addition to the class-specific model, which leads to fewer false positives. As shown in several recent papers, objectness can act as a valuable focus of attention mechanism in many other applications operating on image windows, including weakly supervised learning of object categories, unsupervised pixelwise segmentation, and object tracking in video. Computing objectness is very efficient and takes only about 4 sec. per image. PMID- 22248634 TI - A model-based sequence similarity with application to handwritten word spotting. AB - This paper proposes a novel similarity measure between vector sequences. We work in the framework of model-based approaches, where each sequence is first mapped to a Hidden Markov Model (HMM) and then a measure of similarity is computed between the HMMs. We propose to model sequences with semicontinuous HMMs (SC HMMs). This is a particular type of HMM whose emission probabilities in each state are mixtures of shared Gaussians. This crucial constraint provides two major benefits. First, the a priori information contained in the common set of Gaussians leads to a more accurate estimate of the HMM parameters. Second, the computation of a similarity between two SC-HMMs can be simplified to a Dynamic Time Warping (DTW) between their mixture weight vectors, which significantly reduces the computational cost. Experiments are carried out on a handwritten word retrieval task in three different datasets-an in-house dataset of real handwritten letters, the George Washington dataset, and the IFN/ENIT dataset of Arabic handwritten words. These experiments show that the proposed similarity outperforms the traditional DTW between the original sequences, and the model based approach which uses ordinary continuous HMMs. We also show that this increase in accuracy can be traded against a significant reduction of the computational cost. PMID- 22248635 TI - Diffuse endocrine system, neuroendocrine tumors and immunity: what's new? AB - During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment. PMID- 22248636 TI - Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor. AB - Neuropeptide S (NPS) is the endogenous ligand of a previously orphan receptor now named NPSR. In the brain NPS regulates several biological functions including anxiety, arousal, locomotion, food intake, learning and memory, pain and drug abuse. Mice lacking the NPSR gene (NPSR(-/-)) represent an useful tool to investigate the neurobiology of the NPS/NPSR system. NPSR(-/-) mice have been generated in a 129S6/SvEv genetic background. In the present study we generated CD-1 congenic NPSR(+/+) and NPSR(-/-) mice and investigated their phenotype and sensitivity to NPS in various behavioural assays. The phenotype analysis revealed no locomotor differences between NPSR(+/+) and NPSR(-/-) mice. The behaviour of NPSR(+/+) and NPSR(-/-) mice in the righting reflex test was superimposable. No differences were recorded between the two genotypes in the elevated plus maze, open field and stress-induced hyperthermia tests, with the exception of rearing behaviour that was reduced in knockout animals. Moreover the behaviour of NPSR(+/+) and NPSR(-/-) mice in the forced swimming, novel object recognition and formalin assays was similar. The stimulatory effects of NPS in the locomotor activity test and its anxiolytic-like actions in the elevated plus maze and open field assays were evident in NPSR(+/+) but not NPSR(-/-) animals. In conclusion, the present study indicates that the NPS/NPSR system does not tonically control locomotion, sensitivity to diazepam, anxiety, depressive-like behaviours, memory and pain transmission in mice. Furthermore our results clearly show that the product of the NPSR gene represents the mandatory protein for all the NPS biological effects so far described. PMID- 22248637 TI - Agmatine protects against scopolamine-induced water maze performance impairment and hippocampal ERK and Akt inactivation. AB - Cholinergic brain activity plays a significant role in memory. Scopolamine a muscarinic cholinergic antagonist is known to induce impairment in Morris water maze performance, the task which is mainly dependent on the hippocampus. It is suggested that hippocampal ERK and Akt activation play roles in synaptic plasticity and some types of learning and memory. Agmatine, a polyamine derived from l-arginine decarboxylation, is recently shown to exert some neuroprotective effects. This study was aimed to investigate if agmatine could reverse scopolamine-induced memory impairment and possible hippocampal ERK and Akt activity alteration. Adult male Sprague-Dawley rats weighing 200-250 g were randomly assigned into 5 groups. The animals were trained for 3 days in Morris water maze and in day 4 their memory retention was assessed in probe trial which was consisted of a 60 s trial with no platform. Scopolamine (1 mg/kg/ip) or saline were injected 30 min and agmatine (20 or 40 mg/kg/ip) was administered 60 min before each session. The hippocampi were isolated after behavioral studies and western blotting studies on hippocampal lysates were done to determine the levels of activated ERK and Akt. Scopolamine treatment not only impaired water maze learning and memory, but also decreased the amount of phosphorylated (activated) ERK and Akt. Agmatine pre-treatment prevented both the learning impairment and hippocampal ERK and Akt inactivation induced by scopolamine. It seems that agmatine may act as a candidate substance against amnesia. PMID- 22248638 TI - Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration. AB - Memantine, a non-competitive NMDA receptor antagonist, is used for the treatment of Alzheimer's disease (AD) and off-label as an anti-depressant. Here we investigated possible anti-depressant, cognitive enhancing and neuroprotective effects of memantine in the olfactory bulbectomized (OBX) rat. OBX is used as a screening model for antidepressants and shows cognitive disturbances. In Experiment I, memantine treatment started 14 days after OBX surgery (this setup is similar to what we use for screening of potential antidepressants) and 2 days before surgery in experiment II. In both experiments, memantine (20 mg/kg, p.o) was administered once daily for 28 days. Animals were tested in the open field (locomotor activity), passive avoidance (fear learning and memory), and holeboard (spatial acquisition and memory) before and after the bulbectomy. Memantine, when administered before surgery, prevented OBX-induced hyperactivity and partly fear memory loss. These behavioral effects were present for at least 3 weeks after cessation of treatment. Memantine, however did not improve spatial memory. When administered 2 weeks after OBX surgery, memantine was ineffective in normalizing open field hyperactivity and improving cognitive deficits. Interestingly, after the animals were retrained in passive avoidance, memantine- treated OBX rats (both in experiment I and II) showed improved fear learning and memory. Our findings suggest that memantine has both neuroprotective and cognitive enhancing effects without antidepressant-like properties in the OBX rat. Based on our results, we propose that memantine may be more beneficial to AD patients when administered early in the disease process. PMID- 22248640 TI - The effect of hydrogen nanobubbles on the morphology of gold-gelatin bionanocomposite films and their optical properties. AB - Gold-gelatin bionanocomposite films are prepared by the reduction of gold ions by sodium borohydride in an aqueous solution. It is shown that both the solution and the films on glass substrates contain entrapped hydrogen micro- and nanobubbles with diameters in the range of 200 nm-3 MUm. The optical properties of gold nanoparticles in the presence of gelatin and hydrogen nanobubbles are measured and simulated by using the discrete dipole approximation method. The composite films having micro- and nanobubble inclusions have been found to be very stable. The calculated localized surface plasmon resonance band is found in agreement with the experimental band position only when the presence of hydrogen bubbles around the gold nanoparticles is taken into account. The different morphological features engendered by the presence of the bubbles in the film (gelatin receptacles for the nanoparticles, gelatin hemispheres raised by the bubbles under the surface, cavities on the surface of the film, etc) are described in detail and considered for potential applications. This work is highly relevant to the new and exciting topic of nanobubbles on surfaces and interfaces. PMID- 22248641 TI - Coronavirus infection of rat dorsal root ganglia: ultrastructural characterization of viral replication, transfer, and the early response of satellite cells. AB - Swine hemagglutinating encephalomyelitis virus (HEV) has been shown to have a capability to gain access to the cell bodies of sensory neurons after peripheral inoculation, resulting in ganglionic infection. It is not clearly understood how this virus is replicated within and released from the sensory neurons, and it remains to know how satellite cells response to the HEV invasion. By ultrastructurally examining HEV-infected rat dorsal root ganglia, we found that HEV in the cell bodies of infected neurons budded from endoplasmic reticulum Golgi intermediate compartments, and were assembled either individually within small vesicles or in groups within large vesicles. The progeny virions were released from the sensory neurons mainly by smooth-surfaced vesicle-mediated secretory pathway, which occurred predominantly at the perikaryal projections and infoldings of sensory neurons. Released HEV particles were subsequently taken up by the adjacent satellite cells. Almost all virus particles in the cytoplasm of satellite cells were contained in groups within vesicles and lysosome-like structures, suggesting that these glial cells may restrict the local diffusion of HEV. These observations give some insights into the pathogenesis of coronavirus infection and are thought to help understand the interactions between sensory neurons and their satellite cells. PMID- 22248639 TI - Endocannabinoid analogues exacerbate marble-burying behavior in mice via TRPV1 receptor. AB - Activation of cannabinoid CB(1) receptor is shown to inhibit marble-burying behavior (MBB), a behavioral model for assessing obsessive-compulsive disorder (OCD). Anandamide, an endogenous agonist at CB(1) receptor also activates the transient receptor potential vanilloid type 1 (TRPV1) channels but at a higher concentration. Furthermore, anandamide-mediated TRPV1 effects are opposite to that of the CB(1) receptor. Therefore, the present study was carried out to investigate the influence of low and high doses of anandamide on MBB in CB(1) and TRPV1 antagonist pre-treated mice. The results revealed that i.c.v. administration of lower doses of anandamide (1-10 MUg/mouse) or its analogues (AM404 or URB597; 1-5 MUg/mouse) inhibited MBB indicating the anticompulsive activity. Conversely, at higher doses (40 or 20 MUg/mouse) these compounds increased MBB similar to capsaicin (TRPV1 agonist, 100 MUg/mouse) exhibiting a pro-compulsive effect. Pretreatment with AM251 (CB(1) antagonist, 1 MUg/mouse) antagonized the anticompulsive effect of these compounds, while their pro compulsive effect at higher doses was attenuated by inactive dose of capsazepine (TRPV1 antagonist, 10 MUg/mouse). However, capsazepine per se at a higher dose (100 MUg/mouse) inhibited MBB. When given daily for 14 days, the anticompulsive effect of anandamide and its analogues gradually disappeared, whereas capsazepine either alone or with URB597 produced consistent inhibition of MBB comparable to fluoxetine. Thus, the study indicates the biphasic influence of anandamide on MBB, and chronic administration of capsazepine either alone or with URB597 might be an effective tool in the treatment of OCD. PMID- 22248642 TI - Sequence and phylogenetic analyses of nonstructural protein 2 genes of species B porcine rotaviruses detected in Japan during 2001-2009. AB - Porcine rotavirus B (RVB) has been often detected in diarrhea of suckling and weaned pigs. Because it is difficult to serially cultivate RVBs in cell culture, the number of available sequence data for RNA segments other than VP7 and NSP1 in especially porcine RVBs is still limited. We performed genetic analysis focusing on nonstructural protein 2 (NSP2) using several porcine RVB strains, which were detected in diarrheic feces collected around Japan during 2001-2009. Comparison of NSP2 nucleotide and deduced amino acid sequences from porcine RVB strains exhibited low identities (64.0-99.9% in nt and 66.7-100.0% in aa) to those of other RVB strains. Phylogenetic analysis of RVB NSP2 revealed the presence of four clusters (N1-N4) including human plus murine, bovine and porcine clusters with cut-off values of 75% at the nt and 85% at the aa level. Furthermore, the NSP2 genes of porcine RVBs were divided into three genotypes, of which some porcine RVBs belonged into bovine-cluster. PB-70-H5 and PB-70-H3, which belonged to same pig farm, might be identical in NSP2 gene as shown sequence identity of 99.9%, nevertheless both had different VP7 genes each other. Thus, this data demonstrates the occurrence of gene reassortment among porcine RVBs derived from same pig farm. Our findings presented here would provide more valuable information to elucidate evolution of RVBs. PMID- 22248643 TI - Serial passage of a street rabies virus in mouse neuroblastoma cells resulted in attenuation: potential role of the additional N-glycosylation of a viral glycoprotein in the reduced pathogenicity of street rabies virus. AB - Street rabies viruses are field isolates known to be highly neurotropic. However, the viral elements related to their pathogenicity have yet to be identified at the nucleotide or amino acid level. Here, through 30 passages in mouse neuroblastoma NA cells, we have established an attenuated variant of street rabies virus strain 1088, originating from a rabid woodchuck followed by 2 passages in the brains of suckling mice. The variant, 1088-N30, was well adapted to NA cells and highly attenuated in adult mice after intramuscular (i.m.) but not intracerebral (i.c.) inoculations. 1088-N30 had seven nucleotide substitutions, and the R196S mutation of the G protein led to an additional N glycosylation. Street viruses usually possess one or two N-glycosylation sites on the G protein, 1088 has two, while an additional N-glycosylation site is observed in laboratory-adapted strains. We also established a cloned variant 1088-N4#14 by limiting dilution. Apart from the R196S mutation, 1088-N4#14 possessed only one amino acid substitution in the P protein, which is found in several field isolates. 1088-N4#14 also efficiently replicated in NA cells and was attenuated in adult mice after i.m. inoculations, although it was more pathogenic than 1088 N30. The spread of 1088-N30 in the brain was highly restricted after i.m. inoculations, although the pattern of 1088-N4#14's spread was intermediate between that of the parental 1088 and 1088-N30. Meanwhile, both variants strongly induced humoral immune responses in mice compared to 1088. Our results indicate that the additional N-glycosylation is likely related to the reduced pathogenicity. Taken together, we propose that the number of N-glycosylation sites in the G protein is one of the determinants of the pathogenicity of street rabies viruses. PMID- 22248644 TI - DNP in MRI: an in-bore approach at 1.5 T. AB - We have used liquid state ("Overhauser") Dynamic Nuclear Polarization (DNP) to significantly enhance the signal to noise ratio (SNR) of Magnetic Resonance Imaging (MRI). For the first time this was achieved by hyperpolarizing directly in the MRI-scanner field of 1.5 T in continuous flow mode and immediately delivering the hyperpolarized substance to the imaging site to ensure maximum contrast between hyperpolarized sample and sample at thermal polarization. We achieve a maximum absolute signal enhancement factor of 98; while the hyperpolarized sample is transported at a flow rate of up to 30 ml/h yielding an average flow speed up to 470 mm/s over a distance of approximately 80 mm. A spatial imaging resolution of 100 MUm with a signal to noise ratio of 25 was achieved on the flowing sample. Application to MRI contrast enhancement or microfluidic imaging can be envisaged immediately. PMID- 22248646 TI - Trace metal pollution and its influence on the community structure of soft bottom molluscs in intertidal areas of the Dar es Salaam coast, Tanzania. AB - The influence of trace metal pollution on the community structure of soft bottom molluscs was investigated in intertidal areas of the Dar es Salaam coast. Significant enrichment of As, Mn, Mo, Sb, and Zn in sediments was recorded. Redundancy analysis indicated that trace metal pollution contributed 68% of the variation in community structure. Monte Carlo permutation test showed that As and Sb contributed significantly to variation in species composition. T-value biplots and van Dobben circles showed that the gastropods Acteon fortis, Assiminea ovata, and Littoraria aberrans, were negatively affected by As and Sb, while the bivalve Semele radiata and the gastropod Conus litteratus were only negatively affected by As. Bioaccumulation of As, Cd, Cu, Mo and Zn occurred in the bivalve Mactra ovalina and the gastropod Polinices mammilla. This calls for regular monitoring and management measures. PMID- 22248645 TI - Microvesicles: potential markers and mediators of endothelial dysfunction. AB - PURPOSE OF REVIEW: Microvesicles (also known as microparticles) are small membranous structures that are released from platelets and cells upon activation or during apoptosis. Microvesicles have been found in blood, urine, synovial fluid, extracellular spaces of solid organs, atherosclerotic plaques, tumors, and elsewhere. Here, we focus on new clinical and basic work that implicates microvesicles as markers and mediators of endothelial dysfunction and hence novel contributors to cardiovascular and other diseases. RECENT FINDINGS: Advances in the detection of microvesicles and the use of cell type-specific markers to determine their origin have allowed studies that associated plasma concentrations of specific microvesicles with major types of endothelial dysfunction - namely, inappropriate or maladaptive vascular tone, leukocyte recruitment, and thrombosis. Recent investigations have highlighted microvesicular transport of key biologically active molecules besides tissue factor, such as ligands for pattern-recognition receptors, elements of the inflammasome, and morphogens. Microvesicles generated from human cells under different pathologic circumstances, for example, during cholesterol loading or exposure to endotoxin, carry different subsets of these molecules and thereby alter endothelial function through several distinct, well characterized molecular pathways. SUMMARY: Clinical and basic studies indicate that microvesicles may be novel markers and mediators of endothelial dysfunction. This work has advanced our understanding of the development of cardiovascular and other diseases. Opportunities and obstacles to clinical applications are discussed. PMID- 22248647 TI - Multi-scale distribution and dynamics of bivalve larvae in a deep atoll lagoon (Ahe, French Polynesia). AB - Bivalve larvae and hydrographic parameters were sampled over a range of spatio temporal scales in a deep atoll lagoon. Bivalve larvae abundances were very high throughout the year: 18,550 m(-3) in average. Larvae were (i) concentrated at mid depth with nocturnal ascent and diurnal descent, (ii) heterogeneously dispersed at the lagoon scale, (iii) subject to day-to-day variation in abundance and (iv) transferred between different parts of the lagoon providing evidence of intra lagoonal connectivity. The primacy of physical factors was seen on large spatial scale with the diluting effect of water renewal and transfers by hydrodynamics. On smaller spatial scale, the primacy of biological processes was recognised, with larval swimming activity leading to dial vertical migration correlated with food concentration. Variations in larval abundance were driven by bivalve reproductive activity correlated with meteorological conditions (i.e. windy periods). Finally, relationship between bivalve larvae patterns and pearl oyster (Pinctada margaritifera) settlement structuring is discussed. PMID- 22248648 TI - The use of surface-enhanced Raman scattering (SERS) for detection of PAHs in the Gulf of Gdansk (Baltic Sea). AB - A field operable surface enhanced Raman scattering (SERS) sensor system was applied for the first time under real conditions for the detection of polycyclic aromatic hydrocarbons (PAHs) as markers for petroleum hydrocarbons in the Gulf of Gdansk (Baltic Sea). At six stations, seawater samples were taken, and the sensor system was applied in situ simultaneously. These measurements were compared to the results of conventional GC/MS laboratory analysis of the PAH concentrations in the seawater samples. For a PAH concentration above 150 ng(12PAH)l(-1), there was agreement between the SERS sensor and the GC/MS determinations. A standard addition experiment yielded a PAH concentration of 900 ng l(-1) at the Gdansk Harbor, which was of the same order as the GC/MS determinations of 12PAHs (200 ng(12PAH)l(-1)). The high SERS detection limit for seawater samples is explained by the competition for PAHs between the sensor membrane and particulate matter surfaces. Thus, the SERS sensor can be applied, e.g., as a non-quantitative alarm sensor for relatively high PAH concentrations in heavily polluted waters. The spectral unmixing procedure applied for Gdansk Harbor water confirmed the presence of phenanthrene at the highest concentration ([Phe]=140 ngl(-1)) and of Chr (2.7 ng l(-1)), but it did not detect the other PAHs present in the Gdansk Harbor water, as determined by GC/MS. When compared to the past literature and databases, the SERS spectra indicated the presence of a mixture of molecules consisting of carotenoids, n-alkanes, amines or fatty acids, and benzimidazoles at the coastal station ZN2. The spectra in the offshore direction indicated carboxylic acids. Interpretation of the farthest offshore in situ SERS measurements is difficult, principally due to the limited availability of reference spectra. The detection of the lower PAH concentrations commonly found in Baltic coastal water needs further research and development to obtain better sensitivity of the SERS sensor. However, the high analytical specificity of the SERS sensor also allows the detection of other chemical species that require the development of a SERS/Raman library for specific in situ spectral interpretation. PMID- 22248649 TI - Evaluation of the presence of major anionic surfactants in marine sediments. AB - The contamination of aquatic environments has become the focus of increasing regulation and public concern due to their potential and unknown negative effects on the ecosystems. The present work develops a monitoring and statistical study, based on the analysis of variance test (ANOVA) and the multivariable analysis, both for insoluble soap and LAS in order to compare the behavior of different anionic surfactants in this environmental compartment. First, a novel and successfully validated methodology to analyze insoluble soap in these samples is developed. The matrix effect and the comparison of different extraction techniques were also performed. The optimized analytical methodologies were applied to 48 representative samples collected from the Almeria Coast (Spain) and then a statistical analysis to correlate anionic surfactant concentration and several variables associated with marine sediment samples was also developed. The results obtained showed relevant conclusions related to the environmental behavior of anionic surfactants in marine sediments. PMID- 22248650 TI - [Retinal nerve fiber layer thickness alterations in patients with obstructive sleep apnea]. PMID- 22248651 TI - [Low-fluence photodynamic therapy in chronic central serous chorioretinopathy]. AB - OBJECTIVE: To evaluate safety and efficacy of low-fluence photodynamic therapy (LFPDT) with verteporfin in patients affected with chronic central serous chorioretinopathy (CCSC), in terms of visual acuity (VA) and macular morphology measured with optical coherence tomography (OCT). METHODS: A retrospective, non randomized and interventionist analysis was performed on 16 eyes in 15 patients with CCSC treated with LFPDT. Best corrected visual acuity (BCVA) with ETDRS optotypes and central foveal thickness (CFT) in OCT were evaluated as outcome measures. RESULTS: The mean follow-up was 10.8 months. The mean BCVA improved from 58.12 to 68.68 ETDRS letters, and CFT decreased from 280.5 to 172.18 microns, with subretinal fluid resolution in 14 eyes (87.5%), two of them after a second LFTPD. No complications related to treatment were recorded. CONCLUSIONS: LFPDT with verteporfin can be useful in CCSC to stabilise or improve BCVA, reabsorb subretinal fluid and reduce CFT. Randomised studies with a longer follow up are required to assure the role of this treatment and to optimise parameters for higher efficacy and safety in CCSC patients. PMID- 22248652 TI - [Phacoemulsification and acrylic intraocular lens in uveitis: a comparative study]. AB - OBJECTIVE: To describe the outcomes of phacoemulsification with the implant of an acrylic intraocular lens (IOL) in cataracts of adult patients with and without uveitis METHODS: Descriptive retrospective comparative study of 35 patients (45 eyes) with uveitis (group 1) and 38 (44 eyes) control patients (group 2), who were operated on by the same surgeon, and were homogeneous as regards sex, surgical technique, IOL (hydrophobic or hydrophilic) and follow-up. The pre surgical characteristics of risk, the difficulties and intra-surgical and postsurgical complications, the date of posterior capsulotomy (PC) and the pre- and post-surgical visual acuity (VA), were analysed. RESULTS: In both groups the coaxial phacoemulsification was used in 75% of the eyes, bimanual microincision cataract surgery (MICS) in 20% and micro-coaxial in the rest. The pre-surgical risk factors (P = .002, OR 6.83), the surgical difficulties and complications (P = .001, OR 7.54) and postsurgical complications (P = .069, OR 3.42) were more frequent in the uveitis group. In both 93% and 91% respectively of eyes improved 2 or more lines of VA. After an average follow-up of 4.9 years in both groups, 22.7% and 32% eyes (log-rank P = .357) needed PC. The hydrophilic IOLs needed PC earlier than the hydrophobic ones (log rank P = .001), neither the location nor the uveitis course influenced the PC rate. CONCLUSIONS: The consequences because of previous ocular inflammation make cataract surgery in uveitis more difficult, but with postsurgical complications, visual results and need of PC similar to our patients without inflammation. PMID- 22248653 TI - [Unsuccessful treatment with OK-432 picibanil for orbital lymphangioma]. AB - INTRODUCTION: Lymphangioma is a malformation of the lymphatic system. The classic approach is surgery. We report a case of orbital lymphangioma in a girl who was given OK-432 to avoid surgery and its complications. DISCUSSION: OK-432 is a lyophilized mixture of group A Streptococcus pyogenes which produces a fibrosis limited to the lesion with a high cure rate. The main advantages are the easy intra-lesional application. with no scars and or damage of closed areas. Its main disadvantage is a significant local inflammatory reaction. PMID- 22248654 TI - [Vitreous cyst: a case presentation]. AB - CASE REPORT: We report a case of a 12-year-old patient who complained about visual disturbances in left eye for 6 months. His visual acuity was 1/0.9, funduscopy in left eye revealed a free-floating cyst in the anterior vitreous. Magnetic resonance showed a low intense image in T1, and B-scan ultrasound confirmed a hypoechogenic cyst of 3.2 * 4.3 mm; ultrasound biomicroscopy revealed a normal ciliary body. CONCLUSION: Given the good VA the patient will be monitored periodically. If the cyst interferes with visual axis, management with Nd:YAG or Argon laser photocystotomy or remove it by pars plana vitrectomy has been advocated. PMID- 22248655 TI - [Analysis of prognostic factors by spectral-domain optical coherence tomography in pseudophakic cystoid macular oedema]. PMID- 22248656 TI - [Eye pathology in the paintings of Georges de La Tour (II). Telecanthus: the fortune teller]. PMID- 22248657 TI - [Francisco de Salinas. Musician and blind erudite of the Spanish renaissance]. PMID- 22248658 TI - Electrically driven gallium movement in carbon nanotubes. AB - Electrically driven gallium movement in carbon nanotubes is discussed. A higher current (~15 mA) makes the gallium migrate sharply toward the anode, which increases its mass transport speed with time in the range of 0 to more than 10.345 fg s(-1). In contrast, a lower current (~2 mA) only drives gallium to contact the anode, which decreases the resistance of the nanocomposite sharply, from 2.564 kOmega to 0.4 Omega. These results are valuable for designing electrically driven nanomass delivery and nanoswitches, respectively. PMID- 22248659 TI - Effect of IL28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Although interleukin 28B (interferon, lambda 3) (IL28B) genotype affects the response of patients with chronic hepatitis C to peginterferon and ribavirin, little is known regarding its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and the hepatitis C virus (HCV) protease inhibitor danoprevir. METHODS: We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hours, or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a biphasic model to describe first- and second-phase slopes of viral decay during therapy. RESULTS: At day 14 (the end of interferon free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log(10) IU/mL) than those without (4.59 log(10) IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the beta-phase of viral decay. A mixed effect on the alpha-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up. CONCLUSIONS: IL28B genotype appears to affect early VKs in patients with chronic hepatitis C receiving interferon-free treatment. PMID- 22248660 TI - Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice. AB - BACKGROUND & AIMS: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied, and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression, and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. METHODS: Hypergastrinemic mice infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements, and immunohistochemistry with anti-5-methylcytosine. We also profiled gene expression in the same tissues. RESULTS: We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and immunohistochemistry for lymphocyte markers. CONCLUSIONS: We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation. PMID- 22248662 TI - Response of the upper esophageal sphincter to esophageal distension is affected by posture, velocity, volume, and composition of the infusate. AB - BACKGROUND & AIMS: Studies of the pressure response of the upper esophageal sphincter (UES) to simulated or spontaneous gastroesophageal reflux have shown conflicting results. These discrepancies could result from uncontrolled influence of variables such as posture, volume, and velocity of distension. We characterized in humans the effects of these variables on UES pressure response to esophageal distension. METHODS: We studied 12 healthy volunteers (average, 27 +/- 5 years old; 6 male) using concurrent esophageal infusion and high-resolution manometry to determine UES, lower esophageal sphincter, and intraesophageal pressure values. Reflux events were simulated by distal esophageal injections of room temperature air and water (5, 10, 20, and 50 mL) in individuals in 3 positions (upright, supine, and semisupine). Frequencies of various UES responses were compared using chi(2) analysis. Multinomial logistical regression analysis was used to identify factors that determine the UES response. RESULTS: UES contraction and relaxation were the overriding responses to esophageal water and air distension, respectively, in a volume-dependent fashion (P < .001). Water induced UES contraction and air-induced UES relaxation were the predominant responses among individuals in supine and upright positions, respectively (P < .001). The prevalence of their respective predominant response significantly decreased in the opposite position. Proximal esophageal dp/dt significantly and independently differentiated the UES response to infusion with water or air. CONCLUSIONS: The UES response to esophageal distension is affected by combined effects of posture (spatial orientation of the esophagus), physical properties, and volume of refluxate, as well as the magnitude and rate of increase in intraesophageal pressure. The UES response to esophageal distension can be predicted using a model that incorporates these factors. PMID- 22248661 TI - Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. AB - BACKGROUND & AIMS: Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. METHODS: Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n = 77) or only SMT (SMT group, n = 68). The Prometheus liver support system was used to provide 8 to 11 rounds of FPSA (minimum of 4 hours each) for 3 weeks. Primary end points were survival probabilities at days 28 and 90, irrespective of liver transplantation. RESULTS: Baseline clinical parameters and number of transplant patients were similar between study arms. Serum bilirubin level decreased significantly in the FPSA group but not in the SMT group. In an intention-to treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMT group (P = .70); on day 90, they were 47% and 38%, respectively (P = .35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the 2 groups in the incidence of side effects. CONCLUSIONS: Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients. PMID- 22248663 TI - HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. AB - BACKGROUND & AIMS: Polymorphisms in the IL28B gene have been associated with clearance of hepatitis C virus (HCV), indicating a role for type III interferons (IFNs) in HCV infection. Little is known about the function of type III IFNs in intrinsic antiviral innate immunity. METHODS: We used in vivo and in vitro models to characterize the role of the type III IFNs in HCV infection and analyzed gene expression in liver biopsy samples from HCV-infected chimpanzees and patients. Messenger RNA and protein expression were studied in HCV-infected hepatoma cell lines and primary human hepatocytes. RESULTS: HCV infection of primary human hepatocytes induced production of chemokines and type III IFNs, including interleukin (IL)-28, and led to expression of IFN-stimulated genes (ISGs). Chimpanzees infected with HCV showed rapid induction of hepatic type III IFN, associated with up-regulation of ISGs and minimal induction of type I IFNs. In liver biopsy specimens from HCV-infected patients, hepatic expression of IL-28 correlated with levels of ISGs but not of type I IFNs. HCV infection produced extensive changes with gene expression in addition to ISGs in primary human hepatocytes. The induction of type III IFNs is regulated by IFN regulatory factor 3 and nuclear factor kappaB. Type III IFNs up-regulate ISGs with a different kinetic profile than type 1 IFNs and induce a distinct set of genes, which might account for their functional differences. CONCLUSIONS: HCV infection results predominantly in induction of type III IFNs in livers of humans and chimpanzees; the level of induction correlates with hepatic levels of ISGs. These findings might account for the association among IL-28, level of ISGs, and recovery from HCV infection and provide a therapeutic strategy for patients who do not respond to IFN therapy. PMID- 22248665 TI - Impact of conventional breath inspiratory time during high-frequency jet ventilation in preterm lambs. AB - BACKGROUND: Conventional mechanical ventilator (CMV) breaths during high frequency jet ventilation (HFJV) are advocated to recruit and stabilize alveoli. OBJECTIVES: To establish if CMV breath duration delivered during HFJV influences gas exchange, lung mechanics and lung injury. METHODS: Preterm lambs at 128 days gestational age were studied. HFJV (7 Hz, PEEP 8 cm H(2)O, PIP(HFJV) 40 cm H(2)O, FiO(2) 0.4) with superimposed CMV breaths (PIP(CMV) 25 cm H(2)O, rate 5 breaths/min) was commenced after delivery and continued for 2 h. CMV breath inspiratory time (t(I)) was either 0.5 s (HFJV+CMV(0.5); n = 8) or 2.0 s (HFJV+CMV(2.0); n = 8). Age-matched unventilated controls (UVC) were included for comparison. RESULTS: Serial arterial blood gas analyses were performed. PIP(HFJV) was adjusted to target a PaCO(2) of 45-55 mm Hg. FiO(2) was adjusted to target SpO(2) 90-95%. Pressure-volume curves, broncho-alveolar lavage (BAL) and lung tissue samples were obtained postmortem. Gas exchange, ventilation parameters, static lung compliance and BAL inflammatory markers were not different between HFJV+CMV(0.5) and HFJV+CMV(2.0). Both ventilation groups had higher BAL inflammatory markers and increased iNOS-positive cells on histology compared to UVC, whilst lung tissue IL-1beta and IL-6 mRNA expression was higher in the HFJV+CMV(2.0) group compared to the UVC group. CONCLUSIONS: Preterm lambs were ventilated effectively with HFJV and 5 CMV breaths/min. CMV breath duration did not alter blood gas exchange, ventilation parameters, ex vivo static lung mechanics or markers of lung injury over a 2-hour study, although consistent trends towards increased inflammatory markers with the longer t(I) suggest greater risk of injury. PMID- 22248664 TI - CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice. AB - BACKGROUND & AIMS: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein- and L-arginine-induced acute pancreatitis in mice. METHODS: Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages. RESULTS: Almost all types of immune cells, except for CD11b(high)CD11c(-) cells, were detected in the pancreas of healthy mice. However, activated CD11b(high)CD11c(-) cells, including Gr-1(low) macrophages and Gr-1(high) cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2(-/-) mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b(high)CD11c(-)Gr-1(low) macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b(high)CD11c(-)Gr-1(low) macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1(low) macrophage produced less tumor necrosis factor-alpha than wild-type mice given cerulein, although the absolute number of CD11b(high)CD11c(-)Gr-1(low) macrophages was comparable between strains. Induction of acute pancreatitis by L arginine required induction of macrophage migration by CCL2, via the receptor CCR2. CONCLUSIONS: Cerulein induction of pancreatitis in mice involves migration of CD11b(high)CD11c(-)Gr-1(low) macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3-dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis. PMID- 22248666 TI - HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin. AB - In this work, we designed and developed a two-stage delivery system composed of enteric capsule and cationic nanoparticles for oral delivery of insulin. The enteric capsule was coated with pH-sensitive hydroxypropyl methylcellulose phthalate (HP55), which could selectively release insulin from nanoparticles in the intestinal tract, instead of stomach. The biodegradable poly(lactic-co glycolic acid) (PLGA) was selected as the matrix for loading insulin. Eurdragit((r)) RS (RS) was also introduced to the nanoparticles for enhancing the penetration of insulin across the mucosal surface in the intestine. The nanoparticles were prepared with the multiple emulsions solvent evaporation method via ultrasonic emulsification. The optimized nanoparticles have a mean size of 285nm, a positive zeta potential of 42mV. The encapsulation efficiency was up to 73.9%. In vitro results revealed that the initial burst release of insulin from nanoparticles was markedly reduced at pH 1.2, which mimics the stomach environment. In vivo effects of the capsule containing insulin PLGA/RS nanoparticles were also investigated in diabetic rat models. The oral delivered capsules induced a prolonged reduction in blood glucose levels. The pharmacological availability was found to be approximately 9.2%. All the results indicated that the integration of HP55-coated capsule with cationic nanoparticles may be a promising platform for oral delivery of insulin with high bioavailability. PMID- 22248667 TI - Thermosensitive eyedrops containing platelet lysate for the treatment of corneal ulcers. AB - Corneal lesions cause significant pain and visual impairment and, in many cases, are unresponsive to conventional treatments. Platelet lysate (PL) is an haemoderivative rich in growth factors (GFs) that are released by platelets after freeze-thawing destruction of platelet rich plasma (PRP). The aim of the present work was to develop thermosensitive and mucoadhesive eyedrops to maintain and prolong the contact of platelet lysate (PL) with cornea ulcers. A sterile vehicle based on chondroitin sulphate sodium (CS) and hydroxypropylmethyl cellulose (HPMC) was developed. An extemporaneous loading of the vehicle with PL was performed and the obtained formulation was able to quickly thermogelify at about 32 degrees C and was characterized by good mucoadhesive properties. ELISA evidenced that the growth factor PDGF AB was compatible with the vehicle and stable in the formulation up to 15 days of storage at 2-8 degrees C. In vitro wound healing and proliferation test (performed using rabbit corneal epithelial cells (RCE)) showed that the formulation enhanced cell growth and put in evidence a synergistic effect of CS and PL in stimulating cell proliferation. The overall results indicate that PL loaded in thermosensitive and mucoadhesive eyedrops can be profitably employed to treat corneal lesions. PMID- 22248669 TI - Low pH induced structural reorganization in thylakoid membranes. AB - By using low temperature fluorescence spectroscopy, it has been shown that exposing chloroplast thylakoid membranes to acidic pH reversibly decreases the fluorescence of photosystem II while the fluorescence of photosystem I increases [P. Singh-Rawal et al. (2010) Evidence that pH can drive state transitions in isolated thylakoid membranes from spinach, Photochem Photobiol Sci, 9 830-837]. In order to shed light on the origin of these changes, we performed circular dichroism (CD) spectroscopy on freshly isolated pea thylakoid membranes. We show that the magnitude of the psi-type CD, which is associated with the presence of chirally ordered macroarrays of the chromophores in intact thylakoid membranes, decreases gradually and reversibly upon gradually lowering the pH of the medium from 7.5 to 4.5 (psi, polymer or salt induced). The same treatment, as shown on thylakoid membranes washed in hypotonic low salt medium possessing no psi-type bands, induces no discernible change in the excitonic CD. These data show that while no change in the pigment-pigment interactions and thus in the molecular organization of the bulk protein complexes can be held responsible for the observed changes in the fluorescence, acidification of the medium significantly alters the macro-organization of the complexes, hence providing an explanation for the pH-induced redistribution of the excitation energy between the two photosystems. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22248668 TI - Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. AB - p53 is well known as the "guardian of the genome" for differentiated and neoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for pro-oncogenic cells, p53 also plays an important role as the central regulator of stress response by maintaining cellular homeostasis at the molecular and biochemical level. p53 regulates aerobic respiration at the glycolytic and oxidative phosphorylation (OXPHOS) steps via transcriptional regulation of its downstream genes TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2). p53 negatively regulates glycolysis through activation of TIGAR (an inhibitor of the fructose 2,6-bisphosphate). On the contrary p53 positively regulates OXPHOS through upregulation of SCO2, a member of the COX-2 assembly involved in the electron transport chain. It is interesting to notice that p53 antagonistically regulates the inter-dependent glycolytic and OXPHOS cycles. It is important to understand whether the p53-mediated transcriptional regulation of TIGAR and SCO2 is temporally segregated in cancer cells and what is the relation between these paradoxical regulations of glycolytic pathway with the tumor suppressor activity of p53. In this review we will elucidate the importance of p53-mediated regulation of glycolysis and OXPHOS and its relation with the tumor suppressor function of p53. Further since cellular metabolism shares great relation with the process of aging we will also try and establish the role of p53 in regulation of aging via its transcriptional control of cellular metabolism. PMID- 22248671 TI - Techniques of extracorporeal cytokine removal: a systematic review of the literature. AB - BACKGROUND AND AIMS: Attempts at achieving cytokine homeostasis include blood purification to deliver cytokine removal. Assessment of ex vivo studies for optimal operating conditions is a vital step. METHODS: We conducted a systematic search for ex vivo studies on cytokine removal using known modalities of extracorporeal circulation. We selected 29 articles and analyzed data according to clearance, sieving coefficient, ultrafiltrate concentration and percentage removal. RESULTS: We identified four main techniques for cytokine removal: standard techniques, high cut-off (HCO) techniques, adsorption techniques and combined plasma filtration adsorption. HCO hemofiltration (HCO/HF) showed greatest consistency in cytokine removal among all approaches. Mean albumin clearance with HCO filters was 3.74 ml/min. CONCLUSION: Ex vivo data support the view that HCO/HF is the most consistently effective approach in terms of sieving and clearance. Further investigation of HCO/HF in randomized controlled trials in animal models and humans seems desirable. PMID- 22248672 TI - The hormonal response of older men to sub-maximum aerobic exercise: the effect of training and detraining. AB - The hormonal response of 32 older men (70-80years) to a bout of sub-maximum aerobic exercise was examined before, after 16weeks of resistance or aerobic training and again after 4weeks of detraining. Blood samples were obtained at rest and immediately post sub-maximum exercise (30min @ 70% VO(2) max) to determine the concentrations of growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone (Test), sex hormone-binding globulin (SHBG) and the calculation of free testosterone (FT). Both training groups had significant increases in leg strength and VO(2) max after 16weeks training but leg strength and VO(2) max returned to pre-training levels in the aerobic training and resistance training groups, respectively. During the 20week study there was no change in resting concentrations of any hormones among the three groups. There was no increase in GH, IGF-1 or SHBG immediately post sub-maximum exercise in any of the groups before training, after 16weeks training or after 4weeks detraining. Testosterone and FT increased immediately post sub-maximum exercise within all groups before training, after 16weeks training and after 4weeks detraining with the increase in Test and FT higher after 16weeks of resistance training compared to before training and after 4weeks detraining within the resistance training group. The increased responsiveness of Test and FT after 16weeks of resistance training was lost after 4weeks of detraining. Our results indicate that some physiological and hormonal adaptations gained after 16weeks training are lost after only 4weeks detraining. PMID- 22248670 TI - The roles of Rhodobacter sphaeroides copper chaperones PCu(A)C and Sco (PrrC) in the assembly of the copper centers of the aa(3)-type and the cbb(3)-type cytochrome c oxidases. AB - The alpha proteobacter Rhodobacter sphaeroides accumulates two cytochrome c oxidases (CcO) in its cytoplasmic membrane during aerobic growth: a mitochondrial like aa(3)-type CcO containing a di-copper Cu(A) center and mono-copper Cu(B), plus a cbb(3)-type CcO that contains Cu(B) but lacks Cu(A). Three copper chaperones are located in the periplasm of R. sphaeroides, PCu(A)C, PrrC (Sco) and Cox11. Cox11 is required to assemble Cu(B) of the aa(3)-type but not the cbb(3)-type CcO. PrrC is homologous to mitochondrial Sco1; Sco proteins are implicated in Cu(A) assembly in mitochondria and bacteria, and with Cu(B) assembly of the cbb(3)-type CcO. PCu(A)C is present in many bacteria, but not mitochondria. PCu(A)C of Thermus thermophilus metallates a Cu(A) center in vitro, but its in vivo function has not been explored. Here, the extent of copper center assembly in the aa(3)- and cbb(3)-type CcOs of R. sphaeroides has been examined in strains lacking PCu(A)C, PrrC, or both. The absence of either chaperone strongly lowers the accumulation of both CcOs in the cells grown in low concentrations of Cu(2+). The absence of PrrC has a greater effect than the absence of PCu(A)C and PCu(A)C appears to function upstream of PrrC. Analysis of purified aa(3)-type CcO shows that PrrC has a greater effect on the assembly of its Cu(A) than does PCu(A)C, and both chaperones have a lesser but significant effect on the assembly of its Cu(B) even though Cox11 is present. Scenarios for the cellular roles of PCu(A)C and PrrC are considered. The results are most consistent with a role for PrrC in the capture and delivery of copper to Cu(A) of the aa(3)-type CcO and to Cu(B) of the cbb(3)-type CcO, while the predominant role of PCu(A)C may be to capture and deliver copper to PrrC and Cox11. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. PMID- 22248673 TI - Exchange bias in bulk layered hydroxylammonium fluorocobaltate (NH3OH)2CoF4. AB - The magnetic properties of layered hydroxylammonium fluorocobaltate (NH(3)OH)(2)CoF(4) were investigated by measuring its dc magnetic susceptibility in zero-field-cooled (ZFC) and field-cooled (FC) regimes, its frequency dependent ac susceptibility, its isothermal magnetization curves after ZFC and FC regimes, and its heat capacity. Effects of pressure and magnetic field on magnetic phase transitions were studied by susceptibility and heat capacity measurements, respectively. The system undergoes a magnetic phase transition from a paramagnetic state to a canted antiferromagnetic state exhibiting a weak ferromagnetic behavior at T(C) = 46.5 K and an antiferromagnetic transition at T(N) = 2.9 K. The most spectacular manifestation of the complex magnetic behavior in this system is a shift of the isothermal magnetization hysteresis loop in a temperature range below 20 K after the FC regime-an exchange bias phenomenon. We investigated the exchange bias as a function of the magnetic field during cooling and as a function of temperature. The observed exchange bias was attributed to the large exchange anisotropy which exists due to the quasi-2D structure of the layered (NH(3)OH)(2)CoF(4) material. PMID- 22248676 TI - H2-rich syngas production by fluidized bed gasification of biomass and plastic fuel. AB - This paper reports the results of gasification tests using a catalytic fluidized bed gasifier to obtain a H(2)-rich stream by feeding different pellets made of wood, biomass/plastic and olive husks to the gasifier. The effects of both the steam supply and an in-bed catalyst on gasifier performance have been investigated. In general, pelletization was an effective pre-treatment for improving the homogeneity of the fuel and the reliability of the feeding devices. The use of biomass/plastic pellets in a catalyst bed yielded good results in terms of the hydrogen concentration (up to 32%vol.), even if an increase in tar production and in the fine/carbon elutriation rate was observed in comparison with wood pellets. PMID- 22248674 TI - Nerveless and gutsy: intestinal nutrient sensing from invertebrates to humans. AB - The increasingly recognized role of gastrointestinal signals in the regulation of food intake, insulin production and peripheral nutrient storage has prompted a surge of interest in studying how the gastrointestinal tract senses and responds to nutritional information. Identification of metabolically important intestinal nutrient sensors could provide potential new drug targets for the treatment of diabetes, obesity and gastrointestinal disorders. From a more fundamental perspective, the study of intestinal chemosensation is revealing novel, non neuronal modes of communication involving differentiated epithelial cells. It is also identifying signalling mechanisms downstream of not only canonical receptors but also nutrient transporters, thereby supporting a chemosensory role for "transceptors" in the intestine. This review describes known and proposed mechanisms of intestinal carbohydrate, protein and lipid sensing, best characterized in mammalian systems. It also highlights the potential of invertebrate model systems such as C. elegans and Drosophila melanogaster by summarizing known examples of molecular evolutionary conservation. Recently developed genetic tools in Drosophila, an emerging model system for the study of physiology and metabolism, allow the temporal, spatial and high-throughput manipulation of putative intestinal sensors. Hence, fruit flies may prove particularly suited to the study of the link between intestinal nutrient sensing and metabolic homeostasis. PMID- 22248677 TI - Submicron-patterning of bulk titanium by nanoimprint lithography and reactive ion etching. AB - Nanopatterns on titanium may enhance endosseous implant biofunctionality. To enable biological studies to prove this hypothesis, we developed a scalable method of fabricating nanogrooved titanium substrates. We defined nanogrooves by nanoimprint lithography (NIL) and a subsequent pattern transfer to the surface of ASTM grade 2 bulk titanium applying a soft-mask for chlorine-based reactive ion etching (RIE). With respect to direct write lithographic techniques the method introduced here is fast and capable of delivering uniformly patterned areas of at least 4 cm(2). A dedicated silicon nanostamp process has been designed to generate the required thickness of the soft-mask for the NIL-RIE pattern transfer. Stamps with pitch sizes from 1000 nm down to 300 nm were fabricated using laser interference lithography (LIL) and deep cryogenic silicon RIE. Although silicon nanomachining was proven to produce smaller pitch sizes of 200 nm and 150 nm respectively, successful pattern transfer to titanium was only possible down to a pitch of 300 nm. Hence, the smallest nanogrooves have a width of 140 nm. An x-ray photoelectron spectroscopy study showed that only very few contaminations arise from the fabrication process and a cytotoxicity assay on the nanopatterned surfaces confirmed that the obtained nanogrooved titanium specimens are suitable for in vivo studies in implantology research. PMID- 22248679 TI - Historical perspectives of The American Association for Thoracic Surgery: Alfred Blalock (1899-1964). PMID- 22248680 TI - Trends in isolated coronary artery bypass grafting: an analysis of the Society of Thoracic Surgeons adult cardiac surgery database. AB - OBJECTIVE: Coronary artery bypass grafting (CABG) is the operation most commonly performed by cardiac surgeons. There are few contemporary data examining evolving patient characteristics and surgical outcomes of isolated CABG. We used the Society of Thoracic Surgeons adult cardiac surgery database to characterize trends in patient characteristics and outcomes after CABG over the past decade. METHODS: From 2000 to 2009, 1,497,254 patients underwent isolated primary CABG at Society of Thoracic Surgeons participating institutions. Demographics, operative characteristics, and postoperative outcomes were assessed, and risk-adjusted outcomes were calculated. RESULTS: Compared with the year 2000, patients undergoing isolated primary CABG in 2009 were more likely to have diabetes mellitus (33% vs 40%) and hypertension (71% vs 85%). There were clinically insignificant differences in age, gender, and body surface area. Between 2000 and 2009, there has been a 6.3% and 19.5% increase in the preoperative use of aspirin and beta-blockers, respectively. Between 2004 and 2009, there was a 7.8% increase in the use of angiotension-converting enzyme inhibitors preoperatively. Furthermore, between 2005 and 2009 there was a 3.8% increase in the use of statins preoperatively. The median number of distal anastomoses performed was unchanged between 2000 and 2009 (3; interquartile range, 2-4). There was a significant increase in the use of the internal thoracic artery (88% in 2000 vs 95% in 2009). The predicted mortality rates of 2.3% were consistent between 2000 and 2009. The observed mortality rate over this period declined from 2.4% in 2000 to 1.9% in 2009 representing a relative risk reduction of 24.4%. The incidence of postoperative stroke decreased significantly from 1.6% to 1.2%, representing a risk reduction of 26.4%. There was also a 9.2% relative reduction in the risk of reoperation for bleeding and a 32.9% relative risk reduction in the incidence of sternal wound infection. CONCLUSIONS: Over the past decade, the risk profile of patients undergoing CABG has changed, with fewer smokers, more diabetic patients, and better medical therapy characterizing patients referred for surgical coronary revascularization. The left internal thoracic artery is nearly universally used and outcomes have improved substantially, with a significant decline in postoperative mortality and morbidity. PMID- 22248682 TI - Lung cancer cell invasion and expression of intercellular adhesion molecule-1 (ICAM-1) are attenuated by secretory phospholipase A2 inhibition. AB - OBJECTIVE: Invasive lung tumors are associated with intercellular adhesion molecule-1 (ICAM-1) expression. Secretory phospholipase A(2) (sPLA(2)) enzymes produce inflammatory mediators that stimulate ICAM-1 expression, and upregulation of PLA(2) activity can enhance metastasis. We hypothesize a link between sPLA(2) activity, ICAM-1 expression, and tumor cell invasion. We propose that inhibition of sPLA(2) modulates ICAM-1 expression in cancer cells and attenuates their invasiveness. METHODS: Human lung adenocarcinoma cells (A549) were treated with an ICAM-1 blocking antibody and assayed for invasion. Lung cancer cells (A549 and H358) were then treated with an sPLA(2) inhibitor and evaluated by immunoblotting for ICAM-1 expression. Next cells (A549) treated with sPLA(2) inhibitor were assayed for invasion. Finally, sPLA(2) messenger RNA and protein expression were evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence microscopy, respectively. Statistical analysis was performed by the Student t test or analysis of variance, as appropriate. RESULTS: Antibody blockade of ICAM-1 decreased lung cancer cell invasion. sPLA(2) inhibition significantly reduced ICAM-1 expression and invasion. sPLA(2) inhibition also significantly decreased sPLA(2) mRNA expression and immunofluorescent staining of sPLA(2). CONCLUSIONS: sPLA(2) plays a significant role in mediating the inflammatory signals that induce ICAM-1 expression in lung cancer cells. Inhibition of the enzyme can significantly decrease ICAM-1 expression and subsequent cancer cell invasion. This lays the groundwork for further investigation into the cellular mechanisms of sPLA(2) and its role in lung cancer. PMID- 22248684 TI - Factors associated with 5-year survival in older heart transplant recipients. AB - OBJECTIVES: The aim of the present study was to identify the predictors of 5-year survival in elderly patients undergoing orthotopic heart transplantation (OHT). METHODS: A review of the United Network for Organ Sharing database was conducted of recipients 60 years old or older undergoing OHT from 1995 to 2004. The variables were compared between the 5-year survivors and the patients who died within 5 years of OHT. A multivariate logistic regression model was constructed using the covariates significantly associated with 5-year survival on univariate analysis. RESULTS: A total of 5330 elderly patients underwent OHT during the study period. Of these patients, 3492 (65.5%) were 5-year survivors, 1580 (29.6%) had died within 5 years of OHT and were considered controls, and 258 (4.8%) were lost to follow-up. The predictors of improved 5-year survival included younger age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95-1.00; P = .03), lower creatinine (OR, 0.92; 95% CI, 0.87-0.98; P = .01), white race (OR, 1.23; 95% CI, 1.02-1.49; P = .03), shorter ischemic time (OR, 0.93; 95% CI, 0.87-0.99; P = .02), and younger donor age (OR, 0.99; 95% CI, 0.99-1.00; P = .03). The following significantly reduced the odds of surviving to 5 years: mechanical ventilation (OR, 0.48; 95% CI, 0.33-0.71; P < .001), hypertension (OR, 0.79; 95% CI, 0.69-0.91; P = .001), and diabetes (OR, 0.79; 95% CI, 0.67-0.92; P = .003). Ventricular assist device data were only available for 2538 patients (49.6%). When added to the multivariate model, the use of a ventricular assist device significantly reduced the odds of surviving 5 years after OHT (OR, 0.63; 95% CI, 0.50-0.81; P < .001). CONCLUSIONS: In the present study of more than 5000 elderly OHT patients, younger recipient age, white race, lower creatinine, younger donor age, and shorter ischemic time were associated with improved 5-year survival. In contrast, bridging with a ventricular assist device, mechanical ventilation, hypertension, and diabetes significantly decreased the odds of 5-year survival. These findings might be useful for prognostication in this higher risk patient population. PMID- 22248685 TI - Cardiac herniation during robot-assisted cardiac operation. PMID- 22248686 TI - Left atrial myxoma in association with life-saving mitral stenosis. PMID- 22248687 TI - An unusual caffeic acid derived bicyclic [2.2.2] octane lignan and other constituents from Cordia rufescens. AB - This work reports isolation of an unusual lignan with a bicyclic [2.2.2] octene skeleton, named rufescenolide (1), from stems of Cordia rufescens, along with beta-sitosterol, stigmasterol, syringaldehyde, 3-beta-O-D-glucopyranosyl sitosterol, methyl caffeate, 4-methoxy-protocatechuic acid and methyl rosmarinate. Structural characterizations employed IR spectroscopic, ESIHRMS and mono and dimensional NMR spectroscopy. PMID- 22248688 TI - Is the Modified Early Warning Score (MEWS) superior to clinician judgement in detecting critical illness in the pre-hospital environment? AB - AIM: Physiological track and trigger scores have an established role in enhancing the detection of critical illness in hospitalized patients. Their potential to identify individuals at risk of clinical deterioration in the pre-hospital environment is unknown. This study compared the predictive accuracy of the Modified Early Warning Score (MEWS) with current clinical practice. METHODS: A retrospective observational cohort study of consecutive adult (>=16 yrs) emergency department attendances to a single centre over a two-month period. The outcome of interest was the occurrence or not of an adverse event within 24h of admission. Hospital pre-alerting was used as a measure of current critical illness detection and its accuracy compared with MEWS scores calculated from pre hospital observations. RESULTS: 3504 patients were included in the study. 76 (2.5%) suffered an adverse event within 24 h of admission. Paramedics pre-alerted the hospital in 224 cases (7.3%). Clinical judgement demonstrated a sensitivity of 61.8% (95% CI 51.0-72.8%) with a specificity of 94.1% (95% CI 93.2-94.9%). MEWS was a good predictor of adverse outcomes and hence critical illness detection (AUC 0.799, 95% CI 0.738-0.856). Combination systems of MEWS and clinical judgement may be effective MEWS >=4+clinical judgement: sensitivity 72.4% (95% CI 62.5-82.7%), specificity 84.8% (95% CI 83.52-86.1%). CONCLUSIONS: Clinical judgement alone has a low sensitivity for critical illness in the pre hospital environment. The addition of MEWS improves detection at the expense of reduced specificity. The optimal scoring system to be employed in this setting is yet to be elucidated. PMID- 22248689 TI - The stability of halloysite nanotubes in acidic and alkaline aqueous suspensions. AB - The long term stability of natural halloysite nanotubes was studied at room temperature (22 +/- 2 degrees C) in pure water, acidic and basic aqueous suspensions. The structural and morphological transformations of nanotubes were studied by TEM, SEM, nitrogen adsorption, XRD Raman and FTIR spectroscopy accompanied by monitoring the concentration of dissolved Si(IV) and Al(III) in solution. It has been revealed that, in 1 mol dm(-3) H(2)SO(4) solution, the dissolution of halloysite is initiated on the inner surface of nanotubes, leading to the formation of amorphous spheroidal nanoparticles of SiO(2) whereas, in 1 mol dm(-3) NaOH solution, dissolution of the inner surface of nanotubes is accompanied by the formation of Al(OH)(3) nanosheets. PMID- 22248690 TI - Regulation of neurogenesis and gliogenesis of retinoic acid-induced P19 embryonal carcinoma cells by P2X2 and P2X7 receptors studied by RNA interference. AB - Embryonic carcinoma cells are widely used models for studying the mechanisms of proliferation and differentiation occurring during early embryogenesis. We have now investigated how down-regulation of P2X2 and P2X7 receptor expression by RNA interference (RNAi) affects neural differentiation and phenotype specification of P19 embryonal carcinoma cells. Wild-type P19 embryonal carcinoma cells or cells stably expressing shRNAs targeting P2X2 or P2X7 receptor expression were induced to differentiate into neurons and glial cells in the presence of retinoic acid. Silencing of P2X2 receptor expression along differentiation promoted cell proliferation and an increase in the percentage of cells expressing glial specific GFAP, while the presence of beta-3 tubulin-positive cells diminished at the same time. Proliferation induction in the presence of stable anti-P2X2 receptor RNAi points at a mechanism where glial proliferation is favored over growth arrest of progenitor cells which would allow neuronal maturation. Differently from the P2X2 receptor, inhibition of P2X7 receptor expression during neural differentiation of P19 cells resulted in a decrease in cell proliferation and GFAP expression, suggesting the need of functional P2X7 receptors for the progress of gliogenesis. The results obtained in this study indicate the importance of purinergic signaling for cell fate determination during neural differentiation, with P2X2 and P2X7 receptors promoting neurogenesis and gliogenesis, respectively. The shRNAs down-regulating P2X2 or P2X7 receptor gene expression, developed during this work, present useful tools for studying mechanisms of neural differentiation in other stem cell models. PMID- 22248691 TI - Serum magnesium in the first week of life in extremely low birth weight infants. AB - BACKGROUND: Evidence that antenatal administration of magnesium sulfate (MgSO(4)) to women in preterm labor may confer fetal neuroprotection is growing. MgSO(4) crosses the placenta and can affect the neonate. Magnesium homeostasis in extremely low birth weight (ELBW) infants remains to be clarified. OBJECTIVES: We aimed to assess the natural progression of serum magnesium (Mg) in ELBW infants not exposed to antenatal MgSO(4) during the first month of life. METHODS: Laboratory data of a group of ELBW infants born in a tertiary center over a 1 year period were analyzed. Serum Mg was recorded daily for the first week and thereafter each week for a month for each infant. Concurrent calcium, phosphate and alkaline phosphatase were measured. RESULTS: 51 preterm infants (24 female) with a birth weight <1,000 g were included (33 were born at <27 weeks' gestation). The mean magnesium ranged from 0.9 to 1.1 mmol/l over the first week with a minimum of 0.62 mmol/l and maximum of 1.53 mmol/l. Mg rises in the first few days before stabilizing and remains within a narrow range thereafter. CONCLUSIONS: In ELBW infants, Mg tends to rise initially then stabilize and remain normal thereafter. The effect of antenatal MgSO(4) on magnesium homeostasis requires further study. PMID- 22248693 TI - A true revolution: enhanced motivation of the patient with rapid loss of virus (or rapid negativation of viral load), relationship between viral and histological cure. PMID- 22248692 TI - Superiority of PLK-2 as alpha-synuclein phosphorylating agent relies on unique specificity determinants. AB - Phosphorylation of alpha-synuclein at Ser-129 is of crucial relevance to Parkinson's disease and related synucleinopathies. Here we provide biochemical evidence that PLK2 and to a lesser extent PLK3 are superior over CK2, as catalysts of Ser-129 phosphorylation both in full length alpha-synuclein and in a peptide reproducing the C-terminal segment of the protein. By using substituted peptides we also show that the sequence surrounding Ser-129 is optimally shaped for undergoing phosphorylation by PLK2, with special reference to the two acidic residues at positions n-3 (Glu-126) and n+2 (Glu-131) whose replacement with alanine abrogates phosphorylation. PMID- 22248694 TI - Antiviral activity of the new DAAs for the treatment of hepatitis C virus infection: virology and resistance. AB - The treatment of chronic hepatitis C virus (HCV) infection has substantially evolved over the past decade, following the Consensus Conference organized by the European Association for the Study of the Liver in 1999. Since then, the standard of care (SoC) for patients with chronic hepatitis C has been the combination of pegylated interferon (pegIFN) alpha-2a or -2b and ribavirin. In patients infected with HCV genotype 1, by far the most frequent HCV genotype worldwide, such treatment leads to a cure of infection in only 40-50% of cases. After a decade in which pegIFN alpha and ribavirin therapy was the only available option, triple therapy with HCV protease inhibitors (PIs; boceprevir and telaprevir) in combination with pegIFN alpha and ribavirin has become the new SoC for genotype-1 infected patients. With PI therapy, higher cure rates can be achieved, but specific issues are also raised, such as the emergence of resistance to PIs. For this reason, the present report examines the antiviral activity of PIs and what is currently known about resistance to them, while focusing on telaprevir and boceprevir, two HCV PIs recently licensed for the treatment of treatment-naive and treatment-experienced genotype-1 patients with chronic hepatitis C. The clinical relevance of resistance testing is also discussed. PMID- 22248695 TI - Direct-acting antiviral (DAA) actions in treatment-naive patients. AB - The introduction of telaprevir (TVR) and boceprevir (BOC), the first approved protease inhibitors against hepatitis C virus (HCV), into clinical practice represented the start of an exciting new era of HCV treatment. In addition to improving sustained virological response (SVR) rates in HCV genotype-1 treatment naive patients, these drugs administered as a triple combination with pegylated interferon (pegIFN) and ribavirin (RBV) provide opportunities for more patients to receive shorter durations of treatment (24-28 weeks) than with pegIFN/RBV alone (48 weeks). Also, the use of TVR and BOC is being enhanced by the acquisition of further data on predictors of SVR, thereby increasing patients'chances of being cured of their HCV infection. PMID- 22248696 TI - Antiviral activity of telaprevir and boceprevir for the treatment of hepatitis C virus infection in treatment-experienced patients. AB - Around 50% of hepatitis C virus (HCV)-positive patients infected with genotype 1 are nonresponders to the combination of pegylated interferon (pegIFN) and ribavirin, including relapsers, and partial and null responders and, as such, are exposed to the risk of progression to cirrhosis and its complications, resulting in HCV-related morbidity and mortality. Repeat treatment using the same combination in such patients results in <5% viral eradication and there are no therapeutic prospects for patients who fail, as maintenance therapy has not proved efficacious. The triple association of direct-acting antivirals specific of HCV, and especially the first-generation protease inhibitors boceprevir and telaprevir, increases this percentage to around 65%, with variations according to the previous response to therapy of patients (85% of relapsers, 50% of partial responders and 30% of null responders). These encouraging results extend the therapeutic indications and costs of therapy during virological follow-up, and influence the rules of discontinuation. Information on the management of these new molecules also allows a larger number of patients to be cured and reduces the occurrence of viral resistance. Thus, the aim of the present review is to summarize the efficacy of the triple association of pegIFN, ribavirin and telaprevir or boceprevir in treatment-experienced patients who failed to respond to dual pegIFN and ribavirin therapy. PMID- 22248697 TI - Management of treatment with direct-acting antiviral (DAA) in clinical practice. AB - The triple therapy has brought about a genuine revolution in the care of patients with chronic hepatitis C virus infection, although achieving a high cure rate requires adding disciplines beyond the attending physician when confronted by a motivated patient. The treatment is complex because of the many parameters involved (such as fibrosis score, patient's history of previous antiviral treatment and viral kinetics during treatment). A working knowledge of drug interactions and contraindications for drugs other than antiviral therapy is required, as well as meticulous follow-up. PMID- 22248698 TI - Management of side-effects. AB - The current treatment of chronic hepatitis C is the triple combination of pegylated interferon, ribavirin and a new direct-acting antiviral [either telaprevir (TVR) or boceprevir (BOC)]. This new association produces better viral response rates, but may induce or enhance adverse events, which can lead to discontinuation of treatment. TVR regimens are associated with an increased risk of dermatological side-effects such as rash, albeit generally mild. In these cases, optimal skincare treatments, including emollient creams and topical corticosteroids, allow the continuation of antiviral treatment. In a minority of cases, the rash may be severe and life-threatening, leading to immediate discontinuation of all treatments. The goal for the physician is to differentiate severe cutaneous adverse reactions (SCARs), including DRESS (drug reactions with eosinophilia and systemic symptoms). Anaemia is also more frequent with triple combinations using TVR or BOC. The management of anaemia requires the use of erythropoietin alpha (EPO) and the need to decrease ribavirin doses. Thus, monitoring haemoglobin has to be more frequent in difficult-to-treat patients such as cirrhosis cases; nevertheless, despite the use of EPO and ribavirin-dose adaptation, blood transfusion is sometimes still required. Thus, triple combination therapy with a DAA is effective, but it increases the rate of adverse events, and adds to the well-known adverse effects of pegylated interferon and ribavirin. This suggests the need for a different clinical and biological management of patients treated with the triple combination. PMID- 22248699 TI - Direct-acting antivirals for hepatitis C virus infections in patients co-infected with human immunodeficiency virus. AB - Nearly three-quarters of human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients in France currently need to be cured of their chronic HCV infection. The increase in sustained virological response rates obtained with the recently available HCV protease inhibitors in treatment-naive genotype-1 patients has generated considerable hope in these co-infected patients. However, several particularities (such as a higher baseline HCV load, more advanced liver fibrosis, frequent co-morbidities, and the risk of toxicity and drug-drug interactions) have not allowed the direct extrapolation of the results observed in HCV-monoinfected patients to patients with HIV-HCV co-infection. Yet, despite these uncertainties and the little available data from ongoing trials, several proposals can be made not only because the patients and drugs are ready and waiting, but also because the clock is ticking. In general, it can be advocated that HCV triple therapy should be offered to most HIV-infected patients with advanced liver fibrosis, but should be deferred or discussed on a case-by-case basis in those with mild-to-moderate fibrosis. However, such proposals rely on a relatively small amount of evidence and many questions are still pending, as studies in HIV-HCV co-infected patients have been late in coming and are several years behind those in HCV-monoinfected patients. Thus, this situation, in the context of more rapid and more severe infection, and lower response rates with standard care (pegylated interferon and ribavirin), along with the many potential drug-drug interactions (particularly with antiretroviral therapy), underscores the need for earlier evaluation of new strategies, schedules and new direct acting antivirals in HIV-infected patients. PMID- 22248700 TI - Chronic hepatitis C: treatments of the future. AB - The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance has, up to now, only been applicable to genotype-1 patients. Second-wave and second-generation PIs appear to achieve higher antiviral potency, with pan-genotype activities, fewer side-effects and potential activity against PI-resistant mutation by second generation PIs, through more convenient daily administration. Other direct-acting antivirals (DAAs) include NS5B inhibitors such as nucleoside/nucleotide inhibitors (NIs) and non-nucleoside inhibitors (NNIs). NIs have similar efficacy across all genotypes and present with the highest barrier to resistance of all DAAs to date. PSI-7977, a pyrimidine nucleotide analogue, also has highly potent antiviral activity across all HCV genotypes. In combination with ribavirin in an interferon-free regimen, it can achieve a 100% sustained viral response (SVR) rate in genotype 2/3 treatment-naive patients. In association with pegylated interferon and ribavirin (PR), it achieves an SVR of 91% in genotype-1 naive patients. NNIs in association with PR appear to be less potent, but they may nonetheless play a key role in many of the combination trials including either PIs or NIs. NS5A inhibitors also exhibit highly potent antiviral activity. Evaluation of their activity in combination with PIs demonstrated for the first time that an interferon-free regimen can cure genotype-1b null-responder patients. Furthermore, quadruple therapy with PR can achieve a 100% SVR in genotype-1 null-responder patients. Other players in the field, such as cyclophilin inhibitors and therapeutic vaccines, may have a role in combination with DAAs. The near future of HCV treatment looks promising. However, whether or not DAA combinations will lead to an interferon-free regimen for all patients remains an open question. PMID- 22248702 TI - Magnetic, structural, and thermal properties of CoV2O4. AB - In this paper, we investigate the electric, magnetic, structural, and thermal properties of spinel CoV(2)O(4). The temperature dependence of magnetization shows that, in addition to the paramagnetic-to-ferrimagnetic transition at T(C) = 142 K, two magnetic anomalies exist at 100 K, T(1) = 59 K. Consistent with the anomalies, the thermal conductivity presents two valleys at 100 K and T(1). At the temperature T(1), the heat capacity shows one peak, which cannot be attributed to the structural transition as revealed by the x-ray diffraction patterns for CoV(2)O(4). Below the transition temperature T(1), the ac susceptibility displays the characteristics of a glass. The series of phenomena at T(1) and the orbital state on V(3+) sites are discussed. PMID- 22248701 TI - The dynamics of sexual contact networks: effects on disease spread and control. AB - Sexually transmitted pathogens persist in populations despite the availability of biomedical interventions and knowledge of behavioural changes that would reduce individual-level risk. While behavioural risk factors are shared between many sexually transmitted infections, the prevalence of these diseases across different risk groups varies. Understanding this heterogeneity and identifying better control strategies depends on an improved understanding of the complex social contact networks over which pathogens spread. To date, most efforts to study the impact of sexual network structure on disease dynamics have focused on static networks. However, the interaction between the dynamics of partnership formation and dissolution and the dynamics of transmission plays a role, both in restricting the effective network accessible to the pathogen, and in modulating the transmission dynamics. We present a simple method to simulate dynamical networks of sexual partnerships. We inform the model using survey data on sexual attitudes and lifestyles, and investigate how the duration of infectiousness changes the effective contact network over which disease may spread. We then simulate several control strategies: screening, vaccination and behavioural interventions. Previous theory and research has advanced the importance of core groups for spread and control of STD. Our work is consistent with the importance of core groups, but extends this idea to consider how the duration of infectiousness associated with a particular pathogen interacts with host behaviours to define these high risk subpopulations. Characteristics of the parts of the network accessible to the pathogen, which represent the network structure of sexual contacts from the "point of view" of the pathogen, are substantially different from those of the network as a whole. The pathogen itself plays an important role in determining this effective network structure; specifically, we find that if the pathogen's duration of infectiousness is short, infection is more concentrated in high-activity, high-concurrency individuals even when all other factors are held constant. Widespread screening programmes would be enhanced by follow-up interventions targeting higher-risk individuals, because screening shortens the expected duration of infectiousness and causes a greater relative decrease in prevalence among lower-activity than in higher-activity individuals. Even for pathogens with longer durations of infectiousness, our findings suggest that targeting vaccination and behavioural interventions towards high-activity individuals provides comparable benefits to population-wide interventions. PMID- 22248704 TI - Severity of signs and symptoms in lumbopelvic pain during pregnancy. AB - Data on the severity of signs and symptoms of lumbopelvic pain (LPP) during pregnancy are scarce. Therefore, this cross-sectional study examines the severity of LPP and pain-related signs and symptoms. Women with an uncomplicated pregnancy of 20-30 weeks were invited to participate. They rated their pain and fatigue on a numerical rating scale, and pain location was indicated on a drawing. Disability was scored on the Quebec Back Pain Disability Scale (QBPDS) and urine incontinence on a Likert scale. Physical examination consisted of the Active Straight Leg Raise (ASLR) test, the Posterior Pelvic Pain Provocation (PPPP) test and pain score, and force during isometric bilateral hip adduction. Of all 182 participants, 60.4% reported LPP. Mean pain level was 3.6 (SD 2.2); in 20.0% of the women the score was >5. The mean score on the QBPDS was 27 (SD 16); in 20.9% the score was >40. Compared to women without LPP, women with LPP more frequently suffered back pain in the past (p<0.001), had a higher body mass index (p<0.01), more often had urinary incontinence (p<0.05), had less isometric hip adduction force (p<0.001), had more pain on isometric hip adduction (p<0.01), had a higher ASLR score (p<0.001) and more had often a positive PPPP test (p<0.001). Fatigue was not related to LPP during pregnancy. The main conclusion is that pain and disability of LPP during pregnancy can be interpreted as mild to moderate in most cases, and as severe in about 20%. PMID- 22248703 TI - T cell- but not tumor cell-produced TGF-beta1 promotes the development of spontaneous mammary cancer. AB - During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-beta1. We showed in our recent studies that T cell-produced TGF-beta1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-beta1 produced by tumor cells in tumor development. Here, using a transgenic model of mammary cancer, we report that deletion of TGF-beta1 from tumor cells did not protect mice from tumor development. However, ablation of TGF-beta1 from T cells significantly inhibited mammary tumor growth. Additionally, absence of TGF-beta1 in T cells prevented tumors from advancing to higher pathological grades and further suppressed secondary tumor development in the lungs. These findings reveal T cells but not tumor cells as a critical source of TGF-beta1 that promotes tumor development. PMID- 22248705 TI - Rehabilitative ultrasound measurement of trapezius muscle contractile states in people with mild shoulder pain. AB - INTRODUCTION: The utility of rehabilitative ultrasound imaging (RUSI) for assessing trapezius muscle contractile characteristics was investigated by examining whether muscle thickness changes during contraction (CT) differed between people with and without mild shoulder pain. METHODS: In 18 subjects with mild shoulder pain (aged 28+/-8 years) and 18 matched controls, trapezius muscle thickness change was measured in prone at rest at 0 degrees and during isometric CTs at 90 degrees and 120 degrees of shoulder abduction. Images were taken at four sites using a real-time ultrasound scanner (7-MHz linear transducer, 40 mm footprint). Percentage change in muscle thickness from rest was calculated. Differences between painful and non-painful shoulders and participant groups were examined by analysis of variance (ANOVA) and t-tests. RESULTS: There were no significant differences between groups or sides in trapezius muscle thickness change during CT. There was no significant difference in trapezius muscle resting thickness (RT) between painful and non-painful shoulders in the same subjects. CONCLUSION: Contractile ability of the trapezius muscle, assessed using RUSI was not impaired in subjects with mild shoulder pain during the test manoeuvres used. Further research is warranted involving patients with different severity of symptoms, using other test manoeuvres before RUSI can be advocated for assessing scapular muscle dysfunction. PMID- 22248706 TI - Feasibility and reproducibility of transvaginal, transabdominal, and 3D volume reconstruction sonography for measurement of the corpus callosum at different gestational ages. AB - OBJECTIVE: To compare the feasibility and reproducibility of transvaginal and transabdominal approaches, and 3D volume reconstruction sonography for measurement of corpus callosum (CC) length at different gestational ages. METHODS: Forty-six normal fetuses were examined by 2D and 3D ultrasound at 23-25, 27-28 and 31-32 weeks of gestation. Direct mid-sagittal views were obtained by either a transabdominal and/or transvaginal approach. 3D reconstructed mid sagittal views were obtained by 3D multiplanar manipulations and Volume Contrast Imaging in the C-plane technique (VCI-C) from volumes acquired in axial planes. RESULTS: The CC could be measured in 91% of transvaginal acquisitions, in 52% of transabdominal acquisitions, in 92% of multiplanar reconstructions, and in 86% of VCI-C reconstructions. The success rate was independent of gestational age for transvaginal acquisition and slightly dependent on gestational age for 3D reconstruction techniques. Transabdominal acquisition was dependent on gestational age and fetal presentation. Inter- and intra-observer agreement was slightly better for measurements obtained from direct mid-sagittal views with either transvaginal or transabdominal acquisition than in views obtained by volume reconstruction. The reproducibility of measurements taken in reconstructed mid-sagittal views decreased with gestational age. CONCLUSION: 3D volume reconstruction techniques allow visualization and measurement of the CC in a high percentage of cases, with good reproducibility. PMID- 22248707 TI - A qualitative interview study on effects of diet on children's mental state and performance. Evaluation of perceptions, attitudes and beliefs of parents in four European countries. AB - Nutrition is one of the many factors that influence a child's cognitive development and performance. Understanding the relationship between nutrition and mental performance in children is important in terms of their attainment and productivity both in school and later life. Since parents are seen as nutritional gatekeepers for their children's diets, their views and beliefs are of crucial importance. The present study aims to qualitatively examine parents' perceptions of the relationship between diet and mental performance of children. The study was conducted with a total of 124 parents in four European countries using a semi structured interview schedule. Parents speak of the effects of diet at two levels; the nature of the effects of diet and the characteristics of the foods responsible for these effects. Mental outcomes are related to diet, with the effects perceived to be associated with attention and concentration, often mediated by effects on children's mood and behaviour. Parents categorise foods as 'good' or 'bad' with positive effects related generally to a healthy balanced diet while negative effects are perceived to be associated with sugary and fatty foods. Understanding parental perceptions is important for many purposes including the targeting of dietary advice and prioritising of public health issues. PMID- 22248708 TI - Liking of anthocyanin-rich juices by children and adolescents. AB - There is evidence that a diet rich in plant foods is protective against cardiovascular disease and cancer, partly attributable to secondary plant metabolites such as anthocyanins, a colourful group of flavonoids. As at present children and adolescents do not consume the recommended amounts of fruits and vegetables, one possible way of increasing intake, and particularly intake of anthocyanins, may be an anthocyanin-rich juice, since fruit juice is popular with young Germans. We produced eight different fruit products (six juices, two smoothies), and conducted hedonic tests with participants from the DONALD Study. Paired comparisons showed that most subjects preferred apple to apple-bilberry juice, but grape vs. grape-bilberry juice was liked equally frequently. Rated on a hedonic scale the grape-bilberry mixture was preferred to apple-bilberry, both as juice and as smoothie. With regard to viscosity, juices were preferred to smoothies, both as grape-bilberry and as apple-bilberry. Internal Preference Mapping revealed however consumer subgroups with different preferences, raising the question which product should be promoted in order to reach a large target group. The product richest in anthocyanins, grape-bilberry juice, was accepted very well and may therefore be suitable for promotion to children, although the high sugar content of this juice must be taken into account. PMID- 22248709 TI - Predictors of weight loss success. Exercise vs. dietary self-efficacy and treatment attendance. AB - Pre-treatment diet and exercise self-efficacies can predict weight loss success. Changes in diet self-efficacy across treatment appear to be even stronger predictors than baseline levels, but research on changes in exercise self efficacy is lacking. Using data from a pilot study evaluating tangible reinforcement for weight loss (N=30), we examined the impact of changes in diet and exercise self-efficacy on outcomes. Multiple regression analyses indicated that treatment attendance and changes in exercise self-efficacy during treatment were the strongest predictors of weight loss. Developing weight loss programs that foster the development of exercise self-efficacy may enhance participants' success. PMID- 22248710 TI - The Smart Choices front-of-package nutrition label. Influence on perceptions and intake of cereal. AB - Numerous front-of-package (FOP) nutrition labeling systems exist, but it is unclear if such labels influence behavior. A single-summary label called Smart Choices (SC) appeared briefly on products in the United States in 2009. The current study aimed to evaluate (1) the influence the SC symbol has on the serving and consumption of cereal; and (2) the impact of providing calorie and serving size information on a FOP label. Two hundred and sixteen adults were randomized to a high-sugar breakfast cereal that had either (1) no label; (2) the SC symbol; or (3) a modified SC symbol with serving size information. Participants rated perceptions of healthfulness, taste, and purchase intent, estimated calories per serving and poured and ate the cereal for breakfast. Participants in the SC label conditions were better able to estimate calories per serving, but there were no differences across groups on perceptions of healthfulness, taste, purchase intent, and levels of vitamins, and sugar or amount of cereal poured or consumed. These results suggest that calories per serving information on FOP labels can increase knowledge, but the SC symbol had little impact on behavior. Studies examining FOP label influence on purchasing, consumption, and product reformulation are greatly needed to determine label utility. PMID- 22248711 TI - A randomised phase II study of the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after autologous stem cell transplant for lymphoma and myeloma (PALM study). AB - AIM: To evaluate in a multicentre randomised study the effect on duration of febrile neutropenia (FN), the safety and cost-effectiveness of a single subcutaneous pegfilgrastim injection compared with daily injections of filgrastim after peripheral blood stem cell transplantation in patients receiving high dose chemotherapy for myeloma and lymphoma. METHODS: Patients were randomly assigned to a single dose of pegfilgrastim at day 5 (D5) or daily filgrastim from D5 to the recovery of absolute neutrophil count (ANC) to 0.5 G/L. Duration of FN, of neutrophil and platelet recovery, transfusion and antibiotic requirements were the main end-points of the study. Costs were calculated from D0 until transplant unit discharge. The incremental cost-effectiveness ratio was expressed as the cost per day of FN prevented. Probabilistic sensitivity analysis was performed by non-parametric bootstrap methods. RESULTS: Between October 2008 and September 2009, 10 centres enrolled 151 patients: 80 patients with lymphoma and 71 patients with myeloma. The mean duration of FN was 3.07 days (standard deviation (SD) 1.96) in the pegfilgrastin arm and 3.29 (SD 2.54) in the filgrastim one. Mean total costs were 23,256 and 25,448 euros for pegfilgrastim and filgrastim patients, respectively. There was a 62% probability that pegfilgrastim strictly dominates filgrastim. CONCLUDING STATEMENT: Pegfilgrastim after PBSC transplantation in myeloma and lymphoma is safe, effective when compared with filgrastim and could represent a cost-effective alternative in this setting. PMID- 22248712 TI - All-solid-state flexible supercapacitors based on papers coated with carbon nanotubes and ionic-liquid-based gel electrolytes. AB - All-solid-state flexible supercapacitors were fabricated using carbon nanotubes (CNTs), regular office papers, and ionic-liquid-based gel electrolytes. Flexible electrodes were made by coating CNTs on office papers by a drop-dry method. The gel electrolyte was prepared by mixing fumed silica nanopowders with ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][NTf(2)]). This supercapacitor showed high power and energy performance as a solid-state flexible supercapacitor. The specific capacitance of the CNT electrodes was 135 F g(-1) at a current density of 2 A g(-1), when considering the mass of active materials only. The maximum power and energy density of the supercapacitors were 164 kW kg(-1) and 41 Wh kg(-1), respectively. Interestingly, the solid-state supercapacitor with the gel electrolyte showed comparable performance to the supercapacitors with ionic-liquid electrolyte. Moreover, the supercapacitor showed excellent stability and flexibility. The CNT/paper- and gel based supercapacitors may hold great potential for low-cost and high-performance flexible energy storage applications. PMID- 22248713 TI - National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. AB - Existing standards for screening and management of late effects occurring in children who have undergone hematopoietic cell transplantation (HCT) include recommendations from pediatric cancer networks and consensus guidelines from adult-oriented transplantation societies applicable to all HCT recipients. Although these approaches have significant merit, they are not pediatric HCT focused, and they do not address post-HCT challenges faced by children with complex nonmalignant disorders. In this article we discuss the strengths and weaknesses of current published recommendations and conclude that pediatric specific guidelines for post-HCT screening and management would be beneficial to the long-term health of these patients and would promote late effects research in this field. Our panel of late effects experts also provides recommendations for follow-up and therapy of selected post-HCT organ and endocrine complications in pediatric patients. PMID- 22248714 TI - Decreased serum testosterone levels in long-term adult survivors with fatty liver after childhood stem cell transplantation. AB - Fatty liver and male gonadal dysfunction are potential late effects of therapy in adult survivors treated with stem cell transplantation (SCT) in childhood. Obesity and metabolic syndrome also are associated with low serum testosterone levels in the general population. However, the relationship between the degree of fatty liver and changes in serum testosterone levels in adult survivors has not been fully studied. We reviewed the clinical records of 34 male patients who received allogeneic SCT in childhood or adolescence. The median age at SCT was 10.0 years, and the median follow-up after SCT was 15.9 years. All but one patient showed no tendency toward overweight/obesity during the follow-up period. Fatty liver was diagnosed by ultrasound in 15 patients at 4 to 20 years after SCT. Patients who received cranial radiation therapy before SCT were more likely to develop fatty liver and insulin resistance. Moreover, fatty liver was statistically associated with decreased serum testosterone levels, whereas nonfatty liver was not (median, 527 ng/dL [range, 168-944 ng/dL] versus 302 ng/dL [165-698 ng/dL]; P < .0001). Changes in testosterone levels after SCT are affected not only by primary gonadal dysfunction but also by subsequent development or exacerbation of fatty liver. PMID- 22248715 TI - Intermediate-dose versus low-dose cyclophosphamide and granulocyte colony stimulating factor for peripheral blood stem cell mobilization in patients with multiple myeloma treated with novel induction therapies. AB - Peripheral blood progenitor cell mobilization with intermediate-dose cyclophosphamide (ID-CY) and granulocyte colony-stimulating factor (G-CSF) has been shown to be more efficacious, albeit more toxic, than low-dose cyclophosphamide (LD-CY) mobilization regimens in patients with multiple myeloma treated with conventional therapies. However, the relative importance of cyclophosphamide dose intensity in peripheral blood progenitor cell mobilization after novel induction regimens is not known. Here we report mobilization outcomes of 123 patients who underwent transplantation within 1 year of starting induction chemotherapy with novel agents. We compared consecutive patients undergoing mobilization with ID-CY/G-CSF (3-4 g/m(2)) at one institution (n = 55) with patients receiving LD-CY/G-CSF (1.5 g/m(2)) at a different transplantation center (n = 68). At baseline, the 2 groups were well balanced, except for more frequent previous lenalidomide use in the ID-CY group (P = .04). Compared with LD-CY, ID CY use was associated with higher median peak PB CD34(+) cell count (35/MUL versus 160/MUL; P < .001), CD34(+) cell yield on day 1 of collection (2.6 * 10(6)/kg versus 11.7 * 10(6)/kg, P <= .001), and total CD34(+) cell yield (7.5 * 10(6)/kg versus 16.6 * 10(6)/kg; P <= .001). Six patients in the LD-CY group had mobilization failure, compared with no patients in the ID-CY group. A significantly higher proportion of patients in the LD-CY group (P < .001) were unable to collect >=5 * 10(6)/kg and >=10 * 10(6)/kg CD34(+) cells. Neutrophil and platelet engraftment were significantly faster in the ID-CY group, likely because of higher infused CD34(+) cell doses. In conclusion, compared with LD-CY, ID-CY produced a more robust peripheral blood progenitor cell mobilization and significantly reduced the rates of mobilization failure. These data caution against the use of LD-CY-containing mobilization strategies in patients with multiple myeloma undergoing stem cell collection after novel induction regimens. PMID- 22248717 TI - Do you want to read about a biochemic and genetical analysis of the physiologic role of the autophagical process? No. PMID- 22248716 TI - Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage. AB - Autophagy is the evolutionarily conserved degradation and recycling of cellular constituents. In mammals, autophagy is implicated in the pathogenesis of many neurodegenerative diseases. However, its involvement in acute brain damage is unknown. This study addresses the function of autophagy in neurodegeneration that has been induced by acute focal cerebellar lesions. We provide morphological, ultrastructural, and biochemical evidence that lesions in a cerebellar hemisphere activate autophagy in axotomized precerebellar neurons. Through time course analyses of the apoptotic cascade, we determined mitochondrial dysfunction to be the early trigger of degeneration. Further, the stimulation of autophagy by rapamycin and the employment of mice with impaired autophagic responses allowed us to demonstrate that autophagy protects from damage promoting functional recovery. These findings have therapeutic significance, demonstrating the potential of pro-autophagy treatments for acute brain pathologies, such as stroke and brain trauma. PMID- 22248718 TI - miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. AB - Macroautophagy (autophagy) is the major intracellular degradation pathway for long-lived proteins and organelles. It helps the cell to survive a spectrum of stressful conditions including starvation, growth factor deprivation and misfolded protein accumulation. Moreover, abnormalities of autophagy play a role in major health problems including cancer and neurodegenerative diseases. Yet, mechanisms controlling autophagic activity are not fully understood. Here, we describe hsa-miR-376b (miR-376b) as a new microRNA (miRNA) regulating autophagy. We showed that miR-376b expression attenuated starvation- and rapamycin-induced autophagy in MCF-7 and Huh-7 cells. We discovered autophagy proteins ATG4C and BECN1 (Beclin 1) as cellular targets of miR-376b. Indeed, upon miRNA overexpression, both mRNA and protein levels of ATG4C and BECN1 were decreased. miR-376b target sequences were present in the 3' UTR of ATG4C and BECN1 mRNAs and introduction of mutations abolished their miR-376b responsiveness. Antagomir mediated inactivation of the endogenous miR-376b led to an increase in ATG4C and BECN1 levels. Therefore, miR-376b controls autophagy by directly regulating intracellular levels of two key autophagy proteins, ATG4C and BECN1. PMID- 22248719 TI - Photoluminescence study of low density InAs quantum clusters grown by molecular beam epitaxy. AB - We report a systematic optical spectroscopy study of low density InAs quantum clusters (QCs) grown by molecular beam epitaxy. The photoluminescence (PL) spectra show emission features of a wetting layer (WL) which contains hybridized quantum well states. The low-energy tail of the QCs' PL profile is actually an ensemble of some sharp lines, originating from the emission of different exciton states (e.g. X, X*, XX*) in a single quasi-three-dimensional (Q3D) cluster as detailed in the micro-PL spectra. The temperature dependence of PL spectra indicates photocarrier distribution and transport in the QC-WL system. Furthermore, this small InAs Q3D cluster is integrated with a distributed Bragg reflector structure, and using optical excitation creates a single photon source with the second-order correlation function of g((2))(0) = 0.31 at 16 K. PMID- 22248720 TI - Effect of immunosuppression on pathogenesis of peste des petits ruminants (PPR) virus infection in goats. AB - In this study an attempt to address the effects of immunosuppression on pathogenesis of peste des petits ruminants (PPR) virus infection was undertaken. Cyclophosphamide and dexamethasone were used to immunosuppress the animals. The drug treated animals exhibited severe leukopaenia and lymphopaenia; one of the indicators of immunosuppression. Experimental peste des petits ruminants virus (PPRV) infection was then given to both drug-induced immunosuppressed and non immunosuppressed goats and observed their effects. Findings indicated that, the immunosuppressed goats had a short period of viremia, more extensive and severe disease advancement and higher mortality rate than the non-immunosuppressed goats. PPRV antigen distribution in both ante-mortem and post-mortem materials was extensive and diffused in immunosuppressed animals than that of non immunosuppressed. Some of the atypical organ(s)/tissues like liver, kidney, heart etc showed more antigen load than non-immunosuppressed group. Histopathological and immunohistochemical studies of tissues from the two groups showed that pathological changes in the non-immunosuppressed animals were confined only to gastrointestinal tract, whereas in the immunosuppressed animals histopathological changes and PPRV antigen distribution were more extensive and diffused. The present study indicated that immunosuppression increased the extent and severity of the pathological lesions associated with peste des petits ruminants virus infection. PMID- 22248721 TI - Platinum-based compounds for the treatment of metastatic breast cancer. AB - The role of platinum-based compounds (PBCs) in the treatment of metastatic breast cancer (MBC) has been extensively studied. As single agents, high response rates have been observed in first-line therapy, while results in pretreated patients were discouraging. Regimens containing cisplatin/carboplatin together with taxanes showed the highest efficacy and safety as both first-line and second-line therapy. When administered with vinorelbine, the combination was also active and well tolerated in anthracycline- and taxane-pretreated patients. Combining PBCs with etoposide or nucleoside analogues showed moderate activity, yet high toxicity in the case of etoposide. The overall results for the combination with anthracyclines were disappointing. Addition of trastuzumab to PBC combinations showed remarkable activity and good tolerability in patients with HER2/neu overexpression. The use of cisplatin or carboplatin alongside novel targeted therapeutics for patients with triple-negative MBC seems promising and is being further evaluated. The use of PBCs against MBC requires careful patient selection and combination with the right chemotherapeutic agent. PMID- 22248722 TI - Acute stress differently modulates beta1, beta2 and beta3 adrenoceptors in T cells, but not in B cells, from the rat spleen. AB - OBJECTIVES: Stress-induced rise in circulating catecholamines (CAs), followed by modulation of beta-adrenergic receptors (adrenoceptors, ARs), is one of the pathways involved in the stress-mediated effects of immune functions. The spleen is an organ with a high number of lymphocytes and provides a unique microenvironment in which they reside. Thus, lymphocytes may respond differently to CAs in the spleen than in the circulation. No reports exist concerning the involvement of beta-ARs in stress-mediated effects on T and B cells isolated from the spleen. Therefore, our aim was to investigate the effect of single stress exposure on gene expression and cellular localization of beta-adrenoceptor subtypes in splenic T and B cells. We tried to correlate changes in adrenoceptors with the expression of apoptotic proteins. METHODS: Immobilization (IMMO) was used as a stress model. T and B cells were isolated from rat spleen using magnetically labeled antibodies. The gene expression of individual adrenoceptors and apoptotic proteins was evaluated by real-time PCR. Immunofluorescence was used to evaluate localization and adrenoceptor expression. RESULTS: We have found T cells to be more vulnerable to stress compared to B cells, because of increased beta1-, beta2- and beta3-ARs after a single IMMO. Moreover, beta2-ARs translocated from the nucleus to the plasma membrane in T cells after IMMO. The rise in beta-ARs most probably led to the rise of Bax mRNA and Bax to Bcl-2 mRNA ratio. This might suggest the induction of an apoptotic process in T cells. CONCLUSION: Higher susceptibility of T cells to stress via modulation of beta-ARs and apoptotic proteins might shift the immune responsiveness in the spleen. PMID- 22248723 TI - Immune outcomes of paradoxical sleep deprivation on cellular distribution in naive and lipopolysaccharide-stimulated mice. AB - BACKGROUND/AIMS: Several lines of evidence indicate that sleep loss imposes significant consequences on the host defense system, including changes in cell number, activity and distribution. However, it is not clear whether cellular alterations after sleep deprivation are caused by redistribution to immune organs or by death of these cells or how the response to a nonspecific immune activator would be affected. Therefore, the aim of this study was to assess the leukocyte distribution after paradoxical sleep deprivation (PSD) in saline- and lipopolysaccharide-treated mice. METHODS: Adult inbred mice were paradoxical sleep deprived (72 h), whereas the controls were kept in their home cages. After PSD, both groups received an injection of either saline or lipopolysaccharide (LPS; 1 or 5 MUg/animal, intraperitoneally), 2 h prior to the collection of blood, spleen, lymph nodes and peritoneal wash. Isolated cells were then designated to differential leukocyte count (blood) and flow cytometry analysis of immune cell subsets (immune sites). RESULTS: The data revealed that PSD caused a significant reduction of circulating lymphocytes and a general decrease in all cellular subsets of spleen, mainly T and B cells. However, no alteration in response of PSD was found on other immune sites, such as lymph nodes and peritoneum. Of note, immune cell distribution in response to in vivo LPS stimulation remained unchanged after PSD. CONCLUSIONS: Our study provided original evidence concerning the immune outcomes of PSD, indicating that cellular decrease caused by PSD is not restricted to circulation, but also to immune sites. Taken together, our results could help shed light on the physiological mechanisms of leukocyte trafficking. PMID- 22248724 TI - Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids. AB - OBJECTIVE: Long-term treatment of asthmatic children with low and moderate doses of inhaled corticosteroids (ICS) may result in mild adrenal suppression. Various associations have been shown between adrenal reactivity and single nucleotide polymorphisms (SNPs) related to the hypothalamic-pituitary-adrenal (HPA) axis. We aimed to investigate the genetic contribution of four HPA axis-related SNPs to the individual stress response when on ICS. METHODS: The low dose Synacthen test was performed in 62 asthmatic children (43 males, median age 7.9 years) before and after 3 months of treatment with inhaled fluticasone (200 MUg/day) or budesonide (400 MUg/day). The SNPs determined were: rs1876828 and rs242941 in the corticotropin-releasing hormone receptor 1 (CRHR1) gene, T(-2C) in the promoter region of the melanocortin receptor 2 (MC2R) gene and BclI restriction fragment length polymorphsism in the glucocorticoid receptor (GR) gene. RESULTS: Homozygotes for the variant rs242941 (TT) demonstrated a delayed cortisol response after treatment with ICS compared to heterozygotes (GT) (p = 0.033) and those with the wild-type (GG) genotype (p = 0.018). Homozygotes for the variant rs1876828 (AA) manifested lower baseline cortisol levels before treatment (p = 0.009) compared to the GG genotype and delayed cortisol response after treatment compared to the GA genotype (p = 0.05). BclI heterozygotes for the G allele (GC) demonstrated higher basal cortisol levels before and after treatment with ICS compared to homozygotes (CC) (p = 0.024, p = 0.018). Three SNP interactions were associated with serum cortisol levels. CONCLUSION: There is evidence of a contribution of HPA axis-related genetic variation to the stress response of asthmatic children on ICS. The clinical importance of this finding needs further elucidation. PMID- 22248725 TI - Aquaporin 4 antibodies in the cerebrospinal fluid are helpful in diagnosing Chinese patients with neuromyelitis optica. AB - OBJECTIVE: It was the aim of this study to compare the diagnostic efficiency of anti-aquaporin 4 (AQP4) antibody detection between serum and cerebrospinal fluid (CSF) samples in Chinese patients with central nervous system demyelinating diseases. METHODS: Anti-AQP4 antibodies were detected by a cell-based assay. We calculated the sensitivity, specificity and coherence in 118 patients with neuromyelitis optica (NMO, n = 39), multiple sclerosis (n = 34), longitudinally extensive transverse myelitis (LETM, n = 22), optic neuritis (ON, n = 6), opticospinal multiple sclerosis (n = 8) and acute partial transverse myelitis (n = 9). RESULTS: Forty-four serum samples (33.8%) were positive for anti-AQP4 antibodies. Anti-AQP4 antibody seropositivity was 76.9, 59.1 and 16.7% in patients with NMO, LETM and ON, respectively. Sixty-five CSF samples (50%) were positive for anti-AQP4 antibodies. Anti-AQP4 antibody positivity was 87.1, 81.8, 83.3, 62.5 and 11.8% in patients with NMO, LETM, ON, opticospinal multiple sclerosis and multiple sclerosis, respectively. The kappa value of the coherence test was 0.585 (p < 0.0001) between the two types of samples. The antibody positivity rate was significantly different between the two body fluids (p = 0.0008, McNemar test). The sensitivity and specificity were 74.3 and 100% in serum, 85.7 and 88.2% in CSF, and 94.3 and 88.2% for serum and CSF combined, respectively. CONCLUSION: The sensitivity of anti-AQP4 antibodies in the CSF was higher than that in the serum, and their combined use is helpful in diagnosing Chinese patients with NMO. PMID- 22248726 TI - Immunomodulation of the inflammatory response induced by Androctonus australis hector neurotoxins: biomarker interactions. AB - OBJECTIVE: Androctonus australis hector (Aah) is the most dangerous scorpion in the Maghreb countries. Its venom contains three major neurotoxins (Aah I, Aah II and Aah III), which are responsible for almost all the lethal effects caused in mammals. These toxins act on the voltage-gated sodium channels of excitable cells. The targets and the lethal effects of these toxins have been extensively studied. However, their effects on the induced immune response after envenoming have not deeply elicited. We therefore investigated the effects induced by Aah venom and its toxic components, mainly its main toxin Aah II, on the activation of the inflammatory process. METHODS: Wistar rats were injected by intraperitoneal route with a sublethal dose of Aah venom, FTox-G50, the purified Aah II toxin or with 400 MUl of sterile physiological saline solution. Immunological biomarkers such as MPO, NO and ICAM-1 were analyzed in serum in lung tissue. Cytokine levels were also determined in serum at 3, 6 and 24 h after envenoming. RESULTS: We report in this study that intraperitoneal injection of the venom or its toxins (the whole toxic fraction or Aah II toxin) caused an inflammatory reaction involving increased neutrophil release into blood and neutrophil accumulation in lung tissue. This cell infiltration was associated with the release of NO, histamine, cytokines (IL-1, IL-6, IL-12, IL-4 and IL-5) and ICAM. CONCLUSION: Aah II binding to its targets, in this case Na+ channels, may induce a cascade of events such as inflammatory mediator release and neutrophil migration that could contribute to the exacerbation of the systemic inflammatory response and the development of lung injury following scorpion envenoming. PMID- 22248727 TI - Effector and regulatory T cells in patients with acute optic neuritis. AB - OBJECTIVE: Optic neuritis (ON) is an autoimmune acute demyelinating disease of the optic nerve and may occur in patients with confirmed multiple sclerosis (MS) or as a clinically isolated syndrome. T lymphocytes play a central role in the pathogenesis of MS. The phenotype of different T cell subsets is usually characterized by the expression of distinct cell surface receptors such as CD45RA, CD45RO, CCR7, CD27 and CD28. The aim of this study was to characterize the phenotype of distinct subsets of CD4 and CD8 T cells in patients with isolated ON. METHODS: CD4 and CD8 T cell subsets were characterized by flow cytometry in fresh peripheral blood and cerebrospinal fluid (CSF) samples using the surface markers CD27, CD25, CD45RA, CD45RO and intracellular FOXP3. The T cell subsets expressed in patients with acute ON (n = 64; symptom onset of ON within the preceding 28 days) were compared to those of a gender- and age-matched healthy control (HC) group (n = 32). RESULTS: Both CD4+ and CD8+ naive T cells in the ON group were significantly reduced in the CSF. In contrast, most of the intermediate-stage and late effector CD4+ and CD8+ T cell subsets as well as the CD4+ T regulatory cells were expressed in ON patients, though not at all in the CSF of the HC group. CONCLUSION: These results add important evidence for inflammatory and regulatory activity in ON and early MS. PMID- 22248729 TI - Repeated lipopolysaccharide stimulation induces cellular senescence in BV2 cells. AB - BACKGROUND AND AIM: The dual action of microglia in neurodegenerating diseases has been controversial for some time. Recent studies indicate that microglia senescence might be the key determinant. When microglia age, they function abnormally and fail to respond correctly to stimuli, which eventually promotes neurodegeneration. Accumulating evidence has shown a close relationship between inflammation and aging. Since neuroinflammation is characterized by microglia activation, we assessed if the repeated activation of microglia would lead to senescence. METHOD: The microglia cell line BV2 was repeatedly stimulated every 48 h with lipopolysaccharide (LPS; 10 ng/ml) and senescence was evaluated by beta galactosidase staining and the presence of senescence-associated heterochromatic foci as well as by cell cycle arrest detection by flow cytometry. The senescence associated protein p53 was also detected by Western blot. RESULTS: beta galactosidase staining was barely detectable in control cells, while it tended to increase with repeated LPS stimulation and was positive in most cells after stimulation with LPS 6 times. Similarly, senescence-associated heterochromatic foci were most prominent in cells repeatedly stimulated with LPS, while almost undetectable in control cells or cells receiving a single stimulation. p53 expression was highest in the cells that received LPS stimulation 6 times, and the largest number of cells arrested in the G0/G1 phase was observed in this same group. CONCLUSION: Microglial cells tend to undergo senescence after repeated activation, implying that microglia senescence may start after multiple inflammatory challenges. PMID- 22248730 TI - Predicting the psychophysical similarity of faces and non-face complex shapes by image-based measures. AB - Shape representation is accomplished by a series of cortical stages in which cells in the first stage (V1) have local receptive fields tuned to contrast at a particular scale and orientation, each well modeled as a Gabor filter. In succeeding stages, the representation becomes largely invariant to Gabor coding (Kobatake & Tanaka, 1994). Because of the non-Gabor tuning in these later stages, which must be engaged for a behavioral response (Tong, 2003; Tong et al., 1998), a V1-based measure of shape similarity based on Gabor filtering would not be expected to be highly correlated with human performance when discriminating complex shapes (faces and teeth-like blobs) that differ metrically on a two choice, match-to-sample task. Here we show that human performance is highly correlated with Gabor-based image measures (Gabor simple and complex cells), with values often in the mid 0.90s, even without discounting the variability in the speed and accuracy of performance not associated with the similarity of the distractors. This high correlation is generally maintained through the stages of HMAX, a model that builds upon the Gabor metric and develops units for complex features and larger receptive fields. This is the first report of the psychophysical similarity of complex shapes being predictable from a biologically motivated, physical measure of similarity. As accurate as these measures were for accounting for metric variation, a simple demonstration showed that all were insensitive to viewpoint invariant (nonaccidental) differences in shape. PMID- 22248728 TI - Neuroinflammation: a common pathway in CNS diseases as mediated at the blood brain barrier. AB - The blood-brain barrier (BBB) is not simply a physical barrier but a regulatory interface between the central nervous system (CNS) and immune system. The BBB both affects and is affected by the immune system and connects at many levels with the CNS, including the following: (1) the BBB transports cytokines and secretes various substances with neuroinflammatory properties; (2) transporters are altered in disease states including traumatic injury, Alzheimer's disease and inflammatory processes; (3) cytokines and other immune secretions from the cells comprising the BBB are both constitutive and inducible; (4) immune cells are transported across the BBB by the highly regulated process termed diapedesis, which involves communication and interactions between the brain endothelial cells and the immune cells; (5) the neuroimmune system has various effects on the BBB, including modulation of important transport systems and in extreme pathological conditions even disruption of the BBB, and (6) the brain-to-blood efflux transporter P-glycoprotein is altered in inflammatory conditions, thus affecting drug delivery to the brain. In summary, the BBB is an interactive interface that regulates and defines many of the ways that the CNS and the immune system communicate with one another. PMID- 22248731 TI - Regulation of chemoresistance via alternative messenger RNA splicing. AB - The acquisition of resistance to chemotherapy is a significant problem in the treatment of cancer, greatly increasing patient morbidity and mortality. Tumors are often sensitive to chemotherapy upon initial treatment, but repeated treatments can select for those cells that were able to survive initial therapy and have acquired cellular mechanisms to enhance their resistance to subsequent chemotherapy treatment. Many cellular mechanisms of drug resistance have been identified, most of which result from changes in gene and protein expression. While changes at the transcriptional level have been duly noted, it is primarily the post-transcriptional processing of pre-mRNA into mature mRNA that regulates the composition of the proteome and it is the proteome that actually regulates the cell's response to chemotherapeutic insult, inducing cell survival or death. During pre-mRNA processing, intronic non-protein-coding sequences are removed and protein-coding exons are spliced to form a continuous template for protein translation. Alternative splicing involves the differential inclusion or exclusion of exonic sequences into the mature transcript, generating different mRNA templates for protein production. This regulatory mechanism enables the potential to produce many different protein isoforms from the same gene. In this review I will explain the mechanism of alternative pre-mRNA splicing and look at some specific examples of how splicing factors, splicing factor kinases and alternative splicing of specific pre-mRNAs from genes have been shown to contribute to acquisition of the drug resistant phenotype. PMID- 22248733 TI - Antioxidants for prostate cancer chemoprevention: challenges and opportunities. AB - Extensive research has led to the firm conclusion that antioxidants protect cells from damage caused by oxidative stress and its associated pathological conditions including inflammation. It has also been established that inflammation is a precursor in neoplastic transformation of the prostate. Although, a vast body of experimental and clinical evidence shows efficacy of antioxidants as preventive strategies for prostate cancer, there is a lack of consistent agreement in outcomes especially from recent large-scale randomized clinical trials. Despite these concerns, our understanding of the preventive mechanisms as well as clinical efficacy and safety data indicate that novel antioxidant therapeutics still hold great promise for prostate cancer chemoprevention. We propose that for effective use of antioxidants for prostate cancer prevention, further high impact translational research is needed with special attention on selecting those patients who will benefit from such intervention. Therefore, it is important to validate predictive biomarkers from successful trials and combine this with knowledge of preclinical characterization of antioxidants (and combinations) that will eventually facilitate the development of 'personalized prostate cancer chemoprevention'. In this review, we briefly describe some common and emerging antioxidants that have shown benefits in preclinical and clinical settings. Above all, we focus on summarizing the progress we made thus far in prostate cancer chemoprevention using antioxidants, the heightened interest and challenges in the future. PMID- 22248734 TI - Pyrosequencing-based validation of a simple cell-suspension polymerase chain reaction assay for Campylobacter with application of high-processivity polymerase and novel internal amplification controls for rapid and specific detection. AB - Although Campylobacter is an important food-borne human pathogen, there remains a lack of molecular diagnostic assays that are simple to use, cost-effective, and provide rapid results in research, clinical, or regulatory laboratories. Of the numerous Campylobacter assays that do exist, to our knowledge none has been empirically tested for specificity using high-throughput sequencing. Here we demonstrate the power of next-generation sequencing to determine the specificity of a widely cited Campylobacter-specific polymerase chain reaction (PCR) assay and describe a rapid method for direct cell suspension PCR to quickly and easily screen samples for Campylobacter. We present a specific protocol which eliminates the need for time-consuming and expensive genomic DNA extractions and, using a high-processivity polymerase, demonstrate conclusive screening of samples in <1 h. Pyrosequencing results show the assay to be extremely (>99%) sensitive, and spike-back experiments demonstrated a detection threshold of <10(2) CFU mL(-1). Additionally, we present 2 newly designed broad-range bacterial primer sets targeting the 23S rRNA gene that have wide applicability as internal amplification controls. Empirical testing of putative taxon-specific assays using high-throughput sequencing is an important validation step that is now financially feasible for research, regulatory, or clinical applications. PMID- 22248735 TI - Evaluation of a novel commercial rapid test for dengue diagnosis based on specific IgA detection. AB - The performance of the novel commercial test ASSURE(r) Dengue IgA Rapid test (MP Diagnostics) was evaluated using a panel of 172 sera collected from dengue patients and 47 sera from healthy blood donors. The overall specificity and sensitivity were 61.0% and 85.1%, respectively. However, the positivity rate for IgA went from 33.3% for sera collected the same day of fever onset to 81.2% for sera collected 5 days after fever onset. Infections with serotype 2 viruses were detected more efficiently than those with serotype 1 viruses, and no sera from infections with serotypes 3 and 4 were available. In addition, the kit was twice more efficient at detecting secondary infections than at detecting primary infections. Finally, the ASSURE(r) test showed good repeatability and reproducibility. The results of this study suggest that the ASSURE(r) Dengue IgA Rapid test may become a useful and easy-to-use test for early dengue diagnosis. PMID- 22248736 TI - Diagnostic significance of hepatitis B viral antigens in patients with glomerulonephritis-associated hepatitis B virus infection. AB - Hepatitis B viral infection can lead to hepatitis B virus-associated glomerulonephritis, a clinically significant subtype of secondary nephritis. In the present study, we examined the presence of PreS1/S2 antigen in renal tissues by use of immunohistochemistry and investigated the use of PreS1/S2 and 2 HBV serum antigens, HBe-Ag and HBs-Ag, in the diagnosis. We assessed the presence of these 3 antigens in patients with confirmed hepatitis B virus-associated glomerulonephritis (n = 22) and patients without this disease (n = 19). Our results indicate that the combined use of PreS1/S2-Ag and serum HBe-Ag in the diagnosis of hepatitis B virus-associated glomerulonephritis had good positive predictive value (0.89), modest negative predictive value (0.77), and substantial agreement based on Cohen's kappa coefficient (kappa = 0.660, P < 0.001). We suggest that our results be considered in the development of more definitive diagnostic criteria for hepatitis B virus-associated glomerulonephritis. PMID- 22248737 TI - Development of an ultrasensitive polymerase chain reaction-amplified immunoassay based on mycobacterial RD antigens: implications for the serodiagnosis of tuberculosis. AB - Immuno-polymerase chain reaction (I-PCR) combines the versatility of enzyme linked immunosorbent assay (ELISA) with the exponential amplification power of PCR. The present study was designed to detect antibodies to Mycobacterium tuberculosis complex-specific region of difference (RD) antigens, i.e., early secretory antigenic target-6, culture filtrate protein-10, culture filtrate protein-21, and mycobacterial protein from species tuberculosis-64, as well as antigens in pulmonary tuberculosis patients by I-PCR assay. We could detect ESAT 6 and other RD antigens up to 0.1 fg by I-PCR assay, thus resulting in 10(7) times higher sensitivity than that observed with ELISA. With paired sample analysis based on the detection of antibodies in serum and antigens in sputum of the same individual, the sensitivity of RD multi-antigen cocktail-based I-PCR assay was 72% in smear-negative cases and 91% in smear-positive cases of pulmonary tuberculosis with high specificity values. In extrapulmonary tuberculosis patients, higher sensitivity was observed by detecting cocktail of antigens by I-PCR assay as compared to sensitivity earlier observed in the same samples by ELISA. PMID- 22248738 TI - Explaining health inequality: evidence from the UK. PMID- 22248732 TI - Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. AB - Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed "side population cells," which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the "side population" phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured. PMID- 22248739 TI - Long-term treatment outcome of minor salivary gland carcinoma of the hard palate. AB - Minor salivary gland carcinoma of the hard palate is rare, and its long-term survival rate is high, making it difficult to evaluate the prognostic factors and the efficacy of treatment. This study was designed to evaluate the treatment outcome of minor salivary gland carcinoma of the hard palate. 103 cases of minor salivary gland carcinoma of the hard palate treated with surgery alone or underwent surgery combined with post-operative radiotherapy hospitalized in Cancer Center, Sun Yet-Sen University, from 1968 to 2008 were reviewed retrospectively. The most common histologic types were adenoid cystic carcinoma in 48 patients(46.6%), mucoepidermoid carcinoma in 37(35.92%), malignant mixed tumor in 15(14.56%), and acinic cell carcinoma in 3(2.91%). The median follow-up time was 74.83 months (range 0.9-356.57 months). Overall outcomes at 5 and 10 years were overall survival (OS), 77.9% and 65.7%; recurrence-free survival (RFS), 64.4% and 53.2%; and disease specific survival (DSS), 77.9% and 67.7%, respectively. There was no significant difference in overall survival (P=0.52), recurrence-free survival (P=0.762) and disease specific survival (P=0.449) between patients who underwent surgery alone and those who underwent surgery plus post-operative radiotherapy. Surgery has been accepted as the primary treatment for minor salivary gland carcinoma of hard palate. Sufficient surgical excision with adequate margins is essential for a favorable outcome. We advocate using radiotherapy in the post-operative context for patients with poorly differentiated, cervical lymph node metastasis, positive or close margins, and large primary lesions. PMID- 22248742 TI - [Hemodynamics: from monitoring to therapy]. PMID- 22248741 TI - T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space? AB - T-cell proliferation rates in vitro depend on factors including initial T-cell number, dose of stimulus, culture time, and available physical space. The role of forkhead box P3 (FoxP3) in the identification of T cells with a regulatory phenotype remains controversial in humans. Through 5-carboxyfluorescein diacetate succinimidyl ester labeling of human T cells and subsequent culture of different numbers of T cells and antigen-presenting cells (APC), we studied proliferative T cell responses and FoxP3 expression in divided T cells. T-cell proliferation rates depended on initial T-cell/APC numbers. Proliferation rates decreased when high initial T-cell numbers were increased. FoxP3 expression was expressed exclusively in virtually all divided T cells cultured at high T-cell densities, irrespective of their CD4 nature or cytokine content, and was coexpressed with T bet. However, when T cells were cultured on larger surfaces or at lower initial numbers, FoxP3 expression was not induced in divided T cells, even when most of the cells had undergone cell division. FoxP3(+) T cells generated at high cell densities did not elicit a suppressive phenotype and FoxP3 expression was subsequently lost in time when the stimulus was removed. Therefore, caution should be observed in the use of FoxP3 expression to identify regulatory T cells in humans because its expression may be only a consequence of activation status in a restricted environment. PMID- 22248743 TI - [Advancements in critical care medicine]. PMID- 22248744 TI - [A controversial understanding in the therapy of anti-septic shock]. PMID- 22248740 TI - AHI-1: a novel signaling protein and potential therapeutic target in human leukemia and brain disorders. AB - Progress in the understanding of the molecular and cellular mechanisms of human cancer, including human leukemia and lymphomas, has been spurred by cloning of fusion genes created by chromosomal translocations or by retroviral insertional mutagenesis; a number of oncogenes and tumor suppressors involved in development of a number of malignancies have been identified in this manner. The BCR-ABL fusion gene, originating in a multipotent hematopoietic stem cell, is the molecular signature of chronic myeloid leukemia (CML). Discovery of this fusion gene has led to the development of one of the first successful targeted molecular therapies for cancer (Imatinib). It illustrates the advances that can result from an understanding of the molecular basis of disease. However, there still remain many as yet unidentified mutations that may influence the initiation or progression of human diseases. Thus, identification and characterization of the mechanism of action of genes that contribute to human diseases is an important and opportune area of current research. One promising candidate as a potential therapeutic target is Abelson helper integration site-1(Ahi-1/AHI-1) that was identified by retroviral insertional mutagenesis in murine models of leukemia/lymphomas and is highly elevated in certain human lymphoma and leukemia stem/progenitor cells. It encodes a unique protein with a SH3 domain, multiple SH3 binding sites and a WD40-repeat domain, suggesting that the normal protein has novel signaling activities. A new AHI-1-BCR-ABL-JAK2 interaction complex has recently been identified and this complex regulates transforming activities and drug resistance in CML stem/progenitor cells. Importantly, AHI-1 has recently been identified as a susceptibility gene involved in a number of brain disorders, including Joubert syndrome. Therefore, understanding molecular functions of the AHI-1 gene could lead to important and novel insights into disease processes involved in specific types of diseases. Ultimately, this knowledge will set the stage for translation into new and more effective diagnostic and treatment strategies. PMID- 22248745 TI - [The effect of an optimized resuscitation strategy on prognosis of patients with septic shock: a systematic review]. AB - OBJECTIVE: To determine the treatment effect of an optimized resuscitation strategy on prognosis of patients with septic shock. METHODS: A systematic review of MEDLINE, the Cochrane Library, EMBASE, CBM, CNKI and other sources using a comprehensive strategy was conducted. All randomized controlled trials (RCTs) of treatment of severe sepsis and septic shock were included. The patients were randomized into treatment group and control group. Preplanned subgroup analysis required studies to be categorized based on early (goal-directed therapy accomplished within 6-24 hours) vs. late (initiated after 24 hours or unknown time of resuscitation implementation). Two authors independently extracted data and assessed study quality using standardized methods. Consensus was reached by conference. The Cochrance Collaboration's software RevMan 5.0 was used for data analysis. RESULTS: Eleven studies were included in the final analysis, providing a sample of 2066 patients. The combined results demonstrated a decrease in mortality [odds ratio (OR) = 0.63, 95% confidence interval (95%CI) 0.48-0.84, P = 0.002]; however, there was statistically significant heterogeneity [P = 0.01, I(2) = 55%]. Among the early optimal resuscitation studies (n = 8) there was minimal heterogeneity [P = 0.44, I(2) = 0%] and a significant decrease in mortality (OR = 0.53, 95%CI 0.42-0.66, P < 0.00001) and incidence of multiple organ dysfunction syndrome (MODS, OR = 0.61, 95%CI 0.43-0.85, P = 0.004). For the late resuscitation studies (n = 3), there was statistically significant difference [P = 0.05, I (2)=66%], and there was no significant effect on mortality (OR = 0.89, 95%CI 0.52-1.54, P = 0.68) and incidence of MODS (OR = 0.43, 95%CI 0.17-1.08, P = 0.07). CONCLUSION: This meta-analysis found that the application of an early optimal resuscitation strategy to patients with septic shock imparts a significant reduction in mortality and incidence of MODS. PMID- 22248746 TI - [Influence of albumin as a resuscitation fluid on the prognosis of patients with sepsis: a Meta-analysis]. AB - OBJECTIVE: To compare the effect of albumin as a resuscitation fluid with other fluids in lowering the mortality of patients with sepsis. METHODS: By searching MEDLINE, Embase, Cochrane Central Registration of Controlled Trials databases, the metaRegister of Controlled Trials, the Medical Editors Trial Amnesty Register, and retrieval of the randomized controlled trial (RCT) literature to compare the result of resuscitation using albumin-containing fluid and other fluids. The study population included adult patients who were diagnosed to have sepsis, and the patients with sepsis who were studied as subgroup. The RevMan 5.0 software was used for Meta-analysis, and the main outcome was the mortality of the hospitalized patients. RESULTS: In the 14 RCTs, 1729 patients received the albumin-containing fluid resuscitation or resuscitation with other fluids. It was found that the patients with sepsis were the only research objects in five studies, and in other nine studies patients with sepsis were studied as subgroup. P = 0.98, I (2)=0%, i.e. no heterogenicity, and the fixed effect model was used for combining results. There was no evident difference between the group of patients with sepsis resuscitated by albumin-containing fluids and other fluids [odds ratio (OR) was 0.87, 95% confidence interval (95%CI) 0.71-1.07, P = 0.18]. The pooled OR of resuscitation using high concentration albumin solution (20%) was 1.11, 95%CI 0.71-1.73, P = 0.65, the pooled OR of resuscitation using low concentration albumin solution (4%, 5%) was 0.82, 95%CI 0.65-1.03, P = 0.09. Resuscitation with different concentration of albumin-containing fluids was identical with the whole research results. After rejecting six articles of Boldt and other authors, and also saline versus albumin fluid evaluation (SAFE) study, the sensitivity analysis of the study was performed in order to check whether the data produced decisive significance to the whole research results or not. The whole results did not change after their rejection(Boldt studies were rejected:OR 0.82, 95%CI 0.65-1.02, P = 0.08; SAFE study was rejected: OR 1.05, 95%CI 0.71 1.55, P = 0.82). Therefore the analysis results were satisfactory. CONCLUSION: The Meta-analysis shows that by using albumin-containing fluids for resuscitation can not lower the mortality of sepsis as compared with other fluids. PMID- 22248747 TI - [Short-term intensive glucose control in patients with severe acute pancreatitis]. AB - OBJECTIVE: To investigate effects of intensive glucose control (IGC) on glucose variability (GV) and clinical outcomes in patients with severe acute pancreatitis (SAP), and to assess predictive values of different measures of GV on intensive care unit (ICU) death. METHODS: A prospective, randomized, non-blinded clinical trial was conducted. All adult patients with diagnosis of SAP, who were admitted to ICU of West China Hospital between July 1st 2010 and July 1st 2011, were enrolled. Eligible patients were randomly assigned to receive either IGC to maintain glucose level between 6.1 mmol/L and 8.3 mmol/L or control group (none intervention was given). GV, ICU mortality, the incidence of infection, length of mechanical ventilation and ICU stay of the two groups were compared. The standard deviation of blood glucose level [GLU(SD)], mean amplitude of glycemic excursion [GLU(MAGE)] and glycemic lability index [GLU(GLI)] were chosen as measures of GV to analyze the multi variable correlation between them and ICU mortality, and the ability of these three parameters was assessed in predicting ICU death using area under a receiver operating characteristic curve (AUC). RESULTS: One hundred and twenty-two patients were eligible for the study, and 30 patients with SAP were enrolled in the study, with 15 cases in each group. The basic data of the two groups were comparable. Compared with control group, IGC showed an effect to reduce GV, including GLU(SD) [mmol/L: 1.81 (0.97, 2.65) vs. 2.48 (1.29, 2.87)], GLU(MAGE) [mmol/L: 3.76 (3.67, 5.85) vs. 5.30 (4.35, 6.80)], GLU(GLI) [306.8 (220.6, 613.3) vs. 339.5 (218.4, 423.1)], and lower ICU mortality (13.3% vs. 40.0%), but the difference showed no significant difference (all P > 0.05). It could also shorten the length of ICU stay (days: 11.3 +/- 9.9 vs. 15.8 +/- 7.6, P < 0.01), decrease the incidence of infection of blood stream and the lung (6.7% vs. 40.0%; 33.3% vs. 73.3%, both P < 0.05). A positive correlation between GLU(GLU) and ICU mortality was found (r = 0.371, P = 0.044), but no correlation was found between GLU(SD) or GLU(MAGE) and ICU mortality (r value was -0.144 and 0.065, P value was 0.448 and 0.731). AUC for GLU(SD), GLU(MAGE) and GLU(GLI) was 0.594 [95% confidence interval (95%CI) 0.382-0.805], 0.543 (95%CI 0.287-0.798) and 0.751 (95%CI 0.548-0.954) respectively, and GLU(GLI) was the best predictor of ICU death. CONCLUSIONS: IGC had an effect to reduce GV, decrease ICU mortality, shorten length of ICU stay, and lower the incidence of infection. Compared with GLU(SD) and GLU(MAGE), GLU(GLI) was the best predictor of ICU death. PMID- 22248748 TI - [The occurrence of hypophosphatemia and its prognostic value in intensive care unit patients]. AB - OBJECTIVE: To investigate the occurrence of hypophosphatemia in intensive care unit (ICU) patients, and to study the influence of different levels of phosphorus on the prognosis of patients. METHODS: One hundred and forty-seven patients admitted to Shengjing Hospital during April to November in 2010 were enrolled. The serum phosphorous level was measured consecutively, and the incidence of hypophosphatemia was observed. Acute physiology and chronic health evaluation II (APACHE II ) score, length of ICU-stay, the main laboratory findings and mortality were compared among patients with different serum phosphate levels. Receiver operating characteristic curve (ROC curve) was plotted according to the serum phosphate level and the survivability of patients to study the prognostic value of serum phosphate level in the ICU patients. RESULT: A large number of ICU patients (77.6%) had developed hypophosphatemia, mild in 21, midrange in 70, and marked in 23, amounting to 63.3% of patients suffering from medium and marked hypophosphatemia. The APACHE II score, duration of artificial ventilation (days), length of ICU-stay (days) as well as mortality rate were higher in hypophosphatemia patients compared with those of the normal group (APACHE II score: mild 18.2 +/- 6.0, midrange 21.4 +/- 7.6, marked 25.6 +/- 8.8, normal 18.9 +/- 8.8; length of artificial ventilation: mild 6.6 +/- 5.1, midrange 11.3 +/- 9.5, marked 15.7 +/- 10.4, normal 6.7 +/- 5.9; length of ICU-stay: mild 9.7 +/- 6.4, medium 10.6 +/- 8.2, marked 18.9 +/- 13.1, normal 9.9 +/- 7.1; mortality rate: mild 14.3%, medium 25.7%, marked 39.1%, normal 9.1%). The mortality of ICU patients (22.4%) was negatively correlated with the degree of hypophosphatemia (r = -0.225, P = 0.01). The serum phosphate level had a prognostic value when it was less than 0.40 mmol/L, with sensitivity of 78.6%, specificity of 51.5%. CONCLUSIONS: For most of ICU patients, the serum phosphorus is at a relatively low level. ICU patients have multiple risk factors to develop hypophosphatemia and severe hypophosphatemia is a predictor of a poor prognosis. PMID- 22248749 TI - [A clinical study of pituitrin versus norepinephrine in the treatment of patients with septic shock]. AB - OBJECTIVE: To investigate whether pituitrin can lower 28-day mortality as compared with treatment with norepinephrine (NE) in patients with septic shock. METHODS: Randomized, controlled, open-label trial was conducted. One hundred and thirty-nine septic shock patients with dopamine requirements exceeding 5 MUg*kg( 1)*min(-1) were divided at random into two groups as the study group and control group. All patients enrolled were treated by the same treatment principle and measures. In patients of study group injection of pituitrin 0.017-0.042 U/min (1.0- 2.5 U/h) was given, and if hemodynamics was still unstable, catecholamines was added to obtain the target blood pressure; while in the control group catecholamines was given to maintain stability of hemodynamics. RESULTS: Among 139 patients enrolled in the study, 66 composed of the clinical study group and 73 in the control group. The main principle of the treatment in the two groups was similar. There was no significant difference in overall 28-day mortality rate between study group and control group (40.9% vs. 46.6%, P > 0.05). In patients whose acute physiology and chronic health evaluation II ( APACHE II ) score was less than 25, the mortality of study group was significantly lower than that of control group [10.3% (3/29) vs. 35.7% (10/28), P < 0.05]. The length of stay in intensive care unit [ICU, days: 5(3,8) vs. 5(3,8)], and duration of mechanical ventilation [days: 4.0 (2.8, 6.0) vs. 4.0 (2.0, 5.0)] were similar in two groups (both P > 0.05). The dosage of NE (MUg/min: 7.99 +/- 5.02 vs. 10.12 +/- 5.12) and heart rate (beat/min: 93.27 +/- 7.84 vs. 108.45 +/- 12.31) were significantly lower in study group compared with that of control group (both P < 0.05). Serum creatinine and lactate levels in the two groups were similar at baseline, and creatinine [MUmol/L: 87.5 (62.8, 157.0) vs. 76.0 (52.5, 117.0)] and lactate level (mmol/L: 3.72 +/- 2.47 vs. 3.53 +/- 1.86) were still similar in two groups 24 hours later (all P > 0.05). The rate of use of glucocorticoid (43.9% vs. 31.5%) and heparin in small dosage (42.4% vs. 41.1%) had no significant difference between two groups (both P > 0.05). CONCLUSIONS: Combined use of pituitrin in patients with septic shock can reduce the dosage of catecholamines, and decrease the heart rate. Although it can not lower the overall mortality of septic shock, among patients with less severity whose APACHE II score lower than 25, low-dose pituitrin in conjunction with catecholamine vasopressors can reduce 28-day mortality . PMID- 22248750 TI - [The influence of lactate Ringer solution versus hydroxyethyl starch on coagulation and fibrinolytic system in patients with septic shock]. AB - OBJECTIVE: To investigate the influence of lactate Ringer solution (RL) versus hydroxyethyl starch 130/0.4 (HES130/0.4) solution on coagulation and fibrinolytic system in the patients with septic shock. METHODS: Forty-two consecutive patients with septic shock diagnosed between September 2009 and June 2011 were randomized to two study groups: RL resuscitation group (RL group) with 20 patients, and HES130/0.4 resuscitation group (HES group) with 22 patients. In all of them peripheral blood was collected at four points of time: before resuscitation, 6, 12, 24 hours after resuscitation, and then prothrombin time (PT), activated partial thromboplastin time (APTT) and levels of plasma tissue plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI) were determined. Meanwhile, the patients' outcome and the length of intensive care unit stay (ICU LOS) were recorded. RESULTS: ICU-LOS (days) in HES group was significantly shorter than the RL group (12.5 +/- 8.8 vs. 17.1 +/- 16.6, P < 0.01). Meanwhile, the volume of fluid (L: 2.77 +/- 0.59) as well as vasoactive drugs [MUg*kg( 1)*min(-1): 0.56 +/- 0.15] used in the HES group were significantly lower than RL group (3.46 +/- 0.73, 0.81 +/- 0.41, both P < 0.01). In RL group, 12 patients died and 8 patients survived, while in HES group, 7 patients died and 15 patients survived, showing no difference between two groups. PT, APTT and the levels of t PA showed no significant differences between two groups at different time points, but the levels of plasma PAI (MUg/L) of the HES group decreased gradually, and was significantly lower than that before resuscitation and RL group at 24 hours after resuscitation (41.76 +/- 25.95 vs. 89.11 +/- 14.27, 55.08 +/- 35.43, both P < 0.05). CONCLUSIONS: Both RL and HES130/0.4 fluid resuscitation did not affect the outcome of the patients with septic shock, but the resuscitation efficiency of HES130/0.4 is much better than RL. Both type of fluids did not show the effect on coagulability of the septic patients, but colloid fluid resuscitation may protect the vascular endothelial cell, reduce the inhibition of fibrinolytic system, and alleviate hypercoagulability state of patients in early stage. PMID- 22248751 TI - [The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia]. AB - OBJECTIVE: To observe the clinical effects of 10%, 30% lactate clearance rate and early goal-directed therapy (EGDT) as 6-hour resuscitation goals directing treatment in septic shock patients with severe pneumonia. METHODS: In this randomized, perspective study, septic shock patients with severe pneumonia were divided into control group and experimental group, which included 10% lactate clearance rate group and 30% lactate clearance rate group, adopting random number method. The control group was treated with 6-hour EGDT strategy, and the experimental groups were treated with 10% lactate clearance rate protocol and 30% lactate clearance rate protocol respectively, beside the EGDT. RESULTS: There were 19 patients in control group, and 43 patients in experimental group, which included 22 patients in 10% lactate clearance rate group and 21 patients in 30% lactate clearance rate group. Patients were well matched by basic features. After 48 hours, the acute physiology and chronic health evaluation II (APACHE II ) score of both 10% lactate clearance rate group (13.76 +/- 6.00, P < 0.05) and 30% lactate clearance rate group (13.60 +/- 6.18, P < 0.05) were lower than that of control group (18.15 +/- 6.62). There were no differences in time of mechanical ventilation (hours) between control group and experimental group (10% group 136.90 +/- 100.02, 30% group 97.00 +/- 75.20, control group 152.32 +/- 96.51, P > 0.05). The length in intensive care unit (ICU, days) of 10% and 30% lactate clearance rate groups were significantly shorter than control group (10% group 7.94 +/- 6.00, 30% group 7.51 +/- 3.99, control group 11.31 +/- 5.97, both P < 0.05). The three groups had no differences in 7-day mortality rate (10% group 18.18%, 30% group 14.29%, control group 21.05%, all P > 0.05), but the 28-day mortality of 10% and 30% lactate clearance rate groups were significantly lower than control group (10% group 36.36%, 30% group 28.57%, control group 63.16%), especially in 30% lactate clearance rate group (P < 0.05). CONCLUSION: For the septic shock patients with severe pneumonia, prompt archiving EGDT strategy and 6 hour lactate clearance more than 30% were associated with an optimal outcome. PMID- 22248752 TI - [The clinical application and value of intra-aortic balloon pump in patients with septic shock]. AB - OBJECTIVE: To investigate the clinical efficacy and value of intra-aortic balloon pump (IABP) with vasoactive drugs for septic shock patients. METHODS: A method of single-centre registry was conducted. Data were collected from 78 consecutive septic shock patients in late stage in intensive care unit (ICU) of Beijing Shijitan Hospital diagnosed between July 2006 and October 2010. With the consent of family members of the patients, they were divided into two groups: group A, in whom only vasoactive drugs were used (dopamine + norepinephrine treatment, n = 39), and group B, in whom vasoactive drugs were used combined with IABP (dopamine + norepinephrine + IABP therapy, n = 39). Before and after treatment of two groups, hemodynamic and tissue perfusion monitoring were executed. At the same time, the shock recovery time, the doses of vasoactive drugs, length of ICU stay, and mortality within 28 days were observed. RESULTS: There was no significant difference in all above parameters between two groups. After treatment, heart rate, blood pressure and heart function parameters were significantly improved compared with those before treatment. In group B, mean arterial pressure (MAP, mm Hg,1 mm Hg = 0.133 kPa) 24 hours and 72 hours after IABP, cardiac index [CI, L*min(-1)* m(-2)] after 48 hours of IABP, and in 2 hours after termination of IABP, dopamine dosage [MUg*kg(-1)*min(-1)] in 24, 48, 72 hours after IABP and 2 hours after termination were significantly improved than those in group A (MAP: 53.0 +/- 6.3 vs. 52.1 +/- 6.2, 65.6 +/- 4.3 vs. 65.0 +/- 2.1; CI: 3.40 +/- 0.20 vs. 3.30 +/- 0.50, 3.60 +/- 0.30 vs. 3.60 +/- 0.30; dopamine dosage: 17.5 +/- 1.2 vs. 17.6 +/- 1.3, 10.2 +/- 1.3 vs. 12.8 +/- 1.6, 5.8 +/- 1.5 vs. 6.8 +/- 1.7, 3.0 +/- 0.7 vs. 4.1 +/- 1.3, P < 0.05 or P < 0.01). Compared with group A, shock recovery time (days) of group B was significantly shorter (10.4 +/- 2.2 vs. 14.1 +/- 3.4, P < 0.01) than that of group A; mortality within 28 days was significantly lower (34.1% vs. 45.6%, P < 0.01) in group B; length of ICU stay of two groups showed no significant difference between two groups. CONCLUSIONS: IABP in patients with septic shock significantly improved hemodynamics, increased coronary and systemic tissue perfusion, reduced cardiac afterload, elevated CI, reduced doses of vasoactive drugs, shortened length of ICU stay, improved prognosis, and lowered the mortality rate. IABP had important clinical value, and could be recommended as an additional treatment option in patients with septic shock in whom the effect of drug was poor. PMID- 22248753 TI - [The association between early blood glucose fluctuation and prognosis in critically ill patients]. AB - OBJECTIVE: To investigate the association between early blood glucose level fluctuation and prognosis of critically ill patients. METHODS: A retrospective study involving 95 critically ill patients in intensive care unit (ICU) was conducted. According to the 28-day outcome after admission to ICU, the patients were divided into nonsurvivors (43 cases) and survivors (52 cases), and the blood glucose level in them was monitored in the first 72 hours. Blood glucose concentration at admission (BGadm), mean blood glucose level (MBG), hyperglycemia index (HGI), glycemic lability index (GLI), incidence of hypoglycemia and total dosage of intravenous insulin for each patient were compared. The index as an independent risk factor of mortality was determined by multivariate logistic regression analysis and the predictor value by comparing the area under the receiver operating characteristic curve (ROC curve, AUC) of each index. RESULTS: The BGadm (mmol/L), MBG (mmol/L), HGI and the incidence of hypoglycemia showed no significant differences between nonsurvivors and survivors [BGadm: 9.87 +/- 4.48 vs. 9.26 +/- 3.07, MBG: 8.59 +/- 1.23 vs. 8.47 +/- 1.01, HGI(6.0): 2.45 +/- 0.94 vs. 1.68 +/- 1.05, HGI(8.3): 0.84 +/- 0.70 vs. 0.68 +/- 0.51, the incidence of hypoglycemia: 9.30% vs. 5.77%, all P > 0.05], but acute physiology and chronic health evaluation II (APACHE II ) score, GLI and the total dosage of intravenous insulin (U) were significantly higher in nonsurvivors than survivors [APACHE II score: 23 +/- 6 vs. 19 +/- 6, GLI: 56.96 (65.43) vs. 23.87 (41.62), the total dosage of intravenous insulin: 65.5 (130.5) vs. 12.5 (90.0), all P < 0.05]. Multivariate logistic regression analysis showed that APACHE II score and GLI were both independent risk factors [APACHE II score: odds ratio (OR) = 1.09, 95% confidence interval (95%CI) 1.01-1.17; GLI: OR = 1.03, 95%CI 1.01-1.06, both P < 0.05]. When ROC curve was plotted, the AUC of APACHE II score and GLI was respectively 0.69 and 0.71, and there was no significant difference (P > 0.05). CONCLUSIONS: Early fluctuation of blood glucose is a significant independent risk factor of mortality in critically ill patients. Control the early fluctuation of blood glucose concentration might improve the patients' outcome. PMID- 22248755 TI - [The application of tissue partial pressure of carbon dioxide in monitoring hemorrhagic shock]. PMID- 22248754 TI - [The correlation between brain natriuretic peptide and invasive hemodynamic parameters and their value in prognosis of patients with noncardiac shock]. AB - OBJECTIVE: To examine the correlation between the plasma level of brain natriuretic peptide (BNP) and the hemodynamic parameters collected through Swan Ganz flowing balloon catheter procedure in patients with noncardiac shock, in order to evaluate the potential for BNP to be used as prognostic indicator. METHODS: The plasma BNP and invasive hemodynamic parameters data [central venous pressure (CVP), pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO)] were collected from 21 noncardiac shock patients received Swan-Ganz catheterization throughout a continuous surveillance for 3 days. The BNP, CVP, PAP, PCWP, CO in survivors (n = 8) and non-survivors (n = 13) were compared and the correlation between the value of BNP and the invasive hemodynamic parameters were analyzed using multiple regression. RESULTS: The mean value of BNP (ng/L) was significantly higher in non-survivors (708.06 +/- 242.58 vs. 317.05 +/- 140.21, P < 0.05). In day 1, no significant difference was found in any hemodynamic parameters between non-survivors and survivors. But in day 3, the non-survivors were found to have significantly higher CVP (mm Hg, 1 mm Hg = 0.133 kPa: 13.64 +/- 4.00 vs. 9.92 +/- 1.26, P < 0.05) and lower CO (L/min: 4.61 +/- 2.06 vs. 6.95 +/- 1.28, P < 0.05). The differences in PAP (mm Hg: 20.84 +/- 8.48 vs. 16.82 +/- 4.97) and PCWP (mm Hg: 13.60 +/- 5.71 vs. 12.72 +/- 4.98) remained insignificant (both P > 0.05) between the two groups. The correlation between BNP and the invasive hemodynamic parameters was modest there was no correlation between BNP and CVP, PAP, PCWP, CO (r = 0.157, 0.306, 0.229, -0.269, P = 0.16, 0.25, 0.09, 0.12). CONCLUSIONS: In patients with shock, both plasma BNP and invasive hemodynamic examination showed certain prognostic value. But in noncardiac shock cases, the increased BNP did not correlate with heart function, therefore it could not replace the Swan-Ganz catheter data to guide the treatment in these patients. PMID- 22248756 TI - Fetoscopic release of an amniotic band with risk of amputation: case report and review of the literature. AB - Amniotic bands can cause limb amputation as well as intrauterine fetal demise. Fetoscopic release of amniotic bands has been shown to rescue limb function. Herein, we describe an interesting case of an amniotic band wrapped around the right forearm as well as the umbilical cord, which was released by fetoscopy. Following the procedure, the blood flow in the forearm was restored and the edema gradually reduced. Full functionality of the arm was confirmed after birth, though the esthetic problem of the imprint of the band on the arm persisted. Furthermore, we review the available literature regarding fetoscopic interventions in amniotic band syndrome. PMID- 22248757 TI - The Riata story-where are we now? PMID- 22248758 TI - Application of the soluble salt-assisted route to scalable synthesis of ZnO nanopowder with repeated photocatalytic activity. AB - In this paper, the soluble salt-assisted route has been extended to the low-cost and scalable preparation of ZnO nanostructures via the simple oxidation of Zn Na2SO4 mixture followed by washing with water. The as-prepared ZnO nanopowders are of nanoscaled size, hexagonal phase, and pure, without being stained by Na2SO4. Their optical band gap is 3.22 eV, exhibiting a red-shift of 0.15 eV in comparison with pure ZnO bulk, and their optical absorbance is strong in the region of 200-400 nm, suggesting their full utilization of most of the UV light in sunlight. The product shows evident photocatalytic activity in degradation of RhB under solar light irradiation, and then its solar light degradation efficiency is close to that under UV irradiation, indicating that there is a possibility of practical application. More importantly, the obtained ZnO nanoparticles, because of the quick precipitation by themselves in solution with no stirring, could be easily recycled without any accessorial means such as high speed centrifuge. The low-cost and scalable preparation, high photocatalytic activity, and convenient recycling of this ZnO nanomaterial gives it potential in purifying waste water. Hence the interesting results in this study indicate the wide range of the soluble salt-assisted route for the industrial preparation of many other advanced nanomaterials. PMID- 22248759 TI - The commitment to care. PMID- 22248760 TI - Evaluation of preemptive effect of epidural S(+)-ketamine for hysterectomy: plasmatic concentrations of interleukins. AB - BACKGROUND AND OBJECTIVES: Some studies showed that ketamine inhibits the production of cytokines. The objective of this study was to evaluate the preemptive analgesic effect of epidural S(+)-ketamine in hysterectomy and plasmatic cytokines (IL-6, TNF-alpha and IL-10). METHOD: A double-blinded study with 29 patients was conducted. Patients in Group 1 received 13 mL of 0.25% bupivacaine with 25mg of S(+)- ketamine 30 minutes before surgical incision and 15 mL of saline solution via the epidural route 30 minutes after. Patients in Group 2 received 15 mL of saline solution 30 minutes before the surgical incision, followed by 13 mL of 0.25% bupivacaine with 25mg of S(+)-ketamine 30 minutes after. Postoperative analgesia was made with epidural bupivacaine and fentanyl. Dipyrone 1 g was used whenever required. The following paramenters were evaluated: concentration of cytokines, intensity of pain, time of first request of analgesic and total quantity of analgesic used. RESULTS: Time for the first request for analgesics was 61.5 minutes in Group 1 and 69.0 in Group 2, without difference between these groups. There was no difference for total dose of fentanyl used in Group 1 (221.4 MUg) and Group 2 (223.3 MUg). A similar analgesic effect was obtained in both groups, except in T12 (Group 1 = 2.4+/-3.2; Group 2 = 5.5+/-3.4). No differences in concentration of cytokines were observed. CONCLUSIONS: The epidural injection of 25mg S(+)-ketamine before incision reduced the pain intensity only 12 hours after surgical incision and did not alter concentration of cytokines. PMID- 22248761 TI - Control of pain through epidural block and incidence of cardiac dysrhythmias in postoperative period of thoracic and major abdominal surgical procedures: a comparative study. AB - BACKGROUND AND OBJECTIVES: Upper abdomen and thorax surgeries cause intense pain. Some of postoperative pain main complications are cardiocirculatory complications. The objective of this study was to test the hypothesis that postoperative analgesia with employment of local anesthetics plus spinal opioids may reduce the incidence of cardiovascular complications in postoperative period of patients in these conditions, comparing with classical methods of postoperative analgesia, opioids and NSAIDs, administered upon patient's demand. METHOD: Eighty adult patients, ASA I and II, without ECG alterations, were allocated into two groups of 40: Group A, patients under general anesthesia with propofol, cisatracurium and isoflurane, associated with epidural anesthesia with catheter and control of postoperative analgesia with bupivacaine and epidural morphine; and Group B, patients under general anesthesia with the same drugs and doses of A, plus postoperative analgesia carried out with NSAIDs and intravenous morphine at the end of surgery and in regular intervals. In both groups Holter was applied for 24 hours. Pain evaluation was carried out through visual analog scale. RESULTS: In pain evaluation, an evident predominance of 0 score (p<0.001) was observed in Group A and there was also reduction of blood pressure levels in postoperative period in a more accentuated way. Ventricular and supraventricular dysrhythmias were five times more frequent in Group B (p=0.00001), in which a tendency to a higher frequency of ventricular extrasystoles in age>50 years (22.2% versus 0.0%. p=0.26) was also detected. No significative difference of heart rate among groups (p>0.05) was observed. CONCLUSIONS: The best quality of analgesia in postoperative period, carried out in Group A, reduced the incidence of cardiovascular complications. PMID- 22248762 TI - Postoperative analgesic efficacy of different volumes and masses of ropivacaine in posterior brachial plexus block. AB - BACKGROUND AND OBJECTIVES: The efficacy of posterior brachial plexus block for shoulder surgeries is demonstrated by different authors. However, there is no consensus on the ideal mass and volume of local anesthetic to be employed. The objetive of this study was to compare different volumes and masses of ropivacaine in posterior brachial plexus block in arthroscopic surgeries of the shoulder. METHOD: Sixty patients > 18 years, physical status ASA I and II, scheduled for unilateral arthroscopic surgeries of the shoulder were randomly placed in three groups: A (10 mL to 0.5%), B (20 mL to 0.5%), C (5 mL to 1%). The block was performed with a 22G needle of 100 mm connected to neurostimulator, in a point 3 cm lateral to the midpoint of C6 and C7 interspace, being injected the solution corresponding to each group. The postoperative pain was evaluated at the recovery room and within the first 24 hours of the postoperative period. The groups were compared on length of time until the first complaint of pain, visual numeric scale (VNS) score and morphine consumption within the first 24 hours. RESULTS: There was no statistically significant difference between the three groups related to age, weight and height. There was no difference in length of time until the first complaint of pain, VNS scores over three and morphine consumption in the postoperative period between the groups. CONCLUSIONS: This study concluded that 5 mL of 1% ropivacaine promoted analgesic efficacy similar to 10 mL or 20 mL of 0.5% ropivacaine in the posterior brachial plexus block using neurostimulator. PMID- 22248763 TI - The perioperative effect of increased body mass index on peripheral nerve blockade: an analysis of 528 ultrasound guided interscalene blocks. AB - BACKGROUND AND OBJECTIVES: Obese patients can pose a unique perioperative anesthetic challenge, making regional anesthetic techniques an intriguing means of providing analgesia for this population. Ultrasound guidance has been touted recently as being beneficial for this population in which surface landmarks can become obscured. In this study, the effect of increased Body Mass Index (BMI) on ultrasound guided interscalene peripheral nerve blockade is investigated. MATERIAL AND METHODS: This study is a retrospective review of 528 consecutive patients who received preoperative ultrasound-guided interscalene nerve blocks at the University of Wisconsin Hospital and Clinics. We examined the association between BMI and the following parameters: time required for block placement; presence of Postoperative Nausea and Vomiting (PONV); postoperative Post Anesthesia Care Unit (PACU) pain scores; volume of local anesthetic injected; acute complications; and opioid administration preoperatively, intraoperatively, and postoperatively. Univariate and multivariate least squares and logistic regression models were used. RESULTS: An elevated BMI was associated with an increased: time required for block placement (p-value=0.025), intraoperative fentanyl administration (p-value<0.001), peak PACU pain scores (p-value<0.001), PACU opioid administration (p-value<0.001), PACU oral opioid administration (p value<0.001), total PACU opioid administration (p-value<0.001) and incidence of PACU nausea (p-value=0.025) CONCLUSIONS: Ultrasound guided interscalene nerve blocks for perioperative analgesia can be safely and effectively performed in the obese patient but they may be more difficult to perform and analgesia may not be as complete. PMID- 22248764 TI - Gastric emptying study by scintigraphy in patients with chronic renal failure. AB - BACKGROUND AND OBJECTIVES: This study had the purpose of studying gastric emptying in patients with chronic renal failure. MATERIAL AND METHOD: Thirty patients with chronic renal failure were studied, 16 in conservative clinical treatment and 14 in hemodialysis for over six months. The control group (CTL) was composed of 18 asymptomatic volunteers. The method of gastric emptying study was scintigraphy. The standardized test meal was an omelet of three chicken eggs prepared with colloidal sulfur marked with 185 MBq of 99m technetium. Gastric retention curves were studied and T1/2 of gastric emptying was obtained from them. A T1/2 value corresponding to the average of T1/2 values of control group plus twice standard deviation was considered nornmal. Statistical tests used were chi(2) and Kruskal-Wallis. RESULTS: There was no statistically significant difference with regard to total gastric retention curves and T1/2 of gastric emptying, which was similar in three studied groups. Nine patients had high T1/2 of gastric emptying, above 125 minutes. These patients were equally distributed among both genders and conservative clinical treatment and hemodialysis groups. CONCLUSIONS: We concluded that gastric retention rate and T1/2 of gastric emptying in patients with chronic renal failure in conservative clinical treatment and hemodialysis does not differ from the healthy patients group. Hemodialysis does not seem to reduce the risk of gastric retention in patients with chronic renal failure. PMID- 22248765 TI - Perception of quality of life among anesthesiologists and non-anesthesiologists. AB - BACKGROUND AND OBJECTIVES: Literature points out routine factors with negative impact on anesthesiologists' quality of life. This study aims to compare the perception of quality of life of anesthesiologists and non-anesthesiologists. METHOD: Transversal study based on three specific questionnaires (epidemiological, WHOQOL-BREF and SF-12(r)) applied in anesthesiologists (Group A) and non-anesthesiologists (Group NA), of a general university hospital and a third group of anesthesiologists from inner state (Group I). The analysis of epidemiological variables and the ones related to quality of life domains of WHOQOL were interpreted by multivariate analysis (SPSS program). RESULTS: The number of WHOQOL-BREF respondents were: Group A=67; Group NA=69; Group I=53. The anesthesiologists from Group I were excluded from the study due to an inadequate sample for statistical analysis. The total number of respondents to check the SF 12(r) score was 61 in Group A and 68 in Group NA. For the WHOQOL-BREF tool, the physical domain scores were 72.97+/-11.78 for Group A and 77.17+/-10.85 for Group NA (p<0.05); the psychological domain scores were 66.44+/-13.66 for Group A and 71.79+/-11.48 for Group NA (p<0.05); the social relationship domain scores were 64.67+/-19.08 for Group A and 73.36+/-15.37 for Group NA (p<0.01); and the environment domain scores were 68.14+/-11.56 for Group A and 72.37+/-10.07 for Group NA (p<0.05). In SF-12(r), both physical and mental components did not show statistical differences. CONCLUSIONS: The perception of the anesthesiologists' quality of life was consistently inferior to other physicians in general, for the studied sample. PMID- 22248766 TI - Prevalence of sensitivity signals to latex in meningomyelocele patients undergoing multiple surgical procedures. AB - BACKGROUND AND OBJECTIVES: The number of patients allergic to latex has increased significantly. It is crucial to recognize the cases in order to prevent and apply adequate treatment. The objective of this study was to evaluate the prevalence of allergy to latex in meningomyelocele patients. MATERIALS AND METHODS: A retrospective evaluation of medical records of patients with meningomyelocele diagnosis from January 2002 to December 2007 was conducted. Patients were grouped into allergics and non-allergics. The comparison of groups for gender was made by the Chi-Squared test, the Student's t test was used to compare age, and Mann Whitney test was used to compare groups for clinical manifestations of allergy, number of procedures under anesthesia, hospital admissions and vesical catheterizations. RESULTS: The mean number of procedures under anesthesia was 7 in the group with allergy and 4 in the group without allergy; this difference was statistically significant (p=0.028). The mean number of hospital admissions was 4.5 in the group with allergy and 3.4 in group without allergy and mean vesical catheterization was 24.5 in allergic patients and 21.7 in non allergic ones. CONCLUSIONS: Meningomyelocele patients undergoing multiple procedures under anesthesia have high risk of developing clinical signals of allergy to latex. It is necessary that patients with meningomyelocele diagnosis should undergo exclusively latex-free procedures, avoiding high risk of sensitization and its complications. Specific tests to evaluate sensitization, genetic markers and latex-fruit relationship may contribute to a better understanding of risk factors related to allergy to latex and ways to prevent it. PMID- 22248767 TI - Anesthesiology teaching during undergraduation through an academic league: what is the impact in students' learning? AB - BACKGROUND AND OBJECTIVES: Academic leagues have been consolidated as instruments of medical teaching and for the introducing of medical students to practice of specialties, including anesthesiology. As the role of leagues in the development process of competencies and learning of their students is not well known, the learning of members of an anesthesiology academic league was evaluated after participating in its activities for one year. METHOD: Students of an anesthesiology academic league were followed up from March to December 2010 and evaluated through objective cognitive tests of multiple choice applied before the beginning of activities and after their conclusion. Attendance in activities and epidemiologic profile of students were correlated with the tests results. RESULTS: Twenty medical students from 3rd to 6th year were analyzed, with an average age of 22.8 (21-26) years. The average participation in the proposed activities was 10.4/13 (80%). The average of right answers on the first test was 8.1/17 (47.6%), and 3rd year students had lower grades (p<0.02) compared with other students. In the post league test, the average of right answers was 11.9/17 (70%), showing an improvement in performance (p<0.05), and there was no difference between grades of different years of the medical undergraduation. A strong relationship between participation in activities and improved grades was found (r=0.719; p<0.001). CONCLUSIONS: Students who participated in the league had improvement in knowledge evaluation tests, suggesting that the league is a useful teaching instrument that can provide improved learning of anesthesiology. Participation in activities was connected with improved performance. Activities developed in leagues may have a positive role in students' academic education, more specifically in this article, in anesthesiology. PMID- 22248768 TI - Delayed onset seizures after inguinal herniotomy in a premature infant: a case report. AB - We report a case of a premature neonate born at 34 weeks and operated at 6 weeks of age developing unexplained seizures 10 hours after the end of surgery under single shot caudal epidural analgesia with bupivacaine and lidocaine combined with general anesthesia. PMID- 22248769 TI - Acute respiratory failure during pediatric anesthesia: atelectasis and hypertensive pneumothorax: case report. AB - BACKGROUND AND OBJECTIVES: The main anesthesiologist's task is to ensure appropriate oxygenation of patient. The objective of this report is to describe both diagnosis and behavior in case of acute respiratory failure during anesthesia, with educational purposes. CASE REPORT: Three-year-old child underwent anesthesia for urologic surgery presented respiratory failure by bronchial obstruction by secretion, evolving to atelectasis and hypertensive pneumothorax. We present the evolution of the case and applied treatment means, emphasizing the urgency and drainage technique in hypertensive pneumothorax. CONCLUSIONS: The anesthesiologist's attention to early diagnosis of respiratory complications and knowledge of priority measures in each moment may prevent serious adverse effects. PMID- 22248770 TI - Intracranial subdural hematoma: a rare complication following spinal anesthesia: case report. AB - BACKGROUND AND OBJECTIVES: Intracranial subdural hematoma is a rare complication following spinal anesthesia. The diagnosis is usually difficult because initial symptoms are the same of post-dural puncture headache. The objective was to report a case of early diagnosed subdural hematoma after spinal anesthesia performed with a fine-gauge needle and single puncture. CASE REPORT: 48-year old female patient, ASA I, undergoing spinal anesthesia for surgery to correct urinary incontinence. The spinal anesthesia was performed with 27G Quincke needle and single puncture. There was no unexpected event in the surgery and the patient was discharged. After 48 hours of spinal puncture, the patient reported sudden, strong headache, affecting especially the orbital region, but also the temporal region, with important improvement in dorsal decubitus and followed by two vomiting episodes. A cranial tomography was requested and revealed the presence of an acute left frontotemporoparietal subdural hematoma. A conservative treatment with analgesics, dexamethasone and hydantoin was indicated. After 17 days, the patient had intense headache, followed by dormancy and paresis of right upper limb and speech and behavior disorders. The hematoma was surgically drained. The patient evolved well and without sequelae. CONCLUSIONS: Headache is the most frequent complication after spinal anesthesia and it is considered of benign evolution. In many cases however, it leads to the late or absent diagnosis of potentially fatal conditions, like subdural hematoma. This case describes a rare case of an acute subdural hematoma following spinal anesthesia with fine gauge needle in a patient without risk factors for bleeding. PMID- 22248771 TI - Suprascapular nerve block: important procedure in clinical practice. AB - BACKGROUND AND OBJECTIVES: Shoulder pain is a frequent complaint that results in great functional disability in the affected shoulder as well as the decrease in patients' quality of life. Suprascapular nerve block is an effective therapeutic method and has been increasingly used by anesthesiologists both for regional anesthesia and postoperative analgesia of surgeries carried out in this articulation, which justifies this review, whose main purpose was to describe the applied technique and clinical indications. CONTENT: It is presented the anatomy of suprascapular nerve, since its brachial plexus origin until its terminal branches, as well as general characteristics and technique employed to carry out the block of this nerve, main drugs used, volume and situations that give rise to its applications. CONCLUSIONS: Suprascapular nerve block is a safe and extremely effective procedure in shoulder pain therapy. It also has an easy reproducibility and has been very used by professionals of many medical specialties. When it is well-indicated, this method must be taken into consideration. PMID- 22248772 TI - Bispectral index and other processed parameters of electroencephalogram: an update. AB - BACKGROUND AND OBJECTIVES: The processed analysis of electroencephalogram became extremely important to monitor nervous system, being used to obtain a better anesthetic adequacy. The objective was to conduct a review about each processed parameter, defining its real importance. CONTENT: A review was conducted showing mathematical, physical and clinical aspects as well as their correlations and updates, presenting new integrated parameters. CONCLUSIONS: An adequate analysis of processed parameters of electroencephalogram may provide more intraoperative safety as well as result in a better outcome for the patient. PMID- 22248773 TI - Dexmedetomidine: current role in anesthesia and intensive care. AB - BACKGROUND AND OBJECTIVES: To update and review the application of dexmedetomidine in anesthesia and intensive care. This study is a comprehensive review of clinical uses, pharmacology, pharmacokinetics, mechanism of action and adverse effects of dexmedetomidine. CONTENT: The effective use of sedative hypnotic agents and analgesics is an integral part of comfort and safety of patients. Dexmedetomidine is a potent and highly selective alpha-2 adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties, which has been described as a useful and safe adjunct in many clinical applications. It provides a unique "conscious sedation", analgesia, without respiratory depression. The current reviewed uses include sedation at Intensive Care Unit-ICU (both adult and pediatric), emergency department, regional and general anesthesia, neurosurgery, sedation for pediatric procedures, awake fiber-optic intubation, cardiac surgery and bariatric surgery. CONCLUSIONS: Dexmedetomidine offers a unique ability of providing both sedation and analgesia without respiratory depression. It is a new agent with a wide safety margin, excellent sedative capacity and moderate analgesic properties. Although its wide use is currently in patients of surgical and non-surgical intensive care units, dexmedetomidine seems to have promising future applications in neuroprotection, cardioprotection and renoprotection. More detailed studies are required to define its role as sedative in critical, neurosurgical and pediatric patients, as anesthesia adjunct and sedative during procedures. PMID- 22248774 TI - Is there a recommendation for safety in the practice of regional anesthesia? PMID- 22248775 TI - Evaluation of cytokine levels and pulmonary function in patients undergoing coronary artery bypass graft. PMID- 22248776 TI - Autoimmune thyroiditis in children and adolescents with type 1 diabetes. AB - INTRODUCTION: In children and adolescents with type 1 diabetes coexist some other autoimmune diseases such as autoimmune thyroiditis, celiac disease, Addison's disease or others. AIM OF THE STUDY: was to assess the incidence and risk factors for autoimmune thyroiditis in children and adolescents with type 1 diabetes at the moment of diagnosis. MATERIAL AND METHODS: The study included 382 children, who in the years 2001 to 2010 were diagnosed with type 1 diabetes. The concentrations of antibodies against thyroid peroxidase (anti- TPO), TSH and FT4 were measured and thyroid ultrasound examinations were performed. Children who had not initially shown the presence of anti-TPO had the test repeated at yearly intervals for 2-8 years. RESULTS: At the time of diagnosis of diabetes, elevated anti-TPO titres were found in 14.4% of patients, more often in girls than in boys, p<0.01. Children with a positive anti-TPO titre were on average older than those whose anti-TPO levels were within the normal range, p<0.05. The incidence of elevated titers of anti-TPO increased with age, 20,5% of children above 10 years old had positive anti-TPO, compared to 8.3% of children less than 10 years old, p <0.001. At the time of the onset of diabetes, hypothyroidism was diagnosed in 14.5% of children with elevated anti-TPO, and in 2.1% of the whole group. 4.5% of patients whose levels of anti-TPO were initially normal, within the next 1-8 years had positive antibody titers. CONCLUSIONS: Due to the high incidence of the disease, it is necessary to carry out screenings for autoimmune thyroiditis in children with diabetes at the time of diagnosis and redo them in accordance with the recommendations. PMID- 22248777 TI - [Usefulness of short-term usage of real time continuous glucose monitoring system in achieving metabolic control improvement in adolescents with type 1 diabetes]. AB - INTRODUCTION: Experience with use of real-time continuous glucose monitoring systems (RT-CGMS) in teenagers with diabetes type 1 is limited, and in unselected groups of young patients did not show improvement in metabolic control. AIM OF THE STUDY: The objective of this study was to assess short-term RT-CGMS usage in teenagers with type 1 diabetes, in terms of possibility to improve metabolic control and acceptance of the system. MATERIAL AND METHODS: 40 subjects, aged 14.5+/-2 years on insulin pump therapy were included in the study. Mean diabetes duration was 6+/-3 years and HbA1c level before the study was 8.4+/-1.5%. The analysis was based on single 5-6 days long sensor usage, connected with education of the family. We analysed several parameters of glycaemic variability during the study, and HbA(1)c level before and 2 months after the study. Patients' satisfaction was assessed on the basis of a questionnaire. RESULTS: HbA(1)c level in the whole teenagers group decreased insignificantly by 0.3%; from 8.4+/-1,% to 8.1+/-1.6%. In 24 (60%) patients we showed improvement in HbA(1)c by at least 0.5% (mean 0.9%, from 8.1+/-1.3% to 7.2+/-1.2%; p=0.03). HbA(1)c level was slightly higher in girls than in boys at the beginning of the study and a greater reduction in HbA(1)c was shown for boys. After two months the difference was significant: 8.6+/-1.9% in girls vs. 7.6+/-1.3% in boys, p=0.03. In the group with HbA(1)c decrease and in boys we demonstrated improvement in mean glycaemia and glycaemic variability parameters on the last day of the sensor usage, compared to the first day. In boys however, increased AUC <70 mg/dl/ min was noticed. The patients from the group with HbA(1)c decrease reported fewer problems with system calibration: 3.2 vs. 2.6 score, p=0.03. This group also reported higher satisfaction score connected with new knowledge: 4.0 vs. 3.5, and with quality of life: 4.1 vs. 3.6. CONCLUSIONS: Short-term usage of RT-CGMS, combined with satisfaction questionnaire performed in teenagers with diabetes type 1 can be useful in defining the group of young patients who can benefit from RT-CGMS usage in long-term metabolic control improvement. PMID- 22248778 TI - [Assessment of the influence of puberty on changes in post exercise glycaemia after variable intensity physical effort in children and adolescents with diabetes mellitus type 1 (DM1)]. AB - INTRODUCTION: During the pubertal period the metabolic control is getting worse in the most of patients with type 1 diabetes mellitus (DM1). The insufficient metabolic control may impact the post-exercise glycaemia and cause the acute complications of the diabetes. AIM OF THE STUDY: was to assess the influence of puberty on changes in post exercise glycaemia after variable intensity physical effort in children and adolescents with diabetes mellitus type 1 (DM1). MATERIAL AND METHODS: The study group consisted of 88 children with DM1, 6 to 19 years of age, mean age 13.00+/-2.77 (SD). The subjects were divided into three groups according to pubertal stage (29 prepubertal subjects, 33 pubertal and 26 postpubertal adolescents with DM1). Three tests of increasing intensity were performed, each lasting 20 minutes on three consecutive days. The controls were the same children with no exercise. RESULTS: In prepubertal subjects statistically significant lower levels of glycaemia were found 3 minutes (p<0.05) and 1 hour (p<0.05) after high intensity exercise in comparison to the controls. The pubertal subjects had statistically significant lower levels of glycaemy after high (p<0.001, p<0.01, p<0.05) and moderate intensity exercise (p<0.05, p<0.05, p<0.01 respectively) in all three check points compared to controls. The postpubertal subjects were found to have statistically significant lower levels of glycaemy after moderate intensity exercise 3 minutes (p<0.01) and 1 hour (p<0.05) compared to controls and after high intensity exercises 3 minutes after the exercise (p<0.05). CONCLUSIONS: The rate of changes in post exercise glycaemy level depended on pubertal stage. The most significant decrease in post exercise glycaemy was observed in pubertal subjects. PMID- 22248779 TI - [Body proportions of healthy and short stature adolescent girls]. AB - INTRODUCTION: Regularly conducted assessment of body proportions is of importance as early detection of possible growth disorders and immediate prevention may allow gathering an optimum of child's genetically conditioned level of development. AIM OF THE STUDY: To assess body proportions of adolescent girls, healthy or with growth deficiency. MATERIAL AND METHODS: Three groups were studied: 104 healthy, short-statured girls (body height below the 10th percentile), 84 girls with Turner's syndrome (ZT) and 263 healthy girls of normal stature (between percentiles 25 and 75), all aged 11-15 years. The following measurements were conducted according to common anthropometric standards: body height, sitting body height, shoulder width, upper extremity length and lower extremity length - the last one was computed as the difference between standing and sitting body heights. All measurements were converted to logarithms and allometric linear regressions vs log body height were computed. RESULTS: The Turner girls proved to have allometrically shorter legs (p<0.001) and wider shoulders (p<0.001) compared with both groups of healthy girls, and longer upper extremities (p<0.001) compared with the girls of normal stature. Healthy, short statured girls had longer lower extremities (p<0.001) as compared to other groups; they also had wider shoulders (p<0.001) and longer upper extremities (p<0.001) compared to healthy girls of normal height. CONCLUSIONS: Allometric relations of anthropometric measurements enable a deeper insight into the body proportions, especially in the growth period. The presented discrimination of Turner girls may serve as a screening test, and recommendation for further clinical treatment. PMID- 22248780 TI - The prevalence and correlates of abdominal obesity in female students. AB - INTRODUCTION: The accumulation of fat in the abdomen region has been described as the type of obesity that offers the greatest risk for the health of the individuals. AIM OF THE STUDY: was to determine the prevalence and correlates of abdominal obesity in female university students. MATERIAL AND METHODS: 1129 female students, aged 19-24 were measured for stature, body weight and waist circumference. Each person's height and weight was measured. Underweight, overweight and obesity were determined on the BMI (body mass index) basis, in accordance with WHO standards. Abdominal obesity was defined as waist circumference equal to 80 cm or higher. To assess the socio-economic status (SES), the following factors were analysed: place of residence before entering the university, education of parents and self-assessment of their material condition. A questionnaires was used to evaluate nutritional habits and leisure time physical activities. RESULTS: In the studied group, prevalence of underweight was 11.1%, overweight and obesity - 7.0%. Abdominal adiposity concerned 11.2% of the surveyed students. No significant differences were found between socio-economic groups and the waist circumference and the frequency of abdominal obesity. The results show that the incidence of abdominal obesity is related to numerous unhealthy habits, which relate mainly to the nutrition way and physical inactivity. CONCLUSIONS: The prevalence of abdominal obesity was much higher than the prevalence of general overweight and obesity. The regular recreational physical activity reduces the risk of adiposity located in the abdominal region. PMID- 22248782 TI - [Glucagon and glucagon-like peptides the role in control glucose homeostasis. Part I]. AB - Glucose homeostasis is controlled primarily by the opposing actions of insulin and glucagon, hormones that are secreted by the islets of Langerhans from beta cells and alpha-cells and Delta-cells, their role in glucose homeostasis still needs identifying. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscles and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Glucagon secretion from pancreatic alpha cells is regulated by various mechanisms including glycemia, neural input, and secretion from neighboring beta-cells. Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of glucose. With longer stimulation, glucagon action on the liver results in a glucose-sparing activation of free fatty acid oxidation and production of ketones. PMID- 22248781 TI - [Insulin resistance in children]. AB - Insulin resistance is characterized by decreased tissue sensitivity to insulin. The hallmark of insulin resistance is decreased tissue glucose uptake despite normal or elevated insulin concentration. There has been an upward trend in the incidence of insulin resistance in developed countries, although in pediatric population it is difficult to assess. Both genetic and environmental factors play an important role in the etiology of insulin resistance, namely increased diet caloricity and decreased physical activity. Gradually, this leads to adipose tissue build-up. The role of visceral adipose tissue is of particular importance, mainly due to its significant endocrine activity, leading to adverse metabolic effects. The most important consequences of insulin resistance in children include increased incidence of type 2 diabetes, atherogenic dyslipidemia and arterial hypertension, which lead to increased cardiovascular risk. Children with insulin resistance can develop nonalcoholic steatohepatitis and sleep apnea syndrome. In case of female pediatric patients a higher incidence of polycystic ovary syndrome (PCOS) is observed. Furthermore, the authors reviewed opinions on risk factors for insulin resistance, as well as direct and indirect insulin resistance assessment methods. The article presents the principles of primary and secondary prevention of insulin resistance in children, with particular allowance for dietary recommendations and recommendations to increase physical activity, and, in selected cases, current guidelines on pharmacological treatment. PMID- 22248783 TI - [Nutrigenomics - perspectives of personalized nutrition]. AB - Currently used dietary recommendations and requirements are generalized. It applies to both healthy and ailing individuals. These recommendations are meant to avert leading chronic illnesses such as: type 2 diabetes mellitus, obesity, hyperlipidemia, cardiovascular diseases and hypertension. In the future it might be possible to give dietary advice tailored to every - sick and healthy - individual. Nutrigenomics and nutrigenetics are two fields derived from nutrition science and genetics. Their main goal is to elucidate the influence of interactions between genes and diet on individuals' health. This paper shows the examples of metabolic response changes according to diet and chosen gene polymorphisms. It will enable an effective prevention or management of chronic diseases by accurate diet and lifestyle matched to an individual's genetic makeup. It could be useful especially to define predisposition for type 2 diabetes mellitus in young children. It will be possible to change their diet and lifestyle so that they could avoid this chronic disease. There will also be a possibility to detect early the beginning of the illness and choose/select proper treatment. It is important because type 2 diabetes mellitus frequency is up to 90% of all cases of diabetes mellitus. It's often diagnosed too late and a lot of patients have already developed complications caused by this disease. Successful dietotherapy will also be available in such disease entities as dyslipidemias, hypertension and micro- , macronutrients and vitamins defficiences. PMID- 22248784 TI - [History of diabetology in Lower Silesia]. AB - The authors presented the history of diabetology in the time before and after the 2nd world war, the outstanding diabetological scientists f.e. professor Minkowski, Stolte, Lublin. Further presented was the actual situation and development of the diabetology in Lower Silesia. PMID- 22248785 TI - A two year observation of the process of applying recombinant IGF-1 to treat short stature in children with primary IGF-1 deficiency -- case reports of 3 patients. AB - Growth deficiency is one of the most frequent causes of referral to Endocrinology Outpatient Clinic. IGF-1 (insulin-like growth factor 1) deficiency is one of the rarest causes of short stature. In 2009 in Poland a therapeutic programme was set up for children with severe primary IGF-1 deficiency. The authors present the data of three first polish patients qualified for the rhIGF-1 (recombinant human insulin-like growth factor 1) - mecasermin. The authors conclude that the treatment with rhIGF-1 significantly improves growth velocity in patients with IGF-1 deficiency. During two years of mecasermin treatment no serious side effects were noted. PMID- 22248786 TI - Testicular adrenal rest tumours in boys with congenital adrenal hyperplasia: case report and literature review. AB - Nodular testicular lesions derived from adrenal tissue (testicular adrenal rest tumours - TART) in boys and men with congenital adrenal hyperplasia (CAH) lead to testicular structure damage, spermatogenesis disorders, and infertility. Hyperplasia of the ectopic adrenal tissue in testes is associated with high levels of the adrenocorticotropic hormone (ACTH) in blood serum. The development of non-invasive methods of diagnostic imaging allows detection of testicular lesions in adolescents and children. The basic method for TART detection is imaging with ultrasonography (USG) being the most widely available method. Since these mild testicular lesions can cause impaired fertility, periodic palpation and testicular ultrasonography should be performed in patients with CAH in order to prevent infertility. PMID- 22248787 TI - The nature and timing of family-provider communication in late-stage cancer: a qualitative study of caregivers' experiences. AB - CONTEXT: Family members of people with advanced cancer can experience intensified distress and uncertainty during the final stages of their loved one's illness. Enhanced comprehension about disease progression, symptom management, and options for care can help families adapt, cope, and plan for the future. OBJECTIVES: Guided by concepts from the Sense of Coherence Theory, which illuminates factors that contribute to adaptation in stressful situations, the objective of this study was to explore and describe family caregivers' accounts of the nature and timing of communication they had with a loved one's health care provider(s) during the advanced stages of cancer and before hospice enrollment. METHODS: Retrospective in-depth interviews were conducted with caregivers of 46 people who died of cancer. Interviews were audiotaped, transcribed, and submitted to an iterative process of qualitative data analysis that included 1) systematic coding, 2) the use of data matrices to display summarized results and collapse the codes into themes, 3) and axial coding to characterize the nature of the themes. RESULTS: Overall, communication with providers was found to be either 1) satisfactory or 2) unsatisfactory. Satisfactory communication was 1) compassionate, 2) responsive, and/or 3) dedicated. Unsatisfactory communication was described as 1) sparse, 2) conflicted, 3) contradictory, and/or 4) brink of death. CONCLUSION: Communication with health care providers is critical for helping family caregivers understand and manage the changes that accompany a life limiting illness. Timely communication with information and meaningful discussion about disease progression can help families prepare for the advanced stages of an illness and approaching death. PMID- 22248788 TI - Turning toward dissonance: lessons from art, music, and literature. AB - Conflict and chaos are prevalent in health care, and perhaps especially in palliative care. Typically, our point of entry into our patients' lives is often at the moment of conflict, discord, or intense suffering. Despite this, little in our formal training as clinicians teaches us how to be present for this suffering. Much has been written about the process of communication with regard to giving bad news, handling family meeting conflicts, and negotiating shifting goals of care, but little has been addressed about how to train the clinician to be present with the dissonance and suffering. In this paper, we explore how music, art, and literature teach us how to stay in moments of tension. In turn, lessons on how to learn to lean into the dissonance of many palliative care encounters are extrapolated. PMID- 22248789 TI - Do surrogates have a right to refuse pain medications for incompetent patients? AB - The relief of pain is widely considered to be a basic human right. Physicians are expected to make every attempt to relieve pain and suffering, especially in patients who do not have capacity. This article presents a case in which the family of a woman with severe somatic pain from metastatic breast cancer requests that pain medications be reduced and, at times, held. The ethical issues associated with surrogate decision making and the refusal of medical treatments are reviewed. The obligation to treat pain remains paramount despite family objections. PMID- 22248790 TI - Stimulant laxatives and opioid-induced constipation. AB - Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com). PMID- 22248791 TI - Intravenous lidocaine for management of wound care pain. PMID- 22248792 TI - Acupuncture: what does the most reliable evidence tell us? An update. PMID- 22248793 TI - Persistent PORT-A-CATH(r)-related fistula and fibrosis in a breast cancer patient successfully treated with local ozone application. PMID- 22248794 TI - Persistent hiccups: an unusual presentation and treatment. PMID- 22248795 TI - Reversible, hyperacute allodynia after evacuation of a cervical epidural hematoma. PMID- 22248796 TI - Mathematical optimization of procedures for cryoprotectant equilibration using a toxicity cost function. AB - Cryopreservation nearly universally depends on the equilibration of cells and tissues with high concentrations of permeating chemicals known as cryoprotective agents, or CPAs. Despite their protective properties, CPAs can cause damage as a result of osmotically-driven cell volume changes, as well as chemical toxicity. In this study, we have used previously published data to determine a toxicity cost function, a quantity that represents the cumulative damage caused by toxicity. We then used this cost function to define and numerically solve the optimal control problem for CPA equilibration, using human oocytes as representative cell type with high clinical relevance. The resulting toxicity optimal procedures are predicted to yield significantly less toxicity than conventional stepwise procedures. In particular, our results show that toxicity is minimized during CPA addition by inducing the cell to swell to its maximum tolerable volume and then loading it with CPA while in the swollen state. This counterintuitive result is considerably different from the conventional stepwise strategy, which involves exposure to successively higher CPA concentrations in order to avoid excessive shrinkage. The procedures identified in the present study have the potential to significantly reduce damage due to toxicity and warrant further investigation. PMID- 22248797 TI - Simple bone cyst of the mandibular condyle in a child: report of a case. PMID- 22248798 TI - Effect of chemical and biological degumming on the adsorption of heavy metal by cellulose xanthogenates prepared from Eichhornia crassipes. AB - Cellulose xanthogenates, derived from the straw of Eichhornia crassipes, were prepared as adsorbents for heavy metals by CS(2) sulfonation and magnesium substitution after degumming with alkali, self-isolated A(1) strain and pectase, respectively. The effects of three degumming treatments were compared by functional groups analysis, surface morphology and surface element composition and heavy metal (Pb(2+)) adsorption studies. The results demonstrate that bio degumming treatments by A(1) strain and pectase have weaker degumming effects than alkali treatment. However, the surface characteristics of the bio-degumming products, especially the pectase degumming product, are more beneficial to heavy metal adsorption. In comparison to that of the raw plant materials, the Pb(2+) adsorption performances of the three xanthogenates improved significantly, although no obvious differences being observed among themselves. From an environmental point of view, the two bio-degumming treatments, especially the pectase degumming treatment, are more beneficial to prepare heavy metal adsorbents than the alkali degumming treatment. PMID- 22248799 TI - Flow pattern analysis of a full-scale expanded granular sludge bed-type reactor under different organic loading rates. AB - The hydraulic characteristics of a lab-scale and a full-scale (275 m(3)) expanded granular sludge bed (EGSB)-type reactor under different organic loading rates varying from 10 kg COD m(-3)d(-1) to 45 kg COD m(-3)d(-1) were investigated. A modified combined model composed of two completely mixing regions and a plug flow region was sufficient for simulating the flow pattern of a full-scale EGSB-type reactor. Moreover, the outputs fitted the measured tracer distribution results well. The simplified model structure was in very good agreement with the physical structure of a full-scale EGSB-type reactor. The upflow (liquid+gas) velocity, high concentration of granular sludge, and gas hold-up effect may contribute to the generation of dead spaces (maximum of 19.5%). The bed expansion characteristics indicated that the sludge bed of the EGSB-type reactor performed as a suspended bed, in which the bed expansion was controlled between 20% and 30%, rather than the usually considered expanded bed. PMID- 22248800 TI - Examining structure-activity correlations of some high activity enzyme preparations for low water media. AB - A first study of the comparison of structures of enzymes (by FT-IR and CD) in different high activity (in low water media) preparations is reported. Using chymotrypsin and subtilisin as models, we have studied various factors that distinguish enzyme precipitated and rinsed with propanol (EPRP), crosslinked enzyme aggregates (CLEA), protein coated microcrystals (PCMC) and crosslinked protein coated microcrystals (CLPCMC). The suspensions in organic media were assayed for catalytic activity, and structures were probed by FT-IR and CD measurements. CD studies of enzyme suspensions were possible by using a rotating cell accessory. There was a generally good correlation between higher catalytic activity and retention of native structures. Activity and retention of native structure was always higher if aqueous enzyme solution was added to propanol rather than vice versa in the precipitation step of these preparations. The work identifies factors which may lead to better biocatalyst designs for low water media. PMID- 22248801 TI - Effects of phosphorus concentration on the growth and enzyme production of Phanerochaete chrysosporium. AB - The effects of different phosphorus concentrations in culture media on the growth and enzyme production of Phanerochaete chrysosporium was investigated at a glucose concentration of 10 g L(-1). The results showed that the optimal KH(2)PO(4) concentration was 2.0 g L(-1). Optimal phosphorus content not only supported robust growth of P. chrysosporium, but also helped produce higher yields of manganese-dependent peroxidase (MnP) (324.9 U L(-1)). In addition, the results revealed that a relationship between the consumption of total phosphorus (TP) and fungal growth and enzyme production existed in P. chrysosporium cultures. Over a range of 0-0.5 g L(-1) KH(2)PO(4) concentration in the medium, the biomass and MnP activity increased in proportion to phosphorus concentration. When the KH(2)PO(4) concentration reached 0.5 g L(-1), it was generally found that the increase in biomass gradually slowed down, while MnP production decreased greatly with an increase in phosphorus concentration. PMID- 22248804 TI - The effects of quadriceps strengthening on pain, function, and patellofemoral joint contact area in persons with patellofemoral pain. AB - OBJECTIVE: Patellar malalignment is a major cause of patellofemoral pain syndrome (PFPS), but the relationship between clinical symptoms and changes in patellar position and knee muscle strength has not been confirmed. This study examined the effect of weight training on hip and knee muscle strength, patellofemoral joint contact area, and patellar tilt on subjects with and without PFPS, hoping to develop an optimal rehabilitation protocol for subjects with PFPS. DESIGN: The study uses a prospective independent group comparison. Fifteen subjects with and without PFPS were assessed for knee strength, patellofemoral joint contact area, and patellar tilt angle using magnetic resonance imaging. The subjects with PFPS were also examined and given a numeric pain rating score and a Kujala patellofemoral score. The subjects performed lower-limb weight training 3 times/wk for 8 wks, and the outcomes were assessed both before and after training. RESULTS: Subjects with PFPS have increased their patellofemoral joint contact area after weight training (P < 0.001). No statistical significant change was found on the patellar tilt angle. The isometric and isokinetic knee strength in subjects with and without PFPS have increased after weight training (P value increased from 0.007 to 0.05). Both numeric pain rating and Kujala patellofemoral score in the PFPS group improved after training (P < 0.001). CONCLUSIONS: Weight training exercise increased knee muscle strength and the patellofemoral joint contact area, which could reduce mechanical stress in the joint, improving pain and function in subjects with PFPS. PMID- 22248802 TI - Bmi-1 promotes the chemoresistance, invasion and tumorigenesis of pancreatic cancer cells. AB - BACKGROUND/AIMS: The polycomb protein Bmi-1 plays oncogenic roles in various cancers. Here we aimed to investigate the contribution of Bmi-1 on the malignant behaviors of pancreatic cancer such as chemoresistance, invasion and tumorigenesis. METHODS AND RESULTS: The MTT cell proliferation assay showed that shRNA mediated Bmi-1 knockdown and enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. The transwell invasion assay showed that Bmi-1 knockdown inhibited the invasion of pancreatic cancer cells in vitro. Notably, the reduced abilities of chemoresistance and invasion were associated with the transition from the mesenchymal phenotype to the epithelial phenotype of pancreatic cancer cells. Moreover, Bmi-1 knockdown led to the inhibition of the PI3K-Akt pathway and disrupted the sphere-forming abilities of pancreatic cancer cells. A nude mouse xenograft experiment demonstrated that pancreatic cancer cells depleted of Bmi-1 showed weak tumorigenicity in vivo. CONCLUSION: Our data suggest that Bmi-1 plays an important role in the progression of pancreatic cancer and represents a novel target for antitumor therapy of pancreatic cancer. PMID- 22248805 TI - Construct validity of language independent functional evaluation as used by Spanish-speaking clinicians to evaluate persons with developmental delays. AB - OBJECTIVE: This study aimed to establish the utility of Language Independent Functional Evaluation (LIFE) as used by clinicians. DESIGN: This study was a prospective trial involving 100 Spanish-speaking rehabilitation clients between the ages of 9 and 45 yrs with cognitive disability and 2 rehabilitation clinicians who cared for them at a Colombian inpatient and outpatient rehabilitation facility. Clinicians who had worked with clients for more than 2 mos rated their function using the LIFE and the Spanish-translated Barthel index. RESULTS: Overall LIFE scores correlated well with Barthel scores (r[98] = 0.793, P < 0.0001) and also on an item-to-item basis in all activities except grooming, bowel continence, and bladder continence. CONCLUSIONS: The LIFE is a reliable tool for clinicians to use in the assessment of persons with cognitive disability, regardless of the clinician's language. PMID- 22248806 TI - Staging activity limitation and participation restriction in elderly community dwelling persons according to difficulties in self-care and domestic life functioning. AB - OBJECTIVE: This study aimed to describe the conceptual foundation and development of an activity limitation and participation restriction staging system for community-dwelling people 70 yrs or older according to the severity and types of self-care (activities of daily living [ADLs]) and domestic life (instrumental ADLs (IADLs)) limitations experienced. DESIGN: Data from the second Longitudinal Study of Aging (N = 9447) were used to develop IADL stages through the analyses of self- and proxy-reported difficulties in performing IADLs. An analysis of activity limitation profiles identified hierarchical thresholds of difficulty that defined each stage. IADL stages are combined with ADL stages to profile status for independent living. RESULTS: IADL stages define five ordered thresholds of increasing activity limitations and a ''not relevant'' stage for those who normally have someone else do those activities. Approximately 42% of the population experience IADL limitations. To achieve a stage, a person must meet or exceed stage-specific thresholds of retained functioning defined for each activity. Combined ADL and IADL stages define 29 patterns of activity limitations expressing the individual's potential for participating in life situations pertinent to self-care and independent community life. CONCLUSIONS: ADL and IADL stages can serve to distinguish between groups of people according to both severity and the types of limitations experienced during home or outpatient assessments, in population surveillance, and in research. PMID- 22248807 TI - Comparison of three methods to identify the anaerobic threshold during maximal exercise testing in patients with chronic heart failure. AB - OBJECTIVE: Exercise training efficiently improves peak oxygen uptake (VO2peak) in patients with chronic heart failure. To optimize training-derived benefit, higher exercise intensities are being explored. The correct identification of anaerobic threshold is important to allow safe and effective exercise prescription. DESIGN: During 48 cardiopulmonary exercise tests obtained in patients with chronic heart failure (59.6 +/- 11 yrs; left ventricular ejection fraction, 27.9% +/- 9%), ventilatory gas analysis findings and lactate measurements were collected. Three technicians independently determined the respiratory compensation point (RCP), the heart rate turning point (HRTP) and the second lactate turning point (LTP2). Thereafter, exercise intensity (target heart rate and workload) was calculated and compared between the three methods applied. RESULTS: Patients had significantly reduced maximal exercise capacity (68% +/- 21% of predicted VO2peak) and chronotropic incompetence (74% +/- 7% of predicted peak heart rate). Heart rate, workload, and VO2 at HRTP and at RCP were not different, but at LTP2, these parameters were significantly (P < 0.0001) higher. Mean target heart rate and target workload calculated using the LTP2 were 5% and 12% higher compared with those calculated using HRTP and RCP, respectively. The calculation of target heart rate based on LTP2 was 5% and 10% higher in 12 of 48 (25%) and 6 of 48 (12.5%) patients, respectively, compared with the other two methods. CONCLUSIONS: In patients with chronic heart failure, RCP and HRTP, determined during cardiopulmonary exercise tests, precede the occurrence of LTP2. Target heart rates and workloads used to prescribe tailored exercise training in patients with chronic heart failure based on LTP2 are significantly higher than those derived from HRTP and RCP. PMID- 22248808 TI - Ultrasound-guided diagnosis and treatment of plantar fasciitis. PMID- 22248809 TI - Estimating chemical biotransformation rates from food web concentrations. AB - Biotransformation is widely recognized as the most important and most uncertain determinant of bioaccumulation. A step-wise method for estimating organism specific biotransformation half-lives from field observations and using established food web modeling is developed. As a proof of concept, the method is applied to the case of nine polycyclic aromatic hydrocarbons (PAHs) in a well studied food web in Bohai Bay, China. The estimated half-lives are in good agreement with the existing literature. The proposed biotransformation estimation method, through data mining, for sufficiently defined ecosystems, may greatly reduce the necessary animal testing involved in chemical assessments by providing useful guidance to experimentalists and regulators. PMID- 22248810 TI - Modelling the role of size, edge structure and terminations on the electronic properties of trigonal graphene nanoflakes. AB - Graphene nanoflakes provide a range of opportunities for engineering graphene for future applications, due to the large number of configurational degrees of freedom associated with the addition of different types of corners and edge states in the structure. Since these materials can, in principle, span the molecular to macroscale dimensions, the electronic properties may also be discrete or continuous, depending on the application in mind. However, since the widespread use of graphene nanoflakes will require them to be predictable, stable and robust against variations associated with some degree of structural polydispersivity, the development of a complete understanding of the relationship between structure, properties and property dispersion is essential. In this paper we used electronic structure computer simulations to model the thermodynamic, mechanical and electronic properties of trigonal graphene nanoflakes with acute (highly reactive) corners. We find that these acute corners introduce new features that are different to the obtuse corners characteristic of hexagonal graphene nanoflakes, as well as different electronic states in the vicinity of the Fermi level. The structure and properties are sensitive to size and functionalization, and may provide new insights into the engineering of graphene nanoflake components. PMID- 22248811 TI - Nanotechnology in motion. PMID- 22248813 TI - Translating research into everyday practice--the essential role of pediatric nurses. PMID- 22248812 TI - The bilateral movement condition facilitates maximal but not submaximal paretic limb grip force in people with post-stroke hemiparesis. AB - OBJECTIVES: Although healthy individuals have less force production capacity during bilateral muscle contractions compared to unilateral efforts, emerging evidence suggests that certain aspects of paretic upper limb task performance after stroke may be enhanced by moving bilaterally instead of unilaterally. We investigated whether the bilateral movement condition affects grip force differently on the paretic side of people with post-stroke hemiparesis, compared to their non-paretic side and both sides of healthy young adults. METHODS: Within a single session, we compared: (1) maximal grip force during unilateral vs. bilateral contractions on each side, and (2) force contributed by each side during a 30% submaximal bilateral contraction. RESULTS: Healthy controls produced less grip force in the bilateral condition, regardless of side (-2.4% difference), and similar findings were observed on the non-paretic side of people with hemiparesis (-4.5% difference). On the paretic side, however, maximal grip force was increased by the bilateral condition in most participants (+11.3% difference, on average). During submaximal bilateral contractions in each group, the two sides each contributed the same percentage of unilateral maximal force. CONCLUSIONS: The bilateral condition facilitates paretic limb grip force at maximal, but not submaximal levels. SIGNIFICANCE: In some people with post-stroke hemiparesis, the paretic limb may benefit from bilateral training with high force requirements. PMID- 22248814 TI - Pooled shRNA screen for sensitizers to inhibition of the mitotic regulator polo like kinase (PLK1). AB - RNAi screening holds the promise of systemizing the search for combination therapeutic strategies. Here we performed a pooled shRNA library screen to look for promising targets to inhibit in combination with inhibition of the mitotic regulator polo-like kinase (PLK1). The library contained ~4,500 shRNAs targeting various signaling and cancer-related genes and was screened in four lung cancer cell lines using both high (IC80) and low (IC20) amounts of the PLK1 inhibitor GSK461364. The relative abundance of cells containing individual shRNAs following drug treatment was determined by microarray analysis, using the mock treatment replicates as the normalizing reference. Overall, the inferred influences of individual shRNAs in both high and low drug treatment were remarkably similar in all four cell lines and involved a large percentage of the library. To investigate which functional categories of shRNAs were most prominent in influencing drug response, we used statistical analysis of microarrays (SAM) in combination with a filter for genes that had two or more concordant shRNAs. The most significant functional categories that came out of this analysis included receptor tyrosine kinases and nuclear hormone receptors. Through individual validation experiments, we determined that the two shRNAs from the library targeting the nuclear retinoic acid receptor gene RARA did indeed silence RARA expression and as predicted conferred resistance to GSK461364. This led us to test whether activation of RARA receptor with retinoids could sensitize cells to GSK461364. We found that retinoids did increase the drug sensitivity and enhanced the ability of PLK1 inhibition to induce mitotic arrest and apoptosis. These results suggest that retinoids could be used to enhance the effectiveness of GSK461364 and provide further evidence that RNAi screens can be effective tools to identify combination target strategies. PMID- 22248815 TI - Electrostatic assembly of a DNA superparamagnetic nano-tool for simultaneous intracellular delivery and in situ monitoring. AB - A superparamagnetic gammaFe(2)O(3) nanocarrier was developed, characterized by spectroscopic methods and evaluated for the delivery of a decoy oligonucleotide (dODN) in human colon carcinoma SW 480 cells. This nanoparticle-dODN bioconjugate (gammaFe(2)O(3)@dODN) was designed to target the signal transducer and activator of transcription 3, STAT3, a key regulator of cell survival and proliferation. We exploited a simple precipitation-redispersion mechanism for the direct and one step complexation of a labeled decoy oligonucleotide with iron oxide nanoparticles (NPs). The cell internalization of the decoy gammaFe(2)O(3)@dODN nanoparticles is demonstrated and suggests the potential for DNA delivery in biological applications. Despite the increasing use of NPs in biology and medicine, convenient methods to quantify them within cells are still lacking. In this work, taking advantage of the nonlinear magnetic behavior of our superparamagnetic NPs, we have developed a new method to quantify in situ their internalization by cells. FROM THE CLINICAL EDITOR: In this study, the authors demonstrate methods to quantify superparamagnetic nanocarriers within cells, taking advantage of the nonlinear magnetic behavior of the studied NPs. PMID- 22248816 TI - Improving interstitial transport of macromolecules through reduction in cell volume fraction in tumor tissues. AB - Interstitial transport of large molecules and nanoparticles is an important concern in nanomedicine-mediated cancer treatment. To that end, the current study was proposed to improve the transport through enlargement of extracellular space by treating tumors with hypertonic solution of mannitol and cytotoxic agents (e.g., ethacrynic acid [ECA]), which could effectively shrink and kill cells, respectively. In the study, the improvement in interstitial penetration of dextran was investigated ex vivo using rat fibrosarcoma tissues sectioned into 600 MUm slices. Experimental data showed that the hypertonic solution was more effective than ECA for improving interstitial penetration of dextran with molecular weights ranging from 4000 to 2,000,000. The extent of improvement depended on the size of dextran molecules and the time when the treatment was applied. Results from the study suggested that increases in both size and connectedness of interstitial pathways were important for improvement of interstitial transport of large molecules and nanoparticles. FROM THE CLINICAL EDITOR: This study reports on the optimization of interstitial transport both for large molecules and nanoparticles in nanomedicine-mediated cancer treatment. The study demonstrates that hypertonic solutions could efficiently lead to cancer cell shrinkage and more so than the applied cytotoxic agent thereby improving transport of chemotherapeutic entities. PMID- 22248817 TI - Harnessing nanoparticles to improve toxicity after head and neck radiation. AB - This article reports the evaluation of cerium oxide (CeO(2)) nanoparticles' ability to decrease xerostomia and radiation-induced dermatitis in mice after head and neck radiation. Mice were irradiated using an IC160 x-ray system. Two cohorts were included: (A) No-radiation and (B) 30 Gy/6 fractions, and were randomized into three groups: (1) saline, (2) 15 nM CeO(2) and (3) 15 MUM CeO(2). Stimulated salivary flow and radiation-induced dermatitis were evaluated post radiation. Stimulated sialometry demonstrated improved salivary production in all CeO(2) groups in comparison with controls (flow: 204 vs. 115 MUL/10 minutes, P = 0.0002). One week post radiation, G-III dermatitis decreased in the 15 MUM group in comparison with controls (10% versus 100% incidence, respectively). There was decreased skin hyperpigmentation at 12 weeks in the 15-MUM group in comparison with 15-nM and non-CeO(2) groups (50%, 70%, and 90% G-II, respectively). This study suggests that CeO(2) may be radioprotective for salivary production and reduces G-III dermatitis and skin hyperpigmentation incidence. CeO(2) as radioprotectant may be a feasible concept during radiotherapy. FROM THE CLINICAL EDITOR: This study demonstrates in a mouse model that cerium oxide (CeO(2)) nanoparticles may provide an important mechanism in preventing radiation induced xerostomia, a common complication of head and neck radiation treatments. PMID- 22248818 TI - pH-Dependent nanostructure based on isoquinoline-cyclodextrin conjugate for thrombosis therapy. AB - The modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with beta-cyclodextrin (beta-CD) provides an oral antithrombotic agent, 6-(3'S isoquinoline-3'-carboxylaminoethylamino)-6-deoxy-beta-CD (THIQA-beta-CD). In aqueous solution THIQA-beta-CD undergoes intermolecular inclusion complexation and forms pH-dependent nanostructures. The morphological feature of THIQA-beta-CD is a nanocloud consisting of numerous particles that are 5 nm-6 nm in diameter at pH 3.0. The nanocloud switches to a nanorod ranging from 100 nm to 385 nm in length at pH 7.2, then to nanowires of 50 nm to 530 nm in length at pH 10.1. THIQA-beta-CD, which has unusual nanostructures, offers enhanced stability in blood. Inhibition of thrombin-induced platelet aggregation in vitro and demonstrated antithrombotic efficacy in vivo. This investigation demonstrated that the modification of THIQA with beta-CD is a promising approach for clinical therapy of thrombus disease. The pH-dependent nanostructures of conjugate provide the desired in vivo antithrombotic activity and in vitro stability in blood. FROM THE CLINICAL EDITOR: This study a demonstrates that the modification of 3S 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with beta-cyclodextrin, which leads to pH dependent nanostructure formation, is a promising approach for clinical therapy of thrombotic disease. PMID- 22248819 TI - DNA immunization with HBsAg-based particles expressing a B cell epitope of amyloid beta-peptide attenuates disease progression and prolongs survival in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is an incurable and progressive neurodegenerative senile disorder associated with the brain accumulation of Abeta plaques. Although vaccines that reduce Abeta plaques can control AD, the rationale for their use at the onset of the disease remains debatable. Old humans and mice usually respond poorly to vaccines due to presumably age-related immunological impairments. Here, we report that by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike the Abeta peptide vaccine, DNA immunizations with the amino terminal Abeta(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-Abeta antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced Abeta plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting Abeta(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD. PMID- 22248820 TI - Antibodies against a Plasmodium falciparum antigen PfMSPDBL1 inhibit merozoite invasion into human erythrocytes. AB - One approach to develop a malaria blood-stage vaccine is to target proteins that play critical roles in the erythrocyte invasion of merozoites. The merozoite surface proteins (MSPs) and the erythrocyte-binding antigens (EBAs) are considered promising vaccine candidates, for they are known to play important roles in erythrocyte invasion and are exposed to host immune system. Here we focused on a Plasmodium falciparum antigen, PfMSPDBL1 (encoded by PF10_0348 gene) that is a member of the MSP3 family and has both Duffy binding-like (DBL) domain and secreted polymorphic antigen associated with merozoites (SPAM) domain. Therefore, we aimed to characterize PfMSPDBL1 as a vaccine candidate. Recombinant full-length protein (rFL) of PfMSPDBL1 was synthesized by a wheat germ cell-free system, and rabbit antiserum was raised against rFL. We show that rabbit anti PfMSPDBL1 antibodies inhibited erythrocyte invasion of wild type parasites in vitro in a dose dependent manner, and the specificity of inhibitory activity was confirmed using PfMSPDBL1 knockout parasites. Pre-incubation of the anti PfMSPDBL1 antibodies with the recombinant SPAM domain had no effect on the inhibitory activity suggesting that antibodies to this region were not involved. In addition, antibodies to rFL were elicited by P. falciparum infection in malaria endemic area, suggesting the PfMSLDBL1 is immunogenic to humans. Our results suggest that PfMSPDBL1 is a novel blood-stage malaria vaccine candidate. PMID- 22248821 TI - A Phase 1 clinical trial of Hantaan virus and Puumala virus M-segment DNA vaccines for hemorrhagic fever with renal syndrome. AB - Candidate DNA vaccines for hemorrhagic fever with renal syndrome expressing the envelope glycoprotein genes of Hantaan (HTNV) or Puumala (PUUV) viruses were evaluated in an open-label, single-center Phase 1 study consisting of three vaccination groups of nine volunteers. The volunteers were vaccinated by particle mediated epidermal delivery (PMED) three times at four-week intervals with the HTNV DNA vaccine, the PUUV DNA vaccine or both vaccines. At each dosing, the volunteers received 8 MUg DNA/4 mg gold. There were no study-related serious adverse events, and all injection site pain was graded as mild. The most commonly reported systemic adverse events were fatigue, headache, malaise, myalgia, and lymphadenopathy. Blood samples were collected on days 0, 28, 56, 84, 140, and 180, and assayed for the presence of neutralizing antibodies. In the single vaccine groups, neutralizing antibodies to HTNV or PUUV were detected in 30% or 44% of individuals, respectively. In the combined vaccine group, 56% of the volunteers developed neutralizing antibodies to one or both viruses. These results demonstrate that the HTNV and PUUV DNA vaccines are safe and can be immunogenic in humans when delivered by PMED. PMID- 22248822 TI - FOXL2 impairment in human disease. AB - FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome. PMID- 22248823 TI - Sensitivity of a superconducting nanowire detector for single ions at low energy. AB - We report on the characterization of a superconducting nanowire detector for ions at low kinetic energies. We measure the absolute single-particle detection efficiency eta and trace its increase with energy up to eta = 100%. We discuss the influence of noble gas adsorbates on the cryogenic surface and analyze their relevance for the detection of slow massive particles. We apply a recent model for the hot-spot formation to the incidence of atomic ions at energies between 0.2 and 1 keV. We suggest how the differences observed for photons and atoms or molecules can be related to the surface condition of the detector and we propose that the restoration of proper surface conditions may open a new avenue for SSPD based optical spectroscopy on molecules and nanoparticles. PMID- 22248824 TI - Prognostic impact of Ki-67 overexpression in subgroups categorized according to St. Gallen with early stage breast cancer. AB - BACKGROUND: Ki-67 overexpression has been reported to be related to a poor prognosis for early stage breast cancer. We analyzed whether Ki-67 has a prognostic impact on risk subgroups based on the recommendations at St. Gallen in 2007. METHODS: To determine the impact of Ki-67 on each risk group, a retrospective analysis was performed in patients with breast cancer who underwent curative surgery. Ki-67 was examined by immunohistochemistry with a predefined cutoff level of 10%. RESULTS: A total of 1,166 patients were eligible for this analysis. During the follow-up period, distant metastasis was observed in 164 patients (14.1%), and 80 patients (6.9%) died. Ki-67 overexpression (Ki-67 >= 10%) was identified as an independent prognostic factor for distant-metastatic free survival (DFS) and overall survival (OS) by univariate and multivariate analysis. In the intermediate-risk group, the difference between Ki-67 overexpression and no overexpression was statistically significant in 5-year DFS (90.9 vs. 83.4%, p = 0.002) and OS (98.1 vs. 95.8%, p = 0.002). However, in both the low- and high-risk groups, Ki-67 overexpression was not an independent prognostic factor for either 5-year DFS or OS. CONCLUSIONS: Ki-67 overexpression indicates an unfavorable prognostic impact for DFS and OS. However, this impact is restricted only to those patients classified at intermediate risk. PMID- 22248826 TI - Clinical perspectives of childhood tuberculosis in Taiwan. AB - Tuberculosis (TB) is an important public health issue in Taiwan and worldwide. Taiwan has made major progress in combating TB in the past 40 years. However, childhood TB still constitutes a significant challenge in disease control. From January to mid December 2011, 369 new cases of pediatric TB were confirmed. The relatively low case number and variable clinical presentations made it difficult for early detection. Latent TB infections in children also pose further complexity in clinical management. Knowledge of the clinical features of active and latent TB infection is crucial for efficient TB control. PMID- 22248827 TI - Computed tomography of children with pulmonary Mycobacterium tuberculosis infection. AB - Surveillance and control of tuberculous infection in pediatric patients, especially in those with a contact history, is important to prevent tuberculous infection in the general population. Totally 26 patients, younger than 14 years of age, who had a diagnosis of pulmonary Mycobacterium tuberculosis (TB), underwent both chest radiographs and computed tomography (CT), which were retrospectively reviewed and compared with those of 20 patients with community acquired bacterial pneumonia (CABP). TB patients were commonly afebrile and had less cavitating lesions or pleural fluid than CABP patients had. Focal or sub segmental lung opacities suggested the diagnosis of TB than of CABP. Chest CT could also help to identify enlarged, calcified, necrotic mediastinal lymph nodes, which are less frequently found in CABP and frequently obscured by thymic shadows on chest radiographs of children. Low-dose CT for children or infants suspected to have pulmonary TB infection could help to make the decision of further antibiotic treatment. PMID- 22248825 TI - Sgt1 acts via an LKB1/AMPK pathway to establish cortical polarity in larval neuroblasts. AB - Drosophila neuroblasts are a model system for studying stem cell self-renewal and the establishment of cortical polarity. Larval neuroblasts generate a large apical self-renewing neuroblast, and a small basal cell that differentiates. We performed a genetic screen to identify regulators of neuroblast self-renewal, and identified a mutation in sgt1 (suppressor-of-G2-allele-of-skp1) that had fewer neuroblasts. We found that sgt1 neuroblasts have two polarity phenotypes: failure to establish apical cortical polarity at prophase, and lack of cortical Scribble localization throughout the cell cycle. Apical cortical polarity was partially restored at metaphase by a microtubule-induced cortical polarity pathway. Double mutants lacking Sgt1 and Pins (a microtubule-induced polarity pathway component) resulted in neuroblasts without detectable cortical polarity and formation of "neuroblast tumors." Mutants in hsp83 (encoding the predicted Sgt1-binding protein Hsp90), LKB1, or AMPKalpha all show similar prophase apical cortical polarity defects (but no Scribble phenotype), and activated AMPKalpha rescued the sgt1 mutant phenotype. We propose that an Sgt1/Hsp90-LKB1-AMPK pathway acts redundantly with a microtubule-induced polarity pathway to generate neuroblast cortical polarity, and the absence of neuroblast cortical polarity can produce neuroblast tumors. PMID- 22248828 TI - Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs). AB - Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guerin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-gamma integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-gamma pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-gammaR1, IFN-gammaR2, IL-12p40, IL-12R-beta1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN gamma (autoAbs-IFN-gamma), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent MSMD phenotype lacking BCG induced diseases. PMID- 22248829 TI - Molecular diagnosis of childhood tuberculosis and infection with Bacilli Calmette Guerin in Taiwan. AB - Molecular techniques along with clinical evaluation have been demonstrated to be effective for differentiating childhood tuberculosis (TB), and for establishing an enhanced survey of adverse reactions of Bacilli Calmette-Guerin vaccination in Taiwan. Future development and evaluation of new diagnostics should be prioritized in strengthening the management of childhood TB. PMID- 22248830 TI - Detection of hepatitis C virus subtypes 6a, 6n, 6w and mixed infections using a modified multiplex real-time polymerase chain reaction protocol. AB - BACKGROUND/PURPOSE: In the past few years, many new subtypes in hepatitis C virus (HCV) genotype 6 have been identified. The aim of this study was to modify the multiplex real-time polymerase chain reaction (RT-PCR) protocol and use it to determine the HCV subtypes of a group of Taiwanese injection drug users (IDUs). METHODS: We used 76 serum specimens collected in northern Taiwan in 2008. Multiplex RT-PCR was used for HCV subtyping among those serum samples having anti HCV antibodies. Twenty cases were randomly selected for comparison with subtyping results from Inno-LiPa II tests and phylogenetic tree analysis using NS5B sequences. RESULTS: Multiplex RT-PCR assays showed that 60.5% (46/76) of IDUs had single HCV infection. Three out of 76 (3.9%) had double HCV infection (1b/6a, 2a/2b and 2b/6a). Besides this, 27.6% (21/76) had no HCV signal. One IDU had subtype 6n and two had subtype 6w infection. Inno-LiPa II tests misclassified all 6n and 6w cases as 1b subtype. CONCLUSION: Our modified multiplex RT-PCR protocol can be used to support molecular epidemiological studies and laboratory diagnoses of different HCV subtypes including genotype 6. PMID- 22248831 TI - Assessment of reasons for not intensifying antihypertensive treatment in the Taiwanese population. AB - BACKGROUND/PURPOSE: Despite availability of effective antihypertensives, blood pressure (BP) control is usually inadequate. The Reasons for not Intensifying Antihypertensive Treatment (RIAT) registry evaluated the reasons behind not modifying treatment in an international, cross-sectional study in 16 countries. METHODS AND RESULTS: The Taiwanese cohort of RIAT consisted of 8922 patients with untreated/uncontrolled essential hypertension recruited from 22 centers in the country. At the first visit, physicians selected target BP and antihypertensive treatment, and at the next three visits they measured BP and modified treatment/provided justification for not modifying treatment. Mean target BP selected by physicians was 134.6/84.6 +/- 5.1/5.0 mmHg, respectively. Patients' individual risk stratification determined the BP goals. More patients achieved targets according to the physicians' opinion than based on actual BP measurements: visit 2-50.6% vs. 48.6%; visit 3-58.4% vs. 55.2%; and visit 4-61.2% vs. 57.0%. At each visit, treatment remained unchanged for >60% patients not reaching target; the most common reason for this at visit 2 was the assumption that the time was too short to assess new drug therapy and at visits 3 and 4 was the assumption that target was reached/had almost been reached. CONCLUSION: About 40% Taiwanese hypertensive patients in RIAT did not reach BP targets after an average of 4 months' follow-up. The most common reason for not modifying treatment was the assumption that the target had been reached or had almost been reached. PMID- 22248832 TI - Occupational hand dermatitis among cement workers in Taiwan. AB - BACKGROUND/PURPOSE: Occupational dermatitis among cement workers is a major occupational health concern. The two most important occupational hazards for cement workers are irritant and allergic cement contact dermatitis. The objective of this study was to investigate the severity of occupational cement contact dermatitis and the common allergens among cement workers in Taiwan. METHODS: A total of 97 cement workers from the Cement Workers' Association of Tainan City and County participated in this study. A structured questionnaire was used to evaluate the demographic data and work-related activities of these cement workers. A complete skin examination was conducted, and skin manifestations were assessed by a dermatologist. Allergens from European Standard Tray (Chemotechnique Diagnostic AB, Sweden) with a total of 25 substances were used for patch testing. RESULTS: Our results showed that 65 out of 97 cement workers were suffering from occupational cement hand contact dermatitis. The most affected skin area was the hand. Thickening of the dorsal surface of the hand, especially around the metacarpophalangeal joint area, and hyperkeratosis of the palm were the major skin manifestations. The results of the patch test showed that 24 out of 97 were allergic to potassium dichromate, nine were allergic to thiuram mix, nine were allergic to fragrance mix and seven were allergic to cobalt chloride. The final diagnosis, based on the results of the skin examination and the patch test, showed that 43 of 97 cement workers had irritant cement contact dermatitis and 22 had allergic cement contact dermatitis. CONCLUSION: We conclude that occupational cement hand dermatitis among cement workers is an important and severe issue in Taiwan, and the most common allergens among cement workers are potassium dichromate, thiuram mix, fragrance mix and cobalt chloride. The high positive rate of chromium hypersensitivity among cement workers reflects the urgency to regulate the addition of ferrous sulfate to cement in Taiwan. PMID- 22248833 TI - Immunogenicity and safety of an AS03(A)-adjuvanted H5N1 influenza vaccine in a Taiwanese population. AB - BACKGROUND/PURPOSE: A multicenter study (NCT00449670) conducted across Taiwan, Singapore, Hong Kong and Thailand evaluated the safety and manufacturing consistency of four formulations of an AS03(A)-adjuvanted H5N1 vaccine in terms of immune response against the vaccine-homologous strain (A/Vietnam/1194/2004). This manuscript presents data from the Taiwanese population. METHODS: A total of 400 individuals, aged 18-60 years, were randomized into six groups (2:2:2:2:1:1 ratio) to receive two doses (21 days apart) of one of the four adjuvanted formulations (H5N1-AS03(A)-groups) or one of the two nonadjuvanted formulations (H5N1-DIL-groups). Blood samples collected before vaccination (Day 0) and 21 days after each vaccine dose were analyzed using hemagglutination inhibition (HI) assay. Adverse events were recorded. RESULTS: All four AS03(A)-adjuvanted formulations induced comparable immune responses against the A/Vietnam/1194/2004 strain; following the second dose, immune response in terms of HI antibodies was higher in the H5N1-AS03(A)-groups {seroprotection rate=91.6% [95% confidence interval (CI): 87.9-94.4]; geometric mean titer (GMT)=177.6 (95% CI: 153.2 206.0)} compared with the H5N1-DIL-groups [seroprotection rates=5.0% (95% CI: 1.4 12.3); GMT=6.3 (95% CI: 5.4-7.4)]. Immune response against the heterologous A/Indonesia/05/2005 strain was also stronger in the H5N1-AS03(A)-groups [seroprotection rate=45.6% (95% CI: 40.0-51.4); GMT=20.5 (95% CI: 17.8-23.7)] compared with the H5N1-DIL groups [seroprotection rate=0.0% (95% CI: 0.0-4.5); GMT=5.0 (95% CI: 5.0-5.0)]. The overall reactogenicity profile of the adjuvanted formulations was clinically acceptable. CONCLUSION: The AS03(A)-adjuvanted H5N1 influenza vaccine formulations induced stronger immune response against the vaccine-homologous and heterologous strains than the nonadjuvanted formulations. The AS03(A)-adjuvanted H5N1 vaccine demonstrated a good immunogenicity and an acceptable safety profile in the Taiwanese population. PMID- 22248834 TI - Ketamine-snorting associated cystitis. AB - Ketamine hydrochloride, commonly used as a pediatric anesthetic agent, is an N methyl-D-aspartic (NMDA) acid receptor antagonist with rapid onset and short duration of action. It produces a cataleptic-like state where the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. It has emerged as an increasingly popular choice among young drug users, especially within dance club venues. Cases of bladder dysfunction among recreational ketamine users were reported since Shahani et al first reported nine cases of ketamine-associated ulcerative cystitis in 2007. We report on four patients who had history of ketamine abuse, presenting with dysuria, fluctuating lower urinary tract symptoms (LUTS), lower abdominal or perineal pain, and impaired functional bladder capacities. Urinalysis showed pyuria and microhematuria. Urine culture was sterile. Bladder ulceration with severe diffuse hemorrhage and low bladder capacity were noted under anesthetized cystoscopic examination. Transurethral bladder mucosa biopsy was consistent with chronic cystitis. Cessation of ketamine abuse was the milestone of treatment, followed by the administration of mucosal protective agents, such as pentosan polysulphate or hyaluronic acid. Suprapubic pain was improved in three patients during follow-up. However, the outcome of treatment depends on the severity of the disease process, similar to that of interstitial cystitis (IC). PMID- 22248835 TI - Primary laryngeal tuberculosis. PMID- 22248836 TI - Response to "Medical leaders in Taiwan during Japanese colonization". PMID- 22248837 TI - Adiponectin beyond cardiometabolic disorders. PMID- 22248838 TI - Uncovered issues in the overview of nonalcoholic steatohepatitis. PMID- 22248839 TI - End-of-life care for cancer patients in Taiwan. PMID- 22248840 TI - Using atosiban in uterine contractions of early pregnancies after assisted reproduction. PMID- 22248841 TI - Hepatitis during antituberculosis treatment. PMID- 22248842 TI - The unaffordable cost of socioeconomic growth in disease prevention. PMID- 22248843 TI - [Nighttime blood pressure as new therapeutic target]. PMID- 22248844 TI - [Blood pressure should not exclusively be measured during daytime]. AB - 24-hour ambulatory blood pressure (BP) monitoring has major advantages over conventional BP measurement. The capacity to monitor BP throughout the full 24 hour allows the uncovering of abnormal nocturnal BP patterns. The current evidence shows that nighttime BP better reflects risk than daytime BP. Therefore, it is essential to control both daytime and nighttime BP to maximise the beneficial effects on clinical outcome of antihypertensive therapy. 24-hour ambulatory BP monitoring represents a unique tool to establish the most appropriate antihypertensive drug regimen for the individual patient. PMID- 22248845 TI - [Pancreatic trauma in children--operative versus non-operative treatment]. AB - Pancreatic trauma is more frequent in children than in adults and is often caused by trauma to the upper part of the abdomen. Mortality is low, but morbidity is high. Pancreatic trauma can be treated operatively or non-operatively, but there is disagreement about the optimal treatment strategy for patients with severe pancreatic lesions. In general, good results are achieved with non-operative treatment and secondary surgery is avoided, but prospective trials are needed to evaluate the method. PMID- 22248846 TI - [Optical and video-assisted laryngoscopy in difficult paediatric airways]. AB - Despite ongoing technological advances, direct laryngoscopy still remains the golden standard for endotracheal intubation in children and infants. However, in some infants it is almost impossible to obtain a view of glottis and the vocal cords. In this paper we present an overview of the recent advances in optical and video-assisted laryngoscopy in difficult paediatric airways. PMID- 22248847 TI - [Blood test results are available sooner if Point of Care testing is established in an emergency room]. AB - To determine patient priority and degree of urgency with an objective high quality evaluation, general Point of Care testing (POCT) was established as a novel facility in the emergency department at Holbaek Hospital, a laboratory that provides faster results for common lab tests. When evaluating response time from arrival of the patient to the time at which the test results are available, POCT is not a significantly better test method than ordinary test methods. This indicates that in order to benefit from POCT the time before taking blood samples should be reduced to a minimum. Overcrowding needs to be controlled in order to accomplish this. PMID- 22248848 TI - [Fallopian tube prolapse and Chlamydia peritonitis after vaginal hysterectomy]. AB - Fallopian tube prolapse and tuboovarian abscess are both uncommon complications to hysterectomy. A 42 year-old woman who had undergone vaginal hysterectomy two years prior, presented with pain, fever, and tender polyp-like mass in the vaginal vault and pelvic mass. Surgery revealed a tuboovarian abscess. A histological examination of the mass excised from the vaginal vault confirmed presence of fallopian tube epithelium. A polymerase chain reaction analysis of the peritoneal fluid revealed the presence of Chlamydia. PMID- 22248849 TI - [Conservative management of deformed twin pregnancy]. AB - A twin reversed arterial perfusion (TRAP) sequence was diagnosed in a monochoriotic, diamniotic twin pregnancy at GA 12 weeks + 2 days. According to the parents' wish the pregnancy was managed conservatively with close monitoring, with ultrasound biometry and Doppler flow measurements in the umbilical artery, middle cerebral artery and ductus venosus. At GA 34 weeks + 0 days the TRAP twin was growing rapidly and the amnion fluid index was increasing rapidly. An uncomplicated elective section was performed. The acardiac/pump twin weight ratio was 134%. The pump twin was without sequelae. PMID- 22248850 TI - [Arteriovenous malformation as a cause of intracerebral haemorrhage in a 13 year old girl]. AB - Spontaneous intracranial haemorrhages in children are rare. The leading cause of spontaneous bleeding is a rupture of arteriovenous malformations (AVM). This case study presents a 13 year-old girl with headache and slightly altered mental status due to bleeding from an unknown cerebral AVM. Although the initial symptoms may be non-specific it is a disease, which results in a significant mortality. A physician should keep the diagnosis in mind even though the incidence in children is very low. PMID- 22248851 TI - [Gastric bezoar caused by barium sulphate]. AB - We present the first case of a gastric bezoar caused by barium sulphate acting as an intermittently occluding mass in a patient who had undergone small bowel follow-through on suspicion of small bowel obstruction (SBO) after total pancreatectomy. The patient underwent acute surgery but intermittent symptoms of SBO persisted. A barium bezoar was seen on plain abdominal film and afterwards diluted and fragmented gastroscopically. A barium bezoar giving rise to SBO is a possible complication to barium follow-through in patients with impaired gastric transit time. PMID- 22248852 TI - [Intranasal non-Hodgkin lymphoma diagnosed as subsidiary finding by epistaxis]. AB - A 84 year-old woman was transferred to the ENT ward for treatment of epistaxis. An anterior rhinoscopy revealed a posterior bleeding source which was cauterised. A submucosal bulge was found in the cavity floor and biopsied. Histologic examination showed diffuse large B-cell lymphoma. Oncologic examination disclosed Ann Arbor stage 1A. The patient was treated with chemotherapy followed by involved field radiation therapy. She responded well to the therapy. Intranasal lymphoma is rare in Denmark with an incidence rate of 0,1-0,2 per 100,000 per year. PMID- 22248853 TI - [Cognitive therapy--or?]. PMID- 22248854 TI - Metal lost and found: dissipative uses and releases of copper in the United States 1975-2000. AB - Metals are used in a variety of ways, many of which lead to dissipative releases to the environment. Such releases are relevant from both a resource use and an environmental impact perspective. We present a historical analysis of copper dissipative releases in the United States from 1975 to 2000. We situate all dissipative releases in copper's life cycle and introduce a conceptual framework by which copper dissipative releases may be categorized in terms of intentionality of use and release. We interpret our results in the context of larger trends in production and consumption and government policies that have served as drivers of intentional copper releases from the relevant sources. Intentional copper releases are found to be both significant in quantity and highly variable. In 1975, for example, the largest source of intentional releases was from the application of copper-based pesticides, and this decreased more than 50% over the next 25 years; all other sources of intentional releases increased during that period. Overall, intentional copper releases decreased by approximately 15% from 1975 to 2000. Intentional uses that are unintentionally released such as copper from roofing, increased by the same percentage. Trace contaminant sources such as fossil fuel combustion, i.e., sources where both the use and the release are unintended, increased by nearly 50%. Intentional dissipative uses are equivalent to 60% of unintentional copper dissipative releases and more than five times that from trace sources. Dissipative copper releases are revealed to be modest when compared to bulk copper flows in the economy, and we introduce a metric, the dissipation index, which may be considered an economy-wide measure of resource efficiency for a particular substance. We assess the importance of dissipative releases in the calculation of recycling rates, concluding that the inclusion of dissipation in recycling rate calculations has a small, but discernible, influence, and should be included in such calculations. PMID- 22248855 TI - Hybrid liposomes affect cellular lipid constituents and caveolae structures. AB - We examined alterations of lipid constituents induced by hybrid liposomes (HLs) in cancer cells. As early as 1h after HL treatment, amounts of the raft/caveolae lipids sphingomyelin, ceramide, and ether-type PC were altered. In addition, the structures of caveolae on the cytoplasmic surface of the cell membrane were significantly changed. Our results suggest that alterations of lipid composition in caveolae mediate HL signaling for apoptosis. PMID- 22248856 TI - Reductive activation of 5-fluorodeoxyuridine prodrug possessing azide methyl group by hypoxic X-irradiation. AB - We prepared a 5-fluorodeoxyuridine (5-FdUrd) derivative possessing azide methyl group (N(3)-FdUrd) as a novel radiation-activated prodrug. The parent antitumor agent, 5-FdUrd, was released efficiently from N(3)-FdUrd by hypoxic X irradiation. On the other hand, the activation of N(3)-FdUrd was suppressed upon X-irradiation under aerobic conditions. A biological assay using A549 cells revealed that the cytotoxicity of N(3)-FdUrd was significantly enhanced by hypoxic X-irradiation. PMID- 22248857 TI - Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanine. AB - Efforts to modify the central proline portion of lead compound 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Especially, replacement with alanine afforded compound 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile. PMID- 22248858 TI - Synthesis and antikinetoplastid activity of a series of N,N'-substituted diamines. AB - A series of 25 N,N'-substituted diamines were prepared by controlled reductive amination of free aliphatic diamines with different substituted benzaldehydes. The library was screened in vitro for antiparasitic activity on the causative agents of human African trypanosomiasis, Chagas' disease and visceral leishmaniasis. The most potent compounds were derived from a subset of diamines that contained a 4-OBn substitution, having a 50% parasite growth inhibition in the submicromolar (against Trypanosoma cruzi) or nanomolar (against Trypanosoma brucei and Leishmania donovani) range. We conclude that members of this series of N,N'-substituted diamines provide new lead structures that have potential to treat trypanosomal and leishmanial infections. PMID- 22248859 TI - Precise control of repeating unit composition in biodegradable poly(3 hydroxyalkanoate) polymers synthesized by Escherichia coli. AB - The composition of medium-chain-length (MCL) poly(3-hydroxyalkanoate) (PHA) biopolymers is normally an uncontrollable random mixture of repeating units with differing side chain lengths. Attempts to generate MCL PHA homopolymers and control repeating unit composition have been published in native PHA-producing organisms but have limited ranges for the different sizes of repeating units that can be synthesized. In this study, a new Escherichia coli-based system that exhibits control over repeating unit composition for both MCL PHAs and short chain-length (SCL) PHAs has been developed, covering an unprecedented range of repeating units. The fadB and fadJ genes from the beta-oxidation pathway were eliminated from the chromosome of E. coli LS5218. The subsequent blockage in beta oxidation caused a buildup of enoyl-CoA intermediates, which were converted to PHAs by an (R)-specific enoyl-CoA hydratase (PhaJ4) and PHA synthase [PhaC1(STQK)] expressed from a plasmid DNA construct. Fatty acid substrates were converted to PHAs with repeating units equal in the number of carbon atoms to the fatty acid substrate. The broad substrate specificities of the PhaJ4 and PhaC1(STQK) enzymes allowed for the production of homopolymers with strict control over the repeating unit composition from substrates of four to twelve carbons in length. Polymers were purified and analyzed by GC, GC-MS, and NMR for structural composition and by DSC, TGA, and GPC for thermal and physical characteristics. This study marks the development of the first single biological system to achieve consistent repeating unit control over such a broad range of repeating units in PHAs. PMID- 22248860 TI - Effects of sertraline on behavioral alterations caused by environmental enrichment and social isolation. AB - Environmental conditions are known to play a critical role in the pathogenesis of affective disorders. In this study, the effects of sertraline, a selective serotonin (5-HT) reuptake inhibitor, on anxiety- and depression-like behaviors were investigated in rats reared in different housing conditions. Wistar rats of both sexes were divided into three groups according to their rearing conditions (Enriched = EC, Isolated = IC and Standard = SC), after weaning at postnatal day 21. While animals in control conditions were housed as a group of 4 rats in regular size plexiglass cages, social isolation groups were housed individually in metal cages. Animals in enriched conditions were housed as a group of 12 rats in specially designed cages equipped with different stimulating objects. Six weeks later, activitymeter, elevated plus maze, rotarod, grip, forced swimming and sucrose preference tests were applied to all animals and all of the tests were repeated after i.p. injection of sertraline (10 mg/kg/day) for 7 days. Environmental enrichment reduced the stereotypic behavior, improved the motor coordination and facilitated the learning skills in animals. However, housing conditions affected depression-like parameters, but not anxiety-like parameters. Sertraline treatment reduced the depression-like effect in EC and SC, but not in IC. It decreased anxiety-like behavior in IC while increased in EC. Socially isolated animals preferentially consumed more sucrose and water than the other groups, and interestingly, these differences became more significant following sertraline treatment. These results show that the responses of animals to anti depressive drugs could be differentially affected by the behavioral consequences of the diverse housing conditions. Thus, to improve the treatment of depression; behavioral consequences of diverse housing conditions should be taken into consideration. PMID- 22248861 TI - Molecular dynamics simulations of the interaction of glucose with imidazole in aqueous solution. AB - Molecular dynamics simulations were carried out on a concentrated system of beta d-glucopyranose and imidazole molecules in a periodic box of water at 298K. The purpose of the simulations was to determine whether or not there was any tendency for these two solutes to associate in an aqueous environment, as has previously been observed for other planar functional groups from amino acid side chains, such as the indole group of tryptophan or the phenolic group of tyrosine. A weak stacking interaction between beta-d-glucopyranose, as a model for cellulose, and imidazole was indeed observed, with an energy of ~0.25kcal/mol per pair, less than kT. Somewhat surprisingly, considerable imidazole self-association into small aggregates (dimers and trimers) was also observed, with binding energies of ~0.4kcal/mol per pair, although still less than kT. Considerable non-stacked interactions between glucose and imidazole through hydrogen bonding were also found. These hydrogen bonds primarily involved the N3 atom of imidazole, because the N-H group of N1 was insufficiently polar to compete for water hydrogen bond partners. PMID- 22248863 TI - Combination therapy for pulmonary artery hypertension: what is the evidence? PMID- 22248862 TI - Inactivation of thiol-dependent enzymes by hypothiocyanous acid: role of sulfenyl thiocyanate and sulfenic acid intermediates. AB - Myeloperoxidase (MPO) forms reactive oxidants including hypochlorous and hypothiocyanous acids (HOCl and HOSCN) under inflammatory conditions. HOCl causes extensive tissue damage and plays a role in the progression of many inflammatory based diseases. Although HOSCN is a major MPO oxidant, particularly in smokers, who have elevated plasma thiocyanate, the role of this oxidant in disease is poorly characterized. HOSCN induces cellular damage by targeting thiols. However, the specific targets and mechanisms involved in this process are not well defined. We show that exposure of macrophages to HOSCN results in the inactivation of intracellular enzymes, including creatine kinase (CK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In each case, the active-site thiol residue is particularly sensitive to oxidation, with evidence for reversible inactivation and the formation of sulfenyl thiocyanate and sulfenic acid intermediates, on treatment with HOSCN (less than fivefold molar excess). Experiments with DAz-2, a cell-permeable chemical trap for sulfenic acids, demonstrate that these intermediates are formed on many cellular proteins, including GAPDH and CK, in macrophages exposed to HOSCN. This is the first direct evidence for the formation of protein sulfenic acids in HOSCN-treated cells and highlights the potential of this oxidant to perturb redox signaling processes. PMID- 22248865 TI - Chemical composition, antiproliferative and antioxidant properties of lipid classes in ordinary and dark muscles from chub mackerel (Scomber japonicus). AB - This study investigated to compare lipid profiles in ordinary and dark muscles from chub mackerel and to examine antiproliferative and antioxidative properties of lipid classes. The average levels of neutral lipids (NL), glycolipids (GL), and phospholipids (PL) in ordinary muscle were 92.32+/-0.19%, 5.10+/-0.48%, and 2.58+/-0.46%; in dark muscle were 96.88+/-0.15%, 2.59+/-0.36%, and 0.54+/-0.29%, respectively. The fatty acid composition indicated that PL had a higher percentage of PUFA (especially 22:6n-3) with lower percentages of SFA and MUFA compared to NL and GL (p<0.05). The main ion peaks of GL in ordinary and dark muscles showed that monocharged and bischarged molecular ion were presented at m/z 876.9 and 438.8, respectively. In MTT assay, inhibition of AGS and HT-29 cell proliferation was greatest with the 0.5 and 1.0 mg mL(-1) GL treatments. The GL of ordinary muscle with 0.05 mg mL(-1) concentrations markedly decreased the levels of reactive oxygen species (ROS) induced by H2O2 compared to the control (p<0.05). From our results, GL might have antiproliferative and antioxidant properties based on protective effect against the production of intracellular ROS. PMID- 22248866 TI - Two generation reproduction and teratogenicity studies of feeding quinocetone fed to Wistar rats. AB - To investigate the reproductive toxicity and teratogenic potential of quinocetone, a growth promoting agent, Wistar rats were fed different diets containing 0, 50, 300 and 1800 mg/kg quinocetone or 300 mg/kg olaquindox. Groups of 15 males and 30 females (F(0)) were fed through a 10-week prebreed period as well as during mating, gestation, parturition and lactation. At weaning, 12 males and 24 females of F(1) generation weanlings per group were selected randomly as parents for F(2) generation. Selected F(1) weanlings were exposed to the same diet and treatment as their parents. At the highest quinocetone group, body weights in F(0) and F(1) rats, fetal body weight on day 21 after birth and number of viable fetuses in F(0) and F(1) generation significantly decreased. In teratogenicity study, groups of 12 males and 24 females were fed with the same diets through a 12-week prebreed period and matting periods. Pregnant rats were subjected to cesarean section on GD 20 for teratogenic examination. At the highest quinocetone group, body weights and feed efficiency, fetal body lengths, tail lengths, litter weights and number of viable fetuses significantly decreased. The NOAEL for reproduction/development of quinocetone for rats was estimated to be 300 mg/kg diet. PMID- 22248867 TI - High-speed atomic force microscopy coming of age. AB - High-speed atomic force microscopy (HS-AFM) is now materialized. It allows direct visualization of dynamic structural changes and dynamic processes of functioning biological molecules in physiological solutions, at high spatiotemporal resolution. Dynamic molecular events unselectively appear in detail in an AFM movie, facilitating our understanding of how biological molecules operate to function. This review describes a historical overview of technical development towards HS-AFM, summarizes elementary devices and techniques used in the current HS-AFM, and then highlights recent imaging studies. Finally, future challenges of HS-AFM studies are briefly discussed. PMID- 22248868 TI - Resistance to EGFR inhibitors: molecular determinants and the enigma of head and neck cancer. PMID- 22248869 TI - A survey of psychiatrists' expectations of clinical pharmacists in Riyadh, Saudi Arabia. AB - OBJECTIVES: To measure psychiatrists' experience and their expectations of the role of clinical pharmacists in Riyadh, Saudi Arabia. SUBJECTS AND METHODS: The psychiatrists' experience and their expectations were collected using a 4-part self-completed questionnaire: (a) demographic information, (b) psychiatrists' current expectations of the roles of pharmacists, (c) psychiatrists' actual experience with pharmacists, and (d) psychiatrists' future expectations of pharmacists' roles. Each part included a set of statements for which respondents were asked to indicate their level of agreement using a 5-point Likert scale. RESULTS: Of the 102 questionnaires delivered to the Department of Psychiatry at 7 hospitals, 77 were returned, representing a response rate of 75%. 59 (77%) psychiatrists expected pharmacists to take personal responsibility for resolving any drug-related problems; 62 (81%) expected them to maintain a complete medication profile, and 58 (75%) expected them to educate patients about the safety and appropriate use of their medication. From their current experience with pharmacists, respondents indicated that pharmacists routinely counsel patients (33, 43%), inform them about the most cost-effective alternative (37, 48%), and discuss with them the therapeutic value of the drugs (37, 48%). 49 (63%) of respondents agreed that in the future, pharmacists should routinely adjust the drug therapy for patients under protocol approved by the physician, and 51 (66%) felt that pharmacists should share legal responsibility for clinical outcomes. CONCLUSION: Psychiatrists in Riyadh had great expectations of clinical pharmacists to take personal responsibility for resolving drug-related problems they discovered and to assist in designing drug therapy treatment plans. The psychiatrists' current experience with pharmacists did not, in some cases, meet their expectations. PMID- 22248870 TI - Dual chamber pacing relieves obstruction in Japanese-variant hypertrophic cardiomyopathy. AB - Japanese-variant or apical hypertrophic cardiomyopathy (HCM) is a specific type of HCM, first described in Japan and initially thought to carry a benign prognosis. However, current evidence suggests that these patients experience severe symptoms and are at increased risk of ventricular arrhythmias and death, especially in the presence of an apical akinetic chamber. The management of patients who do not respond to medical therapy is challenging. We describe a patient with Japanese-variant HCM, with an apical akinetic chamber and severe symptoms who failed medical therapy. The use of dual chamber pacing relieved obstruction and significantly improved the patient's symptoms. PMID- 22248872 TI - Lung abscess: update on microbiology and management. AB - A lung abscess is a circumscribed collection of pus in the lung as a result of a microbial infection, which leads to cavity formation and often a radiographic finding of an air fluid level. Patients with lung abscesses commonly present to their primary care physician or to the emergency department with "nonresolving pneumonia." Although, the incidence of lung abscess has declined since the introduction of antibiotic treatment, it still carries a mortality of up to 10% 20%. This article discusses in detail the up-to-date microbiology and the management of lung abscesses. PMID- 22248873 TI - Nanofiltration and sensing of picomolar chemical residues in aqueous solution using an optical porous resonator in a microelectrofluidic channel. AB - For the first time the use of a porous microresonator placed in a microelectrofluidic system for integrated functions of nanofiltration and sensing of small biomolecules and chemical analytes in extremely dilute solution was proposed and investigated. As an example, aminoglycosides in drug residues in food and livestock products were considered as the trace chemical analyte. The filtration process of the charged analyte in aqueous solution driven by an applied electrical field and the accompanying optical whispering-gallery modes in the resonator are modeled. The dynamic process of adsorption and desorption of the analyte onto the porous matrix is studied. Deposition of the analyte inside the porous structure will alter the material refractive index of the resonator, and thus induce an optical resonance frequency shift. By measuring the optical frequency shift, the analyte concentration as well as the absorption/desorption process can be analyzed. Through an intensive numerical study, a correlation between the frequency shift and the analyte concentration and the applied electrical voltage gradient was obtained. This reveals a linear relationship between the resonance frequency shift and the analyte concentration. The applied electrical voltage substantially enhances the filtration capability and the magnitude of the optical frequency shift, pushing the porous resonator-based sensor to function at the extremely dilute picomolar concentration level for small bio/chemical molecules down to the sub-nanometer scale. Moreover, use of the second-order whispering-gallery mode is found to provide better sensitivity compared with the first-order mode. PMID- 22248871 TI - Antihypertensive and metabolic effects of Angiotensin receptor blocker/diuretic combination therapy in obese, hypertensive African American and white patients. AB - A clinical trial showed comparable blood pressure (BP) lowering by valsartan/hydrochlorothiazide and amlodipine/hydrochlorothiazide in obese hypertensive patients. Relative to amlodipine/hydrochlorothiazide, valsartan/hydrochlorothiazide reduced the hyperglycemic response to glucose challenge. An objective of this post hoc analysis was to determine whether this benefit extended to African Americans and whites. Treatments (160/12.5 mg of valsartan/hydrochlorothiazide force titrated to 320/25 mg of valsartan/hydrochlorothiazide at week 4 or 12.5 mg of hydrochlorothiazide force titrated to 25 mg of hydrochlorothiazide at week 4 with 5 and 10 mg of amlodipine added at weeks 8 and 12, respectively) were administered once daily. Both treatments reduced clinic BP from baseline to all visits (P < 0.0001), regardless of race/ethnicity (126 African Americans, 212 whites). In African Americans, there were no significant between-treatment differences in clinic or ambulatory BP lowering at weeks 8 or 16. Whites responded better to valsartan/hydrochlorothiazide. In both racial/ethnic subgroups, the addition of valsartan but not amlodipine mitigated the hyperglycemic response to hydrochlorothiazide through enhanced insulin secretion. Valsartan/hydrochlorothiazide was as effective as amlodipine/hydrochlorothiazide was in reducing BP in obese, hypertensive African Americans and better than amlodipine/hydrochlorothiazide in whites. In both racial/ethnic subgroups, the addition of valsartan to hydrochlorothiazide reduced the negative metabolic effects associated with thiazide therapy. PMID- 22248874 TI - Noncutaneous melanoma have distinct features from each other and cutaneous melanoma. AB - OBJECTIVE: Compared to the cutaneous melanoma, noncutaneous melanomas are relatively rare and have a distinct pattern of behavior. We performed this study to define the clinical characteristics and outcomes of patients with noncutaneous melanomas and emphasize how they differ from cutaneous melanomas. METHODS: 216 patients who were diagnosed with noncutaneous melanoma were assessed and their medical records between 2000 and 2010 were retrieved from the cancer registry. 475 patients with cutaneous melanoma were used for comparison. RESULTS: Of the 216 noncutaneous melanoma patients, 83 had mucosal melanoma, 101 had ocular melanoma and 32 had unknown primaries. For mucosal melanoma, the head and neck was the most common anatomic site (53%), followed by the gastrointestinal tract (37%), female genital (6%) and urinary tract (4%). The majority of the ocular melanomas (94%) originated in the uvea. 32 patients demonstrated a primary unknown disease with regional metastasis as the dominant behavior (72%). Age was found to be statistically significantly different among melanoma patients (p < 0.001). Younger patients had more cutaneous and unknown primary melanomas, whereas older patients had more ocular and mucosal melanoma. In subset analyses, we found significant differences between cutaneous and ocular (p = 0.038) or mucosal (p < 0.001) melanomas. The ratios of metastasis on admission were higher in patients with mucosal (27.7%) and unknown primary (28.1%) melanomas, and lower for ocular (3%) melanomas (p < 0.001). Patients with cutaneous melanoma had an intermediate (12%) ratio. Patients with ocular melanoma had better outcome than patients with other melanoma sites (p < 0.05). While overall survival for cutaneous melanoma was significantly negatively correlated with male gender (p < 0.001), advanced stages (p < 0.001) and old age (p = 0.005), stage IV disease was the only independent prognostic factor in patients with ocular melanoma (p = 0.006). No prognostic factor for outcome was found for either mucosal or unknown primary melanomas. CONCLUSION: The clinical presentations and prognoses of different primary sites of melanoma are distinctive. Therefore, approaches to these melanomas should be different. PMID- 22248875 TI - Fully functional global genome repair of (6-4) photoproducts and compromised transcription-coupled repair of cyclobutane pyrimidine dimers in condensed mitotic chromatin. AB - During mitosis, chromatin is highly condensed, and activities such as transcription and semiconservative replication do not occur. Consequently, the condensed condition of mitotic chromatin is assumed to inhibit DNA metabolism by impeding the access of DNA-transacting proteins. However, about 40 years ago, several researchers observed unscheduled DNA synthesis in UV-irradiated mitotic chromosomes, suggesting the presence of excision repair. We re-examined this subject by directly measuring the removal of UV-induced DNA lesions by an ELISA and by a Southern-based technique in HeLa cells arrested at mitosis. We observed that the removal of (6-4) photoproducts from the overall genome in mitotic cells was as efficient as in interphase cells. This suggests that global genome repair of (6-4) photoproducts is fully functional during mitosis, and that the DNA in mitotic chromatin is accessible to proteins involved in this mode of DNA repair. Nevertheless, not all modes of DNA repair seem fully functional during mitosis. We also observed that the removal of cyclobutane pyrimidine dimers from the dihydrofolate reductase and c-MYC genes in mitotic cells was very slow. This suggests that transcription-coupled repair of cyclobutane pyrimidine dimers is compromised or non-functional during mitosis, which is probably the consequence of mitotic transcriptional repression. PMID- 22248877 TI - Genetic mutations in chronic myelogenous leukemia: when to check and what to do? AB - PURPOSE OF REVIEW: The review will appraise the literature concerning ABL kinase domain mutations that has appeared over the last year and identify new questions, answers to old questions, and discuss new trends in clinical and laboratory based research. RECENT FINDINGS: A concise summary of European LeukemiaNet guidelines for kinase domain mutation studies was published this year. A new controversial topic emerged: the relevance of IC50 data to guide second-line tyrosine kinase inhibitor (TKI) therapy. Although flaws in the methodology have been acknowledged, one group summarily rejected IC50 data and recommended that clinicians use individual patient comorbidities and drug safety profiles. The influence of kinase domain mutations on response to second-line and third-line TKI therapy was also published this year; unexpectedly, kinase domain mutations were found to have no effect on response or survival. However, the presence of a kinase domain mutation did influence survival following hematopoietic stem cell transplantation. Lastly, new findings from laboratories identified transcription factors BCL6 and STAT5 as potential new treatment targets. SUMMARY: The last 12 months has brought much attention to clinical management of patients with kinase domain mutations and identified a new controversy concerning IC50 data use in the clinic. Kinase domain mutations do not appear to influence response to second line and third-line response to TKI therapy. New targets that do not directly involve BCR-ABL added potential new therapeutic approaches. PMID- 22248876 TI - RIM, Munc13, and Rab3A interplay in acrosomal exocytosis. AB - Exocytosis is a highly regulated, multistage process consisting of multiple functionally definable stages, including recruitment, targeting, tethering, priming, and docking of secretory vesicles with the plasma membrane, followed by calcium-triggered membrane fusion. The acrosome reaction of spermatozoa is a complex, calcium-dependent regulated exocytosis. Fusion at multiple sites between the outer acrosomal membrane and the cell membrane causes the release of the acrosomal contents and the loss of the membranes surrounding the acrosome. Not much is known about the molecules that mediate membrane docking in this particular fusion model. In neurons, the formation of the ternary RIM/Munc13/Rab3A complex has been suggested as a critical component of synaptic vesicles docking. Previously, we demonstrated that Rab3A localizes to the acrosomal region in human sperm, stimulates acrosomal exocytosis, and participates in an early stage during membrane fusion. Here, we report that RIM and Munc13 are also present in human sperm and localize to the acrosomal region. Like Rab3A, RIM and Munc13 participate in a prefusion step before the efflux of intra-acrosomal calcium. By means of a functional assay using antibodies and recombinant proteins, we show that RIM, Munc13 and Rab3A interplay during acrosomal exocytosis. Finally, we report by electron transmission microscopy that sequestering RIM and Rab3A alters the docking of the acrosomal membrane to the plasma membrane during calcium-activated acrosomal exocytosis. Our results suggest that the RIM/Munc13/Rab3 A complex participates in acrosomal exocytosis and that RIM and Rab3A have central roles in membrane docking. PMID- 22248878 TI - Optimizing hypomethylating agents in myelodysplastic syndromes. AB - PURPOSE OF REVIEW: Hypomethylating agents (HMAs) improve the outcome of higher risk myelodysplastic syndromes (MDS) and provide multilineage response in lower risk patients but their results must be optimized, especially as the poor outcome of patients after HMA failure is now established. RECENT FINDINGS: Current efforts include evaluation of novel outpatient administration schedules and routes, improving compliance and drug exposure to reach continuous hypomethylation. Novel combination strategies are emerging, with histone deacetylase inhibitors or immunomodulatory compounds, but none has proven superior to HMA single-agent therapy so far. Improved understanding of the epigenetic deregulation of MDS and of HMA's mode of action has allowed putative biomarkers to emerge, including multiple gene methylation patterns, and gene mutations, notably TET2 mutations. As HMAs may elicit antileukemic immune responses, they are also being evaluated in patients eligible for allogeneic stem cell transplantation. SUMMARY: The indication and practical use of HMAs in MDS so far remain those of phase III registration studies, but will hopefully be modified with future results of ongoing clinical and translational research. PMID- 22248879 TI - New induction and postinduction strategies in acute myeloid leukemia. AB - PURPOSE OF REVIEW: Improving or replacing the traditional induction (3 + 7) and consolidation (high-dose cytarabine; Ara-C) as the standard of care for acute myeloid leukemia (AML) has proved disappointing. RECENT FINDINGS: Recent studies have raised the possibility that daunorubicin dose escalation might have the potential to improve survival. Antibody-directed therapy by means of gemtuzumab ozogamicin as an adjunct to induction chemotherapy may yet be a viable option in older patients, and alternative nucleoside analogues in induction could help higher risk subgroups. In consolidation, the number of courses and dose level of Ara-C required are being clarified. New treatments for older patients who will not be subjected to conventional chemotherapy are an active area, but randomized trials have not yet usurped low-dose Ara-C (LDAC). SUMMARY: Recent information in these areas is reviewed. PMID- 22248880 TI - A case of a confusional arousal arising from REM sleep. PMID- 22248881 TI - Eosinophils from patients with type 1 diabetes mellitus express high level of myeloid alpha-defensins and myeloperoxidase. AB - Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of pancreatic beta cells. Recently, small cationic alpha-defensin molecules have been implicated in the pathogenesis of certain inflammatory and autoimmune diseases. The purpose of this study was to assess the alpha-defensin expression in patients with T1D and elucidate the cellular source of their production. Our results show that 30% of patients exhibit increased levels of alpha-defensin mRNAs in their capillary blood. Quantitative RT-PCR performed on FACS-sorted granulocytes identified CD15(dull)/CD14(weak) population as the cellular source of alpha-defensins. Surprisingly, this granulocyte subpopulation displayed augmentation of alpha-defensin expression in all T1D patients tested. The determination of cell surface markers, expression of cell-specific genes and confocal microscopy identified CD15(dull)/CD14(weak) cells as eosinophils. The presence of transcriptionally active eosinophils in diabetic patients suggests that eosinophils could be a part of an intricate innate immune cellular network involved in the development of diabetes. PMID- 22248882 TI - Preparation and characterization of insulin-loaded bioadhesive PLGA nanoparticles for oral administration. AB - Poly(D,L-lactide-co-glycolide) nanoparticles (PLGA-NP) have been extensively used as a drug delivery system for proteins and peptides. However, their negative surface charge decreases bioavailability under oral administration. Recently, cationically modified PLGA-NP has been introduced as novel carriers for oral delivery. The characteristics of the nanoparticles, such as particle size, surface charge, and bioadhesion are considered the most significant determinants of the effect of these nanoparticles both in vitro and in vivo. Our aim was to introduce and evaluate the physiochemical characteristics, bioadhesion, and biological activity of positively charged chitosan-coated PLGA-NP (CS-PLGA-NP), using insulin as a model drug. Results were compared to those of common negatively charged PLGA-NP and the in vitro cytotoxicity of the two types of nanoparticles was examined. These results indicate that both CS-PLGA-NP and PLGA NP had a narrow size distribution, averaging less than 150 nm. CS-PLGA-NP was positively charged (+43.1 +/- 0.3 mV), exhibiting the cationic nature of chitosan, whereas PLGA-NP showed a negative surface charge (-1.72 +/- 0.2 mV). CS PLGA-NP exhibited stronger bioadhesive potency than PLGA-NP and much greater relative pharmacological availability with regard to orally delivered insulin. In addition, an evaluation of cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay showed no increase in toxicity in either kind of nanoparticle during the formulation process. The study proves that CS PLGA-NP can be used as a vector in oral drug delivery systems for proteins and peptides due to its positive surface charge and bioadhesive properties. PMID- 22248883 TI - Real-time monitoring of DNA hybridization and melting processes using a fiber optic sensor. AB - In this paper a fiber optic surface plasmon resonance (FO-SPR) sensor was used to analyze the melting process of DNA linked to silica nanoparticles. Real-time monitoring of a DNA melting process has rarely been studied using surface plasmon resonance (SPR), since most commercial SPR setups do not allow for dynamic and accurate temperature control above 50 degrees C. The FO-SPR sensor platform, with silica nanobead signal amplification, allows sensing inside a standard PCR thermocycler, which makes high resolution DNA melting curve analysis possible. This innovative combination was used to characterize the hybridization and melting events between DNA immobilized on the sensor surface and DNA probes on silica nanoparticles. At optimized hybridization conditions complementary DNA strands of different lengths could be distinguished. While the real-time FO-SPR analysis of DNA hybridization did not result in significant variances, the analysis of DNA melting determined the exact length of overlap and the matching Gibbs energy. PMID- 22248884 TI - Galectin-1 as an oncotarget in gliomas and melanomas. PMID- 22248885 TI - Preemptive analgesia in paediatric surgery. PMID- 22248886 TI - Hypospadias in Sudan, clinical and surgical review. AB - BACKGROUND: Hypospadias is one of the commonest penile abnormalities in new born males, and occurs as a result of a birth defect resulting in a urethral opening anywhere from the glans penis along the ventral aspect of the shaft of the penis up to the scrotum or the perineum in extreme cases. The condition has a huge impact on the patient's psychological, emotional and sexual well being. This study aimed to evaluate the current trend in the treatment of hypospadias in Sudan. MATERIALS AND METHODS: The was a retrospective study done in Elribat university hospital, department of Paediatrics surgery, for patients who underwent hypospadias surgical repair in the period January 2006 to June 2007. RESULTS: There were 50 patients in this study. Regional distribution of the patients showed that 52% of the patients live in Khartoum state, the capital, while 48% were from the peripheries; 12% of patients had family history of similar condition (Hypospadias) and 54% were of low socioeconomic status. Anterior hypospadias was the commonest type (46%), and associated chordee occurred in most of the patients (88%). The most common associated anomalies found were undescended testicles (20%) and inguinal hernia only in 2%. The most common type of repair was MAGPI (meatal advancement and glanuloplasty) with 42% of cases, anterior hypospadias commonest type with 46% of cases, 12% of cases had a family history of the condition and an overall complication rate of 26%. Chordee was the most prevalent association in 88% of cases. CONCLUSION: There is a high familial tendency for hypospadias in Sudan. Associated chordee and other anomalies are in keeping with other reports. Corrective surgery for hypospadias is associated with high complication rate in our setting. Collaboration between surgical specialties such as plastic surgeons, paediatrics urologist and general surgeons may improve the present complication scenario. PMID- 22248887 TI - A practical offer for hypospadias dressing: Allevyn(r). AB - INTRODUCTION: An ideal hypospadias dressing material must be cheap and non allergenic. It also must be easily and quickly applied, non-adherent to the incision, effectively absorb the leakages of the wound, pressurise the flaps and grafts effectively, without damaging the blood circulation, protect against infections, and must be easily and painlessly removable. We use a product that is produced for healing chronic wounds and burns, Allevyn Adhesive(r) , as a wound dressing after hypospadias surgery and circumcision. MATERIALS AND METHODS: We included 61 hypospadias and 85 circumcision cases operated in our clinic between November 2007 and August 2010, for the study. Allevyn Adhesive(r) dressing was used in all the cases. For approximately every 10 patients a sheet sized 22.5 x 22.5 cm was used. RESULTS: We did not meet any difficulty in application and removal of the dressings and the dressing could be performed easily even by inexperienced health personnel. The cost of the application is about $5 for each case. We did not encounter any complications with regard to the dressing during the follow-up. CONCLUSION: We did not encounter any of the complications with Allevyn Adhesive(r) that were seen with the use of traditional dressing products, such as, problems with removal of the dressing, development of maceration secondary to inadequate absorption of leakages from the wound, cohesions of the wound lips, and infections and necrosis of the flaps and grafts, secondary to erroneous locations of the dressings. There was no additional therapeutical cost due to the use of this product. For these reasons we thought that Allevyn Adhesive(r) is a good alternative for the dressing of hypospadias and circumcision. PMID- 22248888 TI - Comparison between late-presenting and isolated neonatal congenital diaphragmatic hernias. AB - PURPOSE: Late-presenting posterolateral congenital diaphragmatic hernias (CDH) are anatomically similar to isolated neonatal CDH but are diagnosed and treated after the first month of life. We aim to characterise the clinical manifestations and short-term postoperative course of this entity and compare it with isolated CDH of the neonatal period. MATERIALS AND METHODS: In the 30-year period from 1980 to 2010, 116 children with CDH were treated at the Aghia Sophia Children's Hospital, Athens, Greece. Twenty-three (19%) of these children were late presenting cases, being diagnosed between the ages of 1 month and 4 years. Ninety three were neonatal cases, of whom 22 (24%) were excluded due to severe associated anomalies, leaving 71 cases of isolated neonatal CDH. We compared these two groups of patients with regard to preoperative symptoms, postoperative hospital stay, time to complete feeding, overall complication rate, and reoperation rate. RESULTS: Isolated neonatal cases presented more often with acute respiratory symptoms (n=25; P= 0.016) and failure to thrive (n= 38; P= 0.03). Late-presenting cases presented more often with chronic respiratory symptoms (n=14;P= 0.0044) or gastrointestinal symptoms (n=12; P= 0.006). Thirty five cases with minor or serious complications were reported in the neonatal group, whereas only five complications were observed in the late-presenting group (P= 0.028). We did not record any recurrences or reoperations in the late presenting group, but we had two recurrences and three reoperations in the neonatal group. Time to full feeds and postoperative hospital stay was shorter in the late-presenting group. CONCLUSIONS: Our data demonstrate differences between the two groups in preoperative symptoms and short-term postoperative complications and short-term outcome. Late-presenting cases of CDH had a greater number of chronic symptoms preoperatively, more favorable postoperative outcomes, and less recurrences and reoperations. PMID- 22248889 TI - Meckel's diverticulum in paediatric practice on Crete (Greece): a 10-year review. AB - BACKGROUND: Although Meckel's diverticulum (MD) is the most prevalent congenital abnormality of the gastrointestinal tract, it has varied presentations and often becomes a diagnostic challenge. The purpose of this study was to review the diverse presentations of MD, record the epidemiologic features for Crete and review the detection techniques and the treatment options. PATIENTS AND METHODS: This was a review of the records of all children who underwent surgery for MD in the department of Paediatric Surgery of the University Hospital of Crete (Greece) between January 1999 and January 2009. RESULT: A total of 45 patients (32 male and 13 female) aged 1 to 13 years (median 10 years) with a diagnosis of MD were retrospectively reviewed. The collected data were analysed, looking at age, gender, clinical features, investigations, histopathological findings and surgical interventions. In 25 patients, MD was an incidental finding at laparotomy because of appendicitis. The remaining 20 patients were symptomatic and presented with various clinical features. Nine patients (19.9%) had clinical features of peritonitis; of these, three had perforated MD and six had Meckel's diverticulitis at laparotomy. Four patients were diagnosed with intestinal obstruction. Seven patients (15.5%) presented with lower gastrointestinal bleeding. Ultrasound scans revealed intussusception in three patients, requiring open reduction. The remaining four patients with bleeding per rectum underwent a Meckel's Tc99 scan that showed a positive tracer. CONCLUSION: All patients with MD underwent Meckel's diverticulectomy with appendicectomy. MD has an incidence of approximately 1 to 2% in our population. It is necessary to maintain a high index of suspicion in the diagnosis of MD paediatric age group because it can be easily misdiagnosed. PMID- 22248890 TI - Is routine histopathology of tonsil specimen necessary? AB - BACKGROUND: Tonsillar diseases are common in paediatric and adult otolaryngological practice. These diseases require tonsillectomy. Specimens are subjected to histopathology routinely in my institution for fear of infections and tumour without consideration for risk factors. The financial burden is on the patients and waste of histopathologist's man hour because other specimens are left un-attended. This study aims to find out the necessity of routine histopathology of tonsil specimens. MATERIALS AND METHODS: A 2 year retrospective review of the histopathological results of two (paediatric and adult) groups of 61 patients managed for tonsillar diseases at the ENT UNIT of Jos University Teaching Hospital from July 2005 to June, 2007. Data extracted included biodata, clinical features and histopathological diagnosis. RESULT: The 61 patients comprise 35 children and 26 adults. The youngest and oldest paediatric patients were 1 year and 3 months and 16 years respectively, a range of 1 year 3 months to 16 years. The youngest and oldest adults were 17 and 50 years with a range of 17 50 years. Groups mean ages were 5.1 and 28.5 years. The gender ratios were 1:2.7 and 1:1.9 respectively. One adult was HIV positive. The histopathological diagnosis were chronic nonspecific tonsillitis in 10(16.6%), follicular tonsillitis in 23(38.3%), chronic suppurative tonsillitis in 10(16.6%), lymphoid hyperplasia in 18(30.0%) and lymphoma in 1(1.0%) respectively. CONCLUSION: Histopathologic request for tonsillectomy specimens should be based on certain risk factors with consideration of the cost to patients and to spare the histopathologist's man hour. PMID- 22248891 TI - Choosing a technique for severe hypospadias. AB - INTRODUCTION: We participate in humanitarian missions in Madagascar during which we treat severe hypospadias. We report our experience and results with these patients, in these conditions, and discuss our choice of technique in this particular setting. MATERIALS AND METHODS: We retrospectively reviewed the data of 27 patients operated for severe hypospadias during our humanitarian missions in Madagascar between November 2006 and September 2009. Twenty one patients underwent a modified Koyanagi procedure, three underwent a Duckett urethroplasty, two an onlay island flap, one an augmented Duckett and one a tubularised plate urethroplasty. Two patients who underwent a modified Koyanagi repair also had a Nesbitt dorsal plication. RESULTS: Patient age at the time of surgery ranged from 22 to 198 months with a median age of 54.1 months. Mean follow-up was 16 months. Of the 21 patients who underwent a modified Koyanagi procedure, 16 presented at least one complication (76%): A fistula developed in 12 patients (57%), meatal regression developed in 7 (33%) and 2 showed complete wound dehiscence (9.5%). None developed stenosis or urethrocoele. CONCLUSION: In this particular setting, the postoperative complication rate is high. Nevertheless, the Koyanagi technique is appropriate, because its complications are easy to treat and there is always sufficient ventral tissue for the secondary operation, if necessary. PMID- 22248892 TI - One-day bowel preparation in children with colostomy using normal saline. AB - BACKGROUND: Colonic and colorectal surgery frequently requires bowel preparation. This is an evaluation of the use of normal saline for one-day bowel preparation in children with colostomy. PATIENTS AND METHODS: A prospective study of 55 children with colostomy who had one-day bowel preparation for colonic and colorectal surgical procedures in a 3-year period. The information, along with clinical data was recorded on a structured proforma. Data were analysed using SPSS version 11.0. RESULTS: There were 33 boys and 22 girls. The median age was 4 years (range, one month - 13 years). The primary diagnosis were as follows: Anorectal malformation, 24 (44%); Hirschsprung's disease, 24 (44%); Faecal incontinence- post-abdominoperineal pull-through, 2 (4%); Penetrating rectal injury, 1 (2%); others, 4(8%). Intraoperative bowel luminal fluid cleanliness was assessed as clear in 36 (62%) and contaminated in 21 (38%). Overall, postoperatively, superficial surgical site infection occurred in 6 (10.9%) patients (2 had clean intraoperative colonic fluid, 5.9%. CONCLUSION: One-day bowel preparation using normal saline is effective and safe in children with colostomy. PMID- 22248893 TI - Comparing caudal and penile nerve blockade using bupivacaine in hypospadias repair surgeries in children. AB - BACKGROUND: Caudal anaesthesia is recommended for most surgical procedures of the lower part of the body, mainly below the umbilicus. It has been well established that a dorsal penile nerve block immediately after surgery decreases postoperative pain in children undergoing hypospadias repair. This study aimed to compare caudal or penile nerve block using bupivacaine in postoperative pain control in hypospadias repair in children. PATIENTS AND METHODS: After local ethical committee approval and obtaining informed parental consent, 85 American society of Anesthesiologists status I and II patients, aged 6 months to 6 years old, undergoing hypospadias repair, were prospectively enrolled in this study. The patients were randomly divided into the following two groups: Caudal block was performed in 44 and penile block was performed in 41 patients. Cardiorespiratory systems data, analgesic requirement and complications were compared between the groups. RESULTS: There were statistically significant haemodynamic (blood pressure and heart rate) alteration during operation in each group (P<0.01). The haemodynamic parameters were stable during operation in successful blocks in both groups. Caudal block success rate is 97.7%, whereas in penile block is 92.6%. Nineteen of 43 patients (44%) in caudal group and 29 of 41 patients (70%) in penile group received analgesia in the postoperative period and this difference was significant between the two groups (P = 0.025). CONCLUSIONS: Without ultrasonography and with blind block, with anatomic landmarks only, the caudal block success rate is high and if there is no contraindication for caudal block, it is the best choice in children under 6 years old (or 25 kg) for hypospadias repair. PMID- 22248894 TI - The paediatric surgeon and his working conditions in Francophone sub-Saharan Africa. AB - BACKGROUND: This study described the current conditions of work of paediatric surgeons in Francophone sub-Saharan Africa (FSSA) and set the debate at the level of the humanist thinking in medicine. PATIENTS AND METHODS: This was a multicentre study from 1 st May to 30 th October 2008. The African Society of paediatric surgeons' directory was used to identify paediatric surgeons in the Francophone's countries in Sub Saharan Africa. The parameters studied were number of surgeons per country, means of training, working conditions, remunerations, needs for continuous training and the research. RESULTS: A total of 41 paediatric surgeons (68.33%) responded. The average number of paediatric surgeons per country was 5. The means of training included government scholarships among 7 paediatric surgeons (17.07%), scholarship from a non-governmental organisations in 14 (34.15%) and self-sponsorships in 20 (48.78%). The average salary was 450 Euros (?) (range: 120-1 400 Euros). Most of the paediatric surgeons (68.29%) had internet services for continuous update courses and research. Thirty six paediatric surgeons (87.80%) had no subscription to specialised scientific journals. CONCLUSION: The paediatric surgeon in FSSA faces many problems related to his working and living conditions that may have a negative impact on their competences. PMID- 22248895 TI - Transanal Swenson's operation for recto-sigmoid Hirschsprung's disease. AB - BACKGROUND: Transanal Swenson's operation is a relatively new single-stage procedure for Hirschsprung's disease. The results of this procedure at our centre are presented. PATIENTS AND METHODS: Seventeen patients of recto-sigmoid Hirschsprung's disease underwent single-stage transanal Swenson's procedure. The diagnosis was based on the evidence of a transition zone on barium enema examination. A full thickness incision was made on the rectal wall posteriorly, 0.5 cm above the dentate line. The mobilised segment was resected about 5 cm above the transition zone. Frozen sections were performed whenever the transition zone was not clearly seen intra-operatively. The operation was completed by full thickness colo-anal anastomosis. RESULTS: There were fourteen male and three female patients. The ages of the patients ranged from two months to eight years (median 14 months). The median hospital stay was four days (range four to seven days). Two patients required additional abdominal mobilisation. The anatomical transition zone as seen intra-operatively correlated with the pathological transition zone in all the cases. Two patients had episodes of post-operative enterocolitis and the other two patients developed stricture of the anastomosis. The follow-up period ranged from six to 45 months (Mean 35.4 months). Post operative soiling was observed in all the patients and lasted from two to six weeks (Mean 3.4 weeks). There were no injuries to the surrounding structures. No patient had voiding disturbances and post-void residual urine was normal in all the patients. Initial increased frequency of bowel movements had settled to one to three per day. CONCLUSIONS: Transanal Swenson's pull through not only avoids laparotomy, but also the problems associated with the muscular cuff of transanal endorectal pull-through. The anatomical transition zone can be safely utilised to decide the resection limits. By a meticulous technique of dissection, injury to the surrounding structures can also be avoided. PMID- 22248896 TI - Our experience with caustic oesophageal burn in south of Iran. AB - CONTEXT: The alkaline oesophageal burn (EB) is a very debilitating injury and common in the southern rural area of Iran, where the air conditioning systems are cleaned with an alkaline liquid, which is accidentally ingested by children. AIMS: The aim is to share our experiences with caustic injury in children. SETTINGS AND DESIGN: A 'before' and 'after' clinical trial. MATERIALS AND METHODS: From November 2006-2009, 35 cases of alkaline burns were referred to our center. All underwent flexible endoscopy and thereafter received steroid, antibiotic and H2 blocker. They subsequently underwent rigid oesophagoscopy, with grade IIb or higher burns, for inserting the two different kinds of stents. RESULTS: Four out of 10 (GIIa <) underwent dilatation occasionally. Fifteen (GIIb) with early large stent (eight weeks) developed complications (three antral contractures, one oesophagotracheal fistula, one tracheobronchial fistula, three perforations, three deaths, and the remaining cases had not undergone dilatation yet. Four out of 10 with (GIIb), who had small stents (Six months) and early gastrostomy needed dilatation every four to six weeks and all recovered, with no significant complications. CONCLUSIONS: Early use of gastrostomy prevents malnutrition in patients. Small size stents are much more tolerable for a prolonged time are not obstructed by saliva that washes the wall of the damaged oesophagus continuously and promotes healing. PMID- 22248897 TI - Appendicitis in paediatric age group: correlation between preoperative inflammatory markers and postoperative histological diagnosis. AB - INTRODUCTION: Clinical diagnosis of appendicitis can be challenging, particularly in the paediatric age group. There is an increased risk of perforation in paediatrics; therefore, a need for sensitive and specific diagnostic tool is mandatory. AIM: The aim of this study is to evaluate the role of preoperative inflammatory markers in supporting the clinical diagnosis of appendicitis in the paediatric age group. MATERIALS AND METHODS: Retrospective study of 268 emergency paediatric appendicectomies performed in a District General Hospital in Wales, over a period of seven years (2002-2009). The data collected from hospital database include preoperative inflammatory markers, C-reactive protein (CRP) and white blood cells count (WBCC) and post-operative histology. Statistical analysis was performed using Fisher's exact test. RESULTS: The median age group in the study was 12 (2-16). 141 (53%) patients were <12 years, while 127 (47%) patients were 12-16 years old. Male : female ratio = 1 : 1 (134 each). Inflammatory markers were not done for 94 patients (35%). CRP was done for 149 cases (55.6%), while WBCC was done for 172 cases (64%). Both markers were done together for 147 cases (54.8%). Histology was positive (inflamed / gangrenous appendix) in 202 cases (75.4%). Eight cases were associated with Enterobious vermicularis infestation and one patient had carcinoid tumour. The sensitivity and specificity of CRP were 82% and 60%, respectively, with positive predictive value (PPV) of 87% (P<0.0001), while those of WBCC were 80% and 59%, respectively, with PPV of 88% (P<0.0001). The sensitivity and specificity of both markers together were 80% and 70%, respectively, with PPV= 81% (P = 3.11E-8). 94 patients (35%) had an appendicectomy operation based on clinical diagnosis alone without preoperative inflammatory markers having been tested. In 28 cases (30%) out of these, postoperative histology revealed normal appendix (P = 0.18). CONCLUSION: CRP and WBCC are simple tests that can provide a significant role supporting the clinical diagnosis of acute appendicitis in the paediatric age group. PMID- 22248898 TI - Urethral duplication in a 12-year-old child. AB - Urethral duplication is a rare congenital malformation affecting mainly boys. The authors report a case in a Cameroonian child who was diagnosed and managed at the Gynaeco-Obstetric and Paediatric Hospital, Yaounde. The malformation was characterized by the presence of an incontinent epispadic urethra and a normal apical urethra. We describe the difficulties faced in the management of this disorder in a developing country. PMID- 22248899 TI - Renal cell carcinoma with MiTF/TFE3 translocation in children: report of a case at the stage of lymph node involvement. AB - Renal cell carcinoma (RCC) is rare in children. Unlike nephroblastoma, however, it does not respond well to chemoradiotherapy. Its treatment is therefore based on surgical removal of the tumour. However, lymphadenectomy for RCC is controversial, and its prognosis is unclear. The authors report a case of RCC with MiTF/TFE3 translocation at the stage of lymph node involvement without metastasis in a boy of age 12, who was treated with radical nephrectomy and limited lymphadenectomy. This tumour constitutes a newly individualised entity in the World Health Organization's 2004 classification. Eighteen months after the operation, the patient was presented with no sign of recurrence. This case aids in showing that lymph node involvement in RCC with translocation in children is not associated with a poor prognosis and that lymphadenectomy during surgery for enlarged nephrectomy is essential. PMID- 22248900 TI - A giant mesenteric lipoblastoma in an 18-month old infant: a case report and review of the literature. AB - Infantile lipoma (or lipoblastoma) of the mesentery is an extremely rare benign tumor of embryonal fat, with 15 cases reported in the English literature until today and only three of them arise from the ileum mesentery. We report an 18 month old boy presenting with a palpable intraabdominal mass arising from the ileum mesentery. Histopathologic and cytogenetic studies confirmed the diagnosis of mesenteric lipoblastoma (or infantile lipoma). Complete excision of the mass was performed. A follow-up examination consisting of physical examination and an abdominal ultrasound at 30 months postoperatively revealed no recurrence. We also present a review of the English literature regarding the presentation and management of mesenteric lipoblastomas in children. PMID- 22248901 TI - Aphallia: a case report and literature review. AB - Aphallia is a complex urogenital malformation. It is rarely described in literature. Treatment calls upon feminising genitoplasty in most cases. Authors describe a case in a neonate, insisting on the sociocultural realities which guided their indications. PMID- 22248902 TI - Paediatrics thyroid cancer in post nuclear accident crisis: roles of paediatrics surgery. PMID- 22248903 TI - Varicocoelectomy in adolescents. PMID- 22248904 TI - Conference experiences of paediatric surgical trainees. PMID- 22248905 TI - Varicocoelectomy in adolescents. PMID- 22248906 TI - Intussusception: a disease with usually delayed presentation. PMID- 22248907 TI - Knowledge and self-reported practice of universal precautions among Kuwait University medical students in their clinical years. AB - OBJECTIVES: This cross-sectional study aimed to assess the knowledge and practice of universal precautions among Faculty of Medicine, Kuwait University, medical students in their clinical years. SUBJECTS AND METHODS: A self-administered questionnaire including 9 knowledge and 9 practice questions of universal precautions was used. A score was calculated for both knowledge and practice. These scores were dichotomized into less than median score (poor) and more than median score (good). 244 students were invited to participate. RESULTS: Of the 244 students, 220 (90.2%) accepted to participate. Of the 9 knowledge questions about universal precautions, 7 were answered correctly by more than 60% (range 64.8-90.4) of the students. All questions regarding the practice of universal precautions were answered correctly by over 60% (range 61.8-96.4) of the students. The prevalence of poor knowledge was 38.2% (84/220) and poor practice was 27.7% (61/220). Grade point average was significantly (p = 0.008) associated with the knowledge status of the respondents; however, it was not significantly associated (p = 0.397) with practice of universal precautions. Furthermore, neither the knowledge status nor any of the sociodemographic variables were significantly associated with the practice of universal precautions. CONCLUSIONS: A substantial number of students of the Faculty of Medicine, Kuwait University, in their clinical years appeared to have poor level of both knowledge and practice of universal precautions. Efforts are needed to optimize the level of knowledge and practice among students to minimize the risk of preventable infections. PMID- 22248908 TI - Clinical and economic aspects of KRAS mutational status as predictor for epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer patients. AB - Treatment of metastasized colorectal cancer (mCRC) patients with anti-epidermal growth factor receptor (EGFR)-directed monoclonal antibodies is driven by the results of the KRAS mutational status (wild type [WT]/mutated [MUT]). To find out as to what extent the treatment selection based on the KRAS status had impact on overall costs, a retrospective analysis was performed. Of 73 mCRC patients 31.5% were MUT carriers. Costs of EGFR inhibitor treatment for WT patients were significantly higher compared to those for patients with MUT (p = 0.005). Higher treatment costs in WT carriers reflect a significantly higher number of treatment cycles (p = 0.012) in this cohort of patients. Savings of drug costs minus the costs for the determination of KRAS status accounted for EUR 779.42 (SD +/ 336.28) per patient per cycle. The routine use of KRAS screening is a cost effective strategy. Costs of unnecessary monoclonal EGFR inhibitor treatment can be saved in MUT patients. PMID- 22248909 TI - CNT loading into cationic cholesterol suspensions show improved DNA binding and serum stability and ability to internalize into cancer cells. AB - Methods which disperse single-walled carbon nanotubes (SWNTs) in water as 'debundled', while maintaining their unique physical properties are highly useful. We present here a family of cationic cholesterol compounds (Chol+) {Cholest-5en-3beta-oxyethyl pyridinium bromide (Chol-PB+), Cholest-5en-3beta oxyethyl N-methyl pyrrolidinium bromide (Chol-MPB+), Cholest-5en-3beta-oxyethyl N methyl morpholinium bromide (Chol-MMB+) and Cholest-5en-3beta-oxyethyl diazabicyclo octanium bromide (Chol-DOB+)}. Each of these could be easily dispersed in water. The resulting cationic cholesterol (Chol+) suspensions solubilized single-walled carbon nanotubes (SWCNTs) by the non-specific physical adsorption of Chol+ to form stable, transparent, dark aqueous suspensions at room temperature. Electron microscopy reveals the existence of highly segregated CNTs in these samples. Zeta potential measurements showed an increase in potential of cationic cholesterol aggregates on addition of CNTs. The CNT-Chol+ suspensions were capable of forming stable complexes with genes (DNA) efficiently. The release of double-helical DNA from such CNT-Chol+ complexes could be induced upon the addition of anionic micellar solution of SDS. Furthermore, the CNT-based DNA complexes containing cationic cholesterol aggregates showed higher stability in fetal bovine serum media at physiological conditions. Confocal studies confirm that CNT-Chol+ formulations adhere to HeLa cell surfaces and get internalized more efficiently than the cationic cholesterol suspensions alone (devoid of any CNTs). These cationic cholesterol-CNT suspensions therefore appear to be a promising system for further use in biological applications. PMID- 22248910 TI - Effects of proton pump inhibitors on pediatric inflammatory esophagogastric polyps. AB - BACKGROUND: The aim of this study was to investigate the effects of proton pump inhibitors on symptomatic inflammatory esophagogastric polyps (IEPs) in a pediatric cohort and to determine the optimal duration of treatment. METHODS: The 11 patients with IEPs were managed with lansoprazole. Follow-up endoscopies were performed at 2 and 6 months after the start of medication. Medication was discontinued when the clinical symptoms completely resolved and the polyp size was reduced by more than 50% compared to the initial size. RESULTS: The initial polyp size was 13.7 +/- 3.3 mm. After 2 months of medication, the polyp size was reduced to 8.0 +/- 5.8 mm. At 6 months, the polyp size was 4.7 +/- 2.2 mm. The mean duration of medication was 4.8 +/- 2.1 months. The duration of medication and the change in the polyp size appeared to have a linear correlation (p < 0.001). According to the formula used to calculate polyp size, the optimal duration of treatment was more than 7 months for complete resolution of the polyps. CONCLUSIONS: Proton pump inhibitor was effective for the treatment of IEPs. About 5 months of lansoprazole was adequate to treat IEPs in children. The optimal duration for complete resolution of the polyp might be more than 7 months. PMID- 22248911 TI - The ratio of S-adenosylmethione and S-adenosyl-homocysteine is increased in the brains of newborn rats in a model of valproic acid teratogenicity. PMID- 22248912 TI - Focus on molecules: ADAMTSL4. PMID- 22248913 TI - SFRP1 promoter methylation and expression in human trabecular meshwork cells. AB - Glaucoma is a leading cause of blindness worldwide. In primary open angle glaucoma (POAG) patients, impaired trabecular meshwork (TM) function results in elevated intraocular pressure (IOP), which is the primary risk factor of developing optic neuropathy. Our previous studies showed that Wnt signaling pathway components are expressed in the human TM (HTM), and the Wnt inhibitor, secreted frizzled-related protein 1 (SFRP1) is elevated in the glaucomatous TM (GTM). Elevated SFRP1 increased IOP in mice eyes and in perfusion cultured anterior segments of the human eye. However, the cause of elevated SFRP1 in the GTM remains unknown. Promoter methylation plays a key role in regulating SFRP1 expression in certain cancer cells. In light of this, we studied whether promoter methylation is also involved in SFRP1 differential expression in the TM. Two normal TM (NTM) and two GTM cell strains were cultured for an additional 7 days after they were confluent. RNA and genomic DNA (gDNA) were isolated simultaneously to compare SFRP1 expression levels by quantitative PCR (qPCR) and to determine SFRP1 promoter methylation status by bisulfite conversion and methylation-sensitive high resolution melting analysis (MS-HRM). To study whether DNA methylation inhibitors affect SFRP1 expression in TM cells, the four TM cell strains were treated with or without 2 MUM 5-aza-2'-deoxycytidine (AZA-dC) for 4 days. RNA was isolated to compare SFRP1 expression by qPCR. In addition, a human cancer cell line, NCI-H460, was used as a positive control. We found that the two GTM cell strains had significantly higher expression levels of SFRP1 than the two NTM cell strains. However, the SFRP1 promoter of all four TM cell strains was unmethylated. In addition, AZA-dC treatment did not affect SFRP1 expression in any of the TM cell strains (n = 3, p > 0.05). In contrast, the hypermethylated SFRP1 promoter of NCI-H460 cells was partially demethylated by the same treatment. AZA-dC treatment also elevated SFRP1 expression by approximately two fold in NCI-H460 cells (n = 3, p < 0.01). Our data suggest that the differential expression of SFRP1 in HTM cells is not due to differential promoter methylation. PMID- 22248914 TI - Association between prescription medications and falls at home among young and middle-aged adults. AB - Using data from a population-based case-control study of people aged 25-60 years in Auckland, New Zealand, the authors investigated the association between medications and fall-related injuries at home. The 335 cases comprised people who died or were admitted to hospital as a result of unintentional falls at home, and the 352 controls were randomly selected from the electoral roll. After controlling for confounding by demographic, personal and lifestyle factors, the use of two or more prescription medications relative to one or no medications was associated with an increased risk of fall injury (OR 2.5, 95% CI 1.3 to 4.8). Antihypertensives and lipid lowering drugs were the most common groups involved. The findings suggest that, as in the case of older people, younger working aged adults who use multiple prescription medications are at increased risk of falls, an aspect that should be considered in falls prevention programmes. PMID- 22248915 TI - Headphone use and pedestrian injury and death in the United States: 2004-2011. AB - BACKGROUND: The association between distraction caused by cell phone use while driving and driver/passenger fatalities has been documented, but the safety risks associated with headphone use by pedestrians remains unknown. OBJECTIVE: To identify and describe pedestrian-vehicle crashes in which the pedestrian was using headphones. METHODS: A retrospective case series was conducted by searching the National Electronic Injury Surveillance System, US Consumer Product Safety Commission, Google News Archives and Westlaw Campus Research databases for reports published between 2004 and 2011 of pedestrian injuries or fatalities from crashes involving trains or motor vehicles. Cases involving headphones were extracted and summarised. The likelihood of headphone involvement was graded on a three-tier scale based on the information found in the article or report. RESULTS: There were 116 reports of death or injury of pedestrians wearing headphones. The majority of victims were male (68%) and under the age of 30 (67%). The majority of vehicles involved in the crashes were trains (55%), and 89% of cases occurred in urban counties. 74% of case reports stated that the victim was wearing headphones at the time of the crash. Many cases (29%) mentioned that a warning was sounded before the crash. CONCLUSIONS: The use of headphones with handheld devices may pose a safety risk to pedestrians, especially in environments with moving vehicles. Further research is needed to determine if and how headphone use compromises pedestrian safety. PMID- 22248916 TI - Cold tolerance and freeze-induced glucose accumulation in three terrestrial slugs. AB - Cold tolerance and metabolic responses to freezing of three slug species common in Scandinavia (Arion ater, Arion rufus and Arion lusitanicus) are reported. Autumn collected slugs were cold acclimated in the laboratory and subjected to freezing conditions simulating likely winter temperatures in their habitat. Slugs spontaneously froze at about -4 degrees C when cooled under dry conditions, but freezing of body fluids was readily induced at -1 degrees C when in contact with external ice crystals. All three species survived freezing for 2 days at -1 degrees C, and some A. rufus and A. lusitanicus also survived freezing at -2 degrees C. (1)H NMR spectroscopy revealed that freezing of body fluids resulted in accumulation of lactate, succinate and glucose. Accumulation of lactate and succinate indicates that ATP production occurred via fermentative pathways, which is likely a result of oxygen depletion in frozen tissues. Glucose increased from about 6 to 22 MUg/mg dry tissue upon freezing in A. rufus, but less so in A. ater and A. lusitanicus. Glucose may thus act as a cryoprotectant in these slugs, although the concentrations are not as high as reported for other freeze tolerant invertebrates. PMID- 22248918 TI - A left-hand superiority for the implicit detection of a rule. AB - We set out to test the hypothesis of right-hemisphere superiority for the implicit detection of a rule. Forty healthy men provided speeded manual responses to randomly presented digits from 1 to 6 (left hand to 1-3, right hand to 4-6). Red digits on trial n signaled that the response on trial n+1 should be made with one hand, blue digits with the other hand. White digits gave no signal (control trials). Half the participants were told that the stimulus color conveyed a rule that could be exploited to improve performance, the other half were not. After completing the first run, participants' awareness of the presence and nature of the rule was assessed and all were debriefed. Participants then performed a second run with identical stimulus conditions. In Run 1, none of the participants reported being aware of the nature of the rule. Reaction times (RTs) were longer after signal than no-signal trials, but only for the left hand. Participants informed about the presence of a rule tended to have longer RTs, irrespective of hand. In Run 2, RTs were shorter after signal than no-signal trials, and there were no differences between hands. The observed RT effect for the left-hand points to a right-hemisphere superiority for the detection and application of a rule in the absence of verbal awareness. Longer (instead of shorter) RTs in the signal trials are discussed in the framework of interhemispheric inhibition. PMID- 22248917 TI - Interventions to improve the performance of HIV health systems for treatment-as prevention in sub-Saharan Africa: the experimental evidence. AB - PURPOSE OF REVIEW: To reduce HIV incidence, treatment-as-prevention (TasP) requires high rates of HIV testing, and antiretroviral treatment (ART) uptake, retention, and adherence, which are currently not achieved in general populations in sub-Saharan Africa. We review the experimental evidence on interventions to increase these rates. RECENT FINDINGS: In four rapid reviews, we found nine randomized controlled trials (RCTs) on HIV-testing uptake, two on ART uptake, one on ART retention, and 15 on ART adherence in sub-Saharan Africa. Only two RCTs on HIV testing investigated an intervention in general populations; the other examined interventions in selected groups (employees, or individuals attending public-sector facilities for services). One RCT demonstrated that nurse-managed ART led to the same retention rates as physician-managed ART, but failed to show how to increase retention to the rates required for successful TasP. Although the evidence on ART adherence is strongest - several RCTs demonstrate the effectiveness of cognitive and behavioural interventions - contradictory results in different settings suggest that the precise intervention content, or the context, are crucial for effectiveness. SUMMARY: Future studies need to test the effectiveness of interventions to increase testing and treatment uptake, retention, and adherence under TasP, that is, ART for all HIV-infected individuals, independent of disease stage. PMID- 22248919 TI - Control of chemical kinetics for sub-10 nm Cu nanoparticles to fabricate highly conductive ink below 150 degrees C. AB - To steadily apply conductive inks that contain Cu nanoparticles (NPs) to inkjet printing of patterns at temperatures below 150 degrees C, the size of the Cu NPs must be reduced. Therefore, we obtained Cu NPs in the range of 9-33 nm, and we studied how their size changes. The variation of the chemical reaction rate changed the size of the Cu NPs for two main reasons. First, the fast transition rate of the Cu precursors at high pH values raises the supersaturation level of the Cu precursor above that of a process with a slow transition rate. The high supersaturation level is generally attributed to the small Cu nuclei and the slow growth caused by their density. Second, the high viscosity of the reaction solution, which occurs because polyvinyl pyrrolidone (PVP) causes an increase in the repulsive force, slows the growth of the Cu NPs at high pH values. The recrystallization temperature of the 9 nm Cu NPs was reduced to 108 degrees C, and a low specific resistivity of 45 MUOmega cm was achieved using the conductive ink prepared with 9 nm Cu NPs at 120 degrees C. This temperature is significantly lower than those reported for other Cu NP inks. Hence, Cu NP conductive ink could considerably reduce costs because of its apparently low temperature, resolving the main bottleneck of inkjet printing on flexible (polymeric) substrates. PMID- 22248920 TI - A risk-adapted strategy of adjuvant paclitaxel/carboplatin in early-stage ovarian cancer: time-dependent effect of 4 versus 6 cycles on outcome. AB - OBJECTIVE: We investigated the efficacy of risk-adapted adjuvant paclitaxel/carboplatin chemotherapy in early-stage ovarian carcinoma. METHODS: Fifty-three patients were treated according to the risk of relapse: patients with stages IA or IB or with grade 1 (low risk) received 4 cycles of paclitaxel and carboplatin; patients with IC/IIA and grade 2 or 3 (high risk) received 6 cycles of chemotherapy. The outcome was compared with that of 95 patients who were all treated with 4 cycles. RESULTS: Median follow-up was 88, 113 and 42 months for the whole cohort, non-risk-adapted and risk-adapted treatment, respectively. Five year relapse-free and disease-specific survival was 86 and 93% for the whole population, 96 and 97% for low-risk and 81 and 91% for high-risk patients. Risk classification was the only significant prognostic factor for relapse-free (p = 0.011) and disease-specific survival (p = 0.039). Among high-risk patients, the administration of 6 cycles was associated with a significantly lower relapse rate after censoring events, which occurred beyond 2 years (3 vs. 18%; p = 0.013), but this difference was diminished at 5 years (23 vs. 25%; p = 0.797). CONCLUSIONS: Six cycles of chemotherapy reduced the risk of relapse within 2 years, but the benefit from two additional cycles beyond this time is questionable. PMID- 22248921 TI - Racial group regard, barrier socialization, and African American adolescents' engagement: patterns and processes by gender. AB - The current study examined gendered processes via 1) profiles of racial barrier socialization, regard for one's racial group (private regard), and behavioral engagement and grades and, 2) gender and private regard as a moderator in the link between barrier messages and academic engagement outcomes. One-hundred and twenty-five African American adolescents (ages 10-14, M = 12.39, SD = 1.07) completed measures of socialization, private regard, grades and behavioral engagement. Latent Profile Analysis revealed a 2-cluster solution fit the data best - 1) High Engagement-Race Salient (HERS) cluster and 2) Low Engagement-Non Salient cluster (LENS). Girls had higher representation in the HERS cluster. When private regard was examined as a moderator, girls' grades were unrelated to barrier socialization and private regard. In contrast, barrier socialization was associated with lower grades for low private regard boys. Findings are discussed in the context of gendered racial school contexts that African American youth must navigate to be academically successful. PMID- 22248923 TI - Kurt Nordstrom (1935-2011). PMID- 22248922 TI - A 29-mer site regulates transcription of the initiator gene as well as function of the replication origin of Vibrio cholerae chromosome II. AB - The region responsible for replication of Vibrio cholerae chromosome II (chrII) resembles those of plasmids that have repeated initiator binding sites (iterons) and an autorepressed initiator gene. ChrII has additional features: Its iterons require full methylation for initiator (RctB) binding, which makes them inactive for a part of the cell cycle when they are hemi-methylated. RctB also binds to a second kind of site, called 39-mers, in a methylation independent manner. This binding is inhibitory to chrII replication. The site that RctB uses for autorepression has not been identified. Here we show that a 29-mer sequence, similar to the 39-mers, serves as that site, as we find that it binds RctB in vitro and suffices to repress the rctB promoter in vivo. The site is not subject to methylation and is likely to be active throughout the cell cycle. The 29-mer, like the 39-mers, could inhibit RctB-dependent mini-chrII replication in Escherichia coli, possibly by coupling with iterons via RctB bridges, as was seen in vitro. The 29-mer thus appears to play a dual role in regulating chrII replication: one independent of the cell cycle, the other dependent upon iteron methylation, hence responsive to the cell cycle. PMID- 22248924 TI - General requirements for protein secretion by the F-like conjugation system R1. AB - Bacterial conjugation disseminates genes among bacteria via a process requiring direct cell contact. The cell envelope spanning secretion apparatus involved belongs to the type IV family of bacterial secretion systems, which transport protein as well as nucleoprotein substrates. This study aims to understand mechanisms leading to the initiation of type IV secretion using conjugative plasmid paradigm R1. We analyze the general requirements for plasmid encoded conjugation proteins and DNA sequence within the origin of transfer (oriT) for protein secretion activity using a Cre recombinase reporter system. We find that similar to conjugative plasmid DNA strand transfer, activation of the R1 system for protein secretion depends on binding interactions between the multimeric, ATP binding coupling protein and the R1 relaxosome including an intact oriT. Evidence for DNA independent protein secretion was not found. PMID- 22248925 TI - In situ monitoring of IncF plasmid transfer on semi-solid agar surfaces reveals a limited invasion of plasmids in recipient colonies. AB - Most natural conjugative IncF plasmids encode a fertility inhibition system that represses transfer gene expression in the majority of plasmid-carrying cells. The successful spread of these plasmids in clinically relevant bacteria has been suggested to be supported by a transitory derepression of transfer gene expression in newly formed transconjugants. In this study, we aimed to monitor the extent of transitory derepression during agar surface matings in situ by comparing plasmid spread of the IncF plasmid R1 and its derepressed mutant R1drd19 at low initial cell densities. A zygotic induction strategy was used to visualize the spatial distribution of fluorescent transconjugants within the heterogeneous environment. Epifluorescence and confocal microscopy revealed different transfer patterns for both plasmids, however, spread beyond the first five recipient cell layers adjacent to the donor cells was not observed. Similar results were observed for other prototypical conjugative plasmids. These results cannot rule out that transitory derepression contributes to the limited R1 plasmid invasion, but other factors like nutrient availability or spatial structure seem to limit plasmid spread. PMID- 22248927 TI - Sex ratio bias in managed populations of hylobatids. AB - A number of explanations have been proposed for the occurrence of sex ratio bias in primates, including the Trivers-Willard hypothesis on differential investment, local resource competition or enhancement as a result of sex-biased dispersal, dominance-related advantages conferred on one sex but not the other, and the fragile male hypothesis. However, none of these theories was thought to be applicable to monogamous primate species. Here, we examine data on zoo-housed populations of three hylobatid species to test the null hypothesis of equal sex ratio. We analyzed over 40 years of demographic data on Nomascus leucogenys, Hylobates lar and Symphalangus syndactylus. We identified a strong male-biased birth sex ratio in N. leucogenys. Male infant mortality was consistently higher than female infant mortality for N. leucogenys, but this difference was not significant. We found that prime-age N. leucogenys females (aged 13-20) produced significantly more male offspring than female offspring, and young S. syndactylus females (<13 years) produced significantly more female offspring. Recent field evidence of more flexible mating systems in H. lar and S. syndactylus may also be occurring in N. leucogenys. However, N. leucogenys has not been well studied in the wild. Ecological differences among species may further contribute to these observed patterns. PMID- 22248926 TI - Disruption of the developmentally-regulated Col2a1 pre-mRNA alternative splicing switch in a transgenic knock-in mouse model. AB - The present study describes the generation of a knock-in mouse model to address the role of type II procollagen (Col2a1) alternative splicing in skeletal development and maintenance. Alternative splicing of Col2a1 precursor mRNA is a developmentally-regulated event that only occurs in chondrogenic tissue. Normally, chondroprogenitor cells synthesize predominantly exon 2-containing mRNA isoforms (type IIA and IID) while Col2a1 mRNA devoid of exon 2 (type IIB) is the major isoform produced by differentiated chondrocytes. Another isoform, IIC, has also been identified that contains a truncated exon 2 and is not translated into protein. The biological significance of this IIA/IID to IIB splicing switch is not known. Utilizing a splice site targeting knock-in approach, a 4 nucleotide mutation was created to convert the 5' splice site of Col2a1 exon 2 from a weak, non-consensus sequence to a strong, consensus splice site. This resulted in apparent expression of only the IIA mRNA isoform, as confirmed in vitro by splicing of a type II procollagen mini-gene containing the 5' splice site mutation. To test the splice site targeting approach in vivo, homozygote mice engineered to retain IIA exon 2 (Col2a1(+ex2)) were generated. Chondrocytes from hindlimb epiphyseal cartilage of homozygote mice were shown to express only IIA mRNA and protein at all pre- and post-natal developmental stages analyzed (E12.5, E16.5, P0, P3, P7, P14, P28 and P70). As expected, type IIB procollagen was the major isoform produced in wild type cartilage at all post-natal time points. Col2a1(+ex2) homozygote mice are viable, appear healthy and display no overt phenotype to date. However, research is currently underway to investigate the biological consequence of persistent expression of the exon 2-encoded conserved cysteine-rich domain in post-natal skeletal tissues. PMID- 22248928 TI - Sex differences in emotional memory consolidation: the effect of stress-induced salivary alpha-amylase and cortisol. AB - This study examined sex differences in the emotional memory consolidation, and the impact of stress-induced cortisol and salivary alpha amylase responses on emotional memory recall. Following baseline salivary measures, 39 healthy women and 41 men viewed 20 neutral and 20 negative arousing images, and then underwent either a cold pressor stress test or control condition, followed by further salivary measures. Participants returned two days later for a free recall test. The stress condition induced greater cortisol response, and negative images were better recalled than neutral. Whereas women displayed greater recall of negative images under stress than men, they recalled fewer negative images in the control condition. Stress-induced cortisol predicted recall of negative images in women, and neutral images in men. This suggests there is an enhanced consolidation of negative images under stress in women that may be a potential mechanism for the greater female prevalence for developing anxiety disorders. PMID- 22248929 TI - Will PI3K pathway inhibitors be effective as single agents in patients with cancer? AB - The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis regulates essential cellular functions including cell survival, proliferation, metabolism, migration, and angiogenesis. The PI3K pathway is activated in human cancers by mutation, amplification, and deletion of genes encoding components of this pathway. The critical role of PI3K in cancer has led to the development of drugs targeting the effector mechanisms of this signaling network. Recent studies have shown that inhibition at multiple levels of the PI3K pathway results in FOXO-dependent feedback reactivation of several receptor tyrosine kinases (RTKs) which, in turn, limit the sustained inhibition of this pathway and attenuates the action of therapeutic antagonists. This suggests that if used as single agents, PI3K pathway inhibitors may have limited clinical activity. We propose herein that to successfully target the output of the PI3K pathway in cancer cells, combination therapies that hinder these compensatory mechanisms should be used. Thus, combination therapies that target RTKs, PI3K, and mTOR activities may be required to maximize the clinical benefit derived from treatment with these inhibitors. PMID- 22248930 TI - The cellular responses and antibacterial activities of silver nanoparticles stabilized by different polymers. AB - Silver nanoparticles (AgNPs) are known for their excellent antibacterial activities. The possible toxicity, however, is a major concern for their applications. Three types of AgNPs were prepared in this study by chemical processes. Each was stabilized by a polymer surfactant, which was expected to reduce the exposure of cells to AgNPs and therefore their cytotoxicity. The polymer stabilizers included poly(oxyethylene)-segmented imide (POEM), poly(styrene-co-maleic anhydride)-grafting poly(oxyalkylene) (SMA) and poly(vinyl alcohol) (PVA). The cytotoxicity of these chemically produced AgNPs to mouse skin fibroblasts (L929), human hepatocarcinoma cells (HepG2), and mouse monocyte macrophages (J774A1) was compared to that of physically produced AgNPs and gold nanoparticles (AuNPs) as well as the standard reference material RM8011 AuNPs. Results showed that SMA-AgNPs were the least cytotoxic among all materials, but cytotoxicity was still observed at higher silver concentrations (>30 ppm). Macrophages demonstrated the inflammatory response with cell size increase and viability decrease upon exposure to 10 ppm of the chemically produced AgNPs. SMA AgNPs did not induce hemolysis at a silver concentration below 1.5 ppm. Regarding the antibacterial activity, POEM-AgNPs and SMA-AgNPs at 1 ppm silver content showed 99.9% and 99.3% growth inhibition against E. coli, while PVA-AgNPs at the same silver concentration displayed 79.1% inhibition. Overall, SMA-AgNPs demonstrated better safety in vitro and greater antibacterial effects than POEM AgNPs and PVA-AgNPs. This study suggested that polymer stabilizers may play an important role in determining the toxicity of AgNPs. PMID- 22248931 TI - Effects of low-level radioactive soil contamination and sterilization on the degradation of radiolabeled wheat straw. AB - After the explosion of reactor 4 in the nuclear power plant near Chernobyl, huge agricultural areas became contaminated with radionuclides. In this study, we want to elucidate whether (137)Cs and (90)Sr affect microorganisms and their community structure and functions in agricultural soil. For this purpose, the mineralization of radiolabeled wheat straw was examined in lab-scale microcosms. Native soils and autoclaved and reinoculated soils were incubated for 70 days at 20 degrees C. After incubation, the microbial community structure was compared via 16S and 18S rDNA denaturing gradient gel electrophoresis (DGGE). The radioactive contamination with (137)Cs and (90)Sr was found to have little effect on community structure and no effect on the straw mineralization. The autoclaving and reinoculation of soil had a strong influence on the mineralization and the community structure. Additionally we analyzed the effect of soil treatment on mineralization and community composition. It can be concluded that other environmental factors (such as changing content of dissolved organic carbon) are much stronger regulating factors in the mineralization of wheat straw and that low-level radiation only plays a minor role. PMID- 22248932 TI - Diapause specific gene expression in the eggs of multivoltine silkworm Bombyx mori, identified by suppressive subtractive hybridization. AB - Molecular mechanism controlling egg diapause remains obscure in silkworm, Bombyx mori. An attempt is made to decipher various molecular events occurring during embryonic diapause in multivoltine silkworm, B. mori. Using suppressive subtractive hybridization (SSH), 186 cDNA clones isolated from both diapause and nondiapause eggs were sequenced. Of the sequenced clones, 29 matched with silkbase entries and these identified putative genes were classified into six functional groups such as regulatory, food utilization, stress response, metabolic, ribosomal and transposable elements. Among these genes, twelve belonged to regulatory group while, one taste receptor type 2 member 117 gene was related to food utilization. One heat shock cognate 70 kDa protein and 3 of the ubiquitin family were identified under stress response category. Similarly, four genes were identified as metabolic genes, 3 belonging to chitin family and one propanediol utilization protein. Of the seven genes identified in ribosomal groups, most of them were 60s ribosomal protein subunits. However, one negative regulation of transcription gene identified was a transposable element. The qPCR analysis confirmed the expression of 21 of the above genes, wherein, 6 were upregulated during diapause, 12 during non-diapause, while, 3 remained unchanged. PMID- 22248933 TI - Characterization of a sigma class glutathione S-transferase gene in the larvae of the honeybee (Apis cerana cerana) on exposure to mercury. AB - Glutathione S-transferases (GSTs) are multifunctional enzymes that are mainly involved in detoxification of endogenous and xenobiotic compounds and oxidative stress resistance in insects. In this study, we identified a sigma class GST from Apis cerana cerana (AccGSTs4). The open reading frame of cDNA was 612 bp and encoded a 203 amino acid polypeptide, which exhibited the structural motif and domain organization characteristic of GST. Homology and evolutionary analysis indicated that the induced amino acid sequence of AccGSTs4 belonged to an insect sigma class group. Expression analysis indicated that AccGSTs4 was presented in all stages of development with high level in 4th instar larvae. Immunolocalization further revealed the distribution of AccGSTs4 in 4th instar larvae. RT-qPCR showed that the transcripts of AccGSTs4 from the larvae were upregulated under dietary HgCl(2). The GST activity under stress was higher than the controls fed on HgCl(2)-free diet. Disc diffusion assay provided evidence of recAccGSTs4 resistance to long-term exposure of HgCl(2) stress. Additionally, analysis of 5'-flanking region further clarified the probable expression patterns of AccGSTs4. Taken together, our findings indicate that the larvae AccGSTs4 may play a role in mercury stress response, and it will help to protect honeybees from heavy metals. PMID- 22248934 TI - Day case surgery in Nigeria. AB - Patient care in Nigeria is mostly government funded, from primary to tertiary levels, with little contribution from private sector and non-governmental organizations. Healthcare provision has become more complex and expensive partly due to increasing population, aging, and frequent cancellations of electives, but also due to the increasing emergence of new diseases, as well as shrinkage of resources in many developing countries like Nigeria, resulting from recent economic downturn, and political instability. Therefore, it is important to introduce and popularize the concept of day case surgery, as this may help hospitals and healthcare providers to streamline resources by reducing length of hospital stay, decreasing morbidity and mortality, and providing valuable bed services to emergencies. It also helps to reduce time lost away from work and indirectly helps to decrease loss of revenue for the individual and state. Many hospitals in Nigeria provide day care services with patients admitted to the general surgical wards, and no dedicated day surgery units (DSUs), as currently practised in developed countries. DSUs are the best way to achieve results and so it is important for all to embrace this concept in order to improve healthcare delivery to the rapidly expanding populations. A systematic search of the current published literature was carried out to look for articles related to day case surgery (day care or day surgery) in Nigeria and to examine some published articles in relation to the surgical subspecialities, with a view to highlighting current practice in Nigeria and how it conforms to ideal practice elsewhere. Recommendations and suggestions are made on how to implement and popularize this concept in our hospitals. PMID- 22248935 TI - Obesity: an emerging disease. AB - Obesity is rapidly becoming an emerging disease in developing countries due to the increasing westernization of societies and change in the lifestyle. The etiology of obesity is said to be multifactorial, with a combination of genetic and environmental factors. Literature has been extensively reviewed to provide a broad overview of obesity. Data for this review were obtained from original articles, review articles and textbooks. Internet search engines were also employed. The years searched were from 1993 to 2008. Obesity, classified in terms of the body mass index and the waist-hip ratio, has several associated co morbidities such as diabetes mellitus, hypertension, degenerative osteoarthritis and infertility. In Nigeria, there is limited information on obesity. A literature review on obesity is necessary to improve the knowledge about obesity in developing countries, its prevention and its management. PMID- 22248936 TI - Demographic and clinical profile of patients with juvenile onset open angle glaucoma in southwestern Nigeria. AB - BACKGROUND: This was a non-comparative, retrospective review of patients diagnosed with juvenile open angle glaucoma (JOAG) in the eye clinic of a tertiary hospital in southwestern Nigeria. OBJECTIVE: To document the demographic characteristics, clinical features and treatment outcome of the patients diagnosed with JOAG. MATERIALS AND METHODS: Data were extracted from the clinical record of patients diagnosed with JOAG in the eye clinic of the University College Hospital, Ibadan, Nigeria, between January 2001 and December 2005. Such data included the basic demographic data, the clinical characteristic of the patients and the outcome of their treatment. RESULTS: Twenty-nine patients were reviewed, which represents 3.4% of all newly diagnosed glaucoma patients seen in the out-patient section of the eye clinic of the University College Hospital, Ibadan, over the period reviewed. Eight (27.6%) patients were aged 20 years and below. The mean age was 25.1 +/- SD 6.0 years. Eighteen (62.1%) had visual acuity of 6/18 or worse in the better eye at the time of presentation. The mean intraocular pressure (IOP) of the patients at presentation was 32.3 +/- SD 15.2 mmHg. Eight (27.6%) patients defaulted within 6 months of presentation. The mean IOP for the 21 patients who were followed up on treatment for a mean period of 9.6 months was 17.0 +/- SD 6.0 mmHg. CONCLUSION: Most patients with JOAG in this review presented with advanced form of the disease. Early detection through parent-driven school eye health program and community-based case detection could help in reducing the scourge arising from JOAG among our population. PMID- 22248937 TI - Sonographic evaluation of uterine cervical dimension within 4-24 weeks of pregnancy. AB - OBJECTIVE: To determine the normal range of uterine cervix within 4-24 weeks of pregnancy and also assess whether variations are related to some selected extraneous human conditions. SETTING AND DESIGN: This was a prospective study conducted in University of Benin Teaching Hospital, Benin, Nigeria, and Nigerian National Petroleum Cooperation Health Centre, Warri, Nigeria. MATERIALS AND METHODS: A prospective ultrasonographic (USS) study of uterine cervical dimension of 150 pregnant women within 4-24 weeks gestational age in two sonographic centers in Nigeria between January 2007 and October 2007 was conducted. The patients were examined by the authors. The uterine cervical dimensions (length, upper lip diameter, and lower lip diameter) were taken by means of ultrasonography. In addition, vital history, height and weight of patients were documented. The vital history included the age, number of childbirths, number of induced abortion, miscarriages and family history of miscarriages. Using Statistical program of social science (SPSS), the data were analyzed. Informed consent was obtained from all the patients and the study was done in line with the ethical guidelines of the centers. RESULTS: The following uterine cervical dimensions were obtained: mean cervical length of 6.14 cm and standard deviation of 2.0, and the upper and lower lips' uterine cervical diameters of 1.81 and 1.76 cm, respectively, with standard deviations of 0.86 and 0.71, respectively. There was no significant correlation of dimensions of uterine cervix to the aforementioned extraneous human condition. However, the increasing number of miscarriages correlated with decreasing length or shortness of the cervix. CONCLUSION: Uterine cervical dimension in pregnancy between 4 and 24 weeks is reproducible with sonographic documentation and the following normal ranges were deduced: cervical length (6.14 +/- 2.0 cm), upper lip (1.81 +/- 0.86 cm) and lower lip (1.76 +/- 0.71 cm). The study revealed that increasing number of miscarriages was associated with effacement or reduction in the cervical length. PMID- 22248938 TI - Incidence and risk factors for traditional eye medicine use among patients at a tertiary eye hospital in Nigeria. AB - OBJECTIVE: To determine the incidence and risk factors for traditional eye medicine use among patients at the Guinness Eye Center Onitsha, Nigeria. MATERIALS AND METHODS: Consecutive new adult ophthalmic patients seen at the Guinness Eye Center Onitsha between January and April 2007 were interviewed on the use of traditional eye medicines and the type of traditional eye medicine used. RESULTS: Of the 500 patients interviewed, 66 (13.2%) had used traditional eye medicines (TEM). The 66 patients, aged 18-84, were made up of 32 males and 34 females. The commonly used TEM were liquid from plant leaves and roots and other concoctions of unknown origin. Conjunctivitis and cataract constituted 54.5% of the ocular problems; 15(22.7%) patients had visual impairment while 5(7.6%) other patients were blind. Risk factors for TEM use include age above 50 years (P<0.001); residence outside Onitsha metropolis (P<0.001) or >= 25 kilometres away from our hospital (P<0.02) and lack of any formal education (P<0.02). Decision to use TEM was not affected bygender (P>0.05); chronic nature (P>0.05) or painfulness of the ocular disease (P>0.05). CONCLUSIONS: Traditional eye medicine is highly patronized by the people. Health education programmes with emphasis on safe eye care practices need be intensified in traditional healers and among the groups at risk. PMID- 22248940 TI - Risk factors and perinatal outcome of umbilical cord prolapse in Ebonyi State University Teaching Hospital, Abakaliki, Nigeria. AB - AIM: The goal of this study was to identify risk factors associated with umbilical cord prolapse and to document the perinatal outcome of cases of cord prolapse. MATERIALS AND METHODS: During the period of the study (from July 1, 2001 and June 30, 2007), forty-six cases of umbilical cord prolapse were identified from the labor ward record and analyzed retrospectively. Associations between cord prolapse and potential risk factors were evaluated by means of the odds ratio. RESULTS: During the period of the study, 46 cases of cord prolapse were encountered out of 10,080 deliveries which was 0.46% of all deliveries. Of the 46 fetuses with umbilical cord prolapse 32.6% had a fetal weight of less than 2.5 kg compared with 15.2% for fetuses in control group (P<0.012). The umbilical cord prolapse occurred in association with breech presentation eleven times (23.9%) and transverse presentation seven times (15.2%). The occurrence of breech presentation among the control cases was 4.3% (P<0.00031), and that of transverse lie was 4.4% (P<0.02007). Among the women that had cord prolapse, 47.8% had unbooked pregnancies compared with the control group with 14.5% (P<0.0000033). Multiparity accounted for 78.3% in the cord prolapse cases and 68.1% in the controls (P=0.19). The perinatal mortality rate was 413/1000. (41.3%), compared to the perinatal mortality of 58/1000 for the control group. CONCLUSIONS: Our findings in this study has confirmed an association between increased risk of umbilical cord prolapse and abnormal fetal presentation, low birth weight and unbooked status. It is therefore suggested that pregnant women should be encouraged to register early in pregnancy for antenatal care and this will enhance the early identification of these risk factors and an appropriate management instituted to reduce perinatal mortality. PMID- 22248939 TI - Copper and selenium status of healthy pregnant women in Enugu, southeastern Nigeria. AB - BACKGROUND: Copper and selenium are important trace elements in man. They function as antioxidants and play roles in oxido-reductase reactions. Several imported multivitamin preparations are given to our women during pregnancy and lactation to correct possible deficiencies. OBJECTIVE: The aim of the study is to determine the serum level of these micronutrients (selenium and copper) in a cross section of pregnant women in Enugu, southeastern Nigeria. MATERIALS AND METHODS: A cross section of 130 healthy pregnant women at different trimesters of pregnancy and 30 non-pregnant controls were selected from two health facilities in Enugu, southeastern Nigeria. Serum from the samples collected was assayed for copper and selenium using atomic absorption spectrophotometer. RESULTS: The mean copper level increased (P = 0.018), while the selenium level decreased (P < 0.0001) as pregnancy advanced. CONCLUSION: High copper levels indicate that supplementation should not be undertaken during normal pregnancy. Dietary intake should be modified to ensure optimal selenium levels during pregnancy. PMID- 22248941 TI - Maternal and perinatal outcome of severe pre-eclampsia in Enugu, Nigeria after introduction of Magnesium sulfate. AB - BACKGROUND: Magnesium sulfate (MgSO4) is the most effective seizure prophylaxis in the management of severe pre-eclampsia, and its use is progressively spreading in our environment. It was introduced at the pioneer teaching hospital of southeastern Nigeria in 2007. A study on the outcome of its use is therefore necessary. OBJECTIVES: The objective was to determine the effect of introducing MgSO4 on the maternal and perinatal outcomes of severe pre-eclampsia in Enugu, South eastern Nigeria. MATERIALS AND METHODS: A retrospective study of all cases of severe pre-eclampsia managed at the University of Nigeria Teaching Hospital Enugu (UNTH), Nigeria, from 1 January 2005 to 31 December 2008 - 2 years before, and 2 years after the introduction of MgSO4 - was performed. RESULT: The prevalence of severe preeclampsia within the study period was 3.3%. The mean age of study participants was 24.5 +/- 2.9 years. Thirty women received MgSO4 while 47 women received diazepam. Eclampsia occurred only in a member of the diazepam group but there were no maternal deaths. Babies from the diazepam group were more likely to have low 1 minute Apgar scores but the association was not significant [OR = 3.08 (95% CI 0.78, 13.33)]. Longer hospital stay was significantly lower among women who received MgSO4 [OR = 0.32 (95% CI 0.11, 0.93)]. Perinatal mortality did not differ between the groups. CONCLUSION: MgSO4 is effective in the management of severe pre-eclamptics at the UNTH, Enugu. Therefore, its accessibility and wider use should be promoted. PMID- 22248942 TI - The influence of socioeconomic status on the hemoglobin level and anthropometry of sickle cell anemia patients in steady state at the Lagos University Teaching Hospital. AB - BACKGROUND: Sickle cell anemia (SCA) has multisystemic manifestations and is associated with severe morbidity and high mortality. It commonly affects growth leading to wasting and stunting. AIMS AND OBJECTIVES: This study aimed to determine the influence of socioeconomic status on the nutritional status using anthropometric measurements and steady-state hemoglobin, of children with homozygous SCA, aged 1 year to 10 years in steady state at the Lagos University Teaching Hospital. MATERIALS AND METHODS: This is a cross-sectional study involving 100 children with SCA and 100 age-, sex-, and social class-matched controls that fulfilled the inclusion criteria. Social class was assessed using educational attainment and occupation of parents. Hemoglobin concentration was determined using the oxy-hemoglobin method. RESULTS: This study demonstrated a significantly lower mean weight and weight-for-height in the SCA patients than those of controls (P < 0.001). By contrast, this study did not demonstrate any statistical significant difference in the mean height and mean body mass index of SCA patients and controls (P = 0.06) and (P = 0.12), respectively. The mean weight, height, and body mass indices of the subjects and controls were consistently below those of the NCHS standards. The magnitude of the difference from the NCHS standard was also more pronounced in the subjects, increased with advancing age and affected male subjects more than females. Progressive declines in the anthropometric attainment and hemoglobin concentration were observed from social class 1 to 4; this was statistically significant in controls (P = 0.00) but not in subjects (P > 0.1). However, SCA patients had significantly lower values than controls in each of the social classes. CONCLUSION: Poor socioeconomic status has an adverse effect on the nutritional status and hemoglobin of SCA patients. PMID- 22248943 TI - Knowledge, attitude, and practice of emergency contraception among medical doctors in Port Harcourt. AB - BACKGROUND: The contraceptive prevalence in our environment is very low with attendant increase in unwanted pregnancy and unsafe abortion. The use of emergency contraception (EC) in women with unprotected intercourse could be the only option that can avoid the unwanted pregnancy and unsafe abortion. OBJECTIVE: The objective was to assess the knowledge, attitude, and practice of emergency contraception among doctors in Port Harcourt. MATERIALS AND METHODS: This is a descriptive cross-sectional study of medical doctors practising in Port Harcourt. Self-administered questionnaires were completed by 100 participants randomly selected from medical doctors present at a general meeting in January 2006. Data collation and analysis was carried out with Microsoft Excel XP software and presented as percentages and proportions. RESULTS: The awareness of EC was high among the doctors in Port Harcourt. However knowledge about its use was poor. Although 98% of them were aware of emergency contraception, 58% could not identify correctly any type. Oral mifepristone (RU486) was the most recognized form of EC identified by 38% of the doctors. Rape would be the commonest indication for emergency contraception as reported by 76% of the doctors, ahead of missed pills by 36% and incestuous sexual intercourse by 46% of the doctors. Postinor (levonorgestrel) given within 72 hours and IUCD inserted within 5 days of intercourse were the commonest forms of EC administered by 26% each of the doctors interviewed. CONCLUSION: Although the awareness of EC is high among the doctors in Port Harcourt, the knowledge and use of EC is low. Therefore there is a need to improve both education and attitude to use of emergency contraception among medical doctors in Port Harcourt. PMID- 22248944 TI - Morphology of colorectal carcinoma among Nigerians: a 30-year review. AB - BACKGROUND: The incidence of colorectal carcinoma has been on the increase in the developing countries, including Nigeria, as a result of change in diet and adoption of western lifestyle. OBJECTIVES: The aim of this review is to highlight the prevalence, age and sex distribution, anatomical location, and morphological characteristics of colorectal carcinomas in Ilorin, Nigeria. MATERIALS AND METHODS: This is a retrospective study of all cases of histologically diagnosed colorectal carcinoma in the University of Ilorin Teaching Hospital, Ilorin, Nigeria, over a 30-year period (January 1979-December 2008), using the departmental record and histological slides of the cases. RESULT: A total of 241 cases of colorectal carcinoma were reported, 144 cases (60%) in males and 96 cases (40%) in females with a male: female ratio of 1.5:1. The peak age of occurrence for males was between 51 and 60 years, while that of the females was between 41 and 50 years. The malignancy was found in the rectum in 60.2% of the cases, while the least affected site is the descending colon (1.2%). The exophytic occluding masses were found in 82.2% of the cases, and the most common histological type is adenocarcinoma (77.2%) with well-, moderately, and poorly differentiated forms constituting 52.3%, 32.8%, and 14.9% respectively. Of the 241 cases that were seen over the last 30 years, 93 cases (38.6%) were seen in the last 5 years. CONCLUSION: Colorectal carcinoma is no longer a rare disease in Nigeria. The surge in the incidence reported in the last 5 years in this center calls for a pragmatic action in its control, with emphasize on colonoscopic screening for those with family history, and possibly making digital rectal examination a mandatory aspect of clinical examination, because most colorectal carcinomas are within the reach of examining finger. PMID- 22248945 TI - Microalbuminuria and hypertensive retinopathy among newly diagnosed nondiabetic hypertensive adult Nigerians. AB - OBJECTIVE: Microalbuminuria (MA) is a marker of vascular damage and has prognostic implications in hypertension. The objective of this study was to determine if the presence of MA increases the risk of hypertensive retinal damage in nondiabetic adult Nigerians with hypertension. MATERIALS AND METHODS: A total of 96 consecutive newly diagnosed hypertensive patients attending the outpatient clinic and who consented and met the criteria for the study were recruited. There was also the same number of age- and sex-matched normotensive controls. RESULTS: MA was present in 31 (32.3%) of the patients and 6 (6.3%) of the controls. The mean (+/-SD) ages of patients with and without MA were 52.5 +/- 11.9 years and 48.3 +/- 13.0 years, respectively. The diastolic blood pressure (P = 0.03) and mean arterial pressure (P = 0.01) were statistically higher in hypertensive patients with MA than in their counterparts without it. Patients with MA were more likely to have hypertensive retinopathy (HRP) than patients without it (71% vs 37%, P = 0.001). Advanced HRP, i.e., Grades III - IV, was more common in patients with MA than in those without it (22.6% vs 1.5%). CONCLUSION: This study shows a high prevalence of HRP in Nigerian hypertensives with MA. PMID- 22248946 TI - Hodgkin lymphoma: clinicopathologic features in Benin City, Nigeria and update on its biology and classification. AB - OBJECTIVE: To review the age incidence, common pathohistologic subtypes, and anatomical nodal sites of lymph nodes involvement for histology. MATERIALS AND METHODS: A 25 (May 1985-June 2010) years retrospective study of all patients who had lymph node biopsy. SETTING: Department of Pathology and Haematology, University of Benin Teaching Hospital, Benin City, Nigeria. RESULTS: Of 821 lymph node biopsies encountered, 56 (6.8%) cases biopsied were for Hodgkin lymphoma (HL). There was a bimodal peak incidence of age interval of 11-15 years and 21-25 years and the relationship between the age and sex distribution was statistically significant (P = 0.03). The overall median age was 23 years with a mean age of 25.6 +/- 2.0 (SEM). Pathological re-appraisal of these 56 cases in the study indicates that mixed cellularity HL constituting 36 cases (64.3%) was the predominant subtype. This was followed by lymphocyte depleted HL with a total of 11 cases (19.6%). The major site of lymph node involvement where biopsy was taken for histological diagnosis was the cervical group of lymph nodes constituting 78.6%. Staging classification of the disease indicates low frequency of early stage disease (I-II) with 19 cases (33.9%) and high frequency of late stage (III IV) with 37 cases (66.1%). CONCLUSION: Patients are predominantly males, children and young adults presenting with cervical lymphadenopathy at late stage of the disease, and a dominance of mixed cellularity and lymphocyte depleted histological subtypes were observed. PMID- 22248947 TI - Treatment of dorsal wrist ganglia by transfixation technique. AB - BACKGROUND: Ganglion is one of the common lesions seen in minor surgical practice. Treatment of dorsal wrist ganglia varies from simple reassurance to excision and advanced endoscopic excision. Irrespective of the treatment modality, recurrence is a common problem. MATERIALS AND METHODS: This study evaluates results of 40 wrist ganglia treated by using the transfixation technique. RESULTS: Out of 40 cases included in this study 38 were completely cured of the symptoms giving a success rate of 95 percent, recurrence was seen in one patient and skin necrosis secondary to tight gauze piece was seen in one patient. DISCUSSION: Comparing with other modalities this method is cost effective, less time consuming, minimally invasive, low rate of recurrence, and can be carried out under local anesthesia, and does not require any special instrument and an easy-to-learn technique. PMID- 22248948 TI - A study on clinical attachment loss and gingival inflammation as etiologic factors in pathologic tooth migration. AB - BACKGROUND: Several etiologic factors have been listed for pathologic migration of periodontally involved teeth based mainly on clinical observations with scarce scientific evidence. Present study was carried out to find out relationship of clinical attachment loss and gingival inflammation with pathologic tooth migration. MATERIALS AND METHODS: A total of 37 patients having 50 pairs of migrated and non-migrated contralateral teeth were taken into consideration. RESULTS: Mean total attachment loss per tooth in migrated and non migrated tooth is 13.32 +/- 0.74 S.E. and 8.34 +/- 0.58 S.E., respectively (P < 0.001), which reveals a positive correlation. There seems to be an association between frequency of migration and severity of attachment loss since highest percentage of migrations were seen in maximum total attachment loss group. Relationship could not be established between severity of attachment loss and severity of migration for which more data may be required. Also, it was seen that gingival index was significantly higher in migrated group. CONCLUSION: Findings suggest that there exists a direct relationship between pathologic migration and clinical attachment loss as well as gingival inflammation. CLINICAL RELEVANCE: Results emphasize the importance of early treatment of periodontitis to curb inflammation, which seems to be more important since it is completely reversible, and attachment loss also in order to prevent unaesthetic complications. Moreover bleeding along with recent change in position of teeth should be considered as important sign of active, moderate to severe periodontal disease by general dentists and hygienists so that they can refer for specialist consultation. PMID- 22248949 TI - Serum creatine kinase and lactate dehydrogenase activities in patients with thyroid disorders. AB - BACKGROUND AND OBJECTIVES: There is the recognition of a pattern of elevations of serum enzymes in hyperthyroid and hypothyroid patients. The aims of this study were to determine the activities of serum creatine kinase (CK) and lactate deydrogenase (LDH) in thyroid disorders, and to evaluate the relationship between CK, LDH and FT4, and TSH levels. MATERIALS AND METHODS: In this retrospective study, thyroid function tests, serum CK and LDH activities were obtained from the medical records of newly diagnosed hyperthyroid and hypothyroid patients attending the Endocrinology Clinic at the University Hospital of the West Indies from 2005- 2009. RESULTS: Elevation of CK activity was found in 5 patients (28%, 5/18) with overt hypothyroidism and in 12 patients (24.0%, 12/50) with subclinical hypothyroidism. The mean CK activity in subclinical hypothyroid patients was 179.80 +/- 125.68 U/L compared with 389.901 +/- 381.20 U/L in overt hypothyroid patients. The elevation of LDH activity was found in 6 patients (33.3%, 6/18) with overt hypothyroidism and in 37 patients (74.0%, 37/50) with subclinical hypothyroidism. In the hypothyroid patients, a positive correlation was found between CK activity and TSH (r = 0.292, P = 0.015), and a negative correlation between CK activity and FT4 (r = - 0.325, P = 0.007); and between FT4 and TSH (r = - 0.371, P = 0.002). CONCLUSION: The significant elevation in serum CK and LDH activities indicates that these can be used as parameters for screening hypothyroid patients but not hyperthyroid patients. PMID- 22248950 TI - Prevalence of symptoms of depression among patients with chronic kidney disease. AB - OBJECTIVE: Depression is the most common psychiatric illness in patients with chronic kidney disease (CKD). Depression has been shown to affect mortality in end-stage renal disease patients. The objective of this study was to determine prevalence of depressive symptoms among CKD patients. MATERIALS AND METHODS: A cross-sectional study of patients with CKD (Stages 3-5) attending the renal clinic of a tertiary hospital was conducted. Demographic and clinical data were documented. A self-administered Zung depression questionnaire was administered. The Zung depression questionnaire has 20 weighted questions. Individuals with a total score of 50 are considered to be depressed, while a score of 70 and above is indicative of severe depression. RESULTS: One hundred and eighteen patients and fifty controls were interviewed. There were 73 (61.9%) males and 45 (38.1%) female patients. The mean age did not differ: males 43.8 +/- 15.4 years, females 43.2 +/- 14.7 yrs, P = 0.83. The prevalence of depression among the CKD patients was 23.7%, while for the control group was 2%; chi2 = 10.14, P < 0.001. Further analysis showed that CKD patients on dialysis were more likely to be depressed than the pre-dialysis patients with frequency of depressive symptoms of 34.5% for dialysis patients versus 13.3% in pre-dialysis patients; chi2 = 6.17, P = 0.01. No difference was observed in the mean Zung score among males, and female patients mean Zung score was 40.1 in females and 40.7 in male patients; P > 0.05. CONCLUSION: Depression is highly prevalent among our patients with CKD and treatment modality was the major predictor of depression among our patients. PMID- 22248951 TI - Knowledge of human immunodeficiency virus post-exposure prophylaxis among doctors in a Nigerian tertiary hospital. AB - BACKGROUND: The mainstay of prevention of occupationally-acquired HIV infection is compliance with universal precautions. Appropriate post-exposure prophylaxis is an integral part of prevention, control and workplace safety. This study was undertaken to assess the level of knowledge of post-exposure prophylaxis (PEP) against human immunodeficiency virus (HIV) among doctors in Federal Medical Centre, Gombe, Nigeria. MATERIALS AND METHODS: Ethical committee approval for the conduct of the study was obtained. Questionnaires were served to all cadres of doctors from house officers to consultants; it was completed and returned on anonymous basis. RESULTS: Sixty six (88.0%) of the 75 distributed questionnaires were returned completed and formed the basis of further analysis. The overall knowledge level of post-exposure prophylaxis against human immunodeficiency virus infection was very low. About 62.1% are aware of the existence of PEP policy in the hospital. The level of knowledge concerning the high-risk fluid and three drugs used in PEP is high. Over 90% are not aware of the risk of sero-conversion following significant needle-sticks injury and mucous membrane exposure. The study also revealed poor knowledge concerning actions to be taken, how soon to commence the PEP treatment and the duration of medication following needle stick injury. More than 50% of the surveyed doctors had experienced significant exposure to potentially infective materials and none reported or sought PEP advice. CONCLUSION: There is the need to educate the doctors and other health workers about the PEP guideline policy, what to do in the event of injury, whom to contact and the importance of seeking urgent advice following injury or exposure. PMID- 22248952 TI - Use of information and communication technology among dental students and registrars at the faculty of dental sciences, University of Lagos. AB - The aim of this study was to investigate the use of information technology amongst dental students, dental nursing students and resident doctors in training at the faculty of dental Surgery University of Lagos. A structured questionnaire was distributed to 58 clinical dental students in 4 th and 5 th years of training in the 2010/2011 academic year, 36 dental nursing students and 63 resident doctors undergoing specialist training. All participants have access to the computers, 2.5% within the University and 31% at home and internet cafes and about 50% have the basic skills required. A significant difference was observed between the resident doctors and clinical dental students (P = 0.003), between resident doctors and dental nursing students (P = 0.0001) when the use of computer for study was compared. Over 95% of participants have access to internet and about 50% of them use the internet for their studies. A significant difference (P = 0.005) was observed between clinical dental students and dental nursing students that use the internet and word processing. The resident doctors used the computers for multimedia and MedLine search tools more than clinical dental students (P = 0.004) and dental nursing students (0.0006). The findings of the study show that dental students and resident doctors in training have the requisite knowledge to operate the computer for use in their study and personal activities. PMID- 22248953 TI - Ocular disorders in children in Zaria children's school. AB - BACKGROUND: The main causes of blindness in children change over time. The prevalence and pattern of eye diseases in children were studied in northern Nigeria 6 years ago. This study like the previous one was a school eye health screening conducted in Zaria children school located at the centre of Zaria, a city in northern Nigeria. AIMS AND OBJECTIVES: to determine the current prevalence and pattern of eye diseases affecting school children in Zaria. This is to serve as a current template for planning eye care for children in Zaria and environs. MATERIALS AND METHODS: a cross sectional study of 327 children who completed a pre-designed school eye screening format was conducted. Consent was obtained from the school authority and the parents before the screening exercise. It involved assessment of visual acuity, anterior and posterior segment examination and colour vision testing. Intraocular pressure measurement and refraction were done for those with indications. RESULT: A total of 327 children were examined, out of which 45.6% (n=149) were males and 54.4% (n=178) were females. M: F=1:1.2. Age range 5-17 yrs with mean of 9.6 +/- 3.1(SD). The commonest causes of eye disorders were refractive errors 8.0% (n=26), allergic conjunctivitis 7.3 % (n=24), glaucoma suspects 3.7% (n=12) and colour deficiency 1.5%(n=5). CONCLUSION: The major causes of childhood eye disorders were uncorrected refractive errors and allergic conjunctivitis. The predominance of uncorrected refractive error is similar to what is obtainable in other parts of the world especially in the urban areas. PMID- 22248954 TI - Melkerssons-Rosenthal syndrome: a case report and review of the literature. AB - Melkerssons-Rosenthal syndrome is a clinical entity identified by the presence of the triad of recurrent facial paralysis, recurrent often permanent (labial) oedema, and to a lesser extent the placation of the tongue. The striking event is that of recurrent lower motor facial paresis. This should arouse the search for the other components of the triad which is not always complete. The major worry of the patients is however the facial paresis/oedema and the attendant inability to close the eyes which might sometimes get infected. Hallmark of management remains physical therapy and corticosteroid and/or antiviral agents. A high index of suspicion is required to make the diagnosis of Melkerssons-Rosenthal syndrome. PMID- 22248955 TI - African traditional medication and keloid formation in herpes zoster ophthalmicus. AB - Keloid scar complicating herpes zoster ophthalmicus (HZO) has not been much reported among Africans despite the African population having dark skin. We report on a middle-aged Nigerian with HZO who developed keloid scar following use of traditional herbs to the herpetic rashes. A 52-year-old immune-competent Nigerian male presented with a 2-week history of vesicular rashes involving the left side of the forehead down to the tip of the nose. He initially presented to an African traditional healer who had advised application of various herbs to the lesion. When he presented to the eye clinic, he was treated for the associated uveitis with significant improvement. The cicatricial skin change gradually became raised with clinical appearance of keloid at 1 year of follow-up. Cicatricial skin changes in HZO are not unusual, but keloid formation among Africans has not been much described. Late presentation, use of traditional herbs some of which have corrosive effect and secondary bacterial infection are the possible factors that may encourage such abnormal wound healing. The myth associated with HZO in the local African setting as well as the fact that African traditional healers are still widely accepted among most African communities may play a role in increasing the risk of keloid formation among our population following HZO infection. PMID- 22248956 TI - Anaesthesia management for thyroidectomy in a non-euthyroid patient following cardiac failure. AB - A 24-year-old male thyrotoxic student of a tertiary institution had thyroidectomy in the presence of a persistently elevated thyroxine (T4) and tri-iodothyronine (T3) levels. He was initially managed for hypertension at a private hospital before he was referred to our hospital for expert management. He had symptoms of thyrotoxicosis three years before presentation at our hospital. Physical examination revealed bilateral anterior neck masses and a diagnosis of toxic goitre was made. The serum T3 and T4 were elevated. Chest X-Ray, electrocardiogram and echocardiography showed abnormal findings. He was commenced on antithyroid drugs. Surgery was postponed several times due to persistently elevated thyroid hormones. However, he developed cardiac failure after six months on medical treatment and was treated with digoxin and frusemide. He had thyroidectomy under general anesthesia after his cardiovascular status was optimized in order to prevent further deterioration of his cardiac function. The anesthetic management is presented and discussed. PMID- 22248957 TI - Rehabilitation of recurrent unicystic ameloblastoma using distraction osteogenesis and dental implants. AB - Ameloblastoma is a true neoplasm of odontogenic epithelial origin. Surgical resection of the ameloblastoma is well-documented and an accepted treatment modality. Vertical distraction of the alveolar process is an efficient method for augmentation. This method of providing additional bone and soft tissue for implant placement is becoming more common. This clinical report describes the use of distraction osteogenesis and fixed implant supported prosthesis to treat a post-surgical alveolar defect as a result of the resection of a unicystic ameloblastoma in the anterior mandibular region. As a result of alveolar distraction a segment of mature bone was transported vertically in order to lengthen the crest, for better implant anchorage. Further clinical and experimental studies of the technique with long-term follow-up are needed, to confirm bone and implant stability, as it relates to alveolar height. PMID- 22248958 TI - Femoral bifurcation with ipsilateral tibia hemimelia: early outcome of ablation and prosthetic fitting. AB - Femoral bifurcation and tibia hemimelia are rare anomalies. Hereby, we present a case report of a 2-year-old boy who first presented in our orthopedic clinic as a 12-day-old neonate, with a grossly deformed right lower limb from a combination of complete tibia hemimelia and ipsilateral femoral bifurcation. Excision of femoral exostosis, knee disarticulation and prosthetic fitting gives satisfactory early outcome. PMID- 22248959 TI - Schistosomal stricture of the ureter-diagnostic dilemma. AB - Chronic schistosomiasis of the urinary tract can present with symptoms unrelated to the disease. A 33-year-old man from Edo State Nigeria presented with recurrent left flank pain. Laboratory investigations did not reveal any cause. Radiological investigation revealed a stricture of the left ureter and hydronephrosis of the left kidney. Management included surgical excision and antischistosomiasis chemotherapy. Histopathological examination of specimen of the ureter obtained after surgical exploration revealed Schistosoma heamatobium ova in the wall of the ureter. PMID- 22248960 TI - Ruptured uterus in a booked patient. AB - Ruptured uterus, a life-threatening obstetric complication, is a rare event among booked patients. We present a case of uterine rupture in a 28-year-old Gravida 2.para 1 +0 , 1 alive with previous lower segment Caesarean scar due to neglected obstructed labor from fetal macrosomia. She presented in labor at 40 weeks of gestation after declining the advice for an elective Caesarean section (C/S) and also signed against medical advice to receive care from a traditional birth attendant. She returned 30 hours later with a ruptured uterus. Findings at operation included a macerated stillbirth weighing 4.30 kg and a lower segment transverse scar rupture. Subtotal hysterectomy and peritoneal lavage were performed. PMID- 22248962 TI - Odontogenic keratocyst: a peripheral variant. AB - Odontogenic keratocyst, which is developmental in nature, is an intraosseous lesion though on rare occasions it may occur in an extraosseous location. The extraosseous variant is referred to as peripheral odontogenic keratocyst. Though, clinically, peripheral odontogenic keratocyst resembles the gingival cyst of adults, it has histologic features that are pathognomonic of odontogenic keratocyst. This article presents a case of this uncommon entity. PMID- 22248961 TI - Armillifer armillatus infection. AB - We report a case of human pentastomiasis in a 70-year-old retired long-distance driver/farmer whose diagnosis was made incidentally while being investigated for a 1-month history of cough and abdominal pain. The chest X-ray revealed multiple comma-shaped and rounded opacities in keeping with Armillifer infection, most likely Armillifer armillatus. The patient made an uneventful recovery after a 10 day course of mebendazole (an antihelminthic) tablet and ciprofloxacin (antibiotic) capsules and was discharged home. He is presently being followed up. This is the first case we have seen in our medical unit thus we are reporting it. PMID- 22248963 TI - Caput medusae in alcoholic liver disease. AB - Caput medusae and palmar erythema are cardinal signs in cirrhosis of liver with portal hypertension. Palmar erythema is described more often as a marker for alcoholic etiology of chronic liver disease. The peripheral stigmata of chronic liver disease are not routinely seen now a days due to early diagnosis and better therapy. We recently encountered an interesting patient of alcoholic liver disease with two classical signs of the disease and report the same for this unusual presentation. PMID- 22248964 TI - Childhood solid tumors. Preface. PMID- 22248966 TI - Wilms tumor: recent advances in clinical care and biology. AB - Wilms tumor is the most common renal malignancy that occurs in childhood. The remarkable evolution of treatment for this malignancy has served as a paradigm for multimodal cancer treatment. A rich database has accrued over time from well controlled clinical trials. Translational research has directly affected patient care by allowing risk-based therapy. This article will summarize advances in our knowledge of the biology of Wilms tumor and describe the impact on clinical treatment of Wilms tumor. PMID- 22248967 TI - Hepatoblastoma: recent developments in research and treatment. AB - Hepatoblastoma is the most common liver tumor of early childhood. According to recent studies its incidence seems to be increasing in North America and Europe. Since new histological variants have been described recently the formerly clear cut distinction of hepatoblastoma and hepatocellular carcinoma may not be valid anymore and a new histological classification will be inaugurated by an international working group. Recent research identified prognostically relevant gene signatures as well as potential molecular targets for therapy of hepatoblastoma. The multicentric study groups in the USA, Europe and Japan recommend cisplatin based chemotherapy for neoadjuvant and adjuvant treatment. However, their risk stratification systems and general treatment strategies differ substantially. Therefore the four groups agreed to pool their patients' data for an analysis of prognostic criteria which can be used for defining common risk groups. While 90% of standard risk and 65% of high risk hepatoblastomas can be cured, the still dismal outcome of multifocal disseminated and metastasising tumors warrants the investigation of new cytotoxic drugs and substances against specific molecular targets. PMID- 22248965 TI - Neuroblastoma. AB - Neuroblastoma is a heterogeneous disease; tumors can spontaneously regress or mature, or display an aggressive, therapy-resistant phenotype. Increasing evidence indicates that the biological and molecular features of neuroblastoma significantly influence and are highly predictive of clinical behavior. Because of this, neuroblastoma has served as a paradigm for biological risk assessment and treatment assignment. Most current clinical studies of neuroblastoma base therapy and its intensity on a risk stratification that takes into account both clinical and biological variables predictive of relapse. For example, surgery alone offers definitive therapy with excellent outcome for patients with low-risk disease, whereas patients at high risk for disease relapse are treated with intensive multimodality therapy. In this review recent advances in the understanding of the molecular genetic events involved in neuroblastoma pathogenesis are discussed, and how they are impacting the current risk stratification and providing potential targets for new therapeutic approaches for children with neuroblastoma. In addition, the results of significant recent clinical trials for the treatment of neuroblastoma are reviewed. PMID- 22248968 TI - Pediatric gastrointestinal stromal tumor. AB - Pediatric gastrointestinal stromal tumor (GIST) is a rare entity that can be quite different from its adult counterpart. This report provides a comprehensive review on the diagnosis and management of this tumor in children and adolescents, including its oncogenesis and associated syndromes. Surgery remains a mainstay of treatment, but there are no standard guidelines available at this time regarding the best practice for multimodality therapy as our understanding of the biology of GIST is still in evolution. Therefore, pediatric patients with GIST should be ideally treated in the context of clinical trials at specialized, multidisciplinary centers throughout the course of their disease, especially because these patients may live for years after diagnosis. PMID- 22248969 TI - Pediatric thyroid cancer. AB - Thyroid cancer is an uncommon childhood malignancy that presents primarily in young children or adolescent females and may be related to radiation exposure or genetic predisposition. Gene alterations, such as RET mutation or RET/PTC rearrangement, are not uncommon. Recent studies have lead to an increased understanding of the role of these particular gene alterations in the diagnosis, prognosis, and treatment of thyroid cancer. Surgery remains the mainstay of treatment for thyroid cancer followed by radioactive iodine when appropriate. In patients with MEN2, prophylactic thyroidectomy is recommended, although a delay in the initial diagnosis is common. With early aggressive treatment and long-term follow-up, these patients generally have excellent outcomes. Recent research suggests potential usefulness of novel therapies directed at oncogenic signaling pathways, modulators of growth, angiogenesis inhibitors, immunomodulators, and gene therapy. PMID- 22248970 TI - Pediatric germ cell tumors. AB - Pediatric germ cell tumors represent a diverse group of tumors that present from in utero through adolescence at many nongonadal locations, from the neck to the sacrococcygeal region. Surgical resection remains the central element of management, and accurate surgical staging is essential to properly ascertain the correct risk-based treatment. The management for all benign tumors (mature and immature teratomas) and select completely resectable malignant tumors is surgery alone. Modern-day chemotherapy is extremely effective in infants and children with unresectable and metastatic disease and these children have a very high survival rate. The use of neoadjuvant chemotherapy allows vital organ preservation and there is no role for resection of vital structures at the time of initial presentation. PMID- 22248971 TI - Recent advances in non-rhabdomyosarcoma soft-tissue sarcomas. AB - Nonrhabdomyosarcoma soft-tissue sarcomas (NRSTS) represent a subgroup of sarcomas that encompass more than 50 distinct histologies. All are rare, but some are more common in patients younger than 20 years of age. The management of patients with many histologies overlap. However, this review will focus on issues unique to a select few NRSTS that are most common in pediatric and adolescent patients. Here, we will discuss the recent advances in the diagnosis, surgical management, and treatment of NRSTS. Adequate surgical local control of the primary tumor is a critical component of the treatment strategy will be emphasized in this review because it determines local and distant recurrence. PMID- 22248972 TI - Update on rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is a malignant childhood tumor of mesenchymal origin that currently has a greater than 70% overall 5-year survival. Multimodality treatment is determined by risk stratification according to pretreatment stage, postoperative group, histology, and site of the primary tumor. Pretreatment staging is dependent on primary tumor site, size, regional lymph node status, and presence of metastases. Unique to RMS is the concept of postoperative clinical grouping that assesses the completeness of disease resection and takes into account lymph node evaluation. At all tumor sites, the clinical grouping, and therefore completeness of resection, is an independent predictor of outcome. Overall, the prognosis for RMS is dependent on primary tumor site, patient age, completeness of resection, extent of disease, including the presence and number of metastatic sites and histology and biology of the tumor cells. Therefore, the surgeon plays a vital role in RMS by contributing to risk stratification for treatment, local control of the primary tumor, and outcome. The current state-of the-art treatment is determined by treatment protocols developed by the Soft Tissue Sarcoma Committee of the children's Oncology Group. PMID- 22248973 TI - Surgical treatment of lung metastases in patients with embryonal pediatric solid tumors: an update. AB - Distant metastases regularly occur in children with solid tumors. The most affected organ is the lung. Nearly in all extracranial pediatric solid tumors, the presence of lung metastases is associated with an adverse prognosis for the children. Therefore, the correct treatment of lung metastases is essential and influences the outcome. Despite different national and international trials for pediatric tumor entities, specific surgical aspects or guidelines for lung metastases are usually not addressed thoroughly in these protocols. The aim of this article is to present the diagnostic challenges and principles of surgical treatment by focusing on the influence of surgery on the outcome of children. Special points of interest are discussed that emphasize sarcomas, nephroblastomas, hepatoblastomas, and other tumors. Surgery of lung metastases is safe, has a positive impact on the patients' prognosis, and should be aggressive depending on the tumor entity. An interdisciplinary approach, including pediatric oncology and radiology, is mandatory in any case. PMID- 22248974 TI - The role of neoadjuvant chemotherapy in children with malignant solid tumors. AB - Pediatric surgeons play a critical role in diagnosing, staging, and treating malignant solid tumors in children. Over the years, the surgical management of the primary tumor site has evolved from an aggressive en-bloc resection at diagnosis to a more tailored surgical approach, often affecting definitive local control after the delivery of neoadjuvant therapy, as currently directed by many solid tumor protocols. In fact, inappropriate upfront resection can lead to unnecessary short- and long-term morbidity, an incomplete resection, and may be associated with a delay in the initiation of the systemic chemotherapy that is critical to the treatment of gross or occult metastatic disease. Therefore, it is important for the pediatric surgeon, as a member of the multidisciplinary team involved in the care of these children, to understand the indications for and implications of neoadjuvant therapy in the treatment of pediatric solid tumors. Here we review the current management of childhood solid tumors focusing on the role of neoadjuvant therapy. PMID- 22248975 TI - Macrolides for the therapy of nosocomial infections. AB - PURPOSE OF REVIEW: Nosocomial infections are an emerging threat. Available solutions are limited due to the multidrug-resistance pattern of the pathogens. Macrolides modulate the immune function of the host and may be active in this setting. RECENT FINDINGS: Findings of in-vitro and experimental animal studies are presented. Clinical studies of community-acquired pneumonia (CAP) and ventilator-associated pneumonia (VAP) are described. SUMMARY: Macrolides decrease production of proinflammatory cytokines by circulating monocytes and by alveolar macrophages and decrease apoptosis of circulating lymphocytes in animal models of acute infections. They also inhibit gene expression of proteins participating in quorum sensing of Pseudomonas aeruginosa. Retrospective cohort studies indicate that addition of a macrolide significantly improves outcome in severe CAP. One randomized, double-blind, clinical study is available. This involves patients with VAP allocated to placebo or intravenous clarithromycin 1 g once daily for 3 days. Clarithromycin treatment significantly decreased time to resolution of VAP and time until weaning from mechanical ventilation. The described findings are promising for the use of macrolides in nosocomial infections. PMID- 22248976 TI - Vascular graft infections. AB - PURPOSE OF REVIEW: This review provides a focus on infections of prosthetic vascular grafts used to treat peripheral arterial diseases. RECENT FINDINGS: The incidence of infections varies between 1 and 6%. Risk factors of infection are not well identified. Main causative pathogens are Gram-negative bacilli, Staphylococcus aureus, and coagulase-negative staphylococci, without clear differences according to location of graft and time of onset of infection. There is no consensual diagnostic criterion. The basic principles for management of graft infections have been known for many years. A surgical approach combining graft excision, complete debridement, and maintaining distal vascular flow is required. Antimicrobial therapy is always instituted to reduce sepsis and prevent secondary graft infection, but there are no evidence-based data to recommend any regimen. However, antibiotics should have bactericidal activity whatever the bacteria growth phase, reduce the microbial burden, penetrate within the biofilm, and prevent further biofilm formation. Mortality and morbidity from these infections remain significant. SUMMARY: A multidisciplinary approach with a limited number of reference centres, recruiting sufficient numbers of patients to perform controlled trials, and to provide expert recommendations, could be the best way to answer unresolved questions and improve the prognosis. PMID- 22248977 TI - Is healthcare-associated pneumonia a distinct entity needing specific therapy? AB - PURPOSE OF REVIEW: Healthcare-associated pneumonia (HCAP) was introduced in 2005 by American Thoracic Society/Infectious Diseases Society of America guidelines as a new entity of pneumonia, resembling nosocomial pneumonia rather than community acquired pneumonia (CAP) in terms of frequency of multidrug-resistant (MDR) pathogens and outcomes, thus requiring broad spectrum initial antimicrobial coverage in order to prevent inadequate treatment and, as a consequence, excess mortality. This concept continues to be a subject of controversy. Main concerns relate to the definition of HCAP, the true frequency of MDR pathogens, and the impact of MDR pathogens on outcomes. RECENT FINDINGS: Definitions of HCAP and the relative frequencies of HCAP defining subgroups were highly variable. All studies demonstrated an increased severity of pneumonia at presentation and an excess mortality from HCAP as compared to CAP. The incidence of MDR pathogens in different observational studies was slightly increased but generally low in most studies originating from Europe, South Korea, Canada, and Japan. However, the data do not support a causal relationship of MDR incidence and excess mortality. Instead, after adjustment for confounders, mortality might be related to hidden or documented treatment restrictions in elderly and severely disabled patients. Accordingly, HCAP guideline concordant antimicrobial treatment did not improve outcomes. SUMMARY: The HCAP concept is based on varying definitions poorly predictive of MDR pathogens. The incidence of MDR pathogens is far lower than supposed in the original guideline document, and MDR pathogens do not seem to be the main cause of excess mortality. Broad antimicrobial coverage does not alter outcomes. As the HCAP concept results in a tremendous overtreatment without any evidence for improved outcomes, it should not be implemented in clinical practice prior to clear evidence that it is superior to a careful assessment of individual risk factors for MDR pathogens. PMID- 22248978 TI - Is a ventilator-associated pneumonia rate of zero really possible? AB - PURPOSE OF REVIEW: The increasing number of hospitals reporting ventilator associated pneumonia (VAP) rates at or close to zero begs the question of whether zero should become the national benchmark for VAP. This article explores the significance of very low VAP rates, reviews differences in surveillance and clinical rates, proposes reasons for their discrepancies, and suggests possible objective alternatives for surveillance. RECENT FINDINGS: Surveillance rates of VAP are decreasing, whereas clinical diagnoses and antibiotic prescribing remain prevalent. This growing discrepancy reflects the lack of objective and definitive signs to diagnose VAP. External reporting pressures may be encouraging stricter interpretation of subjective signs and other surveillance initiatives that can artifactually lower rates. It is impossible to disentangle the relative contribution of care improvements versus surveillance effects to currently observed low VAP rates. SUMMARY: The increasing mismatch between surveillance rates and clinical diagnoses limits the utility of official VAP rates to estimate disease burden and guide quality improvement. Advocates are advised to consider objective alternatives such as average duration of mechanical ventilation, length of stay, mortality, and antibiotic prescribing. Emerging surveillance definitions that use more objective criteria may better reflect and inform future clinical practice. PMID- 22248979 TI - Miltefosine and cutaneous leishmaniasis. AB - PURPOSE OF REVIEW: Miltefosine is a new oral treatment against leishmaniasis. The evidence about its use in New and Old World cutaneous leishmaniasis is presented and discussed. RECENT FINDINGS: Miltefosine is being tested with small clinical trials mainly in endemic cutaneous leishmaniasis regions of South America and Iran. Severe cutaneous leishmaniasis forms successfully treated with miltefosine are reported. SUMMARY: The use of miltefosine in cutaneous leishmaniasis has been addressed in a few clinical trials. An important advantage of this drug is its oral administration when compared with the standard parenteral drugs in the context of a large-scale use in the inner regions of the endemic countries. Miltefosine also shows activity in severe or refractory cases. However, this review points out the need for further investment on clinical research into cutaneous leishmaniasis treatment. PMID- 22248980 TI - New therapy options for MRSA with respiratory infection/pneumonia. AB - PURPOSE OF REVIEW: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent causative agent of nosocomial pneumonia. Because of important clinical consequences of inappropriate treatment, a current review of the potential modifications undergone by S. aureus and adaptation to new treatment options is necessary. RECENT FINDINGS: Vancomycin has been considered the treatment of choice for pneumonia due to MRSA. However, detection of a progressive increase in the minimum inhibitory concentration for this antibiotic, its limited access to the lung parenchyma, and its considerable adverse effects have called into question its position. Linezolid has been shown to have a better pharmacokinetic and safety profiles. The prior uncertainty regarding the clinical superiority of linezolid appears to have been resolved with the publication of a recent trial. Linezolid achieved a higher clinical and microbiological response rate (the latter was not statistically significant), together with a lower incidence of all types of renal adverse effects in patients with nosocomial pneumonia, compared with vancomycin. Tigecycline, teicoplanin and quinupristin/dalfopristin were inferior to the compared drug in their respective clinical trials. The clinical efficacy of telavancin was similar to that of vancomycin. The renal adverse effects of telavancin have to be clarified. Other drugs are efficacious against MRSA but their profile should be evaluated in nosocomial pneumonia. SUMMARY: Current therapeutic alternatives for nosocomial pneumonia due to MRSA appear to be limited to vancomycin and linezolid. However, vancomycin pitfalls, together with the apparent clinical superiority of linezolid, appear to restrict its indication. Telavancin could be a good alternative in patients without basal renal failure. PMID- 22248981 TI - Molecular diagnosis of dermatophyte infections. AB - PURPOSE OF REVIEW: Recent advances in the molecular diagnostics of dermatophytosis may improve speed, specificities and sensitivities. This review provides an update on the current available molecular techniques for the diagnosis of dermatophytosis. RECENT FINDINGS: Molecular diagnostics of dermatophytosis relate to the direct detection of dermatophyte DNA in clinical specimens. Important challenges have been associated with the DNA extraction procedures, which despite improvement still lack consensus, and the fact that phenotypic species classification not always translates into distinct molecular taxonomic entities. Molecular methods are divided into conventional PCR, real time PCR and post-PCR techniques. The former benefits from simplicity and being less expensive to implement, real-time PCR is less laborious, may enable a broader spectrum of simultaneous species detections and the closed system reduces contamination risk, whereas post-PCR strategies may increase the number of species identified but prolong the turnaround time, and the processing of PCR products increases the laboratory contamination risk. SUMMARY: Current molecular methods are on the verge of overcoming most of the early challenges regarding dermatophyte taxonomy, DNA extraction procedures and species specificity, and thus may lead to an increased adoption of such methods. This may point towards a novel consensus in which molecular methods supplement or even replace classical diagnosis of dermatophytosis. PMID- 22248982 TI - The association between race and neighborhood socioeconomic status in younger Black and White adults with chronic pain. AB - Both race and socioeconomic status (SES) contribute to disparities. We assessed the relative roles of neighborhood socioeconomic status (nSES) and race in the chronic pain experience for young adults (<50 years old). Data from a tertiary care pain center was matched to 2000 US Census data to examine the role of race and nSES on chronic pain and its sequelae in 3,730 adults (9.7% black, 61% female) 18 to 49 years old (37 +/- 8 years). Blacks had significantly more pain and disability and lived in lower SES neighborhoods. Living in a lower SES neighborhood was associated with increased sensory, affective, and "other" pain, pain-related disability, and mood disorders. Race was independently associated with affective and "other" pain on the McGill Pain Questionnaire scales, and both disability factors. Racial disparities in sensory pain and mood disorders were mediated by nSES. In every case, race and neighborhood SES played important roles in the outcomes for chronic pain. Age was related to both disability outcomes. Gender was associated with voluntary disability and mood disorders, with men displaying worse outcomes. PERSPECTIVE: Important racial- and SES-related variability in pain related outcomes in young adults with chronic pain were defined. Black race was associated with neighborhood SES, and black race plays an important role in pain outcomes beyond neighborhood SES. PMID- 22248983 TI - Old and new biomarkers for predicting high and low risk microbial infection in critically ill patients with new onset fever: a case for procalcitonin. AB - OBJECTIVES: Fever suggests the presence of microbial infection in critically ill patients. The aim was to compare the role of old and new biomarkers in predicting absence or presence of microbial infection, its invasiveness and severity in critically ill patients with new onset fever. METHODS: We prospectively studied 101 patients in the intensive care unit with new onset fever (>38.3 degrees C). Routine infection parameters, lactate, procalcitonin (PCT), midregional pro adrenomedullin (MR proADM), midregional pro-atrial natriuretic peptide (MR proANP) and copeptin (COP) were measured daily for three days after inclusion. Likelihood, invasiveness (by bloodstream infection, BSI) and severity of microbial infection were assessed by cultures, imaging techniques and clinical courses. RESULTS: All patients had systemic inflammatory response syndrome; 45% had a probable or proven local infection and 12% a BSI, with 20 and 33% mortality in the ICU, respectively. Only peak PCT (cutoff 0.65 ng/mL at minimum) was of predictive value for all endpoints studied, i.e. BSI, septic shock and mortality (high risk infection) and infection without BSI, shock and mortality (low risk infection), at areas under the receiver operating characteristic curves varying between 0.67 (P = 0.003) and 0.72 (P < 0.001). In multivariable analysis, the combination of C-reactive protein and lactate best predicted high risk infection, followed by PCT. For low risk infection, PCT was the single best predictor. CONCLUSIONS: In critically ill patients with new onset fever, plasma PCT as a single variable, among old and new biomarkers, best helps, to some extent, to predict ICU-acquired, high risk microbial infection when peaking above 0.65 ng/mL and low risk infection when peaking below 0.65 ng/mL. PMID- 22248984 TI - Greatly increased risk for prostatic abscess following pyogenic liver abscess: a nationwide population-based study. PMID- 22248985 TI - Giardia duodenalis: dendritic cell defects in IL-6 deficient mice contribute to susceptibility to intestinal infection. AB - Interleukin (IL)-6 is important in numerous infections. IL-6 can promote T cell survival and differentiation toward Th17 cells, as well as B cell proliferation and differentiation to plasma cells. Giardia duodenalis is a protozoan parasite that replicates in the lumen of the small intestine in humans and many other mammals resulting in diarrhea, cramps and developmental delays in children. IL-6 is required for control of this infection, but it is unclear what its role is or which cells are required to produce this cytokine to generate efficient immunity. We have analyzed infections in a series of chimeric mice in which specific cell types lacked the ability to produce IL-6 in order to determine which sources of IL-6 played an important role in controlling this infection. Analysis of bone marrow chimeras indicate that radiation-sensitive, bone-marrow derived cells must produce IL-6. T cell chimeras show that T cell production of IL-6 is not required. Finally, by transferring dendritic cells from wild-type mice into IL-6 deficient recipients, we show that dendritic cell defects are responsible for the inability of IL-6 deficient mice to respond to Giardia challenge. PMID- 22248987 TI - Successive and large-scale synthesis of InP/ZnS quantum dots in a hybrid reactor and their application to white LEDs. AB - We report successive and large-scale synthesis of InP/ZnS core/shell nanocrystal quantum dots (QDs) using a customized hybrid flow reactor, which is based on serial combination of a batch-type mixer and a flow-type furnace. InP cores and InP/ZnS core/shell QDs were successively synthesized in the hybrid reactor in a simple one-step process. In this reactor, the flow rate of the solutions was typically 1 ml min(-1), 100 times larger than that of conventional microfluidic reactors. In order to synthesize high-quality InP/ZnS QDs, we controlled both the flow rate and the crystal growth temperature. Finally, we obtained high-quality InP/ZnS QDs in colors from bluish green to red, and we demonstrated that these core/shell QDs could be incorporated into white-light-emitting diode (LED) devices to improve color rendering performance. PMID- 22248986 TI - Toxoplasma gondii: protective immunity against toxoplasmosis with recombinant actin depolymerizing factor protein in BALB/c mice. AB - Toxoplasmosis is one of the most world-wide spread zoonosis representing a very serious clinical and veterinary problem. There is still need for vaccines for toxoplasmosis. In the present study, we evaluated the protective efficacy of a recombinant actin depolymerizing factor (ADF) subunit vaccine against Toxoplasma gondii infection in BALB/c mice. The recombinant T. gondii ADF protein (rADF) was expressed in Escherichia coli and used as antigens for BALB/c mice immunization. The results indicated that specific antibody and the increased percentage of CD4(+) T lymphocyte were found in vaccinated BALB/c mice with rADF, when compared with adjuvant or PBS groups. After challenged with T. gondii (RH strain) tachyzoites, the survival time of the mice in rADF group was longer than those in the control group. The numbers of brain cysts of the mice in rADF group reduced significantly when compared with those in control groups (P<0.05), and the rate of reduction could reach to around 30%. These results suggest that rADF can generate protective immunity against T. gondii infection in BALB/c mice. PMID- 22248988 TI - Protocol for measurement of mean arterial pressure at 11-13 weeks' gestation. AB - OBJECTIVES: To identify the best protocol for measurement of mean arterial pressure (MAP) in early pregnancy for the prediction of preeclampsia (PE). METHODS: This was a prospective study in singleton pregnancies attending for a routine hospital visit at 11-13 weeks' gestation when a minimum of four recordings of MAP were taken from each arm. The performance of screening for PE by different combinations of MAP was compared to the protocol of the National Heart Foundation of Australia (NHFA). RESULTS: The MAP was measured in 587 (2.4%) cases that developed PE and in 22,900 that were unaffected by hypertensive disorders in pregnancy. The area under the receiver operating characteristic curve (AUROC) for prediction of PE by MAP as recommended by the NHFA protocol was 0.773 (95% CI 0.768-0.778). This AUROC was not significantly different from the AUROC obtained by the average MAP of the first three measurements from one arm (0.765, 95% CI 0.760-0.771) or the average of the first (0.766, 95% CI 0.760 0.771), the first two (0.771, 95% CI 0.766-0.777), or the first three measurements from the two arms (0.773, 95% CI 0.768-0.778). CONCLUSION: Performance of screening for PE by taking the average of a minimum of two measurements from both arms is comparable to the NHFA protocol. PMID- 22248989 TI - The role of microtopography in cellular mechanotransduction. AB - Mechanotransduction is crucial for cellular processes including cell survival, growth and differentiation. Topographically patterned surfaces offer an invaluable non-invasive means of investigating the cell response to such cues, and greater understanding of mechanotransduction at the cell-material interface has the potential to advance development of tailored topographical substrates and new generation implantable devices. This study focuses on the effects of topographical modulation of cell morphology on chromosomal positioning and gene regulation, using a microgrooved substrate as a non-invasive mechanostimulus. Intra-nuclear reorganisation of the nuclear lamina was noted, and the lamina was required for chromosomal repositioning. It appears that larger chromosomes could be predisposed to such repositioning. Microarrays and a high sensitivity proteomic approach (saturation DiGE) were utilised to identify transcripts and proteins that were subject to mechanoregulated changes in abundance, including mediators of chromatin remodelling and DNA synthesis linked to the changes in nucleolar morphology and the nucleoskeleton. PMID- 22248990 TI - Gene delivery using dendrimer-entrapped gold nanoparticles as nonviral vectors. AB - Development of highly efficient nonviral gene delivery vectors still remains a great challenge. In this study, we report a new gene delivery vector based on dendrimer-entrapped gold nanoparticles (Au DENPs) with significantly higher gene transfection efficiency than that of dendrimers without AuNPs entrapped. Amine terminated generation 5 poly(amidoamine) (PAMAM) dendrimers (G5.NH(2)) were utilized as templates to synthesize AuNPs with different Au atom/dendrimer molar ratios (25:1, 50:1, 75:1, and 100:1, respectively). The formed Au DENPs were used to complex two different pDNAs encoding luciferase (Luc) and enhanced green fluorescent protein (EGFP), respectively for gene transfection studies. The Au DENPs/pDNA polyplexes with different N/P ratios and compositions of Au DENPs were characterized by gel retardation assay, light scattering, zeta potential measurements, and atomic force microscopic imaging. We show that the Au DENPs can effectively compact the pDNA, allowing for highly efficient gene transfection into the selected cell lines as demonstrated by both Luc assay and fluorescence microscopic imaging of the EGFP expression. The transfection efficiency of Au DENPs with Au atom/dendrimer molar ratio of 25:1 was at least 100 times higher than that of G5.NH(2) dendrimers without AuNPs entrapped at the N/P ratio of 2.5:1. The higher gene transfection efficiency of Au DENPs is primarily due to the fact that the entrapment of AuNPs helps preserve the 3-dimensional spherical morphology of dendrimers, allowing for more efficient interaction between dendrimers and DNA. With the less cytotoxicity than that of G5.NH(2) dendrimers demonstrated by thiazoyl blue tetrazolium bromide assay and higher gene transfection efficiency, it is expected that Au DENPs may be used as a new gene delivery vector for highly efficient transfection of different genes for various biomedical applications. PMID- 22248991 TI - Opportunities for European obesity research in the coming decade - a perspective from the European association for the study of obesity (EASO). PMID- 22248992 TI - Reduced brain natriuretic peptide levels in class III obesity: the role of metabolic and cardiovascular factors. AB - OBJECTIVE: Brain natriuretic peptide (BNP) has potent lipolytic action and, probably, a role in the biological mechanisms of obesity. Clinically, high levels are found in subjects with heart failure (HF). Low levels and inverse relation to BMI lead to questioning of its clinical utility in obese subjects, but heterogeneous results are found in severe obesity. METHODS: In order to describe BNP behavior and its metabolic and cardiovascular determinants in class III obesity, we performed BNP measurement as well as clinical and echocardiographic evaluation of 89 subjects from two public hospitals in Brazil. Multivariate logistic ordinal regression with BNP tertiles as the dependent variable was performed. RESULTS: Mean (+/- SD) age and BMI (+/- SD) was 44 +/- 11.5 years and 53.2 +/- 7.9 kg/m(2), respectively. 72 (81%) participants were women, and 18 (20%) had HF. Median BNP was 9.5 pg/ml(Q1 4.9; Q3 21.2 pg/ml). 30% of BNP values were below the detection limit of the method. In multivariate analysis, left atrial volume (LAV) was the only determinant of BNP levels (p 0.002) with odds ratio of 1.1 (95% CI 1.03-1.16). CONCLUSION: BNP levels are low in severe obesity, even in subjects with HF. LAV, which marks diastolic dysfunction, determines BNP levels, but not BMI and metabolic abnormalities. PMID- 22248993 TI - The transtheoretical model in weight management: validation of the processes of change questionnaire. AB - OBJECTIVE: The processes of change implied in weight management remain unclear. The present study aimed to identify these processes by validating a questionnaire designed to assess processes of change (the P-Weight) in line with the transtheoretical model. The relationship of processes of change with stages of change and other external variables is also examined. METHODS: Participants were 723 people from community and clinical settings in Barcelona. Their mean age was 32.07 (SD = 14.55) years; most of them were women (75.0%), and their mean BMI was 26.47 (SD = 8.52) kg/m(2). They all completed the P-Weight and the stages of change questionnaire (S-Weight), both applied to weight management, as well as two subscales from the Eating Disorders Inventory-2 and Eating Attitudes Test-40 questionnaires about the concern with dieting. RESULTS: A 34-item version of the P-Weight was obtained by means of a refinement process. The principal components analysis applied to half of the sample identified four processes of change. A confirmatory factor analysis was then carried out with the other half of the sample, revealing that the model of four freely correlated first-order factors showed the best fit (GFI = 0.988, AGFI = 0.986, NFI = 0.986, and SRMR = 0.0559). Corrected item-total correlations (0.322-0.865) and Cronbach's alpha coefficients (0.781-0.960) were adequate. The relationship between the P-Weight and the S Weight and the concern with dieting measures from other questionnaires supported the validity of the scale. CONCLUSION: The study identified processes of change involved in weight management and reports the adequate psychometric properties of the P-Weight. It also reveals the relationship between processes and stages of change and other external variables. PMID- 22248994 TI - Relationship of weight status with mental and physical health in female fibromyalgia patients. AB - OBJECTIVE: To analyze the association of weight status with anxiety, depression, quality of life and physical fitness in fibromyalgia (FM) patients. METHODS: The sample comprised 175 Spanish female FM patients (51.2 +/- 7 years). We assessed quality of life by means of the Short-Form-36 Health Survey (SF36) and anxiety and depression by means of the Hospital Anxiety and Depression Scale (HADS). We used standardized fieldbased fitness tests to assess cardiorespiratory fitness, muscular strength, flexibility, agility, and static and dynamic balance. BMI was calculated and categorized using the international criteria. RESULTS: 33% of the sample was normal-weight, 35% overweight and 33% obese. HADS-anxiety and HADS depression levels increased across the weight status categories. Obese patients had higher anxiety and depression levels compared to normal-weight patients (p < 0.05) whereas no differences were observed between overweight and obese patients. Physical functioning, bodily pain, general health (all p < 0.01) and mental health (p < 0.05) subscales from the SF36 were worse across the weight status categories. Likewise, levels of cardiorespiratory fitness, dynamic balance/motor agility (both p < 0.05) and upper-body flexibility (p < 0.001) decreased as the weight status increased. Pairwise comparisons showed significant differences mainly between the normal-weight versus obese groups. CONCLUSION: Obese female FM patients displayed higher levels of anxiety and depression and worse quality of life, cardiorespiratory fitness, dynamic balance/motor agility and upper-body flexibility than their normal-weight peers. PMID- 22248995 TI - Inverse association between fruit and vegetable intake and BMI even after controlling for demographic, socioeconomic and lifestyle factors. AB - OBJECTIVE: To estimate fruit and vegetable (FV) intake levels of US adult population and evaluate the association between FV intake and BMI status after controlling for confounding demographic, socioeconomic and lifestyle factors. We also sought to identify moderating factors. METHODS: We used 2007 Behavior Risk Factors Surveillance System (N > 400,000) data. FV intake was dichotomized as >=5 servings (FV5+) versus <5 servings/ day. BMI status was categorized as normal, overweight, and obese. Identification of moderators was performed by testing interactions between BMI status and other variables using bivariate analyses followed by multiple logistic regression analysis incorporating complex survey sampling design features. RESULTS: Only 24.6% of US adults consumed >=5 servings per day and less than 4% consumed 9 or more servings. Overweight (% FV5+ = 23.9%) and obese (21.9%) groups consumed significantly less FV than the normal-weight (27.4%) group (p < 0.0001). This inverse association remained significant even after controlling for potential confounding factors. Multivariate analysis identified five significant moderators (p < 0.0001) after controlling for all evaluated variables: race, sex, smoking status, health coverage, and physical activity. Notably, physically inactive obese males tended to consume the least FV (% FV5+ = 14.7%). CONCLUSION: Current US population FV intake level is below recommended levels. The inverse association between FV intake and obesity was significant and was moderated by demographic, socioeconomic status, and lifestyle factors. These factors should be considered when developing policies and interventions to increase FV intake. PMID- 22248996 TI - The association between attachment avoidance and quality of life in bariatric surgery candidates. AB - OBJECTIVE: Patients presenting for bariatric surgery have high rates of psychiatric co-morbidity and reduced health-related quality of life (HRQOL) compared to the general population. In this study, we aimed to determine the relationship between insecure attachment styles and HRQOL in bariatric surgery candidates. METHODS: We assessed depression, social support, attachment avoidance, attachment anxiety, HRQOL (SF-36), and eating disorder psychopathology in 70 consecutive patients assessed for bariatric surgery. SF-36 physical (PCS) and mental component scores (MCS) were compared to a normative sample and analyzed using t-tests. Predictors of HRQOL were analyzed using multiple linear regression analyses. RESULTS: SF-36 PCS and MCS in this pre-bariatric surgery sample were significantly lower than in an age-matched reference population. Depression, attachment anxiety, attachment avoidance and eating disorder psychopathology scores were negatively correlated with SF-36 MCS. Depression was associated with lower SF-36 PCS (p = 0.015). SF-36 MCS were significantly predicted by BDI scores (p < 0.001) and attachment avoidance (p = 0.024) in our multiple regression model. CONCLUSION: This is the first study to demonstrate an association between attachment avoidance and poor mental HRQOL in bariatric surgery candidates. Future studies are needed to examine the effect of attachment avoidance on post-bariatric surgery outcomes. PMID- 22248997 TI - Tracking of leptin, soluble leptin receptor, and the free leptin index during weight loss and regain in children. AB - OBJECTIVE: To investigate changes in leptin and soluble leptin receptor (SLR) concentrations, and in the free leptin index (FLI) during weight loss and subsequent weight regain; and to ascertain whether these indices remain stable in the rank of the distribution in repeated measures (tracking) during perturbations of weight in obese children. DESIGN AND MEASUREMENTS: In a longitudinal study, 115 obese children were examined during a 12- week weight loss programme and 28 months of follow-up. Height, weight, body composition, Tanner stages, testicular size, time of menarche, and concentrations of leptin and SLR were measured at baseline, on days 14, 33, and 82, and from months 10, 16, and 28. RESULTS: During weight loss, leptin decreased and the SLR increased. During weight regain, leptin increased and the SLR decreased. The partial correlation coefficients expressing the relationship between leptin and SLR were significant in girls during both weight loss and weight regain, whereas in boys they were much weaker and not significant. Leptin, SLR and FLI exhibited individual-specific levels (tracking) during weight loss and regain in boys and girls. The observed tracking seemed stronger during weight loss than during weight regain. The observed tracking was independent of both baseline body mass index (BMI) standard deviation score (SDS) and pubertal development at baseline and of subsequent changes in BMI SDS and puberty stages. CONCLUSION: Leptin and the SLR exhibit tracking during weight loss and regain, which indicates individual stability in the leptin system despite challenges of weight. PMID- 22248998 TI - Obesity as a determinant of two forms of bullying in Ontario youth: a short report. AB - OBJECTIVE: Obesity can have negative effects in terms of stigma and discriminatory behavior. Past cross-sectional analyses have shown that overweight and obese youths are more likely to be involved in bullying. Here, we examine such relationships in a longitudinal analysis. Study outcomes were self-reports of: i) physical bullying victimization and perpetration and ii) relational bullying victimization and perpetration. METHODS: Participants were administered the Health Behaviour in School-Age Children Survey in 2006 and then again in 2007, and included 1,738 youths from 17 Ontario high schools. Relationships between adiposity and each of the four forms of bullying were evaluated using multi-level analyses. RESULTS: Excess adiposity was shown to precede bullying involvement in this study. Obese and overweight males reported 2-fold increases in both physical and relational victimization, while obese females reported 3 fold increases in perpetration of relational bullying. Among those free of bullying at baseline (2006), significant increases in perpetration of relational bullying were reported by obese females in 2007 relative to normal-weight females (14.8 vs. 3.8% among normal-weight girls; p = 0.02). CONCLUSIONS: Findings are congruent with previous cross-sectional studies and confirm that obese youths are at increased risk of social consequences attributable to their appearance. PMID- 22248999 TI - Replication of the SH2B1 rs7498665 association with obesity in a Belgian study population. AB - OBJECTIVE: SH2B1 has been identified as an interesting candidate gene for complex obesity through genome-wide association studies. Therefore, we set out to replicate the reported association with rs7498665 in our Belgian study population and to extend our study with an additional tagSNP for the SH2B1 gene region. METHODS: We genotyped both rs7498665 and rs7201929 in a population of 1,045 obese adults and 317 healthy lean individuals. Statistical analyses were performed to evaluate the role of these polymorphisms in the development of obesity. RESULTS: We found that the rs7498665 minor allele increases obesity risk by 26% (OR(age sex adj) = 1.26, 95% CI 1.04-1.52, nominal p = 0.016). Logistic regression showed that the rs7201929 minor allele decreases obesity risk by 24% in the population investigated (OR(age-sex adj) = 0.76, 95% CI 0.61-0.94, nominal p = 0.011). Conditional analyses showed that both associations represent the same association signal (rs7498665 OR(adjusted for rs7201929) = 1.17, 95% CI 0.95-1.45, nominal P = 0.14; rs7201929 OR(adjusted for rs7498665) = 0.82, 95% CI 0.65-1.04, nominal p = 0.10). CONCLUSION: With the current study we were able to replicate and confirm that the SH2B1 gene locus is significantly associated with complex obesity in a Caucasian population. PMID- 22249000 TI - Worksite physical activity interventions and obesity: a review of European studies (the HOPE project). AB - OBJECTIVE: Our aim was to review the effectiveness of physical activity promotion interventions in the worksite setting in Europe in order to identify those studies that had measured obesity-related outcomes and to evaluate how external validity of the findings had been assessed. METHODS: We conducted a review of studies conducted in Europe, published up to December 2009. We assessed levels of evidence regarding effectiveness and analysed external validity using the RE-AIM framework. RESULTS: Studies included (n = 33) were divided in 6 intervention categories. Moderate evidence of effectiveness was found for physical fitness outcomes with exercise training interventions and for physical activity outcomes with active commuting interventions. There was no or inconclusive evidence for obesity-related outcomes for all intervention categories. For external validity, elements receiving the least attention (<20%) were representativeness of participants, setting-level inclusion/exclusion criteria and representativeness, characteristics regarding intervention staff, implementation of intervention, costs, long-term effects and programme sustainability. CONCLUSIONS: Active commuting and exercise training appear as promising approaches to promote physical activity or fitness in the workplace. The effect of interventions on obesity-related outcomes remains to be further investigated. There is a need to better report elements of generalizability and dissemination for translation into practice of worksite physical activity interventions. PMID- 22249001 TI - Naltrexone/bupropion: an investigational combination for weight loss and maintenance. AB - Naltrexone/bupropion is an investigational combination for weight loss and maintenance in patients who are obese or have a BMI >= 27 kg/m(2) with comorbid diabetes, hypertension or hyperlipidemia. Pooled results from four phase 3 trials reveal placebo-subtracted mean weight loss of 4.7% (range 3.2-5.2%) with naltrexone/bupropion after 1 year (p < 0.001 vs. placebo in each trial). The placebo-subtracted proportion of patients achieving >=5% weight loss with naltrexone/bupropion ranged from 26 to 33% (p < 0.001 vs. placebo in each trial). In the majority of phase 3 trials, naltrexone/bupropion significantly improved proportion of patients achieving >=10% weight loss, waist circumference, triglycerides, high-density lipoprotein, fasting insulin, insulin resistance, and obesity-specific quality of life compared to placebo. In patients with diabetes, naltrexone/bupropion therapy decreased hemoglobin A1c (HbA1c) approximately 0.5% more than placebo (p < 0.001). Common side effects associated with naltrexone/bupropion include nausea, constipation, vomiting, dizziness, and dry mouth. Greater improvement in systolic blood pressure and pulse were seen with placebo compared to naltrexone/bupropion (p < 0.001). Further studies are necessary to determine the effect of naltrexone/bupropion on cardiovascular outcomes. The safety and efficacy of naltrexone/bupropion in weight management is reviewed in this article. PMID- 22249002 TI - Cloning, characterization, and expression analysis of a putative 17 beta hydroxysteroid dehydrogenase 11 in the abalone, Haliotis diversicolor supertexta. AB - The 17-beta-hydroxysteroid dehydrogenases (17beta-HSDs) are key enzymes for sex steroid biosynthesis. To date, relatively little is known about the presence and function of 17beta-HSDs in marine gastropods. In the present study, a cDNA sequence encoding putative 17beta-HSD type 11 (17beta-HSD-11) was identified in marine abalone (Haliotis diversicolor supertexta). The full-length cDNA contains 1058bp, including an open reading frame (ORF) of 900bp that encodes a protein of 299 amino acids. Comparative structural analysis revealed that abalone 17beta-HSD 11 shares relatively high homology with other 17b-HSD-11 hormologues, and a lesser degree of amino acid identity with other forms of 17b-HSD, especially in the functional domains, including the cofactor binding domain (TGxxxGxG) and catalytic site (YxxSK). Phylogenetic analysis showed that abalone 17beta-HSD-11 belongs to the short-chain dehydrogenase/reductase (SDR) family. Functional analysis following transient transfection of the ORF into human embryonic kidney 293 (HEK-293) cells indicated that abalone 17beta-HSD-11 has the ability to convert 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) to androsterone (A) and testosterone (T) to androstenedione (4A). Expression analysis in vivo demonstrated that abalone 17beta-HSD-11 is differentially expressed during three stages (non-reproductive, reproductive, and post-reproductive). Taken together, these results indicate that ab-17beta-HSD-11 is an SDR family member with a potential role in steroid regulation during the reproductive stage. PMID- 22249003 TI - Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. AB - Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20 lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC. PMID- 22249004 TI - Alu Sx repeat-induced homozygous deletion of the StAR gene causes lipoid congenital adrenal hyperplasia. AB - Lipoid congenital adrenal hyperplasia (Lipoid CAH) is the most severe form of the autosomal recessive disorder CAH. A general loss of the steroid biosynthetic activity caused by defects in the StAR gene manifests as life-threatening primary adrenal insufficiency. We report a case of Lipoid CAH caused by a so far not described homozygous deletion of the complete StAR gene and provide diagnostic results based on a GC-MS steroid metabolomics and molecular genetic analysis. The patient presented with postnatal hypoglycemia, vomiting, adynamia, increasing pigmentation and hyponatremia. The constellation of urinary steroid metabolites suggested Lipoid CAH and ruled out all other forms of CAH or defects of aldosterone biosynthesis. After treatment with sodium supplementation, hydrocortisone and fludrocortisone the child fully recovered. Molecular genetic analysis demonstrated a homozygous 12.1 kb deletion in the StAR gene locus. The breakpoints of the deletion are embedded into two typical genomic repetitive Alu Sx elements upstream and downstream of the gene leading to the loss of all exons and regulatory elements. We established deletion-specific and intact allele specific PCR methods and determined the StAR gene status of all available family members over three generations. This analysis revealed that one of the siblings, who died a few weeks after birth, carried the same genetic defect. Since several Alu repeats at the StAR gene locus increase the probability of deletions, patients with typical symptoms of lipoid CAH lacking evidence for the presence of both StAR alleles should be analyzed carefully for this kind of disorder. PMID- 22249006 TI - Apelin secretion and expression of apelin receptors in 3T3-L1 adipocytes are differentially regulated by angiotensin type 1 and type 2 receptors. AB - Adipocytes play pivotal roles in regulating metabolism through secretion of a variety of adipokines, which in turn is regulated by other metabolic factors (e.g., insulin). Understanding the regulations of adipokine secretion is important because adipokines are implicated with metabolic disorders, such as, obesity and diabetes mellitus. Here, we investigated the regulatory roles of angiotensin II (AngII) on the secretion of apelin in 3T3-L1 adipocytes, and distinct signaling pathways mediated by AngII receptor type 1 (AT1) and type 2 (AT2) were revealed. It was found that activation of AT1 receptors stimulates apelin secretion in Ca2+, protein kinase C, and MAPK kinase dependent ways while activation of AT2 receptors inhibits apelin secretion through cAMP and cGMP dependent pathways. Furthermore, we demonstrate that the expression of apelin receptor (APJ) is also similarly regulated by AT1 and AT2 receptors. Finally, a detailed AngII signaling map is proposed. PMID- 22249007 TI - Metallothionein deficiency in the injured peripheral nerves of complex regional pain syndrome as revealed by proteomics. AB - Complex regional pain syndrome (CRPS) is characterized by persistent and severe pain after trauma or surgery; however, its molecular mechanisms in the peripheral nervous system are poorly understood. Using proteomics, we investigated whether injured peripheral nerves of CRPS patients have altered protein profiles compared with control nerves. We obtained nerve samples from 3 patients with CRPS-2 who underwent resection of part of an injured peripheral nerve. Sural nerves from fresh cadavers with no history of trauma or neuropathic pain served as controls. Proteomic analysis showed that the number and functional distribution of proteins expressed in CRPS and control nerves was similar. Interestingly, metallothionein was absent in the injured nerves of CRPS-2, although it was readily detected in control nerves. Western blotting further confirmed the absence of metallothionein in CRPS-2 nerves, and immunohistochemistry corroborated the deficiency of metallothionein expression in injured nerves from 5 of 5 CRPS patients and 2 of 2 patients with painful neuromas. In contrast, all control nerves, including 5 sural nerves from fresh cadavers and 41 nerves obtained from surgically resected tumors, expressed MT. Furthermore, expression of S100 as a marker for Schwann cells, and neurofilament M as a marker of axons was comparable in both CRPS-2 and controls. Metallothioneins are zinc-binding proteins that are probably involved in protection against injury and subsequent regeneration after CNS damage. Their absence from the injured peripheral nerves of patients with CRPS-2 suggests a potential pathogenic role in generating pain in the damaged peripheral nerves. PMID- 22249005 TI - The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. AB - There is increasing experimental and epidemiological evidence that fetal programming of genetic systems is a contributing factor in the recent increase in adult obesity and other components of metabolic syndrome. In particular, there is evidence that epigenetic changes associated with the use of manmade chemicals may interact with other factors that influence fetal and postnatal growth in contributing to the current obesity epidemic. The focus of this review is on the developmental effects of estrogenic endocrine disrupting chemicals (EDCs), and more specifically on effects of exposure to the estrogenic EDC bisphenol A (BPA), on adipocytes and their function, and the ultimate impact on adult obesity; BPA exposure also results in impaired reproductive capacity. We discuss the interaction of EDCs with other factors that impact growth during fetal and neonatal life, such as placental blood flow and nutrient transport to fetuses, and how these influence fetal growth and abnormalities in homeostatic control systems required to maintain normal body weight throughout life. PMID- 22249008 TI - Use of titanium expandable vertebral cages in cervical corpectomy. AB - We aimed to investigate the usefulness of titanium expandable cages for vertebral body reconstruction after anterior cervical corpectomy. The records of 29 patients treated with expandable titanium cages for a variety of indications were analysed retrospectively. There was evidence of fusion in all patients. There was no radiographic evidence of more than 4mm subsidence throughout the series. There were no hardware failures. Our results show that expandable titanium cages are safe and useful in anterior cervical corpectomies for providing adequate anterior column support and solid constructs without significant hardware complications or the risk and morbidity associated with the use of strut allograft or autograft. PMID- 22249009 TI - Serotonergic involvement in levodopa-induced dyskinesias in Parkinson's disease. AB - Levodopa-induced dyskinesias (LID) represent a substantial barrier to effective symptomatic management of Parkinson's disease, but current treatment options for this debilitating side effect are limited, despite an increasing understanding of their pathophysiology from animal models. Increasing evidence suggests that serotonin neurons have a pivotal role in the induction and maintenance of dyskinesias, and provide a promising target for anti-dyskinetic therapies. Here, we review the evidence for serotonergic involvement in dyskinesias from animal and human data, and highlight some of the translational gaps which may explain why the success of serotonin autoreceptor agonists as anti-dyskinetic agents in experimental models has failed to be replicated in clinical trials. PMID- 22249010 TI - Probable hereditary multiple system atrophy-autonomic (MSA-A) in a family in the United States. AB - Multiple system atrophy-autonomic (MSA-A) is a typically spontaneous neurological disorder. The disease, distinguished by a "hot cross bun" sign on MRI, causes a series of autonomic dysfunctions including orthostatic hypotension and genitourinary and gastrointestinal problems. We present an 84 year-old woman with MSA-A symptoms who was positive for a "hot cross bun" sign. Genetic testing was used to rule out other possible ataxias. Importantly, the patient's two sisters also presented with similar symptoms indicating a possible autosomal dominant linkage. To our knowledge, this is the first report of hereditary MSA-A in the USA. PMID- 22249011 TI - Reduction of displaced Hangman's fracture by compression across crossed translaminar screws. AB - Hangman's fractures are fractures across the pars interarticularis of C2 with possible subluxation of C2 on C3. However, no criteria have been defined for the specific indications for surgical fixation. We describe a 30-year old man who sustained a displaced Hangman's fracture after a motor vehicle accident. The fracture was successfully reduced, in the operating room, by compression across crossed translaminar screws while lifting C1 relative to C2. Intra-operative reduction of a displaced Hangman's fracture by compression across crossed translaminar screws is safe and technically feasible. PMID- 22249012 TI - Spontaneously ruptured intraspinal epidermoid cyst causing chemical meningitis. AB - We report a 53-year-old woman with a rare ruptured lumbar intraspinal epidermoid cyst causing chemical meningitis evaluated with MRI (including diffusion-weighted imaging), with histopathologic correlation. PMID- 22249013 TI - Anesthetic and analgesic effects in patients undergoing a lumbar laminectomy of spinal, epidural or a combined spinal-epidural block with the addition of morphine. AB - This study was designed to evaluate the anesthetic, analgesic and side effects of spinal, epidural and combined spinal-epidural anesthesia with the addition of morphine for lumbar laminectomy. A total of 66 patients undergoing lumbar laminectomy were included in the present study of whom 64 completed the study. Patients were randomly divided into three groups: (i) spinal anesthesia - the SA group; (ii) epidural anesthesia - the EA group; and (iii) combined spinal epidural anesthesia - the CA group. Demographical data, surgical times and peak sensory levels of groups were similar. Heart rate, mean arterial pressure, and peripheral oxygen saturation did not differ between the three groups. No differences were observed intraoperatively in Ramsey sedation scale (RSS) scores between the groups, but postoperatively, although RSS scores were similar for the EA and CA groups, they were significantly lower for the SA group. The postoperative visual analogue scale pain scores were higher in the SA group compared to the EA and the CA groups except for the second postoperative hour. Time-to-use of the first patient controlled analgesia was similar for all groups. The total consumption of morphine over the 24-hour study period was significantly higher in the SA group compared to the EA and the CA groups. Postoperative nausea and vomiting frequencies were higher in SA group, but pruritus frequency was lower than the EA and the CA groups. In conclusion, although spinal, epidural, and combined spinal-epidural anesthesia are adequate and effective for lumbar laminectomies, epidural and combined spinal-epidural anesthesia techniques are more effective than spinal anesthesia for postoperative analgesia and sedation with lesser side effects. PMID- 22249014 TI - Unusual "double density" colloid cysts. AB - Third ventricular tumors vary in etiology. Treatment and surgical approach usually depends on preoperative diagnosis. Colloid cysts are the most common tumors of the third ventricle and the occurrence of two colloid cysts in the ventricular system is rare. Here we present a patient with paired colloid cysts of the third and lateral ventricles that had different radiographic characteristics, and both of which were resected through a purely endoscopic approach. This is the third reported patient with dual or paired colloid cysts. It is the second report of a lateral and third ventricular cyst, and to our knowledge the first to be successfully managed with purely endoscopic techniques obviating the need for a craniotomy. This report illustrates the importance of a wide differential when investigating intraventricular lesions and provides another example of a purely endoscopic transcortical approach for the resection of colloid cyst. PMID- 22249015 TI - Activities of daily living in motor neuron disease: role of behavioural and motor changes. AB - Impairment in the activities of daily living (ADL) in motor neuron disease (MND) has been little investigated. The contributions of both behavioural and motor changes on functional performance have not been explored. A postal survey in New South Wales, Australia, included assessments of ADL, behavioural change (carer based) and MND severity. Eighty-two patients were subdivided into groups according to onset presentation: bulbar (n=23) and limb (n=59). There were significant differences in ADL performance between limb and bulbar onset groups depending on ADL task. Disability was also dependent on disease severity as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS - R) score. Importantly, variance in ADL scores was dependent on both motor and behavioural factors. This study confirms the progressive disabling nature of MND, which is dependent on disease severity and shows qualitative differences depending on onset presentation. A model combining motor and behavioural changes explained 57% of variance on ADL performance, with important implications for clinical intervention. PMID- 22249016 TI - Multifocal supratentorial diffuse glioma in a young patient with Ollier disease. AB - Ollier disease is a rare disorder characterised by the development of multiple enchondromas in long bones. Here we present a 19-year-old man with Ollier disease who also developed three synchronous brain tumours. Craniotomy, biopsy and debulking was performed for one lesion followed by a period of observation, and 9 months later he underwent a second craniotomy and debulking for symptomatic progression. Histopathological examination revealed a diagnosis of multifocal diffuse glioma (World Health Organization grade II). This report highlights the increased incidence of primary brain tumours in patients with Ollier disease and identifies the importance of screening patients with Ollier disease for primary neoplasms. PMID- 22249017 TI - Are there diurnal variations in the results of the Dix-Hallpike manoeuvre? AB - This study examines diurnal variation in the result of the Dix-Hallpike manoeuvre when testing for benign paroxysmal positional vertigo in a randomised crossover study of the order of diagnostic testing in a community out-reach clinic for a tertiary neurological centre in Wellington, New Zealand. Study participants were adults referred for physiotherapy treatment. Dix-Hallpike manoeuvres were performed to both ears, and groups were randomly allocated to have a morning, then afternoon, sequence of testing or vice versa. The results of the Dix Hallpike manoeuvres were digitally recorded and reviewed by a second blinded assessor. A total of 27 of 50 participants (54%) tested positive on at least one of the days, six of 27 (22%) had discordant results. The difference in marginal proportions was 0% (95% confidence interval: -9.6 to 9.6), p=1.0. The time of day is not a factor in false negative Dix-Hallpike manoeuvres, although 22% of those with positive results tested negative on one of the two measurements. PMID- 22249018 TI - The diagnostic accuracy of selected neurological tests. AB - The diagnostic value and reliability of selected neurological clinical tests was studied in control subjects with normal neuroimaging (n=42), and subjects with a focal brain lesion (n=38). The items were studied by two examiners blinded to group membership and using standardized protocols, and subsequently by a neurologist who was not blinded to diagnosis. The positive likelihood ratios ranged from 1.06 (pronator drift) to 22.11 (single leg stance with eyes open, while the negative likelihood ratios ranged from 0.47 (tandem gait) to 0.97 (pupil symmetry). Three items (single leg stance - eyes closed - firm surface; single leg stance - eyes open - foam surface; and tandem gait) successfully distinguished between the two groups (odds ratio p<0.05). The inter-rater reliability was generally poor, with only tandem gait showing excellent agreement (kappa [K]=0.92). Tandem gait was the only item to show noteworthy agreement (K=0.93) between the examiners and the neurologist. The tests varied considerably in their ability to detect radiologically demonstrated structural brain lesions, and several items were poorly reproducible, questioning their value as part of a routine neurological examination. PMID- 22249019 TI - Surgical approaches to thoracic ossification of the posterior longitudinal ligament. AB - Thoracic ossification of the posterior longitudinal ligament is a rare but debilitating condition. It is most commonly diagnosed in the Japanese population. If left untreated, significant myelopathy and weakness can ensue. Anterior decompression and stabilization is effective but technically demanding and is associated with high rate of complications. Posterior laminectomy appears to be an acceptable approach with lower risks. This work reviews the published literature on this topic and highlights the salient points. PMID- 22249020 TI - Prognostic significance of Tks5 expression in gliomas. AB - A pathological hallmark of gliomas is their extensive invasion into the brain parenchyma regardless of tumour grade. Clinically this is a major factor in tumour recurrence as surgery and adjuvant therapies are unable to eradicate all the infiltrating malignant cells. Tyrosine kinase substrate with five SH3 domains (Tks5, also known as SH3PXD2A) and cortactin are required for the formation of invadopodia, actin-based protrusions of tumour cells with associated proteolytic activity implicated in tumour invasion. We investigated the prognostic significance of Tks5 and cortactin expression in 57 patients with various grades of glioma. Expression of Tks5 or cortactin occurred in all grades of tumours and expression of Tks5, but not cortactin, was associated with significantly reduced patient survival among glioma patients. This association was clearest in patients with low-grade astrocytomas and oligoastrocytomas. These results suggest a prognostic relevance for the Tks5 invadopodial protein in glial-derived brain tumours. PMID- 22249021 TI - A unique presentation of a spinal dural arteriovenous fistula exacerbated by steroids. AB - Spinal dural arteriovenous fistula (DAVF) is an acquired vascular malformation of the spinal cord that presents as a congestive myelopathy resulting from venous hypertension, edema, and ischemia within the cord. Acute clinical exacerbations have been demonstrated in a variety of clinical settings. We report a unique presentation of a 45-year-old male with progressive paraplegia that acutely worsened following three independent treatments with oral and intravenous steroid administration. Spinal angiogram revealed a spinal DAVF at L3 and the patient underwent successful surgical repair. This report highlights the clinical presentation of spinal DAVF and emphasizes the unique and important potential relationship between steroid administration and clinical deterioration. PMID- 22249022 TI - Effects of Cr III and Pb on the bioaccumulation and toxicity of Cd in tropical periphyton communities: Implications of pulsed metal exposures. AB - Metal exposure pattern, timing, frequency, duration, recovery period, metal type and interactions, has obscured effects on periphyton communities in lotic systems. The objective of this study was to investigate the effects of intermittent exposures of Cr III and Pb on Cd toxicity and bioaccumulation in tropical periphyton communities. Natural periphyton communities were transferred to artificial stream chambers and exposed to metal mixtures at different pulse timing, duration, frequency and recovery periods. Chlorophyll a, dry mass and metal accumulation kinetics were recorded. Cr and Pb decrease the toxic effects of Cd on periphyton communities. Periphyton has high Cd, Cr and Pb accumulation capacity. Cr and Pb reduced the levels of Cd sequestrated by periphyton communities. The closer the frequency and duration of the pulse is to a continuous exposure, the greater the effects of the contaminant on periphyton growth and metal bioaccumulation. Light increased toxic and accumulative effects of metals on the periphyton community. PMID- 22249023 TI - Why mercury concentration increases with fish size? Biokinetic explanation. AB - In field-collected juvenile blackhead seabream Acanthopagrus schlegeli schlegeli, measured total mercury (THg) and methylmercury (MeHg) concentrations were related to 0.19 and 0.33 power of fish mass over a wide size range (more than 50-fold). The causative factors remain unclear. In this study, size-dependent biokinetic parameters for both inorganic mercury [Hg(II)] and MeHg were estimated, and their relative contributions to size-related Hg accumulation were further assessed. Except for the MeHg dietary assimilation efficiency (AE), which was not affected by the fish size, other examined biokinetic parameters showed either positive (Hg(II) AE) or negative correlations (growth rate constant-g, dissolved uptake rate constant-k(u) and efflux rate constant-k(e)) with fish size. The biokinetic variation explained the observed allometric pattern of Hg accumulation in juveniles. Especially, both size-related g and k(e) were the key drivers. The current study addressed the importance of size-related biokinetics, in particular the k(e) and g, which have important implications to manage Hg contamination in fisheries. PMID- 22249024 TI - Integrin-dependent Akt1 activation regulates PGC-1 expression and fatty acid oxidation. AB - BACKGROUND: Poly-N-acetyl glucosamine nanofibers derived from a marine diatom have been used to increase cutaneous wound healing. These nanofibers exert their activity by specifically activating integrins, which makes them a useful tool for dissecting integrin-mediated pathways. We have shown that short-fiber poly-N acetyl glucosamine nanofiber (sNAG) treatment of endothelial cells results in increased cell motility and metabolic rate in the absence of increased cell proliferation. RESULTS: Using a Seahorse Bioanalyzer to measure oxygen consumption in real time, we show that sNAG treatment increases oxygen consumption rates, correlated with an integrin-dependent activation of Akt1. Akt1 activation leads to an increase in the expression of the transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). This is not due to increased mitochondrial biogenesis, but is associated with an increase in the expression of pyruvate dehydrogenase kinase 4 (PDK4), suggesting regulation of fatty acid oxidation. Blockade of fatty acid oxidation with etomoxir, an O-carnitine palmitoyltransferase-1 inhibitor, blocks the sNAG-dependent increased oxygen consumption. (3)H-palmitate uptake experiments indicate a PDK4-dependent increase in fatty acid oxidation, which is required for nanofiber-induced cell motility. CONCLUSIONS: Our findings imply a linear pathway whereby an integrin-dependent activation of Akt1 leads to increased PGC-1alpha and PDK4 expression resulting in increased energy production by fatty acid oxidation. PMID- 22249025 TI - Citrate carrier promoter is target of peroxisome proliferator-activated receptor alpha and gamma in hepatocytes and adipocytes. AB - Citrate carrier (CiC), a mitochondrial inner membrane protein, is an essential component of the shuttle system which transports acetyl-CoA from mitochondria to the cytosol where lipogenesis occurs. CiC is regulated by SREBP-1, a transcription factor that controls the expression of several lipogenic genes. CiC is also implicated in cholesterol synthesis, glycolysis and gluconeogenesis, suggesting that besides SREBP-1 other transcription factors could modulate the expression of its gene. Here, we provide evidences demonstrating that CiC expression is regulated by peroxisome proliferator-activated receptor (PPAR) alpha and gamma in hepatocytes and adipocytes, respectively. CiC expression increased in rat BRL-3A hepatocytes treated with WY-14,643, agonist of PPARalpha, and in murine 3T3-L1 adipocytes treated with rosiglitazone, agonist of PPARgamma. The overexpression of PPARalpha/RXRalpha and PPARgamma/RXRalpha heterodimer enhanced CiC promoter activity in BRL-3A and 3T3-L1, respectively. Luciferase reporter gene and gel mobility shift assays indicated that a functional peroxisome proliferator-activated receptor response element (PPRE), identified in the CiC promoter, conferred responsiveness to activation by PPARs. The binding of PPRE of CiC promoter by PPARalpha and PPARgammain vivo was confirmed by ChIP assay in BRL-3A and 3T3-L1 cells, respectively. PMID- 22249026 TI - Diverse biological functions of the SPARC family of proteins. AB - The SPARC family of proteins represents a diverse group of proteins that modulate cell interaction with the extracellular milieu. The eight members of the SPARC protein family are modular in nature. Each shares a follistatin-like domain and an extracellular calcium binding E-F hand motif. In addition, each family member is secreted into the extracellular space. Some of the shared activities of this family include, regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways. Recently, several SPARC family members have been implicated in human disease pathogenesis. This review discusses recent advances in the understanding of the functional roles of the SPARC family of proteins in development and disease. PMID- 22249027 TI - Breast cancer stem cells. AB - Breast cancer stem cells (BCSCs) constitute a subpopulation of tumor cells that express stem cell-associated markers and have a high capacity for tumor generation in vivo. Identification of BCSCs from tumor samples or breast cancer cell lines has been based mainly on CD44(+)/CD24(-/low) or ALDH(+) phenotypes. BCSCs isolation has allowed the analysis of the molecular mechanisms involved in their origin, self-renewal, differentiation into tumor cells, resistance to radiation therapy and chemotherapy, and invasiveness and metastatic ability. Molecular genetic analysis using knockout animals and inducible transgenics has identified NF-kappaB, c-Jun, p21(CIP1), and Forkhead-like-protein Dach1 involvement in BCSC expansion and fate. Clinical analyses of BCSCs in breast tumors have found a correlation between the proportion of BCSCs and poor prognosis. Therefore, new therapies that specifically target BCSCs are an urgent need. We summarize recent evidence that partially explain the biological characteristics of BCSCs. PMID- 22249029 TI - Graphene nanomesh-based devices exhibiting a strong negative differential conductance effect. AB - Using atomistic quantum simulation based on a tight binding model, we have investigated the transport characteristics of graphene nanomesh-based devices and evaluated the possibilities of observing negative differential conductance. It is shown that by taking advantage of bandgap opening in the graphene nanomesh lattice, a strong negative differential conductance effect can be achieved at room temperature in pn junctions and n-doped structures. Remarkably, the effect is improved very significantly (with a peak-to-valley current ratio of a few hundred) and appears to be weakly sensitive to the transition length in graphene nanomesh pn hetero-junctions when inserting a pristine (gapless) graphene section in the transition region between n and p zones. The study therefore suggests new design strategies for graphene electronic devices which may offer strong advantages in terms of performance and processing over the devices studied previously. PMID- 22249028 TI - Murine embryonic stem cell-derived hepatocytes correct metabolic liver disease after serial liver repopulation. AB - Although embryonic stem (ES) cell-derived hepatocytes have the capacity for liver engraftment and repopulation, their in vivo hepatic function has not been analyzed yet. We aimed to determine the metabolic function and therapeutic action of ES cell-derived hepatocytes after serial liver repopulations in fumaryl acetoacetate hydrolase knockout (Fah(-/-)) mice. Albumin expressing (Alb(+)) cells were obtained by hepatic differentiation of ES cells using two frequently reported methods. After transplantation, variable levels of liver repopulation were found in Fah(-/-) mice recipients. FAH expressing (FAH(+)) hepatocytes were found either as single cells or as nodules with multiple hepatocytes. After serial transplantation, the proportion of the liver that was repopulated by the re-transplanted FAH(+) hepatocytes increased significantly. ES cell-derived FAH(+) hepatocytes were found in homogenous nodules and corrected the liver metabolic disorder of Fah(-/-) recipients and rescued them from death. ES cell derived hepatocytes had normal karyotype, hepatocytic morphology and metabolic function both in vitro and in vivo. In conclusion, ES cell-derived hepatocytes were capable of liver repopulation and correction of metabolic defects after serial transplantation. Our results are an important piece of evidence to support future clinical applications of ES cell-derived hepatocytes in treating liver diseases. PMID- 22249030 TI - Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas. AB - Wnt signalling is an important component of vertebrate development, required for specification of the neural crest. Ten Wnt receptors [Frizzled receptor 1-10 (Fzd1-10)] have been identified so far, some of which are expressed in the developing nervous system and the neural crest. Here we show that expression of one such receptors, Fzd6, predicts poor survival in neuroblastoma patients and marks rare, HIF1/2 alpha-positive cells in tumour hypoxic areas. Fzd6 positive neuroblastoma cells form neurospheres with high efficiency, are resistant to doxorubicin killing and express high levels of mesenchymal markers such as Twist1 and Notch1. Expression of Fzd6 is required for the expression of genes of the non canonical Wnt pathway and the spheres forming activity. When transplanted into immunodeficient mice, neuroblastoma cells expressing the Fzd6 marker grow more aggressively than their Fzd6 negative counterparts. We conclude that Fzd6 is a new surface marker of aggressive neuroblastoma cells with stem cell-like features. PMID- 22249031 TI - Should patients receive general anesthesia prior to extubation at the end of life?. AB - Billings has proposed that any potentially conscious and imminently dying patient who is undergoing withdrawal of ventilator support should be offered general anesthesia to fully protect against suffering. Here we examine whether his proposal is compatible with the doctrine of double effect, a philosophical construct that is generally in accord with the legal requirements for palliative care in the United States. We review the essential elements of the doctrine of double effect, and emphasize the importance of pre-medicating patients before ventilator withdrawal (anticipatory dosing) and of titrating medications to the needs of the patient. The doctrine of double effect requires physicians to balance the risk of the patient suffering against the risk of hastening the patient's deathwhen titrating the medications used to provide comfort. We argue that the values and preferences of the patient should determine how these risks are balanced. We therefore agree with Billings that general anesthesia may be indicated for patients who prefer to minimize the risk of suffering while accepting a greater risk of having their death hastened. This approach would not be appropriate, however, for patients who place a higher value upon avoiding the risk of hastening death, even when this involves a greater risk of potential suffering. PMID- 22249032 TI - Is comparing intensive care unit and hospital performance based on administrative data obsolete?. PMID- 22249033 TI - Matrix metalloproteinase-8 as a potential drug target for the therapy of sepsis. PMID- 22249034 TI - Zero risk for central line-associated bloodstream infections ... Is this realistic?. PMID- 22249035 TI - Implications of continuous QT monitoring in the intensive care setting. PMID- 22249036 TI - Shedding an unlovely light on critical care workload. PMID- 22249037 TI - Bioavailability or just availability? How the national propofol shortage example may transform tenets of critical care management. PMID- 22249038 TI - Energy deficit and length of hospital stay can be reduced by a two-step quality improvement of nutrition therapy: the intensive care unit dietitian can make the difference. PMID- 22249039 TI - Comparison of Oligon catheters and chlorhexidine-impregnated sponges with standard catheters for prevention of catheter associated colonization and infection: one size does not fit all. PMID- 22249040 TI - Masseter peripheral tissue oxygenation in sepsis: chew before swallowing whole. PMID- 22249041 TI - Standardizing self-reported surveys in critical care: a good idea. PMID- 22249042 TI - Teleintensive care unit: more information, more questions. PMID- 22249043 TI - Starting point to embark on a widespread use of noninvasive positive pressure ventilation in acute lung injury or early acute respiratory distress syndrome?. PMID- 22249044 TI - Neglect of quality-of-life considerations in intensive care unit family meetings for long-stay intensive care unit patients. PMID- 22249045 TI - Changing the 'flight manifest' for a safer journey*. PMID- 22249046 TI - Why guess when you can see? Heart function and fluid management in dengue shock. PMID- 22249047 TI - Delirium in patients with stroke: the dark side of the moon?. PMID- 22249048 TI - Thumbs up for bevel down. PMID- 22249049 TI - Corticosteroid effects on hemostatic biomarkers in early acute respiratory distress syndrome: does it matter?. PMID- 22249050 TI - Rehabilitating the critically ill: a cultural shift in intensive care unit care. PMID- 22249051 TI - Epithelial to mesenchymal transition: a new twist to biotrauma?. PMID- 22249052 TI - Heta, hexa, penta, tetra-starches: different organs--different effects?. PMID- 22249054 TI - Carbon monoxide and outcome of stroke--a dream CORM true?. PMID- 22249053 TI - How can antibiotics worsen acute kidney injury but improve survival in experimental sepsis?. PMID- 22249055 TI - Ischemia-reperfusion-induced lung injury: could hypercapnia have a therapeutic role?. PMID- 22249056 TI - Gallic treatment is galling to Pseudomonas. PMID- 22249057 TI - Therapeutic hypothermia for acute severe spinal cord injury: ready to start large clinical trials?. PMID- 22249058 TI - Recoupling after cardiac arrest. PMID- 22249059 TI - Acute lung injury: surprisingly common in the neurologic intensive care unit. PMID- 22249060 TI - Statins as neuroprotectants after subarachnoid hemorrhage. PMID- 22249061 TI - Triaging the fittest: practical wisdom versus logical calculus?. PMID- 22249062 TI - Lean Six Sigma: trimming the fat! Effectively managing precious resources. PMID- 22249063 TI - The intensive care unit continuum of care: easing death. PMID- 22249064 TI - How can you mend a broken heart?. PMID- 22249065 TI - The big chill: cooling sickle cells with caution. PMID- 22249066 TI - Tissue selenium concentration increases slowly in critically ill patients compared with plasma. PMID- 22249068 TI - Outcomes in severe sepsis and patients with septic shock do not matter! PIRO is a score to treat severe septic and septic shock patients not to measure outcomes. PMID- 22249070 TI - Autoresuscitation is not a determinant to lower the observation time in declaring death for organ donation. PMID- 22249072 TI - Quantity may be more important than type of intravenous fluid. PMID- 22249074 TI - Small animal model species are not created equal. PMID- 22249076 TI - Thenar tissue oxygen saturation monitoring: noninvasive does not mean simple or accurate! PMID- 22249078 TI - CpG oligonucleotides induce the differentiation of CD4(+)Th17 cells by triggering plasmacytoid dendritic cells in adoptively cell transfer immunotherapy. AB - Our previous data showed that CpG-ODNs could significantly enhance the anti-tumor efficacy of adoptively cell transfer (ACT), which was closely correlated to accumulation of Th17 cells in tumor mass. Here we further investigated that CpG ODNs had no significant effect on the migration and proliferation capacity of Th17 cells in tumor mass. Instead, we showed that CpG-ODNs could induce the differentiation of Th17 cells via dendritic cells (DCs) in tumor infiltrating lymphocytes (TILs). Notably, we found that plasmacytoid dendritic cells (pDCs), but not myeloid dendritic cells (mDCs), were responsible for the Th17 differentiation induced by CpG-ODNs via IL-6, TGF-beta and IFN-alpha in vitro. Finally, we revealed that CpG-ODNs could stimulate pDCs to induce the differentiation of Th17 cells in vivo, which subsequently reduced the tumor size and prolonged the survival of tumor bearing nude mice. These data provided a novel insight into the mechanism of anti-tumor efficacy of CpG-ODNs based therapeutic strategy. PMID- 22249079 TI - Altered balance between Th1 and Th17 cells in circulation is an indicator for the severity of murine acute GVHD. AB - Disbalance of Th1 and Th17 can lead to inflammatory diseases and autoimmunity. Acute graft-versus-host disease (GVHD) is now considered as a compound and dysregulated immune response. Both Th1 and Th17 have been implicated in the pathophysiology of acute GVHD. Disbalance of Th1 and Th17 may also play a critical role in mediating acute GVHD. In this study, we investigated the Th1/Th17 imbalance in peripheral blood through out the pathological process of acute GVHD, using a GVHD model of C57BL/6 (H-2(b)) donor to BALB/c (H-2(d)) recipient. We also analyzed the correlation between Th1/Th17 ratio and severity of acute GVHD, and explored the potential function of Th1/Th17 imbalance in acute GVHD. Recipients received 5*10(6) spleen cells (SP) underwent more severe acute GVHD, compared with the ones received 5*10(5) SP. Severe GVHD bearing recipients had much higher proportion of Th1 cells but lower proportion of Th17 cells, compared with mild GVHD bearing ones. The Th1/Th17 ratios in both groups underwent relative changes according to the changing proportions of Th1 and Th17 cells and showed positive correlation with clinical scores of acute GVHD. We describe the changing proportions of Th1 and Th17 cells in acute GVHD, and we find that Th1/Th17 ratio is an accurate indicator for predicting the severity of acute GVHD. PMID- 22249080 TI - Role of behavioral medicine in primary care. AB - PURPOSE OF REVIEW: Behavioral medicine is a vast field with an ever-increasing knowledge base. We review important findings over the last 18 months. RECENT FINDINGS: We organized advances in behavioral medicine into four main topic areas: the doctor and patient, health-related behavior, integration of behavioral medicine in primary care, and teaching and assessing behavioral medicine competencies in primary care. Section I reviews research on difficult encounters, delivering bad and sad news, and physician well being. Section II examines improvements in the treatment of obesity and tobacco abuse, as well as interventions which boost adherence. Section III discusses advancements in care management and collaborative care in the USA and resource-constrained settings. Finally, section IV deals with teaching and assessing communication skills, behavior change, and professionalism. SUMMARY: Physician skills such as communication, professionalism, behavior change, and self-care are not innate abilities, but teachable and learnable skills. Collaborative care and the integration of behavioral medicine with care for other conditions can benefit patients, and can be done effectively with case management and telemonitoring strategies. Future behavioral medicine research should include evaluation of implementation strategies so that we may incorporate principles of behavioral medicine more widely into clinical practice. PMID- 22249081 TI - Life expectancy and cardiovascular mortality in persons with schizophrenia. AB - PURPOSE OF REVIEW: To assess the impact of cardiovascular disease on the excess mortality and shortened life expectancy in schizophrenic patients. RECENT FINDINGS: Patients with schizophrenia have two-fold to three-fold higher mortality rates compared with the general population, corresponding to a 10-25 year reduction in life expectancy. Although the mortality rate from suicide is high, natural causes of death account for a greater part of the reduction in life expectancy. The reviewed studies suggest four main reasons for the excess mortality and reduced life expectancy. First, persons with schizophrenia tend to have suboptimal lifestyles including unhealthy diets, excessive smoking and alcohol use, and lack of exercise. Second, antipsychotic drugs may have adverse effects. Third, physical illnesses in persons with schizophrenia are common, but diagnosed late and treated insufficiently. Lastly, the risk of suicide and accidents among schizophrenic patients is high. SUMMARY: Schizophrenia is associated with a substantially higher mortality and curtailed life expectancy partly caused by modifiable risk factors. PMID- 22249082 TI - Hormones and schizophrenia. AB - PURPOSE OF REVIEW: It is a well established fact that many serious mental illnesses, in particular psychoses such as schizophrenia, may have a significant hormonal aetiological component. This study aims to discuss the oestrogen protection hypothesis of schizophrenia in particular, with an emphasis on findings from the recent literature in support of this theory. RECENT FINDINGS: Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting a protective role of oestrogen. In-vitro and in-vivo preclinical research has confirmed oestradiol's interactions with central neurotransmitter systems implicated in the pathogenesis of schizophrenia, whereas results from randomized controlled trials investigating the antipsychotic potential of oestrogen have been promising. Research into other neuroactive hormones with possible effects on mental state is a field still in its infancy but is evolving rapidly. SUMMARY: Schizophrenia and related psychoses are pervasive and debilitating conditions, for which currently available treatments are often only partially effective and entail a high risk of serious side effects. Thus, new therapeutic strategies are needed, and the literature reviewed here suggests that hormones such as oestrogen could be a viable option. It is hoped that, with further research and larger trials, the oestrogen hypothesis can be translated into effective clinical practice. PMID- 22249083 TI - Theory of mind and its relevance in schizophrenia. AB - PURPOSE OF REVIEW: Social cognitive impairments are considered to be core features of schizophrenia and have been hypothesized to play a mediator role between basic neurocognition and patients' outcomes. In this context, theory of mind (ToM) abilities are of special relevance, and deficits in this area may represent trait markers of schizophrenia. RECENT FINDINGS: In this review, studies published since September 2010 have been summarized with a particular focus on the relationships between ToM and psychopathology, neurocognition, and psychosocial outcomes in patients with schizophrenia, as well as on ToM abilities in high-risk individuals. In addition, recent neuroimaging data as well as treatment interventions have been described. SUMMARY: The reviewed literature strengthens the hypothesis that ToM deficits have the potential to be valid markers for schizophrenia. PMID- 22249084 TI - Furazolidone in Helicobacter pylori therapy: misunderstood and often unfairly maligned drug told in a story of French bread. PMID- 22249085 TI - Herbal medicine in the treatment of ulcerative colitis. AB - Ulcerative colitis (UC) is a refractory, chronic, and nonspecific disease occurred usually in the rectum and the entire colon. The etiopathology is probably related to dysregulation of the mucosal immune response toward the resident bacterial flora together with genetic and environmental factors. Several types of medications are used to control the inflammation or reduce symptoms. Herbal medicine includes a wide range of practices and therapies outside the realms of conventional Western medicine. However, there are limited controlled evidences indicating the efficacy of traditional Chinese medicines, such as aloe vera gel, wheat grass juice, Boswellia serrata, and bovine colostrum enemas in the treatment of UC. Although herbal medicines are not devoid of risk, they could still be safer than synthetic drugs. The potential benefits of herbal medicine could lie in their high acceptance by patients, efficacy, relative safety, and relatively low cost. Patients worldwide seem to have adopted herbal medicine in a major way, and the efficacy of herbal medicine has been tested in hundreds of clinical trials in the management of UC. The evidences on herbal medicine are incomplete, complex, and confusing, and certainly associated with both risks and benefits. There is a need for further controlled clinical trials of the potential efficacy of herbal medicine approaches in the treatment of UC, together with enhanced legislation to maximize their quality and safety. PMID- 22249086 TI - Furazolidone-based therapies for Helicobacter pylori infection: a pooled-data analysis. AB - BACKGROUND/AIM: Furazolidone-based therapies are used in developing countries to cure Helicobacter pylori infection due to its low cost. The low bacterial resistance toward furazolidone may render appealing the use of this drug even in developed countries. However, some relevant safety concerns do exist in using furazolidone. PATIENTS AND METHODS: This was a systematic review with pooled-data analysis of data regarding both eradication rate and safety of furazolidone-based therapies for H. pylori infection. Intention-to-treat (ITT) and per-protocol (PP) eradication rates were calculated. RESULTS: Following furazolidone-based first line therapy, H. pylori eradication rates were 75.7% and 79.6% at ITT and PP analysis, respectively (P<0.001). The overall incidence of side effects and severe side effects were 33.2% and 3.8%, respectively. At multivariate analysis, only high-dose furazolidone was associated with increased therapeutic success (OR: 1.5, 95% CI: 1.3-2.7; P<0.001), while occurrence of side effects was relevant following treatment for a long duration (OR: 2.9, 95% CI: 2.2-4.1; P<0.001), high-dose furazolidone (OR: 2.3, 95% CI: 1.7-3.2; P<0.001) and bismuth containing regimens (OR: 2.1, 95% CI: 1.5-2.8; P<0.001). CONCLUSIONS: Furazolidone-based regimens usually achieve low eradication rates. Only a high dose regimen improves the cure rate, but simultaneously increases the incidence of severe side effects. Therefore, we suggest that patients have to be clearly informed about the possible genotoxic and carcinogenetic effects for which furazolidone use is not approved in developed countries. PMID- 22249087 TI - Hepatocellular carcinoma in hepatitis D: does it differ from hepatitis B monoinfection? AB - BACKGROUND/AIM: Hepatitis D virus (HDV) superinfection in patients with chronic hepatitis B leads to accelerated liver injury, early cirrhosis, and decompensation. It may be speculated that hepatocellular carcinoma (HCC) may differ in these patients from hepatitis B virus (HBV) monoinfection. The aim of this study was to compare clinical aspects of hepatocellular carcinoma in patients of hepatitis D with HBV monoinfection. PATIENTS AND METHODS: A total of 92 consecutive HCC cases seropositive for antibody against HDV antigen (HDV group) were compared with 92 HBsAg-positive and anti-HDV-negative cases (HBV group). RESULTS: The features including sex, body mass index, presence of ascites, serum biochemistry, gross tumor appearance, child class, barcelona cancer liver clinic and okuda stages were not significantly different between the 2 groups. Decreased liver size was noticed more in cases of HDV compared with HBV group where the liver size was normal or increased (P=0.000). HDV patients had lower platelets (P=0.053) and larger varices on endoscopy (P=0.004). Multifocal tumors and elevated alpha-fetoprotein level >1000 IU/mL were more common in HBV group (P=0.040 and P= 0.061). TNM classification showed more stage III-IV disease in HBV group (P=0.000). CONCLUSION: Decreased liver size and indirect evidence of more severe portal hypertension and earlier TNM stage compared with HBV monoinfection indicate that HDV infection causes HCC in a different way, possibly indirectly by inducing inflammation and cirrhosis. PMID- 22249088 TI - Serologic markers of gluten sensitivity in a healthy population from the western region of Saudi Arabia. AB - BACKGROUND/AIM: To identify the prevalence of gluten sensitivity in a healthy adult Saudi population within a low endemic area of celiac disease using IgA tissue transglutaminase antibody. The study was conducted as a prospective pilot study for Saudi attendees of a blood donation centre at King Faisal Specialist Hospital & Research Centre in Jeddah, Saudi Arabia. PATIENTS AND METHODS: Individuals were invited to participate in the study and screened for gluten sensitivity using immunoglobulin A tissue transglutaminase antibody (IgA TTG) along with serum IgA level. Descriptive data was presented and expressed as mean value; correlation between variables was estimated using Pearson correlation, and nonparametric data using Pearson rho correlation (level of P value <0.05 is considered to be statistically significant). RESULTS: Two hundred and four individuals (122 males and 82 females, mean age 35 years) attending the blood donation centre were screened. Three individuals tested positive for IgA TTG showing normal IgA level (1 female and 2 males) with a 1.5% prevalence in the cohort. CONCLUSIONS: Positive celiac screening is present at a low prevalence rate in our adult population, in which the individuals' age and their serum IgA levels are not associated with the positivity level. A study on a larger scale with the application of histologic confirmation of positive cases is needed. PMID- 22249089 TI - Outpatient blind percutaneous liver biopsy in infants and children: is it safe? AB - BACKGROUND/AIM: We aim to investigate the safety of outpatient blind percutaneous liver biopsy (BPLB) in infants and children with chronic liver disease (CLD). PATIENTS AND METHODS: BPLB was performed as an outpatient procedure using the aspiration Menghini technique in 80 infants and children, aged 2 months to 14 yrs, for diagnosis of their CLD. Patients were divided into three groups: Group 1 (<1 year), group 2 (1-6 yrs), and group 3 (6-14 yrs). The vital signs were closely monitored 1 hr before biopsy, and then 1, 2, 6, and 24 hrs after biopsy. Twenty-four hours pre- and post-biopsy complete blood counts, liver enzymes, prothrombin time (PT), and abdominal ultrasonography, searching for a biopsy induced hematoma, were done for all patients. RESULTS: No mortality or major morbidities were encountered after BPLB. The rate of minor complications was 17.5% including irritability or "pain" requiring analgesia in 10%, mild fever in 5%, and drowsiness for >6 hrs due to oversedation in 2.5%. There was a statistically significant rise in the 1-hr post-biopsy mean heart and respiratory rates, but the rise was non-significant at 6 and 24 hrs except for group 2 where heart rate and respiratory rates significantly dropped at 24 hrs. No statistically significant difference was noted between the mean pre-biopsy and the 1, 6, and 24-hrs post-biopsy values of blood pressure in all groups. The 24 hrs post-biopsy mean hemoglobin and hematocrit showed a significant decrease, while the 24-hrs post-biopsy mean total leucocyte and platelet counts showed non significant changes. The 24-hrs post-biopsy mean liver enzymes were non significantly changed except the 24-hrs post-biopsy mean PT which was found to be significantly prolonged, for a yet unknown reason(s). CONCLUSIONS: Outpatient BPLB performed by the Menghini technique is safe and well tolerated even in infants and young children. Frequent, close monitoring of patients is strongly recommended to achieve optimal patient safety and avoid potential complications. PMID- 22249090 TI - Clinical outcome of acute upper gastrointestinal hemorrhage among patients admitted to a government hospital in Egypt. AB - BACKGROUND/AIM: Acute upper gastrointestinal hemorrhage (AUGIH) is a life threatening emergency that results in high morbidity and mortality. The mortality rate varies between 4% and 14%. The aim of the study was to determine the clinical outcome of AUGIH among patients admitted to a government hospital in Egypt. PATIENTS AND METHODS: This was a cross-sectional hospital-based study performed in 1000 patients presenting with AUGIH over a 7-year period between January 2004 and January 2011. RESULTS: One thousand patients were analyzed. Fifty-four percent were male. Mean age was 52 +/- 17 years. Eighty-eight percent were emergency admissions and 12% were inpatients at the time of bleeding. At presentation 68% had major comorbidity and 50% had liver disease. Seven hundred and twenty-four patients (72%) underwent endoscopy. Bleeding varices accounted for 31% of AUGIH and peptic ulcer 28%. Two hundred and thirty-two patients had endoscopically diagnosed bleeding varices or peptic ulcer with a visible vessel or active bleeding. These received endoscopic therapy. Initial hemostasis was achieved in 207 (89%). Thirteen patients (6%) had therapy at a subsequent endoscopy for further bleeding. Surgery was performed on 9 patients (0.9%) with AUGIH. Complications were reported in 70 patients (7%) mainly liver failure (4%). Six hundred and eighty-four patients (68%) were discharged improved, 162 (16%) left hospital without a diagnosis and 4 (0.4%) were referred to another facility. The overall mortality was 15%. Mortality was 24% in patients >=60 years, 37% among inpatients, and 21% in those who had a major comorbidity. Mortality was 22% in patients who had liver disease and 9% in variceal bleeding. CONCLUSION: The most common cause of AUGIH was variceal in origin. Endoscopic therapy was successful in most cases. Mortality after AUGIH was particularly high among elderly patients, inpatients, and patients who had a major comorbidity, liver disease, and variceal bleeding. PMID- 22249091 TI - Measuring of gastric emptying in Egyptian pediatric patients with portal hypertension by using real-time ultrasound. AB - BACKGROUND/AIM: Among the various methods for evaluating gastric emptying, the real-time ultrasound is safe, does not require intubation, or rely on either radiologic or radionuclide technique. The aim of our work was to measure the gastric emptying in pediatric patients with portal hypertension by using the real time ultrasound. PATIENTS AND METHODS: Forty patients with portal hypertension with mean age 7 +/- 2.8 years and 20 healthy children as a control group underwent gastric emptying study by using real-time ultrasound. The cross sectional area of the gastric antrum was measured in the fasting state and then each subject was allowed to drink tap water then calculated by using formula area (pi longitudinal Chi anteroposterior diameter/4). The intragastric volume was assumed to be directly proportional to the cross-sectional area of the antrum. RESULTS: The mean gastric emptying half-time volume was significantly delayed in portal hypertension patients (40 +/- 6.8 min) compared with the control subjects (27.1 +/- 3.6) min (P<0.05). Patients with extrahepatic portal vein obstruction had significant delayed gastric emptying in comparison to patients with portal hypertension due to other etiologies (36.14 +/- 4.9 vs 44.41 +/- 6.04 min; P<0.01). CONCLUSION: Ultrasound is a noninvasive and a reliable method for measuring gastric emptying in pediatric patients. Gastric emptying was significantly delayed in patients with portal hypertension. Etiology of portal hypertension may influence gastric emptying time in patients with chronic liver disease. PMID- 22249092 TI - The association of metabolic syndrome, insulin resistance and non-alcoholic fatty liver disease in overweight/obese children. AB - BACKGROUND/AIM: To study the prevalence of metabolic syndrome (MS), insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in overweight/obese children with clinical hepatomegaly and/or raised alanine aminotransferase (ALT). PATIENTS AND METHODS: Thirty-three overweight and obese children, aged 2-13 years, presenting with hepatomegaly and/or raised ALT, were studied for the prevalence of MS, IR and NAFLD. Laboratory analysis included fasting blood glucose, serum insulin, serum triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and liver biochemical profile, in addition to liver ultrasound and liver biopsy. RESULTS: Twenty patients (60.6%) were labeled with MS. IR was present in 16 (48.4%). Fifteen (44%) patients had biopsy-proven NAFLD. Patients with MS were more likely to have NAFLD by biopsy (P=0.001). Children with NAFLD had significantly higher body mass index, waist circumference, ALT, total cholesterol, LDL-c, TG, fasting insulin, and lower HDL-c compared to patients with normal liver histology (P< 0.05) and fitted more with the criteria of MS (80% vs. 44%). IR was significantly more common among NAFLD patients (73% vs. 28%). CONCLUSION: There is a close association between obesity, MS, IR and NAFLD. Obese children with clinical or biochemical hepatic abnormalities are prone to suffer from MS, IR and NAFLD. PMID- 22249093 TI - Health care providers' acceptance of unsedated colonoscopy before and after a state-of-the-art lecture on the feasibility of the option. AB - BACKGROUND/AIM: The impact of education on acceptance of unsedated colonoscopy by health care providers is unknown. To test the hypothesis that knowledge imparted by a lecture on unsedated colonoscopy is associated with its enhanced acceptance. SETTINGS AND DESIGN: At the State-of-the-Art Lecture on "Unsedated colonoscopy: Is it feasible?" presented at the 8 th Pan-Arab Conference on Gastroenterology, February, 2011, Riyadh, Saudi Arabia, a questionnaire survey of the audience was undertaken. MATERIALS AND METHODS: An expectation questionnaire was administered before and after the lecture. Attendees responded anonymously. STATISTICAL ANALYSIS USED: The responses of a convenient sample of 49 attendees who provided completed responses to the questionnaire both before and after the lecture were analyzed. Data are expressed as frequency counts and means+/-SEM. Repeated measures analysis of variance (ANOVA), ANOVA with contrasts and Chi-square analysis (Statview II Program for Macintosh computers) were used to assess the data. A P value of <0.05 is considered significant. RESULTS AND CONCLUSIONS: The mean+/-SEM credibility score (maximum possible score=50) was 25.8 +/- 1.8 before and 33.3 +/- 2.1 after the lecture, with a significant improvement in mean score of 7.5 +/- 1.3 (P=0.001, paired t test). Nineteen (39%) respondents were not willing to consider unsedated colonoscopy for themselves before the lecture. This number decreased to 13 (27%) after the lecture. Before the lecture only 4 (8%) respondents were willing to consider unsedated colonoscopy for themselves. After the lecture this number increased to 8 (16%). The data suggest education of healthcare professionals regarding the feasibility of unsedated colonoscopy appears to enhance its acceptance as a credible patient care option at a Pan-Arab Gastroenterology Conference. PMID- 22249094 TI - Mucosal invasion by fusobacteria is a common feature of acute appendicitis in Germany, Russia, and China. AB - BACKGROUND/AIM: To investigate the geographic occurrence of mucosa-invading Fusobacteria in acute appendicitis. PATIENTS AND METHODS: Carnoy- and formalin fixated appendices from Germany, Russia, and China were comparatively investigated. Bacteria were detected using fluorescent in situ hybridization. Cecal biopsies from patients with inflammatory bowel disease and other conditions were used as disease controls. RESULTS: Fusobacteria represented mainly by Fusobacterium nucleatum were the major invasive component in bacterial infiltrates in acute appendicitis but were completely absent in controls. The occurrence of invasive Fusobacteria in Germany, Russia, and China was the same. The detection rate in Carnoy-fixated material was 70-71% and in formalin-fixated material was 30-36%. CONCLUSIONS: Acute appendicitis is a polymicrobial infectious disease in which F. nucleatum and other Fusobacteria play a key role. PMID- 22249095 TI - Caroli's syndrome in a post renal transplant patient: case report and review of the literature. AB - Caroli's syndrome is characterized by bile duct ectasia in association with hepatic fibrosis. It is usually transmitted in an autosomal recessive fashion and has been well documented to be associated with autosomal recessive polycystic kidney disease and occasionally with autosomal dominant polycystic kidney disease. However, there has been only few case reports published with Caroli's syndrome diagnosed postrenal transplantation. PMID- 22249096 TI - Successful closure of pharyngo-cutaneous and phayryngo-tracheal fistulas using removable hypopharyngeal stent after laryngectomy for laryngeal carcinoma. AB - Placement of removable stents to close pharyngo-cutaneous and tracheo-pharyngeal fistulas after laryngectomy has not been reported before. This case presents the feasibility of removable esophageal stent in closing pharyngo-cutaneous and tracheo-pharyngeal fistulas after laryngectomy for laryngeal cancer. Consecutive patients who underwent placement of removable esophageal stent for closing pharyngo-cutaneous and tracheo-pharyngeal fistulas after laryngectomy for laryngeal cancer. Three patients underwent successful stent placement in the hypopharynx. The stents were well tolerated. Patient one had the stent for 14 months, leading to complete healing of the fistula. Removal was successful. The second patient was palliated but died 8 weeks after stent placement. The third patient has successful palliation of his tracheo-esophageal fistula and the stent is being exchanged every 3-4 months to palliate his fistula. Closure of pharyngo cutaneous and tracheo-esophageal fistulas is feasible with esophageal removable stents. These stents provide alternative options when dealing with these challenging problems. PMID- 22249097 TI - Idiopathic adult ileoileal and ileocolic intussusception in situs inversus totalis: a rare coincidence. AB - Situs inversus totalis is a rare autosomal recessive congenital anomaly that is characterized by mirror image anatomy of the abdominal and thoracic organs. We report a case of a 28-year-old male with situs inversus totalis, who developed an idiopathic ileoileal and ileocolic intussusception, which was diagnosed on computed tomography scan. Patient underwent successfully ileal resection and side to-side functional anastomosis of ileum 12 cms from ileocecal junction. Postoperative course was uneventful. To the best of our knowledge, this is the first case of idiopathic adult intussusception with situs inversus totalis in the literature. PMID- 22249098 TI - Sudden onset epigastric pain and vomiting. Diaphragmatic hernia with herniation of stomach. PMID- 22249099 TI - Cardiogenic dysphagia: an unusual case. PMID- 22249100 TI - Immunoprotective role of indoleamine 2,3-dioxygenase in engraftment of allogenic skin substitute in wound healing. AB - Delayed wound healing can significantly impact survival of patients who suffer from severe thermal injury. In general, the use of a wound coverage, particularly with those of bilayer skin substitute, would be ideal to promote healing and prevent infection and fluid loss. Although the use of an autologous skin substitute is desirable, its preparation is time consuming and its immediate availability is impossible. To overcome this difficulty, the authors have previously demonstrated that the expression of indoleamine 2,3 dioxygenase (IDO) could function as a local immune suppressive factor in protecting allogenic fibroblasts and keratinocytes without using any immunosuppressive medication in a wound healing animal model. IDO, which is naturally expressed in the placenta by trophoblast cells during pregnancy, plays an essential role in maternal tolerance toward the fetus. The potent and selective local immunosuppressive function of IDO makes this enzyme a very promising tool for engineering a nonrejectable skin allograft. Here, the authors reviewed and discussed how the expression of IDO by the primary cells of our skin substitute can serve as a source of IDO enzyme activity and generate a tryptophan-deficient environment. Under this condition, only skin cells but not immune cells (CD4(+) and CD8(+) cells) would survive and protect engraftment of this engineered and shelf-ready skin substitute to be used not only as wound coverage but also as a rich source of wound healing promoting factors. Therefore, this review summarizes the body of work on immunoprotective role of IDO in engraftment of allogenic skin substitute in wound healing, which has recently been reported by the authors' research group and others. PMID- 22249101 TI - Carotid rupture following electrical injury: a report of two cases. AB - Electrical injuries often result in extensive tissue damage where vascular damage may occur and result in thrombosis and spontaneous rupture of blood vessels. Rupture of the brachial, radial, ulnar, internal mammary, and obturator arteries has been reported in the literature. The authors present two cases of carotid artery rupture following high-voltage electrical injuries. The first case is a 21 year-old man who was climbing a fence near a high-voltage power line when a gold chain he was wearing around his neck caught on the power line, resulting in a 10% circumferential electrical injury to his neck. He presented with visible arterial bleeding from the large neck wound and was taken to the operating room, where a 1 cm laceration to the carotid artery was repaired with a vein patch. On the second postoperative day, the patch dislodged, and a spontaneous rupture of the common carotid artery occurred. The damaged artery was subsequently ligated. The patient recovered with no neurological sequelae. The second case is a 43-year-old man who suffered a high-voltage injury while working on an electrical panel, resulting in a 50% TBSA full-thickness burn to the face, scalp, trunk, and extremities. Four weeks after admission, a latissimus dorsi myocutaneous free flap was used for coverage of exposed outer table of the skull. Intraoperatively, the carotid artery spontaneously ruptured proximal to where the dissection was being carried out. The patient recovered with no neurological sequelae. High-voltage electrical injury results in significant damage to blood vessels via a number of mechanisms. Rupture of a major vessel is a rare, life-threatening sequelae of electrical injury. PMID- 22249102 TI - A clinimetric overview of scar assessment scales. AB - Standardized validated evaluation instruments are mandatory to increase the level of evidence in scar management. Scar assessment scales are potentially suitable for this purpose, but the most appropriate scale still needs to be determined. This review will elaborate on several clinically relevant scar features and critically discuss the currently available scar scales in terms of basic clinimetric requirements. Many current scales can produce reliable measurements but seem to require multiple observers to obtain these results reliably, which limits their feasibility in clinical practice. The validation process of scar scales is hindered by the lack of a "gold standard" in subjective scar assessment or other reliable objective instruments which are necessary for a good comparison. The authors conclude that there are scar scales available that can reliably measure scar quality. However, further research may lead to improvement of their clinimetric properties and enhance the level of evidence in scar research worldwide. PMID- 22249103 TI - Comparing a single institution's experience with electrical injuries to the data recorded in the National Burn Repository. AB - Electrical injuries usually represent a small proportion of a burn center's admissions. Although burn size may be small, internal tissue damage is sometimes extensive. This study reviews a single institution's experience with electrical injuries and compares it to the multi-institutional data of the National Burn Repository (NBR). The 2009 NBR and the records of a large urban burn center (single institution) were queried for adult electrical injuries over an 8-year period. Data examined included demographics, %TBSA burn, length of stay (LOS), injury circumstance, and disposition. Multiple linear regression models were created to determine factors related to LOS. One hundred ninety-one single institution patients and 2837 multi-institution patients met the criteria. Both cohorts were mostly white males approximately 30 years of age and injuries where often work-related. Single-institution patients had a mean injury size of 4% TBSA, while multi-institution patients had 7%. The most common exposure source was domestic wiring for single-institution patients and electrical power plants/lines for multi-institution patients. Single-institution data showed that females had a shorter LOS than males (P < .0001). Single-institution data showed that independent risk factors for an increased LOS were infection, amputation, fasciotomy, and being Hispanic. Independent risk factors for multi-institution patients were being Hispanic and large %TBSA burn. There was no difference in mortality, gender, age, LOS, or intensive care unit LOS between the cohorts. In this analysis, there was no statistical difference between outcomes in the single or multi-institutional groups. However, injuries reported in the NBR were slightly larger. In both cohorts, an increase in LOS was associated with %TBSA, as expected. Interestingly, Hispanic ethnicity correlated with an increased LOS. Future work will be aimed at understanding this correlation to determine whether it is specific to electrical injury or burns in general. PMID- 22249104 TI - Telemedicine utilization to support the management of the burns treatment involving patient pathways in both developed and developing countries: a case study. AB - This case study reports on the utilization of telemedicine to support the management of the burns treatment in the islands of Sao Tome and Principe by Taipei Medical University-affiliated hospital in Taiwan. The authors share experiences about usage of telemedicine to support treatment of the burn victims in a low-income country that receive reconstructive surgery in a developed country. Throughout the entire care process, telemedicine has been used not only to provide an expert advice from distance but also to help establish and maintain the doctor-patient relationship, to keep patients in contact with their families, and to help educate and consult the medical personal physically present in Sao Tome and Principe. This case study presents the details of how this process has been conducted to date, on what were learned from this process, and on issues that should be considered to improve this process in the future. The authors plan to create instructional videos and post them on YouTube to aid clinical workers providing similar treatment during the acute care and rehabilitation process and also to support eLearning in many situations where it otherwise is not possible to use videoconferencing to establish real-time contact between doctors at the local site and remote specialists. PMID- 22249105 TI - Identification of essential sequences for cellular localization in the muscle specific ubiquitin E3 ligase MAFbx/Atrogin 1. AB - In skeletal muscle atrophy, upregulation and nuclear accumulation of the Ubiquitin E3 ligase MAFbx is essential for accelerated muscle protein loss, but the nuclear/cytoplasmic shuttling of MAFbx is undefined. Here we found that MAFbx contains two functional nuclear localization signals (NLS). Mutation or deletion of only one NLS induced cytoplasmic localization of MAFbx. We identified a non classical NES located in the leucine charged domain (LCD) of MAFbx, which is leptomycin B insensitive. We demonstrated that mutation (L169Q) in LLXXL motif of LCD suppressed cytoplasmic retention of MAFbx. Nucleocytoplasmic shuttling of MAFbx represents a novel mechanism for targeting its substrates and its cytosolic partners in muscle atrophy. PMID- 22249106 TI - Pharmacokinetics and safety profile of tigecycline in children aged 8 to 11 years with selected serious infections: a multicenter, open-label, ascending-dose study. AB - BACKGROUND: Tigecycline, a broad-spectrum antibiotic used for treating serious bacterial infections in adults, may be suitable for pediatric use once an appropriate dosage is determined. OBJECTIVE: The aim of this study was to assess the pharmacokinetic (PK) properties, safety profile, and descriptive efficacy of tigecycline. METHODS: In this Phase II, multicenter, open-label clinical trial, children aged 8 to 11 years with community-acquired pneumonia (CAP), complicated intra-abdominal infection (cIAI), or complicated skin and skin structure infections (cSSSI) were administered tigecycline 0.75, 1, or 1.25 mg/kg. RESULTS: A total of 58 patients received >= 1 dose of tigecycline (31 boys; 44 white; mean age, 10 years; mean weight, 35 kg); 47 had data from samples available for PK analysis. The mean (SD) PK values were: C(max), 1899 (2954) ng/mL; T(max), 0.56 (0.18) hour; between-dose AUC, 2833 (1557) ng . h/mL; weight-normalized clearance, 0.503 (0.293) L/h/kg; and Vd(ss), 4.88 (4.84) L/kg. Overall clinical cure rates at test-of-cure were 94% (16/17), 76% (16/21), and 75% (15/20) in the 0.75-, 1-, and 1.25-mg/kg cohorts, respectively. The rates of protocol violations were higher in the 1- and 1.25-mg/kg groups, resulting in higher proportions of indeterminate clinical cure assessments relative to the 0.75-mg/kg cohort (19% and 15% vs 0%). The most frequent adverse event was nausea, which occurred in 50% of patients overall (29/58) and the prevalence of which was significantly higher in the 1.25-mg/kg group versus the 0.75-mg/kg group (65% vs 18%; P = 0.007). Pharmacodynamic simulations using MIC data from an ongoing microbiological surveillance trial predicted that a dosage of 1.2 mg/kg q12h would lead to therapeutic target attainment levels of up to 82% for the target AUC(0-24)/MIC ratios. CONCLUSION: A tigecycline dosage of ~1.2 mg/kg q12h may represent the most appropriate dosage for subsequent evaluation in Phase III clinical trials in children aged 8 to 11 years with selected serious bacterial infections. ClinicalTrials.gov identifier: NCT00488345. PMID- 22249107 TI - The effects of adiponectin and leptin on human endothelial cell proliferation: a live-cell study. AB - The effect of adiponectin and leptin on the proliferation of the human microvascular endothelial cell line (HMEC-1) was studied in the absence or presence of fetal bovine serum (FBS). The participation of extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI-3K/Akt) pathways in this effect were evaluated. We studied the effect of both adipokines on the motility, mitosis, proliferation and cell death processes of HMEC-1 cells using live-cell imaging techniques. Adiponectin but not leptin further increased the proliferative effect induced by FBS on HMEC-1. This effect seems to be the consequence of an increase in the mitotic index in adiponectin-treated cells when compared to untreated ones. The presence of either the mitogen-activated protein kinase (MAPK) inhibitor (PD98059), or PI-3K inhibitor (LY294002), reduced the effect of adiponectin in a dose-dependent manner. Neither adipokine was able to affect HMEC-1 proliferation in FBS-free conditions. Duration of mitosis, cell motility and the cell death process were similar in all conditions. These data suggest that adiponectin and leptin exert different effects on endothelial cell function. Adiponectin was able to potentiate proliferation of HMEC-1. This effect involves the activation of both PI3-K/Akt and ERK/MAPK pathways. However, it seems to exert minimal effects on HMEC-1 function in the case of leptin. PMID- 22249108 TI - Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion. AB - Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3 positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice. PMID- 22249109 TI - MeCP2+/- mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder. AB - Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD. PMID- 22249111 TI - Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy. AB - Nuclear speckles are essential nuclear compartments involved in the assembly, delivery and recycling of pre-mRNA processing factors, and in the post transcriptional processing of pre-mRNAs. Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of the polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1). Aggregation of expanded PABPN1 into intranuclear inclusions (INIs) in skeletal muscle fibers is the pathological hallmark of OPMD. In this study what we have analyzed in muscle fibers of OPMD patients and in primary cultures of human myoblasts are the relationships between nuclear speckles and INIs, and the contribution of the former to the biogenesis of the latter. While nuclear speckles concentrate snRNP splicing factors and PABPN1 in control muscle fibers, they are depleted of PABPN1 and appear closely associated with INIs in muscle fibers of OPMD patients. The induction of INI formation in human myoblasts expressing either wild type GFP-PABPN1 or expanded GFP-PABPN1-17ala demonstrates that the initial aggregation of PABPN1 proteins and their subsequent growth in INIs occurs at the edges of the nuclear speckles. Moreover, the growing of INIs gradually depletes PABPN1 proteins and poly(A) RNA from nuclear speckles, although the existence of these nuclear compartments is preserved. Time-lapse experiments in cultured myoblasts confirm nuclear speckles as biogenesis sites of PABPN1 inclusions. Given the functional importance of nuclear speckles in the post-transcriptional processing of pre-mRNAs, the INI dependent molecular reorganization of these nuclear compartments in muscle fibers may cause a severe dysfunction in nuclear trafficking and processing of polyadenylated mRNAs, thereby contributing to the molecular pathophysiology of OPMD. Our results emphasize the potential importance of nuclear speckles as nuclear targets of neuromuscular disorders. PMID- 22249110 TI - Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger. AB - Glutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl d-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and NCX(rev) contribute to glutamate-induced DCD is uncertain. Here, we show that both NMDAR and NCX(rev) are critical for DCD in neurons exposed to excitotoxic glutamate. In rat cultured hippocampal neurons, 25 MUM glutamate produced DCD accompanied by sustained increase in cytosolic Na+ ([Na+]c) and plasma membrane depolarization. MK801 and memantine, noncompetitive NMDAR inhibitors, added shortly after glutamate, completely prevented DCD whereas AP-5, a competitive NMDAR inhibitor, failed to protect against DCD. None of the tested inhibitors lowered elevated [Na+]c or restored plasma membrane potential. In the experiments with NCX reversal by gramicidin, MK801 and memantine robustly inhibited NCXrev while AP-5 was much less efficacious. In electrophysiological patch-clamp experiments MK801 and memantine inhibited NCXrev-mediated ion currents whereas AP 5 failed. Thus, MK801 and memantine, in addition to NMDAR, inhibited NCXrev. Inhibition of NCXrev either with KB-R7943, or by collapsing Na+ gradient across the plasma membrane, or by inhibiting Na+/H+ exchanger with 5-(N-ethyl-N isopropyl) amiloride (EIPA) and thus preventing the increase in [Na+]c failed to preclude DCD. However, NCXrev inhibition combined with NMDAR blockade by AP-5 completely prevented DCD. Overall, our data suggest that both NMDAR and NCXrev are essential for DCD in glutamate-exposed neurons and inhibition of individual mechanism is not sufficient to prevent calcium dysregulation. PMID- 22249112 TI - Toxicological evaluation of three contaminants of emerging concern by use of the Allium cepa test. AB - Di(2-ethylhexyl)phthalate, triclosan and propylparaben are contaminants of emerging concern that have been subjected to extensive toxicological studies, but for which limited information is currently available concerning adverse effects on terrestrial plant systems. The Allium cepa test, which is considered one of the most efficient approaches to assess toxic effects of environmental chemicals, was selected to evaluate the potential risks of these ubiquitous pollutants. Our data demonstrate that all three compounds studied may in some way be considered toxic, but different effects were noted depending on the chemical and the end point analysed. Results derived from the analysis of macroscopic parameters used in testing for general toxicity, revealed that while di(2-ethylhexyl)phthalate had no apparent effects, the other two chemicals inhibited A. cepa root growth in a dose-dependent manner. On the other hand, although all three compounds caused alterations in the mitotic index of root-tip cells, propylparaben was the only one that did not show evidence of genotoxicity in assays for chromosome aberrations and micronuclei. The results of the present study clearly indicate that sensitive plant bioassays are useful and complementary tools to determine environmental impact of contaminants of emerging concern. PMID- 22249113 TI - Comet-assay parameters as rapid biomarkers of exposure to dietary/environmental compounds -- an in vitro feasibility study on spermatozoa and lymphocytes. AB - Twelve chemical compounds have been selected for the European NewGeneris study on the basis of their potential to damage DNA, in order to establish adequate and reliable biomarkers of exposure. These genotoxic chemicals include heterocyclic amines, organochlorines, polycyclic aromatic hydrocarbons, mycotoxins, lipid peroxidation products and alcohol. Damage in somatic cells such as lymphocytes could give rise to cancer, while damage in germ cells could not only give rise to cancer but also to heritable defects. The alkaline Comet assay, with and without metabolic activation, as well as the neutral Comet assay were used to assess DNA integrity in spermatozoa and lymphocytes after in vitro treatment with low, middle and high doses of each chemical. DNA-reactive aldehydes generated by lipid peroxidation, food mutagens such as heterocyclic amines, nitrosamine and benzo[a]pyrene produced the highest amounts of DNA damage, even without metabolic activation. Damage seen with the neutral Comet assay - detecting primarily double strand breaks - was lower than with the alkaline assay. In general, there was increased damage in the spermatozoa by comparison with the lymphocytes, with altered slopes in the dose-response curves. The Comet assay with sperm was generally very sensitive in assessing genotoxic damage, with the Comet parameters being good biomarkers of induced DNA damage. Establishing reliable biomarkers of exposure for the evaluation of dietary/environmental carcinogens is of utmost importance to protect our health and the health of our offspring. PMID- 22249114 TI - Cecal volvulus associated with intestinal malrotation presenting as postoperative intestinal obstruction. AB - OBJECTIVE: To report a case of intestinal malrotation predisposing to cecal volvulus following nonabdominal surgery in an adult. PRESENTATION AND INTERVENTION: A 23-year-old male with known anorectal malformation developed a postoperative intestinal obstruction following percutaneous nephrolithotomy for left renal calculus. Computed tomography of the abdomen revealed a grossly dilated cecum (9 cm) with ileocecal junction on the left side and small bowel loops on the right side of the abdomen. The patient underwent emergency exploratory laparotomy and retroperitonealization cecopexy. Bowel functions were normal at the follow-ups. CONCLUSION: This case highlights the importance of suspecting cecal volvulus even following nonabdominal surgery in the presence of predisposing factors. PMID- 22249115 TI - Do false belief and verb non-factivity share similar neural circuits? AB - The present study investigates whether the complement falsity elicited by strong non-factive verbs and the false belief activated by a standard nonverbal false belief task produce similar electrophysiological activities in the brain. The hypothesis is based on the notion that both complement falsity and false belief involve decoupling a false mental representation from reality. Some previous studies have reported a behavioral correlation between children's false belief reasoning and interpretation of strong non-factive verbs together with their false complements, but a neural basis for this correlation has not been found. Our event-related potential (ERP) results with normal adults showed that both nonverbal false belief and strong non-factive verb comprehension elicited a negative late slow waveform divergence compared to their respective baselines. Although these slow waves due to the two types of stimuli had slightly different scalp distributions, both were regarded as reflecting primarily frontal activation. Such ERP similarity provides evidence for a common neural basis shared by nonverbal false belief reasoning and comprehension of strong non factive verbs. PMID- 22249117 TI - Prolonged nitric oxide treatment induces tau aggregation in SH-SY5Y cells. AB - Presence of cytoplasmic tau aggregates is a hallmark of brains in patients with tauopathies such as Alzheimer's disease. However, the mechanism underlying formation of these insoluble tau aggregates remains elusive. In this study, we investigated the impact of prolonged nitric oxide (NO) exposure on neuronal SH SY5Y cells overexpressing human tau. Treatment with the NO donor DETA NONOate for up to 48h resulted in an increase in S-nitrosation of cellular proteins, inactivation of proteasome, and impairment of respiration. Western blot analysis of Triton X-soluble fractions of NO-treated cells revealed that persistent NO treatment increased heterogeneity in tau molecule size, as a result of dephosphorylation, and induced the formation of sodium dodecyl sulfate (SDS) stable oligomeric tau aggregates, stabilized by disulfide bonds. Moreover, further NO treatment induced the formation of SDS-stable insoluble tau mega aggregates that were composed of dephosphorylated full-length tau molecules and other proteins, and were stabilized through disulfide bonds. Evaluation of the role of these tau aggregates as potential seeds for tau fibrillization and elucidation of their formation mechanism in our model, could lead to better understanding of the pathogenesis of tauopathies. PMID- 22249116 TI - Stimulus dynamics increase the self-administration of compound visual and auditory stimuli. AB - Animals will acquire an operant task using sensory stimuli as a primary reinforcer. Many operant tasks use sensory stimuli as cues that are paired with other primary reinforcers. Recent studies have called attention to this potential confound, but there has not been a parametric assessment of the effect of stimulus variability on operant responding. We found that stimulus variability increased the amount of operant responding exhibited by mice, a phenomenon observed under both fixed- and progressive-ratio schedules. PMID- 22249118 TI - Role of neuronal nitric oxide synthase in the antiallodynic effects of intrathecal EGCG in a neuropathic pain rat model. AB - Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is known to have antioxidant activity against nitric oxide (NO) by scavenging free radicals, chelating metal ions, and inducing endogenous antioxidant enzymes. NO and NO synthase (NOS) play an important role in nociceptive processing. In this study, we examined the effects of intrathecal EGCG in neuropathic pain induced by spinal nerve ligation and the possible involvement of NO. Intrathecal EGCG attenuated mechanical allodynia in spinal nerve ligated-rats, compared to sham-operated rats, with a maximal possible effect of 69.2%. This antinociceptive effect was reversed by intrathecal pretreatment with l-arginine, a precursor of NO. Intrathecal EGCG also blocked the increase in nNOS expression in the spinal cord of spinal nerve-ligated rats, but iNOS expression was not significantly suppressed. These findings suggest that intrathecal EGCG could produce an antiallodynic effect against spinal nerve ligation-induced neuropathic pain, mediated by blockade of nNOS protein expression and inhibition of the pronociceptive effects of NO. PMID- 22249119 TI - Distinct mechanisms mediate the reinstatement and spontaneous recovery of extinguished fear in rats. AB - It is controversy whether the summation of new contextual conditioning with residual conditioned response contributes to the reinstatement phenomenon. Here, we examined the summation hypothesis in the auditory conditioned fear paradigm by comparing the freezing levels during pre-tone and tone presentation periods. Unexpectedly, we found that the onset of tone relieves fear during the reinstatement test, which is not predicted by the summation hypothesis; whereas the onset of tone enhances fear during the spontaneous recovery test and early extinction session. These results implicated that return of fear in two conventional assays after extinction, i.e., reinstatement assay and spontaneous recovery assay, are mediated by different mechanisms. PMID- 22249120 TI - Lack of neurofibromatosis type 2 gene promoter methylation in sporadic vestibular schwannomas. AB - BACKGROUND: Vestibular schwannomas (VS) are benign tumors of the nervous system that are usually sporadic but also occur in the inherited disorder neurofibromatosis type 2 (NF2). In VS, losses of chromosomal material and mutations of the NF2 gene have been established to be causative. For a subset of VS without detectable gene alterations, promoter inactivation by hypermethylation has been suggested. However, published data are very limited and contradictory. METHODS: We analyzed NF2 gene promoter methylation in 35 sporadic VS by methylation-specific PCR. RESULTS: Twenty-three of the tumors were informative, showing no promoter methylation. In the remaining 12 tumors, promoter methylation could neither be verified nor excluded. CONCLUSIONS: Our study suggests that NF2 gene inactivation by promoter hypermethylation is a rare or very uncommon mechanism of NF2 gene inactivation in sporadic VS. Other mechanisms destabilizing the NF2 gene product, yet to be identified, might play a role in the genesis of VS apart from the loss or mutation of the NF2 gene. PMID- 22249121 TI - Identification of Trypanosoma brucei leucyl-tRNA synthetase inhibitors by pharmacophore- and docking-based virtual screening and synthesis. AB - Human African trypanosomiasis (HAT), caused by the protozoan parasite Trypanosoma brucei, is a neglected fatal disease. Leucyl-tRNA synthetase (LeuRS), which has been successfully applied in the development of antifungal agent, represents a potential antiprotozoal drug target. In this study, a 3D model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold was discovered and the structure-activity relationship (SAR) studies aided by the docking model and organic synthesis were carried out. Compounds with various substituents on R(1), R(2) and R(3) were synthesized and their SAR was discussed. PMID- 22249122 TI - Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging. AB - SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood-brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed. PMID- 22249123 TI - Synthesis of purine N9-[2-hydroxy-3-O-(phosphonomethoxy)propyl] derivatives and their side-chain modified analogs as potential antimalarial agents. AB - 6-Oxopurine acyclic nucleoside phosphonates (ANPs) have been shown to be potent inhibitors of hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), a key enzyme of the purine salvage pathway in human malarial parasites. These compounds also exhibit antimalarial activity against parasites grown in culture. Here, a new series of ANPs, hypoxanthine and guanine 9-[2-hydroxy-3 (phosphonomethoxy)propyl] derivatives with different chemical substitutions in the 2'-position of the aliphatic chain were prepared and tested as inhibitors of Plasmodium falciparum (Pf) HGXPRT, Plasmodium vivax (Pv) HGPRT and human HGPRT. The attachment of an hydroxyl group to this position and the movement of the oxygen by one atom distal from N(9) in the purine ring compared with 2 (phosphonoethoxy)ethyl hypoxanthine (PEEHx) and 2-(phosphonoethoxy)ethyl guanine (PEEG) changes the affinity and selectivity for human HGPRT, PfHGXPRT and PvHGPRT. This is attributed to the differences in the three-dimensional structure of these inhibitors which affects their mode of binding. A novel observation is that these molecules are not always strictly competitive with 5-phospho-alpha-d ribosyl-1-pyrophosphate. 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]hypoxanthine (iso-HPMP-Hx) is a very weak inhibitor of human HGPRT but remains a good inhibitor of both the parasite enzymes with K(i) values of 2MUM and 5MUM for PfHGXPRT and PvHGPRT, respectively. The addition of pyrophosphate to the assay decreased the K(i) values for the parasite enzymes by sixfold. This suggests that the covalent attachment of a second group to the ANPs mimicking pyrophosphate and occupying its binding pocket could increase the affinity for these enzymes. PMID- 22249124 TI - Inhibition of Dengue virus and West Nile virus proteases by click chemistry derived benz[d]isothiazol-3(2H)-one derivatives. AB - Two click chemistry-derived focused libraries based on the benz[d]isothiazol 3(2H)-one scaffold were synthesized and screened against Dengue virus and West Nile virus NS2B-NS3 proteases. Several compounds (4l, 7j-n) displayed noteworthy inhibitory activity toward Dengue virus NS2B-NS3 protease in the absence and presence of added detergent. These compounds could potentially serve as a launching pad for a hit-to-lead optimization campaign. PMID- 22249127 TI - Safety and efficacy of contraceptive implants for HIV-infected women in Porto Alegre, Brazil. PMID- 22249126 TI - Comparison of two adsorbents for the removal of pentavalent arsenic from aqueous solutions. AB - Two adsorbents, magnesia-loaded fly ash cenospheres (MGLC) and manganese-loaded fly ash cenospheres (MNLC), were prepared by wet impregnation of fly ash cenospheres with MgCl(2) solution or a mixed solution of MnCl(2) and KMnO(4), respectively. Their physicochemical properties were characterized by scanning electron microscopy, X-ray diffractometry, X-ray fluorescence spectrometry, and Fourier transform infrared spectrometry. Sorption experiments were conducted to examine the effects of adsorbent dosage, pH, time, temperature, ionic strength and competing anions on As(V) removal by MGLC and MNLC. Both MGLC and MNLC had greater pH buffering capacity and were less affected by changes in ionic strength. Competing anions (carbonate and dihydric phosphate) had a larger impact on As(V) removal by MNLC than by MGLC. Adsorption on MNLC reached equilibrium at 60 min, while adsorption on MGLC reached equilibrium at 120 min. The Langmuir adsorption isotherm was a good fit for the experimental data of As(V) adsorption on MGLC and MNLC, and the adsorption kinetics for both followed the pseudo-second order rate equation. MGLC and MNLC had a larger removal capacity for As(V) than the cenospheres. Compared with MNLC, MGLC is a better absorbent. PMID- 22249125 TI - Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1. AB - Selenium compounds are known as cancer preventive agents and are also able to ameliorate the toxicity associated with anti-cancer radiation and chemotherapy in mouse models. Sensitivity to the toxicity of chemotherapy is also modulated by the circadian clock, molecular time-keeping system that underlie daily fluctuations in multiple physiological and biochemical processes. Here we show that these two mechanisms are interconnected. By screening a library of small molecules in a cell-based reporter system, we identified L-methyl-selenocysteine as a positive regulator of the core clock protein, BMAL1. L-methyl-selenocysteine up-regulates BMAL1 at the transcriptional level both in cultured cells and in mice. We also show that in tissue culture selenium exerts its action by interfering with TIEG1-mediated repression of Bmal1 promoter. Selenium treatment fails to protect BMAL1-deficient mice from toxicity induced by the chemotherapeutic agent cyclophosphamide but does protect Clock mutant mice deficient in circadian rhythm control but having normal BMAL1. These findings define selenium as circadian modulator and indicate that the tissue protective effect of selenium results, at least in part, from up-regulation of BMAL1 expression and subsequent enhancement of CLOCK/BMAL1-mediated transcription. PMID- 22249128 TI - Transvaginal laparoscopic surgery for ovarian cysts. AB - OBJECTIVE: To evaluate the effectiveness and feasibility of transvaginal laparoscopic surgery (TLS) using endoscopic instruments for management of ovarian cysts. METHODS: In a retrospective study, data from 140 patients with benign ovarian cysts who underwent TLS at Konkuk University Hospital between June 2007 and December 2008 were evaluated. The preoperative characteristics of patients, operative time, blood loss, complications, and postoperative outcomes were evaluated. RESULTS: The mean age of patients was 38 years (range, 16-82 years). TLS was accomplished in 136 women (97.1%). The more common pathology findings included 35 dermoid cysts, 28 endometriotic cysts, 23 mucinous cysts, 21 serous cysts, and 13 functional ovarian cysts. The median operative time was 35 minutes (range 15-110 minutes). The maximum diameter of the ovarian cysts ranged from 3 to 20 cm (mean 6 cm). The median estimated blood loss was 38 mL (range 10-80 mL). No patients received a blood transfusion. All of the patients were discharged within 24 hours of surgery. No major complications occurred. CONCLUSION: Transvaginal laparoscopic surgery was found to be a feasible and cosmetically beneficial surgical technique for managing selected patients with benign ovarian cysts. PMID- 22249129 TI - P2Y receptors regulate proliferation of human pancreatic duct epithelial cells. AB - OBJECTIVES: The aim of this study was to investigate the effect of P2Y receptor activation on proliferation of human pancreatic duct epithelial cells. METHODS: Proliferation was measured by immunoassay for bromodeoxyuridine incorporation into a pancreatic duct epithelial cell line, PANC-1. Expression of P2Y receptors was examined using quantitative reverse transcription-polymerase chain reaction and Western blot. RESULTS: Extracellular nucleotides, adenosine diphosphate (ADP) and uridine diphosphate (UDP), stimulated proliferation of pancreatic duct cells in a concentration-dependent manner. The nucleotide efficacy order was ADP > UDP > uridine triphosphate (UTP) > adenosine triphosphate. P2Y(1) and P2Y(6) receptor blockers, MRS2500 and MRS2578, blocked the effect of ADP and UDP. The signal that transmitted the proliferative activity of ADP and UDP was transducted to phospholipase C, inositol 1,4,5-triphosphate receptor, and protein kinase C. These results indicate involvement of P2Y(1) and P2Y(6) receptors in ADP- and UDP stimulated proliferation. Pancreatic duct cells expressed the messenger RNA transcripts of P2Y receptors, P2Y(1) , P2Y(2), and P2Y(6), and P2Y(1) and P2Y(6) receptor protein. CONCLUSIONS: Extracellular nucleotides increase proliferation of human pancreatic duct epithelial cells by activation of P2Y(1) and P2Y(6) receptors. This provides the basic model for the effect of P2Y receptors on the proliferation of pancreatic duct epithelial cells. PMID- 22249130 TI - Magnetic resonance imaging for pancreatic ductal adenocarcinomas induced by N nitrosobis (2-oxopropyl) amine in Syrian golden hamsters. AB - OBJECTIVES: This study aimed to study magnetic resonance imaging (MRI) findings of pancreatic ductal adenocarcinomas (PDAs) induced by N-nitrosobis (2-oxopropyl) amine (BOP) in Syrian hamsters. METHODS: A total of 101 female hamsters, 8 weeks old, were randomized into 3 groups. They were randomized into a BOP-treated group (n = 80; with weekly subcutaneous injections of BOP [10 mg/kg body weight] for 7 consecutive weeks), a saline-treated group (n = 16), and an untreated group (n = 5). Hamsters underwent abdominal MRI on 1.5-T MR scanners with a dedicated animal radiofrequency coil. Findings of the tumor from the MRI were compared those from histology. RESULTS: Pancreata in the saline-treated and in the untreated groups were normal. In the BOP-treated group, there were 23 and 31 BOP-induced PDAs on macroscopy and microscopy, respectively. Of the PDAs detected on macroscopy, 65.2% were depicted on MRI. As early as 13 and 19 weeks after the first injection of BOP, PDAs in hamsters were found on histology and MRI, respectively. Moreover, the tumor volume on MRI was correlated with the tumor weights excised (r = 0.96, P = 0.000, n = 15). CONCLUSIONS: N-nitrosobis (2-oxopropyl) amine successfully induced PDAs in hamsters. Magnetic resonance imaging has the ability to detect healthy pancreas and PDAs in hamsters and has the potential to monitor the development of PDAs. PMID- 22249131 TI - Long-term prognosis of autoimmune pancreatitis in terms of glucose tolerance. AB - OBJECTIVE: Glucose intolerance is often observed in autoimmune pancreatitis (AIP), although its long-term prognosis after steroid treatment (ST) is still unclear. METHODS: A total of 47 patients with AIP were enrolled. On the basis of the change in hemoglobin A1c (HbA1c) and the use of diabetic medication, prognosis was classified into 3 categories, namely, "improved," "aggravated," and "unchanged." The relation between the result of an initial glucagon tolerance test (DeltaCPR) and the later use of insulin during maintenance ST was examined in 20 patients. The transitions of homeostasis model assessment beta cell and insulin resistance (HOMA-beta and HOMA-R) were analyzed in 16 patients. RESULTS: Glucose tolerance was improved in 6 patients (13%), aggravated in 9 patients (19%), and unchanged in 32 patients (68%). All patients with DeltaCPR less than 0.6 ng/mL were obliged to use insulin even after long-term observation, whereas all patients with DeltaCPR more than 1.0 ng/mL were free from insulin therapy. Moreover, HOMA-beta showed significant improvement after ST (43.9% -> 56.0% in median, P = 0.030), and HOMA-R showed significant aggravation (1.30 -> 1.78, P = 0.039). CONCLUSIONS: Glucose tolerance that is too severely damaged may not recover fully even after ST. Thus, ST should be performed to preserve insulin secretion at the early stage of AIP. PMID- 22249132 TI - Overexpression of FOXM1 is associated with poor prognosis and clinicopathologic stage of pancreatic ductal adenocarcinoma. AB - OBJECTIVES: Oncogenic transcription factor forkhead box M1 (FoxM1)-related clinicopathologic characteristics and prognosis of patients with pancreatic ductal adenocarcinoma (PDA) have not been identified. Our aim of studying FoxM1 expression level and survival rate of PDA is to determine whether FoxM1 is a valuable prognostic predictor for PDA patients. METHODS: Expressional levels of FoxM1 mRNA and protein in paired pancreatic cancer lesions and adjacent noncancerous tissues were examined by reverse transcription-polymerase chain reaction and Western blotting. FoxM1 expression was analyzed by immunohistochemistry in 80 patients with PDA. The correlations between FoxM1 immunostaining levels and clinicopathologic factors, as well as the follow-up data of patients, were analyzed statistically. RESULTS: FoxM1 protein and mRNA levels were elevated in pancreatic carcinoma lesions compared with the paired adjacent noncancerous tissues. A high level of expression of FoxM1 was significantly correlated with clinical staging (P = 0.004), lymph node metastasis (P = 0.009), and histological differentiation (P = 0.017). Patients with a higher FoxM1 expression had a significantly shorter survival time than those patients with lower FoxM1 expression (P < 0.001). The multivariate analysis revealed that FoxM1 could serve as an independent factor of poor prognosis. CONCLUSIONS: Our finding indicates that FoxM1 could be used as prognostic molecular marker and therapeutic target for PDA. PMID- 22249133 TI - Mass transfer limitations in embryoid bodies during human embryonic stem cell differentiation. AB - Due to their ability to differentiate into cell types from all the three germ layers and their potential unlimited capacity for expansion, embryonic stem cells have tremendous potential to treat diseases and injuries. Spontaneous differentiation of human embryonic stem cells (hESCs) is influenced by the size of the differentiating embryoid bodies (EBs). To further understand the dynamics between nutrient mass transfer, EB size, and stem cell differentiation, a transient mass diffusion model of a single hESC EB was constructed. The results revealed that the oxygen concentration at the centers of large EBs (400-MUm radius) was 50% lower when compared to that in smaller EBs (200-MUm radius). In addition, the concentration profile of cytokines within an EB depended strongly on their depletion rate, with higher depletion rates resulting in cytokine concentrations that varied significantly throughout the EB. A comparison of the results of our model with published experimental data reveals a close correlation between the fraction of cells that differentiate to a given lineage and the fraction of cells exposed to different oxygen or cytokine concentrations. This, along with other data from the literature, suggests that diffusive mass transfer influences the differentiation of hESCs within EBs by controlling the spatial distribution of soluble factors. This has important implications for research involving the differentiation of embryonic stem cells in EBs, as well as for bioprocess design and the development of robust differentiation protocols where mass transfer could be altered to control the cell differentiation trajectory. PMID- 22249134 TI - Juvenile exposure to methylphenidate reduces cocaine reward and alters netrin-1 receptor expression in adulthood. AB - The guidance cue netrin-1 acting on mesocorticolimbic dopamine (DA) neurons through its receptor DCC (deleted in colorectal cancer) has been implicated in the neuronal plasticity induced by psychostimulant drugs. We examined in C57/BL6 mice the effects of repeated juvenile methylphenidate (MPH) exposure on cocaine reward sensitivity in adulthood and determined whether early MPH treatment alters adult expression of DCC in mesocorticolimbic DA regions. By using place conditioning, we show that adult mice exposed to MPH during the juvenile period are less sensitive to cocaine-reward compared to saline-controls. Furthermore, by means of immunoblotting, we demonstrate that early MPH treatment attenuates adult DCC expression in the ventral tegmental area (VTA) selectively. These results support previous evidence that developmental MPH treatment diminishes cocaine reward in adulthood and are the first to suggest that DCC in the VTA may participate in this enduring effect. PMID- 22249135 TI - Prolonged elevation in hippocampal Abeta and cognitive deficits following repeated endotoxin exposure in the mouse. AB - Alzheimer's disease (AD) is characterized by neuronal cell death and atrophy in regions of the adult brain, including the hippocampus and cortex, due to formation of amyloid beta (Abeta) plaques and neurofibrillary tangles. The presence of these pathologies can limit normal signaling properties and ultimately lead to learning and memory deficits. Chronic inflammation has been implicated in the onset and progression of these AD-related pathologies. Our study was designed to assess the effects of peripheral inflammation on pathologies associated with AD by using the bacterial endotoxin lipopolysaccharide (LPS). C57BL/6J mice were given intraperitoneal injections of LPS or saline for 1, 3, or 7 consecutive days. Hippocampal tissue from animals receiving LPS contained significantly higher levels of Abeta1-42, a peptide component of AD plaques, than did those from saline control animals. Central and peripheral pro-inflammatory cytokine levels were increased following a single injection of LPS, but retuned to baseline levels before cognitive testing began. We show that one injection of LPS leads to sickness behavior, but 7 consecutive days does not, indicating tolerance to the endotoxin. Cognitive testing was then conducted to determine if whether deficits from increased Abeta1-42 was evident. Results from both Morris water maze and contextual fear conditioning revealed cognitive deficits in LPS-treated mice. In summary, multiple injections of LPS resulted in increased Abeta1-42 in the hippocampus and cognitive deficits in mice. PMID- 22249136 TI - Sensory feedback modulates quipazine-induced stepping behavior in the newborn rat. AB - Research has shown that sensory feedback modulates locomotor behavior in intact as well as spinal adult animals. Here we examined if locomotor activity ("stepping") in newborn rats is influenced by cutaneous and proprioceptive feedback. One-day-old rats were treated with the serotonergic receptor agonist quipazine (3.0mg/kg) to induce air-stepping behavior or with saline (vehicle control). During stepping, a substrate/floor (elastic, stiff, or none) was placed beneath their limbs so that the feet could make plantar surface contact with a substrate. Pups treated with quipazine showed significantly more alternated fore- and hindlimb steps and plantar paw contact with the substrate, compared to pups treated with saline. Pups also made proportionately less contact with the stiff substrate versus the elastic substrate during stepping. Different types of movements made on the substrate (paw pushes, taps, swipes, and stances) were also characterized. These results indicate that sensory feedback modulates locomotor mechanisms and behavior in perinatal rats. PMID- 22249137 TI - Excitotoxic lesions of the medial amygdala attenuate olfactory fear-potentiated startle and conditioned freezing behavior. AB - Conditioned fear is supported by a distributed network that prominently includes lateral and central amygdaloid nuclei. The role of corticomedial amygdaloid nuclei, including the medial nucleus (MeA), in fear acquisition or expression is not well understood. The present study demonstrates that pre-training excitotoxic lesions directed at the MeA disrupted both fear-potentiated startle (FPS) and conditioned freezing behavior elicited by re-exposure to a discrete olfactory cue. In contrast, such lesions had no effect on baseline startle reactivity or contextual FPS. These findings suggest that the MeA plays an obligatory role in either the acquisition or expression of olfactory conditioned fear, not limited by form of behavioral expression, but is not necessary for contextual conditioned fear. PMID- 22249138 TI - A new arteriovenous fistula model to study the development of neointimal hyperplasia. AB - This study describes an alternative arteriovenous fistula (AVF) model in the rat in which the animals develop significant neointimal hyperplasia (NIH) not only at the distal anastomotic site, but also throughout the fistula body. This aortocaval fistula was established by anastomosing the distal end of the renal vein to the abdominal aorta after unilateral nephrectomy. The increased hemodynamic stress resulting from exposing the renal vein to the arterial circulation induced venous NIH as early as 7 days after surgery. This experimental AVF was characterized by the early lack of endothelium, the accumulation of proliferating vascular smooth muscle cells and the neovascularization of the fistula adventitia. In summary, we have described an informative animal model to study the pathobiology of NIH in native AVF. PMID- 22249139 TI - Interaction of poly(N-isopropylacrylamide) (pNIPAM) based nanoparticles and their linear polymer precursor with phospholipid membrane models. AB - Poly(N-isopropylacrylamide) (pNIPAM) is a thermoresponsive polymer which has promising applications in nanomedicine for drug delivery. The cross-linking of pNIPAM based copolymer using the chain collapse method leads to the synthesis of pNIPAM based polymer nanoparticles. This study looks at the interaction of pNIPAM polymers and pNIPAM nanoparticles with biomembrane models of, (i) a dioleoyl phosphatidylcholine (DOPC) monolayer on a mercury (Hg) electrode and (ii) DOPC and dimyristoyl phosphatidylcholine (DMPC) vesicles. The following techniques were used to follow the interactions: Dynamic light scattering (DLS), differential scanning calorimetry (DSC), rapid cyclic voltammetry (RCV) and electrochemical impedance spectroscopy (EIS). Results showed that the polymers interacted more extensively than the nanoparticles with the phospholipid. The interaction of the polymer was more rapid and led to a polymer-phospholipid conjugate whereas the nanoparticle adsorbed on the phospholipid monolayer surface and penetrated the monolayer at longer contact times. The association of the linear polymer with the phospholipid can be related to the larger molecular area available with the pendant -Cl groups and the inherent polymeric flexibility compared to the nanoparticle structure. The apparent dissociation constant for nanoparticles-DOPC complex was K(d,app)=1.67 * 10(-5)+/-1.2 * 10(-6) mol dm(-3). The apparent kinetic constant of nanoparticle penetration through the DOPC monolayer was k(2,app)=1.054 * 10(-2)+/-9.1 * 10(-4) s(-1). It can be concluded therefore that the pNIPAM nanoparticle because of its lower affinity for phospholipids is more appropriate for medical applications. PMID- 22249140 TI - Disorders of eating that are associated with undernutrition and weight loss. Forward. PMID- 22249141 TI - Eating disorders in children and adolescents. PMID- 22249142 TI - Host-tumor interactions in nasopharyngeal carcinomas. AB - Like other human solid tumors, nasopharyngeal carcinoma (NPC) is a tissue and a systemic disease as much as a cell disease. Tumor cell population in NPC is highly heterogeneous. Heavy infiltration by non-malignant leucocytes results at least in part from the production of abundant inflammatory cytokines by the malignant epithelial cells. There is indirect evidence that interactions between stromal and malignant cells contribute to tumor development. Peripheral blood samples collected from NPC patients contain multiple products derived from the tumor, including cytokines, non-cytokine tumor proteins, tumor exosomes and viral nucleic acids. These products represent a potential source of biomarkers for assessment of tumor aggressiveness, indirect exploration of cellular interactions and monitoring of tumor response to therapeutic agents. Most NPC patients are immunocompetent with evidence of active humoral and cellular immune responses against EBV-antigens at the systemic level. Tumor development is facilitated by local immunosuppressive factors which are not fully understood. Local accumulation of regulatory T-cells is probably one important factor. At least two NPC tumor products are suspected to contribute to their expansion, the cytokine CCL20 and the tumor exosomes carrying galectin 9. In the future, new therapeutic modalities will probably aim at breaking immune tolerance or at blocking cellular interactions critical for tumor growth. PMID- 22249143 TI - The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). AB - Although frequently expressed in EBV-positive malignancies, the contribution of the oncogenic latent membrane proteins, LMP1 and LMP2, to the pathogenesis of nasopharyngeal carcinoma (NPC) is not fully defined. As a key effector in EBV driven B cell transformation and an established "transforming" gene, LMP1 displays oncogenic properties in rodent fibroblasts and induces profound morphological and phenotypic effects in epithelial cells. LMP1 functions as a viral mimic of the TNFR family member, CD40, engaging a number of signalling pathways that induce morphological and phenotypic alterations in epithelial cells. Although LMP2A plays an essential role in maintaining viral latency in EBV infected B cells, its role in epithelial cells is less clear. Unlike LMP1, LMP2A does not display "classical" transforming functions in rodent fibroblasts but its ability to engage a number of potentially oncogenic cell signalling pathways suggests that LMP2A can also participate in EBV-induced epithelial cell growth transformation. Here we review the effects of LMP1 and LMP2 on various aspects of epithelial cell behaviour highlighting key aspects that may contribute to the pathogenesis of NPC. PMID- 22249144 TI - The current use of acupuncture during pregnancy and childbirth. AB - PURPOSE OF REVIEW: Acupuncture has a growing clientele during pregnancy, delivery and the puerperium for an ever increasing list of indications. Objective evidence for its benefit is necessary to establish its roles in current practice. RECENT FINDINGS: For many of the current uses, randomized studies when conducted using at least one control group have not established any clear advantages from treatment. Those areas which rely upon subjective assessment of symptoms are particularly difficult to investigate without rigorous blinding strategies, separating those who provide the acupuncture from those assessing outcome. Studies investigating the possible therapeutic benefit of acupuncture for managing intrapartum care require outcomes for nulliparae and multiparae to be analysed separately. SUMMARY: Acupuncture therapy may offer some advantage over conventional treatment in the management of hyperemesis gravidarum and postcaesarean section pain and these areas warrant further study. Rigorous randomized studies, particularly those using objective measures, have failed to identify any obvious benefits from acupuncture for many of the other conditions studied. PMID- 22249145 TI - Prenatal diagnosis of pulmonary hypoplasia. AB - PURPOSE OF REVIEW: To review the most used tests for diagnosis of pulmonary hypoplasia, and their pertinence in different pathological conditions. RECENT FINDINGS: The two-dimensional biometric parameters are not accurate enough to be applied in clinical practice, except for the lung-to-head ratio (LHR): the observed/expected LHR remains the best predictor of pulmonary hypoplasia in fetuses with congenital diaphragmatic hernia. The introduction of three dimensional ultrasound tecniques has allowed to directly measure lung volume. Three-dimensional-derived nomograms seem reliable for the prediction of both normal and pathological pulmonary volumes. MRI is attracting increasing attention. The studies recently published on this method are highly heterogeneous; universally accepted standardized values for the prediction of pulmonary hypoplasia are, hence, not available. Finally, some authors proposed Doppler ultrasound velocimetry to detect changes in pulmonary vascularization that correlate to pulmonary hypoplasia. However, a well-defined test to predict pulmonary hypoplasia has not emerged so far. SUMMARY: The prediction of the lethal type of pulmonary hypoplasia is pivotal to improve counseling and neonatal assistance. There is not a single test that can, at least for now, predict postnatal lung function. For different underlying pathologies, different combinations of clinical, ultrasound, and MRI parameters seem to better assess the risk of pulmonary hypoplasia. PMID- 22249146 TI - Parvovirus B19 in pregnancy: prenatal diagnosis and management of fetal complications. AB - PURPOSE OF REVIEW: Parvovirus B19 infection is often considered a mild and self limiting disease of minor clinical importance. This review aims to raise awareness of recently discovered potentially devastating consequences of this infection in pregnancy, and provides updated guidelines on diagnosis and management. RECENT FINDINGS: In contrast to previous beliefs, parvovirus B19 infection during any stage of pregnancy may not only cause fetal death, but may also result in severe and irreversible neurological sequelae in survivors. Improved diagnostic techniques allow more reliable and earlier diagnosis of fetal disease. SUMMARY: Clinicians need to be aware of the risk of adverse outcome of parvovirus B19 infection in pregnancy, and sometimes the long interval between exposure and fetal symptoms. Accurate diagnosis using PCR and weekly ultrasound checks ups with Doppler measurement of middle cerebral artery flow velocity up to 20 weeks postexposure may improve detection of fetal disease. More timely treatment likely results in improved outcome. PMID- 22249147 TI - Human factors affecting the interpretation of fetal heart rate tracings: an update. AB - PURPOSE OF REVIEW: Human factors can have an important impact on cardiotocography (CTG) interpretation and management decisions, and therefore may directly affect obstetrical outcomes. RECENT FINDINGS: It has been well demonstrated that there is wide observer disagreement over CTG interpretation, particularly in the evaluation of variability, decelerations, and overall tracing classification. The reasons behind this are still incompletely understood, but poor reproducibility can have a profound impact on the technology's accuracy and on its efficacy. Some scientific societies have recently revised their guidelines for CTG interpretation, but no up-to-date universally accepted recommendation exists. In spite of some approximation between the major guideline sets, important differences still exist between them, and they remain complex and prone to memory decay. Regular training in CTG interpretation appears to result in increased knowledge, better observer agreement, and improved quality of care. Computer analysis has also been developed, but remains heavily dependent on staff to confirm interpretation and to decide clinical management. SUMMARY: An international consensus, comprising simpler and more objective interpretation guidelines, together with regular staff training, and improved decision support systems seem to be the way forward for this technology. PMID- 22249148 TI - Valproate-induced teratogenesis in Japanese rice fish (Oryzias latipes) embryogenesis. AB - Fertilized eggs of Japanese rice fish (medaka) at three developmental stages (Iwamatsu stages 4-30) were exposed to waterborne valproic acid (VPA) (0-80 mM) in hatching solution for 48 h. The amount of valproate to cause 50% mortality (IC(50)) is found to be developmental stage-specific. The embryos were more sensitive to valproate at early stages of development (Iwamatsu stages 4-10) than in the embryos in late stages (Iwamatsu stages 17-30). Valproate exposed embryos have microcephaly and disrupted cardiovasculature with delayed vessel circulation, thrombus formation, and slow heart rate. The hatching efficiency is also reduced by valproate exposure due to developmental delay. The mRNA analysis of nine genes belong to oxidative stress (catalase, gsr, gst), neurogenesis (iro3, wnt1, shh, otx2, nlgn3b) and cell cycle regulation (ccna2) have been done. It was observed that the genes belong to oxidative stress remained unaltered after valproate exposure. However, some of the genes belong to neurogenesis (wnt1,shh, otx2 and nlgn3b) and cell cycle (ccna2) showed developmental stage specific alteration after valproate exposure. This study indicates that valproate is able to induce some of the phenotypic features which are analogous to human fetal valproate syndrome (FVS). Modulation of genes expressed in neural tissues indicates that this fish can be used to analyze the mechanisms of many neurobehavioral disorders like Autism spectrum disorder (ASD) in human. PMID- 22249149 TI - Respiration in 2012. PMID- 22249150 TI - Pleural diseases in the molecular era - time for more answers: introduction. PMID- 22249151 TI - Mechanisms of pleural involvement in orphan diseases. AB - Over the past 10 years, the widespread clinical applicability of semi-invasive and noninvasive diagnostic tools including medical thoracoscopy and ultrasonography has expanded the occurrence of pleural effusions to include several rare diseases such as granulomatous, connective tissue and autoimmune disorders including sarcoidosis, granulomatosis with polyangiitis (Wegener's), systemic sclerosis, lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, amyloidosis, Langerhans cell histiocytosis, and others. The purpose of this review is to summarize the current state of the knowledge regarding pathogenetic mechanisms of pleural involvement in rare disease entities and to highlight the need for more efforts to understand the underlying mechanisms for a more effective therapy. PMID- 22249152 TI - Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma. AB - We have previously described an alternatively spliced isoform of IL-4 mRNA that omits exon 2 and is termed IL-4delta2. However, the natural production of IL 4delta2 protein and its association with disease have not been previously assessed due to unavailability of an antibody that interacts with IL-4delta2 without cross-reactivity with full length IL-4. We used a unique monoclonal antibody (mAb) that reacts with IL-4delta2, but not with IL-4, and observed that IL-4delta2 is naturally produced by T cells from patients with asthma, but not from healthy controls. The kinetics of IL-4delta2 and IL-4 production by phorbol myristate acetate (PMA)/ionomycin-activated cells differed, with IL-4delta2 increasing at 48-72h and IL-4 peaking at 24h. The steady-state levels of IL 4delta2 mRNA varied significantly among the donors and were discordant with the corresponding protein levels, suggesting post-transcriptional regulation of protein production. Polarized Th1 or Th2 lymphocytes were not a major source of IL-4delta2. Stimulation of cultured T lymphocytes with IL-4delta2 caused elevated production of IFN-gamma, IL-10, IL-6, MCP-1, and TNF-alpha, with notable differences between patients and controls in the production of IFN-gamma, IL-10, and IL-6. Thus, IL-4delta2 is natively produced not only as mRNA but also as a protein by cells other than Th1 or Th2. It is regulated post-transcriptionally, is associated with allergic asthma, and regulates production of other cytokines by primary T lymphocytes. Alternatively spliced interleukin-4 may be a new biomarker, a pathophysiological player, and possibly a molecular target for future therapies in asthma. PMID- 22249153 TI - Labour analgesia: a randomised, controlled trial comparing intravenous remifentanil and epidural analgesia with ropivacaine and fentanyl. AB - BACKGROUND AND OBJECTIVE: To compare the analgesic efficacy and side-effects of remifentanil intravenous patient-controlled analgesia (IVPCA) with walking epidural analgesia (EDA) during labour. METHODS: Thirty-nine parturient patients of mixed parity, with normal singleton pregnancies, were randomised to receive either remifentanil IVPCA (RA group) or EDA (EA group). The epidural solution contained ropivacaine 1 mg ml-1 and fentanyl 2 MUg ml-1, and the initial dose was 10 ml h-1. Starting bolus of remifentanil was 0.15 MUg kg-1, with subsequent steps of 0.15 MUg kg-1. Lock-out time was 2 min, bolus infusion speed 2 ml min-1 (100 MUg min-1) and there was no background infusion. Visual analogue scale was used for pain assessment. Maternal heart rate, blood pressure, oxygen saturation, respiratory rate, sedation, nausea/vomiting, itching, satisfaction and fetal/neonatal outcome were recorded. RESULTS: Thirty-seven parturient patients were analysed. Both treatments provided good analgesia, but with higher pain scores in the RA group. Pain reduction at the end of first and during second stage and maximum pain reduction were similar (RA/EA group): 27/26 (P = 0.920), 31/29 (P = 0.909) and 61/59 (P = 0.855), respectively. Maternal satisfaction was similar. Two parturients receiving remifentanil (6%) converted to epidural, one because of inadequate analgesia. Remifentanil produced more maternal sedation, desaturation (SaO2 < 92%) and need for supplemental oxygen. Neonatal outcome was reassuring. Highest mean total dose of remifentanil was 0.70 MUg kg-1 (range 0.30 1.05). CONCLUSION: Remifentanil IVPCA and epidural provided effective analgesia, with high maternal satisfaction scores and reassuring neonatal outcome. Remifentanil produced more maternal sedation and oxygen desaturation. Close monitoring is, therefore, mandatory. PMID- 22249154 TI - Meta-analysis: the importance of a proper search strategy. PMID- 22249155 TI - International reporting scale of BCR-ABL1 fusion transcript in chronic myeloid leukemia: first report from India. AB - Achieving a major molecular response (MMR) is an important predictor of progression-free survival in chronic myeloid leukemia patients treated with imatinib. This requires accurate measurement of BCR-ABL1 transcripts normalized to a control gene, as well as defining a level (BCR-ABL1/control gene ratio) that will correlate with sustained clinical response. To make these measurements comparable between laboratories, an international scale (IS) is necessary. A BCR ABL1/control gene ratio of 0.10% represents MMR in the IS. In collaboration with an international reference laboratory in Adelaide, S.A., Australia, we have established and validated a lab-specific conversion factor for expressing BCR ABL1 transcript levels in the IS. In this report, we explain the process and steps involved in obtaining a valid lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS. PMID- 22249156 TI - Electromagnetic irradiation may be a new approach to therapy for peri implantitis. AB - Peri-implantitis can lead to bone destruction around a dental implant through inflammation and immune reactions caused by bacteria adhering to the surface of the implant abutment. Electromagnetic irradiation can inhibit bacterial growth, increase bone formation, decrease bone resorption and reduce the inflammatory response. Our hypothesis is that electromagnetic irradiation may be a new treatment approach for peri-implantitis and may simultaneously maintain bone mass around the dental implant. The results would be more significant when combined with other agents, because the effect of some antibiotics and anti-inflammatory drugs is strengthened by electromagnetic irradiation. This non-invasive therapy is expected to be conducted in a convenient manner, and even by patients at home, thereby facilitating the prevention and treatment of peri-implantitis. PMID- 22249157 TI - Medial prefrontal cortical innervation of the intercalated nuclear region of the amygdala. AB - The projections of the infralimbic area (IL) of the medial prefrontal cortex to the intercalated nuclei (ICNs) of the amygdala are thought to form a critical component of the forebrain circuitry for fear extinction. Despite the importance of these projections, there have been no focussed anatomical studies that have investigated the extent of IL inputs to different portions of the ICN complex. The present investigation used anterograde tract tracing in the rat to study the projections of the ventromedial PFC, including the IL, to the ICNs and surrounding amygdalar regions. Immunohistochemistry for the MU-opioid receptor (MOR) was used to identify the ICNs. At rostral levels of the amygdala there was a very dense projection to a far lateral portion of the capsular subdivision of the central nucleus (CLC) located between the main and medial ICNs, but only very light projections to these ICNs and the lateral ICNs. This distinct portion of the CLC receiving strong IL inputs was termed the capsular infralimbic target zone (CITZ), and was MOR-negative. Likewise, at more caudal levels of the amygdala, IL projections to the medial, lateral, and dorsal ICNs were light to moderate compared with projections to adjacent portions of the basolateral amygdala and amygdalostriatal transitional area. These findings suggest that the putative role of the IL-to-ICN connection in fear inhibition may be mediated by light to moderate projections from the IL to the medial ICN, and that the CITZ may be an equally important amygdalar target for this function. PMID- 22249158 TI - Inverted-U function relating cortical plasticity and task difficulty. AB - Many psychological and physiological studies with simple stimuli have suggested that perceptual learning specifically enhances the response of primary sensory cortex to task-relevant stimuli. The aim of this study was to determine whether auditory discrimination training on complex tasks enhances primary auditory cortex responses to a target sequence relative to non-target and novel sequences. We collected responses from more than 2000 sites in 31 rats trained on one of six discrimination tasks that differed primarily in the similarity of the target and distractor sequences. Unlike training with simple stimuli, long-term training with complex stimuli did not generate target-specific enhancement in any of the groups. Instead, cortical receptive field size decreased, latency decreased, and paired pulse depression decreased in rats trained on the tasks of intermediate difficulty, whereas tasks that were too easy or too difficult either did not alter or degraded cortical responses. These results suggest an inverted-U function relating neural plasticity and task difficulty. PMID- 22249160 TI - Vapor detection enabled by self-assembled colloidal photonic crystals. AB - Here we report the sensitive and reversible detection of vapors by using self assembled colloidal photonic crystals. The condensation of various vapors in the interstitials of silica colloidal photonic crystals leads to red-shift and amplitude reduction of optical stop bands. A linear relationship between wavelength shift and vapor partial pressure has been observed for a variety of vapors including ethanol, water, and toluene. Importantly, the sensitivity of colloidal photonic crystal-based vapor detectors can be improved by nearly two orders of magnitude by using a new full-peak analysis technique that takes advantage of the manifest amplitude reduction of optical stop bands during vapor condensation. Optical simulation based on a scalar-wave approximation model shows that the predicted optical responses during vapor condensation in colloidal photonic crystals agree well with experimental results. The condensation of vapors between submicrometer-scale microspheres, a topic that has received little examination, has also been investigated by both experiments and theoretical calculations. Predictions based on a modified Kelvin equation match with the experiments for a wide range of vapor partial pressures. PMID- 22249159 TI - AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications. AB - The abnormal BCR-ABL oncoprotein is a constitutively active tyrosine kinase driving aberrant proliferation of transformed hematopoietic cells. BCR-ABL regulates activation of many mitogenic and pro-survival pathways, including the PI 3'K/AKT/mTOR pathway that controls various effectors and regulates initiation of mRNA translation in mammalian cells. Although tyrosine kinase inhibitors (TKIs) that target the ABL kinase domain have remarkable clinical activity and have dramatically changed the natural history of Ph+ leukemias, resistance to these agents also develops via a wide range of mechanisms. Efforts to target the PI3'K/AKT/mTOR signaling pathway using kinase inhibitors have been the focus of extensive ongoing investigations by several research groups. Here we review the effects of activation of the AMPK kinase, which regulates downstream targeting and inhibition of mTOR. The potential for future clinical-translational applications of AMPK activators such as AICAR, metformin and resveratrol for the treatment of chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) are discussed. PMID- 22249161 TI - Imaging: Dual-energy CT useful when assessing tophaceous gout. PMID- 22249163 TI - What is the clinical relevance of erosions and joint space narrowing in RA? AB - The association between joint damage and disability in rheumatoid arthritis (RA), especially in the later stages of disease, is a main reason why radiographic joint damage is a common and valid outcome measure in RA clinical trials. Most studies have assessed the effect of global joint damage, which has limited our knowledge regarding the individual effects of erosions and cartilage damage on physical function. However, recent data have indicated that joint space narrowing is more closely related to functional status than erosions. Modern imaging techniques that provide improved assessment of the cartilage itself, instead of only joint space narrowing, might help disentangle the separate associations of erosive bone damage and cartilage damage with physical function in patients with RA. The aim of this article is to discuss the current knowledge within this field and the clinical consequences thereof. PMID- 22249162 TI - Osteoporosis, frailty and fracture: implications for case finding and therapy. AB - In almost all patients with incident fractures, the absolute risk of subsequent fracture and mortality is highest immediately after the fracture is incurred; the risk is substantially increased in frail elderly patients. The risk factors for incident fractures, such as bone fragility, tendency to fall and the presence of metabolic bone disease, remain underdiagnosed and undertreated. Here, we review the evidence that demonstrates the influence of these risk factors on susceptibility to subsequent fracture and mortality after an incident fracture, and discuss the tools available to predict these outcomes. In this Review, we also propose a systematic, coordinator-based approach to assessment of risk, allocation of treatment and follow-up in all patients over 50 years of age who present with a fracture. The aim of this proposed multistep procedure is to improve the prevention of secondary fracture, decrease mortality rates and reduce patient undertreatment or overtreatment. PMID- 22249164 TI - Strong association between mRNA folding strength and protein abundance in S. cerevisiae. AB - One of the open questions in regulatory genomics is how the efficiency of gene translation is encoded in the coding sequence. Here we analyse recently generated measurements of folding energy in Saccharomyces cerevisiae, showing that genes with high protein abundance tend to have strong mRNA folding (mF; R=0.68). mF strength also strongly correlates with ribosomal density and mRNA levels, suggesting that this relation at least partially pertains to the efficiency of translation elongation, presumably by preventing aggregation of mRNA molecules. PMID- 22249166 TI - Ultra-sensitive mid-infrared evanescent field sensors combining thin-film strip waveguides with quantum cascade lasers. AB - We demonstrate ultra-sensitive chemical sensing in the mid-infrared spectral regime with a combination of quantum cascade lasers (QCLs) with GaAs/Al(0.2)Ga(0.8)As strip waveguides fabricated via metal-organic vapor-phase epitaxy (MOVPE) and reactive ion etching (RIE) using evanescent field absorption spectroscopy. These strip waveguides have been designed with a width of 200 MUm, thereby facilitating 2-D confinement and mode-matched propagation of mid-infrared radiation emitted from a distributed feedback (DFB) QCL at a wavelength of 10.3 MUm. Acetic anhydride was detected with a limit of detection (LOD) of 18 pL (19.4 ng) deposited at the waveguide surface by overlapping of the vibrational absorption of the methyl group with the emission frequency of the QCL. The obtained results indicate a remarkable enhancement in sensitivity by three orders of magnitude compared to previously reported multimode planar silver halide waveguides. Further reduction of the waveguide strip width to 50 MUm resulted in an additional sensitivity enhancement yielding a calculated LOD of 0.05 pL for the exemplary analyte acetic anhydride, which is among the most sensitive evanescent field absorption measurements with a miniaturized mid-infrared sensor system reported to date. PMID- 22249165 TI - Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. AB - Autophagy degrades cytoplasmic contents to achieve cellular homeostasis. We show that selective loss of autophagy in hypothalamic proopiomelanocortin (POMC) neurons decreases alpha-melanocyte-stimulating hormone (MSH) levels, promoting adiposity, impairing lipolysis and altering glucose homeostasis. Ageing reduces hypothalamic autophagy and alpha-MSH levels, and aged-mice phenocopy, the adiposity and lipolytic defect observed in POMC neuron autophagy-null mice. Intraperitoneal isoproterenol restores lipolysis in both models, demonstrating normal adipocyte catecholamine responsiveness. We propose that an unconventional, autophagosome-mediated form of secretion in POMC neurons controls energy balance by regulating alpha-MSH production. Modulating hypothalamic autophagy might have implications for preventing obesity and metabolic syndrome of ageing. PMID- 22249167 TI - Update on management of frontal sinus osteomas. AB - PURPOSE OF REVIEW: Endoscopic approaches are used increasingly as an alternative to external approaches in removal of frontal sinus osteoma. The purpose of this article is to review and highlight the recent articles on the management of frontal sinus osteoma over the past 24 months. RECENT FINDINGS: The evolution in endoscopic sinus surgery has allowed rhinologists to expand its indications in managing a wide range of frontal sinus pathologies, including frontal sinus osteomas. The surgeons are attempting endoscopic removal of higher grades of osteomas from frontal sinus, previously thought to be amenable only to external approach on its own or combined with endoscopic approach. Although recent retrospective studies have reported such successful attempts, open approaches, particularly osteoplastic flap, remain an important surgical technique when endoscopic approaches are limited. SUMMARY: The endoscopic approach is effective in surgical management of low-grade osteomas. For higher-grade (grade III and IV) osteomas endoscopic removal is technically challenging and requires availability of advanced instrumentation, including surgical navigation systems, along with surgical expertise.Open approaches to frontal sinus, particularly osteoplastic flap approach, are still valuable as it is a simple and well tolerated method for complete removal of higher-grade osteomas. PMID- 22249168 TI - The value of quality-of-life questionnaires in head and neck cancer. AB - PURPOSE OF REVIEW: To review the recent literature on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients. RECENT FINDINGS: HRQOL is an important part of well designed clinical trials. HRQOL seems to be an independent predictor of survival, but this association may be influenced by various cancer related, personal, biological, psychobehavioural, physical, lifestyle-related, and social factors. Less is known about the course of HRQOL over time and about the same above-mentioned possible factors associated with (change in) HRQOL of HNC patients. Symptom management and psychosocial care may be beneficial for HNC patients to improve HRQOL, but more randomized controlled trials are needed. Studies on HRQOL in HNC are most often based on cross-sectional designs. The variability in the outcome measures hampers the generalizability of the results of these studies. Information on HRQOL of caregivers is scarce. SUMMARY: Better information on all aspects of the course of HRQOL from diagnosis and treatment to long-term survivorship or death is highly needed in both patients and their caregivers, enabling reliable and valid predictive modelling. More evidence of efficacy of (new) treatment options, symptom management, and psychosocial care is needed, also in the context of increasing long-term survival and growing attention for cancer survivorship. PMID- 22249169 TI - Treatment of hypopharyngeal carcinoma with primary chemoradiotherapy: functional morbidity. AB - PURPOSE OF REVIEW: This review aims at unravelling the medical literature which has reported on the treatment of 'larynx preserving' chemoradiotherapy strategies and separating the treatment sites, larynx and hypopharynx, from each other and reporting on the adverse effects and functional outcomes of patients with hypopharyngeal cancer. RECENT FINDINGS: The literature reports on the treatment of advanced laryngeal and hypopharyngeal cancer with chemoradiotherapy together as a 'common cancer site'. Although the chemotherapeutic drugs affect the tumour and the normal tissues similarly in both the larynx and hypopharynx, their effects on the patient groups are different, mainly affecting swallow, airway protection mechanisms and voice/speech to a greater or lesser extent. Pretreatment symptoms and function should be documented subjectively and objectively prior to commencing nonsurgical treatment. Hypopharyngeal cancer should be reported separately, and preferably stratified into the three subsites, according to the T stage of disease rather than TNM stage. Equipment for such testing and the process for such documentation are available in most clinical areas, worldwide. SUMMARY: Future analysis relies on the conscientious monitoring of adverse effects of all treatment modalities and an assessment of function as well as quality of life impact on the patient. Thus, the specialty can make informed decisions on the most appropriate and most suitable mode of treatment for individual patients based upon their tumour, their preoperative organ function, their likely future organ function and the likelihood of cure. PMID- 22249170 TI - Facial reanimation after nerve sacrifice in the treatment of head and neck cancer. AB - PURPOSE OF REVIEW: This article reviews literature on the facial reanimation technique, from direct facial nerve repair and grafting to neuromuscular-free transplantation. The discussion will focus on the indications of the different approaches based on timing of the facial palsy and on patient's features. RECENT FINDINGS: Facial nerve coaptation technique with masseteric nerve, babysitter procedures, and neuromuscular transplantation represent today the gold standard for facial reanimation after facial nerve sacrifice. Surgeon's experience and patient selection have to be considered as other important factors for surgical approach selection. SUMMARY: Facial animation represents a difficult challenge for the reconstructive surgeon. A large number of surgical techniques and modifications have been published, and the appropriate approach must be selected based on the kind of facial palsy, its timing, and the patient's age, prognosis, and general condition. A complete grasp of all the approaches that allows for a target surgery represents today an essential assumption for the facial reanimation. PMID- 22249171 TI - Transoral laser surgery for hypopharyngeal carcinomas. AB - PURPOSE OF REVIEW: Organ preservation strategies are a major focus of interest in head and neck cancer. There are two ways to preserve the function in the treatment of squamous cell carcinomas of the hypopharynx: organ-sparing surgery or neoadjuvant or concomitant chemoradiotherapy. From the surgical point of view, the possibilities of organ sparing have been increased with the use of transoral carbon dioxide laser surgery. Our purpose is to review this technique as a preservation surgical strategy for hypopharyngeal carcinomas. RECENT FINDINGS: The role of primary surgery in the initial treatment of head and neck carcinomas is being reviewed. The transoral laser resection of hypopharyngeal carcinomas is the least established of the transoral laser surgical approaches. Recent data suggest that selected hypopharyngeal tumors may be treated with transoral laser surgery, achieving very good oncologic and functional outcomes. SUMMARY: Transoral carbon dioxide laser surgery is an alternative to treat hypopharyngeal carcinomas. Early tumors may be removed by a transoral approach with high local control rates and function preservation in most of the patients. For more advanced tumors experience is still limited, and the role of this technique has not yet been defined. PMID- 22249172 TI - Evidence based and new developments in re-irradiation for recurrent or second primary head and neck cancers. AB - PURPOSE OF REVIEW: The standard treatment for recurrent or second primary head and neck cancers is surgery which can only be performed in 25% of the patients. For inoperable patients, three options can be discussed: supportive care only, chemotherapy or radiotherapy with or without chemotherapy. The goal of this article is to review the indications and new developments in re-irradiation for recurrent or second primary head and neck cancers. RECENT FINDINGS: The le Groupe d'Etude des Tumeurs de la Tete et du Cou (GETTEC)-le Groupe d'Oncologie et de Radiotherapie Tete et Cou (GORTEC) (99-01) trial showed that radio-chemotherapy improved disease-free survival for a highly selected population. All conventional and conformational radiotherapy series showed improved local control and disease free survival rates, but at the expense of acute and late toxicities demanding a drastic patients selection. New radiotherapy techniques such as intensity modulated radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT) have improved oncological results with reduced toxicities, offering treatments which are spread over six to seven weeks for IMRT and two weeks for SBRT. SUMMARY: Re irradiation is an attractive alternative treatment for selected inoperable patients and its effectiveness can be potentiated by systemic treatments such as chemotherapy or targeted therapy. The development of new radiotherapy techniques such as IMRT and SBRT has improved healthy tissues tolerance and future studies should help define the specific IMRT and SBRT indications. PMID- 22249173 TI - Endoscopic vidian neurectomy: update on techniques and evidence. AB - PURPOSE OF REVIEW: The aim of this work, based on a recent review of the literature, is to update the surgical techniques for endoscopic vidian neurectomy (EVN). RECENT FINDINGS: Traditionally, vidian neurectomy was performed on the orifice of the vidian canal on the posterior surface of the pterygopalatine fossa (PPF) through an open approach. A major advance in vidian neurectomy is to transect the vidian nerve endoscopically. In the past 2 decades, EVN has been developed and has replaced the traditional open approach because of improved visualization of the vidian nerve and the less invasive procedure. In addition, computed tomographic (CT) scanning has become a routine evaluation tool for EVN. SUMMARY: In the past decade, there has been renewed interest in the procedure of vidian neurectomy because endoscopic techniques have greatly improved. The recent evolution of EVN improves the surgical visualization of the vidian nerve and minimizes surgical complications. Preoperative CT imaging is a key element in determining the surgical approach. This study reviews the literature and summarizes the preferred vidian nerve exposure, recent technical refinements, and our current surgical approach. PMID- 22249174 TI - Left main pentaforcation: an uncommon coronary variant detected by multidetector computed tomography. PMID- 22249175 TI - Vagoglossopharyngeal neuralgia treated by microvascular decompression and glossopharyngeal rhizotomy: clinical results of 21 cases. AB - BACKGROUND: Microvascular decompression (MVD) and rhizotomy are all selected for treating vagoglossopharyngeal neuralgia (VGPN). Nonetheless, controversies still exist about their curative effect on VGPN. Here we evaluate the effectiveness of MVD together with rhizotomy of the glossopharyngeal nerve for the treatment of VGPN. METHODS: This study was carried out on 21 patients who were diagnosed with VGPN between the years 2005 and 2010. Patients underwent MVD and glossopharyngeal rhizotomy through a retromastoid keyhole approach. Surgical technique, operation results and complications were our particular concern. RESULTS: Eighteen (85.7%) of 21 patients experienced immediate and complete relief of pain after surgery. In the remaining 3 patients (14.3%), the pain faded away within the following week. No patient complained of dysphonia or dysphagia. All 21 patients reported no change in their outcome at follow-up. CONCLUSIONS: Intracranial vagoglossopharyngeal nerve MVD with glossopharyngeal rhizotomy is an effective and safe procedure to treat VGPN. PMID- 22249176 TI - Nano-indentation of a room-temperature ionic liquid film on silica: a computational experiment. AB - We investigate the structure of the [bmim][Tf(2)N]/silica interface by simulating the indentation of a thin (4 nm) [bmim][Tf(2)N] film by a hard nanometric tip. The ionic liquid/silica interface is represented in atomistic detail, while the tip is modelled by a spherical mesoscopic particle interacting via an effective short-range potential. Plots of the normal force (F(z)) on the tip as a function of its distance from the silica surface highlight the effect of weak layering in the ionic liquid structure, as well as the progressive loss of fluidity in approaching the silica surface. The simulation results for F(z) are in near quantitative agreement with new AFM data measured on the same [bmim][Tf(2)N]/silica interface under comparable thermodynamic conditions. PMID- 22249177 TI - Photosensitization of DNA by beta-carbolines: kinetic analysis and photoproduct characterization. AB - beta-Carbolines (betaCs) are a group of alkaloids present in many plants and animals. It has been suggested that these alkaloids participate in a variety of significant photosensitized processes. Despite their well-established natural occurrence, the main biological role of these alkaloids and the mechanisms involved are, to date, poorly understood. In the present work, we examined the capability of three important betaCs (norharmane, harmane and harmine) and two of its derivatives (N-methyl-norharmane and N-methyl-harmane) to induce DNA damage upon UV-A excitation, correlating the type and extent of the damage with the photophysical characteristics and DNA binding properties of the compounds. The results indicate that DNA damage is mostly mediated by a direct type-I photoreaction of the protonated betaCs after non-intercalative electrostatic binding. Reactive oxygen species such as singlet oxygen and superoxide are not involved to a major extent, as indicated by the only small influence of D(2)O and of superoxide dismutase on damage generation. An analysis with repair enzymes revealed that oxidative purine modifications such as 8-oxo-7,8-dihydroguanine, sites of base loss and single-strand breaks (SSB) are generated by all betaCs, while only photoexcited harmine gives rise to the formation of cyclobutane pyrimidine dimers as well. PMID- 22249178 TI - Structural analysis of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) intracellular domain reveals a conserved interaction epitope. AB - Plasmodium falciparum-infected red blood cells adhere to endothelial cells, thereby obstructing the microvasculature. Erythrocyte adherence is directly associated with severe malaria and increased disease lethality, and it is mediated by the PfEMP1 family. PfEMP1 clustering in knob-like protrusions on the erythrocyte membrane is critical for cytoadherence, however the molecular mechanisms behind this system remain elusive. Here, we show that the intracellular domains of the PfEMP1 family (ATS) share a unique molecular architecture, which comprises a minimal folded core and extensive flexible elements. A conserved flexible segment at the ATS center is minimally restrained by the folded core. Yeast-two-hybrid data and a novel sequence analysis method suggest that this central segment contains a conserved protein interaction epitope. Interestingly, ATS in solution fails to bind the parasite knob associated histidine-rich protein (KAHRP), an essential cytoadherence component. Instead, we demonstrate that ATS associates with PFI1780w, a member of the Plasmodium helical interspersed sub-telomeric (PHIST) family. PHIST domains are widespread in exported parasite proteins, however this is the first specific molecular function assigned to any variant of this family. We propose that PHIST domains facilitate protein interactions, and that the conserved ATS epitope may be targeted to disrupt the parasite cytoadherence system. PMID- 22249179 TI - New molecular bridge between RelA/p65 and NF-kappaB target genes via histone acetyltransferase TIP60 cofactor. AB - The nuclear factor-kappaB (NF-kappaB) family is involved in the expressions of numerous genes, in development, apoptosis, inflammatory responses, and oncogenesis. In this study we identified four NF-kappaB target genes that are modulated by TIP60. We also found that TIP60 interacts with the NF-kappaB RelA/p65 subunit and increases its transcriptional activity through protein protein interaction. Although TIP60 binds with RelA/p65 using its histone acetyltransferase domain, TIP60 does not directly acetylate RelA/p65. However, TIP60 maintained acetylated Lys-310 RelA/p65 levels in the TNF-alpha-dependent NF kappaB signaling pathway. In chromatin immunoprecipitation assay, TIP60 was primarily recruited to the IL-6, IL-8, C-IAP1, and XIAP promoters in TNF-alpha stimulation followed by acetylation of histones H3 and H4. Chromatin remodeling by TIP60 involved the sequential recruitment of acetyl-Lys-310 RelA/p65 to its target gene promoters. Furthermore, we showed that up-regulated TIP60 expression was correlated with acetyl-Lys-310 RelA/p65 expressions in hepatocarcinoma tissues. Taken together these results suggest that TIP60 is involved in the NF kappaB pathway through protein interaction with RelA/p65 and that it modulates the transcriptional activity of RelA/p65 in NF-kappaB-dependent gene expression. PMID- 22249180 TI - The Drosophila juvenile hormone receptor candidates methoprene-tolerant (MET) and germ cell-expressed (GCE) utilize a conserved LIXXL motif to bind the FTZ-F1 nuclear receptor. AB - Juvenile hormone (JH) has been implicated in many developmental processes in holometabolous insects, but its mechanism of signaling remains controversial. We previously found that in Drosophila Schneider 2 cells, the nuclear receptor FTZ F1 is required for activation of the E75A gene by JH. Here, we utilized insect two-hybrid assays to show that FTZ-F1 interacts with two JH receptor candidates, the bHLH-PAS paralogs MET and GCE, in a JH-dependent manner. These interactions are severely reduced when helix 12 of the FTZ-F1 activation function 2 (AF2) is removed, implicating AF2 as an interacting site. Through homology modeling, we found that MET and GCE possess a C-terminal alpha-helix featuring a conserved motif LIXXL that represents a novel nuclear receptor (NR) box. Docking simulations supported by two-hybrid experiments revealed that FTZ-F1.MET and FTZ F1.GCE heterodimer formation involves a typical NR box-AF2 interaction but does not require the canonical charge clamp residues of FTZ-F1 and relies primarily on hydrophobic contacts, including a unique interaction with helix 4. Moreover, we identified paralog-specific features, including a secondary interaction site found only in MET. Our findings suggest that a novel NR box enables MET and GCE to interact JH-dependently with the AF2 of FTZ-F1. PMID- 22249183 TI - Male factor infertility in 2011: semen quality, sperm selection and hematospermia. PMID- 22249184 TI - Surgery: laparoscopic promontofixation is safe and effective for POP. PMID- 22249185 TI - Male factor infertility: effects of ROS and vitamin E on sperm. PMID- 22249187 TI - Prostate cancer in 2011: redefining the therapeutic landscape for CRPC. PMID- 22249189 TI - Prostate cancer: resveratrol and apoptotic proteins enhance radiosensitivity. PMID- 22249191 TI - Incontinence: should we inject the trigone during botulinum toxin injection? PMID- 22249190 TI - Epigenetic regulation in RCC: opportunities for therapeutic intervention? AB - Renal cell carcinoma (RCC) is a constellation of malignancies of different histological subtypes arising from the renal parenchyma. The clear cell histological subtype (ccRCC) accounts for around 75% of RCCs and is characterized by distinct genetic abnormalities, of which the loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is the most common. Inactivation of other tumor suppressor genes such as SETD2, KDM6A, KDM5C and PBRM1 has been reported in ccRCC--notably, the proteins encoded by these genes are involved in histone and chromatin regulation. Furthermore, the PBRM1 and SETD2 genes are located on the short arm of chromosome 3 near the VHL locus. Chromatin and histones modify gene expression and, as a consequence, their function is tightly regulated. Data from RNA interference (RNAi) assays suggest that loss of function of PBRM1 drives proliferation and growth of ccRCC, but the clinical relevance of this is unclear and restoring the function of these genes for therapeutic purposes is likely to be challenging. An improved understanding of histone and chromatin regulation in RCC biology and the consequences of intratumor heterogeneity might identify novel targets in RCC and present alternative therapeutic opportunities. PMID- 22249192 TI - Basic research: GAGging the leaky bladder in IC. PMID- 22249194 TI - The emerging role of diffusion-weighted MRI in prostate cancer management. AB - A significant amount of research has focused on the role of diffusion-weighted MRI (DW-MRI) in the management of patients with prostate cancer. Although uncertainties remain, a clearer picture of where this technique fits into clinical practice is now available. A combination of DW-MRI and T2-weighted MRI (T2W-MRI) demonstrates improved accuracy for lesion detection and localization compared with T2W-MRI alone, and has been suggested as a tool to guide tissue biopsy. DW-MRI could also have roles in active surveillance, evaluating treatment efficacy, and predicting disease recurrence. Furthermore, DW-MRI offers the exciting possibility of gathering information about tumor characteristics and aggressiveness in a noninvasive manner. Validation in large prospective multicenter trials is critical if this technique is to be integrated into current management algorithms for prostate cancer. PMID- 22249195 TI - Optical probes and techniques for O2 measurement in live cells and tissue. AB - In recent years, significant progress has been achieved in the sensing and imaging of molecular oxygen (O(2)) in biological samples containing live cells and tissue. We review recent developments in the measurement of O(2) in such samples by optical means, particularly using the phosphorescence quenching technique. The main types of soluble O(2) sensors are assessed, including small molecule, supramolecular and particle-based structures used as extracellular or intracellular probes in conjunction with different detection modalities and measurement formats. For the different O(2) sensing systems, particular attention is paid to their merits and limitations, analytical performance, general convenience and applicability in specific biological applications. The latter include measurement of O(2) consumption rate, sample oxygenation, sensing of intracellular O(2), metabolic assessment of cells, and O(2) imaging of tissue, vasculature and individual cells. Altogether, this gives the potential user a comprehensive guide for the proper selection of the appropriate optical probe(s) and detection platform to suit their particular biological applications and measurement requirements. PMID- 22249196 TI - Transcriptional control of glutamatergic differentiation during adult neurogenesis. AB - Neurogenesis, the production of new neurons, occurs in two specialized niches in the adult brain, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. In the SGZ, neural stem cells (NSCs) give rise to glutamatergic granule neurons that integrate into the granule cell layer. In the SVZ, NSCs generate a more diverse cohort of new neurons, including GABAergic, dopaminergic, and glutamatergic neurons, all of which migrate to the olfactory bulb through the rostral migratory stream. In both adult neurogenic niches, specific transcription factors have been shown to direct fate specification and lineage commitment. This review summarizes current progress on the transcriptional control of glutamatergic neurogenesis in the SGZ and SVZ, highlighting commonalities as well as differences in their transcriptional programs. In particular, we focus on work from our laboratory and others indicating that precise, sequential expression of transcription factors regulates the progression from NSC to lineage-committed progenitor, and ultimately regulates the production and differentiation of adult-born glutamatergic neurons. PMID- 22249197 TI - Severe asthma in childhood: recent advances in phenotyping and pathogenesis. AB - PURPOSE OF REVIEW: Children with severe asthma have a high degree of respiratory morbidity despite treatment with high doses of inhaled corticosteroids and are therefore very difficult to treat. This review will discuss phenotypic and pathogenic aspects of severe asthma in childhood, as well as remaining knowledge gaps. RECENT FINDINGS: As a group, children with severe asthma have a number of distinct phenotypic features compared with children with mild-to-moderate asthma. Clinically, children with severe asthma are differentiated by greater allergic sensitization, increased exhaled nitric oxide, and significant airflow limitation and air trapping that worsens as a function of age. These findings are accompanied by structural airway changes and increased and dysregulated airway inflammation and oxidant stress which may explain the differential nature of corticosteroid responsiveness in this population. Because children with severe asthma themselves are a heterogeneous group, current efforts are focused on improved definition and sub-phenotyping of the disorder. Whereas the clinical relevance of phenotyping approaches in severe asthma is not yet clear, they may provide important insight into the mechanisms underlying the disorder. SUMMARY: Improved classification of severe asthma through unified definitions, careful phenotypic analyses, and mechanism-focused endotyping approaches may ultimately advance knowledge and personalized treatment. PMID- 22249198 TI - Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer. AB - The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate, and maintenance of stem cells in several tissues. Aberrant activation of Notch signaling has been described in several tumours and in gastric cancer (GC), activated Notch1 has been associated with de-differentiation of lineage committed stomach cells into stem progenitors and GC progression. However, the specific role of the Notch1 ligand DLL1 in GC has not yet been elucidated. To assess the role of DLL1 in GC cancer, the expression of Notch1 and its ligands DLL1 and Jagged1, was analyzed in 8 gastric cancer cell lines (KATOIII, SNU601, SNU719, AGS, SNU16, MKN1, MKN45, TMK1). DLL1 expression was absent in KATOIII, SNU601, SNU719 and AGS. The lack of DLL1 expression in these cells was associated with promoter hypermethylation and 5-aza-2'dC caused up-regulation of DLL1. The increase in DLL1 expression was associated with activation of Notch1 signalling, with an increase in cleaved Notch1 intracellular domain (NICD) and Hes1, and down regulation in Hath1. Concordantly, Notch1 signalling was activated with the overexpression of DLL1. Moreover, Notch1 signalling together with DLL1 methylation were evaluated in samples from 52 GC patients and 21 healthy control as well as in INS-GAS mice infected with H. pylori and randomly treated with eradication therapy. In GC patients, we found a correlation between DLL1 and Hes1 expression, while DLL1 methylation and Hath1 expression were associated with the diffuse and mixed type of gastric cancer. Finally, none of the samples from INS GAS mice infected with H. pylori, a model of intestinal-type gastric tumorigenesis, showed promoter methylation of DLL1. This study shows that Notch1 activity in gastric cancer is controlled by the epigenetic silencing of the ligand DLL1, and that Notch1 inhibition is associated with the diffuse type of gastric cancer. PMID- 22249199 TI - Pathogenicity and proteomic signatures of autoantibodies to Ro and La. AB - Ro/SSA and La/SSB comprise a linked set of autoantigens that are clinically important members of the extractable nuclear antigen family and key translational biomarkers for lupus and primary Sjogren's syndrome. Autoantibodies directed against the Ro60 and La polypeptide components of the Ro/La ribonucleoprotein complex, and the structurally unrelated Ro52 protein, mediate tissue damage in the neonatal lupus syndrome, a model of passively acquired autoimmunity in humans in which the most serious manifestation is congenital heart block (CHB). Recent studies have concentrated on two distinct pathogenic mechanisms by which maternal anti-Ro/La autoantibodies can cause CHB: by forming immune complexes with apoptotic cells in developing fetal heart; and/or by acting as functional autoantibodies that cross-react with and inhibit calcium channels. Although the precise role of the individual autoantibodies is yet to be settled, maternal anti Ro60 and anti-Ro52 remain the most likely culprits. This article will discuss the molecular pathways that culminate in the development of CHB, including the recent discovery of beta2 glycoprotein I as a protective factor, and present a proteomic approach based on direct mass spectrometric sequencing, which may give a more representative snapshot of the idiotype repertoire of these autoantibodies than genomic-based technologies. PMID- 22249200 TI - Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA. AB - Elucidating pathways that regulate cytokine production in the context of autoimmune disease will likely lead to the development of novel therapeutics. Herein, we review data suggesting that microRNAs (miRs) represent one such level of regulatory activity, with particular emphasis on the pathogenesis of rheumatoid arthritis (RA). A series of miRs have been identified to be dysregulated in cell subsets within the articular compartment of patients with RA. These have a critical role in regulating cartilage-invading phenotype of RA synovial fibroblasts. More recently, several studies suggest that miRs also regulate leukocyte activation and cytokine production that in turn contribute to the immunologic component of effector synovial pathology. Together, these observations open an exciting new vista of understanding and therapeutic opportunity for this difficult and common disease. PMID- 22249202 TI - The interplay between endoplasmic reticulum stress and inflammation. AB - Endoplasmic reticulum (ER) stress may be both a trigger and consequence of chronic inflammation. Chronic inflammation is often associated with diseases that arise because of primary misfolding mutations and ER stress. Similarly, ER stress and activation of the unfolded protein response (UPR) is a feature of many chronic inflammatory and autoimmune diseases. In this review, we describe how protein misfolding and the UPR trigger inflammation, how environmental ER stressors affect antigen presenting cells and immune effector cells, and present evidence that inflammatory factors exacerbate protein misfolding and ER stress. Examples from both animal models of disease and human diseases are used to illustrate the complex interactions between ER stress and inflammation, and opportunities for therapeutic targeting are discussed. Finally, recommendations are made for future research with respect to the interaction of ER stress and inflammation. PMID- 22249201 TI - Expression profiles of human interferon-alpha and interferon-lambda subtypes are ligand- and cell-dependent. AB - Recent genome-wide association studies suggest distinct roles for 12 human interferon-alpha (IFN-alpha) and 3 IFN-lambda subtypes that may be elucidated by defining the expression patterns of these sets of genes. To overcome the impediment of high homology among each of the sets, we designed a quantitative real-time PCR assay that incorporates the use of molecular beacon and locked nucleic acid (LNA) probes, and in some instances, LNA oligonucleotide inhibitors. We then measured IFN subtype expression by human peripheral blood mononuclear cells and by purified monocytes, myeloid dendritic cells (mDC), plasmacytoid dendritic cells (pDC), and monocyte-derived macrophages (MDM), and -dendritic cells (MDDC) in response to poly I:C, lipopolysaccharide (LPS), imiquimod and CpG oligonucleotides. We found that in response to poly I:C and LPS, monocytes, MDM and MDDC express a subtype pattern restricted primarily to IFN-beta and IFN lambda1. In addition, while CpG elicited expression of all type I IFN subtypes by pDC, imiquimod did not. Furthermore, MDM and mDC highly express IFN-lambda, and the subtypes of IFN-lambda are expressed hierarchically in the order IFN-lambda1 followed by IFN-lambda2, and then IFN-lambda3. These data support a model of coordinated cell- and ligand-specific expression of types I and III IFN. Defining IFN subtype expression profiles in a variety of contexts may elucidate specific roles for IFN subtypes as protective, therapeutic or pathogenic mediators. PMID- 22249203 TI - ONZIN deficiency attenuates contact hypersensitivity responses in mice. AB - ONZIN is abundantly expressed in immune cells of both the myeloid and lymphoid lineage. Expression by lymphoid cells has been reported to further increase after cutaneous exposure of mice to antigens and haptens capable of inducing contact hypersensitivity (CHS), suggesting that ONZIN has a critical role in this response. Here, we report that indeed ONZIN-deficient mice develop attenuated CHS to a number of different haptens. Dampened CHS responses correlated with a significant reduction in pro-inflammatory IL-6 at the challenge site in ONZIN deficient animals, compared with wild-type controls. Together the study of these animals indicates that loss of ONZIN impacts the effector phase of the CHS response through the regulation of pro-inflammatory factors. PMID- 22249204 TI - Utility of electrochemotherapy in melanoma treatment. AB - PURPOSE OF REVIEW: In the present study, the role of electrochemotherapy (ECT) in the advanced melanoma setting, either as alternative treatment modality to conventional therapies or as palliative care, is reviewed and the perspective to combine ECT with biological response modifiers and immunotherapeutic compounds is discussed. RECENT FINDINGS: ECT refers to the combination of electroporation and administration of anticancer drugs for local treatment of solid neoplasms. Electroporation uses short and intense electric pulses to induce a transient permeabilization of the cell membrane by creation of pores, thus allowing molecules, such as chemotherapeutic agents, to freely diffuse into the cytosol. ECT has shown to be effective and clinically well tolerated in the local control of primary and metastatic solid tumors of diverse histotypes in preclinical and clinical studies, thus, emerging as useful local treatment modality for disseminated superficial melanoma. So far, only a few data on the role of immunological response in ECT-treated patients have been reported. SUMMARY: Treatment regimens combining ECT to biological response modifiers (interleukin-2, interferon) and immunotherapeutic compounds should be further explored in animal and human cancer models; immunotherapy combined to ECT could broaden the therapeutic indications of ECT, by rendering it effective also on distant unreachable or untreated lesions. PMID- 22249205 TI - Analysis of tunnel widening after double-bundle ACL reconstruction. AB - PURPOSE: The purpose of this study was to evaluate the tunnel widening using a multi-planar reformation of MRI (Magnetic Resonance Imaging) in the orientation of the tunnel. The hypotheses of this study were as follows: (1) tunnel widening would be reduced with the above-mentioned technique, (2) the degree of tunnel widening would be different at the site of the tunnels, and (3) the time interval from surgery to MRI acquisition would affect the magnitude of tunnel widening. METHODS: Forty double-bundle ACL reconstructed patients who underwent postoperative MRI were enrolled in this study. The postoperative MRI was performed at 26.7 +/- 7.4 months in terms of time. The tunnel widening was examined using a multi-planar reformation of MRI in the orientation of the tunnel. Site-specific analysis was performed according to the depth (the entrance, mid, and exit portion) and wall (anterior, posterior, medial, and lateral walls). The correlation between MRI and widening was also evaluated. RESULTS: The mean tunnel widening of the femoral AM (Anteromedial), femoral PL (Posterolateral), tibial AM, and tibial PL in terms of the most widened diameter was 1.9 (25.4), 2.1 (30.8), 2.5 (32.8), and 3.2 mm (44.5%), respectively. The tibial PL tunnel showed significant widening than the other tunnels. At the entrance, tunnel widening occurred mostly, followed by the order of the mid and exit portion. Correlation analysis of the time interval of MRI acquisition and tunnel widening showed little association. CONCLUSIONS: Tunnel widening after a double-bundle ACL reconstruction using an outside-in technique with press-fitting of the graft was acceptable compared to previously published studies. The tibial PL tunnel showed the most widening among the 4 tunnels examined with the tunnel entrance being most widened area. LEVEL OF EVIDENCE: Therapeutic case series, Level IV. PMID- 22249207 TI - Ferroportin (SLC40A1) Q248H mutation is associated with lower circulating serum hepcidin levels in Rwandese HIV-positive women. AB - The Q248H mutation in the gene SLC40A1 which encodes for the cellular iron exporter ferroportin is relatively common in Africa. This mutation has been associated with resistance to hepcidin and therefore we hypothesized that iron related parameters and the prevalence of opportunistic infections in HIV might be influenced by the Q248H mutation. We conducted a cross-sectional study among 200 HIV-positive women in the Butare University Teaching Hospital in Rwanda. Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the Q248H mutation. Physical examination was carried out and WHO HIV disease stage classification, complete blood count, CD4 count, indirect measures of iron status, serum hepcidin, and C-reactive protein concentrations were determined. The prevalence of ferroportin Q248H mutation was 6%. Subjects with ferroportin Q248H mutation had significantly higher values for serum ferritin (P = 0.001) and significantly lower values for serum hepcidin (P = 0.001) and transferrin (P = 0.01). Among the 12 HIV + Q248H heterozygotes, 8 suffered from at least one opportunistic infection. There was significantly higher prevalence of pulmonary TB (P = 0.01) and Pneumocystis jiroveci pneumonia (P = 0.02) in subjects with ferroportin Q248H mutation. Low hepcidin levels were found in ferroportin Q248H heterozygotes with HIV infection, notwithstanding the absence of anemia and the higher prevalence of some opportunistic infections. Hepcidin seems to be regulated in a different way in Q248H heterozygotes than is known thus far. PMID- 22249208 TI - Toxoplasmosis after allogeneic stem cell transplantation--a single centre experience. AB - Toxoplasmosis is a rare but possibly underestimated complication following allogeneic stem cell transplantation with a high mortality rate. One reason might be the limitation of the diagnostic instruments relying mainly on imaging and molecular-based techniques. In this report, we present three cases of toxoplasmosis identified among 155 allograft recipients treated at Greifswald University Hospital. Widely disseminated toxoplasmosis was detected post-mortem in two patients allografted for high-risk multiple myeloma. Clinical signs suspicious for toxoplasmosis occurred after days +32 and +75, respectively. In one case, serology and conventional Toxoplasma gondii PCR, targeting the B1 gene, revealed negative results, while in the other patient, toxoplasmosis was not investigated. Both patients received pentamidine for Pneumocystis jirovecii pneumonia (PcP) prophylaxis. The third patient, a 68-year-old woman allografted for AML, developed cerebral toxoplasmosis from day +395 after allogeneic SCT with typical signs in magnetic resonance tomography. Toxoplasma DNA was amplified from one of two samples of cerebrospinal fluid. The patient died of disseminated toxoplasmosis despite immediate initiation of therapy. Retrospective comparative testing of clinical specimens by the conventional T. gondii PCR and by a real time PCR targeting a 529-bp genomic fragment suggests a higher sensitivity of the latter method in our patients. In conclusion, we suggest a rigorous real-time PCR monitoring for high-risk patients or patients with signs of infections suspicious for toxoplasmosis, even though low-copy results are presently difficult to interpret. Our reported cases might also encourage the use of trimethoprim sufmethoxazole instead of pentamidine for PcP prophylaxis in those patients. PMID- 22249206 TI - Epigenetic regulation of genomic integrity. AB - Inefficient and inaccurate repair of DNA damage is the principal cause of DNA mutations, chromosomal aberrations, and carcinogenesis. Numerous multiple-step DNA repair pathways exist whose deployment depends on the nature of the DNA lesion. Common to all eukaryotic DNA repair pathways is the need to unravel the compacted chromatin structure to facilitate access of the repair machinery to the DNA and restoration of the original chromatin state afterward. Accordingly, our cells utilize a plethora of coordinated mechanisms to locally open up the chromatin structure to reveal the underlying DNA sequence and to orchestrate the efficient and accurate repair of DNA lesions. Here we review changes to the chromatin structure that are intrinsic to the DNA damage response and the available mechanistic insight into how these chromatin changes facilitate distinct stages of the DNA damage repair pathways to maintain genomic stability. PMID- 22249209 TI - Association of CD20 levels with clinicopathological parameters and its prognostic significance for patients with DLBCL. AB - Diffuse large B-cell lymphomas (DLBCL) express CD20. CD20 expression is described as negative, weak, or normal as determined by flow cytometry (FCM) and is an important target for the treatment of DLBCL. However, the impact of CD20 levels at onset of the disease on patient prognosis has not been fully elucidated. We analyzed 174 DLBCL cases newly diagnosed between January 1998 and April 2010. The relationship of the association between CD20 levels and patients' backgrounds and prognoses was analyzed using the Kaplan-Meier method and Cox proportional hazard regression. Of the 174 patients, three cases (1.7%) were defined as CD20 negative based on immunohistochemistry (IHC). Although the other 171 cases were positive by IHC, eight cases (4.7%) were defined as negative and 33 cases (19.3%) were defined as weak when analyzed by FCM. Of the 105 patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy, those who were CD20 negative (FCM) showed significantly inferior overall (hazard ratios (HR): 6.79, 95% CI: 1.32-34.96, p = 0.04) and progression-free survival (HR: 7.3, 95% CI: 1.49-35.8, p = 0.04) compared to patients who were CD20 normal. Our findings indicate that the CD20 level (FCM) at onset is an independent predictor of the prognosis of patients with DLBCL. PMID- 22249210 TI - Adult onset of primary hemophagocytic syndrome in subjects carrying PRF1 mutations. PMID- 22249211 TI - Photorelease of tyrosine from alpha-carboxy-6-nitroveratryl (alphaCNV) derivatives. AB - The synthesis of photolabile tyrosine derivatives protected on the phenolic oxygen by the alpha-carboxy-6-nitroveratryl (alphaCNV) protecting group is described. The compounds undergo rapid photolysis at wavelengths longer than 300 nm to liberate the corresponding phenol in excellent yield (quantum yield for the deprotection of tyrosine = 0.19). Further protection of caged tyrosine is possible, yielding N-Fmoc protected derivatives suitable for direct incorporation of caged tyrosine in solid-phase peptide synthesis. PMID- 22249212 TI - Analysis of colorectal cancer morphology in relation to sex, age, location, and family history. AB - BACKGROUND: Studies of colorectal cancer (CRC) have suggested different mechanisms of carcinogenesis in men and women, young and old patients, right- and left sided tumors, and sporadic and familial tumors. These differences might be reflected in morphology. METHODS: CRCs from 1613 patients operated on in 2004 2006 in Sweden were histologically reviewed. Morphology was examined in relation to sex, age groups, location, and family history. RESULTS: Tumors in the right colon were larger, of higher stage, more often poorly differentiated, more mucin producing, more often had a peritumoral lymphocytic infiltrate and a high level of tumor-infiltrating lymphocytes (TILs), and more seldom had an infiltrating margin than tumors in the left colon and rectum (p < 0.0001 for most features). Young patients (<60 years) more seldom had multiple tumors but more often had perineural invasion, an infiltrative tumor margin, and high-stage tumors. Three features, TILs, medullary tumors, and invasive tumor margin, were related to sex. Only vascular invasion was related to familiality. CONCLUSION: Location is the factor that has the most influence on tumor morphology. The results support the idea that different carcinogenic mechanisms may be involved in the right and left colon. Age is the most important determinant for the presence of multiple tumors and is a crucial factor for the aggressiveness of the disease. PMID- 22249214 TI - Body adiposity index indicates only total adiposity, not risk. PMID- 22249215 TI - Update on cardiac stem cell therapy in heart failure. AB - PURPOSE OF REVIEW: Presentation of the current status of cardiac stem cell therapy for the treatment of ischaemic heart failure by highlighting recent clinical results and introducing ongoing trials. Furthermore, necessary upcoming procedural adjustments are discussed. RECENT FINDINGS: During the last decade, stem cell application in the setting of ischaemic heart failure has been evaluated in phase I and II clinical trials, proving safety and feasibility of this approach. Functional results gained so far indicate moderate benefits. However, conclusive evaluation of cell therapy will not be possible before completion of ongoing phase III multicentre trials. Moreover, questions regarding the optimal cell population for treatment in a chronic setting and the favourable time-point of cell delivery have not been ultimately answered. SUMMARY: Cell therapy for the treatment of ischaemic heart failure needs to be evaluated separately from the setting of acute myocardial infarction. In parallel with upcoming clinical evaluation in large-scale trials, further optimization of the 'cell product' regarding the favourable cell type and periprocedural processing, as well as route and time-point of application, is mandatory. PMID- 22249216 TI - Can adult heart failure regimens be applied to children: what works and what does not? AB - PURPOSE OF REVIEW: Review of the evidence for current ambulatory heart failure treatment regimens in adults and their applicability in pediatric heart failure. RECENT FINDINGS: There is promising recent research in treatment with phosphodiesterase-5 inhibitors in single ventricle patients with heart failure, including possible benefits to reduce symptoms and improve exercise tolerance. SUMMARY: Therapies for adults cannot be assumed to be generally applicable to all pediatric heart failure patients, especially in patients with systemic right ventricles or single ventricle physiology. Contrary to adult heart failure regimens, evidence supports treatment of symptomatic, but not asymptomatic, heart failure with angiotensin-converting enzyme inhibitors and beta-blockers in certain pediatric patients. Implantable cardioverter defibrillators continue to be used sparingly in children compared with adults due to low risk of sudden cardiac death. Finally, cardiac resynchronization therapy may be beneficial in children with symptomatic heart failure and moderate to severe dysfunction, although applying adult criteria to children remains a challenge. PMID- 22249213 TI - Mitotic centromere-associated kinesin (MCAK): a potential cancer drug target. AB - The inability to faithfully segregate chromosomes in mitosis results in chromosome instability, a hallmark of solid tumors. Disruption of microtubule dynamics contributes highly to mitotic chromosome instability. The kinesin-13 family is critical in the regulation of microtubule dynamics and the best characterized member of the family, the mitotic centromere-associated kinesin (MCAK), has recently been attracting enormous attention. MCAK regulates microtubule dynamics as a potent depolymerizer of microtubules by removing tubulin subunits from the polymer end. This depolymerizing activity plays pivotal roles in spindle formation, in correcting erroneous attachments of microtubule kinetochore and in chromosome movement. Thus, the accurate regulation of MCAK is important for ensuring the faithful segregation of chromosomes in mitosis and for safeguarding chromosome stability. In this review we summarize recent data concerning the regulation of MCAK by mitotic kinases, Aurora A/B, Polo-like kinase 1 and cyclin-dependent kinase 1. We propose a molecular model of the regulation of MCAK by these mitotic kinases and relevant phosphatases throughout mitosis. An ever-increasing quantity of data indicates that MCAK is aberrantly regulated in cancer cells. This deregulation is linked to increased malignance, invasiveness, metastasis and drug resistance, most probably due to increased chromosomal instability and remodeling of the microtubule cytoskeleton in cancer cells. Most interestingly, recent observations suggest that MCAK could be a novel molecular target for cancer therapy, as a new cancer antigen or as a mitotic regulator. This collection of new data indicates that MCAK could be a new star in the cancer research sky due to its critical roles in the control of genome stability and the cytoskeleton. Further investigations are required to dissect the fine details of the regulation of MCAK throughout mitosis and its involvements in oncogenesis. PMID- 22249217 TI - What's new in Shock, February 2012? PMID- 22249218 TI - Hypothermia for prediction of death in severely injured blunt trauma patients. AB - Hypothermia is considered an independent predictor of death after trauma. The aim of this study was to assess these premises based on data from the TraumaRegistry DGU(r) (TR-DGU) using its outcome predication tool, the Revised Injury Severity Classification (RISC) score, in comparison with three previously published regression models by Shafi, Martin, and Wang. We hypothesized that body temperature on admission would improve accuracy of the RISC score. Data of 5,197 patients with documented body temperature on admission (T) and complete data for RISC score prognosis were selected from TR-DGU. Hypothermia was defined as T of 35 degrees C or less. Patients were divided into hypothermia and normothermia group. Differences were assessed using Mann-Whitney U and chi-squared tests. Statistical significance was accepted at P < 0.01(*). Moreover, we performed multivariate logistic regression analyses using TR-DGU data on the four models (including RISC) with hospital mortality as dependant variable. Results are given as mean or odds ratio (OR) with 95% confidence intervals (95% CIs). Hypothermic patients were more severely injured (Injury Severity Score, 35.0 vs. 29.2 points*) and had higher rates of shock (38.3 vs. 16.8%*), organ failure (71.8 vs. 46%*), and sepsis (17.5 vs. 10.6%*). Survival was worse (29.2 vs. 13.7%*). Comparison of the above models revealed hypothermia as an independent risk factor (Martin: OR, 1.43 [95% CI, 2.21-1.42*]; and Wang: OR, 1.77 [95% CI, 2.21-1.42*]) only, although it would drop out from the model (RISC: OR, 1.12 [95% CI, 1.41 0.89; P = 0.33] and Shafi: OR, 1,.21 [95% CI, 1.60-0.92; P = 0.17]) as long as parameters to indicate hemorrhage and/or coagulopathy were included in sufficient number, a finding confirmed by a subsequent sensitivity analysis. We conclude that hypothermia is a result of injury severity and therefore unlikely to be an independent predictor of mortality. Our data suggest that hypothermia belongs closely to the hemorrhage/coagulopathy group of predictors. PMID- 22249219 TI - Adenosine A2A receptor upregulation in human PMNs is controlled by miRNA-214, miRNA-15, and miRNA-16. AB - Immunosuppressive signaling via the adenosine A2A receptor (A2AR) is an important pathway to control inflammation. In immune cells, expression levels of A2ARs influence responsiveness to inflammatory stimuli. However, mechanisms driving expressional changes of A2ARs are still largely elusive. In the current study, we have investigated the impact of microRNAs (miRNAs) on A2AR expression in human polymorphonuclear leukocytes (PMNs) and T cells. Bioinformatic analyses and reporter gene assays revealed that A2AR expression is controlled by miRNA-214, miRNA-15, and miRNA-16. We detected all three miRNAs in both human PMNs and T cells. However, in PMNs, up to 10-fold higher levels of miRNA-16 and miRNA-214 were detected as compared with T cells. Upon in vitro stimulation, no significant expressional changes occurred. Expression levels of all three miRNAs strongly differed between individuals. A2AR expression also exhibited significant differences between PMNs and T cells: In PMNs, more than a 60-fold increase was seen upon LPS stimulation, whereas in T cells only a 2-fold increase was observed upon anti-CD3/CD28 activation. The extent of A2AR upregulation in PMNs strongly differed between individuals (from less than 10-fold to more than 100-fold). In PMNs, the increase in A2AR mRNA expression upon stimulation was inversely correlated with the expression levels of miRNA-214, miRNA-15, and miRNA-16 (R = 0.87, P < 0.0001); no correlation was found in human T cells. These results indicate that individual miRNA profiles gain important influence on A2AR expression regulation in PMNs upon stimulation. Determination of miRNA expression levels may help to identify patients with an increased risk for severe inflammation. PMID- 22249220 TI - LIPOCALIN-2 is a major acute-phase protein in a rat and mouse model of sterile abscess. AB - Lipocalin-2 (LCN-2) is a 25-kDa secretory protein currently used as a biomarker for renal injury and inflammation. Its source and cause of the increased serum levels are unclear. The current study compares LCN-2 gene expression with known major acute-phase proteins in the liver in a rat and mouse model of turpentine oil-induced sterile abscess. Serum LCN-2 concentrations increased dramatically up to 200-fold (20 MUg/mL) at 48 h after turpentine oil injection. A strong elevation of LCN-2 mRNA in rat liver was observed starting from 4 h up to 48 h after injection, with a maximum (8,738 +/- 2,104-fold) at 24 h, which was further confirmed by Western blot analysis. In contrast, the increases in gene expression of alpha2-macroglobulin, the major acute-phase protein, and hemoxygenase 1, a positive acute-phase protein, were only 1,025 +/- 505-fold and 47 +/- 12-fold, respectively, during acute-phase reaction (APR). No considerable change was observed in LCN-2 mRNA in rat kidney and other organs as compared with liver. Using wild-type mice, a massive increase in gene expression of LCN-2, with a maximum of 2,498 +/- 84-fold in liver, which is similar to that for serum amyloid A (2,825 +/- 233-fold), a major mouse acute-phase protein. However, such an increase was significantly inhibited in interleukin 6 knockout mice during APR. Interleukin 6-treated rat hepatocytes induced a significant time-dependent upregulation of LCN-2.Lipocalin-2 is the major acute-phase protein in rat as compared with alpha2-macroglobulin and hemoxygenase 1 and comparable with serum amyloid A in mouse whose gene expression is mainly controlled by interleukin 6. The liver is the main source of serum LCN-2 in the case of APR. ABBREVIATIONS-LCN 2-lipocalin-2-alpha2M-alpha2-macroglobulin-HO-1-hemoxygenase 1-IL-6-interleukin 6 SAA-serum amyloid A-TO-turpentine oil-APR-acute-phase reaction. PMID- 22249221 TI - Endotoxemia is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control in rats. AB - Cardiac cycle is regulated by a complex interplay between autonomic nervous system and cardiac pacemaker cells. Decreased heart rate variability (HRV) and increased cardiac rhythm regularity are associated with poor prognosis in patients with systemic inflammation (e.g., sepsis). However, the underlying mechanism of decreased HRV in systemic inflammation is not understood. It is known that greater regularity in a complex system could indicate uncoupling of the system's components. The present study aimed to test the hypothesis that impaired responsiveness of cardiac pacemaker to autonomic nervous system may lead to uncoupling of the cardiovascular regulatory mechanisms during systemic inflammation. Systemic inflammation was induced by intraperitoneal injection of endotoxin (lipopolysaccharide, 1 mg/kg) in rats. Cardiovascular signals were recorded in conscious animals using a telemetric system. Heart rate dynamics was analyzed using Poincare plot, and cardiac cycle regularity was assessed by sample entropy analysis. Spontaneously beating atria were isolated, and chronotropic responsiveness to adrenergic and cholinergic stimulation was assessed using standard organ bath. Sample entropy decreased significantly 4 h after endotoxin injection in conscious rats. Vagal modulation of cardiac cycle (as assessed by Poincare plot) also exhibited a significant reduction in endotoxemic rats. Acute endotoxin challenge was associated with a significant hyporesponsiveness of isolated spontaneously beating atria to cholinergic stimulation. The chronotropic responsiveness to adrenergic stimulation was identical in controls and endotoxin treated rats. These data propose that systemic inflammation is linked to reduced cardiac responsiveness to cholinergic stimulation. This may lead to partial uncoupling of cardiac pacemaker cells from autonomic neural control and can explain decreased HRV during systemic inflammation. PMID- 22249222 TI - Economic evaluation of lifestyle interventions to treat overweight or obesity in children. AB - OBJECTIVE: To estimate lifetime cost effectiveness of lifestyle interventions to treat overweight and obese children, from the UK National Health Service perspective. DESIGN: An adaptation of the National Heart Forum economic model to predict lifetime health service costs and outcomes of lifestyle interventions on obesity-related diseases. SETTING: Hospital or community-based weight-management programmes. POPULATION: Hypothetical cohorts of overweight or obese children based on body mass data from the National Child Measurement Programme. INTERVENTIONS: Lifestyle interventions that have been compared with no or minimal intervention in randomized controlled trials (RCTs). MAIN OUTCOME MEASURES: Reduction in body mass index (BMI) standard deviation score (SDS), intervention resources/costs, lifetime treatment costs, obesity-related diseases and cost per life year gained. RESULTS: Ten RCTs were identified by our search strategy. The median effect of interventions versus control from these 10 RCTs was a difference in BMI SDS of -0.13 at 12 months, but the range in effects among interventions was broad (0.04 to -0.60). Indicative costs per child of these interventions ranged from L108 to L662. For obese children aged 10-11 years, an intervention that resulted in a median reduction in BMI SDS at 12 months at a moderate cost of L400 increased life expectancy by 0.19 years and intervention costs were offset by subsequent undiscounted savings in treatment costs (net saving of L110 per child), though this saving did not emerge until the sixth or seventh decade of life. The discounted cost per life year gained was L13 589. Results were broadly similar for interventions aimed at children aged 4-5 years and which targeted both obese and overweight children. For more costly interventions, savings were less likely. CONCLUSION: Interventions to treat childhood obesity are potentially cost effective although cost savings and health benefits may not appear until the sixth or seventh decade of life. PMID- 22249223 TI - Prospective associations of dietary insulin demand, glycemic index, and glycemic load during puberty with body composition in young adulthood. AB - BACKGROUND: Puberty is a so-called critical period for overweight development and is characterized by physiological insulin resistance during mid-puberty. This study addressed the hypothesis that habitual consumption of a diet inducing higher levels of postprandial glycemia or insulinemia during puberty may have an unfavorable effect on the body composition in young adulthood. METHODS: Multivariate regression analysis was performed on 262 participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study with at least two 3-day weighed dietary records during puberty (baseline: girls 9-14 years; boys 10-15 years) and anthropometric measurements in young adulthood (18 25 years). A published dietary glycemic index was assigned to each carbohydrate containing food. Similarly, each food was assigned a food insulin index (insulinemic response to a 1 MJ portion of food relative to 1 MJ of glucose) using 121 values measured at Sydney University. RESULTS: Dietary glycemic index or glycemic load during puberty was not related to body composition in young adulthood. In contrast, a higher dietary insulin index and a higher dietary insulin load during puberty were associated with higher levels of percentage of body fat (%BF) in young adulthood, even after adjustment for early life, socioeconomic and nutritional factors; %BF in energy-adjusted tertiles of dietary insulin index were 22.9 (95% confidence intervals (CI): 21.6, 24.1), 24.5 (23.2, 25.7), 24.7 (23.5, 25.9) %, P (for trend)=0.01; %BF in energy-adjusted tertiles of dietary insulin load were 22.8 (95% CI: 21.5, 24.0), 24.5 (23.2, 25.7), 24.8 (23.6, 26.0) %, P (for trend)=0.01. Adjustment for baseline %BF attenuated these relationships (P (for trend)=0.1 and=0.08, respectively). Dietary insulin demand was not related to body mass index. CONCLUSION: This study suggests a prospective adverse influence of dietary insulin demand during puberty on %BF in young adulthood. Postprandial increases in insulinemia rather than increases in glycemia appear to be implicated in an unfavorable development of body composition. PMID- 22249224 TI - Body mass index versus waist circumference as predictors of mortality in Canadian adults. AB - BACKGROUND: Elevated body mass index (BMI) and waist circumference (WC) are associated with increased mortality risk, but it is unclear which anthropometric measurement most highly relates to mortality. We examined single and combined associations between BMI, WC, waist-hip ratio (WHR) and all-cause, cardiovascular disease (CVD) and cancer mortality. METHODS: We used Cox proportional hazard regression models to estimate relative risks of all-cause, CVD and cancer mortality in 8061 adults (aged 18-74 years) in the Canadian Heart Health Follow Up Study (1986-2004). Models controlled for age, sex, exam year, smoking, alcohol use and education. RESULTS: There were 887 deaths over a mean 13 (SD 3.1) years follow-up. Increased risk of death from all-causes, CVD and cancer were associated with elevated BMI, WC and WHR (P<0.05). Risk of death was consistently higher from elevated WC versus BMI or WHR. Ascending tertiles of each anthropometric measure predicted increased CVD mortality risk. In contrast, all cause mortality risk was only predicted by ascending WC and WHR tertiles and cancer mortality risk by ascending WC tertiles. Higher risk of all-cause death was associated with WC in overweight and obese adults and with WHR in obese adults. Compared with non-obese adults with a low WC, adults with high WC had higher all-cause mortality risk regardless of BMI status. CONCLUSION: [corrected] BMI and WC predicted higher all-cause and cause-specific mortality, and WC predicted the highest risk for death overall and among overweight and obese adults. Elevated WC has clinical significance in predicting mortality risk beyond BMI. PMID- 22249225 TI - Effect of dairy consumption on weight and body composition in adults: a systematic review and meta-analysis of randomized controlled clinical trials. AB - BACKGROUND: Although several observational and experimental studies have investigated the effect of dairy consumption on weight and body composition, results are inconsistent. OBJECTIVE: This systematic review and meta-analysis was conducted to summarize the published evidence from randomized controlled clinical trials (RCTs) regarding the effect of dairy consumption on weight, body fat mass, lean mass and waist circumference (WC) in adults. DESIGN: PubMed, ISI Web of Science, SCOPUS, Science Direct and EMBASE were searched from January 1960 to October 2011 for relevant English and non-English publications. Sixteen studies were selected for the systematic review and fourteen studies were included in meta-analysis. RESULTS: Our search led to 14, 12, 6 and 8 eligible RCTs that had data on weight, body fat mass, lean mass and WC, respectively. Overall, mean difference for the effect of dairy on body weight was -0.61 kg (95% confidence interval (CI): -1.29, 0.07, P=0.08). Increased dairy intake resulted in 0.72 kg (95% CI: -1.29, -0.14, P=0.01) greater reduction in fat mass, 0.58 kg (95% CI: 0.18, 0.99, P<0.01) gain in lean mass and 2.19 cm (95% CI: -3.42, -0.96, P-value <0.001) further reduction in WC than that in controls. Subgroup analysis revealed that increasing dairy intake without energy restriction in both intervention and control groups does not significantly affect weight, body fat mass, lean mass and WC; consumption of high-dairy weight loss diets led to 1.29 kg (95% CI: -1.98, 0.6, P<0.001) greater weight loss, 1.11 kg (95% CI: -1.75, -0.47, P=0.001) greater reduction in body fat mass, 0.72 kg (95% CI: 0.12, 1.32, P=0.02) gain in body lean mass and 2.43 cm (95% CI: -3.42, -1.44, P<0.001) additional reduction in WC compared with controls. CONCLUSION: Increased dairy consumption without energy restriction might not lead to a significant change in weight or body composition; whereas inclusion of dairy products in energy-restricted weight loss diets significantly affects weight, body fat mass, lean mass and WC compared with that in the usual weight loss diets. PMID- 22249226 TI - History matters: childhood weight trajectories as a basis for planning community based obesity prevention to adolescents. AB - OBJECTIVE: To use epidemiological data and a standardized economic model to compare projected costs for obesity prevention in late adolescence accrued using a cross-sectional weight classification for selecting adolescents at age 15 years compared with a longitudinal classification. METHODS: All children born in a Swedish county (population 440 000) in 1991 who participated in all regular measurements of height and weight at ages 5, 10 and 15 years (n=4312) were included in the study. The selection strategies were compared by calculating the projected financial load resulting from supply of obesity prevention services from providers at all levels in the health care system. The difference in marginal cost per 1000 children was used as the primary end point for the analyses. RESULTS: Using the cross-sectional selection strategy, 3.8% of adolescents at age 15 years were selected for evaluation by a pediatric specialist, and 96.2% were chosen for population-based interventions. In the trajectory-based strategy, 2.4% of the adolescents were selected for intensive pediatric care, 1.4% for individual clinical interventions in primary health care, 14.0% for individual primary obesity prevention using the Internet and 82.1% for population-based interventions. Costs for the cross-sectional selection strategy were projected to USD463 581 per 1000 adolescents and for the trajectory based strategy were USD 302 016 per 1000 adolescents. CONCLUSIONS: Using projections from epidemiological data, we found that by basing the selection of adolescents for obesity prevention on weight trajectories, the load on highly specialized pediatric care can be reduced by one-third and total health service costs for obesity management among adolescents reduced by one-third. Before use in policies and prevention program planning, our findings warrant confirmation in prospective cost-benefit studies. PMID- 22249228 TI - Association between dietary scores and 13-year weight change and obesity risk in a French prospective cohort. AB - BACKGROUND/OBJECTIVES: The relationship between diet quality and development of obesity is complex and unresolved. The aim of this study was to assess and compare the predictive value of six different dietary scores on both relative weight change and the risk of obesity after 13 years of follow-up in adults aged 45 years and older. SUBJECTS/METHODS: Six scores reflecting adherence to different nutritional recommendations (the French Programme National Nutrition Sante-Guideline Score (PNNS-GS), the Dietary Guidelines for Americans Index (DGAI), the Diet Quality Index-International (DQI-I), the Mediterranean Diet Scale (MDS), the relative Mediterranean Diet Score (rMED) and the Mediterranean Style Dietary Pattern Score (MSDPS)) were estimated in 3151 participants in the French SU.VI.MAX (SUpplementation en VItamines et Mineraux AntioXydants) study. Associations of dietary scores with 13-year weight change were assessed through multivariate linear regression models, and obesity risk was analyzed with logistic regression, providing odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Except for the MSDPS, higher scores, that is, better adherence to nutritional guidelines or to a Mediterranean diet, were associated with lower weight gain in men (all P-value for trend <0.05). In addition, among men, ORs for becoming obese after 13 years associated with a 1 s.d. increase in dietary scores ranged from 0.63, 95% CI: 0.51, 0.78 for DGAI to 0.72, 95% CI: 0.59, 0.88 for MDS. These associations were weaker or not statistically significant in women. CONCLUSION: Overall, the six dietary scores predicted obesity risk equally well. Among French adults, strong adherence to dietary guidelines appears to be protective with regard to weight gain and obesity, especially in men. PMID- 22249227 TI - A twin study of self-regulatory eating in early childhood: estimates of genetic and environmental influence, and measurement considerations. AB - OBJECTIVE: Children differ greatly in their ability to self-regulate food intake for reasons that are poorly understood. This laboratory-based twin study tested the genetic and environmental contributions to self-regulatory eating and body fat in early childhood. METHODS: A total of 69 4-7 year-old same-sex twin pairs, including 40 monozygotic and 29 dizygotic pairs, were studied. Self-regulatory eating was operationalized as the percentage compensation index (COMPX%), assessed by a 'preload' challenge in which lunch intake was measured following a low- (3 kcal) or high-calorie (159 kcal) drink. Body fat indexes also were measured. The familial association for COMPX% was estimated by an intraclass correlation, and biometric analyses estimated heritability. RESULTS: Children ate more at lunch following the low- compared with high-energy preload (P<0.001), although variability in COMPX% was considerable. Compensation was significantly poorer among African American and Hispanic compared with European American children, and among girls compared with boys. There was a familial association for self-regulatory eating (rho = 0.23, P = 0.03) but no significant genetic component. In all, 22% of the variance in COMPX% was due to shared environmental 'household' factors, with the remaining variance attributable to child-specific 'unique' or 'random' environments. Poorer self-regulatory eating was associated with greater percent body fat (r = -0.21, P = 0.04). CONCLUSIONS: Self-regulatory eating was influenced by environmental factors, especially those differing among siblings. The absence of a significant genetic effect may reflect the age of the sample or could be artifactual due to measurement issues that need to be considered in future studies. PMID- 22249229 TI - The impact of glutathione transferase kappa deficiency on adiponectin multimerisation in vivo. AB - Glutathione transferase Kappa (GSTK1-1) also termed disulfide bond-forming oxidoreductase A-like protein (DsbA-L) has been implicated in the post translational multimerization of adiponectin and has been negatively correlated with obesity in mice and humans. We investigated adiponectin in Gstk1(-/-) mice and surprisingly found no difference in the levels of total serum adiponectin or the level of high molecular weight (HMW) multimers when compared with normal controls. Non-reducing SDS-polyacrylamide gel electrophoresis and western blotting also showed a similar distribution of low, middle and HMW multimers in normal and Gstk1(-/-) mice. Variation in adiponectin has been correlated with glucose tolerance and with the levels of phosphorylated AMP-kinase but we found similar glucose tolerance and similar levels of phospho 5-AMP-activated protein kinase in normal and Gstk1(-/-) mice. Consequently, our findings suggest that GSTK1-1 is not absolutely required for adiponectin multimerization in vivo and alternate pathways may be activated in GSTK1-1 deficiency. PMID- 22249230 TI - Maternal and infant factors associated with neonatal adiposity: results from the Tasmanian Infant Health Survey (TIHS). AB - OBJECTIVE: To examine the maternal and neonatal factors associated with offspring adiposity and the role of birth and placental weight as potential mediators in such associations. DESIGN: The Tasmanian Infant Health Survey was a prospective cohort study conducted between 1988 and 1995 in Australia to investigate the cause of Sudden Infant Death Syndrome. This large infant cohort provides measurement of skinfolds on 7945 mothers and their offspring. SUBJECTS: Participants included singletons born >=37 weeks gestation who were at high risk of sudden infant death syndrome identified through a composite score that included birth weight, maternal age, neonatal gender, season of birth, duration of second-stage labor and intention to breastfeed. MEASUREMENTS: Neonatal adiposity was assessed from skinfold measurements of the subscapular (SSF) and triceps folds (TSF) taken at birth. Maternal early-pregnancy body mass index (BMI) was calculated from self-reported height and weight. Neonatal data were extracted from birth records. Data relating to other environmental exposures were obtained from questionnaires administered when neonates were ~4-days old. RESULTS: In multivariable models, higher maternal adiposity, increasing maternal age, gestation age, delivery by Caesarian section and female gender were associated with larger SSF independent of placental and birth weight (P<0.001). Maternal age and delivery by Caesarian section were significantly associated with larger TSF, whereas gestational age and male gender were associated with thinner TSF independent of placental and birth weight. Higher early-pregnancy BMI, maternal weight gain, maternal age, parity and gestational age were significantly associated with larger placental and birth weight. Smoking during pregnancy was associated with smaller birth weight but not with placental weight. CONCLUSION: In addition to birth weight, maternal adiposity and placental weight were important additional factors associated with neonatal adiposity. PMID- 22249231 TI - Six-minute walking test predicts maximal fat oxidation in obese children. AB - BACKGROUND: Obesity is associated with reduced exercise maximal fat oxidation rate (FATmax), which is generally assessed by cardiopulmonary cycling test. The six-minute walking test (6MWT) presents an alternative method in patients. OBJECTIVE: The aim of this study was to establish a practical reference equation facilitating the prediction of FATmax from the 6 MWT in obese children of both genders. DESIGN: This study is a cross-sectional study using mixed linear and multiple regression models. RESEARCH METHODS AND PROCEDURES: Anthropometric measurements were recorded and submaximal cycling test and 6 MWT conducted for 131 school-aged obese children, 68 boys and 63 girls. A multiple regression analysis for FATmax, including six-minute walking distance (6 MWD), anthropometric and cardiac parameters as the dependent variables, was performed for the two genders separately. RESULTS: Mean 6 MWD and FATmax were 564.9 +/- 53.7 m and 126.5 +/- 12.1 mg min(-1) for boys and 506.7 +/- 55.0 m and 120.7 +/- 10.0 mg min(-1) for girls, respectively. The 6MWD, body mass index, Z-score, fat free mass, waist and hip circumferences (WC and HC), rest heart rate, and systolic and diastolic blood pressures were highly correlated with FATmax for both genders. There was a significant correlation between 6 MWD and FATmax in both boys and girls (r = 0.88 and r = 0.81, P<0.001, respectively). Stepwise regression analyses revealed that the combinations of 6 MWD with HC for boys and 6MWD with WC for girls improved the predictability of the model (R(2) = 0.81 for boys and R(2) = 0.72 for girls; P<0.001). CONCLUSION: In obese children, the 6MWT can be used to predict FATmax when formal test of exercise capacity and gas exchange analysis are unavailable or impractical. It is therefore possible to prescript targeted exercises at FATmax, without performing indirect calorimetry, just from a field test. PMID- 22249233 TI - Micro-invasive glaucoma surgery: current perspectives and future directions. AB - PURPOSE OF REVIEW: There is an increasing interest and availability of micro invasive glaucoma surgery (MIGS) procedures. It is important that this increase is supported by sound, peer-reviewed evidence. This article will define MIGS, review relevant publications in the period of annual review and discuss future directions. RECENT FINDINGS: The results of the pivotal trial comparing a trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA, USA) combined with phacoemulsification to phacoemulsification alone showed a significantly higher percentage of patients with unmedicated intraocular pressure (IOP) <= 21 mmHg, and a comparable safety profile. Initial results are published regarding a second-generation micro-bypass stent (iStent inject, Glaukos Corporation, Laguna Hills, CA, USA), a canalicular scaffold (Hydrus, Ivantis Inc., Irvine, CA, USA) and an ab interno suprachoroidal microstent (CyPass, Transcend Medical, Menlo Park, CA, USA), showing a decrease in mean postoperative IOP. Phaco-Trabectome (Ab interno trabeculectomy Trabectome, NeoMedix Inc., Tustin, CA, USA) was compared to phacotrabeculectomy and showed less IOP reduction, less postoperative complications, and a similar success rate. Similar success rates were found with the comparison of excimer laser trabeculostomy (ELT, AIDA, Glautec AG, Nurnberg, Germany) and selective laser trabeculoplasty. A number of publications review the importance of the location of implantable devices, intraoperative gonioscopy, cost-effectiveness and quality-of-life studies, and randomized clinical trials. SUMMARY: MIGS procedures offer reduction in IOP, decrease in dependence on glaucoma medications and an excellent safety profile. Their role within our glaucoma treatment algorithm continues to be clarified and differs from the role of more invasive glaucoma surgeries such as trabeculectomy or glaucoma drainage devices. PMID- 22249232 TI - Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner. AB - BACKGROUND: The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation. DESIGN AND RESULTS: Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (~33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery. CONCLUSIONS: Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment. PMID- 22249234 TI - Recent clinical pearls from clinical trials in glaucoma. AB - PURPOSE OF REVIEW: Over the past several years, numerous clinical trials in glaucoma have contributed to our understanding of the medical and surgical treatment of the disease. The goal of this review is to summarize the findings and conclusions of what the authors feel are the key clinical trials in glaucoma. RECENT FINDINGS: One of the major findings of Low-Pressure Glaucoma Treatment study was that patients randomized to the brimonidine group were statistically less likely to have progressive visual field loss than those randomized to the timolol group, even though there was no significant difference between the intraocular pressure (IOP)-lowering effect of these two drugs. The Ocular Hypertension Treatment Study has effectively demonstrated that patients with ocular hypertension should be risk stratified prior to initiation of treatment and that it appears to be relatively safe to delay treatment in low-risk patients. The 3-year canaloplasty study demonstrates the long-term safety and efficacy of this surgery. However, it also demonstrates that canaloplasty can deliver a modest IOP reduction and therefore is likely more suited for patients with mild damage and a higher target IOP. The 1-year results from the Ahmed Baerveldt Comparison Study do not demonstrate a clear superiority of one implant over the other. These findings are consistent with prior retrospective studies in the literature. SUMMARY: These four studies have furthered our understanding of the field of glaucoma and provided key insights into the medical and surgical management of patients with this complex disease. PMID- 22249236 TI - Current variations of glaucoma filtration surgery. AB - PURPOSE OF REVIEW: Trabeculectomy continues to be the most effective incisional surgery for uncontrolled glaucoma. Since its introduction by Cairns in 1968, the procedure has undergone numerous modifications. This article will summarize the current variations of glaucoma filtration surgery and evidence-based review of their potential advantages and disadvantages. RECENT FINDINGS: Recent innovations in glaucoma filtration surgery have focused on wound modulation to enhance long term surgical outcomes and the search for a small incision surgery with more predictable outcomes, lower complication rates, and rapid visual recovery. Amniotic membranes, antivascular endothelial growth factor agents, and tissue engineered biodegradable implants are currently being investigated as alternatives to mitomycin C and 5-fluorouracil to reduce inflammation and subsequent bleb failure with fewer complications. The Ex-PRESS glaucoma filtration device appears promising with its unique feature of small-incision surgery, fewer intraoperative and postoperative complications, and its ability to lower intraocular pressure significantly, which appears to be comparable with standard trabeculectomy. SUMMARY: Knowledge and surgical expertise in handling current variations of glaucoma filtration surgery are essential to offer an individualized approach with the overall goal of optimizing surgical outcomes and minimizing complications. PMID- 22249237 TI - Management of immediate and sustained intraocular pressure rise associated with intravitreal antivascular endothelial growth factor injection therapy. AB - PURPOSE OF REVIEW: To summarize the findings of recent reports of short-term and sustained intraocular pressure (IOP) rise associated with intravitreal antivascular endothelial growth factor (VEGF) injections and to guide the management of this infrequent complication. RECENT FINDINGS: Short-term increases in IOP are common immediately after intravitreal anti-VEGF injection. IOP takes longer to reach a safe level in patients with a history of glaucoma or ocular hypertension. Preinjection medicinal therapy and ocular decompression therapy may blunt this short-term IOP rise. Sustained increases in IOP are relatively infrequent, but are likely to necessitate intervention for IOP-lowering. A 'pro re nata' (PRN) injection protocol may obviate the need for intervention. The pathophysiology of sustained IOP rise is poorly understood, but may relate to repackaging processes undertaken by the pharmacies that compound these agents. SUMMARY: Treating physicians should be aware of the potential for short-term and sustained IOP rise associated with intravitreal anti-VEGF injection therapy. Considerations for management include prophylactic IOP-lowering with medicinal therapy and/or preinjection ocular decompression for patients with a history of glaucoma or ocular hypertension and switching to a 'PRN' injection protocol in patients suffering a sustained rise in IOP. PMID- 22249235 TI - The Tube Versus Trabeculectomy Study: interpretation of results and application to clinical practice. AB - PURPOSE OF REVIEW: The Tube Versus Trabeculectomy (TVT) Study is a multicenter randomized clinical trial comparing the safety and efficacy of tube-shunt surgery to trabeculectomy with mitomycin C (MMC) in eyes with previous cataract and/or failed glaucoma surgery. This article interprets results from the TVT Study and applies them to clinical practice. RECENT FINDINGS: Both tube-shunt surgery and trabeculectomy with MMC produced intraocular pressure (IOP) reduction to the low teens throughout the 5-year duration of the study. Tube-shunt surgery was associated with use of more glaucoma medications than trabeculectomy with MMC during the first 2 years of the study, but medical therapy equalized with longer follow-up. Trabeculectomy with MMC had higher rates of surgical failure and reoperation for glaucoma compared with tube-shunt surgery. Vision loss occurred at a similar rate with the two surgical procedures. Early complications were more frequent after trabeculectomy with MMC relative to tube-shunt surgery, but both procedures had similar rates of late postoperative complications and serious complications. SUMMARY: Tube-shunt surgery and trabeculectomy with MMC are both viable surgical options for managing glaucoma in patients who have undergone prior cataract and/or failed filtering surgery. Results of the TVT Study support the expanding use of tube shunts beyond refractory glaucomas. PMID- 22249238 TI - Clinical trials for glaucoma neuroprotection are not impossible. AB - PURPOSE OF REVIEW: To discuss issues that affect development of new glaucoma treatments known as neuroprotection. RECENT FINDINGS: There are barriers to neuroprotection trials for glaucoma. SUMMARY: With design features discussed in the review, neuroprotection trials can be effectively carried out. PMID- 22249239 TI - Mobile phone use and incidence of glioma in the Nordic countries 1979-2008: consistency check. AB - BACKGROUND: Some case-control studies have reported increased risks of glioma associated with mobile phone use. If true, this would ultimately affect the time trends for incidence rates (IRs). Correspondingly, lack of change in IRs would exclude certain magnitudes of risk. We investigated glioma IR trends in the Nordic countries, and compared the observed with expected incidence rates under various risk scenarios. METHODS: We analyzed annual age-standardized incidence rates in men and women aged 20 to 79 years during 1979-2008 using joinpoint regression (35,250 glioma cases). Probabilities of detecting various levels of relative risk were computed using simulations. RESULTS: For the period 1979 through 2008, the annual percent change in incidence rates was 0.4% (95% confidence interval = 0.1% to 0.6%) among men and 0.3% (0.1% to 0.5%) among women. Incidence rates have decreased in young men (20-39 years) since 1987, remained stable in middle-aged men (40-59 years) throughout the 30-year study period, and increased slightly in older men (60-79 years). In simulations, assumed relative risks for all users of 2.0 for an induction time of up to 15 years, 1.5 for up to 10 years, and 1.2 for up to 5 years were incompatible with observed incidence time trends. For heavy users of mobile phones, risks of 2.0 for up to 5 years' induction were also incompatible. CONCLUSION: No clear trend change in glioma incidence rates was observed. Several of the risk increases seen in case-control studies appear to be incompatible with the observed lack of incidence rate increase in middle-aged men. This suggests longer induction periods than currently investigated, lower risks than reported from some case control studies, or the absence of any association. PMID- 22249240 TI - Short-term effects of air pollution on pulse pressure among nonsmoking adults. AB - BACKGROUND: Previous studies on the effects of acute air pollution have focused primarily on blood pressure (BP). METHODS: Our study enrolled 9238 nonsmoking adults over 30 years of age from 6 townships in Taiwan: 1 seaport, 1 urban, 1 industrial, and 3 rural. Using generalized additive models, we evaluated the associations between brachial BP and short-term exposure to 5 air pollutants: particulate matter with diameter <10 MUm (PM(10)), sulfur dioxide (SO(2)), nitrogen dioxide (NO(2)), carbon monoxide (CO), and ozone (O(3)). RESULTS: After adjusting for individual and meteorologic factors, the systolic BP was decreased by all 5 pollutants, whereas the diastolic BP was increased by SO(2), NO(2), and O(3). The pulse pressure was consistently decreased by all 5 pollutants, with changes of -1.5 (95% confidence interval = -2.0 to -1.1), -0.6 (-0.9 to -0.4), 2.4 (-3.0 to -1.8), -1.2 (-1.6 to -0.9), and -1.4 (-1.8 to -0.9) mm Hg for interquartile range increases in 3-day lagged PM(10), SO(2), NO(2), carbon monoxide, and O(3), respectively. PM(10) exposure was more strongly associated with reduction of pulse pressure among men, persons >60 years of age, those with hypertension, and those living in the industrial township. CONCLUSIONS: Short term exposure to air pollution reduces pulse pressure. PM(10) in industrial emissions may contribute to pulse pressure changes. Age, sex, and hypertensive status may modify the effects of PM(10) on pulse pressure. PMID- 22249241 TI - Population heterogeneity in trajectories of midlife blood pressure. AB - BACKGROUND: We investigated whether there are subgroups with different underlying (latent) trajectories of midlife systolic blood pressure (BP), diastolic BP, and pulse pressure in a UK cohort. METHODS: Data are from 1840 men and 1819 women with BP measured at ages 36, 43, and 53 years. We used unconditional growth mixture models to test for the presence of latent trajectory classes. Extracted classes were described in terms of a number of known lifetime risk factors, and linked to the risk of undiagnosed angina (Rose questionnaire) at age 53 years. RESULTS: In both sexes for systolic BP, diastolic BP, and pulse pressure, there was a large "normative" class (>90% of the sample) characterized by gentle annual increases (eg, an increase in male systolic BP of 0.9 mm Hg/year [95% confidence interval = 0.9 to 1.0]), with a smaller class for whom the rate of increase was high (eg, an increase in male systolic BP of 3.1 mm Hg/year [2.8 to 3.4]). In women, there was an additional class for whom BP was high at age 36 and remained high. Persons in the "normative" classes were, on average, heavier at birth and taller at age 7 years, had a lower midlife body mass index, and were less likely to be on antihypertensive medication compared with those in other classes. Among those with no diagnosed cardiovascular disease, those in the classes with more strongly increasing systolic BP and pulse pressure were at greatest risk of angina. CONCLUSION: Our study suggests that in midlife the majority of the population have a gentle underlying increase in BP, but that there also exists an important subgroup in whom BP increases much more markedly. These classes may be useful for identifying those most at risk for cardiovascular disease. PMID- 22249243 TI - Heritability of hearing loss. AB - BACKGROUND: Hearing impairment is one of the most common permanent disabilities in the western world. Although hearing ability normally declines with age, there is great individual variation in age of onset, progression, and severity, indicating that individual susceptibility plays a role. The aim of the present study was to explore the relative importance of genetic and environmental effects in the etiology of impaired hearing. METHODS: From August 1995 to June 1997, the total adult population of Nord-Trondelag County, Norway, was invited to take part in the Nord-Trondelag Health Study. The survey included as an integrated project the Nord-Trondelag Hearing Loss Study with pure-tone audiometry assessment of the standard frequencies 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz on 51,574 participants aged 20 to 101 years. We obtained information from Statistics Norway identifying 11,263 sibling pairs. After age stratification, we assessed similarity in hearing thresholds between siblings using polychoric correlations. The contribution of genetic effects in hearing ability was calculated. RESULTS: The upper limit of the heritability of hearing loss was 0.36. We found little evidence for sex differences in the relative importance of genetic effects. CONCLUSIONS: There is a substantial genetic contribution to individual variation in hearing thresholds. PMID- 22249242 TI - Multidrug resistance among new tuberculosis cases: detecting local variation through lot quality-assurance sampling. AB - BACKGROUND: Current methodology for multidrug-resistant tuberculosis (MDR TB) surveys endorsed by the World Health Organization provides estimates of MDR TB prevalence among new cases at the national level. On the aggregate, local variation in the burden of MDR TB may be masked. This paper investigates the utility of applying lot quality-assurance sampling to identify geographic heterogeneity in the proportion of new cases with multidrug resistance. METHODS: We simulated the performance of lot quality-assurance sampling by applying these classification-based approaches to data collected in the most recent TB drug resistance surveys in Ukraine, Vietnam, and Tanzania. We explored 3 classification systems- two-way static, three-way static, and three-way truncated sequential sampling-at 2 sets of thresholds: low MDR TB = 2%, high MDR TB = 10%, and low MDR TB = 5%, high MDR TB = 20%. RESULTS: The lot quality-assurance sampling systems identified local variability in the prevalence of multidrug resistance in both high-resistance (Ukraine) and low-resistance settings (Vietnam). In Tanzania, prevalence was uniformly low, and the lot quality assurance sampling approach did not reveal variability. The three-way classification systems provide additional information, but sample sizes may not be obtainable in some settings. New rapid drug-sensitivity testing methods may allow truncated sequential sampling designs and early stopping within static designs, producing even greater efficiency gains. CONCLUSIONS: Lot quality assurance sampling study designs may offer an efficient approach for collecting critical information on local variability in the burden of multidrug-resistant TB. Before this methodology is adopted, programs must determine appropriate classification thresholds, the most useful classification system, and appropriate weighting if unbiased national estimates are also desired. PMID- 22249244 TI - Stoichiometry of bacterial anaerobic oxidation of elemental sulfur by ferric iron. AB - The conventional stoichiometry of the oxidation of elemental sulfur by ferric iron in Acidithiobacillus ferrooxidans was not in agreement with our experimental data in terms of ferrous iron and proton formation. Reaction modelling under the actual conditions of bacterial activity resulted in a different stoichiometry, where additional iron species participate in the process to affect the number of released protons. The suggested reaction equation may more accurately predict the intensity of environmental acidification during the anaerobic bioprocess. PMID- 22249245 TI - A transcriptional variant of the LC3A gene is involved in autophagy and frequently inactivated in human cancers. AB - Microtubule-associated protein 1 light chain 3 has an important role in autophagy. The human LC3 gene family has five members, LC3A (variant-1: v1 and 2: v2), LC3B, LC3B2 and LC3C. Although a form of LC3B modified by phosphatidylethanolamine (form-II) is localized in autophagosomes, it is not clear whether other LC3 proteins also function in autophagy. Here, we examined the association between autophagy and human LC3 proteins during starvation- or p53-induced autophagy in Saos-2 cells. In an analysis of the intracellular distribution of each LC3 protein fused with GFP, GFP-LC3Av1 was frequently localized in autophagosomes with a punctate pattern, similar to GFP-LC3B. Further, endogenous LC3Av1 generated form-II and mostly localized in LC3B positive autophagosomes during the induced autophagy. Interestingly, LC3Av1, not LC3B, was frequently inactivated at the transcriptional level in various human cancer cell lines (111/244 cell lines, 45.5%) and its inactivation was due to aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC) cell lines and primary tumors. Restoration of LC3Av1 expression in KYSE170 cells, an LC3Av1 inactivated ESCC cell line, showed the inhibition of tumor growth in vivo. These results suggest that LC3Av1, not only LC3B, functions in autophagy and further, LC3Av1 may be crucial in carcinogenesis. PMID- 22249246 TI - The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response. AB - DNA repair is essential in maintaining genome integrity and defects in different steps of the process have been linked to cancer and aging. It is a long lasting question how DNA repair is spatially and temporarily organized in the highly compartmentalized nucleus and whether the diverse nuclear compartments regulate differently the efficiency of repair. Increasing evidence suggest the involvement of nuclear pore complexes in repair of double-strand breaks (DSBs) in yeast. Here, we show that the human nucleoporin 153 (NUP153) has a role in repair of DSBs and in the activation of DNA damage checkpoints. We explore the mechanism of action of NUP153 and we propose its potential as a novel therapeutic target in cancers. PMID- 22249247 TI - Mutations and deletions of ARID1A in breast tumors. PMID- 22249248 TI - Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression. AB - MicroRNAs (miRNAs) have an important role in a wide range of physiological and pathological processes, and their dysregulation has been reported to affect the development and progression of cancers, including hepatocellular carcinoma (HCC). However, in the plethora of dysregulated miRNAs, it is largely unknown which of them have a causative role in the hepatocarcinogenic process. In the present study, we first aimed to determine changes in the expression profile of miRNAs in human HCCs and to compare them with liver tumors generated in a rat model of chemically induced HCC. We found that members of the miR-100 family (miR-100, miR 99a) were downregulated in human HCCs; a similar downregulation was also observed in rat HCCs. Their reduction was paralleled by an increased expression of polo like kinase 1 (PLK1), a target of these miRNAs. The introduction of miR-100 in HCC cells impaired their growth ability and their capability to form colonies in soft agar. Next, we aimed at investigating, in the same animal model, if dysregulation of miR-100 and PLK1 is an early or late event along the multistep process of hepatocarcinogenesis. The obtained results showed that miR-100 downregulation (i) is already evident in very early preneoplastic lesions generated 9 weeks after carcinogenic treatment; (ii) is also observed in adenomas and early HCCs; and (iii) is not simply a marker of proliferating hepatocytes. To our knowledge, this is the first work unveiling the role of a miRNA family along HCC progression. PMID- 22249249 TI - Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. AB - Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA methylation drivers of chemoresistance. Using isogenic, cisplatin sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/cp70 with the demethylating agent 2-deoxy-5'-azacytidine induces resensitization to cisplatin and re expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS and PSMB9) acquired methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (ARMCX2, COL1A1, MDK, MEST and MLH1) acquired methylation in drug-resistant ovarian cancer-sustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into cells in vitro. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further evaluated as clinical biomarkers of drug resistance. PMID- 22249250 TI - FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-kappaB signaling. AB - Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-kappaB (NF-kappaB) in BLBC cells by increasing p65/RelA protein stability. High NF-kappaB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-kappaB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-kappaB. These results suggest that BLBC cells may rely on FOXC1-driven NF-kappaB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC. PMID- 22249252 TI - The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. AB - Lysophosphatidic acid (LPA) is a biolipid that has diverse biological activities implicated in ovarian cancer initiation and progression. Previous studies have shown the critical role of the Rho/Rho-associated kinase (ROCK) pathway in LPA induced ovarian cancer progression. However, detailed underlying mechanism by which the Rho/ROCK pathway induces ovarian cancer cell invasion is still incompletely understood. In the present study, we observed that the Rho/ROCK pathway is implicated in the production of proteolytic enzymes, leading to LPA induced ovarian cancer cell invasion. LPA induced matrix metalloproteinase (MMP) 9 expression in CAOV-3 and PA-1 cells and urokinase-type plasminogen activator (uPA) expression in SKOV-3 cells. LPA-induced proteolytic enzyme expression was required for the invasion of ovarian cancer cells expressing corresponding enzymes. Pretreatment of cells with a pharmacological inhibitor of Rho/ROCK (Y 27632) or overexpression of a dominant-negative mutant of Rho (Rho N19) profoundly inhibited LPA-induced proteolytic enzyme expression as well as the invasive potential of ovarian cancer cells. In addition, transfection with dominant-negative Ras (Ras N17) significantly inhibited LPA-induced Rho activation as well as MMP-9 and uPA expression. Consistently, Y-27632 reduced LPA induced nuclear factor (NF)-kappaB activation that is critical for proteolytic enzyme expression and cellular invasion. Collectively, we demonstrate a mechanism by which LPA promotes ovarian cancer progression through coordinate activation of a Ras/Rho/ROCK/NF-kappaB signaling pathway and the proteolytic enzyme secretion, providing novel biomarkers and promising therapeutic targets for ovarian cancer cell progression. PMID- 22249251 TI - Stress-induced NQO1 controls stability of C/EBPalpha against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer. AB - Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT enhancer binding protein (C/EBPalpha) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis revealed that disruption of the NQO1 gene in mice and mouse keratinocytes led to degradation of C/EBPalpha and loss of p63 gene expression. p63 promoter mutagenesis, transfection and chromatin immunoprecipitation assays identified a C/EBPalpha-binding site between nucleotide position -185 and -174 that bound to C/EBPalpha and upregulated p63 gene expression. Co-immunoprecipitation and immunoblot analysis demonstrated that 20S proteasomes directly interacted and degraded C/EBPalpha. NQO1 direct interaction with C/EBPalpha led to stabilization of C/EBPalpha against 20S proteasomal degradation. NQO1 protection of C/EBPalpha required binding of NADH with NQO1. Exposure of skin and keratinocytes to the chemical stress agent benzo(a)pyrene led to induction of NQO1 and stabilization of C/EBPalpha protein, resulting in an increase in p63 RNA and protein in wild-type but not in NQO1-/- mice. Collectively, the current data combined with previous data suggest that stress induction of NQO1 through both stabilization of C/EBPalpha and increase in p63 and direct stabilization of p63 controls keratinocyte differentiation, leading to protection against chemical-induced skin carcinogenesis. The studies are significant as 2-4% human individuals are homozygous and 23% are heterozygous for the NQO1P187S mutation and might be susceptible to stress-induced skin diseases. PMID- 22249253 TI - A role for Mediator complex subunit MED13L in Rb/E2F-induced growth arrest. AB - The Rb/E2F pathway is deregulated in virtually all human tumors. It is clear that, in addition to Rb itself, essential cofactors required for transcriptional repression and silencing of E2F target genes are mutated or lost in cancer. To identify novel cofactors required for Rb/E2F-mediated inhibition of cell proliferation, we performed a genome-wide short hairpin RNA screen. In addition to several known Rb cofactors, the screen identified components of the Mediator complex, a large multiprotein coactivator required for RNA polymerase II transcription. We show that the Mediator complex subunit MED13L is required for Rb/E2F control of cell growth, the complete repression of cell cycle target genes, and cell cycle inhibition. PMID- 22249254 TI - Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155. AB - The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3'kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3'kinase activates Akt through its production of 3' phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3'kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34(+) MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3' untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR 155 and miR-210 might serve as novel therapeutic targets in MDS. PMID- 22249255 TI - Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways. AB - Loss of tumour suppressor gene function can occur as a result of epigenetic silencing of large chromosomal regions, referred to as long-range epigenetic silencing (LRES), and genome-wide analyses have revealed that LRES is present in many cancer types. Here we utilize Illumina Beadchip methylation array analysis to identify LRES across 800 kb of chromosome 5q31 in colorectal adenomas and carcinomas (n=34) relative to normal colonic epithelial DNA (n=6). This region encompasses 53 individual protocadherin (PCDH) genes divided among three gene clusters. Hypermethylation within these gene clusters is asynchronous; while most PCDH hypermethylation occurs early, and is apparent in adenomas, PCDHGC3 promoter methylation occurs later in the adenoma-carcinoma transition. PCDHGC3 was hypermethylated in 17/28 carcinomas (60.7%) according to methylation array analysis. Quantitative real-time reverse transcription-polymerase chain reaction showed that PCDHGC3 is the highest expressed PCDH in normal colonic epithelium, and that there was a strong reciprocal relationship between PCDHGC3 methylation and expression in carcinomas (R=-0.84). PCDH LRES patterns are reflected in colorectal tumour cell lines; adenoma cell lines are not methylated at PCDHGC3 and show abundant expression at the mRNA and protein level, while the expression is suppressed in hypermethylated carcinoma cell lines (R=-0.73). Short interfering RNA-mediated reduction of PCDHGC3 led to a decrease of apoptosis in RG/C2 adenoma cells, and overexpression of PCDHGC3 in HCT116 cells resulted in the reduction of colony formation, consistent with tumour suppressor capabilities for PCDHGC3. Further functional analysis showed that PCDHGC3 can suppress Wnt and mammalian target of rapamycin signalling in colorectal cancer cell lines. Taken together, our data suggest that the PCDH LRES is an important tumour suppressor locus in colorectal cancer, and that PCDHGC3 may be a strong marker and driver for the adenoma-carcinoma transition. PMID- 22249256 TI - SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. AB - The epithelial-to-mesenchymal transition (EMT) is a crucial program for the invasion and metastasis of epithelial tumors that involves loss of cell-cell adhesion and increased cell mobility; however, mechanisms underlying this transition are not fully elucidated. Here, we propose a novel mechanism through which the nicotinamide adenine dinucleotide-dependent histone deacetylase SIRT1 regulates EMT in prostate cancer cells through cooperation with the EMT inducing transcription factor ZEB1. We found that forced expression of SIRT1 in non transformed PZ-HPV-7 prostate epithelial cells disrupts the epithelial morphology concomitant with decreased expression of the epithelial marker, E-cadherin, and increased expression of mesenchymal markers. In contrast, silencing SIRT1 in metastatic prostate tumor cells restores cell-cell adhesion and induces a shift toward an epithelial morphology concomitant with increased expression of E cadherin and decreased expression of mesenchymal markers. We also found that SIRT1 has a physiologically relevant role in endogenous EMT induced by EGF signaling in prostate cancer cells. We propose that the regulation of EMT by SIRT1 involves modulation of, and cooperation with, the EMT inducing transcription factor ZEB1. Specifically, we show that SIRT1 silencing reduces expression of ZEB1 and that SIRT1 is recruited to the E-cadherin proximal promoter by ZEB1 to deacetylate histone H3 and to reduce binding of RNA polymerase II, ultimately suppressing E-cadherin transcription. We thus identify a necessary role for ZEB1 in SIRT1-mediated EMT. Finally, we show that reduction of SIRT1 decreases prostate cancer cell migration in vitro and metastasis in vivo in immunodeficient mice, which is largely independent of any general effects of SIRT1 on prostate cancer growth and survival. We therefore identify SIRT1 as a positive regulator of EMT and metastatic growth of prostate cancer cells and our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse EMT and to prevent prostate cancer progression. PMID- 22249257 TI - Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers. AB - We previously demonstrated that the transcription factor NF-E2-related factor2 (Nrf2), expressed abundantly in non-small-cell lung cancer (NSCLC) cells, plays a pivotal role in the proliferation and chemoresistance of NSCLC. Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1). NSCLC cells expressing wild-type EGFR and Keap1 genes show enhanced proliferation on stimulation with EGFR ligand under non-stress conditions. Exposure to cigarette smoke extract (CSE) enhanced cell proliferation by modification of the Nrf2/Keap1 interaction. Although EGFR-tyrosine kinase inhibitor (TKI) inhibited the proliferation of these cells, exposure to CSE attenuated its efficacy. In NSCLC cells with Keap1 gene mutations, Nrf2 was constitutively activated owing to dysfunction of Keap1 and cells proliferated independently of EGFR signaling. Furthermore, EGFR-TKI was unable to inhibit their proliferation. In NSCLC cells with EGFR gene mutations, Nrf2 was constitutively activated by EGFR signaling. In these cells, proliferation was largely dependent on the EGFR signaling pathway. Although these cells were highly sensitive to EGFR-TKI, exposure to CSE or knockdown of Keap1 mRNA reduced sensitivity to EGFR-TKI. We found a case of NSCLC showing resistance to EGFR-TKI despite having EGFR-TKI-sensitive EGFR gene mutation because of dysfunctional mutation in Keap1 gene. Results indicate that oxidative stress reduces the anticancer effects of EGFR-TKI in wild-type Keap1 NSCLC cells. Analysis of Keap1 dysfunction may become a novel molecular marker to predict resistance to EGFR-TKI in NSCLC cells having EGFR-TKI-sensitive EGFR mutations. Finally, as the downstream molecule of both EGFR and Keap1 signaling, Nrf2 is an important molecular target for the treatment of NSCLC, where cells have mutations in EGFR, KRAS or Keap1 genes. PMID- 22249258 TI - Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells. AB - Pharmacological resistance is a serious threat to the clinical success of hormone therapy for breast cancer. The antiproliferative response to antagonistic drugs such as tamoxifen (Tam) critically depends on the recruitment of NCoR/SMRT corepressors to estrogen receptor alpha (ERalpha) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin-1beta (IL 1beta) treatment, the protein Tab2 interacts with ERalpha/NCoR and causes dismissal of NCoR from these genes, leading to loss of the antiproliferative response. In Tam-resistant (TamR) ER-positive breast cancer cells, we observed that Tab2 presents a shift in mobility on sodium dodecyl sulfate--PAGE (SDS-PAGE) similar to that seen in MCF7 wt upon stimulation with IL-1beta, suggesting constitutive activation. Accordingly, TamR treatment with Tab2-specific short interfering RNA, restored the antiproliferative response to Tam in these cells. As Tab2 is known to directly interact with the N-terminal domain of ERalpha, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERalpha/Tab2 interaction in pull-down and co-immunoprecipitation experiments, fused to the carrier TAT peptide to allow internalization. Treatment of TamR cells with this peptide resulted in partial recovery of the antiproliferative response to Tam, suggesting a strategy to revert pharmacological resistance in breast cancer. Silencing of Tab2 in TamR cells by siRNA caused modulation of a gene set related to the control of cell cycle and extensively connected to BRCA1 in a functional network. These genes were able to discern two groups of patients, from a published data set of Tam-treated breast cancer profiles, with significantly different disease-free survival. Altogether, our data implicate Tab2 as a mediator of resistance to endocrine therapy and as a potential new target to reverse pharmacological resistance and potentiate antiestrogen action. PMID- 22249259 TI - Functional interplay between p53 acetylation and H1.2 phosphorylation in p53 regulated transcription. AB - Linker histone H1.2 has been shown to suppress p53-dependent transcription through the modulation of chromatin remodeling; however, little is known about the mechanisms governing the antagonistic effects of H1.2 in DNA damage response. Here, we show that the repressive action of H1.2 on p53 function is negatively regulated via acetylation of p53 C-terminal regulatory domain and phosphorylation of H1.2 C-terminal tail. p53 acetylation by p300 impairs the interaction of p53 with H1.2 and triggers a rapid activation of p53-dependent transcription. Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation. Consistent with these findings, point mutations mimicking modification states of H1.2 and p53 lead to a significant increase in p53-induced apoptosis. These data suggest that p53 acetylation-H1.2 phosphorylation cascade serves as a unique mechanism for triggering p53-dependent DNA damage response pathways. PMID- 22249260 TI - Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma. AB - Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short form ALK protein (ALK(del2-3)) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK(del2-3) was autophosphorylated in NB-1 cells as well as in ALK(del2-3) transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK(del2-3)-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi mediated ALK knockdown resulted in the growth suppression of ALK(del2-3) expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis. PMID- 22249261 TI - Dickkopf 4 (DKK4) acts on Wnt/beta-catenin pathway by influencing beta-catenin in hepatocellular carcinoma. AB - Deregulation of Wnt/beta-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of beta catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/beta-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in beta-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated beta-catenin responsive luciferase activity, and decreased both beta-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n=8), reduction in tumour sizes was observed (P=0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with beta-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of beta-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC. PMID- 22249262 TI - Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1. AB - The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas. PMID- 22249263 TI - Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling. AB - Papillomavirus E6 oncoproteins associate with LXXLL motifs on target cellular proteins to alter their function. Using a proteomic approach, we found the E6 oncoproteins of cutaneous papillomaviruses Bovine Papillomavirus Type 1 (BPV-1) E6 and human papillomavirus (HPV) types 1 and 8 (1E6 and 8E6) associated with the MAML1 transcriptional co-activator. All three E6 proteins bind to an acidic LXXLL motif at the carboxy-terminus of MAML1 and repress transactivation by MAML1. MAML1 is best known as the co-activator and effector of NOTCH-induced transcription, and BPV-1 E6 represses synthetic NOTCH-responsive promoters, endogenous NOTCH-responsive promoters, and is found in a complex with MAML1 in stably transformed cells. BPV-1-induced papillomas show characteristics of repressed NOTCH signal transduction, including suprabasal expression of integrins, talin and basal type keratins, and delayed expression of the NOTCH dependent HES1 transcription factor. These observations give rise to a model whereby papillomavirus oncoproteins, including BPV-1 E6, and the cancer associated HPV-8 E6 repress NOTCH-induced transcription, thereby delaying keratinocyte differentiation. PMID- 22249264 TI - MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma. AB - The c-Src kinase regulates cancer cell invasion through inhibitor of DNA binding/differentiation 1 (ID1). Src and ID1 are frequently overexpressed in human lung adenocarcinoma. The current study aimed at identifying microRNAs (miRNAs) involved in the Src-ID1 signaling in lung cancer. Incubation of lung cancer cells with the Src inhibitor saracatinib led to the upregulation of several miRNAs including miR-29b, which was the most highly upregulated miRNA with predicted binding to the ID1 3'-untranslated region (UTR). Luciferase reporter assays confirmed direct binding of miR-29b to the ID1 3'-UTR. Expression of miR-29b suppressed ID1 levels and significantly reduced migration and invasion. Expression of antisense-miR-29b (anti-miR-29b), on the other hand, enhanced ID1 mRNA and protein levels, and significantly increased lung cancer cell migration and invasion, a hallmark of the Src-ID1 pathway. The ectopic expression of ID1 in miR-29b-overexpressing cells was able to rescue the migratory potential of these cells. Both, anti-miR-29b and ID1 overexpression diminished the effects of the Src inhibitors saracatinib and dasatinib on migration and invasion. Saracatinib and dasatinib decreased c-Myc transcriptional repression on miR-29b and led to increased ID1 protein levels, whereas forced expression of c-Myc repressed miR-29b and induced ID1. In agreement, we showed direct recruitment of c-Myc to the miR-29b promoter. miR-29b was significantly downregulated in primary lung adenocarcinoma samples compared with matched alveolar lung tissue, and miR-29b expression was a significant prognostic factor for patient outcome. These results suggest that miR-29b is involved in the Src ID1 signaling pathway, is dysregulated in lung adenocarcinoma and is a potential predictive marker for Src kinase inhibitors. PMID- 22249265 TI - CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. AB - Protein phosphatase 2A (PP2A) is a critical human tumor-suppressor complex. A recently characterized PP2A inhibitor protein, namely cancerous inhibitor of PP2A (CIP2A), has been found to be overexpressed at a high frequency in most of the human cancer types. However, our understanding of gene expression programs regulated by CIP2A is almost absent. Moreover, clinical relevance of the CIP2A regulated transcriptome has not been addressed thus far. Here, we report a high confidence transcriptional signature regulated by CIP2A. Bioinformatic pathway analysis of the CIP2A signature revealed that CIP2A regulates several MYC dependent and MYC-independent gene programs. With regard to MYC-independent signaling, JNK2 expression and transwell migration were inhibited by CIP2A depletion, whereas MYC depletion did not affect either of these phenotypes. Instead, depletion of either CIP2A or MYC inhibited cancer cell colony growth with statistically indistinguishable efficiency. Moreover, CIP2A depletion was shown to regulate the expression of several established MYC target genes, out of which most were MYC-repressed genes. CIP2A small-interfering RNA-elicited inhibition of colony growth or activation of MYC-repressed genes was reversed at large by concomitant PP2A inhibition. Finally, the CIP2A signature was shown to cluster with basal-type and human epidermal growth factor receptor (HER)2 positive (HER2+) breast cancer signatures. Accordingly, CIP2A protein expression was significantly associated with basal-like (P=0.0014) and HER2+ (P<0.0001) breast cancers. CIP2A expression also associated with MYC gene amplification (P<0.001). Taken together, identification of CIP2A-driven transcriptional signature, and especially novel MYC-independent signaling programs regulated by CIP2A, provides important resource for understanding CIP2A's role as a clinically relevant human oncoprotein. With regard to MYC, these results both validate CIP2A's role in regulating MYC-mediated gene expression and provide a plausible novel explanation for the high MYC activity in basal-like and HER2+ breast cancers. PMID- 22249267 TI - Diversity within the pRb pathway: is there a code of conduct? AB - The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein (pRb) pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post translational modifications that occur on pRb together with its key effector E2F 1. Here we provide an overview of the modifications and consider the possibility of a 'code' that endows pRb with the ability to function in diverse physiological settings. PMID- 22249266 TI - A Notch1-neuregulin1 autocrine signaling loop contributes to melanoma growth. AB - The Notch pathway is an evolutionary conserved signaling cascade that has an essential role in melanoblast and melanocyte stem cell homeostasis. Notch signaling is emerging as a key player in melanoma, the most deadly form of skin cancer. In melanoma, Notch1 is inappropriately reactivated and contributes to melanoma tumorigenicity. Here, we propose a novel mechanism by which Notch1 promotes the disease. We found that Notch1 directly regulates the transcription of neuregulin1 (NRG1) by binding to its promoter region. NRG1 is the ligand for ERBB3 and 4, members of the epidermal growth factor family of receptors that are involved in the genesis and progression of a number of cancers. Notch1 and NRG1 expression are associated in melanoma and inhibition of NRG1 signaling leads to melanoma cell growth inhibition and tumor growth delay. Mechanistically, these effects are associated with the inhibition of the PI3Kinase/Akt signaling pathway and with the accumulation of p27(Kip1). On the other end, addition of recombinant NRG1 can partially restore melanoma cell growth that is inhibited by Notch1 ablation. Taken together, our findings underline a new, previously undescribed autocrine signaling loop between Notch1 and NRG1 that controls melanoma growth and provide experimental evidence that the targeting of Notch and ERBB signaling may represent a novel potential therapeutic approach in melanoma. PMID- 22249268 TI - MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition. AB - Trastuzumab (Herceptin) resistance is a major obstacle in the treatment of patients with HER2-positive breast cancers. We recently reported that the transcription factor Y-box binding protein-1 (YB-1) leads to acquisition of resistance to trastuzumab in a phosphorylation-dependent manner that relies on p90 ribosomal S6 kinase (RSK). To explore how this may occur we compared YB-1 target genes between trastuzumab-sensitive cells (BT474) and those with acquired resistance (HR5 and HR6) using genome-wide chromatin immunoprecipitation sequencing (ChIP-sequencing), which identified 1391 genes uniquely bound by YB-1 in the resistant cell lines. We then examined differences in protein expression and phosphorylation between these cell lines using the Kinexus Kinex antibody microarrays. Cross-referencing these two data sets identified the mitogen activated protein kinase-interacting kinase (MNK) family as potentially being involved in acquired resistance downstream from YB-1. MNK1 and MNK2 were subsequently shown to be overexpressed in the resistant cell lines; however, only the former was a YB-1 target based on ChIP-PCR and small interfering RNA (siRNA) studies. Importantly, loss of MNK1 expression using siRNA enhanced sensitivity to trastuzumab. Further, MNK1 overexpression was sufficient to confer resistance to trastuzumab in cells that were previously sensitive. We then developed a de novo model of acquired resistance by exposing BT474 cells to trastuzumab for 60 days (BT474LT). Similar to the HR5/HR6 cells, the BT474LT cells had elevated MNK1 levels and were dependent on it for survival. In addition, we demonstrated that RSK phosphorylated MNK1, and that this phosphorylation was required for ability of MNK1 to mediate resistance to trastuzumab. Furthermore, inhibition of RSK with the small molecule BI-D1870 repressed the MNK1-mediated trastuzumab resistance. In conclusion, this unbiased integrated approach identified MNK1 as a player in mediating trastuzumab resistance as a consequence of YB-1 activation, and demonstrated RSK inhibition as a means to overcome recalcitrance to trastuzumab. PMID- 22249269 TI - c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. AB - Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133(+)/Nestin(+) population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide- and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133(+)/Nestin(+) cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas. PMID- 22249270 TI - MiR-663, a microRNA targeting p21(WAF1/CIP1), promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma. AB - MicroRNAs (miRNAs) may function as either oncogenes or tumor suppressors in the malignant progression of different tumor types. MiR-663 was recently reported to be decreased and identified as a tumor suppressor in gastric cancer. We also verified its role in repressing cell proliferation of a gastric cancer cell line. In this study, however, miR-663 was found to be upregulated in nasopharyngeal carcinoma (NPC) cells compared with human immortalized nasopharyngeal epithelium cells, using a miRNA microarray, and this higher expression was confirmed in NPC tissue samples. Indeed, inhibition of miR-663 impaired the proliferation of NPC cells in vitro and the NPC tumor growth of xenografts in nude mice. Mechanistically, miR-663 directly targeted p21(WAF1/CIP1) to promote the cellular G1/S transition, as the inhibitory effects of miR-663 on the G1/S transition could be rescued by p21(WAF1/CIP1) silencing. Our results imply that miR-663 may act as an oncogene in NPC. The newly identified miR-663/p21(WAF1/CIP1) axis clarifies the molecular mechanism of NPC cell proliferation and represents a novel strategy for the diagnosis and treatment of patients with NPC. PMID- 22249271 TI - Dental compensation for moderate Class III with vertical growth pattern by extraction of the lower second molars. AB - OBJECTIVES: Analysis of the effects and side effects of treatment of patients with moderate skeletal Class III and vertical growth pattern by means of extraction of the second molars in the lower jaw. PATIENTS AND METHODS: A total of 20 patients with a mean age of 12.9 years were examined retrospectively. Inclusion criteria consisted of a Wits value of 0 to -5, a posterior growth pattern of the mandible (Hasund analysis), an overjet of -2 to 1 mm, and an overbite of 0 to -3 mm. Treatment was performed using a straight-wire appliance. As part of the treatment, the lower second molars were extracted and Class III elastics attached. Cephalograms and orthopantomograms taken before and after treatment were used for evaluation. RESULTS: Treatment resulted in a significant change in the mean overjet from 0.5 mm to 2.1 mm and the attainment of a positive mean overbite of -1.0 mm to 0.9 mm. The occlusal plane rotated anteriorly from 18.8 degrees to 13.7 degrees . The skeletal parameters showed a change in the Wits value from -3.3 mm to -1.4 mm and an anterior mandibular rotation (ML-NSL 35.5 degrees vs. 32.0 degrees ). The soft tissues revealed an increase in the distance between the lower lip and the "esthetic line" to the posterior (-2.0 mm vs. -3.9 mm). CONCLUSION: Dental compensation of moderate skeletal Class III with a tendency to an anterior open bite with vertical growth pattern by extracting the lower second molars, combined with Class III elastics, resulted in an anterior rotation of the occlusal plane and mandible. Eighteen of 20 patients achieved a physiological overjet and positive overbite. A prerequisite for this therapy is the presence of lower wisdom teeth; a potential side effect is elongation of the upper second molars. PMID- 22249272 TI - Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). AB - PURPOSE: To evaluate the efficacy and safety of the combination of gemcitabine (GEM) and S-1 (GS) in comparison to GEM alone (G) for unresectable pancreatic cancer. METHODS: In this multicenter randomized phase II study, we randomly assigned unresectable pancreatic cancer patients to either the GS group or the G group. The GS group regimen consists of intravenous 1,000 mg/m(2) GEM during 30 min on days 1 and 8, combined with 80 mg/m(2) oral S-1 twice daily on days 1-14, repeated every 3 weeks. On the other hand, the G group regimen consists of intravenous 1,000 mg/m(2) GEM on days 1, 8, and 15, repeated every 4 weeks. The primary endpoint was objective response rate (ORR). Secondary end points included treatment toxicity, clinical response benefit, progression-free survival (PFS), and overall survival. RESULTS: We registered 117 patients from 16 institutions between June 2007 and August, 2010. The ORR of the GS group was 28.3%, whereas that of the G group was 6.8%. This difference was statistically significant (P = 0.005). The disease control rate was 64.2% in the GS group and 44.1% in the G group. Median PFS was 6.15 months in the GS group and 3.78 month in the G group. This was also statistically significant (P = 0.0007). Moreover, the median overall survival (OS) of the GS group was significantly longer than that of the G group (13.7 months vs. 8.0 months; P = 0.035). The major grade 3-4 adverse events were neutropenia (54.7% in the GS group and 22.0% in the G group), thrombocytopenia (15.1% in the GS group and 5.1% in the G group), and skin rash (9.4% in the GS group). CONCLUSIONS: The GS group showed stronger anticancer activity than the G group, suggesting the need for a large randomized phase III study to confirm GS advantages in a specific subset. PMID- 22249273 TI - The survival of metallic residues from gunshot wounds in cremated bone: a SEM-EDX study. AB - The research and analysis of gunshot residues has a relevant role in the examination of gunshot wounds. Nevertheless, very little literature exists concerning gunshot wounds on charred material. In this study, 16 adult bovine ribs (eight still with soft tissues and eight totally skeletonized) underwent a shooting test with two types of projectiles (9 mm full metal-jacketed bullet and 9 mm unjacketed bullet). Each rib then underwent a charring process in an electric oven, reaching the stage of complete calcination at 800 degrees C. The area of each entrance wound was analyzed before and after the carbonization process via a scanning electron microscope (SEM) equipped with an energy dispersive X-ray analyzer (EDX). In each sample, metallic residues composed of lead, barium, and antimony were found. These metallic residues were thus preserved also after exposure to the extremely high temperatures reached within the oven, especially with unjacketed bullets, although the particles seem to be more irregular in shape as a result of the heating process. In conclusion, this study proved that gunshot residues survive extremely high temperatures and can be detected via SEM/EDX even in cases of charred tissues. PMID- 22249274 TI - A validation study of the Qiagen Investigator DIPplex(r) kit; an INDEL-based assay for human identification. AB - Marker sets that are based on small insertion/deletion (INDEL) alleles can serve as useful supplementary or stand-alone assays for human identification. A validation study has been performed on a human identification assay based on a panel of 30 INDELs and amelogenin using the Investigator DIPplex(r) kit (Qiagen). The assay was able to type DNA from a number of forensically relevant sample types and obtain full profiles with 62 pg of template DNA and partial profiles with as little as 16 pg of template DNA. The assay is reproducible, precise, and non-overlapping alleles from minor contributors were detectable in mixture analysis ranging from 6:1 to 19:1 mixtures. Population studies were performed on the 30 indels, and there were no significant departures from Hardy-Weinberg equilibrium or significant linkage disequilibrium between the markers (after correction for sampling). In all populations, the random match probability was 1.43 * 10(-11) or less, and the power of exclusion was greater than .999999999. We also discovered several microvariant alleles in our population samples. The data support that the Investigator DIPplex(r) kit provides a powerful supplement or stand-alone capability for human identity testing. PMID- 22249275 TI - Role of estrogen receptor alpha on vaginal epithelialization of patients with Mayer-Rokitansky-Kuster-Hauser syndrome submitted to neovaginoplasty using oxidized regenerated cellulose. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study was to evaluate the expression of estrogen receptor alpha (ERalpha) on the neovaginal tissue of patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome submitted to modified Abbe-McIndoe neovaginoplasty using oxidized regenerated cellulose. METHODS: The current study involved eight subjects with MRKH syndrome. Serial samples of the neovagina were obtained after the surgery and immunohistochemical detection of ERalpha was performed using antibody NCL-L-ER-6F11. RESULTS: The operation was performed successfully in all subjects without complications. A total of 22 samples of neovaginal tissue were analyzed. The expression of ERalpha was detected only 6 months after the surgery, when the neovagina acquired characteristics of normal vagina. CONCLUSION: In our study, the expression of ERalpha occurred when complete epithelialization of vaginal tissue was observed. Other mechanisms may be involved in the formation of vaginal epithelium in patients with MRKH syndrome. PMID- 22249277 TI - Does bladder wall thickness decrease when obstruction is resolved? AB - INTRODUCTION AND HYPOTHESIS: The aim of the current study was to determine if sonographic bladder wall thickness diminishes after symptomatic obstruction is resolved in female patients after stress incontinence surgery. METHODS: Between December 2008 and December 2010, 62 female patients with symptomatic bladder outlet obstruction, as defined by Blaivas, who had undergone prior surgery for urinary stress incontinence were included in the study. The patients' history was taken and symptoms were noted. Patients underwent gynaecological examination, and multichannel urodynamic assessment was performed. Vaginal sonographic assessment of the bladder wall thickness (BWT) was performed before and after urethrolysis. RESULTS: 62 patients were included in this study, 55 of whom had undergone suburethral sling insertion and seven had Burch colposuspension. Postoperatively, BWT decreased significantly from 9.1 mm +/- 2.1 to 7.6 mm +/- 2.2 (p < 0.0001). In seven patients, obstruction was still unresolved postoperatively; of these, two had undergone a retropubic sling insertion and two had a Burch colposuspension. An ROC curve analysis showed a significant positive association between residual urine and persistent obstruction before surgery (AUC 0.76, 95%CI 0.58-0.94; p < 0.05). CONCLUSIONS: If obstruction is resolved, bladder wall thickness decreases. Preoperatively elevated residual urine may increase the risk of persistent obstruction after urethrolysis. PMID- 22249278 TI - Correlation of POP-Q posterior compartment measures with defecatory dysfunction. AB - INTRODUCTION AND HYPOTHESIS: The relationships of Pelvic Organ Prolapse Quantification (POP-Q) items pb and Bp with defecatory dysfunction were evaluated with the hypothesis that increased values for both items would correlate with symptoms of stool trapping. METHODS: Pelvic Floor Distress Inventory (PFDI-20) results and POP-Q exams from 1,663 urogynecology patients were compiled in a database. Rectocele was defined as POP-Q point Bp > -0.5 and perineocele as pb >3. PFDI-20 questions were used to compare defecatory symptoms and bother in women with and without rectocele and perineocele. RESULTS: While perineocele was not associated with symptoms or bother, women with isolated rectoceles had higher rates of splinting (p < 0.001) and incomplete evacuation (p = 0.001) and higher bother scores (p < 0.001) than those with neither rectocele nor perineocele. CONCLUSIONS: The POP-Q Bp point, but not the pb measurement, correlates with symptoms of defecatory dysfunction. PMID- 22249279 TI - Evidence of a functional effect of transient transurethral catheterization on micturition in women. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study is to evaluate the effect of transient catheterization on uroflow parameters. METHODS: Consenting women (ages 18-90) provided an uninstrumented uroflow pre- and post-indicated in urodynamic procedures. Voided volume, Qmax, and Qave were recorded for both uninstrumented uroflows. Uroflow curves were classified as "normal" or "abnormal." Pre- and post-urodynamic uroflow data were compared. RESULTS: Thirty five patients were included in the study. There was a statistically significant decrease in Qave from the pre- to the post-urodynamic uroflows from 14.71 to 10.55 ml/s (p = 0.012). Additionally, 28.6% of uroflow tracing patterns changed from "normal" to "abnormal," whereas only one (2.9%) changed from "abnormal" to "normal" (p = 0.031). CONCLUSIONS: This study showed a degradative effect of transient catheterization on uroflow parameters, suggesting that catheterization may cause more than simply a passive obstructive effect. Urethral stimulation due to catheterization may perturb detrusor urethral function, altering voiding and possibly filling performance. PMID- 22249281 TI - Modified laparoscopic extraperitoneal uterine suspension to anterior abdominal wall: the easier way to treat uterine prolapse. AB - INTRODUCTION AND HYPOTHESIS: To report the outcomes of modified laparoscopic extraperitoneal uterine suspension to anterior abdominal wall for uterine prolapse using mesh. METHODS: Twenty-two patients with uterovaginal prolapse, stage 2 or greater according to pelvic organ prolapse quantification (POP-Q), and with desire for uterine preservation, underwent modified laparoscopic extraperitoneal uterine suspension to the anterior abdominal wall bilaterally using mesh. The outcomes were measured by POP-Q and quality-of-life questionnaires. Intraoperative or postoperative complications were also observed. RESULTS: Patient age was 61.4 +/- 12 years, and parity was 3.3 +/- 1.8. After surgery, there was significant improvement in POP-Q measurements of Ba, Bp, and C (P < 0.001). The objective cure rate at 1 year was 100%. A significant improvement in quality-of-life scores was observed (P < 0.001). There were no major intraoperative or postoperative complications. However, all patients reported postoperative dragging pain at the points of puncture ports where the mesh was fixed to the abdominal wall. The visual analog scale decreased from a mean 3-day score of 2.9-0 at 1-month follow-up. CONCLUSIONS: Modified laparoscopic extraperitoneal uterine suspension to the anterior abdominal wall using mesh is a feasible and effective method for treating uterine prolapse and is easy to perform. PMID- 22249280 TI - Cystocele repair by vaginal route: comparison of three different surgical techniques of mesh placement. AB - INTRODUCTION AND HYPOTHESIS: Different techniques of mesh placement for cystocele repair are known. Our goal was to compare anatomical and functional outcomes of three different techniques of mesh placement over a 3-year follow-up. METHODS: Between March 2003 and June 2004, 230 patients (stage 2-4 pelvic organ prolapse (POP)) were included in a prospective study. For cystocele repair, mesh was implanted either with two arms into the retropubic space (RP) or with two to four arms into the obturator foramen (TO), or fixed to the arcus tendineous fascia pelvis (FG). RESULTS: Patients' distribution is as follows: 142 TO, 32 RP, and 31 FG. Anatomical success (cystocele < stage 2 in the POP staging system) was clearly poorer after the retropubic free technique, with success rates of 69% (RP), 90.1% (TO), and 96.6% (FG) (p = 0.004). POP distress inventory (p < 0.005) and POP impact questionnaire scores were both significantly poorer after RP. CONCLUSIONS: RP technique is less effective than TO and FG techniques. PMID- 22249282 TI - A patient with possible TRALI who developed pulmonary hypertensive crisis and acute pulmonary edema during cardiac surgery. AB - There are very few case reports of transfusion-related acute lung injury (TRALI) under close hemodynamic monitoring. We encountered a case of possible TRALI during on-pump coronary artery bypass grafting (CABG). A 66-year-old man who had undergone on-pump CABG was administered fresh frozen plasma (FFP). One hour after FFP transfusion, pulmonary hypertensive crisis and subsequent hypoxic decompensation occurred. A second cardiopulmonary bypass (CPB) was needed for circulatory and respiratory deterioration. Extracorporeal life support (ECLS), intraaortic balloon pumping (IABP), and nitric oxide therapy were required after the surgery. Despite the severity of the initial state, his recovery was comparatively smooth. ECLS and IABP were removed on postoperative day (POD)1; the patient was extubated and discharged from the ICU on POD7 and POD12, respectively. The diagnosis of TRALI was confirmed by human leukocyte antigen antibody detection in the administered FFP. In addition, lymphocytic immunofluorescence test showed that a cross-match of the plasma from the pooled FFP against the recipient leukocytes was positive. The clinical course of the pulmonary artery hypertension was followed by a decrease in dynamic lung compliance. The mechanism of this phenomenon is unclear. However, it might suggest the possibility of vasoconstriction or obstruction of the peripheral pulmonary artery preceding lung damage, as in the case in animal models reported previously. PMID- 22249283 TI - Effect of endurance exercise on respiratory muscle function in patients with cystic fibrosis. AB - During exercise, patients with cystic fibrosis (CF) dynamically hyperinflate, which imposes both elastic and threshold loads on the inspiratory muscles and places them at a mechanical disadvantage due to muscle shortening. Conversely, dynamic hyperinflation imposes a progressively resistive load and lengthens the expiratory muscles potentially increasing their susceptibility to develop low frequency fatigue (LFF). The aim of the study was to determine whether high intensity endurance exercise leads to the development of LFF in either the diaphragm or expiratory abdominal wall muscles in patients with CF. Ten patients and ten healthy individuals were studied. Twitch transdiaphragmatic pressure (TwP(di)) and twitch abdominal pressure (TwT(10)) were measured before and after exhaustive endurance cycle exercise at 80% of their previously determined maximum work rate. There was no difference in TwP(di) or TwT(10) at 20, 40 or 60 min post exercise compared to pre-exercise resting values in any of the participants, indicating that overt LFF of the respiratory muscles did not develop. PMID- 22249284 TI - Investigation of band offsets of interface BiOCl:Bi2WO6: a first-principles study. AB - Density functional theory calculations are performed to study the band offsets at the interface of two photocatalytic materials BiOCl:Bi(2)WO(6). It is found that the W-O bonded interface shows the most stability. An intrinsic interface fails to enhance the charge-carrier separation due to the improper band alignment between these two materials. Sulfur (S) is proposed to replace the bulk oxygen (O) site and thus tune the band edges of BiOCl to enhance the photocatalytic performance of the heterojunction. Furthermore, the presence of S provides an extra charge to generate a clean interface with minimal gap states that also benefits carrier migration across the heterojunction. PMID- 22249285 TI - Hepatitis B vaccine induces apoptotic death in Hepa1-6 cells. AB - Vaccines can have adverse side-effects, and these are predominantly associated with the inclusion of chemical additives such as aluminum hydroxide adjuvant. The objective of this study was to establish an in vitro model system amenable to mechanistic investigations of cytotoxicity induced by hepatitis B vaccine, and to investigate the mechanisms of vaccine-induced cell death. The mouse liver hepatoma cell line Hepa1-6 was treated with two doses of adjuvanted (aluminium hydroxide) hepatitis B vaccine (0.5 and 1 MUg protein per ml) and cell integrity was measured after 24, 48 and 72 h. Hepatitis B vaccine exposure increased cell apoptosis as detected by flow cytometry and TUNEL assay. Vaccine exposure was accompanied by significant increases in the levels of activated caspase 3, a key effector caspase in the apoptosis cascade. Early transcriptional events were detected by qRT-PCR. We report that hepatitis B vaccine exposure resulted in significant upregulation of the key genes encoding caspase 7, caspase 9, Inhibitor caspase-activated DNase (ICAD), Rho-associated coiled-coil containing protein kinase 1 (ROCK-1), and Apoptotic protease activating factor 1 (Apaf-1). Upregulation of cleaved caspase 3,7 were detected by western blot in addition to Apaf-1 and caspase 9 expressions argues that cell death takes place via the intrinsic apoptotic pathway in which release of cytochrome c from the mitochondria triggers the assembly of a caspase activation complex. We conclude that exposure of Hepa1-6 cells to a low dose of adjuvanted hepatitis B vaccine leads to loss of mitochondrial integrity, apoptosis induction, and cell death, apoptosis effect was observed also in C2C12 mouse myoblast cell line after treated with low dose of vaccine (0.3, 0.1, 0.05 MUg/ml). In addition In vivo apoptotic effect of hepatitis B vaccine was observed in mouse liver. PMID- 22249286 TI - Swelling rather than shrinkage precedes apoptosis in serum-deprived vascular smooth muscle cells. AB - Contrasting cell volume behaviours (swelling vs. shrinkage) are considered as criteria to distinguish necrosis from apoptosis. In this study, we employed a time-lapse, dual-image surface reconstruction technique to assess the volume of single vascular smooth muscle cells transfected with E1A-adenoviral protein (E1A VSMC) and undergoing rapid apoptosis in the absence of growth factors or in the presence of staurosporine. After 30- to 60-min lag-phase, serum-deprived E1A-VSMC volume was increased by ~40%, which preceded maximal increments of caspase-3 activity and chromatin cleavage. Swollen cells underwent rapid apoptotic collapse, documented by plasma membrane budding, and terminated in 10-15 min by the formation of numerous apoptotic bodies. Suppression of apoptosis by inhibition of Na(+),K(+)-ATPase and activation of cAMP signalling with ouabain and forskolin, respectively, completely abolished the swelling of serum-deprived E1A-VSMC. In contrast to serum deprivation, apoptotic collapse of staurosporine treated E1A-VSMC preceded attenuation of their volume by ~30%. Neither transient hyposmotic swelling nor isosmtotic shrinkage triggered apoptosis. Our results show that cell shrinkage can not be considered as ubiquitous hallmark of apoptosis. The involvement of stimulus-specific cell volume perturbations in initiation and progression of apoptosis in vascular smooth muscle cells should be examined further. PMID- 22249287 TI - Association of CTLA-4 gene polymorphisms with sporadic breast cancer risk and clinical features in Han women of northeast China. AB - Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that plays a pivotal role in downregulating T-cell mediated immune responses. To determine the role of CTLA-4 in tumor immunity, and to validate previous results as well, we investigated four tag single nucleotide polymorphisms (SNPs) of CTLA-4 in a relatively large Chinese Han cohort from northeastern China. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 581 patients and 566 age-matched controls. Our data indicated that compared with the common genotype and allele of each SNP, the -1722 CC genotype and C allele showed an increased risk of breast cancer (P = 0.030, odds ratio (OR) = 1.457, 95% confidence internal (CI) 1.036-2.051; P = 0.024, OR = 1.214, 95% CI 1.026-1.436, respectively). The -1661 GG genotype and G allele were also associated with an increased risk of breast cancer (P = 0.018, OR = 1.396, 95% CI 1.058-1.843; P = 0.013, OR = 1.353, 95% CI 1.066-1.717, respectively). In the haplotype analysis, the CAAA haplotype showed a higher frequency in cases (P = 0.004), and this association remained significant after correcting the P value for multiple testing. Associations were shown between the SNPs of CTLA-4 and lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR) and P53 statuses. These results indicate that some SNPs in the CTLA-4 gene may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in Han women in northeastern China. PMID- 22249288 TI - White matter lesions and intra-arterial thrombolysis. AB - The aim of the study was to assess the influence of white matter lesions in patients with acute ischemic stroke treated with intra-arterial thrombolysis (IAT). From September 2003 to January 2010, we treated 400 patients with IAT at our institution. Of these patients, 292 were evaluated with MRI scans and included in this observational study. Clinical data were collected prospectively. Outcome after 3 months was measured with the modified Rankin Scale (mRS); mRS 0-1 was considered as favorable outcome. White matter lesions were scored visually by two observers using the semiquantitative Scheltens and Fazekas scores. Logistic regression analysis was used to identify the association of white matter lesions and clinical outcome, recanalization, and cerebral hemorrhage. The severity of white matter lesions was inversely correlated with favorable outcome, survival and successful recanalization. White matter lesions were an independent predictor of outcome (OR 0.569, p = 0.007) and survival (OR 0.550, p = 0.018) and a weak but independent predictor for recanalization (OR 0.949, p = 0.038). Asymptomatic intracerebral bleeding after IAT was associated with white matter lesions in the basal ganglia in the univariate analysis (p = 0.036), but not after multivariable analysis. The severity of white matter lesions independently predicts clinical outcome and survival in patients treated with IAT. White matter lesions are also a weak but independent predictor for recanalization. Symptomatic intracranial bleeding after IAT are not associated with white matter lesions. Therefore, white matter lesions should not be considered as a contraindication against IAT. PMID- 22249289 TI - Patterns of white matter diffusivity abnormalities in Leber's hereditary optic neuropathy: a tract-based spatial statistics study. AB - Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by retinal ganglion cell degeneration and optic nerve atrophy, leading to a loss of central vision. The aim of this study was to explore the topographical pattern of damage to the brain white matter (WM) tracts from patients with chronic LHON using diffusion tensor (DT) MRI and tract-based spatial statistics (TBSS). Brain dual-echo and DT MRI scans were acquired from 13 patients with chronic LHON and 25 matched controls using a 3.0 T scanner. TBSS analysis was performed using the FMRIB's Diffusion Toolbox. A complete neuro ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary retinal nerve fiber layer thickness (PRNFL) measurements, was obtained in all patients. Mean average and temporal PRNFL thicknesses were decreased significantly in LHON patients. Compared to controls, TBSS analysis revealed significant diffusivity abnormalities in these patients, which were characterized by a decreased fractional anisotropy (FA) and an increased mean diffusivity and radial diffusivity, affecting exclusively the optic tracts and optic radiations (OR). In patients, a significant correlation was found between optic tract average FA and mean visual acuity (r = 0.57, p = 0.04). In LHON patients, DT MRI reveals a microstructural alteration of the WM along the entire visual pathways, with a sparing of the other main WM tracts of the brain. Damage to the OR may be secondary either to trans-synaptic degeneration, which in turn is due to neuroaxonal loss in the retina and optic nerve, or to local mitochondrial dysfunction. PMID- 22249290 TI - Adiponectin inhibits oxidative stress in human prostate carcinoma cells. AB - BACKGROUND: Emerging data suggest that obesity increases the risk of aggressive prostate cancer (PC), but the mechanisms underlying this relationship remain to be fully elucidated. Oxidative stress (OS) is a key process in the development and progression of PC. Adiponectin, an adipocyte-specific hormone, circulates at relatively high levels in healthy humans, but at reduced levels in obese subjects. Moreover, case-control studies also document lower levels of serum adiponectin in PC patients compared with healthy individuals. METHODS: Human 22Rv1 and DU-145 PC cell lines were examined for the generation of OS and detoxification of reactive oxygen species after treatment with adiponectin. Normality was confirmed using the Shapiro-Wilk test and results were analyzed using a one-way analysis of variance. RESULTS: We demonstrate that adiponectin increased cellular anti-oxidative defense mechanisms and inhibited OS in a significant and dose-dependent manner. We show that adiponectin treatment decreased the generation of superoxide anion in both cell lines, whereas the transcript levels of NADPH oxidase (NOX)2 and NOX4 increased. We also found indications of an overall anti-oxidative effect, as the total anti-oxidative potential, catalase activity and protein levels, and manganese superoxide dismutase protein levels increased significantly (P<0.05) in both cell lines after treatment with adiponectin. CONCLUSION: Lower levels of adiponectin in obese individuals may result in higher levels of prostatic OS, which may explain the clinical association between obesity, hypoadiponectinemia and PC. PMID- 22249291 TI - The dynamics of replication licensing in live Caenorhabditis elegans embryos. AB - Accurate DNA replication requires proper regulation of replication licensing, which entails loading MCM-2-7 onto replication origins. In this paper, we provide the first comprehensive view of replication licensing in vivo, using video microscopy of Caenorhabditis elegans embryos. As expected, MCM-2-7 loading in late M phase depended on the prereplicative complex (pre-RC) proteins: origin recognition complex (ORC), CDC-6, and CDT-1. However, many features we observed have not been described before: GFP-ORC-1 bound chromatin independently of ORC-2 5, and CDC-6 bound chromatin independently of ORC, whereas CDT-1 and MCM-2-7 DNA binding was interdependent. MCM-3 chromatin loading was irreversible, but CDC-6 and ORC turned over rapidly, consistent with ORC/CDC-6 loading multiple MCM-2-7 complexes. MCM-2-7 chromatin loading further reduced ORC and CDC-6 DNA binding. This dynamic behavior creates a feedback loop allowing ORC/CDC-6 to repeatedly load MCM-2-7 and distribute licensed origins along chromosomal DNA. During S phase, ORC and CDC-6 were excluded from nuclei, and DNA was overreplicated in export-defective cells. Thus, nucleocytoplasmic compartmentalization of licensing factors ensures that DNA replication occurs only once. PMID- 22249292 TI - Quantitative analysis of the lipidomes of the influenza virus envelope and MDCK cell apical membrane. AB - The influenza virus (IFV) acquires its envelope by budding from host cell plasma membranes. Using quantitative shotgun mass spectrometry, we determined the lipidomes of the host Madin-Darby canine kidney cell, its apical membrane, and the IFV budding from it. We found the apical membrane to be enriched in sphingolipids (SPs) and cholesterol, whereas glycerophospholipids were reduced, and storage lipids were depleted compared with the whole-cell membranes. The virus membrane exhibited a further enrichment of SPs and cholesterol compared with the donor membrane at the expense of phosphatidylcholines. Our data are consistent with and extend existing models of membrane raft-based biogenesis of the apical membrane and IFV envelope. PMID- 22249294 TI - Long-term trends in Chlamydia trachomatis infections and related outcomes in a U.S. managed care population. AB - BACKGROUND: Given recent increasing case rates of Chlamydia trachomatis infection, we evaluated trends in chlamydia rates and related health outcomes in women and men aged 15 to 44 years who were enrolled in a Pacific Northwest health plan. METHODS: We identified chlamydia, pelvic inflammatory disease (PID), ectopic pregnancy, and male urethritis cases occurring annually during 1997-2007 using computerized health plan databases, calculating rates per 100,000 person years (py) by gender and 5-year age groups. We also calculated annual chlamydia testing rates. RESULTS: In women, chlamydia testing rates increased by approximately 23% (220 tests per 1000 py in 1997 to 270 tests per 1000 in 2007). Chlamydia diagnosis rates rose from 449 cases/100,000 py in 1997 to 806/100,000 in 2007, a 79% increase (P = 0.01). Increases were greatest during 2005-2007, also the period of major conversion to nucleic acid amplification test. PID rates in this interval declined steadily from 823 cases/100,000 py to 473/100,000 (P < 0.01). Ectopic pregnancy rates remained unchanged. In men, chlamydia testing rates increased nearly 3.5-fold, from 12 to 42 tests per 1000 py. Chlamydia rates for men also rose significantly throughout the study interval (from 91 cases/100,000 py to 218/100,000; P < 0.01) as did urethritis diagnosis rates (P < 0.01). CONCLUSION: Between 1997 and 2007, annual health plan chlamydia rates increased significantly for both women and men. These trends may be due in part to increased testing rates and increased use of more sensitive tests, but they likely do not explain the increased urethritis rates. During this same interval, we observed steady declines in PID rates, consistent with other national data sources. PMID- 22249293 TI - A molecular switch on an arrestin-like protein relays glucose signaling to transporter endocytosis. AB - Endocytosis regulates the plasma membrane protein landscape in response to environmental cues. In yeast, the endocytosis of transporters depends on their ubiquitylation by the Nedd4-like ubiquitin ligase Rsp5, but how extracellular signals trigger this ubiquitylation is unknown. Various carbon source transporters are known to be ubiquitylated and endocytosed when glucose-starved cells are exposed to glucose. We show that this required the conserved arrestin related protein Rod1/Art4, which was activated in response to glucose addition. Indeed, Rod1 was a direct target of the glucose signaling pathway composed of the AMPK homologue Snf1 and the PP1 phosphatase Glc7/Reg1. Glucose promoted Rod1 dephosphorylation and its subsequent release from a phospho-dependent interaction with 14-3-3 proteins. Consequently, this allowed Rod1 ubiquitylation by Rsp5, which was a prerequisite for transporter endocytosis. This paper therefore demonstrates that the arrestin-related protein Rod1 relays glucose signaling to transporter endocytosis and provides the first molecular insights into the nutrient-induced activation of an arrestin-related protein through a switch in post-translational modifications. PMID- 22249295 TI - Measuring the uptake and impact of Chlamydia screening programs--easier said than done. AB - The passage of the landmark United States (U.S.) Patient Protection and Affordable Care Act (ACA) of 2010 has placed a new emphasis on prevention services, including increased access, coverage, and improved quality of care. In this legislation, chlamydia screening qualifies along with other preventive services (The Patient Protection and Affordable Care Act, P.H. 111-148, March 2010, S2,713) as an essential health service benefit by virtue of having an "A" rating ("strongly recommended") from the U.S. Preventive Services Task Force. However, along with this important commitment of public health resources comes accountability by demonstrating outcomes and results. It should not come as a surprise that in the current era of unprecedented government budget reductions, there is a compelling need for evidence-based prioritization and impact assessment. Funding agencies increasingly need health program data to show the impact of investment in preventive services, and chlamydia screening is no exception. However, measuring the population-level impact of chlamydia screening expansion in the U.S. since the 1980s has been problematic; conflicting data on screening uptake, chlamydia burden, and adverse reproductive outcomes, including pelvic inflammatory disease (PID) and tubal factor infertility, have all been challenging to interpret, despite compelling epidemiologic evidence supporting intervention. PMID- 22249296 TI - Chlamydia trachomatis trends in the United States among persons 14 to 39 years of age, 1999-2008. AB - BACKGROUND: We report the first population-based assessment of national trends in chlamydia prevalence in the United States. METHODS: We investigated trends in chlamydia prevalence in representative samples of the U.S. population aged 14 to 39 years using data from five 2-year survey cycles of the National Health and Nutrition Examination Survey from 1999 to 2008. Prevalence estimates and 95% confidence intervals (CI) are reported stratified by age, gender, and race/ethnicity. Percent change in prevalence over this time period was estimated from regression models. RESULTS: In the 2007-2008 cycle, chlamydia prevalence among participants aged 14 to 39 years was 1.6% (95% CI: 1.1%-2.4%). Prevalence was higher among females (2.2%, 95% CI: 1.4%-3.4%) than males (1.1%, 95% CI: 0.7% 1.7%). Prevalence among non-Hispanic black persons was 6.7% (95% CI: 4.6%-9.9%) and was 2.5% (95% CI: 1.6%-3.8%) among adolescents aged 14 to 19 years. Over the five 2-year cycles, there was an estimated 40% reduction (95% CI: 8%-61%) in prevalence among participants aged 14 to 39 years. Decreases in prevalence were notable in men (53% reduction, 95% CI: 19%-72%), adolescents aged 14 to 19 years (48% reduction, 95% CI: 11%-70%), and adolescent non-Hispanic black persons (45%, reduction, 95% CI: 4%-70%). There was no change in prevalence among females aged 14 to 25 years, the population targeted for routine annual screening. CONCLUSIONS: On the basis of population estimates of chlamydia prevalence, the overall chlamydia burden in the United States decreased from 1999 to 2008. However, there remains a need to reduce prevalence in populations most at risk and to reduce racial disparities. PMID- 22249297 TI - Who participates in the Dutch Chlamydia screening? A study on demographic and behavioral correlates of participation and positivity. AB - BACKGROUND: In the Netherlands, an Internet-based Chlamydia Screening Implementation was initiated in 3 regions, aiming to reduce population prevalence by annual testing and treatment of people aged 16 to 29 years. We studied who was reached in the first screening round by relating participation and chlamydia positivity to sociodemographic and sexual risk factors. METHODS: Data from the 2008/2009 screening round were analyzed (261,025 screening invitations, 41,638 participants). Participation rates were adjusted for the sexually active population. Sociodemographic and behavioral correlates of screening participation and positivity were studied by (multilevel) logistic regression models. RESULTS: The overall adjusted participation rate in the first screening round was 19.5% (95% confidence interval, 19.4-19.7) among sexually active people (women, 25%; men, 13%). Sociodemographic factors associated with lower participation were male gender (odds ratio [OR], male 1 vs. female 1.8), young age (OR, 16-19 1 vs. older groups 1.7-2.1), non-Dutch origin (OR between 0.7-0.9), lower education (OR, low 1 vs. high 1.4), high community risk level (0.8), and low socioeconomic status (0.9). Behavioral factors associated with lower participation were a long standing relationship (0.7) and no reported history or symptoms of sexually transmitted infections (no symptoms, 0.4-0.6) . Factors most strongly related to higher Ct positivity were young age (OR, 1 vs. older groups 0.5-0.8), non-Dutch origin (1.4-2.8), non-Dutch steady partner (1.9-2.7), residence in a high-risk area (1.4-1.5), lower education (high, 0.3-0.5), and a history or symptoms of sexually transmitted infection (no symptoms, 0.4-0.6). CONCLUSIONS: Sociodemographic factors associated with lower participation were also associated with higher Ct positivity, showing that high-risk demographic groups are more difficult to mobilize than low-risk groups. Independent of this, higher behavioral risk levels were associated with higher participation rates, suggesting self-selection for screening based on the persons' risk (perception) in both low- and high community risk groups. Our study shows the complexity of the process, including individual and community factors that also interact, when screening for chlamydia. PMID- 22249298 TI - Male circumcision and genital human papillomavirus: a systematic review and meta analysis. AB - BACKGROUND: Human papillomavirus (HPV) infection is the principal cause of invasive cervical cancer. There is some evidence that male circumcision (MC) may protect against HPV infection and related disease in both men and women. The purpose of this study was to conduct a systematic review of the literature to assess the association between MC and genital HPV infection indicators including genital warts. METHODS: A systematic search of Medline was conducted to identify all relevant studies from February 1971 to August 2010. Effect estimates were included in random effects models. RESULTS: A total of 21 studies with 8046 circumcised and 6336 uncircumcised men were included in the meta-analysis. MC was associated with a statistically significant reduced odds of genital HPV prevalence (odds ratio = 0.57, 95% confidence interval: 0.42-0.77). This association was also observed for genital high-risk HPV prevalence in 2 randomized controlled trials (odds ratio = 0.67, 95% confidence interval: 0.54 0.82). No associations were found between MC and genital HPV acquisition of new infections, genital HPV clearance, or genital warts. CONCLUSIONS: This meta analysis shows a robust inverse association between MC and genital HPV prevalence in men. However, more studies are needed to adequately assess the effect of MC on the acquisition and clearance of HPV infections. MC could be considered as an additional one-time preventative intervention likely to reduce the burden of HPV related diseases both in men and women, particularly among those countries in which HPV vaccination programs and cervical screening are not available. PMID- 22249299 TI - Male circumcision reduces human papillomavirus incidence and prevalence: clarifying the evidence. PMID- 22249300 TI - Access to health services and sexually transmitted infections in a cohort of relocating African American public housing residents: an association between travel time and infection. AB - BACKGROUND: High incidence and prevalence of sexually transmitted infection (STI) in blacks have been attributed to multiple factors. However, few articles have discussed spatial access to healthcare as a driver of disparities. The objective of this analysis was to evaluate the relationship between travel time to a healthcare provider and the likelihood of testing positive for 1 of 3 STIs in a sample of adults living in public housing. METHODS: One hundred and eight black adults in Atlanta, GA from November 2008 to June 2009, completed a survey that queried sexual behavior and healthcare use and had urine tested for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis by molecular methods. Travel time was a continuous variable capturing the number of minutes it took to reach the place where participants received most of their care. Multivariate analyses tested the hypothesis that individuals reporting longer travel times would be more likely to test positive for an STI. Travel time was squared to linearize its relationship to the outcome. RESULTS: Thirty-six residents (37.5%) tested positive for >=1 STI. A curvilinear relationship existed between travel time and STI status. When travel time was <48 minutes, a positive relationship existed between travel time and the odds of testing positive for an STI. An inverse relationship existed when travel time was >=48 minutes. CONCLUSION: Residents of impoverished communities experience a curvilinear relationship between travel time and STI status. We discuss possible factors that might have created this curvilinear relationship, including voluntary social isolation. PMID- 22249301 TI - Patient-delivered partner therapy for chlamydial infections: practices, attitudes, and knowledge of california family planning providers. AB - BACKGROUND: Treatment of sex partners is a core strategy for the control of chlamydia. Innovations such as patient-delivered partner therapy (PDPT) are effective in preventing repeat chlamydial infections, but providers' practice and perceptions of PDPT have not been adequately evaluated. This evaluation describes family planning providers' practices, knowledge, attitudes, and barriers regarding PDPT and assesses factors associated with routine use. METHODS: A cross sectional, self-administered, Internet-based survey of a convenience sample of family planning providers in California was conducted in 2007. Multivariate logistic regression was used to determine predictors associated with routine PDPT use. RESULTS: Of the 286 respondents, 73% reported routinely using PDPT for chlamydia and 77% provided medication to clients for their partner(s). Providers were more likely to offer PDPT for female versus male clients (73% vs. 53%, P < 0.0001). More than 90% agreed that PDPT helped provide better care for clients, was well-received, and protected against reinfection. Common concerns about PDPT included missed counseling opportunities (51%) and incomplete care for partners (42%). Over one-third (41%) identified lack of reimbursement for PDPT as an important barrier to routine use. Independent predictors of routine PDPT use included affiliation with an agency that received free prepackaged single-dose medication for on-site PDPT dispensing (adjusted odds ratio = 2.66, 95% confidence interval: 1.39-5.10) and support of the clinic's medical director (adjusted odds ratio = 4.85, 95% confidence interval: 1.57-14.96). CONCLUSIONS: A majority of providers in this sample reported routinely using PDPT for chlamydia infected clients; provision of prepackaged medication to clinics facilitated use of PDPT. PMID- 22249302 TI - Prevalence and concordance of HPV, HIV, and HSV-2 in heterosexual couples in Kigali, Rwanda. AB - BACKGROUND: In the absence of prospectively collected transmission data, the transmission potential of a sexually transmissible infection (STI) can be estimated by its proxy of concordance in sexual partners. Here we report concordance data of 3 viral STIs: human papillomavirus (HPV), HIV, and herpes simplex virus type 2 (HSV-2) among heterosexual couples in Kigali, Rwanda. METHODS: Cervical and penile HPV typing was performed among 166 community-sampled fertile couples in Kigali, Rwanda (median sampling interval 10 days (interquartile range: 5-36). HIV and HSV-2 serostatus, curable STIs, and sociobehavioral and clinical characteristics were also assessed. RESULTS: Concordance rates for all 3 viral STIs were higher than expected by chance alone. Positive concordance among couples was 25% for HSV-2, 15.7% for any HPV, 8.4% for high-risk (HR)-HPV, and 6% for HIV. HR-HPV prevalence among women and men was 19.9% and 26.5%, respectively. Partner's HIV status was more strongly associated with HR-HPV detection in men (OR: 8.5; confidence interval: 2.9-24.6) than in women (OR: 1.9; confidence interval 0.5-6.7). CONCLUSION: More than half of the couples were discordant for HIV, HPV, and/or HSV-2, indicating that prevention strategies directed to infected cases are important to protect their uninfected sexual partners. PMID- 22249303 TI - Interventions to increase rescreening for repeat chlamydial infection. AB - BACKGROUND: Repeat infection with Chlamydia trachomatis following treatment is common and increases the risk of sequelae. Despite clinical guidelines recommending rescreening within 3 months of treatment, rescreening rates remain low. We undertook a systematic review to identify studies that compared rates of rescreening for repeat chlamydial infection between patients receiving and not receiving an intervention. METHODS: We searched Medline, EMBASE, and conference Web sites from 2000 to September 2010 using variations of the terms "chlamydia" and "rescreening" and "intervention." We used meta-analysis to calculate the overall relative risk (RR) effect on rescreening rates by study design and strategy type. RESULTS: We identified 8 randomized controlled trials (RCTs) and 4 controlled observational studies, all conducted in the United States. Four RCTs assessed mailed screening kits +/- reminders, with an average effect estimate of 1.30 (95% confidence interval [CI]: 1.01-1.50); 2 RCTs assessed motivational interviewing +/- reminders with a summary effect of 2.15 (95% CI: 0.92-3.37); one RCT evaluated the effect of reminders with a RR of 9.67 (95% CI: 1.31-71.31), and another RCT assessed the effect of a $20 patient incentive with a RR of 1.16 (95% CI: 0.62-2.17). Three controlled observational studies assessed reminder strategies with RRs of 1.97 (95% CI: 1.76-2.21), 1.01 (95% CI: 0.66-1.55), and 1.88 (95% CI: 1.58-2.24)-a summary effect was not calculated due to significant heterogeneity; and one controlled observational study assessed the promotion of clinical guidelines with a RR of 1.35 (95% CI: 0.96-1.90). CONCLUSION: The review suggests that the use of mailed screening kits is an important strategy to increase rescreening, reminder systems are promising, and motivational interviewing is worth investigation. PMID- 22249304 TI - Clinical evaluation of the BD ProbeTecTM Neisseria gonorrhoeae Qx amplified DNA assay on the BD ViperTM system with XTRTM technology. AB - BACKGROUND: The excellent sensitivity and specificity of commercially available nucleic acid amplification tests (NAATs) for the identification of Neisseria gonorrhoeae have been demonstrated. This study evaluated the performance of the BD ProbeTecTM N. gonorrhoeae Q (GCQ) Amplified DNA Assay on the BD ViperTM System with XTRTM Technology in a multicenter study. METHODS: Specimens were collected at 7 geographically diverse clinical sites from 1846 women and men attending sexually transmitted disease, family planning, and obstetrics and gynecology clinics. There were 1768 evaluable participants, 994 women and 774 men. GCQ results from female endocervical, self-collected vaginal, male urethral swab specimens, and male and female neat (unpreserved) urine specimens, as well as those obtained using the urine preservative transport (UPT) tube for the GCQ assay were compared with patient infected status (PIS). For each participant, PIS was determined based on the combined results from the reference assays Aptima Combo 2(r) (AC2) and BD ProbeTecTM ET GC Amplified DNA Assay (PT). RESULTS: The sensitivity versus PIS for endocervical, vaginal, and female UPT urine, and female neat urine samples was 98.5%, 100.0%, 98.5%, and 96.9%, respectively; the specificity was 99.7%, 99.1%, 99.7%, and 99.5%, respectively. The sensitivity versus PIS for male urethral swabs and both male UPT and neat urine was 100.0%, with specificities of 99.1% for the urethral swab and UPT urine and 98.9% for the neat urine. The overall GCQ assay performance was not statistically different from that of AC2 or PT. CONCLUSIONS: The GCQ assay demonstrated performance characteristics comparable with other commercially available nucleic acid-based tests such as AC2 and PT. Vaginal swabs, endocervical swabs, urethral swabs, and urine specimens may all be used for gonorrhea screening. PMID- 22249305 TI - Prevalence and risk factors associated with herpes simplex virus-2 infection in a contemporary cohort of HIV-infected persons in the United States. AB - BACKGROUND: We compared the herpes simplex virus type 2 (HSV-2) seroprevalence in a contemporary HIV cohort with the general US population and determined risk factors for HSV-2 infection among HIV-infected persons. METHODS: The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN) Study is a prospective observational cohort of 700 HIV-infected adults enrolled in 4 U.S. cities between 2004 and 2006. At baseline, participants completed a behavioral risk questionnaire and provided specimens for HSV-2 serology. We calculated HSV-2 seroprevalence, standardized by age, gender, and race among HIV-infected persons compared with the general US adult population, using data from the National Health and Nutrition Examination Survey from 2003 to 2006. We examined risk factors associated with HSV-2 infection among HIV-infected persons using multivariate logistic regression. RESULTS: Among 660 (94%) SUN participants with adequate specimens for HSV-2 serologic testing, 548 (83%) were 20 to 49 years old (median age, 39 years; 77% male; 59% non-Hispanic white; median CD4 count, 470 cells/mm; 74% with HIV RNA viral loads <400 copies/mL). HSV 2 seroprevalence was significantly higher among HIV-infected adults (59.7%, 95% confidence interval: 55.8-63.6) compared with the general US population (19.2%, 95% confidence interval: 17.5-21.1). In multivariate analysis, we found that older age, female gender, black non-Hispanic race/ethnicity, being currently unemployed, high-risk anal HPV infection, and longer duration since HIV diagnosis were associated with significantly higher odds of HSV-2 infection. CONCLUSION: HSV-2 seroprevalence is 3 times as high among HIV-infected adults as in the general U.S. population. Clinicians should be aware that increased risk for HSV-2 infection was distributed broadly among HIV-infected persons and not limited to those with high-risk sexual behaviors. PMID- 22249306 TI - Coexistence of Crohn's disease in a patient with systemic lupus erythematosus. AB - The concurrence of inflammatory bowel disease with systemic lupus erythematosus (SLE) is rare. The concomitant diagnosis of Crohn's disease and SLE is even more rare. The patient, a 40-year-old woman, was admitted to our hospital because of relapsing episodes of abdominal pain, diarrheas upper and lower extremities arthralgias, Raynaud's phenomenon with positive antinuclear antibodies, and fever for the last 2 years. The patient was diagnosed elsewhere with SLE and treated with hydroxychloroquine. Her medical history also included tonsillectomy and total hip replacement after a car accident. Family history was unremarkable. Physical examination was unremarkable except of very mild pain at lower left abdominal quadrant. Laboratory tests showed erythrocyte sedimentation rate at 32 mm/h, C-reactive protein at 36 mg/dl, positive rheumatoid factor, and increased C3, C4, positive antinuclear antibodies with the presence of anti-Sm and anti-RNP antibodies. Ileocolonoscopy revealed colonic inflammation with ulcers and pseudopolyps. Subsequent biopsies were diagnostic of Crohn's disease. Patient was diagnosed with Crohn's colitis concomitant to systemic lupus erythematosus and was started on therapy with azathioprine 2 mg/Kg, methylprednisolone 16 mg/d with slow tapering, mesalazine 1.5 g/day, and hydroxychloroquine. Patient is in excellent health status on the six-month follow-up. PMID- 22249307 TI - Chronic pure radiculopathy in patient with organizing epidural hematoma around C8 nerve root. AB - Spontaneously occurring spinal epidural hematomas are uncommon clinical findings, and the chronic form is the rarest and its most frequent location is the lumbar spine. Pure radicular involvement is far less frequent than myelopathy. We report a case of progressive radiculopathy in a 52-year-old man with spontaneously occurring cervical epidural hematoma (SCEH). The patient had left hand weakness and numbness for 4 months. MRI scan showed small space-occupying lesion around left 8th cervical nerve root. After surgery we confirmed chronic organizing epidural hematoma. To the best of our knowledge, this is the second reported case in the worldwide literature of pure radiculopathy in a patient with chronic SCEH. PMID- 22249308 TI - Modic type I change may predict rapid progressive, deforming disc degeneration: a prospective 1-year follow-up study. AB - INTRODUCTION: This prospective magnetic resonance imaging (MRI) study in chronic low-back pain (CLBP) patients evaluated the natural course of degenerative lumbar spine changes in relation to Modic 1 type changes (M1) within 1 year. MATERIALS AND METHODS: From 3,811 consecutive CLBP patients referred to lumbar spine MRI 54 patients with a large M1 were selected using strict exclusion criteria to exclude specific back disorders. Follow-up MRI was obtained within 11-18 months. RESULTS: At baseline M1 was associated with an adjacent endplate lesion in 96% of the cases. In follow-up, an unstable M1 was associated both with an increase of endplate lesions, decrease of disc height and change in disc signal intensity, most found at L4/5 or L5/S1. In disc spaces without M1, progression of degenerative changes was rare. CONCLUSION: Endplate deformation, decreasing disc height and change of disc signal intensity appear essential features of accelerated degenerative process associated with M1. PMID- 22249309 TI - Improving the evaluation of model fit in confirmatory factor analysis: A commentary on Gundy, C.M., Fayers, P.M., Groenvold, M., Petersen, M. Aa., Scott, N.W., Sprangers, M.A.J., Velikov, G., Aaronson, N.K. (2011). Comparing higher order models for the EORTC QLQ-C30. Quality of life research, doi:10.1007/s11136 011-0082-6. AB - This article is a brief commentary in response to "Gundy, C.M., Fayers, P.M., Groenvold, M., Petersen, M. Aa., Scott, N.W., Sprangers, M.A.J., Velikov, G., Aaronson, N.K. (2011). Comparing higher-order models for the EORTC QLQ-C30. Quality of life research, doi: 10.1007/s11136-011-0082-6 ." The commentary argues that approximate goodness-of-fit indexes cannot be used to salvage confirmatory factor models rejected by the Chi-square test of exact fit. Instead, rigorous diagnostic procedures should be used to identify and resolve the particular sources of model misspecification. PMID- 22249310 TI - Construct validity of the EORTC quality of life questionnaire information module. AB - PURPOSE: Providing sufficient information about diagnosis and treatment is an important feature of high-quality patient care in oncology. To measure patient satisfaction with information received, the European Organisation for Research and Treatment of Cancer Quality of Life Group has recently developed a new tool, the information module (INFO25). The aim of this study was to evaluate the scale structure of the INFO25. METHODS: A total of n = 423 patients completed the INFO25 after finishing cancer therapy. The internal consistency of multi-item subscales was calculated using Cronbach's Alpha. The scale structure was evaluated using multi-trait methods and confirmatory factor analysis. RESULTS: Cronbach's Alpha of the multi-item scales ranged from 0.79 to 0.88. Only two items correlated somewhat higher with another scale than with their own, indicating a good scale structure. Construct validity with latent variable models, including a general information factor and four multi-item scales, resulted in the following fit indices CFI = 0.96, RMSEA = 0.08, TLI = 0.99 and WRMR = 1.03. CONCLUSION: The suggested construct of the INFO25 with a total score (general factor) in addition to the subscales is valid. PMID- 22249311 TI - Inhibition of Gsk3beta activity improves beta-cell function in c-KitWv/+ male mice. AB - Previous studies have shown that the stem cell marker, c-Kit, is involved in glucose homeostasis. We recently reported that c-Kit(Wv/+) male mice displayed the onset of diabetes at 8 weeks of age; however, the mechanisms by which c-Kit regulates beta-cell proliferation and function are unknown. The purpose of this study is to examine if c-Kit(Wv/+) mutation-induced beta-cell dysfunction is associated with downregulation of the phospho-Akt/Gsk3beta pathway in c-Kit(Wv/+) male mice. Histology and cell signaling were examined in C57BL/6J/Kit(Wv/+) (c Kit(Wv/+)) and wild-type (c-Kit(+/+)) mice using immunofluorescence and western blotting approaches. The Gsk3beta inhibitor, 1-azakenpaullone (1-AKP), was administered to c-Kit(Wv/+) and c-Kit(+/+) mice for 2 weeks, whereby alterations in glucose metabolism were examined and morphometric analyses were performed. A significant reduction in phosphorylated Akt was observed in the islets of c Kit(Wv/+) mice (P<0.05) along with a decrease in phosphorylated Gsk3beta (P<0.05), and cyclin D1 protein level (P<0.01) when compared with c-Kit(+/+) mice. However, c-Kit(Wv/+) mice that received 1-AKP treatment demonstrated normal fasting blood glucose with significantly improved glucose tolerance. 1-AKP treated c-Kit(Wv/+) mice also showed increased beta-catenin, cyclin D1 and Pdx-1 levels in islets, demonstrating that inhibition of Gsk3beta activity led to increased beta-cell proliferation and insulin secretion. These data suggest that c-Kit(Wv/+) male mice had alterations in the Akt/Gsk3beta signaling pathway, which lead to beta-cell dysfunction by decreasing Pdx-1 and cyclin D1 levels. Inhibition of Gsk3beta could prevent the onset of diabetes by improving glucose tolerance and beta-cell function. PMID- 22249312 TI - Galpha12 activation in podocytes leads to cumulative changes in glomerular collagen expression, proteinuria and glomerulosclerosis. AB - Glomerulosclerosis is a common pathological finding that often progresses to renal failure. The mechanisms of chronic kidney disease progression are not well defined, but may include activation of numerous vasoactive and inflammatory pathways. We hypothesized that podocytes are susceptible to filtered plasma components, including hormones and growth factors that stimulate signaling pathways leading to glomerulosclerosis. Galpha12 couples to numerous G-protein coupled receptors (GPCRs) and regulates multiple epithelial responses, including proliferation, apoptosis, permeability and the actin cytoskeleton. Herein, we report that genetic activation of Galpha12 in podocytes leads to time-dependent increases in proteinuria and glomerulosclerosis. To mimic activation of Galpha12 pathways, constitutively active Galpha12 (QL) was conditionally expressed in podocytes using Nphs2-Cre and LacZ/floxed QLalpha12 transgenic mice. Some QLalpha12(LacZ+/Cre+) mice developed proteinuria at 4-6 months, and most were proteinuric by 12 months. Proteinuria increased with age, and by 12-14 months, many demonstrated glomerulosclerosis with ultrastructural changes, including foot process fusion and both mesangial and subendothelial deposits. QLalpha12(LacZ+/Cre+) mice showed no changes in podocyte number, apoptosis, proliferation or Rho/Src activation. Real-time PCR revealed no significant changes in Nphs1, Nphs2, Cd2ap or Trpc6 expression, but Col4a2 message was increased in younger and older mice, while Col4a5 was decreased in older mice. Confocal microscopy revealed disordered collagen IValpha1/2 staining in older mice and loss of alpha5 without changes in other collagen IV subunits. Taken together, these studies suggest that Galpha12 activation promotes glomerular injury without podocyte depletion through a novel mechanism regulating collagen (alpha)IV expression, and supports the notion that glomerular damage may accrue through persistent GPCR activation in podocytes. PMID- 22249315 TI - Linear scleroderma en coup de sabre affecting the upper eyelid and lashes. PMID- 22249313 TI - SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus. AB - Glomerular parietal epithelial cells (PECs) are precursors to podocytes in mature glomeruli; however, as progenitors, the distinct intrinsic mechanisms that allow for repeated periods of cell-cycle arrest and re-entry of PECs after glomerulogenesis are unknown. Here, we show that the Src-suppressed protein kinase C substrate (SSeCKS), a multivalent scaffolding A kinase anchoring protein, sequesters cyclin D1 in the cytoplasm of quiescent PECs. SSeCKS expression is induced in embryonic PECs, but not in embryonic podocytes, starting at the S phase of glomerulogenesis, and is constitutively expressed postnatally by PECs, but not podocytes, in normal glomeruli. Cyclin D1 was immunoprecipitated with SSeCKS from capsulated glomeruli containing PECs, whereas decapsulated glomeruli without PECs lacked SSeCKS and cyclin D1. Cell-cell contact inhibition of proliferation in cultured PECs induced SSeCKS expression and binding of cyclin D1 by SSeCKS in the cytoplasm, whereas phosphorylation of SSeCKS by activated protein kinase C disrupted binding, resulting in nuclear translocation of cyclin D1. SSeCKS(-/-) mice showed hyperplasia of PECs in otherwise normal glomeruli and developed significantly worse proteinuric glomerular disease, marked by increased PEC proliferation and expression of nuclear cyclin D1, from nephrotoxic nephritis. These results suggest that SSeCKS controls the localization and activity of cyclin D1 in PECs and influences proliferative injury in the glomerulus. PMID- 22249316 TI - Methylglyoxal induces hyperpermeability of the blood-retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases. AB - BACKGROUND: One of the early signs of diabetic retinopathy is the alteration of the blood-retinal barrier (BRB), which may involve the breakdown of endothelial cell tight junctions. Methylglyoxal (MGO) is a cytotoxic metabolite that is produced from glycolysis in vivo. Elevated levels of MGO are observed in a number of pathological conditions, including neurodegenerative disorders and diabetic complications. Herein, we hypothesize that increased levels of MGO disrupt the tight junction protein known as occludin protein by matrix metalloproteinases (MMPs), leading to breakage of the BRB. METHODS: MGO was intravitreally injected into eyes of rats. BRB leakage, MMPs activity, and occludin were investigated in intravitreally MGO-injected eyes. RESULTS: When normoglycemic rats were intravitreally injected with 400 MUM MGO, there was widespread leakage of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) from the retinal vasculature when compared to control retinas. In addition, MGO-injected retinas demonstrated increases of both activity and expression of MMP-2 and MMP-9, and the degradation of occludin was found in the MGO-injected retinas. CONCLUSIONS: The results suggest that the activation of MMPs by elevated levels of MGO in the retina may facilitate an increase in vascular permeability by a mechanism involving proteolytic degradation of occludin. These findings may have implications for the role of MGO in the pathogenesis of diabetic retinopathy. PMID- 22249317 TI - Surveillance of late-onset bleb leak, blebitis and bleb-related endophthalmitis- a UK incidence study. AB - AIMS: To determine the incidence of late-onset bleb leak (BL), blebitis (B) and bleb-related endophthalmitis (BRE) after trabeculectomy surgery, and report the management approaches employed by UK ophthalmologists. METHODS: Prospective case ascertainment study reporting of incident cases fulfilling the study definitions of BL, B and BRE through the reporting mechanism provided by the British Ophthalmic Surveillance Unit (BOSU; United Kingdom) for the period July 2007 to August 2008 (13 months). Two questionnaires completed at initial reporting and 6 months later were used to collect clinical details related to presentation, early and late management and outcome. RESULTS: Ninety-eight cases were reported to the British Ophthalmic Surveillance Unit during the study period. Seventy-one first questionnaires were returned (response rate 72.4%). Of these, 11 were erroneous/duplicated. Sixty second questionnaires were sent out, and of these 37 fully completed questionnaires were returned. Analysis was, therefore, based upon 60 initial and 37 follow-up questionnaires. Overall incidences were estimated for isolated bleb leak (0.22%), blebitis without bleb leak (0.1%), blebitis with bleb leak (0.11%), and BRE with or without bleb leak (0.17%). Visual outcome in the BL group was good; however, in the BRE group half the patients ended with visions of perception of light or worse. There was a great variance in the initial and late management of these conditions. Surgical intervention for bleb leak seemed to result in the best chance of leak closure. CONCLUSIONS: These complications of trabeculectomy surgery are relatively low but potentially visually devastating. This study updates the knowledge of the incidence of these complications, and suggests that no consistent management approach to any of the reported conditions was practised. In view of the potentially catastrophic consequences of these complications, formal guidance as to best practice would be beneficial, and further research to establish this is required. PMID- 22249318 TI - Superior oblique tendon lengthening and medial rectus transposition in the bilateral aplasia of the inferior rectus muscle: SO lengthening in the bilateral aplasia of IR. PMID- 22249319 TI - Importance of checking prehospital neurological findings to reveal incidence of spinal cord concussion. AB - OBJECTIVE: To clarify the incidence and characteristics of spinal cord concussion in an urban city in Japan. METHODS: The current retrospective study was conducted by reviewing the medical records of patients with spinal cord injuries admitted between January 2007 and December 2010. The subjects were divided into two groups: a spinal cord concussion group and a spinal cord injury group. RESULTS: There were 36 patients with spinal cord injuries admitted during this period. Among them, there were 8 patients with spinal cord concussions. No significant differences were apparent between the two groups with regard to sex, mechanism of injury, Glasgow Coma Scale, incidence of shock, inhospital Frankel classification, level of spinal cord injury, frequency of vertebral dislocation/fracture, surgery and the survival rate. However, the mean age in the spinal cord concussion group was lower than that in the spinal cord injury group. The systolic blood pressure, the heart rate and the diameter of minimum spinal canal in the concussion group were all higher than those in the spinal cord injury group. Half of the subjects in the spinal cord concussion group demonstrated immediate neurological improvement between prehospital and inhospital findings, however none of the subjects in the spinal cord injury group demonstrated such improvement. This difference was statistically significant. CONCLUSION: Spinal cord concussion is not rare in urban Japan. Checking neurological findings at the scene leads to the revelation of the true high incidence of spinal cord concussion among spinal cord injuries. PMID- 22249321 TI - To work or not to work: labour market participation of people with spinal cord injury living in Switzerland. AB - STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To establish labour market participation figures of persons with spinal cord injury (SCI) living in Switzerland and to investigate determinants and consequences of having paid work. SETTING: Community. METHODS: A survey among members of the Swiss Paraplegic Association was performed in 2008. Inclusion criteria were: SCI of traumatic or non-traumatic origin, minimum age of 18 years, and living in the community for at least 1 year. A total of 559 persons with SCI returned the questionnaire (response rate 27%), of which 495 (24%) fulfilled the eligibility criteria. Bivariate and logistic regression analyses were performed based on theoretical considerations and relevant determinants found in the literature. RESULTS: Of the respondents of working age, 63.8% were involved in gainful employment. No significant difference between persons with para- and tetraplegia was observed. Logistic regression showed that employment was associated with age, time since onset of SCI, having worked at 2 years after initial rehabilitation, having received vocational counselling, having less pain, more years of education and more perceived importance of work. Working persons achieved a significantly higher total income. The most important reasons to work were not financial, but rather of social nature. Barriers to work were primarily health-related. CONCLUSIONS: We found a relatively high employment rate among the studied persons with SCI living in Switzerland. However, because of the low response, it is difficult to generalise this finding. PMID- 22249322 TI - Cervical multisegmental motor responses in healthy subjects. AB - STUDY DESIGN: Experimental design. OBJECTIVES: This descriptive design study presents multisegmental motor responses in the upper extremities after stimulation of cervical spinal vertebrae. SETTING: Neuro Lab of Texas Woman's University, School of Physical Therapy, Texas, USA. METHODS: In trial 1, C7 spinal segment was electrically stimulated in 13 healthy subjects using surface electrodes while recording responses from abductor digiti minimi (ADM), abductor pollicis brevis (APB), flexor carpi radialis (FCR) and biceps brachii (BB) in the right upper extremity. In trial 2, C7 stimulation was carried out while recording responses from the APB and BB bilaterally. In trial 3, C7 stimulation was carried out while recording responses from the flexor hallucis brevis (FHB), soleus, vastus medialis (VMO) and gluteus medius (GM) in the right lower extremity. The amplitude of the signal and the deflection latency were the measured parameters. Descriptive statistics were completed on the data. RESULTS: Results showed response amplitudes in all muscles of the upper extremities ranging from 328 to 1239 MUV, with the largest recorded from the APB and ADM, then the FCR and BB. Muscular responses were recorded simultaneously in bilateral muscles. Response latency was comparable, in bilateral similar muscles, and was varied from 6 to 16.5 msec, being longer in the ADM and APB, shorter in FCR and shortest in the BB. No lower limb muscles responded to C7 spinal stimulation, using current setup/method. CONCLUSION: These responses appear to be caused by stimulating the dorsal roots or motor nuclei of the cervical region and could be useful in testing patients with cervical spinal disorders. PMID- 22249323 TI - ASIA chart: our contribution. PMID- 22249324 TI - Patients with traumatic spinal cord injuries and their satisfaction with their general practitioner. AB - OBJECTIVE: The objective of this study was to examine how satisfied patients with traumatic spinal cord injury (TSCI) are with their general practitioners (GP). MATERIALS AND METHODS: The study included patients with TSCI, injured in the period 1982-2001 and living in western Norway. We performed a structured telephonic interview of the patients in the period 2004-2007. A total of 105 (59.3%) patients participated. RESULTS: Patients with TSCI were in general satisfied with their GP. Older patients were most satisfied, and patients with incomplete thoracic SCI were least satisfied. Patients with anxiety and/or depression reported low satisfaction with their GP on several parameters. CONCLUSIONS: Patients with incomplete SCI were least satisfied probably because their physicians do not acknowledge their complicated medical complaints and do not meet the patient's expectations. Patients with anxiety and/or depression were more likely to report low satisfaction with their GP. PMID- 22249325 TI - Wheelchair half-marathon race increases natural killer cell activity in persons with cervical spinal cord injury. AB - STUDY DESIGN: Non-randomized study. OBJECTIVE: We reported that individuals with cervical spinal cord injury (CSCI) showed no increase in natural killer cell activity (NKCA) in response to 20-min arm exercise. It could be argued that this lack of response was owing to the short duration and intensity of the exercise. SETTING: The 29th Oita International wheelchair marathon race. METHODS: The present study compared the effects of wheelchair half-marathon race on natural killer (NK) cell count, NKCA and other hematological and hormonal parameters in six subjects with CSCI and seven control subjects with spinal cord injury between T4 and L1 (SCI), before, immediately after and 2 h after recovery. RESULTS: NK cell counts increased at both time points after the race in SCI, but not in CSCI, compared with before the race. NKCA increased immediately in both groups of subjects after the race, and then returned to the pre-race level at 2 h after the race. Plasma cortisol did not change in both groups throughout the study. Plasma adrenaline increased sharply in SCI after the race, then returned to the pre-race level at 2 h after the race, whereas no change was observed in CSCI throughout the study. CONCLUSION: The present study demonstrated that wheelchair half marathon race increases NKCA despite the lack of increase in plasma adrenaline in CSCI, suggesting the activation of NKCA by mechanisms other than circulating adrenaline level. PMID- 22249326 TI - Locomotor programs versus 'conventional' physical therapy? Locomotor training. PMID- 22249327 TI - Editorial Note on: Neurophysiological assessment of spine disorders: old fashion techniques for modern clinical problems. PMID- 22249328 TI - An audit to assess awareness and knowledge of nutrition in a UK spinal cord injuries centre. AB - STUDY DESIGN: A single centre survey. OBJECTIVES: To test: (i) awareness of nutrition screening tools and related care plans and; (ii) nutrition knowledge of doctors, nurses and dietitians working in spinal cord injuries (SCI) centres. METHODS: The 14-item questionnaire was sent to 102 nurses, 17 doctors and 15 dietitians working in UK SCI centres during January-March 2010. RESULTS: Sixty two (46.5%) questionnaires were completed and returned for analysis. The present audit demonstrated that awareness of the need for nutritional screening is good: 83% of staff reported that they are aware there is a nutrition screening tool. This audit also demonstrated areas of poor knowledge, such as calorie content of intravenous fluids, indicators of malnutrition, and choice of nutritional support in malnourished patients. All doctors, but only 38% of nurses, knew how to calculate body mass index. Surprisingly, nearly half (49%) of the participants thought that at least 20% weight loss was required to indicate malnutrition. This high-perceived cut-off point suggests that malnutrition is likely to continue to be undetected and unmanaged. The overall scores (median) showed clear differences in nutritional knowledge between groups (median: dietitians 92.8%; doctors 53.5%; nurses 35.7; P<0.01). This suggests that dietitians could have an important role in training healthcare professionals about nutrition. CONCLUSION: This study highlights the need for further education in SCI medicine in order to improve the efficacy of feeding and nutrition therapy for SCI patients. PMID- 22249329 TI - Technology for mobility in SCI 10 years from now. AB - OBJECTIVES: To identify technological advances and that are likely to have a great impact on the quality of life and participation in individuals with spinal cord injury (SCI). METHODS: In this paper we use the International Classification of Function to frame a discussion on how technology is likely to impact SCI in 10 years. In addition, we discuss the implication of technological advances on future research. RESULTS/CONCLUSION: Although technology advances are exciting, a large challenge for the research community will be how to effectively apply and deploy this technology. Advances occurring in the next 10 years that reduce cost of technology may be more important to the population with SCI than brand new technologies. Social context is everything. As a research community we must advocate for better systems of care. Advocating now for better care will lead to a world in 2020 that is ready to adopt new technologies that are truly transformative. PMID- 22249330 TI - Functional outcome of patients 12 and 48 weeks after acute traumatic tetraplegia and paraplegia: data analysis from 2004-2009. AB - OBJECTIVES: During the first rehabilitation of patients with traumatic spinal cord injuries (SCIs), professional skills are learned, which can be objectified in an independent measurement score. The aims of this study were to record the skills of patients 12 and 48 weeks after acute trauma and perform an analysis of the data to identify provisions of importance. METHODS: All patients from 2004 to 2009 who experienced traumatic SCI were included in this investigation. Data recording were accomplished by the European Multi-Centre Study about Spinal Cord Injury (EMSCI) databank. Patients were divided into tetraplegia and paraplegia groups. Parameters were age at injury, the American Spinal Injury Association Score, level of lesion and spinal cord independence measure (SCIM-Score) 12 and 48 weeks after traumatic spinal cord lesion. A questionnaire was also added to help clarify where deficiencies were prevalent. RESULTS: Data analysis of 103 tetraplegic and 110 paraplegic patients showed no correlation between the ASIA score, level of lesion, age and SCIM score. On average, tetraplegic patients had a SCIM score of 43 points 12 weeks after treatment, with 81% showing an increase to 58 points after 48 weeks. Paraplegic patients showed an average SCIM score of 60 points after 12 weeks, with 71% experiencing an increase to 71 points after 48 weeks. In all, 9% of tetraplegic patients and 19% of paraplegic patients experienced a decrease of SCIM points after 48 weeks, which occurred mainly in the bladder and intestinal control subgroups. Results of the questionnaire were not helpful for clarifying the location of the deficiencies. CONCLUSION: Most of the patients experienced an increase of SCIM points 48 weeks after traumatic SCI. However, data also showed that, especially in paraplegic patients, special attention must be given to bladder and intestinal management to avoid negative late-term consequences. PMID- 22249331 TI - Editorial note on: Quality of life and urological morbidity in tetraplegics with artificial ventilation managed with suprapubic or intermittent catheterization. PMID- 22249332 TI - Question of stamina for the diaphragm. PMID- 22249333 TI - Metabolic decompensation in methylmalonic aciduria: which biochemical parameters are discriminative? AB - Recurrent, life-threatening metabolic decompensations often occur in patients with methylmalonic aciduria (MMAuria). Our study evaluated (impending) metabolic decompensations in these patients aiming to identify the most frequent and reliable clinical and biochemical abnormalities that could be helpful for decision-making on when to start an emergency treatment. Seventy-six unscheduled and 179 regular visits of 10 patients with confirmed MMAuria continuously followed by our metabolic centre between 1975 and 2009 were analysed. The most frequent symptom of an impending acute metabolic decompensation was vomiting (90% of episodes), whereas symptoms of intercurrent infectious disease (29%) or other symptoms (such as food refusal and impaired consciousness) were found less often. Thirty-five biochemical parameters were included in the analysis. Among them, pathological changes of acid-base balance reflecting metabolic acidosis with partial respiratory compensation (decreased pH, pCO(2), standard bicarbonate, and base excess) and elevated ammonia were the most reliable biochemical parameters for the identification of a metabolic decompensation and the estimation of its severity. In contrast, analyses of organic acids, acylcarnitines and carnitine status were less discriminative. In conclusion, careful history taking and identification of suspicious symptoms in combination with a small number of rapidly available biochemical parameters are helpful to differentiate compensated metabolic condition and (impending) metabolic crisis and to decide when to start an emergency treatment. PMID- 22249334 TI - The measurement of urinary Delta1-piperideine-6-carboxylate, the alter ego of alpha-aminoadipic semialdehyde, in Antiquitin deficiency. AB - The assessment of urinary alpha-aminoadipic semialdehyde (alpha-AASA) has become the diagnostic laboratory test for pyridoxine dependent seizures (PDS). alpha AASA is in spontaneous equilibrium with its cyclic form Delta(1)-piperideine-6 carboxylate (P6C); a molecule with a heterocyclic ring structure. Ongoing diagnostic screening and monitoring revealed that in some individuals with milder ALDH7A1 variants, and patients co-treated with a lysine restricted diet, alpha AASA was only modestly increased. This prompted us to investigate the diagnostic power and added value of the assessment of urinary P6C compared to alpha-AASA. Urine samples were diluted to a creatinine content of 0.1 mmol/L, followed by the addition of 0.01 nmol [(2)H(9)]pipecolic acid as internal standard (IS) and 5 MUL was injected onto a Waters C(18) T3 HPLC column. Chromatography was performed using water/methanol 97/3 (v/v) including 0.03 % formic acid by volume with a flow rate of 150 MUL/min and detection was accomplished in the multiple reaction monitoring mode: P6C m/z 128.1 > 82.1; [(2)H(9)]pipecolic acid m/z 139.1 > 93.1. Due to the dualistic nature of alpha-AASA/P6C, and the lack of a proper internal standard, the method is semi quantitative. The intra-assay CVs (n = 10) for two urine samples of proven PDS patients with only modest P6C increases were 4.7% and 8.1%, whereas their inter-assay CVs (n = 10) were 16 and 18% respectively. In all 40 urine samples from 35 individuals with proven PDS, we detected increased levels of P6C. Therefore, we conclude that the diagnostic power of the assessments of urinary P6C and alpha-AASA is comparable. PMID- 22249335 TI - Suberoylanilide hydroxamic acid affects gammaH2AX expression in osteosarcoma, atypical teratoid rhabdoid tumor and normal tissue cell lines after irradiation. AB - PURPOSE: Osteosarcoma and atypical teratoid rhabdoid tumors are tumor entities with varying response to common standard therapy protocols. Histone acetylation affects chromatin structure and gene expression which are considered to influence radiation sensitivity. The aim of this study was to investigate the effect of the combination therapy with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and irradiation on atypical teratoid rhabdoid tumors and osteosarcoma compared to normal tissue cell lines. METHODS: Clonogenic assay was used to determine cell survival. DNA double-strand breaks (DSB) were examined by pulsed-field electrophoresis (PFGE) as well as by gammaH2AX immunostaining involving flow cytometry, fluorescence microscopy, and immunoblot analysis. RESULTS: SAHA lead to an increased radiosensitivity in tumor but not in normal tissue cell lines. gammaH2AX expression as an indicator for DSB was significantly increased when SAHA was applied 24 h before irradiation to the sarcoma cell cultures. In contrast, gammaH2AX expression in the normal tissue cell lines was significantly reduced when irradiation was combined with SAHA. Analysis of initial DNA fragmentation and fragment rejoining by PFGE, however, did not reveal differences in response to the SAHA pretreatment for either cell type. CONCLUSION: SAHA increases radiosensitivity in tumor but not normal tissue cell lines. The increased H2AX phosphorylation status of the SAHA-treated tumor cells post irradiation likely reflects its delayed dephosphorylation within the DNA damage signal decay rather than chromatin acetylation-dependent differences in the overall efficacy of DSB induction and rejoining. The results support the hypothesis that combining SAHA with irradiation may provide a promising strategy in the treatment of solid tumors. PMID- 22249336 TI - Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors. AB - Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A(1), A(2A), or A(3) receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A(2B) receptors. Clofarabine and cladribine both bound to the A(2A) receptor with a K (i) of 17 and 15 MUM, respectively. Clofarabine was the only adenosine analogue to bind to the A(3) receptor with a K (i) of 10 MUM, and none of these compounds bound to the A(2B) receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A(1) receptor. In addition, clofarabine, cladribine, and fludarabine were A(1) agonists (IC(50) 3.1, 30, and 30 MUM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K (i) > 100MUM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs. PMID- 22249337 TI - Effect of dipyrone and thalidomide alone and in combination on STZ-induced diabetic neuropathic pain. AB - Diabetic neuropathy is recognized as one of the most common complications of chronic diabetes, but its pathophysiological mechanism is complex and yet to be completely explored. Monotherapy with conventional analgesics fails to provide adequate pain relief in peripheral diabetic neuropathy. There are a number of evidence suggesting that tumor necrosis factor (TNF-alpha) plays an important role in the pathogenesis of peripheral diabetic neuropathy. TNF-alpha up regulation activates nuclear factor kappaB, which further up-regulates cyclooxygenase (COX)-2 leading to altered prostaglandin profile. Inhibition of TNF-alpha and COX-2 provides beneficial effect on diabetic neuropathy by decreasing the oxidative stress level and by preventing neuronal hypersensitivity due to an increased prostaglandin level. The present study was designed to assess the effect of dipyrone and thalidomide on streptozotocin (STZ)-induced neuropathic pain behavior in rats. STZ 50 mg/kg, i.p. was administered to induce experimental diabetes in the rats. Three weeks following STZ, dipyrone (300 and 600 mg/kg, i.p.) and thalidomide (25 and 50 mg/kg, i.p.) alone and subeffective dose combination of dipyrone and thalidomide (300 and 25 mg/kg(-1), i.p.) administered daily for 2 weeks significantly attenuated thermal hyperalgesia, mechanical allodynia, and formalin-induced phase-2 flinching response. Moreover, the subeffective dose combination of dipyrone and thalidomide and preemptive treatment with thalidomide (50 mg/kg) reduces oxidative stress in diabetic rats. In conclusion, the combination of subeffective dose of dipyrone and thalidomide prevented the development and maintenance of experimental diabetic neuropathy. The combination of thalidomide (TNF-alpha inhibitor) and dipyrone (COX inhibitor) may be used as a potential therapeutic agent for the treatment of diabetic neuropathy. PMID- 22249338 TI - Erratum to: Impaired diffusing capacity for carbon monoxide in children with type 1 diabetes: is this the first sign of long-term complications? PMID- 22249339 TI - In vitro effects of mycophenolic acid on survival, function, and gene expression of pancreatic beta-cells. AB - Post-transplant diabetes mellitus represents an important complication of prolonged immunosuppressive treatment after solid organ transplantation. The immunosuppressive toxicity, responsible for a persistent impairment of glucose metabolism in pancreatic islet-transplanted patients, is mainly attributed to calcineurin inhibitors and steroids, while other immunosuppressive molecules (azathioprine and mycophenolic acid, MPA) are considered not to have a toxic effect. In the present study, in vitro effects of MPA have been investigated in mouse beta-cell lines (betaTC-1 and betaTC-6) and in purified human pancreatic islets. betaTC-1, betaTC-6, and human pancreatic islets were exposed to various concentrations of MPA for different times. Consequently, we evaluated the viability, the induction of apoptosis, the glucose-stimulated insulin secretion, and the expression of beta-cell function genes (Isl1, Pax6, Glut-2, glucokinase) and apoptosis-related genes (Bax and Bcl2). betaTC-1, betaTC-6, and human islets treated, respectively, for 48 and 72 h with 15-30 nM MPA showed altered islet architecture, as compared with control cells. We observed for betaTC-1 and betaTC 6 almost 70% reduction in cell viability; three to sixfold induction of TUNEL/apoptotic-positive cells quantified by FACS analysis. A twofold increase in apoptotic cells was observed in human islets after MPA exposure associated with strong inhibition of glucose-stimulated insulin secretion. Furthermore, we showed significant down-regulation of gene expression of molecules involved in beta-cell function and increase rate between Bax/Bcl2. Our data demonstrate that MPA has an in vitro diabetogenic effect interfering at multiple levels with survival and function of murine and human pancreatic beta-cells. PMID- 22249341 TI - Preoperative patient counseling for diagnostic renal biopsy and complications with renal radiofrequency ablation. AB - PURPOSE: To identify preoperative factors associated with surgical complications and successful diagnostic renal biopsy in both laparoscopic and percutaneous radiofrequency ablation (RFA) of renal masses in order to help aid in preoperative patient counseling for renal RFA. METHODS: We reviewed our Institutional Review Board approved database from November 2001 to January 2011, containing 335 tumors treated with either laparoscopic (LRFA) or percutaneous RFA (CTRFA). Preoperative patient demographics, tumor characteristics, and intraoperative surgical data were collected along with biopsy results and clinicopathologic outcomes. RESULTS: RFA was performed on 335 renal tumors (124 LRFA, 211 CTRFA). Non-diagnostic biopsy occurred in 18 (5.5%) tumors. Of the 317 procedures performed, 121 complications occurred in 103 (30.7%) procedures. Multivariate analysis only showed CTRFA (vs LRFA) to increase the likelihood of non-diagnostic biopsy (OR 5.1, 95% CI 1.2-22, p = 0.032). Increased tumor size (p = 0.007) and synchronous ablations (p = 0.019) increased the risk for major complications, while decreased surgeon experience (p = 0.003) and tumors close to the collecting system (p = 0.005) increased the risk of any complication. CONCLUSIONS: Preoperative recommendations can be made to patients in the future. We suggest counseling patients that when undergoing RFA, percutaneous approach increases the risk of non-diagnostic biopsy, increased tumor size increases the risk of major complications, having more than 1 tumor ablated increases the risk of a major complication, and tumors close to the collecting system may increase the risk of complications. PMID- 22249340 TI - Diet and prostate cancer prevention. AB - PURPOSE: To evaluate the present human-based evidence that diet is related to the risk and outcome of prostate cancer. METHODS: Review of major case-control and cohort studies, and experimental trials evaluating the effect of diet or dietary constituents on the risk of prostate cancer. RESULTS: Although non-experimental studies have suggested several dimensions of diet and several dietary components as related to risk and outcome of prostate cancer, the results of these studies are inconsistent. There is limited evidence that a diet that emphasizes plant products is associated with diminished risk of prostate cancer and of aggressive prostate cancer. CONCLUSION: The non-experimental epidemiologic evidence that has now accrued justifies trials of dietary intervention for those at elevated risk of prostate cancer. PMID- 22249343 TI - Therapeutic monitoring of tranexamic acid concentration: high-throughput analysis with solid-phase microextraction. AB - INTRODUCTION: The controversy still surrounds the optimal dosing regimen of tranexamic acid (TA), primary antifibrinolytic agent used in high-risk surgeries. This study compares the pharmacokinetics profile obtained from the group of patients undergoing heart surgery with the use of cardiopulmonary bypass (CPB) with the theoretical model currently used as an established dosing regimen of TA in cardiac surgery. METHODS: After induction of anesthesia, TA was administered intravenously as a bolus (30 mg/kg) infused over 15 minutes. Bolus was followed by an infusion of 16 mg.kg.h TA until the end of surgery (chest closure of the sternotomy wound). Before initiation of CPB, a bolus of 2 mg/kg was given to the pump prime. Blood samples were collected at baseline and at 30-minute time intervals during the surgery and after surgery. Automated solid-phase microextraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used for the determination of TA concentration. Blinded studies on monitoring of TA concentration were performed on 94 samples. Obtained results were compared with a previously described pharmacokinetic model of TA dosing. RESULTS: The average concentration of TA during the use of CPB was 134 mcg/mL with the relative standard deviation 27%. The observed range of TA concentrations was 70-188 mcg/mL showing that individual patients can significantly exceed the recommended levels proposed by the theoretical model. lower limit of quantification of the proposed method was 1 mcg/mL. Intra- and interday accuracy was +/-10% and precision was <=12% at all concentration levels tested. CONCLUSIONS: The suitability of automated solid-phase microextraction for high throughput clinical analysis was established for the first time. The obtained pharmacokinetic profiles showed significant interpatient variation in the concentration of TA during heart surgery with the use of CPB, which confirms the need of the therapeutic monitoring of this antifibrinolytic agent. PMID- 22249342 TI - Accuracy of preoperative endorectal MRI in predicting extracapsular extension and influence on neurovascular bundle sparing in radical prostatectomy. AB - PURPOSE: To evaluate the accuracy of presurgical endorectal MRI (eMRI) for local staging before radical prostatectomy (RP) and its influence on neurovascular bundle (NVB) resection during radical prostatectomy. PATIENTS AND METHODS: A total of 385 patients with histologically proven prostate cancer (PCa) have been included in this retrospective study between 2004 and 2008. All patients underwent preoperative eMRI at 1.5 T before open RP. Staging results by eMRI were compared with the histopathological findings. The presence of positive surgical margins and extent of nerve-sparing procedure were evaluated. Subgroup analysis of low-risk group and intermediate to high-risk group based on D'Amico criteria was conducted. RESULTS: In 294 (76.4%) patients, pathological stage was correctly predicted, 69 patients (17.9%) were understaged and 22 (5.7%) overstaged. Overall sensitivity, specificity, negative and positive predictive value for predicting extracapsular extension (ECE) were 41.5, 91.8, 78.0 and 69.0%, respectively. One hundred and fifty-two (48.4%) of the patients classified as stage cT2 by eMRI underwent bilateral NVB sparing, whereas 14 (19.7%) patients with reported ECE underwent bilateral NVB sparing (P < 0.01). Overall positive surgical margin rate was 14.8%. Sensitivity of predicting ECE and positive predictive value were lower in the low-risk group than in the intermediate and high-risk group. CONCLUSIONS: eMRI is effective in predicting extracapsular extension in an intermediate to high-risk group. Preoperative eMRI in patients with low-risk criteria is not recommended as a routine assessment modality. eMRI findings did appear to influence surgical strategy as patients with imaging findings suggesting >cT2 disease were less likely to undergo NVB sparing. PMID- 22249344 TI - Pharmacokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations. AB - BACKGROUND: A prolonged-release formulation of tacrolimus for once-daily administration (Tacrolimus QD) has been developed to offer potential improvements in patient adherence. This study compared the pharmacokinetics (PK) of tacrolimus in stable kidney transplant recipients before and after conversion from twice daily tacrolimus (Tacrolimus BID) to Tacrolimus QD. METHODS: This was an open label, multicenter replicate design study in stable adult kidney transplant recipients (>=6 months posttransplantation) maintained on Tacrolimus BID. Patients underwent four sequential 14-day treatment periods of alternating Tacrolimus BID and QD (mg:mg conversion). Four 24-hour PK profiles were collected, one on the last day of each treatment period. Adverse events were also reported. RESULTS: A total of 60 of 69 patients completed all 4 PK profiles. Steady-state tacrolimus area under the curve from 0 to 24 hours and Cmin were comparable for both formulations, with treatment ratio means (90% confidence intervals) of 92.9% (89.8%-96.0%) and 90.9% (87.3%-94.6%), respectively (acceptance interval: 80%-125%). Both formulations were well tolerated, with renal function remaining stable over the 8-week period. There was a good correlation between area under the curve from 0 to 24 hours and Cmin for Tacrolimus QD and BID (r = 0.88 and 0.82, respectively). The relationship between these two parameters was also similar. CONCLUSIONS: The results of this study provide evidence for safe conversion from Tacrolimus BID to QD with appropriate trough concentration monitoring. PMID- 22249345 TI - Gentamicin serum concentrations in patients with gentamicin-PMMA beads for infected hip joints: a prospective observational cohort study. AB - BACKGROUND: Gentamicin-polymethylmethacrylate (PMMA) beads release gentamicin gradually, and high concentrations develop only locally. It is unclear how frequent and in which patients gentamicin serum concentrations are measurable and possibly lead to toxicity. The aim of this study was to investigate the measurability of gentamicin serum concentrations after the implantation of gentamicin-PMMA beads and to assess the nephrotoxicity of these beads. METHODS: In this observational cohort study, gentamicin and creatinine concentrations were measured in 34 serum samples of 23 patients with implanted gentamicin-PMMA beads for infected hip joints with our regular immunoassay (lower limit of quantitation 0.4 mg/L). Samples were also analyzed with an adjusted immunoassay with a lower limit of quantitation of 0.05 mg/L. RESULTS: Gentamicin serum concentrations were >0.4 mg/L in 9 of 34 (26%) of all the samples measured (both after the first implantation and change of beads) and in 5 of 23 patients (22%) after the first implantation of gentamicin-PMMA beads. Gentamicin serum concentrations were >0.05 mg/L in 31 samples (91%). Nephrotoxicity (defined as increase in serum creatinine >44 MUmole/L and/or a relative increase >25%) occurred more frequently in patients with measurable gentamicin serum concentrations than in those without measurable gentamicin serum levels (57% versus 43%, P = 0.02). Both nephrotoxicity and gentamicin serum concentration could not be associated with the number of implanted gentamicin-PMMA beads. CONCLUSIONS: Gentamicin serum concentrations >0.4 mg/L can be measured after the implantation of gentamicin PMMA beads in certain patients with infected hip joints. Furthermore, elevated (>0.4 mg/L) gentamicin serum concentrations are associated with nephrotoxicity in patients with gentamicin-PMMA beads for infected hip joints. PMID- 22249346 TI - Which amphetamine-type stimulants can be detected by oral fluid immunoassays? AB - INTRODUCTION: The use of oral fluid for monitoring drug consumption on roads has many advantages over conventional biological fluids; therefore, several immunoassays have been developed for this purpose. In this work, the ability of 3 commercial immunoassays to detect amphetamine-type stimulants (ATSs) in oral fluid was assessed. In addition, it was reviewed the main controlled ATSs available worldwide, as well as the oral fluid immunological screening tests that have been used for identifying ATSs in drivers. MATERIALS AND METHODS: The analytical specificity of amphetamine direct enzyme-linked immunosorbent assay (ELISA), methamphetamine direct ELISA (Immunalysis Corporation), and Oral-View saliva multidrug of abuse test (Alfa Scientific Designs) was evaluated using ATS spiked oral fluid. Legislation and published articles that report the use of immunological screening tests to detect ATS consumption in conductors were reviewed, including the kit's technical information, project reports, police and drug databases. RESULTS AND DISCUSSION: Even at high concentrations, the tested assays were not able to detect methylphenidate, fenproporex, or diethylpropion, controlled ATSs legally marketed in many countries. CONCLUSIONS: This evidences the need to develop new kits that enable one to control the misuse of prescription ATSs on roads through oral fluid immunoassays. PMID- 22249347 TI - The relevance of factor VIII (FVIII) pharmacokinetics to TDM and hemophilia a treatment: is B domain-deleted FVIII equivalent to full-length FVIII? AB - PURPOSE: Recombinant DNA-derived clotting factor VIII concentrates (rFVIII) potentially have safety advantages over plasma-derived products. Removal of the B domain of the FVIII molecule does not seem to reduce the procoagulant activity and improve the efficiency of the manufacturer. However, when used, clinically possible differences in hemostatic efficacy between the full-length (FL) and B domain-deleted (BDD) molecules have emerged. This article predicts the impact that differences in the pharmacokinetic behavior between BDD- and FL-rFVIII may have on bleed prophylaxis in hemophilia A. METHODS: Published data on the pharmacokinetic and biological effects of FL- and BDD-rFVIII were examined and used well-established proven pharmacokinetic modeling applied to therapeutic target plasma concentrations of FL- and BDD- rFVIII. RESULTS: Biochemical differences between the 2 molecules in standard laboratory assays can be shown and in vivo BDD-rFVIII appears to show a shorter half-life possibly because of greater susceptibility to proteolytic degradation. Theoretical modeling demonstrates that if patients switch between FL-rFVIII to BDD-rFVIII, it could result in very different concentrations of active clotting factor. CONCLUSIONS: As demonstrated, around 40% of patients if switched from FL-rFVIII to BDD-rFVIII would have lower concentrations of FVIII in the blood. It is essential that clinicians are aware of this possibility and that there is sufficient and appropriate follow-up of patients with hemophilia A who are switching the type of factor concentrate used in their treatment. PMID- 22249348 TI - Posaconazole serum level on day 2 predicts steady state posaconazole serum level. PMID- 22249349 TI - Restoration of physical function in patients following total knee arthroplasty: an update on rehabilitation practices. AB - PURPOSE OF REVIEW: Previous studies on rehabilitation following total knee arthroplasty (TKA) demonstrated limited efficacy in increasing long-term outcomes. More recently, several rehabilitation approaches have demonstrated greater efficacy for increasing long-term strength and functional performance outcomes following TKA. RECENT FINDINGS: Neuromuscular electrical stimulation (NMES), applied to the surgical limb's quadriceps muscle for the first 6 weeks following surgery, has been shown to improve the speed of recovery from TKA and leads to long-term increases in strength and functional performance. Rehabilitation programs that incorporate higher intensity, progressive resistive exercises that target all major muscle groups of the lower extremity have demonstrated superior long-term strength and functional gains compared with lower intensity programs. Finally, although the greatest strength and functional losses occur immediately after surgery, there is emerging evidence that strength and functional gains can be made after the acute postoperative recovery period with programs focusing on the use of progressive aquatic exercise or eccentric exercise. SUMMARY: Functional recovery following TKA can be enhanced by the use of NMES and utilization of a comprehensive, higher intensity strength training program in conjunction with traditional rehabilitation approaches. PMID- 22249350 TI - Risk factors for cardiovascular disease in rheumatoid arthritis. AB - PURPOSE OF REVIEW: To highlight recent evidence regarding the contribution of traditional and nontraditional [e.g. inflammatory markers, rheumatoid arthritis (RA) features] risk factors toward the excess cardiovascular risk in RA. RECENT FINDINGS: The impact of traditional risk factors on the development of cardiovascular disease in persons with RA is an area of active research. Some are more prevalent among people with RA (e.g. smoking); others appear to have paradoxical relationships (e.g. body mass index), and findings remain inconsistent with others (e.g. dyslipidemia). Collectively the data suggest that cardiovascular risk factors behave differently in RA. Thus, risk scores developed for the general population based on traditional cardiovascular risk factors alone are unlikely to accurately estimate cardiovascular risk in RA, highlighting the need for RA-specific risk prediction tools.Nontraditional risk factors, in particular RA disease activity/severity measures, including inflammatory markers, disease activity scores, seropositivity, physical disability, destructive changes on joint radiographs, extra-articular manifestations, and corticosteroid use, have repeatedly shown significant associations with increased cardiovascular risk. Medications used to treat RA may also affect cardiovascular risk. A recent meta-analysis suggests that all nonsteroidal anti-inflammatory drugs confer some cardiovascular risk. The cardiovascular risks/benefits associated with use of disease-modifying antirheumatic drugs and/or biologics remain controversial, as does the role of statins in RA. SUMMARY: Cardiovascular disease remains a major problem for people with RA. Future work should focus on further delineating the underlying biological mechanisms involved, developing and evaluating risk assessment tools and biomarkers, as well as prevention/treatment strategies specific to the RA population. PMID- 22249351 TI - Rehabilitation programs for musculoskeletal injuries in military personnel. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize current trends and rehabilitation programs for musculoskeletal injuries in military personnel returning from deployment. RECENT FINDINGS: Musculoskeletal injuries (MSIs) are the leading healthcare problem for military members. Risk factors include participation in sports, carrying heavy loads, older age, female sex, standing for long periods of time, and walking long distances. MSIs may lead to medical discharge from the military. Physical and occupational therapists work at the Combat Support Hospitals to provide rehabilitation care to injured personnel and reduce recovery time by 60% and costs by 123%. The Army Medical Department has developed initiatives to decrease the burden of MSI: musculoskeletal screening and referral tools to assist military medical providers in managing patients with MSI; Pain Management Task Force to optimize care for wounded soldiers; Musculoskeletal Action Plan for injury prevention, early diagnosis and management, and rehabilitation/reintegration following injury; and Musculoskeletal Action Teams to work with military recruits who make up the largest subgroup in the Army with the highest incidence of MSIs. SUMMARY: The US Military is aware of the inherent risks for MSI associated with military training and repeated combat deployments. Rehabilitation efforts have been developed to address the problem. PMID- 22249352 TI - Effect of race/ethnicity on risk, presentation and course of connective tissue diseases and primary systemic vasculitides. AB - PURPOSE OF REVIEW: Understanding the effects of race/ethnicity on the risk and expression of systemic rheumatic diseases has potential clinical implications and provides insight into their etiopathogeneses. This review summarizes knowledge of the effects of race/ethnicity on the following nine conditions: antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), Behcet's disease, dermatomyositis/polymyositis, Henoch-Schonlein purpura, Kawasaki disease, large vessel vasculitis (LVV), primary Sjogren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). RECENT FINDINGS: Distinct racial/ethnic patterns have emerged for most of the conditions considered here. Areas of progress include the finding that the two AAVs, granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis, exhibit distinct racial/ethnic susceptibilities in disease risk. In addition, nonwhites, with known high risk of SLE and SSc, may also be at a high risk for pSS and have more severe disease. Evidence is accumulating that nonwhites are rarely affected by the LVV giant-cell arteritis. Race/ethnicity-specific genetic risk factors were recently detected for GPA. SUMMARY: Epidemiologic data have allowed discerning the racial/ethnic profiles for many of the considered systemic rheumatic conditions. Future challenges will be to unravel the genetic, environmental and/or socio-econonomic determinants of the observed racial/ethnic disparities. More research is needed to clarify the impact of race/ethnicity on the AAV Churg Strauss syndrome, dermatomyositis/polymyositis and Takayasu arteritis. PMID- 22249353 TI - Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention. AB - Multiple studies have shown a correlation between high on-treatment platelet reactivity (HPR) and ischemic complications after percutaneous coronary interventions (PCI); however, the role of platelet reactivity testing in order to adjust clopidogrel dose is debated. We sought to determine whether a strategy incorporating platelet reactivity testing with the Multiplate analyzer to tailor the dose of clopidogrel is superior to standard clopidogrel treatment after PCI. Between May 2008 and June 2009, 192 consecutive patients undergoing PCI were randomized to a tailored treatment strategy using the Multiplate analyzer or to uniform administration of 75 mg clopidogrel. In the tailored group, platelet function was assessed 24 h after clopidogrel loading, and patients with HPR (>46 U) received an additional 600 mg loading dose and 150 mg clopidogrel thereafter for one month. The primary endpoint was the composite of cardiac death, myocardial infarction, ischemic stroke or definite/probable stent thrombosis during six months. In the tailored group, a repeated loading dose of 600 mg clopidogrel significantly decreased platelet reactivity in patients with HPR (61.0 U [IQR: 52.5-71.5] vs. 21.5 U [15.8-30.5]; P < 0.0001) that remained unchanged during the maintenance phase on 150 mg clopidogrel (25.0 U [IQR: 19.8 27.0]; P = 0.20). The incidence of the primary endpoint was significantly higher in the standard clopidogrel group as compared to the Multiplate-tailored arm (5.3% vs. 0%, P = 0.03). In parallel, MACCE-free survival significantly improved in patients with Multiplate-tailored therapy (Kaplan-Meier log-rank: P = 0.02). Increasing the dose of clopidogrel according to the Multiplate assay may reduce ischemic complications in patients on clopidogrel after PCI. PMID- 22249354 TI - Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5 fluorouracil resistance in colorectal cancer. AB - The drug fluorouracil (5-FU) is a widely used antimetabolite chemotherapy in the treatment of colorectal cancer. The gene uridine monophosphate synthetase (UMPS) is thought to be primarily responsible for conversion of 5-FU to active anticancer metabolites in tumor cells. Mutation or aberrant expression of UMPS may contribute to 5-FU resistance during treatment. We undertook a characterization of UMPS mRNA isoform expression and sequence variation in 5-FU resistant cell lines and drug-naive or -exposed primary and metastatic tumors. We observed reciprocal differential expression of two UMPS isoforms in a colorectal cancer cell line with acquired 5-FU resistance relative to the 5-FU-sensitive cell line from which it was derived. A novel isoform arising as a consequence of exon skipping was increased in abundance in resistant cells. The underlying mechanism responsible for this shift in isoform expression was determined to be a heterozygous splice site mutation acquired in the resistant cell line. We developed sequencing and expression assays to specifically detect alternative UMPS isoforms and used these to determine that UMPS was recurrently disrupted by mutations and aberrant splicing in additional 5-FU-resistant colorectal cancer cell lines and colorectal tumors. The observed mutations, aberrant splicing and downregulation of UMPS represent novel mechanisms for acquired 5-FU resistance in colorectal cancer. PMID- 22249355 TI - Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder. AB - We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60 120 mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P<=0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin-releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response. PMID- 22249356 TI - Heterochromatin as an incubator for pathology and treatment non-response: implication for neuropsychiatric illness. AB - Heterochromatin is a higher order assembly that is characterized by a genome-wide distribution, gene-repression, durability and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where downregulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or from misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters, such as heterochromatin protein 1 (HP1) homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genome-wide gene networks, tissue specific ontologies and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic potential of standard pharmacotherapies is achieved, especially in treatment resistant patients. PMID- 22249357 TI - Array-based pharmacogenomics of molecular-targeted therapies in oncology. AB - The advent of microarrays over the past decade has transformed the way genome wide studies are designed and conducted, leading to an unprecedented speed of acquisition and amount of new knowledge. Microarray data have led to the identification of molecular subclasses of solid tumors characterized by distinct oncogenic pathways, as well as the development of multigene prognostic or predictive models equivalent or superior to those of established clinical parameters. In the field of molecular-targeted therapy for cancer, in particular, the application of array-based methodologies has enabled the identification of molecular targets with 'key' roles in neoplastic transformation or tumor progression and the subsequent development of targeted agents, which are most likely to be active in the specific molecular setting. Herein, we present a summary of the main applications of whole-genome expression microarrays in the field of molecular-targeted therapies for solid tumors and we discuss their potential in the clinical setting. An emphasis is given on deciphering the molecular mechanisms of drug action, identifying novel therapeutic targets and suitable agents to target them with, and discovering molecular markers/signatures that predict response to therapy or optimal drug dose for each patient. PMID- 22249358 TI - Prefrontal neuromodulation by nicotinic receptors for cognitive processes. AB - RATIONALE: The prefrontal cortex (PFC) mediates executive functions, a set of control processes that optimize performance on cognitive tasks. It enables appropriate decision-making and mediates adapted behaviors, all processes impaired in psychiatric or degenerative disorders. Key players of normal functioning of the PFC are neurotransmitter (NT) systems arising from subcortical nuclei and targeting PFC subareas and, also, neuronal nicotinic acetylcholine receptors (nAChRs). These ion channels, located on multiple cell compartments in all brain areas, mediate direct cholinergic transmission and modulate the release of NTs that cross onto PFC neurons or interneurons. OBJECTIVE: We compiled current knowledge concerning the role of nAChRs in NT release, focusing on the PFC. We point out plausible mechanisms of interaction among PFC circuits implicated in executive functions and emphasized the role of beta2-containing nAChRs, the high-affinity receptors for acetylcholine (ACh). These receptors are more directly implicated in behavioral flexibility either when located on PFC neurons or in the monoaminergic or cholinergic systems targeting the PFC. RESULTS: We shed light on potentially crucial roles played by nAChRs in complex interactions between local and afferent NTs. We show how they could act on cognition via PFC networks. CONCLUSIONS: nAChRs are crucial for decision-making, during integration of emotional and motivational features, both mediated by different NT pathways in the PFC. We review the knowledge recently gained on cognitive functions in mice and our current understanding of PFC NT modulation. The combination of these data is expected to provide new hypotheses concerning the role of AChRs in cognitive processes. PMID- 22249359 TI - Further characterization of the prototypical nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198 in rodent models of conflict anxiety and despair. AB - RATIONALE: Ro 64-6198, the prototypical non-peptide nociceptin/orphanin FQ peptide (NOP) receptor agonist, has potent anxiolytic-like effects in several preclinical models and species. However the effects of Ro 64-6198 on distinctive anxiety-provoking conditions related to unconditioned conflict behavior as well as its role in despair-like behavior remain to be addressed. OBJECTIVE: Here we examined the effects of Ro 64-6198 on unconditioned conflict anxiety using stimuli with different salience and on regulation of autonomic reactivity and compared these to the effects of benzodiazepine receptor agonists. We also addressed the potential effects of Ro 64-6198 on despair-like behavior. MATERIALS AND METHODS: Ro 64-6198 (0.1 to 10 mg/kg i.p.) and either diazepam or chlordiazepoxide were tested in the Vogel conflict punished drinking test (VCT) in Sprague Dawley rats, in the social approach-avoidance (SAA) test in Lewis rats, in the novelty-induced hypophagia (NIH) in C57BL/6J mice, and in stress induced hyperthermia in NMRI mice, as well as in the forced swim test (FST) in Sprague Dawley rats and the tail suspension test (TST) in C57BL/6J mice. RESULTS: Ro 64-6198 (0.3 to 3 mg/kg) dose-dependently produced anxiolytic-like effects in the VCT, SAA, NIH, and SIH, similar to benzodiazepine receptor agonists. Ro 64 6198 did not alter immobility time in the FST and TST. CONCLUSIONS: Ro 64-6198 produced marked anxiolytic-like effects in response to a variety of mild to strong anxiogenic stimuli, whereas it did not facilitate depression-related behaviors. This data extend previous literature suggesting that NOP receptors are a viable target for the treatment of anxiety disorders. PMID- 22249360 TI - Effect of yohimbine stress on reacquisition of oxycodone seeking in rats. AB - RATIONALE: Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse. OBJECTIVE: To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking. METHODS: One hundred thirty-two male Sprague Dawley rats underwent place conditioning with oxycodone (2 mg/kg, SC; *6 days), extinction (vehicle * 6 days), and reconditioning with 0, 0.25, 2, or 5 mg/kg oxycodone (2 days). Yohimbine (0, 2.5, or 5 mg/kg, IP) was administered 30 min prior to reconditioning. RESULTS: Pretreatment with 2.5 mg/kg yohimbine increased, while 5 mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n = 30) further indicated that the effect of yohimbine was specific to reacquisition. CONCLUSION: The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse. PMID- 22249361 TI - Escalation of cocaine intake with extended access in rats: dysregulated addiction or regulated acquisition? AB - RATIONALE: Understanding the neurobehavioral mechanisms underlying dysregulated cocaine intake is important for the development of new cocaine abuse therapies. OBJECTIVES: The current study determined if cocaine escalation under extended access conditions (6-h access) is regulated by discrimination learning processes. METHODS: Rats were initially trained on cocaine self-administration (0.1 or 0.25 mg/kg/infusion) using a fixed ratio 1 (FR 1) schedule under 1-h access for 12 sessions. Some rats were then trained to self-administer cocaine under 1-h or 6-h access conditions exclusively for 14 additional sessions, while other rats were trained under both 1- and 6-h access conditions that were cued or noncued for 28 additional sessions (14 sessions for each 1- and 6-h access). Two additional groups of rats were initially trained to self-administer cocaine using an FR 1 schedule under 10-min access for 12 sessions; half of the animals were then switched to 60-min access conditions for 14 additional sessions. RESULTS: When access conditions were differentially cued, escalation of cocaine intake was evident in animals with both 1- and 6-h access conditions during the escalation phase. Escalation also was evident in animals initially trained with 10-min access and then switched to 60-min access. CONCLUSIONS: The results demonstrate that dysregulated and regulated intakes can be expressed within the same animal, indicating that escalation is context-dependent. Furthermore, escalated cocaine intake can be expressed under 1-h access conditions. Overall, these results suggest that escalated cocaine intake may be representative of discrimination dependent regulated intake rather than addiction-like, compulsive intake. PMID- 22249362 TI - Characteristics of DSM-IV attention deficit hyperactivity disorder combined and predominantly inattentive subtypes in a Turkish clinical sample. AB - Consecutively referred subjects (N = 537) to an outpatient clinic were evaluated to compare the Attention Deficit Hyperactivity Disorder Combined (ADHD-C) and predominantly inattentive (ADHD-PI) subtypes using parent and teacher ratings and neuropsychological variables. Statistical significance was at P < 0.002 adjusted for multiple comparisons. ADHD-PI subjects were older, more likely to be female, higher socioeconomic status, had lower Child Behavior Checklist and Teacher Report Form Aggression, Delinquency and Social Problems scores, and higher Withdrawal and Competence scores, compared to ADHD-C subjects. Comorbid conduct problems were more common among ADHD-C subjects. There were no differences in terms of anxiety/depression, and neuropsychological measures. The study is unique in that it provides data on a broad range of measures from a middle income developing country with important confirmation of similar pattern of differences and similarities between ADHD-C and ADHD-PI subtypes previously reported in North American and Western European samples. PMID- 22249363 TI - Hydration and interactions in protein solutions containing concentrated electrolytes studied by small-angle scattering. AB - During protein crystallization and purification, proteins are commonly found in concentrated salt solutions. The exact interplay of the hydration shell, the salt ions, and protein-protein interactions under these conditions is far from being understood on a fundamental level, despite the obvious practical relevance. We have studied a model globular protein (bovine serum albumin, BSA) in concentrated salt solutions by small-angle neutron scattering (SANS). The data are also compared to previous studies using SAXS. The SANS results for dilute protein solutions give an averaged volume of BSA of 91,700 A(3), which is about 37% smaller than that determined by SAXS. The difference in volume corresponds to the contribution of a hydration shell with a hydration level of 0.30 g g(-1) protein. The forward intensity I(0) determined from Guinier analysis is used to determine the second virial coefficient, A(2), which describes the overall protein interactions in solution. It is found that A(2) follows the reverse order of the Hofmeister series, i.e. (NH(4))(2)SO(4) < Na(2)SO(4) < NaOAc < NaCl < NaNO(3) < NaSCN. The dimensionless second virial coefficient B(2), corrected for the particle volume and molecular weight, has been calculated using different approaches, and shows that B(2) with corrections for hydration and the non spherical shape of the protein describes the interactions better than those determined from the bare protein. SANS data are further analyzed in the full q range using liquid theoretical approaches, which gives results consistent with the A(2) analysis and the experimental structure factor. PMID- 22249364 TI - Identification of a small-molecule inhibitor of dengue virus using a replicon system. AB - Dengue virus (DENV) is a mosquito-borne human pathogen that causes a serious public-health threat in tropical and subtropical regions of the world. Neither a vaccine to prevent nor an effective therapeutic agent to treat DENV infection is currently available. We established a stable cell line harboring a luciferase reporting DENV subgenomic replicon to screen for inhibitors of DENV. A total of 14,400 small-molecule (MW < 500 Da) chemicals were evaluated for their ability to reduce luciferase reporter activity in cell lysates. One effective compound was identified from the screening. This compound was found to reduce virus production but did not block virus entry in virus-based assay. Mode-of-action analysis revealed that this inhibitor suppressed viral RNA replication but did not affect replicon translation. This compound potentially could be developed as an anti DENV agent and might be useful for dissecting the molecular mechanism of DENV replication. PMID- 22249365 TI - Fuels and chemicals from hemicellulose sugars. AB - Industrial processes of lignocellulosic material have made use of only the hexose component of the cellulose fraction. Pentoses and some minor hexoses present in the hemicellulose fraction, which may represent as much as 40% of lignocellulosic biomass, have in most cases been wasted. The lack of good methods for utilization of hemicellulose sugars is a key obstacle hindering the development of lignocellulose-based ethanol and other biofuels. In this chapter, we focus on the utilization of hemicellulose sugars, the structure of hemicellulose and its hydrolysis, and the biochemistry and process technology involved in their conversion to valuable fuels and chemicals. PMID- 22249367 TI - Increased monocyte expression of sialoadhesin during acute cellular rejection and other enteritides after intestine transplantation in children. AB - BACKGROUND: Sialoadhesin (CD169) facilitates T-cell priming when overexpressed on inflammatory monocytes. Monocyte-derived macrophages prime acute cellular rejection after intestine transplantation (ITx).The purpose of this study was to evaluate whether CD169-expressing activated monocytes associate with or predict ITx rejection. METHODS: After informed consent (ClinicalTrials.gov NCT No. 01163578), activated CD169+CD14+monocytes were measured by flow cytometry in five normal healthy adult volunteers (group A), and 56 children with ITx sampled cross sectionally (group B, 26), longitudinally (group C, 18), or during infection/inflammation without rejection (group D: acute enteritis, 9; Helicobacter pylori, 1; Streptococcal pharyngitis 1; and posttransplant lymphoma, 1). Activated monocytes were tested for correlations with donor-specific alloreactivity in simultaneous mixed lymphocyte co-cultures. RESULTS: Median age was 3 years (range 0.5-21 yr), and distribution of ITx-alone:combined liver-ITx was 25:31. Higher frequencies (%) of activated monocytes were seen during rejection in group B and infection/inflammation without rejection in group D (58 +/- 28 and 73 +/- 26), compared with nonrejectors or normal controls (10.6 +/- 7.9 or 10.7 +/- 6.5, P=0.001). In longitudinal monitoring, rejectors also showed higher activated monocyte frequencies (%) before ITx (64 +/- 26 vs. 13.4 +/- 8.6, P=0.0007) and during acute cellular rejection (55 +/- 28 vs. 22.4 +/- 15, P=0.006) when compared with nonrejectors. Activated monocytes correlated significantly with allospecific CD154+T-cytotoxic memory cells (Spearman r=0.688, P=7.1E-05) and CD154+B cells (r=0.518, P=0.005) in ITx recipients without inflammation/infection but not in group D. CONCLUSIONS: Monocytes overexpress sialoadhesin nonspecifically during ITx rejection and systemic or enteritic inflammatory states. When combined with allospecific T and B cells, this information may differentiate between rejection and other enteritides. PMID- 22249368 TI - [(68)Ga-labeled peptides for clinical trials - production according to the German Drug Act: the Gottingen experience]. AB - The AMG implies far-reaching implications for the synthesis of new radiopharmaceuticals for clinical trials. AIM, METHODS: As a part of the DFG funded Clinical Research Group (KFO 179) a project designated "Immuno-PET for assessment of early response to radiochemotherapy of advanced rectal cancer" was initiated. This trial is focused on a trivalent bispecific humanized monoclonal antibody, and a 68Ga-labeled peptide. Following the new regulatory framework we established a GMP-compliant cleanroom laboratory and applied for a manufacturing permission. RESULTS: During the project constructural, personnel and organizational conditions for a successful application were established, including a quality management system. A GMP-conform cleanroom laboratory class C was constructed, equipped with a two-chamber lock. The actual manufacturing is performed in a closed system with subsequent sterile filtration. The manufacturing processes have been automatised and validated as well as the necessary quality controls. The manufacturing permission was granted after an official inspection. CONCLUSIONS: The new German Drug Act is considered as a break in the production practice of nuclear medicine. The early involvement and communication with the authorities avoids time-consuming and costly planning errors. It is much to be hoped that the new legal situation in Germany will not cause serious impairments in the realization of clinical trials in German nuclear medicine. PMID- 22249369 TI - Laparoscopic radical cystectomy for bladder cancer with prostatic and neurovascular sparing: initial experience. AB - PURPOSE: This study presents our initial experience with laparoscopic radical cystectomy with preservation of the neurovascular bundles and partial prostate for the treatment of bladder cancer. METHODS: Thirty-seven patients with bladder cancer were selected for the study between June 2007 and December 2009. The criteria for patient selection included prostate-specific antigen level below 4.0 ng/mL; negative involvement of the trigone and/or prostatic urethra; and no self reported erectile dysfunction. The surgical procedure included laparoscopic prostate- and neurovascular bundles-sparing cystectomy with an ileal neobladder construction. Mean follow-up was 18 months. RESULTS: All patients underwent laparoscopic resection without requiring a traditional open procedure. The mean operation time was 215 min with a mean volume of intraoperative hemorrhage of 190 mL. After removal of the urinary catheter, all patients had a daytime urinary continence; six had a short period of nighttime urinary incontinence. Most patients reported a strong desire for sexual activity and were able to complete sexual intercourse without auxiliary measures at 3 months postoperatively. Grade 3 complications developed in 2 patients graded by the classification of Clavien system. One patient was diagnosed with pelvic recurrence 16 months postoperatively. CONCLUSION: The laparoscopic radical cystectomy with a partial prostate preservation offers the advantages of a high continence, minimal impairment of erectile function, and low recurrence rate. PMID- 22249370 TI - Multiple brown tumors causing spinal cord compression in association with secondary hyperparathyroidism. AB - BACKGROUND: Brown tumor, a non-neoplastic process resulting from excess osteoclast activity, is found in primary hyperparathyroidism (HPTP) and secondary hyperparathyroidism (HPTS). We report a rare case of multiple spinal cord compression by brown tumors. CASE REPORT: A 47-year-old male with end-stage renal disease caused by hypertensive nephrosclerosis, on hemodialysis for 10 years and diagnosed with severe HPTS, developed back pain and sudden onset of gait difficulties progressing to paraplegia. A previous computed tomography (CT) of the lumbosacral spine demonstrated a solid lesion, located in the body of the sacrum, at S1-S2 level, with fine bone edge sclerosis, suggestive of brown tumor. A magnetic resonance imaging without gadolinium injection was performed. The examination revealed an insufflating bone lesion at thoracic level (T5/T6). Posterior laminectomy was followed by tumor excision. Histopathological analysis showed osteoid tissue streaked by fibroplasia with hemosiderin granulation. CONCLUSION: Differential diagnosis of sudden neurologic deficits and paraplegia in renal patients with secondary HPPT must consider the possibility of brown tumor. PMID- 22249371 TI - Formation of octacalcium phosphates with co-incorporated succinate and suberate ions. AB - Octacalcium phosphates (OCPs) co-incorporated with various molar ratios of succinate and suberate ions were synthesized by wet processing. The interplanar spacings of the (100) planes (d(100)) of OCPs formed in the presence of succinic acid (Suc) or suberic acid (Sub) were larger than those of OCPs formed without addition of a dicarboxylic acid to the reaction solvent. The increases in the interplanar spacings of the (100) planes were caused by substitution of HPO(4)(2 ) by dicarboxylate ions. The OCPs with co-incorporated succinate and suberate ions, i.e. solid solutions of OCP with incorporated Suc and Sub, were formed by reactions in the presence of Suc and Sub. When the Suc/(Suc + Sub) values in the starting compositions were in the range 0.45-1.0, Suc was preferentially incorporated into the OCP. In contrast, when the Sub/(Suc + Sub) values in the starting compositions were in the range 0.60-1.0, Sub was preferentially incorporated into the OCP crystals. PMID- 22249372 TI - Current progress on augmented reality visualization in endoscopic surgery. AB - PURPOSE OF REVIEW: Advancements in surgery are progressing at a rapid rate; however, there are still limitations, including the ability to accurately visualize the target organ, in particular during laparoscopic surgery. Augmented reality visualization is a novel technique that has been developed to allow the fusion of three-dimensional medical images, such as those from transrectal ultrasound or computed tomography/MRI, with live camera images in real-time. In this review, we describe the current advancements and future directions of augmented reality and its application to laparoscopic surgery. RECENT FINDINGS: Geometrically-correct superimposed images can be generated by tracking of the laparoscope and registration of the target organ. The fused image between the live laparoscopic images and the reconstructed three-dimensional organ model aides the surgeon in his or her understanding of anatomical structures. Laparoscopic and robot-assisted surgeries in both general surgery and urology have been performed with technical success to date. The primary limitation of the current augmented reality systems is its infancy in dynamic tracking of organ motion or deformation. Recently, augmented reality systems with organ tracking based on real-time image analysis were developed. Further improvement and/or development of such new technologies would resolve these issues. SUMMARY: Augmented reality visualization is a significant advancement, improving the precision of laparoscopic/endoscopic surgery. New technologies to improve the dynamic tracking of organ motion or deformation are currently under investigation. PMID- 22249373 TI - Intraprostatic targeting. AB - PURPOSE OF REVIEW: The ability to accurately localize and target prostate cancer, whether for staging or future interventions, is an important concept in prostate cancer management. In this review, we describe the emerging technologies that allow for enhanced visualization and precise targeting of the prostate cancer. RECENT FINDINGS: Uses of prostate-specific antigen and conventional prostate biopsy with image-blinded random systematic techniques have led to overdiagnosis of insignificant cancer and underdiagnosis of significant cancer. Active surveillance and focal therapy have become hot topics in prostate cancer management as the incidence of low-risk prostate cancer rises. For either management, it is essential to localize, characterize, and target the clinically important cancer in the prostate. Emerging techniques in ultrasound as well as MRI modalities allow for enhancement of tumor visualization, and characterization. Digital mapping technique of biopsy trajectory is an emerging technique that allows for three-dimensional mapping of biopsy-proven cancer lesions as well as potential future delivery of focal therapy. Molecular or cancer-specific targeting is promising for specific imaging and therapeutic approach at the cell level. SUMMARY: Emerging technologies improve clinically relevant prostate cancer identification using digitalized multiparametric anatomical and functional imaging and enhance the ability to precisely target the known-cancer. PMID- 22249374 TI - Refractory multisystem sarcoidosis responding to infliximab therapy. AB - Chronic progressive multisystem granulomatous disease is seen in 10-30% of patients with sarcoidosis and can result in end organ damage. Corticosteroids are the mainstay of treatment with the addition of cytotoxic agents in severe cases. Some patients are refractory to such treatment and, therefore, management is a challenge. There is currently limited evidence for biological agents such as infliximab, a monoclonal anti-tumor necrosis factor-alpha antibody in the treatment of multisystem sarcoidosis. We report outcomes of three patients with extensive multisystem sarcoidosis refractory to conventional treatment and treated at our center. Clinical assessment and radiographic imaging were used to assess the response to infliximab treatment. Infliximab therapy induced clinical remission in all three patients, and this clinical response correlated with radiographic evidence of the resolution of granulomatous disease. Serum ACE level was reduced in all cases, and daily steroid dosage was reduced. We propose that infliximab can be an effective treatment in patients with multisystem complex sarcoidosis refractory to conventional drug therapy and can result in sustained clinical remission. Our experience supports the urgent need for randomized controlled clinical trials of anti-TNF therapy in refractory systemic sarcoidosis. PMID- 22249377 TI - Chromaffin cells: the peripheral brain. AB - Chromaffin cells probably are the most intensively studied of the neural crest derivates. They are closely related to the nervous system, share with neurons some fundamental mechanisms and thus were the ideal model to study the basic mechanisms of neurobiology for many years. The lessons we have learned from chromaffin cell biology as a peripheral model for the brain and brain diseases pertain more than ever to the cutting edge research in neurobiology. Here, we highlight how studying this cell model can help unravel the basic mechanisms of cell renewal and regeneration both in the central nervous system (CNS) and neuroendocrine tissue and also can help in designing new strategies for regenerative therapies of the CNS. PMID- 22249375 TI - Potential of the HAQ score as clinical indicator suggesting comprehensive multidisciplinary assessments: the Swedish TIRA cohort 8 years after diagnosis of RA. AB - This study explores the potential of the health assessment questionnaire (HAQ) score as a clinical indicator that can be used to suggest comprehensive multidisciplinary assessments, by relating it to more general aspects of disability. In a cohort of 132 patients with early RA (mean age 55, 68% women), 28 joint count Disease Activity Scores (DAS-28), HAQ, and Short Form 36 (SF-36) scores were registered at annual follow-up visits 8 years after diagnosis. The patients were tentatively sub-grouped into a high-HAQ group (HAQ >= 1 at the 8 year follow-up) and a low-HAQ group. The high-HAQ group, comprising 36% of the cohort, had a higher mean HAQ score at inclusion and beyond at all visits compared to the low-HAQ group, and 24% of all individual patients in the high-HAQ group had a HAQ score >= 1 at inclusion. Although the DAS-28 improved in both groups, patients in the high-HAQ group also had significantly more persistent disability according to the SF-36: five scales at each follow-up visit and all eight scales at the majority of the visits. Individual RA patients with HAQ >= 1 probably have considerable persistent disabilities according to the SF-36. The HAQ score could be used as a clinical indicator suggesting comprehensive multidisciplinary assessments of the components of disability and corresponding interventions, in addition to the established use of HAQ at group levels and in parallel with the medication strategy based on DAS-28. PMID- 22249378 TI - Characterization and Safety of Uniform Particle Size NovaSil Clay as a Potential Aflatoxin Enterosorbent. AB - NovaSil (NS) clay, a common anti-caking agent in animal feeds, has been shown to adsorb aflatoxins and diminish their bioavailability in multiple animal models. The safety of long-term dietary exposure to NS has also been demonstrated in a 6 month sub-chronic study in rats and in a 3-month intervention in humans highly exposed to aflatoxins. Uniform particle size NovaSil (UPSN) is a refined material derived from parent NS; it contains lower levels of dioxins/furans, and has been selected for a more consistent uniform particle size. Nevertheless, the efficacy and potential safety/toxicity of UPSN for long term-use has not yet been determined. In this research, 4-week-old male and female Sprague Dawley rats were fed rations free of clay (control) and containing UPSN at low dose (0.25%) and high dose (2%) for 13 weeks. AFB(1) sorption characteristics remained the same for both clays. When compared to the control, total body weight gain was unaffected in either sex at the doses tested. No UPSN-dependent differences in relative organ weights or gross appearance were observed. Isolated differences between UPSN groups and the control were observed for some biochemical parameters and selected vitamins and minerals. None of these differences were dose dependent, and all parameters fell between ranges reported as normal for rats less than 6 month old. The Na/K ratio, Na and vitamin E concentrations were the only parameters that were increased in both males and females in the low dose and high dose UPSN groups. Serum Zn levels in males from the 2% UPSN treatment were lower compared to the control. Serum K levels were lower in the males of UPSN groups than in the control. However, neither Na/K ratio, K, nor Zn values were dose dependent and fell outside ranges reported as normal. These results suggest that dietary inclusion of UPSN at levels as high as 2% (w/w) does not result in overt toxicity. Nevertheless, further research on the effects of clays on Na, Zn, K and vitamin E is warranted. PMID- 22249379 TI - The ethics of organ transplantation: how comprehensive the ethical framework should be? PMID- 22249381 TI - Bilateral abducens paralysis revealing bipartite spheno-occipital synchondrosis fracture in a child: case based update. AB - BACKGROUND: After reviewing the literature about sella turcica and spheno occipital synchondrosis fracture, we present the case of a 6-year-old girl who suffered complex sphenoid bone fracture produced by an indirect mechanism. METHODS: The girl fell from her height after a blunt head injury due to a falling lamppost. RESULTS: Computer tomography (CT) scan showed occipital, sellar and clival fractures with pneumatocephalus. The probable fracture mechanism is contre coup injury linked to osseous and brain oscillations after head trauma. CONCLUSION: Two complications, abducens nerve palsy and cerebrospinal fluid fistula, are observed and discussed. PMID- 22249380 TI - Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells. AB - INTRODUCTION: CD133 (PROM1) is a potential marker for cancer stem cells (CSCs), including those found in brain tumors. Recently, medulloblastoma (MB)-derived CD133-positive cells were found to have CSC-like properties and were proposed to be important contributors to tumorigenicity, cancer progression, and chemoradioresistance. However, the biomolecular pathways and therapeutic targets specific to MB-derived CSCs remain unresolved. MATERIALS AND METHODS: In the present study, we isolated CD133(+) cells from MB cell lines and determined that they showed increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to CD133(-) cells. Bioinformatics analysis suggested that the STAT3 pathway might be important in MB and CD133(+) cells. To evaluate the effects of inhibiting the STAT3 pathway, MB-derived CD133(+/-) cells were treated with the potent STAT3 inhibitor, cucurbitacin I. Treatment with cucurbitacin I significantly suppressed the CSC-like properties and stemness gene signature of MB-derived CD133(+) cells. Furthermore, cucurbitacin I treatment increased the apoptotic sensitivity of MB derived CD133(+) cells to radiation and chemotherapeutic drugs. Notably, cucurbitacin I demonstrated synergistic effects with ionizing radiation to inhibit tumorigenicity in MB-CD133(+)-inoculated mice. RESULTS: These results indicate that the STAT3 pathway plays a key role in mediating CSC properties in MB-derived CD133(+) cells. Targeting STAT3 with cucurbitacin I may therefore represent a novel therapeutic approach for treating malignant brain tumors. PMID- 22249382 TI - Ventriculoperitoneal shunt catheter protrusion through the anus. PMID- 22249384 TI - Living with phenylketonuria from the point of view of children, adolescents, and young adults: a qualitative study. AB - OBJECTIVE: To explore the experiences of patients affected by phenylketonuria, a genetic metabolic disease currently screened during the neonatal period, in whom treatment was begun shortly after birth. Dietary treatment of the metabolic abnormality can prevent effects on the central nervous system through infancy, adolescence, and adulthood, but the associated challenges for personal and social life, such as everyday problems of adherence to a strict regimen, have been inadequately studied. METHOD: A qualitative study was performed using semistructured interviews involving 20 patients aged between 8 and 23 years and referred to a pediatric hospital for phenylketonuria. A thematic framework was formulated in advance which identified the main issues to be investigated, and a list of questions was devised. The interviews were audiotaped and were all transcribed and analyzed by 3 investigators with the support of NVivo software. RESULTS: Patients showed a fair knowledge of their condition but did not feel that they were truly ill. However, they adhered to their treatment regimen although they perceived no direct, immediate, adverse effects of their disease. A long-standing habit of following a demanding diet from infancy emerged from the interviews. A major problem for these patients is the difference perceived when comparing themselves with their peers, and the fear of stigmatization can prevent patients from participating in social occasions during which food is shared. One coping strategy patients may use is to disclose their condition to peers to overcome isolation. CONCLUSIONS: The impact of long-standing, demanding health behaviors on the social life of patients affected by a chronic metabolic disease must be recognized, taking into particular consideration both social functioning and adherence to dietary treatment. PMID- 22249383 TI - Quality of life of very young spina bifida patients after initial surgical treatment. AB - OBJECTIVE: The objectives of this study were to assess the quality of life (QOL) of operated patients with spina bifida (SB) in their initial years and to elucidate the factors affecting the QOL and the timing of proposed interventions. PATIENTS AND METHODS: We studied 18 patients operated on for SB, aging 3 years or more at the time of assessment. The quality of life score was calculated for all the patients by the parental-administered questionnaire method. The impact of all these factors on the social and school lives of these patients was studied. RESULTS: Eleven patients were having neurogenic bladder. Thirteen patients were having stool problems which ranged from mild to severe constipation and soiling. Five patients were having lower limb deformities interfering with normal ambulation. Ten patients were able to walk on their own without any help, four patients were using either crutches or help of the caregiver for ambulation while the remaining four patients were non-ambulatory. Twelve patients were attending school. The calculated QOL scores ranged from 2 to 15. The Barthel Index (BI) ranged from 15 to 100. The QOL questionnaire score and BI were showing significant positive correlation. CONCLUSIONS: The patients operated on for SB commonly have the neurological sequelae. The QOL score identifies the important problems in the initial years after surgery which can help in initiating and maintaining rehabilitative services in these patients. The treatment of urinary and fecal incontinence very early in life will allow these children to have a normal social and school life. PMID- 22249385 TI - Health care needs of children with Down syndrome and impact of health system performance on children and their families. AB - OBJECTIVE: The functional, financial, and social impact on families of children with Down syndrome (DS) in the United States and the role of the US health care system in ameliorating these impacts have not been well characterized. We sought to describe the demographic characteristics and functional difficulties of these children and to determine whether children with DS, compared with children with "intellectual disability" (ID) generally, and compared with other "children and youth with special health care needs" (CYSHCN), are more or less likely to receive health care that meets quality standards related to care coordination and to have their health care service needs met. METHODS: This study analyzed data from the 2005-2006 National Survey of Children with Special Health Care Needs (n = 40,723). Children and youth aged 0 to 17 years with special health care need (CYSHCN) who experience DS (n = 395) and/or IDs (n = 4252) were compared with each other and other CYSHCN on a range of functioning, family impact, and health care quality variables using bivariate and multivariate methods. Data were weighted to represent all CYSHCN in the United States. RESULTS: Compared with CYSHCN without DS, children with DS were significantly less likely to receive comprehensive care within a medical home (29.7% vs 47.3%; p < .001). Parents of children with DS were also significantly more likely to cut back or stop work due to their child's health needs (23.5% vs 55.1%; p < .001). Although overall system performance was poorer for children with DS compared with those with ID and no DS after adjustment for family income, prevalence on most aspects of quality of care and family impacts evaluated were similar for these 2 groups. CONCLUSIONS: In this study, the families of children with DS, and ID generally, are burdened disproportionately when compared with other CYSHCN, reflecting the combination of impairments intrinsic to DS and ID and impacts of suboptimal medical care coordination and social support. PMID- 22249386 TI - A first-principles study of ultrathin nanofilms of MgO-supported TiN. AB - As a first step towards a microscopic understanding of supported ultrathin nanofilms of TiN, we present state-of-the-art density-functional theory (DFT) calculations to investigate the interfacial properties of the TiN/MgO system as a function of film thickness. Optimized atomic geometries, energetics, and analysis of the electronic structure of the TiN/MgO systems are reported. In particular, we find that the work function of 1 ML of TiN(100) on MgO(100) exhibits a significant decrease, rationalized by the large surface dipole moment formation due to the changes in charge densities at the interface of this system. This decrease in the work function of TiN/MgO systems (as compared to pristine MgO(100) surface) could well benefit their application in metal-oxide semiconductor devices as an ideal gate-stack material. PMID- 22249387 TI - The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients. AB - It is well established that hepatocellular carcinoma (HCC) develops in a multistep process, from chronic hepatitis, cirrhosis to HCC. Adipose tissue is not simply an energy storage organ but also a secretory organ, producing a variety of bioactive molecules known as adipokines, including adiponectin and leptin. Hyaluronic acid (HA) is an extracellular matrix protein, often associated with a variety of human cancers. Our retrospective study determines serum levels of adiponectin, leptin, and HA in HCC of cirrhotic and noncirrhotic patients and compares these levels to patients with cirrhosis and normal subjects. Noncirrhotic HCC (n = 19), cirrhotic HCC (n = 50), cirrhosis (n = 36) patients and twenty one age-, sex-, and body mass index (BMI)-matched normal healthy controls were subjected in the present study. Serum adiponectin, leptin, and HA levels were determined using enzyme-linked immunosorbent assay technique. Levels of serum adiponectin were significantly higher in the cirrhosis and cirrhotic HCC groups than in the normal subjects, whereas serum HA levels were found to significantly increase in all three patients groups. The elevation of serum leptin in our HCC patients, regardless of being cirrhotic or noncirrhotic, but not in the patients with cirrhosis, may shed some light on the significance of serum leptin level in HCC. Further studies are recommended to evaluate the prognostic value of serum leptin level in HCC. PMID- 22249388 TI - Serotonin syndrome following overdose of a non-prescription slimming product containing sibutramine: a case report. AB - INTRODUCTION: Non-prescription slimming products are popular and can be easily purchased from the Internet. However, adulteration of these products with undeclared substances including prescription drugs is not uncommon. We report a case of serotonin syndrome after an overdose of a non-prescription product containing sibutramine. CASE REPORT: A 21-year-old woman presented with somnolence, sinus tachycardia, generalised increase in tone, hyper-reflexia and clonus more prominent in the lower limbs after an intentional overdose of a non prescription slimming product obtained from the Internet. The product was later found to contain sibutramine and other substances such as animal thyroid tissues, caffeine and phenolphthalein. Quantitative analysis of patient's serum on presentation revealed a sibutramine concentration of 112 ng/mL, which far exceeded the reported peak serum concentration after a single oral dose of 15 mg (the maximum daily recommended dose). No other culpable agent was identified. The overall clinical presentation was compatible with serotonin syndrome associated with sibutramine overdose. The patient made a full recovery after supportive management. DISCUSSION AND CONCLUSION: This case highlighted the health threat posed by non-prescription slimming products sold over the Internet. Sibutramine overdose can result in serotonin syndrome, as in overdose of other serotonergic agents. Early recognition and timely supportive treatment are essential to ensure a good clinical outcome. PMID- 22249389 TI - Adaptive changes in fatty acid profile of erythrocyte membrane in relation to plasma and red cell metabolic changes in chronic alcoholic men. AB - Chronic alcohol consumption is a major reason for several human diseases, and alcoholism has been associated with a variety of societal problems. Changes in fatty acid metabolism in alcoholics and its effects leading to membrane damage are largely unknown. Therefore, we aimed to investigate the fatty acid composition of erythrocyte membrane phospholipids in relation with plasma lipid profile and other plasma metabolites in chronic alcoholics in comparison with controls. We systematically measured the levels of glucose, lactate and pyruvate in the blood and free amino acids, free fatty acids, mucoproteins and glycolipids, total cholesterol (TC), high-density lipoprotein cholesterol (HDL C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein (VLDL) cholesterol and triglycerides (TG) in plasma of chronic alcoholics and controls. Furthermore, we measured fatty acid composition by gas chromatographic analysis. The fatty acid composition clearly revealed certain changes in chronic alcoholic erythrocyte membrane, chiefly increments in C16:0 and a decrease in C22:4 and C22:6 fatty acids besides the presence of unidentified fatty acids, probably C-24 or C-26 fatty acids. In addition, a significant increase in blood lactate, decrease in blood pyruvate and increased levels of free amino acids and free fatty acids, mucoproteins, VLDL cholesterol, TG and HDL-C in chronic alcoholics were observed with no significant change in plasma TC, LDL-C and glycolipids when compared with controls. Alcohol-induced alterations in plasma and erythrocyte membranes of chronic alcoholics in the present study might be an adaptive response to counteract the deleterious effects of alcohol. The implications of our findings warrant further investigation and needs further in depth study to explore the mechanisms of alcohol-induced membrane changes. PMID- 22249390 TI - Pesticide poisonings in South Korea: findings from the National Hospital Discharge Survey 2004-2006. AB - OBJECTIVES: Pesticide poisoning stands as a major public health issue worldwide. The objective of this study was to examine the epidemiologic characteristics of pesticide-related hospitalizations in South Korea. METHODS: Data from the Korea National Hospital Discharge Survey were analyzed to describe the epidemiologic characteristics of pesticide poisoning among hospitalized patients from 2004 through 2006. Pesticide-related hospitalizations were identified using the International Classification of Diseases, Tenth Revision codes. National estimates of pesticide-related hospitalizations were calculated using sampling weights for number of hospitalizations. RESULTS: A total of 25,982 pesticide related hospitalizations were estimated during the years 2004-2006, yielding an average annual pesticide-related hospitalization rate of 17.8 per 100,000 population in South Korea. Age-specific rates for pesticide-related hospitalization increased with age, with the highest rate noted among those aged 70 or above. The majority of pesticide-related hospitalization was cases of intentional poisoning in rural areas. Seasonal variation in the rate was observed, with summer being the highest among both men and women. CONCLUSIONS: Pesticide-related hospitalization is prevalent and demonstrates demographic and seasonal and regional variations. More effective strategies to reduce pesticide related hospitalizations are required in South Korea. PMID- 22249391 TI - 8-Oxo-7, 8-dihydro-2'-deoxyguanosine as a biomarker of DNA damage by mobile phone radiation. AB - We examined the effect of exposure to mobile phone 1800 MHz radio frequency radiation (RFR) upon the urinary excretion of 8-oxo-7, 8-dihydro-2' deoxyguanosine (8-oxodG), one major form of oxidative DNA damage, in adult male Sprague-Dawley rats. Twenty-four rats were used in three independent experiments (RFR exposed and control, 12 rats, each). The animals were exposed to RFR for 2 h from Global System for Mobile Communications (GSM) signal generator with whole body-specific absorption rate of 1.0 W/kg. Urine samples were collected from the rat while housed in a metabolic cage during the exposure period over a 4-h period at 0.5, 1.0, 2.0 and 4.0 h from the beginning of exposure. In the control group, the signal generator was left in the turn-off position. The creatinine standardized concentrations of 8-oxodG were measured. With the exception of the urine collected in the last half an hour of exposure, significant elevations were noticed in the levels of 8-oxodG in urine samples from rats exposed to RFR when compared to control animals. Significant differences were seen overall across time points of urine collection with a maximum at 1 h after exposure, suggesting repair of the DNA lesions leading to 8-oxodG formation. PMID- 22249392 TI - Hormesis and radiation safety norms. AB - Today's radiation safety norms are based on the linear no-threshold theory (LNT): extrapolation of the dose-response relationships down to the minimal doses, where such relationships are unproven and can be inverse due to hormesis. The most promising way to obtaining reliable data on the dose-effect relationships for low radiation doses would be large-scale animal experiments. Outstanding published data on carcinogenic effects of the doses e.g. below 100 mSv should be verified by experiments. Arguments against applicability of the LNT to the doses comparable to those from the natural radiation background are discussed. Furthermore it is stressed that medical consequences of the Chernobyl accident have been overestimated; and this theme has been exploited to strangle development of atomic energy and to elevate prices for fossil fuels. Worldwide introduction of nuclear energy will be possible only after a concentration of authority within a powerful international executive. It would enable the construction of nuclear reactors in optimally suitable places, considering all sociopolitical, geographical, and geological conditions, which would contribute to the prevention of accidents like in Japan in 2011. A concluding point is that radiation safety norms are exceedingly restrictive and should be revised to become more realistic and workable. Elevation of the limits must be accompanied by measures guaranteeing their strict observance. It is also concluded that there are no evidence-based contraindications to fivefold elevation of the total equivalent effective doses to individual members of the public (up to 5 mSv/year), and doubling of the limits for professional exposures. PMID- 22249393 TI - Antioxidant effects after coffee enema or oral coffee consumption in healthy Thai male volunteers. AB - We designed an open-label, randomized two-phase crossover study to investigate the antioxidant effects after single and multiple doses of a coffee enema versus coffee consumed orally. Eleven healthy subjects were randomly assigned to either receive a coffee enema (3 times weekly for 6 visits) or consume ready-to-drink coffee (2 times daily for 11 days). After a washout period, subjects were switched to receive the alternate coffee procedure. Blood samples were collected at specific time points for the determination of serum levels of glutathione (GSH), malondialdehyde (MDA) and trolox equivalent antioxidant capacity (TEAC). The findings showed that either single or multiple administrations of the coffee enema or orally consumed coffee doses seemed not to produce any beneficial effects to enhance serum GSH levels or to decrease serum MDA levels over the study period of 12 days. In contrast, mean serum TEAC levels at day 12 after the coffee enema and at days 6 and 12 after oral coffee consumption were significantly reduced from their corresponding baseline values. Thus, no beneficial effects with respect to an enhancement of serum GSH and TEAC levels or a decrease in serum MDA concentrations were demonstrated after coffee enema or orally consumed ready-to-drink coffee. PMID- 22249394 TI - Levosimendan infusion improves cardiac output but not blood pressure in a rodent model of severe metoprolol toxicity. AB - Levosimendan (Levo) is an inodilator improving cardiac output (CO) and reducing afterload in heart failure. Previously, we reported that Levo improved CO but not blood pressure (BP) in a rodent model of verapamil poisoning. We theorised that Levo-induced vasodilation should not influence BP to a similar degree in metoprolol poisoning. AIM: To assess the effect of Levo on haemodynamics in a rodent model of metoprolol poisoning. METHOD: Anaesthetized male Wistar rats were infused metoprolol continuously. When the BP dropped to 50% of baseline (time 0) rats received 1 of the 4 treatments: (a) control (0.9% saline bolus + infusion); (b) Levo-l (Levo 36 MUm/kg loading dose followed by 0.6 MUm/kg/min); (c) Levo-I (Levo infusion only at 0.6 MUm/kg/min); and (d) Epi (epinephrine 0.5 MUm/kg/min). All groups received comparable fluid volumes. Haemodynamics were recorded every 10 min for 70 min. CO, mean arterial pressure (MAP) and heart rate (HR) of each group were compared to the control. RESULTS: All groups had comparable baseline and time 0 HR, MAP and CO. Levo-L and Levo-I rats showed significantly greater CO at t = 10 min (p > 0.02 and p > 0.04, respectively). CO was higher at all other time points for both Levo groups. This was not statistically significant. Levo did not improve MAP compared to control. Adrenaline increased MAP but not CO compared to control and Levo groups. CONCLUSION: Levo did not improve MAP but moderately improved CO compared to control in this model of metoprolol poisoning. The response was similar to that reported previously in verapamil-poisoned rats. The improvement in MAP seen with epinephrine was most likely vasoconstriction mediated. PMID- 22249395 TI - Studies on the protective effect of flaxseed oil on cisplatin-induced hepatotoxicity. AB - Cisplatin (CP) is known as one of the most potent chemotherapeutic antitumor drugs. The tissue-specific toxicity of CP in the kidneys is well documented. However, at higher doses less common toxic effects such as hepatotoxicity may arise. Since CP remains one of the most effective antineoplastic drug used in chemotherapy, strategies to protect tissues against CP toxicity are of clinical interest. Recently, omega-3 polyunsaturated fatty acids (PUFAs) from certain plants/seeds notably flaxseed have shown numerous health benefits. In view of this, the present study investigates the protective effect of flaxseed oil (FXO) on CP-induced damage in liver. Rats were pre-fed normal diet and the diet rich in FXO for 10 days and then a single dose of CP (6 mg/kg body weight) was administered intraperitoneally while still on diet. Serum/urine parameters, enzymes of carbohydrate metabolism and oxidative stress were analyzed. CP caused perturbation of the antioxidant defense as reflected by the decrease in the activities of catalase, superoxide dismutase and glutathione peroxidase. Further the activities of various enzymes involved in glycolysis, tricarboxylic acid cycle, gluconeogenesis and hexose monophosphate shunt pathways were determined and were found to be differentially altered by CP treatment. However, these alterations were ameliorated in CP-treated rats fed on FXO. Present results show that dietary supplementation of FXO in CP-treated rats ameliorated CP-induced hepatotoxic and other deleterious effects due to its intrinsic biochemical/antioxidant properties. PMID- 22249396 TI - Soy isoflavones administered pre- and postnatally may affect the ERalpha and ERbeta expression and elements' content in bones of mature male rats. AB - The aim of this study was to assess the influence of soy isoflavones, administered pre- and later postnatally, on the estrogen receptor alpha (ERalpha) and beta (ERbeta) expression in bones and to examine the mineral metabolism of the skeletal system in male rats. In bones, ERs were examined with an immunohistochemical method; in blood, estradiol with chemiluminescence immunoassay and in blood and bones, calcium and magnesium with atomic absorption spectrometry and fluorides with a potentiometric method were examined. Decreased immunoexpression of ERalpha and the increased intensity of immunofluorescence of ERbeta in osteocytes in the femur of experimental rats were observed. In the serum of treated rats, a significantly higher concentration of estradiol and lower calcium were observed. The content of magnesium and fluoride were significantly higher in the bones of the examined animals. The data presented show that pre- and postnatal supplementation of male rats with soy isoflavones may considerably increase the concentration of estrogens in serum, with a concurrent effect on the mineral composition of bones. PMID- 22249397 TI - Evaluation of alpha-D-ribofuranose (D-ribose) toxicity after intravenous administration to rabbits. AB - Rapid intravenous administration of D-ribose may result in a significant reduction in cellular damage in patients with sudden ischemic insults. The development of an effective and clinically safe therapeutic regimen using the intravenous route in critically ill patients especially with cardiac diseases requires a comprehensive assessment of potential toxic effects of the drug in laboratory animals and in human beings. The potential clinical, behavioral, hematological, biochemical, gross pathological and histological toxic effects associated with the intravenous administration of D-ribose in rabbits for 28 days were evaluated in this study. Except for an increase in neutrophil percentage in male rabbits in the D-ribose-treated groups, there were no statistically significant toxic effects induced by daily intravenous administration of the drug in male and female rabbits. Results of this study suggest that D-ribose administered intravenously for 28 days in the rabbit exhibited no toxicity at 420 mg/kg. PMID- 22249398 TI - Importance of attenuating quadriceps activation deficits after total knee arthroplasty. AB - Total knee arthroplasty (TKA) is associated with persistent quadriceps dysfunction. Because quadriceps dysfunction impairs functional performance, minimizing quadriceps dysfunction by attenuating central activation deficits early after surgery may improve function later in life. Rehabilitation strategies incorporating neuromuscular electrical stimulation and early, aggressive quadriceps strengthening may prove beneficial. Furthermore, surgical approaches, such as minimally invasive TKA, may minimize postoperative quadriceps dysfunction. PMID- 22249399 TI - Posttraumatic stress disorder and depression among new mothers at 8 months later of the 2008 Sichuan earthquake in China. AB - On May 12, 2008, a magnitude 8.0 earthquake struck China's southwestern Sichuan province. Recent studies have identified mental health problems among the survivors, but little is known about the impact of the Sichuan earthquake on the mental health of new mothers in the area. The main objective was to assess the impact of the Sichuan earthquake on the posttraumatic stress disorders (PTSD) and depression of new mothers. A total of 317 new mothers were interviewed in the hospital from January 2009 to March 2009. Symptoms of PTSD were measured using the impact of event scale-revised, and symptoms of postpartum depression were measured using the Center for Epidemiologic Studies Depression scale. The prevalence rates of PTSD and postpartum depression were 19.9% and 29.0%, respectively. Women with high earthquake exposure had higher risks of PTSD (odds ratio (OR), 5.91; 95% confidence interval (CI), 1.75-19.97; P < 0.001) and postpartum depression (OR, 7.28; 95% CI, 2.51-21.08; P < 0.001) than women without earthquake experience. In addition, women with low monthly family income and farm workers had a higher risk of having PTSD; women who were unemployed or with lower monthly family income and poor sleep had a higher risk of having depression. Earthquake experience increased the risks of having PTSD and depression among new mothers at 8 months later of the earthquake. PMID- 22249401 TI - Inter-critical and critical excessive daily sleepiness in episodic migraine patients. AB - The objective of this study was to determine the relationship between sleepiness and migraine in the intercritical period and to evaluate the time course of critical drowsiness during the attacks. One hundred patients fulfilling IHCD 2nd (2004) criteria for migraine without aura were compared to 100 healthy subjects. Habitual excessive daily sleepiness, evaluated by means of Epworth Sleepiness Scale, was not more frequent in patients with episodic migraine than in controls (12% migraineurs vs. 8% controls, NS). The analysis of critical sleepiness by means of Stanford Sleepiness Scale (SSS) revealed a beginning of sleepiness increase before the attack onset, starting 12 h before, a peak of SSS values at the migraine attack onset and then a gradual decrease to reach baseline values only 12-24 h later. Moreover, patients responding to symptomatic drugs showed a greater and faster decrease of critical sleepiness in comparison with non responder migraineurs; this finding allows excluding the role of medications in promoting critical somnolence and together with critical drowsiness time-course supports the hypothesis that vigilance impairment could be related to migraine pathogenesis. PMID- 22249402 TI - Withdrawal syndrome after donepezil cessation in a patient with dementia. AB - We describe a 62-year-old female diagnosed with Alzheimer's disease, who had been treated with donepezil for approximately 1 year. When she developed a low-grade fever and digestive complaints, her family physician interpreted these symptoms as side effects of the drug and ordered donepezil to be discontinued. Not only was there no improvement of the somatic symptoms after discontinuation of donepezil, but there was also a worsening of the dementia symptoms, culminating in delirium. When donepezil was re-prescribed, the delirium resolved and the patient's mental state stabilized. The authors urge great caution in discontinuing treatment with acetylcholinesterase inhibitors such as donepezil. PMID- 22249403 TI - Elucidation of matrix effects and performance of solid-phase extraction for LC MS/MS analysis of beta-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB) neurotoxins in cyanobacteria. AB - A liquid chromatography-mass spectrometry (LC-MS/MS) method using hydrophilic interaction liquid chromatography (HILIC) was developed for the analysis of neurotoxins beta-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB), using multiple reaction monitoring (MRM) scan mode. Oasis-MCX and Strata-X C polymeric cation-exchange cartridges were used to clean extracts of cyanobacterial cultures, including two strains of Microcystis aeruginosa and one strain of Nostoc sp. The performance of the solid-phase extraction (SPE) cartridges for BMAA and DAB were evaluated using mixed standards and spiked cyanobacterial extracts, which demonstrated recoveries of BMAA and DAB ranging from 66% to 91%. Matrix effects in LC-MS/MS were evaluated, and while there was no effect on BMAA quantitation, suppression of DAB was found. Full scan (Q1) and enhanced product ion (EPI) monitoring showed that the DAB suppression may be due to closely eluting compounds, including lysine, histidine, arginine and three other compounds with [M + H](+) m/z of 88, 164 and 191. The procedures developed allow the sensitive and effective analysis of trace BMAA and DAB levels in cyanobacteria. While DAB was confirmed to be present, no BMAA was found in the cyanobacterial samples tested in the present study. PMID- 22249404 TI - [Pyoderma gangrenosum following AICD implantation: differential diagnosis to necrotizing fasciitis]. AB - Pyoderma gangrenosum is rarely seen in the surgical disciplines. In the described case the patient was initially diagnosed with necrotizing fasciitis and admitted to the intensive care unit suffering from septic shock. The automated implantable cardioverter defibrillator (AICD), the suspected focus for infection, had already been removed. Following weeks of broad spectrum antibiotics and wound debridement without clinical improvement the alternative diagnosis of pyoderma gangrenosum was reached. Consequently the patient was treated with immunosuppressive therapy and his condition improved rapidly such that he was ultimately discharged to rehabilitation. PMID- 22249406 TI - Valvular disease: the MitraClip in high-risk patients. PMID- 22249407 TI - Interventional cardiology: Radial access improves PCI outcomes. PMID- 22249405 TI - HIV reservoirs and strategies for eradication. AB - Combination antiretroviral therapy (cART) has led to a reduction in morbidity and mortality in HIV-infected patients but therapy is lifelong and there is no cure for HIV. The major barriers to cure include HIV latency, which has been identified in different T-cell subsets, as well as persistence of HIV in anatomical reservoirs. We review recent developments in our understanding of the major reservoirs of HIV in patients on cART as well as how latency is established and maintained in T cells. Finally, we review the scientific rationale of and clinical experience with pharmacotherapeutic strategies aimed at eliminating latently infected cells. PMID- 22249408 TI - Preparation of novel meta- and para-substituted N-benzyl protected quinuclidine esters and their resolution with butyrylcholinesterase. AB - Since the optically active quinuclidin-3-ol is an important intermediate in the preparation of physiologically or pharmacologically active compounds, a new biocatalytic method for the production of chiral quinuclidin-3-ols was examined. Butyrylcholinesterase (BChE; EC 3.1.1.8) was chosen as a biocatalyst in a preparative kinetic resolution of enantiomers. A series of racemic, (R)- and (S) esters of quinuclidin-3-ol and acetic, benzoic, phthalic and isonicotinic acids were synthesized, as well as their racemic quaternary N-benzyl, meta- and para-N bromo and N-methylbenzyl derivatives. After the resolution, all N-benzyl protected groups were successfully removed by catalytic transfer hydrogenation with ammonium formate (10% Pd-C). Hydrolyses studies with BChE confirmed that (R) enantiomers of the prepared esters are much better substrates for the enzyme than (S)-enantiomers. Introduction of bromine atom or methyl group in the meta or para position of the benzyl moiety resulted in a considerable improvement of the stereoselectivity compared to the non-substituted compounds. Optically pure quinuclidin-3-ols were prepared in high yields and enantiopurity by the usage of various N-benzyl protected groups and BChE as a biocatalyst. PMID- 22249409 TI - Quantum dot-conjugated anti-GRP78 scFv inhibits cancer growth in mice. AB - Semiconductor quantum dots (Qdots) have recently been shown to offer significant advantages over conventional fluorescent probes to image and study biological processes. The stability and low toxicity of QDs are well suited for biological applications. Despite this, the potential of Qdots remains limited owing to the inefficiency of existing delivery methods. By conjugating Qdots with small antibody fragments targeting membrane-bound proteins, such as GRP78, we demonstrate here that the Quantum dot- Anti-GRP78 scFv (Qdot-GRP78) retains its immunospecificity and its distribution can be monitored by visualization of multi color fluorescence imaging both in vitro and in vivo. Moreover we demonstrate here for the first time that Qdot-GRP78 scFv bioconjugates can be efficiently internalized by cancer cells, thus upregulate phophosphate-AKT-ser473 and possess biological anti-tumour activity as shown by inhibition of breast cancer growth in a xenograft model. This suggests that nanocarrier-conjugated scFvs can be used as a therapeutic antibody for cancer treatment. PMID- 22249410 TI - Comparative computational studies of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5 carbonitrile derivatives as potential antinociceptive agents. AB - In this study, the antinociceptive properties of 3,4-dihydro-2,6-diaryl-4-oxo pyrimidine-5-carbonitrile derivatives 5a-i at doses of 25 and 50 mg/kg were evaluated in mice, using the abdominal constriction test. Molecular modeling studies were also performed using density functional theory calculations. These data provided information about the electrostatic and ionization potentials and were used to compare the antinociceptive activity of the title compounds. The most active compounds were 3,4-dihydro-2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4 oxo-pyrimidine-5-carbonitrile (5b) and 3,4-dihydro-2,6-diphenyl-4-oxo-pyrimidine 5-carbonitrile (5i), which inhibited the number of abdominal constrictions, at 50 mg/kg dose, in 88.6% and 88% of the sample, respectively. A preliminary SAR study demonstrated that halogen replacement in the phenyl rings of the compounds under study reduces the antinociceptive activity. DFT calculations showed that there is a high correlation between the ionization potentials and the analgesic properties of the compounds. It was found that compounds with a positive ionization potential (compounds 5b and 5i) were found to be the best analgesic drugs in this series. PMID- 22249411 TI - Left atrium measurement in patients suspected of having heart failure with preserved ejection fraction. AB - BACKGROUND: The pathophysiological model of heart failure (HF) with preserved ejection fraction (HFPEF) focuses on the presence of diastolic dysfunction, which causes left atrial (LA) structural and functional changes. The LA size, an indicator of the chronic elevation of the left ventricular (LV) filling pressure, can be used as a marker of the presence of HFPEF, and it is easily obtained. OBJECTIVE: To estimate the accuracy of measuring the LA size by using indexed LA volume and diameter (ILAV and ILAD, respectively) for diagnosing HFPEF in ambulatory patients. METHODS: This study assessed 142 patients (mean age, 67.3 +/ 11.4 years; 75% of the female sex) suspected of having HF, divided into two groups: with HFPEF (n = 35) and without HFPEF (n = 107). RESULTS: The diastolic function, assessed by use of Doppler echocardiography, showed a significant difference between the groups regarding the parameters assessing ventricular relaxation (E': 6.9 +/- 2.0 cm/s vs. 9.3 +/- 2.5 cm/s; p < 0.0001) and LV filling pressure (E/E' ratio: 15.2 +/- 6.4 vs. 7.6 +/- 2.2; p < 0.0001). The ILAV cutoff point of 35 mL/m2 best correlated with the diagnosis of HFPEF, showing sensitivity, specificity, and accuracy of 83%. The ILAD cutoff point of 2.4 cm/m2 showed sensitivity of 71%, specificity of 66%, and accuracy of 67%. CONCLUSION: For diagnosing HFPEF in ambulatory patients, the ILAV proved to be a more accurate parameter than ILAD. On echocardiographic assessment, ILAV, rather than ILAD, should be routinely measured. PMID- 22249412 TI - Self measurement of blood pressure for control of blood pressure levels and adherence to treatment. AB - BACKGROUND: The measurement of blood pressure (BP) by the patient himself without strict protocols, adequate training, and validated equipment at their own household is defined as self measured blood pressure (SMBP). OBJECTIVE: To evaluate the interference of the SMBP in treatment adherence and blood pressure control. METHODS: The study included 57 patients, 38 in the study group (SG) and 19 in the control group (CG). These patients were followed for 12 months and assessed at randomization (V1) as well as in the sixth (V2) and the twelfth month (V3). Compare the mean blood pressure by casual measurement, by SMBP and by ambulatory monitoring of blood pressure (AMBP), laboratory tests and the answers to the questionnaire on lifestyle. The instruments used were: OMRON HEM 714, for SMBP; OMRON 705 CP, for the casual measurement, and Monitor SPACELABS 9002 for the AMBP. RESULTS: The average age was 62.05 +/- 10.78 in the SG and 55.42 +/- 11.87 in the CG (p = 0.03). The values of systolic blood pressure (SBP) by casual measurement in the SG and CG were: 140.01 +/- 16.73 mmHg and 141.79 +/- 23.21 mmHg in V1 (p = 0.72), 135.49 +/- 12.73 mmHg and 145.69 +/- 19.31 mmHg in V2 (p = 0.02), 131.64 +/- 19.28 mmHg and 134.88 +/- 23.21 mmHg at V3 (p = 0.59). The values of diastolic blood pressure (DBP) were: 84.13 +/- 10.71 mmHg and 86.29 +/- 10.35 mmHg in V1 (p = 0.47), 81.69 +/- 10.88 mmHg and 89.61 V2 +/- 11.58 mmHg (p = 0.02), 80.31 +/- 11.83 mmHg and 86 +/- 13.38 mmHg in V3 (p = 0.12). CONCLUSION: Patients in the SG had adherence to non-pharmacological treatment similar to the CG, but they had greater adherence to drug treatment and used fewer antihypertensive drugs. There was no difference between groups when comparing the metabolic profile and renal function. PMID- 22249413 TI - Gastroesophageal junction of Anatolian shepherd dog; a study by topographic anatomy, scanning electron and light microscopy. AB - The aim of this study was to cast a spotlight on the topography and to point out the clinical importance of the gastroesophageal junction (GEJ) in Anatolian Shepherd dogs. Nine Anatolian Shepherd dogs were used to study the morphology of the GEJ. The esophagus was appeared has a portion within the thoracic cavity while no portion of the esophagus presented within the abdominal cavity that documented the absence of the intra-abdominal portion in all studied dogs. The topographic anatomy, scanning electron and light microscopic examinations revealed that the gastroesophageal junction was located at the level of the phrenico-esophageal ligament (PEL) inside the esophageal hiatus. Our results were distinguished the morphology of the esophageal and gastric cardiac mucosa at the level of the gastroesophageal junction by the scanning electron micrographs. The light microscopical examination was explained the PEL attached to the esophageal side in one dog and to the gastric cardiac side in three dogs. PMID- 22249414 TI - Preparation and antibacterial activities of polyaniline/Cu0.05Zn0.95O nanocomposites. AB - Polyaniline/Cu(0.05)Zn(0.95)O (PANI/CZO) nanocomposites were prepared by in situ inverse microemulsion method. Based on the characterization of the crystal structure, chemical composition, and morphology of the samples, it was confirmed that CZO nanoparticles were incorporated into the polyaniline matrix. Studies of the antimicrobial activities of the samples against Staphylococcus aureus, Escherichia coli and Candida albicans were carried out using powder inhibition zone, minimum inhibitory concentration and minimal bactericidal concentrations methods. The results showed clearly that, as an antibacterial agent, PANI/CZO nanocomposites exhibited excellent antibacterial activity against the growth of microorganisms. Furthermore, the antibacterial mechanism of the samples was also deduced in this paper. PMID- 22249416 TI - On the spectral formulation of Granger causality. AB - Spectral measures of causality are used to explore the role of different rhythms in the causal connectivity between brain regions. We study several spectral measures related to Granger causality, comprising the bivariate and conditional Geweke measures, the directed transfer function, and the partial directed coherence. We derive the formulation of dependence and causality in the spectral domain from the more general formulation in the information-theory framework. We argue that the transfer entropy, the most general measure derived from the concept of Granger causality, lacks a spectral representation in terms of only the processes associated with the recorded signals. For all the spectral measures we show how they are related to mutual information rates when explicitly considering the parametric autoregressive representation of the processes. In this way we express the conditional Geweke spectral measure in terms of a multiple coherence involving innovation variables inherent to the autoregressive representation. We also link partial directed coherence with Sims' criterion of causality. Given our results, we discuss the causal interpretation of the spectral measures related to Granger causality and stress the necessity to explicitly consider their specific formulation based on modeling the signals as linear Gaussian stationary autoregressive processes. PMID- 22249415 TI - BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation. AB - Epithelial ovarian cancer (EOC) cells have the ability to form multi-cellular aggregates in malignant ascites which dramatically alters cell signalling, survival, and metastatic potential. Herein, we demonstrate that patient ascites derived EOC cells down-regulate endogenous bone morphogenetic protein (BMP) signalling by decreasing BMP ligand expression when grown in suspension culture to form spheroids. Enforced BMP signalling in these cells via constitutively active BMP type I ALK3(QD) receptor expression causes the formation of smaller, more loosely-aggregated spheroids. Additionally, ALK3(QD)-expressing spheroids have an increased rate of adhesion and dispersion upon reattachment to substratum. Inhibition of endogenous BMP signalling using recombinant Noggin or small molecule inhibitor LDN-193189, on the other hand, opposed these phenotypic changes. To identify potential targets that impact the phenotype of EOC spheroids due to activated BMP signalling, we performed genome-wide expression analyses using Affymetrix arrays. Using the online Connectivity Map resource, the BMP signalling gene expression signature revealed that the AKT pathway is induced by activated BMP signalling in EOC cells; this finding was further validated by phospho-AKT immuno-blotting. In fact, treatment of EOC spheroids with an AKT inhibitor, Akti-1/2, reduced BMP-stimulated cell dispersion during reattachment as compared to controls. Thus, we have identified AKT as being one important downstream component of activated BMP signalling on EOC spheroid pathobiology, which may have important implications on the metastatic potential of this malignancy. PMID- 22249417 TI - Comprehensive two-dimensional gas chromatography in metabolomics. AB - One of the major objectives in metabolomics is the identification of subtle changes in metabolite profiles as affected by genetic or environmental factors. Comprehensive two-dimensional gas chromatography (GC * GC) hyphenated to a fast acquisition mass spectrometer is a well-established analytical technique to study the composition of complex samples due to its enhanced separation capacity, sensitivity, peak resolution, and reproducibility. This review reports applications of GC * GC to metabolomics studies of sample of different types (biofluid, cells, tissue, bacteria, yeast, plants), and discusses its advantages and limitations. PMID- 22249418 TI - Inhibition of bacterial degradation of EtG by collection as dried urine spots (DUS). AB - Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are direct alcohol consumption markers widely used nowadays for clinical and forensic applications. They are detectable in blood and urine even after consumption of trace amounts of ethanol and for a longer time frame, being detectable even when no more ethanol is present. The instability of EtG against bacterial degradation in contaminated urine samples and/or the possible postcollection synthesis of this metabolite in samples containing, e.g., Escherichia coli and ethanol, may cause false identification of alcohol uptake. Therefore, it is of paramount importance to constrict these error sources by inhibition of any bacterial growth causing hydrolization or synthesis of EtG. This study evaluates a new method of collecting urine samples on filter paper, dried urine spots (DUS), for simultaneous detection of EtG, EtS and creatinine, having the great advantage of inhibiting bacterial activity. In addition, a method validation for the determination of EtG and EtS in DUS was performed according to the FDA guidelines. Sterile-filtered urine was spiked with EtG and EtS, inoculated with E. coli and incubated. Liquid and dried urine samples were collected after various time intervals up to 96 h. Liquid samples were frozen immediately after collection, whereas aliquots for DUS were pipetted onto filter paper, allowed to dry and stored at RT until analysis 1 week after. The specimens were analyzed by LC-ESI-MS/MS. As expected, degradation of EtG, but not of EtS, was observed in contaminated liquid urine samples. However, the specimens collected on filter paper and stored at RT showed no degradation during storage. Therefore, collecting urine samples on filter paper for EtG and EtS analysis turns out to be a reliable method to avoid bacterial degradation of EtG and EtS, and consequently, stabilization of these ethanol metabolites is achieved. In addition, simultaneous measurement of creatinine content as an indicator of urine dilution helps to interpret the results. Method validation for EtG and EtS in DUS was satisfactory, showing the linearity of the calibration curves in the studied concentration range, good precision, accuracy and selectivity. PMID- 22249419 TI - Synthesis, structure, and biological activity of novel (oxdi/tri)azoles derivatives containing 1,2,3-thiadiazole or methyl moiety. AB - To develop novel inhibitors of ketol-acid reductoisomerase, a series of (oxdi/tri)azoles derivatives was synthesized and characterized by (1)H NMR, MS, elemental analyses, and crystallography. According to the biological activities of these compounds obtained both in vivo and in vitro, compound 4-cyclopropyl-3 ((4-fluorobenzyl)thio)-5-methyl-4H-1,2,4-triazole showed excellent KARI inhibitory activity (100% at 100 MUg mL (-1) in vitro). In addition, most of the title compounds exhibited good herbicidal activity against Brassica campestris in vivo. PMID- 22249420 TI - [New aspects of congenital melanocytic nevi]. AB - In recent years, prospective studies with increasing patient numbers have been published on the subject of congenital melanocytic nevi (CMN) and neurocutaneous melanocytosis (NCM). Moreover, medical experts and patient support groups have intensified their collaboration. This article summarizes current aspects of pathogenesis, clinical features, and therapy of CMN and NCM. PMID- 22249423 TI - Use of inorganic wastes as immobilizing agents for soluble P in green waste-based composts. AB - PURPOSE: The study examines the effectiveness of red mud, blast furnace (BF) slag, and alum-derived water treatment sludge as immobilizing agents for excessive soluble P that had accumulated in three green waste-based composts. METHODS: The three wastes were applied at 0%, 5%, 10%, and 20% w/w to three different composts, all containing extremely high concentrations of extractable P, and were incubated for 60 days. Water-soluble P was measured regularly throughout the incubation period, and at the end, P extractable with resin, 0.05 M NaHCO(3), and 0.005 M H(2)SO(4) were also measured. RESULTS: In the water extracts, inorganic P made up more than 85% of the total P present. All three materials had the ability to adsorb P and thus lowered water-soluble P concentrations. Water treatment sludge was clearly the most effective material, and this was attributed to its amorphous nature (thus, large Brunauer-Emmett Teller surface area) and its acid pH (6.8) compared with the alkaline pH (10-11) of the other two materials. Water treatment sludge was also the most effective at lowering resin- and NaHCO(3)-extractable P. When H(2)SO(4) was used as the extractant, BF slag tended to be the most effective material at lowering extractable P, followed by water treatment sludge, and red mud. That is, the P immobilized by water treatment sludge was extractable with acid but not with water, resin, or NaHCO(3). CONCLUSIONS: Water treatment sludge has the potential to be used as an effective immobilizing agent for soluble P in composts, and it should be trialed under field conditions. PMID- 22249422 TI - Characterization of carbapenem-nonsusceptible Klebsiella pneumoniae bloodstream isolates at a Taiwanese hospital: clinical impacts of lowered breakpoints for carbapenems. AB - This study was conducted in order to characterize carbapenem-nonsusceptible Klebsiella pneumoniae isolates and to evaluate the impacts of recently lowered interpretative breakpoints for carbapenems for Enterobacteriaceae. Among 152 K. pneumoniae bloodstream isolates suspected as AmpC or extended-spectrum beta lactamase (ESBL) producers, 58 (38.2%) isolates were currently interpreted as nonsusceptible to ertapenem, imipenem, or meropenem, and 42 (72.4%) of them were categorized as carbapenem-susceptible by the previous criteria. The high revision rate was associated with the predominance (79.3%) of DHA-1 among the carbapenem nonsusceptible isolates due to both polyclonal and clonal spread. ESBLs were common (~57%) in both ertapenem-susceptible and -nonsusceptible isolates; however, 84.8% of the carbapenem-nonsusceptible isolates were also AmpC producers. The IMP-8 metallo-beta-lactamase was detected in three isolates. Polyacrylamide gel electrophoresis suggested decreased OmpK35 expression in all but one ertapenem-nonsusceptible isolate, and genetic disruptions of ompK35 and ompK36 were detected in 30 and six ertapenem-nonsusceptible isolates, respectively. A comparison between patients infected by AmpC- or ESBL-producing ertapenem-susceptible (n=62) isolates and those with isolates revised as ertapenem-nonsusceptible (n=41) revealed more cases of malignancies (36.6% versus 14.5%; p=0.01) and higher Charlson score (p=0.033) among the patients with ertapenem-nonsusceptible isolates; however, the acquisition of an isolate revised as carbapenem-nonsusceptible was not identified as an independent mortality risk factor. PMID- 22249424 TI - Extractability of water-soluble soil organic matter as monitored by spectroscopic and chromatographic analyses. AB - PURPOSE: Cold and hot water processes have been intensively used to recover soil organic matter, but the effect of extraction conditions on the composition of the extracts were not well investigated. Our objective was to optimize the extraction conditions (time and temperature) to increase the extracted carbon efficiency while minimizing the possible alteration of water extractable organic matter of soil (WEOM). METHOD: WEOM were extracted at 20 degrees C, 60 degrees C, or 80 degrees C for 24 h, 10-60 min, and 20 min, respectively. The different processes were compared in terms of pH of suspensions, yield of organic carbon, spectroscopic properties (ultraviolet-visible absorption and fluorescence), and by chromatographic analyses. RESULTS: For extraction at 60 degrees C, the time 30 min was optimal in terms of yield of organic carbon extracted and concentration of absorbing and fluorescent species. The comparison of WEOM 20 degrees C, 24 h; 60 degrees C, 30 min; and 80 degrees C, 20 min highlighted significant differences. The content of total organic carbon, the value of specific ultraviolet absorbance (SUVA(254)), the absorbance ratio at 254 and 365 nm (E (2)/E (3)), and the humification index varied in the order: WEOM (20 degrees C, 24 h) < WEOM (80 degrees C, 20 min) < WEOM (60 degrees C, 30 min). The three WEOM contained common fluorophores associated with simple aromatic structures and/or fulvic-like and common peaks of distinct polarity as detected by ultra performance liquid chromatography. CONCLUSIONS: For the soil chosen, extraction at 60 degrees C for 30 min is the best procedure for enrichment in organic chemicals and minimal alteration of the organic matter. PMID- 22249425 TI - Influenza virus resistance to neuraminidase inhibitors: implications for treatment. AB - Oseltamivir and Zanamivir are the two main Neuraminidase inhibitors used for the treatment of Influenza. Oseltamivir resistance has been identified in non pandemic influenza viruses, as well as H1N1 pandemic Influenza A viruses. Resistance is associated with increased morbidity, and poorer outcomes in severely immunocompromised hosts. Newer neuraminidase inhibitors, increased vaccination and combination therapy may be alternatives for the treatment of Influenza in this setting. PMID- 22249426 TI - Loss of Y-chromosome does not correlate with age at onset of head and neck carcinoma: a case-control study. AB - Loss of Y-chromosome has been correlated with older age in males. Furthermore, current evidence indicates that Y-chromosome loss also occurs in several human tumors, including head and neck carcinomas. However, the association between Y nullisomy and the occurrence of neoplasias in elderly men has not been well established. In the present study, the association between Y-chromosome loss and head and neck carcinomas was evaluated by comparison to cells from peripheral blood lymphocytes and normal mucosa of cancer-free individuals matched for age using dual-color fluorescence in situ hybridization. Twenty-one patients ranging in age from 28 to 68 years were divided into five-year groups for comparison with 16 cancer-free individuals matched for age. The medical records of all patients were examined to obtain clinical and histopathological data. None of the patients had undergone radiotherapy or chemotherapy before surgery. In all groups, the frequency of Y-chromosome loss was higher among patients than among normal reference subjects (P < 0.0001) and was not age-dependent. These data suggest that Y-chromosome loss is a tumor-specific alteration not associated with advanced age in head and neck carcinomas. PMID- 22249427 TI - Study of the comprehension of the scientific method by members of a university health research laboratory. AB - In Brazil, scientific research is carried out mainly at universities, where professors coordinate research projects with the active participation of undergraduate and graduate students. However, there is no formal program for the teaching/learning of the scientific method. The objective of the present study was to evaluate the comprehension of the scientific method by students of health sciences who participate in scientific projects in an academic research laboratory. An observational descriptive cross-sectional study was conducted using Edgar Morin complexity as theoretical reference. In a semi-structured interview, students were asked to solve an abstract logical puzzle - TanGram. The collected data were analyzed using the hermeneutic-dialectic analysis method proposed by Minayo and discussed in terms of the theoretical reference of complexity. The students' concept of the scientific method is limited to participation in projects, stressing the execution of practical procedures as opposed to scientific thinking. The solving of the TanGram puzzle revealed that the students had difficulties in understanding questions and activities focused on subjects and their processes. Objective answers, even when dealing with personal issues, were also reflected on the students' opinions about the characteristics of a successful researcher. Students' difficulties concerning these issues may affect their scientific performance and result in poorly designed experiments. This is a preliminary study that should be extended to other centers of scientific research. PMID- 22249428 TI - Distribution of human immunodeficiency virus type 1 subtypes in the State of Amazonas, Brazil, and subtype C identification. AB - Few studies have reported the molecular epidemiological characterization of HIV-1 in the Northern region of Brazil. The present study reports the molecular and epidemiological characterization of 31 HIV-1 isolates from blood donors from the State of Amazonas who donated blood between April 2006 and March 2007. Serum/plasma samples from all donors were screened for HIV antibodies by ELISA and the results confirmed by Western blot analysis. Genomic DNA was extracted from the buffy coat using the Super Quik-Gene-DNA Isolation kit. Nested PCR was performed on the env, gag, and pol regions of HIV-1 using the Gene Amp PCR System 9700. Sequencing reactions were performed using the inner PCR primers and the DYEnamicTM ET Dye Terminator Kit, and phylogenetic analysis was performed using the gag, pol, and env gene sequences. We collected samples from 31 blood donors who tested positive for HIV-1 in confirmatory experiments. The male:female ratio of blood donors was 3.4:1, and the mean age was 32.4 years (range: 19 to 61 years). Phylogenetic analysis showed that subtype B is the most prevalent among Northern Brazilian HIV-1-seropositive blood donors. One HIV-1 subtype C and one circulating recombinant form (CRF_BF) of HIV-1 were identified in the State of Amazonas. This is the first study showing the occurrence of a possible "homogenous" subtype C in this region of Brazil. This finding could contribute to a better characterization of the HIV-1 strains that circulate in the country. PMID- 22249429 TI - Quinones and halogenated monoterpenes of algal origin show anti-proliferative effects against breast cancer cells in vitro. AB - Red and brown algae have been shown to produce a variety of compounds with chemotherapeutic potential. A recent report described the isolation of a range of novel polyhalogenated monoterpene compounds from the red algae Plocamium corallorhiza and Plocamium cornutum collected off the coast of South Africa, together with the previously described tetraprenylquinone, sargaquinoic acid (SQA), from the brown algae Sargassum heterophyllum. In our study, the algal compounds were screened for anti-proliferative activity against metastatic MDA-MB 231 breast cancer cells revealing that a number of compounds displayed anti cancer activity with IC(50) values in the micromolar range. A subset of the compounds was tested for differential toxicity in the MCF-7/MCF12A system and five of these, including sargaquinoic acid, were found to be at least three times more toxic to the breast cancer than the non-malignant cell line. SQA was further analysed in terms of its mechanism of cytotoxicity in MDA-MB-231 cells. The ability to initiate apoptosis was distinguished from the induction of an inflammatory necrotic response via flow cytometry with propidium iodide and Hoescht staining, confocal microscopy with Annexin V and propidium iodide staining as well as the PARP cleavage assay. We report that SQA induced apoptosis while a polyhalogenated monoterpene RU015 induced necrosis in metastatic breast cancer cells in vitro. Furthermore, we demonstrated that apoptosis induction by SQA occurs via caspase-3, -6, -8, -9 and -13 and was associated with down regulation of Bcl-2. In addition, cell cycle analyses revealed that the compound causes G(1) arrest in MDA-MB-231 cells. PMID- 22249430 TI - Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor 1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors. AB - BACKGROUND: Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. METHODS: This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. RESULTS: Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional '3 + 3' design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. CONCLUSIONS: Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors. PMID- 22249431 TI - Development of the 4-3-2-1 meibum expressibility scale. AB - OBJECTIVES: With increased interest in the assessment of meibomian gland dysfunction and evaporative dry eye, there remains a deficit in simple, clinically applicable grading scales for gland expression. A new scale to assess meibum expressibility is described. METHODS: A meibum expressibility scale was developed using a new standardized meibomian gland expression device, which provides constant pressure along the inferior lid. For the scale development, 30 patients (53.0+/-8.49 years; 93.33% female) with mild-to-moderate dry eye were compared with 13 normal, non-dry eye subjects (25.6+/-4.3 years; 46.1% female) using the meibum expression device developed by Korb and Blackie. The device was placed 4 glands lateral to the inferior punctum and 1 mm below the lash line and was held stable for 15 sec. The glands expressing meibum were counted. The weighted kappa statistic was used to evaluate the extent of agreement, and a receiver operating characteristic curve was created to test the proposed scale. RESULTS: The mean number of glands that expressed from the worse lid in the normal group was 3.54+/-1.61, whereas 1.53+/-1.28 glands expressed in the dry eye group. In the dry eye group, 1 subject showed 5 glands expressing, and 29 demonstrated scores of 4 or less. In the normal group, 3 or more glands were expressible in 11 of 13 subjects. CONCLUSIONS: A 4-3-2-1 scoring system is proposed, whereby 4 or greater=normal expressibility, 3=mildly reduced expressibility, 2=moderately reduced expressibility, and 1 or lesser=severely reduced expressibility. Further validation of the scale is warranted. PMID- 22249432 TI - Comparison of automated lamellar keratoplasty and phototherapeutic keratectomy for Salzmann nodular degeneration. AB - PURPOSE: The aim was to compare the outcomes of automated lamellar keratoplasty (ALK) and phototherapeutic keratectomy (PTK) for Salzmann nodular degeneration (SND). METHODS: The records of patients undergoing PTK and ALK for SND at the Cornea services of our tertiary care center from were evaluated retrospectively. RESULTS: Twenty-one eyes of 21 patients underwent ALK, and 28 eyes of 28 patients underwent PTK. The distribution of age, pachymetry, and pretreatment corrected distance visual acuity (CDVA) was similar in both groups. In the PTK group, the mean ablation was 60.71+/-14.3 MUm, the CDVA improved from 0.09 preoperatively to 0.21 at 6 months. None of the cases demonstrated significant scarring or any evidence of infection. In the ALK group, the mean host cut was 8.5+/-0.41 mm, and the donor cut was 8.64+/-0.45 mm, donor thickness 350 MUm, and host cut 250 MUm. The mean CDVA improved from 0.09 preoperatively to 0.24 at 6 months. At 6 months, 2 patients demonstrated persistently high astigmatism (>8 D), and 2 had graft interface infection. The CDVA at 6 months and the overall change in the CDVA in both the groups was similar (P=0.06 and 0.07, respectively, Mann-Whitney U test). However, the epithelialization time was significantly longer in the ALK group. CONCLUSIONS: The PTK for SND achieved equivalent visual results compared with ALK and may have an important keratoplasty sparing role. The incidence of complications was lesser in PTK in our study cohort. PMID- 22249433 TI - Somatostatin receptor scintigraphy in sarcoidosis: relation to selected clinical and laboratory markers. AB - INTRODUCTION: Discriminating between active and inactive sarcoidosis may be problematic in everyday clinical practice. There are numerous biochemical markers used in the diagnosis and monitoring of sarcoidosis. Somatostatin receptor (SR) scintigraphy with the use of 99mTc-octreotide may be used to estimate disease activity. OBJECTIVES: The aim of the paper was to assess the value of traditional biomarkers (serum angiotensin-converting enzyme [SACE], C-reactive protein, markers of calcium metabolism, bronchoalveolar lavage fluid [BALF] lymphocytes) and a novel biomarker, 8-isoprostane (8-IP) in exhaled breath condensate (EBC), in the assessment of sarcoidosis activity in relation to somatostatin receptor scintigraphy. PATIENTS AND METHODS: The study included 32 patients with sarcoidosis. Scintigraphy was performed using somatostatin analogue, 99mTc-HYNIC TOC; planar and SPECT/CT images were recorded. The study group was divided into a subgroup with positive radiotracer uptake (n = 20) and without a visible uptake (n = 12). 8-IP levels were measured in EBC by an immunoenzymatic assay. RESULTS We observed a significantly higher EBC 8-IP levels in the subgroup with positive uptake compared with those with negative uptake (19.1 +/- 19.8 vs. 5.4 +/- 3.5 pg/ml, P = 0.02). The levels of SACE and the percentage of BALF lymphocytes were also nonsignificantly elevated. In the group of patients with positive scintigraphy results, a positive correlation was observed between the uptake ratio and SACE (r = 0.44, P = 0.041). CONCLUSIONS: The results indicate low value of biochemical markers in the assessment of disease activity. SR scintigraphy may have practical usefulness in the monitoring of sarcoidosis. PMID- 22249434 TI - Increasing selectivity of interlimb coordination during spontaneous movements in 2- to 4-month-old infants. AB - In the field of motor development, a question exists whether spontaneous activity in early infancy serves as a precursor to later-emerging goal-directed behaviors. To answer this question, it is necessary to investigate in detail the properties of spontaneous movements in individual infants. In the current study, we longitudinally examined the spontaneous movements of the end points of the limbs in 6 infants aged 2-4 months. Examinations were carried out every week by using a motion analysis system, and the number of recordings performed for each infant varied from 6 to 9 times. Our major finding was that there was an age-related increase in the velocity and position correlation between arms and between legs, whereas there was no significant change in the velocity, duration, and amplitude of movements of individual limbs. That is, the pattern of spontaneous movements changes from a general activity involving all the limbs to an activity involving more selective interlimb coordination from 2 to 4 months of age. These findings suggest that the dissociated movements of a selective combination of arms or legs during spontaneous movements may be a precursor to functionally dissociated movements during goal-directed behaviors. PMID- 22249435 TI - Reduction of heart rate variability after colorectal resections. AB - BACKGROUND: Heart rate variability (HRV) is a sensitive marker of altered sympathetic-parasympathetic function and is reduced in inflammation, illness, and trauma. The effect of major abdominal surgery on the course of HRV parameters is still an issue requiring further investigation. MATERIALS AND METHODS: A prospective, observational study including 40 consecutive patients undergoing elective colorectal surgery under "fast-track" perioperative management. Time and frequency domain parameters of HRV were measured 1 day prior to operation and on days 1-5 postoperatively. General and surgical complications as well as the course of leucocytes and C-reactive protein (CRP) were documented and correlated to the HRV measurements. RESULTS: Time domain parameters of HRV showed a significant decrease compared to the preoperative values on postoperative day 1 and returned to baseline on day 2, demonstrating impaired autonomic regulation in the early postoperative period. No correlation to complications or course of leukocytes or CRP was significant in our study. CONCLUSIONS: Colorectal resections significantly influence the HRV course. The autonomic regulation is reduced in the early postoperative time and all parameters return to baseline until the third day. PMID- 22249436 TI - The effects of rotator cuff tears, including shoulders without pain, on activities of daily living in the general population. AB - BACKGROUND: Few reports have so far evaluated the possible restrictions of activities of daily living (ADL) in patients with asymptomatic rotator cuff tears (RCTs). The purpose of this study was to examine the effects of RCTs, including shoulders without pain, on ADL in the general population. METHODS: We performed medical checkups on 462 individuals (924 shoulders). All participants completed a questionnaire regarding their background and medical history. We then assessed their shoulder functions with the Simple Shoulder Test (SST) and performed US (US) examinations of both shoulders to diagnose RCTs. We divided participants into tear and nontear groups and performed statistical analysis to compare total SST scores and each SST item between groups. Furthermore, we performed the same examinations for participants identified as having shoulders without pain. RESULTS: Among participants, those in the tear group showed significantly lower total SST scores than those in the nontear group. After examining each SST item, a significant difference was observed regarding the ability to sleep comfortably and to lift 3.6 kg to shoulder level. In shoulders without pain, the tear group showed significantly lower total SST scores than the nontear group. A significant difference was observed only regarding the ability to lift 3.6 kg to shoulder level. CONCLUSIONS: In the general population, ADL were restricted in participants with RCTs; they experienced night pain in the shoulder and muscle weakness during shoulder elevation. Furthermore, participants with RCTs, even if the condition itself did not induce any pain, tended to experience muscle weakness during shoulder elevation, thus resulting in restrictions of ADL. PMID- 22249437 TI - Outcome analysis of elderly patients undergoing laparoscopic resection rectopexy for rectal prolapse. AB - PURPOSE: For treatment of rectal prolapse, abdominal approaches are generally offered to younger patients, whereas perineal, less invasive procedures are considered more beneficial in the elderly. The aim of this study was to analyze whether laparoscopic resection rectopexy (LRR) is suitable for older patients. PATIENTS/METHODS: Patients who received LRR for rectal prolapse were selected from a prospective laparoscopic colorectal surgery database. Perioperative and long-term outcome were compared between patients <75 years old (group A) and >=75 years old (group B). RESULTS: Of 154 patients, 111 were in group A and 43 in group B. There was one conversion that occurred in group B. Overall mortality rate was 1.3% (n = 2). Both patients were in group B (group B, 4.7%; p = 0.079). Differences in major and minor complications between the groups were not significant. Rates of improvement for incontinence were 62.7% (group A) and 66.7% (group B; p = 0.716); for constipation, the rates were 78.9% (group A) and 73.3% (group B; p = 0.832). All recurrences occurred in group A (n = 10; overall, 10.3%; group A, 13%). After exclusion of patients who had previously received perineal prolapse surgery, recurrence rate was 3.3% overall (group A, 4.3%). CONCLUSIONS: This study supports the benefits of LRR for rectal prolapse in elderly patients. Age per se is not a contraindication for LRR. Elderly patients encounter complications slightly more frequently (although not statistically significant) than younger patients. Therefore, a very careful patient selection in the elderly is of paramount importance. However, the long-term outcome does not seem to differ between younger and elderly patients. PMID- 22249438 TI - The clinical impact of preoperative percutaneous drainage of abdominopelvic abscesses in patients with Crohn's disease. AB - PURPOSE: Although image-guided percutaneous drainage is increasingly being used to treat Crohn's disease-related abdominopelvic abscesses, surgery is seldom avoided. The aim of this study was to compare outcomes following the treatment of intra-abdominal Crohn's abscesses with percutaneous drainage followed by surgery to those after surgery alone. METHODS: We retrospectively reviewed the charts of patients treated for Crohn's-related abdominopelvic abscesses at Mount Sinai Medical Center between April 2001 and June 2010. Patients who underwent drainage followed by surgery were compared to those who underwent surgery alone. Differences in operative and postoperative outcomes were compared. RESULTS: Seventy patients with Crohn's disease-related abdominopelvic abscesses were identified, 38 (54%) of whom underwent drainage before surgery. Percutaneous drainage was technically successful in 92% of patients and clinically successful in 74% of patients. No differences in rate of septic complications (p = 0.14) or need for stoma creation (p = 0.78) were found. Patients who underwent percutaneous drainage had greater overall hospital lengths of stay (mean 15.8 versus 12.2 days, p = 0.007); 8.6% of patients had long-term postponement of surgery after percutaneous drainage. CONCLUSIONS: In our series, the treatment of Crohn's abscesses with percutaneous drainage prior to surgery did not decrease the rate of postoperative septic complications. PMID- 22249439 TI - A comparison of short-term outcome after laparoscopic, transverse, and midline right-sided colectomy. AB - AIM: The aim of the present study was to compare the laparoscopy, transverse, and midline laparotomy in right-sided colectomies with respect to short- and long term outcome. METHODS: The short- and long-term results of all patients who had an elective right-sided hemicolectomy, from January 2006 to April 2009 for malignant or benign disease, were evaluated according to the surgical technique: laparoscopic, midline, or transverse incision laparotomy. RESULTS: The 75 included patients (41% male) had laparoscopy (n = 30), midline (n = 22), or transverse incision laparotomy (n = 23). Median operating time in the laparoscopy group was significantly longer in comparison to the midline and transverse incision groups (129, 105, and 101 min respectively, p < 0.001). Short-term follow-up revealed a longer median total length of stay in the midline laparotomy group compared to the other groups (9 vs. 7 days, p = 0.026). Thirty-day morbidity was less in the laparoscopy and transverse incision groups compared to the midline laparotomy group (15%, 20%, and 41%; p = 0.06). After excluding patients who had a previous midline incision, an earlier return of bowel function was seen for laparoscopy and transverse hemicolectomy (3 vs. 5 days, p = 0.017). At a median follow-up of 40 months (21-58), four incisional hernias occurred, two in the midline laparotomy group (one operatively corrected) and two in the laparoscopy group. CONCLUSIONS: Although the results of this study need to be interpreted with care, our study shows that laparoscopic and transverse right hemicolectomy are equivalent and have a significant better short-term outcome compared to an open midline approach. In particular, laparoscopy and transverse laparotomy result in >50% reduction in 30-day morbidity, no reoperations, and a shorter median total hospital stay of 2 days. PMID- 22249440 TI - Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability. AB - PURPOSE: High level of microsatellite instability (MSI-H) in colorectal cancer (CRC) is caused by the inactivation of mismatch repair (MMR) genes; however, it is unknown for tumors with low level MSI (MSI-L). The protein complex involving MSH3 preferentially recognizes insertion/deletion loops (IDLs) of two to eight bases and di- and tetranucleotide repeats are affected in the majority of MSI-L CRC. METHODS: We selected 10 and eight MSI-L CRCs from 228 and 204 patients with sporadic and hereditary disease, respectively. The tumors were analyzed for protein expression of MSH3, MSH2, MSH6, MLH1, and PMS2, and for mutations and loss of heterozygosity (LOH) in MSH3. RESULTS: Four tumors showed a markedly reduced MSH3 expression, whereas all 18 tumors had normal expression of the remaining MMR proteins. Twenty-five different sequence variants were identified. None of these results in a truncated protein, though L902W represents the first constitutional missense mutation in MSH3 predicted to be functional based on conservation among mutS homologues. All variants have also been found in normal DNA of the patients and in controls. LOH intragenic to MSH3 was evident for 12 of 16 (75%) informative tumors. CONCLUSIONS: Occurrence of sequence variants in normal DNA of the patients and in controls excludes somatic mutations and mutations specific to the CRC patient population, respectively. In contrast, the high frequency of LOH as well as the aberrant protein expression in some tumors indicates an involvement of MSH3 impairment in MSI-L CRC. PMID- 22249441 TI - Detection of Staphylococcus aureus cell walls by enzyme-linked immunoassay using antibodies prepared from a semi-synthetic peptidoglycan precursor. AB - The peptidoglycan layer of Staphylococcus aureus contains a (Gly)(5) cross-link which is not found in other bacteria, and which could be used to develop a specific immunoassay for detection of S. aureus in MRSA infections. A semi synthetic route was used to prepare the S. aureus peptidoglycan precursor UDPMurNAc-L-Ala-gamma-D-Glu-L-Lys(Gly)(5)-D-Ala-D-Ala, which was covalently attached to carrier protein bovine serum albumin via the UDP nucleotide. Serum raised using this antigen showed specificity for chemically immobilised peptidoglycan monomer containing (Gly)(5), using an ELISA immunoassay. ELISA assays using 0.1 or 1.0 MUg samples of cell walls prepared from two MRSA strains and one penicillin-sensitive S. aureus strain, and from three other bacteria, showed the highest response against cell walls containing (Gly)(5), with a particularly high response against cell walls from one MRSA strain. Competition assays to investigate antibody selectivity demonstrated that the antibody response could be most effectively antagonised using ligands containing (Gly)(5). These data demonstrate that it is possible to generate antibodies with high affinity and selectivity for the (Gly)(5) containing monomer in S. aureus peptidoglycan, that could be used to develop an immunoassay for S. aureus. PMID- 22249442 TI - Gastrointestinal cancer: Combine and conquer. PMID- 22249443 TI - Genetics: Splicing the pieces of the chronic lymphocytic leukemia puzzle. PMID- 22249444 TI - Gynecological cancer: True progress in ovarian cancer or just the tip of the iceberg? PMID- 22249445 TI - Supramolecular architectures assembled from amphiphilic hybrid polyoxometalates. AB - Polyoxometalate (POM)-based inorganic-organic molecular hybrid clusters have been recently recognized as good candidates to design novel multi-functional materials. Tremendous efforts have been invested in synthesizing many interesting hybrid structures with exceptional chemical and physical properties. Grafting organic ligands to the POM clusters render these functional clusters amphiphilic properties. Here we summarize the current progresses and provide some perspectives, from colloidal chemists' point of view, on the self-assembly of the amphiphilic POM-organic hybrids in solution and at interfaces, as well as the related consequent novel features such as enhanced fluorescent properties. PMID- 22249446 TI - miR-21 inhibitor sensitizes human OSCC cells to cisplatin. AB - miR-21 as a tumor oncogenic molecule has been reported. However, whether miR-21 can affect the sensitivity of oral squamous cell carcinoma (OSCC) cells to cisplatin remain unclear. The aim of this study is to evaluate the roles of miR 21 in the sensitivity of OSCC cells to cisplatin. RT-PCR assay was performed to detect the expression of miR-21 in 10 pairs of OSCC and noncancerous tissue samples. Then As-miR-21 oligonucleotides were used to down the miR-21 expression. Finally, the effects of miR-21 downregulation the sensitivity of OSCC cells (CA 27) to cisplatin in vitro were also detected. The level of miR-21 expression in OSCC tissues was significantly higher than that in corresponding noncancerous tissues. Down the expression of miR-21 could significantly inhibit growth and induce apoptosis of CA-27 cells. Moreover, downregulation of miR-21 could sensitize CA-27 cells to cisplatin possibly by increasing cisplatin induced apoptosis. This study demonstrated that combination of cisplatin application with miR-21 downregulation might be a potential strategy for the treatment of human OSCC. PMID- 22249447 TI - Revision of AMBER Torsional Parameters for RNA Improves Free Energy Predictions for Tetramer Duplexes with GC and iGiC Base Pairs. AB - All-atom force fields are important for predicting thermodynamic, structural, and dynamic properties of RNA. In this paper, results are reported for thermodynamic integration calculations of free energy differences of duplex formation when CG pairs in the RNA duplexes r(CCGG)(2), r(GGCC)(2), r(GCGC)(2), and r(CGCG)(2) are replaced by isocytidine-isoguanosine (iCiG) pairs. Agreement with experiment was improved when epsilon/zeta, alpha/gamma, beta, and chi torsional parameters in the AMBER99 force field were revised on the basis of quantum mechanical calculations. The revised force field, AMBER99TOR, brings free energy difference predictions to within 1.3, 1.4, 2.3, and 2.6 kcal/mol at 300 K, respectively, compared to experimental results for the thermodynamic cycles of CCGG -> iCiCiGiG, GGCC -> iGiGiCiC, GCGC -> iGiCiGiC, and CGCG -> iCiGiCiG. In contrast, unmodified AMBER99 predictions for GGCC -> iGiGiCiC and GCGC -> iGiCiGiC differ from experiment by 11.7 and 12.6 kcal/mol, respectively. In order to test the dynamic stability of the above duplexes with AMBER99TOR, four individual 50 ns molecular dynamics (MD) simulations in explicit solvent were run. All except r(CCGG)(2) retained A-form conformation for >=82% of the time. This is consistent with NMR spectra of r(iGiGiCiC)(2), which reveal an A-form conformation. In MD simulations, r(CCGG)(2) retained A-form conformation 52% of the time, suggesting that its terminal base pairs may fray. The results indicate that revised backbone parameters improve predictions of RNA properties and that comparisons to measured sequence dependent thermodynamics provide useful benchmarks for testing force fields and computational methods. PMID- 22249448 TI - TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. AB - Tumor necrosis factor (TNF) plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in diseases such as rheumatoid arthritis and periodontitis. Mechanisms that regulate the direct osteoclastogenic properties of TNF to limit pathological bone resorption in inflammatory settings are mostly unknown. Here, we show that the transcription factor recombinant recognition sequence binding protein at the J(kappa) site (RBP-J) strongly suppresses TNF-induced osteoclastogenesis and inflammatory bone resorption, but has minimal effects on physiological bone remodeling. Myeloid-specific deletion of RBP-J converted TNF into a potent osteoclastogenic factor that could function independently of receptor activator of NF-kappaB (RANK) signaling. In the absence of RBP-J, TNF effectively induced osteoclastogenesis and bone resorption in RANK deficient mice. Activation of RBP-J selectively in osteoclast precursors suppressed inflammatory osteoclastogenesis and arthritic bone resorption. Mechanistically, RBP-J suppressed induction of the master regulator of osteoclastogenesis (nuclear factor of activated T cells, cytoplasmic 1) by attenuating c-Fos activation and suppressing induction of B lymphocyte-induced maturation protein-1, thereby preventing the down-regulation of transcriptional repressors such as IRF-8 that block osteoclast differentiation. Thus, RBP-J regulates the balance between activating and repressive signals that regulate osteoclastogenesis. These findings identify RBP-J as a key upstream negative regulator of osteoclastogenesis that restrains excessive bone resorption in inflammatory settings. PMID- 22249449 TI - Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. AB - Intestinal immunoglobulin A (IgA) ensures host defense and symbiosis with our commensal microbiota. Yet previous studies hint at a surprisingly low diversity of intestinal IgA, and it is unknown to what extent the diverse Ig arsenal generated by somatic recombination and diversification is actually used. In this study, we analyze more than one million mouse IgA sequences to describe the shaping of the intestinal IgA repertoire, its determinants, and stability over time. We show that expanded and infrequent clones combine to form highly diverse polyclonal IgA repertoires with very little overlap between individual mice. Selective homing allows expanded clones to evenly seed the small but not large intestine. Repertoire diversity increases during aging in a dual process. On the one hand, microbiota-, T cell-, and transcription factor RORgammat-dependent but Peyer's patch-independent somatic mutations drive the diversification of expanded clones, and on the other hand, new clones are introduced into the repertoire of aged mice. An individual's IgA repertoire is stable and recalled after plasma cell depletion, which is indicative of functional memory. These data provide a conceptual framework to understand the dynamic changes in the IgA repertoires to match environmental and intrinsic stimuli. PMID- 22249451 TI - The electrodeposition of silver composites using deep eutectic solvents. AB - Silver is an important metal for electronic connectors, however, it is extremely soft and wear can be a significant issue. This paper describes how improved wear resistant silver coatings can be obtained from the electrolytic deposition of silver from a solution of AgCl in an ethylene glycol/choline chloride based Deep Eutectic Solvent. An up to 10-fold decrease in the wear volume is observed by the incorporation of SiC or Al(2)O(3) particles. The work also addresses the fundamental aspect of speciation of silver chloride in solution using EXAFS to probe solution structure. The size but not the nature of the composite particles is seen to change the morphology and grain size of the silver deposit. Grain sizes are shown to be consistent with previous nucleation studies. The addition of LiF is found to significantly affect the deposit morphology and improve wear resistance. PMID- 22249450 TI - Sequential class switching is required for the generation of high affinity IgE antibodies. AB - IgE antibodies with high affinity for their antigens can be stably cross-linked at low concentrations by trace amounts of antigen, whereas IgE antibodies with low affinity bind their antigens weakly. In this study, we find that there are two distinct pathways to generate high and low affinity IgE. High affinity IgE is generated through sequential class switching (MU->gamma->epsilon) in which an intermediary IgG phase is necessary for the affinity maturation of the IgE response, where the IgE inherits somatic hypermutations and high affinity from the IgG1 phase. In contrast, low affinity IgE is generated through direct class switching (MU->epsilon) and is much less mutated. Mice deficient in IgG1 production cannot produce high affinity IgE, even after repeated immunizations. We demonstrate that a small amount of high affinity IgE can cause anaphylaxis and is pathogenic. Low affinity IgE competes with high affinity IgE for binding to Fcepsilon receptors and prevents anaphylaxis and is thus beneficial. PMID- 22249452 TI - [Side effects of tumor pharmacotherapy. What internists should know]. AB - Cytotoxic drugs have been used in the therapy of malignant tumors for the last 70 years. However, side effects of cytotoxic drugs are very common and often dose limiting. Although many protocols have been optimized, side effects are still frequently life-threatening. Nausea and vomiting are among the most frequently reported side effects, in addition to mucositis and fatigue. Bone marrow toxicity can lead to neutropenic sepsis, thrombocytopenic bleeding, or anemia with the respective sequelae. In addition to these unspecific side effects, organ toxicity is class or drug specific and may involve the kidney, liver, heart, lung, skin, or central nervous system. As most protocols can be administered on an outpatient basis, knowledge of these side effects is important for the general internist. PMID- 22249456 TI - Fluorescence spectroscopy as a tool to detect and evaluate glucocorticoid-induced skin atrophy. AB - Topical glucocorticoid (GC) therapy has been successfully used in the treatment of several common cutaneous diseases in clinical practice for a long time, and skin atrophy is one of the most typical cutaneous side effects of this therapy. The aim of this study was to evaluate the potential of noninvasive fluorescence spectroscopy (FS) technique in the detection and classification of GC-induced skin atrophy. A total of 20 male Wistar rats were used in the experimental protocol under controlled environmental conditions and with free access to food. One group received topical application of clobetasol propionate 0.05% for 14 days to induce cutaneous atrophy (atrophic group) and the other (control) group received only vehicle application following the same protocol and schedule. Histological analyses and FS measurements with laser excitation at both 532 nm and 408 nm were obtained on days 1 and 15. The FS results were classified as "normal" or "atrophic" according by histological analysis. Fluorescence spectra obtained with excitation at 408 nm allowed a clear distinction between the control and atrophic groups, and were more informative than the those obtained at 532 nm. Our results reveal that, if correctly applied, FS allows noninvasive evaluation of corticosteroid-induced skin atrophy, and thus represents an important step towards better monitoring of undesirable side effects of cutaneous therapy. PMID- 22249457 TI - Aberrant neuregulin 1 signaling in amyotrophic lateral sclerosis. AB - Neuregulin 1 (NRG1) is a neuron-derived trophic molecule that supports axoglial and neuromuscular development through several alternatively spliced isoforms; its possible role in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) is not known. We analyzed the relationship of NRG1 isoform expression to glial cell activation and motor neuron loss in spinal cords of ALS patients and during disease progression in the superoxide dismutase 1 (SOD1) ALS mouse model. Microgliosis, astrocytosis, and motor neuron loss were observed in the ventral horns in ALS patients and were increased in SOD1 mice along with disease progression. Type III (membrane-bound) NRG1 expression was reduced in parallel with motor neuron loss, but Type I (secreted) NRG1 expression was increased and was associated with glial activation. Increased NRG1 receptor activation was observed on activated microglia in both ALS patients and in SOD1 mice. This activation was observed at the time of disease onset and before upregulation of NRG1 gene expression in the mice. The downregulation of membrane bound Type III NRG1 forms may reflect motor neuron loss, but increased signaling by secreted-type NRG1 isoforms could contribute to disease pathogenesis through glial cell activation. NRG1 might, therefore, represent a novel therapeutic target against disease progression in ALS. PMID- 22249458 TI - Mutant presenilin 2 increases beta-secretase activity through reactive oxygen species-dependent activation of extracellular signal-regulated kinase. AB - Senile plaques composed of beta-amyloid (Abeta) are a pathological hallmark of Alzheimer disease. Presenilin 2 (PS2) mutations increase Abeta generation in the brains of Alzheimer disease patients, but the underlying mechanism of Abeta generation by PS2 mutations remains to be clarified. The Abeta is generated through the sequential cleavage of amyloid precursor protein by beta- and gamma secretases. Here, we show that the PS2 mutation N141I enhances the activity of beta-secretase and expression of the beta-site amyloid precursor protein cleavage enzyme 1, a major neuronal beta-secretase in the brains of PS2 transgenic mice and in PC12 cells overexpressing mutant PS2. In parallel with the increased activity of beta-secretase, activation of extracellular signal-regulated kinase (ERK), Abeta1-40 and Abeta1-42 levels, generation of reactive oxygen species, and lipid peroxidation were higher in the mutant mouse neurons and the PC12 cells. Colocalization of phosphorylated ERK (phospho-ERK) and beta-site amyloid precursor protein cleavage enzyme 1 with hydroxynonenal-histidine was found in the mutant brains. An ERK inhibitor U0126 and an antioxidant N-acetylcysteine prevented the expression and activity of beta-secretase, ERK activation, and reactive oxygen species generation in both neurons and PC12 cells expressing mutant PS2 in a dose-dependent manner. Together, these data suggest that oxidative stress-mediated ERK activation contributes to increases in beta secretase and, thus, an increase of Abeta generation in neuronal cells expressing mutant PS2. PMID- 22249459 TI - Selection of distinct strain phenotypes in mice infected by ovine natural scrapie isolates similar to CH1641 experimental scrapie. AB - A few cases of transmissible spongiform encephalopathies in sheep have been described in France in which the protease-resistant prion protein (PrP(res)) exhibited some features in Western blot of experimental bovine spongiform encephalopathy in sheep. Their molecular characteristics were indistinguishable from those produced in the CH1641 experimental scrapie isolate. Four of these CH1641-like isolates were inoculated intracerebrally into wild-type C57Bl/6 mice. In striking contrast to previous results in ovine transgenic mice, CH1641 transmission in wild-type mice was efficient. Several components of the strain signature, that is, PrP(res) profile, brain distribution, and morphology of the deposits of the disease-associated prion protein, had some similarities with "classical" scrapie and clearly differed from both bovine spongiform encephalopathy in sheep and CH1641 transmission in ovine transgenic mice. These results on CH1641-like isolates in wild-type mice may be consistent with the presence in these isolates of mixed conformers with different abilities to propagate and mediate specific disease phenotypes in different species. PMID- 22249460 TI - Cerebellar ataxia in patients with mitochondrial DNA disease: a molecular clinicopathological study. AB - Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. This is often progressive with onset in young adulthood. We performed a detailed neuropathologic investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathologic investigation showed varying levels of loss of Purkinje cells and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation caused by the presence of microinfarcts, with relative preservation of neuronal cell populations in the olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects. PMID- 22249461 TI - Kuru: genes, cannibals and neuropathology. AB - Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied. PMID- 22249462 TI - Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice. AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that causes degeneration of motor neurons and paralysis. Approximately 20% of familial ALS cases have been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene, but it is unclear how mutations in the protein result in motor neuron degeneration. Transgenic (tg) mice expressing mutated forms of human SOD1 (hSOD1) develop clinical and pathological features similar to those of ALS. We used tg mice expressing hSOD1-G93A, hSOD1-G37R, and hSOD1-wild type to investigate a new subcellular pathology involving mutant hSOD1 protein prominently localizing to the nuclear compartment and disruption of the architecture of nuclear gems. We developed methods for extracting relatively pure cell nucleus fractions from mouse CNS tissues and demonstrate a low nuclear presence of endogenous SOD1 in mouse brain and spinal cord, but prominent nuclear accumulation of hSOD1-G93A, -G37R, and -wild-type in tg mice. The hSOD1 concentrated in the nuclei of spinal cord cells, particularly motor neurons, at a young age. The survival motor neuron protein (SMN) complex is disrupted in motor neuron nuclei before disease onset in hSOD1-G93A and -G37R mice; age-matched hSOD1-wild-type mice did not show SMN disruption despite a nuclear presence. Our data suggest new mechanisms involving hSOD1 accumulation in the cell nucleus and mutant hSOD1-specific perturbations in SMN localization with disruption of the nuclear SMN complex in ALS mice and suggest an overlap of pathogenic mechanisms with spinal muscular atrophy. PMID- 22249464 TI - Efficacy of continuous follow-up for preventing the involuntary readmission of psychiatric patients in Japan: a retrospective cohort study. AB - BACKGROUND: Providing aftercare to psychiatric inpatients is important for preventing frequent readmissions; however, the lack of social resources is a problem in Japan. The prefectural Tama-Fuchu Public Health Centre has attempted to establish a new continuous follow-up system for all discharged psychiatric patients in order to reduce the frequency of readmissions. AIMS: This study aims to evaluate the efficacy of this system. METHODS: The subjects of the present study were 200 psychiatric inpatients from the Tokyo catchment area. The continuous follow-up system was applied to 130 subjects for one year in addition to conventional standard care (the intervention group). Seventy subjects received conventional care alone (the comparison group). The incident rate ratios (IRR) of total and involuntary readmission to hospital were compared by survival analysis. RESULTS: During the observation period, there were 41 readmissions and 29 involuntary readmissions in 49,731 person-days. The patients subjected to continuous follow-up showed a trend towards a lower overall risk of readmission (IRR = 0.56, 95% CI: 0.29-1.10, p = .057) and a significantly reduced risk of involuntary admission (IRR = 0.48, 95% CI: 0.22-0.96, p = .047). CONCLUSION: This study provides empirical evidence that providing continuous follow-up examinations as aftercare for discharged psychiatric patients significantly reduces the incidence of involuntary readmission. PMID- 22249465 TI - Education and employment levels among Jamaican patients newly diagnosed with schizophrenia and bipolar disorder. AB - BACKGROUND: Comparisons between persons with bipolar disorder and those with schizophrenia are not well researched in the Caribbean. AIMS: To compare the educational and occupational attainments in Jamaicans diagnosed with these two disorders. METHODS: Data on diagnosis, educational level, type of employment and other basic socio-demographic variables were collected from Jamaican hospital patients who were newly diagnosed with schizophrenia or bipolar disorder. Fisher's exact and chi2 tests, as well as binary logistic regression, were used to explore how these characteristics varied according to diagnosis. Statistical significance was taken at p < .05. RESULTS: Schizophrenia was associated with significantly lower educational attainment than bipolar disorder (p = .022 for educational level attained; p = .026 for completion of secondary school). The majority (87.1%) of the 93 patients included in the analysis had no specific marketable job skills. However, the proportion of persons with bipolar disorder who had such skills was three times the corresponding proportion of persons with schizophrenia. CONCLUSIONS: The low educational achievement among persons with schizophrenia makes education a potentially important area for interventions targeted at this group. Because gross deficiencies in job skills were common to both patient groups, improvement in job skill levels is an important goal for persons with either of these disorders. PMID- 22249463 TI - Inhibition of JNK by a peptide inhibitor reduces traumatic brain injury-induced tauopathy in transgenic mice. AB - Traumatic brain injury (TBI) is a major environmental risk factor for subsequent development of Alzheimer disease (AD). Pathological features that are common to AD and many tauopathies are neurofibrillary tangles (NFTs) and neuropil threads composed of hyperphosphorylated tau. Axonal accumulations of total and phospho tau have been observed within hours to weeks, and intracytoplasmic NFTs have been documented years after severe TBI in humans. We previously reported that controlled cortical impact TBI accelerated tau pathology in young 3xTg-AD mice. Here, we used this TBI mouse model to investigate mechanisms responsible for increased tau phosphorylation and accumulation after brain trauma. We found that TBI resulted in abnormal axonal accumulation of several kinases that phosphorylate tau. Notably, c-Jun N-terminal kinase (JNK) was markedly activated in injured axons and colocalized with phospho-tau. We found that moderate reduction of JNK activity (40%) by a peptide inhibitor, D-JNKi1, was sufficient to reduce total and phospho-tau accumulations in axons of these mice with TBI. Longer-term studies will be required to determine whether reducing acute tau pathology proves beneficial in brain trauma. PMID- 22249466 TI - The development of direct multicolour fluorescence cross-correlation spectroscopy: towards a new tool for tracking complex biomolecular events in real time. AB - Direct three-colour fluorescence cross-correlation spectroscopy can reveal interactions between three fluorescently labelled biomolecules, giving insight toward the complex events that constitute signal transduction pathways. Here we provide the optical and theoretical basis for this technology and demonstrate its ability to detect specific biological associations between nanoparticle-labelled DNA molecules. PMID- 22249467 TI - RSO interview with Alan Fellman by Rene Michel. PMID- 22249468 TI - RACER: dynamic use of environmental measurement data for decision making and communication. AB - To facilitate access to and use of environmental measurement data, Risk Assessment Corporation has developed a data management system as part of its Risk Analysis, Communication, Evaluation, and Reduction process. The concepts of data consistency are not new, but many data management applications are developed around managing the entire data life cycle, rather than on using the data to reach meaningful conclusions. The RACER process is specifically focused on the efficient use of available data to promote sound decision making. The RACER data management system provides a means of understanding trends in data, comparing data to frequently referenced comparison values, and organizing environmental measurement data for use by other components of the RACER process that evaluate human health impacts. Data transfers to the system can be automated to occur frequently for facilities collecting large volumes of data to achieve a dynamic point of access to measurement data that reflects the most recently available information. Because the RACER process is designed around the most common uses of data, its utility spans a broad range of potential applications, from routine monitoring and reporting to emergency response decision making based on potential human health impacts. Because it is portable and flexible, the elements of the system can be used in any situation where there is a need to efficiently access and interpret environmental measurement data. Its output and functions are equally relevant for small datasets with hundreds of measurements or large and complex datasets with millions of measurements. PMID- 22249469 TI - Minimum detectable concentration as a function of gamma walkover survey technique. AB - Gamma walkover surveys are often performed by swinging the radiation detector (e.g., a 2-inch by 2-inch sodium iodide) in a serpentine pattern at a near constant height above the ground surface. The objective is to survey an approximate 1-m swath with 100% coverage producing an equal probability of detecting contamination at any point along the swing. In reality, however, the detector height will vary slightly along the swing path, and in some cases the detector may follow a pendulum-like motion significantly reducing the detector response and increasing the minimum detectable concentration. This paper quantifies relative detector responses for fixed and variable height swing patterns and demonstrates negative impacts on the minimum detectable concentration. Minimum detectable concentrations are calculated for multiple contaminated surface areas (0.1, 1.0, 3, 10, and 30 m2), multiple contaminants (60Co, 137Cs, 241Am, and 226Ra), and two minimum heights (5 and 10 cm). Exposure rate estimates used in minimum detectable concentration calculations are produced using MicroShieldTM v.7.02 (Grove Software, Inc., 4925 Boonsboro Road #257, Lynchberg, VA 24503) and MDCs are calculated as outlined in NUREG-1575. Results confirm a pendulum-like detector motion can significantly increase MDCs relative to a low flat trajectory, especially for small areas of elevated activity--up to a 47% difference is observed under worst-modeled conditions. PMID- 22249470 TI - An unrecognized occupancy change in the vicinity of a medical linear accelerator. AB - It seems obvious that if a significant increase in occupancy occurs in the immediate vicinity of any radiation room a reexamination of the adequacy of the shielding should be performed. We discuss a facility where a new building was constructed in close proximity to an existing medical linear accelerator and no consideration was given to the consequences of that construction as it might impact the doses received by occupants of the new structure. For more than 10 years some areas in that building may have received exposures greater than the allowed regulatory limit. The situation reported here should serve as a cautionary tale for those who have the responsibility for providing radiation protection at any site where new construction or increases in occupancy might require a reanalysis of the previously designed radiation shielding. PMID- 22249471 TI - Benefits of automated surface decontamination of a radioiodine ward. AB - A floor-washing robot has been acquired to assist physicists with decontamination of radioiodine therapy ward rooms after discharge of the patient at Sir Charles Gairdner Hospital. The effectiveness of the robot in decontaminating the ward has been evaluated. A controlled experiment was performed by deliberately contaminating a polyvinyl chloride flooring offcut with 131I followed by automated decontamination with the robot. The extent of fixed and removable contamination was assessed before and after decontamination by two methods: (1) direct Geiger-Mueller counting and (2) beta-counting wipe tests. Surface contamination was also assessed in situ on the ward by Geiger-Mueller counting and wipe testing. Contamination maps confirmed that contamination was removed rather than spread around by the robot. Wipe testing revealed that the robot was successful in clearing approximately 60-80% of removable contamination. The robotic floor-washing device was considered suitable to provide effective automated decontamination of the radioiodine ward. In addition, the robot affords other benefits: the time spent by the physicists decontaminating the room is greatly reduced offering financial and occupational safety and health benefits. The robot has also found utility in other decontamination applications in the healthcare environment. PMID- 22249472 TI - Isodose curve mappings measured while undergoing rotation for quality assurance testing of a 137Cs irradiator. AB - To enable accurate and reproducible dosimetry for biological sample irradiation in a 137Cs irradiator, routine quality assurance of the dose rate and isodose distributions should be considered. Our previous work demonstrated a means for accurate dose rate quality assurance and for quality assurance of isodose distributions of non-rotational samples. This work presents a means to accurately and cost effectively measure dose distributions within a 137Cs irradiator using rotational geometry, which geometry represent a more typical use of these irradiators. A simple apparatus was developed to hold radiochromic film and was constructed of polymethyl methacrylate. The rotational quality assurance device allowed the comparison of measured radiochromic film vs. manufacturer provided isodose distributions. A good agreement was discovered between the two data sets along the central vertical axis of rotation in the 137Cs irradiator, but a 40-50% smaller 100% isodose region in the horizontal direction. These findings may lead to limiting the overall size of a sample capable of being uniformly irradiated by the 137Cs irradiator at this research institution. The authors propose the construction and use of a simple rotational quality assurance device for routine quality assurance of 137Cs irradiators. PMID- 22249473 TI - Because scientists are unable to explain the unexplained, screening for cardiovascular abnormalities is a good method to protect against sudden unexpected death in patients with epilepsy. PMID- 22249474 TI - The impact of psychiatric diagnosis on treatment adherence and duration among victimized children and adolescents in Sao Paulo, Brazil. AB - OBJECTIVE: Despite the high prevalence of substance abuse and mood disorders among victimized children and adolescents, few studies have investigated the association of these disorders with treatment adherence, represented by numbers of visits per month and treatment duration. We aimed to investigate the effects of substance abuse and mood disorders on treatment adherence and duration in a special program for victimized children in Sao Paulo, Brazil. METHODS: A total of 351 participants were evaluated for psychiatric disorders and classified into one of five groups: mood disorders alone; substance abuse disorders alone; mood and substance abuse disorders; other psychiatric disorders; no psychiatric disorders. The associations between diagnostic classification and adherence to treatment and the duration of program participation were tested with logistic regression and survival analysis, respectively. RESULTS: Children with mood disorders alone had the highest rate of adherence (79.5%); those with substance abuse disorders alone had the lowest (40%); and those with both disorders had an intermediate rate of adherence (50%). Those with other psychiatric disorders and no psychiatric disorders also had high rates of adherence (75.6% and 72.9%, respectively). Living with family significantly increased adherence for children with substance abuse disorders but decreased adherence for those with no psychiatric disorders. The diagnostic correlates of duration of participation were similar to those for adherence. CONCLUSIONS: Mood and substance abuse disorders were strong predictive factors for treatment adherence and duration, albeit in opposite directions. Living with family seems to have a positive effect on treatment adherence for patients with substance abuse disorders. More effective treatment is needed for victimized substance-abusing youth. PMID- 22249476 TI - Vulnerability to AIDS among the elderly in an urban center in central Brazil. AB - OBJECTIVE: As the world population ages with an improved quality of life and sexual longevity, the prevalence of AIDS is rising among the elderly. The purpose of this study was to estimate the vulnerability to AIDS among individuals attending senior community centers in Campo Grande, Mato Grosso do Sul, Brazil. METHOD: This descriptive, exploratory investigation included 329 subjects selected in a probabilistic manner. Individuals with scores on the Mini-Mental State Examination indicating cognitive impairment were excluded from the analyses. Barthel's and Lawton's functional assessment scales were applied. Interviews were conducted to evaluate the presence of cognitive and behavioral factors associated with HIV transmission. RESULTS: Most subjects were non dependent, fell within the 60- to 69-year age bracket and were female. A majority of individuals reported having knowledge about AIDS and were aware that the elderly are vulnerable to the disease. More than a quarter (26.9%) of the sample reported previous HIV testing. No participants reported drug use, homosexual orientation, or alcohol abuse. A minority of participants reported using medication for erectile dysfunction. Casual and multiple partners accounted for 12% and 34% of reported intercourse experiences, respectively. Condom use was reported by 14% of respondents. CONCLUSION: Unprotected sex was the primary factor accounting for vulnerability to AIDS among the elderly. PMID- 22249475 TI - Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil. AB - OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice weekly), or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z scores, weight-for-height z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4 6.6) later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+), with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+) children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+) children and improved delta lactulose/mannitol. Apolipoprotein E4(-) children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may function concomitantly with gut-tropic nutrients to benefit immediate nutritional status, which can translate into better long-term cognitive outcomes. PMID- 22249477 TI - Periodontitis-associated risk factors in pregnant women. AB - OBJECTIVE: The main objective of this study was to investigate the risk factors associated with periodontitis in pregnant women. METHODS: This study was conducted in two stages. In Stage 1, a cross-sectional study was conducted to determine the prevalence of periodontitis among 810 women treated at the maternity ward of a university hospital. In Stage 2, the factors associated with periodontitis were investigated in two groups of pregnant women: 90 with periodontitis and 720 without. A hierarchized approach to the evaluation of the risk factors was used in the analysis, and the independent variables related to periodontitis were grouped into two levels: 1) socio-demographic variables; 2a) variables related to nutritional status, smoking, and number of pregnancies; and 2b) variables related to oral hygiene. Periodontitis was defined as a probing depth >= 4 mm and an attachment loss >= 3 mm at the same site in four or more teeth. A logistic regression analysis was also performed. RESULTS: The prevalence of periodontitis in this sample was 11%. The variables that remained in the final multivariate model with the hierarchized approach were schooling, family income, smoking, body mass index, and bacterial plaque. CONCLUSION: The factors identified underscore the social nature of the disease, as periodontitis was associated with socioeconomic, demographic status, and poor oral hygiene. PMID- 22249478 TI - Regulation of hypoxia-inducible factor-1alpha (HIF-1alpha) expression by interleukin-1beta (IL-1 beta), insulin-like growth factors I (IGF-I) and II (IGF II) in human osteoarthritic chondrocytes. AB - OBJECTIVE: Hypoxia-inducible factor 1 alpha regulates genes related to cellular survival under hypoxia. This factor is present in osteroarthritic chondrocytes, and cytokines, such as interleukin-1 beta, participate in the pathogenesis of osteoarthritis, thereby increasing the activities of proteolytic enzymes, such as matrix metalloproteinases, and accelerating cartilage destruction. We hypothesize that Hypoxia Inducible Factor-1 alpha (HIF-1alpha) can regulate cytokines (catabolic action) and/or growth factors (anabolic action) in osteoarthritis. The purpose of this study was to investigate the modulation of HIF-1alpha in human osteoarthritic chondrocytes by interleukin-1 beta (IL-1beta) and insulin-like growth factors I (IGF-I) and II (IGF-II) and to determine the involvement of the phosphatidylinositol-3-kinase (PI-3K) pathway in this process. METHODS: Human osteroarthritic chondrocytes were stimulated with IL-1beta, IGF-I and IGF-II and LY294002, a specific inhibitor of PI-3K. Nuclear protein levels and gene expression were analyzed by western blot and quantitative reverse transcription polymerase chain reaction analyses, respectively. RESULTS: HIF-1alpha expression was upregulated by IL-1beta at the protein level but not at the gene level. IGF-I treatment resulted in increases in both the protein and mRNA levels of HIF-1alpha , whereas IGF-II had no effect on its expression. However, all of these stimuli exploited the PI-3K pathway. CONCLUSION: IL-1beta upregulated the levels of HIF 1alpha protein post-transcriptionally, whereas IGF-I increased HIF-1alpha at the transcript level. In contrast, IGF-II did not affect the protein or gene expression levels of HIF-1alpha . Furthermore, all of the tested stimuli exploited the PI-3K pathway to some degree. Based on these findings, we are able to suggest that Hypoxia inducible Factor-1 exhibits protective activity in chondrocytes during osteoarthritis. PMID- 22249479 TI - An economic evaluation of antihypertensive therapies based on clinical trials. AB - OBJECTIVE: Hypertension is a major issue in public health, and the financial costs associated with hypertension continue to increase. Cost-effectiveness studies focusing on antihypertensive drug combinations, however, have been scarce. The cost-effectiveness ratios of the traditional treatment (hydrochlorothiazide and atenolol) and the current treatment (losartan and amlodipine) were evaluated in patients with grade 1 or 2 hypertension (HT1-2). For patients with grade 3 hypertension (HT3), a third drug was added to the treatment combinations: enalapril was added to the traditional treatment, and hydrochlorothiazide was added to the current treatment. METHODS: Hypertension treatment costs were estimated on the basis of the purchase prices of the antihypertensive medications, and effectiveness was measured as the reduction in systolic blood pressure and diastolic blood pressure (in mm Hg) at the end of a 12-month study period. RESULTS: When the purchase price of the brand-name medication was used to calculate the cost, the traditional treatment presented a lower cost-effectiveness ratio [US$/mm Hg] than the current treatment in the HT1 2 group. In the HT3 group, however, there was no difference in cost-effectiveness ratio between the traditional treatment and the current treatment. The cost effectiveness ratio differences between the treatment regimens maintained the same pattern when the purchase price of the lower-cost medication was used. CONCLUSIONS: We conclude that the traditional treatment is more cost-effective (US$/mm Hg) than the current treatment in the HT1-2 group. There was no difference in cost-effectiveness between the traditional treatment and the current treatment for the HT3 group. PMID- 22249480 TI - Hemodynamic responses and upper airway morbidity following tracheal intubation in patients with hypertension: conventional laryngoscopy versus an intubating laryngeal mask airway. AB - OBJECTIVES: We compared hemodynamic responses and upper airway morbidity following tracheal intubation via conventional laryngoscopy or intubating laryngeal mask airway in hypertensive patients. METHODS: Forty-two hypertensive patients received a conventional laryngoscopy or were intubated with a intubating laryngeal mask airway. Anesthesia was induced with propofol, fentanyl, and cis atracurium. Measurements of systolic and diastolic blood pressures, heart rate, rate pressure product, and ST segment changes were made at baseline, preintubation, and every minute for the first 5 min following intubation. The number of intubation attempts, the duration of intubation, and airway complications were recorded. RESULTS: The intubation time was shorter in the conventional laryngoscopy group than in the intubating laryngeal mask airway group (16.33 +/- 10.8 vs. 43.04 +/- 19.8 s, respectively) (p<0.001). The systolic and diastolic blood pressures in the intubating laryngeal mask airway group were higher than those in the conventional laryngoscopy group at 1 and 2 min following intubation (p<0.05). The rate pressure product values (heart rate x systolic blood pressure) at 1 and 2 min following intubation in the intubating laryngeal mask airway group (15970.90 +/- 3750 and 13936.76 +/- 2729, respectively) were higher than those in the conventional laryngoscopy group (13237.61 +/- 3413 and 11937.52 +/- 3160, respectively) (p<0.05). There were no differences in ST depression or elevation between the groups. The maximum ST changes compared with baseline values were not significant between the groups (conventional laryngoscopy group: 0.328 mm versus intubating laryngeal mask airway group: 0.357 mm; p = 0.754). The number and type of airway complications were similar between the groups. CONCLUSION: The intense and repeated oropharyngeal and tracheal stimulation resulting from intubating laryngeal mask airway induces greater pressor responses than does stimulation resulting from conventional laryngoscopy in hypertensive patients. As ST changes and upper airway morbidity are similar between the two techniques, conventional laryngoscopy, which is rapid and safe to perform, may be preferred in hypertensive patients with normal airways. PMID- 22249481 TI - Clinical predictors of prosthesis-patient mismatch after aortic valve replacement for aortic stenosis. AB - OBJECTIVE: We sought to ascertain predictors of Patient Prosthesis Mismatch, an independent predictor of mortality, in patients with aortic stenosis using bioprosthetic valves. METHOD: We analyzed 2,107 sequential surgeries. Patient Prosthesis Mismatch was calculated using the effective orifice area of the prosthesis divided by the patient's body surface area. We defined nonsignificant, moderate, and severe Patient Prosthesis Mismatch as effective orifice area indexes of .0.85 cm(2)/m, 0.85-0.66 cm(2)/m(2), and <0.65 cm(2)/m(2), respectively. RESULTS: A total of 311 bioprosthetic patients were identified. The incidence of nonsignificant, moderate, and severe Patient Prosthesis Mismatch was 41%, 42, and 16%, respectively. Severe Patient Prosthesis Mismatch was significantly more prevalent in females (82%). In severe Patient Prosthesis Mismatch, the perfusion and the crossclamp times were considerably lower when compared with nonsignificant Patient Prosthesis Mismatch and moderate Patient Prosthesis Mismatch. Patients with severe Patient Prosthesis Mismatch had a significantly higher likelihood of spending time in the intensive care unit and a significantly longer length of stay in the hospital. Body surface area was not different in severe Patient Prosthesis Mismatch when compared with nonsignificant Patient Prosthesis Mismatch. In-hospital mortality in patients with nonsignificant, moderate, and severe Patient Prosthesis Mismatch was 2.3%, 6.1%, and 8%, respectively. Minimally invasive surgery was significantly associated with moderate Patient Prosthesis Mismatch in 49% of the patients, but not with severe Patient Prosthesis Mismatch. CONCLUSION: Severe Patient Prosthesis Mismatch is more common in females, but not in those with minimal available body surface area. Though operative times were shorter in these patients, intensive care unit and hospital lengths of stay were longer. Surgeons and cardiologists should be cognizant of these clinical predictors and complications prior to valve surgery. PMID- 22249482 TI - Reduced occurrence of programmed cell death and gliosis in the retinas of juvenile rabbits after shortterm treatment with intravitreous bevacizumab. AB - OBJECTIVE: Bevacizumab has been widely used as a vascular endothelial growth factor antagonist in the treatment of retinal vasoproliferative disorders in adults and, more recently, in infants with retinopathy of prematurity. Recently, it has been proposed that vascular endothelial growth factor acts as a protective factor for neurons and glial cells, particularly in developing nervous tissue. The purpose of this study was to investigate the effects of bevacizumab on the developing retinas of juvenile rabbits. METHODS: Juvenile rabbits received bevacizumab intravitreously in one eye; the other eye acted as an untreated control. Slit-lamp and fundoscopic examinations were performed both prior to and seven days after treatment. At the same time, retina samples were analyzed using immunohistochemistry to detect autophagy and apoptosis as well as proliferation and glial reactivity. Morphometric analyses were performed, and the data were analyzed using the Mann-Whitney U test. RESULTS: No clinical abnormalities were observed in either treated or untreated eyes. However, immunohistochemical analyses revealed a reduction in the occurrence of programmed cell death and increases in both proliferation and reactivity in the bevacizumab-treated group compared with the untreated group. CONCLUSIONS: Bevacizumab appears to alter programmed cell death patterns and promote gliosis in the developing retinas of rabbits; therefore, it should be used with caution in developing eyes. PMID- 22249484 TI - Narcolepsy after A/H1N1 vaccination. PMID- 22249483 TI - Paradoxical effects of brain death and associated trauma on rat mesenteric microcirculation: an intravital microscopic study. AB - OBJECTIVE: Experimental findings support clinical evidence that brain death impairs the viability of organs for transplantation, triggering hemodynamic, hormonal, and inflammatory responses. However, several of these events could be consequences of brain death-associated trauma. This study investigated microcirculatory alterations and systemic inflammatory markers in brain-dead rats and the influence of the associated trauma. METHOD: Brain death was induced using intracranial balloon inflation; sham-operated rats were trepanned only. After 30 or 180 min, the mesenteric microcirculation was observed using intravital microscopy. The expression of Pselectin and ICAM-1 on the endothelium was evaluated using immunohistochemistry. The serum cytokine, chemokine, and corticosterone levels were quantified using enzyme-linked immunosorbent assays. White blood cell counts were also determined. RESULTS: Brain death resulted in a decrease in the mesenteric perfusion to 30%, a 2.6-fold increase in the expression of ICAM-1 and leukocyte migration at the mesentery, a 70% reduction in the serum corticosterone level and pronounced leukopenia. Similar increases in the cytokine and chemokine levels were seen in the both the experimental and control animals. CONCLUSION: The data presented in this study suggest that brain death itself induces hypoperfusion in the mesenteric microcirculation that is associated with a pronounced reduction in the endogenous corticosterone level, thereby leading to increased local inflammation and organ dysfunction. These events are paradoxically associated with induced leukopenia after brain damage. PMID- 22249485 TI - Novel compound aquaporin 2 mutations in nephrogenic diabetes insipidus. PMID- 22249486 TI - Intravascular leiomyoma with heart extension. PMID- 22249487 TI - Laparoendoscopic single-site (LESS) repair of lumbar hernia: initial case report. PMID- 22249488 TI - Use of toe clips as a nonlethal index of mercury accumulation and maternal transfer in amphibians. AB - Nonlethal indices of contaminant exposure can facilitate research on the accumulation and effects of contaminants in wildlife. Here, we tested the efficacy of using amputated toes ("toe clips"), a common byproduct when marking amphibians in population and genetic studies, to determine mercury (Hg) concentrations in amphibians. We examined total mercury (THg) concentrations in American toads (Bufo americanus) collected along a contamination gradient at a Hg contaminated field site. We found significant positive correlations between toe THg and blood THg concentrations in adult males and females collected in two different years. We also found that blood and toe clips could be used to predict maternal transfer of Hg, an important mechanism of reproductive toxicity in wildlife. Maternal toe THg concentrations were more highly correlated with egg THg concentrations than were maternal blood THg concentrations. Our results indicate that amputated toes are effective for identifying Hg concentrations in amphibians. PMID- 22249489 TI - Anti-inflammatory efficacy of dexamethasone and Nrf2 activators in the CNS using brain slices as a model of acute injury. AB - Limiting excessive production of inflammatory mediators is an effective therapeutic strategy for many diseases. It's also a promising remedy for neurodegenerative diseases and central nervous system (CNS) injuries. Glucocorticoids are valuable anti-inflammatory agents, but their use is constrained by adverse side-effects. Activators of NF-E2-related factor-2 (Nrf2) signaling represent an attractive anti-inflammatory alternative. In this study, dexamethasone, a synthetic glucocorticoid, and several molecular activators of Nrf2 were evaluated for efficacy in slices of cerebral cortex derived from adult SJL/J mice. Cortical explants increased expression of IL-1beta and TNF-alpha mRNAs in culture within 5 h of sectioning. This expression was inhibited with dexamethasone in the explant medium or injected systemically in mice before sectioning. Semi-synthetic triterpenoid (SST) derivatives, potent activators of the Nrf2 pathway, demonstrated fast-acting anti-inflammatory activity in microglia cultures, but not in the cortical slice system. Quercetin, luteolin, and dimethyl fumarate were also evaluated as molecular activators of Nrf2. While expression of inflammatory mediators in microglia cultures was inhibited, these compounds did not demonstrate anti-inflammatory efficacy in cortical slices. In conclusion, brain slices were amenable to pharmacological modification as demonstrated by anti-inflammatory activity with dexamethasone. The utilization of Nrf2 activators to limit inflammatory mediators within the CNS requires further investigation. Inactivity in CNS tissue, however, suggests their safe use without neurological side-effects in treating non-CNS disorders. Short-term CNS explants may provide a more accurate model of in vivo conditions than microglia cultures since the complex tissue microenvironment is maintained. PMID- 22249490 TI - Sleep-disordered breathing in neurodegenerative diseases. AB - Sleep disorders are common in neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), hereditary ataxias, and Alzheimer's disease (AD). Type, frequency, and severity of sleep disturbances vary depending on each of these diseases. Cell loss of the brainstem nuclei that modulates respiration, and dysfunction of bulbar and diaphragmatic muscles increase the risk for sleep-disordered breathing (SDB) in MSA and ALS. The most relevant SDB in MSA is stridor, whereas in ALS nocturnal hypoventilation due to diaphragmatic weakness is the most common sleep breathing abnormality. Stridor and nocturnal hypoventilation are associated with reduced survival in MSA and ALS. In contrast, sleep apnea seems not to be more prevalent in PD than in the general population. In some PD patients, however, coincidental obstructive sleep apnea (OSA) can be the cause of excessive daytime sleepiness (EDS). SDB can also occur in some hereditary ataxias, such as stridor in spinocerebellar ataxia type 3 (Machado-Joseph disease). The presence of concomitant OSA in patients with AD can have deleterious effects on nocturnal sleep, may result in EDS, and might aggravate the cognitive deficits inherent to the disease. However, whether OSA is more frequent in patients with AD than in the general population is uncertain. Recognition of SDB in neurodegenerative disease is important because they are associated with significant morbidity and potential effective treatments are available. PMID- 22249491 TI - Temozolomide for pediatric high-grade gliomas. PMID- 22249493 TI - Crowded bis ligand complexes of Ttz(Ph,Me) with first row transition metals rearrange due to ligand field effects: structural and electronic characterization (Ttz(Ph,Me) = tris(3-phenyl-5-methyl-1,2,4-triazolyl)borate). AB - The tris(3-phenyl-5-methyl-1,2,4-triazolyl)borate (Ttz(Ph,Me)) ligand provides intermediate steric bulk and forms predominantly bis(ligand) complexes of the form M(Ttz(Ph,Me))(2) with first row divalent transition metals (1(M), M = Zn, Cu, Ni, Co, Fe, Mn). Due to ligand field effects that are greatest with Ni and Cu, ligand rearrangement is favored with these metals and Cu(Ttz(Ph,Me)*)(2) (1(Cu)*) and (Ttz(Ph,Me)*)Ni(Ttz(Ph,Me)) (1(Ni)*) were isolated by selective recrystallization and fully characterized (* indicates a rearranged Ttz ligand with Ph and Me in swapped positions in one triazole ring). For comparison with Co(Ttz(Ph,Me))(2), the less bulky analogs (Ttz(H,H))(2)Co (4) and (Ttz(Me,Me))(2)Co (5) were studied by NMR and EPR spectroscopy, and 5 was crystallographically characterized. These complexes allow for a study of how slight changes in structure and electron donor properties (for Ni and Cu), as well as dramatic changes in steric bulk (for Co), influence the physical properties; specifically there are significant changes in the UV-Vis, EPR and NMR spectra. Bis(ligand) complexes predominate with all metals, but (Ttz(Ph,Me))Ni(OH(2))Cl (2) and (Ttz(Ph,Me))ZnBr (3) were also isolated and these show that Ttz(Ph,Me) is coordinatively flexible. PMID- 22249492 TI - Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy. AB - OBJECTIVE: Recent studies in breast cancer patients and Trastuzumab therapy (Herceptin) showed a development of a toxic cardiomyopathy as a severe complication. The aim of this study was to discover early changes in cardiac function and morphology. METHODS: We studied 42 female patients with Her-2/-neu over-expression in breast cancer by echocardiography before, 3, and 6 months after start of the adjuvant Herceptin therapy. All values were mean value +/- standard deviation. RESULTS: After 3 or 6 months of a trastuzumab therapy we discovered significant increases in the diastolic and systolic left ventricle volume indices (LV-DVI 32.4 +/- 8.5 vs. 38.5 +/- 8.7 vs. 40.3 +/- 10.3 ml/m2, p < 0.001 and LV-SVI 12.6 +/- 4.0 vs. 15.7 +/- 4.7 vs. 17.2 +/- 6.8 ml/m2, p < 0.001), an increase of the end-diastolic and end-systolic LV diameter (LVEDD 46.8 +/- 4.2 vs. 48.0 +/- 4.7 vs. 49.7 +/- 4.5 ml/m2, p < 0.01; LVESD 28.3 +/- 4.2 vs. 31.0 +/- 4.7 vs. 32.3 +/- 4.9 mm, p < 0.001), a reduced systolic ventricle function determined by the tissue Doppler imaging (TDI) velocity (9.2 +/- 2.5 vs. 8.0 +/- 1,7 vs. 7.7 +/- 1.5 cm/s, p < 0.001), fractional shortening (39,6 +/- 7.5 vs. 35.4 +/- 7.4 vs. 35.2 +/- 7.0%, p < 0.01), and the LV-EF Simpson biplane [62.0 +/- 5.1 vs. 60.1 +/- 6.3 (p = ns) vs. 58.4 +/- 7.9%, p < 0.01] compared to pretreatment values. There was also an increase of the left atrial volume index (21.4 +/- 6.2 vs. 26.2 +/- 7.9 vs. 29.7 +/- 8.8 ml/m2, p < 0.001), a decrease of the median TDI atrial velocities (11.9 +/- 2.4 vs. 10.5 +/- 2.8 vs. 10.1 +/- 2.1 cm/s, p < 0.01), an increase of the peak early diastolic filling velocities (73.1 +/- 15.4 vs. 83.1 +/- 16.4 vs. 82.2 +/- 19.4 cm/s, p < 0.05), and an increase of the median mitral valve insufficiency degree (0.64 +/- 0.65 vs. 1.03 +/- 0.76 vs. 1.11 +/- 0.73 degrees , p < 0.001). We could not detect a significant increase in diastolic dysfunction. Also right heart diameters and function did not change significantly. Most patients stayed in an asymptomatic stage of cardiac disease. CONCLUSION: The blockade of Her2/-neu receptors with trastuzumab in patients with breast cancer led to measurable alterations of left ventricular volume, left atrial volume, and systolic function as early as 3 months after start of treatment. PMID- 22249495 TI - Effects of limb immobilization on brain plasticity. AB - OBJECTIVE: Little is known about the effects of reduced sensory input and motor output in the human brain. Therefore, we conducted a longitudinal study to investigate whether limb immobilization after unilateral arm injury is reflected in structural plastic changes in gray matter (cortical thickness) and white matter (fractional anisotropy [FA]). METHODS: We examined 10 right-handed subjects with injury of the right upper extremity that required at least 14 days of limb immobilization. Subjects underwent 2 MRI examinations, the first within 48 hours postinjury and the second after an average time interval of 16 days of immobilization. Based on the MRI scans, we measured cortical thickness of sensorimotor regions and FA of the corticospinal tracts. RESULTS: After immobilization, we revealed a decrease in cortical thickness in the left primary motor and somatosensory area as well as a decrease in FA in the left corticospinal tract. In addition, the motor skill of the left (noninjured) hand improved and is related to increased cortical thickness and FA in the right motor cortex. CONCLUSIONS: The present study illustrates that cortical thickness of the sensorimotor cortex and FA of the corticospinal tract changed during right arm immobilization and that these changes are associated with skill transfer from the right to the left hand. Thus, immobilization induces rapid reorganization of the sensorimotor system. Given that limb immobilization is a standard intervention technique in constraint-induced therapy, therapists should be aware of both the positive and negative effects of this intervention. PMID- 22249496 TI - Periaqueductal gray: an interface for behavioral control. PMID- 22249494 TI - Residual sarcoplasmic reticulum Ca2+ concentration after Ca2+ release in skeletal myofibers from young adult and old mice. AB - Contrasting information suggests either almost complete depletion of sarcoplasmic reticulum (SR) Ca(2+) or significant residual Ca(2+) concentration after prolonged depolarization of the skeletal muscle fiber. The primary obstacle to resolving this controversy is the lack of genetically encoded Ca(2+) indicators targeted to the SR that exhibit low-Ca(2+) affinity, a fast biosensor: Ca(2+) off rate reaction, and can be expressed in myofibers from adult and older adult mammalian species. This work used the recently designed low-affinity Ca(2+) sensor (Kd = 1.66 mM in the myofiber) CatchER (calcium sensor for detecting high concentrations in the ER) targeted to the SR, to investigate whether prolonged skeletal muscle fiber depolarization significantly alters residual SR Ca(2+) with aging. We found CatchER a proper tool to investigate SR Ca(2+) depletion in young adult and older adult mice, consistently tracking SR luminal Ca(2+) release in response to brief and repetitive stimulation. We evoked SR Ca(2+) release in whole-cell voltage-clamped flexor digitorum brevis muscle fibers from young and old FVB mice and tested the maximal SR Ca(2+) release by directly activating the ryanodine receptor (RyR1) with 4-chloro-m-cresol in the same myofibers. Here, we report for the first time that the Ca(2+) remaining in the SR after prolonged depolarization (2 s) in myofibers from aging (~220 MUM) was larger than young (~132 MUM) mice. These experiments indicate that SR Ca(2+) is far from fully depleted under physiological conditions throughout life, and support the concept of excitation-contraction uncoupling in functional senescent myofibers. PMID- 22249497 TI - Neurologists in Iraq: five years later. PMID- 22249498 TI - Early stroke risk and Abcd2 score performance in tissue- vs time-defined tia: a multicenter study. PMID- 22249499 TI - Interictal scalp fast oscillations as a marker of the seizure onset zone. PMID- 22249500 TI - Psychogenic nonepileptic seizures in US veterans. PMID- 22249501 TI - Normal pressure hydrocephalus: measure twice, shunt once. PMID- 22249502 TI - Pearls & Oy-sters: cerebral HSV-2 vasculitis presenting as hemorrhagic stroke followed by multifocal ischemia. PMID- 22249503 TI - Pearls & Oy-sters: unusual manifestations of bilateral carotid artery dissection: deep monocular pains. PMID- 22249505 TI - Teaching NeuroImages: somatic muscle fasciculations detected by electrocardiography. PMID- 22249506 TI - Gas-phase reactions of aryl radicals with 2-butyne: experimental and theoretical investigation employing the N-methyl-pyridinium-4-yl radical cation. AB - Aromatic radicals form in a variety of reacting gas-phase systems, where their molecular weight growth reactions with unsaturated hydrocarbons are of considerable importance. We have investigated the ion-molecule reaction of the aromatic distonic N-methyl-pyridinium-4-yl (NMP) radical cation with 2-butyne (CH(3)C=CCH(3)) using ion trap mass spectrometry. Comparison is made to high level ab initio energy surfaces for the reaction of NMP and for the neutral phenyl radical system. The NMP radical cation reacts rapidly with 2-butyne at ambient temperature, due to the apparent absence of any barrier. The activated vinyl radical adduct predominantly dissociates via loss of a H atom, with lesser amounts of CH(3) loss. High-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry allows us to identify small quantities of the collisionally deactivated reaction adduct. Statistical reaction rate theory calculations (master equation/RRKM theory) on the NMP+2-butyne system support our experimental findings, and indicate a mechanism that predominantly involves an allylic resonance-stabilized radical formed via H atom shuttling between the aromatic ring and the C(4) side-chain, followed by cyclization and/or low-energy H atom beta-scission reactions. A similar mechanism is demonstrated for the neutral phenyl radical (Ph)+2-butyne reaction, forming products that include 3 methylindene. The collisionally deactivated reaction adduct is predicted to be quenched in the form of a resonance-stabilized methylphenylallyl radical. Experiments using a 2,5-dichloro substituted methyl-pyridiniumyl radical cation revealed that in this case CH(3) loss from the 2-butyne adduct is favoured over H atom loss, verifying the key role of ortho H atoms, and the shuttling mechanism, in the reactions of aromatic radicals with alkynes. As well as being useful phenyl radical analogues, pyridiniumyl radical cations may form in the ionosphere of Titan, where they could undergo rapid molecular weight growth reactions to yield polycyclic aromatic nitrogen hydrocarbons (PANHs). PMID- 22249508 TI - Treatment of hypertriglyceridemia with fibric acid derivatives: impact on lipid subfractions and translation into a reduction in cardiovascular events. AB - This review investigates how the treatment of hypertriglyceridemia with fibric acid derivatives impacts lipid concentrations, lipid particle size, and the rate of cardiovascular events: expressly, to decide whether the use of fibric acid derivatives is an effective treatment option in the reduction of cardiovascular endpoints for patients with specific lipid parameters at baseline. Fibric acid derivatives reduce fasting triglyceride (TG) values by 15% to 50% (depending on baseline level) and low-density lipoprotein cholesterol (LDL-C) by 8%, and raise high-density lipoprotein cholesterol (HDL-C) by 9%. In conjunction with a statin, the amount of TG lowering is approximately doubled with the addition of the fibrate. When measured, fibrates decrease the TG concentration of very low density lipoprotein cholesterol particles while increasing the TG content of LDL particles. The mean size of LDL particles increases and there is a substantial reduction in the number and proportion of small, dense LDL. In randomized trials in primary and secondary prevention populations, fibrates were associated with a significant reduction in nonfatal myocardial infarction in most studies. In the subgroup with elevated TG and/or depressed HDL-C at baseline, all trials have found statistically significant relative risk reductions of 27% to 65% in the primary cardiovascular endpoint of myocardial infarction and cardiovascular death. PMID- 22249509 TI - Clinical impact of renal dysfunction in heart failure. AB - Renal impairment in heart failure (HF) patients has been increasingly recognized as an independent risk factor for morbidity and mortality. In the most recent European and American guidelines for HF management, renal dysfunction was considered an index of poor prognosis independent of the presence of other traditionally investigated risk factors. Different mechanisms appear to be implicated in worsening renal function in patients with acute decompensated HF (ADHF) in contrast to chronic HF. In patients with acute ADHF, renal impairment has been attributed to renal hypoperfusion due to reduced cardiac output and decreased systemic blood pressure. In these patients, neurohormonal activation of the renin-angiotensin and sympathetic nervous systems plays a key role. In chronic and clinically stable HF, other mechanisms, including microvascular damage, oxidative stress, inflammation, and fibrosis, lead to a reduced number of functioning nephrons. Differentiating transient functional changes in renal filtration and acute renal tubular injury with loss of functioning nephrons is a critical step in understanding cardiorenal syndromes and selection of patients for novel therapeutic approaches. PMID- 22249510 TI - Galectin-3: a novel blood test for the evaluation and management of patients with heart failure. AB - Replacement of functional myocytes with crosslinked collagen as a result of tissue fibrosis is a final common pathway that is central to the progression of heart failure (HF), irrespective of etiology. In response to a variety of mechanical and neurohormonal stimuli, macrophages secrete galectin-3, which works as a paracrine and endocrine factor to stimulate additional macrophages, pericytes, myofibroblasts, and fibroblasts. The response to this signal is cellular proliferation and secretion of procollagen I. This protein is then irreversibly crosslinked to form collagen and result in cardiac fibrosis. With a commercially available assay, galectin-3 can now be measured in blood and has been found to aid in the prognosis of both systolic and nonsystolic HF. Measurement of galectin-3 before hospital discharge, on outpatient evaluation for suspected HF, and approximately twice per year for those with stable symptoms is supported by the evidence available at this time. Levels > 25.9 ng/mL, independent of symptoms, clinical findings, and other laboratory measures, predict a patient who is likely to have rapid progression of HF, resulting in hospitalization and death. In addition, a doubling in galectin-3 level over the course of 6 months, irrespective of baseline value, identifies a high-risk patient in whom additional care management efforts and advanced therapies could be warranted. PMID- 22249511 TI - Temporal variation of heart failure hospitalization: does it exist? AB - Congestive heart failure (CHF) is the end stage of many cardiac diseases, and one of the leading causes of mortality and morbidity around the world. Coronary heart disease and hypertension (either singly or together) are the main etiology for CHF. It has been reported that major acute cardiovascular events (myocardial infarction, sudden death, cardiac arrest, ischemic and hemorrhagic stroke, pulmonary embolism, rupture/dissection of aortic aneurysms) do not occur randomly through time, but exhibit a specific temporal periodicity characterized by seasonal (winter), weekly (Monday), and circadian (morning) patterns of onset. Thus, because the major causes of CHF present a temporal pattern, in the past several years some studies have investigated the temporal variation of CHF hospitalization and mortality, with results indicating the possibility of a preference for winter months, Mondays, and nighttime, respectively. PMID- 22249512 TI - Incidence of neoplastic disease in cardiac allograft recipients. AB - Incidence of neoplastic disease represents a serious complication after heart transplantation. In this review, the authors discuss the incidence, causes, and types of tumors in cardiac allograft recipients. Prevention and tumor monitoring for early treatment are highlighted. PMID- 22249513 TI - Stormy times: a change of season: embrace the opportunity and make a difference. PMID- 22249514 TI - Cardiology training in the United kingdom. PMID- 22249515 TI - Stenting techniques for patients with bifurcation coronary artery disease. AB - Atherosclerotic lesions at the bifurcation of coronary arteries are associated with higher rates of restenosis following stenting, and can be technically challenging when performing percutaneous coronary intervention (PCI). Many techniques have arisen for PCI of these lesions, often incorporating the use of multiple balloons and the placement of two or more stents. A technique commonly used for bifurcations is kissing balloon angioplasty, in which two balloons are inflated simultaneously to prevent the shifting of plaque into the side branch. Provisional side branch stenting is the technique of using a stent for the main branch, and stenting the side branch only if necessary. Multiple-stent techniques include T-stenting, crush technique, culotte, simultaneous kissing stents, V stenting, and Y-stenting; the goal of these techniques is to provide maximal apposition to the vessel wall with effective drug delivery in the case of drug eluting stents. Additionally, dedicated bifurcation stents also exist, with apertures that allow placement of additional stents. Debulking techniques such as atherectomy can be employed as stand-alone procedures or to debulk lesions prior to bifurcation stenting. Despite these many options for PCI of bifurcation lesions, there are currently inadequate data to indicate which of these techniques is superior, and many trials have found that complex stenting techniques provide no additional benefits when compared with provisional side branch stenting. Additional, well-designed randomized trials evaluating specific stenting techniques are necessary to determine the best practice for bifurcation lesions. PMID- 22249516 TI - Rapid detection of urushiol allergens of Toxicodendron genus using leaf spray mass spectrometry. AB - A new ambient ionization method--leaf-spray mass spectrometry--is used to detect allergenic urushiols directly from poison ivy (T. radicans) leaves with no sample preparation. These simple measurements show all the urushiols previously reported using liquid chromatography mass spectrometry methods. Tandem mass spectrometry analysis of the leaf spray ions confirms the identifications. Enhanced detection of some urushiols was achieved in the negative mode with the addition of chloride anions to the spray solvent. PMID- 22249517 TI - Bone, sweet bone--osteoporotic fractures in diabetes mellitus. AB - Diabetes mellitus adversely affects the skeleton and is associated with an increased risk of osteoporosis and fragility fractures. The mechanisms underlying low bone strength are not fully understood but could include impaired accrual of peak bone mass and diabetic complications, such as nephropathy. Type 1 diabetes mellitus (T1DM) affects the skeleton more severely than type 2 diabetes mellitus (T2DM), probably because of the lack of the bone anabolic actions of insulin and other pancreatic hormones. Bone mass can remain high in patients with T2DM, but it does not protect against fractures, as bone quality is impaired. The class of oral antidiabetic drugs known as glitazones can promote bone loss and osteoporotic fractures in postmenopausal women and, therefore, should be avoided if osteoporosis is diagnosed. A physically active, healthy lifestyle and prevention of diabetic complications, along with calcium and vitamin D repletion, represent the mainstay of therapy for osteoporosis in patients with T1DM or T2DM. Assessment of BMD and other risk factors as part of the diagnostic procedure can help design tailored treatment plans. All osteoporosis drugs seem to be effective in patients with diabetes mellitus. Increased awareness of osteoporosis is needed in view of the growing and aging population of patients with diabetes mellitus. PMID- 22249519 TI - Nonpharmacological interventions for the prevention of type 2 diabetes mellitus. AB - During the past decade, improved understanding of the pathophysiological mechanisms of diabetes development has resulted in advances in therapeutic concepts, but has also supported the potential for diabetes prevention through nonpharmacological means. At the beginning of the century, we experienced a shift in paradigm, as landmark studies have shown that diabetes mellitus is preventable with lifestyle intervention; moderate changes in diet and physical activity produce a substantial and sustained reduction in the incidence of type 2 diabetes mellitus (T2DM) for individuals with impaired glucose tolerance. This evidence must now be translated into clinical and public-health practice, but translational studies have varied in their ability to replicate the results of clinical trials. This variation reflects a number of challenging barriers for diabetes prevention in real-world clinical practice, which makes it necessary to focus on identifying efficient intervention methods and delivery mechanisms. Research is now focusing on these mechanisms, as well as on developing efficient screening and risk-identification strategies and realistic scenarios for public health policy to implement diabetes prevention programs. In this Review, we will discuss these mechanisms and will consider the implications of diabetes prevention for public-health strategy and policy. PMID- 22249518 TI - Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. AB - The discovery of fibroblast growth factor 23 (FGF-23) has expanded our understanding of phosphate and vitamin D homeostasis and provided new insights into the pathogenesis of hereditary hypophosphatemic and hyperphosphatemic disorders, as well as acquired disorders of phosphate metabolism, such as chronic kidney disease. FGF-23 is secreted by osteoblasts and osteocytes in bone and principally targets the kidney to regulate the reabsorption of phosphate, the production and catabolism of 1,25-dihydroxyvitamin D and the expression of alpha Klotho, an anti-ageing hormone. Secreted FGF-23 plays a central role in complex endocrine networks involving local bone-derived factors that regulate mineralization of extracellular matrix and systemic hormones involved in mineral metabolism. Inactivating mutations of PHEX, DMP1 and ENPP1, which cause hereditary hypophosphatemic disorders and primary defects in bone mineralization, stimulate FGF23 gene transcription in osteoblasts and osteocytes, at least in part, through canonical and intracrine FGF receptor pathways. These FGF-23 regulatory pathways may enable systemic phosphate and vitamin D homeostasis to be coordinated with bone mineralization. FGF-23 also functions as a counter regulatory hormone for 1,25-dihydroxyvitamin D in a bone-kidney endocrine loop. FGF-23, through regulation of additional genes in the kidney and extrarenal tissues, probably has broader physiological functions beyond regulation of mineral metabolism that account for the association between FGF-23 and increased mortality and morbidity in chronic kidney disease. PMID- 22249521 TI - Genetics: Genotype-phenotype correlations in patients with CPR deficiency. PMID- 22249520 TI - Sirtuins mediate mammalian metabolic responses to nutrient availability. AB - Metabolic diseases are an increasing threat in developed countries. Dysregulation of metabolic pathways, caused by imbalances in energy homeostasis, leads to obesity, diabetes and cardiovascular disease with devastating results for both individuals and societies. Sirtuins, a conserved family of NAD(+)-dependent deacetylase enzymes found in many species, regulate various metabolic pathways and have emerged as important sensors of energy status in mammals. The nuclear sirtuins, SIRT1, SIRT6 and SIRT7, regulate the activity of key transcription factors and cofactors of numerous metabolic pathways in almost all tissues by linking nutrient signals with the cellular responses to energy demands. The mitochondrial sirtuins, SIRT3, SIRT4 and SIRT5, regulate the activity of important mitochondrial enzymes and drive metabolic cycles in response to fasting and calorie restriction. Accumulating evidence indicates that sirtuins can be beneficial in the prevention of metabolic and age-related diseases and suggests that they can be pharmacologically activated to ameliorate such diseases. This Review describes the latest advances in the understanding of the function of sirtuins as regulators of mammalian metabolism and focuses on the role of these enzymes as mediators of nutrient availability. PMID- 22249522 TI - High expression of GCLC is associated with malignant melanoma of low oxidative phenotype and predicts a better prognosis. AB - Reactive oxygen species (ROS) are strongly implicated in melanoma development, and treatment with antioxidants has shown efficacy in suppressing malignant transition and progression. Here, we investigated the significance of the glutamate-L: -cysteine ligase catalytic subunit (GCLC) expression, a key regulator of glutathione synthesis, for malignant melanoma. A large set of melanoma cell lines (n = 36) was analyzed, and higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation. Moreover, treatment with the antioxidant N-acetylcysteine efficiently reduced the growth speed of several investigated malignant cells. In addition GCLC expression was significantly linked to a prominent set of cellular antioxidants, accounting for the observed lower basal levels of oxidative stress and higher antioxidative capacity. Key attributes defining the malignant phenotype of melanoma cells including survival, invasiveness, and switch from E cadherin to N-cadherin expression were more prominent in cells with lower GCLC expression. Our findings were further corroborated by observations in Rag2(-/ )gammac(-/-)mice, in which melanoma cells with lower GCLC expression depicted a dramatically stronger tumor growth. Furthermore, prognostic significance of GCLC expression was investigated in patients (n = 28) with advanced malignant melanoma. High tumor immunoreactivity for GCLC was a significant determinant for better 5-year overall survival. Conclusively, we show for the first time that GCLC may serve a dual role, as a surrogate marker for cellular redox state as well as malignant potential of melanoma cells. These promising results regarding its prognostic significance as well as its potential as a pharmacological target require further in-depth investigations. PMID- 22249523 TI - Effect of dosing interval duration of intermittent ibandronate treatment on the healing process of femoral osteotomy in a rat fracture model. AB - The effects of bisphosphonate treatment schedule on fracture healing have not previously been tested. We evaluated the effect of ibandronate dosing interval duration on healing following surgical "fracture" (osteotomy) using a rat femoral fracture model. Six-week-old rats (n = 160) underwent osteotomy and were then allocated into vehicle control (CNT) or an ibandronate treatment group: 5 MUg/kg daily (DAY, 5 days/week), 75 MUg/kg once every 3 weeks (I-3), 150 MUg/kg once every 6 weeks (I-6), resulting in the same total ibandronate dose over the study. Rats were killed after 6 or 18 weeks. At 18 weeks, all fracture lines had disappeared in the CNT and I-6 groups; approximately 10% of fracture lines remained in the DAY and I-3 groups. Ibandronate-treated groups showed large callus areas around the fractures, which shrank between 6 and 18 weeks after surgery; the extent of shrinkage decreased with shorter dosing interval. In histomorphometry, callus remodeling was suppressed by ibandronate; this became more apparent at shorter dose intervals. The structural properties of osteotomized femora were increased in the DAY group compared with CNT, but intrinsic material properties reduced inversely and became closer to those of CNT in response to increased dosing interval. Ibandronate induced formation of large calluses around osteotomies but delayed woven bone remodeling into lamellar bone and reduced intrinsic material properties in a rat fracture model. Extending the dosing interval of intermittent ibandronate treatment appeared to reduce the suppression of callus remodeling caused by ibandronate, which would have delayed healing after osteotomy. PMID- 22249524 TI - Decreased bone mineral density in rats rendered follicle-deplete by an ovotoxic chemical correlates with changes in follicle-stimulating hormone and inhibin A. AB - Bone loss during perimenopause, an estrogen-sufficient period, correlates with elevated serum follicle-stimulating hormone (FSH) and decreased inhibins A and B. Utilizing a recently described ovotoxin-induced animal model of perimenopause characterized by a prolonged estrogen-replete period of elevated FSH, we examined longitudinal changes in bone mineral density (BMD) and their association with FSH. Additionally, serum inhibin levels were assessed to determine whether elevated FSH occurred secondary to decreased ovarian inhibin production and, if so, whether inhibins also correlated with BMD. BMD of the distal femur was assessed using dual-energy X-ray absorptiometry (DXA) over 19 months in Sprague Dawley rats treated at 1 month with vehicle or 4-vinylcyclohexene diepoxide (VCD, 80 or 160 mg/kg daily). Serum FSH, inhibins A and B, and 17-beta estradiol (E(2)) were assayed and estrus cyclicity was assessed. VCD caused dose-dependent increases in FSH that exceeded values occurring with natural senescence, hastening the onset and prolonging the duration of persistent estrus, an acyclic but E(2)-replete period. VCD decreased serum inhibins A and B, which were inversely correlated with FSH (r(2) = 0.30 and 0.12, respectively). In VCD rats, significant decreases in BMD (5-13%) occurred during periods of increased FSH and decreased inhibins, while BMD was unchanged in controls. In skeletally mature rats, FSH (r(2) = 0.13) and inhibin A (r(2) = 0.15) correlated with BMD, while inhibin B and E(2) did not. Thus, for the first time, both the hormonal milieu of perimenopause and the association of dynamic perimenopausal changes in FSH and inhibin A with decreased BMD have been reproduced in an animal model. PMID- 22249525 TI - Bisphosphonate binding affinity affects drug distribution in both intracortical and trabecular bone of rabbits. AB - Differences in the binding affinities of bisphosphonates for bone mineral have been proposed to determine their localizations and duration of action within bone. The main objective of this study was to test the hypothesis that mineral binding affinity affects bisphosphonate distribution at the basic multicellular unit (BMU) level within both cortical and cancellous bone. To accomplish this objective, skeletally mature female rabbits (n = 8) were injected simultaneously with both low- and high-affinity bisphosphonate analogs bound to different fluorophores. Skeletal distribution was assessed in the rib, tibia, and vertebra using confocal microscopy. The staining intensity ratio between osteocytes contained within the cement line of newly formed rib osteons or within the reversal line of hemiosteons in vertebral trabeculae compared to osteocytes outside the cement/reversal line was greater for the high-affinity compared to the low-affinity compound. This indicates that the low-affinity compound distributes more equally across the cement/reversal line compared to a high affinity compound, which concentrates mostly near surfaces. These data, from an animal model that undergoes intracortical remodeling similar to humans, demonstrate that the affinity of bisphosphonates for the bone determines the reach of the drugs in both cortical and cancellous bone. PMID- 22249526 TI - Duodenal diverticulitis followed by enterolith-associated small bowel obstruction. PMID- 22249527 TI - Antiplatelet therapy and proton pump inhibition: clinician update. PMID- 22249528 TI - Antiarrhythmic drug therapy for atrial fibrillation. PMID- 22249529 TI - Very late mycotic pseudoaneurysm associated with drug-eluting stent fracture. PMID- 22249530 TI - Multimodality imaging of coronary-subclavian-vertebral steal syndrome. PMID- 22249531 TI - Myocardial deformation imaging: current status and future directions. PMID- 22249533 TI - Functional outcomes after chemoradiotherapy of laryngeal and pharyngeal cancers. AB - Organ preservation regimens that combine chemotherapy and radiotherapy (chemoradiotherapy) are increasingly used as the primary treatment of laryngeal and pharyngeal cancers. Meta-analytic data show a survival benefit with combined modality therapy, but the functional sequelae can be significant. Dysphagia is recognized as a common and often devastating late effect of chemoradiotherapy. This review examines functional outcomes after chemoradiotherapy for laryngeal and pharyngeal cancers, with a particular emphasis on dysphagia. Topics examined include the burden of dysphagia after chemoradiation, pathophysiology of dysphagia, baseline functioning, recommendations to improve long-term function, and voice outcomes. PMID- 22249534 TI - Abstract: the trailer of scientific communication. PMID- 22249535 TI - Early determinants of cardiovascular diseases in the life course: a paradigm shift to prevention. PMID- 22249536 TI - Clinic: the art of balancing disease and subject. PMID- 22249537 TI - Idiopathic spontaneous pneumoperitoneum. PMID- 22249538 TI - Retroperitoneal sarcoma-like malakoplakia. PMID- 22249539 TI - Gastroesophageal reflux disease: drug therapy. PMID- 22249541 TI - Factors associated with nosocomial pneumonia in hospitalized individuals. AB - OBJECTIVE: To identify factors associated with nosocomial pneumonia in individuals admitted to a public hospital in Feira de Santana, Bahia. METHODS: This case control study was carried out in 211 adult individuals (46 cases and 165 controls), of a mean age of 41 years, treated at clinical wards, surgical wards or the adult intensive care unit of Cleriston Andrade General Hospital in Feira de Santana. The cases comprised individuals who developed respiratory tract infections (nosocomial pneumonia) after hospital admission. The controls consisted of patients without nosocomial pneumonia. Information on socioeconomic status, medical history, lifestyle and oral hygiene habits was obtained through interviews. The medical records were checked to verify subjects' health status and the diagnosis of pneumonia. A clinical oral examination was performed by a trained dental surgeon. Odds ratio (OR) was estimated in the bivariate analysis as an association measurement, along with the respective 95% confidence interval through the Mantel-Haenszel method. RESULTS: The frequency of nosocomial pneumonia in the sample was 21.8%. The occurrence of hypertension was higher and hospital stay duration was longer in the cases than in controls (p <= 0.05). Lack of dental floss and mouthwash use were higher in the controls (p = 0.01). CONCLUSION: The findings indicate that arterial hypertension, length of hospital stay of five days and lack of dental floss and mouthwash use are factors likely associated with nosocomial pneumonia, suggesting that these factors should be targeted for effective prevention. PMID- 22249542 TI - Identification of malnutrition risk factors in hospitalized patients. AB - OBJECTIVE: To identify factors associated with the risk of malnutrition in hospitalized patients. METHODS: Cross-sectional study, performed in a general hospital located in Sao Paulo, in a convenience sample of 300 adult individuals, aged 18 to 64 years. A structured questionnaire was applied consisting of anthropometric, clinical and dietary data, and the patients were evaluated and dichotomized into malnourished and non-malnourished. A multiple logistic regression was performed to identify the factors associated with malnutrition. The variables were organized according to the values of odds ratio (OR), confidence interval (95% CI), regression coefficient (beta) and descriptive level of significance (p). RESULTS: The malnutrition occurred in 60.7% and the variables associated with malnutrition were: recent and involuntary weight loss, apparent bony structure, decreased appetite, diarrhea, inadequate energy intake and male sex. CONCLUSION: The factors associated with malnutrition can be identified at hospital admission and lead to a nutritional evaluation that will allow adequate intervention and nutritional therapy. PMID- 22249543 TI - Depression, emotional and social aspects in the abortion context: a comparison between two Brazilian capitals. AB - OBJECTIVE: To assess emotional and social aspects in the experience of abortion and the diagnosis of major depression, comparing women from two Brazilian cities (Sao Paulo--SP, Natal--RN). METHODS: A transversal study was carried out from January 2009 to May 2010, through semi-directed interviews with women undergoing an abortion (up to 22 weeks gestation) treated at university hospitals in Sao Paulo--SP (n = 166) and Natal--RN (n = 150). The Portuguese version of the Primary Care Evaluation of Mental Disorders (PRIME-MD) instrument was applied for the diagnosis of depression. RESULTS: There was no significant difference (p = 0.223) in the proportion of induced abortions when comparing the two capital cities: Natal (7.3%) and Sao Paulo (12.0%). The diagnosis of depression was high among women undergoing an abortion and was significantly higher in Natal than in Sao Paulo (50.7% vs. 32.5%, p < 0.01). Regarding emotional aspects, there was no difference in the occurrence of guilt feelings (Natal 27.7%; Sao Paulo 23.3%; p = 0.447). The partner's involvement was considered satisfactory by women in similar proportions in the two capitals (Natal 62.0%; Sao Paulo 59.0%, p = 0.576). No difference was found in the proportion of women who reported violence, related or not to the abortion (Natal 22.9%; Sao Paulo 16.6%; p = 0.378). CONCLUSION: Although there was no difference between the emotional and social aspects in the comparison between the two capitals, there was a high proportion of women with major depression, more frequent in the city of Natal than in Sao Paulo, which demonstrates the importance of psychosocial support in the women's healthcare system. PMID- 22249544 TI - Quantitative ultrasound and risk of fractures in elderly women. AB - OBJECTIVE: To verify the prevalence of women with risk of fractures estimated by ultrasonometry of the calcaneus (UOC) in a population of elderly women and its association with clinical risk factors. METHODS: Cross-sectional study of which sample was randomly selected and submitted to a structured questionnaire about risk factors for fractures. All women underwent UOC. RESULTS: We studied 168 Caucasian postmenopausal women, with a mean age of 69.56 +/- 6.27 years; 81% of these women had abnormal test results and 41% of the abnormal results were considered higher risk. Women with abnormal test results had lower weight, height and BMI, and had lower values of SOS, BUA, BQI and T-score. After adjustment, BMI remained significant for abnormal UOC (OR = 3.37, 95% CI: 1.19 9.56, p = 0.02), and history of previous fractures for UOC of the higher risk range (OR = 4.44, 95% CI: 1.16-16.96, p = 0.03). CONCLUSION: We observed a high prevalence of risk of fractures determined by the UOC. Our prevalence was higher than those in other Brazilian studies. There was an association between UOC and BMI and previous history of fractures. PMID- 22249545 TI - Risk of overweight and obesity in preschoolers attending private and philanthropic schools. AB - OBJECTIVE: To assess the risk prevalence of overweight and obesity in children enrolled in private and philanthropic preschools in the State of Sao Paulo. METHODS: Comparison of two cross sectional studies with children enrolled in private preschools (PPS) or philanthropic (PHP) of the Sao Paulo Metropolitan Region. Both surveys evaluated the children's environment. To determine the risk of overweight, excess weight and obesity, body mass index (BMI) values were transformed into z scores (according to the World Health Organization - 2006 and 2007). RESULTS: The risk prevalence of overweight (>= 1 BMIz < 2) in PPS was 21.9% and 24.6% in PHP, with PR = 1.12 (95% CI: 0.96-1.32), without statistical difference. Considering the children with overweight or obesity, (BMIz >= 2) the prevalence in PPS was 14.3% and in PHP was 9.0%, with PR = 1.54 (95% CI: 1.23 1.93), p = 0.0002. Overweight and obesity prevalence in males in PPS was 16.4% (n = 409) and in PHP, 11.1% (n = 829), PR = 1.48 (95% CI: 1.10-1.98) and in females it was 12.5% (n = 400) in the PPS and 6.6% (n = 698) in PHP, corresponding to PR = 1.90 (95% CI: 1.30-2.78), both significant differences. CONCLUSION: Both groups showed a similar and very high prevalence of weight excess. However, overweight and obesity showed a higher prevalence in children from private preschools. This indicates that even though a better socioeconomic level is still a risk factor for overweight and obesity in preschoolers, the same does not seem to occur when analyzing the risk of overweight. PMID- 22249546 TI - Influence of body composition on bone mass in children and adolescents. AB - OBJECTIVE: To evaluate the influence of body composition on bone mass in children and adolescents. METHODS: A cross-sectional study with 267 healthy students of both sexes (141 males and 126 females) aged 8 to 18 years. Weight, height, body mass index, lean mass, fat mass, fat mass index, body fat percentage, waist and hip circumferences, and waist-to-hip ratio were evaluated. Bone mass was assessed using ultrasound of hand phalanges (DBM Sonic BP IGEA, Carpi, Italy). RESULTS: Females showed greater bone mass in relation to males with advances in age and pubertal stage. In both sexes, the bone mass showed significant and positive correlations with age, weight, height, body mass index, lean mass, waist and hip circumferences; and negative correlations with waist-to-hip ratio. In females, there was also a positive correlation with fat mass, fat mass index, and body fat percentage. Age and lean mass were predictors for bone mass in males, and age, pubertal stage and fat mass index were predictors in females. CONCLUSION: The correlation between bone mass and body composition occurred in both sexes, with lean mass and fat mass index being the predictor of bone mass in males and females, respectively. PMID- 22249547 TI - Risk factors for alloimmunization in patients with sickle cell anemia. AB - OBJECTIVE: To determine erythrocyte phenotyping in blood donors and patients with sickle cell anemia (SS) treated at Hemocentro of Alagoas and describe the frequency and factors associated with erythrocyte alloimmunization. METHODS: Cross-sectional study with 102 SS patients and 100 blood donors. The following tests were performed: erythrocyte phenotyping, Direct and Indirect antiglobulin test, and detection of irregular antibodies by panel of phenotyped red blood cells. Data were compared by Mann-Whitney, chi-square or Fisher's exact tests. Factors associated with alloimmunization were studied by univariate and multiple logistic regression analysis. RESULTS: The most frequent antigens found in patients and blood donors were: c, e, M, s, JK(a). Significant differences were observed between the frequency of the phenotype of patients and donors in regard to antigens s, FY(a) and JK(b). Of 79 transfused patients, 10 presented positive Indirect Coombs. Thirteen alloantibodies were found, 7 of the Rh system, 2 of Kell and 4 were not identified. Factors associated with alloimmunization were the period of time between the last transfusion and the date of the test and more than 10 red blood cell transfusions. Patients who received more than 10 transfusions were 16.39 (95% CI: 2.23-120.59) times more likely to be alloimmunized than patients with fewer transfusions. CONCLUSION: The prevalence of alloimmunization in SS patients was 12.7%, with 70% of antibodies belonging to the Rh and Kell systems. This study shows the importance of performing erythrocyte phenotyping in blood donors and receptors to decrease the risk of alloimmunization. PMID- 22249548 TI - Obesity and cardiovascular risk factors in school children from Sorocaba, SP. AB - OBJECTIVE: To verify the prevalence of obesity, systemic arterial hypertension (SAH), waist circumference and acanthosis nigricans (AN) in school children from Sorocaba, in 2009 and associate them with risk factors. METHODS: A probabilistic sample study was carried out with 680 children (7-11 years) from 13 public schools from the city of Sorocaba, SP. A questionnaire containing questions on physical activity, time spent watching television, playing with video games and computers (TV/VG/PC), student and parental antecedents of arterial hypertension, renal or cardiac disease, and economic level was applied. On physical examination, weight, height, waist circumference (WC) and blood pressure (BP) were measured; presence of AN was observed. The prevalence of nutritional disorders, SAH, WC increase and presence of AN were calculated. To associate body mass index (BMI) > P85 and BP > P90 with the other variables, chi square or Fisher's exact test (significance p < 0.05) and crude and adjusted prevalence odds ratio (POR) were used. RESULTS: The prevalence of BMI > P85 was 22.1% [95% CI: 19.0-25.3%], of BP > P90 10.9% [95% CI: 8.6- 13.5%], increased WC 15.4% [95% CI: 12.9-17.9%] and AN 3.8% [95% CI: 2.6-5.6%]. Paternal antecedents were associated with weight excess in both analysis (POR: 1.76; 95% CI: 1.05-2.95; p = 0.02). High blood pressure was associated with female sex (POR: 1.90; 95% CI: 1.12-3.23; p = 0.01), more time spent with TV/VG/PC (POR: 1.82; 95% CI: 1.00 3.36; p = 0.03), AN (POR: 8.18; 95% CI: 3.37-19.80; p < 0.00), obesity (POR: 4.09; 95% CI: 2.41-6.94; p < 0.00) and WC (POR: 4.83; 95% CI: 2.77-8.41; p < 0.00). After the multivariate analysis, the female sex (adjusted POR = 2.15; 95% CI: 1.17-3.93) and obesity (adjusted POR = 9.51; 95% CI: 4.77-18.97) remained. CONCLUSION: The prevalence of weight excess, SAH, increased WC and AN in these school children was relevant. This fact justifies the use of these measurements. PMID- 22249549 TI - Anthropometric and body-mass composition suggests an intrinsic feature in Williams-Beuren syndrome. AB - OBJECTIVE: Although considered a well-known condition, there is only one study describing the body composition among individuals with Williams-Beuren syndrome. The aim was to characterize the nutritional status in Brazilian individuals with this condition. METHODS: Cross-sectional study was designed to evaluate clinical and nutritional data of 17 Brazilian patients. Z-scores for height, weight, body mass index, triceps and subscapular skinfold thickness, arm circumference, arm muscle area, arm fat area were calculated. Wilcoxon's test was used to investigate differences between the z-scores of the anthropometrical measures and zero. RESULTS: Four children were considered stunted and two severely malnourished. The z-score mean value for height was -1.14 +/- 1.00 (p-value = 0.004), for weight, -0.67 +/- 1.19 (p-value = 0.0443), for arm circumference, 0.94 +/- 1.14 (p-value = 0.0222), for triceps skinfold thickness, -0.59 +/- 0.63 (p-value = 0.0042) and for arm fat area -0.67 +/- 0.67 (p-value = 0.0061). CONCLUSION: Short stature seen in this series confirms a previous study describing this feature in a German population, which would suggest it as an intrinsic feature in Williams-Beuren syndrome. In addition, skinfold thickness measures have not been previously performed in this syndrome and detected abnormalities in fat stores in this sample. Considering this method a fast and low-cost way to evaluate body composition, similar studies could be performed in other populations in order to better characterize this issue. Morbidity related with this genetics condition and information for clinical investigation and clinical follow-up are also discussed. PMID- 22249550 TI - Chemotherapy beyond first-line in stage IV metastatic non-small cell lung cancer. AB - OBJECTIVE: Platinum-based doublet chemotherapy is considered the standard of care for advanced non-small cell lung cancer (NSCLC). However, prognosis after recurrent or progressive disease following first-line chemotherapy is usually poor. Maintenance chemotherapy, second line treatment and even third line chemotherapy are available for patients with advanced NSCLC. Unfortunately, few patients are candidates for chemotherapy beyond first line. The present study evaluated characteristics of patients with NSCLC and outcomes of the treatment of their metastatic disease, with emphasis on second and third-line chemotherapy. METHODS: This was a retrospective observational study of 2,673 patients with metastatic, stage IV, non-small cell lung cancer admitted for treatment in two Sao Paulo institutions. First-line chemotherapy was defined as the first chemotherapeutic approach administered to the patient. Second and third-line chemotherapy were defined as the systemic treatment administered after discontinuing first-line chemotherapy, either for intolerance or for progressive or recurrent disease. RESULTS: Most patients (57.9%) received first-line chemotherapy, and approximately 23.4% received second-line and 8% third-line regimens. Only 2.5% received fourth-line chemotherapy. Median overall survival (OS) was 8 months (95% CI: 8-9 months). At univariate analyses, gender (p < 0.05), histology, first-line chemotherapy, objective response to first-line chemotherapy and second-line chemotherapy (p < 0.01) were prognostic factors related to overall survival. At multivariate analysis, only performance status (p = 0.04), receiving any second-line chemotherapy (p < 0.01) and response to first line chemotherapy (p < 0.01) were independent predictors of overall survival. CONCLUSION: Second-line chemotherapy is a therapeutic strategy that should be considered for a selected group of patients. Performance status and response to first-line chemotherapy could be determinant characteristics to select patients who might be treated beyond first-line chemotherapy. PMID- 22249551 TI - Risk factors for hypertensive disorders of pregnancy in southern Brazil. AB - OBJECTIVE: The aim of the study was to identify the frequency of risk factors for hypertensive disorders in pregnancy in Southern Brazil. METHODS: The study included 161 patients with hypertensive disorders and 169 control subjects matched by age and ethnicity. The frequency of the risk factors was compared by Fisher's exact test, chi-square and Student's t test. A multivariate logistic regression analysis assessed the independent role of clinical, social and demographic factors which were associated with occurrence of the hypertensive disease in pregnancy in the univariate analysis. RESULTS: Patients enrolled in the study were predominantly Caucasian (73%) and the mean age was 29. In the multivariate analysis, the variables associated were: family history of preeclampsia (p = 0.001; OR = 3.88; 95% CI = 1.77-8.46), diabetes (p = 0.021; OR = 3.87; 95% CI = 1.22-12.27) and chronic hypertension (p = 0.002; OR = 7.05; 95% CI = 1.99-24.93). CONCLUSION: The risk factors associated with hypertensive disorders in pregnancy appear to be similar to those reported in other countries. The knowledge of the risk factors could be helpful in a prenatal care. PMID- 22249552 TI - Assistance model for patients with asthma in the primary care. AB - To create a program structured for the control and prevention towards asthma worsening, it is necessary to settle down actions of regionalization, planning and management. Currently, the Ministerial orders allow each municipality district to cope their needs with local initiatives, based on the search of the health indicators with University partnerships. Taking into account this context, it is feasible the implantation of an effective model through organized demand of attendance flow and physical structure, besides the withdrawal of medications and professional training. To describe the modus operandi situation currently in the Primary Health Care Units regarding these patients' reception, diagnosis, and follow-up, as well as the current situation according to the professional profile and sector. To introduce an assistance model for reception, of these patients in these primary care units. This is a bibliographical review based on the specialized literature such as scientific papers selected through the search on the SciELO and Bireme databases, from Medline and Lilacs data sources. A Committee was set up by members from the Health and Service , the Medical School, and scientific societies for discussion and planning. PMID- 22249553 TI - Endometrium in women with polycystic ovary syndrome during the window of implantation. AB - The human endometrium undergoes to a complex series of proliferative and secretory changes in each menstrual cycle and displays only a short period of receptivity, known as the "window of implantation", necessary for the implantation of the blastocyst in the uterus. The implantation process occurs in a sequential manner, leading to the establishment of pregnancy. Morphofunctional changes during this period may prevent or hinder the implantation. For this reason, the study of the endometrium at this stage is important for the improvement of therapies that may interfere with the mechanisms involved in maternal-embryonic interaction. Several gynecological disorders, including polycystic ovary syndrome (PCOS), are associated with decreased fertility and uterine receptivity. In spite of recent advances in assisted reproduction techniques, allowing the selection of high quality embryos, the implantation rate remains low and has not increased enough in recent decades. This article aims at reviewing the endometrial aspects of the "window of implantation" in women with polycystic ovary syndrome, focusing mainly on adhesion molecules. For that purpose, we analyzed 105 articles published in journals indexed in PubMed in the last 50 years (up to May 2011). In conclusion, the endometrial receptivity seems to be the major limiting factor for the establishment of pregnancy in a large number of gynecological diseases, including PCOS, and treatment to improve implantation rates is likely to be taken towards this direction. PMID- 22249554 TI - Provision of investigational drug after clinical research: review of literature, national and international guidelines. AB - The post-trial access to investigational drugs has been the object of discussion since the late 1980s at least, initially linked to trials carried out in acquired immunodeficiency syndrome and, particularly, in developing countries, where the concern with patient vulnerability is more important. National and international guidelines do mention the subject; however, the complexity of the issue is not easily addressed and usually requires additional and specific discussions. The decision on providing the investigational drug after the trial shall rest on at least two dimensions: efficacy and safety assessments, as the new drug is still on the experimental phase. Each clinical trial shall have its own assessment, taking into account the disease being studied, as well as the study population and their specific needs. Therefore, the nature of post-trial obligations cannot be considered the same in all situations and contexts; nevertheless, it should be assured that the relationship developed between investigators and patients during the study must be always terminated with respect and responsibility. PMID- 22249557 TI - Association between angiotensin-converting enzyme gene polymorphism and diabetic retinopathy in the Chinese population. AB - OBJECTIVE: The angiotensin-converting enzyme (ACE) gene has been implicated in the development of diabetic retinopathy (DR). However, the results have been conflicting. In this study, we performed a meta-analysis to assess the association of insertion/deletion (I/D) polymorphism in the ACE gene with DR in the Chinese population. METHODS: Published literature from PubMed, CNKI, CBM and Wanfang Data were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. RESULTS: Seventeen studies (1039 cases and 1185 controls) for I/D polymorphism in the ACE gene were identified. The results suggested that I/D polymorphism D allele might increase the risk of DR (DD vs. II: OR = 1.73, 95% CI 1.19-2.51; DD+ID vs. II: OR = 1.41, 95% CI 1.16-1.72; DD vs. ID+II: OR = 1.55, 95% CI 1.13-2.12). Subgroup analyses based on the type of DR showed that the effect size was statistically significant for proliferative DR (PDR) (DD vs. II: OR = 2.67, 95% CI 1.53-4.64; DD+ID vs. II: OR = 1.86, 95% CI 1.18-2.93; DD vs. ID+II: OR = 2.22, 95% CI 1.38-3.55), but not for background DR (BDR) (DD vs. II: OR = 1.38, 95% CI 0.85-2.25; DD+ID vs. II: OR = 1.40, 95% CI 0.98-2.02; DD vs. ID+II: OR = 1.15, 95% CI 0.74-1.79). CONCLUSION: The results indicated that I/D polymorphism in the ACE gene was associated with PDR, but not with BDR in the Chinese population. PMID- 22249558 TI - Effect of salinity on the biosynthesis of n-3 long-chain polyunsaturated fatty acids in silverside Chirostoma estor. AB - The genus Chirostoma (silversides) belongs to the family Atherinopsidae, which contains around 150 species, most of which are marine. However, Mexican silverside (Chirostoma estor) is one of the few representatives of freshwater atherinopsids and is only found in some lakes of the Mexican Central Plateau. However, studies have shown that C. estor has improved survival, growth, and development when cultured in water conditions with increased salinity. In addition, C. estor displays an unusual fatty acid composition for a freshwater fish with high docosahexaenoic acid (DHA)/ eicosapentaenoic acid (EPA) ratios. Freshwater and marine fish species display very different essential fatty acid metabolism and requirements, and so the present study investigated long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis to determine the capacity of C. estor for endogenous production of EPA and DHA, and the effect that salinity has on these pathways. Briefly, C. estor were maintained at three salinities (0, 5, and 15 ppt), and the metabolism of 14C-labeled 18:3n-3 was determined in isolated hepatocyte and enterocyte cells. The results showed that C. estor has the capacity for endogenous biosynthesis of LC-PUFA from 18-carbon fatty acid precursors, but that the pathway was essentially only active in saline conditions with virtually no activity in cells isolated from fish grown in freshwater. The activity of the LC-PUFA biosynthesis pathway was also higher in cells isolated from fish at 15 ppt compared with fish at 5 ppt. The activity was around fivefold higher in hepatocytes compared with enterocytes; although the majority of 18:3n-3 was converted to 18:4n-3 and 20:4n-3 in hepatocytes, the proportions of 18:3n-3 converted to EPA and DHA were higher in enterocytes. The data were consistent with the hypothesis that conversion of EPA to DHA could contribute, at least in part, to the generally high DHA/EPA ratios observed in the tissue lipids of C. estor. PMID- 22249559 TI - Primary IgG4-related lymphadenopathy with prominent granulomatous inflammation and reactivation of Epstein-Barr virus. AB - We report a unique case of primary IgG4-related lymphadenopathy showing prominent granulomatous inflammation and Epstein-Barr virus (EBV) reactivation. Involved lymph nodes showed an expanded interfollicular zone with prominent granulomatous inflammation, including a predominance of epithelioid macrophages and occasional Langhans multinucleated giant cells. Bundles of spindle cells were also observed. Intermingled with the granulomatous inflammation were numerous mature plasma cells, eosinophils, and neutrophils. The percentage of IgG4+/IgG+ plasma cells was markedly elevated (70%), along with raised serum IgG4 levels. The plasma cells did not show immunoglobulin light-chain restriction. EBV-positive lymphocytes were scattered throughout the paracortical areas. Corticosteroid treatment was very effective. IgG4-related lymphadenopathy has a broad histological spectrum and might be misdiagnosed due to other conditions which morphologically closely resemble it. The correct diagnosis is important in view of the remarkable response to steroid therapy. PMID- 22249560 TI - Rab25 is overexpressed in Mullerian serous carcinoma compared to malignant mesothelioma. AB - Rab25, an epithelial-specific member of the Rab family of small GTPases, was previously shown to be overexpressed in ovarian/primary peritoneal serous carcinoma compared to malignant mesothelioma using gene expression arrays. The objective of this study was to validate this finding at the mRNA and protein level. Quantitative PCR analysis of 112 Mullerian serous carcinomas (84 effusions, 28 primary ovarian carcinomas) and 22 malignant mesotheliomas (19 effusions, 3 solid specimens) showed significantly higher RAB25 mRNA expression in the former tumor (p < 0.001). Immunohistochemical analysis of Rab25 protein expression in 245 effusions showed significantly higher expression of this protein in Mullerian serous carcinoma compared to malignant mesothelioma (189/209 vs. 12/36 positive tumors, respectively; p < 0.001). Immunostaining of 101 patient-matched solid Mullerian carcinoma specimens (34 primary carcinomas, 67 metastases) showed expression levels comparable to effusions (94/101 positive specimens; p > 0.05). Rab25 mRNA and protein expression levels in Mullerian carcinoma effusions did not correlate with overall or progression-free survival. Our data confirm that Rab25 effectively differentiates Mullerian carcinomas from malignant mesothelioma at the mRNA and protein level, suggesting a role in the diagnostic work-up of serosal cancers. PMID- 22249561 TI - Total antioxidant capacity and total oxidant status of synovial fluids in patients with temporomandibular joint pain and dysfunction. AB - OBJECTIVES: The objective of this study was to investigate whether a relationship exists between total antioxidant capacity (TAC) and total oxidant status (TOS) of synovial fluids (SFs) of temporomandibular joint (TMJ) pain patients with pain and dysfunction. MATERIALS AND METHODS: Forty-two patients with TMJ pain were included in this study. TAC and TOS values of SFs were measured with a novel colorimetric method. Independent t test and correlations were used to analyze the data. RESULTS: TAC of SFs in patients with TMJ pain and limited mouth opening (LMO; n = 21) were significantly lower (P = 0.03) than patients without LMO (n = 21). TOS of SF was negatively correlated with duration of the disease. There was no correlation between TAC, TOS, and VAS scores of the patients as well as age and maximum mouth opening values. CONCLUSIONS: Antioxidant response to oxidative changes (TAC and TOS) in SF decreased as the stage of dysfunction increased. CLINICAL RELEVANCE: Local administration of antioxidant agents might be considered in management of TMJ pain and dysfunction to prevent possible increased oxidative stress. PMID- 22249562 TI - Gingival fluid cytokine expression and subgingival bacterial counts during pregnancy and postpartum: a case series. AB - OBJECTIVES: The aim of this study was to assess gingival fluid (GCF) cytokine messenger RNA (mRNA) levels, subgingival bacteria, and clinical periodontal conditions during a normal pregnancy to postpartum. MATERIALS AND METHODS: Subgingival bacterial samples were analyzed with the checkerboard DNA-DNA hybridization method. GCF samples were assessed with real-time PCR including five proinflammatory cytokines and secretory leukocyte protease inhibitor. RESULTS: Nineteen pregnant women with a mean age of 32 years (S.D. +/- 4 years, range 26 42) participated in the study. Full-mouth bleeding scores (BOP) decreased from an average of 41.2% (S.D. +/- 18.6%) at the 12th week of pregnancy to 26.6% (S.D. +/ 14.4%) at the 4-6 weeks postpartum (p < 0.001). Between week 12 and 4-6 weeks postpartum, the mean probing pocket depth changed from 2.4 mm (S.D. +/- 0.4) to 2.3 mm (S.D. +/- 0.3) (p = 0.34). Higher counts of Eubacterium saburreum, Parvimonas micra, Selenomonas noxia, and Staphylococcus aureus were found at week 12 of pregnancy than at the 4-6 weeks postpartum examinations (p < 0.001). During and after pregnancy, statistically significant correlations between BOP scores and bacterial counts were observed. BOP scores and GCF levels of selected cytokines were not related to each other and no differences in GCF levels of the cytokines were observed between samples from the 12th week of pregnancy to 4-6 weeks postpartum. Decreasing postpartum counts of Porphyromonas endodontalis and Pseudomonas aeruginosa were associated with decreasing levels of Il-8 and Il 1beta. CONCLUSIONS: BOP decreased after pregnancy without any active periodontal therapy. Associations between bacterial counts and cytokine levels varied greatly in pregnant women with gingivitis and a normal pregnancy outcome. Postpartum associations between GCF cytokines and bacterial counts were more consistent. CLINICAL RELEVANCE: Combined assessments of gingival fluid cytokines and subgingival bacteria may provide important information on host response. PMID- 22249563 TI - Self-assembly of dendritic-linear block copolymers with fixed molecular weight and block ratio. AB - Block copolymers built on a dendritic block having fixed molecular weight but different number of peripheral PEG chains were synthesised. At a fixed block ratio, these block copolymers exhibited topological transition of cylindrical micelles depending on the number of PEG chains. PMID- 22249564 TI - Illusion of stroke: intravascular lymphomatosis. AB - We describe an unusual case of cerebral intravascular lymphomatosis wherein the patient presented with multiple embolic strokes predominantly in the posterior circulation. Using this case as an illustration, we review the literature of this malignancy, which consists of extranodal diffuse large B-cell lymphoma. For patients with recurrent stroke-like events without cardiac risk factors, the accurate diagnosis requires a high index of suspicion by the neurologist and a brain biopsy specimen demonstrating lymphoma cells within the lumen of cerebral blood vessels. Intravascular lymphomatosis can be treated with systemic chemotherapies, but the response rate and pattern of relapse remain unknown. PMID- 22249565 TI - Neurology of sleep. PMID- 22249566 TI - A rare cause of headache. PMID- 22249567 TI - Progressive personality and language changes in a 62-year-old woman. AB - A 62-year-old woman with no known psychiatric illness had a 1.5-year history of progressive personality and language changes, leading to a loss of functional independence. Laboratory results revealed elevated autoimmune antibodies. She did not improve on high-dose steroid therapy and continued to deteriorate to her death, 2.5 years after symptom onset. PMID- 22249571 TI - The neurology of decreased activity: abulia. AB - Delirium is sometimes defined as acute onset of either overactivity or underactivity. This article reviews the nature and clinico-anatomical locations of lesions in patients with reduced activity. The term abulia is used to describe global underactivity. Abulia is customarily explained by interruptions in frontal subcortical circuitry. These interruptions can occur with lesions in the frontal lobes, caudate nuclei, midbrain, and thalamus. The article describes the anatomy of frontal and subcortical circuits and reviews in detail individual cases and series of patients with reduced initiative and activity who have had localized central nervous system lesions. PMID- 22249573 TI - Orofacial pain following an invasive dental procedure. AB - Like headache, the etiology of orofacial pain is often an enigma. Orofacial pain resulting from invasive dental procedure may cause a patient to present to a neurologist for diagnosis and treatment. The cases presented here were personally seen by the first author, a consulting neurologist; they illustrate the diversity in clinical presentation and the differences between a musculoskeletal and neuropathic origin of pain. Treatment is touched upon, but is neither exhaustive nor evidence based. PMID- 22249572 TI - An update on the diagnosis and management of dementing conditions. AB - Worsening memory is a common complaint in the elderly and predictably causes affected individuals and their families to wonder whether the underlying cause is Alzheimer disease, the most common form of dementia. Alzheimer disease is a devastating illness that unavoidably leads to a complete loss of independence and, as a result, substantial emotional, physical, and financial distress for patients and their families. The causes and severity of memory impairment in the elderly are diverse, however, so any given case might not necessarily be secondary to a neurodegenerative disorder such as Alzheimer disease. Consequently, it is critical to rule out potentially reversible causes of dementia and to initiate treatment while cognitive and functional deficits are still mild and more likely to respond to treatment. Furthermore, identifying the etiology and defining a suitable treatment plan early in the course of dementia allows patients to be more actively involved in the management of their disease and is more likely to improve quality of life for both patients and caregivers. This review presents the etiology of dementia in the elderly, describes the diagnostic process, and discusses current therapeutic strategies, including pharmacological agents, nonpharmacological interventions, safety assessments, legal issues, and caregiver needs. PMID- 22249574 TI - Narcolepsy: clinical approach to etiology, diagnosis, and treatment. AB - Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness and manifestations of disrupted rapid eye movement sleep stage. The pathologic hallmark is loss of hypocretin neurons in the hypothalamus likely triggered by environmental factors in a susceptible individual. Patients with narcolepsy, in addition to excessive daytime sleepiness, can present with cataplexy, sleep paralysis, sleep fragmentation, and hypnagogic/hypnopompic hallucinations. Approximately 60% to 90% of patients with narcolepsy have cataplexy, characterized by sudden loss of muscle tone. Only 15% of patients manifest all of these symptoms together. Narcolepsy can be misdiagnosed as a psychiatric disorder or even epilepsy. An appropriate clinical history, polysomnogram, Multiple Sleep Latency Test, and, at times, cerebrospinal fluid hypocretin levels are necessary for diagnosis. The treatment of narcolepsy is aimed toward the different symptoms that the patient manifests. Excessive daytime sleepiness is treated with amphetamine-like or non-amphetamine-like stimulants. Cataplexy is treated with sodium oxybate, tricyclic antidepressants, or selective serotonin and norepinephrine reuptake inhibitors. Sleep paralysis, hallucinations, and fragmented sleep may be treated with benzodiazepine hypnotics or sodium oxybate. Patients with narcolepsy should avoid sleep deprivation, sleep at regular hours, and, if possible, schedule routine napping. PMID- 22249575 TI - Robust extraction of P300 using constrained ICA for BCI applications. AB - P300 is a positive event-related potential used by P300-brain computer interfaces (BCIs) as a means of communication with external devices. One of the main requirements of any P300-based BCI is accuracy and time efficiency for P300 extraction and detection. Among many attempted techniques, independent component analysis (ICA) is currently the most popular P300 extraction technique. However, since ICA extracts multiple independent components (ICs), its use requires careful selection of ICs containing P300 responses, which limits the number of channels available for computational efficiency. Here, we propose a novel procedure for P300 extraction and detection using constrained independent component analysis (cICA) through which we can directly extract only P300 relevant ICs. We tested our procedure on two standard datasets collected from healthy and disabled subjects. We tested our procedure on these datasets and compared their respective performances with a conventional ICA-based procedure. Our results demonstrate that the cICA-based method was more reliable and less computationally expensive, and was able to achieve 97 and 91.6% accuracy in P300 detection from healthy and disabled subjects, respectively. In recognizing target characters and images, our approach achieved 95 and 90.25% success in healthy and disabled individuals, whereas use of ICA only achieved 83 and 72.25%, respectively. In terms of information transfer rate, our results indicate that the ICA-based procedure optimally performs with a limited number of channels (typically three), but with a higher number of available channels (>3), its performance deteriorates and the cICA-based one performs better. PMID- 22249576 TI - Surgery versus radiation therapy for stage IB2 cervical carcinoma: a population based analysis. AB - OBJECTIVE: The objective of the study was to examine outcomes in stage IB2 cervical cancer patients undergoing primary surgery versus radiation. METHODS: Stage IB2 cervical cancer patients were identified from the Surveillance, Epidemiology and End Results Public-Use Database from 2000 to 2006. Patients were divided into those receiving radiation (radiation first) or surgery (surgery first) as initial treatment. Overall survival was calculated by Kaplan-Meier method and compared using log-rank test. RESULTS: In total, 770 patients were identified with stage IB2 cervical cancer; 369 received radiation, and 401 received surgery initially. The radiation-first group had larger mean tumor size than the surgery-first group (6.0 vs 5.5 cm, respectively; P < 0.0001). The overall survival was longer in the surgery-first group compared with the radiation-first group (72.0 vs 61.4 months, respectively; P < 0.0001). CONCLUSIONS: Patients undergoing surgery as initial treatment for stage IB2 cervical cancer appear to have improved outcomes in the current era of chemoradiation; however, given the lack of chemotherapy information, a randomized trial will be necessary to see if these results remain valid. PMID- 22249577 TI - Concurrent endometrial intraepithelial carcinoma (EIC) and serous ovarian cancer: can EIC be seen as the precursor lesion? AB - OBJECTIVE: The pathogenesis of serous ovarian carcinoma (SOC) is still unknown. Recently, endometrial intraepithelial carcinoma (EIC) was proposed to be the precursor lesion of SOC. This study examines the model of EIC as precursor for SOC. METHODS: Cases of SOC with a noninvasive or superficially invasive serous lesion, a hyperplastic lesion with/without atypia, or EIC in the endometrium were selected for inclusion in this study. Tissue sections from both ovaries, the fallopian tubes, and the uterus were extensively reviewed by an expert gynecopathologist. For both EIC and SOC, immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor; TP53 mutation analysis; and in situ ploidy analysis were performed. RESULTS: Nine cases of SOC with concurrent EIC in the endometrium were identified. Immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor revealed almost identical expression patterns and similar intensities in each pair of EIC and coincident SOC. Identical TP53 mutations were found in SOC and coinciding EIC in 33% of the cases, suggesting a clonal origin. DNA ploidy analysis, as a marker for neoplastic progression, demonstrated an increased number of aneuploid nuclei in SOC compared to their corresponding EIC (P = 0.039). In addition, the mean amount of DNA per nucleus in SOC was higher (ie, more aneuploid) compared to EIC (P = 0.039). CONCLUSION: This study provides a first indication of EIC as possible precursor lesion for SOC. This finding could have major clinical implications for future ovarian cancer management and underscores EIC as a possible target for early SOC detection and prevention. PMID- 22249578 TI - Psychosocial exposures at work and mental health: potential utility of a job exposure matrix. AB - OBJECTIVE: To examine the associations between psychosocial exposures at work and depressive symptoms by using two independent French national databases. METHODS: A job-exposure matrix of psychosocial work exposures was constructed from data collected by the national medical monitoring of occupational risks survey in 2003. Depressive symptoms came from the 2002 to 2003 decennial health survey. Data were linked by age, occupational group, and economic activity. RESULTS: The crude and adjusted results showed small but significant and systematic associations between job strain and depressive symptoms among men. These associations were much weaker for psychological demands and decision latitude. No statistical associations were observed among women. CONCLUSION: The results suggest that, among men, using independent data on exposure and health, there is a robust association between job strain and depressive symptoms. They contribute to the debate about the causal nature of associations between psychosocial exposures at work and mental health. PMID- 22249580 TI - Mode specific photodissociation of CS2(+) via the A2Pi(u) state: a time-sliced velocity map imaging study. AB - The vibrationally mediated photodissociation of CS(2)(+) cations via the A(2)Pi(u)(nu(1),nu(2),0) state has been studied by means of the velocity map ion imaging technique. The measurements were made with a double resonance strategy. The CS(2)(+) cations were prepared by a (3 + 1) resonance enhanced multiphoton ionization method. The photo-fragment excitation spectrum of S(+) was recorded by scanning the photolysis laser via the A(2)Pi(u)(nu(1),nu(2),0) state. By fixing the photolysis laser wavelength at the specific vibrational state, the (1 + 1) photodissociation images of S(+) photofragments from numerous vibrationally mediated states have been accumulated. The translational energy release spectra derived from the resulting images imply that the co-fragments, CS radicals, are both vibrationally and rotationally excited. The one-photon photodissociation without the vibrational state selection has also been performed. Comparing the vibrationally mediated photodissociation with one-photon photodissociation observations, clear evidence of vibrational state control of the photodissociation process is observed. PMID- 22249579 TI - Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: synthesis, characterization and in vitro antimalarial activity. AB - Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(eta(6)-cym)(L(1))Cl]Cl (1, cym = p-cymene, L(1) = N-(2-((pyridin-2 yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(eta(6)-cym)(L(2))Cl]Cl (2, L(2) = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4 amine) and [Ru(eta(6)-cym)(L(3))Cl] (3, L(3) = N-(2-((2 hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1-3 and ligands L(1), L(2) and L(3), as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4 amine (L(4)), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L(2) also shows good activity against both the chloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR(50)) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR(50) properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L(3) to ruthenium, to give a metal complex (3) with promising antimalarial activity. PMID- 22249581 TI - Letter to the editor: regarding "The utility and limitations of FRAX: a US perspective". PMID- 22249583 TI - [Training in Spain of medical specialists in Preventive Medicine and Public Health]. PMID- 22249584 TI - [Iatrogenesis and quaternary prevention on mental health]. AB - Quaternary prevention avoids or mitigates the consequences of unnecessary or excessive activity of the health system. Iatrogenia produced by care systems activity is a serious public health problem and in mental health is poorly understood. The damage that can be inflicted to patients covers the entire episode of care, from prevention to treatment through the diagnostic process. We review the damage caused by preventive activities as the approach of mourning or debriefing, pharmacological and psychotherapeutic treatments, the iatrogenia produced in diagnosis and the deleterious effects of being under care in the psychiatric system especially related to stigma. Become aware of the seriousness of iatrogenic effects of our "well done" interventions allows foregrounding the importance of quaternary prevention and the need to work with the shared decision making model always considering alternatives and measures to ensure safety and rights of patients. PMID- 22249582 TI - Vitamin D in the new millennium. AB - The incidence of vitamin D deficiency is rising worldwide, yet in the vast majority of patients, the condition remains undiagnosed and untreated. Current evidence overwhelmingly indicates that supplemental doses greater than 800 IU/day have beneficial effects on the musculoskeletal system, improving skeletal homeostasis, thus leading to fewer falls and fractures. Evidence is also accumulating on the beneficial effects of vitamin D on extraskeletal systems, such as improving immune health, autoimmune disorders, cancer, neuromodulation, diabetes, and metabolic syndrome. The cause-effect relationship of vitamin D deficiency with increasing incidences of nonskeletal disorders is being investigated. Published reports support the definition of sufficiency, serum levels of 25-hydroxyvitamin D [25(OH)D] greater than 30 ng/mL (75 nmol/L). To achieve this, most people need vitamin D supplementation ranging from 600 to 2000 IU/day; consumption up to of 5000 international units (IU) per day of vitamin D is reported as safe. Although light-skinned individuals need 1000 IU/day of vitamin D, elderly and dark-skinned individuals are likely to need approximately 2000 IU/day to maintain serum 25(OH)D levels greater than 30 ng/mL. Other vulnerable patients, such as the obese, those who have undergone bariatric surgery, and those with gastrointestinal malabsorption syndromes, may require higher doses of vitamin D to maintain normal serum levels and be healthy. PMID- 22249585 TI - [Diversification and strengthening of services for older people in Spain and Sweden]. AB - Information on public services for older people is often limited to institutional care and Home Help/Home Care, be it for individuals in surveys, statistics for a specific country or for international comparisons. Yet, these two major services are in many countries supplemented - or substituted - by other, minor services. The latter include services such as transportation services, meals-on-wheels, alarm systems and day care. This diversification is the outcome of a rationing of services to achieve a more rational allocation of resources and attempts to keep down costs. In this presentation we use various data sources to provide information on all these types of support for Spain and Sweden. When all of them are considered, service coverage is much higher than by basic services alone, indicating further consolidation of services. Data suggests a high targeting in Sweden, but fragmented delivery in Spain, where - we suspect-users get what is available, with little differentiation between needs. With higher service rates, as in Sweden, there is greater overlap between family care and public services; with lower coverage rates, as in Spain, family care and public services are more often substituted for each other. It is suggested that a range of services, major and minor, may suit the varying needs of older people better - and more efficiently-than the choice between nothing, Home Help or institutional care, but that minor services may also be used as an inexpensive - and sometimes inferior substitute for full support. PMID- 22249586 TI - [Satisfaction of needs of disabled people 60 and over according to care provider. Spain, 2008]. AB - BACKGROUND: In spite of its importance for policy making, there have been few studies examining the satisfaction of care needs by the different care providers. The aims of this paper are: (1) to estimate the prevalence of dissatisfaction of care needs among people older than 59 years receiving care; and (2) to identify what care provider (family care, private care -paid care- or public care) has a higher probability of satisfying the needs of this population. METHODS: This study is based on a sample of 3718 non-institutionalized people older than 59 years from the Survey on Disability, Personal Autonomy and Dependency Situations 2008. The distribution of unmet care needs among different groups of elderly people was cross-tabulated, and a regression logistic model was used to identify factors related to dissatisfaction of care needs. RESULTS: 1,039 (29%) people older than 59 years had dissatisfied care needs. Compared to those receiving only family care, people receiving only public care were more likely to have dissatisfied needs (OR=1.932 sig.=0,001), and people receiving only paid care were less likely to have dissatisfied needs (OR=0.673 sig.=0.015). CONCLUSIONS: People receiving only paid care had a higher probability of having their needs satisfied than any other care combination. Those receiving only public care had a lower probability of having their needs satisfied than people receiving family care or paid care. PMID- 22249588 TI - [Clinical and managerial autonomy. Perception of the coordinators of the health centers in Mallorca, Spain]. AB - BACKGROUND: The self-management has been linked with increased efficiency and job satisfaction. Before any changes aimed at a more autonomous management is important to know the position of professionals and managers. objective: To assess the importance attached by the coordinators of the health centers (HC) to the clinical and managerial autonomy, knowing their decision making capacity and their expectations about the feasibility of implementing a project of self management. METHODS: DESIGN: cross-sectional study, application questionnaire. LOCATION: Primary Care, 2009. PARTICIPANTS: All the coordinators of the HC of Mallorca (N = 47). INTERVENTIONS AND MEASUREMENTS: 27 questions that explore the coordinator's opinion about the importance of the components of the self management, its ability to present intervention, the propensity / aversion to risk, leadership, and the feasibility of a self-management. RESULTS: response rate: 42/47 (89,4%). 42 (100%) attaches the highest importance to the management of human resources, 41 (97,6%) to demand management and 40 (95,2%) to the management of waiting lists. 15 (35,7%) would take a financial risk, 14 (33,3%) were considered trained and 18 (42,9%) were willing to lead a process of self management. 14 (33,3%) thought that the professionals in your team would not be interested in a process of self-management and 29 (69%) believed that others could develop HC of Mallorca. CONCLUSIONS: The respondents were coordinators have a limited ability to decide on the components of the self-management, being risk averse and make a little leadership ability and willingness to self-management projects. PMID- 22249587 TI - [Influence of chronic health problems in dimensions of EQ-5D: study of institutionalized and non-institutionalized elderly]. AB - BACKGROUND: Chronic medical conditions represent risk factors for health related quality of life (HRQOL). The aim of this study is to analyze the influence of self-reported chronic health conditions in HRQOL, measured through the EQ-5D dimensions, in non-institutionalized and institutionalized older adults. METHODS: Data were obtained from two studies of quality of life in population aged 60 years or over, in Spain, with a sample of 1,106 community-dwelling adults and 234 residents of care facilities. To analyse the influence of the most prevalent chronic health conditions on HRQOL multiple logistic regression models were adjusted using as dependent variable each EQ-5D dimension, controlling for socio demographic variables. RESULTS: The chronic health conditions that most influenced the HRQOL of both groups were depression (OR range in the different EQ 5D dimensions: 1.97-6.48), followed by arthrosis/arthritis (OR: 2.81-6.00), sleep problems (OR: 2.81-4.61), diabetes (OR: 1.68-3.44) and hypertension (OR: 1.42 2.45). These problems affected differentially the EQ-5D dimensions and the two groups considered. Pain/discomfort and mobility were the EQ-5D dimensions where more difficulties were reported. CONCLUSIONS: The results of this work indicate that the debilitating effect of chronic health conditions on the HRQOL is different for institutionalized and non-institutionalized older adults. They also highlight the importance of promoting healthy ageing to attenuate the negative impact of chronic health conditions on HRQOL in old age. PMID- 22249589 TI - [The reporting of observational studies: analysis using the STROBE statement]. AB - BACKGROUND: Deficiencies detected in biomedical studies publication different Guidelines to improve. The objective of the study is to assess the communication of observational studies of Cardiovascular and Metabolism therapeutic area (CVM) published in 6 Spanish journals in 2009 using the STROBE statement. METHODS: Cross-sectional analysis of articles related to CVM therapeutic area, published during 2009 in 6 Spanish journals applying the 34 items of the STROBE statement. Descriptive analysis of the results for qualitative variables was performed using a frequency analysis. Quantitative variables were analyzed by sample estimates and dispersion. A comparative analysis of journals was performed using ANOVA with a statistical significance of p<0.05. RESULTS: Throughout 2009, 74 CVM observational studies were published in the evaluated journals. The most frequent design were cohorts 45 (60.8%) and cross-sectional 28 (37.8%). The study main objective was on pathology 55 (74.3%), followed by drug and non-pharmacological interventions 15 (20.3%) and diagnosis 4 (5.4%). The mean of complied items was 20 on 34 (DE+/-3.7), with a maximum of 24 (DE+/-2) in Gaceta Sanitaria and a minimum of 19 (DE+/-2.8) in Hipertension. CONCLUSIONS: Evaluated papers comply with slightly more than a half items (58%) of the STROBE recommendations. The Methods and Results sections showed more deficiencies. PMID- 22249590 TI - [Evaluating colorectal cancer screening strategies (immunological test vs biochemical test) in Catalonia, Spain 2008-2010]. AB - BACKGROUND: The aim of this study was to evaluate the screening strategy (quantitative immunological test vs biochemical test) in a population-based screening program for colorectal cancer (CRC) in Catalonia. METHODS: The fourth round of a screening program for CRC with a fecal occult blood test was implemented in Hospitalet de Llobregat during 2008-2010. A biochemical test was offered to 50,227 individuals and a quantitative immunological test was offered to 12,707 individuals. We analysed differences according to the screening strategy in the following variables: acceptability of the target population (participation, dropouts, and adherence to colonoscopy), diagnostic accuracy (positive predictive value and detection rates), results (size and location of lesions, staging of CRC) and resources (number of colonoscopies needed and time interval between the positive test and colonoscopy). RESULTS: Participation was higher among individuals who used the immunological test (OR: 1.35; CI95%:1.27 1.42). Detection rates for adenomas and cancer were also higher for the immunological test, hightlighting the detection rate for high-risk adenomas (26.70/00 vs. 3.00/00). The positive predictive value for high-risk adenomas was 45.0% and 46.9% in the immunological test and guaiac test, respectively. The number of colonoscopies needed to detect cancer with the immunological test was almost two-fold than those needed with the guaiac test (13.6 vs 7.4). CONCLUSIONS: The immunological test is a good screening strategy particularly sensitive for detecting high-risk adenomas. However, it is paramount to have enough resources to assure the quality of the CRC screening due to the large number of colonoscopies that would be required. PMID- 22249591 TI - [Determination of isothermal areas and selection of representative weather stations in Aragon as a basis for estimating the impact of climate change on the possible relationship between mortality and temperature]. AB - BACKGROUND: In extensive and diversified regions, such as Aragon, it is believed the need to divide them into areas in terms of the available atmospheric variables with a view to select a representative weather station. The objective of this study was to determine the existence of isothermal regions and select representative stations for Aragon in order to carry out further study on the correlation between variables of temperature and daily mortality. METHODS: Daily data on maximum and minimum temperature for the period between January 1987 and December 2006 was selected. In order to determine the isothermal areas a cluster analysis and a discriminate factor analysis were carried out along with a data pretreatment of filled gaps and detection of inhomogeneities in the climatic series. We analyzed data from 93 stations (44 in Huesca, 15 in Teruel and 34 in Zaragoza). RESULTS: The results of the analysis for the regionalization of Aragon lead us to conclude that a unique factor explains the variance of each series; at high temperatures one factor explains 93.43% of the variance and the station with the highest correlation factor is Monflorite-Huesca (correlation = 0.984). At low temperatures one factor explains 90.88% of the variance, with Monegros-Pallaruelo being the station that presents the greatest correlation factor (correlation = 0.976). CONCLUSIONS: It was felt that Aragon was a unique isothermal region with one unique representative station of the temperature variability, Zaragoza Airport with a correlation of 0.980 in maximum temperatures and 0.974 minimum. PMID- 22249592 TI - Novel speech signal processing algorithms for high-accuracy classification of Parkinson's disease. AB - There has been considerable recent research into the connection between Parkinson's disease (PD) and speech impairment. Recently, a wide range of speech signal processing algorithms (dysphonia measures) aiming to predict PD symptom severity using speech signals have been introduced. In this paper, we test how accurately these novel algorithms can be used to discriminate PD subjects from healthy controls. In total, we compute 132 dysphonia measures from sustained vowels. Then, we select four parsimonious subsets of these dysphonia measures using four feature selection algorithms, and map these feature subsets to a binary classification response using two statistical classifiers: random forests and support vector machines. We use an existing database consisting of 263 samples from 43 subjects, and demonstrate that these new dysphonia measures can outperform state-of-the-art results, reaching almost 99% overall classification accuracy using only ten dysphonia features. We find that some of the recently proposed dysphonia measures complement existing algorithms in maximizing the ability of the classifiers to discriminate healthy controls from PD subjects. We see these results as an important step toward noninvasive diagnostic decision support in PD. PMID- 22249593 TI - Three-dimensional statistical model for gingival contour reconstruction. AB - Optimal gingival contours around restored teeth and implants are of critical importance for restorative success and esthetics. This paper describes a novel computer-aided methodology for building a 3-D statistical model of gingival contours from a 3-D scan dental dataset and reconstructing missing gingival contours in partially edentulous patients. The gingival boundaries were first obtained from the 3-D dental model through a discrete curvature analysis and shortest path searching algorithm. Based on the gingival shape differential characteristics, the boundaries were demarcated to construct the gingival contour of each individual tooth. Through B-spline curve approximation to each gingival contour, the control points of the B-spline curves are used as the shape vector for training the model. Statistical analysis results demonstrate that the method can give a simple but compact model that effectively capture the most important variations in arch width and shape as well as gingival morphology and position. Within this statistical model, the morphologically plausible missing contours can be inferred based on a nonlinear optimization fitting from the global similarity transformation, the model shape deformation and a Mahalanobis prior. The reconstruction performance is evaluated through large simulated experimental data and a real patient case, which demonstrates the effectiveness of this approach. PMID- 22249594 TI - Deep tissue photoacoustic imaging using a miniaturized 2-D capacitive micromachined ultrasonic transducer array. AB - In this paper, we demonstrate 3-D photoacoustic imaging (PAI) of light absorbing objects embedded as deep as 5 cm inside strong optically scattering phantoms using a miniaturized (4 mm * 4 mm * 500 MUm), 2-D capacitive micromachined ultrasonic transducer (CMUT) array of 16 * 16 elements with a center frequency of 5.5 MHz. Two-dimensional tomographic images and 3-D volumetric images of the objects placed at different depths are presented. In addition, we studied the sensitivity of CMUT-based PAI to the concentration of indocyanine green dye at 5 cm depth inside the phantom. Under optimized experimental conditions, the objects at 5 cm depth can be imaged with SNR of about 35 dB and a spatial resolution of approximately 500 MUm. Results demonstrate that CMUTs with integrated front-end amplifier circuits are an attractive choice for achieving relatively high depth sensitivity for PAI. PMID- 22249595 TI - Improved surface Laplacian estimates of cortical potential using realistic models of head geometry. AB - Surface Laplacian of scalp EEG can be used to estimate the potential distribution on the cortical surface as an alternative to invasive approaches. However, the accuracy of surface Laplacian estimation depends critically on the geometric shape of the head model. This paper presents a new method for computing the surface Laplacian of scalp potential directly on realistic scalp surfaces in the form of a triangular mesh reconstructed from MRI scans. Unlike previous methods, this algorithm does not resort to any surface fitting proxy and can improve the surface Laplacian estimation of cortical potential patterns by as much as 34% on realistically shaped head models. Simulations and experimental data are presented to demonstrate the advantage of the proposed method over the conventional spherical approximation and the utility of a more accurate surface Laplacian method for estimating cortical potentials from scalp electrodes. PMID- 22249596 TI - Anisotropic processing of laser speckle images improves spatiotemporal resolution. AB - Laser speckle contrast imaging (LSCI) is a full field optical imaging technique, capable of imaging blood flow without the introduction of any exogenous dyes. Spatial and temporal resolution in LSCI images depend on how pixels are chosen from the raw image stack for contrast processing. However, all processing schemes are based on isotropic treatment of the spatial neighborhood about each pixel, restricting further improvement in spatiotemporal resolution and image quality. We present a novel spatiotemporal processing scheme for LSCI where the spatial neighborhood is anisotropic, that is, restricted along a specific direction that matches direction of blood flow. The technique allows for a significant increase in temporal resolution, from conventionally used 40 or 80 frames to just three frames; while simultaneously achieving 23% and 47% higher signal-to-noise ratios over concurrent spatiotemporal schemes, when imaging rapid and slow functional changes in blood flow, respectively. We present the concept, justification, and performance evaluation of the novel scheme and demonstrate its suitability for imaging rapid changes in blood flow. Anisotropic LSCI was able to monitor the heart rate associated fluctuations in intravascular blood flow and showed them to be as high as 28% of the mean. PMID- 22249597 TI - Genome-wide ChIP-seq mapping and analysis reveal butyrate-induced acetylation of H3K9 and H3K27 correlated with transcription activity in bovine cells. AB - Butyrate-induced histone acetylation plays an important role in the regulation of gene expression. However, the regulation mechanisms of histone modification remain largely unclear. To comprehensively analyze histone modification induced by butyrate, we utilized chromatin immunoprecipitation (ChIP) technology combined with next-generation sequencing technology (ChIP-seq) to analyze histone modification (acetylation) induced by butyrate and to map the epigenomic landscape of normal histone H3 and acetylated histone H3K9 and H3K27 on a large scale. To determine the location of histone H3, acetyl-H3K9, and acetyl-H3K27 binding sites within the bovine genome, we analyzed the H3-, acetyl-H3K9-, and acetyl-H3K27-enriched binding regions in the proximal promoter within 5 kb upstream, or at the 5' untranslated region (UTR) from the transcriptional start site (TSS), exon, intron, and intergenic regions (defined as regions 25 kb upstream or 10 kb downstream from the TSS). Our analysis indicated that the distribution of histone H3, acetyl-H3K9, and acetyl-H3K27 correlated with transcription activity induced by butyrate. Using the GADEM algorithm, several motifs were generated for each of the ChIP-seq datasets. A de novo search for H3, acetyl-H3K9, and acetyl-H3K27 binding motifs indicated that histone modification (acetylation) at various locations changes the histone H3 binding preferences. Our results reveal that butyrate-induced acetylation in H3K9 and H3K27 changes the sequence-based binding preference of histone H3 and underlies the potential mechanisms of gene expression regulation induced by butyrate. PMID- 22249598 TI - CT and MRI appearances and radiologic staging of pediatric renal cell carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC) is an uncommon but noteworthy primary pediatric renal malignancy. There is a paucity of published data regarding the CT/MRI appearances and accuracy of pretreatment radiologic staging of this form of cancer in children. OBJECTIVE: To review the various CT/MRI appearances of pediatric RCC and assess the accuracy of pretreatment radiologic staging using these imaging modalities. MATERIALS AND METHODS: Institutional Departments of Pathology and Radiology records were searched from 1995 through 2010 for children (younger than 18 years of age) with RCC. Available pretreatment contrast-enhanced abdominopelvic CT and MRI examinations were reviewed by two radiologists. Pertinent imaging findings were documented by consensus, and correlation was made between radiologic and surgicopathological TNM staging. RESULTS: Pretreatment imaging studies from 10 RCCs in nine children (four girls and five boys; mean age 12.9 years) were reviewed. The mean size of the primary tumor was 6.2 cm (range, 1.5-12.6 cm). Ninety percent of RCCs demonstrated heterogeneous postcontrast enhancement. Fifty percent of masses had associated hemorrhage, while 40% contained internal calcification. Regarding TNM staging, N staging was correct for 10 of 10 tumors, while M staging was correct for 10 of 10 tumors. Imaging correctly staged only 4 of 10 tumors with respect to T stage. Radiologic and surgicopathological overall staging were concordant for 8 of 10 tumors. CONCLUSION: Pediatric RCCs typically present as large, heterogeneous masses, and they commonly hemorrhage and contain internal calcification. Radiologic and surgicopathological overall TNM staging are frequently concordant, although radiologic T staging is often incorrect. PMID- 22249599 TI - MRI at 12 +/- 2 months' corrected age without sedation. PMID- 22249600 TI - Neonatal ischemic brain injury: what every radiologist needs to know. AB - We present a pictorial review of neonatal ischemic brain injury and look at its pathophysiology, imaging features and differential diagnoses from a radiologist's perspective. The concept of perinatal stroke is defined and its distinction from hypoxic-ischemic injury is emphasized. A brief review of recent imaging advances is included and a diagnostic approach to neonatal ischemic brain injury is suggested. PMID- 22249602 TI - [Status epilepticus]. AB - Status epilepticus (SE) is a medical emergency. For diagnostic purposes EEG is mandatory when motor phenomena are absent or when a single seizure evolves into SE with impaired consciousness. The EEG may show focal or generalized status patterns, which must be distinguished from encephalopathies. Initially benzodiazepines are recommended; lorazepam is the drug of choice. When the SE persists, phenytoin, valproate, levetiracetam, lacosamide, and phenobarbital are administered. The choice depends on the underlying comorbidities. In this phase, only phenytoin is licensed. A generalized tonic-clonic status which is refractory is then treated with anesthetics including midazolam, disoprivan, or thiopental. The goal is to achieve burst suppression in the EEG and coadministration of antiepileptic drugs. PMID- 22249601 TI - Contrast-enhanced sonography of malignant pediatric abdominal and pelvic solid tumors: preliminary safety and feasibility data. AB - BACKGROUND: Little information exists regarding pediatric contrast-enhanced US. OBJECTIVE: To assess the safety and feasibility of contrast-enhanced US of pediatric abdominal and pelvic tumors. MATERIALS AND METHODS: This prospective study included eight boys and five girls (mean age, 10.8 years) with abdominal or pelvic tumors. Cohorts of three subjects underwent US with perflutren contrast agent at escalating dose levels. Neurological and funduscopic examination, electrocardiography and continuous pulse oximetry were performed before and after contrast administration. Three radiologists independently scored six imaging parameters on pre- and postcontrast sonography. Inter-reviewer agreement was measured by the Kappa statistic. RESULTS: No neurological, retinal, electrocardiographical or pulse oximetry changes were attributable to the contrast agent. Two subjects reported minor, transient symptoms. Postcontrast US parameter scores improved slightly in 8 of 12 subjects. Postcontrast ultrasound inter-reviewer agreement improved slightly for detection of tumor margins (precontrast = 0.20, postcontrast = 0.26), local tumor invasion (precontrast = 0.01, postcontrast = 0.10) and adenopathy (precontrast = 0.35, postcontrast = 0.44). CONCLUSIONS: Although our sample size is small, perflutren contrast agents appear to be safe and well tolerated in children. Contrast-enhanced sonography of pediatric abdominal and pelvic tumors is feasible, but larger studies are needed to define their safety and efficacy in children. PMID- 22249603 TI - RAPD analysis with the primer L15996 of Brazilian clinical and environmental Cryptococcus neoformans isolates. AB - Different methods have been used to perform the molecular characterization of Cryptococcus neoformans. Among them, RAPD analysis is able to separate isolates of the same species and genotypes. This study aimed to evaluate clinical and environmental C. neoformans isolates from Minas Gerais, Brazil by RAPD and correlate the genetic profiles with the ones obtained by URA5-RFLP, virulence factors and antifungal susceptibility patterns. Forty-five environmental (31 from areas surrounding hospital and 14 from captive bird droppings from pet-shops) and 29 clinical C. neoformans isolates were evaluated. Antifungal susceptibility tests (Clinical and Laboratory Standards Institute), URA5-RFLP analysis and the assessment of virulence factors were performed according to their original descriptions. RAPD profiles were obtained using the L15996 primer (5' CTCCACCATTAGCACCCAAAGC-3'). RAPD analysis generated two to 20 bands for all studied isolates. The isolates presented similarities ranging from 10.8 to 100.0%. Considering a minimum identity score of 50%, four clusters were formed. Cluster I contained 10 pet-shops bird dropping isolates, cluster II contained 22 clinical isolates most of them recovered from cerebrospinal fluid, cluster III contained 14 isolates from hospital surroundings and cluster IV contained 12 environmental isolates most from hospital surroundings. Fourteen isolates were not grouped. The RAPD profiles were clustered according to their source and URA5 RFLP pattern. No correlation between virulence factors or antifungal susceptibility profile with the obtained RAPD profiles was observed. PMID- 22249604 TI - Synthetic peptides mimic gp75 from Paracoccidioides brasiliensis in the diagnosis of paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is a systemic granulomatous disease, endemic in Latin America, caused by the thermal dimorphic fungus Paracoccidioides brasiliensis. Although some fungal antigens have already been characterized and used for serological diagnosis, cross-reactions have been frequently observed. Thus, the examination of fungal forms in clinical specimens or isolation of P. brasiliensis by culture is still the most frequent method for the diagnosis of this mycosis. In this study, a random peptide phage display library was used to select mimotopes of P. brasiliensis, which were employed as antigens in an indirect enzyme-linked immunosorbent assay. The protective monoclonal antibody against experimental PCM (anti-gp75) was used as molecular target to screen a phage display library. That approach led to a synthetic peptide named P2, which was synthesized and tested against PCM patients' sera to check whether it was recognized. There was significant recognition of P2 by sera of untreated PCM patients when compared with normal human sera. Sera from treated PCM group, patients with other mycosis or co-infected with HIV had much lower recognition of P2 than untreated patient group. The test showed a sensitivity of 100 and 94.59% of specificity in relation to human sera control. These data indicate a potential use of P2 as diagnostic tool in PCM. Its application for serological diagnosis of PCM may contribute to the development and standardization of simpler, faster and highly reproducible immunodiagnostic tests at low cost. PMID- 22249608 TI - Synthetic biology: Simplifying design. PMID- 22249610 TI - Familial risks in understanding type 1 diabetes genetics. PMID- 22249615 TI - Gene expression: a simple model for ensuring signalling specificity. PMID- 22249617 TI - Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma. AB - Overexpression of high mobility group AT-hook 1 (HMGA1) is common in human cancers. Little is known about the mechanisms underlying its deregulation and downstream targets, and information about its clinical and biological significance in medulloblastoma (MB) is lacking. Here, we demonstrated frequent genomic gain at 6p21.33-6p21.31 with copy number increase leading to overexpression of HMGA1 in MB. The overexpression correlated with a high proliferation index and poor prognosis. Moreover, we found that hsa-miR-124a targeted 3'UTR of HMGA1 and negatively modulated the expression in MB cells, indicating that loss/downregulation of hsa-miR-124a reported in our previous study could contribute to the overexpression. Regarding the biological significance of HMGA1, siRNA knockdown and ectopic expression studies revealed the crucial roles of HMGA1 in controlling MB cell growth and migration/invasion through modulation of apoptosis and formation of filopodia and stress fibers, respectively. Furthermore, we identified cdc25A as a target of HMGA1 and showed that physical interaction between HMGA1 and the cdc25A promoter is required for transcriptional upregulation. In clinical samples, HMGA1 and cdc25A were concordantly overexpressed. Functionally, cdc25A is involved in the HMGA1 mediated control of MB cell growth. Finally, netropsin, which competes with HMGA1 in DNA binding, reduced the expression of cdc25A by suppression of its promoter activity and inhibited in vitro and in vivo intracranial MB cell growth. In conclusion, our results delineate the mechanisms underlying the deregulation and reveal the functional significance of HMGA1 in controlling MB cell growth and migration/invasion. Importantly, the results highlight the therapeutic potential of targeting HMGA1 in MB patients. PMID- 22249618 TI - Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial. AB - Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy. PMID- 22249619 TI - Saccular intracranial aneurysm: pathology and mechanisms. AB - Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture. PMID- 22249620 TI - The "go or grow" potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress. AB - Glioblastoma (GBM), the most common malignant brain tumor, is among the most lethal neoplasms, with a median survival of approximately 1 year. Prognosis is poor since GBMs possess a strong migratory and highly invasive potential, making complete surgical resection impossible. Reduced expression of carboxypeptidase E (CPE), a neuropeptide-processing enzyme, in a cell death-resistant glioma cell line and lower CPE expression levels in the cohort of GBM samples of The Cancer Genome Atlas compared to normal brain control specimens prompted us to analyze the function of CPE as a putative tumor suppressor gene. In our samples, CPE was also reduced in GBM compared to normal brain with the strongest loss in cells surrounding hypoxic tumor areas as well as in most glioma cell lines and primary glioma cells. In our cohort of glioma patients, loss of CPE predominantly occurred in glioblastomas and was associated with worse prognosis. In glioma cells, CPE overexpression was significantly reduced, whereas knockdown or inhibition enhanced glioma cell migration and invasion. The decreased migratory potential following CPE overexpression was paralleled by altered cellular morphology, promoting a transition to focal adhesions and associated stress fibers. In contrast to the decreased migration, high CPE levels were associated with higher proliferative rates. As microenvironmental regulation cues, we identified CPE as being downregulated upon hypoxia or glucose deprivation. Our findings indicate an oxygen- and nutrition-dependent anti-migratory, but pro proliferative role of CPE in gliomas with prognostic impact for patient survival, thereby contributing to the understanding of the "go or grow" hypothesis in gliomas. PMID- 22249622 TI - Qualities of residency applicants: comparison of otolaryngology program criteria with applicant expectations. AB - OBJECTIVES: To evaluate the criteria used by otolaryngology programs in ranking residency candidates and to compare residency candidate ranking criteria among otolaryngology programs and applicant expectations. DESIGN: Cross-sectional, anonymous survey administered during the 2009 and 2010 match cycles. SETTING: Otolaryngology residency programs. PARTICIPANTS: Otolaryngology residency program applicants (PAs) and otolaryngology program directors (PDs). MAIN OUTCOME MEASURES: The PDs were asked to rank the importance of 10 criteria in choosing a residency candidate on a 20-point scale (with 1 indicating utmost importance; 20, not important at all). The PAs were asked to express their expectations of how candidates should be ranked using those same criteria. RESULTS: The interview and personal knowledge of the applicant (mean rank, 3.63) were the most important criteria to PDs, whereas the interview and letters of recommendation (mean rank, 3.65) were the most important criteria among PAs. Likelihood to rank program highly and ethnicity/sex were the least valued by PDs and PAs. CONCLUSIONS: Although PDs and PAs agree on the least important criteria for ranking otolaryngology residency candidates, they disagree on the most important criteria. This information provides insight into how programs select residency candidates and how this compares with applicant expectations. Furthermore, this information will assist applicants in understanding how they might be evaluated by programs. Improved understanding of the match process may increase the likelihood of having a good fit between otolaryngology programs and matched applicants. PMID- 22249623 TI - Therapeutic sialendoscopy for the management of radioiodine sialadenitis. AB - OBJECTIVE: To describe our experience with therapeutic sialendoscopy for radioiodine (iodine 131 [(131)I]) sialadenitis. DESIGN: Retrospective medical chart review. SETTING: Academic tertiary referral center. PATIENTS: The study included 11 patients who underwent therapeutic sialendoscopy for the treatment of (131)I sialadenitis after failing medical management. INTERVENTIONS: Therapeutic sialendoscopy with dilation and irrigation of the ductal system was performed in all patients. MAIN OUTCOME MEASURES: Patient-reported frequency and severity of symptoms. RESULTS: Our series included 9 women and 2 men (mean age, 51 years; age range, 35-65 years). A total of 23 parotid glands and 5 submandibular glands were treated. Sialendoscopy was possible in all patients, except one in whom the Stensen duct could not be cannulated. Typical endoscopic findings included pale ductal mucosa, thick mucous plugs, ductal debris, and stenosis of the duct. Most patients (91%) reported improvement of symptoms after a single procedure. Complete resolution of symptoms, with sustained benefit, was reported by 6 patients (54%) at a mean follow-up of 18 months. Partial improvement of symptoms, with some persistent intermittent episodes of pain or swelling, was reported by 4 patients (36%). One patient reported no subjective symptomatic improvement after 2 procedures and subsequently underwent a parotidectomy. CONCLUSIONS: Sialendoscopy is useful for the improvement of symptoms due to radioiodine induced sialadenitis in patients who are refractory to conservative medical therapy. Therapeutic sialendoscopy appears to provide effective and sustained symptom improvement in most patients in our experience. PMID- 22249624 TI - Impact of incision and drainage of infected thyroglossal duct cyst on recurrence after Sistrunk procedure. AB - OBJECTIVE: To determine whether incision and drainage of infected thyroglossal duct cysts (TGDCs) is associated with increased risk of recurrence after Sistrunk procedure when compared with antibiotic treatment alone. DESIGN: Retrospective case review. SETTING: Tertiary referral practice. PATIENTS: Patients treated for thyroglossal duct remnants in a tertiary care pediatric center from January 1, 2002, through December 31, 2008. Study subjects were identified using the diagnosis code for TGDC or the procedure code for excision of thyroglossal duct cyst or sinus. MAIN OUTCOME MEASURES: The presence of infection, treatment of infected TGDCs, and relationship between infection, treatment of infection, and recurrence. RESULTS: We identified 120 patients from 2002 through 2008 who met the search criteria. The mean age at the time of presentation was 5.1 years; at the time of surgery, 5.4 years. More than half the patients (58.2%) were male, and the most common presentation was an asymptomatic midline neck mass. Forty nine of our patients (40.8%) had a history of infection and 6 of these (12%) required incision and drainage. The overall recurrence rate was 10.8%. Ten of the patients with preoperative infection (20%) had a recurrence compared with 3 of the 71 patients (4%) without preoperative infection (P = .002). Of all patients with recurrences, only 1 had undergone incision and drainage. CONCLUSIONS: This case series suggests that preoperative infection is associated with an increased recurrence rate. Incision and drainage of an infected TGDC may not increase the risk of postoperative recurrence. The results of this case series may assist in preoperative counseling and management of infected TGDC prior to definitive surgery. PMID- 22249625 TI - Non-cancer-related deaths from suicide, cardiovascular disease, and pneumonia in patients with oral cavity and oropharyngeal squamous carcinoma. AB - OBJECTIVE: To study non-cancer-related mortality rates over time and examine the possible causes for several major deaths in patients with oral cavity and oropharyngeal (OC/OP) cancer. DESIGN: Retrospective cohort analysis using the Surveillance, Epidemiology, and End Results (SEER) cancer registry data of the National Cancer Institute. MAIN OUTCOME MEASURE: Cause-specific mortality rates during the first year after diagnosis of OC/OP cancer were calculated for 4 cohorts (1980-1984, 1990-1994, 2000-2003, and 2004-2007). The percentage changes over time were calculated. Standardized mortality ratios (SMRs) for suicide, cardiovascular disease, and pneumonia were calculated and compared with patient demographic and clinical characteristics. RESULTS: We analyzed data for 32,487 patients in 4 cohorts. From 1980-1984 to 2004-2007, mortality from suicide increased by 406.2% (P = .01), cardiovascular disease-related and pneumonia related mortality decreased by 45.9% (P < .001) and 42.9% (P = .009), respectively, and rates of other non-cancer-related deaths did not change. Compared with the general population, patients diagnosed as having OC/OP cancer were at a significantly higher risk of mortality from suicide (SMR, 7.8; 95% CI, 4.6-12.4; P < .001), cardiovascular disease (SMR, 2.4; 95% CI, 2.1-2.7; P < .001), and pneumonia (SMR, 8.9; 95% CI, 6.8-11.5; P < .001) during the first year after cancer diagnosis. Risk factors for increased mortality included age of 55 to 64 years, marital status (including never married, divorced, or separated), advanced tumor stage (including regional and distant disease), treatment with radiotherapy alone, and pharyngeal tumor location. CONCLUSIONS: Suicide rates have significantly increased in patients with OC/OP cancer since 1980 to 1984. Although cardiovascular disease-and pneumonia-related deaths have significantly decreased over time, they remain higher than the general US population. Increased knowledge of risk factors associated with non-cancer-related mortality in OC/OP cancer may lead to early intervention and enhanced overall survival. PMID- 22249626 TI - Efficacy and safety of central compartment neck dissection for recurrent thyroid carcinoma. AB - OBJECTIVE: To explore the safety and efficacy of central compartment neck dissection (CCND) in the treatment of well-differentiated thyroid carcinoma (WDTC) recurrences in the central compartment of the neck. DESIGN: Retrospective medical chart review. SETTING: Tertiary-care academic hospital. PATIENTS: Eighty two consecutively treated patients with recurrent WDTC, with a median follow-up of 28 months. MAIN OUTCOME MEASURES: Postoperative complications, disease control posttreatment, and normalization of serum thyroglobulin (Tg) level. RESULTS: Eighty-two patients underwent 86 central compartment procedures. Only CCND was performed in 36 patients (42%), while a lateral neck dissection was also required in the remainder. Postoperative hypoparathyroidism was temporary in 17 patients (20%) and permanent in 6 patients (7%). Postoperative intact serum parathyroid hormone level was greater than 15.0 pg/mL (to convert to nanograms per liter, multiply by 1.0) in 81% of patients, accurately predicting eucalcemia postoperatively. Unilateral recurrent laryngeal nerve injury was transient in 3 patients (2% of nerves at risk) and permanent in 3 patients (2%). Seventeen patients (21%) experienced subsequent recurrences after their CCND-2 patients (2%) had recurrence in the central neck, 8 (9%) in the lateral neck, 2 (2%) in the central and lateral neck, and 7 (8%) at distant sites. Twenty-seven patients underwent a CCND alone and were deemed appropriate for efficacy analysis. The Tg level was normalized in 15 patients (56%) in the group overall. Normalization occurred in 10 of the 20 patients (50%) who received sodium iodide I 131 ablation and in 5 of the 7 patients (71%) who did not. CONCLUSION: Central compartment neck dissection is a safe and efficacious procedure for the management of central neck recurrences in WDTC. PMID- 22249627 TI - Radial forearm free flap donor site morbidity: ulnar-based transposition flap vs split-thickness skin graft. AB - OBJECTIVES: To evaluate morbidity associated with the radial forearm free flap donor site and to compare functional and aesthetic outcomes of ulnar-based transposition flap (UBTF) vs split-thickness skin graft (STSG) closure of the donor site. DESIGN: Case-control study. SETTING: Tertiary care institution. PATIENTS: The inclusion criteria were flap size not exceeding 30 cm(2), patient availability for a single follow-up visit, and performance of surgery at least 6 months previously. Forty-four patients were included in the study and were reviewed. Twenty-two patients had UBTF closure, and 22 had STSG closure. MAIN OUTCOME MEASURES: Variables analyzed included wrist mobility, Michigan Hand Outcomes Questionnaire scores, pinch and grip strength (using a dynamometer), and hand sensitivity (using monofilament testing over the radial nerve distribution). In analyses of operated arms vs nonoperated arms, variables obtained only for the operated arms included Vancouver Scar Scale scores and visual analog scale scores for Aesthetics and Overall Arm Function. RESULTS: The mean (SD) wrist extension was significantly better in the UBTF group (56.0 degrees [10.4 degrees ] for nonoperated arms and 62.0 degrees [9.7 degrees ] for operated arms) than in the STSG group (59.0 degrees [7.1 degrees ] for nonoperated arms and 58.4 degrees [12.1 degrees ] for operated arms) (P = .02). The improvement in wrist range of motion for the UBTF group approached statistical significance (P = .07). All other variables (Michigan Hand Outcomes Questionnaire scores, pinch and grip strength, hand sensitivity, and visual analog scale scores) were significantly better for nonoperated arms vs operated arms, but no significant differences were observed between the UBTF and STSG groups. CONCLUSIONS: The radial forearm free flap donor site carries significant morbidity. Donor site UBTF closure was associated with improved wrist extension and represents an alternative method of closure for small donor site defects. PMID- 22249628 TI - The role of molecular markers and tumor histological type in central lymph node metastasis of papillary thyroid carcinoma. AB - OBJECTIVE: To look for genetic mutations that might predict central compartment lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) using strict criteria for N0 and N1 disease. DESIGN: We identified patients with PTC from our institution's pathology archives. Strict criteria were used for assessing the presence or the absence of central neck LNM. Disease was classified as N0 only if a comprehensive ipsilateral and pretracheal central neck dissection was performed and if pathological analysis revealed no evidence of LNM. Primary tumor samples were analyzed for a panel of known or suspected PTC-associated molecular markers, including BRAF, RET -PTC, KRAS, NRAS, HRAS, PIK3CA, and their variants. SETTING: Academic medical center. PATIENTS: Three hundred eighty-nine patients with PTC. MAIN OUTCOME MEASURE: Molecular mutations in tumors with and without LNM. RESULTS: Of 389 identified cases, 209 fit the inclusion criteria, with 158 classified as node positive (N1) and 51 as node negative (N0). The follicular variant histological type was present in 7 of 158 N1 tumors (4.4%) and 24 of 51 N0 tumors (47.1%) and thus was strongly associated with lack of central neck metastasis in this study (odds ratio, 0.05; 95% CI, 0.02-0.14). Predictive factors for central LNM included extracapsular extension, angiolymphatic invasion, and higher T stage (T3 and T4). The BRAF mutation was more prevalent in the classic PTC histological type than the follicular variant. None of the molecular marker mutations that were analyzed in this study, including the BRAF mutation, predicted LNM in classic PTC. CONCLUSIONS: Positive risk factors for central LNM include male sex, extracapsular extension, angiolymphatic invasion, and advanced T stage. The follicular variant histological type has a significantly lower incidence of central neck metastasis. In contrast to recent studies, the BRAF mutation was not significantly associated with central neck LNM from PTC when using a strict definition of a central neck dissection. PMID- 22249629 TI - Supraglottoplasty for occult laryngomalacia to improve obstructive sleep apnea syndrome. AB - OBJECTIVE: To evaluate the polysomnographic outcomes after supraglottoplasty (SGP) performed for obstructive sleep apnea syndrome (OSAS) associated with occult laryngomalacia. DESIGN: Retrospective case series with medical chart review. SETTING: Tertiary pediatric medical center. PATIENTS: Twenty-two patients aged 2 to 17 years met the inclusion criteria of polysomnography-proven OSAS and occult laryngomalacia seen on flexible fiber-optic sleep endoscopy. Infants with congenital laryngomalacia were excluded. INTERVENTION: Carbon dioxide laser SGP was performed either alone or in conjunction with other operations for OSAS. MAIN OUTCOME MEASURE: Preoperative and postoperative nocturnal polysomnographic data were paired and analyzed statistically. RESULTS: Supraglottoplasty for occult laryngomalacia resulted in statistically significant reduction in the apnea hypopnea index (AHI) (from 15.4 to 5.4) (P <.001). Subgroup analysis of children who underwent either SGP alone or in combination with other interventions showed comparable reductions in AHI. Medical comorbidities were associated with worsened postoperative outcomes, although still significantly improved compared with baseline. Overall, 91% of children had an improvement in AHI, and 64% had only mild or no residual OSAS after SGP. CONCLUSION: Supraglottoplasty is an effective technique for the treatment of OSAS associated with occult laryngomalacia. PMID- 22249630 TI - Association between obstructive sleep apnea and sudden sensorineural hearing loss: a population-based case-control study. AB - OBJECTIVE: To examine the putative association between obstructive sleep apnea (OSA) and sudden sensorineural hearing loss (SSNHL) using a nationwide population based data set. Obstructive sleep apnea has been associated with generalized inflammation and nervous-endocrine, cardiovascular, and other systemic biophysiologic phenomena. However, to our knowledge, no investigations have been conducted using large data sets to examine the association between OSA and auditory disorders. DESIGN: Case-control study. PARTICIPANTS: We identified 3192 patients diagnosed with SSNHL from the Taiwan Longitudinal Health Insurance Database as the study group and randomly extracted the data of 15,960 subjects matched by sex, age and year of first SSNHL diagnosis as controls. MAIN OUTCOME MEASURES: Cases of OSA were identified by having been diagnosed as OSA prior to the index date of SSNHL diagnosis. Conditional logistic regression matched on age group and sex was used to assess the possible association between SSNHL and OSA among the sampled patients. RESULTS: Of 19,152 patients, 1.2% had OSA diagnoses prior to the index date; OSA was diagnosed in 1.7% of the SSNHL group and 1.2% of the controls. After adjusting for sociodemographic characteristics and co-morbid medical disorders, we found that male patients with SSNHL were more likely to have prior OSA than controls (odds ratio, 1.48; 95% CI, 1.02-2.16) (P = .04). No such association was found among female patients. CONCLUSIONS: Male patients with SSNHL had a higher proportion of prior OSA than non-SSNHL-diagnosed controls; no such association was found among female patients. Further study will be needed to confirm our findings, explore the underlying pathomechanisms, and investigate the difference between sexes. PMID- 22249631 TI - Vocal outcome after arytenoid adduction and ansa cervicalis transfer. AB - OBJECTIVE: To evaluate the long-term efficacy of arytenoid adduction (AA) combined with ansa cervicalis-recurrent laryngeal nerve anastomosis (ACN-RLN) in the treatment of unilateral vocal fold paralysis. DESIGN: Retrospective review of clinical records. SETTING: Institutional practice. PATIENTS: Nine patients with severe paralytic dysphonia with large glottal gap were included. Voice outcome was followed up over 24 months postoperatively. One patient did not attend the 24 month evaluation. INTERVENTIONS: All patients underwent AA + ACN-RLN. The ansa cervicalis nerve to the sternohyoid muscle was used as the donor nerve. MAIN OUTCOME MEASURES: Maximum phonation time (MPT), pitch range, harmonics-to-noise ratio (HNR), and perceptual voice quality were evaluated preoperatively and postoperatively at 1 to 3 months, 6 to 8 months, 12 to 14 months, and 24 months. RESULTS: All parameters improved significantly after surgery and continued to improve over the 24-month period. The MPT continued to improve over time (P = .01, P = .006, and P = .001 when comparing the 1- to 3-month evaluation with the 6- to 8-month, 12- to 14-month, and 24-month evaluations, respectively). Also, pitch range and HNR showed significant, steady improvement over the 24-month duration of the study. Perceptual voice quality markedly improved at 24 months compared with the 1- to 3-month, 6- to 8-month, and 12- to 14-month follow-ups (P = .004, P = .005, and P = .02, respectively, for grade overall, and P = .004, P = .008, and P = .02, respectively, for breathiness grade). CONCLUSIONS: Treatment with AA + ACN-RLN provides near-normal vocal function in the 24-month follow-up. Therefore, this method could be a successful surgical treatment for severe paralytic dysphonia. PMID- 22249632 TI - A clinical and histopathologic study of jugular bulb abnormalities. AB - OBJECTIVE: To further define the spectrum of clinical presentation and explore the histologic sequelae of jugular bulb abnormalities (JBAs). DESIGN: Retrospective review. SETTING: Academic medical center. PATIENTS: Thirty patients with radiologic evidence of inner ear dehiscence by JBA. MAIN OUTCOME MEASURE: Thirty patients with radiologic inner ear dehiscence by JBA and 1579 temporal bone specimens were evaluated for consequences from JBA. RESULTS: We found that JBA-associated inner ear dehiscence could be identified on computed tomography of the temporal bone but not on magnetic resonance imaging scan. Jugular bulb abnormalities eroded the vestibular aqueduct most often (in 25 patients), followed by the facial nerve (5 patients) and the posterior semicircular canal (4 patients). Half of the patients (15) were asymptomatic. Results from vestibular evoked myogenic potential (VEMP) tests were positive in 8 of 12 patients with inner ear dehiscence. Histologically, only 2 of 41 temporal bones with dehiscence of the vestibular aqueduct demonstrated endolymphatic hydrops. CONCLUSIONS: Jugular bulb abnormalities can erode into the vestibular aqueduct, facial nerve, and the posterior semicircular canal. While symptoms may include pulsatile tinnitus, vertigo, or conductive hearing loss, in contrast to earlier reports, half of the patients were asymptomatic. Dehiscence of vestibular aqueduct rarely leads to clinical or histologic hydrops. The VEMP testing was useful in confirming the presence of inner ear dehiscence due to JBAs. Because the natural history of JBAs is unknown, these patients should be followed closely to evaluate for progression of the JBA or development of symptoms. PMID- 22249633 TI - Surgical management of auricular infantile hemangiomas. AB - OBJECTIVE: To report our experience with surgical management of auricular infantile hemangiomas and reconstruction of the affected ear. DESIGN: Retrospective case series. SETTING: Dedicated Birthmarks and Vascular Anomalies Center in a tertiary pediatric hospital. PATIENTS: Ten patients with surgically treated, histopathologically confirmed auricular infantile hemangiomas. MAIN OUTCOME MEASURES: Outcomes of surgical management. RESULTS: The case series included 5 male and 5 female patients (age range, 4 months to 4 years). Indications for surgery were pain, bleeding, infection, and cosmetic deformity. Four patients had failed prior medical treatment, including pulsed dye laser, topical corticosteroids, and intralesional corticosteroids. Nine patients underwent single-stage resection. Otoplasty reconstruction was performed in 2 patients with hemangioma-induced deformities, while primary Z-plasty closure was performed in 2 patients with extensive lesions. No recurrence or complication has been reported to date. CONCLUSIONS: Most infantile hemangiomas do not require treatment. Surgical excision of auricular infantile hemangiomas at any phase is effective in preventing fibrofatty scarring, reducing cartilage deformities, and treating complicated cases or patients who have failed medical management. Surgical excision with Z-plasty reconstruction is a viable option that should be considered to limit postoperative deformities. PMID- 22249634 TI - Tracheal obstruction due to heterotopic ossification in a tracheostomy scar. PMID- 22249635 TI - Spontaneous cerebrospinal fluid rhinorrhea of the foramen cecum in adulthood. PMID- 22249636 TI - Nasoseptal cholesterol granuloma: a case report and review of pathogenesis. PMID- 22249637 TI - Radiology quiz case 1. Congenital cyst of the newborn. PMID- 22249638 TI - Radiology quiz case 2. Giant cell granuloma (GCG) of the maxilla. PMID- 22249639 TI - Radiology quiz case 3. Meningioma of the geniculate ganglion. PMID- 22249640 TI - Pathology quiz case 1. Soft-tissue perineurioma. PMID- 22249641 TI - Pathology quiz case 2. Osteolipoma of the buccal space. PMID- 22249642 TI - Pathology quiz case 3. Neuroblastoma with cervical metastases. PMID- 22249643 TI - Adolescent female with withdrawal psychosis following abrupt termination of ziprasidone. AB - It is widely known that discontinuation reactions can occur after neuroleptics are stopped resulting in dyskinesia through its effect on the nigrostriatal pathway. Less discussed is the concept of "supersensitivity psychosis" which has been described as a rapid onset of psychosis after a neuroleptic medication has been withdrawn. Although the concept of supersensitivity psychosis has been described with the discontinuation of some neuroleptics, it has not been described with ziprasidone. Furthermore, the following case report is the first time that this phenomenon has been described in an adolescent patient who has discontinued ziprasidone. Reasons for supersensitivity psychosis are explored in addition to suggestions about precautions about prescribing neuroleptics in young people. PMID- 22249644 TI - Tuberculosis-related choriocapillaritis (multifocal-serpiginous choroiditis): follow-up and precise monitoring of therapy by indocyanine green angiography. AB - To report the case of a patient initially diagnosed with acute posterior multifocal placoid pigment epitheliopathy (APMPPE), characterized by relentless evolution despite high-dose steroid therapy. An interferon-gamma release assay (IGRA) indicated a diagnosis of suspected tuberculous choriocapillaritis and the disease responded only to massive inflammation suppressive therapy and antibiotic therapy. Case report. Review of clinical features and investigational procedures. Smoldering relentless evolution and subsequent arrest of progression could be precisely monitored by indocyanine green angiography (ICGA). The patient did not recover after standard anti-tubercolosis (TB) therapy combined with corticosteroid. A fourth antibiotic had to be added in order to stop the progression of the retinal disease. In each case of choriocapillaritis such as APMPPE an infectious cause including TB has to be excluded making IGRA tests unavoidable. As the main structure involved is the choriocapillaris the most precise follow-up or monitoring is obtained with ICGA. PMID- 22249645 TI - Optically probing nanoemulsion compositions. AB - Many types of colloids, including nanoemulsions, which contain sub-100 nm droplets, are dispersed in molecular and micellar solutions, especially surfactant solutions that confer stability. Since it would be desirable to measure the droplet volume fraction phi and surfactant concentration C of a nanoemulsion non-destructively, and since the droplet and surfactant structures are significantly smaller than the shortest wavelengths of visible light, optical refractometry could provide a simple and potentially useful approach. By diluting a silicone oil-in-water nanoemulsion having an unknown phi and C with pure water, measuring its refractive index n(phi,C) using an Abbe refractometer, and fitting the result using a prediction for n that treats the nanoemulsion as an effective medium, we show that phi and C can be deduced accurately over a relatively wide range of compositions. Moreover, we generalize this approach to other types of nanoemulsions in which a molecular constituent partitions in varying degrees between the dispersed and the continuous phases. PMID- 22249646 TI - A unified approach for EIT imaging of regional overdistension and atelectasis in acute lung injury. AB - Patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS) are vulnerable to ventilator-induced lung injury. Although this syndrome affects the lung heterogeneously, mechanical ventilation is not guided by regional indicators of potential lung injury. We used electrical impedance tomography (EIT) to estimate the extent of regional lung overdistension and atelectasis during mechanical ventilation. Techniques for tidal breath detection, lung identification, and regional compliance estimation were combined with the Graz consensus on EIT lung imaging (GREIT) algorithm. Nine ALI/ARDS patients were monitored during stepwise increases and decreases in airway pressure. Our method detected individual breaths with 96.0% sensitivity and 97.6% specificity. The duration and volume of tidal breaths erred on average by 0.2 s and 5%, respectively. Respiratory system compliance from EIT and ventilator measurements had a correlation coefficient of 0.80. Stepwise increases in pressure could reverse atelectasis in 17% of the lung. At the highest pressures, 73% of the lung became overdistended. During stepwise decreases in pressure, previously atelectatic regions remained open at sub-baseline pressures. We recommend that the proposed approach be used in collaborative research of EIT-guided ventilation strategies for ALI/ARDS. PMID- 22249647 TI - Effect of postoperative landiolol administration for atrial fibrillation after off pump coronary artery bypass surgery. AB - AIM: Atrial fibrillation is one of the most common postoperative arrhythmias following cardiac surgery. Despite many clinical studies, there is still no consensus on the most appropriate prevention strategy for atrial arrhythmia. A randomized prospective trial was conducted to determine the efficacy of intravenous landiolol administration in the early period after off-pump coronary artery bypass grafting (CABG) followed by treatment with carvedilol for prevention of atrial fibrillation. METHODS: Seventy consecutive patients were enrolled in the study prospectively. Patients in the treated group received landiolol intravenously (5 MUg/kg/min) in the ICU immediately after surgery. Heart rate was maintained at 60-80 bpm and intravenous landiolol was continued at 0-10 MUg/kg/min until oral drug administration was possible. All patients received oral carvedilol (2.5-5 mg/day) after extubation and this was continued postoperatively. The primary endpoint was the overall development of postoperative atrial fibrillation. RESULTS: Postoperative atrial fibrillation occurred in 4 (11.1%) of the 36 patients in the landiolol group, compared with 11 (32.3%) of the 34 patients in the control group, indicating that development of atrial fibrillation was significantly inhibited by landiolol (P=0.042). No major postoperative complications occurred in the landiolol group. CONCLUSION: Postoperative intravenous landiolol therapy followed by oral carvedilol may be more effective than oral carvedilol alone for prevention of atrial fibrillation after off-pump CABG. We also found that intravenous landiolol is well tolerated after cardiac surgery. PMID- 22249648 TI - Stem cells and repair of the heart: cell-releasing epicardial scaffolds. AB - Cell transplantation represents the last frontier within the treatment of cardiac diseases. From the first paper published in 1992 that has documented the potentials of the transplantation of autologous skeletal muscle cells to treat the damage induced by acute myocardial infarction, innumerable techniques of implantation and types of cells used has been reported, greatly expanding this innovative and appealing field of search in cardiovascular medicine. Despite original promises and expectations, current evidences of stem cell transplantation are still weak and controversial. Therefore, alternative line of research are being explored, particularly in the field of techniques of cell implantation and engraftment. Besides direct implantation or myocardial colonization by bone marrow stimulation, epicardial application of cell delivering systems (scaffold and patches) have gained popularity due to the possibility to apply selectively a cell-containing device which may gradually release the chosen cell type, alone or in combination with trophic substances. The scaffolds have proven to be successful in this respect and may represent a valid alternative to coronary, intra-myocardial, or venous injection of stem cells, or to stem cell stimulating factors. Finally these systems may be applied through minimally invasive procedures and act as external constraint to enhance ventricular reverse remodelling or limit further cardiac dilatation. PMID- 22249649 TI - Long-term membranous glomerulonephritis as the presenting manifestation of systemic lupus erythematosus in a patient with human immunodeficiency virus infection. AB - The coexistence of human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE) is unusual, but the occurrence of SLE after HIV infection is even less common. Both conditions share similar clinical features including constitutional symptoms, facial rash, oral ulcers, alopecia, arthralgias, arthritis, seizures, cytopenias, glomerulonephritis, and antinuclear and antiphospholipid antibodies. This clinical overlap makes the diagnosis of SLE in a patient with pre-existing HIV infection difficult. Furthermore, immune complex glomerulonephritis with features resembling lupus nephritis has been described in HIV-positive patients. We present the case of a 45-year-old Hispanic woman with long-standing HIV infection who developed membranous glomerulonephritis with histological features of lupus nephritis. Five years after onset of renal disease she developed clinically evident SLE. PMID- 22249650 TI - Ataxic sensory neuronopathy in a patient with systemic lupus erythematosus. AB - The occurrence of ataxic sensory neuronopathy (ASN) is rare in patients with connective tissue diseases (CTDs). ASN has been described in case reports and case series in patients with CTDs, mostly Sjogren's syndrome, and most often occurring during middle or old age. ASN in association with systemic lupus erythematosus (SLE) is extremely rare; there has been only one reported case in the literature. In addition, to our knowledge, adolescent onset of symptoms in CTD-associated ASN has not been reported previously. We report the case of a young woman who presented with ASN, characterized by sensory ataxia, with elevated antinuclear antibodies, leukopenia and anemia; she fulfilled the diagnostic criteria for SLE about 7 years after the onset of sensory ataxia. Our case points out that ASN may be the initial presenting feature of SLE. SLE should be included in the differential diagnosis of ASN, especially in patients of young age. PMID- 22249651 TI - The medical care of children with autism. AB - The prevalence of autism spectrum disorder (ASD) has increased considerably in the past decades. The primary care paediatrician plays an important role not only in the early recognition of ASD but also in its chronic management. Paediatricians need to be comfortable with the global care of children with ASD. The diagnostic assessment of children with ASD comprises the medical investigations to identify associated or underlying medical conditions. The most important associated conditions are seizures, feeding and gastrointestinal problems, sleep disturbances and dental abnormalities. The care of ASD patients is very demanding since along with the purely medical issues there are challenging behavioural and psychiatric conditions that need consideration and professional skills. PMID- 22249652 TI - Measurement of fractional synthetic rates of multiple protein analytes by triple quadrupole mass spectrometry. AB - BACKGROUND: Current approaches to measure protein turnover that use stable isotope-labeled tracers via GC-MS are limited to a small number of relatively abundant proteins. We developed a multiplexed liquid chromatography-selected reaction monitoring mass spectrometry (LC-SRM) assay to measure protein turnover and compared the fractional synthetic rates (FSRs) for 2 proteins, VLDL apolipoprotein B100 (VLDL apoB100) and HDL apoA-I, measured by both methods. We applied this technique to other proteins for which kinetics are not readily measured with GC-MS. METHODS: Subjects were given a primed-constant infusion of [5,5,5-D(3)]-leucine (D(3)-leucine) for 15 h with blood samples collected at selected time points. Apolipoproteins isolated by SDS-PAGE from lipoprotein fractions were analyzed by GC-MS or an LC-SRM assay designed to measure the M+3/M+0 ratio at >1% D(3)-leucine incorporation. We calculated the FSR for each apolipoprotein by curve fitting the tracer incorporation data from each subject. RESULTS: The LC-SRM method was linear over the range of tracer enrichment values tested and highly correlated with GC-MS (R(2) > 0.9). The FSRs determined from both methods were similar for HDL apoA-I and VLDL apoB100. We were able to apply the LC-SRM approach to determine the tracer enrichment of multiple proteins from a single sample as well as proteins isolated from plasma after immunoprecipitation. CONCLUSIONS: The LC-SRM method provides a new technique for measuring the enrichment of proteins labeled with stable isotopes. LC-SRM is amenable to a multiplexed format to provide a relatively rapid and inexpensive means to measure turnover of multiple proteins simultaneously. PMID- 22249653 TI - The role of the Auger parameter in XPS studies of nickel metal, halides and oxides. AB - The critical role of the Auger parameter in providing insight into both initial state and final state factors affecting measured XPS binding energies is illustrated by analysis of Ni 2p(3/2) and L(3)M(45)M(45) peaks as well as the Auger parameters of nickel alloys, halides, oxide, hydroxide and oxy-hydroxide. Analyses of the metal and alloys are consistent with other works, showing that final state relaxation shifts, DeltaR, are determined predominantly by changes in the d electron population and are insensitive to inter-atomic charge transfer. The nickel halide Auger parameters are dominated by initial state effects, Deltaepsilon, with increasing positive charge on the core nickel ion induced by increasing electronegativity of the ligands. This effect is much greater than the final state shifts; however, the degree of covalency is reflected in the Wagner plot where the more polarizable iodide and bromide have greater DeltaR. The initial state shift for NiO is much smaller than those of Ni(OH)(2) or NiOOH and the effective oxidation state is much less than that inferred from the average electronegativity of the ligand(s). Auger parameter analysis indicates that the bonding in NiO appears to have stronger contributions from initial state charge transfer from the oxygen ligands than that in the hydroxide and oxyhydroxide consistent with the considerable differences in the Ni-O bond lengths in these compounds with some relaxation of this state occurring during final state phenomena. The Auger parameter of NiOOH is, however, shifted positively, like the iodide, indicating greater polarizability of the ligands and covalency in this bonding. There is support for more direct use of relative bond lengths in interpreting differences between related compounds rather than more general electronegativity or similar parameters. PMID- 22249654 TI - Quenching of tryptophan fluorescence in various proteins by a series of small nickel complexes. AB - A series of twelve anionic, cationic, and neutral nickel(II) complexes have been synthesized and characterized. The interaction of these complexes with bovine serum albumin (BSA), human serum albumin (HSA), lysozyme (Lyso), and tryptophan (Trp) has been studied using steady-state fluorescence spectroscopy. Dynamic and static quenching constants have been calculated, and the role played in quenching by the ligand and complex charge investigated. The nickel complexes showed selectivity towards the different proteins based on the environment surrounding the Trp residue(s). Only small neutral complexes with hydrophobic ligands effectively quenched protein fluorescence via static quenching, with association constants ranging from 10(2) M(-1) (free Trp) to 10(10) M(-1) (lysozyme), indicating a spontaneous and thermodynamically favorable interaction. The number of binding sites, on average, was determined to be one in BSA, HSA and free Trp, and two in lysozyme. PMID- 22249655 TI - Interictal pain in primary headache syndromes. AB - Primary headache disorders are generally characterized by the pain, time course, and associated symptoms of their attacks, but often are accompanied by milder interictal pain. Patients with chronic migraine, chronic tension-type headache, hemicrania continua, and new daily-persistent headache have constant pain more often than not. Patients with trigeminal autonomic cephalalgias such as cluster headache commonly have interictal pain as well, usually much milder and unilateral to the side of attacks. Even those with rare headache types, including hypnic headache and trigeminal neuralgia, commonly have interictal pain. This review describes the incidence of interictal pain in primary headache disorders and suggests the significance and biological meanings of this pain. PMID- 22249656 TI - Colony stimulating factors (CSF) biosimilars. Progress? AB - Biosimilars are equivalent drugs for other biotechnological drugs for which patent has expired. These biopharmaceuticals are often looked upon as simple copies of parent drugs whose goal is solely to potentially generate costs savings. The expansion of available drugs is a subject of attention, criticism and quarrels, often related to a lack of product knowledge. These drugs are copies but need scientific development that must meet many strict rules. Many questions arise in connection with the marketing of several biosimilar drugs in the field of hematopoietic growth factors of white and red cells. Many of them should be discussed. PMID- 22249657 TI - Biosimilars and market access: a question of comparability and costs? AB - This article discusses specific issues related to the market access of biosimilars. Biopharmaceuticals are complex molecules produced by living cells. Copies of these medicines, called biosimilars, are not identical to their reference medicine and therefore specific regulatory requirements apply. When considering the use of biosimilars, the question of the degree of comparability between a biosimilar and the reference biopharmaceutical needs to be considered for registration, pricing and reimbursement purposes in addition to the cost issue. To date, many key concepts (like clinically meaningful differences) remain undefined and the question of the degree of comparability is not yet resolved. PMID- 22249659 TI - Preparing nurses for global health care. PMID- 22249660 TI - Primary health care in municipalities at high risk for malaria. AB - This study aims to characterize aspects of Primary Health Care in the Amazon Region of Brazil, considered as the main endemic area for malaria in the country. The Ministry of Health recommends the expansion of Primary Health Care in endemic areas for malaria. A survey focusing on patients infected with malaria was conducted in 6 municipalities, in January and February 2007, to investigate specific aspects of Primary Health Care. Data was analyzed quantitatively and field records helped to give support to context and policy issues in the visited sites. Quality of access to health services and medicines, continuity of health care, system coordination and community orientation are still incipient in the visited areas. The study showed that there is little integration between Primary Health Care and malaria control in the region, which calls for development of joint strategies and for the strengthening of Primary Health Care per se, as a benefit to the population of this endemic area. PMID- 22249658 TI - The economic pressures for biosimilar drug use in cancer medicine. AB - The main rationale for using biosimilar drugs is for cost saving. The market development for biosimilar drugs will therefore depend on the degree to which cost saving measures are required by nations, medical insurers and individuals and the absolute savings that could be gained by switching from original drugs. This paper is designed to discover the degree to which financial constraints will drive future health spending and to discover if legal or safety issues could impact on any trend. A structured literature search was performed for papers and documents to 27 August 2011. Where multiple sources of data were available on a topic, data from papers and reports by multinational or national bodies were used in preference to data from regions or individual hospitals. Almost all health systems face current significant cost pressures. The twin driver of increasing cancer prevalence as populations age and cancer medicine costs rising faster than inflation places oncology as the most significant single cost problem. For some countries, this is predicted to make medicine unaffordable within a decade. Most developed countries have planned to embrace biosimilar use as a cost-control measure. Biosimilar introduction into the EU has already forced prices down, both the price of biosimilar drugs and competitive price reductions in originator drugs. Compound annual growth rates of use have been predicted at 65.8% per year. Most developed countries have planned to embrace biosimilar use as a major cost control measure. Only legal blocks and safety concerns are likely to act against this trend. For centralised healthcare systems, and those with a strong tradition of generic medicine use, biosimilar use will clearly rise with predictions of more than 80% of prescriptions of some biologic drugs within 1 year of market entry in the USA. Delaying the implementation of such programmes however risks a real crisis in healthcare delivery for many countries and hospitals that few can now afford. PMID- 22249661 TI - Tuberculosis control: decentralization, local planning and management specificities. AB - The goal was to analyze, according to the perception of health managers, the practices that guide tuberculosis control actions in cities in the metropolitan region of Joao Pessoa - PB, Brazil. This qualitative study involved eight professionals in management functions. Testimonies were collected through semi structured interviews between May and June 2009 and organized through content analysis. Despite the acknowledged benefits of tuberculosis control action decentralization, local planning indicates the predominance of a bureaucratic model that is restricted to negotiation and supplies. Local programming is centered on the coordinator, which shows a command line and vertical management that lead to the fragmentation of the work process. Management action should follow an innovative and transformative route that surpasses bureaucratic barriers and faces the biggest challenge it is proposed: to balance professional interrelations with a view to improving health work performance. PMID- 22249662 TI - Malaria control in an Amazon municipality. AB - This study aimed to evaluate the organization of malaria control actions in the Indigenous population of the municipality of Sao Gabriel da Cachoeira, Amazonas, AM, Brazil, from 2003 to 2007. This is an ecological study to evaluate the impact of control measures. Statistical analysis of the indicators revealed that the number of cases showed an increasing trend, with the highest numbers occurring in the rural areas. The same trend was observed for the Annual Parasite Index (API), however the highest APIs were found in the urban areas. The proportion of cases caused by Plasmodium falciparum showed a reduction. Hospitalization and mortality rates presented fluctuations and the fatality rate decreased. The findings indicate that control actions have proved partially effective and that they have provided a broader capacity to detect cases and to provide immediate treatment. Although the municipality still presents a high risk for transmission, the Pluriannual Plan in progress seems to have a good prognosis for the control of the disease, if maintained in a sustainable and permanent way. PMID- 22249663 TI - Participative leadership in the management process of nightshift nursing. AB - This is a qualitative, exploratory, descriptive study, aiming to identify the perceptions of nurses regarding the leadership process and to analyze how this process takes place on the nightshift. Data collection was performed through the Focus Groups Technique, with 13 nightshift nurses of a public teaching hospital. Two categories that resulted from the thematic analysis are the focus of this article: the context of nightshift nursing work and leadership from the perception of the nightshift nurses. Teamwork is an important condition to vitalize the participatory perspective of the leadership process, given the necessary relationship of support and integration, above all in the nightshift nursing work. This exercise challenges the nurse in the solidification of a culture that promotes spaces for reflection regarding the work, integrating leadership with a learning process that is constituted through constructive bonds between the workers. PMID- 22249664 TI - Quality of life in perimenopausal women working in the health and educational system. AB - The objective of this study was to determine the association between the professional activity and the perceived quality of life in climacteric women who work in Health and Education. A descriptive and cross-sectional study was developed in a sample of 203 climacteric women, together with a correlation analysis of labor factors' influence on health-related quality of life. Significant differences were found between working women's quality of life and some labor conditions. The perceived quality of life in perimenopausal women who work in Education is higher than that of those working in Health (p=0.004). Nursing professionals can develop health programs that deal with the work conditions that negatively influence the perceived quality of life in climacteric women. PMID- 22249665 TI - Evaluation of the health-related quality of life of hematopoietic stem cell transplantation patients. AB - This study evaluates the Health-Related Quality of Life of patients undergoing analogous and allogeneic transplantation at three different points in time: before, 30 and 180 days after transplantation, along with correlated clinical and socio-demographic data. Two questionnaires were used for data collection: the first addressed clinical and socio-demographic data and the second was the Functional Assessment Cancer Therapy translated and validated for Brazilian Portuguese. The initial sample was composed of 30 patients while 26 were ultimately evaluated at the three points. The set of results indicated a positive impact on Health-Related Quality of Life six months after transplantation. Despite the fact that there were additional concerns and some aspects such as physical and functional aspects were affected 30 days after the procedure, the Functional Assessment Cancer Therapy scores obtained six months after HSCT improved in all components, reaching levels above those prior to the procedure, especially physical and emotional aspects and the relationship with the physician. PMID- 22249666 TI - Evaluation of prevention and control measures for ventilator-associated pneumonia. AB - This study aimed to evaluate the quality of health care delivered in an Intensive Care Unit, concerning the use of pneumonia prevention and control measures in high-risk patients on mechanical ventilation. In this descriptive and exploratory research, 839 observations of patients under invasive ventilation care were carried out, between November 2009 and January 2010, using the Indicator of Evaluation of Adherence to Prevention and Control Measures in High-risk Patients (IRPR). Some isolated measures that compose the mentioned indicator reached rates close to 100%, but the general compliance rate with all prevention and control measures of ventilator-associated pneumonia was 26.94%. It is concluded that, although the evaluated practices are accomplished at the unit, systematic evaluations of the interventions is needed so as to permit the discussion and practice of other educational strategies by the health team. PMID- 22249667 TI - In-hospital mortality and the Glasgow Coma Scale in the first 72 hours after traumatic brain injury. AB - This study verifies and compares the performance of three different scores obtained in the Glasgow Coma Scale (GCS) in the first 72 hours post trauma in predicting in-hospital mortality. The studied scores included those obtained after initial care was provided at the hospital, and the worst and best scores obtained in the scale in the first 72 hours post trauma. The scale's predictive ability was assessed by the Receiver Operator Characteristic (ROC) curve. A total of 277 victims with different severity levels of blunt traumatic brain injuries were studied. The performance of the three scores that were analyzed to predict hospital mortality was moderate (0.74 to 0.79) and the areas under the curve did not present statistically significant differences. These findings suggest that any of the three studied scores can be applied in clinical practice to estimate the outcome of victims with blunt traumatic brain injuries, taking into consideration the instrument's moderate discriminatory power. PMID- 22249668 TI - Clinical evolution of adult, elderly and very elderly patients admitted in Intensive Care Units. AB - This study compared clinical outcomes among adult, elderly and very elderly patients admitted to Intensive Care Units (ICUs) located in Sao Paulo, Brazil. This retrospective, longitudinal and comparative study included 279 adult (>= 18 and <60 years), 216 elderly (>= 60 and <80 years) and 105 very elderly (>= 80 years) patients. Adult patients differed from other groups regarding the unit to which they were referred and severity, according to the Simplified Acute Physiology Score II. Adults were most frequently sent to hospitalization wards; elderly and very elderly patients who survived hospitalization in critical units showed sharper improvement before discharge. There were differences in relation to mortality between adult and elderly patients, with a higher rate in the elderly group; however, the mortality rate of very elderly and adult patients was similar. In general, the results indicated that older age was not associated with undesirable outcomes in ICUs. PMID- 22249669 TI - Cultural adaptation and validation of the Neuropathy - and Foot Ulcer - Specific Quality of Life instrument (NeuroQol) for Brazilian Portuguese - Phase 1. AB - This methodological study aimed to adapt the Neuropathy - and Foot Ulcer - Specific Quality of Life instrument - NeuroQol to Brazilian Portuguese and to analyze its psychometric properties. Participants were 50 people with peripheral diabetic neuropathy and foot ulcers. The floor and ceiling effects, the convergent and discriminant validity and the reliability were analyzed. The Cronbach's alpha coefficient was used to test the reliability and the Pearson's correlation coefficient to estimate the convergent validity, the Student's t test was used to evaluate the discriminant validity in the comparison of the NeuroQol scores between participants with and without ulcers. Floor and ceiling effects were found in some domains of the NeuroQol. The reliability was satisfactory. The correlations between the domains of the NeuroQol and the SF-36 were negative, significant and of moderate to strong magnitude. The findings show that the Brazilian version of the NeuroQol is reliable and valid and may be employed as a useful tool for improving nursing care for people with DM. PMID- 22249670 TI - Risk of surgical site infection in patients undergoing orthopedic surgery. AB - This study aimed to identify risk factors associated with surgical site infections in orthopedic surgical patients at a public hospital in Minas Gerais, Brazil, between 2005 and 2007. A historical cohort of 3,543 patients submitted to orthopedic surgical procedures. A descriptive analysis was conducted and surgical site infection incidence rates were estimated. To verify the association between infection and risk factors, the Chi-square Test was used. The strength of association of the event with the independent variables was estimated using Relative Risk, with a 95% confidence interval and p<0.05. The incidence of surgical site infection was 1.8%. Potential surgical wound contamination, clinical conditions, time and type of surgical procedure were statistically associated with infection. Identifying the association between surgical site infection and these risk factors is important and contributes to nurses' clinical practice. PMID- 22249671 TI - Endotracheal and upper airways suctioning: changes in newborns' physiological parameters. AB - This study investigated which physiological parameters change when endotracheal and upper airway suctioning is performed immediately before, immediately after and five minutes after this procedure is performed in newborns hospitalized in a Neonatal Intensive Care Unit (NICU). This is a quantitative and longitudinal study, before and after type, performed in the NICU of a public institution in the city of Fortaleza, CE, Brazil. The sample was composed of 104 newborns using oxigenotherapy and who needed endotracheal and upper airway suctioning. The results showed significant alterations in respiratory and heart rates (p<0.05) in neonates using Oxyhood and nasal CPAP while the pulse significantly changed (p<0.05) in newborns placed in oxyhood, using nasal CPAP and Mechanical Ventilation; oxygen saturation was the only parameter that did not alter significantly. We propose that nurses develop non-pharmacological interventions to reduce potential alterations caused in newborns' physiological parameters due to this procedure. PMID- 22249672 TI - Biopsychosocial factors related to the length of hospital stay in older people. AB - This study aimed to know what variables influence increased length of hospital stay. A descriptive, cross-sectional study was conducted through an integrated geriatric assessment of 81 people over 65 years of age, admitted to a tertiary acute care hospital. Data were collected through the Pfeiffer Scale, Barthel Index, Goldberg Questionnaire, Family APGAR and Gijon Scale. The length of hospital stay increased in people over 80 years, people living alone or in a retirement home, patients with great physical dependence and those with a risk or problem of social exclusion. The most influential variable for longer hospitalization was cognitive impairment (p<0.05), due to greater collaboration or desire to overcome the acute stage of the pathology that led to the hospital admission among patients without this condition. PMID- 22249673 TI - Informatics teaching in undergraduate nursing programs at Brazilian public institutions. AB - This descriptive study aimed to verify the inclusion of subjects about informatics in undergraduate nursing programs at Brazilian (state and federal) public education institutions. The programs were located through the e-MEC system. The Internet was used to search for the curricula of the campuses offering the nursing program and identify subjects related to informatics. Eighty one higher education institutions and 123 campuses were located. Only 100 campuses provided the curriculum on the Internet, 35 of which offered the subject. The highest proportion occurred in the Northeast (46.1%) and the lowest in the North (8.6%). The subject is mostly offered as an elective discipline (57%) in the first and second year (80%), with an average workload of 47 classroom hours. The low supply of this undergraduate subject goes against job market trends and the National Curriculum Guidelines for Undergraduate Nursing Programs. PMID- 22249674 TI - Undergraduate students in orthopedic nursing care. AB - This study identifies some undergraduate nursing students' imaginary manifestations concerning themselves and care delivered to patients with orthopedic and/or trauma disorders. The Social Poetics method was used and the research group was composed of 15 undergraduate students. Only the categories and subcategories exclusively related to the "student" are presented in this paper. Data revealed that care provided by orthopedic nursing students is the result of a care relationship that emerges from their sensitivity toward patients and their own knowledge, skills and attitudes. The orthopedic treatment, equipment and procedures, to which patients are submitted, cause important emotional distress for students, empathic behavior and encourage them to search for ways to minimize their patients' pain. All the aspects that permeate care provided by orthopedic nursing students should be identified in order to enable reassessment of the teaching-learning process. PMID- 22249675 TI - Caring for newborns in the presence of their parents: the experience of nurses in the neonatal intensive care unit. AB - The nurse has a key role in involving parents in the care of newborns in the neonatal intensive care unit. The aim of this study was to comprehend how the nurses experience the care provided to newborns in the presence of the parents. This is a qualitative study using social phenomenology, with the participation of seven nurses, interviewed between January and February 2009. The nurses perceived the needs of parents; had positive expectations regarding the care provided and acknowledge themselves to be the link between them, helping them to live with the hospitalized child. However, in emergencies, the nurses had difficulties in caring for the neonate in the presence of the parents. The nurses positively evaluated the presence of parents in the neonatal intensive care unit, involving them permanently in the care of the newborn. The study evokes the emergence of a care context (nurse/neonate/parents) that precedes the proximity between the subjects and the demands presented by them. PMID- 22249676 TI - Experiences with perinatal loss from the health professionals' perspective. AB - The purpose of this paper is to know the experience of health professionals in situations of perinatal death and grief and to describe their action strategies in the management of perinatal loss. A qualitative study with a phenomenological approach was carried out through interviews conducted with 19 professionals. Three thematic categories were identified: Healthcare practice, feelings aroused by perinatal loss and meaning and beliefs about perinatal loss and grief. The results revealed that the lack of knowledge and skills to deal with perinatal loss are identified as the main reason behind unsuitable attitudes that are usually adopted in these situations. This generates anxiety, helplessness and frustration that compromise professional competency. The conclusion reached is that the promotion of training programs to acquire knowledge, skills and abilities in management of perinatal bereavement and the development of a clinical practice guideline for perinatal loss are necessary. PMID- 22249677 TI - Characterization of the hospitalization of children and adolescents with cancer. AB - This study characterizes hospitalizations of children and adolescents with cancer, from 1998 to 2008, to describe the clientele in follow-up in the Regional Health Area of Ribeirao Preto, SP, Brazil. Morbidity was surveyed in Ribeirao Preto, SP, Brazil, using hospitalization data from the Unified Health System. The studied variables included: origin, residence, year when care was provided, deaths, age and gender of patients diagnosed with child and adolescent cancer according to the International Classification of Disease 10th edition, Chapter II. The results indicated 7,234 hospitalizations of individuals younger than 18 years old diagnosed with neoplasm, 95% of which were from Ribeirao Preto, SP, Brazil, and the remainder from cities located in all five of the Brazilian regions. Identifying the characteristics of patients contributes to the identification of information to broaden the sensitization of health professionals concerning the need for secondary preventive actions, such as early diagnosis. PMID- 22249678 TI - Domestic violence: possibilities and limitations in coping. AB - This qualitative study assesses how women, in situations of domestic violence and examined at the Institute of Forensic Medicine, deal with this adversity and identifies protection strategies to cope with it, considering the support required and obtained from their relational and institutional environments. Ten women were interviewed and the data were analyzed using thematic content analysis. Search for help primarily occurs in the women's social milieu, with family and friends and health and legal services being sought. In such a quest, established bonds may either become an obstacle to coping and make these women vulnerable to violence or protect and strengthen them during coping. In the identification of these women's social and health needs, the aggravating circumstances of violence are only superficially addressed by professionals. New strategies to implement professional actions should be devised in order to provide integral and humanized care. PMID- 22249679 TI - The experience of hospitalized children regarding their interactions with nursing professionals. AB - The aim of this study is to describe the experience of children in their interactions with nursing professionals while in hospital. It is a qualitative study supported by the critical incident technique. Data was collected through participant observation and semi-structured interviews with thirty hospitalized children and teenagers between 8 and 14 years old. The results showed that children positively valued nursing care at the hospital and recognized that interactions with nursing staff included social and emotional factors. It is concluded that communication established with children plays a fundamental role to comprehend their experiences while in hospital. Therefore, nurses need to evaluate their strategies and relational skills used to interact with children at the hospital. PMID- 22249680 TI - Self-perceived factors associated with smoking cessation among primary health care nurses: a qualitative study. AB - The aim of this work was to characterize the views of nurses about factors modulating smoking cessation. Results of this study will allow us to design helping interventions with the maximum specificity for nurses. A qualitative study through a semi-structured interview of 15 Primary Health Care nurses who were smokers was performed. In contrast with other studies in which nurses were not aware of any particular social pressure to give up smoking, 18 months after the application of the Anti-Smoking Spanish Law, this feeling was expressed. Therefore, the main reasons for giving up smoking include that smoking in public is every day worse seen, together with a sense of shame and guilt in front of their social and family environment, especially for being a professional group dedicated to health. PMID- 22249681 TI - Hospital discharge plan for patients with congestive heart failure. AB - This integrative review investigates how nurses plan the hospital discharge of patients with Congestive Heart Failure (CHF) since an inadequate discharge plan and patients' subsequent non-adherence to instruction provided upon discharge are indicated as potential factors for re-hospitalization. A total of 24 papers were found in a search carried out in the LILACS and MEDLINE databases between 2004 and 2008, which given the inclusion criteria, were reduced to 14 papers. The papers were analyzed and categorized into "Health Education", and "Nursing Care". The synthesis of results indicates that the discharge plan devised by nurses is based on two categories. The actions of nurses to promote health education can enable patients with CHF to improve self-care. PMID- 22249682 TI - Prognosis of breast cancer during pregnancy: evidence for nursing care. AB - This integrative review analyzed evidence available in the literature concerning the prognosis of breast cancer during pregnancy. The following databases were used for selecting studies: PubMed, CINAHL and LILACS. A total of 240 primary studies were identified; 13 papers were included in the integrative review's sample after reading the titles and abstracts and according to the established inclusion and exclusion criteria. There is evidence indicating that pregnancy does not worsen the evolution of breast cancer and a poor prognosis is related to late stage tumors. Among the gaps identified in the studied theme, the need for further studies addressing nursing care provided to pregnant women with breast cancer is highlighted in order to promote improved care in the context of health care. PMID- 22249683 TI - Ischemic heart disease in women. AB - Nowadays, Coronary Diseases (CDs) represent the main mortality cause in men and women, but there are gender differences regarding their presentation, progression and the way the disease is tackled. This study mainly focuses on reviewing literature about the CD and its gender approach. The authors carried out a search of texts that use qualitative methodology, published between 2003 and 2009 in the following databases: PUBMED, IME, CUIDEN and CINAHL. Factors that hinder the early diagnosis of Ischemic Heart Disease in women are identified as the main findings, and the possible consequences are pointed out. In the fifty-six texts that were selected initially, we can see the difficulty women face to recognize early symptoms of the CD and their low risk perception of this disease. Greater awareness on Ischemic Heart Disease is needed, so that the high morbidity and mortality rates can be reduced. PMID- 22249684 TI - Screening for group B Streptococcus in pregnant women: a systematic review and meta-analysis. AB - Infection with Group B Streptococcus (GBS) is considered an important public health problem. It is associated with: Neonatal sepsis, meningitis, pneumonia, neonatal death, septic abortion, chorioamnionitis, endometritis and other perinatal infections. The aim of this study was to determine the best screening strategy for GBS in pregnant women. For this a systematic review and meta analysis were carried out in the Nursing Department of the Federal University of Sao Paulo, Cochrane Center, Brazil. Sources used were, EMBASE, LILACS, Medline, list of references, personal communication and the Cochrane library. The criterion for the selection of the studies was; studies which analyze some type of screening for GBS in pregnant women. Independent of the comparator, all analyses were in favor of a universal screening program for reducing the incidence of neonatal sepsis. The evidence obtained in this study suggests that the strategy of universal screening of pregnant women associated with the use of prophylactic antibiotics is safe and effective. PMID- 22249686 TI - Effectiveness of an online knowledge training and assessment program for stop smoking practitioners. AB - INTRODUCTION: In English National Health Service (NHS) stop smoking services, stop smoking practitioners (SSPs) provide behavioral support and medication to support smokers wanting to quit. This study aimed to evaluate an evidence-based national online knowledge training program for SSPs developed by the NHS Centre for Smoking Cessation and Training (NCSCT). METHODS: Knowledge required to deliver effective stop smoking interventions was assessed using 25 multiple choice questions drawn randomly from a common larger pool at baseline and after use of the training program in 778 consecutive users. Change in knowledge and association of this change with time spent on the training were assessed. Baseline and change in knowledge of SSPs with different amounts of experience, prior training, and time dedicated to smoking cessation were compared. RESULTS: Knowledge improved from 64.4% correct to 77.7% (p < .001). Time spent on the training predicted improvement. Pretraining knowledge scores differed with experience, prior training, and time practicing. Training improved even the highest performing SSPs and minimized differences between groups. CONCLUSIONS: Knowledge required to deliver effective stop smoking intervention is improved efficiently by using the NCSCT online training program for English smoking cessation practitioners. SSPs with all levels of prior knowledge benefit. PMID- 22249687 TI - A systematic review of smoking cessation intervention studies in China. AB - INTRODUCTION: China has the highest number of tobacco smokers among the world's nations; however, no systematic review has been conducted of clinical trials on the efficacy of smoking cessation interventions in China. This paper summarizes findings of studies in order to compare the effect of pharmacotherapy, counseling, and Traditional Chinese Medicine (TCM) approaches on the abstinence rate. METHODS: Clinical trials of smoking cessation interventions published in English or Chinese were extracted from an electronic search of PubMed and WanFang databases. The search yielded 234 studies from the PubMed and 78 studies from the WanFang. RESULTS: Twenty-nine studies were included in this review. Of these, 11 (37.9%) were randomized controlled trials (RCTs) that assessed the following approaches: counseling (5 studies), TCM (3 studies), pharmacotherapy (1 study), a combination of pharmacotherapy and counseling (1 study), and physician advice (1 study). Pharmacotherapy alone or in combination with counseling generally resulted in a higher abstinence rate than counseling alone. TCM techniques such as acupuncture and ear point seed pressure yielded a much higher abstinence rate than pharmacotherapy and counseling. Findings are inconclusive, however, because most of the TCM studies were noncontrolled trials and did not provide a definition of "abstinence." Findings on the effectiveness of physician advice to quit smoking were also inconclusive. CONCLUSIONS: A review of smoking cessation studies revealed that pharmacotherapy was effective in China. More RCTs of TCM approaches and physician advice are needed with long-term follow-up assessments and biochemical verification of self-reported abstinence before these approaches are adopted as evidence-based smoking cessation interventions in China. PMID- 22249688 TI - A comparison of gambling behavior, problem gambling indices, and reasons for gambling among smokers and nonsmokers who gamble: evidence from a provincial gambling prevalence study. AB - INTRODUCTION: Numerous epidemiological and clinical studies have found that tobacco use and gambling frequently cooccur. Despite high rates of smoking among regular gamblers, the extent to which tobacco potentially influences gambling behavior and vice versa is poorly understood. The current study aimed to provide more insight into this relationship by directly comparing nonsmoking and smoking gamblers on gambling behavior, problem gambling indices, and reasons for gambling. METHODS: The data for this study came from the 2005 Newfoundland and Labrador Gambling Prevalence Study. Gamblers identified as nonsmokers (N = 997) were compared with gamblers who smoke (N = 622) on numerous gambling-related variables. Chi-square analyses were used to compare groups on demographic variables. Associations between smoking status and gambling criteria were assessed with a series of binary logistic regressions. RESULTS: The regression analyses revealed several significant associations between smoking status and past 12-month gambling. Higher problem gambling severity scores, use of alcohol/drugs while gambling, amount of money spent gambling, use of video lottery terminals, and reasons for gambling which focused on positive reinforcement/reward and negative reinforcement/relief were all associated with smoking. CONCLUSIONS: The findings suggest an association between smoking and potentially problematic gambling in a population-based sample. More research focused on the potential reinforcing properties of tobacco on the development and treatment of problematic gambling is needed. PMID- 22249689 TI - Post-operative infection and prophylactic antibiotic administration after radical cystectomy with orthotopic neobladder urinary diversion. AB - The purpose of this study was to investigate the association between prophylactic antibiotic administration (PAA) and post-operative infection in radical cystectomy with orthotopic neobladder urinary diversion carried out for patients with bladder cancer. Fifty-seven consecutive cases were analyzed retrospectively. Post-operative infections were categorized as urinary tract, wound, and remote infections. We used the antibiotics tazobactam/piperacillin (TAZ/PIPC), sulbactam/ampicillin (SBT/ABPC), flomoxef (FMOX), cefazolin (CEZ), cefotiam (CTM), and cefmetazole (CMZ). Twenty-five (43.9%) patients had post-operative infections. Five of these (8.77%) patients had wound infections, 22 (38.6%) patients had urinary tract infections, and 2 (3.51%) had remote infections. Our statistical analysis demonstrated that the patients with TAZ/PIPC used for PAA (5/18: 27.8%) had a significantly lower post-operative infection rate than patients with other antibiotics (24/39: 61.5%) (p = 0.0442). In addition, the patients with a shorter-duration PAA (within 72 h after the operation (48-72 h)) had a significantly lower rate of post-operative infections (12/33: 36.4%) than those with longer-duration PAA (longer than 72-96 h after the operation) (16/24: 66.7%) (p = 0.0239). Taken together, these results suggest that TAZ/PIPC with shorter PAA duration (within 72 h) might lead to a lower rate of post-operative infections. In conclusion, our data showed that PAA with TAZ/PIPC with a shorter duration PAA (within 72 h) might be recommended for radical cystectomy with orthotopic neobladder reconstruction. A prospective study based on our data is desirable to establish or revise guidelines for prophylactic medication for preventing post-operative infection after radical cystectomy with orthotopic neobladder urinary diversion. PMID- 22249690 TI - Risk of ischemia in glioma surgery: comparison of first and repeat procedures. AB - The role of repeat resection in the multimodal treatment of gliomas is unclear. Repeat surgery theoretically carries a higher risk of inducing neurological deficits, which might even out any advantage of cytoreduction. We sought to determine whether the occurrence of perioperative infarction is higher for repeat surgery than for first surgery, and sought to identify factors associated with the occurrence of postoperative infarction. Therefore, we searched our database to identify patients who were operated for primary or recurrent glial tumors between October 2007 and October 2010. We analyzed 177 procedures, of which 130 (73.4%) were first surgeries and 47 (26.5%) were repeat. Initial WHO grades, KPS scores, and age were evenly distributed between the groups. Forty-six (26.0%) patients had new DWI lesions on their postoperative MRI scan. Eighteen (10.2%) patients had new lesions greater than 4 cm(3). Among these were 11 (6.2%) patients, for whom the new lesion caused neurologic deficit. There was no difference between first and repeat surgery with regard to the occurrence of new DWI lesions (27.7 vs. 21.3%, P = 0.77) or neurological deficits (10.0 vs. 10.6%, P = 1.0). Tumor location in the insula, operculum, and temporal lobe was found to be significantly associated with the occurrence of new DWI lesions. We conclude that repeat surgery should not be withheld as a treatment option for patients with recurrent gliomas for fear of a higher risk of postoperative infarction or new neurologic deficit than the first surgery. PMID- 22249691 TI - Physiological 18F-FDG uptake by the spinal cord: is it a point of consideration for cancer patients? AB - It is essential to be familiar with normal patterns of (18)F FDG distribution in the whole body for accurate PET interpretation. We assessed FDG uptake by the spinal cord to evaluate its characteristics in cancer patients. For 101 cancer patients who underwent (18)F FDG PET/CT the spinal cord along its segments was visually assessed for FDG uptake, regarding MaxSUV-measurement >=1 as cut-off point. This assessment was correlated with the patient's database variables. MRI and FDG PET-CT follow-up were included in the evaluation of positive subjects with FDG cord uptake. Forty-nine (48.5%) were positive for FDG cord uptake. The most encountered sites were the eleventh and twelfth dorsal vertebrae (36/49; 73.5%), all cervical (24/49; 49%), and the first lumbar segments (19/49; 38.7%). 38/49 (77.6%) and 11/49 (22.4%) were detected in the winter and summer, respectively (P = 0.007). MRI was available for 25 of the positive FDG cord uptake patients and showed no cord abnormalities, and in follow-up FDG PET-CT studies within 3-6 months 41/49 (83.7%) faded completely, while stationary or reduced uptake was observed for the remainder (8/49; 16.3%). FDG uptake in multiple consecutive segments of the spinal cord is not uncommon in cancer patients. This must be recognized as physiological, to avoid misdiagnosis as malignant involvement. Such physiological uptake is mostly encountered in the cervical, last two dorsal, and first lumbar levels, and quite frequently in winter. PMID- 22249693 TI - Initial experience with bendamustine in patients with recurrent primary central nervous system lymphoma: a case report. AB - Novel therapeutic options for patients with recurrent primary central nervous system lymphoma (RPCNSL) are needed. Bendamustine, a bifunctional purine analog/alkylating agent, is approved for use in patients with progressive systemic indolent non-Hodgkin's B-cell lymphomas. Limited data suggests that bendamustine may partition into the brain in the setting of a disrupted blood brain barrier. This report describes the first known experience of patients with RPCNSL treated with bendamustine. Therapy was well-tolerated and best response was noted as stable disease after eight cycles of bendamustine followed by a subsequent local systemic recurrence found at five months follow-up. CNS involvement in this patient remained stable 20 + months post-bendamustine treatment. Based on our observations, further neuropharmacokinetic and efficacy studies with bendamustine may be warranted in this patient population. PMID- 22249694 TI - [Vertebroplasty for long-term pain reduction in osteoporotic vertebral body compression fractures. What is proven and what is unclear?]. PMID- 22249695 TI - [Update: minimally invasive intervention techniques]. PMID- 22249692 TI - Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway. AB - Glioma stem-like cells (GSCs) may be the initiating cells in glioblastoma (GBM) and contribute to the resistance of these tumors to conventional therapies. Development of novel chemotherapeutic agents and treatment approaches against GBM, especially those specifically targeting GSCs are thus necessary. In the present study, we found that a novel Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway inhibitor (WP1193) significantly decreased the proliferation of established glioma cell lines in vitro and inhibit the growth of glioma in vivo. To test the efficacy of WP1193 against GSCs, we then administrated WP1193 to GSCs isolated and expanded from multiple human GBM tumors. We revealed that WP1193 suppressed phosphorylation of JAK2 and STAT3 with high potency and demonstrated a dose-dependent inhibition of proliferation and neurosphere formation of GSCs. These effects were at least due in part to G1 arrest associated with down-regulation of cyclin D1 and up regulation of p21( Cip1/Waf-1 ). Furthermore, WP1193 exposure decreased expression of stem cell markers including CD133 and c-myc, and induced cell death in GSCs through apoptosis. Taken together, our data indicate that WP1193 is a potent small molecule inhibitor of the JAK2/STAT3 pathway that shows promise as a therapeutic agent against GBM by targeting GSCs. PMID- 22249696 TI - [Radiofrequency ablation - is a technique finished?]. AB - According to current scientific investigations radiofrequency ablation (RFA) as a local ablative tumor therapy for unresectable liver malignancies is currently accepted as the best therapeutic choice. The results of randomized trials justify RFA for small hepatocellular carcinomas (HCC) and RFA is considered to be a viable alternative to resection for inoperable patients with limited hepatic metastatic disease, especially from colorectal cancer (CRC LM). However, surgical resection still remains the gold standard for resectable CRC LM. The intraprocedural image guidance modality of choice is computed tomography (CT) alongside CT fluoroscopy. Contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI) are used for preprocedural lesion detection and differentiation as well as for follow-up and can be used to perform RFA procedures as well. This article highlights new developments in RFA. PMID- 22249697 TI - [Laser ablation. Do we still need it?]. AB - Laser ablation (LA) is momentarily the only invasive ablation procedure besides radiofrequency ablation (RFA) which can be performed entirely under magnetic resonance imaging (MRI) guidance. The long-term outcome and morbidity profiles are broadly identical for both modalities, excluding the RFA-specific prevalence for skin burns. The technical and logistic disadvantages of LA have been overcome since the introduction of miniaturized two-component applicators. The main advantage of LA is its superior MRI compatibility. Interference-free imaging during LA allows MR thermometric real-time therapy control without the need for RF filters. High-resolution thermometry in the target zone only makes sense without the extinction artifact of a metal probe and this condition is met only by the glass fibers of LA. An independent therapy monitoring is crucial in modern scenarios of oncologic quality management. PMID- 22249698 TI - [Microwave tumor ablation. New devices, new applications?]. AB - CLINICAL ISSUE: The majority of patients with hepatic malignancies are not amenable to surgical resection. In some of these cases minimally invasive ablative therapies are a treatment option. STANDARD TREATMENT: Besides radiofrequency ablation, the most common ablative therapies are cryoablation, laser ablation and microwave ablation. TREATMENT INNOVATIONS: The classic fields of application of microwave ablation are the treatment of malignancies of the liver, kidneys and lungs. Furthermore, cases of treatment of bone tumors and tumors of the adrenal gland have been reported as well as treatment of secondary hypersplenism. PERFORMANCE: The manufacturers of microwave systems pursue different strategies to reach an optimal ablation zone, such as water or gas cooling of the antenna, the simultaneous use of different antennas or an automatic modulation of the microwave energy and frequency. ACHIEVEMENTS: In contrast to other tumor ablation methods microwave ablation causes a direct heating of a tissue volume, thus this method is less vulnerable to the cooling effect of vessels in the ablation zone. Moreover the electric conductivity of the treated tissue does not influence microwave radiation so that microwave ablation has advantages for the treatment of high-resistance organs, such as the lungs or bone. Some publications have shown that microwave ablation causes larger ablation zones in less time in comparison to radiofrequency ablation. PRACTICAL RECOMMENDATIONS: Classic indications for microwave ablation are the treatment of malignancies of the liver, lungs and kidneys. Initial technical problems have been solved, so that an increasing significance of the microwave ablation among the ablative therapies is to be expected. PMID- 22249699 TI - [Cryoablation - back again?]. AB - CLINICAL ISSUE: Primary and secondary liver tumors often limit patient outcome and only a minority of patients are eligible for potential curative surgery. Minimally invasive treatments, such as radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation are alternative treatment options in a curative and palliative setting. One major limitation of RFA and MWA is the limited size of tumor ablation. Furthermore during the procedure the ablation size can only be roughly estimated using RFA and MWA. STANDARD TREATMENT: RFA is the standard modality of minimally invasive tumor therapy. In comparison cryoablation is rarely used despite its advantages. TREATMENT INNOVATIONS: Argon-helium-based cryoablation systems of the newest generation combine the advantage of small diameter applicators comparable with those of RFA and MWA systems with intrinsic advantages. ACHIEVEMENTS: Cryoablation is a minimally invasive treatment option with advantages, such as virtually unlimited ablation size, real-time visualization using computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound and intrinsic analgesic effects. On the other hand it is not very time-efficient in comparison to MWA. Especially in liver metastases RFA is the preferred treatment option. PRACTICAL RECOMMENDATIONS: Cryoablation is a fascinating treatment option in minimally invasive tumor treatment. It demonstrates good results in hepatocellular carcinoma within the Milan criteria and T1a renal cell carcinoma. Furthermore it is a well-established treatment modality for palliative pain management in bone tumors. PMID- 22249700 TI - [Irreversible electroporation - a new kid on the block?]. AB - CLINICAL/METHODICAL ISSUE: Minimally invasive tumor therapies are well established options in multi-modal oncological therapy regimes. So far the methods applied have been of a thermal nature and thus there are inherent limitations, most of all the so-called heat-sink effect. STANDARD RADIOLOGICAL METHODS: Radiofrequency ablation (RFA) and laser-induced thermotherapy (LITT) are well-established techniques. METHODICAL INNOVATIONS: Irreversible electroporation (IRE) could potentially become a novel therapy option with an enlarged spectrum of treatable lesions, i.e. close to blood vessels and potentially a lower rate of complications. PERFORMANCE: The IRE technique is currently the subject of early prospective trials and clinical studies have not yet shown any serious side effects. However, complete tumor ablation was not achieved in all cases (46 out of 69). ACHIEVEMENTS: Preclinical as well as clinical studies seem to show a promising efficiency in tumor ablation as well as a favorable complication profile especially with tumors in thermally critical locations. PRACTICAL RECOMMENDATIONS: Clinical long-term studies are currently under way assessing safety as well as efficiency. The data published so far look promising and considerably enlarge the spectrum of ablation techniques. PMID- 22249701 TI - [Transarterial ablation of hepatocellular carcinoma. Status and developments]. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and represents the main cause of death among European patients with liver cirrhosis. Only 30-40% of patients diagnosed with HCC are candidates for curative treatment options (e.g. surgical resection, liver transplantation or ablation). The remaining majority of patients must undergo local regional and palliative therapies. Transvascular ablation of HCC takes advantage of the fact that the hypervascularized HCC receives most of its blood supply from the hepatic artery. In this context transvascular ablation describes different therapy regimens which can be assigned to four groups: cTACE (conventional transarterial chemoembolization), bland embolization (transarterial embolization TAE), DEB-TACE (TACE with drug-eluting beads, DEB) and SIRT (selective internal radiation therapy, radioembolization). Conventional TACE is the most common type of transvascular ablation and represents a combination of intra-arterial chemotherapy and embolization with occlusion of the arterial blood supply. However, there is no standardized regimen with respect to the chemotherapeutic drug, the embolic agent, the usage of lipiodol and the interval between the TACE procedures. Even the exact course of a cTACE procedure (order of chemotherapy or embolization) is not standardized. It remains unclear whether or not intra arterial chemotherapy is definitely required as bland embolization using very small, tightly calibrated spherical particles (without intra-arterial administration of a chemotherapeutic drug) shows tumor necrosis comparable to cTACE. For DEB-TACE microparticles loaded with a chemotherapeutic drug combine the advantages of cTACE and bland embolization. Thereby, a continuing chemotherapeutic effect within the tumor might cause a further increase in intratumoral cytotoxicity and at the same time a decrease in systemic toxicity. PMID- 22249702 TI - [Stereotaxy and robotics for ablation - toy or tool?]. AB - CLINICAL AND METHODOLOGICAL ISSUES: Ablative technologies allow local curative tumor treatment by thermal tissue damage. An important prerequisite is the coverage of all tumor cells. Tumor size is the most important limiting factor. STANDARD RADIOLOGICAL METHODS: The drawbacks of conventional computed tomography/ultrasound/magnetic resonance imaging (CT/US/MRI) guided radiofrequency ablation (RFA) are the absence of planning software, imprecise probe placement, imprecise control of probe placement and the ablation zone as well as the lack of reliability and reproducibility. METHODOLOGICAL INNOVATIONS: Stereotactic and robot-assisted systems allow planning of multiple probe positions based on CT/MRI and positron emission tomography (PET) planning data. The probes can be precisely placed according to the coordinates of the image datasets. PERFORMANCE: The 1 and 3 year survival rates after stereotactic RFA (SRFA) of cholangiocellular carcinoma were 91% and 70% respectively and the median overall survival was 60 months. After SRFA of 189 colorectal liver metastases in 63 patients there was no significant difference in local recurrence rates between tumors < 3 cm (17.7%), 3-5 cm (11.1%) and > 5 cm (17.4%). The median overall survival was 33.2 months and the 1, 3, and 5 year overall survival rates after SRFA in patients with resectable colorectal cancer were 92%, 66% and 48%, respectively. ACHIEVEMENTS: In our opinion the excellent and, to a large extent user-independent results justify the increased efforts in time and costs especially for the treatment of patients with large and irregular tumors. PRACTICAL RECOMMENDATIONS: Stereotaxy and robotics are valuable tools for effective tumor ablation especially of large tumors and are likely to gain in importance in the next few years. PMID- 22249703 TI - [Ultrasound-guided image fusion with computed tomography and magnetic resonance imaging. Clinical utility for imaging and interventional diagnostics of hepatic lesions]. AB - Abdominal ultrasound is often the first-line imaging modality for assessing focal liver lesions. Due to various new ultrasound techniques, such as image fusion, global positioning system (GPS) tracking and needle tracking guided biopsy, abdominal ultrasound now has great potential regarding detection, characterization and treatment of focal liver lesions. Furthermore, these new techniques will help to improve the clinical management of patients before and during interventional procedures. This article presents the principle and clinical impact of recently developed techniques in the field of ultrasound, e.g. image fusion, GPS tracking and needle tracking guided biopsy and discusses the results based on a feasibility study on 20 patients with focal hepatic lesions. PMID- 22249704 TI - [Update on interstitial brachytherapy]. AB - CLINICAL/METHODICAL ISSUE: Minimally invasive treatment procedures, such as image guided local tumour ablation have gained increasing relevance in oncologic concepts. Limitations of thermal ablation procedures have led to the development of percutaneous, computed tomography (CT) guided brachytherapy. STANDARD RADIOLOGICAL METHODS: Thermal ablation procedures, such as radiofrequency ablation (RFA) and laser-induced thermotherapy (LITT) show limitations regarding maximum tumour size (<5 cm), cooling effects of adjacent vessels and surrounding risk structures. METHODICAL INNOVATIONS: The image-guided interstitial brachytherapy allows the single application of high-dose rate (HDR) irradiation with an extensive protracted cytotoxic effect. Adjacent risk structures play a minor role due to the steep dose gradient outside the clinical target volume. PERFORMANCE: Studies using CT-guided brachytherapy resulted in a local tumour control rate of approximately 90% after 12 months in the treatment of hepatocellular carcinoma (HCC) and 70-90% in the treatment of colorectal metastases or cholangiocellular carcinoma (CCC). Similar response rates were also seen in the treatment of metastases of renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) or neuroendocrine tumours. In colorectal liver metastases and HCC the method has proven to have a positive impact on prognosis. ACHIEVEMENTS: In contrast to thermal ablation the method can be used without restriction with respect to tumour location. Cooling effects do not play a role. It has already been applied in more than 5,000 cases and it is used in clinical routine. PRACTICAL RECOMMENDATIONS: Image-guided brachytherapy is safe and effective and has found its way into the clinical routine. PMID- 22249705 TI - [Radiology and pregnancy. Principles, general requirements and exposure]. AB - In a radiology department there are frequently asked questions associated with pregnant and breast feeding women. These are related to either pregnant patients or staff members or the questions are centered on the fetus as a patient. For pregnant patients the potential exposure to the mother and the fetus related to the imaging modality selected as well as the effects of the necessary contrast media must be taken into account. Even for methods without ionizing radiation possible limitations in the use for pregnant women must be discussed. Finally, this medical check defines the imaging modality and the necessary protocol and contrast media. The present article describes the legal requirements in Germany, the technical exposure and pharmacological risks for the pregnant woman and the fetus regarding imaging modalities with and without ionizing radiation. The forthcoming second article will address the risk analysis for examinations with ionizing radiation and will present recommendations for typical clinical imaging problems. PMID- 22249707 TI - Group-sensitive multiple kernel learning for object recognition. AB - In this paper, a group-sensitive multiple kernel learning (GS-MKL) method is proposed for object recognition to accommodate the intraclass diversity and the interclass correlation. By introducing the "group" between the object category and individual images as an intermediate representation, GS-MKL attempts to learn group-sensitive multikernel combinations together with the associated classifier. For each object category, the image corpus from the same category is partitioned into groups. Images with similar appearance are partitioned into the same group, which corresponds to the subcategory of the object category. Accordingly, intraclass diversity can be represented by the set of groups from the same category but with diverse appearances; interclass correlation can be represented by the correlation between groups from different categories. GS-MKL provides a tractable solution to adapt multikernel combination to local data distribution and to seek a tradeoff between capturing the diversity and keeping the invariance for each object category. Different from the simple hybrid grouping strategy that solves sample grouping and GS-MKL training independently, two sample grouping strategies are proposed to integrate sample grouping and GS-MKL training. The first one is a looping hybrid grouping method, where a global kernel clustering method and GS-MKL interact with each other by sharing group-sensitive multikernel combination. The second one is a dynamic divisive grouping method, where a hierarchical kernel-based grouping process interacts with GS-MKL. Experimental results show that performance of GS-MKL does not significantly vary with different grouping strategies, but the looping hybrid grouping method produces slightly better results. On four challenging data sets, our proposed method has achieved encouraging performance comparable to the state-of-the-art and outperformed several existing MKL methods. PMID- 22249708 TI - Image fusion using higher order singular value decomposition. AB - A novel higher order singular value decomposition (HOSVD)-based image fusion algorithm is proposed. The key points are given as follows: 1) Since image fusion depends on local information of source images, the proposed algorithm picks out informative image patches of source images to constitute the fused image by processing the divided subtensors rather than the whole tensor; 2) the sum of absolute values of the coefficients (SAVC) from HOSVD of subtensors is employed for activity-level measurement to evaluate the quality of the related image patch; and 3) a novel sigmoid-function-like coefficient-combining scheme is applied to construct the fused result. Experimental results show that the proposed algorithm is an alternative image fusion approach. PMID- 22249709 TI - Entropy-functional-based online adaptive decision fusion framework with application to wildfire detection in video. AB - In this paper, an entropy-functional-based online adaptive decision fusion (EADF) framework is developed for image analysis and computer vision applications. In this framework, it is assumed that the compound algorithm consists of several subalgorithms, each of which yields its own decision as a real number centered around zero, representing the confidence level of that particular subalgorithm. Decision values are linearly combined with weights that are updated online according to an active fusion method based on performing entropic projections onto convex sets describing subalgorithms. It is assumed that there is an oracle, who is usually a human operator, providing feedback to the decision fusion method. A video-based wildfire detection system was developed to evaluate the performance of the decision fusion algorithm. In this case, image data arrive sequentially, and the oracle is the security guard of the forest lookout tower, verifying the decision of the combined algorithm. The simulation results are presented. PMID- 22249710 TI - Scale-invariant features for 3-D mesh models. AB - In this paper, we present a framework for detecting interest points in 3-D meshes and computing their corresponding descriptors. For that, we propose an intrinsic scale detection scheme per interest point and utilize it to derive two scale invariant local features for mesh models. First, we present the scale-invariant spin image local descriptor that is a scale-invariant formulation of the spin image descriptor. Second, we adapt the scale-invariant feature transform feature to mesh data by representing the vicinity of each interest point as a depth map and estimating its dominant angle using the principal component analysis to achieve rotation invariance. The proposed features were experimentally shown to be robust to scale changes and partial mesh matching, and they were compared favorably with other local mesh features on the SHREC'10 and SHREC'11 testbeds. We applied the proposed local features to mesh retrieval using the bag-of features approach and achieved state-of-the-art retrieval accuracy. Last, we applied the proposed local features to register models to scanned depth scenes and achieved high registration accuracy. PMID- 22249711 TI - Higher degree total variation (HDTV) regularization for image recovery. AB - We introduce novel image regularization penalties to overcome the practical problems associated with the classical total variation (TV) scheme. Motivated by novel reinterpretations of the classical TV regularizer, we derive two families of functionals involving higher degree partial image derivatives; we term these families as isotropic and anisotropic higher degree TV (HDTV) penalties, respectively. The isotropic penalty is the L(1) - L(2) mixed norm of the directional image derivatives, while the anisotropic penalty is the separable L(1) norm of directional derivatives. These functionals inherit the desirable properties of standard TV schemes such as invariance to rotations and translations, preservation of discontinuities, and convexity. The use of mixed norms in isotropic penalties encourages the joint sparsity of the directional derivatives at each pixel, thus encouraging isotropic smoothing. In contrast, the fully separable norm in the anisotropic penalty ensures the preservation of discontinuities, while continuing to smooth along the linelike features; this scheme thus enhances the linelike image characteristics analogous to standard TV. We also introduce efficient majorize-minimize algorithms to solve the resulting optimization problems. The numerical comparison of the proposed scheme with classical TV penalty, current second-degree methods, and wavelet algorithms clearly demonstrate the performance improvement. Specifically, the proposed algorithms minimize the staircase and ringing artifacts that are common with TV and wavelet schemes, while better preserving the singularities. We also observe that anisotropic HDTV penalty provides consistently improved reconstructions compared with the isotropic HDTV penalty. PMID- 22249712 TI - Image editing with spatiograms transfer. AB - Histogram equalization is a well-known method for image contrast enhancement. Nevertheless, as histograms do not include any information on the spatial repartition of colors, their application to local image editing problems remains limited. To cope with this lack of spatial information, spatiograms have been recently proposed for tracking purposes. A spatiogram is an image descriptor that combines a histogram with the mean and the variance of the position of each color. In this paper, we address the problem of local retouching of images by proposing a variational method for spatiogram transfer. More precisely, a reference spatiogram is used to modify the color value of a given region of interest of the processed image. Experiments on shadow removal and inpainting demonstrate the strength of the proposed approach. PMID- 22249713 TI - Synthetic aperture radar autofocus based on a bilinear model. AB - Autofocus algorithms are used to restore images in nonideal synthetic aperture radar imaging systems. In this paper, we propose a bilinear parametric model for the unknown image and the nuisance phase parameters and derive an efficient maximum-likelihood autofocus (MLA) algorithm. In the special case of a simple image model and a narrow range of look angles, MLA coincides with the successful multichannel autofocus (MCA). MLA can be interpreted as a generalization of MCA to a larger class of models with a larger range of look angles. We analyze its advantages over previous extensions of MCA in terms of identifiability conditions and noise sensitivity. As a byproduct, we also propose numerical approximations to the difficult constant modulus quadratic program that lies at the core of these algorithms. We demonstrate the superior performance of our proposed methods using computer simulations in both the correct and mismatched system models. MLA performs better than other methods, both in terms of the mean squared error and visual quality of the restored image. PMID- 22249714 TI - 3-D discrete shearlet transform and video processing. AB - In this paper, we introduce a digital implementation of the 3-D shearlet transform and illustrate its application to problems of video denoising and enhancement. The shearlet representation is a multiscale pyramid of well localized waveforms defined at various locations and orientations, which was introduced to overcome the limitations of traditional multiscale systems in dealing with multidimensional data. While the shearlet approach shares the general philosophy of curvelets and surfacelets, it is based on a very different mathematical framework, which is derived from the theory of affine systems and uses shearing matrices rather than rotations. This allows a natural transition from the continuous setting to the digital setting and a more flexible mathematical structure. The 3-D digital shearlet transform algorithm presented in this paper consists in a cascade of a multiscale decomposition and a directional filtering stage. The filters employed in this decomposition are implemented as finite-length filters, and this ensures that the transform is local and numerically efficient. To illustrate its performance, the 3-D discrete shearlet transform is applied to problems of video denoising and enhancement, and compared against other state-of-the-art multiscale techniques, including curvelets and surfacelets. PMID- 22249715 TI - Enzymatic decolorization of spent textile dyeing baths composed by mixtures of synthetic dyes and additives. AB - The effects of different components of real dyeing bath formulations, such as the equalizing and fixing additives-acids, salts, and surfactants-on the decolorization catalyzed by Funalia trogii enzymatic extracts, were investigated to understand their influence on the recalcitrance to biodegradation of this type of wastewater. The decolorization of selected dyes and dye mixtures after tissue dyeing was performed in the presence/absence of auxiliary compounds. All spent dyeing baths were enzymatically decolorized to different extents, by the addition of extracts containing laccase only or laccase plus cellobiose dehydrogenase. Whereas surfactant auxiliaries, in some instances, inhibit the decolorization of spent dyeing baths, in several occurrences the acid/salt additives favor the enzymatic process. In general, the complete spent dyeing formulations are better degraded than those containing the dyes only. The comparison of extracellular extracts obtained from spent straws from the commercial growth of Pleurotus sp. mushrooms with those from F. trogii reveals similar decolorization extents thus allowing to further reduce the costs of bioremediation. PMID- 22249716 TI - Analysis of alkane-dependent methanogenic community derived from production water of a high-temperature petroleum reservoir. AB - Microbial assemblage in an n-alkanes-dependent thermophilic methanogenic enrichment cultures derived from production waters of a high-temperature petroleum reservoir was investigated in this study. Substantially higher amounts of methane were generated from the enrichment cultures incubated at 55 degrees C for 528 days with a mixture of long-chain n-alkanes (C(15)-C(20)). Stoichiometric estimation showed that alkanes-dependent methanogenesis accounted for about 19.8% of the total amount of methane expected. Hydrogen was occasionally detected together with methane in the gas phase of the cultures. Chemical analysis of the liquid cultures resulted only in low concentrations of acetate and formate. Phylogenetic analysis of the enrichment revealed the presence of several bacterial taxa related to Firmicutes, Thermodesulfobiaceae, Thermotogaceae, Nitrospiraceae, Dictyoglomaceae, Candidate division OP8 and others without close cultured representatives, and Archaea predominantly related to uncultured members in the order Archaeoglobales and CO(2)-reducing methanogens. Screening of genomic DNA retrieved from the alkanes-amended enrichment cultures also suggested the presence of new alkylsuccinate synthase alpha-subunit (assA) homologues. These findings suggest the presence of poorly characterized (putative) anaerobic n alkanes degraders in the thermophilic methanogenic enrichment cultures. Our results indicate that methanogenesis of alkanes under thermophilic condition is likely to proceed via syntrophic acetate and/or formate oxidation linked with hydrogenotrophic methanogenesis. PMID- 22249717 TI - Fungal aryl-alcohol oxidase: a peroxide-producing flavoenzyme involved in lignin degradation. AB - Aryl-alcohol oxidase (AAO) is an extracellular flavoprotein providing the H(2)O(2) required by ligninolytic peroxidases for fungal degradation of lignin, the key step for carbon recycling in land ecosystems. O(2) activation by Pleurotus eryngii AAO takes place during the redox-cycling of p-methoxylated benzylic metabolites secreted by the fungus. Only Pleurotus AAO sequences were available for years, but the number strongly increased recently due to sequencing of different basidiomycete genomes, and a comparison of 112 GMC (glucose-methanol choline oxidase) superfamily sequences including 40 AAOs is presented. As shown by kinetic isotope effects, alcohol oxidation by AAO is produced by hydride transfer to the flavin, and hydroxyl proton transfer to a base. Moreover, site directed mutagenesis studies showed that His502 activates the alcohol substrate by proton abstraction, and this result was extended to other GMC oxidoreductases where the nature of the base was under discussion. However, in contrast with that proposed for GMC oxidoreductases, the two transfers are not stepwise but concerted. Alcohol docking at the buried AAO active site resulted in only one catalytically relevant position for concerted transfer, with the pro-R alpha hydrogen at distance for hydride abstraction. The expected hydride-transfer stereoselectivity was demonstrated, for the first time in a GMC oxidoreductase, by using the (R) and (S) enantiomers of alpha-deuterated p-methoxybenzyl alcohol. Other largely unexplained aspects of AAO catalysis (such as the unexpected specificity on substituted aldehydes) can also be explained in the light of the recent results. Finally, the biotechnological interest of AAO in flavor production is extended by its potential in production of chiral compounds taking advantage from the above-described stereoselectivity. PMID- 22249718 TI - In vitro synthesis of polyhydroxyalkanoate (PHA) incorporating lactate (LA) with a block sequence by using a newly engineered thermostable PHA synthase from Pseudomonas sp. SG4502 with acquired LA-polymerizing activity. AB - Recently, we succeeded in isolating a thermotolerant bacterium, Pseudomonas sp. SG4502, which is capable of accumulating polyhydroxyalkanoate (PHA) even at 55 degrees C, as a source of thermostable enzymes. In this study, we cloned a pha locus from the bacterium and identified two genes encoding PHA synthases (PhaC1(SG) and PhaC2(SG)). Two mutations, Ser324Thr and Gln480Lys, corresponding to those of a lactate (LA)-polymerizing enzyme (LPE) from mesophilic Pseudomonas sp. 61-3 were introduced into PhaC1(SG) to evaluate the potential of the resulting protein as a "thermostable LPE". The mutated PhaC1(SG) [PhaC1(SG)(STQK)] showed high thermal stability in synthesizing P(LA-co-3HB) in an in vitro reaction system under a range of high temperatures. Requirement of 3HBCoA as a priming unit for LA polymerization by the LPE has been suggested in both of the in vitro and in vivo experiments. Based on the finding, the PhaC1(SG)(STQK)-mediated synthesis of a LA-based copolymer with a block sequence was achieved in the in vitro system by sequential feeding of the corresponding two substrates. This in vitro reaction system using the thermostable LPE provides us with a versatile way to synthesize the various types of LA-based copolymers with desired sequence patterns, random or block, depending on the way of supplying hydroxyalkanoates (mixed or sequential feeding). PMID- 22249719 TI - Intestinal microbiota associated with differential feed conversion efficiency in chickens. AB - Analysis of model systems, for example in mice, has shown that the microbiota in the gastrointestinal tract can play an important role in the efficiency of energy extraction from diets. The study reported here aimed to determine whether there are correlations between gastrointestinal tract microbiota population structure and energy use in chickens. Efficiency in converting food into muscle mass has a significant impact on the intensive animal production industries, where feed represents the major portion of production costs. Despite extensive breeding and selection efforts, there are still large differences in the growth performance of animals fed identical diets and reared under the same conditions. Variability in growth performance presents management difficulties and causes economic loss. An understanding of possible microbiota drivers of these differences has potentially important benefits for industry. In this study, differences in cecal and jejunal microbiota between broiler chickens with extreme feed conversion capabilities were analysed in order to identify candidate bacteria that may influence growth performance. The jejunal microbiota was largely dominated by lactobacilli (over 99% of jejunal sequences) and showed no difference between the birds with high and low feed conversion ratios. The cecal microbial community displayed higher diversity, and 24 unclassified bacterial species were found to be significantly (<0.05) differentially abundant between high and low performing birds. Such differentially abundant bacteria represent target populations that could potentially be modified with prebiotics and probiotics in order to improve animal growth performance. PMID- 22249720 TI - Disruption of the acetate kinase (ack) gene of Clostridium acetobutylicum results in delayed acetate production. AB - In microorganisms, the enzyme acetate kinase (AK) catalyses the formation of ATP from ADP by de-phosphorylation of acetyl phosphate into acetic acid. A mutant strain of Clostridium acetobutylicum lacking acetate kinase activity is expected to have reduced acetate and acetone production compared to the wild type. In this work, a C. acetobutylicum mutant strain with a selectively disrupted ack gene, encoding AK, was constructed and genetically and physiologically characterized. The ack (-) strain showed a reduction in acetate kinase activity of more than 97% compared to the wild type. The fermentation profiles of the ack (-) and wild-type strain were compared using two different fermentation media, CGM and CM1. The latter contains acetate and has a higher iron and magnesium content than CGM. In general, fermentations by the mutant strain showed a clear shift in the timing of peak acetate production relative to butyrate and had increased acid uptake after the onset of solvent formation. Specifically, in acetate containing CM1 medium, acetate production was reduced by more than 80% compared to the wild type under the same conditions, but both strains produced similar final amounts of solvents. Fermentations in CGM showed similar peak acetate and butyrate levels, but increased acetoin (60%), ethanol (63%) and butanol (16%) production and reduced lactate (-50%) formation by the mutant compared to the wild type. These findings are in agreement with the proposed regulatory function of butyryl phosphate as opposed to acetyl phosphate in the metabolic switch of solventogenic clostridia. PMID- 22249721 TI - Enzymatic biotransformation of ginsenoside Rb1 to 20(S)-Rg3 by recombinant beta glucosidase from Microbacterium esteraromaticum. AB - Microbacterium esteraromaticum was isolated from ginseng field. The beta glucosidase gene (bgp1) from M. esteraromaticum was cloned and expressed in Escherichia coli BL21 (DE3). The bgp1 gene consists of 2,496 bp encoding 831 amino acids which have homology to the glycosyl hydrolase family 3 protein domain. The recombinant beta-glucosidase enzyme (Bgp1) was purified and characterized. The molecular mass of purified Bgp1 was 87.5 kDa, as determined by SDS-PAGE. Using 0.1 mg ml(-1) enzyme in 20 mM sodium phosphate buffer at 37 degrees C and pH 7.0, 1.0 mg ml(-1) ginsenoside Rb1 was transformed into 0.444 mg ml(-1) ginsenoside Rg3 within 6 h. The Bgp1 sequentially hydrolyzed the outer and inner glucose attached to the C-20 position of ginsenosides Rb1. Bgp1 hydrolyzed the ginsenoside Rb1 along the following pathway: Rb1 -> Rd -> 20(S)-Rg3. This is the first report of the biotransformation of ginsenoside Rb1 to ginsenoside 20(S) Rg3 using the recombinant beta-glucosidase. PMID- 22249722 TI - SUMO fusion system facilitates soluble expression and high production of bioactive human fibroblast growth factor 23 (FGF23). AB - As a key humoral regulator of phosphate homeostasis and its involvement in the pathogenesis of human disease, human fibroblast growth factor 23 (hFGF23) has become a particularly attractive therapeutic target. To prepare soluble and bioactive recombinant human FGF23 to meet the increasing demand in its pharmacological application, small ubiquitin-related modifier (SUMO)-FGF23 fusion gene and FGF23 non-fusion gene were amplified by standard PCR methods and cloned into vector pET-22b and pET-3c, then transformed into Escherichia coli Rosetta (DE3) and BL21 (DE3). The best combination of plasmid and host strain was screened, and only Rosetta (DE3)/pET-SUMO-FGF23 was screened for rhFGF23 protein expressed. The average bacterial yield and the soluble expression level of recombinant hFGF23 of three batches attained 687 +/- 18 g and 30 +/- 1.5%, respectively, after treatment with 0.4 mM isopropyl-thio-beta-galactopyranoside for 19 h at 16 degrees C in a 30-L fermentor, after which it was purified by DEAE Sepharose FF and nickel nitrilotriacetic acid affinity chromatography. Once cleaved by the SUMO protease, the recombinant human FGF23 was released from the fusion protein. The purity of rFGF23 was shown by high performance liquid chromatography to be greater than 90% and the yield was 60 +/- 1.5 mg/L. In vitro data showed that the purified rFGF23 can induce the phosphorylation of mitogen activated protein kinases in the glioma U251 cell. The results of in vivo animal experiments also showed that rFGF23 could decrease the concentration in the plasma of normal rats fed with a fixed formula diet. PMID- 22249723 TI - Characterization of alcohol dehydrogenase 3 of the thermotolerant methylotrophic yeast Hansenula polymorpha. AB - In this study, we identified and characterized mitochondrial alcohol dehydrogenase 3 from the thermotolerant methylotrophic yeast Hansenula polymorpha (HpADH3). The amino acid sequence of HpADH3 shares over 70% of its identity with the alcohol dehydrogenases of other yeasts and exhibits the highest similarity of 91% with the alcohol dehydrogenase 1 of H. polymorpha. However, unlike the cytosolic HpADH1, HpADH3 appears to be a mitochondrial enzyme, as a mitochondrial targeting extension exists at its N terminus. The recombinant HpADH3 overexpressed in Escherichia coli showed similar catalytic efficiencies for ethanol oxidation and acetaldehyde reduction. The HpADH3 displayed substrate specificities with clear preferences for medium chain length primary alcohols and acetaldehyde for an oxidation reaction and a reduction reaction, respectively. Although the H. polymorpha ADH3 gene was induced by ethanol in the culture medium, both an ADH isozyme pattern analysis and an ADH activity assay indicated that HpADH3 is not the major ADH in H. polymorpha DL-1. Moreover, HpADH3 deletion did not affect the cell growth on different carbon sources. However, when the HpADH3 mutant was complemented by an HpADH3 expression cassette fused to a strong constitutive promoter, the resulting strain produced a significantly increased amount of ethanol compared to the wild-type strain in a glucose medium. In contrast, in a xylose medium, the ethanol production was dramatically reduced in an HpADH3 overproduction strain compared to that in the wild-type strain. Taken together, our results suggest that the expression of HpADH3 would be an ideal engineering target to develop H. polymorpha as a substrate specific bioethanol production strain. PMID- 22249724 TI - Degradation of the novel herbicide ZJ0273 by Amycolatopsis sp. M3-1 isolated from soil. AB - ZJ0273, propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy) benzylamino) benzoate, is a novel and broad-spectrum herbicide. In this study, 15 bacteria capable of utilizing ZJ0273 as the sole carbon source were isolated from soil. One of the isolates belonged to the family Amycolatopsis and was designated to Amycolatopsis sp. M3-1; at 30 degrees C and pH 7.0, degradation rate of ZJ0273 could reach at 59.3% and 68.5% in 25 days and 60 days, respectively. Furthermore, six metabolites (M1-M6) during the degradation of ZJ0273 by Amycolatopsis sp. M3-1 were identified by a combination with multi-position (14)C-labeled compounds (B ZJ0273 and C-ZJ0273), chromatography, liquid scintillation spectrometer, and LC MS, a novel pathway of ZJ0273 degradation by Amycolatopsis sp. M3-1 was proposed based on the identified metabolites and their biodegradation courses. ZJ0273 was initially hydrolyzed into M1 (4-(2-(4,6-dimethoxypyrimidin-2-yloxy) benzylamino) benzoic acid), then further oxidized into M3 (2-(4,6-dimethoxypyrimidin-2-yloxy) benzoic acid). M1 also could undergo a carbonylation into M2 (4-(2-(4,6 dimethoxypyrimidin-2-yloxy) benzamido) benzoic acid), and then its C-N and C-O bonds were cleaved to yield M3 (2-(4,6-dimethoxypyrimidin-2-yloxy) benzoic acid) and M4 (4,6-dimethoxypyrimidin-2-ol), respectively. Moreover, another two new metabolites, M5 (2-(4-hydroxy, 6-methoxypyrimidin-2-yloxy) benzoic acid) and M6 (2, 4-dihydroxy-pyrimidine) were found. M5 was formed through de-methyl of M3 and then hydrolyzed into M6. PMID- 22249725 TI - Optimization of enzymatic hydrolysis of pretreated rice straw and ethanol production. AB - Cellulase, Tween 80, and beta-glucosidase loading were studied and optimized by response surface methodology to improve saccharification. Microwave alkali pretreated rice straw used as substrate for onsite enzyme production by Aspergillus heteromorphus and Trichoderma reesei. The highest enzymatic hydrolysis (84%) was obtained from rice straw at crude enzyme loading of 10 FPU/gds of cellulase, 0.15% Tween 80, and 100 international unit/g dry solids of beta-glucosidase activities. Enzymatic hydrolyzate of pretreated rice straw was used for ethanol production by Saccharomyces cerevisiae, Scheffersomyces stipitis, and by co-culture of both. The yield of ethanol was 0.50, 0.47, and 0.48 g(p)/g(s) by S. cerevisiae, S. stipitis, and by co-culture, respectively, using pretreated rice straw hydrolyzate. The co-culture of S. cerevisiae and S. stipitis produced 25% more ethanol than S. cerevisiae alone and 31% more ethanol than S. stipitis alone. During anaerobic fermentation 65.08, 36.45, and 50.31 MUmol/ml CO(2) released by S. cerevisiae, S. stipitis, and by co-culture, respectively. The data indicated that saccharification efficiency using optimized crude enzyme cocktail was good, and enzymatic hydrolyzate could be fermented to produce ethanol. PMID- 22249727 TI - Transplantation: Potential of intestinal microbiota profile as a diagnostic biomarker of small bowel transplant rejection. PMID- 22249728 TI - Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach. AB - Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis. NAFLD affects both adults and children who present with particular risk factors, including obesity, sedentary lifestyle and/or a predisposing genetic background. The escalation of the prevalence of NAFLD in children worldwide is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. The etiopathogenesis of primary NAFLD in children is unknown; however, considerable knowledge about the mechanisms of liver damage that occur during disease progression has been gathered over the past 30 years. Understanding the pathogenetic mechanisms, together with the histological pattern, provide the basis to characterize potential early predictors of the disease, suitable noninvasive diagnostic tools and design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD that showed encouraging results, to date, no treatment guidelines exist for children with NAFLD. In this Review, we provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis and treatment of NAFLD in children and adolescents. PMID- 22249729 TI - IBS: Blocking the neurokinin 1 receptor reduces anxiety and pain in women with IBS. PMID- 22249730 TI - Transplantation: Expression levels of iron homeostasis genes predict liver graft tolerance. PMID- 22249733 TI - Dyspepsia: Acotiamide can relieve symptoms of functional dyspepsia. PMID- 22249734 TI - Pancreas: Cortical thickness--a useful indicator in painful chronic pancreatitis? PMID- 22249735 TI - IBD: Phase II results for IBD drugs. PMID- 22249736 TI - Esophageal cancer: Matrix metalloproteinase 10 is associated with survival in patients with esophageal squamous cell carcinoma. PMID- 22249737 TI - Obesity: Reduction in hepatic left lobe volume is a good indicator of metabolic improvement after bariatric surgery. PMID- 22249740 TI - Hepatitis: Brain endothelial cells support HCV entry and replication. PMID- 22249741 TI - A successful birth of healthy monozygotic dichorionic diamniotic (DD) twins of the same gender following a single vitrified-warmed blastocyst transfer. AB - PURPOSE: To report the world's first case of live monozygotic dichorionic diamniotic (DD) twins after a single vitrified-warmed blastocyst transfer in a cycle during which hormone supplements were given. METHODS AND RESULTS: The patient was a 39-year-old woman with tubal factor infertility. Six oocytes were retrieved and three blastocysts were vitrified after insemination with her husband's sperm. Two months later, a single warmed blastocyst was transferred on the fifth day after progesterone supplementation during the luteal phase. Two gestational sacs and fetuses with heartbeats showing lambda sign under ultrasonography were recognized at 7 weeks of gestation and the patient gave birth to two female infants at gestational 33 weeks. The pathological examination demonstrated that the DD twin placentas fused in the third trimester. CONCLUSIONS: This report suggests that the splitting of the transferred embryo took place after the blastocyst stage and the popular credo that the timing of embryo division governs the placental configuration of monozygotic twins (MZT) must be re-examined as to its veracity. PMID- 22249742 TI - Ani s 1 and Ani s 7 recombinant allergens are able to differentiate distinct Anisakis simplex-associated allergic clinical disorders. AB - Diagnosis in gastro-allergic anisakiasis (GAA) is straightforward, when clinical history is combined with further allergological evaluation of specific IgE by means of skin prick test and serum specific IgE. In Anisakis simplex sensitisation associated chronic urticaria (CU+), clinical evaluation of possible previous parasitism is difficult, and positive serum specific IgE could be due to cross-reactivity or other unknown factors. In this study, we evaluated the association between IgE seropositivity to the recombinant allergens Ani s 1 and Ani s 7 and several A. simplex-associated allergic disorders. Twenty-eight patients with GAA and 40 patients with CU+ were studied and their IgE responses were compared with a control group composed of patients with chronic urticaria not sensitized to A. simplex (CU-) according to the skin prick test, as well as a group of 15 healthy subjects not referring urticaria or currently A. simplex associated symptoms. 82.1% of GAA patients and 42.5% of CU+ patients were positive for Ani s 1 (P < 0.001), while the Ani s 7 allergen was recognized by 92.9 and 92.5% of sera from patients with GAA and CU+, respectively. The combined positivity obtained for both allergens reached 100% in GAA, and 95% in CU+. IgE determinations to Ani s 1 and Ani s 7 allergens are useful to diagnose the Anisakis infections and to differentiate among several A. simplex-associated allergic disorders. The IgE responses to Ani s 1 are mainly associated with GAA, while this molecule cannot be considered a major allergen in CU+ patients. PMID- 22249743 TI - Exploring the role of prolactin in psoriasis. AB - Prolactin (PRL) is well recognised for its role(s) in mammary gland development and function. Moreover, its role in skin biology, including the potent regulation of human hair growth, is becoming clearer. Less widely appreciated, however, is the potential role of PRL in the pathobiology of psoriasis. While the relationship between PRL and psoriasis remains enigmatic, several recent publications on the PRL-psoriasis connection have demonstrated a reawakening of interest in this conundrum. We take the occasion of these reports to underscore the importance of dissecting the role(s) of PRL in the aetiopathology of psoriasis, not least since this may help to identify novel hormonal treatment strategies in its management. PMID- 22249744 TI - Automatic image annotation and retrieval using group sparsity. AB - Automatically assigning relevant text keywords to images is an important problem. Many algorithms have been proposed in the past decade and achieved good performance. Efforts have focused upon model representations of keywords, whereas properties of features have not been well investigated. In most cases, a group of features is preselected, yet important feature properties are not well used to select features. In this paper, we introduce a regularization-based feature selection algorithm to leverage both the sparsity and clustering properties of features, and incorporate it into the image annotation task. Using this group sparsity-based method, the whole group of features [e.g., red green blue (RGB) or hue, saturation, and value (HSV)] is either selected or removed. Thus, we do not need to extract this group of features when new data comes. A novel approach is also proposed to iteratively obtain similar and dissimilar pairs from both the keyword similarity and the relevance feedback. Thus, keyword similarity is modeled in the annotation framework. We also show that our framework can be employed in image retrieval tasks by selecting different image pairs. Extensive experiments are designed to compare the performance between features, feature combinations, and regularization-based feature selection methods applied on the image annotation task, which gives insight into the properties of features in the image annotation task. The experimental results demonstrate that the group sparsity-based method is more accurate and stable than others. PMID- 22249745 TI - Influence of electron correlation and degeneracy on the Fukui matrix and extension of frontier molecular orbital theory to correlated quantum chemical methods. AB - The Fukui function is considered as the diagonal element of the Fukui matrix in position space, where the Fukui matrix is the derivative of the one particle density matrix (1DM) with respect to the number of electrons. Diagonalization of the Fukui matrix, expressed in an orthogonal orbital basis, explains why regions in space with negative Fukui functions exist. Using a test set of molecules, electron correlation is found to have a remarkable effect on the eigenvalues of the Fukui matrix. The Fukui matrices at the independent electron model level are mathematically proven to always have an eigenvalue equal to exactly unity while the rest of the eigenvalues possibly differ from zero but sum to zero. The loss of idempotency of the 1DM at correlated levels of theory causes the loss of these properties. The influence of electron correlation is examined in detail and the frontier molecular orbital concept is extended to correlated levels of theory by defining it as the eigenvector of the Fukui matrix with the largest eigenvalue. The effect of degeneracy on the Fukui matrix is examined in detail, revealing that this is another way by which the unity eigenvalue and perfect pairing of eigenvalues can disappear. PMID- 22249746 TI - Induction of trimeric [Mg3(OH)(CO2)6] in a porous framework by a desymmetrized tritopic ligand. AB - The use of a desymmetrized tritopic ligand with both carboxyl and pyridyl functionalities leads to the first occurrence of the [Mg(3)(MU(3)-OH)(CO(2))(6)] trimer as the 3-D framework building block in a porous crystal that shows relatively high H(2) uptake (1.37% at 77 K and 1 atm). PMID- 22249747 TI - Pharmacophore modeling, molecular docking, and molecular dynamics simulation approaches for identifying new lead compounds for inhibiting aldose reductase 2. AB - Aldose reductase 2 (ALR2), which catalyzes the reduction of glucose to sorbitol using NADP as a cofactor, has been implicated in the etiology of secondary complications of diabetes. A pharmacophore model, Hypo1, was built based on 26 compounds with known ALR2-inhibiting activity values. Hypo1 contains important chemical features required for an ALR2 inhibitor, and demonstrates good predictive ability by having a high correlation coefficient (0.95) as well as the highest cost difference (128.44) and the lowest RMS deviation (1.02) among the ten pharmacophore models examined. Hypo1 was further validated by Fisher's randomization method (95%), test set (r = 0.91), and the decoy set shows the goodness of fit (0.70). Furthermore, during virtual screening, Hypo1 was used as a 3D query to screen the NCI database, and the hit leads were sorted by applying Lipinski's rule of five and ADME properties. The best-fitting leads were subjected to docking to identify a suitable orientation at the ALR2 active site. The molecule that showed the strongest interactions with the critical amino acids was used in molecular dynamics simulations to calculate its binding affinity to the candidate molecules. Thus, Hypo1 describes the key structure-activity relationship along with the estimated activities of ALR2 inhibitors. The hit molecules were searched against PubChem to find similar molecules with new scaffolds. Finally, four molecules were found to satisfy all of the chemical features and the geometric constraints of Hypo1, as well as to show good dock scores, PLPs and PMFs. Thus, we believe that Hypo1 facilitates the selection of novel scaffolds for ALR2, allowing new classes of ALR2 inhibitors to be designed. PMID- 22249748 TI - First- and second-row transition metal oxa-aza macrocyclic complexes: a DFT study of an octahedral conformation. AB - A theoretical study of structures of the 1,7,1 l,17-tetraoxa-2,6,12,16-tetraaza cycloeicosane ligand ([20]AneN(4)O(4)) coordinated to Fe(2+), Co(2+), Ni(2+), Ru(2+), Rh(2+), and Pd(2+) transition metals ions was carried out with the DFT/B3LYP method. Complexes were fully optimized in C(s) symmetry with the metal ions coordinated either to nitrogen (1a) or oxygen atoms (1b). For all the cases performed in this work, 1a was always more stable than 1b. Considering each row it is possible to see that the binding energy increases with the atomic number. The M(2+) cation binding energies increase in the following order: Fe(2+) 80 years, respectively), those who lived without a partner (single, divorced or widowed), and those who had no formal schooling or had a functional disability preventing them from performing basic activities for daily living were more likely to be institutionalized. An inverse trend between the incidence of elderly institutionalization and the level of physical activity was observed, where somewhat active and inactive subjects were more likely to be institutionalized (OR = 1.71 and OR = 4.73, respectively). CONCLUSIONS: Of the factors examined, age > 80 years, living without a partner and being physically inactive were the indicators most strongly associated with institutionalization. The encouragement of informal care through cultural and educational activities focused on the role of the family in caring for the elderly can prevent the institutionalization of these individuals. PMID- 22249757 TI - On the use of qualitative methods in Collective Health, or the lack of a theory. AB - The present study problematizes certain uses of qualitative in the field of collective health methods, which are characterized by a lack of theoretical references and gloss over the rationality involved in their use as a technique exclusively. The proliferation and acceptance of such studies probably occur due to the strength of the instrumental rationality with which they have been conducted. Although frequently observed in a careful way, the results are not always supported by a careful presentation of the theoretical framework that underlies the interpretation. The use of "validated" techniques, the discourses constructed, and narratives of the actions of the "subjects" studied do not commit the researcher to the process of investigation, as they are separated from the historical-spatial contextualization and the theoretical-methodological landmark that imprint a historical and social sense to studies. PMID- 22249758 TI - Association between physical activity and quality of life in adults. AB - OBJECTIVE: To summarize and analyze evidences of the association between physical activity and quality of life. METHODS: Systematic literature review in three electronic databases -PubMed, Lilacs and SciELO- using the following descriptors: "physical activity," "motor activity," "exercise," "walking," "running," "physical fitness," "sport," "life style," "quality of life," "WHOQOL" and "SF." There were selected 38 studies published between 1980 and 2010 that used any instrument to measure physical activity and any version of the Medical Outcomes Study 36-Item Short-Form Health Survey or the World Health Organization Quality of Life to assess quality of life. RESULTS: Most studies reviewed were cross sectional (68%), 18% experimental, 8% prospective follow-up cohort and 5% mixed design (cross-sectional and longitudinal). The most widely used questionnaire to assess quality of life was SF-36 (71%), and physical activity was self-reported in 82% of the studies reviewed. Higher level of physical activity was associated with better perception of quality of life in the elderly, apparently healthy adults and individuals with different clinical conditions. CONCLUSIONS: There is a positive association between physical activity and quality of life that varies according to the domain analyzed. PMID- 22249759 TI - [Incentive Award in Science and Technology for Brazilian Unified Health System: a decade of history]. PMID- 22249762 TI - Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. AB - Reviews of therapeutic drugs usually focus on the highly selected and closely monitored patient populations from randomized controlled trials. The objective of this study was to review systematically the tolerability and adherence of multiple sclerosis disease-modifying therapies, using data from both randomized controlled trials and observational settings. Relevant literature was identified using predefined search terms, and adverse event and study discontinuation data were extracted and categorized according to study type (randomized controlled trial or observational) and study duration. A total of 151 papers were selected for analysis; 33% were classified as randomized controlled trials and 62% as observational studies. Most of the papers concerned interferon preparations and glatiramer acetate; the limited available information on mitoxantrone and natalizumab precluded extensive examination of these. The most common adverse events were flu-like symptoms (interferon therapies only) and injection-site reactions. Mean discontinuation rates ranged from 16% to 27%. There were no marked differences in tolerability or adherence data from randomized controlled trials and observational studies, but the incidence of adverse events remained high in lengthy studies and discontinuations accumulated with time. The present systematic review of randomized clinical trial and observational data highlights the tolerability and adherence issues associated with commonly used first-line multiple sclerosis treatments. PMID- 22249761 TI - Effect of praziquantel on adult Echinostoma paraensei worms in experimentally infected mice. AB - Echinostomiasis is a food-borne intestinal, snail-mediated parasitosis caused principally by ingestion of snails infected with digenean trematodes of the Echinostoma genus. The treatment and control of trematodiasis is usually done by administration of praziquantel (PZQ). In this study, we evaluated the effect on Echinostoma paraensei of different doses of praziquantel through analysis of morphological parameters using light microscopy, scanning electron microscopy, and confocal scanning laser microscopy along with parasitological data. We used 30 female mice aged 4 weeks. Each animal was given 40 metacercarie of E. paraensei by gavage. The animals were divided into five groups, each group containing six animals, where one group was utilized as untreated control. Two weeks after infection, the mice were given praziquantel by gavage at total dosages of 12.5, 25, 50 or 100 mg/kg by body weight. Two days after treatment, the mice were euthanized in a CO(2) chamber for recovery of helminths in the small intestine. The doses of 50 and 100 mg/kg of praziquantel eliminated all the worms. There were significant differences (p<0.05) between all the treated groups when compared to the control group. The body morphology showed contraction with vacuolization of the parenchyma, and the spine of the peristomic collar was not evident by light microscopy. The scanning electron microscopy revealed that the other doses caused retraction of spines of the peristomic collar and also the tegument spines at the body edge, as well as the development of vesicles and peeling; all these alterations were more evident at the dose of 25 mg/kg. In turn, the confocal scanning laser microscopy revealed vacuolization and disorganization of spines and vitelline glands. E. paraensei responds differently to experimental treatment with praziquantel according to the doses utilized causing morphological alteration and even worm elimination. PMID- 22249763 TI - EMG and EPP-integrated human-machine interface between the paralyzed and rehabilitation exoskeleton. AB - Although a lower extremity exoskeleton shows great prospect in the rehabilitation of the lower limb, it has not yet been widely applied to the clinical rehabilitation of the paralyzed. This is partly caused by insufficient information interactions between the paralyzed and existing exoskeleton that cannot meet the requirements of harmonious control. In this research, a bidirectional human-machine interface including a neurofuzzy controller and an extended physiological proprioception (EPP) feedback system is developed by imitating the biological closed-loop control system of human body. The neurofuzzy controller is built to decode human motion in advance by the fusion of the fuzzy electromyographic signals reflecting human motion intention and the precise proprioception providing joint angular feedback information. It transmits control information from human to exoskeleton, while the EPP feedback system based on haptic stimuli transmits motion information of the exoskeleton back to the human. Joint angle and torque information are transmitted in the form of air pressure to the human body. The real-time bidirectional human-machine interface can help a patient with lower limb paralysis to control the exoskeleton with his/her healthy side and simultaneously perceive motion on the paralyzed side by EPP. The interface rebuilds a closed-loop motion control system for paralyzed patients and realizes harmonious control of the human-machine system. PMID- 22249764 TI - On the structural elucidation of GalNAc-GD1a. PMID- 22249765 TI - Classic 18.5- and 21.5-kDa myelin basic protein isoforms associate with cytoskeletal and SH3-domain proteins in the immortalized N19-oligodendroglial cell line stimulated by phorbol ester and IGF-1. AB - The 18.5-kDa classic myelin basic protein (MBP) is an intrinsically disordered protein arising from the Golli (Genes of Oligodendrocyte Lineage) gene complex and is responsible for compaction of the myelin sheath in the central nervous system. This MBP splice isoform also has a plethora of post-translational modifications including phosphorylation, deimination, methylation, and deamidation, that reduce its overall net charge and alter its protein and lipid associations within oligodendrocytes (OLGs). It was originally thought that MBP was simply a structural component of myelin; however, additional investigations have demonstrated that MBP is multi-functional, having numerous protein-protein interactions with Ca2+-calmodulin, actin, tubulin, and proteins with SH3-domains, and it can tether these proteins to a lipid membrane in vitro. Here, we have examined cytoskeletal interactions of classic 18.5-kDa MBP, in vivo, using early developmental N19-OLGs transfected with fluorescently-tagged MBP, actin, tubulin, and zonula occludens 1 (ZO-1). We show that MBP redistributes to distinct 'membrane-ruffled' regions of the plasma membrane where it co-localizes with actin and tubulin, and with the SH3-domain-containing proteins cortactin and ZO 1, when stimulated with PMA, a potent activator of the protein kinase C pathway. Moreover, using phospho-specific antibody staining, we show an increase in phosphorylated Thr98 MBP (human sequence numbering) in membrane-ruffled OLGs. Previously, Thr98 phosphorylation of MBP has been shown to affect its conformation, interactions with other proteins, and tethering of other proteins to the membrane in vitro. Here, MBP and actin were also co-localized in new focal adhesion contacts induced by IGF-1 stimulation in cells grown on laminin-2. This study supports a role for classic MBP isoforms in cytoskeletal and other protein protein interactions during membrane and cytoskeletal remodeling in OLGs. PMID- 22249766 TI - Management of infrapopliteal peripheral arterial occlusive disease. AB - OPINION STATEMENT: The management of infrapopliteal peripheral arterial occlusive disease (PAD) is challenging. For patients with asymptomatic disease or claudication, exercise and optimal medical management, including antiplatelet agents, blood pressure control, statin therapy and tight glucose control for patients with diabetes mellitus, are the mainstays of therapy. However, patients with isolated tibial artery occlusive disease often have diabetes mellitus or renal insufficiency and present with critical limb ischemia (CLI). CLI is advanced occlusive disease marked by the development of rest pain, ischemic ulceration, or gangrene and is associated with a high mortality rate. Limb salvage requires an intervention in cases of CLI, but careful operative planning is required as patients often have multilevel disease and limited options for revascularization. A surgical bypass with a vein graft remains the best treatment for infrapopliteal PAD, especially in patients with a life expectancy of over 2 years. Balloon angioplasty can play an important role in limb salvage, especially for patients lacking adequate vein for bypass, at high operative risk, or with a life expectancy of less than 2 years. However, a lack of rigorous trials has left unanswered questions as to the efficacy of infrapopliteal angioplasty with or without stents compared to bypass surgery. As such, endovascular therapy is currently not a proven treatment for intermittent claudication. Patients who are unable to undergo a revascularization procedure for infrapopliteal CLI have few options besides amputation or palliation. New therapies, such as drug-eluting stents, drug-coated balloons, and stem cell therapy are under development, but their efficacy and effectiveness remain unproven. PMID- 22249767 TI - Evaluation of the single yeast cell's adhesion to ITO substrates with various surface energies via ESEM nanorobotic manipulation system. AB - Cell-surface adhesion force is important for cell activities and the development of bio materials. In this paper, a method for in situ single cell (W303) adhesion force measurement was proposed based on nanorobotic manipulation system inside an environment scanning electron microscope (ESEM). An end effector was fabricated from a commercial atomic force microscope (AFM) cantilever by focused ion beam (FIB) etching. The spring constant of it was calibrated by nanomanipulation approach. Three kinds of hydrophilic and hydrophobic ITO plates were prepared by using VUV-irradiation and OTS coating techniques. The shear adhesion strength of the single yeast cell to each substrate was measured based on the deflection of the end effector. The results demonstrated that the cell adhesion force was larger under the wet condition in the ESEM environment than in the aqueous condition. It also showed that the cell adhesion force to hydrophilic surface was larger than that to the hydrophobic surface. Studies of single cell's adhesion on various plate surfaces and environments could give new insights into the tissue engineering and biological field. PMID- 22249769 TI - Optimal contrast material concentration for distinguishing among carotid artery lumen, carotid stent, and neck in cone-beam computed tomography during carotid angiography: basic and clinical studies. AB - PURPOSE: To explore the optimal contrast material (CM) concentration for distinguishing CM, carotid stent (CS), and neck components in cone-beam computed tomography (CBCT) during carotid angiography (CBCT-CA). MATERIALS AND METHODS: A neck phantom containing CS and contrast-filled imitation vessels of 9 mm diameter was scanned using CBCT. CM (300 mgI/ml) was used in concentrations of 100, 50, 33, 10, 5, and 1%. In a clinical study, 30 patients with a CS (Precise or Wallstent) underwent CBCT-CA with CM injected at a rate of 3 ml/s and a concentration of 10 or 20%. RESULTS: In the basic study, CBCTA using 5% CM enabled clear distinction among the three components under windowing at 1500 width and 300 center, and showed the exact diameter of the imitation vessel. Pixel values of CM inside the Precise and the Wallstent were 622.2 +/- 32.9 (mean +/- SD) and 746.0 +/- 27.9, respectively. In the clinical study using CM at concentrations of 10 and 20%, pixel values of CM inside the Wallstent were 632.3 +/- 69.2 and 1024.5 +/- 99.0, respectively. CONCLUSION: Optimal CM concentration for distinguishing among the three components was 5% in the basic study; the optimal concentration was 10% in the clinical study. PMID- 22249770 TI - Reconstruction of nonunion tibial fractures in war-wounded Iraqi civilians, 2006 2008: better late than never. AB - OBJECTIVE: To describe medical care and surgical outcome after functional reconstructive surgery in late-presenting patients who already had at least one prior operation. DESIGN: Retrospective review of medical care and surgical outcome from August 2006 to December 2008 using patient records for initial data with active follow-up for the latest outcome information. SETTING: Medecins sans Frontieres surgical programme in Jordan Red Crescent Hospital, Amman, Jordan. PATIENTS: Sixty-two civilians with nonunion tibial fractures caused by war related trauma in Iraq; 53 completed follow-up. INTERVENTION: Amputation and/or reconstruction. MAIN OUTCOME MEASUREMENTS: Late surgical complications (after the patient's return to Iraq) were analyzed for infection recurrence, bone union, and functional condition (defined using the Short Musculoskeletal Functional Assessment score). RESULTS: Almost three fourths of patients arrived with infected injuries, 9 of whom had amputation as the initial surgery; the rest, and all uninfected patients, had reconstruction. Excluding loss to follow-up, only 4 of 53 (8%) patients who arrived with an infected injury had infection recurrence. Excluding loss to follow-up and amputation, 2 of 14 (14%) patients in the uninfected and 5 of 30 (17%) in the infected injury group did not achieve successful tibial union. Mean Dysfunctional and Bothersome Indices overall were 27.1 and 29.8, respectively, with similar results for all 3 groups (amputations, uninfected, and infected injuries). CONCLUSIONS: Our study shows that patients with infected and uninfected injuries surgically treated in Amman achieved similar outcomes. Despite late presentation, our patients had a comparable outcome to other studies dealing with early reconstruction. Reconstruction for the infected group required longer treatment time. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22249771 TI - A COMPREHENSIVE FRAMEWORK FOR CLASSIFICATION OF NUCLEI IN DIGITAL MICROSCOPY IMAGING: AN APPLICATION TO DIFFUSE GLIOMAS. AB - In this paper, we present a comprehensive framework to support classification of nuclei in digital microscopy images of diffuse gliomas. This system integrates multiple modules designed for convenient human annotations, standard-based data management, efficient data query and analysis. In our study, 2770 nuclei of six types are annotated by neuropathologists from 29 whole-slide images of glioma biopsies. After machine-based nuclei segmentation for whole-slide images, a set of features describing nuclear shape, texture and cytoplasmic staining is calculated to describe each nucleus. These features along with nuclear boundaries are represented by a standardized data model and saved in the spatial relational database in our framework. Features derived from nuclei classified by neuropathologists are retrieved from the database through efficient spatial queries and used to train distinct classifiers. The best average classification accuracy is 87.43% for 100 independent five-fold cross validations. This suggests that the derived nuclear and cytoplasmic features can achieve promising classification results for six nuclear classes commonly presented in gliomas. Our framework is generic, and can be easily adapted for other related applications. PMID- 22249772 TI - Stable carbon isotope composition (delta13C values) of the halogenated monoterpene MHC-1 as found in fish and seaweed from different marine regions. AB - Six samples of the red seaweed Plocamium cartilagineum (two both from Helgoland/Germany, Ireland, and the Antarctic) were analyzed by stable isotope analysis. The bulk delta(13)C values (-31 to -380/00) confirmed that this seaweed was exceptionally highly depleted in (13)C. The delta(15)N values were in the reported range for algae, and a moderate correlation between (13)C and (15)N content was observed. These measurements indicated that the season had a higher impact on the delta(13)C values than the location. Compound specific carbon isotope analysis by gas chromatography coupled with isotope ratio mass spectrometry (GC-IRMS) was used to verify an even stronger depletion in (13)C in the halogenated natural product (HNP) MHC-1 isolated from the seaweed samples. The delta(13)C values of MHC-1 in the range -42 to -450/00 are the lightest determined to date for polyhalogenated compounds in the molecular mass range between 250 and 800 Da. MHC-1 was also isolated from two fish samples. The much higher (13)C content in MHC-1 from the fish samples (-35.6 to -39.20/00) indicated carbon isotope enrichment due to partial transformation. In processes such as the reductive debromination, the partial transformation is associated with an increase in the (13)C content in the remaining non-metabolized share of a compound. Stable isotope analysis may thus provide insights into the degree of transformation of HNPs in environmental samples. PMID- 22249773 TI - Ligand expansion in ligand-based virtual screening using relevance feedback. AB - Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally homogeneous sets of actives are being sought. PMID- 22249774 TI - Looking forward into the next 25 years: the 25th anniversary issue of the Journal of Computer-Aided Molecular Design. PMID- 22249775 TI - Rituximab-induced direct inhibition of T-cell activation. AB - BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, is reported to increase the T-cell-dependent infection risk. The current study was designed to investigate whether rituximab interferes with T-cell activation. PATIENTS AND METHODS: Patients with non-Hodgkin lymphoma receiving 4-6 courses of 375 mg/m(2) rituximab underwent detailed assessment of T-cell activation pre- and post rituximab. A similar analysis assessed the in vitro effect of rituximab on T-cell activation in response to allogeneic dendritic cells (allo-DCs) and other stimuli. RESULTS: Patients receiving rituximab exhibited a significant decline in IL-2 and IFN-gamma levels in peripheral blood, most prominent after repeated rituximab courses. Evaluation at 3 months after rituximab therapy showed restoration of inflammatory cytokine production. Similarly, in vitro stimulation of peripheral blood mononuclear cells in the presence of rituximab resulted in a significant decrease in T-cell activation markers, inflammatory cytokine production and proliferative capacity. These effects were also observed using B cell-depleted T cells (CD3(+)CD25(-)CD19(-)) and were accompanied with disappearance of CD3(+)CD20(dim) T-cell population. CONCLUSION: Rituximab administration results in transient, dose-dependent T-cell inactivation. This effect is obtained even in B-cell absence and may increase the infection risk. PMID- 22249776 TI - Long-term results of 32-mm alumina-on-alumina THA for avascular necrosis of the femoral head. AB - BACKGROUND: Ceramic bearings in total hip arthroplasty (THA) have been introduced in clinical practice to minimize the problem of polyethylene particle-induced osteolysis. The aim of the study is to report the results of 68 consecutive alumina-on-alumina THAs done in 61 patients for avascular necrosis (AVN) of the femoral head. MATERIALS AND METHODS: In all implants a press-fit cup was used; it was combined with a 32-mm alumina head and with titanium-alloy stems. The mean age at surgery was 50 years. At an average follow-up of 13 years two hips have been revised, one for periprosthetic infection and one for excessive abduction of the cup. RESULTS: No revision for aseptic loosening is recorded; one anatomical cementless femoral stem had radiological evidence of definite aseptic loosening. No dislocations occurred, and no osteolysis was observed. CONCLUSIONS: The results support the application of alumina-alumina THA for long-lasting replacements. PMID- 22249777 TI - Acute kidney injury in 2011: Biomarkers are transforming our understanding of AKI. AB - Acute kidney injury (AKI) is a syndrome of decreased renal function that is associated with an increased risk of death. Studies from 2011, particularly in the field of AKI biomarkers, have provided important insights into the diagnosis, prognosis, and treatment of AKI. These advances are now being brought to the bedside to improve diagnosis and treatment of AKI. PMID- 22249778 TI - A novel pathogenetic concept-antiviral immunity in lupus nephritis. AB - Lupus nephritis is a complication of systemic lupus erythematosus, a heterogeneous autoimmune syndrome involving multiple pathways. Accumulating data from the fields of genetics, clinical science, transcriptomics and basic immunology indicate that antiviral immunity has relevance in the pathogenesis of lupus nephritis. This idea is based on the existence of genetic variants that promote the persistence of nuclear particles in the extracellular space or inside lysosomes. Such nuclear particles mimic viral particles and their RNA or DNA components activate viral nucleic acid recognition receptors in antigen presenting cells. These autoadjuvant effects of endogenous nucleic acids promote an inappropriate immune interpretation of the nuclear particles during antigen presentation. This process fosters the expansion of autoreactive T cells and B cells, which promotes autoantibody production and immune complex glomerulonephritis. The release of interferon alpha sets off an antiviral immune response with a coordinated induction of hundreds of antiviral genes both inside and outside the kidney. In this article we summarize the available data indicating that innate immunity triggers antiviral immunity in systemic lupus erythematosus. We also discuss the related implications for innovative therapeutic strategies. PMID- 22249779 TI - Xerostomia in patients on chronic hemodialysis. AB - Xerostomia is the subjective feeling of a dry mouth, which is relatively common in patients on chronic hemodialysis. Xerostomia can be caused by reduced salivary flow secondary to atrophy and fibrosis of the salivary glands, use of certain medications, restriction of fluid intake and old age. In patients undergoing hemodialysis, xerostomia is associated with the following problems: difficulties in chewing, swallowing, tasting and speaking; increased risk of oral disease, including lesions of the mucosa, gingiva and tongue; bacterial and fungal infections, such as candidiasis, dental caries and periodontal disease; interdialytic weight gain resulting from increased fluid intake; and a reduction in quality of life. Unfortunately, no effective treatment exists for xerostomia in patients on chronic hemodialysis. The stimulation of salivary glands by mechanical means (such as chewing gum) or pharmacological agents (such as pilocarpine and angiotensin-converting-enzyme inhibitors, the latter alone or in combination with angiotensin-receptor blockers), as well as saliva substitutes, are all ineffective, or effective only in the short term. Xerostomia remains a frustrating symptom for patients on hemodialysis, and further efforts should be made to find an effective treatment for it in the near future. PMID- 22249780 TI - Cardiovascular disease: salt and cardiovascular risk. PMID- 22249781 TI - Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa. AB - BACKGROUND: Pregnancy-induced hypertension (PIH) is associated with adverse fetal and maternal outcome. The role of medication to control blood pressure (BP) in mild to moderate PIH is controversial. AIMS: We conducted a prospective study to investigate whether pharmacological treatment of mild to moderate PIH is effective in improving maternal and fetal outcomes. METHODS: A total of 150 consecutive pregnant women without proteinuria and with physician-recorded systolic BP of 140-160 mmHg and/or diastolic BP of 90-105 mmHg on two occasions >=6 h apart between 20 and 38 weeks of gestation were randomly allocated to receive either labetalol or methyldopa (50 patients each) plus standard care (treatment group) or only standard care (50 patients) (control group). RESULTS AND CONCLUSIONS: As compared to the control group, the treatment group had lower rates of severe PIH (28% vs. 10%, P = 0.005), proteinuria (28% vs. 12%, P = 0.016), hospitalization before term (28% vs. 14%, P = 0.041), and delivery by cesarean section (38% vs. 22%, P = 0.042). In a multivariable logistic regression model that adjusted for maternal age, weight, parity, previous PIH, and baseline hemoglobin, resting heart rate, and BP levels, antihypertensive therapy was associated with a lower incidence of adverse maternal events (P = 0.011). Compared to the control group, the treatment group had lower incidence of SGA babies (40% vs. 23%, P = 0.033), preterm birth (36% vs. 14%, P = 0.002), and admission to neonatal unit (30% vs. 15%, P = 0.036). After adjustment for maternal age, weight, baseline hemoglobin, resting heart rate, BP level, parity and previous history of PIH, fetal death, preterm delivery or SGA baby, antihypertensive therapy was associated with a lower incidence of adverse perinatal events (P = 0.016). Maternal and perinatal mortality rates were not significantly different between treatment and control groups. In conclusion, pharmacological treatment of mild to moderate PIH is associated with lower rate of some maternal and fetal-neonatal non-fatal adverse events compared to no routine use of antihypertensive therapy. PMID- 22249782 TI - [Hypertrophic pulmonary osteoarthropathy as a cue for NSCLC: four cases in the light of the current literature]. AB - Hypertrophic pulmonary osteoarthropathy (often referred to as Marie-Bamberger syndrome) occurs in 1 - 5 % of all patients with non-small cell lung cancer (NSCLC) as a paraneoplastic syndrome. The complete syndrome is characterised by clubbing of the fingers and toes (often without hypoxia) and pain in the joints and tubular bones. On the basis of four clinical cases, this article shows that this syndrome can precede tumour-specific symptoms and that it is still often overlooked by physicians. An early suspicion of this syndrome is of great clinical value because it can lead to a diagnosis of NSCLC at an earlier tumour stage. In addition to the case reports, the current literature on hypertrophic pulmonary osteoarthropathy is reviewed in this article, with special reference to pathogenetic concepts und to therapeutic options. PMID- 22249783 TI - Use of antidepressants and the risk of type 2 diabetes mellitus: a nested case control study. AB - BACKGROUND: Recent evidence from case reports, observational studies, and randomized trials suggests that long-term use of antidepressants increases the risk of developing diabetes. However, the nature of the relationship between antidepressants and diabetes remains unclear. OBJECTIVE: To determine whether there is an association between antidepressant use and the risk of developing type 2 diabetes mellitus. METHODS: A nested case-control study using the Texas Medicaid prescription claims database was conducted. Data were extracted for new users of either antidepressant agents (exposed) or benzodiazepines (unexposed) from January 1, 2002 through December 31, 2009. Patients aged 18-64 years without a history of diabetes were included in the cohort. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the risk of diabetes associated with antidepressant exposure was computed using conditional logistic regression, controlling for demographic and clinical covariates. MAIN OUTCOME MEASURE: Development of type 2 diabetes mellitus. RESULTS: Among the total sample (N = 44,715), the majority were in the exposed (N = 35,552) vs. the unexposed (N = 9,163) group. A total of 2,943 cases of type 2 diabetes mellitus and 11,748 matched controls (1:4) were identified using risk-set sampling. Cases and controls were matched using age and gender. Antidepressant use was associated with an increase in the risk of (type-2) diabetes when compared to benzodiazepine use [Adjusted Odds Ratio (OR) = 1.512; 95% CI 1.345-1.700]. The association was observed with serotonin-norepinephrine reuptake inhibitors (OR = 1.742; 95% CI 1.472-2.060), tricyclic antidepressants (OR = 1.533; 95% CI 1.295-1.814), selective serotonin reuptake inhibitors (OR = 1.457; 95% CI 1.279-1.659), "Other" antidepressants (OR = 1.318; 95% CI 1.129-1.540). CONCLUSIONS: Antidepressant use was associated with an increased risk of (type-2) diabetes. This association was observed for tricyclic antidepressants, serotonin-reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and other antidepressants. PMID- 22249784 TI - Kinetic and thermodynamic analysis for lipase-catalyzed hydrolytic resolution of (R,S)-alcohols though their azolyl carbamates. AB - A new approach to the lipase-catalyzed hydrolytic resolution of (R,S)-azolyl carbamates for obtaining chiral azolyl carbamates and alcohol is described. With (R,S)-1-phenylethyl azolyl carbamates as the model substrates, the best reaction condition of using (R,S)-1-phenylethyl 4-bromopyrazole carbamate (1) as the substrate in water-saturated diisopropyl ether at 45 degrees C is selected. The kinetic constants, and hence enantiomeric ratio of 124, are then estimated from the kinetic analysis by considering the alcohol inhibition effect, with which theoretical time-course conversions for both enantiomers are numerically solved and agree with the experimental data. The thermodynamic parameters -DeltaDeltaH and -DeltaDeltaS satisfying a linear enthalpy-entropy compensation relationship of -DeltaDeltaS = -38.84 + 3.29(-DeltaDeltaH) are further estimated. An extension of the resolution platform to (R,S)-4-bromopyrazole carbamates derived from other (R,S)-alcohols (4, 5, 7) is also addressed. PMID- 22249785 TI - Iron therapy: a piece in the puzzle of allogeneic blood saving strategies with a relevant role in patients' blood management. PMID- 22249786 TI - Adolescents and blood donation: motivations, hurdles and possible recruitment strategies. AB - BACKGROUND: For years researchers have been trying to determine what factors influence a person's choice to give blood, with the aim of translating the data collected into ever more concrete operative methods for recruiting new donors and managing and using blood to meet the needs of the donor. Adolescents are a potential source of great interest not only for the blood they could supply, but also because information on the subject of "giving blood" could favour the spread of healthy lifestyles and contribute to the development of a mature, responsible civic culture. The aim of the present study was to investigate the motivations and obstacles to giving blood among adolescents and strategies to recruit donors from this group of subjects. MATERIALS AND METHODS: A self-report questionnaire was given to 3,050 pupils in 11 high schools in the Lombardy Region (Italy) (Age range: 13-21 years, mean 16.5, SD=1.65, males=47.7%, females=52.3%). The questionnaire comprised 14 items that addressed motivations and obstacles to giving blood and recruitment strategies in adolescents, knowledge about the world of blood donation and socio-demographic information. Descriptive analyses (frequencies, means and standard deviations), chi squared test (chi(2)) and the t test (t) for independent samples were conducted. RESULTS AND DISCUSSION: The data collected regarding the three abovementioned areas of investigation (motivations, obstacles and recruitment strategies) were analysed with respect to gender. The results yielded some interesting information on which to build hypotheses concerning the pre-established objectives, including the importance of active involvement of adolescents by the organisations charged with promoting blood collection, emphasising the important role of the school and giving the adolescents the chance to meet with an expert on blood donation. PMID- 22249788 TI - Statins and anti-inflammatory therapies for subarachnoid hemorrhage. AB - OPINION STATEMENT: Aneurysmal subarachnoid hemorrhage (SAH) induces a potent inflammatory cascade that contributes to endothelial dysfunction, imbalance of vasoactive substances (excess endothelin, depletion of nitric oxide), and arterial vasospasm. This process results in delayed cerebral ischemia, a major cause of neurologic disability in those surviving the initial hemorrhage. The only therapy shown to be effective in improving neurologic outcomes after SAH is a calcium-channel antagonist, nimodipine (although it achieved this result without reducing vasospasm). A number of novel therapies have been explored to inhibit the development of vasospasm and reduce the burden of ischemia and cerebral infarction. Statins are promising candidates, as they block multiple aspects of the inflammatory pathway that contributes to ischemic brain injury. Early clinical trials have produced conflicting results, however, and the adoption of statins in clinical practice should await the results of larger, more definitive studies. Though endothelin-receptor antagonists showed promise in significantly reducing vasospasm in preliminary trials, their failure to improve clinical outcomes in phase 3 studies has been disappointing, highlighting the complex link between vasospasm and ischemia. Future directions in the quest to improve outcomes of patients with SAH may need to approach ischemia as a multifactorial process with inflammatory, vasoactive, and ionic/metabolic components. PMID- 22249789 TI - Potential relationship among three antioxidant enzymes in eliminating hydrogen peroxide in penaeid shrimp. AB - Antioxidant enzymes, such as glutathione peroxidase (GPx), catalase (CAT), and peroxiredoxin (Prx), are essential components in cells to eliminate excessive reactive oxygen species such as hydrogen peroxide (H(2)O(2)). GPx, CAT, and Prx genes have been reported in penaeid shrimp, and they showed different expression profiles at transcription or protein level when shrimps were challenged by microbes. In order to learn the relationship among the above three genes in their function, GPx, CAT, and Prx transcripts were analyzed, and the variation of GPx and CAT enzyme activity was detected when shrimp was injected with H(2)O(2) or one antioxidant enzyme gene was silenced in shrimp by double-strand RNA injection. The results indicated that there existed some relationships among three antioxidant enzyme genes, CAT, GPx, and Prx in shrimp at transcriptional level. The transcription of CAT and GPx could be directly induced by H(2)O(2) injection, while the transcription of Prx cannot be induced by H(2)O(2). Decreased transcription level of CAT or GPx could lead to increased transcription of the other two genes, which suggested that there existed some compensation among these three antioxidant enzyme genes. These data can help us to understand the roles of antioxidant enzymes in crustacean. PMID- 22249791 TI - Medical education: simulation and virtual reality. PMID- 22249790 TI - Stress levels over time in the introduced ascidian Styela plicata: the effects of temperature and salinity variations on hsp70 gene expression. AB - Species distribution, abundance, and long-term survival are determined by biotic and abiotic regimes. However, little is known about the importance of these factors in species range expansion. Styela plicata is a solitary ascidian introduced all over the world by ship fouling, including salt marsh habitats, where introduced populations must tolerate high seasonal variations in temperature and salinity. To determine the seasonal stress levels in a salt marsh population of S. plicata, we quantified heat shock protein (hsp70) gene expression using quantitative real-time PCR throughout a 2-year cycle. Results showed that hsp70 expression varied over time, with higher stress levels recorded in summer and winter. Periodic conditions of high temperatures, particularly when coupled with low salinities, increased hsp70 gene expression. Mortality events observed every year around June were concurrent with sharp increases in temperature (>6 degrees C), indicating that drastic changes in abiotic factors may overwhelm the observed stress response mechanisms. Determining the ability of introduced species to cope with stress, and the thresholds above which these mechanisms fail, is fundamental to predict the potential expansion range of introduced species and design efficient containment plans. PMID- 22249792 TI - Cyclooxygenase-2 and human epidermal growth factor receptor type 2 (HER-2) expression simultaneously in invasive and in situ breast ductal carcinoma. AB - CONTEXT AND OBJECTIVE: Cyclooxygenase-2 (COX-2) and human epidermal growth factor receptor type 2 (HER-2) are associated with tumorigenesis. Studies have shown that HER-2 can regulate COX-2 expression. The aim of this study was to evaluate the correlation between COX-2 and HER-2 expression in normal breast epithelium and in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) present in the same breast. DESIGN AND SETTING: Cross-sectional study at the Mastology Unit of the Department of Gynecology and Obstetrics, Santa Casa de Misericordia de Sao Paulo Hospital. METHODS: COX-2 and HER-2 were detected using immunohistochemistry on 100 tissue fragments. HER-2 > +2 was subjected to fluorescence in situ hybridization (FISH). RESULTS: COX-2 expression was detected in 87%, 85% and 75% of IDC, DCIS and normal epithelium, respectively. HER-2 expression was detected in 34% of IDC and 34% of DCIS. COX-2 in DCIS correlated with HER-2 in IDC (P = 0.049) and DCIS (P = 0.049). COX-2 in normal epithelium correlated with HER-2 in IDC (P = 0.046) and DCIS (P = 0.046). COX-2 in IDC was not associated with HER-2 (P = 0.235). Comparison between COX-2 and HER-2 in DCIS showed that there was a statistically significant difference with regard to nuclear grades II and III and presence of comedonecrosis (P < 0.001). In IDC, there was significant expression with nuclear grades II and III and histological grade II (P < 0.001). CONCLUSIONS: Our findings provide evidence that HER-2 and COX-2 regulate each other. PMID- 22249793 TI - Factors relating to failure to quit smoking: a prospective cohort study. AB - CONTEXT AND OBJECTIVE: Considering the difficulties in stopping smoking, this article aimed to identify factors relating to failure of attempts to quit smoking among smokers who sought care at an outpatient clinic in a general university hospital. DESIGN AND SETTING: Prospective cohort study evaluating 100 smokers who sought treatment at the Psychoactive Substances Outpatient Clinic. METHODS: The variables gathered were sociodemographic factors; degree of dependence (Fagerstrom questionnaire); stage of motivation for change (University of Rhode Island Change Assessment Scale); and presence of depression and anxiety (Hospital Anxiety and Depression Scale). The patients were followed up after 4, 8, 12 and 24 weeks to identify factors relating to failure to quit smoking. RESULTS: The patients were mostly women (75%), between 40 and 59 years of age (67%); with incomplete elementary education (60%); with leisure activities (57%); suffering from tobacco-related disease (53%); with previous attempts to quit smoking (70%); with a medical recommendation to stop (51%); with encouragement to stop (66%); and with a high degree of dependence (78%). The main motivational stage was contemplation/action (43%); the anxiety rate was 64% and the depression rate was 39%. The quitting rate was 66% among adherents and 17% among non-adherents (P < 0.001). Lack of success was correlated with absence of leisure, higher education and absence of tobacco-related disease. CONCLUSION: The variables of lack of leisure activities, higher education and/or lack of tobacco-related disease correlated with failure to quit smoking among smokers who sought treatment at an outpatient clinic in a tertiary general hospital. PMID- 22249794 TI - Insulin stimulation of Akt/PKB phosphorylation in the placenta of preeclampsia patients. AB - CONTEXT AND OBJECTIVE: Preeclampsia is a multi-systemic disease and one of the most frequent severe health problems during pregnancy. Binding of insulin triggers phosphorylation and activates cytoplasmic substrates such as phosphatidylinositol 3 kinase (PI3K). Phosphorylation of membrane phosphoinositide 2 (PIP2) to phosphoinositide 3 (PIP3) by PI3K starts Akt/PKB activation. Defects in phosphorylation of the insulin receptor and its substrates have an important role in insulin resistance. Studies have shown that insulin resistance is associated with preeclampsia and its pathophysiology. The aim here was to investigate insulin stimulation of the Akt/PKB pathway in the placenta, in normal and preeclampsia parturients. DESIGN AND SETTING: Cross-sectional study in a tertiary public university hospital. METHODS: Placentas were collected from 12 normal and 12 preeclampsia patients. These were stimulated and analyzed using Western blot to quantify the Akt/PKB phosphorylation. RESULTS: The insulin stimulation was confirmed through comparing the stimulated group (1.14 +/- 0.10) with the non-stimulated group (0.91 +/- 0.08; P < 0.001). The phosphorylation of Akt/PKB did not differ between the placenta of the normal patients (1.26 +/- 0.16) and those of the preeclampsia patients (1.01 +/- 0.11; P = 0.237). CONCLUSIONS: In vitro insulin stimulation of the human placenta has been well established. There was no difference in Akt/PKB phosphorylation, after stimulation with insulin, between placentas of normal and preeclampsia patients. Nevertheless, it cannot be ruled out that the Akt/PKB signaling pathway may have a role in the pathophysiology of preeclampsia, since the substrates of Akt/PKB still need to be investigated. PMID- 22249795 TI - Immunophenotypic characterization of acute leukemia at a public oncology reference center in Maranhao, northeastern Brazil. AB - CONTEXT AND OBJECTIVES: The incidence of acute leukemia (AL) subtypes varies according to geographical distribution. The aim here was to determine the incidence of morphological and immunophenotypic AL subtypes in the state of Maranhao, Brazil, and to correlate the expression of aberrant phenotypes in children with acute lymphoblastic leukemia (ALL) with prognostic factors. DESIGN AND SETTING: Single prospective cohort study at a public oncology reference center in Maranhao. METHODS: Seventy AL cases were diagnosed between September 2008 and January 2010. For the diagnosis, complete blood cell counts, myelograms (at diagnosis and at the end of the induction phase), cytochemical analysis and immunophenotyping were performed. RESULTS: Among adult patients (n = 22), the incidence of AL types was: ALL (22.7%) and acute myeloid leukemia (AML) (77.3%). The subtype AML M0 occurred most frequently (29.4%). In children (n = 48), the types were: AML (18.7%), most frequently subtype AML M4 (33.4%); biphenotypic acute leukemia (BAL) (4.2%); and ALL (77.1%), including the subtypes B-ALL (72.9%) and T-ALL (27.1%). Among the children with ALL, there were no statistically significant differences between patients with and without aberrant phenotypes, in relation to hematological parameters and treatment response. CONCLUSION: This work demonstrates that the frequencies of AML M0 cases among adults and T-ALL cases among children in Maranhao were high. This suggests that there may be differences in AML subtype incidence, as seen with ALL subtypes, in different regions of Brazil. No association was found between the expression of aberrant phenotypes and prognostic factors, in children with ALL. PMID- 22249796 TI - Analysis of CD83 antigen expression in human breast fibroadenoma and adjacent tissue. AB - CONTEXT AND OBJECTIVE: Dendritic cell maturation is considered essential for starting an immune response. The CD83 antigen is an important marker of dendritic cell maturation. The objectives here were to analyze CD83 antigen expression in human breast fibroadenoma and breast tissue adjacent to the lesion and to identify clinical factors that might influence this expression. DESIGN AND SETTING: This was a retrospective study at a public university hospital, in which 29 histopathological samples of breast fibroadenoma and adjacent breast tissue, from 28 women of reproductive age, were analyzed. METHODS: The immunohistochemistry method was used to analyze the cell expression of the antigen. The antigen expression in the cells was evaluated by means of random manual counting using an optical microscope. RESULTS: Positive expression of the CD83 antigen in the epithelial cells of the fibroadenoma (365.52; standard deviation +/- 133.13) in relation to the adjacent breast tissue cells (189.59; standard deviation +/- 140.75) was statistically larger (P < 0.001). Several clinical features were analyzed, but only parity was shown to influence CD83 antigen expression in the adjacent breast tissue, such that positive expression was more evident in nulliparous women (P = 0.042). CONCLUSIONS: The expression of the CD83 antigen in the fibroadenoma was positive and greater than in the adjacent breast tissue. Positive expression of the antigen in the adjacent breast tissue was influenced by parity, and was significantly more evident in nulliparous women. PMID- 22249797 TI - The influence of lower-limb dominance on postural balance. AB - CONTEXT AND OBJECTIVE: Maintainance of postural balance requires detection of body movements, integration of sensory information in the central nervous system and an appropriate motor response. The purpose of this study was to evaluate whether lower-limb dominance has an influence on postural balance. DESIGN AND SETTING: This was a cross-sectional study conducted at Faculdade de Medicina da Universidade de Sao Paulo (FMUSP) and at Hospital do Coracao (HCor). METHODS: Forty healthy sedentary males aged 20 to 40 years, without any injuries, were evaluated. A single-foot balance test was carried out using the Biodex Balance System equipment, comparing the dominant leg with the nondominant leg of the same individual. The instability protocols used were level 8 (more stable) and level 2 (less stable), and three instability indices were calculated: anteroposterior, mediolateral and general. RESULTS: The volunteers' mean age was 26 +/- 5 years (range: 20-38), mean weight 72.3 +/- 11 kg (range: 46-107) and mean height 176 +/ 6 cm (range: 169-186). Thirty-four of them (85%) presented right-leg dominance (defined according to which leg they used for kicking) and six (15%) had left-leg dominance. There were no significant differences between the dominant and nondominant legs at the two levels of stability (eight and two), for any of the instability indices (general, anteroposterior and mediolateral). CONCLUSION: The lower-limb dominance did not influence single-foot balance among sedentary males. PMID- 22249798 TI - Effectiveness of electrical stimulation on rehabilitation after ligament and meniscal injuries: a systematic review. AB - CONTEXT AND OBJECTIVE: Electrical stimulation (ES) is widely used to strengthen muscles following ligament and meniscal injuries. The aim of this study was to evaluate the effectiveness of ES for rehabilitation after soft tissue injuries of the knee treated surgically or conservatively. DESIGN AND SETTING: Systematic review at the Brazilian Cochrane Center. METHODS: We searched the Cochrane Central Register of Controlled Trials (2010, Issue 12), Medline (Medical Analysis and Retrieval System Online) via PubMed (1966 to December 2010), Embase (Excerpta Medica database, 1980 to December 2010), Lilacs (Literatura Latino-Americana e do Caribe em Ciencias da Saude, 1982 to December 2010), and PEDro (Physiotherapy Evidence Database, 1929 to December 2010). The studies included were randomized controlled trials using ES to increase muscle strength for rehabilitation of patients with soft tissue injuries of the knee. Two authors independently evaluated studies for inclusion and performed data extraction and methodological quality assessment. RESULTS: Seventeen studies evaluating ES after anterior cruciate ligament reconstruction and two studies evaluating ES after meniscectomy were included. There was a statistically significant improvement in quadriceps strength through ES (mean difference, MD: -32.7; 95% confidence interval, CI: 39.92 to -25.48; n = 56) and in functional outcomes (MD -7; -12.78 to -1.22; n = 43) six to eight weeks after surgical reconstruction of the anterior cruciate ligament. CONCLUSION: There is evidence that ES coupled with conventional rehabilitation exercises may be effective in improving muscle strength and function two months after surgery. PMID- 22249799 TI - Primary epidermoid carcinoma of the breast presenting as a breast abscess and sepsis. AB - CONTEXT: Squamous cell carcinoma (SCC) of the breast is an extremely rare form of cancer, accounting for approximately 0.04% of all malignant breast tumors. To date, only a limited number of cases of SCC of the breast have been reported, and most of them presented like the usual breast carcinomas. CASE REPORT: A 39-year old woman presented with a large breast abscess and signs of sepsis. After surgical debridement of the lesion, histopathological examination of the abscess capsule revealed the presence of SCC of the breast. The definitive treatment for the tumor consisted of modified radical mastectomy with resection of the residual lesion in the right breast. CONCLUSIONS: This unusual case illustrates how an apparently benign disorder such as a breast abscess might be related to a clinically occult malignancy. A review of the literature on SCC of the breast is presented. PMID- 22249800 TI - New report of two patients with mosaic trisomy 9 presenting unusual features and longer survival. AB - CONTEXT: Mosaic trisomy 9 is considered to be a rare chromosomal abnormality with limited survival. Our objective was to report on two patients with mosaic trisomy 9 presenting unusual findings and prolonged survival. CASE REPORTS: The first patient was a boy aged six years and five months presenting weight of 14.5 kg (< P3), height of 112 cm (P10), head circumference of 49 cm (P2), prominent forehead, triangular and asymmetric face, thin lips, right microtia with overfolded helix, small hands, micropenis (< P10), small testes and hallux valgus. His lymphocyte karyotype was mos 47,XY,+9[4]/46,XY[50]. Additional cytogenetic assessment of the skin showed normal results. The second patient was a two-year-old girl who was initially assessed at five months of age, when she presented weight of 5.3 kg (< P3), height of 61.5 cm (P2-P10), head circumference of 40.5 cm (P25), sparse hair, micrognathia, right ear with overfolded helix and preauricular pit, triphalangeal thumbs and sacral dimple. She also had a history of congenital heart disease, hearing loss, hypotonia, delayed neuropsychomotor development and swallowing disorder. Her lymphocyte karyotype was mos 47,XX,+9[3]/46,XX[69]. Both patients had unusual clinical findings (the first, hemifacial hypoplasia associated with microtia, with a phenotype of oculo auriculo-vertebral spectrum, and the second, triphalangeal thumbs and hearing loss) and survival greater than what is usually described in the literature (< 1 year). Further reports will be critical for delineating the clinical features and determining the evolution of patients with mosaic trisomy 9. PMID- 22249801 TI - NFkappaB inhibitors as a potential novel hypothesized treatment for psoriasis. PMID- 22249804 TI - Khat use among Somali mental health service users in South London. AB - PURPOSE: Khat use has been suggested to be associated with psychosis, but its prevalence and associations among mental health service users have not been described in either traditional use countries or countries with immigrant populations from traditional use countries. We aimed to investigate the clinical and demographic associations of khat use in a sample of Somali users of mental health service users in South London. METHODS: We used an electronic case register of 150,000 mental health patients to investigate the associations of khat use among all 240 Somali patients in the database. We used logistic regression to generate adjusted estimates for a range of exposure variables and used multiple imputation as a principled approach to missing data. RESULTS: Khat use or non-use was recorded for 172 patients (72% of the total), of whom 80 (47%) were current users. Khat use was very strongly associated with ICD-10 primary diagnosis of schizophrenia, psychosis or drug and alcohol disorder (compared to ICD-10 F43 stress-related disorders and other non-psychotic disorders), male gender, harmful or dependent use of alcohol, and detention under the Mental Health Act. CONCLUSIONS: Recording and monitoring of khat use need to be more consistent in clinical settings, and further studies are required to investigate the much higher rates of use among those with psychotic disorders compared to non psychotic disorders. PMID- 22249805 TI - Determination of IgG and IgA antibodies against native gliadin is not helpful for the diagnosis of coeliac disease in children up to 2 years old. AB - OBJECTIVE: Assays for antibodies against native gliadin (anti-nGli) are still often assumed to perform better in the diagnosis of coeliac disease in young children than tests for antibodies to deamidated gliadin (anti-dGli), tissue transglutaminase (anti-tTG), and endomysium (EmA). We compared the performance of assays for anti-nGli, anti-dGli, anti-tTG, and EmA in this age group. METHODS: We investigated retrospectively 184 children (42 with coeliac disease under normal diet and 142 controls) up to 2 years of age. Immunoglobulin (Ig) A- and IgG-anti dGli, IgA- and IgG-anti-nGli, IgA- and IgG-anti-tTG, and IgA-EmA were measured in serum. Areas under receiver operating characteristics curves, sensitivities, specificities, positive and negative predictive values, positive and negative likelihood ratios, as well as diagnostic odds ratios were calculated. RESULTS: From all of the tests investigated, only assays for IgG-anti-dGli, IgA-anti-tTG, and IgA-EmA had high specificity (>= 0.96) connected with high sensitivity (>= 0.86), with high positive predictive values (>= 0.52 and >= 0.69 at pretest probabilities of 0.05 and 0.1, respectively) and negative predictive values (>= 0.99 and >= 0.98 at pretest probabilities of 0.05 and 0.1, respectively). These assays also showed high positive likelihood ratio (>= 24) at low negative likelihood ratio (<= 0.15) and high diagnostic odds ratios (>= 136). CONCLUSIONS: Our results do not support the use of assays of anti-nGli to diagnose coeliac disease in young children. IgA-anti-tTG, IgA-EmA, and IgG-anti-dGli perform better than anti-nGli. PMID- 22249806 TI - Evaluation of risk factors for bleeding after liver biopsy in children. AB - OBJECTIVES: Acetylsalicylic acid is used in liver-transplanted children to prevent thrombosis of the hepatic artery. We evaluated whether acetylsalicylic acid and other risk factors were associated with bleeding after percutaneous liver biopsy. METHODS: Medical charts, laboratory results, imaging studies, and anesthesia charts of 275 ultrasound-guided liver biopsy procedures in 190 children were reviewed. A total of 178 biopsies were performed on native livers and 97 on transplanted livers. RESULTS: Three major and 28 minor bleeding incidents were found. The mortality rate was 0%. Acetylsalicylic acid had been given the last 5 days before 55 of the biopsy procedures and no increased risk of bleeding was found (odds ratio 0.96 [0.37-2.26]; P = 1.00). Low-molecular-weight heparin and biopsies from focal lesions were risk factors for bleeding complications. Acute liver failure was associated with increased risk for major complications (odds ratio 26.1 [3.3-205]; P = 0.01) and was a risk factor for major bleeding. Postbiopsy ultrasound the day after the procedure (n = 266 [96% of 275 biopsies]) revealed minor bleeding after 7.1% of the biopsies and after 2.6% of the ultrasounds revealed unsuspected bleeding, but none of these required intervention. CONCLUSIONS: Ultrasound-guided liver biopsy in children is a procedure with a low rate of major complications and a high rate of minor bleeding not requiring intervention. Treatment with low-dose acetylsalicylic acid did not increase bleeding incidence or total complication rate. Low-molecular weight heparin and biopsies from focal lesions were risk factors for bleeding complications. Routine ultrasound the day after the procedure did not change handling of the patients. PMID- 22249807 TI - Factors associated with peptide-based formula prescription in a pediatric intensive care unit. AB - OBJECTIVES: There is no evidence-based consensus on the use of peptide-based formulas for critically ill children. The present study aimed to identify the factors associated with the choice of peptide-based formulas in the first enteral nutrition prescription for critically ill children and to compare the direct costs of the enteral formulas used in a pediatric intensive care unit. METHODS: In a prospective study, children admitted to the intensive care unit and receiving tube feeding for >=48 hours were evaluated. The potential exposure variables for the use of peptide-based formulas as the first nutrition prescription were age, sex, malnutrition, sepsis/septic shock, fasting period >2 days, use of alpha-adrenergic drugs before initiating first diet, and the revised Pediatric Index of Mortality score. A direct cost comparison of prescribed formulas was performed. RESULTS: Of 291 patients included, 85 (29.2%) were given peptide-based formulas in the first nutrition prescription. This choice was independently associated with malnutrition (odds ratio [OR] 2.94; 95% confidence interval [CI] 1.60%-5.39%; P < 0.01), fasting period >2 days (OR 3.46; 95% CI 1.93%-6.20%; P < 0.01), and use of alpha-adrenergic drugs (OR 2.32; 95% CI 1.24% 4.31%; P < 0.01). Peptide-based formula costs were up to 10 times higher than standard polymeric formula costs. CONCLUSIONS: The choice of peptide-based formula as the first enteral nutrition prescription is associated with the greater severity of patients' clinical status-patients receiving alpha-adrenergic drugs, those who are malnourished, and those with longer fasting periods. These prescriptions engender costs higher than those associated with standard polymeric formula. PMID- 22249808 TI - Leptin receptors. AB - The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS "feeding" circuitry-the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy. PMID- 22249809 TI - The role of neuropeptide Y in energy homeostasis. AB - When administered into the brain, NPY acts at Y1 and Y5 receptors to increase food intake. The response occurs with a short latency and is quite robust, such that exogenous NPY is generally considered to be the most potent of a growing list of orexigenic compounds that act in the brain. The role of endogenous NPY is not so straightforward, however. Evidence from diverse types of experiments suggests that rather than initiating behavioral eating per se, endogenous NPY elicits autonomic responses that prepare the individual to better cope with consuming a calorically large meal. PMID- 22249810 TI - The neuroendocrine circuitry controlled by POMC, MSH, and AGRP. AB - Obesity is one of the most challenging health problems worldwide. Over the past few decades, our knowledge concerning mechanisms of weight regulation has increased tremendously leading to the identification of the leptin-melanocortin pathway. The filling level of energy stores is signaled to the brain, and the information is integrated by hypothalamic nuclei, resulting in a well orchestrated response to food intake and energy expenditure to ensure constant body weight. One of the key players in this system is proopiomelanocortin (POMC), a precursor of a variety of neuropeptides. POMC-derived alpha- and beta-MSH play an important role in energy homeostasis by activating melanocortin receptors expressed in the arcuate nucleus (MC3R) and in the nucleus paraventricularis (MC4R). Activation of these two G protein-coupled receptors is antagonized by agouti-related peptide (AgRP). Naturally occurring mutations in this system were identified in patients suffering from common obesity as well as in patients demonstrating a phenotype of severe early-onset obesity, adrenal insufficiency, red hair, and pale skin. Detailed understanding of the complex system of POMC AgRP-MC3R-MC4R and their interaction with other hypothalamic as well as peripheral signals is a prerequisite to combat the obesity epidemic. PMID- 22249812 TI - The central insulin system and energy balance. AB - Insulin acts throughout the body to reduce circulating energy and to increase energy storage. Within the brain, insulin produces a net catabolic effect by reducing food intake and increasing energy expenditure; this is evidenced by the hypophagia and increased brown adipose tissue sympathetic nerve activity induced by central insulin infusion. Reducing the activity of the brain insulin system via administration of insulin antibodies, receptor antisense treatment, or receptor knockdown results in hyperphagia and increased adiposity. However, despite decades of research into the role of central insulin in food intake, many questions remain to be answered, including the underlying mechanism of action. PMID- 22249813 TI - Peripheral signals modifying food reward. AB - The pleasure derived from eating may feel like a simple emotion, but the decision to eat, and perhaps more importantly what to eat, involves central pathways linking energy homeostasis and reward and their regulation by metabolic and endocrine factors. Evidence is mounting that modulation of the hedonic aspects of energy balance is under the control of peripheral neuropeptides conventionally associated with homeostatic appetite control. Here, we describe the significance of reward in feeding, the neural substrates underlying the reward pathway and their modification by peptides released into the circulation from peripheral tissues. PMID- 22249814 TI - The role of ghrelin in the control of energy balance. AB - Ghrelin is the only potent orexigenic peptide in circulation. It stimulates food intake and leads to positive energy balance, adipogenesis, and body weight gain. However, the physiological significance of ghrelin in the regulation of energy homeostasis is controversial, since loss of ghrelin function in rodents does not necessarily lead to anorexia and weight loss. In this chapter, we discuss the metabolic function of ghrelin and are highlighting recent findings including the discovery and function of ghrelin-acylating enzyme ghrelin O-acyltransferase (GOAT). Based on available published data, we conclude that ghrelin is a principally important endogenous regulator of energy balance, which however may affect both food intake and systemic metabolism via independent mechanisms. Importantly, ghrelin, when acylated by GOAT, might represent a key molecular link between the sensing of consumed calories and the neuroendocrine control of energy homeostasis. Thus, agents antagonizing the action of ghrelin may have therapeutic potential in the therapy of obesity. PMID- 22249815 TI - Anorexigenic effects of GLP-1 and its analogues. AB - GLP-1 receptors are expressed in the brain, especially in the regions responsible for the regulation of food intake, and intracerebroventricular injection of GLP-1 results in inhibition of food intake. Peripheral administration of GLP-1 dose dependently enhances satiety and reduces food intake in normal and obese subjects as well as in type 2 diabetic patients. So far, the mechanisms by which GLP-1 exerts its effects are not completely clear. Interactions with neurons in the gastrointestinal tract or possibly direct access to the brain through the blood brain barrier as observed in rats are possible and discussed in this chapter as well as a novel hypothesis based on the finding that GLP-1 is also expressed in taste cells. Finally, the role of GLP-1 receptor agonists as a possible treatment option in obesity is discussed as well as the role of GLP-1 in the effects of bariatric surgery on adiposity and glucose homeostasis. PMID- 22249816 TI - CCK, PYY and PP: the control of energy balance. AB - The control of food intake consists of neural and hormonal signals between the gut and central nervous system (CNS). Gut hormones such as CCK, PYY and PP signal to important areas in the CNS involved in appetite regulation to terminate a meal. These hormones can act directly via the circulation and activate their respective receptors in the hypothalamus and brainstem. In addition, gut vagal afferents also exist, providing an alternative pathway through which gut hormones can communicate with higher centres through the brainstem. Animal and human studies have demonstrated that peripheral administration of certain gut hormones reduces food intake and leads to weight loss. Gut hormones are therefore potential targets in the development of novel treatments for obesity and analogue therapies are currently under investigation. PMID- 22249811 TI - Neuropeptides controlling energy balance: orexins and neuromedins. AB - In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight. PMID- 22249817 TI - Effects of amylin on eating and adiposity. AB - Amylin's best investigated function is to reduce eating via a meal size effect by promoting meal-ending satiation. This effect seems to depend on an activation of specific area postrema neurons. Brain areas that convey the neural signal to the forebrain include the nucleus of the solitary tract and the lateral parabrachial nucleus. Acute application of amylin modulates the activity of hypothalamic areas involved in the control of eating, namely, the lateral hypothalamic area and possibly the ventromedial hypothalamic nucleus. Amylin also interacts with other satiating signals, such as cholecystokinin, presumably in the brainstem. Interestingly, amylin also exhibits characteristics of adiposity signals; plasma levels of amylin are higher in obese individuals, chronic infusion of amylin into the brain reduces body weight gain and adiposity, and infusion of amylin antagonists increases adiposity. Furthermore, amylin maintains energy expenditure at higher levels than would be expected considering its body weight-lowering effect. However, much less is known (e.g., site of action, signaling pathways, differential activation of brain sites, and, most importantly, physiological relevance) with respect to its role as adiposity signal and regulator of energy expenditure than about its satiating action. Notwithstanding, and perhaps because amylin resistance does not seem to be a general and prohibitive concomitant of obesity, animal data and recent clinical data in humans indicate that amylin is a very promising candidate for the treatment of obesity. Amylin seems to be particularly effective when combined with other hormones such as leptin. PMID- 22249818 TI - Intestinal microbiota and obesity. AB - The human gut harbors a highly diverse microbial ecosystem of approximately 400 different species, which is characterized by a high interindividual variability. The intestinal microbiota has recently been suggested to contribute to the development of obesity and the metabolic syndrome. Transplantation of gut microbiota from obese mice to nonobese, germ-free mice resulted in transfer of metabolic syndrome-associated features from the donor to the recipient. Proposed mechanisms for the role of gut microbiota include the provision of additional energy by the conversion of dietary fiber to short-chain fatty acids, effects on gut-hormone production, and increased intestinal permeability causing elevated systemic levels of lipopolysaccharides (LPS). This metabolic endotoxemia is suggested to contribute to low-grade inflammation, a characteristic trait of obesity and the metabolic syndrome. Finally, activation of the endocannabinoid system by LPS and/or high-fat diets is discussed as another causal factor. In conclusion, there is ample evidence for a role of gut microbiota in the development of obesity in rodents. However, the magnitude of its contribution to human obesity is still unknown. PMID- 22249819 TI - Sensing of glucose in the brain. AB - The brain, and in particular the hypothalamus and brainstem, have been recognized for decades as important centers for the homeostatic control of feeding, energy expenditure, and glucose homeostasis. These structures contain neurons and neuronal circuits that may be directly or indirectly activated or inhibited by glucose, lipids, or amino acids. The detection by neurons of these nutrient cues may become deregulated, and possibly cause metabolic diseases such as obesity and diabetes. Thus, there is a major interest in identifying these neurons, how they respond to nutrients, the neuronal circuits they form, and the physiological function they control. Here I will review some aspects of glucose sensing by the brain. The brain is responsive to both hyperglycemia and hypoglycemia, and the glucose sensing cells involved are distributed in several anatomical sites that are connected to each other. These eventually control the activity of the sympathetic or parasympathetic nervous system, which regulates the function of peripheral organs such as liver, white and brown fat, muscle, and pancreatic islets alpha and beta cells. There is now evidence for an extreme diversity in the sensing mechanisms used, and these will be reviewed. PMID- 22249820 TI - Role of CD36 in oral and postoral sensing of lipids. AB - Obesity and associated plethora of diseases constitute a major public health challenge worldwide. The conjunction of profound changes in our lifestyle and a thrifty genetic that evolved in an environment of food scarcity largely explains this epidemic situation. Food abundance promotes our specific appetite for the more palatable food generally rich in lipids. It is noteworthy that this attraction for fatty food is not specific to humans. Rats and mice also spontaneously prefer lipid-rich food in a free-choice situation. Detection of lipids in food requires the presence of specific sensors located in strategic places (e.g., oral cavity, small intestine, brain) whose activation results in a modulation of the eating behavior. Recent data strongly suggest that the glycoprotein CD36 plays a significant role in this sensing system. PMID- 22249821 TI - Intestinal sensing of nutrients. AB - Ingestion of a meal triggers a range of physiological responses both within and outside the gut, and results in the remote modulation of appetite and glucose homeostasis. Luminal contents are sensed by specialised chemosensitive cells scattered throughout the intestinal epithelium. These enteroendocrine and tuft cells make direct contact with the gut lumen and release a range of chemical mediators, which can either act in a paracrine fashion interacting with neighbouring cells and nerve endings or as classical circulating hormones. At the molecular level, the chemosensory machinery involves multiple and complex signalling pathways including activation of G-protein-coupled receptors and solute carrier transporters. This chapter will discuss our current knowledge of the molecular mechanisms underlying intestinal chemosensation with a particular focus on the relatively well-characterised nutrient-triggered secretion from the enteroendocrine system. PMID- 22249822 TI - Reuptake inhibitors of dopamine, noradrenaline, and serotonin. AB - Pharmacological inhibition of monoamine reuptake transporters has been known for many years as an effective therapy to reduce food intake and body weight in obese subjects. However, most of the marketed drugs failed after a distinct period in clinical use and had to be withdrawn because of serious adverse effects resulting in a negative benefit-risk profile. The most common side effects for this drug class included increases in systemic or pulmonary blood pressure and/or heart rate, cardiac valvulopathies, higher cardiovascular event rates, psychiatric disorders, or high abuse potential. The recent withdrawal of sibutramine as result of its adverse actions on the cardiovascular system highlighted again the problems with this drug class in antiobesity therapy. Recent developments to combine reuptake inhibitors with other drug classes, for example, opioid antagonists seem to be a promising approach to improve the benefit-risk profile of these compounds.This chapter will discuss the history of this drug class in appetite control, its mechanism of action, and the clinical effects of selected drugs from this class. PMID- 22249823 TI - 5-HT(2C) receptor agonists and the control of appetite. AB - The role of serotonin (5-HT) in appetite control is well recognised. 5-HT drugs reduce food intake in rodents in a manner consistent with an enhancement of satiety. In humans, they have been shown to reduce caloric intake, an effect associated with reduced hunger and increased satiety. These effects appear to be mediated, at least in part, by the 5-HT(2C) receptor subtype. 5-HT-acting drugs such as fenfluramine, d-fenfluramine, and sibutramine have provided effective anti-obesity treatments in the past. However, more selective agents are needed that produce the same changes in eating behaviour and induce weight loss without unacceptable side effects. Lorcaserin, a selective 5-HT(2C) receptor agonist, is a novel anti-obesity agent that reduces both energy intake and body weight. The effects of lorcaserin on eating behaviour remain to be characterised as does its behavioural specificity. PMID- 22249824 TI - Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight. AB - The endocannabinoid system consists of lipid-derived agonists that activate cannabinoid (CB) receptors. CB receptor agonists, namely, the phytocannabinoid Delta(9)-THC and the endocannabinoid anandamide, increase hunger sensation and food intake. These discoveries led to the clinical use of Delta(9)-THC derivatives for the treatment of cancer and HIV-related nausea and cachexia. Animal studies clarified the important role of CB1 receptors in the hypothalamus and in the limbic system in mediating orexigenic effects. In parallel, data on CB1-specific blockade either by drugs or by genetic ablation further demonstrated that CB1 inhibition protects against weight gain induced by high-fat feeding and reduces body weight in obese animals and humans. The mechanisms of weight reduction by CB1 blockade are complex: they comprise interactions with several orexigenic and anorexigenic neuropeptides and hormones, regulation of sympathetic activity, influences on mitochondrial function, and on lipogenesis. Although these mechanisms appear to be mainly mediated by the CNS, weight loss also occurs when drugs that do not reach CNS concentrations sufficient to inhibit CB1 signaling are used. The development of peripherally restricted CB1 inverse agonists and antagonists opened new routes in CB1 pharmacology because centrally acting CB1 inverse agonists, e.g., rimonabant and taranabant, exerted unacceptable side effects that precluded their further development and application as weight loss drugs. Tissue and circulating endocannabinoid concentrations are often increased in animal models of obesity and in obese humans, especially those with visceral fat accumulation. Thus, further research on CB1 inhibition is still promising to treat human obesity. PMID- 22249825 TI - Antiobesity effects of melanin-concentrating hormone receptor 1 (MCH-R1) antagonists. AB - Despite remarkable progress in the elucidation of energy balance and regulation, the development of new antiobesity drugs is still at the stage of infancy. This review describes the MCH and MCH receptor system with regard to its involvement in energy homeostasis and summarizes the pharmacological profiles of selected small molecule MCH-R1 antagonists that are relevant for their development as antiobesity drugs. Although their clinical value still has to be demonstrated, and challenges with regard to unwanted side effects remain to be resolved, MCH-R1 antagonists may provide an effective pharmacotherapy for the treatment of obesity in the near future. PMID- 22249826 TI - Appetite-modifying effects of bombesin receptor subtype-3 agonists. AB - Studies on bombesin-like peptides (BLP) and their respective mammalian receptors (Bn-r) have demonstrated a significant biological impact on a broad array of physiological and pathophysiological conditions. Pharmacological experiments in vitro and in vivo as well as utilization of genetic rodent models of the gastrin releasing peptide receptor (GRP-R/BB2-receptor), neuromedin B receptor (NMB-R/BB1 receptor), and the bombesin receptor subtype-3 (BRS-3/BB3-receptor) further delineated their role in health and disease. All three mammalian bombesin receptors have been shown to possess some role in the regulation of energy balance and appetite and satiety. Compelling experimental evidence has accumulated indicating that the orphan BRS-3 is an important regulator of body weight, energy expenditure, and glucose homeostasis. BRS-3 possesses no high affinity to the endogenous bombesin-like peptides (BLP) bombesin, GRP, and NMB, and its endogenous ligand remains unknown. Recently, the synthesis of novel, selective high-affinity BRS-3 agonists and antagonists has been accomplished and has demonstrated that BRS-3 regulates energy balance independent of other established pathways. Accordingly, the availability of new BRS-3 selective agonists and antagonists will facilitate further elucidation of its role in energy homeostasis and provides a potential approach for the pharmacological treatment of obesity. PMID- 22249827 TI - Weight-reducing side effects of the antiepileptic agents topiramate and zonisamide. AB - Drug-induced weight alteration can be a serious side effect that applies to several therapeutic agents and must be referred to in the respective approved labeling texts. The side effect may become health threatening in case of significant weight change in either direction. Several antiepileptic drugs (AEDs) are associated with weight gain such as gabapentin, pregabalin, valproic acid, and vigabatrin and to some extent carbamazepine. Others are weight neutral such as lamotrigine, levetiracetam, and phenytoin or associated with slight weight loss as, e.g., felbamate. The focus of this chapter is on the two AEDs causing strong weight loss: topiramate and zonisamide. For both drugs, several molecular mechanisms of actions are published. We provide a review of these potential mechanisms, some of which are based on in vivo studies in animal models for obesity, and of clinical studies exploring these two drugs as single entities or in combinations with other agents. PMID- 22249828 TI - The oncology pharmacy in cancer care delivery in a resource-constrained setting in western Kenya. AB - The movement to deliver cancer care in resource-limited settings is gaining momentum, with particular emphasis on the creation of cost-effective, rational algorithms utilizing affordable chemotherapeutics to treat curable disease. The delivery of cancer care in resource-replete settings is a concerted effort by a team of multidisciplinary care providers. The oncology pharmacy, which is now considered integral to cancer care in resourced medical practice, developed over the last several decades in an effort to limit healthcare provider exposure to workplace hazards and to limit risk to patients. In developing cancer care services in resource-constrained settings, creation of oncology pharmacies can help to both mitigate the risks to practitioners and patients, and also limit the costs of cancer care and the environmental impact of chemotherapeutics. This article describes the experience and lessons learned in establishing a chemotherapy pharmacy in western Kenya. PMID- 22249829 TI - Delayed and forgone care for families with chronic conditions in high-deductible health plans. AB - BACKGROUND: High-deductible health plans (HDHPs) are an increasingly common strategy to contain health care costs. Individuals with chronic conditions are at particular risk for increased out-of-pocket costs in HDHPs and resulting cost related underuse of essential health care. OBJECTIVE: To evaluate whether families with chronic conditions in HDHPs have higher rates of delayed or forgone care due to cost, compared with those in traditional health insurance plans. DESIGN: This mail and phone survey used multiple logistic regression to compare family-level rates of reporting delayed/forgone care in HDHPs vs. traditional plans. PARTICIPANTS: We selected families with children that had at least one member with a chronic condition. Families had employer-sponsored insurance in a Massachusetts health plan and >12 months of enrollment in an HDHP or a traditional plan. MAIN MEASURES: The primary outcome was report of any delayed or forgone care due to cost (acute care, emergency department visits, chronic care, checkups, or tests) for adults or children during the prior 12 months. RESULTS: Respondents included 208 families in HDHPs and 370 in traditional plans. Membership in an HDHP and lower income were each independently associated with higher probability of delayed/forgone care due to cost. For adult family members, the predicted probability of delayed/forgone care due to cost was higher in HDHPs than in traditional plans [40.0% vs 15.1% among families with incomes <400% of the federal poverty level (FPL) and 16.0% vs 4.8% among those with incomes >=400% FPL]. Similar associations were observed for children. CONCLUSIONS: Among families with chronic conditions, reporting of delayed/forgone care due to cost is higher for both adults and children in HDHPs than in traditional plans. Families with lower incomes are also at higher risk for delayed/forgone care. PMID- 22249830 TI - Antihypertensive peptides from food proteins: a review. AB - High blood pressure is considered as a significant health problem worldwide. In addition to numerous preventive and therapeutic drug treatments, important advances have been achieved in the identification of dietary compounds that may contribute to cardiovascular health. Among these compounds, peptides with antihypertensive properties received special attention in the past 15 years. Although milk proteins are still the main source of antihypertensive peptides, recently a remarkable increase has been noticed in the report of antihypertensive peptides released from other dietary sources. Most of these peptides have demonstrated their properties by in vitro assays. However, the evidence for their beneficial antihypertensive effects has to be based on animal experiments and clinical trials. This paper reviews the current data of the blood pressure lowering activity of food-derived peptides demonstrated in vivo (animal models and humans). Other aspects, such as the mechanism of action and bioavailability of these peptides which play a key role in their antihypertensive effects are also summarized in this review. PMID- 22249831 TI - Effects of Lyrm1 knockdown on mitochondrial function in 3 T3-L1 murine adipocytes. AB - To explore the effects of Lyrm1 knockdown on the mitochondrial function of 3 T3 L1 adipocytes using small interfering RNA (siRNA). 3 T3-L1 preadipocytes were infected with either a negative control (NC) expression lentivirus or a Lyrm1 shRNA expression lentivirus and induced to differentiate. The knockdown efficiency of Lrym1-specific shRNA in 3 T3-L1 cells was evaluated by real-time PCR. The ultrastructure of the mitochondria in adipocytes was visualized using transmission electron microscopy after differentiation. The levels of mitochondrial DNA copy numbers and Ucp2 mRNA were detected by real-time quantitative PCR. The levels of ATP production was detected using a photon counting luminometer. The mitochondrial membrane potential and ROS levels of cells were analyzed with a FACScan flow cytometer using Cell Quest software. Cells transfected with lentiviral-Lyrm1-shRNA showed a significantly reduced transcription of Lyrm1 mRNA compared with NC cells. The size and ultrastructure of mitochondria in Lyrm1 knockdown adipocytes was similar to those of the NC cells. There was no significant difference in mtDNA copy number between the two groups. The total level of ATP production, mitochondrial membrane potential and Ucp2 mRNA expression levels were dramatically increased in adipocytes transfected with Lyrm1 RNAi. Furthermore, the level of ROS was dramatically decreased in Lyrm1 knockdown adipocytes. Knockdown of the Lyrm1 gene in adipocytes resulted in dramatically increased cellular ATP production, mitochondrial membrane potentials and levels Ucp2 mRNA, while ROS levels were significantly decreased. These results imply that mitochondrial function is improved in adipocytes after the knockdown of Lyrm1. PMID- 22249832 TI - Open and closed cavity mastoid operations: comparing early hearing results. AB - The aim of the study is to compare audiological results in patients treated surgically with either an open or closed cavity mastoidectomy. A prospective review of a single surgeon's case series based at two district general hospitals. All patients with 1-year post-operative hearing results following an open or closed cavity mastoid surgery were included. Outcome measured included the preoperative and postoperative air-bone gap (ABG). Belfast rule of thumb was used to assess the benefit from middle ear surgery. A total of 128 patients were identified from the database with 1 year post-operative hearing results. Sixty three patients had undergone an open cavity mastoidectomy and 65 had a closed cavity mastoidectomy. The mean post-operative ABG in patients with open cavity mastoidectomy was 24 dB and for closed cavity 21 dB (p = 0.12). There was no statistical difference between open and closed cavity mastoidectomy with or without ossiculoplasty and if the underlying pathology was squamous or mucosal disease. However, patient with post-operative ABG below or equal to 20 dB was 41% for closed cavity compared to 21% for open cavity. Using the Belfast rule of thumb, 79% of the patients in both groups had successful hearing results post surgery. The 1-year post-operative audiological results between open and closed cavity masoidectomy showed no statistical difference. The pathology affecting the middle ear also had no influence on the hearing results between the two groups. However, there was a higher percentage of patients with closed cavity procedures who had a post-operative ABG that was below or equal to 20 dB. PMID- 22249833 TI - A time-saving method for recording chemosensory event-related potentials. AB - The objective of this study was to reduce the recording duration of chemosensory event-related potentials (CSERP) and thereby to make the method more suitable for routine clinical use. Measurements were performed in the Department of Otorhinolaryngology of the university hospital of Cologne. Two protocols with different sequences [inter-stimulus intervals (ISI)-standard sequence: 30 s; PRS 15: pseudo-randomized sequence, mean ISI of 15 s] were applied to 40 volunteers to record CSERPs. To compare CSERP recordings under optimal and adverse test conditions, 20 younger/normosmic adults and 20 older/hyposmic participants were included in this study. Olfactory function was gauged using the "Sniffin'Sticks" test. For CSERP recordings, phenylethyl alcohol, hydrogen sulfide and carbon dioxide were used for olfactory or trigeminal stimulation, respectively. Both ISI protocols allowed recording CSERPs under optimal and adverse test conditions and distinguishing both groups by latencies (p <= 0.015). The time requirement for the recording of CSERPs with the PRS-15 sequence was less than 30 min. The pseudo randomized sequence allowed the recording of diagnostically conclusive CSERPs in both groups and saved approximately 40% of the measuring time. This seems to be especially useful in cases where a yes/no answer (e.g., medical reports, exclusion of anosmia) is required. Shortening the time requirement significantly allows applying CSERPs to larger populations of patients with olfactory impairment. PMID- 22249834 TI - Post-treatment late complications of nasopharyngeal carcinoma. AB - Radiotherapy (RT) or concurrent chemoradiation therapy (CCRT) is not only effective at patients' survival rates, but also produces undesirable late complications. The purpose of this study is to investigate the post-treatment late complications in nasopharyngeal carcinoma (NPC) patients, and to analyze the individual impact factors. We enrolled 188 newly diagnosed NPC patients who had received complete treatments and at least 3 years' follow-up between March 1984 and March 2010. Late complications were modified from the Toxicity Criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer. Of 188 patients, 132 were male and 56 were female. Eighty-eight patients received CCRT and the other 100 patients received RT alone. The median follow-up duration was 7.34 years (range 3.30-26.54). Only 5.3% of patients reported no complication during post-treatment follow-up. The most common major and minor complications were osteoradionecrosis (10.1%) and xerostomia (56.4%), respectively. There was no impact factor for age, underlying disease, and cancer staging. However, there was a negative impact factor for xerostomia and limb numbness in the CCRT group compared with the RT group. Besides, re-radiation for recurrent patients could increase the risk of major complications. Fortunately, these major complications were reduced after the introduction of intensity-modulated radiotherapy in 2003. The improvement of treatment modality decreased the risk of major complications. Physicians should pay more attentions and improve patients' quality of life during follow-up. PMID- 22249835 TI - Complications of chronic suppurative otitis media: a retrospective review. AB - The purpose of this study was to review our patients with complications of chronic suppurative otitis media (CSOM) and compare with literature. This retrospective study was performed over 10 years in our tertiary referral university hospital. During this period 4,630 patients with CSOM were admitted to the department and 906 patients underwent a surgery. From the records of the 4,630 patients, 121 patients (2.6%) with complications were identified. Of the 906 CSOM patients that underwent a surgery, 511 had cholesteatoma, and 395 had granulation and/or polyp tissue. Ninety-four of 511 (18.4%) patients with cholesteatoma and 27 of 395 (6.8%) patients with granulation and/or polyp tissue had a complication. Of the 121 complicated CSOM patients, 57 extracranial (47.1%) and 37 intracranial (30.6%). Multiple combined complications were occurred in 27 (22.3%) patients. The mastoid abscess was the commonest extracranial complication (28.3%); it was followed by labyrinthitis (9%), facial nerve paralysis (8.4%), and Bezold's abscess (1.3%). The most common intracranial complication was lateral sinus thrombophlebitis (19.5%), followed by perisigmoid sinus abscess (13.5%), meningitis (9%), brain abscess (6.5%), and extradural abscess (4.5%). Most frequent intraoperative finding of complicated CSOM patients was cholesteatoma, with the exception of patients with facial nerve paralysis. There was no mortality in any of our patients. The additional morbidities were recorded in 25 patients (20.6%). In this study, we emphasize the importance of an accurate and early diagnosis, followed by adequate surgical therapy and a multidisciplinary approach. PMID- 22249836 TI - Functional endoscopic surgery of paranasal fungus ball: clinical outcome, patient benefit and health-related quality of life. AB - Paranasal fungus ball can cause chronic rhinosinusitis. Removal via functional endoscopic sinus surgery is usually performed; however objective data on the overall benefit and patient satisfaction are very scarce. The study focuses on the clinical outcome and the quality of life following endoscopic surgery due to fungus ball sinusitis. Forty patients diagnosed with fungus ball sinusitis who underwent functional endoscopic surgery were included. Epidemiologic data, pre-, intra- and postoperative findings were recorded. Surgical success, the detailed benefit and the health-related quality of life were objectively assessed 1 year after the surgery based on a standardized questionnaire (modified SNOT 20) and the Glasgow Benefit Inventory. Health-related quality of life improved significantly in >90% of patients (p < 0.05). There were no serious complications or recurrences. As the treatment of choice functional endoscopic sinus surgery of paranasal fungus ball sinusitis is associated with exceptionally high patient satisfaction. PMID- 22249837 TI - The value of PET/CT to assess clinically negative necks. AB - The aim was to evaluate the efficacy of [(18)F]-2-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in evaluating metastasis of head and neck squamous cell carcinoma (HNSCC) to the cervical lymph nodes, with specific attention to the efficacy in regard to clinically negative necks. This was a retrospective review of 243 patients with HNSCC between years 2005 and 2007 treated at a comprehensive cancer care institution who underwent pre-operative PET/CT and neck dissection with either an N0 (112 patients) or N+ (131 patients) clinical nodal status. PET/CT findings were correlated with histopathological results of surgical specimens. A majority of the primary sites were oral cavity and oropharynx (70%), followed by larynx, unknown primary and hypopharynx. In the group of 112 patients who underwent 144 neck dissections with N0 nodal status, sensitivity, specificity, positive predictive value (PPV) and negative predictive (NPV) and accuracy were 57, 82, 59, 80 and 74%, respectively. In the group of 131 patients who underwent 169 neck dissections with N+ nodal status, sensitivity, specificity, PPV, NPV and accuracy were 93, 70, 96, 58 and 91%, respectively. PET/CT has a much reduced rate of efficacy for the clinically negative neck compared to the clinically positive neck. PET/CT in its current stage does not appear to offer an advantage in staging the clinically N0 neck due to high rates of false positives and negatives. PMID- 22249838 TI - Multiple sclerosis: 'Outside-in' demyelination in MS. PMID- 22249840 TI - Skepticism about thrombolytics in stroke is not unreasonable. PMID- 22249839 TI - Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. AB - The past two decades have witnessed the emergence of a new and expanding field of neurological diseases--the genetic ion channelopathies. These disorders arise from mutations in genes that encode ion channel subunits, and manifest as paroxysmal attacks involving the brain or spinal cord, and/or muscle. The voltage gated P/Q-type calcium channel (P/Q channel) is highly expressed in the cerebellum, hippocampus and cortex of the mammalian brain. The P/Q channel has a fundamental role in mediating fast synaptic transmission at central and peripheral nerve terminals. Autosomal dominant mutations in the CACNA1A gene, which encodes voltage-gated P/Q-type calcium channel subunit alpha(1) (the principal pore-forming subunit of the P/Q channel) are associated with episodic and progressive forms of cerebellar ataxia, familial hemiplegic migraine, vertigo and epilepsy. This Review considers, from both a clinical and genetic perspective, the various neurological phenotypes arising from inherited P/Q channel dysfunction, with a focus on recent advances in the understanding of the pathogenetic mechanisms underlying these disorders. PMID- 22249841 TI - Epilepsy: Determinants of quality of life in epilepsy go beyond seizure-related variables. PMID- 22249842 TI - Systemic treatment with pulsed electromagnetic fields do not affect bone microarchitecture in osteoporotic rats. AB - PURPOSE: Pulsed electromagnetic fields (PEMF) are currently used in the treatment of spinal fusions and non-unions. There are indications that PEMF might also be effective in the treatment of osteoporosis. In this study we examined whether whole-body PEMF treatment affects the bone microarchitecture in an osteoporotic rat model. METHODS: Twenty-week-old female rats were ovariectomised (n=20). Four different PEMF treatment protocols based on previous experimental studies and based on clinically used PEMF signals were examined (2 h/day, 5 days/week). A control group did not receive PEMF. At zero, three and six weeks cancellous and cortical bone architectural changes at the proximal tibia were evaluated using in vivo microCT scanning. RESULTS: PEMF treatment did not induce any changes in cancellous or cortical bone compared to untreated controls. CONCLUSIONS: Although previous studies have shown strong effects of PEMF in osteoporosis we were unable to demonstrate this in any of the treatment protocols. Using in vivo microCT scanning we were able to identify small bone changes in time. Subtle differences in the experimental set-up might explain the differences in study outcomes in the literature. Since PEMF treatment is safe, future experimental studies on the effect of PEMF on bone can better be performed directly on humans, eliminating the potential translation issues between animals and humans. In this study we found no support for the use of PEMF in the treatment of osteoporosis. PMID- 22249843 TI - Risk factors for post-traumatic osteoarthritis of the ankle: an eighteen year follow-up study. AB - PURPOSE: Long-term studies evaluating risk factors for development of ankle osteoarthritis (OA) following malleolar fractures are sparse. METHODS: We conducted a retrospective cohort study including consecutive patients treated by open reduction and internal fixation for malleolar fracture between January 1988 and December 1997. Perioperative information was obtained retrospectively. Patients were evaluated clinically and radiographically 12-22 years postoperatively. Radiographic ankle OA was determined on standardised radiographs using the Kellgren and Lawrence scale (grade 3-4=advanced OA). Uni- and multivariate regression analyses were performed to determine risk factors for OA. RESULTS: During the inclusion period, 373 fractures (372 patients; 9% Weber A, 58% Weber B, 33% Weber C) were operated upon. The mean age at operation was 42.9 years. There were 102 patients seen at follow-up (mean follow-up 17.9 years). Those not available did not differ in demographics and fracture type from those seen. Advanced radiographic OA was present in 37 patients (36.3%). Significant risk factors were: Weber C fracture, associated medial malleolar fracture, fracture-dislocation, increasing body mass index, age 30 years or more and length of time since surgery. CONCLUSIONS: Advanced radiographic OA was common 12-22 years after malleolar fracture. The probability of developing post-traumatic OA among patients having three or more risk factors was 60-70%. PMID- 22249845 TI - RANK, RANKL and OPG expressions in a permanent molar with a replacement resorption. AB - The aim of this study was to explore the expression of RANK, RANKL and OPG during ankylosis. Structural details and immunohistochemical investigations of the expression of RANK, RANKL and OPG in an extracted secondary retained permanent molar of a 12-year-old girl are reported. Woven and lamellar bones were observed in the thickness of the remodeled dental wall and a tertiary dentin was noticed around the pulp cavity. The resorbing multinucleated cells expressed TRAP and RANK but few of them also expressed RANKL. Both odontoblasts and osteoblasts expressed TRAP and RANK, but the expression of RANKL was limited to osteoblasts. OPG remained undetected. The present case reveals unusual expression of RANKL in the resorbing cells, TRAP and RANK in both osteoblasts and odontoblasts, and a failure of detection of OPG. These proteins could be involved in the pathogenesis of tooth ankylosis. PMID- 22249844 TI - Effect of PDGF-BB combined with EDTA gel on adhesion and proliferation to the root surface. AB - Periodontal regeneration using EDTA or PDGF showed promising results, but the effect of combined application was still unclear. This study aimed to verify the effect of EDTA and/or PDGF application on root adhesion and proliferation of PDL fibroblast cells. Eighty specimens were prepared from forty periodontitis teeth and made five groups: (1) diseased (untreated), (2) SRP (scaling root planing), (3) EDTA (24%), (4) PDGF (25 ng/ml) and (5) Combined application of EDTA and PDGF. Periodontal ligament cells were cultured on the above conditioned dentin plate, and SEM examination was preformed and cells were counted within a representative standard area for both cell morphology and density. All groups including untreated showed significantly increase of adhered cells from baseline to 7 days. Among them, rate of increase was much higher in EDTA, PDGF, and combined groups. ANOVA test indicated that the number of cells in PDGF and combined groups was significantly higher than diseased group at 1 day. On day 7, PDGF and combined groups showed significantly higher number of adhesion cells than that found in the diseased, SRP and EDTA groups. Thus, root conditioning with EDTA enhanced cell adhesion more than SRP alone. There was no significant difference of cell number between PDGF and combined group. Combined application of EDTA and PDGF increased significantly PDL cell adhesion than EDTA alone. PDGF alone, however, also showed comparable effect to combined application at all periods. Thus, synergistic effect between PDGF and EDTA was not observed. PMID- 22249846 TI - Detection of experimentally induced root fractures on digital and conventional radiographs: an in vitro study. AB - This study compared the diagnostic accuracy of digital radiographic images with conventional radiographs for the detection of experimentally induced root fractures. Horizontal fractures were induced by a mechanical force to the root of 15 single rooted teeth. Vertical fractures were induced in 15 single rooted teeth and 15 molars, respectively, by disk cutting. The teeth were mounted in dried mandibles and were radiographed with the parallel technique using a CCD-based Planmeca imaging system and F-speed films. Seven observers recorded their findings and then 2 pairs of them examined the same images together. Az values expressed the diagnostic accuracy of the imaging systems and the degree of agreement was estimated using the Cohen's kappa statistic. The areas under the ROC curves (Az) in single rooted teeth were 0.61 for conventional radiography and 0.64 for digital radiography. Digital imaging system did not perform significantly better than conventional one (p > 0.01). Digital radiographs (Az: 0.72) provided higher detection accuracy in molars than conventional images (Az: 0.51) (p = 0.0102). The digital images scored higher kappa values with narrower range than conventional. Observers in pairs did not perform significantly better than individually. The results were not affected by the observers but were affected by the cases (p < 0.001). Digital images were equivalent to F-speed films for the detection of root fractures in single rooted teeth. The digital system performed significantly better than the conventional in detecting root fractures in molars. PMID- 22249848 TI - Impact of payer status on treatment options for acute cholecystitis: will health care reform help us close the gap? PMID- 22249847 TI - beta-blocker continuation after noncardiac surgery: a report from the surgical care and outcomes assessment program. AB - BACKGROUND: Despite limited evidence of effect, beta-blocker continuation has become a national quality improvement metric. OBJECTIVE: To determine the effect of beta-blocker continuation on outcomes in patients undergoing elective noncardiac surgery. DESIGN, SETTING, AND PATIENTS: The Surgical Care and Outcomes Assessment Program is a Washington quality improvement benchmarking initiative based on clinical data from more than 55 hospitals. Linking Surgical Care and Outcomes Assessment Program data to Washington's hospital admission and vital status registries, we studied patients undergoing elective colorectal and bariatric surgical procedures at 38 hospitals between January 1, 2008, and December 31, 2009. MAIN OUTCOME MEASURES: Mortality, cardiac events, and the combined adverse event of cardiac events and/or mortality. RESULTS: Of 8431 patients, 23.5% were taking beta-blockers prior to surgery (mean [SD] age, 61.9 [13.7] years; 63.0% were women). Treatment with beta-blockers was continued on the day of surgery and during the postoperative period in 66.0% of patients. Continuation of beta-blockers both on the day of surgery and postoperatively improved from 57.2% in the first quarter of 2008 to 71.3% in the fourth quarter of 2009 (P value <.001). After adjusting for risk characteristics, failure to continue beta-blocker treatment was associated with a nearly 2-fold risk of 90 day combined adverse event (odds ratio, 1.97; 95% CI, 1.19-3.26). The odds were even greater among patients with higher cardiac risk (odds ratio, 5.91; 95% CI, 1.40- 25.00). The odds of combined adverse events continued to be elevated 1 year postoperatively (odds ratio, 1.66; 95% CI, 1.08-2.55). CONCLUSIONS: beta-Blocker continuation on the day of and after surgery was associated with fewer cardiac events and lower 90-day mortality. A focus on beta-blocker continuation is a worthwhile quality improvement target and should improve patient outcomes. PMID- 22249849 TI - Can We Safely State That Laparoscopic Roux-en-Y Gastric Bypass Is a Better Weight Loss Procedure Than Adjustable Band Gastroplasty?: Comment on "Roux-en-Y Gastric Bypass vs Gastric Banding for Morbid Obesity". PMID- 22249850 TI - Roux-en-Y gastric bypass vs gastric banding for morbid obesity: a case-matched study of 442 patients. AB - HYPOTHESIS: Gastric banding (GB) and Roux-en-Y gastric bypass (RYGBP) are used in the treatment of morbidly obese patients. We hypothesized that RYGBP provides superior results. DESIGN: Matched-pair study in patients with a body mass index (BMI) less than 50. SETTING: University hospital and regional community hospital with a common bariatric surgeon. PATIENTS: Four hundred forty-two patients were matched according to sex, age, and BMI. INTERVENTIONS: Laparoscopic GB or RYGBP. MAIN OUTCOME MEASURES: Operative morbidity, weight loss, residual BMI, quality of life, food tolerance, lipid profile, and long-term morbidity. RESULTS: Follow-up was 92.3% at the end of the study period (6 years postoperatively). Early morbidity was higher after RYGBP than after GB (17.2% vs 5.4%; P<.001), but major morbidity was similar. Weight loss was quicker, maximal weight loss was greater, and weight loss remained significantly better after RYGBP until the sixth postoperative year. At 6 years, there were more failures (BMI>35 or reversal of the procedure/conversion) after GB (48.3% vs 12.3%; P<.001). There were more long term complications (41.6% vs 19%; P.001) and more reoperations (26.7% vs 12.7%; P<.001) after GB. Comorbidities improved more after RYGBP. CONCLUSIONS: Roux-en-Y gastric bypass is associated with better weight loss, resulting in a better correction of some comorbidities than GB, at the price of a higher early complication rate. This difference, however, is largely compensated by the much higher long-term complication and reoperation rates seen after GB. PMID- 22249851 TI - Payer status and treatment paradigm for acute cholecystitis. AB - HYPOTHESIS: Medicaid recipients who present to the emergency department with acute cholecystitis (AC) would have reduced access to cholecystectomy compared with a similar population of private insurance carriers. DESIGN: The Nationwide Inpatient Sample (NIS) database from 1998 to 2008. PARTICIPANTS: Emergent hospitalizations (843 179) with AC as a primary diagnosis. INTERVENTIONS: Insurance type was analyzed against cholecystectomy in propensity score-matched cohorts. MAIN OUTCOME MEASURES: Surgical intervention and surgical outcomes. RESULTS: Approximately 200 000 patients were in each matched cohort. The median age of the matched patients was 43.9 years, 76% were women, and the mean Charlson Comorbidity Index was 0.5. While 89% of the private insurance cohort underwent cholecystectomy during their hospitalization, only 83% of the Medicaid population received equivalent care (P.001). The Medicaid cohort also had reduced rates of laparoscopic surgery (78% vs 69%; P.001) and an increased conversion rate from laparoscopic to open surgery (3.9% vs 3.0%; P.001). While disparities in the rates of laparoscopic surgery between the 2 groups sequentially narrowed during the 10-year period, overall disparities in surgical treatment remained constant over time. CONCLUSIONS: Medicaid payer status confers inferior access to surgical treatment for AC. While this finding may be due in part to patients' health beliefs and physician preferences, the magnitude of difference suggests that health systems factors may provide a significant contribution toward clinical decision making in this entity. PMID- 22249852 TI - Long-term and perioperative corticosteroids in anastomotic leakage: a prospective study of 259 left-sided colorectal anastomoses. AB - OBJECTIVE: To determine the risk factors for symptomatic anastomotic leakage (AL) after colorectal resection. DESIGN: Review of records of patients who participated in the Analysis of Predictive Parameters for Evident Anastomotic Leakage study. SETTING: Eight health centers. PATIENTS: Two hundred fifty-nine patients who underwent left-sided colorectal anastomoses. INTERVENTION: Corticosteroids taken as long-term medication for underlying disease or perioperatively for the prevention of postoperative pulmonary complications. MAIN OUTCOME MEASURES: Prospective evaluations for risk factors for symptomatic AL. RESULTS: In 23% of patients, a defunctioning stoma was constructed. The incidence of AL was 7.3%. The clinical course of patients with AL showed that in 21% of leaks, the drain indicated leakage; in the remaining patients, computed tomography or laparotomy resulted equally often in the detection of AL. In 50% of patients with AL, a Hartmann operation was needed. The incidence of AL was significantly higher in patients with pulmonary comorbidity (22.6% leakage), patients taking corticosteroids as longterm medication (50% leakage), and patients taking corticosteroids perioperatively (19% leakage). Perioperative corticosteroids were prescribed in 8% of patients for the prevention of postoperative pulmonary complications. CONCLUSIONS: We found a significantly increased incidence of AL in patients treated with long-term corticosteroids and perioperative corticosteroids for pulmonary comorbidity. Therefore, we recommend that in this patient category, anastomoses should be protected by a diverting stoma or a Hartmann procedure should be considered to avoid AL. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1258 PMID- 22249853 TI - Substitution of the catalytic metal and protein PEGylation enhances activity and stability of bacterial phosphotriesterase. AB - Phosphotriesterase, a pesticide-degrading enzyme, from Flavobacterium sp. was cloned and expressed in Escherichia coli. The catalytic zinc ions were replaced by cobalt atoms increasing the catalytic activity of phosphotriesterase on different pesticides. This metal substitution increased the catalytic activity from 1.4 times to 4 times according to the pesticide. In order to explain this catalytic increase, QM/MM calculations were performed. Accordingly, the HOMO energy of the substrate is closer to the LUMO energy of the cobalt-substituted enzyme. The chemical modification of the enzyme surface with poly(ethylene glycol) increased the thermostability and stability against metal chelating agents of both metal phosphotriesterase preparations. PMID- 22249854 TI - One-step expression and tyrosine O-sulfonation of Ax21 in Escherichia coli. AB - Ax21 (activator of Xa21-mediated immunity), a pathogen-associated molecular pattern secreted by Xanthomonas oryzae pv. oryzae, can be perceived by a membrane located pattern recognition receptor Xa21 and triggered immune responses in rice. An Ax21-derived peptide (17-amino acid) containing a sulfated tyrosine-22 (axY(S)22) is sufficient for Ax21 activity. Here, we expressed Ax21 and O sulfated its tyrosine-22 through coexpressing a putative tyrosine sulfotransferase, raxST, and two other genes involved in the synthesis of 3' phosphoadenosine 5'-phosphosulfate in Escherichia coli BL21 (DE3). The sulfated Ax21 fused with a histidine tag in its N-terminus was extracted and bound onto a Ni-NTA agarose and then cleaved with Factor Xa and CNBr in turn. Deltaax21Y(S)22, a 36-amino acid peptide covering axY(S)22 in the lysate supernatant, was finally yielded after ultrafiltration. The purified peptide was further verified by Tricine-SDS-PAGE and isoelectrofocusing electrophoresis. Lesion length analysis, reactive oxygen species production, and mitogen-activated protein kinase (MAPK) activation of rice leaves inoculated with Deltaax21Y(S)22 confirmed the activity of the sulfated peptide. Overall, this study successfully established an efficient system for expression and purification of a sulfated peptide. In addition, the sulfotransferase activity of RaxST was confirmed for the first time. PMID- 22249855 TI - Covalent immobilization of cellulases onto a water-soluble-insoluble reversible polymer. AB - The covalent immobilization of a commercial preparation of cellulase on a reversibly soluble-insoluble enteric polymer Eudragit S-100 by carbodiimide coupling was carried out. The characteristics of covalent Eudragit cellulase were evaluated using Fourier transform infrared (FTIR) spectra, circular dichroism (CD) spectra, and fluorescence spectra. FTIR, CD, and fluorescence measurements also revealed that the cellulases were covalently bonded to the supports. Covalent Eudragit cellulase had binding efficiency of 81.08% which was higher than the noncovalent Eudragit cellulase 56.83%. The relative activity of the native cellulase and covalent Eudragit cellulase increased and reached the maximum (at pH 5.0, 50 degrees C) and then decreased with further increases in pH and temperature. The covalent Eudragit cellulase shows higher stability especially at higher pH and temperature. The K (m) value of covalent Eudragit cellulase (4.78 g.L(-1)) was decreased compared to that of the native cellulase (2.89 g.L(-1)). The affinity of the cellulase to its substrate was increased when it was immobilized on Eudragit S-100. PMID- 22249856 TI - Spontaneous umbilical cerebrospinal fluid fistula due to transdermal dislocation of the ventriculoperitoneal distal shunt ending--a case report. PMID- 22249857 TI - Toxic effects of nicotinamide methylation on mouse brain striatum neuronal cells and its relation to manganese. AB - OBJECTIVE: It is well known that manganese (Mn) exposure is involved in parkinsonism. The aim of our study was to test the hypotheses that Mn affects nicotinamide N-methyltransferase (NNMT) activity, increases the metabolism of nicotinamide (NA) to 1-methylnicotinamide (MNA), and leads to neurocytotoxicity. METHODS: Following demonstration of the effects of Mn concentrations on the survival rate of Mouse CD1 brain striatum neuronal cells (MS cells), the effect of Mn on NNMT activity was investigated by comparing the difference in the amount of MNA produced after various Mn concentrations were added to mouse brain cytosol fractions as an enzyme solution. Toxicity induced by MNA and its precursor NA on MS cells was measured. RESULTS: The survival rate of MS cells decreased significantly with increasing concentrations of Mn in the culture medium. With respect to the influence of Mn on NNMT activity, NNMT activity increased significantly at Mn concentrations of 1 MUmol/mg protein. MNA and NA neurotoxicity were compared by comparing cell survival rate. Cell survival rate dropped significantly when the cells were cultivated with 10 mM of MNA. There was also a tendency for the survival rate to fall following the addition of 10 mM NA; however, the difference with the control was not significant. CONCLUSIONS: Our study suggests the possibility that Mn causes increased NNMT activity, thereby increasing MNA levels in the brain and bringing about neuron death. Daily absorption of Mn and NA may thus contribute to idiopathic Parkinson's disease. PMID- 22249858 TI - Internal energy deposition and ion fragmentation in atmospheric-pressure mid infrared laser ablation electrospray ionization. AB - Mid-infrared laser ablation of water-rich targets at the maximum of the 2.94 MUm absorption band is a two-step process initiated by phase explosion followed by recoil pressure induced material ejection. Particulates and/or droplets ejected by this high temperature high pressure process can be ionized for mass spectrometry by charged droplets from an electrospray. In order to gauge the internal energy introduced in this laser ablation electrospray ionization (LAESI(r)) process, we apply the survival yield method and compare the results with electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI). The results indicate that LAESI yields ions with internal energies indistinguishable from those produced by ESI. This finding is consistent with the recoil pressure induced ejection of low micrometre droplets that does not significantly change the internal energy of solute molecules. PMID- 22249859 TI - Professional driving and prolapsed lumbar intervertebral disc diagnosed by magnetic resonance imaging: a case-control study. AB - OBJECTIVES: The aim of this study was to investigate whether whole-body vibration (WBV) is associated with prolapsed lumbar intervertebral disc (PID) and nerve root entrapment among patients with low-back pain (LBP) undergoing magnetic resonance imaging (MRI). METHODS: A consecutive series of patients referred for lumbar MRI because of LBP were compared with controls X-rayed for other reasons. Subjects were questioned about occupational activities loading the spine, psychosocial factors, driving, personal characteristics, mental health, and certain beliefs about LBP. Exposure to WBV was assessed by six measures, including weekly duration of professional driving, hours driven at a spell, and current 8-hour daily equivalent root-mean-square acceleration A(8). Cases were sub-classified according to whether or not PID/nerve root entrapment was present. Associations with WBV were examined separately for cases with and without these MRI findings, with adjustment for age, sex, and other potential confounders. RESULTS: Altogether 237 cases and 820 controls were studied, including 183 professional drivers and 176 cases with PID and/or nerve root entrapment. Risks associated with WBV tended to be lower for LBP with PID/nerve root entrapment but somewhat higher for risks of LBP without these abnormalities. However, associations with the six metrics of exposure were all weak and not statistically significant. Neither exposure-response relationships nor increased risk of PID/nerve root entrapment from professional driving or exposure at an A(8) above the European Union daily exposure action level were found. CONCLUSIONS: WBV may be a cause of LBP but it was not associated with PID or nerve root entrapment in this study. PMID- 22249861 TI - Inhibitor development in two patients with mild haemophilia A - spontaneous disappearance and no recurrence of the inhibitor after re-challenge. AB - Inhibitors against factor VIII (FVIII) complicate the treatment of patients with haemophilia. In mild haemophilia, the development of antibodies against FVIII is rare. However, the occurrence of an inhibitor in mild haemophilia changes the bleeding phenotype from mild to severe, and thus becomes a major clinical problem. We report on two patients with mild haemophilia A (FVIII level 8 and 27%, respectively), who have a missense mutation in exon 16 (G to A transition in codon 1773) and exon 22 (T to C transition in codon 2096), respectively. Both mutations have not been described in the Haemophilia A Mutation, Structure Test and Resource Site. Our patients developed high titer inhibitors following an intensive FVIII replacement therapy due to a muscle bleeding and after a polytrauma. During the presence of the inhibitor, AICC or FVIIa was successfully used as bypassing agent. In both patients the inhibitor disappeared spontaneously. Years after the development of the inhibitor, the patients again received FVIII concentrates. Reappearance of the inhibitor was not observed in either patient. The reported cases indicate that inhibitors in patients with mild haemophilia might be transient and disappear spontaneously. Therefore, the necessity of immune tolerance therapy, which is costly and strenuous for the patients, should be critically examined for each individual patient and a watch and wait strategy might be advisable. PMID- 22249862 TI - Ability of the Masimo pulse CO-Oximeter to detect changes in hemoglobin. AB - The decision to administer blood products is complex and multifactorial. Accurate assessment of the concentration of hemoglobin [Hgb] is a key component of this evaluation. Recently a noninvasive method of continuously measuring hemoglobin (SpHb) has become available with multi-wavelength Pulse CO-Oximetry. The accuracy of this device is well documented, but the trending ability of this monitor has not been previously described. Twenty patients undergoing major thoracic and lumbar spine surgery were recruited. All patients received radial arterial lines. On the contralateral index finger, a R1 25 sensor (Rev E) was applied and connected to a Radical-7 Pulse CO-Oximeter (both Masimo Corp, Irvine, CA). Blood samples were drawn intermittently at the anesthesia provider's discretion and were analyzed by the operating room satellite laboratory CO-Oximeter. The value of Hgb and SpHb at that time point was compared. Trend analysis was performed by the four quadrant plot technique, testing directionality of change, and Critchley's polar plot method testing both directionality and magnitude of the change in values. Eighty-eight samples recorded at times of sufficient signal quality were available for analysis. Four quadrant plot analysis revealed 94% of data within the quadrants associated with the correct direction change, and 90% of data points lay within the analysis bounds proposed by Critchley. Pulse CO Oximetry offers an acceptable trend monitor in patients undergoing major spine surgery. Future work should explore the ability of this device to detect large changes in hemoglobin, as well as its applicability in additional surgical and non-surgical patient populations. PMID- 22249863 TI - Finite-element simulations of the influence of pore wall adsorption on cyclic voltammetry of ion transfer across a liquid-liquid interface formed at a micropore. AB - Adsorption onto the walls of micropores was explored by computational simulations involving cyclic voltammetry of ion transfer across an interface between aqueous and organic phases located at the micropore. Micro-interfaces between two immiscible electrolyte solutions (micro-ITIES) have been of particular research interest in recent years and show promise for biosensor and biomedical applications. The simulation model combines diffusion to and within the micropore, Butler-Volmer kinetics for ion transfer at the liquid-liquid interface, and Langmuir-style adsorption on the pore wall. Effects due to pore radius, adsorption and desorption rates, surface adsorption site density, and scan rates were examined. It was found that the magnitude of the reverse peak current decreased due to adsorption of the transferring ion on the pore wall; this decrease was more marked as the scan rate was increased. There was also a shift in the half-wave potential to lower values following adsorption, consistent with a wall adsorption process which provides a further driving force to transfer ions across the ITIES. Of particular interest was the disappearance of the reverse peak from the cyclic voltammogram at higher scan rates, compared to the increase in the reverse peak size in the absence of wall adsorption. This occurred for scan rates of 50 mV s(-1) and above and may be useful in biosensor applications using micropore-based ITIES. PMID- 22249864 TI - Tinnitus & early endolymphatic hydrops. PMID- 22249867 TI - Persian language version of the "Tinnitus Handicap Inventory": translation, standardization, validity and reliability. AB - Tinnitus is a debilitating condition that is widespread yet difficult to successfully diagnose and treat. This symptom can seriously affect the individual's life quality. OBJECTIVES: The aim of current study was to compose and validate a Persian version of the Tinnitus Handicap Inventory (THI-P). MATERIALS AND METHODS: The linguistic validation of the original version of THI into Persian version (THI-P) included translation, back translation and data gathering. The THI-P was administered to 112 tinnitus subjects. Age, gender, medical history and tinnitus characteristics were recorded as baseline information. All participants complained of chronic unilateral or bilateral subjective idiopathic tinnitus lasting for at least 6 months before consulting about their tinnitus. RESULTS: There was no significant difference between gender, age, hearing impairment and total score and subscales of THI-P. Pearson product-moment correlations revealed adequate test-retest reliability for the THI P (r = 0.96). Cronbach's-alpha coefficient indicated adequate internal stability of the THI-P (r= 0.943), with a total item correction varying between r=0.939 and r=0.944, indicating its reproducibility. CONCLUSION: The present study proved the internal consistency/ coherency of the Persian version of THI (THI-P). This provides satisfactory application in clinical/research environments. PMID- 22249868 TI - Auditory middle latency responses in individuals with debilitating tinnitus. AB - Many researchers have investigated the possibility of using auditory evoked potentials (AEPs) to objectively diagnose tinnitus. Published AEP studies suggest differences in neural activity in individuals with tinnitus compared to control groups, but the results are not consistent. There is a great deal of variability seen in auditory evoked- and event-related potentials in the tinnitus population, which reflects AEP variability in general. At the present time, there is not a specific AEP measure able to objectively diagnose tinnitus. The auditory middle latency response (AMLR) has not been extensively examined to determine its potential as an objective measure of tinnitus; therefore, this study examined the AMLR in fourteen individuals with and without severe tinnitus to determine its potential as a diagnostic measure of tinnitus. The data from this study revealed similar AMLR results between groups. This outcome suggests that this AMLR protocol may not be specific enough to detect neurophysiological changes associated with tinnitus. PMID- 22249869 TI - A multi-centre study on the long-term benefits of tinnitus management using Neuromonics Tinnitus Treatment. AB - INTRODUCTION: The Neuromonics Tinnitus Treatment is based on individually customized acoustic stimulation and structured counseling. OBJECTIVES: To assess the long-term clinical outcomes of the Neuromonics Tinnitus Treatment, specifically, to determine whether benefits achieved at the conclusion of the prescribed treatment program were retained over the longer term. MATERIALS AND METHODS: This study involved 70 subjects who had previously undergone the treatment across six clinics located in Australia and United States. Patients had concluded the treatment at least six, and up to 36 months, before the commencement of this study. The Tinnitus Reaction Questionnaire was used to assess tinnitus distress, and patients were asked to report on percentage of time of awareness of and disturbance by their tinnitus. Long-term data were compared to data reported throughout the course of the treatment. RESULTS AND CONCLUSIONS: Patients achieved statistically significant improvement of their tinnitus distress. The success rate (at least 40% reduction in TRQ score) for this cohort of patients was 75.7% at the conclusion of the program and the majority of patients sustained the benefits in the long-term. Results revealed that NTT provides a consistent and stable relief of tinnitus distress. PMID- 22249870 TI - Comorbidity of chronic tinnitus and mental disorders. AB - OBJECTIVE: Complaining of psychiatric symptoms is more common among individuals suffering from tinnitus. The aim of this study is to determine the psychiatric diagnosis and symptoms of patients with chronic tinnitus. MATERIALS AND METHODS: Four hundred patients with chronic tinnitus from the registry of Otorhinolaryngology Research Center of Rasoul General Hospital, Tehran, Iran were enrolled. The study instruments were Structured Clinical Interview for DSM-III-R, axis I psychiatric disorders, Tinnitus Handicap Index (THI) and Symptom Check List-90-Revised. RESULTS: The lifetime and current psychiatric disorders among patients with chronic tinnitus were 60% and 55% respectively. Depressive and anxiety disorders were the most common type. Females with severe THI were 75.6% versus 63.9% in men. DISCUSSION: The comorbidity of chronic tinnitus with depressive and anxiety disorders is more common. This may have treatment implication to alleviate the stress and dysfunction resulted from chronic tinnitus. PMID- 22249871 TI - Auditory monitoring by means of evaluation of the cochlea in soldiers of the Brazilian Army exposed to impulse noise. AB - INTRODUCTION: Exposure to continuous or impulse noise may lead to High Sound Pressure Induced Hearing Loss (HSPIHL) or to acoustic trauma in soldiers. Auditory evaluation by means of evoked otoacoustic emissions (EOAE) has been demonstrating its importance in the detection of subtle changes in cochlear function still unidentified in threshold tone audiometry in subjects exposed to noise. OBJECTIVE: Studying Distortion product otoacoustic emissions (DPOAEs) before and after exposure to impulse noise in soldiers of the Brazilian Army. MATERIAL AND METHOD: This is an analytical, observational, longitudinal and prospective study. Auditory evaluation was performed by means of DPOAEs in 60 soldiers before and after exposure to impulse noise, of whom 30 were reevaluated immediately after exposure and 30 were reevaluated 24 hours after exposure. RESULTS: The statistical analysis revealed that both groups reevaluated after exposure to impulse noise showed a decrease in amplitudes in comparison with the tests before exposure. As for the signal/noise ratio, there was a significant difference at the frequencies of 6 and 8KHz and there was a significant association between a tinnitus complaint and the group reevaluated immediately after exposure to noise. CONCLUSION: The DPOAE test proved sensitive to detect subtle shifts after exposure to impulse noise, both with regard to the amplitude criterion and with regard to the signal/noise ratio even 24 hours after exposure. This demonstrated the applicability of the DPOAE test in monitoring the hearing of soldiers exposed to impulse noise. PMID- 22249872 TI - Eyes as windows on brain pressure. AB - The eyes are acoustically continuous with the brain and inner ear tissues as regards matched impedances, based on tissue densities; thus, vibration of one site will be reflected in all sites. As a result, the eye reflects the acoustic properties of the brain under pressure, which can be used as a metric of intracranial pressure as demonstrated in a brain/eye balloon model. Further, the model supports the observation that vibration delivered to the eye, if of sufficient intensity, can be perceived as sound, resulting in an eye audiogram similar to that obtained conventionally by bone conduction on the mastoid or forehead. The eye can therefore be considered an acoustical window to the brain and inner ear. PMID- 22249873 TI - Benign paroxysmal positional vertigo: diagnosis and treatment. AB - Benign paroxysmal positional vertigo is a common disorder in Neurotology. This vestibular syndrome is characterized by transient attacks of vertigo, caused by change in head position, and associated with paroxysmal characteristic nystagmus. The symptoms result from movement of the free floating otoconia particles in the endolymph or their attachment to the cupulae of the semicircular canal. The diagnosis is essentially clinical and should be confirmed by performing diagnostic maneuvers. Treatment is based on the identification of the affected semicircular canal and performance of liberatory maneuvers or repositioning of free floating particles of otoliths. The effectiveness varies from 70 to 100%. PMID- 22249874 TI - Controlled study of the frequency of anti-HSP 70 with the ELISA and the Western Blot methods in patients with Meniere Disease. AB - OBJECTIVES: To establish the frequency of auto-antibodies anti-HSP 70 using ELISA and Western Blot (WB) methods and to compare the results of each method among patients with the Meniere's Disease (MD) and internal ear diseases (IED) who do not fulfill criteria for MD. Sensibility, specificity and predictive values of anti-HSP70 test in diagnosis of MD were calculated. STUDY: Prospective, case control. METHODS: Blood samples were collected from 31 patients with MD and 78 patients with non Meniere IED. Data regarding cochlear and vestibular symptoms were obtained and blood sample was tested. RESULTS: ELISA tests results were positive in 4(13%) patients and results of WB were positive in 8(26%) patients. Among patients with positive ELISA results, 1 patient presented active disease and in the remaining 3 patients the disease was inactive. Among the 8 WB positive patients, only 2 patients presented active disease. Statistical analyses did not establish any association between serologic findings and clinical factors of MD. CONCLUSION: The presence of anti-HSP70 using the ELISA and the WB methods did not demonstrate clinical value for the diagnosis of MD. We did not find association between idiopathic MD nor unspecific etiology MD and the presence of anti-HSP70 auto-antibodies. PMID- 22249875 TI - Noninvasive acoustic intracranial pressure measurement through the eye. AB - Fluid pressure increase in the brain, contained in the skull, is a serious medical condition that can be life threatening. Intracranial pressure changes can be detected noninvasively using acoustic stimulation and analysis. The brain and eye are coupled resonant systems that will respond in a predictable fashion to brain pressure increases, given the constraints of the bioboundary (skull) conditions. Changes in acoustic damping in the eye co-vary with changes in cerebrospinal fluid or intracranial pressure. Feasibility of this approach is demonstrated in a preliminary study of five patients. PMID- 22249876 TI - Otoneurological findings in spinocerebellar ataxia. AB - OBJECTIVE: Describe findings observed in ENG of patients with spinocerebellar ataxias. METHOD: Forty-three patients were studied, and the following procedures were carried out: anamnesis, otorhinolaryngological and vestibular evaluation (ENG). RESULTS: The clinical findings in the entire group of patients were: gait disturbances (83.72%), speech difficulties (48.83%), dizziness (41.86%) and dysphagia (39.53%). Vestibular examination disclosed abnormal caloric exam (83.71%) and saccadic movements (69.76%) with the highest rates of abnormality. The overall presence of alterations in vestibular tests was (90.70%), and the most frequent finding was central vestibular disorder in (74.42%) of patients. CONCLUSION: The study showed that alterations in ENG are related to the severity of SCAs or clinical stage of the disease. We emphasize the importance of studying the vestibular system concomitantly to clinical and genetic follow up. PMID- 22249877 TI - Phase 2 study examining magnesium-dependent tinnitus. AB - BACKGROUND: Recent studies in noise-induced and idiopathic sensorineural hearing loss have suggested that magnesium supplementation may lessen both hearing loss and the severity of tinnitus in patients. Further epidemiological evidence indicates that all age groups of Americans fall short of the recommended daily allowance for magnesium by 100 mg daily. PURPOSE: The purpose of this study was to examine any potential benefit in lessening the severity of tinnitus in patients taking supplemental magnesium. RESEARCH DESIGN: The study was a single arm, open-label, before-and-after study of oral magnesium (532 mg per day) in 26 patients for 3 months. Tinnitus severity was evaluated and recorded daily by the patient using the Tinnitus Distress Rating (TDR) scale of 0 (no tinnitus) to 10 (worst possible tinnitus). The Tinnitus Handicap Inventory (THI) was administered before and at the end of the study, and scores were converted to the grades of the 5-item Tinnitus Severity Scale (TSS). The purpose of this phase 2 study was to investigate whether the treatment was effective at all, and, as such, a placebo control was not performed. All data were collected at Mayo Clinic in Scottsdale, Arizona, between March 6 and December 10, 2008. STUDY SAMPLE: Patients with moderate to very severe tinnitus (TDR score of 3 through 8). INTERVENTION: Daily magnesium supplementation, 532 mg; patient completion of the THI; and daily self-report of TDR. DATA COLLECTION AND ANALYSIS: The main outcome measures were mean TDR scale scores and THI scores as converted to TSS grades. The primary analysis was done on the basis of intention to treat. RESULTS: Twenty six patients were enrolled; 19 completed the study. The extent of handicap, as measured by THI/TSS, for subjects with slight or greater impairment was significantly decreased (P=.03). Patients who ranked slight or greater on the THI/TSS before intervention showed a significant decrease in the severity of their tinnitus at post-testing (P=.008). CONCLUSION: The results suggest that magnesium may have a beneficial effect on perception of tinnitus-related handicap when scored with the THI. PMID- 22249878 TI - Electronystagmographic analysis of optokinetic and smooth pursuit eye movement disorders in vestibular lesions. AB - The electronystagmographical analysis of the eye movements is an important method in the evaluation and topical diagnostic procedure of several vestibular lesions. The aim of the study was to compare the electronystagmographical results of the optokinetic and the smooth pursuit eye-movement, and their sensitivity in several vestibular disorders. The patients were divided into five groups: right and left unilateral and bilateral peripheral lesions, central vestibular dysfunction, and normal vestibular function. In patients with normal vestibular system the optokinetic eye movement was pathological in 9.53% of patients, while the smooth pursuit eye movements were pathological in 8.3% of patients with normal vestibular function. In unilateral lesions, 17.42% of the OKNs were pathological, compared with the smooth pursuit test's 20.3% pathological ratio. In the bilateral peripheral vestibular dysfunction the ratio of the pathological eye movements was 28% equally with to two methods. In central vestibular lesions 22.72% of the patients had abnormal optokinetic eye movements, and the smooth pursuit eye movement was abnormal in 41.6%. Our results show that in the unilateral peripheral vestibular lesions the smooth pursuit eye movement examination seems to be more sensitive than the OKN test, while in central dysfunctions the smooth pursuit eye movement examination is more sensitive than OKN examination. PMID- 22249880 TI - AAO-HNS International Tinnitus Mini-Seminar 9/12/11: implants attempting tinnitus relief. PMID- 22249881 TI - Electromyographic analysis of anterior temporalis and superficial masseter muscles in mandibular angle fractures--a pilot study. AB - INTRODUCTION: Fracture of the mandible occurs more frequently and the surgical anatomy of the mandible and adjacent structures is extremely important in understanding the pattern of fracture, the displacement of fractured fragments, and factors necessary for uncomplicated healing. In the field of dentistry, surface electromyography, electrokinesiography, and more recently, TMJ sound analysis have been particularly important developments. Previous electromyographic studies involving anterior temporalis and superficial masseter have been conducted in mandibular condylar fractures and in orthognathic and cosmetic procedures of the jaws. MATERIALS AND METHODS: This experimental study was undertaken to measure the electrical activity of the anterior temporalis and superficial masseter muscles in mandibular angle fracture cases (n = 6) and the changes in the electrical activity over a period of 6 months. RESULTS: The study shows that muscle activity increases significantly over a period of time but never matches the muscle activity of the normal subjects of same sex and age in a follow-up of 6 months post-trauma. DISCUSSION: Electrodiagnostic testing is a potentially valuable tool for the management of patients who have suffered craniomaxillofacial trauma. Electromyography is being employed in clinical practice, and allows the inclusion of quantitative data on the qualitative aspects of a diagnosis. These data are often of significant importance in the correct management of therapy and patient follow-up, particularly if the subject is at risk of developing a different and/or more serious disease. PMID- 22249882 TI - Severe florid cemento-osseous dysplasia: a case report treated conservatively and literature review. AB - BACKGROUND: Florid cemento-osseous dysplasia (FCOD) has been described as a condition that characteristically affects the jaws of middle-aged black women. Radiographically, FCOD appears as dense, lobulated masses, often symmetrically located in various regions of the jaws. FCOD is usually asymptomatic. In severe cases, focal expansion may occur due to infection. Management of the symptomatic patient is more difficult due to the avascular nature of the lesion which contributes to susceptibility severe infection, bone sequestration, and osteomyelitis when surgery is performed. CASE REPORT: This paper presents a rare case of severe FCOD; the black woman patient was diagnosed based on clinical and radiographic findings and treated conservatively. The examination of panoramic radiographs revealed a multiple sclerotic masses with radiolucent borders, found in the mandible and maxilla which were symmetrical at presentation. The patient continuous with the follow-up. DISCUSSION: This report confirms that a diagnosis can be made with accurate clinical and radiographic assessment. The correct selection of treatment for FCOD depends on this information. PMID- 22249884 TI - Recognition and separation of sulfate anions. AB - This tutorial review focuses on some recent aspects in the development of synthetic receptors for selective sulfate anion recognition and separation, with a special emphasis to: (i) receptors for selective recognition of sulfate in organic and aqueous media and (ii) receptors for separation of sulfate from water via liquid-liquid extraction and crystallization. PMID- 22249883 TI - Comparison of Chloroflexus aurantiacus strain J-10-fl proteomes of cells grown chemoheterotrophically and photoheterotrophically. AB - Chloroflexus aurantiacus J-10-fl is a thermophilic green bacterium, a filamentous anoxygenic phototroph, and the model organism of the phylum Chloroflexi. We applied high-throughput, liquid chromatography-mass spectrometry in a global quantitative proteomics investigation of C. aurantiacus cells grown under oxic (chemoorganoheterotrophically) and anoxic (photoorganoheterotrophically) redox states. Our global analysis identified 13,524 high-confidence peptides that matched to 1,286 annotated proteins, 242 of which were either uniquely identified or significantly increased in abundance under photoheterotrophic culture condition. Fifty-four of the 242 proteins are previously characterized photosynthesis-related proteins, including chlorosome proteins, proteins involved in the bacteriochlorophyll biosynthesis, 3-hydroxypropionate (3-OHP) CO(2) fixation pathway, and components of electron transport chains. The remaining 188 proteins have not previously been reported. Of these, five proteins were found to be encoded by genes from a novel operon and observed only in photoheterotrophically grown cells. These proteins candidates may prove useful in further deciphering the phototrophic physiology of C. aurantiacus and other filamentous anoxygenic phototrophs. PMID- 22249885 TI - Two Japanese cases of pigmentary glaucoma followed for 15 and 16 years following laser peripheral iridotomy. AB - PURPOSE: To report two Japanese cases of pigmentary glaucoma (PG) treated with laser peripheral iridotomy (LPI) that were followed for 15 and 16 years, respectively. METHODS: The medical records of two patients with PG who were successfully treated with LPI were reviewed. Changes in the intraocular pressure (IOP) were followed. RESULTS: Case 1 was that of a 35-year-old man with LPI who underwent argon laser trabeculoplasty twice. He required ocular hypotensive drugs to maintain the IOP at normal levels. Case 2 involved a 36-year-old man with LPI who required ocular hypotensive drugs to maintain his IOP at the low-teen level. The IOP of both patients was unstable during the first 6-8 years following the LPI, but showed a decrease at each annual follow-up examination up to the age of 50 years. CONCLUSIONS: Although only two cases were followed, we conclude that the long-term effects of LPI may play a role, at least partly, in stabilizing the IOP at the low-teen level. Both patients were relatively young at the time of the LPI, and age may have been a factor in the stabilization process. Our findings confirm similar findings in Western countries. PMID- 22249886 TI - Cefepime dosing in the morbidly obese patient population. AB - Proper dosing of specific antibiotics in morbidly obese patients has been studied inadequately. However, these data are beneficial as this patient population is at an increased risk to develop postoperative infections. Cefepime is an antibiotic used for the treatment of both gram-positive and especially gram-negative infections; administration of the appropriate dose in the morbidly obese population is crucial. We therefore examined the pharmacokinetics of cefepime in patients with body mass index >40 kg/m(2). Ten morbidly obese patients, with a mean [+/-SD] estimated glomerular filtration rate of 108.4 +/- 34.6 mL/min, undergoing elective weight loss surgical procedures were administered cefepime in addition to standard prophylactic cefazolin and studied. Serial serum cefepime concentrations were analyzed after dosing using a validated high performance liquid chromatography method. Pharmacokinetics and duration above the minimum inhibitory concentration (MIC) were determined using a protein binding value of 15% and a MIC threshold of 8 MUg/mL. Mean free cefepime concentrations for t = 30, 120, and 360 min were 69.6, 31.6, and 9.2 MUg/mL, respectively. The dosing interval was calculated to maintain the free concentration above the MIC (fT > MIC) for 60% of the interval. This was determined to be 10.12 h, including time for infusion. There was no toxicity. Based on this analysis, an increased dose of 2 g every 8 h is necessary to maintain an adequate fT > MIC throughout the dosing interval. Further studies are necessary to determine the efficacy of this regimen in the settings of active infections and critical illness. PMID- 22249887 TI - Myocardial insulin signaling and glucose transport are up-regulated in Goto Kakizaki type 2 diabetic rats after ileal transposition. AB - BACKGROUND: Ileal transposition (IT) as one of the effective treatments for non obese type 2 diabetes mellitus has been widely investigated. However, the mechanisms underlying profound improvements in glucose homeostasis are still uncertain. Our objective was to explore the myocardial insulin signal transduction and glucose disposal in non-obese type 2 diabetes mellitus rats after IT surgery. METHODS: Adult male Goto-Kakizaki (GK) rats or Sprague-Dawley (SD) rats were randomly assigned to diabetic IT, diabetic sham-IT, and non diabetic control SD groups. Food intake, body weight, fasting plasma glucose, insulin tolerance, and serum glucagon-like peptide-1 (GLP-1) were measured. Subsequently, the myocardial glucose uptake and the protein levels of insulin receptor-beta (IR-beta), phosphorylated IR-beta, insulin receptor substrate 1 (IRS-1), phosphorylated IRS-1, and IRS-1-associated phosphatidylinositol-3 kinase (PI3K) from myocardial cell lysates were evaluated. We also assessed the expression of glucose transporter 4 (GLUT4) in both skeletal muscle and myocardial cell lysates. RESULTS: Compared to sham operations within 6 months, IT surgery for GK rats did (1) result in less food intake and reduced body weight gain over time, (2) improve plasma glucose homeostasis with increased serum GLP-1 secretion and myocardial glucose uptake, (3) increase protein expression of insulin signaling pathway, including IR-beta, IRS-1 and their phosphorylation levels, and IRS-1-associated PI3K in the myocardium, and (4) enhance the protein levels of membrane GLUT4 in skeletal muscle and myocardium. CONCLUSIONS: IT surgery ameliorates glucose disorder in GK type 2 diabetic rats. Meanwhile, IT surgery is effective in up-regulating both myocardial insulin signaling and glucose disposal within 6 months. PMID- 22249888 TI - The value of the computed tomographic obstruction index in the identification of massive pulmonary thromboembolism. AB - PURPOSE: In this study, the pulmonary arterial computed tomography obstruction index ratio, which indicates the degree and extent of thrombotic arterial occlusion, was calculated in cases with pulmonary thromboembolism. Our objectives were to investigate the value of this index for the identification of cases with massive pulmonary thromboembolism and to search for correlations between this index and clinical parameters. MATERIALS AND METHODS: Data from 68 patients were evaluated retrospectively. For the clinical evaluation, the Wells scoring system was used. Pulmonary computed tomographic angiography examinations were acquired using an eight-channel multidetector computed tomography. The presence of arterial filling defects was recorded, and the clot burden was quantified based on the degree and extent of thrombotic arterial occlusion. RESULTS: According to the Wells scoring system, the patients were assigned to low (n = 14), moderate (n = 34), and high clinical (n = 20) possibility groups, and the difference among the mean pulmonary arterial computed tomography obstruction index ratios of the three groups was significant (P = 0.001). A positive correlation was observed between the pulmonary arterial computed tomography obstruction index ratio and the Wells score (r = 0.470, P < 0.001). The pulmonary arterial computed tomography obstruction index ratio cut-off point was determined to be 40% for the discrimination of massive and nonmassive cases (sensitivity, 72.7%; specificity, 91.4%). CONCLUSION: We found that in cases where the pulmonary arterial computed tomography obstruction index ratio was above 40%, a diagnosis of massive pulmonary thromboembolism was demonstrated. Furthermore, a positive correlation between the obstruction index and the Wells score suggested the use of a clinical evaluation as a means of developing a recommendation regarding the thrombotic load. PMID- 22249889 TI - Maternal zinc supplementation improves spatial memory in rat pups. AB - A large body of evidence supports an opinion that adequate dietary zinc is essential for prenatal and postnatal brain development. Behavioural effects of maternal supplementation with ZnSO(4) were analysed in rat pups with the Morris water task performance, a hole board and a T-maze. Wistar females during pregnancy and lactation received a drinking water solution of ZnSO(4) at doses of 16 mg/kg (group Zn16) or 32 mg/kg (group Zn32). Behavioural tests were conducted on the 4-week-old male rat pups. Zinc concentration in the serum, hippocampus and prefrontal cortex of offsprings was determined by means of atomic absorption techniques. The Newman-Keuls multiple comparison test revealed an increase of climbing in the Zn16 group in comparison to the control group (Con) and the Zn32 group during the hole board test. ANOVA for repeated measures showed a significant memory improvement in both supplemented groups compared to the control in the probe trial on day 5 of the water maze test. ZnSO(4) treatment significantly elevated zinc levels in the rat serum. Follow-up data on brain content of zinc in the hippocampus revealed significant differences between the groups and in supplemented groups correlated with crossings above the original platform position. These findings suggest that pre- and postnatal zinc supplementation may improve cognitive development in rats. PMID- 22249890 TI - Proteomic analysis of protein adsorption capacity of different haemodialysis membranes. AB - Protein-adsorptive properties are a key feature of membranes used for haemodialysis treatment. Protein adsorption is vital to the biocompatibility of a membrane material and influences membrane's performance. The object of the present study is to investigate membrane biocompatibility by correlating the adsorbed proteome repertoire with chemical feature of the membrane surfaces. Dialyzers composed of either cellulose triacetate (Sureflux 50 L, effective surface area 0.5 m(2); Nipro Corporation, Japan) or the polysulfone-based helixone (FX40, effective surface area 0.4 m(2); Fresenius Medical Care AG, Germany) materials were employed to develop an ex vivo apparatus to study protein adsorption. Adsorbed proteins were eluted by a strong chaotropic buffer condition and investigated by a proteomic approach. The profiling strategy was based on 2D electrophoresis separation of desorbed protein coupled to MALDI-TOF/TOF analysis. The total protein adsorption was not significantly different between the two materials. An average of 179 protein spots was visualised for helixone membranes while a map of retained proteins of cellulose triacetate membranes was made up of 239 protein spots. The cellulose triacetate material showed a higher binding capacity for albumin and apolipoprotein. In fact, a number of different protein spots belonging to the gene transcript of albumin were visible in the cellulose triacetate map. In contrast, helixone bound only a small proportion of albumin, while proved to be particularly active in retaining protein associated with the coagulation cascade, such as the fibrinogen isoforms. Our data indicate that proteomic techniques are a useful approach for the investigation of proteins surface-adsorbed onto haemodialysis membranes, and may provide a molecular base for the interpretation of the efficacy and safety of anticoagulation treatment during renal replacement therapy. PMID- 22249892 TI - [New neurostimulation techniques in adicctions]. AB - Addiction is associated with changes in brain activation patterns. In recent years new techniques of neurostimulation that can alter the activity of brain circuits have been developed, and are being explored in the treatment of addictions. The most important of these techniques are Transcranial Magnetic Stimulation (TMS), Transcranial Direct Electrical Stimulation (tDCS), Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS). The findings reported are clearly still insufficient for them to be considered as therapeutic alternatives in substance use disorders. PMID- 22249893 TI - [Decision-making in drug-dependent patients]. AB - INTRODUCTION: The somatic marker hypothesis proposes that certain body signals guide decision-making processes in an adaptive direction. To see the influence of these markers on decision-making we used the Iowa Gambling Task, through which several studies have shown impaired decision-making in drug-dependent patients. OBJECTIVE: To assess the performance of a sample of drug-dependent patients in a task that is sensitive to the measurement of decision-making process, so as to see whether there are significant alterations, and to compare the performance of these patients with that of non-users (in the normal and inverted versions). METHOD: The sample consisted of 66 people (33 addicts and 33 control participants). We used a semi-structured interview on socio-demographic variables and two versions of the "Cartas" task, a computerised version of the Iowa Gambling Task. Result. Significant differences were found between the control and experimental groups in execution of the normal task, but not of the inverted version. In total, 75.76% of the drug-dependent patients showed impaired task performance, as against 24.24% who performed it correctly. DISCUSSION: The results indicate the presence of alterations in the decision-making processes of drug-dependent patients, who did not perform as well as the control group. This may be due to difficulty in generating somatic states according to possible future consequences (myopia about the future) in patients addicted to drugs. PMID- 22249894 TI - [Follow-up of alcohol and/or cocaine dependents after their discharge from a therapeutic community: a pilot study]. AB - In Spain, the Therapeutic Community (TC) constitutes a common model of treatment in the field of addictions, although there hardly exists any investigation about its efficiency and the persistence of its attainments. AIMS: To evaluate the short, half and long term effects of treatment of addiction to alcohol or cocaine in the TC run by "Fundacion Salud y Comunidad" (Foundation Health and Community). DESIGN: descriptive pilot study, with a sequential design of cohort. 91 users completed a survey specifically designed to know their evolution at different follow-up periods (1, 3, 5 or 10 years after their exit from the TC): socio demographic, psychoactive substance use, other variables related to the stay at the TC. Changes between before the TC and the present time regarding variables such as academic, labour, drug consumption, health, family and social adaptation and their criminal behaviour are described. RESULTS: the cohorts showed a relatively common previous socio-demographic pattern having received a similar treatment. The users reported to have diminished the frequent consumption of the main drug, having 48.9% never relapsed even through an occasional consumption of the drug/s. Also they perceived to have improved their health and family relations, as well as their aggressive behaviour and legal problems linked with their consumption of drug/s. CONCLUSIONS: after their rehabilitation in a TC, the users report a global decrease of the consumption of drugs and perceive an improvement of their health, family relations, violence and other problems linked to their former drug use. PMID- 22249895 TI - A change of paradigm in the treatment of low-severity alcohol-dependent patients. AB - Introduction Recent pharmacotherapy findings from new alcohol reduction programmes could change the paradigm of alcohol-dependence treatment. MATERIAL AND METHOD: This study reviews the neurobiological background and pharmacotherapy of alcohol-dependence disorder, focusing on opioid receptor antagonists, abstinence-oriented treatment and moderation-oriented treatment. RESULTS: 1. Alcohol-dependence treatment programs show only low to moderate efficacy. 2. Patients usually show low motivation to sustain abstinence but high motivation to reduce alcohol use. 3. A treatment program based on continued reduction of drinking and associated with intermittent treatment with naltrexone can be useful for low-severity alcohol-dependent patients. DISCUSSION: Although high severity alcohol-dependent patients should stop drinking alcohol, low severity patients may have the option of reducing their alcohol consumption if they take an opioid antagonist medication every day that they decide to drink alcohol. In the short term, the continuing drinking-reduction programmes may reduce the number of drinks per drinking day and in the long term, they may progressively decrease the obsession for drinking, alcohol seeking behavior, and related medical, behavioral and social disorders. To change the paradigm in the treatment of alcohol dependence disorder there is a need for further randomized controlled trials in order to assess their efficacy and tolerability. PMID- 22249896 TI - [Alcoholic patients hospitalized in a psychiatry unit: mortality at 14 years]. AB - INTRODUCTION: Alcoholic patients show a high mortality rate. We know about the increased mortality of outpatients following specialized treatment for alcohol abuse and inpatients with organic diseases related to alcohol, but it is not clear whether alcoholics with a comorbid psychiatric profile also die prematurely. OBJECTIVE: To investigate clinical characteristics, therapeutic evolution, survival, and factors that can better predict mortality. MATERIALS: 14 year longitudinal monitoring of 91 patients hospitalized in 1993 for detoxification in a psychiatric unit and who subsequently received outpatient treatment. RESULTS: Patients show a high prevalence of psychiatric disorders (40.6%) and multiple periods of previous treatment (78%). After 14 years the mortality rate was 34.1%. Deceased patients more often presented cognitive decline and were more often on pensions. They were also taking more antidepressants, had less family support and were more likely to have relapsed into alcohol use. DISCUSSION: Many of the factors that predict higher mortality are age-related. In younger patients, the presence of neuropsychological deterioration symptoms may indicate a premature organic disorder and probably greater risk of treatment failure, poor physical care and traumatic physical and mental situations, all of which would also increase the likelihood of premature mortality. PMID- 22249897 TI - [Tobacco industry strategies to attract young smokers in Spain: a review of companies' internal documents]. AB - BACKGROUND: Tobacco companies' strategies to promote tobacco use and undermine tobacco control policy are key in tobacco use among young people. The analysis of tobacco companies' internal documents can be instrumental in identifying those strategies, improving social support for tobacco control policy, and planning public health interventions. The goal of this study was to identify and analyze internal documents related to the activities of tobacco companies during the 1980s and 90s aimed at promoting smoking in young Spaniards. METHODS: Electronic search by key word of tobacco industry documents held at the Legacy Tobacco Documents Library. RESULTS: More than 1,000 documents were identified and reviewed, including letters, messages, memos, and other documents. Seventeen documents related to the objective of the study are analyzed and discussed. CONCLUSIONS: Tobacco companies funded and conducted activities aimed at maintaining high smoking incidence and prevalence in Spain. These activities, which included research, cigarette and packaging design, promotion, and social and political manipulation, may have had an impact on current levels of tobacco use in Spain. PMID- 22249898 TI - [Individual and population-based strategies for tobacco control]. AB - The population strategy for intervention on risk factors became known through the work of Geoffrey Rose in the field of public health and preventive medicine in relation to cardiovascular diseases in the late twentieth century. Currently, one of the risk factors with the most impact on health is the smoking epidemic. The aim of this study is to describe and put into practice the preventive medicine strategies proposed by Geoffrey Rose in the control of this smoking epidemic. To illustrate the situation, we have used the data on salivary cotinine concentration from a representative sample of the adult population in the city of Barcelona. In conclusion, public tobacco control policies worldwide should take into account the utility of the population strategy for addressing this important health issue, without ignoring "high risk" interventions of proven effectiveness. PMID- 22249899 TI - [Access to treatment for people with alcohol and other substance abuse problems]. AB - OBJECTIVES: IATPAD (Improvement in Access to Treatment for People with Alcohol and Drug Related Problems) is a European study. The study's main objective was to detect barriers and facilitators associated with access to treatment among patients with problems related to alcohol and drug use. This article presents the quantitative findings from Cataluna (Spain). METHODS: Multicentric, cross sectional study. Three main treatment entry points were assessed: General Psychiatry (CSMA), Out-patient Addiction Centers (CAS) and Primary Care (CAP). Centres were randomly selected. The Medical Condition Regard Scale was used to measure regard for working with different patient groups (diabetes, depression, patients with problems related to alcohol and patients with problems related to drugs). RESULTS: Differences were detected in regard towards working with patients with alcohol, drugs and depression by treatment entry point. Professionals from the CASs reported higher regard towards working with substance users than professionals from CSMAs (p<0,001) or professionals from CAPs (p<0,001). CONCLUSIONS: The attitudes of professionals towards patients with substance use disorders are important for treatment engagement. Treatment policy needs to consider how to improve staff attitudes. PMID- 22249900 TI - [Social context variables and their influence on the occurrence of problematic situations associated with alcohol use in adolescents]. AB - This study focuses on the problematic situations adolescents have to face resulting from their own alcohol use. These situations were described according to their type and frequency of occurrence, and possible explanatory variables were explored. In particular, we considered the effect of perceived peer intake of alcohol, social and family permissiveness, patterns of use and parental norms. The sample comprised 9276 adolescents from nine cities and municipalities in Colombia, with an average age of 14. Results indicate that the most common problematic situations experienced by the adolescents are: getting drunk, vomiting, and having problems at home or with one's boyfriend or girl friend because of the drinking. As in previous studies, the behavior of peers is associated with severity of the drinking-related problems experienced by the adolescents. The study also suggests that easy access to alcohol is related to the perception that their peers use it, and appears to be more closely associated with the possibility of accessing alcohol at parties and among friends than with the perception that it is easy to buy it. It was also found that excessive drinking habits were associated with greater likelihood of negative consequences, that in Colombia the presence of alcohol use in the family is associated with fewer reports of extreme and difficult situations, and that having problems at home because of alcohol use is associated with a larger number of problems such as drunkenness and vomiting, among others. PMID- 22249901 TI - A case of late-onset right ventricular failure after implantation of a continuous flow left ventricular assist device. AB - Postoperative right ventricular failure is usually apparent perioperatively or soon after left ventricular assist device insertion. Here, we report a case complicated by right ventricular failure that manifested 3 weeks after HeartMate II implantation. This case is also unique because the postoperative right ventricular failure was progressive over the years. We discuss how the smaller size of the left ventricle and untreated tricuspid regurgitation contributed to the development of right ventricular failure in this case. PMID- 22249902 TI - Working memory effects of gap-predictions in normal adults: an event-related potentials study. AB - The current study examined the relationship between verbal memory span and the latency with which a filler-gap dependency is constructed. A previous behavioral study found that low span listeners did not exhibit antecedent reactivation at gap sites in relative clauses, in comparison to high verbal memory span subjects (Roberts et al. in J Psycholinguist Res 36(2):175-188, 2007), which suggests that low span subjects are delayed at gap filling. This possibility was examined in the current study. Using an event-related potentials paradigm, it was found that low span subjects have an onset latency delay of about 200 ms in brain responses to violations of syntactic expectancies after the gap site, thus providing a time course measure of the delay hypothesized by previous literature. PMID- 22249903 TI - A non-fullerene small molecule as efficient electron acceptor in organic bulk heterojunction solar cells. AB - A novel n-type small molecule FFI-1 was synthesized as the electron acceptor to replace PCBM in solution-processed organic BHJ solar cells. Its LUMO level (around -3.5 eV) both matches the work function of the cathode and increases V(OC) of the devices, making it a promising acceptor candidate. With P3HT: FFI-1 (1:2 w/w) as active layer and LiF/Al as the cathode, the best power conversion efficiency (PCE) reaches 1.86%. PMID- 22249904 TI - Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK. AB - Insulin and insulin-like growth factor 1 (IGF-1) are evolutionarily conserved hormonal signalling molecules, which influence a wide array of physiological functions including metabolism, growth and development. Using genetic mouse studies, both insulin and IGF-1 have been shown to be anabolic agents in osteoblasts and bone development primarily through the activation of Akt and ERK signalling pathways. In this study, we examined the temporal signalling actions of insulin and IGF-1 on primary calvarial osteoblast growth and differentiation. First, we observed that the IGF-1 receptor expression decreases whereas insulin receptor expression increases during osteoblast differentiation. Subsequently, we show that although both insulin and IGF-1 promote osteoblast differentiation and mineralization in vitro, IGF-1, but not insulin, can induce osteoblast proliferation. The IGF-1-induced osteoblast proliferation was mediated via both MAPK and Akt pathways because the IGF-1-mediated cell proliferation was blocked by U0126, an MEK/MAPK inhibitor, or LY294002, a PI3-kinase inhibitor. Osteocalcin, an osteoblast-specific protein whose expression corresponds with osteoblast differentiation, was increased in a dose- and time-dependent manner after insulin treatment, whereas it was decreased with IGF-1 treatment. Moreover, insulin treatment dramatically induced osteocalcin promoter activity, whereas IGF 1 treatment significantly inhibited it, indicating direct effect of insulin on osteocalcin synthesis. PMID- 22249905 TI - Supramolecular isomerism of a metallocyclic dipyridyldiamide ligand metal halide system generating isostructural (Hg, Co and Zn) porous materials. AB - We show how crystallisation of supramolecular isomers of a dynamic coordination system generates a series of isostructural porous materials. These mercury, cobalt and zinc metallocyclic materials show permanent porosity and exhibit single-crystal-to-single-crystal transformations. PMID- 22249906 TI - Real-time prescription surveillance and its application to monitoring seasonal influenza activity in Japan. AB - BACKGROUND: Real-time surveillance is fundamental for effective control of disease outbreaks, but the official sentinel surveillance in Japan collects information related to disease activity only weekly and updates it with a 1-week time lag. OBJECTIVE: To report on a prescription surveillance system using electronic records related to prescription drugs that was started in 2008 in Japan, and to evaluate the surveillance system for monitoring influenza activity during the 2009-2010 and 2010-2011 influenza seasons. METHODS: We developed an automatic surveillance system using electronic records of prescription drug purchases collected from 5275 pharmacies through the application service provider's medical claims service. We then applied the system to monitoring influenza activity during the 2009-2010 and 2010-2011 influenza seasons. The surveillance system collected information related to drugs and patients directly and automatically from the electronic prescription record system, and estimated the number of influenza cases based on the number of prescriptions of anti influenza virus medication. Then it shared the information related to influenza activity through the Internet with the public on a daily basis. RESULTS: During the 2009-2010 influenza season, the number of influenza patients estimated by the prescription surveillance system between the 28th week of 2009 and the 12th week of 2010 was 9,234,289. In the 2010-2011 influenza season, the number of influenza patients between the 36th week of 2010 and the 12th week of 2011 was 7,153,437. The estimated number of influenza cases was highly correlated with that predicted by the official sentinel surveillance (r = .992, P < .001 for 2009-2010; r = .972, P < .001 for 2010-2011), indicating that the prescription surveillance system produced a good approximation of activity patterns. CONCLUSIONS: Our prescription surveillance system presents great potential for monitoring influenza activity and for providing early detection of infectious disease outbreaks. PMID- 22249907 TI - Person mobility in the design and analysis of cluster-randomized cohort prevention trials. AB - Person mobility is an inescapable fact of life for most cluster-randomized (e.g., schools, hospitals, clinic, cities, state) cohort prevention trials. Mobility rates are an important substantive consideration in estimating the effects of an intervention. In cluster-randomized trials, mobility rates are often correlated with ethnicity, poverty and other variables associated with disparity. This raises the possibility that estimated intervention effects may generalize to only the least mobile segments of a population and, thus, create a threat to external validity. Such mobility can also create threats to the internal validity of conclusions from randomized trials. Researchers must decide how to deal with persons who leave study clusters during a trial (dropouts), persons and clusters that do not comply with an assigned intervention, and persons who enter clusters during a trial (late entrants), in addition to the persons who remain for the duration of a trial (stayers). Statistical techniques alone cannot solve the key issues of internal and external validity raised by the phenomenon of person mobility. This commentary presents a systematic, Campbellian-type analysis of person mobility in cluster-randomized cohort prevention trials. It describes four approaches for dealing with dropouts, late entrants and stayers with respect to data collection, analysis and generalizability. The questions at issue are: 1) From whom should data be collected at each wave of data collection? 2) Which cases should be included in the analyses of an intervention effect? and 3) To what populations can trial results be generalized? The conclusions lead to recommendations for the design and analysis of future cluster-randomized cohort prevention trials. PMID- 22249908 TI - Novel application of Ag nanoclusters in fluorescent imaging of human serum proteins after native polyacrylamide gel electrophoresis (PAGE). AB - We have developed a novel application for DNA oligonucleotide-stabilized Ag nanoclusters in fluorescent imaging of human serum proteins after native polyacrylamide gel electrophoresis (PAGE). Oligonucleotide-stabilized Ag nanoclusters were used as fluorescent probes for direct detection of proteins after native PAGE. Some relatively low-abundance proteins, such as alpha-1 antichymotrypsin (ACT) and alpha-2-glycoprotein 1, zinc (ZAG) were easily detected by oligonucleotide-stabilized Ag nanocluster-based fluorescent imaging and identified by MS and MS/MS techniques, without the need of expensive antibodies or tedious immunoassay procedures. The pH condition for the oligonucleotide-stabilized Ag nanocluster solution was optimized and the possible mechanism of interaction between proteins and DNA oligonucleotide-stabilized Ag nanoclusters was analyzed. As a novel fluorescent detection method it is simple, fast, nontoxic and sensitive, and it shows great analytical potential in proteome research and in biochemistry. PMID- 22249909 TI - Effect of therapeutic hyperoxia on maximal oxygen consumption and perioperative risk stratification in chronic obstructive pulmonary disease. AB - BACKGROUND: Maximal consumption of oxygen ( VO(2)max) during exercise is used in patients with chronic obstructive pulmonary disease (COPD) to stratify perioperative risk. However, the impact of therapeutic hyperoxia (i.e., use of supplemental oxygen to prevent hypoxemia during exercise) on ( VO(2)max and other ventilatory parameters during maximal exercise in the resting normoxic COPD population is poorly defined. METHODS: A randomized, double-blind crossover study was performed in which resting normoxic subjects (n=16) with COPD underwent two standard symptom-limited, ramped-protocol bicycle ergometry cardiopulmonary exercise tests >5 days apart with FiO(2) of 0.21 (control) and ~0.28 (therapeutic hyperoxia). VO(2)max and other ventilatory parameters were compared using a paired two-sample t-test. RESULTS: Therapeutic hyperoxia significantly increased VO(2)max (12.2 +/- 2.9 vs. 13.6 +/- 3.8 ml/kg/min, P = 0.03), partial pressure of end-tidal carbon dioxide, and oxygen saturation and significantly decreased VE VCO(2) slope, but it did not affect exercise time, maximum watts achieved, maximum minute ventilation, or change in end-expiratory lung volume. Three of four subjects with VO(2)max <10 ml/kg/min without supplemental oxygen increased VO(2)max to >=10 ml/kg/min on therapeutic hyperoxia and potentially changed perioperative risk category. CONCLUSIONS: Therapeutic hyperoxia in a resting normoxic COPD population significantly improves VO(2)max and may change perioperative risk stratification by conventional criteria. Further studies are needed to determine if this change in stratification is appropriate. PMID- 22249910 TI - Primary hydatid cyst of the chest wall. PMID- 22249911 TI - The use of 2,2'-dithiobis(5-nitropyridine) (DTNP) for deprotection and diselenide formation in protected selenocysteine-containing peptides. AB - In contrast to the large number of sidechain protecting groups available for cysteine derivatives in solid phase peptide synthesis, there is a striking paucity of analogous selenocysteine Se-protecting groups in the literature. However, the growing interest in selenocysteine-containing peptides and proteins requires a corresponding increase in availability of synthetic routes into these target molecules. It therefore becomes important to design new sidechain protection strategies for selenocysteine as well as multiple and novel deprotection chemistry for their removal. In this paper, we outline the synthesis of two new Fmoc selenocysteine derivatives [Fmoc-Sec(Meb) and Fmoc-Sec(Bzl)] to accompany the commercially available Fmoc-Sec(Mob) derivative and incorporate them into two model peptides. Sec-deprotection assays were carried out on these peptides using 2,2'-dithiobis(5-nitropyridine) (DTNP) conditions previously described by our group. The deprotective methodology was further evaluated as to its suitability towards mediating concurrent diselenide formation in oxytocin templated target peptides. Sec(Mob) and Sec(Meb) were found to be extremely labile to the DTNP conditions whether in the presence or absence of thioanisole, whereas Sec(Bzl) was robust to DTNP in the absence of thioanisole but quite labile in its presence. In multiple Sec-containing model peptides, it was shown that bis-Sec(Mob)-containing systems spontaneously cyclize to the diselenide using 1 eq DTNP, whereas bis-Sec(Meb) and Sec(Bzl) models required additional manipulation to induce cyclization. PMID- 22249912 TI - One-pot organocatalytic tandem aldol/polycyclization reactions between 1,3 dicarbonyl compounds and alpha,beta,gamma,delta-unsaturated aldehydes for the straightforward assembly of cyclopenta[b]furan-type derivatives: new insight into the Knoevenagel reaction. AB - A new cascade pathway viable for Knoevenagel chemistry that involves the coupling between 1,3-dicarbonyl systems and alpha,beta,gamma,delta-unsaturated aldehydes has been developed. The process comprises the combination of a classic aldol-type condensation and a rare spontaneous metal-free cycloisomerization, representing a convergent and innovative approach for the stereoselective synthesis of cyclopenta[b]furan-type derivatives. The scope and limitations with respect to both reaction partners and mechanistic features were investigated. Meaningfully, our study provides valuable guidance concerning the structural and electronic effects controlling the reactivity of conjugated polyene carbonyl systems. PMID- 22249913 TI - Parasagittal zones in the cerebellar cortex differ in excitability, information processing, and synaptic plasticity. AB - At the molecular and circuitry levels, the cerebellum exhibits a striking parasagittal zonation as exemplified by the spatial distribution of molecules expressed on Purkinje cells and the topography of the afferent and efferent projections. The physiology and function of the zonation is less clear. Activity dependent optical imaging has proven a useful tool to examine the physiological properties of the parasagittal zonation in the intact animal. Recent findings show that zebrin II-positive and zebrin II-negative zones differ markedly in their responses to parallel fiber inputs. These findings suggest that cerebellar cortical excitability, information processing, and synaptic plasticity depend on the intrinsic properties of different parasagittal zones. PMID- 22249914 TI - Asymptomatic remote cerebellar hemorrhage: CT and MRI findings. AB - The aim of this study was to evaluate the computed tomography (CT) and magnetic resonance imaging findings (MRI) of asymptomatic remote cerebellar hemorrhage (RCH) at the preoperative, early postoperative, and postoperative period. A total of 983 consecutive adult patients who underwent supratentorial craniotomies were included in the study. The ethics committee approved the study. The patient's clinical records and radiological examinations were retrospectively analyzed. All patients had preoperative CT and MRI examinations, immediate postoperative CT, and postoperative MRI within 24 h. The patients with the radiological diagnosis of RCH were followed up to 5 years. Eight asymptomatic RCH cases were recruited. The prevalence of asymptomatic RCH was 0.8% in our series. RCH was unilateral in two patients and bilateral in six patients. The postoperative CT was positive in two cases. The hemorrhage presented on MRI as folial linear hypointensities in six cases. In three cases (including one mixed case), punctate hypointense spots were identified at the superior cerebellar folia. Diffuse hemorrhage in the cerebellar tonsil, subarachnoid hemorrhage, and hemorrhage in the cerebellar vermis and the ventricles were also seen. The MRI findings were stable up to 5 years. The prevalence of asymptomatic RCH is higher than previously reported. Immediate postoperative CT is usually unremarkable; however, MRI demonstrates various hemorrhagic patterns at the cerebellum other than classical "zebra sign". This condition is self-limiting and no further investigation or follow-up study is required. In the proper clinical setting, the awareness of different hemorrhagic patterns in patients with RCH would prevent unnecessary investigations. PMID- 22249915 TI - Long-term physical activity outcomes of home-based lifestyle interventions among breast and prostate cancer survivors. AB - PURPOSE: Few studies have investigated long-term effects of physical activity (PA) interventions. The goal of this study was to evaluate whether or not increased levels of moderate to vigorous physical activity (MVPA) were maintained by cancer survivors 1 year after receipt of two home-based interventions. METHODS: The FRESH START trial randomized 543 breast and prostate cancer survivors to 1-of-2 mailed print diet and exercise interventions: sequentially tailored vs. standardized (attention control). Each arm received eight mailings over a 1-year period, with follow-up at 1 and 2 years. This analysis focuses solely on the 400 participants who had suboptimal levels of MVPA at baseline (measured by the 7-Day Physical Activity Recall) and who completed the 2-year study. RESULTS: Median minutes of MVPA at baseline, 1-year and 2-year follow-up in the tailored intervention arm were as follows: 0, 90, and 60 min/week, respectively. The corresponding values in the attention control group were 0, 30, and 30 min/week. Significant improvements in MVPA from baseline to 2-year follow up were observed in both study arms (p < 0.01). While significant between-arm differences were observed at 1-year follow-up (p < 0.01), there was only the suggestion of a trend (p = 0.08) at 2-year follow-up. CONCLUSIONS: This study provides evidence that mailed-print exercise interventions result in significant and sustainable improvements in MVPA among newly diagnosed cancer survivors that are observed well after the intervention is complete. While tailored interventions, as compared to standardized materials, appear to produce superior improvements in MVPA initially, these differences diminish over time. PMID- 22249916 TI - Epidemiology of Clostridium difficile-associated disease in internal medicine wards in northern Italy. AB - Clostridium difficile-associated disease (CDAD) is a growing health care problem. Elderly patients with multiple comorbidities and repeated hospitalization are at high risk for developing the disease. Few data are available on epidemiology of CDAD in Italy and no studies have focused on CDAD burden in internal medicine wards. We retrospectively analysed all CDAD cases in four internal medicine wards of a city hospital in northern Italy and reviewed the medical records of patients who developed CDAD during hospitalization. We identified 146 newly acquired cases, yielding a cumulative incidence of 2.56 per 100 hospitalizations and an incidence rate of 23.3 per 10,000 patient-days. Main risk factors were advanced age and length of hospitalization. A high proportion of CDAD patients had several comorbidities and had been treated with more than one antibiotic. The incidence is among the highest previously reported, this may be due to the characteristics of patients admitted to internal medicine wards and to the wards per se. We conclude that efforts are needed to reduce CDAD's burden in this setting, paying attention to logistics, patients care and antibiotic use. PMID- 22249917 TI - 96 hours ECG monitoring for patients with ischemic cryptogenic stroke or transient ischaemic attack. AB - Atrial fibrillation (AF) is intermittent in 30% of patients with cardioembolic stroke and, therefore, might not be seen in a single standard ECG recording. The aim of this study was to evaluate if prolonged ECG monitoring (96 h) finds episodes of intermittent AF beyond the 24 h ECG monitoring in patients with cryptogenic stroke or transient ischemic attack (TIA). We prospectively evaluated consecutive patients affected by cryptogenic stroke or TIA who had sinus rhythm on a 12-lead ECG on admission, and during ECG monitoring performed in the acute phase (for at least 24 h). Patients had continuous 96 h Holter ECG monitoring within 30 days from stroke onset. 114 patients were included in the study (mean age 63.1 +/- 15.1, 59 males). AF was found in 29 patients (24.3%). In 20 patients, AF was found in the first 24 h of recording, and in nine patients after 24 h. In addition, several other dysrhythmias such as supraventricular ectopic activity (33), ventricular tachycardia (10), sinus pause (4) and sinus-atrial block (1) were found. In patients with cryptogenic stroke or TIA, 96 h ECG monitoring detected a high rate of AF. One-third of AF was seen beyond 24 h of ECG monitoring. PMID- 22249919 TI - C5a receptor (CD88) inhibition improves hypothermia-induced neuroprotection in an in vitro ischemic model. AB - The concept of 'salvageble penumbra' has prompted both scientists and physicians to explore various neuroprotective approaches that could be beneficial during stroke therapy. Unfortunately, most of them have proved ineffective in targeting multiple cellular death cascades incited within the ischemic penumbra. Hypothermia has been shown to be capable of addressing this problem to some extent. Although many studies have shown that hypothermia targets several cellular processes, its effects on innate immune receptor-mediated apoptotic death still remain unclear. Moreover, whether inhibiting the signaling of innate immune receptors like complement anaphylatoxin C5a receptor (CD88) plays a role in this hypothermic neuroprotection still need to be deciphered. Using various types of ischemic insults in different neuronal cells, we confirm that hypothermia does indeed attenuate apoptotic neuronal cell death in vitro and this effect can be further enhanced by pharmacologically blocking or knocking out CD88. Thus, our study raises a promising therapeutic possibility of adding CD88 antagonists along with hypothermia to improve stroke outcomes. PMID- 22249920 TI - A longitudinal examination of a pay-for-performance program for diabetes care: evidence from a natural experiment. AB - BACKGROUND: Numerous studies have examined the impacts of pay-for-performance programs, yet little is known about their long-term effects on health care expenses. OBJECTIVES: This study aimed to examine the long-term effects of a pay for-performance program for diabetes care on health care utilization and expenses. METHODS: This study represents a nationwide population-based natural experiment with a 4-year follow-up period under a compulsory universal health insurance program in Taiwan. The intervention groups consisted of 20,934 patients enrolled in the program in 2005, and 9694 patients continuously participated in the program for 4 years. Two comparison groups were selected by propensity score matching from patients seen by the same group of physicians. Generalized estimating equations were used to estimate differences-in-differences models to examine the effects of the pay-for-performance program. RESULTS: Patients enrolled in the pay-for-performance program underwent significantly more diabetes specific examinations and tests after enrollment; the differences between the intervention and comparison groups declined gradually over time but remained significant. Patients in the intervention groups had a significantly higher number of diabetes-related physician visits in only the first year after enrollment and had fewer diabetes-related hospitalizations in the follow-up period. Concerning overall health care expenses, patients in the intervention groups spent more than the comparison group in the first year; however, the continual enrollees spent significantly less than their counterparts in the subsequent years. CONCLUSIONS: The program seemed to achieve its primary goal in improving health care and providing long-term cost benefits. PMID- 22249921 TI - Variability in case-mix adjusted in-hospital cardiac arrest rates. AB - BACKGROUND: It is unknown how in-hospital cardiac arrest (IHCA) rates vary across hospitals and predictors of variability. OBJECTIVES: Measure variability in IHCA across hospitals and determine if hospital-level factors predict differences in case-mix adjusted event rates. RESEARCH DESIGN: Get with the Guidelines Resuscitation (GWTG-R) (n=433 hospitals) was used to identify IHCA events between 2003 and 2007. The American Hospital Association survey, Medicare, and US Census were used to obtain detailed information about GWTG-R hospitals. PARTICIPANTS: Adult patients with IHCA. MEASURES: Case-mix-adjusted predicted IHCA rates were calculated for each hospital and variability across hospitals was compared. A regression model was used to predict case-mix adjusted event rates using hospital measures of volume, nurse-to-bed ratio, percent intensive care unit beds, palliative care services, urban designation, volume of black patients, income, trauma designation, academic designation, cardiac surgery capability, and a patient risk score. RESULTS: We evaluated 103,117 adult IHCAs at 433 US hospitals. The case-mix adjusted IHCA event rate was highly variable across hospitals, median 1/1000 bed days (interquartile range: 0.7 to 1.3 events/1000 bed days). In a multivariable regression model, case-mix adjusted IHCA event rates were highest in urban hospitals [rate ratio (RR), 1.1; 95% confidence interval (CI), 1.0-1.3; P=0.03] and hospitals with higher proportions of black patients (RR, 1.2; 95% CI, 1.0-1.3; P=0.01) and lower in larger hospitals (RR, 0.54; 95% CI, 0.45-0.66; P<0.0001). CONCLUSIONS: Case-mix adjusted IHCA event rates varied considerably across hospitals. Several hospital factors associated with higher IHCA event rates were consistent with factors often linked with lower hospital quality of care. PMID- 22249922 TI - Physician patient-sharing networks and the cost and intensity of care in US hospitals. AB - BACKGROUND: There is substantial variation in the cost and intensity of care delivered by US hospitals. We assessed how the structure of patient-sharing networks of physicians affiliated with hospitals might contribute to this variation. METHODS: We constructed hospital-based professional networks based on patient-sharing ties among 61,461 physicians affiliated with 528 hospitals in 51 hospital referral regions in the US using Medicare data on clinical encounters during 2006. We estimated linear regression models to assess the relationship between measures of hospital network structure and hospital measures of spending and care intensity in the last 2 years of life. RESULTS: The typical physician in an average-sized urban hospital was connected to 187 other doctors for every 100 Medicare patients shared with other doctors. For the average-sized urban hospital an increase of 1 standard deviation (SD) in the median number of connections per physician was associated with a 17.8% increase in total spending, in addition to 17.4% more hospital days, and 23.8% more physician visits (all P<0.001). In addition, higher "centrality" of primary care providers within these hospital networks was associated with 14.7% fewer medical specialist visits (P<0.001) and lower spending on imaging and tests (-9.2% and -12.9% for 1 SD increase in centrality, P<0.001). CONCLUSIONS: Hospital-based physician network structure has a significant relationship with an institution's care patterns for their patients. Hospitals with doctors who have higher numbers of connections have higher costs and more intensive care, and hospitals with primary care-centered networks have lower costs and care intensity. PMID- 22249923 TI - Improving the quality of pressure ulcer care with prevention: a cost effectiveness analysis. PMID- 22249925 TI - A new model for breaking bad news to people with intellectual disabilities. AB - OBJECTIVES: To develop a model for breaking bad news that meets the needs of people with intellectual disabilities (IDs). DESIGN: A two-phase qualitative study featuring: (I) focus group meetings, on-line focus groups and one-to-one interviews; (II) structured feedback from participants and other stakeholders. SETTING: Participants were drawn from National Health Service hospitals, Primary Care Trusts, independent organisations and on-line forums across England. PARTICIPANTS: 109 participants were purposively selected: 21 people with mild/moderate IDs, 28 family carers, 26 ID professionals and 34 general health professionals. OUTCOME MEASURE: Feedback on a preliminary model for breaking bad news to people with IDs was collected from 60 participants and other stakeholders to assess relevance and acceptability, before the model was finalised. RESULTS: Breaking bad news is best seen as a process, not an event or a linear series of events. Bad news situations usually constitute a wide range of discrete items or chunks of information. 'Building a foundation of knowledge' is central to the model. Information needs to be broken down into singular chunks of knowledge that can be added over time to people's existing framework of knowledge. Three other aspects should be considered at all times: capacity, people and support. CONCLUSIONS: Patients who have IDs do not easily process verbal information in a clinical setting. The new model for breaking bad news to people with IDs needs to be tested in practice using robust outcome measures. The model's relevance to wider patient groups should also be evaluated. PMID- 22249926 TI - Resource utilization and cost analyses of home-based palliative care service provision: the Niagara West End-of-Life Shared-Care Project. AB - BACKGROUND: Increasing emphasis is being placed on the economics of health care service delivery - including home-based palliative care. AIM: This paper analyzes resource utilization and costs of a shared-care demonstration project in rural Ontario (Canada) from the public health care system's perspective. DESIGN: To provide enhanced end-of-life care, the shared-care approach ensured exchange of expertise and knowledge and coordination of services in line with the understood goals of care. Resource utilization and costs were tracked over the 15 month study period from January 2005 to March 2006. RESULTS: Of the 95 study participants (average age 71 years), 83 had a cancer diagnosis (87%); the non cancer diagnoses (12 patients, 13%) included mainly advanced heart diseases and COPD. Community Care Access Centre and Enhanced Palliative Care Team-based homemaking and specialized nursing services were the most frequented offerings, followed by equipment/transportation services and palliative care consults for pain and symptom management. Total costs for all patient-related services (in 2007 $CAN) were $1,625,658.07 - or $17,112.19 per patient/$117.95 per patient day. CONCLUSION: While higher than expenditures previously reported for a cancer only population in an urban Ontario setting, the costs were still within the parameters of the US Medicare Hospice Benefits, on a par with the per diem funding assigned for long-term care homes and lower than both average alternate level of care and hospital costs within the Province of Ontario. The study results may assist service planners in the appropriate allocation of resources and service packaging to meet the complex needs of palliative care populations. PMID- 22249927 TI - The taxonomy, biology and chemistry of the fungal Pestalotiopsis genus. AB - A growing body of evidence indicates that the Pestalotiopsis genus represents a huge and largely untapped resource of natural products with chemical structures that have been optimized by evolution for biological and ecological relevance. So far, 196 secondary metabolites have been encountered in this genus. This review systematically surveys the taxonomy, biology and chemistry of the Pestalotiopsis genus. It also summarises the biosynthetic relationships and chemical synthesis of metabolites from this genus. There are 184 references. PMID- 22249929 TI - A halogen-bonding catenane for anion recognition and sensing. PMID- 22249930 TI - Effects of indoleamine 2,3-dioxygenases in carbon tetrachloride-induced hepatitis model of rats. AB - Indoleamine 2,3-dioxygenase (IDO) converts tryptophan to l-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, to investigate the effects of IDO in carbon tetrachloride (CCl(4) )-induced hepatitis model, the levels of IDO enzymic activities in the mock group, the control group and the 1-methyl-D-tryptophan (1 MT)-treated group were confirmed by determination of l-kynurenine concentrations. Serum alanine aminotransferase levels in 1-MT-treated rats after CCl(4) injection significantly increased compared with those in mock and control groups. In CCl(4) induced hepatitis models, tumour necrosis factor-alpha (TNF-alpha) is critical in the development of liver injury. The mRNA expression and secretion levels of TNF alpha in the liver from 1-MT-treated rats were more enhanced compared with those in the mock and the control groups. Moreover, the levels of cytokine and chemokine from mock, control group and 1-MT-treated rats after treated with CCl(4) were analyzed by ELISA, and the level of interleukin-6 was found to increase in 1-MT-treated rats. It was concluded that the deficiency of IDO exacerbated liver injury in CCl(4)-induced hepatitis and its effect may be connected with TNF-alpha and interleukin-6. PMID- 22249933 TI - Unsymmetrical p-carborane backbone as a linker for donor-acceptor dyads. AB - Fluorescent nanorods: Donor-acceptor dyads based on novel unsymmetrically disubstituted closo-1,12-dicarbadecaboranes have been prepared in a completely controlled manner by using a three-step procedure. Dyads with different donor acceptor spacing were thereby obtained. Efficient energy transfer from the donor to the acceptor was determined in fluid solution at room temperature. PMID- 22249931 TI - Bosentan, an endothelin receptor antagonist, ameliorates collagen-induced arthritis: the role of TNF-alpha in the induction of endothelin system genes. AB - OBJECTIVE: Endothelins (ETs) are involved in several inflammatory events. The present study investigated the efficacy of bosentan, a dual ETA/ETB receptor antagonist, in collagen-induced arthritis (CIA) in mice. TREATMENT: CIA was induced in DBA/1J mice. Arthritic mice were treated with bosentan (100 mg/kg) once a day, starting from the day when arthritis was clinically detectable. METHODS: CIA progression was assessed by measurements of visual clinical score, paw swelling and hypernociception. Histological changes, neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints. Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology. PreproET-1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time PCR. The differences were evaluated by one-way ANOVA or Student's t test. RESULTS: Oral treatment with bosentan markedly ameliorated the clinical aspects of CIA (visual clinical score, paw swelling and hyperalgesia). Bosentan treatment also reduced joint damage, leukocyte infiltration and pro-inflammatory cytokine levels (IL-1beta, TNFalpha and IL-17) in the joint tissues. Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after bosentan treatment. PreproET mRNA expression increased in PBMCs from rheumatoid arthritis (RA) patients but returned to basal level in PBMCs from patients under anti-TNF therapy. In-vitro treatment of PBMCs with TNFalpha upregulated ET system genes. CONCLUSION: These findings indicate that ET receptor antagonists, such as bosentan, might be useful in controlling RA. Moreover, it seems that ET mediation of arthritis is triggered by TNFalpha. PMID- 22249934 TI - Study of the chemical mechanism involved in the formation of tungstite in benzyl alcohol by the advanced QEXAFS technique. AB - Insight into the complex chemical mechanism for the formation of tungstite nanoparticles obtained by the reaction of tungsten hexachloride with benzyl alcohol is presented herein. The organic and inorganic species involved in the formation of the nanoparticles were studied by time-dependent gas chromatography and X-ray diffraction as well as by time-resolved in situ X-ray absorption near edge structure and extended X-ray absorption fine structure spectroscopy. Principal component analysis revealed two intermediates, which were identified as WCl(4) and WOCl(4) by using linear combination analysis. Quick-scanning extended X-ray absorption fine structure spectroscopy enabled the time-dependent evolution of the starting compound, the intermediates and the product to be monitored over the full reaction period. The reaction starts with fast chlorine substitution and partial reduction during the dissolution of the tungsten hexachloride in benzyl alcohol followed by the generation of intermediates with W=O double bonds and finally the construction of the W-O-W network of the tungstite structure. PMID- 22249932 TI - The B-cell superantigen Finegoldia magna protein L causes pulmonary inflammation by a mechanism dependent on MyD88 but not B cells or immunoglobulins. AB - OBJECTIVE AND DESIGN: To determine whether Finegoldia magna protein L (PL) causes lung inflammation and, if so, whether the response is dependent on its immunoglobulin (Ig)-binding B-cell superantigenic property. MATERIAL: Pulmonary inflammatory reactions were analyzed at various time points after intratracheal administration of PL to various strains of mice. RESULTS: PL caused peribronchial and perivascular inflammation that peaked at 18-24 h. Polymorphonuclear cells (PMNs) began to accumulate in bronchoalveolar lavage fluid (BALF) of PL challenged mice by 4 h and accounted for >90% of leukocytes by 18-24 h. Inflammation was marked by the appearance of MIP-2, KC, TNF-alpha, and IL-6 in the BALF with peak levels attained 4 h after PL administration. PL-induced pulmonary inflammation was associated with increased airway hyper-reactivity following inhalation of methacholine. The inflammatory reaction was unabated in mice lacking B cells and immunoglobulins. In contrast, PL-induced inflammation was abrogated in MyD88-deficient mice. PL-induced responses required alveolar macrophages. CONCLUSIONS: These results strongly suggest that PL-induced lung inflammation is dependent on an innate MyD88-dependent pathway rather than the Ig binding properties of this microbial B cell superantigen. We propose that this pulmonary inflammatory reaction is caused by the interaction of PL with a Toll like receptor expressed on alveolar macrophages. PMID- 22249935 TI - Stereoselective synthesis of fully protected (2S,4S,6S)-2-amino-6-hydroxy-4 methyl-8-oxodecanoic acid (AHMOD). AB - The stereocontrolled synthesis of fully protected (2S,4S,6S)-2-amino-6-hydroxy-4 methyl-8-oxodecanoic acid was accomplished using a glutamate derivative as starting material. The key steps of this stereochemical synthetic pathway involved an Evans asymmetric alkylation, a Sharpless asymmetric epoxidation, and a Grignard reaction. PMID- 22249937 TI - Maintenance of arachidonic acid and evidence of Delta5 desaturation in cats fed gamma-linolenic and linoleic acid enriched diets. AB - Cats have limited Delta6 desaturase activity. However, gamma-linolenate (GLA) feeding may by-pass the Delta6 desaturase step allowing arachidonate (ARA) accumulation via Delta5-desaturation. Alternatively, high dietary linoleate (LNA) may induce limited Delta6 desaturase also resulting in ARA accumulation. Fatty acid profiles were determined after feeding high LNA, high GLA, or adequate LNA diets. Adult female cats (n = 29) were assigned to one of three groups and fed for 8 weeks. Plasma samples were collected at weeks 0, 2, 4 and 8 for plasma triacylglycerol (TAG), total cholesterol (TC), lipoprotein (LP), and plasma and red blood cell membrane phospholipid fatty acid determinations. Time, but no diet, effects were observed for TAG, TC, and LP fractions at weeks 2 and 4 with significant increases likely due to increased dietary fat. However, all values were within feline normal limits. The GLA diet resulted in increased dihomo-gamma linolenic acid (DGLA) and ARA as early as week 2, supporting a ?5 desaturase. Further evidence of Delta5 desaturase was found at high dietary LNA with the appearance of a novel fatty acid, 20:3 ?7, 11, 14, apparently formed via ?5 desaturation and chain elongation of LNA. However, Delta6 desaturase induction at high dietary LNA concentration was not observed. Cats are able to maintain plasma and red blood cell ARA when fed a practical diet containing GLA using what appears to be an active Delta5 desaturase enzyme. PMID- 22249939 TI - Silica nanocontainers for active corrosion protection. AB - Novel self-healing protective coatings with nanocontainers of corrosion inhibitors open new opportunities for long-term anticorrosion protection of different metallic materials. In this paper a new type of functional nanoreservoir based on silica nanocapsules (SiNC) synthesized and loaded with corrosion inhibitor 2-mercaptobenzothiazole (MBT) in a one-stage process is reported for the first time. Unlike conventional mesoporous silica nanoparticles, SiNC possess an empty core and shell with gradual mesoporosity, arising from the particular conditions of the synthetic route adopted, which confers significant loading capacity and allows prolonged and stimuli-triggered release of the inhibiting species. The kinetics of inhibitor release was studied at different pH values and concentrations of NaCl. The results show a clear dependence of the release profiles on corrosion relevant triggers such as pH and Cl(-) concentration. When SiNC loaded with MBT are dispersed in NaCl solution, there is a significant decrease of the corrosion activity on aluminium alloy 2024. More importantly, when SiNC-MBT is added to a conventional water-based coating formulation, the modified coating hampers corrosion activity at the metal interface, better than in the case of direct addition of corrosion inhibitor. Furthermore, self-healing is observed before and after artificially inflicting defects in the modified coatings. As a result, the developed nanocontainers show high potential to be used in new generation of active protective coatings. PMID- 22249938 TI - Absorption and metabolism of cis-9,trans-11-CLA and of its oxidation product 9,11 furan fatty acid by Caco-2 cells. AB - Furan fatty acids (furan-FA) can be formed by auto-oxidation of conjugated linoleic acids (CLA) and may therefore be ingested when CLA-containing foodstuff is consumed. Due to the presence of a furan ring structure, furan-FA may have toxic properties, however, these substances are toxicologically not well characterized so far. Here we show that 9,11-furan-FA, the oxidation product of the major CLA isomer cis-9,trans-11-CLA (c9,t11-CLA), is not toxic to human intestinal Caco-2 cells up to a level of 100 MUM. Oil-Red-O staining indicated that 9,11-furan-FA as well as c9,t11-CLA and linoleic acid are taken up by the cells and stored in the form of triglycerides in lipid droplets. Chemical analysis of total cellular lipids revealed that 9,11-furan-FA is partially elongated probably by the enzymatic activity of cellular fatty acid elongases whereas c9,t11-CLA is partially converted to other isomers such as c9,c11-CLA or t9,t11-CLA. In the case of 9,11-furan-FA, there is no indication for any modification or activation of the furan ring system. From these results, we conclude that 9,11-furan-FA has no properties of toxicological relevance at least for Caco-2 cells which serve as a model for enterocytes of the human small intestine. PMID- 22249940 TI - A two-photon turn-on probe for glucose uptake. AB - We report a two-photon turn-on probe (AS1) that can be excited by 780 nm femto second pulses and visualize glucose uptake and the changes in the intracellular glucose concentration in live cells and tissue by two-photon microscopy. PMID- 22249941 TI - Alogliptin as an initial therapy in patients with newly diagnosed, drug naive type 2 diabetes: a randomized, control trial. AB - The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naive subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naive patients who visited the outpatient units. The patients randomly received 12.5-25 mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-R (HOMA-R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from 10.51 to 8.74% for alogliptin and from 10.01 to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA-R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is superior. (2) Both alogliptin and traditional Japanese diet have favorable effects on atherogenic lipid profiles. PMID- 22249943 TI - P-bodies and their functions during mRNA cell cycle: mini-review. AB - P-bodies (processing bodies) are observed in different organisms such as yeast, Caenorhabditis elegans and mammals. A typical eukaryotic cell contains several types of spatially formed granules, such as P-bodies, stress granules and a variety of ribonucleoprotein bodies. These microdomains play important role in mRNA processing, including RNA interference, repression of translation and mRNA decay. The P-bodies components as well as stress granules may play an important role in host defense against viral infection. The complete set of P-bodies protein elements is still poor known. They contain conserved protein core limited to different organisms or to stress status of the cell. P-bodies are related also to some neuronal mRNA granules as well as to maternal RNA granules or male germ cell granules. In this mini-review, we focus on the structure of P-bodies and their function in the mRNA utilization and processing because of the high mRNA's dynamics between different cellular compartments and its key role in modulation of gene expression. PMID- 22249942 TI - CRH-R1 and CRH-R2 differentially modulate dendritic outgrowth of hippocampal neurons. AB - Corticotropin-releasing hormone (CRH) has been implicated to be involved in the development of dendrites in brain. In the present study, we examined the effect of CRH on dendrite outgrowth in primary cultured hippocampal neurons and defined the specific CRH receptor subtype involved. Treatment of neurons with increasing concentration of CRH resulted in an increase in the total dendritic branch length (TDBL) of neurons compared with untreated neurons over 2-4 days period of treatment. These effects can be reversed by the specific CRH-R1 antagonist antalarmin but not by the CRH-R2 antagonist astressin 2B. Treatment of neurons with urocortin II, the exclusive CRH-R2 agonist, significantly decreased TDBL of the cultured neurons. These effects can be reversed by the CRH-R2 antagonist astressin 2B. Our results suggest that CRH-R1 and CRH-R2 differentially modulate the dendritic growth of hippocampal neurons in culture. PMID- 22249944 TI - Individualized fludarabine-based regimen in elderly patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - INTRODUCTION: The aim of this study was to investigate the efficacy and safety of a fludarabine-based individualized regimen in elderly patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). METHODS: Sixteen patients were treated with the individual regimen of fludarabine combined with rituximab. Adverse reactions and efficacy of treatment were observed. RESULTS: Sixteen patients received a total of 69 courses of immunochemotherapy, with an average administration of 275 mg fludarabine per person. The overall response rate was 81.3% (13/16), in which seven cases (43.8%) achieved complete remission, six cases (37.5%) achieved partial remission, two cases (12.5%) had stable disease, and one case (6.3%) developed disease progression. The most frequent side effect was myelosuppression. Two patients experienced grade 3-4 cytopenia, one case developed a grade 3 infection, and no treatment-related death was observed. CONCLUSION: The individual regimen of fludarabine combined with rituximab demonstrated marked clinical efficacy and acceptable toxicity in elderly patients with CLL/SLL. PMID- 22249945 TI - Improving anharmonic infrared spectra using semiclassically prepared molecular dynamics simulations. AB - Classical molecular dynamics is a convenient method for computing anharmonic infrared spectra of polyatomic molecules and condensed phase systems. However it does not perform well for predicting accurate intensities and it lacks nuclear quantization, two deficiencies that are usually accounted for by empirical scaling factors. In this paper we show on the examples of the trans isomer of nitrous acid and naphthalene that both issues can be alleviated by preparing the initial conditions according to semiclassical quantization based on a normal mode representation. The method correctly reproduces fundamental frequencies obtained with quantum mechanical methods. At increasing temperatures, the effective frequencies are found to follow the same trends as path-integral based methods. In the low-temperature limit, the band intensities predicted by the method are also found to agree with quantum mechanical considerations. PMID- 22249947 TI - Internal functionalization of three-dimensional covalent organic frameworks. PMID- 22249946 TI - CD34 marks angiogenic tip cells in human vascular endothelial cell cultures. AB - The functional shift of quiescent endothelial cells into tip cells that migrate and stalk cells that proliferate is a key event during sprouting angiogenesis. We previously showed that the sialomucin CD34 is expressed in a small subset of cultured endothelial cells and that these cells extend filopodia: a hallmark of tip cells in vivo. In the present study, we characterized endothelial cells expressing CD34 in endothelial monolayers in vitro. We found that CD34-positive human umbilical vein endothelial cells show low proliferation activity and increased mRNA expression of all known tip cell markers, as compared to CD34 negative cells. Genome-wide mRNA profiling analysis of CD34-positive endothelial cells demonstrated enrichment for biological functions related to angiogenesis and migration, whereas CD34-negative cells were enriched for functions related to proliferation. In addition, we found an increase or decrease of CD34-positive cells in vitro upon exposure to stimuli that enhance or limit the number of tip cells in vivo, respectively. Our findings suggest cells with virtually all known properties of tip cells are present in vascular endothelial cell cultures and that they can be isolated based on expression of CD34. This novel strategy may open alternative avenues for future studies of molecular processes and functions in tip cells in angiogenesis. PMID- 22249948 TI - Weakly associated TFPB anions are superior to PF6 anions when preparing (pseudo)rotaxanes from crown ethers and secondary dialkylammonium ions. AB - Making the right choice: Tetrakis(3,5-trifluoromethylphenyl)borate (TFPB) counter anions can facilitate the threading of dibenzylammonium (DBA(+)) ions through macrocycles in cases where the corresponding PF(6)(-) salts fail to exhibit complexation. PMID- 22249949 TI - Synthesis of anticancer heptapeptides containing a unique lipophilic beta(2,2) amino acid building block. AB - We report a series of synthetic anticancer heptapeptides (H-KKWbeta(2,2) WKK NH(2)) containing eight different central lipophilic beta(2,2) -amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC(50) values of 9-23 um against human Burkitt's lymphoma and murine B-cell lymphoma and were all nonhaemolytic (EC(50) > 200 um). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability. PMID- 22249951 TI - Calcium-amidoborane-ammine complexes: thermal decomposition of model systems. AB - Hydrocarbon-soluble model systems for the calcium-amidoborane-ammine complex Ca(NH(2)BH(3))(2)?(NH(3))(2) were prepared and structurally characterized. The following complexes were obtained by the reaction of RNH(2)BH(3) (R = H, Me, iPr, DIPP; DIPP = 2,6-diisopropylphenyl) with Ca(DIPP-nacnac)(NH(2))?(NH(3))(2) (DIPP nacnac = DIPP-NC(Me)CHC(Me)N-DIPP): Ca(DIPP-nacnac)(NH(2)BH(3))?(NH(3))(2), Ca(DIPP-nacnac)(NH(2)BH(3))?(NH(3))(3), Ca(DIPP-nacnac)[NH(Me)BH(3)]?(NH(3))(2), Ca(DIPP-nacnac)[NH(iPr)BH(3)]?(NH(3))(2), and Ca(DIPP nacnac)[NH(DIPP)BH(3)]?NH(3). The crystal structure of Ca(DIPP nacnac)(NH(2)BH(3))?(NH(3)(3) showed a NH(2)BH(3)(-) unit that was fully embedded in a network of BH???HN interactions (range: 1.97(4)-2.39(4) A) that were mainly found between NH(3) ligands and BH(3) groups. In addition, there were N-H???C interactions between NH(3) ligands and the central carbon atom in the ligand. Solutions of these calcium-amidoborane-ammine complexes in benzene were heated stepwise to 60 degrees C and thermally decomposed. The following main conclusions can be drawn: 1) Competing protonation of the DIPP-nacnac anion by NH(3) was observed; 2) The NH(3) ligands were bound loosely to the Ca(2+) ions and were partially eliminated upon heating. Crystal structures of [Ca(DIPP nacnac)(NH(2)BH(3))?(NH(3))](infinity), Ca(DIPP nacnac)(NH(2)BH(3))?(NH(3))?(THF), and [Ca(DIPP-nacnac){NH(iPr)BH(3)}](2) were obtained. 3) Independent of the nature of the substituent R in NH(R)BH(3), the formation of H(2) was observed at around 50 degrees C. 4) In all cases, the complex [Ca(DIPP-nacnac)(NH(2))](2) was formed as a major product of thermal decomposition, and its dimeric nature was confirmed by single-crystal analysis. We proposed that thermal decomposition of calcium-amidoborane-ammine complexes goes through an intermediate calcium-hydride-ammine complex which eliminates hydrogen and [Ca(DIPP-nacnac)(NH(2))](2). It is likely that the formation of metal amides is also an important reaction pathway for the decomposition of metal amidoborane-ammine complexes in the solid state. PMID- 22249952 TI - Cerebral vasospasm after transsphenoidal resection of pituitary macroadenomas: report of 3 cases and review of the literature. AB - BACKGROUND: Delayed ischemic events due to vasospasm are a well-known complication of aneurysmal subarachnoid hemorrhage (SAH). Severe vasospasm in other neurosurgical settings is not as well recognized. Delay in diagnosis and treatment of vasospasm in such settings may be associated with significant neurological morbidity. OBJECTIVE: To present three cases of symptomatic delayed cerebral vasospasm after transsphenoidal resection of pituitary macroadenomas. METHODS: Transsphenoidal resection in all cases was complicated by peritumoral hemorrhage with extension into the subarachnoid space. Two of the 3 patients required re-operation to evacuate the hematoma in the tumor bed because of progressive worsening neurological deficits. RESULTS: All 3 patients developed vasospasm of the intracranial vessels, starting as early as postoperative day 5 and appearing as late as postoperative day 10. Comparisons to the non-vascular pre-operative magnetic resonance imaging studies confirmed the "de-novo" nature of the vasospasm based on the caliber of the flow voids. CONCLUSION: Transsphenoidal surgery complicated by peritumoral hemorrhage is associated with a significant risk of neurological morbidity because of delayed cerebral vasospasm. Early recognition and management according to guidelines used for postaneurysmal SAH may help to improve outcomes in these patients. PMID- 22249950 TI - Coronary heart disease in young adults. AB - Despite the recent decline in mortality from coronary heart disease (CHD), this disease remains the leading killer of US adults of all ages. CHD in young adults is not as well characterized as CHD in older individuals because it occurs less frequently, but this disease can have devastating consequences for young patients and their families. As in older adults, the majority of coronary events in young adults are related to atherosclerosis, and one or more of the traditional CHD risk factors is typically present. Young patients, however, are more likely than older patients to be smokers, male, obese, and to have a positive family history. Risk factor reduction is thus of major importance in managing young CHD patients. Approximately 20% of CHD in young adults, however, is related to non atherosclerotic factors, such as coronary abnormalities, connective tissue disorders, and autoimmune diseases. Cocaine and other illicit drug use have been increasingly associated with acute myocardial infarction and accelerated atherosclerosis. The differences in etiologies and risk profiles of younger and older CHD patients result in differences in disease progression, prognosis, and treatment. Limited data suggest that prognosis may be better in the young population, although long-term mortality studies have suggested otherwise. Screening for CHD in the young population may help to improve prognosis in young patients by detecting subclinical disease, although more studies are necessary to establish reference limits for this young population. Additional research must also focus on treatment concerns that are specific to young patients. PMID- 22249953 TI - Oriented and selective enzyme immobilization on functionalized silica carrier using the cationic binding module Z basic2: design of a heterogeneous D-amino acid oxidase catalyst on porous glass. AB - D-amino acid oxidase from Trigonopsis variabilis (TvDAO) is applied in industry for the synthesis of pharmaceutical intermediates. Because free TvDAO is extremely sensitive to exposure to gas-liquid interfaces, biocatalytic processing is usually performed with enzyme immobilizates that offer enhanced stability under bubble aeration. We herein present an "Immobilization by Design" approach that exploits engineered charge complementarity between enzyme and carrier to optimize key features of the immobilization of TvDAO. A fusion protein between TvDAO and the positively charged module Z(basic2) was generated, and a corresponding oppositely charged carrier was obtained by derivatization of mesoporous glass with 3-(trihydroxysilyl)-1-propane-sulfonic acid. Using 250 mM NaCl for charge screening at pH 7.0, the Z(basic2) fusion of TvDAO was immobilized directly from E. coli cell extract with almost absolute selectivity and full retention of catalytic effectiveness of the isolated enzyme in solution. Attachment of the homodimeric enzyme to the carrier was quasi-permanent in low salt buffer but fully reversible upon elution with 5 M NaCl. Immobilized TvDAO was not sensitive to bubble aeration and received substantial (>= tenfold) stabilization of the activity at 45 degrees C as compared to free enzyme, suggesting immobilization via multisubunit oriented interaction of enzyme with the insoluble carrier. The Z(basic2) enzyme immobilizate was demonstrated to serve as re-usable heterogeneous catalyst for D-amino acid oxidation. Z(basic2) mediated binding on a sulfonic acid group-containing glass carrier constitutes a generally useful strategy of enzyme immobilization that supports transition from case-specific empirical development to rational design. PMID- 22249954 TI - Psychological trauma and PTSD in HIV-positive women: a meta-analysis. AB - Women bear an increasing burden of the HIV epidemic and face high rates of morbidity and mortality. Trauma has been increasingly associated with the high prevalence and poor outcomes of HIV in this population. This meta-analysis estimates rates of psychological trauma and posttraumatic stress disorder (PTSD) in HIV-positive women from the United States. We reviewed 9,552 articles, of which 29 met our inclusion criteria, resulting in a sample of 5,930 individuals. The findings demonstrate highly disproportionate rates of trauma exposure and recent PTSD in HIV-positive women compared to the general population of women. For example, the estimated rate of recent PTSD among HIV-positive women is 30.0% (95% CI 18.8-42.7%), which is over five-times the rate of recent PTSD reported in a national sample of women. The estimated rate of intimate partner violence is 55.3% (95% CI 36.1-73.8%), which is more than twice the national rate. Studies of trauma-prevention and trauma-recovery interventions in this population are greatly needed. PMID- 22249955 TI - Prevalence of HIV risk behaviors among undocumented Central American immigrant women in Houston, Texas. AB - Undocumented Central American immigrants in the United States are disproportionately affected by HIV infection. However, epidemiological data on sexual behaviors among undocumented women are sparse and the extent to which behaviors vary by duration of residence in the U.S.is largely unknown. In 2010, we used respondent driven sampling to conduct an HIV behavioral survey among Central American immigrant women residing in Houston, Texas without a valid U.S. visa or residency papers. Here we describe the prevalence of sexual risk behaviors and compare recent (5 years or less in the U.S.) and established immigrants (over 5 years in the U.S.) to elucidate changes in sexual risk behaviors over time. Our data suggest that recent immigrants have less stable sexual partnerships than established immigrants, as they are more likely to have multiple and concurrent sexual partnerships, as well as partnerships of shorter duration. PMID- 22249956 TI - Injection drug use and HIV antiretroviral therapy discontinuation in a Canadian setting. AB - We investigated whether drug-related behaviors predicted antiretroviral therapy (ART) discontinuation among a cohort of injection drug users (IDU) in a Canadian setting. Cox regression analyses were used to investigate the impact of drug use patterns on rates of ART discontinuation among a sample of HIV-positive IDU in Vancouver, Canada between May 1996 and April 2008. In total, 408 HIV-positive IDU initiated ART during the study period, among whom 257 (63.0%) discontinued ART at least once. Rates of ART discontinuation were not significantly elevated among those who reported ongoing injection of heroin, cocaine, or other illicit drugs in comparison to those who reported not injecting drugs. However, public drug use was significantly predictive of ART discontinuation. Our findings may contribute to a reconsideration of the role of active drug use in determining retention in ART programs among IDU. PMID- 22249957 TI - Prescription profiles for pharmacological treatment of Japanese inpatients with schizophrenia: comparison between 2007 and 2009. AB - BACKGROUND AND OBJECTIVE: Pharmacological treatment of schizophrenic patients in Japan is characterized by polypharmacy with high doses of antipsychotics. In this study, we examined the profiles of antipsychotic drug therapy in 2007 and 2009 to determine if there have been any recent shifts in treatment strategy. METHOD: The subjects were schizophrenic inpatients (ICD-10-F20) admitted to 100 hospitals in 2007 and 152 hospitals in 2009. Information on the psychotropic agents prescribed on specified days in November 2007 and 2009 was acquired for each patient. RESULTS: Although no changes were observed in the rate of antipsychotic medications being prescribed, the rate of antipsychotic monotherapy in 2009 increased significantly. In 2007, among 15,761 patients, 4977 (31.6%) received antipsychotic monotherapy (i.e., administration of a single antipsychotic medication). In 2009, among 22,911 patients, 7741 (33.8%) received antipsychotic monotherapy. CONCLUSION: The rate of use of antipsychotic monotherapy has gradually increased, although the total dose has not changed significantly. The increase in the concomitant use of two or more second-generation antipsychotics is a recent trend in Japan, despite the lack of information on the efficacy and safety of this treatment strategy. PMID- 22249958 TI - Remote monitoring and follow-up of cardiovascular implantable electronic devices in the Netherlands : An expert consensus report of the Netherlands Society of Cardiology. AB - Remote monitoring of cardiac implanted electronic devices (CIED: pacemaker, cardiac resynchronisation therapy device and implantable cardioverter defibrillator) has been developed for technical control and follow-up using transtelephonic data transmission. In addition, automatic or patient-triggered alerts are sent to the cardiologist or allied professional who can respond if necessary with various interventions. The advantage of remote monitoring appears obvious in impending CIED failures and suspected symptoms but is less likely in routine follow-up of CIED. For this follow-up the indications, quality of care, cost-effectiveneness and patient satisfaction have to be determined before remote CIED monitoring can be applied in daily practice. Nevertheless remote CIED monitoring is expanding rapidly in the Netherlands without professional agreements about methodology, responsibilities of all the parties involved and that of the device patient, and reimbursement. The purpose of this consensus document on remote CIED monitoring and follow-up is to lay the base for a nationwide, uniform implementation in the Netherlands. This report describes the technical communication, current indications, benefits and limitations of remote CIED monitoring and follow-up, the role of the patient and device manufacturer, and costs and reimbursement. The view of cardiology experts and of other disciplines in conjunction with literature was incorporated in a preliminary series of recommendations. In addition, an overview of the questions related to remote CIED monitoring that need to be answered is given. This consensus document can be used for future guidelines for the Dutch profession. PMID- 22249959 TI - Excess-electron injection and transfer in terthiophene-modified DNA: terthiophene as a photosensitizing electron donor for thymine, cytosine, and adenine. AB - Excess-electron transfer (EET) in DNA has attracted wide attention owing to its close relation to DNA repair and nanowires. To clarify the dynamics of EET in DNA, a photosensitizing electron donor that can donate an excess electron to a variety of DNA sequences has to be developed. Herein, a terthiophene (3T) derivative was used as the photosensitizing electron donor. From the dyad systems in which 3T was connected to a single nucleobase, it was revealed that (1) 3T* donates an excess electron efficiently to thymine, cytosine, and adenine, despite adenine being a well-known hole conductor. The free-energy dependence of the electron-transfer rate was explained on the basis of the Marcus theory. From the DNA hairpins, it became clear that (1) 3T* can donate an excess electron not only to the adjacent nucleobase but also to the neighbor one nucleobase further along and so on. From the charge-injection rate, the possibilities of smaller beta value and/or charge delocalization were discussed. In addition, EET through consecutive cytosine nucleobases was suggested. PMID- 22249961 TI - Analysis of peptide uptake and location of root hair-promoting peptide accumulation in plant roots. AB - Peptide uptake by plant roots from degraded soybean-meal products was analyzed in Brassica rapa and Solanum lycopersicum. B. rapa absorbed about 40% of the initial water volume, whereas peptide concentration was decreased by 75% after 24 h. Analysis by reversed-phase HPLC showed that number of peptides was absorbed by the roots during soaking in degraded soybean-meal products for 24 h. Carboxyfluorescein-labeled root hair-promoting peptide was synthesized, and its localization, movement, and accumulation in roots were investigated. The peptide appeared to be absorbed by root hairs and then moved to trichoblasts. Furthermore, the peptide was moved from trichoblasts to atrichoblasts after 24 h. The peptide was accumulated in epidermal cells, suggesting that the peptide may have a function in both trichoblasts and atrichoblasts. PMID- 22249962 TI - First experience with the new portable extracorporeal membrane oxygenation system Cardiohelp for severe respiratory failure in adults. AB - BACKGROUND: Over the last decade, technical improvements in extracorporeal membrane oxygenation (ECMO) equipment have reduced procedure-related complications and have made ECMO an effective option for patients with acute respiratory distress syndrome (ARDS) if conventional therapy fails. METHODS: In this report, we present our early experience with the Cardiohelp, a new portable miniaturized ECMO system, in 22 consecutive patients with ARDS. All patients were placed on venovenous ECMO. Cannulas were inserted percutaneously, employing the Seldinger technique. Data were collected prospectively. RESULTS: The median patient age was 47 years (36 to 61). Fifteen patients from regional hospitals were too unstable for conventional transport and were placed on Cardiohelp at the referring hospital and then transported to our institution. The patients were transported by ambulance (n=2) or helicopter (n=13) over a distance of 50-250 km. Cardiohelp support resulted in immediate improvement of gas exchange and highly protective ventilation. The median duration of support was 13 days (8 to 19). An exchange of the device was necessary in 9 patients. Sixteen patients (72.7%) were successfully weaned from ECMO and fifteen patients (68.2%) survived. Device related complications were not observed. CONCLUSIONS: The compact portable ECMO device Cardiohelp is a highly effective method to secure vital gas exchange and to reduce further ventilator-induced lung injury in patients with acute respiratory failure. Crucial technical innovations and ease of device transport and implantation allow location-independent stabilization with consecutive inter hospital transfer. PMID- 22249963 TI - Early outcomes of carotid artery stenting. AB - BACKGROUND AND AIM: Ischemic cerebrovascular events are the most common reason for patients to be bedridden and the third most common reason for death. Many studies in recent years have demonstrated that carotid artery stenting (CAS) may be an alternative to carotid endarterectomy (CEA). In this study, we aimed to report early outcomes of patients who were treated with CAS in our clinic and discuss practicability, advantages and safety of CAS. METHODS AND FINDINGS: Eighty patients who underwent CAS between December 2009 and May 2011 were eligible. The mean age was 65 years (range, 49 - 89 years). Of the study group, 73.75% were males and 26.25% were female. The percentage of asymptomatic patients was 11.7%, and the remaining patients were symptomatic. A distal embolic protection device (Angioguard(r)) was used in 22% of the patients whereas, in the other patients (78%), a proximal blockage system (Mo.MA(r)) was used. Self expandable hybrid stents were implanted in all patients and post-dilatation was performed after implantation. None of the patients suffered from stroke, myocardial infarction or death due to CAS during their hospital stay. The mean follow-up period was 10 months (range 2 - 18 months) after discharge. None of the patients had died or had a stroke, a transient ischemic attack (TIA), or a myocardial infarction during the follow-up period. Re-stenosis was not observed in the follow-up carotid Doppler ultrasonography; flow rates were within normal limits. CONCLUSION: No major complication was observed during the early follow-up period in patients who underwent CAS in our clinic. Only 2 (2.5%) patients showed transient numbness and weakness and these did not lead to morbidity. In the management guide of extracranial carotid and vertebral artery diseases, CAS, in the light of recent studies, is recommended as an alternative to CEA in recommendations for revascularization. One of the important issues emphasized in this guide is the experience of centers. Very low complication rates after CAS suggested that, with suitable patient selection and an experienced team, similar results may be obtained. PMID- 22249964 TI - Extracorporeal membrane oxygenation following pediatric cardiac surgery: development and outcomes from a single-center experience. AB - Extracorporeal membrane oxygenation (ECMO) has emerged as an effective mechanical support following cardiac surgery with respiratory and cardiac failure. However, there are no clear indications for ECMO use after pediatric cardiac surgery. We retrospectively reviewed medical records of 76 pediatric patients [mean age, 10.8 months (0-86); mean weight, 5.16 kg (1.16-16.5)] with congenital heart disease who received ECMO following cardiac surgery between January 1997 and October 2010. Forty-five patients were treated with an aggressive ECMO approach (aggressive ECMO group, April 2005-October 2010) and 31 with a delayed ECMO approach (delayed ECMO group, January 1997-March 2005). Demographics, diagnosis, operative variables, ECMO indication, and duration of survivors and non-survivors were compared. Thirty-four patients (75.5%) were successfully weaned from ECMO in the aggressive ECMO group and 26 (57.7%) were discharged. Conversely, eight patients (25.8%) were successfully weaned from ECMO in the delayed ECMO group and two (6.5%) were discharged. Forty-five patients with shunted single ventricle physiology (aggressive: 29 patients, delayed: 16 patients) received ECMO, but only 15 (33.3%) survived and were discharged. The survival rate of the aggressive ECMO group was significantly better when compared with the delayed ECMO group (p<0.01). Also, ECMO duration was significantly shorter among the aggressive ECMO group survivors (96.5 +/- 62.9 h, p<0.01). Thus, the aggressive ECMO approach is a superior strategy compared to the delayed ECMO approach in pediatric cardiac patients. The aggressive ECMO approach improved our outcomes of neonatal and pediatric ECMO. PMID- 22249965 TI - Factors associated with difficult electronic health record implementation in office practice. AB - Little is known about physicians' perception of the ease or difficulty of implementing electronic health records (EHR). This study identified factors related to the perceived difficulty of implementing EHR. 163 physicians completed surveys before and after the implementation of EHR in an externally funded pilot program in three Massachusetts communities. Ordinal hierarchical logistic regression was used to identify baseline factors that correlated with physicians' report of difficulty with EHR implementation. Compared with physicians with ownership stake in their practices, physician employees were less likely to describe EHR implementation as difficult (adjusted OR 0.5, 95% CI 0.3 to 1.0). Physicians who perceived their staff to be innovative were also less likely to view EHR implementation as difficult (adjusted OR 0.4, 95% CI 0.2 to 0.8). Physicians who own their practice may need more external support for EHR implementation than those who do not. Innovative clinical support staff may ease the EHR implementation process and contribute to its success. PMID- 22249966 TI - Visualizing the operating range of a classification system. AB - The performance of a classification system depends on the context in which it will be used, including the prevalence of the classes and the relative costs of different types of errors. Metrics such as accuracy are limited to the context in which the experiment was originally carried out, and metrics such as sensitivity, specificity, and receiver operating characteristic area--while independent of prevalence--do not provide a clear picture of the performance characteristics of the system over different contexts. Graphing a prevalence-specific metric such as F-measure or the relative cost of errors over a wide range of prevalence allows a visualization of the performance of the system and a comparison of systems in different contexts. PMID- 22249967 TI - Validity of electronic health record-derived quality measurement for performance monitoring. AB - BACKGROUND: Since 2007, New York City's primary care information project has assisted over 3000 providers to adopt and use a prevention-oriented electronic health record (EHR). Participating practices were taught to re-adjust their workflows to use the EHR built-in population health monitoring tools, including automated quality measures, patient registries and a clinical decision support system. Practices received a comprehensive suite of technical assistance, which included quality improvement, EHR customization and configuration, privacy and security training, and revenue cycle optimization. These services were aimed at helping providers understand how to use their EHR to track and improve the quality of care delivered to patients. MATERIALS AND METHODS: Retrospective electronic chart reviews of 4081 patient records across 57 practices were analyzed to determine the validity of EHR-derived quality measures and documented preventive services. RESULTS: Results from this study show that workflow and documentation habits have a profound impact on EHR-derived quality measures. Compared with the manual review of electronic charts, EHR-derived measures can undercount practice performance, with a disproportionately negative impact on the number of patients captured as receiving a clinical preventive service or meeting a recommended treatment goal. CONCLUSION: This study provides a cautionary note in using EHR-derived measurement for public reporting of provider performance or use for payment. PMID- 22249969 TI - The application of amine-terminated silicon quantum dots on the imaging of human serum proteins after polyacrylamide gel electrophoresis (PAGE). AB - Novel amine-terminated silicon (Si) quantum dots (QDs) were synthesized and applied for the detection of human serum proteins on gels directly after polyacrylamide gel electrophoresis (PAGE). The diameter of these stable amine terminated Si QDs was in the range of 0.5-2.0 nm. In this study, the fluorescent imaging conditions, such as the buffer solution, pH value, buffer concentration and quantity of Si QDs, were optimized and the possible mechanisms of Si QDs protein interaction were analyzed. The mode of Si QDs and human serum albumin association was found to occur by hydrogen bond interactions; this was probably attributed to the interaction between the amino group of amine-terminated Si QDs and the carboxyl group of proteins. Meanwhile, human serum proteins separated by native 1D and native 2D electrophoresis were detected by Si QD-based fluorescent imaging. Some proteins, such as isoform 1 of alpha-1-antitrypsin, complement C3 (Fragment) and hemopexin, which were identified by mass spectrometry (MS), were easily detected by using Si QDs, but not with CBB-R250 staining. The Si QDs-based fluorescent imaging technique with high resolution is a sensitive and dependable method for direct detection of human serum proteins, and has enormous potential in clinical diagnosis. PMID- 22249968 TI - Impact of data fragmentation across healthcare centers on the accuracy of a high throughput clinical phenotyping algorithm for specifying subjects with type 2 diabetes mellitus. AB - OBJECTIVE: To evaluate data fragmentation across healthcare centers with regard to the accuracy of a high-throughput clinical phenotyping (HTCP) algorithm developed to differentiate (1) patients with type 2 diabetes mellitus (T2DM) and (2) patients with no diabetes. MATERIALS AND METHODS: This population-based study identified all Olmsted County, Minnesota residents in 2007. We used provider linked electronic medical record data from the two healthcare centers that provide >95% of all care to County residents (ie, Olmsted Medical Center and Mayo Clinic in Rochester, Minnesota, USA). Subjects were limited to residents with one or more encounter January 1, 2006 through December 31, 2007 at both healthcare centers. DM-relevant data on diagnoses, laboratory results, and medication from both centers were obtained during this period. The algorithm was first executed using data from both centers (ie, the gold standard) and then from Mayo Clinic alone. Positive predictive values and false-negative rates were calculated, and the McNemar test was used to compare categorization when data from the Mayo Clinic alone were used with the gold standard. Age and sex were compared between true-positive and false-negative subjects with T2DM. Statistical significance was accepted as p<0.05. RESULTS: With data from both medical centers, 765 subjects with T2DM (4256 non-DM subjects) were identified. When single-center data were used, 252 T2DM subjects (1573 non-DM subjects) were missed; an additional false positive 27 T2DM subjects (215 non-DM subjects) were identified. The positive predictive values and false-negative rates were 95.0% (513/540) and 32.9% (252/765), respectively, for T2DM subjects and 92.6% (2683/2898) and 37.0% (1573/4256), respectively, for non-DM subjects. Age and sex distribution differed between true-positive (mean age 62.1; 45% female) and false-negative (mean age 65.0; 56.0% female) T2DM subjects. CONCLUSION: The findings show that application of an HTCP algorithm using data from a single medical center contributes to misclassification. These findings should be considered carefully by researchers when developing and executing HTCP algorithms. PMID- 22249970 TI - No association between hormonal abnormality and sexual dysfunction in Japanese schizophrenia patients treated with antipsychotics. AB - OBJECTIVE: Although sexual dysfunction is believed to be caused by hormonal abnormalities, few reports have studied sexual dysfunction and its association with hormonal abnormalities in Asian populations with schizophrenia. METHODS: We employed a cross-sectional, case-control survey design to collect data from 191 (108 men) Japanese schizophrenia outpatients treated with antipsychotics and 182 (49 men) healthy subjects. Sexual dysfunction was evaluated using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. We measured plasma concentrations of prolactin in both genders and testosterone in men and estradiol in women. RESULTS: Multiple regression analyses revealed the following findings: the number of antipsychotics correlated with diminished sexual desire (standardized beta = 0.241, p < 0.05); the dose of antipsychotics correlated with gynecomastia (standardized beta = 0.277, p < 0.01), increased sexual desire (standardized beta = 0.229, p < 0.05), and ejaculatory dysfunction (standardized beta = 0.248, p < 0.05); and the dose of antipsychotics correlated with menorrhagia in women (standardized beta = 0.284, p < 0.05). However, neither plasma concentrations of prolactin, testosterone nor estradiol correlated with sexual dysfunction. CONCLUSIONS: The present study demonstrated that an association between sex hormone abnormalities and sexual dysfunction is unlikely but that the dose or number of antipsychotics is associated with some sexual dysfunction. PMID- 22249971 TI - Influence of flow rate and scaffold pore size on cell behavior during mechanical stimulation in a flow perfusion bioreactor. AB - Mechanically stimulating cell-seeded scaffolds by flow-perfusion is one approach utilized for developing clinically applicable bone graft substitutes. A key challenge is determining the magnitude of stimuli to apply that enhances cell differentiation but minimizes cell detachment from the scaffold. In this study, we employed a combined computational modeling and experimental approach to examine how the scaffold mean pore size influences cell attachment morphology and subsequently impacts upon cell deformation and detachment when subjected to fluid flow. Cell detachment from osteoblast-seeded collagen-GAG scaffolds was evaluated experimentally across a range of scaffold pore sizes subjected to different flow rates and exposure times in a perfusion bioreactor. Cell detachment was found to be proportional to flow rate and inversely proportional to pore size. Using this data, a theoretical model was derived that accurately predicted cell detachment as a function of mean shear stress, mean pore size, and time. Computational modeling of cell deformation in response to fluid flow showed the percentage of cells exceeding a critical threshold of deformation correlated with cell detachment experimentally and the majority of these cells were of a bridging morphology (cells stretched across pores). These findings will help researchers optimize the mean pore size of scaffolds and perfusion bioreactor operating conditions to manage cell detachment when mechanically simulating cells via flow perfusion. PMID- 22249973 TI - Oxidative Mizoroki-Heck-type reaction of arylsulfonyl hydrazides for a highly regio- and stereoselective synthesis of polysubstituted alkenes. PMID- 22249975 TI - Overexpression of RIN1 associates with tumor grade and progression in patients of bladder urothelial carcinoma. AB - Ras and Rab interactor 1 (RIN1) is an effector of H-Ras, which plays an important role in the development and progression of carcinomas, but it has not been reported in bladder cancer. Hence, the association of RIN1 expression with prognosis of bladder urothelial carcinoma (UC) was examined. RIN1 mRNA and protein expression in 20 paired UCs and the adjacent normal tissues was detected by quantitative reverse transcription polymerase chain reaction and Western blot. The expression of RIN1 protein in 96 specimens of UCs and 22 specimens of adjacent normal bladder tissues were analyzed by immunohistochemistry. The overall survival (OS) was assessed by univariate and multivariate analysis. Moreover, the progression-free survival (PFS) and recurrence-free survival (RFS), classified by the clinicopathologic features with RIN1 expression, were assessed by multivariate analysis. RIN1 mRNA and protein level was higher in UCs than in the adjacent normal tissues (P < 0.01). Enhanced RIN1 immunoexpression was associated with high histologic grades (P = 0.046), cancer progression (P = 0.047) as well as Ki-67 expression (P = 0.023). Furthermore, the 5-year survival rate was 29% in the subgroup with high level of RIN1 expression, while it was 43% in the subgroup with normal level of RIN1 expression (P < 0.05). Importantly, RIN1 level was revealed as the significant independent prognostic factor for death (P = 0.023) and progression (P = 0.003), but a weak contribution for recurrence (P = 0.063). Collectively, RIN1 expression could be a potential prognostic predictor for UC patients. PMID- 22249974 TI - Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE tag with a GGGC chelator for 99mTc-labelling at the C terminus. AB - Affibody molecules are a class of small (ca.7 kDa) robust scaffold proteins with high potential as tracers for radionuclide molecular imaging in vivo. Incorporation of a cysteine-containing peptide-based chelator at the C terminus provides an opportunity for stable labelling with the radionuclide (99m)Tc. The use of a GGGC chelator at the C terminus has provided the lowest renal radioactivity retention of the previously investigated peptide-based chelators. Previously, it has also been demonstrated that replacement of the His(6)-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine glutamate (HEHEHE)-tag permits purification of affibody molecules by immobilized metal ion affinity chromatography (IMAC) and provides low hepatic accumulation of radioactivity of conjugates site-specifically labelled at the C terminus using several different nuclides. We hypothesized that the combination of a HEHEHE-tag at the N terminus and a GGGC chelator at the C terminus of an affibody molecule would be a favourable format permitting IMAC purification and providing low uptake in excretory organs. To investigate this hypothesis, a (HE)(3)-Z(HER2:342) GGGC affibody molecule was generated. It could be efficiently purified by IMAC and stably labelled with (99m)Tc. (99m)Tc-(HE)(3)-Z(HER2:342)-GGGC preserved specific binding to HER2-expressing cells. In NMRI mice, hepatic uptake of (99m)Tc-(HE)(3)-Z(HER2:342)-GGGC was lower than the uptake of the control affibody molecules, (99m)Tc-Z(HER2:2395)-VDC and (99m)Tc-Z(HER2:342)-GGGC. At 1 and 4 h after injection, the renal uptake of (99m)Tc-(HE)(3)-Z(HER2:342)-GGGC was 2-3-fold lower than uptake of (99m)Tc-Z(HER2:2395)-VDC, but it was substantially higher than uptake of (99m)Tc-Z(HER2:342)-GGGC. Further investigation indicated that a fraction of (99m)Tc was chelated by the HEHEHE-tag which caused a higher accumulation of radioactivity in the kidneys. Thus, a combination of a HEHEHE-tag and the GGGC chelator in targeting scaffold proteins was found to be undesirable in the case of (99m)Tc labelling due to a partial loss of site-specificity of nuclide chelation. PMID- 22249976 TI - Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum based chemotherapy among advanced non-small cell lung cancer patients. AB - The excision repair cross-complementation group 1 (ERCC1) plays an essential role in DNA repair and has been linked to resistance to platinum-based anticancer drugs among advanced non-small cell lung cancer (NSCLC) patients. We systematically evaluate whether ERCC1 Asn118Asn and C8092A genetic variants are associated with treatment response of platinum chemotherapy. We preformed a meta analysis using ten eligible cohort studies (including 11 datasets) with a total of 1,252 NSCLC patients to summarize the existing data on the association between the ERCC1 Asn118Asn and C8092A polymorphisms and response to platinum regiments. Odds ratio or hazard ratio with 95% confidence interval were calculated to estimate the correlation. We found that neither ERCC1 C8092A polymorphism nor Asn118Asn variant is associated with different response of platinum-based treatment among advanced NSCLC patients. Additionally, these two genetic variants are not related to treatment response in either Caucasian patients or Asian patients. Our meta-analysis indicates that the ERCC1 Asn118Asn and C8092A polymorphisms may not be good prognostic biomarkers for platinum-based chemotherapy in patients with stage III-IV NSCLC. PMID- 22249977 TI - Impact of codon 72 Arg > Pro single nucleotide polymorphism in TP53 gene in the risk of kangri cancer: a case control study in Kashmir. AB - Kangri cancer found only in Kashmir (north India) is a unique thermally induced squamous cell carcinoma of the skin that develops because of chronic and persistent irritation due to the use of a kangri (a brazier) by the Kashmiri people to combat the chilling cold temperature during winter. Being unique to this region, the molecular etiology of the invasive kangri cancer is not known fully. The TP53 gene, codon 72 polymorphism (Arg72Pro), has been found to be associated with cancer susceptibility but has not been investigated in kangri cancer risk. A case control study was conducted to find the genotype distribution of TP53 Arg72Pro SNP and to elucidate the possible role of this SNP as risk factor in kangri cancer development. Using the polymerase chain reaction restriction fragment length polymorphism approach, we tested the genotype distribution of 106 kangri cancer patients in comparison with 200 cancer-free controls from the same geographical region. A significant difference was observed between the control and kangri cancer patients with odds ratio = 2.02 and 95% confidence interval = 1.2-3.3 (p = 0.01). Interestingly, the proline form was abundantly observed in advanced-grade tumors (p < 0.05). We also found a significant association of the variant allele (GC + CC) with male subjects and patients >45 years of age (p < 0.05). Thus, it is evident from our study that Arg72Pro SNP is implicated in kangri cancer and that the rare, proline-related allele is connected with higher susceptibility to kangri cancer. PMID- 22249978 TI - CYP2E1 PstI/RsaI polymorphism and interaction with alcohol consumption in hepatocellular carcinoma susceptibility: evidence from 1,661 cases and 2,317 controls. AB - Many studies have suggested that cytochrome P450 2E1 (CYP2E1) gene might be involved in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, the authors performed a meta analysis to clarify the association between Pst I/Rsa polymorphism in the CYP2E1 gene and HCC risk. PubMed and China National Knowledge Infrastructure were searched for eligible publications. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects model. Fifteen studies (1,661 HCC cases and 2,317 controls) were identified for the data analysis. The overall result showed that there was no statistically significant association between CYP2E1 Pst I/Rsa polymorphism and HCC risk (c2/c2 vs. c1/c1, OR = 0.73, 95% CI 0.50-1.06; c1/c2 vs. c1/c1, OR = 1.00, 95% CI 0.76-1.33; c2/c2+ c1/c2 vs. c1/c1, OR = 0.99, 95% CI 0.77-1.26; c2/c2 vs. c1/c2+ c1/c1, OR = 0.73, 95% CI 0.50-1.06). Further stratified analyses indicated that the habitual alcohol drinkers with c2 alleles were more likely to develop HCC (OR = 1.73, 95% CI 1.19-2.51), compared with the non-habitual drinkers with c1 homozygote. The meta-analysis indicated that CYP2E1 Pst I/Rsa polymorphism was not associated with HCC risk, while the interaction between Pst I/Rsa polymorphism and alcohol consumption increased the risk of HCC. PMID- 22249979 TI - The effect of cost on adherence to prescription medications in Canada. AB - BACKGROUND: Many patients do not adhere to treatment because they cannot afford their prescription medications, putting them at increased risk of adverse health outcomes. We determined the prevalence of cost-related nonadherence and investigated its associated characteristics, including whether a person has drug insurance. METHODS: Using data from the 2007 Canada Community Health Survey, we analyzed the responses of 5732 people who answered questions about cost-related nonadherence to treatment. We determined the national prevalence of cost-related nonadherence and used logistic regression to evaluate the association between cost-related nonadherence and a series of demographic and socioeconomic variables, including province of residence, age, sex, household income, health status and having drug insurance. RESULTS: Cost-related nonadherence was reported by 9.6% (95% confidence interval [CI] 8.5%-10.6%) of Canadians who had received a prescription in the past year. In our adjusted model, we found that people in poor health (odds ratio [OR] 2.64, 95% CI 1.77-3.94), those with lower income (OR 3.29, 95% CI 2.03-5.33), those without drug insurance (OR 4.52, 95% CI 3.29-6.20) and those who live in British Columbia (OR 2.56, 95% CI 1.49-4.42) were more likely to report cost-related nonadherence. Predicted rates of cost-related nonadherence ranged from 3.6% (95% CI 2.4-4.5) among people with insurance and high household incomes to 35.6% (95% CI 26.1%-44.9%) among people with no insurance and low household incomes. INTERPRETATION: About 1 in 10 Canadians who receive a prescription report cost-related nonadherence. The variability in insurance coverage for prescription medications appears to be a key reason behind this phenomenon. PMID- 22249980 TI - Tracking opioid use vital to avoiding scourge. PMID- 22249981 TI - Pfizer advertises smoking cessation drug despite health warnings. PMID- 22249982 TI - Five things to know about...Esotropia. PMID- 22249983 TI - A pituitary mass as consequence of a decimal error in levothyroxine dose. PMID- 22249984 TI - Sex selection migrates to Canada. PMID- 22249985 TI - "It's a girl!"--could be a death sentence. PMID- 22249987 TI - Canada's new ethical guidelines for research with humans: a critique and comparison with the United States. PMID- 22249988 TI - Swallowing the pharmaceutical waters. PMID- 22249989 TI - Teaming up to make meaningful use of electronic health records. PMID- 22249990 TI - Impact of PubMed search filters on the retrieval of evidence by physicians. AB - BACKGROUND: Physicians face challenges when searching PubMed for research evidence, and they may miss relevant articles while retrieving too many nonrelevant articles. We investigated whether the use of search filters in PubMed improves searching by physicians. METHODS: We asked a random sample of Canadian nephrologists to answer unique clinical questions derived from 100 systematic reviews of renal therapy. Physicians provided the search terms that they would type into PubMed to locate articles to answer these questions. We entered the physician-provided search terms into PubMed and applied two types of search filters alone or in combination: a methods-based filter designed to identify high quality studies about treatment (clinical queries "therapy") and a topic-based filter designed to identify studies with renal content. We evaluated the comprehensiveness (proportion of relevant articles found) and efficiency (ratio of relevant to nonrelevant articles) of the filtered and nonfiltered searches. Primary studies included in the systematic reviews served as the reference standard for relevant articles. RESULTS: The average physician-provided search terms retrieved 46% of the relevant articles, while 6% of the retrieved articles were relevant (corrected) (the ratio of relevant to nonrelevant articles was 1:16). The use of both filters together produced a marked improvement in efficiency, resulting in a ratio of relevant to nonrelevant articles of 1:5 (16 percentage point improvement; 99% confidence interval 9% to 22%; p < 0.003) with no substantive change in comprehensiveness (44% of relevant articles found; p = 0.55). INTERPRETATION: The use of PubMed search filters improves the efficiency of physician searches. Improved search performance may enhance the transfer of research into practice and improve patient care. PMID- 22249991 TI - Cervical cancer among Aboriginal women in Canada. PMID- 22249992 TI - Antimicrobial activity of peptides derived from human beta-amyloid precursor protein. AB - Antimicrobial peptides are important effector molecules of the innate immune system. Here, we describe that peptides derived from the heparin-binding disulfide-constrained loop region of human beta-amyloid precursor protein are antimicrobial. The peptides investigated were linear and cyclic forms of NWCKRGRKQCKTHPH (NWC15) as well as the cyclic form comprising the C-terminal hydrophobic amino acid extension FVIPY (NWCKRGRKQCKTHPHFVIPY; NWC20c). Compared with the benchmark antimicrobial peptide LL-37, these peptides efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram positive Staphylococcus aureus and Bacillus subtilis, and the fungi Candida albicans and Candida parapsilosis. Correspondingly, fluorescence and electron microscopy demonstrated that the peptides caused defects in bacterial membranes. Analogously, the peptides permeabilised negatively charged liposomes. Despite their bactericidal effect, the peptides displayed very limited hemolytic activities within the concentration range investigated and exerted very small membrane permeabilising effects on human epithelial cells. The efficiency of the peptides with respect to bacterial killing and liposome membrane leakage was in the order NWC20c > NWC15c > NWC15l, which also correlated to the adsorption density for these peptides at the model lipid membrane. Thus, whereas the cationic sequence is a minimum determinant for antimicrobial action, a constrained loop-structure as well as a hydrophobic extension further contributes to membrane permeabilising activity of this region of amyloid precursor protein. PMID- 22249993 TI - Catalytic four-electron oxidation of water by intramolecular coupling of the oxo ligands of a bis(ruthenium-bipyridine) complex. AB - A bis(ruthenium-bipyridine) complex bridged by 1,8-bis(2,2':6',2''-terpyrid-4' yl)anthracene (btpyan), [Ru(2)(MU-Cl)(bpy)(2)(btpyan)](BF(4))(3) ([1](BF(4))(3); bpy = 2,2'-bipyridine), was prepared. The cyclic voltammogram of [1](BF(4))(3) in water at pH 1.0 displayed two reversible [Ru(II),Ru(II)](3+)/[Ru(II),Ru(III)](4+) and [Ru(II),Ru(III)](4+)/[Ru(III),Ru(III)](5+) redox couples at E(1/2)(1) = +0.61 and E(1/2)(2) = +0.80 V (vs. Ag/AgCl), respectively, and an irreversible anodic peak at around E = +1.2 V followed by a strong anodic currents as a result of the oxidation of water. The controlled potential electrolysis of [1](3+) ions at E = +1.60 V in water at pH 2.6 (buffered with H(3)PO(4)/NaH(2)PO(4)) catalytically evolved dioxygen. Immediately after the electrolysis of the [1](3+) ion in H(2)(16)O at E = +1.40 V, the resultant solution displayed two resonance Raman bands at nu = 442 and 824 cm(-1). These bands shifted to nu = 426 and 780 cm(-1), respectively, when the same electrolysis was conducted in H(2)(18)O. The chemical oxidation of the [1](3+) ion by using a Ce(IV) species in H(2)(16)O and H(2)(18)O also exhibited the same resonance Raman spectra. The observed isotope frequency shifts (Deltanu = 16 and 44 cm(-1)) fully fit the calculated ones based on the Ru O and O-O stretching modes, respectively. The first successful identification of the metal-O-O-metal stretching band in the oxidation of water indicates that the oxygen-oxygen bond at the stage prior to the evolution of O(2) is formed through the intramolecular coupling of two Ru-oxo groups derived from the [1](3+) ion. PMID- 22249994 TI - Re: "Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study". PMID- 22249995 TI - Silicon ameliorates manganese toxicity in cucumber by decreasing hydroxyl radical accumulation in the leaf apoplast. AB - This work was focused on the role of silicon (Si) in amelioration of manganese (Mn) toxicity caused by elevated production of hydroxyl radicals (.OH) in the leaf apoplast of cucumber (Cucumis sativus L.). The plants were grown in nutrient solutions with adequate (0.5 MUM) or excessive (100 MUM) Mn concentrations with or without Si being supplied. The symptoms of Mn toxicity were absent in the leaves of Si-treated plants subjected to excess Mn, although the leaf Mn concentration remained extremely high. The apoplastic concentration of free Mn(2+) and H(2)O(2) of high Mn-treated plants was significantly decreased by Si treatment. Si supply suppressed the Mn-induced increased abundance of peroxidase (POD) isoforms in the leaf apoplastic fluid, and led to a rapid suppression of guaiacol-POD activity under excess Mn. The spin-trapping reagent 5 (diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide was used to detect .OH by electron paramagnetic resonance spectroscopy. Although supplying Si markedly decreased the accumulation of .OH in the leaf apoplast with excess Mn, adding monosilicic acid to the Mn(2+)/H(2)O(2) reaction mixture did not directly affect the Fenton reaction in vitro. The results indicate that Si contributes indirectly to a decrease in .OH in the leaf apoplast by decreasing the free apoplastic Mn(2+), thus regulating the Fenton reaction. A direct inhibitory effect of Si on guaiacol-POD activity (demonstrated in vitro) may also contribute to decreasing the POD-mediated generation of .OH. PMID- 22249996 TI - Feedback inhibition of the general phenylpropanoid and flavonol biosynthetic pathways upon a compromised flavonol-3-O-glycosylation. AB - Flavonols, phenylalanine-derived secondary metabolites, have protective and regulatory functions in plants. In Arabidopsis thaliana, they are consecutively glycosylated at their 3-OH and 7-OH groups. UGT78D1 and UGT78D2 are the major flavonol 3-O-glycosyltransferases in Arabidopsis leaves. The ugt78d1 ugt78d2 double mutant, which was strongly compromised in the initial 3-O-glycosylation, showed a severe and specific repression of flavonol biosynthesis, retaining only one-third of the wild-type level. This metabolic phenotype was associated with a repressed transcription of several flavonol biosynthetic genes including the committed step chalcone synthase [(CHS) or TRANSPARENT TESTA 4 (TT4)]. Furthermore, the committed step of the upstream, general phenylpropanoid pathway, phenylalanine ammonia-lyase (PAL), was down-regulated in its enzyme activity and in the transcription of the flavonol-related PAL1 and PAL2. However, a complete blocking of flavonoid biosynthesis at CHS released PAL inhibition in a tt4 ugt78d1 ugt78d2 line. PAL activity was even enhanced in the flavonol synthase 1 mutant, which compromises the final formation of flavonol aglycones. The dependence of the PAL feedback inhibition on flavonols was confirmed by chemical complementation of tt4 ugt78d1 ugt78d2 using naringenin, a downstream flavonoid intermediate, which restored the PAL repression. Although aglycones were not analytically detectable, this study provides genetic evidence for a novel, flavonol-dependent feedback inhibition of the flavonol biosynthetic pathway and PAL. It was conditioned by the compromised flavonol-3-O-conjugation and a decrease in flavonol content, yet dependent on a residual, flavonol synthase 1 (FLS1)-related capacity to form flavonol aglycones. Thus, this regulation would not react to a reduced metabolic flux into flavonol biosynthesis, but it might prevent the accumulation of non-glycosylated, toxic flavonols. PMID- 22249997 TI - Ecosystem focused therapy in poststroke depression: a preliminary study. AB - OBJECTIVE: Poststroke depression (PSD) occurs in the context of abrupt, often catastrophic disability that finds the patient and his or her family unprepared. We developed the ecosystem focused therapy (EFT), a systematic intervention aimed to increase the PSD patient's and his or her ecosystem's abilities to address the "psychosocial storm" of PSD and utilize available treatments effectively and efficiently. This is a preliminary study of its efficacy. DESIGN: A total of 24 PSD patients were randomly assigned to receive weekly sessions of EFT or a comparison condition consisting of systematic Education on Stroke and Depression and their treatment for 12 weeks. RESULTS: Ecosystem Focused Therapy may be more efficacious than Education on Stroke and Depression in reducing depressive symptoms and signs, in leading to a higher remission rate, and in ameliorating disability in PSD. Reduction of disability in the early part of the trial mediated later improvement in depressive symptomatology. Similarly, reduction in depressive symptoms and signs early on mediated later improvement in disability. CONCLUSION: These encouraging findings require replication. Beyond its potential direct benefits in PSD, EFT may provide an appropriate context for efficient and timely administration of pharmacotherapy and of physical, speech, and occupational therapy thus maximizing their efficacy. PMID- 22249998 TI - Isolation and comparison of tribe-specific centromeric repeats within Bovidae. AB - A taxonomic division of the family Bovidae (Artiodactyla) is difficult and the evolutionary relationships among most bovid subfamilies remain uncertain. In this study, we isolated the cattle satellite I clone BTREP15 (1.715 satellite DNA family) and autosomal centromeric DNAs of members of ten bovid tribes. We wished to determine whether the analysis of fluorescence in situ hybridization patterns of the cattle satellite I clone (BTREP15) and tribe-specific centromeric repeats isolated by laser microdissection would help to reveal some of the ambiguities occurring in the systematic classification of the family Bovidae. The FISH study of the presence and distribution of the cattle satellite I clone BTREP15 (1.715 satellite DNA family) within members of ten bovid tribes was not informative. FISH analysis of autosomal centromeric DNA probes in several species within one tribe revealed similar hybridization patterns in autosomes confirming tribal homogeneity of these probes. Sex chromosomes showed considerable variation in sequence composition and arrangement not only between tribes but also between species of one tribe. According to our findings it seems that Oreotragus oreotragus developed its own specific satellite DNA which does not hybridize to any other bovid species analysed. Our results suggest O. oreotragus as well as Aepyceros melampus may be unique species not particularly closely related to any of the recognized bovid tribes. This study indicates the isolation of tribe specific centromeric DNAs by laser microdissection and cloning the sequence representing the main motif of these repetitive DNAs could offer the perspectives for comparative phylogenetic studies. PMID- 22249999 TI - Closed system isolation and scalable expansion of human placental mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) are emerging as a leading cellular therapy for a number of diseases. However, for such treatments to become available as a routine therapeutic option, efficient and cost-effective means for industrial manufacture of MSC are required. At present, clinical grade MSC are manufactured through a process of manual cell culture in specialized cGMP facilities. This process is open, extremely labor intensive, costly, and impractical for anything more than a small number of patients. While it has been shown that MSC can be cultivated in stirred bioreactor systems using microcarriers, providing a route to process scale-up, the degree of numerical expansion achieved has generally been limited. Furthermore, little attention has been given to the issue of primary cell isolation from complex tissues such as placenta. In this article we describe the initial development of a closed process for bulk isolation of MSC from human placenta, and subsequent cultivation on microcarriers in scalable single-use bioreactor systems. Based on our initial data, we estimate that a single placenta may be sufficient to produce over 7,000 doses of therapeutic MSC using a large scale process. PMID- 22250002 TI - Electrophilic arene hydroxylation and phenol O-H oxidations performed by an unsymmetric MU-eta(1):eta(1)-O2-peroxo dicopper(II) complex. AB - Reactions of the unsymmetric dicopper(II) peroxide complex [Cu(II)(2)(MU eta(1):eta(1)-O(2))(m-XYL(N3N4))](2+) (1 O(2), where m-XYL is a heptadentate N based ligand), with phenolates and phenols are described. Complex 1 O(2) reacts with p-X-PhONa (X = MeO, Cl, H, or Me) at -90 degrees C performing tyrosinase like ortho-hydroxylation of the aromatic ring to afford the corresponding catechol products. Mechanistic studies demonstrate that reactions occur through initial reversible formation of metastable association complexes [Cu(II)(2)(MU eta(1):eta(1)-O(2))(p-X-PhO)(m-XYL(N3N4))](+) (1 O(2)?X-PhO) that then undergo ortho-hydroxylation of the aromatic ring by the peroxide moiety. Complex 1 O(2) also reacts with 4-X-substituted phenols p-X-PhOH (X = MeO, Me, F, H, or Cl) and with 2,4-di-tert-butylphenol at -90 degrees C causing rapid decay of 1 O(2) and affording biphenol coupling products, which is indicative that reactions occur through formation of phenoxyl radicals that then undergo radical C-C coupling. Spectroscopic UV/Vis monitoring and kinetic analysis show that reactions take place through reversible formation of ground-state association complexes [Cu(II)(2)(MU-eta(1):eta(1)-O(2))(X-PhOH)(m-XYL(N3N4))](2+) (1 O(2)?X-PhOH) that then evolve through an irreversible rate-determining step. Mechanistic studies indicate that 1 O(2) reacts with phenols through initial phenol binding to the Cu(2)O(2) core, followed by a proton-coupled electron transfer (PCET) at the rate determining step. Results disclosed in this work provide experimental evidence that the unsymmetric 1 O(2) complex can mediate electrophilic arene hydroxylation and PCET reactions commonly associated with electrophilic Cu(2)O(2) cores, and strongly suggest that the ability to form substrate?Cu(2)O(2) association complexes may provide paths to overcome the inherent reactivity of the O(2) binding mode. This work provides experimental evidence that the presence of a H(+) completely determines the fate of the association complex [Cu(II)(2)(MU eta(1):eta(1)-O(2))(X-PhO(H))(m-XYL(N3N4))](n+) between a PCET and an arene hydroxylation reaction, and may provide clues to help understand enzymatic reactions at dicopper sites. PMID- 22250000 TI - The importance of peripheral sequences in determining the metal selectivity of an in vitro-selected Co(2+) -dependent DNAzyme. AB - DNAzymes are catalytically active DNA molecules that use metal cofactors for their enzymatic functions. While a growing number of DNAzymes with diverse functions and metal selectivities have been reported, the relationships between metal ion selectivity, conserved sequences and structures responsible for selectivity remain to be elucidated. To address this issue, we report biochemical assays of a family of previously reported in vitro selected DNAzymes. This family includes the clone 11 DNAzyme, which was isolated by positive and negative selection, and the clone 18 DNAzyme, which was isolated by positive selection alone. The clone 11 DNAzyme has a higher selectivity for Co(2+) over Pb(2+) compared with clone 18. The reasons for this difference are explored here through phylogenetic comparison, mutational analysis and stepwise truncation. A novel DNAzyme truncation method incorporated a nick in the middle of the DNAzyme to allow for truncation close to the nicked site while preserving peripheral sequences at both ends of the DNAzyme. The results demonstrate that peripheral sequences within the substrate binding arms, most notably the stem loop, loop II, are sufficient to restore its selectivity for Co(2+) over Pb(2+) to levels observed in clone 11. A comparison of these sequences' secondary structures and Co(2+) selectivities suggested that metastable structures affect metal ion selectivity. The Co(2+) selectivity of the clone 11 DNAzyme showed that the metal ion binding and selectivities of small, in vitro selected DNAzymes may be more complex than previously appreciated, and that clone 11 may be more similar to larger ribozymes than to other small DNAzymes in its structural complexity and behavior. These factors should be taken into account when metal-ion selectivity is required in rationally designed DNAzymes and DNAzyme-based biosensors. PMID- 22250003 TI - The Biofuel Feedstock Genomics Resource: a web-based portal and database to enable functional genomics of plant biofuel feedstock species. AB - Major feedstock sources for future biofuel production are likely to be high biomass producing plant species such as poplar, pine, switchgrass, sorghum and maize. One active area of research in these species is genome-enabled improvement of lignocellulosic biofuel feedstock quality and yield. To facilitate genomic based investigations in these species, we developed the Biofuel Feedstock Genomic Resource (BFGR), a database and web-portal that provides high-quality, uniform and integrated functional annotation of gene and transcript assembly sequences from species of interest to lignocellulosic biofuel feedstock researchers. The BFGR includes sequence data from 54 species and permits researchers to view, analyze and obtain annotation at the gene, transcript, protein and genome level. Annotation of biochemical pathways permits the identification of key genes and transcripts central to the improvement of lignocellulosic properties in these species. The integrated nature of the BFGR in terms of annotation methods, orthologous/paralogous relationships and linkage to seven species with complete genome sequences allows comparative analyses for biofuel feedstock species with limited sequence resources. Database URL: http://bfgr.plantbiology.msu.edu. PMID- 22250004 TI - Investigating the stability of neuropsychiatric sub-syndromes with progression of dementia: a 2-year prospective study. AB - OBJECTIVES: Previous studies have identified sub-syndromes of behavioral and psychological symptoms of dementia. But because of their cross-sectional design, the stability of these sub-syndromes over time remains unknown. METHOD: Behavioral and psychological symptoms of dementia of 84 participants (out of an original sample of 144 patients) with Alzheimer's disease and vascular dementia were assessed by using the Neuropsychiatric Inventory every six months for two years. Principal component factor analysis with Varimax rotation was used to detect neuropsychiatric sub-syndromes at each time point. RESULTS: The 12 symptoms were reduced to four factors at baseline, 12, 18, and 24 months and three factors at six months. None of the factor structures matched the four sub syndromes previously identified by studies. The most stable group of symptoms were a combination of "psychosis" and "hyperactivity" symptoms (delusions, hallucinations, irritability, agitation), which became stable at 18 months. CONCLUSIONS: The pattern of behavioral and psychological symptoms of dementia sub syndromes over time has not been studied before, and this research suggests that some stability is evident particularly during the later stages of the disease process. These findings have implications for patients and their caregiver. PMID- 22250005 TI - Using zebrafish to unravel the genetics of complex brain disorders. AB - The zebrafish has been prominently utilized in developmental biology for the past three decades and numerous genetic tools have been developed for it. Due to the accumulated genetic knowledge the zebrafish has now been considered an excellent research tool in other disciplines of biology too, including behavioral neuroscience and behavior genetics. Given the complexity of the vertebrate brain in general and the large number of human brain disorders whose mechanisms remain mainly unmapped in particular, there is a substantial need for appropriate laboratory research organisms that may be utilized to model such diseases and facilitate the analysis of their mechanisms. The zebrafish may have a bright future in this research field. It offers a compromise between system complexity (it is a vertebrate similar in many ways to our own species) and practical simplicity (it is small, easy to keep, and it is prolific). These features have made zebrafish an excellent choice, for example, for large scale mutation and drug screening. Such approaches may have a chance to tackle the potentially large number of molecular targets and mechanisms involved in complex brain disorders. However, although promising, the zebrafish is admittedly a novel research tool and only few empirical examples exist to support this claim. In this chapter, first I briefly review some of the rapidly evolving genetic methods available for zebrafish. Second, I discuss some promising examples for how zebrafish have been used to model and analyze molecular mechanisms of complex brain disorders. Last, I present some recently developed zebrafish behavioral paradigms that may have relevance for a spectrum of complex human brain disorders including those associated with abnormalities of learning and memory, fear and anxiety, and social behavior. Although at this point co-application of the genetics and behavioral approaches is rare with zebrafish, I argue that the rapid accumulation of knowledge in both of these disciplines will make zebrafish a prominent research tool for the genetic analysis of complex brain disorders. PMID- 22250006 TI - Solute-induced microstructural transition from weak aggregates towards a curved film of surface-active extractants. PMID- 22250007 TI - Assemblies of mesoporous FAU-type zeolite nanosheets. PMID- 22250008 TI - Polymer-supported enantioselective bifunctional catalysts for nitro-Michael addition of ketones and aldehydes. AB - Introduction of an L-amino acid as a spacer and a urea-forming moiety in a polymer-supported bifunctional urea-primary amine catalyst, based on (1R, 2R)-(+) 1,2-diphenylethylenediamine, significantly improves the catalyst's activity and stereoselectivity in the asymmetric addition of ketones and aldehydes to nitroolefins. Yields and enantioselectivities, unprecedented for immobilized catalysts, were obtained with such challenging donors as acetone, cyclopentanone, and alpha,alpha-disubstituted aldehydes, which usually perform inadequately in this reaction (particularly when a secondary-amine-based catalyst is used). Remarkably, though in the examined catalysts the D-amino acids as spacers were significantly inferior to the L isomers, for the chosen configuration of the diamine (match-mismatch pairs) the size of the side chain of the amino acid hardly influenced the enantioselectivity of the catalyst. These results, combined with the reactivity profile of the catalysts with substrates bearing two electron withdrawing groups and the behavior of the catalysts' analogues based on tertiary (rather than primary) amine, suggest an enamine-involving addition mechanism and a particular ordered C-C bond-forming transition state as being responsible for the catalytic reactions with high enantioselectivity. PMID- 22250009 TI - The effect of surface charge property on Escherichia coli initial adhesion and subsequent biofilm formation. AB - Polyethylene (PE) sheets were modified by radiation-induced graft polymerization (RIGP) of an epoxy-group containing monomer glycidyl methacrylate (GMA). The epoxy group of GMA was opened by introducing sodium sulfite (SS) and diethylamine (DEA) as representatives of negatively and positively charged functional groups, respectively. These modified surfaces by RIGP, termed GMA, SS, and DEA sheets, were investigated to elucidate their effects on initial adhesion and subsequent biofilm formation of Escherichia coli. Initial adhesion test revealed that E. coli density and viability were governed by sheet surface electrostatic property: E. coli cell density on the DEA sheet was 23 times higher than that on the SS sheet after 8 h incubation. The viability of E. coli cells dramatically decreased after contact with the DEA sheet, but remained high on the SS sheet. E. coli biofilm structure on the DEA sheet was dense, homogeneous, and uniform, with biomass higher than that of the GMA and SS sheets by factors of 14.0 and 37.5, respectively. On the contrary, biofilm structure on the SS sheet was sparse, heterogeneous, and mushroom-shaped. More than 40% of E. coli biofilm on the DEA sheet was retained under a high liquid shear force condition (5,000 s(-1)), whereas 97% and 100% of biofilms on the GMA and SS sheets were sloughed, indicating that E. coli biofilm robustness depends on surface charge property of the substratum. This suggests that substratum surface fabrication by RIGP may enhance or suppress biofilm formation, a finding with potentially important practical implications. PMID- 22250010 TI - ACR Appropriateness Criteria(r) ipsilateral radiation for squamous cell carcinoma of the tonsil. AB - BACKGROUND: Controversy exists as to the criteria for selecting patients with carcinoma of the tonsil for treatment with ipsilateral radiotherapy (RT). METHODS: The American College of Radiology (ACR) Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of treatment procedures by the panel. In those instances where evidence is not definitive, expert opinion may be used to recommend treatment. RESULTS: The ACR Expert Panel on Radiation Oncology Head and Neck Cancer developed consensus recommendations for selecting patients with tonsillar carcinoma for ipsilateral RT. CONCLUSION: Patients that are appropriate for ipsilateral RT have less than 1 cm of tumor invasion into the soft palate or base of tongue, and nodal stage of N0 to 1. PMID- 22250011 TI - Glucose hypometabolism in primary visual cortex is commonly associated with clinical features of dementia with Lewy bodies regardless of cognitive conditions. AB - BACKGROUND: Although metabolic reduction in the primary visual cortex on [(18) F] fluoro-d-glucose (FDG) positron emission tomographic (PET) scans is the hallmark of dementia with Lewy bodies (DLB) for differential diagnosis from Alzheimer's disease, the clinical significance of the metabolic pattern in patients without dementia remains unknown. The purpose of this study was to investigate the clinical profiles of patients without dementia with the metabolic pattern and its relevance to DLB. METHODS: Of 145 individuals who underwent (18) F-FDG PET, 25 patients with glucose hypometabolism in the primary visual cortex were identified based on three-dimensional stereotactic surface projection images through comparison with a normative database. The frequency of core and suggestive clinical features of DLB was compared between the groups with and without the metabolic pattern. RESULTS: Of 25 patients with glucose hypometabolism in the primary visual cortex, 12 exhibited more than two core features of DLB (probable DLB group) and 6 had rapid eye movement sleep behavior disorder (possible DLB group). Three patients exhibited memory loss without any core or suggestive features but with reduced cardiac iodine-123 metaiodobenzylguanidine uptake. Ten of these 21 patients exhibited no dementia. The proportion of individuals in the probable and possible DLB groups was significantly higher in the group with glucose hypometabolism in the primary visual cortex. CONCLUSION: Glucose hypometabolism in the primary visual cortex is commonly associated with the clinical features of DLB regardless of cognitive conditions. Continued follow-up of these patients without dementia with the metabolic pattern is warranted to determine if they represent the prodromal state of DLB. PMID- 22250012 TI - Characterization of KCNQ1 atrial fibrillation mutations reveals distinct dependence on KCNE1. AB - The I(Ks) potassium channel, critical to control of heart electrical activity, requires assembly of alpha (KCNQ1) and beta (KCNE1) subunits. Inherited mutations in either I(Ks) channel subunit are associated with cardiac arrhythmia syndromes. Two mutations (S140G and V141M) that cause familial atrial fibrillation (AF) are located on adjacent residues in the first membrane-spanning domain of KCNQ1, S1. These mutations impair the deactivation process, causing channels to appear constitutively open. Previous studies suggest that both mutant phenotypes require the presence of KCNE1. Here we found that despite the proximity of these two mutations in the primary protein structure, they display different functional dependence in the presence of KCNE1. In the absence of KCNE1, the S140G mutation, but not V141M, confers a pronounced slowing of channel deactivation and a hyperpolarizing shift in voltage-dependent activation. When coexpressed with KCNE1, both mutants deactivate significantly slower than wild-type KCNQ1/KCNE1 channels. The differential dependence on KCNE1 can be correlated with the physical proximity between these positions and KCNE1 as shown by disulfide cross linking studies: V141C forms disulfide bonds with cysteine-substituted KCNE1 residues, whereas S140C does not. These results further our understanding of the structural relationship between KCNE1 and KCNQ1 subunits in the I(Ks) channel, and provide mechanisms for understanding the effects on channel deactivation underlying these two atrial fibrillation mutations. PMID- 22250014 TI - Cost of dementia in Switzerland. AB - QUESTIONS UNDER STUDY: The aim of this study was (a) to estimate the cost of dementia in Switzerland, (b) to compare the average annual cost for people with dementia who live at home and those living in an institution and (c) to analyse how the average cost per person with dementia who lives at home increases with the severity of dementia. METHODS: This prevalence-based cost-of-illness study from a societal perspective combined top-down and bottom-up approaches and included both direct and indirect costs of dementia. Cost estimations were based on Swiss national statistics and surveys, as well as international reviews and expert interviews. RESULTS: The total annual cost of dementia amounted up to CHF 6.3 billion for the year 2007. Together, institutional and informal care accounted for over 90% of the cost. The average annual cost was estimated at CHF 55'300 per person with dementia who lives at home and at CHF 68'900 per person who lives in an institution. The cost per person living at home with severe dementia was nearly five times the cost per person with mild dementia. CONCLUSIONS: The present study indicates that dementia imposes a considerable economic burden on Swiss society. The cost of dementia is dominated by the costs of care. Diagnosis and treatment related costs are minor. These findings are consistent with contemporary international studies on the subject. The contribution of informal caregivers is substantial since they account for 44% of the total cost of dementia (based on market cost valuation). Given demographic developments in Switzerland, healthcare decision making should have an interest in securing this potential for the future. PMID- 22250015 TI - Beyond exchangeability: the other conditions for causal inference in medical research. PMID- 22250016 TI - Thiolate-induced metal adatom trapping at solid-liquid interfaces. PMID- 22250013 TI - Functional significance of the taper of vertebrate cone photoreceptors. AB - Vertebrate photoreceptors are commonly distinguished based on the shape of their outer segments: those of cones taper, whereas the ones from rods do not. The functional advantages of cone taper, a common occurrence in vertebrate retinas, remain elusive. In this study, we investigate this topic using theoretical analyses aimed at revealing structure-function relationships in photoreceptors. Geometrical optics combined with spectrophotometric and morphological data are used to support the analyses and to test predictions. Three functions are considered for correlations between taper and functionality. The first function proposes that outer segment taper serves to compensate for self-screening of the visual pigment contained within. The second function links outer segment taper to compensation for a signal-to-noise ratio decline along the longitudinal dimension. Both functions are supported by the data: real cones taper more than required for these compensatory roles. The third function relates outer segment taper to the optical properties of the inner compartment whereby the primary determinant is the inner segment's ability to concentrate light via its ellipsoid. In support of this idea, the rod/cone ratios of primarily diurnal animals are predicted based on a principle of equal light flux gathering between photoreceptors. In addition, ellipsoid concentration factor, a measure of ellipsoid ability to concentrate light onto the outer segment, correlates positively with outer segment taper expressed as a ratio of characteristic lengths, where critical taper is the yardstick. Depending on a light-funneling property and the presence of focusing organelles such as oil droplets, cone outer segments can be reduced in size to various degrees. We conclude that outer segment taper is but one component of a miniaturization process that reduces metabolic costs while improving signal detection. Compromise solutions in the various retinas and retinal regions occur between ellipsoid size and acuity, on the one hand, and faster response time and reduced light sensitivity, on the other. PMID- 22250017 TI - From cryptic chromosomal lesions to pathologically relevant genes: integration of SNP-array with gene expression profiling in myelodysplastic syndrome with normal karyotype. AB - Myelodysplastic syndrome (MDS), a clonal disorder originating from hematopoietic stem cell, is characterized by a progressive character often leading to transformation to acute myeloid leukemia. We used single nucleotide polymorphism arrays (SNP-A) to identify previously cryptic chromosomal abnormalities such as copy number alterations and uniparental disomies (UPD) in cytogenetically normal MDS. In the aberrant regions, we attempted to localize candidate genes with potential relevance to the disease. Using SNP-A, we analyzed peripheral blood granulocytes from 37 MDS patients. The analysis identified 13 cryptic chromosomal defects in 10 patients (27%). Four UPD (affecting chromosomes 3q, 7q, 17q, and 20p), 5 deletions and 4 duplications were detected. Gene expression data measured on CD34+ cells were available for 4 patients with and 6 patients without SNP-A lesions. We performed an integrative analysis of genotyping and gene expression microarrays and found several genes with an altered expression located in the aberrant regions. The expression microarrays suggested BMP2 and TRIB3 located in 20p UPD as potential candidate genes contributing to MDS. We showed that the genome-wide integrative approach is beneficial to the comprehension of molecular backgrounds of diseases with incompletely understood etiopathology. PMID- 22250019 TI - Citizens' values regarding research with stored samples from newborn screening in Canada. AB - OBJECTIVES: Newborn screening (NBS) programs may store bloodspot samples and use them for secondary purposes. Recent public controversies and lawsuits over storage and secondary uses underscore the need to engage the public on these issues. We explored Canadian values regarding storage and use of NBS samples for various purposes and the forms of parental choice for anonymous research with NBS samples. METHODS: We conducted a mixed-methods, public engagement study comprising 8 focus groups (n = 60), an educational component, deliberative discussion, and pre- and post-questionnaires assessing knowledge and values toward storage and parental choice. RESULTS: Canadian citizens supported the storage of NBS samples for quality control, confirmatory diagnosis, and future anonymous research (>90%). There was broad support for use of NBS samples for anonymous research; however, opinions were split about the extent of parental decision-making. Support for a "routinized" approach rested on trust in authorities, lack of concern for harms, and an assertion that the population's interest took priority over the interests of individuals. Discomfort stemmed from distrust in authorities, concern for harms, and prioritizing individual interests, which supported more substantive parental choice. Consensus emerged regarding the need for greater transparency about the storage and secondary use of samples. CONCLUSIONS: Our study provides novel insights into the values that underpin citizens' acceptance and discomfort with routine storage of NBS samples for research, and supports the need to develop well-designed methods of public education and civic discourse on the risks and benefits of the retention and secondary use of NBS samples. PMID- 22250018 TI - Public attitudes regarding the use of residual newborn screening specimens for research. AB - BACKGROUND AND OBJECTIVES: Many state newborn screening (NBS) programs retain residual NBS bloodspots after the completion of screening. Potential uses for residual specimens include laboratory quality assurance, biomedical research, and, rarely, forensic applications. Our objective was to evaluate public opinion about the policies and practices relevant to the retention and use of residual bloodspots for biomedical research. METHODS: A total of 3855 respondents were recruited using 3 methods: focus groups (n = 157), paper or telephone surveys (n = 1418), and a Knowledge Networks panel (n = 2280). Some participants (n = 1769) viewed a 22-minute movie about the retention and use of residual specimens while other participants were provided only written information about this practice. All participants were surveyed using a 38-item questionnaire. RESULTS: A diverse set of participants was recruited. Respondents were very supportive of NBS in general and accepting of the use of residual bloodspots for important research activities. Respondents were evenly divided on the acceptability of NBS without parental permission, but the majority of respondents supported the use of an "opt in" process for parental permission for residual bloodspot retention and use. Viewing the educational movie was associated with greater support for bloodspot retention and use. CONCLUSIONS: Our results show that the general public surveyed here was supportive of NBS and residual sample retention and research use. However, there was a clear preference for an informed permission process for parents regarding these activities. Education about NBS was associated with a higher level of support and may be important to maintain public trust in these important programs. PMID- 22250020 TI - Newborn dried blood spot screening: residual specimen storage issues. PMID- 22250021 TI - Lead poisoning in United States-bound refugee children: Thailand-Burma border, 2009. AB - BACKGROUND: Elevated blood lead levels lead to permanent neurocognitive sequelae in children. Resettled refugee children in the United States are considered at high risk for elevated blood lead levels, but the prevalence of and risk factors for elevated blood lead levels before resettlement have not been described. METHODS: Blood samples from children aged 6 months to 14 years from refugee camps in Thailand were tested for lead and hemoglobin. Sixty-seven children with elevated blood lead levels (venous >=10 ug/dL) or undetectable (capillary <3.3 ug/dL) blood lead levels participated in a case-control study. RESULTS: Of 642 children, 33 (5.1%) had elevated blood lead levels. Children aged <2 years had the highest prevalence (14.5%). Among children aged <2 years included in a case control study, elevated blood lead levels risk factors included hemoglobin <10 g/dL, exposure to car batteries, and taking traditional medicines. CONCLUSIONS: The prevalence of elevated blood lead levels among tested US-bound Burmese refugee children was higher than the current US prevalence, and was especially high among children <2 years old. Refugee children may arrive in the United States with elevated blood lead levels. A population-specific understanding of preexisting lead exposures can enhance postarrival lead-poisoning prevention efforts, based on Centers for Disease Control and Prevention recommendations for resettled refugee children, and can lead to remediation efforts overseas. PMID- 22250022 TI - Enhancing accurate identification of food insecurity using quality-improvement techniques. AB - BACKGROUND AND OBJECTIVES: Infants who live in households experiencing food insecurity are at risk for negative health and developmental outcomes. Despite large numbers of households within our population experiencing food insecurity, identification of household food insecurity during standard clinical care is rare. The objective of this study was to use quality-improvement methods to increase identification of household food insecurity by the second-year pediatric residents working in the Pediatric Primary Care Center from 1.9% to 15.0% within 6 months. A secondary aim was to increase the proportion of second-year pediatric residents identifying food insecurity. METHODS: A team was formed to identify key drivers thought to be critical to the process of identifying food insecurity during well-child care. This project addressed 5 key drivers and tested interventions based on these drivers over a 6-month period at a hospital-based primary care site that serves ~15 000 children from underserved neighborhoods. Tests included implementing an evidence-based electronic screen for food insecurity, educational interventions to improve understanding of food insecurity, empowerment exercises targeting clinicians and families, and gaining buy-in and support from ancillary personnel. RESULTS: Implementation of these changes led to an increase in the identification rate of household food insecurity from 1.9% to 11.2% over the 6 months (P < .01). The proportion of residents identifying food insecurity increased from 37.5% to 91.9% (P < .01). CONCLUSIONS: Application of quality-improvement methods in a primary care clinic increased ability to effectively screen and positively identify households with food insecurity in this population. PMID- 22250023 TI - Cardiac screening prior to stimulant treatment of ADHD: a survey of US-based pediatricians. AB - OBJECTIVES: To determine pediatricians' attitudes, barriers, and practices regarding cardiac screening before initiating treatment with stimulants for attention-deficit/hyperactivity disorder. METHODS: A survey of 1600 randomly selected, practicing US pediatricians with American Academy of Pediatrics membership was conducted. Multivariate models were created for 3 screening practices: (1) performing an in-depth cardiac history and physical (H & P) examination, (2) discussing potential stimulant-related cardiac risks, and (3) ordering an electrocardiogram (ECG). RESULTS: Of 817 respondents (51%), 525 (64%) met eligibility criteria. Regarding attitudes, pediatricians agreed that both the risk for sudden cardiac death (SCD) (24%) and legal liability (30%) were sufficiently high to warrant cardiac assessment; 75% agreed that physicians were responsible for informing families about SCD risk. When identifying cardiac disorders, few (18%) recognized performing an in-depth cardiac H & P as a barrier; in contrast, 71% recognized interpreting a pediatric ECG as a barrier. When asked about cardiac screening practices before initiating stimulant treatment for a recent patient, 93% completed a routine H & P, 48% completed an in-depth cardiac H & P, and 15% ordered an ECG. Almost half (46%) reported discussing stimulant-related cardiac risks. Multivariate modeling indicated that >=1 of these screening practices were associated with physicians' attitudes about SCD risk, legal liability, their responsibility to inform about risk, their ability to perform an in-depth cardiac H & P, and family concerns about risk. CONCLUSIONS: Variable pediatrician attitudes and cardiac screening practices reflect the limited evidence base and conflicting guidelines regarding cardiac screening. Barriers to identifying cardiac disorders influence practice. PMID- 22250024 TI - Comparison of the US and Australian cystic fibrosis registries: the impact of newborn screening. AB - BACKGROUND AND OBJECTIVES: National data registries for cystic fibrosis (CF) enable comparison of health statistics between countries. We examined the US and Australian CF data registries to compare demographics, clinical practice and outcome measures. METHODS: We compared the 2003 US and Australian registries. Differences in pulmonary and growth outcomes were assessed by creating models controlling for differences in age, gender, genotype, and diagnosis after newborn screening. RESULTS: Data on 12 994 US and 1220 Australian patients aged <=18 years were analyzed. A significant difference was noted in the proportion who had been diagnosed after newborn screening (Australian 65.8% vs United States 7.2%; P < .001). Australian children had significantly greater mean height percentile (41.0 vs 32.6; P < .001) and weight percentile (43.5 vs 36.1; P = .028) than US children. Mean forced expiratory volume in 1 second (FEV(1)) percent predicted adjusted for age, gender, and genotype was similar in the 2 countries (P = .80). Patients diagnosed after newborn screening had higher mean FEV(1) (5.3 [95% confidence interval (CI): 3.6-7.0]) percent predicted and BMI (0.26 [95% CI: 0.09 0.43]). Mean FEV(1) of Australian patients diagnosed after newborn screening was lower by 5.2 (95% CI: 2.8-7.6) percent predicted compared with US children. CONCLUSIONS: Children diagnosed with CF after newborn screening benefited from better lung function and BMI than those diagnosed clinically. The benefit of newborn screening on lung function was significantly less in Australian children compared with US children. Statistical comparisons between CF registries are feasible and can contribute to benchmarking and improvements in care. PMID- 22250025 TI - Multicenter analysis of quality indicators for children treated in the emergency department for asthma. AB - OBJECTIVE: To test the hypothesis that an association exists between process and outcome measures of the quality of acute asthma care provided to children in the emergency department. METHODS: Investigators at 14 US sites prospectively enrolled consecutive children 2 to 17 years of age presenting to the emergency department with acute asthma. In models adjusted for variables commonly associated with the quality of acute asthma care, we measured the association between 7 measures of concordance with national asthma guideline-recommended processes and 2 outcomes. Specifically, we modeled the association between 5 receipt/nonreceipt process measures and successful discharge and the association between 2 timeliness measures and admission. RESULTS: In this cohort of 1426 patients, 62% were discharged without relapse or ongoing symptoms (successful discharge), 15% were discharged with relapse or ongoing symptoms, and 24% were admitted. The composite score for receipt of all 5 receipt/nonreceipt process measures was 84%, and for timeliness measures, 57% receive a timely corticosteroid and 92% a timely beta-agonist. Our adjusted models showed no association between process and outcome measures, with 1 exception: timely beta agonist administration was associated with admission, likely reflecting confounding by severity rather than a true process-outcome association. CONCLUSIONS: We found no clinically significant association between process and outcome quality measures in the delivery of asthma-related care to children in a multicenter study. Although the quality of emergency department care does not predict successful discharge, other factors, such as outpatient care, may better predict outcomes. PMID- 22250026 TI - Genetic causes of macroglossia: diagnostic approach. AB - OBJECTIVE: Evaluate the contribution of standard diagnostic tests for macroglossia when clinical features are not suggestive of Beckwith-Wiedemann syndrome (BWS). METHODS: A retrospective analysis of data from clinical, laboratory, and imaging information from children with macroglossia seen at Cincinnati Children's Hospital Medical Center between 1997 and 2010 was performed. RESULTS: One hundred thirty-five children with macroglossia were identified. Macroglossia was the main reason for consultation in 84 children. Patients were classified on initial examination as isolated macroglossia (n = 24), provisional BWS (n = 36), and syndromic (n = 24). A final diagnosis was reached in 74 patients, and in 10 patients the reason for macroglossia remained undetermined. Among the elucidated cases, BWS was the most common cause of macroglossia (39/84). Six of the 24 patients in the isolated macroglossia group had an abnormal molecular test for BWS (P = .006). Thirteen diagnostic conditions were confirmed in this study, and 42% of the population had a specific diagnosis that was not BWS (35/84). CONCLUSIONS: These results can be used to improve our strategy in the evaluation of macroglossia. Distinction between isolated macroglossia and BWS may be difficult when only taking into account clinical features. These findings suggest that all patients with apparently isolated macroglossia have at least initial evaluation with abdominal ultrasounds and molecular studies for BWS before a final diagnosis is given. BWS was the most common cause of macroglossia even in the absence of additional clinical findings. PMID- 22250027 TI - Maternal asthma medication use and the risk of selected birth defects. AB - OBJECTIVES: Approximately 4% to 12% of pregnant women have asthma; few studies have examined the effects of maternal asthma medication use on birth defects. We examined whether maternal asthma medication use during early pregnancy increased the risk of selected birth defects. METHODS: National Birth Defects Prevention Study data for 2853 infants with 1 or more selected birth defects (diaphragmatic hernia, esophageal atresia, small intestinal atresia, anorectal atresia, neural tube defects, omphalocele, or limb deficiencies) and 6726 unaffected control infants delivered from October 1997 through December 2005 were analyzed. Mothers of cases and controls provided telephone interviews of medication use and additional potential risk factors. Exposure was defined as maternal periconceptional (1 month prior through the third month of pregnancy) asthma medication use (bronchodilator or anti-inflammatory). Associations between maternal periconceptional asthma medication use and individual major birth defects were estimated by using adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: No statistically significant associations were observed for maternal periconceptional asthma medication use and most defects studied; however, positive associations were observed between maternal asthma medication use and isolated esophageal atresia (bronchodilator use: aOR = 2.39, 95%CI = 1.23, 4.66), isolated anorectal atresia (anti-inflammatory use: aOR = 2.12, 95%CI = 1.09, 4.12), and omphalocele (bronchodilator and anti-inflammatory use: aOR = 4.13, 95%CI = 1.43, 11.95). CONCLUSIONS: Positive associations were observed for anorectal atresia, esophageal atresia, and omphalocele and maternal periconceptional asthma medication use, but not for other defects studied. It is possible that observed associations may be chance findings or may be a result of maternal asthma severity and related hypoxia rather than medication use. PMID- 22250028 TI - Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop. AB - Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials. PMID- 22250029 TI - Pertussis Pseudo-outbreak linked to specimens contaminated by Bordetella pertussis DNA From clinic surfaces. AB - BACKGROUND AND OBJECTIVES: We investigated a pertussis outbreak characterized by atypical cases, confirmed by polymerase chain reaction (PCR) alone at a single laboratory, which persisted despite high vaccine coverage and routine control measures. We aimed to determine whether Bordetella pertussis was the causative agent and advise on control interventions. METHODS: We conducted case ascertainment, confirmatory testing for pertussis and other pathogens, and an assessment for possible sources of specimen contamination, including a survey of clinic practices, sampling clinics for B pertussis DNA, and review of laboratory quality indicators. RESULTS: Between November 28, 2008, and September 4, 2009, 125 cases were reported, of which 92 (74%) were PCR positive. Cases occurring after April 2009 (n = 79; 63%) had fewer classic pertussis symptoms (63% vs 98%; P < .01), smaller amounts of B pertussis DNA (mean PCR cycle threshold value: 40.9 vs 33.1; P < .01), and a greater proportion of PCR-positive results (34% vs 6%; P < .01). Cultures and serology for B pertussis were negative. Other common respiratory pathogens were detected. We identified factors that likely resulted in specimen contamination at the point of collection: environmentally present B pertussis DNA in clinics from vaccine, clinic standard specimen collection practices, use of liquid transport medium, and lack of clinically relevant PCR cutoffs. CONCLUSIONS: A summer pertussis pseudo-outbreak, multifactorial in cause, likely occurred. Recommendations beyond standard practice were made to providers on specimen collection and environmental cleaning, and to laboratories on standardizing PCR protocols and reporting results, to minimize false-positive results from contaminated clinical specimens. PMID- 22250030 TI - Successful treatment of type 1 diabetes and seizures with combined ketogenic diet and insulin. AB - Diabetic ketoacidosis (DKA) is a life-threatening condition and a major cause of morbidity and mortality in children with type 1 diabetes mellitus. The deficiency of insulin leads to metabolic decompensation, causing hyperglycemia and ketosis that resolves with the administration of insulin and fluids. However, an induced state of ketosis is the basis for the success of the ketogenic diet (KD), which is an effective therapy for children with intractable epilepsy. We report the case of a 2-year-old girl who presented to the emergency department with 1-week history of decreased activity, polyuria, and decreased oral intake. Her past medical history was remarkable for epilepsy, for which she was started on the KD with a significant improvement. Her laboratory evaluation was compatible with DKA, and fluids and insulin were given until correction. Because of concerns regarding recurrence of her seizures, the KD was resumed along with the simultaneous use of insulin glargine and insulin aspart. Urine ketones were kept in the moderate range to keep the effect of ketosis on seizure control. Under this combined therapy, the patient remained seizure-free with no new episodes of DKA. PMID- 22250032 TI - Late intravenous immunoglobulin treatment in patients with Kawasaki disease. AB - OBJECTIVE: To evaluate the effectiveness of intravenous immunoglobulin (IVIG) treatment of Kawasaki disease >=10 days after illness onset. METHODS: We selected patients initially treated with IVIG on days 11 to 20 in the database of the 20th nationwide survey in Japan. We then selected pair-matched control subjects of the same gender and age, who were initially treated with IVIG on days 4 to 8 with the same dose at the same institutions. We compared the proportions of additional treatments and coronary artery lesions (CALs) between the groups. We also compared fractional changes in various laboratory data before and after IVIG. Fractional change was defined as follows: (Y - X)/X, in which X represents the data before treatment and Y the data after treatment. RESULTS: One hundred fifty patients (75 pairs) were studied. The proportion of patients who received additional treatments among those given initial IVIG after days 10 was slightly lower than those treated earlier (12% vs 16%). The fractional changes in the white blood cell count, % neutrophils, and C-reactive protein were similar. Among all patients, the proportions of CALs during the convalescent phase were significantly higher in the late than in the early group (27% vs 1%). Among patients who had not developed CALs before initial treatment, the proportions with CALs during the acute phase were similar (8% vs 8%). CONCLUSIONS: IVIG treatment >=10 days after illness onset achieves resolution of inflammation but was found to be insufficient for preventing CALs. PMID- 22250031 TI - Trends in US pediatric drowning hospitalizations, 1993-2008. AB - BACKGROUND: In the United States, drowning is the second leading cause of unintentional injury death in children aged 1 to 19 years, accounting for nearly 1100 deaths per year. Although a decline in overall fatal drowning deaths among children has been noted, national trends and disparities in pediatric drowning hospitalizations have not been reported. METHODS: To describe trends in pediatric drowning in the United States and provide national benchmarks for state and regional comparisons, we analyzed existing data (1993-2008) from the Nationwide Inpatient Sample, the largest, longitudinal, all-payer inpatient care database in the United States. Children aged 0 to 19 years were included. Annual rates of drowning-related hospitalizations were determined, stratified by age, gender, and outcome. RESULTS: From 1993 to 2008, the estimated annual incidence rate of pediatric hospitalizations associated with drowning declined 49% from 4.7 to 2.4 per 100 000 (P < .001). The rates declined for all age groups and for both males and females. The hospitalization rate for males remained consistently greater than for females at each point in time. Rates of fatal drowning hospitalization declined from 0.5 (95% confidence interval, 0.4-0.7) deaths per 100 000 in 1993 1994 to 0.3 (95% confidence interval, 0.2-0.4) in 2007-2008 (P < .01). No difference was observed in the mean hospital length of stay over time. CONCLUSIONS: Pediatric hospitalization rates for drowning have decreased over the past 16 years. Our study provides national estimates of pediatric drowning hospitalization that can be used as benchmarks to target and assess prevention strategies. PMID- 22250033 TI - Long-lived room-temperature near-IR phosphorescence of BODIPY in a visible-light harvesting N^C^N Pt(II)-acetylide complex with a directly metalated BODIPY chromophore. AB - Room-temperature long-lived near-IR phosphorescence of boron-dipyrromethene (BODIPY) was observed (lambda(em) = 770 nm, Phi(P) = 3.5 %, tau(P) = 128.4 MUs). Our molecular-design strategy is to attach Pt(II) coordination centers directly onto the BODIPY pi-core using acetylide bonds, rather than on the periphery of the BODIPY core, thus maximizing the heavy-atom effect of Pt(II). In this case, the intersystem crossing (ISC) is facilitated and the radiative decay of the T(1) excited state of BODIPY is observed, that is, the phosphorescence of BODIPY. The complex shows strong absorption in the visible range (epsilon = 53,800 M(-1) cm(-1) at 574 nm), which is rare for Pt(II)-acetylide complexes. The complex is dual emissive with (3)MLCT emission at 660 nm and the (3)IL emission at 770 nm. The T(1) excited state of the complex is mainly localized on the BODIPY moiety (i.e. (3)IL state, as determined by steady-state and time-resolved spectroscopy, 77 K emission spectra, and spin-density analysis). The strong visible-light harvesting ability and long-lived T(1) excite state of the complex were used for triplet-triplet annihilation based upconversion and an upconversion quantum yield of 5.2 % was observed. The overall upconversion capability (eta = epsilon*Phi(UC)) of this complex is remarkable considering its strong absorption. The model complex, without the BODIPY moiety, gives no upconversion under the same experimental conditions. Our work paves the way for access to transition metal complexes that show strong absorption of visible light and long-lived (3)IL excited states, which are important for applications in photovoltaics, photocatalysis, and upconversions, etc. PMID- 22250035 TI - Interlayer for modified cathode in highly efficient inverted ITO-free organic solar cells. AB - Inverted polymer solar cells with a bottom metal cathode modified by a conjugated polymer interlayer show considerable improvement of photocurrent and fill factor, which is due to hole blocking at the interlayer, and a modified surface energy which affects the nanostructure in the TQ1/[70]PCBM blend. PMID- 22250036 TI - TENS - an alternative to antiviral drugs for acute herpes zoster treatment and postherpetic neuralgia prevention. AB - QUESTIONS UNDER STUDY: To evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) in treatment of Herpes zoster (HZ), and prevention of postherpetic neuralgia (PHN) compared with antiviral drugs. PHN is frequent complication of HZ and may last for months, its treatment isn't very successful. Nonpharmacological regimens for treatment of HZ and prevention of PHN haven't been evaluated. METHODS: Retrospective observational study of medical records of patients of three family physicians in Health centre Litija, Slovenia was done. 109 of 6613 patients on their lists had HZ from 1999 to 2008. 102 medical records were analyzed (6 could not be reached; one patient with corneal HZ was excluded). RESULTS: Four treatment groups were compared: only TENS therapy, only antiviral drug, antiviral drug and TENS, no therapy (neither antiviral drug or TENS). All groups were similar with respect to demographic characteristics of patients with HZ. Patients treated only with TENS had no PHN, 28.6% of patients treated with antiviral drugs had PHN. Less analgesic drugs have been prescribed to patients treated only with TENS. CONCLUSION: Study suggests TENS may be safe adjunct or even alternative to antiviral drugs for treatment of acute HZ. It looks that TENS may be at least as good as antiviral drugs for treatment of HZ, and it may be better in reducing and preventing PHN - such conclusion would necessitate controlled, prospective study. Use of TENS provided pain relief and resolution of skin lesions with no higher rate of other HZ complications compared to antiviral therapy. PMID- 22250037 TI - Surface modification by electrostatic self-assembly followed by covalent fixation. PMID- 22250038 TI - Effects of tiotropium and formoterol on quiet breathing pattern assessed by optoelectronic plethysmography in COPD patients: a pilot study. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a disease characterized by an airflow limitation that is not fully reversible. beta(2) agonists and anticholinergics represent the most effective therapeutic options. Optoelectronic plethysmography (OEP) is a novel technology, which provides noninvasive steady-state measurements of chest wall kinematics, together with the assessment of the relative contribution of all different thoracic and abdominal compartments to tidal volume. OBJECTIVES: The aim of this pilot study was to investigate the changes in quiet breathing due to different long-acting bronchodilators (namely, formoterol and tiotropium) administered to COPD patients of different severity. METHODS: Eight moderate-to-severe COPD patients were studied according to a randomized crossover design. All subjects received both the long-acting bronchodilators: formoterol (long-acting beta(2)-agonist, 24 ug) and tiotropium (long-acting anticholinergic bronchodilator, 18 ug). The effect of bronchodilators on quiet breathing was evaluated by means of OEP at base conditions, and 2 and 7 hours after inhalation. RESULTS: Both bronchodilators caused changes in the quiet breathing pattern in COPD patients that had previously reported only negligible changes in FEV(1) (DeltaFEV(1) = 2.6% after salbutamol). The main changes were observed in increased ventilation per minute, inspiratory and expiratory flow, and decreased breath-by-breath variability. Formoterol induced its main effects during the first 2 hours after inhalation, while tiotropium caused improvements between 2 and 7 hours. CONCLUSION: Even though a greater cohort of COPD patients is needed in order to confirm the present results, this pilot study reports a novel piece of evidence concerning the effects of bronchodilators on quiet breathing pattern in severe and very severe COPD patients. PMID- 22250040 TI - Redox-active, organometallic surface-relief gratings from azobenzene-containing polyferrocenylsilane block copolymers. AB - Organometallic gratings: the ionic self-assembly of metal-containing block copolymer polyelectrolytes and azobenzene chromophores is exploited for the efficient production of stable photo-induced surface-relief gratings. We show that feature sizes can be tuned using simple redox chemistry, and that the chromophores can be removed during plasma treatment to yield ceramic-based optical materials. PMID- 22250039 TI - Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-associated glomus tumors. AB - Neurofibromatosis type 1 (NF1) is a common, autosomal dominant, tumor predisposition syndrome that arises secondary to mutations in NF1. Glomus tumors are painful benign tumors that originate from the glomus body in the fingers and toes due to biallelic inactivation of NF1. We karyotyped cultures from four previously reported and one new glomus tumor and hybridized tumor (and matching germline) DNA on Illumina HumanOmni1-Quad SNP arrays (~ 1 * 10(6) SNPs). Two tumors displayed evidence of copy-neutral loss of heterozygosity of chromosome arm 17q not observed in the germline sample, consistent with a mitotic recombination event. One of these two tumors, NF1-G12, featured extreme polyploidy (near-tetraploidy, near-hexaploidy, or near-septaploidy) across all chromosomes. In the remaining four tumors, there were few cytogenetic abnormalities observed, and copy-number analysis was consistent with diploidy in all chromosomes. This is the first study of glomus tumors cytogenetics, to our knowledge, and the first to report biallelic inactivation of NF1 secondary to mitotic recombination of chromosome arm 17q in multiple NF1-associated glomus tumors. We have observed mitotic recombination in 22% of molecularly characterized NF1-associated glomus tumors, suggesting that it is a not uncommon mechanism in the reduction to homozygosity of the NF1 germline mutation in these tumors. In tumor NF1-G12, we hypothesize that mitotic recombination also "unmasked" (reduced to homozygosity) a hypomorphic germline allele in a gene on chromosome arm 17q associated with chromosomal instability, resulting in the extreme polyploidy. PMID- 22250041 TI - Synthesis of thermo- and pH-sensitive polyion complex micelles for fluorescent imaging. AB - Two thermo- and pH-sensitive polypeptide-based copolymers, poly(N isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-poly(L-lysine) (P(NIPAAm-co HMAAm)-b-PLL, P1) and poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b poly(glutamic acid) (P(NIPAAm-co-HMAAm)-b-PGA, P2), have been designed and synthesized by the ring-opening anionic polymerization of N-carboxyanhydrides (NCA) with amino-terminated P(NIPAAm-co-HMAAm). It was found that the block copolymers exhibit good biocompatibility and low toxicity. As a result of electrostatic interactions between the positively charged PLL and negatively charged PGA, P1 and P2 formed polyion complex (PIC) micelles consisting of polyelectrolyte complex cores and P(NIPAAm-co-HMAAm) shells in aqueous solution. The thermo- and pH-sensitivity of the PIC micelles were studied by UV/Vis spectrophotometry, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Moreover, fluorescent PIC micelles were achieved by introducing two fluorescent molecules with different colors. Photographs and confocal laser scanning microscopy (CLSM) showed that the fluorescence-labeled PIC micelles exhibit thermo- and pH-dependent fluorescence, which may find wide applications in bioimaging in complicated microenvironments. PMID- 22250042 TI - [Hepatocellular carcinoma: what's new?]. PMID- 22250044 TI - Continuous-flow synthesis of the anti-malaria drug artemisinin. PMID- 22250043 TI - The alternative lengthening of telomeres pathway may operate in non-neoplastic human cells. AB - The alternative lengthening of telomeres (ALT) mechanism represents an alternative to the enzyme telomerase in the maintenance of mammalian telomeres in 25-60% of sarcomas and a minority of carcinomas (about 5-15%). ALT-positive cells are distinguished by long and heterogeneous telomere length distributions by terminal restriction fragment (TRF) Southern blotting. Another diagnostic marker of ALT is discrete nuclear co-localized signals of telomeric DNA and the promyelocytic leukaemia protein (PML), referred to as ALT-associated PML bodies (APBs). Recently, we detected smaller sized co-localized PML and telomere DNA (APB-like) bodies in endothelial cells adjacent to astrocytoma tumour cells in situ. In this study, we examined a wide variety of non-neoplastic tissues, and report that co-localized signals of PML and telomere DNA are present in endothelial, stromal, and some epithelial cells. Co-localized signals of PML and telomere DNA showed an increased frequency in non-neoplastic cells with DNA damage. These results suggest that a mechanism similar to that in ALT-positive tumours also operates in non-neoplastic cells, which may be activated by DNA damage. PMID- 22250045 TI - Images in vascular medicine: a case of Bockenheimer's syndrome (genuine diffuse phlebectasia). PMID- 22250046 TI - The impact of the genetic background on the genome make-up of tumor cells. AB - Endometrial adenocarcinoma (EAC) is the most common form of malignancy in the female genital tract, ranking as the fourth leading form of invasive tumors that affect women. The BDII inbred rat strain has been used as a powerful tumor model in studies of the genetic background of EAC. Females from the BDII strain are prone to develop tumors with an incidence of more than 90%. Development of EAC in BDII female rats has similarities in pathogenesis, histopathological, and molecular properties to that of human, and thus represents a unique model for analysis of EAC tumorigenesis and for comparative studies in human EACs. In a previous study, a set of rat EAC cell lines derived from tumors developed in female crossprogenies between BDII and nonsusceptible rat strains were analyzed by spectral karyotyping (SKY). Here we present an analysis with specific focus on the impact of different genetic backgrounds on the rate and occurrence of genetic aberrations in experimental tumors using data presented in the previous report. We could reveal that the ploidy state, and the abundance and type of structural as well as numerical change differed between the two genetic setups. We have also identified chromosomes harboring aberrations independent of genetic input from the nonsusceptible strains, which provide valuable information for the identification of the genes involved in the development of EAC in the BDII model as well as in human endometrial tumors. PMID- 22250047 TI - Organic thermoelectric materials and devices based on p- and n-type poly(metal 1,1,2,2-ethenetetrathiolate)s. AB - A series of metal coordination polymers containing 1,1,2,2-ethenetetrathiolate (ett) linking bridge (poly[Ax(M-ett)]) are synthesized. The Seebeck coefficients of these conducting materials are high, and vary according to the center metals and counter cations. The TE device fabricated demonstrates the great potentials of these materials for TE applications. PMID- 22250048 TI - Lattice effects on the spin-crossover profile of a mononuclear manganese(III) cation. AB - Six solvated salts of a mononuclear manganese(III) complex with a chelating hexadentate Schiff base ligand are reported. One member of the series, [MnL]PF(6)?0.5 CH(3)OH (1), shows a rare low-spin (LS) electronic configuration between 10-300 K. The remaining five salts, [MnL]NO(3)?C(2)H(5)OH(2), [MnL]BF(4)?C(2)H(5)OH(3), [MnL]CF(3)SO(3)?C(2)H(5)OH (4), [MnL]ClO(4)?C(2)H(5)OH (5) and [MnL]ClO(4)?0.5 CH(3)CN (6), all show gradual incomplete spin-crossover (SCO) behaviour. The structures of all were determined at 100 K, and also at 293 K in the case of 3-6. The LS salt [MnL]PF(6)?0.5 CH(3)OH is the only member of the series that does not exhibit strong hydrogen bonding. At 100 K two of the four SCO complexes (2 and 4) assemble into 1D hydrogen-bonded chains, which weaken or rupture on warming. The remaining SCO complexes 3, 5 and 6 do not form 1D hydrogen-bonded chains, but instead exhibit discrete hydrogen bonding between cation/counterion, cation/solvent or counterion/solvent and show no significant change on warming. PMID- 22250049 TI - New gastroprotective labdeneamides from (4S,9R,10R) methyl 18-carboxy-labda 8,13(E)-diene-15-oate. AB - Starting from the diterpene (4S,9R,10R) methyl 18-carboxy-labda-8,13(E)-dien-15 oate (PMD) and its 8(9)-en isomer [PMD 8(9)-en], 11 amides were prepared and assessed for a gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice. Basal cytotoxicity of the compounds was determined on the following human cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). All compounds are described for the first time. At the single oral dose of 0.1 mg/kg, compounds 1, 10, and 11 presented a strong gastroprotective effect, at least comparable with that of the reference compound lansoprazole at 1 mg/kg, reducing gastric lesions by 76.7, 67.7, and 77.2 %, respectively. The leucyl amide methyl ester 3, tryptophanyl amide methyl ester 5, and benzyl amide 6 of PMD presented a selective basal cytotoxicity on Hep G2 cells with IC50 values of 136.8, 105.3, and 94.2 uM, respectively, while the IC50 values towards AGS cells were 439.5, 928.0, and 937.3 uM, respectively. The three compounds did not affect fibroblast viability with IC50 values > 1000 uM. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines. PMID- 22250050 TI - High propene/propane selectivity in isostructural metal-organic frameworks with high densities of open metal sites. PMID- 22250051 TI - Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene. AB - High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation "hotspot" at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma. PMID- 22250052 TI - Hydrogen passivation induced dispersion of multi-walled carbon nanotubes. AB - A method combining hydrogen passivation and ultrasonication was developed for the first time to disperse multi-walled carbon nanotubes (MWCNTs) in ethanol solution and epoxy resin. Excellent dispersion of MWCNTs was achieved in both media. Three point bending tests of the MWCNT/epoxy nanocomposites revealed a remarkable increase in elastic modulus with increasing MWCNT content. PMID- 22250053 TI - [Bronchiolitis. Part 1--anatomic features, classification, clinical presentation and imaging]. AB - The term "bronchiolitis" refers to a broad spectrum of common conditions related to the small airways associated with a miscellaneous aetiology, histology, clinical features and course. Due to their variability, bronchiolar disorders are generally difficult to diagnose. History (smoking, collagen vascular disease, inhalational injury, medication usage, and organ transplant) may point towards a bronchiolar process. In addition, signs of systemic and pulmonary infection and evidence of air trapping may provide diagnostic hints. Although clinical presentation, physical examination, pulmonary function tests (obstructive ventilatory defect), and plain chest radiographs may demonstrate abnormalities suggesting small airways involvement, they are often non-specific and rarely diagnostic. In contrast, the high-resolution CT (HR-CT) scanning of the chest provides three distinct HR-CT patterns that assist in the diagnosis and differential diagnosis of bronchiolar conditions: (i) a tree-in-bud pattern, (ii) ill-defined centrilobular ground-glass nodules, and (iii) a mosaic attenuation pattern (best visible on expiratory images). The present paper summarises the current knowledge, the classification, imaging, and the clinical presentation of bronchiolar disorders. PMID- 22250054 TI - [Expert dialogue: neuroendocrine tumours of the lungs and gastroenteropancreatic system]. AB - BACKGROUND: Neuroendocrine tumours of the lung exhibit an increasing incidence and prevalence. However, data on the diagnosis of and therapy for these tumours are sparse compared to neuroendocrine tumours of the gastroenteropancreatic system. METHODS: The present article reflects a dialogue between experts on neuroendocrine tumors of the lung and the gastroenteropancreatic system held on February 25th and 26th in Weimar, Germany. RESULTS: Many similarities exist between neuroendocrine tumours of the lung and the gastroenteropancreatic system but there are also significant differences. Similarities exist mainly concerning pathology, diagnosis and therapy. Differences exist regarding the systemic therapy and the significantly lower incidence of paraneoplastic syndromes. Somatostatin receptor PET/CT with gallium-68 labelled somatostatin analogues and peptide receptor radiotherapy are innovative methods for the diagnosis of and therapy for neuroendocrine tumours of the lung. The first treatment option remains complete resection of the tumour. Small molecules like everolimus (Afinitor(r)) have been tested in clinical trials and have been shown to prolong progression-free survival. CONCLUSIONS: Additional studies are necessary and efforts should be undertaken to establish a registry to increase data on methods suitable for he diagnosis of and therapy for neuroendocrine tumours of the lung. PMID- 22250055 TI - A strategy for the high dispersion of PtRu nanoparticles onto carbon nanotubes and their electrocatalytic oxidation of methanol. AB - Carbon nanotubes (CNTs) were non-covalently functionalized by 1 pyrenecarboxaldehyde (PCA) via pi-pi stacking interactions. PCA not only acts as the reductant for the deposition of PtRu nanoparticles, but the oxidation product of PCA can also effectively anchor and stabilize the in-situ-produced PtRu NPs on the surface of CNTs. Transmission electron microscopy demonstrates that PtRu NPs are uniformly dispersed on the surface of CNTs with small particles sizes of about 1.7 nm. The obtained PtRu-NP/CNT composites have higher electrochemical surface areas, electrocatalytic activities, and better stability towards methanol oxidation compared to PtRu NPs supported on pristine CNTs. PMID- 22250056 TI - Von Meyenburg complexes: a rare cause for multiple hepatic lesions on transabdominal ultrasound. PMID- 22250057 TI - Neoadjuvant therapy of pancreatic cancer: the emerging paradigm? AB - Pancreatic cancer remains one of the deadliest cancers due to difficulty in early diagnosis and its high resistance to chemotherapy and radiation. It is now clear that even patients with potentially resectable disease require multimodality treatment including chemotherapy and/or radiation to improve resectability and reduce recurrence. Tremendous efforts are currently being invested in refining preoperative staging to identify optimal surgical candidates, and also in developing various neoadjuvant or adjuvant regimens to improve surgical outcome. Although at present no studies have been done to directly compare the benefit of neoadjuvant versus adjuvant approaches, accumulating evidence suggests that the neoadjuvant approach is probably beneficial for a subset of the patient population, particularly those with borderline resectable disease in which complete surgical resection is almost certainly unachievable. In this article, we review the literature and rationales of neoadjuvant chemotherapy and chemoradiation, as well as their potential limitations and caveats. We also review the pathological findings following neoadjuvant therapies, and potential surgical complications that may be associated with neoadjuvant therapies. PMID- 22250058 TI - An O-centered structure of the trinuclear copper center in the Cys500Ser/Glu506Gln mutant of CueO and structural changes in low to high X-ray dose conditions. PMID- 22250059 TI - Initial and subsequent therapy for newly diagnosed type 2 diabetes patients treated in primary care using data from a vendor-based electronic health record. AB - BACKGROUND: Diabetes is a leading cause of death and disability, and its prevalence is increasing. When diet fails, patients with type 2 diabetes mellitus (T2DM) are prescribed oral hypoglycemics for glycemic control. Few studies have explored initial use or change from initial oral hypoglycemic therapy in the primary care setting. We aimed to describe the utilization of initial oral hypoglycemics among newly diagnosed patients with diabetes from 1998-2009 and changes from initial to subsequent therapy among patients prescribed older oral hypoglycemic agents using electronic health records. METHODS: This observational cohort study used electronic health records from newly diagnosed patients with T2DM between 1 January 1998 and 31 March 2009 at two large health systems in the USA. Oral hypoglycemics included older (biguanide, sulfonylurea, and thiazolidinedione) and newer agents (incretin mimetic agents, alpha-glucosidase inhibitors, and D-phenylalanine derivatives). Multinomial regression models were fit to evaluate initial older oral hypoglycemic medication. We used incidence density sampling and conditional logistic regression models to evaluate predictors of regimen change. RESULTS: Most patients were treated from the biguanide class of oral hypoglycemics (67%), but there were differences in initial prescribing by age and race. HbA1c (Odds Ratio for HbA1c 7.0-8.9 vs < 7.0, 5.87 [95% Confidence Interval: 3.62-9.52]; Odds Ratio for HbA1c >= 9 vs < 7.0, 20.25 [95% Confidence Interval: 8.32-49.29] and Black people (Odds Ratio, 0.29 [95% Confidence Interval: 0.14, 0.60]) versus White people were associated with regimen change in the adjusted analysis. CONCLUSIONS: Clinical and demographic characteristics influence choice and duration of initial oral hypoglycemic treatment as well as regimen changes. PMID- 22250060 TI - From monolayer to multilayer N-channel polymeric field-effect transistors with precise conformational order. AB - Monolayer field-effect transistors based on a high-mobility n-type polymer are demonstrated. The accurate control of the long-range order by Langmuir-Schafer (LS) deposition yields dense polymer packing exhibiting good injection properties, relevant current on/off ratio and carrier mobility in a staggered configuration. Layer-by-layer LS film transistors of increasing thickness are fabricated and their performance compared to those of spin-coated films. PMID- 22250061 TI - Designing fluorinated cinchona alkaloids for enantioselective catalysis: controlling internal rotation by a fluorine-ammonium ion gauche effect (phi(NCCF)). AB - The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8-C9 (tau(1)) and C9-C4' (tau(2)) bonds giving rise to four low energy conformers (1; anti-closed, anti-open, syn-closed, and syn-open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine-ammonium ion gauche effect (sigma(C-H) -> sigma(C-F)*; F(delta-)???N(+)) encodes for two out of the four possible conformers (2). This constitutes a partial solution to the long-standing problem of governing internal rotations in cinchonium-based catalysts relying solely on a fluorine conformational effect. PMID- 22250062 TI - On the existence of A-site deficiency in perovskites and its relation to the electrochemical performance. AB - The low range of A-site deficiency in perovskite structures with Ni cations was verified by neutron powder diffraction, transmission electron microscopy, and thermogravimetric analysis. A thermodynamic approach has been utilized, for the first time, to predict the extent of A-site deficiencies within the perovskite structure, introducing simple prediction criteria that could be adopted for designing advanced materials. PMID- 22250063 TI - Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. AB - OBJECTIVE: To assess the effect of dietary flavonoids on cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes on established statin and hypoglycemic therapy. RESEARCH DESIGN AND METHODS: Despite being medicated, patients with type 2 diabetes have elevated CVD risk, particularly postmenopausal women. Although dietary flavonoids have been shown to reduce CVD risk factors in healthy participants, no long-term trials have examined the additional benefits of flavonoids to CVD risk in medicated postmenopausal women with type 2 diabetes. We conducted a parallel-design, placebo-controlled trial with type 2 diabetic patients randomized to consume 27 g/day (split dose) flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] and 100 mg isoflavones [aglycone equivalents)]/day) or matched placebo for 1 year. RESULTS: Ninety-three patients completed the trial, and adherence was high (flavonoid 91.3%; placebo 91.6%). Compared with the placebo group, the combined flavonoid intervention resulted in a significant reduction in estimated peripheral insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] -0.3 +/- 0.2; P = 0.004) and improvement in insulin sensitivity (quantitative insulin sensitivity index [QUICKI] 0.003 +/- 0.00; P = 0.04) as a result of a significant decrease in insulin levels (-0.8 +/- 0.5 mU/L; P = 0.02). Significant reductions in total cholesterol:HDL-cholesterol (HDL-C) ratio (-0.2 +/- 0.1; P = 0.01) and LDL cholesterol (LDL-C) (-0.1 +/- 0.1 mmol/L; P = 0.04) were also observed. Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention (flavonoid +0.1 +/- 0.3 vs. placebo 1.1 +/- 0.3; P = 0.02). No effect on blood pressure, HbA(1c), or glucose was observed. CONCLUSIONS: One-year intervention with flavan-3-ols and isoflavones improved biomarkers of CVD risk, highlighting the additional benefit of flavonoids to standard drug therapy in managing CVD risk in postmenopausal type 2 diabetic patients. PMID- 22250064 TI - Retinal vascular geometry predicts incident renal dysfunction in young people with type 1 diabetes. AB - OBJECTIVE: To examine the relationship between retinal vascular geometry parameters and development of incident renal dysfunction in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a prospective cohort study of 511 adolescents with type 1 diabetes of at least 2 years duration, with normal albumin excretion rate (AER) and no retinopathy at baseline while attending an Australian tertiary-care hospital. AER was quantified using three overnight, timed urine specimen collections and early renal dysfunction was defined as AER >7.5 MUg/min. Retinal vascular geometry (including length-to-diameter ratio [LDR] and simple tortuosity [ST]) was quantified from baseline retinal photographs. Generalized estimating equations were used to examine the relationship between incident renal dysfunction and baseline venular LDR and ST, adjusting for age, diabetes duration, glycated hemoglobin (A1C), blood pressure (BP), BMI, and cholesterol. RESULTS: Diabetes duration at baseline was 4.8 (IQR 3.3-7.5) years. After a median 3.7 (2.3-5.7) years follow-up, 34% of participants developed incident renal dysfunction. In multivariate analysis, higher retinal venular LDR (odds ratio 1.7, 95% CI 1.2-2.4; quartile 4 vs. 1-3) and lower venular ST (1.6, 1.1-2.2; quartile 1 vs. 2-4) predicted incident renal dysfunction. CONCLUSIONS: Retinal venular geometry independently predicted incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may help to elucidate early mechanistic pathways for microvascular complications. Retinal venular geometry may be a useful tool to identify individuals at high risk of renal disease early in the course of diabetes. PMID- 22250066 TI - A new direction in C-H alkenylation: silanol as a helping hand. PMID- 22250065 TI - "Onion skin" sign in an ovarian mucinous cyst. AB - The sonographic "onion skin" sign was initially described as concentric echogenic layers in mucinous tumors unrelated to the female reproductive system. Typically, the sonographic appearance of ovarian mucinous cystadenoma includes numerous septa and fine, gravity-dependent echoes. We present a case of the "onion skin" sign in a mucinous ovarian tumor. PMID- 22250067 TI - Protein-assisted synthesis of double-shelled CaCO3 microcapsules and their mineralization with heavy metal ions. AB - Calcium carbonate (CaCO(3)) is one of the most abundant and important biominerals in nature. Due to its biocompatibility, biodegradability and nontoxicity, CaCO(3) has been investigated extensively in recent years for various fundamental properties and technological applications. Inspired by basic wall structures of cells, we report a protein-assisted approach to synthesize CaCO(3) into a double shelled structural configuration. Due to varying reactivities of outer and inner shells, the CaCO(3) microcapsules exhibit different sorption capacities and various resultant structures toward different kinds of heavy metal ions, analogical to biologically controlled mineralization (BCM) processes. Surprisingly, three mineralization modes resembling those found in BCM were found with these bacterium-like "CaCO(3) cells". Our investigation of the cytotoxicity (MTT assay protocol) also indicates that the CaCO(3) microcapsules have almost no cytotoxicity against HepG2 cells, and they might be useful for future application of detoxifying heavy metal ions after further study. PMID- 22250068 TI - Solid-state structure of bromine azide. PMID- 22250069 TI - Aortic annulus rupture during transcatheter aortic valve implantation: safe aortic root replacement. PMID- 22250070 TI - Sf-6d population norms. AB - The derivation of population norms using simple generic health-related quality of life measures to inform policy has been recommended in the literature. This letter illustrates the derivation of population norms for the SF-6D in the United Kingdom. It uses a sample of 22,166 respondents from the 2010 wave of the study Understanding Society. Understanding Society is a national representative sample of British citizens. The survey of this study contains the SF-12. It is possible to derive health state utilities from the SF-12 (and from the SF-36) using a relatively new instrument, the SF-6D. The SF-12 and the SF-36 belong to the most widely used generic health-related quality of life measures. Mean SF-6D utility scores for males and females are 0.81 and 0.79, respectively. Especially the older age categories have lower utility scores. The younger age categories have slightly higher utility scores. From a list of 17 conditions, people with congestive heart failure had the lowest (0.60) and people with diabetes the highest (0.76) SF-6D scores. This letter encourages the health economics research community to derive SF-6D population norms to inform policy. PMID- 22250071 TI - Fe-catalyzed multicomponent reactions: the regioselective alkoxy allylation of activated olefins and its application in sequential Fe catalysis. AB - We present herein a versatile and broadly applicable Fe-catalyzed regioselective alkoxy allylation of activated double bonds. Substituted allylic carbonates are converted into the corresponding sigma-enyl Fe complexes by reaction with Bu(4)N[Fe(CO)(3)(NO)] (TBAFe) at 30 degrees C. The liberated alkoxide adds to an activated double bond with the generation of a C-nucleophile, which is trapped by the sigma-enyl Fe complex in a regioselective manner. Alternatively, the alkoxide acts as a base in deprotonating an external pronucleophile, which undergoes Michael addition. The method is characterized by a broad functional group tolerance, mild reaction conditions, low catalyst loadings, and high regioselectivities in favor of the ipso-substitution product. PMID- 22250072 TI - Can we predict allograft tolerance in experimental animal models of transplantation? PMID- 22250073 TI - Born with low birth weight in rural Southern India: what are the metabolic consequences 20 years later? AB - OBJECTIVE: Low birth weight (LBW) is common in the Indian population and may represent an important predisposing factor for type 2 diabetes (T2D) and the metabolic syndrome. Intensive metabolic examinations in ethnic LBW Asian Indians have been almost exclusively performed in immigrants living outside India. Therefore, we aimed to study the metabolic impact of being born with LBW in a rural non-migrant Indian population. SUBJECTS AND METHODS: One hundred and seventeen non-migrant, young healthy men were recruited from a birth cohort in a rural part of south India. The subjects comprised 61 LBW and 56 normal birth weight (NBW) men, with NBW men acting as controls. Subjects underwent a hyperinsulinaemic euglycaemic clamp, i.v. and oral glucose tolerance tests and a dual-energy X-ray absorptiometry scan. The parents' anthropometric status and metabolic parameters were assessed. RESULTS: Men with LBW were shorter (167+/-6.4 vs 172+/-6.0 cm, P<0.0001), lighter (51.9+/-9 vs 55.4+/-7 kg, P=0.02) and had a reduced lean body mass (42.1+/-5.4 vs 45.0+/-4.5 kg, P=0.002) compared with NBW controls. After adjustment for height and weight, the LBW subjects had increased diastolic blood pressure (77+/-6 vs 75+/-6 mmHg, P=0.01). Five LBW subjects had impaired glucose tolerance. In vivo insulin secretion and peripheral insulin action were similar in both the groups. Mothers of the LBW subjects were 3 cm shorter than the control mothers. CONCLUSION: Only subtle features of the metabolic syndrome and changes in body composition among LBW rural Indians were found. Whether other factors such as urbanisation and ageing may unmask more severe metabolic abnormalities may require a long-term follow-up. PMID- 22250075 TI - Impact of the etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome. AB - Acute kidney injury (AKI) at the time of liver transplantation (LT) has been associated with increased morbidity and mortality. In patients with potentially reversible renal dysfunction, predicting whether there will be sufficient return of native kidney function is sometimes difficult. Previous studies have focused mainly on the effect of the severity of renal dysfunction or the duration of pretransplant dialysis on posttransplant outcomes. We performed a retrospective analysis of patients who underwent LT at our center after Model for End-Stage Liver Disease-based allocation so that we could determine the impact of the etiology of AKI [acute tubular necrosis (ATN) versus hepatorenal syndrome (HRS)] on post-LT outcomes. The patients were stratified according to the severity of AKI at the time of LT as described by the Risk, Injury, Failure, Loss, and End Stage Kidney Disease (RIFLE) classification: risk, injury, or failure. The RIFLE failure group was further subdivided according to the etiology of AKI: HRS or ATN. The patient survival and renal outcomes 1 and 5 years after LT were significantly worse for those with ATN. At 5 years, the incidence of chronic kidney disease (stage 4 or 5) was statistically higher in the ATN group versus the HRS group (56% versus 16%, P < 0.001). A multivariate analysis revealed that the presence of ATN at the time of LT was the only variable associated with higher mortality 1 year after LT (P < 0.001). Our study is the first to demonstrate that the etiology of AKI has the greatest impact on patient and renal outcomes after LT. PMID- 22250074 TI - Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly. AB - OBJECTIVE: To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR QoL) in relation to disease control in patients with acromegaly. DESIGN: This is a cross-sectional study in two tertiary referral centers in The Netherlands. PATIENTS AND METHODS: One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS. RESULTS: IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85+/-1.52 vs 0.25+/-1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44+/-0.72 vs SSTA-, n=44, IGF1 SDS 0.41+/-0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA. CONCLUSION: QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels. PMID- 22250076 TI - Subjective and objective perception of orthodontic treatment need: a systematic review. AB - The aim of this work was to investigate the published evidence on the comparison of self-perception and diagnosis of orthodontic treatment need. A search of Cochrane Library, MEDLINE, Scopus databases, and archives of two orthodontic journals was carried out from January 1966 to August 2011 by the two authors using Medical Subject Heading terms. Studies that investigated solely either self perception of orthodontic need by laypersons or assessment of orthodontic need by professionals were excluded from the data analysis. The methodological soundness of each study and the aggregate level of evidence were evaluated according to predetermined criteria. Moderate level of evidence, the relatively highest grade, was assigned to 9.1 per cent of the 22 studies, finally included in the data analysis. The overall evidence level provided by the evaluated publications was rated as limited. However, the existing body of evidence indicated a highly variable association between self-perception of orthodontic treatment need and orthodontist's assessment. Future controlled studies with well-defined samples and common assessment methodology will clarify further the relationship between perception of treatment need by laypersons and orthodontists and enhance international comparison and development of health care strategies. PMID- 22250077 TI - Antiretroviral medication and HIV prevention: new steps forward and new questions. AB - During the past 2 years, several pivotal clinical trials have proven that the use of antiretrovirals by HIV-infected and at-risk uninfected persons can decrease the probability of HIV being transmitted sexually. The initial chemoprophylaxis studies evaluated tenofovir administered topically or orally (with or without emtricitabine). However, several questions remain. Some subsequent primary prevention studies did not replicate the results of the initial studies, raising questions about differences in the behaviors of participants in each study (in particular about medication adherence), as well as whether pharmacologic or local mucosal factors might explain the variable efficacy estimates. Other antiretrovirals and delivery systems are being evaluated to maximize the efficacy of primary chemoprophylactic approaches. At present, increasing access to antiretroviral treatment globally is a priority, because expanding access to medication that can prevent morbidity and mortality is itself an important public health goal and may reasonably be expected to decrease HIV incidence. However, for treatment as prevention to be maximally effective, increases in HIV testing, health care workers, and infrastructure are needed, in addition to medications and laboratory support for clinical monitoring. A combination of approaches is needed to most quickly decrease the current trends in HIV incidence, including early diagnosis and initiation of treatment for HIV-infected persons. These approaches can be coupled with appropriately tailored interventions for populations at greatest risk for infection (for example, men who have sex with men and sex workers), including male circumcision, behavioral interventions, and chemoprophylaxis. However, a substantial gap exists between current expenditures and unmet needs, which suggests that mobilization of political will is needed for this combination approach to be successful. PMID- 22250078 TI - Liver transplantation in septuagenarians receiving model for end-stage liver disease exception points for hepatocellular carcinoma: the national experience. AB - Current liver allocation policy in the United States grants liver transplant candidates with stage T2 hepatocellular carcinoma (HCC) a priority Model for End Stage Liver Disease (MELD) score of 22, regardless of age. Because advanced age may portend an increase in all-cause mortality after transplantation for any diagnosis, the aim of this study was to examine overall posttransplant survival in elderly patients with HCC versus younger cohorts. Based on Organ Procurement and Transplantation Network data, Kaplan-Meier 5-year survival rates were compared. Recipients undergoing primary liver transplantation were stratified into cohorts based on age (<70 or >= 70 years) and the receipt of MELD exception points for HCC. Log-rank and Wilcoxon tests were used for statistical comparisons. In 2009, 143 transplants were performed for patients who were 70 years old or older. Forty-two percent of these patients received a MELD exception for HCC. Regardless of the diagnosis, the overall survival rate was significantly attenuated for the septuagenarians versus the younger cohort. After 5 years of follow-up, this disparity exceeded 10% to 15% depending on the populations being compared. The 1-, 2-, 3-, 4-, and 5-year actuarial survival rates were 88.4%, 83.2%, 79.6%, 76.1%, and 72.7%, respectively, for the patients who were younger than 70 years and 81.1%, 73.8%, 67.1%, 61.9%, and 55.2%, respectively, for the patients who were 70 years old or older. Five-year survival was negatively affected for patients with HCC who were younger than 70 years; this disparity was not observed for patients with HCC who were 70 years old or older. In conclusion, although patients who are 70 years old or older compose a small fraction of transplant recipients in the United States, patients in this group undergoing transplantation for HCC form an even smaller subset. Overall, transplantation in this age group yields outcomes inferior to those for younger cohorts. However, unlike patients who are less than 70 years old and receive MELD exception points, overall liver transplant survival is not affected by HCC at an advanced age. PMID- 22250079 TI - Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness. AB - We established a diphtheria toxin (DT)-based conditional deletion system using Il4 enhancer elements previously shown to be specific for IL-4 production in mast cells (MCs) or basophils (Mas-TRECK and Bas-TRECK mice). DT treatment of Bas TRECK mice resulted in specific deletion of basophils, whereas both MCs and basophils were deleted in Mas-TRECK mice. DT-treated Mas-TRECK mice had impaired passive cutaneous anaphylaxis, IgE-mediated passive systemic anaphylaxis, and IgE mediated chronic allergic inflammation, whereas DT-treated Bas-TRECK mice had impaired IgE-mediated chronic allergic inflammation. Using these mice, we also sought to tease out the role of MCs and basophils in airway hyperresponsiveness (AHR). Although MC deletion resulted in a slight increase in basal Ag-specific IgE levels and significant increases in basal IgE levels, we found that this deletion markedly impaired the AHR effector phase and was accompanied by decreased histamine levels. By contrast, basophil deletion had no effect on the AHR effector phase or on IgE production induced by systemic OVA immunization. Our results, using these newly established Mas-TRECK and Bas-TRECK models, demonstrated an indispensable role for MCs as effector cells in AHR. PMID- 22250080 TI - A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement. PMID- 22250081 TI - B lymphocytes treated in vitro with antigen coupled to cholera toxin B subunit induce antigen-specific Foxp3(+) regulatory T cells and protect against experimental autoimmune encephalomyelitis. AB - The ability of activated B cells to protect against various experimental autoimmune or allergic diseases makes them attractive for use in cell-based therapies. We describe an efficient way to generate B cells with strong suppressive functions by incubating naive B cells with a relevant Ag conjugated to cholera toxin B subunit (CTB). This allows most B cells, irrespective of BCR, to take up and present Ag and induces their expression of latency-associated polypeptide (LAP)/TGF-beta and after adoptive transfer also their production of IL-10. With OVA as model Ag, when naive T cells were cocultured in vitro with B cells pretreated with OVA conjugated to CTB (OVA/CTB) Ag-specific CD4(+) Foxp3 regulatory T (Treg) cells increased >50-fold. These cells effectively suppressed CD25(-)CD4(+) effector T (Teff) cells in secondary cultures. Adoptive transfer of OVA/CTB-treated B cells to mice subsequently immunized with OVA in CFA induced increase in Foxp3 Treg cells together with suppression and depletion of Teff cells. Likewise, adoptive transfer of B cells pulsed with myelin oligodendrocyte glycoprotein peptide(35-55) (MOGp) conjugated to CTB increased the number of Treg cells, suppressed MOGp-specific T cell proliferation and IL-17 and IFN-gamma production, and prevented the development of experimental autoimmune encephalomyelitis. Similar effects were seen when B cells were given "therapeutically" to mice with early-stage experimental autoimmune encephalomyelitis. Our results suggest that B cells pulsed in vitro with relevant Ag/CTB conjugates may be used in cell therapy to induce Ag-specific suppression of autoimmune disease. PMID- 22250082 TI - Tetracyclines convert the osteoclastic-differentiation pathway of progenitor cells to produce dendritic cell-like cells. AB - Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF kappaB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti-GM-CSF-neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c(+) cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion. PMID- 22250083 TI - Cutting edge: IL-21 derived from human follicular helper T cells acts as a survival factor for secondary lymphoid organ, but not for bone marrow, plasma cells. AB - IL-21 induces the differentiation of activated B lymphocytes into plasma cells (PC), but its direct effect on PC remains uncertain. This study analyzes the role of IL-21 on human in vivo-generated PC. IL-21R was clearly expressed on PC from the human tonsil, the lymph node, and the spleen (secondary lymphoid organs [SLO]) but barely on terminally mature bone marrow PC. IL-21 enhanced Ig secretion by isolated SLO PC but not bone marrow PC. Tonsillar T follicular helper (Tfh) lymphocytes are known to secrete IL-21. Purified Tfh cells induced a marked increase of Ig production by tonsillar PC, and this effect was impaired when endogenous IL-21 production was blocked. IL-21 provoked a rapid and transient phosphorylation of STAT3 in tonsillar PC. Tfh cells or exogenous IL-21 reduce tonsillar PC apoptosis and increases PC recovery but does not modify their nonproliferating status. These results suggest that IL-21 derived from Tfh cells acts as a survival factor for SLO PC in vivo. PMID- 22250084 TI - Membrane-tethered MUC1 mucin is phosphorylated by epidermal growth factor receptor in airway epithelial cells and associates with TLR5 to inhibit recruitment of MyD88. AB - MUC1 is a membrane-tethered mucin glycoprotein expressed on the apical surface of mucosal epithelial cells. Previous in vivo and in vitro studies established that MUC1 counterregulates airway inflammation by suppressing TLR signaling. In this article, we elucidate the mechanism by which MUC1 inhibits TLR5 signaling. Overexpression of MUC1 in HEK293 cells dramatically reduced Pseudomonas aeruginosa-stimulated IL-8 expression and decreased the activation of NF-kappaB and MAPK compared with cells not expressing MUC1. However, overexpression of MUC1 in HEK293 cells did not affect NF-kappaB or MAPK activation in response to TNF alpha. Overexpression of MyD88 abrogated the ability of MUC1 to inhibit NF-kappaB activation, and MUC1 overexpression inhibited flagellin-induced association of TLR5/MyD88 compared with controls. The MUC1 cytoplasmic tail associated with TLR5 in all cells tested, including HEK293T cells, human lung adenocarcinoma cell line A549 cells, and human and mouse primary airway epithelial cells. Activation of epidermal growth factor receptor tyrosine kinase with TGF-alpha induced phosphorylation of the MUC1 cytoplasmic tail at the Y46EKV sequence and increased association of MUC1/TLR5. Finally, in vivo experiments demonstrated increased immunofluorescence colocalization of Muc1/TLR5 and Muc1/phosphotyrosine staining patterns in mouse airway epithelium and increased Muc1 tyrosine phosphorylation in mouse lung homogenates following P. aeruginosa infection. In conclusion, epidermal growth factor receptor tyrosine phosphorylates MUC1, leading to an increase in its association with TLR5, thereby competitively and reversibly inhibiting recruitment of MyD88 to TLR5 and downstream signaling events. This unique ability of MUC1 to control TLR5 signaling suggests its potential role in the pathogenesis of chronic inflammatory lung diseases. PMID- 22250085 TI - ExoS and ExoT ADP ribosyltransferase activities mediate Pseudomonas aeruginosa keratitis by promoting neutrophil apoptosis and bacterial survival. AB - Pseudomonas aeruginosa is a leading cause of blinding corneal ulcers worldwide. To determine the role of type III secretion in the pathogenesis of P. aeruginosa keratitis, corneas of C57BL/6 mice were infected with P. aeruginosa strain PAO1 or PAK, which expresses ExoS, ExoT, and ExoY, but not ExoU. PAO1- and PAK infected corneas developed severe disease with pronounced opacification and rapid bacterial growth. In contrast, corneas infected with DeltapscD or DeltapscJ mutants that cannot assemble a type III secretion system, or with mutants lacking the translocator proteins, do not develop clinical disease, and bacteria are rapidly killed by infiltrating neutrophils. Furthermore, survival of PAO1 and PAK strains in the cornea and development of corneal disease was impaired in DeltaexoS, DeltaexoT, and DeltaexoST mutants of both strains, but not in a DeltaexoY mutant. DeltaexoST mutants were also rapidly killed in neutrophils in vitro and were impaired in their ability to promote neutrophil apoptosis in vivo compared with PAO1. Point mutations in the ADP ribosyltransferase (ADPR) regions of ExoS or ExoT also impaired proapoptotic activity in infected neutrophils, and exoST(ADPR-) mutants replicated the DeltaexoST phenotype in vitro and in vivo, whereas mutations in rho-GTPase-activating protein showed the same phenotype as PAO1. Together, these findings demonstrate that the pathogenesis of P. aeruginosa keratitis in ExoS- and ExoT-producing strains is almost entirely due to their ADPR activities, which subvert the host response by targeting the antibacterial activity of infiltrating neutrophils. PMID- 22250086 TI - Activation of the NLRP3 inflammasome by group B streptococci. AB - Group B Streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show in this study that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1beta and IL-18. IL-1beta release required both pro-IL-1beta transcription and caspase-1-dependent proteolytic cleavage of intracellular pro IL-1beta. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro-IL-1beta mRNA in response to GBS. Pro-IL-1beta cleavage and secretion of the mature IL-1beta form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis associated speck-like protein containing a caspase activation and recruitment domain adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of beta-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, apoptosis-associated speck-like protein, or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome. PMID- 22250087 TI - Allergen-specific CTL require perforin expression to suppress allergic airway inflammation. AB - Allergen-specific CTL have a protective effect on allergic airway inflammation, a function thought to be mediated by cytokines, especially IFN-gamma. However, the contribution of cytotoxic function to this protective effect has not been investigated. We examined the contribution of cytotoxic function to the therapeutic effect of allergen-specific CTL in allergic airway inflammation. We used a murine model of allergic airway inflammation in which mice were sensitized to OVA and then challenged with the same Ag via the intranasal route. CTL were elicited in these mice by immunization with dendritic cells (DC) or by adoptive transfer of in vitro-activated CD8(+) T cells. Hallmark features of allergic asthma, such as infiltration of eosinophils in the bronchoalveolar lavage fluid and mucus production, were assessed. Suppression of allergic airway inflammation by allergen-specific CTL was critically dependent on the expression of perforin, a key component of the cytotoxic machinery. Both perforin-sufficient and perforin deficient allergen-specific CTL were recovered from the lungs of allergen sensitized mice and upregulated CD69 expression and secreted the cytokines IFN gamma and TNF-alpha upon intranasal allergen challenge. However, only perforin sufficient CTL inhibited eosinophil infiltration in the airway, mucus production, and cytokine accumulation in the bronchoalveolar lavage fluid. Treatment with allergen-specific CTL, but not their perforin-deficient counterparts, was also associated with a decrease in the number of DC in the mediastinal lymph node. Our data suggest that the cytotoxic function of allergen-specific CD8(+) T cells is critical to their ability to moderate allergic airway inflammation. PMID- 22250088 TI - Th2 skewing by activation of Nrf2 in CD4(+) T cells. AB - NF erythroid 2-related factor 2 (Nrf2) is a transcription factor that mediates the upregulation of a battery of cytoprotective genes in response to cell stress. Recent studies showed that Nrf2 also modulates immune responses and exhibits anti inflammatory activity. In this article, we demonstrate that a common food preservative, tert-butylhydroquinone, can activate Nrf2 in T cells, as evidenced by Nrf2 binding to the antioxidant response element and the subsequent upregulation of Nrf2 target genes. The activation of Nrf2 suppresses IFN-gamma production, while inducing the production of the Th2 cytokines IL-4, IL-5, and IL 13. Nrf2 activation also suppresses T-bet DNA binding and promotes GATA-binding protein 3 DNA binding. Collectively, the present studies suggested that Nrf2 activation skews CD4(+) T cells toward Th2 differentiation and, thus, represents a novel regulatory mechanism in CD4(+) T cells. Further studies are needed to determine whether the commercial use of Nrf2 activators as food preservatives promotes food allergies in humans. PMID- 22250089 TI - Human MSH6 deficiency is associated with impaired antibody maturation. AB - Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of gammaH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions. PMID- 22250090 TI - Human gammadelta T lymphocytes are licensed for professional antigen presentation by interaction with opsonized target cells. AB - Activated human blood gammadelta T cells have also been previously demonstrated to behave as professional APCs, although the processes that control APC function have not been characterized. n this study, we show that the acquisition of potent APC function by human blood gammadelta T cells is achieved after physical interaction with an Ab-coated target cell, a process that we refer to as licensing. In cancer models, licensing of gammadelta T cells by tumor-reactive mAbs promotes the uptake of tumor Ags and professional presentation to tumor reactive alphabeta T cells. We propose that licensing by Ab is a mechanism whereby the adaptive properties of gammadelta T cells are induced by their innate functions in a spatially and temporally controlled manner. PMID- 22250091 TI - Synergism between curdlan and GM-CSF confers a strong inflammatory signature to dendritic cells. AB - A simultaneous engagement of different pathogen recognition receptors provides a tailor-made adaptive immunity for an efficient defense against distinct pathogens. For example, cross-talk of TLR and C-type lectin signaling effectively shapes distinct gene expression patterns by integrating the signals at the level of NF-kappaB. In this study, we extend this principle to a strong synergism between the dectin-1 agonist curdlan and an inflammatory growth factor, GM-CSF. Both together act in synergy in inducing a strong inflammatory signature that converts immature dendritic cells (DCs) to potent effector DCs. A variety of cytokines (IL-1beta, IL-6, TNF-alpha, IL-2, and IL-12p70), costimulatory molecules (CD80, CD86, CD40, and CD70), chemokines (CXCL1, CXCL2, CXCL3, CCL12, CCL17), as well as receptors and molecules involved in fugal recognition and immunity such as Mincle, dectin-1, dectin-2, and pentraxin 3 are strongly upregulated in DC treated simultaneously with curdlan and GM-CSF. The synergistic effect of both stimuli resulted in strong IkappaBalpha phosphorylation, its rapid degradation, and enhanced nuclear translocation of all NF-kappaB subunits. We further identified MAPK ERK as one possible integration site of both signals, because its phosphorylation was clearly augmented when curdlan was coapplied with GM-CSF. Our data demonstrate that the immunomodulatory activity of curdlan requires an additional signal provided by GM-CSF to successfully initiate a robust beta-glucan-specific cytokine and chemokine response. The integration of both signals clearly prime and tailor a more effective innate and adaptive response against invading microbes and fungi. PMID- 22250092 TI - CD69 regulates type I IFN-induced tolerogenic signals to mucosal CD4 T cells that attenuate their colitogenic potential. AB - CD69 is highly expressed by lymphocytes at mucosal surfaces. We aimed to investigate the role of CD69 in mucosal immune responses. The expression of CD69 by CD4 T cells isolated from the spleen, mesenteric lymph nodes, small intestinal lamina propria, and colonic lamina propria was determined in specific pathogen free B6 and TCR transgenic animals, as well as in germ-free B6 mice. Transfer colitis was induced by transplanting RAG(-/-) mice with B6 or CD69(-/ )CD45RB(high) CD4 T cells. CD69 expression by CD4 T cells is induced by the intestinal microflora, oral delivery of specific Ag, and type I IFN (IFN-I) signals. CD4 T cells from CD69(-/-) animals produce higher amounts of the proinflammatory cytokines IFN-gamma, TNF-alpha, and IL-21, whereas the production of TGF-beta1 is decreased. CD69-deficient CD4 T cells showed reduced potential to differentiate into Foxp3(+) regulatory T cells in vivo and in vitro. The transfer of CD69(-/-)CD45RB(high) CD4 T cells into RAG(-/-) hosts induced an accelerated colitis. Oral tolerance was impaired in CD69(-/-) and IFN-I receptor 1-deficient mice when compared with B6 and OT-II * RAG(-/-) animals. Polyinosinic polycytidylic acid treatment of RAG(-/-) mice transplanted with B6 but not CD69( /-) or IFN-I receptor 1-deficient CD45RB(high) CD4 T cells attenuated transfer colitis. CD69 deficiency led to the increased production of proinflammatory cytokines, reduced Foxp3(+) regulatory T cell induction, impaired oral tolerance, and more severe colitis. Hence, the activation Ag CD69 plays an important role in regulating mucosal immune responses. PMID- 22250094 TI - Increasing smokers' risk perception improves CT screening participation. PMID- 22250093 TI - PSGL-1 regulates the migration and proliferation of CD8(+) T cells under homeostatic conditions. AB - P-selectin glycoprotein ligand-1 (PSGL-1), a heavily glycosylated sialomucin expressed on most leukocytes, has dual function as a selectin ligand for leukocyte rolling on vascular selectins expressed in inflammation and as a facilitator of resting T cell homing into lymphoid organs. In this article, we document disturbances in T cell homeostasis present in PSGL-1(null) mice. Naive CD4(+) and CD8(+) T cell frequencies were profoundly reduced in blood, whereas T cell numbers in lymph nodes and spleen were at or near normal levels. Although PSGL-1(null) T cells were less efficient at entering lymph nodes, they also remained in lymph nodes longer than PSGL-1(+/+) T cells, suggesting that PSGL-1 supports T cell egress. In addition, PSGL-1(null) CD8(+) T cell proliferation was observed under steady-state conditions and PSGL-1(null) CD8(+) T cells were found to be hyperresponsive to homeostatic cytokines IL-2, IL-4, and IL-15. Despite these disturbances in T cell homeostasis, PSGL-1(null) mice exhibited a normal acute response (day 8) to lymphocytic choriomeningitis virus infection but generated an increased frequency of memory T cells (day 40). Our observations demonstrate a novel pleiotropic influence of PSGL-1 deficiency on several aspects of T cell homeostasis that would not have been anticipated based on the mild phenotype of PSGL-1(null) mice. These potentially offsetting effects presumably account for the near-normal cellularity seen in lymph nodes of PSGL-1(null) mice. PMID- 22250096 TI - A puzzling tumour. PMID- 22250097 TI - Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. AB - RATIONALE: Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied. OBJECTIVE: This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia. METHODS AND RESULTS: Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2. CONCLUSIONS: Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs. PMID- 22250098 TI - Clinical validity of plasma and urinary desmosine as biomarkers for chronic obstructive pulmonary disease. AB - BACKGROUND: Although an increased concentration of degraded elastin products in patients with chronic obstructive pulmonary disease (COPD) has been reported for many years, its clinical validity and utility remain uncertain due to technical difficulties, small study groups and the unknown relationship between exacerbation and elastin degradation. The objectives of this study were to determine the validity of urinary and blood total desmosine/isodesmosine in patients with COPD and asthma and to evaluate their relationship to exacerbation status and lung function. METHODS: Urinary and blood desmosine levels were measured using validated isotopic dilution liquid chromatography-tandem mass spectrometry methods. RESULTS: 390 study participants were recruited from the following groups: healthy volunteers, stable asthma, stable and 'during an exacerbation' COPD. Compared with healthy non-smokers, we found increased urinary or blood desmosine levels in patients with COPD, but no differences in patients with asthma or healthy smokers. The elevation of urinary desmosine levels was associated with the exacerbation status in patients with COPD. Approximately 40% of patients with stable and 'during an exacerbation' COPD showed elevated blood desmosine levels. Blood desmosine levels were strongly associated with age and were negatively correlated with lung diffusing capacity for carbon monoxide. CONCLUSION: The results suggest that urinary desmosine levels are raised by exacerbations of COPD whereas blood desmosine levels are elevated in a subgroup of patients with stable COPD and reduced lung diffusing capacity. The authors speculate that a raised blood desmosine level may identify patients with increased elastin degradation suitable for targeted therapy. Future prospective studies are required to investigate this hypothesis. PMID- 22250099 TI - National audit of supported discharge programmes for management of acute exacerbations of chronic obstructive pulmonary disease 2008. AB - The 2008 U.K. national chronic obstructive pulmonary disease (COPD) audit examined the use of supported discharge programmes (SDPs) in clinical practice against British Thoracic Society guidelines. 98% of acute U.K. trusts participated. SDPs were available in 142 of 239 (59%) units. 1630 of 8971 (18%) patients with COPD were treated within SDPs. Median (IQR) stay in hospital for patients within SDPs and those not accepted for SDPs was 3 (1-6) days and 6 (3 11) days (p<0.001), and mortality within 90 days of admission was 4.3% and 6.7%, respectively. SDPs within the U.K. are safe and effective and reduce length of hospital stay without adverse effects on mortality. PMID- 22250100 TI - Novel strategies for the management of right ventricular failure with pulmonary hypertension. AB - The authors report a case where four novel strategies were successfully used in the management of advanced right ventricular failure with severe pulmonary hypertension and complex adult congenital heart disease. These included combination and optimisation of three advanced therapies for pulmonary hypertension, therapeutic abdominal paracentesis, correction of underlying metabolic/endocrine disturbance and a new inotropic agent. PMID- 22250101 TI - Unflued gas heaters and respiratory symptoms in older people with asthma. AB - BACKGROUND: Unflued gas heaters (UFGHs) and cookers are a major contributor to air pollution in homes. Gas appliances have been associated with adverse respiratory outcomes in children and, less consistently, adults. There have been very few studies on the effects of gas appliances on the respiratory health of older people. OBJECTIVES: This study investigated the daily lung function and respiratory symptoms of older people (>55 years of age) who did and did not use an UFGH as a primary source of heating. METHODS: 71 patients with asthma were recruited for the study. Each patient participated for one 12-week winter period. All patients recorded daytime and night-time symptoms in a diary and completed morning and evening peak flow and forced expiratory volume in 1 s for the study period. General estimating equations were used to measure the associations between symptoms and lung function outcomes and same and previous day (lag 1) UFGH exposure. RESULTS: Same and previous day (lag 1) UFGH exposure was associated with significantly increased ORs for wheeze and dyspnoea compared with days on which no heating was used. Furthermore, there were significant increases in the average odds of reported wheeze and dyspnoea per hour of UFGH heater use. Small but significant reductions in morning to evening peak flow and forced expiratory volume in 1 s were observed on the days an UFGH was used compared with days when other heating was used or there was no heating. CONCLUSION: Exposure to UFGHs may have a detrimental effect on symptoms and lung function in older people with mild to moderate asthma. PMID- 22250104 TI - Geriatric surgery: past, present, and future. PMID- 22250105 TI - Little effect of insurance status or socioeconomic condition on disparities in minority appendicitis perforation rates. AB - OBJECTIVE: To estimate how much of the gap in appendicitis perforation rates between minority and white children is explained by differences in socioeconomic and insurance factors. DESIGN: Observational analysis of hospital discharge information. SETTING: The Healthcare Cost and Utilization Project database. PARTICIPANTS: Appendicitis perforation rates determined from the Healthcare Cost and Utilization Project database of hospital discharges from 2001 to 2008. MAIN OUTCOME MEASURES: The proportion of the gap between perforation rates explained by various patient- and hospital-level variables. RESULTS: There were no disparities observed in adult appendicitis perforation rates. The perforation rate for white children was 26.7%; black children, 35.5%; and Latino children, 36.5%. Gap analysis showed that only 12.0% of the difference in perforation rates between black and white children was explained by insurance status and only 12.7% of the difference between Latino and white children was explained. Income level only accounted for 7.2% of the gap for black children and 6.1% for Latino children. Age explained one-third of the gap for Latino children and one-third was not accounted for by measurable variables. Two-thirds of the difference between appendicitis perforation rates between black and white children was not explained by measurable factors. CONCLUSIONS: A very small amount of the gap between minority and white children's appendicitis rates is explained by the proxy factors for health insurance and poverty status that might relate to health care access. Appendicitis perforation rates are not an appropriate indicator of health care access. PMID- 22250106 TI - Combined CD133/CD44 expression as a prognostic indicator of disease-free survival in patients with colorectal cancer. AB - HYPOTHESIS: Because of some inconsistencies in the traditional model of human colorectal carcinogenesis, the cancer stem cell (CSC) model was recently proposed, in which tumor results from neoplastic transformation of stem cells, which become CSCs. Identification of CSCs by expression of surface antigens remains a critical issue because no biomarker has been shown to be completely reliable. CD133 and CD44 are commonly used as CSC markers, and correlation of their expression with colorectal cancer (CRC) clinicopathological features and outcomes may be useful. DESIGN: Pilot study. SETTING: University hospital. PATIENTS: Thirty-six consecutive patients with CRC. CD133 and CD44 expression (alone or combined) was determined in nontumor cells and in tumor cells by flow cytometry, which identified viable cells only. MAIN OUTCOME MEASURES: Correlation of CD133 and CD44 expression with each other, with other prognostic indicators, and with disease-free survival. RESULTS: CD133 and CD44 expression was significantly higher in tumor cells than in nontumor cells, and expression of one did not necessarily correlate with expression of the other. CD133 or CD44 expression alone was variable, while combined CD133/CD44 expression identified a small subset of cells positive for CRC. CD133 or CD44 overexpression was not associated with CRC recurrence; only high frequencies of CD133(+)/CD44(+) cells were a strong indicator of worse disease-free survival and an independent risk factor for CRC recurrence. CONCLUSION: Evaluation of combined CD133/CD44 expression could be useful to identify putative colorectal CSCs and tumors with a poor prognosis. PMID- 22250107 TI - Colorectal cancer stem cells--hype or real?: comment on "Combined CD133+/CD44+ expression as a prognostic indicator of disease-free survival in patients with colorectal cancer". PMID- 22250108 TI - Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients. AB - OBJECTIVE: To evaluate improvements in operative and long-term results following surgery for hilar cholangiocarcinoma. DESIGN: Retrospective multicenter study including 17 Italian hepatobiliary surgery units. PATIENTS: A total of 440 patients who underwent resection for hilar cholangiocarcinoma from January 1, 1992, through December 31, 2007. MAIN OUTCOME MEASURES: Postoperative mortality, morbidity, overall survival, and disease-free survival. RESULTS: Postoperative mortality and morbidity after liver resection were 10.1% and 47.6%, respectively. At multivariate logistic regression, extent of resection (right or right extended hepatectomy) and intraoperative blood transfusion were independent predictors of postoperative mortality (P = .03 and P = .006, respectively); in patients with jaundice, mortality was also higher without preoperative biliary drainage than with biliary drainage (14.3% vs 10.7%). During the study period, there was an increasingly aggressive approach, with more frequent caudate lobectomies, vascular resections, and resections for advanced tumors (T stage of 3 or greater and tumors with poor differentiation). Despite the aggressive approach, the blood transfusion rate decreased from 81.0% to 53.2%, and mortality slightly decreased from 13.6% to 10.8%. Median overall survival significantly increased from 16 to 30 months (P = .05). At multivariate analysis, R1 resection, lymph node metastases, and T stage of 3 or greater independently predicted overall and disease-free survival. CONCLUSIONS: Surgery for hilar cholangiocarcinoma has improved with decreased operative risk despite a more aggressive surgical policy. Long-term survival after liver resection has also increased, despite the inclusion of cases with more advanced hilar cholangiocarcinoma. Preoperative biliary drainage was a safe strategy before right or right extended hepatectomy in patients with jaundice. Pathologic factors independently predicted overall and disease-free survival at multivariate analysis. PMID- 22250109 TI - Stenting and the rate of pancreatic fistula following pancreaticoduodenectomy. AB - OBJECTIVE: To evaluate the efficacy of transanastomotic pancreatic duct internal stenting in the reduction of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy. DESIGN: Retrospective study. SETTING: Mayo Clinic. PATIENTS: Between January 1, 1999, and September 30, 2010, 553 patients underwent pancreaticoduodenectomy by a single surgeon. MAIN OUTCOME MEASURES: Rates of POPF, morbidity, and mortality between stent and no-stent groups. RESULTS: The clinically relevant POPF (International Study Group on Pancreatic Fistula definition grade B or C) rates in the stent and no-stent groups were similar (9.6% [43 of 449 patients] and 12.5% [13 of 104 patients], respectively; P = .38). Postoperative outcomes and morbidity were also similar between the 2 groups. Mortality was 0.7% (3 of 449 patients) for the stent group and 1.0% (1 of 104 patients) for the no-stent group. Four patients (0.9%) required endoscopic retrieval of the anastomotic stent. In subset analysis, the clinically relevant POPF rates in patients with a small pancreatic duct (<=3 mm; n = 167) were similar in the stent and no-stent groups (17.7% [23 of 130 patients] and 24.3% [9 of 37 patients], respectively; P = .38). In patients with a soft pancreatic gland (n = 64), rates of clinically relevant pancreatic fistulae were also similar in the stent and no-stent groups (31.7% [13 of 41 patients] and 17.4% [4 of 23 patients], respectively; P = .20). CONCLUSIONS: Internal transanastomotic pancreatic duct stenting does not decrease the frequency or severity of POPF. The effect of stenting on long-term anastomotic patency warrants further investigation. PMID- 22250110 TI - The right way to do a Whipple procedure: comment on "Stenting and the rate of pancreatic fistula following pancreaticoduodenectomy". PMID- 22250111 TI - Oncological efficiency analysis of laparoscopic liver resection for primary and metastatic cancer: a single-center UK experience. AB - OBJECTIVE: To assess the oncological efficiency of laparoscopic minor and major hepatectomy for primary and metastatic liver malignant neoplasms. DESIGN: Retrospective single-center study. SETTING: Tertiary university hospital. PATIENTS: One hundred twenty-eight patients undergoing 133 laparoscopic liver resections for malignant diseases. MAIN OUTCOME MEASURES: Perioperative results and midterm overall and disease-free survival. RESULTS: Surgical indications were colorectal carcinoma liver metastasis (n = 83), hepatocellular carcinoma (n = 18), neuroendocrine tumor metastasis (n = 17), non-colorectal carcinoma liver metastasis (n = 11), lymphoma (n = 2), and intrahepatic cholangiocarcinoma (n = 2). Two patients had 2-stage laparoscopic resections for bilobar colorectal carcinoma liver metastasis. Three patients had repeated liver resection for recurrent colorectal carcinoma liver metastasis. Forty-two major hepatectomies (32%) were performed. The median operative time was 210 minutes (range, 30-480 minutes). The median postoperative length of stay was 4 days (range, 1-15 days). Seven patients required conversion to formal open surgery and 4 patients required conversion to a laparoscopic-assisted procedure. Sixteen patients (13%) developed significant postoperative complications. One patient (0.8%) died in the hospital. In the 17 patients with neuroendocrine tumor metastasis, 6 (35%) had microscopic positive resection margins. Most of these patients underwent debulking and cytoreductive surgery. A microscopic negative resection margin was obtained in the remaining 112 of 116 resections (97%). We recorded 2-year overall survivals of 80%, 77%, and 91% in the groups with colorectal carcinoma liver metastasis, hepatocellular carcinoma, and neuroendocrine tumor metastasis, respectively. CONCLUSIONS: Our data support the safety and oncological efficiency of laparoscopic resection for liver malignant neoplasms. Adequate patient selection and extensive experience in hepatic and laparoscopic surgery are essential prerequisites to optimize outcomes. PMID- 22250112 TI - Laparoscopic vs open liver resection: comment on "Oncological efficiency analysis of laparoscopic liver resection for primary and metastatic cancer". PMID- 22250113 TI - Surgical outcomes and transfusion of minimal amounts of blood in the operating room. AB - OBJECTIVE: To examine outcomes in patients who receive small amounts of intraoperative blood transfusion. DESIGN: Longitudinal, uncontrolled observational study evaluating results of intraoperative transfusion in patients entered into the American College of Surgeons National Surgical Quality Improvement Program database. We made propensity-matched comparisons between patients who received and did not receive intraoperative transfusion to minimize confounding when estimating the effect of intraoperative transfusion on postoperative outcomes. SETTING: We queried the American College of Surgeons National Surgical Quality Improvement Program database for patients undergoing operations between January 1, 2005, and December 31, 2009. PATIENTS: A large sample of surgical patients from 173 hospitals throughout the United States. MAIN OUTCOME MEASURES: Operative mortality and serious perioperative morbidity (>=1 of 20 complications). RESULTS: After exclusions, 941,496 operations were analyzed in patients from 173 hospitals. Most patients (893,205 patients [94.9%]) did not receive intraoperative transfusions. Patients who received intraoperative infusion of 1 unit of packed red blood cells (15,186 patients [1.6%]) had higher unadjusted rates of mortality and more serious morbidity. These rates further increased with intraoperative transfusion of more than 1 unit of packed red blood cells in a dose-dependent manner. After propensity matching to adjust for multiple preoperative risks, transfusion of a single unit of packed red blood cells increased the multivariate risk of mortality, wound problems, pulmonary complications, postoperative renal dysfunction, systemic sepsis, composite morbidity, and postoperative length of stay compared with propensity-matched patients who did not receive intraoperative transfusion. CONCLUSIONS: There is a dose-dependent adverse effect of intraoperative blood transfusion. It is likely that a small, possibly discretionary amount of intraoperative transfusion leads to increased mortality, morbidity, and resource use, suggesting that caution should be used with intraoperative transfusions for mildly hypovolemic or anemic patients. PMID- 22250114 TI - Minimal transfusions: comment on "Surgical outcomes and transfusion of minimal amounts of blood in the operating room". PMID- 22250116 TI - Informed consent, trainees, and the cost of full disclosure: comment on "Training surgeons and the informed consent process: routine disclosure of trainee participation and its effect on patient willingness and consent rates". PMID- 22250117 TI - Ethnicity, insurance status, and hospitals serving predominantly minorities: comment on "Association between hospitals caring for a disproportionately high percentage of minority patients with trauma and increased mortality due to trauma". PMID- 22250118 TI - Synoptic operative reports: comment on "The computerized synoptic operative report". PMID- 22250119 TI - Vagotomy, inflammation, and the injured patient: comment on "Vagus nerve and postinjury inflammatory response". PMID- 22250121 TI - Experience be a jewel: comment on "The perforated duodenal diverticulum". PMID- 22250120 TI - The perforated duodenal diverticulum. AB - OBJECTIVE: To perform a literature review of perforated duodenal diverticulum with attention to changes in management. DATA SOURCES: We searched PubMed for relevant studies published from January 1, 1989, through August 1, 2011. In addition, we identified and reviewed 4 cases at our institution. STUDY SELECTION: Search phrases were perforated duodenal diverticulum and duodenal diverticulitis. DATA EXTRACTION: Patient demographics, clinical characteristics, radiologic findings, treatment, and outcomes were obtained. RESULTS: We reviewed 39 studies producing 57 cases, which were combined with the 4 at our institution for a total of 61 patients. The addition of 2 previous series revealed a total of 162 patients in the world literature. Perforations were most commonly located in the second or third portion of the duodenum (60 of 61 cases [98%]), and the most frequent cause was diverticulitis (42 of 61 [69%]). There has been a dramatic improvement in the preoperative diagnosis of perforated diverticula. Only 13 of 101 reported cases (13%) were correctly diagnosed before 1989, and 29 of 61 (48%) in the present series were identified with radiologic examinations. Most patients in the current series (47 of 61) underwent operative treatment for their perforation, although 14 underwent successful nonoperative management. Complications were reported in 17 of 47 patients in the surgical group (36%), whereas only 1 complication was seen in patients undergoing nonoperative management. Mortality in the surgical group was 6% (3 of 47), and no deaths were reported in the nonoperative group. CONCLUSIONS: Perforation of a duodenal diverticulum is rare, with only 162 cases reported in the world literature. Nonoperative management has emerged as a safe, practical alternative to surgery in selected patents. PMID- 22250122 TI - Surgical management of the succinate dehydrogenase-associated familial paraganglioma syndromes. AB - Paragangliomas are rare neuroendocrine tumors arising from the neural crest cells in the extra-adrenal location. Paragangliomas can be sporadic or associated with a range of endocrine and genetic syndromes in 25% to 30% of all cases. Specifically, succinate dehydrogenase gene mutations are involved in the development of paraganglioma syndromes type 1 through type 4. In this article, we will describe 2 cases of succinate dehydrogenase-associated familial paraganglioma syndrome and provide a review of the existing literature on the condition's etiologic factors, diagnosis, and management. PMID- 22250123 TI - Image of the month. Low-grade neuroendocrine carcinoma arising from a tailgut cyst. PMID- 22250124 TI - Image of the month. Disseminated coccidioidomycosis. PMID- 22250125 TI - The effect of HLA-DR matching on pediatric kidney transplantation. PMID- 22250126 TI - Neuroendocrine liver metastasis: transplant as part of multimodality liver directed therapy. PMID- 22250129 TI - New 2, 6-modified Bodipy sensitizers for dye-sensitized solar cells. PMID- 22250128 TI - Patterns of repeat-induced point mutation in transposable elements of basidiomycete fungi. AB - Transposable elements (TEs) are ubiquitous genomic parasites that have prompted the evolution of genome defense systems that restrict their activity. Repeat induced point mutation (RIP) is a homology-dependent genome defense that introduces C-to-T transition mutations in duplicated DNA sequences and is thought to control the proliferation of selfish repetitive DNA. Here, we determine the taxonomic distribution of hypermutation patterns indicative of RIP among basidiomycetes. We quantify C-to-T transition mutations in particular di- and trinucleotide target sites for TE-like sequences from nine fungal genomes. We find evidence of RIP-like patterns of hypermutation at TpCpG trinucleotide sites in repetitive sequences from all species of the Pucciniomycotina subphylum of the Basidiomycota, Microbotryum lychnidis-dioicae, Puccinia graminis, Melampsora laricis-populina, and Rhodotorula graminis. In contrast, we do not find evidence for RIP-like hypermutation in four species of the Agaricomycotina and Ustilaginomycotina subphyla of the Basidiomycota. Our results suggest that a RIP like process and the specific nucleotide context for mutations are conserved within the Pucciniomycotina subphylum. These findings imply that coevolutionary interactions between TEs and a hypermutating genome defense are stable over long evolutionary timescales. PMID- 22250127 TI - Dynamics and adaptive benefits of protein domain emergence and arrangements during plant genome evolution. AB - Plant genomes are generally very large, mostly paleopolyploid, and have numerous gene duplicates and complex genomic features such as repeats and transposable elements. Many of these features have been hypothesized to enable plants, which cannot easily escape environmental challenges, to rapidly adapt. Another mechanism, which has recently been well described as a major facilitator of rapid adaptation in bacteria, animals, and fungi but not yet for plants, is modular rearrangement of protein-coding genes. Due to the high precision of profile-based methods, rearrangements can be well captured at the protein level by characterizing the emergence, loss, and rearrangements of protein domains, their structural, functional, and evolutionary building blocks. Here, we study the dynamics of domain rearrangements and explore their adaptive benefit in 27 plant and 3 algal genomes. We use a phylogenomic approach by which we can explain the formation of 88% of all arrangements by single-step events, such as fusion, fission, and terminal loss of domains. We find many domains are lost along every lineage, but at least 500 domains are novel, that is, they are unique to green plants and emerged more or less recently. These novel domains duplicate and rearrange more readily within their genomes than ancient domains and are overproportionally involved in stress response and developmental innovations. Novel domains more often affect regulatory proteins and show a higher degree of structural disorder than ancient domains. Whereas a relatively large and well conserved core set of single-domain proteins exists, long multi-domain arrangements tend to be species-specific. We find that duplicated genes are more often involved in rearrangements. Although fission events typically impact metabolic proteins, fusion events often create new signaling proteins essential for environmental sensing. Taken together, the high volatility of single domains and complex arrangements in plant genomes demonstrate the importance of modularity for environmental adaptability of plants. PMID- 22250130 TI - The Baby Boomers' intergenerational relationships. AB - PURPOSE: As Baby Boomers enter late life, relationships with family members gain importance. This review article highlights two aspects of their intergenerational relationships: (a) caregiving for aging parents and (b) interactions with adult children in the context of changing marital dynamics. DESIGN AND METHODS: The researchers describe three studies: (a) the Within Family Differences Study (WFDS) of mothers aged 65-75 and their multiple grown children (primarily Baby Boomers) ongoing since 2001; (b) the Family Exchanges Study (FES) of Baby Boomers aged 42-60, their spouses, parents, and multiple grown children ongoing since 2008; and (c) the Longitudinal Study of Generations (LSoG) of 351 three generation families started when the Baby Boomers were teenagers in 1971, with interviews every 3-5 years from 1985 to 2005. RESULTS: These studies show that the Baby Boomers in midlife navigate complex intergenerational patterns. The WFDS finds aging parents differentiate among Baby Boomer children in midlife, favoring some more than others. The FES shows that the Baby Boomers are typically more involved with their children than with their aging parents; Boomers' personal values, family members' needs, and personal rewards shape decisions about support. The LSoG documents how divorce and remarriage dampen intergenerational obligations in some families. Moreover, loosening cultural norms have weakened family bonds in general. IMPLICATIONS: Reviews of these studies provide insights into how the Baby Boomers may negotiate caregiving for aging parents as well as the likelihood of family care they will receive when their own health declines in the future. PMID- 22250131 TI - Water bathing alters threat perception in starlings. AB - The majority of bird taxa perform water bathing, but little is known about the adaptive value of this behaviour. If bathing is important for feather maintenance then birds that have not bathed should have poorer feather condition, compromised escape ability and therefore increased responsiveness to cues of predation. We conducted two experiments examining the behaviour of captive starlings responding to conspecific alarm calls. Birds that had no access to bathing water showed a decreased willingness to feed and increased their vigilance behaviour following an alarm call. We argue that birds denied access to bathing water interpreted an ambiguous cue of threat as requiring more caution than birds that had access, consistent with higher levels of anxiety. Our results support the provision of bathing water for captive birds as an important welfare measure. PMID- 22250132 TI - High five! PMID- 22250133 TI - Nanoscience makes catalysis greener. PMID- 22250135 TI - Metal nanoparticles as heterogeneous Fenton catalysts. AB - The Fenton reaction (the generation of hydroxyl radicals from hydrogen peroxide) is the most useful method for degradation of organic pollutants in aqueous solution at moderate concentrations. In this Review we summarize the use of metal nanoparticles, either unsupported or deposited on large-surface-area solids, as Fenton catalysts. The Review complements two other reviews in the field of heterogeneous Fenton catalysis using aluminosilicates and carbonaceous materials. Herein, particular emphasis is given to the reaction conditions in which these catalysts are used, highlighting the operating mechanism and the relative efficiency of the materials. Aspects such as leaching of the metal to the solution, reusability, and the concentration of hydrogen peroxide used are analyzed in detail. Besides a critical description of the present status of the field, future trends and the need to establishing valid comparisons to assess the relative efficiencies of the materials are commented on. PMID- 22250136 TI - Chiral ammonium-capped rhodium(0) nanocatalysts: synthesis, characterization, and advances in asymmetric hydrogenation in neat water. AB - Optically active amphiphilic compounds derived from N-methylephedrine, N methylprolinol, or cinchona derivatives possessing bromide or chiral lactate counterions were efficiently used as protective agents for rhodium(0) nanoparticles. The full characterization of these surfactants and the obtained nanocatalysts was performed by means of different techniques. These spherical nanoparticles, with sizes between 0.8-2.5 nm depending on the stabilizer, were evaluated in the hydrogenation of model substrates in neat water as a green solvent. The rhodium catalysts showed relevant kinetic properties, but modest enantiomeric excess values of up to 13 % in the hydrogenation of ethyl pyruvate. They were also investigated in the hydrogenation of disubstituted arenes, such as m-methylanisole, providing interesting catalytic activities and a preferential cis selectivity of around 80 %; however, no asymmetric induction was observed. PMID- 22250137 TI - A versatile route to core-shell catalysts: synthesis of dispersible M@oxide (M=Pd, Pt; oxide=TiO2, ZrO2) nanostructures by self-assembly. AB - A method, based on self assembly, for preparing core-shell nanostructures that are dispersible in organic solvents is demonstrated for Pd and Pt cores with CeO(2), TiO(2), and ZrO(2) shells. Transmission electron microscopy (TEM) of these nanostructures confirmed the formation of distinct metal cores, approximately 2 nm in diameter, surrounded by amorphous oxide shells. Functional catalysts were prepared by dispersing the nanostructures onto an Al(2)O(3) support; and vibrational spectra of adsorbed CO, together with adsorption uptakes, were used to demonstrate the accessibility of the metal core to CO and the porous nature of the oxide shell. Measurements of water-gas-shift (WGS) rates demonstrated that these catalysts exhibit activities similar to that of conventional supported catalysts despite having lower metal dispersions. Pd-based CeO(2) and TiO(2) core-shell catalysts exhibit significant transient deactivation, which is probably caused by a decrease in the exposed metal surface area due to the ease of reduction of the shells. Alternatively, Pt-based analogous core-shell catalysts do not exhibit such a transient decrease. Both Pd- and Pt-based ZrO(2) core-shell catalysts deactivate at a significantly lower rate due to the less reducible nature of the ZrO(2) shell. PMID- 22250139 TI - Bone bruise, lipohemarthrosis, and joint effusion in CT of non-displaced hip fracture. AB - BACKGROUND: A suspected occult hip fracture after normal radiography is not uncommon in an elderly person after a fall. Despite a lack of robust validation in the literature, computed tomography (CT) is often used as secondary imaging. PURPOSE: To assess the frequency and clinical utility of non-cortical skeletal and soft tissue lesions as ancillary fracture signs in CT diagnosis of occult hip fractures. MATERIAL AND METHODS: All fracture signs (cortical and trabecular fractures, bone bruise, joint effusion, and lipohemarthrosis) were recorded in 231 hip low-energy trauma cases with CT performed after normal or equivocal radiography in two trauma centers. RESULTS: There were no fracture signs in 110 patients. Twelve of these had a joint effusion. In 121 patients with 46 cervical hip fractures and 75 trochanteric fractures one or more fracture signs were present. Cortical fractures were found in 115 patients. Bone bruise was found in 119 patients, joint effusion in 35, and lipohemarthrosis in 20 patients. CONCLUSION: Ancillary signs such as bone bruise and lipohemarthrosis can strengthen and sometimes indicate the diagnosis in CT of occult hip fractures. Joint effusion is a non-specific sign. PMID- 22250140 TI - A hand in the heart. PMID- 22250141 TI - High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. AB - BACKGROUND: Low serum 25-hydroxyvitamin D (25-[OH]D) levels have been associated with lower FEV(1), impaired immunologic control, and increased airway inflammation. Because many patients with chronic obstructive pulmonary disease (COPD) have vitamin D deficiency, effects of vitamin D supplementation may extend beyond preventing osteoporosis. OBJECTIVE: To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations. DESIGN: Randomized, single-center, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00666367) SETTING: University Hospitals Leuven, Leuven, Belgium. PATIENTS: 182 patients with moderate to very severe COPD and a history of recent exacerbations. INTERVENTION: 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year. MEASUREMENTS: The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalization, time to second exacerbation, FEV(1), quality of life, and death. RESULTS: Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV(1), hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042). LIMITATION: This was a single-center study with a small sample size. CONCLUSION: High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations. PRIMARY FUNDING SOURCE: Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT TBM). PMID- 22250142 TI - Cardiovascular mortality in women with obstructive sleep apnea with or without continuous positive airway pressure treatment: a cohort study. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for cardiovascular death in men, but whether it is also a risk factor in women is unknown. OBJECTIVE: To investigate whether OSA is a risk factor for cardiovascular death in women and assess whether continuous positive airway pressure (CPAP) treatment is associated with a change in risk. DESIGN: Prospective, observational cohort study. SETTING: 2 sleep clinics in Spain. PATIENTS: All women consecutively referred for suspected OSA between 1998 and 2007. INTERVENTION: Every woman had a diagnostic sleep study. Women with an apnea-hypopnea index (AHI) less than 10 were the control group. Obstructive sleep apnea was diagnosed when the AHI was 10 or higher (classified as mild to moderate [AHI of 10 to 29] or severe [AHI >=30]). Patients with OSA were classified as CPAP-treated (adherence >=4 hours per day) or untreated (adherence <4 hours per day or not prescribed). Participants were followed until December 2009. MEASUREMENTS: The end point was cardiovascular death. RESULTS: 1116 women were studied (median follow-up, 72 months [interquartile range, 52 to 88 months]). The control group had a lower cardiovascular mortality rate (0.28 per 100 person-years [95% CI, 0.10 to 0.91]) than the untreated groups with mild to moderate OSA (0.94 per 100 person-years [CI, 0.10 to 2.40]; P = 0.034) or severe OSA (3.71 per 100 person-years [CI, 0.09 to 7.50]; P < 0.001). Compared with the control group, the fully adjusted hazard ratios for cardiovascular mortality were 3.50 (CI, 1.23 to 9.98) for the untreated, severe OSA group; 0.55 (CI, 0.17 to 1.74) for the CPAP-treated, severe OSA group; 1.60 (CI, 0.52 to 4.90) for the untreated, mild to moderate OSA group; and 0.19 (CI, 0.02 to 1.67) for the CPAP-treated, mild to moderate OSA group. LIMITATION: The study was observational and not randomized, and OSA was diagnosed by 2 different methods. CONCLUSION: Severe OSA is associated with cardiovascular death in women, and adequate CPAP treatment may reduce this risk. PRIMARY FUNDING SOURCE: None. PMID- 22250143 TI - Virtual autopsy as an alternative to traditional medical autopsy in the intensive care unit: a prospective cohort study. AB - BACKGROUND: Autopsy is an important educational and quality-control tool in the intensive care unit (ICU), but rates of traditional medical autopsies have declined worldwide. "Virtual" autopsy involving only advanced radiographic techniques might provide an alternative approach to postmortem examinations. OBJECTIVE: To assess the value of postmortem multidetector computed tomography as an alternative to medical autopsy. DESIGN: Prospective cohort study. (ClinicalTrials.gov registration number: NCT01040520) SETTING: 9 ICUs in a single academic medical center. Consent for both medical and virtual autopsies was sought from the families of all consecutive patients who died in the ICU between 1 January and 30 June 2010. Clinical records were reviewed to determine whether unsuspected autopsy findings would have altered care if known (major diagnosis) or would not have altered care (minor diagnosis). RESULTS: Of 285 patients, 47 underwent both virtual and medical autopsy. Of 196 clinical diagnoses made before death, 173 (88%) were identified by virtual autopsy and 183 (93%) by medical autopsy. Fourteen new major and 88 new minor diagnoses were detected by any autopsy method. The main diagnoses missed by virtual autopsy were cardiovascular events (9 of 72) and cancer (12 of 30). In contrast, medical autopsy missed 13 traumatic fractures and 2 pneumothoraces. Among 115 additional patients in whom only virtual autopsy was performed, 11 new major diagnoses were made. LIMITATION: Virtual autopsy was performed in only 57% of patients (n = 162); among this group, consent for traditional medical autopsy was obtained for only one third. CONCLUSION: Virtual autopsy may be useful for identifying diagnoses that traditionally have been identified by medical autopsy. This may also hold true, at least in part, for the educational aspect of medical autopsy (confirming antemortem clinical diagnoses). Further studies are required to confirm these preliminary results. PRIMARY FUNDING SOURCE: University Medical Center Hamburg Eppendorf, Germany. PMID- 22250144 TI - Risk factors and precipitants of long-term disability in community mobility: a cohort study of older persons. AB - BACKGROUND: Relatively little is known about why older persons develop long-term disability in community mobility. OBJECTIVE: To identify the risk factors and precipitants for long-term disability in walking a quarter mile and driving a car. DESIGN: Prospective cohort study from March 1998 to December 2009. SETTING: Greater New Haven, Connecticut. PARTICIPANTS: 641 persons, aged 70 years or older, who were active drivers or nondisabled in walking a quarter mile. Persons who were physically frail were oversampled. MEASUREMENTS: Candidate risk factors were assessed every 18 months. Disability in community mobility and exposure to potential precipitants, including illnesses or injuries leading to hospitalization or restricted activity, were assessed every month. Disability that lasted 6 or more consecutive months was considered long-term. RESULTS: 318 (56.0%) and 269 (53.1%) participants developed long-term disability in walking and driving, respectively. Seven risk factors were independently associated with walking disability and 8 were associated with driving disability; the strongest associations for each outcome were found for older age and lower score on the Short Physical Performance Battery. The precipitants had a large effect on long term disability, with multivariate hazard ratios for each outcome greater than 6.2 for hospitalization and greater than 2.4 for restricted activity. The largest differences in absolute risk were generally observed in participants with a specific risk factor who were subsequently hospitalized. LIMITATIONS: The observed associations may not be causal. The severity of precipitants was not assessed. The effect of the precipitants may have been underestimated because their exposure after the initial onset of disability was not evaluated. CONCLUSION: Long-term disability in community mobility is common among older persons. Multiple risk factors, together with subsequent precipitants, greatly increase the likelihood of long-term mobility disability. PRIMARY FUNDING SOURCE: National Institute on Aging, National Institutes of Health. PMID- 22250145 TI - Wheeled mobility (wheelchair) service delivery: scope of the evidence. AB - Identifying the appropriate wheelchair for a person who needs one has implications for both disabled persons and society. For someone with severe locomotive problems, the right wheelchair can affect mobility and quality of life. However, policymakers are concerned about the increasing demand for unnecessarily elaborate chairs. The Office of Inspector General, U.S. Department of Health and Human Services, issued 4 reports between 2009 and 2011 detailing fraud and misapplication of Medicare funds for powered wheelchairs, more than a decade after similar concerns were first raised by 4 contractors who process claims for durable medical equipment. Subsequent concerns have arisen about whether some impaired persons who need wheeled mobility devices may now be inappropriately denied coverage. A transparent, evidence-based approach to wheeled mobility service delivery (the matching of mobility-impaired persons to appropriate devices and supporting services) might lessen these concerns. This review describes the process of wheeled mobility service delivery for long-term wheelchair users with complex rehabilitation needs and presents findings from a survey of the literature (published and gray) and interviews with key informants. Recommended steps in the delivery process were identified in textbooks, guidelines, and published literature. Delivery processes shared many commonalities; however, no research supports the recommended approaches. A search of bibliographic databases through March 2011 identified 24 studies that evaluated aspects of wheeled mobility service delivery. Most were observational, exploratory studies designed to determine consumer use of and satisfaction with the process. The evidence base for the effectiveness of approaches to wheeled mobility service delivery is insufficient, and additional research is needed to develop standards and guidelines. PMID- 22250146 TI - Appropriate use of screening and diagnostic tests to foster high-value, cost conscious care. AB - Unsustainable rising health care costs in the United States have made reducing costs while maintaining high-quality health care a national priority. The overuse of some screening and diagnostic tests is an important component of unnecessary health care costs. More judicious use of such tests will improve quality and reflect responsible awareness of costs. Efforts to control expenditures should focus not only on benefits, harms, and costs but on the value of diagnostic tests meaning an assessment of whether a test provides health benefits that are worth its costs or harms. To begin to identify ways that practicing clinicians can contribute to the delivery of high-value, cost-conscious health care, the American College of Physicians convened a workgroup of physicians to identify, using a consensus-based process, common clinical situations in which screening and diagnostic tests are used in ways that do not reflect high-value care. The intent of this exercise is to promote thoughtful discussions about these tests and other health care interventions to promote high-value, cost-conscious care. PMID- 22250147 TI - Exposing unethical human research: the transatlantic correspondence of Beecher and Pappworth. AB - Henry K. Beecher and Maurice H. Pappworth were the 2 most prominent medical whistleblowers in research ethics of the 20th century. Independently, both wrote highly controversial and ultimately influential articles and books. Although their work is now well-known in clinical research circles, their collaboration is not. Pappworth's article "Human Guinea Pigs: A Warning" was published in 1962; in it, he discussed a series of published studies that he considered unethical. Beecher read it and wrote to Pappworth seeking help. The current article reconstructs, from Beecher and Pappworth's correspondence in 1965-1966, an important juncture in the genesis of modern clinical research ethics. Although they shared much in common, they differed radically in the strategies they adopted: Beecher chose to conceal the identities of individuals, whereas Pappworth believed that only by naming and shaming could any expose act as a deterrent. Their correspondence reveals how the 2 men shared their ideas and their material and provided each other with much-needed support. It also tracks the development of Beecher's shift from a position initially indistinguishable from Pappworth's toward the one he adopted when his seminal article of 1966 was published. PMID- 22250148 TI - Severe vitamin D deficiency: a prerequisite for COPD responsiveness to vitamin D supplementation? PMID- 22250149 TI - To image or to autopsy? PMID- 22250150 TI - Mobilizing to address increasing population disability. PMID- 22250151 TI - High-value testing begins with a few simple questions. PMID- 22250152 TI - The waiting room. PMID- 22250153 TI - Traditional Chinese herbal therapy as a treatment option for H1N1 influenza. PMID- 22250154 TI - Impact of the "July effect" on patient outcomes. PMID- 22250155 TI - Impact of the "July effect" on patient outcomes. PMID- 22250156 TI - Impact of the "July effect" on patient outcomes. PMID- 22250157 TI - Clinical decision rules for excluding pulmonary embolism. PMID- 22250158 TI - The bedside evaluation. PMID- 22250159 TI - The bedside evaluation. PMID- 22250160 TI - Recurrent stress cardiomyopathy induced by Sudafed PE. PMID- 22250161 TI - Summaries for patients: Vitamin D treatment of chronic obstructive pulmonary disease. PMID- 22250162 TI - Summaries for patients: Risk for death from cardiovascular disease in women with obstructive sleep apnea. PMID- 22250163 TI - Summaries for patients: Why do many older persons become disabled in walking and driving? PMID- 22250164 TI - Apixaban reduced stroke and systemic embolism compared with warfarin in atrial fibrillation. PMID- 22250165 TI - Rivaroxaban reduced stroke and systemic embolism compared with warfarin in nonvalvular AF. PMID- 22250166 TI - Review: Interventions to reduce dietary salt do not reduce mortality or morbidity. PMID- 22250167 TI - Review: Interventions to reduce or modify dietary fat reduce cardiovascular events. PMID- 22250168 TI - Cytisine increased smoking cessation in adults. PMID- 22250169 TI - Insulin secretagogues were associated with increased mortality compared with metformin in type 2 diabetes. PMID- 22250170 TI - Acetylcysteine did not reduce kidney injury in at-risk patients having vascular angiography. PMID- 22250171 TI - The RenalGuard system reduced kidney injury more than a control system in high risk patients. PMID- 22250172 TI - Azithromycin once daily for 1 year reduced acute COPD exacerbations. PMID- 22250173 TI - Review: Gestalt or clinical decision rules have limited sensitivity and specificity for detecting acute PE. PMID- 22250174 TI - Adding a panel manager to EMR reminders improved some preventive care processes. PMID- 22250175 TI - An 11-item index predicted 5-year and 9-year mortality in community-dwelling elderly adults. PMID- 22250176 TI - Accelerated partner therapy: a promising new partner treatment option. PMID- 22250177 TI - What role should criminal justice play in the fight against STIs? PMID- 22250178 TI - Cephalosporin resistant Neisseria gonorrhoeae: time to consider gentamicin? PMID- 22250179 TI - HIV shedding in the oral cavity: an assessment of HIV type, immunovirologic, demographic and oral factors. AB - OBJECTIVE: To quantify the prevalence and burden of HIV type 2 (HIV-2) and HIV-1 RNA in the oral cavity of antiretroviral therapy-naive HIV-infected Senegalese individuals and to identify correlates of oral HIV viral loads. DESIGN: A cross sectional study of 163 HIV-1 and 27 HIV-2-infected antiretroviral therapy-naive Senegalese adults. METHODS: Participants received clinical and oral exams and provided blood and oral wash samples for viral load and plasma CD4 count ascertainment. Logistic and interval regression models were used to identify univariate and multivariable associations between presence and level of oral HIV RNA and various immunovirologic, local and demographic factors. RESULTS: Presence of detectable oral HIV RNA was less common in HIV-2-infected compared with HIV-1 infected study participants (33% vs 67%, OR 0.25, 95% CI 0.11 to 0.59). HIV type was no longer associated with oral shedding of HIV when plasma viral load was considered. Detection of oral HIV RNA was associated with increased plasma viral load in both HIV-1-infected and HIV-2-infected individuals (HIV-1, OR 1.89, 95% CI 1.24 to 2.61; HIV-2, OR 1.93, 95% CI 1.1 to 3.39). Oral HIV-1 detection was also associated with periodontal disease (OR 3.02, 95% CI 1.16 to 7.87). CONCLUSIONS: Oral shedding of HIV-2 RNA is less common than HIV-1 RNA, a likely consequence of lower overall viral burden. Both systemic and local factors may contribute to shedding of HIV in the oral cavity. PMID- 22250180 TI - Distinct HIV discordancy patterns by epidemic size in stable sexual partnerships in sub-Saharan Africa. AB - OBJECTIVE: To describe patterns of HIV infection among stable sexual partnerships across sub-Saharan Africa (SSA). METHODS: The authors defined measures of HIV discordancy and conducted a comprehensive quantitative assessment of discordancy among stable partnerships in 20 countries in SSA through an analysis of the Demographic and Health Survey data. RESULTS: HIV prevalence explained at least 50% of the variation in HIV discordancy, with two distinct patterns of discordancy emerging based on HIV prevalence being roughly smaller or larger than 10%. In low-prevalence countries, approximately 75% of partnerships affected by HIV are discordant, while only about half of these are discordant in high prevalence countries. Out of each 10 HIV infected persons, two to five are engaged in discordant partnerships in low-prevalence countries compared with one to three in high-prevalence countries. Among every 100 partnerships in the population, one to nine are affected by HIV and zero to six are discordant in low prevalence countries compared with 16-45 and 9-17, respectively, in high prevalence countries. Finally, zero to four of every 100 sexually active adults are engaged in a discordant partnership in low-prevalence countries compared with six to eight in high-prevalence countries. CONCLUSIONS: In high-prevalence countries, a large fraction of stable partnerships were affected by HIV and half were discordant, whereas in low-prevalence countries, fewer stable partnerships were affected by HIV but a higher proportion of them were discordant. The findings provide a global view of HIV infection among stable partnerships in SSA but imply complex considerations for rolling out prevention interventions targeting discordant partnerships. PMID- 22250181 TI - Incarceration, high-risk sexual partnerships and sexually transmitted infections in an urban population. AB - OBJECTIVES: The authors examined the associations between personal and partner incarceration, high-risk sexual partnerships and biologically confirmed sexually transmitted infection (STI) in a US urban population. METHODS: Data from a probability survey of young adults 15-35 years of age in Baltimore, Maryland, USA, were analysed to assess the prevalence of personal and partner incarceration and its association with several measures of high-risk sexual partnerships including multiple partners, partner concurrency and current STI. RESULTS: A history of incarceration was common (24.1% among men and 11.3% among women). Among women with an incarcerated partner in the past year (15.3%), the risk of current STI was significantly increased (adjusted prevalence ratio=2.3, 95% CI 1.5 to 3.5). Multiple partners (5+) in the past year and partner concurrency were disproportionately high among men and women who had been incarcerated or who had sexual partner(s) or who had recently been incarcerated. These associations remained robust independent of personal socio-demographic factors and illicit drug use. CONCLUSIONS: Incarceration may contribute to STI risk by influencing engagement in high-risk behaviours and by influencing contact with partners who engage in risky behaviours and who hence have elevated risk of infection. PMID- 22250183 TI - Screening older cancer patients: first evaluation of the G-8 geriatric screening tool. AB - BACKGROUND: Development of a geriatric screening tool is necessary to identify elderly cancer patients who would benefit from comprehensive geriatric assessment (CGA). We develop and evaluate the G-8 screening tool against various reference tests. PATIENTS AND METHODS: Analyses were based on 364 cancer patients aged>70 years scheduled to receive first-line chemotherapy included in a multicenter prospective study. The G-8 consists of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age. Our primary reference test is based on a set of seven CGA scales: Activities Daily Living (ADL), Instrumental ADL, MNA, Mini-Mental State Exam, Geriatric Depression Scale, Cumulative Illness Rating Scale-Geriatrics, and Timed Get Up and Go. We considered the presence of at least one questionnaire with an impaired score as an abnormal reference exam. Additional reference exams are also discussed. RESULTS: The prevalence of being at risk varied from 60% to 94% according to the various definitions of the reference test. When considering the primary reference test, a cut-off value of 14 for the G-8 tool provided a good sensitivity estimate (85%) without deteriorating the specificity excessively (65%). CONCLUSION: The G-8 shows good screening properties for identifying elderly cancer patients who could benefit from CGA. PMID- 22250182 TI - Race and hormone receptor-positive breast cancer outcomes in a randomized chemotherapy trial. AB - BACKGROUND: The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy. METHODS: The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline- and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided. RESULTS: Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P < .001) and a higher body mass index (median: 31.7 vs 27.4 kg/m(2); P < .001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor-positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor-positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival (P = .027) but not for overall survival (P = .086). CONCLUSION: Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor-positive breast cancer. PMID- 22250184 TI - Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. AB - BACKGROUND: Published genotype/phenotype data on McArdle disease are limited in sample size. A single national (Spanish) registry of patients with McArdle disease was created with the purpose of analysing their genotypic and phenotypic characteristics. METHODS: A cross sectional study was conducted, collecting demographic, family history, clinical, genotype and functional capacity data from all patients diagnosed with McArdle disease in the Spanish National Health System up to December 2010. RESULTS: 239 cases were recorded (all of Caucasian descent, 102 women; mean+/-SD age 44+/-18 years (range 9, 93)); prevalence of ~1/167 000 people. Two mutant PYGM alleles were identified in 99.6% of cases. Although there was heterogeneity in the severity of symptoms, there were four common diagnostic features: (1) 99.5% of patients reported a history of acute crises of exercise intolerance (accompanied by recurrent myoglobinuria in 50% of cases); (2) in 58% of patients, symptoms started in the first decade of life; (3) 86% of patients repeatedly experienced the 'second wind' phenomenon over life; and (4) 99% of patients had a high basal serum level of total creatine kinase (>200 U/l). Clinical presentation of the disease was similar in men and women and worsened with age. Patients who were physically active had higher levels of cardiorespiratory fitness (by 23%, p=0.003) and were more likely to improve their clinical course over a 4 year period compared with inactive patients (OR 225; 95% CI 20.3 to 2496.7). CONCLUSIONS: The main clinical features of McArdle disease are generally homogeneous and frequently appear during childhood; clinical condition deteriorates with ageing. Active patients have a better clinical outcome and functional capacity. PMID- 22250185 TI - Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson's disease. PMID- 22250186 TI - The function of 'functional': a mixed methods investigation. AB - OBJECTIVE: The term 'functional' has a distinguished history, embodying a number of physiological concepts, but has increasingly come to mean 'hysterical'. The DSM-V working group proposes to use 'functional' as the official diagnostic term for medically unexplained neurological symptoms (currently known as 'conversion disorder'). This study aimed to explore the current neurological meanings of the term and to understand its resilience. DESIGN: Mixed methods were used, first interviewing the neurologists in a large UK region and then surveying all neurologists in the UK on their use of the term. RESULTS: The interviews revealed four dominant uses--'not organic', a physical disability, a brain disorder and a psychiatric problem--as well as considerable ambiguity. Although there was much dissatisfaction with the term, the ambiguity was also seen as useful when engaging with patients. The survey confirmed these findings, with a majority adhering to a strict interpretation of 'functional' to mean only 'not organic', but a minority employing it to mean different things in different contexts - and endorsing the view that 'functional' would one day be a neurological construct again. CONCLUSIONS: 'Functional' embodies real divisions in neurologists' conceptualisation of unexplained symptoms and, perhaps, between those of patients and neurologists: its diversity of meanings allows it to be a common term while meaning different things to different people, or at different times, and thus conceal some of the conflict in a particularly contentious area. This flexibility may help explain the term's longevity. PMID- 22250187 TI - Prediction of sentinel lymph node positivity by growth rate of cutaneous melanoma. AB - OBJECTIVE: To determine whether growth rate (GR) of cutaneous melanoma predicts the histological sentinel lymph node (SLN) positivity. DESIGN: Retrospective cohort study. SETTING: Two tertiary melanoma referral centers. PATIENTS: A total of 698 patients with invasive primary cutaneous melanoma in whom the SLN was identified between January 1, 2000, and June 30, 2010. MAIN OUTCOME MEASURE: Based on previous studies, a surrogate measure for GR in primary invasive melanoma was calculated as the ratio of Breslow thickness to time to melanoma development. RESULTS: The SLN was positive in 20.2% of patients. Multivariate logistic regression analysis revealed that GR, Breslow thickness, and the presence of microscopic satellitosis were independently associated with SLN positivity. The probability of SLN positivity was 8.2% for slow-growth melanomas (<0.10 mm/mo) compared with 19.8% for intermediate-growth melanomas (0.10-0.50 mm/mo) and 37.7% for fast-growth melanomas (>0.50 mm/mo). Growth rate was not an independent predictive factor for survival. CONCLUSION: Growth rate of primary cutaneous melanoma, together with Breslow thickness and the presence of microscopic satellitosis, predicts the histological SLN positivity. PMID- 22250188 TI - Communication about family members' risk of melanoma: self-reported practices of dermatologists in the United States. AB - OBJECTIVES: To assess current self-reported communication and screening practices of dermatologists to their patients with melanoma about family members' risk of melanoma at the time of diagnosis and to understand the barriers that dermatologists encounter in communicating risk to patients. DESIGN: Descriptive survey study. SETTING: Office-based practicing physicians in the United States. PARTICIPANTS: One thousand dermatologists. MAIN OUTCOME MEASURE: Melanoma risk communication practices. RESULTS: Of 974 eligible dermatologists, 406 completed the survey (response rate, 41.7%). Almost 85% of dermatologists reported that they often or always communicate risk to patients with melanoma about their first degree relatives, and almost 80% reported that they often or always advise their patients with melanoma that their older children (18 years) may be at greater risk of skin cancer. However, less than 50% of dermatologists routinely offered to screen first-degree relatives who live nearby, while only 19.7% used medical record reminders to note communication of melanoma risk to family members. Most dermatologists reported no major barriers to melanoma risk communication. However, the presence of "any risk communication barrier" (time constraints, absence of guidelines, or lack of written material) was associated with reduced melanoma risk communication practices by dermatologists. CONCLUSIONS: The observed high rates of self-reported risk communication by dermatologists to patients with melanoma about their first-degree family members are encouraging. However, the reported low rates of actual screening of first-degree relatives warrant easy-to-administer office-based medical record reminders to facilitate and optimize screening of at-risk relatives. PMID- 22250190 TI - The children and sunscreen study: a crossover trial investigating children's sunscreen application thickness and the influence of age and dispenser type. AB - OBJECTIVES: To measure the thickness at which primary schoolchildren apply sunscreen on school day mornings and to compare it with the thickness (2.00 mg/cm(2)) at which sunscreen is tested during product development, as well as to investigate how application thickness was influenced by age of the child (school grades 1-7) and by dispenser type (500-mL pump, 125-mL squeeze bottle, or 50-mL roll-on). DESIGN: A crossover quasiexperimental study design comparing 3 sunscreen dispenser types. SETTING: Children aged 5 to 12 years from public primary schools (grades 1-7) in Queensland, Australia. PARTICIPANTS: Children (n=87) and their parents randomly recruited from the enrollment lists of 7 primary schools. Each child provided up to 3 observations (n=258). INTERVENTION: Children applied sunscreen during 3 consecutive school weeks (Monday through Friday) for the first application of the day using a different dispenser each week. MAIN OUTCOME MEASURE: Thickness of sunscreen application (in milligrams per square centimeter). The dispensers were weighed before and after use to calculate the weight of sunscreen applied. This was divided by the coverage area of application (in square centimeters), which was calculated by multiplying the children's body surface area by the percentage of the body covered with sunscreen. RESULTS: Children applied their sunscreen at a median thickness of 0.48 mg/cm(2). Children applied significantly more sunscreen when using the pump (0.75 mg/cm(2)) and the squeeze bottle (0.57 mg/cm(2)) compared with the roll-on (0.22 mg/cm(2)) (P<.001 for both). CONCLUSIONS: Regardless of age, primary schoolchildren apply sunscreen at substantially less than 1.00 mg/cm(2), similar to what has been observed among adults. Some sunscreen dispensers seem to facilitate thicker application than others. PMID- 22250189 TI - Phase I clinical trial of O6-benzylguanine and topical carmustine in the treatment of cutaneous T-cell lymphoma, mycosis fungoides type. AB - OBJECTIVES: To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea] following intravenous O6 benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions. DESIGN: Open-label, dose-escalation, phase I trial. SETTING: Dermatology outpatient clinic and clinical research unit at a university teaching hospital. PATIENTS: A total of 21 adult patients (11 male, 10 female)with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine. INTERVENTION: Treatment once every 2 weeks with 120 mg/m(2) intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6 alkylguanine-DNA alkyltransferase activity. MAIN OUTCOME MEASURES: Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens. RESULTS: A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyltransferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzylguanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P=.02) and inversely with area under the curve of O6 alkylguanine-DNA alkyltransferase over 1 week (P=.01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55 0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug. CONCLUSION: O6 benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses. PMID- 22250191 TI - Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management. AB - BACKGROUND: Painful lobular panniculitis appears to be a novel cutaneous adverse effect of selective BRAF inhibitors. OBSERVATION: We report the clinical course and management in 2 women with metastatic melanomas harboring the BRAF(V600E) mutation, who developed panniculitis with arthralgia during therapy with selective oral BRAF inhibitors. Panniculitis with arthralgia was the acute presenting adverse effect in both patients. Painful, red, nodular lesions were located on the upper and lower extremities. Biopsy specimens of the nodules showed a mild, predominantly lobular neutrophilic panniculitis. Analgesic and anti-inflammatory treatment improved panniculitis and arthralgia in both cases. It was also necessary to reduce the BRAF inhibitor dose in 1 patient. CONCLUSIONS: During therapy with selective BRAF inhibitors, panniculitis with arthralgia represents a new adverse effect that can require dose reduction. In case of this adverse effect, treatment with nonsteroidal anti-inflammatory drugs, such as etoricoxib, should be initiated early to keep patients on treatment and to avoid drug discontinuation and tumor progression. PMID- 22250192 TI - Trends in melanoma mortality among non-Hispanic whites by educational attainment, 1993-2007. AB - OBJECTIVE: To evaluate overall trends in melanoma mortality rates among non Hispanic whites by educational level. DESIGN: Descriptive study. SETTING: Death certificate records from 26 states, representing approximately 45% of the US population as reported by the National Center for Health Statistics, with recorded educational level information and population data from the US Bureau of Census Current Population Survey. PATIENTS: Recorded deaths from malignant melanoma in non-Hispanic whites reported from 1993 through 2007. MAIN OUTCOME MEASURES: Age-standardized mortality rates for melanoma were evaluated by educational attainment (a marker of socioeconomic status) among non- Hispanic whites (aged 25-64 years) from 1993 through 2007. Rate ratios assessed the time trend in age-adjusted death rates by sex and educational level. Mortality differentials in educational level were measured using the regression-based Relative Index of Inequality. All statistical tests were 2-sided. RESULTS: Melanoma mortality declined significantly between 1993-1997 and 2003-2007 in men (RR [rate ratio], 0.916; 95% CI, 0.878-0.954; P.001) and women (RR, 0.907; 95% CI, 0.857-0.957; P.001). However, these declines occurred only among the most educated persons (>=13 years of education irrespective of sex), and nonsignificant increases were found among the least-educated individuals, specifically men (P=.17). As a result, the Relative Index of Inequality by education in melanoma mortality in 2003-2007 relative to 1993-1997 (baseline) widened by 51.7% in men and by 35.7% in women. CONCLUSIONS: Recent declines in melanoma mortality rates among non-Hispanic whites in the United States mainly reflect declines among the most-educated individuals. The widening disparities in melanoma mortality rates by education calls for early detection strategies to effectively target high-risk, less-educated, non-Hispanic white individuals. PMID- 22250193 TI - Motor anticipation failure in infants with autism: a retrospective analysis of feeding situations. AB - Previous studies on autism have shown a lack of motor anticipation in children and adults with autism. As part of a programme of research into early detection of autism, we focussed on an everyday situation: spoon-feeding. We hypothesize that an anticipation deficit may be found very early on by observing whether the baby opens his or her mouth in anticipation of the spoon's approach. The study is based on a retrospective analysis from family home movies. Observation of infants later diagnosed with autism or an autism spectrum disorder (ASD) (n = 13) and infants with typical development (n = 14) between 4 and 6 months old show that the autism/ASD group has an early anticipation deficit. PMID- 22250194 TI - A systematic review of training programs for parents of children with autism spectrum disorders: single subject contributions. AB - AIM: The purpose of this systematic review was to examine research utilizing single subject research designs (SSRD) to explore the effectiveness of interventions designed to increase parents' ability to support communication and social development in children with autism spectrum disorders (ASDs). METHOD: Included studies were systematically assessed for methodological quality (Logan et al., 2008; Smith et al., 2007) and intervention effects. Data examining participant characteristics, study methodology, outcomes, and analysis were systematically extracted. RESULTS: Eleven SSRD parent-training intervention studies examining 44 participants with ASD were included. Overall, the studies were of moderate quality and reported increases in parent skills and child language and communication outcomes. INTERPRETATION: The results supported by improvement rate difference (IRD) analysis indicated several interventions demonstrated positive effects for both parent and child outcomes. However, limited generalization and follow-up data suggested only one intervention demonstrated parents' accurate and ongoing intervention implementation beyond training. PMID- 22250195 TI - Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP. AB - Neural Wiskott-Aldrich syndrome protein (N-WASP) is involved in tight regulation of actin polymerization and dynamics. N-WASP activity is regulated by intramolecular interaction, binding to small GTPases and tyrosine phosphorylation. Here, we report on a novel regulatory mechanism; we demonstrate that N-WASP interacts with dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A). In vitro kinase assays indicate that Dyrk1A directly phosphorylates the GTPase-binding domain (GBD) of N-WASP at three sites (Thr196, Thr202 and Thr259). Phosphorylation of the GBD by Dyrk1A promotes the intramolecular interaction of the GBD and verprolin, cofilin and acidic (VCA) domains of N-WASP, and subsequently inhibits Arp2/3-complex-mediated actin polymerization. Overexpression of either Dyrk1A or a phospho-mimetic N-WASP mutant inhibits filopodia formation in COS-7 cells. By contrast, the knockdown of Dyrk1A expression or overexpression of a phospho-deficient N-WASP mutant promotes filopodia formation. Furthermore, the overexpression of a phospho-mimetic N-WASP mutant significantly inhibits dendritic spine formation in primary hippocampal neurons. These findings suggest that Dyrk1A negatively regulates actin filament assembly by phosphorylating N-WASP, which ultimately promotes the intramolecular interaction of its GBD and VCA domains. These results provide insight on the mechanisms contributing to diverse actin-based cellular processes such as cell migration, endocytosis and neuronal differentiation. PMID- 22250196 TI - Soluble molecules are key in maintaining the immunomodulatory activity of murine mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) possess both immuno-privileged and immuno inhibitory properties that contribute to their therapeutic effects. Ex vivo expansion is required to obtain sufficient cells for therapy, but might also alter their immunological properties. To date there has been no systematic study of MSC immunobiology during extended culture. Here, we demonstrate that both immuno-privilege and immunosuppressive properties of MSCs change with increasing passage. We demonstrate that although MSCs exhibit powerful immunosuppressive effects through secretion of transforming growth factor-beta (TGF-beta) and induction of interleukin-10, these effects are diminished by a concomitant increase in MSC immunogenicity. Interferon-gamma treatment for 3 days induced extendedly cultured MSCs to express significantly higher levels of major histocompatibility complex class I. In vivo, this results in cells that induce significant delayed-type hypersensitivity reactions in allogeneic recipients. Importantly, these effects are alleviated by isolation of the transplanted MSCs using a semi-permeable barrier. Under these conditions, even MSCs cultured through as many as 14 passages still exhibit immuno-inhibitory effects in vivo. Furthermore, the levels of anti-inflammatory molecule TGF-beta secreted by MSCs were maintained in the extended culture. These data shed light on the variable results of allogeneic MSCs in transplantation and suggest alternative strategies for prolonging the effect of allogeneic MSCs in cell-based therapy. PMID- 22250197 TI - The integrator complex is required for integrity of Cajal bodies. AB - The nucleus in eukaryotic cells is a highly organized and dynamic structure containing numerous subnuclear bodies. The morphological appearance of nuclear bodies seems to be a reflection of ongoing functions, such as DNA replication, transcription, repair, RNA processing and RNA transport. The integrator complex mediates processing of small nuclear RNA (snRNA), so it might play a role in nuclear body formation. Here, we show that the integrator complex is essential for integrity of the Cajal body. Depletion of INTS4, an integrator complex subunit, abrogated 3'-end processing of snRNA. A defect in this activity caused a significant accumulation of the Cajal body marker protein coilin in nucleoli. Some fractions of coilin still formed nucleoplasmic foci; however, they were free of other Cajal body components, such as survival of motor neuron protein (SMN), Sm proteins and snRNAs. SMN and Sm proteins formed striking cytoplasmic granules. These findings demonstrate that the integrator complex is essential for snRNA maturation and Cajal body homeostasis. PMID- 22250198 TI - Adenylate cyclase 5 coordinates the action of ADP, P2Y1, P2Y13 and ATP-gated P2X7 receptors on axonal elongation. AB - In adult brains, ionotropic or metabotropic purinergic receptors are widely expressed in neurons and glial cells. They play an essential role in inflammation and neurotransmission in response to purines secreted to the extracellular medium. Recent studies have demonstrated a role for purinergic receptors in proliferation and differentiation of neural stem cells although little is known about their role in regulating the initial neuronal development and axon elongation. The objective of our study was to investigate the role of some different types of purinergic receptors, P2Y1, P2Y13 and P2X7, which are activated by ADP or ATP. To study the role and crosstalk of P2Y1, P2Y13 and P2X7 purinergic receptors in axonal elongation, we treated neurons with specific agonists and antagonists, and we nucleofected neurons with expression or shRNA plasmids. ADP and P2Y1-GFP expression improved axonal elongation; conversely, P2Y13 and ATP-gated P2X7 receptors halted axonal elongation. Signaling through each of these receptor types was coordinated by adenylate cyclase 5. In neurons nucleofected with a cAMP FRET biosensor (ICUE3), addition of ADP or Blue Brilliant G, a P2X7 antagonist, increased cAMP levels in the distal region of the axon. Adenylate cyclase 5 inhibition or suppression impaired these cAMP increments. In conclusion, our results demonstrate a crosstalk between two metabotropic and one ionotropic purinergic receptor that regulates cAMP levels through adenylate cyclase 5 and modulates axonal elongation triggered by neurotropic factors and the PI3K-Akt-GSK3 pathway. PMID- 22250199 TI - The nucleoporin-like protein NLP1 (hCG1) promotes CRM1-dependent nuclear protein export. AB - Translocation of transport complexes across the nuclear envelope is mediated by nucleoporins, proteins of the nuclear pore complex that contain phenylalanine glycine (FG) repeats as a characteristic binding motif for transport receptors. CRM1 (exportin 1), the major export receptor, forms trimeric complexes with RanGTP and proteins containing nuclear export sequences (NESs). We analyzed the role of the nucleoporin-like protein 1, NLP1 (also known as hCG1 and NUPL2) in CRM1-dependent nuclear transport. NLP1, which contains many FG repeats, localizes to the nuclear envelope and could also be mobile within the nucleus. It promotes the formation of complexes containing CRM1 and RanGTP, with or without NES containing cargo proteins, that can be dissociated by RanBP1 and/or the cytoplasmic nucleoporin Nup214. The FG repeats of NLP1 do not play a major role in CRM1 binding. Overexpression of NLP1 promotes CRM1-dependent export of certain cargos, whereas its depletion by small interfering RNAs leads to reduced export rates. Thus, NLP1 functions as an accessory factor in CRM1-dependent nuclear protein export. PMID- 22250200 TI - A conserved membrane-binding domain targets proteins to organelle contact sites. AB - Membrane contact sites (MCSs), where the membranes of two organelles are closely apposed, are regions where small molecules such as lipids or calcium are exchanged between organelles. We have identified a conserved membrane-binding domain found exclusively in proteins at MCSs in Saccharomyces cerevisiae. The synaptotagmin-like-mitochondrial-lipid binding protein (SMP) domain is conserved across species. We show that all seven proteins that contain this domain in yeast localize to one of three MCSs. Human proteins with SMP domains also localize to MCSs when expressed in yeast. The SMP domain binds membranes and is necessary for protein targeting to MCSs. Proteins containing this domain could be involved in lipid metabolism. This is the first protein domain found exclusively in proteins at MCSs. PMID- 22250201 TI - The MCM-associated protein MCM-BP is important for human nuclear morphology. AB - Mini-chromosome maintenance complex-binding protein (MCM-BP) was discovered as a protein that is strongly associated with human MCM proteins, known to be crucial for DNA replication in providing DNA helicase activity. The Xenopus MCM-BP homologue appears to play a role in unloading MCM complexes from chromatin after DNA synthesis; however, the importance of MCM-BP and its functional contribution to human cells has been unclear. Here we show that depletion of MCM-BP by sustained expression of short hairpin RNA (shRNA) results in highly abnormal nuclear morphology and centrosome amplification. The abnormal nuclear morphology was not seen with depletion of other MCM proteins and was rescued with shRNA resistant MCM-BP. MCM-BP depletion was also found to result in transient activation of the G2 checkpoint, slowed progression through G2 and increased replication protein A foci, indicative of replication stress. In addition, MCM-BP depletion led to increased cellular levels of MCM proteins throughout the cell cycle including soluble MCM pools. The results suggest that MCM-BP makes multiple contributions to human cells that are not limited to unloading of the MCM complex. PMID- 22250202 TI - Cdt1p, through its interaction with Mcm6p, is required for the formation, nuclear accumulation and chromatin loading of the MCM complex. AB - Regulation of DNA replication initiation is essential for the faithful inheritance of genetic information. Replication initiation is a multi-step process involving many factors including ORC, Cdt1p, Mcm2-7p and other proteins that bind to replication origins to form a pre-replicative complex (pre-RC). As a prerequisite for pre-RC assembly, Cdt1p and the Mcm2-7p heterohexameric complex accumulate in the nucleus in G1 phase in an interdependent manner in budding yeast. However, the nature of this interdependence is not clear, nor is it known whether Cdt1p is required for the assembly of the MCM complex. In this study, we provide the first evidence that Cdt1p, through its interaction with Mcm6p with the C-terminal regions of the two proteins, is crucial for the formation of the MCM complex in both the cytoplasm and nucleoplasm. We demonstrate that disruption of the interaction between Cdt1p and Mcm6p prevents the formation of the MCM complex, excludes Mcm2-7p from the nucleus, and inhibits pre-RC assembly and DNA replication. Our findings suggest a function for Cdt1p in promoting the assembly of the MCM complex and maintaining its integrity by interacting with Mcm6p. PMID- 22250203 TI - Lateral spacing of adhesion peptides influences human mesenchymal stem cell behaviour. AB - Mesenchymal stem cells (MSCs) have attracted great interest in recent years for tissue engineering and regenerative medicine applications due to their ease of isolation and multipotent differentiation capacity. In the past, MSC research has focussed on the effects of soluble cues, such as growth factors and cytokines; however, there is now increasing interest in understanding how parameters such as substrate modulus, specific extracellular matrix (ECM) components and the ways in which these are presented to the cell can influence MSC properties. Here we use surfaces of self-assembled maleimide-functionalized polystyrene-block poly(ethylene oxide) copolymers (PS-PEO-Ma) to investigate how the spatial arrangement of cell adhesion ligands affects MSC behaviour. By changing the ratio of PS-PEO-Ma in mixtures of block copolymer and polystyrene homopolymer, we can create surfaces with lateral spacing of the PEO-Ma domains ranging from 34 to 62 nm. Through subsequent binding of cysteine-GRGDS peptides to the maleimide terminated end of the PEO chains in each of these domains, we are able to present tailored surfaces of controlled lateral spacing of RGD (arginine-glycine-aspartic acid) peptides to MSCs. We demonstrate that adhesion of MSCs to the RGD functionalized block-copolymer surfaces is through specific attachment to the presented RGD motif and that this is mediated by alpha5, alphaV, beta1 and beta3 integrins. We show that as the lateral spacing of the peptides is increased, the ability of the MSCs to spread is diminished and that the morphology changes from well-spread cells with normal fibroblastic morphology and defined stress-fibres, to less-spread cells with numerous cell protrusions and few stress fibres. In addition, the ability of MSCs to form mature focal adhesions is reduced on substrates with increased lateral spacing. Finally, we investigate differentiation and use qRT-PCR determination of gene expression levels and a quantitative alkaline phosphatase assay to show that MSC osteogenesis is reduced on surfaces with increased lateral spacing while adipogenic differentiation is increased. We show here, for the first time, that the lateral spacing of adhesion peptides affects human MSC (hMSC) properties and might therefore be a useful parameter with which to modify hMSC behaviour in future tissue engineering strategies. PMID- 22250204 TI - Quantitative mapping of averaged focal adhesion dynamics in migrating cells by shape normalization. AB - The spatially ordered formation and disassembly of focal adhesions is a basic requirement for effective cell locomotion. Because focal adhesions couple the contractile actin-myosin network to the substrate, their distribution determines the pattern of traction forces propelling the cell in a certain direction. In the present study, we quantitatively analyzed the spatial patterning of cell substrate adhesion in migrating cells by mapping averaged focal adhesion growth dynamics to a standardized cell coordinate system. These maps revealed distinct zones of focal adhesion assembly, disassembly and stability and were strongly interrelated with corresponding actin flow and traction force patterns. Moreover, the mapping technique enables precise detection of even minute responses of adhesion dynamics upon targeted signaling perturbations. For example, the partial inhibition of vinculin phosphorylation was followed by the reduced number of newly formed adhesions, whereas growth dynamics of existing adhesions remained unaffected. PMID- 22250206 TI - Sporadic hemiplegic migraine with normal imaging as the initial manifestation of CADASIL. AB - BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be present with negative family history and, especially in younger patients, with normal brain magnetic resonance. For this reason, those CADASIL patients that present only with migraine may be misdiagnosed. In the case of migraine with motor aura, sporadic hemiplegic migraine (SHM) is one of the possible misdiagnoses. CASE RESULTS: We present a case of a patient who, in the first years of her disease, met the clinical criteria for SHM. A diagnosis of CADASIL was considered only when her sister presented with headache and an unknown leukoencephalopathy. CONCLUSIONS: This case illustrates the need for a careful review of the clinical and family history during the follow-up of primary headaches. PMID- 22250205 TI - Loss of Scribble causes cell competition in mammalian cells. AB - In Drosophila, normal and transformed cells compete with each other for survival in a process called cell competition. However, it is not known whether comparable phenomena also occur in mammals. Scribble is a tumor suppressor protein in Drosophila and mammals. In this study we examine the interface between normal and Scribble-knockdown epithelial cells using Madin-Darby Canine Kidney (MDCK) cells expressing Scribble short hairpin RNA (shRNA) in a tetracycline-inducible manner. We observe that Scribble-knockdown cells undergo apoptosis and are apically extruded from the epithelium when surrounded by normal cells. Apoptosis does not occur when Scribble-knockdown cells are cultured alone, suggesting that the presence of surrounding normal cells induces the cell death. We also show that death of Scribble-knockdown cells occurs independently of apical extrusion. Finally, we demonstrate that apoptosis of Scribble-knockdown cells depends on activation of p38 mitogen-activated protein kinase (MAPK). This is the first demonstration that an oncogenic transformation within an epithelium induces cell competition in a mammalian cell culture system. PMID- 22250207 TI - Association analysis of STX1A gene variants in common forms of migraine. AB - OBJECTIVES: To examine the association of genetic variants in the syntaxin 1A gene (STX1A) with common forms of migraine, and perform a combined analysis of the data from the current study and previously published reports. METHODS: We investigated the parent-to-offspring transmission of rs6951030, rs4363087 and rs2293489 in 191 family trios, each with a proband with childhood-onset migraine, and performed a case-control analysis between the probands and 223 unrelated controls. In addition, we performed a combined data analysis with an overall sample of 567 migraine patients and 720 unrelated controls and performed a migraine-specific gene-network analysis. RESULTS: The transmission disequilibrium test revealed significant transmission distortion of rs4363087 in migraine overall (OR = 1.56, p = 0.006; p = 0.01 after correction for multiple testing) and migraine without aura (OR = 1.58, p = 0.01; corrected p = 0.04). Two-marker haplotype analysis revealed transmission distortion of A-G (rs6951030-rs4363087; OR = 1.47, p = 0.01) and A-C (rs4363087-rs2293489; OR = 0.66, p = 0.01). Combined analysis showed significant association of rs941298 with migraine overall (OR = 1.28, p = 0.004) and migraine without aura (OR = 1.3, p = 0.008). Network analysis identified 24 genes relating STX1A to other migraine candidate genes, including KCNK18 (TRESK channel) involved in the cytoplasmatic calcium signalling together with syntaxin 1A. CONCLUSION: Our results provide support for the hypothesis that STX1A represents a susceptibility gene for migraine. PMID- 22250208 TI - Self-reported muscle pain in adolescents with migraine and tension-type headache. AB - AIM: To identify possible associations between muscular pain and headache in adolescents in a large population-based sample. METHODS: Grammar school students were invited to fill in a questionnaire on headache and associated lifestyle factors. Headache was classified according to the German version of the International Classification of Headache Disorders (2nd edition). Muscular pain was assessed via denoting affected areas in schematic drawings of a body and via provoked muscular pain on controlled movements of head, neck and shoulder regions. RESULTS: Prevalence of any headache within the previous 6 months exceeded 80%. In all subjects muscular pain or pain on movement was most prominent in the neck and shoulder region, ranging from 9% to 27% in the non headache population to up to 63% for individuals with migraine or mixed migraine and tension-type headache (TTH). Frequency of muscular pain increased significantly with growing chronicity of TTH. INTERPRETATION: A strong association between muscle pain in the neck/shoulder region and headache was observed, pointing to the importance of muscular pain for headache in adolescents. Also, in this age group muscular pain appears to be of particular importance in chronic TTH and - unexpectedly - in migraine, which is the most important new finding in our study. PMID- 22250209 TI - Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? AB - Anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to be effective at improving vision in patients with macular oedema due to diabetic retinopathy and vein occlusions, but blocking VEGF at least in theory could be detrimental to vascular integrity. For this reason, some patients with macular ischaemia were excluded from studies showing the effectiveness of therapy. A considerable number of patients present with mixed pathology of macular oedema and macular ischaemia and it is often impossible to determine the degree to which ischaemia accounts for decreased vision. In this review, the authors have dealt with the specific question of whether or not there is evidence to support potential worsening of the macular perfusion and visual function after anti-VEGF treatment with bevacizumab or ranibizumab for macular oedema secondary to diabetic retinopathy or retinal vein occlusions, especially if there is coexisting macular ischaemia. The authors conclude that anti-VEGF therapy rarely seems to further compromise the retinal circulation; however, worsening of macular ischaemia in the long term cannot be definitely excluded, particularly in eyes with significant ischaemia at baseline and after repeated intraocular anti VEGF injections. The decision to offer prolonged anti-VEGF treatment in cases of significant coexisting macular ischaemia should not be based only on measurements of macular thickness; instead repeat fluorescein angiograms should be performed. PMID- 22250210 TI - Precise temporal association between cortical potentials evoked by motor imagination and afference induces cortical plasticity. AB - In monkeys, the repeated activation of somatosensory afferents projecting onto the motor cortex (M1) has a pivotal role in motor skill learning. Here we investigate if sensory feedback that is artificially generated at specific times during imagination of a dorsiflexion task leads to reorganization of the human M1. The common peroneal nerve was stimulated to generate an afferent volley timed to arrive during specific phases of the cortical potential generated when a movement was imagined (50 repetitions). The change in the output of M1 was quantified by applying single transcranial magnetic stimuli to the area of M1 controlling the tibialis anterior muscle. The results demonstrated that the concomitance between the cognitive process of movement (motor imagination) and the ascending volley due to the peripheral nerve stimulation can lead to significant increases in cortical excitability. These increases were critically dependent on the timing between the peripherally generated afferent volley and the cortical potential generated during the imagined movement. Only if the afferent volley arrived during the peak negative deflection of the potential, were significant alterations in motor cortical output attained. These results demonstrate that an artificially generated signal (the peripheral afferent volley) can interact with a physiologically generated signal in humans leading to plastic changes within the M1, the final output stage for movement generation within the human brain. The results presented may have implications in systems for artificially inducing cortical plasticity in patients with motor impairments (neuromodulation). PMID- 22250211 TI - S-glutathionylation of troponin I (fast) increases contractile apparatus Ca2+ sensitivity in fast-twitch muscle fibres of rats and humans. AB - Oxidation can decrease or increase the Ca2+ sensitivity of the contractile apparatus in rodent fast-twitch (type II) skeletal muscle fibres, but the reactions and molecular targets involved are unknown. This study examined whether increased Ca2+ sensitivity is due to S-glutathionylation of particular cysteine residues. Skinned muscle fibres were directly activated in heavily buffered Ca2+ solutions to assess contractile apparatus Ca2+ sensitivity. Rat type II fibres were subjected to S-glutathionylation by successive treatments with 2,2' dithiodipyridine (DTDP) and glutathione (GSH), and displayed a maximal increase in pCa50 (-log10 [Ca2+] at half-maximal force) of ~0.24 pCa units, with little or no effect on maximum force or Hill coefficient. Partial similar effect was produced by exposure to oxidized gluthathione (GSSG, 10 mM) for 10 min at pH 7.1, and near-maximal effect by GSSG treatment at pH 8.5. None of these treatments significantly altered Ca2+ sensitivity in rat type I fibres. Western blotting showed that both the DTDP-GSH and GSSG-pH 8.5 treatments caused marked S glutathionylation of the fast troponin I isoform (TnI(f)) present in type II fibres, but not of troponin C (TnC) or myosin light chain 2. Both the increased Ca2+ sensitivity and glutathionylation of TnI(f) were blocked by N-ethylmaleimide (NEM). S-nitrosoglutathione (GSNO) also increased Ca2+ sensitivity, but only in conditions where it caused S-glutathionylation of TnI(f). In human type II fibres from vastus lateralis muscle, DTDP-GSH treatment also caused similar increased Ca2+ sensitivity and S-glutathionylation of TnI(f). When the slow isoform of TnI in type I fibres of rat was partially substituted (~30%) with TnI(f), DTDP-GSH treatment caused a significant increase in Ca2+ sensitivity (~0.08 pCa units). TnIf in type II fibres from toad and chicken muscle lack Cys133 present in mammalian TnIf, and such fibres showed no change in Ca2+ sensitivity with DTDP GSH nor any S-glutathionylation of TnI(f) (latter examined only in toad). Following 40 min of cycling exercise in human subjects (at ~60% peak oxygen consumption), TnI(f) in vastus lateralis muscle displayed a marked increase in S glutathionylation (~4-fold). These findings show that S-glutathionylation of TnI(f), most probably at Cys133, increases the Ca2+ sensitivity of the contractile apparatus, and that this occurs in exercising humans, with likely beneficial effects on performance. PMID- 22250212 TI - Functional characteristics of parvalbumin- and cholecystokinin-expressing basket cells. AB - Cortical neuronal network operations depend critically on the recruitment of GABAergic interneurons and the properties of their inhibitory output signals. Recent evidence indicates a marked difference in the signalling properties of two major types of perisomatic inhibitory interneurons, the parvalbumin- and the cholecystokinin-containing basket cells. Parvalbumin-expressing basket cells are rapidly recruited by excitatory synaptic inputs, generate high-frequency trains of action potentials, discharge single action potentials phase-locked to fast network oscillations and provide fast, stable and timed inhibitory output onto their target cells. In contrast, cholecystokinin-containing basket cells are recruited in a less reliable manner, discharge at moderate frequencies with single action potentials weakly coupled to the phases of fast network oscillations and generate an asynchronous, fluctuating and less timed inhibitory output. These signalling modes are based on cell type-dependent differences in the functional and plastic properties of excitatory input synapses, integrative qualities and in the kinetics and dynamics of inhibitory output synapses. Thus, the two perisomatic inhibitory interneuron types operate with different speed and precision and may therefore contribute differently to the operations of neuronal networks. PMID- 22250213 TI - Spontaneous cluster activity in the inferior olivary nucleus in brainstem slices from postnatal mice. AB - A distinctive property of the cerebellar system is olivocerebellar modules, where synchronized electrical activity in neurons in the inferior olivary nucleus (IO) evokes organized activity in the cerebellar cortex. However, the exact function of these modules, and how they are developed, is still largely unknown. Here we show that the IO in in vitro slices from postnatal mice spontaneously generates clusters of neurons with synchronous Ca(2+) transients. Neurons in the principal olive (PO), and the vestibular-related dorsomedial cell column (dmcc), showed an age-dependent increase in spontaneous calcium transients. The spatiotemporal activity pattern was occasionally organized in clusters of co-active neighbouring neurons,with regular (16 min-1) and irregular (2-3 min(-1)) repeating cluster activity in the dmcc and PO, respectively. IO clusters had a diameter of 100-170 MUm, lasted~1 s, and increased in occurrence from postnatal day P5.5 to P12.5, followed by a sharp drop to near zero at P15.5. IO clusters were overlapping, and comprised nearly identical neurons at some time points, and a varied subset of neurons at others. Some neurons had hub-like properties, being co-active with many other neighbours, and some were co-active with separate clusters at different times. The coherence between calcium transients in IO neurons decreased with Euclidean distance between the cells reaching low values at 100-200 MUm distances. Intracellular recordings from IO neurons during cluster formation revealed the presence of spikelet-like potentials, suggesting that electrical coupling between neighbouring IO neurons may serve as a synchronizing mechanism. In conclusion, the IO shows spontaneous cluster activity under in vitro conditions, coinciding with a critical postnatal period in olivocerebellar development. We propose that these clusters may be forerunners of the ensembles of IO neurons shown to be co-active in adult animals spontaneously and during motor acts. PMID- 22250214 TI - Cotransport of water by Na+-K+-2Cl- cotransporters expressed in Xenopus oocytes: NKCC1 versus NKCC2. AB - The NKCC1 and NKCC2 isoforms of the mammalian Na+-K+-2Cl- cotransporter were expressed in Xenopus oocytes and the relation between external ion concentration and water fluxes determined.Water fluxes were determined from changes in the oocytes volume and ion fluxes from 86Rb+ uptake. Isotonic increases in external K+ concentration elicited abrupt inward water fluxes in NKCC1; the K+ dependence obeyed one-site kinetics with a K0.5 of 7.5 mM. The water fluxes were blocked by bumetanide, had steep temperature dependence and could proceed uphill against an osmotic gradient of 20 mosmol l-1. A comparison between ion and water fluxes indicates that 460 water molecules are cotransported for each turnover of the protein. In contrast, NKCC2 did not support water fluxes.Water transport in NKCC1 induced by increases in the external osmolarity had high activation energy and was blocked by bumetanide. The osmotic effects of NaCl were smaller than those of urea and mannitol. This supports the notion of interaction between ions and water in NKCC1 and allows for an estimate of around 600 water molecules transported per turnover of the protein. Osmotic gradients did not induce water transport in NKCC2. We conclude that NKCC1 plays a direct role for water balance in most cell types, while NKCC2 fulfils its role in the kidney of transporting ions but not water. The different behaviour of NKCC1 and NKCC2 is discussed on the basis of recent molecular models based on studies of structural and molecular dynamics. PMID- 22250217 TI - Evidence and desperation in off-label prescribing: recombinant factor VIIa. PMID- 22250215 TI - Differential expression and function of nicotinic acetylcholine receptors in the urinary bladder epithelium of the rat. AB - It has been previously determined that the epithelial lining of the urinary bladder, or urothelium, expresses two subtypes of nicotinic acetylcholine receptors (nAChRs) that mediate distinct physiological effects in vivo. These effects include inhibition of bladder reflexes through alpha7 receptors and an excitation of bladder reflexes through alpha3-containing (alpha3*) receptors. It is believed that urothelial receptors mediate their effects through modulating the release of neurotransmitters such as ATP that subsequently influence bladder afferent nerve excitability. Therefore, we examined the distribution of nAChRs in the urothelium, as well as their ability to influence the release of the neurotransmitter ATP. Immunofluorescent staining of both whole bladder tissue and primary urothelial cultures from the rat demonstrated that the urothelium contains both alpha3* and alpha7 receptors. In primary urothelial cultures, alpha7 stimulation with choline (10 MUM to 1 mM) caused a decrease in basal ATP release while alpha3* stimulation with cytisine (1-100 MUM) caused a concentration-dependent, biphasic response, with low concentrations (1-10 MUM) inhibiting release and higher concentrations (50-100 MUM) increasing release. These responses were mirrored in an in vitro, whole bladder preparation. In vivo, excitation of bladder reflexes in response to intravesical cytisine (100 MUM) is blocked by systemic administration of the purinergic antagonist PPADS (1 or 3 MUg kg(-1)). We also examined how each receptor subtype influenced intracellular Ca2+ levels in cultured urothelial cells. nAChR stimulation increased [Ca2+]i through distinct mechanisms: alpha7 through a ryanodine-sensitive intracellular mechanism and alpha3* through extracellular influx. In addition, our findings suggest interactions between nAChR subtypes whereby activation of alpha7 receptors inhibited the response to a subsequent activation of alpha3* receptors, preventing the increase in [Ca2+]i previously observed. This inhibitory effect appears to be mediated through protein kinase A- or protein kinase C-mediated pathways. PMID- 22250218 TI - Clinical prediction rules. PMID- 22250216 TI - Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold-induced myotonia in French Canadians. AB - M1476I, a French Canadian founder mutation of Na+ channel Nav1.4, causes potassium-aggravated myotonia, with cold-induced myotonia as the most distinctive clinical feature. Mexiletine, a class 1B local anaesthetic, relieves the myotonic symptoms of patients carrying the M1476I mutation. We used the patch-clamp method to investigate the functional characteristics of this mutation by heterologous expression in tsA201 cells. The M1476I mutation caused an increased persistent Na+ current, a 2- to 3-fold slower fast inactivation, a 6.4 mV depolarizing shift in the midpoint of steady-state inactivation, and an accelerated recovery from fast inactivation compared to the wild-type (WT) channel. Cooling slowed the kinetics of both channel types and increased the amplitude of the persistent current in M1476I channels.Mexiletine suppressed the persistent Na+ current generated by the M1476I mutation and blocked both WT and M1476I channels in a use dependent manner. The inactivation-deficient M1476I channels were less susceptible to mexiletine during repetitive pulses. The decreased use-dependent block of M1476I channels might have resulted from the slower onset of mexiletine block, and/or the faster recovery from mexiletine block, given that the affinity of mexiletine for the inactivated state of the WT and mutant channels was similar. Increased extracellular concentrations of potassium had no effect on either M1476I or WT currents. These results indicated that cooling can augment the disruption of the voltage dependence of fast inactivation by M1476I channels. PMID- 22250219 TI - The greening of medicine. PMID- 22250220 TI - Peers defeat government plan to withdraw benefits from sick and disabled people after a year. PMID- 22250221 TI - Cardiovascular researcher fabricated data in studies of red wine. PMID- 22250222 TI - NHS compensation fund gets 185m pound bailout as claims rise by 30% in a year. PMID- 22250223 TI - Dutch GP association is fined 7.7m euro for anticompetitive behaviour. PMID- 22250224 TI - Diagnosis and management of ANCA associated vasculitis. PMID- 22250225 TI - Staging anorexia nervosa could improve outcomes, say experts. PMID- 22250226 TI - Institutions must do more to eliminate research misconduct, meeting hears. PMID- 22250227 TI - US broadcast regulator says "sponsorship" of news should be disclosed. PMID- 22250228 TI - Flu vaccine investigator is suspended for four months for research fraud. PMID- 22250229 TI - Interstitial granulomatous dermatitis with arthritis responding to tocilizumab. PMID- 22250230 TI - Practice gaps. Missing genital lichen sclerosus in patients with morphea: don't ask? Don't tell?: comment on "High frequency of genital lichen sclerosus in a prospective series of 76 patients with morphea". PMID- 22250231 TI - Relationship between the depth of facial wrinkles and the density of the retinacula cutis. AB - OBJECTIVE: To identify whether there is a relationship between the depth of facial wrinkles and the density of the retinacula cutis in the subcutaneous tissue of the skin. DESIGN: Wrinkle depth was assessed with image analysis on the forehead and the lateral canthus of human cadavers. The density of the retinacula cutis was measured in Azan-Mallory-stained skin sections obtained around the wrinkles. SETTING: Gross Anatomy Section, Kagoshima University Graduate School of Medical and Dental Sciences. PARTICIPANTS: Fifty-five male and female cadavers (35-93 years old). MAIN OUTCOME MEASURES: The maximum depth of each wrinkle was used to represent the wrinkle's degree. In the skin sections, the density of the retinacula cutis was measured around the deepest point of each wrinkle in a 1-mm wide area (the wrinkle-specific area) and a 10-mm-wide area that included the wrinkle (the wrinkle-inclusive area). RESULTS: In both the wrinkle-specific and wrinkle-inclusive areas, the retinacula cutis densities became lower in the forehead and in the lateral canthus areas. When a wrinkle was shallow, the density was lower in the wrinkle-specific area than in the wrinkle-inclusive area. With wrinkle progression, the density difference between the wrinkle specific and the wrinkle-inclusive areas gradually decreased until there was no apparent difference. CONCLUSIONS: Facial wrinkles seem to develop above sites of reduced lower retinacula cutis density. As a wrinkle develops, the density decreases in both the wrinkle-specific and the wrinkle-inclusive areas, whereas the density difference between those areas vanishes. PMID- 22250233 TI - Impact of live interactive teledermatology on diagnosis, disease management, and clinical outcomes. AB - OBJECTIVE: To assess the impact of live interactive teledermatology consultations on changes in diagnosis, disease management, and clinical outcomes. DESIGN: We conducted a retrospective analysis of 1500 patients evaluated via live interactive teledermatology between 2003 and 2005 at the University of California, Davis. We compared diagnoses and treatment plans between the referring physicians and the teledermatologists. Patients with 2 or more teledermatology visits within a 1-year period were assessed for changes in clinical outcomes. SETTING: Academic medical center with an established teledermatology program since 1996. PARTICIPANTS: Medical records were evaluated for 1500 patients who underwent live interactive teledermatology consultation. Patients seen for more than 1 teledermatology visit were included in the clinical outcome assessment. INTERVENTION: Live interactive teledermatology consultation. MAIN OUTCOME MEASURES: Changes in diagnosis, disease management, and clinical outcome. RESULTS: Compared with diagnoses and treatment plans from referring physicians, the 1500 live interactive teledermatology consultations resulted in changes in diagnosis in 69.9% of patients and changes in disease management in 97.7% of patients. Among 313 patients with at least 2 teledermatology visits within 1 year, clinical improvement was observed in 68.7% of patients. Multivariate analysis showed that changes in diagnosis (P = .01), changes in disease management (P < .001), and the number of teledermatology visits (P < .001) were significantly associated with improved clinical outcomes. CONCLUSIONS: Live interactive teledermatology consultations result in changes in diagnosis and disease management in most consultations. The numbers of live interactive teledermatology visits and changes in diagnosis and disease management are significantly associated with improved clinical outcomes. PMID- 22250234 TI - Practice gaps. Prescribing patterns by dermatologists and primary care providers for pediatric psoriasis: comment on "Trends in pediatric psoriasis outpatient health care delivery in the United States". PMID- 22250236 TI - A novel mutation in the PORCN gene underlying a case of almost unilateral focal dermal hypoplasia. AB - BACKGROUND: Focal dermal hypoplasia (also known as Goltz syndrome) is an X-linked dominant syndrome characterized by patchy hypoplastic skin with soft-tissue, skeletal, dental, and ocular defects that are secondary to mutations in the PORCN gene. To our knowledge, only 5 cases of focal dermal hypoplasia with unilateral presentation have been reported, and molecular studies were not performed in any of the cases. OBSERVATIONS: A 17-year-old girl was seen with features of almost unilateral focal dermal hypoplasia. These included left cleft hand, dental dysplasia, left mammary hypoplasia, deviation of the sacral line, raspberrylike papillomas in the perianal region, syndactyly of the second and third digits of the left foot, and linear streaks of dermal hypoplasia and pigmented lesions on her left hemibody. CONCLUSIONS: Mutation analysis of PORCN revealed a novel heterozygous mutation in exon 10, c.854-855insACCTGAC; [p.T285fsX316], resulting in a premature stop signal. Analysis of the X-chromosome inactivation status was performed on blood and skin DNA samples, showing random inactivation in blood and unaffected skin and skewed inactivation in affected skin, highlighting the role of X-chromosome inactivation in X-linked disease expression. PMID- 22250238 TI - Polarized microscopy as a helpful tool to distinguish chronic nonscarring alopecia from scarring alopecia. AB - BACKGROUND: Nonscarring alopecia differs from scarring alopecia on pathologic examination by the preservation of follicular units and lack of follicular dropout. However, long-standing cases of active nonscarring hair loss can show follicular dropout on pathologic examination and can be difficult to interpret. OBSERVATIONS: We describe a patient with nonscarring alopecia that was misdiagnosed as scarring alopecia due to difficulty in distinguishing between scarred tracts (follicular dropout) and long-persisting fibrovascular streamers. Polarized light microscopy permits us to distinguish follicular scars from fibrous streamers because the fibrous streamers are birefringent negative for collagen. The main advantages of polarized microscopy are that it is fast and cost free and can screen all sections within minutes; it is also easy to interpret for beginners because there is a built-in control of birefringent positive dermal collagen. CONCLUSION: Polarized light can be used in the pathological evaluation of hair loss to distinguish between the follicular scars in scarring alopecia and the fibrovascular streamers in long-standing nonscarring alopecia. PMID- 22250239 TI - Consensus guidelines for the management of plaque psoriasis. AB - The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations. PMID- 22250240 TI - Cancer risk in patients with chronic urticaria: a population-based cohort study. AB - OBJECTIVE: To investigate the relative risk of cancer among patients with chronic urticaria in the Taiwanese population. DESIGN: Retrospective population-based cohort study. SETTING: The National Health Insurance Research Database of Taiwan from January 1, 1996, through December 31, 2008. PARTICIPANTS: A total of 12,720 patients with chronic urticaria, with long-term antihistamine use and no history of malignant tumors, autoimmune diseases, atopy, or allergic diseases. MAIN OUTCOME MEASURE: Relative cancer risk calculated by standardized incidence ratios. RESULTS: There were 704 cancers among chronic urticaria patients. An increased risk of cancer (standardized incidence ratio, 2.2; 95% CI, 2.0-2.3), especially hematologic malignant tumor (4.1; 3.1-5.4), was observed. The relative risk of cancer varied by age and was highest among those aged 20 to 39 years in comparison with the general population. Most cancer cases were detected within the first year of diagnosis. The risk of non-Hodgkin lymphoma was greatest (standardized incidence ratio, 4.4; 95% CI, 3.0-6.1) among the hematologic cancers. CONCLUSIONS: Patients with chronic urticaria are at increased risk of cancer, especially hematologic malignant tumors. Further studies are needed to delineate the associations. PMID- 22250242 TI - Imiquimod vs cryotherapy for molluscum contagiosum: a randomized controlled trial. PMID- 22250244 TI - Blistering mucosal eruption in a young woman with systemic lupus erythematosus. PMID- 22250245 TI - Erythematous patches on the chest. PMID- 22250246 TI - Firm nodule on the shoulder. PMID- 22250247 TI - Reticulate hyperpigmentation of the vulva. PMID- 22250248 TI - A small study of the relationship between abobotulinum toxin A concentration and forehead wrinkle reduction. PMID- 22250249 TI - Practice gaps. Dilution, reconstitution, and complexity: comment on "A small study of the relationship between abobotulinum toxin A concentration and forehead wrinkle reduction". PMID- 22250250 TI - Implementation of the federal excise tax on indoor tanning services in Illinois. PMID- 22250251 TI - Attitudes toward indoor tanning among users of sunless tanning products. PMID- 22250252 TI - Photodynamic therapy with 5-aminolevulinic acid intralesional injection for pyogenic granuloma. PMID- 22250253 TI - A population-based study of acne and body mass index in adolescents. PMID- 22250254 TI - Narrowband UV-B phototherapy during pregnancy and folic acid depletion. PMID- 22250255 TI - Interferon-gamma release assay. PMID- 22250256 TI - Resolution of skin maladies of the trapped Chilean miners: the unplanned underground copper-impregnated antifungal socks "trial". PMID- 22250257 TI - An acrochordon-like melanoma metastasis. PMID- 22250258 TI - A novel application of topical rapamycin formulation, an inhibitor of mTOR, for patients with hypomelanotic macules in tuberous sclerosis complex. PMID- 22250259 TI - Atypical gingivitis heralding a case of orofacial granulomatosis. PMID- 22250260 TI - Congenital mucinous eccrine nevi in an infant with chronic granulomatous disease. PMID- 22250261 TI - White shiny structures in melanoma and BCC. PMID- 22250262 TI - The nasal valve dilemma: the narrow straw vs the weak wall. PMID- 22250263 TI - Retrospective review of resorbable plate fixation in pediatric craniofacial surgery: long-term outcome. PMID- 22250264 TI - Nasal batten grafts: are patients satisfied? AB - OBJECTIVES: To learn how nasal batten grafts affect patients' assessment of their nasal airway patency and to determine the extent to which patients believe batten grafts altered their appearance. METHODS: A prospective survey study of 18 patients in a tertiary veterans hospital who had nasal airway obstruction (NAO) due to nasal valve collapse was completed. Patients had placement of bilateral polyethylene batten grafts during a 36-month study period. The Nasal Obstruction Symptom Evaluation (NOSE) validated survey was used to measure a patient's subjective postoperative change in nasal airway obstruction. In addition, the patients were asked to rate the extent their appearance had changed. RESULTS: All patients presented with complaints of NAO due to nasal valve collapse either in isolation or in combination with another anatomical source of obstruction. The nasal valve collapse was identified by clinical examination. All patients had preoperative photographs. Most patients had a trial with an intranasal stent before opting for surgical implantation of the batten grafts. The results of the NOSE survey demonstrate significant improvement in nasal obstruction. Patients also reported only a minimal change in appearance. There was 1 patient with implant extrusions and only a few implants were removed. CONCLUSIONS: Nasal airway obstruction due to nasal valve collapse can be effectively treated with polyethylene batten grafts. The implants are well tolerated, and patients report a significant improvement in NAO. There is little risk of implant extrusion, exposure, or intolerance. In addition, patients did not note a significant change to their appearance. PMID- 22250265 TI - Mechanical analysis of the effects of cephalic trim on lower lateral cartilage stability. AB - OBJECTIVE: To determine how mechanical stability changes in the lower lateral cartilage (LLC) after varying degrees of cephalic resection in a porcine cartilage nasal tip model. METHODS: Alar cartilage was harvested from fresh porcine crania (n = 14) and sectioned to precisely emulate a human LLC in size and dimension. Flexural mechanical analysis was performed both before and after cephalic trims of 0 (control), 4, and 6 mm. Cantilever deformation tests were performed on the LLC models at 3 locations (4, 6, and 8 mm from the midline), and the integrated reaction force was measured. An equivalent elastic modulus of the crura was calculated assuming that the geometry of the LLC model approximated a modified single cantilever beam. A 3-dimensional finite element model was used to model the stress distribution of the prescribed loading conditions for each of the 3 types of LLC widths. RESULTS: A statistically significant decrease (P = .02) in the equivalent elastic modulus of the LLC model was noted at the most lateral point at 8 mm and only when 4 mm of the strut remained (P = .05). The finite element model revealed that the greatest internal stresses was at the tip of the nose when tissue was flexed 8 mm from the midline. CONCLUSION: Our results provide the mechanical basis for suggested clinical guidelines stating that a residual strut of less than 6 mm can lead to suboptimal cosmetic results owing to poor structural support of the overlying skin soft-tissue envelope by an overly resected LLC. PMID- 22250266 TI - Anatomic variations found on dissection of depressor septi nasi muscles in cadavers. AB - OBJECTIVES: To define variations of the depressor septi muscle in Iranians; to provide guidance for modification of this muscle during rhinoplasty in patients with an active muscle and short upper lip; and to correlate our findings with our clinical experience to develop the applied algorithms. METHODS: This study was conducted by dissecting 82 depressor septi nasi muscles in 41 Iranian cadavers. Origin and insertion points of each muscle were studied. RESULTS: Three variations were found in muscle insertion points: periosteal, orbicularis oris, and floating. Forty-four percent of the muscles were inserted into the periosteum of the maxilla (n = 36); 39% of muscles were inserted into the orbicularis oris muscle (n = 32); and 17% were diminutive or floating (n = 14). Periosteal insertion was thicker and stronger than the other variations. In all cadavers, the origin of the muscle was medial crus of alar cartilage and caudal of the nasal septum. CONCLUSIONS: This cadaveric dissection showed that the percentage of depressor septi muscle insertions is not similar to that found in other surveys. In this study, periosteal insertion of the depressor septi muscle was the most common variation. PMID- 22250268 TI - Orthodromic temporalis tendon transfer: anatomical considerations. AB - OBJECTIVES: To define (1) at-risk structures during the orthodromic temporalis tendon transfer and (2) achievable tendon length without temporal releasing incisions or perioral lengthening materials. METHODS: Ten fresh cadavers provided 20 hemifaces for dissection. Measurements and photographic documentation were used to examine the parotid duct, masseteric artery, inferior alveolar nerve, internal maxillary artery, and mobilized tendon relative to adjacent landmarks. RESULTS: The parotid duct was found in a reproducible region posterior to the melolabial crease and inferior to a parotid duct reference line. The masseteric artery was found posterior to the posterior-most attachment of the tendon at its exit from the sigmoid notch (mean, 14.5 mm). The inferior alveolar nerve was found posterior to the anterior edge of the ascending ramus (mean, 18.3 mm). The internal maxillary artery coursed superiorly from posterior to anterior along the medial mandible near the coronoidectomy site. The tendon reached beyond the melolabial crease in 17 of 20 hemifaces (85%). CONCLUSIONS: The parotid duct reference line and the melolabial crease allow estimation of the parotid duct location. Anatomical relationships between the tendon, parotid duct, neurovasculature, and anatomical landmarks underscore the importance of deliberate soft-tissue retraction and subperiostial elevation to minimize injury. The tendon alone usually provides adequate length for orthodromic suspension. PMID- 22250267 TI - Intraoperative suction-assisted evaluation of the nasal valve in rhinoplasty. AB - OBJECTIVE: To introduce and analyze suction-assisted analysis of nasal valve strength in functional septorhinoplasty. This is a novel method for helping the surgeon analyze the integrity of a patient's airway during surgery. METHODS: In this prospective study, 20 patients who underwent functional septorhinoplasty were analyzed. Negative pressure using suction tubing was placed at the nasal sill, and measurements of the amount of maximal depression of the nasal valve were performed in the operating room immediately before incision and immediately after closure of the incisions. RESULTS: All 20 patients had an immediate decrease in the deviation of the weakest point of the valve, with a mean change of 2.14 mm. The change on both sides was statistically significant (paired t test, P < .001). This novel method helped the surgeons decide which grafts provided the most immediate structural benefit. CONCLUSIONS: Structure-based septorhinoplasty can immediately improve the strength of the nasal valve. Suction assisted analysis of the nasal valve can be a useful "real-time" tool for determining which maneuvers improve the strength of the nasal valve. PMID- 22250269 TI - New technique for medial canthoplasty that incorporates modified v-w epicanthoplasty. AB - Telecanthus, which is the lateral displacement of the medial canthus, can be a congenital deformity or can occur after facial trauma. Several epicanthoplasty methods have been described, but the orbitonasal angle and appropriate shape cannot be reconstructed in Asians. We solved this problem by using a dog-ear effect. This article describes a new design for epicanthoplasty and its results. PMID- 22250270 TI - Zygomaticomaxillary complex fractures. PMID- 22250272 TI - The effect of rhinoplasty on perceived age. PMID- 22250271 TI - Physician confidence in fillers and neurotoxins: a national survey. PMID- 22250273 TI - The four seasons: winter, by Francois Boucher. PMID- 22250274 TI - Perioperative care of neonates with Down's syndrome: should it be different? PMID- 22250275 TI - Anaesthesia awareness: 3 years of progress. PMID- 22250276 TI - Postoperative intravenous morphine titration. AB - Relief of acute pain during the immediate postoperative period is an important task for anaesthetists. Morphine is widely used to control moderate-to-severe postoperative pain and the use of small i.v. boluses of morphine in the post anaesthesia care unit allows a rapid titration of the dose needed for adequate pain relief. The essential principle of a titration regimen must be to adapt the morphine dose to the pain level. Although morphine would not appear to be the most appropriate choice for achieving rapid pain relief, this is the sole opioid assessed in many studies of immediate postoperative pain management using titration. More than 90% of the patients have pain relief using a protocol of morphine titration and the mean dose required to obtain pain relief is 12 (7) mg, after a median of four boluses. Sedation is frequent during i.v. morphine titration and should be considered as a morphine-related adverse event and not evidence of pain relief. The incidence of ventilatory depression is very low when the criteria to limit the dose of i.v. morphine are enforced. Morphine titration can be used with caution in elderly patients, in children, or in obese patients. In practice, i.v. morphine titration allows the physician to meet the needs of individual patients rapidly and limits the risk of overdose making this method the first step in postoperative pain management. PMID- 22250277 TI - Hydroxyethyl starch in patients with trauma. PMID- 22250280 TI - Low-flow anaesthesia and carbon monoxide in paediatric patients. PMID- 22250281 TI - Optimized method for correct left-sided central venous catheter placement under electrocardiographic guidance. PMID- 22250282 TI - Optimizing cerebral oxygenation in anaesthetized patients with carotid artery stenosis: the influence of inspired oxygen fraction. PMID- 22250284 TI - Combined technique using videolaryngoscopy and Bonfils for a difficult airway intubation. PMID- 22250285 TI - Therapeutic hypothermia: heat transfer from warmed tracheal tubes to oesophageal temperature probes poses risk of life-threatening overcooling. PMID- 22250286 TI - Management of postoperative respiratory failure in a patient with acute diaphragmatic status dystonicus. PMID- 22250289 TI - Myo9b and RICS modulate dendritic morphology of cortical neurons. AB - Regulated growth and branching of dendritic processes is critical for the establishment of neuronal circuitry and normal brain functions. Rho family GTPases, including RhoA, Rac1, and Cdc42, play a prominent role in dendritic development. RhoA inhibits dendritic branching and growth, whereas Rac1/Cdc42 does the opposite. It has been suggested that the activity of RhoA must be kept low to allow dendritic growth. However, how neurons restrict the activation of RhoA for proper dendritic development is not clear. In the present study, we undertook a comprehensive loss-of-function analysis of putative RhoA GTPase activating proteins (RhoA GAPs) in the cortical neurons. The expression of 16 RhoA GAPs was detected in the developing rat brain, and RNA interference experiments suggest that 2 of them, Myo9b and RICS, are critical regulators of dendritic morphogenesis. Knockdown of either Myo9b or RICS in cultured cortical neurons or developing cortex resulted in decreased dendrite length and number. Inhibition of RhoA/ROCK signaling restores the defects of dendritic morphology induced by knockdown of Myo9b or RICS. These data demonstrate that Myo9b and RICS repress RhoA/Rock signaling and modulate dendritic morphogenesis in cortical neurons, providing evidence for critical physiological function of RhoA GAPs in regulation of dendritic development. PMID- 22250291 TI - Interaction between bottom-up saliency and top-down control: how saliency maps are created in the human brain. AB - Whether an object captures our attention depends on its bottom-up salience, that is, how different it is compared with its neighbors, and top-down control, that is, our current inner goals. At which neuronal stage they interact to guide behavior is still unknown. In a functional magnetic resonance imaging study, we found evidence for a hierarchy of saliency maps in human early visual cortex (V1 to hV4) and identified where bottom-up saliency interacts with top-down control: V1 represented pure bottom-up signals, V2 was only responsive to top-down modulations, and in hV4 bottom-up saliency and top-down control converged. Two distinct cerebral networks exerted top-down control: distractor suppression engaged the left intraparietal sulcus, while target enhancement involved the frontal eye field and lateral occipital cortex. Hence, attentional selection is implemented in integrated maps in visual cortex, which provide precise topographic information about target-distractor locations thus allowing for successful visual search. PMID- 22250290 TI - Interactions between transient and sustained neural signals support the generation and regulation of anxious emotion. AB - Anxious emotion can manifest on brief (threat response) and/or persistent (chronic apprehension and arousal) timescales, and prior work has suggested that these signals are supported by separable neural circuitries. This fMRI study utilized a mixed block-event-related emotional provocation paradigm in 55 healthy participants to simultaneously measure brief and persistent anxious emotional responses, testing the specificity of, and interactions between, these potentially distinct systems. Results indicated that components of emotional processing networks were uniquely sensitive to transient and sustained anxious emotion. Whereas the amygdala and midbrain showed only transient responses, the ventral basal forebrain and anterior insula showed sustained activity during extended emotional contexts that tracked positively with task-evoked anxiety. States of lesser anxiety were associated with greater sustained activity in the ventromedial prefrontal cortex. Furthermore, ventromedial prefrontal recruitment was lower in individuals with higher scores on intolerance of uncertainty measures, and this hyporecruitment predicted greater transient amygdala responding to potential threat cues. This work demonstrates how brain circuitries interact across temporal scales to support brief and persistent anxious emotion and suggests potentially divergent mechanisms of dysregulation in clinical syndromes marked by brief versus persistent symptoms of anxiety. PMID- 22250293 TI - Retraction. Neurological effects of aromatase deficiency in the mouse. PMID- 22250292 TI - [Fatality, lethality or mortality?]. PMID- 22250294 TI - [The sealing of the round window by sudden hearing loss - a treatment with questionable rationale and uncertain results]. PMID- 22250295 TI - Excessive iodine intake during pregnancy in Somali refugees. AB - Iodine deficiency and excess are both associated with adverse health consequences, with fetuses, children and pregnant women being most vulnerable to the devastating effects of severe deficiency. It is often assumed that the iodine status of a population if displaced or in a remote or emergency situation is low. However, there is little evidence available to support this assumption, especially among long-term food-aid-dependent pregnant women. An effectiveness trial of a prenatal multiple-micronutrient supplement that contained 150 ug day( 1) iodine was conducted in two refugee camps in the North Eastern Province of Kenya in 2002. Urinary iodine concentration (UIC) was measured in a subsample of pregnant women attending antenatal care in Dagahaley (control camp) (n = 74) and Ifo (intervention camp) (n = 63). There was no significant difference in median UIC between the two camps (P = 0.118). The combined median UIC was 730 ug L(-1) (interquartile range, 780) (5.77 umol L(-1)) and exceeded the upper safe limit of 500 ug L(-1) (3.95 umol L(-1)) for pregnant women (P < 0.001), indicating excessive iodine intake. About 20% of the study subjects had 'more than adequate' urinary iodine, while over 71% had excessive UIC. Salt iodine content varied between 5.1 and 80.1 ppm in the five market salt samples analysed. In conclusion, excessive iodine intake was evident in the Dadaab refugee camps. Further research needs to be conducted to investigate the source of excess iodine, to determine the measures needed to address excessive iodine intake and to reconsider the World Health Organization/World Food Programme/United Nations Children's Fund guidance on supplementation of vulnerable groups in emergencies. PMID- 22250297 TI - Retraction. Failed fertilization after clinical intracytoplasmic sperm injection. PMID- 22250296 TI - A man for all seasons. A tribute to Manfred Anke. PMID- 22250298 TI - An inn salesman with jocular symptoms. PMID- 22250299 TI - The 2012 version of the gene table of monogenic neuromuscular disorders. PMID- 22250300 TI - What does an SNM name change mean to SNMTS? PMID- 22250301 TI - Social pleiotropy and the molecular evolution of honey bee vitellogenin. AB - In this issue of Molecular Ecology, Kent et al. (2011) describe the adaptive evolution of honey bee vitellogenin that belongs to a phylogenetically conserved group of egg yolk precursors. This glyco-lipoprotein leads a double life: it is central to egg production in the reproductive queen caste, and a regulator of social behaviour in the sterile worker caste. Does such social pleiotropy constrain molecular evolution? To the contrary; Kent et al. show that the vitellogenin gene is under strong positive selection in honey bees. Rapid change has taken place in specific protein regions, shedding light on the evolution of novel vitellogenin functions. PMID- 22250302 TI - The relative role of relatives in conspecific brood parasitism. AB - Conspecific brood parasites lay their eggs in the nests of other females in the same population, leading to a fascinating array of possible 'games' among parasites and their hosts (Davies 2000; Lyon & Eadie 2008). Almost 30 years ago, Andersson & Eriksson (1982) first suggested that perhaps this form of parasitism was not what it seemed--indeed, perhaps it was not parasitism at all!Andersson & Eriksson (1982) observed that conspecific brood parasitism (CBP) was disproportionally common in waterfowl (Anatidae), a group of birds for which natal philopatry is female-biased rather than the more usual avian pattern of male-biased natal philopatry. Accordingly, Andersson (1984) reasoned (and demonstrated in an elegantly simple model) that relatedness among females might facilitate the evolution of CBP--prodding us to reconsider it as a kin-selected and possibly cooperative breeding system rather than a parasitic interaction. The idea was much cited but rarely tested empirically until recently--a number of new studies, empowered with a battery of molecular techniques, have now put Andersson's hypothesis to the test (Table 1). The results are tantalizing, but also somewhat conflicting. Several studies, focusing on waterfowl, have found clear evidence that hosts and parasites are often related (Andersson & Ahlund 2000; Roy Nielsen et al. 2006; Andersson & Waldeck 2007; Waldeck et al. 2008; Jaatinen et al. 2009; Tiedemann et al. 2011). However, this is not always the case (Semel & Sherman 2001; Anderholm et al. 2009; and see Poysa 2004). In a new study reported in this issue of Molecular Ecology, Jaatinen et al. (2011a) provide yet another twist to this story that might explain not only why such variable results have been obtained, but also suggests that the games between parasites and their hosts--and the role of kinship in these games--may be even more complex than Andersson (1984) imagined. Indeed, the role of kinship in CBP may be very much one of relative degree! PMID- 22250304 TI - Shifting post production patterns: exploring changes in New Zealand's seafood processing industry. AB - This paper examines the changing nature of New Zealand's seafood companies' production practices. The past 15 years has seen the offshore outsourcing of post harvest fish gain unprecedented momentum. The growth in offshore processing is a further stage in an increasingly globalised fisheries value chain. Fish is head and gutted, frozen and then transported to processing sites in China where it is thawed, value-added processed and refrozen for export to the original sourcing country or third country markets. Reasons advanced by the industry for this shift in production practices include quota reductions, increasing production costs and the sale of trawlers. PMID- 22250305 TI - Collaboration in genocide: the Ottoman Empire 1915-1916, the German-occupied Baltic 1941-1944, and Rwanda 1994. AB - This article develops a new paradigm for the study of collaboration by applying the concept to events outside the context of the Second World War. The authors examine three instances of collaboration in twentieth-century mass killings, seeking to situate them within the framework of genocide. Using a multidisciplinary approach, the article questions the validity of explanations of conflict predicated on the existence of binary systems-explanations that appear frequently in comparative genocide studies. The authors relate the decision to participate in mass murder to the history of structural inequality within a given society. The article concludes that, however vague, the concept of collaboration is useful in accentuating a bottom-up approach in the study of genocide. PMID- 22250306 TI - The global and the local: mapping changes in Irish childhood. PMID- 22250307 TI - "The necessity for better bodies to perpetuate our institutions, insure a higher development of the individual, and advance the conditions of the race." Physical culture and the formation of the self in the late nineteenth and early twentieth century USA. AB - This article explores the significance of sports and physical exercise in the turn-of-the-century culture and society of the U.S. It depicts how physical fitness became a decisive feature of collective and individual self-perception and was understood as being at the core of a successful shaping of both the self and of the American body politic. I concentrate in particular on paradigms and strategies of human resources management to exemplify the overarching significance of physical fitness as it established itself at the heart of the USA's enterprise culture that began to emerge in the later nineteenth century. American peculiarities will be considered, alongside ties and allusions to European, and particularly British, developments. PMID- 22250308 TI - Writing sex and sexuality: archives of colonial North India. AB - This article focuses on disparate sites and subjects to reflect on and problematize the relationship between sexuality and the archives in colonial north India. I dwell on how 'recalcitrant' and hidden histories of sexuality can be gleaned by not only expanding our arenas of archives, but also by decentering and recasting colonial archives. I do so by specifically investigating some of the "indigenous" writings in Hindi, through texts concerning homosexuality, sex manuals, the writings of a woman ayurvedic practitioner, didactic literature and its relationship to Dalit (outcaste) sexuality, and current popular Dalit literature and its representations of the past. The debate for me here is not about the flaws of archival uses but rather of playing one archive against another, of appropriating many parallel, alternative, official, and popular archives simultaneously to shape a more nuanced and layered understanding of sexuality. PMID- 22250309 TI - 'Til death parts us: women's domestic partnerships in eighteenth-century Brittany. AB - This article investigates the legal provision for two adult, unmarried women to create a "perpetual society" with one another found in the customary code of 1725 for the French province of Brittany. This arrangement allowed women who shared a household to designate one another as primary heir and to protect their community property from the claims of others. Evidence of this arrangement demonstrates that single women in some places had options outside of marriage and the convent. The contracts filed by the women also reveal the extent to which this arrangement went beyond considerations of property to express both affection and loyalty. Available to siblings as well as to pairs of unrelated women, this union is likely not the equivalent of same-sex marriage. It does however broaden our knowledge of the meaning of marriage, partnership, and kin in early modern Europe. PMID- 22250310 TI - "A matter of physical health and strength": disciplining the female body and reproducing the Czech national community in the mid-nineteenth century. AB - An 1850 article "Uzavirani snatku" ("Marriage") by Czech physician Jan Spott outlined the requirements for those who considered themselves part of the Czech national community. Spott stressed that those concerned with the future national existence had to educate themselves and each other to create healthy offspring. I examine Spott's article with regard to contemporary ideas about fitness, the role of women, the need to discipline the female body, as well as the importance of education in reproducing the community. This article's analysis - set in the broader context of the history of women, medicine, and nationalisms - shows that nation-oriented education could be perceived as a way to ensure the nation's future existence while simultaneously emphasizing the responsibility of individuals, and particularly women, for the reproduction of the community. Spott's propositions are significant to other nineteenth-century national movements and to postnational contexts where national fitness is a concern. PMID- 22250311 TI - The survey project: researching women's everyday experience and envisioning modernity in rural Bohemia at the end of the Second World War. AB - This article examines a survey of rural Czech women conducted in 1944-1945. It argues that the survey tells two very different stories. First, the survey provides an unvarnished look into the everyday material circumstances of a few rural Czech women. But for all they tell us about the material conditions of these rural women's lives, the surveys tell us very little about their ideals, hopes, and dreams. The surveys do, however, reveal quite a bit about the inner motivations of the very different group of women who commissioned this research, a group known as the Women's Center. Reading in between the lines of these texts shows how the activists of the Women's Center imagined modernity in the countryside. Theirs was a vision of rational households, technological advances, and good taste, even in rural villages. PMID- 22250312 TI - "Pictures with a purpose": the birth control debate on the big screen. AB - In the first half of the twentieth century, birth control advocates used the mass media to reframe contraception from a private, secret matter to an acceptable part of life fit for public discussion. Although their campaign began in print, they quickly embraced the more far-reaching medium of film to deliver their message. This article argues that birth control advocates circumvented the Comstock Act in the early decades of the twentieth century by taking up this new medium as part of a long-running strategy to publicize the birth control movement. Their efforts shaped both the public debate on the topic and the development of motion picture censorship. PMID- 22250313 TI - Marrying into the European family of nations: national disorder and upset gender roles in post-Communist Romanian film. AB - Drawing on recent Romanian films, this article explores the distinctive post communist concerns with national relocation in the symbolic geography of Europe. The focus on tragic comedies, an increasingly popular genre in Eastern European cinematography, foregrounds the critical usage of irony to express skepticism about the inclusive nature of geopolitical projects such as the European Union by national communities situated at its periphery. While the tragic comedies examined here are successful in challenging official narratives of European belonging, they rely on highly gendered scripts that prove more resilient to ironic reworkings. The movies resort to gendered plots and family tropes, representing Romania's efforts to receive European recognition as attempts to "marry into" the European Union. The larger thrust of this article is to open complex notions such as "Europe," "nation," and "gender," which are notoriously prone to essentialization, to a deconstructive analysis as systems of differentiation. PMID- 22250314 TI - The case of the missing girls: sex ratios in fifteenth-century Tuscany. AB - This article addresses the apparent shortage of women in the 1427 Florentine Catasto, perhaps the most complete premodern European demographic source. It argues that the shortage exists because it was only when they entered their first marriage that Tuscan women were viewed as complete, gendered beings by their families, government officials, and society. Before marriage, a woman's place within the household, her gender, and even her existence were liminal, at least in Tuscan documents. The result is that the ratio of men to women is more balanced for that portion of the population past the age of marriage for women. Shifting the analysis from infants and men, where it has traditionally lain, to young adult women explains the gender imbalance in the documentation and provides a deeper understanding of the ways that gender, adulthood, and identity intersected in premodern Europe. PMID- 22250315 TI - [Cardiovascular diseases and inflammation]. PMID- 22250316 TI - [Left #7 lymph node dissection during thoracoscopic surgery]. PMID- 22250317 TI - Questions histologic diagnosis as a prognostic indicator. PMID- 22250318 TI - Gender disparity in the veterinary profession. PMID- 22250319 TI - Solo practitioners see a place for themselves. PMID- 22250320 TI - Corporate practice becomes part of the landscape. PMID- 22250321 TI - Dental scaling now a veterinary procedure in California: regulations clarified, scaling illegal for unlicensed persons. PMID- 22250322 TI - Presidential order targets drug shortages: FDA report analyzes problem, identifies action steps for agency. PMID- 22250323 TI - Questions--and cases--mount in seal disease outbreak: mystery illness killing Arctic ringed seals may be spreading. PMID- 22250324 TI - FDA analyzing pet foods for Salmonella contamination. PMID- 22250325 TI - Captive wildlife rules get added scrutiny: AVMA, VMAs, state governments considering changes. PMID- 22250326 TI - Neb. deal to create market project, avert ballot initiative. PMID- 22250327 TI - Re: in the eye of the Cuban epidemic neuropathy storm: Rosaralis Santiesteban MD, PhD. PMID- 22250328 TI - Re: Equity matters. PMID- 22250329 TI - Agricultural improvement and highland clearance: the Isle of Arran, 1766-1829. PMID- 22250330 TI - Proceedings of the 2010 International Conference on Biofabrication (BF2010). October 4-6, 2010. Philadelphia, Pennsylvania, USA. PMID- 22250331 TI - Wireless. PMID- 22250332 TI - Benefits of starting an EMBS student club/chapter at your university. PMID- 22250333 TI - Round two: doubt. PMID- 22250334 TI - The last summer of your life. PMID- 22250335 TI - Delving into BioMEMS. PMID- 22250336 TI - Genetic toxicology. Principles and methods. Preface II. PMID- 22250337 TI - Roundtable: regulation. Do managers need a GMC? PMID- 22250338 TI - Reconfiguration. Legal challenges threaten to sink vital redesign of services. PMID- 22250339 TI - Commissioning. Procurement concerns slow CCG choice. PMID- 22250340 TI - On healing our finances. PMID- 22250341 TI - On problematic procurement. Our goods vehicles are clapped out. PMID- 22250342 TI - Non-clinical skills. Build your skills. PMID- 22250344 TI - Employers. Change for better ... or worse? PMID- 22250343 TI - Heart of England. Staying in. PMID- 22250345 TI - Work experience. Working it out. PMID- 22250346 TI - Leadership academy. People to lift the NHS higher. PMID- 22250347 TI - Workforce. Success is a team effort. PMID- 22250348 TI - Workforce. Lead from the middle. PMID- 22250349 TI - Dementia. Help patients see more clearly. PMID- 22250350 TI - The chemical within. BPA is everywhere. Is it dangerous? We don't really know. PMID- 22250351 TI - Decoding breast cancer. A gene test lets some patients with early tumors skip radiation. PMID- 22250353 TI - Your use of pronouns reveals your personality. PMID- 22250352 TI - Putting the social into science. Forget about nature vs. nurture. The answer lies in between. PMID- 22250354 TI - The power of collective ambition. AB - In the past few years, some companies have not just weathered the economic storm: They've emerged stronger than ever. How did such players as Four Seasons, Sephora, and Standard Chartered Bank defy conventional logic? Instead of pursuing a single ambition, such as profits, employees defined a collective ambition. As a result, those organizations deepened their engagement with employees and other stakeholders and became sustainably profitable. Purpose, a company's reason for existence, is the central element of collective ambition. The other elements- vision, targets and milestones, strategic and operational priorities, brand promise, core values, and leader behaviors--must be aligned to serve the company's purpose. Articulating the elements of collective ambition can give everyone in the organization a better sense of the company's purpose and how they can contribute to it. Purpose does not have to be about saving the world; providing excellent entertainment or banking services is just as meaningful a purpose as improving health care in emerging economies--as long as it is an authentic representation of why the company exists. To shape and then achieve a collective ambition, companies must strengthen their organizational glue (the collaborative engagement that creates a unified culture) and grease (the disciplined execution that enterprisewide change initiatives require). PMID- 22250355 TI - Who really makes the big decisions in your company? AB - In many companies, the top management team is officially responsible for helping the CEO make a company's big decisions. But another, unofficial group usually does that job de facto. That's the way it should be, argues Frisch, of the Strategic Offsites Group, provided that the CEO is deliberate in devising the role of this informal and unnamed "kitchen cabinet." Problems can nevertheless arise when senior executives learn about important decisions after the fact, mistakenly assume that they have real power to protect their departments, and find themselves in a system where the way decisions are actually made goes unacknowledged. The key, according to Frisch, is to make better use of senior executives' time and talents by giving them specific responsibilities that complement--but do not overlap--the advisory duties of the kitchen cabinet. A CEO who explicitly acknowledges the role of her cabinet and strikes the right balance between it and her official advisory group of executives can get the best from both. PMID- 22250357 TI - Myopic watchdog? Critics blast first shaming of insurer for rate hikes. PMID- 22250356 TI - Cloudy outlook. Supercommittee failure leaves healthcare providers questioning future cuts, impact on hospitals. AB - President Barack Obama responded to the failure of the so-called supercommittee with a message that he won't allow Congress to water down the automatic cuts triggered under the August deficit law, which would include a 2% reduction in Medicare payments. PMID- 22250358 TI - Exceptions to the rule. Protection for agent, broker fees approved. PMID- 22250359 TI - Hospital merger challenged. FTC keeps up interest in healthcare deals. PMID- 22250360 TI - Open and shut case. Hospital deal creates debate over records law. PMID- 22250361 TI - International partnership. U.S. to train Saudis in hospital management. PMID- 22250362 TI - No solutions here. Politicos fail on the economy while forgetting what happened in the past. PMID- 22250363 TI - Don't mail it in. Express Scripts-Medco deal would doom community pharmacists. PMID- 22250364 TI - Risk reduction. Efforts to reduce radiation exposure increase as awareness grows. PMID- 22250366 TI - [Indicators for quality of care. Severe problems with methods of observation]. AB - Recently, there has been increasing concern about indicators for quality of care systems. Much energy has been devoted to the development of these indicators, but after a couple of years many professionals in the care organizations are complaining that the validity is extremely doubtful. In this editorial a fundamental problem is discussed, namely the reliability of the observations. In all scientific fields many precautions are necessary, for example in meteorology measuring the temperature in open air. In the manuals about the indicators of care two methods of observation are mentioned. In the first one patients are interviewed. The results seem very unreliable, because of socially desirable answers. For example, in nursing homes the patients are extremely dependent on the care-giver and it is likely they avoid complaints. The second method is used for gathering data about the frequency of falls, decubitus and so on. This is carried out by the care professionals. It goes without saying that the resulting data are vulnerable to manipulation, because of the great interests of the professionals and of the organizations involved. This problem was already described by the sociologist Blau 50 years ago. It is suggested to make a new start on a small scale with only a few indicators. It is necessary to work with unobtrusive measures-e.g. undercover observations- for observing behaviour instead of asking questions. And in the second case data should be gathered by separate organizations that are completely independent. Patients deserve that the representation of their situation should be guaranteed by scientific standards. PMID- 22250365 TI - Out of the spotlight. Pressure eases on private, for-profit nursing homes. PMID- 22250367 TI - [Caring friends and neighbors as informal caregivers of older adults: A comparison with offspring]. AB - This study compared informal care to older, non-coresiding adults provided by friends and neighbours and informal care by children or their partners. Using data from a Dutch representative survey among informal caregivers conducted by CBS and SCP, caregivers of friends (n=133), neighbours (n=108) and parents (n=1,008) were compared with one another to investigate care that friends and neighbours provide to the elderly non-coresiding adults (age 55 and over). Nine percent of those providing care to someone outside the household were friends and nine percent were neighbours. Friends, like children, usually provide long lasting care, up to four or five years. Friends are similar to neighbours in the number of hours that they provide care. Friends and neighbours experience a lower caregiver burden than children. However, when fulfilling multiple caring tasks, both friends and children, have a greater chance of experiencing higher levels of burden. When there were other caregivers to help, friends experienced a small reduction in burden. Friends and neighbours deserve to be recognized as informal caregivers by policy makers and they deserve attention and support along with family caregivers. PMID- 22250368 TI - [Discussing the resuscitation policy at a geriatric ward: the experience of patients or their representatives]. AB - AIM: To identify geriatric patients' and their surrogate decision makers' experience with regard to discussing cardio pulmonary resuscitation (CPR) policy. METHODS: This is a prospective, observational, explorative survey. During 10 weeks, all patients admitted to a geriatric ward of a general Dutch hospital or their representatives were asked for their experience regarding discussion of the resuscitation policy with the physician in attendance. Discussing this policy is a standard procedure at the first day of admission. We also asked on several factors which could influence their experience and on factors to improve discussing resuscitation policies. The primary outcome was the participant's satisfaction expressed on a scale of 1 to l0 regarding satisfaction with the CPR discussion. RESULTS: Seventy-six participants were included, of which 29 patients and 47 surrogate decision makers. Discussing the resuscitation policy took an average of 4,5 minutes (SD 3.2) to complete. In 70% (n=53) of cases a do-not resuscitate decision was made. Discussing the resuscitation policy was experienced positive, with an average rate of 7,8 (SD 1.5). A total of 121 positive comments were made, as opposed to 70 negative comments. When they talked about their resuscitation policy, most patients expressed positive emotional responses. As most important improvements were mentioned: a better introduction to discussing this subject (17%), a better explanation of resuscitation and chances of survival (17%) and providing information prior to admission to the ward, so that patient and surrogate decision maker have been informed that the resuscitation policy will be discussed (12%). CONCLUSION: Most patients and relatives in this study wished to discuss their resuscitation policy with physicians. Still, there is room for improvement in several respects. Patients and surrogate decision makers are in favour of discussing the standard resuscitation policy with the doctor, and evaluate this conversation with a 7.8 / 10. In order to improve both discussing the CPR policy preparing the patient and his representatives and communicating more extensively during the interview are recommended. PMID- 22250369 TI - [Geriatric consulting by a qualified elderly care physician in general practice]. AB - An innovative project is presented, in which general practitioners, an elderly care physician and specialized nurses work together. The primary aim of the project was early detecting of frail community dwelling elderly and to give them adequate treatment and support, to enable them to stay in their own home situation as long as possible. The detection of frail elderly was performed by mean of the Easycare instrument. Results collected from October 2007 - July 2009 are presented in this article. The findings show that particularly elderly with symptoms of dementia have been detected. The main actions were provision of integrated psychogeriatric care according to a tailormade integral care plan and starting or extending home care. Elderly with somatic problems were seen mostly in one time consultations. The satisfaction about the care provided in the project was high, both for participating patients and professionals. In the pilot a tendency was also found towards fewer referrals to hospital (specialists) and towards a reduction of the number of acute admissions to the nursing home. PMID- 22250370 TI - Mortality. Quality measures set to usurp mortality rates. PMID- 22250371 TI - Mortality. Child surgery networks 'vital' to cutting deaths. PMID- 22250372 TI - An award winning talent for disruption. Interview by Alastair McLellan. PMID- 22250373 TI - Value. A golden opportunity. PMID- 22250374 TI - Estates. Block contracts. PMID- 22250375 TI - Technology. Delays expected. PMID- 22250376 TI - Strategy. Draw battle lines over local need. PMID- 22250377 TI - What's needed for reprocessing, storage of laryngoscope blades? PMID- 22250378 TI - ASCs get pay hike, reprieve on quality reporting. PMID- 22250379 TI - CMS overturns its rule on advance patient notice. PMID- 22250380 TI - [Disinfectology as a subject of differentiation in hygiene science]. AB - The paper provides a rationale for the need for developing the decontamination - actively health-promoting area of hygiene science and practice to neutralize (decontaminate) different pathogens just in the environment where they enter during its inadequate, ineffective, or quite impossible protection from contamination. As of now, there are no physical decontamination technologies or ineffective attempts to make harmless chemical pathogens in the environment; at the same time it is stated that there are scientifically grounded biological decontamination and disinfectology technologies to neutralize biological pathogens just in the environment and on its different objects. To solve these problems requires hygienic competence, particularly the substantiation of hygienic standards for disinfectants in the environment and the elaboration of hygienically safe regimens of their application. In this connection, disinfectology is the most hygienic branch of all antiepidemic ones of preventive medicine. The development of disinfectology as a fruitful alliance of hygiene and epidemiology allowed a system of governmental management and control of unspecific prophylaxis to be developed and introduced in Russia, which contributes to a reduction in or at least stabilization of the incidence of infectious diseases in the country. PMID- 22250381 TI - [Parasitic factor and cancer]. AB - There is opinion in the literature as to that liver trematode infections, such as opisthorchiasis, clonorchiasis, fascioliasis, and metorchiasis, can induce cancer of the liver pancreas, intestine - this all is clinically observed. The authors were the first in world practice to show the development of a hepatic blastomatous process in animals (albino rats, cats) with opisthorchiasis in 13%; cancer developed in 28 and 56% with the use of a hepatotropic carcinogen and combined (opisthorchiasis + a carcinogen) exposure, respectively. Throughout his life, a human being can easily catch these trematodes that have carcinogenic activity and these diseases concurrent with household and food carcinogens can give rise to tumors in the liver pancreas and intestine. Timely diagnosis and specific anthelmintic therapy are necessary to prevent parasitic cancer. PMID- 22250382 TI - [Lead and children's health: results of some Russian studies in 2000-2009]. AB - Environmental pollution by lead and its effects on human health continue to remain one of the most urgent problems of environmental hygiene. The paper gives the results of basic environmental and epidemiological studies conducted in different regions of the country, which prove elevated lead levels in the blood of examined children. The role of the influence of household factors on the elevation of blood lead levels in a child is shown, by using a town that has no large sources of lead emission as an example. Evidence is provided that a program should be elaborated to reduce a risk for human lead poisoning, which involves the introduction of methods for the biomonitoring and treatment of children having elevated blood lead levels. PMID- 22250383 TI - [Ecological and economic approaches to removing radioactively dangerous objects from service]. AB - The paper considers major ecological and economic problems when removing radiation dangerous objects from service and rehabilitating the areas, which require their solution: the absence of specific guidelines for ranking the contaminated lands exposed to radioactive and chemical pollution from the potential risk to the population and environment; no clear criteria for ceasing area rehabilitation works; radiation exposure levels for the population living in the areas after rehabilitation; allowable levels of residual specific activity, and levels of heavy metals in soil, surface and underground water and bed sediment. The cost such works is the most important and decisive problem. A decision-making algorithm consisting of three main blocks: organizational technical, engineering, geological and medicoecological measures is proposed to solve managerial, economic, and scientific problems. PMID- 22250384 TI - [Experimental estimation of the hazard from combustion products of waste polymeric materials]. AB - The object of the study was waste polymeric materials. Its aim was to reveal the hazard of their combustion. Conditions occurring in the combustion of waste polymeric materials were simulated; methods for chemical analysis were used; biotesting was performed. The study revealed a high hazard from combustion products of waste polymeric materials. PMID- 22250385 TI - [Comprehensive hygienic assessment of solaria]. AB - The paper gives data on the positive and negative effects of human exposure to ultraviolet radiation (UVR). It provides the hygienic characteristics of solaria used to produce an artificial tan. This device has been found to present a high health risk to its users. There are considerable problems in the hygienic assessment of this type of exposure. The ways of solving the arising problems in developing the metrological monitoring of UVR and compiling a document regulating the sanitary-and-epidemiological surveillance of solaria are defined. PMID- 22250386 TI - [Incidence of non-communicable diseases and health risks due to potable water quality]. AB - Iron and fluorine concentrations and water mineralization and hardness, which exceeded the maximum allowable concentrations, were found to cause an increase in overall morbidity and morbidity from skeletal-and-muscular, urogenital, and digestive system involvement in the population of the Krasnoyarsk Region. A quantitative relationship were found between the concentrations of iron, the hardness and dry residue of water and the incidence rates of urogenital, skeletal and-muscular and digestive diseases. The consumption of potable water contaminated with chloroform and methane tetrachloride presents unacceptable carcinogenic risks to the population of the Krasnoyarsk Region. PMID- 22250387 TI - [Hygienic assessment of the characteristics of centralized hot water supply in case of Moscow]. AB - The paper considers the characteristics of domestic hot water consumption by Moscow dwellers. It gives the results of questionnaire surveys in 100 respondents aged 20-80 years about the modes and intensity of hot water use, by indicating the time and frequency of contact with hot water complaints about hot water supply. According to the authors'studies, the daily consumption of hot water per capita was 1.1-2 times greater than that of cold water; at the same time the total water use remained to be 1.3-3 times less than the Moscow standard levels. Top stationary point measurements of water temperature showed the noncompliance with its hygienic requirements: 95 of 98 hot water samples had a temperature of 5 22 degrees C less than the standard temperature (60 degrees C). A decrease in hot water temperature in the centralized hot water supply systems creates conditions for Legionella pneumophila propagation and ensures no hot water safety with regards to the possible development of Legionella pneumonia. PMID- 22250388 TI - [Water treatment from viruses using heterogeneous sensitizer based on polycationic aluminum phthalocyanine]. AB - The authors propose a new heterogeneous photo sensitizer containing aluminum tetrakis [bis(cholinyl)phenylthio)] phthalocyanine grafted onto silica as an active phase. A poliovirus type 1 LSc2ab and RNA-containing phage MS2 model was used to show that the sensitizer had photo decontaminating activity against viruses and may be used to purify water from viral contamination. The mechanism for removal of viruses from water is two-step and involves the adsorption of the virus on the heterogeneous sensitizer particles and the photodynamic inactivation of the adsorbed virus. PMID- 22250389 TI - [Environmental and hygienic aspects of the prevention of arterial hypertension in able-bodied people]. AB - The performed studies have established that the negative influence of poor manufacturing factors of textile, cement, and electromechanical enterprises is potentiated by poor environmental conditions, which increases a risk for arterial hypertension in able-bodied people. PMID- 22250390 TI - [Criteria for determining the adaptation of children to studying loads]. AB - Three hundred and two Krasnoyarsk gymnasium students were examined to define criteria for determining the adaptation to high schooling loads. The values of the emotional status and adaptive processes were studied in children with varying resistance and varying mastering capacities; the impact of cardiovascular parameters on their adaptive process was defined The criteria for estimating the adaptation to high schooling loads were the presence or absence of acute chills and neurotic reactions, cardiovascular performance, and psychoemotional status. PMID- 22250391 TI - [Headache in the population of schoolchildren: prevalence, pattern, risk factors]. AB - The paper discusses the prevalence, pattern, and risk factors of childhood headache (HA) according to questionnaire data from 1074 general educational school pupils. Periodic HA was reported by 42.1% of the children. There was a preponderance of exercise-induced HA (30.6%) and migraine (7.8%). There was an age and gender determination of childhood HA frequency; there was a predominance of chronic exercise-induced HA, migraine, and their concomitant forms in female adolescents. There was a high comorbidity of primary HA with other psychosomatic disorders mainly with autonomic dysfunction and emotional disorders. The risk factors for chronic HA were a poor family history (familial psychogenias, pain family history, low'socioeconomic status family), and school stress. The clinical form of cephalgia, comorbidities, and predictive factors should be taken into account to prevent and treat HA. The use of the international diagnostic criteria developed by the experts of the HA Association is of cardinal importance in improving the diagnosis of childhood HA. PMID- 22250392 TI - [Hygienic aspects of healthy life style development in students]. AB - Medical students have shown a high prevalence of major behavioral factors of health risk, such as inadequate physical activity, changes in the routine, nutrition quality, study-and-rest regimens, as well as smoking and frequent alcohol use. Proposals to educate the students on the importance of living a healthy lifestyle are given. PMID- 22250393 TI - [Molecular genetic mechanisms of individual sensitivity to synthetic fatty acids in case of valproic acid]. AB - Individual sensitivity to structural analogues of free fatty acids (FFA), some of which are endocrine destructors, resulting in hormonal metabolic disturbances, was studied using valproic acid (VA) as an example. The individual sensitivity was considered by the example of polymorphism in the PPAR@g2 gene. The homozygous genotype Pro12Pro of this gene was proved to be responsible for weight gain and development of insulin resistance during VA administration, which should be kept in mind when developing the safe levels of exposure to FFA-like substances. PMID- 22250395 TI - [Enhanced serum DNAase activity in hypersensitization to pollen allergens]. AB - Factor analysis of cross-sensitization to 24 common allergens and correlation analysis of the relationship between the hypersensitivity to the allergens and some biochemical markers (the intensity of serum chemiluminescence, the content of SH-groups, and the activity of lysosomal enzymes) of the health status were carried out in a sample of Moscow residents with allergic diseases. A significant correlation was found between the serum levels of specific IgE antibodies to pollen allergens and the activity of serum acid DNAase (R = 0.498; p = 0.009; N = 67). The revealed regularity may be used to devise a test for the differential diagnosis of pollenoses and suggests that there are possible differences in the levels of apoptosis and cytogenetic damages between patients with pollenoses and those with other allergic diseases. PMID- 22250394 TI - [Contribution of polymorphic variants of the genes of xenobiotic transformation enzymes, antioxidative defense, and DNA repair to the development of individual predisposition to hepatobiliary and reproductive system diseases in petrochemical workers]. AB - The paper gives the basic results of studying the polymorphic loci of the genes of xenobiotic transformation enzymes, antioxidative defense, and DNA repair in petrochemical workers. Polymerase chain reaction-restriction fragment length polymorphism assay was used to identify markers of the predisposition to the development of toxic hepatitis in men and impaired reproduction in women. PMID- 22250396 TI - [Evaluation of the biological effects of chemical substances on albino rat offspring]. AB - The paper provides the results of experimental studies of the impact of vinyl chloride or sublimate intoxication in male albino rats on the functional state of the nervous system of their offspring. Retarded sensorimotor development was revealed in the neonatal offspring. The pubertal offspring showed behavioral pattern disintegrity that was characterized by changes in motor activity and orientative-exploratory responses and by anxiety. There was abnormal impulse conduction in the neuromuscular apparatus of the hind legs of albino rats and morphological changes in the structure of nervous tissue. PMID- 22250397 TI - [Phenotypic manifestation and trans-conversion of primary genetic material damages considered in the alpha-test on the yeast Saccharomyces cerevisiae]. AB - Primary (spontaneous and externally induces) damages to genetic material frequently lead to heritable changes (gene mutations, chromosome aberrations and nondisjunction), which may cause cancer inherent and inborn diseases. It is suggested that primary damages may affect a phenotype until they are repaired or become mutations during inaccurate repair The alpha-test on the yeast Saccharomyces cerevisiae can answer the fundamental questions as the nature of primary damages that can be phenotypically manifested, their occurrence, conversion to each other and repair or conversion to heritable changes in genetic material. PMID- 22250398 TI - [Adaptive capacities of children with different number of congenital morphogenetic variants]. AB - Adaptive capacities were studied in 6-7-year-ol apparently healthy children in relation to the number of congenital morphogenetic variants (CMVs). The most markedly reduced adaptive capacities were revealed in children with 5 CMVs or more. PMID- 22250399 TI - [Effect of genetically modified plants on the development of rat progeny]. AB - The paper presents the results of evaluating the effect of genetically modified (GM) maize on the prenatal and postnatal development of rat progeny in three generations. An experiment used 280 adult rats (160 females and 120 males) and 1545 infant rats of the first month of life. The animals were divided into 2 groups: 1) those given a diet including GM maize (an experimental group); 2) those fed on its isogenic control (a control group). The maize was included into the diet in maximally possible amount that did not impair the balance of essential nutrients (31.4% caloric value). Analysis of the data obtained from studies of the prenatal (preimplantation and postimplantation death and fetal somatometric parameters) and postnatal (physical development, survival, changes in somatometric parameters) development of rat offspring revealed no effect of GM maize as compared to the isogenic control. All the parameters were in the normal physiological range typical of the animals of this species and age. Thus, dietary intake of the given amount of GM maize had no impact on rat progeny development. PMID- 22250400 TI - [Multiple environmental risk for cancer in population of industrial town]. AB - The investigation was undertaken in the town of Novodvinsk to assess multiple environmental population health risks from exposures to carcinogens by inhalation, oral, and dermal routes. Local exposure factors were studied in a longitudinal study by interviewing 1963 subjects according to a questionnaire. The levels of 11 carcinogens were estimated in 4 environmental media: ambient air; drinking water soil, and foodstuffs. The risk assessment model comprised three exposure routes: inhalation, oral, and dermal. Lifetime average daily doses and factors of the carcinogenic potential were used for risk assessment. Total cancer risk (TCR) across all the exposure routes was 1.4x10@-3. The contribution of oral, inhalation, and dermal routes to TCR was 94.8% (1.4x10@-3), 4.8% (6.8x10@-5), and 0.4% (5.4x10@-6), respectively. The leading environmental media for carcinogens are foodstuffs, whose contribution to the oral route was 81.3% (1.1x10@-3), and drinking water whose contribution was 18.7% (2.5x10@-4). The major contaminants contributing to cancer risk were arsenic (1. 1x10@-3), nickel (2.5x10@-4), and chloroform (3. 7x10@-5). PMID- 22250401 TI - [Classification of substances to predict the order of magnitude of their safe water levels in terms of carcinogenic effect]. AB - A classification has been developed to predict the safe water levels of chemical compounds in terms of their carcinogenic effect, by using as the base the LTD@10 value that is a lower 95% confidence limits for the lowest dose that statistically significantly causes a 10% increase in the incidence of cancer in laboratory animals continuously receiving a daily dose of the compound throughout their life, which is given in the CPDB internet resource, and the carcinogenicity classification adopted by the International Agency or Research on Cancer Based on an analysis ofthe maximum allowable concentration (MAC) of the standardized water substances in terms of their carcinogenic effect, the authors determined MA4 C ranges corresponding to different classes in accordance with the proposed classification. They predicted the orders of magnitude of MAC of the standardized water substances without taking into account their carcinogenic effect and those of four substances unstandardized in Russia. PMID- 22250402 TI - [Dependence of carcinogenic properties of benzene derivatives on structure of their substituents adjusted for biotransformation]. AB - An oxenoid model of the effect of cytochrome P450 and quantum chemical calculations were used to study a relationship of the carcinogenic activity of the benzene derivatives C6H5-X and C6H4-XY to the nature of the substituents X and Y For mono- and disubstituted benzenes, the methods based on the neglect of diatomic differential overlap was used to calculate the minimal values of AE for this compound, which is the minimum difference in the complete energies of the arenoxide intermediate OC6-H5-X or OC6H4-XY with one tetraedrically coordinated carbon atom in the benzene ring in reference to the initiar molecule of substituted benzene. The boundary value of the parameter deltaE min' which separated cancerogenic compounds from noncancerogenous ones was determined. A classification for nitrosubstituted benzenes was clarified using the parameter characterizing bioactivation via nitro group reduction to form phenylhydroxylamines and then nitrenic ions. PMID- 22250403 TI - [Clinical evaluation of 24 cases of primary thyroid malignant lymphoma]. AB - OBJECTIVES: We analyzed open biopsy in diagnosing primary thyroid lymphoma (PTL) and tumor management with compression symptoms and therapy. METHODS: We retrospectively studied 24 subjects diagnosed with PTL from December 1997 to June 2010. RESULTS: Open biopsy was done in 23 of 24 subjects. Incisional biopsy was done in 14, 13 of whom yielded sufficient materials in the first biopsy. Excisional biopsy was done in the remaining 9, 2 of whom developed permanent recurrent laryngeal nerve palsy after biopsy. The five with airway obstruction underwent incisional biopsy followed by immediate steroid administration of dexamethasone or methylprednisolone. All had histopathologically confirmed diagnosis and airway symptoms were resolved within a few days. Multidisciplinary therapy including chemotherapy, radiotherapy, and surgery was applied in 20 of 24 subjects. Single therapy was done in 4-chemotherapy in 2 and radiotherapy and surgery in 1 each. Overall results were satisfactory, with a 92% 10-year disease free survival rate and an 86% 10-year overall survival rate based on the Kaplan Meier method with 46-month median follow up. CONCLUSION: When diagnosing PTL, especially large tumors spreading into extrathyroid tissue, incisional biopsy is more advantageous in histopathological diagnosis than excisional biopsy due to the lower risk of surgical complications. In a case involving a small intrathyroidal nodule, excisional biopsy is safer and more diagnostically accurate. In an airway obstruction emergency, once a definitive diagnosis is made, steroid administration plus endotracheal intubation, if necessary, for airway management is optimal management. Subjects with stage IE mucosa-associated lymphoid tissue (MALT) lymphomas can be treated with radiotherapy or surgery alone. Those with diffuse large B-cell lymphoma (DLBCL) or greater than stage IE MALT lymphoma, however, should be treated with multidisciplinary therapy because they have a potentially poor outcome. PMID- 22250404 TI - [Three cases of renal cell carcinoma metastasizing to the head and neck]. AB - Renal cell carcinoma (RCC) tends to metastasize hematogenously, although metastasis to the head and neck is rare. We report 3 cases of RCC head and neck metastasis within the last 6 years. CASE 1: A 74-yearold woman presented with cervical metastasis from RCC 4 years after right total nephrectomy, involving modified neck dissection. She later had additional surgery and radiation for further distant metastases, survived almost 5 years after the first neck metastasis. CASE 2: A 60-year-old man showed metastatic RCC in the right parotid gland 3 years after right total nephrectomy, involving superficial parotidectomy. CASE 3: A 54-year-old man presented with a metastasis lesion from RCC to the right maxillary sinus 7 years after left total nephrectomy, involving total maxillectomy. Distant metastasis reportedly often occurs long after initial primary RCC treatment. Physicians considering metastatic RCC in differential head and neck diagnosis and resection could conceivably promote better prognosis. PMID- 22250405 TI - [Non-specific exercise therapy for benign paroxysmal postural vertigo]. AB - We treated 1145 patients diagnosed as having benign paroxysmal postural vertigo at the Toho University Medical Center Sakura Hospital from August 2007 to July 2009 by the exercise therapy developed by us. The most advantageous characteristic of our method is that patients can perform the exercises themselves at their own pace in their homes, even if the affected side cannot be identified and/or the patients have any orthopedic cervical and/or spinal problems. In 80.7% and 91.7% of the patients in our case series, the vertigo was no longer present at one and three months, respectively. In addition, the vertigo disappeared within two weeks in the patients who were examined within one week of the start of the symptom. The longer the period between the onset of vertigo and the hospital visit, the longer the period needed for control of the symptom. PMID- 22250406 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Editorial: The current trends and perspective in laboratory testing]. PMID- 22250407 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: I. Generalities; 1. Preanalytical factors affecting clinical tests using blood specimens]. PMID- 22250408 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: I. Generalities; 2. The state and future of point of care-testing]. PMID- 22250409 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: I. Generalities; 3. A commentary on guidelines for gene-based testing]. PMID- 22250410 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: I. Generalities; 4. Japanese medical insurance and clinical laboratory testing]. PMID- 22250411 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 1. Current evaluation of cardiovascular disease]. PMID- 22250412 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 2. Respiratory diseases]. PMID- 22250413 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 3. Digestive system diseases, 1) Digestive tract]. PMID- 22250414 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests: 3. Digestive system diseases, 2) Recent advance of clinical laboratory in the liver, biliary and pancreatic diseases]. PMID- 22250415 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 4. Hematological diseases, 1) Blood cell counts and leukocyte differentials]. PMID- 22250416 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 4. Hematological diseases, 2) Thrombosis and hemostasis laboratory tests]. PMID- 22250417 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 5. Kidney and urinary tract disease]. PMID- 22250418 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 6. Endocrinological disorders]. PMID- 22250419 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 7. Metabolic disease: dyslipidemia, diabetes, metabolic syndrome]. PMID- 22250420 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 8. Recent advances of laboratory medicine in rheumatic and allergic diseases]. PMID- 22250421 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests 9. Up-to-date examinations in neurological disorders]. PMID- 22250422 TI - [Update information for physicians on laboratory tests: recent progress in clinical laboratory testing. Topics: II. Particulars with special emphasis on novel laboratory tests; 10. Laboratory testing for infectious diseases]. PMID- 22250423 TI - [Discussion meeting on the relevance of genetic testing in clinical practice]. PMID- 22250424 TI - [Case report; a case of cardiac tumor diagnosed with Erdheim-Chester disease]. PMID- 22250425 TI - [Case report: a case of anterocollis ameliorated by trihexyphenidyl]. PMID- 22250426 TI - [Case report: a case of PTH-rP producing apocrine adenocarcinoma]. PMID- 22250427 TI - [Case report: a case of platypnea orthodeoxia syndrome with patent foramen ovale]. PMID- 22250428 TI - [Case report; a case of Diphyllobothrium nihonkaiense infection probably caused by eating raw trout]. PMID- 22250429 TI - [Case report; a case suspected that methotrexate-associated lymphoproliferative disorders was developed in the course of therapy of rheumatoid arthritis]. PMID- 22250430 TI - [Case report; a case of Cushing's disease presenting mainly masculinization without typical clinical features]. PMID- 22250431 TI - [The cutting-edge of medicine; myelodysplastic syndromes--recent development in diagnosis and treatment]. PMID- 22250432 TI - [The cutting-edge of medicine; progress of research on renin-angiotensin system in chronic kidney disease]. PMID- 22250433 TI - [The cutting-edge of medicine; cross-talk between airway and vascular remodeling]. PMID- 22250434 TI - [Series: Knowledge of emergency required for internist; acute heart failure]. PMID- 22250435 TI - [Report from the 12th Tokai Chapter Educational Seminar: immunological abnormalities in disorders of internal medicine]. PMID- 22250436 TI - [Series: Let's think-clinical quiz (question): A 45-year-old man who was admitted because of arthralgia, sinusitis, and fever]. PMID- 22250437 TI - [Series: Diagnosis at a glance]. PMID- 22250438 TI - [Series: Clinical study from Japan and its reflections; Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT)]. PMID- 22250439 TI - [Series: For attending physicians; professionalism; the practice of medical professionalism education for the medical students at Keio University]. PMID- 22250440 TI - [Activation syndrome in the Japanese court]. AB - Since the February 2004 FDA advisory's warning of activation syndrome involving antidepressants, growing concerns have emerged over aggression and violence reported in subjects prescribed these drugs. However, activation syndrome remains poorly defined, and controversy regarding the nature of this syndrome continues in the field of psychiatry. Here, we present four medico-legal cases involving activation syndrome, in which one of us served as an expert witness. Analysis of the court's decisions indicated that the court appeared to focus on whether the acts were associated with the subjects' personality or not, leaving the controversy over activation syndrome as an open question. These cases highlighted the need for joint examination by jurists and psychiatrists, since society is likely to continue to be faced with cases of behavioral problems associated with the use of antidepressants. PMID- 22250441 TI - [A report on attempted suicide cases involving patients accepted by public health care institutions]. AB - We investigated attempted suicide cases, both successful and failed involving patients, accepted by public health care institutions in Shiga Prefecture, whose population is about 1. 4 million, from the 12th January 2010 to 14th February 2010. Prefectural emergency hospitals, fire stations, and pathologists cooperated in the investigation, and the cases were reported with the age and sex as well as the means and results of the attempts. How these institutions cooperated in the cases was also reported. A total number of 104 people attempted suicide, in which 40 people (38.5%) succeeded, 54 people (51.9%) failed, and the outcome was unknown in 10 people (9.6%). Forty-one people (39.4%) were in their 30s, being the most common age group. Successful suicides were most prominent among elderly males, and failed attempts were most prominent among young females. Hanging and poisonous gassing were the common means of suicide among the successful cases, and overdose, drinking, and wrist -cutting were the common means among the failed attempts. Sixty-four people (61.5%) were admitted to public emergency hospitals, 51 people (49.0%) were rescued by fire workers, and 34 people (32.7%) were sent for autopsy following police reports on fatal cases as suicide. Successful suicides and males were mostly sent for pathological examination without any coordinated care from different medical institutions, whereas, failed cases and females were often taken care of by several institutions. Five people (4.8%) were referred for psychiatric help. Suicide intervention needs to take account of differences in the sex, age, means, and other characteristics of those who attempt suicide. Each institution plays an important role, and they need to cooperate in order to establish an effective intervention. PMID- 22250442 TI - [Cognition, behavior and emotion in psychotherapy--an example of cognitive behavioral therapy for depression]. AB - The development of neuroimaging methods has enabled significant advances toward elucidating the mechanism of cognition, behavior and emotion. This article first reviews recent human neuroimaging studies that examined the neurocircuitry of emotion and emotion regulation. Next, we review the neuroimaging literature of the effects of cognitive behavioral therapy for depression. Lastly, we provide the brain mechanism that the emotional support regulates psychological pain in ostracism, and then discuss a biological model of psychotherapy. We hope that the present review can help us, not only to better understand the biological basis of cognition, behavior and emotion in psychotherapy, but also to be aware of effects of psychotherapy on brain. PMID- 22250443 TI - [The cognitive point of view in psychodynamic psychotherapy: mentalization-based treatment]. AB - Mentalization, the capacity to understand the mental state of oneself and others which underlies overt behaviour, is a developmental achievement through the context of attachment relationship during infancy and childhood. Mentalization based treatment (MBT) is a psychotherapy that promote the further development of mentalizing. MBT for borderline personality disorder (BPD), developed and manualised by Peter Fonagy and Anthony Bateman, is well-known. According to them, vulnerability to a loss in mentalizing particularly in interpersonal or stressful circumstances is a core feature of BPD. For these patients, traditional psychotherapy would produce iatrogenic harms rather than some improvements. To avoid those iatrogenic effects, MBT therapist takes the stance of "not-knowing". Therapist stimulates the patient's mentalizing, and makes the patient have some inquisitiveness about the mental states of oneself and others. For this purpose, the triad of "event-belief-affect" is explored. At first, the problematic act of the patient is detected. Secondly, rewinding to the time when that problematic act has arisen, the therapist collaborate with the patient to identify the event that provokes the failure of mentalization, and to clarify the affect of patient at the moment. Thirdly, to gain alternative perspectives, that situation is explored through the emotional context. Finally, the specific maladaptive belief which causes a disruption of mentalizing is identified. When the same pattern of mentalizing failure is occurred in the process of the therapy, it was brought up in the "here and now" relationship between the patient and therapist. As seen above, MBT, which explores the relationship between affect and belief, has some technical features similar to cognitive behaviour therapy, which explores the relationship between maladaptive schema and dysfunctional cognition or problematic feeling. However, to the extent of focusing on the "here and now" relationship between patient and therapist, and of placing an emphasis on the context of transference, MBT is still psychodynamic psychotherapy. PMID- 22250444 TI - [Adding the perspective of emotion on cognitive rehabilitation]. AB - Cognitive rehabilitation has been gradually disseminated in Japan lately. Cognitive rehabilitation is distinct from other psychosocial rehabilitation methods, which aims to enhance cognitive function per se, by various training tools, using paper and pencil tasks, computer games, etc. It stands on the hypothesis that enhancing cognitive function should lead to improvement in social functioning. However, it is becoming clear that cognitive rehabilitation on its own is not strongly effective on social functioning, but rather it appears effective when combined with other methods of rehabilitation. Moreover, it does not treat the emotional problems, which is essential considering the treatment endpoint, to enhance "subjective well-being". Emotional problems arise much often at social interaction in patients with schizophrenia, which can be amended by improving their social cognition as well as social skills. Recently, one of the social cognition training programs has been developed in USA by Penn and his colleagues, named SCIT (Social Cognition and Interaction Training) . The program treats a number of factors involved in social cognition, a) emotion perception, b) attributional style, and c) theory of mind, using various techniques such as Socrates quotes. In previous studies, SCIT showed good effectiveness in various aspects of social cognition for inpatients, whereas the finding was not as clear for outpatients. It may be assumed that integrating SCIT into a cognitive rehabilitation program should alleviate emotional stress the patients often encounter at social interaction in their daily activities. Presumably the next candidate target for psychosocial treatments coming after cognition and emotion should be "intrinsic motivation". PMID- 22250445 TI - [Pervasive developmental disorder in adults; importance of diagnosis in concern to the type of ego structure with PDD]. AB - Most adult patients with pervasive developmental disorder (PDD) who consult with psychiatrists for the first time may have normal intelligence. In diagnosing high functioning PDD to adult patients, we should pay much attention to psychological consistency which exists between developmental problems in childhood, developed personality, recent problems in social adjustment, and manifested psychiatric symptoms. In order to understand these relationships, considering the patients' type of ego structure ("PDD ego type") seems to be useful. "PDD ego type" is characterized by their unique self-universe image which takes form of grid one (just like a touch panel), which is decisively different from the form of a radial or concentric circle held by most people (Jung, C.G). This self-universe image characterizes adult PDD patients' psychiatric symptoms, unsuitable social performance, and their "personality." PMID- 22250446 TI - [The changes of PDD symptoms according to their mental growth]. AB - We proposed and compared 3 cases with PDD whose clinical problems are varied according to their mental growth. Although common clinical symptoms were not found, when deciding their behavior, all of the cases have different priorities to people withoue PDD, and their relationship with social interaction was confused. Our understanding is that concept of "developmental disorder" may be helpful to comprehend young adults' behavioral problems, though it may have some risk for over-diagnosing. PMID- 22250447 TI - [Adult pervasive developmental disorder: introducing multidimensional trait assessment for PDD diagnosis and the working diagnosis of probable PDD]. AB - This paper proposes how adult pervasive developmental disorder (PDD) should be diagnosed. PDD patients diagnosed in adulthood for the first time differ from PDD children in the following points: first, they have comparatively inconspicuous PDD traits which have gone unnoticed for years, and second, the PDD features can be modified by comorbid psychiatric disorders. It has also been reported that PDD symptoms such as social interaction disturbance or communicative problems of verbal patients with autism would gradually improve with maturity. These factors make the clinical entity of adult PDD obscure. Therefore, it is difficult to diagnose adult PDD based on the categorical concept of disorder only from assessing present status without taking a precise developmental history. On the other hand, there is the concept of "Autism spectrum disorder (ASD)". This concept of a spectrum could be adapted for adult cases including a wide range of PDD. To do so, however, two issues must be resolved: 1) whether it is possible to set a common diagnostic threshold, and 2) how the use of the term "spectrum" invites the misperception of PDD as only unidimensional. For their resolution, the author proposes two novel concepts: multidimensional trait assessment for PDD (or ASD) diagnosis and a working diagnosis of probable PDD (or ASD). The former can be depicted as a radiating chart having multi-axes of PDD (or ASD) traits, whereas a spectrum assessment would be only a single point on a straight line. This trait assessment can provide tailor-made help for individual patients. The latter can allow proper treatment of underdiagnosed patients who have obvious PDD features but a poor developmental history. These concepts will enable us to treat elusive cases of adult PDD. PMID- 22250448 TI - [Value of ancillary testing in the diagnosis of pervasive developmental disorder in adults]. AB - Recently, there has been increasing interest in adults with pervasive developmental disorder (PDD) who seek general psychiatric services for various psychiatric problems. The diagnosis of PDD requires the careful collection of information about the patient's developmental history. A structured diagnostic interview is useful and should be performed, but has limitations now. The clinical value of the measurement of the Wechsler Adult Intelligence Scale, the Autism-Spectrum Quotient Japanese Version, and the Pervasive Developmental Disorders Autism Society Japan Rating Scale was demonstrated by a questionnaire survey that the authors conducted in 2010. These additional tests are useful if interpreted with caution. For example, a discrepancy between the performance intelligence quotient (IQ) and the verbal IQ in the Wechsler Adult Intelligence Scale does not by itself diagnose PDD. We examined whether the Japanese version of the National Adult Reading Test (Japanese Adult Reading Test; JART), a valid scale for evaluating pre-morbid IQ in patients with schizophrenia, and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) are useful for discriminating between PDD and schizophrenia. Sixteen patients with adult PDD and 16 patients with schizophrenia matched for age, education and sex participated in this study. In addition, the two groups were matched for JART and the Global Assessment of Functioning scores. All subjects were scored on the JART and WAIS-R after giving informed consent for the study. The result was that significant diagnosis-by-IQ examination interactions were found (F [1, 30]=10.049, P=0.003). Also, the WAIS-R scores of the PDD group were higher than those of the schizophrenia group (P=0.002) when the two groups were matched for JART. In conclusion, the comparison of IQ in the PDD group and in the schizophrenia group by JART and WAIS R might be an easy and useful method for helping to discriminate between PDD and schizophrenia. In addition, the difference in IQ scores measured by JART and by WAIS-R may be helpful in diagnosing PDD. The diagnosis of PDD in adults may be assisted by the use of these additional tests. PMID- 22250449 TI - [The biological characteristics of pervasive developmental disorder]. AB - Individuals with Asperger's disorder and high functioning autism often don't have diagnosis during the childhood because of their high intelligence. It is not easy to diagnose adults as pervasive developmental disorder, because the information about their state and episodes in the childhood depends on the retrospective memories by caregivers and themselves. Although some researchers proposed that biological indicators might be useful for diagnosis, they have not found reliable indicators yet. Diagnosis of pervasive developmental disorder based only on biological indicators has limitations, because pervasive developmental disorder is biologically heterogeneous, and the diagnosis criteria were made based on abnormal behaviors, but not on the biological characteristics. However it is expected that the biological indicators that are useful to diagnose will be found in the near future. The outlines of neuroimaging and eye tracking studies that are relatively simple and useful methods, including findings of our studies, are introduced in this review. PMID- 22250450 TI - [Discussion meeting on problems of the enterohemorrhagic Escherichia coli]. PMID- 22250451 TI - [Information technology use in preventing infection]. AB - Infection prevention requires handling enormous amounts of medical information collection, analysis, and delivery--a cumbersome, inefficient process. Hospital information system (HIS) data not intended for preventing infection cannot be used directly for such prevention. The rapid introduction of information technology in infection prevention can potentially solve these problems. The IT based infection prevention system (ITIPS) structure depends on the purpose specified, however, and using this information in hospitals requires that the detailed HIS structure be clarified, especially the connection between HIS and ITIPS. The future ITIPS role is envisioned in early infection detection and warning. This, in turn, requires that ITIPS field operational support systems for medical staff mature further. PMID- 22250452 TI - [Sequence analysis subtyping of the 56-kDa protein-encoding gene of Karp-type Orientia tsutsugamushi isolated in scrub typhus cases]. AB - To determine the Karp-type Orientia tsutsugamushi subtype in northern Japan, i.e., Yamagata, Niigata, and Akita Prefectures, we analyzed the partial nucleotide sequence of the 56-kDa protein-encoding gene of 30 isolates from scrub typhus cases. Based on sequencing results, we classified isolates into two groups of 27 and 3 isolates. Nucleotide sequences of 27 isolates were homologous to the yeo-joo strain, classified as a JP-1 subtype. The three isolates were each homologous to a stain of CMM1, KNP1, or KNP2, classified as JP-2 subtypes. Phylogenetic tree analysis showed the 27 isolates forming a cluster with the yeo joo strain and the three isolates with the CMM, KNP1, and KNP2 strains and therefore belonging to these subtypes. The Karp-type O. tsutsugamushi JP-2 subtype predominates in Japan, the JP-1 subtype probably the predominates in the area investigated. O. tsutsugamushi JP-1 subtype strains must therefore be isolated from subjects in this area and comprehensively studied. PMID- 22250453 TI - [Chickenpox case estimation in acyclovir pharmacy survey and early bioterrorism detection]. AB - OBJECTIVE: Early potential health hazards and bioterrorism threats require early detection. Smallpox cases caused by terrorist could, for example, be treated by prescribing acyclovir to those having fever and vesicle exanthema diagnosed as chicken pox. We have constructed real-time pharmacy surveillance scenarios using information technology (IT) to monitor acyclovir prescription. METHODS: We collected the number of acyclovir prescriptions from 5138 pharmacies using the Application Server Provider System (ASP) to estimate the number of cases. We then compared the number of those given acyclovir under 15 years old from pharmacy surveillance and sentinel surveillance for chickenpox under the Infection Disease Control Law. RESULTS: The estimated number of under 15 years old prescribed acyclovir in pharmacy surveillance resembled sentinel surveillance results and showed a similar seasonal chickenpox pattern. The correlation coefficient was 0.8575. The estimated numbers of adults, older than 15 but under 65 years old, and elderly, older than 65, prescribed acyclovir showed no clear seasonal pattern. DISCUSSION: Pharmacy surveillance for acyclovir identified the baseline and can be used to detect unusual chickenpox outbreak. Bioterrorism attack could potentially be detected using smallpox virus when acyclovir prescription for adults suddenly increases without outbreaks in children or the elderly. This acyclovir prescription monitoring such as an application is, to our knowledge, the first of its kind anywhre. PMID- 22250454 TI - [Clinical investigation of nine pediatric Japanese spotted fever cases]. AB - To clarify the clinical manifestations of pediatric Japanese spotted fever (JSF), which remain unclear, we retrospectively reviewed the records of 9 consecutive hospitalized children 5 boys and 4 girls aged 0-15 years (median: 2.3) whose diagnosis was patients with JSF who were serologically confirmed from April 2008 to October 2009. We initially studied the polymerase chain reaction (PCR) assay validity for specific Rickettsia japonica DNA in the blood. We also studied febrile duration, the history of contact with tick-infested areas, body temperature, eschars at tick bite sites, skin rash, treatment drugs, and laboratory data. Five of the 9 (56%) had positive PCR tests. Prehospitalization febrile duration was 1-5 days. Five had had contact with tick-infested areas and 4 had not despite living near such areas. Body temperature was 40 degrees C in 7. Only 4 had eschars at bite sites. Characteristic spotted palmar and/or plantar erythema seen in 8 was useful in diagnosis. Laboratory studies showed typical hyponatremia of < 135mEq/L in 6 JSF was diagnosed easily at hospitalization in 7. Diagnosis in a 2-month-old infant proved difficults, however, worsening the child's condition and causing hepatosplenomegaly, thrombocytopenia, anemia, and hyperferritinema. The infant was treated with high-dose gamma-globulin and azithromycin (AZM) followed by minocycline (MINO). Another case was difficult to diagnose due to clinical manifestations consistent with Kawasaki disease. The child was treated with high-dose gamma-globulin and AZM. Three of the 9 were treated with MINO alone and 4 with combined MINO and new quinolones. Fever was resolved within 2 days of treatment in all cases. Our findings show that children with high fever and spotted palmar and/or plantar erythema should be treated immediately for JSF in prevalent areas, even in the absence of eschars. PMID- 22250455 TI - [An open, noncomparative multicenter study of the efficacy and safety of itraconazole injections and high dose capsules in chronic pulmonary aspergillosis]. AB - BACKGROUND: Itraconazole (ITCZ) is a novel triazole antifungal with a broad spectrum including Aspergillus species. We conducted a three-month open, noncomparative multicenter study of the efficacy and safety of ITCZ injections and high dose capsules in chronic pulmonary aspergillosis. METHODS: Patients with chronic pulmonary aspergillosis received intravenous injection of ITCZ (200mg) (twice a day for the first two days, then once a day for the following 3-12 days) prior to the oral administration of ITCZ capsules (200mg) twice a day. Radiologic findings by chest CT and clinical symptoms were evaluated at baseline and 12 weeks later. We also measured ITCZ plasma trough concentrations after two weeks and four weeks of the study. RESULTS: Twenty patients were included in the study, among which 14 patients presented with chronic necrotizing pulmonary aspergillosis (CNPA) and 6 presented with pulmonary aspergilloma. The efficacy evaluation was available in 17 patients (CNPA, 12 patients; aspergilloma, 5 patients). Radiological improvement was observed in nine (52.9%, 95%CI: 31.0% 73.8%) patients (CNPA, 7 patients; aspergilloma, 2 patients). One patient with aspergilloma showed deterioration. The clinical symptoms showed significant improvement on expectoration, bloody sputum, and pyrexia. Two patients had to stop treatment with ITCZ because of congestive heart failure. Other adverse effects were reported but did not lead to the discontinuation of treatment, as follows: hepatic dysfunction, two patients; hypokalemia, nine patients. In two patients who combined pulmonary Mycobacterium avium complex disease coadministration of ITCZ and rifampicin was done. Their ITCZ plasma concentrations were extremely low, and one of them was the only deterioration case in the primarily radiologic evaluation. CONCLUSION: Itraconazole injections and high dose capsules maintenance therapy is effective in treating chronic pulmonary aspergillosis. PMID- 22250456 TI - [Macrolide resistance and detection in Mycoplasma pneumoniae at Kansai Medical University Hirakata Hospital]. AB - Mycoplasma pneumoniae causes bronchitis and pneumonia predominantly in subjects 5 to 20 years old. M. pneumoniae is detected by measuring specific antibodies and/or isolating the microorganism, but the frequency of false-positive/negative results, and the culture time required until isolation pose problems. We detected M. pneumoniae using real-time PCR with clinical specimens. We also determined the drug sensitivity of isolated M. pneumoniae and searched for the gene mutation responsible for macrolide resistance. In 275 cases of suspected M. pneumoniae infection, positive cases in real-time PCR numbered 40 (14.5%). Of these, 16 showed positive culture (5.8%). Of these 16, A2063G point mutation that causes macrolide resistance was found in 12. Drug sensitivity testing showed resistance to clarithromycin (MIC> or =64 microg/ml) in 11 and susceptibility in 4 (MIC 0.0039 microg/ml). The clarithromycin resistance ratio was 75%. Growth was insufficient for testing in 1 case. M. pneumoniae was susceptible to minocycline and all quinolone drugs. M. pneumoniae detection using real-time PCR proved much more sensitive than conventional culture. Macrolide resistance results correlated well with genomic mutation. Our study's macrolide resistance ratio was high at 75% possibly due to a restricted subject population that had been administered macrolide drugs elsewhere but with an unsatisfactory outcome. The increasing number of reports on macrolide resistance requires that we monitor drug resistance trends, particularly among macrolide derivatives. PMID- 22250457 TI - [Japanese HIV-infected men who have sex with men screened for anal intraepithelial neoplasia]. AB - The prevalence of and the risk factors for abnormal anal cytology among Japanese men who have sex with men (MSM) who have human immunodeficiency virus (HIV) infection have not been fully investigated up to now. We conducted a nested case control study of 81 HIV-infected Japanese MSM treated with antiretroviral therapy at a sexuality minority affirmative clinic between April 2010 and March 2011. Results showed that 41 (50.6%) of the 81 had normal anal cytology, 13 (16.0%) atypical squamous cells, 24 (29.6%) low-grade squamous intraepithelial lesions, and 3 (3.7%) high-grade squamous intraepithelial lesions. No carcinoma cases were seen. Multivariate analysis showed abnormal anal cytology to be associated with a history of genital condyloma (OR 4.19, p = .021). We concluded that abnormal anal cytology was common among HIV-infected Japanese MSM. Effective screening and management should be planned for precancerous anal lesions. PMID- 22250458 TI - [Etiological bacterial level in enterohemorrhagic Escherichia coli infection feces and chromogenic culture medium CHROMagar STEC usefulness]. AB - We report a case of enterohemorrhagic Escherichia coli (EHEC) infection in which EHEC was not detected by culture on DHL agar medium. The proportion of EHEC bacterial count to enterobacterial count in feces was 1.7%, and the detection probability by 5-colony angling was low (8.1%). The probability of angling detection using CHROMagar STEC, a chromogenic medium for detecting EHEC, was high (100%). An additional and collection test was done using E. coli bacterial solutions to which two main sera groups--O157 and O26 were added. The maximum detectable level in the bacterial solution with O157 was 10(3)-10(4) CFU/mL in DHL and 10(2) CFU/mL in CHROMagar STEC. Bacterial solution levels with O26 were 10(3) CFU/mL in DHL and 10(2) CFU/mL in CHROMagar STEC. Assuming that the EHEC bacterial amount in feces of those with EHEC infection is low, we speculated that CHROMagar STEC may be useful as on EHEC screening medium. PMID- 22250459 TI - [A case of severe influenza (H1N1) 2009 virus pneumonia identified by virus culture instead of PCR]. AB - A 70-year-old man was being treated for asthma and chronic obstructive pulmonary disease, which had been well controlled. He was seen at our emergency outpatient department on October 24, 2009, for respiratory distress and mild fever. Point-of care testing for influenza, general bacteria, and acid-fast bacilli in the sputum, were negative. With antibiotics ineffective, his respiratory status worsened, requiring him to be intubated and ventilated mechanically. Steroid pulse therapy temporarily improved his condition, as confirmed by imaging studies, but he died on hospital day 38. Polymerase chain reaction (PCR) analysis of tracheal secretion and bronchial washings collected on hospital day 14 and 21 were negative for influenza (H1N1) 2009 virus, which was identified in a subsequent culture. Negative results for reverse transcriptase-PCR analysis leave (H1N1) 2009 virus unable to be diagnosed clinically. Culture tests and repeated PCR analysis have been done in cases of strongly suspected clinical infection to confirm results. Our case, in which the virus was identified by culture, suggests that the viral load may have been too low or the time of culture inappropriate. PMID- 22250460 TI - [Emphysematous pyelonephritis and cystitis concurrence; A case report]. AB - We report a case of emphysematous pyelonephritis coexisting with emphysematous cystitis. A 57-year-old woman seen for abdominal pain, diarrhea, and high fever had been referred after computed tomography (CT) elsewhere had shown an air density mass in the left kidney and pelvis. Abdominal CT on admission showed emphysematous change in the left renal parenchyma and intramural bladder. Serum analysis results showed disseminated intravascular coagulation (DIC) and uncontrolled diabetes. Klebsiella pneumoniae was isolated in the blood. She was diagnosed with sepsis based on these findings due to concurrent emphysematous pyelonephritis and cystitis caused by K. pneumoniae. She was treated conservatively with meropenem, intravenous immunoglobulin, and gabexate mesilate and cured. Concurrent emphysematous cystitis and pyelonephritis is rare., with ours only the fourth case reported in Japan. PMID- 22250461 TI - [A case of infective Aerococcus urinae endocarditis successfully treated by aortic valve replacement]. AB - Aerococcus urinae is a endocarditis rare causative organism with low virulene. We report an A. urinae endocarditis case treated by aortic valve replacement. An 80 year-old woman hospitalized for urinary tract infection and hydronephrosis due to three-week renal calculi. Blood culture on admission isolated Streptococcus acidominimus. During the course, she was transferred to our care for surgical intervention after developing congestive heart failure due to severe aortic regurgitation. Echocardiographic findings indicated infective endocarditis. She underwent aortic valve replacement, and gram staining of the resected valve tissue showed gram-positive cocci, although valve culture was negative. PCR amplification and DNA sequencing using the valve material matched an A. urinae sequence. The woman recovered and was discharged six weeks after antibiotic treatment. PMID- 22250462 TI - [Infantile meningitis caused by respiratory syncytial virus]. AB - Respiratory syncytial (RS) virus commonly causes infantile respiratory tract infection causing significant morbidity and mortality, but rarely meningitis. We report a case of meningitis caused by RS virus subgroup B in a 56-day-old boy admitted for high fever who underwent blood examination and lumbar puncture. Empirical chemotherapy was started with intravenous ampicillin, gentamicin, and cefotaxime based on laboratory data on CSF cells (84/microL) and serum CRP (13.8mg/dL) data. RS virus subgroup B was only detected using real-time PCR comprehensive reverse transcription from the first CSF, but no bacterial gene was detected. No bacteria grew from his CSF, urine, or blood. Fever and serum CRP dropped in a few days. He had neither seizures nor disturbance of consciousness and was discharged on day 11 after admission. No evidence of encephalopathy was detected in brain MRI or electroencephalography. RS virus rarely causes meningitis, but a percentage of RS-virus-infected infants exhibit symptoms such as seizure and disturbance of consciousness. We should recognize that the RS virus may cause neurological complications associated with high morbidity and mortality. PMID- 22250463 TI - [Comparative performance of tuberculin skin test and QuantiFERON TB-gold in contact investigations for tuberculosis]. AB - OBJECTIVES: To evaluate the performances of the QuantiFERON TB-Gold assay (QFT) and tuberculin skin test (TST) and to examine how a latent tuberculosis infection (LTBI) should be diagnosed in contact investigations of children aged 6 to 17 years. METHODS: A total of 232 boys and girls aged 6 to 17 years who were in contact with 134 culture-confirmed pulmonary tuberculosis patients (index cases) were examined both with QFT and TST. Factors influencing the results of the tests and their interactions were evaluated with multivariate analyses. RESULTS: Two variables (whether household contact and with/without contact with a cavitary disease patient) were found to significantly predict a positive QFT result. Positive TST defined with erythema being either greater than 20 mm or 30mm correlated significantly with two variables (whether household contact and with/without contact with a smear positive patient). There was moderate agreement between QFT and TST (positivity defined as with erythema greater than 30mm), with kappa=0.49, for contacts aged 6 to 11 years. Among contacts aged 6 to 11 years, 14 had a negative QFT result and TST with erythema greater than 30 mm. Of these 14, 7 contacts (50%) of smear positive index case were not indicated for LTBI treatment. CONCLUSIONS: When diagnosing LTBI among contacts aged 6 to 11 years who show negative QFT and strong TST reactions, we should take into consideration the factors related with a higher probability to the risk of infection. Because a history of past BCG vaccination is more likely to affect TST results in those aged 12 to 17 years than in younger subjects, greater care must be taken when evaluating the TST of these contacts. PMID- 22250464 TI - [Problems of tuberculosis patients under dialysis in Tama area, Tokyo]. AB - OBJECTIVES: Patients undergoing renal dialysis (dialysis patients) are generally known to have a higher risk of tuberculosis (TB). In order to address this problem effectively, analyses were made of the characteristics of active TB patients under dialysis in the Tama Area of Tokyo. SUBJECTS AND METHODS: Dialysis patients were selected from the list of TB patients who were newly registered at seven public health centers in the Tama Area between 2007 and 2009. The incidence rate of TB in dialysis patients was calculated. Their personal profiles such as age, affected organs, results of sputum smear, modes of case detection, and delay in case detection, were reviewed in comparison with those in TB patients not undergoing dialysis. RESULTS: Dialysis patients had 8.34 times higher TB incidence rate than non-dialysis subjects. They were more likely to have extra pulmonary TB. The dialysis patients visited doctors sooner after the appearance of symptoms, which resulted in a higher proportion of smear-negative TB among them. Periodic chest X-ray examination at dialysis clinics played an important role in early TB diagnosis. CONCLUSION: It is important for dialysis clinics to maintain a high index of TB, since dialysis patients are at a higher risk of TB. In addition, careful attention should be paid to a patient's past history of TB infection, as well as to the findings of periodic chest X-ray examinations. PMID- 22250465 TI - [Factors related to the occurrence of multi- (extensively-) drug resistant tuberculosis (M/XDR-TB) in our hospital]. AB - OBJECTIVE: To analyze the clinical characteristics of multi- (extensively-) drug resistant tuberculosis (M/XDR-TB) in our hospital. MATERIALS AND METHODS: One hundred and forty-one cases diagnosed with MDR-TB and thirteen cases with XDR-TB admitted to our hospital over the last nine years were enrolled in this study. RESULTS: The gender distribution was: ninety-nine males and forty-two females in MDR-TB and nine males and four females in XDR-TB. The mean age was 52.0 years in males and 43.1 years in females in the MDR-TB patients, and 49.1 years in males and 42.0 years in females in the XDR-TB patients. There were 11 Chinese patients and 7 Koreans, as well as 8 patients from other countries abroad. Eighty-four (59.6%) MDR-TB patients and 9 (69.2%) XDR-TB patients had a smoking history. Diabetes mellitus was seen in 30 MDR-TB and 3 XDR-TB patients. The period from manifestation to the first visit to our hospital was 41.5 months on average in the MDR-TB patients, and 79.6 months in the XDR-TB patients. The average period from first diagnosis of TB to that of M/XDR-TB was 30.9 months in the MDR and 56.8 months in the XDR. Thirty (21.3%) MDR-TB patients and one (7.7%) XDR-TB patient were first diagnosed in our hospital. One-hundred and fifteen patients (81.6%) with MDR-TB and 6 (46.1%) with XDR-TB achieved negative sputum bacteriological conversion. Fifty-six cases (48.7%) of 115 MDR-TB and all (100%) of the XDR-TB patients underwent surgical treatment. Sixteen (11.3%) MDR-TB and 3 (23.1%) XDR-TB patients died. Thirty of the MDR-TB and 1 of the XDR-TB patients had never been previously treated for tuberculosis. Twelve (8.5%) MDR-TB and 5 (38.5%) XDR-TB patients had been treated with four drugs including isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA), and either ethambutol (EB) or streptomycin (SM) in previous hospitals. Twenty-five (17.7%) MDR-TB and 5 (38.5%) XDR-TB patients had been treated with three drug regimens not including PZA in previous hospitals. CONCLUSION: M/XDR-TB is a man-made disease and can be infectious. Even the current standard regimens can produce M/ XDR-TB, if they are used improperly and carelessly. Great care should be taken to prevent XDR and MDR TB. PMID- 22250466 TI - [Comparison of conventional tuberculin skin test and QFT-2G, a new method for diagnosis of tuberculosis infection, with the use of the contact score]. AB - BACKGROUND: QuantiFERON TB-Gold (QFT) has recently been developed as a new method for diagnosing tuberculosis (TB) infection. To evaluate the usefulness of QFT, we analyzed the relationship between QFT and the closeness of contact with a source of infection, in comparison with that of the tuberculin skin test (TST). METHODS: Male (n=322) and female (n=340) subjects (4-75 years old) who had contact with an index case received QFT and TST. The diagnostic criterion for TB infection with TST was defined as a test with an erythema diameter of > or = 30 mm. The closeness of contact with an index case was quantified in the "contact score," based on the information obtained with a questionnaire. RESULTS: There was a significant positive correlation between the contact score and QFT-positive rate, while there was no such relationship for TST positivity. The odds ratios for positive QFT rate for the subjects in the 3rd and 4th quartile groups of contact score (taking the QFT-positive rate in the lowest score quartile as unity) were 3.40 (95% confidence interval: 1.07-10.76, p<0.05) and 7.62 (95% confidence interval: 2.60-22.37, p<0.01), respectively. These odds ratios were also significantly greater than unity after adjustment for age, sex, history of BCG vaccination and history of health care-related jobs. There was a wide difference in the QFT-positive rates between the 2nd and 3rd quartiles of contact score (3.5% vs. 11.9%). The borderline value of the contact score between these two quartiles corresponded to 200, which could be a cutoff value for defining a high risk contact. CONCLUSION: The QFT-positive rates correlated well with closeness of contact, while TST showed a poor correlation. Thus, QFT is considered more useful than TST for diagnosing tuberculosis infection. PMID- 22250467 TI - [Development of cervical tuberculous lymphadenitis in a patient with Crohn's disease receiving infliximab despite of chemoprophylaxis with isoniazid]. AB - We herein report a case of a 41-year-old female with a 14-year history of Crohn's disease who had been treated with diet and mesalazine. Because of inadequate control, therapy with infliximab was planned. She had a positive result on the interferon-gamma release assay (QuantiFERON TB). After active tuberculosis was ruled out by chest x-ray and computed tomography, she was started on a six-month course of isoniazid 7 weeks prior to starting infliximab. After 10 doses of infliximab (15 months of therapy), she presented with pain of cervical lymphadenopathy. A biopsy of the lymph nodes revealed Langhans giant cells from granulomas and a positive result of polylmerase chain reaction for Mycobacterium tuberculosis. The treatment with infliximab was discontinued and anti tuberculosis therapy was started. Although treatment for latent tuberculosis infection lowers the risk of reactivation of tuberculosis due to tumor necrosis factor alpha-blockers, it cannot completely inactivate tuberculosis. Despite the completion of chemoprophylaxis, patients receiving such agents should be instructed to watch out for any symptoms associated with pulmonary and extrapulmonary tuberculosis such as fever, cough, malaise, body weight loss, night sweating and lymphadenopathy, and they should also be closely followed up. PMID- 22250468 TI - [Tuberculosis annual report 2009--series 7. Condition of TB (2)]. AB - We report on the TB surveillance data for 2009 in Japan regarding HIV infection, diabetes, and drug susceptibility test results, which were added to the central TB surveillance database from 2007. In the present TB surveillance system, we cannot obtain reliable data about whether or not HIV tests were done in each case. Thus, we report only the number of TB patients diagnosed as having HIV infection. The number of newly notified TB cases reported as having HIV from 2007 2009 is 176. Of those, 155 (88.1%) were male and 21 (11.9%) were female, and 39 (22.2%) were foreigners. The frequency of TB-associated diabetes in newly notified TB cases in 2009 was 12.6% (3,043/24,170) in total, 14.5% in males, and 9.5% in females. Drug susceptibility test results were obtained in 6,920 culture positive pulmonary TB cases through the surveillance system in 2009. This figure accounted for 63.5% of all culture-positive pulmonary cases. In primary cases, the frequencies of MDR, any INH resistance, and any RFP resistance were 0.5%, 4.4%, and 0.8%, respectively, and in re-treatment cases, they were 3.6%, 11.6%, and 5.0%, respectively. In primary pulmonary cases theses drug resistance rates have been stable over this 3-year period (2007-2009), but in pulmonary cases undergoing re-treatment, the frequency has decreased (for example, the MDR rate in re-treatment pulmonary cases was 7.2% in 2007, 5.1% in 2008, and 3.6% in 2009). Of all MDR pulmonary cases, 17.9% (10/56) were foreigners in 2009. PMID- 22250469 TI - Integration. The many questions we still need to answer on integration. PMID- 22250470 TI - Foundation status. Trusts demand pound 350 million to stay in FT pipeline. PMID- 22250471 TI - Politicians vs reality. PMID- 22250472 TI - On commissioning and integration. Join hands for a unifying purpose. PMID- 22250473 TI - The next generation. PMID- 22250474 TI - Patient access. How to wipe out a growing killer. PMID- 22250475 TI - Patient and public engagement. Get everybody in on the action. PMID- 22250476 TI - Mental health. The gold standard for screening. PMID- 22250477 TI - The role of hydrogen peroxide and other reactive oxygen species in wound healing. AB - Wound healing is a complex physiological process important for tissue homeostasis. An acute injury initiates massive cell migration, proliferation and differentiation, synthesis of extracellular matrix components, scar formation and remodelling. Blood flow and tissue oxygenation are parts of the complex regulation of healing. Higher organisms utilize molecular oxygen as a terminal oxidant. This way of gaining energy for vital processes such as healing leads to the production of a number of oxygen compounds that may have a defensive or informatory role. They may be harmful when present in high concentrations. Both the lack and the excess of reactive oxygen species may influence healing negatively. PMID- 22250478 TI - Bronchial asthma and obesity in childhood. AB - Bronchial asthma and obesity is among a group ofmultietiologic complex diseases which influence each other in their origin, and development. The impact on the patient's quality of life and prognosis is significant, health costs included. Because of the increasing prevalence worldwide, there has been an increase in the amount of studies dealing with reciprocal associations between asthma and obesity. PMID- 22250479 TI - Detection of toxoplasmosis in environmental samples at a wet market of a capital city centre. AB - The local Chow Kit market is the largest wet market in the city of Kuala Lumpur. It is very close to the biggest government hospital in the city centre. However, the level of cleanliness in this area is always questionable and a matter of concern. The aim of this study was to identify the prevalence of T. gondii oocyst in water samples used by hawkers in that market and tissue cysts in rats' brains captured from the same area. Water samples were taken to the parasitology laboratory at the National Universtiy of MalaysiaUniversity and a sugar flotation concentration method was used. Supernatant microscopical examination was then performed. A total of 752 slides were screened for the presence of T. gondii oocyst. A hundred rats wandering in the same area were also captured by the hawkers using mousetraps. After each animal was sacrificed, and an electric microtome was used to cut out serial sections 5 microm thick from the rat brains. The de-waxed tissue sections were stained by the progressive Haematoxylin and Eosin (H&E) stain for microscopical examination. A total of 1000 slides were screened under a light microscope to detect the presence of T. gondii brain cysts. All the water samples were found to be negative for T. gondii oocyst. Out of the 100 rats captured, three rats were found to possess T. gondii cysts in their brains. Water samples reflect minimal or no solid food contamination, while the 3% of positive brain cysts influence the researchers to broaden their investigations for future projects. PMID- 22250480 TI - Analysis of D1853N ATM polymorphism in radiosensitive patients with cervical carcinoma. AB - Clinical oncologists have been focusing their efforts on attempting to define risk groups of patients with unusual biological reactions to the recommended therapy regimens using molecular biology techniques. THE AIMS OF OUR STUDY WERE: (i) to find a design and validate a method for fast and reliable analysis of the D1853N (5557G>A) genetic polymorphism in the ATM (ataxia-telangiectasia mutated) gene; (ii) to use side-directed mutagenesis to generate ATM 5557A-positive DNA (reference ATM5557A DNA); and (iii) to analyze a group of patients suffering from cervical carcinoma with adverse responses to radiotherapy. The 5557A variant was found in three of twenty women (15%). Our data show that the prevalence of the 5557A allelic variant in cervical cancer subjects with adverse responses after irradiation probably does not differ from the prevalence common in Caucasians. A larger population study should confirm these preliminary results. PMID- 22250481 TI - Factor V Leiden mutation and its impact on pregnancy complications. AB - OBJECTIVE: The aim of this prospective study was to find the association between the factor V Leiden mutation and adverse pregnancy outcomes. METHODS: This study is an analysis of a prospective observational study of the frequency of placenta mediated complications of factor V Leiden mutation carriers. We compared pregnancy outcomes of 11 women with a heterozygous form of the factor V Leiden mutation with 41 women of a control group. RESULTS: All pregnancies ended with delivery of a living infant. None of the 52 pregnancies were complicated by venous thromboembolism. There were a few significant differences regarding placenta-mediated complications. The gestational age at delivery showed small significant differences. There was a significant difference in the birth weight deviation in percentage between FVL carriers and controls. The incidence of blood loss exceeding 1000 ml was higher in the control group. CONCLUSIONS: Carriership of the factor V Leiden mutation did not affect the incidence of preeclampsia. Adverse pregnancy outcomes such as placental abruption were rare. Eclampsia, intrauterine fetal death and venous thromboembolism did not occur. Our results provide evidence that the maternal heterozygous FVL mutation did not increase the risk of an adverse pregnancy outcome. PMID- 22250482 TI - Clear cell odontogenic carcinoma of the maxilla. AB - Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic tumor associated with aggressive clinical behavior, metastasis and low survival. We report a case of CCOC affecting the maxilla of 62 year-old woman. It was first described as a clinicopathological entity in 1985 and to date only 67 cases were described in the English literature. We are understanding of the behavior of this carcinomas was depend on limited case reports. For these reason we found important to report this case of CCOC in the maxilla. PMID- 22250483 TI - Case report of ruptured non-communicating right rudimentary horn pregnancy: an acute emergency. AB - Ruptured pregnancy in the rudimentary horn of women who have had a vaginal delivery is rare and unpredictable. However, when undiagnosed, this condition could lead to maternal morbidity and mortality. We report a pregnancy at 19 weeks gestation presented with acute abdomen and hypovolemic shock. She was initially thought to have an intrauterine pregnancy with the provisional diagnosis of a ruptured uterus. Intraoperatively, a ruptured non-communicating right rudimentary horn with ex utero pregnancy was discovered. PMID- 22250484 TI - Pneumocystis pneumonia during medicamentous treatment of Cushing's syndrome--a description of two cases. AB - Only a few cases of pneumocystis pneumonia (PCP) in Cushing's syndrome have been published in the literature so far. In the majority of these patients, the pneumonia occurred after reduction of the hypercortisolism with medicamentous treatment. We report two cases of PCP during conservative treatment of hypercortisolism. We describe clinical, imaging and laboratory findings in two patients and review published cases of pneumocystits pneumonia in Cushing's syndrome. A 60-year-old woman and 20-year-old man with Cushing's syndrome due to ectopic ACTH syndrome were treated at our department. Both developed pneumocystis pneumonia early after treatment with ketoconazole and ethomidate bromide had been introduced and the levels of cortisol rapidly decreased. PCP prophylaxis in patients with high cortisolemia should be started before treatment of hypercortisolism in current practice. Gradual lowering of plasma cortisol should also reduce the risk of infection by Pneumocystis jiroveci. PMID- 22250485 TI - Unilateral intercordal neural communication coexistent with variant branching pattern of posterior cord of brachial plexus. AB - Variant branching pattern of the cords of brachial plexus coupled with erroneous communications has been an area of concern for surgeons opting to explore this region. Anaesthetic blocks and surgical approaches are the highlights of these interventions, where a keen familiarization of the anatomy of this region is mandatory. The present case description reports a unilateral variant branching pattern of the posterior cord coexistent with a neural communication between lateral and medial cords in an adult male cadaver. This intercordal neural communication between lateral and medial cords was oriented obliquely and measured 2.2 cm in length. Furthermore, the posterior cord revealed a variant branching pattern. It branched into three upper subscapular nerves and a common trunk for the thoracodorsal and lower subscapular nerves. The lowest of the three upper subscapular nerves gave a communicating twig to the thoracodorsal nerve. Inspite of uncountable reports on variations ofbrachial plexus, descriptions regarding anomalous branching patterns hold enormous clinical significance for the radiologists, anesthetists and surgeons, besides being of academic interest for the anatomists. PMID- 22250486 TI - Put on notice. New York report could have hospital execs, boards looking over their shoulders. AB - A New York state commission wants to give state officials the power to remove management and boards at poorly performing hospitals in Brooklyn and possibly recognition that the borough's healthcare system is dysfunctional. "There's some competition that really doesn't benefit anybody" and is inefficient, says Richard Becker, left, of Brooklyn Hospital Center. PMID- 22250487 TI - Few gains, some slips. Survey looks at performance of hospital boards. PMID- 22250488 TI - CMS succession plan. Tavenner's confirmation prospects appear bright. PMID- 22250489 TI - Advocate says farewell. Supporters see big things in Berwick's future. PMID- 22250491 TI - Lost opportunity? Extension to speed EHR adoption too late for some. PMID- 22250490 TI - Insurance infusion. Nearly $220 million awarded for exchanges. PMID- 22250492 TI - Pressure point. Downsized NLRB rules don't appease critics. PMID- 22250493 TI - Imaging transparency. Usage, reporting requirements are hot topics. PMID- 22250494 TI - Science friction. No matter what the data says, some of us always find room for doubt, denial. PMID- 22250495 TI - Hitting closer to home. Underserved patients get better cancer care at community centers. PMID- 22250496 TI - A new rural route. Healthcare coalition, lawmakers drive effort to make rural health clinics eligible for federal incentive payments. PMID- 22250497 TI - Hitting the reset button. More states consider return to rate-setting. PMID- 22250498 TI - Where do you stand? Maintenance of certification process sparks debate. PMID- 22250499 TI - Making the transition to 5010 and ICD-10. Preparing now for these mandated changes is the key to successful conversion and use. PMID- 22250500 TI - The many sides of patient care. Doing right by a patient doesn't always involve diagnosing and treating illness. PMID- 22250501 TI - In bad faith. A former health plan medical director repents for denying care to patients. PMID- 22250502 TI - Immunizations and the WIC program. Combining services benefits children, parents, healthcare system. PMID- 22250503 TI - Planning your exit strategy. A smooth transition to a comfortable retirement requires years of advance preparation. PMID- 22250504 TI - Optimism may reduce malpractice risk. PMID- 22250506 TI - Working with industry. Don't be squeamish: learn to embrace innovation. PMID- 22250505 TI - Not cost-effective by design. Healthcare financing reform may share the same fate as the Titanic. PMID- 22250507 TI - Innovation. 'Innovate in six areas or face penalties'. PMID- 22250508 TI - Special treatment. PMID- 22250509 TI - Coming of age or over the hill? PMID- 22250510 TI - Special report. Hot topic. PMID- 22250511 TI - Shifting the centre of gravity. PMID- 22250512 TI - Innovation. An encounter with less fiery dragons. PMID- 22250513 TI - Academic health system. Qatar's quest for excellence. PMID- 22250514 TI - Safety. Create a stronger voice for change. PMID- 22250515 TI - [Molecular hyperspectral imaging (MHSI) system and application in biochemical medicine]. AB - A novel molecular hyperspectral imaging (MHSI) system based on AOTF (acousto optic tunable filters) was presented. The system consists of microscope, AOTF based spectrometer, matrix CCD, image collection card and computer. The spectral range of the MHSI is from 550 to 1 000 nm. The spectral resolution is less than 2 nm, and the spatial resolution is about 0.3 microm. This paper has also presented that spectral curves extracted from the corrected hyperspectral data of the sample, which have been preprocessed by the gray correction coefficient, can more truly represent biochemical characteristic of the sample. The system can supply not only single band images in the visible range, but also spectrum curve of random pixel of sample image. This system can be widely used in various fields of biomedicine, clinical medicine, material science and microelectronics. PMID- 22250516 TI - [Rapid detection of Escherichia coli O157 : H7 using surface plasmon resonance (SPR) biosensor]. AB - A biosensor based on surface plasmon resonance (SPR) was developed for rapid detection of Escherichia coli O157 : H7. BIACORE 3000 SPR instrument and a dextran-modified sensor chip (CM5) were used. After activation with EDC/NHS, anti E. coli O157 : H7 antibody was immobilized on the gold surface of the SPR sensor, and then following ethanolamine was injected, and the chip was ready for E. coli O157 : H7. Regeneration was achieved using NaOH in order to detect several samples. The limit of detection was found to be 3 x 10(5) CFU x mL(-1) for E. coli O157 : H7, and the change of RU was linearly correlated with the concentration of E. coli O157 : H7 cells (R2 = 0.99). The detection time ranged from 5 to 7 min, and the result of regeneration was effective which allowed the chip to be reused for more than 50 samples. This method is convenient, and stable, and shows potentials for applications in food areas. PMID- 22250517 TI - [Transmission efficiency analysis of near-field fiber probe using FDTD simulation]. AB - A fiber probe is the key component of near-field optical technology which is widely used in high resolution imaging, spectroscopy detection and nano processing. How to improve the transmission efficiency of the fiber probe is a very important problem in the application of near-field optical technology. Based on the results of 3D-FDTD computation, the dependence of the transmission efficiency on the cone angle, the aperture diameter, the wavelength and the thickness of metal cladding is revealed. The authors have also made a comparison between naked probe and the probe with metal cladding in terms of transmission efficiency and spatial resolution. In addition, the authors have discovered the fluctuation phenomena of transmission efficiency as the wavelength of incident laser increases. PMID- 22250518 TI - [Studies on the anomalous IR properties of CoPt nanorods]. AB - One-dimensional CoPt nanorods were obtained through the galvanic displacement reaction and chemical reduction. The average diameter of the nanorods was measured to be about 166.3 nm and the length was mostly between 1.0 and 5.0 microm obtained from the scanning electron microscopy (SEM) measurement. The IR optical properties of the CoPt nanorods and bulk Pt were investigated by in situ FTIR reflection spectroscopy employing CO adsorption as probe reaction at the solid/gas interface. The results of in situ FTIR indicated that bulk Pt shows a normal IR optical property and the CoPt nanorods display abnormal infrared effects (AIREs). The authors can obtain the same results whether the CoPt nanorods were loaded on glassy carbon (GC) or Au substrates. These results demonstrated that the AIREs were generated mainly by CoPt nanorods and the influence of the substrate materials can be neglected. The study confirmed that one-dimensional CoPt nanorods show AIREs, and throw a new sense to comprehend the anomalous IR properties observed on low-dimensional nanomaterials. PMID- 22250519 TI - [Study on spectral gain characterization of FWM processes with multi-frequency pumps in photonic crystal fiber]. AB - Spectral gain induced by four-wave-mixing with multi-frequency pump was investigated by exploiting the data signal and continue lights co-propagation in dispersion flattened high nonlinear photonic crystal fiber (PCF). The effects of wavelength drift of pump lights, polarization state of orthogonal or parallel of pump lights, polarization mismatch of signal light versus orthogonal pump lights, total power of signal and probe light on the spectrum gain were analyzed. The results show that good FWM gain effects with multi-frequency pump can be obtained in 36.4 nm wavelength range when power ratio of pump to probe light is appropriate and with identical polarization. Furthermore, the gain of FWM with multi-frequency pump is very sensitive to polarization fluctuation and the different idle waves obtain different gain with the variation in signal polarization state. Moreover, the impact of pump numbers was investigated. The obtained results would be helpful for further research on ultrahigh-speed all optical signal processing devices exploiting the FWM with multi-frequency pump in PCF for future photonics network. PMID- 22250520 TI - [A review of classification methods of remote sensing imagery]. AB - Remote sensing data classification is an important way of information extraction and a hot research topic of remote sensing technique. Classification method of remote sensing data is an important issue, and effective selection of appropriate classifier is especially significant for improving classification accuracy. Along with the development of remote sensing technique, traditional parametric classifier is difficult to meet accuracy requirement, leading to the rapid development of intelligent algorithm based non-parametric classifiers. Recently, combined classifiers become a new hot topic for its ability of utilizing complement information of single classifier. In the present paper, characters and advantages of different classifiers as well as the research prospect are analyzed. The paper provides a scientific reference for the development of remote sensing data classification technique. PMID- 22250521 TI - [Terahertz spectroscopic investigation of lanthanide-doped nano-TiO2]. AB - Lanthanide-doped nano-TiO2 samples with different Ti/Ln (Ln = Ce, Nd, and Sm) were synthesized by sol-gel method. The samples were characterized by X-ray diffraction(XRD), Fourier transform infrared spectroscopy(FTIR), X-ray photoelectron spectroscopy (XPS) and terahertz time-domain spectroscopy (THz TDS). The results indicate that Ce, Nd, and Sm ions were uniformly dispersed into the TiO2; and the infrared activities of lanthanide-deped nano-TiO2 were much stronger than Undoped nano-TiO2, the refractive index of anatase TiO2 declines with frequency increasing in the frequency range of 0.2-1.70 THz at room temperature, and it exhibits anomalous dispersion. Unique characteristic absorption peaks at 1.35 and 1.58 THz were observed from Ce-doped nano-TiO2. Compared with undoped nano-TiO2, the absorption edges of Ce-doped nano-TiO2 were red-shifted remarkably and those of Nd and Sm ions doped nano-TiO2 were blue shifted. Sm-doped nano-TiO2 has induced the least dielectric losses in the frequency range of 0.2-1.7 THz, and the average value is 0.05. PMID- 22250522 TI - [Terahertz spectroscopic investigation of elaidic acid]. AB - The optical properties of elaidic acid in the THz band were investigated by using THz time-domain spectroscopy (THZ-TDS). The absorption and refractive index spectra in the frequency range from 0.5 to 2.5 THz were obtained at room temperature under nitrogen atmosphere, and the results show that elaidic acid had some characteristic absorption peaks, and the average refractive index of the sample was 1.43. The structure and vibrational frequencies of elaidic acid molecule in the THz range were simulated by the B3LYP algorithm of density functional theory, and the THz characteristic absorption peaks of elaidic acid molecule were identified by using Gaussian View software. The results show that the experimental and theoretical results agree in general, and the observed absorption peaks in the THz range were mainly caused by the intramolecular and intermolecular vibrations jointly. At the same time, the fingerprint spectra of elaidic acid in the THz band verify that the time-domain terahertz spectroscopy can be used to detect oleic acid, and this study provides a new experimental method for the detection of trans fatty acids in food. PMID- 22250523 TI - [Influence of laser power and incident angle as well as testing distance on laser inducted breakdown spectroscopy (LIBS) technology for spectroscopy diagnosis and multi-element analysis]. AB - Laser inducted breakdown spectroscopy (LIBS) technology has been used widely for the multi-element analysis of different samples and also an effective way to realize the spectroscopy diagnosis applied to calculating the electron temperature and vibration-rotation temperature etc of some certain elements. It is a highly effective measurement for its non-contact and nondestructive on-line analysis with the help of a high-speed response CCD camera. In the present paper, the authors tested an alley though LIBS technology to determine its elements in terms of species and quantities and also discussed some influences of the incident angle and the power changes of the laser beam as well as the measurement distance changes on the experimental results and and gave appropriate theoretical explanation. PMID- 22250524 TI - [Application of data fusion of microscopic spectral imaging in reservoir characterization]. AB - In recent years, spectral imaging technique has been applied widely in mineralogy and petrology. The technique combines the spectral technique with imaging technique. The samples can be analyzed and recognized both in spectra and space by using the technique. However, the problem is how to acquire the needful information from a large number of data of spectral imaging, and how to enhance the needful information. In the present paper, the experimental data were processed by using the technique of data fusion of microscopic spectral imaging. The space distribution map of chemical composition and physical parameters of samples were obtained. The result showed that the distribution of different hydrocarbon in the reservoirs, pore connectivity, etc. were revealed well. The technique of data fusion of microscopic spectral imaging provided a new method for reservoir characterization. PMID- 22250525 TI - [Simulation of polarization SAR imaging of ocean surface]. AB - The polarization synthetic aperture radar (SAR) imaging simulation is of great significance to ocean surface scattering. According to the theory of wind-wave spectrum, rough ocean surface was modeled in the present paper using the two scale-model. This treatment takes both the large scale and small scale surface into account. By using the velocity bunching (VB) theory, Bragg scattering model and the small perturbation model (SPM), the polarization SAR system can simulate the ocean surface with various parameters and ocean states. The effects of the parameters of ocean waves and the parameters of SAR system were analyzed. Finally, some useful conclusions were drawn, which are helpful for extracting the information of ocean surface. The method is an effective way in the ocean SAR design and the ocean surface research. PMID- 22250526 TI - [Measuring method of spatial and spectral distribution of hollow cathode lamp]. AB - In the present paper, the authors propose a method to measure the spatial and spectral distribution of hollow cathode lamp by imaging spectrometer. A push broom convex grating imaging spectrometer based on Offner system is presented, with wavelength range 400-1 000 nm, field angle 22 degrees and spectral resolution 2-3 nm. The spatial distribution of Hg hollow cathode lamp was measured for the first time; this gives the spatial intensity distribution for different wavelengths and spectral distribution at different positions, with high spatial and spectral resolution. Also the hyperspectral data under different working current condition was obtained in order to analyze the differences of the distribution. It will be a powerful tool for the spatial and spectral properties measurement of hollow cathode lamps and other kinds of light sources. PMID- 22250527 TI - [Study of plasma temperature measurements for oxygen discharge]. AB - A radio-frequency discharge setup was constructed by two shell-shaped copper electrodes and a 30 cm long pyrex glass tube (i. d. = 1.65 cm) to examine the gas temperature of oxygen plasma in electric discharge oxygen iodine laser. The discharge was supplied by a 500 watt, 13.56 MHz radio-frequency power. The gas pressure in the discharge cavity was 1 330 Pa. The temperature of oxygen discharge plasma was measured by using the P branch of O2 (b, v = 0) rotational emission spectrum. Two methods were used to deduce the oxygen gas temperature. They are Boltzman plotting method and computer simulating spectrum method, respectively. Gauss fitting method was used to distinguish spectrum peaks for lower resolution spectrum. The spectrum peak area was used to characterize the optical emission intensity. The gas temperature of oxygen discharge plasma was obtained by Boltzmann plotting method. Alternatively, the optical emission spectrum was simulated by computer modeling with spectrometer slit function which was obtained by He-Ne laser. Consequently, the gas temperature of oxygen plasma was obtained by comparing the computer simulating spectrum and the experimentally observed spectrum according to the least square fitting rule. The measurement results with the two methods agree well. It was concluded that the simple optical technique can be used conveniently in the temperature diagnostics of oxygen radio frequency discharge plasma. PMID- 22250528 TI - [The spectral response analysis of activated GaN photocathode]. AB - GaN photocathode has a wide applicaion in ultraviolet detection because of the outstanding performance. GaN photocathode was activated in ultrahigh vacuum (UHV) system by Cs/O, and the reflection-mode quantum efficiency (QE) was analyzed. The QE is 30%-10% corresponding to the wavelength 240-350 nm, and the QE curve is flat. The QE reaches the maximum of 30% at 240 nm. Compared with the abroad result, the QE obtained by us is still inadequate at the short wavelength The atom arrangement of GaN (0001) was studied. The atom arrangement on the surface was simulated by 3D, and in this way the adsorption of Cs on the GaN(0001) was speculated. PMID- 22250529 TI - [Measurement of OH radicals in flame with high resolution differential optical absorption spectroscopy]. AB - The present paper describes a new developed high resolution differential optical absorption spectroscopy instrument used for the measurement of OH radicals in flame. The instrument consists of a Xenon lamp for light source; a double pass high resolution echelle spectrometer with a resolution of 3.3 pm; a multiple reflection cell of 20 meter base length, in which the light reflects in the cell for 176 times, so the whole path length of light can achieve 3 520 meters. The OH radicals'6 absorption lines around 308 nm were simultaneously observed in the experiment. By using high resolution DOAS technology, the OH radicals in candles, kerosene lamp, and alcohol burner flames were monitored, and their concentrations were also inverted. PMID- 22250530 TI - [Study of the physical properties of SnS thin films deposited by ultrasonic spray pyrolysis method]. AB - In the present paper, SnS thin films were deposited by ultrasonic spray pyrolysis method. The influence of the three different precursor concentrations on the properties of SnS thin films was compared. XRD shows that when precursor solution is thiourea (0.5 mol x L(-1)) + tin tetrachloride (0.5 mol x L(-1)) + deionized water, there are SnS and SnO2 mixed phases; when precursor solution is thiourea (0.6 mol x L(-1)) + tin tetrachloride (0.5 mol x L(-1)) + deionized water, SnS phase is the dominant diffraction peak, although a certain amount of SnO2 phase is contained; when precursor solution is thiourea (0.7 mol x L(-1)) + tin tetrachloride (0.5 mol x L(-1)) + deionized water, thin film after being annealed is single SnS thin film with orthorhombic structure. SEM shows that films are uniform and dense. Furthermore, the particles of films are bigger when thiourea concentration is higher. Transmittance spectrum shows that the influence of precursor concentration on transmittance of thin films is less. Dark I-V and C-V tests of the devices show that junction characteristics of the devices were similar when prepared by three different concentrations of precursor solution, and as the thiourea concentration is higher, the carrier concentration is relatively larger. PMID- 22250531 TI - [Investigation on the molecular structures and electronic absorption spectra of Tanshinone II A and Tanshinone II A -Cu(II) complex]. AB - Using an intensified spectroscopic detector CCD, the UV-Vis absorption spectra of tanshinone II A and Tanshinone II A-Cu(II) complex were acquired. The stable geometric structures of Tanshinone II A and Tanshinone II A -Cu(II) complex were obtained by using density functional theory method. Based on the optimized geometric structures, the electronic absorption spectra of Tanshinone II A and Tanshinone II A-Cu(II) complex in gas phase and in ethanol solution were calculated by using time-dependent density functional theory. Results show that the solvent effect induces the red shift of spectrum for Tanshinone II A and the blue shift of spectrum for Tanshinone II A-Cu(II) complex. The calculated absorption spectra including the solvent effect are in good agreement with the experimental results. The present work first measured and computed the electronic absorption spectra of Tanshinone II A-Cu(II) complex. PMID- 22250532 TI - [Research on LC-based spectral imaging system for visible band]. AB - LC-based tunable filter with large aperture has been developed utilizing the effect of electric controlled birefringence. Spectral test indicated that this filter can operate in the visible band with an average 20 nm FWHM. A small scale spectral imaging system was established based on this tunable filter. Spectral imaging experiments on a certain number of samples show that this system can be tuned continuously with random-access selection of any wavelength, and has a higher level of resolving power in respect of both imaging and spectral tuning in the visible band, which has a brilliant application potentiality in biology, iatrology, environmental protection, resource detection through hyper-spectral imaging or ultra-spectral imaging. PMID- 22250533 TI - [Luminescence characteristics of PVK doped with Eu-complex Eu(UVA)3Phen]. AB - The present work investigates the photoluminescence (PL) and electroluminescence (EL) characteristics of Eu-complex Eu (UVA)3Phen doped PVK with different doping concentrations. The results indicate that there exists Forster energy transfer from PVK to Eu(UVA)3 phen in the mixed system. It can get good color purity by optimizing the doping concentration of host and guest materials. And the authors can obtain the best doping concentration to be 4% in EL device. PMID- 22250534 TI - [The property of white powder LED with different ratio of phosphor]. AB - White powder light emitting diodes (LED) with different color temperature were made by using different ratio of yellow to orange silicate phosphor. When the ratio of yellow to orange phosphor was less than 7, the peak wavelength of yellow light in spectra was about 570 nm and the wavelength was about 590 nm as the ratio was greater than 7. With the color temperature increasing, the color rendering index and the luminous efficiency increased at the beginning and then decreased. And color temperature of 5 521 K is the optimal value. The reason was the ineffective excitation of blue light due to higher concentration of phosphor and excess red light in spectra. In contrast, blue light was not excited effectively and red light in spectra was little when the color temperature was higher than 5 521 K. The luminous efficiency was decreased, and the decreased magnitude was inconsistency with the testing temperature from 10 to 80 degrees C. This suggests that, besides Auger recombination, the decrease in excitation efficiency of yellow and orange phosphors is different as the temperature rises and orange phosphor's temperature characteristic is superior to that of yellow phosphor. PMID- 22250535 TI - [Influence of P3HT : PCBM film formation process on the performance of polymer solar cells]. AB - The performance of heterojunction polymer solar cells (PSCs) based on poly(3 hexylthiophene) (P3HT) and [6, 6]-phenyl C61-butyric acid methyl ester (PCBM) blends was investigated by changing P3HT : PCBM film fabrication procedures with fast growth and slow growth methods, respectively. The optimal time of slow growth of P3HT : PCBM films was gotten after we systematically changed spin coating time and preset time before annealing blended films. When P3HT = PCBM film was spin coated at the speed of 800RPM and spin time ranged from 50 to 80 sec, and then put in petri dish for 30 min before annealing blended films, the power conversion efficiency (PCE) of PSCs reached 3%. Yet PCE of PSCs based on P3HT : PCBM with fast-growth was only 1.8%. The improved PCE is attributable to the reasonable phase-separation between P3HT and PCBM blended film, which boosted carriers transport and hop. The result indicates that half an hour of preset time for P3HT : PCBM films before annealing can efficiently finish the slow-growth of blended films, which can save time and decrease cost to fabricate efficient PSCs. PMID- 22250536 TI - [Near infrared reflectance spectroscopy (NIRS): a novel approach to reconstructing historical changes of primary productivity in Antarctic lake]. AB - Compared with traditional chemical analysis methods, reflectance spectroscopy has the advantages of speed, minimal or no sample preparation, non-destruction, and low cost. In order to explore the potential application of spectroscopy technology in the paleolimnological study on Antarctic lakes, we took a lake sediment core in Mochou Lake at Zhongshan Station of Antarctic, and analyzed the near infrared reflectance spectroscopy (NIRS) data in the sedimentary samples. The results showed that the factor loadings of principal component analysis (PCA) displayed very similar depth-profile change pattern with the S2 index, a reliable proxy for the change in historical lake primary productivity. The correlation analysis showed that the values of PCA factor loading and S2 were correlated significantly, suggesting that it is feasible to infer paleoproductivity changes recorded in Antarctic lakes using NIRS technology. Compared to the traditional method of the trough area between 650 and 700 nm, the authors found that the PCA statistical approach was more accurate for reconstructing the change in historical lake primary productivity. The results reported here demonstrate that reflectance spectroscopy can provide a rapid method for the reconstruction of lake palaeoenviro nmental change in the remote Antarctic regions. PMID- 22250537 TI - [Determination of amino acid contents in cottonseeds using near infrared reflectance spectroscopy]. AB - A total of 445 samples with great variability in amino acid contents were harvested for different seasons in different regions for developing calibration equations of amino acid content in cottonseeds. The spectral data of cotton kernel powder was processed using the first derivative mathematical treatment combined with SNV and de-trend, as well as modified partial least squares (MPLS) regression method. The chemometric models for 17 amino acids present in cottonseed were developed, and 12 of them were excellent for the determination of related amino acids, namely asparagic acid, threonine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, phenylalanine, lysine, histidine, and arginine, with RPDc of 3.735-7.132 and determination coefficient (r2) of 0.910 0.979 in external validation. For those 12 amino acids, their values predicted by NIRS are comparable to those obtained by the chemical method with good accuracy. The RPDc of serine, methionine, tyrosine and proline were 2.205 -2.814, and their determination coefficient (r2) were 0.800-0.830 in external validation. For those 4 amino acids, the values from NIRS are not so accurate as chemical analysis, but could be used in sample screening in cotton breeding program. While the equation for cystine was useless as its RPDc was only 1.358, which was not suitable for estimating its content in cottonseeds. PMID- 22250538 TI - [Application of two FTIR pattern recognition methods to the Zanthoxylum nitidum geographical origins determination]. AB - In the present work, the authors explored a rapid method of the Zanthoxylum nitidum geographical origins determination. Based on Fourier transform infrared spectroscopy (FTIR) technology, the band of 1 800-400 cm(-1) which is the IR fingerprint of Zanthoxylum nitidum, the Fisher ratio and the soft independent modeling of class analogies (SIMCA) were used to build a classification model. Respectively, four kinds of Zanthoxylum nitidum in the Guangxi region were detected by the model, and the model was verified by calculating their recognition rate and rejection rate. The results show that the authors can accurately extract the overall information of Chinese herbal medicines by using the FTIR, also established a pattern recognition model to predict unknown samples, and obtained satisfactory recognition rate and rejection rate, indicating that the model has stronger ability of identification. The detection on real time was carried out rapidly with the Fisher model, suggesting that the model has more practical value. PMID- 22250539 TI - [A novel approach to NIR spectral quantitative analysis: semi-supervised least squares support vector regression machine]. AB - In near infrared spectral quantitative analysis, the precision of measured samples' chemical values is the theoretical limit of those of quantitative analysis with mathematical models. However, the number of samples that can obtain accurately their chemical values is few. Many models exclude the amount of samples without chemical values, and consider only these samples with chemical values when modeling sample compositions' contents. To address this problem, a semi-supervised LS-SVR (S2 LS-SVR) model is proposed on the basis of LS-SVR, which can utilize samples without chemical values as well as those with chemical values. Similar to the LS-SVR, to train this model is equivalent to solving a linear system. Finally, the samples of flue-cured tobacco were taken as experimental material, and corresponding quantitative analysis models were constructed for four sample compositions' content(total sugar, reducing sugar, total nitrogen and nicotine) with PLS regression, LS-SVR and S2 LS-SVR. For the S2 LS-SVR model, the average relative errors between actual values and predicted ones for the four sample compositions' contents are 6.62%, 7.56%, 6.11% and 8.20%, respectively, and the correlation coefficients are 0.974 1, 0.973 3, 0.923 0 and 0.948 6, respectively. Experimental results show the S2 LS-SVR model outperforms the other two, which verifies the feasibility and efficiency of the S2 LS-SVR model. PMID- 22250540 TI - [Quantitative analysis of hybrid maize seed purity using near infrared spectroscopy]. AB - A quantitative identification model for testing the purity of hybrid maize seeds was built by near infrared reflectance spectroscopy with quantitative partial least squares (QPLS). The NIR spectra of 123 seeds powder samples (Nongda108 and mother178) with the purity of 600-100% were collected using MPA spectrometer. All samples were divided into two groups: calibration set (82 samples) and validation set (41 samples). Synergy interval partial least squares (SiPLSu) was used for selecting effective spectral regions and building models. The influences of different spectral regions and different calibration samples on the prediction results and different main components were compared. The result showed that the spectral regions 6 000 8 000, 6 000-9 000 and 6 000-10 000 cm(-1) all had better prediction results (R2 over 95%). Spectral region 6 000-10 000 cm(-1) was regarded the optimum spectral region for building the model with less main components(8), and the determination coefficient (R2) of calibration and validation sets were 96.61% and 97.67% respectively, SEC (standard error of calibration) and SEP (standard error of prediction) were 2.15% and 1.78% respectively, RSDs (relative standard deviation) were 2.04% and 1.94% respectively. Even with different calibration samples, the average determination coefficients (R2) of calibration and validation sets were 96.21% and 95.75%, SEC (standard error of calibration) and SEP (standard error of prediction) were 2.29% and 2.23% respectively, RSDs (relative standard deviation) were 2.81% and 2.73% respectively, which further proved the model's stability. With the increase in the number of main components, the identification rates in calibration set and validation set gradually increased, when the number of main components reached 8, the model determination coefficients reached the best (96.61% and 97.67%), and related coefficients of true value and predicted value were 98.29% and 98.87% respectively. The results have important value for rapid and accurate testing of hybrid maize seed purity. PMID- 22250541 TI - [Analysis of different parts of scorpio by Fourier transform infrared spectroscopy]. AB - Fourier transform infrared (FTIR) spectroscopy and second derivative IR spectroscopy were applied to analyze and evaluate different parts of Scorpio. The second derivative IR spectra show clear differences while the origin spectra are quite similar. It was found that proteins are the dominant components in each part and the tail has distinct proteins compared to the others; fats are mainly stored in the trunk; sulfates are ubiquitous in all parts. Interestingly, the back part of the trunk of degenerative Scorpio contains some purine. It was demonstrated that FTIR spectroscopy integrated with second derivative IR spectroscopy not only can offer a fast, comprehensive and objective methodology for analyzing and evaluating the micro-differences among the various parts of same medicinal materials, but also can provide a rational guidance for medicinal and pharmacological studies. PMID- 22250542 TI - [Similarity analysis of FTIR of Lapis Micae Aureum]. AB - Similarity analysis of FTIR of Lapis Micae Aureum was carried out to find out the relationship between similarity of infrared spectra and the quality of medicine samples, and try to provide a new method for its quality assessment. FTIR was used to analyze Lapis Micae Aureum samples. Then 6 samples with good quality were picked up to establish a reference infrared spectra by their infrared spectra. Correlation coefficient method and the included angle cosine method were used to calculate the similarity between sample's infrared spectra and the reference infrared spectra. For all those 19 samples with characters in accordance with Ch. P, the similarity is above 0.94, and for the others the similarity is less than 0.94. Although some samples' source meets the requirement of Ch. P, but with poor quality by traditional experience, the similarity is lower than those of good quality. It was concluded that the similarity of infrared spectra of Lapis Micae Aureum is closely related to the quality of medicines. As a result, similarity analysis of FTIR of Lapis Micae Aureum is reliable, and can be used for its quality assessment. PMID- 22250543 TI - [Research on the method of interference correction for nondispersive infrared multi-component gas analysis]. AB - A method of interference correction for nondispersive infrared multi-component gas analysis was described. According to the successive integral gas absorption models and methods, the influence of temperature and air pressure on the integral line strengths and linetype was considered, and based on Lorentz detuning linetypes, the absorption cross sections and response coefficients of H2O, CO2, CO, and NO on each filter channel were obtained. The four dimension linear regression equations for interference correction were established by response coefficients, the absorption cross interference was corrected by solving the multi-dimensional linear regression equations, and after interference correction, the pure absorbance signal on each filter channel was only controlled by the corresponding target gas concentration. When the sample cell was filled with gas mixture with a certain concentration proportion of CO, NO and CO2, the pure absorbance after interference correction was used for concentration inversion, the inversion concentration error for CO2 is 2.0%, the inversion concentration error for CO is 1.6%, and the inversion concentration error for NO is 1.7%. Both the theory and experiment prove that the interference correction method proposed for NDIR multi-component gas analysis is feasible. PMID- 22250544 TI - [Application of near infrared spectroscopy (NIR) for evaluating cheese quality]. AB - Near infrared spectrocopy, widely used in food industry, is a fast, nondestructive analysis method. Although it has been in the detection of the quality of cheese for many years, related research is few in our country. The principle of near infrared spectroscopy and the characteristics are introduced. Cheese process, shrinkage control, maturation process, shelf life, brand classification and detection of components in the application of near infrared spectroscopy are summarized. There is great potential to apply near infrared spectroscopy in cheese quality analysis. It is an urgent task to promote the application of near infrared spectroscopy and the development of China's cheese industry. PMID- 22250545 TI - [Determination of Leymus chinensis quality by near infrared reflectance spectroscopy]. AB - One hundred fifty Leymus chinensis samples with different growth stage, areas, and preparing method (oven-drying and shading natural dry), were selected to study the potential of determination of crude protein (CP), neutral detergent fiber (NDF) and acid detergent fiber (ADF) in the present research. The quality parameters of Leymus chinensis were firstly predicted using the near infrared reflectance spectroscopy in China. The three models were validated by cross validation and external-validation. The results indicated that the NIRS models of Leymus chinensis quality prediction highly accessed the precision of chemical analysis. The coefficient of correlation of cross-validation of crude protein, neutral detergent fiber and acid detergent fiber were 0.963 7, 0.959 4 and 0.947 9, and the RMSECV of the three models were 1.41%, 1.27% and 1.27%, respectively; the correlation coefficients of external-validation were 0.965, 0.956 and 0.953, and all the ratios of standard deviation to root mean square error of prediction were higher than 3. Thus it can be testified that using NIRS analysis can rapidly and accurately determine the quality of Leymus chinensis. This method is of great significance for quick analysis of the trait of Leymus chinensis production and screening of breeding materials in Leymus spp. research of China. PMID- 22250546 TI - [Prediction of minced pork quality attributes using visible and near infrared reflectance spectroscopy]. AB - The objective of the present study was to estimate minced pork meat quality using visible and near infrared (Vis-NIR) spectroscopy. Two hundred twenty five carcasses samples from longissimus dorsi muscle were scanned over the Vis-NIR spectral range from 350 to 1 015 nm and analysed for intramuscular fat (IMF), protein and moisture according to the official methods. Wavelet transform was employed to eliminate the spectra noise. Partial least square regression (PLSR) and support vector machine (SVM) were used to develop Vis-NIR spectroscopy models for chemical composition detection. According to calibration statistics, the best model to predict intramuscular fat content was developed by SVM with the denoised spectra, the correlation coefficient was 0.889 for calibration and 0.888 for validation. For protein and moisture, the best model was achieved with the PLS method with the correlation coefficient of 0.869 and 0.881 for protein calibration and validation sets and 0.877 and 0.848 for moisture calibration and validation sets, respectively. And all the ratios of standard deviation of validation set to root mean square error of prediction (RPD) were not more than 3.0. Results indicated that it was possible to predict chemical composition in minced pork meat. As a fast predictor of meat quality using Vis-NIR spectroscopy, it is necessary to improve the precision and the robustness of the model for practice. PMID- 22250547 TI - [Hydration of liquid ethanol probed by Raman spectra]. AB - In order to study the concentration dependence of the molecular interactions in ethanol-water hydrogen bonded system, Raman spectra of ethanol-water mixtures with different water contents were obtained at room temperature. It was found that the positions of the 3 C-H stretching vibration bands of ethanol molecule located in the range of 2 800-3 050 cm(-1) would generally present blue shifts when more water was added into the mixture; at the same time, however, the C-O stretching vibration band located at around 1 048 cm(-1) showed an opposite behavior. The different hydration, which is induced by hydrogen bonding, which happened in different concentration mixtures, was thought to be responsible for this situation, the hydration process of liquid ethanol was thus deduced: when adding a small amount of water into pure ethanol, and clusters containing one water molecule and several ethanol molecules were formed instead of ethanol self association short chain clusters existing in pure ethanol; the clusters would combine more water molecules to form ringlike clusters through hydrogen bond association when adding more water into the mixture, then a temporary saturation would be seen when the volume percent of water reached 50%, and this saturation state would last until the water content reached 70 vol%; after that, the large number of water molecules would dissociate the ringlike clusters to smaller clusters and then associate to the ends of these dissociated clusters through hydrogen bonding; in addition, the improper hydrogen bonding between oxygen atom of water molecule and C-H bond of ethanol molecule is considered to be formed after the content of water reached a high value. PMID- 22250548 TI - [Raman spectroscopic study of the complex and quantitative analysis in the system CuCl2-H2O and FeCl3-H2O]. AB - In the present paper, the Raman peaks of complex in the CuCl2-H2O system and FeCl3-H2O system were studied in detail. In the CuCl2-H2O system, the superimposed characteristic peaks of various complex formed by Cu2+ and Cl- (such as [CuCl4]2- and [CuCl6]4-) may be formed the peak of 286 cm(-1), and the superimposed characteristic peaks of various complex formed by Cu2+ hydrate([Cu(H2O)4]2+ and [Cu(H2O)6]2+ based) may be formed the peak of 412 cm( 1); Through the analysis of peak parameters, we has founded two quantitative relationships: (1) The peak intensity ratio (I1 I3I 400 or I2/I3 400) of 286 cm( 1) (or 412 cm(-1)) and OH stretching Raman spectrum of water (at 3 400 cm(-1)) and concentration; (2) The integral area of 286 cm(-1) (or 412 cm(-1)) and concentration. In the FeCl3-H2O system, 173 and 331 cm(-1) might be attributed to [FeCl4]- that is the most common form of FeCl3 complex in aqueous solution. The superimposed characteristic peaks of various complex formed by Fe3+ and Cl- (such as [FeCl]2+, [FeCl2]+ etc) may be formed the broad peak of 173 cm(-1), and the superimposed characteristic peaks of various complex formed by Fe3+ hydrate([Fe(H2O)4]3+ and [Fe(H2O)6]3+ based) may be formed the broad weak peak behind of 331 cm(-1). Through the analysis of peak parameters, we has founded two quantitative relationships: (1) The integral area of 331 cm(-1) (A2) and concentration; (2) The integral area ratio of 173 and 331 cm(-1) (A1/A2) and concentration. PMID- 22250549 TI - [A fast classification method for petroleum products based on the Raman spectroscopy]. AB - A fast and effective method for classification of petroleum products based on Raman spectroscopy is proposed. A knowledge base composed by Raman spectra of training samples, intra-class feature spectra and intra-class thresholds of all classes was firstly established. Then, correlation coefficients between the test sample and the intra-class feature spectra were calculated. If the maximal correlation coefficient of the test sample is larger than or equal to the corresponding intra-class threshold, the test sample is determined to belong to the corresponding class. For 96 petroleum product samples belonging to 7 classes and 4 unknown samples, the experimental results show that this method can accurately classify known test samples and can also find the unknown test samples. This method costs little calculation time and human interference. Moreover, it can be easily implemented in the practical application. PMID- 22250550 TI - [Nondestructive imaging of elements distribution in biomedical samples by X-ray fluorescence computed tomography]. AB - X-ray fluorescence computed tomography is a stimulated emission tomography that allows nondestructive reconstruction of the elements distribution in the sample, which is important for biomedical investigations. Owing to the high flux density and easy energy tunability of highly collimated synchrotron X-rays, it is possible to apply X-ray fluorescence CT to biomedical samples. Reported in the present paper, an X-ray fluorescence CT system was established at Shanghai Synchrotron Radiation Facility for the investigations of trace elements distribution inside biomedical samples. By optimizing the experiment setup, the spatial resolution was improved and the data acquisition process was obviously speeded up. The maximum-likelihood expectation-maximization algorithm was introduced for the image reconstruction, which remarkably improved the imaging accuracy of element distributions. The developed system was verified by the test sample and medical sample respectively. The results showed that the distribution of interested elements could be imaged correctly, and the spatial resolution of 150 m was achieved. In conclusion, the developed system could be applied to the research on large-size biomedical samples, concerning imaging accuracy, spatial resolution and data collection time. PMID- 22250551 TI - [Fluorescence spectroscopic characteristics of fulvic acid from the long-term located fertilization in black soil]. AB - In order to investigate the effect of long-term located fertilization on soil fulvic acid (FA), in this study, four soil samples were taken from black soil with long-term located fertilization (about 30 year) in Harbin, Heilongjiang province. The fertilization treatments included control (CK), N, P and K fertilization (NPK), horse manure (OM), combination of organic manure and chemical fertilizations (MNPK). Soil FA was extracted from the samples and purified. The excitation, emission, synchronous, and three-dimensional-excitation emission matrix fluorescence spectroscopy (3DEEM) characteristics of the FA were determined. The excitation, emission and synchronous scan spectra all indicated that the main peaks of FA in the NPK treatment exhibited a significantly blue shift compared with CK, while those of MNPK, OM treatment caused a red shift to some extent. 3DEEM spectra of FA in all treatments exhibited four peaks (peak a, peak b, peak c, and peak d), compared with FA in CK, the wavelengths shift tendency of peak a, peak b, and peak c of FA 3DEEM in NPK, MNPK and OM treatments were similar to that of traditional spectra in FA. In order to provide quantitative information of FA humification degree in different treatments, we investigated the fluorescence index f450/500 (FI), area integration (A370-600 nm, A1 370-412 nm, A4 538-600 nm). Compared with CK, the f450/500, ratio of A1/A in NPK and A4/A in MNPK treatment increased by 4.62%, 6.12%, 7.22%, respectively. However, the f450/500, the ratio of A1/A in MNPK and A4/A in NPK treatment decreased by 3.86%, 15.31%, and 7.22% respectively. This indicated that NPK application gave a lower degree of FA humification, and combination of organic manure and chemical fertilizations would lead to a greater degree of FA aromatization in black soil with long-term located fertilization than CK. PMID- 22250552 TI - [Fluorescence spectra and absorption spectra of carvacrol]. AB - Fluorescence spectra and absorption spectra of carvacrol, an active component of Chinese herbal medicines, have been studied. The ionization constant and fluorescence quantum yield of carvacrol were measured according to spectral data. Under the condition of pH < 2.0, fluorescence intensity of carvacrol increases with the increase in pH value. In the range of pH 2.0-8.0, carvacrol gives a strong and steady fluorescence with maximum excitation wavelength 278 nm and emission wavelength 306 nm. When pH > 8.0, the fluorescence intensity decreases with the increase in pH value. Ionization constant of carvacrol was measured to be pK(a) = 10.44 +/- 0.06 using a pH-absorbance method; and pK(a) = 10.40 +/- 0.04 using a pH-fluorescence method. Fluorescence intensity of carvacrol was remarkably enhanced when methanol was added into its aqueous solution. Using L tryptophane as a reference, the fluorescence quantum yield of carvacrol aqueous solution was measured to be 0.121 at excitation wavelength 278 nm; while in a solution containing 80% methanol, the quantum yield was measured to be 0.324. PMID- 22250553 TI - [Fluorescence of early stage leachates DOM using RO membrane as tertiary treatment]. AB - In the present study, fluorescence spectra of the dissolved organic matter (DOM) extracted from early stage leachate samples obtained from biologically pretreated leachate fed to RO tertiary treatment, the permeated, the concentrate, and liquids collected after cleaning the membrane with acid and then with base were determined. The results of synchronous fluorescence spectra analysis showed the RO membrane effectively removed the high content of organic matter corresponding to short wavelengths of 280, 340, and 370 nm of the feed. Liquids collected after cleaning membrane with acid and base showed obvious influence on the organic pollutant matters in the range of 300-420 nm. The results of three-dimensional excitation-emission matrix (3D-EEM) fluorescence spectra showed three protein like peaks, namely low-excitation wavelength, tyrosine-like high-excitation wavelength, tyrosine-like high-excitation wavelength, tryptophan-like and two fulvic-like peaks, visible and ultra visible fulvic-like were found in the feed. The permeated contains two peaks with higher intensity than the feed, low excitation wavelength tyrosine-like and high excitation wavelength tyrosine-like, while the other three peaks were shown in the concentrate. The acid and the base cleaning had great influence on the molecule chemical structure of the organic pollutants on the RO membrane and caused obvious location shifts. It can be concluded that the RO mainly separated the fulvic matter in the early stage leachate and the fouling consisted of fulvic-like matter together with the protein-like, and low-excitation wavelength tyrosine-like. PMID- 22250554 TI - Spectral target-detecting system using sine-wave modulation. AB - Target detection is one of the key technology of precision chemical application. Previously the digital coding modulation technique was commonly used to emit and receive the optical signal in the target detection systems previously in China. It was difficult to adjust the output power, and the anti-interference ability was weak in these systems. In order to resolve these problems, the target detection method based on analog sine-wave modulation was studied. The spectral detecting system was set up in the aspects of working principle, electric circuit, and optical path. Lab testing was performed. The results showed that the reflected signal from the target varied inversely with detection distances. It indicated that it was feasible to establish the target detection system using analog sine-wave modulation technology. Furthermore, quantitative measurement of the reflected optical signal for near-infrared and visible light could be achieved by using this system. The research laid the foundation for the future development of the corresponding instrument. PMID- 22250555 TI - [Flower species identification and coverage estimation based on hyperspectral remote sensing data in Hulunbeier grassland]. AB - Monitoring grassland species and area real-timely and accurately is of great significance in species diversity research, as well as in sustainable development of ecosystem. Flowers have their own unique spectral characteristics. Compared with the nutrient stage, species are more easily identified by florescence. So, florescence is a critical period for identification. In the present paper, spectral differences among such flowers as Galium verum Linn., Hemerocallis citrina Baroni, Serratula centauroides Linn., Clematis hexapetala Pall., Lilium concolor var. pulchellum, Lilium pumilum and Artemisia frigida Willd. Sp. Pl. were found, along with identification methods, by analyzing canopies spectra and parametrizing characteristics. Verification results showed that when the coverage of flowers was greater than 10%, the accuracy of identification methods would be higher than 90%. On this basis, linear unmixing model was adopted to calculate the area of flowers in quadrates. Results showed that linear unmixing model was an effective method for estimating the coverage of flowers in grassland because the accuracy was about 4%. PMID- 22250556 TI - [A snow depth inversion method for the HJ-1B satellite data]. AB - The importance of the snow is self-evident, while the harms caused by the snow have also received more and more attention. At present, the retrieval of snow depth mainly focused on the use of microwave remote sensing data or a small amount of optical remote sensing data, such as the meteorological data or the MODIS data. The small satellites for environment and disaster monitoring of China are quite different form the meteorological data and MODIS data, both in the spectral resolution or spatial resolution. In this paper, aimed at the HJ-1B data, snow spectral of different underlying surfaces and depths were surveyed. The correlation between snow cover index and snow depth was also analyzed to establish the model for the snow depth retrieval using the HJ-1B data. The validation results showed that it can meet the requirements of real-time monitoring the snow depth on the condition of conventional snow depth. PMID- 22250557 TI - [Study of environmental vegetation index based on environment satellite CCD data and LAI inversion]. AB - The present study used the PROSAIL forward model to simulate vegetation canopy spectrum, introducing blue and green bands to amend the effects of atmosphere and soil background, and constructing HuanJing vegetation Index (HJVI) to avoid premature saturation. Based on ground observation data of different typical winter wheat, we established HJVI-LAI long time series inversion models and implemented different varieties cross-validation to the models. The results show that the LAI inversion model of HJVI has higher precision than similar vegetation index model, has good universality, and can be applied to remote sensing multi temporal winter wheat growth monitoring and LAI inversion. PMID- 22250558 TI - [Remote sensing of pollutant gases using brightness temperature and principal component analysis]. AB - On the mobile platform, the remote sensing system for pollutant gases can not effectively obtain background spectra. It is the key step to remove background information and extract target spectral characteristics utilizing specific algorithm. The present paper addressed an algorithm based on principal component iterative fitting and brightness temperature spectrum. The algorithm didn't require strict measurement of instrumental response function. Combining the temperature spectrum, principal component analysis and iterative fitting algorithm, the target spectral feature could be effectively extracted. PMID- 22250559 TI - [Atmospheric correction method for HJ-1 CCD imagery over waters based on radiative transfer model]. AB - Atmospheric correction is a bottleneck in quantitative application of Chinese satellites HJ-1 data to remote sensing of water color. According to the characteristics of CCD sensors, the present paper made use of air-water coupled radiative transfer model to work out the look-up table (LUT) of atmospheric corrected parameters, and thereafter developed pixel-by-pixel atmospheric correction method over waters accomplishing the water-leaving remote sensing reflectance with accessorial meteorological input. The paper validates the HJ-1 CCD retrievals with MODIS and in-situ results. It was found that the accuracy in blue and green bands is good. However, the accuracy in red or NIR bands is much worse than blue or green ones. It was also demonstrated that the aerosol model is a sensitive factor to the atmospheric correction accuracy. PMID- 22250560 TI - [Vegetation water content retrieval and application of drought monitoring using multi-spectral remote sensing]. AB - The vegetation is one of main drying carriers. The change of Vegetation Water Content (VWC) reflects the spatial-temporal distribution of drought situation and the degree of drought. In the present paper, a method of retrieving the VWC based on remote sensing data is introduced and analyzed, including the monitoring theory, vegetation water content indicator and retrieving model. The application was carried out in the region of Southwest China in the spring, 2010. The VWC data was calculated from MODIS data and spatially-temporally analyzed. Combined with the meteorological data from weather stations, the relationship between the EWT and weather data shows that precipitation has impact on the change in vegetation moisture to a certain extent. However, there is a process of delay during the course of vegetation absorbing water. So precipitation has a delaying impact on VWC. Based on the above analysis, the probability of drought monitoring and evaluation based on multi-spectral VWC data was discussed. Through temporal synthesis and combined with auxiliary data (i. e. historical data), it will help overcome the limitation of data itself and enhance the application of drought monitoring and evaluation based on the multi-spectral remote sensing. PMID- 22250561 TI - [The retrieval of fine and coarse aerosol from MODIS]. AB - Generally, aerosols over land are composed of fine and coarse aerosols, which have different optical properties. How to derive the fine mode and coarse mode aerosols from satellite observations is an important issue in the aerosol retrieving. In the present paper, information of aerosol models (including refractive index and size distribution function) was retrieved from the ground based measurement of the AERONET/PHOTONS site in Beijing. The retrievals indicate that, aerosols over Beijing have a bi-model distribution, and the optical properties of fine and coarse aerosols are distinct. Based on the dark dense vegetation (DDV) method, optical depth of the fine, coarse and total aerosols were derived from MODIS data over Beijing area in 2007. The validation of these satellite retrievals shows that from MODIS data, the optical depth of fine and total aerosols can be retrieved well (with correlation coefficients greater than 0.8), and so can the Angstrom exponent (having a correlation coefficient of 0.517). However, relatively poor results were obtained when retrieving the optical depth of coarse aerosols. PMID- 22250562 TI - [A spatial adaptive algorithm for endmember extraction on multispectral remote sensing image]. AB - Due to the problem that the convex cone analysis (CCA) method can only extract limited endmember in multispectral imagery, this paper proposed a new endmember extraction method by spatial adaptive spectral feature analysis in multispectral remote sensing image based on spatial clustering and imagery slice. Firstly, in order to remove spatial and spectral redundancies, the principal component analysis (PCA) algorithm was used for lowering the dimensions of the multispectral data. Secondly, iterative self-organizing data analysis technology algorithm (ISODATA) was used for image cluster through the similarity of the pixel spectral. And then, through clustering post process and litter clusters combination, we divided the whole image data into several blocks (tiles). Lastly, according to the complexity of image blocks' landscape and the feature of the scatter diagrams analysis, the authors can determine the number of endmembers. Then using hourglass algorithm extracts endmembers. Through the endmember extraction experiment on TM multispectral imagery, the experiment result showed that the method can extract endmember spectra form multispectral imagery effectively. What's more, the method resolved the problem of the amount of endmember limitation and improved accuracy of the endmember extraction. The method has provided a new way for multispectral image endmember extraction. PMID- 22250563 TI - [Biosorption properties of extracellular polymeric substances produced by sulfate reducing bacteria towards Cu(II) ion]. AB - The purpose of the present study was to investigate the Cu2+ biosorption properties of extracellular polymeric substances (EPS) produced by sulfate reducing bacteria. The composition and physicochemical characteristics of EPS were determined. The adsorption characteristics of EPS towards Cu2+ were examined using thermodynamic equilibrium equations and determined by FTIR and SEM-EDS. The EPS was shown to have a strong copper-binding capacity and the biosorption data obtained were well described by the Freundlich isotherm model. The results of FTIR spectra and SEM-EDS confirmed the importance of the C-O-C group, -OH group and carbonyl group from polysaccharides and proteins in Cu2+ sorption by EPS. These findings suggest the potential of EPS produced by sulfate-reducing bacteria for the removal of Cu(II) ion from aqueous solution. PMID- 22250564 TI - [The response characteristics of TM image reflectance to the arid region of soil moisture]. AB - The response characteristics of TM image to the soil moisture in the Tarim River are the research object. Selected the image spectrum (R), spectrum reciprocal (1/R), the logarithm of reciprocal spectrum lg(1/R) and removal normalized difference vegetation index (R(c)) of four spectral index were selected to establish the soil moisture content prediction model, the variance test was used to validate the model significance, the model accuracy level was divided by the posterior variance examination. The results showed that: the model accuracy of the logarithm of reciprocal spectrum lg(1/R) prediction of soil moisture is the highest, and achieved a good level for the monitoring of soil moisture content (0 - 30 cm). The model accuracy of the spectral (R) and spectral reciprocal (1/R) prediction of soil moisture is lower than logarithm of reciprocal spectrum with only the individual layers (0-30, 0-50 cm, etc.) reaching the qualified level or narrouly qualified level. The model accuracy of the removal normalized difference vegetation index (R(c)) prediction of soil moisture is the lowest. Besides, the best prediction depth of every model is the depth of 0-30 cm, and if the soil depth is too deep or too shallow, the prediction accuracy will decrease. PMID- 22250565 TI - [Research on carbon monoxide multi-parameter detection based on ultra-narrow linewidth laser]. AB - Through measuring and analyzing the infrared absorption spectrum of carbon monoxide, a kind of carbon monoxide multi-parameter detection system was designed based on the characteristics of ultra-narrow-linewidth laser and the spectrum scanning technology. A ultra-narrow-linewidth tunable semiconductor laser was utilized as light source and carbon monoxide temperature detection was achieved by measuring direct absorption spectra at different temperatures. According to temperature data and the principle of differential absorption concentration detection, carbon monoxide concentration and temperature were obtained simultaneously. With the spectrum scanning technology of ultra-narrow-linewidth laser, the spectra of carbon monoxide near the region of 6 354.179 and 6 383.09 cm(-1) at different temperatures were measured, and also analyzed and fitted by Voigt profile. Finally the experiments indicate that the temperature measurement relative error is less than 4% and relative temperature fluctuation is less than 3.5%; the concentration measurement relative error is less than 5%, and the minimum detectable carbon monoxide is 0.05%. The multi-parameter detecting system has advantages of high accuracy and good stability, and can be used in power transformer fault gases on-line monitoring in real time. PMID- 22250566 TI - [Research on identification of cucumber, stem and leaf based on spectrum analysis technology]. AB - To be able to quickly identify the cucumber real time, the present paper studied the near infrared reflectance characteristics of cucumber, stem and leaf. Spectral reflectance of 138 samples (46 cucumbers, 46 stems and 46 leaves) was collected using near infrared spectroscopy in the band range of 600-1 099 nm indoor. After Savitzky-Golay smoothing preprocessing, random 108 spectral samples were put forward as calibration set. The weighted deviation method was used for choosing the spectral bands 690-950 nm that include much more information. The samples were analyzed by PCA method to extract the principal component scores, combining the Mahalanobis distance method the recognition model was established, and seven abnormal samples were excluded. The partial least squares (PLS) model was established by remaining 101 samples spectra of calibration set, which was used for predicting the validation set (30 samples except of the calibration set). The result shows that the correlation of the predicted value and the actual value reaches up to 0.994 1, and the correct recognition rate is 100%. This significantly illustrates that the near infrared spectral reflectance characteristics are different among the cucumbers, stems and leaves, which can be successfully applied to recognition of cucumber by the method. The developed technique can provide a new method for cucumber identification. PMID- 22250567 TI - [Spectrophotometry analysis of different valence state of vanadium in vanadium battery electrolyte]. AB - In the present paper, oxalic acid was used to reduce V(V) ion to V(IV) ion, then its complex with V(IV) was formed. By this method, four valence states of vanadium ions had different characteristic absorption peaks in the UV-Visible range. Based on these characteristic absorption peaks, qualitative and quantitative spectrophotometric analysis methods for different valence states of vanadium in vanadium battery electrolyte were established. The results showed that the related coefficients of four standard curves of different valence states were greater than 0.999 0, linearity ranges were 0.326-2.445, 0.326 -2.445, 0.720 5.403, and 1.784-13.437 g x L(-1), respectively. The measurement of samples suggested that the spectrophotometric analysis method was suitable for analyzing the concentration of valence states of vanadium with the RSDs (n = 6) in the range of 0.594%-3.535%. PMID- 22250568 TI - [Optimization of ultrasound-assisted extraction combined with AFS by response surface methodology for rapid determination of trace mercury in tea leaves]. AB - A rapid ultrasound-assisted extraction (UAE) procedure was developed for the determination of trace mercury (Hg) in tea leaves combined with atomic fluorescence spectrometry. Three variables including sonication time (St), ultrasonic bath temperature (T) and HNO3 : H2O2 (1 : 1, phi) volume (A2) showed the significant effect on extraction rate of total Hg evaluated by a Plackett Burman design, and they were further optimized by a central composite design and response surface methodology. The results showed that the optimum extraction conditions were as follows: presonication time 6 min, St 8. 1 min, T 70. 5 degreesC, A2 4. 4 mL, and sample mass 300 mg. GBW10016 (tea leaves) was used as certified reference material; for comparative purposes, a microwave-assisted digestion (MAD) was used. The result obtained by optimized UAE method showed good agreement with the certified values. Under optimal conditions, recovery was evaluated to be 94.2% - 102.0% and the limit of detection 0.007 8 microg x L(-1). The relative standard deviation (RSD) of replicate measurements was generally less than 10%. The proposed UAE method was successfully applied to the determination of Hg in 63 samples of fresh tea leaves and 10 different branded tea samples. No significant differences were established between the analytical results of UAE method and MAD method. The Hg concentrations of them were found in the range of 4.6-17.3 microg x kg(-1) on a dried basis, which were within the permissible limit of the NY659-2003. PMID- 22250569 TI - [The recycling rate and budget of trace element Mn and Cu in agroecosystem using ICP-AES]. AB - The recycling rate and budget of Mn and Cu under different fertilization regimes by using long-term field experiment and ICP-AES analysis were investigated in the present paper. The results showed that the recycling rates of Mn and Cu were greater than 80% because of sediment recycling type, and the values increased with the amount of feed stuffs increasing. Both the two elements under different fertilization regimes showed budget deficit, with the deficit order of M< (or < or =)NPK + M < CK < NPK, showing that chemical fertilizer application might induce severe deficit, while application of recycling organic matter might minimize the unbalance. PMID- 22250570 TI - [Determination of components in chromium-containing refractory with X-ray fluorescence spectrometry]. AB - Components like SiO2, Al2 O3, Fe2O3, CaO, MgO and Cr2 O3 dominate the performance of chromium-containing amorphous refractory. That's still a hard task for product evaluation and quality control for amorphous refractory due to various component content, less available standard product and difficulty in fusion bead preparation. In the present study, series calibration standards were made from reagents and marked standards depend upon the content of components in real samples. The fusion bead was prepared with lithium tetraborate-lithium metaborate (67 : 33 by weight) as mixed flux and ammonium iodide as release agent, which was added during fusion process. The calibration curve derivated from the relationship between light intensity and components concentration and calibrated by theoretical alpha coefficient. The results of measurement were consistent with standard by this newly developed method. And good precision was also achieved in determination of real amorphous samples. It is easy in operation with less time spent, and practical in application. PMID- 22250571 TI - [A novel spectrum feature extraction method]. AB - The present focuses on the celestial spectra feature extraction problem, which is a key procedure in automatic spectra classification. By extracting features, the authors can reduce redundancy, alleviate noise influence, and improve accuracy and efficiency in spectra classification. The authors introduced a novel feature analysis framework STP (space transformation and partition), which focuses on four essential components in feature extraction: decompose and reorganize spectrum components, reorganize, alleviate noise influence and eliminate redundancy. Based on STP, we can analyze most of the available feature extraction methods, for example, the unsupervised methods principal component analysis (PCA), wavelet transform, the supervised methods support vector machine (SVM), relevance vector machine (RVM), linear discriminant analysis (LDA), etc. We introduced a novel feature analysis framework and proposed a novel feature extraction method. The outstanding characteristics of the proposed method are its simplicity and efficiency. Researches show that it is sufficient to extract features by the proposed method in some cases, and it is not necessary to use the sophisticated methods, which is usually more complex in computation. The proposed method is evaluated in classifying Galaxy and QSO spectra, which is disturbed by red shift and is representative in automatic spectra classification research. The results are practical and helpful to gain novel insight into the traditional feature extraction methods and design more efficient spectrum classification method. PMID- 22250572 TI - [Effect of spectrum distortion on modulation transfer function in imaging fiber optic spectrometer]. AB - Imaging fiber bundles were introduced to dispersion imaging spectrometer and substituted for slit, connecting the telescope and spectrometer to yield the imaging fiber-optic spectrometer. It is a double sampling system, the misalignment between image of optical fiber and detector pixel has arisen because of the spectrum distortion of spectrometer, which affected the second sampling process, and the modulation transfer function (MTF) therefore degraded. Optical transfer function of sampling process was derived from line spread function. The effect of spectrum distortion on system MTF was analyzed, and a model evaluating the MTF of imaging fiber-optic spectrometer was developed. Compared to the computation model of MTF of slit imaging spectrometer, a MTF item of sampling by optical fiber and a MTF item of misalignment arising from spectrum distortion were added in this model. Employing this, the MTF of an airborne imaging fiber optic spectrometer for visible near infrared band was evaluated. The approach ro deriving and developing the MTF model has a reference signification for the computation of MTF of double sampling system, which can direct the design of imaging fiber-optic spectrometer also. PMID- 22250573 TI - [Analysis of collimation error in Fourier transform infrared spectrometer based on step mirrors]. AB - The collimation error in Fourier transform spectrometer has many effects on the interferogram and the spectrogram. By means of modulation, the authors found the reverse of contrast in the interferogram and the side slope noise in the spectrogram due to the collimation error. The authors analyzed the signal-to noise ratio and resolution at different factor of beam divergence. When the factor of the beam divergence is 0.15 degrees x mm(-1), the signal-to-noise ratio can reduce to 6 dB and the resolution can go bad to 13.4 cm(-1). PMID- 22250574 TI - [Hadamard transform spectrometer mixed pixels' unmixing method]. AB - Hadamard transform imaging spectrometer is a multi-channel digital transform spectrometer detection technology, this paper based on digital micromirror array device (DMD) of the Hadamard transform spectrometer working principle and instrument structure, obtained by the imaging sensor mixed pixel were analyzed, theory derived the solution of pixel aliasing hybrid method, simulation results show that the method is simple and effective to improve the accuracy of mixed pixel spectrum more than 10% recovery. PMID- 22250575 TI - [A digital micromirror device-based Hadamard transform near infrared spectrometer]. AB - A Hadamard transform near infrared spectrometer based on a digital micromirror device was constructed. The optical signal was collected by optical fiber, a grating was used for light diffraction, a digital micromirror device (DMD) was applied instead of traditional mechanical Hadamard masks for optical modulation, and an InGaAs near infrared detector was used as the optic sensor. The original spectrum was recovered by fast Hadamard transform algrithms. The advantages of the spectrometer, such as high resolution, signal-noise-ratio, stability, sensitivity and response speed were proved by experiments, which indicated that it is very suitable for oil and food-safety applications. PMID- 22250576 TI - The tale of the hearts: deciding on abortion in Ethiopia. AB - In contemporary Ethiopia, abortion decision-making is a challenging process involving moral and/or religious dilemmas, as well as considerations of health and safety. Amidst widespread condemnation of female premarital sex and clear moral sanction against induced abortion, young Ethiopian women are nevertheless sexually active and induced abortions are still sought and performed, with the potential for grave physical harm and social stigmatization. This paper examines young unmarried Ethiopian women's narratives of abortion decision-making. In particular, it identifies and explores the operations of a particular discursive shape from within in such narratives, here described as The tale of the hearts. Analysing The tale of the hearts as a decision-making resource, it is argued, allows us to explore the particular, local, historical and cultural character of Ethiopian women's abortion decision-making dilemmas and the culturally available resources contributing to their resolution. PMID- 22250577 TI - An effective polymer cross-linking strategy to obtain stable dispersions of upconverting NaYF4 nanoparticles in buffers and biological growth media for biolabeling applications. AB - Ligands on the nanoparticle surface provide steric stabilization, resulting in good dispersion stability. However, because of their highly dynamic nature, they can be replaced irreversibly in buffers and biological medium, leading to poor colloidal stability. To overcome this, we report a simple and effective cross linking methodology to transfer oleate-stabilized upconverting NaYF(4) core/shell nanoparticles (UCNPs) from hydrophobic to aqueous phase, with long-term dispersion stability in buffers and biological medium. Amphiphilic poly(maleic anhydride-alt-1-octadecene) (PMAO) modified with and without poly(ethylene glycol) (PEG) was used to intercalate with the surface oleates, enabling the transfer of the UCNPs to water. The PMAO units on the phase transferred UCNPs were then successfully cross-linked using bis(hexamethylene)triamine (BHMT). The primary advantage of cross-linking of PMAO by BHMT is that it improves the stability of the UCNPs in water, physiological saline buffers, and biological growth media and in a wide range of pH values when compared to un-cross-linked PMAO. The cross-linked PMAO-BHMT coated UCNPs were found to be stable in water for more than 2 months and in physiological saline buffers for weeks, substantiating the effectiveness of cross-linking in providing high dispersion stability. The PMAO-BHMT cross-linked UCNPs were extensively characterized using various techniques providing supporting evidence for the cross-linking process. These UCNPs were found to be stable in serum supplemented growth medium (37 degrees C) for more than 2 days. Utilizing this, we demonstrate the uptake of cross-linked UCNPs by LNCaP cells (human prostate cancer cell line), showing their utility as biolabels. PMID- 22250580 TI - Clinical and magnetic resonance imaging features of canine compressive cervical myelopathy with suspected hydrated nucleus pulposus extrusion. AB - OBJECTIVE: To describe clinical and magnetic resonance imaging features in dogs with compressive cervical myelopathy due to acute suspected hydrated nucleus pulposus extrusion. DESIGN: Retrospective case series. ANIMALS: Ten dogs with compressive cervical myelopathy caused by acute suspected hydrated nucleus pulposus extrusion. MATERIALS AND METHODS: Medical records and magnetic resonance images of dogs evaluated from 2005 through 2010 were reviewed. The inclusion criteria were clinical signs compatible with cervical myelopathy, magnetic resonance imaging of the spine performed within 48 hours after onset, magnetic resonance imaging findings consistent with compressive suspected hydrated nucleus pulposus extrusion, complete medical records and follow-up information. RESULTS: Six dogs were presented with acute onset tetraplegia and four dogs with acute onset of nonambulatory tetraparesis. Compromised respiratory function was present in three dogs. Compressive suspected hydrated nucleus pulposus extrusion was found on magnetic resonance imaging at the C4-C5 (n=6), C3-C4 (n=3) and C5-C6 (n=1) intervertebral disc spaces. Seven dogs underwent surgical treatment and three dogs were treated conservatively. All dogs except one regained ambulatory status within two weeks after the onset, and had a favourable outcome. CLINICAL SIGNIFICANCE: Compressive myelopathy caused by acute suspected hydrated nucleus pulposus extrusion has not been reported previously and, even though neurological deficits can be severe on presentation, outcome is favourable. PMID- 22250581 TI - Quantitative variation in effector activity of ToxA isoforms from Stagonospora nodorum and Pyrenophora tritici-repentis. AB - ToxA is a proteinaceous necrotrophic effector produced by Stagonospora nodorum and Pyrenophora tritici-repentis. In this study, all eight mature isoforms of the ToxA protein were purified and compared. Circular dichroism spectra indicated that all isoforms were structurally intact and had indistinguishable secondary structural features. ToxA isoforms were infiltrated into wheat lines that carry the sensitivity gene Tsn1. It was observed that different wheat lines carrying identical Tsn1 alleles varied in sensitivity to ToxA. All ToxA isoforms induced necrosis when introduced into any Tsn1 wheat line but we observed quantitative variation in effector activity, with the least-active version found in isolates of P. tritici-repentis. Pathogen sporulation increased with higher doses of ToxA. The isoforms that induced the most rapid necrosis also induced the most sporulation, indicating that pathogen fitness is affected by differences in ToxA activity. We show that differences in toxin activity encoded by a single gene can contribute to the quantitative inheritance of necrotrophic virulence. Our findings support the hypothesis that the variation at ToxA results from selection that favors increased toxin activity. PMID- 22250582 TI - The GCR1 and GPA1 participate in promotion of Arabidopsis primary root elongation induced by N-acyl-homoserine lactones, the bacterial quorum-sensing signals. AB - Many gram-negative bacteria use N-acyl-homoserine lactones (AHL) as quorum sensing signals to coordinate their collective behaviors. Accumulating evidence indicates that plants can respond to AHL. However, little is known about the molecular mechanism of plants reacting to these bacterial signals. In this study, we show that the treatment of Arabidopsis roots with N-3-oxo-hexanoyl-homoserine lactone (3OC6-HSL) and N-3-oxo-octanoyl-homoserine lactone (3OC8-HSL) resulted in significant root elongation. The genetic analysis revealed that the T-DNA insertional mutants of gcr1, encoding a G-protein-coupled receptor GCR1, were insensitive to 3OC6-HSL or 3OC8-HSL in assays of root growth. The loss-of function mutants of the sole canonical Galpha subunit GPA1 showed no response to AHL promotion of root elongation whereas Galpha gain-of-function plants overexpressing either the wild type or a constitutively active version of Arabidopsis Galpha exhibited the exaggerated effect on root elongation caused by AHL. Furthermore, the expression of GCR1 and GPA1 were significantly upregulated after plants were contacted with both AHL. Taken together, our results suggest that GCR1 and GPA1 are involved in AHL-mediated elongation of Arabidopsis roots. This provides insight into the mechanism of plant responses to bacterial quorum sensing signals. PMID- 22250583 TI - Broad-spectrum acquired resistance in barley induced by the Pseudomonas pathosystem shares transcriptional components with Arabidopsis systemic acquired resistance. AB - Inducible resistance responses play a central role in the defense of plants against pathogen attack. Acquired resistance (AR) is induced alongside defense toward primary attack, providing broad-spectrum protection against subsequent pathogen challenge. The localization and molecular basis of AR in cereals is poorly understood, in contrast with the well-characterized systemic acquired resistance (SAR) response in Arabidopsis. Here, we use Pseudomonas syringae as a biological inducer of AR in barley, providing a clear frame of reference to the Arabidopsis-P. syringae pathosystem. Inoculation of barley leaf tissue with the nonadapted P. syringae pv. tomato avrRpm1 (PstavrRpm1) induced an active local defense response. Furthermore, inoculation of barley with PstavrRpm1 resulted in the induction of broad-spectrum AR at a distance from the local lesion, "adjacent" AR, effective against compatible isolates of P. syringae and Magnaporthe oryzae. Global transcriptional profiling of this adjacent AR revealed similarities with the transcriptional profile of SAR in Arabidopsis, as well as transcripts previously associated with chemically induced AR in cereals, suggesting that AR in barley and SAR in Arabidopsis may be mediated by analogous pathways. PMID- 22250584 TI - Sugarwin: a sugarcane insect-induced gene with antipathogenic activity. AB - In sugarcane fields, colonization of the stalk by opportunistic fungi usually occurs after the caterpillar Diatraea saccharalis attacks the sugarcane plant. Plants respond to insect attack by inducing and accumulating a large set of defense proteins. Two homologues of a barley wound-inducible protein (BARWIN), sugarcane wound-inducible proteins SUGARWIN1 and SUGARWIN2, have been identified in sugarcane by an in silico analysis. Antifungal properties have been described for a number of BARWIN homologues. We report that a SUGARWIN::green fluorescent protein fusion protein is located in the endoplasmic reticulum and in the extracellular space of sugarcane plants. The induction of sugarwin transcripts occurs in response to mechanical wounding, D. saccharalis damage, and methyl jasmonate treatment. The accumulation of transcripts is late induced and is restricted to the site of the wound. Although the transcripts of sugarwin genes were strongly increased following insect attack, the protein itself did not show any effect on insect development; rather, it altered fungal morphology, leading to the apoptosis of the germlings. These results suggest that, in the course of evolution, sugarwin-encoding genes were recruited by sugarcane due to their antipathogenic activity. We rationalize that sugarcane is able to induce sugarwin gene expression in response to D. saccharalis feeding as a concerted plant response to the anticipated invasion by the fungi that typically penetrate the plant stalk after insect damage. PMID- 22250586 TI - IGF-1 deficiency in combination with a low basic hBD-2 and hBD-3 gene expression might counteract malignant transformation in pleomorphic adenomas in vitro. AB - This study investigated the IGF-1-influence on oncological relevant genes in pleomorphic adenomas. Therefore A64-tumor cells were stimulated by recombinant IGF-1. After RNA-extraction, transcript levels of hBD-1, hBD-2, hBD-3, DEFA1/3, DEFA4, S100A4, Psoriasin, DOC-1, EGF, EGFR, and IGFR were analyzed by qRT-PCR at t = 0, 4, 8, 24, 48, and 72 hr. The gene-products were visualized by immunostaining. A64-tumor-cells were deficient for hBD-1 and IGF-1. IGF-1 downregulates hBD-2 and hBD-3 without influencing hBD-1-expression. IGF-1 only slightly affects DEFA1/3-, DEFA4-, S100A4-, Psoriasin-, DOC-1-, EGF-, EGFR-, and IGFR-gene-expression. IGF-1-deficiency combined with low basic hBD-2-gene expression and hBD-3-gene-expression might counteract, whereas hBD-1-deficiency promotes malignant transformation in pleomorphic adenomas. PMID- 22250585 TI - Drug-induced parkinsonism in the elderly: incidence, management and prevention. AB - Drug-induced parkinsonism (DIP) has been claimed to be the most prevalent cause of secondary parkinsonism in clinical practice in the Western world. Since the first descriptions in the early 1950s the prevalence of DIP seems to be increasing and approaching that of idiopathic Parkinson's disease (iPD) due to the aging of the population and the rising of polypharmacotherapy. Despite the wide interest this subject has raised in the past, it seems to be frequently overlooked by the medical community. It is particularly burdensome for the elderly and its management includes recognition of symptoms and identification of risk factors and offending agents. Prompt discontinuation of the causative agent leads to a marked improvement, although the condition might persist or remit slowly in up to 10% of the patients. Risk factors for developing DIP include older age; female sex; cognitive impairment; potency, dose and length of treatment; pre-existing extrapyramidal signs; and, very likely, a background of inherited predisposition. The main causative agents are dopamine receptor antagonists but the list of drugs without such a well known and straightforward mechanism of action is large. All antipsychotics, including atypicals (except clozapine) may produce parkinsonism. Although many drugs cause parkinsonism in a dose-related manner, there is an enormous variation in individual susceptibility. The clinical syndrome is less likely to produce tremor than iPD, and is more likely to be symmetrical, but the two syndromes might not be distinguished in any individual patient. Functional neuroimaging tests, which use ligands that bind to the dopamine transporter, are useful for distinguishing iPD from DIP in doubtful cases in patients treated with antipsychotics. The estimated presynaptic dopamine secreting neurons should be diminished in iPD but normal in DIP produced by dopamine receptor blockers, as assessed by molecular imaging techniques evaluating striatal dopamine transporters (DATs). Prompt recognition and discontinuation of the culprit are the keys to the management of DIP. In persistent cases, specific therapies including anticholinergics and amantadine may provide symptomatic relief. Levodopa and dopamine receptor agonists might be an option in selected cases in which dopamine nerve terminal defects are present. The weight and scope of DIP varies with the age and underlying health of the patient, imposing a significant burden on the elderly who, in many cases, experience significant functional deterioration that leads to hospitalization and has vast economic consequences. This article reviews the epidemiology, pathogenic mechanisms, implicated drugs, clinical features and management of DIP and highlights the need for increased awareness of this iatrogenic condition. PMID- 22250588 TI - Neurocognitive effects of chemotherapy and endocrine therapies in the treatment of breast cancer: recent perspectives. AB - With an estimated 207,090 patients diagnosed with breast cancer in 2010, the role of chemotherapy-induced cognitive impairment is of growing importance. Studies to determine the impact of chemotherapy-induced cognitive impairment have been hindered by difficulties in study-design, in particular, study methodology. Here, we present a review of existing studies and discuss several mechanisms for chemotherapy-induced neurocognitive impairment in breast cancer patients, such as direct neurotoxic injury, telomere shortening, oxidative stress, cytokine dysregulation, estrogen-mediated effects, and the role of certain genetic polymorphisms. Decreased estrogen levels may serve as a link between multiple mechanisms potentiating the effects of the chemotherapy-induced cognitive impairment. PMID- 22250587 TI - Loperamide, an FDA-approved antidiarrhea drug, effectively reverses the resistance of multidrug resistant MCF-7/MDR1 human breast cancer cells to doxorubicin-induced cytotoxicity. AB - Loperamide is an FDA-approved antidiarrhea drug which acts on the MU-opioid receptors in the mesenteric plexus of large intestine and exhibits limited side effects. We hypothesized that loperamide might reverse the multidrug resistance (MDR) of human cancer cells to chemotherapeutic agents. MCF-7/MDR1 cells express high level of MDR1 and are resistant to doxorubicin. We found that loperamide significantly enhanced the cytotoxicity of doxorubicin to MCF-7/MDR1 cells in a dose-dependent manner. In conclusion, loperamide reversed the resistance of MCF 7/MDR1 cells to doxorubicin, suggesting that chemotherapy in combination with loperamide may benefit patients with MDR tumors once applied in clinic. PMID- 22250589 TI - Quality of life and toxicity of stereotactic radiotherapy in pancreatic tumors: a case series. AB - AIM: To analyze the results of extracranial stereotactic radiotherapy (ESRT) experience in pancreatic cancer patients. METHODS: Four noncoplanar fixed beams were used in all patients. RESULTS: Analysis of 16 patients was carried out. Overall response rate was 56.2%. Fifteen patients experienced local and/or distant progression of disease (median follow-up: 24 months). Two-year local progression-free, distant progression-free, and overall survivals were 85.7%, 58.7%, and 50.0%, respectively. Toxicity was less than grade 2 in all, although 1 patient had severe duodenal bleeding. Quality of life scores were unchanged. CONCLUSIONS: ESRT was associated with low complication rate, and not worsening the patients' quality of life. PMID- 22250590 TI - Validation of the Chinese version of the Life Orientation Test with a robust weighted least squares approach. AB - Of the several measures of optimism presently available in the literature, the Life Orientation Test (LOT; Scheier & Carver, 1985) has been the most widely used in empirical research. This article explores, confirms, and cross-validates the factor structure of the Chinese version of the LOT with ordinal data by using robust weighted least squares (robust WLS) estimation within the Taiwanese cultural context. Results of exploratory and confirmatory factor analyses using 3 different samples (N(total) = 1,119) show that the factor structure of the Chinese version of the LOT is better conceptualized as a correlated 2-factor model than a single-factor model. The composite reliability was 0.7 for the "disagreement on optimism" factor and 0.74 for the "agreement on optimism" factor. In addition, comparison results of the 2 estimators using empirical data and simulation data suggest that robust WLS is less biased than maximum likelihood (ML) for estimating factor loadings and interfactor correlations in the factor analytic model of the Chinese version of the LOT. PMID- 22250591 TI - The positivity scale. AB - Five studies document the validity of a new 8-item scale designed to measure positivity, defined as the tendency to view life and experiences with a positive outlook. In the first study (N = 372), the psychometric properties of Positivity Scale (P Scale) were examined in accordance with classical test theory using a large number of college participants. In Study 2, the unidimensionality of the P Scale was corroborated with confirmatory factor analysis in 2 independent samples (N1 = 322; N2 = 457). In Study 3, P Scale invariance across sexes and its relations with self-esteem, life satisfaction, optimism, positive negative affect, depression, and the Big Five provided further evidence of the internal and construct validity of the new measure in a large community sample (N = 3,589). In Study 4, test-retest reliability of the P Scale was found in a sample of college students (N = 262) who were readministered the scale after 5 weeks. In Study 5, measurement invariance and construct validity of P Scale were further supported across samples in different countries and cultures, including Italy (N = 689), the United States (N = 1,187), Japan (N = 281), and Spain (N = 302). Psychometric findings across diverse cultural context attest to the robustness of the P Scale and to positivity as a basic disposition. PMID- 22250592 TI - Development and initial validation of the Adolescent Responses to Body Dissatisfaction measure. AB - One community sample (N = 607) of youths generated self-reported responses to body dissatisfaction, from which the Adolescent Responses to Body Dissatisfaction (ARBD) inventory was constructed. A 2nd, similar sample (N = 830) completed this measure as well as measures of coping, body dissatisfaction, body mass index, depressive symptoms, and disordered eating behaviors. Evidence of 6 ARBD factors emerged: Self-Acceptance, Compensatory Thinking, Diet/Exercise, Anxious Responding, Appearance Strategies, and Social Comparison. Subscales based on these factors provided evidence of convergent, discriminant, construct, and incremental validity. Sex and ethnic differences were also evident. Adolescents' use of Self-Acceptance and Compensatory Thinking strategies appeared to attenuate the relation between body dissatisfaction and psychopathology, whereas use of Diet/Exercise and Anxious Responding appeared to exacerbate this relation, especially in adolescents who were not overweight. The ARBD provides a window into potentially healthy and unhealthy ways in which adolescents cope with body dissatisfaction. PMID- 22250593 TI - Anger and postcombat mental health: validation of a brief anger measure with U.S. soldiers postdeployed from Iraq and Afghanistan. AB - The involvement of anger in the psychological adjustment of current war veterans, particularly in conjunction with combat-related posttraumatic stress disorder (PTSD), warrants greater research focus than it has received. The present study concerns a brief anger measure, Dimensions of Anger Reactions (DAR), intended for use in large sample studies and as a screening tool. The concurrent validity, discriminant validity, and incremental validity of the instrument were examined in conjunction with behavioral health data for 3,528 treatment-seeking soldiers who had been in combat in Iraq and Afghanistan. Criterion indices included multiple self-rated measures of psychological distress (including PTSD, depression, and anxiety), functional difficulties (relationships, daily activities, work problems, and substance use), and violence risk. Concurrent validity was established by strong correlations with single anger items on 4 other scales, and discriminant validity was found against anxiety and depression measures. Pertinent to the construct of anger, the DAR was significantly associated with psychosocial functional difficulties and with several indices of harm to self and to others. Hierarchical regression performed on a self/others harm index found incremental validity for the DAR, controlling for age, education, military component, officer rank, combat exposure, PTSD, and depression. The ability to efficiently assess anger in at-risk military populations can provide an indicator of many undesirable behavioral health outcomes. PMID- 22250594 TI - Development of a measure of the experience of being bullied in youth. AB - The Personal Experiences Checklist (PECK) was developed to provide a multidimensional assessment of a young person's personal experience of being bullied that covered the full range of bullying behaviors, including covert relational forms of bullying and cyber bullying. A sample of 647 school children were used to develop the scale, and a 2nd sample of 218 children completed the PECK and a battery of measures of bullying (including peer nomination), anxiety, depression, and self-esteem, to provide validity evidence. Test-retest reliability was assessed in a further sample of 78 students. Four factors emerged from a principal axis factoring consistent with the domains of relational-verbal bullying, cyber bullying, physical bullying, and bullying based on culture and were confirmed with confirmatory factor analysis. The data also supported a higher order bullying factor with direct effects on these 4 factors. All PECK scales showed good to excellent internal consistency (Cronbach's alpha range = .78-.91) and adequate test-retest reliability (range r = .61-.86). Most, but not all, expected relations were found with alternative methods of assessing bullying and measures of psychopathology. Taken together, the PECK provides a promising comprehensive and behaviorally focused dimensional measure of bullying. PMID- 22250595 TI - Using dynamic risk and protective factors to predict inpatient aggression: reliability and validity of START assessments. AB - The Short-Term Assessment of Risk and Treatability (START; C. D. Webster, M. L. Martin, J. Brink, T. L. Nicholls, & S. L. Desmarais, 2009; C. D. Webster, M. L. Martin, J. Brink, T. L. Nicholls, & C. Middleton, 2004) is a relatively new structured professional judgment guide for the assessment and management of short term risks associated with mental, substance use, and personality disorders. The scheme may be distinguished from other violence risk assessment instruments because of its inclusion of 20 dynamic factors that are rated in terms of both vulnerability and strength. This study examined the reliability and validity of START assessments in predicting inpatient aggression. Research assistants completed START assessments for 120 male forensic psychiatric patients through review of hospital files. They also completed Historical-Clinical-Risk Management 20 (HCR-20; C. D. Webster, K. S. Douglas, D. Eaves, & S. D. Hart, 1997) and Hare Psychopathy Checklist: Screening Version (PCL:SV; S. D. Hart, D. N. Cox, & R. D. Hare, 1995) assessments. Outcome data were coded from hospital files for a 12 month follow-up period using the Overt Aggression Scale (OAS; S. C. Yudofsky, J. M. Silver, W. Jackson, J. Endicott, & D. W. Williams, 1986). START assessments evidenced excellent interrater reliability and demonstrated both predictive and incremental validity over the HCR-20 Historical subscale scores and PCL:SV total scores. Overall, results support the reliability and validity of START assessments and use of the structured professional judgment approach more broadly, as well as the value of using dynamic risk and protective factors to assess violence risk. PMID- 22250596 TI - A comparison of diversity, frequency, and severity self-reported offending scores among female offending youth. AB - [Correction Notice: An Erratum for this article was reported in Vol 24(3) of Psychological Assessment (see record 2012-04601-001). The article contained a number of errors which are corrected in the erratum.] Despite general consensus over the value of measuring self-reported offending, discrepancies exist in methods of scoring self-reported offending and the length of the reference period over which offending is assessed. This analysis compared the concurrent interassociations and longitudinal predictive strength of diversity, frequency, and severity offending scores measured over the past 6 months and diversity and severity scores measured "ever" between assessments. For violent offending, different scorings were highly correlated and equally predictive of adulthood offending. For nonviolent offending, there was significant continuity in diversity and severity-weighted diversity scores over the transition to adulthood but not in nonviolent frequency or severity-weighted frequency scores. Results support the use of offending diversity scores rather than offending frequency scores and highlight the importance of examining nonviolent and violent offending as separate constructs. PMID- 22250597 TI - Compliance to a cell phone-based ecological momentary assessment study: the effect of time and personality characteristics. AB - Ecological momentary assessment (EMA) is a method that is now widely used to study behavior and mood in the settings in which they naturally occur. It maximizes ecological validity and avoids the limitations of retrospective self reports. Compliance patterns across time have not been studied. Consistent compliance patterns could lead to data not missing at random and bias the results of subsequent analyses. In order to use modern statistical approaches for handling missing data, it is important to include variables predicting missing values into the statistical analysis. Therefore, these predictors have to be known and measured. The authors collected data on 3 four-item mood scales measuring well-being, wakefulness, and nervousness on 6 occasions per day for 7 days (N = 305) and examined compliance rate across time, within day, and within week. Results show good global compliance (mean compliance: 74.9% of calls answered). Compliance varied more within day than within week. Within day, it was lower for the first call of the day between 9 p.m. and 11 p.m. and higher for the call between 5 p.m. and 7 p.m. Within week, calls were equally answered across days of the week, but, as the study progressed, there was a slight drop in compliance with a progressive decrease that was stronger for the first 2 calls. Compliance on the person level did not depend on personality or on satisfaction with life. Practical consequences of the results for conducting ambulatory assessment studies are discussed, and some recommendations are given. PMID- 22250598 TI - Development and validation of Big Four personality scales for the Schedule for Nonadaptive and Adaptive Personality--Second Edition (SNAP-2). AB - Recently, integrative, hierarchical models of personality and personality disorder (PD)--such as the Big Three, Big Four, and Big Five trait models--have gained support as a unifying dimensional framework for describing PD. However, no measures to date can simultaneously represent each of these potentially interesting levels of the personality hierarchy. To unify these measurement models psychometrically, we sought to develop Big Five trait scales within the Schedule for Nonadaptive and Adaptive Personality--Second Edition (SNAP-2). Through structural and content analyses, we examined relations between the SNAP 2, the Big Five Inventory (BFI), and the NEO Five-Factor Inventory (NEO-FFI) ratings in a large data set (N = 8,690), including clinical, military, college, and community participants. Results yielded scales consistent with the Big Four model of personality (i.e., Neuroticism, Conscientiousness, Introversion, and Antagonism) and not the Big Five, as there were insufficient items related to Openness. Resulting scale scores demonstrated strong internal consistency and temporal stability. Structural validity and external validity were supported by strong convergent and discriminant validity patterns between Big Four scale scores and other personality trait scores and expectable patterns of self-peer agreement. Descriptive statistics and community-based norms are provided. The SNAP-2 Big Four Scales enable researchers and clinicians to assess personality at multiple levels of the trait hierarchy and facilitate comparisons among competing big-trait models. PMID- 22250599 TI - Comparative study on the antioxidant activities of the different extracts and the composition of the oil extracted by n-hexane from Iranian Vitex pseudo-negundo. AB - Antioxidant activities of different extracts obtained from the aerial parts of Vitex pseudo-negundo from Kashan, central Iran, were evaluated for the first time in this study using beta-carotene/linoleic acid and scavenging of free-radical (DPPH) assays. Water extract showed the highest activity in both assays. GC-MS analysis of the oil extracted by n-hexane revealed 46 compounds with trans-beta farnesene being the main component. Several new compounds, not reported in the previous literature, were identified in the essential oil of this chemo-type. PMID- 22250600 TI - The impact of depression and sense of coherence on emotional and social loneliness among nursing home residents without cognitive impairment - a questionnaire survey. AB - AIMS AND OBJECTIVES: To analyse the relationships between depressive symptoms, sense of coherence and emotional and social loneliness among nursing home residents without cognitive impairment. BACKGROUND: Depression symptoms and loneliness are major health problems for older people. Sense of coherence, which is based on a salutogenic theoretical framework, is a strong determinant of positive health and successful coping and is associated with well-being and depression among older people. Few studies have explored the relationships between depression symptoms, sense of coherence and emotional and social loneliness among nursing home residents. DESIGN: A cross-sectional, descriptive, correlational design. METHODS: Sample - 227 residents 65-102 years old from 30 nursing home residing >= six months. All had a Clinical Dementia Rating <= 0.5 and could converse. Residents were interviewed using the Social Provisions Scale, Geriatric Depression Scale and Sense of Coherence Scale (SOC-13). Possible relationships between these were analysed, controlled for sex, age, marital status, education, length of stay and comorbidity. RESULTS: Before adjustment, Geriatric Depression Scale was associated with attachment and social integration. After adjustment, Geriatric Depression Scale was still associated with attachment and social integration. Further adjusting for Sense of Coherence Scale reduced the association between Geriatric Depression Scale and attachment and even more so for the association between Geriatric Depression Scale and social integration. Sense of coherence and Geriatric Depression Scale did not interact, and SOC-13 was associated with attachment and social integration. CONCLUSIONS: Depression symptoms contribute to emotional and social loneliness. Independent of sense of coherence, depression symptoms are associated with emotional loneliness, sense of coherence influence emotional and social loneliness. RELEVANCE TO CLINICAL PRACTICE: Clinical nurses should observe residents closely for signs of depression and loneliness and support their sense of coherence to reduce emotional and social loneliness. PMID- 22250601 TI - Cytologic features and diagnostic accuracy of analysis of effusions for detection of ovarian carcinoma in dogs. AB - BACKGROUND: Presence of an abdominal effusion is a typical presenting sign associated with ovarian carcinoma (OC) in dogs. OBJECTIVES: The aims of this study were to describe the cytologic features of effusions associated with OC and to evaluate the diagnostic accuracy of such features for the diagnosis of OC in dogs. METHODS: Cytologic evaluations of 7 OC-associated peritoneal effusions in dogs were used to define cytomorphologic features of this neoplasm. Then, in a blinded study to evaluate the accuracy of these features in identifying OC, 2 independent board-certified clinical pathologists reviewed 82 pleural, pericardial, and abdominal effusions resulting from OC (n = 7), other neoplasms (n = 40), and non-neoplastic disorders (n = 35). The clinical pathologists were instructed to identify all samples containing papillary structures typically seen in OC and then apply the cytomorphologic criteria determined in the first part of the study to diagnose OC. RESULTS: Effusions associated with OC contained blood and had moderate to high cellularity, with neoplastic cells arranged in a prominent papillary pattern in which intercellular spaces were not clearly evident. Individual cells were approximately 30 MUm in diameter, with mild anisocytosis and anisokaryosis, moderate amounts of pale blue cytoplasm, and round to oval paracentral nuclei with fine chromatin and poorly distinct small nucleoli. Using these cytologic features to identify OC in the 82 effusions, sensitivity was 86% and 100% and specificity was 57% and 97% for the 2 clinical pathologists. Overall accuracies in distinguishing OC from other effusions were 98.8% and 93.9%. CONCLUSION: Based on this preliminary study, effusion cytology from intact female dogs affected by OC appears to be useful in suggesting a diagnosis of neoplasia. The presence of cells with a prominent and uniform papillary pattern in peritoneal and pleural effusions in dogs with appropriate signalment and clinical signs should prompt a search for primary ovarian neoplasia. PMID- 22250602 TI - Production methodologies of polymeric and hydrogel particles for drug delivery applications. AB - INTRODUCTION: Polymeric particles are ideal vehicles for controlled delivery applications due to their ability to encapsulate a variety of substances, namely low- and high-molecular mass therapeutics, antigens or DNA. Micro and nano scale spherical materials have been developed as carriers for therapies, using appropriated methodologies, in order to achieve a prolonged and controlled drug administration. AREAS COVERED: This paper reviews the methodologies used for the production of polymeric micro/nanoparticles. Emulsions, phase separation, spray drying, ionic gelation, polyelectrolyte complexation and supercritical fluids precipitation are all widely used processes for polymeric micro/nanoencapsulation. This paper also discusses the recent developments and patents reported in this field. Other less conventional methodologies are also described, such as the use of superhydrophobic substrates to produce hydrogel and polymeric particulate biomaterials. EXPERT OPINION: Polymeric drug delivery systems have gained increased importance due to the need for improving the efficiency and versatility of existing therapies. This allows the development of innovative concepts that could create more efficient systems, which in turn may address many healthcare needs worldwide. The existing methods to produce polymeric release systems have some critical drawbacks, which compromise the efficiency of these techniques. Improvements and development of new methodologies could be achieved by using multidisciplinary approaches and tools taken from other subjects, including nanotechnologies, biomimetics, tissue engineering, polymer science or microfluidics. PMID- 22250603 TI - Multiplex reverse transcription polymerase chain reaction to study the expression of virulence and stress response genes in Staphylococcus aureus. AB - Staphylococcus aureus survives well in different stress conditions. The ability of this organism to adapt to various stresses is the result of a complex regulatory response, which is attributed to regulation of multiple genes. The aims of the present study were (1) to develop a multiplex PCR for the detection of genes which are involved in stress adaptation (asp23, dnaK, and groEL); alternative sigma factor (sigB) and virulence determination (entB and spa) and (2) to study the expression of these genes during stress conditions for S. aureus culture collection strains (FRI 722 and ATCC 6538) and S. aureus food isolates at mRNA level using multiplex reverse transcription polymerase chain reaction (RT PCR). During heat shock treatment groEL, dnaK, asp23, sodA, entB, spa, and sigB genes were up regulated up to 2.58, 2.07, 2.76, 2.55, 3.55, 2.71, and 2.62- folds, respectively, whereas in acid shock treatment, sodA and groEL were up regulated; dnaK was downregulated; and entB and sigB genes were not expressed in food isolates. Multiplex PCR assay standardized in this study offers an inexpensive alternative to uniplex PCR for detection of various virulence and stress response genes. This study is relevant to rapid and accurate detection of potential pathogenic S. aureus in foods. PMID- 22250604 TI - Non-pharmacological intervention for dementia patients. PMID- 22250605 TI - Negative impact of migraine on quality of life after 4 weeks of treatment in patients with major depressive disorder. AB - AIM: The impact of migraine on health-related quality of life (HRQoL) among patients with major depressive disorder (MDD) after acute antidepressant treatment has not been addressed. The aim of the present study was to investigate whether or not the negative impact of migraine on HRQoL among outpatients with MDD continued to have an effect after 4 weeks of venlafaxine treatment. METHODS: A total of 135 outpatients with MDD were enrolled, who were then treated with venlafaxine 75 mg per day for 4 weeks in the present open-label study. Migraine was diagnosed based on the International Classification of Headache Disorders (2nd edn). Changes in Short-Form 36 (SF-36) and Hamilton Depression Rating Scale (HAMD) scores were the outcome measures. Multiple linear regression was used to assess whether migraine was an independent factor predicting SF-36 score after treatment. RESULTS: Seventy-two participants (18M/54F) completed the 4-week treatment. Subjects with migraine had a poorer HRQoL in terms of bodily pain and mental health at baseline. Subjects with and without migraine showed significant improvement in all SF-36 subscales and depression after treatment, but subjects with migraine still had a poorer HRQoL regarding bodily pain and physical functioning after treatment as compared with those without migraine. Migraine could predict a negative outcome after treatment in the subscales of physical functioning, role limitations-physical, and role limitations-emotional. CONCLUSIONS: Migraine may have a negative impact on the improvement of partial SF 36 subscales, especially on functional recovery, after acute treatment among outpatients with MDD. Whether additional intervention besides antidepressant treatment for migraine is indicated may need further study. PMID- 22250606 TI - Medical students' beliefs and attitudes towards schizophrenia before and after undergraduate psychiatric training in Greece. AB - AIMS: The aim of the present study was to explore medical students' beliefs and attitudes towards people with schizophrenia (PwS) prior to receiving any training in psychiatry and to assess the impact of the psychiatric placement on changing them. METHODS: A questionnaire addressing beliefs, attitudes and desired social distance from PwS was distributed to all final year medical students before the beginning of their 4-week undergraduate psychiatric placement and upon its completion. RESULTS: Students did not endorse stereotypes commonly attached to PwS, such as being dangerous, lazy or of lower intelligence, but they held the view that PwS are unpredictable and suffer from split personality. Furthermore, the baseline level of desired social distance was found to increase as the intimacy of the interaction increased, and the only variable associated with it was personal experience of serious mental illness. Moreover, the placement was found to have either no influence at all or in a negative direction. Upon its completion more students were found to believe that PwS cannot recover, have no insight into their condition, cannot make reasonable decisions, cannot work in regular jobs and are dangerous to the public. No difference was recorded in social distance scores. CONCLUSIONS: A close and critical examination of the various elements of the undergraduate placement in psychiatry is needed in order to develop an evidence-based, fully rounded education with an anti-stigma orientation. PMID- 22250607 TI - Multi-channel near-infrared spectroscopy shows reduced activation in the prefrontal cortex during facial expression processing in pervasive developmental disorder. AB - AIM: The purpose of the present study was to investigate whether individuals with pervasive developmental disorders (PDD) show differential activation during an emotional activation task compared with age- and sex-matched controls, by measuring changes in the concentration of oxygenated (oxyHb) and deoxygenated (deoxyHb) hemoglobin, using near-infrared spectroscopy (NIRS). METHODS: Fourteen patients with PDD and 14 age- and sex-matched healthy controls participated in the study. The relative changes of concentrations of oxyHb and deoxyHb were measured on NIRS during an implicit processing task of fearful expression using Japanese standard faces. RESULTS: PDD patients had significantly reduced oxyHb changes in the prefrontal cortex (PFC) compared to healthy controls. CONCLUSION: PFC dysfunction may exist in PDD. PMID- 22250608 TI - Reduced left uncinate fasciculus fractional anisotropy in deficit schizophrenia but not in non-deficit schizophrenia. AB - AIMS: Schizophrenia is a psychiatric disorder manifesting with heterogeneous symptom clusters and clinical presentations. The deficit syndrome is the condition defined by the existence of primarily negative symptoms, and patients with the deficit syndrome differ from non-deficit patients on measures of brain structure and function. In the current study, by using diffusion tensor imaging (DTI), we investigated the frontotemporal connectivity that is hypothesized to differ between deficit and non-deficit schizophrenia. METHODS: Twenty-nine patients and 17 healthy controls were included in the study. The patients had deficit (n = 11) or non-deficit (n = 18) schizophrenia and they were evaluated clinically with the Schedule for Deficit Syndrome (SDS) and Positive and Negative Syndrome Scale (PANSS). Diffusion-based images were obtained with a 1.5T Siemens Magnetic Resonance Imaging machine and analyses were carried out with Functional Magnetic Resonance Imaging of the Brain Library Software - Diffusion tool box software. RESULTS: The fractional anisotropy values in the left uncinate fasciculus of schizophrenia patients with the deficit syndrome were lower than those of non-deficit patients and the controls. There were no differences between non-deficit schizophrenia patients and controls. CONCLUSION: These findings provide evidence of left uncinate fasciculus damage resulting in disrupted communication between orbitofrontal prefrontal areas and temporal areas in deficit schizophrenia patients. PMID- 22250609 TI - Acute and transient psychotic disorders versus persistent delusional disorders: a comparative longitudinal study. AB - AIM: The aim of this work is to investigate differences between two non schizophrenic, non-organic psychotic disorders, namely persistent delusional disorders (PDD) and acute and transient psychotic disorders (ATPD) according to ICD-10. METHOD: In a prospective and longitudinal study, we compared all 43 inpatients with PDD who were treated at Halle-Wittenberg University Hospital during a 14-year period to a previously investigated cohort of 41 patients with ATPD in regard to demography, long-term symptomatic outcome, and social consequences. Sociobiographical data were collected using a semi-structured interview. Follow-up investigations were performed at a mean of 10-12 years after the onset of the disorder using standardized instruments. RESULTS: With the exception of the duration of the psychotic symptoms, the PDD patients were significantly different from the ATPD patients on various levels, such as sex ratio (female predominance only in ATPD), age at onset (older in PDD), the number of preceding stressful life-events in the index hospitalization (more frequent in ATPD), richness and variety of symptoms (higher in ATPD), and persistence of positive psychotic symptoms (in PDD). Patients with PDD had significantly less re hospitalizations during the course of their illness. Long-term outcome was marked by chronicity of delusional symptoms and lower global functioning in PDD than in ATPD, while negative symptoms and loss of independence were infrequent in both conditions. CONCLUSIONS: PDD differs from ATPD not only in the duration of the psychotic symptoms, but also in a variety of significant variables. They appear to be two separate entities within a psychotic spectrum. PMID- 22250610 TI - Naturalistic exploration of the effect of osmotic release oral system methylphenidate on remission rate and functional improvement in Taiwanese children with attention-deficit-hyperactivity disorder. AB - AIM: To determine the differences in the remission rate, recovery rate, functional improvement, and treatment adherence related to treatment with short acting immediate-release methylphenidate (IR-MPH) and long-acting osmotic-release oral system-methylphenidate (OROS-MPH) in a naturalistic setting among Taiwanese children with attention-deficit-hyperactivity disorder (ADHD). METHODS: A total of 757 children with ADHD, aged 6-18 years, was evaluated using the following in order determine functional improvement and treatment adherence: the Chinese version of the Swanson, Nolan, and Pelham, version IV scale (SNAP-IV-C), Clinical Global Impression-ADHD-Severity (CGI-S) to measure remission and recovery rates, the Chinese version of the Social Adjustment Inventory for Children and Adolescents (CSAICA), and caregiver's satisfaction rate, treatment adherence, and frequency of adverse effects. RESULTS: According to the SNAP-IV-C scores, the remission rate was 30.72%, and the recovery rate was 16.38%. Compared to short acting IR-MPH, OROS-MPH was associated with greater functional improvement and treatment adherence among children with ADHD. CONCLUSION: OROS-MPH treatment at the adequate dosage can achieve higher remission and recovery rates, produce greater functional improvement, and result in better treatment adherence than IR MPH treatment. PMID- 22250611 TI - Prevalence and relation of dementia to various factors in Parkinson's disease. AB - AIMS: Parkinson's disease is a chronic neurodegenerative disorder characterized by bradykinesia, rigidity, and resting tremor. Dementia, among its non-motor symptoms, is a debilitating complication affecting intellectual functioning. The aim of the present study was to determine the prevalence of dementia in Parkinson's disease and its relation to age, gender and stage of the disease. METHODS: A retrospective chart analysis was performed on Parkinson's disease patients seen in a community-based Parkinson's disease and movement disorder clinic between 2005 and 2010. RESULTS: A total of 310 patients were included in this survey, among whom 61 patients (19.7%) with Parkinson's disease met the criteria for dementia. Age was found to be a significant factor in developing dementia, with 90% of patients with dementia aged >=70. Gender, however, was not correlated with dementia in Parkinson's disease. On analysis of stage at which dementia developed, progression of the disease was positively correlated with prevalence of dementia. CONCLUSIONS: As age increases, the chances of developing dementia increase. Dementia, contrarily, is not selective between genders. The likelihood of developing dementia increases as the stage of disease advances. Further research is required in order to understand underlying mechanisms of dementia in Parkinson's disease. PMID- 22250612 TI - Hyperprolactinemia induced by low-dosage amisulpride in Korean psychiatric patients. AB - AIM: Amisulpride at low dosages enhances dopaminergic neurotransmission by preferentially blocking presynaptic D2/D3 receptors. Thus, low dosages of amisulpride are expected not to increase prolactin levels. The aim of this study was to examine whether low dosages of amisulpride can increase serum levels of prolactin or not clinically in Korean patients. METHOD: Serum prolactin levels were measured in 20 Korean patients (12 men and eight women) with various diagnoses who were treated with less than 300 mg of amisulpride per day. RESULTS: The mean dosage of amisulpride was 195.0 +/- 51.0 mg/day, and serum level of prolactin was 76.1 +/- 43.4 ng/mL. The prolactin level was significantly higher in women (110.7 +/- 49.3 ng/mL) than in men (53.1 +/- 15.9 ng/mL) after administering amisulpride (P = 0.021), while the dosage of amisulpride did not differ significantly between men (200.0 +/- 42.6 mg/day) and women (187.5 +/- 64.1 mg/day) (P = 0.576). CONCLUSIONS: The low dosages of amisulpride elevate serum prolactin level in the majority of patients. This finding indicates that the dose-reduction of amisulpride has little effect to relieve amisulpride induced hyperprolactinemia at therapeutic dosages. Clinicians should monitor serum prolactin level even when low dosages of amisulpride are administered. PMID- 22250613 TI - Usefulness of reminiscence therapy for community mental health. AB - Reminiscence therapy workshops for health-care professionals (total, n = 105: four trainees in their 20, seven in their 30s, 13 in their 40s, 30 in their 50s, 41 in their 60, five in their 70s, one in their 80s, and four of unknown age) were held, and group work with reminiscence therapy was provided to local residents (total, n = 151; mean age, 73.6 +/- 10.6 years). Comparison of pre- and post-workshop questionnaires showed that rates of interest and understanding of trainees increased after the workshop. Concerning group work, 89.2% of the participants felt that reminiscence therapy would prove helpful in their life. Reminiscence therapy may be useful in improving mental health in local residents. PMID- 22250614 TI - Mirtazapine as an alternative for selective-serotonin-reuptake-inhibitor-induced syndrome of inappropriate secretion of antidiuretic hormone. PMID- 22250615 TI - Case of bilateral self-enucleation in Korea. PMID- 22250616 TI - Augmentation with ramelteon to achieve remission in geriatric major depression. PMID- 22250617 TI - Is melatonin an adjunctive stabilizer? PMID- 22250618 TI - Resumption of food and fluid intake in Alzheimer's disease with severe apathy following intravenous citalopram. PMID- 22250619 TI - Posttreatment quantification of patient experiences with full-arch implant treatment using a modification of the OHIP-14 questionnaire. AB - Patient well-being is always the goal of rehabilitation of edentulism; however, evaluations of treatment success often overlook the patient's subjective feelings about comfort, function, speech, social image, social inhibitions, psychological discomfort, and/or disabilities. The purpose of this study was to assess these patient responses using an oral health questionnaire. To assess such feelings, a self-administered 20-question multiple-choice patient-reported Edentulous Patient Impact Questionnaire was developed, based upon the previously validated Oral Health Impact Profile patient-assessment tool. Responses were solicited from randomly selected patients treated with an implant-supported, fixed, immediately loaded full arch prosthesis. The questionnaires were completed by 250 patients. Of the respondents, 95% described themselves as being either extremely satisfied (74%) or satisfied (21%) with their new teeth, and 98% said they would definitely recommend similar treatment (88%) or consider recommending it (10%) to a friend or colleague. Based upon an oral health impact survey completed by 250 patients treated with full-arch implant-supported, immediately loaded fixed dental prostheses, it appears that patient satisfaction is high and that treated patients would generally be willing to recommend this treatment to others. PMID- 22250620 TI - Dermatologic infestations. AB - Head lice are transmitted by head to head contact. Optimal therapy includes malathion lotion 0.5% repeated in one week left on for 30 minutes to 8 hours. Spinosad topical suspension 0.9% repeated in one week left on for 10 minutes is another option. Scabies is transmitted mainly by direct contact but also via heavily infested fomites due to crusted scabies. Permethrin 5% cream to the body repeated in four days is often sufficient; however, scalp treatment with malathion lotion 0.5% is helpful in crusted scabies and in infested children. Oral ivermectin 200 mcg/kg is another option, repeated in four days. For scabies more than lice, fomites should be placed in a drier at 60 degrees C for 10 minutes to kill the arthropods. Treatment of close contacts in both cases will control outbreaks and repeated infestations. Both have been associated with methicillin-resistant Staphylococcus aureus infection. Bed bugs are a common cause for papular urticaria. Identification of the insect in the mattress or bedding confirms the diagnosis. Prevention involves encasing the mattress in a sealed plastic cover and extermination. Delusions of parasitosis is a diagnosis of exclusion that is best treated with an antipsychotic. PMID- 22250621 TI - Idiopathic granulomatous lobular mastitis. AB - Idiopathic granulomatous lobular mastitis (IGLM) is a rare breast condition with prominent skin findings. It is typically seen in young parous women. Painful breast masses, draining sinuses, scarring, and breast atrophy are the main clinical manifestations. IGLM can resemble a variety of other inflammatory and neoplastic processes of the breast. It is thought to result from obstruction and rupture of breast lobules. Extravasated breast secretions then induce an inflammatory reaction. Corynebacteria have also been implicated in the pathogenesis. Treatment is surgical, but systemic corticosteroids, methotrexate, and antibiotics also play a role. PMID- 22250622 TI - Prurigo pigmentosa in Korea: clinicopathological study. AB - BACKGROUND: Prurigo pigmentosa (PP) is an inflammatory dermatosis characterized by recurrent pruritic erythematous papules, mainly located on the trunk. It was first described by Nagashima in 1971 in Japan. Since then, more than 300 cases have been reported in Japan, but reports from other parts of the world are quite rare. MATERIALS AND METHODS: We studied clinical and histopathological data from six patients with PP diagnosed in our hospital and 43 patients (18 reports) who were diagnosed with PP in Korea between 1988 and 2008. RESULTS: The number of Korean patients reported in recent years is higher than the number of other non Japanese patients reported. Clinicopathological characteristics in Korean patients were not significantly different from those previously reported. Therapeutic results with minocycline were successful in our patients. CONCLUSIONS: We suspect that PP is not uncommon in Korea, and the disease may be underestimated. Strict restriction of diet as well as known associated factors like wet condition are suggested as one of the important factors contributing to the occurrence of PP in Korea. PMID- 22250623 TI - Quality of life among Malaysian patients with vitiligo. AB - BACKGROUND: Vitiligo is a chronic disease and can have significant impairment on patients' quality of life (QoL). Studies have shown that limitations in QoL are similar in magnitude to patients with other chronic skin diseases like psoriasis. The objective of this study was to assess the quality of life (QoL) of patients with vitiligo attending the dermatology clinic of a tertiary hospital in Malaysia. METHODS: All patients with a clinical diagnosis of vitiligo who were seen at our dermatology clinic and phototherapy daycare center from September 15 to November 20, 2009 were invited to participate. RESULTS: A total of 102 patients with vitiligo were included in this survey (56.9% females, 43.1% males; mean age 43.6). The mean DLQI score +/- SD was 6.40 +/- 5.17. The highest mean DLQI score was seen in the patient group aged 30-59 years (mean score 7.05). Malays had significantly higher DLQI scores compared with Indians (P = 0.026). CONCLUSION: Patients in our cohort showed a moderate limitation of QoL, comparable to that of other chronic skin diseases. Management should focus not only on medical treatment but also psychological aspects, hence better QoL and treatment outcomes. PMID- 22250624 TI - Oleoma: rare complication of mesotherapy for cellulite. AB - BACKGROUND: Mesotherapy or intradermotherapy is used as a cosmetic procedure for many purposes, among them for cellulite. METHODS: We report a case of oleoma on the thighs and buttocks that appeared two years after the injection of an unknown substance for improvement of cellulite. RESULTS: Lesions and associated pruritus resolved with colchicine, leaving depressed scars. CONCLUSIONS: Serious and peer reviewed investigations must be performed to certify the efficacy and safety of this procedure. PMID- 22250625 TI - Head lice infestation in schoolchildren and related factors in Mafraq governorate, Jordan. AB - BACKGROUND: Little is known about the effect of socioeconomic status on the infestation by head lice in schoolchildren in Jordan. MATERIALS AND METHODS: A cross-sectional school-based study was conducted from December 2009 to February 2010. A list of all primary schools in Mafraq governorate was obtained (394 primary schools). Eight primary schools were randomly selected (four male schools and four female schools). Data were collected by five well-trained nurses. Hair was examined for head lice as well as for eggs/nits. Analysis of data was conducted by using SPSS software version 16. The chi-square test was used to assess statistical significance of subgroup differences in the prevalence of infestation, and multivariate logistic regression was used to control for potential confounding. RESULTS: Out of 1550 primary schoolchildren screened, 412 (26.6%) were infected with lice, 163 (19.6%) boys and 249 (34.7%) girls. The results showed significant variations in head lice infestation by factors such as gender, age, and socioeconomic variables (family income, father's education, mother's education, number of rooms, number of siblings younger than 15 years, frequency of hair washing per week, and bathing per week). There was no significant variation in lice infestation with parents' occupation (P > 0.05). CONCLUSIONS: Socioeconomic status is a major factor influencing the occurrence of pediculosis capitis among schoolchildren in both sexes. Improving standards of living and personal hygiene might significantly reduce pediculosis capitis in schoolchildren in Jordan. PMID- 22250626 TI - Skin diseases in Greek and immigrant children in Athens. AB - OBJECTIVES: This study aimed to characterize the spectrum of skin diseases affecting children in Greece. METHODS: We retrospectively studied data for 4071 children, aged 0-12 years, who were examined and diagnosed with dermatoses at the outpatient clinic of a university dermatological hospital between December 2005 and August 2007. To evaluate changes in disease patterns, these data were compared with data for a cohort of 12,700 children diagnosed with skin diseases at the same clinic two to three decades earlier (in 1977, 1980, and 1983). RESULTS: The most frequent disease was dermatitis/eczema (34.7%), with atopic dermatitis found in 20.7% of children, contact dermatitis in 6.9%, pityriasis alba in 2.1%, and seborrheic dermatitis in 1.8%. Infections (19.3%), nevi (5.6%), scabies (4.8%), and insect bites (4.3%) followed. More viral (12%) than bacterial (3.7%) and fungal (3.6%) infections were noted. Warts constituted 53.2% of viral infections. Immigrants had an increased risk for bacterial infections and scabies. CONCLUSIONS: Children diagnosed with skin diseases 24-30 years earlier were younger; exhibited lower prevalences of dermatitis/eczema (P = 0.01), viral infections (P < 0.001) and nevi (P < 0.001); higher prevalences of bacterial and fungal infections (P < 0.001) and insect bites (P < 0.01); and similar rates of scabies (P = 0.17). This study documents the high prevalence of atopic dermatitis in the region, the increasing incidence of viral infections and nevi, and the continuing problem of scabies, especially in immigrants. PMID- 22250627 TI - Skin infections and infestations in prison inmates. AB - BACKGROUND: Skin infections and infestations are common in a prison environment. The prison is in dynamic equilibrium with the larger society. Hence, it serves as a reservoir of infections which can spread to the larger society. The study sets out to find out how rampant these infections might be in the prison and the factors responsible. MATERIALS AND METHODS: Inmates at a Nigerian prison in Ilesha, Osun State, were examined for skin infections. Personal hygiene and living conditions were critically examined. RESULTS: The overall prevalent rate of infectious dermatoses was 49.2% (150/305). There were 178 infections. Dermatophytes accounted for 64%, pityriasis versicolor 27%, bacterial infections 3.4%, and others 5.6%. Only frequency of soap use and accommodation arrangement significantly contributed to the overall prevalence. However, infectious dermatoses were significantly affected by prison status (PP = 0.04), frequency of bath (PP = 0.025), changing of clothing (PP = 0.05), accommodation arrangement (P = 0.0001), frequency of soap usage (P = 0.005), and toilet facility (P = 0.001). The HIV status of the inmates was unknown. Hence, effect of HIV infection cannot be ascertained. CONCLUSION: Skin infections and infestations are common in prison. A change in living conditions and personal hygiene will definitely help in reducing these infections. PMID- 22250628 TI - A recurrent missense mutation of keratin 1 gene in a Chinese family with epidermolytic hyperkeratosis (severe palmoplantar hyperkeratosis, type 1). AB - BACKGROUND: Epidermolytic hyperkeratosis (EHK) is an autosomal dominantly inherited genodermatosis manifesting with blistering and erythroderma in infancy and widespread hyperkeratosis of the skin, particularly over flexural areas, in adulthood. It can be classified into six clinical phenotypes. CASE REPORT: We report the case of a 25-year-old man who presented with severe palmoplantar thickening and hyperkeratosis over the flexures for nearly 24 years. Histopathological findings showed characteristic features of EHK, and EHK type PS 1 (severe palmoplantar hyperkeratosis, type 1) was suspected. Further investigation revealed that his father, sister, and nephew (the son of his sister) were similarly affected. A heterozygous missense mutation in exon 7 of KRT1 (c.1436T>C), resulting in an isoleucine to threonine substitution at codon 479 (designated p.I479T), was detected in all affected individuals within the pedigree. DISCUSSION: Up to now, there has been one sporadic case and one family (including 14 affected individuals) with EHK type PS-1 reported since DiGiovanna and Bale described 25 patients (from two families) with EHK type PS-1 out of 51 patients (from 21 families) with EHK. Although the mutation (c.1436T>C) in KRT1 reported here is a recurrent one, it has not been reported in Chinese patients with EHK. It is interesting to note that the same mutation in KRT1 can cause different phenotypes of EHK. CONCLUSIONS: We expand the clinical heterogeneity of EHK due to the same mutation (c.1436T>C) in KRT1 and enrich the database of the KRT1 gene mutations underlying EHK in the Chinese population. PMID- 22250629 TI - Cojedes: a leprosy hyperendemic state. AB - BACKGROUND: Leprosy is a chronic infectious disease produced by Mycobacterium leprae. In 1997 Venezuela reached the goal of elimination of leprosy as a public health problem (according to the World Health Organization a prevalence rate of <= 1/10,000 inhabitants), but five states still had prevalence rates over that goal. For this study we selected Cojedes State, where prevalence rates remain over the elimination goal. OBJECTIVE: Evaluate the real leprosy situation in high prevalence areas of Cojedes State. MATERIALS AND METHODS: Seven communities of Cojedes State were selected because they had the highest historic prevalence, as well as the highest prevalence in the year to be studied (1997). RESULTS: A rank correlation using Spearman's test comparing historical prevalence rates (1946 1996) and detection rates (1998-2004) gave a statistically significant P < 0.05 value. Diagnosed leprosy cases were as follows: age: 3.2% under 15 years old; sex: male/female rates between 60% and 91.66% males. The highest number of cases were paucibacillary forms: indeterminate leprosy (33.07%) and borderline tuberculoid leprosy (32.28%); tuberculoid leprosy (7.00%); and multibacillary cases (lepromatous leprosy, LL) were only 2.36%. Bacteriologically, 18.52 patients were M. leprae positive. At the moment of diagnosis, 96.6% showed no disabilities, 3.4% showed grade I disabilities, and there were no grade II or III disabilities. CONCLUSION: This study confirms that several communities in Cojedes State have extremely high leprosy rates. PMID- 22250630 TI - Paracoccidioidomycosis: chronic adult unifocal form. AB - Paracoccidioidomycosis is a highly prevalent systemic mycosis in Brazil. The primary cutaneous form is rare and occurs in the absence of pulmonary involvement. Lesions located in the distal regions of the lower limbs are not uncommon and particularly in the feet may go unnoticed or even be confused with infectious or neoplastic lesions of different etiologies. We report a case of paracoccidioidomycosis affecting the left great toe of a man, leading to complete destruction of the nail plate. Treatment was done with the sulfamethoxazole plus trimethoprim with excellent results. PMID- 22250631 TI - Two pediatric cases of Microsporum persicolor infection. PMID- 22250632 TI - Turner syndrome with a ring X chromosome and atypical skin manifestation: port wine stain. PMID- 22250633 TI - The successful treatment of flat warts with auricular acupuncture. AB - BACKGROUND: Flat warts are a common presenting complaint in adolescents and adults and may be a cosmetic problem as well. Patients suffering from flat warts are often unsatisfied with conventional medical care because of adverse effects such as intolerable pain, hyperpigmentation, hypopigmentation, or occasionally allergic contact dermatitis. To offset the possibilities of hyperpigmentation, hypopigmentation, and scar formation, the method of auricular acupuncture was used. METHODS: Single-blind method adopted, 60 subjects with flat warts were all outpatients and randomly allocated to a treatment group or a control group, with 30 patients in each group. Thirty subjects in the treatment group were treated with weekly auricular acupuncture for 10 weeks while the other subjects in the control group were treated with 0.1% of tretinoin ointment topically for 10 weeks. RESULTS: Sixteen subjects in the treatment group (53.33%) recovered fully from flat warts without recurrence during the ensuing six months' follow-up after 10 weeks' surgery compared with only one subject in the control group (3.33%). The therapeutic effect of the treatment group was statistically better than that of the control group by Mann-Whitney U-test with SPSS software (P < 0.01). During the treatment period and the ensuing six months' follow-up, no adverse effects were observed by the investigators or reported by patients. CONCLUSIONS: Our findings suggest that auricular acupuncture may be a viable alternative for the treatment of flat warts. Larger randomized studies are needed to fully evaluate auricular acupuncture against more conventional treatments, and these are planned. PMID- 22250634 TI - Treatment of folliculitis decalvans with tacrolimus ointment. AB - Folliculitis decalvans is an embarrassing and challenging disease with no established treatment guidelines. In this paper, we described four patients with this disease treated successfully with Tacrolimus ointment. All of them showed significant control of the condition, stopping inflammatory lesions and progression of the disease, although weak transitory outbreaks of inflammatory lesions were observed in some cases. Alopecia and tufted hairs remained unchanged. The discontinuation of the therapy produced rapid relapses in all cases. Close monitoring of these patients is recommended due to the potential risk of malignant transformation of the disease. PMID- 22250635 TI - Genital and inguinal cutaneous toxicity in male and female patients treated with sunitinib. AB - BACKGROUND: Sunitinib is an orally tyrosine kinase inhibitor currently approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma (RCC) and gastrointestinal stromal tumor. Several cutaneous toxicities have been observed with Sunitinib and among those scrotal cutaneous toxicity could affect 12.5% of patients after an average 66 days of exposure to treatment. OBJECTIVE: We report the first case of a female patient who develops vulvar toxicity during sunitinib treatment. SUBJECTS AND METHODS: A 68-year-old female patient was treated with sunitinib at standard dose of 50 mg/daily for four weeks on and two weeks off, for advanced clear cell RCC. During week 2 of the second cycle of sunitinib, the patient reported vulvar pain and itching. RESULTS: Local examination revealed erythema of the outer lips and two erythematosus areas localized on the upper medial area of the legs. The sunitinib was discontinued, and the signs and symptoms disappeared completely seven days after drug interruption without any specific treatment. CONCLUSION: Female genital cutaneous toxicity with sunitinib shows a similar behavior as found in males, and both should be carefully evaluated even if the treatment discontinuation is generally not required. PMID- 22250636 TI - The management of EGFR inhibitor adverse events: a case series and treatment paradigm. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are widely used medications in the treatment of cancers. OBJECTIVE: To review the cutaneous adverse events related to EGFR inhibitors. METHODS: A retrospective chart review of all cases referred for the management of cutaneous adverse events after the initiation of EGFR inhibitor therapy between the years of 2006 and 2009 was performed. The study was approved by the institutional review board. RESULTS: Four men and 11 women had cutaneous adverse events while receiving erlotinib (mean dose: 112.5 mg) for lung and pancreatic cancer. The most common cutaneous adverse reaction observed was a papulopustular rash in 12 cases (80%). Eczema and xerosis were the only findings in three patients, alopecia in one case, and nail changes in three cases. The treatment modalities prescribed were doxycycline and topical antibiotics for the papulopustular rash; topical high potency steroids, tacrolimus, pimecrolimus, and moisturizers for xerosis and eczema; and cetirizine for the pruritus. The paronychia was treated with warm soaks, topical steroids, and podiatry referral. The majority of patients improved with symptomatic therapy, with the exception of one patient who experienced herpes zoster super infection and Stevens-Johnson syndrome. The patient was hospitalized and required discontinuation of the erlotinib therapy. CONCLUSION: The most common cutaneous adverse event in our cohort was papulopustular rash, followed by eczema and xerosis. Patients were managed with symptom target therapy, and suspension of the EGFR inhibitor was rarely required. As the use of EGFR inhibitors increases, it is important to promptly identify and treat adverse events. Further studies are necessary to develop targeted therapeutic and preventative measures. PMID- 22250637 TI - Epidemiologic aspects of seborrheic keratoses. PMID- 22250638 TI - Actinic reticuloid presented as facies leonine. PMID- 22250639 TI - Sequential therapy in plaque psoriasis using the " Hit and Run " approach: infliximab followed by efalizumab. PMID- 22250642 TI - Cellular response to antitumor cis-Dichlorido platinum(II) complexes of CDK inhibitor Bohemine and its analogues. AB - The cellular and molecular pharmacology of the new class of anticancer drugs, in which the CDK inhibitor bohemine and its analogues are coordinated to Pt(II) to form cisplatin derivatives, was investigated. The results revealed the unique anticancer profile of a cisplatin-derived platinum(II) dichlorido complex involving N(7)-coordinated bohemine (C1). Although the IC(50) values were ~6-fold higher for C1 than for cisplatin in cisplatin-sensitive tumor cells, the tumor cells in which C1 was also active are those which acquired resistance to cisplatin. In addition, among the novel conjugates of bohemine and its analogues with cisplatin, marked selectivity of C1 for tumor cells relative to the nontumorigenic, normal cells was observed. However, coordination of bohemine to platinum in C1 considerably reduced one of the dual functionalities anticipated to be effective after C1 reaches the nucleus. Further studies performed in the cells with wt p53 status show differences between cisplatin and C1 at the level of cell cycle regulation. Impedance-based real-time monitoring of the effects of C1 and cisplatin on cell growth supported the thesis that critical differences exist in the rate and mechanisms of cell kill caused by the two agents and that C1 was a more potent inducer of apoptosis and/or necrosis than cisplatin. The results also showed that the distinct differences in cell killing observed for C1 and cisplatin might be associated with processes at the DNA level. The DNA binding experiments carried out in a cell-free medium demonstrated that modification reactions resulting in the irreversible coordination of C1 to DNA were slower than that of cisplatin. Transcription mapping experiments and determination of interstrand cross-linking efficiency of C1 suggested that several aspects of DNA binding mode of C1 and cisplatin were similar. It was concluded that C1 remains a promising prototype of compounds for the generation of novel drug candidates with cytotoxicity profiles different from those of the platinum drugs currently in use. PMID- 22250643 TI - Reed-Sternberg-like cells of ALK-positive anaplastic large cell lymphoma with near-tetraploidy. PMID- 22250644 TI - Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study. AB - BACKGROUND: Photodynamic therapy (PDT) is an attractive therapy for nonmelanoma skin cancers and actinic keratoses (AKs). Daylight-mediated PDT is a simple and tolerable treatment procedure for PDT. Methyl aminolaevulinate (MAL)-PDT is approved for the treatment of thin or nonhyperkeratotic AKs on the face and scalp. However, thick AK lesions are often treated as well when present in the field-cancerized treatment area. OBJECTIVES: In a randomized multicentre study to evaluate efficacy of daylight-mediated PDT for different severity grades of AKs. METHODS: One hundred and forty-five patients with a total of 2768 AKs (severity grades I-III) of the face and scalp were randomized to either 11/2 or 21/2 h exposure groups. After application of a sunscreen (sun protection factor 20) and gentle lesion preparation, MAL was applied to the entire treatment area. Patients left the clinic immediately after application and exposed themselves to daylight according to randomization. Daylight exposure was monitored with a wrist-borne dosimeter. RESULTS: No difference in lesion response was found between the 11/2 and 21/2 h exposure group. The mean lesion response rate was significantly higher in grade I lesions (75.9%) than in grade II (61.2%) and grade III (49.1%) lesions (P < 0.0001). Most grade II (86%) and III AKs (94%) were in complete response or reduced to a lower lesion grade at follow-up. Large variations in response rate of grade II and III AKs were found between centres. No association was found between response rate and light dose in patients who received an effective light dose of > 3.5 J cm(-2). CONCLUSIONS: Daylight-mediated PDT of moderate to thick AKs was less effective than daylight-mediated PDT of thin AKs especially in some centres. However, nearly all thicker lesions (grades II and III) were reduced to a lower lesion grade at 3 months after a single treatment of daylight-mediated PDT. PMID- 22250645 TI - A virtual learning community for interprofessional education. PMID- 22250646 TI - Endothelin-1 and endothelin a receptor immunoreactivity is increased in patients with diabetic nephropathy. AB - BACKGROUND: Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria. MATERIALS AND METHODS: This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR. CONCLUSION: In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases. PMID- 22250648 TI - A novel immunohistochemical sequential multi-labelling and erasing technique enables epitope characterization of bone marrow pericytes in primary myelofibrosis. AB - AIM: In Philadelphia (Ph)-negative chronic myeloproliferative neoplasms, increased microvascular density, bizarre vessel architecture and increased number of pericytes are among the distinct histopathological features. The aim of this study was to characterize bone marrow pericytes in primary myelofibrosis (PMF) using a novel multi-labelling immunohistochemical technique. METHODS AND RESULTS: Bone marrow biopsies from a normal donor (n = 1) and patients with PMF (n = 3) were subjected to an immunohistochemical sequential multi-labelling and erasing technique (SE-technique). Antigens of interest in the first and/or second layer were detected with an immunoperoxidase system and visualized with aminoethylcarbazole. After imaging, erasing and blocking of immunoreagents, the slides were stained with a traditional double immunolabelling procedure. In addition, we applied a Photoshop(r) colour palette, creating a single composite image of the sequential staining procedures. We successfully applied four layers of antibodies on one slide using CD146, smooth muscle actin, CD34, CD271 and Ki67 in different combinations. The SE-technique significantly improves morphological and phenotypical studies in bone marrow specimens. CONCLUSIONS: To our knowledge, the SE-technique is the first to multi-label antigens, identifying vessel and pericyte architecture in bone marrow by light microscopy. This technique may unravel novel aspects of the composition of the microvessel structures in patients with PMF and related neoplasms. PMID- 22250647 TI - Risky decision-making: an FMRI study of youth at high risk for alcoholism. AB - BACKGROUND: Adolescents with a family history of alcoholism (FHP) are at risk for developing an alcohol use disorder (AUD), and some studies indicate that FHP individuals show deficits in executive functioning. The ability to make adaptive decisions is one aspect of successful executive functioning that is often measured during risk-taking tasks; however, this behavior has not been examined in FHP youth. As impaired decision-making could predispose FHP youth to make poor choices related to alcohol use, the current study examined the neural substrates of risk-taking in FHP adolescents and their family history negative (FHN) peers. METHODS: Thirty-one (18 FHP, 13 FHN) youth between 13 and 15 years old were included in this study. All youth had used little to no alcohol prior to study involvement. Functional magnetic resonance imaging was used to examine the neural substrates of risk-taking during the Wheel of Fortune (WOF) decision-making task (Ernst et al., 2004) in FHP and FHN youth. RESULTS: FHP youth did not differ from FHN youth in risk-taking behavior, but showed less brain response during risky decision-making in right dorsolateral prefrontal cortex and right cerebellar regions compared with FHN peers. CONCLUSIONS: Despite no behavioral differences on the WOF decision-making task, FHP youth exhibited atypical neural response during risk-taking compared with FHN peers. Atypical brain activity, in regions implicated in executive functioning could lead to reduced cognitive control, which may result in risky choices regarding alcohol use. This could help explain the higher rates of AUDs seen in FHP adolescents. Further examination of risky behavior and associated brain response over the course of adolescence is necessary to characterize the vulnerabilities of FHP youth in the absence of alcohol abuse. PMID- 22250649 TI - Advanced glycation end products as environmental risk factors for the development of type 1 diabetes. AB - The globally rising incidence of Type 1 diabetes (T1D) is no longer restricted to individuals with higher risk genotypes, but is now significantly increasing in a population with lower risk genotypes, likely as the result of environmental factors. In this review, we discuss the potential of advanced glycation end products (AGEs) as environmental contributors to the development of T1D. AGEs are nonenzymatically formed protein modifications found in the body, as well as, consumed in our daily diets. To date, many studies have provided evidence of AGE involvement in beta cell dysfunction, whether by AGE modification itself or via interaction with AGE receptors. The receptor for AGE (RAGE) and AGE-receptor-1 (AGE-R1) are of particular interest, given that studies have demonstrated the deleterious effects of RAGE modulation and the protection afforded by AGE-R1 in the context of diabetes. More interestingly, we have recently found that two RAGE polymorphism are predictive of T1D in humans while the third is protective. Moreover, soluble RAGE (sRAGE) levels (a circulating competitive inhibitor of RAGE) were greatly reduced at seroconversion to autoantibodies in both children on high risk of T1D background and in an animal model of autoiummune diabetes. Taken together with the fact that AGEs have also shown to be involved in immunomodulation, it is tempting to postulate that dietary AGEs, RAGE and even AGE-R1 could be working synergistically or independently to breach the tightly regulated immune system, providing a missing link in the development of T1D. PMID- 22250650 TI - Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. AB - The adenosine pathway is a powerful evolutionarily selected mechanism aimed at a fine modulation of inflammatory responses and protection of tissues from injuries. Adenosine exerts its modulatory effects via interaction with G protein coupled receptors, designated as A(1), A(2A), A(2B) and A(3). In this regard, extracellular adenosine concentrations are critical in determining its ability of regulating several biological functions. The levels achieved by adenosine in close proximity of its receptors are strictly regulated by a variety of dynamic mechanisms, including intracellular and extracellular biosynthesis, transport and metabolism, based on tissue energy status. In this context, the catabolic enzyme adenosine deaminase (ADA) represents a critical checkpoint in the regulation of extracellular adenosine levels and, consequently, in the control of receptor stimulation, thus playing a pivotal role in the modulation of purinergic responses to several pathophysiological events, such as chronic pulmonary diseases, rheumatoid arthritis, inflammatory bowel diseases and sepsis. This article reviews current data on the role played by ADA in the regulation of immune system activity through its modulation of adenosine pathways. Particular attention has been paid to the involvement of ADA in the pathophysiology of relevant inflammatory diseases. In addition, the interest in designing and developing novel ADA inhibitors, as new tools potentially useful for the therapeutic management of inflammatory disorders, has been discussed. PMID- 22250651 TI - Molecular profiling: an essential technology enabling personalized medicine in breast cancer. AB - Breast cancer is the most common non-cutaneous cancer diagnosed in women in the United States and the second most common cause of cancer-related mortality. Over the past two decades, the progress in screening and adjuvant systemic therapies noticeably improved the survival rate. However, traditional methods of characterizing tumors are imprecise and create heterogeneous groupings of tumors and patients. As a result, despite the important medical advances in diagnosis and treatment of breast cancer, one-third of the patients with initial breast tumor have recurrence of the disease 10 years after the diagnosis. Therefore, novel tools for discovery of strong prognostic and predictive markers that can be used to identify patients at high risk for relapse and aid in the selection of the most appropriate therapy are needed. This review analyzes some recent achievements in the development of such tools. PMID- 22250652 TI - To cardiovascular disease and beyond: new therapeutic perspectives of statins in autoimmune diseases and cancer. AB - Statins have been successfully used in patients with hypercholesterolemia and cardiovascular diseases, but there is increasing evidence that they exert effects by much exceeding the lowering of cholesterol levels. Statins have antiatherosclerotic, antiinflammatory, antioxidant, immunomodulatory and antithrombotic effects. These "pleiotropic" effects stem from their inhibition of prenylation of the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins modulate immune responses by altering cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Anti-inflammatory and immunosuppressory properties of statins provide the rationale for their potential application in conditions in which the inflammation and immune response represent key pathogenic mechanisms, such as antiphospholipid syndrome, rheumatoid arthritis and systemic lupus erythematosus. Reduction of atherosclerosis progression in autoimmunity is also a very important effect. Statins pathways of action in systemic autoimmune diseases, and their potential therapeutic use are discussed in this review. The inhibition of mevalonate pathway by statins impairs modification of Ras and Rho GTPases, which play key roles in signaling pathways related to tumor formation, metastasis and cell death. There is experimental and clinical evidence that statins may improve the therapeutic outcome of anticancer drugs. Thus, this review will also discuss recent insights into the molecular mechanisms underlying the anticancer effects of statins and their assessment as promising candidates for inclusion into current therapeutic regimens for the treatment of malignant diseases. PMID- 22250654 TI - Long-acting antipsychotic medications. AB - Antipsychotic medicines are the cornerstone pharmacotherapy for patients with psychotic disorders. Early and continuous management of psychoses improves the quality of life, decreases hospitalization and reduces medical costs. However, many psychotic patients are not fully compliant with treatment, and thus they more often experience a relapsing course with a suboptimal clinical outcome. Long term parenteral antipsychotic agents may improve compliance by offering clear evidence of medication non-compliance and documented drug administration monitoring. Using injection therapy might be especially beneficial to poorly compliant individuals with their first-psychotic episode and those with severe psychopathology or comorbid substance abuse. The availability of five different antipsychotic drug depot medications offers diverse treatment options which can be individualized for each case. PMID- 22250655 TI - Apixaban: a new player in the anticoagulant class. AB - Apixaban (BMS-562247-01) is a compound being investigated as an anticoagulant. Apixaban molecule is developed in a joint venture by Pfizer and Bristol-Myers Squibb. Apixaban, a coagulation factor Xa inhibitor, approved in the E.U. in 2011 for the prevention of venous thromboembolic events in adult patients, who have undergone elective hip or knee replacement. The Apixaban based drug will be marketed under the brand name Eliquis(r) and is expected to rack up annual sales of over $2.5 billion. Apixaban is expected to provide stiff competition to warfarin, a popular blood thinner used in Europe. Warfarin is known to cause some serious side effects in patients. Apixaban, as compared with aspirin, reduced the risk of stroke or systemic embolism in patients experiencing atrial fibrillation by more than 50% (from 3.7% per annum with aspirin to 1.6% per annum with apixaban). Apixaban exhibits superiority to enoxaparin in preventing thrombosis in patients undergoing elective hip replacement surgery with similar bleeding rates. Apixaban is a highly selective and potent Factor Xa Inhibitor with Ki=0 8nM to both free as well as prothrombinase bound FXa. In X-ray crystal structure studies indicate that the pyrazole N-2 nitrogen atom interacts with backbone of Gln192 and the carbonyl oxygen of carboxamide interacts with NH of Gly216. The orientation of phenyllactum in the S4 region indiacates an edge to face interaction with Trp215, which is positioned between the Tyr99 and Phe174. In the present review, we have tried to cover comparative study of various FXa inhibitors and point out apixaban in the various aspect including molecular chemistry, physical properties, commercial synthesis, current patent status, crystalline polymorphic forms, molecular receptor interaction, pharmacophore rational, mechanism of action, clinical studies, preclinical, adverse effect, available formulation, dose regimen and co-therapy, thus giving emphasis on medicinal chemistry aspects. PMID- 22250656 TI - Omega-3 polyunsaturated fatty acids and cognition in a college-aged population. AB - The cognitive influences of omega-3 polyunsaturated fatty acids (n-3 PUFA) remain unclear throughout the life span. Dietary n-3 PUFA appear cognitively beneficial prenatally and neuroprotective at later age; however, researchers using supplementation designs have reported disparate findings across age groups. Few studies have examined the cognitive impact of n-3 PUFA during young adulthood. This study assessed the cognitive effects of fish oil supplementation at college age, hypothesizing benefits on affect, executive control, inhibition, and verbal learning and memory. College-aged participants were assigned to active (n = 20, 5 men; age = 19.9, sage = 1.8) or placebo (n = 21, 7 men; age = 20.4, sage = 1.6) treatments, receiving fish oil (480 mg DHA/720 mg EPA) or coconut oil, respectively. Both groups completed four weeks of supplementation. At baseline and posttreatment, the researchers administered the Rey Auditory Verbal Learning Test (RAVLT; Lezak, 1995), Stroop Color and Word Test (SCWT; Golden & Freshwater, 2002), Trail Making Test (TMT; Corrigan & Hinkeldey, 1987; Gaudino, Geisler, & Squires, 1995; Lezak, 1995), and Positive and Negative Affect Schedule (PANAS; Watson, Clark, & Tellegen, 1988). Repeated-measures ANOVAs indicated no benefits of fish oil on the SCWT, RAVLT Stages 1 to 5, or PANAS. An interaction occurred between condition and time of measurement (i.e., baseline and posttreatment) on RAVLT Stages 6 and 7, and placebo significantly improved TMT performance over fish oil. The benefits of n-3 PUFA on RAVLT performance derived more from depreciated placebo performance than improved performance due to fish oil. The placebo gain on TMT performance likely derived from a learning effect. Together, these results present limited cognitive benefits of n-3 PUFA at college age; however, the treatment may have been subtherapeutic, with a larger sample needed to generalize these results. PMID- 22250658 TI - Eye-contact perception in schizophrenia: relationship with symptoms and socioemotional functioning. AB - Accurately perceiving self-referential social signals, particularly eye contact, is critical to social adaptation. Schizophrenia is often accompanied by deficits in social cognition, but it is unclear whether this includes gaze discrimination deficits. This study investigated whether eye-contact perception is preserved or impaired and if it is related to symptoms and broader socioemotional functioning in schizophrenia. Twenty-six participants with schizophrenia (SCZ) and 23 healthy controls (HC) made eye-contact judgments for faces in varying gaze direction (from averted to direct in ten 10% increments), head orientation (forward, 30 degrees averted), and emotion (neutral, fearful). Psychophysical analyses for forward faces showed that SCZ began endorsing eye contact with weaker eye-contact signal and their eye-contact perception was less of a dichotomous function, as compared with HC. SCZ were more likely than HC to endorse eye contact when gaze was ambiguous, and this overperception of eye contact was modulated by head orientation and emotion. Overperception of eye contact was associated with more severe negative symptoms. Decreased categorical gaze perception explained variance of socioemotional deficits in schizophrenia after taking basic neurocognition into consideration, suggesting the relationship was not solely due to a general deficit problem. These results were discussed in relation to the nature of categorical gaze perception and its significance to clinical and functional presentations of schizophrenia. PMID- 22250657 TI - Behavioral effects of prenatal ketamine exposure in rhesus macaques are dependent on MAOA genotype. AB - Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is used in anesthetic, abuse, and therapeutic contexts. Recent evidence suggests that ketamine may affect not only glutamate systems, but may also act on receptors in the dopamine and serotonin systems. Because monoamine neurotransmitters play important trophic roles in prenatal development, we hypothesized that the behavioral consequences of prenatal exposure to ketamine may be moderated by genotype of the promoter in the monoamine oxidase-A (MAOA) gene. Eighty-two infant rhesus monkeys were identified that had known dates of conception and exposures to ketamine during gestation. Animals were tested at 3-4 months of age on a battery of tests assessing responsiveness to maternal separation, recognition memory, and contact with novel objects. Animals were classified by putative activity levels for the MAOA genotype. The effects of prenatal ketamine exposure were seen only in the context of MAOA genotype. Greater exposure to ketamine resulted in increased activity, less willingness to perform in the memory task, and reduced emotionality and novel-object contact, but only for individuals with the low-activity genotype. Nearly all effects of ketamine were the result of first- and second-trimester exposure. MAOA genotype moderates the role of prenatal ketamine exposure at time points in gestation earlier than have been shown in past research, and is particularly evident for measures of emotionality. These results support the idea that ketamine's use might be best considered in light of individuals' genetic characteristics. PMID- 22250659 TI - Assessing emotion sensitivity in female offenders with borderline personality symptoms: results from a fear-potentiated startle paradigm. AB - An instructed fear-conditioning paradigm was used to measure fear-potentiated startle (FPS) in a sample of 80 Caucasian, female offenders assessed using the Personality Assessment Inventory-Borderline Features Scale (Morey, 1991). As predicted, women with higher levels of Borderline Personality Disorder (BPD) symptoms showed significantly greater FPS than women with lower levels when required to focus attention on the threat-relevant dimension of the experimental stimuli. However, FPS was not greater for women with higher levels of BPD symptoms in the two conditions that required participants to direct attention away from the threat-relevant dimension. These results highlight the importance of attention for moderating the association between BPD symptoms and exaggerated responses to threat-relevant information and may, therefore, help to resolve the inconsistent evidence on emotional reactivity in BPD. Moreover, the potential importance of attentional factors in BPD may shed new light on prominent symptoms of the disorder and existing theoretical perspectives on BPD. PMID- 22250660 TI - DSM-5 personality traits and DSM-IV personality disorders. AB - Two issues pertinent to the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) proposal for personality pathology, the recovery of DSM-IV personality disorders (PDs) by proposed DSM-5 traits and the validity of the proposed DSM-5 hybrid model, which incorporates both personality pathology symptoms and maladaptive traits, were evaluated in a large undergraduate sample (N = 808). Proposed DSM-5 traits as assessed with the Personality Inventory for DSM-5 explained a substantial proportion of variance in DSM-IV PDs as assessed with the Personality Diagnostic Questionnaire-4+, and trait indicators of the 6 proposed DSM-5 PDs were mostly specific to those disorders with some exceptions. Regression analyses support the DSM-5 hybrid model in that pathological traits, and an indicator of general personality pathology severity provided incremental information about PDs. Findings are discussed in the context of broader issues around the proposed DSM-5 model of personality disorders. PMID- 22250661 TI - Using latent class growth analysis to form trajectories of premorbid adjustment in schizophrenia. AB - Premorbid adjustment varies widely among individuals with schizophrenia and has been shown to bear significantly on prodrome and onset characteristics, and on cognition, symptoms, and functioning after onset. The current analysis focused on the Premorbid Adjustment Scale, a retrospective measure assessing social and academic function at several time points from early childhood to illness onset. In an effort to explore discrete developmental subtypes, we applied latent class growth analysis to data from the Premorbid Adjustment Scale in our sample of individuals with schizophrenia (N = 208), finding three latent trajectory classes. The first of these classes showed consistently adequate-to-good social and academic functioning before onset; the second showed initially good function and deterioration with time until onset; the third showed poor functioning in childhood that deteriorated further during the years up to diagnosis. The classes differed significantly in terms of age of onset, processing speed, and functioning after onset. There were no significant differences in symptomatology. Our findings illustrate a potentially powerful methodological approach to the problem of heterogeneity in schizophrenia research, and add weight to the notion that aspects of premorbid history may be useful for subtyping schizophrenia patients. The potential implications of this subtyping strategy, including those pertaining to potential genetics studies, are discussed. PMID- 22250662 TI - Trust and responsiveness in strain-test situations: a dyadic perspective. AB - In this behavioral observation study, the authors tested predictions derived from various trust models concerning how individuals who are high vs. low in chronic trust perceive and behave during strain-test discussions with their romantic partners. Partners in 92 married/cohabitating couples identified and discussed 2 major strain-test issues in their relationship. Each partner (when in the role of asker) identified something she or he really wanted to do or accomplish that required the greatest sacrifice by his or her partner (in the responding role). Each videotaped discussion was then rated by trained coders. The results revealed that (a) high trust responders were more accommodating during the strain-test discussions than low trust responders; (b) high trust askers were more open/collaborative with the accommodation they received during the discussions than low trust askers; (c) high trust askers overestimated the amount of accommodation they received from their responding partners (relative to coder's ratings); (d) when in discussions that were more threatening, high trust askers showed a correction effect by reporting larger pre- to postdiscussion increases in state trust; and (e) when asked to make larger sacrifices, high trust responders showed a similar correction effect by displaying greater accommodation. These findings are discussed in terms of mutual responsiveness processes in relationships. PMID- 22250664 TI - Histone H3 phosphorylation, immediate-early gene expression, and the nucleosomal response: a historical perspective. AB - Histone H3 is modified at serines 10 and 28 in interphase cells following activation of the RAS-MAPK or p38-MAPK pathways by growth factors or stress. These modifications are involved in the regulation of immediate-early genes, including Jun and Fos, whose increased expression is a trademark of various cancers. This review outlines the series of discoveries that led to the characterization of these modifications, the kinase, MSK1/2, which is activated by both MAPK pathways and directs phosphorylation of H3, and the mechanistic function of these modifications in transcriptional activation. Research examining the effect of deregulated MSK1/2 in human disorders, namely cancer, is evaluated. Recently, a number of reports proposed novel, intervening pathways leading to enrichment of phosphorylated serine 10 and 28 and the activation of MSK1/2. These novel pathways predict an even more complicated signalling mechanism for cell growth, apoptosis, and the immune response, suggesting that MSK1/2 is intrinsically responsible for an even greater number of biological processes. This review proposes that MSK1/2 is an optimal target for cancer therapy, based on its fundamental role in transmitting external signals into varied responses involved in cancer development. PMID- 22250665 TI - Clinical predictors of non-diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: a single centre review. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is reportedly the leading cause of end-stage renal disease (ESRD) worldwide. However, non-diabetic renal diseases (NDRD) are not uncommon among T2DM patients with renal involvement. Our study aimed to examine the prevalence of NDRD in T2DM and clinical markers for diabetic nephropathy (DN) and NDRD and to determine the role of renal biopsy in T2DM patients and its impact on clinical practice. METHODS: We conducted a retrospective analysis of T2DM patients in whom renal biopsies were performed from January 2004 to March 2008 (n = 110). RESULTS: Biopsy results were divided into three groups: group I/pure DN (62.7%), group II/isolated NDRD (18.2%), and group III/mixed lesions (19.1%). The causes of NDRD in decreasing order of frequency were acute interstitial nephritis, glomerulonephritides, hypertensive renal disease, and acute tubular necrosis. Significant clinical markers for DN are presence of diabetic retinopathy and longer duration of diabetes. For NDRD, useful clinical markers include the presence of acute renal failure and microscopic hematuria. In the DN subgroup, Indians had significantly shorter duration of diabetes on biopsy compared with Malays and Chinese. CONCLUSIONS: NDRD is prevalent in T2DM patients, and given its potentially treatable nature, renal biopsy should be considered in T2DM patients with nephropathy, especially in those with atypical features. PMID- 22250666 TI - Does a self-management education program have the same impact on emotional and functional dimensions of HRQoL? AB - Most previous research evaluating the effect of interventions on HRQoL in COPD patients has focused on measuring HRQoL using aggregated questionnaire scores, increasing the risk of false-negative results. There is also evidence to suggest that self-evaluations of functional status are less likely to be modified over time relative to self-evaluation of emotional status. This study was a secondary analysis of a prospective study that compared the efficacy of a self-management education program (SM) on emotional and functional dimensions of HRQoL. One hundred and ten patients were recruited from the Sacre-Coeur Hospital of Montreal (Canada). Patients were included in either the SM group (n = 60) or the usual care group (UC, n = 50). The SM group underwent a 4-week intervention based on content featured in "Living Well with COPD" program. Patients were assessed pre and 12-months post-intervention; the primary outcome was net change in the emotional and functional subscales scores of the St-George's Respiratory Questionnaire (SGRQ) and Short-Form health survey questionnaire (SF-36). Only the emotional dimension scores of both the SGRQ (impact) and the SF-36 (mental component summary) were statistically and clinically improved in the SM group compared to UC. Also, the 12-month adjusted between-group difference in the SGRQ impact scores was 3-fold higher than the minimum clinically important difference in SM vs. UC patients. HRQoL needs to be regarded as a combination of distinct self-evaluations with unique dynamics over time. This distinction should be taken into account in program development and evaluation, to choose intervention components likely to impact on both types of self-evaluations related to HRQoL. PMID- 22250667 TI - Testing the efficacy of a new procedure for reducing faking on personality tests within selection contexts. AB - The authors propose a new procedure for reducing faking on personality tests within selection contexts. This computer-based procedure attempts to identify and warn potential fakers early on during the testing process and then give them a chance for recourse. Two field studies were conducted to test the efficacy of the proposed procedure. Study 1 participants were 157 applicants competing for 10 staff positions at a large university located in a southern city in the People's Republic of China. In Study 1, potential fakers received a warning message, whereas nonfakers received a nonwarning (control) message. Study 2 participants were 386 Chinese college students applying for membership of a popular student organization at the same university where Study 1 was conducted. In Study 2, the warning and control messages were randomly assigned to all applicants. Results showed some promise for the proposed procedure, but several practical issues need to be considered. PMID- 22250668 TI - Does power corrupt or enable? When and why power facilitates self-interested behavior. AB - Does power corrupt a moral identity, or does it enable a moral identity to emerge? Drawing from the power literature, we propose that the psychological experience of power, although often associated with promoting self-interest, is associated with greater self-interest only in the presence of a weak moral identity. Furthermore, we propose that the psychological experience of power is associated with less self-interest in the presence of a strong moral identity. Across a field survey of working adults and in a lab experiment, individuals with a strong moral identity were less likely to act in self-interest, yet individuals with a weak moral identity were more likely to act in self-interest, when subjectively experiencing power. Finally, we predict and demonstrate an explanatory mechanism behind this effect: The psychological experience of power enhances moral awareness among those with a strong moral identity, yet decreases the moral awareness among those with a weak moral identity. In turn, individuals' moral awareness affects how they behave in relation to their self-interest. PMID- 22250669 TI - More than just the mean: moving to a dynamic view of performance-based compensation. AB - Compensation decisions have important consequences for employees and organizations and affect factors such as retention, motivation, and recruitment. Past research has primarily focused on mean performance as a predictor of compensation, promoting the implicit assumption that alternative aspects of dynamic performance are not relevant. To address this gap in the literature, we examined the influence of dynamic performance characteristics on compensation decisions in the National Basketball Association (NBA). We predicted that, in addition to performance mean, performance trend and variability would also affect compensation decisions. Results revealed that performance mean and trend, but not variability, were significantly and positively related to changes in compensation levels of NBA players. Moreover, trend (but not mean or variability) predicted compensation when controlling for future performance, suggesting that organizations overweighted trend in their compensation decisions. Theoretical and practical implications are discussed. PMID- 22250671 TI - Building bridges between theory and practice in medical education using a design based research approach: AMEE Guide No. 60. AB - Medical education research has grown enormously over the past 20 years, but it does not sufficiently make use of theories, according to influential leaders and researchers in this field. In this AMEE Guide, it is argued that design-based research (DBR) studies should be conducted much more in medical education design research because these studies both advance the testing and refinement of theories and advance educational practice. In this Guide, the essential characteristics of DBR as well as how DBR differs from other approach such as formative evaluation are explained. It is also explained what the pitfalls and challenges of DBR are. The main challenges deal with how to insure that DBR studies reveal findings that are of a broader relevance than the local situation and how to insure that DBR contributes toward theory testing and refinement. An example of a series of DBR studies on the design of a teaching portfolio in higher education that is aimed at stimulating a teacher's professional development is described, to illustrate how DBR studies actually work in practice. Finally, it is argued that DBR-studies could play an important role in the advancement of theory and practice in the two broad domains of designing or redesigning work-based learning environments and assessment programs. PMID- 22250670 TI - Fast and simultaneous determination of urinary 8-hydroxy-2'-deoxyguanosine and ten monohydroxylated polycyclic aromatic hydrocarbons by liquid chromatography/tandem mass spectrometry. AB - 8-Hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, has been extensively studied to assess human exposure to carcinogenic compounds. Previous studies have associated levels of human urinary hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) with those of 8-OHdG. However, measurements of OH PAHs and 8-OHdG in urine are often conducted with two different analytical methods, which is both costly and time-consuming. In this study, a novel method is described to quickly and simultaneously quantify ten urinary OH-PAHs and 8 OHdG through high pressure liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). Urine samples undergo solid phase extraction and concentration and then are analyzed by an optimized HPLC/MS/MS method operated in the negative electrospray ionization (ESI) and multiple reaction monitoring (MRM) mode. Deuterated, (15)N and (13)C- labeled analogues are used as internal standards. Simultaneous analysis of urinary 8-OHdG and OH-PAHs are completed within 16 min. Calibration curves of all target analytes show favorable linearity within the concentration range of 0.3-10.0 MUg/L for 8-OHdG and 0.05-15 MUg/L for different OH-PAHs. The method detection limits (MDLs) in pooled urine range from 0.023 MUg/L to 0.625 MUg/L. The method shows satisfactory accuracy and precision when we analyzed varied levels spiked in pooled urine. Recoveries for 8 of the 10 OH PAHs were in the range of 100 +/- 15% with a variation coefficient of less than 20%. Thirty-four real urine samples were analyzed for all target analytes. Except 3-OHF, most compounds could be quantified. PMID- 22250672 TI - What impact do structured educational sessions to increase emotional intelligence have on medical students? BEME Guide No. 17. AB - BACKGROUND: Emotional intelligence (EI) is a type of social intelligence that involves monitoring, discriminating between and using emotions to guide thinking and actions. EI is related to interpersonal and communication skills, and is important in the assessment and training of medical undergraduates. AIM: This review aimed to determine the impact of structured educational interventions on the EI of medical students. METHODS: We systematically searched 14 electronic databases and hand searched high yield journals. We looked at changes in EI and related behaviour of medical students, assessed using Kirkpatrick's hierarchy, provided they could be directly related to the content of the educational intervention. RESULTS: A total of 1947 articles were reviewed, of which 14 articles met the inclusion criteria. CONCLUSIONS: The use of simulated patients is beneficial in improving EI when introduced in interventions later rather than earlier in undergraduate medical education. Regardless of duration of intervention, interventions have the best effects when delivered: (1) over a short space of time; (2) to students later in their undergraduate education and; (3) to female students. This should be taken into account when designing and delivering interventions. Emphasising the importance of empathetic qualities, such as empathetic communication style should be made explicit during teaching. PMID- 22250673 TI - The feasibility, reliability, and validity of a post-encounter form for evaluating clinical reasoning. AB - BACKGROUND: Developing feasible, reliable and valid methods for the evaluation of clinical reasoning is challenging. AIM: To explore feasibility, reliability, and validity evidence for a post-encounter form assessing clinical reasoning. METHOD: A free-text, post-encounter form was used in an Objective Structured Clinical Examination (OSCE) station to assess clinical reasoning for end-of-second-year medical students. Feasibility was assessed by time to complete form. Inter-rater reliability was assessed by kappa. Validity evidence was obtained by comparing scores from individual items on the post-encounter form and other components in this OSCE station (i.e., standardized patient checklist and oral presentation rating form). Additional validity evidence was gathered by comparing scores on this station with other course performance graded events. RESULTS: Feasibility and estimated reliability were high, and several lines of validity evidence were supported. CONCLUSIONS: The scores from an end-of-second-year, medical school, post-encounter form yielded adequate psychometric properties and can be used for the evaluation of clinical reasoning. Moreover, this form of assessment and its scoring could translate to other venues. PMID- 22250674 TI - Faculty development projects for international health professions educators: Vehicles for institutional change? AB - BACKGROUND: Projects are an important tool in faculty development, and project emphasis may offer insights into perceived education priorities. Impact of projects has been focused on individuals, not institutions or health. AIM: Education innovation projects of Fellows in an international faculty development program were examined to better understand perceived needs in health professions education and institutional impact of projects. METHOD: Four hundred and thirty five projects were analyzed to identify focus areas. Fellows were asked to identify changes in their schools and communities resulting from their projects. RESULTS: New education methods and curriculum change were common project focus areas. Regional differences were evident with a higher percentage of education methods projects by Fellows residing in India (52%), compared with South Africa (25%) and Brazil (24%). Fifty-six percent of projects were incorporated into the curriculum and/or incorporated as institutional policy. One-third to two-thirds of respondents noted improved teaching quality, collaboration, education research interest, assessment, student performance, and curriculum alignment with community health needs. CONCLUSION: National differences in project focus may offer insight into local conditions and needs. High rates of diffusion of projects and impact on faculty, students, and curriculum suggest that faculty development projects may be a strategy for institutional change in resource limited environments. PMID- 22250675 TI - Preparing health professions education leaders worldwide: A description of masters-level programs. AB - PURPOSE: Until 1996, there were only 7 masters-level programs in health professions education (HPE); currently, there are 76 such programs. The purpose of this article is to provide information and perspectives about the available masters programs in HPE worldwide, with a focus on their mission, objectives, content, instructional strategies, format, duration, and cost, as well as the similarities and differences among them. METHOD: A literature and web search was conducted to develop a complete list of programs that offer a masters degree in HPE or closely related areas. RESULTS: Forty three percent [43% (33)] of these programs are in Europe, 20% (15) in North America, 17% (13) in Asia, 7% (5) in Latin America, 5% (4) in the Middle East, 5% (4) in Australia, and 3% (2) in Africa. The mission of these masters programs is to prepare leaders in HPE or sometimes narrowly focusing on clinical or dental education. The content is addressed in core courses and electives, generally grouped under the following headings: curriculum development, instructional methods/teaching and learning, assessment strategies, program evaluation, research design, and sometimes leadership and management. Medical schools sponsor approximately two-thirds of these programs, and the average duration for completion is 2 years. The vast majority of these programs are offered in English. CONCLUSION: The commonalities among these programs include focus, content, and educational requirements. The variations are mostly in organization and structure. There is a need to establish criteria and mechanisms for evaluation of these programs. The geographic maldistribution of these programs is a major concern. PMID- 22250676 TI - Virtual reality-based medical training and assessment: The multidisciplinary relationship between clinicians, educators and developers. AB - BACKGROUND: The current focus on patient safety and evidence-based medical education has led to an increased interest in utilising virtual reality (VR) for medical training. The development of VR-based systems require experts from different disciplines to collaborate with shared and agreed objectives throughout a system's development process. Both the development of technology as well as the incorporation and evaluation of relevant training have to be given the appropriate attention. AIM: The aim of this article is to illustrate how constructive relationships can be established between stakeholders to develop useful and usable VR-based medical training systems. METHODS: This article reports a case study of two research projects that developed and evaluated a VR based training system for spinal anaesthesia. RESULTS: The case study illustrates how close relationships can be established by champion clinicians leading research in this area and by closely engaging clinicians and educators in iterative prototype design throughout a system's development process. CONCLUSION: Clinicians and educators have to strive to get more involved (ideally as champions of innovation) and actively guide the development of VR-based training and assessment systems. System developers have to strive to ensure that clinicians and educators are participating constructively in the developments of such systems. PMID- 22250677 TI - Two conscientious guinea pigs: A participant student view of the conscientiousness index. PMID- 22250678 TI - Case study of a framing effect in course evaluations. AB - BACKGROUND: When new elements are included in the medical curriculum and the total time frame remains unchanged, established disciplines have to shorten their courses. This might bring about frustration among the teachers and students concerned, which in turn might affect how other courses are perceived. FINDINGS: Two course evaluations, one before and one after a major change in the curriculum were compared. Comments were also analysed. We found that the students' and teachers' frustration influenced the students' evaluations of a new course in the philosophy of medicine and accordingly brought about an unintended message effect referred to as a framing effect. CONCLUSIONS: The results of this observational study indicate that a negative framing effect might influence course-evaluations. We suggest that this study might be used as a point of departure for further empirical studies about negative framing effects. PMID- 22250679 TI - A national survey of international electives for medical students in Japan: 2009 2010. AB - BACKGROUND AND OBJECTIVES: International electives can provide experiences for medical students to learn about health systems and foster critical self reflection. So far, little is known about the status of Japanese students' engagement in international electives. We sought to provide information about the internationalization of Japanese medical education by clarifying the current situations of international electives. METHOD: We undertook a cross-sectional national 17-item questionnaire survey of program officers in all medical schools in Japan in February 2010. RESULTS: Sixty-five (81.3%) of 80 Japanese medical schools responded to the questionnaire. 462 Japanese medical students (3% of all students in their clinical years) travelled to North America (45.5%), Asia (25.0%), or Western Europe (24.4%) to study abroad. The number of students who participated in international electives was significantly increased when academic credit was available (median 6 vs. 1, p < 0.001) and institutional affiliations were present (median 7 vs. 2 students, p < 0.001). Most students were evaluated by means of written assignment on return. DISCUSSION AND CONCLUSION: About 3% of Japanese medical students participate in international clinical exchanges. Academic credit and institutional affiliations appear to promote greater utilization of international exchange opportunities. PMID- 22250680 TI - Faculty development: On becoming a medical educator. PMID- 22250681 TI - The role of ad-hoc interpreters in teaching communication skills with ethnic minorities. PMID- 22250683 TI - PPE: A UK perspective, 'All for one, NOT one for all'. PMID- 22250685 TI - DREEM - Time to evaluate? PMID- 22250686 TI - PBL performance correlates with content acquisition assessment: A study in a hybrid PBL program at Alfaisal University. PMID- 22250687 TI - General practice teachers. PMID- 22250688 TI - Handover education in UK medical schools: Current practices and implications for educators. PMID- 22250690 TI - The good student is more than a listener - The 12+1 roles of the medical student. AB - BACKGROUND: The process of medical education, particularly in the fast evolving new era of medical metaschools, is a broad and complex issue. Harden & Crosby claimed that a good teacher is more than a lecturer, and identified 12 roles that certify a good and capable teacher. However, this is only half the truth: the good student is more than a listener. Teaching-and-learning is not simply a one way process, and, as medical students are not children, the relationship between teacher and students involves andragogy rather than pedagogy. We therefore propose the 12+1 roles of the student. SUMMARY OF WORK: The Harden & Crosby paper was distributed in a class of 90 third year Ioannina University medical students, who were asked to think about the student's roles. A small discussion group brainstormed ideas, which were then refined further by the authors. SUMMARY OF RESULTS: 12+1 roles of the good medical student were produced and grouped into six areas: information receiver, in lectures and clinical context; role model in learning, in class, with the added subarea of comparative choice of role models; teaching facilitator and teacher's mentor; teacher's assessor and curriculum evaluator; active participator and keeping-up with curriculum; resource consumer/co-creator and medical literature researcher. The ideal student should fulfil the majority if not all of these complementary roles. TAKE-HOME MESSAGE: These 12+1 student's roles are complementary to the 12 roles of the teacher and help reshaping our understanding of today's medical education process. PMID- 22250691 TI - New directions in e-learning research in health professions education: Report of two symposia. AB - BACKGROUND: The use of Computer Assisted Instruction (CAI) is rising across health professions education. Research to date is of limited use in guiding the implementation and selection of CAI innovations. AIMS: In the context of two symposia, systemic reviews were discussed that evaluate literature in Internet based learning, Virtual Patients, and animations. Each session included a debate with the goal of reaching consensus on best current practices and future research. METHODS: Thematic analysis of the discussions was performed to arrange the questions by theme, eliminate redundancy, and craft them into a cohesive narrative. RESULTS: The question analysis revealed that there are clear advantages to the use of CAI, and that established educational theories should certainly inform the future development and selection of CAI tools. Schools adopting CAI need to carefully consider the benefits, cost, available resources, and capacity for teachers and learners to accept change in their practice of education. Potential areas for future research should focus on the effectiveness of CAI instructional features, integration of e-learning into existing curricula and with other modalities like simulation, and the use of CAI in assessment of higher-level outcomes. CONCLUSIONS: There are numerous opportunities for future research and it will be important to achieve consensus on important themes. PMID- 22250692 TI - Does a summative portfolio foster the development of capabilities such as reflective practice and understanding ethics? An evaluation from two medical schools. AB - Portfolios need to be evaluated to determine whether they encourage students to develop in capabilities such as reflective practice and ethical judgment. The aims of this study were (i) to determine whether preparing a portfolio helps promote students' development in a range of capabilities including understanding ethical and legal principles, reflective practice and effective communication, and (ii) to determine to what extent the format of the portfolio affected the outcome by comparing the experiences of students at two different medical schools. A questionnaire was designed to evaluate undergraduate medical students' experiences of completing a portfolio at two medical schools. A total of 526 (45% response rate) students answered the on-line questionnaire. Students from both medical schools gave the highest ranking for the portfolio as a trigger for reflective practice. 63% of students agreed their portfolio helped them develop reflective practice skills (p < 0.001), whereas only 22% disagreed. 48% of students agreed portfolios helped them understand ethical and legal principles whereas 29% disagreed (p < 0.001). In contrast, only 34% of students thought the portfolio helped them to develop effective communication. Students perceive portfolio preparation as an effective learning tool for the development of capabilities such as understanding ethical and legal principles and reflective practice, whereas other capabilities such as effective communication require complementary techniques and other modes of assessment. PMID- 22250693 TI - Problem based learning approaches to the technology education of physical therapy students. AB - BACKGROUND: Problem-Based Learning (PBL) is a whole-curriculum concept. AIM: This study aimed to compare learning preferences and strategies between physical therapy students taught by PBL and those receiving conventional lectures on massage therapy, trauma physical therapy, and electrotherapy, hydrotherapy, and thermotherapy. METHODS: This quasi-experimental study included 182 male and female students on physical therapy diploma courses at three universities in Andalusia (Spain). The Canfield Learning Skills Inventory (CLSI) was used to assess learning strategies and the Approaches to Study Skills Inventory for Students (ASSIST) to analyze study preferences. RESULTS: At the end of the academic year 2009/10, physical therapy students taught by PBL considered the most important learning strategies to be group work, study organization, relationship of ideas, and academic results. In comparison to conventionally taught counterparts, they considered that PBL reduced lack of purpose, memorizing without relating, the law of minimum effort, and fear of failure. Among these PBL students, the most highly rated study preferences were: organization of course tasks, cordial interaction with the teacher, learning by reading and images, and direct hands-on experience. CONCLUSION: For these physical therapy students, PBL facilitates learning strategies and study preferences in comparison to conventional teaching. PMID- 22250694 TI - Use of individualized learning plans among fourth-year sub-interns in pediatrics and internal medicine. AB - BACKGROUND: Individualized Learning Plans (ILPs) are an effective tool for promoting self-directed learning among residents. However, no literature details ILP use among medical students. METHODS: Fifty fourth-year sub-interns in pediatrics and internal medicine created ILPs, including a self-assessment of strengths and weaknesses based on ACGME core competencies and the setting of learning objectives. During weekly follow-up meetings with faculty mentors and peers, students discussed challenges and revised goals. Upon completion of the rotation, students completed a survey of Likert-scale questions addressing satisfaction with and perceived utility of ILP components. RESULTS: Students most often self-identified strengths in the areas of Professionalism and Interpersonal and Communication Skills and weaknesses in Patient Care and Systems-Based Practice. Eighty-two percent set at least one learning objective in an identified area of weakness. Students expressed high confidence in their abilities to create achievable learning objectives and to generate strategies to meet those objectives. Students agreed that discussions during group meetings were meaningful, and they identified the setting learning objectives and weekly meetings as the most important elements of the exercise. CONCLUSIONS: Fourth-year sub-interns reported that ILPs helped them to accomplish rotation goals, with the setting of learning objectives and weekly discussions being the most useful elements. PMID- 22250695 TI - A novel resident-as-teacher training program to improve and evaluate obstetrics and gynecology resident teaching skills. AB - BACKGROUND: Residents play a significant role in teaching, but formal training, feedback, and evaluation are needed. AIMS: Our aims were to assess resident teaching skills in the resident-as-teacher program, quantify correlations of faculty evaluations with resident self-evaluations, compare resident-as-teacher evaluations with clinical evaluations, and evaluate the resident-as-teacher program. METHOD: The resident-as-teacher training program is a simulated, videotaped teaching encounter with a trained medical student and standardized teaching evaluation tool. Evaluations from the resident-as-teacher training program were compared to evaluations of resident teaching done by faculty, residents, and medical students from the clinical setting. RESULTS: Faculty evaluation of resident teaching skills in the resident-as-teacher program showed a mean total score of 4.5 +/- 0.5 with statistically significant correlations between faculty assessment and resident self-evaluations (r = 0.47; p < 0.001). However, resident self-evaluation of teaching skill was lower than faculty evaluation (mean difference: 0.4; 95% CI 0.3-0.6). When compared to the clinical setting, resident-as-teacher evaluations were significantly correlated with faculty and resident evaluations, but not medical student evaluations. Evaluations from both the resident-as-teacher program and the clinical setting improved with duration of residency. CONCLUSIONS: The resident-as-teacher program provides a method to train, give feedback, and evaluate resident teaching. PMID- 22250696 TI - Global health education for medical students: New learning opportunities and strategies. AB - BACKGROUND: A new course was offered to introduce basic global health concepts to all first year Johns Hopkins medical students, that took advantage of new distance learning capacity to connect medical students in Baltimore with students and faculty in Uganda, Ethiopia, Pakistan and India. AIMS: Lessons learned from the launch of this new course will optimize the conduct of future global health courses at JHUSOM and may be of value to other institutions. METHODS: Feedback from the Hopkins students was obtained through an on-line structured course evaluation questionnaire. Unstructured student and faculty feedback from partners institutions was solicited via email. RESULTS: Students reported high levels of satisfaction with the course content and format, as well as achievement of course competencies and objectives. CONCLUSIONS: Distance learning can support unique, high-quality medical educational experiences that leverage technology and global connectivity, but also the power of group learning and "South-to-North" capacity building. PMID- 22250697 TI - On the road: Medical students' experiences on paramedic placements. AB - BACKGROUND: Undergraduate students' in several Australian medical courses undertake short placements with Paramedics to increase their awareness of biopsychosocial factors affecting health, provide opportunities to apply knowledge and clinical skills in health contexts and to develop inter professional knowledge. AIM: The purpose of this study was to provide the first report of medical students experiences on Paramedic placements, by identifying the opportunities and range of clinical activities they experienced, and to seek feedback to improve placements. METHODS: Students (n = 33, 72% response rate) completed an 11-question post-placement survey requiring Likert-scale responses with open-ended questions requiring narrative responses. RESULTS: Students employed communicative, observational and basic clinical skills 'on the job' during the placement. They had exposure to a range of experiences from non emergency patient transfers to violence and intoxication, trauma, suicide and death. Students witnessed the importance of different individuals as well as the importance of the inter-professional network in delivering pre-hospital care. Overall, students were over-confident of their abilities, but found the placements to be valuable learning opportunities that met the intended outcomes. CONCLUSION: Suggested improvements include better orientation, management of expectations and debriefing, shifts with a higher rate of call outs, direct clinical teaching and introduction of a 'patient journey' approach to the placement. PMID- 22250698 TI - Laryngospasm and hypoxia after intramuscular administration of ketamine to a patient in excited delirium. AB - An advanced life support emergency medical services (EMS) unit was dispatched with law enforcement to a report of a male patient with a possible overdose and psychiatric emergency. Police restrained the patient and cleared EMS into the scene. The patient was identified as having excited delirium, and ketamine was administered intramuscularly. Sedation was achieved and the patient was transported to the closest hospital. While in the emergency department, the patient developed laryngospasm and hypoxia. The airway obstruction was overcome with bag-valve-mask ventilation. Several minutes later, a second episode of laryngospasm occurred, which again responded to positive-pressure ventilation. At this point the airway was secured with an endotracheal tube. The patient was uneventfully extubated several hours later. This is the first report of laryngospam and hypoxia associated with prehospital administration of intramuscular ketamine to a patient with excited delirium. PMID- 22250699 TI - Bioequivalence challenges in development of fixed-dose combination products: looking beyond reformulation. AB - INTRODUCTION: Bioequivalence study is a critical step in the development of novel fixed-dose combination products (FDCPs). While bioequivalence of prototype FDCP to the approved monocomponent products facilitates speedier development and approval, lack of bioequivalence often leads to development delays due to reformulation. AREAS COVERED: Pharmacokinetic (PK) interaction is one of those issues that often have the potential to completely derail the product development process. The objective of the present article is to highlight PK challenges along with strategies to resolve them. EXPERT OPINION: A rationale development approach that integrates formulation and clinical insight, so as to understand the clinical significance of non-bioequivalence, would help to minimize the development timeline. While bioequivalence should always be the initial goal in the formulation development, failure to meet it should not immediately lead to reformulation. Instead, evaluating the PK of actives in FDCPs in approved market products, and their consequent clinical implications, would help to make rationale and pragmatic decisions. Such an approach will facilitate the initiation of clinical studies, without increasing the risk of failing to meet safety and efficacy end points, and in turn will significantly improve the productivity. PMID- 22250700 TI - LC determination and pharmacokinetic study of the main phenolic components of Portulaca oleracea L. extract in rat plasma after oral administration. AB - This study investigated the pharmacokinetics of hesperidin (HP), ferulic acid (FA) and p-coumaric acid (CA) in rat plasma after oral administration of Portulaca oleracea L. extract (POE). The plasma concentrations were determined by HPLC with vitexin-2"-O-rhamnoside (VR) as internal standard. The calibration curves were linear over the range 0.1-5 ug mL(-1), 0.1-5 ug mL(-1)and 0.015-3 ug mL(-1) for HP, FA and CA, respectively. The validated method was suitable to the pharmacokinetic study of HP, FA and CA in rats after oral administration at a single dose of POE. PMID- 22250701 TI - Experimental study on dynamic interfacial tension with mixture of SDS-PEG as surfactants in a coflowing microfluidic device. AB - In this work, a coflowing microfluidic device was used to determine the influence of different mixed sodium dodecyl sulfate (SDS)-poly(ethylene glycol) (PEG) compound systems on dynamic interfacial tension and, by extension, corresponding emulsion droplet sizes. The aqueous solutions were used as the continuous phase in the microfluidic device, while octane was used as the organic dispersed phase. Combined SDS-PEG systems lower the interfacial tension more than either component can alone up to the critical aggregation concentration (CAC) of SDS. Octane droplet sizes produced in the microfluidic device using combined SDS-PEG systems were smaller than those produced using SDS alone, and a reduction in dynamic interfacial tension as determined by drop size followed a pattern similar to that observed in the static case (PEG4000 > PEG600 > PEG400 > PEG200 > PEG8000) with the exception of PEG8000. Finally, a previously formulated model relating interfacial tension to droplet size was used to estimate the dynamic interfacial tensions in the microfluidic device. PMID- 22250702 TI - Quantitative protease cleavage site profiling using tandem-mass-tag labeling and LC-MALDI-TOF/TOF MS/MS analysis. AB - Knowledge of cleavage site specificity and activity are major prerequisites for understanding protease function. On the basis of a recently presented approach for proteomic identification of cleavage sites (PICS) in proteome-derived peptide libraries, we developed an isobaric labeling quantitative LC-MALDI-TOF/TOF MS/MS approach (Q-PICS) for simultaneous determination of cleavage site specificity and robust relative quantification of proteolytic events. For GluC-protease, 737 cleavage sites were identified in a yeast proteome-derived peptide library; 94.0% showed the typical GluC specificity for peptide bonds at glutamyl and aspartyl residues. The six-plex tandem mass tagging strategy allowed for three simultaneous replicates in a single run, guaranteeing high confidence and robust statistics for quantitative measurements. Using the quantitative capacity of Q PICS, we performed a comparison of cleavage site specificity of GluC in two different buffer systems. The results support earlier findings describing that apparent difference between the buffer systems are probably caused by the inhibitory effect of bicarbonate on the overall GluC activity and that the preference for Glu-X bonds compared to Asp-X bonds is independent of the buffer system used. PMID- 22250703 TI - Modeling analyte transport and capture in porous bead sensors. AB - Porous agarose microbeads, with high surface to volume ratios and high binding densities, are attracting attention as highly sensitive, affordable sensor elements for a variety of high performance bioassays. While such polymer microspheres have been extensively studied and reported on previously and are now moving into real-world clinical practice, very little work has been completed to date to model the convection, diffusion, and binding kinetics of soluble reagents captured within such fibrous networks. Here, we report the development of a three dimensional computational model and provide the initial evidence for its agreement with experimental outcomes derived from the capture and detection of representative protein and genetic biomolecules in 290 MUm porous beads. We compare this model to antibody-mediated capture of C-reactive protein and bovine serum albumin, along with hybridization of oligonucleotide sequences to DNA probes. These results suggest that, due to the porous interior of the agarose bead, internal analyte transport is both diffusion and convection based, and regardless of the nature of analyte, the bead interiors reveal an interesting trickle of convection-driven internal flow. On the basis of this model, the internal to external flow rate ratio is found to be in the range of 1:170 to 1:3100 for beads with agarose concentration ranging from 0.5% to 8% for the sensor ensembles here studied. Further, both model and experimental evidence suggest that binding kinetics strongly affect analyte distribution of captured reagents within the beads. These findings reveal that high association constants create a steep moving boundary in which unbound analytes are held back at the periphery of the bead sensor. Low association constants create a more shallow moving boundary in which unbound analytes diffuse further into the bead before binding. These models agree with experimental evidence and thus serve as a new tool set for the study of bioagent transport processes within a new class of medical microdevices. PMID- 22250704 TI - Analysis of early kidney damage in hospitalized patients with chronic kidney disease: a multicenter study. AB - BACKGROUND: To identify the risk factors for early kidney damage in hospitalized Chinese patients with chronic kidney disease (CKD). METHODS: A total of 12 multicenter cross-sectional studies were conducted between January 2005 and January 2006 in Chinese CKD patients with estimated glomerular filtration rate (eGFR) equal to or more than 30 mL/min/1.73 m2 in Shanghai. CKD was defined according to the K/DOQI guideline. GFR was estimated by the simplified modification of diet in renal disease equation. The demographic, clinical, and laboratory data were collected through a questionnaire and analyzed among eligible patients stratified by three different CKD groups (CKD stages 1, 2, and 3). The relevant clinical and laboratory risk factors for early kidney damage with a GFR < 90 mL/min/1.73 m2 were determined by logistic regression. RESULTS: A total of 822 CKD patients were enrolled in this study. There were significant differences in age and gender among patients with CKD stages 1, 2, and 3. The prevalence of hypertension, cardiovascular disease, cerebral vascular disease, anemia, and hyperuricemia increases when the eGFR declines. Logistic analysis showed that age, hypertension, anemia, and hyperuricemia were independently associated with early kidney damage. CONCLUSIONS: In CKD patients, we have identified only age, hypertension, anemia, and hyperuricemia as the risk factors for early kidney damage. Risk factors should be managed to prevent accelerated kidney damage in CKD patients. PMID- 22250705 TI - Development of interprofessional education in mental health practice: adapting the Leicester Model. AB - Mental health provides a unique opportunity for health and social care students to experience interprofessional team working and collaborative practice. We tested whether we could introduce interprofessional learning into this area of collaborative practice by choosing to adapt and use a robust practice-based interprofessional education model. We outline the steps taken to adopt and adapt the model, which includes using action research principles. The research phase consisted of three cycles of teaching and evaluation. Both qualitative and quantitative data were collected from all stakeholders, patients (n = 6), students (n = 300) and facilitators (n = 6). Qualitative data (focus groups, interviews and free text questionnaires) were analyzed using principles from grounded theory Stages 1 and 2; quantitative data were analyzed using SPSS. Problems and difficulties which led to changes in the course structure and delivery were identified. In the final phase, all students significantly achieved their learning outcomes (p < 0.01 to p < 0.001). The action learning approach for implementation helped to modify the course content and develop shared ownership by students, patients, clinicians and educators. The model provided a guide for replication and the final course adhered to interprofessional principles because patients with complex mental health problems were central to the learning, it overcame the theory-practice gap, the students gained insights into the realities of everyday team working and the experience of clinical uncertainty and, in addition, the learning interfaced with uniprofessional knowledge concerning mental health. The research findings highlight that patients with mental health problems can contribute to interprofessional teaching in the community. PMID- 22250706 TI - Editorial: Drug development in dermatology: new targets for old diseases? PMID- 22250707 TI - Psoriasis, from pathogenesis to therapeutic strategies: IL-21 as a novel potential therapeutic target. AB - Psoriasis is a common (1-3% of the population worldwide), multifactorial, immune mediated chronic skin disease. In psoriasis pathogenesis an over-reaction of local innate immune response initiates inflammation with subsequent involvement of adaptive immune response leading to the production of a panel of cytokines, chemokines and growth factors leading to epidermal hyperplasia. Recently, IL-21 has been involved in this process as this cytokine is overexpressed in psoriatic skin and can cause epidermal hyperplasia and inflammation when injected intradermally into mice. Moreover blockade of IL-21 with a human antibody against IL-21 reduces the epidermal thickness and the expression of Th1 and Th17 genes in the well-characterized model of human psoriasis-xenograft mouse. Therefore, the inhibition of this cytokine may be therapeutically effective in the treatment of psoriasis. Here we will review recent data on psoriasis pathogenesis focusing on the role of IL-21 as novel therapeutic target. PMID- 22250708 TI - Role of defensins and cathelicidin LL37 in auto-immune and auto-inflammatory diseases. AB - Defensins and cathelicidins are anti-microbial peptides (AMPs) that act as natural antibiotics and are part of the innate immune defence in many species. We consider human defensins and LL37, the only human member of the cathelicidin family. In particular, we refer to the human alpha-defensins called human neutrophil peptides (HNP1 through 4), which are produced by neutrophils, HD5 and HD6, mainly expressed in Paneth cells of intestine, the human beta-defensins HBD1, HBD2 and HBD3, synthesized by epithelial cells and LL37, which is located in granulocytes, but is also produced by epithelial cells of the skin, lungs, and gut. In the last years, the study of AMPs activity and regulation has allowed to understand the important role of these peptides not only in the innate defence mechanisms against bacteria, viruses, fungi, but also in the regulation of immune cell activation and migration. Complementary studies have disclosed a role for AMPs in modulating many physiological processes that involve non-immune cells, such as activation of wound healing, angiogenesis, cartilage remodeling. Due to the pleiotropic tasks of these peptides, many of them are now being discovered to contribute to immune pathology of chronic diseases that affect skin, gut, joints; this is supported by many examples of immune-mediated pathologies in which their expression is disregulated. In this article we review the current literature that suggests a role for human defensins and LL37 in pathogenic mechanisms of several chronic diseases that are considered of auto-immune or auto-inflammatory origin. PMID- 22250709 TI - New pharmaceutical concepts for sebaceous gland diseases: implementing today's pre-clinical data into tomorrow's daily clinical practice. AB - The human sebaceous gland is a microscopic branched type multiacinar gland been present everywhere on the body except on the palms and soles, whereas they are sparsely located on the dorsum of hands and feet. Several medical conditions are related with sebaceous gland pathology, such as acne, sebaceous hyperplasia, sebaceous adenoma and sebaceous carcinoma. Acne is a common, complex, chronic disorder of the human pilosebaceous unit that mostly occurs in adolescence and young adulthood. The sebaceous gland plays an exquisite role in the initiation of the disease. The multifactorial nature of the pathogenesis of acne includes increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, interaction with neuropeptides and dysregulation of the hormone microenvironment, follicular hyperkeratinization and inflammation maintained by Propionbacterium acnes products within the follicle. On the other hand, the sebaceous gland, as a major and critical compartment of human skin, is also affected through ageing, both intrinsic and extrinsic, which lead to distinct clinical and histological changes. Intrinsic ageing of the sebaceous gland is determined primarily by genetic factors and hormonal status, with androgens playing a major role. A clinical manifestation associated with intrinsic ageing changes is skin xerosis. Extrinsic ageing of human sebaceous gland is mainly caused by accumulating UV irradiation, especially UVA. Photoageing of sebaceous gland is expressed with a wide spectrum of benign and malignant sebaceous tumours, such as sebaceous hyperplasia, sebaceous carcinoma and Muir-Torre syndrome. This review will focus on the pathogenesis of the most common sebaceous gland diseases and their molecular pathways which may represent future pharmaceutical targets. PMID- 22250710 TI - Gene therapy of skin adhesion disorders (mini review). AB - Gene therapy is a potential treatment for severe inherited disorders for which there is little hope of finding a conventional cure. These include lethal diseases like immunodeficiencies and metabolic disorders, and non lethal conditions associated to poor quality of life and life-long symptomatic treatments, like muscular dystrophy, cystic fibrosis or thalassemia. Skin adhesion defects belong to both groups. For the non-lethal forms, gene therapy, or transplantation of cultured skin derived from genetically corrected epidermal stem cells, represents a very attractive therapeutic option, and potentially a definitive treatment. Recent advances in gene transfer and stem cell culture technology are making this option closer than ever. This paper critically reviews the progress and prospects of gene therapy for skin adhesion defects, and the factors currently limiting its development. PMID- 22250711 TI - Apoptotic pathways in the pathogenesis of pemphigus: targets for new therapies. AB - Pemphigus is a group of rare autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins, desmogleins, induce loss of cell-cell adhesion (acantholysis). In addition to steric hindrance and activation of intracellular phosphorylation cascade signaling pathways, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis. We review the literature examining the role of apoptosis in pemphigus. Current data recognize a central role of apoptosis in the mechanisms of blister induction. In particular, here we stress the key role of FasL in pemphigus, as it is able to first induce apoptosis, then acantholysis. Being pro apoptotic molecules important in blister formation, they could represent new specific targets for pemphigus treatment. PMID- 22250712 TI - Influence of specific amino acid side-chains on the antimicrobial activity and structure of bovine lactoferrampin. AB - Lactoferrin is an 80 kDa iron binding protein found in the secretory fluids of mammals and it plays a major role in host defence. An antimicrobial peptide, lactoferrampin, was identified through sequence analysis of bovine lactoferrin and its antimicrobial activity against a wide range of bacteria and yeast species is well documented. In the present work, the contribution of specific amino acid residues of lactoferrampin was examined to evaluate the role that they play in membrane binding and bilayer disruption. The structures of all the bovine lactoferrampin derivatives were examined with circular dichroism and nuclear magnetic resonance spectroscopy, and their interactions with phospholipids were evaluated with differential scanning calorimetry and isothermal titration calorimetry techniques. From our results it is apparent that the amphipathic N terminal helix anchors the peptide to membranes with Trp 268 and Phe 278 playing important roles in determining the strength of the interaction and for inducing peptide folding. In addition, the N-terminal helix capping residues (DLI) increase the affinity for negatively charged vesicles and they mediate the depth of membrane insertion. Finally, the unique flexibility in the cationic C-terminal region of bovine lactoferrampin does not appear to be essential for the antimicrobial activity of the peptide. PMID- 22250713 TI - Hospitalized patients' acceptability of nurse-delivered screening, brief intervention, and referral to treatment. AB - BACKGROUND: Inpatient healthcare providers in the United States may soon be required to offer alcohol screening, brief intervention, and referral to treatment (SBIRT) for hospital accreditation, but little is known about inpatient acceptability for SBIRT, particularly when performed by nonphysician providers such as nurses. The purpose of this study was to assess patient acceptability for and comfort with nurse-delivered SBIRT care among hospitalized patients and to identify factors associated with SBIRT acceptability. METHODS: We conducted a cross-sectional survey of 370 hospitalized medical-surgical patients at a large university-affiliated medical center, which is part of the U.S. Department of Veterans Affairs. RESULTS: Patient acceptability for 8 of 10 individual nurse delivered SBIRT tasks was >84%. Patients were more accepting of SBIRT tasks if they felt able to determine their alcohol risk, able to reduce alcohol-related health risks, and expressed some degree of concern about their own use of alcohol. Approximately 20% of patients reported some degree of personal discomfort with alcohol-related discussions. Patients who were less comfortable with these discussions had lower perceived ability to reduce alcohol-related health risk, were >60 years old, had a positive AUDIT-C screening, and were of nonblack race. CONCLUSIONS: Among hospitalized patients, patient acceptability for nurse-delivered SBIRT is high, and alcohol-related risk perceptions appear to be important factors associated with acceptability for SBIRT tasks. Providers can proceed with greater confidence in SBIRT-related discussions with most hospitalized patients but may need particular sensitivity and skill addressing alcohol with patient subgroups such as older patients and those with positive alcohol screenings. PMID- 22250714 TI - Magnetic resonance imaging enhancement of intervertebral disc disease in 30 dogs following chemical fat saturation. AB - OBJECTIVE: To describe the patterns of enhancement of extradural intervertebral disc on chemically fat saturated gadolinium-enhanced magnetic resonance images and to investigate the clinical and pathological associations with enhancement. METHODS: Medical records and magnetic resonance images were reviewed from 30 dogs with histopathologically confirmed disc disease and enhancement on a T1-weighted postcontrast fat saturated sequence. RESULTS: Median duration of neurological signs was 4 days and the most common grade of severity was II, seen in 46.6% of dogs. Homogeneous, heterogeneous and peripheral patterns of disc enhancement were described, with peripheral enhancement most commonly identified (57% of dogs). There were no clinical or pathological differences between the dogs with each of the patterns. The mean signal intensity of a region of interest within the extruded disc material and contrast-to-noise ratio of the disc material were significantly higher on postcontrast T1-weighted fat saturated images (P=<0.0001 each). CLINICAL SIGNIFICANCE: The use of fat saturated gadolinium-enhanced magnetic resonance imaging can detect enhancement of extradural disc material. Patterns of enhancement are not associated with the clinical presentation or pathological features. PMID- 22250716 TI - New model of radiation-induced skin ulcer in rats. AB - Our aim was to provide a new animal model for intractable skin ulcers in irradiated rats. Twenty-four rats were irradiated with total single radiographic irradiation doses of 10, 15, 20, and 30 Gy. The skin was observed for 6 months. In the 10-Gy group, there were no visible changes to the skin. In the 15-Gy group, epilation and depigmentation were seen about 2 weeks after irradiation. In the groups over 20-Gy, minor erosion or skin ulcers appeared in most rats. The wounds healed in the 20-Gy group, but many in the 30-Gy group could not be healed. A further 36 rats were irradiated with 20 Gy, and this was followed by the creation of cutaneous full-thickness defects at different periods. The size of the wounds was measured on days 0, 3, 5, 7, 10, and 14. Delayed wound healing was found in the irradiated groups compared with the unirradiated group (p = 0.01). There were no differences in the time of ulceration, except in the Day 7 group (p = 0.03). PMID- 22250717 TI - Fixation of trapezial implants in a trapeziometacarpal total joint prosthesis tested in a model of porcine bone. AB - High aseptic loosening rates have been reported in total joint prostheses of the carpometacarpal joint of the thumb, particularly in the trapezial component. The primary fixation of new implants may be tested in cadaver bones, but the anatomy of the pig is in many ways similar to that of the human, so we compared the central carpal bone from the forefoot of 6-month-old pigs, which has a saddle joint surface similar to the trapezium, to the trapezium in patients with carpometacarpal osteoarthritis. The mean (SD) bone mineral density of the 13 pig forefoot bones was 0.88 (0.12) g/cm(2) compared with 0.63 (0.16) g/cm(2) in the 31 human trapeziums. The measured size of the porcine bones was slightly larger than that of the human trapeziums. The similarity in form, size, and bone mineral density means that the central bone of the forefoot of 6-month-old pigs may be used for fixation tests in trapezial implants. PMID- 22250718 TI - Closure or reduction of the donor defect of a sural flap with a purse-string suture: long-term results. AB - We aimed to reduce the defect with a purse-string suture to minimise the deformity of the flap donor area and to assess the later efficiency at long-term follow-up. We studied 20 patients who required a sural flap for the reconstruction of defects of the lower extremity. The mean (SD) area of the donor defect was roughly 28.7 (20.3) cm(2). The mean (SD) defect area after closure with a purse-string was 8.2 (5.8) cm(2) (p < 0.001). The measurements made in the third year were 8.4 (5.3) cm(2). The purse-string can be used successfully in the distal lower extremity, the long-term cosmetic outcome is good, and the scar has not expanded since the postoperative period. PMID- 22250719 TI - Rising incidence of Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare, aggressive, skin cancer of obscure histogenesis, the incidence of which is rising. There is no consensus on the optimal treatment. Our aim was to evaluate the staging, investigation, treatment, and follow-up of MCC in eastern Denmark, and to investigate the incidence. We suggest guidelines for treatment. First we reviewed the medical records of 51 patients diagnosed with MCC from 1995 until 2006 in eastern Denmark. The nation wide incidence of MCC was extracted from the Danish Cancer Registry for the calculations for the period 1986-2003. We reviwed published papers about MCC based on a MEDLINE search. Fourteen of the 51 patients developed recurrence, and 37 (73%) died during the study period. Mean follow-up was 13 months (range 1 122). A total of 153 patients were identified in the Danish Cancer Registry, and showed that incidence rates had increased 5.4 fold over the 18 year period from 1986 until 2003. Rates were highest in people over the age of 65. Recommended treatment with curative intent includes excision of the primary tumour with wide margins, excision of the sentinel node, computed tomogram (CT) or positron emission tomography (PET) of the thorax and abdomen, and adjuvant radiotherapy to the surgical bed. In the case of advanced disease, systemic palliative chemotherapy remains a possibility. There is a need for prospective multicentre evaluation of staging investigations and treatment of MCC. PMID- 22250720 TI - Clinical experience of the treatment of giant congenital benign tumours of the back. AB - Congenital giant benign tumours of the back are rarely seen or reported. They pose two challenges to plastic surgeons: copious intraoperative bleeding, and an extensive raw area left after removal of the tumour. We have treated five cases of congenital giant benign tumour of the back. The largest was a neurofibroma in a woman, which weighed 36.29 kg and she had 10,000 ml of blood transfused to replace the blood loss during operation. We achieved total excision of the tumours in all cases and covered the extensive wounds with skin harvested from the tumours themselves in one stage. Among the five cases, four were neurofibromas and one was a giant naevus. All grafted skin took, and there were no recurrences. The tumours were radically excised in one stage and the extensive wounds covered with the skin with good take and no risk of recurrence. PMID- 22250721 TI - Body-contouring with radiofrequency-assisted liposuction. AB - Liposculpturing is the most frequently performed procedure in the aesthetic clinical practice. The techniques have evolved into significant modification during the past few decades with introduction of several new devices, leading to superior outcome. Radiofrequency-assisted liposuction (RFAL) have revolutionised body contouring techniques by providing simultaneous fat liquefaction, coagulation of blood vessels, and skin tightening in the tissues. In this study we discuss our preliminary experience with RFAL in treating patients for aesthetic body contouring and patients with HIV-related lipohypertrophy. Forty two patients were treated with RFAL for cosmetic concerns, and eight were treated for HIV-related lipohypertrophy after unsuccessful outcome with other techniques. Significant reduction of adipose tissue with marked tightening of the skin was noted in all the patients. Clinical results were impressive in terms of pain, recovery, and patient satisfaction. Remarkable improvement was observed in patients with HIV-related cervical lipohypertrophy and gynaecomastia with fibrous fatty tissue. Two patients suffered superficial burns and were managed conservatively. Our experience suggests that controlled application of radiofrequency power for liposculpturing may open up a new horizon of non excisional lipectomy in the future. PMID- 22250722 TI - Reconstruction of a fingertip with a thenar perforator island flap. AB - We raised thenar island flaps that were supplied by perforators that originated in the superficial palmar arch or the superficial palmar branch of the radial artery for the reconstruction of fingertip defects in eight patients. The flap was so well-vascularised that a large flap with increased mobility could be raised. The donor site was covered with well-vascularised thick tissue, and skin grafting of the donor site was avoided in all cases. No patient developed a complication, and all flaps survived. Functional and cosmetic results of both fingertips and donor sites were excellent. A perforator island flap from the thenar eminence can be raised easily without injuring any digital and palmar arteries. They have a good colour and texture that matches the fingertips and donor site defects on the palm. PMID- 22250723 TI - Prenatally-detected giant lymphatic malformation. AB - We present a case of a giant lymphatic malformation of the chest and abdominal wall that was diagnosed in the third trimester of pregnancy. It was treated by one stage excision with good functional and cosmetic outcomes. PMID- 22250724 TI - Bilateral macrodystrophia lipomatosa of the upper extremities with syndactyly and multiple lipomas. AB - Macrodystrophia lipomatosa is a rare disease that causes congenital local gigantism of part of an extremity, which is characterised by an increase in all mesenchymal elements, particularly fibroadipose tissue. This is the first report to our knowledge of a case of histologically confirmed bilateral macrodystrophia lipomatosa of the upper extremities with syndactyly and multiple lipomas. PMID- 22250725 TI - Sixty-year follow-up in an untreated patient with Kienbock disease. AB - Kienbock disease can be treated either conservatively or by various operations. We describe the findings of the progression of Kienbock disease over 60 years in an 84-year-old man who had had no surgical treatment. This is the longest follow up ever reported to our knowledge of a patient with avascular necrosis of the lunate. PMID- 22250726 TI - HMGA2 is commonly expressed in uterine serous carcinomas and is a useful adjunct to diagnosis. AB - AIMS: Serous carcinoma is the prototype of type 2 uterine carcinoma. In many cases, establishing a diagnosis is straightforward, but problems can arise in that papillary variants of endometrioid carcinoma may be mistaken for serous carcinoma, and glandular variants of serous carcinoma may be misdiagnosed as endometrioid carcinoma. Markers such as p53, oestrogen receptor and p16 may be of use in problematic cases, but there is overlap and these may not therefore be of value in an individual case. It has been shown recently that high-mobility group AT-hook 2 (HMGA2) is expressed by most ovarian serous carcinomas, and our aim was to ascertain whether it is also expressed in uterine serous carcinoma and of value in its distinction from endometrioid carcinoma. METHODS AND RESULTS: Whole tissue sections of uterine serous (n = 33) and endometrioid (n = 38) carcinoma were immunostained using HMGA2 antibody. As many of the diagnostic problems relate to the distinction between serous carcinoma and grade 3 endometrioid carcinoma, tissue microarrays (TMAs) containing uterine serous (n = 71) and uterine grade 3 endometrioid (n = 68) carcinomas were also stained. Staining was classified as negative (totally negative or occasional nuclei positive), 1+ (<10% of nuclei positive), 2+ (10-49% of nuclei positive), 3+ (50-74% of nuclei positive), or 4+ (>=75% of nuclei positive). On the whole tissue sections, positive staining was also classified as weak, moderate, or strong, and an immunohistochemical composite score, taking into account both extent and intensity of staining, was calculated. On whole tissue sections, there was a statistically significant difference between HMGA2 staining in serous and endometrioid carcinomas with regard to both extent and composite score, with higher expression in serous carcinomas (P < 0.0001). Thirty of 33 (91%) serous carcinomas were positive, usually with diffuse (3+ or 4+) staining. All five cases of serous endometrial intraepithelial carcinoma (EIC) (the postulated precursor of uterine serous carcinoma) were positive, as were 14 of 38 (37%) endometrioid carcinomas, usually with 1+ or 2+ staining. There was a statistically significant difference in HMGA2 staining in the TMAs between the serous and grade 3 endometrioid carcinomas, with higher expression in the former (P < 0.0001). CONCLUSIONS: Immunoreactivity for HMGA2 is diffusely positive in whole tissue sections in most uterine serous carcinomas and negative in most endometrioid carcinomas, although, as with other markers, there is overlap in individual cases. In conjunction with other markers, HMGA2 may be of value in problematic uterine carcinomas where the differential diagnosis includes serous and endometrioid carcinoma. As HMGA2 is expressed in serous EIC, this suggests that it may be implicated in the early development of uterine serous carcinoma. PMID- 22250727 TI - Effect of orange juice's processing on the color, particle size, and bioaccessibility of carotenoids. AB - This study was aimed at assessing the differences between industrially processed and hand-squeezed orange juices (OJs) in relation to their color, particle size, carotenoid content, and carotenoid bioaccessibility. Specifically, industrial samples of fresh squeezed OJs after the finishing steps (FISO) and the same OJs after pasteurization (PISO), as well as hand-squeezed OJs (HSO) were studied. The results showed that the HSO and PISO were different (p < 0.05) in terms of color (darker and more reddish vs brighter, more yellowish and colorful), particle size (volume and surface area mean diameter), and total carotenoid content (29 +/- 5 and 22 +/- 3 mg/L, respectively). On the other hand, the industrial extraction of OJs reduced the particle size distribution, and accordingly, the relative bioaccessibility of bioactive carotenoids increased (p < 0.01). Independently of the type of OJ, the bioaccessibility of carotenoids in decreasing order was the following: alpha-carotene > beta-cryptoxanthin > beta-carotene > zeaxanthin > lutein. PMID- 22250728 TI - Tracking earthworm communities from soil DNA. AB - Earthworms are known for their important role within the functioning of an ecosystem, and their diversity can be used as an indicator of ecosystem health. To date, earthworm diversity has been investigated through conventional extraction methods such as handsorting, soil washing or the application of a mustard solution. Such techniques are time consuming and often difficult to apply. We showed that combining DNA metabarcoding and next-generation sequencing facilitates the identification of earthworm species from soil samples. The first step of our experiments was to create a reference database of mitochondrial DNA (mtDNA) 16S gene for 14 earthworm species found in the French Alps. Using this database, we designed two new primer pairs targeting very short and informative DNA sequences (about 30 and 70 bp) that allow unambiguous species identification. Finally, we analysed extracellular DNA taken from soil samples in two localities (two plots per locality and eight samples per plot). The two short metabarcode regions led to the identification of a total of eight earthworm species. The earthworm communities identified by the DNA-based approach appeared to be well differentiated between the two localities and are consistent with results derived from inventories collected using the handsorting method. The possibility of assessing earthworm communities from hundreds or even thousands of localities through the use of extracellular soil DNA will undoubtedly stimulate further ecological research on these organisms. Using the same DNA extracts, our study also illustrates the potential of environmental DNA as a tool to assess the diversity of other soil-dwelling animal taxa. PMID- 22250729 TI - The quality of veterinary in-clinic and reference laboratory biochemical testing. AB - BACKGROUND: Although evaluation of biochemical analytes in blood is common in veterinary practice, studies assessing the global quality of veterinary in-clinic and reference laboratory testing have not been reported. OBJECTIVE: The aim of this study was to assess the quality of biochemical testing in veterinary laboratories using results obtained from analyses of 3 levels of assayed quality control materials over 5 days. METHODS: Quality was assessed by comparison of calculated total error with quality requirements, determination of sigma metrics, use of a quality goal index to determine factors contributing to poor performance, and agreement between in-clinic and reference laboratory mean results. The suitability of in-clinic and reference laboratory instruments for statistical quality control was determined using adaptations from the computerized program, EZRules3. RESULTS: Reference laboratories were able to achieve desirable quality requirements more frequently than in-clinic laboratories. Across all 3 materials, > 50% of in-clinic analyzers achieved a sigma metric >= 6.0 for measurement of 2 analytes, whereas > 50% of reference laboratory analyzers achieved a sigma metric >= 6.0 for measurement of 6 analytes. Expanded uncertainty of measurement and +/- total allowable error resulted in the highest mean percentages of analytes demonstrating agreement between in-clinic and reference laboratories. Owing to marked variation in bias and coefficient of variation between analyzers of the same and different types, the percentages of analytes suitable for statistical quality control varied widely. CONCLUSION: These findings reflect the current state-of-the-art with regard to in-clinic and reference laboratory analyzer performance and provide a baseline for future evaluations of the quality of veterinary laboratory testing. PMID- 22250730 TI - Declines in employer-sponsored insurance between 2000 and 2008: examining the components of coverage by firm size. AB - OBJECTIVE: To examine trends in employer-sponsored health insurance coverage rates and its associated components between 2000 and 2008, to provide a baseline for later evaluations of the Affordable Care Act, and to provide information to policy makers as they design the implementation details of the law. DATA SOURCES: Private sector employer data from the 2000, 2001, and 2008 Medical Expenditure Panel Survey-Insurance Component (MEPS-IC). STUDY DESIGN: We examine time trends in employer offer, eligibility, and take-up rates. We add a new dimension to the literature by examining dependent coverage and decomposing its trends. We investigate heterogeneity in trends by firm size. DATA COLLECTION: The MEPS-IC is an annual survey, sponsored by the Agency for Healthcare Research and Quality and conducted by the U.S. Census Bureau. The MEPS-IC obtains information on establishment characteristics, whether an establishment offers health insurance, and details on up to four plans. PRINCIPAL FINDINGS: We find that coverage rates for workers declined in both small and large firms. In small firms, coverage declined due to a drop in both offer and take-up rates. In the largest firms, offer rates were stable and the decline was due to falling take-up rates. In addition, enrollment shifted toward single coverage and away from dependent coverage in both small and large firms. For small firms, this shift was due to declining offer and take-up rates for dependent coverage. In large firms, offers of dependent coverage were stable but take-up rates dropped. Within the category of dependent coverage, the availability of employee-plus-one plans increased in all firm size categories, but take-up rates for these plans declined in small firms. PMID- 22250731 TI - A case of false-negative monochromator phototesting in a patient with chronic actinic dermatitis taking prednisolone. PMID- 22250732 TI - Polymorphism of insulin-like growth factor 1 gene is associated with breast muscle yields in chickens. AB - Insulin-like growth factor-1 (IGF1) plays an important role in muscle development in chickens. In this study, an F2 chicken population of 362 individuals, obtained from an intercross between high breast muscle yield line males and low breast muscle yield (LB) line females, was constructed for investigating the associations between IGF1 gene and breast muscle yields. The IGF1 sequence was investigated in the grandparents. There were no differences in the exon sequences. However, sequence analysis of the IGF1 promoter revealed a known single nucleotide polymorphism (g.570C>A) in LB line grandparents. PCR - restriction fragment length polymorphism was used for screening the F2 population, which was evaluated for body weight (BW), carcass weight (CW), breast muscle weight (BMW), and breast fillet weight (BFW). Significant associations with the polymorphism were detected for BMW, BFW, BMW% and BFW%, although there were no associations between the polymorphism and BW or CW. The allelic effect on BMW, BFW, BMW% and BFW% acted in additive and dominance modes. We confirmed that the g.570C>A polymorphism is significantly associated with breast muscle yields in the F2 population. Therefore, this polymorphism in the IGF1 gene may help improve breast muscle yields by marker-assisted selection. PMID- 22250733 TI - Identification of divergently selected regions between Japanese Black and Holstein cattle using bovine 50k SNP array. AB - Differences between average allelic frequencies of genes that relate to traits suggest that it would be evidence of artificial selections. Sliding window approach is a useful method to identify genomic regions that have been differently selected between two breeds. The objective of this study was to identify the divergently selected regions between Japanese Black (JB) and Japanese Holstein (JH) cattle based on genotypic information obtained through a high-density single nucleotide polymorphism (SNP) panel. After genotyping of 54 001 SNP markers on 100 animals (50 JB and 50 JH), 40 635 SNPs were suitable for the analysis. For each of these SNPs, the absolute difference between allelic frequencies of JB and JH was calculated. In the current study, 10 consecutive SNPs were defined as components of a window. For each window, the average difference in allelic frequency was calculated. This was termed sliding window average difference (SWAD). Among 40 055 windows, we focused on 39 windows with the largest SWAD. This was equivalent to 0.1% of all windows and the SWAD was more than 0.435. Some of these windows overlapped and were distributed in 11 regions. These regions were in good agreement with reported quantitative trait locus, therefore would be selection signatures and good candidates that harbor the causative mutations. PMID- 22250734 TI - Population structure of pigs determined by single nucleotide polymorphisms observed in assembled expressed sequence tags. AB - We have collected more than 190000 porcine expressed sequence tags (ESTs) from full-length complementary DNA (cDNA) libraries and identified more than 2800 single nucleotide polymorphisms (SNPs). In this study, we tentatively chose 222 SNPs observed in assembled ESTs to study pigs of different breeds; 104 were selected by comparing the cDNA sequences of a Meishan pig and samples of three way cross pigs (Landrace, Large White, and Duroc: LWD), and 118 were selected from LWD samples. To evaluate the genetic variation between the chosen SNPs from pig breeds, we determined the genotypes for 192 pig samples (11 pig groups) from our DNA reference panel with matrix-assisted laser desorption ionization time-of flight mass spectrometry. Of the 222 reference SNPs, 186 were successfully genotyped. A neighbor-joining tree showed that the pig groups were classified into two large clusters, namely, Euro-American and East Asian pig populations. F statistics and the analysis of molecular variance of Euro-American pig groups revealed that approximately 25% of the genetic variations occurred because of intergroup differences. As the F(IS) values were less than the F(ST) values(,) the clustering, based on the Bayesian inference, implied that there was strong genetic differentiation among pig groups and less divergence within the groups in our samples. PMID- 22250735 TI - Association of toll-like receptor 2 polymorphisms with somatic cell score in Xinjiang Brown cattle. AB - This study aims to identify single nucleotide polymorphisms (SNPs) and haplotypes in the TLR2 gene, and analyze the association of SNPs or haplotypes and somatic cell scores in 151 Xinjiang Brown cattle and 138 Holsteins to evaluate the role of TLR2 during intramammary infections. TLR2 coding region was amplified by PCR and screened for SNP sequencing. Genotypes and frequencies of SNPs were identified. Finally, the associations of genotypes or haplotypes and somatic cell scores (SCS) were analyzed. The results showed that: (i) 15 SNPs (E+653, E+945, E+978, E+1010, E+1250, E+1688, E+1707, E+1779, E+1782, E+1891, E+1995, E+2025, E+2055, E+2214 and E+2295) were observed and detected from 289 cows; (ii) distribution of the 14 SNPs were significantly different from Xinjiang Brown cattle and Holstein (P<0.001) except for the E+945 (P>0.05); (iii) in 11 SNPs (E+945, E+978, E+1010, E+1688, E+1707, E+1779, E+1782, E+1995, E+2025, E+2055 and E+2214), the SCS of AB genotype was lower than AA (P<0.05) in Xinjiang Brown cattle; and (iv) haplotypes composed of the above-mentioned 11 SNPs were constructed. The SCS of cattle with Hap5 was lower than that of Hap3 (P<0.05). This suggests that Hap5 might play an important role in sub-mastitis resistance in Xinjiang Brown cattle. PMID- 22250736 TI - Addition of erythrocytes to in vitro culture medium attenuates the detrimental effects of reactive oxygen species on bovine preimplantation embryo development. AB - Erythrocytes were recently found to improve the early development of mice embryos by their antioxidant effect. The purpose of the present study was to examine the effect of erythrocytes on the in vitro development of bovine in vitro fertilized (IVF) embryos in medium supplemented with reactive oxygen species (ROS). IVF embryos were cultured in CR1aa medium supplemented with oxidizing agents, 0.5mmol/L hypoxanthine and 0.01U/mL xanthine oxidase (HX/XOD), in the presence and absence of erythrocytes (5*10(4) , 5*10(5) , 5*10(6) and 5*10(7) erythrocytes/mL). After 8 days, blastocysts were examined with a stereomicroscope. HX/XOD blocked development to the blastocyst stage (HX/XOD: 0%, control: 33%), but in the presence of both erythrocytes and HX/XOD, blastocyst development was restored to about one-third to two-thirds the normal rate (5*10(5) to 5*10(7) erythrocytes/mL: 12 to 23%). Furthermore, adding erythrocytes or erythrocyte hemolysate to medium without HX/XOD increased the blastocyst rate. These results suggest that the addition of erythrocytes can attenuate the detrimental effects of ROS on embryo development in bovine species as well as in mice. PMID- 22250737 TI - Effects of a combination of hinokitiol (beta-thujaplicin) and an organic acid mixture on ruminal fermentation in heifers fed a high-grain diet. AB - This study evaluated the effects of hinokitiol (a natural antibacterial compound extracted from Thujopsis dolabrata var. hondai) and an organic acid mixture (citrate content 50%) on ruminal fermentation. Antibacterial properties were examined by measuring minimal inhibitory concentration. Hinokitiol at 1.56ug/mL or an organic acid mixture at 1600ug/mL inhibited Streptococcus bovis growth. The combination of 0.78ug/mL hinokitiol and 200ug/mL of an organic acid mixture also inhibited S. bovis growth. Both hinokitiol and the hinokitiol and an organic acid mixture combination showed strong antibacterial properties on Gram-positive bacteria such as S. bovis, but relatively weak antibacterial activities on Gram negative bacteria such as Megasphaera elsdenii. Three ruminally cannulated heifers were fed a bloat-producing diet containing barley, pelleted alfalfa meal, soybean meal and salt without long-cut roughage to investigate the ruminal characteristics in vivo. Feeding to heifers a bloat-producing diet containing 7.8mg/kg hinokitiol and 0.2% of an organic acid mixture significantly decreased the increase in stable ingesta volume. Hinokitiol or an organic acid mixture did not affect ruminal volatile fatty acids, protozoa and bacteria. These results suggest that a combination of hinokitiol and an organic acid mixture might reduce frothy bloat in cattle fed high-grain diets. PMID- 22250738 TI - Bean husks as a supplemental fiber for ruminants: potential use for activation of fibrolytic rumen bacteria to improve main forage digestion. AB - This study evaluated the suitability of easily digested fiber sources as a supplemental fiber to improve overall fiber digestion in ruminants. First, the degradation of five fibrous feedstuffs and the stimulatory effects on rumen bacteria were examined in situ. Chickpea and lablab bean husks were selected for their potential use due to their large degradable fraction (>94%), which had a stimulatory effect on fibrolytic rumen bacteria such as Fibrobacter succinogenes. Second, a possible improvement in the digestibility of rice straw diet by husk supplementation was monitored in vivo. Four dietary treatments comprising RS (rice straw and concentrate), CHM (RS supplemented with Myanmar chickpea husk), CHE (RS with Egyptian chickpea husk) and LH (RS with lablab bean husk) were allocated to four wethers. The digestibility of acid detergent fiber was 3.1-5.5% greater in CHM and LH than RS. Total volatile fatty acid concentration was higher in LH than other treatments. Acetate proportion was higher in LH than RS. Ruminal abundance of F. succinogenes was 1.3-1.5 times greater in CHM and LH than RS. These results suggest that bean husk supplementation, especially lablab bean husk, might improve the nutritive value of rice straw diet by stimulating fibrolytic bacteria. PMID- 22250739 TI - Effects of plane of nutrition on growth, feed intake, digestibility and nitrogen balance in Murrah graded male buffalo (Bubalus bubalis) calves in Nepal. AB - An experiment was conducted using 17 male buffalo calves to assess the effects of plane of nutrition on dry matter intake (DMI), daily gain (DG), body size measurement, apparent digestibility and nitrogen (N) balance. To attain 250kg BW, the calves were allocated into three groups: H, L-H and L, receiving the concentrate at 1.50% of BW, 0.75% of BW until 190kg BW and 1.50% thereafter and 0.75% of BW, respectively. The animals had ad libitum access to urea-treated rice straw (UTRS). The DMI of UTRS through the experiment was higher in L and L-H than H, showing 3.52, 2.90 and 2.62kg/day, respectively (P<0.01), but the total DMI did not differ among the treatment groups. The DG throughout the experiment was high in the order of H, L-H and L, showing 0.72, 0.57 and 0.45kg, respectively (P<0.01). The digestibility of DM, organic matter, crude protein, neutral and acid detergent fiber and N retention were higher in H than in L (P<0.05). The findings of this study thus revealed the greater DG has an advantage of shortening the growing period around 3months, and consequently increasing benefit in fattening of buffalo calves in Nepal. PMID- 22250740 TI - Effects of fermented mushroom (Flammulina velutipes) by-product diets on growth performance and carcass traits in growing-fattening Berkshire pigs. AB - This study was conducted to investigate effects of fermented mushroom (Flammulina velutipes) by-product diets on the growth performance and carcass traits in growing-fattening Berkshire pigs. The fermented diets mainly contained 40.0% mushroom by-product, 20.0% formula feed, 26.0% rice bran and supplemental 0.1% probiotics. The mixed ingredients were fermented for 5days at room temperature. Berkshire pigs (n=225) were divided into five groups and three replications. The basal diets (C) were substituted by 10% (T1), 30% (T2), 50% (T3) and 70% (T4) fermented mushroom by-product diets. Crude protein concentration and total calorie in fermented diets were significantly increased (P<0.05) at the end of fermentation days compared with initial fermentation day. Body weight gain, feed efficiency and carcass weight were significantly lower (P<0.05) in the T2, T3 and T4 groups than in the control group. Carcass grade was significantly better (P<0.05) in the pigs fed fermented diets than in the pigs fed control diet and the ratio of high grade (1 plus 2 grades) was higher in the fermented diet groups compared with the control group. Therefore, although a diet of fermented mushroom by-product decreased growth performance and feed efficiency, it improved the carcass grade in Berkshire pigs. PMID- 22250741 TI - Bromocriptine inhibits salsolinol-induced prolactin release in male goats. AB - The secretion of prolactin (PRL) is under the dominant and tonic inhibitory control of dopamine (DA); however, we have recently found that salsolinol (SAL), an endogenous DA-derived compound, strongly stimulated the release of PRL in ruminants. The aim of the present study was to clarify the inhibitory effect of DA on the SAL-induced release of PRL in ruminants. The experiments were performed from late June to early July. Male goats were given a single intravenous (i.v.) injection of SAL (5mg/kg body weight (BW)), a DA receptor antagonist (sulpiride, 0.1mg/kg BW), or thyrotropin-releasing hormone (TRH, 1ug/kg BW) before and after treatment with a DA receptor agonist (bromocriptine), and the effect of DA on SAL induced PRL release was compared to that on sulpiride- or TRH-induced release. Bromocriptine completely inhibited the SAL-induced release of PRL (P<0.05), and the area under the response curve (AUC) for a 120-min period after the treatment with bromocriptine was 1/28 of that for before the treatment (P<0.05). Bromocriptine also completely inhibited the sulpiride-induced release (P<0.05). The AUC post-treatment was 1/17 that of pre-treatment with bromocriptine (P<0.05). Bromocriptine also inhibited the TRH-induced release (P<0.05), though not completely. The AUC post-treatment was 1/3.8 that of pre-treatment (P<0.05). These results indicate that DA inhibits the SAL-induced release of PRL in male goats, and suggest that SAL and DA are involved in regulating the secretion of PRL. They also suggest that in terms of the regulatory process for the secretion of PRL, SAL resembles sulpiride but differs from TRH. PMID- 22250742 TI - Immunomodulatory effects of Alliums and Ipomoea batata extracts on lymphocytes and macrophages functions in White Leghorn chickens: in vitro study. AB - We previously described that supplementary garlic, onion and purple sweet potato (PSP) enhance humoral immune response in White Leghorn chickens. In the present in vitro study, we investigated the effects of garlic (GE), onion (OE) and PSP (PSPE) extracts on proliferation, interleukin (IL)-2 and interferon (INF)-gamma gene expression of stimulated lymphocytes. The effects on microbicidal activity, reactive oxygen species (ROS) and nitric oxide (NO) productions of stimulated peritoneal macrophages were studied as well. The results showed that GE augmented Concanavalin A (ConA)-induced splenocytes (4, 8 and 16ug/mL) and thymocytes (2, 4 and 8ug/mL) proliferations, and gene expression of IL-2 (8 and 16ug/mL) and INF gamma (16ug/mL). None of the examined extracts had mitogenic effect nor stimulated bursacytes response to phorbol 12-myristate 13-acetate (PMA). Macrophages exhibited superior microbicidal activity and ROS production with GE at 4 and 8ug/mL and with OE at 25.6ug/mL. None of the extracts showed stimulatory effects on NO production. The extracts showed concentration-dependent inhibitory effects on all measured parameters at higher concentrations. Taken together, it is likely that garlic has direct stimulatory effects on immune cell functions, whereas the in vitro inhibitory effects of onion and PSP were likely attributed to high flavonoid contents. PMID- 22250743 TI - Effects at early stage of life of elevated milk replacer feeding on growth rate, plasma IGF-I concentration and intestinal nutrient transporter expression in Holstein bull calves. AB - In order to evaluate the effects of an elevated amount of modified milk replacer on body weight, daily gain, starter intake, plasma endocrine parameters and expression of nutrient transporters in small intestinal epithelia, Holstein bull calves (n=24) were fed for 60days either with the usual amount of 24% crude protein (CP) and 20% fat milk (CF) replacer (C group), or with a double amount of a modified milk replacer of 28% CP and 16% CF (E group). Body weight from D20 to D60 and daily gain before D40 was greater or tended to be greater for the E group than the C group. Plasma concentrations of insulin-like growth factor-1 (IGF-I) and insulin were greater for the E group than the C group on D28 but not on D56, without changing plasma growth hormone levels. Gene expression for sodium dependent glucose transporter 1 and fatty acid translocase (CD36) was altered in day- and intestine-dependent manners. From these findings, we conclude that an elevated intake of milk replacer given up to 40days old is sufficient to enhance body weight, which may be associated with increased plasma IGF-I concentrations, in Holstein bulls. PMID- 22250744 TI - The W- and Z-linked EE0.6 sequences used for molecular sexing of captive Japanese crested ibis on Sado Island. AB - The Japanese crested ibis Nipponia nippon is a critically threatened bird. Accurate sexing is necessary to perform effective management of captive breeding toward a national project for a tentative release of the Japanese crested ibis on Sado Island. A PCR-based sexing method targeting a 0.6 kb EcoRI fragment (EE0.6) sequence on W chromosome with AWS03 and USP3 primers has been developed for the Japanese crested ibis. However, the primers were selected from the EE0.6 sequences from bird species other than the Japanese crested ibis. In this study, we determined the W- and Z-linked EE0.6 sequences in the Japanese crested ibis, and clarified Japanese crested ibis sequence mismatch in the binding sites of the primers. Further, we found no polymorphism in the primer binding sites among five founder birds for the Sado captive Japanese crested ibis population. These findings validated the PCR-based sexing method with the AWS03 and USP3 as accurate molecular sexing methods of captive Japanese crested ibis on the Sado Island. Additionally, we designed a primer set for a novel PCR-based sexing, based on the EE0.6 sequences obtained in this study. This novel sexing method may be useful for future ecological research following the release of Japanese crested ibis on Sado Island. This is the first report to show the EE0.6 sequences in Japanese crested ibis. PMID- 22250745 TI - Expression analysis of an alpha-1, 3-galactosyltransferase, an enzyme that creates xenotransplantation-related alpha-Gal epitope, in pig preimplantation embryos. AB - alpha-1,3-Galactosyltransferase (alpha-GalT), an enzyme creating Galalpha1-3Gal (alpha-Gal) epitope on the cell surface in some mammalian species such as pigs, is known to be a key factor that causes hyperacute rejection upon transplantation from pigs to humans. To establish the RNA interference-based suppression of endogenous alpha-GalT messenger RNA (mRNA) synthesis in porcine preimplantation embryos, we determined the suitable embryonic stage at which stage such approach is possible by using the semi-quantitative RT-PCR (qRT-PCR) and the cytochemical method using a fluorescence-labeled Bandeiraea simplicifolia Isolectin B(4) (BS I-B(4) ). Staining with BS-I-B(4) demonstrated that alpha-Gal epitope expression was first recognized at the 8-cell stage, and increased up to the hatched blastocyst stage. Single embryo-based qRT-PCR also confirmed this pattern. These results indicate that creation of alpha-Gal epitope is proceeded by de novo synthesis of alpha-GalT mRNA in porcine preimplantation embryos with peaking at the blastocyst stage. PMID- 22250746 TI - Small regulatory RNAs control the multi-cellular adhesive lifestyle of Escherichia coli. AB - Small regulatory RNA molecules have recently been recognized as important regulatory elements of developmental processes in both eukaryotes and bacteria. We here describe a striking example in Escherichia coli that can switch between a single-cell motile lifestyle and a multi-cellular, sessile and adhesive state that enables biofilm formation on surfaces. For this, the bacterium needs to reprogramme its gene expression, and in many E. coli and Salmonella strains the lifestyle shift relies on control cascades that inhibit flagellar expression and activate the synthesis of curli, extracellular adhesive fibres important for co aggregation of cells and adhesion to biotic and abiotic surfaces. By combining bioinformatics, genetic and biochemical analysis we identified three small RNAs that act by an antisense mechanism to downregulate translation of CsgD, the master regulator of curli synthesis. Our demonstration that basal expression of each of the three RNA species is sufficient to downregulate CsgD synthesis and prevent curli formation indicates that all play a prominent role in the curli regulatory network. Our findings provide the first clue as to how the Rcs signalling pathway negatively regulates curli synthesis and increase the number of small regulatory RNAs that act directly on the csgD mRNA to five. PMID- 22250747 TI - Rapid detection, characterization, and enumeration of foodborne pathogens. AB - As food safety management further develops, microbiological testing will continue to play an important role in assessing whether Food Safety Objectives are achieved. However, traditional microbiological culture-based methods are limited, particularly in their ability to provide timely data. The present review discusses the reasons for the increasing interest in rapid methods, current developments in the field, the research needs, and the future trends. The advent of biotechnology has introduced new technologies that led to the emergence of rapid diagnostic methods and altered food testing practices. Rapid methods are comprised of many different detection technologies, including specialized enzyme substrates, antibodies and DNA, ranging from simple differential plating media to the use of sophisticated instruments. The use of non-invasive sampling techniques for live animals especially came into focus with the 1990s outbreak of bovine spongiform encephalopathy that was linked to the human outbreak of Creutzfeldt Jakob's Disease. Serology is still an important tool in preventing foodborne pathogens to enter the human food supply through meat and milk from animals. One of the primary uses of rapid methods is for fast screening of large number of samples, where most of them are expected to be test-negative, leading to faster product release for sale. This has been the main strength of rapid methods such as real-time Polymerase Chain Reaction (PCR). Enrichment PCR, where a primary culture broth is tested in PCR, is the most common approach in rapid testing. Recent reports show that it is possible both to enrich a sample and enumerate by pathogen-specific real-time PCR, if the enrichment time is short. This can be especially useful in situations where food producers ask for the level of pathogen in a contaminated product. Another key issue is automation, where the key drivers are miniaturization and multiple testing, which mean that not only one instrument is flexible enough to test for many pathogens but also many pathogens can be detected with one test. The review is mainly based on the author's scientific work that has contributed with the following new developments to this field: (i) serologic tests for large-scale screening, surveillance, or eradication programs, (ii) same-day detection of Salmonella that otherwise was considered as difficult to achieve, (iii) pathogen enumeration following a short log-phase enrichment, (iv) detection of foodborne pathogens in air samples, and finally (v) biotracing of pathogens based on mathematical modeling, even in the absence of isolate. Rapid methods are discussed in a broad global health perspective, international food supply, and for improvement of quantitative microbial risk assessments. The need for quantitative sample preparation techniques, culture-independent, metagenomic-based detection, online monitoring, a global validation infrastructure has been emphasized. The cost and ease of use of rapid assays remain challenging obstacles to surmount. PMID- 22250748 TI - alpha-Terpinene, an antioxidant in tea tree oil, autoxidizes rapidly to skin allergens on air exposure. AB - The monoterpene alpha-terpinene is used as a fragrance compound and is present in different essential oils. It is one of the components responsible for the antioxidant activity of tea tree oil. alpha-Terpinene is structurally similar to other monoterpenes, e.g., limonene, known to autoxidize on air exposure and form allergenic compounds. The aim of the present study was to investigate the possible autoxidation of alpha-terpinene at room temperature. To investigate the sensitization potency of air-exposed alpha-terpinene and the oxidation products formed, the murine local lymph node assay was used. Chemical analysis showed that alpha-terpinene degrades rapidly, forming allylic epoxides and p-cymene as the major oxidation products and also hydrogen peroxide. Thus, the oxidation pathway differs compared to that of, e.g., limonene, which forms highly allergenic hydroperoxides as the primary oxidation products on autoxidation. The sensitization potency of alpha-terpinene was increased after air-exposure. The allylic epoxides and a fraction, in which only an alpha,beta-unsaturated aldehyde could be identified, were shown to be strong sensitizers in the local lymph node assay. Thus, we consider them to be the major contributors to the increased sensitization potency of the autoxidized mixture. We also investigated the presence of alpha-terpinene and its oxidation products in four different tea tree oil samples of various ages. alpha-Terpinene and its oxidation products were identified in all of the tea tree oil samples. Thus, from a technical perspective, alpha-terpinene is a true antioxidant since it autoxidizes rapidly compared with many other compounds, preventing these from degradation. However, as it easily autoxidizes to form allergens, its suitability can be questioned when used in products for topical applications, e.g., in tea tree oil but also in cosmetics and skin care products. PMID- 22250749 TI - Autolytic degradation of skipjack tuna during heating as affected by initial quality and processing conditions. AB - Several factors were studied as affecting protein degradation and texture of skipjack tuna muscle following ambient pressure thermal processing (precooking). These included degree of mushy tuna syndrome (MTS) evidenced in the raw meat, raw meat pH, abusive thawing/holding, and precooking temperature/time. Slurries and intact pieces from frozen skipjack tuna, either tempered for 2 h or thawed and held at 25 degrees C for 22 h (abusive treatment) were heated at temperatures ranging from 40 to 80 degrees C for up to 2 h, and also at 90 degrees C for 1 h, with or without prior adjustment of pH to 5 or 7 to favor cathepsin or calpain activity, respectively. Proteolysis of precooked samples was monitored by Lowry assay and SDS-PAGE; cooked texture of intact meat was measured using a Kramer shear press and by sensory profile analysis. Proteolysis maximally occurred in slurries of skipjack tuna muscle that had been abusively stored (22 h at 25 degrees C) and adjusted to pH 5 prior to heating at 55 degrees C. Intact pieces of tuna abusively thawed/held for 22 h with subsequent heating at 55 degrees C also evidenced the most proteolysis and were the least firm in texture. Raw fish that evidenced higher severity of MTS when raw displayed higher levels of proteolysis prior to cooking, which were further increased after cooking at 55 degrees C. PRACTICAL APPLICATION: The kinetic data presented here can be used to optimize processing conditions for skipjack tuna canning to minimize textural degradation and optimize quality. PMID- 22250750 TI - Association of chemotherapeutic drugs with dendrimer nanocarriers: an assessment of the merits of covalent conjugation compared to noncovalent encapsulation. AB - Cancer is a leading cause of death within developed nations, and part of this morbidity is due to difficulties associated with its treatment. Currently, anticancer therapy relies heavily upon the administration of small molecule cytotoxic drugs that attack both cancerous and noncancerous cells due to limited selectivity of the drugs and widespread distribution of the cytotoxic molecules throughout the body. The antitumor efficacy and systemic toxicity of existing chemotherapeutic drugs can, however, be improved by employing formulation and particle engineering approaches. Thus, drug delivery systems can be developed that more specifically target tumor tissue using both passive (such as the enhanced permeation and retention effect) and active (through the use of cancer targeting ligands) modalities. Dendrimers are one such system that can be developed with high structural monodispersity, long plasma circulation times and precise control over surface structure and biodistribution properties. Chemotherapeutic drugs can be associated with dendrimers via covalent conjugation to the surface, or via encapsulation of drugs within the structure. Each of these approaches has demonstrated therapeutic benefit relative to the administration of free drug. Thus far, however, there has not been a systematic review toward which drug association approach will provide the best outcomes in terms of antitumor efficacy and systemic toxicity. Hence, the current literature is reviewed here and recommendations are proposed as to the suggested approach to develop dendrimers as tumor targeted drug-delivery vectors. PMID- 22250751 TI - Water-insoluble condensed tannins content of young persimmon fruits-derived crude fibre relates to its bile acid-binding ability. AB - In this study, we prepared crude fibre samples from young fruits of 10 persimmon (Diospyros kaki) cultivars and from young fruits of Japanese pear (Pyrus pyrifolia var. culta) and peach (Prunus persica) and compared their bile acid binding abilities in vitro. All crude fibre samples from young fruits of persimmon were able to bind to cholic acid in a 4 mM cholic acid solution, but crude fibre samples from young fruits of Japanese pear and peach did not show bile acid-binding ability. The bile acid-binding ability was strongly correlated with the water-insoluble condensed tannins content in crude fibre samples (r = 0.909, p < 0.001). These results indicate that the water-insoluble condensed tannins content in young fruits of persimmon is related to its bile acid-binding ability. PMID- 22250752 TI - Structure-activity relationship of novel menaquinone-4 analogues: modification of the side chain affects their biological activities. AB - We synthesized new vitamin K analogues with demethylation or reduction of the double bonds of the side chain of menaquinone-4 (MK-4) and evaluated their SXR mediated transcriptional activity as well as the extent of their conversion to MK 4. The results indicated that the analogue with the methyl group deleted at the 7' site of the side chain part affected conversion activity to MK-4. In contrast, a decrease in the number of the double bonds in the side chain moiety appeared to decrease the SXR-mediated transcriptional activity. PMID- 22250753 TI - Release of tissue-specific proteins into coronary perfusate as a model for biomarker discovery in myocardial ischemia/reperfusion injury. AB - Diagnosis of acute coronary syndromes is based on protein biomarkers, such as the cardiac troponins (cTnI/cTnT) and creatine kinase (CK-MB) that are released into the circulation. Biomarker discovery is focused on identifying very low abundance tissue-derived analytes from within albumin-rich plasma, in which the wide dynamic range of the native protein complement hinders classical proteomic investigations. We employed an ex vivo rabbit model of myocardial ischemia/reperfusion (I/R) injury using Langendorff buffer perfusion. Nonrecirculating perfusate was collected over a temporal profile of 60 min reperfusion following brief, reversible ischemia (15 min; 15I/60R) for comparison with irreversible I/R (60I/60R). Perfusate proteins were separated using two dimensional gel electrophoresis (2-DE) and identified by mass spectrometry (MS), revealing 26 tissue-specific proteins released during reperfusion post-15I. Proteins released during irreversible I/R (60I/60R) were profiled using gel-based (2-DE and one-dimensional gel electrophoresis coupled to liquid chromatography and tandem mass spectrometry; geLC-MS) and gel-free (LC-MS/MS) methods. A total of 192 tissue-specific proteins were identified during reperfusion post-60I. Identified proteins included those previously associated with I/R (myoglobin, CK MB, cTnI, and cTnT), in addition to examples currently under investigation in large cohort studies (heart-type fatty acid binding protein; FABPH). The postischemic release profile of a novel cardiac-specific protein, cysteine and glycine-rich protein 3 (Csrp3; cardiac LIM domain protein) was validated by Western blot analysis. We also identified Csrp3 in serum from 6 of 8 patients postreperfusion following acute myocardial infarction. These studies indicate that animal modeling of biomarker release using ex vivo buffer perfused tissue to limit the presence of obfuscating plasma proteins may identify candidates for further study in humans. PMID- 22250754 TI - Chiral interactions of the drug propranolol and alpha1-acid-glycoprotein at a micro liquid-liquid interface. AB - The investigation of chiral interactions of drugs with plasma proteins is of fundamental importance for drug efficacy and toxicity studies. In this paper, we demonstrate a simple liquid-liquid interface procedure for investigating chiral interactions. Chiral discrimination of the enantiomers of a basic drug, propranolol, was achieved at a micro liquid-liquid interface, using alpha(1)-acid glycoprotein (AGP) as a chiral acute phase plasma protein. When the protein is added to an aqueous phase containing the enantiomers of propranalol hydrochloride, the binding of (S)- and (R)-propranolol hydrochloride to the protein results in a decrease in the cyclic voltammetry (CV) and differential pulse voltammetry (DPV) current responses corresponding to the decrease in transfer of propranolol at an aqueous-1,2-dichloroethane interface. This decrease is a consequence of the complexation of the drug and the protein. The complex drug-protein does not transfer across the interface nor changes the transfer potential of the uncomplexed form of propranolol enantiomers. The bound concentration of propranolol enantiomers in the presence of AGP was found to be greater for (S)-propranolol than (R)-propranolol for solutions containing constant concentrations of AGP (50 MUM). Scatchard analysis yielded association constants of 2.7 and 1.3 * 10(5) M(-1) for (S)- and (R)-propranolol, respectively. PMID- 22250755 TI - Fortuitous vasculitis. AB - A 43-year-old man with a cardiac device for dilated cardiomyopathy presented with fever, night sweats, and weight loss. Investigations revealed pancytopenia, acute renal failure, abnormal lung function, and raised inflammatory markers. A renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis. He was diagnosed with pulmonary-renal antineutrophil cytoplasmic antibody-negative systemic small vessel vasculitis. He commenced immunosuppression with prednisolone and cyclophosphamide with recovery from pancytopenia and improvement in renal function 3 months later. Subsequently, a bone marrow culture grew Mycobacterium fortuitum. Isolation on repeat peripheral mycobacterial blood cultures prompted treatment with ciprofloxacin and clarithromycin. Four months later, he presented with neutropenic sepsis, influenza A/H1N1, and Aspergillus flavus pneumonia. Despite treatment he deteriorated. A transthoracic echocardiogram revealed a vegetation on the right ventricular pacing wire. The device was removed. The vegetation revealed acid and alcohol fast bacilli on Ziehl-Neelsen staining and grew M. fortuitum on culture, sensitive to ciprofloxacin and clarithromycin. Despite device removal and antimicrobial therapy, the patient succumbed to treatment-related complications. The association between glomerulonephritis and endocarditis is well known; however, this is the first case to our knowledge describing pauci-immune necrotizing crescentic glomerulonephritis in the context of M. fortuitum endocarditis. Clinicians should maintain a high index of suspicion for endocarditis in patients with a cardiac device who present with fever and pauci-immune necrotizing crescentic glomerulonephritis. Patients should be investigated with mycobacterial blood cultures, at least three sets of standard blood cultures and transthoracic and transesophageal echocardiography. Clinicians should beware the perils of immunosuppression in the face of an occult sepsis. PMID- 22250756 TI - Evaluation of endothelial cells differentiated from amniotic fluid-derived stem cells. AB - Amniotic fluid holds great promise as a stem cell source, especially in neonatal applications where autologous cells can be isolated and used. This study examined chemical-mediated differentiation of amniotic fluid-derived stem cells (AFSC) into endothelial cells and verified the function of AFSC-derived endothelial cells (AFSC-EC). AFSC were isolated from amniotic fluid obtained from second trimester amnioreduction as part of therapeutic intervention from pregnancies affected with twin-twin transfusion syndrome. Undifferentiated AFSC were of normal karyotype with a subpopulation of cells positive for the embryonic stem cell marker SSEA4, hematopoietic stem cell marker c-kit, and mesenchymal stem cell markers CD29, CD44, CD73, CD90, and CD105. Additionally, these cells were negative for the endothelial marker CD31 and hematopoietic differentiation marker CD45. AFSC were cultured in endothelial growth media with concentrations of vascular endothelial growth factor (VEGF) ranging from 1 to 100 ng/mL. After 2 weeks, AFSC-EC expressed von Willebrand factor, endothelial nitric oxide synthase, CD31, VE-cadherin, and VEGF receptor 2. Additionally, the percentage of cells expressing CD31 was positively correlated with VEGF concentration up to 50 ng/mL, with no increase at higher concentrations. AFSC-EC showed a decrease in stem cells markers c-kit and SSEA4 and were morphologically similar to human umbilical vein endothelial cells (HUVEC). In functional assays, AFSC-EC formed networks and metabolized acetylated low-density lipoprotein, also characteristic of HUVEC. Nitrate levels for AFSC-EC, an indirect measure of nitric oxide synthesis, were significantly higher than undifferentiated controls and significantly lower than HUVEC. These results indicate that AFSC can differentiate into functional endothelial-like cells and may have the potential to provide vascularization for constructs used in regenerative medicine strategies. PMID- 22250757 TI - Psychological entropy: a framework for understanding uncertainty-related anxiety. AB - Entropy, a concept derived from thermodynamics and information theory, describes the amount of uncertainty and disorder within a system. Self-organizing systems engage in a continual dialogue with the environment and must adapt themselves to changing circumstances to keep internal entropy at a manageable level. We propose the entropy model of uncertainty (EMU), an integrative theoretical framework that applies the idea of entropy to the human information system to understand uncertainty-related anxiety. Four major tenets of EMU are proposed: (a) Uncertainty poses a critical adaptive challenge for any organism, so individuals are motivated to keep it at a manageable level; (b) uncertainty emerges as a function of the conflict between competing perceptual and behavioral affordances; (c) adopting clear goals and belief structures helps to constrain the experience of uncertainty by reducing the spread of competing affordances; and (d) uncertainty is experienced subjectively as anxiety and is associated with activity in the anterior cingulate cortex and with heightened noradrenaline release. By placing the discussion of uncertainty management, a fundamental biological necessity, within the framework of information theory and self organizing systems, our model helps to situate key psychological processes within a broader physical, conceptual, and evolutionary context. PMID- 22250759 TI - Investigating phenotypic variability in Colletotrichum lindemuthianum populations. AB - Colletotrichum lindemuthianum, causal agent of anthracnose in the common bean, has wide genetic variability. Differential bean cultivars and morphological and physiological characteristics were used to analyze 74 isolates of C. lindemuthianum collected in two counties in the state of Minas Gerais, Brazil. Six different races were found, with a predominance of race 65 at both locations. Isolates were classified according to their sensitivities to the fungicide thiophanate-methyl, normally used in the control of common bean anthracnose. In all, ~10% of isolates were resistant to the fungicide in vitro. Characteristics such as indexes of mycelia growth rate, colony diameter, sporulation capacity, and percentage of germination demonstrated the high genetic variability of C. lindemuthianum. We also observed variation in conidial cytology. The conidia of most isolates showed septa formation after germination, in contrast to septa absence, previously reported in the literature. Sexual and asexual reproduction were evaluated for mechanisms that may contribute in the generation of variability in C. lindemuthianum. Conidial anastomosis tubes were commonly found, indicating that asexual reproduction can help increase variability in this species. Information from this study confirmed high variability in C. lindemuthianum and will guide future studies in basic knowledge and applied technologies. PMID- 22250760 TI - Human adipose-derived mesenchymal stem cells: serial passaging, doubling time and cell senescence. AB - Adult adipose-derived mesenchymal stem cells (AD-MSC) are very interesting to our research group because they are easy to harvest, they are abundant in humans, and they have potential clinical applications in autologous cell therapy for disc degeneration. We examined these cells through sequential serial passages to assess osteogenic and chondrogenic capabilities, mean doubling time and cell senescence. Osteogenic and chondrogenic potencies were maintained through 13 passages. Mean passage doubling time increased significantly with increasing passage number. When donor age was evaluated, passages 1-4 from older donors had significantly longer doubling times compared to cells from younger donors. Passages 5-11 showed similar findings when analyzed by donor age. The mean percent senescence increased significantly with cell passaging, rising from 0% at passage 1 to 3.4% at passage 13. These novel data suggest that caution should be exercised when using AD-MSC with long passage times. PMID- 22250761 TI - Water release through plant roots: new insights into its consequences at the plant and ecosystem level. AB - Hydraulic redistribution (HR) is the passive movement of water between different soil parts via plant root systems, driven by water potential gradients in the soil-plant interface. New data suggest that HR is a heterogeneous and patchy process. In this review we examine the main biophysical and environmental factors controlling HR and its main implications at the plant, community and ecosystem levels. Experimental evidence and the use of novel modelling approaches suggest that HR may have important implications at the community scale, affecting net primary productivity as well as water and vegetation dynamics. Globally, HR may influence hydrological and biogeochemical cycles and, ultimately, climate. PMID- 22250762 TI - Effects of delayed anticoagulation and use of evacuated tubes on non-activated thrombelastography in dogs. AB - BACKGROUND: The effects of delayed anticoagulation and use of evacuated vacuum tubes in the collection of whole blood for nonactivated thrombelastography (TEG) are not known. OBJECTIVES: The objective of this study was to examine the effects of delayed anticoagulation and use of vacuum-assisted blood collection tubes on results of nonactivated TEG. METHODS: Twelve clinically healthy adult dogs were used in each of 3 studies. For each study, nonactivated TEG results from paired blood samples were compared. In study 1, the effect of delayed citrate anticoagulation was evaluated by collecting samples either into syringes containing citrate or into empty syringes followed by transfer to nonevacuated tubes containing citrate. In study 2, the effect of vacuum assistance in blood transfer was evaluated by collecting samples into syringes containing citrate and transferring either to nonevacuated plastic tubes or to evacuated plastic tubes. In study 3, the combined effects of delayed anticoagulation and vacuum assistance in blood transfer were evaluated by collecting samples into syringes containing citrate or into empty syringes followed by transfer to evacuated tubes containing citrate. Thrombelastographic analysis was performed in duplicate at 39 degrees C after a 40-minute rest period. RESULTS: The collection methods that delayed anticoagulation and/or used evacuated tubes yielded samples that appeared more coagulable compared with samples not exposed to delay or evacuated tubes. CONCLUSION: Methods by which samples are collected affect results of nonactivated TEG and should be considered when establishing reference intervals, interpreting results, and publishing TEG results. PMID- 22250763 TI - First trimester sonographic determination of foetal gender: a cost effective non invasive technique for prenatal screening of haemophilia in low income countries. PMID- 22250764 TI - Psoriasis phototherapy experience from a Lisbon unit: a still valid therapeutic approach in the 21st century. AB - INTRODUCTION: During the last half of the 20th century, the use of UVB therapy and photochemotherapy (PUVA), were one of the mainstays of treatment for psoriasis. However, accompanying to the advent of the most recent era of psoriasis, with targeted biologic therapy has been a decline in the frequency of phototherapy. This does not diminish its known clinical effects. OBJECTIVE: To perform a retrospective analysis of demographic, clinical and therapeutic variables of psoriatic patients treated with phototherapy in the last 10 years, when biological therapies become available. Also, review some of the published phototherapy and biological therapy data in psoriasis. METHODS: Psoriatic patients were treated between 1st January 2000 and 31st December 2010 in a Lisbon Phototherapeutic unit. Psoriatic arthritis patients were excluded. Regimes used included PUVA (systemic or topical), Re PUVA, UVAB (broad band) or combined options. RESULTS: During this period, 211 patients were treated with phototherapy; 40% (85/211) UVAB, 31% (64/211) topical PUVA, 23% (49/211) systemic PUVA and 6% (13/211) Re PUVA. Mean follow-up period was 18 months (Min 1; Max 120). The average age was 45 years old (mean 44.80; Min 10; Max 80; SD 16.31), 54% (114/211) of patients were female and 46% (97/211) were male. Of all 211 psoriasis patients, 54% (144/211) had plaque psoriasis diagnosis, 31% (66/211) palmoplantar psoriasis and 15% (41/211) guttate psoriasis. Regardless the phototherapy modality used, substantial BSA improvements were achieved in all psoriasis groups. DISCUSSION: Current advancements in therapeutics enjoyed today include the advent of the biologics and other immunomodulating systemic agents. However, attending to the responses achieved, and considering other variables like well-known side effects and cost, photo(chemo)therapy will remain an essential method of treatment for psoriasis vulgaris in the 21st century. PMID- 22250765 TI - The leaves of Stevia rebaudiana (Bertoni), their constituents and the analyses thereof: a review. AB - The plant Stevia rebaudiana is well-known due to the sweet-tasting ent-kaurene diterpenoid glycosides. Stevioside and rebaudioside A are the most abundant and best analyzed, but more than 30 additional steviol glycosides have been described in the scientific literature to date. Most of them were detected in the last two years. This paper reviews these new compounds and provides an overview about novel trends in their determination, separation, analysis, detection, and quantification. The detection and analysis of further constituents such as nonglycosidic diterpenes, flavonoids, chlorogenic acids, vitamins, nutrients, and miscellaneous minor compounds in the leaves of Stevia rebaudiana are reviewed as well. A critical review of the antioxidant capacity of Stevia leaves and its analysis is also included. These different aspects are discussed in consideration of the scientific literature of the last 10 years. PMID- 22250766 TI - Development and application of quality index method scheme in a shelf-life study of wild and fish farm affected bogue (Boops boops, L.). AB - Quality index method scheme was developed for raw bogue (Boops boops) and evaluated it in a shelf-life study, using samples from wild fish aggregations at fish farms (BF) and from area not influenced by the fish farms (BW). Different environment influenced the shelf life of bogues; thus the maximum ice storage, evaluated from cooked samples, was found to be 17 d for BF and 12 d for BW. The calculated quality indexes (QIs) evolved linearly with storage time on ice (QI(BF) = 0.968x + 0.583, R(2) = 0.947, Std. Err. Est. = 1.41; QI(BW) = 1.212x + 0.474, R(2) = 0.972, Std. Err. Est. = 0.95). The multivariable analysis was used to identify the most effective variables during spoilage evolution. The sum of all demerit points showed higher correlation (R > 0.99) then any single parameters itself, indicating that the individual parameters could not replace the usage of 20 demerit points QIM scoring scheme in sensory assessment. The impact of farming cages was observed in fat (BF > 19%; BW < 2%) and water content (BF = 55%; BW = 77%) of bogues, but also in pH, dielectric properties, thiobarbituric acid index, and volatile amine changes. High correlations of these parameters with storage time and sensory assessment were observed. PRACTICAL APPLICATIONS: The catch landings of bogue make this species very important in the Mediterranean fishery production. The effect of finfish farms makes individual fish samples of this species different in size and chemical content, thus changing the rate and in which their postmortem changes occur. The practical use of the article is a new developed and species adopted descriptive scheme for bogue, ready to use for scientific and industrial freshness assessment providing the information on fish quality and its remaining shelf life in ice, taking into account the environmental conditions such as catching ground. PMID- 22250767 TI - Improving the evidence base in clinical nutrition, public health nutrition and epidemiology, nutritional science and dietetic professional practice. PMID- 22250768 TI - Prenatal alcohol exposure patterns and alcohol-related birth defects and growth deficiencies: a prospective study. AB - BACKGROUND: The physical features of fetal alcohol syndrome include smooth philtrum, thin vermillion border, short palpebral fissures, microcephaly, and growth deficiencies on weight and height. However, little is known about the specific quantities of alcohol exposure, pattern of drinking, timing of exposure, and magnitude of risk for each of these features. METHODS: Using data on 992 subjects collected prospectively in California between 1978 and 2005, we examined the patterns and timing of alcohol exposure in relation to these features. Structural features were assessed by a dysmorphologist who performed a blinded physical examination of all infants. Patterns of drinking were evaluated by drinks per day, number of binge episodes, and maximum number of drinks. Timing of exposure was evaluated 0 to 6 weeks postconception, 6 to 12 weeks postconception, first trimester, second trimester, and third trimester. RESULTS: Higher prenatal alcohol exposure in every pattern was significantly associated with the incidence of smooth philtrum but not with short palpebral fissures. The strongest associations were with timing of exposure in the second half of the first trimester (RR 1.25, 95% CI 1.14 to 1.36 for average number of drinks per day; RR 1.17, 95% CI 1.09 to 1.26 for maximum number of drinks in 1 episode). Similarly, thin vermillion border was most strongly associated with exposure in the second half of the first trimester. Findings with respect to timing of exposure were similar for microcephaly and reduced birth weight. However, reduced birth length was increased with exposure in any trimester. These associations were linear, and there was no evidence of a threshold. CONCLUSIONS: Reduced birth length and weight, microcephaly, smooth philtrum, and thin vermillion border are associated with specific gestational timing of prenatal alcohol exposure and are dose related without evidence of a threshold. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy. PMID- 22250769 TI - What is considered important for life balance? Similarities and differences among some working adults. AB - Life balance seems subjective, health related, and multidimensional. However, the concept is complex. Exploring what people themselves consider more or less important for their life balance and whether this differs between people would develop new knowledge. Q methodology was chosen for the present study, in which 32 working men and women without recent long-term sick leave participated. They sorted 42 statements regarding life balance according to their importance for each participant's life balance. The analysis resulted in four different viewpoints concerning life balance. All four viewpoints considered good relationships with those closest to them, as well as knowing that these people were doing well, as important. Each viewpoint also showed a unique orientation towards what was considered important for life balance: occupational balance (viewpoint 1), self-actualization (viewpoint 2), self-awareness (viewpoint 3), and reciprocal relationships (viewpoint 4). The results. showed support for life balance as being a subjective, multidimensional, and health-related phenomenon. The results demonstrated the importance of relationships for life balance and heterogeneity in what people considered important for their own life balance. PMID- 22250770 TI - Editorial: From structural plasticity to functional diversity of 7TMRs: biased agonism and beyond. PMID- 22250775 TI - Development of short forms from the PROMISTM sleep disturbance and Sleep-Related Impairment item banks. AB - This article reports on the development of short forms from the Patient-Reported Outcomes Measurement Information System (PROMISTM) Sleep Disturbance (SD) and Sleep-Related Impairment (SRI) item banks. Results from post-hoc computerized adaptive testing (CAT) simulations, item discrimination parameters, item means, and clinical judgments were used to select the best-performing 8 items for SD and SRI. The final 8-item short forms provided less test information than the corresponding full banks, but correlated strongly with the longer forms. The short forms had greater measurement precision than the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), as indicated by larger test information values across the continuum of severity, despite having fewer total items--a major advantage for both research and clinical settings. PMID- 22250776 TI - PROMISTM of improved tools for assessing sleep and wake function: commentary on "Development of short forms from the PROMISTM sleep disturbance and sleep-related impairment item banks". PMID- 22250771 TI - Ventral pallidum mediates amygdala-evoked deficits in prepulse inhibition. AB - Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. It is defined as a reduction in magnitude of a startle response when a startling stimulus is preceded by a weaker "prepulse." PPI has been found to be altered in patients with schizophrenia, autism spectrum disorders, and other neuropsychiatric illnesses. As such, the neural substrates regulating PPI are of particular interest. Previous studies using lesions, selective blockade of N methyl-d-aspartate (NMDA) receptors, and pharmacological disinhibition have demonstrated that impairment of the function of the basolateral and lateral nuclei of the amygdala (BLA) disrupts PPI. However, transient gamma aminobutyric acid-mediated (GABA-mediated) inactivation of BLA has not been evaluated for effects on PPI. Furthermore, the downstream projection targets that mediate BLA evoked disruptions of PPI have not been elucidated. Thus, in the present study, we evaluated the effect on PPI of bilateral and unilateral inactivation of BLA, by microinfusion of the GABA-A receptor agonist, muscimol. We found that either bilateral or unilateral inactivation impaired PPI. Because unilateral inactivation was sufficient to impair PPI, we hypothesized that this was due to an indirect activation of a downstream target of BLA, the ventral pallidum (VP). Because VP inhibition normalizes PPI deficits evoked from nucleus accumbens (Kodsi & Swerdlow, 1994), we next tested the degree to which VP inhibition would normalize PPI deficits evoked from BLA. We unilaterally inactivated BLA with concurrent inactivation of VP and found that VP inactivation blocked BLA-evoked deficits in PPI. We suggest that BLA inactivation disrupts PPI through disinhibition of VP. PMID- 22250777 TI - Bi-directional associations between psychological arousal, cortisol, and sleep. AB - The aim was to elucidate the possible bi-directional relation between daytime psychological arousal, cortisol, and self-reported sleep in a group of healthy employees in active employment. Logbook ratings of sleep (Karolinska Sleep Questionnaire), stress, and energy, as well as positive and negative experiences in work and private life, were collected together with salivary cortisol over 3 days (n = 265). Higher bedtime ratings of stress and problems during the day were associated with morning ratings of poor sleep. Poorer morning ratings of sleep were associated with higher ratings of stress and problems during the day. The results underpin the possibility that arousal and poor sleep might create a self reinforcing vicious circle that negatively affects a person's well-being. PMID- 22250778 TI - Attention deficit hyperactivity disorder and sleep disturbances: consideration of parental influence. AB - Parent report of sleep-related problems among children with attention deficit hyperactivity disorder (ADHD) is common and may stem from several different factors. This study examined the extent to which parental influence predicted sleep problems among 67 children, ages 5 to 12, meeting a research diagnosis of ADHD. The majority of parents/caregivers (73%) reported significant child sleep difficulties. Parental implementation of daily routines added to the explained variance in bedtime resistance after considering child and family characteristics (e.g., age, medication, and family income) but was not a significant predictor of sleep problems overall. Parenting stress was not a significant predictor of child sleep problems. Results suggest that implementation of consistent routines, especially those related to bedtime, may be a key factor in facilitating improved sleep among children who display behaviors consistent with ADHD. PMID- 22250780 TI - Family socioeconomic status and sleep patterns of young adolescents. AB - This study examined associations among socioeconomic status (SES), SES-related variables, and sleep in young middle school adolescents. Participants included 155 seventh-graders attending two urban New England middle schools. Aspects of the SES environment included parent demographic variables (e.g., income and education), neighborhood environment, and family home environment. Students completed 1 week of actigraphy to estimate sleep patterns. Results demonstrated that the timing and consistency of school-night sleep were associated with demographic and behavioral aspects of SES, whereas weekend sleep schedules were associated with demographic, behavioral, and neighborhood aspects of SES. Finally, regularity in school-night and weekend sleep schedules were associated with demographic and neighborhood aspects of SES. PMID- 22250779 TI - The association of race/ethnicity with objectively measured sleep characteristics in older men. AB - This study examined the association between race/ethnicity and objectively measured sleep characteristics in a large sample of older men. Black men had significantly shorter total sleep time (6.1 hr vs. 6.4 hr), longer sleep latency (28.7 min vs. 21.9 min), lower sleep efficiency (80.6% vs. 83.4%), and less slow wave sleep (4.9% vs. 8.8%) than White men, even after controlling for social status, comorbidities, body mass index, and sleep-disordered breathing. Hispanic men slept longer (6.7 hr) at night than Black (6.1 hr) and Asian American men (6.1 hr). This study supports significant variations in sleep characteristics in older men by race/ethnicity. PMID- 22250781 TI - Identification of novel adenosine A(2A) receptor antagonists by virtual screening. AB - Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). By use of ligand docking and Biophysical Mapping (BPM), hits 1 and 5 were optimized to potent and selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- to >100-fold selective versus adenosine A(1); 14-16 from 1, pK(I) = 7.9-9.0, 19- to 59-fold selective). PMID- 22250782 TI - Deployment of a mixed-mode data collection strategy does not reduce nonresponse bias in a general population health survey. AB - OBJECTIVE: To assess nonresponse bias in a mixed-mode general population health survey. DATA SOURCES: Secondary analysis of linked survey sample frame and administrative data, including demographic and health-related information. STUDY DESIGN: The survey was administered by mail with telephone follow-up to nonrespondents after two mailings. To determine whether an additional mail contact or mode switch reduced nonresponse bias, we compared all respondents (N = 3,437) to respondents from each mailing and telephone respondents to the sample frame (N = 6,716). PRINCIPAL FINDINGS: Switching modes did not minimize the under representation of younger people, nonwhites, those with congestive heart failure, high users of office-based services, and low-utilizers of the emergency room but did reduce the over-representation of older adults. CONCLUSIONS: Multiple contact and mixed-mode surveys may increase response rates, but they do not necessarily reduce nonresponse bias. PMID- 22250783 TI - The role of all-trans retinoic acid in bleomycin-induced pulmonary fibrosis in mice. AB - Much evidence suggests that immune imbalance in the lung plays a crucial role in the development of pulmonary fibrosis. Recently, all-trans retinoic acid (ATRA) shifting the regulatory T/T-helper 17 (Treg/Th17) profile had been proven in some diseases. However, to date, the effect of ARTA of pulmonary fibrosis has not been examined from this aspect. The objective of this study was to study the effect of ATRA on bleomycin-induced pulmonary fibrosis in mice and its possible mechanism. Pulmonary fibrosis was induced in C57BL/6 male mice by intratracheal instillation of bleomycin (5 mg.kg(-1)), which were randomly divided into control, bleomycin, and ATRA groups. Five mice in each group were sacrificed on day 28 after intratracheal instillation. Hemotoxylin and eosin (H&E) and Masson staining were used for pathological examination, and hydroxyproline in lung tissue was measured. Interleukin (IL)-17A protein expression was observed in lung with immunohistochemistry. The expression of IL-17A, IL-10, IL-6, and transforming growth factor (TGF)-beta mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Th17 and Treg expression in spleen lymphocytes were measured by flow cytometry. H&E and masson staining and expression of hydroxyproline showed that ATRA significantly alleviated lung fibrosis than in the bleomycin group. The expression of IL-17A, IL-10, IL-6, and TGF-beta mRNAs were higher in the bleomycin group than in the normal group. ATRA can decrease these cytokines except for IL-10. CD4+CD25+ Treg cell ratio in the bleomycin group was significantly lower than normal, but CD4+IL-17+ T cells was higher; ARTA reversed this kind of expression. ATRA may ease the bleomycin-induced pulmonary fibrosis by inhibiting the expression of IL-6 and TGF-beta, shifting the Treg/Th17 ratio and reducing the secretion of IL-17A. PMID- 22250784 TI - Carnivore diet analysis based on next-generation sequencing: application to the leopard cat (Prionailurus bengalensis) in Pakistan. AB - Diet analysis is a prerequisite to fully understand the biology of a species and the functioning of ecosystems. For carnivores, traditional diet analyses mostly rely upon the morphological identification of undigested remains in the faeces. Here, we developed a methodology for carnivore diet analyses based on the next generation sequencing. We applied this approach to the analysis of the vertebrate component of leopard cat diet in two ecologically distinct regions in northern Pakistan. Despite being a relatively common species with a wide distribution in Asia, little is known about this elusive predator. We analysed a total of 38 leopard cat faeces. After a classical DNA extraction, the DNA extracts were amplified using primers for vertebrates targeting about 100 bp of the mitochondrial 12S rRNA gene, with and without a blocking oligonucleotide specific to the predator sequence. The amplification products were then sequenced on a next-generation sequencer. We identified a total of 18 prey taxa, including eight mammals, eight birds, one amphibian and one fish. In general, our results confirmed that the leopard cat has a very eclectic diet and feeds mainly on rodents and particularly on the Muridae family. The DNA-based approach we propose here represents a valuable complement to current conventional methods. It can be applied to other carnivore species with only a slight adjustment relating to the design of the blocking oligonucleotide. It is robust and simple to implement and allows the possibility of very large-scale analyses. PMID- 22250785 TI - Construction of a tubular scaffold that mimics J-shaped stress/strain mechanics using an innovative electrospinning technique. AB - Soft tissues such as blood vessel, lung, ureter, skin, etc., possess mechanical behavior characterized by a "J"-shaped curve on a stress-strain diagram with a low-stiffness highly elastic zone giving rise to a high-stiffness zone. This mechanical behavior may be adaptive and protective against aneurysm formation in tissues whose primary loading is pressure-based. "J"-shaped behavior arises from the synergistic interplay of two main structural proteins: collagen and elastin. An innovative electrospinning technique has been utilized to form tubular scaffold composites with structural features reminiscent of the corrugated laminae seen in blood vessels. In doing so, tubular scaffolds have been fabricated with complex "J"-shaped behavior through the use of elastic polyurethane and reinforcing poly-glycolic acid (PGA) woven mesh. In these studies, corrugated laminae were formed on the 175 MUm and 1.5 mm scale. Initial moduli were 0.5+/-0.17 MPa (mean+/-standard deviation) giving rise to stiffer moduli of 36.09+/-6.72 MPa at a strain of 1.31+/-0.15. Burst pressures were physiologically relevant at 3095+/-1016 mmHg. The toughness of these prototypes was 6.3+/-1.9 MJ/m(3). The ability to employ different materials and different formation parameters utilizing this technique promises the ability to match complex stress-strain behaviors in soft tissues with a high degree of fidelity. PMID- 22250786 TI - Immunocytochemical localization of cytoplasmic and nuclear intermediate filaments in the bovine ovary during folliculogenesis. AB - The cellular cytoskeleton is composed of three fibrillar systems, namely actin microfilaments, microtubules and intermediate filaments (IFs). It not only is a structural system, which mediates functional compartmentalization, but also contributes to many cellular processes such as transport, mitosis, secretion, formation of cell extensions, intercellular communication and apoptosis. In this study, we have examined the distribution of four groups of IFs [cytokeratins (CKs), vimentin, desmin and lamins] in the somatic and germinal cells of the bovine ovary using RT-PCR and immunohistochemical techniques. Using RT-PCR, specific transcripts for all intermediate proteins studied (CK8, CK18, desmin, vimentin, lamin A/C and lamin B1) were detected. A characteristic immunohistochemical staining pattern was observed for the different IFs within the ovary. In this study, we used antibodies against type I CK (acidic CKs: CK14, CK18 and CK19) and type II CK (basic CKs: CK5 and CK8). Among these, only antibodies against CK18 gave a characteristic pattern of immunostaining in the ovary, which included the surface epithelium, the follicle cells, the endothelium of blood vessels and rete ovarii. Antibodies against all other CKs resulted in a weak staining of a limited number of cellular structures (CK5 and CK19) or were completely negative (CK8 and CK14, apart from the surface epithelium). Vimentin antibodies resulted occasionally in a weak staining of the granulosa cells of primary and secondary follicles. In late secondary follicles, the basal and the most apical follicle cells contacting the zona pellucida usually showed a marked immunostaining for vimentin. In antral follicles, three different immunostaining patterns for vimentin were observed. Desmin immunostaining was confined to the smooth muscle cells of blood vessels. Although mRNA for lamin A/C and lamin B1 could be demonstrated using RT-PCR, no immunostaining was found for lamins, neither in the follicle cells nor in the oocytes. PMID- 22250787 TI - Cost-effectiveness achieved through changing the composition of renal replacement therapy in Japan. AB - OBJECTIVE: The cost-effectiveness of renal replacement therapy (RRT) is affected by the composition of treatment. This study aimed to estimate the costs and outcomes associated with changing the composition of RRT modality over time. METHODS: By using clinical and cost data from a systematic review, a Markov model was developed to assess the costs and benefits of the four main treatments available for RRT in Japan. The model included direct health service costs and quality-adjusted life years (QALY). Sensitivity analyses were performed to assess the robustness of the results. RESULTS: Over the 15-year period of the model, the current composition of RRT (i.e., the base composition of RRT) was $84,008/QALY. The most cost-effective treatment was when the likelihood of a living donor transplant was increased by 2.4-times ($70,581/QALY). Compared with the base composition of RRT, dominant treatments with respect to cost-effectiveness were when the likelihood of a deceased donor transplant was increased by 22-times and when the likelihood of a pre-emptive living donor transplant was increased by 2.4 times. Little difference was found between these two treatments. One-way sensitivity analysis did not change the cost effectiveness except for costs of chronic hemodialysis and a living donor transplant in subsequent years. LIMITATIONS: It is difficult to increase the rate of transplant overall in the shorter term nationally and internationally. CONCLUSIONS: Appropriate distribution of all transplant options and hemodialysis is necessary to achieve the most cost-effective solution. PMID- 22250788 TI - Dissociating expectancy of shock and changes in skin conductance: an investigation of the Perruchet effect using an electrodermal paradigm. AB - Is human Pavlovian conditioning driven by a unitary, propositional system (as claimed by Mitchell, De Houwer, & Lovibond, 2009) or by dual systems; one under conscious control, symbolic in nature, and requiring effort to deploy, and the other utilizing associative processes and automatic in its operation (McLaren, Green, & Mackintosh, 1994)? Past research has suggested that for electrodermal conditioning to occur in humans, conscious awareness of the contingencies is necessary to produce conditioned responding (e.g., Hinchy, Lovibond, & Ter-Horst, 1995), as predicted by single process theories that attribute the conditioned response (CR) to conscious expectancy of the shock. In this article, the authors examined the Perruchet effect (Perruchet, 1985), using an electrodermal paradigm to determine whether there is any role for associative processes in human electrodermal conditioning. The authors attempted to replicate the basic effect, whereby expectancy of an unconditioned stimulus (US) increases over a run of nonreinforced trials while the CR to the conditional stimulus (CS) declines, and the complementary pattern in which expectancy decreases over a run of reinforced trials while the CR to the CS grows in strength. In line with these patterns, the change in skin conductance response (our CR) as a function of US run length was found to follow a linear trend opposite to that of conscious expectancy of shock with respect to US run length. This dissociation supports a dual-processing system account of human Pavlovian conditioning, with conscious, controlled processes governing expectancy (and subject to the gambler's fallacy), whereas automatic, associative processes determine at least some of the strength of the CR to the CS. PMID- 22250789 TI - The content of compound conditioning. AB - In three experiments using Pavlovian conditioning of magazine approach, rats were trained with a compound stimulus, AB, and were concurrently trained with stimulus B on its own. The reinforcement rate of B, rB, was either 1/2, 2/3, or 2/5 of rAB. After extended training, the conditioning strength of A was assessed using probe trials in which A was presented alone. Responding during A was compared with that during AB, B, and a third stimulus, C, for which rC = rAB - rB. In each experiment, the rats' response rate during A was almost identical to that during C (and during B, when rB = 1/2rAB). This suggests that, during AB conditioning, the rats had learned about rA as being equal to [rAB - rB], and implies that the content of their learning was a linear function of r. The findings provide strong support for rate-based models of conditioning (e.g., Gallistel & Gibbon, 2000). They are also consistent with the associative account of learning defined in the Rescorla and Wagner (1972) model, but only if the learning rate during reinforcement equals that during nonreinforcement. PMID- 22250790 TI - Temporal properties of visual search in pigeon target localization. AB - To examine the mechanisms and time course of visual search behavior, we rewarded 6 experienced pigeons for locating and pecking at an odd target region randomly embedded in a larger rectangular array of contrasting distractor elements. On two target test trials, a flanking secondary target region was briefly presented (100, 250, or 500 ms) after display onset with stimulus onset asynchrony values of 0, 50, 100, 175, 250, 375, 500, 1000, 2000, and 3000 ms. Two types of interference effects were possibly identified with target localization accuracy. One type occurred early in processing, where the secondary target appeared to interfere with search behavior, perhaps involving mechanisms similar to inhibition of return. A second type of interference was isolated that appeared to be time locked to responding and might occur at a postsearch stage of processing. Several possible connections of these effects to established mechanisms in human visual search and attention are suggested. PMID- 22250791 TI - Multiple histopathological skin alterations in a hemodialysis patient with severe pruritus. AB - Pruritus is an alarming symptom in patients with end-stage renal disease (ESRD) accompanied by sleep disturbances and physical and mental disorders. Although its prevalence is very high among hemodialysis patients (90%), its etiology and its successful treatment have been unconfirmed (Melo N, Elias R, Castro M, Romao G, Abensur H. Pruritus in hemodialysis patients: The problem still remains. Hemodial Int. 2009;13:38-42.). Common pruritus etiologies, such as high parathyroid hormone levels, dialysis inadequacy, and iron deficiency are matters of conflict. The case of a hemodialysis patient with consistent itching and a variety of cutaneous eruptions, which after performing skin biopsy were explored and cured, is described. This article addresses the possibility of other causes of pruritus in ESRD and encourages watchful waiting with simple medical interventions, which would relieve patients' symptoms. PMID- 22250793 TI - Bioanalytical method development: considering information from a suite of complementary methods. PMID- 22250794 TI - A step forward in miRNA diagnostics: new and improved protocols for miRNA measurement. PMID- 22250795 TI - LGC: clinical about clinical measurement. AB - LGC is the UK's designated National Measurement Institute for chemical and bioanalytical measurement, and through this role improves the quality and international acceptance of measurements performed within the UK. This research spotlight, highlighting measurement 'across the scale', from elemental analysis and small molecules, through to proteins, DNA and RNA and on to whole cells and tissues, demonstrates how LGC is supporting the clinical sector by ensuring sound measurement practice that underpins clinical efficacy, quality assurance and patient safety. PMID- 22250796 TI - An alternative solution to overcome carryover issues in bioanalysis. AB - LC-MS/MS instruments are considered as the analytical technique of choice for bioanalytical assays. The LC-MS/MS technique acquired this status due to its robustness, specificity, sensitivity and good precision and accuracy. Nonetheless, with the use of these instruments, users also have to deal with some complex analytical problems such as carryover. Even if carryover is well known and widely discussed, it still remains a common issue in bioanalytical work. Although new autosampler instruments manufactured are specifically designed to fix the problem, the issue is still present because methods developed by the industry also change and evolve with the instrument. Requests for wider dynamic ranges and the use of a very sensitive detector that can reach very low LOQ are among the reasons. This article reviews the causes of carryover and proposes an autosampler needle seat backflush as a novel solution to address the issue. PMID- 22250797 TI - Use of relative 12C/14C isotope ratios to estimate metabolite concentrations in the absence of authentic standards. AB - BACKGROUND: There is considerable interest in the determination of relative abundances of human metabolites in plasma (and potentially excreta) with reasonable accuracy early on in the drug development process in order to make scientifically sound decisions with regard to the presence of potentially active or toxic disproportionate metabolites. At this point, authentic metabolite standards are generally not available. RESULTS: A new methodology is proposed for the estimation of metabolite concentrations in the absence of authentic standards. A reference sample containing radiolabeled metabolites of interest is produced by incubating the (14)C-labeled drug in vitro, and mixed with a sample to be quantitated containing the unlabeled metabolites. The (12)C/(14)C isotope ratio is measured with high-resolution ESI-MS for each metabolite, and used as a basis for quantitation of the cold metabolite based on the concentration of radioactive metabolite, determined from independent analysis of the radioactive sample with LC-radiochemical detection. The (14)C-labeled metabolite serves as an isotopically labeled internal standard, which corrects for any variations in injection volume, sample preparation, MS intensity drift, matrix effects and/or saturation of electrospray ionization. The approach was validated by the analysis of solutions containing variable amounts of the analyte with a fixed amount of radioactive standard on a QToF Synapt((r)) G2 MS system. The same methodology was also successfully applied to first-in-human plasma samples analyzed on a LTQ Orbitrap((r)). CONCLUSION: The metabolite abundances obtained by (12)C/(14)C isotope ratio measurements showed suitable accuracy and precision and were very close to those obtained with matrix mixing. The parent drug concentrations also corresponded well with the bioanalytical results obtained with a validated LC MS/MS method. PMID- 22250798 TI - Determination of lumefantrine in small-volume human plasma by LC-MS/MS: using a deuterated lumefantrine to overcome matrix effect and ionization saturation. AB - BACKGROUND: To support pediatric study, a method to determine lumefantrine (LF) with small sample volume is needed. Matrix effect (ME) is a daunting issue in LF quantification in human plasma with LC-MS/MS. RESULTS: Here we report an LC-MS/MS method with a deuterated LF as the internal standard (IS). Plasma sample (25 ul) was acidified with 5% formic acid prior to extraction with ethyl acetate. The recovery was over 80%. The absolute ME was within the range of 100 +/- 8% for both LF and the IS, but cumulative ME was observed via large variation of IS signal. The cumulative ME and ionization saturation were overcome with the co eluting LF-D(9) as the IS. The linear range of calibration curve was 50-20,000 ng/ml. CONCLUSION: ME and ionization saturation was overcome with a deuterated IS. The method utilized a small sample volume, suitable for pediatric study with capillary tube blood collection method. PMID- 22250799 TI - Two-step derivatization procedures for the ionization enhancement of anabolic steroids in LC-ESI-MS for doping control analysis. AB - BACKGROUND: Two-step derivatization procedures were developed for the enhancement of the positive ESI in LC-MS detection of anabolic androgenic steroids, a class of prohibited substances with limited ionization efficiency in atmospheric pressure interfaces. The developed procedures are based on the esterification of hydroxyl groups of anabolic steroids with picolinic acid, followed by conversion of carbonyl groups to Schiff bases by either Girard's reagent T or 2-hydrazino pyridin. RESULTS: Ionization efficiency for the model derivatized compounds 19 norandrosterone (nandrolone main metabolite) and methasterone was higher by almost two orders of magnitude compared with the respective efficiency of the underivatized compounds. CONCLUSION: The obtained derivatives provided a significant improvement in the ESI sensitivity, compared with those of underivatized molecules in positive LC-ESI-ion trap-MS full-scan mode. PMID- 22250800 TI - Miniaturized immunoassays: moving beyond the microplate. AB - After more than 40 years, immunoassays are still the backbone of protein biomarker analysis in clinical diagnostics and drug development. They have come a long way since their inception, incorporating technical developments including monoclonal antibodies, novel labels and lately microfluidics. A number of microfluidic platforms have been tested, such as centrifugational compact disc assays, lab-on-a-chip, arrays and digital electrochemical assays. This review focuses on commercial applications of microfluidic immunoassays with reference to some applied academic examples of interest. Advantages and disadvantages of the platform technologies are discussed in general. PMID- 22250801 TI - Metabolism of biologics: biotherapeutic proteins. AB - Recombinant therapeutic protein drugs have now been in clinical use for nearly three decades and have advanced considerably in complexity over this time period. Regulatory approvals of some early pioneering protein drugs did not require characterization of metabolism, but more recently regulatory expectations and guidance have appropriately evolved. Sponsors may now be expected to investigate metabolism of newer biologics as the structural complexity of proteins has increased markedly, particularly with the introduction of conjugated and modified proteins. This review discusses the value and need for metabolite characterization of some therapeutic proteins by presenting select examples. Regulatory expectations will undoubtedly evolve further with the development of other novel macromolecular biologic therapeutics based on modified nucleic acids, novel conjugated lipids and polysaccharides. PMID- 22250802 TI - Recent developments in MS for small molecules: application to human doping control analysis. AB - Recent developments in MS for the detection of small molecules in the context of doping control analysis are reviewed. Doping control analysis is evolving together with MS, which is the technique of choice in order to accomplish the analytical requirements in this field. Since these analytical requirements for the detection of a doping agent depend on the substance, in the first section we review the different scenarios. The commonly established approaches, together with their achievements and drawbacks are described. New developments in hyphenated MS techniques (both GC-MS/MS and LC-MS/MS) concerning interfaces and analyzers are mentioned. The use (or potential use) of these developments in order to minimize the limitations of the commonly established approaches in the doping control field is discussed. Finally, a brief discussion about trends and remaining limitations is presented. PMID- 22250803 TI - Chemical derivatization as a tool for optimizing MS response in sensitive LC MS/MS bioanalysis and its role in pharmacokinetic studies. AB - Chemical derivatization is the only technique that directly affects the physicochemical property of an analyte in an LC-MS/MS assay platform. On the other side, current MS instruments are extremely sensitive, but still their absolute sensitivity is analyte-dependent. In this review, first, difficulty in analyzing neutral compounds and introducing acidity/basicity and/or proton affinity will be described. Second, the sweet spot of the conventional MS ion source across clogP values is presented. Third, optimization of hydrophilicity/hydrophobicity by derivatization is described. Lastly, development of a new derivatizing reagent specifically designed for LC-MS/MS is described and its significance in pharmacokinetic analysis is discussed. PMID- 22250805 TI - Diagnostic accuracy of brush cytology in canine chronic intranasal disease. AB - BACKGROUND: Most cases of canine chronic intranasal disease cannot be differentiated based on clinical examination alone, and biopsy is often required for a definitive diagnosis. Nonsurgical cytologic and histologic biopsy techniques represent desirable diagnostic approaches. OBJECTIVE: The aim of this retrospective study was to determine the diagnostic accuracy of brush cytology in differentiating non-neoplastic and neoplastic diseases in dogs with chronic intranasal disease. METHODS: Cytologic samples of lesions in dogs with chronic intranasal disease were obtained by brushing over a 12-year period. All dogs had complete physical examinations as well as radiographic, rhinoscopic, and cytologic evaluation. Histologic diagnosis, follow-up clinical information, or both were used as the gold standard, and dogs free of disease or with no progression of disease at 1 year were considered negative for neoplasia. Indicators of performance of brush cytology in detecting neoplasia were calculated and included sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio. RESULTS: Samples of nasal brushings from 138 dogs were evaluated. Of 62 cases of neoplastic disease, true-positive and false-negative diagnoses were made using cytologic evaluation in 44 (71.0%) and 18 (29.0%) cases, respectively. False-negative diagnoses of neoplasia were not attributed to low cellularity, but to the presence of inflammatory cells that masked neoplastic cells. Brush cytology had a sensitivity of 0.71, specificity of 0.99, positive likelihood ratio of 53.94, negative likelihood ratio of 0.29, and diagnostic odds ratio of 188.33. CONCLUSIONS: Brush cytology has good diagnostic accuracy for chronic intranasal lesions in dogs. PMID- 22250806 TI - Evidence for overlooked mechanisms of long-distance seed dispersal to and between oceanic islands. PMID- 22250807 TI - Emotion experience and regulation in China and the United States: how do culture and gender shape emotion responding? AB - Culture and gender shape emotion experience and regulation, in part because the value placed on emotions and the manner of their expression is thought to vary across these groups. This study tested the hypothesis that culture and gender would interact to predict people's emotion responding (emotion intensity and regulatory strategies). Chinese (n=220; 52% female) and American undergraduates (n=241; 62% female) viewed photos intended to elicit negative emotions after receiving instructions to either "just feel" any emotions that arose (Just Feel), or to "do something" so that they would not experience any emotion while viewing the photos (Regulate). All participants then rated the intensity of their experienced emotions and described any emotion-regulation strategies that they used while viewing the photos. Consistent with predictions, culture and gender interacted with experimental condition to predict intensity: Chinese men reported relatively low levels of emotion, whereas American women reported relatively high levels of emotion. Disengagement strategies (especially distancing) were related to lower emotional intensity and were reported most often by Chinese men. Taken together, findings suggest that emotion-regulation strategies may contribute to differences in emotional experience across Western and East Asian cultures. PMID- 22250808 TI - Interim data on long-term efficacy, safety and tolerability of a plasma-derived factor VIII concentrate in 109 patients with severe haemophilia A. AB - The aim of this open-label, multicentre and multinational post-marketing surveillance was to investigate clinical effectiveness, safety and tolerability of a plasma-derived and vWF containing factor VIII product (FVIII/VWF) in patients with severe haemophilia A. Long-term effectiveness, safety and tolerability were investigated in a total of 109 haemophilia A patients treated for prophylaxis or on-demand, as required. Interim data collected until June 2010 are presented. Most patients (99/109; 90.8%) were previously treated patients (PTPs). Mean observation period was 82.6 months. Overall, patients received 105 131 425 IU haemoctin SDH during 68 624 administrations. Each patient was given a mean of 635.4 injections, whereby about half of the administrations were given for treatment of bleeding episodes (46.9%) and the other administrations for prophylactic reasons (53.1%). Patients on prophylaxis had a median of 0.8 bleeding episodes per month. The expected therapeutic effect was reached in 99.3% of treatments. The incidence of clinically relevant inhibitor formation in patients with severe haemophilia (FVIII activity <= 1%) was 1.2% for PTPs. One previously untreated patient with severe haemophilia had a clinically relevant transient inhibitor. No treatment related transmissions of hepatitis A, B and C and HIV 1/2 were observed. German patients had a higher extent of exposure and experienced less bleeding episodes than Hungarian patients. In conclusion, haemoctin SDH was effective, safe and well tolerated in long-term prophylaxis and treatment on demand. PMID- 22250809 TI - Cellular uptake of nanoparticles by membrane penetration: a study combining confocal microscopy with FTIR spectroelectrochemistry. AB - It is well-known that nanomaterials are capable of entering living cells, often by utilizing the cells' endocytic mechanisms. Passive penetration of the lipid bilayer may, however, occur as an alternative process. Here we have focused on the passive transport of small nanoparticles across the plasma membranes of red blood cells, which are incapable of endocytosis. By using fluorescence microscopy, we have observed that zwitterionic quantum dots penetrate through the cell membranes so that they can be found inside the cells. The penetration induced structural changes of the lipid bilayer were explored by surface-enhanced infrared absorption spectroscopy and electrochemistry studies of model membranes prepared on solid supports with lipid compositions identical to those of red blood cell membranes. A detailed analysis of the infrared spectra revealed a markedly enhanced flexibility of the lipid bilayers in the presence of nanoparticles. The electrochemistry data showed that the overall membrane structure remained intact; however, no persistent holes were formed in the bilayers. PMID- 22250810 TI - Optimization of a sponge cake formulation with inulin as fat replacer: structure, physicochemical, and sensory properties. AB - The effects of several fat replacement levels (0%, 35%, 50%, 70%, and 100%) by inulin in sponge cake microstructure and physicochemical properties were studied. Oil substitution for inulin decreased significantly (P < 0.05) batter viscosity, giving heterogeneous bubbles size distributions as it was observed by light microscopy. Using confocal laser scanning microscopy the fat was observed to be located at the bubbles' interface, enabling an optimum crumb cake structure development during baking. Cryo-SEM micrographs of cake crumbs showed a continuous matrix with embedded starch granules and coated with oil; when fat replacement levels increased, starch granules appeared as detached structures. Cakes with fat replacement up to 70% had a high crumb air cell values; they were softer and rated as acceptable by an untrained sensory panel (n = 51). So, the reformulation of a standard sponge cake recipe to obtain a new product with additional health benefits and accepted by consumers is achieved. Practical Application: In this study, fat is replaced by inulin in cakes, which is a fiber mainly obtained from chicory roots. Sponge cake formulations with reductions in fat content up to 70% are achieved. These high-quality products can be labeled as "reduced in fat" according to U.S. FDA (2009) and EU regulations (European-Union 2006). PMID- 22250811 TI - Syntheses of novel protein products (milkglyde, saliglyde, and soyglyde) from vegetable epoxy oils and gliadin. AB - The aqueous alcohol-soluble fraction of wheat gluten is gliadin. This component has been implicated as the causative principle in celiac disease, which is a physiological condition experienced by some infants and adults. The outcome of the ingestion of whole wheat products by susceptible individuals is malabsorption of nutrients resulting from loss of intestinal vili, the nutrient absorption regions of the digestive system. This leads to incessant diarrhea and weight loss in these individuals. Only recently has this health condition been properly recognized and accurately diagnosed in this country. The culprit gliadin is characterized by preponderant glutamine side-chain residues on the protein surface. Gliadin is commercially available as a wheat gluten extract, and in our search for new biobased and environmentally friendly products from renewable agricultural substrates, we have exploited the availability of the glutamine residues of gliadin as synthons to produce novel elastomeric nonfood products dubbed "milkglyde", "saliglyde", and soyglyde from milkweed, salicornia and soybean oils. The reaction is an amidolysis of the oxirane groups of derivatized milkweed, salicornia, and soybean oils under neat reaction conditions with the primary amide functionalties of glutamine to give the corresponding amidohyroxy gliadinyl triglycerides, respectively. The differential scanning calorimetry, thermogravimetric analyses, and rheological data from a study of these products indicate properties similar to those of synthetic rubber. PMID- 22250812 TI - Allopurinol-induced palisaded neutrophilic and granulomatous dermatitis. AB - We describe a 64-year-old man with past chronic myeloid leukemia. Palisading neutrophilic granulomatous dermatitis of the hands was diagnosed and related to recent allopurinol intake. Allopurinol is known to rarely cause granulomatous reactions, but this appears to be the first case of palisading neutrophilic granulomatous dermatitis induction. Possible mechanisms include immune complex deposition, an immune response directed against the metabolites of allopurinol, or allopurinol hypersensitivity exclusively localized to the skin. PMID- 22250813 TI - Novel CaO-SiO2 sorbent and bifunctional Ni/Co-CaO/SiO2 complex for selective H2 synthesis from cellulose. AB - Catalysis- and sorption-enhanced biomass gasification is a promising route to high-purity hydrogen (H(2)); however, most CaO-based sorbents for CO(2) capture have poor surface area and mechanical properties, lose carrying capacity over multiple uses, and have insufficient porosity to accommodate extra catalyst sites. We aimed to develop a high-surface-area CaO-SiO(2) framework onto which catalysts could be grafted. The best CaO-SiO(2) sorbent (n(Ca)/n(Si) = 2:1) maintained a CaO conversion of 65% even after 50 carbonation-decarbonation cycles, better than commercial micrometer-sized CaO or tailored CaO, because of stabilization via Ca-O-Si interactions and an ordered porous structure. Bimetallic catalyst grains (Ni/Co alloy, <20 nm) could be evenly loaded onto this structure by impregnation. The resulting bifunctional complex produced H(2) at nearly the same rate as a mixture of catalyst and commercial CaO while using less total sorbent/catalyst. Furthermore, this complex was much more durable due to its higher coking resistance and stable structure. After 25 carbonation decarbonation cycles, the new catalyst-sorbent complex enhanced the H(2) yield from cellulose far more than a mixture of catalyst and commercial CaO did following the same treatment. PMID- 22250814 TI - Activity-dependent actin dynamics are required for the maintenance of long-term plasticity and for synaptic capture. AB - The maintenance of long-lasting forms of plasticity, such as long-term potentiation (LTP) is dependent on the capture of plasticity-related proteins (PRPs) in an input-specific manner - synaptic capture. Here, it is shown that LTP, induced at Schaffer collaterals-CA1 synapses in acute rat hippocampal slice preparation, is not sensitive to protein synthesis inhibition if N-methyl-d aspartate (NMDA) receptors are blocked, suggesting that synaptic activation is involved in the modulation of LTP maintenance. Similarly, it was found that synaptic activation also determines the sensitivity of LTP to manipulations of the actin cytoskeleton dynamics. Suspending synaptic activation or concomitant NMDA receptor inhibition is sufficient to rescue the impairment on LTP maintenance induced by actin polymerization blockade. Additionally, concomitant inhibition of protein degradation can partially prevent the LTP decay observed under actin polymerization blockade, suggesting that protein degradation is involved in the destabilization of LTP maintenance induced by actin polymerization blockade. Taken together, these observations suggest that LTP maintenance is determined by a balance of synthesis and degradation of PRPs modulated by synaptic activation and actin dynamics. Finally, it was uncovered that inhibition of actin depolymerization blocks synaptic capture, whereas inhibition of actin polymerization can extend the temporal window for synaptic capture. Additionally, inhibition of actin polymerization can rescue the impairment in synaptic capture induced by CaMKII inhibition, suggesting a link between CaMKII activation and modulation of actin dynamics during synaptic capture. These results show that an activity-dependent regulation of actin dynamics plays a critical role in LTP maintenance and synaptic capture. PMID- 22250815 TI - Cellular anatomy, physiology and epileptiform activity in the CA3 region of Dcx knockout mice: a neuronal lamination defect and its consequences. AB - We report data on the neuronal form, synaptic connectivity, neuronal excitability and epileptiform population activities generated by the hippocampus of animals with an inactivated doublecortin gene. The protein product of this gene affects neuronal migration during development. Human doublecortin (DCX) mutations are associated with lissencephaly, subcortical band heterotopia, and syndromes of intellectual disability and epilepsy. In Dcx(-/Y) mice, CA3 hippocampal pyramidal cells are abnormally laminated. The lamination defect was quantified by measuring the extent of the double, dispersed or single pyramidal cell layer in the CA3 region of Dcx(-/Y) mice. We investigated how this abnormal lamination affected two groups of synapses that normally innervate defined regions of the CA3 pyramidal cell membrane. Numbers of parvalbumin (PV)-containing interneurons, which contact peri-somatic sites, were not reduced in Dcx(-/Y) animals. Pyramidal cells in double, dispersed or single layers received PV-containing terminals. Excitatory mossy fibres which normally target proximal CA3 pyramidal cell apical dendrites apparently contact CA3 cells of both layers in Dcx(-/Y) animals but sometimes on basilar rather than apical dendrites. The dendritic form of pyramidal cells in Dcx(-/Y) animals was altered and pyramidal cells of both layers were more excitable than their counterparts in wild-type animals. Unitary inhibitory field events occurred at higher frequency in Dcx(-/Y) animals. These differences may contribute to a susceptibility to epileptiform activity: a modest increase in excitability induced both interictal and ictal-like discharges more effectively in tissue from Dcx(-/Y) mice than from wild-type animals. PMID- 22250816 TI - Dispositional empathy modulates vicarious effects of dynamic pain expressions on spinal nociception, facial responses and acute pain. AB - Pain communication is thought to promote automatic vicarious self-protective responses as well as empathic concern towards others' suffering. This duality was recently highlighted in a study showing that highly empathic individuals display increased vicarious facilitation of low-level pain processing (nociceptive flexion reflex, NFR) combined with an unexpected reduced facilitation of self pain perception (pain ratings) while viewing static pictures evoking pain in others. The present study sought to test further the moderating effects of dispositional empathy on vicarious responses induced by viewing dynamic pain expressions. Twenty-four healthy volunteers viewed 1-s videos showing different levels of pain expression before noxious electric shocks were delivered to the sural nerve. Viewing stronger pain expressions generally increased shock-pain unpleasantness ratings, the amplitude of the NFR, and facial responses (corrugator muscle) to the noxious stimulation. However, self-pain ratings (intensity and unpleasantness) increased less or were reduced following clips of pain expression in individuals scoring higher on the Empathy Quotient. These results suggest that vicarious processes facilitate low-level defensive responses, while the experience of self-pain and the associated negative affect may be partly tuned-down by higher-order empathic processes. PMID- 22250818 TI - Dissociation between unconscious motor response facilitation and conflict in medial frontal areas. AB - Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless modulate behavior. The neuronal correlates of behavioral manifestations of visuomotor priming remain debated, particularly with respect to the distribution and direction (i.e. increase or decrease) of activity changes in medial frontal areas. Here, we predicted that these discrepant results could be accounted for by two automatic and unconscious processes embedded in this task: response conflict and facilitation. We used event-related functional magnetic resonance imaging (fMRI), as 24 healthy participants had to respond, as fast as possible, to a target arrow presented immediately after a subliminal masked prime arrow. There were three experimental conditions defined by the prime-target relationship: compatible, incompatible, and neutral. The classical visuomotor priming effect was reproduced, with relatively longer reaction times (RTs) in incompatible trials. Longer RTs in incompatible than in neutral trials were specifically associated with stronger blood oxygen level-dependent (BOLD) activity in a conflict-related network comprising the anterior cingulate cortex and right frontal associative areas. Motor response facilitation as shown by shorter RTs in compatible than in neutral trials was associated with reduced activation in a motor preparation network including the medial and lateral premotor cortices, as a result of the repetition suppression of the fMRI BOLD signal. The present results provide new insights into automatic and unconscious visuomotor priming processes, suggesting an involvement of either a cognitive or motor network, depending on the prime-target relationship. PMID- 22250820 TI - Brazilian pioneers in artificial organs and heart surgery. PMID- 22250817 TI - Regulator of calmodulin signaling knockout mice display anxiety-like behavior and motivational deficits. AB - Regulator of calmodulin (CaM) signaling (RCS), when phosphorylated by protein kinase A (PKA) on Ser55, binds to CaM and inhibits CaM-dependent signaling. RCS expression is high in the dorsal striatum, nucleus accumbens and amygdala, suggesting that the protein is involved in limbic-striatal function. To test this hypothesis, we examined RCS knockout (KO) mice in behavioral models dependent on these brain areas. Mice were tested for food-reinforced instrumental conditioning and responding under a progressive ratio (PR) schedule of reinforcement and in models of anxiety (elevated plus maze and open field). While RCS KO mice showed normal acquisition of a food-motivated instrumental response, they exhibited a lower breakpoint value when tested on responding under a PR schedule of reinforcement. RCS KO mice also displayed decreased exploration in both the open arms of an elevated plus maze and in the center region of an open field, suggesting an enhanced anxiety response. Biochemical studies revealed a reduction in the levels of dopamine and cAMP-regulated phosphoprotein (DARPP-32) in the striatum of RCS KO mice. DARPP-32 is important in reward-mediated behavior, suggestive of a possible role for DARPP-32 in mediating some of the effects of RCS. Together these results implicate a novel PKA-regulated phosphoprotein, RCS, in the etiology of motivational deficits and anxiety. PMID- 22250822 TI - The kinetics of cardiopulmonary bypass: a dual-platform proteomics study of plasma biomarkers in pediatric patients undergoing cardiopulmonary bypass. AB - This study was designed to investigate the expression kinetics and patterns of plasma biomarkers throughout the pediatric cardiopulmonary bypass (CPB) procedure to help predict those patients most at risk for complications. This study sampled plasma from pediatric CPB patients at five time points before, during, and after CPB. A dual-platform proteomics approach was then utilized which incorporated two dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption ionization-time-of-flight/time-of-flight tandem mass spectrometry, and multi-analyte profile (MAP) assays to identify changes in expression of plasma protein biomarkers and characterize the patterns of these changes. A combined total of 134 proteins were identified with significant changes between the two platforms, with 53 coming from 2D-DIGE, 90 from MAP, and nine proteins that were identified using both methods. The proteins were then divided into 12 major groups based on the expression patterns, and two of the most clinically relevant proteins having the greatest changes in expression were selected from each group to use as "predictor biomarkers." A potential model for prediction of patient outcome was then generated using these 24 proteins. The patterns of biomarker expression during pediatric CPB may provide insight into the prediction, prevention, or treatment of complications resulting from CPB, thereby helping to improve the outcomes of pediatric CPB patients and reduce the incidence of complications. PMID- 22250823 TI - Family communication patterns moderate the relationship between psychological reactance and willingness to talk about organ donation. AB - Considerable research has investigated how psychological reactance affects individuals' responses to health promotion messages, but little is known about how family processes might moderate the reactance process. In this study, 301 participants were exposed to a persuasive message about organ donation. The moderating role of family communication patterns in the reactance process was tested using hierarchical regression. We found that family conversation orientation had a direct effect on willingness to talk with family members about being an organ donor and that family conformity orientation and family conversation orientation each interacted with reactance to predict willingness to communicate with family about donation. Theoretically, these results extend psychological reactance theory by considering how interpersonal factors affect the reactance process. Practically, the findings suggest that for optimal impact, family processes should be considered in the design of messages promoting organ donation. PMID- 22250824 TI - Phonological skills and their role in learning to read: a meta-analytic review. AB - The authors report a systematic meta-analytic review of the relationships among 3 of the most widely studied measures of children's phonological skills (phonemic awareness, rime awareness, and verbal short-term memory) and children's word reading skills. The review included both extreme group studies and correlational studies with unselected samples (235 studies were included, and 995 effect sizes were calculated). Results from extreme group comparisons indicated that children with dyslexia show a large deficit on phonemic awareness in relation to typically developing children of the same age (pooled effect size estimate: -1.37) and children matched on reading level (pooled effect size estimate: -0.57). There were significantly smaller group deficits on both rime awareness and verbal short term memory (pooled effect size estimates: rime skills in relation to age-matched controls, -0.93, and reading-level controls, -0.37; verbal short-term memory skills in relation to age-matched controls, -0.71, and reading-level controls, 0.09). Analyses of studies of unselected samples showed that phonemic awareness was the strongest correlate of individual differences in word reading ability and that this effect remained reliable after controlling for variations in both verbal short-term memory and rime awareness. These findings support the pivotal role of phonemic awareness as a predictor of individual differences in reading development. We discuss whether such a relationship is a causal one and the implications of research in this area for current approaches to the teaching of reading and interventions for children with reading difficulties. PMID- 22250825 TI - Induction of apoptosis in HL-60 cells through the ROS-mediated mitochondrial pathway by ramentaceone from Drosera aliciae. AB - Ramentaceone (1) is a naphthoquinone constituent of Drosera aliciae that exhibits potent cytotoxic activity against various tumor cell lines. However, its molecular mechanism of cell death induction has still not been determined. The present study demonstrates that 1 induces apoptosis in human leukemia HL-60 cells. Typical morphological and biochemical features of apoptosis were observed in 1-treated cells. Compound 1 induced a concentration-dependent increase in the sub-G1 fraction of the cell cycle. A decrease in the mitochondrial transmembrane potential (DeltaPsim) was also observed. Furthermore, 1 reduced the ratio of anti apoptotic Bcl-2 to pro-apoptotic Bax and Bak, induced cytochrome c release, and increased the activity of caspase 3. The generation of reactive oxygen species (ROS) was detected in 1-treated HL-60 cells, which was attenuated by the pretreatment of cells with a free radical scavenger, N-acetylcysteine (NAC). NAC also prevented the increase of the sub-G1 fraction induced by 1. These results indicate that ramentaceone induces cell death through the ROS-mediated mitochondrial pathway. PMID- 22250826 TI - Teleconference etiquette. PMID- 22250827 TI - Public services for children with special needs: discrimination by diagnosis? AB - In July 2011, the Australian federal government announced expansion of early intervention funding. Children diagnosed with cerebral palsy, Down syndrome, Fragile X syndrome and hearing and vision impairments are now eligible in addition to the existing funding for children diagnosed with autistic disorders. By deciding who gets the funding according to a set of accepted diagnoses, many children with equivalent if not greater levels of early intervention special need are excluded. In this viewpoint, we consider the fairness of this approach, and argue that while it may make sense from a political point of view, it is hard to justify, and possibly even discriminatory, from clinical, ethical and legal perspectives. PMID- 22250828 TI - Recruitment challenges and recommendations for adolescent obesity trials. AB - AIM: To report our experiences with recruiting overweight and obese 13- to 16 year-olds for the Loozit(r) weight management randomised control trial (RCT) and to identify effective strategies for recruiting adolescents from the community to a treatment trial. METHODS: The Loozit RCT is a two-arm, community-based, lifestyle intervention that aims to evaluate the effect of additional therapeutic contact provided via telephone coaching and electronic communications as an adjunct to the Loozit group programme. Strategic areas that were targeted to recruit adolescents included media, schools, health professionals and community organisations. The programme aimed to recruit a cohort of 12-16 adolescents (body mass index z-score range 1.0-2.5) aged 13-16 years every 3 months over 3 years. Information regarding recruitment and eligibility to participate was initially assessed during a telephone screen. The relative cost effectiveness of recruitment strategies was determined based on recruitment rates and costs including administrative costs and research assistant time. RESULTS: Out of 474 enquiries, 32% resulted in an enrollment to the RCT. Newspaper articles and school newsletters accounted for nearly 60% of enquiries and enrollments and were the most cost-effective recruitment strategies. Common reasons for ineligibility for inclusion in the RCT were adolescents being too young (21%) and parents consenting but adolescents refusing to participate (17%). CONCLUSIONS: The most successful recruitment strategies for the Loozit RCT were local newspapers and school newsletters. Future studies should consider involving a Public Relations department and other potentially cost-effective strategies such as peer recruitment. PMID- 22250829 TI - Low calcium. PMID- 22250831 TI - Snoring and blood pressure. PMID- 22250833 TI - Late preterm infants and therapeutic hypothermia. PMID- 22250834 TI - Infantile cardiac haemangioma with large pericardial effusion diagnosed during acute bronchiolitis episode. PMID- 22250835 TI - Birth injury-related diaphragmatic paralysis manifesting as protracted vomiting and CPAP dependency. PMID- 22250837 TI - The boy who didn't like me. PMID- 22250838 TI - Choosing and using geospatial displays: effects of design on performance and metacognition. AB - Interactive display systems give users flexibility to tailor their visual displays to different tasks and situations. However, in order for such flexibility to be beneficial, users need to understand how to tailor displays to different tasks (to possess "metarepresentational competence"). Recent research suggests that people may desire more complex and realistic displays than are most effective (Smallman & St. John, 2005). In Experiment 1, undergraduate students were tested on a comprehension task with geospatial displays (weather maps) that varied in the number of extraneous variables displayed. Their metacognitive judgments about the relative effectiveness of the displays were also solicited. Extraneous variables slowed response time and increased errors, but participants favored complex maps that looked more realistic about one third of the time. In Experiment 2, the eye fixations of undergraduate students were monitored as they performed the comprehension task. Complex maps that looked more realistic led to more eye fixations on both task-relevant and task-irrelevant regions of the displays. Experiment 3 compared performance of experienced meteorologists and undergraduate students on the comprehension and metacognitive tasks. Meteorologists were as likely as undergraduate students to prefer geographically complex (realistic) displays and more likely than undergraduates to opt for displays that added extraneous weather variables. However, meteorologists were also slower and less accurate with complex than with simple displays. This work highlights the importance of empirically testing principles of visual display design and suggests some limits to metarepresentational competence. PMID- 22250839 TI - The reliability of cone-beam computed tomography to assess bone density at dental implant recipient sites: a histomorphometric analysis by micro-CT. AB - OBJECTIVES: The aim of this study was to objectively assess the reliability of the cone-beam computed tomography (CBCT) as a tool to pre-operatively determine radiographic bone density (RBD) by the density values provided by the system, analyzing its relationship with histomorphometric bone density expressed as bone volumetric fraction (BV/TV) assessed by micro-CT of bone biopsies at the site of insertion of dental implants in the maxillary bones. MATERIAL AND METHODS: Thirty nine bone biopsies of the maxillary bones at the sites of 39 dental implants from 31 edentulous healthy patients were analyzed. The NobelGuideTM software was used for implant planning, which also allowed fabrication of individual stereolithographic surgical guides. The analysis of CBCT images allowed pre operative determination of mean density values of implant recipient sites along the major axis of the planned implants (axial RBD). Stereolithographic surgical guides were used to guide implant insertion and also to extract cylindrical bone biopsies from the core of the exact implant site. Further analysis of several osseous micro-structural variables including BV/TV was performed by micro-CT of the extracted bone biopsies. RESULTS: Mean axial RBD was 478 +/- 212 (range: 144 953). A statistically significant difference (P = 0.02) was observed among density values of the cortical bone of the upper maxilla and mandible. A high positive Pearson's correlation coefficient (r = 0.858, P < 0.001) was observed between RBD and BV/TV, with the regression equations: (1) Axial RBD = -19.974 + 10.238.BV/TV; (2) BV/TV = 14.258 + 0.72.Axial RBD. RBD was also positively correlated with the trabecular thickness (Tb.Th) and trabecular number (Tb.N), but negatively correlated with trabecular separation (Tb.Sp), structural model index, and inverse connectivity (Tb.Pf). Density values upper than 450 were associated with BV/TV upper than 50%, mean Tb.Th upper than 0.2 mm, mean Tb.Sp lower than 0.3 mm, and mean Tb.N upper than 2. CONCLUSION: RBD assessed by CBCT has a strong positive correlation with BV/TV assessed by micro-CT at the site of dental implants in the maxillary bones. Pre-operative estimation of density values by CBCT is a reliable tool to objectively determine bone density. PMID- 22250840 TI - Ectopic bone regeneration by human bone marrow mononucleated cells, undifferentiated and osteogenically differentiated bone marrow mesenchymal stem cells in beta-tricalcium phosphate scaffolds. AB - Tissue engineering approaches using the combination of porous ceramics and bone marrow mesenchymal stem cells (BMSCs) represent a promising bone substitute for repairing large bone defects. Nevertheless, optimal conditions for constructing tissue-engineered bone have yet to be determined. It remains unclear if transplantation of predifferentiated BMSCs is superior to undifferentiated BMSCs or freshly isolated bone marrow mononucleated cells (BMNCs) in terms of new bone formation in vivo. The aim of this study was to investigate the effect of in vitro osteogenic differentiation (beta-glycerophosphate, dexamethasone, and l ascorbic acid) of human BMSCs on the capability to form tissue-engineered bone in unloaded conditions after subcutaneous implantation in nude mice. After isolation from human bone marrow aspirates, BMNCs were divided into three parts: one part was seeded onto porous beta-tricalcium phosphate ceramics immediately and transplanted in a heterotopic nude mice model; two parts were expanded in vitro to passage 2 before cell seeding and in vivo transplantation, either under osteogenic conditions or not. Animals were sacrificed for micro-CT and histological evaluation at 4, 8, 12, 16, and 20 weeks postimplantation. The results showed that BMSCs differentiated into osteo-progenitor cells after induction, as evidenced by the altered cell morphology and elevated alkaline phosphatase activity and calcium deposition, but their clonogenicity, proliferating rate, and seeding efficacy were not significantly affected by osteogenic differentiation, compared with undifferentiated cells. Extensive new bone formed in the pores of all the scaffolds seeded with predifferentiated BMSCs at 4 weeks after implantation, and maintained for 20 weeks. On the contrary, scaffolds containing undifferentiated BMSCs revealed limited bone formation only in 1 out of 6 cases at 8 weeks, and maintained for 4 weeks. For scaffolds with BMNCs, woven bone was observed sporadically only in one case at 8 weeks. Overall, this study suggests that ectopic osteogenesis of cell/scaffold composites is more dependent on the in vitro expansion condition, and osteo-differentiated BMSCs hold the highest potential concerning in vivo bone regeneration. PMID- 22250842 TI - Polymelous layer chick displaying additional malformations of the hind gut: case report and in-depth review of related literature. AB - A case report of a male 6-day-old male layer chick featuring incomplete polymelia of the hind limbs and hindgut malformations is presented. The chick was submitted to computed tomography (CT) examination and subsequent anatomical dissection. Apart from the two supernumerary hind limbs, the anatomical dissection revealed additional hindgut alterations: three uniform-sized caeca flanked the ileum, and the rectum branched into paired cloacae. The supernumerary hind limbs were localized caudal to the normal hind limbs in an inverted position and were attached to pelvic girdle elements and to a curtate pygostyle. They featured a prominent unpaired femur besides paired tibiotarsi, tarsometatarsi and species specific phalanges of the toes. Additionally, two separate bones attached to the caudoventral aspect of the regular hip bones were developed. The supernumerary limbs were in part mobile and received nerve and vascular supply. Digital 3D reconstruction based on the CT datasets revealed the osseous components of the malformed body parts. The possible morphogenesis including an in-depth literature review and the clinical implications of the reported malformations are discussed. PMID- 22250843 TI - The influence of the perception of a familial climate on job performance: mediation of loyalty to supervisors and moderation of filial behaviour. AB - With a collectivist cultural perspective, we examined the positive effects of employees' perceptions of a familial climate on loyalty to supervisors, the mediation of loyalty between perception of a familial climate and job performance, and the moderation of employees' filial behaviour on the relationship between perception of a familial climate and loyalty. The participants consisted of 247 supervisor-and-subordinate dyads in Taiwan. The results supported our hypotheses. Through the mechanisms of family behaviour transference, social identification and supervisor-subordinate exchange, perception of an organizational familial climate enhanced loyalty to supervisors. Furthermore, loyalty to supervisors mediated the relationship between perception of a familial climate and job performance. Filial behaviour moderated the relationship between perception of a familial climate and loyalty; thus, the relationship of perception of a familial climate and loyalty was stronger for employees with low levels of filial behaviour and weaker for employees with high levels of filial behaviour. These findings are discussed in terms of their theoretical and practical implications for future research and management practices. PMID- 22250844 TI - Editorial: reducing cardiovascular risk: is low-density lipoprotein-cholesterol (LDL-C) lowering enough? PMID- 22250845 TI - Validation of a portable hand-held whole-blood ketone meter for use in cats. AB - BACKGROUND: Urinary dipsticks are the most frequent method used for screening of ketones in animals, but this method has many drawbacks. In human medicine, portable meters that measure ketones in whole blood have largely replaced urinary dipsticks. OBJECTIVE: The aim of this prospective study was to validate a portable whole-blood ketone meter for use in cats. METHODS: Sixty-two cats (11 clinically healthy, 51 with diabetes mellitus) were included in the study. The concentration of beta-hydroxybuyrate (beta-HB) was measured in venous and capillary blood with a hand-held ketone meter (Precision Xceed; assay range 0-8 mmol/L) and compared with a spectrophotometric method. Precision, accuracy, and the effects of hematocrit and anticoagulants were evaluated. RESULTS: Between-run precision using low- and high-concentration control solutions was 8.1% and 2.6%, respectively; within-run coefficient of variation determined using 12 feline blood samples was 2.8%. In the 62 cats, beta-HB concentrations measured with the portable ketone meter ranged from 0-7.4 mmol/L (median 0.9 mmol/L). When beta-HB concentrations measured by the portable meter were < 4.0 mmol/L there was good agreement with the reference method, but concentrations > 4.0 mmol/L were lower than those obtained by the reference method in 20 of 24 cats (83%). There was good correlation between capillary and venous measurements. Results were not affected by hematocrits from 0.17 to 0.50 L/L, but EDTA was not a suitable anticoagulant. CONCLUSION: Measurement of beta-HB concentration in peripheral or capillary blood by an easy-to-use portable ketone meter was suitable for detecting ketonemia in cats. Underestimation of beta-HB concentration was observed at higher values, but results were sufficiently high to aid in diagnosing diabetic ketoacidosis. PMID- 22250846 TI - Photocatalytic degradation efficiency and mechanism of microcystin-RR by mesoporous Bi2WO6 under near ultraviolet light. AB - Microcystin-RR (MC-RR) is one of the most common cyanotoxin microcystins in fresh water and is of great concern due to its potential hepatotoxicity. In the present study, Bi(2)WO(6) was synthesized with a hydrothermal method by varying the pH of the reaction solution in the range of 1-11. The surface area of the catalysts decreased, but the crystallinity and crystal size increased with the pH. The adsorption and degradation capacities of the catalysts decreased with increasing the preparation solution pH. The Bi(2)WO(6) prepared at pH 1 (Bi(2)WO(6)-pH1) displayed the highest adsorption and degradation capacity to MC-RR even though it consisted of randomly aggregated particles. Nearly 100% of MC-RR at 10 mg L(-1) was removed after 30 min of irradiation of near-ultraviolet light (300-400 nm) in a solution with Bi(2)WO(6) concentration of 0.2 g L(-1). The photodegradation efficiency of Bi(2)WO(6)-pH1 was greater in acid medium than in basic solutions. Several intermediate products were observed and identified by liquid chromatography/mass spectrometry/mass spectrometry, and a unique photodegradation pathway was proposed. It was assumed that a photo-Kolbe process happened at the site carboxyl acid group of the d-Glu residue by the photogenerated holes, producing a hydroperoxyl product at m/z 513.8. This intermediate could be further decomposed to an alcohol product at m/z 505.8 and a ketone product at m/z 504.8. The aromatic ring and diene bond of the Adda chain could also be attacked by the holes and form phenol and diol products. PMID- 22250847 TI - The influence of neurocognitive impairment on HIV treatment outcomes among drug involved people living with HIV/AIDS. AB - Findings to date indicate that it is feasible to deliver a brief behavioral risk reduction/medication adherence group intervention to HIV-infected injection drug users in a community-based setting. HIV infection and substance abuse can result in neurocognitive impairment and this is directly relevant to intervention development, because a significant number of people living with HIV/AIDS have a positive history of substance abuse and being able to successfully participate in behavioral interventions often requires a relatively high level of cognitive performance. The aim of the current study was to evaluate if changes in information, motivation, and behavior skills with respect to medication adherence, sex- and drug-risk behavior outcomes from baseline to post intervention are predicted by cognitive impairment following the brief four session Holistic Health for HIV intervention for HIV-infected Drug Users (3H+). Significant associations were found between change in motivation and certain neurocognitive performance domains. Findings suggest that it may be helpful to specifically tailor such behavioral interventions to accommodate cognitive impairment. PMID- 22250849 TI - Stigma of mental illness and service use in the military. AB - BACKGROUND: Many service members do not utilize the available services designed to assist them in coping with post-traumatic stress disorder and other mental health problems that emerge during active duty. AIMS: In the current paper, we discuss the possible role stigma plays in the underutilization of treatments in the military, and attempt to transfer a well-articulated framework for understanding stigma and stigma-change in civilian populations to the military context. METHODS: The literature was searched for papers reviewing negative beliefs about mental illness and fears of stigmatization and underutilization of treatments, especially as relevant to service members. RESULTS: We explain how public stigma, self stigma, and label avoidance may emerge as barriers to care seeking and service participation in soldiers, and propose approaches/strategies for change. We then discuss a number of recent applications of these approaches in both civilian and military initiatives. CONCLUSIONS: Stigma-change programs specifically created by/for the military that integrate components of education and direct contact with respected peers or veterans who have coped with mental health problems may have great utility at both the early stages of military training and later, when soldiers return from theatres of operation. PMID- 22250848 TI - The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. AB - BACKGROUND AND PURPOSE: Although naturally occurring polyamines are indispensable for a variety of cellular events in eukaryotic cells, little attention has been paid to their physiological and pathological significance in bone remodelling to date. In this study, we evaluated the pharmacological properties of several natural polyamines on the functionality and integrity of bone in both in vitro and in vivo experiments. EXPERIMENTAL APPROACH: Mice were subjected to ovariectomy (OVX) and subsequent oral supplementation with either spermidine or spermine for determination of the bone volume together with different parameters regarding bone formation and resorption by histomorphometric analyses in vivo. Pre-osteoclasts were cultured with receptor activator of NF-kappaB ligand (RANKL), with or without spermidine and spermine to determine cellular maturation by tartrate-resistant acid phosphatase (TRAP) staining and cellular viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide reduction in vitro. KEY RESULTS: Spermidine or spermine, given in drinking water for 28 days, significantly prevented the increased osteoclast surface/bone surface ratio and the reduced bone volume following OVX in mice. Either spermidine or spermine significantly inhibited the increased number of multinucleated TRAP-positive cells in osteoclasts cultured with RANKL in a concentration-dependent manner without affecting cell survival. CONCLUSIONS AND IMPLICATIONS: The natural polyamines spermidine and spermine prevented OVX-induced bone loss through the disruption of differentiation and maturation of osteoclasts, rather than affecting osteoblasts. The supplementation with these natural polyamines could be beneficial for the prophylaxis as well as therapy of metabolic bone diseases such as post-menopausal osteoporosis. PMID- 22250850 TI - Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database. AB - Neutralizing inhibitors develop in 20-30% of patients with severe factor VIII (FVIII) deficiency. It is well established that Blacks have a higher prevalence of inhibitors than Whites. This is the first study to definitively demonstrate increased inhibitor prevalence in the Hispanic population. We compared inhibitor prevalence among various racial and ethnic groups in a cross-sectional analysis of 5651 males with severe haemophilia A that participated in the Universal Data Collection project sponsored by the Centers for Disease Control and Prevention. We used logistic regression analysis to control for potential confounding variables. We assigned as Hispanic those participants who were white and labelled themselves Hispanic. The prevalence of high-titre inhibitors in the Hispanic participants was 24.5% compared to 16.4% for White non-Hispanic patients (OR 1.4, 95% CI 1.1, 1.7). Possibilities as to the underlying cause of increased inhibitor prevalence in minority ethnic populations include polymorphisms in the FVIII molecule, HLA subtypes and differing inflammatory responses. A better understanding may lead to tailored treatment programmes, or other therapies, to decrease or prevent inhibitor development. PMID- 22250851 TI - Interpretation training in individuals with generalized social anxiety disorder: a randomized controlled trial. AB - OBJECTIVE: To examine the efficacy of a multisession computerized interpretation modification program (IMP) in the treatment of generalized social anxiety disorder (GSAD). METHOD: The sample comprised 49 individuals meeting diagnostic criteria for GSAD who were enrolled in a randomized, double-blind placebo controlled trial comparing IMP (n = 23) with an interpretation control condition (ICC; n = 26). The interpretation training procedures comprised a word-sentence association task in which participants decided whether a word implying a threatening or benign meaning was related to an ambiguous social scenario. In the IMP group, participants were reinforced for interpreting ambiguous social information in a nonthreatening and more benign manner. In the ICC group, participants were reinforced with equal frequency for interpreting ambiguous social information in either a threatening or benign manner. RESULTS: Intent-to treat and completer analyses revealed that IMP significantly decreased threat interpretations and increased benign interpretations from pre- to post-assessment relative to the ICC group. Moreover, IMP participants displayed significantly larger reductions in clinician-rated social anxiety symptoms and functional impairment as well as self-reported trait anxiety and depression relative to ICC participants. Groups did not differ on change in self-rated social anxiety symptoms. Participants no longer meeting DSM-IV criteria for GSAD at post assessment were 65% in IMP and 13% in ICC. CONCLUSIONS: These results suggest that computerized interpretation training procedures may be beneficial for treating social anxiety disorder. PMID- 22250852 TI - A randomized trial of contingency management delivered by community therapists. AB - OBJECTIVE: Contingency management (CM) is an evidence-based treatment, but few clinicians deliver this intervention in community-based settings. METHOD: Twenty three clinicians from 3 methadone maintenance clinics received training in CM. Following a didactics seminar and a training and supervision period in which clinicians delivered CM to pilot patients, a randomized trial evaluated the efficacy of CM when delivered entirely by clinicians. Sixteen clinicians treated 130 patients randomized to CM or standard care. In both conditions, urine and breath samples were collected twice weekly for 12 weeks. In the CM condition, patients earned the opportunity to win prizes ranging in value from $1 to $100 for submitting samples negative for cocaine and alcohol. Primary treatment outcomes were retention, longest continuous period of abstinence, and proportion of negative samples submitted. RESULTS: Patients randomized to CM remained in the study longer (9.5 +/- 3.6 vs. 6.7 +/- 5.0 weeks), achieved greater durations of abstinence (4.7 +/- 4.7 vs. 1.7 +/- 2.7 weeks), and submitted a higher proportion of negative samples (57.7% +/- 40.0% vs. 29.4% +/- 33.3%) than those assigned to standard care. CONCLUSIONS: These data indicate that, with appropriate training, community-based clinicians can effectively administer CM. This study suggests that resources ought to be directed toward training and supervising community based providers in delivering CM, as patient outcomes can be significantly improved by integrating CM in methadone clinics. PMID- 22250853 TI - Onset of alcohol or substance use disorders following treatment for adolescent depression. AB - OBJECTIVE: This study tested whether positive response to short-term treatment for adolescent major depressive disorder (MDD) would have the secondary benefit of preventing subsequent alcohol use disorders (AUD) or substance use disorders (SUD). METHOD: For 5 years, we followed 192 adolescents (56.2% female; 20.8% minority) who had participated in the Treatment for Adolescents with Depression Study (TADS; TADS Team, 2004) and who had no prior diagnoses of AUD or SUD. TADS initial treatments were cognitive behavior therapy (CBT), fluoxetine alone (FLX), the combination of CBT and FLX (COMB), or clinical management with pill placebo (PBO). We used both the original TADS treatment response rating and a more restrictive symptom count rating. During follow-up, diagnostic interviews were completed at 6- or 12-month intervals to assess onset of AUD or SUD as well as MDD recovery and recurrence. RESULTS: Achieving a positive response to MDD treatment was unrelated to subsequent AUD but predicted a lower rate of subsequent SUD, regardless of the measure of positive response (11.65% vs. 24.72%, or 10.0% vs. 24.5%, respectively). Type of initial MDD treatment was not related to either outcome. Prior to depression treatment, greater involvement with alcohol or drugs predicted later AUD or SUD, as did older age (for AUD) and more comorbid disorders (for SUD). Among those with recurrent MDD and AUD, AUD preceded MDD recurrence in 24 of 25 cases. CONCLUSION: Effective short-term adolescent depression treatment significantly reduces the rate of subsequent SUD but not AUD. Alcohol or drug use should be assessed prior to adolescent MDD treatment and monitored even after MDD recovery. PMID- 22250854 TI - Evaluating the predictive validity of suicidal intent and medical lethality in youth. AB - OBJECTIVES: To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. METHOD: Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically hospitalized adolescents (M(age at hospitalization) = 14.83; 51% female; 80% Caucasian) were characterized with the Subjective Intent Rating Scale and Lethality of Attempt Rating Scale. Anderson Gill recurrent events survival models and generalized estimating equations were used to assess predictive validity. Generalized linear models were used to examine stability of characteristics across attempts. RESULTS: Neither intent nor lethality from the most recent attempt predicted future attempts. The highest level of intent and most severe lethality of attempts during the follow-up predicted subsequent attempts, but the degree to which highest intent and most severe lethality contributed to prediction after considering methods of suicide attempts, past number of attempts, or psychiatric diagnoses was mixed. Across successive attempts, there was little consistency in reported characteristics. Intent and lethality were related to each other only for attempts occurring in early adulthood. CONCLUSIONS: Highest intent and lethality were better predictors of future attempts than intent and lethality of the most recent attempt. However, these characteristics should be considered as predictors only within the context of other factors. For youth, clinicians should not infer true intent from the lethality of attempts, nor assume that characteristics of future suicide attempts will be similar to those of previous attempts. PMID- 22250855 TI - A randomized controlled trial of Internet-delivered cognitive behavior therapy and acceptance and commitment therapy in the treatment of tinnitus. AB - OBJECTIVE: Our aim in this randomized controlled trial was to investigate the effects on global tinnitus severity of 2 Internet-delivered psychological treatments, acceptance and commitment therapy (ACT) and cognitive behavior therapy (CBT), in guided self-help format. METHOD: Ninety-nine participants (mean age = 48.5 years; 43% female) who were significantly distressed by tinnitus were recruited from the community. Participants were randomly assigned to CBT (n = 32), ACT (n = 35), or a control condition (monitored Internet discussion forum; n = 32), and they were assessed with standardized self-report measures (Tinnitus Handicap Inventory; Hospital Anxiety and Depression Scale; Quality of Life Inventory; Perceived Stress Scale; Tinnitus Acceptance Questionnaire) at pre-, posttreatment (8 weeks), and 1-year follow-up. RESULTS: Mixed-effects linear regression analysis of all randomized participants showed significant effects on the primary outcome (Tinnitus Handicap Inventory) for CBT and for ACT compared with control at posttreatment (95% CI [-17.03, -2.94], d = 0.70, and 95% CI [ 16.29, -2.53], d = 0.68, respectively). Within-group effects were substantial from pretreatment through 1-year-follow-up for both treatments (95% CI [-44.65, 20.45], d = 1.34), with no significant difference between treatments (95% CI [ 14.87, 11.21], d = 0.16). CONCLUSIONS: Acceptance-based procedures may be a viable alternative to traditional CBT techniques in the management of tinnitus. The Internet can improve access to psychological interventions for tinnitus. PMID- 22250856 TI - Development of formulations to improve the controlled-release of linalool to be applied as an insecticide. AB - In recent studies, insecticide activity of a monoterpene, linalool, has been demonstrated, finding, however, limitations in application because of its rapid volatilization. Potential effectiveness of microcapsules and effects of various types of matrices on its stability as controlled-release systems for the slow volatilization of linalool to be applied as insecticide were evaluated. To study controlled-release, linalool was entrapped into microcapsules, inclusion complexes, and beads, obtained by different methods, inverse gelation (IG1, IG2, IG3, IG4, and IG5), oil-emulsion-entrapment (OEE), interfacial coacervation (INCO), and chemical precipitation (Cyc5 and Cyc10). The encapsulation yield turned out to be different for each formulation, reaching the maximum retention for IG1 and OEE. In controlled-release, OEE followed by INCO presented a long time necessary for releasing as a result of the presence of glycerol or chitosan. These results pointed out remarkable differences in the release behavior of linalool depending on matrix composition and the method of encapsulation. PMID- 22250857 TI - Public discourses about teenage pregnancy: disruption, restoration, and ideology. AB - Two recent incidents in the United States generated a wealth of public discourses about a particular reproductive health issue: adolescent childbearing. As the media, political pundits, and private citizens pondered the meaning of these events, they expressed viewpoints, explanations, and possible solutions in mass mediated outlets. We examined the discourses communicated in such outlets to understand how public discussion of teenage pregnancy reveals ideological assumptions about reproductive health, ideal family forms, and the expected life course. PMID- 22250858 TI - Sclareol exhibits anti-inflammatory activity in both lipopolysaccharide stimulated macrophages and the lambda-carrageenan-induced paw edema model. AB - Sclareol (1) is a natural fragrance compound used widely in the cosmetic and food industries. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and the lambda-carrageenan-induced edema mouse paw model were applied to examine the anti inflammatory potential of 1 and its possible molecular mechanisms. The experimental results obtained demonstrated that this compound inhibited cell growth, nitric oxide (NO) production, and the expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins in LPS-stimulated macrophages. Compound 1 also reduced paw edema, the tissue content of NO, tumor necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA), iNOS and COX-2 protein expression, and neutrophil infiltration within the tissues after lambda carrageenan stimulation. The present study suggests that the anti-inflammatory mechanisms of 1 might be related to a decrease of inflammatory cytokines and an increase of antioxidant enzyme activity. PMID- 22250859 TI - Caries experience in a sample of adolescents and young adults with cleft lip and palate in Brazil. AB - Objective : To compare the caries experience of adolescents and young adults with cleft lip and/or palate (CL/P) with a noncleft control group. Design : Thirty CL/P subjects and 30 controls were clinically examined to obtain the decayed, missing and filled teeth (DMFT) and the decayed, missing and filled surfaces (DMFS) indices, gingival bleeding index, plaque index, and active caries lesions. Data concerning oral hygiene, access to fluoridated water, mother's education level, and family income were also collected. Setting : Pro-Smile Center, a reference center for the treatment of facial deformities, Alfenas, Minas Gerais, Brazil. Subjects : Subjects aged 12 to 21 years with CL/P and without associated syndromes were matched to noncleft controls by sex, age, living habits, and use of orthodontic devices. Null Hypothesis Formulated Prior to Data Collection : Caries experience in CL/P adolescents and young adults is similar to that observed in noncleft controls. Statistical Analysis : Data were analyzed using SPSS 17.0 software for Windows Data Editor. The CL/P and control groups were compared using the McNemar test, paired t test and Wilcoxon test. A significance level of 5% was adopted for all tests. Results : There were no significant differences between the groups for oral hygiene and contact with fluoride. Significant differences were found in per capita income, presence of active caries, decayed surfaces, plaque index, and gingival bleeding. Conclusions : The caries experience of CL/P subjects was higher than that of the noncleft individuals. PMID- 22250860 TI - Neuropeptide Y stimulates food intake in the Zebrafish, Danio rerio. AB - Neuropeptide Y (NPY) is a potent orexigenic neuropeptide implicated in feeding regulation in mammals. However, except for the case of the goldfish, the involvement of NPY in the feeding behaviour of teleost fish has not well been studied. Therefore, we investigated the role of NPY in food intake using a zebrafish (Danio rerio) model because the molecular bases of NPY and its receptor have been well studied in this species. We examined the effect of feeding status on NPY-like immunoreactivity and the expression level of the NPY transcript in the brain. The number of neuronal cells showing NPY-like immunoreactivity in the hypothalamic regions, including the periventricular nucleus of posterior tuberculum and the posterior tuberal nucleus, was significantly increased in fish fasted for 7 days. NPY mRNA levels in the hypothalamus, but not the telencephalon, obtained from fish fasted for 7 days were higher than those in fish that had been fed normally. We then investigated the effect of i.c.v. administration of NPY on food intake. Cumulative food intake was significantly increased by i.c.v. administration of NPY (at 1 and 10 pmol/g body weight; BW) during a 60-min observation period. The NPY-induced orexigenic action (at 10 pmol/g BW) was blocked by treatment with a NPY Y1 receptor antagonist, BIBP-3226, at 100 pmol/g BW. These results indicate that NPY acts as an orexigenic factor in the zebrafish. PMID- 22250861 TI - Development and validation of a real-time TaqMan assay for the detection and enumeration of Pseudomonas fluorescens ATCC 13525 used as a challenge organism in testing of food equipments. AB - Pseudomonas fluorescens ATCC 13525 is used as the challenge organism to evaluate the efficacy of the clean-in-place (CIP) process of food equipment (automatic ice maker) as per NSF/ANSI Standard 12. Traditional culturing methodology is presently used to determine the concentration of the challenge organism, which takes 48 h to confirm the cell density. Storage of the challenge preparation in the refrigerator might alter the cell density as P. fluorescens is capable of growing at 4 degrees C. Also, background organism can grow on the Pseudomonas F agar (PFA) used for the recovery of P. fluorescens thus affecting the results of the test. Real-time TaqMan assay targeting the cpn60 gene was developed for the enumeration and the identification of P. fluorescens because of its specificity, accuracy, and shorter turnaround time. The TaqMan primer-probe pair developed using the Allele ID(r) 7.0 probe design software was highly specific and sensitive for the target organism. The sensitivity of the assay was 10 colony forming units (CFU)/mL. The assay was also successful in determining the concentration of the challenge preparation within 2 h. Based on these observations, TaqMan assay targeting the cpn60 gene can be efficiently used for strain level identification and enumeration of bacteria. PRACTICAL APPLICATION: Pseudomonas fluorescens ATCC 13525 is used as a challenge organism in the efficacy testing of clean-in-place process of food equipments. Currently, culturing technique is used for its identification and estimation, which is not only time-consuming but also prone to error. Real-time TaqMan assay is more specific, sensitive, and accurate along with a shorter turnaround time compared to culturing techniques, thereby increasing the overall quality of the testing methodology to evaluate the clean-in-place process critical for the food industry to protect public health and safety. PMID- 22250862 TI - Relationship between urinary podocytes and kidney diseases. AB - Podocyte loss is an important component of disease progression in glomerular diseases. To some extent, the loss of podocytes can predict the degree of damage and the advancement of renal disease. Detecting the loss of podocytes in the urine could be a valuable, noninvasive method for obtaining information about the activity of the disease or the disease type, allowing the early diagnosis of glomerular diseases. One of the most robust markers that has been successfully used for urinary podocyte diagnostics is podocalyxin (PDX). PDX is a sialoprotein that is expressed on podocytes and on a variety of nonrenal cells as well as on glomerular endothelial and parietal epithelial cells. Therefore, podocyte loss can be detected by the amount of PDX in the urine. The relationship between urinary podocytes and renal diseases is supported by the detection of podocytes in patients with immunoglobulin A (IgA) nephropathy, Henoch-Schonlein purpura nephritis, lupus nephritis, diabetic nephropathy, and focal segmental glomerulosclerosis. The use of technology for detecting podocytes in the urine would have broad implications for the evaluation of disease activity, the degree of dedifferentiation, and the possibility of regeneration. PMID- 22250863 TI - From vanadium naphthalene (V(n-1)Np(n)) sandwich clusters to VNp sandwich nanowire: structural, energetic, electronic, and magnetic properties. AB - The structural, energetic, electronic, and magnetic properties of a series of vanadium naphthalene (V(n-1)Np(n)) sandwich clusters (SWCs) and the VNp sandwich nanowire (SWN) were investigated by means of density functional theory computations. In the energetically most preferred configuration of each V(n 1)Np(n) SWC and SWN, the two nearest-neighbor Np rings form a 45 degrees rotation angle, the two second-nearest-neighbor Np rings are parallel to each other, and V atoms align in a zigzag chain. The local magnetic moments in V(n 1)Np(n) SWCs favor antiferromagnetic coupling due to the superexchange mechanism. Especially, both electron and hole injection can switch V(n-1)Np(n) SWCs and VNp SWN from the antiferromagnetic state to the ferromagnetic state, thus manipulating the magnetization direction. These results suggest the potential applications of V(n-1)Np(n) SWCs and VNp SWN in spintronics. PMID- 22250864 TI - Positionally defined, binary semiconductor nanoparticles synthesized by scanning probe block copolymer lithography. AB - We report the first method for synthesizing binary semiconductor materials by scanning probe block copolymer lithography (SPBCL) in desired locations on a surface. In this work, we utilize SPBCL to create polymer features containing a desired amount of Cd(2+), which is defined by the feature volume. When they are subsequently reacted in H(2)S in the vapor phase, a single CdS nanoparticle is formed in each block copolymer (BCP) feature. The CdS nanoparticles were shown to be both crystalline and luminescent. Importantly, the CdS nanoparticle sizes can be tuned since their diameters depend on the volume of the originally deposited BCP feature. PMID- 22250865 TI - Measuring the interrelations among multiple paradigms of visual attention: an individual differences approach. AB - A large part of the empirical research in the field of visual attention has focused on various concrete paradigms. However, as yet, there has been no clear demonstration of whether or not these paradigms are indeed measuring the same underlying construct. We collected a very large data set (nearly 1.3 million trials) to address this question. We tested 257 participants on nine paradigms: conjunction search, configuration search, counting, tracking, feature access, spatial pattern, response selection, visual short-term memory, and change blindness. A fairly general attention factor was identified. Some of the participants were also tested on eight other paradigms. This general attention factor was found to be correlated with intelligence, visual marking, task switching, mental rotation, and Stroop task. On the other hand, a few paradigms that are very important in the attention literature (attentional capture, consonance-driven orienting, and inhibition of return) were found to be dissociated from this general attention factor. PMID- 22250866 TI - Great expectations: temporal expectation modulates perceptual processing speed. AB - In a crowded dynamic world, temporal expectations guide our attention in time. Prior investigations have consistently demonstrated that temporal expectations speed motor behavior. We explore effects of temporal expectation on perceptual speed in three nonspeeded, cued recognition paradigms. Different hazard rate functions for the cue-stimulus foreperiod were used to manipulate temporal expectations. By computational modeling we estimated two distinct components of visual attention: the temporal threshold of conscious perception (t0 ms) and the speed of subsequent encoding into visual short-term memory (v items/s). Notably, these components were measured independently of any motor involvement. The threshold t0 was unaffected by temporal expectation, but perceptual processing speed v increased with increasing expectation. By employing constant hazard rates to keep expectation constant over time, we further confirmed that the increase in perceptual speed was independent of the cue-stimulus duration. Thus, our results strongly suggest temporal expectations optimize perceptual performance by speeding information processing. PMID- 22250867 TI - Perceptual fading without retinal adaptation. AB - A retinally stabilized object readily undergoes perceptual fading and disappears from consciousness. This startling phenomenon is commonly believed to arise from local bottom-up sensory adaptation to edge information that occurs early in the visual pathway, such as in the lateral geniculate nucleus of the thalamus or retinal ganglion cells. Here we use random dot stereograms to generate perceivable contours or shapes that are not present on the retina and ask whether perceptual fading occurs for such "cortical" contours. Our results show that perceptual fading occurs for "cortical" contours and that the time a contour requires to fade increases as a function of its size, suggesting that retinal adaptation is not necessary for the phenomenon and that perceptual fading may be based in the cortex. PMID- 22250868 TI - Clinical and radiographic changes at implants supporting single-unit crowns (SCs) and fixed dental prostheses (FDPs) with one cantilever extension. A retrospective study. AB - OBJECTIVES: To evaluate the clinical and radiographic changes at implants in posterior maxillary and mandibular areas supporting single-unit crowns (SCs) and fixed dental prostheses (FDPs) with one mesial or distal cantilever extension after an observation period of at least 3 years. MATERIAL AND METHODS: Seventeen subjects with 19 implant-supported SCs and 21 subjects with 21 implant-supported FDPs fulfilled the inclusion criteria. All FDPs were supported by two implants and had a span of 3-4 units. All reconstructions were incorporated in the posterior maxilla or mandible. The mesial and distal radiographic marginal bone loss from baseline (i.e. delivery of the reconstruction) to the follow-up examination was averaged and compared between SCs supporting one cantilever extension with that of implants supporting FDPs adjacent to or distant from the cantilever extension. Changes in mean pocket probing depth (PPD) were calculated and compared between the three groups. RESULTS: The mean observation period was 78.2 +/- 34.5 months for SCs supported by one implant and 67.8 +/- 29.8 months for FDPs supported by two implants. No implant loss occurred, yielding a 100% survival rate. At baseline, the mean radiographic bone levels +/- SD were 2.6 +/- 0.3 mm for implants supporting SCs, 2.6 +/- 0.3 mm for implants of FDPs adjacent to the cantilever extension, and 2.4 +/- 0.5 mm for implants of FDPs distant from the cantilever extension. At follow-up, the corresponding mean bone levels +/- SD were 2.7 +/- 0.4, 2.7 +/- 0.5, and 2.8 +/- 0.5 mm, respectively. No statistically significant differences (P > 0.05) were observed comparing the mean marginal bone loss between the three groups. Moreover, mean changes in PPD between baseline and follow-up were not statistically significantly different (P > 0.05) between the three groups. CONCLUSION: The presence of one mesial or distal cantilever extension in the posterior maxilla or mandible does not jeopardize the marginal bone levels of implants supporting SCs or short-span FDPs after a mean observation period of at least 5 years. PMID- 22250869 TI - Building for the future of rural health. PMID- 22250870 TI - Who should receive recruitment and retention incentives? Improved targeting of rural doctors using medical workforce data. AB - OBJECTIVE: The objective of this study was to define an improved classification for allocating incentives to support the recruitment and retention of doctors in rural Australia. DESIGN AND SETTING: Geo-coded data (n = 3636 general practitioners (GPs)) from the national Medicine in Australia: Balancing Employment and Life study were used to examine statistical variation in four professional indicators (total hours worked, public hospital work, on call after hours and difficulty taking time off) and two non-professional indicators (partner employment and schooling opportunities) which are all known to be related to difficulties with recruitment and retention. MAIN OUTCOME MEASURES: The main outcome measure used for the study was an association of six sentinel indicators for GPs with practice location and population size of community. RESULTS: Four distinct homogeneous population size groups were identified (0 5000, 5001-15,000, 15,001-50,000 and >50,000). Although geographical remoteness (measured using the Australian Standard Geographical Classification-Remoteness Areas (ASGC-RA)) was statistically associated with all six indicators (P < 0.001), population size provided a more sensitive measure in directing where recruitment and retention incentives should be provided. A new six-level rurality classification is proposed, based on a combination of four population size groups and the five ASGC-RA levels. A significant increase in statistical association is measured in four of six indicators (and a slight increase in one indicator) using the new six-level classification versus the existing ASGC-RA classification. CONCLUSIONS: This new six-level geographical classification provides a better basis for equitable resource allocation of recruitment and retention incentives to doctors based on the attractiveness of non-metropolitan communities, both professionally and non-professionally, as places to work and live. PMID- 22250871 TI - Farming suicides during the Victorian drought: 2001-2007. AB - OBJECTIVE: The objective of this study was to determine whether farming suicides increased in Victoria during the prolonged drought in south eastern Australia and gain an understanding of Victorian farming suicides during the period. METHOD: Intentional self-harm deaths of farmers and primary producers notified to the Victorian State Coroner from 2001 to 2007 were examined to identify characteristics and determine whether the annual number of farming suicides increased. RESULTS: Farming suicides accounted for just over 3% of Victorian suicides. The total number of farming suicides was 110 for the period and ranged between 11 and 19 deaths per year, rising and falling inconsistently from year to year. Males accounted for nearly 95% of farming suicides, with firearms and hanging the most frequently used methods, and most deaths occurring between 30 and 59 years of age. CONCLUSIONS: The small number of relevant cases and fluctuations in the annual number of deaths provides no evidence of a pattern of increasing farming suicides during the drought years, when there was approximately one suicide every 3 weeks. Given the elevated suicide risk in male farmers and association with multiple psychosocial and environmental factors, it cannot be concluded, however, that suicide risk itself did not increase during this period of heightened uncertainty and stress. Drought should not be dismissed among the many risk factors, and it is possible that increased mental health awareness and community support programs targeting drought-affected areas contributed to improved management of stress and suicide risk in regional and rural Victoria over the past decade. PMID- 22250872 TI - Design, implementation and initial assessment of the Northern Territory Point-of Care Testing Program. AB - OBJECTIVE: The objective of the study was to improve pathology services in selected remote health centres from the Northern Territory (NT) through the implementation of a quality managed point-of-care pathology testing (POCT) service. DESIGN: Study of the efficacy of the POCT service after 1 year and qualitative survey of POCT device operators. SETTING: The study was set in thirty three remote health centres in the NT administered by the NT Department of Health. PARTICIPANTS: Remote health centre staff at participating remote health centres participated in the study. INTERVENTIONS: The introduction of the i-STAT device to perform on-site POCT. MAIN OUTCOME MEASURES: The main outcome measures used in the study were the number of remote staff trained, volume of testing performed and satisfaction of POCT device operators. RESULTS: One hundred and sixty-four health professional staff were trained to perform i-STAT POCT during the first year of the program. A total of 2290 POCT tests were performed on the i STAT. The volume of testing consistently increased across the year. Tests for international normalised ratio were the most frequently performed (averaging 70 tests per month). Stakeholder satisfaction with the i-STAT device was high, with a statistically significant improvement in satisfaction levels with pathology service provision being reported after the introduction of POCT. Greater than 80% of respondents stated POCT was more convenient than the laboratory service and assisted in the stabilisation of acutely ill patients. CONCLUSIONS: The NT POCT Program has been operationally effective and well received by staff working as i STAT POCT operators in remote health centres. Retention of remote health centre staff is the most significant challenge to ensuring the program's long-term viability. PMID- 22250873 TI - Communicating about breast cancer: rural women's experience of interacting with their surgeon. AB - OBJECTIVE: This study examined rural women's satisfaction with the interaction and communication with their surgeon during diagnosis and treatment planning for early breast cancer. Differences in satisfaction were investigated between treatment groups (mastectomy and breast conservation surgery) and demographic variables (age, marital status, education level, employment status and place of residence). Practice was compared with clinical practice guidelines. DESIGN: The study was designed as a cross-sectional survey. SETTING: The study was set in Eastern regional Victoria, Australia. PARTICIPANTS: Seventy women diagnosed with early breast cancer participated in the study. MAIN OUTCOME MEASURES: The main outcome measures used by the study were satisfaction in three areas of practice: (i) telling a woman she has breast cancer; (ii) providing information and involving the woman in the decision-making; and (iii) preparing the woman for specific management. RESULTS: No differences in satisfaction were found between treatment groups and demographic variables. Overall, women in this study were highly satisfied (>93%) with the interaction and communication with their surgeon. Women reported that the surgeon created a supportive environment for discussion, that they were provided with adequate information and referrals, and that they were actively involved in the decision-making. Practice could have been improved for women who were alone at diagnosis as women without a partner made a quicker decision about treatment. CONCLUSION: Rural women in Victoria Australia were largely satisfied with the interaction and communication with their surgeon during diagnosis and treatment planning for early breast cancer. Current practice was predominately in line with clinical practice guidelines. PMID- 22250874 TI - Why does a rural background make medical students more likely to intend to work in rural areas and how consistent is the effect? A study of the rural background effect. AB - OBJECTIVE: Evidence indicates that medical graduates with a rural background are more likely to become rural doctors than those with an urban background (the rural background effect (RBE)). Exactly why this is so has rarely been studied. This study sought to identify the role of social, environmental and economic factors in addition to isolation characterising rural environments that either explain or modify the association between rural background and becoming a rural doctorrural practice intention. DESIGN AND SETTING: Secondary analysis of linked databases from the Medical Schools Outcomes Database (MSOD), Australian Bureau of Statistics and other government sources. PARTICIPANTS: Seven thousand four hundred twenty-two commencing medical students who took part in the MSOD survey and for whom external data could be linked. RESULTS: No social, environmental or economic factor studied or isolation significantly contributed to explaining the RBE, although there is some evidence that areas of more attractive climate strengthen the RBE. However, even when the RBE is at its weakest, it remains a strong, positive predictor of attraction to rural practice. CONCLUSION: Why the RBE occurs remains unexplained. Evidence was found of a reduced RBE under certain climatic conditions and personal circumstances, but further work is required to better understand why rural background is so strongly related with rural medical intention and practice. PMID- 22250875 TI - Personal-professional boundary issues in the satisfaction of rural clinicians recruited from within the community: findings from an exploratory study. AB - OBJECTIVE: The objective of this paper is to highlight, from within a broad study of recruitment/retention, findings that identify personal-professional boundaries as key challenges for rural child and youth mental health clinicians recruited from within the community. DESIGN: Two mixed methods online questionnaires followed by semistructured telephone interviews with a small subset of respondents were administered to clinicians, team leaders, supervisors and managers whose practice responsibilities encompass rural settings in three regions of British Columbia, Canada. PARTICIPANTS: Forty-four clinicians and 27 team leaders/managers participated in the survey while eight clinicians and one team leader/manager participated in the semistructured interviews. Half the clinician respondents were recruited from within the community. Of those recruited from outside the community, half had prior experience living or working in a rural community. MAIN OUTCOME MEASURES: Levels of satisfaction with lifestyle, practice and preparation for practice were compared across categories of respondents identified earlier. Open-ended comments were coded by theme and also compared across categories of respondents. RESULTS: While expressing their higher levels of satisfaction with rural lifestyle and professional practice, clinicians recruited from within rural communities report significant initial and ongoing stress related to personal-professional boundaries and dual relationships. They also report lower levels of satisfaction with orientation and preparation for practice relevant to dealing with these stressors. CONCLUSION: Prior attachment to rural communities, increasingly viewed as an effective recruitment and retention strategy, requires better preparation and ongoing supports to enable practitioners to deal with dual relationships and the personal professional boundary issues that are a direct consequence of their attachments. PMID- 22250876 TI - Managing oesophageal perforation in a rural hospital: the merits of supportive measures and simple surgical interventions. PMID- 22250877 TI - ENRICHing the rural clinical experience for undergraduate health science students: a short report on inter-professional education in Broken Hill. PMID- 22250878 TI - Do not move the furniture and other advice for new remote area nurses (RANs). PMID- 22250880 TI - Need to pay for CQI efforts. PMID- 22250881 TI - The FIFO conundrum. PMID- 22250883 TI - Lanthanide paramagnetic probes for NMR spectroscopic studies of fast molecular conformational dynamics and temperature control. Effective six-site proton exchange in 18-crown-6 by exchange spectroscopy. AB - (1)H and (13)C NMR measurements are reported for the CDCl(3) and CD(2)Cl(2) solutions of [La(18-crown-6)(NO(3))(3)] (I), [Pr(18-crown-6) (NO(3))(3)] (II), [Ce(18-crown-6)(NO(3))(3)] (III), and [Nd(18-crown-6)(NO(3))(3)] (IV) complexes. Temperature dependencies of the (1)H NMR spectra of paramagnetic II-IV have been analyzed using the dynamic NMR (DNMR) methods for six-site exchange. Two types of conformational dynamic processes were identified (the first one is conditioned by interconversion of complex enantiomeric forms and pseudorotation of a macrocycle molecule upon the C(2) symmetry axis; the second one is conditioned by macrocycle molecule inversion). Application of exchange spectroscopy (2D-EXSY) of DNMR for investigation of this dynamic system (II-IV) simplifies the assignment of the NMR signals and represents the first experimental study of multisite exchange. In the present work, the methodology of paramagnetic 4f (Ce, Pr, and Nd) probe applications for the study of free-energy, enthalpy, and entropy changes in chemical exchange processes, as well as the advantages of this method in a comparison with DNMR studies of diamagnetic substances, is discussed. In particular, as a result of paramagnetic chemical shifts in 4f complexes, the range of measurable rate constants expands considerably compared to the analogous range in diamagnetic compounds. Coordination compounds investigated in the paper represent new types of thermometric NMR sensors and lanthanide paramagnetic probes for in situ temperature control in solution. PMID- 22250882 TI - Tracking hypoxic signaling in encapsulated stem cells. AB - Oxygen is not only a nutrient but also an important signaling molecule whose concentration can influence the fate of stem cells. This study details the development of a marker of hypoxic signaling for use with encapsulated cells. Testing of the marker was performed with adipose-derived stem cells (ADSCs) in two-dimensional (2D) and 3D culture conditions in varied oxygen environments. The cells were genetically modified with our hypoxia marker, which produces a red fluorescent protein (DsRed-DR), under the control of a hypoxia-responsive element (HRE) trimer. For 3D culture, ADSCs were encapsulated in poly(ethylene glycol) based hydrogels. The hypoxia marker (termed HRE DsRed-DR) is built on a recombinant adenovirus and ADSCs infected with the marker will display red fluorescence when hypoxic signaling is active. This marker was not designed to measure local oxygen concentration but rather to show how a cell perceives its local oxygen concentration. ADSCs cultured in both 2D and 3D were exposed to 20% or 1% oxygen environments for 96 h. In 2D at 20% O(2), the marker signal was not observed during the study period. In 1% O(2), the fluorescent signal was first observed at 24 h, with maximum prevalence observed at 96 h as 59%+/-3% cells expressed the marker. In 3D, the signal was observed in both 1% and 20% O(2). The onset of signal in 1% O(2) was observed at 4 h, reaching maximum prevalence at 96 h with 76%+/-4% cells expressing the marker. Interestingly, hypoxic signal was also observed in 20% O(2), with 13%+/-3% cells showing positive marker signal after 96 h. The transcription factor subunit hypoxia inducible factor-1alpha was tracked in these cells over the same time period by immunostaining and western blot analysis. Immunostaining results in 2D correlated well with our marker at 72 h and 96 h, but 3D results did not correlate well. The western blotting results in 2D and 3D correlated well with the fluorescent marker. The HRE DsRed-DR virus can be used to track the onset of this response for encapsulated, mesenchymal stem cells. Due to the importance of hypoxic signaling in determination of stem cell differentiation, this marker could be a useful tool for the tissue engineering community. PMID- 22250884 TI - In vitro targeting of avidin-expressing glioma cells with biotinylated persistent luminescence nanoparticles. AB - Far red emitting persistent luminescence nanoparticles (PLNP) were synthesized and functionalized with biotin to study their targeting ability toward biotin binding proteins. First, the interaction of biotin-decorated PLNP with streptavidin, immobilized on a plate, was shown to be highly dependent on the presence of a PEG spacer between the surface of the nanoparticles and the biotin ligand. Second, interaction between biotin-PEG-PLNP and free neutravidin in solution was confirmed by fluorescence microscopy. Finally, in vitro binding study on BT4C cells expressing lodavin fusion protein, bearing the extracellular avidin moiety, showed that such biotin-covered PLNP could successfully be targeted to malignant glioma cells through a specific biotin-avidin interaction. The influence of nanoparticle core diameter, incubation time, and PLNP concentration on the efficiency of targeting is discussed. PMID- 22250885 TI - Error reduction therapy in reducing struggle and grope behaviours in apraxia of speech. AB - We report an intervention study focused on the speech production difficulties present in acquired apraxia of speech (AOS). The intervention was a self administered computer therapy that targeted whole word production and incorporated error reduction strategies. The effectiveness of the therapy was contrasted to that of a visuospatial sham computer program, and performance across treated words, and two sets of matched words, was assessed. Two groups of participants completed the study which employed a two-phase cross-over treatment design. Participants were randomly assigned to a speech first or sham first condition. Treatments were administered for six weeks, with a four week rest between interventions. Participants were assessed five times in total; twice at baseline, once following each of the intervention phases, and once following a lapse of eight weeks after the end of the second phase of intervention. The occurrence of accurate word production and speech characterised by struggle and groping behaviours was recorded on a repetition task. Participants showed significant gains in speech accuracy and fluency, and reductions in articulatory groping and struggle behaviours following the use of the speech program. These gains were largely maintained once the therapy was withdrawn. PMID- 22250886 TI - Patient perspectives on tobacco cessation services for persons living with HIV/AIDS. AB - With the advent of highly active antiretroviral therapy, the survival for HIV infected individuals has increased, but other health-related behaviors have been largely unaddressed. Tobacco use is of primary concern, given its prevalence and the medical implications of smoking among these patients. Improving responsiveness to the needs, values, and preferences of patients (i.e., patient centeredness) is a focus for increasing participation in systems of care. To assess the social, cultural, and educational barriers limiting use of smoking cessation services by HIV-positive individuals, two focus groups were conducted at a Louisiana HIV outpatient clinic. Questions addressed smoking history, knowledge of and access to cessation services, and knowledge of effects of smoking on disease progression and medication efficacy. Identified themes included a desire for increased and more specific information on the health effects of smoking as related to the patients' HIV status, difficulty in quitting, motivation, and the increased burden of medication. These results provide recommendations for designing, for HIV-infected smokers, patient-centered treatment of tobacco use, including providing relevant knowledge, access to cessation services, and more effective messages related to the impact of tobacco use on disease progression. PMID- 22250887 TI - Synthesis and antityrosinase mechanism of benzaldehyde thiosemicarbazones: novel tyrosinase inhibitors. AB - p-Hydroxybenzaldehyde thiosemicarbazone (HBT) and p-methoxybenzaldehyde thiosemicarbazone (MBT) were synthesized and established by (1)H NMR and mass spectra. Both compounds were evaluated for their inhibition activities on mushroom tyrosinase and free-cell tyrosinase and melanoma production from B(16) mouse melanoma cells. Results showed that both compounds exhibited significant inhibitory effects on the enzyme activities. HBT and MBT decreased the steady state of the monophenolase activity sharply, and the IC(50) values were estimated as 0.76 and 7.0 MUM, respectively. MBT lengthened the lag time, but HBT could not. HBT and MBT inhibited diphenolase activity dose-dependently, and their IC(50) values were estimated as 3.80 and 2.62 MUM, respectively. Kinetic analyses showed that inhibition type by both compounds was reversible and their mechanisms were mixed-type. Their inhibition constants were also determined and compared. The research may supply the basis for the development of new food preservatives and cosmetic additives. PMID- 22250889 TI - Anatomical architecture of the brachial plexus in the common hippopotamus (Hippopotamus amphibius) with special reference to the derivation and course of its unique branches. AB - The anatomy of the brachial plexus in the common hippopotamus (Hippopotamus amphibius), which has not been previously reported, was first examined bilaterally in a newborn hippopotamus. Our observations clarified the following: (1) the brachial plexus comprises the fifth cervical (C5) to first thoracic (T1) nerves. These formed two trunks, C5-C6 and C7-T1; in addition, the axillary artery passed in between C6 and C7, (2) unique branches to the brachialis muscle and those of the lateral cutaneous antebrachii nerves ramified from the median nerve, (3) nerve fibre analysis revealed that these unique nerve branches from the median nerve were closely related and structurally similar to the musculocutaneous (MC) nerve; however, they had changed course from the MC to the median nerve, and (4) this unique branching pattern is likely to be a common morphological feature of the brachial plexus in amphibians, reptiles and certain mammals. PMID- 22250890 TI - The relationship between the youth psychopathic traits inventory and psychopathology in a U.S. community sample of male youth. AB - The Youth Psychopathic Traits Inventory (YPI) is a self-report measure of juvenile psychopathic traits. Validity data for this measure are limited, especially for nonreferred samples. This report investigated the concurrent validity of the YPI by assessing 171 nonreferred male youth (M age = 12.96 years) with a battery of self-, parent-, and peer-report measures including the Child Behavior Checklist (CBCL), the Reactive-Proactive Aggression Questionnaire (RPQ), the Antisocial Process Screening Device (APSD), and a peer-sociometric measure of aggression. Results confirmed the expected correlations between the YPI and measures of proactive aggression, other externalizing and internalizing behavior, and parent-report psychopathic-like traits. In addition, cluster analyses of YPI scores revealed 2 groups of youth (low vs. high) who scored differently on measures of externalizing behavior. This study supports the utility of the YPI as a research tool for assessing juvenile psychopathic traits. PMID- 22250891 TI - Anthracyclinones from Micromonospora sp. AB - Four new anthracyclinones, 4,6,11-trihydroxy-9-propyltetracene-5,12-dione (1), 1 methoxy-9-propyltetracene-6,11-dione (2), 7,8,9,10-tetrahydro-9-hydroxy-1-methoxy 9-propyltetracene-6,11-dione (3), and 10beta-carbomethoxy-7,8,9,10-tetrahydro 4,6,7alpha,9alpha,11-pentahydroxy-9-propyltetracene-5,12-dione (4), were isolated from a strain of Micromonospora sp. associated with the tunicate Eudistoma vannamei. All structures were established by 1D and 2D NMR (COSY, HSQC, HMBC, NOESY) and HRESIMS experiments. Compounds 1 and 4 were cytotoxic against the HCT 8 human colon adenocarcinoma cell line, with IC(50) values of 12.7 and 6.2 MUM, respectively, while compounds 2 and 3 were inactive. PMID- 22250892 TI - Prenatal diagnosis for haemophilia: a nationwide survey among female carriers in the Netherlands. AB - Carriers of haemophilia face difficult choices regarding prenatal diagnosis, but little is known about the determinants that influence their decisions. The aim of this study was to assess the incidence of prenatal diagnosis and potential determinants affecting the choice for prenatal diagnosis. A nationwide survey was performed among all women who underwent carriership testing for haemophilia in the Netherlands between 1992 and 2004. Prenatal diagnosis was assessed in 207 carriers of haemophilia A or B who had been pregnant. Prenatal diagnosis was categorized into early first trimester (Y-PCR testing or chorionic villus sampling) often intended to prevent the birth of a child with haemophilia, and into late prenatal diagnosis (amniocentesis or ultrasound assessment) aimed at obstetrical management. Of 207 carriers 112 (54%) underwent prenatal diagnosis. Forty-eight women underwent early prenatal diagnosis and 64 women underwent late prenatal diagnosis. In 26 pregnancies early prenatal diagnosis was positive for haemophilia, and in 18 of these pregnancies termination was opted for. The choice for early prenatal diagnosis was associated with a liberal view towards termination of pregnancy (relative risk (RR) 12.5; 95% confidence interval (CI) 3.1-51.2), severe haemophilia in the family (RR 20.2; CI 2.7-153.6), absence of a religion (RR 1.9; CI 1.1-3.1) and older age (RR 2.0; CI 1.0-3.9). The choice for late prenatal diagnosis was associated with birth year after 1970 (RR 2.3; CI 1.5 3.5) and a previous child with haemophilia (RR 2.2; CI 1.4-3.4). More than half of all Dutch haemophilia carriers underwent prenatal diagnosis. Several determinants were strongly associated with prenatal diagnosis. PMID- 22250888 TI - Revisiting cardiovascular regeneration with bone marrow-derived angiogenic and vasculogenic cells. AB - Cell-based therapy has emerged as a promising therapy for cardiovascular disease. Particularly, bone marrow (BM)-derived cells have been most extensively investigated and have shown encouraging results in preclinical studies. Clinical trials, however, have demonstrated split results in post-myocardial infarction cardiac repair. Mechanistically, transdifferentiation of BM-derived cells into cardiovascular tissue demonstrated by earlier studies is now known to play a minor role in functional recovery, and humoral and paracrine effects turned out to be main mechanisms responsible for tissue regeneration and functional recovery. With this advancement in the mechanistic insight of BM-derived cells, new efforts have been made to identify cell population, which can be readily isolated and obtained in sufficient quantity without mobilization and have higher therapeutic potential. Recently, haematopoietic CD31(+) cells, which are more prevalent in bone marrow and peripheral blood, have been revealed to have angiogenic and vasculogenic activities and strong potential for therapeutic neovascularization in ischaemic tissues. This article will cover the recent advances in BM-derived cell-based therapy and implication of CD31(+) cells. PMID- 22250893 TI - Involvement of corticotrophin-releasing hormone and corticosteroid receptors in the brain-pituitary-gill of tilapia during the course of seawater acclimation. AB - The mRNA expression of genes for corticotrophin-releasing hormone (CRH) and the hormone receptors CRH-receptor/CRH-R, glucocorticoid receptor 1/2 (GR1/2) and mineralocorticoid receptor (MR) was studied in the brain, pituitary and gill of tilapia (Oreochromis mossambibus) during salinity and handling stress by real time quantitative-polymerase chain reaction analysis. The results indicated that the transcripts of CRH and CRH-R were increased in the forebrain, midbrain and gill, whereas elevated hypothalamic CRH mRNA suppressed the CRH-R mRNA in the pituitary in seawater (SW) fish. The levels of plasma osmolality and cortisol were significantly increased in SW compared to freshwater fish. The up-regulation of GR1, GR2, MR and alpha-NKA (Na(+) /K(+) -ATPase) transcripts in SW fish provided evidence that cortisol responds to stress and involves ion-base regulation via the GR1, GR2 and MR receptors in the gill. These data suggest that GR1, GR2 and MR have a pivotal role in the brain and gill. GR1, GR2 and MR expression may be dependent on CRH and cortisol expression in the brain and gill. In addition, we performed in situ hybridisation analysis to localise and differentiate the CRH, CRH-R, GR1, GR2 and MR transcripts in the brain of FW- and SW-acute acclimated tilapia during salinity stress. In almost all transcripts, the hybridisation signal was significantly abundant in the SW-acute acclimated tilapia brain, especially in the dorsal ventral cephalon, dorsal nucleus preopticus pars magnocellularis and dorsal nucleus preopticus pars parvocellularis. Salinity stress induced differential and specific responses in the gill and brain compared to handling stress. PMID- 22250894 TI - The relation between polyculturalism and intergroup attitudes among racially and ethnically diverse adults. AB - Research on intergroup ideologies (colorblindness, multiculturalism) has increased our understanding of intergroup attitudes. This article reports empirical tests of the relation between a newly studied ideology, polyculturalism (ideology focusing on interactions and connections among racial/ethnic groups), and intergroup attitudes. Across four studies (with racially/ethnically diverse U.S. undergraduates, and Black and White American adults), greater endorsement of polyculturalism was related to greater equality beliefs; appreciation for and comfort with diversity; willingness for intergroup contact; and endorsement of liberal immigration and affirmative action policies. Polyculturalism explained unique variance after controlling for colorblindness, multiculturalism, assimilation ideology, social dominance orientation, and right-wing authoritarianism. Implications and future directions of studying polyculturalism are discussed. PMID- 22250895 TI - Discrimination, acculturation, acculturative stress, and Latino psychological distress: a moderated mediational model. AB - Prior research has found that perceived discrimination is associated with adverse mental health outcomes among Latinos. However, the process by which this relationship occurs remains an understudied area. The present study investigated the role of acculturative stress in underlying the relationship between perceived discrimination and Latino psychological distress. Also examined was the ability of acculturation to serve as a moderator between perceived discrimination and acculturative stress. Among a sample of Latino adults (N = 669), moderated mediational analyses revealed that acculturative stress mediated the perceived discrimination-psychological distress relationship, and that the link between perceived discrimination and acculturative stress was moderated by Anglo behavioral orientation but not Latino behavioral orientation. The findings are discussed within a stress and coping perspective that identifies the psychological consequences associated with perceived discrimination and acculturative stress. PMID- 22250896 TI - The psychological costs of painless but recurring experiences of racial discrimination. AB - When studying discrimination, it is important to examine both perceived frequency and stress associated with these experiences, as well as the interplay between these two dimensions. Using data from Latino/a participants (N = 168), we found an interaction effect of the reported frequency and reported stressfulness of discrimination on psychological distress (depression and anxiety), such that frequency predicted greater psychological distress for low-stress events, but high-stress events were associated with greater distress regardless of frequency. In addition, using the constructs of "stated" and "derived" stressfulness, we found that the frequency of experiences of discrimination that were rated as less stressful were, in fact, correlated with greater psychological distress. Discrimination events not experienced as stressful nonetheless may have negative implications for the target, especially if they occur frequently. PMID- 22250897 TI - Secondary transfer effects of interracial contact: the moderating role of social status. AB - The contact hypothesis asserts that intergroup attitudes can be improved when groups have opportunities to interact with each other. Recent research extending the contact hypothesis suggests that contact with a primary outgroup can decrease bias toward outgroups not directly involved in the interaction, which is known as the secondary transfer effect (STE). The present study contributes to growing research on STEs by investigating effects among Asian, Black, Hispanic, and White undergraduate students (N = 3,098) attending 28 selective colleges and universities. Using hierarchical linear modeling, our results reveal numerous positive STEs among Asian, Black, and Hispanic college students. No significant STEs were observed among White students. Mediated moderation analyses support an attitude generalization mechanism, because STEs were explained by changes in attitudes toward the primary outgroup. This research speaks to equivocal findings in the extant STE literature and highlights directions for future research on social cohesion and bias reduction. PMID- 22250898 TI - Perceived utility of emotion: the structure and construct validity of the Perceived Affect Utility Scale in a cross-ethnic sample. AB - This study introduces a new measure of the perceived utility of emotion, which is the degree to which emotions are perceived to be useful in achieving goals. In this study, we administered this new measure, the Perceived Affect Utility Scale (PAUSe), to a sample of 142 European American and 156 East Asian American college students. Confirmatory factor analyses provided support for a new, culturally informed parsing of emotion and for perceived utility of emotion to be distinguishable from ideal affect, a related but separate construct. Next, we explored the potential importance of perceived utility of emotion in cultural research. Through path analyses, we found that: (a) culturally relevant variables (e.g., independence) played a mediating role in the link between ethnic group and perceived utility of emotion; and (b) perceived utility of emotion played a mediating role in the link between culturally relevant variables and ideal affect. In particular, perceived utility of self-centered emotions (e.g., pride) was found to be associated with independence and ideal affect of those same emotions. In contrast, perceived utility of other-centered emotions (e.g., appreciation) was found to be associated with interdependence, dutifulness/self discipline, and ideal affect of those same emotions. Implications for perceived utility of emotion in understanding cultural factors are discussed. PMID- 22250899 TI - Validation of Social Connectedness in Mainstream Society and the Ethnic Community Scales. AB - This study examined the psychometric properties of the Social Connectedness in Mainstream Society (SCMN) and the Social Connectedness in the Ethnic Community (SCETH) Scales in two groups of ethnic minorities. We especially examined their theoretical/conceptual and empirical viability in relation to other established constructs of general social connectedness, acculturation, and enculturation. Analyses of two sets of survey data from 200 Mexican American students in California and 134 Asian international students in Minnesota supported (a) construct validity of the SCMN and the SCETH as related but distinct structures, (b) convergent and discriminant validity in relation to acculturation and enculturation, and (c) high reliability. The examination of incremental validity in predicting subjective well-being further supported their distinctive utility in addition to other established constructs of general social connectedness, acculturation, enculturation, ethnic identity, and other group orientation. Implications for future research and practice are discussed. PMID- 22250900 TI - Use of cognitive question testing methodologies in participant action research: implementing the Three-Step Test-Interview Method in Indian county. AB - This study describes the use of cognitive question testing methods to pretest a Web-based questionnaire designed to gather information from American Indian and Alaska Native (AI/AN) youth between the ages of 18 and 25. The questionnaire included items related to risk and resiliency factors as well as potentially sensitive topics of victimization and delinquency. Question testing was completed with a sample of 15 youth living in three different regions of the United States. The Three Step Test Interview Method was modified to collect information related to interface usability, cognitive response, and cultural interpretation of survey items. Data collected from the question testing process resulted in questionnaire changes that included query wording, the inclusion and exclusion of survey items based on cultural input, the reordering and rendering of survey items, and improvements in interface usability. Implications for survey research with the AI/AN youth population are discussed. PMID- 22250901 TI - Being mixed: who claims a biracial identity? AB - What factors determine whether mixed-race individuals claim a biracial identity or a monoracial identity? Two studies examine how two status-related factors-race and social class-influence identity choice. While a majority of mixed-race participants identified as biracial in both studies, those who were members of groups with higher status in American society were more likely than those who were members of groups with lower status to claim a biracial identity. Specifically, (a) Asian/White individuals were more likely than Black/White or Latino/White individuals to identify as biracial and (b) mixed-race people from middle-class backgrounds were more likely than those from working-class backgrounds to identify as biracial. These results suggest that claiming a biracial identity is a choice that is more available to those with higher status. PMID- 22250904 TI - The role of aquaporin 4 in the brain. AB - Emerging evidence suggests that aquaporin (AQP) 4 water channels play an important role in water homeostasis in the brain. These water channels are most abundant in the cell membrane of astrocytes, but are also present within ependymal cell membranes and in osmosensory areas of the hypothalamus. Water transport through AQP4 depends on concentration gradients across the membrane, but the rate of transport is determined by the capacity of astrocytes to up- and down-regulate AQP4 numbers, their location within the membrane, and the overall permeability of the channel. Other functions of brain AQP4 involve potassium uptake and release by astrocytes, migration of glial cells, glial scarring, and astrocyte-to-astrocyte cell communication. AQP water channels are involved in formation and control of edema in the brain and in multiple disease processes in the brain, such as seizures and tumors. There is abundant scientific literature on AQP4 describing its structure, function, location, and role in water homeostasis and edema in the brain. Investigation of AQP expression in the canine and feline brain should be pursued so that clinically relevant comparisons between findings in mice, rats, and people and animal patients can be made. PMID- 22250905 TI - Metacognitive monkeys or associative animals? Simple reinforcement learning explains uncertainty in nonhuman animals. AB - Monkeys will selectively and adaptively learn to avoid the most difficult trials of a perceptual discrimination learning task. Couchman, Coutinho, Beran, and Smith (2010) have recently demonstrated that this pattern of responding does not depend on animals receiving trial-by-trial feedback for their responses; it also obtains if experience of the most difficult trials occurs only under conditions of deferred feedback. Couchman et al. argued that this ruled out accounts based on low-level processes of associative learning and instead required explanation in terms of metacognitive processes of decision monitoring. Contrary to this argument, a simple associative model of reinforcement learning is shown to account for the key findings of Couchman et al.'s empirical study, along with several other findings that have previously been claimed to challenge associative models. PMID- 22250906 TI - Can fluency be interpreted as novelty? Retraining the interpretation of fluency in recognition memory. AB - Stimuli that are processed fluently tend to be regarded as more familiar and are more likely to be classified as old on a recognition test compared with less fluent stimuli. Recently it was shown that the standard relationship between fluency and positive recognition judgments can be reversed if participants are trained that previously studied stimuli are associated with lower levels of fluency. Under such conditions, fluent stimuli are more likely to be classified as new on a recognition test (C. Unkelbach, 2006), which suggests that the interpretation of fluency is malleable and context dependent. Five experiments investigated the resilience of this reversed fluency effect. Using 2 different fluency manipulations, the finding of a reversed fluency effect after training was replicated. However, it was also found that the reversal depends on explicit feedback during training and is specific to the particular fluency manipulation used during training. Moreover, it was found that the reversal did not generalize to similar memory judgments. The balance of experimental results suggest that the standard interpretation of fluency as indicating higher levels of familiarity is quite stable and is resistant to reinterpretation. PMID- 22250907 TI - Evaluative priming of naming and semantic categorization responses revisited: a mutual facilitation explanation. AB - The evaluative priming effect (i.e., faster target responses following evaluatively congruent compared with evaluatively incongruent primes) in nonevaluative priming tasks (such as naming or semantic categorization tasks) is considered important for the question of how evaluative connotations are represented in memory. However, the empirical evidence is rather ambiguous: Positive effects as well as null results and negatively signed effects have been found. We tested the assumption that different processes are responsible for these results. In particular, we argue that positive effects are due to target encoding facilitation (caused by a congruent prime), while negative effects are due to prime-activation maintenance (caused by a congruent target) and subsequent response conflict. In 4 experiments, we used a negative prime-target stimulus onset asynchrony (SOA) to minimize target-encoding facilitation and maximize prime maintenance. In a naming task (Experiment 1), we found a negatively signed evaluative priming effect if prime and target competed for naming responses. In a semantic categorization task (i.e., person vs. animal; Experiments 2 and 3), response conflicts between prime and target were significantly larger in case of evaluative congruence compared with incongruence. These results corroborate the theory that a prime has more potential to interfere with the target response if its activation is maintained by an evaluatively congruent target. Experiment 4a/b indicated valence specificity of the effect. Implications for the memory representation of valence are discussed. PMID- 22250908 TI - Integration of pragmatic and phonetic cues in spoken word recognition. AB - Although previous research has established that multiple top-down factors guide the identification of words during speech processing, the ultimate range of information sources that listeners integrate from different levels of linguistic structure is still unknown. In a set of experiments, we investigate whether comprehenders can integrate information from the 2 most disparate domains: pragmatic inference and phonetic perception. Using contexts that trigger pragmatic expectations regarding upcoming coreference (expectations for either he or she), we test listeners' identification of phonetic category boundaries (using acoustically ambiguous words on the /hi/~/?i/ continuum). The results indicate that, in addition to phonetic cues, word recognition also reflects pragmatic inference. These findings are consistent with evidence for top-down contextual effects from lexical, syntactic, and semantic cues, but they extend this previous work by testing cues at the pragmatic level and by eliminating a statistical frequency confound that might otherwise explain the previously reported results. We conclude by exploring the time course of this interaction and discussing how different models of cue integration could be adapted to account for our results. PMID- 22250909 TI - Extensions of the survival advantage in memory: examining the role of ancestral context and implied social isolation. AB - Recent work (e.g., Nairne & Pandeirada, 2010) has shown that words are remembered better when they have been processed for their survival value in a grasslands context than when processed in other contexts. It has been suggested that this is because human memory systems were shaped by evolution specifically to help humans survive. Thus far, the survival processing advantage has mainly been shown with grasslands contexts, which are thought to be particularly relevant to human evolution. The present study demonstrated the survival processing advantage with other contexts (e.g., lost in a jungle), including with contexts that should not, in and of themselves, be relevant to human evolution (e.g., lost in outer space). We further examined whether implied social isolation plays a critical role in the survival advantage to memory by comparing scenarios in which the person is alone versus with other people present (e.g., lost at sea alone or with others), and whether the perceived source of danger is social isolation or other human attackers. A survival advantage was shown in both the isolation and the group settings, and whether the primary source of danger was isolation or other human attackers did not matter. These findings suggest that the survival advantage in memory is not dependent on evolutionarily relevant physical contexts (e.g., grasslands) or particular sources of perceived danger (social isolation vs. perceived attackers), showing the advantage to be robust and applicable to a variety of scenarios. PMID- 22250910 TI - Retrieval from memory: vulnerable or inviolable? AB - We show that retrieval from semantic memory is vulnerable even to the mere presence of speech. Irrelevant speech impairs semantic fluency--namely, lexical retrieval cued by a semantic category name--but only if it is meaningful (forward speech compared to reversed speech or words compared to nonwords). Moreover, speech related semantically to the retrieval category is more disruptive than unrelated speech. That phonemic fluency--in which participants are cued with the first letter of words they are to report--was not disrupted by the mere presence of meaningful speech, only by speech in a related phonemic category, suggests that distraction is not mediated by executive processing load. The pattern of sensitivity to different properties of sound as a function of the type of retrieval cue is in line with an interference-by-process approach to auditory distraction. PMID- 22250911 TI - Individual differences in working memory capacity predict action monitoring and the error-related negativity. AB - Neuroscience suggests that the anterior cingulate cortex (ACC) is responsible for conflict monitoring and the detection of errors in cognitive tasks, thereby contributing to the implementation of attentional control. Though individual differences in frontally mediated goal maintenance have clearly been shown to influence outward behavior in interference-rich contexts, it is unclear whether corresponding differences exist in neural responses that arise out of the ACC. To investigate this possibility, we conducted an electrophysiological study using a variant of the Simon Task, recording event-related potentials (ERPs) in healthy normal individuals with varying working memory capacity (high vs. low spans; a behavioral proxy for variability in goal maintenance). Primary analyses focused on the magnitude of the error-related negativity (ERN), a response-locked ERP component associated with the commission of errors thought to arise because of action monitoring in the ACC. Our results revealed that frontally mediated working memory capacity may alter error monitoring by the ACC, with high spans showing a greater ERN than low spans. These individual differences were also observed in the posterror positivity, a response-locked ERP component associated with updating cognitive strategies, suggesting greater awareness of errors with increased working memory capacity. These results are interpreted within 2-process models of attentional control, suggesting individuals with greater working memory capacity may better maintain task goals by more strongly biasing neural activity in frontal-executive networks. PMID- 22250912 TI - Pseudohomophone priming in lexical decision is not fragile in a sparse lexical neighborhood. AB - In lexical decision, to date few studies in English have found a reliable pseudohomophone priming advantage with orthographically similar primes (the klip plip effect; Frost, Ahissar, Gotesman, & Tayeb, 2003; see Rastle & Brysbaert, 2006, for a review). On the basis of the Bayseian reader model of lexical decision (Norris, 2006, 2009), we hypothesized that this was because in previous studies, lexical decisions could have been made without finding a match between the input and a unique lexical representation. Consistent with our hypothesis, we found that words from dense neighborhoods showed neither an orthographic form priming effect nor a pseudohomophone priming advantage; in contrast, with words from a sparse lexical neighborhood, a sizeable orthographic form priming effect was found, and a robust pseudohomophone priming advantage, which was not limited to the overlap of onset phoneme, was also observed. Identity primes produced greater facilitation than pseudohomophone primes. We consider the implication of these findings for the role of assembled phonology in lexical access. PMID- 22250913 TI - Does delaying judgments of learning really improve the efficacy of study decisions? Not so much. AB - A widely held assumption in metamemory is that better, more accurate metamemory monitoring leads to better, more efficacious restudy decisions, reflected in better memory performance--we refer to this causal chain as the restudy selectivity hypothesis. In 3 sets of experiments, we tested this hypothesis by factorially manipulating metamemory monitoring accuracy and self-regulation of study. To manipulate monitoring accuracy, we compared judgments of learning (JOLs) made contemporaneously with a delayed retrieval attempt to JOLs either made at a delay without attempting retrieval or made immediately after study; in previous studies, delayed retrieval-based JOLs have robustly predicted recall with greater relative accuracy than have the other JOL types. To manipulate self regulation of study, in Experiments 1A-1C and 2A-2C, we compared conditions in which participants' restudy selections were honored with conditions in which they were completely or randomly dishonored; in Experiments 3A-3C, we randomly honored or dishonored half of the restudy selections and half of the nonselections. Results revealed that the benefit of delayed, retrieval-based JOLs for final memory performance was due largely to the selection of more items for restudy rather than to better discriminations between items that would benefit more versus less from restudy. In most cases, gains in recall due to greater self regulation of study did not increase with better monitoring accuracy; when they did, the effect was extremely small. The surprising conclusion was that restudy decisions were not very much more efficacious under conditions that yield greater monitoring accuracy than under those that do not. PMID- 22250914 TI - The role of attention for context-context binding of intrinsic and extrinsic features. AB - There is converging evidence that the feeling of conscious recollection is usually accompanied by the bound retrieval of context features of the encoding episode (e.g., Meiser, Sattler, & Weibetaer, 2008). Recently, however, important limiting conditions have been identified for the binding between context features in memory. For example, focusing on the semantics of the stimuli during encoding eliminates binding between perceptual context features (Meiser & Sattler, 2007). In the present research, we investigated the interplay of the focus of attention during encoding and stimulus characteristics in context-context binding. In particular, it has been suggested that context features differ in the degree to which they can be regarded as intrinsic or extrinsic to the items and that intrinsic features might be given more attentional processing during encoding than extrinsic features (e.g., Ecker, Zimmer, & Groh-Bordin, 2007a). In two experiments, we manipulated the "intrinsicality" of context features to investigate whether context-context binding might be limited to features that are in the focus of processing. Multinomial modeling analyses revealed that while context-context binding was eliminated for incidentally processed extrinsic context features (Experiment 1), it was preserved for intentionally processed extrinsic context features (Experiment 2). PMID- 22250915 TI - Protein traffic in Gram-negative bacteria--how exported and secreted proteins find their way. AB - Gram-negative bacteria assemble many proteins into the inner and outer membranes and export a large number of proteins to the periplasm or to the extracellular medium. During the billions of years bacteria have been around, they have evolved a number of different pathways with sophisticated machines to accurately and efficiently move proteins from one location to another. In this review, we first introduce specific proteins that are representative substrates of the protein transport pathways and describe their function. Then, their specific routes from synthesis to their destinations are described mentioning the signal peptide that may initiate their export and discuss what is known about the folding state of the substrates during transport. The membrane translocation device involved, the energy source required for transport, and whether a chaperone is needed will be discussed. PMID- 22250916 TI - Change in working alliance and recovery in severe mental illness: an exploratory study. AB - BACKGROUND: Consumer-defined recovery from schizophrenia spectrum disorders and other recurring psychotic illnesses ("serious mental illness", "SMI") emphasize re-establishment of a personally meaningful life. The working alliance ("the alliance") is highlighted as important in facilitating recovery, however there is little empirical evidence concerning the relationship between the alliance and recovery in populations with SMI. AIMS: The aim is to explore the relationship between the alliance and recovery over time in a sample with SMI. METHOD: Sixty one individuals with SMI receiving case management support from mental health services in Australia were recruited by their mental health workers and completed measures of working alliance and recovery. Measures were collected by the workers during regular counselling sessions on two separate occasions. The average time between measurement times was 6 months apart. RESULTS: Multiple regression analyses indicated that changes in the alliance predicted recovery, but changes in recovery also predicted the alliance. No definitive conclusions regarding the causal direction of the relationship between the alliance and recovery could be drawn. CONCLUSIONS: The results provide preliminary evidence that improvement in the alliance positively influences gains in recovery and that gains in recovery also facilitate stronger alliance in SMI. These findings support an emphasis on the alliance. PMID- 22250917 TI - A comparison of mandibular denture base deformation with different impression techniques for implant overdentures. AB - PURPOSE: This study aimed to evaluate mandibular denture base deformation along with three impression techniques used for implant-retained overdenture. MATERIALS AND METHODS: Ten edentulous patients (five men and five women) received two implants in the canine region of the mandible and three duplicate mandibular overdentures which were constructed with mucostatic, selective pressure, and definitive pressure impression techniques. Ball abutments and respective gold matrices were used to connect the overdentures to the implants. Six linear strain gauges were bonded to the lingual polished surface of each duplicate overdenture at midline and implant areas to measure strain during maximal clenching and gum chewing. RESULTS: The strains recorded at midline were compressive while strains at implant areas were tensile. Clenching recorded significant higher strain when compared with gum chewing for all techniques. The mucostatic technique recorded the highest strain and the definite pressure technique recorded the lowest. There was no significant difference between the strain recorded with mucostatic technique and that registered with selective pressure technique. The highest strain was recorded at the level of ball abutment's top with the mucostatic technique during clenching. CONCLUSION AND RECOMMENDATION: Definite pressure impression technique for implant-retained mandibular overdenture is associated with minimal denture deformation during function when compared with mucostatic and selective pressure techniques. Reinforcement of the denture base over the implants may be recommended to increase resistance of fracture when mucostatic or selective pressure impression technique is used. PMID- 22250919 TI - Predictive factors for percutaneous nephrolithotomy outcomes in neurogenic bladder population. AB - PURPOSE: To review experience performing percutaneous nephrolithotomy (PCNL) on patients with neurogenic bladder, evaluating predictors for increased length of stay (LOS), intensive care unit (ICU) stay, stone-free rate, and number of procedures and outcomes measures between spinal cord injury (SCI) and spina bifida (SB) patients. PATIENTS AND METHODS: We retrospectively reviewed our PCNLs from January 1, 2002 to December 31, 2009 and identified 47 patients. Data collected included LOS, ICU stay, stone-free rate, complications, and total procedures. RESULTS: A total of 66 PCNLs were performed on 47 patients. The mean LOS was 5.3 days, and nine patients needed ICU stay (mean 13.9 d). Initial stone free rate was 60.6%, and final stone-free rate was 69.7%. Multiple access was associated with increased LOS (P=0.01), ICU stay (P<0.01), transfusion (P<0.01), and pulmonary complications (P=0.03). Upper-pole access was associated with decreased initial stone-free rate (P=0.04). Midpolar access predicted increased final stone-free rate (P=0.04). Mean stone size was 3.31 cm and was predictive of an increased number of procedures (P=0.04). Larger stone size was also predictive of decreased initial stone-free rate (P=0.03) and final stone-free rate (P=0.05). There were no statistically significant differences between SCI and SB patients in terms of outcomes. CONCLUSIONS: Increasing stone size and multiple access were predictors of adverse outcomes, and location of access affected stone-free status. We found no differences in outcomes between SB and SCI patients. To our knowledge, this is the largest series reported regarding PCNLs in this patient population. PMID- 22250918 TI - Gastric metaplasia and Helicobacter pylori infection in hemodialysis patients. AB - BACKGROUND: Upper gastrointestinal (UGI) symptoms are common in hemodialysis (HD) patients, while gastric metaplasia (GM) and Helicobacter pylori infections are key causes for UGI symptoms. This study is targeted to compare GM and H. pylori infections in patients with different durations of HD. METHODS: A total of 406 subjects from Ningbo Urology and Nephrology Hospital were included. The mean age of subjects was 44.7 +/- 13.5 years; 62.9% were male; and subjects were divided into four groups according to different HD durations. Upper endoscopy and lesion were performed in these patients and methylene blue staining was used in detecting H. pylori and GM. RESULTS: Erosive gastritis was the most common symptom in uremic subjects. GM was found in 139 patients. The longer the dialysis duration, the higher the incidence rate of GM (p < 0.05). H. pylori infection accounted for 24.1% in HD patients. The occurrence of H. pylori infection decreased as dialysis periods progressed within the first 4-year follow-up after the start of HD. CONCLUSIONS: Almost all patients with HD experienced gastrointestinal discomfort in the current patient cohort. The most common mucosal lesion observed in our study pool was chronic erosive gastritis. The overall incidence of GM was normal at 35.0%, since quite a part of patients are the elderly group in this study. We need not worry about this too much, unless the HD patients have registered for renal transplantation or are suffering from severe gastrointestinal discomfort. PMID- 22250920 TI - Venous thromboembolism in patients with heart failure: in-hospital and chronic use of anti-coagulants for prevention. AB - Heart failure (HF) is a common clinical syndrome characterized by high morbidity and frequent hospitalizations. HF is an independent and major risk factor for venous thromboembolism (VTE) and VTE occurring in patients with HF carries a worse prognosis. The present review will focus on short and long term role of anti-coagulants in prevention of venous thrombosis in HF patients. We will also be discussing the recently investigated and patented anti-coagulants which could have a role in this specific population. PMID- 22250921 TI - Unusually fast 1,6-h shifts of enolic hydrogens in peroxy radicals: formation of the first-generation C2 and C3 carbonyls in the oxidation of isoprene. AB - In a theoretical investigation using the CBS-QB3//UB3LYP/6-31+G** method supported by higher-level computations such as CBS-QB3//UQCISD/6-31+G**, the 1,6 H shifts of the enolic hydrogen in peroxy radicals of the type Z-HO-CH?CH-CH(2) OO(*) were found to face exceptionally low energy barriers of only about 11 kcal mol(-1)--i.e., 6-9 kcal mol(-1) lower than the barriers for similar shifts of alkane hydrogens--such that they can proceed at unequaled rates of order 10(5) to 10(6) s(-1) at ambient temperatures. The unusually low barriers for enolic 1,6-H shifts in peroxy radicals, characterized here for the first time to our knowledge, are rationalized. As cases in point, the secondary peroxy radicals Z HO-CH?C(CH(3))-CH(OO(*))-CH(2)OH (case A) and Z-HO-CH?CH-C(CH(3))(OO(*))-CH(2)OH (case B) derived from the primary Z-delta-hydroxy-peroxy radicals in the oxidation of isoprene, are predicted to undergo 1,6-H shifts of their enolic hydrogens at TST-calculated rates in the range 270-320 K of k(T)(A) = 5.4 * 10( 4) * T(5.04) * exp(-1990/T) s(-1) and k(T)(B) = 109 * T(3.13) * exp(-3420/T) s( 1), respectively, i.e., 2.0 * 10(6) and 6.2 * 10(4) s(-1), respectively, at 298 K, far outrunning in all relevant atmospheric and laboratory conditions their reactions with NO proposed earlier as their dominant pathways (Dibble J. Phys. Chem. A 2004, 108, 2199). These fast enolic-H shifts are shown to provide the explanation for the first-generation formation of methylglyoxal + glycolaldehyde, and glyoxal + hydroxyacetone in the oxidation of isoprene under high-NO conditions, recently determined by several groups. However, under moderate- and low-NO atmospheric conditions, the fast interconversion and equilibration of the various thermally labile, initial peroxy conformers/isomers from isoprene and the isomerization of the initial Z-delta-hydroxy-peroxy radicals, both recently proposed by us (Peeters et al. Phys. Chem. Chem. Phys. 2009, 11, 5935), are expected to substantially reduce the yields of the small carbonyls at issue. PMID- 22250922 TI - Quest for the best: effects of errorless and active encoding on word re-learning in semantic dementia. AB - Semantic dementia is a neurocognitive disorder characterised by a steady and progressive loss of semantic knowledge in the presence of relatively preserved other cognitive skills. Recent treatment studies have proven that language rehabilitation aimed at anomia in semantic dementia can be successful. The objective of this study was to examine the separate and interactive effects of errorless vs. errorful and active vs. passive learning approaches to anomia and their effects on naming and comprehension of treated items, as well as maintenance and generalisation of treatment gains. Seven participants with semantic dementia re-learned two sets of words (one for which participants retained auditory comprehension, and one for which they did not) in each of four different treatment methods based on those approaches. Errorless learning proved more successful than errorful learning in restoring lexical representations in all but one participant while there was no interaction between effects of errorless and active approaches on treatment success. Maintenance of treatment gains showed an advantage for errorless learning at one but not three months post treatment, although all overall gains were maintained to a significant degree at both time points. Effects of both treatment and maintenance were stronger for items for which participants showed preserved auditory comprehension. The results are discussed in a framework of progressive language disorders and applicability of errorless methods to language rehabilitation in semantic dementia. PMID- 22250923 TI - Preparation of free, soluble conjugate, and insoluble-bound phenolic compounds from peels of rambutan (Nephelium lappaceum) and evaluation of antioxidant activities in vitro. AB - The soluble phenolic compounds of rambutan peels (RP) were extracted by microwave assisted extraction (MAE) and the operating parameters were optimized. The optimal conditions obtained were ethanol concentration of 80.85%, extraction time of 58.39 s, and the ratio of liquid to solid of 24.51:1. The soluble phenolic content by MAE was 213.76 mg GAE/g DW. The free, soluble conjugate, and insoluble boaund phenolic compounds were prepared by alkaline hydrolysis, and the contents of 3 fractions were 185.12, 27.98 and 9.37 mg GAE/g DW, respectively. The contents of syringic acid and p-coumaric acid were high in the free fraction, showing 16.86 and 19.44 mg/g DW, and the soluble conjugate and insoluble-bound phenolics were mainly composed of gallic acid and caffeic acid. Furthermore, the antioxidant activities of 3 fractions were evaluated in 5 model systems. Results indicated that the free fraction had high antioxidant activities, compared with the soluble conjugate and insoluble-bound fractions. PMID- 22250924 TI - Synthesis and structural investigation of a unique columnar phase in the Bi2O3 TeO2-V2O5 System. AB - A new columnar phase Bi(11.65)Te(1.35)V(5)O(34-delta) (delta ~ 1.3) containing VO(4) tetrahedra has been identified for the first time in the Bi(2)O(3)-TeO(2) V(2)O(5) system. The phase formation and the extent of substitution of Te(4+) for Bi(3+) ions in order to stabilize V(5+) in this composition have been confirmed by the single crystal analysis, combined with the powder X-ray diffraction of the solid state synthesized bulk crystalline samples. The oxide crystallizes in a monoclinic crystal system, space group P2/c, with unit cell parameters a = 11.4616(7) A, b = 5.7131(3) A, c = 23.5090(18) A, beta = 101.071 degrees (6) (Z = 2). The structure retains the basic features of the columnar oxides with the presence of [Bi(10.65)Te(1.35)O(14)](n)(9.35n+) columns along the (010) direction, surrounded by (VO(4)) tetrahedra placed in the planes parallel to (100) and (001), with an isolated bismuth atom in between the columns. The composition with a limited Te(4+) substitution, Bi(11.65)Te(1.35)V(5)O(34-delta) (delta ~ 1.3), exists with a surprisingly high oxygen deficiency as compared to the stoichiometrically known columnar oxides such as Bi(13)Mo(4)VO(34), Bi(12)Te(1)Mo(3)V(2)O(34), and Bi(11)Te(2)Mo(2)V(3)O(34). The structure of this interesting member of the columnar family of oxides based on the single crystal X ray diffraction and the Raman spectroscopic studies indicates the possibility of the distribution of the oxygen vacancies among the VO(4) tetrahedral units. Further confirmation for the formation of vanadium stabilized columnar structures has been provided by the successful preparation of Bi(11.65)Te(1.35)V(4)CrO(34 delta) (delta ~ 0.83) and Bi(11.65)Te(1.35)V(4)WO(34-delta) (delta ~ 0.83) phases. Preliminary investigation of the photocatalytic efficiencies of the oxides Bi(11.65)Te(1.35)V(5)O(34-delta), Bi(11.65)Te(1.35)V(4)CrO(34-delta), and Bi(11.65)Te(1.35)V(4)WO(34-delta) revealed moderate photocatalytic activities for the decomposition of the dyes such as Rhodamine B under UV-vis light irradiation. PMID- 22250925 TI - Cognitive factors and willingness to participate in an HIV vaccine trial among HIV-positive injection drug users. AB - There are gaps in our knowledge of the role cognitive factors play in determining people's willingness to participate (WTP) in therapeutic HIV vaccine trials. Using a cross-sectional study of HIV-positive injection drug users (IDU), we determined the role of three cognitive factors: HIV treatment optimism, self efficacy beliefs, and knowledge of vaccine trial concepts in relation to WTP in a hypothetical phase 3 therapeutic HIV vaccine trial. WTP was 54%. Participants tended to be low in HIV treatment optimism (mean = 3.9/10), high in self-efficacy (mean = 79.8/100), and low in knowledge (mean = 4.1/10). Items pertaining to HIV treatment optimism and knowledge of HIV vaccine trial concepts were generally unrelated to WTP. An increase in self-efficacy had a statistically significant positive association with WTP (OR = 1.61, 95% CI = 1.04-2.46, p < 0.05). Furthermore, most of these HIV-positive participants had high levels of self efficacy, so we are most confident about this relationship at such levels. These findings indicate that interventions focused on increasing self-efficacy could enhance WTP among HIV-positive IDU. PMID- 22250927 TI - Method validation for the determination of total mercury in fish muscle by cold vapour atomic absorption spectrometry. AB - A method was validated for the determination of total Hg in fish muscle using continuous flow cold vapour atomic absorption (CVAAS) after microwave digestion in closed vessels. The method was validated according to European Union Regulations 333/2007 and 657/2002, considering the maximum level for the metal in fish, established by European Union regulation 1881/2006. The procedure for determining linear range, selectivity, recovery, precision, trueness, decision limit (CCalpha), detection capability (CCbeta), measurement uncertainty and robustness of the method is reported. The results of the validation process demonstrate the method fulfils the provisions of the Commission Regulation. The selectivity study indicated that there was no matrix effect on the calibration curve between the concentration range of 1.0 and 30.0 ug Hg l(-1). The mean recovery calculated at six levels of fortification was in the range of 94-104%. The limit of detection (LOD) and limit of quantification (LOQ) values were 4.90 and 15.7 ug kg(-1), while the CCalpha and CCbeta values were 0.517 and 0.533 mg kg(-1), respectively, for the maximum contaminant level of 0.500 mg kg(-1). The relative expanded measurement uncertainty of the method was 0.055 mg kg(-1). The method was not affected by slight variations of some critical factors (ruggedness minor changes) as sample mass and volume of the HNO(3) and H(2)O(2) used in the digestion step. The method allowed accurate confirmation analyses of the CRM DORM 3. In fact, the Z-scores attained in a proficiency test round were well below the reference value of 2.0, proving the excellent performance of the laboratory. PMID- 22250926 TI - Inhibition of P-glycoprotein enhances transport of imipramine across the blood brain barrier: microdialysis studies in conscious freely moving rats. AB - BACKGROUND AND PURPOSE: Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB. EXPERIMENTAL APPROACH: Intracerebral microdialysis in rats was used to monitor brain levels of imipramine and desipramine following i.v. imipramine administration, with or without pretreatment with one of the P-gp inhibitors verapamil or cyclosporin A (CsA). Plasma drug levels were also determined at regular intervals. KEY RESULTS: Pretreatment with either verapamil or CsA resulted in significant increases in imipramine concentrations in the microdialysis samples, without altering imipramine plasma pharmacokinetics. Furthermore, pretreatment with verapamil, but not CsA, led to a significant elevation in plasma and brain levels of desipramine. CONCLUSIONS AND IMPLICATIONS: The present study demonstrated that P gp inhibition enhanced the intracerebral concentration of imipramine , thus supporting the hypothesis that P-gp activity restricts brain levels of certain antidepressants, including imipramine. These findings may help to explain reports of a beneficial response to adjunctive therapy with verapamil in TRD. PMID- 22250929 TI - The impact of an objective structured teaching evaluation on faculty teaching skills. AB - BACKGROUND: Objective structured teaching evaluations (OSTEs) have been utilized to evaluate educational curricula and for resident and faculty development. PURPOSE: This study examines the impact of an OSTE on faculty teaching effectiveness and faculty satisfaction. METHODS: From 2004 to 2007, 46 faculty members participated in the OSTE. Faculty assessed their teaching abilities with a retrospective pre-post-test analysis. Faculty teaching evaluations for the 6 months before and after the OSTE were compared. Faculty participants completed satisfaction questionnaires regarding their OSTE experience and made teaching plans for the future. RESULTS: After the OSTE, faculty reported statistically significant improvements in all self-assessed teaching skills. There was, however, no improvement in their teaching evaluations. Faculty satisfaction with the OSTE experience was high. They indicated teaching plans incorporating lessons from the OSTE. CONCLUSIONS: Faculty felt the OSTE was a rewarding experience and reported improvement in their teaching abilities; however, faculty teaching evaluations did not improve. PMID- 22250930 TI - Attitudes of affiliate faculty members toward medical student summative evaluation for clinical clerkships: a qualitative analysis. AB - BACKGROUND: Summative evaluation of medical students is a critical component of the educational process. Despite extensive literature on evaluation, few studies have centered on affiliate faculty members' attitudes toward summative evaluation of students, though it has been suggested that these attitudes influence their effectiveness as evaluators. PURPOSE: The objective is to examine affiliate faculty members' attitudes toward clinical clerkship evaluation using primarily qualitative research methods. METHODS: The study used a nonexperimental research design and employed mixed methods. Data were collected through interviews, focus groups, and a questionnaire from 11 affiliate faculty members. RESULTS: Themes emerging from the data fell into three broad categories: (a) factors that influence grading, (b) consequences of negative evaluations, and (c) disconnections in the grading process. The quantitative portion of the study revealed important discrepancies supporting the use of qualitative methods. CONCLUSIONS: The study highlights faculty members' struggles with the evaluative process and emphasizes the need for improvements in evaluation tools and faculty development. PMID- 22250931 TI - Human error and patient safety: interdisciplinary course. AB - BACKGROUND: The medical community has only recently begun to address how human error affects patient safety. In order to confront human error in medicine, there is a need to teach students who are entering the health professions how potential errors may manifest and train them to prevent or mitigate these problems. PURPOSE: The objective is to describe a semester-long, interdisciplinary, human error and patient safety course taught at the University of South Florida. METHODS: Six interdisciplinary groups, composed of students from five of the university's colleges, were formed. The curriculum consisted of expert lecturers, readings, case studies, and analysis of patient safety problems. Students were evaluated based on their group's work on the final project and peer evaluations. RESULTS: Nursing students scored the highest in each category evaluated. Physicians and medical students had the lowest evaluations in team participation and active engagement. All students rated the course highly and indicated that it enhanced their ability to work in interprofessional settings. CONCLUSIONS: The students showed improved knowledge and substantive skill level relative to patient safety and human error concepts. Working in interdisciplinary teams gave the students a better understanding of the role each discipline can have in improving health care systems and health care delivery. PMID- 22250932 TI - Using a virtual training program to train community neurologist on EEG reading skills. AB - BACKGROUND: EEG training requires iterative exposure of different patterns with continuous feedback from the instructor. This training is traditionally acquired through a traditional fellowship program, but only 28% of neurologists in training plan to do a fellowship in EEG. PURPOSE: The purpose of this study was to determine the value of online EEG training to improve EEG knowledge among general neurologists. METHODS: The participants were general neurologists invited through bulk e-mail and paid a fee to enroll in the virtual EEG program. A 40 question pretest exam was performed before training. The training included 4 online learning units about basic EEG principles and 40 online clinical EEG tutorials. In addition there were weekly live teleconferences for Q&A sessions. At the end of the program, the participants were asked to complete a posttest exam. RESULTS: Fifteen of 20 participants successfully completed the program and took both the pre- and posttest exams. All the subjects scored significantly higher in the posttest compared to their baseline score. The average score in the pretest evaluation was 61.7% and the posttest average was 87.8% (p = .0002, two tailed). CONCLUSIONS: Virtual EEG training can improve EEG knowledge among community neurologists. PMID- 22250933 TI - Evaluation of medical career-counseling resources across Canada. AB - BACKGROUND: North American medical school accreditation requires career counseling. PURPOSE: The Memorial University of Newfoundland (MUN) MedCAREERS program was implemented in 2000 before published evidence of efficacy of Canadian medical school career-counseling programs existed. METHODS: Data were gathered initially through the Canadian Residency Matching Service Post-Match Survey in 2003 and subsequently through the Canadian Graduation Questionnaire from 2006 to 2008. The overall response rate was 61%. Perceived benefits and efficacy of the MUN MedCAREERS Web site and several career-counseling resources were determined along with participation rates encompassing a 6-year period. RESULTS: Most career counseling resources were perceived as helpful, regardless of participation rate. CONCLUSIONS: Our goal was to provide information on an array of career-counseling resources so that Canadian medical schools can avail of appropriate resources and select activities to help students make informed decisions about their specialty choice. Planners of career-counseling activities may wish to consider elements that students find most helpful. PMID- 22250934 TI - Transition to life--a sendoff to the real world for graduating medical students. AB - Graduating medical students will enter the workforce, often for the first time. Many have spent the past 20 years as students, receiving financial support from parents, and have not managed real-life issues such as financial planning, real estate, balancing well-being with employment, and integrating into a new community with stressful working conditions. To address a perceived need, we designed an intervention to introduce graduating medical students to financial planning, real estate choices, physician wellness during relocation/internship, and traits of efficient interns. The objectives of this study are to (a) assess baseline experience, knowledge, and comfort of seniors about "real-life" experiences, and (b) assess the efficacy of a 4-hr educational intervention on perceptions of understanding financial planning, real estate choices, intern preparedness, and physician wellness. Acute Care College seniors (classes of 2009 and 2010) attended the intervention after match day and completed a survey to gather demographic data and assess preexisting knowledge and a postintervention survey (1-7 Likert scale). Forty-nine students (45% male; M age = 25.5 years) participated. Prior experiences: 43% no break in education, 51% no full-time job, 38% never signed a rental lease and 94% had not purchased real estate, 90% did not have (or were not aware of having) disability insurance, and 82% had educational debt exceeding $50,000. Following the workshop, students felt more confident in their understanding of life skills topics (real estate, 83%; financial planning, 94%; well-being, 86%). Our workshop assisted in preparing for life after medical school for 98% of the participants. Graduating medical students can gain knowledge about real-life responsibilities and confidence during an educational session prior to starting residency. PMID- 22250935 TI - Reflective writing in the internal medicine clerkship: a national survey of clerkship directors in internal medicine. AB - BACKGROUND AND PURPOSE: Reflective writing programs have been implemented at many medical schools, but it is unclear to what extent and how they are structured. METHODS: We surveyed the 107 Clerkship Directors of Internal Medicine member institutions on use of reflective writing assignments during the internal medicine clerkship. RESULTS: Eighty-six of 107 (80%) institutional members completed the survey. Thirty-five percent reported having a reflective writing assignment, 48% did not, and 6% did not but were considering starting one within the next 2 years. Of the 30 assignments, most were partially structured (60%), involved small-group discussion (57%), and provided individual student feedback (73%). A minority (30%) contributed to the students' grade. Respondents believed assignments contributed to students' learning in multiple domains, most often Professionalism (97%) and Communication (77%). CONCLUSIONS: Although reflective writing programs were common, variability existed in their structure. Further research is needed to determine how best to implement them. PMID- 22250936 TI - Meeting the family: promoting humanism in gross anatomy. AB - BACKGROUND: Human dissection commonly occurs early in the undergraduate medical school curriculum, thus presenting an immediate opportunity for educators to teach and encourage humanistic qualities of respect, empathy, and compassion. PURPOSE: The purpose of this study was to measure the impact of the Donor Luncheon, a unique program in which medical students meet the families of the anatomical donor prior to dissection in the anatomy course at the University of Oklahoma College of Medicine. METHODS: Students were randomized into groups of 8 to attend the luncheon and either met with family of the donor or attended the luncheon with no donor family present. A questionnaire measured students' attitudes at 2 weeks, 6 weeks, and at the conclusion of the anatomy course. RESULTS: Factor analysis revealed 5 scales. Analysis revealed statistically significant differences across time for Donor as Person, Dissection Process, and Donor as Patient and statistically significant differences between groups for Donor as Person and Donor as Patient. CONCLUSIONS: These results suggest that this program can provide students with the opportunity to maintain more humanistic attitudes at the beginning of their medical education career. PMID- 22250937 TI - First-year medical students' willingness to participate in peer physical examination. AB - BACKGROUND: There is little research on student attitudes toward participating in peer physical examination (PPE). PURPOSE: This study explored first-year medical students' attitudes toward PPE and their willingness to participate in PPE before they had experience with PPE as part of their course. METHODS: First-year medical students (n = 119) rated their willingness to participate in PPE for 15 body regions, with male or female peers, and when examining or being examined by others. Attitudes toward participating in PPE were also assessed. RESULTS: Low sensitivity examinations (e.g., hands, head) in PPE were generally accepted by male and female students. Significant variation in willingness across different body regions was, however, evident for male and female students depending on the type of examination and their examination partner's gender. Students generally held positive attitudes toward participating in PPE as part of the course. Moreover, students with more positive attitudes provided higher ratings of willingness to participate in PPE for all examination types. CONCLUSIONS: Findings suggest high levels of willingness to participate in PPE for low sensitivity examinations of the kind employed in university teaching contexts. Nonetheless, gender effects appear more complex than previously described, and for some regions of the body, there are subtle preferences for particular examination types, in particular performing examinations, rather than being examined. PMID- 22250938 TI - The effect of computerized provider order entry on medical students' ability to write orders. AB - BACKGROUND: Computerized provider order entry (CPOE) is being implemented at increasing numbers of U.S. hospitals, yet the effects of CPOE on medical student education are largely unstudied. PURPOSE: The objective is to investigate the effects of CPOE on medical students' ability to write orders for patients. METHODS: One hundred forty-three medical students who began their Basic Medicine clerkship between March 2003 and April 2004 were asked to write mock admission orders for a patient with pneumonia after the 1st month of their clerkship. Students had spent the month at 1 of 3 hospitals: 1 using CPOE, 1 paper orders, and 1 that began using CPOE midway through this study. Admission orders were scored for the presence of specific orders and features. RESULTS: One hundred twenty students attempted to write admission orders. Students who trained at hospitals using CPOE and those who trained at hospitals using paper orders included expected basic, lifesaving, and higher level orders at similar rates. No significant differences in order clarity or inclusion of unnecessary orders were found for the 2 groups. No significant differences were found when controlling for school year and 4 modifiable rotation features. CONCLUSIONS: When admission order completeness and quality for medical students who trained at hospitals using CPOE were compared to those who trained using handwritten orders, no important differences were found. PMID- 22250939 TI - The curriculum development process for an international emergency medicine rotation. AB - BACKGROUND: Completion of electives abroad is not a new phenomenon for physicians in training. Benefits to the physician and the host country's population have been sufficiently described in the literature; however, many academic residency programs lack an international health curriculum that incorporates both the Accreditation Council for Graduate Medical Education's core and specialty specific competencies. DESCRIPTION: The goal of this project was to develop a curriculum for emergency medicine residents completing International Emergency Medicine (IEM) rotations. EVALUATION: A literature search was conducted to review available international rotation curricula and the curriculum development process. A committee was formed to create an IEM rotation, borrowing philosophical premises from the educational literature, particularly experientialism. CONCLUSIONS: The resulting article describes the curriculum development process and provides a curriculum template for medical specialties to utilize when sending residents abroad. PMID- 22250940 TI - A review of primary care training programs in correctional health for physicians. AB - BACKGROUND: Despite the health consequences of incarceration, there are no national standards for teaching physicians about correctional health. The purpose of this study was to survey existing correctional health training programs for primary care physicians. SUMMARY: Programs were identified through literature and Web search, snowballing, and professional meetings. Programs were contacted and asked to complete a survey. Correctional health programs exist in a variety of disciplines. We identified 22 in primary care. Programs seek to improve public health, reduce stigma, and recruit physicians to correctional health. Curricula covered specific health problems as well as the impact of incarceration on families and communities. Relationships between the academic center and the correctional facilities were varied. Barriers include issues of security, time, financial resources, and stigma. Programs evaluate their learners, as well as educational and clinical outcomes. CONCLUSIONS: A variety of correctional health programs currently exist. A national model curriculum could strengthen teaching in correctional health. PMID- 22250944 TI - Ambient ionization-accurate mass spectrometry (AMI-AMS) for the identification of nonvisible set-off in food-contact materials. AB - Set-off is the unintentional transfer of substances used in printing from the external printed surface of food packaging to the inner, food-contact surface. Ambient ionization-accurate mass spectrometry (AMI-AMS) detected and identified compounds from print set-off not visible to the human eye. AMI mass spectra from inner and outer surfaces of printed and nonprinted food packaging were compared to detect and identify nonvisible set-off components. A protocol to identify unknowns was developed using a custom open-source database of printing inks and food-packaging compounds. The protocol matched print-related food-contact surface ions with the molecular formulas of common ions, isotopes, and fragments of compounds from the database. AMI-AMS was able to detect print set-off and identify seven different compounds. Set-off on the packaging samples was confirmed using gas chromatographic-mass spectrometric (GC-MS) analysis of single sided solvent extracts. N-Ethyl-2(and 4)-methylbenzenesulfonamide, 2,4-diphenyl-4 methyl-1(and 2)-pentene, and 2,4,7,9-tetramethyl-5-decyne-4,7-diol were present on the food-contact layer at concentrations from 0.21 to 2.7 +/- 1.6 MUg dm-2, corresponding to nearly milligram per kilogram concentrations in the packaged food. Other minor set-off compounds were detected only by AMI-AMS, a fast, simple, and thorough technique to detect and identify set-off in food packaging. PMID- 22250945 TI - DBU-promoted cyclization of ortho-(3-hydroxy-1-alkynyl)benzamide: synthesis of trans-3,4-dihydroisoquinolin-1(2H)-ones and (E)-4-(1-alkenyl)isoquinolin-1(2H) ones. AB - DBU-promoted cyclization of ortho-(3-hydroxy-1-alkynyl)benzamide is presented, providing an efficient method for the synthesis of trans-3,4-dihydroisoquinolin 1(2H)-ones and (E)-4-(1-alkenyl)isoquinolin-1(2H)-ones under mild conditions. PMID- 22250946 TI - Effect of estrous cycle phase on clinical pathology values in beagle dogs. AB - BACKGROUND: In dogs, the diestrus phase is considerably longer than in most domestic animals, and is characterized by high circulating progesterone concentrations that may influence clinical pathology values. OBJECTIVE: The objective of this retrospective study was to investigate differences in clinical pathology data in dogs in diestrus compared with data from dogs in all other phases of the estrous cycle. METHODS: Phase of the estrous cycle was determined by histologic evaluation of reproductive tissues from 86 control female Beagles that had participated in 23 toxicity studies. Serum biochemical, hematologic, and urinalysis values from dogs in diestrus were compared with data from dogs in all other estrous cycle phases using a 2-tailed t-test. RESULTS: In Beagles in diestrus (n = 38), serum cholesterol concentrations and eosinophil counts were 35% (P < .0001) and 45.8% (P = .0035) higher, respectively, than for Beagles in all other phases of the estrous cycle (n = 48). Furthermore, Beagles in diestrus had 14% lower AST activity (P = .0011), 1% lower chloride concentration (P = .0224), 7.8% lower hemoglobin concentration (P < .0001), 7.8% lower RBC count (P < .0001), and 7.6% lower hematocrit (P < .0001) compared with female dogs in all other phases of the estrous cycle. Urine values did not differ significantly between groups. CONCLUSIONS: Differences in clinical pathology values between dogs in different phases of the estrous cycle could potentially confound interpretation of data in toxicity studies, which often have small group sizes. Interpretation of clinical pathology data in female dogs should be performed with due consideration given to the phase of the estrous cycle. PMID- 22250947 TI - Structure and dynamics of the excited states of 1,3-diarylisobenzofurans: an experimental and theoretical study. AB - The emission properties of a series of substituted 1,3-diarylisobenzofurans have been studied. Most compounds exhibit very intense emission in the nanosecond timescale at room temperature as well as at 77 K. The room temperature emission is attributed to the deactivation of a twisted intramolecular charge transfer excited state, based on its energy, shape and solvent dependence. The experimental results are strongly supported by a theoretical study on one representative compound. The DFT/TD-DFT calculations demonstrate that the initial excited state relaxes toward a twisted structure. PMID- 22250948 TI - Micro-mechanical bond strength tests for the assessment of the adhesion of GIC to dentine. AB - BACKGROUND: The aim of this study is to critically evaluate the bond strength (BS) of Glass-Ionomer Cements (GIC) to dentine with microtensile (MUTBS) and microshear (MUSBS) BS tests by assessing their rankings and failure patterns. METHODS: Samples were made on flat dentine surfaces and submitted to MUTBS and MUSBS. The materials used were: high viscosity GIC (KetacTM Molar Aplicap-KM), resin-modified GIC (Fuji II-FII), nano-filled resin-modified GIC (KetacTM N100 N100) and an etch-and-rinse adhesive system with a composite resin (AdperTM Single Bond 2 and Z100TM-Z100). All tests were performed with a Universal Testing Machine (24 h water storage, crosshead speed of 1 mm/min). Debonded surfaces were examined with a stereomicroscope (*40) to identify the failure mode. The data was analyzed with two-way ANOVA (p < 0.05) and LSD test. RESULTS: Means were statistically different regarding the tests and materials, indicating that values for BS obtained for each material depend on the test performed. Failure analysis revealed that failures produced by MUTBS were mainly cohesive for KM and FII. MUSBS failures were mainly adhesive or mixed for all materials. For the MUTBS, the rank was Z100 > FII > KM = N100, whereas for the MUSBS it was Z100 = FII = KM > N100. CONCLUSION: It may be concluded that distinct micro-mechanical tests present different failure patterns and rankings depending on the material to be considered. PMID- 22250949 TI - Controlled lateral manipulation of molecules on insulating films by STM. AB - On metallic and semiconductor surfaces functional nanostructures can be built with atomic scale precision using the tip of an atomic force microscope/scanning tunneling microscope. In contrast, controlled lateral manipulation on insulators has not been reported. The traditional pushing and pulling based manipulation methods cannot be used for molecules adsorbed on insulating films because of the unfavorable ratio between diffusion barrier and desorption energy. Here, we demonstrate that molecules adsorbed on insulating films can be laterally manipulated in a controlled way by injecting inelastically tunneling electrons at well-defined positions in a molecule. The technique was successfully applied to several different molecules. PMID- 22250950 TI - Natural history of platelet antibody formation against alphaIIbbeta3 in a French cohort of Glanzmann thrombasthenia patients. AB - Treatment of the bleeding syndrome in Glanzmann thrombasthenia (GT) is often complicated by naturally occurring isoantibodies directed against the alphaIIbbeta3 integrin that cause the removal of or render ineffective transfused donor platelets. Such antibodies are produced after transfusion or pregnancy when the patient's immune system comes into contact with normal platelets. Despite many reports of anti-alphaIIbbeta3 antibodies in GT patients, there is no consensus pertaining to their frequency, their long-term evolution in the circulation, or their formation in relation to either (i) the extent of the alphaIIbbeta3 deficiency in the patient's platelets or (ii) the nature of the genetic defect (ITGA2B or ITGB3 genes). Antibody screening was performed on a large series of 24 GT patients in South-West France dividing the patients into two cohorts: (i) 16 patients with the French gypsy mutation (c.1544 + 1G>A) within ITGA2B that gives platelets totally lacking alphaIIbbeta3 and (ii) 8 patients carrying other defects of ITGA2B or ITGB3 with different expression levels of alphaIIbbeta3. Our results confirm that patients with premature termination mutations resulting in platelets lacking alphaIIbbeta3 are the most susceptible to form isoantibodies, a finding that may be useful in deciding the choice of therapy between platelet transfusion and the use of recombinant factor VIIa (FVIIa). PMID- 22250951 TI - Intracranial angioplasty and stent placement after stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) trial: present state and future considerations. AB - OBJECTIVE: The results of prematurely terminated stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) due to excessively high rate of stroke and death in patients randomized to intracranial stent placement is expected to affect the practice of endovascular therapy for intracranial atherosclerotic disease. The purpose of this report is to review the components of the designs and methods SAMMPRIS trial and to describe the influence of those components on the interpretation of trial results. METHODS: A critical review of the patient population included in SAMMPRIS is conducted with emphasis on "generalizability of results" and "bias due to cherry picking phenomenon." The technical aspects of endovascular treatment protocol consisting of intracranial angioplasty and stent placement using the Gateway balloon and Wingspan self-expanding nitinol stent and credentialing criteria of trial interventionalists are reviewed. The influence of each component is estimated based on previous literature including multicenter clinical trials reporting on intracranial angioplasty and stent placement. RESULTS: The inclusion criteria used in the trial ensured that patients with adverse clinical or angiographic characteristics were excluded. Self-expanding stent as the sole stent, technique of prestent angioplasty, periprocedural antiplatelet treatment, and intraprocedural anticoagulation are unlikely to adversely influence the results of intracranial stent placement. A more permissive policy toward primary angioplasty as an acceptable treatment option may have reduced the overall periprocedural complication rates by providing a safer option in technically challenging lesions. The expected impact of a more rigorous credentialing process on periprocedural stroke and/or death rate following intracranial stent placement in SAMMPRIS such as the one used in carotid revascularization endarterectomy versus stenting trial remains unknown. CONCLUSION: The need for developing new and effective treatments for patients with symptomatic intracranial stenosis cannot be undermined. The data support modification but not discontinuation of our approach to intracranial angioplasty and/or stent placement for intracranial stenosis. There are potential patients in whom angioplasty and/or stent placement might be the best approach, and a new trial with appropriate modifications in patient selection and design may be warranted. PMID- 22250953 TI - The effectiveness of implementing an electronic health record on diabetes care and outcomes. AB - OBJECTIVE: To assess the impact of electronic health record (EHR) implementation on primary care diabetes care. DATA SOURCES: Charts were abstracted semi-annually for 14,051 diabetes patients seen in 34 primary care practices in a large, fee for-service network from January 1, 2005 to December 31, 2010. The study sample was limited to patients aged 40 years or older. STUDY DESIGN: A naturalistic experiment in which GE Centricity Physician Office-EMR 2005 was rolled out over a staggered 3-year schedule. DATA COLLECTION: Chart audits were conducted using the AMA/Physician Consortium Adult Diabetes Measure set. The primary outcome was the HealthPartners' "optimal care" measure: HbA1c <= 8 percent; LDL cholesterol < 100 mg/dl; blood pressure < 130/80 mmHg; not smoking; and documented aspirin use in patients >= 40 years of age. PRINCIPAL FINDINGS: After adjusting for patient age, sex, and insulin use, patients exposed to the EHR were significantly more likely to receive "optimal care" when compared with unexposed patients (p < .001), with an estimated difference of 9.20 percent (95% CI: 6.08, 12.33) in the final year between exposed patients and patients never exposed. Components of the optimal care bundle showing positive improvement after adjustment were systolic blood pressure <80 mmHg, diastolic blood pressure <130 mmHg, aspirin prescription, and smoking cessation. Among patients exposed to EHR, all process and outcome measures except HbA1c and lipid control showed significant improvement. CONCLUSION: Implementation of a commercially available EHR in primary care practice may improve diabetes care and clinical outcomes. PMID- 22250954 TI - The Golgi-associated long coiled-coil protein NECC1 participates in the control of the regulated secretory pathway in PC12 cells. AB - Golgi-associated long coiled-coil proteins, often referred to as golgins, are involved in the maintenance of the structural organization of the Golgi apparatus and the regulation of membrane traffic events occurring in this organelle. Little information is available on the contribution of golgins to Golgi function in cells specialized in secretion such as endocrine cells or neurons. In the present study, we characterize the intracellular distribution as well as the biochemical and functional properties of a novel long coiled-coil protein present in neuroendocrine tissues, NECC1 (neuroendocrine long coiled-coil protein 1). The present study shows that NECC1 is a peripheral membrane protein displaying high stability to detergent extraction, which distributes across the Golgi apparatus in neuroendocrine cells. In addition, NECC1 partially localizes to post-Golgi carriers containing secretory cargo in PC12 cells. Overexpression of NECC1 resulted in the formation of juxtanuclear aggregates together with a slight fragmentation of the Golgi and a decrease in K+-stimulated hormone release. In contrast, NECC1 silencing did not alter Golgi architecture, but enhanced K+ stimulated hormone secretion in PC12 cells. In all, the results of the present study identify NECC1 as a novel component of the Golgi matrix and support a role for this protein as a negative modulator of the regulated trafficking of secretory cargo in neuroendocrine cells. PMID- 22250957 TI - Renal failure in the recent 2011 Escherichia coli O104:H4 outbreak: a summary on up-to-date data. AB - The recent 2011 Escherichia coli outbreak in Europe is considered as one of the biggest E. coli outbreak in the modern medical history. Although the induction of renal impairment is well described in E. coli infection, the specific knowledge on E. coli O104:H4 is very limited. To add up to known knowledge, the author hereby summarizes up-to-date information on renal failure among patients in 2011 E. coli O104:H4 outbreak. PMID- 22250958 TI - Robot-assisted and laparoscopic partial nephrectomy with near infrared fluorescence imaging. AB - BACKGROUND AND PURPOSE: Recent literature has focused on the importance of maximal nephron preservation during partial nephrectomy to avoid complications associated with chronic renal insufficiency. Accurate differentiation of tumor from normal surrounding parenchyma is critical to ensure excessive normal renal tissue is not made ischemic or excised along with the tumor. The feasibility of a novel intraoperative imaging technique to differentiate tumor from surrounding parenchyma during laparoscopic and robot-assisted partial nephrectomy was evaluated. PATIENTS AND METHODS: Patients who were scheduled to undergo laparoscopic or robot-assisted partial nephrectomy were recruited from April 2009 to July 2010. The Endoscopic SPY Imaging System was used as an adjunct to intraoperative imaging in all cases. Patients received intravenous injections of indocyanine green (ICG), which was visualized intraoperatively with the near infrared fluorescence (NIRF) imaging capability of the SPY scope. The degree of tumor fluorescence compared with surrounding renal parenchyma was qualitatively assessed before tumor resection, and partial nephrectomy was then performed with standard techniques while intermittently using NIRF imaging. RESULTS: Nineteen patients underwent intravenous administration of ICG followed by NIRF during partial nephrectomy. Average tumor size was 3.0 cm (range 0.8-5.9 cm). Thirteen masses were malignant on final pathology results, and all of these were seen to be hypofluorescent compared with surrounding renal parenchyma during intraoperative imaging. The imaging behavior of benign tumors ranged from isofluorescent to hyperfluorescent compared with normal parenchyma. No complications were associated with ICG injection. CONCLUSION: NIRF imaging after intravenous ICG administration may be a useful intraoperative imaging tool to differentiate malignant tumors from normal renal parenchyma during laparoscopic and robot-assisted partial nephrectomy. Advanced intraoperative imaging techniques such as this one may become increasingly helpful as more complicated tumors are resected with minimally invasive approaches. PMID- 22250959 TI - Crisis resolution teams in the UK and elsewhere. AB - BACKGROUND: Crisis resolution and home treatment teams (CRTs) and home treatment teams have been established nationwide in the UK to reduce admissions to psychiatric hospitals. However, the evidence for CRTs was limited at the time of their introduction. AIMS: Review of the literature accumulated since the national rollout of CRTs in 2000. METHOD: Systematic narrative literature review utilising British Nursing Index, Cinahl, Embase, Medline and PsyINFO. RESULTS: The search revealed one randomised controlled trial and a number of naturalistic studies. The balance of evidence suggests that CRTs can reduce hospital beds and costs with similar symptomatic outcome and service user satisfaction, but there is no evidence that CRTs are the only way to do so. There is no conclusive evidence that CRTs cause an increase in serious and untoward incidents (SUIs) or compulsory admissions. CONCLUSIONS: Currently, there is no compelling evidence for the widespread implementation of CRTs. In the future, the incidence of compulsory admissions and SUIs needs to be studied at a national level, CRTs have to be compared with other methods to reduce hospital admissions and studies need to specify sample and treatment characteristics with greater detail. PMID- 22250960 TI - Simultaneous measurement of total acid content and soluble salt-free solids content in Chinese vinegar using near-infrared spectroscopy. AB - Total acid content (TAC) and soluble salt-free solids content (SSFSC) in Chinese vinegar are 2 important indicators in the assessment of its quality. This paper shows the feasibility to determine TAC and SSFSC in Chinese vinegar by near infrared (NIR) spectroscopy. Synergy interval partial least square (Si-PLS) algorithm was performed to calibrate the regression model. The number of PLS factors and the number of intervals were optimized simultaneously by cross validation. The performance of the model was evaluated according to root mean square error of prediction (RMSEP) and correlation coefficient (R) in the prediction set. The optimum Si-PLS model for TAC was achieved with RMSEP = 0.264 g/100 mL and R(p) = 0.9655; the optimum Si-PLS model for SSFSC was achieved with RMSEP = 1.93 g/100 mL and R(p) = 0.9302. The overall results demonstrated that NIR spectroscopy combined with Si-PLS could be utilized to determinate TAC and SSFSC in Chinese vinegar, and NIR spectroscopy has a potential to be used in vinegar industry. PMID- 22250961 TI - Community-dwelling persons with dementia: what do they need? What do they demand? What do they do? A systematic review on the subjective experiences of persons with dementia. AB - OBJECTIVES: Including the perspectives of persons with dementia (PwD) is essential in order to organize care structures for them. With this systematic review, we set out to screen the existing scientific evidence on self-expressions of community-dwelling individuals with dementia in order to provide a research base for developing an intervention for persons in early stages of the disease. The leading research questions for this review are: What needs do PwD living at home express? What are their subjective demands? What do they do to cope with their situation? METHODS: We performed a systematic literature review of review publications on subjective experiences of PwD. The publications were analysed using MAXQDA 10 to perform a thematic analysis. RESULTS: We identified 41 relevant reviews, of which 6 met our inclusion criteria. PwD experience the whole range of human emotions. Their needs and demands do not differ significantly from those of other groups of patients with chronic conditions. Coming to terms with the disease and maintaining normality appeared to be major themes. With regard to expectations from the side of professional health care, the need for accompanying, continuous support and counselling appeared to be central. Furthermore, disclosure of diagnosis represents a critical stage for PwD, but our findings indicated that they prefer to be included in this process. CONCLUSIONS: PwD are well able to express their needs. They should be included in research since they can provide valuable findings. Furthermore, those findings should be implemented in applied dementia care. PMID- 22250956 TI - A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets. AB - To establish the druggability of a target, genetic validation needs to be supplemented with pharmacological validation. Pharmacological studies, especially in the kinase field, are hampered by the fact that many reference inhibitors are not fully selective for one target. Fortunately, the initial trickle of selective inhibitors released in the public domain has steadily swelled into a stream. However, rationally picking the most selective tool compound out of the increasing amounts of available inhibitors has become progressively difficult due to the lack of accurate quantitative descriptors of drug selectivity. A recently published approach, termed 'selectivity entropy', is an improved way of expressing selectivity as a single-value parameter and enables rank ordering of inhibitors. We provide a guide to select the best tool compounds for pharmacological validation experiments of candidate drug targets using selectivity entropy. In addition, we recommend which inhibitors to use for studying the biology of the 20 most investigated kinases that are clinically relevant: Abl (ABL1), AKT1, ALK, Aurora A/B, CDKs, MET, CSF1R (FMS), EGFR, FLT3, ERBB2 (HER2), IKBKB (IKK2), JAK2/3, JNK1/2/3 (MAPK8/9/10), MEK1/2, PLK1, PI3Ks, p38alpha (MAPK14), BRAF, SRC and VEGFR2 (KDR). PMID- 22250962 TI - Patient satisfaction with treatment in first-episode psychosis. AB - PURPOSE: To examine first-episode psychotic patients' satisfaction with elements of a comprehensive 2-year treatment program. SUBJECTS AND METHOD: The TIPS (Early Treatment and Intervention in Psychosis) project provided a 2-year treatment program consisting of milieu therapy (inpatient), individual psychotherapy, family intervention and medication. Of 140 patients at baseline, 112 were included at 2-year follow-up. Eighty-four participants were interviewed using a questionnaire eliciting levels of satisfaction with different treatment elements at two of the four sites. RESULTS: Participants and non-participants did not differ on demographic or clinical data at baseline. Of those participating, 75% were satisfied with treatment in general. Individual and milieu therapy received higher rating than medication or family intervention. No predictors of general satisfaction with treatment were found, but continuously psychotic patients were the least satisfied with medication treatment. DISCUSSION: As in most patient satisfaction studies within mental health treatment networks, there was high level of general satisfaction with the total package of treatment but considerable variation in satisfaction for specific interventions. In this sample of first-episode psychosis patients, there was general satisfaction with treatments based on one-to-one relationships while multi-family group intervention was consistently valued less enthusiastically. PMID- 22250963 TI - The Kids' Inpatient Database (KID) and data mining in nursing. PMID- 22250964 TI - Mexican American mothers' eating and child feeding behaviors. AB - OBJECTIVE: The purpose of this study of Mexican-American mothers of 2-6 year old children was to explore the relationships among maternal attitude, perceived behavioral controls, mother's intent, mother's regulation of her own Simple Carbohydrate Intake (SCI), and mother's child feeding behaviors. The overall objective was to increase understanding of the complex process of intention to eat healthy. METHODS: A prospective exploratory design using a convenience sample of a cohort of 82 Mexican-American mothers was used in this study. Structured questionnaires were selected to measure cognitive restraint, disinhibition, hunger, intent to regulate SCI, and mothers' monitoring, restricting, and pressuring of children's diets. Descriptive statistics and correlations were analyzed for each relationship. RESULTS: The relationships between disinhibition, hunger, cognitive restraint, and the intent variable were significant. More than half of these mothers reported limiting soda and candy for themselves. According to the Food Frequency Questionnaire, mothers were regulating only one-third of simple carbohydrate items they intended to regulate. Significant relationships were found between mothers' regulation of her specific SCI and her control of child feeding behaviors including pressuring, monitoring, and restricting. CONCLUSION: The findings support the idea that mother's eating behaviors, attitudes, and intent may affect how they feed their pre-school children. Nurses need to develop and test interventions targeted at educating Mexican-American mothers about healthy food choices and healthy child feeding behaviors. PMID- 22250965 TI - Parental stress in families of children with a genetic disorder/disability and the resiliency model of family stress, adjustment, and adaptation. AB - BACKGROUND: Research suggests that parents of children with disabilities endure increased amounts of stress but also experience positive outcomes. PURPOSE: To further investigate findings from focus group interviews that explored parental stress in families of children with disabilities using a sequential mixed methods design. METHOD: This study sought to model parental stress using the McCubbin and McCubbin (1993) Resiliency Model of Stress, Adjustment, and Adaptation using qualitative and quantitative data collected sequentially. Twenty-five parents of children with autism spectrum disorder, cerebral palsy, Down syndrome, and sickle cell disease participated in a 2-step study that encompassed qualitative followed by quantitative data ascertainment. RESULTS: Parents who quantitatively experienced high stress or low stress used different behavioral themes to describe their experience qualitatively. Positive appraisals, resources, and ability to engage in problem solving and coping were associated with family resiliency. PMID- 22250966 TI - The costs of caring for a child with an autism spectrum disorder. AB - BACKGROUND: The primary purpose of this exploratory autism research was to examine the lived experiences of female primary caregivers of children with an autism spectrum disorder (ASD). METHODS: Specifically the costs and benefits of the primary caregivers' experiences were examined through semi-structured one-one one interviews. The specific focus of this paper was to examine the costs of caring for a child with an ASD, whereby costs did not refer solely to monetary costs, but were related to all aspects of the caregivers' lives. Interviews were completed with 8 mothers of children that had been formally diagnosed with an ASD. RESULTS: Undoubtedly all family members within the family unit were affected by a child's diagnosis with ASD as evidenced by the costs revealed by mothers. The subthemes derived from the theme of costs included the following: financial and work costs, costs to the health of family, social costs, and costs to overall family life. The results from this research provide evidence of the challenges associated with caring for a child with an ASD. CONCLUSIONS: It is anticipated that the insights provided by these mothers can act as a source of support for others faced with a similar situation. Additionally health care professionals may be able to use the knowledge gained from such qualitative endeavors in order to help parents cope more effectively with their caregiving responsibilities associated with children with ASDs. The mothers within this study are remarkable women that, for the most part, were able to rise above the negatives/costs associated with caring for a child with an ASD and find the silver linings amidst the turmoil. As remarkable as these women are in the daily struggles they face with their children, it is evident that more resources and support are required to assist these women and their families. PMID- 22250968 TI - Ethanol reforming on Co(0001) surfaces: a density functional theory study. AB - A computational study using density functional theory is carried out to investigate the reaction mechanism of ethanol steam reforming on Co(0001) surfaces. The adsorption properties of the reactant, possible intermediates, and products are carefully examined. The reaction pathway and related transition states are also analyzed. According to our calculations, the reforming mechanism primarily consisting of dehydrogenation steps of ethanol, ethoxy, methanol, methoxy, and formic acid, is feasible on Co(0001) surfaces. It is also found that the reaction of formaldehyde yielding formic acid and hydrogen may not be an elementary reaction. The dehydrogenation of ethoxy possesses the highest barrier and is accordingly identified as the rate-determining step. PMID- 22250969 TI - Zinc-substituted cytochrome P450cam: characterization of protein conformers F420 and F450 by photoinduced electron transfer. AB - Metal substitution of heme proteins is widely applied in the study of biologically relevant electron transfer (ET) reactions. It has been shown that many modified proteins remain in their native conformation and can provide useful insights into the molecular mechanism of electron transfer between the native protein and its substrates. We investigated ET reactions between zinc-substituted cytochrome P450(cam) and small organic compounds such as quinones and ferrocene, which are capable of accessing the protein's hydrophobic channel and binding close to the active site, like its native substrate, camphor. Following the substitution method developed by Gunsalus and co-workers [Wagner, G. C., et al. (1981) J. Biol. Chem. 256, 6262-6265], we have identified two dominant forms of the zinc-substituted protein, F450 and F420, that exhibit different photophysical and photochemical properties. The ET behavior of F420 suggests that hydrophobic redox-active ligands are able to penetrate the hydrophobic channel and place themselves in the direct vicinity of the Zn-porphyrin. In contrast, the slower ET quenching rates observed in the case of F450 indicate that the association is weak and occurs outside of the protein channel. Therefore, we conclude that F420 corresponds to the open structure of the native cytochrome P450(cam) while F450 has a closed or partially closed channel that is characteristic of the camphor containing cytochrome P450(cam). The existence of two distinct conformers of Zn bound P450(cam) is consistent with the findings of Goodin and co-workers [Lee, Y. T., et al. (2010) Biochemistry 49, 3412-3419] and has significant consequences for future electron transfer studies on this popular metalloenzyme. PMID- 22250970 TI - Group service in macaques (Macaca fuscata), capuchins (Cebus apella) and marmosets (Callithrix jacchus): a comparative approach to identifying proactive prosocial motivations. AB - Proactive, that is, spontaneous, prosociality reflects a psychological interest in the welfare of others and has been reported in callitrichid monkeys, capuchin monkeys (Cebus apella), and humans, but not in chimpanzees. One explanation for the co-occurrence of proactive prosociality in these species is that it is linked to shared infant care (cooperative breeding); alternatively, it might merely reflect unusually high social tolerance or be mediated by advanced cognitive abilities. To date, distinguishing between these alternative explanations is difficult, partly because available evidence is restricted to only a handful of species and partly because methodological differences thwart comparisons across studies. Here, we present an experimental paradigm called group service, which allows estimation of both social tolerance and proactive prosociality in group settings. Its simplicity makes it intuitively plausible to subjects and allows testing a broad variety of species, including in zoos. We applied the test to independently breeding Japanese macaques (Macaca fuscata), cooperatively breeding common marmosets (Callithrix jacchus), and capuchin monkeys with an intermediate breeding system. Social tolerance was slightly higher in marmosets than capuchins and much higher in both compared to macaques, but only marmosets provided a service to other group members. Furthermore, we validated the group service paradigm in the common marmosets by comparing their performance to earlier data. Although our results are consistent with the cooperative breeding hypothesis, a comprehensive evaluation requires adding data from additional groups and species, which should be facilitated by the group service approach. PMID- 22250971 TI - |(C4NH12)4|[M4Al12P16O64] (M = Co, Zn): new heteroatom-containing aluminophosphate molecular sieves with two intersecting 8-ring channels. AB - Two novel heteroatom-containing aluminophosphate molecular sieves, |(C(4)NH(12))(4)|[M(4)Al(12)P(16)O(64)] (denoted MAPO-CJ69, M = Co and Zn), have been solvothermally synthesized using diethylamine as the structure-directing agent. The framework of MAPO-CJ69 exhibits a new zeolite topology which is constructed by strict alternation of metal-centered (Al/M)O(4) tetrahedra and PO(4) tetrahedra to form a three-dimensional anionic [M(4)Al(12)(PO(4))(16)](4-) framework. The structure contains two intersecting 8-ring channels along the [010] and [001] directions, and the protonated diethylamine cations reside in the 8-ring channels to achieve charge neutrality. The structure of MAPO-CJ69 is composed of the 4-4- secondary building unit (SBU), which has been found in some known zeolites, such as AFR, SFO, ZON, OWE, etc. The structural relationships between these zeolites have been discussed. PMID- 22250972 TI - Isolation and structure elucidation of highly antioxidative 3,8"-linked biflavanones and flavanone-C-glycosides from Garcinia buchananii bark. AB - The aim of this study was to identify antioxidants from Garcinia buchananii bark extract using hydrogen peroxide scavenging and oxygen radical absorbance capacity (ORAC) assays. LC-MS/MS analysis, 1D- and 2D-NMR, and circular dichroism (CD) spectroscopy led to the unequivocal identification of the major antioxidative molecules as a series of three 3,8"-linked biflavanones and two flavanone-C glycosides. Besides the previously reported (2R,3R,2"R,3"R)-naringenin-C-3/C-8" dihydroquercetin linked biflavanone (GB-2; 4) and (2R,3S,2"R,3"R)-manniflavanone (3), whose stereochemistry has been revised, the antioxidants identified for the first time in Garcinia buchananii were (2R,3R)-taxifolin-6-C-beta-D glucopyranoside (1), (2R,3R)-aromadendrin-6-C-beta-D-glucopyranoside (2), and the new compound (2R,3S,2"S)-buchananiflavanone (5). The H2O2 scavenging and the ORAC assays demonstrated that these natural products have an extraordinarily high antioxidative power, especially (2R,3S,2"R,3"R)-manniflavanone (3) and GB-2 (4), with EC50 values of 2.8 and 2.2 MUM, respectively, and 13.73 and 12.10 MUmol TE/ MUmol. These findings demonstrate that G. buchananii bark extract is a rich natural source of antioxidants. PMID- 22250973 TI - What is your diagnosis? Blood film from a boa constrictor. PMID- 22250974 TI - Validation of the Lund-Malmo, Chronic Kidney Disease Epidemiology (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations to estimate glomerular filtration rate in a large Swedish clinical population. AB - OBJECTIVE: The aim of this study was to validate externally the Swedish Lund Malmo revised creatinine-based glomerular filtration rate (GFR) equations (LM Revised) in a Swedish cohort in comparison with the North American Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI) equations. MATERIAL AND METHODS: The study included 1397 examinations [median age 61 years, median body mass index (BMI) 26 kg/m(2)] in 996 patients referred for iohexol clearance (median 44 ml/min/1.73 m(2)). Bias, precision [interquartile range (IQR)], accuracy expressed as percentage of estimates +/- 10% (P(10)) and +/- 30% (P(30)) of measured GFR, and classification ability for five GFR stages (<15, 15-29, 30-59, 60-89 and >=90 ml/min/1.73 m(2)) were compared. RESULTS: Overall, all three equations performed satisfactorily: LM Revised, MDRD, CKD-EPI showed, respectively, a median bias of -5.8%, -2.2% and 1.7%, IQR 11.9, 12.3 and 11.7 ml/min/1.73 m(2), P(10) 35%, 34% and 38%, P(30) 84%, 79% and 79% and correctly classified GFR stages 68%, 65% and 69%. LM Revised was at least as accurate in terms of P(30) as the other equations at GFR intervals <90, while CKD EPI was the only unbiased and the most accurate equation at >=90 ml/min/1.73 m(2). LM Revised was more stable in terms of bias and accuracy across age and BMI groups than MDRD and CKD-EPI. Both MDRD and CKD-EPI overestimated measured GFR among elderly patients and in the small group of underweight men. CONCLUSION: The ideal all-purpose GFR prediction equation does not exist. LM Revised should be preferred in patients with suspected or known renal insufficiency, while CKD-EPI is most useful in settings where patients with no a priori suspicion of renal impairment are evaluated. Differences in creatinine measurements between laboratories may limit the generalizability of the present validation. PMID- 22250975 TI - Effect of UV-A irradiance on lipid accumulation in Nannochloropsis oculata. AB - Lipids produced by microalgae can be grouped into two categories, storage lipids and structural lipids. Storage lipids are mainly triglycerides (TGs) made up of saturated fatty acids; TGs can be transesterified to produce biodiesel. Structural lipids are made of polyunsaturated fatty acids (PUFAs), which are essential nutrients for aquatic animals and humans. The objectives of this study were: (1) to determine the effect of UV-A at different levels of exposure on total lipid accumulation in Nannochloropsis oculata and check for reciprocity and (2) to study the interactive effect of UV-A and nutrient concentration on lipid accumulation in N. oculata. Objective 1 was accomplished by testing the effects of a range of UV-A irradiance (I), duration of exposure (T) and UV-A doses (I * T) on lipid production by N. oculata. If the same doses have a similar effect, irrespective of I and T, reciprocity holds. UV-A treatments significantly increased the chlorophyll-specific lipid concentration of N. oculata cells, and we were unable to falsify that reciprocity holds. Objective 2 was addressed by a factorial bioassay experiment with manipulated nutrient and UV-A levels. UV-A and decreased nutrients had a synergistic effect on chlorophyll-specific lipid concentration of N. oculata, resulting in higher lipid:chl ratios. PMID- 22250976 TI - Imaging Schottky barriers and ohmic contacts in PbS quantum dot devices. AB - We fabricated planar PbS quantum dot devices with ohmic and Schottky type electrodes and characterized them using scanning photocurrent and photovoltage microscopies. The microscopy techniques used in this investigation allow for interrogation of the lateral depletion width and related photovoltaic properties in the planar Schottky type contacts. Titanium/QD contacts exhibited depletion widths that varied over a wide range as a function of bias voltage, while the gold/QD contacts showed ohmic behavior over the same voltage range. PMID- 22250977 TI - Methods used for prevention of white spot lesion development during orthodontic treatment with fixed appliances. AB - OBJECTIVES: The aim of this study was to survey methods that Dutch orthodontists use to prevent development or progression of enamel decalcifications during orthodontic treatment. MATERIALS AND METHODS: A pre-tested questionnaire was sent by post to all orthodontists in the Netherlands with a private practice (n = 189). RESULTS: The response rate was 81%. At the start of orthodontic treatment a basic practice protocol for prevention of enamel demineralization was used by 93% of the orthodontists. This included oral hygiene instructions (92%) and the advice for additional use of a fluoride mouth rinse (64%). Other preventive measures were rarely prescribed. About 85% of those who prescribed a fluoride mouth rinse advised to rinse once a day, directly after evening tooth brushing. CONCLUSIONS: The results suggest that the commonly used practice of fluoride mouth rinsing directly after evening tooth brushing by orthodontic patients during fixed appliance treatment ignores actual evidence of preventive advices. This study recommends mouth rinsing at another moment than after evening tooth brushing, thus increasing the frequency of fluoride intakes, which might enhance the effectiveness in preventing WSL development or progression during orthodontic treatment. PMID- 22250978 TI - alpha-Amidoalkylating agents from N-acyl-alpha-amino acids: 1-(N acylamino)alkyltriphenylphosphonium salts. AB - N-Acyl-alpha-amino acids were efficiently transformed in a two-step procedure into 1-N-(acylamino)alkyltriphenylphosphonium salts, new powerful alpha amidoalkylating agents. The effect of the alpha-amino acid structure, the base used [MeONa or a silica gel-supported piperidine (SiO(2)-Pip)], and the main electrolysis parameters (current density, charge consumption) on the yield and selectivity of the electrochemical decarboxylative alpha-methoxylation of N-acyl alpha-amino acids (Hofer-Moest reaction) was investigated. For most proteinogenic and all studied unproteinogenic alpha-amino acids, very good results were obtained using a substoichiometric amount of SiO(2)-Pip as the base. Only in the cases of N-acylated cysteine, methionine, and tryptophan, attempts to carry out the Hofer-Moest reaction in the applied conditions failed, probably because of the susceptibility of these alpha-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyalkyl)amides was effectively displaced with the triphenylphosphonium group by dissolving an equimolar amount of N-(1-methoxyalkyl)amide and triphenylphosphonium tetrafluoroborate in CH(2)Cl(2) at room temperature for 30 min, followed by the precipitation of 1-N (acylamino)alkyltriphenylphosphonium salt with Et(2)O. PMID- 22250979 TI - Pharmacokinetics and 48 week efficacy of adjusted dose indinavir/ritonavir in rifampicin-treated HIV/tuberculosis-coinfected patients: a pilot study. AB - HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/MUl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure. PMID- 22250981 TI - Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies. AB - In the last three decades there have been dramatic improvements in the availability and quality of treatment for people with inherited coagulation disorders. Indeed, the improvement of methods of purification and viral inactivation for plasma-derived coagulation factor concentrates first and then the development of products utilizing recombinant DNA technology have greatly improved the life expectancy of hemophiliacs, which has progressively become similar to that of males in the general population. Nowadays, the most frequent complication of factor replacement therapy for hemophilia is the development of inhibitors. However, no studies so far have systematically analysed the type and incidence of other adverse reactions following the administration of coagulation factor concentrates. The aim of this systematic review was to screen the published literature data to evaluate the types and frequencies of non-thrombotic , non-inhibitor-associated adverse reactions to coagulation factor concentrates in patients with hemophilia A, hemophilia B and von Willebrand's disease. On behalf the European Haemophilia Safety Surveillance System (EUHASS), a systematic review of the prospective studies published in the last 20 years was performed using electronic databases and article references. Both severe and mild adverse events following infusion of coagulation factor concentrates are relatively rare in patients with inherited coagulation disorders; the most common events are of an allergic type. There are no differences in the rate of adverse events caused by plasma-derived or recombinant products. On the whole, these data confirm the high degree of safety of the products currently used for replacement therapy. PMID- 22250980 TI - Epithelial Na+ channel activity in human airway epithelial cells: the role of serum and glucocorticoid-inducible kinase 1. AB - BACKGROUND AND PURPOSE: Glucocorticoids appear to control Na+ absorption in pulmonary epithelial cells via a mechanism dependent upon serum and glucocorticoid-inducible kinase 1 (SGK1), a kinase that allows control over the surface abundance of epithelial Na+ channel subunits (alpha-, beta- and gamma ENaC). However, not all data support this model and the present study re evaluates this hypothesis in order to clarify the mechanism that allows glucocorticoids to control ENaC activity. EXPERIMENTAL APPROACH: Electrophysiological studies explored the effects of agents that suppress SGK1 activity upon glucocorticoid-induced ENaC activity in H441 human airway epithelial cells, whilst analyses of extracted proteins explored the associated changes to the activities of endogenous protein kinase substrates and the overall/surface expression of ENaC subunits. KEY RESULTS: Although dexamethasone induced (24 h) ENaC activity was dependent upon SGK1, prolonged exposure to this glucocorticoid did not cause sustained activation of this kinase and neither did it induce a coordinated increase in the surface abundance of alpha-, beta- and gamma-ENaC. Brief (3 h) exposure to dexamethasone, on the other hand, did not evoke Na+ current but did activate SGK1 and cause SGK1-dependent increases in the surface abundance of alpha-, beta- and gamma-ENaC. CONCLUSIONS AND IMPLICATIONS: Although glucocorticoids activated SGK1 and increased the surface abundance of alpha-, beta- and gamma-ENaC, these responses were transient and could not account for the sustained activation of ENaC. The maintenance of ENaC activity did, however, depend upon SGK1 and this protein kinase must therefore play an important but permissive role in glucocorticoid-induced ENaC activation. PMID- 22250982 TI - Traumatic subperiostial emphysema caused by hyperpneumatization of the temporal and occipital bone. AB - Hyperpneumatization of the temporal bone with extension into the occipital bone and even the parietal bones is a rare condition. We report a case in which the patient suffered periodically from a palpable mass in the parietal-occipital region which originated from extensive occipital bone pneumatization. Computed tomography examination revealed extensive temporal and occipital pneumatization and subperiosteal pneumatoceles, which was corrected by surgery. PMID- 22250983 TI - Postshockwave lithotripsy outcome evaluation in ureteral stones: comparison between noncontrast computed tomography and plain abdominal radiography. AB - BACKGROUND AND PURPOSE: There are no definite data indicating which modality to use to assess the efficacy of shockwave lithotripsy (SWL). Usually, plain abdominal radiography (PAR) is recommended in percutaneous nephrolithotomy (PCNL) afterward and in the follow-up of asymptomatic stones, whereas noncontrast CT (NCCT) is recommended in cases of residual fragments. We compared the efficacies of PAR and NCCT in terms of assessing the outcome of SWL treatment for radiopaque ureteral stones. PATIENTS AND METHODS: Those patients with renal colic and a radiopaque ureteral stone of 5 to 20 mm that was detected on PAR were included in the study; body mass index (BMI) values were calculated and recorded. Patients whose PAR revealed opacities suspicious for ureteral stones were evaluated with NCCT at 3-mm slices. Stone status was assessed with PAR and NCCT on post-SWL day 3. Detection of no stone, a residual fragment of <= 4 mm, and a residual fragment of >4 mm was defined as success, clinically insignificant residual fragments, and failure, respectively. RESULTS: On post-SWL day 3, both PAR and NCCT revealed stones in 31 patients, and no stones were seen in either modality in 29 patients. NCCT revealed stones whereas PAR had negative results for stones in two patients. These patients had upper ureteral stones of 7.5 mm (6-9 mm) before SWL. Mean stone size on NCCT after SWL was 2.5 mm (1-4 mm). Mean BMI of these two patients was 27.72, and mean BMI of the patients with upper ureteral stones that were revealed by both PAR and NCCT was 27.68; these two values were statistically similar. CONCLUSION: PAR is capable of detecting clinically significant residual fragments, and patients can be followed up with PAR alone after SWL treatment for radiopaque ureteral stones. This approach both decreases the cost and prevents excessive radiation exposure. PMID- 22250984 TI - CsrA modulates luxR transcript levels in Vibrio fischeri. AB - The quorum-sensing and CsrA regulons of Vibrios control overlapping cellular functions during growth. Hence, the potential exists for regulatory network interactions between the pathways that enable them to be coordinately controlled. In Vibrio cholerae, CsrA indirectly modulates the activity of LuxO in the quorum sensing signaling pathway. In this study, it was demonstrated that in Vibrio fischeri, CsrA causes an increase in the transcript levels of a downstream quorum sensing regulatory gene, luxR, which does not exist in the V. cholerae system. In V. fischeri, the increase in luxR transcripts caused by CsrA does not depend on the LitR transcriptional activator nor does the CsrA effect seem to occur through the global regulator cAMP-CRP. Thus, there appears to be more than one mechanism whereby the CsrA and quorum-sensing pathways integrate regulatory outputs in Vibrios. PMID- 22250986 TI - Association of conicity index and renal progression in pre-dialysis chronic kidney disease. AB - BACKGROUND/OBJECTIVES: Abdominal fat deposition is represented by means of the conicity index (CI), an anthropometric estimate that models the relative accumulation of abdominal fat. We examined the influence of markers of cardiovascular disease in terms of inflammation and lipid profile and body fat distribution on the progression of renal disease in patients with stable chronic kidney disease (CKD) stages 3-5. MATERIAL AND METHODS: We studied 104 pre dialysis CKD patients (64 males, 62%; age 64.6 +/- 14.7 years). Glomerular filtration rate (GFR) was estimated (44.62 +/- 14.38 mL/min/1.73 m2) by modification of diet in renal disease formula. GFR values were estimated at baseline and at the end of the 12-month follow-up. Patients were stratified into three groups: group 1 had a loss of GFR >=20%; group 2 had a loss of GFR 10-20%; and group 3 patients had stable renal functions or GFR change <10% at the end of 12 months. Body mass index (BMI), waist/hip ratio (WHR), and CI were subsequently computed. Renal resistive index (RRI) was measured using Doppler ultrasonography. RESULTS: CI was strongly correlated with total cholesterol (r = 0.37, p < 0.01), low-density lipoprotein (LDL) (r = 0.53, p < 0.01), C-reactive protein (r = 0.21, p < 0.05), and serum potassium (r = 0.216, p < 0.02), whereas BMI and WHR were not associated with these parameters. The values of CI, serum cholesterol, LDL, alkaline phosphatase, alanine aminotransferase, lactate dehydrogenase activity, the degree of proteinuria and microalbuminuria, and RRI were significantly lower in group 3. In linear regression model, LDL (r2 = 0.17, p = 0.02), uric acid (r2 = 0.19, p < 0.01), and RRI (r2 = 0.64, p < 0.01) were independently associated with CI for all groups. CONCLUSION: CI is an independent predictor of systemic inflammation, cardiovascular risk, and GFR in patients during the pre-dialysis period. PMID- 22250985 TI - n-3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate dependent actin remodelling during CD4+ T-cell activation. AB - n-3 PUFA (polyunsaturated fatty acids), i.e. DHA (docosahexaenoic acid), found in fish oil, exhibit anti-inflammatory properties; however, the molecular mechanisms remain unclear. Since PtdIns(4,5)P2 resides in raft domains and DHA can alter the size of rafts, we hypothesized that PtdIns(4,5)P2 and downstream actin remodelling are perturbed by the incorporation of n-3 PUFA into membranes, resulting in suppressed T-cell activation. CD4+ T-cells isolated from Fat-1 transgenic mice (membranes enriched in n-3 PUFA) exhibited a 50% decrease in PtdIns(4,5)P2. Upon activation by plate-bound anti-CD3/anti-CD28 or PMA/ionomycin, Fat-1 CD4+ T-cells failed to metabolize PtdIns(4,5)P2. Furthermore, actin remodelling failed to initiate in Fat-1 CD4+ T-cells upon stimulation; however, the defect was reversed by incubation with exogenous PtdIns(4,5)P2. When Fat-1 CD4+ T-cells were stimulated with anti-CD3/anti-CD28 coated beads, WASP (Wiskott-Aldrich syndrome protein) failed to translocate to the immunological synapse. The suppressive phenotype, consisting of defects in PtdIns(4,5)P2 metabolism and actin remodelling, were recapitulated in CD4+ T cells isolated from mice fed on a 4% DHA triacylglycerol-enriched diet. Collectively, these data demonstrate that n-3 PUFA, such as DHA, alter PtdIns(4,5)P2 in CD4+ T-cells, thereby suppressing the recruitment of WASP to the immunological synapse, and impairing actin remodelling in CD4+ T-cells. PMID- 22250987 TI - The experience of worry among young and older adults in the United States and Germany: a cross-national comparison. AB - This study compared adult age-related differences in the experience of worry within two cultures. Data were collected from 173 Germans and 263 Americans (within the United States) on a general worry scale and two hypothesized correlates of worry (life events and locus of control). Results indicated that there were age differences on all of the hypothesized correlates of worry as well as the measure of worry, with younger adults reporting more worries than did older adults. Differences were found between the two countries on the hypothesized correlates (with the exception of internal locus of control) and one subscale of the worry measure. More importantly, structural equation modeling indicated that the hypothesized correlates of worry differentially contributed to the prediction of worry across the two cultures and across the two age groups. That is, with one minor exception, the hypothesized correlates did not predict worry within the German sample, but did predict worry within the American sample. Among the younger adult American sample, endorsement of external locus of control and life events predicted worry, but among the older American sample, positive endorsement of internal locus of control predicted worry. PMID- 22250988 TI - The prevalence of atrial fibrillation in a geographically well-defined population in northern Sweden: implications for anticoagulation prophylaxis. AB - OBJECTIVES: The aims of this study were to evaluate the community-based prevalence of atrial fibrillation (AF) in a western society using a geographically well-defined population in the northern part of Sweden as a reference and to estimate the proportion of patients eligible for oral anticoagulation (OAC) prophylactic therapy according to the stroke risk indices CHADS2 and CHA2 DS2 -VASc. Bleeding risk was assessed using the HAS-BLED score. DESIGN: The study population was recruited from AURICULA, a Swedish national quality register for patients receiving anticoagulation treatment. All patients with the diagnosis AF in the catchment area are registered in AURICULA. RESULTS: Of the 65 532 inhabitants in the catchment area, 1616 were diagnosed with AF (1200 cases were characterized as chronic AF). Thus, the overall prevalence of AF was 2.5%. The prevalence increased with age from 6.3% in patients over 55 years of age to 13.8% in those over 80 years. The prevalence was higher in men than in women in all age groups. Overall, 56.3% and 85.1% of the population were at high risk of stroke (>=2 points) according to CHADS2 and CHA2 DS2 -VASc, respectively. In addition, 26.9% had an increased bleeding risk according to HAS-BLED. CONCLUSION: Within this large Caucasian population, we identified the highest community-based prevalence of AF to date. The prevalence was strongly associated with increasing age and male gender. Using CHA2 DS2 -VASc instead of CHADS(2) widened the indication for OAC prophylactic therapy of AF in this population. PMID- 22250989 TI - Effects of heating rate and pH on fracture and water-holding properties of globular protein gels as explained by micro-phase separation. AB - The effect of heating rate and pH on fracture properties and held water (HW) of globular protein gels was investigated. The study was divided into 2 experiments. In the 1st experiment, whey protein isolate (WPI) and egg white protein (EWP) gels were formed at pH 4.5 and 7.0 using heating rates ranging from 0.1 to 35 degrees C/min and holding times at 80 degrees C up to 240 min. The 2nd experiment used one heating condition (80 degrees C for 60 min) and probed in detail the pH range of 4.5 to 7.0 for EWP gels. Fracture properties of gels were measured by torsional deformation and HW was measured as the amount of fluid retained after a mild centrifugation. Single or micro-phase separated conditions were determined by confocal laser scanning microscopy. The effect of heating rate on fracture properties and HW of globular protein gels can be explained by phase stability of the protein dispersion and total thermal input. Minimal difference in fracture properties and HW of EWP gels at pH 4.5 compared with pH 7.0 were observed while WPI gels were stronger and had higher HW at pH 7.0 as compared to 4.5. This was due to a mild degree of micro-phase separation of EWP gels across the pH range whereas WPI gels only showed an extreme micro-phase separation in a narrow pH range. In summary, gel formation and physical properties of globular protein gels can be explained by micro-phase separation. PRACTICAL APPLICATION: The effect of heating conditions on hardness and water-holding properties of protein gels is explained by the relative percentage of micro-phase separated proteins. Heating rates that are too rapid require additional holding time at the end-point temperature to allow for full network development. Increase in degree of micro-phase separation decreases the ability for protein gels to hold water. PMID- 22250991 TI - Polyunsaturated fatty acids confer cryoresistance on megakaryocytes generated from cord blood and also enhance megakaryocyte production from cryopreserved cord blood cells. AB - BACKGROUND AIMS: Previous data have shown that the addition of docosahexanoic acid (DHA)/arachidonic acid (AA) has a beneficial effect on cytokine-mediated in vitro generation of megakaryocytes (MK) from umbilical cord blood (UCB).Cryopreservation forms an inherent part of UCB banking and MK progenitors are known to be very sensitive to the stresses of freezing. It is therefore imperative to generate functional cells from cryopreserved cells, and the generated cells need to be cryopreserved until used. In the present study, cryopreservation of ex vivo-expanded MK as well as MK generation from cryopreserved UCB samples was investigated. METHODS: MK generated with or without DHA/AA were cryopreserved in freezing medium containing 10% dimethyl sulfoxide (DMSO). Freezing efficacy was tested by quantitating MK after revival. Cryopreserved CD34(+) cells were cultured with stem cell factor (SCF) and thrombopoietin (TPO), in the presence and absence of DHA/AA for 10 days, and then quantitated for MK. Results. We observed a 1.5-3-fold increase in MK numbers, their progenitor content and their expression of phenotypic markers and MK related transcription factors. DHA/AA sets showed a 2-5-fold improved engraftment in NOD/SCID mice. These data showed that the beneficial effect of DHA/AA obtained during MK expansion was not altered after freezing stress. The enhancement in MK generation obtained from fresh cord blood (CB) cells was reproduced with comparable efficiency when we used cryopreserved CB samples. CONCLUSIONS: Taken together, our data suggest that in vitro-generated DHA/AA MK survive cryoinjuries in a functionally better state. DHA/AA support a more efficient generation of MK from cryopreserved UCB. PMID- 22250990 TI - Deletion of the alpha immunoglobulin chain membrane-anchoring region reduces but does not abolish IgA secretion. AB - Class switching and plasma cell differentiation occur at a high level within all mucosa-associated lymphoid tissues. The different classes of membrane immunoglobulin heavy chains are associated with the Igalpha/Igbeta heterodimer within the B-cell receptor (BCR). Whether BCR isotypes convey specific signals adapted to the corresponding differentiation stages remains debated but IgG and IgA membranes have been suggested to promote plasma cell differentiation. We investigated the impact of blocking expression of the IgA-class BCR through a 'alphaDeltatail' targeted mutation, deleting the Calpha immunoglobulin gene membrane exon. This allowed us to evaluate to what extent class switching and plasma cell differentiation can be concurrent processes, allowing some alphaDeltatail(+/+) B cells with an IgM BCR to directly differentiate into IgA plasma cells and yield serum secreted IgA in spite of the absence of membrane IgA(+) B lymphocytes. By contrast, in secretions the secretory IgA was very low, indicating that J-chain-positive plasma cells producing secretory IgA overwhelmingly differentiate from previously class-switched membrane IgA(+) memory B cells. In addition, although mucosa-associated lymphoid tissues are a major site for plasma cell accumulation, alphaDeltatail(+/+) mice showed that the gut B-cell lineage homeostasis is not polarized toward plasma cell differentiation through a specific influence of the membrane IgA BCR. PMID- 22250992 TI - Evaluating outcomes of therapies offered by occupational therapists in adult mental health. AB - BACKGROUND: Attitudes towards the use of outcome measures by professionals working in mental health have been shown to be variable. Occupational therapists appear to have difficulty specifying goals and measuring the outcomes of interventions. AIMS: To measure the outcomes of therapies offered by occupational therapists and to assess concurrent validity of the Van du Toit Model of Creative Ability (VdT MoCA) assessment. METHOD: The Global Assessment of Functioning (GAF), VdT MoCA assessment and Canadian Occupational Performance Measure (COPM) were used. Changes in mean scores on the measures were assessed using appropriate tests. Correlations between measures were assessed using Spearman's non parametric test. RESULTS: Mean post-therapy scores were significantly higher than pre-therapy scores on all three measures. VdT MoCA assessment scores pre- and post-therapy were highly correlated with GAF scores. The COPM outcome scores were uncorrelated with VdT MoCA assessment and GAF scores. CONCLUSIONS: The results offer a promising indication that occupational therapy interventions may increase functioning and thus aid clients' recovery. The VdT MoCA assessment is promising as a measure of improvement in functioning. Further research is needed to confirm these results and to further explore issues around occupational therapists' use of outcome measures. PMID- 22250993 TI - Lanthanum carbonate reduces urine phosphorus excretion: evidence of high-capacity phosphate binding. AB - The effectiveness of phosphate binders can be assessed by evaluating urinary phosphorus excretion in healthy volunteers, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. Healthy volunteers were enrolled into one of five separate randomized trials; four were open label and one double blind. Following a screening period of <=28 days, participants received differing tablets containing lanthanum carbonate [LC, 3000 mg/day of elemental lanthanum (in one study other doses were also used)]. Participants received a standardized phosphate diet and remained in the relevant study center throughout the duration of each treatment period. The end point in all studies was the reduction in urinary phosphorus excretion. Reductions in mean 24-h urinary phosphorus excretion in volunteers receiving a lanthanum dose of 3000 mg/day were between 236 and 468 mg/day over the five separate studies. These data in healthy volunteers can be used to estimate the amount of reduction of dietary phosphate absorption by LC. The reduction in 24-h urinary phosphorus excretion per tablet was compared with published data on other phosphate binders. Although there are limitations, evidence suggests that LC is a very effective phosphate binder in terms of binding per tablet. PMID- 22250994 TI - Serum transthyretin concentration is decreased in dogs with nonthyroidal illness. AB - BACKGROUND: Hypothyroidism in dogs is often difficult to diagnose owing to nonspecific clinical signs and laboratory test results that can be mimicked by nonthyroidal illness (NTI). Thyroxine (T4) circulates in blood mainly bound to T4 binding globulin and, to a lesser degree, transthyretin (TTR) and albumin. The concentration of total T4 depends on the concentrations of these binding proteins. OBJECTIVES: We hypothesized that dogs with NTI and decreased serum total T4 concentrations would have decreased serum TTR concentrations. The objective of the study was to measure and compare serum TTR concentrations in healthy dogs, in dogs with NTI and low serum T4 concentrations, and in dogs with hypothyroidism. METHODS: Assignment of dogs to 3 groups was based on physical examination and serum concentrations of T4 and TSH (mean +/- SD): for healthy dogs (n = 13), T4 was 24.8 +/- 3.6 nmol/L and TSH was 0.15 +/- 0.08 MUg/L; for dogs with NTI and low T4 (n = 20), T4 was 3.2 +/- 3.0 nmol/L and TSH was 0.18 +/- 0.13 MUg/L; and for hypothyroid dogs (n = 19), T4 was 5.3 +/- 4.3 nmol/L and TSH was 2.33 +/- 1.90 MUg/L). TTR concentrations in serum were determined semiquantitatively using western blot analysis. RESULTS: Serum TTR concentration (mean +/- SD) was decreased in the dogs with NTI (24.8 +/- 7.9 mg/L) compared with that of hypothyroid dogs (41.1 +/- 21.4 mg/L, P = .0035). Differences were not found between TTR concentrations in clinically healthy dogs (33.3 +/- 10.1 mg/L) and hypothyroid dogs or dogs with NTI. CONCLUSIONS: Serum TTR concentrations were significantly decreased in dogs with NTI and low T4 compared with concentrations in hypothyroid dogs. Additional studies should be done to determine if TTR concentrations can discriminate between dogs with NTI and low T4 and dogs with primary hypothyroidism. PMID- 22250995 TI - Role of O2 + QOOH in low-temperature ignition of propane. 1. Temperature and pressure dependent rate coefficients. AB - The kinetics of the reaction of molecular oxygen with hydroperoxyalkyl radicals have been studied theoretically. These reactions, often referred to as second O(2) addition, or O(2) + QOOH reactions, are believed to be responsible for low temperature chain branching in hydrocarbon oxidation. The O(2) + propyl system was chosen as a model system. High-level ab initio calculations of the C(3)H(7)O(2) and C(3)H(7)O(4) potential energy surfaces are coupled with RRKM master equation methods to compute the temperature and pressure dependence of the rate coefficients. Variable reaction coordinate transition-state theory is used to characterize the barrierless transition states for the O(2) + QOOH addition reactions as well as subsequent C(3)H(6)O(3) dissociation reactions. A simple kinetic mechanism is developed to illustrate the conditions under which the second O(2) addition increases the number of radicals. The sequential reactions O(2) + QOOH -> OOQOOH -> OH + keto-hydroperoxide -> OH + OH + oxy-radical and the corresponding formally direct (or well skipping) reaction O(2) + QOOH -> OH + OH + oxy-radical increase the total number of radicals. Chain branching through this reaction is maximized in the temperature range 600-900 K for pressures between 0.1 and 10 atm. The results confirm that n-propyl is the smallest alkyl radical to exhibit the low-temperature combustion properties of larger alkyl radicals, but n-butyl is perhaps a truer combustion archetype. PMID- 22250996 TI - Measurement invariance of big-five factors over the life span: ESEM tests of gender, age, plasticity, maturity, and la dolce vita effects. AB - This substantive-methodological synergy applies evolving approaches to factor analysis to substantively important developmental issues of how five-factor approach (FFA) personality measures vary with gender, age, and their interaction. Confirmatory factor analyses (CFAs) conducted at the item level often do not support a priori FFA structures, due in part to the overly restrictive assumptions of CFA models. Here we demonstrate that exploratory structural equation modeling (ESEM), an integration of CFA and exploratory factor analysis, overcomes these problems with the 15-item Big Five Inventory administered as part of the nationally representative British Household Panel Study (N = 14,021; age: 15-99 years, Mage = 47.1). ESEM fitted the data substantially better and resulted in much more differentiated (less correlated) factors than did CFA. Methodologically, we extended ESEM (introducing ESEM-within-CFA models and a hybrid of multiple groups and multiple indicators multiple causes models), evaluating full measurement invariance and latent mean differences over age, gender, and their interaction. Substantively the results showed that women had higher latent scores for all Big Five factors except for Openness and that these gender differences were consistent over the entire life span. Substantial nonlinear age effects led to the rejection of the plaster hypothesis and the maturity principle but did support a newly proposed la dolce vita effect in old age. In later years, individuals become happier (more agreeable and less neurotic), more self-content and self-centered (less extroverted and open), more laid back and satisfied with what they have (less conscientious, open, outgoing and extroverted), and less preoccupied with productivity. PMID- 22250997 TI - Adult outcomes as a function of an early childhood educational program: an Abecedarian Project follow-up. AB - Adult (age 30) educational, economic, and social-emotional adjustment outcomes were investigated for participants in the Abecedarian Project, a randomized controlled trial of early childhood education for children from low-income families. Of the original 111 infants enrolled (98% African American), 101 took part in the age 30 follow-up. Primary indicators of educational level, economic status, and social adjustment were examined as a function of early childhood treatment. Treated individuals attained significantly more years of education, but income-to-needs ratios and criminal involvement did not vary significantly as a function of early treatment. A number of other indicators were described for each domain. Overall, the findings provide strong evidence for educational benefits, mixed evidence for economic benefits, and little evidence for treatment related social adjustment outcomes. Implications for public policy are discussed. PMID- 22250998 TI - Developmental changes in sexual prejudice from early to late adolescence: the effects of gender, race, and ideology on different patterns of change. AB - This study documented significant changes in prejudice toward gay and lesbian individuals among adolescents from the ages of 12 to 18 years. Moreover, in line with developmental theories of prejudice, there was substantial variability in these patterns, partially predicted by the gender and ideological beliefs (reflected by social dominance orientation [SDO]) of individuals. Boys reported higher prejudice at age 12 than girls. SDO also accounted for initial differences in levels of prejudice. Further, although prejudice toward gay men did decrease among girls over time, it did not decrease among boys. Prejudice toward lesbians decreased at similar rates for boys and girls. These different trajectories are explained within the context of gender socialization processes during adolescence. In addition, fluctuations in adolescents' own SDO corresponded with fluctuations in their level of prejudice, over and above those tied to age related changes. This association was even stronger among those with overall higher SDO tendencies than others. However, SDO, when treated as a stable invariant factor, did not predict different patterns of progressive age-related change in prejudice. These results extend the research on sexual prejudice by examining it within a broader and more dynamic developmental framework, in greater alignment with developmental theories of prejudice. PMID- 22250999 TI - Beneficial effects of disengagement from futile struggles with occupational planning: a contextualist-motivational approach. AB - Globalized labor markets confront many adults, both employed and unemployed, with demands arising from career uncertainty that have the potential to jeopardize their occupational planning. This article investigated how individuals in different regions of Germany, which are characterized by different economic opportunities, negotiate such demands to pursue a career. The central hypothesis is that under unfavorable economic conditions, disengagement from demands of career planning, in terms of reducing commitment to their mastery, will predict positive changes in subjective well-being. This was tested using a sample of N = 806 adults living in 91 regions of Germany. Results suggest that disengagement predicts increased subjective well-being, but only if individuals report a very high load of demands of career planning and live in regions characterized by particularly poor opportunities for goal striving. It is concluded that disengagement can be an adaptive way of mastering occupational planning under particularly disadvantageous circumstances. PMID- 22251000 TI - The impact of stress on the life history strategies of African American adolescents: cognitions, genetic moderation, and the role of discrimination. AB - The impact of 3 different sources of stress--environmental, familial (e.g., low parental investment), and interpersonal (i.e., racial discrimination)--on the life history strategies (LHS) and associated cognitions of African American adolescents were examined over an 11-year period (5 waves, from age 10.5 to 21.5). Analyses indicated that each one of the sources of stress was associated with faster LHS cognitions (e.g., tolerance of deviance, willingness to engage in risky sex), which, in turn, predicted faster LHS behaviors (e.g., frequent sexual behavior). LHS, then, negatively predicted outcome (resilience) at age 21.5 (i.e., faster LHS -> less resilience). In addition, presence of the risk ("sensitivity") alleles of 2 monoamine-regulating genes, the serotonin transporter gene (5HTTLPR) and the dopamine D4 receptor gene (DRD4), moderated the impact of perceived racial discrimination on LHS cognitions: Participants with more risk alleles (higher "sensitivity") reported faster LHS cognitions at age 18 and less resilience at age 21 if they had experienced higher amounts of discrimination and slower LHS and more resilience if they had experienced smaller amounts of discrimination. Implications for LHS theories are discussed. PMID- 22251001 TI - Hydrolysis of isoflavone glycosides by a thermostable beta-glucosidase from Pyrococcus furiosus. AB - The recombinant beta-glucosidase from the hyperthermophilic archaeon Pyrococcus furiosus was purified with a specific activity of 330 U/mg for genistin by His trap chromatography. The specific activity of the purified enzyme followed the order genistin > daidzin > glycitin> malonyl glycitin > malonyl daidzin > malonyl genistin. The hydrolytic activity for genistin was highest at pH 6.0 and 95 degrees C with a half-life of 59 h, a K(m) of 0.5 mM, and a k(cat) of 6050 1/s. The enzyme completely hydrolyzed 1.0 mM genistin, daidzin, and glycitin within 100, 140, and 180 min, respectively. The soybean flour extract at 7.5% (w/v) contained 1.0 mM genistin, 0.9 mM daidzin, and 0.3 mM glycitin. Genistin, daidzin, and glycitin in the soybean flour extract were completely hydrolyzed after 60, 75, and 120 min, respectively. Of the reported beta-glucosidases, P. furiosusbeta-glucosidase exhibited the highest thermostability, k(cat), k(cat)/K(m), yield, and productivity for hydrolyzing genistin. These results suggest that this enzyme may be useful for the industrial hydrolysis of isoflavone glycosides. PMID- 22251002 TI - Giant coupling effect between metal nanoparticle chain and optical waveguide. AB - We demonstrate that the optical energy carried by a TE dielectric waveguide mode can be totally transferred into a transverse plasmon mode of a coupled metal nanoparticle chain. Experiments are performed at 1.5 MUm. Mode coupling occurs through the evanescent field of the dielectric waveguide mode. Giant coupling effects are evidenced from record coupling lengths as short as ~560 nm. This result opens the way to nanometer scale devices based on localized plasmons in photonic integrated circuits. PMID- 22251003 TI - The effects of interference on recognition of haptic pictures in blindfolded sighted participants: the modality of representation of haptic information. AB - Haptic picture recognition was tested in 36 undergraduate students to determine whether haptic representations are visual or multi-modal. Participants explored target haptic pictures and were asked to recognize the target from three alternatives. Each participant completed eight control and eight interference trials in visual, lexical and tactile recognition modalities. For interference, participants were assigned to either an articulatory suppression (repeat "the" at a constant rate) or a visual interference (watch a visual display) condition, to prevent recoding into a verbal or visual code. The results showed that accuracy was higher at control compared to interference trials and for tactile compared to lexical recognition. Additionally, lexical and tactile recognition decreased with articulatory suppression whereas only tactile recognition decreased with visual interference. These findings suggest that haptic pictures may be represented by coordinating visual and verbal codes. PMID- 22251004 TI - In this issue: targeting Human Papilloma Virus-associated disease, from cervical to head and neck carcinoma...and more. AB - This issue of the International Reviews of Immunology hosts a diverse range of topics, ranging from cancer immunotherapy, to severe combined immunodeficiency syndromes in man and alternative treatments for autoimmunity. The emphasis of the issue is on cervical and head and neck carcinoma, significantly related to Human Papilloma Viruses. While the development of anti-HPV prophylactic vaccines represents one of the most remarkable triumphs of modern medicine, there is much more to be done in terms of advancing safe and effective treatments for cervical and head-and-neck cancers. We also host a review on congenital severe combined immunodeficiencies, a field that allowed unprecedented insight into the connection between the immune system, microbes, autoimmunity and cancer. Last but not least, we host a review dedicated to critically analyzing alternative treatments for Inflammatory Bowel Disease, as adjuncts to conventional therapies, based on solid scientific evidence and complementary mechanism of action. PMID- 22251005 TI - Perspective for prophylaxis and treatment of cervical cancer: an immunological approach. AB - As the second most common cause of cancer-related death in women, human papilloma virus (HPV) vaccines have been a major step in decreasing the morbidity and mortality associated with cervical cancer. An estimated 490,000 women are diagnosed with cervical cancer each year. Increasing knowledge of the HPV role in the etiology of cervical cancer has led to the development and introduction of HPV-based vaccines for active immunotherapy of cervical cancer. Immunotherapies directed at preventing HPV-persistent infections. These vaccines are already accessible for prophylaxis and in the near future, they will be available for the treatment of preexisting HPV-related neoplastic lesions. PMID- 22251006 TI - Immunological treatment options for locoregionally advanced head and neck squamous cell carcinoma. AB - Patients with squamous cell carcinoma of the head and neck (HNSCC) are usually treated by a multimodal approach with surgery and/or radiochemotherapy as the mainstay of local-regional treatment in cases with advanced disease. Both chemotherapy and radiation therapy have the disadvantage of causing severe side effects, while the clinical outcome of patients diagnosed with HNSCC has remained essentially unchanged over the last decade. The potential of immunotherapy is still largely unexplored. Here the authors review the current status of the art and discuss the future challenges in HNSCC treatment and prevention. PMID- 22251007 TI - Severe combined immunodeficiences: new and old scenarios. AB - Severe combined immunodeficiencies (SCIDs) represent a group of distinct congenital disorders affecting either cell-mediated or humoral immunity, which lead invariably to severe and life-threatening infections. The different forms of SCID are currently classified according to the presence or absence of T, B, and NK cells. This greatly helps define the site of the blockage during the differentiation process. Even though SCID patients share common clinical features, such as opportunistic infections and failure to thrive, irrespective of the underlying pathogenetic mechanism, the discovery of new causative gene alterations led to identify novel complex clinical phenotypes, sometimes associated to extrahematopoietic manifestations. In a few cases, the presenting signs may be peculiar to that specific form and physicians should be alerted in recognizing such complex phenotypes, in order to avoid delay in the diagnostic procedures. The aim of this review is to alert care-givers to take into account also the less frequent clinical features and novel pathogenic mechanisms to direct the functional and molecular studies toward a certain genetic alteration. PMID- 22251010 TI - Effects of short and long-term indapamide treatments on urinary calcium excretion in patients with calcium oxalate dihydrate urinary stone disease: a pilot study. AB - OBJECTIVE: The aim of this study was to determine the relative calcium-reducing effects of indapamide at 6 and 18 months using a dose of 1.5 mg/day. MATERIAL AND METHODS: Twenty-two patients with idiopathic hypercalciuria and calcium oxalate dihydrate urinary stone disease (minimum one stone episode) were selected. Each patient began a therapy regime of 1.5 mg indapamide sustained release taken once a day in the evening. Under basal conditions and after 6 and 18 months of treatment, subjects submitted urine and blood samples for analysis. The primary aim of this study was to assess the effects on excretion and concentration of calcium in urine. RESULTS: For 2 h urine, there was a mean decrease in urinary calcium concentration of 47%, whereas urinary calcium concentrations decreased by 53% in 24 h urine (p < 0.05) at 6 months of treatment. Blood urate levels rose by 19% (p < 0.05). Treatment for 18 months resulted in significant reduction in urinary calcium levels, by approximately 48% (p < 0.05) in both 2 h and 24 h urine. A 21% increase in urate levels in the blood was observed (p < 0.05). The remaining parameters remained unaltered. CONCLUSIONS: Owing to the low effective dosage of indapamide (1.5 mg/day) and the lack of any severe side-effects, this drug would appear to be a good candidate for use in the control of hypercalciuria. As such, it could prove efficacious in the prevention of recurrent kidney stones that are often associated with this condition. PMID- 22251008 TI - Alternative medicines as emerging therapies for inflammatory bowel diseases. AB - Inflammatory bowel disease (IBD) can be divided into two major categories, ulcerative colitis (UC) and Crohn disease (CD). While the main cause(s) of IBD remain unknown, a number of interventional and preventive strategies have been proposed for use against CD and UC. Many reports have focused on the use of alternative natural medicines as potential therapeutic interventions in IBD patients with minimal side effects. While the use of alternative medicines may be effective in IBD patients that are refractory to corticosteroids or thiopurins, alternative treatment strategies are limited and require extensive clinical testing before being optimized for use in patients. PMID- 22251009 TI - Primary drug resistance in South Africa: data from 10 years of surveys. AB - HIV-1 transmitted drug resistance (TDR) could reverse the gains of antiretroviral rollout. To ensure that current first-line therapies remain effective, TDR levels in recently infected treatment-naive patients need to be monitored. A literature review and data mining exercise was carried out to determine the temporal trends in TDR in South Africa. In addition, 72 sequences from seroconvertors identified from Africa Centre's 2010 HIV surveillance round were also examined for TDR. Publicly available data on TDR were retrieved from GenBank, curated in RegaDB, and analyzed using the Calibrated Population Resistance Program. There was no evidence of TDR from the 2010 rural KwaZulu Natal samples. Ten datasets with a total of 1618 sequences collected between 2000 and 2010 were pooled to provide a temporal analysis of TDR. The year with the highest TDR rate was 2002 [6.67%, 95% confidence interval (CI): 3.09-13.79%; n=6/90]. After 2002, TDR levels returned to <5% (WHO low-level threshold) and showed no statistically significant increase in the interval between 2002 and 2010. The most common mutations were associated with NNRTI resistance, K103N, followed by Y181C and Y188C/L. Five sequences had multiple resistance mutations associated with NNRTI resistance. There is no evidence of TDR in rural KwaZulu-Natal. TDR levels in South Africa have remained low following a downward trend since 2003. Continuous vigilance in monitoring of TDR is needed as more patients are initiated and maintained onto antiretroviral therapy. PMID- 22251011 TI - The clinical impact of single inhaler therapy in asthma. AB - BACKGROUND: Low-dose budesonide/formoterol combination used in the SMART fashion with symptom-reactive supplemental dosing has been reported to reduce asthma exacerbations as compared to the use of budesonide alone or to lower doses of budesonide/formoterol without supplemental dosing. OBJECTIVE: We undertook to review the non-exacerbation outcomes of SMART therapy and to assess the patient education implications of this treatment strategy. MATERIALS & METHODS: Systematic review. RESULTS: Patients treated with this strategy appear to be under-treated in that the majority fail to achieve guideline-defined control standards. The SMART strategy has not been tested against equivalent or higher doses of budesonide/formoterol given in symptom-prevention fashion. Existing educational strategies that focus on recognition of poor disease control may not be applicable with SMART therapy and the use of action plans has not been clarified with this symptom-reactive strategy. There is some evidence from that the current clinical use of SMART therapy may be contaminated frequently by the concurrent prescription of short-acting bronchodilators. There is no information on long-term outcomes with a symptom-reactive ICS/LABA strategy but the use of the strategy for one year has been associated with rising sputum and airway biopsy eosinophil counts. CONCLUSION: Despite fewer severe exacerbations with SMART therapy as compared to ICS monotherapy or lower dose ICS/LABA therapy, the strategy produces poor day-to-day control of symptoms and is associated with increasing inflammation. CLINICAL RELEVANCE: The symptom-reactive strategy described as SMART therapy is associated with poor symptom control of asthma. PMID- 22251012 TI - [3,3]-Sigmatropic shifts and retro-ene rearrangements in cyanates, isocyanates, thiocyanates, and isothiocyanates of the form RX-YCN and RX-NCY. AB - Retro-ene type [2pi + 2pi + 2sigma] and [3,3]-sigmatropic shift reactions involving the substituent groups R in heteroatom-substituted cyanates and thiocyanates RX-YCN and the isomeric isocyanates and isothiocyanates of the type RX-NCY (X = CR(2), NR', O, or S; Y = O or S) have been investigated computationally at the B3LYP/6-311++G(d,p) level. Retro-ene reactions of alkyl derivatives of the title compounds afford alkenes, imines, carbonyl and thiocarbonyl compounds together with HNCO (HNCS) or HOCN (HSCN). [3,3] Sigmatropic shifts (hetero-Cope rearrangements) of the corresponding allyl, propargyl, benzyl, and aryl derivatives causes allylic rearrangements, propargyl allenyl rearrangement, conversion of benzyl cyanates to o-isocyanatotoluenes, and conversion of N-cyanatoarylamines to o-isocyanatoanilines, etc. The corresponding rearrangements of allyl thiocyanates, arylamino thiocyanates and isothiocyanates, and arylsulfenyl thiocyanates and isothiocyanates are also described. PMID- 22251013 TI - The role of surface implant treatments on the biological behavior of SaOS-2 osteoblast-like cells. An in vitro comparative study. AB - OBJECTIVES: The aim of this study was an in vitro comparison of osteoblast adhesion, proliferation and differentiation related to six dental implants with different surface characteristics, and to determine if the interaction between cells and implant is influenced by surface structure and chemical composition. MATERIAL AND METHODS: Six types of implants were tested, presenting four different surface treatments: turned, sandblasted, acid-etched, anodized. The implant macro- and microstructure were analyzed using SEM, and the surface chemical composition was investigated using energy-dispersive X-ray analysis. SaOS-2 osteoblasts were used for the evaluation of cell adhesion and proliferation by SEM, and cell viability in contact with the various surfaces was determined using cytotoxicity MTT assays. Alkaline phosphatase (ALP) enzymatic activity in contact with the six surfaces was evaluated. Data relative to MTT assay and ALP activity were statistically analyzed using Kruskal-Wallis not parametric test and Nemenyi-Damico-Wolfe-Dunn post hoc test. RESULTS: All the implants tested supported cell adhesion, proliferation and differentiation, revealing neither organic contaminants nor cytotoxicity effects. The industrial treatments investigated changed the implant surface microscopic aspect and SaOS-2 cell morphology appeared to be influenced by the type of surface treatment at 6, 24, and 72 h of growth. SaOS-2 cells spread more rapidly on sandblasted surfaces. Turned surfaces showed the lowest cell proliferation at SEM observation. Sandblasted surfaces showed the greatest ALP activity values per cell, followed by turned surfaces (P < 0.05). CONCLUSIONS: On the base of this in vitro investigation, differently surfaced implants affected osteoblast morphology, adhesion, proliferation, and differentiation. Sandblasted surfaces promoted the most suitable osteoblast behavior. PMID- 22251014 TI - The highly leukotoxic JP2 clone of Aggregatibacter actinomycetemcomitans in localized and generalized forms of aggressive periodontitis. AB - OBJECTIVE: To investigate the presence of A. actinomycetemcomitans, including the highly virulent JP2 clone, in young adult patients with aggressive periodontitis, and associate the findings with the two forms of the disease. MATERIALS AND METHODS: Seventy Moroccan subjects with aggressive periodontitis, aged less than 35 years, were recruited. Among these, 41 had LAgP and 29 had GAgP. Plaque samples were collected from periodontal pockets and examined using a PCR that detects the presence of A. actinomycetemcomitans and which differentiates between JP2 and non-JP2 genotypes of the bacterium. RESULTS: total of 58 (83%) from the 70 AgP patients were positive for A. actinomycetemcomitans, among whom 77% were positives for the JP2 clone. The JP2 clone was detected in 34 (83%) of the LAgP patients compared to 20 (69%) of the GAgP patients (p = 0.17). Fourteen (20%) of the patients harbored non-JP2 genotypes of A. actinomycetemcomitans, although most of these patients (10/14) also harbored the JP2 clone. CONCLUSIONS: The presence of the JP2 clone of A. actinomycetemcomitans is strongly associated with both LAgP and GAgP in young adults in Morocco. This implies that treatment of AgP in this population should include microbiological screening and aim at eradication of the bacterium when present. PMID- 22251016 TI - Aortic interruption presenting with recurrent ischemic strokes in an adult. AB - Presentation of an interrupted aortic arch (IAA) in adulthood is extremely rare. Nonhemorrhagic stroke has not been reported previously in any adult with IAA. We, herein, describe a formerly asymptomatic 52-year-old male presenting with recurrent vertebrobasilar circulation ischemic strokes resulting from accelerated atherosclerotic arteriopathy secondary to IAA associated upper body hypertension. Surgical correction of IAA led to treatment of hypertension and cessation of ischemic attacks together with regression of collateral arterial networks as shown by computer tomography angiography. PMID- 22251017 TI - Clevidipine : a state-of-the-art antihypertensive drug under the scope. AB - INTRODUCTION: Clevidipine butyrate is the first intravenous antihypertensive drug to be approved by the FDA over the last decade. This medication is approved for use in the USA, Australia and New Zealand, but is still pending for approval in Europe. It is a new agent that might change the current management for severe acute hypertension in the critical care, emergency and perioperative areas. AREAS COVERED: This systematic review summarizes the pharmacological and clinical characteristics of this third-generation dihydropyridine intravenous calcium channel blocker, and was done using the literature available from the first publication in 1999 up until now, including the pivotal trials that led to its approval. EXPERT OPINION: This agent is arterially selective, has an ultrashort half-life, with no CYP-mediated interactions with other medications and is easily titratable. These characteristics place it in a unique category compared with other commonly used antihypertensives. Clevidipine butyrate reaches target systolic blood pressure in more than 90% of patients, within 30 min. It has a low incidence of adverse reactions and is generally well tolerated. The main goal of this review is to provide healthcare providers with a comprehensive appraisal of this promising medication. PMID- 22251015 TI - Fasitibant chloride, a kinin B2 receptor antagonist, and dexamethasone interact to inhibit carrageenan-induced inflammatory arthritis in rats. AB - BACKGROUND AND PURPOSE: Bradykinin, through the kinin B2 receptor, is involved in inflammatory processes related to arthropathies. B2 receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated. EXPERIMENTAL APPROACH: Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1beta, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h. KEY RESULTS: The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg9-[Leu8]-bradykinin (B2 receptor, leukotriene, catecholamine and B1 receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg9-[Leu8]-bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg9-[Leu8]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment. CONCLUSIONS AND IMPLICATIONS: Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B2 receptor, or through the indirect effects mediated by release of eicosanoids and cytokines. PMID- 22251018 TI - Free-living and aggregate-associated Planctomycetes in the Black Sea. AB - We examined the distribution of uncultured Planctomycetes phylotypes along depth profiles spanning the redox gradient of the Black Sea suboxic zone to gain insight into their respective ecological niches. Planctomycetes phylogeny correlated with depth and chemical profiles, implying similar metabolisms within phylogenetic groups. A suboxic zone sample was split into > 30 and < 30 MUm fractions to examine putative aggregate-attached and free-living Planctomycetes. All identified Planctomycetes were present in the > 30 MUm fraction except for members of the Scalindua genus, which were apparently free-living. Sequences from Candidatus Scalindua, known to carry out the anammox process, formed two distinct clusters with nonoverlapping depth ranges. One cluster, only 97.1% similar to the named species, was present at high nitrite/nitrate and low ammonium concentrations in the upper suboxic zone. We propose this sequence type be named 'Candidatus Scalindua richardsii'. A second cluster, containing sequences more similar to 'Candidatus Scalindua sorokinii', was present at high ammonium and low nitrite conditions in the lower suboxic zone. Sequences obtained from the sulfidic zone (1000 m depth) yielded Planctomycetes from two uncharacterized Planctomycetacia clusters and three potentially new genera as well as sequences from the uncultured OP3 phylum. PMID- 22251019 TI - Evaluation of the quality of deep frying oils with Fourier transform near infrared and mid-infrared spectroscopy. AB - Deep frying oils are subjected to high temperature and prolonged heating that may lead to a series of quality and safety problems for fried foods. This study evaluated the quality of deep frying oils collected from a local college canteen (n = 132) with Fourier transform mid-infrared (FT-IR) and Fourier transform near infrared (FT-NIR) spectroscopy. Partial least squares (PLS) regression was used to correlate spectral data with free fatty acids (FFA) and peroxide (PO) values of frying oils. The coefficient of determination (R(2)), standard error of prediction (SEP), and the RPD (ratio of the standard deviation of data set to the SEP) were used as indicators for the predictability of the PLS models. The FT-IR and FT-NIR methods exhibited similar predictability for the FFA values (FT-IR: R(2) = 0.954, SEP = 0.14, RPD = 4.48; FT-NIR: R(2) = 0.948, SEP = 0.14, RPD = 4.38). Although the predictability of the FT-IR method for the PO values was not as satisfactory as that of the FT-NIR method (FT-IR: R(2) = 0.893, SEP = 6.17, RPD = 2.93; FT-NIR: R(2) = 0.953, SEP = 4.15, RPD = 4.36), both FT-IR and FT-NIR methods could be used as simple and rapid approaches to determining the quality of deep frying oils. PMID- 22251020 TI - Does comorbid depression predict subsequent adverse life events in youth with attention-deficit/hyperactivity disorders? AB - OBJECTIVES: Studies have primarily focused on adverse life events (ALEs) as potential causes rather than as outcomes of pediatric depression. The current study prospectively examines ALEs in a sample of youth with attention deficit/hyperactivity disorders (ADHD) to determine whether having a major depressive disorder (MDD) at baseline (T1) predicts counts of child-dependent or child-independent ALEs at a second assessment (T2) ~ 8 months later. METHODS: Subjects with ADHD 11-18 years old were drawn mostly from a tertiary mental health clinic and evaluated with semi-structured diagnostic interviews, and parent and teacher questionnaires of ADHD severity. Eighteen with and 61 without initial MDD at T1 were compared at T2 regarding counts of subsequent overall, child-dependent, and child-independent ALEs reported on life events questionnaires by the child or parent. RESULTS: The group initially with MDD had higher overall ALEs (p=0.01) and child-dependent ALEs (p <= 0.001) but not child independent ALEs (p=0.12) at T2 relative to the nondepressed group, although only 3 of 18 continued to meet full criteria for MDD. The group initially with MDD also had a higher baseline ADHD severity (p=0.04) and proportion of oppositional or conduct disorders (p=0.004). In multivariate analyses, the group initially having MDD had a higher adjusted mean at T2 of child-dependent ALEs (p=0.02), but not of overall ALEs (p=0.06), after controlling for other T1 variables, including ALEs of the same type, ADHD severity, externalizing disorders, and the interaction of externalizing disorders with MDD. CONCLUSIONS: These findings suggest that child-dependent ALEs are potentially an important outcome after youth with ADHD have an episode of MDD. Youth with ADHD who develop comorbid MDD should be closely monitored and offered interventions to address the potential burden of child-dependent ALEs lingering after a depressive episode. PMID- 22251021 TI - Treatment of culturally diverse children and adolescents with depression. AB - This article is written for the practitioners treating depression in ethnic minority youth. It will review the context in which services are delivered to these youth: Researchers have recognized persistent ethnic differences in terms of utilization of services and unmet need. Furthermore, when ethnic minority youth do receive pediatric mental health care, the services that they receive may differ from those given to White patients. The reasons for these discrepancies have been examined in numerous studies, and have included contextual variables (economics, availability, and accessibility of services), patient variables (differences in prevalence or manifestation of the disorder, cultural beliefs and attitudes, preferential use of alternative or informal services, health literacy, and adherence), and provider variables (referral bias and patient-provider communication). Information about the differences between White and minority youth in the pharmacodynamics and pharmacokinetics of the antidepressant response is still limited. There are significant challenges for developing evidence-based guidelines that inform practice with these youth, hinging on both the underrepresentation of ethnic minority groups in clinical trials, and the great variability in biological and cultural characteristics of individuals in ethnic minority categories. Awareness on the part of the practitioner of the cultural variables that influence help-seeking and ongoing utilization of mental health services may aid in the engagement, effective treatment, and retention of ethnic minority children and adolescents with depression. However, given the great heterogeneity that exists within any cultural grouping, clinicians will need to integrate information about cultural patterns with that obtained from the individual patient and family to inform optimal practices for each patient. This article is written to enhance awareness on the part of the practitioner as to the variables that influence psychiatric care for depression in culturally diverse youth. The mental health needs of minority youth are not well served: They are treated less frequently, and when they are treated, the services they receive are less frequently adequate. The reasons that have been proposed for the disparities in their care, particularly with regard to diagnosis and treatment for depression, will be reviewed. They include contextual factors (such as economics, insurance, and other variables affecting the availability of services) patient and family factors (such as prevalence, symptom presentation, and values and beliefs that influence whether patients are referred to and avail themselves of services), and provider factors (such as referral bias and patient-provider communication, which affect whether patients engage and stay in treatment). The implications for the practitioner treating ethnic minority youth with depression will be discussed. Culture, as used in this article, refers to the common values, beliefs, and social behaviors of individuals with a shared heritage. Some aspects of culture that are likely to influence service utilization include health beliefs, particularly regarding models of mental illness, and level of stigma toward mental health treatment, which are frequently shared by individuals in a cultural group. However, some caveats for the explanatory potential of "culture" should be kept in mind. Conventions for naming groups vary between investigators and over time (e.g., the restriction of the category "White" into "White NonHispanic," is quite recent). Although heterogeneity is assumed within a named cultural or racial group, the terms Hispanic, Asian, and African-American incorporate subgroups can be very different in linguistic, historical, and geographical ancestry (e.g., Stewart 2008 ), and each group incorporates individuals who may not share any components of their historical heritage. Even among those with historical ties, values, beliefs, and social behaviors can vary according to the extent to which they identify with the mainstream culture. Social class frequently creates a "culture" of its own, with individuals in the same social class across traditional cultural groupings sharing disparities in care, and many beliefs and values. Individuals are likely to belong to numerous "cultures," and may not share specific typical behaviors or beliefs with any of them. PMID- 22251023 TI - An open-label safety and pharmacokinetics study of duloxetine in pediatric patients with major depression. AB - OBJECTIVE: This preliminary, 32-week study assessed the safety, tolerability, and pharmacokinetics of duloxetine in pediatric patients (aged 7-17 years) with major depressive disorder. METHODS: Patients received flexible duloxetine doses of 20 120 mg once daily, with dose changes made based on clinical improvement and tolerability. Pharmacokinetic samples were collected across all duloxetine doses, and data were analyzed using population modeling. Primary outcome measures included treatment-emergent adverse events (TEAEs), vital signs, and Columbia Suicide Severity Rating Scale (C-SSRS). RESULTS: Of the 72 enrolled patients, 48 (66.7%) completed acute treatment (18 weeks) and 42 (58.3%) completed extended treatment. Most patients (55/72; 76%) required doses >= 60 mg once daily to optimize efficacy based on investigator judgment and Clinical Global Impressions Severity score. Body weight and age did not significantly affect duloxetine pharmacokinetic parameters. Typical duloxetine clearance in pediatric patients was ~ 42%-60% higher than that in adults. Four patients (5.6%) discontinued due to TEAEs. Many (36/72, 50%) patients experienced potentially clinically significant (PCS) elevations in blood pressure, with most cases (21/36, 58%) being transient. As assessed via C-SSRS, one nonfatal suicidal attempt occurred, two patients (2.8%) experienced worsening of suicidal ideation, and among the 19 patients reporting suicidal ideation at baseline, 17 (90%) reported improvement in suicidal ideation. CONCLUSION: Results suggested that pediatric patients generally tolerated duloxetine doses of 30 to 120 mg once daily, although transient PCS elevations in blood pressure were observed in many patients. Pharmacokinetic results suggested that adjustment of total daily dose based on body weight or age is not warranted for pediatric patients and different total daily doses may not be warranted for pediatric patients relative to adults. PMID- 22251022 TI - Out of the black box: treatment of resistant depression in adolescents and the antidepressant controversy. AB - OBJECTIVE: The purpose of this article is to describe the effects of the pediatric antidepressant controversy on the Treatment of Serotonin-Selective Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) trial. METHOD: Adolescents, ages 12-18 years, with SSRI resistant depression were randomized to one of four treatments for a 12 week trial: Switch to different SSRI, switch to an alternate antidepressant (venlafaxine), switch to an alternate SSRI plus cognitive behavior therapy (CBT), or switch to venlafaxine plus CBT. RESULTS: The health advisories and "black box" warnings regarding suicidality and antidepressants in adolescents occurred during the course of the TORDIA trial. Revisions to the protocol, multiple-consent form changes, and re-consenting of patients were necessary. Recruitment of participants was adversely affected. CONCLUSION: Despite a cascade of unforeseen events that delayed the completion of the study, the TORDIA trial resulted in clinically important information about treatment-resistant depression in adolescents. PMID- 22251024 TI - Adjunctive sleep medications and depression outcome in the treatment of serotonin selective reuptake inhibitor resistant depression in adolescents study. AB - OBJECTIVE: In the Treatment of Resistant Depression in Adolescents, study participants who received medication for sleep had a lower response rate. This report sought to clarify this finding. METHOD: Depressed adolescents who had not responded to a previous adequate serotonin-selective reuptake inhibitor (SSRI) trial were randomly assigned to another SSRI, venlafaxine, another SSRI+cognitive behavior therapy (CBT), or venlafaxine+CBT. Augmentation with sleep medication was permitted as clinically indicated. RESULTS: Youth who received trazodone were six times less likely to respond than those with no sleep medication (adjusted odds ratio [OR]=0.16, 95% confidence interval [CI]: 0.05-0.50, p=0.001) and were three times more likely to experience self-harm (OR=3.0, 95% CI: 1.1-7.9, p=0.03), even after adjusting for baseline differences associated with trazodone use. None (0/13) of those cotreated with trazodone and either paroxetine or fluoxetine responded. In contrast, those treated with other sleep medications had similar rates of response (60.0% vs. 50.4%, chi(2)=0.85, p=0.36) and of self-harm events (OR=0.5, 95% CI: 0.1-2.6, p=0.53) as those who received no sleep medication. CONCLUSIONS: These findings should be interpreted cautiously because these sleep agents were not assigned randomly, but at clinician discretion. Nevertheless, they suggest that the use of trazodone for the management of sleep difficulties in adolescent depression should be re-evaluated and that future research on the management of sleep disturbance in adolescent depression is needed. The very low response rate of participants cotreated with trazodone and either fluoxetine or paroxetine could be due to inhibition of CYP 2D6 by these antidepressants. PMID- 22251025 TI - Treatment of youth depression in primary care under usual practice conditions: observational findings from Youth Partners in Care. AB - OBJECTIVES: The effectiveness of treatments for youth depression in primary care, under usual practice conditions, is largely unstudied. This study aims at estimating the effect of "appropriate treatment," defined as treatment that approximates guideline standards, on clinical outcomes for depressed primary care youth patients by using observational analyses from a randomized trial. METHODS: Participants were 344 youths aged 13-21 enrolled in the Youth Partners in Care trial. Youths screening positive for depression from six primary care practices in five different health care organizations were randomly assigned to either (1) usual care enhanced by provider education on depression evaluation and management, or (2) a quality improvement (QI) intervention designed to improve access to antidepressant medications and/or cognitive behavior therapy for depression; usual practice conditions otherwise applied. Observational analysis was conducted on the effects of appropriate treatment (antidepressant medication use by algorithms or 6 or more psychotherapy visits) on severe depression (Center for Epidemiologic Studies-Depression score >= 24) at 6 months. Selection into treatment is accounted for by using instrumental variables analysis, with randomized QI intervention status as the instrument. RESULTS: At 6 months, youths receiving "appropriate treatment," compared with others, were significantly less likely to have severe depression (10.9% vs. 45.2%, p<0.0001). Similar findings were observed among youths with depressive disorders and sub-syndromal depressive symptoms, and among Latino and other youths. CONCLUSIONS: Among depressed primary care youths, care that approximates guideline standards but retains leniency substantially reduces the likelihood of severe depression at 6 months. Such findings apply to youths with or without depressive disorder, and among Latino youth. PMID- 22251026 TI - Trends in youth antidepressant dispensing and refill limits, 2000 through 2009. AB - BACKGROUND: Antidepressant (AD) dispensing for depression in youth declined in the years following the 2003-04 Food and Drug Administration actions regarding increased risk of suicidal behavior. OBJECTIVE: To extend observation of youth AD dispensing and associated characteristics through 2009 to determine if AD dispensing continues to decline, has stabilized, or has rebounded. DESIGN: Retrospective time series design. SAMPLE: Youth (n=57,782) ages 10 to 17 inclusive. RESULTS: Both new (incident) and refill AD dispensing continued to decline through 2009, with no sign of leveling off. However, among youth who started AD treatment the cumulative supply of AD medication remained consistent across the pre- and postperiods, suggesting that cumulative treatment episode duration has not been degraded--possibly as a function of greater days supply with each new refill in the postperiod. Prescribers dramatically curtailed preauthorized refills in the postwarning period. CONCLUSION: Declines in AD dispensing to depressed youth may not reflect less intensive treatment for those youth who persist beyond the initial dispense. Lower rates of preauthorized refills may have been an attempt by prescribers to encourage return visits to evaluate response and adverse consequences. PMID- 22251027 TI - Inhibition of protein kinase B activity induces cell cycle arrest and apoptosis during early G1 phase in CHO cells. AB - Inhibition of PKB (protein kinase B) activity using a highly selective PKB inhibitor resulted in inhibition of cell cycle progression only if cells were in early G1 phase at the time of addition of the inhibitor, as demonstrated by time lapse cinematography. Addition of the inhibitor during mitosis up to 2 h after mitosis resulted in arrest of the cells in early G1 phase, as deduced from the expression of cyclins D and A and incorporation of thymidine. After 24 h of cell cycle arrest, cells expressed the cleaved caspase-3, a central mediator of apoptosis. These results demonstrate that PKB activity in early G1 phase is required to prevent the induction of apoptosis. Using antibodies, it was demonstrated that active PKB translocates to the nucleus during early G1 phase, while an even distribution of PKB was observed through cytoplasm and nucleus during the end of G1 phase. PMID- 22251028 TI - Intelligent real-time therapy: harnessing the power of machine learning to optimise the delivery of momentary cognitive-behavioural interventions. AB - BACKGROUND: Experience sampling methodology (ESM) [Csikszentmihalyi, M. & Larson, R. (1987). Validity and reliability of the experience-sampling method. Journal of Nervous and Mental Disease, 175(9), 526-536] has been used to elucidate the cognitive-behavioural mechanisms underlying the development and maintenance of complex mental disorders as well as mechanisms involved in resilience from such states. We present an argument for the development of intelligent real-time therapy (iRTT). Machine learning and reinforcement learning specifically may be used to optimise the delivery of interventions by observing and altering the timing of real-time therapies based on ongoing ESM measures. AIMS: The aims of the present article are to outline the principles of iRTT and to consider how it would be applied to complex problems such as suicide prevention. METHODS: Relevant literature was identified through use of PychInfo. RESULTS: iRTT may provide an important and ecologically valid adjunct to traditional CBT, providing a means of balancing population-based data with individual data, thus addressing the "knowledge-practice gap" [Tarrier, N. (2010b). The cognitive and behavioral treatment of PTSD, what is known and what is known to be unknown: How not to fall into the practice gap. Clinical Psychology: Science and Practice, 17(2), 134-143] and facilitating the delivery of interventions in situ, thereby addressing the "therapy-real-world gap". CONCLUSIONS: iRTT may provide a platform for the development of individualised and multifaceted momentary intervention strategies that are ecologically valid and aimed at attenuating pathological pathways to complex mental health problems and amplifying pathways associated with resilience. PMID- 22251029 TI - Coinheritance of three novel FV gene mutations in a patient with a severe FV deficiency. PMID- 22251030 TI - Asymmetrical diruthenium complex bridged by a redox-active ligand. AB - The asymmetrical dinuclear complex [(acac)(2)Ru1(MU-abpy)Ru2(Cym)Cl]PF(6) ([2]PF(6)), with acac(-) = acetylacetonato = 2,4-pentanedionato, abpy = 2,2' azobis(pyridine), and Cym = p-cymene = 1-isopropyl-4-methylbenzene, has been obtained from the mononuclear precursors [Ru(acac)(2)(abpy)] and [Ru(Cym)Cl(2)](2). X-ray crystal structure analysis suggests the oxidation state formulation [(acac)(2)Ru1(III)(MU-abpy(*-))Ru2(II)(Cym)Cl](+) for 2(+), with antiferromagnetic coupling between one Ru(III) center and the radical-anion bridging ligand (abpy(*-)), based on the N-N distance of 1.352(3) A. As appropriate references, the newly synthesized mononuclear [(abpy)Ru(II)(Cym)Cl]PF(6) ([1]PF(6)) with an unreduced N?N double bond at d(NN) = 1.269(4) A and the symmetrical dinuclear [(acac)(2)Ru(2.5)(MU-abpy(* ))Ru(2.5)(acac)(2)] with d(NN) = 1.372(4) A (rac isomer) support the above assignment for 2(+) as an asymmetrical mixed-valent configuration bridged by a radical ligand. Reversible one-electron oxidation leads to a dication, 2(2+), with largely metal-centered spin (EPR: g(1) = 2.207, g(2) = 2.155, and g(3) = 1.929), and a weak intervalence charge-transfer absorption at 1700 nm, as observed by spectroelectrochemistry. These results support a description of 2(2+) as [(acac)(2)Ru1(III)(MU-abpy(0))Ru2(II)(Cym)Cl](2+). Density functional theory (DFT) calculations suggest that the first reduction of [2]PF(6) also involves the bridging ligand, leading to [(acac)(2)Ru1(III)(MU-abpy(2-))Ru2(II)(Cym)Cl] (2). Experimentally, the first reduction of 2(+) is not fully reversible, with evidence for the loss of chloride to form [(acac)(2)Ru1(MU-abpy)Ru2(Cym)](+) (2a(+); g(1) = 2.454, g(2) = 2.032, and g(3) = 1.947). Further reduction produces [(acac)(2)Ru1(II)(MU-abpy(2-))Ru2(II)(Cym)] (2a), which forms [(acac)(2)Ru1(II)(MU-abpy(2-))Ru2(I)(Cym)](-)/[(acac)(2)Ru(II)(MU-abpy(* ))Ru(0)(Cym)](-) (2a(-)) in yet another one-electron step (g(1) = 2.052, g(2) = 2.008, and g(3) = 1.936). The major electronic transitions for each redox state have been assigned by time-dependent DFT calculations. PMID- 22251031 TI - Efficacy of botulinum toxins on bruxism: an evidence-based review. AB - The objective of this study was to assess the efficacy of botulinum toxins on bruxism. Electronic databases (PubMed, Embase and Science Citation Index), websites (Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) and the literature database of SIGLE (System for Information on Grey Literature in Europe) were searched from January 1990 to April 2011 for randomised controlled trials or nonrandomised studies assessing the efficacy of botulinum toxins on bruxism. There was no language restriction. Through a predefined search strategy, we retrieved 28 studies from PubMed, 94 from Embase, 60 from the Science Citation Index, two ongoing clinical trials and two from the Cochrane Central Register of Controlled Trials. Of these, only four studies met our inclusion criteria and were finally included. Of the four included studies, two were randomised controlled trials and two were controlled before-and-after studies. These studies showed that botulinum toxin injections can reduce the frequency of bruxism events, decrease bruxism-induced pain levels and satisfy patients' self-assessment with regard to the effectiveness of botulinum toxins on bruxism. In comparison with oral splint, botulinum toxins are equally effective on bruxism. Furthermore, botulinum toxin injections at a dosage of <100 U are safe for otherwise healthy patients. Botulinum toxin injections are effective on bruxism and are safe to use. Therefore, they can be used clinically for otherwise healthy patients with bruxism. PMID- 22251032 TI - Anticariogenic effect of xylitol versus fluoride - a quantitative systematic review of clinical trials. AB - The objective of this study was to appraise the clinical evidence and its bias risk regarding the anticariogenic effect of xylitol in comparison with that of fluoride. Databases were searched for clinical trials up to 18 March 2011. Article inclusion criteria were as follows: caries-related primary outcomes were tested; xylitol was compared with topical fluoride in some form; two-arm (or more) clinical trial including test/control group(s); prospective study design. Article exclusion criteria were as follows: no computable data were reported; test and control groups were not followed up in the same way; chewing gum was the main form of clinical application in either group. Individual continuous datasets were extracted from accepted articles. Selection and performance/detection bias were assessed. Sensitivity analysis was used to investigate attrition bias risk. Egger's regression and funnel plot was used to investigate publication bias risk. Twelve articles were included. Of these, six were accepted and six excluded, and 21 continuous datasets were extracted. Owing to the high clinical heterogeneity, no meta-analysis was performed. The addition of xylitol to existing fluoride regimes may be beneficial in the prevention of caries. However, all identified trials were limited by potential risk of selection, performance/detection and attrition bias. The funnel plot and Egger's regression results (-2.80; 95% confidence interval -4.01, -1.58; P = 0.0001) indicated possible publication bias risk. External fluoride access may have confounded the measured anticariogenic effect of xylitol. The evidence found contains a high risk of bias and may be limited by confounder effects. Future high-quality randomised controlled trials are needed in order to provide conclusive evidence on this topic. PMID- 22251033 TI - Use of mobile telephone short message service as a reminder: the effect on patient attendance. AB - BACKGROUND: Nonattendance for hospital outpatient appointments is a major burden on healthcare systems and the estimated financial loss can be high. Various reasons for patients not attending have been reported, including the patient/carer forgetting the appointment and confusion over the date and time of the appointment. Various reminder systems have been trialled across a variety of clinical settings. More recently, short message service (SMS) text messaging has emerged as a viable approach for delivering reminders to outpatients at a relatively low cost. AIMS AND OBJECTIVES: To evaluate the effect of appointment reminders, sent as SMS text messages to patients' mobile telephones, on attendance at outpatient clinics at the ITS Centre for Dental Studies and Research (ITS-CDSR), Muradnagar, Ghaziabad, Uttar Pradesh, India. MATERIALS AND METHODS: The study was conducted at ITS-CDSR in the Departments of Prosthodontics, Endodontics, Orthodontics and Paedodontics. Patients attending these departments for a period of 4 months and those who had provided a contact mobile number were sent an SMS reminder. RESULTS: In this study, 206 subjects (male, 124; female, 82) participated, 96 (male, 57; female, 39) of whom were in the test group and 110 (male, 67; female, 43) of whom were in the control group. The rate of attendance on time was found to be significantly higher in the test group (79.2%) than in the control group (35.5%). CONCLUSION: The study results indicate that sending appointment reminders as text messages to patients is an effective strategy to reduce nonattendance rates. PMID- 22251034 TI - A survey on oral health status and treatment needs of life-imprisoned inmates in central jails of Karnataka, India. AB - BACKGROUND: The prison population is a unique and challenging one with many health problems, including poor oral health. In a developing country like India, oral health problems of the prisoners had received scant attention. OBJECTIVES: To assess the oral health status and treatment needs of life imprisoned inmates and to know the existing oral health care facilities available in central jails of Karnataka. MATERIALS AND METHODOLOGY DESIGN: Cross sectional survey PARTICIPANTS: A systematically selected sample of 800 life imprisoned inmates, were interviewed and examined using modified WHO oral health assessment proforma (1997). RESULTS: The prevalence of caries was 97.5% mean Decayed Missing Filled Teeth(DMFT) was 5.26; Majority of the study population had Community Periodontal Index(CPI) score of 2, whereas 21.6% had at least one sextant with a CPI score of 4. 41.1% prisoners were severely affected with loss of attachment. 8.8% inmates had dentures. Oral sub mucous fibrosis was observed among 9.9% of prisoners. 97.4% of the subjects needed oral hygiene instruction, 87.6% needed restoration, 62.1% extraction of teeth and 32.2% needed prosthesis. Bangalore and Mysore central jail had oral health care facilities on regular basis. CONCLUSION: This study emphasises the need for special attention from government and voluntary organisations to improve the oral health of inmates. PMID- 22251035 TI - Evaluation of mineral trioxide aggregate (MTA) versus calcium hydroxide cement (Dycal((r)) ) in the formation of a dentine bridge: a randomised controlled trial. AB - AIM: To assess the effectiveness of mineral trioxide aggregate (MTA) used as an indirect pulp-capping material in human molar and premolar teeth. METHODOLOGY: We conducted a clinical evaluation of 60 teeth, which underwent an indirect pulp capping procedure with either MTA or calcium hydroxide cement (Dycal((r)) ). Calcium hydroxide was compared with MTA and the thickness of the newly formed dentine was measured at regular time intervals. The follow-up was at 3 and 6 months, and dentine formation was monitored by radiological measurements on digitised images using Mesurim Pro((r)) software. RESULTS: At 3 months, the clinical success rates of MTA and calcium hydroxide were 93% and 73%, respectively (P = 0.02). At 6 months, the success rate was 89.6% with MTA, and remained steady at 73% with calcium hydroxide (P = 0.63). The mean initial residual dentine thickness was 0.23 mm, and increased by 0.121 mm with MTA and by 0.136 mm with calcium hydroxide at 3 months. At 6 months, there was an increase of 0.235 mm with MTA and of 0.221 mm with calcium hydroxide. CONCLUSIONS: A higher success rate was observed in the MTA group relative to the Dycal((r)) group after 3 months, which was statistically significant. After 6 months, no statistically significant difference was found in the dentine thickness between the two groups. Additional histological investigations are needed to support these findings. PMID- 22251036 TI - Frequency and distribution of root-filled teeth and apical periodontitis in an adult population of Barcelona, Spain. AB - AIM: To determine the prevalence of apical periodontitis (AP) and the frequency of root canal treatment in a sample of Spanish adults. DESIGN: A descriptive cross-sectional study. SETTING: Barcelona, Spain. PARTICIPANTS: A total of 397 adult subjects, 49% males and 51% females. METHODS: Digital panoramic radiographs were used. Periapical status was scored according to the periapical index. Results were analysed statistically using the chi-squared test and logistic regression. RESULTS: Radiographic signs of AP in one or more teeth were found in 135 patients (34%). The prevalence of AP was significantly higher in males (42.3%) than females (26.1%) [odds ratio (OR)=2.1; 95% confidence interval (95% CI)= 1.4-3.2; P= 0.0007]. At least one root-filled tooth (RFT) was found in 233 patients (59%). Twenty-six per cent of subjects with RFT had at least one RFT with AP. The prevalence of AP increased with age (P < 0.05). Patients with RFT showed a higher prevalence of AP (42%) relative to patients without RFT (23%) (OR = 2.4; 95% CI = 1.5-3.7; P = 0.00013). Adjusting for age, gender and teeth number, endodontic status remained significantly associated with periapical status (OR = 2.3; 95% CI = 1.4-3.6; P = 0.0005). CONCLUSIONS: Both the prevalence of AP and the frequency of root canal treatment are high among Spanish adults. AP affects more frequently RFT relative to untreated teeth. Patients with one or more RFT have a greater likelihood of having AP than patients without RFT. PMID- 22251037 TI - Paradigm shift in the effective treatment of caries in schoolchildren at risk. AB - BACKGROUND: Silver diamine fluoride (SDF) is an effective agent for the arrest of caries in children, is easy to apply and can be used outside the clinical environment. Interim restorative treatment (IRT) using glass ionomer cement has also been claimed to be a simple and effective method to arrest caries in deciduous teeth. OBJECTIVE: To examine whether, for underprivileged schoolchildren with cavities, treatment with 30% SDF gives better results than IRT for carries arrest. METHOD: This randomised controlled study compares the effect of IRT (FUJI IX) with 30% SDF in 91 children aged 5-6 years. RESULTS: After 1 year, treatment with SDF was more effective [relative risk (RR) = 66.9%] than IRT (RR = 38.6%) for the arrest of caries; this was statistically significant (P < 0.05). CONCLUSION: The SDF technique showed better results than IRT for the arrest of cavities in deciduous teeth, indicating that its use for underprivileged communities may justify a paradigm shift in paediatric dentistry. PMID- 22251038 TI - Occupational health problems of dentists in the United Arab Emirates. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of some occupationally related health problems among dentists in the United Arab Emirates (UAE). METHOD: A cross-sectional study using the one-stage complex sampling technique to evaluate the results of a self-reporting questionnaire distributed to 844 dentists working in three cities (Abu Dhabi, Dubai and Sharjah) in UAE. RESULTS: Seven hundred and thirty-three (87%) dentists, aged 22-70 years, responded. The most common occupational health problems were musculoskeletal pain [497 (68%)] and percutaneous injury [306 (42%)]. Around one-fifth [135 (18%)] of dentists had a history of contact dermatitis, mostly caused by latex gloves, 53% had eye problems and 5% had hearing problems. CONCLUSIONS: As exposure to potential infectious agents is of concern, continuing education in the avoidance of percutaneous injuries would be beneficial. Further studies are needed to identify the causes of musculoskeletal pain and the appropriate interventions to reduce its prevalence; similar measures are required to reduce exposure to agents which may produce contact dermatitis. The awareness of occupational health problems should be highlighted at all clinical and research symposia. PMID- 22251039 TI - Disseminated protothecosis diagnosed by evaluation of CSF in a dog. AB - A 5-year-old female spayed Shetland Sheepdog Mix dog was evaluated for a history of recent seizure activity, progressive hind limb ataxia, polyuria, and polydipsia and no history of gastrointestinal signs. Physical examination findings included conscious proprioceptive deficits, ataxia, and anterior uveitis along with a hypermature cataract in the right eye. Results of a CBC, serum biochemical profile, urinalysis, and computed tomography scan of the brain were unremarkable. Cerebrospinal fluid (CSF) analysis revealed marked eosinophilic pleocytosis and rare organisms consistent with Prototheca spp within neutrophils and macrophages. On postmortem histologic examination, mononuclear inflammation and numerous intralesional algal organisms, similar to those seen on the cytologic preparation of CSF, were found in the brain, eyes, kidneys, and heart. Abnormalities were not detected on gross and histologic examination of the gastrointestinal tract. Cultures of CSF and subdural/olfactory bulb, but not intestinal tract, yielded growth of Prototheca spp, and PCR analysis and DNA sequencing confirmed the organism as Prototheca zopfii genotype 2. We have reported a rare case of disseminated protothecosis that was diagnosed by evaluation of CSF in a dog presented with neurologic signs and no overt enteric disease. Protothecosis should be considered as a rare cause of seizures, even in the absence of obvious enteric signs, and should be included in the differential diagnosis of eosinophilic pleocytosis. PMID- 22251040 TI - 7-fluoroindole as an antivirulence compound against Pseudomonas aeruginosa. AB - The emergence of antibiotic resistance has necessitated new therapeutic approaches for combating persistent bacterial infection. An alternative approach is regulation of bacterial virulence instead of growth suppression, which can readily lead to drug resistance. The virulence of the opportunistic human pathogen Pseudomonas aeruginosa depends on a large number of extracellular factors and biofilm formation. Thirty-one natural and synthetic indole derivatives were screened. 7-fluoroindole (7FI) was identified as a compound that inhibits biofilm formation and blood hemolysis without inhibiting the growth of planktonic P. aeruginosa cells. Moreover, 7FI markedly reduced the production of quorum-sensing (QS)-regulated virulence factors 2-heptyl-3-hydroxy-4(1H) quinolone, pyocyanin, rhamnolipid, two siderophores, pyoverdine and pyochelin. 7FI clearly suppressed swarming motility, protease activity and the production of a polymeric matrix in P. aeruginosa. However, unlike natural indole compounds, synthetic 7FI did not increase antibiotic resistance. Therefore, 7FI is a potential candidate for use in an antivirulence approach against persistent P. aeruginosa infection. PMID- 22251041 TI - Genotoxic evaluation for the tricyclic antidepressant drug, amitriptyline. AB - Tryptizol((r)) [amitriptyline HCl (AT); El-Kahira Pharmacological and Chemical Co., Cairo, Egypt], a widely used antidepressant drug in Egypt, was evaluated for its genotoxicity. The evaluation was performed in somatic (bone marrow) and germ (spermatocytes) cells, as well as well as the sperm morphology (i.e., head and tail) and count of the resulting sperm. Three doses were tested (low, medium, and high); they were chosen according to the drug manufacturer. The low-dose group received orally 1 mg/kg body weight (b.w.) daily for a total period of 1 month; the medium-dose group received 1 mg/kg b.w. daily for 15 days and 2 mg/kg b.w. daily for another 15 days; and the high-dose group received 1 mg/kg b.w. daily for 10 days, then 2 mg/kg b.w. daily for another 10 days and, finally, 4 mg/kg b.w. daily for 10 more days. The results showed that AT treatment induced structural and numerical chromosome abnormalities in somatic cells (bone marrow) and germ cells (spermatocytes). Moreover, AT significantly reduced both the mitotic index and meiotic activity after the different treatments used. AT was found to increase significantly the incidence of sperm-cell head and tail abnormalities. The sperm-cell count was also significantly decreased with the 3 doses tested. In general, results of chromosome abnormalities in both somatic and germ cells as well as sperm morphology and count showed that the effect of AT was dose dependent. The results of the current study showed that AT is a genotoxic agent for both somatic and germ cells and should be taken under special precautions and medical supervision. PMID- 22251042 TI - Postural epigastric pain: a challenging symptom for cytomegalovirus (CMV) gastritis. AB - Abstract Postural epigastric pain is an uncommon symptom and is hardly acquired unless specifically asked to the patient. Here we present a cytomegalovirus (CMV) gastritis case in a renal transplant patient with postural epigastric pain. A 36 year-old male was admitted to our clinic on the 50th day of renal transplantation with postural epigastric pain. All investigations were unremarkable except biopsy proven CMV gastritis and increased CMV viral load. The patient was free of symptom after ganciclovir treatment. Postural epigastric pain has not been described together with a clinical entity. Although not proved yet, it can be regarded as a unique symptom of CMV gastritis. Renal transplant patients presenting with postural epigastric pain which is not relieved with acid suppression should raise suspicion of CMV gastritis and this has to be confirmed by endoscopy and biopsy. PMID- 22251043 TI - Reliving emotional personal memories: affective biases linked to personality and sex-related differences. AB - Although available evidence suggests that the emotional valence and recollective properties of autobiographical memories (AMs) may be influenced by personality- and sex-related differences, overall these relationships remain poorly understood. The present study investigated these issues by comparing the effect of general personality traits (extraversion and neuroticism) and specific traits linked to emotion regulation (ER) strategies (reappraisal and suppression) on the retrieval of emotional AMs and on the associated postretrieval emotional states, in men and women. First, extraversion predicted recollection of positive AMs in both men and women, whereas neuroticism predicted the proportion of negative AMs in men and the frequency of rehearsing negative AMs in women. Second, reappraisal predicted positive AMs in men, and suppression predicted negative AMs in women. Third, while reliving of positive memories had an overall indirect effect on postretrieval positive mood through extraversion, reliving of negative AMs had a direct effect on postretrieval negative mood, which was linked to inefficient engagement of suppression in women. Our findings suggest that personality traits associated with positive affect predict recollection of positive AMs and maintenance of a positive mood, whereas personality traits associated with negative affect, along with differential engagement of habitual ER strategies in men and women, predict sex-related differences in the recollection and experiencing of negative AMs. These findings provide insight into the factors that influence affective biases in reliving AMs, and into their possible link to sex-related differences in the susceptibility to affective disorders. PMID- 22251044 TI - Executive control attenuates emotional effects-For high reappraisers only? AB - Irrelevant emotional information influences adaptive behavior. Previous results demonstrated that executive control may help reduce such influence. The current research studied the relationship between the tendency to use emotion regulation strategies (e.g., reappraisal and suppression) and the ability of executive control to reduce emotional interference. Our results demonstrate that negative stimuli disrupt performance in congruent flanker trials, regardless of individual tendencies to use reappraisal or suppression. In contrast, negative stimuli did not disrupt performance in incongruent trials in people who report frequent use of reappraisal. This pattern appeared both when a negative stimulus appeared before and after the flanker target and was not modulated by suppression level. We suggest that people who tend to use reappraisal have improved ability of executive control to reduce emotional effects. PMID- 22251045 TI - FACSGen 2.0 animation software: generating three-dimensional FACS-valid facial expressions for emotion research. AB - In this article, we present FACSGen 2.0, new animation software for creating static and dynamic three-dimensional facial expressions on the basis of the Facial Action Coding System (FACS). FACSGen permits total control over the action units (AUs), which can be animated at all levels of intensity and applied alone or in combination to an infinite number of faces. In two studies, we tested the validity of the software for the AU appearance defined in the FACS manual and the conveyed emotionality of FACSGen expressions. In Experiment 1, four FACS certified coders evaluated the complete set of 35 single AUs and 54 AU combinations for AU presence or absence, appearance quality, intensity, and asymmetry. In Experiment 2, lay participants performed a recognition task on emotional expressions created with FACSGen software and rated the similarity of expressions displayed by human and FACSGen faces. Results showed good to excellent classification levels for all AUs by the four FACS coders, suggesting that the AUs are valid exemplars of FACS specifications. Lay participants' recognition rates for nine emotions were high, and comparisons of human and FACSGen expressions were very similar. The findings demonstrate the effectiveness of the software in producing reliable and emotionally valid expressions, and suggest its application in numerous scientific areas, including perception, emotion, and clinical and neuroscience research. PMID- 22251046 TI - Bursting with anxiety: adult social referencing in an interpersonal balloon analogue risk task (BART). AB - This study developed an interpersonal modification of the balloon analogue risk task (BART) to assess effects of a friend's real-time facial expressions on coparticipants' risk-taking. Twenty pairs of male friends and 20 pairs of female friends completed two counterbalanced versions of BART, one framed in terms of monetary gain, and the other framed in terms of avoiding loss. Each pair included a player who performed the task across both trials and a reference person in a separate cubicle connected via a soundless video link. In the suppression condition, reference persons were told to minimize facial expressions of anxiety as balloons inflated. In the expression condition, they were told to freely express anxiety. As predicted, players took greater risks and burst more balloons in the suppression condition, but only under the gain frame. Players' BART scores across both frames were also significantly negatively correlated with reference persons' scores on a questionnaire measure of dispositional expressivity (BEQ), confirming that other people's expressions can moderate one's own risk-taking. PMID- 22251047 TI - Attachment dismissal predicts frontal slow-wave ERPs during rejection by unfamiliar peers. AB - Attachment representations are thought to provide a cognitive-affective template, guiding the way individuals interact with unfamiliar social partners. To examine the neural correlates of this process, we sampled event-related potentials (ERPs) during exclusion by unfamiliar peers to differentiate insecure-dismissing from securely attached youth, as indexed by the child attachment interview. Thirteen secure and 10 dismissing 11- to 15-year-olds were ostensibly connected with two peers via the Internet to play a computerized ball-toss game. Actually, peers were computer generated, first distributing the ball evenly, but eventually excluding participants. Afterward children rated their distress. As in previous studies, distress was related to a negative left frontal slow wave (500-900 ms) during rejection, a waveform implicated in negative appraisals and less approach motivation. Though attachment classifications were comparable in frontal ERPs and distress, an attachment-related dismissal dimension predicted a negative left frontal slow wave during rejection, suggesting that high dismissal potentially involves elevated anticipation of rejection. As expected, dismissal and self reported distress were uncorrelated. Yet, a new approach to quantifying the dissociation between self-reports and rejection-related ERPs revealed that dismissal predicted underreporting of distress relative to ERPs. Our findings imply that evaluations and regulatory strategies linked to attachment generalize to distressing social contexts in early adolescence. PMID- 22251048 TI - Age-related decrease in recognition of emotional facial and prosodic expressions. AB - The recognition of nonverbal emotional signals and the integration of multimodal emotional information are essential for successful social communication among humans of any age. Whereas prior studies of age dependency in the recognition of emotion often focused on either the prosodic or the facial aspect of nonverbal signals, our purpose was to create a more naturalistic setting by presenting dynamic stimuli under three experimental conditions: auditory, visual, and audiovisual. Eighty-four healthy participants (women = 44, men = 40; age range 20 70 years) were tested for their abilities to recognize emotions either mono- or bimodally on the basis of emotional (happy, alluring, angry, disgusted) and neutral nonverbal stimuli from voice and face. Additionally, we assessed visual and auditory acuity, working memory, verbal intelligence, and emotional intelligence to explore potential explanatory effects of these population parameters on the relationship between age and emotion recognition. Applying unbiased hit rates as performance measure, we analyzed data with linear regression analyses, t tests, and with mediation analyses. We found a linear, age related decrease in emotion recognition independent of stimulus modality and emotional category. In contrast, the improvement in recognition rates associated with audiovisual integration of bimodal stimuli seems to be maintained over the life span. The reduction in emotion recognition ability at an older age could not be sufficiently explained by age-related decreases in hearing, vision, working memory, and verbal intelligence. These findings suggest alterations in social perception at a level of complexity beyond basic perceptional and cognitive abilities. PMID- 22251049 TI - When trying is not enough: emotion regulation and the effort-success gap in bipolar disorder. AB - Bipolar disorder (BD) is presumed to involve difficulties in emotion regulation. Little is known, however, about the specific emotion regulation profile associated with this disorder. The present study examined the use of specific emotion regulation strategies among individuals with BD (n = 37) and healthy controls (n = 38). Participants' spontaneous use of reappraisal and suppression, as well as their associated effort and success at regulating their emotions, was measured in the context of three emotionally evocative films (neutral, happy, sad). Results indicated that the BD participants made greater use of spontaneous suppression and reappraisal across all films compared to the control group. BD participants also reported greater effort, but less success, when spontaneously regulating emotions. These findings suggest that bipolar disorder is associated with less success when regulating emotions despite a widespread engagement of regulatory efforts. Discussion focuses on the disjunction between troubled emotion functioning in bipolar disorder and sustained efforts to modify intense emotions. PMID- 22251050 TI - Priming the activation of fear and disgust: evidence for semantic processing. AB - Given that semantic processes mediate early processes in the elicitation of emotions, we expect that already activated emotion-specific information can influence the elicitation of an emotion. In Experiment 1, participants were exposed to masked International Affective Picture System (IAPS) pictures that elicited either disgust or fear. Following the presentation of the primes, other IAPS pictures were presented as targets that elicited either disgust or fear. The participants' task was to classify the target picture as either disgust or fear evoking. In Experiment 2, we substituted the IAPS primes with facial expressions of either disgust or fear. In Experiment 3, we substituted the IAPS primes with the words disgust or fear. In all three experiments, we found that prime-target combinations of the same emotion were responded to faster than prime-target combinations of different emotions. Our findings suggest that the influence of primes on the elicitation of emotion is mediated by activated schemata or appraisal processes. PMID- 22251051 TI - Implicit affective evaluation of visual symmetry. AB - Symmetry and beauty are strongly linked, but is the positive response to visual symmetry automatic? We used the Implicit Association Test (IAT) to measure the valence of visual regularities in the absence of overt judgments. In our first experiment, participants classified dot patterns as random or having an axis of reflection, and words as positive or negative. When the same button was used to report reflection and positive words, responses were faster than when the same button was used to report reflection and negative words. We take this association to indicate an implicit preference for reflectional patterns. In subsequent experiments, a reflected pattern was preferred to a rotation or translation, and a rotational pattern was preferred to random patterns. In some cases these results were not in agreement with verbally reported preferences, but implicit preferences were always predicted by the speed at which patterns could be identified. We conclude that the IAT can unearth an automatic affective response produced by perceptual fluency. PMID- 22251052 TI - Blinded by taboo words in L1 but not L2. AB - The present study compares the emotionality of English taboo words in native English speakers and native Chinese speakers who learned English as a second language. Neutral and taboo/sexual words were included in a Rapid Serial Visual Presentation (RSVP) task as to-be-ignored distracters in a short- and long-lag condition. Compared with neutral distracters, taboo/sexual distracters impaired the performance in the short-lag condition only. Of critical note, however, is that the performance of Chinese speakers was less impaired by taboo/sexual distracters. This supports the view that a first language is more emotional than a second language, even when words are processed quickly and automatically. PMID- 22251053 TI - Emotional intelligence: a theoretical framework for individual differences in affective forecasting. AB - Only recently have researchers begun to examine individual differences in affective forecasting. The present investigation was designed to make a theoretical contribution to this emerging literature by examining the role of emotional intelligence in affective forecasting. Emotional intelligence was hypothesized to be associated with affective forecasting accuracy, memory for emotional reactions, and subsequent improvement on an affective forecasting task involving emotionally evocative pictures. Results from two studies (N = 511) supported our hypotheses. Emotional intelligence was associated with accuracy in predicting, encoding, and consolidating emotional reactions. Furthermore, emotional intelligence was associated with greater improvement on a second affective forecasting task, with the relationship explained by basic memory processes. Implications for future research on basic and applied decision making are discussed. PMID- 22251055 TI - Distinct processing for pictures of animals and objects: evidence from eye movements. AB - Many studies have suggested that emotional stimuli orient and engage attention. There is also evidence that animate stimuli, such as those from humans and animals, cause attentional bias. However, categorical and emotional factors are usually mixed, and it is unclear to what extent human context influences attentional allocation. To address this issue, we tracked participants' eye movements while they viewed pictures with animals and inanimate images (i.e., category) as focal objects. These pictures had either negative or neutral emotional valence, and either human body parts or nonhuman parts were near the focal objects (i.e., context). The picture's valence, arousal, position, size, and most of the low-level visual features were matched across categories. The results showed that nonhuman animals were more likely to be attended to and to be attended to for longer times than inanimate objects. The same pattern held for the human contexts (vs. nonhuman contexts). The effects of emotional valence, category, and context interacted. Specifically, in images with a negative valence, focal animals and objects with human context had comparable numbers of gaze fixations and gaze duration. These results highlighted the attentional bias to animate parts of a picture and clarified that the effects of category, valence, and picture context interacted to influence attentional allocation. PMID- 22251054 TI - Affective state influences perception by affecting decision parameters underlying bias and sensitivity. AB - Studies of the effect of affect on perception often show consistent directional effects of a person's affective state on perception. Unpleasant emotions have been associated with a "locally focused" style of stimulus evaluation, and positive emotions with a "globally focused" style. Typically, however, studies of affect and perception have not been conducted under the conditions of perceptual uncertainty and behavioral risk inherent to perceptual judgments outside the laboratory. We investigated the influence of perceivers' experienced affect (valence and arousal) on the utility of social threat perception by combining signal detection theory and behavioral economics. We compared 3 perceptual decision environments that systematically differed with respect to factors that underlie uncertainty and risk: the base rate of threat, the costs of incorrect identification threat, and the perceptual similarity of threats and nonthreats. We found that no single affective state yielded the best performance on the threat perception task across the 3 environments. Unpleasant valence promoted calibration of response bias to base rate and costs, high arousal promoted calibration of perceptual sensitivity to perceptual similarity, and low arousal was associated with an optimal adjustment of bias to sensitivity. However, the strength of these associations was conditional upon the difficulty of attaining optimal bias and high sensitivity, such that the effect of the perceiver's affective state on perception differed with the cause and/or level of uncertainty and risk. PMID- 22251056 TI - Three cases of granulocyte colony-stimulating factor-producing urinary upper tract carcinomas. AB - This report presents three cases of urinary upper tract carcinomas producing granulocyte colony-stimulating factor (G-CSF), with high blood leukocyte counts and poor prognoses. Case 1 was a 73-year-old man who underwent nephroureterectomy for left renal pelvic carcinoma. Pathologically, urothelial carcinoma (UC), high grade, was observed, and immunohistochemical analysis showed positive staining for G-CSF. Progressive disease (PD) was observed despite administration of systemic chemotherapy for disease relapse, and the patient died 4.5 months after the operation. Case 2 was a 74-year-old man who had left renal pelvic carcinoma with para-aortic lymph-node metastases. The serum G-CSF was elevated (169 pg/ml). The patient refused any aggressive treatment, and died 2.3 months after his first visit to the hospital. Case 3 was a 75-year-old woman who had left renal pelvic carcinoma with adrenal metastasis. Biopsy confirmed the diagnosis as UC with squamous differentiation, and the serum G-CSF was elevated (138 pg/ml). Systemic chemotherapy was administered. However, the patient showed PD, and died 6.9 months after her first visit to the hospital. Effective treatment strategies are warranted for carcinomas producing G-CSF. Elucidation of the actions of G-CSF on both the carcinoma cells and the tumor microenvironment may contribute to the development of useful strategies. PMID- 22251057 TI - Mutation analysis of barley malt protein Z4 and protein Z7 on beer foam stability. AB - Beer foam stability is an important characteristic. It has been suggested that isoforms of protein Z, that is, protein Z4 and protein Z7, contribute to beer foam stability. We investigated the relationship between beer foam stability and protein Z4 and protein Z7 using their deficient mutants. As a protein Z4 deficient mutant, cv. Pirkka was used. Protein Z7 deficiency was screened in 1564 barley accessions in the world collection of Okayama University, Japan. The barley samples from normal, protein Z4-deficient, protein Z7-deficient, and double-deficient were genotyped in F(2) populations and then pooled based on the DNA marker genotypes of protein Z4 and protein Z7. For a brewing trial, F(5) pooled subpopulations were used. After malting and brewing, the foam stability was determined, and the results showed that the levels of foam stability in the four samples were comparable. Two-dimensional gel electrophoresis was used to investigate the proteome in these beer samples. The results showed that low molecular weight proteins, including lipid transfer protein (LTP2), in the deficient mutants were higher than those in the normal sample. Our results suggest that the contribution of protein Z4 and protein Z7 to beer foam stability was not greater than that of other beer proteins. PMID- 22251058 TI - Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival. AB - BACKGROUND AND PURPOSE: Sphingosine kinase 1 catalyses formation of the bioactive lipid, sphingosine 1-phosphate, which protects cancer cells from apoptosis. Therefore, sphingosine kinase 1 is a novel target for intervention with anti cancer agents. We have assessed the effect of the anti-cancer agent, resveratrol and its dimers (ampelopsin A and balanocarpol) on sphingosine kinase 1 activity and on survival of MCF-7 breast cancer cells. EXPERIMENTAL APPROACH: Ampelopsin A and balanocarpol were purified from Hopea dryobalanoides and their effect on sphingosine kinase 1 activity and expression, [(3)H] thymidine incorporation, ERK 1/2 phosphorylation and PARP activity assessed in MCF-7 cells. KEY RESULTS: Resveratrol, ampelopsin A and balanocarpol were novel inhibitors of sphingosine kinase 1 activity. Balanocarpol was a mixed inhibitor (with sphingosine) of sphingosine kinase 1 with a K(ic) = 90 +/- 10 uM and a K(iu) of ~500 uM. Balanocarpol and ampelopsin A also induced down-regulation of sphingosine kinase 1 expression and reduced DNA synthesis, while balanocarpol stimulated PARP cleavage in MCF-7 breast cancer cells. Resveratrol was a competitive inhibitor (with sphingosine) of sphingosine kinase 1 with a K(ic) = 160 +/- 40 uM, reduced sphingosine kinase 1 expression and induced PARP cleavage in MCF-7 cells. CONCLUSIONS AND IMPLICATIONS: Each molecule of balanocarpol may bind at least two sphingosine kinase 1 catalytic molecules to reduce the activity of each simultaneously. These findings suggest that resveratrol, ampelopsin A and balanocarpol could perturb sphingosine kinase 1-mediated signalling and this might explain their activity against MCF-7 breast cancer cells. PMID- 22251059 TI - Copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids using (trifluoromethyl)trimethylsilane. AB - Trifluoromethylated acetylenes and arenes are widely applicable in the synthesis of pharmaceuticals and agrochemicals. In 2010, our group has reported the copper mediated oxidative trifluomethylation of terminal alkynes and aryl boronic acids. This method allows a wide range of functional group tolerant trifluoromethylated acetylenes and arenes to be easily prepared. After the preliminary mechanistic studies of the oxidative trifluoromethylation of terminal alkyne, an efficient copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids has been developed. The catalytic protocol is successfully achieved by adding both the substrate and a portion of CF(3)TMS slowly using a syringe pump to the reaction mixture. PMID- 22251060 TI - Severe asthma: from characteristics to phenotypes to endotypes. AB - Asthma, and severe asthma, in particular, is increasingly recognized as a heterogeneous disease. While traditional views of asthma have centered around a childhood onset disease with an allergic component, several large scale network studies are now confirming that severe asthma can present in multiple different ways, only 30-50% of which meet traditional childhood onset allergic criteria. To understand the different groups better, initial studies have attempted to define phenotypes of severe asthma. A phenotype is defined as the integration of different characteristics that are the product of the interaction of the patient's genes with the environment. Both clinical and statistical approaches have identified at least 3-5 phenotypes of severe asthma. However, these phenotypes, in isolation, do not identify the immunopathology that makes these clinical phenotypes distinct or identifies a target population for a specific approach to therapy. As biological characteristics are identified, phenotypes should continue to evolve towards asthma endotypes. The identification of these endotypes, either by matching biology, genetics and therapeutic responses to therapy with clinically or statistically defined phenotypes or through unbiased genetic and genomic approaches, remains limited. Moving forward, this integration of genetics, biology and clinical characteristics should substantially enhance our ability to effectively treat complex heterogeneous diseases, such as severe asthma. PMID- 22251061 TI - Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump. AB - BACKGROUND: Delivery of powder formulations to the nose is an attractive alternative for many drugs and vaccines. This study compared the regional nasal deposition and clearance patterns of lactose powder delivered by the OptiNose powder device (Opt-Powder; OptiNose US Inc., Yardley, PA, USA) to that of liquid aerosol administered via a traditional hand-actuated liquid spray pump (Rexam SP270, Rexam Pharma, France). METHODS: The study was an open-label, crossover design in seven healthy subjects (five females, two males). The regional nasal deposition and clearance patterns of the Opt-Powder device were compared to a traditional liquid spray pump by dynamic gamma camera imaging after administration of either (99m)Tc-labeled lactose powder or liquid (99m)Tc- diethelyne triamine pentaacetic acid-aerosol. The gamma camera images were scaled and aligned with sagittal magnetic resonance images to identify nasal regions. Possible deposition of radiolabeled material in the lungs following both methods of delivery was also evaluated. RESULTS: Both powder and spray were distributed to all of the nasal regions. The Opt-Powder device, however, achieved significantly larger initial deposition in the upper and middle posterior regions of the nose than spray (upper posterior region; Opt-Powder 18.3% +/- 11.5 vs. Spray 2.4% +/- 1.8, p<0.02; sum of upper and middle posterior regions; Opt-Powder 53.5% +/- 18.5 vs. Spray 15.7% +/- 13.8, p<0.02). The summed initial deposition to the lower anterior and posterior regions for spray was three times higher compared to Opt-Powder (Opt-Powder 17.4% +/- 24.5 vs. Spray 59.4% +/- 18.2, p<0.04). OptiNose powder delivery resulted in more rapid overall nasal clearance. No lung deposition was observed. CONCLUSIONS: The initial deposition following powder delivery was significantly larger in the ciliated mucosa of the upper and posterior nasal regions, whereas less was deposited in the lower regions. Overall nasal clearance of powder was slower initially, but due to retention in anterior nonciliated regions the overall nasal clearance after spray was slower. PMID- 22251062 TI - Cross-contextual stability of bullying victimization: a person-oriented analysis of cyber and traditional bullying experiences among adolescents. AB - Using a person-oriented approach the study examined whether bullying victimization at school continued into cyberspace victimization in a large sample of high school students in Lithuania (N = 1667, 58% girls), age 15-19 (M = 17.29, SD = 0.95). Three forms of traditional bullying (verbal, physical and relational) and seven forms of cyberbullying victimization through cell phones and computers were included in the analysis. The findings revealed that 35% of traditional bullying victims were also bullied in cyberspace. In particular, adolescents who experienced predominantly verbal and relational bullying at school, showed a higher risk of victimization in cyberspace a year later, while this was not observed for predominantly physical forms of traditional bullying. The findings point to the importance of a cross-contextual perspective in studies on stability of bullying victimization. PMID- 22251063 TI - Accelerated bone formation on photo-induced hydrophilic titanium implants: an experimental study in the dog mandible. AB - OBJECTIVES: The purpose of this study was to investigate the effect of photo induced hydrophilic titanium dioxide (TiO2) on serum fibronectin (sFN) attachment, and further to evaluate initial osseointegration responses in the dog mandibles. MATERIALS AND METHODS: To apply the anatase TiO2 film, plasma source ion implantation (PSII) method followed by annealing was employed for the titanium disks and implants, which were then illuminated with UV-A for 24 h for the experimental groups. Non-deposited titanium disks and implants were prepared for the control group. Surface characterization was performed using the interferometer and contact angle analyzer. The attachments of sFN were evaluated using fluorescence emission analysis. Thereafter both groups of implants were placed in the mandible of six beagle dogs. Bone response was investigated with histological and histomorphometrical analyses after periods of 2 and 4 weeks. RESULTS: The experimental groups exhibited strong hydrophilicity under UV-A illumination and showed significant improvement in sFN attachment. And further, the experimental implants enhanced the bone formation with the bone-to-implant contact of 42.7% after 2 weeks of healing (control: 28.4%). CONCLUSIONS: The combined applications of plasma fibronectin and PSII to produce hydrophilic titanium surfaces could accelerate early osseointegration. PMID- 22251064 TI - Damping of acoustic vibrations of single gold nanoparticles optically trapped in water. AB - We combine ultrafast pump-probe spectroscopy with optical trapping to study homogeneous damping of the acoustic vibrations of single gold nanospheres (80 nm diameter) and nanorods (25 nm diameter by 60 nm length) in water. We find a significant particle-to-particle variation in damping times. Our results indicate that vibrational damping occurs not only by dissipation into the liquid, but also by damping mechanisms intrinsic to the particle. Our experiment opens the study of mechanisms of intrinsic mechanical dissipation in metals at frequencies 1-1000 GHz, a range that has been difficult to access thus far. PMID- 22251066 TI - Rifaximin for the treatment of irritable bowel syndrome. AB - INTRODUCTION: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS. AREAS COVERED: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed. EXPERT OPINION: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized. PMID- 22251065 TI - Phylodynamic and phylogeographic patterns of the HIV type 1 subtype F1 parenteral epidemic in Romania. AB - In the late 1980s an HIV-1 epidemic emerged in Romania that was dominated by subtype F1. The main route of infection is believed to be parenteral transmission in children. We sequenced partial pol coding regions of 70 subtype F1 samples from children and adolescents from the PENTA-EPPICC network of which 67 were from Romania. Phylogenetic reconstruction using the sequences and other publically available global subtype F sequences showed that 79% of Romanian F1 sequences formed a statistically robust monophyletic cluster. The monophyletic cluster was epidemiologically linked to parenteral transmission in children. Coalescent-based analysis dated the origins of the parenteral epidemic to 1983 [1981-1987; 95% HPD]. The analysis also shows that the epidemic's effective population size has remained fairly constant since the early 1990s suggesting limited onward spread of the virus within the population. Furthermore, phylogeographic analysis suggests that the root location of the parenteral epidemic was Bucharest. PMID- 22251067 TI - Allele-specific amplification of the complete HLA-C gene from genomic DNA - a novel Cw4 allele (C*04:71) with a Cw1 motif in the peptide-binding site. AB - To determine the complete sequence of a newly identified human leukocyte antigen (HLA)-C allele, we designed a method where the full genomic sequence of HLA-C*04 was amplified in isolation from the patient second HLA-C allele in a single polymerase chain reaction (PCR), using primers spanning its 5'- and 3' untranslated regions. The new allele, officially designated HLA-C*04:71, differs from HLA-C*04:01:01:01 by two single-nucleotide polymorphisms: one determines substitution of phenylalanine for serine 9 at the B pocket of the peptide-binding site; the second substitution is a new polymorphism in intron 5. Phe-9 is characteristic of Cw1 alleles and its presence in C*04:71 most likely affects its peptide-binding repertoire. The principle we have used for C*04:71 isolation could be adapted for unambiguous sequence-based HLA-C typing of selected samples in a clinical setting. PMID- 22251068 TI - Back-scattered and secondary electron images of scanning electron microscopy in dentistry: a new method for surface analysis. AB - OBJECTIVE: A scanning electron microscope (SEM) is a popular tool for investigating the root canal surface to visualize dentinal tubules, the smear layer and various root canal filling materials in endodontics. Most of the SEM micrographs taken in endodontic research are in secondary electrons (SE) mode, in which the topographic view of a subject can be demonstrated without giving any information about the real structure. Back-scattered electron (BSE) images are also used, which reveal some information about the internal structure while providing no topographic details. The aim of this study was to investigate the possibility of using back-scattered (BSE) and secondary electron (SE) mode of scanning electron microscopy (SEM) together for obtaining detailed information about biomaterials in relation to dental structures. MATERIALS AND METHODS: Mesiobuccal roots of four permanent maxillary molars were cleaned and shaped with rotary instruments. Two samples were obturated with gutta-percha and sealer. After 2 weeks, gutta-perch was removed using rotary instruments and chloroform. In the other phase of the study, white mineral trioxide aggregate was mixed and packed into five glass tubes and exposed to blood, deionized water, synthetic tissue fluid and egg white. All the samples were prepared for visualization under SE and BSE modes of SEM to observe the characteristics of material remnants and surface structures. RESULTS: BSE mode illustrated different grey scale views which made it possible to differentiate dentin chips from filling material remnants on the surface of root canal dentin. In addition, SE mode focused on image topography, while a BSE detector showed new texture formation on the surface of white mineral trioxide aggregate exposed to proteinaceous fluids such as blood or egg white. CONCLUSIONS: Mapping BSE and SE micrographs helped us to better understand the structure of materials on the surface of root canal dentin and MTA. Moreover, analysis of structure of materials on the surface of root canal dentine and MTA can be performed better by mapping of BSE and SE micrographs. PMID- 22251069 TI - Thermal inactivation of Escherichia coli O157:H7 inoculated at different depths of non-intact blade-tenderized beef steaks. AB - Studies evaluated thermal inactivation of Escherichia coli O157:H7 inoculated at different depths of simulated blade-tenderized non-intact steaks. Fresh beef slices (0.3 or 0.6 cm thick) were stacked on top of each other to form 2.4 or 1.2 cm thick steaks. Steaks were blade-tenderized and then inoculated with rifampicin resistant Escherichia coli O157:H7 (8 strain mixture; 4 log CFU/cm(2)) on the surface or between slices, vacuum-packaged, and stored at 4 or -20 degrees C for 5 d before cooking. Steaks were cooked by pan-broiling or roasting to a geometric center temperature of 60 degrees C. Frozen samples were either cooked from the frozen state or after thawing to approximately 4 or 25 degrees C. In steaks inoculated on the external surface and cooked by pan-broiling, pathogen survivors recovered from thinner (1.2 cm) steaks were greater (P < 0.05) than those recovered from thicker (2.4 cm) steaks. Cooking steaks from a frozen state or after thawing (4 or 25 degrees C) did not (P >= 0.05) affect extent of pathogen inactivation. Survivors after pan-broiling of 2.4 cm thick steaks increased (P < 0.05) from 0.3 to 1.3 log CFU/cm(2) for surface-inoculated steaks to 2.5 to 3.2 log CFU/cm(2) for samples inoculated at the center (1.2 cm depth). In comparison, overall thermal destruction of the pathogen in steaks cooked by roasting was less, and survivor counts were generally not different (P >= 0.05) at each depth of inoculation. These data should be useful in development of lethality guidelines to ensure safe consumption of non-intact meat products. PRACTICAL APPLICATION: Results of this study should be useful for developing cooking guidelines, for foodservice establishments and consumers, to ensure safe consumption of non-intact meat products. PMID- 22251070 TI - Identification of abnormal stem cells using Raman spectroscopy. AB - The clinical use of stem cells in cell-based therapeutics for degenerative diseases requires development of criteria for defining normal stem cells to ensure safe transplantation. Currently, identification of abnormal from normal stem cells is based on extensive ex vivo and in vivo testing. Raman microscopy is a label-free method for rapid and sensitive detection of changes in cells' bio molecular composition. Here, we report that by using Raman spectroscopy, we were able to map the distribution of different biomolecules within 2 types of stem cells: adult human bone marrow-derived stromal stem cells and human embryonic stem cells and to identify reproducible differences in Raman's spectral characteristics that distinguished genetically abnormal and transformed stem cells from their normal counterparts. Raman microscopy can be prospectively employed as a method for identifying abnormal stem cells in ex vivo cultures prior to clinical transplantation. PMID- 22251071 TI - Common genetic risk variants of TLR2 are not associated with periodontitis in large European case-control populations. AB - AIM: Involvement of TLR2 in the pathophysiology of periodontitis has widely been discussed, but hitherto, no validated genetic associations were reported. Previous association studies lacked sufficient statistical power and adequate haplotype information to draw unambiguous conclusions. The aim of this study was to comprehensively investigate TLR2 linkage disequilibrium (LD) regions for their potential associations with periodontitis in two large analysis populations of aggressive (AgP) and chronic periodontitis (CP) of North West European descent. MATERIALS AND METHODS: The study population comprised 598 AgP patients, 914 CP patients and 1804 healthy controls. Analysis of TLR2 LD regions was performed with haplotype tagging SNPs (tagSNPs) using SNPlex and TaqMan genotyping assays. Genotypic, dominant, multiplicative, and recessive genetic models were tested. The genotypes were adjusted for the covariates smoking, diabetes, and gender. Resequencing was performed by Sanger technology. RESULTS: Upon covariate adjustment and correction for multiple testing, no tagSNPs showed significant associations with AgP or CP. Targeted resequencing of exon 3 in 47 AgP cases identified carriership of two common and three rare variants. CONCLUSION: Common LD regions of TLR2 do not show genetic associations with periodontitis in the North West European population. Resequencing of exon 3 could not identify disease associated rare variants in TLR2. PMID- 22251072 TI - National prevalence of oral HPV infection and related risk factors in the U.S. adult population. AB - This article reviews the rapidly growing evidence that oral human papilloma viruses (HPV) infection contributes to the risk of oral squamous cell carcinoma. It also reports the first nationally representative estimates of oral HPV prevalence in the United States adult population. An estimated 7.3% (95% CI: 6.0, 8.9) of the U.S. population had one or more oral HPV types detected in oral rinse; 3.1% (95%CI: 2.4, 3.9) of the U.S. population had one or more oncogenic HPV types. A substantial excess risk of HPV infection in men is not explained by education, smoking, age of sexual debut, or number of lifetime sex partners. Based on the published finding from a case-control study, where there was an odds ratio of 2.6 (95% CI: 1.5, 4.2) for the association of head and neck cancer oncogenic oral HPV infection, the estimated population attributable risk for head and neck cancer in the U.S. population was 4.7%. In other words, there would be a 4.7% reduction in incidence rate of head and neck cancer in the United States if oncogenic HPV infection could be prevented. The results also provide population data that help evaluate the likely public health benefits of prophylactic vaccination against oral HPV acquisition. PMID- 22251073 TI - Vertebral artery ostial stenosis: prevalence by digital subtraction angiography, MR angiography, and CT angiography. AB - BACKGROUND AND PURPOSE: (1) To determine the prevalence of vertebral arterial ostial stenosis (VOS) as determined by the "gold standard" of digital subtraction angiography (DSA). (2) To learn the correlation between vertebral ostial stenosis and study indication. (3) To determine the ability of contrast-enhanced magnetic resonance angiography (CE MRA) and computed tomographic angiography (CTA) to reflect the true prevalence of vertebral ostial stenosis as determined by DSA. METHODS: Three hundred and twenty-nine patients who underwent DSA had recorded evaluation of 443 vertebral artery origins. Cases were categorized by patient age and study indication. Similar numbers of CTA and MRA studies were assessed. RESULTS: The prevalence of VOS in the study population was 5.4%. VOS was not observed in patients under 40 years of age, and was seen in 12.5% of patients over 70 years. CE MRA demonstrated decreased signal at the vertebral origins consistent with stenosis in 20% of patients. CTA estimated VOS at .8%, and yielded 7.3% of studies, which were nondiagnostic for VOS. CONCLUSION: The prevalence of VOS as determined by DSA is low and increases with patient age and correlates with factors such as anterior infarct (18.4%), posterior infarct (33.3%), carotid atherosclerosis (30.8%), and vertebrobasilar insufficiency (33%). Patients being evaluated for reasons less closely correlated with atherosclerotic disease, such as arteriovenous malformation (AVM) or hemorrhage showed a lower prevalence of VA stenosis (brain aneurysm or AVM 5/121, 4.1%, brain hemorrhage 5/153, 3.3%). Routine clinical MRA significantly overestimates VOS prevalence, and findings suggest that CTA underestimates the degree and prevalence of VOS. PMID- 22251074 TI - "Confronted with paperwork": information and documentation in peer support. AB - BACKGROUND: Peer support has a unique philosophy of practice, which is reflected in the way information is handled. AIMS: To describe the way peer supporters use documentation in their work and explore tensions this generates. METHODS: Qualitative study based on two individual or group interviews with each of 37 peer supporters and peer-support managers in Aotearoa New Zealand. RESULTS: Peer supporters challenged disciplinary uses of documentation by either keeping minimal information about their interactions with peers, or keeping notes in a collaborative, empowering and transparent manner. This generated tensions with regard to the wider mental health system, particularly in relation to an emerging national database of mental health service use. CONCLUSIONS: Funders and planners need to be aware of the reasons for some peer-support services' reluctance to participate in mental health information strategies. Peer-support documentation approaches might usefully be adopted across the mental health sector. PMID- 22251075 TI - Effect of season on heavy metal contents and chemical compositions of chub mackerel (Scomber japonicus) muscle. AB - Seasonal variations of heavy metals concentrations and overall chemical compositions were determined in chub mackerel caught in the Southern Sea of Korea. The average mercury and lead content varied between 0.04 and 0.08 mg/kg and between 0.01 and 0.02 mg/kg, respectively. Seasonal variations were not detected in lead, but mercury displayed maximal values in winter (P < 0.05). A distinct seasonal pattern was found in crude fat content with maximal values in December and minimal values in April. Fatty acid composition showed that monounsaturated fatty acids levels were the highest in August, while polyunsaturated fatty acids (PUFA) levels were the highest in April. The major contributing factors to the seasonal variation of PUFA amounted to 20:5n-3 and 22:6n-3. The total amino acids content varied from 180.6 to 187.7 mg/g. There were no significant seasonal variations in total amounts of amino acids. Practical Application: Mackerel (Scomber japonicus) is one of the most important fishing resources in Korea. The effects of polyunsaturated fatty acids (PUFA) on the human body have been identified, and consequently, the intake of fish lipids has steadily increased among the human population. There have been few studies on safety and alterations in chemical composition of mackerel attributed to seasonal fluctuations. Therefore, the results presented in this study could be used to improve the safety and nutrition information available to consumers. PMID- 22251076 TI - Quasi-periodic nanoripples in graphene grown by chemical vapor deposition and its impact on charge transport. AB - The technical breakthrough in synthesizing graphene by chemical vapor deposition methods (CVD) has opened up enormous opportunities for large-scale device applications. To improve the electrical properties of CVD graphene grown on copper (Cu-CVD graphene), recent efforts have focused on increasing the grain size of such polycrystalline graphene films to 100 MUm and larger. While an increase in grain size and, hence, a decrease of grain boundary density is expected to greatly enhance the device performance, here we show that the charge mobility and sheet resistance of Cu-CVD graphene is already limited within a single grain. We find that the current high-temperature growth and wet transfer methods of CVD graphene result in quasi-periodic nanoripple arrays (NRAs). Electron-flexural phonon scattering in such partially suspended graphene devices introduces anisotropic charge transport and sets limits to both the highest possible charge mobility and lowest possible sheet resistance values. Our findings provide guidance for further improving the CVD graphene growth and transfer process. PMID- 22251078 TI - Ru-OSO coordination photogenerated at 100 K in tetraammineaqua(sulfur dioxide)ruthenium(II) (+/-)-camphorsulfonate. AB - The photoinduced O-bound coordination mode in RuSO(2) complexes, previously observed only at 13 K, has been generated at 100 K in tetraammineaqua(sulfur dioxide)ruthenium(II) (+/-)-camphorsulfonate. This coordination state, often denoted MS1, decays to the eta(2)-bound MS2 state, with an estimated half-life of 3.4(8) h and a long-lived population of 2.9(4)% at 120 K. PMID- 22251077 TI - Recent advances in therapeutic cancer vaccines. PMID- 22251079 TI - Efficacy of tadalafil in chronic hypobaric hypoxia-induced pulmonary hypertension: possible mechanisms. AB - The present study was carried out to investigate the effects of long-acting phosphodiesterase five inhibitor, tadalafil, on pulmonary hypertension induced by chronic hypobaric hypoxia in rats. Adult Albino Wistar rats were exposed to 2 weeks of hypobaric hypoxia for 8 h daily and treated with tadalafil or tempol, a standard antioxidant agent. Right ventricular systolic pressure (RVSP) was taken as an index for pulmonary arterial pressure; malondialdehyde, reduced glutathione and superoxide dismutase were chosen as the markers of oxidative stress; serum tumour necrosis factor alpha (TNF-alpha) levels and inflammatory changes in lungs were assessed for inflammation. Chronic hypobaric hypoxia was found to induce pulmonary hypertension, as it significantly (P < 0.001) increased RVSP. Chronic hypobaric hypoxia also leads to an increase in oxidative stress as was evidenced by an increase in malondialdehyde levels (P < 0.001) and a significant decrease in (P < 0.001) reduced glutathione levels and superoxide dismutase activity. Chronic hypobaric hypoxia-induced inflammation was revealed by lung histology and increase in serum TNF-alpha levels. Tadalafil significantly prevented (P < 0.001) rise in hypobaric hypoxia-induced rise in RVSP. Tadalafil partially while tempol completely reversed hypobaric hypoxia-induced oxidative stress. Lung inflammation and serum TNF-alpha levels were significantly attenuated by both tadalafil and tempol. However, effect of tadalafil on inflammation was more marked than that of tempol. These data indicate that tadalafil possess antioxidant as well as antinflammatory action in addition to its vasodilatory property. All these three actions combined may have positive impact of tadalafil in the treatment of hypobaric hypoxia-induced pulmonary hypertension. PMID- 22251080 TI - Influence of formulation parameters on dissolution rate enhancement of glyburide using liquisolid technique. AB - The aim of this study was to investigate the use of liquisolid technique in improving the dissolution of glyburide in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with Propylene glycol, as liquid vehicle. Microcrystalline cellulose was used as a carrier material, silica as a coating material and croscaremellose as a disintegrant. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with direct compressed non-micronized and micronized tablets of glyburide using USP II, paddle apparatus at 50 rpm for 60 min using 900 ml of 0.05 M Phosphate Buffer, pH 7.5. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with propylene glycol were not affected by ageing significantly, as f2 value found between aged and fresh samples was 51.92. Differential scanning calorimetry revealed that the drug has got solubilized in the liquid vehicle. This was further supported by the powder X-ray diffraction studies of pure drug and the liquisolid powder system. It can be concluded that it is possible to load poorly soluble drug into liquisolid tablets by addition of PVP to the liquid vehicle. This is valuable for the preparation of liquisolid tablets of poorly soluble drugs. The liquisolid tablets prepared with PVP showed a remarkably improved dissolution rate in comparison with DC tablet and other formulations. PMID- 22251081 TI - Compositions and methods for treatment of Parkinson's disease: a patent evaluation of WO2011/102847A1. AB - BACKGROUND: The application (WO2011/102847A1) deals with methods useful for the treatment of Parkinson's disease (PD). OBJECTIVE: It aims at producing mature and functional midbrain dopaminergic (mDA) neurons useful for the treatment of PD. METHODS: mDA neurons were produced from neural progenitor cells or stem cells by activating both the Wnt-Lmx1a/Lmx1b and the SHH-FoxA2 signaling pathways. RESULTS: The level of the proteins of these two synergic pathways is increased, as well as their biological activity. CONCLUSION: The invention provides a method for treating or preventing PD by increasing the level of at least one protein involved in an autoregulatory pathway, which is fundamental during mDA neurons differentiation. PMID- 22251083 TI - Mechanistic variations in ionic hydrogenation of unsaturated phosphine and amine boranes. AB - Internal hydride transfer occurs when tethered carbocations are generated from unsaturated phosphine or phosphinite boranes. 3-Methylenecyclohexyl-derived boranes 12 or 18 react with MsOH to give ionic hydrogenation products with high syn-selectivity. With unsaturated amine boranes, initial hydrogen evolution gives BH(2)(OMs) complexes, but IH occurs using excess MsOH in a slower second stage. A diastereoselective reaction occurs from 26b using camphorsulfonic acid (first stage) and MsOH (second stage), affording 33 (68% ee) after hydrolysis. PMID- 22251082 TI - Pharmacological dissection of K(v)7.1 channels in systemic and pulmonary arteries. AB - BACKGROUND AND PURPOSE: The aim of this study was to characterize the functional impact of KCNQ1-encoded voltage-dependent potassium channels (K(v)7.1) in the vasculature. EXPERIMENTAL APPROACH: Mesenteric arteries, intrapulmonary arteries and thoracic aortae were isolated from adult rats. K(v)7.1 channel expression was established by fluorescence immunocytochemistry. Wire myography determined functionality of these channels in response to selective blockers and activators. Xenopus oocytes expressing K(v)7.1 channels were used to assess the effectiveness of selective K(v)7.1 channel blockers. KEY RESULTS: K(v)7.1 channels were identified in arterial myocytes by immunocytochemistry. K(v)7.1 blockers HMR1556, L-768,673 (10 uM) and JNJ39490282 (JNJ282; 1 uM) had no contractile effects in arteries, whereas the pan-K(v)7 channel blocker linopirdine (10 uM) evoked robust contractions. Application of two compounds purported to activate K(v)7.1 channels, L-364 373 (R-L3) and mefenamic acid, relaxed mesenteric arteries preconstricted by methoxamine. These responses were reversed by HMR1556 or L 768,673 but not JNJ282. Similar effects were observed in the thoracic aorta and intrapulmonary arteries. CONCLUSIONS AND IMPLICATIONS: In contrast to previous assumptions, K(v)7.1 channels expressed in arterial myocytes are functional ion channels. Although these channels do not appear to contribute to resting vascular tone, K(v)7.1 activators were effective vasorelaxants. PMID- 22251084 TI - The analysis of near full-length genome sequences of HIV type 1 subtype A viruses from Russia supports the monophyly of major intrasubtype clusters. AB - The HIV-1 epidemic in Russia has been insufficiently studied, with only 11 complete genome sequences from this country currently available, only three of which are of the locally predominant genetic form, the former Soviet Union (FSU) subtype A variant (A(FSU)). Here we analyze 10 newly derived A(FSU) near full length genome sequences from Russia. Samples were selected based on phylogenetic clustering in protease-reverse transcriptase in two of the major A(FSU) clusters, V77I(PR) (n=6), widely circulating in Russia and other FSU countries, and A(SP1) (n=4), predominant in St. Petersburg. The phylogenetic analysis shows that the V77I(PR) genomes group in a monophyletic cluster together with 10 previously obtained A(FSU) genome sequences from Uzbekistan, Kazakhstan, Russia, and Cyprus, all bearing the V77I substitution in protease. Similarly, the four A(SP1) genomes group in a monophyletic cluster. These results therefore show that the monophyly of V77I(PR) and A(SP1) A(FSU) clusters is supported in near complete genomes. PMID- 22251085 TI - Osseointegration of two different phosphate ion-containing titanium oxide surfaces in rabbit cancellous bone. AB - OBJECTIVE: This study assessed the osseointegration of grit-blasted titanium (Ti) implants with a hydrophilic phosphate ion-incorporated oxide surface in rabbit cancellous bone, and compared its bone healing with commercially available phosphate-incorporated clinical implants obtained by micro-arc oxidation (TiUnite, TU implant). MATERIAL AND METHODS: The hydrophilic phosphate incorporated Ti surface (P implant) was produced by hydrothermal treatment on grit-blasted moderately rough-surfaced clinical implant. The TU surface was used as a control. The surface characteristics were evaluated by field emission scanning electron microscopy, X-ray photoelectron spectroscopy, optical profilometry, and inductively coupled plasma-atomic emission spectroscopy (ICP AES). Thirty-two threaded implants with lengths of 10 and 3.3 mm diameter (16 P implants and 16 TU implants) were placed in the femoral condyles of 16 New Zealand White rabbits. Histomorphometric analysis, removal torque tests, and surface analysis of the torque-tested implants were performed 4 weeks after implantation. RESULTS: The P and TU implants displayed micro-rough surface features with similar Ra values at the micron-scale. ICP-AES analysis revealed that both the P and TU implants released phosphate ions into the solution. The torque-tested P and TU implants exhibited a considerable quantity of bone attached to the surface. The P implants exhibited significantly higher bone implant contact percentages, both in terms of the all threads region and the total lateral length of implants compared with the TU implants (P < 0.01), but no statistical difference was found for the removal torque values. CONCLUSION: These results suggest that the phosphate-incorporated Ti oxide surface obtained by hydrothermal treatment achieves rapid osseointegration in cancellous bone by increasing the degree of bone-implant contact. PMID- 22251086 TI - Cytotoxicity evaluation of Curcuma zedoaria (Christm.) Roscoe fluid extract used in oral hygiene products. AB - OBJECTIVE: This in vitro study evaluated the cytotoxic effects of the Curcuma zedoaria (Christm.) Roscoe (popular name: zedoary) fluid extract, as used in preparations for oral hygiene, mostly for anti-septic purposes. MATERIALS AND METHODS: The cell viability and cell growth were assessed by Trypan blue dye exclusion assay using the LMF cell line derived from oral mucosa. Cell viability (short-term assay) was measured 0, 6, 12 and 24 h after contact with the fluid extract. Cell growth (long-term assay) was analyzed in 1, 3, 5 and 7 days. The experimental groups were those testing the fluid extract obtained from the zedoary rhizome and the extractor liquid (ethanol 70 degrees GL) in the concentrations of 0.01-0.0001% v/v. Fresh DMEM were used in the control cultures. RESULTS: Short-term assay-all studied cultures maintained stable cell viability; Long-term assay-there was progressive cell growth in all studied cultures. CONCLUSION: According to the results, the zedoary fluid extract presents low cytotoxicity and probably can be used in the oral hygiene products. PMID- 22251087 TI - Human temporomandibular joint and myofascial pain biochemical profiles: a case control study. AB - Neurobiological mechanisms of human musculoskeletal pain are poorly understood. This case-control study tested the hypothesis that biomarkers within temporomandibular muscle and joint disorders (TMJD) subjects' masseter muscles or temporomandibular joint (TMJ) synovial fluid correlate with plasma biomarker concentrations. Fifty subjects were recruited and categorized into TMJD cases (n=23) and pain-free controls (n=27) at the University of Minnesota School of Dentistry. Prior to specimen collection, pain intensity and pressure pain threshold masseter muscles and the TMJs were assessed. We collected venous blood; biopsied masseter muscle; and sampled TMJ synovial fluid on the subjects' side of maximum pain intensity. We assayed these tissues for the presence of nerve growth factor (NGF), bradykinin (BK), leukotreine B(4) (LTB(4) ) and prostaglandin E(2) (PGE(2) ), F(2) -isoprostane (F(2) I) and substance P (SP). The data was analyzed using Spearman Correlation Coefficients. We found that only plasma concentrations of bradykinin statistically correlated with synovial fluid concentrations (rho= 0.48, P=0.005), but no association was found between pain intensities. The data suggests that biomarkers used to assess TMJD need to be acquired in a site specific manner. We also discovered that F(2) I concentrations were associated with muscle pain intensity and muscle pressure pain threshold (PTT) (beta=0.4, 95%CI: 0.03-0.8) and joint PPT (beta=0.4, 95%CI: 0.07-0.8) suggesting that muscle oxidative stress is involved in myofascial pain and that F(2) -I may be a biomarker for myofascial pain. PMID- 22251089 TI - Optimization of EBSD parameters for ultra-fast characterization. AB - Ultra-fast pattern acquisition of electron backscatter diffraction and offline indexing could become a dominant technique over online electron backscatter diffraction to investigate the microstructures of a wide range of materials, especially for in situ experiments or very large scans. However, less attention has been paid to optimize the parameters related to ultra-fast electron backscatter diffraction. The present results show that contamination on a clean and unmounted specimen is not a problem even at step sizes as small as 1 nm at a vacuum degree of 6.1 * 10(-5) Pa. There exists an optimum step size at about 50 data acquisition board units. A new and easy method to calculate the effective spatial resolution is proposed. Effective spatial resolution tends to increase slightly as the probe current increases from 10 to 100 nA. The fraction of indexed points decreases slightly as the frame rate increases from 128 patterns per second (pps) to 835 pps by compensating the probe current at the same ratio. The value 96 * 96 is found to be the optimum pattern resolution to obtain optimum speed and image quality. For a fixed position of electron backscatter diffraction detector, the fraction of indexed points as a function of working distance has a maximum value and drops sharply by shortening the working distance and it decreases slowly with increasing the working distance. PMID- 22251088 TI - Genome-wide analysis of oral squamous cell carcinomas revealed over expression of ISG15, Nestin and WNT11. AB - BACKGROUND: Multistep pathways and mechanisms are involved in the development of oral cancer. Chromosomal alterations are one of such key mechanisms implicated oral carcinogenesis. Therefore, this study aims to determine the genomic copy number alterations (CNAs) in oral squamous cell carcinoma (OSCC) using array comparative genomic hybridization (aCGH) and in addition attempt to correlate CNAs with modified gene expression. MATERIALS AND METHODS: Genome-wide screening was performed on 15 OSCCs using high-density aCGH. On the basis of pathway analysis, three genes (ISG15, Nestin and WNT11) which mapped to CNA regions were selected for further evaluation of their mRNA expression using quantitative reverse transcriptase PCR (qRT-PCR). RESULTS: Copy number alterations were observed on multiple genomic regions, including amplifications on 1p, 3q, 5p, 6p, 7p, 8q, 9q, 11q, 12q, 16p, 18p and deletions on 3p, 7q, 8p, 11q, 19q and 20q. Among the three selected genes, ISG15 had the highest mRNA expression level with a 22.5-fold increase, followed by Nestin with a 4.5-fold increase and WNT11 with a 2.5-fold increase. CONCLUSIONS: This study has identified several major CNAs in oral cancer genomes and indicated that this correlates with over expression of the ISG15, WNT11, and Nestin genes. PMID- 22251090 TI - Mechanical properties of asphalt binders evaluated by atomic force microscopy. AB - Atomic Force Microscopy was employed in order to relate the features observed on the surface of a 50/70 asphalt binder according to its local stiffness and elastic recovery. Indentations were performed in different points of the surface and a significant variation of elasticity was observed between the points on the so-called bee structure and the matrix. Also, indentations varying the maximum force were performed on similar white spots in the bee structure and the recovery was followed up to 1 h after indentation. It was observed that the elastic recovery is very much dependent on the colloidal structure of the bee. The final surface state of the binder, close to the bee for usual bees is not the same as the initial one indicating severe plastic deformation. Also, permanent phase change could be observed for bright spots presented in not well-structured bee arrangements. A surface hardening was observed in the bee region. PMID- 22251091 TI - Online counselling for eating disorders: reaching an underserved population? AB - BACKGROUND: A substantial proportion of individuals suffering from eating disorders (ED) seek help late and many never access treatment. Internet-based services may have the potential to reach these underserved individuals by providing low-intense support and facilitating access to regular healthcare. METHOD: Two hundred and thirty-eight individuals who used a counselling service for ED via email and/or moderated forums were surveyed. Acceptance of the service, users' satisfaction, utilization of other services, and attitudes towards Internet-based interventions were assessed. RESULTS: Participants reported substantial ED symptoms (67.4% reported bingeing, 42.2% self-induced vomiting, and 18.0% a body mass index below 17.5). Both forum and email counselling were rated very positively. More than half of the participants (57.3%) stated that this was the first time they ever accessed professional help. Half of these reported that they engaged in additional services after registering for the online program and most of them stated that they would have not done so without the online service. DISCUSSION: The Internet-based service proved well accepted in the target group. It reaches a substantial percentage of individuals with ED-related impairment that would have stayed without any professional support otherwise. The service also facilitated access to the regular healthcare system for a subgroup of participants. PMID- 22251093 TI - Synthesis of panchromatic Ru(II) thienyl-dipyrrin complexes and evaluation of their light-harvesting capacity. AB - Ru(II) complexes with 5-(3-thienyl)-4,6-dipyrrin (3-TDP), containing 2,2' bipyridine (bpy) or 4,4'-bis(methoxycarbonyl)-2,2'-bipyridine (dcmb) as coligands, have been prepared and extensively characterized. Crystal structure determination of [Ru(bpy)(2)(3-TDP)]PF(6) (1a) and [Ru(bpy)(3-TDP)(2)] (2) reveals that the 3-thienyl substituent is rotated with respect to the plane of the dipyrrinato moiety. These complexes, as well as [Ru(dcmb)(2)(3-TDP)]PF(6) (1b), act as panchromatic light absorbers in the visible range, with two strong absorption bands observable in each case. A comparison to known Ru(II) complexes and quantum-chemical calculations at the density functional theory (DFT) level indicate that the lower-energy band is due to metal-to-ligand charge transfer (MLCT) excitation, although the frontier occupied metal-based molecular orbitals (MOs) contain significant contributions from the 3-TDP moiety. The higher energy band is assigned to the pi-pi* transition of the 3-TDP ligand. Each complex exhibits an easily accessible one-electron oxidation. According to DFT calculations and spectroelectrochemical experiments, the first oxidation takes place at the Ru(II) center in 1a, but is shifted to the 3-TDP ligand in 1b. An analysis of MO energy diagrams suggests that complex 1b has potential to be used for light harvesting in the dye-sensitized (Gratzel) solar cell. PMID- 22251092 TI - Emerging roles for ubiquitin in adenovirus cell entry. AB - Adenovirus relies on numerous interactions between viral and host cell proteins to efficiently enter cells. Undoubtedly, post-translational modifications of host and cellular proteins can impact the efficiency of this cell entry process. Ubiquitylation, once simply thought of as a modification targeting proteins for proteasomal degradation, is now known to regulate protein trafficking within cells, protein-protein interactions and cell signalling pathways. Accumulating evidence suggests that protein ubiquitylation can influence all stages of the life cycle of other viruses such as cell entry, replication and egress. Until recently, the influence of ubiquitylation has only been documented during adenovirus replication. This review highlights the most recent evidence demonstrating direct engagement of host ubiquitylation and SUMOylation machinery by adenovirus during cell entry. Additionally, potential roles for host protein ubiquitylation and the potential for adenovirus regulation of host ubiquitylation machinery during cell entry are discussed. PMID- 22251094 TI - Novel dihydroquinoline-based MABAs; clues to the identity of LAS-190792: evaluation of WO20111411802. AB - Bifunctional aromatic compounds are claimed to contain a beta(2) agonist pharmacophore linked by a flexible lipophilic spacer incorporating a trans-4 aminocyclohexanol group to a muscarinic antagonist pharmacophore. The compounds display nanomolar affinity at both beta(2) and M(3) receptors and a prolonged duration of action in animal models. This application is the first from Almirall claiming such compounds although it has recently disclosed that LAS-190792 is progressing toward clinical development. PMID- 22251095 TI - Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3 kinase inhibition. AB - BACKGROUND AND PURPOSE: Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting beta(2) -agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling. EXPERIMENTAL APPROACH: Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC(50) values on TNF-alpha-induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H(2) O(2) ) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma. KEY RESULTS: PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10(-9) M) and salmeterol (SM, 10(-8) M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H(2) O(2) exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H(2) O(2) -induced PI3Kdelta-dependent (PKB) phosphorylation. H(2) O(2) decreased SM-induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H(2) O(2) was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3Kdelta inhibitor. CONCLUSION AND IMPLICATIONS: FM reversed oxidative stress-induced corticosteroid insensitivity and decreased beta(2) adrenoceptor-dependent cAMP production via inhibition of PI3Kdelta signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD. PMID- 22251096 TI - Polyphenol compounds in artichoke plant tissues and varieties. AB - Polyphenol compounds, particularly caffeoylquinic acids and flavonoids, were measured in different tissues and developmental stages of 6 artichoke varietal types diffused in the Mediterranean region. Flower heads were subdivided into external, intermediate, internal bracts, and receptacle, while leaves were collected at the vegetative and productive stages. The main polyphenols detected were chlorogenic acid, cynarin, luteolin 7-O-rutinoside, and luteolin 7-O glucoside. "Violet de Provence" artichoke proved to retain the highest content of total phenols. Single polyphenols accumulated preferentially in specific parts of capitula. In leaves, most polyphenols were detected in the productive stage of the plant. Altogether, results provide useful indications for the promotion of artichoke as nutraceutical food and for the extraction of health-promoting substances in particular tissues/stages of the artichoke plant. PRACTICAL APPLICATION: We describe the content of phenolic compounds in various artichoke tissues, developmental stages, and varieties. Results indicate that artichoke leaves represent an important source of these health-promoting compounds, also useful for phytopharmaceutical applications. A wider utilization of specific artichoke types should be strongly encouraged not only as a food for the fresh market, as they are now used, but also for the pharmaceutical industry, since the content of phenolic compounds is abundant both in the heads and in the leaves. PMID- 22251097 TI - Endovascular treatment of cerebral aneurysms at a low-volume institution: a viable alternative? PMID- 22251098 TI - Neonatal phototherapy: choice of device and outcome. PMID- 22251099 TI - Preparation and characterization of free films of high amylose/pectin mixtures cross-linked with sodium trimetaphosphate. AB - High amylose and pectin were mixed at 1:1 mass ratio and cross-linked with sodium trimetaphosphate (STMP) in alkaline medium. Films were prepared from aqueous dispersions of these cross-linked polymer blend at three different concentrations (3, 4 and 5%), by solvent casting method. Characterization of the films included thickness, surface morphology, water uptake, water vapor permeability (WVP), tensile strength measurements and enzymatic digestion. The cross-linking allowed to obtain films with improved mechanical properties and reduced WVP. The high resistance to enzymatic digestion exhibited by these films represents a promising approach to their application in the development of colon drug delivery systems. PMID- 22251100 TI - Tandem migration-carboalkoxylation of o-isocyanophenyl acetals leading to benzoxazoles. AB - An efficient approach to benzoxazoles via tandem migration-carboalkoxylation of o isocyanophenyl acetals has been developed. Both a Lewis acid and base are essential for this reaction, and the BF(3).OEt(2)/2,4,6-collidine combination is the best choice for cooperative transformation. PMID- 22251101 TI - Biomimetic monolayer and bilayer membranes made from amphiphilic block copolymer micelles. AB - The deposition of amphiphilic poly(ethylene oxide)-block-poly(butadiene) (PEO-b PBD) copolymer micelles is demonstrated on solid substrates. Depending upon surface chemistry, micelle adsorption creates either monolayer or bilayer films. Lateral diffusion measurements reveal that strong coupling between hydrophilic surfaces and PEO blocks creates immobile bilayers, while monolayers retain the fluidity previously observed in vesicular assemblies. PMID- 22251102 TI - The role of steroids in treating septic shock. PMID- 22251103 TI - Surgery and cardiovascular outcomes: an untapped public health benefit that potentially saves lives. PMID- 22251104 TI - The influence of surgery on the onset of symptomatic coronary artery disease. AB - We speculated that asymptomatic patients undergoing routine surgery might be at higher risk of subsequent cardiac events. We studied 183,534 patients with no prior admission for heart disease, aged 50-75 years, admitted electively for one of five operations considered medium to low risk of peri-operative cardiac morbidity, between January 1997 and December 2005. Controls were generated from linked records. Within 3 years 3444 (1.9%) patients undergoing operations had subsequent myocardial infarction/acute coronary syndrome (MI/ACS) compared with 3708 (2.0%) controls (p < 0.001). Overall 8406 (4.6%) patients undergoing surgery had MI/ACS compared with 9306 (5.1%) controls (p < 0.001). Of patients undergoing surgery, 20.2% died compared with 25.7% of controls (p < 0.001). Patients undergoing certain surgical procedures did not have a higher incidence of readmission for cardiac events, but had a general survival benefit compared with other elective hospital admissions. Assessment for surgery may represent a health benefit beyond the original surgery. PMID- 22251105 TI - Easy and difficult nasal intubation--a randomised comparison of Macintosh vs Airtraq(r) laryngoscopes. AB - A new Airtraq((r)) laryngoscope has been developed for nasal intubation. We prospectively compared tracheal intubation efficiency of the Airtraq for nasotracheal intubation vs that of the Macintosh laryngoscope in 200 patients. Depending on pre-operative airway evaluation, the patients were allocated to expected easy (n = 100) or difficult (n = 100) intubation groups, on the basis of mouth opening <= 2.5 cm, modified Mallampati score of 4, history of difficult intubation, obvious tumour or swelling. Patients were randomly allocated to the Macintosh or nasotracheal Airtraq technique. All easy intubations were successfully performed with the respective technique. In the expected difficult intubation group, the success rate was higher (47/50 vs 33/50; p < 0.01), the glottis view was better (Cormack and Lehane 1/2/3/4 grades: 29/17/1/3 vs 5/11/18/16, p < 0.01), mean (SD) intubation time was shorter (45(46) s vs 77(47)s, p < 0.01) and the number of optimising manoeuvres was reduced with the nasotracheal Airtraq compared with the Macintosh, respectively. For difficult nasal intubations, the nasotracheal Airtraq is more effective than the Macintosh laryngoscope. PMID- 22251106 TI - Limited maximal flow rate of target-controlled remifentanil infusion and induced cough. AB - This study evaluated the effect of limiting maximal infusion-pump flow rate on suppression of remifentanil-induced cough during target-controlled infusion. Two hundred and ten patients were randomly assigned to receive remifentanil at an effect-site concentration of 4.0 ng.ml(-1) with maximal flow rate limited to 100 (group R(100)), 200 (group R(200)), or 1200 ml.h(-1) (group R(1200)). The number of episodes of cough were recorded and graded as mild (1-2), moderate (3-4), or severe (5 or more). The incidence of cough was 2.9% in group R(100), 5.7% in group R(200) and 25.7% in group R(1200). Patients in group R(100) and R(200) had a significantly lower incidence of cough than those in group R(1200) (p < 0.05). Zero, two and five patients coughed a moderate amount in groups R(100), R(200) and group R(1200), respectively (p < 0.05). Limiting maximal infusion rate during remifentanil TCI suppressed remifentanil-induced cough. PMID- 22251108 TI - Pharmacogenetics and anaesthesia: the value of genetic profiling. AB - Approximately 50 years ago, pharmacogenetics was described as a new field of medicine that may explain human drug action. Anaesthesia played a key role in the early investigations. An understanding of how a person's DNA influences drug metabolism and effectiveness may allow individually tailored prescriptions, improving outcomes and safety. The ultimate goal of pharmacogenetic research is to offer tailored personalised medicine to improve both the efficacy of medication and patient safety by helping to predict risk of adverse outcomes. In this review, we present a selection of historical landmarks where anaesthesia has been a catalyst for pharmacogenetic development. We examine the level of evidence and cite examples of candidate genes and common polymorphisms known to alter the response to peri-operative medication. Finally, we set forth current views and potential exciting perspectives that may arise from the application of pharmacogenetics to the daily practice of anaesthesia and pain medicine. PMID- 22251107 TI - Development of workplace-based assessments of non-technical skills in anaesthesia. AB - Non-technical skills are recognised as crucial to good anaesthetic practice. We designed and evaluated a specialty-specific tool to assess non-technical aspects of trainee performance in theatre, based on a system previously found reliable in a recruitment setting. We compared inter-rater agreement (multir-ater kappa) for live assessments in theatre with that in a selection centre and a video-based rater training exercise. Twenty-seven trainees participated in the first in theatre assessment round and 40 in the second. Round- 1 scores had poor inter rater agreement (mean kappa = 0.20) and low reliability (generalisability coefficient G = 0.50). A subsequent assessor training exercise showed good inter rater agreement, (mean kappa = 0.79) but did not improve performance of the assessment tool when used in round 2 (mean kappa = 0.14, G = 0.42). Inter-rater agreement in two selection centres (mean kappa = 0.61 and 0.69) exceeded that found in theatre. Assessment tools that perform reliably in controlled settings may not do so in the workplace. PMID- 22251109 TI - Spinal anaesthesia for caesarean delivery in a parturient with babesiosis and Lyme disease. AB - We present a case of a parturient with babesiosis and Lyme disease who was scheduled for elective caesarean section. The caesarean section was performed under spinal anaesthesia, and the patient had a coronary artery dissection 4 days postoperatively. Neuraxial anaesthesia and possible mechanisms for the coronary artery dissection in a patient with babesiosis and Lyme disease are discussed. PMID- 22251110 TI - Anaesthesia in the obese patient: the ramped position revisited. PMID- 22251111 TI - Measuring academic productivity. PMID- 22251113 TI - Don't forget mentoring. PMID- 22251114 TI - Are anaesthetists sure of the catheter length inserted into the epidural space? PMID- 22251116 TI - Validation of the LiDCOTM pulse contour system in patients with impaired left ventricular function. PMID- 22251117 TI - Central venous pressure waveform interference. PMID- 22251118 TI - Fracture of a GlideScope cobalt blade. PMID- 22251119 TI - Dexamathasone and ondansetron in paediatric tonsillectomy. PMID- 22251120 TI - Comment on "fracture of a GlideScope cobalt blade". PMID- 22251121 TI - Dexamathasone and ondansetron in paediatric tonsillectomy. PMID- 22251122 TI - More on cutting tracheal tubes in situ. PMID- 22251124 TI - Scissors to cut the tracheal tube. PMID- 22251125 TI - Wrong site surgical checks: the 'fallible indelible'. PMID- 22251126 TI - Even more on cutting tracheal tubes in situ. PMID- 22251127 TI - Jedi grip and single-handed ultrasound guided-regional anaesthesia. PMID- 22251129 TI - Recycling glass and metal in the anaesthetic room. PMID- 22251130 TI - Acute l-arginine supplementation increases muscle blood volume but not strength performance. AB - l-Arginine (L-arg) is an amino acid precursor to nitric oxide (NO). Dietary supplements containing L-arg have been marketed with the purpose of increasing vasodilation, thereby elevating blood flow to the exercising muscle and enhancing the metabolic response to exercise. Our goal was to identify the acute effect of L-arg supplementation on biceps strength performance, indicators of NO production (nitrite and nitrate - NOx), and muscle blood volume (Mbv) and oxygenation (Mox) during recovery from 3 sets of resistance exercise. Fifteen males participated in a randomized, double-blind, placebo-controlled study. After withdrawing resting blood samples, the subjects were supplemented with 6 g of L-arg (ARG) or placebo (PLA). Monitoring of Mbv and Mox with near-infrared spectroscopy began 30 min after supplementation and lasted for 60 min. The exercise protocol (3 sets of 10 maximal voluntary contractions of isokinetic concentric elbow extension at 60 degrees .s(-1), 2-min rest between sets) was initiated 80 min after supplementation. Blood samples were drawn at 30, 60, 90, and 120 min after supplementation. Repeated measures ANOVA showed that Mbv significantly (p <= 0.05) increased in ARG compared with the PLA during the recovery period of each set of resistance exercise. NOx, Mox, peak torque, total work, and set total work were not significantly different between groups. We found that acute L-arg supplementation increases Mbv during recovery from sets of resistance exercise with no increase in strength performance. It is still premature to recommend nutritional supplements containing L-arg as an ergogenic aid to increase muscle strength during resistance training in healthy subjects. PMID- 22251131 TI - bFGF-induced human periodontal ligament fibroblasts proliferation through T-type voltage-dependent calcium channels. AB - OBJECTIVE: To test the hypothesis that T-type voltage-dependent calcium channels (T-CaCNs) are involved in basic fibroblast growth factor (bFGF)-induced proliferation of human periodontal ligament fibroblasts (HPLFs). MATERIALS AND METHODS: This study examined the expression of the T-type calcium channel sub units Ca(V) 3.1, Ca(V) 3.2 and Ca(V) 3.3 in HPLFs by real-time PCR. Mibefradil, a T-CaCNs antagonist, was used to block the effect of T-CaCNs and the proliferation of HPLFs was evaluated by the water-soluble tetrazolium (WST) assay. The level of intracellular calcium was measured by laser confocal microscopy. RESULTS: Expression of the three subunits of T-CaCNs in HPLFs was detected, which was strongly up-regulated upon stimulation by bFGF. The proliferation of HPLFs induced by bFGF was decreased significantly by treatment with Mibefradil. This effect was associated with the decreased expression of T-CaCNs and a decreased level of intracellular calcium. CONCLUSIONS: Expression of the T-CaCNs affected the proliferation of HPLFs that was induced by bFGF, indicating that T-CaCNs could be important in mediating periodontal ligament (PDL) remodeling. PMID- 22251133 TI - Is there a need for a ski helmet mandatory for children? PMID- 22251132 TI - Including the p53 ELAV-like protein-binding site in vector cassettes enhances transgene expression in rat submandibular gland. AB - OBJECTIVE: ELAV-like proteins regulate mRNA stability and/or translation. We evaluated whether inclusion of binding sites for ELAV-like HuR proteins in vector cassettes could improve transgene expression in the salivary gland. METHODS: Western blots and immunofluorescence staining were used to determine whether HuR protein was expressed in salivary cells and tissue. HuR binding sites were inserted into the pACEF1alpha-luc-BGH expression plasmid. Cell lines were transfected with plasmids in vitro and luciferase expression measured. Rat submandibular glands were transfected in vivo with plasmids containing ELAV-like HuR protein-binding sites. An adenoviral vector with p53 ELAV-like HuR protein binding site was generated and also tested in vivo. Four unique 29mer HuR shRNA constructs were used in A5 cells to evaluate whether there was a specific interaction between HuR protein and the p53 HuR protein-binding site. RESULTS: Salivary cells express HuR protein. Inclusion of the p53 ELAV-like HuR protein binding site resulted in high luciferase activity in salivary cells in vitro, with similar results in vivo. In vitro shRNA data demonstrated that the high luciferase activity was mediated by the interaction between HuR protein and the p53 HuR protein-binding site. The AdEF1alpha-luc-p53BGH, including this binding site, mediated very high luciferase activity, ~4-fold that seen with the CMV promoter, in rat submandibular glands. CONCLUSIONS: Including the p53 ELAV-like protein-binding site in transgene cassettes may enhance therapeutic vectors intended for use with salivary glands. PMID- 22251134 TI - Validity and reliability of the Portuguese version of Mandibular Function Impairment Questionnaire. AB - The aim of this study is to evaluate the validity and reliability of the Mandibular Function Impairment Questionnaire (MFIQ) (Portuguese version). Face and content validity of the Portuguese version were performed. To assess reproducibility of the data gathered with MFIQ, it was applied to 62 individuals who completed the questionnaire on two occasions. Validity and reliability of the data gathered with MFIQ were evaluated in a sample of 249 patients. Construct related validity was assessed through factorial validity (by means of a confirmatory factor analysis), and convergent and discriminant validities were assessed, respectively, by the average variance extracted (AVE), composite reliability (CC) and bivariate correlations between factors. The internal consistency was estimated by the standardised Cronbach's alpha coefficient (alpha) and reproducibility by the intra-class correlation coefficient (ICC). All the items of MFIQ showed content validity. Reproducibility was excellent in both the 'functional capacity' dimension (D1) (ICC(D1) =0.895, 95% CI=0.832 to 0.935) and the 'feeding' dimension (D2) (ICC(D2) =0.825, 95% CI= 0.726 to 0.891). Items 1, 2, 6 and 7 of D1 had factor weights below the desired cut-off (0.5), and overall fit of the original bifactorial structure of the MFIQ was poor [(confirmatory fit index) CFI= 0.850, (goodness of fit index) GFI= 0.781, (root mean square error of approximation) RMSEA= 0.118]. Thus, these items were excluded, and the new, reduced version of the MFIQ showed good fit (CFI=0.933, GFI=0.879, RMSEA=0.099). The convergent validity was adequate (AVE>=0.5, CC>=0.7) for both factors. However, their discriminant validity was low (AVE(D1) = 0.51 and AVE(D2) = 0.66 0.05). However, HEBP significantly decreased the bond strength of RelyX(TM) Unicem when compared to the control (p < 0.05). Conclusion. The tetracycline HCl and CHX solutions do not have beneficial effects on u-PO bond strengths of self-adhesive resin cements. Additionally, the results of this study do not justify the use of self-adhesive resin cements, following HEBP treatment of dentin. CLINICAL SIGNIFICANCE: The application of topical HEBP solution treatment to dentin could have adverse effects on the u-PO bond strengths of RelyX(TM) Unicem. PMID- 22251144 TI - The risk of preterm delivery prior to 34 weeks in women presenting with antepartum haemorrhage of unknown origin. AB - BACKGROUND: The management of antepartum haemorrhage of unknown origin (APHUO) remote from term remains controversial. AIM: To determine the rate and risk factors in predicting preterm delivery among women presenting with APHUO before 34 weeks of gestation. METHODS: All singleton pregnancies with the first episode of APHUO before 34 weeks of gestation who delivered between January 1995 and December 2004 were reviewed. The predictability of risk factors was assessed by both univariate and multivariate analysis. The cumulative rates of preterm delivery prior to 34 weeks were compared by using the Kaplan-Meier survival analysis and log-rank test between those with and those without risk factors. RESULTS: The rates of preterm delivery prior to 34 and 37 weeks of gestation were 7.3 and 17%, respectively. Uterine contractions, persistent bleeding, two or more episodes of APHUO and a history of spontaneous preterm deliveries were significant risk factors for preterm birth prior to 34 weeks in a multivariate logistic regression. Women with one risk factor had a hazard ratio of 5.5 (95% CI: 3.2-9.6) in having preterm delivery prior to 34 weeks compared with those without risk factors, whereas women with any two risk factors had a hazard ratio of 5.2 (95% CI: 2.1-12.9) compared with those with one risk factor. CONCLUSIONS: APHUO prior to 34 weeks of gestation is associated with three to fivefold increased risk of preterm delivery. Identification of several risk factors could further help to predict early preterm delivery and appropriate triage management. PMID- 22251145 TI - Synthesis and properties of amphiphilic photoresponsive gelators for aromatic solvents. AB - A sugar-based photoresponsive supergelator, N-glycosylazobenzene that shows selective gelation of aromatic solvents is described. The partial trans-cis isomerization of the azobenzene moiety allows photoinduced chopping of the entangled gel fibers to short fibers, resulting in controlled fiber length and gel-sol transition. The gelator is useful for the selective removal of toxic aromatic solvents from water. PMID- 22251147 TI - Single-molecule force-clamp experiments reveal kinetics of mechanically activated silyl ester hydrolysis. AB - We have investigated the strength of silyl ester bonds formed between carboxymethylated amylose (CMA) molecules and silane-functionalized silicon oxide surfaces using AFM-based single-molecule force spectroscopy in the force-clamp mode. Single tethered CMA molecules were picked up, and bond lifetimes were determined at constant clamp forces of 0.8, 1.0, and 1.2 nN at seven temperatures between 295 and 320 K at pH 2.0. The results reveal biexponential rupture kinetics. To obtain the reaction rate constants for each force and temperature individually, the results were analyzed with a biexponential kinetic model using the maximum likelihood estimation (MLE) method. The force-independent kinetic and structural parameters of the underlying bond rupture mechanisms were extracted by fitting the entire data set with a parallel MLE fit procedure using the Zhurkov/Bell model and, alternatively, an Arrhenius kinetics model combined with a Morse potential as an analytic representation of the binding potential. With activation energies between 37 and 40 kJ mol(-1), and with Arrhenius prefactors between 5 * 10(4) and 2 * 10(6) s(-1), the results point to the hydrolysis of the silyl ester bond. PMID- 22251146 TI - Mandibular and dental manifestations of Gaucher disease. AB - Gaucher disease is a systemic lysosomal storage disorder with a high prevalence among Ashkenazi Jews. It is caused by an inherited deficiency of the lysosomal enzyme glucocerebrosidase. Common signs and symptoms include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal involvement. Oral and dental manifestations are less commonly seen. These manifestations are often asymptomatic, although they may be detected by routine dental x-rays. There are several case reports and a few larger series published describing patients with Gaucher disease who have mandibulo-maxillofacial involvement. This review aims to examine the oral manifestations observed in Gaucher disease and to suggest practical guidelines for dealing with these often worrisome signs. Among the critical issues are the benign nature of Gaucher cell infiltration of the mandible and the critical importance of being prepared for postprocedure bleeding and/or infections. Therefore, it is essential that dental practitioners be aware of the possible oral and dental complications of Gaucher disease, as well as the available treatment modalities. PMID- 22251148 TI - New clinical evidence of silodosin, an alpha(1A) selective adrenoceptor antagonist, in the treatment for lower urinary tract symptoms. AB - Lower urinary tract symptoms associated with benign prostatic hyperplasia are highly prevalent in older men. Pharmacological treatment is the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. The first choice in the pharmacological treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia is the alpha(1) adrenoceptor antagonists. Many alpha(1) -adrenoceptor antagonists are available in the world. Silodosin is an alpha(1) -adrenoceptor antagonist developed by Kissei Pharmaceutical, and has a specific selectivity for the alpha(1A-) adrenoceptor subtype. By antagonizing alpha(1A) -adrenoceptor in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. As a result of the high affinity for the alpha(1A) -adrenoceptor than for the alpha(1B) -adrenoceptor, silodosin minimizes the propensity for blood pressure related adverse effects caused by blockade of alpha(1B) -adrenoceptor. The efficacy and safety of silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia was first reported by Japanese investigators in 2006. At present, silodosin is used in many countries. In the present review, we summarize the new clinical evidence for lower urinary tract symptoms associated with benign prostatic hyperplasia and introduce the data supporting the new clinical indications of silodosin. PMID- 22251149 TI - Self-reported bruxism and temporomandibular disorders: findings from two specialised centres. AB - The aims of this investigation were to report the frequency of temporomandibular disorders (TMD) diagnoses and the prevalence of self-reported awake and sleep bruxism as well as to describe the possible differences between findings of two specialised centres as a basis to suggest recommendations for future improvements in diagnostic homogeneity and accuracy. A standardised Research Diagnostic Criteria for TMD (RDC/TMD) assessment was performed on patients attending both TMD Clinics, viz., at the University of Padova, Italy (n=219; 74% women) and at the University of Tel Aviv, Israel (n=397; 79% women), to assign axis I physical diagnoses and to record data on self-reported awake and sleep bruxism. Significant differences were shown between the two clinic samples as for the frequency of TMD diagnoses (chi-square, P<0.001) and the prevalence of at least one positive response to bruxism items (chi-square, P<0.001). The more widespread use of TMJ imaging techniques in one clinic sample led to a higher prevalence of multiple diagnoses, and the higher prevalence of self-reported bruxism in patients with myofascial pain alone described in the other clinic sample was not replicated, suggesting that the different adoption of clinical and imaging criteria to diagnose TMD may influence also reports on their association with bruxism. From this investigation, it emerged that the features of the study samples as well as the different interpretation of the same diagnostic guidelines may have strong influence on epidemiological reports on bruxism and TMD prevalence and on the association between the two disorders. PMID- 22251150 TI - Kainate receptor-mediated depression of glutamatergic transmission involving protein kinase A in the lateral amygdala. AB - Kainate receptors (KARs) have been described as modulators of synaptic transmission at different synapses. However, this role of KARs has not been well characterized in the amygdala. We have explored the effect of kainate receptor activation at the synapse established between fibers originating at medial geniculate nucleus and the principal cells in the lateral amygdala. We have observed an inhibition of evoked excitatory postsynaptic currents (eEPSCs) amplitude after a brief application of KARs agonists KA and ATPA. Paired-pulse recordings showed a clear pair pulse facilitation that was enhanced after KA or ATPA application. When postsynaptic cells were loaded with BAPTA, the depression of eEPSC amplitude observed after the perfusion of KAR agonists was not prevented. We have also observed that the inhibition of the eEPSCs by KARs agonists was prevented by protein kinase A but not by protein kinase C inhibitors. Taken together our results indicate that KARs present at this synapse are pre-synaptic and their activation mediate the inhibition of glutamate release through a mechanism that involves the activation of protein kinase A. PMID- 22251153 TI - Penicillium camemberti and Penicillium roqueforti enhance the growth and survival of Shiga toxin-producing Escherichia coli O157 under mild acidic conditions. AB - The effects of secondary starter molds of common mold-ripened cheeses on the Shiga toxin-producing Escherichia coli (STEC) O157 were assessed in 3 model systems. In the 1st model, 8 STEC O157 strains were incubated in the spent culture of Penicillium camemberti or Penicillium roqueforti under mild acidic conditions at 25 degrees C. In the spent cultures of the mold at pH 4.8 to 5.0, the lag times of STEC O157 growth were significantly shorter than those observed in fresh medium. Analyses of the spent culture of P. camemberti showed that the causative agents of the growth enhancement were produced by the mold in response to an acidic environment and were not fully inactivated in heat treatment. In the 2nd model, P. camemberti and STEC O157 were cocultured in acidified milk at 25 degrees C. The population of STEC O157 reached 10(8) CFU/mL in the presence of the mold, whereas the population steadily declined in the absence of the mold. Although this growth enhancement was partially attributable to alkalization by the mold, it was observed even when the pH of this model was stabilized. In the 3rd model, 2 STEC O157 strains were incubated in the spent cultures of molds at pH 4.5 at 10 degrees C. In the spent culture, proportions of injured cells were significantly lower and D values were significantly higher than those in control, except one STEC O157 strain in the spent culture of P. camemberti. These results showed that the molds could enhance the growth and survival of STEC O157 by changing the environment. Practical Application: This study demonstrated that molds in foods can improve the growth and survival of the Shiga toxin-producing Escherichia coli O157. Because microbial interactions are ubiquitous in food, our results provide an important insight for understanding the behavior of microorganisms in food. PMID- 22251152 TI - Key role of PI3Kgamma in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration. AB - BACKGROUND AND PURPOSE: Vascular smooth muscle cell (SMC) migration within the arterial wall is a crucial event in atherogenesis and restenosis. Monocyte chemotactic protein-1/CC-chemokine receptor 2 (MCP-1/CCR2) signalling is involved in SMC migration processes but the molecular mechanisms have not been well characterized. We investigated the role of PI3Kgamma in SMC migration induced by MCP-1. EXPERIMENTAL APPROACHES: A pharmacological PI3Kgamma inhibitor, adenovirus encoding inactive forms of PI3Kgamma and genetic deletion of PI3Kgamma were used to investigate PI3Kgamma functions in the MCP-1 and platelet-derived growth factor (PDGF) signalling pathway and migration process in primary aortic SMC. KEY RESULTS: The gamma isoform of PI3K was shown to be the major signalling molecule mediating PKB phosphorylation in MCP-1-stimulated SMC. Using a PI3Kgamma inhibitor and an adenovirus encoding a dominant negative form of PI3Kgamma, we demonstrated that PI3Kgamma is essential for SMC migration triggered by MCP-1. PDGF receptor stimulation induced MCP-1 mRNA and protein accumulation in SMCs. Blockade of the MCP-1/CCR2 pathway or pharmacological inhibition of PI3Kgamma reduced PDGF-stimulated aortic SMC migration by 50%. Thus PDGF promotes an autocrine loop involving MCP-1/CCR2 signalling which is required for PDGF mediated SMC migration. Furthermore, SMCs isolated from PI3Kgamma-deficient mice (PI3Kgamma(-/-)), or mice expressing an inactive PI3Kgamma (PI3Kgamma(KD/KD)), migrated less than control cells in response to MCP-1 and PDGF. CONCLUSIONS AND IMPLICATIONS: PI3Kgamma is essential for MCP-1-stimulated aortic SMC migration and amplifies cell migration induced by PDGF by an autocrine/paracrine loop involving MCP-1 secretion and CCR2 activation. PI3Kgamma is a promising target for the treatment of aortic fibroproliferative pathologies. PMID- 22251155 TI - Prosthodontists as deans. PMID- 22251154 TI - Two new C19-diterpenoid alkaloids from Aconitum transsectum. AB - Two new C(19)-diterpenoid alkaloids, named aconitramines D (1) and E (2), were isolated from the roots of Aconitum transsectum. Based on comprehensive spectroscopic analyses including IR, ESI-MS, HR-ESI-MS, and 1D and 2D NMR, their structures were elucidated as 18-demethoxyltransconitine A (1) and 8-O-anisoyl-14 hydroxylacoforesticine (2). PMID- 22251157 TI - Extranodal Rosai-Dorfman disease of the kidney and bone. PMID- 22251158 TI - Bcr-Abl dependent post-transcriptional activation of NME2 expression is a specific and common feature of chronic myeloid leukemia. AB - We have previously identified NME2 (Nm23-H2) as a tumor antigen in a patient with chronic myeloid leukemia (CML). Here we investigated the association between NME2 and Bcr-Abl. NME2 protein was highly overexpressed in the cytoplasm of peripheral blood mononuclear cells from 29/30 patients with CML at diagnosis and 10/10 patients resistant to imatinib. Protein was overexpressed in the absence of increased levels of mRNA and was limited to Bcr-Abl + populations, being absent from Bcr-Abl - patient cells, normal donors and 14/15 acute myeloid leukemia (AML) samples. Furthermore, the Bcr-Abl dependent overexpression of NME2 protein was reversed specifically by tyrosine kinase inhibitor (TKI) treatment of Ba/F3 expressing wild-type and TKI-sensitive, but not TKI-resistant, mutants of Bcr Abl. The post-transcriptional up-regulation of the tumor antigen NME2 is therefore a common and specific property of CML closely associated with Bcr-Abl activity. PMID- 22251159 TI - High-oil-load encapsulation of medium-chain triglycerides and D-limonene mixture in modified starch by spray drying. AB - Oil mixtures of medium-chain triglycerides (MCT) and D-limonene in mixing ratios from 10 to 100 wt% were encapsulated in modified starch (wall material) by spray drying to produce oil-rich powders. The oil load (mass ratio of oil mixture to wall material) of the infeed emulsion markedly influenced the properties of the infeed liquid and the characteristics of the resulting powder. The viscosity of the infeed liquid and the particle size of the powder exponentially decreased with increasing oil load, while the emulsion droplet size in the infeed liquid increased. In addition, retention of D-limonene during spray drying also decreased markedly with increasing oil load. Irrespective of the different oil loads and concentrations of the wall material, D-limonene retention was well correlated with the emulsion droplet diameter of the infeed liquid. The encapsulation efficiency of the oil mixture exhibited a maximum value (almost 100%) at an oil load between 0.5 and 1.0, before decreasing at higher oil loads. At an oil load of 2.0, the encapsulation efficiency of D-limonene was reduced to almost zero, while around 40% of the initial MCT was encapsulated in the powder. The increase in oil load also led to increased amounts of surface oil of MCT and D-limonene in the resulting powder due to the increasing emulsion droplet diameter of the infeed liquids. PRACTICAL APPLICATION: This study proposes the microencapsulation of medium-chain triglycerides under high-oil-load conditions by spray drying. The powders prepared by this process provide significant benefits in terms of rapid energy conversion after consumption without accumulation in the body. Important quality factors of the powder products such as the encapsulation efficiency and the amount of surface oil were examined to understand the optimum process conditions for spray drying. PMID- 22251160 TI - Using multiple databases to produce comprehensive follow-up in an effort to enhance evaluation of outcome measurements: surgical ablation (Maze) exemplar. AB - Improving outcomes is a central theme in the national healthcare reform discussions and the ongoing debate centers on ways to limit escalating costs while maintaining excellent patient outcomes. Facilities need to be able to make sense of their "numbers," implement appropriate change in practice, evaluate the impact of this change, and understand what the new numbers are really conveying to the public. The need for a dynamic, longitudinal data system that allows rapid response to new insights and discoveries must be available on a local level. Atrial fibrillation, an electrical conduction disorder of the heart that carries significant morbidity with its onset, is a chronic condition that currently affects over 2 million people in the United States. Our institute has performed over 450 surgeries for atrial fibrillation and is one of the few facilities nationwide that offers surgery for atrial fibrillation. As an exemplar, we describe our experience with the establishment of a database process that links hospital databases together as well as creates a patient's longitudinal record of follow-up that includes later events, interventions, and outcomes out to 5 years. Furthermore, we discuss how these data have changed our practice and go beyond the reporting of just numbers. PMID- 22251163 TI - Highly enantioselective total synthesis of (+)-isonitramine. AB - A new efficient enantioselective synthetic method of (+)-isonitramine is reported. (+)-Isonitramine was obtained in 12 steps (98% ee and 43% overall yield) from delta-valerolactam via enantioselective phase-transfer catalytic alkylation, Dieckman condensation, and diastereoselective reduction as key steps. PMID- 22251165 TI - Magnetic resonance enterography guiding treatment in children with Crohn's jejunoileitis. AB - AIM: To determine the usefulness of magnetic resonance enterography (MRE) in treatment for paediatric patients with Crohn's disease. METHODS: To evaluate small bowel involvement, 45 children with Crohn's disease were scheduled for MRE. Two radiologists blinded to the patient data independently re-evaluated the images. Findings in images were compared to macroscopic findings at surgery or endoscopy. RESULTS: The terminal ileum was visualized in all with a completed procedure (43/45). The treatment remained conservative in 74% after imaging. In all 13 patients who underwent ileocolonoscopy within 3 months of MRE, the MRE findings were comparable with the macroscopic findings or revealed a more extensive disease. Bowel resection was performed in 26% after imaging. The macroscopic findings in the bowel corresponded to the MRE findings in 73%. In three MRE suggested a more severe disease than was verified intraoperatively. CONCLUSIONS: Magnetic resonance enterography identifies disease involvement in the small bowel in young patients with Crohn's disease and may guide decisions on the need for intestinal surgery or adjustment of medication. PMID- 22251164 TI - Characteristics of the actions by which 5-hydroxytryptamine affects electrical and mechanical activities in rabbit jugular vein graft. AB - BACKGROUND AND PURPOSE: The vasomodulating actions of 5-HT in vein grafts, and the underlying mechanisms, remain to be fully clarified. Here, we characterized the actions by which 5-HT affects electrical and mechanical activities in rabbit autologous jugular vein grafts. EXPERIMENTAL APPROACH: Smooth muscle cell (SMC) membrane potential and isometric tension were measured in vein grafts 4 weeks after implantation into carotid arteries. Changes in the expression of 5-HT receptor subtypes and in myosin heavy chain isoforms (SM1, SM2 and SMemb) were examined by immunohistochemistry and Western blot analysis. KEY RESULTS: The walls of grafted veins displayed massive increases in the number of SM1- and SM2 positive SMCs. 5-HT induced a large depolarization and contraction that were each reduced by both 5-HT(2A) - and 5-HT(1B/1D) -receptor antagonists. The 5-HT induced contraction was not modified by a 5-HT7 -receptor antagonist. The 5-HT7 receptor-selective agonist AS 19 did not induce relaxation during the contraction to prostaglandin F(2alpha) . Immunohistochemical and Western blot analyses revealed that immunoreactive responses against 5-HT(2A) and 5-HT(1B/1D) receptors were increased in the vein graft. CONCLUSIONS AND IMPLICATIONS: 5-HT is able to induce a large contraction in rabbit autologous jugular vein grafts through (i) an increased number of differentiated contractile SMCs; (ii) an increased number of SMCs expressing contractile 5-HT(2A) - and 5-HT(1B/1D) receptors; and (iii) a down-regulation of the function of the relaxant SMC 5-HT7 receptors. These changes in the vein graft may help it to resist the higher pressure present on the arterial side of the circulation. PMID- 22251166 TI - Contribution of the OBSCN nonsynonymous variants to aspirin exacerbated respiratory disease susceptibility in Korean population. AB - Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca(2+) by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003-0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03-0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics. PMID- 22251167 TI - Comparison of corticosterone responses to acute stressors: chronic jugular vein versus trunk blood samples in mice. AB - A commonly used method for obtaining blood samples from mice is decapitation. However, there is an obvious need for repeated blood sampling in mice under stress-free conditions. Here, we describe a simple technique to repeatedly collect blood samples from conscious, freely moving mice through a chronically implanted jugular vein catheter. Furthermore, we compare plasma corticosterone (CORT) concentrations in samples obtained through the catheter 1 day after surgery with samples taken from trunk blood obtained under basal or acute stress conditions. CORT concentrations in repeated 100-MUl venous blood samples were found to be similar to trunk blood samples both under basal conditions and after stressor exposure collected at identical time points (at 5, 15, and 60 min). Using both techniques, we demonstrate a progressive increase in CORT levels until 15 min after termination of stressor exposure and a decrease towards baseline values 60 min later. Anxiety-related behavior, as assessed on the elevated plus maze 3-4 days after surgery, did not differ between catheterized and non catheterized mice. Our results provide evidence for application of jugular vein catheterization as a technique for repeated blood sampling in conscious laboratory mice. Use of this technique will greatly reduce the number of animals required for experiments involving endocrine endpoints. PMID- 22251170 TI - Methoxylated fatty acids from the bark of Fraxinus sieboldiana. AB - Nine new fatty acid derivatives, including seven methoxylated (1, 2, and 4-8) and two hydroxylated (3 and 9) fatty acids, have been isolated from the ethanol extract of the stem bark of Fraxinus sieboldiana. Their structures were determined by spectroscopic methods including IR, MS, 1D, and 2D NMR experiments. The 3- or 9-methoxylated fatty acids are reported for the first time in nature. PMID- 22251169 TI - Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor. AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that that contributes to infarct size following focal cerebral ischemia. However, little is known about the role of 20-HETE in global cerebral ischemia or neonatal hypoxia-ischemia (H-I). The present study examined the effects of blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-n-butyl-2 methylphenyl) formamidine (HET0016) in neonatal piglets after H-I to determine if it protects highly vulnerable striatal neurons. Administration of HET0016 after H I improved early neurological recovery and protected neurons in putamen after 4 days of recovery. HET0016 had no significant effect on cerebral blood flow. cytochrome P450 4A immunoreactivity was detected in putamen neurons, and direct infusion of 20-HETE in the putamen increased phosphorylation of Na(+), K(+) ATPase and NMDA receptor NR1 subunit selectively at protein kinase C-sensitive sites but not at protein kinase A-sensitive sites. HET0016 selectively inhibited the H-I induced phosphorylation at these same sites at 3 h of recovery and improved Na(+), K(+) -ATPase activity. At 3 h, HET0016 also suppressed H-I induced extracellular signal-regulated kinase 1/2 activation and protein markers of nitrosative and oxidative stress. Thus, 20-HETE can exert direct effects on key proteins involved in neuronal excitotoxicity in vivo and contributes to neurodegeneration after global cerebral ischemia in immature brain. PMID- 22251171 TI - Simultaneous generation of binary and normal data with specified marginal and association structures. AB - Situations in which multiple outcomes and predictors of different distributional types are collected are becoming increasingly common in biopharmaceutical practice, and joint modeling of mixed types has been gaining popularity in recent years. Evaluation of various statistical techniques that have been developed for mixed data in simulated environments necessarily requires joint generation of multiple variables. This article is concerned with building a unified framework for simulating multiple binary and normal variables simultaneously given marginal characteristics and association structure via combining well-established results from the random number generation literature. We illustrate the proposed approach in two simulation settings where we use artificial data as well as real depression score data from psychiatric research, demonstrating a very close resemblance between the specified and empirically computed statistical quantities of interest through descriptive and model-based tools. PMID- 22251172 TI - Power analyses for negative binomial models with application to multiple sclerosis clinical trials. AB - We use negative binomial (NB) models for the magnetic resonance imaging (MRI) based brain lesion count data from parallel group (PG) and baseline versus treatment (BVT) trials for relapsing remitting multiple sclerosis (RRMS) patients, and describe the associated likelihood ratio (LR), score, and Wald tests. We perform power analyses and sample size estimation using the simulated percentiles of the exact distribution of the test statistics for the PG and BVT trials. When compared to the corresponding nonparametric test, the LR test results in 30-45% reduction in sample sizes for the PG trials and 25-60% reduction for the BVT trials. PMID- 22251173 TI - Sample size calculation through the incorporation of heteroscedasticity and dependence for a penalized t-statistic in microarray experiments. AB - When identifying the differentially expressed genes (DEGs) in microarray data, we often observe heteroscedasticity between groups and dependence among genes. Incorporating these factors is necessary for sample size calculation in microarray experiments. A penalized t-statistic is widely used to improve the identifiability of DEGs. We develop a formula to calculate sample size with dependence adjustment for the penalized t-statistic. Sample size is determined on the basis of overall power under certain conditions to maintain a certain false discovery rate. The usefulness of the proposed method is demonstrated by numerical studies using both simulated data and real data. PMID- 22251174 TI - A bayesian dose-finding design adapting to efficacy and tolerability response. AB - We propose a new adaptive Bayesian design, explicitly modeling the trade-off between efficacy and tolerability in dose-finding studies. This design incorporates a continuous efficacy variable and a dichotomous tolerability variable. This adaptive design was developed in the context of a drug under development for treatment of major depression, but is easily extended to any setting with a continuous efficacy and a dichotomous tolerability or safety variable. The goal is to identify a target dose that was most efficacious while still being safe. Via simulations under various scenarios we show that our design performs extremely efficiently. Our design incorporates stopping rules, adaptive allocation, and dose-response estimation (for both efficacy and tolerability), among other features. We present various metrics from our simulation study, and conclude that this is an extremely efficient way of characterizing the risk benefit profile of a drug during clinical development. PMID- 22251175 TI - An adaptive group sequential phase II design to compare treatments for survival endpoints in rare patient entities. AB - For rare diseases, standard treatments are often not available and essential study parameters are difficult or impossible to obtain. Therefore, designs of clinical trials for these diseases are often based on little information. Adaptive designs allow such trials to be started and to gain information during the study. Motivated by a trial for a rare subtype of renal-cell carcinoma, we present a two-stage adaptive design for right-censored time-to-event data and a two-sided test. After the first stage, one can stop for futility or continue with reestimated sample size. The properties of such designs are analyzed by simulation studies. PMID- 22251176 TI - Phase II cancer clinical trials with heterogeneous patient populations. AB - The patient population for a Phase II trial often consists of multiple subgroups in terms of risk level. In this case, a popular design approach is to specify the response rate and the prevalence of each subgroup, to calculate the response rate of the whole population by the weighted average of the response rates across subgroups, and to choose a standard Phase II design such as Simon's optimal or minimax design to test the response rate for the whole population. In this case, although the prevalence of each subgroup is accurately specified, the observed prevalence among the accrued patients to the study may be quite different from the expected one because of the small sample size, which is typical in most Phase II trials. The fixed rejection value for a chosen standard Phase II design may be either too conservative (i.e., increasing the false rejection probability of the experimental therapy) if the trial accrues more high-risk patients than expected, or too anti-conservative (i.e., increasing the false acceptance probability of the experimental therapy) if the trial accrues more low-risk patients than expected. We can avoid such problems by adjusting the rejection values, depending on the observed prevalence from the trial. In this paper, we investigate the performance of the flexible designs compared with the standard design with fixed rejection values under various settings. PMID- 22251177 TI - Missing data mechanisms in a dose-finding adaptive trial. AB - Although adaptive trials have become popular, little research has been done to investigate the effect of missing data in adaptive trials. We consider three different types of missing data mechanisms-missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR)-and introduce the "mixture missing mechanism" (MMM) to an adaptive three-period crossover study that uses the "maximizing procedure." These results are compared to a traditional nonadaptive equal allocation crossover study. Simulations suggest that certain missing data mechanisms can result in biased estimates. For equal allocation, the bias is uniform between treatments so treatment comparisons are unbiased. However, for the maximizing procedure, the bias is not uniform between treatments, so treatment comparisons are biased. For the MNAR and MMM mechanisms, unusually large bias occurs in the placebo group, leading to a substantial loss of power. PMID- 22251178 TI - Stopping guidelines for harm in a study designed to establish the safety of a marketed drug. AB - In a study designed to establish the safety of a marketed drug, interim analyses performed to detect harm can protect trial participants and the wider public before the final analysis occurs. Monitoring for harm within a safety study is different from monitoring for benefit, so techniques commonly used in an efficacy study of an experimental drug may not apply. We propose potentially more suitable techniques in this setting, including a novel spending function and conditional power. These techniques have reasonable operating characteristics in a simulation. The appropriate technique to implement will depend on circumstances of specific to the individual safety study. PMID- 22251179 TI - Sample size determination for alternate periods of use study designs with binary responses. AB - In this article, we consider several study designs that arise in practice, which are variations of standard crossover designs. Often, they may result from modifications made to a standard crossover design due to practical considerations. Characteristic features of the studies we are concerned with are (a) treatments consist of external use of products with little or no possibility of carry over effects, and (b) the periods of use are dictated by the subjects or by some specific event, such as diaper leakage or menstrual flow. We consider a number of such study designs for estimating the difference in the efficacy of two treatments or test products. We provide brief descriptions of studies to motivate the study design, the underlying data structure, and computations of the variances of the usual unbiased estimators of the difference in efficacy, and the sample size formulas. The situations considered here cover a number of popular crossover designs. The objective of our work is to provide guidance to members of a wide audience on how to answer the sample size question for their own nonstandard situations. We conclude the article with a brief report on a simulation study we conducted to investigate the impact of estimation on the sample size determination and consequently on the actual power realized in an effort to promote the "best practice" of checking whether the recommended sample sizes indeed achieve the desired level of power. PMID- 22251180 TI - Test procedures for disease prevalence with partially validated data. AB - Investigating the prevalence of a disease is an important topic in medical studies. Such investigations are usually based on the classification results of a group of subjects according to whether they have the disease. To classify subjects, screening tests that are inexpensive and nonintrusive to the test subjects are frequently used to produce results in a timely manner. However, such screening tests may suffer from high levels of misclassification. Although it is often possible to design a gold-standard test or device that is not subject to misclassification, such devices are usually costly and time-consuming, and in some cases intrusive to the test subjects. As a compromise between these two approaches, it is possible to use data that are obtained by the method of double sampling. In this article, we derive and investigate four test statistics for testing a hypothesis on disease prevalence with double-sampling data. The test statistics are implemented through both the asymptotic method suitable for large samples and approximate unconditional method suitable for small samples. Our simulation results show that the approximate unconditional method usually produces a more satisfactory empirical type I error rate and power than its asymptotic counterpart, especially for small to moderate sample sizes. The results also suggest that the score test and the Wald test based on an estimate of variance with parameters estimated under the null hypothesis outperform the others. An real example is used to illustrate the proposed methods. PMID- 22251181 TI - Delayed effects in the exposure-response analysis of clinical QTc trials. AB - In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration-QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized. PMID- 22251186 TI - Substance P alterations in skin and brain of chronically stressed atopic-like mice. AB - BACKGROUND: Stress is known to worsen the symptoms of atopic eczema (AE). Substance P is likely to play an important role in the development and pathogenesis of AE. OBJECTIVE: To examine a possible connection between chronic mild stress and changes in the expression of substance P and its receptor (R) neurokinin (NK) 1 in the skin and stress-related brain regions in NC/Nga atopic like mice. METHODS: The mice were divided into three groups (eight animals per group): SE (stressed eczematous), NSE (non-stressed eczematous) and SC (stressed control). Ears and brains of the mice were investigated using immunohistochemistry and RT-PCR. RESULTS: In the skin, there was a decrease in the number of substance P immunoreactive nerve fibres in SE compared with SC group. RT-PCR showed a strong tendency to an increase in mRNA for NK1R in the skin of SE compared with NSE mice. There was an increase in the number of mast cells and the degree of their degranulation in the SE compared with both other groups. A decrease in substance P immunoreactivity in medial hippocampus was found in SE compared with NSE animals. In prefrontal cortex and central amygdala, there were no significant differences in substance P immunoreactivity between the three groups. CONCLUSION: Exposure to chronic mild stress in NC/Nga atopic-like mice may result in altered expression patterns of substance P in the skin and hippocampus. PMID- 22251182 TI - Average cost-effectiveness ratio with censored data. AB - In cost-effectiveness analysis, interest could lie foremost in the incremental cost-effectiveness ratio (ICER), which is the ratio of the incremental cost to the incremental benefit of two competing interventions. The average cost effectiveness ratio (ACER) is the ratio of the cost to benefit of an intervention without reference to a comparator. A vast literature is available for statistical inference of the ICERs, but limited methods have been developed for the ACERs, particularly in the presence of censoring. Censoring is a common feature in prospective studies, and valid analyses should properly adjust for censoring in cost as well as in effectiveness. In this article, we propose statistical methods for constructing a confidence interval for the ACER from censored data. Different methods-Fieller, Taylor, bootstrap-are proposed, and through simulation studies and data analysis, we address the performance characteristics of these methods. PMID- 22251187 TI - PCR detection and identification of histamine-forming bacteria in filleted tuna fish samples. AB - Total of 14 filleted yellowfin tuna fish (Thunnus albacares) sold in wholesale fish market and supermarkets in Milan, Italy, were purchased and tested to determine microbial count, histamine level, histamine-forming bacteria, and their ability to produce histamine in culture broth. Although histamine level was less than 10 ppm, many samples showed high total viable bacterial and enterobacterial counts that reached dangerous levels after temperature abuse for short periods of time. A PCR assay targeting a 709-bp fragment of the histidine decarboxylase gene (hdc) revealed that 30.5% of the 141 enteric bacteria isolated from samples were positive and potentially able to produce histamine. The hdc positive strains were mainly isolated from fish bought at wholesale fish market, where we observed several possible risk factors, such as handling in poor and non-refrigerated conditions during fillet preparation. These positive strains were identified as Citrobacter koseri/Enterobacter spp. and Morganella morganii, by 16S/23S rRNA internal transcribed spacer amplification and 16S rRNA sequence analysis. The strains showed a variable ability of histamine production, with Morganella morganii being the most active histamine-producing species. A direct DNA extraction from fish and a PCR targeting the hdc gene showed a high degree of concordance with the results obtained through microbiological and chemical analyses, and could aid in the prompt detection of potentially contaminated fish products, before histamine accumulates. PRACTICAL APPLICATION: The use of methods for the early and rapid detection of bacteria producing biogenic amines is important for preventing accumulation of these toxic substances in food products. In this study, we used a molecular approach for the detection of histamine forming bacteria in fish. PCR-based methods require expensive equipment and a high degree of training for the user, but are fast (< 24 h) and reliable. They now represent the best predictive methods to identify a potential risk factor in fish products during processing, storage, and marketing and can be used in the investigation of risk reduction strategies. PMID- 22251188 TI - Performance of the Canadian CT Head Rule and the New Orleans Criteria for predicting any traumatic intracranial injury on computed tomography in a United States Level I trauma center. AB - OBJECTIVES: This study compared the clinical performance of the Canadian CT Head Rule (CCHR) and the New Orleans Criteria (NOC) for detecting any traumatic intracranial lesion on computed tomography (CT) in patients with a Glasgow Coma Scale (GCS) score of 15. Also assessed were ability to detect patients with "clinically important" brain injury and patients requiring neurosurgical intervention. Additionally, the performance of the CCHR was assessed in a larger cohort of those presenting with GCS of 13 to 15. METHODS: This prospective cohort study was conducted in a U.S. Level I trauma center and enrolled a consecutive sample of mildly head-injured adults who presented to the emergency department (ED) with witnessed loss of consciousness, disorientation or amnesia, and GCS 13 to 15. The rules were compared in the group of patients with GCS 15. The primary outcome was prediction of "any traumatic intracranial injury" on CT. Secondary outcomes included "clinically important brain injury" on CT and need for neurosurgical intervention. RESULTS: Among the 431 enrolled patients, 314 patients (73%) had a GCS of 15, and 22 of the 314 (7%) had evidence of a traumatic intracranial lesion on CT. There were 11 of 314 (3.5%) who had "clinically important" brain injury, and 3 of 314 (1.0%) required neurosurgical intervention. The NOC and CCHR both had 100% sensitivity (95% confidence interval [CI] = 82% to 100%), but the CCHR was more specific for detecting any traumatic intracranial lesion on CT, with a specificity of 36.3% (95% CI = 31% to 42%) versus 10.2% (95% CI = 7% to 14%) for NOC. For "clinically important" brain lesions, the CCHR and the NOC had similar sensitivity (both 100%; 95% CI = 68% to 100%), but the specificity was 35% (95% CI = 30% to 41%) for CCHR and 9.9% (95% CI = 7% to 14%) for NOC. When the rules were compared for predicting need for neurosurgical intervention, the sensitivity was equivalent at 100% (95% CI = 31% to 100%) but the CCHR had a higher specificity at 80.7% (95% CI = 76% to 85%) versus 9.6% (95% CI = 7% to 14%) for NOC. Among all 431 patients with a GCS score 13 to 15, the CCHR had sensitivities of 100% (95% CI = 84% to 100%) for 27 patients with clinically important brain injury and 100% (95% CI = 46% to 100%) for five patients requiring neurosurgical intervention. CONCLUSIONS: In a U.S. sample of mildly head-injured patients, the CCHR and the NOC had equivalently high sensitivities for detecting any traumatic intracranial lesion on CT, clinically important brain injury, and neurosurgical intervention, but the CCHR was more specific. A larger cohort will be needed to validate these findings. PMID- 22251189 TI - Normalization of vital signs does not reduce the probability of acute pulmonary embolism in symptomatic emergency department patients. AB - OBJECTIVES: In a patient with symptoms of pulmonary embolism (PE), the presence of an elevated pulse, respiratory rate, shock index, or decreased pulse oximetry increases pretest probability of PE. The objective of this study was to evaluate if normalization of an initially abnormal vital sign can be used as evidence to lower the suspicion for PE. METHODS: This was a prospective, noninterventional, single-center study of diagnostic accuracy conducted on adults presenting to an academic emergency department (ED), with at least one predefined symptom or sign of PE and one risk factor for PE. Clinical data, including the first four sets of vital signs, were recorded while the patient was in the ED. All patients underwent computed tomography pulmonary angiography (CTPA) and had 45-day follow up as criterion standards. Diagnostic accuracy of each vital sign (pulse rate, respiratory rate, shock index, pulse oximetry) at each time was examined by the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 192 were enrolled, including 35 (18%) with PE. All patients had vital signs at triage, and 174 (91%), 135 (70%), and 106 (55%) had second to fourth sets of vital signs obtained, respectively. The initial pulse oximetry reading had the highest AUC (0.63, 95% confidence interval [CI] = 0.50 to 0.76) for predicting PE, and no other vital sign at any point had an AUC over 0.60. Among patients with an abnormal pulse rate, respiratory rate, shock index, or pulse oximetry at triage that subsequently normalized, the prevalences of PE were 18, 14, 19, and 33%, respectively. CONCLUSIONS: Clinicians should not use the observation of normalized vital signs as a reason to forego objective testing for symptomatic patients with a risk factor for PE. PMID- 22251190 TI - Intranasal fentanyl and high-concentration inhaled nitrous oxide for procedural sedation: a prospective observational pilot study of adverse events and depth of sedation. AB - OBJECTIVES: Nitrous oxide (N(2)O) is an attractive agent for pediatric procedural sedation and analgesia (PSA) with rapid onset and offset of sedation. However, it has limited analgesic efficacy. Intranasal fentanyl (INF) provides nonparenteral analgesia. There are currently no data on the combined use of N(2)O and INF for PSA in children. The authors set out to prospectively assess the depth of sedation and incidence of adverse events when N(2)O and INF are used in combination in pediatric patients. METHODS: This was a prospective observational pilot study of combined N(2)O and INF for PSA at a tertiary children's hospital emergency department (ED). INF was administered at a precalculated dose of 1.5 MUg/kg for preascertained weight ranges. N(2)O concentration, dose, timing of INF, adverse events, and sedation depth were recorded. Sedation depth was recorded using the University of Michigan Sedation Scale (UMSS). RESULTS: A total of 41 patients, aged 1 to 14 years, received INF within 2 hours prior to N(2)O. N(2)O was administered at a maximal concentration of 70% in 40 patients, and at 50% in one patient. Most patients (80%) were minimally to moderately sedated (sedation score 1 or 2). Deep sedation (sedation score 3) was recorded in 14.6% of patients (95% confidence interval [CI] = 3.4% to 24.6%). No patients had serious adverse events; vomiting was recorded in 19.5% (95% CI = 7.4% to 31.6%). There were two patients (4.9%) who were deeply sedated and vomited during the procedure. CONCLUSIONS: There were no serious adverse events identified in this pilot study of combined N(2)O and INF. However, there was an increased incidence of vomiting and deeper levels of sedation when compared to published data of single-agent use of N(2)O, which could lead to more serious adverse events. Further investigation is needed to establish the analgesic efficacy of combining N(2)O and INF and to clarify the safety profile before this combination can be recommended for PSA in children. PMID- 22251191 TI - Root causes of errors in a simulated prehospital pediatric emergency. AB - OBJECTIVES: Systematic evaluation of prehospital provider performance during actual resuscitations is difficult. Although prior studies reported pediatric drug-dosing mistakes and other types of management errors, the underlying causes of those errors were not investigated. The objective of this study was to identify causes of errors during a simulated, prehospital pediatric emergency. METHODS: Two-person emergency medical services (EMS) crews from five geographically diverse agencies participated in a validated simulation of an infant with altered mental status, seizures, and respiratory arrest using their own equipment and drugs. A scoring protocol was used to identify errors. A debriefing conducted by a trained facilitator immediately after the simulated event elicited root causes of active and latent errors, which were analyzed by thematic qualitative assessment methods. RESULTS: Forty-five crews completed the study. Clinically important themes that emerged from the data included oxygen delivery, equipment organization and use, glucose measurement, drug administration, and inappropriate cardiopulmonary resuscitation. Delay in delivery of supplemental oxygen resulted from two different automaticity errors and a 54% failure rate in using an oropharyngeal airway (OPA). Most crews struggled to locate essential pediatric equipment. Three found broken or inoperable bag/valve/masks (BVMs), resulting in delayed ventilation. Some mistrusted their intraosseous (IO) injection gun device; others used it incorrectly. Only 51% of crews measured blood glucose; some discovered that glucometers were not stored in their sealed pediatric bags. The error rate for diazepam dosing was 47%; for midazolam, it was 60%. Underlying causes of dosing errors were found in four domains (cognitive, procedural, affective, and teamwork), and they included incorrect estimates of weight, incorrect use of the Broselow pediatric emergency tape, faulty recollection of doses, difficulty with calculations under stress, mg/kg to mg to mL conversion errors, inaccurate measurement of volumes, use of the wrong end of prefilled syringes, and failure to crosscheck doses with partners. CONCLUSIONS: Simulation, followed immediately by facilitated debriefing, uncovered underlying causes of active cognitive, procedural, affective, and teamwork errors, latent errors, and error-producing conditions in EMS pediatric care. PMID- 22251192 TI - They always will be with us. PMID- 22251193 TI - Developing a diagnosis-based severity classification system for use in emergency medical services for children. AB - OBJECTIVES: Lack of adequate risk adjustment methodologies has hindered the progress of emergency medicine health services research. The authors hypothesized that a consensus-derived, diagnosis-based severity classification system (SCS) would be significantly associated with actual measures of emergency department (ED) resource use and could ultimately be used to examine severity-adjusted outcomes across patient populations. METHODS: A panel of subject matter experts used consensus methods to assign severity scores (1 = lowest severity to 5 = highest severity) to 3,041 ED International Classifications of Diseases (ICD), 9th revision, diagnosis codes. SCS scores were assigned to ED visits using the visit diagnosis code with the highest severity. We tested the association between the SCS scores and measures of ED resource use in three data sets: the Pediatric Emergency Care Applied Research Network Core Data Project (PCDP), the National Hospital Ambulatory Medical Care Survey (NHAMCS), and the Connecticut state ED data set. RESULTS: There was a significant association between the five-level SCS and all six measures of resource use: triage category, disposition, ED resource use, Current Procedural Terminology Evaluation and Management (CPT E&M) codes, ED length of stay, and ED charges within the three ED data sets. CONCLUSIONS: The SCS demonstrates validity in its strong association with actual ED resource use. The use of readily available ICD-9 diagnosis codes makes the SCS useful as a risk adjustment tool for health services research. PMID- 22251194 TI - Lung sound patterns help to distinguish congestive heart failure, chronic obstructive pulmonary disease, and asthma exacerbations. AB - OBJECTIVES: Although congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and asthma patients typically present with abnormal auscultatory findings on lung examination, respiratory sounds are not normally subjected to rigorous analysis. The aim of this study was to evaluate in detail the distribution of respiratory sound intensity in CHF, COPD, and asthma patients during acute exacerbation. METHODS: Respiratory sounds throughout the respiratory cycle were captured and displayed using an acoustic-based imaging technique. Breath sound distribution was mapped to create a gray-scale sequence of two dimensional images based on intensity of sound (vibration). Consecutive CHF (n = 22), COPD (n = 19), and asthma (n = 18) patients were imaged at the time of presentation to the emergency department (ED). Twenty healthy subjects were also enrolled as a comparison group. Geographical area of the images and respiratory sound patterns were quantitatively analyzed. RESULTS: In healthy volunteers and COPD patients, the median (interquartile range [IQR]) geographical areas of the vibration energy images were similar, at 75.6 (IQR = 6.0) and 75.8 (IQR = 10.8) kilopixels, respectively (p > 0.05). Compared to healthy volunteers and COPD patients, areas for CHF and asthma patients were smaller, at 66.9 (IQR = 9.9) and 53.9 (IQR = 15.6) kilopixels, respectively (p < 0.05). The geographic area ratios between the left and right lungs for healthy volunteers and CHF and COPD patients were 1.0 (IQR = 0.2), 1.0 (IQR = 0.2), and 1.0 (IQR = 0.1), respectively. Compared to healthy volunteers, the geographic area ratio between the left and right lungs for asthma patients was 0.5 (IQR = 0.4; p < 0.05). In healthy volunteers and CHF patients, the ratios of vibration energy values at peak inspiration and expiration (peak I/E ratio) were 4.6 (IQR = 4.4) and 4.7 (IQR = 3.5). In marked contrast, the peak I/E ratios of COPD and asthma patients were 3.4 (= 2.1) and 0.1 (IQR = 0.3; p < 0.05), respectively. CONCLUSIONS: The pilot data generated in this study support the concept that relative differences in respiratory sound intensity may be useful in distinguishing acute dyspnea caused by CHF, COPD, or asthma. PMID- 22251195 TI - Re: "Immediate complications of intravenous contrast for computed tomography imaging in the outpatient setting are rare". PMID- 22251198 TI - Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres (pattern 1) shows superior survival to patterns 2 and 3: a meta-analysis of 56 cases. AB - AIMS: Angioimmunoblastic T-cell lymphoma (AITL) may present in patterns 1, 2 or 3, representing those with hyperplastic, regressed or effaced germinal centres (GCs), respectively, but the prognostic utility of this subclassification has not been previously validated. METHODS AND RESULTS: Twenty-five cases of AITL were reviewed immunohistologically and with in-situ hybridization for Epstein-Barr virus-encoded RNA and polymerase chain reaction for T-cell receptor gamma and immunoglobulin heavy chain clonality and followed for up to 120 months. Four cases had conventional hyperplastic GCs, two had floral GCs, and one had progressively transformed GCs, consistent with pattern 1 and one additional case had hyalinized GCs, consistent with pattern 2. The remaining 17 (pattern 3) cases lacked morphologically discernible GCs. The Kaplan-Meier survival distribution of pattern 1 cases (5-year survival 83%) was superior to that of pattern 2 and 3 cases [5-year-survival 36% (P = 0.0417)] only when combined with the 31 cases, seven of which were pattern 1, that Attygalle et al. had followed for up to 247 months and previously published. Furthermore, the development of B-lineage (classical Hodgkin or diffuse large-cell) lymphoma was associated exclusively with pattern 3 (P = 0.0057). CONCLUSIONS: Pattern 1 represents an indolent phase/grade of AITL, unassociated with the development of secondary B-lineage lymphoma and uninfluenced by treatment regimen. PMID- 22251199 TI - A fish eye out of water: epithelial surface projections on aerial and aquatic corneas of the 'four-eyed fish' Anableps anableps. AB - BACKGROUND: Vertebrate corneas feature a variety of microprojections, to which a tear film adheres. These microprojections are formed by folds in epithelial cell membranes, which increase surface area, stabilise the tear film and enhance movement of nutritional and waste products across cell membranes. Differences in corneal microprojections among vertebrates have been correlated with habitat and differ markedly between terrestrial and aquatic species. METHODS: This study investigated epithelial microprojections of both the aerial (dorsal) and aquatic (ventral) corneal surfaces of the 'four-eyed fish' Anableps anableps using scanning electron microscopy. RESULTS: The central region of the dorsal cornea, which projects above the water, had a density of 16,387 +/- 3,995 cells per mm(2) , while the central region of the ventral cornea (underwater) had a density of 22,428 +/- 6,387 cells per mm(2), a difference that suggests an environmental adaptation along the two visual axes. Both corneal surfaces were found to possess microridges rather than microvilli or microplicae characteristic of terrestrial/aerial vertebrates. Microridges were 142 +/- 9 nm wide and did not differ (p = 0.757) between dorsal and ventral corneas. Microridges were consistently separated by a distance of 369 +/- 9 nm across both corneas. CONCLUSION: Dorsal-ventral differences in corneal epithelial cell density in Anableps anableps suggest a difference in osmotic pressure of the two corneas. The modest differences in the microprojections indicate that the need to secure the tear film underlying each optical axis is of prime importance, due to the likelihood that a persistent layer of water normally covers both dorsal and ventral corneal surfaces and that maintaining a transparent optical pathway for vision is critical for a species prone to predation from both above and below the water's surface. PMID- 22251200 TI - Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis. AB - Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis. A retrospective review of the clinical records and radiological images of 205 patients with tuberous sclerosis complex (TSC) was performed to evaluate the prevalence and progression of hepatic lesions; examine the association of hepatic phenotype with genotype, age, and gender; and investigate the relationships between hepatic, renal, and pulmonary involvement. Hepatic angiomyolipomas (AML), cysts, and other benign lesions were identified in 30% of the cohort, and some lesions grew significantly over time. However, no patient had clinical symptoms or complications from hepatic lesions. TSC2 patients exhibited a higher frequency of AML compared to TSC1 patients (p = 0.037), and patients with no mutation identified exhibited a higher frequency of cysts compared to TSC2 patients (p = 0.023). Age was positively correlated with frequency of hepatic involvement (p < 0.001), whereas hepatic phenotype was independent of gender. Presence of hepatic AML was associated with presence of renal AML (p = 0.001). These findings confirm a high rate of asymptomatic hepatic lesions in TSC and further characterize the TSC phenotype. PMID- 22251201 TI - Time for a neurorestorative therapy in stroke. AB - Stroke remains one of the main causes of death and disability worldwide. The aging of the population is likely to result in a dramatic increase in the burden of stroke. Thus, it is not surprising that the pharmaceutical industry has invested much money in the development of pharmacotherapies for ischemic stroke. Promising experimental data, however, have almost consistently failed to produce a clinically effective neuroprotective or neurorestorative drug. Only intravenous recombinant tissue plasminogen activator (rtPA) has been approved for the treatment of acute ischemic stroke. Many pharmaceutical companies have scaled down their stroke programs and despite the unmet need, activity in the field is almost frozen. Trafermin, a recombinant form of human basic fibroblast growth factor (bFGF), is a good example of a translational failure in neuroprotection. However, trafermin may also promote neuronal plasticity after cerebral insults. Thus, clinical trials with trafermin in stroke are warranted but should be based on neuronal restoration rather than acute neuroprotection. PMID- 22251202 TI - Histology of micro polyps in chronic endometritis. PMID- 22251203 TI - The need for measurement of efficiency in Greek primary healthcare: the case for rural Southern and Western Greece. PMID- 22251204 TI - A systematic review of worldwide incidence of nonmelanoma skin cancer. AB - BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common cancer affecting white-skinned individuals and the incidence is increasing worldwide. OBJECTIVES: This systematic review brings together 75 studies conducted over the past half century to look at geographical variations and trends worldwide in NMSC, and specifically incidence data are compared with recent U.K. cancer registry data. METHODS: Following the development of a comprehensive search strategy, an assessment tool was adapted to look at the methodological quality of the eligible studies. RESULTS: Most of the studies focused on white populations in Europe, the U.S.A. and Australia; however, limited data were available for other skin types in regions such as Africa. Worldwide the incidence for NMSC varies widely with the highest rates in Australia [>1000/100, 000 person-years for basal cell carcinoma (BCC)] and the lowest rates in parts of Africa (< 1/100, 000 person years for BCC). The average incidence rates in England were 76.21/100, 000 person years and 22.65/100, 000 person-years for BCC and squamous cell carcinoma (SCC), respectively, with highest rates in the South-West of England (121.29/100, 000 person-years for BCC and 33.02/100, 000 person-years for SCC) and lowest rates by far in London (0.24/100, 000 person-years for BCC and 14.98/100, 000 person-years for SCC). The incidence rates in the U.K. appear to be increasing at a greater rate when compared with the rest of Europe. CONCLUSIONS: NMSC is an increasing problem for health care services worldwide. This review highlights a requirement for prevention studies in this area and the issues surrounding incomplete NMSC registration. Registration standards of NMSC should be improved to the level of other invasive disease. PMID- 22251205 TI - Effects of combinations of malathion and cypermethrin on survivability and time of metamorphosis of tadpoles of Indian cricket frog (Fejervarya limnocharis). AB - This study was undertaken to determine the effect of environmentally realistic concentrations of two commonly used pesticides viz., malathion and cypermethrin, using a fully 3 * 3 factorial experiments on the survivability and time of metamorphosis in a common rice paddy field frog (cricket frog) Fejervarya limnocharis under laboratory conditions. The results suggest that cypermethrin is more toxic than malathion and combinations of higher concentrations of cypermethrin (50 MUg/L) with malathion (250 and 500 MUg/L) are more deleterious to the survivability of tadpoles. With increasing cypermethrin concentration, the survivability of tadpole decreased (r = -0.986, P = 0.108). But cypermethrin alone induced early metamorphosis among the surviving tadpoles. However, there was a delay in the time required for metamorphosis induced by malathion and its combination with cypermethrin. The delay in metamorphosis may indicate the altered physiological fitness of the individual. The emergent froglets will be subjected to environmental stressors like high temperature and less humidity of post-monsoon tropical climate that could enhance negative influence triggered by pesticides. PMID- 22251206 TI - Bioaccessibility of arsenic in various types of rice in an in vitro gastrointestinal fluid system. AB - Rice can be a major contributor to dietary arsenic exposure because of the relatively high total arsenic concentration compared to other grains, especially for people whose main staple is rice. This study employed in vitro gastrointestinal fluid digestion to determine bioaccessible or gastrointestinal fluid extractable arsenic concentration in rice. Thirty-one rice samples, of which 60 % were grown in the United States, were purchased from food stores in New York City. Total arsenic concentrations in these samples ranged from 0.090 +/ 0.004 to 0.85 +/- 0.03 mg/kg with a mean value of 0.275 +/- 0.161 mg/kg (n = 31). Rice samples with relatively high total arsenic (>0.20 mg/kg, n = 18) were treated by in vitro artificial gastrointestinal fluid digestion, and the extractable arsenic ranged from 53 % to 102 %. The bioaccessibility of arsenic in rice decreases in the general order of extra long grain, long grain, long grain parboiled, to brown rices. PMID- 22251207 TI - Temporal variability in 20 chemical elements content of Parasol Mushroom (Macrolepiota procera) collected from two sites over a few years. AB - Mature specimens of Parasol Mushroom were collected annually in the outskirts of the Siemiany (2000-2003) and Rafa (2001-2003) sites in the northern part of Poland to examine temporal variations and similarities in the composition of 20 chemical elements. Analysis was done under the same condition and using well validated analytical methods. Elements were determined by inductively coupled plasma-atomic emission spectroscopy and cold vapour-atomic absorption spectroscopy (Hg). The ranges of Ag, Al, Ba, Ca, Cd, Co, Cu, Cr, Fe, Hg, K, Mg, Mn, Na, Ni, P, Pb, Rb, Sr and Zn concentrations in the caps of fruiting bodies were similar (p > 0.05; Mann-Whitney U test) for both geographically distant sites, and these specimens from Rafa were more contaminated with Pb (p < 0.05; Mann-Whitney U test). The annual collections of caps in the Siemiany site varied in Ag, Al, Ba, Ca, Cd, Co, Cu, Fe, Hg, Na, Rb and Sr and contents (0.05 < p < 0.001), while they were similar in Cr, K, Mg, Mn, Ni, P, Pb and Zn (p > 0.05; Mann-Whitney U test). The annual collections of specimens from the Rafa site varied in contents of Ag, Al, Ba, Ca, Fe, Hg, K, Mg, Mn, P, Rb and Zn (p > 0.05), while they were similar in Cd, Co, Cr, Cu, Na, Ni, Pb and Sr (p < 0.05). The results of this study imply that metallic elements content of Parasol Mushroom collected at the same undisrupted sites, and hence keeping the same geochemical condition for mushroom development and fructification (the same stands and probably the same mycelia), can fluctuate over the years or the life-span of mycelium. Hence, when assessing the nutritional value of essential metallic elements and status of non-essential or toxic metallic elements in Parasol's Mushroom caps (and probably also of other mushrooms species) to man, the possible fluctuation in contents over time have to be taken into account. PMID- 22251208 TI - Effect of fly ash on sorption behavior of metribuzin in agricultural soils. AB - This investigation was undertaken to determine the effect of two different fly ashes [Kota and Inderprastha (IP)] amendment on the sorption behavior of metribuzin in three Indian soil types. The IP fly ash was very effective in increasing the metribuzin sorption in the soils. The sorption with IP amendment was increased by 15-92%, whereas with the Kota fly ash an increase in sorption by 13-38% was noted. The adsorption isotherms fitted very well to the Freundlich adsorption equation and, in general, slope (1/n) values less then unity were observed. Although both the fly ashes significantly decreased metribuzin desorption, the IP fly ash was comparatively more effective in retaining metribuzin in the soils. Metribuzin sorption in the IP fly ash-amended soils showed strong correlation with the fly ash content and compared to K(f)/K(d) values, K(FA) values (sorption normalized to fly ash content) showed less variation. Metribuzin sorption-desorption did not correlate to the organic carbon content of the soil-fly ash mixture. The study demonstrates that all coal fly ashes may not be effective in enhancing the sorption of metribuzin in soils to the same extent. However, among the fly ashes used in this study, the IP fly ash was observed to be significantly effective in enhancing the sorption of metribuzin in soils. This may play an important role in reducing the run off and leaching losses of the herbicide by retaining it in the soil. PMID- 22251209 TI - Effects of carbaryl, chlorpyrifos and endosulfan on growth, reproduction and respiration of tropical epigeic earthworm, Perionyx excavatus (Perrier). AB - Effects of sub-lethal doses of carbaryl (1-Naphthyl-methylcarbamate), chlorpyrifos (O,O-diethyl O-3,5,6-trichloro-2-pyridinyl-phosphorothioate) and endosulfan (6,7,8,9,10,10-Hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3 benzodioxathiepin-3-oxide), respectively a carbamate, an organophosphate and an organochlorine insecticide on growth, reproduction and respiration of the tropical earthworm, Perionyx excavatus (Perrier) were investigated under laboratory conditions. The results showed significant reduction in biomass, production and hatching of cocoon and production of juveniles of the worms exposed to 0.75 to 3.03 mg/kg soil of carbaryl, 0.91 to 3.65 mg/kg soil of chlorpyrifos and 3.75 to 15.0 MUg/kg soil of endosulfan corresponding to 12.5 to 50 % of LC(50) value of the respective insecticide for P. excavatus. Endosulfan was found most dangerous among the three insecticides followed by carbaryl and chlorpyrifos. There was no hatching of the worms at endosulfan treatment 5.0 MUg/kg soil (25 % LC(50)) or above while the highest dose of carbaryl and chlorpyrifos (50 % of LC(50)) rendered respectively 87.13 and 24.84 % reductions in hatching as compared to control. Chlorpyrifos produced no change in respiration of the worms except at the highest dose, while the worms showed an increase in evolution of CO(2) at all doses of carbaryl and endosulfan. Based on the recommended agricultural dose of each insecticide, it was concluded that application of endosulfan and carbaryl was potentially dangerous to earthworms. PMID- 22251210 TI - Persistence of repeated triadimefon application and its impact on soil microbial functional diversity. AB - The effects of repeated applications of the fungicide triadimefon in agricultural soil on the microbial functional diversity of the soil and on the persistence of the fungicide in the soil were investigated under laboratory conditions. The degradation half-lives of triadimefon at the recommended dosage, simulated by a first-order kinetic model, were 23.90, 22.95, and 21.52 days for the first, second, and third applications, respectively. Throughout this study, no significant inhibition of the Shannon-Wiener index (H') was observed. However, the Simpson index (1/D) and the McIntosh index (U) were obviously reduced (p <= 0.05) during the initial 3 days after the first triadimefon application and thereafter, gradually recovered to or exceeded the level of the control soil. A similar trend in variation but with a faster recovery in the 1/D and U was observed after the second and third triadimefon applications, respectively. Taken together, the above results indicate that the repeated application of triadimefon enhanced the degradation rate of the fungicide and the recovery rate of the soil microbial functional diversity. It is concluded that repeated triadimefon applications in soil have a transient or temporary inhibitory effect on soil microbial communities. PMID- 22251211 TI - Use of quantitative-structure property relationship (QSPR) and artificial neural network (ANN) based approaches for estimating the octanol-water partition coefficients of the 209 chlorinated trans-azobenzene congeners. AB - Polychlorinated azobenzenes (PCABs) can be found as contaminant by products in 3,4-dichloroaniline and its derivatives and in the herbicides Diuron, Linuron, Methazole, Neburon, Propanil and SWEP. Trans congeners of PCABs are physically and chemically more stable and so are environmentally relevant, when compared to unstable cis congeners. In this study, to fulfill gaps on environmentally relevant partitioning properties of PCABs, the values of n-octanol/water partition coefficients (log K(OW)) have been determined for 209 congeners of chloro-trans-azobenzene (Ct-AB) by means of quantitative structure-property relationship (QSPR) approach and artificial neural networks (ANN) predictive ability. The QSPR methods used based on geometry optimalization and quantum chemical structural descriptors, which were computed on the level of density functional theory (DFT) using B3LYP functional and 6-311++G basis set in Gaussian 03 and of the semi-empirical quantum chemistry method (PM6) of the molecular orbital package (MOPAC). Polychlorinated dibenzo-p-dioxins (PCDDs), -furans (PCDFs) and -biphenyls (PCBs), to which PCABs are related, were reference compounds in this study. An experimentally obtained data on physical and chemical properties of PCDD/Fs and PCBs were reference data for ANN predictions of log K(OW) values of Ct-ABs in this study. Both calculation methods gave similar results in term of absolute log K(OW) values, while the models generated by PM6 are considered highly efficient in time spent, when compared to these by DFT. The estimated log K(OW) values of 209 Ct-ABs varied between 5.22-5.57 and 5.45-5.60 for Mono-, 5.56-6.00 and 5.59-6.07 for Di-, 5.89-6.56 and 5.91-6.46 for Tri-, 6.10-7.05 and 6.13-6.80 for Tetra-, 6.43-7.39 and 6.48-7.14 for Penta-, 6.61-7.78 and 6.98-7.42 for Hexa-, 7.41-7.94 and 7.34-7.86 for Hepta-, 7.99-8.17 and 7.72 8.20 for Octa-, 8.35-8.42 and 8.10-8.62 for NonaCt-ABs, and 8.52-8.60 and 8.81 8.83 for DecaCt-AB. These log K(OW) values shows that Ct-ABs are compounds of relatively low environmental mobility (log K(OW) > 4.5) and of significant bioaccumulation potential. PMID- 22251212 TI - Ecotoxicological assessment of doxycycline in soil. AB - Doxycycline has been used in continually increasing quantities for mass treatment of food animals because of its greater bioavailability relative to older tetracyclines. The study presented in this paper was undertaken to investigate the degradation rate of the tetracycline derivative in manure-amended soil. In the present experiment, following composting, the doxycycline-contaminated manure was applied to agricultural land, and a field study was performed to investigate the degradation rate of doxycycline in soil. By the end of the 20-week sampling period, about 20 %, 33 % and 18 % of the initial doxycycline concentrations could be measured in soil samples taken at three different soil depths. The calculated half-life of doxycycline in the soil was 66.5, 76.3 and 59.4 days at depths of 0 cm, 25 cm and 50 cm, respectively. The potential effect of doxycycline on soil microbial activity was demonstrated by the nitrogen transformation test performed in compliance with the Organisation for Economic Co-operation and Development (OECD) Guideline No. 216. On day 28, the following nitrate concentrations of the control soil sample were found in the soil samples treated with different amounts of doxycycline: 76.9 %, 53.0 %, 65.6 %, 59.7 % and 77.1 %. PMID- 22251213 TI - Design and development of novel insect growth regulators: synthesis, characterization and effect of benzoyl thymyl thioureas and ureas on total haemocyte count of Dysdercus koenigii. AB - Insect-growth regulators (IGRs) have been receiving foremost attention as potential means of selective insect control. Benzoyl phenyl urea (BPU) is a well known IGR having chitin synthesis inhibitor activity. Mimics of BPU have been synthesized by suitable derivatization of a naturally occurring monoterpenoid, thymol (2-isopropyl-5-methyl phenol) to form a = series of substituted benzoyl thymyl thioureas (BTTUs) [IVa-f] and benzoyl thymyl ureas (BTUs) [Va-f]. The synthesized compounds have been characterized by (1)H and (13)C NMR, LC-MS and elemental analysis. These derivatives have been screened for their effect on total haemocyte count of Dysdercus koenigii. It has been observed that the introduction of substituted benzoyl thiourea and urea linkage into a thymol ring via an amino group results in higher activity than the parent compound thymol and a comparable pattern of results with the standard insect-growth regulators, Penfluron. Urea [Va-f] compounds exhibited greater effect on Total Haemocyte Count (THC) than thiourea [IVa-f]. Fluoro substitution enhanced the effect on THC more than chloro substituted compounds, while ortho-substitution resulted in a better effect than para-substitution. The results described in this paper are promising and provide new array of synthetic chemicals that may be utilized as insect growth regulators. PMID- 22251214 TI - Fate of napropamide herbicide in selected Malaysian soils. AB - This study was carried out to determine the sorption-desorption, degradation and leaching of napropamide in selected Malaysian soils. The sorption capacities of the selected Malaysian soils for napropamide were the following in descending order: Linau > Teringkap > Gunung Berinchang > Jambu > Rudua > Baging soil. The results indicate that napropamide degradation decreased with increasing soil sorption capacity. Napropamide was leached out earlier in the Baging soil than the other soils. Overall, the application of napropamide in the selected Malaysian soils would not pose a threat to the environment except in soil with low organic matter and clay content and high hydraulic conductivity, such as the Baging soil. PMID- 22251215 TI - Rapid detection of E. coli O157:H7 on turnip greens using a modified gold biosensor combined with light microscopic imaging system. AB - This research aims to demonstrate the feasibility of a modified gold biosensor to detect E. coli O157:H7 in leafy turnip greens. The gold biosensor was modified with dithiobis-succinimidyl propionate (DSP) and/or protein A or G. The gold biosensor modified with DSP (Gold-DSP) was combined with a light microscopic imaging system (LMIS). The optimal concentration and specificity of anti-E. coli O15 polyclonal antibodies (pAbs) on the biosensor were determined. The reliability of Gold-DSP biosensor was investigated by determining the sensitivity, specificity, and limit of detection (LOD) of the Gold-DSP combined with LMIS. The Gold-DSP combined with LMIS was applied to turnip greens for E. coli O157:H7 detection. The modification of Gold biosensor with DSP significantly increased the detected number of E. coli O157:H7. The specificity of pAbs was sufficient to react with target E. coli O157:H7 among the tested bacterial culture. The optimum concentration of pAbs was determined as 200 MUg/mL. The sensitivity, specificity, and LOD of Gold-DSP combined with LMIS were determined as 100%, 90%, and 10(3) CFU/25 mm(2) , respectively. When applied to turnip greens, the Gold-DSP combined with LMIS could detect 2641 +/- 394 and 15383 +/- 3853 cell/mm(2) with the initial concentrations of 10(1) and 10(2) CFU/25 g turnip greens, respectively, after 10 h-enrichment. Overall, this research suggested that the Gold-DSP combined with LMIS could be used to detect E. coli O157:H7 on turnip greens qualitatively and quantitatively. PMID- 22251216 TI - The metabolically active subpopulation in Pseudomonas aeruginosa biofilms survives exposure to membrane-targeting antimicrobials via distinct molecular mechanisms. AB - Biofilms are reported to be inherently refractory toward antimicrobial attack and, therefore, cause problems in industrial and medical settings. Pseudomonas aeruginosa biofilms contain subpopulations that exhibit high metabolic activity and subpopulations that exhibit low metabolic activity. We have found that membrane-targeting antimicrobials such as colistin, EDTA, SDS, and chlorhexidine specifically kill the inactive subpopulation in P. aeruginosa biofilms, whereas the active subpopulation survives exposure to these compounds. Because treatment of P. aeruginosa biofilms with the membrane-targeting compounds colistin, EDTA, SDS, and chlorhexidine resulted in the same spatial distribution of live and dead bacteria, we investigated whether tolerance to these compounds originated from the same molecular mechanisms. Development of colistin-tolerant subpopulations was found to depend on the pmr genes encoding lipopolysaccharide modification enzymes, as well as on the mexAB-oprM, mexCD-oprJ, and muxABC-opmB genes encoding antimicrobial efflux pumps, but does not depend on the mexPQ-opmE efflux pump genes. Development of chlorhexidine-tolerant subpopulations was found to depend on the mexCD-oprJ genes, but does not depend on the pmr, mexAB-oprM, mexPQ-opmE, or muxABC-opmB genes. Tolerance to SDS and EDTA in P. aeruginosa biofilms is linked to metabolically active cells, but does not depend on the pmr, mexAB, mexCD, mexPQ, or muxABC genes. Our data suggest that the active subpopulation in P. aeruginosa biofilms is able to adapt to exposure to membrane-targeting agents through the use of different genetic determinants, dependent on the specific membrane-targeting compound. PMID- 22251217 TI - A new phenylpropanoid glucoside from the aerial parts of Lygodium japonicum. AB - A new compound, 4-O-caffeoyl-D-glucopyranose (1), and a new natural product, 3-O caffeoyl-D-glucopyranose (2), together with six known compounds (3-8) were isolated from the aerial parts of Lygodium japonicum. Their structures were elucidated on the basis of extensive spectroscopic data analyses. The oxygen radical absorbance capacity assay was applied to evaluate their antioxidative capacities in vitro, which revealed that 1-8 showed strong antioxidative properties. PMID- 22251218 TI - A longitudinal social network analysis of peer influence, peer selection, and smoking behavior among adolescents in British schools. AB - OBJECTIVE: Similarity in smoking behavior among adolescent friends could be caused by selection of friends on the basis of behavioral similarity, or by influence processes, where behavior is changed to be similar to that of friends. The main aim of the present study is to disentangle selection and influence processes and study changes over time in these processes using new methods of longitudinal social network analysis. METHODS: The sample consists of 1716 adolescents (mean age at baseline = 12.17 years, SD = .38) in 11 British schools participating in the control group of the ASSIST (A Stop Smoking in School Trial) study. The design was longitudinal with three observations at one-year intervals. At each observation, participants were asked to report on their smoking behavior and friendship networks. An actor-based model of friendship network and smoking behavior coevolution (a statistical model for the simultaneously occurring changes in friendship nominations and smoking) was analyzed, capable of modeling possible changes occurring between observations, allowing alternative influence and selection mechanisms to be investigated, and avoiding the violation of assumptions of statistical independence of observed data. RESULTS: Adolescent's tendency to select friends based on similar smoking behavior was found to be a stronger predictor of smoking behavior than friends' influence. The proportion of smoking behavior similarity explained by smoking-based selection of friends increased over time, whereas the proportion explained by influence of friends decreased. CONCLUSIONS: Smoking prevention should not solely focus on social influence but also consider selection processes and changes in both processes over time during adolescence. PMID- 22251220 TI - Evaluative threat and ambulatory blood pressure: cardiovascular effects of social stress in daily experience. AB - OBJECTIVE: Physiological effects of social evaluation are central in models of psychosocial influences on physical health. Experimental manipulations of evaluative threat evoke substantial cardiovascular and neuroendocrine responses in laboratory studies, but only preliminary evidence is available regarding naturally occurring evaluative threats in daily life. In such nonexperimental ambulatory studies, it is essential to distinguish effects of evaluative threat from related constructs known to alter stress, such as ability perceptions and concerns about appearance. METHODS: 94 married, working couples (mean age 29.2 years) completed a 1-day (8 a.m. to 10 p.m.) ambulatory blood pressure protocol with random interval-contingent measurements using a Suntech monitor and Palm Pilot-based measures of control variables and momentary experiences of social evaluative threat, concerns about appearance, and perceived ability. RESULTS: In hierarchical analyses for couples and multiple measurement occasions (Proc Mixed; SAS) and controlling individual differences (BMI, age, income) and potential confounds (e.g., posture, activity), higher reports of social-evaluative threat were associated with higher concurrent systolic (estimate = .87, SE = .34) and diastolic blood pressure (estimate = 1.06; SE = .26), both p < .02. Effects of social-evaluative threat remained significant when perceived ability and appearance concerns were controlled. CONCLUSIONS: Naturally occurring social evaluative threat during daily activity is associated with increased systolic and diastolic blood pressure. Given associations between ambulatory blood pressure and risk of cardiovascular disease, the findings support conceptual models of threats to the social self as a potentially important influence on physical health. PMID- 22251221 TI - Treatment of anetoderma occurring after resolution of Stevens-Johnson syndrome using an ablative 10,600-nm carbon dioxide fractional laser. PMID- 22251222 TI - The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices. AB - In this study, we report that spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ST101; previously coded as ZSET1446) targets T-type voltage-gated calcium channels in mediating improved cognition in the CNS. We prepared rat somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM ST101, and performed immunoblotting and electrophysiological analyses using various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat cortical slices with a range of ST101 concentrations significantly increased calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation following a bell-shaped dose-response curve, with 0.1 nM ST101 representing the maximally effective concentration. protein kinase Calpha autophosphorylation was also significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate effect on CaMKII autophosphorylation but no effect on hippocampal protein kinase Calpha autophosphorylation in slice preparations. Consistent with increased cortical CaMKII autophosphorylation, AMPA-type glutamate receptor subunit 1 (Ser-831) phosphorylation as a CaMKII post-synaptic substrate was significantly increased by treatment with 0.1-1 nM ST101, whereas phosphorylation of the pre-synaptic substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII autophosphorylation seen following 0.1 nM ST101 treatment was significantly inhibited by pre-treatment with 1 MUM mibefradil, a T-type VGCC inhibitor, but not with N-type (omega-conotoxin), P/Q-type (omega-agatoxin) or L type (nifedipine) VGCC inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term potentiation in cortical but not hippocampal slices. Enhanced long-term potentiation in cortical slices was totally inhibited by 1 MUM mibefadil treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells over-expressing recombinant human Ca(V) 3.1 (alpha1G) T-channels and treated with 0.1 nM ST101 showed significant increases in T-type VGCC currents. These results indicate that T-type VGCCs are direct molecular targets for the novel cognitive enhancer ST101, a potential Alzheimer disease therapeutic. PMID- 22251223 TI - Unusual case of severe late-onset cytomegalovirus-induced hemorrhagic cystitis and ureteritis in a renal transplant patient. AB - Cytomegalovirus (CMV) infection is common in solid organ transplant recipients and accounts for the majority of graft compromise. Major risk factors include primary exposure to CMV infection at the time of transplantation and the use of antilymphocyte agents such as OKT3 (the monoclonal antibody muromonab-CD3) and antithymocyte globulin. It most often develops during the first 6 months after transplantation. Although current prophylactic strategies and antiviral agents have led to decreased occurrence of CMV disease in early posttransplant period, the incidence of late-onset CMV disease ranges from 2% to 7% even in the patients receiving prophylaxis with oral ganciclovir. The most common presentation of CMV disease in transplant patients is CMV pneumonitis followed by gastrointestinal disease. Hemorrhagic cystitis is a common complication following hematopoietic stem cell transplantation. The condition is usually due to cyclophosphamide-based myeloablative regimens and infectious agents. Even in these settings, CMV-induced cases occur only sporadically. Ureteritis and hemorrhagic cystitis due to CMV infection after kidney transplantation is reported very rarely on a case basis in the literature so far. We report here a case of late-onset CMV-induced hemorrhagic cystitis and ureteritis presenting with painful macroscopic hematuria and ureteral obstruction after 4 years of renal transplantation. The diagnosis is pathologically confirmed by the demonstration of immunohistochemical staining specific for CMV in a resected ureteral section. We draw attention to this very particular presentation of CMV hemorrhagic cystitis with ureteral obstruction in order to emphasize atypical presentation of tissue-invasive CMV disease far beyond the timetable for posttransplant CMV infection. PMID- 22251224 TI - The impact of parental drinking on children's use of health care. AB - While a significant body of literature documents the health problems of children caused by and/or associated with parental alcohol misuse, little research has been conducted on the relationship between parental problem drinking and children's use of health care. We should expect to see an increase in children's health care if alcohol-misusing parents were responsive to their children's higher physical and mental health needs. Contrarily, it would decrease (conditional on health status) if alcohol-misusing parents were irresponsive to those needs. Analyzing a nationally representative sample of parents and children, we find a positive and significant association between parental high intensity drinking and pediatric visits for their children.We also find evidence linking parental drinking to more emergency room use. These findings suggest that the impact of parental drinking on child wellbeing should be considered when assessing the full costs of alcohol misuse. PMID- 22251225 TI - Neutrophil gelatinase-associated lipocalin regulates intracellular accumulation of Rh123 in cancer cells. AB - Multidrug resistance (MDR) is a major problem facing patients with cancer. Although Neutrophil gelatinase-associated lipocalin (NGAL) is highly expressed in various cancers, the possible role of NGAL in MDR is still obscure. In this article, we evaluated the effect of NGAL on Rh123 accumulation in cancer cells. NGAL was first down-regulated by short hairpin RNA-mediated interference. In correlation with the reduced NGAL expression, intracellular Rh123 accumulation was significantly decreased. We finally observed that inhibiting both of the ERK1/2 and p38 MAPK could seriously down-regulate NGAL expression and also decrease the intracellular accumulation of Rh123, indicating that NGAL-mediated Rh123 accumulation is regulated by the phosphorylation of ERK1/2 and p38 MAPK. Pretreatment of MDA-MB-231 with NGAL recombinant protein and antibody had significant effects on the intracellular accumulation of Rh123, whereas little effect was observed in K562 cells treated with the same method, suggesting that NGAL was involved in the regulation of Rh123 accumulation in these two types of cancers, although different pathways. Here we provide new evidence that directly shows the possibility of small chemical substances Rh123 intracellular accumulation that is regulated by NGAL. These results suggest the possibility of NGAL involvement in drug transportation and cancer MDR formation, and indicate the potential of NGAL in cancer therapy. PMID- 22251226 TI - The efficacy and safety of etanercept when used with as-needed adjunctive topical therapy in a randomised, double-blind study in subjects with moderate-to-severe psoriasis (the PRISTINE trial). AB - OBJECTIVE: To assess the efficacy and safety of two etanercept dose regimens for psoriasis treatment. METHODS: Subjects were >=18 years old with stable moderate to-severe plaque psoriasis. Subjects were randomised to etanercept 50 mg once weekly (QW) or 50 mg twice weekly (BIW) double-blind for 12 weeks, followed by 50 mg QW open label in all subjects through week 24. Only mild topical corticosteroids were permitted on scalp, axillae and groin for first 12 weeks; topical medications (corticosteroids of all potencies, vitamin D analogues and combination products) were allowed as needed for second 12 weeks at physicians' discretion, consistent with "real-world" therapeutic practice. An independent ethics committee reviewed and approved the study protocol. RESULTS: At week 24, 59.9% and 78.2% in the QW/QW and BIW/QW groups achieved PASI 75 improvement. Mean percentage PASI improvement in these groups was 58.5% and 74.1% at week 12 and 70.7% and 81.3% at week 24. Although permitted from weeks 12 to 24, topical agents were used in only 27.7% and 22.6% in the QW/QW and BIW/QW groups by week 24. CONCLUSION: Both etanercept regimens were efficacious in moderate-to-severe psoriasis, although the BIW/QW regimen consistently provided higher response rates than the QW/QW regimen. More potent topical medications were used electively in <25% of subjects in each group. PMID- 22251227 TI - Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model. AB - BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA-1a might therefore be preventable by a prophylactic regimen of inducing antibody mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof-of-concept study investigated whether passive administration of anti-beta3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT. STUDY DESIGN AND METHODS: A murine model of FNAIT using beta3 integrin (GPIIIa)-deficient (beta3-/-) mice was employed for this study. AMIS in beta3-/- mice was induced by intravenous administration of human anti-HPA-1a immunoglobulin G or murine anti-beta3 antisera given as prophylaxis after transfusion of HPA-1a-positive human PLTs or murine wild-type PLTs, respectively. RESULTS: AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose-dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead-born pups in mice receiving high-dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight. CONCLUSION: This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT. PMID- 22251228 TI - Microwave-promoted catalyst- and solvent-free aza-Diels-Alder reaction of aldimines with 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil. AB - A microwave-promoted aza-Diels-Alder reaction between 6-[2-(dimethylamino)vinyl] 1,3-dimethyluracil and aldimines has been developed for the construction of dihydropyrido[4,3-d]pyrimidines. Urea is effectively employed as an environmentally benign source of ammonia in the absence of any catalyst or solvent. The key step in the reaction is in situ generation and trapping of the reactive aldimine formed from urea and aldehyde by the diene system of the uracil. The reaction is clean, and excellent yields are obtained in a matter of a few minutes. PMID- 22251230 TI - A psychodermatology clinic: the concept, the format, and our observations from Israel. AB - The connection between the brain and the skin is more than a physiologic fact. Skin conditions can impose great effects on every field in the patients' lives. Reciprocally, skin diseases can be evoked by psychological problems. A psychodermatology clinic is the format that enables dermatology patients to receive a comprehensive approach to their skin condition as well as to the difficulties it imposes on their lives, and vice versa. Although the notion that skin and mind are connected and have bilateral influences that should be addressed is now appreciated, it is surprising that such clinics are not more prevalent. In the literature there are only a few descriptions of such clinics, and even fewer descriptions of their format and their working formulations with their pluses and minuses. In this article, we describe in detail the working formulation of a new psychodermatology clinic in Israel, as well as our therapeutic methods, data, conclusions, and observations after the first 3 years. During a 3-year period, 124 patients were seen in our psychodermatology clinic, presenting with a vast array of dermatologic complaints. One of our major observations was that lack of proper patient-doctor communication resulted in the development of misconceptions about the disease, low compliance, and even long lasting psychological difficulties. Another important observation was that there is a true need for such a clinic, among patients as well as among their doctors. PMID- 22251231 TI - The long-term cost-effectiveness of obesity prevention interventions: systematic literature review. AB - Obesity prevention provides a major opportunity to improve population health. As health improvements usually require additional and scarce resources, novel health technologies (interventions) should be economically evaluated. In the prevention of obesity, health benefits may slowly accumulate over time and it can take many years before an intervention has reached full effectiveness. Decision-analytic simulation models (DAMs), which combine evidence from diverse sources, can be utilized to evaluate the long-term cost-effectiveness of such interventions. This literature review summarizes long-term economic findings (defined as >= 40 years) for 41 obesity prevention interventions, which had been evaluated in 18 cost utility analyses, using nine different DAMs. Interventions were grouped according to their method of delivery, setting and risk factors targeted into behavioural (n=21), community (n=12) and environmental interventions (n=8). The majority of interventions offered good value for money, while seven were cost-saving. Ten interventions were not cost-effective (defined as >50,000 US dollar), however. Interventions that modified a target population's environment, i.e. fiscal and regulatory measures, reported the most favourable cost-effectiveness. Economic findings were accompanied by a large uncertainty though, which complicates judgments about the comparative cost-effectiveness of interventions. PMID- 22251232 TI - Ankle brachial index is a valuable index of the severity of atherosclerotic renal artery stenosis. AB - OBJECTIVE: The objective of this study was to investigate the relationship between the ankle brachial index (ABI) and the severity of atherosclerotic renal artery stenosis (ARAS). MATERIAL AND METHODS: In total, 138 patients with a complete clinical record were enrolled in this study. The severity of ARAS was judged by renal artery angiography and the ABI was measured according to the method recommended by the American Heart Association. RESULTS: Hypertension, coronary artery disease, chronic renal dysfunction and hyperlipidaemia were significantly increased in the ARAS group (p < 0.05 or 0.01), and the ARAS patients were significantly older than the non-ARAS patients (p < 0.05). There were 31 cases of mild renal artery stenosis, 26 of midrange stenosis, 14 of severe stenosis and 16 of bilateral stenosis. In total, 104 cases had a normal ABI, while 34 cases had an abnormal ABI (<=0.9). Abnormal ABI values were not significantly correlated with mild ARAS, but the abnormal ABI value in patients with midrange and severe ARAS was approximately four times the normal ABI in these patients. CONCLUSION: ABI is a valuable predictive index of midrange to severe ARAS. PMID- 22251233 TI - Association studies of Toll-like receptor gene polymorphisms with allograft survival in renal transplant recipients of North India. AB - Organ transplantation itself inevitably activates the innate immune system by Toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association of TLR2, TLR3, and TLR9 polymorphisms of donor-recipient pairs and acute rejection in renal transplant patients of North India. TLR2 (-196 to -174 del), TLR3 (c.1377C/T; rs 3775290), and TLR9 (+2848 G/A; rs 352140) were genotyped using DNA samples from 200 donor recipient pairs of live donor kidney transplantation by applying Restriction Fragment Length Polymorphism (RFLP) methodology. The variant allele frequency of TLR2 (-196 to -174 del) was significantly different between recipients and donors (7.5% vs. 5.0%; p = 0.049; OR = 3.9; 95% CI = 1.01-15.32). However, no significant association for allograft rejection was observed in transplant recipients for TLR3 and TLR9. Interestingly, a low prevalence of AA genotype of TLR9 + 2848 G>A was observed in rejecters when compared with non-rejecters, demonstrating protective association with allograft rejection (OR = 0.30, 95% CI = 0.12-0.88, p = 0.028). An allele in patients was also observed to be associated with higher rejection-free survival (log-rank = 0.044). These TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with renal graft rejection. PMID- 22251234 TI - Changes in attitudes toward interprofessional health care teams and education in the first- and third-year undergraduate students. AB - The interprofessional education (IPE) program at Gunma University, Maebashi, Japan, implements a lecture style for the first-year students and a training style for the third-year students. Changes in the scores of modified Attitudes Toward Health Care Teams Scale (ATHCTS) and those of modified Readiness of health care students for Interprofessional Learning Scale (RIPLS) at the beginning and the end of the term were evaluated in the 2008 academic year. Two hundred and eighty-five respondents of a possible 364 completed the survey. In both the scales, the overall mean scores declined significantly after the lecture-style learning in the first-year students, while the scores improved significantly after the training-style learning in the third-year students. Exploratory factor analysis revealed that the modified ATHCTS was composed of three subscales, and the modified RIPLS two subscales. Analyses using regression factor scores revealed that the scores of "quality of care delivery" subscale in the modified ATHCTS and those of "expertise" subscale in the modified RIPLS declined significantly in the first-year students. Consequently, IPE programs may be introduced early in the undergraduate curriculum to prevent stereotyped perceptions for IPE, and comprehensive IPE curricula may result in profound changes in attitudes among participating students. PMID- 22251235 TI - Reversible posterior leukoencephalopathy in the course of Goodpasture syndrome. AB - Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by headache, altered consciousness, seizures, and cortical blindness. The most frequent etiological factors are hypertension, kidney diseases, and immunosuppressive drugs such as steroids and cyclophosphamide. Herein we present a case of a 22-year-old female patient presented with alveolar hemorrhage and acute renal failure necessitating hemodialysis. In renal biopsy, necrotizing crescentic glomerulonephritis and immunofluorescence pattern compatible with Goodpasture syndrome were found. Anti-glomerular basement membrane antibody result was positive. At follow-up, respiratory failure ensued, steroid pulse treatment was started, and she was transferred to intensive care unit (ICU). In the ICU, she had visual disturbances and blindness together with seizures. Cranial magnetic resonance imaging (MRI) revealed irregular T2- and fluid attenuated inversion recovery (FLAIR)-weighted lesions in bilateral occipital lobes. On clinical and radiological grounds, RPLS was diagnosed. With the supportive and anti-hypertensive treatment, RPLS was resolved without a sequela. Subsequent cranial MRI was totally normal. In the literature, RPLS associated with Goodpasture syndrome was reported only once. Hypertension and methylprednisolone might be the responsible etiologies in this case. PMID- 22251236 TI - A comparative in vitro evaluation of two different magnetic devices detecting the stability of osseo-integrated implants. AB - BACKGROUND AND OBJECTIVE: It is unknown whether the resonance frequency analysis (RFA) measurements made by two different magnetic resonance frequency analysers are comparable. This in vitro study was designed to compare the RFA measurements made by the two magnetic resonance frequency analysers and to evaluate the intra- and interobserver reliability of the magnetic devices. MATERIAL AND METHODS: Thirty-two implants were placed in four cow ribs. The RFA value of each implant was measured by five different examiners. The measurements were repeated five times, in both the buccal and mesial directions, for each implant at 2 h intervals, and the averages of registered implant stability quotient (ISQ) units were recorded as the buccal ISQ value and the mesial ISQ value for every implant. RESULTS: No statistically significant differences (p>0.05) were observed between the RFA measurements made by the two magnetic devices. The intra-observer reliability of both devices was excellent, whereas the interobserver reliability of the devices was poor. CONCLUSION: The results of the RFA measurements of both tested devices overlap. Although both devices show excellent intra-observer reliability, there are variations between the measurements of different examiners. PMID- 22251237 TI - Microencapsulation of bioactives in cross-linked alginate matrices by spray drying. AB - Microencapsulation of biomolecules, cells and chemicals is widely used in the food and pharmaceutical industries to improve stability, delivery and to control the release of encapsulated moieties. Among encapsulation matrices, alginate is preferred due to its low cost, biodegradability and biocompatibility. Current methods for producing stable alginate gels involve dropping alginate suspensions into divalent cation solutions. This procedure is difficult to scale-up and produces undesirably large alginate beads. In our novel encapsulation method, alginate gelation occurs during spray drying upon volatilisation of a base and rapid release of otherwise unavailable calcium ions. The resulting particles, with median particle sizes in the range 15-120 um, are insoluble in solution. Cellulase and hemicellulase activities encapsulated by this method were not compromised during spray drying and remained stable over prolonged storage. The procedure described here offers a one-step alternative to other encapsulation methods that are costly and difficult to scale-up. PMID- 22251238 TI - Tamoxifen-loaded nanoparticles based on a novel mixture of biodegradable polyesters: characterization and in vitro evaluation as sustained release systems. AB - Nanoparticles (NP) from mixtures of two poly(D,L-lactide-co-caprolactone) (PLC) copolymers, PLC 40/60 and PLC 86/14, with poly(D,L-lactide) (PDLLA) and PCL were prepared: PLC 40/60-PCL (25:75), PLC 86/14-PCL (75:25) and PLC 86/14-PLA (75:25). Tamoxifen was loaded with encapsulation efficiency between 65% and 75% (29.9-36.3 ug TMX/ mg NP). All selected systems showed spherical shape and nano-scale size. TMX-loaded NPs were in the range of 293-352 nm. TMX release from NP took place with different profiles depending on polymeric composition of the particles. After 60 days, 59.81% and 82.65% of the loaded drug was released. The cytotoxicity of unloaded NP in MCF7 and HeLa cells was very low. Cell uptake of NP took place in both cell types by unspecific internalization in a time dependent process. The administration of 6 and 10 um TMX by TMX-loaded NP was effective on both cellular types, mainly in MCF7 cells. PMID- 22251239 TI - Poly(methyl methacrylate) particulate carriers in drug delivery. AB - Poly(methyl methacrylate) (PMMA) is one of the most widely explored biomedical materials because of its biocompatibility, and recent publications have shown an increasing interest in its applications as a drug carrier. PMMA-based particulate carriers (PMMA(P)) can be prepared either by polymerization methods or from pre formed polymer-based techniques. Potential biomedical application of these particles includes their use as adjuvant for vaccines and carrier of many drugs as antibiotics and antioxidants via different routes of administration. Release of drugs from PMMA(P) occurs typically in a biphasic way with an incomplete drug release. To improve release profiles, recent strategies are focusing on increasing polymer hydrophilicity by synthesizing functionalized PMMA microspheres or by formulating PMMA composites with hydrophilic polymers. This review examines the current status of preparation techniques, drug release kinetics, biomedical applications and toxicity of these nano/micro PMMA-based particulate carriers. PMID- 22251240 TI - Ciprofloxacin hydrochloride-loaded glyceryl monostearate nanoparticle: factorial design of Lutrol F68 and Phospholipon 90G. AB - PURPOSE: This investigation was undertaken to develop glyceryl monostearate (Geleol)-based solid lipid nanoparticles (SLNs) of a hydrophilic drug ciprofloxacin HCl. METHODS: Hansen's solubility parameter study was carried out in screening of a suitable carrier and solvent system. Subsequently, SLNs were prepared by solvent diffusion evaporation method and investigated for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE) and drug release behaviour. RESULTS: Variations in SLN composition resulted in particle sizes between 170 and 810 nm and ZPs between 8 and 14 mV. The maximum EE was found to be 26.3% with particle size of 188.8 nm. SLN can sustain the release of drug for up to 15 h and it shows Higuchi matrix model as the best-fitted model. SLNs were stable without aggregation of particles under storage conditions. CONCLUSIONS: The results of this study provide the framework for further study involving the SLN formulation for hydrophilic drug molecule. PMID- 22251241 TI - Role of glutathione S-transferases in melanoma susceptibility: association with GSTP1 rs1695 polymorphism. AB - BACKGROUND: Glutathione S-transferases (GSTs) GSTM1, GSTT1 and GSTP1 are multifunctional enzymes involved in the detoxification of a wide range of reactive oxygen species produced during melanin synthesis and oxidative stress processes. OBJECTIVES: Single nucleotide polymorphisms (SNPs) in GSTP1 and copy number variants in GSTM1 and GSTT1 may be candidate low-penetrance variants with a role in susceptibility to malignant melanoma (MM). METHODS: In this case control study, 562 Spanish patients with sporadic MM and 338 cancer-free control subjects were included, and the role of polymorphisms in these GST genes was investigated. Genotypes were established by quantitative real-time polymerase chain reaction for GSTM1 and GSTT1 while TaqMan probes were used to genotype GSTP1 SNPs. RESULTS: The GSTP1 polymorphism rs1695, which encodes the amino acid change p.Ile105Val, was individually associated with MM [odds ratio (OR): 1.32, 95% confidence interval (CI): 1.06-1.63]. Furthermore, individuals carrying one or two MC1R nonsynonymous changes and GSTP1 rs1695 rare allele had an increased risk of developing MM (OR: 3.34, 95% CI: 1.42-8.09 and OR: 20.42, 95% CI: 2.80 417.42, respectively). CONCLUSIONS: This is the first time that the GSTP1 rs1695 polymorphism is reported to be associated with MM. In addition, this study is one of the largest GST polymorphism studies undertaken in the Spanish population and the first time that copy number variants have been scrutinized in relation to MM. PMID- 22251242 TI - Substance abuse and criminal thinking: testing the countervailing, mediation, and specificity hypotheses. AB - The purpose of this study was to determine (a) which of 2 dimensions of criminal thinking (proactive and/or reactive) correlates with prior substance abuse; (b) whether criminal thinking mediates the relationship between prior substance abuse and recidivism; (c) if a direct relationship exists between specific drugs of abuse and specific criminal thinking styles. First, the reconstructed Proactive (Prc) and Reactive (Rrc) Criminal Thinking scores from the Psychological Inventory of Criminal Thinking Styles (PICTS; Walters, 1995) were correlated with a dichotomous measure of prior substance abuse and a continuous measure of the number of substances abused in a sample of 2877 male federal prisoners (age: M = 34.96, SD = 9.89, range = 18-84; race: 63.6% Black, 17.3% White, 17.6% Hispanic, 1.4% other). The results indicated that only the Rrc score correlated significantly with prior substance abuse when the effect of the alternative measure (Prc in the case of Rrc and Rrc in the case of the Prc) was controlled through partial correlations. Second, reactive criminal thinking was found to mediate the relationship between a history of prior substance abuse and subsequent recidivism in a subsample of 1101 inmates who were released from prison during a 1- to 76-month follow-up. Third, both specific (alcohol with cutoff; marijuana with cognitive indolence) and global (heroin, cocaine, and amphetamine with cutoff, cognitive indolence, and discontinuity) drug-criminal thinking correlations were obtained. These results suggest that reactive criminal thinking plays a potentially important role in the drug-crime relationship. PMID- 22251243 TI - Traumatic intrusion of permanent teeth: 10 years follow-up of 2 cases. AB - Intrusive luxation is a kind of traumatic injury characterized by an axial displacement of the tooth toward the alveolar bone. Its main causes are bicycle accidents, sports/recreational activities, and falls or collisions. Treatment strategies include waiting for the tooth to return to its position, immediate surgical repositioning, and repositioning through dental traction by orthodontic devices. In order to decide which treatment to follow, the degree of root formation, the patient's age, and intrusion severity should be taken into consideration. This study aimed to report a 10-year follow-up of two patients that suffered permanent incisor (PI) traumatic injury who had a similar root development (incomplete rooting) but different results. In the first case, the treatment of choice was follow-up. The patient showed gingival alteration and root resorption of tooth 21. Calcium hydroxide therapy and root canal filling were performed twice because of not attending callback. After finishing the endodontic treatment, follow-up visits showed no abnormalities. In the second case, the treatment of choice was watch and wait to the teeth 11 and 21. After 7 months spontaneous eruption of both teeth was detected. Radiographic examination showed atypical root formation and almost completely pulp canal obliteration, 8 years later. In the follow-up, visit after 10 years was observed complete crow and pulp canal obliteration. It was concluded that PI intrusion treatments are good intervention alternatives, as they proved to be successful after a 10-year follow-up period. PMID- 22251244 TI - Double trichophytic closure with wavy two-layered closure for optimal hair transplantation scar. PMID- 22251245 TI - Assay dilution factors confound measures of total antioxidant capacity in polyphenol-rich juices. AB - The extent to which sample dilution factor (DF) affects total antioxidant capacity (TAC) values is poorly understood. Thus, we examined the impact of DF on the ORAC, FRAP, DPPH, and total phenols (TP) assays using pomegranate juice (PJ), grape juice (GJ), selected flavonoids, ascorbic acid, and ellagic acid. For ORAC, GJ was comparable to PJ at DF 750, but at DF 2000, the ORAC value of GJ was 40% more than PJ. Increasing DF increased GJ and PJ, DPPH, TP, and FRAP values 11% and 14%, respectively. Increased test concentrations of quercetin and catechin resulted in 51% and 126% greater ORAC values, but decreased naringenin by 68%. Flavonoids, but not ellagic acid or ascorbic acid, may contribute to the dilution effect on the variation of final TAC values. Thus, reporting TAC or TP using a single DF may introduce uncertainty about the confidence of TAC assay values, especially when comparing different juices. These results underscore the importance of using compatible test standards for reporting TAC values. PRACTICAL APPLICATION: Total antioxidant capacity (TAC) values such as the ORAC assay are increasingly used for comparison of polyphenol-rich foods and beverages. Choice of standards and test concentrations, even within the linear range of standards, may introduce variation probably due to synergy/antagonism between antioxidant and thereby, confound final TAC values. Thus, test concentration or dilution factors of samples should be considered in the design of TAC assays and interpretation of their results. PMID- 22251246 TI - Novel pathway directed by sigma E to cause cell lysis in Escherichia coli. AB - A large number of Escherichia coli cells become viable but nonculturable at early stationary phase, most of which are directed to lysis in cells with an enhanced active sigma(E) level. In this study, we examined the effect of small noncoding RNAs, MicA and RybB, as sigma(E) regulon as well as regulators of outer membrane protein (Omp) genes, on the lysis process. micA- and rybB-disrupted mutations almost completely suppressed the cell lysis. Increased expression of micA and rybB or disrupted mutation of ompA, ompC and ompW led to a significant level of cell lysis. The suppression by Mg(2+) was found to maintain the integrity of the Omp-repressed outer membrane. Taken together, the results suggest that the cell lysis proceeds in the cascade of sigma(E) -> expression of micA and rybB -> reduction in Omp proteins -> disintegration of the outer membrane. PMID- 22251247 TI - Modulation of MICA on the surface of Chlamydia trachomatis-infected endocervical epithelial cells promotes NK cell-mediated killing. AB - Chlamydia trachomatis serovars D-K are obligate intracellular bacteria that have tropism for the columnar epithelial cells of the genital tract. Chlamydia trachomatis infection has been reported to induce modifications in immune cell ligand expression on epithelial host cells. In this study, we used an in vitro infection model that resulted in a partial infection of C. trachomatis-exposed primary-like immortalized endocervical epithelial cells (A2EN). Using this model, we demonstrated that expression of the natural killer (NK) cell activating ligand, MHC class I-related protein A (MICA), was upregulated on C. trachomatis infected, but not on noninfected bystander cells. MICA upregulation was concomitant with MHC class I downregulation and impacted the susceptibility of C. trachomatis-infected cells to NK cell activity. The specificity of MICA upregulation was reflected by a higher cytolytic activity of an NK cell line (NK92MI) against C. trachomatis-infected cells compared with uninfected control cells. Significantly, data also indicated that NK cells exerted a partial, but incomplete sterilizing effect on C. trachomatis as shown by the reduction in recoverable inclusion forming units (IFU) when cocultured with C. trachomatis infected cells. Taken together, our data suggest that NK cells may play a significant role in the ability of the host to counter C. trachomatis infection. PMID- 22251249 TI - Intraorbital meningioma: resection through modified orbitozygomatic craniotomy. AB - Intraorbital meningiomas are challenging lesions to excise because of their location and the restricted surgical corridor available due to the presence of important neighboring structures. Lesions located in the posterior one-third of the orbit require skull base approaches for their exposure and safe resection. Frontoorbital and modified orbitozygomatic (OZ) craniotomies may facilitate the exposure and resection of masses in the posterior intraorbital space. Specifically, the one-piece modified OZ craniotomy provides many advantages of the "full" OZ craniotomy (which includes a more extensive zygomatic osteotomy). The modified OZ approach minimizes the extent of frontal lobe retraction and provides ample amount of space for the surgeon to exploit all the working angles to resect the tumor. The following video presentation discusses the nuances of technique for resection of an intraorbital meningioma through modified OZ approach and optic nerve decompression. The nuances of technique will be discussed. The video can be found here: http://youtu.be/fP5X2QNr5qk. PMID- 22251248 TI - Promoting nerve cell functions on hydrogels grafted with poly(L-lysine). AB - We present a novel photopolymerizable poly(L-lysine) (PLL) and use it to modify polyethylene glycol diacrylate (PEGDA) hydrogels for creating a better, permissive nerve cell niche. Compared with their neutral counterparts, these PLL grafted hydrogels greatly enhance pheochromocytoma (PC12) cell survival in encapsulation, proliferation, and neurite growth and also promote neural progenitor cell proliferation and differentiation capacity, represented by percentages of both differentiated neurons and astrocytes. The role of efficiently controlled substrate stiffness in regulating nerve cell behavior is also investigated and a polymerizable cationic small molecule, [2 (methacryloyloxy)ethyl]-trimethylammonium chloride (MTAC), is used to compare with this newly developed PLL. The results indicate that these PLL-grafted hydrogels are promising biomaterials for nerve repair and regeneration. PMID- 22251250 TI - Endoscopic endonasal transplanum transtuberculum approach for resection of retrochiasmatic craniopharyngioma. AB - Retrochiasmatic craniopharyngiomas are formidable cranial base tumors to resect because of their intimate relationship with neighboring critical neurovascular structures, particularly the undersurface of the optic chiasm and hypothalamus. Radical resection offers the best chance of minimizing tumor recurrence, although this may be associated with significant surgical morbidity. Although various transcranial approaches have been utilized (transbasal subfrontal, frontobasal interhemispheric, pterional, orbitozygomatic, and petrosal) for resection of retrochiasmatic craniopharyngiomas, each is associated with some degree of brain retraction, and direct visualization of the retrochiasmatic region is often incomplete, therefore resulting in blind dissection. The endoscopic endonasal transplanum transtuberculum approach provides the most direct route to the retrochiasmatic region while affording unmatched visualization of the undersurface of the optic chiasm, third ventricle, and hypothalamus. This advantage allows for direct bimanual tumor dissection off of these critical structures by using microsurgical principles. The endonasal route also has the advantage of avoiding brain retraction and risk of cerebral edema that can be associated with transcranial approaches. In this operative video atlas report, the authors demonstrate their step-by-step techniques for resection of a suprasellar retrochiasmatic craniopharyngioma using a purely endoscopic endonasal transplanum transtuberculum approach. They describe and illustrate the operative nuances and surgical pearls to safely and efficiently perform the approach, tumor resection, and multilayered reconstruction of the cranial base defect. The video can be found here: http://youtu.be/ZIbJvAyRxYU. PMID- 22251251 TI - Expanded endoscopic endonasal transcribriform approach for resection of anterior skull base olfactory schwannoma. AB - Anterior skull base (ASB) schwannomas are extremely rare and can often mimic other pathologies involving the ASB such as olfactory groove meningiomas, hemangiopericytomas, esthesioneuroblastomas, and other malignant ASB tumors. The mainstay of treatment for these lesions is gross-total resection. Traditionally, resection for tumors in this location is performed through a bifrontal transbasal approach that can involve some degree of brain retraction or manipulation for tumor exposure. With the recent advances in endoscopic skull base surgery, various ASB tumors can be resected successfully using an expanded endoscopic endonasal transcribriform approach through a "keyhole craniectomy" in the ventral skull base. This approach represents the most direct route to the anterior cranial base without any brain retraction. Tumor involving the paranasal sinuses, medial orbits, and cribriform plate can be readily resected. In this video atlas report, the authors demonstrate their step-by-step techniques for resection of an ASB olfactory schwannoma using a purely endoscopic endonasal transcribriform approach. They describe and illustrate the operative nuances and surgical pearls to safely and efficiently perform the approach, tumor resection, and multilayered reconstruction of the cranial base defect. The video can be found here: http://youtu.be/NLtOGfKWC6U. PMID- 22251252 TI - Modified one-piece extended transbasal approach for resection of giant anterior skull base sinonasal teratocarcinosarcoma. AB - The transbasal approach is considered the workhorse for removing a variety of benign and malignant tumors of the anterior skull base. In some instances, removal of the supraorbital bar in addition to a standard bifrontal craniotomy (extended transbasal approach) allows for additional basal exposure, thereby minimizing brain retraction. In this operative video atlas report, the authors describe and demonstrate a modified one-piece extended transbasal craniotomy that incorporates the anterior wall of the frontal sinus. The inferior margin of the osteotomy is made as low as possible through the anterior wall of the frontal sinus, starting at the nasofrontal suture and extending laterally over both orbital rims by following the contour of the anterior skull base in the coronal orientation. This modification provides an excellent line of sight to the anterior skull base without any obstruction from bone overhang, which obviates the need for any supraorbital rim removal. Removal of a giant anterior skull base sinonasal teratocarcinosarcoma via the modified one-piece extended transbasal approach is demonstrated in this operative video atlas. The authors describe and illustrate the operative nuances and surgical pearls to safely and efficiently perform the approach, tumor resection, and multilayered reconstruction of the cranial base defect. The video can be found here: http://youtu.be/x1lTtfqKIV0. PMID- 22251253 TI - Endoscopic endonasal craniopharyngioma resection. AB - The authors present the case of a 21-year-old female with a progressive bitemporal hemianopsia. Cranial MR imaging revealed a large cystic suprasellar, retrochiasmatic lesion consistent with craniopharyngioma. The lesion was fully resected through an endoscopic endonasal transsphenoidal and transplanum approach. Closure of the resultant dural defect was performed with a bilayer fascia lata button and autologous mucoperichondrial nasoseptal flap. Each portion of this procedure was recorded and is presented in an edited high-definition format. The video can be found here: http://youtu.be/i3-qieLlbVk. PMID- 22251254 TI - Endoscopic endonasal repair of spontaneous CSF fistulae. AB - The authors present a fully endoscopic endonasal repair of a spontaneous CSF leak caused by a defect in the anterior fossa floor. Patients were positioned supine in a Mayfield headholder in slight extension. A complete ethmoidectomy was performed to expose the defect. The middle turbinate was removed to increase visualization and allow for more working room. The defect was identified and exposed. A nasoseptal flap was raised and placed over the defect. A free-mucosal graft fashioned from the removed middle turbinate was placed on the nasoseptal donor site. The video can be found here: http://youtu.be/gAN2cvQVXCE. PMID- 22251255 TI - Dorsal variant blister aneurysm repair. AB - Dorsal variant proximal carotid blister aneurysms are treacherous lesions to manage. It is important to recognize this variant on preoperative angiographic imaging, in anticipation of surgical strategies for their treatment. Strategies include trapping the involved segment and revascularization if necessary. Other options include repair of the aneurysm rupture site directly. Given that these are not true berry aneurysms, repair of the rupture site involves wrapping or clip-grafting techniques. The case presented here was a young woman with a subarachnoid hemorrhage from a ruptured dorsal variant blister aneurysm. The technique used is demonstrated in the video and is a modified clip-wrap technique using woven polyester graft material. The patient was given aspirin preoperatively as preparation for the clip-wrap technique. It is the authors' current protocol to attempt a direct repair with clip-wrapping and leaving artery sacrifice with or without bypass as a salvage therapy if direct repair is not possible. Assessment of vessel patency after repair is performed by intraoperative Doppler and indocyanine green angiography. Intraoperative somatosensory and motor evoked potential monitoring is performed in all cases. The video can be found here: http://youtu.be/crUreWGQdGo. PMID- 22251256 TI - Endoscopic endonasal approach for a tuberculum sellae meningioma. AB - The authors present the technical and anatomical nuances needed to perform an endoscopic endonasal removal of a tuberculum sellae meningioma. The patient is a 47-year-old female with headaches and an incidental finding of a small tuberculum sellae meningioma with no vascular encasement, no optic canal invasion, but mild inferior to superior compression of the cisternal segment of the left optic nerve. Neuroophthalmology assessment revealed no visual defects. Treatment options included clinical observation with imaging follow-up studies, radiosurgery, and resection. The patient elected to undergo surgical removal and an endonasal endoscopic approach was the preferred surgical option. Preoperative radiological studies showed the presence of an osseous ring between the left middle and anterior clinoids, the so-called carotico-clinoidal ring. The surgical implications of this finding and its management are illustrated. The surgical anatomy of the suprasellar region is reviewed, including concepts such as the chiasmatic sulcus and limbus sphenoidale, medial and lateral optico-carotid recesses, and the paraclinoidal and supraclinoidal segments of the internal carotid artery. Emphasis is made in the importance of exposing the distal dural ring of the internal carotid artery and the precanalicular segment of the optic nerve for adequate intradural dissection. The endonasal route allows for early coagulation of the tumor meningeal supply and extensive resection of dural attachments, and importantly, provides an inferior to superior access to the infrachiasmatic region that facilitates complete tumor removal without any manipulation of the optic nerve. The lateral limit of dural removal is formed by the distal dural ring, which is gently coagulated after the tumor is resected. A 45 degrees scope is used to inspect for any residual tumor, in particular at the entrance of the optic nerve into the optic canal and at the most anterior margin of the exposure (limbus sphenoidale). The steps for reconstruction are detailed and include intradural placement of dural substitute and extradural placement of the nasoseptal flap. The nuances for proper harvesting, positioning, and reinforcement of the flap are described. No lumbar drain was used. The patient had an uneventful recovery with no CSF leak or any other complications. Imaging follow-up at 6 months showed complete removal of the tumor. The patient had no sinonasal or neurological symptoms, and olfaction was fully preserved. The video can be found here: http://youtu.be/kkuV-yyEHMg. PMID- 22251257 TI - Occlusal concepts application in resolving implant prosthetic failure: case report. AB - The prosthetic management of a poor implant treatment is presented in this case report. The recommended occlusion concepts for implant-supported prostheses were applied for the resolution of the case. The rehabilitation of the posterior segments provided a mutually protected occlusion with adequate distribution of the axial and lateral bite forces with stable posterior occlusion. The clinical exam indicated the need for modification in the vertical dimension of occlusion. Sufficient interocclusal rest space was present to test the alteration in the vertical dimension. The aim was to achieve an occlusion scheme that followed four specific criteria: (1) centric contacts and centric relation of the jaw-to-jaw position; (2) anterior guidance only; (3) shallow anterior angle of tooth contact; and (4) vertical dimension of occlusion with acceptable tooth form and guidance. The success of an oral rehabilitation relies in following the aforementioned criteria, appropriate interaction between the dental laboratory technician and the clinician, careful elaboration of the provisional rehabilitation with all the desired details to be reproduced in the final prosthetic restoration and sufficient follow-up time of the provisional prostheses before placing the final restoration. PMID- 22251258 TI - Disease severity impairs sleep quality in allergic rhinitis (The SOMNIAAR study). AB - BACKGROUND: Sleep is impaired in allergic rhinitis (AR) patients, with subsequent effects on daytime performance and health-related quality of life (QOL). Sleep quality in AR has rarely been considered through validated tools and consensus classifications. OBJECTIVE: To evaluate sleep quality and daytime somnolence in AR patients, and to estimate its relationship to disease severity according to Allergic Rhinitis and Its Impact on Asthma (ARIA) conventional and modified classifications, as well as in terms of QOL and comorbidities. METHODS: Allergic rhinitis adult patients were evaluated through a prospective, observational, multicentre survey in Spain. Symptoms were assessed using the Total Symptoms Score (TSS), specific QOL by the Rhinitis Quality of Life Questionnaire (RQLQ), sleep quality by Pittsburgh scale, and diurnal somnolence by a scale based on Epworth's, all recorded in a unique visit. RESULTS: A total of 2275 patients were included. According to ARIA criteria, 50.2% had persistent and 49.8% intermittent rhinitis, whereas 87.6% were classified as moderate-severe and 12.4% as mild; 52.8% had poor sleep quality, with a global median score for Pittsburgh scale of 6 (normal < 5) and 21.1% suffered from excessive diurnal somnolence. Correlation between Pittsburgh scale and RQLQ was moderate (r = 0.54). Among symptoms, nasal obstruction and concomitant asthma mainly, contributed to bad sleep quality. In a logistic regression model, moderate-severe rhinitis and nasal obstruction were all associated with a worse sleep quality. CONCLUSIONS AND CLINICAL RELEVANCE: Sleep quality is altered in AR patients. Sleep quality was worse in moderate severe, and particularly in severe AR. Nasal obstruction and RQLQ deterioration are associated with a poorer sleep quality. Sleep impairment is common in allergic rhinitis, particularly in more severe forms. Nasal obstruction and concomitant asthma should be considered as contributing factors. CAPSULE SUMMARY: This is a large epidemiological survey of patients with allergic rhinitis showing a strong relationship between disease severity, as assessed by a consensus classification, and sleep impairment, as measured by a validated sleep quality tool. PMID- 22251260 TI - A conceptual framework for assessing interorganizational integration and interprofessional collaboration. AB - The need for collaboration in health and social welfare is well documented internationally. It is related to the improvement of services for the users, particularly target groups with multiple problems. However, there is still insufficient knowledge of the complex area of collaboration, and the interprofessional literature highlights the need to develop adequate research approaches for exploring collaboration between organizations, professionals and service users. This paper proposes a conceptual framework based on interorganizational and interprofessional research, with focus on the concepts of integration and collaboration. Furthermore, the paper suggests how two measurement instruments can be combined and adapted to the welfare context in order to explore collaboration between organizations, professionals and service users, thereby contributing to knowledge development and policy improvement. Issues concerning reliability, validity and design alternatives, as well as the importance of management, clinical implications and service user involvement in future research, are discussed. PMID- 22251259 TI - Cost-effectiveness of cervical cancer screening: cytology versus human papillomavirus DNA testing. AB - OBJECTIVE: To determine the most cost-effective screening programme for cervical cancer. DESIGN: Cost-effectiveness analysis from a societal perspective. SETTING: The Netherlands. POPULATION: Dutch women who have not been invited for human papillomavirus (HPV) vaccination. METHODS: We calibrated the microsimulation screening analysis (MISCAN) model to Dutch epidemiological data. We used this model to consider nine screening strategies that use: (i) cytological testing with cytology triage for borderline/mildly abnormal smears; (ii) HPV testing with cytology triage for HPV-positive smears; or (iii) cytological testing with HPV triage for borderline/mildly abnormal smears. For each strategy, we varied the number of screening rounds, the time interval, the age of the first screening, and the type of cytological testing (conventional or liquid-based cytology). MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) gained and costs from a societal perspective. RESULTS: Under the base-case assumptions, primary HPV testing with cytology triage is the most cost-effective strategy. Using cost effectiveness thresholds of ? 20,000 and ? 50,000 per QALY gained yields optimal screening programmes with three and seven screening rounds, respectively. The results are sensitive to several uncertain model inputs, most importantly the costs of the HPV test. For women aged 32 years or younger, primary cytology screening is more cost-effective than primary HPV testing. CONCLUSIONS: Increasing the interval between screening rounds and changing the primary test from cytology to HPV testing can improve the effectiveness and decrease the costs of cervical cancer screening in the Netherlands. PMID- 22251261 TI - Primary cutaneous nocardiosis caused by Nocardia beijingensis. PMID- 22251262 TI - Cell permeability, migration, and reactive oxygen species induced by multiwalled carbon nanotubes in human microvascular endothelial cells. AB - Multiwalled carbon nanotubes (MWCNT) have elicited great interest in biomedical applications due to their extraordinary physical, chemical, and optical properties. Intravenous administration of MWCNT-based medical imaging agents and drugs in animal models was utilized. However, the potential harmful health effects of MWCNT administration in humans have not yet been elucidated. Furthermore, to date, there are no apparent reports regarding the precise mechanisms of translocation of MWCNT into target tissues and organs from blood circulation. This study demonstrates that exposure to MWCNT leads to an increase in cell permeability in human microvascular endothelial cells (HMVEC). The results obtained from this study also showed that the MWCNT-induced rise in endothelial permeability is mediated by reactive oxygen species (ROS) production and actin filament remodeling. In addition, it was found that MWCNT promoted cell migration in HMVEC. Mechanistically, MWCNT exposure elevated the levels of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) in HMVEC. Taken together, these results provide new insights into the bioreactivity of MWCNT, which may have implications in the biomedical application of MWCNT in vascular targeting, imaging, and drug delivery. The results generated from this study also elucidate the potential adverse effects of MWCNT exposure on humans at the cellular level. PMID- 22251263 TI - Absolute and relative organ weight trends in B6C3F1 mice. AB - Since the early 1970s, the National Cancer Institute (NCI) and National Toxicology Program (NTP) have conducted carcinogenesis and toxicology studies on several hundred chemicals using the B6C3F1 mouse. A number of publications have examined growth, survival, and tumor incidence over time, including the impact of changes in housing and diet. However, no reports have been published to date examining the variation in organ weights over time, especially in light of reported body weight effects associated with housing and diet changes. Therefore, all available absolute and relative organ weight data for untreated control B6C3F1 mice were collected from 2-wk, 3-mo, and 15-mo NCI/NTP investigations with report dates through August 2010 in order to examine organ weight changes over time and by study type. Study data were grouped into 5-yr intervals by initiation date. Body weights in males increased over time except in 2-wk studies, while body weights in females rose through 1993 and remained constant or declined thereafter. Higher body weights were noted in individually housed mice, and in drinking water studies compared to feed or inhalation studies. Elevated organ weights were typically associated with increased body weights except that lower organ weights were evident as early as 2-wk on study with the introduction of the NTP-2000 diet in 1994. Relative organ weights decreased over time in males and females. Finally, organ weight coefficients of variation (standard deviation/mean) declined over time in 2-wk, 3-mo, and 15-mo studies, which may reflect improved data collection methods or reduced interlaboratory variability. PMID- 22251264 TI - Toxicity of naphthenic acids to wood frog tadpoles (Lithobates sylvaticus). AB - Increased incidences of mortality and adverse effects have been described for wildlife exposed to oil-sands-process-affected waters (OSPW). Naphthenic acids (NA) were identified as a primary toxic component of OSPW, yet little information exists regarding NA-induced toxicity in aquatic vertebrates. Amphibian larvae may be particularly susceptible to exposure to OSPW in groundwater surrounding oil sands regions, and increased frequency of mortality and adverse developmental effects were noted in exposed tadpoles. Despite this, there are no published studies investigating the effects of NA exposure on developing tadpoles. LC50 values of 4.76 mg/L NA were found for tadpoles at an early developmental stage (Gosner stage 28), and even greater toxicity with more developed tadpoles at 96 h, with an LC50 value of 3.04 mg/L in Gosner stage 36 tadpoles. These values are well below NA concentrations found in OSPW tailing ponds and similar to levels identified in groundwater in the Athabasca Oil Sands region. PMID- 22251265 TI - Traffic air pollution and risk of death from ovarian cancer in Taiwan: fine particulate matter (PM2.5) as a proxy marker. AB - The relationship between mortality attributed to ovarian cancer and exposure to ambient air pollutants was examined using an ecological design. The study areas consisted of 61 municipalities in Taiwan. Air quality data for recorded concentrations of fine particulate matter (PM2.5) from study municipalities for 2006-2009 were obtained as a marker of traffic emissions. These were used as a proxy for polycyclic aromatic hydrocarbons (PAH) exposure. Age-standardized mortality rates for ovarian cancer were calculated for the study municipalities for the years 1999-2008. A weighted multiple regression model was employed to calculate the adjusted risk ratio (RR) in relation to PM2.5 levels. After adjusting for urbanization level and fertility rate, the adjusted RR values (95% confidence interval [CI]) for ovarian cancer were 1.2 (1.02-1.41) for the municipalities with PM2.5 levels between 30.48 MUg/m3 and 39.41 MUg/m3 and 1.2 (1.03-1.39) for the municipalities with PM2.5 levels between 39.48 MUg/m3 and 51.1 MUg/m3, compared to the municipalities with PM2.5 levels less than 30.39 MUg/m3. Results showed that individuals who resided in municipalities with higher levels of PM2.5, a proxy measure of PAH, were at an increased risk of death from ovarian cancer compared to those subjects living in municipalities with the lowest PM2.5. The findings of this study warrant further investigation into the role of exposure to air pollutants in the etiology of ovarian cancer development. PMID- 22251266 TI - Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite. AB - In former mine workers and residents of Libby, Montana, exposure to amphibole contaminated vermiculite has been associated with increased incidences of asbestosis and mesothelioma. In this study, long-term effects of Libby amphibole (LA) exposure were investigated relative to the well-characterized amosite asbestos in a rat model. Rat-respirable fractions of LA and amosite (aerodynamic diameter<=2.5 MUm) were prepared by water elutriation. Male F344 rats were exposed to a single dose of either saline, amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal (IT) instillation. One year after exposure, asbestos exposed rats displayed chronic pulmonary inflammation and fibrosis. Two years postexposure, lung inflammation and fibrosis progressed in a time- and dose dependent manner in LA-exposed rats, although the severity of inflammation and fibrosis was smaller in magnitude than in animals exposed to amosite. In contrast, gene expression of the fibrosis markers Col 1A2 and Col 3A1 was significantly greater in LA-exposed compared to amosite-exposed rats. There was no apparent evidence of preneoplastic changes in any of the asbestos-exposed groups. However, all asbestos-exposed rats demonstrated a significant increase in the expression of epidermal growth factor receptor (EGFR) 2 yr after instillation. In addition, only LA-exposed rats showed significant elevation in mesothelin (Msln) and Wilms' tumor gene (WT1) expression, suggesting possible induction of tumor pathways. These results demonstrate that a single IT exposure to LA is sufficient to induce significant fibrogenic, but not carcinogenic, effects up to 2 yr after exposure that differ both in quality and magnitude from those elicited by amosite administration at the same mass dose in F344 rats. Data showed that LA was on a mass basis less potent than amosite. PMID- 22251267 TI - The role of nafamostat mesylate in continuous renal replacement therapy among patients at high risk of bleeding. AB - Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill patients with acute kidney injury. The objectives of this retrospective study were to assess the effect of nafamostat on circuit patency of CRRT and the safety regarding bleeding complications in patients at high risk of bleeding. We conducted a retrospective study of 243 CRRT patients at high risk of bleeding. We started CRRT without anticoagulation, and nafamostat was used if hemofilter lifespan was less than 12 h. The average hemofilter lifespan was measured before and after drug infusion to evaluate the efficacy of nafamostat. The frequency and number of red blood cell (RBC) transfusions were measured to assess the safety of nafamostat. Of the 243 patients, 62 (25.5%) received nafamostat. In nafamostat group, the hemofilter lifespan was lengthened from 10.2 (7.5-13.0) h to 19.8 (12.6-26.6) h after drug infusion (p < 0.001). The hemofilter lifespan was 27.5 (17.5-38.2) h in anticoagulation-free group. The frequency of RBC transfusion during CRRT did not differ between the nafamostat group and the anticoagulation-free group (71% vs. 70%, p = NS). The median number of RBC units transfused per CRRT day was also not different between the two groups [0.7 (0.5-1.0) units/day vs. 0.7 (0.4-1.1) units/day; p = NS]. The use of nafamostat in patients at high risk of bleeding who require CRRT effectively lengthened the filter survival time without an increase in RBC transfusion. However, 74.5% of patients at high risk of bleeding maintained an acceptable CRRT hemofilter lifespan without circuit anticoagulation. PMID- 22251268 TI - Selecting a linear mixed model for longitudinal data: repeated measures analysis of variance, covariance pattern model, and growth curve approaches. AB - With increasing popularity, growth curve modeling is more and more often considered as the 1st choice for analyzing longitudinal data. Although the growth curve approach is often a good choice, other modeling strategies may more directly answer questions of interest. It is common to see researchers fit growth curve models without considering alterative modeling strategies. In this article we compare 3 approaches for analyzing longitudinal data: repeated measures analysis of variance, covariance pattern models, and growth curve models. As all are members of the general linear mixed model family, they represent somewhat different assumptions about the way individuals change. These assumptions result in different patterns of covariation among the residuals around the fixed effects. In this article, we first indicate the kinds of data that are appropriately modeled by each and use real data examples to demonstrate possible problems associated with the blanket selection of the growth curve model. We then present a simulation that indicates the utility of Akaike information criterion and Bayesian information criterion in the selection of a proper residual covariance structure. The results cast doubt on the popular practice of automatically using growth curve modeling for longitudinal data without comparing the fit of different models. Finally, we provide some practical advice for assessing mean changes in the presence of correlated data. PMID- 22251269 TI - Taxometric analysis as a general strategy for distinguishing categorical from dimensional latent structure. AB - Statistical analyses investigating latent structure can be divided into those that estimate structural model parameters and those that detect the structural model type. The most basic distinction among structure types is between categorical (discrete) and dimensional (continuous) models. It is a common, and potentially misleading, practice to apply some method for estimating a latent structural model such as factor analysis without first verifying that the latent structure type assumed by that method applies to the data. The taxometric method was developed specifically to distinguish between dimensional and 2-class models. This study evaluated the taxometric method as a means of identifying categorical structures in general. We assessed the ability of the taxometric method to distinguish between dimensional (1-class) and categorical (2-5 classes) latent structures and to estimate the number of classes in categorical datasets. Based on 50,000 Monte Carlo datasets (10,000 per structure type), and using the comparison curve fit index averaged across 3 taxometric procedures (Mean Above Minus Below A Cut, Maximum Covariance, and Latent Mode Factor Analysis) as the criterion for latent structure, the taxometric method was found superior to finite mixture modeling for distinguishing between dimensional and categorical models. A multistep iterative process of applying taxometric procedures to the data often failed to identify the number of classes in the categorical datasets accurately, however. It is concluded that the taxometric method may be an effective approach to distinguishing between dimensional and categorical structure but that other latent modeling procedures may be more effective for specifying the model. PMID- 22251270 TI - Prevention of Staphylococcus aureus biofilm formation and reduction in established biofilm density using a combination of phage K and modified derivatives. AB - AIMS: To investigate the ability of a mixture of phage K and six of its modified derivatives to prevent biofilm formation by Staphylococcus aureus and also to reduce the established biofilm density. METHODS AND RESULTS: The bioluminescence producing Staph. aureus Xen29 strain was used in the study, and incubation of this strain in static microtitre plates at 37 degrees C for 48 h confirmed its strong biofilm-forming capacity. Subsequently, removal of established biofilms of Staph. aureus Xen29 with the high-titre phage combination was investigated over time periods of 24 h, 48 h and 72 h. Results suggested that these biofilms were eliminated in a time-dependent manner, with biofilm biomass reduction significantly greater after 72 h than after 24-48 h. In addition, initial challenge of Staph. aureus Xen29 with the phage cocktail resulted in the complete inhibition of biofilm formation over a 48-h period with no appearance of phage resistance. CONCLUSIONS: In general, our findings demonstrate the potential use of a modified phage combination for the prevention and successful treatment of Staph. aureus biofilms, which are implicated in several antibiotic-resistant infections. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the first use of phage K for the successful removal and prevention of biofilms of Staph. aureus. PMID- 22251272 TI - Interplay between shape and roughness in early-stage microcapillary imbibition. AB - Flows in microcapillaries and associated imbibition phenomena play a major role across a wide spectrum of practical applications, from oil recovery to inkjet printing and from absorption in porous materials and water transport in trees to biofluidic phenomena in biomedical devices. Early investigations of spontaneous imbibition in capillaries led to the observation of a universal scaling behavior, known as the Lucas-Washburn (LW) law. The LW allows abstraction of many real-life effects, such as the inertia of the fluid, irregularities in the wall geometry, and the finite density of the vacuum phase (gas or vapor) within the channel. Such simplifying assumptions set a constraint on the design of modern microfluidic devices, operating at ever-decreasing space and time scales, where the aforementioned simplifications go under serious question. Here, through a combined use of leading-edge experimental and simulation techniques, we unravel a novel interplay between global shape and nanoscopic roughness. This interplay significantly affects the early-stage energy budget, controlling front propagation in corrugated microchannels. We find that such a budget is governed by a two-scale phenomenon: The global geometry sets the conditions for small scale structures to develop and propagate ahead of the main front. These small scale structures probe the fine-scale details of the wall geometry (nanocorrugations), and the additional friction they experience slows the entire front. We speculate that such a two-scale mechanism may provide a fairly general scenario to account for extra dissipative phenomena occurring in capillary flows with nanocorrugated walls. PMID- 22251271 TI - "It was just an unconditional gift." Self reflections of non-directed living kidney donors. AB - Non-directed living kidney donation is an important emerging type of donation, but there are concerns about ulterior motives and irrational decision-making. This study aimed to elicit the motivations and experiences of non-directed living kidney donors. Qualitative interviews were conducted with all 18 people who donated a kidney in the transplant unit of the South Island, New Zealand. Six major themes were identified: offering the chance of life (opportunity for normalcy in the recipient, good samaritanism), determination (resolute personal decision, rooted in stability, urgency, opportuneness), minimizing perceived risks (live with one kidney, trust in the medical system, physical and genetic resilience, taking chances, mental preparation, mild inconvenience), preserving anonymity (protecting donor anonymity, respecting recipient choice, receiving appreciation, knowing recipient outcomes, developing relationships), donor support (psychologic preparation, efficient coordination, reimbursement of expenses), and gaining benefits (improved fitness, empowerment and satisfaction, connectedness). Non-directed living kidney donors want to offer someone a chance of normal life; a decision driven by resoluteness and a sense of urgency. Kidney donation is perceived to offer improved fitness, and a sense of empowerment, satisfaction, and connectedness. Reluctance to consider non-directed donation programs solely on concerns of unrealistic or ill-motivations and potential feelings of donor regret appear unwarranted. PMID- 22251273 TI - Biomarkers in colorectal cancer. PMID- 22251274 TI - Association between psychological measures and brain natriuretic peptide in heart failure patients. AB - OBJECTIVE: Brain natriuretic peptide (BNP) is a promising marker for heart failure diagnosis and prognosis. Although psychological factors also influence heart failure (HF) prognosis, this might be attributed to confounding by BNP. Our aim was to examine the association between multiple psychological markers using a prospective study design with repeated N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements. DESIGN: The sample comprised 94 outpatients with systolic HF (80% men; mean age =62.2 +/- 9.3). The psychological markers (i.e., anxiety, depression, and Type D personality), assessed with the Hospital Anxiety and Depression Scale (HADS), the Beck Depression Inventory (BDI), and the Type D Scale (DS14) were assessed only at baseline. Plasma NT-proBNP levels were measured at baseline and at 9 months. RESULTS: The prevalence of anxiety, depression, and Type D personality at baseline was 23.4% (HADS-A), 17.0% (HADS D), 46.6% (BDI), and 21.3% (DS14), respectively. At baseline, none of the psychological risk markers were associated with NT-proBNP levels (all p >.05). In the subset of patients with scores on psychological risk markers both at baseline and at 9 months, there were no association between anxiety (p =0.44), depression (HADS-D: p =0.90; BDI: p =0.85), and Type D (p =0.63) with NT-proBNP levels using ANOVA for repeated measures. CONCLUSIONS: Our findings indicate that measures frequently used in HF to assess psychological risk markers are unconfounded by NT proBNP. Futher studies are warranted to replicate these findings and examine whether psychological risk markers are independent predictors of prognosis in HF or an artifact that may be attributed to other biological or behavioral mechanisms. PMID- 22251277 TI - Tooth mobility changes subsequent to root fractures: a longitudinal clinical study of 44 permanent teeth. AB - The purpose of this study was to analyze tooth mobility changes in root-fractured permanent teeth and relate this to type of interfragment healing (hard tissue healing (HT), interfragment healing with periodontal ligament (PDL) and nonhealing with interposition of granulation tissue (GT) because of pulp necrosis in the coronal fragment. Furthermore, the effect of age, location of the fracture on the root, and observation period on mobility values was analyzed. Mobility values were measured for 44 of 95 previous reported root-fractured permanent incisors. Mobility changes were measured with a Muhlemanns periodontometer and noninjured incisors served as controls. The mobility values represented the labial-lingual excursion of the root measured in MUm when the tooth received a frontal and a palatal impact of 100 g force. In 18 cases of hard tissue healing (HT), a slightly increased mobility was seen after 3 months and 1 year, and a normalization of mobility value was usually found after 5 and 10 years. In 17 cases of PDL healing, generally a higher mobility was found in comparison with root fractures healing with hard tissue, and a consistent decrease in mobility value was found in the course of the 10 year observation period. A tendency for reduced mobility over time was found, a relation that could possibly be explained by the known general decrease in tooth mobility with increasing age. Finally, nine cases of nonhealing with initial interposition of granulation tissue (GT) because of pulp necrosis in the coronal fragment resulted in increasing mobility values possibly related to a lateral breakdown of the PDL in relation to the fracture line. In control teeth, a lowering of mobility was found over the course of a 10-year observation period. In conclusion, mobility changes appeared to reflect the radiographic healing stages and known age effects upon tooth mobility. PMID- 22251275 TI - Eosinophils in glioblastoma biology. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review. PMID- 22251276 TI - The architecture and ppGpp-dependent expression of the primary transcriptome of Salmonella Typhimurium during invasion gene expression. AB - BACKGROUND: Invasion of intestinal epithelial cells by Salmonella enterica serovar Typhimurium (S. Typhimurium) requires expression of the extracellular virulence gene expression programme (ST(EX)), activation of which is dependent on the signalling molecule guanosine tetraphosphate (ppGpp). Recently, next generation transcriptomics (RNA-seq) has revealed the unexpected complexity of bacterial transcriptomes and in this report we use differential RNA sequencing (dRNA-seq) to define the high-resolution transcriptomic architecture of wild-type S. Typhimurium and a ppGpp null strain under growth conditions which model ST(EX). In doing so we show that ppGpp plays a much wider role in regulating the S. Typhimurium ST(EX) primary transcriptome than previously recognised. RESULTS: Here we report the precise mapping of transcriptional start sites (TSSs) for 78% of the S. Typhimurium open reading frames (ORFs). The TSS mapping enabled a genome-wide promoter analysis resulting in the prediction of 169 alternative sigma factor binding sites, and the prediction of the structure of 625 operons. We also report the discovery of 55 new candidate small RNAs (sRNAs) and 302 candidate antisense RNAs (asRNAs). We discovered 32 ppGpp-dependent alternative TSSs and determined the extent and level of ppGpp-dependent coding and non-coding transcription. We found that 34% and 20% of coding and non-coding RNA transcription respectively was ppGpp-dependent under these growth conditions, adding a further dimension to the role of this remarkable small regulatory molecule in enabling rapid adaptation to the infective environment. CONCLUSIONS: The transcriptional architecture of S. Typhimurium and finer definition of the key role ppGpp plays in regulating Salmonella coding and non-coding transcription should promote the understanding of gene regulation in this important food borne pathogen and act as a resource for future research. PMID- 22251278 TI - Current treatment of severe asthma. AB - Severe asthma is considered a heterogeneous disease in which a variety of clinical, physiological and inflammatory markers determine disease severity. Pivotal studies in the last 5 years have led to substantial progress in many areas, ranging from a more accurate definition of truly severe, refractory asthma, to classification of the disease into distinct clinical phenotypes, and introduction of new therapies. This review focuses on three common clinical phenotypes of severe asthma in adults (early onset severe allergic asthma, late onset non-atopic eosinophilic asthma, late onset non-eosinophilic asthma with obesity), and provides an overview of recent developments regarding treatment options that are best suited for each of these phenotypes. PMID- 22251279 TI - Usefulness of Technetium-99 m-2-methoxy-isobutyl-isonitrile liver scintigraphy for evaluating disease activity of non-alcoholic fatty liver disease. AB - AIM: Non-alcoholic steatohepatitis (NASH) is a progressive form of non alcoholic fatty liver disease (NAFLD). Therefore, it is important to evaluate disease activity and distinguish NASH from simple steatosis in NAFLD. Technetium 99 m-2-methoxy-isobutyl-isonitrile ((99m) Tc-MIBI) is a lipophilic cation designed for myocardial perfusion scintigraphy in the diagnosis of ischemic heart diseases, and its retention reflects mitochondrial function. It was reported that hepatic mitochondrial abnormalities would be an important predictive factor for NASH disease progression. The aim of this study was to examine the clinical usefulness of (99m) Tc-MIBI liver scintigraphy for evaluating disease activity of NAFLD and distinguishing NASH from simple steatosis in patients with NAFLD. METHODS: Twenty-six patients with biopsy-proven NAFLD were enrolled. Clinicolaboratory tests and (99m) Tc-MIBI liver scintigraphy were performed. To evaluate hepatic uptake, regions of interest were set at the liver and heart, and the uptake ratio of the liver to heart (liver/heart ratio) was calculated. RESULTS: All patients with NAFLD were classified into three groups according to the NAFLD activity score: non-NASH (simple steatosis) (n = 4), borderline NASH (n = 11), and NASH (n = 11). Liver/heart ratios were significantly lower in NASH than in simple steatosis (P < 0.05). Moreover, liver/heart ratios were significantly correlated with NAFLD activity scores among the patients (r = 0.413, P < 0.05). CONCLUSIONS: The present study indicates that (99m) Tc-MIBI liver scintigraphy would be a useful non-invasive functional imaging method with which to evaluate disease activity of NAFLD and distinguish NASH from simple steatosis. PMID- 22251280 TI - Interaction between nuclear graphite and molten fluoride salts: a synchrotron radiation study of the substitution of graphitic hydrogen by fluoride ion. AB - The interaction between nuclear graphite and molten fluoride salts (46.5 mol % LiF/11.5 mol % NaF/42 mol % KF) is investigated by synchrotron X-ray diffraction and C K-edge X-ray absorption near-edge structure (XANES). It is found that there are a large number of H atoms in IG-110 nuclear graphite, which is attributed to the residual C-H bond after the graphitization process of petroleum coke and pitch binder. The elastic recoil detection analysis indicates that H atoms are uniformly distributed in IG-110 nuclear graphite, in excellent agreement with the XANES results. The XANES results indicate that the immersion in molten fluoride salts at 500 degrees C led to H atoms in nuclear graphite partly substituted by the fluorine from fluoride salts to form C-F bond. The implications of these findings are discussed. PMID- 22251281 TI - Reproducibility of quantitative (R)-[11C]verapamil studies. AB - BACKGROUND: P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R) [11C]verapamil data. METHODS: Dynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures. RESULTS: Analysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data. CONCLUSION: The model of choice for analysing (R)-[11C]verapamil data is a constrained two tissue compartment model. PMID- 22251282 TI - Isomorphs in model molecular liquids. AB - Isomorphs are curves in the phase diagram along which a number of static and dynamic quantities are invariant in reduced units (Gnan, N.; et al. J. Chem. Phys.2009, 131, 234504). A liquid has good isomorphs if and only if it is strongly correlating, i.e., if the equilibrium virial/potential energy fluctuations are more than 90% correlated in the NVT ensemble. Isomorphs were previously discussed with a focus on atomic systems. This paper generalizes isomorphs to liquids composed of rigid molecules and study the isomorphs of systems of small rigid molecules: the asymmetric dumbbell model, a symmetric inverse power-law dumbbell, and the Lewis-Wahnstrom o-terphenyl (OTP) model. For all model systems, the following quantities are found to a good approximation to be invariant along an isomorph: the isochoric heat capacity, the excess entropy, the reduced molecular center-of-mass self-part of the intermediate scattering function, and the reduced molecular center-of-mass radial distribution function. In agreement with theory, we also find that an instantaneous change of temperature and density from an equilibrated state point to an isomorphic state point leads to no relaxation. The isomorphs of the Lewis-Wahnstrom OTP model were found to be more approximative than those of the asymmetric dumbbell model; this is consistent with the OTP model being less strongly correlating. The asymmetric dumbbell and Lewis-Wahnstrom OTP models each have a "master isomorph"; i.e., the isomorphs have identical shape in the virial/potential energy phase diagram. PMID- 22251283 TI - Influence of abutment screw design and surface coating on the bending flexural strength of the implant set. AB - The purpose of this study was to analyze the influence of the setting and the presence of solid lubricant on the abutment screw surface on the flexural strength of the joint implant/abutment/screw. Forty abutments were connected to external hex implants, divided into 4 groups (n = 10): FE (titanium alloy screw threaded in the extremity), LE (titanium alloy screw with solid lubricant and thread in the extremity), FT (titanium alloy screw with threaded in all its length), and LT (titanium alloy screw with solid lubricant and thread in all its length). Through the mechanical flexural test, the implant/abutment resistance was evaluated with load applied perpendicular to the long axis in a mechanical testing machine (EMIC) under a speed of 0.5 mm/min. Data were submitted to a statistics test, and results showed statistically significant differences between the FE group and the other groups, and the FE group showed the lowest values. The LE group showed greater values than the LT group, and the values were statistically significant. According to the methodology used, it can be concluded that within noncoated titanium screws, a screw threaded along its entire length provided greater rigidity to the implant set, while with the screw containing solid lubricant, the screw threaded in all its length provided less rigidity of the implant set than screws with the thread only on the end. Among screws with the same geometry, those with the solid lubricant are statistically higher than those which do not have threads just at the end, but those with threads along their entire length do not show statistically significant differences. PMID- 22251285 TI - What's happened to Staphylococcus intermedius? Taxonomic revision and emergence of multi-drug resistance. AB - Staphylococcus intermedius has been the predominant coagulase-positive Staphylococcus isolated from canine skin and mucosae and the most commonly reported staphylococcal pathogen in small animal practice for the last 35 years. Although microbiological tests have historically indicated variability in biochemical characteristics amongst S. intermedius isolates from animals, an acceptable level of diagnostic accuracy for clinical purposes was readily achievable with routine phenotypic testing. However, three recent developments have changed our understanding of the term "S. intermedius" and have challenged veterinary bacteriologists to ensure correct species identification of pathogenic staphylococci from small animals. First, the increasing recognition of meticillin resistant Staphylococcus aureus in small animal practice and its human health implications demand accurate species identification. Secondly, the application of molecular techniques to analysis of staphylococcal isolates has led to a revised taxonomy and canine isolates of S. intermedius being re-named S. pseudintermedius. Thirdly, the recent, rapid emergence of meticillin- and multi drug-resistant strains of Staphylococcus pseudintermedius (MRSP) has become a major therapeutic challenge in veterinary practice worldwide, including the UK. This article discusses the background of the recent taxonomic changes within the genus Staphylococcus and reviews the key features of MRSP and its implications for day-to-day laboratory diagnosis and small animal practice. PMID- 22251286 TI - Editorial. Looking back. PMID- 22251284 TI - Gap1 functions as a molecular chaperone to stabilize its interactive partner Gap3 during biogenesis of serine-rich repeat bacterial adhesin. AB - Serine-rich repeat glycoproteins (SRRPs) are important bacterial adhesins that are conserved in streptococci and staphylococci. Fimbriae-associated protein (Fap1) from Streptococcus parasanguinis, was the first SRRP identified; it plays an important role in bacterial biofilm formation. A gene cluster encoding glycosyltransferases and accessory secretion components is required for Fap1 biogenesis. Two glycosylation-associated proteins, Gap1 and Gap3 within the cluster, interact with each other and function in concert in Fap1 biogenesis. Here we report the new molecular events underlying contribution of the interaction to Fap1 biogenesis. The Gap1-deficient mutant rendered Gap3 unstable and degraded in vitro and in vivo. Inactivation of a gene encoding protease ClpP reversed the phenotype of the gap1 mutant, suggesting that ClpP is responsible for degradation of Gap3. Molecular chaperone GroEL was co-purified with Gap3 only when Gap1 was absent and also reacted with Gap1 monoclonal antibody, suggesting that Gap1 functions as a specific chaperone for Gap3. The N-terminal interacting domains of Gap1 mediated the Gap3 stability and Fap1 biogenesis. Gap1 homologues from Streptococcus agalactiae and Staphylococcus aureus also interacted with and stabilized corresponding Gap3 homologues, suggesting that the chaperone activity of the Gap1 homologues is common in biogenesis of SRRPs. PMID- 22251287 TI - Vowels in early words: an event-related potential study. AB - Previous behavioural research suggests that infants possess phonologically detailed representations of the vowels and consonants in familiar words. These tasks examine infants' sensitivity to mispronunciations of a target label in the presence of a target and distracter image. Sensitivity to the mispronunciation may, therefore, be contaminated by the degree of mismatch between the distracter label and the heard mispronounced label. Event-related potential (ERP) studies allow investigation of infants' sensitivity to the relationship between a heard label (correct or mispronounced) and the referent alone using single picture trials. ERPs also provide information about the timing of lexico-phonological activation in infant word recognition. The current study examined 14-month-olds' sensitivity to vowel mispronunciations of familiar words using ERP data from single picture trials. Infants were presented with familiar images followed by a correct pronunciation of its label, a vowel mispronunciation or a phonologically unrelated non-word. The results support and extend previous behavioural findings that 14-month-olds are sensitive to mispronunciations of the vowels in familiar words using an ERP task. We suggest that the presence of pictorial context reinforces infants' sensitivity to mispronunciations of words, and that mispronunciation sensitivity may rely on infants accessing the cross-modal associations between word forms and their meanings. PMID- 22251288 TI - Social factors in the development of early executive functioning: a closer look at the caregiving environment. AB - This study investigated prospective links between quality of the early caregiving environment and children's subsequent executive functioning (EF). Sixty-two families were met on five occasions, allowing for assessment of maternal interactive behavior, paternal interactive behavior, and child attachment security between 1 and 2 years of age, and child EF at 2 and 3 years. The results suggested that composite scores of parental behavior and child attachment were related to child performance on EF tasks entailing strong working memory and cognitive flexibility components (conflict-EF). In particular, child attachment security was related to conflict-EF performance at 3 years above and beyond what was explained by a combination of all other social antecedents of child EF identified thus far: child verbal ability and prior EF, family SES, and parenting behavior. Attachment security may thus play a meaningful role in young children's development of executive control. PMID- 22251289 TI - Does theory of mind performance differ in children with early-onset and regressive autism? AB - A deficit in theory of mind (ToM), or the ability to infer the mental states of others, has been implicated as one of the major characteristics of Autism Spectrum Disorder (ASD); however, little attention has been devoted to possible differences in ToM ability within ASD. The current study examined ToM performance in children with early-onset autism and regressive autism in comparison to typically developing children. Results indicated that children in the regressive autism group performed significantly better than the early-onset autism group on the non-verbal appearance-reality task. Additionally, Fisher's exact tests indicated a pattern of lowest scores in the early-onset group and highest scores in the typically developing group, whereas the regressive autism group tended to score in between the early-onset and typically developing groups. The apparent heterogeneity in ToM performance within ASD could account for the lack of universality in ToM ability found in previous studies. PMID- 22251290 TI - Action production influences 12-month-old infants' attention to others' actions. AB - Recent work implicates a link between action control systems and action understanding. In this study, we investigated the role of the motor system in the development of visual anticipation of others' actions. Twelve-month-olds engaged in behavioral and observation tasks. Containment activity, infants' spontaneous engagement in producing containment actions; and gaze latency, how quickly they shifted gaze to the goal object of another's containment actions, were measured. Findings revealed a positive relationship: infants who received the behavior task first evidenced a strong correlation between their own actions and their subsequent gaze latency of another's actions. Learning over the course of trials was not evident. These findings demonstrate a direct influence of the motor system on online visual attention to others' actions early in development. PMID- 22251292 TI - Collaborative partner or social tool? New evidence for young children's understanding of joint intentions in collaborative activities. AB - Some children's social activities are structured by joint goals. In previous research, the criterion used to determine this was relatively weak: if the partner stopped interacting, did the child attempt to re-engage her? But re engagement attempts could easily result from the child simply realizing that she needs the partner to reach her own goal in the activity (social tool explanation). In two experiments, 21- and 27-month-old children interacted with an adult in games in which they either did or did not physically need the partner to reach a concrete goal. Moreover, when the partner stopped interacting, she did so because she was either unwilling to continue (breaking off from the joint goal) or unable to continue (presumably still maintaining the joint goal). Children of both age groups encouraged the recalcitrant partner equally often whether she was or was not physically needed for goal attainment. In addition, they did so more often when the partner was unable to continue than when she was unwilling to continue. These findings suggest that young children do not just view their collaborative partners as mindless social tools, but rather as intentional, cooperative agents with whom they must coordinate intentional states. PMID- 22251291 TI - Does causal action facilitate causal perception in infants younger than 6 months of age? AB - Previous research has established that infants are unable to perceive causality until 61/4 months of age. The current experiments examined whether infants' ability to engage in causal action could facilitate causal perception prior to this age. In Experiment 1, 41/2-month-olds were randomly assigned to engage in causal action experience via Velcro sticky mittens or not engage in causal action because they wore non-sticky mittens. Both groups were then tested in the visual habituation paradigm to assess their causal perception. Infants who engaged in causal action - but not those without this causal action experience - perceived the habituation events as causal. Experiment 2 used a similar design to establish that 41/2-month-olds are unable to generalize their own causal action to causality observed in dissimilar objects. These data are the first to demonstrate that infants under 6 months of age can perceive causality, and have implications for the mechanisms underlying the development of causal perception. PMID- 22251293 TI - Refining the understanding of inhibitory processes: how response prepotency is created and overcome. AB - Understanding (a) how responses become prepotent provides insights into when inhibition is needed in everyday life. Understanding (b) how response prepotency is overcome provides insights for helping children develop strategies for overcoming such tendencies. Concerning (a), on tasks such as the day-night Stroop like task, is the difficulty with inhibiting saying the name of the stimulus due to the name being semantically related to the correct response or to its being a valid response on the task (i.e. a member of the response set) though incorrect for this stimulus? Experiment 1 (with 40 4-year-olds) suggests that prepotency is caused by membership in the response set and not semantic relation. Concerning (b), Diamond, Kirkham and Amso (2002) found that 4-year-olds could succeed on the day-night task if the experimenter sang a ditty after showing the stimulus card, before the child was to respond. They concluded that it was because delaying children's responses gave them time to compute the correct answer. However, Experiment 2 (with 90 3-year-olds) suggests that such a delay helps because it gives the incorrect, prepotent response time to passively dissipate, not because of active computation during the delay. PMID- 22251294 TI - Visually guided step descent in children with Williams syndrome. AB - Individuals with Williams syndrome (WS) have impairments in visuospatial tasks and in manual visuomotor control, consistent with parietal and cerebellar abnormalities. Here we examined whether individuals with WS also have difficulties in visually controlling whole-body movements. We investigated visual control of stepping down at a change of level in children with WS (5-16-year olds), who descended a single step while their movement was kinematically recorded. On each trial step height was set unpredictably, so that visual information was necessary to perceive the step depth and position the legs appropriately before landing. Kinematic measures established that children with WS did not use visual information to slow the leg at an appropriate point during the step. This pattern contrasts with that observed in typically developing 3- and 4-year-old children, implying severe impairment in whole-body visuomotor control in WS. For children with WS, performance was not significantly predicted by low-level visual or balance problems, but improved significantly with verbal age. The results suggest some plasticity and development in WS whole-body control. These data clearly show that visuospatial and visuomotor deficits in WS extend to the locomotor domain. Taken together with evidence for parietal and cerebellar abnormalities in WS, these results also provide new evidence for the role of these circuits in the visual control of whole-body movement. PMID- 22251295 TI - I'll have what she's having: the impact of model characteristics on children's food choices. AB - This research investigates children's use of social categories in their food selection. Across three studies, we presented preschoolers with sets of photographs that contrasted food-eating models with different characteristics, including model gender, race (Black, White), age (child or adult), and/or expression (acceptance or rejection of the food). Children were asked to pick between the photographs to choose which food they would like for snack. Results demonstrated that preschoolers prefer foods being eaten by models with positive over negative expressions, foods being eaten by child over adult models, and foods being eaten by child models of the same gender as themselves over models of the other gender. This work connects with previous research on children's understanding of social categories and also has important practical implications for how characteristics of a food-eating model can affect children's willingness to try new foods. PMID- 22251296 TI - Genetic and environmental relationships between head circumference growth in the first year of life and sociocognitive development in the second year: a longitudinal twin study. AB - Although growth in head circumference (HC) during infancy is known to predict later childhood outcomes, the mechanisms underlying this association with later sociocognitive abilities remain undetermined. Thus, using a sample of 241 pairs of normally developing Japanese twins, this study investigated the underpinnings of the association between HC growth (difference between HC at birth and at 10 months) and sociocognitive abilities at 19 months as measured by 10 items from the M-CHAT. Phenotypic correlations between HC at birth and sociocognitive abilities and between HC growth and sociocognitive abilities were marginal and not significant. However, multivariate genetic analyses using Cholesky decomposition revealed that genetic influences on HC growth and those on sociocognitive abilities were negatively associated. On the other hand, shared and nonshared environmental influences on HC growth were positively associated with influences on sociocognitive abilities. Genetic and environmental influences on HC at birth were not significantly associated with influences on sociocognitive abilities. These results help to clarify the role of brain growth during infancy in the subsequent development of sociocognitive abilities and highlight the importance of examining the different roles of genetic and environmental influences in studies of these areas. PMID- 22251297 TI - Eighteen- and 24-month-old infants correct others in anticipation of action mistakes. AB - Much of human communication and collaboration is predicated on making predictions about others' actions. Humans frequently use predictions about others' action mistakes to correct others and spare them mistakes. Such anticipatory correcting reveals a social motivation for unsolicited helping. Cognitively, it requires forward inferences about others' actions through mental attributions of goal and reality representations. The current study shows that infants spontaneously intervene when an adult is mistaken about the location of an object she is about to retrieve. Infants pointed out a correct location for an adult before she was about to commit a mistake. Infants did not intervene in control conditions when the adult had witnessed the misplacement, or when she did not intend to retrieve the misplaced object. Results suggest that preverbal infants anticipate a person's mistaken action through mental attributions of both her goal and reality representations, and correct her proactively by spontaneously providing unsolicited information. PMID- 22251299 TI - Children's essentialist reasoning about language and race. AB - Across four studies, we directly compared children's essentialist reasoning about the stability of race and language throughout an individual's lifespan. Monolingual English-speaking children were presented with a series of images of children who were either White or Black; each face was paired with a voice clip in either English or French. Participants were asked which of two adults each target child would grow up to be - one who was a 'match' to the target child in race but not language, and the other a 'match' in language but not race. Nine- to 10-year-old European American children chose the race-match, rather than the language-match. In contrast, 5-6-year-old European American children in both urban, racially diverse, and rural, racially homogeneous environments chose the language-match, even though this necessarily meant that the target child would transform racial categories. Although surprising in light of adult reasoning, these young children demonstrated an intuition about the relative stability of an individual's language compared to her racial group membership. Yet, 5-6-year-old African American children, similar to the older European American children, chose the race-match, suggesting that membership in a racial minority group may highlight children's reasoning about race as a stable category. Theoretical implications for our understanding of children's categorization of human kinds are discussed. PMID- 22251298 TI - Developmental changes in the discrimination of dynamic human actions in infancy. AB - Recent evidence suggests that adults selectively attend to features of action, such as how a hand contacts an object, and less to configural properties of action, such as spatial trajectory, when observing human actions. The current research investigated whether this bias develops in infancy. We utilized a habituation paradigm to assess 4-month-old and 10-month-old infants' discrimination of action based on featural, configural, and temporal sources of action information. Younger infants were able to discriminate changes to all three sources of information, but older infants were only able to reliably discriminate changes to featural information. These results highlight a previously unknown aspect of early action processing, and suggest that action perception may undergo a developmental process akin to perceptual narrowing. PMID- 22251300 TI - Reading acquisition enhances an early visual process of contour integration. AB - The acquisition of reading has an extensive impact on the developing brain and leads to enhanced abilities in phonological processing and visual letter perception. Could this expertise also extend to early visual abilities outside the reading domain? Here we studied the performance of illiterate, ex-illiterate and literate adults closely matched in age, socioeconomic and cultural characteristics, on a contour integration task known to depend on early visual processing. Stimuli consisted of a closed egg-shaped contour made of disconnected Gabor patches, within a background of randomly oriented Gabor stimuli. Subjects had to decide whether the egg was pointing left or right. Difficulty was varied by jittering the orientation of the Gabor patches forming the contour. Contour integration performance was lower in illiterates than in both ex-illiterate and literate controls. We argue that this difference in contour perception must reflect a genuine difference in visual function. According to this view, the intensive perceptual training that accompanies reading acquisition also improves early visual abilities, suggesting that the impact of literacy on the visual system is more widespread than originally proposed. PMID- 22251303 TI - HIV care need not hamper maternity care: a descriptive analysis of integration of services in rural Malawi. AB - OBJECTIVE: To evaluate the use of reproductive health care and incidence of paediatric HIV infection during the expansion of antiretroviral therapy and services for the prevention of mother-to-child transmission in rural Malawi, and the influence of integration of these HIV-related services into general health services. DESIGN: Descriptive analysis. SETTING: Thyolo District, with a population of 600,000, an HIV prevalence of 21% and a total fertility rate of 5.7 in 2004. POPULATION: Women attending reproductive health services care in 2005 and 2010. METHODS: Review of facility records and databases for routine monitoring. MAIN OUTCOME MEASURES: Use of antenatal, intrapartum, postpartum, family planning and sexually transmitted infection services; incidence of HIV infection in infants born to mothers who received prevention of mother-to-child transmission care. RESULTS: There was a marked increase in the uptake of perinatal care: pregnant women in 2010 were 50% more likely to attend at least one antenatal visit (RR 1.50, 95% CI 1.48-1.51); were twice as likely to deliver at a healthcare facility (RR 2.05, 95% CI 2.01-2.08); and were more than four times as likely to present for postpartum care (RR 4.40, 95% CI 4.25-4.55). Family planning consultations increased by 40% and the number of women receiving treatment for sexually transmitted infections doubled. Between 2007 and 2010, the number of HIV-exposed infants who underwent testing for HIV went up from 421 to 1599/year, and the proportion testing positive decreased from 13.3 to 5.0%; infants were 62% less likely to test HIV positive (RR 0.38, 95% CI 0.27-0.52). CONCLUSIONS: During the expansion and integration of HIV care, the use of reproductive health services increased and the outcomes of infants born to HIV infected mothers improved. HIV care may be successfully integrated into broader reproductive health services. PMID- 22251301 TI - Genetically influenced change in sensation seeking drives the rise of delinquent behavior during adolescence. AB - Sensation seeking is associated with an increased propensity for delinquency, and emerging research on personality change suggests that mean levels of sensation seeking increase substantially from childhood to adolescence. The current study tested whether individual differences in the rate of change of sensation seeking predicted within-person change in delinquent behavior and whether genetically influenced differences in rate of personality change accounted for this association. Sensation seeking and delinquent behavior were assessed biennially between ages 10-11 and 16-17 in a nationally representative sample of 7675 youths from the National Longitudinal Study of Youth: Children and Young Adults (CNLSY). Analyses using latent growth curve modeling found that within-person change in sensation seeking was significantly and positively correlated with within-person change in delinquency from childhood to adolescence. Furthermore, behavioral genetic analyses of a subset of 2562 sibling pairs indicated that there were substantial genetic influences on both initial levels of sensation seeking and change in sensation seeking during early adolescence, with over 80% of individual differences in change due to genetic factors. Finally, these genetically driven increases in sensation seeking were most important for predicting increases in delinquency, whereas environmental paths between sensation seeking and delinquency were not significant. These results suggest that developmental changes in delinquent behaviors during adolescence are driven by a genetically governed process of personality change. PMID- 22251304 TI - Injectable, mixed natural-synthetic polymer hydrogels with modular properties. AB - A series of synthetic oligomers (based on the thermosensitive polymer poly(N isopropylacrylamide) and carbohydrate polymers (including hyaluronic acid, carboxymethyl cellulose, dextran, and methylcellulose) were functionalized with hydrazide or aldehyde functional groups and mixed using a double-barreled syringe to create in situ gelling, hydrazone-cross-linked hydrogels. By mixing different numbers and ratios of different reactive oligomer or polymer precursors, covalently cross-linked hydrogel networks comprised of different polymeric components are produced by simple mixing of reactive components, without the need for any intermediate chemistries (e.g., grafting). In this way, hydrogels with defined swelling, degradation, phase transition, drug binding, and mechanical properties can be produced with properties intermediate to those of the mixture of reactive precursor polymers selected. When this modular mixing approach is used, one property can (in many cases) be selectively modified while keeping other properties constant, providing a highly adaptable method of engineering injectable, rapidly gelling hydrogels for potential in vivo applications. PMID- 22251305 TI - Cultivars, culture conditions, and harvest time influence phenolic and ascorbic acid contents and antioxidant capacity of strawberry (Fragaria x ananassa). AB - Strawberries are a good source of micronutrients, especially antioxidant phenolics. More information is needed to better exploit the health-promoting effect of such fruits. Several studies focused on the effects of genotype, cultural practices, and seasonal variation on the antioxidant potential of strawberries, but often yielding contradictory results and/or focusing on only 1 source of variability. In the present study, we showed that total phenolic compounds, ascorbic acid, and antioxidant capacity strongly differed between genotypes of strawberry. The precise results revealed the importance of genetic background for the antioxidant capacity and for the content of total phenolics (with up to 3.3-fold variations). Other parameters may also influence the antioxidant capacity in strawberry such as harvest time, culture conditions, and environmental factors. Moreover, in this study, the harvesting time (at the same ripening stage) appeared to be very important, more important than genotype. Variations of the antioxidant capacity of up to 4.1-folds were observed following the harvesting time of "Elsanta" cultivar. PRACTICAL APPLICATION: This article compares the antioxidant capacity and the content in ascorbic acid and phenolic compounds of strawberries of different varieties and of fruits harvested from April to December at the same ripening stage. The importance of strawberry antioxidant capacity resides in its benefits for human health. PMID- 22251306 TI - An interprofessional education pilot program in maternity care: findings from an exploratory case study of undergraduate students. AB - An interprofessional team of maternity care providers and academics developed a pilot interprofessional education (IPE) program in maternity care for undergraduate students in nursing, midwifery and medicine. There are few published studies examining IPE programs in maternity care, particularly at the undergraduate level, that examine long-term outcomes. This paper outlines findings from a case study that explored how participation in an IPE program in maternity care may enhance student knowledge, skills/attitudes, and may promote their collaborative behavior in the practice setting. The program was launched at a Canadian urban teaching hospital and consisted of six workshops and two clinical shadowing experiences. Twenty-five semi-structured, in-depth interviews were completed with nine participants at various time points up to 20 months post program. Qualitative analysis of transcripts revealed the emergence of four themes: relationship-building, confident communication, willingness to collaborate and woman/family-centered care. Participant statements about their intentions to continue practicing interprofessional collaboration more than a year post-program lend support to its sustained effectiveness. The provision of a safe learning environment, the use of small group learning techniques with mixed teaching strategies, augmented by exposure to an interprofessional faculty, contributed to the program's perceived success. PMID- 22251307 TI - Predictive value according to location of incidental focal colorectal fluorodeoxyglucose uptake on positron emission tomography scans. PMID- 22251308 TI - Age group and sex differences in performance on a computerized neurocognitive battery in children age 8-21. AB - OBJECTIVE: Examine age group effects and sex differences by applying a comprehensive computerized battery of identical behavioral measures linked to brain systems in youths that were already genotyped. Such information is needed to incorporate behavioral data as neuropsychological "biomarkers" in large-scale genomic studies. METHOD: We developed and applied a brief computerized neurocognitive battery that provides measures of performance accuracy and response time for executive-control, episodic memory, complex cognition, social cognition, and sensorimotor speed domains. We tested a population-based sample of 3,500 genotyped youths ages 8-21 years. RESULTS: Substantial improvement with age occurred for both accuracy and speed, but the rates varied by domain. The most pronounced improvement was noted in executive control functions, specifically attention, and in motor speed, with some effect sizes exceeding 1.8 standard deviation units. The least pronounced age group effect was in memory, where only face memory showed a large effect size on improved accuracy. Sex differences had much smaller effect sizes but were evident, with females outperforming males on attention, word and face memory, reasoning speed, and all social cognition tests and males outperforming females in spatial processing and sensorimotor and motor speed. These sex differences in most domains were seen already at the youngest age groups, and age group * sex interactions indicated divergence at the oldest groups with females becoming faster but less accurate than males. CONCLUSIONS: The results indicate that cognitive performance improves substantially in this age span, with large effect sizes that differ by domain. The more pronounced improvement for executive and reasoning domains than for memory suggests that memory capacities have reached their apex before age 8. Performance was sexually modulated and most sex differences were apparent by early adolescence. PMID- 22251309 TI - Capturing the fragile X premutation phenotypes: a collaborative effort across multiple cohorts. AB - OBJECTIVE: To capture the neuropsychological profile among male carriers of the FMR1 premutation allele (55-200 CGG repeats) who do not meet diagnostic criteria for the late-onset fragile X-associated tremor/ataxia syndrome, FXTAS. METHOD: We have initiated a multicenter collaboration that includes 3 independent cohorts, totaling 100 carriers of the premutation and 216 noncarriers. The initial focus of this collaboration has been on executive function. Four executive function scores are shared among the 3 cohorts (Controlled Oral Word Association Test, Stroop Color-Word Test, and Wechsler backward digit span and letter-number sequencing) whereas additional executive function scores are available for specific cohorts (Behavior Dyscontrol Scale, Hayling Sentence Completion Test Part B, and Wisconsin Card Sorting Test). Raw scores were analyzed by using statistical models that adjust for cohort-specific effects as well as age and education. RESULTS: Carriers scored significantly lower compared to noncarriers on the Stroop Color-Word Test (p = .01), Hayling Sentence Completion Test Part B (p < .01), and Behavioral Dyscontrol Scale (p = .03), with the Hayling displaying a significant age-related decline (p = .01), as assessed by an age and repeat length-group interaction. Follow-up analysis of the collective data did not identify any specific age groups or repeat length ranges (i.e., low premutation = 55-70 repeats, midpremutation = 71-100 repeats, high premutation = 101-199 repeats) that were associated with an increased risk of executive function deficits. CONCLUSIONS: Preliminary analyses do not indicate global executive function impairment among male carriers without FXTAS compared to noncarriers. However, impairment in inhibitory capacity may be present among a subset of carriers, though the risk factors for this group do not appear to be related to age or repeat length. PMID- 22251310 TI - Decision-making impairment on the Iowa Gambling Task after endovascular coiling or neurosurgical clipping for ruptured anterior communicating artery aneurysm. AB - OBJECTIVE: To investigate decision-making deficits after anterior communicating artery aneurysm (ACoA) rupture and to compare the effects of two treatments. METHOD: The sample included 40 patients with subarachnoid hemorrhage secondary to ruptured ACoA with a favorable neurological outcome and a control group of 31 subjects matched by age, sex, and years of education. Twenty patients had surgical interventions (clipping) and 20 had received endovascular treatment. Decision-making was assessed by the Iowa Gambling Task (IGT). We used the Expectancy Valence model to examine the different components associated with the IGT. RESULTS: ACoA patients performed significantly worse on the IGT than controls, we observed poorly performance on IGT in 70% of the patients. Comparing the groups according to type of intervention, we found that clipped patients performed significantly worse than controls on the IGT, whereas coiled patients did not differ significantly from controls or clipped patients; however, coiled patients performed worse than controls on the last block of the task. Patients with frontal lesions selected significantly more cards from the disadvantageous deck. IGT performance correlated with other tests of executive functions such as the perseverative errors and non perseverative errors of Wisconsin Card Sorting Tests, and verbal fluency test, but not with working memory tests. According to the Expectancy Valence model, patients with frontal lesions showed a greater tendency to focus on recent outcomes and ignore or rapidly discount past outcomes, and tended to have a more erratic response pattern. CONCLUSIONS: Our results suggest that patients with subarachnoid hemorrhage secondary to ruptured ACoA have deficits in decision-making under ambiguity. The main cause of this deficit is the presence of frontal lesions. Moreover, clipped patients, but not coiled patients, showed deficits in taking decisions in comparison with controls. Our results suggest that the IGT may help to identify neuropsychological sequelae in these patients. PMID- 22251311 TI - Mild cognitive impairment is associated with selected functional markers: integrating concurrent, longitudinal, and stability effects. AB - OBJECTIVE: We examined functional performance on multiple indicators for two cognitive status groups: (a) not impaired controls (NIC) and (b) mild cognitive impairment (MCI). We identified functional markers associated with differences, changes, and stability in cognitive status. METHOD: In the Victoria Longitudinal Study (VLS) we examined cognitive status group effects in (a) cross-sectional functional performance, (b) longitudinal stability, (c) longitudinal functional performance change, and (d) functional marker prediction of later cognitive status. We assembled markers from five continuous clusters of MCI-related functional factors: biological vitality, activity lifestyle, psychosocial affect, subjective health, and global cognition. We used a cross-sectional sample and a two-wave longitudinal sample, stratified by age (mid-old, old-old) and cognitive status (MCI, NIC). RESULTS: First, cross-sectional results showed that eight markers differentiated MCI and NIC adults, with the latter performing uniformly better. The groups differed on diastolic blood pressure, body mass index, positive and negative affect, MMSE, and the lifestyle indicators of self maintenance, travel, and novel cognitive activities. Second, Wave 1 to Wave 2 stabilities in cognitive status classification were high. Third, several markers differentiated the stable (NIC-to-NIC, MCI-to-MCI) from the unstable (NIC-to-MCI, MCI-to-NIC) cognitive status groups. Fourth, five relevant markers for identifying older adults at risk for cognitive status changes were: diastolic blood pressure, self-maintenance activities, novel cognitive activities, positive affect, and global cognitive status. CONCLUSION: Selected risk and protective factors differentiate persons classified with MCI from those not currently cognitively impaired, both cross-sectionally and longitudinally. PMID- 22251312 TI - Predicted outcomes of vaccinating wildlife to reduce human risk of Lyme disease. AB - Vaccination efforts for Lyme disease prevention in humans have focused on wildlife reservoirs to target the causative agent, Borrelia burgdorferi, for elimination in vector ticks. Multiple host species are involved in the transmission and maintenance of the bacterium, but not all host species can be vaccinated effectively. To evaluate vaccinating a subset of hosts in the context of host-tick interactions, we constructed and evaluated a dynamic model of B. burgdorferi transmission in mice. Our analyses indicate that on average, a mouse targeted vaccine is expected to proportionally reduce infection prevalence among ticks by 56%. However, relative to mouse vaccination, human risk of exposure is dominated by the number of tick bites received per person, the proportion of tick blood meals taken from the highly reservoir-competent white-footed mouse relative to other hosts, and the average number of tick bites per mouse. Variation in these factors reduces the predictability of vaccination outcomes. Additionally, contributions of nonmouse hosts to pathogen maintenance preclude elimination of B. burgdorferi through mouse vaccination alone. Our findings indicate that to increase the impact of wildlife vaccination, reducing tick populations by acaricide application, in addition to targeting additional reservoir-competent host species, should be employed. PMID- 22251313 TI - Variations of renal artery in 820 patients using 64-detector CT-angiography. AB - PURPOSE: Renal artery variations are important for clinical reasons. The aim of this study is to determine the originating level and variations of renal arteries with 64-channel multidetector computed tomography (MDCT). MATERIALS AND METHODS: In a university hospital, 820 patients who underwent MDCT angiography of the abdominal aorta were retrospectively evaluated. The number, early division (ED), and originating level of renal artery were evaluated retrospectively. Variations of the renal artery on both sides, the difference between the genders with variations of the renal artery, were compared with chi-square test. RESULTS: Renal artery originating from the level of L1-L2 intervertebral disc was found in 37.0% and 38.9% of patients on the right and left sides, respectively. Renal artery variations, including extrarenal artery (ERA), were found in 27% and ED in 26.7% of the patients. Significant differences were found in ED and ERA prevalence for genders (p = 0.006 and p = 0.043, respectively). The prevalence of both variations is higher in males. CONCLUSIONS: An awareness of renal vascular variations is very important for both surgeons and radiologists. In this series, renal arterial variations were found in approximately one-fourth of the study population. PMID- 22251314 TI - Effect of switching from telmisartan, valsartan, olmesartan, or losartan to candesartan on morning hypertension. AB - The Candesartan Cooperative Research of Therapy Design for Early Morning Hypertension in CHIBA was designed to investigate whether switching from angiotensin II receptor blockers (ARBs) except candesartan to candesartan might be effective in Japanese patients with morning hypertension. Seventy-eight mild to moderate hypertensive patients, who were treated with the standard doses of ARBs except candesartan (losartan, 50 mg; valsartan, 80 mg; telmisartan, 40 mg; or olmesartan, 20 mg), were entered into 12-week treatment period with candesartan 8 mg according to a multicenter, open-label design. Morning and office blood pressures (BPs) were significantly reduced (morning, -10.1 +/- 10.5/ 4.5 +/- 8.4 mm Hg; office, -13.1 +/- 17.3/-6.2 +/- 11.3 mm Hg) after medication change. Target BPs (morning BPs <= 135/85 mm Hg and office BPs <= 140/90 mm Hg) achievement rates were 42.9% in the morning and 64.3% at office. No adverse events were recognized in all patients. Candesartan treatment significantly reduced the morning and office BPs compared with other ARBs in Japanese patients with morning hypertension. PMID- 22251316 TI - Fighting high molecular weight in bioactive molecules with sub-pharmacophore based virtual screening. AB - A new subpharmacophore-based virtual screening method is introduced. Subpharmacophores are derived from large active molecules to detect small bioactive molecules as seeds for starting points in medicinal chemistry programs. A large data set was assembled from the ChEMBL database to check the validity of this approach. Molecules for 133 targets with molecular weights between 450 and 850 were selected as queries. For the query molecules, the pharmacophore descriptors were calculated. Up to 56 000 subpharmacophore descriptors with five to seven pharmacophore points were derived from the query pharmacophores. The subpharmacophore descriptors were used as queries to screen 1079 test data sets, containing decoys and spike molecules. A maximum upper molecular weight limit of 400 Da was set for the test molecules. Three different chemical fingerprint descriptors were used for comparison purposes. The subpharmacophore approach detected active molecules for 85 out of 133 targets and outperformed the chemical fingerprints. This ligand-based virtual screening experiment was triggered by the needs of medicinal chemistry. Applying the subpharmacophore method in a medicinal chemistry program, where a lead molecule with a molecular weight of 800 Da was available, resulted in a new series of molecules with molecular weights below 400. PMID- 22251315 TI - Absence of DNMT3A gene mutation in chronic myeloid leukemia patients in blast crisis. PMID- 22251317 TI - Maternal control of seed size by EOD3/CYP78A6 in Arabidopsis thaliana. AB - Seed size in higher plants is coordinately determined by the growth of the embryo, endosperm and maternal tissue, but relatively little is known about the genetic and molecular mechanisms that set final seed size. We have previously demonstrated that Arabidopsis DA1 acts maternally to control seed size, with the da1-1 mutant producing larger seeds than the wild type. Through an activation tagging screen for modifiers of da1-1, we have identified an enhancer of da1-1 (eod3-1D) in seed size. EOD3 encodes the Arabidopsis cytochrome P450/CYP78A6 and is expressed in most plant organs. Overexpression of EOD3 dramatically increases the seed size of wild-type plants, whereas eod3-ko loss-of-function mutants form small seeds. The disruption of CYP78A9, the most closely related family member, synergistically enhances the seed size phenotype of eod3-ko mutants, indicating that EOD3 functions redundantly with CYP78A9 to affect seed growth. Reciprocal cross experiments show that EOD3 acts maternally to promote seed growth. eod3-ko cyp78a9-ko double mutants have smaller cells in the maternal integuments of developing seeds, whereas eod3-1D forms more and larger cells in the integuments. Genetic analyses suggest that EOD3 functions independently of maternal factors DA1 and TTG2 to influence seed growth. Collectively, our findings identify EOD3 as a factor of seed size control, and give insight into how plants control their seed size. PMID- 22251318 TI - Comparative assessment of validity and reliability of the Oral Impacts on Daily Performance (OIDP) frequency scale: a cross-sectional survey among adolescents in Davanagere city, Karnataka, India. AB - AIM: To evaluate reliability and validity of an abbreviated version of the Oral Impact on Daily Performance (OIDP) questionnaire and to analyse the interrelationship between OIDP scores, socio-demographic characteristics and oral health status among high school children in Davanagere city, Karnataka, India. MATERIALS AND METHODS: This cross-sectional survey was conducted with 900 school children aged between 12 and 15. The subjects were randomly selected from six high schools. Selected subjects completed a survey instrument predesigned to measure subjective oral health indicators including the eight-item OIDP frequency scores. The study participants were clinically examined for dental caries, and they completed a self-administered questionnaire about demographic information and oral behaviours. RESULTS: 44% of the students reported at least one oral impact in the previous 6 months. The reliability of the instrument was measured in terms of Cronbach's alpha for the OIDP frequency. It was found to be 0.81. Eating was the most common performance affected (33%) followed by cleaning teeth (22%) and speaking (20%). The severity of impacts was low for relaxing and carrying out works. CONCLUSION: The OIDP frequency score has acceptable psychometric properties in the context of an oral health survey among high school children of Davanagere city, Karnataka, India. PMID- 22251320 TI - Tacit knowledge in dental clinical teaching. AB - The term 'tacit' is used to describe knowledge that is not necessarily understood in words. We frequently make use of such knowledge without conscious awareness that we are doing so. This article explores two different conceptions of tacit knowledge and considers their implications for the clinical teaching of dentistry. It recognises the communication barrier that clinical dependence on tacit knowledge creates between teacher and student. It identifies the ability to surface tacit clinical knowledge for the student as one of the most significant skills of the clinical teacher. Finally, the article examines the potential for conflict between the evidence-based practice paradigm, with its dependence on codified, explicit knowledge and the notion of clinical practice, which is at least partly experiential and tacit. PMID- 22251322 TI - Students' satisfaction with electrical handpieces in an educational setting. AB - OBJECTIVE: This article presents the evaluation and outcome of improvements carried out at Case Western Reserve School of Dental Medicine (CWRU) based on feedback provided by students during implementation of electrical handpieces technology in the school. METHODOLOGY: Students were surveyed in February 2010 (first survey) regarding their satisfaction with the existing clinical set-up for electrical handpieces. Following a change in clinical setting and integration of the control box into the dental unit in November 2010, students were administered the same survey as in February 2010 (second survey). RESULTS: There was an increased level of satisfaction with electric handpieces in the new clinical setting; these levels were significant regarding the ergonomics of the handpiece and clinical setting, operation of the handpiece, and technical maintenance. There was a significant shift from those who were categorically against using electrical handpieces after graduation towards those were 'not sure' regarding the adoption of electric technology in their practice. CONCLUSIONS: Specifically improving the clinical setting of a control box for electrical handpieces can influence overall student perception regarding the quality of handpieces and their operation. PMID- 22251321 TI - Placing dental clinicians within the normative base regarding vicarious response. AB - This paper describes the development and psychometric properties of the Curtin Vicarious Response Scales (CVRS), a research tool specifically developed to evaluate emotional reponsivity in clinical practice and in undergraduate training. The measure yields scores on three substantive scales, (I) Perspective Taking, the capacity to shift perspectives and to step outside of self when dealing with other people, (II) Empathy, the ability to understand another?s mental and emotional states and (III) Emotional Lability, affective sensitivity and changeability. The construct validity of the CVRS is unequivocal and concurrent validation demonstrates its expected place within personality space. The psychometric properties of the device demonstrate its viability as a research tool in the area of Empathy and Emotional Responsivity. PMID- 22251323 TI - Improving teamwork between students from two professional programmes in dental education. AB - In Sweden, the National Board of Health and Welfare forecasts a decrease in dentists with 26% and an increase in dental hygienists with 47% until the year of 2023. This, together with changes in both epidemiology, especially of dental caries, and political priorities, calls for an effective and well-developed cooperation between dentists and dental hygienists in future dentistry. Hence, the aim of this project was to investigate whether highlighting teamwork during the undergraduate studies of dental students and dental hygiene students could improve the students' holistic view on patients as well as their knowledge of and insight into each other's future professions. Thirty-four dental students and 24 dental hygiene students participated in the study. At the beginning of their final year in undergraduate education, a questionnaire testing the level of knowledge of the dental hygienists' clinical competences was completed by both groups of students. In addition, activities intending to improve teamwork quality included the following: (i) a seminar with a dentist representing the Public Dental Health Services in Sweden, (ii) dental students as supervisors for dental hygiene students, (iii) planning and treatment for shared patients and (iv) students' presentations of the treatments and their outcomes at a final seminar. The project was ended by the students answering the above-mentioned questionnaire for the second time, followed by an evaluation of the different activities included in the study. The knowledge of dental hygienists' competences showed higher scores in almost all questions. Both groups of students considered the following aspects important: seminars with external participants, dental students acting as supervisors and planning and treating shared patients. By initiating and encouraging teamwork between dental students and dental hygiene students, it is possible to increase knowledge on dental hygienists' competence and also to develop and strengthen a holistic view on patients and dental work, thereby preparing both groups of students for their professional life. PMID- 22251324 TI - Does performance in selection processes predict performance as a dental student? AB - OBJECTIVE: This study investigated associations between the performance of dental students in each of the three components of the selection procedure [academic average, Undergraduate Medicine and Health Sciences Admission Test (UMAT) and structured interview], socio-demographic characteristics and their academic success in an undergraduate dental surgery programme. MATERIALS AND METHODS: Longitudinal review of admissions data relating to students entering dental education at the University of Otago, New Zealand, between 2004 and 2009 was compared with academic performance throughout the dental programme. RESULTS AND DISCUSSION: After controlling for variables, pre-admission academic average, UMAT scores and interview performance did not predict performance as a dental student. Class place in second year, however, was a strong predictor of class place in final year. Multivariate analysis demonstrated that the best predictors of higher class placement in the final year were New Zealand European ethnicity and domestic (rather than international) student status. Other socio-demographic characteristics were not associated with performance. These interim findings provide a sound base for the ongoing study. CONCLUSION: The study found important socio-demographic differences in pre-admission test scores, but those scores did not predict performance in the dental programme, whether measured in second year or in final year. PMID- 22251325 TI - Stress and burnout in postgraduate dental education. AB - INTRODUCTION: High levels of stress and burnout have been documented among dental students and practicing dentists, but evidence among dental residents and postgraduate students is lacking. MATERIALS AND METHODS: Ninety-nine postgraduate students enrolled in clinical, non-clinical and PhD programmes in the Athens University School of Dentistry completed the Graduate Dental Environment Stress (GDES) questionnaire and the Maslach Burnout Inventory. Perceived stress was measured in two domains, academic (GDES-A) and clinical (GDES-C) and burnout was measured using the scales of emotional exhaustion (EE), depersonalisation (DP) and personal accomplishment (PA). Analyses relied on descriptive, univariate and multivariate methods based on ANOVA and generalised linear models. RESULTS: Participants' mean age was 30 years; two-thirds were women and practised dentistry independently of their graduate studies. Residents in clinical programmes reported significantly higher levels of perceived stress compared to non-clinical and PhD students (P<0.05). There were no gender differences in perceived stress. Forty per cent of respondents were burnout 'cases' on the EE scale, while this proportion was 38% for reduced PA and smaller, 13% for DP. Perceived stress was positively correlated with all burnout dimensions, whereas independent dental practice and higher age had a protective effect. CONCLUSIONS: High rates of burnout manifestations were detected among this sample of Greek postgraduate dental students. Perceived stress correlated with burnout and was more pronounced among those enrolled in clinical residency compared to non clinical and PhD programmes. PMID- 22251326 TI - Dynamic Systems (Complexity) theory as a new conceptual model for researching PBL in dental education. AB - Although problem-based learning (PBL) was introduced into dental education some 20 years ago, there have been relatively few well-designed studies carried out to clarify whether, how or why it works in a dental context. This paper introduces the Dynamic Systems (Complexity) theory as a new and potentially productive theoretical framework for researching PBL in dental education. This framework emphasises the importance of emergent self-organisation, perception and brain plasticity in learning. In this paper, a brief overview of the history of PBL in dentistry is presented and then the fundamentals of a Dynamic Systems Approach (DSA) are explained, drawing on two recently published papers advocating the DSA in medical education and teacher education. We focus on three key points related to this new approach: emergent self-organisation rather than simple construction of knowledge; the notion that perception drives the learning process; and the brain as the substrate of all learning. The paper also suggests how the DSA can help us move forward, both in terms of the future application of PBL in dental education and also in relation to posing new types of research questions. PMID- 22251327 TI - Using online periodontal case-based discussions to synchronize theoretical and clinical undergraduate dental education. AB - BACKGROUND: Clinical experience is important in undergraduate dental education, but (suitable) patients to learn from are often lacking. Online case-based discussions were introduced to overcome patient dependency and to synchronize theoretical with clinical education. MATERIALS AND METHODS: Undergraduate dental students in groups of 5-7 discussed online clinical case reports presenting either minor (2nd year) or complex periodontal pathology (3rd year). Each case consisted of a brief patient history, extra- and intra-oral clinical pictures, periodontal chart, peri-apical and/or orthopantomographic radiographs. Students had to discuss diagnosis and treatment planning. Questionnaires assessed students' and supervisors' general appreciation (score on 20), time investment and opinions about organisation, relation case/course content, future planning, learning effect and online environment (5-point Likert scale). A crossover design with three tests (pre-test, test in between and post-test) was used to investigate whether the frequency of case introduction (one case per week vs. one case element per week) had an effect on learning. Data was analysed with descriptive statistics (questionnaires) and repeated measures ANOVA (crossover design). RESULTS: Students (n=119) and supervisors (n=9) highly appreciated the exercise. Students reported spending on average 74 min per week to read a case, prepare and post messages. Supervisors' total time investment was 342 min per semester to create a case, provide online feedback and to prepare a live discussion. No significant differences in test-scores were found between the two modalities of case introduction. CONCLUSION: Online case-based discussions, in conjunction with a theoretical course, are valuable additions to the dental curriculum, especially to reinforce the transition from theory to clinical practice. PMID- 22251328 TI - Continuing dental education: evaluation of the effectiveness of a disinfection and decontamination course. AB - AIM: To evaluate a disinfection and decontamination dental postgraduate course run by the Wales Dental Postgraduate Deanery between 2008 and 2010. METHODS: Pre- and post-course multiple choice questionnaires were completed by 1177 course attendees. Mean scores before and after participation on the training course were compared and analysed. RESULTS: Mean pre-course score was 45.3%, rising to 87.0% in the post-course assessment, reflecting an improvement of 41.8%. Prior to training, 30.7% achieved a satisfactory score of 13/20 (65%) compared to 98.3% on completion of training. Dental technicians were found to score significantly lower than other occupation groups both before and after course attendance. Decade of graduation had no effect on results. Theoretical microbiology was the question area which showed least improvement. CONCLUSION: Attending the disinfection and decontamination course significantly improved participants' knowledge. Theoretical microbiology, as a topic area, may be targeted for improvements in future courses to improve results further. PMID- 22251330 TI - Teaching of dentistry to medical students in English at the Jagiellonian University, Krakow, Poland. AB - The significance of teaching dental subjects to medical students as well as medicine to dental students is considered. The authors' experience in teaching dentistry to medical students in English at the University of Krakow is described. PMID- 22251332 TI - Students' engagement with their group in a problem-based learning curriculum. AB - INTRODUCTION: In a new enquiry-based learning dental curriculum, problem-based learning (PBL) was chosen as a central methodology because it promotes a collaborative and constructive approach to learning. However, inevitably, some groups function worse than others. This study explores the relationship between group functionality and individuals' results on knowledge-based assessment. It also sought to establish whether using the Belbin team role theory could improve group functionality. METHODS: Students completed the Belbin team role inventory that assigns individuals to a team role type and were allocated to either an ideal Belbin group or a control group. To evaluate the functionality of the groups, Macgowan's group engagement measure was completed after 18 and 31 weeks for each student by their group facilitator. The scores were summed and averaged giving a group engagement score for each group. Relationships between group engagement, individual performance in assessment in weeks 18 and 31 and Belbin and non-Belbin teams were investigated. RESULTS: Individual group engagement scores and performance in the knowledge tests had a statistically significant positive relationship despite the small number of students involved (62). However, no correlation was shown between Belbin groups and group engagement scores. CONCLUSIONS: Those students who engaged most with the PBL process performed markedly better in assessments of knowledge. Using Belbin's team role theory to place students in PBL groups in an effort to increase group functionality had no effect when compared with non-Belbin control groups. PMID- 22251331 TI - Dentistry a second time? AB - INTRODUCTION: Dentistry in Jordan is an attractive profession due to the high social standard it provides. This study aimed to investigate whether dentists would choose dentistry again and whether their professional expectations would change after years of practice. Of special interest were possible differences according to gender, age, degree and place of work. METHODS: A self-completion questionnaire was filled by a stratified random sample of 355 dentists in Jordan using closed questions. The questionnaire included professional, social and economic factors that influenced people's choice of dentistry and whether they would choose it again and the reasons for that. RESULTS: The results showed that 52% of dentists who returned the questionnaire had dentistry as their first choice; the most important determining factor was the dentist's grades in the general secondary education. Fifty-two per cent stated that they would not choose it for the second time, the main reason being the health problems acquired through the profession and the low income. Helping others and the social standard dentistry provides were the main reasons given for dentists to choose dentistry again. CONCLUSION: We report that more than half of the dentists included in this study would not 'choose dentistry again' as their profession regardless of age, gender and degree. This is mainly due to health problems acquired and the low income. We found that job satisfaction is highly affected by the workplace, and that more females are dissatisfied by the profession. This suggests that cultural background strongly affects the career decision. PMID- 22251333 TI - Does empathy change in first-year dental students? AB - INTRODUCTION: Professionalism is a central tenet of the dental undergraduate curriculum. Dental undergraduate curricula and standards expect the dentist to put the patient's interests first, and in this respect, an important attitude is empathy. OBJECTIVE: This study examined the self-reported empathy levels of first year dental students before and after an early analytical exposure to behavioural sciences and the clinical encounter. METHOD: First-year dental undergraduates were given an attitudinal questionnaire to complete before and after the behavioural science course. The questionnaire consisted of the HP version of the Jefferson Scale of Physician Empathy and the Patient-Practitioner Orientation Scale. Paired non-parametric tests and Spearman's Rho correlations, along with simple descriptive statistics, were used to test the statistical significance of observations. RESULTS: A total of 66 paired questionnaires were returned, giving a response rate of 75%. There were no correlations between age and total mean score of JSPE or PPOS, and no gender differences. There was a significant increase (P<0.01) in empathy as measured by the JSPE between pre- and post-course scores. The PPOS did not record any significant change in the sharing, caring or total scale scores pre- to post-course. CONCLUSION: The modified JSPE has potential utility in assessing the cognitive-affective aspect of dental students' empathy. Using the JSPE, short-term measurable empathy changes can be detected in first-year dental undergraduates after the structured and assessed analytical introduction to the clinical encounter and environment. PMID- 22251334 TI - A comparison of computer- and hand-generated clinical dental notes with statutory regulations in record keeping. AB - INTRODUCTION: Dental patient records should be of high quality, contain information to allow for good continuity of care and clinical defence (should the need ever arise) and, ideally, facilitate clinical audit. Handwritten dental records have been assessed for their compliance to statutory regulations, but the same cannot be levelled at computer-generated notes. This study aimed to compare and analyse the compliance of both methods of data recording with statutory regulations. METHOD: Fifty consecutive sets of handwritten notes and 50 sets of computer-generated notes were audited for compliance with a number of legal requirements and desirable characteristics for dental records and the results compared. The standard set for compliance with all characteristics was 100%. RESULTS: The computer-generated notes satisfied the set standard for 8 of the 11 legal requirements and three of six desirable characteristics. The handwritten notes satisfied the set standard for 1 of 11 legal requirements and none of the desirable characteristics. A statistical difference (using a 95% confidence interval) between the two methods was observed in 5 of 11 legal characteristics and three of six desirable characteristics, all of which were in favour of computer-generated notes. CONCLUSIONS: Within the limitations of this study, computer-generated notes achieved a much higher compliance rate with the set parameters, making defence in cases of litigation, continuity of care and clinical audit easier and more efficient. PMID- 22251335 TI - Student perceptions of syndicate learning: tutor-less group work within an undergraduate dental curriculum. AB - This paper describes the implementation of syndicate learning (tutor-less group working) to teach the basic principles and skills of removable partial denture design within an undergraduate dental curriculum at the University of Glasgow. Student perceptions of syndicate group learning were collected through using questionnaires with Likert scales and through focus group interviews. The majority of students expressed positive views of syndicate learning that focused on the following themes: the added value of the group in terms of learning and in terms of social cohesion; the sense of responsibility to peers that led them to work harder; the autonomy of tutor-less groups that led them to improve their ability to justify their work; and the effectiveness of the syndicate groups in comparison with other learning methods. On the basis of these findings along with reports from students that learning about group roles enhanced their preparation for future work, we argue that syndicate learning can offer some valuable benefits to the undergraduate dental curriculum. PMID- 22251336 TI - Assessing professionalism within dental education; the need for a definition. AB - Professionalism is a broad competency needed by dentists to act effectively and efficiently and is seen as a central part of both undergraduate and postgraduate curricula. Assessment is vital in education to assess progress and direct future learning. It is also an essential part of good professional regulation, which depends upon high quality assessment to maintain credibility. Educators must produce clear expectations that students can strive for. Thus dental educators are required to understand precisely what is meant by "professionalism" in relation to dentistry in order to both teach and assess it. The aim of this paper is to explain the importance of professionalism, explore its features and its assessment as described in the literature. The paper concludes that without a validated definition of this construct, assessment of professionalism within dental education will be compromised. PMID- 22251337 TI - Dentists reflect on their problem-based education and professional satisfaction. AB - AIM: To determine the way in which Malmo University dental graduates perceive their problem-based dental education and evaluate their professional satisfaction. METHOD: The first five cohorts (graduating in years 1995-1999) of the problem-based curriculum were invited to participate. Of 166 graduates, 77% responded to a questionnaire comprising 20 questions on aspects of their dental education, professional situations and interest in postgraduate education. They were asked to rank their perception of their dental education and satisfaction with their professional situation on a visual analogue scale (VAS) with endpoints ranging from 'Not at all' (1) to 'Very well' (10). For other statements, the markings were made on a Likert scale from 1 (not important/not satisfied) to 5 (very important/very satisfied). There were also open-ended questions. RESULTS: Most respondents perceived their education to prepare them well for a career in dentistry (median score VAS 8), and 90% rated above six on a VAS for their professional satisfaction as dentists. Importance and satisfaction were highly correlated with principles of the curriculum: holistic view, oral health, lifelong learning, integration between theory and clinic, and clinical competence. Forty-five per cent of the graduates noted the problem-based learning approach as the most valuable asset of their education, and 19% cited training in oral surgery as a deficit. Of the respondents, 77% expressed interest in specialist training and 55% in research education. CONCLUSION: Problem-based education was perceived to prepare graduates well for their profession, and their professional satisfaction was high. PMID- 22251338 TI - Experiences in adding multiple-choice questions to an objective structural clinical examination (OSCE) in undergraduate dental education. AB - In the University of Oulu, the competencies of fourth-year dental students have traditionally been assessed with a written examination before they go to work for the first time as dentists outside the Institute of Dentistry. In 2009, the objective structural clinical examination (OSCE) modified with multiple-choice questions was introduced as a tool for assessing clinical competencies. The aim of the study was to evaluate the validity of the modified OSCE (m-OSCE) by measuring the attitude of examiners (teachers) and dental students towards the m OSCE and to evaluate whether the OSCE is preferred to the written examination in the assessment of knowledge and clinical skills. Additionally, the aim was to evaluate the reliability of the multiple-choice examination. Altogether 30 students (86%) and 11/12 examiners (92%) responded to the questionnaire. Most of the students considered the multiple-choice questions easy, but complained about the complex formulation of the questions. The test stations were easy for 87% of the students, but the time allocated was too short. Most of the students (73%) and examiners (91%) preferred the m-OSCE to the written examination. All students and examiners found the immediate assessment of the tasks good. Based on the evaluations of m-OSCE, it could be concluded that both students and examiners preferred the m-OSCE to the pure written examination in assessment, which indicate that m-OSCE had good face validity. Combining multiple methods in assessment of knowledge and clinical skills whilst simultaneously taking into account the feasibility and available resources provides more valid results. PMID- 22251339 TI - Three ways of understanding development as a teacher. AB - The demands on faculty in terms of teaching are increasing, but until recently there has been little discussion of how faculty perceive that development as a teacher can be achieved or what approaches they use or suggest themselves. The aim of this study is to explore how teachers in dentistry and medicine understand development as teachers. For this study, 20 teachers were interviewed. The interviews were analysed using a phenomenographic approach. Three different ways of understanding development were identified: 1) Development as a dental or medical clinician/expert as the teacher role is seen as a tacit part of the role of the clinician. 2) Experience and professional and personal maturation, related to personal and professional development and confidence in ones clinical role. 3) Knowledge in education and systematic teacher training as in this category, being a teacher is seen as a separate role from that of being a clinician. The differences in these three ways of understanding development as a teacher are shown in their different aims of development, what kind of knowledge that may be used and what methods they suggested. The way teachers understand what it means to develop as a teacher will affect their motivation for engaging in development activities, which activities they choose and their own aims of development. This means that awareness of teachers' understanding of development is central when developing support or faculty development activities for teachers. PMID- 22251340 TI - Knowledge, educational experiences and attitudes towards child abuse amongst Jordanian dentists. AB - BACKGROUND: Signs of physical abuse often present in the oro-facial region and dentists are in a strategic position to recognise and report suspected cases. The aim of this study was to assess the knowledge, educational experiences and attitudes of Jordanian dentists towards child abuse and to assess their educational needs. METHODS: A cross-sectional survey of a random sample of Jordanian dentists (n=400) was conducted using an anonymous, self-administered structured questionnaire. RESULTS: The response rate was 64%. Thirty-four per cent (n=88) of the respondents reported having formal training in recognising and reporting child abuse, and 42% (n=106) had post-qualification/continuing education training on the topic. Half of the dentists (127/256) suspected a case of child abuse in the past 5 years, but only 12% (31/256) reported their suspicions. The main reasons for not reporting suspicions of abuse were fear from anger of parents (43%), uncertainty about diagnosis (41%) and uncertainty about referral procedures (41%). Those dentists who had formal training in dental school (P=0.0001) and post-qualification courses in child abuse (P=0.006) were significantly more likely to report suspicions. CONCLUSIONS: A significant gap existed between recognising signs of physical child abuse and responding effectively. Improvements in child abuse education and continuing education courses are advised to provide dentists in Jordan with adequate knowledge of indicators of physical child abuse and to inform them on the protocol to follow when suspicions arise. PMID- 22251341 TI - First-year oral health and dentistry student perceptions of future professional work. AB - OBJECTIVES: To explore and compare how pre-doctoral dentistry (BDS) and oral health (BOH) students characterise their future professional work at the start and end of their first-year professional programme. MATERIALS AND METHODS: All BDS and BOH students were given an anonymous survey on the first and last days of their 2009 course. Start and end surveys (ES) were completed by 75% of BDS (51) and 83% of BOH students (33). This paper examines students' responses to two questions asking them to identify a situation characterising their future professional work and a professional difficulty they would likely encounter. Student responses were analysed inductively to identify key themes and confirm each theme's 'weighting' based on frequency of mention. RESULTS: Students' answers to both questions revealed eight characterisations of future professional work involving the following: restorative tasks, patient-related concerns, patient emotion and behaviour, population-level/public health concerns, disease prevention and monitoring, communication, teamwork and self-management. In ES responses, BDS students emphasised restorative tasks as central to a dentist's work, and in both surveys perceived 'dealing with patients' as a central difficulty. In contrast, BOH students' answers to both questions revealed a patient care emphasis, and in both surveys, BOH students emphasised patient related concerns as a likely difficulty. CONCLUSION: Bachelor of Dentistry students characterised their work as primarily interventive, and BOH students, as primarily patient-centred, communicative, and preventive. Whilst BDS students apparently valued restorative capabilities, BOH students valued the ability to ensure patient well-being. Further research will examine students' differing perceptions and how these change over time. PMID- 22251342 TI - A community of learners in the evidence-based dental clinic. AB - An increasing emphasis has been placed on the need for an evidence-based approach in dentistry. This calls for effort in dental education to develop and implement tools for the application of evidence in clinical decision-making (evidence-based decision-making, EBDM). AIM: To evaluate whether the implementation of a community of learners (COL) within a clinical EBDM course enables students, clinical teachers and scientists to discuss the application of evidence in clinical decision-making and whether it stimulates a scientific approach in students. MATERIAL AND METHODS: A clinical course in EBDM was created. Students presented and discussed patient cases in a COL of student-peers, clinical teachers and scientists. From the discussion, clinical questions arose and were translated into PICO format (Problem, Intervention, Comparison and Outcome). Students searched for evidence in the literature. Four weeks later, they presented and discussed the evidence found. Before and after the implementation of the course, students, clinical teachers and scientists completed a questionnaire anonymously on the procedure adopted, its content, the learning outcomes and their appreciation of this course. Assessment of the competence EBDM was performed at the end of the course. Grading scores of students in the COL were compared with scores of a student group that did not participate in the COL and were not advised by scientists. RESULTS: Evaluation showed that scientists, clinical teachers and students gradually became more positive on the adopted procedure, content, learning outcomes and the appreciation of this course (ANOVA Bonferoni P<0.05). The student's evaluation showed the development of a more scientific approach. Assessment scores of EBDM were sufficient and promising. CONCLUSION: A stimulating arena was created: a COL, in which the evidence used in clinical decision-making, was discussed. The COL involved dental students, clinical teachers and scientists. In this setting, an EBDM course appeared to result in a more scientific approach from dental students. The COL provided a good working concept for EBDM in dental education. PMID- 22251343 TI - Academic integrity and plagiarism: perceptions and experience of staff and students in a school of dentistry: a situational analysis of staff and student perspectives. AB - INTRODUCTION: This project has investigated student and staff perceptions and experience of plagiarism in a large Australian dental school to develop a response to an external audit report. METHODS: Workshops designed to enhance participants' understanding of plagiarism and to assist with practical ways to promote academic integrity within the school were provided to all students and staff. Anonymous surveys were used to investigate perceptions and experience of plagiarism and to assess the usefulness of the workshops. RESULTS: Most participants felt that plagiarism was not a problem in the school, but a significant number were undecided. The majority of participants reported that the guidelines for dealing with plagiarism were inadequate and most supported the mandatory use of text-matching software in all courses. High proportions of participants indicated that the workshops were useful and that they would consider improving their practice as a result. CONCLUSIONS: The study provided data that enhanced understanding of aspects of plagiarism highlighted in the report at the school level and identified areas in need of attention, such as refining and raising awareness of the guidelines and incorporation of text matching software into courses, as well as cautions to be considered (how text matching software is used) in planning responsive action. PMID- 22251344 TI - Acquiring psychomotor skills in operative dentistry: do innate ability and motivation matter? AB - OBJECTIVE: The acquisition of psychomotor skills is a key competence in the practice of dentistry, and innate abilities and motivation have been shown to influence motor performance. However, the explicit integration of these factors into the design of research projects about skill acquisition in dentistry has been limited. Therefore, the purpose of this study was to provide a comprehensive analysis of how dental students' abilities and motivation affected their performance in an operative task. METHODS: A longitudinal study with two cohorts of dental students was conducted in laboratory classes forming part of an operative technique course. A range of standardised psychometric tests was used to assess different abilities before completing a cavity preparation on Frasaco teeth. This was followed immediately by completion of an Intrinsic Motivation Inventory. RESULTS: Low but statistically significant correlations (P<0.05) were found between dental performance and psychomotor ability (r=0.22), and also dental performance and motivation (r=0.19). A significant difference (P<0.05) was found in the grades obtained for the cavity preparation exercise in one cohort between students with higher levels of psychomotor ability compared with those with lower levels (Tracing scores) (P<0.05). No significant differences in grades obtained for the cavity preparation exercise were found between students with higher and lower levels of motivation. CONCLUSION: Both innate psychomotor ability and motivation showed only weak positive associations with dental performance on cavity preparation exercises. Our study suggests that student related factors only provide limited information to explain differences in performance or to be useful as specific predictors of future performance by individuals. PMID- 22251345 TI - An assessment of oral health promotion programmes in the United Kingdom. AB - BACKGROUND: Improving oral health and reducing tooth decay is a key area for action, both in the United Kingdom (UK) and overseas. The World Health Organization (WHO) has highlighted the unique advantage schools have in promoting oral health. AIM: We summarise current oral health promotion strategies in the United Kingdom and estimate the spread of their use as well as their impact on oral health and influence on the oral health-related knowledge and behaviour in a patient population. METHODS: A structured overview of published papers, government publications, official government websites and policy reports. A cross sectional study of patients referred for a tooth extraction in one dental surgery in south-east London. Statistical methods consisted of logistic and ordinal regressions to model the likelihood of exposure to oral health promotion and of obtaining higher levels of knowledge of oral health issues, respectively. Linear regression was used to model the level of oral health and knowledge of oral health issues. RESULTS: We found three main promotion programmes, namely, National Healthy Schools (NHS), Sure Start and Brushing for life plus a small number of local initiatives. Sure Start targets disadvantaged areas, but is limited. In our observational study, 34% of the patients reported exposure to a settings-based oral health education programme: Sure Start (5%), NHS (7%) and other (22%). This exposure was not influenced by age or gender, but an association with education was detected. Although oral health promotion was not found to influence the actual knowledge of oral health issues, it was found to influence some oral health-related attitudes and perceptions. CONCLUSIONS: Participation in an oral health promotion programme was found to be significantly associated with the patients' education, their belief that they can prevent oral disease and the subjective perception of their own oral health. The WHO principles need to be embedded across all schools to achieve a true national oral health promotion programme for the United Kingdom. The National Healthy Schools programme provides the perfect platform. PMID- 22251346 TI - Introduction of a robot patient into dental education. AB - In recent years, with the increasing social awareness of safety in medical practice, improving clinical skills has become very important, especially for recently graduated dentists. Traditionally, mannequins have been used for clinical skill training, but a mannequin is quite different from a real patient because they have no autonomous movement or conversational ability. This indicates that pre-clinical simulation education is inadequate. We have, therefore, developed a robot patient that can reproduce an authentic clinical situation for dental clinical training. The robot patient, designed as a full body model with a height of 157 cm, has eight degrees of freedom in the head and the ability to perform various autonomous movements. Moreover, saliva secretion and conversation with the trainee can be reproduced. We have introduced the robot patient into an objective structured clinical examination targeted at fifth-grade students in our dental school to evaluate their skills in cavity preparation, whilst considering the safety of the treatment. As a result, many of the students were able to deal appropriately with a patient's unexpected movement. Moreover, results of a questionnaire survey showed that almost all the students recognised the educational value of the robot patient especially for 'risk management', and they preferred the robot patient to traditional mannequins. Practical application of the robot patient in dental clinical education was evaluated through the experiences of the fifth-grade students, which showed the effectiveness of the robot patient in the dental field. PMID- 22251347 TI - The importance of teaching communication in dental education. A survey amongst dentists, students and patients. AB - The aim of our study was to evaluate the subjective importance of teaching communication in the dental curriculum by conducting a survey amongst dentists, students and patients. Three questionnaires about communication-related issues were developed in which different questions could be rated on a five-point Likert scale. These questions included the subjective importance of the dental team's friendliness, an elaborated consultation, modern office equipment or the dentist's technical skills. Seven hundred and twenty-nine questionnaires were completed [233 by dentists (32%), 310 by students (43%) and 185 by patients (25%)]. Eighty-seven percentage of the dentists, 84% of the students and 84% of the patients supported an integration of communicational issues in dental education; 94.7% of the dentists and 77.2% of the patients attached vital importance to the dentist-patient relationship regarding the therapeutic outcomes. Dentists with prior communicational training experience would spend significantly (P<0.001) more money for further courses. The results show the publicly perceived importance of integrating aspects of communication in dental education. PMID- 22251349 TI - Identifying student profiles and their impact on academic performance in a Brazilian undergraduate student sample. AB - The recognition of the student profile provides strategic information for planning educational policies in the university environment. The aims of this study were to identify natural segmentation of freshman undergraduate dental students based on demographic, socioeconomic and educational variables, and to subsequently investigate their impact on academic performance of Brazilian undergraduate students. Cluster analysis (two-step algorithm) was used to segment students who entered dental school in the time period from 1999 to 2001 (n=158) into groups based on responses to a questionnaire completed by students at the time of the admission examination. Clustering analysis revealed three natural groups. Age, the parents' level of education, and performance on the first admission test were the most important variables for cluster segmentation. Cluster 1 (n=42; 26.6%) was characterized by female students with higher socioeconomic status and better previous educational indicators. Cluster 2 (n=62; 39.2%) represented disadvantaged socioeconomic profiles, with a predominance of females and older students. Cluster 3 (n=54; 34.2%) showed similar socioeconomic characteristics to cluster 1, except for male prevalence, higher age, and experiencing difficulty in the admission test. Clusters' academic performance was satisfactory in both overall course and course groups (grade point average of at least 7.0), with average ranging from 7.89 (SD=0.44) to 8.13 (SD=0.31) and 7.37 (SD=0.75) to 8.31(SD=0.26), respectively. Our findings provide encouraging evidence for the current context of equality of access to education and reveal the importance of financial support to maximize successful educational experiences of socioeconomically disadvantaged dental students. PMID- 22251348 TI - A national survey of UK final year students' opinion of undergraduate oral surgery teaching. AB - BACKGROUND: A national survey was undertaken to establish a baseline of our final year students' perception of how their undergraduate oral surgery education has equipped them for key areas of general dental practice. MATERIALS AND METHODS: Questionnaires were distributed to the 13 UK schools with final year students, towards the end of the academic year in 2009. The questionnaires were completed anonymously and were optically scanned. RESULTS: In total, 632 questionnaires were returned, which represents 66% of the students of the graduating year. The majority (83%) of the respondents perceived that the teaching in oral surgery had given them sufficient knowledge to undertake independent practise. Most respondents (99%) felt confident to perform forceps exodontia, but confidence in the various aspects of surgical exodontia was lower. A majority (83%) had experience of an outreach scheme performing forceps exodontia (75%) and surgical exodontia (16%) in this environment. Twenty per cent indicated a desire to undertake a career in oral surgery, 6% in oral and maxillofacial surgery and 35% in another speciality. CONCLUSION: This survey suggests that the majority of the students perceive that the oral surgery education has prepared them well for key areas of general practice. It also suggests that there is, however, a need to provide further improvement in the delivery of surgical skills and knowledge. PMID- 22251350 TI - Online discussion boards in dental education: potential and challenges. AB - BACKGROUND: Online discussion boards may enhance critical analysis and reflection, and promote the acquisition of knowledge. AIMS: To assess the effectiveness of online discussion board as a pedagogical tool in augmenting face to-face teaching in dental education. METHOD: Data were collected from a discussion archive offered through the E-course website of the School of Dentistry, University of Birmingham, UK in 2008. A multi-component metric included; participation, social learning, cognitive processing, role of instructors, and quality of discussion. Messages were coded for 14 variables to evaluate these dimensions. Data were analyzed using content analysis methodology and a complete message was uses as the unit of analysis. RESULTS: There were no significant difference in participation between students and instructors (P<0.05). Social interaction with peers appeared only through students posting messages with open questions (27/135 messages). The discussion board was mainly used by students to understand concepts (27/102 messages) and apply procedural knowledge (17/102 messages). Instructors were mainly replying to students' messages with (49/120 messages) or without (54/120 messages) proposing another action. CONCLUSIONS: Online discussion boards were found to be successful pedagogical tools in dental education. Further development of instructor-led discussion approach is needed to promote higher level learning and collaborative thinking. PMID- 22251351 TI - Transcultural skills content in a dental curriculum: a comparative study. AB - BACKGROUND: Australia has the highest proportion of immigrants in the world (24% of the population is overseas-born, compared to 22% in New Zealand, 19% in Canada and 12% in the USA). In this context, dental students have become increasingly diverse in a milieu where patients are derived from increasingly diverse backgrounds. AIM: The study aims to analyse the degree to which transcultural and communication skills content is currently embedded in the medical, physiotherapy and dental curricula at a major Australian university. MATERIALS AND METHODS: Undergraduate dental, medical and physiotherapy curricula were compared and critically assessed. Researchers considered the amount of transcultural and communication skills content, the number of formal contact hours for each course and the number of teaching staff involved. In addition, 21 interviews were conducted with staff at the three schools, who were involved in the curriculum development process. RESULTS: The medical and physiotherapy curricula had an explicit focus on transcultural and communication skills as a major and continuing element, delivered by teaching staff from a wide variety of academic and professional backgrounds. In contrast, the dental course showed an under representation of transcultural and communication skills content which was taught by a limited number of staff from the School of Dental Science. CONCLUSIONS: In marked contrast to medical and physiotherapy curricula, transcultural and communication skills content had a low formal profile in the dental curriculum. A curriculum review process may be a positive step towards the development of a new training curriculum giving higher priority to transcultural and communication skills to support more effective workforce development. PMID- 22251352 TI - Creating effective and engaging information literacy programmes for the dental curriculum. AB - In this time of rapid expansion of the scientific knowledge base, subject matter runs the risk of becoming outdated within a relatively short time. Instead of adding more content to already crowded curricula, the focus should be on equipping students to adapt to their changing world. The ability to access, evaluate and apply new knowledge for the benefit of patients has been acknowledged as an important goal for dental education. Information literacy is key to achieving this. A template for an Information Literacy programme for undergraduate students is described. This was embedded within a compulsory course for each of the first and second years of the Bachelor of Oral Health programme and consisted of a hands-on workshop (attendance voluntary), information literacy quiz, self-evaluation and a summative assessment task, with the second year of the programme building upon the learning of the previous year. Effectiveness was measured in terms of demonstration of information literacy skills and confidence in using these skills. Integration of this programme within the learning activities and assessment of first- and second-year courses resulted in enhanced information literacy skills and confidence. Self-perceived high skill levels may be a potential barrier to student engagement with information literacy programmes. PMID- 22251353 TI - Awareness, knowledge and practice of evidence-based dentistry amongst dentists in Kuwait. AB - This study assessed the awareness, knowledge and practice of evidence-based dentistry (EBD) amongst dentists working in the public sector in Kuwait. Of the 150 randomly selected dentists from all five health districts in Kuwait who had originally been approached, 120 participated by completing a pre-tested, self administered questionnaire (80% response rate). Whereas 60.9% of the group stated that they practice EBD most of the time, fewer (40.8%) had a reasonable understanding of EBD based upon tested knowledge scores of EBD-related topics. Clinical decisions appeared to be mostly based on the clinician's own judgment (73.3%) rather than on evidence-based sources such as PubMed (28.3%) or the Cochrane Library (6.7%). A number of within-group differences were noted, with women (P<0.05), those working in a particular district (P<0.05), those with <10years' experience (P=0.05), those whose first dental qualification had been obtained in Kuwait (P<0.05), and those who had had any EBD training (P<0.05) showing greater knowledge of EBD. Training in EBD was felt necessary by a majority of the group, and this may be facilitated if dental centres have access to evidence-based sources to remove some of the possible barriers to implementation of EBD. PMID- 22251354 TI - Teaching of direct composite restoration repair in undergraduate dental schools in the United Kingdom and Ireland. AB - AIM: To investigate aspects of the teaching of restoration repair as a minimally invasive alternative to the replacement of defective direct composite restorations in teaching programmes in undergraduate curricula in dental schools in the United Kingdom and Ireland. METHODS: An online questionnaire which sought information in relation to the current teaching of composite restoration repair was developed and distributed to the 17 established UK and Irish dental schools with undergraduate teaching programmes in Spring 2010. RESULTS: Completed responses were received from all 17 schools (response rate= 100%). Fifteen schools reported that they included teaching of repair techniques for defective direct composite restorations in their programme. Of the two remaining schools, one indicated that it would introduce teaching of repair techniques during the next five years. The most common indication for a composite repair was that of 'tooth substance preservation' (15 schools). The defects in restorations considered appropriate for repair rather than replacement by the largest number of schools included partial loss of restoration (13 schools) and marginal defects (12 schools). The most commonly taught surface treatment when performing a repair was mechanical roughening of the existing composite with removal of the surface layer (14 schools). Thirteen schools taught etching and the application of an adhesive bonding agent to the prepared surfaces, while the most commonly taught material for completing the repair was a hybrid composite resin (12 schools). Popular finishing implements included diamond finishing instruments (13 schools) and finishing discs (11 schools). CONCLUSION: Not withstanding reluctance amongst general dental practitioners, the teaching of repair of a defective composite restoration, rather than total restoration replacement, is firmly established within UK and Irish dental school programmes. Repair techniques have clear advantages for patients, not least including a minimally invasive approach to treatment and avoidance of unnecessary loss of tooth tissue and pulpal damage. Dental practitioners should look more to repair techniques when managing defective composite restorations and clinical dental teachers should continue to research and refine composite repair techniques. PMID- 22251355 TI - Changing assessment practice through in situ faculty development. AB - The aim of this article is to describe the process of an in situ staff development process with the objective to influence change in assessment practice. An in situ training course focusing on writing questions for written examinations, but also including some contextual aspects of assessment practice, was therefore developed and implemented. The anticipated change was measured against Kirkpatrick's four levels for evaluating training programmes. As a whole, the reaction from the participants was positive (Kirkpatrick Level 1), and in a number of instances, learning, which includes changes in attitude, knowledge and skills (Kirkpatrick Level 2) and change in behaviour (Kirkpatrick Level 3), was observed. To conclude, the staff development initiative in the form of in situ assessment training facilitated change resulting in an improvement in assessment practice in the School in a relatively short period of time. PMID- 22251356 TI - Perceived relevance of oral biology by dental students. AB - OBJECTIVES: This study investigated the perception that dental students have regarding the relevance of oral biology (OB) to dental education and dentistry in general. Moreover, this study analysed students' attitude towards OB learning approaches and resources. METHODS: A questionnaire based on a Likert scale was used to survey pre-clinical/second (BDS2)- and final/fifth (BDS5)-year dental students at the School of Dentistry of the University of Birmingham (United Kingdom). In comparison, a small group of postgraduate specialist registrars were surveyed to evaluate the attitudes of practising dentists. RESULTS: The results show that all study groups expressed a high level of perceived relevance of OB to dentistry. Students' perception of OB for dental education, clinical training and practice also scored high. More than 40% of undergraduate students and about 55% of the postgraduates indicated a perceived change in their attitude towards OB with time characterised by increased appreciation of the subject. Lectures were considered as the most important teaching approach, whereas 'group poster projects' ranked lowest. Of the different study resources, lecture handouts received the overall highest importance score. CONCLUSIONS: The results indicate that dental students considered OB relevant for dental education and dentistry and suggest a positive attitude towards the subject. This study also suggested that dental students prefer teacher-centred/led teaching rather than student directed learning of OB. The article addresses the role of OB and science-related research projects within the dental curriculum and discusses that close integration of basic sciences with dental education may enrich dental education and overall learning experience. PMID- 22251357 TI - Students' perceptions of the educational environment in a Greek Dental School, as measured by DREEM. AB - AIM: The aim of this study was to estimate the dental students' perceptions of their educational environment and to identify any differences related both to their gender and semester of studies. MATERIALS AND METHODS: The translated and validated in Greek Dundee Ready Education Environment Measure (DREEM) questionnaire was distributed to all 2nd- to 5th-year students of the Athens Dental School. The questionnaire consisted of 50 statements organised in five subscales (perceptions of learning, teachers, atmosphere, academic self perceptions and social self-perceptions). Internal validity was checked with Cronbach alpha. Confirmatory factor analysis (CFA) was performed under the same conditions as the original inventory. Mean statement, subscale and overall scores were calculated and given as percentages. RESULTS: The response rate was 64%. Overall Cronbach alpha was 0.93 (excellent). CFA produced five meaningful subscales, not matching the original ones. The overall DREEM mean score was 56%. Gender did not influence the findings. The students' perceptions of the educational environment with the exception of the academic self-perceptions were more positive in the pre-clinical years. Statistically significant differences were revealed only for the 'learning' subscale between the 3rd- and the 4th-year students. Seventy-eight percent of the statements were in the positive side. The lowest scores were related to students' stress, tiredness and lack of appropriate feedback from the teachers, and the highest were related to accommodation, school friends and perceptions that they feel socially comfortable in class. CONCLUSIONS: Students' perceptions of the educational environment were reasonably positive, with no gender difference. However, some weaknesses were identified, particularly in the clinical years. Further research is needed to clarify appropriate interventions. PMID- 22251358 TI - Digital interactive learning of oral radiographic anatomy. AB - INTRODUCTION: Studies reporting high number of diagnostic errors made from radiographs suggest the need to improve the learning of radiographic interpretation in the dental curriculum. Given studies that show student preference for computer-assisted or digital technologies, the purpose of this study was to develop an interactive digital tool and to determine whether it was more successful than a conventional radiology textbook in assisting dental students with the learning of radiographic anatomy. MATERIALS AND METHODS: Eighty eight dental students underwent a learning phase of radiographic anatomy using an interactive digital tool alongside a conventional radiology textbook. The success of the digital tool, when compared to the textbook, was assessed by quantitative means using a radiographic interpretation test and by qualitative means using a structured Likert scale survey, asking students to evaluate their own learning outcomes from the digital tool. RESULTS: Student evaluations of the digital tool showed that almost all participants (95%) indicated that the tool positively enhanced their learning of radiographic anatomy and interpretation. DISCUSSION: The success of the digital tool in assisting the learning of radiographic interpretation is discussed in the broader context of learning and teaching curricula, and preference (by students) for the use of this digital form when compared to the conventional literate form of the textbook. CONCLUSION: Whilst traditional textbooks are still valued in the dental curriculum, it is evident that the preference for computer-assisted learning of oral radiographic anatomy enhances the learning experience by enabling students to interact and better engage with the course material. PMID- 22251359 TI - Evaluation of a blended learning course for teaching oral radiology to undergraduate dental students. AB - AIMS: The purpose of this study was to develop and implement a blended course (a combined face-to-face and online instruction) on undergraduate oral radiology and evaluate it by comparing its educational effectiveness (derived from students' performance and answers to questionnaires) to a conventional course's. Students' attitudes concerning the blended methodology were also registered. METHODOLOGY: An original course was developed and implemented, and its electronic version was uploaded to an e-learning educational platform. The course was attended by two groups of final-year students, who were taught by either the conventional face-to face methodology or the blended learning methodology. Students answered a series of questionnaires, before and after following the course, regarding their perceptions, attitudes and evaluation of the course. Additionally, they completed knowledge assessment tests and their grades (before and after the course) were compared. Educational effectiveness of the course was determined by analysing the results of the questionnaires and the tests. RESULTS: Students in the blended group performed significantly better than their colleagues of the conventional group in the post-course knowledge test, and female students of the blended group performed better than male students. Students evaluated high the course content, organisation, educational material, and the blended group students additionally appreciated the course design and clarity of instructions. Students' attitudes towards elements of blended learning (effectiveness, motivation and active engagement) were very positive. Most of the blended group students, who attended the face-to-face meeting (approx. 91%), evaluated it as helpful for summarising the subject and clarifying difficult issues. CONCLUSIONS: Blended learning is effective and well evaluated by dental students and can be implemented in undergraduate curriculum for teaching oral radiology. PMID- 22251360 TI - Self-perceived preparedness for dental practice amongst graduates of The University of Hong Kong's integrated PBL dental curriculum. AB - OBJECTIVES: To determine how prepared for dental practice graduates from the integrated problem-based learning (PBL) dental undergraduate curriculum at The University of Hong Kong (HKU) perceive themselves to be and to identify factors associated with self-perceived preparedness. MATERIALS AND METHODS: A postal questionnaire was sent to five cohorts of dentists who had graduated from HKU's integrated PBL curriculum between 2004 and 2008. Using a 4-point Likert scale, the questionnaire assessed the self-perceived level of preparedness in 59 competencies grouped in nine domains. Responses were dichotomised into 'poorly prepared' and 'well prepared'. RESULTS: The response rate was 66% (159/241). The mean proportion (+/-standard deviation) of respondents indicating well preparedness was 72.0+/-15.1% overall, and for each domain was as follows: general patient management, 93.1+/-12.1%; practice management, 81.0+/-22.2%; periodontology and dental public health, 73.5+/-19.3%; conservative dentistry, 92.5+/-13.1%; oral rehabilitation, 62.8+/-24.0%; orthodontics, 23.0+/-32.9%; managing children and special-needs patients, 64.8+/-28.9%; oral and maxillofacial surgery, 52.2+/-25.2%; and drug and emergency management, 84.7+/ 22.6%. The odds of self-perceived well-preparedness were increased for cohorts graduating in 2004 and 2005 and graduates working in a non-solo dental practice. CONCLUSIONS: Dental graduates of HKU's integrated PBL curriculum felt well prepared for the most fundamental aspects of dental practice. However, apparent deficiencies of training in orthodontics and oral and maxillofacial surgery will need to be addressed by continuing education, postgraduate training and planning for the new 6-year undergraduate curriculum in 2012. PMID- 22251361 TI - Our readers can become writers: yes, we mean you! PMID- 22251366 TI - Size- and dimensionality-dependent thermodynamic properties of ice nanocrystals. AB - Although the melting of ice is the most ubiquitous phase transition, (pre)melting and the quasi-liquid layer remain a matter of debate, and little is known about the relationship between the thermodynamic properties of ice nanocrystals and their size and dimensionality. Here, we model analytically the size- and dimensionality-dependent melting temperature, premelting temperature, and melting enthalpy of hydrogen-bonded ice nanocrystals. These three thermodynamic parameters are found to increase with increasing size and dimensionality where the size effect is principle while the dimensionality effect is secondary, and the size dependence of premelting temperature almost follows the same trend as that of melting temperature. The model predictions correspond to the available molecular dynamic simulation and experimental results of ice nanoparticles and nanowires. These agreements enable us to determine theoretically the thickness of the quasi-liquid layer for the first time, which is found to be not constant but slightly increase with increasing size and thus accounts for the occurrence of different reported thicknesses of the quasi-liquid layer. PMID- 22251367 TI - Species-specific DNA probe and development of a quantitative PCR assay for the detection of Morganella morganii. AB - AIMS: To develop a SYBR Green quantitative PCR assay (qPCR) for the specific detection of Morganella morganii, a fish pathogen responsible for the Histamine Fish Poisoning. METHODS AND RESULTS: A new primer set, amplifying a 179-bp fragment of the 16S rRNA gene, was selected for specificity, and 14 M. morganii strains and 32 non-Morganella strains were evaluated. The melting temperature of 84 degrees C was consistently specific for the amplicon. Two standard curves were constructed: the minimum detection sensitivity was 0.563 pg of pure DNA, corresponding to DNA extracted from nine cells of M. morganii. The qPCR assay was evaluated in experiments with seeded fish samples, and the regression coefficient values were calculated. CONCLUSIONS: A highly specific and rapid assay was developed for the detection of M. morganii in tuna fish samples. SIGNIFICANCE AND IMPACT OF THE STUDY: This method represents the first study about the quantification of pathogenic M. morganii in fish products. This approach can be utilized to prevent the presence of this undesirable species in the food chain. PMID- 22251368 TI - Plasma uric acid remains a marker of poor outcome in hypertensive pregnancy: a retrospective cohort study. AB - OBJECTIVE: To examine the relationship between hyperuricaemia, haemoconcentration and maternal and fetal outcomes in hypertensive pregnancies. DESIGN: Retrospective analysis of a database of hypertensive pregnancies. SETTING: St George Hospital, a major obstetric unit in Australia. POPULATION: A cohort of 1880 pregnant women without underlying hypertension or renal disease, referred for management of pre-eclampsia or gestational hypertension. METHODS: Demographic, clinical and biochemical data at time of referral and delivery were collected for each pregnancy. Women were grouped according to diagnosis (pre eclampsia or gestational hypertension) and logistic regression analysis was used to determine the relationship between uric acid, haemoglobin, haematocrit and adverse outcomes; an alpha level of P < 0.01 was used for statistical significance. MAIN OUTCOME MEASURES: Composites of adverse maternal and fetal outcomes. RESULTS: In women with 'benign' GH (without proteinuria or any other maternal clinical feature of pre-eclampsia) gestation-corrected hyperuricaemia was associated with increased risk of a small-for-gestational-age infant (OR 2.5; 95% CI 1.3-4.8) and prematurity (OR 3.2; 95% CI 1.4-7.2), but not with adverse maternal outcome. In the whole cohort of hypertensive pregnant women (those with pre-eclampsia or gestational hypertension) the risk of adverse maternal outcome (OR 2.0; 95% CI 1.6-2.4) and adverse fetal outcome (OR 1.8; 95% CI 1.5-2.1) increased with increasing concentration of uric acid. Hyperuricaemia corrected for gestation provided additional strength to these associations. Haemoglobin and haematocrit were not associated with adverse pregnancy outcome. CONCLUSIONS: Hyperuricaemia in hypertensive pregnancy remains an important finding because it identifies women at increased risk of adverse maternal and particularly fetal outcome; the latter, even in women with gestational hypertension without any other feature of pre-eclampsia. PMID- 22251369 TI - Examining "success" in post-hip fracture care transitions: a strengths-based approach. AB - Transitions between health care settings are a high-risk period for care quality and patient safety (Coleman, 2003; Picker Institute, 1999), particularly for older patients - such as those with hip fracture - who have complex needs and may undergo multiple care transitions. We sought to understand the key elements of "success" in care transition. Using a strengths-based perspective (Rapp, 1998; Saleebey, 2006), we focused on interprofessional health care providers' perspectives of what constitutes a "good" care transition for elderly hip fracture patients. As part of a larger ethnographic field study, semi-structured interviews were conducted with 17 health providers across a number of disciplines employed across the continuum of post-hip fracture management in British Columbia, Canada. We found two hallmarks of "success" in care transitions: a focus on process - information gathering and communication, and a focus on outcomes - autonomy and care pathways. Strategies for promoting and improving success, such as using practitioner-driven ground-up solutions to address challenges in care transitions, are highlighted. PMID- 22251370 TI - Effects of koji fermented phenolic compounds on the oxidative stability of fish miso. AB - In the present study, Aspergillus oryzae-inoculated koji inhibited lipid oxidation in fermented fish paste rich in polyunsaturated fatty acids following a long fermentation period. The fermentation of koji by A. oryzae liberated several bioactive phenolic compounds, including kojic acid and ferulic acid, which were the most abundant. A linear correlation between several phenolic compounds and their bioactive properties, including their radical-scavenging activity, reducing power, metal-chelating activity, and ability to inhibit linoleic acid oxidation was observed. This suggested an important role of koji phenolics in the oxidative stability of fermented fish paste. The activities of different carbohydrate cleaving enzymes, including alpha-amylase, cellulase, and beta-glucosidase, were positively correlated with the liberation of several phenolic compounds through koji fermentation. Thus, the application of koji offers a novel strategy to enhance the oxidative stability of newly developed fermented fish miso. PRACTICAL APPLICATION: Application of traditional Japanese koji fermentation technique to develop an aroma enriched fish meat bases seasoning has been established. Aspergillus oryzae-inoculated koji releases several carbohydrate-cleaving enzymes, including alpha-amylase, cellulose, and beta-glucosidase, which led to the liberation of several phenolic compounds during fermentation. Improvement of oxidative stability of the fermented fish meat paste by koji phenolics suggests a useful strategy to uplift the value of different trash fish meat-based seasoning through proper utilization of the present technique. PMID- 22251371 TI - Multifunctional coating films by layer-by-layer deposition of cellulose and chitin nanofibrils. AB - An environmentally benign surface modification process for plastic films was demonstrated by fabricating composite coatings through layer-by-layer assembly with green solid materials: aqueous dispersions of two kinds of crystalline polysaccharide nanofibrils. Anionic cellulose nanofibrils were obtained by the TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated oxidation of native cellulose, while cationic beta-chitin nanofibrils were prepared by the protonation of squid pen chitin. Uniform layer depositions, driven by electrostatic attraction and enhanced by hydrogen bonding, were observed on silicon wafers and then reproduced onto poly(ethylene terephthalate) films. Contact angle measurements and dyeing tests on the resulting films revealed their hydrophilic nature and the sorption of both charged and uncharged substances. Antireflection properties were also confirmed via the light transmittance measurements. As might be presumed from all these properties, this composite coating exhibited its unique behavior largely due to its structure, which was distinct from both those of nanofibril cast films and polymer films. PMID- 22251372 TI - Postmortem cardiac tissue maintains gene expression profile even after late harvesting. AB - BACKGROUND: Gene expression studies can be used to help identify disease associated genes by comparing the levels of expressed transcripts between cases and controls, and to identify functional genetic variants (expression quantitative loci or eQTLs) by comparing expression levels between individuals with different genotypes. While many of these studies are performed in blood or lymphoblastoid cell lines due to tissue accessibility, the relevance of expression differences in tissues that are not the primary site of disease is unclear. Further, many eQTLs are tissue specific. Thus, there is a clear and compelling need to conduct gene expression studies in tissues that are specifically relevant to the disease of interest. One major technical concern about using autopsy-derived tissue is how representative it is of physiologic conditions, given the effect of postmortem interval on tissue degradation. RESULTS: In this study, we monitored the gene expression of 13 tissue samples harvested from a rapid autopsy heart (non-failed heart) and 7 from a cardiac explant (failed heart) through 24 hours of autolysis. The 24 hour autopsy simulation was designed to reflect a typical autopsy scenario where a body may begin cooling to ambient temperature for ~12 hours, before transportation and storage in a refrigerated room in a morgue. In addition, we also simulated a scenario wherein the body was left at room temperature for up to 24 hours before being found. A small fraction (< 2.5%) of genes showed fluctuations in expression over the 24 hr period and largely belong to immune and signal response and energy metabolism-related processes. Global expression analysis suggests that RNA expression is reproducible over 24 hours of autolysis with 95% genes showing < 1.2 fold change. Comparing the rapid autopsy to the failed heart identified 480 differentially expressed genes, including several types of collagens, lumican (LUM), natriuretic peptide A (NPPA) and connective tissue growth factor (CTGF), which allows for the clear separation between failing and non-failing heart based on gene expression profiles. CONCLUSIONS: Our results demonstrate that RNA from autopsy-derived tissue, even up to 24 hours of autolysis, can be used to identify biologically relevant expression pattern differences, thus serving as a practical source for gene expression experiments. PMID- 22251373 TI - Identification and evaluation of novel synovial tissue biomarkers in rheumatoid arthritis by laser scanning cytometry. AB - INTRODUCTION: Suitable biomarkers are essential for therapeutic strategies in personalized medicine in terms of diagnosis as well as of prognosis. With highly specific biomarkers, it is possible, for example, to identify patients with poor prognosis, which enables early intervention and intensive treatment. The aim of this study was to identify and validate biomarkers and possible combinations for a prospective use in immunoscintigraphy, which may improve diagnosis of rheumatoid arthritis (RA) patients with consideration of inflammatory activity in the affected joints. Therefore, we tested several monoclonal antibodies (mAbs) directed against cellular-surface molecules on cells likely to be involved in the pathogenesis of RA. METHODS: Synovial tissue from patients with long-standing RA (accompanied by synovitis with varying states of current activity) and patients with acute non-RA arthritis were stained for surface molecules on different cell types by using fluorochrome-labeled antibodies. Tissue analysis was done by laser scanning cytometry (LSC), and statistical evaluation, by discriminant analysis and ROC analysis. RESULTS: CD11b, HLA-DR, CD90, and CD64 revealed significant differences between tissues from patients with RA and acute non-RA arthritis. Especially with the expression of CD64, both patient cohorts could be discriminated with high sensitivity and specificity. RA classification was improved by simultaneously investigating the expression of two or three different surface proteins, such as HLA-DR, CD90, and CD29 in the tissue. The simultaneous analysis of CD64 together with CD304 or the combination of CD11b and CD38 was suitable for the identification of RA patients with high current activity in synovitis. CONCLUSIONS: In this study, we showed that LSC is a novel reliable method in biomarker prevalidation in RA. Hence, identified mAbs in situ may allow their potential use in in vivo approaches. Moreover, we proved that biomarker combination analysis resulted in better discrimination than did single-marker analysis. Combinations of these markers make a novel and reliable panel for the discrimination between RA and acute non-RA arthritis. In addition, further expedient combinations may be novel promising biomarker panels to identify current activity in synovitis in RA. PMID- 22251374 TI - Use of a gentamicin-impregnated collagen sheet (Collatamp((r)) ) following implantation of a sacral nerve stimulator for faecal incontinence. PMID- 22251376 TI - An experience of arteriovenous fistulas created for hemodialysis in the largest health center in eastern Turkey. AB - BACKGROUND: The aim of the study was to evaluated the primary and secondary (after reoperation) patency rates and some effect factors in fistula patency for hemodialysis patients. MATERIAL AND METHODS: Over a 10-year period, 1529 arteriovenous fistulas (AVFs) were fashioned in 1003 (611 males, 392 females; median age range 7-72) patients using the native vascular tissue and prosthetic graft material. We also evaluated the effects of various factors in fistula patency and primary and secondary patency rates in AVF patients. RESULTS: The primary patencies of fistulas in this series were 72%, 64%, 51%, 41%, and 26%, and secondary patencies were 79%, 70%, 56%, 46%, and 33% at 6 months, 1, 2, 4, and 6 years, respectively. There was no statistically significant difference between the primary and secondary patencies (p = 0.082) in the 6-year follow-up. Factors affecting the patency of fistulas were diabetes mellitus (p < 0.005), hypertension (p < 0.005), and smoking habits (p < 0.005). CONCLUSION: Even if shown to be not statistically significant, successful surgical revision after fistula occlusion improves secondary patency with potential benefits in terms of patient morbidity. Besides, the AVF patency was shortened in chronic renal insufficiency patients with diabetes mellitus, hypertension, and smoking habits. PMID- 22251375 TI - Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes. AB - BACKGROUND: Japanese encephalitis virus (JEV) infection is a major cause of acute encephalopathy in children, which destroys central nervous system (CNS) cells, including astrocytes and neurons. Matrix metalloproteinase (MMP)-9 has been shown to degrade components of the basal lamina, leading to disruption of the blood brain barrier (BBB) and to contribute to neuroinflammatory responses in many neurological diseases. However, the detailed mechanisms of JEV-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells) are largely unclear. METHODS: In this study, the effect of JEV on expression of MMP-9 was determined by gelatin zymography, western blot analysis, RT-PCR, and promoter assay. The involvement of AP-1 (c-Jun and c-Fos), c-Src, PDGFR, PI3K/Akt, and MAPKs in these responses were investigated by using the selective pharmacological inhibitors and transfection with siRNAs. RESULTS: Here, we demonstrate that JEV induces expression of pro form MMP-9 via ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent, AP-1 activation in RBA-1 cells. JEV-induced MMP-9 expression and promoter activity were inhibited by pretreatment with inhibitors of AP-1 (tanshinone), c-Src (PP1), PDGFR (AG1296), and PI3K (LY294002), and by transfection with siRNAs of c-Jun, c-Fos, PDGFR, and Akt. Moreover, JEV-stimulated AP-1 activation was inhibited by pretreatment with the inhibitors of c-Src, PDGFR, PI3K, and MAPKs. CONCLUSION: From these results, we conclude that JEV activates the ROS/c-Src/PDGFR/PI3K/Akt/MAPKs pathway, which in turn triggers AP-1 activation and ultimately induces MMP-9 expression in RBA-1 cells. These findings concerning JEV-induced MMP-9 expression in RBA-1 cells imply that JEV might play an important role in CNS inflammation and diseases. PMID- 22251378 TI - Paediatric cardiac rehabilitation in congenital heart disease: a systematic review. AB - BACKGROUND: Advances in medical and surgical care have contributed to an important increase in the survival rates of children with congenital heart disease. However, survivors often have decreased exercise capacity and health related issues that affect their quality of life. Cardiac Rehabilitation Programmes have been extensively studied in adults with acquired heart disease. In contrast, studies of children with congenital heart disease have been few and of limited scope. We therefore undertook a systematic review of the literature on cardiac rehabilitation in children with congenital heart disease to systematically assess the current evidence regarding the use, efficacy, benefits, and risks associated with this therapy and to identify the components of a successful programme. METHODS: We included studies that incorporated a cardiac rehabilitation programme with an exercise training component published between January, 1981 and November, 2010 in patients under 18 years of age. RESULTS: A total of 16 clinical studies were found and were the focus of this review. Heterogeneous methodology and variable quality was observed. Aerobic and resistance training was the core component of most studies. Diverse variables were used to quantify outcomes. No adverse events were reported. CONCLUSIONS: Cardiac Rehabilitation Programmes in the paediatric population are greatly underutilised, and clinical research on this promising form of therapy has been limited. Questions remain regarding the optimal structure and efficacy of the programmes. The complex needs of this unique population also mandate that additional outcome measures, beyond serial cardiopulmonary exercise testing, be identified and studied. PMID- 22251377 TI - Endothelial dysfunction in the human umbilical artery due to preeclampsia can be prevented by sildenafil. AB - OBJECTIVES: We aimed to determine the effects of sildenafil in human umbilical artery preparation taken from preeclamptic or normal pregnant women, also to investigate underlying mechanisms in these effects. STUDY DESIGN: Eighteen pregnant women with preeclampsia and 18 healthy pregnant women were involved. Relaxation responses of sildenafil in presence and absence of nitric oxide (NO) synthase inhibitor, N-[omega]-nitro-L-arginine methyl ester (L-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), were compared between the preeclampsia group and control group. RESULTS: Sildenafil-induced relaxation responses were significantly attenuated in the presence of preeclampsia, L-NAME or ODQ, but not totally abolished. Interestingly, except with ODQ incubation, in all set of experiments maximal relaxation response was achieved by sildenafil. CONCLUSION: These data indicate that sildenafil might effect vascular responsiveness of human umbilical artery through the involvement of NO/cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways. Further investigations are needed to clarify the exact mechanisms. PMID- 22251379 TI - Can an old dog learn (and want to experience) new tricks? Cognitive training increases openness to experience in older adults. AB - The present study investigated whether an intervention aimed to increase cognitive ability in older adults also changes the personality trait of openness to experience. Older adults completed a 16-week program in inductive reasoning training supplemented by weekly crossword and Sudoku puzzles. Changes in openness to experience were modeled across four assessments over 30 weeks using latent growth curve models. Results indicate that participants in the intervention condition increased in the trait of openness compared with a waitlist control group. The study is one of the first to demonstrate that personality traits can change through nonpsychopharmocological interventions. PMID- 22251380 TI - Age differences in visual statistical learning. AB - Recent work has shown that older adults' lessened inhibitory control leads them to inadvertently bind co-occurring targets and distractors. Although this hyper binding effect may lead to the formation of more superfluous associations, and thus greater interference at retrieval for older adults, it may also lead to a greater knowledge of information contained within the periphery of awareness. On the basis of evidence that younger adults only show learning for statistical regularities contained within attended information, we asked whether older adults may also show learning for regularities contained within to-be-ignored information. Older and younger adults viewed a series of red and green pictures and performed a 1-back task on one of the colors. Unbeknownst to participants, both color streams were organized into triplets that occurred sequentially. Implicit memory for the triplets from both the attended and ignored streams was tested using a speeded detection task. Replicating previous work, younger adults demonstrated more learning for the attended triplets than the unattended triplets. Older adults, however, demonstrated similar learning for both the attended and ignored triplets, suggesting that contrary to popular belief, they may actually know more than younger adults about the world around them, including how seemingly irrelevant events co-occur. PMID- 22251382 TI - The use of a 'bleach-etch-seal' deproteinization technique on MIH affected enamel. AB - AIMS: To ascertain whether deproteinization pretreatment of molar-incisor hypomineralization (MIH) enamel affects resin sealant infiltration. DESIGN: Thirty one extracted MIH teeth were divided into three sections and randomly allocated into the Control (etch and FS), Treatment 1 (5% NaOCl, etched and fissure sealed), and Treatment 2 (5% NaOCl and fissure sealed with no etch) groups. Two hundred seventy nine sealant tag/enamel grade observations were recorded by scanning electron microscopy. RESULTS: Control and Treatment 1 were similar in their outcomes, and Treatment 2 was markedly different. There was no statistical evidence to suggest that there was any difference between Treatment 1 and the Control Treatment (95% CI, 0.52, 1.51; P = 0.6). There was a marked difference between Treatment 2 and the Control Treatment (95% CI, 0.07, 0.25; P < 0.001). All treatments also demonstrated a high-predicted probability of obtaining 'poor' sealant tags (Control = 47%, Treatment 1 = 49%, and Treatment 2 = 40%). CONCLUSIONS: The findings suggest that there was no significant difference in the tag quality between the conventional technique (Control) and the 'bleach-etch-seal' technique (Treatment 1). There was no benefit in pre treating with NaOCl alone (without etch) before sealing. This research also showed that there was a high-predicted probability of obtaining 'poor' sealant tags in MIH enamel, regardless of which of the three treatments was used. PMID- 22251381 TI - Age-related differences in recognition memory for items and associations: contribution of individual differences in working memory and metamemory. AB - Ability to form new associations between unrelated items is particularly sensitive to aging, but the reasons for such differential vulnerability are unclear. In this study, we examined the role of objective and subjective factors (working memory and beliefs about memory strategies) on differential relations of age with recognition of items and associations. Healthy adults (N = 100, age 21 to 79) studied word pairs, completed item and association recognition tests, and rated the effectiveness of shallow (e.g., repetition) and deep (e.g., imagery or sentence generation) encoding strategies. Advanced age was associated with reduced working memory (WM) capacity and poorer associative recognition. In addition, reduced WM capacity, beliefs in the utility of ineffective encoding strategies, and lack of endorsement of effective ones were independently associated with impaired associative memory. Thus, maladaptive beliefs about memory in conjunction with reduced cognitive resources account in part for differences in associative memory commonly attributed to aging. PMID- 22251383 TI - ROP11 GTPase negatively regulates ABA signaling by protecting ABI1 phosphatase activity from inhibition by the ABA receptor RCAR1/PYL9 in Arabidopsis. AB - The phytohormone abscisic acid (ABA) regulates many key processes in plants, such as seed germination, seedling growth, and abiotic stress tolerance. In recent years, a minimal set of core components of a major ABA signaling pathway has been discovered. These components include a RCAR/PYR/PYL family of ABA receptors, a group of PP2C phosphatases, and three SnRK2 kinases. However, how the interactions between the receptors and their targets are regulated by other proteins remains largely unknown. In a companion paper published in this issue, we showed that ROP11, a member of the plant-specific Rho-like small GTPase family, negatively regulates multiple ABA responses in Arabidopsis. The current work demonstrated that the constitutively active ROP11 (CA-ROP11) can modulate the RCAR1/PYL9-mediated ABA signaling pathway based on reconstitution assays in Arabidopsis thaliana protoplasts. Furthermore, using luciferase complementation imaging, yeast two-hybrid assays, co-immunoprecipitation assays in Nicotiana benthamiana and bimolecular fluorescence complementation assays, we demonstrated that CA-ROP11 directly interacts with ABI1, a signaling component downstream of RCAR1/PYL9. Finally, we provided biochemical evidence that CA-ROP11 protects ABI1 phosphatase activity from inhibition by RCAR1/PYL9 and thus negatively regulates ABA signaling in plant cells. A model of how ROP11 acts to negatively regulate ABA signaling is presented. PMID- 22251384 TI - Grafts too big or too small: business as usual in pediatric liver transplantation. PMID- 22251386 TI - Introduction to special issue: changing health: acting and reacting, challenges for social work theory and practice. The 6th International Conference on Social Work in Health and in Mental Health, Dublin, Ireland 2010. PMID- 22251387 TI - Parental concerns about disclosure of a child's HIV/AIDS status in Singapore. AB - A qualitative study was conducted to examine parental concerns over the issue of disclosure with those whose children were diagnosed with HIV/AIDS. Semi structured interviews were conducted with seven parents and the main issues that arose from the interviews were (a) parents' explanation of their children's medical condition; (b) factors that influence disclosure; (c) factors that hinder disclosure; and (d) parents' perception on the appropriate time for disclosure. Parents viewed disclosure as a single event, as opposed to an ongoing process where varying levels of information on the illness was to be provided in accordance to the children's individual cognitive and emotional development. PMID- 22251385 TI - Plasmodium chabaudi AS induces pregnancy loss in association with systemic pro inflammatory immune responses in A/J and C57BL/6 mice. AB - The molecular mechanisms that underlie poor birth outcomes in malaria during pregnancy remain poorly defined. To assess the role of host immune responses, mice known to respond differentially to Plasmodium chabaudi AS infection were studied. Following infection at day 0 of pregnancy, A/J mice developed significantly higher parasitemia than C57BL/6 (B6) mice and succumbed to infection. Both strains had evidence of parasite accumulation in the placenta at mid-gestation and aborted, with significantly higher embryo loss in infected A/J mice on day 9. While infection-induced systemic tumour necrosis factor (TNF) and interleukin (IL)-1beta in the latter were significantly higher at day 11, day 10 IL-10 levels were higher in B6 mice. No differences in the levels of splenic lymphocyte subsets, neutrophils or monocytes between infected pregnant A/J and B6 mice were observed, with most cell types expanding in response to infection regardless of pregnancy. Antibody ablation of TNF exacerbated infection in A/J mice and did not ameliorate pregnancy outcome. Thus, malaria induces poor pregnancy outcome in both the mouse strains in the context of quantitatively different systemic inflammatory responses. Further evaluation of the roles of soluble and cellular immune components, particularly at the uteroplacental level, will be required to define the most critical pregnancy-compromising mechanisms. PMID- 22251388 TI - Social workers' role in combating the new epidemic of type 2 diabetes in children: clinical interventions at the Hall Family Center for pediatric endocrinology and diabetes. AB - A variety of modalities can be employed by social work within the hospital setting to combat the phenomenon of obesity and the type 2 diabetes that it triggers in children. These issues are now plaguing our pediatric population. Social workers can provide meaningful interventions to foster needed lifestyle changes. These may include a combination of individual, family, group, and outreach medical education modalities, as well as provision of concrete services such as food stamps. Social workers are uniquely qualified to evaluate and address the underlying psychosocial stressors that may be obstacles to a child's successful adherence to recommended medical protocol. In the urban clinical setting of the Hall Family Center at Mount Sinai, offering a "menu" of flexible options has helped to engage families and motivate patients to adopt new healthy habits. PMID- 22251389 TI - Everyone's business: developing an integrated model of care to respond to child abuse in a pediatric hospital setting. AB - In pediatric hospitals, social work plays a central role in the prevention, identification, and management of child abuse. Children who are suspected of having been abused or neglected require an evaluation of their psychosocial situation. As an integral member of the health care team, the social worker is well placed to undertake comprehensive psychosocial assessments including information on the child's development, parental capacity, family, and community supports. Current practice approaches have seen a shift away from a narrow, "expert" approach to child protection. This article describes the development of an integrated model of social work service delivery to better respond to vulnerable and at-risk children in a pediatric hospital setting. Developing a new model of service required strategic planning, consultation, and endorsement from senior hospital management. The new model aimed to ensure a high quality, responsive social work service to children at risk of physical abuse, neglect, or cumulative harm. The change necessitated understanding of current research evidence, development of best practice guidelines, and effective communication with staff and external stakeholders. Policy development, implementation of practice guidelines, staff training, data collection, and service evaluation are described. The role of social work management and leadership were central in creating change. Visionary leadership is widely regarded as key to successful organizational change. The management approach included consultation with staff, building commitment to the need for change, addressing staff concerns, and providing a vision of enhanced client outcomes as a result of the change process. This article provides a candid overview of challenges and barriers to change. Change strategies described are easily transferable to other social work settings. PMID- 22251390 TI - Promoting recovery through peer support: possibilities for social work practice. AB - The Recovery Approach has been adopted by mental health services worldwide and peer support constitutes one of the main elements of recovery-based services. This article discusses the relevancy of recovery and peer support to mental health social work practice through an exploration of social work ethics and values. Furthermore, it provides an exploration of how peer support can be maximized in groupwork to assist the social work clinician to promote recovery and well-being. More specifically, this article discusses how the narrative therapy concepts of "retelling" and "witnessing" can be used in the context of peer support to promote recovery, and also how social constructionist, dialogical, and systemic therapy approaches can assist the social work practitioner to enhance peer support in recovery oriented groupwork. PMID- 22251391 TI - Suicide attempt presentations at the emergency department: outcomes from a pilot study examining precipitating factors in deliberate self-harm and issues in primary care physician management. AB - The aim of this study was to examine the psychosocial precipitating factors of people presenting to the emergency department (ED) due to attempted suicide. Demographic, diagnostic and service use data were collected for a 6-week period. All patients were referred for primary care physician (PCP) management, with a sample followed up for secondary analysis of precipitants to self-harm and follow up outcomes. Results of the study showed that key psychosocial stressors that triggered suicidality were relationship issues and recent unemployment, with depression present in 92% of cases. While 83% of patients followed attended their first PCP appointment, 50% discontinued by 3 months. The conclusion of this study is that psychosocial crises and depression are key factors in suicide attempts. Assertive crisis intervention, facilitated linkage to community services, and greater monitoring are recommended. PMID- 22251392 TI - Moving an evidence-based intervention into routine mental health care: a multifaceted case example. AB - Many evidence-based interventions fail to translate into routine care for individuals experiencing significant mental health disorders. Moving the evidence based intervention from the controlled research settings to the broader mental health systems is an ongoing challenge for administrators and practitioners in the mental health delivery network. In the United States, the movement to bring evidence-based mental health interventions into the public mental health system to enhance consumer recovery and improve outcomes has been a major thrust of federal and state efforts over the past 10 years (IOM, 2006; New Freedom Commission on Mental Health, 2003; Michigan Mental Health Commission, 2004; U.S. Department of Health and Human Services, 1999). Using a multifaceted case example, this article will address one state's efforts to implement an evidence based intervention, Family Group Psychoeducation (FPE), into routine care for individuals living with schizophrenia and their families. The Consolidated Framework for Implementation Research (CFIR) (Damshcroder et al., 2009) guides the discussion of the dissemination efforts. This CFIR framework involves examining five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. PMID- 22251393 TI - Uptake of divalent ions (Mn+2 and Ca+2) by heat-set whey protein gels. AB - Divalent salts are used commonly for gelation of polymer molecules. Calcium, Ca(+2), is one of the most common divalent ions that is used in whey protein gels. Manganese, Mn(+2), is also divalent, but paramagnetic, enhancing relaxation decay rates in magnetic resonance imaging (MRI) and can be used as a probe to understand the behavior of Ca(+2) in whey protein gels. The objective of this study was to investigate the diffusion of Ca(+2) and Mn(+2) ions in heat-set whey protein gels by using MRI and nuclear magnetic resonance (NMR) relaxometry. Whey protein gels were immersed in solutions containing MnCl(2) and CaCl(2) at neutral pH. Images obtained with gels immersed in MnCl(2) solution revealed a relaxation sink region in the gel's surface and the thickness of the region increased with time. These "no signal" regions in the MR images were attributed to uptake of Mn(+2) by the gel. Results obtained with CaCl(2) solution indicated that since Ca(+2) did not have the paramagnetic effect, the regions where Ca(+2) diffused into the gel exhibited a slight decrease in signal intensity. The relaxation spectrums exhibited 3 populations of protons, for gels immersed in MnCl(2) solution, and 2 populations for gels in CaCl(2) solution. No significant change in T(2) distributions was observed for the gels immersed in CaCl(2) solution. The results demonstrated that MRI and NMR relaxometry can be used to understand the diffusion of ions into the whey protein gel, which is useful for designing gels of different physical properties for controlled release applications. PRACTICAL APPLICATION: Design of food systems for delivery of bioactive compounds requires knowledge of diffusion rates and structure. Utilizing magnetic resonance imaging the diffusion rates of ions can be measured. Relaxation spectra could yield information concerning molecular interactions. PMID- 22251394 TI - Detection of methicillin-resistant Staphylococcus aureus in Iberian pigs. AB - AIMS: Iberian pigs are bred in Spain for the production of high-value dry-cured products, whose export volumes are increasing. Animals are typically reared outdoors, although indoor farming is becoming popular. We compared carriage of methicillin-resistant Staphylococcus aureus (MRSA) in Iberian pigs, raised indoors and outdoors, with intensively farmed Standard White pigs. METHODS AND RESULTS: From June 2007 to February 2008, 106 skin swabs were taken from Iberian pigs and 157 samples from SWP at slaughterhouses in Spain. We found that Iberian pigs carried MRSA, although with a significantly lower prevalence (30/106; 28%) than SWP (130/157; 83%). A higher prevalence of indoor Iberian pigs compared with animals reared under outdoor conditions was not significant; however, all but one positive indoor Iberian pig samples were detected from one slaughterhouse. Overall, 16 different spa types were identified, with t011 predominating in all three animal populations. A subset of isolates was characterized by MLST. Most of these belonged to ST398. MRSA isolates from Iberian pigs presented a higher susceptibility to antibiotics than those isolated from SWP. CONCLUSIONS: Despite limited contact with humans, pigs raised outdoors are colonized by an MRSA population that genetically overlaps with that of intensively farmed pigs, although antimicrobial resistance is lower. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge, this is the first detection of MRSA in food animals raised in free-range conditions. PMID- 22251395 TI - Patient or physician safety? Physicians' views of informed consent and nurses' roles in an Indonesian setting. AB - Informed consent is a reflection of patients' autonomy in health decision-making. The main responsibility lies with the doctor. In practice, the nurses' contributions matter as well. This paper presents a case study that explored physicians' perceptions of the existing informed consent process, their suggestions for improvement and their views on the nurses' roles in this process. A two-phase approach was conducted. First, six physicians with different expertise were interviewed. Second, after attending presentations about informed consent and physician-patient relationship principles, 32 physicians were asked to complete an open-ended questionnaire. Data were analyzed by two independent coders and emerging themes were compared. The results of the questionnaires and the interviews were triangulated. Of 32 physicians attending the presentations, 24 (75%) completed the questionnaire. The results indicate that physicians perceive patients, physicians and the hospital as main factors influencing the process of informed consent. Physicians' misinterpretation of informed consent principles, (mis)perceptions regarding patients and their family, and deficient hospital policy and support challenge the informed consent process. Physicians value nurses' roles, provided nurses have sufficient clinical knowledge, sound comprehension of informed consent principles and effective communication skills. PMID- 22251396 TI - Maternal sepsis: a Scottish population-based case-control study. AB - OBJECTIVE: To describe the risk of maternal sepsis associated with obesity and other understudied risk factors such as operative vaginal delivery. DESIGN: Population-based, case-control study. SETTING: North NHS region of Scotland. POPULATION: All cases of pregnant, intrapartum and postpartum women with International Classification of Disease-9 codes for sepsis or severe sepsis recorded in the Aberdeen Maternal and Neonatal Databank (AMND) from 1986 to 2009. Four controls per case selected from the AMND were frequency matched on year-of delivery. METHODS: Cases and controls were compared; significant variables from univariable regression were adjusted in a multivariable logistic regression model. MAIN OUTCOME MEASURES: Dependent variables were uncomplicated sepsis or severe ('near-miss') sepsis. Independent variables were demographic, medical and clinical delivery characteristics. Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) are reported. RESULTS: Controlling for mode of delivery and demographic and clinical factors, obese women had twice the odds of uncomplicated sepsis (OR 2.12; 95% CI 1.14-3.89) compared with women of normal weight. Age <25 years (OR 5.15; 95% CI 2.43-10.90) and operative vaginal delivery (OR 2.20; 95% CI 1.02-4.87) were also significant predictors of sepsis. Known risk factors for maternal sepsis were also significant in this study (OR for uncomplicated and severe sepsis respectively): multiparity (OR 6.29, 12.04), anaemia (OR 3.43, 18.49), labour induction (OR 3.92 severe only), caesarean section (OR 3.23, 13.35), and preterm birth (OR 2.46 uncomplicated only). CONCLUSIONS: Obesity, operative vaginal delivery and age <25 years are significant risk factors for sepsis and should be considered in clinical obstetric care. PMID- 22251397 TI - Topical vitamin A treatment of recalcitrant common warts. AB - BACKGROUND: Common warts (verruca vulgaris) are benign epithelial proliferations associated with human papillomavirus (HPV) infection. Salicylic acid and cryotherapy are the most frequent treatments for common warts, but can be painful and cause scarring, and have high failure and recrudescence rates. Topical vitamin A has been shown to be a successful treatment of common warts in prior informal studies. CASE: The subject is a healthy, physically-active 30 old female with a 9 year history of common warts on the back of the right hand. The warts resisted treatment with salicylic acid, apple cider vinegar and an over-the counter blend of essential oils marketed for the treatment of warts. Daily topical application of natural vitamin A derived from fish liver oil (25,000 IU) led to replacement of all the warts with normal skin. Most of the smaller warts had been replaced by 70 days. A large wart on the middle knuckle required 6 months of vitamin A treatment to resolve completely. CONCLUSION: Retinoids should be further investigated in controlled studies to determine their effectiveness in treating common warts and the broad range of other benign and cancerous lesions induced by HPVs. PMID- 22251398 TI - Modeling temperature dependency of amine basicity using PCM and SM8T implicit solvation models. AB - PCM and SM8T continuum solvation models are used to study the temperature dependency of a set of amines in the temperature range 273-393 K using density functional theoretical calculations. Gaseous phase calculations are done using B3LYP and M06 functionals at the 6-311++G(d,p) basis set level. pK(a) values calculated computationally are compared with experimental values in the given temperature region using both continuum solvation models. The continuum solvation models predict the temperature trends of pK(a) compared to experimental trends very nicely. Accurate pK(a) values at 298 K are however required as input to the model. The absolute values of pK(a) values are not reproduced well by these continuum solvation models, and a correction term is therefore introduced. A set of 10 amines, which have potential for CO(2) capture, and where also a large experimental data set of temperature dependent pK(a) values is available, were studied in this work. The temperature dependency of pK(a) values of amines provides a basis for selection for optimum solvents for postcombustion CO(2) capture processes. PMID- 22251399 TI - Effects of supplemental erythropoietin on its receptor expression and signal transduction pathways in rat model of retinal detachment. AB - PURPOSE: The aim of this study was to investigate the effects of supplemental erythropoietin (EPO) on its receptor (EPOR) and signal transduction pathways in rat model of retinal detachment (RD). METHODS: To investigate the effect of EPO on EPOR expression in RD rats 100, 200 or 400 ng EPO was injected into the vitreous cavity immediately after RD model was induced. Western blot and immunohistochemistry analyses were performed to measure EPOR expression. To investigate the effect of EPO on signal transduction pathways in RD rats single dose of 400 ng EPO was injected into the vitreous cavity immediately after RD model was induced. The total and phosphorylated levels of JAK2, Akt, ERK-1/2, STAT5 and NF-kappaB were assessed by western blot. RESULTS: Western blot analysis showed that, compared with the normal control group, EPOR expression in the neurosensory retina was significantly increased in experimental RD groups (P < 0.05), but the differences were not significant between experimental RD groups (P > 0.05). Immunohistochemical examination indicated that EPOR staining on retinas became strongly positive 3 days after RD, with no significant difference in staining intensities between the treatment groups. Phosphorylated levels of JAK2, Akt, ERK-1/2, STAT5, and NF-kappaB were enhanced 3 days after RD, but only JAK2, Akt, and ERK-1/2 phosphorylation was further enhanced by 400 ng EPO treatment (P < 0.05). CONCLUSIONS: Supplementary EPO cannot affect EPOR expression in detached retina, but EPO may activate both PI-3K/Akt and MAPK/ERK-1/2 signal transduction pathways in RD model. PMID- 22251400 TI - Histopathological evaluation of anterior lamellar corneal tissue-on/-off storage conditions on DSAEK donor tissue after storage in organ culture. AB - PURPOSE: To compare the quality of corneal endothelium of precut Descemet stripping automated endothelial keratoplasty (DSAEK) tissue when transported with and without the anterior lamellar corneal tissue (ALCT) when organ-culture corneal storage methods are used. METHODS: After microkeratome-assisted excision of anterior corneal lamella, five pairs of corneas (10 eyes) were stored either with the ALCT on the stroma (five eyes) or with ALCT off the stroma (five eyes) in organ-culture medium. Three pairs (six matched corneas) were left in the transport medium for 24 h prior to the microkeratome cut. Two pairs (four matched corneas) were left in the transport medium for 48 h prior to the microkeratome cut. All cuts were performed using a 300 (four eyes) or 350 (six eyes) microns head. A vital dye assay (alizarin red S and trypan blue) was used to identify devitalized and necrotic endothelial cells. RESULTS: In all matched cases, there was no difference between the endothelial cell appearance with or without the anterior corneal lamella. In all cases, there was no evidence for trypan blue stained cells beyond that normally seen on acceptable transplantable corneas and there was no evidence of loss of cells or any lifting of Descemet's membrane. CONCLUSIONS: There is no difference between the quality of the donor endothelial cell appearance with ALCT-on or -off when the donor cornea is stored using the organ-culture system of corneal storage. Organ-culture storage system is a safe and effective system in regard to preparation and transport of donor lenticules for DSAEK. PMID- 22251401 TI - Effects of tissue fixation on light scatter by PCO. AB - PURPOSE: To investigate whether light scattering of posterior capsule opacifications (PCOs) changes after fixation with paraformaldehyde (PFA). METHODS: The intraocular lens with the lens capsule were extracted from pseudophakic donor eyes. Images of the extracted sample were acquired pre and post PFA-fixation using a dark field microscope. Light scatter intensity was measured for different regions pre and post fixation. RESULTS: The regression lines between the light intensities measured pre and post fixation for the three color channels showed the same slope of 0.96. Also the correlation coefficients were the same for the three color channels, namely 0.97. CONCLUSIONS: Scattering intensities of PCO tissue pre and post fixation are quantitatively similar. The effects of fixation on the optical properties of PCO can be considered small. PMID- 22251403 TI - Hofmeister phenomena: an update on ion specificity in biology. PMID- 22251405 TI - The role of surgery in the treatment of colorectal metastases from primary skin melanoma. AB - AIM: The study assessed the role of colorectal surgery in the treatment of metastatic melanoma and identified patients who can most benefit from surgical resection. METHOD: A retrospective analysis was made of 34 consecutive patients with skin melanoma who underwent surgical resection of large bowel metastasis. RESULTS: The median disease-free interval between diagnosis of the primary and metastatic melanoma was 24 (7-98) months. Nine (27%) patients underwent emergency surgery for obstruction and 25 (73%) had an elective procedure. Resection with curative intent was performed in 14 (41%) and palliative resection in 20 (59%) patients. There was no postoperative mortality and morbidity occurred in 9%. The median survival following surgery was 11.5 (4-68) months. The 1-, 2- and 5-year survival rates were 50%, 32% and 17% respectively. Median survival was significantly increased in patients without extra-abdominal metastases, with no evidence of non-large-bowel metastases, if the disease-free interval was longer than 24 months and when curative resection was performed. In multivariate analysis, an apparently complete or palliative resection and the absence or presence of extra-abdominal metastases were the most important prognostic factors. CONCLUSION: An aggressive surgical approach to large bowel metastatic melanoma results in good palliation and effective relief of symptoms with acceptable morbidity and mortality. PMID- 22251404 TI - A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activation. AB - INTRODUCTION: Celecoxib, a highly specific cyclooxygenase-2 (COX-2) inhibitor has been reported to have COX-2-independent immunomodulatory effects. However, celecoxib itself has only mild suppressive effects on arthritis. Recently, we reported that a 4-trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2-inhibitory activity inhibits secretion of IL-12 family cytokines through a COX-2-independent mechanism that involves Ca2+-mediated intracellular retention of the IL-12 polypeptide chains. In this study, we explored the capacity of TFM-C as a new therapeutic agent for arthritis. METHODS: To induce collagen-induced arthritis (CIA), DBA1/J mice were immunized with bovine type II collagen (CII) in Freund's adjuvant. Collagen antibody-induced arthritis (CAIA) was induced in C57BL/6 mice by injecting anti-CII antibodies. Mice received 10 MUg/g of TFM-C or celecoxib every other day. The effects of TFM-C on clinical and histopathological severities were assessed. The serum levels of CII-specific antibodies were measured by ELISA. The effects of TFM-C on mast cell activation, cytokine producing capacity by macrophages, and neutrophil recruitment were also evaluated. RESULTS: TFM-C inhibited the severity of CIA and CAIA more strongly than celecoxib. TFM-C treatments had little effect on CII-specific antibody levels in serum. TFM-C suppressed the activation of mast cells in arthritic joints. TFM-C also suppressed the production of inflammatory cytokines by macrophages and leukocyte influx in thioglycollate-induced peritonitis. CONCLUSION: These results indicate that TFM-C may serve as an effective new disease-modifying drug for treatment of arthritis, such as rheumatoid arthritis. PMID- 22251406 TI - An in vivo investigation of salivary properties, enamel hypomineralisation, and carious lesion severity in a group of Iraqi schoolchildren. AB - BACKGROUND: Hypomineralised enamel is a prevalent, congenital defect vulnerable to deteriorate post-eruptively particularly in the presence of an unfavourable oral environment. AIMS: To assess the influence of salivary characteristics on the clinical presentation of hypomineralisation lesions diagnosed in first permanent and second primary molars and to evaluate caries severity in relation to the defect's clinical presentation. DESIGN: Recruitment consisted of 445 seven to nine-year-old participants, of whom 152 were diagnosed as having molar hypomineralisation (MH); the remaining unaffected subjects (N = 293) were considered their controls for saliva analysis. Dental caries status was assessed in 300 subjects of saliva sub-sample, equally divided as MH-affected and non affected children. The International Caries Detection and Assessment System was used for caries detection. Salivary flow rates, viscosity, pH, and buffering capacity were determined. RESULTS: Molar hypomineralisation-affected children have significantly higher mean caries scores compared to the non-affected group. Dentinal carious lesions were ten times more frequent in teeth with post-eruptive breakdown (PEB) than with teeth with opacities only. Low salivary flow rates (LSFR), moderately viscous saliva, and low pH were significantly more common in the affected group. LSFR and moderate and highly acidic saliva were more likely associated with PEB. CONCLUSION: Demarcated hypomineralised enamel is a dynamic defect highly influenced by individual characteristics of the oral environment. PMID- 22251407 TI - Guidelines for the New Nordic Diet. AB - OBJECTIVE: Diet has a significant impact on health, and ensuring that the population eats a healthy diet remains a public health challenge. Research is needed in order to improve the palatability of a healthy diet and make it attractive to the consumer. It has also been suggested that dietary recommendations should be tailored to regional conditions. The OPUS (Optimal well being, development and health for Danish children through a healthy New Nordic Diet) project investigates whether it is possible to develop a healthy New Nordic Diet (NND) that is palatable, environmentally friendly and based on foods originating from the Nordic region. The present paper describes the overall guidelines for the NND, developed and investigated in the multidisciplinary, 5 year OPUS research project. All guidelines are described in relation to the key principles: health, gastronomic potential and Nordic identity, and sustainability. RESULTS: The NND is described by the overall guidelines: (i) more calories from plant foods and fewer from meat; (ii) more foods from the sea and lakes; and (iii) more foods from the wild countryside. These overall guidelines result in a set of proposed dietary components which will be presented in a subsequent paper. CONCLUSIONS: Both the guidelines and the diet are composed taking the potential health-promoting properties and Nordic identity of the NND into account, as well as concern for environmental issues and gastronomic potential. PMID- 22251408 TI - Efficacy and tolerability of intravenous paricalcitol in calcitriol-resistant hemodialysis patients with secondary hyperparathyroidism: 12-month prospective study. AB - RATIONALE/OBJECTIVES: Data are limited regarding the use of paricalcitol in calcitriol-resistant patients with secondary hyperparathyroidism (SHPT). We aimed to evaluate the effects of paricalcitol in calcitriol-resistant hemodialysis patients with SHPT. METHODS: This is a 12-month, open-label, prospective study. Forty patients with calcitriol-resistant and/or calcitriol-intolerant SHPT were included. After a washout period, all patients converted to paricalcitol with a 1:3 conversion ratio. Serum calcium and phosphorus were monitored monthly, while serum intact parathyroid hormone (iPTH) once in every 3 months. Paricalcitol dose was reduced or discontinued in case of hypercalcemia and/or hyperphosphatemia. Pre- and posttreatment electrolyte and iPTH values were compared with Student's t test and Wilcoxon signed-rank test, respectively. MAIN FINDINGS: Forty patients completed the study. Mean initiation dose of paricalcitol was 23 +/- 7 MUg/week. Mean serum calcium was 8.9 +/- 0.8 mg/dL at baseline and 9.4 +/- 0.7 mg/dL at study end (p = 0.07). Mean monthly serum phosphorus levels stayed stable. Paricalcitol was effective in reducing iPTH levels when compared with pretreatment values (747.9 +/- 497.2 pg/mL, 307.3 +/- 417.1 pg/mL, respectively; p < 0.001). Thirty-two patients had to discontinue intravenous (IV) paricalcitol at some time during their treatment. Main reasons for discontinuation were as follows: hyperphosphatemia (58%), hypercalcemia (25%), and iPTH < 150 pg/mL (17%). PRINCIPLE CONCLUSIONS: Paricalcitol was found to be effective in reducing iPTH levels in calcitriol-resistant patients with SHPT despite relatively frequent drug discontinuation rates. PMID- 22251409 TI - Transplanting across a positive crossmatch in pediatric heart transplantation. PMID- 22251410 TI - Insights into the structure and assembly of Escherichia coli outer membrane protein A. AB - Outer membrane protein A (OmpA) of Escherichia coli is a paradigm for the biogenesis of outer membrane proteins; however, the structure and assembly of OmpA have remained controversial. A review of studies to date supports the hypothesis that native OmpA is a single-domain large pore, while a two-domain narrow-pore structure is a folding intermediate or minor conformer. The in vitro refolding of OmpA to the large-pore conformation requires isolation of the protein from outer membranes with retention of an intact disulfide bond followed by sufficient incubation in lipids at temperatures of >= 26 degrees C to overcome the high energy of activation for refolding. The in vivo maturation of the protein involves covalent modification of serines in the eighth beta-barrel of the N-terminal domain by oligo-(R)-3-hydroxybutyrates as the protein is escorted across the cytoplasm by SecB for post-translational secretion across the secretory translocase in the inner membrane. After cleavage of the signal sequence, protein chaperones, such as Skp, DegP and SurA, guide OmpA across the periplasm to the beta-barrel assembly machinery (BAM) complex in the outer membrane. During this passage, a disulfide bond is formed between C290 and C302 by DsbA, and the hydrophobicity of segments of the C-terminal domain, which are destined for incorporation as beta-barrels in the outer membrane bilayer, is increased by covalent attachment of oligo-(R)-3-hydroxybutyrates. With the aid of the BAM complex, OmpA is then assembled into the outer membrane as a single domain large pore. PMID- 22251411 TI - Ecology of the microbiome of the infected root canal system: a comparison between apical and coronal root segments. AB - AIM: To evaluate the microbial ecology of the coronal and apical segments of infected root canal systems using a complete sampling technique and next generation sequencing. METHODOLOGY: The roots of 23 extracted teeth with apical periodontitis were sectioned in half, horizontally, and cryo-pulverized. Bacterial communities were profiled using tagged 454 pyrosequencing of the 16S rDNA hypervariable V5-V6 region. RESULTS: The sequences were classified into 606 taxa (species or higher taxon), representing 24 bacterial phyla or candidate divisions and one archaeal phylum. Proteobacteria were more abundant in the apical samples (P < 0.05), whilst Actinobacteria were in significantly higher proportions in the coronal samples. The apical samples harboured statistically significantly more taxa than the coronal samples (P = 0.01) and showed a higher microbial diversity. Several taxa belonging to fastidious obligate anaerobes were significantly more abundant in the apical segments of the roots compared with their coronal counterparts. CONCLUSIONS: Endodontic infections are more complex than reported previously. The apical part of the root canal system drives the selection of a more diverse and more anaerobic community than the coronal part. The presence of a distinct ecological niche in the apical region explains the difficulty of eradication of the infection and emphasizes the need for new treatment approaches to be developed. PMID- 22251412 TI - Dynamic DNA cytosine methylation in the Populus trichocarpa genome: tissue-level variation and relationship to gene expression. AB - BACKGROUND: DNA cytosine methylation is an epigenetic modification that has been implicated in many biological processes. However, large-scale epigenomic studies have been applied to very few plant species, and variability in methylation among specialized tissues and its relationship to gene expression is poorly understood. RESULTS: We surveyed DNA methylation from seven distinct tissue types (vegetative bud, male inflorescence [catkin], female catkin, leaf, root, xylem, phloem) in the reference tree species black cottonwood (Populus trichocarpa). Using 5-methyl cytosine DNA immunoprecipitation followed by Illumina sequencing (MeDIP-seq), we mapped a total of 129,360,151 36- or 32-mer reads to the P. trichocarpa reference genome. We validated MeDIP-seq results by bisulfite sequencing, and compared methylation and gene expression using published microarray data. Qualitative DNA methylation differences among tissues were obvious on a chromosome scale. Methylated genes had lower expression than unmethylated genes, but genes with methylation in transcribed regions ("gene body methylation") had even lower expression than genes with promoter methylation. Promoter methylation was more frequent than gene body methylation in all tissues except male catkins. Male catkins differed in demethylation of particular transposable element categories, in level of gene body methylation, and in expression range of genes with methylated transcribed regions. Tissue-specific gene expression patterns were correlated with both gene body and promoter methylation. CONCLUSIONS: We found striking differences among tissues in methylation, which were apparent at the chromosomal scale and when genes and transposable elements were examined. In contrast to other studies in plants, gene body methylation had a more repressive effect on transcription than promoter methylation. PMID- 22251413 TI - Parent-adolescent report correspondence on adolescent substance abuse among teens in residential rehabilitation. AB - Research on the correspondence between adolescent and parent reports of adolescent substance abuse has typically been conducted on adolescent outpatient treatment samples, or on non-treatment samples. In the current study, fifty adolescents receiving residential substance abuse treatment, and their parents were assessed separately regarding the teen's substance use (e.g., cigarettes, alcohol, marijuana, other illicit drugs) during the 90 days preceding adolescent treatment entry. Correspondence between reporters was for the most part fair to excellent, with observed discrepancies generally due to parents providing lower estimates of use than did adolescents. Multiple regression analysis revealed that higher discrepancy between reporters occurred when the parent was younger, when the parent encountered fewer problems due to the teen's substance use, when the adolescent attended more probation or parole meetings, the fewer the number of days the adolescent was incarcerated, and the fewer days the adolescent lived at home prior to treatment. Results from exploratory analyses suggest that parents and adolescents are more discrepant when the assessment occurs later in the adolescent's treatment program. Overall, results suggest that in the absence of a cooperative teen, parental report of the adolescent's previous substance use could serve as a good proxy among families in which the adolescent is entering residential substance abuse treatment. PMID- 22251414 TI - Bioinspired synthesis of a hollow metallic microspiral based on a spirulina bioscaffold. AB - Bioinspired synthesis approaches aim to take advantage of the morphology and structural features of biological materials for the development of functional micro/nanodevices. In this Letter, we report that a unicellular algae known as a Spirulina was applied as a bioscaffold for the synthesis of hollow metallic Cu microspirals with length of 200-300 MUm. The electroless deposition method was employed to cover the spirulina forming the spiral. The nanomechanical properties of the spiral were investigated by using the nanoindentation technique. The results showed the hardness and elastic modulus of the spiral were 0.63-0.68 GPa and 12.35-12.63 GPa, respectively. Other metallic or alloy spirals could also be synthesized by using the spirulina as a bioscaffold with low cost and high reproducibility, and the obtained spirals could be promising materials as functional micro/nanodevices for microelectromechanical systems. PMID- 22251415 TI - High prevalence of male hypogonadism and sexual dysfunction in long-term clinically stable heart transplantation recipients. PMID- 22251416 TI - Excess risk of mortality and cardiovascular events associated with smoking among patients with diabetes: meta-analysis of observational prospective studies. AB - BACKGROUND: Numerous studies have demonstrated that both smoking and diabetes are risk factors for mortality and caused-specific cardiovascular events. However, few studies systematically investigated to what extent the excess risk could be attributed to smoking among diabetic patients. METHODS: Literature references were searched up to April 2011 in MEDLINE and EMBASE, supplemented by manual searches. Inclusion criteria were prospective cohort studies, assessment of the association between smoking and total mortality, cardiovascular death, incidence of coronary heart disease (CHD), stroke and myocardial infarction (MI) in diabetic patients. RESULTS: Of 3758 studies in the literature searched, 46 were eligible with approximately 130,000 diabetic patients. The relative risk (RR) comparing smokers with nonsmokers was 1.48[95% confidential interval (CI): 1.34 1.64] for total mortality (27 studies), 1.36(1.22-1.52) for cardiovascular mortality (9 studies), 1.54(1.31-1.82) for CHD (13 studies), 1.44(1.28-1.61) for stroke (9 studies) and 1.52(1.25-1.83) for MI (7 studies). Furthermore, the excess risk was observed among former and current smokers with a greater risk in current smokers. Subgroup analysis showed that the increased risk appeared to be consistent regardless of several study characteristics with the RRs ranging from 1.31 to 1.94 for all-cause mortality, 1.37 to 2.28 for CHD, 1.21 to 1.87 for stroke, 1.13 to 1.74 for cardiovascular mortality and 1.15 to 2.01 for MI. CONCLUSION: Smoking amplified the risk of mortality as well as cardiovascular events and the effect size for CHD appeared to be higher than other events in diabetic patients. Moreover, a trend of decreasing risk was observed among smoking quitters. PMID- 22251417 TI - Reference standard for serum bile acids in pregnancy. AB - OBJECTIVE: Obstetric cholestasis (OC) is a liver disorder characterised by pruritus and elevated serum bile acids (SBA) that affects one in 200 pregnant women. It is associated with adverse perinatal outcomes such as premature delivery and stillbirth. Mild OC is defined as SBA levels of 10-39 MUmol/l, and severe OC is defined by levels >40 MUmol/l. SBA levels in normal pregnancy have not been investigated. We aimed to establish reference values for SBA in healthy pregnant women across different trimesters of pregnancy. DESIGN: Cross-sectional analysis of SBA levels. SETTING: A large tertiary referral university teaching maternity hospital. POPULATION: Healthy pregnant women with a singleton pregnancy and a body mass index (BMI) < 40, excluding women with significant alcohol intake, history of liver disease, prior cholecystectomy and OC. METHODS: Cross sectional analysis of SBA levels at 12, 20, 28 and 36 weeks of gestation, and on days 1-3 postpartum. MAIN OUTCOME MEASURES: SBA levels in MUmol/l. RESULTS: A total of 219 women attending for antenatal care were recruited, and SBA levels were assayed at 12, 20, 28 and 36 weeks of gestation, and up to 72 hours postpartum (n = 44-49 cases at each stage). The majority were white European women, with a median age of 30 years (range 17-46 years) and median BMI of 25 (range 18-38). Values of SBA ranged from 0.3 to 9.8 MUmol/l in 216 women, with only three measurements outside this range. There were no significant changes throughout pregnancy. CONCLUSIONS: SBA values in uncomplicated pregnancies are consistent, regardless of gestation, and are not elevated in pregnancy. The current reference values for the diagnosis of OC appear to be appropriate. PMID- 22251418 TI - Long-term quality of life in patients with permanent sigmoid colostomy. AB - AIM: The study aimed to assess quality of life (QoL) in patients with a sigmoid colostomy using a simple general and disease-specific instrument. A subgroup not doing well was identified and examined further. METHOD: The Short Health Scale (SHS) is a four-item instrument exploring severity of symptoms, function in daily life, worry, and general well-being, using visual analogue scales ranging from 0 to 100 where 100 is the worst possible situation. The SHS was delivered to 206 patients with a sigmoid colostomy. It was returned by 181 (87.9%) patients [88 men; median age 73 (33-91) years]. Follow-up was 61 (10-484) months for 178 (86.4%) patients returning usable questionnaires. A subgroup of 16 patients scoring more than 50 in all four items of the SHS was further examined with StomaQOL where 100 is best possible. RESULTS: The median score for severity of symptoms was 18 (2-95), function in daily life 21 (0-95), worry 17 (3-98) and general well-being 22 (0-99). A score of < 50 in the SHS was recorded in 84.9%, 82.1%, 79.9% and 70.5% respectively. In the group scoring more than 50 in all four items patients diagnosed with irritable bowel syndrome constituted 43.8% to compare with 5.6% in the entire study group (P < 0.001). Median score for StomaQOL was 37 (22-62) in this group. CONCLUSION: Most patients with a permanent sigmoid colostomy have a good QoL consistent with previous findings. However, this is reduced in a subgroup of patients diagnosed with irritable bowel syndrome. PMID- 22251419 TI - Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. AB - BACKGROUND: Irritable bowel syndrome with constipation (IBS-C) significantly decreases quality of life and the ability to perform daily living activities. AIM: To demonstrate the long-term safety, tolerability and patient outcomes of lubiprostone in patients with IBS-C. METHODS: This extension study enrolled 522 IBS-C patients who had completed one of two randomised phase 3 studies. All enrolled patients received open-label lubiprostone orally for 36-weeks (8 mcg, twice daily). The primary objective was the assessment of long-term safety and tolerability, monitored via adverse events (AEs), laboratory parameters and vital signs. Additional outcome endpoints included monthly responder rates and patient evaluations of IBS-C symptom severity and impact on quality of life. RESULTS: The evaluable safety population comprised of 520 patients; 476 of which had patient reported outcome data available. The overall safety profile of lubiprostone during this study was similar to that observed in the preceding phase 3 studies. The most common AEs were diarrhoea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%) and abdominal distention (5.8%). Diarrhoea and nausea were the most common treatment-related AEs. No serious AEs were considered treatment-related. Seventeen patients discontinued due to a treatment-related AE, of which diarrhoea and nausea accounted for six (1.2%) and three (0.6%) respectively. For responder rates and patient-evaluated parameters (n = 476), all groups experienced significant improvements from baseline, with initial improvements maintained throughout the study. CONCLUSION: In patients with irritable bowel syndrome with constipation, lubiprostone 8 mcg twice daily was found to be safe and well tolerated over 9-13 months of treatment. PMID- 22251420 TI - Human cytomegalovirus tegument proteins (pp65, pp71, pp150, pp28). AB - Human cytomegalovirus (HCMV), a member of the Betaherpesvirinae sub-family of Herpesviridae family, is a widespread pathogen that infects a majority of the world's population by early adulthood. In individuals whose immune systems are immature or weakened, HCMV is a significant pathogen causing morbidity and mortality. There is no effective vaccine and only limited antiviral treatments against HCMV infection to date. A possible target for novel antiviral treatments is the HCMV proteins that localize to the tegument of the virion, since they play important roles in all stages of the viral life cycle, including, viral entry, gene expression, immune evasion, assembly, and egress. The most likely tegument protein candidates are pp65 (immune evasion), pp71 (gene expression), and pp150 and pp28 (assembly and egress). Although the subcellular localization of these proteins has been identified during HCMV infections in vitro, their localization patterns have not been determined when each protein is expressed individually in living cells. Thus, the objective of this review is elucidate the HCMV tegument as well as present current research findings concerning the subcellular localization of the tegument proteins pp65, pp71, pp150, and pp28 as fusions to one of several fluorescent proteins. PMID- 22251421 TI - Integrative role of neuropeptides and cytokines in cancer anorexia-cachexia syndrome. AB - BACKGROUND: The cachexia anorexia syndrome is a complex metabolic syndrome associated with cancer and some other palliative conditions characterized by involuntary weight loss involving fat and muscle, weight loss, anorexia, early satiety, fatigue, weakness due to shifts in metabolism caused by tumour by products and cytokines. Various neuropeptides like Leptin, neuropeptide Y, melanocortin, agouti-related peptides have been known to regulate appetite and body weight. METHOD: A comprehensive literature search was carried out on the websites of Pubmed Central (http://www.pubmedcentral.nih.gov/), National Library of Medicine (http://www.ncbl.nlm.nih.gov) and various other net resources. RESULT: Data from observational studies shows that various cytokines (TNF-alpha, IL-6 and IL-1) are associated with metabolic changes resulting in cachexia in cancer patients. These cytokines may mimic the action of various neuropeptides resulting in anorexia, various metabolic effects resulting from enhanced catabolic state and weight loss. CONCLUSION: There is a need to understand and explore the role of various neuropeptides and cytokines in the pathophysiology of cancer-anorexia syndrome so that therapeutic measures may be designed for effective palliative care. PMID- 22251422 TI - Insights on urinary NGAL obtained in a primary care setting. AB - BACKGROUND: A majority of patients developing acute kidney injury (AKI) receive medical care from their primary care physicians prior to the occurrence of conditions that predispose them to this complication. METHODS: To characterize the uNGAL concentrations in primary care patients and to assess these concentrations with regard to different reference intervals, we conducted a multicenter, cross-sectional study with random selection of general practitioners (GP) from all GP offices in seven Swiss cantons. 1000 adults (566 females; mean age 57+/-17 years) were included. RESULTS: The median absolute uNGAL was 21 ng/L. Elevated uNGAL (>100 ng/L) together with normal kidney test results (eGFR and albuminuria) were found in 6.5% of all patients. Females had a significantly higher uNGAL than did males. Among a multitude of different clinical and laboratory variables, only age, gender, liver function parameters, WBC and CRP were significantly associated with uNGAL levels in a multivariate analysis. When examining the proposed KDIGO classification of chronic kidney disease, the uNGAL levels at the given eGFR stages changed with increasing albuminuria stages and vice versa. CONCLUSIONS: Age, gender, markers of inflammation and liver function, exert influences on uNGAL concentrations. A substantial proportion of patients exhibited normal kidney testing together with elevated uNGAL, potentially identifying patients with increased renal stress and at increased risk for the development of AKI. PMID- 22251423 TI - NAMPT (visfatin) and AKT1 genetic variants associate with myocardial infarction. AB - BACKGROUND: High plasma levels of the adipokine NAMPT (or visfatin) have been associated with cardiovascular disease. However experimental data suggest that NAMPT, via Akt signaling, protects the myocardium against hypoxic insults. We studied whether the NAMPT rs1319501, AKT1 rs3730358, p53 rs1042522, Mdm2 rs2279744 or eNOS rs1799983 SNP:s linked to NAMPT and Akt signaling associate with risk of myocardial infarction (MI). METHODS: Cases were 828 men and 346 women aged 45-70 who had suffered a first MI. Control individuals, 1062 men and 513 women, were randomly chosen from the study base. We employed unconditional logistic regression analysis. RESULTS: The rs1319501 minor allele associated with MI among women aged 45-60; odds ratio (OR) under a recessive model of inheritance: 2.96 (95% confidence interval [CI] 1.06-8.29). Replication analysis in an independent material yielded OR point estimates in the same direction. The rs3730358 minor allele associated with low MI risk in men aged 45-60 (OR dominant model: 0.72, 95% CI 0.53-0.97), an association completely attenuated by adjusting for inflammatory markers. CONCLUSIONS: The NAMPT rs1319501 minor allele associates with increased MI risk in young women. In young men a protective effect of the AKT1 rs3730358 minor allele was suggested, possibly related to an attenuated inflammation. PMID- 22251424 TI - Dead-end hollow-fiber ultrafiltration for concentration and enumeration of Escherichia coli and broad-host-range plasmid DNA from wastewater. AB - Broad-host-range plasmids can facilitate dissemination of antibiotic resistance determinants among diverse bacterial populations. We evaluated hollow-fiber ultrafiltration for increases in detection efficiency of broad-host-range plasmids and Escherichia coli DNA in wastewater. Ultrafiltration followed by PCR showed limited increases in DNA detection and quantification in effluent compared with membrane filtration alone. PMID- 22251425 TI - Confined nanospaces in metallocages: guest molecules, weakly encapsulated anions, and catalyst sequestration. PMID- 22251426 TI - Hyperuricemia and untreated gout are poor prognostic markers among those with a recent acute myocardial infarction. AB - INTRODUCTION: Patients with a history of myocardial infarction (MI) are often at risk for complications, including subsequent MI and death. Use of prognostic markers may aid in preventing these poor outcomes. Hyperuricemia is associated with increased risk for coronary heart disease (CHD) and/or mortality; however, it is unknown if serum urate (sUA) levels predict outcomes in patients with previous MI. The purpose of this study was to assess hyperuricemia as a biomarker of CHD outcomes in such patients. METHODS: These were post hoc analyses of datasets from the Aspirin Myocardial Infarction Study, a 1:1 randomized, double blind clinical trial, conducted from 1975 to 1979, that examined mortality rates following daily aspirin administration over three years in individuals with documented MI. The primary outcome measures were all-cause death, CHD mortality, coronary incidence, and stroke by quartile of baseline sUA. A sub-analysis of all outcome measures in the presence or absence of gouty arthritis was also performed. RESULTS: Of 4,524 enrolled participants, data on 4,352 were analyzed here. All outcomes were greatest for patients in the fourth sUA quartile. In multivariate regression models, the hazard ratios (HR) for patients in the highest quartile were 1.88 for all-cause mortality (95% confidence interval (CI), 1.45 to 2.46), 1.99 for CHD mortality (95% CI, 1.49 to 2.66), and 1.36 for coronary incidence (95% CI, 1.08 to 1.70). Participants with untreated gout had an adjusted hazard ratio ranging from 1.5 to 2.0 (all P < 0.01) for these outcomes. Participants with gout who were receiving treatment did not exhibit this additional risk. CONCLUSIONS: sUA and untreated gout may be independent prognostic markers for poor all-cause and CHD mortality in patients with recent acute MI. PMID- 22251427 TI - A controlled, longitudinal study of home visits compared to telephone contacts to prevent early childhood caries. AB - BACKGROUND: Home visits (HV) provide excellent opportunities for health promotion. AIM: This longitudinal study compared the effects of HV and telephone contacts (TC) in preventing early childhood caries (ECC) and colonisation of mutans streptococci (MS) and lactobacilli (LB) from 0 to 24 months. DESIGN: A total of 325 children were recruited from community health centres at mean age of 42 days, and randomly assigned to receive either HV or TC. A total of 188 children completed three, 6 monthly HV, and another 58 had three, 6 monthly TC. An additional 40 age-matched children from childcare facilities served as reference controls (RC). At 24 months, all groups were examined at a community dental clinic. RESULTS: At 24 months, three HV children of 188 (1.5%) had caries, compared to four TC of 58 (6.8%) and nine RC of 40 (22.5%) (P < 0.001 for HV versus RC; P = 0.05 for HV versus TC and P = 0.03 for TC versus RC). There were also more children with MS in the TC (47%) and RC (35%) compared to HV (28%) group (P = 0.01 and P = 0.02). CONCLUSIONS: Home visits and telephone contacts conducted 6 monthly from birth are effective in reducing ECC prevalence by 24 months. PMID- 22251428 TI - Methotrexate: a detailed review on drug delivery and clinical aspects. AB - INTRODUCTION: Uses of methotrexate (MTX) are well established for the treatment of various types of malignancy, psoriasis, rheumatological diseases and the medical termination of pregnancy. Formulation and targeting approaches for MTX with controlled release carriers, multiparticulate systems, prodrug and drug conjugates have been found to improve bioavailability, reduce adverse effects and maximize clinical efficacy, compared with conventional methods. AREAS COVERED: This exhaustive literature survey on different electronic databases covers drug delivery and clinical trials on MTX. This review deals with the challenges and achievements of controlled release, multiparticulate, prodrug and drug conjugate systems of MTX. EXPERT OPINION: Therapeutic drug monitoring of MTX is crucial to attain a good efficacy. In spite of the advantages of multiparticulate, prodrug and drug conjugates, clinical applications of such formulations of MTX are still under infancy. These drug delivery systems require the special attention of medical experts for its wider clinical usage, and pharmaceutical experts for its scale-up. The combination of MTX with other antineoplastic and immunosuppressants should also be subjected to clinical trials, such as the combination of misoprostol with MTX in abortion. PMID- 22251429 TI - Implications of the WHO Child Growth Standards in rural Honduras. AB - OBJECTIVE: The present study analysed the impact of using the 2006 WHO Child Growth Standards ('the WHO standards') compared with the 1977 National Center for Health Statistics (NCHS) international growth reference ('the NCHS reference') on the calculated prevalence of chronic malnutrition in children aged 6.0-59.9 months. DESIGN: Anthropometric data were collected as part of a cross-sectional study exploring the association between household environments and nutritional status of children. Z-scores were computed for height-for-age (HAZ), weight-for age (WAZ) and weight-for-height (WHZ) using each reference/standard. Results were compared using Bland-Altman plots, percentage agreement, kappa statistics, line graphs and proportion of children in Z-score categories. SETTING: The study was conducted in thirteen rural villages within Honduras's department of Intibuca. SUBJECTS: Children aged 6.0-59.9 months were the focus of the analysis, and households with children in this age range served as the sampling unit for the study. RESULTS: The WHO standards yielded lower means for HAZ and higher means for WAZ and WHZ compared with the NCHS reference. The WHO standards and NCHS reference showed good agreement between Z-score categories, except for HAZ among males aged 24.0-35.9 months and WHZ among males aged >24.0 months. Using the WHO standards resulted in higher proportions of stunting (low HAZ) and overweight (high WHZ) and lower proportions of underweight (low WAZ). The degree of difference among these measures varied by age and gender. CONCLUSIONS: The choice of growth reference/standard employed in nutritional surveys may have important methodological and policy implications. While ostensibly comparable, data on nutritional indicators derived with different growth references/standards must be interpreted cautiously. PMID- 22251430 TI - Time-resolved spectroscopy of ultrafast photoisomerization of octopus rhodopsin under photoexcitation. AB - A primary process in vision is the cis-trans photoisomerization of a chromophore of rhodopsin, called retinal. In the present work, we have performed ultrafast time-resolved spectroscopy of octopus rhodopsin using a sub-5-fs pulse laser. In comparison with our previous study on bacteriorhodopsin, we found that octopus rhodopsin follows similar dynamics after photoexcitation but with different time constants. Spectrogram analysis showed that a C?N stretching mode appeared directly after photoexcitation. After reaching the conical intersection region at 80 fs, the overlapping hydrogen out-of-plane and in-plane C?C-H modes emerged as distinct peaks at ~200 fs, finishing a rapid relaxation along the coordinate related with these modes. The intensities of these peaks and a C?C stretching mode were found to be modulated at a period of ~500 fs, reflecting torsional motion around the C?C double bond before thermalization with the distribution of structural variations in the all-trans structure in configuration space. PMID- 22251431 TI - Two experimental tests of relational models of procedural justice: non instrumental voice and authority group membership. AB - In both a laboratory experiment (in Australia) using university as the basis of group membership, and a scenario experiment (in India) using religion as the basis of group membership, we observe more favourable respect and fairness ratings in response to an in-group authority than an out-group authority who administers non-instrumental voice. Moreover, we observe in our second experiment that reported likelihood of protest (herein called "social-change voice") was relatively high following non-instrumental voice from an out-group authority, but relatively low following non-instrumental voice from an in-group authority. Our findings are consistent with relational models of procedural justice, and extend the work by examining likely use of alternative forms of voice as well as highlighting the relative importance of instrumentality. PMID- 22251432 TI - Role of alpha-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. AB - Parkinson's disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of alpha synuclein (alpha-syn) in the central nervous system. Aggregation of alpha-syn into oligomers with a ring-like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms and the potential sequence of events involved in the formation of pore-like structures are unclear. We utilized computer modeling and cell-based studies to investigate the process of oligomerization of wild-type and A53T mutant alpha-syn in membranes. The studies suggest that alpha-syn penetrates the membrane rapidly, changing its conformation from alpha-helical towards a coiled structure. This penetration facilitates the incorporation of additional alpha-syn monomers in the complex, and the subsequent displacement of phospholipids and the formation of oligomers in the membrane. This process occurred more rapidly, and with a more favorable energy of interaction, for mutant A53T compared with wild-type alpha-syn. After 4 ns of simulation of the protein-membrane model, alpha-syn had penetrated through two thirds of the membrane. By 9 ns, the penetration of the annular alpha-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant alpha-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) alpha-syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures, resulting in greater neuronal permeability, as demonstrated with the calcein efflux assay. These studies provide a sequential molecular explanation for the process of alpha-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD. PMID- 22251433 TI - Characterisation of the mgo operon in Pseudomonas syringae pv. syringae UMAF0158 that is required for mangotoxin production. AB - BACKGROUND: Mangotoxin is an antimetabolite toxin that is produced by strains of Pseudomonas syringae pv. syringae; mangotoxin-producing strains are primarily isolated from mango tissues with symptoms of bacterial apical necrosis. The toxin is an oligopeptide that inhibits ornithine N-acetyl transferase (OAT), a key enzyme in the biosynthetic pathway of the essential amino acids ornithine and arginine. The involvement of a putative nonribosomal peptide synthetase gene (mgoA) in mangotoxin production and virulence has been reported. RESULTS: In the present study, we performed a RT-PCR analysis, insertional inactivation mutagenesis, a promoter expression analysis and terminator localisation to study the gene cluster containing the mgoA gene. Additionally, we evaluated the importance of mgoC, mgoA and mgoD in mangotoxin production. A sequence analysis revealed an operon-like organisation. A promoter sequence was located upstream of the mgoB gene and was found to drive lacZ transcription. Two terminators were located downstream of the mgoD gene. RT-PCR experiments indicated that the four genes (mgoBCAD) constitute a transcriptional unit. This operon is similar in genetic organisation to those in the three other P. syringae pathovars for which complete genomes are available (P. syringae pv. syringae B728a, P. syringae pv. tomato DC3000 and P. syringae pv. phaseolicola 1448A). Interestingly, none of these three reference strains is capable of producing mangotoxin. Additionally, extract complementation resulted in a recovery of mangotoxin production when the defective mutant was complemented with wild-type extracts. CONCLUSIONS: The results of this study confirm that mgoB, mgoC, mgoA and mgoD function as a transcriptional unit and operon. While this operon is composed of four genes, only the last three are directly involved in mangotoxin production. PMID- 22251434 TI - Ligustrazine derivatives. Part 4: design, synthesis, and biological evaluation of novel ligustrazine-based stilbene derivatives as potential cardiovascular agents. AB - A series of novel stilbene derivatives containing ligustrazinyl moiety was designed, synthesized, and assayed for their protective effects on damaged endothelial cells. The results showed that most ligustrazinyl stilbene derivatives exhibited high protective effects on the human umbilical vascular endothelial cells (HUVECs) damaged by hydrogen peroxide in comparison with Ligustrazine. The stilbene derivatives A6, A9, A11, A21, A24, A25, and A27 exhibited high potency with low EC(50) values ranged from 0.0249 MUm to 0.0898 mm. Compound A27 displayed EC(50) 0.0249 MUm, which is 30,000 times higher than that of Ligustrazine, presenting a most promising lead for further investigation. Structure-activity relationships were briefly discussed. PMID- 22251435 TI - C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn's disease: a post-hoc analysis from ACCENT I. AB - BACKGROUND: Secondary loss of response to anti-TNF-alpha therapy is observed in Crohn's disease patients. AIM: Serum C-reactive protein (CRP) levels at baseline and after infliximab induction therapy at week 14 were assessed as predictors for maintained response or remission through 54 weeks of treatment in patients with Crohn's disease who responded to induction therapy. METHODS: ACCENT I was a multicenter, randomised, placebo-controlled study. Patients who received infliximab induction (weeks 0, 2 and 6) and maintenance (5 or 10 mg/kg every 8 weeks beginning at week 14) therapy were considered. Patients in clinical response or remission to induction therapy at week 14 (n = 212 or n = 138 respectively) were analysed. Associations between CRP levels (cut-off points 0.5 3.0 mg/dL), baseline disease variables and maintained clinical response or remission during maintenance therapy were assessed. RESULTS: A significant association was observed between baseline CRP levels and maintained remission. Forty-five percent of patients with baseline CRP >= 0.7 mg/dL vs. 22.0% with CRP < 0.7 mg/dL maintained remission (P = 0.012). CRP normalisation during infliximab treatment (decrease from 0.5 mg/dL at baseline to < 0.5 mg/dL at week 14) resulted in higher probability of maintained response (P < 0.001) or remission (P = 0.052). At week 14 low CRP levels were associated with maintained response (56.6% of patients with CRP < 0.5 mg/dL vs. 37.2% with higher CRP, P = 0.005). No optimal predictive CRP cut-off point was observed. CONCLUSIONS: High baseline CRP levels increased the likelihood of maintained remission. Normalised CRP levels at week 14 increased the likelihood of maintained response or remission during 1 year of infliximab maintenance therapy ( CLINICAL TRIAL: NCT00207662). PMID- 22251436 TI - Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. AB - INTRODUCTION: The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX). METHODS: This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components. RESULTS: Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%). CONCLUSIONS: Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00427934. PMID- 22251437 TI - An acidic phospholipase A2 with antibacterial activity from Porthidium nasutum snake venom. AB - Snake venoms are complex mixtures of proteins among which both basic and acidic phospholipases A(2) (PLA(2)s) can be found. Basic PLA(2)s are usually responsible for major toxic effects induced by snake venoms, while acidic PLA(2)s tend to have a lower toxicity. A novel PLA(2), here named PnPLA(2), was purified from the venom of Porthidium nasutum by means of RP-HPLC on a C18 column. PnPLA(2) is an acidic protein with a pI of 4.6, which migrates as a single band under both non reducing and reducing conditions in SDS-PAGE. PnPLA(2) had a molecular mass of 15,802.6 Da, determined by ESI-MS. Three tryptic peptides of this protein were characterized by HPLC-nESI-MS/MS, and N-terminal sequencing by direct Edman degradation showing homology to other acidic PLA(2)s from viperid venoms. PnPLA(2) displayed indirect hemolytic activity in agarose erythrocyte-egg yolk gels and bactericidal activity against Staphylococcus aureus in a dose-dependent manner, with a MIC and MBC of 32 MUg/mL. In addition, PnPLA(2) showed a potent inhibitory effect on platelet aggregation with doses up to 40 MUg/mL. This acidic PLA(2), in contrast to basic enzymes isolated from other viperid snake venoms, was not cytotoxic to murine skeletal muscle myoblasts C(2)C(12). This is the first report on a bactericidal protein of Porthidium nasutum venom. PMID- 22251438 TI - Preoperative MRI sphincter morphology and anal manometry: can they be markers of functional outcome following anterior resection for rectal cancer? AB - AIM: Good functional outcome following anterior resection (AR) for rectal cancer is an important clinical goal, but its prediction has proven difficult. Assessments such as anal manometry have been advocated as a potential tool but functional anatomy as depicted on MRI has not been investigated. This study looked at whether sphincter complex measurements recorded from preoperative staging MRIs and preoperative anal manometry have any correlation with functional outcome. METHOD: Consecutive patients with rectal adenocarcinoma underwent preoperative manometric assessment and MRI staging. MRIs were assessed with regard to anorectal angle, puborectalis thickness, canal length and external and internal anal sphincter thickness. Functional outcome was categorized into three groups according to the number of adverse postoperative symptoms (frequency, urgency, leakage, diarrhoea, use of pads, use of antidiarrhoeal medication): 0, 1 and >= 2. This was evaluated 1 year following surgery and 6 months following stoma reversal where applicable. Univariate analysis of an ordinal regression model was performed with significance at the 5% level. RESULTS: Thirty patients were assessed. No single preoperative manometric parameter proved significant (P > 0.05). Only puborectalis thickness showed a significant (P = 0.01) relationship with the number of adverse symptoms suffered postoperatively. On receiver operating characteristics analysis, a cut-off value of 3.5 mm gave an optimal sensitivity of 0.5 (95% CI, 0.17-0.83) and specificity of 0.86 (95% CI, 0.64 0.96). CONCLUSIONS: Measurements of the puborectalis thickness on preoperative staging MRIs for rectal cancer may help predict functional outcome following AR. Prospective assessment of larger numbers with a fully validated continence score are required to evaluate these findings further. PMID- 22251439 TI - Solid-state NMR analyses reveal the structure dependence of the molecular dynamics for omega-amino acids. AB - The molecular dynamics of metabolites is structure dependent and vitally important for the interactive functions in their potential applications as natural materials. To understand the relationship between molecular structure and dynamics, the molecular motions of four structurally related omega-amino acids (beta-alanine, gamma-aminobutyric acid, 5-aminovaleric acid, and 6-aminocaproic acid) were investigated by measuring their proton spin-lattice relaxation times (T(1), T(1rho)) as a function of temperature (180-440 K). (13)C CPMAS NMR and DSC analyses were performed to obtain complementary information. All of these omega amino acids showed no phase transition in the temperature range studied but had outstandingly long proton T(1) at 300 MHz and even at 20 MHz for the deuterated forms. The molecular dynamics of all these omega-amino acids were dominated by the reorientation motions of amino groups and backbone motions except in beta alanine. The activation energies for amino group reorientations were positively correlated with the strength of hydrogen bonds involving these groups in the crystals and the carbon-chain lengths, whereas such energies for the backbone motions were inversely correlated with the carbon-chain lengths. These findings provided essential information for the molecular dynamics of omega-amino acids and demonstrated the combined solid-state NMR methods as a useful approach for understanding the structural dependence of molecular dynamics. PMID- 22251440 TI - Challenges in the pharmaceutical development of lipid-based short interfering ribonucleic acid therapeutics. AB - INTRODUCTION: Harnessing RNA interference as a therapeutic approach has the potential to significantly expand the druggable target space, offering new hope for treatment of diseases that cannot be addressed with existing classes of drugs. A number of siRNA therapeutics have already progressed into preclinical and clinical development. Of these, lipid-based systems have emerged as one of the most mature classes of systemic delivery technologies. Despite tremendous advances in development, a number of significant challenges must still be addressed to enable commercialization of a lipid-based siRNA pharmaceutical product. AREAS COVERED: This review addresses specific challenges inherent to the pharmaceutical development of lipid-based siRNA therapeutics. Focus is placed on the development of a robust manufacturing process, the setting of appropriate product specifications and controls, development of strategies to assess and ensure product stability, and the evaluation of product comparability throughout development. EXPERT OPINION: Discovering and developing a lipid-based siRNA therapeutic that can be commercialized requires engineering a particle that selectively and efficiently delivers the cargo to the target tissue and cellular compartment. The particle assembly must be strictly controlled and physical properties thoroughly characterized to successfully develop an understanding of particle attributes that influence in vivo pharmaceutical properties. Correlation of particle physio-chemical properties to product performance is the foundation for advancements in discovery and assuring quality in a commercial drug product. Although difficult, we believe these development challenges can be addressed with appropriate scientific resources and that the industry will continue to progress siRNA therapeutic candidates through clinical development. PMID- 22251441 TI - Wild boar: an increasing concern for Aujeszky's disease control in pigs? AB - BACKGROUND: The goal of this study was describing the temporal evolution of Aujeszky's disease virus (ADV) contact prevalence among Eurasian wild boar (Sus scrofa) populations under different management regimes and contact likelihoods with domestic pigs. Given the recent increase in wild boar abundance throughout Europe, we hypothesized that wild boar contact with ADV would remain stable in time even after significant reduction of ADV prevalence in domestic pigs. RESULTS: Sera from 1659 wild boar were collected from 2000 to 2010 within 6 areas of the Iberian Peninsula and tested for the presence of antibodies against ADV by ELISA. According to sampling date, wild boar were grouped into three time periods. ADV prevalence was compared through period both globally and by geographic area. Overall seroprevalence for the ten-year study period was 49.6 +/ 2.4%. The highest seroprevalence was recorded in areas with intense wild boar management. The annual proportion of positive wild boar sampling sites remained stable through the study period, while the percentage of domestic pig AD positive counties decreased from 70% in 2003 to 1.7% in 2010. CONCLUSIONS: Results presented herein confirmed our hypothesis that ADV would remain almost stable in wild boar populations. This evidences the increasing risk wild boar pose in the final stages of ADV eradication in pigs and for wildlife conservation. PMID- 22251442 TI - Have regulatory efforts to reduce organophosphorus insecticide exposures been effective? AB - BACKGROUND: The Food Quality Protection Act (FQPA) was signed into law in 1996 to strengthen the regulation of pesticide tolerances in food. Organophosphorus (OP) insecticides were the first group of pesticides reviewed by the U.S. Environmental Protection Agency (EPA) under the new law. OBJECTIVE: Our goal was to determine whether urinary concentrations of dialkylphosphate (DAP) metabolites of OP pesticides declined between the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999-2004. METHODS: Using mass spectrometry-based methods, we analyzed urine samples from a nationally representative sample of 2,874 adults 20-59 years of age in NHANES 1999-2004 and samples from a non nationally representative sample of 197 adult participants for NHANES III (1988 1994) for six common DAP metabolites of OP pesticides. RESULTS: Median urinary DAP concentrations decreased by more than half between NHANES III and NHANES 2003 2004. Reductions of about 50%-90% were also observed for 95th percentile concentrations of five of the six metabolites. Frequencies of detection (FODs) decreased in all six metabolites (< 50% reduction). On average, median and 95th percentile concentrations and FODs showed a larger decrease in diethylphosphate metabolites than dimethylphosphate metabolites. CONCLUSIONS: Human exposure to OP insecticides as assessed by urinary DAP concentrations has decreased since the implementation of the FQPA, although we cannot be certain that U.S. EPA actions in response to the FQPA directly caused the decrease in DAP concentrations. PMID- 22251443 TI - Impending macrosomia: will induction of labour modify the risk of caesarean delivery? AB - OBJECTIVE: To compare the annual incidence rates of caesarean delivery between induction of labour and expectant management in the setting of macrosomia. DESIGN: This is a retrospective cohort study. SETTING: Deliveries in the USA in 2003. POPULATION: Singleton births of macrosomic neonates to low-risk nulliparous women at 39 weeks of gestation and beyond. METHODS: Women who had induction of labour at 39 weeks of gestation with a neonatal birthweight of 4000 +/- 125 g (3875-4125 g) were compared with women who delivered (either induced or spontaneous labour) at 40, 41 or 42 weeks (i.e. expectant management), assuming an intrauterine fetal weight gain of 200 g per additional week of gestation. Similar comparisons were made at 40 and 41 weeks of gestation. Chi-square test and multivariable logistic regression analysis were used for statistical comparison. MAIN OUTCOME MEASURES: Method of delivery, 5-minute Apgar scores, neonatal injury. RESULTS: There were 132,112 women meeting the study criteria. In women whose labours were induced at 39 weeks and who delivered a neonate with a birthweight of 4000 +/- 125 g, the frequency of caesarean was lower compared with women who delivered at a later gestational age (35.2% versus 40.9%; adjusted OR 1.25, 95% CI 1.17-1.33). This trend was maintained at both 40 weeks (36.1% versus 42.6%; adjusted OR 1.31, 95% CI 1.23-1.40) and 41 weeks (38.9% versus 41.8%; adjusted OR 1.16, 95% CI 1.06-1.28) of gestation. CONCLUSIONS: In the setting of known birthweight, it appears that induction of labour may reduce the risk of caesarean delivery. Future research should concentrate on clinical and radiological methods to better estimate birthweight to facilitate improved clinical care. These findings deserve examination in a large, prospective, randomised trial. PMID- 22251444 TI - Quantitative structure-property relationship modeling of diverse materials properties. PMID- 22251445 TI - Mortality and causes of death among violent offenders and victims--a Swedish population based longitudinal study. AB - BACKGROUND: Most previous studies on mortality in violent offenders or victims are based on prison or hospital samples, while this study analyzed overall and cause specific mortality among violent offenders, victims, and individuals who were both offenders and victims in a general sample of 48,834 18-20 year-old men conscripted for military service in 1969/70 in Sweden. METHODS: Each person completed two non-anonymous questionnaires concerning family, psychological, and behavioral factors. The cohort was followed for 35 years through official registers regarding violent offenses, victimization, and mortality. The impact of violence, victimization, early risk factors and hospitalization for psychiatric diagnosis or alcohol and drug misuse during follow up on mortality was investigated using Cox proportional hazard regression analyses. RESULTS: Repeat violent offenses were associated with an eleven fold higher hazard of dying from a substance-related cause and nearly fourfold higher hazard of dying from suicide. These figures remained significantly elevated also in multivariate analyses, with a 3.03 and 2.39 hazard ratio (HR), respectively. Participants with experience of violence and inpatient care for substance abuse or psychiatric disorder had about a two to threefold higher risk of dying compared to participants with no substance use or psychiatric disorder. CONCLUSIONS: Violent offending and being victimized are associated with excess mortality and a risk of dying from an alcohol or drug-related cause or suicide. Consequently, prevention of violent behavior might have an effect on overall mortality and suicide rates. Prevention of alcohol and drug use is also warranted. PMID- 22251446 TI - Energy and electron transfer from fluorescent mesostructured organosilica framework to guest dyes. AB - Energy and electron transfer from frameworks of nanoporous or mesostructured materials to guest species in the nanochannels have been attracting much attention because of their increasing availability for the design and construction of solid photofunctional systems, such as luminescent materials, photovoltaic devices, and photocatalysts. In the present study, energy and electron-transfer behavior of dye-doped periodic mesostructured organosilica films with different host-guest arrangements were systematically examined. Fluorescent tetraphenylpyrene (TPPy)-silica mesostructured films were used as a host donor. The location of guest perylene bisimide (PBI) dye molecules, acting as an acceptor, could be controlled on the basis of the molecular design of the PBI substituent groups. PBI dyes with bulky substituents and polar anchoring groups were located at the pore surface with low self-aggregation, which induced efficient energy or electron transfer because of the close host-guest arrangement. However, PBI dye with bulky and hydrophobic substituents was located in the center of template surfactant micelles; the fluorescence emission from the host TPPy groups was hardly quenched when the host-guest distance was longer than the critical Forster radius (ca. 4.5 nm). The relationship between the energy or electron-transfer efficiency and the location of guest species in the channels of mesostructured organosilica was first revealed by molecular design of the PBI substituents. PMID- 22251447 TI - Evolutionarily conserved protein arginine methyltransferases in non-mammalian animal systems. AB - Protein arginine methylation is catalyzed by members of the protein arginine methyltransferase (PRMT) family. In the present review, nine PRMTs identified in mammals (human) were used as templates to survey homologous PRMTs in 10 animal species with a completed sequence available in non-mammalian vertebrates, invertebrate chordates, echinoderms, arthropods, nematodes and cnidarians. We show the conservation of the most typical type I PRMT1 and type II PRMT5 in all of the species examined, the wide yet different distribution of PRMT3, 4 and 7 in non-mammalian animals, the vertebrate-restricted distribution of PRMT8 and the special reptile/avian-deficient distribution of PRMT2 and 6. We summarize the basic functions of each PRMT and focus on the current investigations of PRMTs in the non-mammalian animal models, including Xenopus, fish (zebrafish, flounder and medaka), Drosophila and Caenorhabditis elegans. Studies in the model systems not only complement the understanding of the functions of PRMTs in mammals, but also provide valuable information about their evolution, as well as their critical roles and interplays. PMID- 22251448 TI - Calorimetric behavior of phosphatidylcholine/phosphatidylethanolamine bilayers is compatible with the superlattice model. AB - Differential scanning calorimetry was used to study the phase behavior of binary lipid bilayers consisting of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of varying acyl chain length. A two-state transition model was used to resolve the individual transition components, and the two-state transition enthalpy, the relative enthalpy, and the transition temperature of each component were plotted as a function of composition. Intriguingly, abrupt changes in these thermodynamic parameters were observed at or close to many "critical" X(PE) values predicted by the superlattice model proposing that phospholipids with different headgroups tend to adopt regular rather than random lateral distributions. Statistical analysis indicated that the agreement between the observed and predicted "critical" compositions is highly significant. Accordingly, these data provide strong evidence that the molecules in PC/PE bilayers tend to adopt regular, superlattice-like lateral arrangements, which could be involved in the regulation of the lipid compositions of biological membranes. PMID- 22251449 TI - P50 suppression in human discrimination fear conditioning paradigm using danger and safety signals. AB - Auditory P50 suppression, which is assessed using a paired auditory stimuli (S1 and S2) paradigm to record the P50 mid-latency evoked potential, is assumed to reflect sensory gating. Recently, P50 suppression deficits were observed in patients with anxiety disorders, including panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder, as we previously reported. The processes of fear conditioning are thought to play a role in the pathophysiology of anxiety disorders. In addition, we found that the P50 sensory gating mechanism might be physiologically associated with fear conditioning and extinction in a simple human fear-conditioning paradigm that involved a light signal as a conditioned stimulus (CS+). Our objective was to investigate the different patterns of P50 suppression in a discrimination fear-conditioning paradigm with both a CS+ (danger signal) and a CS- (safety signal). Twenty healthy volunteers were recruited. We measured the auditory P50 suppression in the control (baseline) phase, in the fear-acquisition phase, and in the fear-extinction phase using a discrimination fear-conditioning paradigm. Two-way (CSs vs. phase) Analysis of variance with repeated measures demonstrated a significant interaction between the two factors. Post-hoc LSD analysis indicated that the P50 S2/S1 ratio in the CS+ acquisition phase was significantly higher than that in the CS- acquisition phase. These results suggest that the auditory P50 sensory gating might differ according to the cognition of the properties (potentially dangerous or safe) of the perceived signal. PMID- 22251450 TI - Adrenal hormone response and psychophysiological correlates under psychosocial stress in individuals with irritable bowel syndrome. AB - OBJECTIVE: In this study, we investigated levels and relative ratios of adrenal hormones (including cortisol, dehydroepiandrosterone [DHEA], and DHEA-sulfate [DHEA-S]) and their psychophysiological correlates under acute psychosocial stress in individuals with irritable bowel syndrome (IBS). METHODS: Fifty-three college students participated in the study (male: 42, female: 11; mean age: 22.64years), including 13 individuals with IBS (IBS group) and 40 individuals without IBS (control group). The participants were exposed to a standardized laboratory stressor, which included delivering a speech and performing a mental arithmetic task. We measured subjective stress levels and salivary cortisol, DHEA, and DHEA-S levels at relevant time points before, during, and after the tasks. RESULTS: DHEA-S level and the DHEA-S/DHEA ratio in the IBS group were significantly lower than those in the control group, and the cortisol/DHEA-S ratio in the IBS group was higher than that in the control group throughout the experiment. In the IBS group, the appraisal of a threat was positively correlated with cortisol levels (r=0.61), and the appraisal of controllability was negatively correlated with cortisol levels (r=-0.64) and with the cortisol/DHEA ratio (r=-0.71). The control group showed a significant positive correlation between the appraisal of threat and cortisol levels (r=0.32). CONCLUSION: The present study indicates that individuals with IBS had lower DHEA-S levels, and that their stressful cognitive appraisals under acute psychosocial stress caused the effects of cortisol to dominate. This adrenal hormone response may be involved in exacerbating abdominal symptoms in individuals with IBS. PMID- 22251452 TI - Biological immunomodulators improve the healing rate in surgically treated perianal Crohn's fistulas. AB - AIM: The role of biological therapy in perianal fistulas associated with Crohn's disease (CD) is uncertain as available data are confused and conflicting. In order to provide some clarity to the issue we have examined a large cohort of patients with perianal fistulas and CD and stratified them according to use of biological agents. METHOD: Patients with perianal Crohn's fistulas treated between June 1999 and June 2009 were stratified according to use of biological agents and outcome was examined. Healing was defined as absence of fistula or drainage. Prior to surgery perianal sepsis was eradicated with drains or setons. Endpoints were defined as either complete healing, improvement (minimal symptoms and drainage) or unhealed, as noted at subsequent outpatient follow-up. Variables assessed were age, body mass index, smoking, perineal involvement with Crohn's granuloma and type of procedure. Fisher's exact test and chi(2) test were used for analysis. RESULTS: Two hundred and eighteen patients had anal fistulas and CD. Mean follow-up was 3.2+/-3 years with mean age 38.8+/-12.2years and body mass index of 25.3+/-6. One hundred and seventeen patients (53.7%) underwent surgery alone (Group A) and 101 patients (46.3%) underwent surgery and biological immunomodulator treatments (Group B). Demographic data and CD history were similar between groups. Surgeries included seton drainge (n=90), fistulotomy (n=22), rectal advancement flap (n=39), fistulotomy plus seton (n=47) and others (n=20). Overall improvement in Group A was in 42 patients (35.9%) vs 72 patients (71.3%) in Group B (P=0.001). There was no significant difference in other studied variables between both groups. CONCLUSIONS: There is a definite role for biological therapy as an adjuvant to surgery in patients with perianal fistulas and CD. PMID- 22251451 TI - MIBE acts as antagonist ligand of both estrogen receptor alpha and GPER in breast cancer cells. AB - INTRODUCTION: The multiple biological responses to estrogens are mainly mediated by the classical estrogen receptors ERalpha and ERbeta, which act as ligand activated transcription factors. ERalpha exerts a main role in the development of breast cancer; therefore, the ER antagonist tamoxifen has been widely used although its effectiveness is limited by de novo and acquired resistance. Recently, GPR30/GPER, a member of the seven-transmembrane G protein-coupled receptor family, has been implicated in mediating the effects of estrogens in various normal and cancer cells. In particular, GPER triggered gene expression and proliferative responses induced by estrogens and even ER antagonists in hormone-sensitive tumor cells. Likewise, additional ER ligands showed the ability to bind to GPER eliciting promiscuous and, in some cases, opposite actions through the two receptors. We synthesized a novel compound (ethyl 3-[5-(2 ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]but-2-enoate), referred to as MIBE, and investigated its properties elicited through ERalpha and GPER in breast cancer cells. METHODS: Molecular modeling, binding experiments and functional assays were performed in order to evaluate the biological action exerted by MIBE through ERalpha and GPER in MCF7 and SkBr3 breast cancer cells. RESULTS: MIBE displayed the ability to act as an antagonist ligand for ERalpha and GPER as it elicited inhibitory effects on gene transcription and growth effects by binding to both receptors in breast cancer cells. Moreover, GPER was required for epidermal growth factor receptor (EGFR) and ERK activation by EGF as ascertained by using MIBE and performing gene silencing experiments. CONCLUSIONS: Our findings provide novel insights on the functional cross-talk between GPER and EGFR signaling. Furthermore, the exclusive antagonistic activity exerted by MIBE on ERalpha and GPER could represent an innovative pharmacological approach targeting breast carcinomas which express one or both receptors at the beginning and/or during tumor progression. Hence, the simultaneous inhibition of both ERalpha and GPER may guarantee major therapeutic benefits in respect to the use of a selective estrogen receptor antagonist. PMID- 22251453 TI - Early hospital discharge of infants born to group B streptococci-positive mothers: a decision analysis. AB - OBJECTIVE: To compare the cost-effectiveness of an additional 24-hour inpatient observation for asymptomatic term neonates born to group B streptococcus (GBS) colonised mothers with adequate intrapartum antibiotic prophylaxis (IAP) after an initial 24-hour in-hospital observation. DESIGN: Cost-effectiveness analysis from a societal perspective. SETTING: United States. POPULATION: Asymptomatic term neonates born to GBS-colonised mothers with IAP after an initial 24-hour in hospital observation. METHODS: Monte Carlo simulation for a decision tree model incorporating the following chance events: development of GBS sepsis during the second 24 hours of life, development of GBS sepsis between 48 hours and 7 days of life, prompt versus delayed treatment for sepsis, neonatal mortality and long term health sequelae. MAIN OUTCOME MEASURES: Expected cost and quality-adjusted life years (QALYs), Incremental cost-effectiveness ratio (ICER). RESULTS: Delayed, versus early, hospital discharge results in similar mean expected QALYs, but substantially higher expected cost. The mean difference in QALY is 0.00016 (95% CI 0.00005-0.00040), whereas the mean difference in cost is $1170.96 (95% CI $750.13-1584.32). The ICER is estimated to be $9,771,520.87 per QALY (95% CI $2,573,139.89-24,407,017.82). The proportion of early-onset GBS that develops during the second 24 hours of life, the cost of 24 hours of inpatient observation, and the probability of long-term sequelae following prompt versus delayed treatment play important roles in determining the cost-effectiveness of delayed hospital discharge. CONCLUSION: Cost-effectiveness analysis suggests that with adequate IAP, discharging asymptomatic term neonates to home after 24 hours is the preferred approach compared with 48 hours inpatient observation. PMID- 22251456 TI - Controlling the assembly of nanoparticle mixtures with two orthogonal polymer complexation reactions. AB - Self-assembly from mixed dispersions of three sizes of monodisperse polystyrene nanoparticles, large (L), medium (M), and small (S), was controlled by coating each particle type with either a monofunctional or bifunctional polymer capable of participating in specific complexation reactions. The complexation reactions were (1) complexation between phenolic polymers and polyethylene glycol (PEG) containing polymers and (2) condensation of phenylboronic acid containing polymers with polyols. These complexation reactions function independently and can be "turned off" independently; phenylboronic acid complexation was reversed by lowering the pH, whereas the interactions of phenolic copolymers with PEG copolymers could be reversed by adding excess PEG homopolymer. The specificity and reversibility of the interactions was demonstrated by the formation of simple binary aggregates from mixtures. The bifunctional copolymers were poly(vinyl phenol-co-diallyldimethyl ammonium chloride), Ph-DADMAC, and poly(3-acrylamide phenylboronic acid-co-PEG methacrylate), PBA-PEG. The monofunctional polymer was polyvinylalcohol, PVA. Ph-DADMAC forms complexes with PBA-PEG (H-bonding) and with anionic surfaces or polymers (electrostatic/polyelectrolyte complexation). PBA-PEG complexes with Ph-DADMAC (H-bonding) and with PVA (boronate ester formation). PVA does not interact with Ph-DADMAC; therefore, PVA coated particles do not deposit onto Ph-DADMAC coated particles. PMID- 22251454 TI - Interleukin-1 receptor role in the viability of corneal myofibroblasts. AB - The purpose of this study was to investigate the role of interleukin-1 (IL-1) in modulating myofibroblast viability in mouse corneas with stromal opacity. Twenty four female B6; 129S1-Il1r1tm1Roml/J homozygous IL-1RI knockout mice and 24 control B6129SF2/J mice were included in this study. Each mouse had opacity generating irregular phototherapeutic keratectomy (PTK) performed with an excimer laser in one eye. Groups of 8 mice from each group were euthanized at one month, three months and six months after surgery and the eyes cryo-preserved. The contralateral eye served as unwounded control. Immunohistochemistry was performed for alpha-smooth muscle actin (SMA) in central sections of all corneas. The TUNEL assay for apoptosis was performed on 8 sections of four eyes from each group. No SMA+ cells were detected in the stroma of unwounded control or knockout corneas. SMA+ myofibroblast density was significantly higher (p < 0.001) in the IL-1RI knockout group than in the control group at one month, three and six months after irregular PTK. Mean TUNEL+ stromal cells in the anterior 50 MUm of stroma was significantly lower in the IL-1RI knockout group compared to the control group at six months after irregular PTK (p = 0.04). These results corroborate the findings of recent in vitro work that demonstrated an antagonistic effect of TGFbeta and IL-1 on myofibroblast viability, and found that IL-1-triggered myofibroblast apoptosis was suppressed by TGFbeta. Thus, IL-1 is an important modulator of myofibroblast viability during corneal wound healing. PMID- 22251455 TI - Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage. AB - Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO(3)). Intravenous (IV) administration of NaIO(3) up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5-20 mg/kg) produced concentration-dependent changes in visual function as measured by full-field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1-P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with >=10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration dependent outer retinal damage that correlates with functional changes. We conclude that NaIO(3,) is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors. PMID- 22251457 TI - Forms of benefit sharing in global health research undertaken in resource poor settings: a qualitative study of stakeholders' views in Kenya. AB - BACKGROUND: Increase in global health research undertaken in resource poor settings in the last decade though a positive development has raised ethical concerns relating to potential for exploitation. Some of the suggested strategies to address these concerns include calls for providing universal standards of care, reasonable availability of proven interventions and more recently, promoting the overall social value of research especially in clinical research. Promoting the social value of research has been closely associated with providing fair benefits to various stakeholders involved in research. The debate over what constitutes fair benefits; whether those that addresses micro level issues of justice or those focusing on the key determinants of health at the macro level has continued. This debate has however not benefited from empirical work on what stakeholders consider fair benefits. This study explores practical experiences of stakeholders involved in global health research in Kenya, over what benefits are fair within a developing world context. METHODS AND RESULTS: We conducted in depth interviews with key informants drawn from within the broader health research system in Kenya including researchers from the mainstream health research institutions, networks and universities, teaching hospitals, policy makers, institutional review boards, civil society organisations and community representative groups.The range of benefits articulated by stakeholders addresses both micro and macro level concerns for justice by for instance, seeking to engage with interests of those facilitating research, and the broader systemic issues that make resource poor settings vulnerable to exploitation. We interpret these views to suggest a need for global health research to engage with current crises that face people in these settings as well as the broader systemic issues that produce them. CONCLUSION: Global health research should provide benefits that address both the micro and macro level issues of justice in order to forestall exploitation. Embracing the two is however challenging in terms of how the various competing interests/needs should be balanced ethically, especially in the absence of structures to guide the process. This challenge should point to the need for greater dialogue to facilitate value clarification among stakeholders. PMID- 22251458 TI - Global trends in the use of insecticides to control vector-borne diseases. AB - BACKGROUND: Data on insecticide use for vector control are essential for guiding pesticide management systems on judicious and appropriate use, resistance management, and reduction of risks to human health and the environment. OBJECTIVE: We studied the global use and trends of insecticide use for control of vector-borne diseases for the period 2000 through 2009. METHODS: A survey was distributed to countries with vector control programs to request national data on vector control insecticide use, excluding the use of long-lasting insecticidal nets (LNs). Data were received from 125 countries, representing 97% of the human populations of 143 targeted countries. RESULTS: The main disease targeted with insecticides was malaria, followed by dengue, leishmaniasis, and Chagas disease. The use of vector control insecticides was dominated by organochlorines [i.e., DDT (dichlorodiphenyltrichloroethane)] in terms of quantity applied (71% of total) and by pyrethroids in terms of the surface or area covered (81% of total). Global use of DDT for vector control, most of which was in India alone, was fairly constant during 2000 through 2009. In Africa, pyrethroid use increased in countries that also achieved high coverage for LNs, and DDT increased sharply until 2008 but dropped in 2009. CONCLUSIONS: The global use of DDT has not changed substantially since the Stockholm Convention went into effect. The dominance of pyrethroid use has major implications because of the spread of insecticide resistance with the potential to reduce the efficacy of LNs. Managing insecticide resistance should be coordinated between disease-specific programs and sectors of public health and agriculture within the context of an integrated vector management approach. PMID- 22251459 TI - Animal models of Parkinson's disease. AB - Animal models of Parkinson's disease (PD) have been widely used in the past four decades to investigate the pathogenesis and pathophysiology of this neurodegenerative disorder. These models have been classically based on the systemic or local (intracerebral) administration of neutoxins that are able to replicate most of the pathological and phenotypic features of PD in mammals (i.e. rodents or primates). In the last decade, the advent of the 'genetic era' of PD has provided a phenomenal enrichment of the research possibilities in this field, with the development of various mammalian (mice and, more recently, rats) and non mammalian transgenic models that replicate most of the disease-causing mutations identified for monogenic forms of familial PD. Both toxic and transgenic classes of animal PD models have their own specificities and limitations, which must be carefully taken into consideration when choosing the model to be used. If a substantial and reproducible nigrostriatal lesion is required (e.g. for testing therapeutic interventions aimed at counteracting PD-related cell death), a classic toxic model such as one based on the administration of 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine or 6-hydroxydopamine will adequately serve the purpose. On the other hand, if selected molecular mechanisms of PD pathogenesis must be investigated, transgenic models will offer invaluable insights. Therefore, until the 'perfect' model is developed, indications to use one model or another will depend on the specific objectives that are being pursued. PMID- 22251461 TI - Laboratory snack food intake, negative mood, and impulsivity in youth with ADHD symptoms and episodes of loss of control eating. Where is the missing link? AB - To compare laboratory food intake, negative mood and trait impulsivity and their association with attention deficit hyperactivity disorder (ADHD) and loss of control (LOC) eating in youth (middle childhood to early adolescence). Ninety 10 14 year old youths with symptoms of ADHD, symptoms of LOC eating, and control participants took part in a laboratory snack food meal after having rated trait impulsivity. Negative mood was self-reported pre and post snack food meal, while representativeness of eating behavior and liking of the food was assessed post laboratory snack food meal. The ADHD group consumed more snack food than the other groups. Food intake was not influenced by negative mood or trait impulsivity. All groups exhibited a decrease in negative mood from pre to post food intake that was not accounted for by level of hunger or liking of the food. The greater food intake of the ADHD group compared to the other groups may contribute to the development of overweight and therefore be in accordance with the high co-morbidity reported between ADHD and obesity in youth. The influence of impulsivity and negative mood on food intake could not be shown, which corroborates a recent review on the association of negative mood and bingeing in adults but needs further assessment, particularly in the younger age groups. PMID- 22251460 TI - A validated HPLC method with fluorescence detection for the glucuronides of Combretastatin A1 in human plasma, and studies on their cis-trans isomerisation. AB - Two monoglucuronides (CA1G1 and CA1G2) of the catecholic cis-stilbene Combretastatin A1 (CA1, OXi4500), have been identified in a clinical trial of the bisphosphate prodrug of OXi4500, OXi4503. A validated assay for the two glucuronides in human plasma using HPLC with fluorescence detection after post column photolysis is described. The assay was linear over the range 25 nM (CA1G1) or 50 nM (CA1G2) - 5000 nM, R(2)>= 0.996. The intra-day precision for CA1G1 was better than 8.7% RSD (19.4% at the LLOQ), and the inter-day precision was better than 5.5% RSD (7.6% at the LLOQ). The intra- and inter-day accuracies were better than +/- 12.6% relative error (14.8% at the LLOQ) and 4.8% (5.4% at the LLOQ) respectively. For CA1G2, the intra-day precision was better than 5.7% RSD (7.5% at the LLOQ), and the inter-day precision was better than 4.8% RSD (11.9% at the LLOQ). The intra- and inter-day accuracies were better than +/- 10.1% relative error (12.6% at the LLOQ) and 2.2% (3.8% at the LLOQ) respectively. Recovery from plasma was measured at three concentrations (125, 625 and 2500nM). Mean recovery of CA1G1 was 94.5% and ranged from 94.4 to 99.2%. Mean recovery of CA1G2 was 90.7%, range 88-92%. During the validation process, one of the isomers was unexpectedly found to be unstable. CA1G1, substituted ortho to the stilbene, was relatively stable, but the meta-substituted CA1G2 readily converted from the cis stilbene conformation to the trans isomer. This was catalysed by acid and heavy metals, and could be inhibited by antioxidants such as ascorbic acid. Isomerisation could also be induced by one-electron oxidation processes such as horseradish peroxidase and azide radicals. PMID- 22251462 TI - Nanocrystalline hydroxyapatite bone substitute leads to sufficient bone tissue formation already after 3 months: histological and histomorphometrical analysis 3 and 6 months following human sinus cavity augmentation. AB - PURPOSE: In this study the de novo bone formation capacity of a nanocrystalline hydroxyapatite bone substitute was assessed 3 and 6 months after its insertion into the human sinus cavity. MATERIALS AND METHODS: Sinus cavity augmentation was performed in a total of 14 patients (n = 7 implantation after 3 months; n = 7 implantation after 6 months) with severely atrophic maxillary bone. The specimens obtained after 3 and 6 months were analyzed histologically and histomorphometrically with special focus on bone metabolism within the residual bone and the augmented region. RESULTS: This study revealed that bone tissue formation started from the bone-biomaterial-interface and was directed into the most cranial parts of the augmented region. There was no statistically significant difference in new bone formation after 3 and 6 months (24.89 +/- 10.22% vs 31.29 +/- 2.29%), respectively. CONCLUSIONS: Within the limits of the present study and according to previously published data, implant insertion in regions augmented with this bone substitute material could be considered already after 3 months. Further clinical studies with bone substitute materials are necessary to validate these findings. PMID- 22251463 TI - A non-cold-inducible cold shock protein homolog mainly contributes to translational control under optimal growth conditions. AB - Cold shock proteins (Csps) include both cold-induced and non-cold-induced proteins, contrary to their name. Cold-induced Csps are well studied; they function in cold acclimation by controlling transcription and translation. Some Csps have been reported to contribute to other cellular processes. However, the functions of non-cold-induced Csps under optimal growth conditions remain unknown. To elucidate these functions, we used transcriptome and proteome analyses as comprehensive approaches and have compared the outputs of wild-type and non-cold-induced Csp-deletion mutant cells. As a model organism, we selected Thermus thermophilus HB8 because it has only two csp genes (ttcsp1 and ttcsp2); ttCsp1 is the only non-cold-induced Csp. Surprisingly, the amount of transcripts and proteins upon deletion of the ttcsp1 gene was quite different. DNA microarray analysis revealed that the deletion of ttcsp1 did not affect the amount of transcripts, although the ttcsp1 gene was constantly expressed in the wild-type cell. Nonetheless, proteomic analysis revealed that the expression levels of many proteins were significantly altered when ttcsp1 was deleted. These results suggest that ttCsp1 functions in translation independent of transcription. Furthermore, ttCsp1 is involved in both the stimulation and inhibition of translation of specific proteins. Here, we have determined the crystal structure of ttCsp1 at 1.65 A. This is the first report to present the structure of a non cold-inducible cold shock protein. We also report the nucleotide binding affinity of ttCsp1. Finally, we discuss the functions of non-cold-induced Csps and propose how they modulate the levels of specific proteins to suit the prevailing environmental conditions. PMID- 22251464 TI - Authorship in Hepatobilary & Pancreatic Diseases International. PMID- 22251465 TI - Current therapy of hilar cholangiocarcinoma. AB - BACKGROUND: Hilar cholangiocarcinoma (HC) is an adenocarcinoma of the extrahepatic biliary tree arising from the main left or right hepatic ducts or their confluence. This tumor is still considered to be difficult to treat or to cure. DATA SOURCES: We reviewed the medical literature on HC. Relevant and updated information on this tumor was analyzed in a concise and easy-to-read manner. The article is not intended to be a systematic review, but an extensive search was conducted on PubMed and MEDLINE using the keywords "hilar cholangiocarcinoma" and "Klatskin tumor" until July 2011. RESULTS: The selection and the timing of management options for patients with HC are determined by the degree of certainty of the diagnosis, the general condition of the patients, the underlying liver function and the stage of the disease. Current treatment of HC can be divided into curative and palliative treatment. For the curative treatment, local excision should only be used on small tumors which are confined to the bile duct wall and Bismuth I papillary carcinoma. Partial hepatectomy should be combined with caudate lobe resection and porta-hepatis lymph node dissection. The results of these major resections can be improved with portal vein embolization, and staging laparoscopy and laparoscopic ultrasound. The role of preoperative biliary drainage is controversial. Autotransplantation for HC gave disappointing results while the Mayo Protocol of chemoradiation for selecting patients with unresectable HC for orthotopic liver transplantation has been widely accepted. Palliative treatment included bypass surgery, endoscopic or percutaneous stenting, photodynamic therapy, intraluminal brachytherapy, and external radiation and systemic therapy. CONCLUSIONS: Adequate surgery with R0 resection should be the main goal of treatment. For patients with unresectable HC, treatment aims to improve the quality and quantity of their survival. PMID- 22251466 TI - Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis, is a recognized risk factor for hepatocellular carcinoma (HCC). However, detailed analysis of the clinical features in patients with NAFLD and their association with HCC is lacking. This study aimed to update the clinical features of patients with NAFLD-associated HCC. DATA SOURCES: The clinical data of patients with NAFLD-associated HCC from 25 studies published between 1990 and 2010 in the Pubmed database were comprehensively reviewed. RESULTS: In a total of 169 patients with NAFLD-associated HCC, 72.8% were male. The median age at abnormal liver function tests and diagnosis of NAFLD and HCC was 60, 64 and 67 years, respectively. Most patients were obese (75%) and diabetic (59.8%), 32.3% had dyslipidemia, and 53% had hypertension. Nearly all patients (98.6%, 71/72) were complicated with at least one metabolic disorder. The majority (76%) of the HCC patients had a solitary tumor nodule, with the tumor size ranging from 0.8 to 20 cm in diameter (mean 3.4 cm). Most (61.1%) of the patients had moderately differentiated HCC. In 40.2% of the patients, HCC occurred in the absence of cirrhosis. Among 130 patients, 57.7% underwent hepatectomy and 14.6% received liver transplantation. The mean follow-up of the treated patients for 25 months showed that 32.4% (24/74) died and 18.8% (9/48) had recurrence. CONCLUSIONS: Patients with NAFLD-associated HCC are usually accompanied with metabolic disorders. Regular surveillance in patients with NAFLD for HCC is necessary, especially for elderly men with metabolic syndrome. PMID- 22251467 TI - Posttraumatic stress disorder after liver transplantation. AB - BACKGROUND: Liver transplantation can lead to the development of posttraumatic stress disorder (PTSD), but the risk factors associated with this progression are not well understood. To study this syndrome in adult liver transplant recipients, a cross-sectional investigation of 296 recipients at our hospital was carried out between January and June 2010. METHODS: Study participants completed two questionnaires [a PTSD self-rating scale (PTSD-SS) and a validated Chinese version of the Medical Outcomes Study Short Form-36 (SF-36)]. Clinical and demographic data were collected from the records of the Chinese Liver Transplant Registry and via questionnaires. RESULTS: The prevalence of full PTSD and partial PTSD (that met the criteria for 2 of the 3 symptom clusters) was 3.7% and 5.4%, respectively, for all transplant recipients. Significant differences between the recipients with no PTSD, partial PTSD, and full PTSD were found in all SF-36 domains except for physical functioning (P=0.466). In general, domain scores were the highest in the recipients who did not meet the criteria for PTSD and the lowest in the recipients who met the criteria for full PTSD. Greater severity of posttraumatic stress symptoms was correlated with poorer quality of life, especially in the bodily pain (P=0.004), social functioning (P=0.001), role emotional (P=0.048), and mental health (P<0.001) domains. The model for end-stage liver disease (MELD) scores, complications, and educational status were identified by multiple regression analysis as risk factors for developing PTSD. CONCLUSIONS: PTSD occurred after liver transplantation and was significantly associated with decreased quality of life. Higher MELD scores and complications after transplantation were risk factors that contributed to PTSD, and higher education was a protective factor. PMID- 22251468 TI - Postreperfusion syndrome during orthotopic liver transplantation: a single-center experience. AB - BACKGROUND: Marked hemodynamic alteration, commonly referred to as postreperfusion syndrome (PRS), often occurs after revascularization of the donor organ during orthotopic liver transplantation (OLT) and is associated with poor outcomes. This study aimed to investigate the incidence, predictive factors and clinical outcomes of PRS in Chinese patients following OLT at a liver transplantation center in China. METHODS: Over a 5-year period, 330 consecutive patients who had undergone OLT for hepatocellular carcinoma or cirrhosis were included in this retrospective study. PRS was defined as a >30% decrease in the mean arterial pressure compared with that before revascularization for more than 1 minute during the first 5 minutes of graft reperfusion. The patients were divided into 2 groups according to the development of PRS: group 1 (patients with PRS, n=56) and group 2 (patients without PRS, n=274). The demographic characteristics, operative and postoperative courses, and outcomes of the patients were analyzed using SPSS version 18.0. RESULTS: Multivariate regression analysis showed that left ventricular diastolic dysfunction determined by echocardiography and prolonged cold ischemia time were the independent risk factors for PRS. More patients in group 1 showed postoperative renal dysfunction than those in group 2 (19.23% vs 8.4%). Moreover, patients in group 1 also had higher intraoperative (7.14% vs 0%) and postoperative mortalities (26.92% vs 12.04%). CONCLUSION: Left ventricular diastolic dysfunction and prolonged cold ischemia time contribute to a high incidence of PRS, which is associated with adverse outcomes in Chinese patients following OLT. PMID- 22251469 TI - Changes of gut bacteria and immune parameters in liver transplant recipients. AB - BACKGROUND: Liver transplantation is one of the most effective therapeutic options for patients with end-stage liver diseases, and gut microbiota is actively involved in potential infections in pretransplant and posttransplant patients. However, the diversity of gut microbiota and its relationship with the immune parameter of liver transplantation recipients are not well understood. METHODS: We collected fresh feces and blood samples from 190 participants in China from November 2004 to May 2008, including 28 healthy volunteers, 51 cirrhotic patients and 111 liver-transplanted patients. Six interesting gut bacteria, plasma endotoxin, serum cytokines (i.e., tumor necrosis factor alpha and interleukin-6) and fecal secretory IgA (SIgA) were investigated by real-time quantitative PCR, chromogenic limulus amoebocyte assay, sandwich-type enzyme linked immunosorbent assay and radioimmunoassay, respectively. RESULTS: All Eubacteria, Bifidobacterium spp., Faecalibacterium prausnitzii and Lactobacillus spp. were significantly lower in the liver transplantation recipients while Enterobacteriaceae and Enterococcus spp. were significantly higher (P<0.05). Except for Enterococcus spp., other bacteria showed a tendency to restore to normal level along with the time after liver transplantation. Plasma endotoxin, interleukin-6 and fecal SIgA in cirrhotic patients increased significantly, but not in liver transplantation recipients. Plasma endotoxin and interleukin-6 were negatively correlated with all Eubacteria and the Bacteroides-Prevotella group, while tumor necrosis factor alpha was not significantly correlated with these six gut bacteria in cirrhotic patients. CONCLUSIONS: Our study demonstrates that abundant gut bacteria were altered significantly in both cirrhotic and liver transplantation patients, while plasma endotoxin and interleukin-6 increased remarkably in cirrhotic patients, showing significant correlations with gut microbiota. Interestingly, our data show a tendency for these gut bacteria to restore to normal levels in liver transplantation recipients. PMID- 22251470 TI - Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy. AB - BACKGROUND: Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis, which correlate with recurrence after surgical treatment and poor prognosis. HCC may be an unusual cancer affected by continuous inflammation that can lead to consistent upregulation of transforming growth factor-beta (TGF-beta). Chronic inflammation shifts hepatocytic TGF-beta signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway. In this study, we investigated the functional roles of Smad3 and its phosphoisoforms in the progression of HCC. METHODS: Tumor tissue microarrays of samples from 272 HCC patients who underwent curative surgical resection were used to detect the expression of Smad3, Smad4, pSmad3C (S423/425), pSmad3L (T179), pSmad3L (S204), and pSmad3L (S213). Disease-specific death was defined as 1) tumor occupying more than 80% of the liver, 2) portal venous tumor thrombus (PVTT) proximal to the second bifurcation, 3) obstructive jaundice due to tumor, 4) distant metastases, or 5) variceal hemorrhage with PVTT proximal to the first bifurcation. At the time of analysis, tumor recurrence was detected in 184 (67.6%) patients, and 96 (35.3%) had died of HCC. RESULTS: Nuclear and cytoplasmic localization of Smad3, and nuclear localization of Smad4 were observed in 18.0%, 9.9%, and 9.2% of HCCs, respectively. The rates of Smad3 phosphoisoform-immunoreactive HCC varied according to the location of phosphorylation: pSmad3C (S423/425) 8.1%, pSmad3L (T179) 2.6%, pSmad3L (S204) 2.2%, and pSmad3L (S213) 10.3%. Multivariate analyses revealed that pSmad3C (S423/425) (P=0.022) was an independent predictor of longer recurrence-free survival. pSmad3L (S213) (P=0.006), intrahepatic metastasis, multicentric occurrence, and liver cirrhosis were independent predictors of shorter recurrence free survival. Cytoplasmic Smad3 (P=0.006), larger tumor size, and intrahepatic metastasis were independent predictors of shorter disease-specific survival. Only pSmad3L (S213) did not show an unfavorable influence on recurrence-free survival (P=0.331) on univariate analysis. CONCLUSIONS: pSmad3C (S423/425), pSmad3L (S213), and Smad3 may be predictors of prognosis in HCC patients after curative hepatectomy. pSmad3C (S423/425) and pSmad3L (S213) may be used as immunohistochemical biomarkers to identify patients with a high risk of recurrence. PMID- 22251471 TI - Beneficial effects of splenectomy on liver regeneration in a rat model of massive hepatectomy. AB - BACKGROUND: Small-for-size syndrome is a widely recognized clinical complication after living donor liver transplantation or extended hepatectomy due to inadequate liver mass. The purpose of this study was to investigate the role of splenectomy in rats after massive hepatectomy, a surrogate model of small-for size graft. METHODS: Rats were divided into eight groups, each with 20 animals: 50% hepatectomy (50% Hx), 50% hepatectomy+splenectomy (50% Hx+Sp), 60% Hx, 60% Hx+Sp, 70% Hx, 70% Hx+Sp, 90% Hx and 90% Hx+Sp. The following parameters were evaluated: liver function tests (ALT, AST and TBIL), liver regeneration ratio, DNA synthesis, proliferation cell nuclear antigen, hepatic oxygen delivery (HDO2) and hepatic oxygen consumption (HVO2). RESULTS: The liver regeneration ratio was enhanced in the Hx+Sp groups (P<0.05). In addition, compared with the Hx groups, the Hx+Sp groups had better liver functions (P<0.05). DNA synthesis and proliferation cell nuclear antigen were also increased in the Hx+Sp groups compared with the Hx groups (P<0.05). Furthermore, in the Hx+Sp groups, HDO2 and HVO2 were increased over those in the Hx groups (P<0.05), and were positively correlated with the liver regeneration ratio. CONCLUSIONS: Splenectomy significantly improved liver function, and enhanced DNA synthesis and proliferation cell nuclear antigen after massive hepatectomy in rats. This operation could be mediated through increased HDO2 and HVO2, which facilitate liver regeneration. PMID- 22251472 TI - Ex vivo-expanded bone marrow stem cells home to the liver and ameliorate functional recovery in a mouse model of acute hepatic injury. AB - BACKGROUND: Stem cell transplantation provides a theoretical approach for liver regeneration medicine; it may promote liver regeneration and self-repair. However, the transplantation of bone marrow-mesenchymal stem cells expanded ex vivo as a therapy for liver disease has rarely been investigated. This study aimed to explore whether bone marrow stem cells expanded ex vivo home to the liver and foster hepatic recovery after CCl4 injury. METHODS: Bone marrow cells from BALB/c mice were expanded ex vivo by multiple-passage cultivation, characterized by cytoflow immunofluorescence, and pre-labeled with PKH26 before intravenous infusion into animals treated with CCl4. The integration of bone marrow cells into the liver was examined microscopically, and plasma hepatic enzymes were determined biochemically. RESULTS: Cultured bone marrow cells exhibited antigenic profiles comparable to those of primary medullary stem cells. Double immunofluorescence showed colocalization of these cells with proliferative activity and albumin expression in the liver of CCl4-treated mice. Densitometry showed increased in situ cell proliferation (50+/-14 vs 20+/-3 cells/high-power field, P<0.05) and albumin expression (149+/-25 vs 20+/-5 cells/high-power field, P<0.05) in the liver, as well as reduced serum aminotransferase levels (P<0.05) and better survival rates (P<0.05) in animals receiving cultured bone marrow cells relative to controls. CONCLUSIONS: Ex vivo-expanded bone marrow cells are capable of relocating to and proliferating in the chemically-injured liver. Transplantation of these pluripotent stem cells appears to improve serum indices of liver function and survival rate in mice after CCl4-induced hepatic damage. PMID- 22251473 TI - Computed tomography perfusion study of hemodynamic changes and portal hyperperfusion in a rabbit model of small-for-size liver. AB - BACKGROUND: Portal hyperperfusion in the small-for-size (SFS) liver can threaten survival of rabbits. Therefore, it is important to understand the hemodynamic changes in the SFS liver. METHODS: Twenty rabbits were divided into two groups: a control group and a modulation group. The control group underwent an extended hepatectomy. The modulation group underwent the same procedure plus splenectomy to reduce portal blood flow. CT perfusion examinations were performed on all rabbits before and after operation. Perfusion parameter values, especially portal vein perfusion (PVP), were analyzed. RESULTS: PVP in the modulation group was lower than in the control group after operation (P=0.002). In the control group, postoperative PVP increased by 193.7+/-55.1% compared with preoperative PVP. A weak correlation was found between the increased percentage of PVP and resected liver-to-body weight ratio (RLBWR) (r=0.465, P=0.033). In the modulation group, postoperative PVP increased by 101.4+/-32.5%. No correlation was found between the increased percentage of PVP and RLBWR (r=0.167, P=0.644). Correlations were found between PVP and serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin after surgery (P<0.05). CONCLUSION: We successfully evaluated the characteristics of hemodynamic changes as well as the effects of splenectomy in the SFS liver in rabbits by the CT technique. PMID- 22251474 TI - Roux-en-Y choledochojejunostomy using novel magnetic compressive anastomats in canine model of obstructive jaundice. AB - BACKGROUND: The traditional hand-sewn Roux-en-Y choledochojejunostomy is technically complicated, and the incidence of postoperative complications has remained high. A set of novel magnetic compressive anastomats was introduced to facilitate choledochojejunostomy and improve the prognosis of patients. METHODS: After ligating the common bile duct for 7 days, 16 dogs were randomly divided into two groups (n=8 per group). Anastomats were used in the study group, and the traditional hand-sewn method was used in the control group for standard Roux-en-Y choledochojejunostomy. We compared the operation time, incidence of complications, gross appearance, and pathological disparity in stoma between the two groups in 1-month and 3-month follow-up examinations. RESULTS: The time spent on constructing the anastomosis for the study group was significantly shortened. Although no anastomotic stenosis occurred in the two groups, the narrowing rate of biliary-enteric anastomosis was much higher in the control group. There was one case of bile leakage in the control group, whereas no bile leakage occurred in the study group. A smoother surface, an improved layer apposition, and a lower local inflammatory response were identified in the anastomosis of the study group. CONCLUSION: The structures of the novel magnetic compressive anastomats are simple, and they are time-saving, safe and efficient for performing Roux-en-Y choledochojejunostomy procedures in a canine model of obstructive jaundice. PMID- 22251475 TI - Matched-pair analysis of postoperative morbidity and mortality for pancreaticogastrostomy and pancreaticojejunostomy using mattress sutures in soft pancreatic tissue remnants. AB - BACKGROUND: After pancreaticoduodenectomy, the incidence of postoperative pancreatic fistula remains high, especially in patients with "soft" pancreatic tissue remnants. No "gold standard" surgical technique for pancreaticoenteric anastomosis has been established. This study aimed to compare the postoperative morbidity and mortality of pancreaticogastrostomy and pancreaticojejunostomy for "soft" pancreatic tissue remnants using modified mattress sutures. METHODS: Seventy-five patients who had undergone pancreaticogastrostomy and 75 who had undergone pancreaticojejunostomy after pancreaticoduodenectomy between 2002 and 2008 were retrospectively compared using matched-pair analysis. A modified mattress suture technique was used for the pancreaticoenteric anastomosis. Patients with an underlying "hard" pancreatic tissue remnant, as in chronic pancreatitis, were excluded. Both groups were homogeneous for age, gender, and underlying disease. Postoperative morbidity, mortality, and preoperative and operative data were analyzed. RESULTS: There were no significant differences between the groups for the incidence of postoperative pancreatic fistula (10.7% in both). Postoperative morbidity and mortality, median operation time, median length of hospital stay, intraoperative blood loss, and the amount of intraoperatively transfused erythrocyte concentrates also did not significantly differ between the groups. Patient age >65 years (P=0.017), operation time >350 minutes (P=0.001), and intraoperative transfusion of erythrocyte concentrates (P=0.038) were identified as risk factors for postoperative morbidity. CONCLUSIONS: Our results showed no significant differences between the groups in the pancreaticogastrostomy and pancreaticojejunostomy anastomosis techniques using mattress sutures for "soft" pancreatic tissue remnants. In our experience, the mattress sutures are safe and simple to use, and pancreaticogastrostomy in particular is feasible and easy to learn, with good endoscopic accessibility to the anastomosis region. However, the location of the anastomosis and the surgical technique need to be individually evaluated to further reduce the incidence of postoperative pancreatic fistula. PMID- 22251476 TI - Triglyceride levels and apolipoprotein E polymorphism in patients with acute pancreatitis. AB - BACKGROUND: Hypertriglyceridemia is an unusual cause of acute pancreatitis and sometimes considered to be an epiphenomenon. This study aimed to investigate the clinical and analytical features and the APOE genotypes in patients with acute pancreatitis and severe hypertriglyceridemia. METHODS: We undertook a one-year, prospective study of patients with acute pancreatitis whose first laboratory analysis on admission to the emergency department included measurement of serum triglycerides. The APOE genotype was determined and the patients answered an established questionnaire within the first 24 hours concerning their alcohol consumption, the presence of co-morbidities and any medications being taken. The patients' progression, etiological diagnosis, hospital stay and clinical and radiological severity were all recorded. RESULTS: Hypertriglyceridemia was responsible for 7 of 133 cases of pancreatitis (5%); the remaining cases were of biliary (53%), idiopathic (26%), alcoholic (11%) or other (5%) origin. Compared with these remaining cases, the patients with hypertriglyceridemia were significantly younger, had more relapses, and more often had diabetes mellitus. They usually consumed alcohol or consumed it excessively on the days before admission. Also, the epsilon4 allele of the APOE gene was more common in this group (P<0.05). CONCLUSION: One of 20 episodes of acute pancreatitis is caused by hypertriglyceridemia and it is linked to genetic (epsilon4 allele) and comorbid factors such as diabetes and, especially, alcohol consumption. PMID- 22251477 TI - Risk factors for postoperative pancreatic fistula in patients with insulinomas: analysis of 292 consecutive cases. AB - BACKGROUND: Pancreatic fistula (PF) remains the most challenging complication in pancreatic surgery, yet few published studies have focused on the risk factors for postoperative PF in patients undergoing surgery for insulinomas. METHODS: From January 1990 to February 2010, a total of 292 patients with insulinomas underwent surgery at Peking Union Medical College Hospital. Demographic data, intraoperative procedures, and postoperative data were collected. Particular attention was paid to variables associated with PF as defined by the International Study Group of Pancreatic Fistula (ISGPF). Univariate and multivariate analyses were used to identify possible risk factors for PF. RESULTS: PF was found in 132 (45.2%) patients, of whom 90 were classified into ISGPF grade A, 33 grade B, and 9 grade C. Multivariate analysis showed that male patients (OR=2.56; P=0.007) and operative time >180 minutes (OR=3.756; P<0.0001) were independent risk factors for clinical PF. Pancreatic resection with stapler was a protective factor for both total PF (OR=0.022; P=0.010) and clinical PF (OR=0.097; P=0.007). CONCLUSIONS: Male gender and operative time >180 minutes were independent risk factors for clinical PF, while pancreatic resection with a stapler was a protective factor. Whether body mass index (BMI) and other variables during operation are risk factors of PF needs further study. PMID- 22251478 TI - Rare presentation of Brunner's gland adenoma: another differentiation in patients with recurrent "idiopathic" pancreatitis. AB - BACKGROUND: Brunner's gland adenoma (BGA) is an unusual benign neoplasm arising from Brunner's glands in the duodenum. When symptomatic it presents either with duodenal obstruction or bleeding. However, pancreatitis secondary to ampullary obstruction from a BGA is very rare. METHODS: A 23-year-old female presented with recurrent episodes of "idiopathic" pancreatitis. She was extensively investigated and was found to have a large polypoid BGA, intermittently obstructing the ampulla. This created a ball-valve effect causing secondary intermittent obstruction of the pancreatic duct resulting in pancreatitis. The condition was cured surgically, through transduodenal excision of the BGA. We reviewed the surgical literature pertaining to these unusual and similar causes of obstructive pancreatitis, not related to gallstones. RESULTS: BGA of the duodenum is a rare cause of pancreatitis. Extensive investigations should be carried out in all cases of unexplained pancreatitis before classifying the condition as "idiopathic". Discovery of a lesion of this nature gives an opportunity to provide a permanent surgical cure. CONCLUSIONS: BGA adds an unusual etiology for pancreatitis. All patients with pancreatitis should undergo extensive investigations before being termed "idiopathic". Surgical excision of the BGA provides a definitive curative treatment for the adenoma and pancreatitis. PMID- 22251479 TI - One-step fabrication of polymeric Janus nanoparticles for drug delivery. AB - With its unique structure of two compartments, Janus particles can be used for many applications for which monomorphic particles are inadequate, including to be used as a drug delivery system to deliver multiple payloads with widely different solubility. Here we report on a fluidic nanoprecipitation system (FNPS), capable of fabricating biocompatible Janus polymeric nanoparticles comprised of the FDA approved polymer poly(lactic-co-glycolic acid) (PLGA). The FNPS contains dual inlets, one for each half of the particle, that insert into the precipitation stream. The system provides a one-step approach for production of Janus polymeric particles with submicrometer diameters and is likely amenable to substantial scale-up. To the best of our knowledge, this is the first demonstration of biocompatible Janus nanoparticles that encapsulate a hydrophobic drug (paclitaxel) on one side and a hydrophilic drug (doxorubicin hydrochloride) on the other. PMID- 22251480 TI - Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML. AB - Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. PMID- 22251482 TI - A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload. AB - This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (DeltaLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean DeltaLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for DeltaLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators. PMID- 22251481 TI - The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. AB - The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37,415 cases and 84,406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed. PMID- 22251484 TI - [Thyroid and hepatitis C]. AB - Autoimmune thyroid diseases are complex diseases that develop as a result of interactions between genetic, epigenetic and environmental factors. IFNa therapy of chronic HCV infection is associated with subclinical or clinical thyroiditis, while the relationship between thyroiditis and virus C infection is still debated. PMID- 22251483 TI - Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy. AB - Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8(+) T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8(+) T cells markedly up regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor alpha chain), and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8(+) T cells expressing NKG2D, granzyme B, and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Treatment of TCR transgenic mice bearing nonantigen expressing tumors with immunotherapy still resulted in significant antitumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8(+) CD25(-) cells within the tumor site. These findings demonstrate that memory CD8(+) T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species. PMID- 22251486 TI - The right stuff. PMID- 22251485 TI - Fixed implant-retained rehabilitation of the edentulous maxilla: 11-year results of a prospective study. AB - OBJECTIVES: The aim of the present study was to assess long-term survival and success rates of implants in the edentulous maxilla restored with an implant supported fixed prosthesis. MATERIALS AND METHODS: Seventeen edentulous patients received six to eight implants and implant-supported fixed prostheses by one surgeon. Yearly recalls were conducted by two examiners over a period of 11 years. Survival and success rates (biological complications) were determined; marginal bone loss was examined radiographically. Furthermore, microbiological tests as well as test for interleukin-1 composite genotype were assessed and potential risk factors were evaluated. RESULTS: After a mean time of 11.26 years, 15 patients of 17 could be reexamined. Out of 94 implants, three were lost in one patient. Mean marginal bone loss reached 0.88 mm, two patients (at seven implants) showed bone loss of >=3.2 mm. Survival rate of implants reached 96.8%. Success rates on implant level hit 92.6% according to the criteria of Albrektsson and colleagues and 83.0% in accordance with Karoussis and colleagues. One prosthesis had to be renewed. CONCLUSION: Within the limitation of this study, restoration of the edentulous maxilla with an implant-supported fixed prosthesis represents an effective tool for rehabilitation over a period of 11 years. PMID- 22251487 TI - Enhancing the utility of surgical simulation: from proficiency to automaticity. PMID- 22251488 TI - Traumatic intracerebral hemorrhage--to operate or not? PMID- 22251489 TI - Epidermal electronics. PMID- 22251490 TI - The visual dimensions of future neurosurgical education. PMID- 22251491 TI - Dissecting a complex neurosurgical illustration: step-by-step development. AB - Modern computer graphics software has enabled the medical illustrator to render very complex anatomy by composing many different layers of drawings simultaneously. This and the author's capacity to take an "editorial" approach to compress several chronological events into a single, comprehensive two dimensional illustration are analyzed in a step-by-step process. Through a series of images, the article provides a visual synopsis of the development of an illustration for an extensive clinical case: total sacrectomy performed through an all-posterior approach. Originally given as a slide presentation at the American Association of Neurological Surgeons Theodore Kurze Lecture in April 2011, the article provides some detailed notes on the techniques the author used to develop a comprehensive neurosurgical illustration. PMID- 22251492 TI - Ein Heldenleben: a life in neurosurgery. PMID- 22251493 TI - Avoiding (and reporting) complications: when nerves pay a price. PMID- 22251494 TI - Neuroethical principles of deep-brain stimulation. PMID- 22251495 TI - Shunts and aneurysms. PMID- 22251496 TI - Does aneurysm treatment modality influence the incidence of shunt-dependent hydrocephalus? PMID- 22251497 TI - The necessity of preserving brain functions in glioma surgery: the crucial role of intraoperative awake mapping. PMID- 22251498 TI - Surgery for glioblastoma multiforme: striking a balance. PMID- 22251499 TI - The National Cancer Institute's SEER registry and primary malignant osseous spine tumors. PMID- 22251500 TI - Trigeminal neuralgia: diagnosis and treatment. PMID- 22251501 TI - The putative role of pericytes in tumor angiogenesis. PMID- 22251502 TI - Deep brain stimulation and ethics: perspectives from a multisite qualitative study of Canadian neurosurgical centers. AB - OBJECTIVE: Deep brain stimulation (DBS) is an approved neurosurgical intervention for motor disorders such as Parkinson disease. The emergence of psychiatric uses for DBS combined with the fact that it is an invasive and expensive procedure creates important ethical and social challenges in the delivery of care that need further examination. We endeavored to examine health care provider perspectives on ethical and social challenges encountered in DBS. METHODS: Health care providers working in Canadian DBS surgery programs participated in a semistructured interview to identify and characterize ethical and social challenges of DBS. A content analysis of the interviews was conducted. RESULTS: Several key ethical issues, such as patient screening and resource allocation, were identified by members of neurosurgical teams. Providers described challenges in selecting patients for DBS on the basis of unclear evidence-based guidance regarding behavioral issues or cognitive criteria. Varied contexts of resource allocation, including some very challenging schemas, were also reported. In addition, the management of patients in the community was highlighted as a source of ethical and clinical complexity, given the need for coordinated long-term care. CONCLUSIONS: This study provides insights into the complexity of ethical challenges that providers face in the use of DBS across different neurosurgical centers. We propose actions for health care providers for the long-term care and postoperative monitoring of patients with DBS. More data on patient perspectives in DBS would complement the understanding of key challenges, as well as contribute to best practices, for patient selection, management, and resource allocation. PMID- 22251503 TI - Incidence of ventricular shunt placement for hydrocephalus with clipping versus coiling for ruptured and unruptured cerebral aneurysms in the Nationwide Inpatient Sample database: 2002 to 2007. AB - BACKGROUND: Few studies have compared the incidence of ventricular shunt placement for hydrocephalus after clipping versus coiling of cerebral aneurysms. OBJECTIVE: The Nationwide Inpatient Sample (NIS) database was used to compare, on a national level, the incidence of ventricular shunt placement after clipping versus coiling of ruptured and unruptured aneurysms. METHODS: Hospitalizations for clipping and coiling of ruptured and unruptured aneurysms from 2002 to 2007 were collected from the NIS by cross-matching International Classification of Diseases-9 codes for diagnoses of subarachnoid hemorrhage or unruptured cerebral aneurysm with procedure codes for clipping or coiling. The incidence of ventricular shunt placement for hydrocephalus after clipping and coiling was compared using generalized linear models with generalized estimating equations (GEE) to adjust for patient- and hospital-specific factors and correlation between admissions. RESULTS: Of 10,899 ruptured aneurysm patients (6593 clipping, 4306 coiling), clipping had a similar incidence of ventricular shunt placement (9.3%) compared to coiling (10.5%) (odds ratio = 0.984; 95% confidence interval = 0.85, -1.14; P value = 0.833 after adjustment for patient-specific and hospital specific factors). Likewise, of 9686 unruptured aneurysm patients (4483 clipping, 5203 coiling), clipping had similar incidence of ventricular shunt placement (0.4%) compared to coiling (0.5%) (odds ratio = 0.763; 95% confidence interval = 0.37, -1.58; P value = 0.465 after adjustment for patient-specific and hospital specific factors). Predictors of shunt placement in ruptured aneurysm patients were age, comorbidity score, admission type, payer, and hospital aneurysm volume. Predictors of shunt placement in unruptured aneurysm patients were comorbidity score and admission type. CONCLUSIONS: In an observational study, clipping and coiling of ruptured and unruptured cerebral aneurysms are associated with similar incidences of ventricular shunt placement for hydrocephalus. PMID- 22251504 TI - Surgically treated brain tumors: a retrospective case series of 10,009 cases at a single institution. AB - OBJECTIVE: To evaluate the chronologic trends in brain tumor surgery at a single institution over 53 years (1957-2009). METHODS: Data were collected from medical records and documents (eg, daily records, surgical notes, or electronic databases) preserved in the library of the Department of Neurosurgery, Seoul National University College of Medicine. RESULTS: During the period 1957-2009, 10,009 brain tumors were surgically treated. Glial tumor (25.2%) was the most frequently reported histologic category. Meningioma and pituitary adenoma accounted for 17.5% and 17.1% of the histologies. In children <20 years old, astrocytoma (16.7%), embryonal tumor (16.2%), and germ cell tumor (11.9%) were the most common histologies. The chronologic trend for changes in proportions of individual brain tumor surgeries showed that cases of glioma have gradually increased since the 1980s, whereas cases of benign extra-axial tumors, including meningioma, sellar tumor, and schwannoma, have decreased. This trend implies that the presurgical diagnosis of glioma has increased owing to modern imaging technologies, and alternative treatment options, such as radiosurgery or observation, have been more frequently applied over time to benign extra-axial tumors. Simultaneously, the surgical management of lymphoma and metastatic tumor has increased gradually. CONCLUSIONS: This article describes the largest series of chronologic analysis of brain tumor surgeries conducted at a single institution and reflects the longitudinal trends by treatment option in incidences of selected brain tumors. PMID- 22251505 TI - Long-term 25-year follow-up of surgically treated parasagittal meningiomas. AB - BACKGROUND: Parasagittal meningiomas are either treated with conservative surgery or aggressive surgery with extensive vascular reconstructions to achieve radicality. The optimal management is subject to controversy. A prerequisite for good management and for design of relevant studies is the knowledge of natural history after radical and subtotal surgery. METHODS: All patients operated for parasagittal meningiomas at Karolinska Hospital between 1975 and 1979 were identified. This cohort of 51 patients was retrospectively analyzed to obtain 25 year follow-up data. Data were obtained from medical charts at all treating hospitals, the Swedish cancer registry, and the Swedish registry of causes of death. Radiology reports and images were reviewed. All patients still alive were contacted for visits, interviews, and radiologic imaging when indicated. Karnofsky index, Simpson grade, and pathologic examinations were obtained. RESULTS: The total recurrence rate after 25 years was 47%. Ten- and 25-year recurrence rates for radically operated parasagittal meningioma (Simpson grade 1 2) were 13% and 38%, respectively. The recurrence rates increased with increasing Simpson grades; 10- and 25-year recurrence rates in the Simpson grade 4 group were 62% and 69%, respectively. The relative risk for recurrence in Simpson grade 4 patients was 1.78 compared to Simpson grade 1-3 patients. The 10- and 25-year mortality rates were 33% and 63%, respectively. Of the total mortality 50% was caused by the tumor after 10 years and 48% after 25 years. CONCLUSIONS: A 25-year follow-up was necessary to estimate the long-term outcomes of parasagittal meningiomas. It is necessary to consider long-term recurrences and morbidity as important factors when managing patients with parasagittal meningiomas whose life expectancies are not diminished by old age or co-morbidities. The long-term outcomes must also be considered when evaluating different treatment modes, as "cure" of parasagittal meningiomas cannot be evaluated without sufficient follow up. PMID- 22251506 TI - The risk of getting worse: surgically acquired deficits, perioperative complications, and functional outcomes after primary resection of glioblastoma. AB - OBJECTIVE: Gross total resection (GTR) prolongs survival but is unfortunately not achievable in the majority of patients with glioblastoma multiforme (GBM). Cytoreductive debulkings may relieve symptoms of mass effect, but it is unknown how long such effects sustain and to what degree the potential benefits exceed risks. We explore the impact of surgical morbidity on functional outcome and survival in unselected GBM patients. METHODS: We retrospectively included 144 consecutive adult patients operated on for primary GBM at a single institution between 2004 and 2009. Reporting of adverse events was done in compliance with Good Clinical Practice Guidelines. RESULTS: A total of 141 (98%) operations were resections and 3 (2%) were biopsies. A decrease in Karnofsky performance status (KPS) scores was observed in 39% of patients after 6 weeks. There was a significant decrease between pre- and postoperative KPS scores (P < 0.001). Twenty-two (15.3%) patients had surgically acquired neurological deficits. Among patients who underwent surgical resection, those with surgically acquired neurological deficits were less likely to receive radiotherapy (P < 0.001), normofractioned radiotherapy (P = 0.010), and chemotherapy (P = 0.003). Twenty eight (19.4%) patients had perioperative complications. Among patients who underwent surgical resection, those with perioperative complications were less likely to receive normofractioned radiotherapy (P = 0.010) and chemotherapy (P = 0.009). Age (P = 0.019), surgically acquired neurological deficits (P < 0.001), and surgical complications (P = 0.006) were significant predictors for worsened functional outcome after 6 weeks. GTR (P = 0.035), perioperative complications (P = 0.008), radiotherapy (P < 0.001), and chemotherapy (P = 0.045) were independent factors associated with 12-month postoperative survival. CONCLUSION: Patients with perioperative complications and surgically acquired deficits were less likely to receive adjuvant therapy. While cytoreductive debulking may not improve survival in GBM, it may decrease the likelihood of patients receiving adjuvant therapy that does. PMID- 22251507 TI - Association of extent of local tumor invasion and survival in patients with malignant primary osseous spinal neoplasms from the surveillance, epidemiology, and end results (SEER) database. AB - BACKGROUND: Malignant osseous spinal neoplasms are aggressive tumors associated with poor outcomes despite aggressive multidisciplinary measures. It remains unknown whether increased local tumor invasion at time of treatment predicts worse survival. The surveillance, epidemiology, and end results (SEER) registry was reviewed to determine whether extent of local tumor invasion at presentation was independently associated with overall survival. METHODS: The SEER registry (1973-2003) was queried to identify cases of histologically confirmed primary spinal chordoma, chondrosarcoma, osteosarcoma, or Ewing sarcoma. Extent of local invasion was defined at time of care by histology, radiology, or intraoperative assessment and classified as confined (tumor within periosteum), local invasion (extension to surrounding tissues), or distal metastasis. The association of extent of local tumor invasion with overall survival was assessed by Cox analysis. RESULTS: One thousand eight hundred ninety-two patients were identified (414 chordoma, 579 chondrosarcoma, 430 osteosarcoma, 469 Ewing sarcoma). Overall median survival was histology specific (osteosarcoma, 11 months; Ewing sarcoma, 26 months; chondrosarcoma, 37 months; chordoma, 50 months) and correlated with extent of local tissue invasion or metastasis at presentation. Presence of metastasis was associated with marked decrease in survival (P < 0.001) for all tumor types. For patients with isolated spine tumors, neoplasms confined within the periosteum were associated with improved overall survival independent of age, radiotherapy, or surgical resection for chordoma (hazard ratio [HR], 0.50; P = 0.08), chondrosarcoma (HR, 0.62; P = 0.03), and osteosarcoma (HR, 0.68; P = 0.05), but not Ewing sarcoma (HR, 0.62; P = 0.27). CONCLUSIONS: The preoperative radiographic recognition of local tissue invasion may identify patients with a more aggressive tumor and help guide the level of aggressiveness in subsequent treatment strategies. PMID- 22251508 TI - Long-term follow-up of patients treated with percutaneous balloon compression for trigeminal neuralgia in Taiwan. AB - OBJECTIVE: This study aimed to evaluate the outcomes and complication rates associated with percutaneous balloon compression (PBC) for trigeminal neuralgia for a 10-year follow-up period. METHODS: A total of 185 patients with trigeminal neuralgia were treated with an initial PBC between July 2000 and December 2001 and were followed up until July 2010. PBC was performed under general anesthesia with endotracheal intubation. Meckel's cave was cannulated with a No. 4 Fogarty catheter, and the balloon was inflated for 70-90 seconds. RESULTS: Treatment and long-term follow-up was completed for 130 of the 185 patients. The mean length of the follow-up period was 8.9 years. Sixty-two patients (47.7%) were 65 years of age or older. Seventy-eight patients (60%) had pain involving the ophthalmic or multiple trigeminal divisions. One hundred twenty-two patients (93.8%) experienced immediate relief from neuralgia after the procedure. No pain recurred within 3 months. Seventeen patients (14%) had recurrent symptoms within 2 years. Twenty-three patients (18.9%) had recurrent symptoms within 3 years. Thirty-six patients (29.5%) had recurrent symptoms within 5 years. A total of 46 patients (37.7%) had recurrent symptoms during the entire study period. CONCLUSIONS: PBC is a technically simple, less painful procedure carried out under brief general anesthesia and is well tolerated by patients. The operation success rate is high, and the recurrence rate is similar to that of other reports. We also found that longer compression time resulted in longer symptom-free periods. PMID- 22251509 TI - Fenestration of supraclinoid internal carotid artery and associated aneurysm: embryogenesis, recognition, and management. AB - OBJECTIVE: Fenestration of internal carotid artery (ICA) is extremely rare and may be associated with aneurysms arising from the fenestrated segment. Here we report two cases with successful surgical clipping of associated saccular aneurysms, and we systematically review the 12 previously reported cases. METHODS: In one case of 39-year-old female patient, the aneurysm and fenestration were found incidentally in the course of a workup for headaches and a thyroid nodule. In the second case, a 32-year-old female patient, the aneurysm was associated with subarachnoid hemorrhage in the setting of suspected postpartum eclampsia. In both instances the fenestration involved the supraclinoid ICA, and the aneurysm arose from the duplicated segment proximal to the origin of the posterior communicating artery. The aneurysms were more proximal than typical posterior communicating artery aneurysms, and fenestration was suspected by rotational three-dimensional angiography, and confirmed at surgery. RESULTS: In both instances the aneurysm was approached via an extended pterional craniotomy. In one case, partial anterior clinoidectomy was necessary, along with decompression of the optic nerve canal for optimal exposure of the aneurysm neck. Clip reconstruction was successful, obliterating the aneurysm and preserving ICA patency. CONCLUSIONS: ICA fenestration should be considered when one analyzes ventral supraclinoid ICA aneurysms. In these and other reported cases, aneurysm is generally amenable to surgical clipping despite broad neck incorporating the fenestrated arterial segment. PMID- 22251510 TI - Brainstem tethering with Ondine's curse. AB - BACKGROUND: Brainstem tethering is a rare disease. CASE DESCRIPTION: We report and discuss a 20-year-old patient who experienced paroxysmal apnea (a symptom of Ondine's curse) during sleeping, causing him to wake up and control his breathing consciously. A magnetic resonance imaging study revealed that his medulla oblongata was twisted and displaced posteriorly by an abnormal tissue cord. An operation was performed to detether the tethered brainstem, with a satisfying result reached. CONCLUSION: Brainstem tethering is a rare but late complication of occipital encephalocele with insufficient operation. The symptoms of this disease are related to the dysfunction of the medulla oblongata and their adjunctive nerves. Magnetic resonance imaging can be used to identify the abnormal region and distinguish it from other medulla oblongata diseases. Surgery in the early stage of the brainstem tethering is helpful, but ventriculoperitoneal shunting is unnecessary or cannot be performed before detethering, although these patients usually have ventricular dilation. PMID- 22251511 TI - An intramedullary tuberculous abscess of the conus in a 5-year-old child presenting with urinary dysfunction. AB - OBJECTIVE: To report a case of the primary presence of an intramedullary tuberculous abscess in the conus medullaris with neither a history of contact nor tuberculous infection elsewhere in the body. CASE DESCRIPTION: A 5-year-old boy progressed from urinary hesitancy and frequency to complete urinary retention over the course of 1 month. He was seronegative for human immunodeficiency virus. Magnetic resonance imaging (MRI) showed a D11-L1, well-circumscribed, intramedullary mass within the conus, which was hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging with a thin-walled enhancing capsule. A D11-L2 laminectomy revealed a tense dura and expanded cord with no arachnoidal adhesions. A midline myelotomy and capsular fenestration released thick yellowish, creamy pus. The histology showed loose aggregates of epithelioid cells and a mixed leukocyte population including polymorphonuclear leukocytes and mononuclear cells without formed granulomas. Ziehl-Neelsen staining showed acid fast bacilli of Mycobacterium tuberculosis. The patient showed rapid improvement of sphincteric function with four-drug antituberculous therapy (ATT). CONCLUSIONS: To the best of the authors' knowledge, an intramedullary conus tuberculous abscess in a young child presenting with urinary dysfunction has never been reported. Perhaps hematogenous spread of M. tuberculosis within the conus, encapsulated proliferation and caseating necrosis (owing to delayed-type hypersensitivity), and an osmotic increase in the fluid content were responsible for its genesis and for the lack of arachnoidal adhesions around the cord. Surgical decompression of the abscess established the diagnosis, increased penetrability of ATT, and decreased the biologic load of bacteria, achieving a good recovery. PMID- 22251512 TI - Large hemangiopericytoma associated with arteriovenous malformations and dural arteriovenous fistulae. AB - BACKGROUND: Hemangiopericytomas are rare vascular tumors of the central nervous system. Although hemangiopericytomas have been associated with other vascular malformations, there is no report of an intracranial hemangiopericytoma found in association with multiple arteriovenous malformations and dural arteriovenous fistulae. CASE DESCRIPTION: We present the case of an otherwise healthy 25-year old woman who presented with a large hemangiopericytoma involving the superior sagittal sinus. The highly vascular nature of the lesion, the total occlusion of the sinus anterior to the tumor, and the presence of multiple arteriovenous malformations and dural arteriovenous fistulae complicated resection of this tumor. CONCLUSION: To our knowledge, no prior report has described a tumor of this magnitude in association with multiple AVMs and dAVFs. PMID- 22251513 TI - Design parameters for a robust superhydrophobic electrospun nonwoven mat. AB - Electrospun nonwoven mats exhibiting extreme hydrophobicity have recently attracted much attention for their use in a wide range of applications. These materials are highly heterogeneous and irregular in structure, and accordingly, the design parameters of such materials need to be carefully chosen for obtaining higher apparent contact angles along with the robust composite solid-liquid-vapor interface. Here, we present two dimensionless design parameters, namely, the spacing ratio and pressure difference across the liquid-vapor interface, for enhancing the stability of the Cassie regime. These design parameters are essentially dependent upon the structural characteristics of the electrospun mat and equilibrium contact angle of the liquid. Interestingly, the stability of the composite interface is a trade-off between these dimensionless parameters. Moreover, the pressure difference across the interface can significantly increase by reducing the fiber diameter to nanoscale. The stability of the Cassie state in an electrospun nonwoven mat consisting of lower fiber volume fractions at the nanostructural scale can restore superhydrophobicity even after the impact of a rainfall. PMID- 22251514 TI - A comprehensive review of intake estimates of di-isononyl phthalate (DINP) based on indirect exposure models and urinary biomonitoring data. AB - Di-isononyl phthalate (DINP) is a high molecular weight general purpose plasticizer used principally in the manufacture of flexible polyvinyl chloride (PVC) articles. DINP metabolites can be measured in biological media such as blood and urine. However, measurement of a substance in the blood or urine does not by itself mean that the chemical causes or is associated with adverse health outcomes. This is particularly pertinent given the advances in modern analytical techniques whereby ever diminishing trace amounts of substances can be detected. Therefore, it is a scientific necessity that risk assessors understand the relationship of biomonitoring data to estimation of exposure so that appropriate comparisons can be made to the no observed adverse effects levels (NOAELs) or other points of departure from toxicological studies in animals. In this paper, estimates of daily DINP intake are calculated for various population segments based on urinary biomonitoring data and are compared to estimates of exposure based on indirect methods and to health-based exposure guidance values. In general, intake estimates converge on a mean of 1-2MUg/kg/day regardless of source of exposure or population cluster; a value 2-orders of magnitude lower than health-based exposure guidance values, ranging from 120 to 290MUg/kg/day, which have been established by regulatory authorities and other authoritative bodies as representing acceptable levels. PMID- 22251515 TI - Common bile duct dilatation after cholecystectomy: open versus laparoscopic procedure. AB - BACKGROUND/AIMS: Cholecystectomy as a factor causing common bile duct (CBD) dilatation has been debated. The aim of this study was to investigate CBD dilatation after cholecystectomy in patients with a preoperative CBD diameter of <6mm. METHODOLOGY: We retrospectively analyzed the cases of 101 patients who underwent cholecystectomy. These patients were divided into 2 groups, the open cholecystectomy group (OC group) and the laparoscopic cholecystectomy group (LC group). RESULTS: The postoperative mean CBD diameter was 5.80+/-0.49mm in the OC group and 5.75+/-0.47mm in the LC group; the diameters were not significantly different between the 2 groups (p<0.6699). With regard to the change in body weight after surgery, in the OC group 71.1%, patients gained weight, 20% showed no change and 8.9% lost weight; the corresponding numbers in the LC group were 75%, 23.2% and 1.8% patients, respectively. Thus, there were no significant differences in terms of weight changes between the 2 groups (p<0.6607, p<0.6973 and p<0.1690, respectively). CONCLUSIONS: For patients with preoperative CBD diameters of <6mm no compensatory dilatation occurs after open or laparoscopic cholecystectomy. PMID- 22251516 TI - Is early laparoscopic cholecystectomy a safe procedure in patients when the duration of acute cholecystitis is more than three days? AB - BACKGROUND/AIMS: The role of laparoscopic cholecystectomy for patients with acute cholecystitis and symptoms for >3 days is debated. Our purpose was to compare the results of laparoscopic cholecystectomy in patients with acute cholecystitis and symptoms for <= 3 days and >3 days. METHODOLOGY: Sixty patients with acute cholecystitis had a laparoscopic cholecystectomy performed by the same surgeon. There were 39 patients in the short group (symptoms <= 3 days) and 21 patients in the long group (symptoms >3 days). Demographic data, surgical findings and clinical results were analyzed. RESULTS: There were no significant differences in age, gender, comorbidities, abnormal liver function tests, white bile, gallbladder empyema, blood loss, conversion rate, postoperative hospital stay or complication rates between the groups. The mean duration of acute cholecystitis was 1.9 days in the short group and 5.3 days in the long group (p<0.0001). The long group had a longer operating time (p=0.004) and a higher rate of subhepatic drains (p=0.014). CONCLUSIONS: Laparoscopic cholecystectomy is a safe and feasible procedure for patients with acute cholecystitis when the duration of symptoms is >3 days, however, a higher conversion rate is seen for acute chronic cholecystitis. PMID- 22251517 TI - Pitfalls of pancreatobiliary endoscopy after Billroth II gastrectomy. AB - BACKGROUND/AIMS: The aim of this retrospective study is the analysis of the success rate of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in our group of patients with Billroth II gastrectomy. METHODOLOGY: The study of the group was carried out during 14 years, i.e. from November 1994 to December 2008. It retrospectively evaluates 120 patients with Billroth II gastrectomy. RESULTS: A cannulation success rate of 90.8% (109 of 120 patients) was reached in performing ERCP in 120 patients with Billroth II gastrectomy. There were normal ERCP results in 4 patients. ERCP results in the remaining 105 patients were pathological. Endoscopic treatment was started in all of these 105 patients immediately after diagnostic ERCP. Overall, therapeutic ERCP was completely successful in 91 of 105 patients (86.66%) who were originally treated with endoscopy. CONCLUSIONS: ERCP in patients with Billroth II gastrectomy is much more demanding in contrast with standard procedure due to different postoperative anatomy. ERCP success is determined mainly by great personal experience and skillfulness of the endoscopist. ERCP performed lege artis in patients with Billroth II gastrectomy is a highly effective and safe method where the success rate reached can be almost the same as in a normal anatomical situation. PMID- 22251518 TI - Laparoscopic cholecystectomy in the elderly and young: a comparative study. AB - BACKGROUND/AIMS: To assess the safety and effectiveness of simple laparoscopic cholecystectomy in the elderly patients and to compare it with that in younger patients. METHODOLOGY: All patients underwent laparoscopic cholecystectomy in a four year period in a university hospital were retrospectively studied. They were divided in two groups according to the age: group A (65 years and above) and group B (below 65 years). Information about the diagnosis, operation time, intraoperative complications, conversion to open cholecystectomy, length of hospital stay, morbidity and mortality were collected. RESULTS: A total of 1539 patients underwent laparoscopic cholecystectomy during the study period, 234 (15.2%) patients in group A and 1305 (84.8%) patients in group B. Group A experienced higher rates of conversion to laparotomy (9% vs. 2.1%, p<0.005), longer operative time (105.5 vs. 89.7 minutes, p<0.005), longer hospital stay (6.2 vs. 2.1 days, p<0.005) and more morbidity (13.7% vs. 5.1%, p<0.005). The overall mortality was 0.3% with no significant statistical difference between both groups. CONCLUSIONS: Laparoscopic cholecystectomy is feasible in the elderly patients with low mortality and morbidity. However, it is associated with higher conversion rate, longer operation time, longer hospital stay and higher morbidity compared with younger patients. PMID- 22251519 TI - Endocrine cells in the human common bile duct in patients with obstructive jaundice. AB - BACKGROUND/AIMS: There was no data about endocrine cells in the extrahepatic bile duct in secondary cholangitis due to obstructive jaundice. The aim of the present study is to investigate immunohistochemically the endocrine cell types in the lower part of the human common bile duct in biopsy samples, collected during drainage because of complete or incomplete obstruction, caused mainly by stones. We explained the presence of various hormone-producing endocrine cells in this region with the regulation of physiological and pathological processes there. METHODOLOGY: We used light and electron microscopic immunohistochemistry. RESULTS: More gastrin-positive, somatostatin-positive, secretin-positive, serotonin-positive, chromogranin- A-positive and synaptophysin-positive endocrine cells were found compared to control preparations. CONCLUSIONS: Occurrence of endocrine cells may relate to disturbed bile flow and to formation of calculi. Endocrine cell hyperplasia may be related to longstanding inflammation as in chronic cholecystitis and all secreted hormones from the described ECs can support pathologic process in the choledochus, i.e. inflammation, increased mucus secretion, fibrosis, muscle contraction, etc. We may state that various ECs (similar to those in duodenum) present in the lower part of the large bile duct and their hormones exert action on physiology (motility, secretion) and pathology (inflammation and fibrosis) in that part of the biliary tree. PMID- 22251520 TI - Is lymph-node micrometastasis in gallbladder cancer a significant prognostic factor? AB - BACKGROUND/AIMS: The purpose of our study was to investigate prognostic significance of lymph-node micrometastasis in gallbladder carcinoma. METHODOLOGY: In total, 1,094 lymph nodes from 41 patients who had undergone radical resection with lymph-node dissection, including para-aortic lymph nodes were stained with hematoxylin and eosin (H&E) and immunostained with anti-cytokeratin 7/8 antibody. Micrometastasis in each lymph node was defined as tumor cells that were detectable only by immunohistochemical evaluation and were not detected by H&E staining. RESULTS: Metastases were detected in 163 lymph nodes (14.9%) by H&E staining. Micrometastases were found in 25 of the remaining lymph nodes (2.3%). Among 24 patients with lymph node metastasis based on the H&E staining, 12 had micrometastases. Of the 17 patients in whom lymph-node metastasis was not detected by the H&E staining, one was found to have micrometastasis. Micrometastasis correlated significantly with lymph node metastasis on H&E staining and pN (Tumor-Node-Metastasis 5th ed.). On multivariate analysis of data from 17 node-positive patients who underwent curative resection, micrometastasis and microscopic venous invasion were significant prognostic factors. CONCLUSIONS: Our findings suggest that micrometastasis might be traces of scatter of cancer cells to the whole body rather than an event in an initial stage of the metastasis. PMID- 22251521 TI - Fourteen year surgical experience of gallbladder cancer: validity of curative resection affecting survival. AB - BACKGROUND/AIMS: Early diagnosis and R0 resection of gallbladder cancer offer a chance for cure. The aims of this retrospective study were to determine the clinicopathologic prognostic factors affecting survival and recurrence. METHODOLOGY: Between 1995 and 2008, a total of 69 patients with gallbladder cancer who underwent surgical exploration or resection were reviewed retrospectively. RESULTS: Of the 69 patients, 34 achieved R0 resection (49.3%). The overall survival rates were 36.6% at 3 years and 24.4 % at 5 years. Multivariate analysis for overall survival demonstrated that non-R0 resection, lymph node dissection, infiltrative tumors, moderate to poor differentiation and depth of invasion were significant independent predictors of poor prognosis. Recurrence occurred in 21 patients. The seventh edition of American Joint Committee on Cancer staging system provided relatively better prediction of survival in patients with gallbladder cancer. CONCLUSIONS: R0 resection and lymph node dissection is an important surgical strategy to improve overall survival. Infiltrative tumor was an independent prognostic factor for disease free survival. PMID- 22251522 TI - TLR4 expression in normal gallbladder, chronic cholecystitis and gallbladder carcinoma. AB - BACKGROUND/AIMS: Chronic inflammation is a risk factor for gallbladder carcinoma. The molecular mechanisms linking inflammation and gallbladder carcinogenesis are incompletely understood. Toll-like receptors are involved in inflammatory response and play an important role in the innate immune system by initiating and directing immune response to pathogens. We tested the hypothesis that TLR4 participated in the development of gallbladder carcinoma through investigating the expression of TLR4 in chronic cholecystitis, gallbladder carcinoma and normal gallbladder. METHODOLOGY: The expression of TLR4 in 30 specimens of chronic calculous cholecystitis, 13 specimens of gallbladder adenocarcinoma and 10 specimens of normal gallbladder tissue was determined by immunohistochemistry, western blotting analysis and quantitative RT-PCR. RESULTS: We showed that TLR4 was mostly localized to the glandular and luminal epithelium of gallbladder. TLR4 expression was lower in gallbladder carcinoma tissue than in chronic cholecystitis and normal gallbladder tissue, whereas the difference between chronic cholecystitis tissue and normal gallbladder tissue was not statistically significant. CONCLUSIONS: The expression of TLR4 may be closely associated with the course of gallbladder carcinoma. PMID- 22251523 TI - Mechanical and preventable factors of bile duct injuries during laparoscopic cholecystectomy. AB - Bile duct injury (BDI) occurring during cholecystectomy has been proposed as the most serious and important cause of morbidity after this procedure. A literature review was performed about the mechanical and preventable factors of bile duct injury listed on Medline databases. Although most injuries occur within the surgeon's first 100 laparoscopic cholecystectomies, it has been suggested that most general surgeons may encounter bile duct injuries. Several techniques have been proposed to avoid this injury. Sound knowledge of anatomy regarding the hepatobiliary system, good surgical skills, awareness of this problem, and referral to higher centres if injury ensues, seem to be the appropriate course of action towards prevention. PMID- 22251524 TI - Serum and tissue vascular endothelial growth factor predicts prognosis in hepatocellular carcinoma patients after partial liver resection. AB - BACKGROUND/AIMS: To explore the effect of vascular endothelial growth factor (VEGF) expression on prognosis of hepatocellular carcinoma (HCC) after partial liver resection. METHODOLOGY: The expression of VEGF in 64 preoperative serum and resection specimens of HCC, confirmed by pathology, was detected by enzymelinked immunosorbent assay (ELISA) and immunohistochemistry. Correlations of VEGF level to clinicopathological features were analyzed. Cox regression model was used to analyze the recurrence risk factors after hepatectomy. RESULTS: Serum level of VEGF in HCC patients was 334.50+/-247.62pg/mL, significantly higher than healthy control group (p<0.01); it was also significantly higher in recurrent group than in non-recurrent group (p<0.05). VEGF was expressed in cytoplasm of HCC specimens. The positive rates of VEGF was significantly higher in recurrent group than in non-recurrent group (85.0% vs. 54.5%, p<0.05). The 1-, 2- and 3-year disease-free survival rates were significantly higher in VEGF(-) group than in VEGF(+) group (81.3% vs. 52.2%, 68.8% vs. 33.3%, and 62.5% vs. 29.1%, p<0.01). The overall survival rates of VEGF(-) subgroup was borderline significant higher than that of VEGF(+) subgroup (p=0.068). Multivariate analysis revealed that preoperative macroscopically disseminated nodules, tumor micrometastasis, serum and tissue VEGF level were independent recurrence risk factors. CONCLUSIONS: Serum and tissue VEGF level of HCC patients ascends distinctly, correlates to the recurrence of HCC after partial liver resection which can be used to estimate the risk of postoperative recurrence of HCC. PMID- 22251525 TI - B1 versus B2 Dukes stage rectal cancer: prospective evaluation of 87 patients in a single institution and quest for re-evaluation of the current protocol. AB - BACKGROUND/AIMS: Current protocols indicate surgery as single modality of therapy for B1 stage rectal cancer and surgery with adjuvant therapy for B2 stage. The aim of our study was to analyze the five-year survival rate for patients with surgically treated B1 and B2 rectal cancer and to assess the impact of adjuvant therapy on overall survival. METHODOLOGY: Our epidemiological clinical study was based on a prospective analysis of 87 cases of B1 (n=32) and B2 (n=55) rectal cancers operated between 2000 and 2003. Survival evaluation was done through a prospective cohort followup study. RESULTS: There were 33 female and 54 males with a median age of 60 years (IQR 39-74). Tumor location was low rectum for 23 patients (26.4%), medium rectum for 30 patients (34.5%) and high rectum at 34 patients (37.9%). We performed Miles operation in 42 cases, Dixon resection in 26 cases and Hartmann operation in 18 patients. There was no difference in the number and type of postoperative complications between groups. There were no local recurrences in the B1 stage group but 7 cases (12.7%) in the B2 stage group. Distant metastases were recorded in 8 patients (25%) in the B1 group and 2 patients (3.6%) in the B2 group. The survival rate at 5 years (S5) was better for the B2 stage S5=69.9% than B1 stage S5=53.5% (p=0.001). CONCLUSIONS: Patients with B1 stage rectal cancer might benefit from adjuvant/neoadjuvant therapy. PMID- 22251526 TI - Feasibility of solo laparoscopic colorectal resection. AB - BACKGROUND/AIMS: To demonstrate the feasibility of solo laparoscopic colorectal resection (SLCR) is performed by the laparoscopist only. This study is an evaluation of the feasibility of SLCR for patients with colorectal cancer. METHODOLOGY: Fifty-one consecutive patients received SLCR from 2008 to 2009. The procedure was performed with four trocars and one laparoscopist. The short-term outcomes and complications were investigated retrospectively. RESULTS: The median age of the patients was 67 years (range 42-81). The median operating time for SLCR was 168 minutes (range 90-268). For one patient (1.96%) conversion to open surgery was required. Anastomotic leakage developed in 1 (1.96%) patient and ileus developed in 2 (3.9%). The median postoperative hospital stay was 8 (range 6-60) days without in-hospital deaths. CONCLUSIONS: In our experience, SLCR for patients with colorectal cancer is feasible and compares favorably with the standard technique. The diminished need for human operative assistance provides significant economic and organizational benefits. PMID- 22251527 TI - The efficacy of oral tegafur-uracil as maintenance therapy following intravenous 5-fluorouracil chemotherapy in stage III colon cancer. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the impact on disease-free survival (DFS) of adding oral tegafur-uracil (UFT) to intravenous 5-fluorouracil (5-FU) as surgical adjuvant chemotherapy for stage II and III colon cancer. METHODOLOGY: The authors retrospectively analyzed 148 patients treated from 2000 through 2005 with pathologically confirmed stage II or III colon cancer. Forty seven patients were treated with 6 cycles of 5-FU+leucovorin (5-FU group) and the other 101 patients were treated with same above regimen followed by an additional 12 cycles of UFT+leucovorin (LV) for 28 days with a 7-day rest period (5-FU+UFT group). RESULTS: The median follow-up time was 64.9 months (range 15.3-95.2 months) and mean age was 58.8+/-10.8. The clinical characteristics of the 5 FU+UFT and 5-FU groups were similar. Furthermore, for all study subjects and stage II patients, 3-year DFS rates were not significantly different between two groups. However, for stage III patients, 3-year DFS rates were 80.0% and 60.7% in the 5-FU+UFT and 5-FU groups, respectively (HR=0.32; p=0.01; 95% CI=0.13-0.76). CONCLUSIONS: The addition of UFT to 5-FU was found that significantly improve DFS in patients with stage III colon cancer. The authors cautiously suggest UFT as a maintenance therapy following 5-FU chemotherapy could be another option in stage III colon cancer patients. PMID- 22251528 TI - Feasibility study of adjuvant chemotherapy with S-1 (TS-1; tegafur, gimeracil and oteracil potassium) for colorectal cancer. AB - BACKGROUND/AIMS: The aim of this study is to evaluate feasibility and safety of 3 week method (3-week administration and 1-week withdrawal) for colorectal cancer as adjuvant chemotherapy with an oral anticancer drug, S-1. METHODOLOGY: Forty two patients with stage II or III colorectal cancer who underwent curative resection in our hospital during a one year period in 2005 were enrolled in the preliminary pilot study. Between 2006 and 2007, 104 patients with stage II or III colorectal cancer who underwent curative resection in our hospital were chosen and were randomly divided into two groups, 3-week method or 4-week method (4-week administration and 2-week withdrawal) for a prospective randomized trial. RESULTS: The one-year completion rate in the 3-week method group was 98% (50/51) which was significantly better than that in the 4-week method group, 68% (36/53) (p=0.035). There were no grade 3 or 4 adverse reactions in both laboratory and clinical findings in the pilot study and in the prospective randomized trial. CONCLUSIONS: Three-week method of S-1 administration had good feasibility, easily manageable toxicity, high accumulated dose in one year and good compliance. The 3 week method with S-1 may be a standard adjuvant chemotherapy schedule for colorectal cancer. PMID- 22251529 TI - Single-incision laparoscopic ileoproctostomy for chronic constipation. AB - A 56-year-old woman who had undergone cesarean section thirty-five years ago and appendectomy forty years ago was referred to our department for surgical treatment of chronic constipation of over thirty years duration. She underwent laparoscopic ileoproctostomy using a single incision laparoscopic surgery (SILS) in July 2009. After laparoscopic mobilization of the ileocecal portion, the terminal ileum was transected by a stapler. Ileoproctostomy was performed by a circular stapler inserted transanally after the placement of an anvil on the ileal stump. The duration of the operation was 90 minutes and perioperative blood loss was less than 10mL. Her postoperative course was uneventful and she was discharged ten days after the operation. After discharge her bowel habits have been regular without any laxatives. SILS has been performed since the late 1990s for a wide variety of surgical procedures. To our knowledge however, this is the first report of ileoproctostomy using SILS for chronic constipation. PMID- 22251530 TI - Characteristics of serious complicated gastroduodenal ulcers in Japan. AB - BACKGROUND/AIMS: Even in Japan where the incidence of H. pylori infection is high, patients with gastroduodenal ulcers caused by NSAIDs are on the increase. A prospective study was conducted to elucidate the characteristics of gastroduodenal ulcers complicated with ulcerous hemorrhage and perforation among Japanese. METHODOLOGY: The subjects were 305 consecutive cases with hemorrhaging ulcers and 76 consecutive cases with perforated ulcers basis at Kagawa Prefectural Central Hospital between January 2000 and December 2008. These subjects were divided into 3 groups (lowdose aspirin, non-aspirin NSAIDs and non NSAIDs) and were further stratified by the presence of an H. pylori infection. RESULTS: The 76 perforating ulcers were composed of 54 non-NSAIDs ulcers and 22 NSAIDs-related ulcers. The 305 hemorrhaging ulcers were composed of 156 non NSAIDs ulcers, 94 non-aspirin NSAIDs ulcers and 55 on low-dose aspirin. The mortality for the non-aspirin NSAIDs group (12.8%, 12/94) and for the low-dose aspirin group (10.9%, 6/55) was significantly higher (p<0.01 and p<0.05, respectively) than the corresponding figure (2.6%, 4/156) for the non-NSAIDs group. The causes of death were exacerbation of or complications from the background diseases (Charlson Co-morbidity Index 3<=) (Odds ratios (OR) 6.01, 95% CI (1.98-18.89)). CONCLUSIONS: Approximately 50% of the gastroduodenal ulcers with complications found in Japanese are NSAIDs-related and may take a fatal turn. It is necessary to take measures to prevent the complicated ulcers corresponding to risk factors such as the severity of background diseases. PMID- 22251531 TI - Technical considerations in laparoscopic staging for advanced gastric cancer. AB - BACKGROUND/AIMS: Staging laparoscopy is useful for increasing the accuracy of preoperative tumor staging. Diagnostic laparoscopy has therefore been introduced to prevent unnecessary laparotomy in patients with unresectable cancers. However, the technique of laparoscopic observation remains controversial. In this study, we determined the efficacy of hand-assisted laparoscopic staging. METHODOLOGY: We retrospectively studied 44 patients who underwent conventional (LS group) or hand assisted laparoscopic staging (HALS group). RESULTS: The T factors of the TNM staging system was accurately determined in 95% of the patients in the HALS group and 58.3% of the patients in the LS group (p<0.0060). A total of 33.3% tumors in the LS group and 10% in the HALS group were judged to be unresectable. The overall mean survival was longer in the HALS group (20.3+/-12.2 months) than in the LS group (15.8+/-11.9 months). CONCLUSIONS: Laparoscopic diagnosis and staging of advanced gastric cancer are reliable. Moreover hand-assisted laparoscopic staging enables the accurate assessment of tumor resectability. PMID- 22251532 TI - Percutaneous drainage in conservative therapy for perforated gastroduodenal ulcers. AB - BACKGROUND/AIMS: The management of peptic ulcers has dramatically changed and the incidence of elective surgery for gastroduodenal peptic ulcers has markedly decreased; hence, the incidence of emergency surgery for perforated peptic ulcers has slightly increased. In select cases, conservative therapy can be used as an alternative for treating perforated gastroduodenal ulcers. In this study, we evaluated the efficacy of percutaneous abdominal drainage for the conservative treatment of perforated gastroduodenal ulcers. METHODOLOGY: We retrospectively studied 51 patients who had undergone conservative therapy for perforated gastroduodenal ulcers. These patients were divided into 2 groups on the basis of the initial treatment with conservative therapy with or without percutaneous drainage: group PD included patients who had undergone percutaneous drainage and group NPD, patients who had undergone non-percutaneous drainage. RESULTS: In the PD group, 14.3% (n=3) of the patients did not respond to conservative therapy, while this value was 43.3% (n=13) in the NPD group. The 2 groups differed significantly with respect to conversion from conservative therapy to surgery (p<0.0352). CONCLUSIONS: Conservative therapy for perforated gastroduodenal ulcers should be performed only in the case of patients meeting the required criteria; its combination with percutaneous intraperitoneal drainage is effective as initial conservative therapy. PMID- 22251533 TI - Clinical features and management of duodenal fistula in patients with Crohn's disease. AB - BACKGROUND/AIMS: Duodenal fistula is rare in patients with Crohn's disease and almost all patients require surgery. Generally surgery for duodenal CD and reconstruction is considered difficult. We reviewed the clinical features of duodenal fistula with CD and considered suitable preoperative treatments. METHODOLOGY: We reviewed the records of 10 patients with duodenal fistula complicating CD between September 1974 and April 2009. RESULTS: Mean age at surgery was 31.5 years (range 22-36). Mean duration from onset of CD or previous surgery was 49.8 months (range 1.5-172.6). All patients were treated with total parenteral nutrition before surgery, 3 patients with steroids and 1 patient with infliximab. Synergistic effects of these immunomodulators were not examined in this study. Although preoperative treatments improved the values of CD activity index (p<0.01) all patients required surgical treatment. Duodenal fistula in all patients resulted from intrinsic CD lesion at the colon or ileum. Although immunmodulators had no additional effects on shortening hospital stay or improving activity index, simple fistula repair was performed in all patients. CONCLUSIONS: Although the additional effects of immunomodulators were not confirmed, the sufficient preoperative treatment for duodenal fistula with CD to reduce disease activity seems likely to facilitate subsequent minimal surgery. PMID- 22251534 TI - Laparoscopic approach for the multiple abdominal vascular entrapment syndrome. AB - We report an unusual case of a 25-year-old man affected by several vascular entrapment abdominal processes: celiac axis compression or Dunbar syndrome, superior mesenteric artery syndrome or Wilkie's disease and Nutcracker syndrome implying compression of the left renal vein. We discuss the diagnosis that was established by contrast-enhanced spiral computed tomography scan and magnetic resonance angiography. Once diagnosed the patient was treated conservatively by enteral high caloric diet in order to obtain a weight gain, however as it did not relieve the symptomatology of pain and vomit we opted for a surgical procedure. The therapeutic options were reviewed, highlighting the laparoscopic approach, which was the one we chose since it provides a less invasive procedure than open surgery but is an equally effective method of treatment. PMID- 22251535 TI - Gastrointestinal metastases from breast cancer: report of two cases. AB - Metastatic involvement of the gastrointestinal (GI) tract secondary to breast cancer (BC) is rare and usually occurs in patients with lobular BC. We report 2 cases with GI presentations of metastatic BC. In the first case endoscopy and endoscopic ultrasonography because of abdominal discomfort, tenesmus and rectal bleeding demonstrated liver, gastric and rectal metastases with histological and immunohistological patterns of metastatic lobular BC. In the second case gastric involvement, endoscopically presented as a solid nodular lesion in the gastric body and fundus with involvement of the gastro-esophageal junction, was established with clinical symptoms of solid food dysphagia and dyspepsia; the metastatic infiltration from ductal BC was proven histologically and immunohistochemically. The GI metastases were presented 5 and 7 years after radical mastectomy because of lobular and ductal BC respectively. The cases are of interest with a feature of liver and GI metastases in double sites (stomach and rectum) from lobular BC, as well as solid gastric metastasis from ductal BC. They illustrate the need for special attention to GI metastatic disease in patients with invasive BC who present with non-specific GI symptoms. PMID- 22251536 TI - Management of vascular complications after living donor liver transplantation. AB - BACKGROUND/AIMS: Vascular complications after liver transplantation remain a major source of morbidity and mortality for recipients especially those receiving LDLT owing to the complex vascular reconstruction. METHODOLOGY: During the period from May 1999 to May 2004, 518 LDLT were performed in the Department of Liver Transplantation and Immunology, Kyoto University Hospital, Japan. RESULTS: The recipients were 261 males and 257 females. Pediatric cases were 230. The indications were cholestatic diseases in 42.5%, chronic hepatocellular diseases (CHD) in 13.3%, HCC in 18.5%, other tumors in 2.7% and others in 23%. Small for- size grafts in 4.8%, accepted size grafts in 16.0%, optimum size grafts in 74.5% and large-for-size grafts in 4.6%. Vascular complications occurred during hospital stay in 6.4%, within 3 months from discharge in 2.5% and after 3 months from discharge in 6.0%. The success rate of the management of HAT was 83.3%, portal vein complications was 97.6% and hepatic vein complications was 84.6%. CONCLUSIONS: Careful preoperative evaluation and the proper intraoperative techniques in vascular reconstruction prevent vascular complications. Intraoperative microsurgical technique for hepatic artery reconstruction decreases hepatic artery complications. Routine post transplant Doppler examination should be performed at least twice a day for the first week after the operation. Immediate surgical intervention is required for acute vascular complications, whereas late complications may be treated by balloon angioplasty and endoluminal stent to avoid late complications and even mortality. PMID- 22251537 TI - Are there any similarities in the hepatic vascular anatomy among blood relatives? AB - BACKGROUND/AIMS: The existence of similarities in the hepatic vascular anatomy among blood relatives (BR) have never been studied before. Since in living donor liver transplantation (LDLT), the donor may be a BR, an opportunity is available to assess whether there are similarities in the hepatic vascular anatomy among BR. METHODOLOGY: We conducted an analysis of 61 LDLT during the period from January 2004 to August 2008. Based on preoperative multi-detector computed tomography data, the hepatic arteries (HA) were classified into 4 groups, the portal vein (PV) was classified into 2 groups and the right hepatic vein (RHV) was classified into 2 groups. The data of each group were then compared between BR (n=47) and NBR (n=14). RESULTS: With regard to the HA anatomy, 30 cases (68%) of the BR donor matched that of the recipient and 9 cases (69%) in the NBR donor. The PV anatomy was matched in 41 cases (87%) of BR donor and 11 cases (79%) in the NBR donor. The anatomy of the RHV was matched in 25 cases (53%) in the BR donor and 9 cases (64%) in NBR donor. There was no significant difference in all contexts. CONCLUSIONS: No similarities were therefore observed in the hepatic vascular anatomy among BR. PMID- 22251538 TI - Interleukin-1beta and interleukin-1 receptor accessory protein gene polymorphisms are associated with persistent hepatitis B virus infection. AB - BACKGROUND/AIMS: The reasons for persistent HBV infection are unknown, but they are probably related to host immune factors. IL-1beta plays significant roles in inflammation and immune defense via IL-1RAcP. We investigated whether genetic polymorphisms of IL-1beta and IL-1RAcP genes are associated with persistent HBV infection and the presence of HCC. METHODOLOGY: We enrolled a total of 292 patients with chronic HBV infection (111 with chronic hepatitis, 95 with liver cirrhosis and 86 with HCC) and 107 healthy individuals who recovered from HBV infection. We assessed 28 SNPs in IL- 1beta and IL-1RAcP genes by using Illumina's Sentrix array matrix chip. RESULTS: IL-1beta-2023 C allele, IL-1RAcP 8261 T allele and -8183 A allele were significantly associated with persistent HBV infection (OR=1.63, p=0.03, OR=0.64, p<0.01 and OR=0.20, p=0.01, respectively). IL- 1beta 289 C allele was marginally associated with an increased risk for the presence of HCC (OR=1.55, p=0.04). On the haplotype analysis, IL 1beta-2023C/-581C/2893C haplotype and IL-1RAcP -8261T/-8183A haplotype were associated with persistent HBV infection. There was no significant association between the haplotypes of IL-1beta/IL-1RAcP and the presence of HCC. CONCLUSIONS: The genetic polymorphisms of IL-1beta-2023 C allele, IL- 1RAcP -8261 T allele and -8183 A allele are probable host factors for persistent HBV infection. PMID- 22251539 TI - Strategy for synchronous and multiple liver metastasis. AB - BACKGROUND/AIMS: Surgical indications for resection of synchronous metastasis from colorectal cancer (CRC) and the optimal timing of hepatectomy are still controversial and widely debated. METHODOLOGY: Synchronous and multiple metastatic liver tumors were detected in 57 patients since May 2005. Our treatment policy was to perform hepatectomy if the resection could be done with no limit on size and number of tumors. However, if curative resection could not be done, chemotherapy was begun and timing for the possibility of a radical operation was planned immediately. RESULTS: In 37 patients whose tumors were located only in the liver, primary tumor resection was performed in 16 patients and after tumor-decreasing by chemotherapy, in 7 patients. In 20 patients in whom chemotherapy was performed first, after controlling the distant metastasis, hepatectomy was performed in 3 patients and staged hepatectomy was performed in 10. Recurrence was detected after hepatectomy in 75.0% of simultaneous resection cases and in 70.0% of staged cases. In the recurrence cases, early detection after tumor resection occurred in 58.3% of the simultaneous and 14.2% of the staged. CONCLUSIONS: The present data show that neoadjuvant chemotherapy does not increase the risk of postoperative complications or the surgical difficulties of hepatectomy for colorectal metastases. PMID- 22251540 TI - Genetic polymorphism of two enzymes with alcoholic liver disease in Northeast China. AB - BACKGROUND/AIMS: Alcohol abuse is becoming an increasingly severe problem among the Han, Mongol and Chaoxian nationalities in the northeast of China. The study aimed to investigate the relationship between alcoholic liver disease (ALD) and the genetic polymorphism of two enzymes, cytochrome P450IIE1 (CYPIIE1) and glutathione S-transferase P1 (GSTP1) in patients of three nationalities. METHODOLOGY: Peripheral blood was collected from 353 Chinese patients with ALD, 300 alcohol-dependent patients without liver disease (alcoholic) and 360 healthy controls. Each group included patients from the Han, Mongol and Chaoxian nationalities. PCR-restriction fragment length polymorphism (PCR-RFLP) was used in this research. RESULTS: Regardless of nationality patients who carried the rare CYPIIE1 C2 and GSTP1 Val allele were at higher risk of ALD. The frequency of C2 and Val in patients with ALD was 50.00% and 26.98% in the Han, 31.36% and 22.87% in the Mongol and 45.87% and 22.02% in the Chaoxian, respectively. No significant differences were seen in the frequency of either the C2 or Val alleles in ALD, among the three nationalities. In each nationality, the frequency of both the C2 and Val alleles was significantly higher in ALD compared to alcoholic and healthy controls. CONCLUSIONS: In this group of Chinese patients, we found that regardless of nationality, patients with ALD tended to carry the C2 allele and the Val allele. This may indicate a causal relationship between these polymorphic alleles that lead to the development of ALD. PMID- 22251541 TI - Pre-core/basal-core promoter and reverse transcriptase mutations in chronic HBV infected-patients. AB - BACKGROUND/AIMS: Some HBV mutations have been shown to have an association with liver disease. The aim of the study was to investigate the incidence of mutations in hepatitis B virus (HBV) pre-core/basal core promoter (BCP) and reverse transcriptase (RT) regions and their relationship with disease progression in chronic HBV-infected patients. METHODOLOGY: A total of 133 patients were enrolled in this study, comprising the acute-on-chronic hepatitis B liver failure (ACLF HBV) and chronic hepatitis B (CHB) patients. The pre-core/ BCP and RT gene fragments were amplified by high-fidelity PCR. Mutations of pre-core/BCP and RT regions were examined by direct sequencing. RESULTS: There were no significant differences in age, the average level of ALT and course of disease between the ACLF-HBV and CHB groups. The HBeAg positive rate and average values of HBV-DNA loads of the ACLF-HBV patients were lower than that of CHB patients. In HBV pre core/ BCP region, the point mutations T1753C (39.06% vs. 21.74%, p<0.01), A1762T (26.56% vs. 13.04%, p<0.05), G1764A (31.25% vs. 18.84%, p<0.01), G1896A (29.69% vs. 15.94%, p<0.05) and G1899 (23.44% vs. 10.14%, p<0.05) were significantly more frequent in the ACLFHBV than CHB patients. For combined mutations, A1762T+G1764A (23.43% vs. 11.59 %, p<0.05) and G1896A+ G1899A (21.88% vs. 13.04%, p<0.05) were significantly more frequent in ACLF-HBV than CHB patients. However, there were no significant differences in RT mutations between two groups. CONCLUSIONS: ACLFHBV patients had more frequent mutations in HBV precore/ BCP region than that of CHB patients. Some mutations in HBV pre-core/BCP region might be related to the aggravation of chronic HBV infection. PMID- 22251542 TI - Management of cytomegalovirus infection after living donor liver transplantation. AB - BACKGROUND/AIMS: Few studies on Cytomegalovirus (CMV) infection in adult-to-adult living donor liver transplantation (LDLT) have been reported. The aim of this study was to analyze the incidence, risk factors and management of CMV infection after LDLT. METHODOLOGY: Retrospective analysis was performed with 72 consecutive adult cases. RESULTS: CMV antigenemia was demonstrated in 31 (43.1%) patients and 9 patients (12.5%) manifested fever. Twelve patients were treated with intravenous ganciclovir (GCV) injection. There was improvement in 10 patients; foscanet concomitant with CMV-IG was administered in one patient who had an adverse effect resulting in improvement and another one resulted in death from sepsis. Twelve patients were given oral valganciclovir (VGCV) and all showed improvement. ABO incompatible transplantation was associated with CMV infection after LDLT in both the univariate (p=0.005) and multivariate analyses (p=0.04). After discharge 12 out of 63 patients (19%) suffered from CMV infection and all of them were taking steroid. CONCLUSIONS: ABO incompatible transplantation was demonstrated as a risk factor for CMV infection during hospitalization. After discharge immunosuppressive status seemed to be more essential as a predictor for CMV infection. Routine examination to detect CMV antigenemia is needed especially in patients with potentially over-immunosuppressive conditions in out-patient clinics. PMID- 22251543 TI - Inhibition of transforming growth factor beta-1 augments liver regeneration after partial portal vein ligation in a porcine experimental model. AB - BACKGROUND/AIMS: TGF-beta1 is a pleiotropic cytokine that is over expressed in terminal phase of liver regeneration. METHODOLOGY: Twenty-four hours after partial portal vein ligation monoclonal antibody against TGF-beta1 (TGF-beta1 group, 7 piglets) or physiological solution (control group, 9 piglets) were applied into the central venous catheter. The biochemical parameters (bilirubin, urea, creatinine, alkaline phosphatase, gamma- glutamyl transferase, cholinesterase, aspartate aminotransferase, alanine aminotransferase and albumin) were assessed. The compensatory hypertrophy of the non-occluded liver lobes was evaluated by periodic ultrasonography during the next fourteen days and by histological examination. RESULTS: The acceleration of growth of the hypertrophic liver lobes was maximal between 3rd and 7th postoperative days in comparison with the control group (p<0.05). No important differences in the biochemical or studied histological parameters were proved. CONCLUSIONS: The present study describes a new usage of monoclonal antibody against TGF-beta1 in large animal experimental model of partial portal vein ligation. PMID- 22251544 TI - Rational surgical aggression in multimodal treatment of liver colorectal metastases. AB - BACKGROUND/AIMS: The purpose of this study was to analyze the influence of aggressive surgery regarding resection of liver metastases (LM) from colorectal cancer (CRC) on morbidity, mortality and survival rates and to establish utility of multimodal strategies increasing resectability rates of liver metastases. METHODOLOGY: Two hundred twenty eight consecutive patients with CRC LMs operated from January 2004 to October 2009 were presented. They underwent 137 curative liver resections. We have used extended criteria for respectability including the possibility to spare 2 adjacent liver segments. Multimodal approaches meaning transformation of primary unresectable LMs to resectable ones were used in 46 cases. During the final decision intraoperative ultrasonography took an important part. RESULTS: The resectability in presented series was 46% for synchronous LM and 76% for metachronous. Aggressive surgical approach was applied in 75 patients. The average rate of intraoperative hemorrhage was 300mL. Postoperative complications occurred in 25.5% of patients. Two patients died postoperatively. CONCLUSIONS: Rational surgical behavior in context of multimodal approach to LMs of CRC can increase chances of resectability and long-term survival without influencing morbidity and mortality. PMID- 22251545 TI - Non-colorectal liver metastases: surgical treatment options. AB - BACKGROUND/AIMS: Due to different biological characteristics of non-colorectal liver metastasizes (NCLM), surgical treatment, especially it's long term results, is a topic of discussion. The aim of the study was to evaluate the single center experience with surgical treatment of NCLM. METHODOLOGY: Seventy two patients were prospectively included. The average length of time after the primary surgery was 3.9 years (0-8.5 years). RFA prevailed -50 patients (69.4%), resection presenting 30.6%. Preoperative chemotherapeutical downstaging or portal vein embolization was performed on 12 patients (16.7%). Resectable or radiofrequency ablation (RFA) treatable extrahepatic metastasizes were removed in 26 patients (36.1%). RESULTS: One, three and five years patient survival after the liver resection or RFA was 88.6, 72.5 and 36.9%. The best survival rate was in patients with carcinoid (5 years-100%), breast cancer (5 years-33.8%), renal carcinoma (3 years-44.4% ) and gynecological tumors metastasizes (2 years-72.9%). With regards to long-term survival of patients, we did not find any statistically significant difference between RFA and resection. Patients with extrahepatic metastasizes had worse prognosis (p<0.01). CONCLUSIONS: Liver resection and RFA in NCLM have an unambiguous place in multi-modal curative strategy. The decision for surgical treatment of patients suffering from NCLM, is strictly individual with the aim of achieving qualitative long-term survival. PMID- 22251546 TI - Safety and efficacy of trans arterial chemoembolization with drug-eluting beads in hepatocellular cancer: a systematic review. AB - BACKGROUND/AIMS: The aim of this review was to compare current conventional TACE to the drug eluting beads loaded with doxorubicin (DEBDOX) device in the treatment of HCC. METHODOLOGY: A recent hepatocellular consensus discussion was convened to review all recent and past literature in the use of hepatic directed therapies to compare the safety, efficacy and overall survival of the available hepatic directed therapies in the management of hepatocellular cancer. A review of all publications in peer review journals in the English Language from 1995 to 2007 was performed. RESULTS: The DEBDOX are an effective therapy with a favorable pharmacokinetic profile with significantly less systemic doxorubicin exposure when compared to conventional TACE. The DEBDOX had a significant (p<0.05) advantage in objective response in the more advanced patients (defined as Child Pugh B, ECOG 1, recurrent disease and bilobar disease; p=0.038) and overall disease control in the more advanced patients (p=0.026). The DEBDOX Bead was also found to have a highly significant (p<0.01) advantage in the reduction of doxorubicin associated side effects (p=0.0001) in all patients. CONCLUSIONS: The current collective data on the use of DEBDOX Bead in HCC patients provides sufficient evidence to support its use as a safe and effective chemo-embolic treatment in intermediate HCC patients. There is growing evidence to support the its use is superior to conventional doxorubicin TACE. PMID- 22251547 TI - Pancreatic duct patency after pancreaticoduodenectomy for dilated pancreatic ducts. AB - BACKGROUND/AIMS: It is important to prevent pancreatic leakage and maintain pancreatic duct patency after pancreaticoduodenectomy (PD). We used an implantation method and a pancreatic stent in pancreaticogastrostomy (PG) and achieved good results without pancreatic leakage; however, PG strictures were observed in some cases. Using a pancreatic stent, we evaluated the early postoperative changes in the remnant pancreatic duct diameter in patients with a mildly dilated pancreatic duct. METHODOLOGY: We retrospectively analyzed 46 patients with a mildly dilated pancreatic duct (diameter 4-7mm) who underwent PD with PG. They were divided into 2 groups on the basis of the surgical treatment they received for pancreatic stump: Group C included patients who underwent complete ligation of the pancreatic duct with a pancreatic stent (complete external drainage of the pancreatic juice), and Group I included patients who underwent pancreatic duct-to-mucosa anastomosis with a pancreatic stent (incomplete external drainage of the pancreatic juice). RESULTS: The postoperative mean diameter of the remnant pancreatic duct was significantly smaller in Group I (6.22+/-0.81mm) than in Group C (6.80+/-1.10mm) (p<0.0466). CONCLUSIONS: To prevent pancreatic leakage and maintain pancreatic duct patency, duct-to-mucosa anastomosis with a pancreatic stent is useful for patients with a dilated pancreatic duct. PMID- 22251548 TI - Should pancreaticoduodenectomy be performed in the elderly? AB - BACKGROUND/AIMS: Pancreaticoduodenectomy (PD) is indicated in benign or malignant pancreatic head diseases. It is a difficult operation with high morbidity especially in elderly patients. The aim of our study was to determine whether pancreaticoduodenectomy is associated with higher morbidity and mortality in patients >= 70 years old. METHODOLOGY: During 17 years, 173 patients were operated by Whipple intervention, whatever the disease. From a prospective database, patients were divided in 2 groups (Group A >= 70 years old, Group B <70). RESULTS: Postoperative mortality was not significantly higher in elderly (12% vs. 4.1%; p=0.06). However, re-intervention and morbidity were more important in univariate analysis (p=0.03 and p=0.002 respectively). In multivariate analysis, age >= 70 years old was not an independent prognostic factor of mortality (p=0.27) and re-intervention (p=0.07). Whereas age (p=0.04) and preoperative morbidity (p=0.02) were independent prognostic factors of morbidity. CONCLUSIONS: PD requires careful patient selection. However, age should not be a limiting factor. PMID- 22251549 TI - Surgical potentialities for the treatment of pancreatic cancer. AB - BACKGROUND/AIMS: The incidence of pancreatic cancer is rising in all developed countries. The aim of this study is to define the surgical options in the treatment protocols for this disease and to evaluate the effect of radical resections. METHODOLOGY: One hundred ninety six consecutive patients with pancreatic cancer, operated in our department in a 4-year period, were evaluated. Among them, 106 were radically operated and the rest underwent palliative procedures. RESULTS: Twenty-eight of the presented patients underwent pancreatic resection with simultaneous vessle resection, venous in 26 cases and arterial in 2 cases. Seventeen extended resections were made. The rate of postoperative morbidity of the radically operated was 36.8% (39 patients). Early bleeding (10 cases) and pancreatic fistula (10 cases) were the most common major complications. The 3-year survival rate of the radically operated patients was 21.5% vs. 0% in these with palliative procedures. The data analysis revealed no statistically significant difference in the survival of patients with modifications of pancreaticoduodenectomy, Whipple and PPPD (p=0.065). CONCLUSIONS: The radical surgery ensures better long-term results. We recommend this type of surgery to be concentrated in highly specialized centers in order to improve the outcome. PMID- 22251550 TI - Evaluation of the clinical relevance of hrgA gene in patients with Helicobacter pylori infection. AB - BACKGROUND/AIMS: Patients with gastric cancer in some Asian populations were infected more frequently with hrgA-positive H. pylori. The aim of this study was to examine the usefulness of hrgA to predict the clinical outcome of H. pylori infection. METHODOLOGY: Forty four patients with gastric cancer (35 intestinal and 9 diffuse type cancer) and 51 control subjects were studied. Presence of hrgA gene in H. pylori strains isolated from biopsy specimens was examined by PCR. Biopsy specimens were also obtained for histological assessment of gastritis. RESULTS: Nine of 44 patients with gastric cancer (20.4%) and 11 of 51 control subjects (21.6%) were infected with hrgA-positive strain (NS). In patients with gastric cancer, prevalence of hrgA-positive strain was 20.0% in patients with intestinal type cancer (7/35) and 22.2% with diffuse type cancer (2/9) (NS). In control subjects, the prevalence of hrgA-positive infection was not associated with gastric mucosal inflammatory infiltration and glandular atrophy. CONCLUSIONS: Infection with hrgA-positive strain was not frequent among patients with gastric cancer. Presence of hrgA gene would not be a useful marker to predict clinical outcome of patients infected with H. pylori in this series of Japanese patients. PMID- 22251551 TI - Pathological complete response of synchronous multiple liver metastases associated with advanced gastric cancer to gastrectomy and prompt S-1 treatment in combination with fractional cisplatin: report of a case. AB - Systemic chemotherapy is the treatment recommended for prolonged survival in cases of metastatic gastric cancer. There have been a number of clinical reports of surgical resection of liver metastasis in selected patients with gastric cancer. Here, we report on a case of treatment of far advanced gastric cancer with synchronous multiple liver metastases with prompt S-1 in combination with fractional cisplatin sandwiched between twostage surgery. Metastases including peritoneal dissemination and extensive lymph node involvement were absent so it was feasible to completely remove all of the macroscopic liver metastases. Each step of the chemotherapy progressed satisfactorily and histological examination after the hepatectomy yielded a pathologically complete response of liver metastases from the gastric cancer. This strategy provides a promising treatment for far advanced gastric cancer with a limited number of synchronous liver metastases. The referral to surgical oncology is a crucial step for the documentation of pathological complete response. PMID- 22251552 TI - Quinolinic acid: neurotoxicity. AB - This minireview series reviews some of the most recent findings about quinolinic acid's cellular toxicity and its implications in diseases such as HIV associated neurocognitive disorders, depressive disorders and schizophrenia, and finally therapeutic strategies with drugs able to interfere with quinolinic acid production and/or effects. PMID- 22251553 TI - Conventional multi-slice computed tomography (CT) and cone-beam CT (CBCT) for computer-assisted implant placement. Part I: relationship of radiographic gray density and implant stability. AB - PURPOSE: The relationship of conventional multi-slice computed tomography (CT)- and cone beam CT (CBCT)-based gray density values and the primary stability parameters of implants that were placed by stereolithographic surgical guides were analyzed in this study. MATERIALS AND METHODS: Eighteen edentulous jaws were randomly scanned by a CT (CT group) or a CBCT scanner (CBCT group) and radiographic gray density was measured from the planned implants. A total of 108 implants were placed, and primary stability parameters were measured by insertion torque value (ITV) and resonance frequency analysis (RFA). Radiographic and subjective bone quality classification (BQC) was also classified. Results were analyzed by correlation tests and multiple regressions (p < .05). RESULTS: CBCT based gray density values (765 +/- 97.32 voxel value) outside the implants were significantly higher than those of CT-based values (668.4 +/- 110 Hounsfield unit, p < .001). Significant relations were found among the gray density values outside the implants, ITV (adjusted r(2) = 0.6142, p = .001 and adjusted r(2) = 0.5166, p = .0021), and RFA (adjusted r(2) = 0.5642, p = .0017 and adjusted r(2) = 0.5423, p = .0031 for CT and CBCT groups, respectively). Data from radiographic and subjective BQC were also in agreement. CONCLUSIONS: Similar to the gray density values of CT, that of CBCT could also be predictive for the subjective BQC and primary implant stability. Results should be confirmed on different CBCT scanners. PMID- 22251554 TI - Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma. AB - (153)Sm-ethylenediamine tetramethylene phosphonic acid ((153)Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of (153)Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radiobiologic modeling and examined the relationship between tumor AD and response. METHODS: Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of (153)Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of (153)Sm-EDTMP (37.0-51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after (153)Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates. RESULTS: On average, a 5-fold increase in the AA led to a 4 fold increase in the mean tumor AD over the high- versus low-dose-treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low dose therapy were 1.48-14.6 and 0.98-3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93-59.3 and 1.89-12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively). CONCLUSION: The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low- and high-dose therapy, respectively. A dose-response relationship was observed for transient tumor volume shrinkage. PMID- 22251556 TI - Role of PET/CT in staging and evaluation of treatment response after 3 cycles of chemotherapy in locally advanced retinoblastoma: a prospective study. AB - The present study prospectively evaluated the role of (18)F-FDG PET/CT for staging, neoadjuvant chemotherapy response evaluation, and final outcome assessment in International Retinoblastoma Staging System (IRSS) stage III retinoblastoma. METHODS: Twenty-five consecutive IRSS stage III patients, with a median age of 3 y, were prospectively enrolled after ethics approval. All patients received neoadjuvant chemotherapy followed by enucleation, radiotherapy, and adjuvant chemotherapy. PET/CT was performed at baseline (PET/CT-1) and after 3 cycles of neoadjuvant chemotherapy (PET/CT-2). All 25 patients underwent PET/CT 1, and 21 of 25 patients underwent PET/CT-2. PET/CT-1 was compared with routine staging, and response on PET/CT-2 was assessed by criteria from the European Organization for Research and Treatment of Cancer response. Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis, and differences between the groups were compared using log-rank test. A P value of 0.05 or less was considered significant. RESULTS: Increased (18)F-FDG uptake was noted in primary extraocular tumor in all patients, except 5 with bilateral retinoblastoma (one eye with advanced and the other eye with intraocular disease) in whom the intraocular tumor did not show (18)F-FDG uptake. Five of 22 IRSS stage IIIA patients with clinically negative cervical lymph node involvement were found to have uptake in cervical lymph nodes on PET/CT-1, and 2 of 3 IRSS stage IIIB patients with pathologically confirmed cervical lymph node involvement did not show any uptake in the involved lymph nodes. No significant difference in EFS and OS was seen between IRSS stage IIIA and IIIB patients using routine staging or PET/CT staging (P >= 0.05); however, there was a trend toward better OS in patients with IRSS stage IIIB disease on PET/CT (P = 0.065). There was no significant discordance between routine staging and PET/CT staging (P = 0.256). The 8 patients with optic nerve uptake had lower EFS (P = 0.0001) and OS (P = 0.0009) than did 17 patients without optic nerve uptake on PET/CT-1. The 17 patients with complete response or partial response had better EFS (P = 0.042) and OS (P = 0.026) than did the 4 patients with progressive disease on PET/CT-2. CONCLUSION: Optic nerve uptake at baseline on PET/CT and response after neoadjuvant chemotherapy according to criteria from the European Organization for Research and Treatment of Cancer are strong predictors of EFS and OS in IRSS stage III retinoblastoma. PMID- 22251555 TI - Quantitative preclinical imaging of TSPO expression in glioma using N,N-diethyl-2 (2-(4-(2-18F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3 yl)acetamide. AB - There is a critical need to develop and rigorously validate molecular imaging biomarkers to aid diagnosis and characterization of primary brain tumors. Elevated expression of translocator protein (TSPO) has been shown to predict disease progression and aggressive, invasive behavior in a variety of solid tumors. Thus, noninvasive molecular imaging of TSPO expression could form the basis of a novel, predictive cancer imaging biomarker. In quantitative preclinical PET studies, we evaluated a high-affinity pyrazolopyrimidinyl-based TSPO imaging ligand, N,N-diethyl-2-(2-(4-(2-(18)F-fluoroethoxy)phenyl)-5,7 dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((18)F-DPA-714), as a translational probe for quantification of TSPO levels in glioma. METHODS: Glioma bearing rats were imaged with (18)F-DPA-714 in a small-animal PET system. Dynamic images were acquired simultaneously on injection of (18)F-DPA-714 (130-200 MBq/0.2 mL). Blood was collected to derive the arterial input function (AIF), with high-performance liquid chromatography radiometabolite analysis performed on selected samples for AIF correction. Compartmental modeling was performed using the corrected AIF. Specific tumor cell binding of DPA-714 was evaluated by radioligand displacement of (3)H-PK 11195 with DPA-714 in vitro and displacement of (18)F-DPA-714 with an excess of DPA-714 in vivo. Immediately after imaging, tumor and healthy brain tissues were harvested for validation by Western blotting and immunohistochemistry. RESULTS: (18)F-DPA-714 was found to preferentially accumulate in tumors, with modest uptake in the contralateral brain. Infusion with DPA-714 (10 mg/kg) displaced (18)F-DPA-714 binding by greater than 60% on average. Tumor uptake of (18)F-DPA-714 was similar to another high-affinity TSPO imaging ligand, (18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline, and agreed with ex vivo assay of TSPO levels in tumor and healthy brain. CONCLUSION: These studies illustrate the feasibility of using (18)F-DPA-714 for visualization of TSPO-expressing brain tumors. Importantly, (18)F-DPA-714 appears suitable for quantitative assay of tumor TSPO levels in vivo. Given the relationship between elevated TSPO levels and poor outcome in oncology, these studies suggest the potential of (18)F-DPA-714 PET to serve as a novel predictive cancer imaging modality. PMID- 22251557 TI - Defective trafficking of rhodopsin and its role in retinal degenerations. AB - Retinitis pigmentosa is a retinal degeneration transmitted by varied modes of inheritance and affects approximately 1 in 4000 individuals. The photoreceptors of the outer retina, as well as the retinal pigmented epithelium which supports the outer retina metabolically and structurally, are the retinal regions most affected by the disorder. In several forms of retinitis pigmentosa, the mislocalization of the rod photoreceptor protein rhodopsin is thought to be a contributing factor underlying the pathophysiology seen in patients. The mutations causing this mislocalization often occur in genes coding proteins involved in ciliary formation, vesicular transport, rod outer segment disc formation, and stability, as well as the rhodopsin protein itself. Often, these mutations result in the most early-onset cases of both recessive and dominant retinitis pigmentosa, and the following presents a discussion of the proteins, their degenerative phenotypes, and possible treatments of the disease. PMID- 22251558 TI - Adherens junction assembly and function in the Drosophila embryo. AB - Adherens junctions are essential for the development and physiology of epithelial tissues. The Drosophila embryo is an excellent model for understanding adherens junction assembly, maintenance, and regulation during tissue development. Here, I review our current state of knowledge in this model system. The review begins by outlining the structure of the cadherin-catenin complex in Drosophila including core (DE-cadherin, Armadillo, alpha-catenin, and p120-catenin) and peripheral proteins. Then, it summarizes adherens junction assembly at cellularization and maturation at gastrulation. Finally, the regulation of adherens junctions during tissue morphogenesis is discussed. This discussion compares major morphogenetic events in the embryo (invagination of the ventral furrow, convergent extension of the germband, flattening of the amnioserosa, maintenance of tissue borders, epithelial branching, lumen formation, cell delamination, cell division, apoptosis, and dorsal closure) and common mechanisms involved (myosin activity, endocytosis, and mesenchymal-to-epithelial transitions). PMID- 22251559 TI - New insights into the regulation of myosin light chain phosphorylation in retinal pigment epithelial cells. AB - The retinal pigment epithelium (RPE) plays an essential role in the function of the neural retina and the maintenance of vision. Most of the functions displayed by RPE require a dynamic organization of the acto-myosin cytoskeleton. Myosin II, a main cytoskeletal component in muscle and non-muscle cells, is directly involved in force generation required for organelle movement, selective molecule transport within cell compartments, exocytosis, endocytosis, phagocytosis, and cell division, among others. Contractile processes are triggered by the phosphorylation of myosin II light chains (MLCs), which promotes actin-myosin interaction and the assembly of contractile fibers. Considerable evidence indicates that non-muscle myosin II activation is critically involved in various pathological states, increasing the interest in studying the signaling pathways controlling MLC phosphorylation. Particularly, recent findings suggest a role for non-muscle myosin II-induced contraction in RPE cell transformation involved in the establishment of numerous retinal diseases. This review summarizes the current knowledge regarding myosin function in RPE cells, as well as the signaling networks leading to MLC phosphorylation under pathological conditions. Understanding the molecular mechanisms underlying RPE dysfunction would improve the development of new therapies for the treatment or prevention of different ocular disorders leading to blindness. PMID- 22251560 TI - Cell biology of the chloroplast symbiosis in sacoglossan sea slugs. AB - Chloroplasts removed from their species of origin may survive for various periods and even photosynthesize in foreign cells. One of the best studied and impressively long, naturally occurring examples of chloroplast persistence, and function inside foreign cells are the algal chloroplasts taken up by specialized cells of certain sacoglossan sea slugs, a phenomenon called chloroplast symbiosis or kleptoplasty. Among sacoglossan species, kleptoplastic associations vary widely in length and function, with some animals immediately digesting chloroplasts, while others maintain functional plastids for over 10 months. Kleptoplasty is a complex process in long-term associations, and research on this topic has focused on a variety of aspects including plastid uptake and digestive physiology of the sea slugs, the longevity and maintenance of symbiotic associations, biochemical interactions between captured algal plastids and slug cells, and the role of horizontal gene transfers between the sea slug and algal food sources. Although the biochemistry underlying chloroplast symbiosis has been extensively examined in only a few slug species, it is obvious that the mechanisms vary from species to species. In this chapter, we examine those mechanisms from early discoveries to the most current research. PMID- 22251561 TI - Regulation of intraflagellar transport and ciliogenesis by small G proteins. AB - Cilia rely on their distinctive protein compositions to function. Proteins gain access to the privileged ciliary compartment through two major routes, membrane trafficking and intraflagellar transport (IFT). Recent advances have provided two possible models for ciliary membrane transport: lateral diffusion and retention, and targeted vesicle transport. The Rab11-Rab8 cascade, which was originally discovered in the yeast's secretion pathway for bud formation, is shown to be required for cilia membrane assembly. Small GTPases, including two IFT particle subunits, and Ran, the master regulator for nuclear-cytoplasmic transport, are implicated in various aspects of IFT, a fundamental process required for the assembly of the microtubule-based backbone of cilia. This chapter reviews the key steps of ciliogenesis and possible mechanisms of IFT regulation, with emphasis on the regulatory roles of small GTPases and their regulators. PMID- 22251562 TI - Emerging roles for renal primary cilia in epithelial repair. AB - Primary cilia are microscopic sensory antennae that cells in many vertebrate tissues use to gather information about their environment. In the kidney, primary cilia sense urine flow and are essential for the maintenance of epithelial architecture. Defects of this organelle cause the cystic kidney disease characterized by epithelial abnormalities. These findings link primary cilia to the regulation of epithelial differentiation and proliferation, processes that must be precisely controlled during epithelial repair in the kidney. Here, we consider likely roles for primary cilium-based signaling during responses to renal injury and ensuing epithelial repair processes. PMID- 22251563 TI - Mechanisms of cardiogenesis in cardiovascular progenitor cells. AB - Self-renewing cells of the vertebrate heart have become a major subject of interest in the past decade. However, many researchers had a hard time to argue against the orthodox textbook view that defines the heart as a postmitotic organ. Once the scientific community agreed on the existence of self-renewing cells in the vertebrate heart, their origin was again put on trial when transdifferentiation, dedifferentiation, and reprogramming could no longer be excluded as potential sources of self-renewal in the adult organ. Additionally, the presence of self-renewing pluripotent cells in the peripheral blood challenges the concept of tissue-specific stem and progenitor cells. Leaving these unsolved problems aside, it seems very desirable to learn about the basic biology of this unique cell type. Thus, we shall here paint a picture of cardiovascular progenitor cells including the current knowledge about their origin, basic nature, and the molecular mechanisms guiding proliferation and differentiation into somatic cells of the heart. PMID- 22251565 TI - Reduced cortical thickness in non-medicated patients with obsessive-compulsive disorder. AB - Increasing evidence suggests the presence of grey matter volume abnormalities in patients with obsessive-compulsive disorder (OCD) and the mediation of the expression of different OCD symptoms by discrete neural systems of the brain. However, limited studies have investigated the abnormalities of cortical thickness, and their results are comparatively inconsistent, possibly owing to the inclusion of medicated patients. Therefore, this study investigated cortical thickness abnormalities using surface-based analysis to identify distinct neural correlates of each symptom dimension in non-medicated patients with OCD. Thirty non-medicated patients with OCD and 30 age- and gender-matched healthy controls underwent magnetic resonance imaging. Group comparison of cortical thickness was performed using surface-based analysis. We also conducted correlation analysis between cortical thickness and each symptom dimension score. Compared to the healthy controls, the OCD patients had statistically significant reduction in cortical thickness in the cluster that contained the left superior temporal gyrus and posterior insular cortex (p<.05, corrected); no areas of the brain had significantly greater cortical thickness. Negative correlation was also found between cortical thickness and "cleaning" dimension scores in the left postcentral and right superior parietal gyri. The present results suggest that cortical thinning in the region that contains the left superior temporal gyrus and posterior insula may underlie pathophysiology of OCD and that discrete neural systems may mediate the "cleaning" symptom dimension. PMID- 22251564 TI - Membrane trafficking and phagosome maturation during the clearance of apoptotic cells. AB - Apoptosis is a cellular suicide process that quietly and efficiently eliminates unwanted or damaged cells. In metazoans, cells that undergo apoptosis are swiftly internalized by phagocytes and subsequently degraded inside phagosomes through phagosome maturation, a process that involves the fusion between phagosomes and multiple kinds of intracellular organelles and the gradual acidification of phagosomal lumen. In recent years, rapid progress has been made, in particular, through studies conducted in the model organism, the nematode Caenorhabditis elegans, in understanding the membrane trafficking events and molecular mechanisms that govern the degradation of apoptotic cells through phagosome maturation. These studies revealed the novel and essential functions of a large number of proteins, including the large GTPase dynamin, multiple Rab small GTPases and their regulatory proteins, the lipid second messenger PtdIns(3)P and its effectors, and unexpectedly, the phagosomal receptors for apoptotic cells, in promoting phagosome maturation. Further, novel signaling pathways essential for phagosome maturation have been delineated. Here, we discuss these exciting new findings, which have significantly deepened and broadened our understanding of the mechanisms that regulate the interaction between intracellular organelles and phagosomes. PMID- 22251566 TI - Cannabinoid receptor signaling and modulation of monoamines: implications for psychiatric and neurological disorders. PMID- 22251568 TI - Short-chain dehydrogenases/reductases in cyanobacteria. AB - The short-chain dehydrogenases/reductases (SDRs) represent a large superfamily of enzymes, most of which are NAD(H)-dependent or NADP(H)-dependent oxidoreductases. They display a wide substrate spectrum, including steroids, alcohols, sugars, aromatic compounds, and xenobiotics. On the basis of characteristic sequence motifs, the SDRs are subdivided into two main (classical and extended) and three smaller (divergent, intermediate, and complex) families. Despite low residue identities in pairwise comparisons, the three-dimensional structure among the SDRs is conserved and shows a typical Rossmann fold. Here, we used a bioinformatics approach to determine whether and which SDRs are present in cyanobacteria, microorganisms that played an important role in our ecosystem as the first oxygen producers. Cyanobacterial SDRs could indeed be identified, and were clustered according to the SDR classification system. Furthermore, because of the early availability of its genome sequence and the easy application of transformation methods, Synechocystis sp. PCC 6803, one of the most important cyanobacterial strains, was chosen as the model organism for this phylum. Synechocystis sp. SDRs were further analysed with bioinformatics tools, such as hidden Markov models (HMMs). It became evident that several cyanobacterial SDRs show remarkable sequence identities with SDRs in other organisms. These so-called 'homologous' proteins exist in plants, model organisms such as Drosophila melanogaster and Caenorhabditis elegans, and even in humans. As sequence identities of up to 60% were found between Synechocystis and humans, it was concluded that SDRs seemed to have been well conserved during evolution, even after dramatic terrestrial changes such as the conversion of the early reducing atmosphere to an oxidizing one by cyanobacteria. PMID- 22251569 TI - The broad field of forensic pharmacy. AB - Forensic pharmacy is application of the sciences of drugs to legal issues. Forensic pharmacists engage in work relating to litigation, the regulatory process, and the criminal justice system. Forensic pharmacy overlaps with many other forensic fields. Pharmacists hold a variety of positions with local, state, and federal governments. Many pharmacists do freelance work as forensic litigation consultants. A forensic pharmacist can be a valuable resource in legal cases relating to malpractice, adverse drug reactions, drunk and drugged driving, health care fraud, poisoning, and numerous other types of civil and criminal cases. PMID- 22251567 TI - Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology. AB - Mescaline and phencyclidine (PCP) are potent hallucinogenic agents affecting human and animal behavior. As their psychotropic effects remain poorly understood, further research is necessary to characterize phenotypes they evoke in various animal models. Zebrafish (Danio rerio) are rapidly emerging as a new model organism for neuroscience research. Here, we examine the effects of mescaline (5-20mg/l) and PCP (0.5-3mg/l) in several zebrafish paradigms, including the novel tank, open field and shoaling tests. Mescaline and PCP dose dependently increased top activity in the novel tank test, also reducing immobility and disrupting the patterning of zebrafish swimming, as assessed by ethograms. PCP, but not mescaline, evoked circling behavior in the open field test. At the highest doses tested, mescaline markedly increased, while PCP did not affect, zebrafish shoaling behavior. Finally, 20mg/l mescaline did not alter, and 3mg/l PCP elevated, whole-body cortisol levels. Overall, our studies indicate high sensitivity of zebrafish models to hallucinogenic compounds with complex behavioral and physiological effects. PMID- 22251570 TI - Dietary methylmercury and vegetable oil affects brain lipid composition in Atlantic salmon (Salmo salar L.). AB - The interaction between methylmercury (MeHg) and marine fatty acids is of great interest in risk benefit assessments, and is increasingly important also in fish nutrition when fish oil is replaced with vegetable oils. To assess the effects of replacing fish oil (high dietary n-3/n-6 ratio) by soybean oil (low dietary n-3/n 6 ratio) in combination with MeHg, Atlantic salmon (Salmo salar L.) were fed experimental diets (fish oil (FO) or vegetable oil (VO) based, with or without the addition of MeHg) for 3 months. As expected replacing dietary fish oil by soybean oil had greater effect on the fatty acid composition in white muscle compared to brain. In brain, the relative levels of 18:2 n-6 and 20:4 n-6 increased in all lipid classes in fish fed the VO based diets whereas the levels of marine omega-3 PUFA (polyunsaturated fatty acid) were unaffected. Different dietary lipid sources did not affect the accumulation of mercury in brain nor muscle. However, exposure to dietary MeHg resulted in decreased levels of 20:4 n 6 (arachidonic acid; ARA) in phosphatidylinositol in brain of VO fed fish. The decreased amounts of ARA in VO fish is suggested to be caused by interaction between high n-6 level and MeHg. PMID- 22251571 TI - Combined treatment of HEDTA and propolis prevents aluminum induced toxicity in rats. AB - A study was undertaken to evaluate protective effect of chelating agent, N-(2 hydroxy ethyl ethylene diamine triacetic acid) [HEDTA] with and without propolis against aluminum (Al) induced toxicity in liver, kidney and brain. Toxicity was induced by single administration of aluminum nitrate at a dose of 32.5mg/kg (1/2 of LD(50)). HEDTA (20mg/kg, ip), propolis (200mg/kg, po), and combination of HEDTA and propolis, respectively, were administered for 3 days after 24h of Al exposure. Significant enhancement in AST, ALT, uric acid, urea, cholesterol, and triglyceride contents was found in serum, whereas albumin was decreased after Al exposure. Hepatic, renal, and neuronal LPO were found significantly increased after Al exposure, whereas it inhibited AChE activity in forebrain, midbrain, and hindbrain. Al significantly reduced the activity of adenosine triphosphatase, superoxide dismutase and catalase and GSH contents in hepatic, renal and nervous tissues. However, individual treatment of HEDTA and propolis restored biochemical parameters towards control but combined treatment of HEDTA and propolis offered better protection in comparison to monotherapy. Combined treatment of HEDTA and propolis preserved histological features, mitigated oxidative stress and improved liver, kidney and brain functions more profoundly. PMID- 22251572 TI - EC-SOD induces apoptosis through COX-2 and galectin-7 in the epidermis. AB - BACKGROUND: Extracellular superoxide dismutase (EC-SOD) is an anti-oxidant enzyme found in the extracellular matrix of tissues, and plays an important role in the prevention of many diseases caused by oxidative stress. However, other functions of EC-SOD in epidermis are not well known. OBJECTIVE: We investigated the functions of EC-SOD in epidermis using keratinocyte cell line and EC-SOD transgenic mice. METHODS: Expression of galectin-7 in pEC-SOD transfected cells or skin of EC-SOD transgenic mice was detected by western blot analysis. The percentage of apoptotic cells was determined by propidium iodide staining and subsequent FACS analysis. COX-2 siRNA or scrambled siRNA was transfected into HaCaT cells and western blot analysis was performed to detect pro-apoptotic protein levels. RESULTS: The epidermis of EC-SOD transgenic mice was thinner than wild type mice. In addition, we showed that the thin epidermis of EC-SOD transgenic mice results from the apoptosis of epidermal cells. To elucidate which molecules are involved in EC-SOD-induced apoptosis, we utilized two-dimensional electrophoresis; the results showed that the epidermis of EC-SOD transgenic mice produces more galectin-7, a pro-apoptotic factor, than the wild type. Furthermore, we showed that the transfection of EC-SOD-expressing plasmids induces the production of galectin-7, and pro-apoptotic proteins in keratinocytes. This suggests that EC-SOD induces apoptosis through increased galectin-7 expression. Finally, we demonstrated that EC-SOD-induced galectin-7 results from the production of COX-2. CONCLUSION: Our results imply that EC-SOD plays a role not only as a reactive oxygen species scavenger, but also as a pro apoptotic factor via COX-2/galectin-7 pathways in the epidermis. PMID- 22251573 TI - Kinetics of hydrolysis and mutational analysis of N,N-diethyl-m-toluamide hydrolase from Pseudomonas putida DTB. AB - The initial step in the biodegradation pathway of N,N-diethyl-m-toluamide (DEET) in Pseudomonas putida strain DTB is catalyzed by DEET hydrolase (DthA), which hydrolyzes the amide bond to yield 3-methylbenzoic acid and diethylamine. In order to extend our understanding of DthA, the enzyme was purified and characterized. The enzyme is most active at pH 7.9, and is probably a tetramer in its native state. The kinetic parameters of the wild-type enzyme are K(m) = 10.2 +/- 0.8 MUm, k(cat) = 5.53 +/- 0.09 s(-1) , and k(cat) /K(m) = (5.4 +/- 0.4) * 10(5) m(-1) .s(-1) . Mild substrate inhibition was observed with DEET concentrations over 500 MUm. A homology model of DthA was used to guide mutational analysis of the active site, confirming that the catalytic triad is formed by Ser166, Ap292, and His320. The oxyanion hole is formed by the side chain OH of Tyr84 and the backbone amide of Trp167, with the Tyr84 OH being essential for enzyme activity. The DthA model also revealed a hydrophobic substrate-binding pocket comprosed of Trp167, Met170, and Trp214. W167A and M170A mutations decreased enzymatic activity and exacerbated substrate inhibition, whereas Trp214, which probably plays a role in substrate recognition, was essential for enzymatic activity. The pH rate profile of DthA was fitted to two ionizable groups (pK(a1) = 6.1 and pK(a2) = 9.9) that probably correspond to Nepsilon of His320 and the OH of Tyr84, respectively. In addition to catalyzing the hydrolysis of DEET, DthA hydrolyzed a variety of esters and amides. PMID- 22251574 TI - Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years. AB - AIMS: To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D. METHODS: T1D children (n=260, median age at diagnosis 9.4, range 0.9-14.7 years) were tested for GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q autoantibodies (A) at diagnosis, and 3-6 years after diagnosis when also fasting and stimulated RBF were determined. RESULTS: For every 1-year increase in age at diagnosis of TID, the odds of detectable C-peptide increased 1.21 (1.09, 1.34) times for fasting C-peptide and 1.28 (1.15, 1.42) times for stimulated C-peptide. Based on a linear model for subjects with no change in IA-2A levels, the odds of detectable C-peptide were 35% higher than for subjects whose IA-2A levels decreased by half (OR=1.35 (1.09, 1.67), p=0.006); similarly for ZnT8WA (OR=1.39 (1.09, 1.77), p=0.008) and ZnT8QA (OR=1.55 (1.06, 2.26) p=0.024). Such relationship was not detected for GADA or ZnT8RA. All OR adjusted for confounders. CONCLUSIONS: Age at diagnosis with T1D was the major predictor of detectable C-peptide 3-6 years post-diagnosis. Decreases in IA-2A, and possibly ZnT8A, levels between diagnosis and post-diagnosis were associated with a reduction in RBF post-diagnosis. PMID- 22251575 TI - Effects of alendronate on human osteoblast-like MG63 cells and matrix metalloproteinases. AB - OBJECTIVE: The objective of this study was to examine the effects of alendronate on the expression and activity of matrix metalloproteinases (MMPs) and the expression of the tissue inhibitors of MMPs (TIMPs) from human osteoblast-like MG63 cells. MATERIALS AND METHODS: MG63 cells were exposed to various concentrations of alendronate. Cell proliferation and cytotoxicity were evaluated by water-soluble tetrazolium-1 and lactate dehydrogenase, respectively. MG63 mediated collagen degradation was assessed utilising Type I collagen assays. Conditioned media and membrane extracts were collected for Western blot analyses of select MMPs and TIMPs. Gelatin zymography gels were incubated with alendronate to assess its effects on MMP-2 activity. RESULTS: Alendronate affected MG63 proliferation and cytotoxicity at concentrations equal to/or greater than 10(-5) M (all p < 0.05). There were no significant differences in the collagen degrading ability of treated cells at non-toxic levels vs. untreated cells. Alendronate had no effects on the expression of MMP-2 or MT1-MMP (membrane type-1 MMP) in the conditioned media or membrane extracts, and of MMP-1 or TIMP-2 in the conditioned media. TIMP-2 in the membrane extracts was not detectable. MMP-2 activity in the zymograms was inhibited by 10(-3) and 10(-2) M alendronate. CONCLUSION: Alendronate at 10(-5) M or higher was toxic to the cells. Alendronate at 10(-8) to 10(-6) M did not alter the expression of MMP-1, MMP-2, MT1-MMP or TIMP-2, as well as did not alter collagen degradation. Alendronate inhibited MMP-2 activity at 10(-3) and 10(-2) M in the zymograms. In conclusion, non-toxic levels of alendronate (10(-8) to 10(-6) M) did not alter MMP expression in MG63 cells or inhibit MMP-2 activity. PMID- 22251576 TI - Characterization of a novel tyrosinase inhibitor, (2RS,4R)-2-(2,4 dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384). AB - BACKGROUND: We synthesized (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4 carboxylic acid (MHY384) as a potential tyrosinase inhibitor and investigated its antityrosinase activity. METHODS: The structure of MHY384 was established using (1)H and (13)C NMR spectroscopy and mass spectral analyses. To investigate dual mechanisms of action of MHY384 for the inhibition of melanin synthesis, we confirmed the inhibitory effect of tyrosinase catalytic activity of MHY384. Then, we confirmed the inhibitory effect of MHY384 on transcription of tyrosinase mRNA through alpha-MSH-induced cAMP-PKA-MITF signaling. In addition, we supported the inhibitory mechanism of MHY384 against tyrosinase using a kinetic study and docking programs. RESULTS: To determine how MHY384 regulates melanogenesis, we measured melanin levels and expression of the genes for microphthalmia-associated transcription factor (MITF) and tyrosinase in alpha-melanocyte-stimulating hormone (alpha-MSH)-induced B16F10 melanoma cells. MHY384 potently inhibited tyrosinase activity and melanin production in B16F10 melanoma cells. Through docking models, we were able to construct the tertiary structure of mushroom tyrosinase and simulate its docking with MHY384. The result supports that MHY384 strongly interacts with tyrosinase residues in the active site and it can directly inhibit tyrosinase. To investigate additional mechanisms of action of MHY384, we confirmed that the inhibition of tyrosinase activity was found to be due to the modulation of the expression of tyrosinase and its transcription factor, MITF, through cAMP, which regulates protein kinase A. CONCLUSIONS: This study strongly indicates that the depigmenting effect of MHY384 results from the down-regulation of MITF and tyrosinase through direct tyrosinase inhibition. GENERAL SIGNIFICANCE: Our findings suggest that MHY384 can be an effective skin whitening agent. PMID- 22251577 TI - Concentration fluctuations in binary fluid membranes. AB - We investigate the dynamics of critical fluctuations in binary fluid membranes using a two-dimensional hydrodynamic model with momentum decay to the surrounding water. In particular, the decay rate of concentration fluctuations is obtained analytically. In the limit of small wavenumber q with respect to the correlation length, the decay rate is proportional to q2, as usual. In the large-q limit, however, the effective diffusion coefficient increases only logarithmically with q. PMID- 22251578 TI - The role of attractive many-body interaction in the gas-liquid transition of mercury. AB - The equation of state for expanded fluid mercury based on the variational associating fluid theory is developed to elucidate the mechanisms of the gas liquid transition in terms of microscopic interatomic interaction. The theory describes the interaction of an atom with its neighbouring atoms through an effective many-body potential, which is constructed through quantum-chemical calculations of cohesive energies for selected geometries of clusters and bulk crystals. The overall feature of the observed gas-liquid coexistence curve is reproduced accurately without introducing phenomenological adjustable parameters. It is shown that the local aggregation of atoms produces a strong cohesive force due to a change in the local electronic states, which plays a crucial role in the gas-liquid transition. The predicted phase behaviour is consistent with the picture of inhomogeneous expansion, in which the average coordination number is nearly proportional to the average density along the coexistence curve. PMID- 22251579 TI - Stochastic method for accommodation of equilibrating basins in kinetic Monte Carlo simulations. AB - A computationally simple way to accommodate 'basins' of trapping states in standard kinetic Monte Carlo simulations is presented. By assuming that the system is effectively equilibrated in the basin, the residence time (time spent in the basin before escape) and the probabilities for transitions to states outside the basin may be calculated. This is demonstrated for point defect diffusion over a periodic grid of sites containing a complex basin. PMID- 22251580 TI - Hidden octupole order in URu2Si2. AB - We propose that the hidden order in URu2Si2 is an incommensurate octupole order, which is derived from a spin-1 XXZ model with XX octupole and Z dipole interactions based on the singlet-doublet crystal-field level scheme. The octupole moments break time-reversal invariance and give rise to finite hyperfine fields on the nuclei of the ligand Si and Ru ions. In order for the hyperfine fields to be observed as a nuclear magnetic resonance (NMR) linewidth, the order must be incommensurate, with the ordering vector determined so as to account for the 29Si NMR linewidth data quantitatively. PMID- 22251581 TI - Negative refraction via domain wall resonances in a homogeneous mixture of ferro- and nonmagnetic substances. AB - We deliver the general conditions on the synthetic proportions for a homogeneous mixture of ferro- and nonmagnetic substances to become left-handed. As an alternative for left-handed metamaterials, we consider mixing ferromagnetic materials with nonmagnetic microscopic particles. In the mixture, the ferromagnetic material provides the needed permeability via domain wall resonances at high frequencies, whereas the nonmagnetic material gives the required permittivity. Using the effective medium theory, we have found that when the concentration of the nonmagnetic particles falls into a certain range, the refractive index of the mixture is negative, n<0, which includes the double negative (epsilon<0 and MU<0) and other cases (e.g. epsilon<0 and MU>0). We finally give the requirements on the microscopic material properties for the ferromagnetic materials to reach the domain wall resonances at high frequencies. PMID- 22251582 TI - Complex phase behaviour from simple potentials. AB - Simple pair potentials, where the term 'simple' denotes potentials that are isotropic and refer to one-component systems, can be used to describe effective interactions among substances with supramolecular architecture. By suitably choosing the functional dependence on the intermolecular distance, through such potentials it is possible to take into account, in an average way, the effect of the internal degrees of freedom of the macromolecules. This may give rise to phase phenomena that are radically different from those characterizing typical monoatomic systems. Here we review a number of simple model potentials presenting unusual, i.e. not argon-like, features and discuss the role of attraction and repulsion in determining their phase behaviour. PMID- 22251583 TI - Interfaces and fluctuations in confined polymeric liquid mixtures: from immiscible to near critical systems. AB - In this paper the structure of the interface between polymer films is discussed to elucidate fluctuations and confinement effects in fluid polymer mixtures. The neutron reflectivity technique has been employed to investigate the dependence of the structure of the interface on the degree of immiscibility of the polymers over a wide range, as criticality is approached, and to characterize it in terms of intrinsic width, as calculated by mean field theories, and capillary fluctuations. For more immiscible systems, as the degree of incompatibility between the polymers is decreased, the width of the interface increases slowly, and it is independent of the molecular weight of the polymers. Closer to the critical point the dependence on the degree of miscibility becomes stronger and the way in which the interfacial width diverges, as criticality is approached, is related to both chain length and Flory-Huggins interaction parameter (chi). The results have been compared to the predictions of mean field theories. Self consistent field numerical calculations, with the additional contribution due to capillary waves, provide a good description of the width of the interface between two polymer bulk phases, in particular at higher and intermediate degrees of immiscibility-the product of the Flory-Huggins interaction parameter chi and the number N of monomers of the chain, chiN. For more miscible systems a crossover is observed to a region where the square gradient theory in the weak segregation limit better approximates the experimental results. Moreover, the mechanisms by which confinement affects the interface have been investigated. To understand the relative importance of the long ranged van der Waals forces and short ranged 'truncation forces' in modifying thermally excited fluctuations at the polymer/polymer interface, the thickness dependence of the interfacial width has been studied for different degrees of miscibility, approaching criticality. The results show a gradual transition from a region where long ranged dispersion forces are dominant in influencing the capillary wave spectrum, for higher degrees of immiscibility, to a region where short ranged forces-connected to the presence of the walls-become more important and the dependence of the interfacial width on film thickness is stronger. The thickness dependence of the interfacial width was also studied for systems with different molecular weights in different conditions of miscibility, to investigate the effects of a confined geometry on polymers with different chain lengths as criticality is approached. PMID- 22251584 TI - Ultraviolet photoinduced weak bonds in aryl-substituted polysilanes. AB - The susceptibility of aryl-substituted polysilylenes to photodegradation by ultraviolet (UV) radiation is examined on the prototypical materials poly[methyl(phenyl)silylene] (PMPSi) and poly[(biphenyl-4-yl)methylsilylene] (PBMSi). We extend the scope of our last paper (Schauer et al 2004 Polym. Degrad. Stabil. 84 383) with the elucidation of the degradation mechanisms for two different degradation wavelengths: 266 and 355 nm. The main purpose of this paper was to study photoluminescence (PL) after major degradation, predominantly in long-wavelength range 400-600 nm, studying the disorder, dangling bonds (DBs) and weak bonds (WBs) created by the degradation process. We claim that the PL of the 500-600 nm band is related to the existence of WBs on the Si chain and originates in the sigma(*)-sigma exciton migration at room temperature by diffusion, free electron-hole formation, trapping in WBs and subsequent radiative recombination by tunnelling. Increase of the normalized PL 520-540 nm band after UV degradation can be then evaluated as the increase of the density of states (DOS) of WBs. The efficiency of the WB creation in PMPSi is greater for 266 nm irradiation, supporting the notion of the suppressed exciton transport compared to the less energetical photon of 355 nm, where the WB creation is lowered due to the exciton migration to longer segments and/or already existing defects. For PBMSi the WB creation kinetics for 355 nm degradation is similar to that of PMPSi. The 266 nm degradation results then support the model calculations of DB and WB reconstruction in the more rigid Si skeleton. PMID- 22251585 TI - A simple physical description of DNA dynamics: quasi-harmonic analysis as a route to the configurational entropy. AB - It has become increasingly apparent that the dynamic as well as the structural properties of biological macromolecules are important to their function. However, information concerning molecular flexibility can be difficult to obtain experimentally at the atomic level. Computer modelling techniques such as molecular dynamics (MD) have therefore proved invaluable in advancing our understanding of biomolecular flexibility. This paper describes how a combination of atomistic MD simulations and quasi-harmonic analysis can be used to describe the dynamics of duplex DNA, with a particular emphasis on methods for calculating differences in configurational entropies. We demonstrate that DNA possesses remarkably simple mechanical properties relative to globular proteins, making it an ideal system for exploring biomolecular flexibility in general. Our results also highlight the importance of solvent viscosity in determining the dynamic behaviour of DNA in aqueous solution. PMID- 22251586 TI - In situ XAFS and XRD studies of pressure-induced local structural change in liquid AgI. AB - In order to examine the pressure-induced structural change of liquid silver iodide (AgI), high-pressure and high-temperature in situ x-ray absorption fine structure (XAFS) and x-ray diffraction (XRD) studies have been carried out up to 1200 K and 6 GPa. The modifications in the x-ray absorption near edge structure (XANES) spectra and x-ray structure factors, S(Q), with increasing pressure provide evidence for changes in the short-range order of liquid AgI. The I-Ag bond length in liquid AgI increases by compression up to 2 GPa, which proposes that components with higher coordination than fourfold are introduced. The I-Ag bond length decreases monotonically with compression above 2 GPa, indicating that the structural change involving a coordination-number change is completed below 2 GPa and then a high-pressure form of liquid AgI is stabilized. Comparing the I-Ag bond lengths of liquid AgI with those of crystalline phases, we conclude that the high-pressure form of liquid AgI has a rocksalt-like structure with large vacancies. PMID- 22251587 TI - Fluid-fluid demixing transitions in colloid-polyelectrolyte star mixtures. AB - We derive effective interaction potentials between hard, spherical colloidal particles and star-branched polyelectrolytes of various functionalities f and smaller size than the colloids. The effective interactions are based on a Derjaguin-like approximation, which is based on previously derived potentials acting between polyelectrolyte stars and planar walls. On the basis of these interactions we subsequently calculate the demixing binodals of the binary colloid-polyelectrolyte star mixture, employing standard tools from liquid-state theory. We find that the mixture is indeed unstable at moderately high overall concentrations. The system becomes more unstable with respect to demixing as the star functionality and the size ratio grow. PMID- 22251588 TI - Spin ladder with anisotropic ferromagnetic legs in a transverse magnetic field. AB - We have studied the ground-state phase diagram of a two-leg spin ladder with anisotropic ferromagnetic leg couplings under the influence of a symmetry breaking transverse magnetic field by the exact diagonalization technique. In the case of antiferromagnetic coupling between legs we identified two phase transitions in the plane of magnetic field versus interchain coupling strength. The first corresponds to the transition from the gapped rung-singlet phase to the gapped stripe-ferromagnetic phase. The second represents the transition from the gapped stripe-ferromagnetic phase into the fully polarized ferromagnetic phase. PMID- 22251589 TI - Effect of nonlinear interactions on resonant states of the random dimer model. AB - A simple Kronig-Penney model for 1D mesoscopic systems with delta peak potentials is used to study numerically the effect of non-linear interaction on the resonant states of the random dimer model. It is shown that the nonlinear interaction increases or decreases the width of the resonances depending on both its sign and strength. The resonance width DeltaE is a power law decaying with the system size as L(-gamma). The exponent gamma decreases linearly with the nonlinear interaction strength when the dimer impurity concentration increases. The resonance energy states, in these systems, are shifted depending on the kind of interaction. Further investigations are provided on the effect of nonlinearity on conductance fluctuations near the resonances. PMID- 22251590 TI - In-plane orientation effect on the melting behaviour of YBCO thin film. AB - By means of high-temperature optical microscopy (HTOM), a 60 degrees C gap in initial melting temperature between two YBa2Cu3O(x) (Y123) thin films was found in situ. Using these two films as seeds, liquid phase epitaxy (LPE) dipping experiments showed the same tendency in the melting behaviour. The in-plane orientation was detected by x-ray diffraction (XRD) pole figure. On the basis of results from HTOM, LPE and XRD, it was unveiled that the interface structure has a predominant influence on the melting mode. A semi-coherent interface suppresses not only the melting growth but also the melting nucleation, while an incoherent interface encourages both of them. (In this work, melting of YBCO refers to the peritectic decomposition of Y123.). PMID- 22251591 TI - Spectroscopic investigation of CaAl12O19:M3+ upon UV/vacuum-UV excitation: a comparison with SrAl12O19:M3+ (M = Pr,Cr). AB - In order to evaluate the possibility of using Cr3+ co-doping to modify the emission properties of Pr3+-based quantum cutting phosphors, which emit one ultraviolet (UV) and one visible photon from each vacuum-UV photon absorbed, into phosphors that emit two visible photons, the optical spectroscopies between 150 and 750 nm of CaAl12O19:M3+ (M = Pr,Cr) were investigated and compared with those of SrAl12O19:M3+ using synchrotron radiation as one of the excitation sources. When Pr3+ is excited to its 4f5d states, cascade emission of UV photons from the 1S0 state followed by visible photons from the 3P0 state are both observed in (Ca,Sr)Al12O19:Pr3+. Similar to SrAl12O19:M3+, there exist desirable spectral overlaps between Pr3+ 1S0 emissions and the Cr3+ higher multiplet absorptions in CaAl12O19, which should be favourable to the energy transfer from Pr3+ 1S0 to Cr3+, converting the UV photon from Pr3+ 1S0 into the red Cr3+ emission. However, the host absorption band and the Cr3+-related charge transfer band have an unfavourable overlap with the Pr3+ 4f5d states in the vacuum-UV region, preventing efficient selective Pr3+ excitation under radiation of Xe discharge, a prerequisite for the quantum cutting process. PMID- 22251592 TI - The effect of magnetic field on a nonballistic spin field effect transistor. AB - A spin field effect transistor (FET) made of a nonballistic quantum wire with a single transport channel is considered in the presence of a magnetic field. The magnetic field includes either the externally applied field or the stray field due to ferromagnetic contacts used as injector and collector. When a magnetic field is applied the conductance fluctuations alter the spin precession and moreover spin flip occurs if the magnetic field is perpendicular to the Rashba field. Necessary conditions for a successful spin FET operation is obtained in the presence of a magnetic field. PMID- 22251593 TI - Aluminium-induced nanocrystalline Ge formation at low temperatures. AB - The present work contributes to establishing the role of hydrogenation and of the substrates in the aluminium-induced crystallization process of amorphous germanium layers. For such a purpose, four series of a-Ge(Al) samples, deposited under identical nominal conditions, were studied: hydrogenated samples, H-free samples, and samples deposited on crystalline silicon and on glass substrates, respectively. On purpose, the impurity concentration was kept at a doping level (10-5<[Al/Ge]<2 * 10-3). Furthermore, the films were submitted to isochronal cumulative thermal annealing in the 200-550 degrees C range. Raman scattering spectroscopy was used to characterize the crystallization process. The role of Al impurity as a precursor seed for the crystallization of a-Ge:H has been clearly established, confirming that the metal-induced crystallization (MIC) phenomenon occurs at an atomic level. Moreover, it has been found that hydrogenation and the periodic nature of the substrate play a fundamental role in the appearance of crystal seeds at low temperatures. The evolution of crystallization with annealing temperature and the analysis of the distribution of crystallite sizes indicate that the formation of crystal seeds occurs at the amorphous film substrate interface. The importance of fourfold-coordinated aluminium as the embryo of nanocrystal formation is discussed. PMID- 22251594 TI - Thermal and non-thermal photoinduced phenomena in alpha'-NaV2O5. AB - Transient reflectance changes induced by pulsed photo-excitation with 1.55 and 3.1 eV photons were studied in sodium vanadate, alpha'-NaV2O5. At low excitation densities, the response shows a slow rising with a time constant of 3 ps, while at higher excitation density, the rising becomes fast with a time constant of 500 fs. Oscillation in reflectance was also observed and ascribed to an acoustic phonon burst. The transient spectra were compared to the temperature difference reflectance spectra, and the photocreated states are understood as the high temperature state of the high-temperature phase. On the other hand, the fast rising components are ascribed to non-thermal creation of the charge-disordered phase. PMID- 22251595 TI - Metamaterials at zero frequency. AB - We investigate the problem of designing metamaterial structures which operate at very low frequencies. As an example, we consider the case of a DC magnetic cloak, which requires a variable, anisotropic magnetic permeability with both paramagnetic and diamagnetic components. We show that a structure based on superconducting components is the key to diamagnetism at low frequencies, and present a metamaterial design which meets the requirements of the cloak. PMID- 22251596 TI - Structural, electronic and vibrational properties of small Ga(x)N(y) (x+y = 2-5) nanoclusters: a B3LYP-DFT study. AB - An ab initio study of the stability, structural and electronic properties has been made for 49 gallium nitride nanoclusters, Ga(x)N(y) (x+y = 2-5). Among the various configurations corresponding to a fixed x+y = n value, the configuration possessing the maximum value of binding energy (BE) is named as the most stable structure. The vibrational and optical properties have been investigated only for the most stable structures. A B3LYP-DFT/6-311G(3df) method has been employed to optimize the geometries of the nanoclusters fully. The binding energies (BEs), highest-occupied and lowest-unoccupied molecular orbital (HOMO-LUMO) gaps and the bond lengths have been obtained for all the clusters. We have considered the zero point energy (ZPE) corrections ignored by the earlier workers. The adiabatic and vertical ionization potentials (IPs) and electron affinities (EAs), charge on atoms, dipole moments, vibrational frequencies, infrared intensities (IR Int.), relative infrared intensities (Rel. IR Int.) and Raman scattering activities have been investigated for the most stable structures. The configurations containing the N atoms in majority are seen to be the most stable structures. The strong N-N bond has an important role in stabilizing the clusters. For clusters containing one Ga atom and all the others as N atoms, the BE increases monotonically with the number of the N atoms. The HOMO-LUMO gap and IP fluctuate with the cluster size n, having larger values for the clusters containing odd number of N atoms. On the other hand, the EA decreases with the cluster size up to n = 3, and shows slow fluctuations thereafter for the larger clusters. In general, the adiabatic IP (EA) is smaller (greater) than the vertical IP (EA) because of the lower energies of the most stable ground state of the cationic (anionic) clusters. The optical absorption spectrum or electron energy loss spectrum (EELS) is unique for every cluster, and may be used to characterize a specific cluster. All the predicted physical quantities are in good agreement with the experimental data wherever available. The growth of these most stable structures should be possible in experiments. PMID- 22251597 TI - NMR and spin relaxation in systems with magnetic nanoparticles. AB - The 1H NMR spectra and spin dynamics of the host systems have been studied in liquid and solid suspensions of gamma-Fe2O3 nanoparticles. Significant broadening of 1H NMR spectra and growing relaxation rates were observed with increased concentration of nanoparticles in the liquid systems, with the relation T1/T2 depending on the particular host. Solid systems demonstrate inhomogeneous broadening of the spectra and practically no dependence of T1 upon the nanoparticle concentration. We explain the experimental results taking into account the predomination of self-diffusion as a source of the relaxation in liquid suspensions, and estimate effective parameters of relaxation in the systems under study. PMID- 22251598 TI - Spectral properties of rotating electrons in quantum dots and their relation to quantum Hall liquids. AB - The exact diagonalization technique is used to study many-particle properties of interacting electrons with spin, confined in a two-dimensional harmonic potential. The single-particle basis is limited to the lowest Landau level. The results are analysed as a function of the total angular momentum of the system. Only at angular momenta corresponding to the filling factors 1, 1/3, 1/5, etc is the system fully polarized. The lowest energy states exhibit spin waves, domains, and localization, depending on the angular momentum. Vortices exist only at excited polarized states. The high angular momentum limit shows localization of electrons and separation of the charge and spin excitations. PMID- 22251599 TI - Crystalline electric field effects in the filled skutterudite compound PrOs4P12. AB - The filled skutterudite compound PrOs4P12 was synthesized in single-crystal form using a molten metal flux growth technique. Low-temperature magnetization, specific heat, and electrical resistivity measurements showed no indication of a phase transition down to 0.1 K but had features indicative of crystalline electric field (CEF) effects. Analyses of these features in terms of a cubic CEF suggest a Gamma1 singlet or a Gamma3 doublet ground state separated by 30-50 K from a Gamma5 triplet first excited state. PMID- 22251600 TI - Structure and magnetic properties of RE4CoCd and RE4RhCd (RE = Tb, Dy, Ho). AB - New rare earth metal rich cadmium compounds RE4CoCd and RE4RhCd (RE = Tb, Dy, Ho) were prepared by high-frequency melting of the elements in sealed tantalum tubes. The samples were studied by x-ray powder and single-crystal diffraction. All the compounds crystallize with Gd4RhIn-type structure, with space group [Formula: see text]. The structures are built up from rigid three-dimensional networks of condensed, cobalt (rhodium) centred trigonal RE6 prisms. The voids left by these networks are filled by Cd4 cluster units and the coordination number 14 polyhedra of the RE1 atoms. The terbium and dysprosium compounds in both series undergo antiferromagnetic ordering, whereas the holmium compounds exhibit ferromagnetic ordering. The magnetic ordering in these compounds is characterized by broad peaks around the transition temperatures. The results of detailed crystallographic investigations and preliminary magnetic and specific heat studies are presented and discussed in this work. PMID- 22251601 TI - Cation occupancies in Mg, Co, Ni, Zn, Al ferrite spinels: a multi-element EXAFS study. AB - The distribution of cations between tetrahedral (A) sites and octahedral (B) sites in ferrite spinels has been studied using K-edge x-ray absorption spectroscopy. The samples include natural and synthetic end-member magnetites (Fe3O4), a natural Mn- and Zn-rich magnetite (franklinite) and synthetic binary, ternary and quaternary ferrites of stoichiometry M(2+)M2(3+)O4, where M(2+) = Mg, Co, Ni, Zn and M(3+) = Fe, Al. XAS data were obtained for all metals. Complete, unfiltered, EXAFS spectra were refined to determine the percentage distribution of each element over the A and B sites and these data were combined with microprobe analyses to quantify the tetrahedral occupancy for each element in each sample. Measured site occupancies and an internally consistent set of (M O)(A) and (M-O)(B) bond lengths were used to calculate unit-cell parameters, which show excellent agreement with measured values, pointing to the reliability of the measured occupancy factors. The average occupancies determined for the tetrahedral sites in ferrites are (atoms per formula unit) Mg 0.44, Co 0.24, Ni 0.11, Zn 0.76, Al 0.11 and Fe(3+) 0.92-0.19. The wide range found for Fe(3+) is consistent with it playing a relatively passive role by making good any A-site deficit left by the other competing cations. PMID- 22251602 TI - Post-annealing effect on the electronic structure of Mn atoms in Ga(1-x)Mn(x)As probed by resonant inelastic x-ray scattering. AB - The electronic structure of as-grown and post-annealed Ga(1-x)Mn(x)As epilayers (x~0.055) has been investigated using resonant inelastic x-ray scattering. Mn L2,3 x-ray emission spectra show that the integral intensity ratio of Mn L2 to L3 emission lines increases with annealing temperature and comes close to that of manganese oxide. The oxygen K-emission/absorption spectra of post-annealed Ga0.945Mn0.055As show 1.5-3.0 times higher degree of oxidation on the film surface than that of the as-grown sample. These experimental findings are attributed to the diffusion of Mn impurity atoms from interstitial positions in the GaAs host lattice to the surface where they are passivated by oxygen. PMID- 22251603 TI - Severe food insecurity is associated with obesity among Brazilian adolescent females. AB - OBJECTIVE: To determine whether household food insecurity (HFI) is associated with a higher prevalence of excessive weight (EW) in a large random sample of Brazilian female adolescents. DESIGN: Nationally representative cross-sectional study. EW was the outcome variable (BMI >= 85th percentile of WHO reference for adolescents aged 15-18 years and BMI >= 25 kg/m(2) for those aged 19 years). HFI was measured with the Brazilian Food Insecurity Scale. Associations were measured using crude and adjusted prevalence ratios (PR) with 95 % confidence intervals through Poisson regression models taking into account the complex sampling design. SETTING: Data were derived from the third wave of the Demographic and Health Survey conducted in 2006-2007, in Brazil. SUBJECTS: The sample included 1529 female adolescents aged 15-19 years. RESULTS: The prevalence of any level of HFI was 40.8 %, with 26.6 % of households experiencing mild, 9.4 % moderate and 4.8 % severe food insecurity. The overall prevalence of EW was 21.9 % (12.9 % were overweight and 9.0 % obese). EW prevalence among those living in severely, moderately and mildly food-insecure households was 36.8 %, 14.9 % and 16.5 %, respectively (P for the overall association = 0.036). Women living in severely food-insecure households had an increased prevalence of EW compared with their food-secure counterparts (PR = 1.96; 95 % CI 1.18, 3.27; P = 0.007), after adjusting for important confounders. CONCLUSIONS: The study suggests that severe but not mild or moderate HFI is independently associated with EW among adolescents residing in Brazil, a middle-income country undergoing the nutrition transition. PMID- 22251604 TI - Immunoproteomics based identification of thioredoxin reductase GliT and novel Aspergillus fumigatus antigens for serologic diagnosis of invasive aspergillosis. AB - BACKGROUND: There has been a rising incidence of invasive aspergillosis (IA) in critically ill patients, even in the absence of an apparent predisposing immunodeficiency. The diagnosis of IA is difficult because clinical signs are not sensitive and specific, and serum galactomannan has relatively low sensitivity in this group of patients. Therefore, more prompt and accurate disease markers for early diagnosis are needed. To establish disease markers demands a thorough knowledge of fungal antigens which may be detected in the serum or other body fluids of patients. Herein we report novel immunodominant antigens identified from extracellular proteins of Aspergillus fumigatus. RESULTS: Extracellular proteins of A. fumigatus were separated by two-dimensional electrophoresis (2-DE) and probed with the sera from critically ill patients with proven IA. The immunoreactive protein spots were identified by MALDI-TOF mass spectrometry (MALDI-TOF -MS). Forty spots from 2DE gels were detected and 17 different proteins were identified as immunogenic in humans. Function annotation revealed that most of these proteins were metabolic enzymes involved in carbohydrate, fatty acid, amino acid, and energy metabolism. One of the proteins, thioredoxin reductase GliT (TR), which showed the best immunoactivity, was analyzed further for secretory signals, protein localization, and homology. The results indicated that TR is a secretory protein with a signal sequence exhibiting a high probability for secretion. Furthermore, TR did not match any human proteins, and had low homology with most other fungi. The recombinant TR was recognized by the sera of all proven IA patients with different underlying diseases in this study. CONCLUSIONS: The immunoreactive proteins identified in this study may be helpful for the diagnosis of IA in critically ill patients. Our results indicate that TR and other immunodominant antigens have potential as biomarkers for the serologic diagnosis of invasive aspergillosis. PMID- 22251606 TI - A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. AB - Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated. Accordingly, the current study evaluated the ability of five different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production after 4 and 24 h stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-alpha and NO production. We then investigated whether these effects might involve either beta-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling is involved in regulating the anti-inflammatory response. These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties. PMID- 22251605 TI - Serum sTNF-R1, IL-6, and the development of fatigue in patients with gastrointestinal cancer undergoing chemoradiation therapy. AB - Although evidence of inflammation and fatigue has been noted in cancer survivors, whether inflammation is linked to the expression of fatigue and other symptoms arising from concurrent chemoradiation therapy (CXRT) has not been well studied. Patients undergoing CXRT for locally advanced colorectal or esophageal cancer (n=103) reported multiple symptoms weekly via the M. D. Anderson Symptom Inventory (MDASI) from start of therapy. Serum samples were collected weekly to examine changes in inflammatory markers (interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist (IL-1RA), vascular endothelial growth factor (VEGF), and soluble receptor 1 for tumor necrosis factor (sTNF-R1)) via enzyme-linked immunosorbent assay. Relationships between symptom severity and inflammatory marker concentration levels were estimated using mixed-effect regression analysis, controlled for week of therapy, age, sex, body mass index, pre-CXRT tumor stage, pre-CXRT chemotherapy, pre-CXRT statin use, and type of cancer. Fatigue was the most severe symptom over time, its development profile shared with pain, distress, drowsiness, poor appetite, and disturbed sleep. sTNF-R1 and IL-6 shared a similar pattern of symptom development, with significant increase during CXRT and decrease after completion of CXRT. Serum concentrations of sTNF R1 were positively associated over time with the severity of fatigue (p=0.00097), while sTNF-R1 and IL-6 were positively related to the severity of a component score of the six most severe symptoms (both p<0.0001). This longitudinal study suggests a role for over-expressed sTNF-R1 and IL-6 in the development of fatigue and other severe sickness symptoms during CXRT in patients with colorectal or esophageal cancer. PMID- 22251607 TI - Post-transfusion survival of biotin-labeled allogeneic RBCs in adult horses. AB - BACKGROUND: Post-transfusion survival of allogeneic RBCs has been reported to be much shorter in horses than in other species. We hypothesized that post transfusion survival of biotinylated allogeneic equine RBCs would be greater than the survival previously reported from studies using radioactive RBC-labeling techniques. OBJECTIVE: The study objective was to determine post-transfusion survival of N-hydroxysuccinimide (NHS)-biotin-labeled allogeneic equine RBCs transfused into adult horses. METHODS: Horses were adults and included 5 donors and 5 recipients. All horses were blood-typed, and donors were paired with recipients based upon blood type and crossmatch results. Donor blood was collected in a volume of 4 L into citrate phosphate dextrose adenine-1 and stored for 24 hours, labeled with NHS-biotin, and re-infused into recipients. Post transfusion blood samples were collected at 15 minutes and at 1, 2, 3, 5, 7, 14, 21, 28, and 35 days. Biotin-labeled RBCs were detected by flow cytometry using streptavidin-phycoerythrin. Post-transfusion survival at 24 hours, lifespan, and half-life of biotinylated RBCs were determined. RESULTS: Mean +/- SD survival of biotinylated RBCs at 24 hours post-transfusion was 95 +/- 24%; the mean lifespan of transfused allogeneic RBCs was 39 days based on calculation of a linear regression survival curve, and mean post-transfusion RBC half-life was 20 days. CONCLUSIONS: Post-transfusion survival of 24-hour stored equine allogeneic RBCs was greater than previously reported but less than that observed for other companion animal species. Mechanisms for the relatively short post-transfusion lifespan of allogeneic equine RBCs remain unknown and warrant further study. PMID- 22251608 TI - Reliability, comparative validity and stability of dietary patterns derived from an FFQ in the Tehran Lipid and Glucose Study. AB - The aim of the present study was to assess the reliability, comparative validity and stability of dietary patterns defined by factor analysis for participants of the Tehran Lipid and Glucose Study. A total of 132 subjects, aged >= 20 years, completed a 168-item FFQ (FFQ1, FFQ2) twice, with a 14-month interval. Over this duration, twelve dietary recalls (DR) were collected each month. To assess the stability of the FFQ, participants completed the third FFQ (FFQ3) after 8 years. Following these, two dietary patterns--the 'Iranian Traditional' and the 'Western'--were derived from FFQ1 and FFQ2 and the mean of DR (mDR); and three dietary patterns were identified from FFQ3: the 'Iranian Traditional', the 'Western' and the 'Combined'. The reliability correlations between factor scores of the two FFQ were 0.72 for the Iranian Traditional and 0.80 for the Western pattern; corrected month-to-month variations of DR correlations between the FFQ2 and mDR were 0.48 for the first and 0.75 for the second pattern. The 95 % limits of agreement for the difference between factor scores obtained from FFQ2 and mDR lay between -1.58 and +1.58 for the Iranian Traditional and between -1.33 and +1.33 for the Western pattern. The intra-class correlations between FFQ2 and FFQ3 were -0.09 (P = 0.653) and 0.49 (P <0.001) for the 'Iranian Traditional' and the 'Western', respectively. These data indicate reasonable reliability and validity of the dietary patterns defined by factor analysis. Although the Western pattern was found to be fairly stable, the Iranian Traditional pattern was mostly unstable over the 8 years of the study period. PMID- 22251611 TI - Absolute and relative quantification of placenta-specific micrornas in maternal circulation with placental insufficiency-related complications. AB - Placental insufficiency-related complications are one of the leading causes of maternal and perinatal morbidity and mortality. This study investigated the quantification of placenta-specific microRNAs (miRNAs) in the maternal circulation during gestation in a cohort of women with normally progressing pregnancies, the differentiation between placental insufficiency-related complications and normally progressing pregnancies, and the differentiation between placental insufficiency and normally progressing pregnancies during the early stages of gestation. Both absolute and relative quantification of placenta specific miRNAs (ie, miR-516-5p, miR-517*, miR-518b, miR-520a*, miR-520h, miR 525, and miR-526a) was determined in 50 women with normally progressing pregnancies, 32 with complicated pregnancies [21 with preeclampsia with or without intrauterine growth retardation (IUGR) and 11 with IUGR], and 7 women with pregnancies at various gestational stages who later developed preeclampsia and/or IUGR using real-time PCR and a comparative C(T) method relative to normalization factor (ie, geometric mean of ubiquitous miR-16 and let-7d). Both quantification approaches revealed significant increases in extracellular placenta-specific miRNA levels over time in women with normally progressing pregnancies; however, they were not able to differentiate between normally progressing and complicated pregnancies at the time of preeclampsia and/or IUGR onset. Nevertheless, significant elevation of extracellular miRNA levels was observed during early gestation (ie, within the 12th to 16th weeks) in pregnancies with later onset of preeclampsia and/or IUGR. Early gestation extracellular miRNA screening can differentiate between women with normally progressing pregnancies and those who may later develop placental insufficiency related complications. PMID- 22251609 TI - Detection of hypermethylated vimentin in urine of patients with colorectal cancer. AB - We demonstrated previously that urine contains low-molecular-weight (LMW) (<300 bp), circulation-derived DNA that can be used to detect cancer-specific mutations if a tumor is present. The goal of this study was to develop an assay to detect the colorectal cancer (CRC)-associated, circulation-derived, epigenetic DNA marker hypermethylated vimentin gene (mVIM) in the urine of patients with CRC. An artificial 18-nucleotide DNA sequence was tagged at the 5' end of the primers of the first PCR cycle to increase the amplicon size, which was then integrated into the primers of the second PCR cycle. A quantitative MethyLight PCR-based assay targeting a 39-nucleotide template was developed and used to quantify mVIM in CRC tissues and matched urine samples. mVIM was detected in 75% of LMW urine DNA samples from patients with CRC (n = 20) and in 10% of urine samples of control subjects with no known neoplasia (n = 20); 12 of 17 LMW urine DNA samples (71%) but only 2 of 17 high-molecular-weight urine DNA samples (12%) from patients with mVIM-positive tissues contained detectable mVIM, suggesting that the mVIM detected in LMW urine DNA is derived from the circulation. The detection of mVIM in urine was significantly associated with CRC compared with controls (P < 0.0001, by Fisher's exact test). A potential urine test for CRC screening using epigenetic markers is discussed. PMID- 22251610 TI - Stability of PCR targets for monitoring minimal residual disease in neuroblastoma. AB - In neuroblastoma (NB) patients, minimal residual disease (MRD) can be detected by real-time quantitative PCR (qPCR) using NB-specific target genes, such as PHOX2B and TH. However, it is unknown whether the mRNA levels of these targets vary either during treatment or at relapse. If marker genes are not stably expressed, estimation of MRD levels in bone marrow (BM) or peripheral blood will be hampered. We studied the stability of a panel of qPCR markers in primary tumors at diagnosis compared with i) paired metastasis (n = 7), ii) treated (n = 10), and iii) relapse (n = 6) tumors. We also compared relative expression of the targets in iv) primary tumors and BM at diagnosis (n = 17), v) BM and peripheral blood at diagnosis (n = 20), vi) BM at diagnosis and during treatment (n = 26), and vii) BM from different puncture sides (n = 110). Especially at diagnosis, PCR target expression is quite stable. Accurate quantification is possible when expression level can be related to the primary tumor; however, PCR target expression can alter on treatment and at relapse. If the median value of relative expression of a panel of PCR targets is used, most variations due to treatment and outgrowth of subclones level out, allowing for reliable application and quantification of MRD-PCR targets in NB patients. PMID- 22251612 TI - Implications for powering biomarker discovery studies. AB - This study examined variations in gene expression between FFPE blocks within tumors of individual patients. Microarray data were used to measure tumor heterogeneity within and between patients and disease states. Data were used to determine the number of samples needed to power biomarker discovery studies. Bias and variation in gene expression were assessed at the intrapatient and interpatient levels and between adenocarcinoma and squamous samples. A mixed model analysis of variance was fitted to gene expression data and model signatures to assess the statistical significance of observed variations within and between samples and disease states. Sample size analysis, adjusted for sample heterogeneity, was used to determine the number of samples required to support biomarker discovery studies. Variation in gene expression was observed between blocks taken from a single patient. However, this variation was considerably less than differences between histological characteristics. This degree of block-to block variation still permits biomarker discovery using either macrodissected tumors or whole FFPE sections, provided that intratumor heterogeneity is taken into account. Failure to consider intratumor heterogeneity may result in underpowered biomarker studies that may result in either the generation of longer gene signatures or the inability to identify a viable biomarker. Moreover, the results of this study indicate that a single biopsy sample is suitable for applying a biomarker in non-small-cell lung cancer. PMID- 22251613 TI - On the correlation between fragility and stretching in glass-forming liquids. AB - We study the pressure and temperature dependences of the dielectric relaxation of two molecular glass-forming liquids, dibutyl phthalate and m-toluidine. We focus on two characteristics of the slowing down of relaxation, the fragility associated with the temperature dependence and the stretching characterizing the relaxation function. We combine our data with data from the literature to revisit the proposed correlation between these two quantities. We do this in light of constraints that we suggest to put on the search for empirical correlations among properties of glass-formers. In particular, we argue that a meaningful correlation is to be looked for between stretching and isochoric fragility, as both seem to be constant under isochronic conditions and thereby reflect the intrinsic effect of temperature. PMID- 22251614 TI - Mortality among adults: gender and socioeconomic differences in a Brazilian city. AB - BACKGROUND: Population groups living in deprived areas are more exposed to several risk factors for diseases and injuries and die prematurely when compared with their better-off counterparts. The strength and patterning of the relationships between socioeconomic status and mortality differ depending on age, gender, and diseases or injuries. The objective of this study was to identify the magnitude of social differences in mortality among adult residents in a city of one million people in Southeastern Brazil in 2004-2008. METHODS: Forty-nine health care unit areas were classified into three homogeneous strata using 2000 Census small-area socioeconomic indicators. Mortality rates by age group, sex, and cause of death were calculated for each socioeconomic stratum. Mortality rate ratios (RR) and 95% confidence intervals were estimated for the low and middle socioeconomic strata compared with the high stratum. RESULTS: In general, age specific mortality rates showed a social gradient of increasing risks of death with decreasing socioeconomic status. The highest mortality rate ratios between low and high strata were observed in the 30-39 age group for males (RR = 1.74, 95% CI 1.59-1.89), and females (RR = 1.90, 95% CI 1.65-2.15). Concerning specific diseases and injuries, the greatest inequalities between low and high strata were found for homicides (RR = 2.44, 95% CI 2.27-2.61) and traffic accidents (RR = 1.64, 95% CI 1.45-1.83) among males. For women, the highest inequalities between the low and high strata were for chronic respiratory diseases (RR = 2.19, 95% CI 1.94-2.45) and acute myocardial infarction (RR = 1.93, 95% CI 1.79-2.07). Only breast cancer showed a reversed social gradient (RR = 0.70, 95% CI 0.48-0.92). Inequalities in circulatory and respiratory diseases mortality were greater among females than among males. CONCLUSIONS: Substandard living conditions are related to unhealthy behaviors, as well as difficulties in accessing health care. Therefore, the Brazilian Health System (SUS) must ensure greater access to primary and hospital care, and develop programs that promote healthier lifestyles among vulnerable groups to reduce social inequalities in mortality. Moreover, because deaths from external causes are concentrated in poor areas, cooperative and coordinated intersectoral actions should be taken to combat the deadly violence cycle. PMID- 22251615 TI - Tibolone increases bone mineral density but also relapse in breast cancer survivors: LIBERATE trial bone substudy. AB - INTRODUCTION: The Livial Intervention Following Breast Cancer: Efficacy, Recurrence and Tolerability Endpoints (LIBERATE: Clinical http://Trials.gov number NCT00408863), a randomized, placebo-controlled, double-blind trial that demonstrated that tibolone (Livial), a tissue-selective hormone-replacement therapy (HRT), increased breast cancer (BC) recurrence HR 1.40 (95% CI, 1.14 to 1.70; P = 0.001). A subgroup of women was entered into a study of bone mineral density (BMD). METHODS: Women with surgically excised primary BC (T1-3, N0-2, M 0) within the last 5 years, complaining of vasomotor symptoms, were assigned to tibolone, 2.5 mg daily, or placebo treatment for a maximum of 5 years. The BMD substudy enrolled 763 patients, using dual-energy X-ray absorptiometry (DXA) scanning at baseline and at 2 years. RESULTS: In the bone substudy, 699 of 763 women were eligible (345 allocated to tibolone, and 354, to placebo). After undergoing DXA scans, 300 (43%) women had normal BMD; 317 (45%), osteopenia; and 82 (11.7%), osteoporosis. Low body-mass index (P < 0.001), Asian race (P < 0.001), and late age at menarche (P < 0.04) predicted low bone mass at baseline. Tibolone increased BMD by 3.2% at the lumbar spine and 2.9% at the hip compared with placebo (both P < 0.001). The majority of fractures (55%) occurred in osteopenic patients. Women with normal BMD had increased recurrence with tibolone, 22 (15.6%) of 141 compared with placebo, 11 (6.9%) of 159 (P = 0.016), whereas no increased BC recurrence was seen in women with low BMD; 15 (7.4%) of 204 taking tibolone versus 13 (6.7%) of 195 taking placebo. CONCLUSIONS: Tibolone is contraindicated after BC treatment, as it increases BMD and BC recurrence. Risk of BC recurrence was elevated in BC women with normal BMD (compared with low) who took tibolone. PMID- 22251616 TI - Dominance of multidrug resistant CC271 clones in macrolide-resistant streptococcus pneumoniae in Arizona. AB - BACKGROUND: Rates of resistance to macrolide antibiotics in Streptococcus pneumoniae are rising around the world due to the spread of mobile genetic elements harboring mef(E) and erm(B) genes and post-vaccine clonal expansion of strains that carry them. RESULTS: Characterization of 592 clinical isolates collected in Arizona over a 10 year period shows 23.6% are macrolide resistant. The largest portion of the macrolide-resistant population, 52%, is dual mef(E)/erm(B)-positive. All dual-positive isolates are multidrug-resistant clonal lineages of Taiwan19F-14, mostly multilocus sequence type 320, carrying the recently described transposon Tn2010. The remainder of the macrolide resistant S. pneumoniae collection includes 31% mef(E)-positive, and 9% erm(B)-positive strains. CONCLUSIONS: The dual-positive, multidrug-resistant S. pneumoniae clones have likely expanded by switching to non-vaccine serotypes after the heptavalent pneumococcal conjugate vaccine release, and their success limits therapy options. This upsurge could have a considerable clinical impact in Arizona. PMID- 22251617 TI - Barium proctography vs magnetic resonance proctography for pelvic floor disorders: a comparative study. AB - AIM: Accurate and reliable imaging of pelvic floor dynamics is important for tailoring treatment in pelvic floor disorders; however, two imaging modalities are available. Barium proctography (BaP) is widely used, but involves a significant radiation dose. Magnetic resonance (MR) proctography allows visualization of all pelvic midline structures but patients are supine. This project investigates whether there are measurable differences between BaP and MR proctography. Patient preference for the tests was also investigated. METHODS: Consecutive patients referred for BaP were invited to participate (National Research Ethics Service approved). Participants underwent BaP in Poole and MR proctography in Dorchester. Proctograms were reported by a consultant radiologist with pelvic floor subspecialization. RESULTS: A total of 71 patients were recruited. Both tests were carried out on 42 patients. Complete rectal emptying was observed in 29% (12/42) on BaP and in 2% (1/42) on MR proctography. Anismus was reported in 29% (12/42) on BaP and 43% (18/42) on MR proctography. MR proctography missed 31% (11/35) of rectal intussusception detected on BaP. In 10 of these cases no rectal evacuation was achieved during MR proctography. The measure of agreement between grade of rectal intussusception was fair (kappa=0.260) although MR proctography tended to underestimate the grade. Rectoceles were extremely common but clinically relevant differences in size were evident. Patients reported that they found MR proctography less embarrassing but harder to empty their bowel. CONCLUSIONS: The results demonstrate that MR proctography under-reports pelvic floor abnormalities especially where there has been poor rectal evacuation. PMID- 22251618 TI - Back-reactions, short-circuits, leaks and other energy wasteful reactions in biological electron transfer: redox tuning to survive life in O(2). AB - The energy-converting redox enzymes perform productive reactions efficiently despite the involvement of high energy intermediates in their catalytic cycles. This is achieved by kinetic control: with forward reactions being faster than competing, energy-wasteful reactions. This requires appropriate cofactor spacing, driving forces and reorganizational energies. These features evolved in ancestral enzymes in a low O(2) environment. When O(2) appeared, energy-converting enzymes had to deal with its troublesome chemistry. Various protective mechanisms duly evolved that are not directly related to the enzymes' principal redox roles. These protective mechanisms involve fine-tuning of reduction potentials, switching of pathways and the use of short circuits, back-reactions and side paths, all of which compromise efficiency. This energetic loss is worth it since it minimises damage from reactive derivatives of O(2) and thus gives the organism a better chance of survival. We examine photosynthetic reaction centres, bc(1) and b(6)f complexes from this view point. In particular, the evolution of the heterodimeric PSI from its homodimeric ancestors is explained as providing a protective back-reaction pathway. This "sacrifice-of-efficiency-for-protection" concept should be generally applicable to bioenergetic enzymes in aerobic environments. PMID- 22251619 TI - Distribution of SCCmec-associated phenol-soluble modulin in staphylococci. AB - The recently described phenol-soluble modulin PSM-mec was detected in Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus fleuretti, Staphylococcus hominis, Staphylococcus pseudintermedius, Staphylococcus saprophyticus, Staphylococcus simulans and Staphylococcus vitulinus from different hosts (humans, goats, dogs, cats, pigs, cattle and turkeys). It was identified in isolates harbouring SCCmec types II, IIA, IIB, IID, III, VIII and in some irregular or truncated elements. PMID- 22251620 TI - Anti-inflammatory effects of resveratrol occur via inhibition of lipopolysaccharide-induced NF-kappaB activation in Caco-2 and SW480 human colon cancer cells. AB - Resveratrol, a polyphenol abundantly found in grapes and red wine, exhibits beneficial health effects due to its anti-inflammatory properties. In the present study, we evaluated the effect of resveratrol on inflammatory responses induced by lipopolysaccharide (LPS) treatment of human intestinal Caco-2 and SW480 cell lines. In the LPS-treated intestinal cells, resveratrol dose-dependently inhibited the expression of inducible NO synthase (iNOS) mRNA as well as protein expression, resulting in a decreased production of NO. In addition, Toll-like receptor-4 expression was significantly diminished in LPS-stimulated cells after resveratrol pre-treatment. To investigate the mechanisms by which resveratrol reduces NO production and iNOS expression, we examined the activation of inhibitor of kappaB (IkappaB) in LPS-stimulated intestinal cells. Results demonstrated that resveratrol inhibited the phosphorylation, as well as the degradation, of the IkappaB complex. Overall, these results show that resveratrol is able to reduce LPS-induced inflammatory responses by intestinal cells, interfering with the activation of NF-kappaB-dependent molecular mechanisms. PMID- 22251621 TI - Comparison of noninvasive photodynamic therapy dosimetry methods using a dynamic model of ALA-PDT of human skin. AB - A numerical model of ALA photodynamic therapy of human skin was used to calculate photosensitizer fluorescence and singlet-oxygen luminescence (SOL) observable at the skin surface during treatment. From the emissions, three practical dose metrics were calculated: the fractional fluorescence bleaching metric (FFBM) given by F(0)/F, where F is photosensitizer protoporphyrin IX (PpIX) fluorescence and F(0) is its initial value, the absolute fluorescence bleaching metric (AFBM) given by F(0)-F, and the cumulative SOL (CSOL). These three metrics can be measured during clinical PDT treatment, but their relation to actual singlet oxygen distribution in the skin is complex and may depend on treatment parameters such as irradiance. Using the model, the three metrics were compared to the average singlet-oxygen dose in the dermis. Despite the complex dependence of (1)O(2) concentration on depth, a roughly linear correlation was found for all three dose metrics. The correlation for the FFBM was not robust when treatment parameters were varied and this metric was especially sensitive to the initial PpIX concentration and its depth dependence. The AFBM was less sensitive to treatment conditions but CSOL demonstrated the best overall performance. PMID- 22251622 TI - Substance abuse treatment client experience in an employed population: results of a client survey. AB - BACKGROUND: Understanding client perspectives on treatment is increasingly recognized as key to improving care. Yet information on the perceptions and experiences of workers with private insurance coverage who receive help for substance use conditions is relatively sparse, particularly in managed behavioral health care organization (MBHO) populations. Furthermore, the role of several factors including prior service use has not been fully explored. METHODS: Employees covered by a large MBHO who had received substance abuse services in the past year were surveyed (146 respondents completed the telephone survey and self-reported service use). RESULTS: The most common reasons for entering treatment were problems with health; home, family or friends; or work. Prior treatment users reported more reasons for entering treatment and more substance use-related work impairment. The majority of all respondents felt treatment helped a lot or some. One quarter reported getting less treatment than they felt they needed. DISCUSSION AND CONCLUSIONS: Study findings point to the need to tailor treatment for prior service users and to recognize the role of work in treatment entry and outcomes. Perceived access issues may be present even among insured clients already in treatment. PMID- 22251624 TI - Melting of cubic boron nitride at extreme pressures. AB - Due to its large pressure range of stability and inert nature, cubic boron nitride has been proposed as a potential pressure standard for high pressure experiments. It is extremely refractive upon compression, although its melting temperature is not known beyond 10 GPa. We apply first-principles molecular dynamics to evaluate the thermodynamics of zincblende structured (cubic) and liquid boron nitride at extreme temperatures and pressures, and compute the melting curve up to 1 TPa by integration of the Clapeyron equation. The resulting equations of state reveal that liquid boron nitride becomes denser than the solid phase at pressures of around 0.5 TPa. This is expressed as a turnover in the melting curve, which reaches a maximum at 510 GPa and 6550 +/- 700 K. The origin of this density crossover is explained in terms of the underlying liquid structure, which diverges from that of the zincblende structured solid as the phases are compressed. PMID- 22251623 TI - Differential changes in gene expression in rainbow trout hepatocytes exposed to extracts of oil sands process-affected water and the Athabasca River. AB - The oil sands region of northern Alberta represents the world's largest reserves of bitumen, and the accelerated pace of industrial extraction activity has raised concern about the possible impacts on the Athabasca River and its tributaries. An ecotoxicogenomic study was undertaken on Oncorhynchus mykiss trout hepatocytes exposed to extracts of water samples near the oil sand development area, as well as to oil sands process-affected water (OSPW) extracts using the quantitative reverse transcriptase polymerase chain reaction technique. The expression of the following genes (mRNA) was monitored to track changes in xenobiotic biotransformation (CYP1A1, CYP3A4, glutathione S-transferase, multi-drug resistance transporter), estrogenicity (estrogen receptor and vitellogenin), oxidative stress (superoxide dismutase and metallothionein) and DNA repair activity (DNA ligase). The extent of DNA-aromatic hydrocarbon adducts was also determined in cells by immuno-staining. A comparative analysis of gene expression between the river/lake and OSPW samples revealed that CYP3A4, metallothioneins, DNA ligase and GST genes, were specifically expressed by OSPW. Cells exposed to OSPW, commercial naphthenic acids, and benzo(a)pyrene showed increased polyaromatic hydrocarbon DNA-adducts, as determined by cell immunofluorescence analysis. Other genes were induced by all types of water samples, although the induction potential was stronger in OSPW most of the time (e.g., VTG gene was expressed nearly 15-fold by surface waters from the lake and river samples but increased to a maximum of 31-fold in OSPW). A multivariate discriminant function analysis revealed that the lake and river water samples were well discriminated from the OSPW. The CYP3A4 gene was the most highly expressed gene in cells exposed to OSPW and responded less to the lake or river water in the Athabasca River area. This study identified a suite of gene targets that responded specifically to OSPW extracts, which could serve as toxicogenomic fingerprints of OSPW contamination. PMID- 22251625 TI - Household secondhand smoke exposure of elementary schoolchildren in Southern Taiwan and factors associated with their confidence in avoiding exposure: a cross sectional study. AB - BACKGROUND: Exposure to household Secondhand Smoke (SHS) poses a major health threat to children after an indoor smoking ban was imposed in Taiwan. This study aimed to assess the household SHS exposure in elementary school children in southern Taiwan and the factors associated with their avoidance of SHS exposure before and after the implementation of Taiwan's new Tobacco Hazards Prevention Act in 2009. METHODS: In this cross-sectional school-based study, data on household SHS exposure, avoidance of SHS and related variables was obtained from the 2008 and 2009 Control of School-aged Children Smoking Study Survey. A random sample of 52 elementary schools was included. A total of 4450 3-6 graders (aged 8 13) completed the questionnaire. Regression models analyzed factors of children's self-confidence to avoid household SHS exposure. RESULTS: Over 50% of children were found to have lived with a family member who smoked in front of them after the new law enacted, and 35% of them were exposed to household SHS more than 4 days a week. Having a positive attitude toward smoking (beta = -0.05 to -0.06) and high household SHS exposure (beta = -0.34 to -0.47) were significantly associated with a lower avoidance of SHS exposure. Comparing to girls, boys had lower scores in their knowledge of tobacco hazards; and this factor was significantly related to their SHS avoidance (beta = 0.13-0.14). CONCLUSIONS: The intervention program should enhance school children do actively avoid exposure to SHS in home settings, and more importantly, provide tobacco hazard knowledge to male students to avoid exposure to household SHS for themselves. The results also provide further evidence that Tobacco Hazards Prevention Act should perhaps be extended to the family environment in order to protect children from the hazards of household SHS exposure. PMID- 22251626 TI - MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7. AB - INTRODUCTION: C-C chemokine receptor type 7 (CCR7) plays an important role in chemotactic and metastatic responses in various cancers, including breast cancer. In the present study, the authors demonstrated that microRNA (miRNA) let-7a downregulates CCR7 expression and directly influences the migration and invasion of breast cancer cells. METHODS: The expression of CCR7, its ligand CCL21, and let-7a was detected in breast cancer cell lines and in breast cancer patient tissues. Synthetic let-7a and an inhibitor of let-7a were transfected into MDA-MB 231 and MCF-7 breast cancer cells, respectively, and cell proliferation, cell migration, and invasion assays were performed. To confirm the fact that 3'UTR of CCR7 is a direct target of let-7a, a luciferase assay for the reporter gene expressing the let-7a binding sites of CCR7 3'UTR was used. An in vivo invasion animal model system using transparent zebrafish embryos was also established to determine the let-7a effect on breast cancer cell invasion. RESULTS: First, a higher expression of both CCR7 and CCL21 in malignant tissues than in their normal counterparts from breast cancer patients was observed. In addition, a reverse correlation in the expression of CCR7 and let-7a in breast cancer cell lines and breast cancer patient tissues was detected. Synthetic let-7a decreased breast cancer cell proliferation, migration, and invasion, as well as CCR7 protein expression in MDA-MB-231 cells. The let-7a inhibitor reversed the let-7a effects on the MCF-7 cells. The 3'UTR of CCR7 was confirmed as a direct target of let-7a by using the luciferase assay for the reporter gene expressing let-7a CCR7 3'UTR binding sites. Notably, when analyzing in vivo invasion, MDA-MB 231 cells after synthetic let-7a transfection were unable to invade the vessels in zebrafish embryos. CONCLUSIONS: The results from the present study suggest that targeting of CCL21-CCR7 signaling is a valid approach for breast cancer therapy and that let-7a directly binds to the 3'UTR of CCR7 and blocks its protein expression, thereby suppressing migration and invasion of human breast cancer cells. Furthermore, the present study underscores the therapeutic potential of let-7a as an antitumor and antimetastatic manager in breast cancer patients. PMID- 22251628 TI - Projecting insect voltinism under high and low greenhouse gas emission conditions. AB - We develop individual-based Monte Carlo methods to explore how climate change can alter insect voltinism under varying greenhouse gas emissions scenarios by using input distributions of diapause termination or spring emergence, development rate, and diapause initiation, linked to daily temperature and photoperiod. We show concurrence of these projections with a field dataset, and then explore changes in grape berry moth, Paralobesia viteana (Clemens), voltinism that may occur with climate projections developed from the average of three climate models using two different future emissions scenarios from the International Panel of Climate Change (IPCC). Based on historical climate data from 1960 to 2008, and projected downscaled climate data until 2099 under both high (A1fi) and low (B1) greenhouse gas emission scenarios, we used concepts of P. viteana biology to estimate distributions of individuals entering successive generations per year. Under the low emissions scenario, we observed an earlier emergence from diapause and a shift in mean voltinism from 2.8 to 3.1 generations per year, with a fraction of the population achieving a fourth generation. Under the high emissions scenario, up to 3.6 mean generations per year were projected by the end of this century, with a very small fraction of the population achieving a fifth generation. Changes in voltinism in this and other species in response to climate change likely will cause significant economic and ecological impacts, and the methods presented here can be readily adapted to other species for which the input distributions are reasonably approximated. PMID- 22251627 TI - Integration of gene-based markers in a pearl millet genetic map for identification of candidate genes underlying drought tolerance quantitative trait loci. AB - BACKGROUND: Identification of genes underlying drought tolerance (DT) quantitative trait loci (QTLs) will facilitate understanding of molecular mechanisms of drought tolerance, and also will accelerate genetic improvement of pearl millet through marker-assisted selection. We report a map based on genes with assigned functional roles in plant adaptation to drought and other abiotic stresses and demonstrate its use in identifying candidate genes underlying a major DT-QTL. RESULTS: Seventy five single nucleotide polymorphism (SNP) and conserved intron spanning primer (CISP) markers were developed from available expressed sequence tags (ESTs) using four genotypes, H 77/833-2, PRLT 2/89-33, ICMR 01029 and ICMR 01004, representing parents of two mapping populations. A total of 228 SNPs were obtained from 30.5 kb sequenced region resulting in a SNP frequency of 1/134 bp. The positions of major pearl millet linkage group (LG) 2 DT-QTLs (reported from crosses H 77/833-2 * PRLT 2/89-33 and 841B * 863B) were added to the present consensus function map which identified 18 genes, coding for PSI reaction center subunit III, PHYC, actin, alanine glyoxylate aminotransferase, uridylate kinase, acyl-CoA oxidase, dipeptidyl peptidase IV, MADS-box, serine/threonine protein kinase, ubiquitin conjugating enzyme, zinc finger C- * 8-C * 5-C * 3-H type, Hd3, acetyl CoA carboxylase, chlorophyll a/b binding protein, photolyase, protein phosphatase1 regulatory subunit SDS22 and two hypothetical proteins, co-mapping in this DT-QTL interval. Many of these candidate genes were found to have significant association with QTLs of grain yield, flowering time and leaf rolling under drought stress conditions. CONCLUSIONS: We have exploited available pearl millet EST sequences to generate a mapped resource of seventy five new gene-based markers for pearl millet and demonstrated its use in identifying candidate genes underlying a major DT-QTL in this species. The reported gene-based markers represent an important resource for identification of candidate genes for other mapped abiotic stress QTLs in pearl millet. They also provide a resource for initiating association studies using candidate genes and also for comparing the structure and function of distantly related plant genomes such as other Poaceae members. PMID- 22251629 TI - Regulation of migration in Mythimna separata (Walker) in China: a review integrating environmental, physiological, hormonal, genetic, and molecular factors. AB - Each year the Mythimna separate (Walker), undertakes a seasonal, long-distance, multigeneration roundtrip migration between southern and northern China. Despite its regularity, the decision to migrate is facultative, and is controlled by environmental, physiological, hormonal, genetic, and molecular factors. Migrants take off on days 1 or 2 after eclosion, although the preoviposition period lasts ~7 d. The trade-offs among the competing physiological demands of migration and reproduction are coordinated in M. separata by the "oogenesis-flight syndrome." Larvae that experience temperatures above or below certain thresholds accompanied by appropriate humidity, short photoperiod, poor nutrition, and moderate density tend to develop into migrants. However, there is a short window of sensitivity within 24 h after adult eclosion when migrants can be induced to switch to reproductive residents if they encounter extreme environmental factors including starvation, low temperature and long photoperiod. Juvenile hormone (JH) titer is low before migration but high titers are associated with termination of migratory behavior and the switch to reproduction. Early release of JH by the corpora allata in environmentally stressed 1-d old adults, otherwise destined by larval conditions to be migrants, switches them to residents. Offspring inherit parental additive genetic effects governing migratory behavior. However, they also retain flexibility in expression of both flight and reproductive life history traits. The insect neuropeptide, allatotropin, which activates corpora allata to synthesize JH, controls adult flight and reproduction. Future research directions to better understand regulation of migration in this species are discussed. PMID- 22251630 TI - Between a rock and a hard place: impact of nest selection behavior on the altitudinal range of an alpine ant, Formica neorufibarbis. AB - Formica neorufibarbis Emery is a dominant alpine ant in North America. Above timberline, colonies nest under rocks, placing brood against the rock surface to warm during the day. We tested the hypothesis that nest rock preference represents a mechanism of behavioral thermoregulation and used a demographic model to explore its impact on the species' altitudinal range. Under sunny conditions rocks provide warm microclimates. Across a 400-m altitudinal gradient from below timberline to high alpine tundra, nest rocks warmed on average 5 degrees C above ambient at mid-day, but cooled to near ambient before dawn. Soil was warmer at mid-day under rocks occupied by ants than under randomly chosen unoccupied rocks in the same area. Occupied nest rocks were painted white or black to manipulate temperature and test its impact on colony occupancy. In addition, black-painted and white-painted rocks of similar size were placed in the field to test for a temperature effect on nest site colonization. Likelihood of nest persistence and colonization decreased under cooler, white-painted rocks and depended strongly on rock warming capacity. Experimental results showed that nest site colonization and occupancy are favored in microsites maintaining mid day temperature >=22 degrees C. Across the altitudinal gradient, 66-90% of nest microsites occupied by F. neorufibarbis met this temperature threshold. Conversely, none of the exposed microsites and only 15% of those microsites under randomly selected rocks warmed to 22 degrees C at the high altitude site (3,900 m). Results support the conclusion that nest site preference contributes to the broad altitudinal distribution of F. neorufibarbis. PMID- 22251631 TI - Populations of the northern grasshopper, Melanoplus borealis (Orthoptera: Acrididae), in Alaska are rarely food limited. AB - In some systems, grasshoppers appear to be food limited in most years, whereas in other systems top down forces, for example, predators, are more often implicated in population regulation. Sustainable strategies to manage grasshopper populations through habitat management require knowledge of the forces that regulate grasshopper populations. This experiment was undertaken to determine whether populations of Melanoplus borealis (Fieber), a common pest species in Alaska, are food-limited in Alaska. Cages were set up in a fallow field near Delta Junction, AK, in 3 yr (2007-2009). In 2007 and 2008, fertilizer was added to half the plots to increase primary production, and, in all years, cages within each plot were stocked with 0, 5, 9, or 13 fourth-instar M. borealis (equivalent to 0, 20, 36, or 52 grasshoppers/m(2)). Grasshoppers in each cage were counted weekly. Near the end of the growing season, surviving female grasshoppers (~40% of the original number) were collected. Femur length was taken as a measure of adult size, and functional ovarioles were counted as a measure of current fecundity. If the grasshoppers were food limited, we expected to see significant effects of either density or fertilizer on grasshopper survival, size, or fecundity. The fertilizer treatment greatly increased primary production in both years. Neither fertilizer treatment nor grasshopper density had consistent effects on survival, size, or potential fecundity, leading us to conclude that food is seldom limiting to populations in the interior of Alaska at densities <50 m(-2). PMID- 22251632 TI - Factors influencing the geographical distribution of Dendroctonus rhizophagus (Coleoptera: Curculionidae: Scolytinae) in the Sierra Madre Occidental, Mexico. AB - The bark beetle, Dendroctonus rhizophagus Thomas & Bright, is endemic to the Sierra Madre Occidental (SMOC) in Mexico. This bark beetle is a major pest of the seedlings and young saplings of several pine species that are of prime importance to the nation's forest industry. Despite the significance of this bark beetle as a pest, its biology, ecology, and distribution are poorly known. Three predictive modeling approaches were used as a first approximation to identify bioclimatic variables related to the presence of D. rhizophagus in the SMOC and to obtain maps of its potential distribution within the SMOC, which is a morphotectonic province. Our results suggest that the bark beetle could have an almost continuous distribution throughout the major mountain ranges of the SMOC. This beetle has a relatively narrow ecological niche with respect to some temperature and precipitation variables and inhabits areas with climatic conditions that are unique from those usually prevalent in the SMOC. However, the bark beetle has a broad ecological niche with respect to the number of hosts that it attacks. At the macro-scale level, the D. rhizophagus distribution occurs within the wider distribution of its main hosts. The limit of the geographical distribution of this bark beetle coincides with the maximum temperature isotherms. Our results imply a preference for temperate habitats, which leads to the hypothesis that even minor changes in climate may have significant effects on its distribution and abundance. PMID- 22251633 TI - The value of woody hedgerows for moth diversity on organic and conventional farms. AB - Habitat destruction and degradation are important drivers of biodiversity loss within agro-ecosystems. However, little is known about the effect of farming practices and the value of woody hedgerows on Lepidoptera in North America. The purpose of this work was to study moth diversity in woody hedgerows and croplands of organic and conventional farms. In addition, the influence of vegetation composition and abiotic variables on species richness, abundance, and composition was examined. Moths were sampled with light traps during six weeks in the summer of 2001. Vegetation data and abiotic variables were obtained for all sites. In total, 26,020 individuals from 12 families and 408 species were captured. Most species were uncommon. Only 35 species included >100 individuals while for 71% of species <10 individuals were found. The Noctuidae represented 221 species and 85% of all individuals captured. Woody hedgerows harbored more species and in greater number than croplands. There was no significant difference in moth diversity between organic and conventional farms, except that the Notodontidae were significantly more species rich in organic than in conventional sites. Results show that species richness, abundance, and composition were greatly influenced by habitat types (hedgerow versus crop field) and abiotic variables (minimum temperature which was correlated to moon illumination, rainfall, and cloud cover). Moth species composition was significantly correlated to vegetation composition. This study broadens our understanding of the factors driving moth diversity and expands our knowledge of their geographic range. The maintenance of noncrop habitats such as woody hedgerows within agro-ecosystems seems paramount to preserving the biodiversity and abundance of many organisms, including moths. PMID- 22251634 TI - Differential effects of weather and natural enemies on coexisting aphid populations. AB - Study of mechanisms responsible for regulating populations of living organisms is essential for a better comprehension of the structure of biological communities and evolutionary forces in nature. Aphids (Hemiptera: Sternorrhyncha) comprise a large and economically important group of phytophagous insects distributed worldwide. Previous studies determined that density-dependent mechanisms play an important role in regulating their populations. However, only a few of those studies identified specific factors responsible for the observed regulation. Time series data used in this study originated from the untreated control plots that were a part of potato (Solanum tuberosum L.) insecticide trials in northern Maine from 1971 to 2004. The data set contained information on population densities of three potato-colonizing aphid species (buckthorn aphid, Aphis nasturtii; potato aphid, Macrosiphum euphorbiae; and green peach aphid, Myzus persicae) and their natural enemies. We used path analysis to explore effects of weather and natural enemies on the intrinsic growth rates of aphid populations. Weather factors considered in our analyses contributed to the regulation of aphid populations, either directly or through natural enemies. However, direct weather effects were in most cases detectable only at P <= 0.10. Potato aphids were negatively affected by both fungal disease and predators, although buckthorn aphids were negatively affected by predators only. Parasitoids did not have a noticeable effect on the growth of any of the three aphid species. Growth of green peach aphid populations was negatively influenced by interspecific interactions with the other two aphid species. Differential population regulation mechanisms detected in the current study might at least partially explain coexistence of three ecologically similar aphid species sharing the same host plant. PMID- 22251635 TI - Cascading indirect effects in a coffee agroecosystem: effects of parasitic phorid flies on ants and the coffee berry borer in a high-shade and low-shade habitat. AB - Nonconsumptive effects (NCE) of parasites on hosts vary with habitat complexity thereby modifying trait-mediated effects on lower trophic levels. In coffee agroecosystems, Pseudacteon sp. phorid fly parasites negatively affect Azteca instabilis F. Smith ants via NCE thereby indirectly benefiting prey. It is unknown how differences in habitat complexity influence Azteca-phorid interactions or how phorids affect the coffee berry borer (Hypothenemus hampei Ferrari), an important pest of coffee (Coffea arabica L). We tested the following hypotheses in field and lab experiments to find the impact of NCE of phorids on A. instabilis and trait-mediated indirect effects of phorids on the coffee berry borer: (1) Phorid effects on A. instabilis differ between complex and simple shade habitats and (2) Phorids, by modifying A. instabilis behavior, indirectly affect coffee berry borer abilities to invade coffee berries. Phorids had greater impacts on A. instabilis activity in low-shade farms, but differences in phorid impacts were not mediated by phorid density or light availability. In the lab, phorids had strong cascading effects on abilities of A. instabilis to deter coffee berry borers. Without phorids, A. instabilis limited coffee berry borer attacks, whereas when the coffee berry borer was alone or with A. instabilis and phorids, more coffee fruits were attacked by coffee berry borer. These results indicate that A. instabilis has stronger biological control potential in high shade farms, but the exact mechanism deserves further attention. PMID- 22251636 TI - Association of Ovavesicula popilliae (Microsporida: Ovavesiculidae) with winter mortality of larvae and reduced fecundity of female Japanese beetles (Coleoptera: Scarabaeidae). AB - Populations of Japanese beetle at sites in Michigan where Ovavesicula popilliae (Andreadis) was introduced in 1999 and 2000 were compared with nearby control sites from fall of 2005 through spring of 2008. Percent infection by O. popilliae and winter mortality of Japanese beetle were determined by sampling larvae in October and April from 12 golf holes on six courses in southeast Michigan and eight holes on four courses in southwest Michigan. Adult Japanese beetles were also collected from these golf courses in July and August of 2007 to determine the impact of O. popilliae-infection on egg development in females. In southeast Michigan, O. popilliae appeared to spread rapidly from the 100 m(2) plots where it was previously introduced to surrounding golf course holes between 2000 and 2006. However, data from southwest Michigan suggests that O. popilliae had already been introduced into the area. Regression analysis of data from all 20 golf course holes gives a significant relationship between percent infection of larvae with O. popilliae and winter mortality of Japanese beetle. Mean winter mortality of larvae around golf course holes where <10% were infected with O. popilliae was 24.7% compared with 41.7% mortality where 10-30% were infected, and 72.0% mortality where >30% were infected. Females infected with O. popilliae contained 50% fewer mature eggs than uninfected females. In addition, females from golf courses where all of the fairways and roughs were treated annually with imidacloprid contained 48% fewer mature eggs than females from golf courses where insecticides were only used on the fairways or not at all. PMID- 22251637 TI - Effect of several different pollens on the bio-ecological parameters of the predatory mite Typhlodromus athenas Swirski and Ragusa (Acari: Phytoseiidae). AB - The development, survivorship, and reproduction of the predacious mite Typhlodromus athenas Swirski and Ragusa were studied in the laboratory by rearing the predator on nine different plant pollens [almond(Prunus amygdalis Batsch), apple (Malus domestica Borkh.), apricot (Prunus armeniaca L.), cherry (Prunus avium L.), pear (Pyrus communis L.), plum (Prunus domestica L.), walnut (Juglans regia L.), olive (Olea europaea L.), Typha sp.], and pollen collected from bee hives. All experiments were conducted in environmental chambers at 20 +/- 1 degrees C, 65% RH, and a photoperiod of 16:8 (L:D) h. Survival during immature development ranged from 81.1 to 96.0%. The shortest mean developmental time from egg to adult with respect to the range of pollen species was recorded for females and males fed on almond pollen (10.76 +/- 0.18 and 10.45 +/- 0.21 d, respectively), while the longest was on beehive pollen (26.97 +/- 0.23 and 24.00 +/- 0.25 d for females and males, respectively). Female longevity varied from 51.63 +/- 5.52 d (olive pollen) to 102.81 +/- 6.60 d (pear pollen), while fecundity ranged from 5.33 +/- 2.35 eggs per female (beehive pollen) to 26.43 +/ 1.73 eggs per female (almond pollen). The diet consisting of almond pollen resulted in the highest intrinsic rate of natural increase (r(m)) (1.00 d(-1)) and pollen collected from bee hives resulted in the lowest (0.013 d(-1)). These results showed that various pollen could favor the development of T. athenas, and also support the view that alternative food resources may play an important role in the field for sustaining and increasing the predator's population. PMID- 22251638 TI - Biology and host range of Tecmessa elegans (Lepidoptera: Notodontidae), a leaf feeding moth evaluated as a potential biological control agent for Schinus terebinthifolius (Sapindales: Anacardiaceae) in the United States. AB - During surveys for natural enemies that could be used as classical biological control agents of Schinus terebinthifolius Raddi (Brazilian pepper), the caterpillar, Tecmessa elegans Schaus (Lepidoptera: Notodontidae), was recorded feeding on the leaves of the shrub in South America. The biology and larval and adult host range of this species were examined to determine the insect's suitability for biological control of this invasive weed in North America and Hawaii. Biological observations indicate that the larvae have five instars. When disturbed, the late instar larvae emit formic acid from a prothoracic gland that may protect larvae from generalist predators. Larval host range tests conducted both in South and North America indicated that this species feeds and completes development primarily on members of the Anacardiaceae within the tribe Rhoeae. Oviposition tests indicated that when given a choice in large cages the adults will select the target weed over Pistacia spp. However, considering the many valued plant species in its host range, especially several North American natives, this species will not be considered further for biological control of S. terebinthifolius in North America. PMID- 22251639 TI - Pollination value of male bees: the specialist bee Peponapis pruinosa (Apidae) at summer squash (Cucurbita pepo). AB - Male bees can be abundant at flowers, particularly floral hosts of those bee species whose females are taxonomic pollen specialists (oligolecty). Contributions of male bees to host pollination are rarely studied directly despite their prevalence in a number of pollination guilds, including those of some crop plants. In this study, males of the oligolectic bee, Peponapis pruinosa Say, were shown to be effective pollinators of summer squash, Cucurbita pepo L. Seven sequential visits from male P. pruinosa maximized squash fruit set and growth. This number of male visits accumulated during the first hour of their foraging and mate searching at flowers soon after sunrise. Pollination efficacy of male P. pruinosa and their abundances at squash flowers were sufficient to account for most summer squash production at our study sites, and by extrapolation, to two-thirds of all 87 North American farms and market gardens growing squashes that were surveyed for pollinators by collaborators in the Squash Pollinators of the Americas Survey. We posit that the substantial pollination value of male Peponapis bees is a consequence of their species' oligolecty, their mate seeking strategy, and some extreme traits of Cucurbita flowers (massive rewards, flower size, phenology). PMID- 22251640 TI - Forested landscapes promote richness and abundance of native bees (Hymenoptera: Apoidea: Anthophila) in Wisconsin apple orchards. AB - Wild bees provide vital pollination services for many native and agricultural plant species, yet the landscape conditions needed to support wild bee populations are not well understood or appreciated. We assessed the influence of landscape composition on bee abundance and species richness in apple (Malus spp.) orchards of northeastern Wisconsin during the spring flowering period. A diverse community of bee species occurs in these apple orchards, dominated by wild bees in the families Andrenidae and Halictidae and the honey bee, Apis mellifera L. Proportion of forest area in the surrounding landscape was a significant positive predictor of wild bee abundance in orchards, with strongest effects at a GIS (Geographic Information Systems) buffer distance of 1,000 m or greater. Forest area also was positively associated with species richness, showing strongest effects at a buffer distance of 2,000 m. Nonagricultural developed land (homes, lawns, etcetera) was significantly negatively associated with species richness at buffer distances >750 m and wild bee abundance in bowl traps at all distances. Other landscape variables statistically associated with species richness or abundance of wild bees included proportion area of pasture (positive) and proportion area of roads (negative). Forest area was not associated with honey bee abundance at any buffer distance. These results provide clear evidence that the landscape surrounding apple orchards, especially the proportion of forest area, affects richness and abundance of wild bees during the spring flowering period and should be a part of sustainable land management strategies in agro-ecosystems of northeastern Wisconsin and other apple growing regions. PMID- 22251641 TI - Field and vegetable crops as hosts of larval western spotted cucumber beetle (Coleoptera: Chrysomelidae). AB - The western spotted cucumber beetle, Diabrotica undecimpunctata undecimpunctata Mannerheim, is an important pest of melons (Cucurmis melo L.) in northern California. Recent observations indicate that adults are using alfalfa (Medicago sativa L.) as a feeding host and larvae may be developing on the roots. Greenhouse studies were conducted during the winters of 2009 and 2010 in which larval development was compared on the roots of six field and vegetable crops commonly grown in the southern Sacramento Valley. The growth parameters used to evaluate the hosts were larval and pupal head capsule width, body width, and body length as well as total survival percentage and survival percentage to the third instar. According to larval growth and survivorship in 2009, maize (Zea mays L.) was the best host, followed by alfalfa and tomato (Solanum lycopersicum L.) that were roughly equivalent to one another. Melon was a slightly weaker host than alfalfa and tomato; sunflower (Helianthus annuus L.) was a completely incompatible host and thus dropped from the 2010 study. In 2010, melon was the weakest host for larval development. Maize was the superior host again followed closely by alfalfa that performed slightly better than tomato and lima bean (Phaseolus lunatus L.). Data suggest that larval western spotted cucumber beetles may primarily develop outside of melon fields and the adults emigrate to melons. PMID- 22251642 TI - Endophyte-mediated resistance to black cutworm as a function of plant cultivar and endophyte strain in tall fescue. AB - To improve Neotyphodium endophyte-mediated resistance to black cutworm Agrotis ipsilon (Hufnagel) (BCW), a series of experiments was conducted by using several different cultivars of tall fescue, Schedonorus arundinaceus (Schreb.) Dumort. in combination with several different haplotypes of the endophyte Neotyphodium coenophialum (Morgan-Jones & Gams) (plant cultivar * endophyte haplotype = plant line), each producing unique alkaloid profiles. BCW settling response, survival at 5 and 10 d, and larval biomass varied significantly among plant lines. In general, greater variation BCW performance was observed within a single plant cultivar infected with different endophyte haplotypes than among different plant cultivars infected with the same endophyte haplotype, but comparisons among the former were far more numerous. Although five endophyte-mediated alkaloids representing three alkaloid classes were quantified in the plants, the pyrrolizidine alkaloid N-acetyl norloline was consistently the single best predictor of BCW performance. BCW settling response, 5-d survival, and 10-d survival decreased as levels of the alkaloid N-acetyl norloline increased. The same three response variables also decreased with increasing levels of peramine, but increased with increasing levels of ergovaline. Minor variation in endophyte infection levels occurring among infected plant lines had no significant influence on BCW performance. Results indicate a potentially important role for N-acetyl norloline and peramine in providing resistance to black cutworm whereas ergovaline appears to be much less important. Therefore, endophyte haplotypes expressing high levels of N-acetyl norloline and peramine may be of particular importance for developing 'friendly' endophyte-enhanced turf and pasture grasses that resist challenging lepidopteran pests, although remaining safe for wildlife and grazing mammals. PMID- 22251643 TI - Interspecific variation in resistance of Asian, European, and North American birches (Betula spp.) to bronze birch borer (Coleoptera: Buprestidae). AB - Bronze birch borer (Agrilus anxius Gory) is the key pest of birches (Betula spp.) in North America, several of which have been recommended for ornamental landscapes based on anecdotal reports of borer resistance that had not been confirmed experimentally. In a 20-yr common garden experiment initiated in 1979 in Ohio, North American birch species, including paper birch (Betula papyrifera Marshall), 'Whitespire' gray birch (Betula populifolia Marshall), and river birch (Betula nigra L.), were much more resistant to bronze birch borer than species indigenous to Europe and Asia, including European white birch (Betula pendula Roth), downy birch (Betula pubescens Ehrh.), monarch birch (Betula maximowicziana Regel), and Szechuan white birch (Betula szechuanica Jansson). Within 8 yr of planting, every European white, downy, and Szechuan birch had been colonized and killed, although 100% of monarch birch had been colonized and 88% of these plants were killed after nine years. Conversely, 97% of river birch, 76% of paper birch, and 73% Whitespire gray birch were alive 20 yr after planting, and river birch showed no evidence of colonization. This pattern is consistent with biogeographic theory of plant defense: North American birch species that share a coevolutionary history with bronze birch borer were much more resistant than naive hosts endemic to Europe and Asia, possibly by virtue of evolution of targeted defenses. This information suggests that if bronze birch borer were introduced to Europe or Asia, it could threaten its hosts there on a continental scale. This study also exposed limitations of anecdotal observation as evidence of host plant resistance. PMID- 22251644 TI - Spatial variability of western bean cutworm (Lepidoptera: Noctuidae) pheromone trap captures in sprinkler irrigated corn in eastern Colorado. AB - Strategies for controlling pests are an integral part of any agricultural management plan. Most field crops, such as wheat (Triticum spp.) and corn (Zea mays L.) are managed as if they are homogeneous units. However, pests within fields are rarely homogenous. Development of plans that use targeted pest control tactics requires knowledge of the ecological drivers of the pest species. That is, by understanding the spatio-temporal factors influencing pest populations, we can develop management strategy to prevent or reduce pest damage. This study was conducted to quantify variables influencing the spatial variability of adult male western bean cutworm, Striacosta albicosta (Smith). Striacosta albicosta moths were collected in pheromone traps in two center pivot, irrigated corn fields near Wiggins, CO. We hypothesized that moth abundance would be influenced by the distance from the edge of the field, distance to nearest alternative corn crop and affected by anisotropic effects, such as prevailing wind direction. Greater trap catches of S. albicosta in each of the fields were found with increased proximity to the edge of the field, if the nearest neighboring crop was corn. Prevailing wind direction and directional effects were found to influence abundance. Results serve as a first step toward building a precision pest management system for controlling S. albicosta. PMID- 22251645 TI - Direct sampling of resting codling moth (Lepidoptera: Tortricidae) adults in apple tree canopies and surrounding habitats. AB - Field investigations were conducted to determine the resting locations of codling moth (Cydia pomonella [L.]) (Lepidoptera: Tortricidae) males and females in mating disrupted and nondisrupted apple (Malus domestica Borkh.) orchard plots. A custom-made sampling device, consisting of a leaf blower converted into a powerful vacuum, yielded 20-24% success in recovering marked moths, released in the tree canopy in orchards. Four collections each were made between 0900 and 1800 hours and 1800 and 2200 hours in 2005. Ninety-four moths were collected during the 1800-2200 hours samples. In mating disruption plots, 42% of females and 22% of males were found in the top third of the tree canopy (3.0-4.5m), 46% females and 43% males in the middle third (1.5-3.0m), and 12% female and 35% male in the lower third (0-1.5m). In nondisrupted plots 36.4% of females and 40% of males were in the top third of the canopy, 36.4% females and 52% males in the middle third, and 27.2% females and 8% males in the lower third of the tree canopy. Daylight vacuum sampling recovered only one female and two male moths from the top, four males from the middle and one male from the lower third of the tree canopy. Release-recapture studies of marked adult codling moths were conducted in 2006-2007 in screened tents to determine within orchard habitats for adult moths during 0900-1800 hours. Of moths recaptured, 14.6% of females and 13.5% of males were from the ground (herbicide strip and drive-row grass) and 32.9% of females and 24.6% of males were captured in the tree canopy 16-h post release, 17.4% of females and 3.4% of males from the ground and 26.5% of females and 38.2% of males in the tree 40-h post release, and 15.1% of females and 18.6% of males from the ground and 15.7 of females and 25.5% of males in the tree 64-h post release. Application of pyrethrum + PBO by using an orchard blast sprayer in 2007 resulted in the recapture of 28% and 37% of laboratory reared male and female moths, respectively, from trees during 0900-1800 h. Our results suggest that distributing pheromone dispensers throughout the tree canopy may be more effective than placing them in one location, such as near the tree crown. PMID- 22251646 TI - Inhibition of microorganisms on a carrion breeding resource: the antimicrobial peptide activity of burying beetle (Coleoptera: Silphidae) oral and anal secretions. AB - Competition between scavengers and microorganisms for the nutrients within carrion is well documented. As a significant contributor to food web energetics, carrion serves not only as a food source for scavengers, but also as a reproductive resource for many insects. One example are the burying beetles of the Nicrophorus genus (Coleoptera: Silphidae) whose reproduction is dependent on locating and successfully sequestering vertebrate carrion. Throughout the cooperative preparation of carrion and feeding of the larval offspring, parental beetles coat the carrion with oral and anal secretions known to attenuate the growth of molds and bacteria in the laboratory. We test the hypotheses that Nicrophorus secretions attenuate the growth of naturally occurring microorganisms likely to be found colonizing the carrion resource, and that the active antimicrobial components of the secretions are small antimicrobial peptides (AMPs) similar to those produced by other insects. PMID- 22251647 TI - Detectability of the emerald ash borer (Coleoptera: Buprestidae) in asymptomatic urban trees by using branch samples. AB - The emerald ash borer, Agrilus planipennis Fairmaire, is an exotic invasive insect causing extensive mortality to ash trees, Fraxinus spp., in Canada and the United States. Detection of incipient populations of this pest is difficult because of its cryptic life stages and a multiyear time lag between initial attack and the appearance of signs or symptoms of infestation. We sampled branches from open-grown urban ash trees to develop a sample unit suitable for detecting low density A. planipennis infestation before any signs or symptoms are evident. The sample unit that maximized detection rates consisted of one 50-cm long piece from the base of a branch >=6 cm diameter in the midcrown. The optimal sample size was two such branches per tree. This sampling method detected ~75% of asymptomatic trees known to be infested by using more intensive sampling and ~3 times more trees than sampling one-fourth of the circumference of the trunk at breast height. The method is less conspicuous and esthetically damaging to a tree than the removal of bark from the main stem or the use of trap trees, and could be incorporated into routine sanitation or maintenance of city-owned trees to identify and delineate infested areas. This research indicates that branch sampling greatly reduces false negatives associated with visual surveys and window sampling at breast height. Detection of A. planipennis-infested asymptomatic trees through branch sampling in urban centers would provide landowners and urban foresters with more time to develop and implement management tactics. PMID- 22251648 TI - Spatial dependence, dispersion, and sequential sampling of Anaphothrips obscurus (Thysanoptera: Thripidae) in timothy. AB - The spatial distribution and dispersion of Anaphothrips obscurus (Muller) (Thysanoptera: Thripidae) was examined with the goal of establishing a sequential sampling plan for this pest in timothy, Phleum pratense L. (Poaceae). Approximately 16 different California timothy fields were sampled twice yearly from 2006 to 2008 using direct observation and the beat cup method. For direct observation, the number of thrips on each leaf of the plant was counted. For the beat cup method, tillers were tapped into a cup and dislodged thrips were counted. Samples were separated by ~3 m in 2006 and 2007 and exactly 3 m in 2008. Spatial autocorrelation of intrafield population distribution was tested for significance in 2008 using Moran's I, but autocorrelation was not detected. The population dispersion was assessed by Taylor's power law and was determined to be aggregated and density-dependent. Intraplant population dispersion and distribution for each year were also evaluated for adults, larvae, and total thrips. All lifestages were highly spatially dependent and more thrips were found near the top of the plant than the bottom. Direct observation proved to be a more accurate and precise method than the beat cup method, especially when thrips abundances were greater than one. However, the number of samples required to provide an accurate level of precision was unrealistic for both methods. A sequential sampling plan was evaluated, but was not practical for the beat cup method because few thrips were found using this method. Because there was no spatial autocorrelation at sampling distances of 3 m, samples can be taken at intervals at 3 m to obtain spatially independent population abundance estimates. PMID- 22251649 TI - Influence of native flowering plant strips on natural enemies and herbivores in adjacent blueberry fields. AB - Conservation plantings of native wildflowers were established adjacent to highbush blueberry (Vaccinium corymbosum L.) fields to test the hypothesis that provision of resources for natural enemies increases their abundance in adjacent crop fields without increasing the abundance of pest insects. For two growing seasons, natural enemies and herbivorous insects were sampled in fields with flowering borders and in control fields where growers maintained standard mown grass perimeters. Insects were categorized according to their trophic level and their potential pest status, and their abundance was compared between years and between treatments. Syrphid flies (Diptera: Syrphidae) were significantly more abundant in fields with conservation strips, as were plant bugs (Hemiptera: Miridae), thrips (Thysanoptera: Thripidae), and hoppers (Hemiptera: Auchenorrhyncha). Aphids (Hemiptera: Aphididae), thrips, fruit flies (Diptera: Tephritidae), and pirate bugs (Hemiptera: Anthocoridae) decreased significantly in abundance from 2007 to 2008. Beneficial insect abundance in crop fields increased in the latter half of the season in both years and this increase was more pronounced in fields adjacent to conservation plantings. We discuss the implications of these findings for pest management and conservation of biodiversity in farmland. PMID- 22251650 TI - Comparison of trapping for eggs, females, and males of the naval orangeworm (Lepidoptera: Pyralidae) in almonds. AB - The navel orangeworm is the primary insect pest of almonds in California, and egg traps are the primary means of monitoring this pest. A previous study found that the current use of 2-4 traps per 64 ha block usually is not sufficient to provide management information specifically for that block. In this study, we compare data from large grids of egg traps in varied commercial almond orchards with trapping data for females and males, with the objective of finding a more cost effective monitoring program using currently available attractants. The proportion of egg traps with eggs was highly correlated with mean eggs per egg trap, and with females and males trapped simultaneously at the same location. Almond variety and the type of bait used had little impact on the relationship between the proportion of egg traps with eggs and the number of eggs per traps. Traps in orchards with more unharvested (mummy) almonds had more eggs, suggesting that navel orangeworm abundance affected traps more than competition from mummies. Laboratory experiments comparing age-specific oviposition in two-choice and no-choice situations found that younger, more fecund females laid a greater proportion of eggs on the preferred substrate in a two-choice situation, but that age-specific fecundity was not different between substrates in no-choice tests. These findings indicate that the proportion of egg traps with eggs provides a more stable indication of navel orangeworm phenology than mean eggs per trap. We suggest that similar information could be obtained in a more cost-effective manner with female trapping. PMID- 22251651 TI - Contact sex pheromones identified for two species of longhorned beetles (Coleoptera: Cerambycidae) Tetropium fuscum and T. cinnamopterum in the subfamily Spondylidinae. AB - Male Tetropium fuscum (F.) and T. cinnamopterum Kirby mated with live and dead (freeze-killed) conspecific females upon antennal contact, but did not respond to dead females after cuticular waxes were removed by hexane rinsing. Significantly fewer males of each species attempted to copulate with live or dead heterospecific females than with conspecifics, indicating that mate recognition was mediated by species-specific contact sex pheromones in the female's cuticular hydrocarbons. GC/MS analysis of T. fuscum elytra identified n-alkanes and mono methyl branched alkanes of which 11-methylheptacosane and 3- and 5 methyltricosanes were dominant in females. Full male responses, including copulatory behavior, were restored with application of enantiomerically pure synthetic (S)-11-methyl-heptacosane at 40 MUg/female (one female equivalent) but not with racemic or (R)-11-methyl-heptacosane. The cuticular hydrocarbons on T. cinnamopterum elytra included 11-methyl-heptacosane as well as n-alkanes, methyl branched alkanes, mono-alkenes, and (Z, Z)-6, 9-alkadienes. (Z)-9-pentacosene, (Z)-9-heptacosene, and 11-methyl-heptacosane were female dominant, but only (Z)-9 pentacosene elicited precopulatory behaviors in conspecific males at levels similar to those behaviors elicited by unrinsed females, but elicited copulation in fewer than half of males. At female equivalent dosages (10 MUg), neither (Z)-9 heptacosene nor (S)-11-methyl- heptacosane elicited responses in males that were significantly different from those responses to a rinsed female but when applied together, the proportion of males responding was significantly increased. 11 methyl-heptacosene is thus a contact pheromone component common to both species, which may explain the heterospecific mating attempts by some males. PMID- 22251652 TI - A compound produced by fruigivorous Tephritidae (Diptera) larvae promotes oviposition behavior by the biological control agent Diachasmimorpha longicaudata (Hymenoptera: Braconidae). AB - Tephritid fruit fly parasitoids use fruit-derived chemical cues and the vibrations that result from larval movements to locate hosts sequestered inside fruit. However, compounds produced by the larvae themselves have not been previously described nor their significance to parasitoid foraging determined. We collected the volatiles from four species of tropical and subtropical Tephritidae: Anastrepha suspensa (Loew), Bactrocera dorsalis Hendel, Bactrocera cucurbitae Coquillett, and Ceratitis capitata (Wiedemann), representing two subfamilies (Dacinae and Trypetinae). Para-ethylacetophenone, an analog of a known tephritid parasitoid attractant, was a major constituent of all four, and was not associated with larvae of another acalypterate fly, Drosophila melanogaster Meigen, or with the calypterate Musca domestica L. It also was present in volatiles from whole, A. suspensa infested fruits of Eugenia uniflora (L.). Para-ethylacetophenone was not necessarily produced as a direct consequence of fruit consumption because it also was detected from larvae that developed in two artificial diets and in spent diets subsequent to larval development. Sensillae on both the antennae and ovipositor of the opiine braconid fruit fly parasitoid, Diachasmimorpha longicaudata (Ashmead) responded to the para ethylacetophenone in larval volatiles and as a synthetic. Although a potential cue to foraging parasitoids, para-ethylacetophenone showed no long range (>1m) attractiveness to the adult female parasitoid, but did stimulate ovipositor insertion and oviposition into both a natural (fruit) and an artificial (parafilm) substrate. Thus it may prove useful in colonizing and mass-rearing opine fruit fly parasitoids. PMID- 22251653 TI - Temperature influences the handling efficiency of an aphid parasitoid through body size-mediated effects. AB - It is well known that increasing the ambient temperature increases the metabolic rate and consequently, the foraging rate of most insects. However, temperature experienced during the immature stages of insects affects their adult size (an inverse relationship). Because body size is generally correlated to foraging success, we hypothesized that temperature indirectly influences the foraging efficiency of adult insects through developmental effects. We first investigated the role of parasitoid: host body size ratio on the handling time of Aphidius colemani (Viereck) (Hymenoptera: Braconidae), then tested the prediction that increasing temperature during immature development increases the handling time of adults. As expected, parasitoids took longer to handle large aphids than small aphids. However, large parasitoids did not have shorter handling times than small parasitoids except when attacking large (adult) aphids. Developmental temperature had the predicted effect on parasitoids: Individuals reared at 25 degrees C were smaller than those insects reared at 15 degrees C. Parasitoids reared at 15 degrees C had similar short handling times for both first instar and adult aphids, whereas parasitoids reared at 25 degrees C took longer to handle adult aphids than first instar aphids. The size-mediated effect of temperature through development on parasitoid efficiency was opposite to the more familiar direct effect of temperature through metabolic rate. We conclude that the net effect of temperature on foraging insects will depend on its relative influence on immature and adult stages. PMID- 22251654 TI - The impact of transgenic wheat expressing GNA (snowdrop lectin) on the aphids Sitobion avenae, Schizaphis graminum, and Rhopalosiphum padi. AB - This study investigated the impact of transgenic wheat expressing Galanthus nivalis agglutinin (GNA), commonly known as snowdrop lectin, on three wheat aphids: Sitobion avenae (F.), Schizaphis graminum (Rondani), and Rhopalosiphum padi (L.). We compared the feeding behavior and the life-table parameters of aphids reared on GNA transgenic wheat (test group) and those aphids reared on untransformed wheat (control group). The results showed that the feeding behaviors of S. avenae and S. graminum on GNA transgenic wheat were affected. Compared with the control group, they had shorter initial probing period, longer total nonprobing period, shorter initial and total phloem sap ingestion phase (waveform E2), shorter duration of sustained ingestion (E (pd) > 10 min), and lower percentage of phloem phase of the total observation time. Moreover, S. graminum made more probes and had a longer total duration of extracellular stylet pathway (waveform C). The fecundity and intrinsic rate of natural increase (r(m)) of S. avenae and S. graminum on the transgenic wheat were lowered in the first and second generations, however, the survival and lifespan were not affected. The effects of the GNA expressing wheat on S. graminum and S. avenae were not significant in the third generation, suggesting rapid adaptation by the two aphid species. Despite the impact we found on S. avenae and S. graminum, transgenic GNA expressing wheat did not have any effects on R. padi. PMID- 22251655 TI - Evaluating the non-rice host plant species of Sesamia inferens (Lepidoptera: Noctuidae) as natural refuges: resistance management of Bt rice. AB - Although rice (Oryza sativa L.) lines that express Bacillus thuringiensis (Bt) toxins have shown great potential for managing the major Lepidoptera pests of rice in southern China, including Sesamia inferens, their long-term use is dependent on managing resistance development to Bt toxins in pest populations. The maintenance of "natural" refuges, non-Bt expressing plants that are hosts for a target pest, has been proposed as a means to minimize the evolution of resistance to Bt toxins in transgenic plants. In the current study, field surveys and greenhouse experiments were conducted to identify host plants of S. inferens that could serve as "natural" refuges in rice growing areas of southern China. A field survey showed that 34 plant species in four families can be alternative host plants of S. inferens. Based on injury level under field conditions, rice (Oryza sativa L.); water oat (Zizania latifolia Griseb.); corn (Zea mays L.); tidalmarsh flatsedge (Cyperus serotinus Rottb.); and narrow-leaved cat-tail (Typha angustifolia Linn.) were identified as the primary host plant species of S. inferens. Greenhouse experiments further demonstrated that water oat, corn, and narrow-leaved cat-tail could support the survival and development of S. inferens. Interestingly, greenhouse experiments showed that S. inferens preferred to lay eggs on tidalmarsh flatsedge compared with the other three nonrice host species, although no pupae were found in the plants examined in field surveys. Few larvae were found to survive on tidalmarsh flatsedge in greenhouse bioassays, suggesting that tidalmarsh flatsedge could serve as a "dead-end" trap crop for S. inferens, but is not a candidate to serve as natural refuge to maintain susceptible S. inferens. Overall, these results suggest that water-oat, corn, and narrow-leaved cat-tail might serve as "natural refuge" for S. inferens in rice planting area of southern China when Bt rice varieties are planted. PMID- 22251656 TI - Reproductive, endocrine and metabolic feto-maternal features and placental gene expression in a swine breed with obesity/leptin resistance. AB - The current study was conducted in a swine breed (Iberian pig) with a genotype that predisposed the pig to obesity. The aim of the study was to determine the morphological, metabolomic and endocrine features of early conceptuses and to elucidate how placental gene expression (related to placentation, angiogenesis and fetal nutrition), maternal hormones and the metabolome affect the fetal environment and fetal growth. Conceptus viability and growth were found to be related to maternal endocrine (plasma progesterone levels) and metabolic features (plasma levels of leptin, cholesterol, HDL-c, LDL-c and triglycerides). These features were related to the placental expression of the vascular endothelial growth factor A (VEGFA) and leptin (LEP) genes, the placental efficiency and, thus, the nutrition and the metabolism of the fetus (availability of glucose, triglycerides and cholesterol, as HDL-c). Viability of conceptuses in females with evidence of dyslipidemia (low plasma levels of total cholesterol due to low HDL-c concentration but high levels of triglycerides) was diminished. The availability of nutrients and metabolic substrates to the conceptus was also affected in females with higher fat deposition and evidence of dyslipidemia. In conclusion, the conceptus viability and growth appear to be strongly related to maternal metabolic features and, thus, affected in females with alterations in lipid metabolism. PMID- 22251657 TI - Inclusion of celecoxib into fibrous ordered mesoporous carbon for enhanced oral bioavailability and reduced gastric irritancy. AB - Fibrous ordered mesoporous carbon (FOMC) was developed as a new drug delivery system for loading an insoluble drug, designed to be orally administered, and then to enhance the drug loading capacity, improve the dissolution rate, enhance the oral bioavailability and reduce the gastric damage. Celecoxib (CEL) was chosen as a model drug. The nanostructures and effect of different pore sizes (4.4-7.0 nm) on drug loading and release properties were studied. The results showed that FOMC has a high drug loading capacity (0.599 g/g, drug weight/carrier weight) and the dissolution rate of CEL from FOMC was much faster than pure crystalline CEL using buffer (pH 6.8) as a dissolution medium. Moreover, the oral bioavailability of CEL loaded into FOMC was significantly improved compared with that of CEL capsules and the gastric damage caused by CEL which was loaded in FOMC was also reduced, demonstrating the protective effect of FOMC. PMID- 22251658 TI - Brillouin zone unfolding of complex bands in a nearest neighbour tight binding scheme. AB - Complex bands k(?)(E) in a semiconductor crystal, along a general direction n, can be computed by casting Schrodinger's equation as a generalized polynomial eigenvalue problem. When working with primitive lattice vectors, the order of this eigenvalue problem can grow large for arbitrary n. It is, however, possible to always choose a set of non-primitive lattice vectors such that the eigenvalue problem is restricted to be quadratic. The complex bands so obtained need to be unfolded onto the primitive Brillouin zone. In this paper, we present a unified method to unfold real and complex bands. Our method ensures that the measure associated with the projections of the non-primary wavefunction onto all candidate primary wavefunctions is invariant with respect to the energy E. PMID- 22251659 TI - Dose-response effects of an antimicrobial peptide, a cecropin hybrid, on growth performance, nutrient utilisation, bacterial counts in the digesta and intestinal morphology in broilers. AB - The aim of the present study was to evaluate the feasibility of an antimicrobial peptide, cecropin A(1-11)-D(12-37)-Asn (CADN), as an alternative to antibiotic growth promoter (AGP) in poultry diets. A total of 1500 14-d-old indigenous male chickens (222 (sd 13) g) were randomly allocated to five groups with five replicate cages of sixty birds each, and fed ad libitum five grower diets and subsequently five finisher diets for 14 d each. The diets were made up by supplementing their basal diets with a CADN liquid sample (CADNL) at 0, 2, 4, 6 and 8 ml/kg, respectively. During the feeding period, a metabolic experiment was carried out to determine the apparent digestibility of diethyl ether extract, nitrogen retention and apparent metabolisable energy of the diet sample fed to each cage of chicks. At the end of the feeding experiment, one chick from each cage was killed for bacteriological, light microscopic and scanning electron microscopic examination of the intestinal villi. CADN had a negative linear, positive quadratic and negative linear effect on feed intake (F), weight gain (G) and feed:gain ratio (F:G), respectively, for the growers; it had a quadratic effect on F, G or F:G for the finishers; it increased nutrient utilisation for both growers and finishers; it decreased aerobic bacterial counts in both jejunal and caecal digesta in a dose-dependent manner; it enhanced intestinal villus heights in a dose-dependent manner and made the duodenum villi of the CADNL8 group at 42 d appear as a netted leaf-like structure. CADN is therefore a possible alternative to AGP in broiler feeds. PMID- 22251660 TI - A review of population-based prevalence studies of physical activity in adults in the Asia-Pacific region. AB - BACKGROUND: Physical activity (PA) surveillance is an important component of non communicable disease risk factor monitoring, and occurs through national and international surveillance systems. This review identifies population PA estimates for adults in the Asia-Pacific region, and examines variation in trends and prevalence rates obtained using different PA measures. METHODS: Data were obtained from a MEDLINE search; World Health Organization's Global Health Infobase; Government websites and reference lists of relevant papers. Inclusion criteria included: national studies or those reporting large scale population level data; data published from 2000 to 2010 and trend data prior; sample sizes over n = 1000, or fewer subjects in small nations. RESULTS: In total, 56 population surveys from 29 Asia-Pacific countries were identified. Data on 'sufficient physical activity' amongst adults were available from 45 studies (80%), with estimates ranging from 7% to 93% (median 62%, inter-quartile range 40%-85%). For 14 countries, estimates of 'sufficient activity' were documented in multiple surveys using different methods, with the largest variation from 18% to 92% in Nepal. Median or mean MET-minutes/day, reported in 20 studies, ranged from 6 to 1356. Serial trend data were available for 11 countries (22%), for periods spanning 2-10 years. Of these, five countries demonstrated increases in physical activity over time, four demonstrated decreases and three showed no changes. CONCLUSIONS: Many countries in the Asia-Pacific region collect population-level PA data. This review highlights differences in estimates within and between countries. Some differences may be real, others due to variation in the PA questions asked and survey methods used. Use of standardized protocols and measures, and combined reporting of data are essential goals of improved international PA surveillance. PMID- 22251661 TI - Preoperative muscle weakness as defined by handgrip strength and postoperative outcomes: a systematic review. AB - BACKGROUND: Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform "bedside" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery. METHODS: PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay. RESULTS: Nineteen clinical studies (17 prospective; 4 in urgent surgery) comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies). CONCLUSIONS: Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity. PMID- 22251662 TI - Selective binding of CD4 and CD8 T-cells to antigen presenting cells for enrichment of CMV and HIV specific T-lymphocytes. AB - Adherent antigen presenting cells (APC) pulsed with protein or peptide antigens were used to capture specific CD4 or CD8 T-cells derived from established T-cell lines or from PBMC of immune subjects based on physiological interaction between TCR and MHC-peptide complex. This method could be applied independently of epitope specificity, HLA restriction alleles, activation markers and secreted cytokines, parameters required by other methods for selection of specific T cells. Non specific T-cells were removed by applying a 1g force that did not affect binding of specific T-lymphocytes. Lymphocyte selection was specific and the average recovery was 36% for CD4 T-cells. CD8 T-cells proved trickier to purify, since solid phase APC were recognized as targets for cytotoxicity. Specificity was comparable to CD4 cells, but the average recovery for CD8 cells was 26%. No residual alloreactivity was detected in expanded T-cells. Frequency and recovery of specific T-cells were comparable to other current technologies, such as generation of T-cell lines and cytokine capture method. Since antigen and IL2 are the only reagents added to the cultures, this physiological procedure can be proposed for selection and expansion of pathogen specific T-cells not only for research purposes, but also for adoptive reconstitution of immunocompromised subjects if performed under GMP conditions. PMID- 22251663 TI - A new enzyme-linked immunosorbent assay recognizing both rat and human activated coagulation Factor XII (FXIIa). AB - We describe the first sandwich enzyme-linked immunosorbent assay (ELISA) capable of recognizing both rat and human activated coagulation Factor XII (FXIIa). Increased plasma concentrations of FXIIa have been associated with adverse outcomes in several cardiovascular disease states. In humans, the FXIIa antigen in plasma is quantified by a direct sandwich ELISA employing an antibody (mAb 2/215) raised against its beta-fragment (beta-FXIIa), but this assay is unable to detect rat beta-FXIIa antigen. Thus, experimental models are at present limited in their capacity to reveal mechanisms by which FXIIa might contribute to cardiovascular pathology. Consistent with overlap between human and rat FXIIa protein epitope sequences, Western blot analysis and ELISA demonstrate that another previously developed antibody against human FXIIa (mAb 201/9) detects beta-FXIIa in both human and rat plasma, with no evidence for cross-reactivity with the FXII zymogen or FXIIa complexed with its endogenous inhibitor. The mAb 201/9 based ELISA identified similar elevations in FXIIa in plasma from rats and humans with chronic renal failure. The capacity of this ELISA to identify rat plasma FXIIa has potential application to a wide range of experimental models of human cardiovascular disease. PMID- 22251664 TI - Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup. AB - INTRODUCTION: We recently found that platelet cytochrome c oxidase (COX) activities and quantities in 6-month-survival septic patients are significantly higher than those of patients who died before 6 months. Other studies suggested that the mitochondrial DNA (mtDNA) genotype could play a major role in sepsis survival. Given that COX catalytic subunits are encoded by mtDNA, the objective of the present study was to explore whether mtDNA population genetic variation could affect COX activity and quantity and favors sepsis survival. METHODS: A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints. RESULTS: Patients with the JT mtDNA haplogroup (n=15) showed higher COXq/CSa ratio at day 4 (P=0.04) and day 8 (P=0.02) than those with other haplogroups (n=81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio=0.18; 95% confidence interval=0.04 to 0.94; P=0.04) and COXq/CSa ratio (odds ratio=0.53; 95% confidence interval=0.30 to 0.93; P=0.03) were associated with 1-month survival after controlling for age and lactic acid levels. CONCLUSIONS: The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups. PMID- 22251665 TI - First principles study of phosphorus and boron substitutional defects in Si-XII. AB - We present a first principles study of boron and phosphorus substitutional defects in Si-XII. Recent results from nanoindentation experiments reveal that the Si-XII phase is semiconducting and has the interesting property that it can be doped n- and p-type at room temperature without an annealing step. Using the hybrid functional of Heyd, Scuseria and Ernzerhof (HSE), we examine the formation energies of the B and P defects at the two distinct atomic sites in Si-XII to find on which site the substitutional defects are more easily accommodated. We also estimate the thermodynamic transition levels of each defect in its relevant charge states. The hybrid calculations also give an independent prediction that Si-XII is semiconducting, in agreement with recent experimental data. PMID- 22251666 TI - Predictive value of positron emission tomography-computed tomography image fusion in the diagnosis of head and neck cancer: does it really improve staging and management? AB - AIMS: To determine (1) the accuracy of positron emission tomography - computed tomography in the diagnosis of head and neck cancer, (2) the learning curve involved, and (3) whether its use alters patient management. MATERIALS AND METHODS: A retrospective study including 80 patients with head and neck cancer who underwent positron emission tomography - computed tomography image fusion at Blackpool Victoria Hospital. RESULTS: Fifty-three patients underwent positron emission tomography - computed tomography for staging (32 for detection of a primary tumour and 21 for detection of distant metastasis) and 27 for detection of loco-regional recurrence. Ten primary tumours and 20 recurrences were accurately diagnosed by this method. Eighteen patients had their tumour stage and management modified as a result of this method of imaging. The effect of the learning curve resulted in better true positive detection rates, one year after introduction (81 versus 61 per cent). The sensitivity and specificity of this method in detecting head and neck cancer were 70 and 42 per cent, respectively, whereas those of conventional imaging were 73 and 51 per cent, respectively. CONCLUSION: Compared with magnetic resonance imaging, the benefits of positron emission tomography - computed tomography may be limited to diagnosis of recurrence, as it is less hindered by tissue fibrosis, radiotherapy-related oedema, scarring and inflammation. PMID- 22251668 TI - Performance characteristics of a novel megavoltage cone-beam-computed tomography device. AB - In this work, the image quality of a novel megavoltage cone-beam-computed tomography (CBCT) scanner is compared to three other image-guided radiation therapy devices by analysing images of different-sized quality assurance phantoms. The following devices are compared in terms of image uniformity, signal to-noise ratio, contrast-to-noise ratio (CNR), electron density to HU conversion, presampling modulation transfer function (MTF(pre)) and combined spatial resolution and noise (Q-factor): (i) the Siemens Artiste kilovoltage (kV) (121 kV) CBCT device, (ii) the Artiste treatment beam line (TBL), 6 MV, (iii) the Tomotherapy (3.5 MV) fan-beam CT and (iv) Siemens' novel approach using a carbon target for a dedicated imaging beam line (IBL), 4.2 MV. Machine settings were selected to produce the same imaging dose for all devices. For a head phantom, IBL scans display CNR values 2.6 +/- 0.3 times higher than for the TBL at the same dose level (for a CT-number range of -200 to -60 HU). kV CBCT, on the other hand, displays CNR values 7.9 +/- 0.3 times higher than the IBL. There was no significant deviation in spatial resolution between IBL, TBL and Tomotherapy in terms of 50% and 10% MTF(pre). For kV CBCT, the MTF(pre) was significantly higher than those for other devices. In our Q-factor analysis, the IBL (14.6) scores higher than the TBL (7.9) and Tomotherapy (9.7) due to its lower noise level. The linearity of electron density to HU conversion is demonstrated for different sized phantoms. Employing the IBL instead of the TBL significantly reduces the imaging dose by up to a factor of 5 at a constant image quality level, providing an immediate benefit for the patient. PMID- 22251667 TI - Type D personality is associated with impaired psychological status and unhealthy lifestyle in Icelandic cardiac patients: a cross-sectional study. AB - BACKGROUND: Type D (distressed) personality has been associated with adverse cardiac prognosis and poor emotional well-being in cardiac patients, but it is still unclear what mechanisms link Type D personality with poor clinical outcomes in cardiac patients. In the present cohort of Icelandic cardiac patients, we examined potential pathways that may explain this relationship. The objectives were to examine 1) the association between Type D personality and impaired psychological status, and to explore whether this association is independent of disease severity; and 2) the association between Type D personality and an unhealthy lifestyle. METHODS: A sample of 268 Icelandic coronary angiography patients (74% males (N = 199); mean age 62.9 years (SD 10.5), range 28-85 years) completed the Type D Scale (DS14), Hospital Anxiety and Depression Scale (HADS), and Perceived Stress Scale (PSS) at hospitalization. Health-related behaviors were assessed 4 months following angiography. Clinical data were collected from medical files. RESULTS: Type D personality was associated with an increased risk of anxiety (OR 2.97, 95% CI:1.55-5.69), depression (OR 4.01, 95% CI:1.42-11.29), and stress (OR 5.99, 95% CI:3.08-11.63), independent of demographic variables and disease severity. Furthermore, fish consumption was lower among Type Ds, as 21% of Type Ds versus 5% of non-Type Ds consumed fish < 1 a week (p < 0.001). Type D patients were also more likely to smoke at follow-up (22% versus 10%, p = 0.024) and to use antidepressants (17% versus 9%, p = 0.049) and sleeping pills (49% versus 33%, p = 0.019) compared to non-Type Ds. Type D personality was not associated with other health-related behaviors, aside from trends towards less fruit and vegetable consumption, and more weight gain. CONCLUSION: Type D personality was associated with psychological distress and an unhealthy lifestyle in Icelandic cardiac patients. Future studies should further investigate the association between Type D personality and health-related behaviors. PMID- 22251669 TI - Immediate occlusal loading of NanoTiteTM tapered implants: a prospective 1-year clinical and radiographic study. AB - BACKGROUND: During the last decade, high success rates have been reported for implants placed with immediate loading procedures, especially when bone quality and quantity provide good implant stability. In many of these studies, straight walled implants with moderately rough surfaces were employed. Tapered implants are becoming increasingly more popular due to standardized drilling protocols and reports of high initial primary stability. PURPOSE: The aim of the present prospective, single center clinical study was to evaluate surface topographical analysis and the clinical and radiographic outcomes of the NanoTiteTM (BIOMET 3i, Palm Beach Gardens, FL, USA) Tapered Implant when used for immediate loading of fixed prostheses and single-tooth restorations. MATERIALS AND METHODS: Forty-two patients who needed implant treatment and met admission criteria agreed to participate in the study and were consecutively enrolled. Surgical implant placement requirements consisted of a final torque of a least 30 Ncm prior to final seating and an implant stability quotient above 55. A total of 139 NanoTite Tapered implants (112 maxillary and 27 mandibular) were placed by one investigator, and the majority of these implants (n = 77/55%) were placed in posterior regions, and in soft bone (n = 90/65%). A total of 57 prosthetic constructions were evaluated consisting of 20 single-tooth restorations, 30 fixed partial dentures, and 7 complete, fixed maxillary restorations. Radiographs were taken at baseline and at 12 months of follow-up. RESULTS: Of the 139 study implants, one implant failure was declared. The overall cumulative survival rate at 1 year is 99.4%. Mean marginal bone resorption is 1.01 mm (SD 0.85) during the first year of function. CONCLUSION: Although limited to the short follow-up, immediate loading of NanoTite Tapered implants seems to be a viable option in implant rehabilitation, when insertion torque of at least 30 Ncm is achieved. Further studies are needed to authenticate the finding of this study. PMID- 22251670 TI - GDNF protects enteric glia from apoptosis: evidence for an autocrine loop. AB - BACKGROUND: Enteric glia cells (EGC) play an important role in the maintenance of intestinal mucosa integrity. During the course of acute Crohn's disease (CD), mucosal EGC progressively undergo apoptosis, though the mechanisms are largely unknown. We investigated the role of Glial-derived neurotrophic factor (GDNF) in the regulation of EGC apoptosis. METHODS: GDNF expression and EGC apoptosis were determined by immunofluorescence using specimen from CD patients. In primary rat EGC cultures, GDNF receptors were assessed by western blot and indirect immunofluorescence microscopy. Apoptosis in cultured EGC was induced by TNF-alpha and IFN-gamma, and the influence of GDNF on apoptosis was measured upon addition of GDNF or neutralizing anti-GDNF antibody. RESULTS: Increased GDNF expression and Caspase 3/7 activities were detected in in specimen of CD patients but not in healthy controls. Moreover, inactivation of GDNF sensitized in EGC cell to IFN gamma/TNF-alpha induced apoptosis. CONCLUSIONS: This study proposes the existence of an autocrine anti-apoptotic loop in EGC cells which is operative in Crohn's disease and dependent of GDNF. Alterations in this novel EGC self-protecting mechanism could lead to a higher susceptibility towards apoptosis and thus contribute to disruption of the mucosal integrity and severity of inflammation in CD. PMID- 22251672 TI - Scoliosis short-term rehabilitation (SSTR) according to 'Best Practice' standards are the results repeatable? AB - Claims have been made in a pilot study that a new form of short-term rehabilitation according to 'Best Practice' standards would change signs and symptoms of patients with scoliosis in the short-term. Aim of this study is to repeat the study published 2010 with a larger sample of patients using the same protocol. Both authors have undergone training in this special approach to scoliosis rehabilitation in 2010. MATERIALS AND METHODS: 34 patients with Adolescent Idiopathic Scoliosis (AIS), 32 girls and 2 boys, average age 13.7 years and an average Cobb angle of 28.7 degrees (21-43 degrees) underwent Scoliosis Short-Term Rehabilitation (SSTR) of seven days. Two days with an intensity of 3 * 90 min sessions/day, and five days with an intensity of 2 * 60 min sessions/day. Angle of trunk rotation (ATR) was measured before and after the time of treatment as well as the active correctability of the ATR after the programme as it has been done in the pilot investigation. Additionally to that, we also recorded the changes in Vital Capacity (VC) before and after the programme. RESULTS: ATR was reduced significantly from 11,5 degrees to 8,4 degrees, the active correctability as measured with the Scoliometer (TM) was also reduced significantly from the ATR after treatment 8,9 degrees to 6,5 degrees in the patients with thoracic curves. VC improved significantly (P < 0,05) from 2073 ml to 2326 ml. DISCUSSION: The results achieved in the pilot investigation published previously are repeatable. The deformity of the trunk can be reduced significantly after SSTR. During the pilot study VC was not investigated. In our study VC improved significantly. Therefore, also shorter rehabilitation times with an appropriate programme seem to be able to change signs and symptoms of a patient with scoliosis. Like the out-patient Schroth programme as described in a study from Turkey, the SSTR provides benefits leading to an improvement of the condition. CONCLUSION: Out-patient rehabilitation following the Scoliologic (TM) 'Best Practice' standards seems to provide an improvement of signs and symptoms of scoliosis patients in this study using a pre-/post prospective design. The results of the pilot study therefore seem to be repeatable. PMID- 22251671 TI - Vaccine applications of flow cytometry. AB - Highly effective vaccines have yet to be identified for many widespread infectious diseases including HIV, tuberculosis and malaria. Many vaccine candidates for these diseases have been designed to induce both cellular and humoral immunity, and measurement of the induced cellular immune response and antibody response is critical for monitoring immunogenicity. The flow cytometric intracellular cytokine staining assay is one of the primary assays for enumerating vaccine-induced T cells in vaccine clinical trials. The assay is flexible, allowing for measurement of various cytokines or functions and phenotyping markers, and the assay can be validated. Changes in other cell types such as innate immune cells are monitored by flow cytometric phenotyping assays. Cell sorting of vaccine-induced T cells and B cells is used to allow genomic and transcriptional analysis of these cells. Thus, flow cytometric methods are commonly used in trials testing the next generation of vaccines. PMID- 22251673 TI - High affinity (3)H-phenylalanine uptake by brush border membrane vesicles from whole larvae of Aedes aegypti (AaBBMVw). AB - Brush border membrane vesicles from whole Aedes aegypti larvae (AaBBMVw) are confirmed to be valid preparations for membrane transport studies. The Abdul-Rauf and Ellar method was used to isolate AaBBMVw that were frozen, stored for several months, transported to a distant site, thawed and used to study Na(+)-coupled, (3)H-labeled, phenylalanine (Phe) uptake. The affinity for all components of the uptake was very high with half maximal values in the sub-micromolar range. By contrast a K(0.5)(Phe) of 0.2mM and a K(0.5)(Na) of 26 mM were calculated from Phe-induced electrical currents in Xenopus oocytes that were heterologously expressing the Anopheles gambiae symporter (co-transporter), AgNAT8, in a buffer with 98 mM Na(+). What accounts for the >1000-fold discrepancy in affinity for substrates between the BBMV and oocyte experiments? Is it because Ae. aegypti were used to isolate BBMVw whereas An. gambiae were used to transfect oocytes? More likely, it is because BBMVw were exposed to [Na(+)] in the micromolar range with the transporter(s) being surrounded by native lipids. By contrast, the oocyte measurements were made at [Na(+)] 100,000 times higher with AgNAT8 surrounded by foreign frog lipids. The results show that AaBBMVw are osmotically sealed; the time-course has a Na(+)-induced overshoot, the pH optimum is ~7 and the K(0.5) values for Phe and Na(+) are very low. The transport is virtually unchanged when Na(+) is replaced by K(+) or Li(+) but decreased by Rb(+). This approach to resolving discrepancies between electrical data on solute transporters such as AgNAT8 that are over-expressed in oocytes and flux data on corresponding transporters that are highly expressed in native membrane vesicles, may serve as a model for similar studies that add membrane biochemistry to molecular biology in efforts to identify targets for the development of new methods to control disease-vector mosquitoes. PMID- 22251674 TI - Slc4-like anion transporters of the larval mosquito alimentary canal. AB - Mosquito larvae exhibit luminal pH extremes along the axial length of their alimentary canal that range from very alkaline (pH>10) in the anterior midgut to slightly acid in the hindgut. The principal buffer in the system is thought to be bicarbonate and/or carbonate, because the lumen is known to contain high levels of bicarbonate/carbonate and is surrounded by various epithelial cell types which express a variety of carbonic anhydrases. However, the precise mechanisms responsible for the transport of bicarbonate/carbonate into and out of the lumen are unclear. In the present study, we test the hypothesis that SLC4-like anion transporters play a role in bicarbonate/carbonate accumulation in the larval mosquito alimentary canal. Molecular, physiological and immnuohistochemical characterizations of Slc4-like transporters in the gut of larval mosquitoes (Aedes aegypti and Anopheles gambiae) demonstrate the presence of both a Na(+) independent chloride/bicarbonate anion exchanger (AE) as well as a Na(+) dependent anion exchanger (NDAE). Notably, immunolocalization experiments in Malpighian tubules show that the two proteins can be located in the same tissue, but to different cell types. Immunolabeling experiments in the gastric caecae show that the two proteins can be found in the same cells, but on opposite sides (basal vs. apical). In summary, our results indicate that the alimentary canal of larval mosquitoes exhibits robust expression of two SLC4-like transporters in locations that are consistent with a role in the regulation of luminal pH. The precise physiological contributions of each transporter remain to be determined. PMID- 22251675 TI - Geographic distribution and relative abundance of the invasive glassy-winged sharpshooter: effects of temperature and egg parasitoids. AB - The capacity to predict the geographic distribution and relative abundance of invasive species is pivotal to developing policy for eradication or control and management. Commonly used methods fall under the ambit of ecological niche models (ENMs). These methods were reviewed and shortcomings identified. Weather-driven physiologically based demographic models (PBDMs) are proposed that resolve many of the deficiencies of ENMs. The PBDM approach is used to analyze the invasiveness of the polyphagous glassy-winged sharpshooter (Homalodisca vitripennis [Germar]), a pest native to the southeastern United States and northeastern Mexico that extended its range into California in 1989. Glassy winged sharpshooter vectors the pathogenic bacterium, Xylella fastidiosa (Wells) that causes Pierce's disease in grape and scorch-like diseases in other plants. PBDMs for glassy-winged sharpshooter and its egg parasitoids (Gonatocerus ashmeadi Girault and G. triguttatus Girault) were developed and linked to a PBDM for grape published by Wermelinger et al. (1991). Daily weather data from 108 locations across California for the period 1995-2006 were used to drive the PBDM system, and GRASS GIS was used to map the simulation results. The geographic distribution of glassy-winged sharpshooter, as observed, is predicted to be largely restricted to the warm areas of southern California, with the action of the two egg parasitoids reducing its abundance >90%. The average indispensable mortality contributed by G. triguttatus is <1%. A temperature-dependent developmental rate model for X. fastidiosa was developed that suggests its geographic range is also limited to the warm inland areas of southern California. Biological control of glassy-winged sharpshooter further decreases the pathogen's relative range. Climate warming scenarios of +2 degrees C and +3 degrees C suggest that the distribution and severity of glassy-winged sharpshooter and X. fastidiosa will increase in the agriculturally rich central valley of California. The utility of holistic analyses for formulating control policy and tactics for invasive species is discussed. PMID- 22251676 TI - Atta sexdens (L.) (Hymenoptera: Formicidae) demography in the Colombian Amazon: an evaluation of the palatable forage hypothesis. AB - This study tested expectations of the palatable forage hypothesis for Atta sexdens (L.). Literature records on Atta and Acromyrmex nest density in the Neotropics were analyzed and A. sexdens demographical aspects were studied in six transects located along the Colombian Amazon River. Literature research results did not show that Atta and Acromyrmex nest densities are consistently higher in disturbed habitats. In transects, 56 active and 182 inactive nests were found in 2008. Higher active nest numbers and densities were determined for 1992, 1999, and 2006. Nests were present in old forest, in agricultural plot and grassland secondary forest, and absent from open spaces around houses, grasslands, agricultural plots, and a particular sector of old forest. Nest densities were higher in secondary forest. Between 1992 and 2008, the size of disturbed areas increased, whereas nest numbers and densities diminished. Average nest age was higher in secondary forest, but maximum nest age was comparable in the three habitats. On average, nests were superficially larger in old forest. Nests were mostly established in old forest, at sites without fallen trees. Almost all of those currently present in secondary forest were established in old forest before any disturbance occurred. In disturbed habitats, nest inactivity was slightly higher and possibly affected by human control efforts. This study suggested that the palatable forage hypothesis alone did not explain observed demographic patterns. Soil physiochemical variables or microclimatic conditions also are thought to play important roles in determining A. sexdens demography. PMID- 22251677 TI - Consequences of narrow temperature tolerance for a pinyon pine sawfly, Neodiprion edulicolus. AB - Temperate insect species are predicted to fare better in the face of climate change, because of their wider temperature tolerance, than are tropical species. Predictions are less certain, however, for temperate species with narrow temperature optima. Larvae of the sawfly Neodiprion edulicolus Ross are susceptible to cold weather and rarely occur above 1,900 m elevation near Sunset Crater, AZ, even though their host trees (Pinus edulis Englemann) are abundant up to 2,300 m. During 12 yr of monitoring, the population of sawflies below 1,850 m declined significantly in years when April minimum temperatures were either unusually low or unusually high. Sawfly larvae transferred to host trees above 1,900 m were unable to sustain populations despite abundant host trees and high survival of transferred larvae. Cold temperatures delayed and thereby disrupted the sawfly life cycle. Overall, limited temperature tolerance of N. edulicolus larvae was the most likely cause of the decline of this sawfly population between 1994 and 2006. If April minimum temperatures continue to rise on average and interannual variation remains the same, the frequency of suboptimal high temperatures will increase. Soon, N. edulicolus, along with other species with narrow temperature optima, may be forced to disperse, adapt exceptionally quickly, or face extinction. PMID- 22251678 TI - Chalkbrood transmission in the alfalfa leafcutting bee: the impact of disinfecting bee cocoons in loose cell management systems. AB - Understanding pathogen transmission could illuminate new methods for disease prevention. A case in point is chalkbrood in the alfalfa leafcutting bee [Megachile rotundata (F.)]. Propagation of this solitary bee is severely hampered by chalkbrood, a larval disease caused by Ascosphaera aggregata (Ascomycota). Alfalfa leafcutting bees nest in existing cavities in wood or hollow reeds and overwinter as larvae. In the early summer, emerging adults frequently must chew through dead, diseased siblings that block their exit, becoming contaminated with chalkbrood spores in the process. When alfalfa leafcutting bees are used as a commercial pollinator, the cocoons are removed from nesting boards to reduce chalkbrood transmission, but the disease is still common. To determine if these removed cocoons (called loose cells) are an important source of disease transmission, they were disinfected with a fungicide before bees were incubated, and released in the field. Chalkbrood prevalence among the progeny of the treated bees was reduced up to 50% in one field trial, but not significantly when tested in an on-farm trial. Thus, substantial disease transmission still occurred when the loose cells were disinfected, and even when clean nesting materials were used. In conclusion, pathogen transmission must still be occurring from another source that has yet to be identified. Another possible source of transmission could arise from bees that emerge midsummer in populations with a high percent of multivoltinism, but dirty nesting boards and feral bees also may be minor sources of transmission. PMID- 22251679 TI - Population growth and development of Liposcelis pearmani (Psocoptera: Liposcelididae) at constant temperatures and relative humidities. AB - Psocids of genus Liposcelis are now considered serious pests of stored products. We investigated the effects of eight temperatures (22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5, and 40.0 degrees C) and four relative humidities (43, 55, 63, and 75%) on population growth and development of the psocid Liposcelis pearmani Lienhard. L. pearmani did not survive at 37.5 and 40.0 degrees C, at all relative humidities tested; at 43% RH, at all temperatures tested; and at 55% RH, at 32.5 and 35 degrees C. The greatest population growth was recorded at 32.5 degrees C and 75% RH (32-fold growth). L. pearmani males have two to four nymphal instars, and the percentages of males with two, three, and four instars were 17, 63, and 20%, respectively. Female L. pearmani have two to five instars, and the percentages of females with two, three, four, and five instars were 5, 39, 55, and 1%, respectively. We developed temperature-dependent development equations for male and female eggs, individual nymphal, combined nymphal, and combined immature stages. Based on 30-d population growth, L. pearmani cannot survive at temperatures >35.0 degrees C; does not thrive at low relative humidities (55%), at temperatures above 25 degrees C; and has a high optimum relative humidity for population growth (75%). Therefore, we expect it to have a more limited distribution compared with other Liposcelis species. These data provide a better understanding of how temperature and RH may influence L. pearmani population dynamics and can be used in population growth models to help develop effective management strategies for this psocid, and to predict its occurrence. PMID- 22251680 TI - Spider assemblages in the overstory, understory, and ground layers of managed stands in the western boreal mixedwood forest of Canada. AB - Logging is the main human disturbance in the boreal forest; thus, understanding the effects of harvesting practices on biodiversity is essential for a more sustainable forestry. To assess changes in spider composition because of harvesting, samples were collected from three forest layers (overstory, understory, and ground) of deciduous and conifer dominated stands in the northwestern Canadian boreal mixedwood forest. Spider assemblages and feeding guild composition were compared between uncut controls and stands harvested to 20% retention. In total, 143 spider species were collected, 74 from the ground, 60 from the understory, and 71 from the overstory, and species composition of these three pools differed considerably among layers. Distinctive spider assemblages were collected from the canopy of each forest cover type but these were only slightly affected by harvesting. However, logging had a greater impact on the species composition in the understory and ground layers when compared with unharvested controls. Guild structure differed among layers, with wandering and sheet-weaving spiders dominant on the ground while orb-weaving and ambush spiders were better represented in the understory and overstory, respectively. Given the ecological importance of spiders and the expectation of faunal changes with increased harvesting, further efforts toward the understanding of species composition in higher strata of the boreal forest are needed. PMID- 22251681 TI - Molecular characterization of Bemisia tabaci populations in Tunisia: genetic structure and evidence for multiple acquisition of secondary symbionts. AB - A survey was conducted during 2009-2010 seasons to identify the distribution of Bemisia tabaci (Gennadius) biotypes in Tunisia. The genetic affiliation of collected populations was determined by polymerase chain reaction (PCR) restriction fragment-length polymorphism (TaqI) of the mitochondrial cytochrom oxidase I (mtCOI) gene. Results, validated by sequencing and phylogenetic analysis, allowed the clustering of sampled sweetpotato whiteflies into B and Q biotypes. As B. tabaci harbors the obligatory bacterium Portiera aleyrodidarum, and a diverse array of secondary symbionts including Rickettsia, Hamiltonella, Wolbachia, Cardinium, Arsenophonus, and Fritschea, we report here the infectious status of Tunisian populations by secondary symbionts to find out a correlation between bacterial composition to biotype. The genetic variability and structure of B. tabaci populations in Tunisia was driven by analysis of molecular variance (AMOVA) and the hypothesis of isolation by distance was explored. Selective neutrality and genetic haplotype network tests suggested that Tunisian sweetpotato whiteflies have been undergoing a potential expansion followed by gene flow restriction. PMID- 22251682 TI - A test using Wolbachia bacteria to identify Eurasian source populations of cabbage seedpod weevil, Ceutorhynchus obstrictus (Marsham), in North America. AB - Previous research using mitochondrial haplotypes indicates that North American populations of cabbage seedpod weevil, Ceutorhynchus obstrictus (Marsham), originated from at least two separate introductions from source populations in Eurasia. We tested this hypothesis by comparing the genetic variation of symbiotic Wolbachia bacteria in C. obstrictus among seven North American and four European populations. Because Wolbachia are maternally inherited, infections acquired by a host species at one geographic location theoretically may be present in derivative populations that have established in new regions. Use of the conserved MLST Wolbachia genes gatB, coxA, hcpA, fbpA, and ftsZ identified one strain present in all beetles. Use of the variable wsp gene identified three distinct isolates of this strain that appear to co-occur in all populations and potentially in all individuals. Use of the variable wspB gene provided independent support for the presence of these isolates and evidence of a wspB pseudogene. The lack of genetic variation for these Wolbachia genes among host populations prevents their use to clarify the origins of C. obstrictus in North America. However, the results are an interesting example illustrating disjunction in genetic variation between mitochondria and a maternally-inherited symbiont. PMID- 22251683 TI - Temperature alters the relative abundance and population growth rates of species within the Dendroctonus frontalis (Coleoptera: Curculionidae) community. AB - Temperature has strong effects on metabolic processes of individuals and demographics of populations, but effects on ecological communities are not well known. Many economically and ecologically important pest species have obligate associations with other organisms; therefore, effects of temperature on these species might be mediated by strong interactions. The southern pine beetle (Dendroctonus frontalis Zimmermann) harbors a rich community of phoretic mites and fungi that are linked by many strong direct and indirect interactions, providing multiple pathways for temperature to affect the system. We tested the effects of temperature on this community by manipulating communities within naturally infested sections of pine trees. Direct effects of temperature on component species were conspicuous and sometimes predictable based on single species physiology, but there were also strong indirect effects of temperature via alteration of species interactions that could not have been predicted based on autecological temperature responses. Climatic variation, including directional warming, will likely influence ecological systems through direct physiological effects as well as indirect effects through species interactions. PMID- 22251684 TI - Foraging behavior of the coccinellid Nephus includens (Coleoptera: Coccinellidae) in response to Aphis gossypii (Hemiptera: Aphididae) with particular emphasis on larval parasitism. AB - This study assessed the effect of parasitism of Nephus includens (Col.: Coccinellidae) larvae by Homalotylus flaminius (Hym.: Encyrtidae) on the predation rates of the predator on the cotton aphid, Aphis gossypii Glover (Hem.: Aphididae) by deriving functional responses for second- and fourth-instar predators at prey densities ranging from 10 to 80 aphids per arena. The relationship between the functional and numerical responses of adult females of N. includens also was determined for prey densities ranging from 10 to 140 aphids per arena. Predation rates of unparasitized and parasitized second-instar N. includens were both fit by a type II functional response model with parameters as follows: unparasitized (a = 0.0768 hours(-1) and T(h) = 0.975 h) and parasitized (a = 0.0787 hours(-1) and T(h) = 0.8823 hours). Predation rates of unparasitized and parasitized fourth-instar N. includens were fit by type III and II models, respectively, with the following parameters: unparasitized (b = 0.1702 hours(-1) and T(h) = 0.2369 hours) and parasitized (a = 0.038 h(-1) and T(h) = 0.539 h). The unparasitized fourth-instar was the most voracious stage, having the highest attack rate and lowest handling time. Considering these attributes, it would seem to be the most effective stage of this predator against A. gossypii. Adult female lady beetles (N. includens) showed a type III functional response and their numerical response increase to prey density was curvilinearly related to prey density, with the highest number of eggs being produced at highest prey densities. The maximum saturation level for both predation and egg production for adult females occurred at a prey density of 120 aphids. Thus, a ratio 1:120 (predator:prey) should be used when releasing this species for augmentative biological control. Release of either fourth-instar or adult stage N. includens should be minimized the potentially negative effect of parasitism by H. flaminius on early developmental stages, and hence increase its efficiency in biocontrol programs. PMID- 22251685 TI - Bactrocera invadens (Diptera: Tephritidae), a new invasive fruit fly pest for the Afrotropical region: host plant range and distribution in West and Central Africa. AB - In 2003, the invasive fruit fly Bactrocera invadens Drew, Tsuruta & White (Diptera: Tephritidae) (Drew et al. 2005), of possible Sri Lankan origin, has been detected in the East and about 1 yr later in West Africa. In regular surveys in Benin and Cameroon covering 4 yr, samples from 117 plant species across 43 families have been obtained. Incubation of field-collected fruits demonstrate that in West and Central Africa (WCA) B. invadens is highly polyphagous, infesting wild and cultivated fruits of at least 46 species from 23 plant families with guava (Psidium spp.), mango (Mangifera spp.), and citrus (spp.), and the wild hosts tropical almond (Terminalia catappa L.), African wild mango (Irvingia gabonensis (Aubry-Lecomte) Baill.), and sheanut (Vitellaria paradoxa C.F.Gaertn.) showing the highest infestation index. B. invadens occurs in 22 countries of WCA with new records for Angola, Central African Republic, the Congo, DR Congo, Equatorial Guinea, Gabon, Gambia, Guinea Bissau, Mali, Mauritania, Niger, and Sierra Leone. Overall, the pest has spread across a North South distance of ?5,000 km representing a contiguous area of >8.3 million km(2) within WCA. B. invadens has adapted to a wide range of ecological and climatic conditions extending from low land rainforest to dry savanna. Because of its highly destructive and invasive potential, B. invadens poses a serious threat to horticulture in Africa if left uncontrolled. Moreover, the presence of this quarantine pest causes considerable restrictions on international trade of affected crops. PMID- 22251686 TI - Vision should not be overlooked as an important sensory modality for finding host plants. AB - In the last 50 yr, the role of vision in insect interactions with host plants has received relatively little attention. This lack of research is associated with a number of assumptions about chemical cues being the ultimate sensory determinants of host finding. This article presents arguments and detailed evidence to refute these assumptions. Insects from essentially all phytophagous orders use vision for locating host plants, and some recent examples have shown that vision can be even more important than olfaction. Moreover, a number of insects have the ability to visually differentiate host species. This ability means that the visual capabilities of phytophagous insects should not be underestimated. Visual cues always should be considered and integrated into studies of host finding. PMID- 22251687 TI - Orientation behavior of the predator Laricobius nigrinus (Coleoptera: Derodontidae) to hemlock woolly adelgid and host tree odors in a multi-chambered olfactometer. AB - We studied the adult ambulatory response of the predator, Laricobius nigrinus Fender (Coleoptera: Derodontidae), to odors from its prey, Adelges tsugae Annand, the hemlock woolly adelgid, and foliage of hemlock woolly adelgid, host hemlocks (Tsuga spp.), and other conifers. Both the predator and hemlock woolly adelgid are apparently native to western North America, but the predator is being released in the eastern United States, which has different hemlock species, for biological control of a lineage of hemlock woolly adelgid inadvertently introduced from Japan. L. nigrinus responded to odors from hemlock woolly adelgid host trees, but not to odors from hemlock woolly adelgid. L. nigrinus collected from hemlock woolly adelgid-infested western hemlock were more strongly attracted to odors from western hemlock [Tsuga heterophylla (Rafinesque) Sargent] than eastern hemlock [Tsuga canadensis (L.) Carriere] in most trials. Odors from western white pine (Pinus monticola Douglas ex D. Don) and white spruce [Picea glauca (Moench) Voss] were as attractive as western hemlock odors whereas odors from Douglas-fir [Pseudotsuga menziesii variety menziesii (Mirbel)] and ponderosa pine (Pinus ponderosa Douglas ex Lawson) were avoided. L. nigrinus reared on hemlock woolly adelgid-infested eastern hemlock in the laboratory were lethargic and were not attracted to either eastern or western hemlock odors. Predators collected in the field and tested monthly from December to March responded similarly each month, except February, when they flew rather than walked in the olfactometer, suggesting a period of dispersal or mate finding at that time of year. The implications of these results for programs to release L. nigrinus in the eastern United States for control of hemlock woolly adelgid are discussed. PMID- 22251688 TI - Evaluation of yellow sticky traps for monitoring the population of thrips (Thysanoptera) in a mango orchard. AB - Populations of several thrips species were estimated using yellow sticky traps in an orchard planted with mango, Mangifera indica L. during the dry and wet seasons beginning in late 2008-2009 on Penang Island, Malaysia. To determine the efficacy of using sticky traps to monitor thrips populations, we compared weekly population estimates on yellow sticky traps with thrips population sizes that were determined (using a CO(2) method) directly from mango panicles. Dispersal distance and direction of thrips movement out of the orchard also were studied using yellow sticky traps placed at three distances from the edge of the orchard in four cardinal directions facing into the orchard. The number of thrips associated with the mango panicles was found to be correlated with the number of thrips collected using the sticky trap method. The number of thrips captured by the traps decreased with increasing distance from the mango orchard in all directions. Density of thrips leaving the orchard was related to the surrounding vegetation. Our results demonstrate that sticky traps have the potential to satisfactorily estimate thrips populations in mango orchards and thus they can be effectively employed as a useful tactic for sampling thrips. PMID- 22251689 TI - Response of grape root borer (Lepidoptera: Sesiidae) neonates to root extracts from Vitaceae species and rootstocks. AB - Observations at regular intervals of the location of newly hatched grape root borer, Vitacea polistiformis (Harris), larvae moving freely within circular petri dish bioassays were used to measure and compare their response to dry filter paper discs treated with ethanol- or hexane-based extracts of roots from known and potential Vitaceae hosts and a nonhost. Larvae responded most strongly to discs treated with ethanol extracts, suggesting the presence of behaviorally active, polar compounds associated with roots. In single extract bioassays comparing extract versus solvent treated discs, larvae responded positively to ethanol extracts from all Vitis species and rootstocks and Virginia creeper [Parthenocissus quinquefolia (L.) Planch.], but not to apple (Malus domestica Borkh). Paired extract bioassays, in which an extract from the commercially important 3309 rootstock was used as the standard and presented simultaneously with extracts from other root sources, revealed examples of equal, significantly weaker and significantly stronger responses to the 3309 extract. Extracts of the 420 A and V. riparia 'Gloire' rootstocks appeared to possess qualities that elicited a consistently greater response than to 3309 extract in these pair-wise comparisons. The active compounds were eluted in ethanol during a 30-min extraction; larvae responded equally to 30- and 60-min 3309 root extracts in paired extract bioassays. Larvae responded equally to extracts of 3309 roots from three spatially separate vineyards in northern Virginia. These results are discussed in relation to the subterranean, plant-insect interactions of grape root borer neonates with the numerous native and non-native Vitis species that may serve as hosts in the eastern United States. PMID- 22251690 TI - Relative abundance and flight phenology of two pheromone types of Acrobasis nuxvorella (Lepidoptera: Pyralidae). AB - Two synthetic sex pheromones have been developed and are currently used to detect the flight of the pecan nut casebearer, Acrobasis nuxvorella Neunzig, the most damaging pest of pecan [Carya illinoinensis (Wangenh.) K. Koch]. One pheromone (referred to as standard) is attractive to moths in the southern United States, but not in Mexico. The other pheromone (referred to as Mexican) is attractive to moths in the southern United States and in Mexico. These two pheromones have been implemented by producers as an important tool in monitoring the activity of this pest and have allowed for more efficient pesticide use. In the future, these pheromones could be used as a means of population reduction through pheromone based control methods. Trapping data taken over a 3-yr period were used to determine if phenological differences exist between pheromone types of pecan nut casebearer. The relative abundance of each pheromone type at several locations in the United States also was evaluated. Results of this study indicate that no phenological differences exist between the two pheromone types studied in the United States and that significantly more males are attracted to field-deployed pheromone traps baited with the standard pheromone than to traps baited with the Mexican pheromone. PMID- 22251691 TI - Examining the spatial distribution of flower thrips in southern highbush blueberries by utilizing geostatistical methods. AB - Flower thrips (Frankliniella spp.) are one of the key pests of southern highbush blueberries (Vaccinium corymbosum L. x V. darrowii Camp), a high-value crop in Florida. Thrips' feeding and oviposition injury to flowers can result in fruit scarring that renders the fruit unmarketable. Flower thrips often form areas of high population, termed "hot spots", in blueberry plantings. The objective of this study was to model thrips spatial distribution patterns with geostatistical techniques. Semivariogram models were used to determine optimum trap spacing and two commonly used interpolation methods, inverse distance weighting (IDW) and ordinary kriging (OK), were compared for their ability to model thrips spatial patterns. The experimental design consisted of a grid of 100 white sticky traps spaced at 15.24-m and 7.61-m intervals in 2008 and 2009, respectively. Thirty additional traps were placed randomly throughout the sampling area to collect information on distances shorter than the grid spacing. The semivariogram analysis indicated that, in most cases, spacing traps at least 28.8 m apart would result in spatially independent samples. Also, the 7.61-m grid spacing captured more of the thrips spatial variability than the 15.24-m grid spacing. IDW and OK produced maps with similar accuracy in both years, which indicates that thrips spatial distribution patterns, including "hot spots," can be modeled using either interpolation method. Future studies can use this information to determine if the formation of "hot spots" can be predicted using flower density, temperature, and other environmental factors. If so, this development would allow growers to spot treat the "hot spots" rather than their entire field. PMID- 22251692 TI - Evidence for a volatile pheromone in Agrilus planipennis Fairmaire (Coleoptera: Buprestidae) that increases attraction to a host foliar volatile. AB - Analysis by gas chromatography/mass spectrometry (GC/MS) of volatiles from virgin female emerald ash borer, Agrilus planipennis Fairmaire confirmed the emission of (3Z)-lactone [(3Z)-dodecen-12-olide] but not its geometric isomer, (3E)-lactone [(3E)-dodecen-12-olide]. Gas chromatographic/electroantennographic (GC/EAD) analysis of synthetic (3Z)-lactone, which contained 10% (3E)-lactone, showed a strong response of male and female antennae to both isomers. EAG analysis with 0.01- to 100-MUg dosages showed a positive dose response, with females giving significantly higher responses than males. In field experiments with sticky purple prism traps, neither lactone isomer affected catches when combined with ash foliar or cortical volatiles (green leaf volatiles or Phoebe oil, respectively). However, on green prism traps, the (3Z)-lactone significantly increased capture of male A. planipennis when traps were deployed in the canopy. Captures of males on traps with both (3E)-lactone and (3Z)-hexenol or with (3Z) lactone and (3Z)-hexenol were increased by 45-100%, respectively, compared with traps baited with just (3Z)-hexenol. In olfactometer bioassays, males were significantly attracted to (3E)-lactone, but not the (3Z)-lactone or a 60:40 (3E):(3Z) blend. The combination of either (3E)- or (3Z)-lactone with Phoebe oil was not significantly attractive to males. Males were highly attracted to (3Z) hexenol and the (3Z)-lactone + (3Z)-hexenol combination, providing support for the field trapping results. These data are the first to demonstrate increased attraction with a combination of a pheromone and a green leaf volatile in a Buprestid species. PMID- 22251693 TI - Effect of temperature on post-wintering development and total lipid content of alfalfa leafcutting bees. AB - Temperature plays an important role in effective management of the alfalfa leafcutting bee [Megachile rotundata (F.); Megachilidae], the major commercial pollinator of seed alfalfa [Medicago sativa (L.); Fabaceae] in North America. To improve our understanding of threshold and optimum rearing temperatures of M. rotundata, we examined the effect of temperature on postwintering development by using a greater number of temperature treatments than applied in previous studies (19 versus eight or fewer) and analytical tools formulated to model nonlinear relationships between temperature and insect development rates. We also tested the hypothesis that rearing temperature influences adult body lipid content at emergence, which could affect adult survival, establishment and performance as a pollinator, and reproductive success. We found that the Lactin-2 and Briere-2 models provided the best fits to data and gave reasonable estimates of lower (16 18 degrees C) and upper (36-39 degrees C) developmental thresholds and optimum (33-34 degrees C) rearing temperatures for maximizing development rate. Bees successfully emerged over a broad range of temperatures (22-35 degrees C), but variation in development rate among individuals reared at the same temperature was lowest at 31-33 degrees C. The optimum rearing temperature to maximize the proportion of body lipids in adults was 27-29 degrees C. Our results are discussed in relation to previous findings and speak to the difficulties in designing practical rearing guidelines that simultaneously maximize development rate, survival, and adult condition, while synchronizing adult emergence with alfalfa bloom. PMID- 22251694 TI - The influence of host fruit and temperature on the body size of adult Ceratitis capitata (Diptera: Tephritidae) under laboratory and field conditions. AB - The adult body size of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), varies in natural conditions. Body size is an important fitness indicator in the Mediterranean fruit fly; larger individuals are more competitive at mating and have a greater dispersion capacity and fertility. Both temperature during larval development and host fruit quality have been cited as possible causes for this variation. We studied the influence of host fruit and temperature during larval development on adult body size (wing area) in the laboratory, and determined body size variation in field populations of the Mediterannean fruit fly in eastern Spain. Field flies measured had two origins: 1) flies periodically collected throughout the year in field traps from 32 citrus groves, during the period 2003-2007; and 2) flies evolved from different fruit species collected between June and December in 2003 and 2004. In the lab, wing area of male and female adults varied significantly with temperature during larval development, being larger at the lowest temperature. Adult size also was significantly different depending on the host fruit in which larvae developed. The size of the flies captured at the field, either from traps or from fruits, varied seasonally showing a gradual pattern of change along the year. The largest individuals were obtained during winter and early spring and the smallest during late summer. In field conditions, the size of the adult Mediterannean fruit fly seems apparently more related with air temperature than with host fruit. The implications of this adult size pattern on the biology of C. capitata and on the application of the sterile insect technique are discussed. PMID- 22251695 TI - Effects of variable and constant temperatures on the embryonic development and survival of a new grape pest, Xylotrechus arvicola (Coleoptera: Cerambycidae). AB - Xylotrechus arvicola Olivier (Coleoptera: Cerambycidae) has become a new expanding pest in grape (Vitis spp.) crops. To better improve control tactics, the consequences of 11 constant (12, 15, 18, 21, 24, 27, 30, 32, 34, 35 and 36 degrees C) and nine variable temperatures (with equal mean temperatures at each of the nine constant rates ranging from 15 to 35 degrees C) on survival and embryonic development were studied. The eggs were able to complete development at constant temperatures between 15 and 35 degrees C, with mortality rates at the extremes of the range of two and 81.5%, respectively. Using variable temperatures a mortality rate of 38.9% at a mean temperature of 15 degrees C and 99% at 35 degrees C was observed. The range of time for embryonic development was 29.5 d at 15 degrees C to 6 d at 32 degrees C at constant temperatures, and from 29.6 d at 15 degrees C to 7.2 d at 32 degrees C at variable temperatures. The goodness-of-fit of different development models was evaluated for the relationship between the development rate and temperature. The models that gave the best fit were the Logan type III for constant temperatures and the Briere for variable temperatures. Optimum temperatures were estimated to be from 31.7 to 32.9 degrees C. The models that best described embryo development under natural field conditions were the Logan type III model for constant temperatures (98.7% adjustment) and the Lactin model for variable temperatures (99.2% adjustment). Nonlinear models predicted faster development at constant temperatures and slower development at variable ones when compared with real field development, whereas the linear model always predicted faster development than what actually took place. PMID- 22251696 TI - Development time and predation rate of Podisus maculiventris (Hemiptera: Pentatomidae) feeding on Microtheca ochroloma (Coleoptera: Chrysomelidae). AB - Microtheca ochroloma Stal is a beetle native to South America and was introduced to the United States in 1945. Since then, M. ochroloma has become a serious pest in crucifer crops because of the lack of natural enemies. The objective of this study was to measure the predation rate and development time of the commercially available predator Podisus maculiventris (Say) feeding on M. ochroloma at four constant temperatures in the laboratory as a first step to evaluating the predator's capability as a biological control agent of the pest. Nymphal development of P. maculiventris increased from 23 d at 25 degrees C to 99 d at 15 degrees C. There was no development of first instar or egg hatch at 10 degrees C. Number of fourth-instar M. ochroloma killed during nymphal development varied significantly from 65 at 15 degrees C to 53 at 20 degrees C because of length of the nymphal period. A mean total of 741 eggs of M. ochroloma were consumed during nymphal development at 25 degrees C. Adult P. maculiventris preyed on nine and 12 times more fourth-instar M. ochroloma during 10 d at 20 degrees and 25 degrees C, respectively, than at 15 degrees C. We conclude that P. maculiventris can develop successfully on a diet of eggs or fourth-instar M. ochroloma, but its predation and development rates will be significantly curtailed during the cool months from November to March when M. ochroloma is a key pest of organically grown crucifers in Florida. PMID- 22251697 TI - Non-target effects of transgenic blight-resistant American chestnut (Fagales: Fagaceae) on insect herbivores. AB - American chestnut [Castanea dentata (Marshall) Borkhausen], a canopy dominant species across wide swaths of eastern North America, was reduced to an understory shrub after introduction of the blight fungus [Cryphonectria parasitica (Murrill) Barr] in the early 1900s. Restoration of American chestnut by using biotechnology is promising, but the imprecise nature of transgenesis may inadvertently alter tree phenotype, thus potentially impacting ecologically dependent organisms. We quantified effects of genetic engineering and fungal inoculation of trees on insect herbivores by using transgenic American chestnuts expressing an oxalate oxidase gene and wild-type American and Chinese (C. mollissima Blume) chestnuts. Of three generalist folivores bioassayed, only gypsy moth [Lymantria dispar (L.)] was affected by genetic modification, exhibiting faster growth on transgenic than on wild-type chestnuts, whereas growth of polyphemus moth [Antheraea polyphemus (Cramer)] differed between wild-type species, and fall webworm [Hyphantria cunea (Drury)] performed equally on all trees. Inoculation of chestnuts with blight fungus had no effect on the growth of two herbivores assayed (polyphemus moth and fall webworm). Enhanced fitness of gypsy moth on genetically modified trees may hinder restoration efforts if this invasive herbivore's growth is improved because of transgene expression. PMID- 22251698 TI - Western corn rootworm (Coleoptera: Chrysomelidae) dispersal and adaptation to single-toxin transgenic corn deployed with block or blended refuge. AB - A simulation model of the temporal and spatial dynamics and population genetics of western corn rootworm, Diabrotica virgifera virgifera LeConte, was created to evaluate the use of block refuges and seed blends in the management of resistance to transgenic insecticidal corn (Zea mays L.). This Bt corn expresses one transgenic corn event, DAS-59122-7, that produces a binary insecticidal protein toxin (Cry34Ab1/Cry35Ab1) and provides host-plant resistance. The model incorporates the latest information about larval and adult behavior. Results of this modeling effort indicate that the seed-blend scenarios in many cases produced equal or greater durability than block refuges that were relocated each year. Resistance evolved in the most likely scenarios in 10-16 yr. Our standard analysis presumed complete adoption of 59122 corn by all farmers in our hypothetical region, no crop rotation, and 100% compliance with Insect Resistant Management (IRM) regulations. As compliance levels declined, resistance evolved faster when block refuges were deployed. Seed treatments that killed the pest when applied to all seeds in a seed blend or just to seeds in Bt corn blocks delayed evolution of resistance. Greater control of the pest population by the seed treatment facilitated longer durability of the transgenic trait. Therefore, data support the concept that pyramiding a transgenic insecticidal trait with a highly efficacious insecticidal seed treatment can delay evolution of resistance. PMID- 22251699 TI - Psychological and physiological effects of caring for patients with treatment resistant depression. AB - BACKGROUND: Carers of patients with psychiatric disorders show high levels of anxiety and depression, possibly mediated through disruption of the hypothalamo pituitary-adrenal (HPA) axis. Among carers of patients with treatment-resistant depression (TRD), we set out to determine the psychological and physiological (HPA axis) consequences of caring, and the association of these consequences with long-term outcome in patients. METHOD: Thirty-five informal carers of patients with severe TRD requiring in-patient treatment were recruited and compared with 23 controls. HPA-axis activity was assessed by measuring post-awaking salivary cortisol. The Involvement Evaluation Questionnaire (IEQ) and the General Health Questionnaire-12 (GHQ-12) were administered to measure carer burden and psychiatric caseness respectively. Independent t tests were used to compare differences between carers and controls and a linear regression model was used to determine the association of post-awakening cortisol with carer status while controlling for confounding variables. Data on long-term patient outcome (12 to 83 months), measured using the Hamilton Depression Rating Scale (HAMD), were also obtained and linear regression was used to determine the association between cortisol output in carers and remission status in patients. RESULTS: Carers experienced high carer burden and high psychiatric caseness. Carers showed reduced cortisol output after awakening, calculated as the area under the curve with respect to ground (AUCg), which remained significant after controlling for potential confounders. In a linear regression model, non-remission in patients was associated with reduced cortisol output in carers. CONCLUSIONS: Caring for patients with TRD is associated with adverse psychological and physiological changes suggesting hypocortisolism post-awakening. These changes are associated with poor patient outcome. PMID- 22251700 TI - Plasmacytoid dendritic cells lead the charge against tumors. AB - Imiquimod is a TLR agonist that is used as an antitumor agent, mainly against skin tumors. Its clinical benefits are well described in several studies; however, the mechanisms behind its antitumor effects are not completely understood. In this issue of the JCI, Drobits and colleagues demonstrate that topical application of imiquimod suppresses cutaneous melanoma by TLR7-dependent recruitment and transformation of plasmacytoid dendritic cells into killer cells; this occurs independently of conventional adaptive immune mechanisms. PMID- 22251702 TI - IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. AB - HBV infection remains a leading cause of death worldwide. IFN-alpha inhibits viral replication in vitro and in vivo, and pegylated IFN-alpha is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-alpha suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-alpha inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and subgenomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of IFN-alpha resulted in cccDNA-bound histone hypoacetylation as well as active recruitment to the cccDNA of transcriptional corepressors. IFN-alpha treatment also reduced binding of the STAT1 and STAT2 transcription factors to active cccDNA. The inhibitory activity of IFN-alpha was linked to the IRSE, as IRSE-mutant HBV transcribed less pgRNA and could not be repressed by IFN-alpha treatment. Our results identify a molecular mechanism whereby IFN-alpha mediates epigenetic repression of HBV cccDNA transcriptional activity, which may assist in the development of novel effective therapeutics. PMID- 22251701 TI - Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. AB - The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for lamellipodial protrusion. This process required a PI3K-, Cas-, and Crk1/2-dependent signaling mechanism distinct from the previously described nephrin-Nck1/2 pathway necessary for assembly and polymerization of actin filaments. Our present findings also support the hypothesis that mechanisms governing lamellipodial protrusion in culture are similar to those used in vivo during foot process effacement in a subset of glomerular diseases. In mice, podocyte-specific deletion of Crk1/2 prevented foot process effacement in one model of podocyte injury and attenuated foot process effacement and associated proteinuria in a delayed fashion in a second model. In humans, focal adhesion kinase and Cas phosphorylation - markers of focal adhesion complex-mediated Crk dependent signaling - was induced in minimal change disease and membranous nephropathy, but not focal segmental glomerulosclerosis. Together, these observations suggest that activation of a Cas-Crk1/2-dependent complex is necessary for foot process effacement observed in distinct subsets of human glomerular diseases. PMID- 22251703 TI - Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. AB - Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key. Among the immune cells suggested to be involved are plasmacytoid DCs (pDCs). However, a direct contribution of pDCs to tumor killing in vivo and the mechanism of their recruitment to imiquimod-treated sites have never been demonstrated. Using a mouse model of melanoma, we have now demonstrated that pDCs can directly clear tumors without the need for the adaptive immune system. Topical imiquimod treatment led to TLR7-dependent and IFN alpha/beta receptor 1-dependent (IFNAR1-dependent) upregulation of expression of the chemokine CCL2 in mast cells. This was essential to induce skin inflammation and for the recruitment of pDCs to the skin. The recruited pDCs were CD8alpha+ and induced tumor regression in a TLR7/MyD88- and IFNAR1-dependent manner. Lack of TLR7 and IFNAR1 or depletion of pDCs or CD8alpha+ cells from tumor-bearing mice completely abolished the effect of imiquimod. TLR7 was essential for imiquimod-stimulated pDCs to produce IFN-alpha/beta, which led to TRAIL and granzyme B secretion by pDCs via IFNAR1 signaling. Blocking these cytolytic molecules impaired pDC-mediated tumor killing. Our results demonstrate that imiquimod treatment leads to CCL2-dependent recruitment of pDCs and their transformation into a subset of killer DCs able to directly eliminate tumor cells. PMID- 22251704 TI - Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of function mutations in the gene encoding beta-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of beta-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic beta-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by beta-catenin and activation of the NF-kappaB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver beta-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic beta catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in beta catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro- and antiinflammatory mediators, beta-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most beta-catenin-activated HCCs are of better prognosis. PMID- 22251705 TI - Epidemiology of respiratory viral infections in two long-term refugee camps in Kenya, 2007-2010. AB - BACKGROUND: Refugees are at risk for poor outcomes from acute respiratory infections (ARI) because of overcrowding, suboptimal living conditions, and malnutrition. We implemented surveillance for respiratory viruses in Dadaab and Kakuma refugee camps in Kenya to characterize their role in the epidemiology of ARI among refugees. METHODS: From 1 September 2007 through 31 August 2010, we obtained nasopharyngeal (NP) and oropharyngeal (OP) specimens from patients with influenza-like illness (ILI) or severe acute respiratory infections (SARI) and tested them by RT-PCR for adenovirus (AdV), respiratory syncytial virus (RSV), human metapneumovirus (hMPV), parainfluenza viruses (PIV), and influenza A and B viruses. Definitions for ILI and SARI were adapted from those of the World Health Organization. Proportions of cases associated with viral aetiology were calculated by camp and by clinical case definition. In addition, for children < 5 years only, crude estimates of rates due to SARI per 1000 were obtained. RESULTS: We tested specimens from 1815 ILI and 4449 SARI patients (median age = 1 year). Proportion positive for virus were AdV, 21.7%; RSV, 12.5%; hMPV, 5.7%; PIV, 9.4%; influenza A, 9.7%; and influenza B, 2.6%; 49.8% were positive for at least one virus. The annual rate of SARI hospitalisation for 2007-2010 was 57 per 1000 children per year. Virus-positive hospitalisation rates were 14 for AdV; 9 for RSV; 6 for PIV; 4 for hMPV; 5 for influenza A; and 1 for influenza B. The rate of SARI hospitalisation was highest in children < 1 year old (156 per 1000 child years). The ratio of rates for children < 1 year and 1 to < 5 years old was 3.7:1 for AdV, 5.5:1 for RSV, 4.4:1 for PIV, 5.1:1 for hMPV, 3.2:1 for influenza A, and 2.2:1 for influenza B. While SARI hospitalisation rates peaked from November to February in Dadaab, no distinct seasonality was observed in Kakuma. CONCLUSIONS: Respiratory viral infections, particularly RSV and AdV, were associated with high rates of illness and make up a substantial portion of respiratory infection in these two refugee settings. PMID- 22251706 TI - Peters anomaly with post axial polydactyly, bilateral camptodactyly and club foot in a Kenyan neonate: a case report. AB - INTRODUCTION: A case of bilateral Peters anomaly with bilateral post axial polydactyly, bilateral camptodactyly, and club foot was examined in a neonatal Kenyan baby girl of African descent who had been delivered in the hospital and admitted to the newborn unit. She died aged five days. There are no cases of Peters anomaly recorded in Africa according to a literature search. In addition, available data point to the majority of the principal associations in Peters anomaly to be genitourinary anomalies, making this case a rare one in its isolated collection of musculoskeletal associations. CASE PRESENTATION: A Kenyan baby girl of African descent who was born through a caesarean section presented in the new born unit of our hospital with bilateral corneal opacities, bilateral polydactyly, camptodactyly and club foot. CONCLUSION: This is a rare case of Peters anomaly and its association with multiple musculoskeletal abnormalities makes it special. PMID- 22251707 TI - A U-shaped relationship between systolic blood pressure and panic symptoms: the HUNT study. AB - BACKGROUND: Previous studies on the relationship between blood pressure (BP) and psychological morbidity are conflicting. To resolve this confusing picture we examined the hypothesis that there is a non-linear relationship between panic and systolic BP (SBP) and explored the association of generalized anxiety symptoms with SBP. Method We used data from the population-based Nord-Trondelag health study (HUNT) in which all 92 936 individuals aged >=20 years residing in one Norwegian county were invited to participate. Panic was assessed using one item from the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS) and generalized anxiety with the remaining six items of this subscale. SBP was the mean of two measurements by an automatic device. RESULTS: A total of 64 871 respondents had SBP recorded (70%). Both unadjusted (n=61 408) and adjusted analyses provided evidence for a non-linear relationship between panic and SBP, represented by a U-shaped curve with a minimum prevalence of panic at around 140 mmHg. The relationship was strengthened after adjustment for confounders, with the quadratic term significantly associated with panic (p=0.03). Generalized anxiety symptoms were associated only with low SBP. CONCLUSIONS: The U-shaped relationship between SBP and panic provides a unifying explanation for the separate strands of published literature in this area. The results support the hypothesis that high BP and panic disorder could share brainstem autonomic and serotonergic abnormalities. By contrast, generalized anxiety symptoms were more common only at lower BPs, suggesting that any biological link between panic and high BP does not extend to generalized anxiety. PMID- 22251708 TI - Hypoparathyroidism in an Egyptian child with Hutchinson-Gilford progeria syndrome: a case report. AB - INTRODUCTION: Hutchinson-Gilford progeria syndrome is a rare genetic disorder. It is reported to be present in one in eight million and is characterized by severe growth failure, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, early atherosclerosis and facial features that resemble those of an aged person. Apart from diabetes mellitus, there are no reported abnormalities of thyroid, parathyroid, pituitary or adrenal function. Here, we report the case of a 10-year-old Egyptian child with Hutchinson-Gilford progeria syndrome and hypoparathyroidism. CASE PRESENTATION: A 10-year-old Egyptian boy was referred to our institution for an evaluation of recurrent attacks of muscle cramps, paresthesia of his fingertips and perioral numbness of two months duration. On examination, we found dilated veins present over his scalp with alopecia and frontal bossing, a beaked nose, thin lips, protruding ears, a high pitched voice with sparse hair over his eyebrows and eyelashes and micrognathia but normal dentition. His eyes appeared prominent and our patient appeared to have poor sexual development. A provisional diagnosis of progeria was made, which was confirmed by molecular genetics study. Chvostek's and Trousseau's signs were positive. He had low total calcium (5.4 mg/dL), low ionized calcium (2.3 mg/dL), raised serum phosphate (7.2 mg/dL), raised alkaline phosphatase (118 U/L) and low intact parathyroid hormone (1.2 pg/mL) levels. He was started on oral calcium salt and vitamin D; his symptoms improved with the treatment and his serum calcium, urinary calcium and alkaline phosphates level were monitored every three months to ensure adequacy of therapy and to avoid hypercalcemia. CONCLUSION: Routine checking of serum calcium, phosphorus and parathyroid hormone will help in the early detection of hypoparathyrodism among children with progeria. PMID- 22251709 TI - The C allele of JAK2 rs4495487 is an additional candidate locus that contributes to myeloproliferative neoplasm predisposition in the Japanese population. AB - BACKGROUND: Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative neoplasms (MPNs) characterized in most cases by a unique somatic mutation, JAK2 V617F. Recent studies revealed that JAK2 V617F occurs more frequently in a specific JAK2 haplotype, named JAK2 46/1 or GGCC haplotype, which is tagged by rs10974944 (C/G) and/or rs12343867 (T/C). This study examined the impact of single nucleotide polymorphisms (SNPs) of the JAK2 locus on MPNs in a Japanese population. METHODS: We sequenced 24 JAK2 SNPs in Japanese patients with PV. We then genotyped 138 MPN patients (33 PV, 96 ET, and 9 PMF) with known JAK2 mutational status and 107 controls for a novel SNP, in addition to two SNPs known to be part of the 46/1 haplotype (rs10974944 and rs12343867). Associations with risk of MPN were estimated by odds ratios and their 95% confidence intervals using logistic regression. RESULTS: A novel locus, rs4495487 (T/C), with a mutated T allele was significantly associated with PV. Similar to rs10974944 and rs12343867, rs4495487 in the JAK2 locus is significantly associated with JAK2-positive MPN. Based on the results of SNP analysis of the three JAK2 locus, we defined the "GCC genotype" as having at least one minor allele in each SNP (G allele in rs10974944, C allele in rs4495487, and C allele in rs12343867). The GCC genotype was associated with increased risk of both JAK2 V617F-positive and JAK2 V617F-negative MPN. In ET patients, leukocyte count and hemoglobin were significantly associated with JAK2 V617F, rather than the GCC genotype. In contrast, none of the JAK2 V617F-negative ET patients without the GCC genotype had thrombosis, and splenomegaly was frequently seen in this subset of ET patients. PV patients without the GCC genotype were significantly associated with high platelet count. CONCLUSIONS: Our results indicate that the C allele of JAK2 rs4495487, in addition to the 46/1 haplotype, contributes significantly to the occurrence of JAK2 V617F-positive and JAK2 V617F-negative MPNs in the Japanese population. Because lack of the GCC genotype represents a distinct clinical-hematological subset of MPN, analyzing JAK2 SNPs and quantifying JAK2 V617F mutations will provide further insights into the molecular pathogenesis of MPN. PMID- 22251710 TI - Grasshopper fecundity responses to grazing and fire in a tallgrass prairie. AB - Grasshopper abundance and diversity vary with management practices such as fire and grazing. Understanding how grasshopper life history traits such as fecundity respond to management practices is key to predicting grasshopper population dynamics in heterogeneous environments. Landscape-level experimental fire and bison grazing treatments at the Konza Prairie Biological Station (Manhattan, KS) provide an opportunity to examine how management affects grasshopper fecundity. Here we report on grasshopper fecundity for nine common species at Konza Prairie. From 2007 to 2009, adult female grasshoppers were collected every 3 wk from eight watersheds that varied in fire and grazing treatments. Fecundity was measured by examining female reproductive tracts, which contain a record of past and current reproductive activity. Body size was a poor predictor of fecundity for all species. Despite large differences in vegetation structure and composition with management regime (grazing and fire interval), we observed little effect of management on grasshopper fecundity. Habitat characteristics (grasshopper density, vegetation biomass, and vegetation quality; measured in 2008 and 2009) were better predictors of past fecundity than current fecundity, with species-specific responses. Fecundity increased throughout the summer, indicating that grasshoppers were able to acquire sufficient nutritional resources for egg production in the early fall when vegetation quality is generally low. Because fecundity did not vary across management treatments, population stage structure may be more important for determining population level reproduction than management regime at Konza Prairie. PMID- 22251711 TI - Extensive settlement of the invasive MEAM1 population of Bemisia tabaci (Hemiptera: Aleyrodidae) in the Caribbean and rare detection of indigenous populations. AB - Bemisia tabaci populations belonging to Middle East-Asia Minor one (MEAM1) and Mediterranean (MED) groups (formerly biotype B and Q, respectively) have spread throughout the world. Although the introduction of MEAM1 is documented from several Caribbean islands, it is generally not known whether MED has also been introduced; whether indigenous populations have survived; and if in the affirmative, to which group(s) they belonged. Whiteflies were collected from seven islands on various plant species. The prevalence of MEAM1 and non-MEAM1 individuals was assessed using a microsatellite approach validated with sequences of the mitochondrial cytochrome oxidase I (mtCOI) gene. Of the 262 samples tested, 247 exhibited the MEAM1 pattern, whereas none showed the MED pattern. The mtCOI gene was partially sequenced from a sample of individuals exhibiting MEAM1 (n = 15) and non-MEAM1 patterns (n = 8) and compared with type sequences. The 15 individuals exhibiting the MEAM1 pattern were confirmed to belong to MEAM1. Of the eight individuals representative of the six non-MEAM1 patterns, two belonged to the indigenous New World (NW) group of B. tabaci (NW), one belonged to a distinct species of Bemisia, and five belonged to MEAM1. One individual belonging to NW exhibited 99.9% nucleotide identity with a NW individual from Puerto Rico. The other was identified as the most divergent individual of the North and Central American genetic cluster. We conclude that a highly homogenous MEAM1 population has extensively settled in the Caribbean and that heterogeneous NW populations were still detectable although severely displaced. PMID- 22251712 TI - Discovery dominance tradeoff: the case of Pheidole subarmata and Solenopsis geminata (Hymenoptera: Formicidae) in neotropical pastures. AB - Interspecific competition has been shown to play a role in the structure of ant communities. However, the role of foraging behavior and the type of competition that results from this behavior has been less investigated. Here we present results from baiting experiments at various scales to determine the degree of exploitative and interference competition between two Neotropical ants (Hymenoptera: Formicidae) in pastures in the Atlantic coast of Nicaragua. Results suggest that the coexistence of Solenopsis geminata (Fabricius) and Pheidole subarmata (Mayrs) in Neotropical pastures is the result of a discovery/dominance tradeoff between these two species. Although S. geminata is a good interference competitor and can defend large resources, P. subarmata is a good exploitative competitor and arrives at resources faster than S. geminata. In an environment with mixed resources (large and small), these two species can co-exist. We discuss the implication of this for the invasion potential of S. geminata. PMID- 22251713 TI - Factors influencing bark beetle outbreaks after forest fires on the Iberian Peninsula. AB - Fires are among the most globally important disturbances in forest ecosystems. Forest fires can be followed by bark beetle outbreaks. Therefore, the dynamic interactions between bark beetle outbreaks and fire appear to be of general importance in coniferous forests throughout the world. We tested three hypotheses of how forest fires in pine ecosystems (Pinus pinaster Alton and P. radiata D. Don) in Spain could alter the population dynamics of bark beetles and influence the probability of further disturbance from beetle outbreaks: fire could affect the antiherbivore resin defenses of trees, change their nutritional suitability, or affect top-down controls on herbivore populations. P. radiata defenses decreased immediately after fire, but trees with little crown damage soon recovered with defenses higher than before. Fire either reduced or did not affect nutritional quality of phloem and either reduced or had no effect on the abundance, diversity, and relative biomass of natural enemies. After fire, bark beetle abundance increased via rapid aggregation of reproductive adults on scorched trees. However, our results indicate that for populations to increase to an outbreak situation, colonizing beetles must initiate attacks before tree resin defenses recover, host trees must retain enough undamaged phloem to facilitate larval development, and natural enemies should be sufficiently rare to permit high beetle recruitment into the next generation. Coincidence of these circumstances may promote the possibility of beetle populations escaping to outbreak levels. PMID- 22251714 TI - The Argentine ant persists through unfavorable winters via a mutualism facilitated by a native tree. AB - Mutualisms and facilitations can fundamentally change the relationship between an organism's realized and fundamental niche. Invasive species may prove particularly suitable models for investigating this relationship as many are dependent on finding new partners for successful establishment. We conducted field-based experiments testing whether a native tree facilitates the successful survival of the invasive Argentine ant, Linepithema humile (Mayr), through unfavorable winter conditions in the southeastern United States. We found Argentine ant nests aggregated around the native loblolly pine, Pinus taeda L., during the winter months. The bark of this tree absorbed enough radiant solar energy to reach temperatures suitable for Argentine ant foraging even when ambient temperatures should have curtailed all foraging. Conversely, foraging ceased when the trunk was shaded. The sun-warmed bark of this tree gave the Argentine ant access to a stable honeydew resource. Argentine ants were not found on or near deciduous trees even though bark temperatures were warm enough to permit Argentine ant foraging on cold winter days. Augmenting deciduous trees with sucrose water through the winter months lead to Argentine ant nests remaining at their base and Argentine ants foraging on the tree. The Argentine ant requires both foraging opportunity and a reliable winter food source to survive through unfavorable winter conditions in the southeastern United States. The loblolly pine provided both of these requirements extending the realized niche of Argentine ants beyond its fundamental niche. PMID- 22251715 TI - Facilitation of a native pest of rice, Stenotus rubrovittatus (Hemiptera: Miridae), by the non-native Lolium multiflorum (Cyperales: Poaceae) in an agricultural landscape. AB - Source populations of polyphagous pests often occur on host plants other than the economically damaged crop. We evaluated the contribution of patches of a non native meadow grass, Lolium multiflorum Lam. (Poaceae), and other weeds growing in fallow fields or meadows as source hosts of an important native pest of rice, Stenotus rubrovittatus (Matsumura) (Hemiptera: Miridae), in an agricultural landscape of northern Japan. Periodical censuses of this mirid bug by using the sweeping method, vegetation surveys, and statistical analysis revealed that L. multiflorum was the only plant species that was positively correlated with the density of adult S. rubrovittatus through two generations and thus may be the most stable and important host of the mirid bug early in the season before the colonization of rice paddies. The risk and cost of such an indirect negative effect on a crop plant through facilitation of a native pest by a non-native plant in the agricultural landscape should not be overlooked. PMID- 22251716 TI - Seasonal infestations of two stem borers (Lepidoptera: Crambidae) in noncrop grasses of Gulf Coast rice agroecosystems. AB - Infestations of two stem borers, Eoreuma loftini (Dyar) and Diatraea saccharalis (F.) (Lepidoptera: Crambidae), were compared in noncrop grasses adjacent to rice (Oryza sativa L.) fields. Three farms in the Texas rice Gulf Coast production area were surveyed every 6-8 wk between 2007 and 2009 using quadrat sampling along transects. Although D. saccharalis densities were relatively low, E. loftini average densities ranged from 0.3 to 5.7 immatures per m(2) throughout the 2-yr period. Early annual grasses including ryegrass, Lolium spp., and brome, Bromus spp., were infested during the spring, whereas the perennial johnsongrass, Sorghum halepense (L.) Pers., and Vasey's grass, Paspalum urvillei Steud., were infested throughout the year. Johnsongrass was the most prevalent host (41-78% relative abundance), but Vasey's grass (13-40% relative abundance) harbored as much as 62% of the recovered E. loftini immatures (during the winter). Young rice in newly planted fields did not host stem borers before June. April sampling in fallow rice fields showed that any available live grass material, volunteer rice or weed, can serve as a host during the spring. Our study suggests that noncrop grasses are year-round sources of E. loftini in Texas rice agroecosystems and may increase pest populations. PMID- 22251717 TI - Short-term effects of a summer wildfire on a desert grassland arthropod community in New Mexico. AB - Surface-active arthropods were sampled after a lightning-caused wildfire in desert grassland habitat on the Sevilleta National Wildlife Refuge, Socorro County, NM. Pitfall traps (n = 32 per treatment) were used to evaluate species specific "activity-density" indices after the June wildfire in both burned and unburned areas. In total, 5,302 individuals were collected from 69 taxa. Herbivore activity-densities generally decreased, whereas predators often increased in the burned area; pitfall trap bias likely contributed to this latter observation. Fire caused the virtual extirpation of scaly crickets (Mogoplistidae), field crickets (Gryllidae), and camel crickets (Raphidophoridae), but recolonization began during the first postfire growing season. Several grasshoppers (Acrididae) also exhibited significant postfire declines [Ageneotettix deorum (Scudder), Eritettix simplex (Scudder), Melanoplus bowditchi Scudder, and Amphitornus coloradus (Thomas)]. Some beetles showed lower activity-density, including Pasimachus obsoletus LeConte (Carabidae) and Eleodes extricatus (Say) (Tenebrionidae). Taxa exhibiting significant postfire increases in activity-density included acridid grasshoppers (Aulocara femoratum (Scudder), Hesperotettix viridis (Thomas), Trimerotropis pallidipennis (Burmeis.), and Xanthippus corallipes Haldeman); carabid beetles (Amblycheila picolominii Reiche, Cicindela punctulata Olivier), tenebrionid beetles (Eleodes longicollis LeConte, Edrotes rotundus (Say), Glyptasida sordida (LeConte), Stenomorpha consors (Casey); the centipedes Taiyubius harrietae Chamberlin (Lithobiidae) and Scolopendra polymorpha Wood (Scolopendridae); scorpions (Vaejovis spp.; Vaejovidae); and sun spiders (Eremobates spp.; Eremobatidae). Native sand roaches (Arenivaga erratica Rehn, Eremoblata subdiaphana (Scudder); Polyphagidae) displayed no significant fire response. Overall, arthropod responses to fire in this desert grassland (with comparatively low and patchy fuel loads) were comparable to those in mesic grasslands with much higher and more continuous fuel loads. PMID- 22251718 TI - The combined effects of exogenous and endogenous variability on the spatial distribution of ant communities in a forested ecosystem (Hymenoptera: Formicidae). AB - Spatial patterns observed in ecosystems have traditionally been attributed to exogenous processes. Recently, ecologists have found that endogenous processes also have the potential to create spatial patterns. Yet, relatively few studies have attempted to examine the combined effects of exogenous and endogenous processes on the distribution of organisms across spatial and temporal scales. Here we aim to do this, by investigating whether spatial patterns of under-story tree species at a large spatial scale (18 ha) influences the spatial patterns of ground foraging ant species at a much smaller spatial scale (20 m by 20 m). At the regional scale, exogenous processes (under-story tree community) had a strong effect on the spatial patterns in the ground-foraging ant community. We found significantly more Camponotus noveboracensis, Formica subsericae, and Lasius alienus species in black cherry (Prunis serotine Ehrh.) habitats. In witch-hazel (Hamamelis virginiana L.) habitats, we similarly found significantly more Myrmica americana, Formica fusca, and Formica subsericae. At smaller spatial scales, we observed the emergence of mosaic ant patches changing rapidly in space and time. Our study reveals that spatial patterns are the result of both exogenous and endogenous forces, operating at distinct scales. PMID- 22251719 TI - Matrix habitat and plant damage influence colonization of purple loosestrife patches by specialist leaf-beetles. AB - The characteristics of the matrix, that is, the unsuitable habitat connecting host-plant patches may facilitate or limit herbivore movement thus affecting their population dynamics. We evaluated the effect of matrix habitat, distance between patches, and plant damage on movement of two leaf-beetles (Galerucella calmariensis Linnaeus and G. pusilla Duft) introduced to North America as biocontrol agents of the invasive purple loosestrife (Lythrum salicaria Linnaeus). Mark-recapture/resight experiments indicated (1) that leaf-beetles are more likely to colonize purple loosestrife patches surrounded by meadow than forest; (2) that previously attacked purple loosestrife plants are more likely to be colonized by Galerucella spp. than unattacked plants, especially in the forest habitat; and (3) that leaf beetle colonization of purple loosestrife decreased with distance from release point. Low colonization rates of purple loosestrife patches embedded in forests suggest either insufficient detection or active avoidance of such habitats. Biological control programs intend to manage dispersal of specialized insect herbivores for the purpose of sufficient and sustained control of their host plants. Such management needs to be informed by knowledge of interactions of habitat structure, plant damage, and dispersal capabilities of herbivores to facilitate release programs and control at the local and regional level. PMID- 22251720 TI - The impact of overgrazing on dung beetle diversity in the Italian Maritime Alps. AB - Dung beetles (Coleoptera: Scarabaeidae) are undoubtedly the most typical and ecologically relevant insects of grazed alpine habitats because they provide valuable ecological services such as biological pest control and soil fertilization. Despite the great ecological contribution of these insects to pasture ecosystem functioning, little is known about their direct or indirect relationships with pastoral activities. The main aim of the study was to assess whether dung beetle diversity was influenced by different intensities of cattle grazing. Dung beetle communities of two adjacent alpine valleys within the Maritime Alps Natural Park (north-western Italian Alps), representing overgrazed and ungrazed pastures, were studied by pitfall trapping. A hierarchical design (three levels: valleys, transects, and replicates) was established for additive partitioning of gamma-diversity and Indicator Species Analysis. Evenness and Shannon diversity were significantly higher at the ungrazed than at the overgrazed site because abundances were much more evenly distributed at the former than at the latter site (where one species was dominant over all the others). Dung beetle abundance and species richness of the overgrazed graminaceous pasture vegetation types were in most cases significantly lower than those of the ungrazed nongraminaceous vegetation type. In the additive partitioning of gamma -diversity analysis relative to the whole study area, the randomization procedure indicated that the contribution of beta to gamma diversity was significantly different from that expected by chance, suggesting that one or more environmental factors has intervened to change the partition of total diversity in the system considered. The analysis of the preferences and fidelity of species (Indicator Species Analysis) showed that only one species chose overgrazed pastures; all the others positively selected the ungrazed site, or the only ungrazed pasture vegetation type (Rumicetum alpini Beger) occurring at the overgrazed site. Results conformed to evidences that overgrazing represents a serious threat to the conservation of alpine dung beetles. To conserve local dung beetle assemblages, especially in protected areas, cattle overgrazing should be avoided. This does not mean, however, that pastoral activities are incompatible with biodiversity conservation. The contemporaneous presence of wild ungulates and low intensity extensive pastoral activities may be useful to preserve both local dung beetle assemblages and alpine pasture ecosystems. PMID- 22251721 TI - Ground beetle (Coleoptera: Carabidae) phenology, diversity, and response to weed cover in a turfgrass ecosystem. AB - Despite being fragmented and highly disturbed habitats, urban turfgrass ecosystems harbor a surprising diversity of arthropods. The suitability of turf as arthropod habitat, however, likely depends on the extent and types of pesticides and fertilizers used. For example, moderate levels of weed cover in low-input lawns may provide alternative food resources. We conducted a 2-yr field study to: 1) characterize the ground beetle (Carabidae) species assemblage in turfgrass, and 2) assess the direct and indirect effects of lawn management on carabid communities. Weed cover and beetle activity were compared among four lawn management programs: 1) consumer/garden center, 2) integrated pest management (IPM), 3) natural organic, and 4) no-input control. Nearly 5,000 carabid beetles across 17 species were collected with the predator Cyclotrachelus sodalis LeConte numerically dominating the trap catch (87% and 45% of individuals in 2005 and 2006, respectively). Populations of C. sodalis underwent a distinct peak in activity during the third week of June, whereas omnivorous and granivorous species tended to occur at far lower levels and were less variable over the season. We found no evidence for direct effects of lawn management on carabid species diversity; however, we detected an indirect effect mediated by variation in weed cover. Seed-feeding species were positively correlated with turf weeds early in 2006, whereas strictly predaceous species were not. Thus, turf management programs that lead to changes in plant species composition (i.e., herbicide regimes) may indirectly shape epigeal arthropod communities more strongly than the direct effects of insecticide use. PMID- 22251722 TI - Gut microbiota in nymph and adults of the giant mesquite bug (Thasus neocalifornicus) (Heteroptera: Coreidae) is dominated by Burkholderia acquired de novo every generation. AB - The coreid bug Thasus neocalifornicus Brailovsky and Barrera, commonly known as the giant mesquite bug, is a ubiquitous insect of the southwestern United States. Both nymphs and adults are often found aggregated on mesquite trees (Prosopis spp.: Fabaceae) feeding on seedpods and plant sap. We characterized the indigenous bacterial populations of nymphs and adults of this species by using molecular and phylogenetic techniques and culturing methods. Results show that this insect's bacterial gut community has a limited diversity dominated by Burkholderia associates. Phylogenetic analysis by using 16s rRNA sequences suggests that these beta-Proteobacteria are closely related to those symbionts obtained from other heteropteran midgut microbial communities but not to Burkholderia symbionts associated with other insect orders. These bacteria were absent from the eggs and were not found in all younger nymphs, suggesting that they are acquired after the insects have hatched. Rearing experiments of nymphs with potentially Burkholderia contaminated soil suggested that if this symbiont is not acquired, giant mesquite bugs experience higher mortality. Egg, whole-body DNA extractions of younger nymphs, and midgut DNA extractions of fifth-instar nymphs and adults also revealed the presence of alpha-Proteobacteria from the Wolbachia genus. However, this bacterium was also present in reproductive organs of adults, indicating that this symbiont is not specific to the gut. PMID- 22251723 TI - Comparison of midgut bacterial diversity in tropical caterpillars (Lepidoptera: Saturniidae) fed on different diets. AB - As primary consumers of foliage, caterpillars play essential roles in shaping the trophic structure of tropical forests. The caterpillar midgut is specialized in plant tissue processing; its pH is exceptionally alkaline and contains high concentrations of toxic compounds derived from the ingested plant material (secondary compounds or allelochemicals) and from the insect itself. The midgut, therefore, represents an extreme environment for microbial life. Isolates from different bacterial taxa have been recovered from caterpillar midguts, but little is known about the impact of these microorganisms on caterpillar biology. Our long-term goals are to identify midgut symbionts and to investigate their functions. As a first step, different diet formulations were evaluated for rearing two species of tropical saturniid caterpillars. Using the polymerase chain reaction (PCR) with primers hybridizing broadly to sequences from the bacterial domain, 16S rRNA gene libraries were constructed with midgut DNA extracted from caterpillars reared on different diets. Amplified rDNA restriction analysis indicated that bacterial sequences recovered from the midguts of caterpillars fed on foliage were more diverse than those from caterpillars fed on artificial diet. Sequences related to Methylobacterium sp., Bradyrhizobium sp., and Propionibacterium sp. were detected in all caterpillar libraries regardless of diet, but were not detected in a library constructed from the diet itself. Furthermore, libraries constructed with DNA recovered from surface-sterilized eggs indicated potential for vertical transmission of midgut symbionts. Taken together, these results suggest that microorganisms associated with the tropical caterpillar midgut may engage in symbiotic interactions with these ecologically important insects. PMID- 22251724 TI - Interaction between Uroplata girardi (Coleoptera: Chrysomelidae) and Ophiomyia camarae (Diptera: Agromyzidae) on a shared host Lantana camara (Verbenaceae). AB - Multiple releases of insect agents intended to target a single plant pest species could result in competitive interactions that in turn might affect the community structure of the phytophagous insects. Two leaf-feeding biological control agents, Uroplata girardi Pic (Coleoptera: Chrysomelidae) and Ophiomyia camarae Spencer (Dipetera: Agromyzidae), were released against the weed Lantana camara L. (Verbenaceae) in South Africa in the 1970s and 2001, respectively. Since the population explosion of O. camarae in 2005, a decline of U. girardi populations had been observed in KwaZulu-Natal (KZN) humid coast, leading to speculation that negative interaction may be operating between the agents. The study therefore was conducted to determine the competitive effect of O. camarae on U. girardi. The study showed that 76% of O. camarae larval mines were formed on uninfested (clean) compared with only 24% formed on U. girardi-infested leaves, suggesting that the fly chose to lay more eggs on clean leaves. Almost the same number of U. girardi larval mines was formed on both O. camarae-infested and clean leaves, indicating that U. girardi females in this case oviposited indiscriminately on the two types of leaves. The survival of U. girardi was 53.8% when reared on clean leaves compared with only 14.6% survival on O. camarae infested leaves. At the end of the sampling period, densities of U. girardi was over two times higher in single-species than in combined-species treatment. Releasing both agents together did not significantly affect O. camarae densities during the sampling period. In the field, O. camarae densities increased rapidly from spring to autumn, whereas those of U. girardi remained consistently low during the same period. The bias toward oviposition on clean leaves in O. camarae enables its larvae to avoid unfavorable encounters with U. girardi larvae, thus enhancing its development and survival. The apparent inability of U. girardi to distinguish between suitable and unsuitable leaves for oviposition could compromise the fitness of this beetle, and this could explain the suppression of U. girardi populations during summer when O. camarae populations begin to increase rapidly. This study provides evidence for an asymmetric interaction between two introduced agents, and therefore highlights the importance of conducting interaction studies on agents with extensive niche overlap before their release into the environment. PMID- 22251725 TI - Cicadomorpha insects associated with bacterial leaf scorch infected oak in central New Jersey. AB - Potential insect vectors for transmission of oak leaf scorch caused by Xylella fastidiosa Wells et al., in pin and red oaks in New Jersey were surveyed by placing yellow sticky card traps in tree canopies and fogging with pyrethrin insecticide during 2002-2006. Thirty-seven Cicadomorpha species were collected from 20 genera in Membracidae, Cicadellidae, Aphrophoridae, and Clastopteridae. Of the 12,880 potential vectors collected, 91.4% were Membracidae, 6.9% were Cicadellidae, and 1.7% were Aphrophoridae and Clastopteridae. Fogging collected more insect species and individuals than sticky card collections. Sticky card sampling, done more frequently and at a larger number of locations provided similar community structure information as fogging. Sticky card collections of the dominant treehopper species, Ophiderma definita Woodruff were male biased when females were gravid. O. definita populations peaked in early June, comprised 68.2% of the total collection, and were more abundant in pin oaks than red oaks. Graphocephala versuta (Say) peaked in mid-July, comprising 6.2% of the total collection. Higher Cicadomorpha populations were observed in asymptomatic oak canopies than in neighboring X. fastidiosa infected oaks. Individual insect specimens collected from oaks were subjected to a X. fastidiosa DNA assay by polymerase chain reaction amplification. The average X. fastidiosa positive rate was 13.89% for all specimens tested. Eleven treehopper species, six leafhopper species, and four spittlebug species tested DNA positive for X. fastidiosa. PMID- 22251726 TI - Influence of honey bee, Apis mellifera, hives and field size on foraging activity of native bee species in pumpkin fields. AB - The purpose of this study was to identify bee species active in pumpkin fields in New York and to estimate their potential as pollinators by examining their foraging activity. In addition, we examined whether foraging activity was affected by either the addition of hives of the honey bee, Apis mellifera L., or by field size. Thirty-five pumpkin (Cucurbita spp.) fields ranging from 0.6 to 26.3 ha, 12 supplemented with A. mellifera hives and 23 not supplemented, were sampled during peak flowering over three successive weeks in 2008 and 2009. Flowers from 300 plants per field were visually sampled for bees on each sampling date. A. mellifera, Bombus impatiens Cresson, and Peponapis pruinosa (Say) accounted for 99% of all bee visits to flowers. A. mellifera and B. impatiens visited significantly more pistillate flowers than would be expected by chance, whereas P. pruinosa showed no preference for visiting pistillate flowers. There were significantly more A. mellifera visits per flower in fields supplemented with A. mellifera hives than in fields not supplemented, but there were significantly fewer P. pruinosa visits in supplemented fields. The number of B. impatiens visits was not affected by supplementation, but was affected by number of flowers per field. A. mellifera and P. pruinosa visits were not affected by field size, but B. impatiens visited fewer flowers as field size increased in fields that were not supplemented with A. mellifera hives. Declining A. mellifera populations may increase the relative importance of B. impatiens in pollinating pumpkins in New York. PMID- 22251727 TI - Influence of corn on stink bugs (Heteroptera: Pentatomidae) in subsequent crops. AB - In southeastern United States farmscapes, corn, Zea mays L., is often closely associated with peanut, (Arachis hypogaea L.), cotton, (Gossypium hirsutum L.), or both. The objective of this 3-yr on-farm study was to examine the influence of corn on stink bugs (Heteroptera: Pentatomidae), Nezara viridula (L.), and Euschistus servus (Say), in subsequent crops in these farmscapes. Adults of both stink bug species entered corn first, and seasonal occurrence of stink bug eggs, nymphs, and adults indicated that corn was a suitable host plant for adult survival and nymphal development to adults. Stink bug females generally oviposited on cotton or peanut near the interface, or common boundary, of the farmscape before senescence of corn, availability of a new food, or both. Adult stink bugs dispersed from crop to crop at the interface of a farmscape in response to senescence of corn, availability of new food, or both. In corn cotton farmscapes, adult stink bugs dispersed from senescing corn into cotton to feed on bolls (fruit). In corn-peanut farmscapes, adult stink bugs dispersed from senescing corn into peanut, which apparently played a role in nymphal development in these farmscapes. In the corn-cotton-peanut farmscape, stink bug nymphs and adults dispersed from peanut into cotton in response to newly available food, not senescence of peanut. Stink bug dispersal into cotton resulted in severe boll damage. In conclusion, N. viridula and E. servus are generalist feeders that exhibit edge-mediated dispersal from corn into subsequent adjacent crops in corn-cotton, corn-peanut, and corn-peanut-cotton farmscapes to take advantage of suitable resources available in time and space for oviposition, nymphal development, and adult survival. Management strategies for crops in this region need to be designed to break the cycle of stink bug production, dispersal, and expansion by exploiting their edge-mediated movement and host plant preferences. PMID- 22251728 TI - Survival of three commercially available natural enemies exposed to Michigan wildflowers. AB - Flowering plants are often used in habitat management programs to conserve the arthropod natural enemies of insect pests. In this study, nine species of flowering plants representing six families commonly found in North America east of the Rocky Mountains were evaluated based on how much they extended the lifespans of three commercially available natural enemy species in cages with cut flower stems compared with cages containing water only. The natural enemies used in the experiments were a lady beetle (Coleoptera: Coccinellidae: Hippodamia convergens Guerin-Meneville), a predatory bug (Heteroptera: Anthocoridae: Orius insidiosus (Say)), and an aphid parasitoid (Hymenoptera: Braconidae: Aphidius colemani Viereck). The plant species that most extended the lifespans of all three natural enemies were Monarda fistulosa L. (Lamiaceae), Solidago juncea Aiton (Asteraceae), and Daucus carota L. (Apiaceae). Agastache nepetoides (L.) Kuntze (Lamiaceae), Lobelia siphilitica L. (Campanulaceae), and Trifolium pratense L. (Fabaceae) were intermediate in their support of natural enemies. One plant species, Penstemon hirsutus (L.) Willdenow (Scrophulariaceae), did not contribute to the longevity of natural enemies any more than water alone. These results emphasize the need for multi-species evaluations of flowering plants for conservation biocontrol programs, and the variability in plant value for natural enemies. PMID- 22251729 TI - No evidence for enemy release during range expansion of an evergreen tree in northern Europe. AB - Plant distributions are dynamic but the role of plant-insect interactions in controlling range dynamics is not well understood. Enemy release, for example could facilitate plant range expansion under climate change. We conducted a transplant experiment with the evergreen tree Ilex aquifolium L. in both the historical and the expanding range in Denmark to study possible effects of geographical position, small-scale distance, and plant types on presence and performance of the monophagous insect leaf-miner Phytomyza ilicis Curtis. The leaf miner was present in the entire range of I. aquifolium in Denmark, and there were no differences in emergence success depending on geographical position. Small-scale distance to existing adult plants influenced the activity of the insect on the transplants, and oviposition density was negatively correlated with distance to adult plants. Plant type had an effect on leaf miner feeding, oviposition and mining, and the native provenance of I. aquifolium supported higher densities than two cultivars. There was no evidence that enemy release facilitates the current range expansion of I. aquifolium. PMID- 22251730 TI - Grapevine genotype susceptibility to Xylella fastidiosa does not predict vector transmission success. AB - For vector-borne diseases, interactions between vector, host, and pathogen can influence patterns of disease spread. In particular, previous studies suggest that host genotype may influence disease dynamics because of differences in susceptibility to the pathogen and, therefore, subsequent vector transmission efficiency from these plants. We tested this hypothesis by using the pathogenic bacterium Xylella fastidiosa, the etiological agent of Pierce's disease in grapevines, and its leafhopper vector Homalodisca vitripennis (Germar). Pathogen infection level and transmission efficiency among several widely cultivated red and white wine, table, and raisin grape cultivars, were compared with the expectation that vector transmission rate would differ among cultivars, because of underlying differences in susceptibility to infection. The 14 grapevine genotypes evaluated showed significant differences among cultivars in the populations of X. fastidiosa that developed in petioles. 'Flame seedless' hosted the highest bacterial populations, between 1.81 and 2.05 times higher than the least susceptible 'Merlot', 'Crimson seedless', 'Grenache Noir', and 'Rubired'. Although the transmission rate of X. fastidiosa by H. vitripennis varied substantially (zero to 33%), it was not significantly different among cultivars. These results suggest that either the relationship between vine infection level and transmission is weaker than previously reported, or innate differences in vector preference among cultivars confounded any effects of vine susceptibility to infection. PMID- 22251731 TI - Influence of host tree condition on the performance of Tetropium fuscum (Coleoptera: Cerambycidae). AB - Tetropium fuscum (F.) attacks weakened Norway spruce, Picea abies (L.) Karst., in its native Europe and may colonize healthy spruce in Nova Scotia, Canada. We used manipulative field experiments to evaluate: 1) the development of T. fuscum on apparently healthy red spruce (Picea rubens Sarg.) in Nova Scotia; 2) the influence of red spruce physiological condition (healthy, girdled or cut) on T. fuscum performance; and 3) the impact of natural enemies and competitors on T. fuscum performance when developing on trees of varying condition. Tetropium fuscum successfully developed on healthy red spruce. Survival was higher on healthy than on girdled or cut trees when larvae were exposed to natural enemies and competitors. The benefits of reduced competition and parasitism on healthy trees appeared to compensate for any reductions in nutritional quality, increase in host resistance, or both. In contrast, when T. fuscum were protected from natural enemies, apparent survival was highest on girdled trees. Tetropium fuscum development took longer on healthy than on cut or girdled trees, and emerged adults were largest on healthy trees. The disparities in adult sizes among the three treatments may mean that healthy trees are more nutritious. Alternatively, the differences may indicate that a greater amount of time was spent feeding in healthy than in girdled or cut trees. Tree condition appears to have a direct impact on the success of T. fuscum, influencing survival, development time, and adult size, and may mediate the impact of natural enemies and competitors, further affecting T. fuscum performance. PMID- 22251732 TI - Analysis of vertical distributions and effective flight layers of insects: three dimensional simulation of flying insects and catch at trap heights. AB - The mean height and standard deviation (SD) of flight is estimated for over 100 insect species from their catches on several trap heights reported in the literature. The iterative equations for calculating mean height and SD are presented. The mean flight height for 95% of the studies varied from 0.17 to 5.40 m, and the SD from 0.12 to 3.83 m. The relationship between SD and mean flight height (X) was SD = 0.711X(-0.7849), n = 123, R(2) = 0.63. In addition, the vertical trap catches were fit to normal distributions and analyzed for skew and kurtosis. The SD was used to calculate an effective flight layer used in transforming the spherical effective attraction radius (EAR) of pheromone-baited traps into a circular EAR(c) for use in two-dimensional encounter rate models of mass trapping and mating disruption using semiochemicals. The EAR/EAR(c) also serves to reveal the attractive strength and efficacy of putative pheromone blends. To determine the reliability of mean flight height and SD calculations from field trapping data, simulations of flying insects in three dimensions (3D) were performed. The simulations used an algorithm that caused individuals to roam freely at random but such that the population distributed vertically according to a normal distribution of specified mean and SD. Within this 3D arena, spherical traps were placed at various heights to determine the effects on catch and SD. The results indicate that data from previous field studies, when analyzed by the iterative equations, should provide good estimates of the population mean height and SD of flight. PMID- 22251733 TI - Ant mimicry lessens predation on a North American jumping spider by larger salticid spiders. AB - Ant-like appearance (myrmecomorphy) has evolved >70 times in insects and spiders, accounting for >2,000 species of myrmecomorphic arthropods. Most myrmecomorphic spiders are considered to be Batesian mimics; that is, a palatable spider avoids predation through resemblance to an unpalatable ant-although this presumption has been tested in relatively few cases. Here we explicitly examined the extent to which Peckhamia picata (Salticidae), a North American ant-mimicking jumping spider, is protected from four species of jumping spider predators, relative to nonmimetic salticids and model ants. In addition, we conducted focused behavioral observations on one salticid predator, Thiodina puerpera, to determine the point at which the predators' behaviors toward model, mimic, and nonmimic diverge. We also examined the behaviors of Peckhamia in the presence of Thiodina. We found that mimetic jumping spiders were consumed less than a third as often as nonmimetic jumping spiders, suggesting that Peckhamia does indeed gain protection as a result of its resemblance to ants, and so can be considered a Batesian mimic. Furthermore, our focal predator did not consume any ant mimicking spiders, and seemed to categorize Peckhamia with its model ant early in the hunting sequence. Such early determination of prey versus nonprey may be the result of speed-accuracy trade-offs in predator decision-making. PMID- 22251734 TI - Relative humidity preference and survival of starved Formosan subterranean termites (Isoptera: Rhinotermitidae) at various temperature and relative humidity conditions. AB - Foraging groups of Formosan subterranean termites, Coptotermes formosanus Shiraki were tested for their relative humidity (RH) preference in a humidity gradient arena in the laboratory at a constant temperature of 26 degrees C. Five RH levels (9%, 33%, 53%, 75%, and 98%) were maintained in the test arena comprising of a series of closed containers by using dry silica gel, saturated salt solutions, or distilled water alone. Termites gradually aggregated to the highest RH chamber in the arena. After 1 h, a significantly greater percentage of termites (~46%) aggregated to the highest RH chamber (98%) than to the lower RH chambers (<=75%). After 12 h, > 97% of the termites aggregated to the 98% RH chamber. In survival tests, where termites were exposed to 15 combinatorial treatments of five RH levels (9%, 33%, 53%, 75%, and 98%) and three temperatures (20 degrees C, 28 degrees C, and 36 degrees C) for a week, the survival was significantly influenced by RH, temperature, and their interaction. A significantly higher mortality was observed on termites exposed to <=75% RH chambers than to 98% RH chamber at the three temperatures and significantly lower survival was found at 36 degrees C than at 28 degrees C or 20 degrees C. The combination of temperature and RH plays an important role in the survival of C. formosanus. PMID- 22251735 TI - Effects of trap type, placement and ash distribution on emerald ash borer captures in a low density site. AB - Effective methods for early detection of newly established, low density emerald ash borer (Agrilus planipennis Fairmaire) infestations are critically needed in North America. We assessed adult A. planipennis captures on four types of traps in a 16-ha site in central Michigan. The site was divided into 16 blocks, each comprised of four 50- by 50-m cells. Green ash trees (Fraxinus pennsylvanica Marshall) were inventoried by diameter class and ash phloem area was estimated for each cell. One trap type was randomly assigned to each cell in each block. Because initial sampling showed that A. planipennis density was extremely low, infested ash logs were introduced into the center of the site. In total, 87 beetles were captured during the summer. Purple double-decker traps baited with a blend of ash leaf volatiles, Manuka oil, and ethanol captured 65% of all A. planipennis beetles. Similarly baited, green double-decker traps captured 18% of the beetles, whereas sticky bands on girdled trees captured 11% of the beetles. Purple traps baited with Manuka oil and suspended in the canopies of live ash trees captured only 5% of the beetles. At least one beetle was captured on 81% of the purple double-decker traps, 56% of the green double-decker traps, 42% of sticky bands, and 25% of the canopy traps. Abundance of ash phloem near traps had no effect on captures and trap location and sun exposure had only weak effects on captures. Twelve girdled and 29 nongirdled trees were felled and sampled in winter. Current-year larvae were present in 100% of the girdled trees and 72% of the nongirdled trees, but larval density was five times higher on girdled than nongirdled trees. PMID- 22251736 TI - Analysis of the spatio-temporal distribution of Eurygaster integriceps (Hemiptera: Scutelleridae) by using spatial analysis by distance indices and geostatistics. AB - Eurygaster integriceps Puton (Hemiptera: Scutelleridae) is the most serious insect pest of wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) in Iran. In this study, spatio-temporal distribution of this pest was determined in wheat by using spatial analysis by distance indices (SADIE) and geostatistics. Global positioning and geographic information systems were used for spatial sampling and mapping the distribution of this insect. The study was conducted for three growing seasons in Gharamalek, an agricultural region to the west of Tabriz, Iran. Weekly sampling began when E. integriceps adults migrated to wheat fields from overwintering sites and ended when the new generation adults appeared at the end of season. The adults were sampled using 1- by 1-m quadrat and distance-walk methods. A sweep net was used for sampling the nymphs, and five 180 degrees sweeps were considered as the sampling unit. The results of spatial analyses by using geostatistics and SADIE indicated that E. integriceps adults were clumped after migration to fields and had significant spatial dependency. The second- and third-instar nymphs showed aggregated spatial structure in the middle of growing season. At the end of the season, population distribution changed toward random or regular patterns; and fourth and fifth instars had weaker spatial structure compared with younger nymphs. In Iran, management measures for E. integriceps in wheat fields are mainly applied against overwintering adults, as well as second and third instars. Because of the aggregated distribution of these life stages, site-specific spraying of chemicals is feasible in managing E. integriceps. PMID- 22251737 TI - Within-tree distributions of the Sirex noctilio Fabricius (Hymenoptera: Siricidae)--parasitoid complex and development of an optimal sampling scheme. AB - Little is known about the introduced European woodwasp, Sirex noctilio F. (Hymenoptera: Siricidae), and its hymenopteran parasitoid complex in North America. To assess within-tree and landscape-level densities and distributions of these insects, and develop a more cost effective approach for sampling and monitoring S. noctilio, 18 infested pines (12 P. resinosa Aiton and six P. sylvestris L.) were felled from six stands within three regions in central New York and cut into 0.5-m bolts. Bolts were carefully split to recover all siricids (S. noctilio and native siricids) and parasitoids. In total, 2,558 siricids were recovered; 1,972 siricid larvae and 586 teneral adult S. noctilio. Parasitism of siricids, a majority of which were S. noctilio based on larval rearing results, was 16.4% with Ibalia leucospoides ensiger Norton causing 10.7% of the documented mortality. Numbers of siricids and parasitoids declined 33-86% from the northern to the southern sampling regions, peak insect densities occurred in sections of the bole 15-19 cm in diameter and numbers of insects were generally higher in P. sylvestris than P. resinosa according to the highest ranked zero-inflated poisson and probit regression models. Bark thickness was not correlated with siricid or parasitoid species densities. We also describe sampling plans where as few as two 0.5-m samples from infested trees provided reliable within-tree insect densities. PMID- 22251738 TI - Sampling efficacy for the red imported fire ant Solenopsis invicta (Hymenoptera: Formicidae). AB - Cost-effective detection of invasive ant colonies before establishment in new ranges is imperative for the protection of national borders and reducing their global impact. We examined the sampling efficiency of food-baits and pitfall traps (baited and nonbaited) in detecting isolated red imported fire ant (Solenopsis invicta Buren) nests in multiple environments in Gainesville, FL. Fire ants demonstrated a significantly higher preference for a mixed protein food type (hotdog or ground meat combined with sweet peanut butter) than for the sugar or water baits offered. Foraging distance success was a function of colony size, detection trap used, and surveillance duration. Colony gyne number did not influence detection success. Workers from small nests (0- to 15-cm mound diameter) traveled no >3 m to a food source, whereas large colonies (>30-cm mound diameter) traveled up to 17 m. Baited pitfall traps performed best at detecting incipient ant colonies followed by nonbaited pitfall traps then food baits, whereas food baits performed well when trying to detect large colonies. These results were used to create an interactive model in Microsoft Excel, whereby surveillance managers can alter trap type, density, and duration parameters to estimate the probability of detecting specified or unknown S. invicta colony sizes. This model will support decision makers who need to balance the sampling cost and risk of failure to detect fire ant colonies. PMID- 22251739 TI - Self-selection of two diet components by Tenebrio molitor (Coleoptera: Tenebrionidae) larvae and its impact on fitness. AB - We studied the ability of Tenebrio molitor L. (Coleoptera: Tenebrionidae) to self select optimal ratios of two dietary components to approach nutritional balance and maximum fitness. Relative consumption of wheat bran and dry potato flakes was determined among larvae feeding on four different ratios of these components (10, 20, 30, and 40% potato). Groups of early instars were provided with a measured amount of food and the consumption of each diet component was measured at the end of 4 wk and again 3 wk later. Consumption of diet components by T. molitor larvae deviated significantly from expected ratios indicating nonrandom self-selection. Mean percentages of dry potato consumed were 11.98, 19.16, 19.02, and 19.27% and 11.89, 20.48, 24.67, and 25.97% during the first and second experimental periods for diets with 10, 20, 30, and 40% potato, respectively. Life table analysis was used to determine the fitness of T. molitor developing in the four diet mixtures in a no-choice experiment. The diets were compared among each other and a control diet of wheat bran only. Doubling time was significantly shorter in groups consuming 10 and 20% potato than the control and longer in groups feeding on 30 and 40% potato. The self-selected ratios of the two diet components approached 20% potato, which was the best ratio for development and second best for population growth. Our findings show dietary self-selection behavior in T. molitor larvae, and these findings may lead to new methods for optimizing dietary supplements for T. molitor. PMID- 22251740 TI - Aquatic respiration as a potential survival mechanism of Brephidium pseudofea (Lepidoptera: Lycaenidae) larvae to intertidal environments. AB - The eastern pygmy blue, Brephidium pseudofea (Morrison) (Lepidoptera: Lycaenidae: Polyommatinae), inhabits intertidal environments that are periodically flooded. The immature stages are subject to salt or brackish water inundation during this time and therefore must endure many stressors, including respiratory limitation and salt exposure. Our goal was to investigate possible mechanisms used by the larval stages of B. pseudofea to endure periodic tidal inundation by using physiological and morphological analyses in comparison with several species of terrestrial lepidopteran larvae. A review of tidal charts showed that the immature stages of B. pseudofea would be prone to complete inundation two to five times per month during the summer months (May to August) and partial submersion for up to 20 d per month during the rest of the year. Larvae of several terrestrial lepidopteran species studied consumed oxygen under water for a limited period, but B. pseudofea demonstrated substantially higher oxygen consumption. Light microscopy of B. pseudofea larvae revealed small air pockets in and around the spiracles when submerged in tap water; these air pockets disappeared when exposed to detergent solution. The resulting air pockets may function as a diffusion layer for oxygen to be absorbed from the surrounding water or may act in conjunction with trans-cuticular gas exchange to meet the larva's respiratory needs. Morphological examination by scanning electron microscopy showed that B. psudofea larvae have distinctively small, clavate setae that appear insufficient to effectively support a functional plastron. PMID- 22251741 TI - Population structure and spatial influence of agricultural variables on Hessian fly populations in the southeastern United States. AB - Population structure dictates the evolution of each population, and thus, the species as a whole. Incorporating spatial variables with population genetic statistics allows for greater discovery beyond traditional population genetics alone and can inform management decisions. The understanding of population structure in Hessian fly, Mayetiola destructor (Say), a pest of wheat, has been limited in the past. We scored 14 microsatellite loci from 12 collections of Hessian fly in the southeastern United States. Through Bayesian clustering analysis, we found two major populations of Hessian fly covering the entire southeastern United States. We evaluated correlations between agriculturally significant spatial variables and population genetic differentiation to test if genetic structure has an ecological component in a wheat agro-ecosystem. Our results suggest the total amount of alternative host plants in the county may be driving some genetic differentiation. Although planting date may also be influential, geographic distance, mean annual temperature, and harvested wheat for grain do not seem to be contributing factors. The ecological or spatial component to population structure, however, may be minimal compared to factors such as genetic drift. PMID- 22251742 TI - Host race evolution in Schizaphis graminum (Hemiptera: Aphididae): nuclear DNA sequences. AB - The greenbug aphid, Schizaphis graminum (Rondani) was introduced into the United States in the late 1880s, and quickly was established as a pest of wheat, oat, and barley. Sorghum was also a host, but it was not until 1968 that greenbug became a serious pest of it as well. The most effective control method is the planting of resistant varieties; however, the occurrence of greenbug biotypes has hampered the development and use of plant resistance as a management technique. Until the 1990s, the evolutionary status of greenbug biotypes was obscure. Four mtDNA cytochrome oxidase subunit I (COI) haplotypes were previously identified, suggesting that S. graminum sensu lato was comprised of host-adapted races. To elucidate the current evolutionary and taxonomic status of the greenbug and its biotypes, two nuclear genes and introns were sequenced; cytochrome c (CytC) and elongation factor 1-alpha (EF1-alpha). Phylogenetic analysis of CytC sequences were in complete agreement with COI sequences and demonstrated three distinct evolutionary lineages in S. graminum. EF1-alpha DNA sequences were in partial agreement with COI and CytC sequences, and demonstrated two distinct evolutionary lineages. Host-adapted races in greenbug are sympatric and appear reproductively isolated. Agricultural biotypes in S. graminum likely arose by genetic recombination via meiosis during sexual reproduction within host-races. The 1968 greenbug outbreak on sorghum was the result of the introduction of a host race adapted to sorghum, and not selection by host resistance genes in crops. PMID- 22251743 TI - Seasonal expression of Bt proteins in transgenic rice lines and the resistance against Asiatic rice borer Chilo suppressalis (Walker). AB - Laboratory bioassays and field surveys were carried out to compare the resistance of three transgenic rice (Oryza sativa L.) lines including Bt-DL expressing a single gene cry1Ab, Bt-KF6 expressing stacked genes cry1Ac and CpTI genes and Bt SY63 expressing a fusion gene cry1Ab/cry1Ac, respectively, to an important rice pest Chilo suppressalis (Walker). In addition, enzyme-linked immunosorbent assays (ELISA) were conducted to monitor the Bt protein expressions in rice leaves and stems at different rice growth stages. Results showed that all the transgenic rice lines exhibited significantly high resistance to the pest compared with their corresponding nontransformed isolines. Among the transgenic rice lines, Bt SY63 and Bt-KF6 had higher resistance to C. suppressalis at early growth stage, but lower resistance at late stages, while the pest resistance of Bt-DL was relatively stable throughout the growing season. The results were consistent with ELISA results showing that Bt protein levels in Bt-SY63 or Bt-KF6 leaves decreased in late growth stages, but were relatively stable in Bt-DL at all growth stages. This demonstrates that the resistance to a pest by Bt plants is positively correlated with Cry protein expression levels in plant tissues. Compared with Bt-SY63 and Bt-KF6, the Bt protein expression levels were significantly lower in Bt-DL, while its resistance to C. suppressalis was the highest. This may suggest that C. suppressalis is more susceptible to Cry1Ab than to Cry1Ac. The data from the current study are valuable for decision-making for commercial use of Bt rice lines and development of appropriate pest control and resistance management strategies for the transgenic rice lines. PMID- 22251744 TI - No impact of transgenic nptII-leafy Pinus radiata (Pinales: Pinaceae) on Pseudocoremia suavis (Lepidoptera: Geometridae) or its endoparasitoid Meteorus pulchricornis (Hymenoptera: Braconidae). AB - To investigate the biosafety to insects of transgenic Pinus radiata D. Don containing the antibiotic resistance marker gene nptII and the reproductive control gene leafy, bioassays were conducted with an endemic lepidopteran pest of New Zealand plantation pine forests and a hymenopteran endoparasitoid. Larvae of the common forest looper, Pseudocoremia suavis (Butler), were fed from hatching on P. radiata needles from either one of two nptII-leafy transgenic clones, or an isogenic unmodified control line. For both unparasitized P. suavis and those parasitized by Meteorus pulchricornis (Wesmael), consuming transgenic versus control pine had no impact on larval growth rate or mass at any age, larval duration, survival, pupation or successful emergence as an adult. Total larval duration was 1 d (3%) longer in larvae fed nptII-2 than nptII-1, but this difference was considered trivial and neither differed from the control. In unparasitized P. suavis larvae, pine type consumed did not affect rate of pupation or adult emergence, pupal mass, or pupal duration. Pine type had no effect on the duration or survival of M. pulchricornis larval or pupal stages, mass of cocoons, stage at which they died, adult emergence, or fecundity. Parasitism by M. pulchricornis reduced P. suavis larval growth rate, increased the duration of the third larval stadium, and resulted in the death of all host larvae before pupation. The lack of impact of an exclusive diet of nptII-leafy transgenic pines on the life history of P. suavis and M. pulchricornis suggests that transgenic plantation pines expressing nptII are unlikely to affect insect populations in the field. PMID- 22251745 TI - Morphometric characterization of the first blastomeres of rainbow trout (Oncorhynchus mykiss). AB - In the following investigation the morphometric characteristics of the first two blastomeres of rainbow trout (Oncorhynchus mykiss) were determined. Embryos were incubated at 9 degrees C and then fixed in a Stockard solution every 30 min starting from 8.5 to 12.5 h of incubation post fertilization. Embryonic discs were extracted and microphotographs were taken with Q Capture Pro 5.0 software using a stereomicroscope Olympus SZX7. The average size of the blastodiscs was 941.22 +/- 160.42 MUm. The first cleavage finished after approximately 12 h of incubation. The first two blastomeres were regularly symmetrical in their morphology. Blastomere 1 had an average length (L) of 942.68 +/- 105.56 MUm and width (W) of 467.34 +/- 64.33 MUm. Blastomere 2 had an average length of 887.60 +/- 101.65 and width of 454.49 +/- 47.25 MUm (n = 91). Significant differences were found between the length and width of blastomeres 1 and 2. The proportion between the length of blastomeres 1 and 2 was 0.94 +/- 0.07 (n = 91); between the width of blastomeres 1 and 2 it was 0.88 +/- 0.11 (n = 91); and the width/length ratio was 0.51 +/- 0.09 (n = 182). It was concluded that rainbow trout blastomeres tend to be asymmetrical in length with a higher dispersion of widths. PMID- 22251746 TI - Femtosecond laser nanostructuring for femtosensitive DNA detection. AB - In this paper, a new concept to achieve improved probe-target recognition has been devised by introducing a novel class of DNA-functionalized three-dimensional (3D), stand-free, and nanostructured electrodes. The gold nanofibrous electrodes were created using MHZ ultrafast laser material processing in air at ambient conditions. The developed nanofibrous DNA biosensor was characterized by cyclic voltammetry with the use of ferrocyanide as an electrochemical redox indicator. Currently, electrochemical signal enhancement which is of great significance for improving the sensitivity in DNA detection remains a great challenge. Through, enhanced surface area-to-volume ratio and more efficient arrangement of probe molecules on nanofibrous electrodes, our newly developed electrode system overcomes some of the sensitivity challenges of the existing systems. This nanofiber-based system realizes femtomolar (fM) sensitivity toward complementary target DNA, and demonstrates a very wide dynamic range (from 1 fM to 1 nM). PMID- 22251747 TI - A selective and sensitive D-xylose electrochemical biosensor based on xylose dehydrogenase displayed on the surface of bacteria and multi-walled carbon nanotubes modified electrode. AB - A novel Nafion/bacteria-displaying xylose dehydrogenase (XDH)/multi-walled carbon nanotubes (MWNTs) composite film-modified electrode was fabricated and applied for the sensitive and selective determination of d-xylose (INS 967), where the XDH-displayed bacteria (XDH-bacteria) was prepared using a newly identified ice nucleation protein from Pseudomonas borealis DL7 as an anchoring motif. The XDH displayed bacteria can be used directly, eliminating further enzyme-extraction and purification, thus greatly improved the stability of the enzyme. The optimal conditions for the construction of biosensor were established: homogeneous Nafion MWNTs composite dispersion (10 MUL) was cast onto the inverted glassy carbon electrode, followed by casting 10-MUL of XDH-bacteria aqueous solution to stand overnight to dry, then a 5-MUL of Nafion solution (0.05 wt%) is syringed to the electrode surface. The bacteria-displaying XDH could catalyze the oxidization of xylose to xylonolactone with coenzyme NAD(+) in 0.1M PBS buffer (pH7.4), where NAD(+) (nicotinamide adenine dinucleotide) is reduced to NADH (the reduced form of nicotinamide adenine dinucleotide). The resultant NADH is further electrocatalytically oxidized by MWNTs on the electrode, resulting in an obvious oxidation peak around 0.50 V (vs. Ag/AgCl). In contrast, the bacteria-XDH-only modified electrode showed oxidation peak at higher potential of 0.7 V and less sensitivity. Therefore, the electrode/MWNTs/bacteria-XDH/Nafion exhibited good analytical performance such as long-term stability, a wide dynamic range of 0.6 100 MUM and a low detection limit of 0.5 MUM D-xylose (S/N=3). No interference was observed in the presence of 300-fold excess of other saccharides including D glucose, D-fructose, D-maltose, D-galactose, D-mannose, D-sucrose, and D cellbiose as well as 60-fold excess of L-arabinose. The proposed microbial biosensor is stable, specific, sensitive, reproducible, simple, rapid and cost effective, which holds great potential in real applications. PMID- 22251748 TI - Severe lactic acidosis and acute renal failure following ingestion of metformin and kerosene oil: a case report. AB - INTRODUCTION: Kerosene is a freely accessible hydrocarbon used in Sri Lankan (and other Asian) households for cooking and for lighting lamps. Kerosene poisoning is rarely reported among adults and its toxicological effects are not well known. Metformin is a commonly used oral hypoglycemic drug and its overdose leads primarily to lactic acidosis. Combined poisoning of metformin and kerosene and their interactions have not been reported. CASE PRESENTATION: An 18-year-old, previously healthy, unmarried Sinhalese woman was referred following ingestion of 17.5 g of metformin and approximately 200 mL of kerosene oil in a suicide attempt. She had vomiting, burning epigastric pain, and a hypoglycemic seizure (capillary blood glucose of 42 mg/dL). Subsequently, she developed severe lactic acidosis followed by acute renal insufficiency, was treated with sodium bicarbonate, and underwent intermittent hemodialysis with bicarbonate. She recovered completely. CONCLUSIONS: This report proposes possible interactions that occur between metformin and kerosene that augment toxicity when the two are ingested together. It also stresses the importance of early treatment with intermittent hemodialysis in severe lactic acidosis with maintenance of blood glucose. PMID- 22251749 TI - How many births in sub-Saharan Africa and South Asia will not be attended by a skilled birth attendant between 2011 and 2015? AB - BACKGROUND: The fifth Millennium Development Goal target for 90% of births in low and middle income countries to have a skilled birth attendant (SBA) by 2015 will not be met. In response to this, policy has focused on increasing SBA access. However, reducing maternal mortality also requires policies to prevent deaths among women giving birth unattended. We aimed to generate estimates of the absolute number of non-SBA births between 2011 and 2015 in South Asia and sub Saharan Africa, given optimistic assumptions of future trends in SBA attendance. These estimates could be used by decision makers to inform the extent to which reductions in maternal mortality will depend on policies aimed specifically at those women giving birth unattended. METHODS: For each country within South Asia and sub-Saharan Africa we estimated recent trends in SBA attendance and used these as the basis for three increasingly optimistic projections for future changes in SBA attendance. For each country we obtained estimates for the current SBA attendance in rural and urban settings and forecasts for the number of births and changes in rural/urban population over 2011-2015. Based on these, we calculated estimates for the number of non-SBA births for 2011-2015 under a variety of scenarios. RESULTS: Conservative estimates are that there will be between 130 and 180 million non-SBA births in South Asia and sub-Saharan Africa from 2011 to 2015 (90% of these in rural areas). Currently, there are more non SBA births per year in South Asia than sub-Saharan Africa, but our projections suggest that the regions will have approximately the same number of non-SBA births by 2015. We also present results for each of the six countries currently accounting for more than 50% of global maternal deaths. CONCLUSIONS: Over the next five years, many millions of women within South Asia and sub-Saharan Africa will give birth without an SBA. Efforts to improve access to skilled attendance should be accompanied by interventions to improve the safety of non-attended deliveries. PMID- 22251750 TI - Characteristics of induced ventricular fibrillation cycle length in symptomatic Brugada syndrome patients. AB - BACKGROUND: Limited information is available on the ventricular fibrillation (VF) spectrum in Brugada syndrome (BS) patients. We clarified differences in the VF cycle length (CL) using fast-Fourier transformation (FFT) analysis in symptomatic and asymptomatic BS patients. METHODS AND RESULTS: VF was induced by pacing from the right ventricular (RV) apex and/or RV outflow tract (RVOT) for >8s. A 4096 point FFT analysis of results from 28 male BS patients (51.1 +/- 13.7 years old) was performed. Dominant frequency (DF) from phases 1 (4s) to 6 was obtained at 2 s intervals. The average DF from surface and intracardiac electrograms (ECG: DF(ECG); ICE: DF(ICE,), respectively) was compared between symptomatic and asymptomatic patients. Symptomatic patients had a significantly shorter effective refractory period at a CL of 600 ms at the RVOT than asymptomatic patients. DF(ECG) significantly increased with phase (5.64 +/- 0.32 Hz in phase 1 to 6.16 +/- 0.52 Hz in phase 6) and was significantly higher in symptomatic patients than in asymptomatic patients. DF(ICE) had the same characteristics as DF(ECG). CONCLUSIONS: Induced VF in BS patients can be characterized using FFT analysis. Our data support the hypothesis that symptomatic patients have a significantly shorter VF CL than asymptomatic patients. PMID- 22251751 TI - Natural history of stent edge dissection, tissue protrusion and incomplete stent apposition detectable only on optical coherence tomography after stent implantation - preliminary observation - . AB - BACKGROUND: The clinical impact of stent edge dissection, tissue protrusion, and incomplete stent apposition (ISA) after stent implantation, detectable only on optical coherence tomography (OCT), is still unknown because the natural course has not been investigated. METHODS AND RESULTS: All consecutive patients with angina pectoris in whom both intravascular ultrasound (IVUS) and OCT were performed immediately after stenting and at follow-up were included in the present study. The natural history of OCT-detected stent edge dissection, tissue protrusion, and ISA during follow-up was investigated. A total of 36 patients with 39 lesions was analyzed. At baseline, OCT showed 12 stent edge dissections, 25 tissue protrusions, and 8 ISAs, whereas IVUS demonstrated 6 stent edge dissections, 5 tissue protrusions, and 3 ISAs. All IVUS findings were clearly visualized on OCT. The maximum length of dissection flap and depth of ISA visualized on OCT were significantly shorter than those visualized on IVUS. Maximum length of tissue protrusion tended to be smaller on OCT than on IVUS. At follow-up (median 188 days), all findings noted on OCT were healed or resolved without any restenosis or thrombus formation. CONCLUSIONS: Acute findings after stenting, such as edge dissection, tissue protrusion, and ISA, detectable only on OCT, tended to be smaller than those seen on both OCT and IVUS. The majority of OCT-detected acute findings resolved completely at follow-up. PMID- 22251752 TI - Effect of dust storm events on daily emergency admissions for cardiovascular diseases. AB - BACKGROUND: Dust storm is a meteorological phenomenon and dust particles have been suspected as harmful to heart and lungs. The aim of this study was to investigate the association between coarse particles and emergency hospital admissions for cardiovascular diseases (CVD) in Hong Kong. METHODS AND RESULTS: Data on mean daily emergency admissions for CVD to major hospitals in Hong Kong, concentrations of air pollutants and meteorological variables from January 1998 to December 2002 were obtained from several government departments. We identified 5 dust storm days during the study period. Independent t-tests were used to compare the mean daily number of admissions on dust storm and non-dust storm days. Case-crossover analysis, using the Poisson regression, was used to examine the effects of coarse particles' concentration on emergency hospital admissions for CVD. A marginally significant increase in emergency hospital admissions for ischemic heart disease (IHD) was found with RR=1.04 (95% confidence interval: 1.00, 1.08) per 10 ug/m(3) increase in the concentration of coarse particles. CONCLUSIONS: This study demonstrated a marginally significant increase in emergency hospital admissions for IHD on the day of dust storm events in Hong Kong, when the levels of coarse particles were very high. Further studies are required to assess the role of coarse particles on cardiac health. PMID- 22251753 TI - Sample size in receiver-operating characteristic (ROC) curve analysis. PMID- 22251755 TI - Managing poorly performing clinicians: health care providers' willingness to pay for independent help. AB - OBJECTIVE: To determine the willingness to pay (WTP) of senior managers in the UK National Health Service (NHS) for services to help manage performance concerns with doctors, dentists and pharmacists. METHODS: A discrete choice experiment (DCE) was used to elicit senior managers' preferences for a support service to help manage clinical performance concerns. The DCE was based on: a literature review; interviews with support service providers and clinical professional bodies; and discussion groups with managers. From the DCE responses, we estimate marginal WTP for aspects of support services. RESULTS: 451 NHS managers completed the DCE questionnaire. NHS managers are willing to pay for: advice, 'facilitation', and behavioural, health, clinical and organisational assessments. Telephone advice with written confirmation was valued most highly. NHS managers were willing to pay L161.56 (CI: L160.81-L162.32) per year per whole time equivalent doctor, dentist or pharmacist, for support to help manage clinical performance concerns. Marginal WTP varied across respondent subgroups but was always positive. CONCLUSIONS: Health care managers valued help in managing the clinicians' performance, and were willing to pay for it from their organisations' limited funds. Their WTP exceeds the current cost of a UK body providing similar support. Establishing a central body to provide such services across a health care system, with the associated economies of scale including cumulative experience, is an option that policy makers should consider seriously. PMID- 22251756 TI - Allostatic load and health status of African Americans and whites. AB - OBJECTIVES: To compare health risks in 84 healthy African American and 45 white men and women after calculating allostatic load (AL) from biologic, psychosocial, and behavioral measures. METHODS: Participants (18-45 years) ranging in weight from normal to obese and without hypertension or diabetes. Fitness, body fat, CRP, mood, social support, blood pressure, sleep and exercise habits, coping, and insulin responses were dichotomized as low/high risk and summed for AL. RESULTS: African Americans (3.4+/-1.9) had significantly higher AL than that of whites (2.4+/-1.9; P<0.05). Significantly more African Americans had AL>=3 (67.9%) than did whites (48.9%). CONCLUSIONS: Identifying cumulative AL may help identify and address the underpinnings of health disparities in African Americans. PMID- 22251757 TI - Victimization and health risk factors among weapon-carrying youth. AB - OBJECTIVE: To compare health risks of 2 subgroups of weapon carriers: victimized and nonvictimized youth. METHODS: 2003-2007 NYC Youth Risk Behavior Surveys were analyzed using bivariate analyses and multinomial logistic regression. RESULTS: Among NYC teens, 7.5% reported weapon carrying without victimization; 6.9% reported it with victimization. Both subgroups were more likely than non-weapon carriers to binge drink, use marijuana, smoke, fight, and have multiple sex partners; weapon carriers with victimization also experienced persistent sadness and attempted suicide. CONCLUSIONS: Subgroups of weapon carriers have distinct profiles. Optimal response should pair disciplinary action with screening for behavioral and mental health concerns and victimization. PMID- 22251758 TI - Using nominal technique to inform a sexual health program for black youth. AB - OBJECTIVES: To describe how nominal group technique (NGT) was used to inform the development of a sexual health education program for black high school youth in the South. METHODS: NGT was used with a community advisory board (CAB) to obtain information regarding the key components of a sexual health program for youth in their community. RESULTS: The CAB identified 5 priorities to include in the program: sex education, "keeping it real," responsibility/consequences, self esteem, and female aggressiveness. CONCLUSIONS: Findings can be useful in modeling the successful use of NGT as a formative step toward developing health education programs for minority youth. PMID- 22251759 TI - Neighborhood environment, self-efficacy, and physical activity in urban adolescents. AB - OBJECTIVES: To test the pathways between perceptions of built environment factors and physical activity in urban youth. METHODS: Three hundred fifty high school students' perceptions of neighborhood, and barrier self efficacy were measured by a Web survey. Physical activities were assessed using a one-week diary and accelerometers. RESULTS: Land-use mix/accessibility and neighborhood satisfaction had direct pathways to walking. Barrier self-efficacy had a direct pathway to walking. In addition, land use, specifically neighborhood accessibility, influenced adolescents' walking behavior via self-efficacy. Similar pathways were found in MVPA models. CONCLUSIONS: Neighborhood factors appear to work together with self-efficacy to facilitate physical activity. PMID- 22251760 TI - Fruit/vegetable intake and physical activity among adults with high cholesterol. AB - OBJECTIVES: To determine whether hypercholesterolemic adults followed healthy eating and appropriate physical activity. METHODS: Using the 2007 Behavioral Risk Factor Surveillance System, we measured >=5 servings of fruits and vegetables/day and Healthy People 2010 recommended physical activity. RESULTS: Of 363,667 adults >=18 years, 37.3% had hypercholesterolemia. The percentages of healthy eating and physical activity were lower among those with hypercholesterolemia than among those without (23.8% vs 27.9% for healthy eating [P< 0.001], 43.1% vs 51.7% for physical activity [P<0.001]). CONCLUSION: Hypercholesterolemic adults are less likely to practice healthy eating and to engage in physical activity than are those without hypercholesterolemia. PMID- 22251761 TI - Beliefs and intentions for skin protection and UV exposure in young adults. AB - OBJECTIVE: To evaluate Fishbein's integrative model in predicting young adults' skin protection, sun exposure, and indoor tanning intentions. METHODS: Two hundred twelve participants completed an online survey. RESULTS: Damage distress, self-efficacy, and perceived control accounted for 34% of the variance in skin protection intentions. Outcome beliefs and low self-efficacy for sun avoidance accounted for 25% of the variance in sun exposure intentions. Perceived damage, outcome evaluation, norms, and indoor tanning prototype accounted for 32% of the variance in indoor tanning intentions. CONCLUSIONS: Future research should investigate whether these variables predict exposure and protection behaviors and whether intervening can reduce young adults' skin cancer risk behaviors. PMID- 22251762 TI - Identifying correlates of young adults' weight behavior: survey development. AB - OBJECTIVE: To describe the development and psychometric properties of survey measures relevant to eating, physical activity, and weight-related behaviors among young adults. METHODS: Focus groups and reliability testing guided the development of the Project EAT-III survey. The final survey was completed by 2287 young adults. RESULTS: The systematic process employed led to a psychometrically sound and developmentally appropriate survey. Test-retest reliabilities for items included on the final survey were mostly moderate to good, and Cronbach alphas were >0.7 for 83% of developed scales. CONCLUSIONS: Future studies may find the systematic process used to be helpful in creating other weight-related surveys. PMID- 22251763 TI - "Exercise dependence"--a problem or natural result of high activity? AB - OBJECTIVES: To compare physical activity (PA) and exercise dependence (ED) in 267 weight-loss maintainers (WLM) and 213 normal-weight (NW) controls. METHODS: PA and ED assessed via accelerometery and the Exercise Dependence Questionnaire. RESULTS: WLM had higher PA levels and ED scores than those of NW (P< 0.0001). WLM status (P=.006) and higher PA (P=.0001) were independently related to higher ED, although effect sizes were larger for PA. Exercising for weight control was the ED domain that most discriminated WLM from NW. CONCLUSIONS: WLM have higher ED scores than do NW, but this is mostly due to exercising for weight control. PMID- 22251764 TI - Gender, acculturation, food patterns, and overweight in Korean immigrants. AB - OBJECTIVE: To describe acculturation, food patterns, overweight, and gender differences among Korean immigrants in the United States. METHODS: A cross sectional exploratory survey assessed acculturation, food frequencies, and weight status of 195 Korean immigrants. RESULTS: Acculturated Korean immigrants (score >=2.5) were more likely to consume both healthy and unhealthy US foods. Acculturation was not associated with overweight. Men were more likely to be acculturated (OR=2.46; CI=1.26-4.79) and overweight (OR=5.08; CI=2.37-10.90) than women. Moreover, overweight men reported more frequent consumption of fast foods, hot dogs (OR=2.92;CI=1.18-7.22), and tacos (OR=4.12;CI=1.60-10.62) than did nonoverweight men. CONCLUSION: Dietary interventions in Korean immigrants should take gender differences in acculturation and food patterns into account. PMID- 22251765 TI - Design, baseline results of Irbid longitudinal, school-based smoking study. AB - OBJECTIVE: To compare patterns of water pipe and cigarette smoking in an eastern Mediterranean country. METHODS: In 2008, 1781 out of 1877 seventh graders enrolled in 19 randomly selected schools in Irbid, Jordan, were surveyed. RESULTS: Experimentation with and current water pipe smoking were more prevalent than cigarette smoking (boys: 38.7% vs 26.8%; 20.2% vs 9.0%, girls: 21.2% vs 9.5%; and 7.5% vs 2.3%, P<0.05 for all). Parent- and peer-smoking correlated more strongly with water pipe than with cigarette smoking. CONCLUSION: Water-pipe smoking is more prevalent than cigarette smoking at this early age. PMID- 22251766 TI - Weight status in US youth: the role of activity, diet, and sedentary behaviors. AB - OBJECTIVES: To assess associations of physical activity, diet, and sedentary behaviors with overweight and obesity. METHODS: Analyses of the NHANES 2003-06 were conducted among 2368 US adolescents, ages 12-19. Self-reported diet and sedentary behavior measures were used; physical activity was assessed using accelerometers. RESULTS: Television/video viewing (OR=1.84; CI=1.24, 2.69), physical activity (OR=0.75; CI=0.59, 0.95), and fiber intake (OR=0.96; CI=0.92, 0.99) were associated with obesity whereas television/video viewing was a risk factor for overweight (OR=1.57; CI=1.1, 2.63). CONCLUSIONS: Findings using accelerometer-measured physical activity are consistent with results from other studies using self-reported measurements. No interactions with ethnicity and gender were found. PMID- 22251767 TI - Food and Drug Administration evaluation and cigarette smoking risk perceptions. AB - OBJECTIVES: To examine the relationship between a belief about Food and Drug Administration (FDA) safety evaluation of cigarettes and smoking risk perceptions. METHODS: A nationally representative, random-digit-dialed telephone survey of 1046 adult current cigarette smokers. RESULTS: Smokers reporting that the FDA does not evaluate cigarettes for safety (46.1%), exhibited greater comprehension of the health risks of smoking and were more likely (48.5%) than other participants (33.6%) to report quit intentions. Risk perceptions partially mediated the relationship between FDA evaluation belief and quit intentions. CONCLUSIONS: These findings highlight the need for proactive, effective communication to the public about the aims of new tobacco product regulations. PMID- 22251768 TI - Pedometer use in university freshmen: a randomized controlled pilot study. AB - OBJECTIVES: To describe activity patterns associated with a pedometer intervention in university freshmen and compare the intervention participants to controls for several health outcomes. METHODS: Forty-six university freshmen were randomized to a group that wore a pedometer across the academic year with a goal of 10,000 steps/day or to a control group. RESULTS: Pedometer counts were highest initially but decreased over the academic year. December presented the fewest counts. There was little difference between groups in fitness or body composition. CONCLUSIONS: Consideration of high-risk months and recommended steps/day may be important to effectively use pedometers to influence some health outcomes in university freshmen. PMID- 22251769 TI - The protective function of neighborhood social ties on psychological health. AB - OBJECTIVE: To examine relations between neighborhood characteristics and psychological health, specifically whether neighborhood trust and cooperation buffers the effects of neighborhood disorder on depression and aggressive behavior. METHODS: The sample was composed of 127 urban, African American young adults from Trenton, NJ. RESULTS: The protective function of neighborhood social interactions depended on the outcome, such that trust and cooperation among neighbors moderated the effect of neighborhood disorder on aggression but not depression. CONCLUSIONS: Results confirm the importance of taking an ecological approach to study and promote the emotional and behavioral health of young adults living in urban communities. PMID- 22251770 TI - Weight misperception and health risk behaviors among early adolescents. AB - OBJECTIVES: To examine associations between weight misperception and youth health risk and protective factors. METHODS: Three thousand ten US seventh-graders (72.1% white, mean age: 12.7 years) self-reported height, weight, risk, and protective factors. Analyses were conducted to determine cross-sectional and longitudinal associations between weight overestimation and health risk and protective factors. RESULTS: Risk and protective factors had significant cross sectional associations with weight overestimation. However, only depressive symptoms and reduced optimism predicted weight overestimation in eighth grade. Weight overestimation did not predict engagement in risky behaviors. CONCLUSIONS: Weight overestimation and risk factors appear to co-occur, suggesting a constellation of risk that warrants further research. PMID- 22251771 TI - Physical activity and self-regulation strategy use in adolescents. AB - OBJECTIVE: To examine the degree to which the use of selected theoretically derived self-regulation strategies (eg, goal setting) could predict adolescents' self-reported leisure-time physical activity behavior. METHOD: Two hundred thirty three (M age = 15.88) high school students completed measures assessing their self-regulation strategy use and their level of physical activity. RESULTS: Correlational analysis showed self-regulation strategy use was significantly related to adolescent physical activity. Regression analysis also revealed that goal setting and a causal attribution dimension accounted for 10.7% of the variance reported in adolescents' physical activity. CONCLUSION: There is a significant positive relationship between adolescent leisure-time physical activity and certain theoretically derived self-regulation strategies. PMID- 22251773 TI - Listening to the patient as a possible route to cost-effective rehabilitation: a case report. AB - INTRODUCTION: Adolescents with cerebral palsy often do not need a specific rehabilitative treatment; however, when specific needs are expressed, clinicians should listen and try to answer them. CASE PRESENTATION: We present the case of a 17-year-old Italian male patient with hemiplegia who had received standard physiotherapy and, ultimately, after a period of adapted physical activity performed in a group, was under consideration for discharge. However, due to unsatisfactory hand control, he asked for help to reach a personal goal, the ability to drive a motorbike, without surgery. Functional taping showed efficacy, but was neither cost-effective nor practical for the patient and his family; by contrast, a dynamic orthosis associated with training in a real-life environment was instead successful. CONCLUSION: The present case underlines the importance of considering solutions involving the motivation and compliance of the patient in order to improve his activity and participation. PMID- 22251772 TI - Co-culture of buffalo (Bubalus bubalis) preantral follicles with antral follicles: a comparative study of developmental competence of oocytes derived from in vivo developed and in vitro cultured antral follicles. AB - The present study was undertaken to examine whether the presence of antral follicles (AFs) affects the survival, growth and steroidogenesis of preantral follicles (PFs) and compare the maturation and developmental competence of buffalo oocytes derived from in vivo developed and in vitro cultured AFs. Two experiments were carried out. In experiment I, PFs (200-250 MUm) were isolated and cultured with or without AFs (3-5 mm) in TCM-199 medium that contained 10% fetal bovine serum (FBS), 1% insulin transferin selenium (ITS), 20 ng/ml epidermal growth factor (EGF), 0.5 MUg/ml follicle-stimulating hormone (FSH) and 100 ng/ml insulin-like growth factor (IGF)-I. In experiment II, in vitro developmental competence was compared for the cumulus-oocyte complexes (COCs) recovered from in vivo developed and in vitro cultured AFs. Survival, growth, development of antrum, accumulation of estradiol and progesterone was (P < 0.05) higher when PFs were co-cultured with AFs. Developmental competence of both types of follicular oocytes did not differ significantly in terms of maturation and cleavage rate, but morula and blastocyst production rate were (P < 0.05) higher with in vivo developed AFs as compared with the in vitro cultured antral follicular oocytes. In conclusion, co-culture of PFs with AFs supports long-term survival and growth of buffalo PFs and this co-culture system plays a dual role for in vitro production of embryos as well as understanding the relationship between developing PFs and AFs. PMID- 22251774 TI - An ectopic ACTH-producing small cell lung carcinoma associated with enhanced corticosteroid biosynthesis in the peritumoral areas of adrenal metastasis. AB - A 60-year-old Japanese male presented with swelling of bilateral cervical lymph nodes was subsequently diagnosed as the late stage of primary small cell lung carcinoma (SCLC). He was then treated with cisplatin and irinotecan as first-line chemotherapy, but hypokalemia with muscle weakness of the bilateral legs became gradually noticeable following two months of effective chemotherapy. A computed tomography (CT) scan revealed enlargement of bilateral adrenal glands and abdominal and mediastinal lymph nodes, though primary lung tumor remained the same in size. An ectopic ACTH-producing syndrome (EAS) was subsequently revealed by the following endocrinological studies. Hypokalemia was clinically improved by the treatment with metyrapone and the second-line chemotherapy with amrubicin for SCLC was started, but the patient died 12 days after the second-line chemotherapy. Post-mortem examination revealed ACTH immunoreactivity in tumor cells of all the metastatic lesions. Non-neoplastic adrenal cortex demonstrated hyperplasia associated with lipid depletion and marked expression of steroidogenic enzymes, especially in cortical cells around tumor infiltration, suggestive of paracrine ACTH stimulation of cortisol production. This is the first report evaluating expression of steroidogenic enzymes in adrenal cortex especially adjacent to the adrenal metastasis in the patients with EAS due to SCLC. These findings suggest that ACTH producing adrenal metastasis can induce EAS more frequently and severely, and that the symptoms and examination of EAS should be monitored carefully in the patients with adrenal metastasis of SCLC. PMID- 22251775 TI - Autocatalysed oxidative modifications to 2-oxoglutarate dependent oxygenases. AB - Ferrous iron and 2-oxoglutarate-dependent oxygenases and related enzymes catalyse a range of oxidative reactions, possibly the widest of any enzyme family. Their catalytic flexibility is proposed to be related to their nonhaem iron-binding site, which utilizes two or three protein-based ligands. A possible penalty for this flexibility is that they may be more prone to oxidative damage than the P450 oxidases, where the iron is arguably located in a more controlled environment. We review the evidence for autocatalysed oxidative modifications to 2-oxoglutarate dependent oxygenases, including the recently reported studies on human enzymes, as well as the oxidative fragmentations observed in the case of the plant ethylene-forming enzyme (1-aminocyclopropane-1-carboxylic acid oxidase). PMID- 22251776 TI - The development of quality indicators to improve psychosocial care in dementia. AB - BACKGROUND: The evidence for the effectiveness of psychosocial interventions in dementia care is growing but the implementation of available evidence is not automatic. Our objective was to develop valid quality indicators (QIs) for psychosocial dementia care that facilitate the implementation process in various countries and settings. METHODS: A RAND-modified Delphi technique was used to develop a potential set of QIs. Two multidisciplinary, international expert panels were involved in achieving content and face validity. Consensus on the final set was reached after a conference meeting where a third panel of dementia experts discussed measurability and applicability of the potential set. A retrospective cohort study was conducted to study the feasibility of using the final set in day care centers, hospitals, and nursing homes in Spain and The Netherlands. RESULTS: A total of 104 recommendations were selected from guidelines and systematic reviews and appraised for their contribution to improving the quality of dementia care by 49 dementia experts. Twenty-five experts attended the conference meeting and reached consensus on a set of 12 QIs representing the key elements of effective psychosocial care, such as shared decision-making and interventions tailored to needs and preferences. Data from 153 patient records showed that all but one QI subitem were applicable to all three settings in both countries. CONCLUSION: Our multidisciplinary and multinational strategy resulted in a set of unique QIs that aims exclusively at assessing the quality of psychosocial dementia care. Following implementation, these QIs will assist dementia care professionals to individualize and tailor psychosocial interventions. PMID- 22251777 TI - A population-based cohort study of chest x-ray screening in smokers: lung cancer detection findings and follow-up. AB - BACKGROUND: Case-control studies of mass screening for lung cancer (LC) by chest x-rays (CXR) performed in the 1990s in scarcely defined Japanese target populations indicated significant mortality reductions, but these results are yet to be confirmed in western countries. To ascertain whether CXR screening decreases LC mortality at community level, we studied a clearly defined population-based cohort of smokers invited to screening. We present here the LC detection results and the 10-year survival rates. METHODS: The cohort of all smokers of > 10 pack-years resident in 50 communities of Varese, screening eligible (n = 5,815), in July 1997 was invited to nonrandomized CXR screening. Self-selected participants (21% of cohort) underwent screening in addition to usual care; nonparticipants received usual care. The cohort was followed-up until December 2010. Kaplan-Meier LC-specific survival was estimated in participants, in nonparticipants, in the whole cohort, and in an uninvited, unscreened population (control group). RESULTS: Over the initial 9.5 years of study, 67 LCs were diagnosed in screening participants (51% were screen-detected) and 178 in nonparticipants. The rates of stage I LC, resectability and 5-year survival were nearly twice as high in participants (32% stage I; 48% resected; 30.5% 5-year survival) as in nonparticipants (17% stage I; 27% resected; 13.5% 5-year survival). There were no bronchioloalveolar carcinomas among screen-detected cancers, and median volume doubling time of incidence screen-detected LCs was 80 days (range, 44-318), suggesting that screening overdiagnosis was minimal. The 10 year LC-specific survival was greater in screening participants than in nonparticipants (log-rank, p = 0.005), and greater in the whole cohort invited to screening than in the control group (log-rank, p = 0.001). This favourable long term effect was independently related to CXR screening exposure. CONCLUSION: In the setting of CXR screening offered to a population-based cohort of smokers, screening participants who were diagnosed with LC had more frequently early-stage resectable disease and significantly enhanced long-term LC survival. These results translated into enhanced 10-year LC survival, independently related to CXR screening exposure, in the entire population-based cohort. Whether increased long-term LC-specific survival in the cohort corresponds to mortality reduction remains to be evaluated. TRIAL REGISTRATION NUMBER: ISRCTN90639073. PMID- 22251778 TI - Relationship between smokers' modes of entry into quitlines and treatment outcomes. AB - OBJECTIVES: To assess the relationship between the mode of entry into a quitline service and subsequent tobacco use treatment outcomes. METHODS: A retrospective study using logistic regression analysis of 11,040 Arizona Smokers' Helpline (ASHLine) clients was conducted to determine whether self- or medical referrals were related to 7- and 30-day point prevalence tobacco treatment outcomes at 7 months postquit. RESULTS: Smokers referred to the ASHLine by a health care provider were more likely to quit smoking than were those who self-referred. CONCLUSIONS: Mode of entry into a quitline service for smoking cessation is related to treatment outcomes. Reasons for this outcome are uncertain and require additional research. PMID- 22251779 TI - Classroom norms and individual smoking behavior in middle school. AB - OBJECTIVES: To investigate whether smoking prevalence in grade-level networks influences individual smoking, suggesting that peers are important social multipliers in teen smoking. METHODS: We measured gender-specific, grade-level recent and life-time smoking among urban middle-school students who participated in Project Northland Chicago in a longitudinal cohort design. RESULTS: Within schools, grade-level recent smoking had comparable effects on girls' and boys' individual-level smoking. Grade-level lifetime smoking had a greater effect on girls' smoking. CONCLUSION: Interventions can target middle school classes and schools broadly, without making the identification of friendship networks a concern. PMID- 22251780 TI - Classes of depression, anxiety, and functioning in acute coronary syndrome patients. AB - OBJECTIVES: To describe change in subgroups characterized by patterns of depression, anxiety, and functional impairment; examine treatment effects on subgroup membership; examine effects of sex and age on subgroup membership. METHODS: Latent class models were used to meet the first 2 objectives using 79 patients with depression/anxiety. Generalized estimating equations were used to meet the third objective. RESULTS: Three subgroups characterized by different combinations of psychiatric disorders and functioning were identified. Patients who received treatment were more likely to transition to a less impaired subgroup. CONCLUSIONS: Unique information about holistic treatment effects can be gained when multiple outcomes are considered simultaneously. PMID- 22251781 TI - An introduction to item response theory for health behavior researchers. AB - OBJECTIVE: To introduce item response theory (IRT) to health behavior researchers by contrasting it with classical test theory and providing an example of IRT in health behavior. METHOD: Demonstrate IRT by fitting the 2PL model to substance use survey data from the Adolescent Health Risk Behavior questionnaire (n=1343 adolescents). RESULTS: An IRT 2PL model can produce viable substance use scores that differentiate different levels of substance use, resulting in improved precision and specificity at the respondent level. CONCLUSION: IRT is a viable option for health researchers who want to produce high-quality scores for unidimensional constructs. The results from our example-although not flawless demonstrate the feasibility of IRT in health behavior research. PMID- 22251782 TI - Potential moderating role of seat belt law on the relationship between seat belt use and adverse health behavior. AB - OBJECTIVE: To determine the potential moderating effect of seat belt law on seat belt compliance among persons who engage in adverse health behaviors. METHODS: Self-reported use of seat belts and adverse health behaviors in a 2008 US state based population survey. RESULTS: Seat belt law moderates the use of seat belts among males and females who smoked, males who were physically inactive, and males and females who engaged in multiple risk behaviors. CONCLUSION: There is a need to supplement legislative interventions with more focused behavioral approaches to further increase seat belt compliance among persons who engage in adverse risk behaviors. PMID- 22251783 TI - Differences in amounts and types of physical activity by obesity status in US adults. AB - OBJECTIVES: To describe the physical activity patterns across levels of obesity among US adults. METHODS: The frequency, intensity, and duration of physical activities were compared across obesity status in 7695 adults from NHANES, 1999 2006. RESULTS: Significantly more normal-weight adults engaged in moderate- and vigorous- intensity activities and for a longer duration than did their overweight or obese counterparts. Lower intensity, longer duration walking contributed to nearly half of all moderate activity among obese subjects. CONCLUSIONS: Significant differences exist in intensity, frequency, and duration of physical activity by weight status. This information suggests a targeted approach to current physical activity interventions be explored. PMID- 22251784 TI - Store and restaurant advertising and health of public housing residents. AB - OBJECTIVES: To determine relationships between food and beverage signs and health. METHODS: In 12 public housing neighborhoods, food and alcohol signs were counted for stores and restaurants. Health and demographic data were from 373 adults. RESULTS: Multilevel modeling showed higher BMI was related to more store and restaurant alcohol signs, higher blood pressure, nonsmokers, and females. Higher dietary fat consumption was related to more store and restaurant alcohol and fewer low-calorie healthy signs, lower fruit consumption, fewer minutes walked, and white and Hispanic/Latino ethnicity. CONCLUSIONS: Signs in stores and restaurants are related to BMI and dietary fat consumption among residents. PMID- 22251786 TI - Hurried driver dispositions: their relationship to risky traffic behaviors. AB - OBJECTIVE: To examine the relationship of driver dispositions with traffic safety behaviors and beliefs. METHODS: A random digit-dial telephone survey was conducted of 796 licensed drivers. RESULTS: Binary and multivariate logistic regression analyses compared hurried and nonhurried drivers and found that hurried drivers were more likely to admit to a variety of risky behaviors. They were also less likely to believe they would be ticketed for speeding and to report wearing their seat belt than were nonhurried drivers. CONCLUSIONS: More research is needed into identifying the underlying motivational factors of hurried drivers and what countermeasures will be most effective for them. PMID- 22251785 TI - Cigarette smoking behaviors and beliefs in persons living with HIV/AIDS. AB - OBJECTIVE: To measure biopsychosocial domains related to tobacco use in persons living with HIV/AIDS (PLWHAs). METHODS: Cross-sectional interview study of 60 PLWHA smokers randomly selected from an HIV clinic. RESULTS: Participants averaged 14.4 cigarettes daily. Sixty-five percent were moderately or highly nicotine dependent, and most were motivated to quit. Substance use and depression were very common. Most reported that smoking helped them cope with depression, anxiety, and anger. Twenty-seven percent thought (mistakenly) that smoking raised their T-cell counts and/or helped fight infections. Referrals to quitlines or cessation programs were uncommon. CONCLUSIONS: Smoking among PLWHAs is a challenging problem requiring targeted intervention strategies. PMID- 22251787 TI - College students' perceived disease risk versus actual prevalence rates. AB - OBJECTIVE: To compare college students' perceived disease risk with disease prevalence rates. METHODS: Data were analyzed from 625 college students collected with an Internet-based survey. Paired t-tests were used to separately compare participants' perceived 10-year and lifetime disease risk for 4 diseases: heart disease, cancer, diabetes, and overweight/obesity. RESULTS: Respondents estimated their risk of developing heart disease as lower than cancer, yet rated their risk of developing heart disease as higher than diabetes and being overweight/obese. CONCLUSION: Incongruence between college students' perceived disease risk and disease prevalence rates calls for improved public health education. PMID- 22251788 TI - The interplay between affect and theory of planned behavior variables. AB - OBJECTIVES: To assess whether affective evaluations of health behaviors moderate or mediate the influence of theory of planned behavior (TPB) variables on intention. METHODS: For each of 20 health behaviors, respondents (N=300) completed questionnaire measures of affective evaluation, attitude, subjective norm, perceived behavioral control, and intention. RESULTS: Analyses using path modeling revealed that affective evaluation of the behaviors did not moderate the influence of the TPB variables on intention, but it partially mediated the influence of attitude and perceived behavioral control on intention. CONCLUSIONS: These results emphasize the importance of affective evaluation as a target for health communication. PMID- 22251789 TI - Commercial sex worker use among male Chinese rural-urban migrants. AB - OBJECTIVE: To explore HIV/AIDS sexual risk behaviors and specifically the use of commercial sex workers among Chinese male rural-urban migrants. METHODS: The study design is loosely based on diffusion of innovation theory and examines the hedonistic tendencies of this group. Survey data were collected from male rural to urban migrants by an anonymous questionnaire in 2 Chinese cities. RESULTS: A total of 1595 migrant workers were included in this study. At the time of this study, 27.6% had used commercial sex workers, and 79.9% of those did so for the first time after moving to the cities. CONCLUSION: Findings suggest that interventions to reduce use of commercial sex workers should be implemented before or as soon as possible after rural urban males move to urban environments. PMID- 22251790 TI - Dual use of cigarettes and smokeless tobacco among South African adolescents. AB - OBJECTIVES: To determine factors associated with dual use of tobacco products in a population of black South African adolescents. METHODS: Data were obtained from a self-administered questionnaire completed by a representative sample of grade 8 students from 21 randomly selected secondary state schools in the Limpopo Province, South Africa (n=1878). RESULTS: Of the respondents, 11.4% used smokeless tobacco (SLT), and 55.2% of SLT users also smoked cigarettes (dual users). Dual users were more likely to be vulnerable to depression, engage in binge drinking, smoke cannabis, and attend schools without rules against smoking. CONCLUSION: Dual tobacco use forms part of multiple-risk-taking behavior. PMID- 22251791 TI - Media use and perceived risk as predictors of marijuana use. AB - OBJECTIVES: To assess the influence of media use and perceived risk on marijuana use outcomes. METHODS: With survey data from 750 US young adults, structural equation modeling tested how attitudes, behaviors, and behavioral intention specific to marijuana use are influenced by perceived personal and societal risk of marijuana use, media campaign exposure, and news use. RESULTS: Perceived societal risk had significant effects, though not as strong as perceived personal risk. Campaign exposure had favorable effects whereas those of news use were mixed. CONCLUSIONS: Perceived personal risk and perceived societal risk should be considered when designing preventive media campaigns. PMID- 22251792 TI - Successful treatment of Chlamydophila pneumoniae acute respiratory distress syndrome with extracorporeal membrane oxygenator: a case report and diagnostic review. AB - INTRODUCTION: Chlamydophila pneumoniae is a respiratory pathogen known to infect the upper and lower respiratory tracts. Infection severity can range from sub clinical pulmonary infection to acute respiratory distress syndrome. CASE PRESENTATION: A previously healthy 62-year-old Caucasian man was admitted to our hospital for acute respiratory failure. Serum samples obtained every week starting from the day of admission showed clear-cut seroconversion for C. pneumoniae antibodies. All other cultures obtained during the first days of hospitalization were negative. Despite maximal ventilatory support (high positive end expiratory pressure, fraction of inspired oxygen of 1.0, nitric oxide inhalation, neuromuscular blocking agents and prone positioning), our patient remained severely hypoxemic, which led us to initiate an extracorporeal membrane oxygenation treatment. Extracorporeal membrane oxygenation and hemodiafiltration were withdrawn on day 12. Our patient was extubated on day 18 and discharged from our Intensive Care Unit on day 20. He went home a month later. CONCLUSION: We describe the first published case of acute respiratory distress syndrome due to C. pneumoniae infection successfully treated by extracorporeal membrane oxygenation, a very useful tool in this syndrome. A quick and specific method for the definite diagnosis of Chlamydophila infection should be developed. PMID- 22251793 TI - Proteomic screening for Rho-kinase substrates by combining kinase and phosphatase inhibitors with 14-3-3zeta affinity chromatography. AB - The small GTPase RhoA is a molecular switch in various extracellular signals. Rho kinase/ROCK/ROK, a major effector of RhoA, regulates diverse cellular functions by phosphorylating cytoskeletal proteins, endocytic proteins, and polarity proteins. More than twenty Rho-kinase substrates have been reported, but the known substrates do not fully explain the Rho-kinase functions. Herein, we describe the comprehensive screening for Rho-kinase substrates by treating HeLa cells with Rho-kinase and phosphatase inhibitors. The cell lysates containing the phosphorylated substrates were then subjected to affinity chromatography using beads coated with 14-3-3 protein, which interacts with proteins containing phosphorylated serine or threonine residues, to enrich the phosphorylated proteins. The identities of the molecules and phosphorylation sites were determined by liquid chromatography tandem mass spectrometry (LC/MS/MS) after tryptic digestion and phosphopeptide enrichment. The phosphorylated proteins whose phosphopeptide ion peaks were suppressed by treatment with the Rho-kinase inhibitor were regarded as candidate substrates. We identified 121 proteins as candidate substrates. We also identified phosphorylation sites in Partitioning defective 3 homolog (Par-3) at Ser143 and Ser144. We found that Rho-kinase phosphorylated Par-3 at Ser144 both in vitro and in vivo. The method used in this study would be applicable and useful to identify novel substrates of other kinases. PMID- 22251794 TI - Ultraviolet a induces endoplasmic reticulum stress response in human dermal fibroblasts. AB - The endoplasmic reticulum (ER) stress response is a cytoprotective mechanism against the accumulation of unfolded proteins in the ER (ER stress) that consists of three response pathways (the ATF6, IRE1 and PERK pathways) in mammals. These pathways regulate the transcription of ER-related genes through specific cis acting elements, ERSE, UPRE and AARE, respectively. Because the mammalian ER stress response is markedly activated in professional secretory cells, its main function was thought to be to upregulate the capacity of protein folding in the ER in accordance with the increased synthesis of secretory proteins. Here, we found that ultraviolet A (UVA) irradiation induced the conversion of an ER localized sensor pATF6alpha(P) to an active transcription factor pATF6alpha(N) in normal human dermal fibroblasts (NHDFs). UVA also induced IRE1-mediated splicing of XBP1 mRNA as well as PERK-mediated phosphorylation of an alpha subunit of eukaryotic initiation factor 2. Consistent with these observations, we found that UVA increased transcription from ERSE, UPRE and AARE elements. From these results, we concluded that UVA irradiation activates all branches of the mammalian ER stress response in NHDFs. This suggests that the mammalian ER stress response is activated by not only intrinsic stress but also environmental stress. PMID- 22251795 TI - Cisterna-specific localization of glycosylation-related proteins to the Golgi apparatus. AB - The Golgi apparatus is an intracellular organelle playing central roles in post translational modification and in the secretion of membrane and secretory proteins. These proteins are synthesized in the endoplasmic reticulum (ER) and transported to the cis-, medial-and trans-cisternae of the Golgi. While trafficking through the Golgi, proteins are sequentially modified with glycan moieties by different glycosyltransferases. Therefore, it is important to analyze the glycosylation function of the Golgi at the level of cisternae. Markers widely used for cis-, medial- and trans-cisternae/trans Golgi network (TGN) in Drosophila are GM130, 120 kDa and Syntaxin16 (Syx16); however the anti-120 kDa antibody is no longer available. In the present study, Drosophila Golgi complex localized glycoprotein-1 (dGLG1) was identified as an antigen recognized by the anti-120 kDa antibody. A monoclonal anti-dGLG1 antibody suitable for immunohistochemistry was raised in rat. Using these markers, the localization of glycosyltransferases and nucleotide-sugar transporters (NSTs) was studied at the cisternal level. Results showed that glycosyltransferases and NSTs involved in the same sugar modification are localized to the same cisternae. Furthermore, valuable functional information was obtained on the localization of novel NSTs with as yet incompletely characterized biochemical properties. PMID- 22251796 TI - Wounding coordinately induces cell wall protein, cell cycle and pectin methyl esterase genes involved in tuber closing layer and wound periderm development. AB - Little is known about the coordinate induction of genes that may be involved in agriculturally important wound-healing events. In this study, wound-healing events were determined together with wound-induced expression profiles of selected cell cycle, cell wall protein, and pectin methyl esterase genes using two diverse potato genotypes and two harvests (NDTX4271-5R and Russet Burbank tubers; 2008 and 2009 harvests). By 5 d after wounding, the closing layer and a nascent phellogen had formed. Phellogen cell divisions generated phellem layers until cessation of cell division at 28 d after wounding for both genotypes and harvests. Cell cycle genes encoding epidermal growth factor binding protein (StEBP), cyclin-dependent kinase B (StCDKB) and cyclin-dependent kinase regulatory subunit (StCKS1At) were induced by 1 d after wounding; these expressions coordinated with related phellogen formation and the induction and cessation of phellem cell formation. Genes encoding the structural cell wall proteins extensin (StExt1) and extensin-like (StExtlk) were dramatically up regulated by 1-5 d after wounding, suggesting involvement with closing layer and later phellem cell layer formation. Wounding up-regulated pectin methyl esterase genes (StPME and StPrePME); StPME expression increased during closing layer and phellem cell formation, whereas maximum expression of StPrePME occurred at 5-14 d after wounding, implicating involvement in later modifications for closing layer and phellem cell formation. The coordinate induction and expression profile of StTLRP, a gene encoding a cell wall strengthening "tyrosine-and lysine-rich protein," suggested a role in the formation of the closing layer followed by phellem cell generation and maturation. Collectively, the genes monitored were wound-inducible and their expression profiles markedly coordinated with closing layer formation and the index for phellogen layer meristematic activity during wound periderm development; results were more influenced by harvest than genotype. Importantly, StTLRP was the only gene examined that may be involved in phellogen cell wall thickening after cessation of phellogen cell division. PMID- 22251797 TI - Molecular characterization of an anthocyanin-related glutathione S-transferase gene in cyclamen. AB - Anthocyanins are a subclass of flavonoids and are a major contributor to flower colors ranging from red to blue and purple. Previous studies in model and ornamental plants indicate a member of the glutathione S-transferase (GST) gene family is involved in vacuolar accumulation of anthocyanins. In order to identify the anthocyanin-related GST in cyclamen, degenerate PCR was performed using total RNA from immature young petals. Four candidates of GSTs (CkmGST1 to CkmGST4) were isolated. Phylogenetic analysis indicated that CkmGST3 was closely related to PhAN9, an anthocyanin-related GST of petunia, and this clade was clustered with other known anthocyanin-related GSTs. Expression analysis at different developmental stages of petals revealed that CkmGST3 was strongly expressed in paler pigmented petals than in fully pigmented petals, in contrast to the constitutive expression of the other three candidates during petal development. This expression pattern of CkmGST3 was correlated with those of other anthocyanin biosynthetic genes such as CkmF3'5'H and CkmDFR2. Molecular complementation of Arabidopsis tt19, a knockout mutant of an anthocyanin-related GST gene, demonstrated that CkmGST3 could complement the anthocyanin-less phenotype of tt19. Transgenic plants that expressed the other three CkmGSTs did not show anthocyanin accumulation. These results indicate CkmGST3 functions in anthocyanin accumulation in cyclamen. PMID- 22251798 TI - Comprehensive analysis of differential genes and miRNA profiles for discovery of topping-responsive genes in flue-cured tobacco roots. AB - Decapitation/topping is an important cultivating measure for flue-cured tobacco, and diverse biology processes are changed to respond to the topping, such as hormonal balance, root development, source-sink relationship, ability of nicotine synthesis and stress tolerance. The purpose of this study was to clarify the molecular mechanism involved in the response of flue-cured tobacco to topping. The differentially expressed genes and micro RNAs (miRNAs) before and after topping were screened with a combination of suppression subtractive hybridization (SSH) and miRNA deep sequencing. In all, 560 differently expressed clones were sequenced by SSH, and then 129 high quality expressed sequence tags were acquired. These expressed sequence tags were mainly involved in secondary metabolism (13.5%), hormone metabolism (4%), signaling/transcription (17.5%), stress/defense (20%), protein metabolism (13%), carbon metabolism (7%), other metabolism (12%) and unknown function (13%). The results contribute new data to the list of possible candidate genes involved in the response of flue-cured tobacco to topping. NAC transcription factor, a differential gene identified by SSH, had been proved to have a role in the regulation of nicotine biosynthesis. High-throughput sequencing of two small RNA libraries in combination with SSH screening revealed 15 differential miRNAs whose target genes were identical to some differential genes identified in SSH, suggesting that miRNAs play a critical role in post-transcriptional gene regulation in the response of flue-cured tobacco to decapitation. Based on the role of these miRNAs and differential genes identified from SSH in response to topping, an miRNA mediated model for flue cured tobacco in response to topping is proposed. PMID- 22251799 TI - Living with mild cognitive impairment: the patient's and carer's experience. AB - BACKGROUND: Mild cognitive impairment (MCI) is a relatively common condition and rates of diagnosis are likely to increase in the near future. Little is known about the experiences of patients with MCI and their carers nor about the most appropriate interventions to support this group. METHODS: The existing literature on this topic up to July 2011 was identified via systematic searches of the Embase and Medline databases, the Cochrane Library and relevant sections of the National Electronic Library for Health. The main search term "mild cognitive impairment" was used in combination with other relevant terms. The reference lists of reviewed articles were also examined for any additional papers of significance. Papers identified by this method were examined and those deemed relevant were included in this review. RESULTS: Twenty-one suitable papers were identified for inclusion in this review, a relatively small number. The studies reviewed suggest that patients with MCI and their carers face a variety of practical and emotional challenges. No interventional studies of support have been undertaken, but the authors of relevant observational studies have suggested provision of information, psychosocial support and strategies to enhance patient interaction with carers and social contacts. CONCLUSIONS: MCI results in significant challenges for both patients and their carers. Further work is required in order to establish the best way to help patients and carers meet these challenges. PMID- 22251800 TI - DNA methylation regulates expression of VEGF-R2 (KDR) and VEGF-R3 (FLT4). AB - BACKGROUND: Vascular Endothelial Growth Factors (VEGFs) and their receptors (VEGF Rs) are important regulators for angiogenesis and lymphangiogenesis. VEGFs and VEGF-Rs are not only expressed on endothelial cells but also on various subtypes of solid tumors and leukemias contributing to the growth of the malignant cells. This study was performed to examine whether VEGF-R2 (KDR) and VEGF-R3 (FLT4) are regulated by DNA methylation. METHODS: Real-time (RT) PCR analysis was performed to quantify KDR and FLT4 expression in some ninety leukemia/lymphoma cell lines, human umbilical vein endothelial cells (HUVECs) and dermal microvascular endothelial cells (HDMECs). Western blot analyses and flow cytometric analyses confirmed results at the protein level. After bisulfite conversion of DNA we determined the methylation status of KDR and FLT4 by DNA sequencing and by methylation specific PCR (MSP). Western blot analyses were performed to examine the effect of VEGF-C on p42/44 MAPK activation. RESULTS: Expression of KDR and FLT4 was observed in cell lines from various leukemic entities, but not in lymphoma cell lines: 16% (10/62) of the leukemia cell lines expressed KDR, 42% (27/65) were FLT4 positive. None of thirty cell lines representing six lymphoma subtypes showed more than marginal expression of KDR or FLT4. Western blot analyses confirmed KDR and FLT4 protein expression in HDMECs, HUVECs and in cell lines with high VEGF-R mRNA levels. Mature VEGF-C induced p42/44 MAPK activation in the KDR- /FLT4(+) cell line OCI-AML1 verifying the model character of this cell line for VEGF-C signal transduction studies. Bisulfite sequencing and MSP revealed that GpG islands in the promoter regions of KDR and FLT4 were unmethylated in HUVECs, HDMECs and KDR(+) and FLT4(+) cell lines, whereas methylated cell lines did not express these genes. In hypermethylated cell lines, KDR and FLT4 were re-inducible by treatment with the DNA demethylating agent 5 Aza-2'deoxycytidine, confirming epigenetic regulation of both genes. CONCLUSIONS: Our data show that VEGF-Rs KDR and FLT4 are silenced by DNA methylation. However, if the promoters are unmethylated, other factors (e.g. transactivation factors) determine the extent of KDR and FLT4 expression. PMID- 22251801 TI - Effect of maternal body mass index on pregnancy outcome and newborn weight. AB - BACKGROUND: Maternal obesity has been associated with adverse pregnancy outcomes, such as pre-eclampsia, eclampsia, pre- and post-term delivery, induction of labor, macrosomia, increased rate of caesarean section, and post-partum hemorrhage. The objective of this study was to determine the effect of maternal Body Mass Index (BMI) on pregnancy outcomes. METHODS: 1000 pregnant women were enrolled in the study. In order to explore the relationship between maternal first trimester Body Mass Index and pregnancy outcomes, participants were categorized into five groups based on their first trimester Body Mass Index. The data were analyzed using Pearson Chi-square tests in SPSS 18. Differences were considered significant if p < 0.05. RESULTS: Women with an above-normal Body Mass Index had a higher incidence of pre-eclampsia, induction of labor, caesarean section, pre-term labor, and macrosomia than women with a normal Body Mass Index (controls). There was no significant difference in the incidence of post-term delivery between the control group and other groups. CONCLUSION: Increased BMI increases the incidence of induction of labor, caesarean section, pre-term labor and macrosomia. The BMI of women in the first trimester of pregnancy is associated with the risk of adverse pregnancy outcome. PMID- 22251802 TI - Proteome analysis of cerebrospinal fluid in healthy beagles and canine encephalitis. AB - We performed proteomics analysis of the cerebrospinal fluid (CSF) of healthy dogs and dogs with meningoencephalitis of unknown etiology (MUE). By comparing two dimensional electrophoreses (2DE), an upregulated spot was found in MUE dogs. This protein was identified as a neuron-specific enolase (NSE) by analysis with MALDI-TOF mass spectrometry. In comparing dot blots using an antibody against NSE, the NSE levels in the CSF of MUE dogs was significantly higher than that of the controls. NSE is a diagnostic marker of neuroendocrine tumors, brain injury and spinal cord trauma in humans. It seems that the NSE concentration in the CSF is increased by cellular destruction in canine encephalitis. Though elevation of NSE may not be specific in canine encephalitis because the NSE level was increased in other CNS diseases, further study including measurement with serum is necessary. PMID- 22251803 TI - Sugar expressions on the vaginal epithelium in pregnant mice. AB - Sugar expressions were examined on the epithelium of both the middle portion of the vagina and the vaginal portion of the cervical canal (CC) in pregnant mice to understand the pathogenesis of bacterial infection in the female reproductive organ by using a panel of lectins. As a result, N-acetylglucosamine was positive before pregnant day (P) 7 but negative after P10 and at diestrus on both the vagina and the CC. In addition, some differences in sugar expressions were seen between them. These results suggest that sugar expressions on the mucosal surface would change not only site-specifically but also time-dependently, and these sugar differences indicate the possibility of the alteration of the settled bacterial species on the vaginal mucosa in pregnancy. PMID- 22251805 TI - When do we choose the 'better balance' ear for cochlear implants? AB - OBJECTIVES: In cochlear implant planning, the ear with poorer vestibular function, as determined through electronystagmography (ENG), is often selected as the site for implantation since surgery carries a low risk of iatrogenic labyrinthine injury. We sought to determine reasons for placing a cochlear implant in the 'better balance' ear. METHODS: A retrospective cohort study of patients implanted with a cochlear implant at a tertiary care center from 1984 to June 2009 was performed. Based on ENG results, patients with asymmetric caloric reduction were identified. Of these patients, those who were implanted in the 'better balance' ear were selected for chart review. The charts were reviewed to determine rationale for ear selection. RESULTS: Of the 724 cochlear implant patients implanted from 1984 to June 2009, ENG tests demonstrated that 130 (18%) had asymmetric abnormal responses. Thirty five (27%) of the patients with asymmetric abnormal responses were implanted in the 'better balance' ear. Review of these 35 patient charts revealed that reasons for selection of the 'better balance' ear fell into four categories: anatomical contraindications, attempting to attain binaural hearing, avoiding implantation of an ear with marked auditory deprivation, and patient preference. DISCUSSION: Based on our current practice, we have identified four situations in which patients were implanted in the 'better balance' ear, and subsequently developed an algorithm to aid surgeons in side selection for cochlear implantation. Further study and validation of this algorithm is recommended. PMID- 22251806 TI - Clinical evaluation of cochlear implant sound coding taking into account conjectural masking functions, MP3000TM. AB - Efficacy of the SPEAK and ACE coding strategies was compared with that of a new strategy, MP3000TM, by 37 European implant centers including 221 subjects. The SPEAK and ACE strategies are based on selection of 8-10 spectral components with the highest levels, while MP3000 is based on the selection of only 4-6 components, with the highest levels relative to an estimate of the spread of masking. The pulse rate per component was fixed. No significant difference was found for the speech scores and for coding preference between the SPEAK/ACE and MP3000 strategies. Battery life was 24% longer for the MP3000 strategy. With MP3000 the best results were found for a selection of six components. In addition, the best results were found for a masking function with a low-frequency slope of 50 dB/Bark and a high-frequency slope of 37 dB/Bark (50/37) as compared to the other combinations examined of 40/30 and 20/15 dB/Bark. The best results found for the steepest slopes do not seem to agree with current estimates of the spread of masking in electrical stimulation. Future research might reveal if performance with respect to SPEAK/ACE can be enhanced by increasing the number of channels in MP3000 beyond 4-6 and it should shed more light on the optimum steepness of the slopes of the masking functions applied in MP3000. PMID- 22251807 TI - How we do it: adaptation of music instruction for pediatric cochlear implant recipients. AB - This paper outlines the skills required for participation in structured music programs and possible adaptations to facilitate successful participation by pediatric cochlear implant recipients. Common curricular components that present the structural features of music and the implications for perceptual and music production skills are discussed. A checklist of practical recommendations for clinicians, educators, and parents is provided to ensure success in integrating cochlear implant recipients into early childhood music programs. PMID- 22251808 TI - Preliminary results and technique for electrophysiological intra-operative monitoring of residual hearing during cochlear implantation. AB - AIMS: To assess the feasibility of intra-operative monitoring of residual hearing using electrocochleography (ECOG) during cochlear implantation. We present our methods and preliminary results. METHODS: We attempted to monitor 21 consecutive paediatric and adult subjects during cochlear implantation. All subjects were implanted via a promontory cochleostomy with full electrode insertions of Cochlear(TM) Nucleus(r) (Cochlear Nucleus, Cochlear Ltd, Australia) devices: 8 with straight electrodes and 13 with contoured electrodes. Baseline recordings were made after the completion of the posterior tympanotomy, and subsequently at stages of the cochleostomy and electrode insertion. RESULTS: We were unable to obtain recordings on five patients because the ear-insert tubing kinked, which disrupted transmission of the stimulus. Five had insufficient cochlear function to be able to record a baseline ECOG. No subjects in whom we were able to obtain a satisfactory baseline ECOG (n=11) had a reduction in ECOG action potential (AP) amplitude, morphology or threshold up to completion of the cochleostomy. Seven maintained an unchanged ECOG throughout the procedure to full insertion. An implant had to be replaced because of a faulty straight electrode in one patient. The amplitude significantly reduced during insertion of the replacement array. Two had a reduction in amplitude, threshold, and shape of the wave related to inadvertent suction of the perilymph. Subsequently, one maintained this changed ECOG to the end of the procedure, but the other progressed to complete loss of the ECOG during insertion of the array. One other subject had a significant reduction in the amplitude during insertion of the electrode from a depth of approximately 18mm to full insertion. CONCLUSIONS: Intra-operative monitoring of residual hearing may be possible in most patients undergoing cochlear implantation. This pilot study suggests that cochleostomy is not associated with intra-operative loss of residual hearing; ECOG can be preserved during the procedure in most patients; intra-operative loss of hearing is most likely to occur when the tip of the array reaches the basal turn of the cochlea. This risk may increase if the array has to be removed and re-inserted. Suction of perilymph causes immediate changes, which may not recover. PMID- 22251809 TI - Flat-panel computed tomography versus multislice computed tomography to evaluate cochlear implant positioning. AB - OBJECTIVE: To evaluate and compare image quality between flat-panel volumetric computed tomography (fpVCT) and multislice CT (msCT) in temporal bones with cochlear implants (CIs), and to evaluate fpVCT imaging for accuracy in determining CI electrode positioning. METHODS: Six cadaveric temporal bones were imaged prior to CI using fpVCT. Each bone was implanted with an electrode array and rescanned in order to create radial reformatted images through each electrode contact. Electrode-modiolar interval (EMI) distances were measured. The bones were fixed and cut in order to grossly evaluate for CI intrascalar positioning and insertional trauma. MAIN OUTCOME MEASURE: To compare image quality between fpVCT and msCT in temporal bones with CI, and to evaluate the utility of fpVCT in post-implantation temporal bone analysis. RESULTS: The mean EMI distances did not differ significantly between fpVCT and msCT images, while the image quality was significantly better for fpVCT. Furthermore, information about intracochlear trauma and intrascalar electrode array positioning can be ascertained using this radiographic technique. CONCLUSION: fpVCT and msCT do not differ significantly in the evaluation of EMI distances in implanted temporal bones, but the image quality is significantly better using fpVCT. Additionally, useful information regarding intracochlear trauma, electrode depth of insertion, and intrascalar positioning can be gained from fpVCT imaging. Given the ease of use, superior image quality, improved convenience, reduced levels of radiation, and agreement with histology, fpVCT is a valuable option for post-implantation temporal bone imaging. PMID- 22251810 TI - Prevention and management of cochlear implant infections. AB - Understanding the issues of infection related to an implantable medical device is crucial to all cochlear implant teams. Furthermore, given the risk of central nervous system complications and the relatively high quantity of underlying resource investment associated with cochlear implantation, the stakes of infection are high. The optimal strategies to prevent and manage such infections are still evolving as good-quality prospective data to guide such management decisions are not yet abundant within the medical literature and many recommendations are based on retrospective reviews or anecdotal evidence. We will outline a general strategy to deal with cochlear implant-related infection based on both the authors' experience and the published literature. PMID- 22251812 TI - Applying a subtraction technique to minimize cochlear implant artifact with soundfield and direct audio input stimulations. AB - We explored the feasibility of a subtraction technique described by Friesen and Picton to remove the cochlear implant (CI) artifact to long duration stimuli in the soundfield and using direct input all through the participant's preferred MAP. Friesen and Picton previously explored this technique by recording cortical potentials in four CI users with 1000 pulse per second (pps) stimuli, bypassing the speech processor. Cortical auditory evoked potentials (N1-P2) to 1000 Hz tones were recorded from a post-lingually deafened adult with three different stimulus presentation setups: soundfield to processor T-mic (SF), soundfield to lapel mic (SF-LM), and direct input (DI). Stimuli were presented at 65 dB SPL(A). The SF setup required stabilizing the head to minimize changes in magnitude for the CI artifact. The SF-LM and DI setups did not require head stabilization, but were evaluated as alternatives to the SF setup. Clear N1-P2 responses were obtained with comparable waveform morphologies, amplitudes, and latencies despite some differences in the magnitude of the CI artifact for the different stimulus presentation setups. The results of this study demonstrate that subtraction technique is feasible for recording N1-P2 responses in CI users, though further studies are needed for the three stimulation setups. PMID- 22251811 TI - Electron microscopy changes of cochlear implant electrodes with permanently high impedances. AB - OBJECTIVE: Impedance measurements by means of telemetry have provided us with an objective test of cochlear implant function. Unmeasurable impedance suggests a possible defect on the corresponding channel of the electrode. However, increasing impedances could suggest inflammatory and/or proliferating processes along the electrode. In this report we examined correlations between high impedance, measured in vivo and in vitro findings on the electrode surfaces. METHOD: We describe recurrent increases in cochlear implant electrode impedance in the same channels, which could initially be reversed by reprogramming the implant, and with anti-inflammatory treatment using cortisone and antibiotics. Subsequently, however, the impedances remained consistently high, indicating a cochlear implant defect. After the removal of the cochlear implant, the electrodes were examined using light and scanning electron microscopy. RESULTS: Examination of the electrodes with normal impedance values revealed, in the great majority of the electrodes, silver shining surfaces. On the other hand, electrodes with high impedances were found coated with tissue. Further analysis of these electrodes using scanning electron microscopy also demonstrated surface changes. DISCUSSION: Persistently high impedances were related to changes on the electrodes' surface and to coating with tissue in this case. These changes can result in adhesive processes and technical malfunction, leading to explantation and difficult re-implantation. Therefore, close and professional supervision of cochlear implant patients is needed. PMID- 22251813 TI - Improved hearing with cochlear implantation in Fabry's disease. AB - OBJECTIVE: To describe our center's experience with cochlear implantation in patients suffering from Fabry's disease, an inherited mutation resulting in an alpha-galactosidase A enzyme deficiency. CLINICAL PRESENTATION: Case report of two patients aged 49 and 59 at implant, with genetically confirmed Fabry's disease and progressive hearing loss. INTERVENTION: Surgical implantation of Clarion (Advanced Bionics) and Nucleus Freedom (Cochlear) cochlear implants. CONCLUSION: Cochlear implantation improves hearing discrimination by 60 points on the HINT scale. This suggests that cochlear implantation is a safe and effective intervention that improves hearing discrimination in patients suffering from Fabry's disease. PMID- 22251814 TI - Cochlear implantation in superficial siderosis: a viable option? AB - OBJECTIVE: Superficial siderosis of the central nervous system is characterized by accumulation of haemosiderin in the subpial layers of the brain and spinal cord. The evidence largely suggests a retro-cochlear cause for hearing loss with questionable involvement of cochlea. We present our experience with two patients of superficial siderosis who underwent cochlear implantation, and discuss their outcomes and the underlying pathology. CLINICAL PRESENTATION: The first patient developed a gradually progressive, profound hearing loss over 25 years, clinical diagnosis being made on MRI scans. The second patient was referred to us with bilateral sensorineural hearing loss, tinnitus, ataxia, dementia, seizures, and visual impairment. INTERVENTION: Both underwent cochlear implantation for auditory rehabilitation. The first patient gained significant benefit, whereas the second patient has not developed any meaningful auditory stimulation at 9 month post-operative follow-up. CONCLUSION: Hearing loss due to superficial siderosis even though predominantly retro-cochlear may be successfully rehabilitated with a cochlear implant. However, outcomes are variable and more evidence regarding experience with cochlear implant in such patients with long term follow-up is desirable. PMID- 22251815 TI - Cochlear implant magnet extrusion with subsequent surgical replacement and restoration of full implant use without the need for device explantation. AB - OBJECTIVE AND IMPORTANCE: We recount the unusual case of a young boy whose removable cochlear implant magnet extruded through the skin after becoming displaced after several episodes of direct but minor head trauma. This article outlines a course of clinical management that resulted in the successful re implantation of a new magnet without infective sequelae and the need for device explantation. CLINICAL PRESENTATION: The child presented with recurrent erythema and swelling at the implant site. In retrospect, subtle magnet displacement was not readily identified on initial imaging. The external magnet required an increase in strength while local swelling settled, but subsequently had to be reduced as the magnet was drawn gradually to the skin surface. Full extrusion took place, but in the absence of any obvious infection, the site healed quickly. INTERVENTION AND TECHNIQUE: The external device was retained with a self adhesive disc for 1 year, during which time the patient was observed closely for signs of local infection. The child was subsequently admitted for surgical re exploration and insertion of a new magnet. Care was taken to re-establish the integrity of the fibrous pocket that surrounded the cochlear implant. CONCLUSION: This uneventful intervention was followed by the resumption of full and unimpaired implant use. At the time of this article submission, the child is now 5 years post-extrusion and continues to do well in full-time education. PMID- 22251816 TI - Delayed retroauricular cerebrospinal fluid (CSF) collection in cochlear implantation. AB - In the literature, this is the first description of a delayed retroauricular cerebrospinal fluid (CSF) collection in a child after 18 months of cochlear implantation. During surgical revision, anomalous thinning of the dura and leakage of CSF was found beneath the receiver, requiring local sealing and repositioning. Exposure of the dura is a procedure usually performed during housing of the receiver to avoid excessive protrusion of the implant in subjects with insufficient bone thickness. In most cases, this has proved to be a safe procedure. However, in some cases, as in children, exposure of the dura should be undertaken with care. PMID- 22251817 TI - Coming of age: reflections on old age psychiatry as a specialty in the National Health Service, 1989-2010. PMID- 22251818 TI - Performance of a simple chromatin-rich segmentation algorithm in quantifying basal cell carcinoma from histology images. AB - BACKGROUND: The use of digital imaging and algorithm-assisted identification of regions of interest is revolutionizing the practice of anatomic pathology. Currently automated methods for extracting the tumour regions in basal cell carcinomas are lacking. In this manuscript a colour-deconvolution based tumour extraction algorithm is presented. FINDINGS: Haematoxylin and eosin stained basal cell carcinoma histology slides were digitized and analyzed using the open source image analysis program ImageJ. The pixels belonging to tumours were identified by the algorithm, and the performance of the algorithm was evaluated by comparing the pixels identified as malignant with a manually determined dataset.The algorithm achieved superior results with the nodular tumour subtype. Pre processing using colour deconvolution resulted in a slight decrease in sensitivity, but a significant increase in specificity. The overall sensitivity and specificity of the algorithm was 91.0% and 86.4% respectively, resulting in a positive predictive value of 63.3% and a negative predictive value of 94.2% CONCLUSIONS: The proposed image analysis algorithm demonstrates the feasibility of automatically extracting tumour regions from digitized basal cell carcinoma histology slides. The proposed algorithm may be adaptable to other stain combinations and tumour types. PMID- 22251819 TI - A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients. AB - BACKGROUND: The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients. METHODS: The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays. RESULTS: Over a mean follow up period of 5.3 (+/- 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05 1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05). CONCLUSIONS: For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings. PMID- 22251820 TI - Clinicopathological study on poorly differentiated adenocarcinoma of the colon. AB - Clinicopathological characteristics and grading of poorly differentiated colon adenocarcinoma (Por) were discussed. A total of 1074 patients with colon cancer underwent surgical treatment at Kurume University Hospital in Fukuoka, between 1985 and 2005. Clinicopathological characteristics of 88 cases (8%) of Por and 986 cases (92%) of well differentiated tubular adenocarcinoma/moderately differentiated tubular adenocarcinoma (Tub1/Tub2) were studied. A multiple classification analysis showed that Por was more frequently observed in the right colon than Tub1/Tub2, and that the ratio of macroscopic types 3 and 4 was significantly higher in Por. Significant differences were also observed with regard to lymph vessel and perineural invasion. There were no significant differences between recurrence-free survivals of Por and Tub1/Tub2 after radical resection in Stages II and III. Recurrence of Por was significantly higher in peritonea and lymph nodes. These findings indicate that Por, which is generally considered to have a poor prognosis, has a similar recurrence rate to that of Tub1/Tub2 after the performance of radical surgery. PMID- 22251821 TI - Edaravone attenuates impairment of synaptic plasticity in granule cell layer of the dentate gyrus following traumatic brain injury. AB - Effects of edaravone, a free radical scavenger, on post-traumatic impairment of long-term potentiation (LTP) were examined in granule cell layers of the dentate gyrus (DG) in vitro. Field EPSPs (fEPSPs) evoked by stimulation of the perforant path (PP) were recorded extracellularly in the DG one week after a moderate impact applied by a fluid percussion injury (FPI) device. High frequency stimulation (HFS) of the PP caused LTP of the fEPSP-slope in slices from naive and sham-operated rats, however, the LTP was strongly depressed in slices from FPI rats. Intraperitoneal administration of edaravone 15 min after FPI prevented the hyperactivities of DG neurons and attenuated impairment of the LTP in FPI rat dentate granular cells. In vitro application of spermine NONOate (sp-NO), a nitric oxide (NO) donor, for 30 min produced a gradual increase in the fEPSP slope, lasting for more than 2 h. Edaravone attenuated the enhancement of the fEPSP-slope induced by sp-NO. After sp-NO treatment HFS could not produce an obvious LTP in the DG granule cell layer. Pretreatment of DG slices with edaravone prevented the sp-NO-induced impairment of LTP. These results suggest that administration of edaravone after FPI protects against post-traumatic impairment of LTP in granule cell layers of the DG, possibly by scavenging NO related radicals. PMID- 22251822 TI - Can renal infarction occur after renal cyst aspiration? Case report. AB - Renal infarction (RI) is a rarely seen disorder, and the diagnosis is often missed. The two major causes of RI are thromboemboli originhating from a thrombus in the heart or aorta, and in-situ thrombosis of a renal artery. We report a case of RI that developed due to renal artery and vein thrombosis, as confirmed by pathological evaluation of the nephrectomy material, three weeks after renal cyst aspiration. PMID- 22251823 TI - Giant liposarcoma occupying most of the hemi-thorax and resected in the supine position: report of a rare case. AB - Liposarcoma originating in the thoracic cavity is not common. It has been reported that neither chemotherapy nor radiotherapy is effective, and that surgical resection is the only therapeutic option. There have been several cases reported of a large liposarcoma compressing adjacent organs such as the lung and the heart. In such cases, careful management is required to prevent adverse cardiopulmonary events during resection. Here we report a rare case of a 52-year old male who had a giant liposarcoma occupying the majority of the right thorax. The patient was placed in the supine position, and the tumor was resected through an anterior thoracotomy. Percutaneous cardiopulmonary support (PCPS) was prepared in case of need. However, we succeeded in resecting the huge tumor without use of PCPS. We were unable to completely resect the tumor because it originated from the posterior mediastinum and extended into the left thorax. The resected tumor weighed 3,500 g and was 28 cm in largest diameter. The postoperative course was uneventful, except for hypoxemia lasting a few days caused by re-expansion edema in the lung. The patient was discharged and is alive at five years to date. PMID- 22251824 TI - Giant malignant phyllodes tumor: a case report. AB - We present a case of a 57-year-old woman with a giant malignant phyllodes tumor (PT) in her right breast, with maximum diameter of 20 cm. The core-needle and excisional biopsy specimens were diagnosed as suspicious for low-grade myofibroblastic sarcoma (LGMS). The subsequent total mastectomy with partial resection of the pectoral muscles showed predominance of stromal hypercellularity without an epithelial component. However, we diagnosed this as a malignant PT because focal areas showed a leaf-like pattern. In the case of large malignant PTs that exhibit stromal predominance, it can be difficult to distinguish between a pure sarcoma and malignant PT. It is important to thoroughly examine multiple sections from the view point of residual epithelial structure in morphological diagnosis. PMID- 22251826 TI - Docking and 3D-QSAR investigations of pyrrolidine derivatives as potent neuraminidase inhibitors. AB - Docking studies of pyrrolidine derivatives indicated that Trp178, Arg371, and Tyr406 were the key residues in the active pocket of influenza neuraminidase (NA). Hydrogen bond and electrostatic factors mainly influenced interactions between pyrrolidine derivatives and NA. Moreover, there was a significant correlation between binding affinity (total scores) and the experimental pIC(50) . Meanwhile, 3D-QSAR models of 87 pyrrolidine derivatives were developed to understand chemical-biological interactions governing their activities toward NA. Furthermore, R(2) , Q(2) , , and of the models were from 0.731 to 0.830, from 0.560 to 0.611, from 0.762 to 0.875, and from 0.649 to 0.856, respectively. QSAR modeling results elucidated that hydrogen bonds and electrostatic factors highly contributed to inhibitory activity, which was unanimous in the docking results. PMID- 22251827 TI - Health care reform implementation and occupational therapy. PMID- 22251828 TI - Neurocognitive habilitation therapy for children with fetal alcohol spectrum disorders: an adaptation of the Alert Program(r). AB - OBJECTIVE: This study evaluated the effectiveness of neurocognitive habilitation, a group therapy intervention for foster and adoptive caregivers and their children who were prenatally exposed to alcohol. METHOD: Participants were recruited from clients seeking evaluation for fetal alcohol syndrome (FAS) and alcohol-related neurodevelopmental disorder (ARND) and were randomly assigned to treatment and no-treatment control groups. Forty children participated in the treatment program and were compared with 38 control participants using the Behavior Rating Inventory of Executive Function (BRIEF) and the Roberts Apperception Test for Children (RATC). RESULTS: Significant differences between the treatment and control groups were demonstrated on the BRIEF and on the RATC, suggesting that the intervention improved executive functioning and emotional problem-solving skills. CONCLUSION: These findings yield promising evidence of the effectiveness of the neurocognitive habilitation intervention in improving executive functioning and emotional problem solving in children with FAS or ARND. PMID- 22251829 TI - Predictive ability of 2-day measurement of active range of motion on 3-mo upper extremity motor function in people with poststroke hemiparesis. AB - OBJECTIVE. We determined (1) whether active range of motion (AROM) of shoulder flexion and wrist extension measured at the initial therapy evaluation in the acute hospital predicted upper-extremity (UE) motor function 3 mo after stroke and (2) whether the presence of nonmotor impairments influenced this prediction. METHOD. We collected AROM data from 50 people with stroke during their initial acute hospital therapy evaluation and UE motor function data 3 mo later. Multiple regression techniques determined the predictive ability of initial AROM on later UE motor function. RESULTS. Initial AROM explained 28% of the variance in UE motor function 3 mo poststroke. Nonmotor deficits did not contribute to the variance. CONCLUSION. Compared with later AROM measurements, initial values did not adequately predict UE motor function 3 mo after stroke. Clinicians should use caution when informing clients of UE functional prognosis in the early days after stroke. PMID- 22251830 TI - Modifying health outcome measures for people with aphasia. AB - OBJECTIVE: The goal for this study was to determine methods to modify outcome measures for people with aphasia and to provide beginning support for the efficacy of these suggested modifications. METHOD: Twenty-nine community-dwelling people with aphasia participated. Modified outcome measures included the Stroke Impact Scale, the 36-item short form Medical Outcomes Study, Reintegration to Normal Living Scale, and Activity Card Sort. Participants were supported in their responses by systematically applying a hierarchy of support. An Independence Scale score was determined for each measure for each participant. RESULTS: Data from an examiner-rated Independence Scale, internal consistency of participants' responses, correlations among subscale scores across measures, and correlations between aphasia severity and reported outcome provide evidence that people with aphasia are able to understand and respond with these supports. CONCLUSION: We provide key recommendations for making self-report measures accessible for people with aphasia. PMID- 22251832 TI - Motion aftereffect in depth based on binocular information. AB - We examined whether a negative motion aftereffect occurs in the depth direction following adaptation to motion in depth based on changing disparity and/or interocular velocity differences. To dissociate these cues, we used three types of adapters: random-element stereograms that were correlated (1) temporally and binocularly, (2) temporally but not binocularly, and (3) binocularly but not temporally. Only the temporally correlated adapters contained coherent interocular velocity differences while only the binocularly correlated adapters contained coherent changing disparity. A motion aftereffect in depth occurred after adaptation to the temporally correlated stereograms while little or no aftereffect occurred following adaptation to the temporally uncorrelated stereograms. Interestingly, a monocular test pattern also showed a comparable motion aftereffect in a diagonal direction in depth after adaptation to the temporally correlated stereograms. The lack of the aftereffect following adaptation to pure changing disparity was also confirmed using spatially separated random-dot patterns. These results are consistent with the existence of a mechanism sensitive to interocular velocity differences, which is adaptable (at least in part) at binocular stages of motion-in-depth processing. We did not find any evidence for the existence of an "adaptable" mechanism specialized to see motion in depth based on changing disparity. PMID- 22251833 TI - Two operational modes in the perception of shape from shading revealed by the effects of edge information in slant settings. AB - The perception of shape from shading (SFS) has been an active research topic for more than two decades, yet its quantitative description remains poorly specified. One obstacle is the variability typically found between observers during SFS tasks. In this study, we take a different view of these inconsistencies, attributing them to uncertainties associated with human SFS. By identifying these uncertainties, we are able to probe the underlying computation behind SFS in humans. We introduce new experimental results that have interesting implications for SFS. Our data favor the idea that human SFS operates in at least two distinct modes. In one mode, perceived slant is linear to luminance or close to linear with some perturbation. Whether or not the linear relationship is achieved is influenced by the relative contrasts of edges bounding the luminance variation. This mode of operation is consistent with collimated lighting from an oblique angle. In the other mode, recovered surface height is indicative of a surface under lighting that is either diffuse or collimated and frontal. Shape estimates under this mode are partially accounted for by the "dark-is-deep" rule (height ? luminance). Switching between these two modes appears to be driven by the sign of the edges at the boundaries of the stimulus. Linear shading was active when the boundary edges had the same contrast polarity. Dark-is-deep was active when the boundary edges had opposite contrast polarity. When both same-sign and opposite sign edges were present, observers preferred linear shading but could adopt a combination of the two computational modes. PMID- 22251834 TI - Distractors slow information accumulation in simple feature search. AB - M. Carrasco and B. McElree (2001) presented a speed-accuracy trade-off experiment, investigating covert attention in visual search. One of the conclusions from Carrasco and McElree was that adding distractors to a single feature search does not decrease the speed with which information is accumulated about target identity. We present a reanalysis of the relevant data from Carrasco and McElree in which we demonstrate that their conclusion was incomplete and we demonstrate a processing speed advantage for single feature search displays with no distractors compared with displays with distractors. This finding is confirmed in a new speed-accuracy trade-off experiment presented here. Further, we demonstrate that increasing the display duration increases the processing speed of displays with distractors but not for displays without distractors. We discuss these results in relation to theories of visual attention and the debate between graded and fixed architecture accounts for attentional allocation. PMID- 22251835 TI - Unawareness of memory impairment in dementia: a population-based study. AB - BACKGROUND: Unawareness of cognitive deficit in people with dementia (PwD) has wide clinical implications, impacting on help-seeking behavior, treatment compliance, and patient safety. Most studies on unawareness among PwD have been conducted in small clinical samples. This study investigated the frequency of unawareness of memory impairment in dementia, exploring regional differences and sociodemographic and health status correlates in large population-based surveys. METHODS: Community samples (total n = 15,022) from three world regions (Latin America, China, and India) were obtained using cross-sectional population-based surveys. Out of these, 897 (5.97%) PwD with memory impairment were identified using standardized interviews, diagnostic algorithms (DSM-IV or 10/66 criteria), and neuropsychological memory assessment. Unawareness of memory deficits was ascertained from the participants' subjective report. The frequency of unawareness was calculated for each region and associations with demographic variables and health status were investigated using prevalence ratios and Poisson regressions. RESULTS: Regional differences in frequency of unawareness were found, from 63% in China to 81% in India. Unawareness was associated with depression in China and Latin America, dementia severity in India and Latin America, and education and socioeconomic level in Latin America. CONCLUSIONS: Unawareness of memory impairment in PwD varies across international regions. Our data support the notion that unawareness should be seen not only as a common neurobiological feature of dementia, increasing with severity of dementia, but also as a phenomenon influenced by social and cultural factors. PMID- 22251836 TI - Recognition memory for Braille or spoken words: an fMRI study in early blind. AB - We examined cortical activity in early blind during word recognition memory. Nine participants were blind at birth and one by 1.5years. In an event-related design, we studied blood oxygen level-dependent responses to studied ("old") compared to novel ("new") words. Presentation mode was in Braille or spoken. Responses were larger for identified "new" words read with Braille in bilateral lower and higher tier visual areas and primary somatosensory cortex. Responses to spoken "new" words were larger in bilateral primary and accessory auditory cortex. Auditory cortex was unresponsive to Braille words and occipital cortex responded to spoken words but not differentially with "old"/"new" recognition. Left dorsolateral prefrontal cortex had larger responses to "old" words only with Braille. Larger occipital cortex responses to "new" Braille words suggested verbal memory based on the mechanism of recollection. A previous report in sighted noted larger responses for "new" words studied in association with pictures that created a distinctiveness heuristic source factor which enhanced recollection during remembering. Prior behavioral studies in early blind noted an exceptional ability to recall words. Utilization of this skill by participants in the current study possibly engendered recollection that augmented remembering "old" words. A larger response when identifying "new" words possibly resulted from exhaustive recollecting the sensory properties of "old" words in modality appropriate sensory cortices. The uniqueness of a memory role for occipital cortex is in its cross-modal responses to coding tactile properties of Braille. The latter possibly reflects a "sensory echo" that aids recollection. PMID- 22251837 TI - Complicated secondary pneumonia after swine-origin influenza A virus infection in an immunocompetent patient. AB - The pandemic of the swine-origin influenza A virus (S-OIV) in 2009 demonstrated severe viral pneumonia followed by acute respiratory distress syndrome (ARDS). Although ARDS would be caused by the influenza virus pneumonia itself, it has remained unclear whether other respiratory viral or bacterial infections coexist with S-OIV pneumonia. We report an immunocompetent patient with methicillin resistant Staphylococcus aureus (MRSA) and Herpes simplex virus (HSV) pneumonia secondary to S-OIV infection. A 57-year-old man previously without major medical illness was admitted to our hospital with severe pneumonia accompanied by ARDS due to S-OIV. In his clinical course, anti-influenza treatment was not effective. Sputum culture revealed the presence of MRSA, and HSV was isolated in broncho alveoler lavage (BAL) fluid. Administration of an antiviral agent (acyclovir), an antibacterial agent (linezolid), and a corticosteroid (methylprednisolone) successfully improved the pneumonia and ARDS. HSV pneumonia can scarcely be seen in healthy people. However recently it has been recognized as a ventilator associated pneumonia. Although coexistence of Streptococcus pneumoniae and MRSA was reported in S-OIV pneumonia, secondary viral infection has not been reported. The present report is the first patient with HSV pneumonia secondary to S-OIV infection. We propose that a possibility of hidden HSV pneumonia should be taken into consideration in patients with prolonged severe pneumonia due to influenza infection. PMID- 22251838 TI - Gene expression in tumor cells and stroma in dsRed 4T1 tumors in eGFP-expressing mice with and without enhanced oxygenation. AB - BACKGROUND: The tumor microenvironment is pivotal in tumor progression. Thus, we aimed to develop a mammary tumor model to elucidate molecular characteristics in the stroma versus the tumor cell compartment by global gene expression. Secondly, since tumor hypoxia influences several aspects of tumor pathophysiology, we hypothesized that hyperoxia might have an inhibitory effect on tumor growth per se. Finally, we aimed to identify differences in gene expression and key molecular mechanisms, both in the native state and following treatment. METHODS: 4T1 dsRed breast cancer cells were injected into eGFP expressing NOD/SCID mice. Group 1 was exposed to 3 intermittent HBO treatments (Day 1, 4 and 7), Group 2 to 7 daily HBO treatments (both 2.5 bar, 100% O2, a 90 min), whereas the controls were exposed to a normal atmosphere. Tumor growth, histology, vascularisation, cell proliferation, cell death and metastasis were assessed. Fluorescence activated cell sorting was used to separate tumor cells from stromal cells prior to gene expression analysis. RESULTS: The purity of sorted cells was verified by fluorescence microscopy. Gene expression profiling demonstrated that highly expressed genes in the untreated tumor stroma included constituents of the extracellular matrix and matrix metalloproteinases. Tumor growth was significantly inhibited by HBO, and the MAPK pathway was found to be significantly reduced. Immunohistochemistry indicated a significantly reduced microvessel density after intermittent HBO, whereas daily HBO did not show a similar effect. The anti-angiogenic response was reflected in the expression trends of angiogenic factors. CONCLUSIONS: The present in vivo mammary tumor model enabled us to separate tumor and stromal cells, and demonstrated that the two compartments are characterized by distinct gene expressions, both in the native state and following HBO treatments. Furthermore, hyperoxia induced a significant tumor growth-inhibitory effect, with significant down-regulation of the MAPK pathway. An anti-angiogenic effect after intermittent HBO was observed, and reflected in the gene expression profile. PMID- 22251840 TI - Optical coherence tomography of radiation optic neuropathy. AB - BACKGROUND AND OBJECTIVE: To quantitatively study morphologic optic disc and retinal changes in patients with radiation optic neuropathy (RON) using optical coherence tomography (OCT). PATIENTS AND METHODS: This study is a retrospective clinical case series of ten patients with acute RON. Each had been treated with palladium-103 ophthalmic plaque therapy for choroidal melanoma. OCT images were taken at the time of the initial RON diagnosis to measure cup depth, cup width, edema, vasculature diameter, and retinal thickness. RESULTS: All patients with acute RON showed optic disc edema, increased optic disc thickness, and decreased optic cup depth. The average papillary retinal thickness was 341.6 MUm and the average optic cup depth was 168 MUm. Retinal arteries showed a mean decrease in diameter of 32.5%. All patients with RON in the study showed a decrease in cumulative peripapillary retinal thickness. CONCLUSION: This study shows that RON manifests characteristic retinal and optic disc changes that can be evaluated quantitatively by OCT. PMID- 22251841 TI - 24-Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular AMD: 6-month safety and functional outcomes. AB - BACKGROUND AND OBJECTIVE: To describe the 6-month safety and preliminary efficacy outcomes of the use of 24-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: A single treatment of a non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 24 Gy was administered in one session through three locations in the inferior pars plana in a consecutive series of patients with neo vascular AMD (treatment naive and previously treated). Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity examinations were performed at 1 week, 1 month, and monthly thereafter with quarterly fluorescein angiography. RESULTS: Nineteen patients completed 6 months of follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 38.3 +/- 19.5 letters. At 6 months, the corresponding ETDRS score was 44.7 +/- 16.8 letters. At 6 months, the mean change in visual acuity was 6.4 +/- 9.8 ETDRS letters. Patients received an average of 0.4 additional ranibizumab injections following the initial two mandated injections. CONCLUSION: A single treatment of external 24-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement in visual acuity in patients with neovascular AMD at 6 months, with no radiation-related adverse effects. PMID- 22251842 TI - Reproducibility of retinal blood flow measurements derived from semi-automated Doppler OCT analysis. AB - BACKGROUND AND OBJECTIVE: To evaluate reproducibility and intergrader agreement of total retinal blood flow (TRBF) measurements obtained by semi-automated grading of Doppler Fourier-domain optical coherence tomography (FD-OCT) scans. PATIENTS AND METHODS: Doppler FD-OCT scans were obtained from 20 eyes of 18 subjects (10 glaucomatous, 10 normal). Scans were obtained using a circumpapillary scan protocol and analyzed using the Doppler OCT of Retinal Circulation software (version 2). Two masked, independent human graders manually refined the scans, adding or deleting vessels, changing vessel boundaries, and classifying vessels as veins or arteries. TRBF was calculated automatically by software summing flow in all veins. Agreement between various vessel parameters and TRBF values generated by the graders was analyzed. RESULTS: Mean difference and mean absolute difference (+/- standard deviation, range) for TRBF were -0.55 (+/- 5.37, -8.53 to 13.6) and 3.84 (+/- 3.70, 0 to 13.6) MUL/min, respectively, with an intraclass correlation (ICC) of 0.933 and limits of agreement (95% confidence interval [CI]) of -11.1 to +10.0. Venous area measurements showed similar levels of agreement with mean difference and mean absolute difference (+/ standard deviation, range) of -2.91 (+/- 4.29, -10.95 to 6.43) and 3.59 (+/- 3.70, 0 to 10.9) mm(2) with an ICC of 0.933 and limits of agreement (95% CI) were -11.3 and +05.5. The agreement for vessel identification between graders was almost perfect with a weighted kappa of 0.86. CONCLUSION: Reproducible measurements of TRBF can be obtained from Doppler OCT data using semi-automated software with manual refinement. These findings should be of value in future studies evaluating retinal blood flow in various diseases. PMID- 22251843 TI - Five-year results of 5-fluorouracil augmented needling revision of failing blebs. AB - BACKGROUND AND OBJECTIVE: To report the 5-year intraocular pressure (IOP) outcomes of patients requiring a 5-fluorouracil (5-FU) needling revision compared to a matched sample. PATIENTS AND METHODS: Forty eyes receiving 5-FU bleb needling revision were matched to 40 patients not needled. IOP was recorded preoperatively and annually to 5 years. The main outcome measure was surgical success: IOP control without medications or surgery. RESULTS: Thirty-two patients with 5-FU needling revision (80.0%) required anti-glaucoma medication postoperatively versus 28 control patients (70%) (P > .05). Thirty-two patients with 5-FU needling revision were complete or qualified successes compared to 36 control patients (P = .34). Eight patients with 5-FU needling revision (20%) had a reoperation versus 4 control patients (10%) (P > .05). CONCLUSION: 5-FU needling revision can produce long-term IOP control levels similar to those who did not require the procedure. No statistically significant differences between the two groups was seen in either the use of medications or further surgery. PMID- 22251844 TI - In vitro analysis of Nd:YAG laser damage to hydrophilic intraocular lenses. AB - BACKGROUND AND OBJECTIVE: Damaged optics of an intraocular lens (IOL) can impair visual functioning. Damage can occur during the manufacturing process, during implantation, or during post-implantation Nd:YAG laser posterior capsulotomy. An in vitro experiment was performed to identify the potential IOL damage patterns associated with the use of the Nd:YAG laser for posterior capsulotomy. PATIENTS AND METHODS: A review of the literature regarding Nd:YAG laser damage to IOLs was performed. The objectives were to describe the damage patterns to a sample IOL by performing virtual posterior capsulotomies. RESULTS: Patterns of damage were demonstrated and described. CONCLUSION: Although optic damage can occur with use of the Nd:YAG laser, it is infrequent and usually the result of improper depth of focus. PMID- 22251845 TI - Clinical evaluation of a new donor graft inserter for Descemet's stripping automated endothelial keratoplasty. AB - BACKGROUND AND OBJECTIVE: To present clinical outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) using a newly developed donor graft inserter, the Tan EndoGlide (AngioTech, Reading, PA/Network Medical Products, North Yorkshire, UK). PATIENTS AND METHODS: Six eyes of six patients with bullous keratopathy were treated with DSAEK using the Tan EndoGlide. Intraoperative and postoperative complications, postoperative donor endothelial cell densities (ECDs), and best-corrected visual acuity were recorded. RESULTS: Five cases had no difficulties during donor graft loading into the Tan EndoGlide; however, the donor graft was folded inside-out into the Tan EndoGlide in one case, resulting in severe endothelial cell loss. All patients achieved a visual acuity of 20/63 or better at 12 months, with four patients reaching better than 20/32. Excluding the case with the graft folded inside-out, postoperative ECDs were 2,041 cells/mm(2) (mean loss: 22.9%) at 6 months and 1,973 cells/mm(2) (mean loss: 24.6%) at 12 months. CONCLUSION: In this small preliminary series, the clinical outcome with the Tan EndoGlide was comparable to or better than that achieved with the conventional technique. Additional studies using a larger number of patients are required to fully evaluate the usefulness and potential advantages of this new donor graft inserter. PMID- 22251846 TI - A minimally invasive jet injector for intravitreal and subconjunctival injection. AB - BACKGROUND AND OBJECTIVE: To evaluate a minimally invasive injector for intravitreal and subconjunctival administration of medications. MATERIALS AND METHODS: The device has a microneedle that communicates with an internal formulation chamber. A piercing depth-limiting flange restricts microneedle penetration to a depth of less than 1 mm and defines the location of the pars plana from the limbus. The jet injector creates a force of up to 1,000 psi, forcing the medication through the remaining sclera/choroid thickness. The device was tested in 28 enucleated rabbit eyes and 9 experimental and 4 control rabbit eyes to define jet pressure for subconjunctival and intravitreal injection. RESULTS: Injection pressures of 76 to 156 psi were needed for subconjunctival injection and 974 psi for intravitreal injection. Clinical and histologic examinations did not reveal damage to intraocular structures. CONCLUSION: The semi-automated jet injector facilitated intravitreal/subconjunctival injection. The microneedle-assisted jet injector minimized the risk of wet injection by anchoring the microneedle in the sclera. PMID- 22251847 TI - Transscleral drainage of subretinal/suprachoroidal silicone oil. AB - Silicone oil migration into the subretinal space following vitreoretinal surgery may occur in complex cases of retinal detachment with proliferative vitreoretinopathy. This complication prevents achievement of the primary goal (ie, to attach the retina) and fails to provide the internal tamponade, leading to a permanent decrease in visual acuity. Successful and complete removal of the subretinal oil is a challenge. Internal drainage as described earlier in the literature advocates a large relaxing retinotomy. The authors describe two similar cases, one with retinal detachment secondary to type II iridochoroidal coloboma wherein the oil had passed into the subretinal space and the other with diabetes mellitus and retinal detachment with oil in the suprachoroidal space. In both cases, silicone oil was removed successfully through a transscleral approach. The transscleral approach for removal of subretinal/suprachoroidal oil appears to be relatively safe, less time-consuming, and effective. PMID- 22251848 TI - Slit-lamp-adapted ultra-high resolution OCT for imaging the posterior segment of the eye. AB - The purpose of this study was to determine the feasibility of a slit-lamp-adapted ultra-high resolution optical coherence tomography device with improved image resolution for imaging the retinal nerve fiber layer. The authors described the system configuration, build-up, and test results of a small sample of human subjects. The comparison with a commercially available device was also included. PMID- 22251850 TI - Resection of colorectal liver metastases in the elderly: does age matter? AB - AIM: Despite the incidence of colorectal cancer increasing with age the proportion of patients undergoing surgery for colorectal liver metastases decreases dramatically in the elderly. Is this referral or selection bias justified? METHOD: A prospective database of resection for colorectal liver metastases at a single centre was retrospectively analysed to compare the outcome in patients aged >=75 years (group E) with those aged <75 years (group Y). Data were analysed using the Kaplan-Meier method with Cox regression modelling. RESULTS: Of 1443 resections, 151 (10.5%) in group E were compared with 1292 (89.5%) in group Y. The two groups were matched apart from higher American Society of Anesthesiology scores (P=0.001) and less use of chemotherapy (P=0.01) in the elderly. Perioperative morbidity and 90-day mortality were higher in the elderly compared with the younger group (32.5%vs 21.2%, P=0.02, and 7.3%vs 1.3%, P=0.001). In the last 5 years, mortality in the elderly improved and was no longer significantly different from that of the younger patients [n=2/76 (2.6%) vs n=9/559 (1.6%); P=0.063]. The 5-year survival was similar in groups E and Y for cancer-specific (41.4%vs 41.6%, P=0.917), overall (37.0%vs 38.2%) and median (44.1 months vs 43.6 months, P=0.697) survival respectively. CONCLUSION: In the elderly liver resection for metastatic disease can be performed with acceptable mortality and morbidity with as good a prospect of survival as for younger patients. PMID- 22251849 TI - The association of Toll-like receptor 4 gene polymorphisms with the development of emphysema in Japanese subjects: a case control study. AB - BACKGROUND: The principal role of Toll-like receptor 4 (TLR4) is the induction of immune responses to lipopolysaccharides. Previously, mice deficient in the TLR4 gene exhibited up-regulation of the NADPH oxidase system in the lungs. This resulted in increased oxidant generation and elastolytic activity, which led to pulmonary emphysema. It was suggested that TLR4 might maintain constitutive lung integrity by modulating oxidant generation. We investigated whether single nucleotide polymorphisms (SNPs) in the TLR4 gene were associated with the emphysema phenotype in Japanese subjects with chronic obstructive pulmonary disease (COPD). RESULTS: Seven SNPs in the TLR4 gene (rs10759930, rs1927914, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953) were genotyped with allelic discrimination assays. The frequencies of SNPs were compared between 106 patients with the emphysema phenotype of COPD and 137 healthy smokers. We found that the positivity of the individuals with the major G allele of rs11536889 was significantly less in the emphysema group than the control group (p = 0.019). The frequencies of the minor C allele and the distribution of the CC genotype as well as the frequency of the major haplotype that carried the minor C allele of rs11536889 were all significantly higher in the emphysema group than the control group (p = 0.0083, 0.019, and 0.004, respectively). Furthermore, the strength of the association of the CC genotype with the emphysema phenotype was in an odds ratio of 2.60 with 95% confidence intervals from 1.17 to 5.78. However, these significances were not apparent after adjust for age and smoking history by logistic regression. No associations were observed between the rs11536889 and the low attenuation area score, the forced expiratory volume, and the carbon monoxide diffusion capacity in the emphysema group. CONCLUSIONS: The minor C allele of the rs11536889 SNP in the TLR4 gene is likely associated with the risk of developing emphysema in the Japanese population. PMID- 22251852 TI - Structure-based rationale design and synthesis of aurantiamide acetate analogues towards a new class of potent analgesic and anti-inflammatory agents. AB - A series of new aurantiamide acetate analogues were synthesized by modifying its N-terminal substitution and the amino acid residue. The structure of all these compounds was established on the basis of analytical and spectral studies. All the new derivatives were evaluated in vivo for their analgesic activity by tail flick method in mice and anti-inflammatory activity against carrageenan-induced oedema in albino rats at different doses (25, 50 and 100 mg/kg body weight). All the compounds exhibited significant pharmacological activity with no ulcerogenic liability. In particular, pentapeptides and tricosamers (30 amino acids) containing analogues have demonstrated high potency than the reference standards. These compounds hold promise for further development. PMID- 22251853 TI - Serotonin syndrome during treatment with low dose of escitalopram associated with miconazole mucoadhesive tablet: a suspected drug interaction. AB - Antidepressant treatments, including selective serotonin reuptake inhibitors, are associated in older adults with an increased risk of adverse effects compared to younger adults. This is partly explained by multiple drug use causing drug-drug interactions. In the present report, we describe a case of serotonin syndrome in an 88-year-old woman receiving a low dose of escitalopram. The onset of this episode could have been induced by a drug-drug interaction with an acute treatment by miconazole gingival adhesive tablets. The lack of pharmacokinetic data in the elderly population should prompt us to be especially cautious about prescription of this new formulation of miconazole in association with drugs metabolized by cytochromes P450 isoenzymes. PMID- 22251854 TI - The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats. AB - AIM: To examine whether the prevention of post-operative duodenal ileus by treatment with parecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, affects the ability of the duodenum to respond to luminal hypertonicity. METHODS: The proximal duodenums of anaesthetized rats were perfused with hypertonic NaCl solutions with osmolalities of 400, 500, 600 or 700 mOsm kg(-1) , and the effects on mucosal permeability, motility, transepithelial net fluid flux and effluent osmolality were assessed in the absence (control) and presence of parecoxib. RESULTS: Parecoxib-treated, but not control animals, exhibited duodenal contractions, which were reduced by the nicotinic receptor antagonists mecamylamine and hexamethonium and by perfusion with 700 mOsm kg(-1) . All animals responded to luminal hypertonicity with induction of net fluid secretion, which peaked at an osmolality of 500 mOsm kg(-1) . The hypertonicity-induced increases in fluid secretion were twofold greater in parecoxib-treated than in control rats and attenuated by nicotinic receptor blockade. The decrease in luminal osmolality correlated with the osmolality of the perfusion solution in both control and parecoxib-treated animals but the osmolality-adjusting capability was markedly better in the latter group. Rats exposed to duodenal luminal distension responded to hypertonicity with a greater fluid secretion and a larger decrease in luminal osmolality than control rats. Perfusion with 700 mOsm kg(-1) increased mucosal permeability in parecoxib-treated animals only, an effect abolished by nicotinic receptor blockade. CONCLUSION: Parecoxib markedly improved the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of COX-2 and stimulation of nicotinic acetylcholine receptors. PMID- 22251855 TI - [Introduction: from the presumptive to the functional ovary]. PMID- 22251856 TI - [Genetics of early ovarian differentiation: recent data]. AB - Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY gene. Recent genetic and transcriptomic studies challenge this view and show that two master pathways simultaneously repress male-specific genes and activate female-specific genetic cascades. This antagonistic action is maintained from embryonic stages to adulthood. The differentiation of the ovarian somatic component is regulated by both the forkhead transcription factor FOXL2 (alone or in combination with oestrogens according to the species) and beta-catenin pathway activated by Wnt4 and Rspo1. The sex-specific change in the fate of primordial germ cells depends on the gonad environment. Female gonocytes actively proliferate by mitosis then enter meiosis I until the diplotene stage. Primordial follicle formation occurs when oocytes are individually surrounded with pre-granulosa cells. In mammals, the population of primordial follicles serves as a resting and finite pool of oocytes available during the female reproductive life span. Recent data on factors controlling these molecular processes will be presented in this review. PMID- 22251857 TI - [Reconsidering the roles of female germ cells in ovarian development and folliculogenesis]. AB - The production of fertilizable ova is the consequence of multiple events that start as soon as ovarian development and culminate at the time of ovulation. Throughout their development, germ cells are associated with companion somatic cells, which ensure germ cell survival, growth and maturation. Data obtained in vitro and in vivo on several animal models of germ cell depletion have led to uncover the many roles of germ cells on both ovarian development and folliculogenesis. During ovarian development, germ cells become progressively enclosed within epithelial structures called "ovigerous cords" constituted by pregranulosa cells, lined by a basement membrane. At the end of ovarian development, ovigerous cords fragment into primordial follicles, which are epithelial units constituted by an oocyte surrounded by a single layer of granulosa cells. Germ cells are necessary for the fragmentation of ovigerous cords into follicles, since in their absence, no follicle will form. Germ cells also ensure the differentiation of the ovarian somatic lineage, and they may inhibit the testis-differentiating pathway by preventing the conversion of pregranulosa cells into Sertoli cells, their counterpart in the testis. Regularly, primordial follicles are recruited into the growing follicle pool and initiate their growth. They develop through primary, preantral, antral and preovulatory stages before being ovulated. Interestingly, the action of the oocyte on companion somatic cells tightly depends on the follicular stage. In primordial follicles, the oocyte prevents the transdifferentiation of granulosa cells into cells resembling Sertoli cells. By contrast, as soon as the follicle enters growth, the oocyte regulates the functional differentiation of granulosa cells and at the latest stages, it prevents their premature maturation into luteal cells. Overall, these data demonstrate that the female germ cell act on companion somatic cells to regulate ovarian development and folliculogenesis, thereby actively supporting its own maturation. PMID- 22251858 TI - [Cryopreserved ovaries: models of experimental grafting]. AB - Childhood cancers account for 1% of malignant tumors. As a result of advances in treatment, almost 80% of children and adolescents who currently receive a diagnosis of cancer become long-term survivors. Assessment of potential for fertility preservation should thus be a systematic element of care for children treated for a malignant tumor (high-dose chemotherapy with alkylizing agents, radiation therapy including the gonads) or those receiving hematopoietic stem cell grafts for malignant or benign disease (sickle-cell anemia, immune deficit). Potential adverse consequences of treatment include impaired puberty and fertility due to gonadal removal, genital tract injury or damage to germ cells from adjuvant therapy. Advances in assisted reproductive technologies have led to new possibilities for the prevention and treatment of infertility. Among them, cryopreservation of ovarian tissue appears to be the most promising, or perhaps the only one available before puberty with encouraging results. Nevertheless the uncertainties, or even risks, related to these treatments, should not be neglected. We review experimental data in mouse and sheep animal models. The results demonstrate that immature ovarian grafting can restore spontaneous puberty and fertility in both models. This study addresses the very important issue of epigenetics, and provides valuable information for the study of ovarian transplantation, suggesting that these procedures do not perturb normal epigenetic marks. These results are highly relevant to the question of immature cortex reimplantation. PMID- 22251859 TI - [The rebirth of the ultrastructure of cilia and flagella]. AB - The sensory and motility functions of eukaryotic cilia and flagella are essential for cell survival in protozoans and for cell differentiation and homoeostasis in metazoans. Ciliary biology has benefited early on from the input of electron microscopy. Over the last decade, the visualization of cellular structures has greatly progressed, thus it becomes timely to review the ultrastructure of cilia and flagella. Briefly touching upon the typical features of a 9+2 axoneme, we dwell extensively on the transition zone, the singlet zone, the ciliary necklace, cap and crown. The relation of the singlet zone to sensory and/or motile function, the link of the ciliary cap to microtubule dynamics and to ciliary beat, the involvement of the ciliary crown in ovocyte and mucosal propulsion, and the role of the transition zone/the ciliary necklace in axonemal stabilization, autotomy and as a diffusion barrier will all be discussed. PMID- 22251860 TI - RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. AB - BACKGROUND: RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. METHODS: Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9) and normal controls (N = 7) were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups). RESULTS: Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down) in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size < 500 nt. Gene ontology of the down-regulated genes indicated these are coding for ribosomal proteins and genes related to ribosome production. CONCLUSIONS: Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size < 500 nt. PMID- 22251861 TI - Diagnostic accuracy of narrow-band imaging for the differentiation of neoplastic from non-neoplastic colorectal polyps: a meta-analysis. AB - AIM: Narrow-band imaging (NBI) is a novel imaging technology that makes the superficial vasculature of gastrointestinal mucosa visible. However, the real accuracy for the differentiation of neoplastic from non-neoplastic polyps by NBI for the colorectum is still unknown. METHOD: A meta-analysis was carried out of studies which assessed the precision of NBI in the diagnosis of colorectal neoplastic polyps. Searches included PubMed and Embase and two reviewers independently assessed their quality with a modified version of the quadas and stard tools. The study pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and area under the curve (AUC). RESULTS: There were 11 relevant original papers which fulfilled the inclusion criteria. The pooled sensitivity and specificity were 0.92 (95% CI 0.90-0.93) and 0.83 (95% CI 0.81-0.86) respectively. The AUC for NBI was 0.95 [SE 0.01; DOR 53.72 (95% CI 35.66-80.92)]. The sensitivity and specificity were 0.92 (95% CI 0.90-0.94) and 0.81 (95% CI 0.78-0.84) with magnification, and 0.91 (95% CI 0.88-0.93) and 0.86 (95% CI 0.82 0.89) without magnification. For the mucosal pattern sensitivity and specificity were 0.90 (95% CI 0.85-0.940) and 0.88 (95% CI 0.82-0.93), and for vascular pattern intensity they were 0.92 (95% CI 0.90-0.94) and 0.88 (95% CI 0.83-0.91). CONCLUSION: Narrow-band imaging, with or without magnification, has a high diagnostic precision for colorectal neoplastic polyps using either vascular pattern intensity or mucosal pattern assessment as the measure. PMID- 22251862 TI - Agriculture and health. PMID- 22251863 TI - Reviewing a patient with coeliac disease. PMID- 22251864 TI - Effectiveness of agricultural interventions that aim to improve nutritional status of children: systematic review. AB - OBJECTIVE: To assess the effectiveness of agricultural interventions in improving the nutritional status of children in developing countries. DESIGN: Systematic review. DATA SOURCES: Published and unpublished reports (after 1990) in English identified by searching 10 databases (Agris, Econlit, Eldis, IBSS, IDEAS, IFPRI, Jolis, PubMed, Web of Science, and World Bank), websites, previous systematic reviews, and reference lists and by contacting experts. STUDY SELECTION: Included studies assessed effects of agricultural interventions aiming at improving the nutritional status of children (bio-fortification, home gardens, small scale fisheries and aquaculture, dairy development, and animal husbandry and poultry development). Only studies that used a valid counterfactual analysis were included. Before/after studies and participants/non-participants comparisons affected by selection bias were excluded. Data analysis Results were analysed for four intermediate outcomes (programme participation, income, dietary diversity, and micronutrient intake) and one final outcome (prevalence of under-nutrition). Analysis was by summary tables of mean effects and by meta-analysis (for vitamin A absorption). RESULTS: The review included 23 studies, mostly evaluating home garden interventions. The studies reviewed did not report participation rates or the characteristics of participants in programmes. The interventions had a positive effect on the production of the agricultural goods promoted, but not on households' total income. The interventions were successful in promoting the consumption of food rich in protein and micronutrients, but the effect on the overall diet of poor people remains unclear. No evidence was found of an effect on the absorption of iron, but some evidence exists of a positive effect on absorption of vitamin A. Very little evidence was found of a positive effect on the prevalence of stunting, wasting, and underweight among children aged under 5. CONCLUSIONS: The question posed by the review cannot be answered with any level of confidence. The data available show a poor effect of these interventions on nutritional status, but methodological weaknesses of the studies cast serious doubts on the validity of these results. More rigorous and better designed studies are needed, as well as the establishment of agreed quality standards to guide researchers in this important area. PMID- 22251866 TI - Argentinean court upholds fines against GSK and two doctors for malpractice during vaccine trial. PMID- 22251865 TI - Lifebox: give a little, help a lot. PMID- 22251851 TI - Growth differences between North American and European children at risk for type 1 diabetes. AB - AIM: To evaluate the relationships between early growth and regional variations in type 1 diabetes (T1D) incidence in an international cohort of children with familial and genetic risk for T1D. METHODS: Anthropometric indices between birth to 5 yr of age were compared among regions and T1D proband in 2160 children participating in the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk study. RESULTS: Children in Northern Europe had the highest weight z-score between birth to 12 months of age, while those in Southern Europe and U.S.A. had the lowest weight and length/height z-scores at most time points (p < 0.005 to p < 0.001). Few differences in z-score values for weight, height, and body mass index were found by maternal T1D status. Using International Obesity Task Force criteria, the obesity rates generally increased with age and at 5 yr were highest in males in Northern Europe (6.0%) and in females in Canada (12.8%). However, no statistically significance difference was found by geographic region. In Canada, the obesity rate for female children of mothers with and without T1D differed significantly at 4 and 5 yr (6.0 vs. 0.0% and 21.3 vs. 1.9%, respectively; p < 0.0125) but no differences by maternal T1D status were found in other regions. CONCLUSIONS: There are regional differences in early childhood growth that are consistent with the higher incidence of T1D in Northern Europe and Canada as compared to Southern Europe. Our prospective study from birth will allow evaluation of relationships between growth and the emerging development of autoimmunity and progression to T1D by region in this at-risk population of children. PMID- 22251867 TI - Negative caregiving effects among caregivers of veterans with dementia. AB - OBJECTIVES: : This investigation was guided by the stress process model and had two objectives: first, to describe the extent of negative caregiving effects for family caregivers of veterans with dementia, and second, to identify salient predictors of negative caregiving effects. DESIGN: : Data were obtained from baseline, structured telephone interviews with family caregivers of veterans enrolled in "Partners in Dementia Care," a clinical trial testing a care coordination intervention. PARTICIPANTS: : The study included 486 family caregivers of veterans with dementia who received primary care from the Department of Veterans Affairs healthcare system and lived at home. MEASUREMENT: : Six negative caregiving effects were described as follows: unmet needs, four role and intrapsychic strains, and depression. Predictive factors included the following: cognitive impairment, behavior problems, personal care dependency, number of chronic conditions, and characteristics of the caregiving context. RESULTS: : Sizeable portions of caregivers experienced negative caregiving effects; most common were unmet needs, social isolation, and depression. Cognitive, behavioral, and functional symptoms of dementia and other coexisting chronic conditions explained significant variation in all negative caregiving effects. Caregiving context had little impact. Behavior problems were the most consistent predictor; personal care dependency and other chronic conditions were also important. CONCLUSIONS: : Family caregivers, the foundation of long-term care for veterans with dementia who live at home, experience a variety of negative caregiving effects. Negative effects are greater when veterans exhibit behavior problems, require extensive assistance with personal care, and have a greater number of coexisting chronic conditions. Negative caregiving effects are an important target for interventions that support family caregivers and promote continued care at home. PMID- 22251868 TI - The association between mental health and cognitive screening scores in older veterans. AB - OBJECTIVES: : To examine overall cognitive screening results and the relationship between cognitive screen score and sociodemographic characteristics, reason for referral, and clinical outcomes of older veterans referred by primary care for a behavioral health assessment. DESIGN: : Cross-sectional, naturalistic study. SETTING: : Primary care clinics affiliated with two VA Medical Centers. PARTICIPANTS: : The sample included 4,325 older veterans referred to the Behavioral Health Laboratory who completed an initial mental health/substance abuse assessment. Veterans were categorized into the following three groups on the basis of cognitive status: within normal limits, possible cognitive impairment, and possible dementia. MEASUREMENTS: : Sociodemographic and clinical data on reason for referral, cognitive functioning (i.e., Blessed Orientation Memory-Concentration test), and behavioral health assessment outcomes were extracted from patients' medical records. Data were analyzed using multiple linear and logistic regressions. RESULTS: : Results of cognitive screenings indicated that the majority of the sample was within normal limits (62.5%), with 25.8%, 8.1%, and 3.6% of patients evidencing possible cognitive impairment, possible dementia, and Blessed Orientation-Memory-Concentration scores of 17 or more, respectively. With regard to reason for referral, patients with greater cognitive impairment were more likely to be identified by the antidepressant case finder than patients with less impairment. Increased age, non-white ethnicity, self-perceived inadequate finances, major depressive disorder, and symptoms of psychosis were associated with greater cognitive impairment. CONCLUSIONS: : Findings highlight the importance of evaluating cognitive status in older adults who are referred for a behavioral health assessment and/or receive a new mental health/substance abuse diagnosis. Doing so has the potential to improve recognition and treatment of cognitive impairment and dementia, thereby improving quality of care for many older adults. PMID- 22251869 TI - Xanthomata and diabetes in an adolescent with familial dysbetalipoproteinemia 9 yr after valproate-induced pancreatitis. AB - A 14-yr-old girl presented with eruptive xanthomata and hypertriglyceridemia. This rare presentation led to diagnoses of diabetes and familial dysbetalipoproteinemia. Type 1 diabetes is a common childhood illness often presenting in adolescence. However, this patient's past medical history revealed valproate-induced severe acute pancreatitis with necrosis at the age of 5 yr. Diabetes, in this case, developed 9 yr later as a result of inadequate pancreatic tissue to support increasing insulin requirements during growth and adolescence. Diabetes was discovered only after the appearance of cutaneous eruptive xanthomata, which appeared due to the previously undiagnosed genetic dyslipidemia. Although the relationship between xanthomata, hypertriglyceridemia, and diabetes may be well known in adults, in children, xanthomata are very rarely the presenting feature of diabetes of any cause. The patient was treated with insulin which induced rapid resolution of hypertriglyceridemia and gradual disappearance of xanthomata. This case acknowledges the rarity of diabetes presenting with xanthomata in adolescence, highlights the importance of searching for an underlying dyslipidemia in such a case, and presents diabetes as a long term complication of acute pancreatitis in children. PMID- 22251870 TI - Age and sex effects on the association between body composition and bone mineral density in healthy Chinese men and women. AB - OBJECTIVE: Many studies have examined the relationships between body composition and bone mineral density (BMD), but little attention has been given to how these relationships vary by age and sex. The aim of this study was to investigate the distributions of lean mass (LM), fat mass (FM), and BMD and the correlation between body composition and BMD in Chinese men and women of different ages. METHODS: In total, the body compositions of 1,475 men and 1,534 women aged 20 to 96 years were analyzed. Using dual-energy x-ray absorptiometry, we measured the BMD of the spine, femur, and total body and the LM, FM, and percentage of body fat (Fat %). The population was divided into groups based on age and sex: young, premenopausal, and postmenopausal women and young, middle-aged, and older men. The correlations between BMD and variables of body composition were investigated using the Pearson correlation test and multiple regression analysis. RESULTS: The peak BMD values of the spine, femur, and total body are observed in women aged 30 to 39, 20 to 29, and 30 to 39 years, respectively, and in men aged 20 to 29 years at all sites. The peak LM, FM, and Fat % values were observed at age 40 to 49, 60 to 69, and 70 to 79 years in women, respectively, and at 40 to 49, 70 to 79, and 70 to 79 years in men, respectively. A statistically significant correlation was observed between LM and BMD of all sites (r = 0.253-0.591, P < 0.01) in all groups. However, FM was significantly correlated to BMD only in postmenopausal women and older men (r = 0.089-0.336, P < 0.01). Fat % negatively correlated to BMD in young people (r = -0.169 to -0.366, P < 0.05). When stepwise regression models were analyzed, LM remained the strongest predictor of total body, spine, and femur BMD (standardized coefficients = 0.264-0.637, P < 0.001) in Chinese men and women of different ages. CONCLUSIONS: We believe that LM is the strongest predictor of BMD at all ages for Chinese men and women, even though positive correlations between FM and BMD existed in old people. PMID- 22251871 TI - Lactoferrin protects against lipopolysaccharide-induced acute lung injury in mice. AB - Lactoferrin (LF) plays various anti-inflammatory roles in inflammation experimentally induced by lipopolysaccharides (LPS). But the protective effects of LF on LPS-induced acute lung injury (ALI) have not been elucidated. In this study, we aimed to study the effects of LF on ALI caused by LPS in mice. At 1h before or after LPS injection, an intraperitoneal injection of LF (5mg/body) was administered. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses 12h after LPS exposure. We found that both prophylactic and therapeutic administration of LF significantly decreased the W/D ratio of the lung and protein concentration in the BALF. LF significantly reduced the pulmonary myeloperoxidase activity and the number of total cells in the BALF 12h after LPS challenge. LF treatment markedly attenuated lung edema, alveolar hemorrhage and inflammatory cells infiltration. Moreover, LF also decreased the production of TNF-alpha and increased interleukin 10 in the BALF. These results firstly indicate that LF may protect against LPS induced ALI in mice. PMID- 22251872 TI - Protein-RNA interactions: new genomic technologies and perspectives. AB - RNA-binding proteins are key players in the regulation of gene expression. In this Progress article, we discuss state-of-the-art technologies that can be used to study individual RNA-binding proteins or large complexes such as the ribosome. We also describe how these approaches can be used to study interactions with different types of RNAs, including nascent transcripts, mRNAs, microRNAs and ribosomal RNAs, in order to investigate transcription, RNA processing and translation. Finally, we highlight current challenges in data analysis and the future steps that are needed to obtain a quantitative and high-resolution picture of protein-RNA interactions on a genome-wide scale. PMID- 22251873 TI - Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription. AB - Dosage compensation is an epigenetic mechanism that normalizes gene expression from unequal copy numbers of sex chromosomes. Different organisms have evolved alternative molecular solutions to this task. In Drosophila melanogaster, transcription of the single male X chromosome is upregulated by twofold in a process orchestrated by the dosage compensation complex. Despite this conceptual simplicity, dosage compensation involves multiple coordinated steps to recognize and activate the entire X chromosome. We are only beginning to understand the intriguing interplay between multiple levels of local and long-range chromatin regulation required for the fine-tuned transcriptional activation of a heterogeneous gene population. This Review highlights the known facts and open questions of dosage compensation in D. melanogaster. PMID- 22251874 TI - Rare and common variants: twenty arguments. AB - Genome-wide association studies have greatly improved our understanding of the genetic basis of disease risk. The fact that they tend not to identify more than a fraction of the specific causal loci has led to divergence of opinion over whether most of the variance is hidden as numerous rare variants of large effect or as common variants of very small effect. Here I review 20 arguments for and against each of these models of the genetic basis of complex traits and conclude that both classes of effect can be readily reconciled. PMID- 22251875 TI - Prevalence of vertebral fractures in women and men in the population-based Tromso Study. AB - BACKGROUND: Osteoporotic vertebral fractures are, as the hip fractures, associated with increased morbidity and mortality. Norway has one of the highest reported incidences of hip fractures in the world. Because of methodological challenges, vertebral fractures are not extensively studied. The aim of this population based study was to describe, for the first time, the age- and sex specific occurrence of osteoporotic vertebral fractures in Norway. METHODS: Data was collected in the Tromso Study, 2007/8 survey. By the use of dual x-ray absorptiometry (GE Lunar Prodigy) vertebral fracture assessments were performed in 2887 women and men aged from 38 to 87 years, in addition to measurements of bone mineral density at the femoral sites. Information on lifestyle was collected through questionnaires. Comparisons between fractures and non-fractures were done sex stratified, by univariate analyses, adjusting for age when relevant. RESULTS: The prevalence of vertebral fractures varied from about 3% in the age group below 60 to about 19% in the 70+ group in women, and from 7.5% to about 20% in men, with an overall prevalence of 11.8% in women and 13.8% in men (p = 0.07). Among those with fractures, only one fracture was the most common; two and more fractures were present in approximately 30% of the cases. Fractures were seen from the fourth lumbar to the fifth thoracic vertebrae, most common between first lumbar and sixth thoracic vertebrae. The most common type of fracture was the wedge type in both sexes. Bone mineral density at the hip differed significantly according to type of fracture, being highest in those with wedge fractures and lowest in those with compression fractures. CONCLUSIONS: The prevalence of vertebral fractures increased by age in women and men, but the overall prevalence was lower than expected, considering the high prevalence of hip and forearm fractures in Norway. In both sexes, the wedge type was the fracture type most frequently observed and most common in the thoracic region. PMID- 22251876 TI - An efficient one pot transfer hydrogenation and N-alkylation of quinolines with alcohols mediated by Pd/C/Zn. AB - A Pd/C/Zn mixture with alcohols has been revealed to be an efficient transfer hydrogenation system to quinolines. Furthermore, the metals mixture is able to activate alcohols as N-alkylating agents in a hydrogen autotransfer process. 1,2,3,4-Tetrahydroquinolines and N-alkylated tetrahydroquinolines from quinolines have been obtained with excellent yields in one step. PMID- 22251877 TI - 'Trainee' evaluation of the English National Training Programme for laparoscopic colorectal surgery. AB - AIM: The aim of this study was to review trainees' opinions of the training they had received through the National Training Programme (NTP). METHOD: An online questionnaire was distributed to NTP trainees who had completed five or more training episodes within the programme. Demographic data were collected. Opinion was given using a five-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = undecided, 4 = agree, 5 = strongly agree). Percentages, mean values and SD were presented. ANOVA and Mann-Whitney U-tests were used to examine the impact of different factors on ratings and the difference between ratings, respectively. RESULTS: Fifty-four registered trainees fulfilled the inclusion criteria, and 37 (69% response rate) completed the questionnaire. Teaching sessions were organized using an inreach (11%), in-house (11%), outreach (27%) or combination (51%) system of training. Trainees felt that their trainers seldom cancelled sessions (93%), that it was easy to organize (92%) and consent (100%) the patient, and that their hospital was supportive of training (97%). Trainees stated that overall their trainers were excellent at training (Likert scale = 4.71 +/- 0.46) and that they received regular feedback (87%). The only variable to have a significant impact on the level of NTP approval was whether the trainee was able to choose his or her trainer (supportive of NTP, chose trainer P = 0.050; critical of NTP, chose trainer P = 0.020). CONCLUSION: The large majority of trainees was highly satisfied with the training received in this innovative programme, irrespective of region or training structure used, thus demonstrating acceptability of the programme in its current form. PMID- 22251878 TI - PdTe: a strongly coupled superconductor. AB - We report the electrical transport, magnetic, and thermodynamic properties of polycrystalline PdTe which exhibits superconductivity below 4.5 K. Using the measured values for the lower (H(c1)) and upper (H(c2)) critical fields, and the specific heat C(p), we estimate the thermodynamic critical field H(c)(0), coherence length xi(0), penetration depth lambda(0), and the Ginzburg-Landau parameter kappa. Compared with band structure calculations, the density of states at the Fermi level is enhanced due to electron-phonon coupling with lambda(ep) = 1.4. Furthermore, the large values of DeltaC(p)/gamma(n)T(c) and 2Delta(0)/k(B)T(c) suggest that PdTe is a strongly coupled superconductor. PMID- 22251879 TI - Clinical, aesthetic, and patient-related outcome of immediately loaded single implants in the anterior maxilla: a prospective study in extraction sockets, healed ridges, and grafted sites. AB - PURPOSE: The objective of this prospective clinical study was to document the overall treatment outcome of immediately loaded single Astra Tech OsseospeedTM (Astra Tech AB, Molndal, Sweden) implants placed in extraction sockets, healed ridges, and grafted sites. MATERIALS AND METHODS: Forty-eight patients in need of a single implant in the anterior maxilla (15-25) were recruited. Patients were allocated to a conventional implant treatment (CIT) or immediate implant treatment (IIT) group on the basis of specific criteria. If the buccal bone plate was damaged or missing upon tooth removal, patients were allocated to a grafted implant treatment (GIT) group. Irrespective of the treatment concept, implants were immediately provisionalized. Hard and soft tissue alterations, aesthetic parameters (pink and white esthetic scores, [PES and WES]) and patient's opinion (Oral Health Impact Profile [OHIP-14] questionnaires) were registered at different time points. RESULTS: After 1 year of function, the overall implant survival rate was 98% with one failure following IIT. The mean bone level to the implant-abutment interface was 0.65 (SD 0.79), 0.85 (SD 0.64), and 0.56 mm (SD 0.44) for CIT, IIT, and GIT. Complete papilla loss was rare following either strategy. Mean midfacial recession amounted to 1.00 (SD 1.15), 0.12 (SD 0.78), and 0.49 mm (SD 0.82) for CIT, IIT, and GIT, respectively. The aesthetic outcome showed a mean PES of 10.30 (SD 1.89) and mean WES of 7.11 (SD 2.14), all patients considered. Patient's satisfaction showed a significant improvement after 1 year of function on all seven domains (p < .001). CONCLUSIONS: This prospective study showed that single implants clinically and aesthetically perform well under immediate non-occlusal loading conditions in the premaxilla. In this context, it is of pivotal importance to stress that patients were carefully selected for IIT and GIT. PMID- 22251880 TI - The new brain: concepts, challenges, and opportunities for mental health nursing. AB - The new paradigm that the brain is able change itself (neuroplasticity) is acknowledged and teased out in terms of the ramifications for mental illnesses. Parallel studies in pain (central sensitization) and mirror neurones are examined to conceptually clarify these ramifications in relation to mental health, and to expand our understanding of empathy and social inclusion beyond good ideas to being a part of our nature. The paper then focuses on making clear what the concepts, challenges, and opportunities for mental health nursing might be; even advancing possibilities for recovery through better understanding the third space or intersubjective. What ramifications this has for mental health nursing is reviewed in terms of a paradigm change and the necessity for conceptual clarity, as it relates to the uniqueness of the person right before our very eyes. The author contends that to embrace this new paradigm is not only necessary but ethically obligatory, as it opens up new possibilities for understanding ourselves and this changeable person. PMID- 22251881 TI - Declining use of radiotherapy in stage I and II Hodgkin's disease and its effect on survival and secondary malignancies. AB - PURPOSE: Concerns regarding long-term toxicities have led some to withhold radiotherapy (RT) for the treatment of Stage I and II Hodgkin's disease (HD). The present study was undertaken to assess the use of RT for HD and its effect on overall survival and the development of secondary malignancies. METHODS AND MATERIALS: The present study included data from the Surveillance, Epidemiology, and End Results database from patients aged >= 20 years who had been diagnosed with Stage I or II HD between 1988 and 2006. Overall survival was estimated using the Kaplan-Meier method, and the Cox multivariate regression model was used to analyze trends. RESULTS: A total of 12,247 patients were selected, and 51.5% had received RT. The median follow-up for the present cohort was 4.9 years, with 21% of the cohort having >10 years of follow-up. Between 1988 and 1991, 62.9% had undergone RT, but between 2004 and 2006, only 43.7% had undergone RT (p < .001). The 5-year overall survival rate was 76% for patients who had not received RT and 87% for those who had (p < .001). The hazard ratio adjusted for other variables in the regression model showed that patients who had not undergone RT (hazard ratio, 1.72; 95% confidence interval, 1.72-2.02) was associated with significantly worse survival compared with patients who had received RT. The actuarial rate of developing a second malignancy was 14.6% vs. 15.0% at 15 years for those who had and had not undergone RT, respectively (p = .089). CONCLUSIONS: The present study is one of the largest studies to examine the role of RT for Stage I and II HD. Our results revealed a survival benefit with the addition of RT with no increase in the development of secondary malignancies compared with patients who had not received RT. Furthermore, the present nationwide study revealed a >20% absolute decrease in the use of RT from 1988 to 2006. PMID- 22251882 TI - Cloning, soluble expression, rapid purification and characterization of human Cofilin1. AB - Cofilin1 is an actin-binding protein that plays a critical role in the regulation of actin cytoskeleton and consequently affects various physiological processes. In this study, the human Cofilin1 cDNA was cloned into the expression vector pET 28a(+) with a 6 * His tag and expressed as soluble protein in Escherichia coli BL21(DE3). Approximately 78 mg of Cofilin1, which showed high activity as determined by native PAGE, could be purified from each liter of LB medium by His tag affinity chromatography and gel filtration. Further, high-titer IgG against Cofilin1 was positively detected after immunization in rabbits and the polyclonal antibodies were purified and identified. Together, this report provides the first protocol to efficiently obtain human Cofilin1 with high biological activity and immunogenicity using E. coli BL21 (DE3) expression system. PMID- 22251883 TI - Preparation and characterization of a poly(methyloctadecylsiloxane) thermally immobilized onto zirconized silica stationary phase for high-performance liquid chromatography. AB - This study describes the preparation and characterization of a HPLC stationary phase (SP) obtained by deposition of poly(methyloctadecylsiloxane) (PMODS) onto the surface of porous zirconized silica particles, followed by thermal immobilization. The SP were characterized using elemental analysis and infrared and (29)Si NMR spectroscopies, while their chromatographic behaviors were investigated by separation of selected neutral, acidic and basic compounds of different test mixtures (Engelhardt, SRM 870 and Tanaka tests). The preparation of the metalized support and the thermal immobilization of PMODS onto zirconized silica, optimized by experimental design, produced a SP based on PMODS that showed high values of efficiency (up to 85000 plates/m) and appropriate asymmetry factors. The presence of zirconium on the surface significantly decreases silica solubility in severe conditions (alkaline mobile phase at pH 10 and high temperature), increasing column lifetime. PMID- 22251884 TI - Novel peptide ligand with high binding capacity for antibody purification. AB - Small synthetic ligands for protein purification have become increasingly interesting with the growing need for cheap chromatographic materials for protein purification and especially for the purification of monoclonal antibodies (mAbs). Today, Protein A-based chromatographic resins are the most commonly used capture step in mAb down stream processing; however, the use of Protein A chromatography is less attractive due to toxic ligand leakage as well as high cost. Whether used as an alternative to the Protein A chromatographic media or as a subsequent polishing step, small synthetic peptide ligands have an advantage over biological ligands; they are cheaper to produce, ligand leakage by enzymatic degradation is either eliminated or significantly reduced, and they can in general better withstand cleaning in place (CIP) conditions such as 0.1M NaOH. Here, we present a novel synthetic peptide ligand for purification of human IgG. Immobilized on WorkBeads, an agarose-based base matrix from Bio-Works, the ligand has a dynamic binding capacity of up to 48 mg/mL and purifies IgG from harvest cell culture fluid with purities and recovery of >93%. The binding affinity is ~105 M-1 and the interaction is favorable and entropy-driven with an enthalpy penalty. Our results show that the binding of the Fc fragment of IgG is mediated by hydrophobic interactions and that elution at low pH is most likely due to electrostatic repulsion. Furthermore, we have separated aggregated IgG from non aggregated IgG, indicating that the ligand could be used both as a primary purification step of IgG as well as a subsequent polishing step. PMID- 22251885 TI - Study on a pseudo-simulated moving bed with solvent gradient for ternary separations. AB - There is a trapping effect on the solute in the simulated moving bed (SMB) with solvent gradient. As the eluotropic strength of the liquid in zone II (between the extract-port and feed-port) is higher than that in zone III (between the feed port and the raffinate-port), the solute can move forward in zone II but backward in zone III to be trapped in the two zones consequently. On this basis, a pseudo SMB was proposed to separate the medium retained solute from a ternary mixture by selectively trapping the medium retained solute. Once the columns in zones II and III are saturated with the target solute, the solvent dissolving the feed is introduced at the feed-port to remove the least retained solute from the raffinate-port and the most retained solute from the extract-port. Finally, the target solute is recovered. A model simulation was used to investigate the behavior and performance of a system operating with this technology. The results showed that increasing the columns in zone III could trap more target solutes since the eluotropic strength decreased from zone II to zone III. Partial recovery in combination with incomplete purification could improve the separation performance in terms of the productivity and solvent consumption without losing purity. PMID- 22251886 TI - Gas chromatography-full scan mass spectrometry determination of traces of chemical warfare agents and their impurities in air samples by inlet based thermal desorption of sorbent tubes. AB - A sensitive gas chromatography-mass spectrometry (GC-MS) based analytical method was developed for detection of the chemical warfare agents (CWA) and related compounds in air/vapor samples. The method uses a Tenax TA packed GC liner as an air/vapor sampling tube and Programmable Temperature-Vaporization (PTV) GC inlet as the thermal desorber. This approach eliminates secondary focusing step and allows transfer of desorbed analytes as sharp bands directly to the head of GC column. Use of a Peltier element for rapid cooling eliminates need for an external coolant. Minimal logistic and hardware needs make the method relatively inexpensive and especially suitable for a mobile laboratory. The limits of detection (LODs) of 0.8-2.9ng on tube for selected nerve and blister agents were achieved in the full scan MS mode. Simple derivatization method applied for detection of Lewisites 1 and 2 did not affect simultaneous analysis of other agents. The method was extensively evaluated with authentic CWA during the field trainings of the inspectors from the Organization for the Prohibition of Chemical Weapons (OPCW). The environmental area and personal samples were collected for a semi-quantitative determination of averaged airborne CWA concentration levels. PMID- 22251887 TI - Analysis of halonitriles in drinking water using solid-phase microextraction and gas chromatography-mass spectrometry. AB - Halonitriles are a class of nitrogen-containing disinfection by-products (DBPs) that have been reported to be more toxic and carcinogenic than the regulated DBPs. While haloacetonitriles (HANs) are often measured in drinking waters, there is little information on the formation, characteristics, and occurrence of other, higher molecular weight halonitriles. Halopropionitriles and halobutyronitriles have been predicted to be highly toxic and carcinogenic, and may have sufficient potency and selectivity to account for epidemiological associations of chlorinated and chloraminated water with adverse health effects. This paper reports on the development, optimisation, and validation of a simple, robust, and sensitive analytical method for the determination of halonitriles in waters, as well as the application of the method to study the formation and characteristics of halonitriles. This is the first reported method development for analysis halopropionitriles and halobutyronitriles, and the first study on their formation and occurrence as DBPs in drinking waters. The new method uses headspace solid phase microextraction to extract the halonitriles from water, which are then analysed using gas chromatography-mass spectrometry (HS SPME/GC-S). The method demonstrated good sensitivity (detection limits: 0.9-80 ng L-1) and good precision (repeatability: 3.8-12%), and is linear over three orders of magnitude. Matrix effects from raw drinking water containing organic carbon (4.1 mg L-1) were shown to be negligible in the analysis of halonitriles. The optimised method was used to study the stability and persistence of halonitriles in aqueous samples, and the formation and occurrence of halonitriles in waters. Results from laboratory-scale disinfection experiments showed that haloacetonitriles were formed in chlorinated and chloraminated samples, but 2,2-dichloropropionitrile was only measured in chloraminated samples. Results from surveys of several drinking water distribution systems confirmed the laboratory findings. PMID- 22251888 TI - A 3D-geometric model for the deformation of a transversally loaded muscle. AB - Very recent measurements provided data on the ratio between the change in length of the active fibres and the lifting height of a mass compressing the muscle belly transversally to the direction of fibre contraction. In this study, we present additional data of the change in the third (unloaded) muscle dimension, extracted from the same contraction experiments. Using this data set for validation, we verify whether body models of two different geometries, cylindrical or ellipsoidal, can explain the three-dimensional deformation of a contracting muscle, when volume constancy is required as a constraint. Presetting the contractile length change and using this constraint, an additional equation is needed for model predictions. To that, we minimise the sum of the squared and weighted circumference length changes. With a specific set of the three penalty weights, it turns out that the ellipsoid model can explain the three-dimensional deformation. The set of penalty weights can also be interpreted as an anisotropic stiffness distribution of the connective tissue of the muscle belly. In various loading situations, our ellipsoidal model may help to predict the corresponding deformation scenarios or to calculate the stiffness distribution from measured load and deformation data. PMID- 22251889 TI - Improved haplotype assembly using Xor genotypes. AB - Given a set of aligned fragments, haplotype assembly is the problem of finding the haplotypes from which the fragments have been read. The problem is important because haplotypes contain SNP information, which is essential to many genomic analyses such as the analysis of potential association between certain diseases and genetic variations. The current state-of-the-art haplotype assembly algorithm, HapSAT, does not exploit genotype information and only receives a read matrix as input. However, the imminent importance of haplotypes and inexpensiveness of genotype information motivate for exploiting genotype information to obtain more accurate haplotypes. In this paper, an improved haplotype assembly method, xGenHapSAT, is proposed, which exploits xor genotype information for more accurate haplotype assembly. Xor genotype information is even less expensive than full genotype information, e.g., using the Denaturing High-Performance Liquid Chromatography (DHPLC) technique. It is shown that using this inexpensively obtainable information significantly improves the accuracy of the assembled haplotypes. In addition, a new, more efficient, Max-2-SAT formulation is adopted in xGenHapSAT, which, on average, increases the speed of the algorithm. Moreover, the proposed xGenHapSAT method replaces the current state-of-the-art haplotype assembly method based on genotype information. Finally, our state-of-the-art haplotype assembly software, HapSoft, which includes both xGenHapSAT and HapSAT, is made freely available for research purposes. PMID- 22251890 TI - Invertebrate learning and memory: Fifty years of olfactory conditioning of the proboscis extension response in honeybees. AB - The honeybee Apis mellifera has emerged as a robust and influential model for the study of classical conditioning, thanks to the existence of a powerful Pavlovian conditioning protocol, the olfactory conditioning of the proboscis extension response (PER). In 2011, the olfactory PER conditioning protocol celebrates 50 years since it was first introduced by Kimihisa Takeda in 1961. Here, we review its origins, developments, and perspectives in order to define future research avenues and necessary methodological and conceptual evolutions. We show that olfactory PER conditioning has become a versatile tool for the study of questions in extremely diverse fields in addition to the study of learning and memory and that it has allowed behavioral characterizations, not only of honeybees, but also of other insect species, for which the protocol was adapted. We celebrate, therefore, Takeda's original work and prompt colleagues to conceive and establish further robust behavioral tools for an accurate characterization of insect learning and memory at multiple levels of analysis. PMID- 22251891 TI - Methylphenidate enhances extinction of contextual fear. AB - Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders. PMID- 22251892 TI - Amyloid fibrillation in native and chemically-modified forms of carbonic anhydrase II: role of surface hydrophobicity. AB - Chemical modification or mutation of proteins may bring about significant changes in the net charge or surface hydrophobicity of a protein structure. Such events may be of major physiological significance and may provide important insights into the genetics of amyloid diseases. In the present study, fibrillation potential of native and chemically-modified forms of bovine carbonic anhydrase II (BCA II) were investigated. Initially, various denaturing conditions including low pH and high temperatures were tested to induce fibrillation. At a low pH of around 2.4, where the protein is totally dissociated, the apo form was found to take up a pre-molten globular (PMG) conformation with the capacity for fibril formation. Upon increasing the pH to around 3.6, a molten globular (MG) form became abundant, forming amorphous aggregates. Charge neutralization and enhancement of hydrophobicity by methylation, acetylation and propionylation of lysine residues appeared very effective in promoting fibrillation of both the apo and holo forms under native conditions, the rates and extents of which were directly proportional to surface hydrophobicity, and influenced by salt concentration and temperature. These modified structures underwent more pronounced fibrillation under native conditions, than the PMG intermediate form, observed under denaturing conditions. The nature of the fibrillation products obtained from intermediate and modified structures were characterized and compared and their possible cytotoxicity determined. Results are discussed in terms of the importance of surface net charge and hydrophobicity in controlling protein aggregation. A discussion on the physiological significance of the observations is also presented. PMID- 22251894 TI - Expression, purification and preliminary biochemical and structural characterization of the leucine rich repeat namesake domain of leucine rich repeat kinase 2. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. Much research effort has been directed towards the catalytic core region of LRRK2 composed of GTPase (ROC, Ras of complex proteins) and kinase domains and a connecting COR (C-terminus of ROC) domain. In contrast, the precise functions of the protein-protein interaction domains, such as the leucine-rich repeat (LRR) domain, are not known. In the present study, we modeled the LRRK2 LRR domain (LRR(LRRK2)) using a template assembly approach, revealing the presence of 14 LRRs. Next, we focused on the expression and purification of LRR(LRRK2) in Escherichia coli. Buffer optimization revealed that the protein requires the presence of a zwitterionic detergent, namely Empigen BB, during solubilization and the subsequent purification and characterization steps. This indicates that the detergent captures the hydrophobic surface patches of LRR(LRRK2) thereby suppressing its aggregation. Circular dichroism (CD) spectroscopy measured 18% alpha-helices and 21% beta-sheets, consistent with predictions from the homology model. Size exclusion chromatography (SEC) and dynamic light scattering measurements showed the presence of a single species, with a Stokes radius corresponding to the model dimensions of a protein monomer. Furthermore, no obvious LRR(LRRK2) multimerization was detected via cross-linking studies. Finally, the LRR(LRRK2) clinical mutations did not influence LRR(LRRK2) secondary, tertiary or quaternary structure as determined via SEC and CD spectroscopy. We therefore conclude that these mutations are likely to affect putative LRR(LRRK2) inter- and intramolecular interactions. PMID- 22251893 TI - Solution structure of native and recombinant expressed toxin CssII from the venom of the scorpion Centruroides suffusus suffusus, and their effects on Nav1.5 sodium channels. AB - The three-dimensional structures of the long-chain mammalian scorpion beta-toxin CssII from Centruroides suffusus suffusus and of its recombinant form, HisrCssII, were determined by NMR. The neurotoxin CssII (nCssII) is a 66 amino acid long peptide with four disulfide bridges; it is the most abundant and deadly toxin from the venom of this scorpion. Both native and recombinant CssII structures were determined by nuclear magnetic resonance using a total of 828 sequential distance constraints derived from the volume integration of the cross peaks observed in 2D NOESY spectra. Both nCssII and HisrCssII structures display a mixed alpha/beta fold stabilized by four disulfide bridges formed between pairs of cysteines: C1-C8, C2-C5, C3-C6, and C4-C7 (the numbers indicate the relative positions of the cysteine residues in the primary structure), with a distortion induced by two cis-prolines in its C-terminal part. The native CssII electrostatic surface was compared to both the recombinant one and to the Cn2 toxin, from the scorpion Centruroides noxius, which is also toxic to mammals. Structural features such N- and C-terminal differences could influence toxin specificity and affinity towards isoforms of different sub-types of Na(v) channels. PMID- 22251895 TI - What causes latitudinal gradients in species diversity? Evolutionary processes and ecological constraints on swallowtail biodiversity. AB - The latitudinal diversity gradient (LDG) is one of the most striking ecological patterns on our planet. Determining the evolutionary causes of this pattern remains a challenging task. To address this issue, previous LDG studies have usually relied on correlations between environmental variables and species richness, only considering evolutionary processes indirectly. Instead, we use a phylogenetically integrated approach to investigate the ecological and evolutionary processes responsible for the global LDG observed in swallowtail butterflies (Papilionidae). We find evidence for the 'diversification rate hypothesis' with different diversification rates between two similarly aged tropical and temperate clades. We conclude that the LDG is caused by (1) climatically driven changes in both clades based on evidence of responses to cooling and warming events, and (2) distinct biogeographical histories constrained by tropical niche conservatism and niche evolution. This multidisciplinary approach provides new findings that allow better understanding of the factors that shape LDGs. PMID- 22251896 TI - Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo. AB - To date, 11C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands (18F-PBR111, 11C PBR28, 11C-DPA713) and 11C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data. The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BP(ND)]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between subject performance was characterised in terms of the number of subjects required to distinguish between different populations. The results indicated that the within-subject variability for 18F-PBR111, 11C-PBR28 and 11C-DPA713 (0.9% to 2.2%) was significantly lower than 11C-(R)-PK11195 (16% to 36%) for HABs and MABs in both normal and diseased states. For between-subject studies, sample sizes required to detect 50% differences in TSPO density with the 2nd generation tracers are approximately half that required with 11C-(R)-PK11195 when binding class information is known a priori. As binding class can be identified using a simple genetic test or from peripheral blood assays, the combination of binding class information with 2nd generation TSPO imaging data should provide superior tools to investigate inflammatory processes in humans in vivo. PMID- 22251898 TI - Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. Foreword. PMID- 22251897 TI - RhoA/ROCK-dependent moesin phosphorylation regulates AGE-induced endothelial cellular response. AB - BACKGROUND: The role of advanced glycation end products (AGEs) in the development of diabetes, especially diabetic complications, has been emphasized in many reports. Accumulation of AGEs in the vasculature triggers a series of morphological and functional changes in endothelial cells (ECs) and induces an increase of endothelial permeability. This study was to investigate the involvement of RhoA/ROCK-dependent moesin phosphorylation in endothelial abnormalities induced by AGEs. METHODS: Using human dermal microvascular endothelial cells (HMVECs), the effects of human serum albumin modified-AGEs (AGE HSA) on the endothelium were assessed by measuring monolayer permeability and staining of F-actin in HMVECs. Activations of RhoA and ROCK were determined by a luminescence-based assay and immunoblotting. Transfection of recombinant adenovirus that was dominant negative for RhoA (RhoA N19) was done to down regulate RhoA expression, while adenovirus with constitutively activated RhoA (RhoA L63) was transfected to cause overexpression of RhoA in HMVECs. H-1152 was employed to specifically block activation of ROCK. Co-immunoprecipitation was used to further confirm the interaction of ROCK and its downstream target moesin. To identify AGE/ROCK-induced phosphorylation site in moesin, two mutants pcDNA3/HA-moesinT(558A) and pcDNA3/HA-moesinT(558D) were applied in endothelial cells. RESULTS: The results showed that AGE-HSA increased the permeability of HMVEC monolayer and triggered the formation of F-actin-positive stress fibers. AGE-HSA enhanced RhoA activity as well as phosphorylation of ROCK in a time- and dose-dependent manner. Down-regulation of RhoA expression with RhoA N19 transfection abolished these AGE-induced changes, while transfection of RhoA L63 reproduced the AGE-evoked changes. H-1152 attenuated the AGE-induced alteration in monolayer permeability and cytoskeleton. The results also confirmed the AGE induced direct interaction of ROCK and moesin. Thr558 was further identified as the phosphorylating site of moesin in AGE-evoked endothelial responses. CONCLUSION: These results confirm the involvement of RhoA/ROCK pathway and subsequent moesin Thr558 phosphorylation in AGE-mediated endothelial dysfunction. PMID- 22251899 TI - Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine. PMID- 22251900 TI - A monoubiquitylation pore anchor. PMID- 22251902 TI - Making fat. PMID- 22251901 TI - The unfolded protein response: controlling cell fate decisions under ER stress and beyond. AB - Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1alpha (IRE1alpha) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed. PMID- 22251904 TI - AMPK moonlights in mitosis. PMID- 22251903 TI - Illuminating the functional and structural repertoire of human TBC/RABGAPs. AB - The Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs) are characterized by the presence of highly conserved TBC domains and act as negative regulators of RABs. The importance of TBC/RABGAPs in the regulation of specific intracellular trafficking routes is now emerging, as is their role in different diseases. Importantly, TBC/RABGAPs act as key regulatory nodes, integrating signalling between RABs and other small GTPases and ensuring the appropriate retrieval, transport and delivery of different intracellular vesicles. PMID- 22251905 TI - Patient education from the Journal of Midwifery & Women's Health: Share with women. PMID- 22251906 TI - Directive versus supportive approaches used by midwives when providing care during the second stage of labor. AB - INTRODUCTION: Although the risks associated with using sustained and forceful maternal bearing-down efforts during the second stage of labor have been well documented, most women who give birth in the United States bear down in response to direction from care providers about when and how to push rather than in response to their own physiologic urges. The purpose of this study was to describe the practices used by certified nurse-midwives/certified midwives (CNMs/CMs) in response to maternal bearing-down efforts when caring for women in second-stage labor and to identify factors associated with the use of supportive approaches to second-stage labor care. METHODS: A national survey of 705 CNMs/CMs was conducted using mailed questionnaires. The instrument was an 84-item, fixed choice questionnaire using Likert type scales that had been validated. A 72.6% response rate was achieved, and 375 of the respondents cared for women during the second stage of labor. RESULTS: Most CNMs/CMs (82.4%) often or almost always supported women without epidural anesthesia to initiate bearing-down efforts only when the woman felt an urge to do so. When caring for women without an epidural, most of the respondents (67%) reported that they often or almost always supported a woman's spontaneous bearing-down efforts without providing direction. Most participants reported using more directive practices when caring for women with epidural anesthesia. Whether caring for women with or without an epidural, most respondents (77.1% and 79.6%, respectively) often or almost always provided more direction as the fetal head emerged and the final stretching of the perineum was taking place. A change in fetal heart tones that led the midwife to believe the birth needed to occur quickly was the circumstance that had the greatest degree of influence on the participant's (90.6%) decision to provide more direction during bearing-down efforts. Many participants indicated that they also were influenced to provide more direction when women in labor asked for more direction (73.3%) or appeared to be fatigued (74.6%). DISCUSSION: The majority of CNMs/CMs use supportive approaches to bearing-down efforts during second-stage labor care and most used directive approaches as an intervention aimed at avoiding potential problems. PMID- 22251907 TI - First birth cesarean and risk of antepartum fetal death in a subsequent pregnancy. AB - INTRODUCTION: To examine the relationship between first birth by cesarean and antepartum fetal death in a subsequent pregnancy in a large, hospital-based population. METHODS: Data for this retrospective cohort study were taken from a database of all women who gave birth at Brigham and Women's Hospital during 4 waves of data collection beginning in 1994 and ending in 2002. We calculated the risk of antepartum fetal death in the subsequent pregnancy for women whose first birth was by cesarean compared to women with a vaginal first birth. Survival analysis was used to examine the influence of gestational age at birth. RESULTS: Of 10,996 women who met inclusion criteria, 22% (n = 2450) had first births by cesarean, and 78% (n = 8546) had vaginal first births. The risk of antepartum fetal death in the subsequent pregnancy for women whose first birth was by cesarean was significantly greater than the risk for women whose first birth was vaginal (odds ratio 2.6; 95% confidence interval, 1.1-6.2). The relationship between first birth cesarean and antepartum fetal death in a subsequent pregnancy differed by gestational age at birth, with no excess risk among women with a previous cesarean birth who gave birth before 34 weeks' gestation but with a substantially increased risk for women who gave birth at 34 or more weeks' gestation (unadjusted hazard ratio = 5.6; 95% confidence interval, 1.6-19.8). Hazard ratio estimates for the association remained significant in bivariate models when adjusted for maternal height, weight, age, hypertension, and diabetes. DISCUSSION: In these data, first birth by cesarean was associated with an increased risk of antepartum fetal death in a subsequent pregnancy. Our findings suggest that antepartum fetal deaths in subsequent pregnancies might be prevented by avoiding primary cesarean birth. PMID- 22251908 TI - Skilled birth attendants in Mexico: how does care during normal birth by general physicians, obstetric nurses, and professional midwives compare with World Health Organization evidence-based practice guidelines? AB - INTRODUCTION: We evaluated the quality of basic obstetric care provided by Mexican general physicians, obstetric nurses, and professional midwives compared with World Health Organization (WHO) guidelines for evidence-based practices and national guidelines. METHODS: Vaginal births were observed in 5 hospitals in 5 states from June 2006 until July 2007. We created 5 indices based on WHO guidelines and national standards for care during normal birth. These indices included 1) favorable practices at admission, 2) favorable practices during labor, birth, and immediately postpartum, 3) harmful or excessively used practices, 4) newborn practices, and 5) obstetric outcomes. We assessed each provider type's performance as high or low compared with the WHO standard and performed bivariate and multivariate logistic regression analyses to assess the association between indices, patient characteristics, and provider type, adjusting for standard errors for intragroup correlation. RESULTS: We observed 876 independently managed vaginal births. Adjusted regression analyses compared with the general physicians standard revealed significant results for favorable care by obstetric nurses on admission (odds ratio [OR] 6.25; 95% confidence interval [CI], 2.08-18.84); for care by professional midwives (OR 21.08; 95% CI, 4.24-104.94) and obstetric nurses (OR 7.88; 95% CI, 2.76-22.52) during labor, birth, and postpartum; and for newborn practices by obstetric nurses (OR 4.14; 95% CI, 1.08-15.90). Professional midwives were least likely to perform harmful/excessively used practices during labor, birth, and the postpartum period (OR 0.06; 95% CI, 0.00-0.35). DISCUSSION: Professional midwives and obstetric nurses perform equally or better than general physicians when assessed by use or misuse of evidence-based practices. Professional midwives are an underutilized resource in Mexico. If integrated into the mainstream Mexican health system, they may improve the quality of obstetric care. PMID- 22251909 TI - Evaluation of a student-nurse doula program: an analysis of doula interventions and their impact on labor analgesia and cesarean birth. AB - INTRODUCTION: The aim of this study was to describe specific doula interventions, explore differences in doula interventions by attending provider (certified nurse midwife vs obstetrician), and examine associations between doula interventions, labor analgesia, and cesarean birth in women receiving doula care from student nurses. METHODS: A secondary analysis of data from the Birth Companions Program at the Johns Hopkins University School of Nursing was conducted using t tests, chi-square statistics, and logistic regression models. RESULTS: In the 648 births in the sample, doulas used approximately 1 more intervention per labor with certified nurse-midwife clients compared to obstetrician clients. In multivariate analysis, the increase in the total number of interventions provided by doulas was associated with decreased odds of epidural (adjusted odds ratio [AOR] 0.92; 95% confidence interval [CI], 0.86-0.98) and cesarean birth (AOR 0.90; 95% CI, 0.85-0.95). When examined separately, a greater number of physical interventions was associated with decreased odds of epidural (AOR 0.85; 95% CI, 0.78-0.92) and cesarean birth (AOR 0.80; 95% CI, 0.73-0.88), but number of emotional/informational interventions was not. DISCUSSION: Student nurses trained as doulas have the opportunity to provide a variety of interventions for laboring clients. An increase in the number of interventions, especially physical interventions, provided by doulas may decrease the likelihood of epidural use and cesarean birth. PMID- 22251910 TI - Clinician perceptions of providing natural family planning methods in Title X funded clinics. AB - INTRODUCTION: Natural family planning (NFP) methods are effective for contraception with proper and consistent use. However, only 1% of patients at federally funded Title X family planning clinics select NFP as a contraceptive method. The goal of this study was to understand from clinicians' perspectives the barriers and facilitators to providing NFP methods. METHODS: Six telephone focus groups were conducted with 29 clinicians from Title X clinics across the United States and Puerto Rico. A hermeneutic method was used to analyze data for related themes. RESULTS: The overarching theme from the study was that participants had a strong desire to teach their patients how their bodies work and to empower them to learn to control fertility. Four subthemes emerged: patient misinformation and misunderstanding about fertility; provider ideas about ideal types of candidates for NFP; inconsistent patient teaching strategies; and lack of time to teach NFP methods. DISCUSSION: There is a need for increased NFP training for providers and efficient NFP patient teaching strategies to meet the needs of patients with limited knowledge about fertility. PMID- 22251911 TI - Impact of dietary folate intake on depressive symptoms in young women of reproductive age. AB - INTRODUCTION: Folate deficiencies may be linked to depressive disorders among persons suffering from neurological and psychiatric problems. The purpose of the present study was to evaluate the impact of dietary folate intake on depressive symptoms in young Japanese women of reproductive age. METHODS: The study was conducted in Japan in 2009 with 141 Japanese women aged 18 to 28 years. A Japanese version of the Center for Epidemiologic Studies Depression (CES-D) scale was used to screen for depressive symptoms. Dietary intake was investigated by a diet history questionnaire. Nonfasting blood samples were collected from the women to measure folate and homocysteine levels. RESULTS: The proportion of women with lower folate intake (< 240 MUg/d) was significantly higher in the women with CES-D scores greater than or equal to 19 when compared with the folate levels in those with CES-D scores less than 19 (75.0% vs 43.6%, respectively; P < .001). Logistic regression analysis revealed significant associations between CES-D scores greater than or equal to 19, low folate intake, and low vitamin B(6) intake when adjusted for age, living status, smoking, and body mass index. Adequate folate intake of more than the recommended dietary allowance (RDA) level of 240 MUg per day was independently related to a decreased risk of depression (adjusted odds ratio 0.22; 95% confidence interval, 0.11-0.56; P < .001). DISCUSSION: Multiple logistic regression analysis revealed a reduced incidence of depression in women whose intake of folate exceeded the RDA of 240 MUg per day. This finding suggests that dietary folate intake may be causally related to depressive symptoms in women of reproductive age. If results of studies powered to determine causal relationships are similarly positive, folate supplementation could reduce the incidence of depression. PMID- 22251912 TI - Facilitators and barriers of independent decisions by midwives during labor and birth. AB - INTRODUCTION: The purpose of this study was to explore the factors that affect labor management decisions of midwives in hospitals and freestanding birth centers. METHODS: A qualitative study was conducted using one-on-one tape recorded interviews of midwives who had experience managing labor and birth in both hospitals and freestanding birth centers. Ten interviews consisting of several open-ended questions were conducted, coded, and analyzed in a stepwise fashion to identify codes, categories, and themes. Seven participants reviewed the final framework and confirmed credibility and trustworthiness. RESULTS: Four overall themes were identified: trust birth, the woman, the environment, and the labor team. DISCUSSION: When making labor management decisions, midwives are affected by their trust in birth, the woman, the health care team, and the birth environment. Midwives report more resistance when making labor management decisions in hospitals. The findings of this study provide insight into both the decision making of midwives and how factors in different environments, in this case hospitals and freestanding birth centers, influence the ability of midwives to make independent labor management decisions. PMID- 22251913 TI - Shoulder dystocia and postpartum hemorrhage simulations: student confidence in managing these complications. AB - INTRODUCTION: Simulation is an effective teaching strategy for educating health professionals. However, little is known about the effectiveness of simulations in midwifery education. The purpose of this project was to determine whether the use of high-fidelity simulations for the obstetric emergencies of shoulder dystocia and postpartum hemorrhage increases student confidence in managing these complications. METHODS: The participants were registered nurses enrolled in a graduate midwifery education program in the Southeastern United States. Student confidence in learning to manage shoulder dystocia and postpartum hemorrhage was studied in 2 groups of students. The control group (n = 10) received standard teaching methods consisting of discussion, watching a video, and low-fidelity teaching methods. The intervention group (n = 18) received a high-fidelity simulation learning experience. Student confidence was measured before and after each learning experience using a validated, 8-item, Likert-type scale. RESULTS: In the control group, student confidence did not significantly increase after a classroom discussion or low-fidelity simulation experience. Student confidence increased significantly (P < .01) after the high-fidelity simulation learning experiences. When the differences between the pretest and posttest scores were compared for the control and intervention groups, there was a moderate effect size (0.54) for the intervention group for the shoulder dystocia simulations and a large effect size (1.68) for the postpartum hemorrhage simulations. CONCLUSION: High-fidelity simulations for shoulder dystocia and postpartum hemorrhage significantly increased student confidence in managing these complications. PMID- 22251914 TI - Psychological and behavioral traits associated with eating disorders and pregnancy: a pilot study. AB - INTRODUCTION: The aims of this pilot study were to determine the feasibility of conducting a large-scale study exploring the extent to which self-report psychological and behavioral traits associated with eating disorders occur during pregnancy, to test the design, and to gather preliminary data on the magnitude of the problem. Although eating disorders are estimated to affect 5.9% of women of childbearing age, little is known about pregnancy in women who have an undocumented history of disordered eating behavior in the United States. Understanding and identifying eating disorders is important because optimal maternal nutrition contributes to favorable pregnancy and neonatal outcomes. METHODS: In our study using a retrospective descriptive design, a convenience sample of 54 postpartum women aged 19 to 43 years voluntarily completed a demographic questionnaire and the Eating Disorder Inventory-3 (EDI-3) before discharge from the hospital. Medical records were reviewed for documented eating disorders. RESULTS: Fifteen women (27.8%) had scores on the EDI-3 indicating that they had psychological and behavioral traits associated with eating disorders. One (1.85%) of the 54 participants' medical records listed a history of an eating disorder. DISCUSSION: Exploration of self-report symptoms associated with eating disorders during pregnancy warrants further investigation. Health professionals providing care to pregnant women should assess all clients for eating disorders throughout pregnancy and the postpartum period, regardless of history. PMID- 22251915 TI - Midwives' perceptions of providing stop-smoking advice and pregnant smokers' perceptions of stop-smoking services within the same deprived area of London. AB - INTRODUCTION: To identify and juxtapose midwives' perceptions of providing stop smoking advice and pregnant smokers' perceptions of stop-smoking services. METHODS: A qualitative design was used in an attempt to expose and compare in depth perceptions of midwives and pregnant smokers. Three focus groups lasting approximately 1 hour and involving 15 midwives were carried out, and 10 pregnant smokers participated in semistructured interviews. The qualitative data were analyzed by using the full version of grounded theory. RESULTS: The perceptions of midwives regarding provision of advice were related to outcome of advice, the relationship with patients, personal experiences, attributes, perception of role, the impact of external factors, and aspects related to pregnant smokers and pregnancy. Pregnant smokers' perceived barriers and facilitators to approaching stop-smoking services were categorized into areas of smoking behavior, advice from health professionals, stop-smoking services, and negative perceptions of pregnant women who smoke. DISCUSSION: In theory, many of the perceived barriers to providing advice could be overcome by implementing effective mandatory training for midwives. However, real issues, such as lack of time, have a major impact on the provision of advice. Pregnant smokers expect and appreciate receiving stop-smoking advice from midwives. Yet, they tend to have negative expectations of stop-smoking services, although the experiences of those who have attended these services are positive. Raising awareness of stop-smoking support for pregnant women is crucial in empowering women to make informed choices about their health and the health of their children. PMID- 22251917 TI - Epidural fever and its implications for mothers and neonates: taking the heat. AB - Epidural fever is a maternal temperature elevation seen in women who use epidural analgesia during labor. It occurs in a subset of laboring women after epidural administration and is noninfectious in origin. Epidural fever is not associated with neonatal sepsis, but it often is difficult to distinguish from chorioamnionitis, a condition that can cause neonatal sepsis. Because of this, neonates born to mothers who experience fever during labor are often evaluated for sepsis. Potential solutions to this problem include establishing better methods to distinguish between epidural fever and chorioamnionitis and making alternative methods of pain relief available to laboring women. PMID- 22251916 TI - The Health Belief Model can guide modern contraceptive behavior research and practice. AB - INTRODUCTION: Theory-based research is needed to understand poor contraceptive behavior and related reproductive health sequelae. The purpose of this review was to examine the Health Belief Model (HBM) as a comprehensive, well-tested social cognitive framework suitable for explaining and predicting contraceptive behavior. METHODS: Existing literature, including editorials and research reports, describing HBM-guided contraceptive research between January 1966 and February 2011 was retrieved from established electronic databases. After consideration of inclusion/exclusion criteria, 10 articles were included in the review. RESULTS: Issues in original family planning applications of HBM included inconsistent conceptualizations of contraceptive behavior and limited use of all HBM constructs in research surveys, interventions, and analyses. Knowledge of contraceptive behavior has evolved, warranting more comprehensive use of the HBM for pertinent reproductive health contexts, behaviors, and methods. DISCUSSION: With more rigorous applications, the HBM can help us understand modern contraceptive behavior determinants and facilitate strategies to prevent unintended pregnancy and promote positive family planning outcomes. PMID- 22251918 TI - Guidelines for Papanicolaou test screening and follow-up. PMID- 22251920 TI - Share with women. Second stage of labor: pushing your baby out. PMID- 22251921 TI - Sigma-2 ligands induce tumour cell death by multiple signalling pathways. AB - BACKGROUND: The sigma-2 receptor has been identified as a biomarker of proliferating cells in solid tumours. In the present study, we studied the mechanisms of sigma-2 ligand-induced cell death in the mouse breast cancer cell line EMT-6 and the human melanoma cell line MDA-MB-435. METHODS: EMT-6 and MDA-MB 435 cells were treated with sigma-2 ligands. The modulation of multiple signaling pathways of cell death was evaluated. RESULTS: Three sigma-2 ligands (WC-26, SV119 and RHM-138) induced DNA fragmentation, caspase-3 activation and PARP-1 cleavage. The caspase inhibitor Z-VAD-FMK partially blocked DNA fragmentation and cytotoxicity caused by these compounds. These data suggest that sigma-2 ligand induced apoptosis and caspase activation are partially responsible for the cell death. WC-26 and siramesine induced formation of vacuoles in the cells. WC-26, SV119, RHM-138 and siramesine increased the synthesis and processing of microtubule-associated protein light chain 3, an autophagosome marker, and decreased the expression levels of the downstream effectors of mammalian target of rapamycin (mTOR), p70S6K and 4EBP1, suggesting that sigma-2 ligands induce autophagy, probably by inhibition of the mTOR pathway. All four sigma-2 ligands decreased the expression of cyclin D1 in a time-dependent manner. In addition, WC 26 and SV119 mainly decreased cyclin B1, E2 and phosphorylation of retinoblastoma protein (pRb); RHM-138 mainly decreased cyclin E2; and 10 MUM siramesine mainly decreased cyclin B1 and pRb. These data suggest that sigma-2 ligands also impair cell-cycle progression in multiple phases of the cell cycle. CONCLUSION: Sigma-2 ligands induce cell death by multiple signalling pathways. PMID- 22251923 TI - Who needs a bag? PMID- 22251922 TI - HPV DNA testing in population-based cervical screening (VUSA-Screen study): results and implications. AB - BACKGROUND: Human papillomavirus (HPV) testing is more sensitive than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We evaluated the performance of high-risk HPV (hrHPV) testing in routine screening. METHODS: In all, 25,871 women (29-61) enrolled in our population-based cohort study were offered both cytology and hrHPV testing. High-risk HPV-positive women with normal cytology and an age-matched subcohort of hrHPV-negative women with normal cytology were invited for repeat testing after 1 and/or 2 years and were referred for colposcopy if they presented with abnormal cytology and/or a positive hrHPV test. The hrHPV-positive women with borderline or mild dyskaryosis (BMD) and all women with moderate dyskaryosis or worse (>BMD) were directly referred for colposcopy. Women with BMD and an hrHPV-negative test were advised to repeat cytology at 6 and 18 months and were referred for colposcopy if the repeat cytology test was abnormal. The main outcome measure was CIN grade 3 or worse (CIN3+). Results were adjusted for non-attendance at repeat testing. RESULTS: The hrHPV-positive women with abnormal cytology had a CIN3+ risk of 42.2% (95% confidence interval (CI): 36.4-48.2), whereas the hrHPV-positive women with normal cytology had a much lower risk of 5.22% (95% CI: 3.72-7.91). In hrHPV positive women with normal cytology, an additional cytology step after 1 year reduced the CIN3+ risk to only 1.6% (95% CI: 0.6-4.9) if the repeat test was normal. The CIN3+ risk in women with hrHPV-positive normal cytology was higher among women invited for the first time (29-33 years of age) (9.1%; 95% CI: 5.6 14.3) than among older women (3.0%; 95% CI: 1.5-5.5). CONCLUSION: Primary hrHPV screening with cytology triage in women aged ?30 years is an effective way to stratify women on CIN3+ risk and seems a feasible alternative to cytological screening. Repeat cytology after 1 year for hrHPV-positive women with normal cytology is however necessary before returning women to routine screening. PMID- 22251924 TI - Effect of dilute CHO beverages on performance in cool and warm environments. AB - PURPOSE: The efficacy of drinks containing low concentrations of CHO (2%-6%) on physical performance in cool and warm environments was evaluated. METHODS: In two separate but related studies, 24 healthy males completed a familiarization trial and four trials to volitional exhaustion (TTE) at 70% VO2max in cool conditions (10 degrees C, n = 12) or 60% VO2max in a warm environment (30 degrees C, n = 12). Subjects ingested 0%, 2%, 4%, or 6% CHO solutions (sucrose, glucose, and fructose in a ratio of 50:25:25) immediately before exercise and every 10 min during exercise. RESULTS: TTE in 10 degrees C was 102.6 +/- 33.9, 109.2 +/- 33.9, 121.0 +/- 25.7, and 122.4 +/- 29.9 min in the 0%, 2%, 4%, and 6% trials, respectively (P = 0.012). Compared with the 0% trial, TTE was longer in the 4% (P = 0.032, effect size (ES) = 0.72) and 6% (P = 0.044, ES = 0.66) trials. In addition, TTE was longer in the 6% trial than in the 2% trial (P = 0.025). TTE was also significantly influenced by drink CHO content at 30 degrees C (0% = 94.5 +/- 24.5 min, 2% = 104.1 +/- 20.1 min, 4% = 105.5 +/- 26.7 min, 6% = 112.0 +/- 28.7 min; P = 0.046). No differences in TTE were apparent between the 0% and the 2% or 4% trials, but TTE was longer in the 6% trial compared with the placebo (P = 0.045, ES = 0.62). HR, core temperature, or rates of substrate oxidation were not affected by drink CHO content. CONCLUSIONS: These results demonstrate significant improvements in exercise capacity over the placebo trial when 4% and 6% CHO solutions were ingested at 10 degrees C and a 6% CHO drink was ingested at 30 degrees C. PMID- 22251925 TI - Carbamazepine-induced hypogammaglobulinemia. AB - Carbamazepine is used to control seizures. Its common side effects are sleep disorders, anorexia, nausea, vomiting, polydipsia, irritability, ataxia, and diplopia. Involvement of the immune system is rare, and few cases of decreased immunoglobulin levels have been reported. We describe a patient with low immunoglobulin levels due to carbamazepine use who presented with recurrent urinary tract infection. Intravenous immunoglobulin was administered, and immunoglobulin levels increased to safer levels after discontinuation of carbamazepine. Previous reports describe severe infection after carbamazepine induced hypogammaglobulinemia. Therefore, in patients using antiepileptics, particularly carbamazepine, serum immunoglobulin levels should be checked in those with recurrent infections. PMID- 22251926 TI - Differences in iron deficiency anemia and mean platelet volume between children with simple and complex febrile seizures. AB - OBJECTIVE: The relationship between iron deficiency anemia and febrile seizures (FSs) were examined in several studies before. The aim of our study is to find out the differences regarding iron deficiency anemia, demographic characteristics and mean platelet volume (MPV) which is an inflammatory marker between simple and complex febrile seizure groups. METHODS: In this study, the authors investigated the recordings of 493 children with a diagnosis of simple and complex febrile seizure, aged between 6 months and 6 years, followed between 2002 and 2010 retrospectively. RESULTS: Mean age and male/female ratio were similar in two groups. There was no significant difference regarding with age, gender and family history of FS between two groups. We found significant difference statistically with respect to gestational age, consanguinity, family history of epilepsy and birth weight between two groups. The mean levels of Hb, Htc, MCV were lower and Plt and RDW levels were higher in children with CFS than SFS group, the differences were statistically significant (p: 0.001). A higher proportion of children with CFS (16.2%) had iron deficiency anemia compared to SFS group (12.1%). Mean platelet volume (MPV) of CFS (7.99+/-0.96fL) were significantly lower than that of SFS group (8.77+/-0.75) (p<0.001). CONCLUSIONS: The results of this study suggests that iron deficiency anemia is more frequently seen among the patients with CFS than the patients with SFS. The lower levels of MPV as an inflammatory marker, supports the idea that CFS is a brain inflammatory disease and the consequence of this inflammatory mechanism is the development of the epilepsy. Further studies are necessary to highlight the relationship between iron metabolism, inflammation and seizures. PMID- 22251927 TI - Estradiol induces partial desensitization of serotonin 1A receptor signaling in the paraventricular nucleus of the hypothalamus and alters expression and interaction of RGSZ1 and Galphaz. AB - Hyperactivity of hypothalamic-pituitary mediated hormone responses, such as to stimulation with a serotonin 1A (5-HT(1A)) receptor agonist, are a feature of depression which are normalized with clinical improvement during drug therapy. We previously reported that SSRIs induce desensitization of 5-HT(1A) receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) while estradiol benzoate (EB) produces a more rapid, partial desensitization. In the current study, time course and dose-response experiments demonstrated that two once daily doses of EB is the minimum needed to induce the desensitization response as indicated by 5-HT(1A) receptor-stimulated release of oxytocin and that 10 MUg/kg/day EB produces the maximal response, a partial desensitization of approximately 40%. The effects of two once daily injections of 10 MUg/kg/day EB on Galphaz and RGSZ1 proteins were examined as components of the 5-HT(1A) receptor signaling system, which mediates the release of oxytocin and adrenocorticotropic hormone. RGSZ1 appears to be a major target for EB-mediated responses in the 5-HT(1A) receptor signaling system. A 55 kD membrane-associate RGSZ1 protein was greatly increased in the PVN and rest of the hypothalamus and moderately increased in the dorsal hippocampus and amygdala after EB treatment as well as after an acute dose of a 5-HT(1A) receptor agonist. These results suggest that EB is a candidate for adjuvant therapy with SSRIs to hasten the therapeutic response and that RGSZ1 is a major target of EB therapy which could be explored as a target for novel therapeutic approaches for the treatment of depression. PMID- 22251928 TI - Multi-domain GFP-like proteins from two species of marine hydrozoans. AB - Proteins homologous to Green Fluorescent Protein (GFP) are widely used as genetically encoded fluorescent labels. Many developments of this technology were spurred by discoveries of novel types of GFP-like proteins (FPs) in nature. Here we report two proteins displaying primary structures never before encountered in natural FPs: they consist of multiple GFP-like domains repeated within the same polypeptide chain. A two-domain green FP (abeGFP) and a four-domain orange fluorescent FP (Ember) were isolated from the siphonophore Abylopsis eschscholtzii and an unidentified juvenile jellyfish (order Anthoathecata), respectively. Only the most evolutionary ancient domain of Ember is able to synthesize an orange-emitting chromophore (emission at 571 nm), while the other three are purely green (emission at 520 nm) and putatively serve to maintain the stability and solubility of the multidomain protein. When expressed individually, two of the green Ember domains form dimers and the third one exists as a monomer. The low propensity for oligomerization of these domains would simplify their adoption as in vivo labels. Our results reveal a previously unrecognized direction in which natural FPs have diversified, suggesting new avenues to look for FPs with novel and potentially useful features. PMID- 22251929 TI - Implication of local moment at Ti and Fe sites for the electrical and magneto transport properties of degenerate semiconducting Ti1-xFexO2-d epitaxial films. AB - We have investigated the effect of local magnetic moment on the electrical and magneto-transport properties of thin films of the degenerate semiconductor Ti(1 x)Fe(x)O(2-d) (x = 0,0.04). The electrical measurements of these films reveal high temperature metallic behavior and resistivity minima. The behavior below the resistivity minimum temperature is ascribed to Kondo like scattering. The coupling between the local moment and the charge carriers is reflected in the magnetoresistance measurements in these films. This work indicates competition between the magnetic ordering mechanism by J(RKKY) and the moment screening mechanism by J(Kondo). Accordingly the role of carrier density in achieving the magnetic ordering in such materials either by defect engineering or by transition metal doping is discussed. PMID- 22251930 TI - Temporal relationship between awakening and seizure onset in nocturnal partial seizures. AB - Clinical awakening can be seen just before or after seizure onsets. In this study we determined the time between onset of seizures and awakening in patients with frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). Sixty-eight patients who underwent video-EEG monitoring with simultaneous PSG were retrospectively examined. TLE or FLE patients having seizures during sleep were included. Seizure onset and awakening onset were marked according to clinical and electrophysiological features. The duration between awakening and seizure onset was compared in patients with TLE and FLE. Twenty-five patients who had been diagnosed with TLE (17) or FLE (8) had a total of 75 seizures during sleep. All seizures except one, occurred during NREM sleep in both TLE and FLE patients. The seizure onsets were before awakening in 49 seizures (FLE: 20, TLE: 29) and the awakening preceded the seizure onsets in 12 seizures (FLE: 3, TLE: 9). The duration between seizure onset and the awakening was shorter in FLE, either in seizures with preceding awakening or not (p=0.014, p=0.015). Awakening was mostly seen after onset of seizures rather than before, especially in TLE. But in patients with FLE the duration between seizure onset and awakening was shorter. The localization of epileptic activity may play a role for the timing of awakening mechanisms during nocturnal partial seizures. PMID- 22251931 TI - Post-cardiac arrest brain injury: pathophysiology and treatment. AB - Cardiac arrest is a leading cause of death that affects more than a million individuals worldwide every year. Despite the recent advancement in the field of cardiac arrest and resuscitation, the management and prognosis of post-cardiac arrest brain injury remain suboptimal. The pathophysiology of post-cardiac arrest brain injury involves a complex cascade of molecular events, most of which remain unknown. Considering that a potentially broad therapeutic window for neuroprotective drug therapy is offered in most successfully resuscitated patient after cardiac arrest, the need for further research is imperative. The aim of this article is to present the major pathophysiological disturbances leading to post-cardiac arrest brain injury, as well as to review the available pharmacological therapies. PMID- 22251932 TI - Polysomnographic measures of disturbed sleep are associated with reduced quality of life in multiple sclerosis. AB - BACKGROUND: The relationship of objective sleep parameters with health-related quality of life (HRQoL) in multiple sclerosis (MS) has not been studied. OBJECTIVE: To evaluate the relationship between polysomnographic (PSG) parameters and HRQoL in MS. METHODS: Ambulatory MS patients without a known sleep disorder completed the Short Form (36) Health Survey (SF-36), pain visual analog scale, and two consecutive overnight PSGs. HRQoL was assessed using SF-36 Physical and Mental Component Summary (PCS, MCS) scores. Standard objective PSG measures of sleep quality were determined. The relationship between objective sleep parameters and HRQoL was evaluated with multivariate linear regression, adjusting for age, sex, body mass index, disability, and pain. RESULTS: 62 MS patients were included. PSG measures of sleep disruption including stage changes, awakenings, time in N1 sleep, and apnea-hypopnea and total arousal indices were negatively associated (p<0.05) with MCS scores (lower scores indicating poorer HRQoL). PSG parameters reflective of better sleep quality including total sleep time, sleep efficiency, and time in REM sleep were positively associated with MCS scores. PSG parameters were not significantly associated with PCS scores. CONCLUSIONS: PSG documented sleep disruption negatively impacts, while better objective sleep quality positively impacts on the mental domain of HRQoL in MS. PMID- 22251933 TI - NGF and nitrosative stress in patients with Huntington's disease. AB - INTRODUCTION: Huntington's disease (HD) is a neurodegenerative genetic disorder caused by expansion of polyglutamine repeats in the huntingtin gene and characterised by the loss of striatal and cortical neurons. Few studies to date have focussed on peripheral neurotrophic-factor levels in patients with HD. OBJECTIVE: To measure plasma NGF levels in Huntington's disease and investigate their correlation with disease intensity. MATERIALS AND METHODS: Nineteen patients with HD and nineteen age- and sex-matched healthy subjects took part in this cross-sectional study. Plasma levels of NGF, BDNF, GDNF, nitrotyrosine, and myeloperoxidase (MPO) were measured; lactate dehydrogenase (LDH) levels were determined and white blood cell (WBC) counts were evaluated. RESULTS: NGF levels were significantly lower, nitrotyrosine levels were higher and LDH activity was greater in HD patients than in healthy subjects. There was no significant difference in MPO levels or WBC counts, whereas the MPO/WBC ratio was considerably higher in HD patients. The data obtained suggested that biochemical and haematological changes correlated with disease severity. CONCLUSION: NGF levels are lower in HD patients than in healthy subjects. However, further research is required to confirm the role of NGF in HD. PMID- 22251934 TI - Neurophysiological characteristics of MuSK antibody positive myasthenia gravis mice: focal denervation and hypersensitivity to acetylcholinesterase inhibitors. AB - Myasthenia Gravis (MG) patients with antibodies against the muscle specific tyrosine kinase (MuSK+) typically present with focal fatigue and atrophy of the facial and bulbar muscles, along with unbeneficial reactions upon administration of acetylcholinesterase inhibitors (AChEIs). This study addresses the neurophysiological characteristics in facial versus limb muscles, before and after intraperitoneal injection of AChEIs, in mice immunized with MuSK. We performed in-vivo neurophysiological examinations in the masseter and gastrocnemius muscles of mice with MuSK+experimental autoimmune MG (EAMG) and in healthy control mice before and after administration of AChEIs. Abnormal spontaneous activity (fibrillations) was observed in the masseter muscle of MuSK+mice. Furthermore, 94% of MuSK-immunized mice displayed so called extra discharges (EDs) upon administration of a therapeutic AChEI dose, in contrast to 22% of the control mice, indicating neuromuscular hyperactivity. These findings support functional denervation in the masseter muscle and neuromuscular hypersensitivity already at a standard dose of AChEIs in MuSK+EAMG. PMID- 22251935 TI - Hot melt poly-epsilon-caprolactone/poloxamine implantable matrices for sustained delivery of ciprofloxacin. AB - It has been suggested that prevention and treatment of osteomyelitis could be achieved through local drug delivery using implantable devices, which provide therapeutic levels at the infection site with minimum side-effects. Physical blends of polycaprolactone (PCL) and poloxamine (Tetronic(r)) were prepared by applying a solvent-free hot melting approach to obtain cytocompatible implants with a tunable bioerosion rate, ciprofloxacin release profile and osteoconductive features. Differential scanning calorimetry and X-ray analysis indicate that the hydrophilic poloxamine varieties T908, T1107, and T1307 are miscible with PCL, while the hydrophobic block copolymer T1301 is immiscible. Incorporation of the block copolymer at weight ratios ranging from 25 to 75 wt.% led to matrices with viscoelastic parameters in the range of those of fresh cortical bone. Once immersed in buffer the matrices underwent a similar weight loss in the first week to the content of poloxamine, followed by a slower erosion rate due to PCL. The initial rapid erosion and the increase in porosity partially explain the observed burst of ciprofloxacin release, which is more intense in the PCL:T1301 formulation due to drug/T1301 repulsion due to polarity. The matrices sustained ciprofloxacin release for several months (<50% released after 3 months) and showed in vitro efficacy against Staphylococcus aureus, eradicating the bacteria in less than 48 h. PCL:poloxamine was cytocompatible with osteoblasts and the matrices prepared with low proportions of T908 were also compatible with mesenchymal stem cell differentiation to osteoblasts. The influence of the nature and proportion of temperature-responsive poloxamine on the performance of PCL implantable systems was determined. PMID- 22251936 TI - Adhesion and cohesion in structures containing suspended microscopic polymeric films. AB - This paper presents a novel technique for the characterization of adhesion and cohesion in suspended micro-scale polymeric films. The technique involves push out testing with probes that are fabricated using focused ion beam techniques. The underlying stresses associated with different probe tip sizes were computed using a finite element model. The critical force for failure of the film substrate interface is used to evaluate adhesion, while the critical force for penetration of the film determines cohesion. When testing a standard material, polycarbonate, a shear strength of approximately 70 MPa was calculated using the Mohr-Coulomb theory. This value was shown to be in agreement with the results in the literature. The technique was also applied to the measurement of adhesion and cohesion in a model drug-eluting stent (the NevoTM Sirolimus Eluting Coronary Stent) containing suspended microscopic polymeric films in metallic Co-Cr alloy reservoirs. The cohesive strength of the formulation was found to be comparable with that of plastics such as those produced by reaction injection molding and high-density polyethylene. PMID- 22251938 TI - New criteria for histologic grading of colorectal cancer. AB - Conventional tumor grading systems based on the degree of tumor differentiation may not always be optimal because of difficulty in objective assessment and insufficient prognostic value for decision making in colorectal cancer (CRC) treatment. This study aimed to determine the importance of assessing the number of poorly differentiated clusters as the primary criterion for histologic grading of CRC. Five hundred consecutive patients with curatively resected stage II and III CRCs (2000 to 2005) were pathologically reviewed. Cancer clusters of >=5 cancer cells and lacking a gland-like structure were counted under a *20 objective lens in a field containing the highest number of clusters. Tumors with <5, 5 to 9, and >=10 clusters were classified as grade (G)1, G2, and G3, respectively (n=156, 198, and 146 tumors, respectively). Five-year disease-free survival rates were 96%, 85%, and 59% for G1, G2, and G3, respectively (P<0.0001). Poorly differentiated clusters affected survival outcome independent of T and N stages and could help in more effective stratification of patients by survival outcome compared with tumor staging (Akaike information criterion, 1086.7 vs. 1117.0; Harrell concordance index, 0.73 vs. 0.67). The poorly differentiated cluster-based grading system showed a higher weighted kappa coefficient for interobserver variability (5 observers) compared with conventional grading systems (mean, 0.66 vs. 0.52; range, 0.55 to 0.73 vs. 0.39 to 0.68). Our novel histologic grading system is expected to be less subjective and more informative for prognostic prediction compared with conventional tumor grading systems and TNM staging. It could be valuable in determining individualized postoperative CRC treatment. PMID- 22251937 TI - Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. AB - Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients. PMID- 22251939 TI - Optimal lymph node harvest in rectal cancer (UICC stages II and III) after preoperative 5-FU-based radiochemotherapy. Acetone compression is a new and highly efficient method. AB - INTRODUCTION: Preoperative 5-fluorouracil-based radiochemotherapy (RCT), followed by total mesorectal excision, is accepted as standard therapy in rectal cancers (UICC stages II and III). The accurate evaluation of ypN status after RCT with valuable lymph node (LN) harvest is essential for postoperative risk-adapted treatment decisions. Actual numbers of assessed LNs and validity of ypN status vary extensively depending on the methods used. MATERIAL AND METHODS: This prospective study validates the acetone compression (AC), whole mesorectal compartment embedding (WME), and fat clearance (FC) methods for LN retrieval in n=257 rectal cancer specimens obtained from 2 high-volume surgical centers. For optimal LN retrieval, the AC method (n=161 specimens: 52 cases with RCT, 109 cases without RCT) was compared with the WME (n=64 cases, with RCT) and FC methods (n=32 cases: 17 cases with RCT, 15 cases without RCT). The efficacy of LN retrieval, costs involved, and molecular diagnostics were measured. RESULTS: Using the AC method, 41 LNs (mean; range 14 to 86 LNs) were detectable in total mesorectal excision specimens after RCT and 44 LNs (mean; range 9 to 78 LNs) in cases without RCT. The LN yield after RCT obtained by using the AC method was equivalent to that of the WME method (mean 32 LNs/specimen; range 12 to 81 LNs) but demonstrated a better time and cost-efficacy. In addition, the AC method facilitated assessment of any tumor deposits, including perineural invasion, and did not hamper molecular analyses. The AC method increased LN retrieval 4- to-6 fold as compared with the literature and 2-fold compared with manual dissection after the FC method. DISCUSSION: The AC method is the method of choice for accurate LN staging in locally advanced rectal cancer, especially after preoperative RCT, and is well suited for routine gastrointestinal pathology workup. PMID- 22251940 TI - Cyclin D1-negative blastoid mantle cell lymphoma identified by SOX11 expression. AB - SOX11 expression has been recently shown to be useful in the diagnosis of mantle cell lymphoma (MCL), including cyclin D1-negative MCL with typical morphology. We evaluated SOX11 expression pattern in B-cell non-Hodgkin lymphoma (B-NHL) subtypes to confirm specificity and used it as a feature to identify the first reported cases of cyclin D1-negative blastoid MCL. SOX11 expression was evaluated by immunohistochemistry in 140 cases of mature B-NHL, including 4 cases of suspected blastoid MCL that lacked cyclin D1 expression and 8 cases of CD5 positive diffuse large B-cell lymphoma (DLBL). In addition, 5 cases of B or T lymphoblastic lymphoma were included. Nuclear expression of SOX11 was found in cyclin D1-positive MCL (30/30, 100%) and in a case of cyclin D1-negative MCL with typical morphology. SOX11 was also expressed in Burkitt lymphoma (1/5, 20%) and lymphoblastic lymphoma (2/3 T-LBLs, 2/2 B-LBLs, overall 4/5, 80%), whereas all cases of DLBL (including CD5 DLBL) and other small B-NHL were negative. The 4 suspected cases of blastoid MCL were also SOX11. These cases had a complex karyotype that included 12p abnormalities. We confirmed prior reports that stated that SOX11 nuclear expression was a specific marker for MCL, including cyclin D1 negative MCL with typical morphology. To our knowledge, this is the first report regarding its use in identifying cases of cyclin D1-negative blastoid MCL. Routine use of SOX11 in cases of suspected CD5 DLBL might help identify additional cases of cyclin D1-negative blastoid MCL. PMID- 22251941 TI - Prognostic factors in central neurocytomas: a multicenter study of 71 cases. AB - Central neurocytoma (CN) is a rare intraventricular tumor presenting a benign histologic appearance and favorable prognosis after surgery. In contrast, "atypical" CN is defined by a high MIB1 proliferation index and/or histologic features of malignancy, which are associated with a poorer outcome. This variant of CN remains somewhat controversial. To better characterize CN and its "atypical" variant, a retrospective multicenter study was conducted on 71 patients presenting with CN. A statistical analysis of clinical, radiologic, and histologic data was conducted to validate prognostic factors. The immunohistochemical phenotype of CNs, analyzed by tissue microarrays, and the MIB1 index were evaluated for 45 cases. Tissue microarrays validated the expression of neuronal markers synaptophysin and NeuN, but not that of glial markers glial fibrillary acidic protein and oligodendrocyte transcription factor 2. In the univariate analysis, a tumor volume >=30 cm (P=0.025), incomplete surgery (P=0.033), and a mitotic count >=3 per 10 high-power fields (P=0.009) were predictors of a higher risk of recurrence, unlike the other usual histologic features of malignancy and the high MIB1 index. Partial surgery was the only criterion associated with a poorer outcome in the multivariate model. Our results, based on a large multicenter series, show the striking homogeneity of CNs and do not support the use of histologic criteria as reliable markers to define an "atypical" group of CNs. Our study suggests that the extent of surgery is the main factor to be considered in the prognostic assessment of patients with CN. PMID- 22251942 TI - Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting. AB - High overexpression of somatostatin receptors in neuroendocrine tumors allows imaging and radiotherapy with radiolabeled somatostatin analogues. To ascertain whether a tumor is suitable for in vivo somatostatin receptor targeting, its somatostatin receptor expression has to be determined. There are specific indications for use of immunohistochemistry for the somatostatin receptor subtype 2A, but this has up to now been limited by the lack of an adequate reliable antibody. The aim of this study was to correlate immunohistochemistry using the new monoclonal anti-somatostatin receptor subtype 2A antibody UMB-1 with the gold standard in vitro method quantifying somatostatin receptor levels in tumor tissues. A UMB-1 immunohistochemistry protocol was developed, and tumoral UMB-1 staining levels were compared with somatostatin receptor binding site levels quantified with in vitro I-[Tyr]-octreotide autoradiography in 89 tumors. This allowed defining an immunohistochemical staining threshold permitting to distinguish tumors with somatostatin receptor levels high enough for clinical applications from those with low receptor expression. The presence of >10% positive tumor cells correctly predicted high receptor levels in 95% of cases. In contrast, absence of UMB-1 staining truly reflected low or undetectable somatostatin receptor expression in 96% of tumors. If 1% to 10% of tumor cells were stained, a weak staining intensity was suggestive of low somatostatin receptor levels. This study allows for the first time a reliable recommendation for eligibility of an individual patient for in vivo somatostatin receptor targeting based on somatostatin receptor immunohistochemistry. Under optimal methodological conditions, UMB-1 immunohistochemistry may be equivalent to in vitro receptor autoradiography. PMID- 22251943 TI - Primary bone marrow lymphoma: an uncommon extranodal presentation of aggressive non-hodgkin lymphomas. AB - Bone marrow involvement by lymphoma is considered a systemic dissemination of the disease arising elsewhere, although some tumors may arise primarily in the bone marrow microenvironment. Primary bone marrow lymphoma (PBML) is a rare entity whose real boundaries and clinicobiological significance are not well defined. Criteria to diagnose PBML encompass isolated bone marrow infiltration, with no evidence of nodal or extranodal involvement, including the bone, and the exclusion of leukemia/lymphomas that are considered to primarily involve the bone marrow. Twenty-one out of 40 lymphomas retrospectively reviewed by the International Extranodal Lymphoma Study Group from 12 institutions in 7 different countries over a 25-year period fulfilled the inclusion criteria. These cases comprised 4 follicular lymphomas (FLs), 15 diffuse large B-cell lymphomas (DLBCLs), and 2 peripheral T-cell lymphomas, not otherwise specified. The FL cases showed paratrabecular infiltration, BCL2 protein and CD10 expression, and BCL2 gene rearrangement. DLBCL showed nodular infiltration in 6 cases and was diffuse in 9 cases; it also showed positivity for BCL2 protein (9/10) and IRF4 (6/8). Median age was 65 years with male predominance. All but 3 FL patients were symptomatic. Most cases presented with cytopenias and high lactate dehydrogenase. Four patients (3 FL cases and 1 DLBCL case) had leukemic involvement. Most DLBCL patients received CHOP-like or R-CHOP-like regimens. The outcome was unfavorable, with a median overall survival of 1.8 years. In conclusion, PBML is a very uncommon lymphoma with particular clinical features and heterogenous histology. Its recognition is important to establish accurate diagnosis and adequate therapy. PMID- 22251944 TI - Signet ring cell carcinoma of the testis: clinicopathologic and molecular evidence for germ cell tumor origin--a case report. AB - Development of a somatic-type malignancy from a mixed germ cell tumor is a rare but recognized event and typically represented by sarcoma or, less commonly, by carcinoma. This phenomenon is generally believed to result from progression of a teratomatous component. In many cases, because of intermingling of other germ cell tumor components, the diagnosis is apparent; however, in rare cases, metastatic carcinoma to the testis or a novel primary tumor may be a diagnostic consideration. In this study, we report the clinicopathologic, immunohistochemical, and molecular features of a 53-year-old man, whose testicular tumor was composed entirely of signet ring cells, mimicking metastatic carcinoma. Subsequent retroperitoneal lymph node dissection revealed metastatic deposits composed of teratoma and yolk sac tumor, in addition to signet ring cell carcinoma. Fluorescence in situ hybridization for abnormalities of chromosome 12p revealed the presence of i(12p) in both the teratoma and signet ring cell carcinoma in the metastasis and in signet ring cells in the testis, supporting a common germ cell origin. Our report indicates that signet ring carcinoma cells in an orchiectomy specimen, although usually strongly suggestive of metastatic adenocarcinoma from a primary tumor in another organ, may be a primary testicular neoplasm of germ cell tumor origin. This is the first report of testicular signet ring cell carcinoma of germ cell tumor derivation. PMID- 22251945 TI - Gastritis cystica profunda versus invasive adenocarcinoma. PMID- 22251946 TI - Gastritis cystic profunda versus adenocarcinoma. PMID- 22251947 TI - Detection of colonic ganglion cells by immunohistochemistry: a comparative study. PMID- 22251948 TI - Understanding and planning ecological restoration of plant-pollinator networks. AB - Theory developed from studying changes in the structure and function of communities during natural or managed succession can guide the restoration of particular communities. We constructed 30 quantitative plant-flower visitor networks along a managed successional gradient to identify the main drivers of change in network structure. We then applied two alternative restoration strategies in silico (restoring for functional complementarity or redundancy) to data from our early successional plots to examine whether different strategies affected the restoration trajectories. Changes in network structure were explained by a combination of age, tree density and variation in tree diameter, even when variance explained by undergrowth structure was accounted for first. A combination of field data, a network approach and numerical simulations helped to identify which species should be given restoration priority in the context of different restoration targets. This combined approach provides a powerful tool for directing management decisions, particularly when management seeks to restore or conserve ecosystem function. PMID- 22251949 TI - Small surfactant-like peptides can drive soluble proteins into active aggregates. AB - BACKGROUND: Inactive protein inclusion bodies occur commonly in Escherichia coli (E. coli) cells expressing heterologous proteins. Previously several independent groups have found that active protein aggregates or pseudo inclusion bodies can be induced by a fusion partner such as a cellulose binding domain from Clostridium cellulovorans (CBDclos) when expressed in E. coli. More recently we further showed that a short amphipathic helical octadecapeptide 18A (EWLKAFYEKVLEKLKELF) and a short beta structure peptide ELK16 (LELELKLKLELELKLK) have a similar property. RESULTS: In this work, we explored a third type of peptides, surfactant-like peptides, for performing such a "pulling-down" function. One or more of three such peptides (L6KD, L6K2, DKL6) were fused to the carboxyl termini of model proteins including Aspergillus fumigatus amadoriase II (AMA, all three peptides were used), Bacillus subtilis lipase A (LipA, only L6KD was used, hereinafter the same), Bacillus pumilus xylosidase (XynB), and green fluorescent protein (GFP), and expressed in E. coli. All fusions were found to predominantly accumulate in the insoluble fractions, with specific activities ranging from 25% to 92% of the native counterparts. Transmission electron microscopic (TEM) and confocal fluorescence microscopic analyses confirmed the formation of protein aggregates in the cell. Furthermore, binding assays with amyloid-specific dyes (thioflavin T and Cong red) to the AMA-L6KD aggregate and the TEM analysis of the aggregate following digestion with protease K suggested that the AMA-L6KD aggregate may contain structures reminiscent of amyloids, including a fibril-like structure core. CONCLUSIONS: This study shows that the surfactant-like peptides L6KD and it derivatives can act as a pull-down handler for converting soluble proteins into active aggregates, much like 18A and ELK16. These peptide-mediated protein aggregations might have important implications for protein aggregation in vivo, and can be explored for production of functional biopolymers with detergent or other interfacial activities. PMID- 22251950 TI - Captured at last: a catalyst-substrate adduct and a Rh-dihydride solvate in the asymmetric hydrogenation by a Rh-monophosphine catalyst. AB - The mechanism of asymmetric hydrogenation catalyzed by [Rh(NBD)((R) PhenylBinepine)(2)]SbF(6)1 has been studied by NMR experiments and DFT computations. Either the low-temperature hydrogenation of the catalyst-substrate adduct 4 or the reaction of solvate dihydride 6 with MAC produced the hydrogenation product with over 99% ee (S). PMID- 22251951 TI - European and American suspected and confirmed pulmonary embolism populations: comparison and analysis. AB - BACKGROUND: If the prevalence of pulmonary embolism (PE) differs significantly between the US and Europe, this observation could reduce the generalizability of diagnostic protocols for PE derived in either location. OBJECTIVE: To determine possible causes and potential clinical consequences of these PE prevalence differences. METHODS: Secondary analysis of three prospectively collected multicenter samples (two French and one from the US) including 3174 European and 7940 American PE-suspected patients in Emergency departments (ED) (117 for Europe and 12 for US). Comparison of clinical features, resource use and outcomes of European- and US-suspected PE populations in ED. RESULTS: European patients evaluated for PE were significantly older and had a higher clinical pretest probability (CPP) for PE. The final PE prevalence was significantly higher in Europe, in the overall sample (26.5% vs. 7.6%) and in each level of CPP. Suspected European patients categorized as low CPP had a higher posttest probability than US low CPP patients. Suspected US patients categorized as high CPP had a much lower posttest probability of PE than in Europe. The mean number of tests performed for one PE diagnosis was lower in Europe (7.4 vs. 21.6). Among patients diagnosed with PE, European patients had a higher mean severity of illness score and a higher PE-mortality rate (3.4% vs. 0.7%). CONCLUSIONS: Among patients suspected of a PE and those ultimately diagnosed with a PE, European patients had higher acuity, a higher pretest probability and worse outcome than US patients. The present study underscores the importance of disease prevalence for pretest probability scoring approaches and for significance interpretation of imaging tests. PMID- 22251954 TI - Recruiting adaptive cellular stress responses for successful brain ageing. AB - Successful ageing is determined in part by genetic background, but also by experiential factors associated with lifestyle and culture. Dietary, behavioural and pharmacological interventions have been identified as potential means to slow brain ageing and forestall neurodegenerative disease. Many of these interventions recruit adaptive cellular stress responses to strengthen neuronal networks and enhance plasticity. In this Science and Society article, we describe several determinants of healthy and pathological brain ageing, with insights into how these processes are accelerated or prevented. We also describe the mechanisms underlying the neuroprotective actions of exercise and nutritional interventions, with the goal of recruiting these molecular targets for the treatment and prevention of neurodegenerative disease. PMID- 22251957 TI - Neural development: Clustering connections. PMID- 22251956 TI - Activity-dependent neurotransmitter respecification. AB - For many years it has been assumed that the identity of the transmitters expressed by neurons is stable and unchanging. Recent work, however, shows that electrical activity can respecify neurotransmitter expression during development and in the mature nervous system, and an understanding is emerging of the molecular mechanisms underlying activity-dependent transmitter respecification. Changes in postsynaptic neurotransmitter receptor expression accompany and match changes in transmitter specification, thus enabling synaptic transmission. The functional roles of neurotransmitter respecification are beginning to be understood and appear to involve homeostatic synaptic regulation, which in turn influences behaviour. Activation of this novel form of plasticity by sensorimotor stimuli may provide clinical benefits. PMID- 22251958 TI - Psychiatric disorders: Why two is better than one. PMID- 22251960 TI - Neurodegenerative disease: Preventing 'SIRTain' death by mutant huntingtin. PMID- 22251965 TI - Sensation and perception of sucrose and fat stimuli predict the reinforcing value of food. AB - Chronic overeating can lead to weight gain and obesity. Sensory system function may play a role in the types of foods people select and the amount of food people eat. Several studies have shown that the orosensory components of eating play a strong role in driving food intake and food selection. In addition, previous work has shown that motivation to get food, or the reinforcing value of food, is a predictor of energy intake. The purpose of this study was to test the hypothesis that higher detection thresholds and lower suprathreshold intensity ratings of sweet and fat stimuli are associated with greater reinforcing value of food. In addition, we sought to determine if the sensory ratings of the stimuli would differ depending on whether they were expectorated or swallowed. The reinforcing value of food was measured by having participants perform operant responses for food on progressive ratio schedules of reinforcement. Taste detection thresholds and suprathresholds for solutions containing varied concentrations of sucrose and fat were also measured in two different Experiments. In Experiment 1, we found that sucrose, but not fat, detection predicted the reinforcing value of food with the reinforcing value of food increasing as sucrose detection threshold increased (indicating poorer detection). In Experiment 2, we found that lower suprathreshold ratings of expectorated fat and sucrose predicted greater reinforcing value of food. In addition, higher detection thresholds for fat stimuli (indicating poorer detection) were associated with greater reinforcing value of food. When taken together, these studies suggest that there is a relationship between taste detection and perception and reinforcing value of food and that these relationships vary based on whether the stimulus is swallowed or expectorated. PMID- 22251966 TI - Anogenital distance as a predictor of attractiveness, litter size and sex ratio of rabbit does. AB - In the case of some mammalian species, females with larger anogenital distance (AGD) have smaller litters, where the sex ratio is male-biased. The first aim of the present study was to test whether this phenomenon exists in the Lagomorph group, especially in rabbits. The results revealed that does with large AGD have significantly smaller and lighter litters with a male biased sex ratio; with fewer females but not more males. The second aim of the present study was to test whether males differentiate between females differing in their AGD and are thus capable of choosing the more fertile and fecund does. Males showed a stronger response to the chin marks of females with small AGD than to the marks of females with large AGD. Our results suggest that variation in the prenatal hormonal environment, reflected through variation in AGD, could have long-term consequences on mate choice and population dynamics. PMID- 22251963 TI - Interneuron dysfunction in psychiatric disorders. AB - Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons - the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more effective therapeutic interventions. PMID- 22251967 TI - Treating cancer with amplitude-modulated electromagnetic fields: a potential paradigm shift, again? PMID- 22251969 TI - Characterization and identification of suspected counterfeit miltefosine capsules. AB - Recently, it was revealed that generic miltefosine capsules for the treatment of visceral leishmaniasis, a fatal parasitic disease, were possibly counterfeit products. Here we report on the methods to characterize and identify miltefosine in pharmaceutical products and the procedures that were used to assess the quality of these suspected counterfeit products. Characterization and identification of miltefosine were done with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), Fourier transform infrared (FT-IR) spectroscopy and near-infrared (NIR) spectroscopy. Moreover, a simple, rapid and inexpensive colorimetric test was developed and evaluated for the detection of miltefosine in pharmaceutical products that can be used in the field. The complementary analytical techniques presented here were able to determine qualitatively or (semi-)quantitatively the presence or absence of miltefosine in pharmaceutical preparations and could identify suspected counterfeit miltefosine capsules. This finding of a suspected counterfeit drug intended to treat a neglected disease in a resource-poor country emphasizes the urgent need to develop more simple inexpensive assays to evaluate drug quality for use in the field. PMID- 22251968 TI - Comparison of visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer. AB - BACKGROUND: Immunohistochemistry of Ki-67 protein is widely used to assess tumour proliferation, and is an established prognostic factor in breast cancer. There is interest in automating the assessment of Ki-67 labelling index (LI) with possible benefits in handling increased workload, with improved accuracy and precision. PATIENTS AND METHODS: Visual and automated assessment of Ki-67 LI and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microarrays (n=379 patients) immunostained for Ki-67 were scored visually and automatically with the Slidepath Tissue IA system. RESULTS: Visual and automated Ki-67 LI were in excellent agreement (ICCC=0.96, P<0.001). On univariate analysis, visual (P<0.001) and automated Ki67 LI (P<0.05) were associated with cancer-specific survival in patients with invasive ductal breast cancer overall and in patients who received endocrine therapy (Tamoxifen) (P<0.01 for visual and P<0.05 for automated scoring). CONCLUSION: Automated assessment of Ki-67 LI would appear to be comparable to visual Ki-67 LI. However, automated Ki 67 LI assessment was inferior in predicting cancer survival in patients with breast cancer, including patients who received Tamoxifen. PMID- 22251970 TI - Generalized path integral method for Elliott-Yafet spin relaxations in quantum wells and narrow wires. AB - We generalized the semiclassical path integral method originally used in the D'yakonov-Perel' mechanism to study the spin relaxation of the Elliott-Yafet mechanism in low-dimensional systems. In quantum wells, the spin properties calculated by this method confirmed the experimental results. In two-dimensional narrow wires, size and impurity effects on the Elliott-Yafet relaxation were predicted, including the wire-width-dependent relaxation time, the polarization evolution on the sample boundaries, and the relaxation behavior during the diffusive-ballistic transition. These properties were compared with those of the D'yakonov-Perel' relaxation calculated under similar conditions. For ballistic narrow wires, we derived an exact relation between the Elliott-Yafet relaxation time and the wire width, which confirmed the above simulations. PMID- 22251971 TI - The interplay between the Escherichia coli Rho guanine nucleotide exchange factor effectors and the mammalian RhoGEF inhibitor EspH. AB - Rho GTPases are important regulators of many cellular processes. Subversion of Rho GTPases is a common infection strategy employed by many important human pathogens. Enteropathogenic Escherichia coli and enterohemorrhagic Escherichia coli (EPEC and EHEC) translocate the effector EspH, which inactivates mammalian Rho guanine exchange factors (GEFs), as well as Map, EspT, and EspM2, which, by mimicking mammalian RhoGEFs, activate Rho GTPases. In this study we found that EspH induces focal adhesion disassembly, triggers cell detachment, activates caspase-3, and induces cytotoxicity. EspH-induced cell detachment and caspase-3 activation can be offset by EspT, EspM2, and the Salmonella Cdc42/Rac1 GEF effector SopE, which remain active in the presence of EspH. EPEC and EHEC therefore use a novel strategy of controlling Rho GTPase activity by translocating one effector to inactivate mammalian RhoGEFs, replacing them with bacterial RhoGEFs. This study also expands the functional range of bacterial RhoGEFs to include cell adhesion and survival. IMPORTANCE: Many human pathogens use a type III secretion system to translocate effectors that can functionally be divided into signaling, disabling, and countervirulence effectors. Among the signaling effectors are those that activate Rho GTPases, which play a central role in coordinating actin dynamics. However, many pathogens also translocate effectors with antagonistic or counteractive functions. For example, Salmonella translocates SopE and SptP, which sequentially turn Rac1 and Cdc42 on and off. In this paper, we show that enteropathogenic E. coli translocates EspH, which inactivates mammalian RhoGEFs and triggers cytotoxicity and at the same time translocates the bacterial RhoGEFs EspM2 and EspT, which are insensitive to EspH, and so neutralizes EspH-induced focal adhesion disassembly, cell detachment, and caspase-3 activation. Our data point to an intriguing infection strategy in which EPEC and EHEC override cellular Rho GTPase signaling by disabling mammalian RhoGEFs and replacing them with with bacterial RhoGEFs that promote cell adhesion and survival. PMID- 22251974 TI - A prospective, randomized trial comparing expansile cervical laminoplasty and cervical laminectomy and fusion for multilevel cervical myelopathy. AB - BACKGROUND: Controversy exists as to the best posterior operative procedure to treat multilevel compressive cervical spondylotic myelopathy. OBJECTIVE: To determine clinical, radiological, and patient satisfaction outcomes between expansile cervical laminoplasty (ECL) and cervical laminectomy and fusion (CLF). METHODS: We performed a prospective, randomized study of ECL vs CLF in patients suffering from cervical spondylotic myelopathy. End points included the Short Form-36, Neck Disability Index, Visual Analog Scale, modified Japanese Orthopedic Association score, Nurick score, and radiographic measures. RESULTS: A survey of academic North American spine surgeons (n = 30) demonstrated that CLF is the most commonly used (70%) posterior procedure to treat multilevel spondylotic cervical myelopathy. A total of 16 patients were randomized: 7 to CLF and 9 to ECL. Both groups showed improvements in their Nurick grade and Japanese Orthopedic Association score postoperatively, but only the improvement in the Nurick grade for the ECL group was statistically significant (P < .05). The cervical range of motion between C2 and C7 was reduced by 75% in the CLF group and by only 20% in the ECL group in a comparison of preoperative and postoperative range of motion. The overall increase in canal area was significantly (P < .001) greater in the CLF group, but there was a suggestion that the adjacent level was more narrowed in the CLF group in as little as 1 year postoperatively. CONCLUSION: In many respects, ECL compares favorably to CLF. Although the patient numbers were small, there were significant improvements in pain measures in the ECL group while still maintaining range of motion. Restoration of spinal canal area was superior in the CLF group. PMID- 22251975 TI - Microdiscectomy improves pain-associated depression, somatic anxiety, and mental well-being in patients with herniated lumbar disc. AB - BACKGROUND: Emotional distress and depression are common psychological disturbances associated with low-back and leg pain. The effects of lumbar discectomy on pain, disability, and physical quality of life are well described. The effects of discectomy on emotional distress and mental well-being are less well understood. OBJECTIVE: To assess the effect of microdiscectomy on depression, somatization, and mental well-being in patients with herniated lumbar discs. METHODS: Patients undergoing surgical discectomy for single-level, herniated lumbar disc were prospectively evaluated preoperatively, and at 6 weeks and 3, 6, and 12 months postoperatively. Back and leg pain, depression, somatic perception, and mental well-being were assessed. RESULTS: One hundred patients were enrolled. All were available for 1-year follow-up. Preoperatively, the visual analog scale for low-back pain (BP-VAS), visual analog scale for leg pain (LP-VAS), Zung Self-Rating Depression Scale (ZUNG), Modified Somatic Perception Questionnaire (MSPQ), and Medical Outcomes Short Form-36 mental component summary scale (SF-36-MCS) were 6.3 +/- 2.5, 6.3 +/- 2.5, 19 +/- 11, 9 +/- 7, and 4 +/- 14. BP-VAS and LP-VAS significantly improved by 6 weeks. Significant improvement in SF-36-MCS was observed by 6 weeks postoperatively, improvement in MSPQ score was observed 3 months postoperatively, and improvement in the ZUNG depression score was observed 12 months postoperatively. No statistical difference occurred during the remainder of follow-up for any outcome measured once improvement reached statistical significance. Eighteen patients were somatized preoperatively, 67% of which were nonsomatized 1 year postoperatively. Ten patients were clinically depressed preoperatively, 70% of which were nondepressed 1 year postoperatively. Improvement in SF-36-MCS, ZUNG, and MSPQ correlated (P < .001) with improvement in BP-VAS and LP-VAS. CONCLUSION: The majority of patients somatized or depressed preoperatively returned to good mental well-being postoperatively. Improvement in pain and overall mental well-being was seen immediately after discectomy. Improvement in somatic anxiety and depression occurred months later. Microdiscectomy significantly improves pain-associated depression, somatic anxiety, and mental well-being in patients with herniated lumbar disc. PMID- 22251972 TI - Roles of the nuclear lamina in stable nuclear association and assembly of a herpesviral transactivator complex on viral immediate-early genes. AB - Little is known about the mechanisms of gene targeting within the nucleus and its effect on gene expression, but most studies have concluded that genes located near the nuclear periphery are silenced by heterochromatin. In contrast, we found that early herpes simplex virus (HSV) genome complexes localize near the nuclear lamina and that this localization is associated with reduced heterochromatin on the viral genome and increased viral immediate-early (IE) gene transcription. In this study, we examined the mechanism of this effect and found that input virion transactivator protein, virion protein 16 (VP16), targets sites adjacent to the nuclear lamina and is required for targeting of the HSV genome to the nuclear lamina, exclusion of heterochromatin from viral replication compartments, and reduction of heterochromatin on the viral genome. Because cells infected with the VP16 mutant virus in1814 showed a phenotype similar to that of lamin A/C(-/-) cells infected with wild-type virus, we hypothesized that the nuclear lamina is required for VP16 activator complex formation. In lamin A/C(-/-) mouse embryo fibroblasts, VP16 and Oct-1 showed reduced association with the viral IE gene promoters, the levels of VP16 and HCF-1 stably associated with the nucleus were lower than in wild-type cells, and the association of VP16 with HCF-1 was also greatly reduced. These results show that the nuclear lamina is required for stable nuclear localization and formation of the VP16 activator complex and provide evidence for the nuclear lamina being the site of assembly of the VP16 activator complex. IMPORTANCE: The targeting of chromosomes in the cell nucleus is thought to be important in the regulation of expression of genes on the chromosomes. The major documented effect of intranuclear targeting has been silencing of chromosomes at sites near the nuclear periphery. In this study, we show that targeting of the herpes simplex virus DNA genome to the nuclear periphery promotes formation of transcriptional activator complexes on the viral genome, demonstrating that the nuclear periphery also has sites for activation of transcription. These results highlight the importance of the nuclear lamina, the structure that lines the inner nuclear membrane, in both transcriptional activation and repression. Future studies defining the molecular structures of these two types of nuclear sites should define new levels of gene regulation. PMID- 22251978 TI - Application of the RELY study to lifetime risks of atrial fibrillation: implications for spontaneous intracranial hemorrhage. PMID- 22251979 TI - Neuronal transplants reconstitute complex neuronal circuitry and rescue phenotype. PMID- 22251980 TI - Powder time? Reducing spinal postoperative infections with intrawound application of antibiotic powder. PMID- 22251981 TI - Methods of resistance to epidermal growth factor receptor inhibition in glioblastoma multiforme. PMID- 22251982 TI - Surface topography can be used to instruct stem cell fate. PMID- 22251983 TI - Hospital boards changing with new challenges. PMID- 22251984 TI - Drowsy mice: induced spindling and thalamic bursting studied via an optogenetic technique. PMID- 22251985 TI - The contribution of Notch signaling to glioblastoma via activation of cancer stem cell self-renewal: the role of the endothelial network. PMID- 22251986 TI - Cost effectiveness of lumbar fusion improves with time. PMID- 22251988 TI - Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Introduction and Part I: Neuroanatomy. AB - We present a short historical review on the major institutions and figures that contributed to make Paris a renowned centre of physiology and neurology during the xixth and the first half of the xxth centuries. We purposely chose to focus on the period 1800-1950, as 1800 corresponds to the development of brain science and 1950 marks the true beginning of neuroscience. Our presentation is divided into four chapters, matching the main disciplines which have progressed and contributed the most to the knowledge we have of the brain sciences: anatomy, physiology, neurology, and psychiatry-psychology. The present article is the first of four parts of this review, which includes an introduction followed by the chapter on neuroanatomy and on anatomo-pathology, which includes biographical sketches of Felix Vicq d'Azyr, Francois-Xavier Bichat, Franz Joseph Gall, Jean Cruveilhier, Jules Bernard Luys, Paul Broca, Louis Ranvier, Andre-Victor Cornil, Albert Gombault, Jean Nageotte and Rene Couteaux. PMID- 22251989 TI - Special focus: influenza vaccines. PMID- 22251991 TI - Letter from the editor. PMID- 22251992 TI - The importance of influenza prevention for public health. AB - Annual epidemics of seasonal (inter-pandemic) influenza represent a significant burden on society in terms of morbidity, mortality, hospitalizations and lost working time. The impact of influenza depends on a mix of direct and indirect effects and is not easy to assess. Nevertheless there is a consensus in considering influenza prevention and mitigation high priorities for public health. We review the available evidence to assess the impact of influenza prevention focusing especially on vaccines and immunization strategies. PMID- 22251993 TI - Clinical and laboratory diagnosis of influenza. AB - The clinical diagnosis of influenza can be very difficult or rather easy depending on the circumstances. It's easy when the epidemiological context is appropriate; the patient is a school kid or a teenager, and the symptoms are typical. On the other hand, it is hard when it fails to match any of the above premises, the more imformation that is missing, the more difficult it becomes. The symptomatology is correlated with age; therefore, typical clinical manifestations are only referred from 3-4 y old: rhinitis, fever with or without chills, cough, headache, joint and muscle pain and malaise. The patient often says he/she "feels sick" but his/her general condition is not at all serious. A rapid influenza diagnosis has been shown to reduce unnecessary test and antibiotics in pediatric patients and allows rational use of antivirals, early discharge from emergency departments and hospital wards, appropriate infection control measures and cohorting of infected patients. Tests that yield results in a timely manner that can influence clinical management are recommended to guide patient care. Results of testing should take into account the a priori likelihood of influenza infection based on the patient's signs and symptoms, the sensitivity and specificity of the test used, and information on circulation of influenza in the community. Failing to use the option of microbiological diagnosis when appropriate is a missed opportunity that can generate anxiety without justification, avoid unnecessarily antibiotics, omit antiviral therapy when convenient, and a teaching possibility. PMID- 22251994 TI - New technologies for influenza vaccines. AB - Influenza vaccine preparations have been administered to humans since the late 1930s, and the diversity of approaches in licensed trivalent seasonal or monovalent pandemic products is unparalleled by vaccines against any other target. These approaches include inactivated whole virus vaccines, detergent or solvent "split" vaccines, subunit vaccines, live attenuated vaccines, adjuvanted vaccines, intramuscular vaccines, intradermal vaccines, intranasal vaccines, egg produced vaccines and mammalian cell culture-produced vaccines. The challenges of influenza immunization, including multiple co-circulating strains, antigenic change over time, a broad age spectrum of disease, and the threat of pandemics, continue to drive the development of new approaches. This review describes some of the new approaches to influenza immunization that are the subjects of active research and development. PMID- 22251995 TI - Live attenuated intranasal influenza vaccine. AB - Annual vaccination is the most effective means of preventing and controlling influenza epidemics, and the traditional trivalent inactivated vaccine (TIV) is by far the most widely used. Unfortunately, it has a number of limitations, the most important of which is its poor immunogenicity in younger children and the elderly, the populations at greatest risk of severe influenza. Live attenuated influenza vaccine (LAIV) has characteristics that can overcome some of these limitations. It does not have to be injected because it is administered intranasally. It is very effective in children and adolescents, among whom it prevents significantly more cases of influenza than the traditional TIV. However, its efficacy in adults has not been adequately documented, which is why it has not been licensed for use by adults by the European health authorities. LAIV is safe and well tolerated by children aged > 2 y and adults, but some concerns arisen regarding its safety in younger children and subjects with previous asthma or with recurrent wheezing. Further studies are needed to solve these problems and to evaluate the possible role of LAIV in the annual vaccination of the general population. PMID- 22251996 TI - Ten lessons for the next influenza pandemic-an English perspective: a personal reflection based on community surveillance data. AB - We review experience in England of the swine flu pandemic between May 2009 and April 2010. The surveillance data from the Royal College of General Practitioners Weekly Returns Service and the linked virological data collected in the integrated program with the Health Protection Agency are used as a reference frame to consider issues emerging during the pandemic. Ten lessons are summarized. (1) Delay between illness onset in the first worldwide cases and virological diagnosis restricted opportunities for containment by regional prophylaxis. (2) Pandemic vaccines are unlikely to be available for effective prevention during the first wave of a pandemic. (3) Open, realistic and continuing communication with the public is important. (4) Surveillance programs should be continued through summer as well as winter. (5) Severity of illness should be incorporated in pandemic definition. (6) The reliability of diagnostic tests as used in routine clinical practice calls for further investigation. (7) Evidence from serological studies is not consistent with evidence based on health care requests made by sick persons and is thus of limited value in cost effectiveness studies. (8) Pregnancy is an important risk factor. (9) New strategies for administering vaccines need to be explored. (10) Acceptance by the public and by health professionals of influenza vaccination as the major plank on which the impact of influenza is controlled has still not been achieved. PMID- 22251997 TI - Influenza viruses: from birds to humans. AB - Avian influenza viruses are the precursors of human influenza A viruses. They may be transmitted directly from avian reservoirs, or infect other mammalian species before subsequent transmission to their human host. So far, avian influenza viruses have caused sporadic-yet increasingly more frequently recognized-cases of infection in humans. They have to adapt to and circulate efficiently in human populations, before they may trigger a worldwide human influenza outbreak or pandemic. Cross-species transmission of avian influenza viruses from their reservoir hosts-wild waterbirds-to terrestrial poultry and to humans is based on different modes of transmission and results in distinctive pathogenetic manifestations, which are reviewed in this paper. PMID- 22251998 TI - Benefits to mother and child of influenza vaccination during pregnancy. AB - Influenza virus infection contributes to substantial morbidity and mortality globally. Included in the list of groups at higher risk of either influenza infection or severe complications following influenza infection are pregnant women and their newborns. Influenza vaccination offers a safe and effective means to prevent or lessen the severity of influenza infections. Recent research has helped elucidate the impact of influenza infection and vaccination on pregnant women and their newborn children and young infants. This review summarizes recent findings in this area and identifies additional gaps in the evidence base that need to be addressed to appropriately inform vaccination policies worldwide, to protect pregnant women and their children from influenza and related complications. PMID- 22251999 TI - Economic value of influenza vaccination. AB - Influenza epidemics are responsible for high mortality and morbidity rates in particular among elderly and high risk groups. This review is aimed at assessing the economic value of vaccination in these groups. A search of full economic evaluations of influenza vaccination in comparison with no interventions was performed on PubMed from January 1990 to May 2011. Only economic evaluations dealing with elderly and high risk groups were considered. The quality of selected articles was assessed through Drummond's checklist. Sixteen cost effectiveness analyses and four cost-benefit analyses were included: overall, the quality of studies was fairly good. The vaccination was demonstrated to be cost effective or cost-saving in almost all studies, independently by the perspective and the type of analysis. Influenza vaccination is a worthwhile intervention from the pharmacoeconomic view-point, anyway a standardization of methods should be desirable in order to guarantee the comparability and transferability of results. PMID- 22252000 TI - Influenza vaccination coverage rate in children: reasons for a failure and how to go forward. AB - Based on an increasingly extensive literature expressing the large interest in the field, this paper gives an overview of different aspects of influenza prevention in children. It relies on paradoxes. First, the heaviest part of the burden is well demonstrated in the youngest infants by numerous epidemiological data elsewhere. On the contrary, with older children, the prevention by influenza vaccines is more efficacious-without notable side effects. Second, the available TIV vaccines are 60 years old and the requests of registration and regulation of vaccines have evolved. There is a specific need in children: it is time to re discuss the pragmatic utilization of influenza vaccines (full dose in the youngest patient? More flexibility regarding the interval between the two required doses in vaccine-naive children), and to change from a compassionate use to a targeted research and adapted vaccines considering the limits of TIV in the youngest children. Third, influenza virus transmission is the highest in children in semi-close communities (day-care centers, schools), diffusing to households and more largely to the population. A restricted policy on high risk groups (roughly 10% in a pediatric population, all medical conditions including asthma, for whom influenza vaccine coverage is a 15-75% range) is far below the estimated threshold of 45% coverage rate to limit the virus circulation by an indirect impact during seasonal epidemics. Fourth, public health decisions in the vaccination field are usually taken from top to bottom. The pandemic A/H1N1 has toughly demonstrated that "forgetting" about the perception and expectations of the public and the parents nearly created conflicts and at least a strong resistance impeding the quality of a program worked on for a long time ahead. Fifth, and not the least, HCPs are pivotal in influenza vaccination mostly trusted by the parents. Too often, they are not backed by a national and clear support and they need to reinforce their knowledge on the disease and the vaccines. PMID- 22252001 TI - Correlates of vaccine protection from influenza and its complications. AB - Despite use of influenza vaccines for more than 65 y, influenza and its complications are a major cause of morbidity and mortality worldwide. Most deaths during influenza virus infections are due to underlying co-morbidities or secondary bacterial pneumonia. The measures of immune response currently used for licensure of influenza vaccines are relevant mainly for protection from viral infection in healthy adults. Development of new or improved influenza vaccines will require a definition of novel, and specific correlates of protection. These correlates should associate immune responses with outcomes that are relevant to specific risk groups, such as asthma exacerbation, hospitalization or disruptions to care or daily activities. Assessment of vaccine effectiveness for both viral and bacterial vaccines should include measures of impact on secondary bacterial pneumonia. PMID- 22252002 TI - Clinical and socioeconomic impact of pediatric seasonal and pandemic influenza. AB - Influenza is frequent among otherwise healthy day-care and school-aged children. Recent studies have demonstrated its significant effect on various outcome factors, including significantly more school and parental work absenteeism, and secondary illnesses among family members. Other studies have shown that the potential benefit of vaccinating children against influenza extends to other members of their families, thus supporting earlier economic modeling analyses of immunization programs. Although there are some differences in the clinical and socio-economic impact of seasonal and pandemic influenza, the benefits of vaccination are similar in both cases. The vaccination of otherwise healthy children may significantly reduce direct and indirect influenza-related costs, which supports the recommendation to make wider use of influenza vaccine in healthy children of any age in order to reduce the burden of infection on the community. PMID- 22252003 TI - Influenza vaccination for older adults. AB - Influenza vaccines were developed in the 1930s and were shown in randomized clinical trials to prevent influenza in young healthy adults. The significant morbidity and mortality associated with influenza in adults, age 65 y and older, prompted the early recommendation for influenza vaccination in that age group, based on efficacy data in younger adults. Subsequently a number of studies have demonstrated vaccine effectiveness in older adults, but it appears to be lower than in younger adults. New vaccines are being developed with enhanced immunogenicity to improve the protection of older adults. In the meantime, the currently licensed influenza vaccines need to be administered annually to prevent the estimated 90,000 hospitalizations and 5,000 deaths attributed to influenza in adults >=65 y of age each year. PMID- 22252004 TI - Adjuvanted influenza vaccines. AB - The search for adjuvants has been stimulated by the need to ensure greater protection against influenza among subjects who show a reduced immune response to conventional influenza vaccines. Aluminum salts have long been used but are not considered satisfactory. This has led to the development of other possible compounds, sometimes on the basis of new knowledge concerning the mechanisms regulating the immune response to infections. Some of the new adjuvants (emulsions and virosomes) have been widely evaluated, and the apparently good results have led to the registration of adjuvanted influenza vaccines for use in humans, at least in some countries and in some subjects. In other cases, the adjuvants have been mainly or exclusively studied in experimental animals, and are unlikely to be used in humans in the near future. However, even in the case of those for which a considerable amount of data are available, assessments of their superiority over conventional influenza vaccines have mainly been based on immunogenicity studies, and have not been confirmed by comparative, randomized, double-blind clinical trials. Moreover, the very few human data comparing different adjuvants are frequently conflicting. The aim of this review is to discuss the characteristics and advantages of the adjuvants that have so far been used and to describe some of the new adjuvants that are still in the development phase. PMID- 22252005 TI - Recommendations for the use of influenza vaccine in pediatrics. AB - Every year for the last few decades, the health authorities of most countries throughout the world have issued specific recommendations for the prevention and treatment of pediatric influenza, including recommendations concerning the use of vaccines. However, different evaluations of the importance of the disease and the efficacy of influenza vaccination frequently lead to conflicting recommendations. This is clearly demonstrated not only by the differences in the subjects for whom the vaccine is recommended, but also by the inaccurate manner in which subjects at risk of influenza-related complications are defined. Only further studies that consider the burden of the disease and vaccine efficacy in adequate numbers of healthy children and high-risk children with different chronic underlying diseases can overcome all of the current limitations and significantly improve vaccination coverage in both categories. PMID- 22252006 TI - The rationale for quadrivalent influenza vaccines. AB - Two antigenically distinct lineages of influenza B viruses have circulated globally since 1985. However, licensed trivalent seasonal influenza vaccines contain antigens from only a single influenza B virus and thus provide limited immunity against circulating influenza B strains of the lineage not present in the vaccine. In recent years, predictions about which B lineage will predominate in an upcoming influenza season have been no better than chance alone, correct in only 5 of the 10 seasons from 2001 to 2011. Consequently, seasonal influenza vaccines could be improved by inclusion of influenza B strains of both lineages. The resulting quadrivalent influenza vaccines would allow influenza vaccination campaigns to respond more effectively to current global influenza epidemiology. Manufacturing capacity for seasonal influenza vaccines has increased sufficiently to supply quadrivalent influenza vaccines, and methods to identify the influenza B strains to include in such vaccines are in place. Multiple manufacturers have initiated clinical studies of quadrivalent influenza vaccines. Data from those studies, taken together with epidemiologic data regarding the burden of disease caused by influenza B infections, will determine the safety, effectiveness, and benefit of utilizing quadrivalent vaccines for the prevention of seasonal influenza disease. PMID- 22252007 TI - Clinical and socioeconomic impact of seasonal and pandemic influenza in adults and the elderly. AB - Influenza epidemics and pandemics carry a heavy socioeconomic burden. Hospitalization and treatment are more often necessary in high-risk patients, such as the elderly. However, the impact of influenza is not negligible even in adults, mainly because of lost productivity. The World Health Organization estimates that seasonal influenza causes 250,000-500,000 deaths worldwide each year; however, mortality may be very high in pandemic periods. Many estimates of the costs of seasonal influenza have been made in various socioeconomic contexts. For instance, among the adult population in Italy, a cost of ?940.39 per case has been estimated. In the US, the average annual influenza burden in 18-49-y-old adults without underlying medical conditions is judged to include approximately 32,000 hospitalizations and 680 deaths. Estimating the influenza burden is a useful aid to determining the best influenza vaccination strategy and preventive and clinical treatments. PMID- 22252008 TI - Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. AB - Chloroquine (CQ) is a 4-aminoquinoline drug used for the treatment of diverse diseases. It inhibits lysosomal acidification and therefore prevents autophagy by blocking autophagosome fusion and degradation. In cancer treatment, CQ is often used in combination with chemotherapeutic drugs and radiation because it has been shown to enhance the efficacy of tumor cell killing. Since CQ and its derivatives are the only inhibitors of autophagy that are available for use in the clinic, multiple ongoing clinical trials are currently using CQ or hydroxychloroquine (HCQ) for this purpose, either alone, or in combination with other anticancer drugs. Here we show that in the mouse breast cancer cell lines, 67NR and 4T1, autophagy is induced by the DNA damaging agent cisplatin or by drugs that selectively target autophagy regulation, the PtdIns3K inhibitor LY294002, and the mTOR inhibitor rapamycin. In combination with these drugs, CQ sensitized to these treatments, though this effect was more evident with LY294002 and rapamycin treatment. Surprisingly, however, in these experiments CQ sensitization occurred independent of autophagy inhibition, since sensitization was not mimicked by Atg12, Beclin 1 knockdown or bafilomycin treatment, and occurred even in the absence of Atg12. We therefore propose that although CQ might be helpful in combination with cancer therapeutic drugs, its sensitizing effects can occur independently of autophagy inhibition. Consequently, this possibility should be considered in the ongoing clinical trials where CQ or HCQ are used in the treatment of cancer, and caution is warranted when CQ treatment is used in cytotoxic assays in autophagy research. PMID- 22252010 TI - Leptin regulates sugar and amino acids transport in the human intestinal cell line Caco-2. AB - AIM: Studies in rodents have shown that leptin controls sugars and glutamine entry in the enterocytes by regulating membrane transporters. Here, we have examined the effect of leptin on sugar and amino acids absorption in the human model of intestinal cells Caco-2 and investigated the transporters involved. METHODS: Substrate uptake experiments were performed in Caco-2 cells, grown on plates, in the presence and the absence of leptin, and the expression of the different transporters in brush border membrane vesicles was analysed by Western blot. RESULTS: Leptin inhibited 0.1 mm alpha-methyl-D-glucoside uptake after 5 or 30 min treatment and decreased SGLT1 protein abundance in the apical membrane. Uptake of 20 MUm glutamine and 0.1 mm phenylalanine was also inhibited by leptin, indicating sensitivity to the hormone of the Na(+) -dependent neutral amino acid transporters ASCT2 and B(0) AT1. This inhibition was accompanied by a reduction in the transporters expression at the brush border membrane. Leptin also inhibited 1 mm proline and beta-alanine uptake in Na(+) medium at pH 6, conditions for optimal activity of the H(+) -dependent neutral amino acid transporter PAT1. In this case, abundance of PAT1 in the brush border membrane after leptin treatment was not modified. Interestingly, leptin inhibitory effect on beta-alanine uptake was reversed by the PKA inhibitor H-89 suggesting involvement of PKA pathway in leptin's regulation of PAT1 activity. CONCLUSION: These data show in human intestinal cells that leptin can rapidly control the activity of physiologically relevant transporters for rich-energy molecules, that is, D-glucose (SGLT1) and amino acids (ASCT2, B(0) AT1 and PAT1). PMID- 22252009 TI - Amino acids downregulate the expression of several autophagy-related genes in rainbow trout myoblasts. AB - Many fish species experience long periods of fasting often associated with seasonal reductions in water temperature and prey availability or spawning migrations. During periods of nutrient restriction, changes in metabolism occur to provide cellular energy via catabolic processes. Muscle is particularly affected by prolonged fasting as proteins of this tissue act as a major energy source. However, the molecular components involved in muscle protein degradation as well as the regulatory networks that control their function are still incompletely defined in fish. The present work aimed to characterize the response of the autophagy-lysosomal degradative pathway to nutrient and serum availability in primary culture of rainbow trout myoblasts. In this aim, 4-day-old cells were incubated in a serum and amino acid-rich medium (complete medium), a serum and amino acid-deprived medium (minimal medium) or a minimal medium plus amino acids, and both the transcription-independent short-term response and the transcription dependent long-term response of the autophagy-lysosomal degradative pathway were analyzed. We report that serum and amino acids withdrawal is accompanied by a rapid increase of autophagosome formation but also by a slower induction of the expression of several autophagy-related genes (LC3B, gabarapl1, atg4b). We also showed that this latter response is controlled by amino acid (AA) availability and that both TOR-dependent and TOR-independent pathways are involved in this effect. Together these results suggest an important role for AA released by muscle proteolysis during the fasting period in regulating the subtle balance between using proteins as disposable furniture to provide energy, and conserving muscle through protein sparing. PMID- 22252011 TI - Proteomic and biochemical analysis of maize anthers after cold pretreatment and induction of androgenesis reveals an important role of anti-oxidative enzymes. AB - In stress conditions, microspores and young pollen grains can be switched from their normal pollen development toward an embryogenic pathway via a process called androgenesis. Androgenic embryos can produce completely homozygous, haploid or double-haploid plants. This study aimed to investigate changes in the abundance of protein species during cold pretreatment and subsequent cultivation of maize anthers on induction media using gel-based proteomics. Proteins upregulated on the third day of anther induction were identified and discussed here. Simultaneous microscopic observations revealed that the first division occurred in microspores within this period. Using 2-D electrophoresis combined with MALDI TOF/TOF MS/MS analysis 19 unique proteins were identified and classified into 8 functional groups. Proteins closely associated with metabolism, protein synthesis and cell structure were the most abundant ones. Importantly, ascorbate peroxidase, an enzyme decomposing hydrogen peroxide, was also upregulated. Isozyme analysis of peroxidases validated the proteomic data and showed increased peroxidase activities during androgenic induction. Further, the isozyme pattern of SOD revealed increased activity of the MnSOD, which could provide hydrogen peroxide as a substrate for in vivo peroxidase reactions (including ascorbate peroxidase). Together, these data reveal the role of enzymes controlling oxidative stress during induction of maize androgenesis. PMID- 22252012 TI - Robust, small-scale cultivation platform for Streptomyces coelicolor. AB - BACKGROUND: For fermentation process and strain improvement, where one wants to screen a large number of conditions and strains, robust and scalable high throughput cultivation systems are crucial. Often, the time lag between bench scale cultivations to production largely depends on approximate estimation of scalable physiological traits. Microtiter plate (MTP) based screening platforms have lately become an attractive alternative to shake flasks mainly because of the ease of automation. However, there are very few reports on applications for filamentous organisms; as well as efforts towards systematic validation of physiological behavior compared to larger scale are sparse. Moreover, available small-scale screening approaches are typically constrained by evaluating only an end point snapshot of phenotypes. RESULTS: To address these issues, we devised a robust, small-scale cultivation platform in the form of MTPs (24-square deepwell) for the filamentous bacterium Streptomyces coelicolor and compared its performance to that of shake flasks and bench-scale reactors. We observed that re designing of medium and inoculum preparation recipes resulted in improved reproducibility. Process turnaround time was significantly reduced due to the reduction in number of unit operations from inoculum to cultivation. The incorporation of glass beads (o 3 mm) in MTPs not only improved the process performance in terms of improved oxygen transfer improving secondary metabolite production, but also helped to transform morphology from pellet to disperse, resulting in enhanced reproducibility. Addition of MOPS into the medium resulted in pH maintenance above 6.50, a crucial parameter towards reproducibility. Moreover, the entire trajectory of the process was analyzed for compatibility with bench-scale reactors. The MTP cultivations were found to behave similar to bench-scale in terms of growth rate, productivity and substrate uptake rate and so was the onset of antibiotic synthesis. Shake flask cultivations however, showed discrepancy with respect to morphology and had considerably reduced volumetric production rates of antibiotics. CONCLUSION: We observed good agreement of the physiological data obtained in the developed MTP platform with bench-scale. Hence, the described MTP-based screening platform has a high potential for investigation of secondary metabolite biosynthesis in Streptomycetes and other filamentous bacteria and the use may significantly reduce the workload and costs. PMID- 22252013 TI - Polyhydroxylated sterols from the Indonesian soft coral Sinularia sp. and their effect on farnesoid X-activated receptor. AB - Chemical investigation of the Indonesian soft coral Sinularia sp. resulted in the isolation of three known (1, 2 and 7) and five new (3-6 and 8) sterols, characterized by either 24-methylcholestane or gorgostane skeletons. The stereostructures of the new compounds have been elucidated by application of HR MS and 2D NMR techniques. The isolated steroids have been evaluated for their interaction with the farnesoid X-activated receptor (FXR) and some of them, including the new compound 3 and gorgosterol (7), showed a consistent antagonistic activity, potentially useful for the treatment of cholestasis. The FXR antagonistic activity of gorgosterol (7) was also supported by gene expression experiments. Our results represent the first evaluation of soft coral steroids for interaction with nuclear receptors and qualify gorgosterol (7) as a new chemotype of FXR antagonist. PMID- 22252014 TI - Chronic kidney disease in type 2 diabetes patients in France: prevalence, influence of glycaemic control and implications for the pharmacological management of diabetes. AB - AIM: Type 2 diabetes mellitus (T2DM) is often associated with chronic kidney disease. For this reason, this article reviews the relationship between treatment of T2DM and renal disease. METHOD: The review presents the recent French data on the management of diabetes in patients with renal impairment, and discusses the implications of renal disease for the treatment of such patients. Prescribing data are presented for various antidiabetic treatments, and the use of the more commonly prescribed medications is discussed with reference to T2DM patients with renal disease. RESULTS: In France, it is estimated that 4-5% of the general population has T2DM and that almost 40% of patients with end-stage renal failure have diabetes. Diabetes and renal disease are both risk factors for cardiovascular morbidity and mortality. Glycaemic control is pivotal in T2DM patients for minimizing the risk of vascular complications and hypoglycaemic episodes, particularly in patients with renal disease who also have a higher risk of hypoglycaemia. Whereas poorly controlled glycaemia increases the risk of renal disease and its progression, the risk is diminished in patients treated intensively for diabetes and in those who achieve stable glycaemic control. Intensive multitargeted treatment can also help to decrease cardiovascular morbidity and mortality, especially if started early in patients who have not yet developed macrovascular complications. CONCLUSION: In recent years, considerable improvement has been observed in France regarding the follow-up of diabetic patients. Less extensive, but nonetheless significant, improvement has also been observed in glycaemic control. However, even though treatment decisions generally take renal function into account, some at-risk treatments are often still being used in patients with renal insufficiency. PMID- 22252015 TI - Inflammation and type 2 diabetes. AB - Low-grade inflammation is a common feature in subjects with type 2 diabetes (T2D). Heart disease, the metabolic syndrome and T2D all have in common the increased concentration of circulatory cytokines as a result of inflammation. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral actions. This review focuses on C-reactive protein (CRP), a well established marker of the development of inflammation, on tumour necrosis factor (TNF)-alpha, an inflammatory marker strongly associated with diabetes, and on adiponectin, a cytokine produced by adipose tissue and associated with insulin sensitivity. While it is clear from the literature that these cytokines play a major role in the development of T2D or, in the case of adiponectin, its prevention, the best strategy for favourably altering the inflammatory response is still a matter of debate. PMID- 22252016 TI - Production of novel fusarielins by ectopic activation of the polyketide synthase 9 cluster in Fusarium graminearum. AB - Like many other filamentous fungi, Fusarium graminearum has the genetic potential to produce a vast array of unknown secondary metabolites. A promising approach to determine the nature of these is to activate silent secondary metabolite gene clusters through constitutive expression of cluster specific transcription factors. We have developed a system in which an expression cassette containing the transcription factor from the targeted PKS cluster disrupts the production of the red mycelium pigment aurofusarin. This aids with identification of mutants as they appear as white colonies and metabolite analyses where aurofusarin and its intermediates are normally among the most abundant compounds. The system was used for constitutive expression of the local transcription factor from the PKS9 cluster (renamed FSL) leading to production of three novel fusarielins, F, G and H. This group of compounds has not previously been reported from F. graminearum or linked to a biosynthetic gene in any fungal species. The toxicity of the three novel fusarielins was examined against colorectal cancer cell lines where fusarielin H was more potent than fusarielin F and G. PMID- 22252017 TI - A change from second- to first-order transition in (La(1-x)Eu(x))0.67Ca0.33MnO3 (0 <= x <= 0.2). AB - A detailed investigation of the paramagnetic to ferromagnetic transition in (La(1 x)Eu(x))(0.67)Ca(0.33)MnO(3) having small Eu(3+)-content (0 <= x <= 0.2) has been carried out through resistivity and magnetization measurements. X-ray diffraction patterns of the compounds reveal a single phase (La(1 x)Eu(x))(0.67)Ca(0.33)MnO(3) (0 <= x <= 0.2) of an orthorhombic crystal structure after annealing the precursor at 800 degrees C for 2 h in air. With increasing Eu(3+)-content, the second-order transition (at x = 0 and 0.1) changes to first order at x = 0.2. The experimental results demonstrate thermomagnetic irreversibility of the transition for x = 0.2 composition. This arises between the supercooling and superheating regimes where both the ferromagnetic and paramagnetic phases coexist. PMID- 22252019 TI - Hierarchical cobalt iron oxide nanoarrays as structured catalysts. AB - Large-scale arrays of hierarchical cobalt iron oxide nanowires with preferentially exposed reactive crystal planes have been fabricated for use as structured catalysts, which showed high catalytic activity and excellent cycling stability. PMID- 22252018 TI - Plasma membrane calcium pump (PMCA) isoform 4 is targeted to the apical membrane by the w-splice insert from PMCA2. AB - Local Ca(2+) signaling requires proper targeting of the Ca(2+) signaling toolkit to specific cellular locales. Different isoforms of the plasma membrane Ca(2+) pump (PMCA) are responsible for Ca(2+) extrusion at the apical and basolateral membrane of polarized epithelial cells, but the mechanisms and signals for differential targeting of the PMCAs are not well understood. Recent work demonstrated that the alternatively spliced w-insert in PMCA2 directs this pump to the apical membrane. We now show that inserting the w-insert into the corresponding location of the PMCA4 isoform confers apical targeting to this normally basolateral pump. Mutation of a di-leucine motif in the C-tail thought to be important for basolateral targeting did not enhance apical localization of the chimeric PMCA4(2w)/b. In contrast, replacing the C-terminal Val residue by Leu to optimize the PDZ ligand site for interaction with the scaffolding protein NHERF2 enhanced the apical localization of PMCA4(2w)/b, but not of PMCA4x/b. Functional studies showed that both apical PMCA4(2w)/b and basolateral PMCA4x/b handled ATP-induced Ca(2+) signals with similar kinetics, suggesting that isoform specific functional characteristics are retained irrespective of membrane targeting. Our results demonstrate that the alternatively spliced w-insert provides autonomous apical targeting information in the PMCA without altering its functional characteristics. PMID- 22252020 TI - The influence of aspirin dose and glycemic control on platelet inhibition in patients with type 2 diabetes mellitus. AB - BACKGROUND: Low-dose aspirin seems to offer no benefit in the primary prevention of cardiovascular disease in type 2 diabetes mellitus (DM2). The anti-platelet effect may be diminished by poor glycemic control or inadequate dosing of aspirin. OBJECTIVES: To study the effects of both glycemic control and increasing aspirin dose on platelet response to aspirin in DM2 patients and matched controls. PATIENTS/METHODS: Platelet effects of increasing doses of aspirin (30, 100 and 300 mg daily) were prospectively assessed in 94 DM2 patients and 25 matched controls by measuring thromboxane levels in urine (11-dhTxB2) and platelet aggregation using VerifyNow((r)) and light transmission aggregometry (LTA). DM2 patients were stratified for glycemic control (hemoglobin-A1c [HbA1c] <= 53, 53-69, >= 69 mmol mol(-1)). RESULTS: At baseline, median 11-dhTxB2 excretion was higher in the poorly controlled patients (77 ng mmol(-1)), and the moderately controlled (84 ng mmol(-1)) compared with the well-controlled patients (64 ng mmol(-1)) and controls (53 ng mmol(-1)), P < 0.01. Next, 30 mg of aspirin reduced 11-dhTxB2 excretion to 31, 29 and 24 ng mmol(-1) in the poorly, moderately and well-controlled patients, respectively, and to 19 ng mmol(-1) in controls, P < 0.001. VerifyNow((r)) and LTA were also incompletely suppressed in DM2 patients using 30 mg of aspirin, but 100 mg resulted in similar platelet suppression in all groups, with no additional effect of 300 mg. CONCLUSIONS: DM2 patients with inadequate glycemic control (HbA1c > 53 mmol mol(-1)) have higher baseline platelet activity and incomplete suppression of platelet activity with 30 mg of aspirin. However, 100 mg of aspirin leads to optimal inhibition irrespective of glycemic control, and 300 mg does not further improve platelet suppression. PMID- 22252021 TI - Breaking bad news: a guide for effective and empathetic communication. AB - Breaking negative news to patients is a common occurrence for nurse practitioners. This difficult task requires patience and refined communication skills, and must be approached with empathy for all parties involved. There are several ways to deliver bad news to patients successfully using patient-centered communication techniques and methods. PMID- 22252022 TI - Creating a heart healthy future with the Million Hearts initiative. PMID- 22252023 TI - Utilizing the NONPF program director manual. PMID- 22252027 TI - Opening doors for nonphysician colonoscopists. AB - The current need for colonoscopies is high and steadily growing. Many healthcare facilities are finding that there is a shortage of specialized physicians to perform this procedure. By training nonphysician providers who have previously screened for colorectal cancer and performed colonoscopies safely and accurately, this shortage can be eliminated. PMID- 22252028 TI - Hypertensive African American women and the DASH diet. AB - This integrative review identifies barriers to implementing the Dietary Approaches to Stop Hypertension (DASH) diet in hypertensive African American women. Databases were searched for original research published between 1999 and 2009. Barriers included clinicians' low adherence to nutritional counseling and patients' lack of knowledge regarding nutrition and the consequences of hypertension. PMID- 22252029 TI - Helping patients through the pain of infertility. AB - While males and combined couple factors play a large part in infertility cases, women often carry the physical, social, and emotional burden of these diagnoses. Nurse practitioners are in a prime position to assess women at risk for infertility, initiate an investigation to identify potential etiologies, refer women to specialized centers, and provide them with ongoing care and support through this difficult period in their lives. PMID- 22252031 TI - Adventures in anesthetic mechanisms. PMID- 22252032 TI - Close quarters: an introspective. PMID- 22252035 TI - Polyoxometalate-directed assembly of water-soluble AgCl nanocubes. AB - "Out-of-pocket" association of Ag(+) to the tetradentate defect site of mono vacant Keggin and Wells-Dawson polyoxometalate (POM) cluster-anions is used to direct the formation of water-soluble AgCl nanocubes. PMID- 22252036 TI - Polymer dynamics in responsive microgels: influence of cononsolvency and microgel architecture. AB - The dynamics of polymers on the nm and ns scales inside responsive microgels was probed by means of Neutron Spin Echo (NSE) experiments. Four different microgels were studied: poly(N-isopropylacrylamide) (PNIPAM) and poly(N,N diethylacrylamide) (PDEAAM) microgels, a P(NIPAM-co-DEAAM) copolymer microgel and a core-shell microgel with a PDEAAM core and a PNIPAM shell. These four different microgel systems were investigated in a D(2)O/CD(3)OD solvent mixture with a molar CD(3)OD fraction of x(MeOD) = 0.2 at 10 degrees C. The PNIPAM and the P(NIPAM-co-DEAAM) microgels are in the collapsed state under these conditions. They behave as solid diffusing objects with only very small additional contributions from internal motions. The PDEAAM particle is swollen under these conditions and mainly Zimm segmental dynamics can be detected in the intermediate scattering function at high momentum transfer. A cross-over to a collective diffusive motion is found for smaller q-values. The shell of the PDEAAM-core PNIPAM-shell particle is collapsed, which leads to a static contribution to S(q,t); the core, however, is swollen and Zimm segmental dynamics are observed. However, the contributions of the Zimm segmental dynamics to the scattering function are smaller as compared to the pure PDEAAM particle. Interestingly the values of the apparent solvent viscosities inside the microgels as obtained from the NSE experiments are higher than for the bulk solvent. In addition different values were obtained for the PDEAAM microgel, and the PDEAAM-core of the PDEAAM core-PNIPAM-shell particle, respectively. We attribute the strongly increased viscosity in the PDEAAM particle to enhanced inhomogeneities, which are induced by the swelling of the particle. The different viscosity inside the PDEAAM-core of the PDEAAM-core-PNIPAM-shell microgel could be due to a confinement effect: the collapsed PNIPAM-shell restricts the swelling of the PDEAAM-core and may modify the hydrodynamic interactions in this restricted environment inside the microgel. PMID- 22252034 TI - CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. AB - Adipose tissue macrophages (ATMs) accumulate in fat during obesity and resemble foam cells in atherosclerotic lesions, suggesting that common mechanisms underlie both inflammatory conditions. CX(3)CR1 and its ligand fractalkine/CX(3)CL1 contribute to macrophage recruitment and inflammation in atherosclerosis, but their role in obesity-induced adipose tissue inflammation is unknown. Therefore, we tested the hypothesis that CX(3)CR1 regulates ATM trafficking to epididymal fat and contributes to the development of adipose tissue inflammation during diet induced obesity. Cx(3)cl1 and Cx(3)cr1 expression was induced specifically in epididymal fat from mice fed a high-fat diet (HFD). CX(3)CR1 was detected on multiple myeloid cells within epididymal fat from obese mice. To test the requirement of CX(3)CR1 for ATM trafficking and obesity-induced inflammation, Cx(3)cr1(+/GFP) and Cx(3)cr1(GFP/GFP) mice were fed a HFD. Ly-6c(Low) monocytes were reduced in lean Cx(3)cr1(GFP/GFP) mice; however, HFD-induced monocytosis was comparable between strains. Total ATM content, the ratio of type 1 (CD11c(+)) to type 2 (CD206(+)) ATMs, expression of inflammatory markers, and T-cell content were similar in epididymal fat from obese Cx(3)cr1(+/GFP) and Cx(3)cr1(GFP/GFP) mice. Cx(3)cr1 deficiency did not prevent the development of obesity-induced insulin resistance or hepatic steatosis. In summary, our data indicate that CX(3)CR1 is not required for the recruitment or retention of ATMs in epididymal adipose tissue of mice with HFD-induced obesity even though CX(3)CR1 promotes foam cell formation. This highlights an important point of divergence between the mechanisms regulating monocyte trafficking to fat with obesity and those that contribute to foam cell formation in atherogenesis. PMID- 22252037 TI - The impact of blood pressure hemodynamics in acute ischemic stroke: a prospective cohort study. AB - OBJECTIVE: To assess relationships between blood pressure hemodynamic measures and outcomes after acute ischemic stroke, including stroke severity, disability and death. METHODS: The study cohort consisted of 189 patients who presented to our emergency department with ischemic stroke of less than 24 hours onset who had hemodynamic parameters recorded and available for review. Blood pressure (BP) was non-invasively measured at 5 minute intervals for the length of the patient's emergency department stay. Systolic BP (sBP) and diastolic BP (dBP) were measured for each patient and a differential (the maximum minus the minimum BP) calculated. Three outcomes were studied: stroke severity, disability at hospital discharge, and death at 90 days. Statistical tests used included Spearman correlations (for stroke severity), Wilcoxon test (for disability) and Cox models (for death). RESULTS: Larger differentials of either dBP (p = 0.003) or sBP (p < 0.001) were significantly associated with more severe strokes. A greater dBP (p = 0.019) or sBP (p = 0.036) differential was associated with a significantly worse functional outcome at hospital discharge. Those patients with larger differentials of either dBP (p = 0.008) or sBP (0.007) were also significantly more likely to be dead at 90 days, independently of the basal BP. CONCLUSION: A large differential in either systolic or diastolic blood pressure within 24 hours of symptom onset in acute ischemic stroke appears to be associated with more severe strokes, worse functional outcome and early death. PMID- 22252038 TI - Implications of sentinel lymph node mapping on nodal staging and prognosis in colorectal cancer. AB - AIM: Sentinel lymph node (SN) mapping for staging in colorectal cancer remains controversial and needs to be validated before it can be implemented in daily practice. We prospectively assessed the effect of SN mapping on nodal staging and its implication on survival in patients with colorectal cancer. METHOD: Between November 2005 and July 2009, 331 patients underwent a resection for colorectal cancer. In 189 patients (group A) an ex-vivo SN procedure was performed with immunohistochemical analysis of the SN. Tumour cell deposits between 0.2 mm and 2.0 mm were referred to as micrometastases (pN1mi+). The remaining patients (n = 142, group B) had standard nodal staging. Multivariate Cox regression analysis was performed to identify prognostic factors for disease recurrence. RESULTS: The average number of harvested lymph nodes was higher in group A than in group B (15.5 +/- 7.3 vs 12.1 +/- 5.2, P < 0.0001). After conventional staging, 81 (43%) patients of group A were judged to have nodal metastasis. This increased to 89 (47%) patients when immunohistochemically detected micrometastases were included. In group B, 50 (35%) patients had nodal metastasis. During follow up, a lower recurrence rate was seen in N0 patients after SN mapping compared with the conventional staging group (4%vs 15.2%, P = 0.04). The SN procedure (hazard ratio = 4.1) was an independent predictor of disease recurrence. CONCLUSION: The SN procedure results in a more accurate staging of patients with colorectal cancer. This is reflected by a better prognosis of N0 patients after SN mapping. PMID- 22252039 TI - Rethinking credible evidence synthesis. PMID- 22252040 TI - Does anyone understand the government's plan for the NHS? PMID- 22252041 TI - Search for evidence goes on. PMID- 22252042 TI - Questions remain over safety and effectiveness of oseltamivir. PMID- 22252043 TI - The effect of high versus low loading on bone strength in middle life. AB - While bone mass and geometry are largely genetically determined, mechanical loading is considered to be an important additional determinant. This study investigates to what extent very high mechanical loading begun at a young age and sustained afterward can affect tibia bone mass and geometry in middle age. Cohorts from a common ethnic background, with a history of very high and very low tibia bone loading based on an assessment of their activities according their strain levels were compared. The study hypothesis was that the tibia bone density and geometric strength parameters would be greater in the high bone loading cohort. Subjects from a group of elite infantry recruits who sustained a 31% incidence of stress fractures during their basic training in 1983, were reviewed 25 years later. The tibia bone strength of 25 of these soldiers, 11 of whom had sustained stress fractures, was compared to a group of 20 subjects who received exemption from military service in 1982-5 because they were religious scholars and who continued these studies afterwards. Anthropometric measurements were made. The bone density and geometric strength of the tibia was assessed by quantitative computerized tomography (QCT). The average daily dietary intake and metabolic expenditure of subjects were assessed by questionnaires. At the 25 year follow-up soldiers were on an average 3 cm taller than the religious scholars (p=0.02) and had lower abdominal girths (p=0.03). There was no difference in the tibia cortical density between cohorts in spite of the fact that the religious scholars had lower daily calcium intakes (p=0.02). Soldiers had stronger tibias based on geometric engineering criteria. The mean area moments of inertia (p=0.02, p=0.04) and polar moments of inertia (p=0.02) were 16% larger in the soldier cohort. By multivariate regression analysis greater height, weight and daily energy expenditure were related to larger bone geometric strength parameters. According to semipartial eta-square analysis, between 39% to 45% of the variance in the area moments of inertia between the cohorts was attributable to these three parameters. The religious scholars burned less calories daily, principally because they did no sport activity (p=0.001). There was no difference in tibia bone strength parameters between soldiers who did and did not sustain stress fractures in their 1983 basic training. In conclusion, in a middle age population with a common ethnic origin, the high bone loading cohort had stronger tibias than the low bone loading cohort based on larger geometric strength properties and not because of higher cortical density. In spite of being at the extremes of the bone loading spectra, the tibia area moment of inertia of the two cohorts in this study differed by only 16%, with part of this difference attributable to factors other than bone loading. We do not know for sure if the difference in the geometric properties is related to high bone loading or whether people with stronger bones are more likely to engage in high bone loading. Healthy male subjects who sustained stress fractures at a young age do not have weaker tibias at middle age according to QCT measurements. PMID- 22252044 TI - Micro and macroarchitectural changes at the tibia after botulinum toxin injection in the growing rat. AB - The aim of this study was to analyze bone microarchitecture and macroarchitecture of tibia in a disuse model in growing rats. Eight-weeks-old Copenhagen rats were injected intramuscularly with 1.5 units BTX in the quadriceps muscle of the right hind limb. Saline injection was done at the left hind limb to serve as control. Five rats were killed at day 1 and represented the baseline group (D1), 5 rats were killed at day 14 (D14), 5 at day 21 (D21), 5 at day 28 (D28) and 5 at day 35 (35). For each group, muscle surface, parameters of bone microarchitecture and macroarchitecture (including length, width and curvature of the tibia) were measured using microtomography. Paralysis occurred as soon as day 2. At the left hind limb, muscle surface area, cortical thickness, cross sectional total area and growth in length significantly increased during the time study. At the right hind limb, muscle surface area, bone trabecular volume, and cortical thickness decreased as soon as day 14 associated with an increased cortical porosity. Growth in length did not differ from left side; cross sectional total area did not increase and the diaphyseal cross section acquired a more rounded shape. There was no modification of the curvature between right and left hind limbs during the time study. In this murine model of unilateral muscle paralysis in growing animals, we showed a rapid muscle loss leading to a decreased growth in width; however growth in length and curvature were unaltered. PMID- 22252047 TI - Antimicrobial resistance, virulence profiles, and phylogenetic groups of fecal Escherichia coli isolates: a comparative analysis between dogs and their owners in Japan. AB - In this study, fecal Escherichia coli isolates (n=188) from 34 dog-owner pairs and 26 healthy control humans (2 isolates per individual) were tested for susceptibility to 6 antimicrobials and screened for virulence genes. Genetic diversity between canine and owner isolates was evaluated by pulsed-field gel electrophoresis (PFGE). Canine isolates exhibited significantly different rates of resistance to four and two antimicrobials, compared to control and owner isolates, respectively. Of the genes examined, the prevalence of sfa, hly, and cnf genes in canine isolates were higher than in control isolates, but not than in owner isolates. These results suggest that characteristics of owner isolates are somewhat similar to canine isolates, compared to isolates from non-dog owners. In addition, PFGE analysis revealed that transfer of E. coli between owners and their dogs had occurred within 3/34 (8.8%) households. Considering the effects of dog ownership on the population of E. coli isolates from owners, further epidemiological studies are required. PMID- 22252046 TI - Antioxidant activity and protection of pancreatic beta-cells by embelin in streptozotocin-induced diabetes. AB - OBJECTIVES: The aim of the present study was to evaluate the antioxidant potential of embelin in streptozotocin-induced diabetes. METHODS: Diabetes was induced in rats fasted overnight by the administration of a single dose of streptozotocin, and analyzed for blood, serum, and biological and histological pancreatic tissue parameters in intact control, diabetic, and embelin-treated diabetic rats (n = 9) at the dose levels of 15, 25, and 30 mg/kg/day for 21 days. RESULTS: Diabetes caused highly significant abnormalities in blood, serum, and pancreatic tissue biochemical parameters. Embelin and glibenclamide administration to diabetic rats caused a highly significant decline in the blood glycated hemoglobin and serum glucose levels and nitric oxide activity, with a concomitant increase in the serum insulin level (P < 0.001). Furthermore, embelin and glibenclamide treatment increased the pancreatic antioxidant enzyme status (superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase, glutathione S-transferase, and ascorbic acid), and also decreased the thiobarbituric acid reactive oxygen species contents (P < 0.001). The histoarchitecture of the diabetic rats typically showed a degenerated pancreas with reduced beta-cell counts, while embelin treatment was shown to significantly regenerate islet cells. CONCLUSION: The study proves the potent antioxidant activity of embelin, which has been found to be effective in managing severe hyperglycemia. PMID- 22252048 TI - Vacuum-assisted closure therapy in the management of patients undergoing vulvectomy. AB - OBJECTIVES: To investigate whether systematic postoperative VAC therapy could improve vulvectomy healing. STUDY DESIGN: We reviewed medical data from 54 women who underwent in the period of March 2006 to December 2009 radical vulvectomy or wide local vulvectomy with defect volume >40cm(3). Patients were divided into two groups according to immediate postoperative care. Patients treated with systematic vacuum-assisted closure (VAC) therapy immediately after surgery were included in the "VAC group" while patients receiving conventional care (CC) were included in the "CC group". RESULTS: The characteristics of the VAC group (n=30) and CC group (n=24) were similar and there were no significant differences in operative data, histological results or oncologic follow-up. The median length of use of VAC was 11 days after surgery (6-38). The length of hospital stay for patients in the VAC group and CC group was 17.8 (+/-8.7) and 18.4 days (+/-9.9) (p=0.8) respectively. The lengths of complete healing were 44.4 (+/-18.4) vs. 60.2 (+/-28.7) days (p=0.0175) respectively. CONCLUSIONS: In our study we proved that using VAC dressing immediately after vulvectomy (at least 6cm*7cm) for 11 days reduces the total length of cicatrization by approximately 16 days. PMID- 22252049 TI - Higher prevalence of obesity among children with asthma. AB - The aim of this study is to investigate the association between childhood obesity and asthma, and whether this relationship varies by race/ethnicity. For this population-based, cross-sectional study, measured weight and height, and asthma diagnoses were extracted from electronic medical records of 681,122 patients aged 6-19 years who were enrolled in an integrated health plan 2007-2009. Weight class was assigned based on BMI-for-age. Overall, 18.4% of youth had a history of asthma and 10.9% had current asthma. Adjusted odds of current asthma for overweight, moderately obese, and extremely obese youth relative to those of normal weight were 1.22 (95% confidence interval (CI): 1.20, 1.24), 1.37 (95% CI: 1.34, 1.40), and 1.68 (95% CI: 1.64, 1.73), respectively (P trend < 0.001). Black youth are nearly twice as likely (adjusted odds ratio (OR) = 1.93, 95% CI: 1.89, 1.99), and Hispanic youth are 25% less likely (adjusted OR = 0.75, 95% CI: 0.74, 0.77), to have current asthma than to non-Hispanic white youth. However, the relationship between BMI and asthma was strongest in Hispanic and weakest in black youth. Among youth with asthma, increasing body mass was associated with more frequent ambulatory and emergency department visits, as well as increased inhaled and oral corticosteroid use. In conclusion, overweight, moderate, and extreme obesity are associated with higher odds of asthma in children and adolescents, although the association varies widely with race/ethnicity. Increasing BMI among youth with asthma is associated with higher consumption of corticosteroids and emergency department visits. PMID- 22252051 TI - Disruption of memory reconsolidation impairs storage of other, non-reactivated memory. AB - Two hypotheses were tested in this study. First, blockade of neural activity by lidocaine immediately following the retrieval of a memory may impair the reconsolidation and subsequent expression of that memory. Second, a non-retrieved memory would not be affected by this lidocaine treatment. Since the basolateral nucleus of the amygdala (BLA) is involved in emotion-related memory, an intra-BLA lidocaine infusion was used immediately after the retrieval of two emotion related memories, the step-through passive avoidance response (PA) and cocaine induced conditioned place preference (CPP). Intra-BLA lidocaine infusion immediately after cocaine-induced CPP retrieval diminished CPP magnitude in retests. However, intra-BLA lidocaine infusion alone did not affect cocaine induced CPP performance. Intra-BLA lidocaine infusion immediately after PA retrieval decreased PA performance in retests. Omission of PA retrieval procedure, intra-BLA lidocaine infusion did not affect subsequent PA performance. Surprisingly, intra-BLA lidocaine infusion immediately following the retrieval of PA or cocaine-induced CPP diminished both PA and cocaine-induced CPP performance in the retests. Finally, Fos-staining results revealed that a number of BLA neurons were activated by the retrieval of both cocaine-induced CPP and PA. We conclude that inactivation of neural activity in BLA immediately following retrieval of a fear or cocaine-conditioned memory can impair subsequent expression of both memories. More importantly, retrieval of a memory does not seem to be an absolute condition for rapidly changing the memory. PMID- 22252050 TI - Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation. AB - BACKGROUND: Tocotrienols (T3) and tocopherols (T), both members of the natural vitamin E family have unique biological functions in humans. T3 are detected in circulating human plasma and lipoproteins, although at concentrations significantly lower than alpha-tocopherol (alpha-T). T3, especially alpha-T3 is known to be neuropotective at nanomolar concentrations and this study evaluated the postprandial fate of T3 and alpha-T in plasma and lipoproteins. METHODS: Ten healthy volunteers (5 males and 5 females) were administered a single dose of vitamin E [526 mg palm tocotrienol-rich fraction (TRF) or 537 mg alpha-T] after 7 d pre-conditioning on a T3-free diet. Blood was sampled at baseline (fasted) and 2, 4, 5, 6, 8, and 24 h after supplementation. Concentrations of T and T3 isomers in plasma, triacylglycerol-rich particles (TRP), LDL, and HDL were measured at each postprandial interval. RESULTS: After TRF supplementation, plasma alpha-T3 and gamma-T3 peaked at 5 h (alpha-T3: 4.74 +/- 1.69 MUM; gamma-T3: 2.73 +/- 1.27 MUM). delta-T3 peaked earlier at 4 h (0.53 +/- 0.25 MUM). In contrast, alpha-T peaked at 6 h (30.13 +/- 2.91 MUM) and 8 h (37.80 +/- 3.59 MUM) following supplementation with TRF and alpha-T, respectively. alpha-T was the major vitamin E isomer detected in plasma, TRP, LDL, and HDL even after supplementation with TRF (composed of 70% T3). No T3 were detected during fasted states. T3 are detected postprandially only after TRF supplementation and concentrations were significantly lower than alpha-T. CONCLUSIONS: Bio-discrimination between vitamin E isomers in humans reduces the rate of T3 absorption and affects their incorporation into lipoproteins. Although low absorption of T3 into circulation may impact some of their physiological functions in humans, T3 have biological functions well below concentration noted in this study. PMID- 22252052 TI - [Update on the management of desmoids tumors]. AB - Desmoids tumors are rare fibrous tumors of soft tissue. These tumors are located in the abdominal wall, abdomen or extra abdominal. Parietal location is very common among pregnant women and in postpartum period. Hormonal factors are implicated as well. Starting from the observation of 30-year-old patient, in whom a soft tissue mass in the abdominal wall was discovered in the post-partum period, we then emphasize the potential role of cross sectional imaging (ultrasound, CT and especially MRI) in the diagnostic approach, which was confirmed by postoperative pathological examination. PMID- 22252053 TI - [Study of surplus cost of robotic assistance for radical hysterectomy, versus laparotomy and standard laparoscopy]. AB - OBJECTIVES: The study purpose was to compare the costs among robotic, laparoscopic and open radical hysterectomy for cervical cancer. PATIENTS AND METHODS: Thirty-seven patients underwent robotic radical hysterectomy for cervical cancer. Cases were performed by three surgeons, at two institutions, and were retrospectively reviewed to perform a cost comparison between all three modalities. We included costs for edible materials in anesthesia and surgery, but costs for staff and indirect financial expenses were excluded. Those data are compared to open and laparoscopic radical hysterectomy data. RESULTS: The average cost for robotic assistance presented a surplus of 1796 euros compare to laparotomy and 1313 euros compare to standard laparoscopy in 2008, and 1320 and 837 euros respectively. DISCUSSION AND CONCLUSION: The average cost for radical hysterectomy was highest for robotic, followed by standard laparoscopy, and least for laparotomy. However, over only 2 years of use, this difference tends to decrease. Medico-economic impact is the main restraint for robotic assistance development, and needs to be assessed permanently. PMID- 22252054 TI - [Hymenal examination of under age children with a context of sexual assault]. AB - The hymeneal examination is often considered as the key of the gyneacological examination of a young girl victim of sexual assault, mainly because the concept of penetration is important under the French criminal code. However, the amount medical literature related to this topic is poor. The hymen examination must be conducted under strict conditions, by qualified personnel and as soon as possible after the alleged assault.The only kind of anomaly that can confirm a penetration is an injury to the posterior hymen extending up its base. The sensitivity of this sign is, however, low and its absence does not suggest that of penetration. A vaginal penetration does not always break the hymen, especially among adolescents. Moreover, the hymen can heal and thus it makes the examination difficult when it occurs a long time after the facts. Examination of the hymen is rarely the decisive factor in the forensic assessment of a young victim of sexual assault. PMID- 22252055 TI - Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta. AB - The placenta is essential for sustaining the growth of the fetus. An increased endoplasmic reticulum (ER) stress has been associated with the impaired placental and fetal development. Cadmium (Cd) is a potent teratogen that caused fetal malformation and growth restriction. The present study investigated the effects of maternal Cd exposure on placental and fetal development. The pregnant mice were intraperitoneally injected with CdCl(2) (4.5mg/kg) on gestational day 9. As expected, maternal Cd exposure during early limb development significantly increased the incidences of forelimb ectrodactyly in fetuses. An obvious impairment in the labyrinth, a highly developed tissue of blood vessels, was observed in placenta of mice treated with CdCl(2). In addition, maternal Cd exposure markedly repressed cell proliferation and increased apoptosis in placenta. An additional experiment showed that maternal Cd exposure significantly upregulated the expression of GRP78, an ER chaperone. Moreover, maternal Cd exposure induced the phosphorylation of placental eIF2alpha, a downstream molecule of PERK signaling. In addition, maternal Cd exposure significantly increased the level of placental CHOP, another target of PERK signaling, indicating that the unfolded protein response (UPR) signaling was activated in placenta of mice treated with CdCl(2). Interestingly, alpha-phenyl-N-t butylnitrone, a free radical spin-trapping agent, significantly alleviated Cd induced placental ER stress and UPR. Taken together, these results suggest that reactive oxygen species (ROS)-mediated ER stress might be involved in Cd-induced impairment on placental and fetal development. Antioxidants may be used as pharmacological agents to protect against Cd-induced fetal malformation and growth restriction. PMID- 22252056 TI - The nature of the magnetism in quasi-2D layered alpha-Ni(OH)2. AB - The two layered hexagonal hydroxides of Ni are beta-Ni(OH)(2) and alpha Ni(OH)(2); beta-Ni(OH)(2) is now known to be an antiferromagnet whereas the nature of the magnetism in alpha-Ni(OH)(2) is not yet well established. Here, the magnetic properties of alpha-Ni(OH)(2) with lattice parameters a = 3.02 A and c = 8.6 A, and flower-like morphology with petal thickness of approximately equal to 50 A are reported. Temperature (2-300 K) and magnetic field (up to 65 kOe) dependence of the magnetization and ac susceptibility at f = 0.1-1000 Hz were measured. Analysis of the data yields ferromagnetic ordering in the system with T(C) is approximately equal to 16 K. In addition, a nanosize related blocking temperature T(B) = 8 K and spin-glass-like ordering of the surface spins near 3.5 K are inferred from the ac frequency and dc magnetic field dependence of these transitions. Fitting to the high temperature series and quasi-2D nature of the system is used to determine J(1)/k(B) = 4.38 K (J(2)/k(B) = 0.14 K) for the intraplane (interplane) exchange coupling between the Ni(2+) ions. PMID- 22252057 TI - Stigmas and stereotypes. PMID- 22252059 TI - Increasing patient education for heart failure. PMID- 22252062 TI - Safety tips for intense pulsed light therapy. PMID- 22252066 TI - Echoes of 3 west. PMID- 22252068 TI - Wake up to better PowerPoint presentations. PMID- 22252069 TI - Culturally competent care: are we there yet? PMID- 22252070 TI - Smoking cessation. PMID- 22252071 TI - Don't abandon the "second victims" of medical errors. PMID- 22252072 TI - Finding personal freedom in nursing. PMID- 22252073 TI - Vascular access challenges: small, fragile veins and tissue-paper skin. PMID- 22252074 TI - Using elastomeric infusion pumps for traumatic rib fracture pain. PMID- 22252075 TI - What's the significance of the ANC? PMID- 22252076 TI - Malignant spinal cord compression. PMID- 22252077 TI - Microwave-assisted synthesis of highly luminescent CdSeTe@ZnS-SiO2 quantum dots and their application in the detection of Cu(II). AB - Highly luminescent and low toxic glutathione-capped CdSeTe@ZnS-SiO(2) quantum dots were successfully synthesized via a promising microwave strategy, and then applied in the detection of Cu(2+). PMID- 22252080 TI - Should androgen supplementation be used for poor ovarian response in IVF? AB - Poor ovarian response is reported in 9-24% of IVF cycles. Several interventions have been proposed to improve the outcome, although evidence to support these has been scant. There has been interest in the use of adjuvant androgens in this context and a recent worldwide survey showed that nearly a quarter of IVF clinicians used dehydroepiandrosterone (DHEA) in poor responders. We examine the rationale for the use of adjuvant androgens and suggest that the current clinical uncertainty should be addressed by a randomized controlled trial of DHEA in poor responders. PMID- 22252081 TI - Alkaline and neutral Comet assay profiles of sperm DNA damage in clinical groups. AB - BACKGROUND: The analysis of sperm DNA fragmentation has become a new marker to predict male infertility, and many techniques have been developed. The sperm Comet assay offers the possibility of differentiating single- and double-stranded DNA (ssDNA and dsDNA) breaks, which could have different effects on fertility. The objective of this study was to perform a descriptive characterization of different groups of patients, such as those with asthenoteratozoospermic (ATZ) with or without varicocele, oligoasthenoteratozoospermic (OATZ) or balanced chromosome rearrangements, as compared with fertile donors. The Comet assay was used to investigate sperm samples for ssDNA and dsDNA breaks. METHODS AND RESULTS: The analysis of alkaline and neutral Comet assays in different groups of patients showed different sperm DNA damage profiles. Most fertile donors presented low values for ssDNA and dsDNA fragmentation (low-equivalent Comet profile), which would be the best prognosis for achieving a pregnancy. OATZ, ATZ and ATZ with varicocele presented high percentages of ssDNA and dsDNA fragmentation (high-equivalent Comet assay profile), ATZ with varicocele being associated with the worst prognosis, due to higher levels of DNA fragmentation. Rearranged chromosome carriers display a very high variability and, interestingly, two different profiles were seen: a high-equivalent Comet assay profile, which could be compatible with a bad prognosis, and a non-equivalent Comet assay profile, which has also been found in three fertile donors. CONCLUSIONS: Comet assay profiles, applied to different clinical groups, may be useful for determining prognosis in cases of male infertility. PMID- 22252082 TI - Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis. AB - BACKGROUND: The objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA). METHODS: Three hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was >= 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model. RESULTS: After multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3). CONCLUSIONS: In case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy. PMID- 22252083 TI - Glucose-induced increase in circulating progenitor cells is blunted in polycystic amenorrhoeic subjects. AB - BACKGROUND: Glucose-induced kinetics of bone marrow-derived stem cells in healthy females is presently unknown. The objectives of this study were to determine whether circulating levels of CD133(+), CD34(+) and CD133(+)CD34(+) cells increase in response to glucose load in healthy females and whether the kinetics is altered in amenorrhoeic women. The other objective of the work was to compare the endothelial differentiation potential of peripheral blood-derived endothelial progenitor cells (EPCs) from healthy versus amenorrhoeic women. METHODS: In this case-control study, 44 amenorrhoeic subjects and 36 age-matched females with no menstrual disturbance were recruited at Apollo Hospitals, a Tertiary health care center in Chennai, India. Circulating bone marrow-derived stem cells were measured by two color direct flow cytometry. Cultured progenitor cells were characterized at Day 7 and 14 for expression of endothelial markers and production of nitric oxide (NO) via immunofluoroscence. RESULTS: The amenorrhoeic subjects were insulin resistant with homeostatic model of assessment of insulin resistance values of 3.33 +/- 0.3 versus 1.75 +/- 0.148 observed for controls (P< 0.0001). Among the amenorrhoeic subjects, 38 subjects had polycystic ovaries with no signs of hyperandrogenism. Fasting levels of CD133(+), CD34(+) and CD133(+)CD34(+) cells were reduced in amenorrhoeic subjects (P< 0.001). There was a 1.5 to 2-fold increase in the circulating levels of these cells in response to 75 g oral glucose challenge at 1 and 2 h post-load conditions in controls, which was significantly blunted for CD133(+) (P< 0.001) and CD133(+)CD34(+) (P< 0.001) cells in amenorrhoeic subjects. A positive correlation was observed between estrogen and fasting CD133(+) (r= 0.205, P= 0.070), CD34(+) (r= 0.249, P= 0.027) and CD133(+)CD34(+) (r= 0.217, P= 0.055) cell counts. Additionally, fasting counts for CD34(+) and CD133(+)CD34(+) cells positively correlated with FSH and inversely correlated with LH and C-peptide in the polycystic group. Cultured cells from polycystic subjects exhibited reduced adherence to fibronectin and expressed lower levels of endothelial nitric-oxide synthase and NO. CONCLUSIONS: Oral glucose-induced increase in circulating numbers of CD133(+) and CD133(+)CD34(+) cells and endothelial differentiation potential of peripheral blood-derived EPCs is attenuated in insulin resistant amenorrhoeic subjects. PMID- 22252084 TI - Gonadotrophin-releasing hormone antagonist induces apoptosis in human decidual stromal cells: effect on GADD45alpha and MAPK signaling. AB - BACKGROUND: The impact of gonadotrophin-releasing hormone (GnRH) antagonists used in IVF protocols on endometrial tissue remodeling, embryo implantation and the programming of early pregnancy is still unclear. Pregnancy and infant outcomes after treatment with GnRH antagonist for IVF are particular causes of concern. The purpose of this study was to investigate the mechanisms of GnRH antagonist induced apoptosis of human decidual stromal cells and the effects of GnRH antagonist on the activation of ERK1/2, JNK and GADD45alpha signaling. METHODS: Human decidual stromal cells were isolated from decidual tissue. The expression of GnRH-I receptor (GnRH-IR) was examined by immunoblot analysis and immunohistochemistry. The cells were treated with the GnRH antagonist, Cetrorelix. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay was used to examine cell viability. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling assay were used as indicators for cell apoptosis. Mitogen-activated protein kinase function was tested for the elucidation of intracellular signalings through the pre-treatment of stromal cells with ERK1/2 (U0126) and JNK (SP600125) inhibitors prior to the Cetrorelix treatment. To characterize the signaling pathway of GnRH antagonist, the endogenous GnRH-IR and GADD45alpha were knocked down by specific small interfering RNA (siRNA). RESULTS: The GnRH-IR is expressed in human decidual stromal cells. Treatment with GnRH antagonist decreased cell viability, induced apoptosis and increased the phosphorylation of ERK1/2 and JNK. Cells pre-treated with U0126 and SP600125 were rescued from the GnRH antagonist-mediated inhibition of cell growth and did not exhibit GnRH antagonist-induced apoptosis and downstream GADD45alpha signaling. GnRH antagonist-mediated cell growth inhibition and apoptosis were also abolished by the knockdown of the endogenous GnRH-IR or GADD45alpha with siRNAs. CONCLUSIONS: The GnRH antagonist suppresses the growth of decidual stromal cells by inducing apoptosis through the GnRH-IR and through the ERK1/2 and JNK phosphorylation-dependent induction of GADD45alpha signaling. These results indicate that ERK1/2, JNK and GADD45alpha are coordinately regulated by the GnRH antagonist through the GnRH-IR to induce apoptosis in human decidual stromal cells, suggesting that the GnRH antagonist may play a role in decidual programming in human pregnancy. PMID- 22252085 TI - Vascular architecture of human uterine cervix visualized by corrosion casting and scanning electron microscopy. AB - BACKGROUND: In contrast to the uterine corpus, the vascular architecture of the human cervix has been the subject of only a few studies, mostly dealing with the ectocervical mucosal vessels. This study presents the vascular system of the cervical wall surrounding the endocervical canal visualized by the best currently available technique, corrosion casting combined with scanning electron microscopy. METHODS: Uteri collected at autopsy (n= 20) were perfused via afferent vessels with fixative followed by Mercox resin and corroded after polymerization of the resin. The obtained vascular casts of the cervix visualizing all vessels including capillaries were examined in the scanning electron microscope. RESULTS: The vascular system of the cervix was nearly completely replicated in only two (10%) of the samples. In the wall of the cervix, four distinct vascular zones surrounding the endocervical canal were observed: (i) the outer zone containing larger vessels, arteries and veins of 0.3 1 mm diameter; (ii) the zone containing arterioles and venules; (iii) the zone of endocervical mucosal capillaries showing a very high density, parallel arrangement and relatively few interconnections and (iv) the innermost, subepithelial zone containing small veins running along the endocervical canal. CONCLUSIONS: Despite the loss of the delicate ectocervical mucosal vessels from the cast during the corrosion step, we have successfully visualized the majority of the cervical vasculature. The vascular pattern of the human cervix, especially that of the endocervical mucosa, may facilitate the adaptation of the cervical vasculature to the extensive remodeling of the cervix during parturition. PMID- 22252086 TI - Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support. AB - BACKGROUND: Triggering ovulation by GnRH agonist (GnRHa) in GnRH antagonist IVF protocols coupled with adequate luteal phase support has recently been suggested as a means to prevent ovarian hyperstimulation syndrome (OHSS). Our objective was to examine the outcome of fresh embryo transfer (f-ET) after triggering ovulation by GnRHa and providing intensive luteal phase supplementation, compared with that of the next first frozen-thawed embryo transfer (ft-ET) after cycles with the same protocol and cryopreservation of all the embryos. METHODS: We performed a cohort study at a university-based IVF clinic. The study population was patients at high risk for OHSS. A daily dose of 50 mg i.m. progesterone in oil and 6 mg of oral 17-beta-estradiol initiated on oocyte retrieval day in the f-ET group (n= 70). In the ft-ET group (n= 40) the embryos were cryopreserved and transferred in the next cycle. RESULTS: The live birth rate per f-ET was 27.1 versus 20% in the ft-ET groups [P = 0.4; rate ratio = 1.36 (0.65-2.81)]. The implantation, pregnancy and spontaneous abortion rates were comparable in both groups. None of the patients developed OHSS. CONCLUSIONS: In this observational cohort study, we showed that triggering ovulation with GnRHa and intensive luteal phase support is a promising new modality to prevent OHSS without the cost of cycle cancellation, ET deferral and reduced clinical pregnancy rates. Confirmation of these findings by RCTs is now required. PMID- 22252087 TI - Association between oocyte donation and maternal and perinatal outcomes in women aged 43 years or older. AB - BACKGROUND: Although older maternal age is a risk factor for pregnancy complications, an increasing number of women delay conception until the age of 40, and some must resort to IVF with oocyte donation. Our objective was to study the association between IVF, both with and without oocyte donation, and maternal and perinatal outcomes in a population of older women. METHODS: This retrospective study covered all women, aged 43 or more, who gave birth between 2008 and 2010. Univariate and multivariate analyses with logistic regression models were used to compare maternal and perinatal outcomes as a function of mode of conception: without IVF, with IVF using own oocytes or with IVF and oocyte donation. RESULTS: The study included 380 women, including 40 who had IVF without oocyte donation (10.5%) and 104 who had both (27.4%). There were 326 singleton and 54 multiple pregnancies. Overall, the complication rate was high: 8.7% pre eclampsia, 6.1% gestational diabetes, 20.2% preterm delivery and 8.2% very preterm delivery (before 33 weeks), 44.8% Cesarean sections and 7.4% severe post partum hemorrhage (PPH). The pre-eclampsia rate differed significantly between the groups (3.8% after no IVF, 10.0% after IVF only and 19.2% after IVF with oocyte donation, P< 0.001). After adjustment, the risk of pre-eclampsia was significantly higher in women with donated oocytes compared with pregnant women without IVF [adjusted OR = 3.3 (1.2-8.9)]. The rate of twin pregnancy was significantly higher in women with IVF and oocyte donation (39.4 versus 15.0% with IVF only and 2.5% without IVF, P< 0.001). Twin pregnancy was significantly associated with the risk of preterm delivery [adjusted OR = 8.9 (4.0-19.9)] and PPH [adjusted OR = 3.5 (1.3-9.5)]. CONCLUSION: In women aged 43 years or older, pregnancies obtained by IVF with oocyte donation are associated with higher rates of pre-eclampsia and twin pregnancies than those obtained without IVF or with IVF using their own oocytes. PMID- 22252088 TI - New cases of accessory and cavitated uterine masses (ACUM): a significant cause of severe dysmenorrhea and recurrent pelvic pain in young women. AB - BACKGROUND: To raise awareness about the accessory and cavitated uterine masses (ACUM) with functional endometrium as a different entity from adult adenomyosis and to highlight the importance of a correct diagnosis, we studied four new cases of ACUM and 15 cases reported as juvenile cystic adenomyoma (JCA) by reviewing the literature from the last year. This entity is problematic because of a broad differential diagnosis, including rudimentary and cavitated uterine horns; and is generally underdiagnosed, being more frequent than previously thought. METHODS: We report four cases of young women who underwent surgery in our hospital from January to July 2011 after presenting with an ACUM. We also reviewed and tabulated the cases from literature beginning in 2010. Main outcome measures were diagnostic tools, surgical and histopathological findings and improvement of symptoms. RESULTS: The addition of the four cases reported here to the 15 published as JCA raises the total number of cases of ACUMs to 19, which is more than all of the cases reported prior to 2010. In our cases, it is interesting to highlight that one of them also had an adjacent accessory rudimentary tube and another had two ACUMs at the same location. All patients suffered from severe dysmenorrhea and pelvic pain and were young women. Suspicion, transvaginal ultrasound and magnetic resonance image were found to be the best diagnostic tools. Most of the cases were treated by laparoscopic tumorectomy. CONCLUSIONS: ACUMs are generally underdiagnosed and often reported as JCAs but they are not adenomyosis. Early surgical treatment involving the laparoscopic or laparotomic removal of the mass could prevent the usual prolonged suffering of these young women. In our opinion, this entity is a new variety of Mullerian anomaly. PMID- 22252089 TI - Relationship quality in lesbian and heterosexual couples undergoing treatment with assisted reproduction. AB - BACKGROUND: One of the major factors impacting on a couple's relationship is the desire to have children. To many couples having a child is a confirmation of their love and relationship and a means to deepen and develop their intimate relationship. At the same time parental stress can impact on relationship quality. Relationship quality in lesbian couples is, currently, sparsely studied. The aim of the present study was to compare lesbian and heterosexual couples' perceptions of their relationship quality at the commencement of assisted reproduction, and to relate this to background data such as educational level, having previous children and, for lesbian couples, the use of a known versus anonymous donor. METHODS: The present study is part of the prospective longitudinal 'Swedish study on gamete donation', including all fertility clinics performing donation treatment in Sweden. Of a consecutive cohort of 214 lesbian couples about to receive donor insemination and 212 heterosexual couples starting regular IVF treatment, 166 lesbian couples (78% response) and 151 heterosexual couples (71% response) accepted participation in the study. At commencement of assisted reproduction participants individually completed questionnaires including the instrument 'ENRICH', which is a standardized measure concerning relationship quality. RESULTS: In general, the couples rated their relationship quality as good, the lesbian couple better than the heterosexuals. In addition, the lesbian women with previous children assessed their relationship quality lower than did the lesbian woman without previous children. For heterosexual couples previous children did not influence their relationship quality. Higher educational levels reduced the satisfaction with the sexual relationship (P = 0.04) for treated lesbian women, and enhanced the rating of conflict resolution for treated lesbian women (P = 0.03) and their partners (P = 0.02). Heterosexual women with high levels of education expressed more satisfaction with communication in their relationship (P = 0.02) than did heterosexual women with lower educational levels. CONCLUSIONS: In this Swedish study sample of lesbian and heterosexual couples' relationships, we found that they were generally well adjusted and stable in their relationships when starting treatment with donated sperm or IVF, respectively. However, where lesbian women had children from a previous relationship, it decreased relationship quality. For the heterosexual couples previous children did not affect relationship quality. PMID- 22252090 TI - The effect of combined oral contraceptives and age on dysmenorrhoea: an epidemiological study. AB - BACKGROUND: Combined oral contraceptives (COCs) are widely advocated as treatment for primary dysmenorrhoea, but their efficacy has been questioned in a Cochrane review. The aim of this study was to evaluate COCs and the influence of age on the severity of dysmenorrhoea. METHODS: Postal questionnaires regarding weight/height, contraception, pregnancy history and other reproductive health factors were sent to random samples of 19-year-old women born in 1962 (n = 656), 1972 (n = 780) and 1982 (n = 666) resident in the city of Gothenburg in 1981, 1991 and 2001. The responders were assessed again 5 years later at the age of 24 years. Current severity of dysmenorrhoea was measured on each occasion by a verbal multidimensional scoring system (VMS) and by a visual analogue scale (VAS). RESULTS: The severity of dysmenorrhoea was lower (P< 0.0001) in COC users compared with non-users. In a longitudinal analysis of the severity of dysmenorrhoea, COC use and increasing age, independently of each other, were associated with the severity of dysmenorrhoea (COC use, VMS score: a reduction of 0.3 units/VAS: a reduction of 9 mm, both P< 0.0001; increasing age, VMS score: a reduction of 0.1 units per 5 years, P< 0.0001/VAS: a reduction of 5 mm per 5 years, P< 0.0001). Childbirth also reduced the severity of dysmenorrhoea (VAS, P< 0.01 with a reduction of 7 mm). Women from the 82-cohort reported a greater severity of dysmenorrhoea compared with the 62 and 72 cohorts at both 19 and 24 years of age. CONCLUSIONS: In this longitudinal case-control study, COC use and increasing age, independent of each other, reduced the severity of dysmenorrhoea. COC use reduced the severity of dysmenorrhoea more than increasing age and childbirth. There was a trend over time regarding the severity of dysmenorrhoea where women from the 82-cohort reported a greater severity of dysmenorrhoea compared with the 62 and 72 cohorts. PMID- 22252091 TI - Small molecule screening identifies targetable zebrafish pigmentation pathways. AB - Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investigate the effects of a few of these compounds in further detail. We identified and confirmed 57 compounds that altered pigment cell patterning, number, survival, or differentiation. Additional tissue targets and toxicity of small molecules are also discussed. Given that the majority of cell types, including pigment cells, are conserved between zebrafish and other vertebrates, we present these chemicals as molecular tools to study developmental processes of pigment cells in living animals and emphasize the value of zebrafish as an in vivo system for testing the on- and off-target activities of clinically active drugs. PMID- 22252092 TI - Regioselectivity of aliphatic versus aromatic hydroxylation by a nonheme iron(II) superoxo complex. AB - Many enzymes in nature utilize molecular oxygen on an iron center for the catalysis of substrate hydroxylation. In recent years, great progress has been made in understanding the function and properties of iron(IV)-oxo complexes; however, little is known about the reactivity of iron(II)-superoxo intermediates in substrate activation. It has been proposed recently that iron(II)-superoxo intermediates take part as hydrogen abstraction species in the catalytic cycles of nonheme iron enzymes. To gain insight into oxygen atom transfer reactions by the nonheme iron(II)-superoxo species, we performed a density functional theory study on the aliphatic and aromatic hydroxylation reactions using a biomimetic model complex. The calculations show that nonheme iron(II)-superoxo complexes can be considered as effective oxidants in hydrogen atom abstraction reactions, for which we find a low barrier of 14.7 kcal mol(-1) on the sextet spin state surface. On the other hand, electrophilic reactions, such as aromatic hydroxylation, encounter much higher (>20 kcal mol(-1)) barrier heights and therefore are unlikely to proceed. A thermodynamic analysis puts our barrier heights into a larger context of previous studies using nonheme iron(IV)-oxo oxidants and predicts the activity of enzymatic iron(II)-superoxo intermediates. PMID- 22252093 TI - Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users. AB - BACKGROUND: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known. OBJECTIVES: In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated. PATIENTS/METHODS: In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (< 2 and > 3.5) or severe overanticoagulation (INR > 6) for different time periods after treatment initiation. RESULTS: Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6 months. CONCLUSIONS: Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy. PMID- 22252094 TI - Symptom specificity in the acute treatment of Major Depressive Disorder: a re analysis of the treatment of depression collaborative research program. AB - BACKGROUND: Antidepressant medications, Cognitive-Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT) are equally efficacious in the acute treatment of Major Depressive Disorder (MDD). Nevertheless, remission rates remain unacceptably low. Examining the differential time course of remission of specific symptom clusters across treatments may provide a basis for assigning patients to treatments that have the highest chance of being effective. METHODS: This study re-analyzed data from the NIMH Treatment of Depression Collaborative Research Project (TDCRP), which included 250 adult outpatients with MDD randomized to 16 weeks of CBT, IPT, imipramine+clinical management (IMI-CM), or pill placebo (PLA CM). We derived four symptom factors from the 23-item Hamilton Depression Rating Scale, and three symptom factors from the Beck Depression Inventory. Within subject hierarchical regression models were specified to examine the linear and quadratic patterns of symptom remission over five assessment points. RESULTS: IMI CM produced a more rapid rate of remission than CBT or IPT for both the somatic/vegetative and cognitive-affective symptoms of MDD. There were no statistically significant differences in the rates of improvement of any of the symptom factors between the IMI-CM and PLA-CM groups. LIMITATIONS: Some core symptoms of depression were excluded due to low factor loadings. Past research has argued that the CBT arm in the TDCRP may have been weak. CONCLUSIONS: We failed to find evidence that treatments act preferentially on specific symptom clusters. Therefore, the symptoms of MDD may be inter-dependent when it comes to their courses of remission in treatment. PMID- 22252095 TI - Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. AB - BACKGROUND: Despite the old Kraepelinean concept that bipolar disorder (BD) does not evolve with cognitive decline, the presence of cognitive impairment, especially executive dysfunction has been recognized in BD patients. Brain derived neurotrophic factor (BDNF) and pro-inflammatory molecules are important contributors to the pathophysiology of BD, and imbalance in peripheral levels of these molecules may be implicated in the cognitive decline observed in BD patients. We aimed to investigate the executive performance of BD type I euthymic patients and its relation with the plasma levels of BDNF, TNF-alpha and its related soluble receptors (sTNFR1 and sTNFR2). METHODS: We evaluated executive functioning through the Frontal Assessment Battery (FAB). Plasma levels of BDNF, TNF-alpha, sTNFR1 and sTNFR2 were measured using enzyme-linked immunosorbent assay (ELISA) in 25 euthymic type I BD patients and 25 age and gender matched healthy controls. RESULTS: BD patients had an impairment in executive functioning (p<0.006), particularly sensitivity of interference (p=0.02), inhibitory control (p=0.02), and increased BDNF plasma levels (p=0.001) in comparison with controls. Plasma levels of TNF-alpha were correlated with inhibitory control in BD patients (rho=0.50, p=0.02) while motor programming was negatively correlated with sTNFR2 plasma levels (rho=-0.47, p=0.02) in controls. Executive function correlated with age and MMSE, but not with BDNF, neither was influenced by psychiatric and clinical comorbidities nor medications in use. CONCLUSION: BDNF is altered in BD but do not correlate with executive functioning. PMID- 22252096 TI - Synthesis of inorganic polymers using fly ash and primary lead slag. AB - The present work reports on the synthesis and properties of inorganic polymers ("geopolymers") made of 100% fly ash from lignite's combustion, 100% primary lead slag and mixtures of the two. In the inorganic polymers with both fly ash and lead slag the main crystalline phases detected are wustite, magnetite, sodium zinc silicate, quartz, anorthite, and gehlenite; litharge partially dissolves. FTIR analysis in these samples revealed that the main peaks and bands of end members also exist, along with a new amorphous reaction product. In terms of microstructure, both fly ash and lead slag dissolve and contribute in the binding phase whereas the larger particles act as aggregates. For an increasing lead slag in the composition, the binding phase is changing in chemistry and reaches PbO values higher than 50 wt.% for the 100% lead slag inorganic polymer. Regarding the properties of fly ash and lead slag inorganic polymers, compressive strength is higher than 35 MPa in all cases and water absorption diminishes as the lead slag content increases. A comparison of leaching results before and after polymerisation reveals that pH is an important factor as Pb is immobilised in the binding phase, unlike Zn and As. PMID- 22252097 TI - Minocycline inhibits growth of epithelial ovarian cancer. AB - OBJECTIVE: These studies were designed to determine whether minocycline inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved. MATERIALS AND METHODS: The effect of minocycline on ovarian cancer cell proliferation, cell cycle progression and apoptosis was assessed using human ovarian cancer cell lines OVCAR-3, SKOV-3 and A2780. Then, the capacity of minocycline to inhibit growth of OVCAR-3 xenografts in female nude mice was examined. RESULTS: Minocycline inhibited cell proliferation and colony formation, down-regulated cyclins A, B and E leading to arrest of cells in the G(0) phase of the cycle and suppression of DNA synthesis. Furthermore, exposure of these cells to minocycline led to DNA laddering, activation of caspase-3 and cleavage of PARP 1. In nude mice bearing sub-cutaneous tumors, minocycline suppressed tumor proliferation index, angiogenesis and tumor growth. CONCLUSION: These findings provide the initial basis for further evaluation of minocycline in the treatment of ovarian cancer. PMID- 22252098 TI - Characteristics of success in mentoring and research productivity - a case control study of academic centers. AB - OBJECTIVES: While mentoring has been associated with research productivity, the specific characteristics of successful mentoring have not been well studied. Thus, we performed a case-control study to identify characteristics of successful mentoring programs. METHODS: Institutions were divided based on number of plenary research presentations at an annual society meeting over 6years. Case institutions (Group A) had more presentations vs. controls (Group B). A survey of professors and research fellows assessed characteristics of their mentoring program. Chi-square and logistic regression analyses were performed. RESULTS: Of 159 surveyed, response rates were 46% for professors and 51% for fellows. Compared to Group B, Group A was more likely to have: an additional year of protected fellowship research training (62% vs. 24%; p=0.003), an established program to connect a mentor and mentee with similar research interests (52% vs. 27%; p=0.049), methods to provide feedback to mentors (62% vs. 29%; p=0.01), require mentee research progress reports (45% vs. 21%; p=0.047), and report ease of identifying a mentor (90% vs. 69%; p=0.046). On multivariate analyses, the additional year of research training (OR=7.53, 95% CI: 2.10-27.09; p=0.002) and ease at identifying a research mentor (OR=7.45, 95% CI: 1.44-38.6; p=0.017) remained as independent factors associated with higher research productivity. CONCLUSIONS: Our data suggest that programs can enhance research productivity with the incorporation of accountability features including formalized reports of progress and mentorship feedback in fellowship training. Facilitating the identification of a mentor and providing an additional year of research may be independent factors associated with research productivity. PMID- 22252099 TI - Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. AB - OBJECTIVES: To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines. METHODS: ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway. RESULTS: Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC(50) values of 1-5nM and 5-10nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index<1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line. CONCLUSIONS: Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer. PMID- 22252100 TI - Synergistic effect on biofilm formation between Fusobacterium nucleatum and Capnocytophaga ochracea. AB - The formation of dental plaque biofilm by specific Gram-negative rods and spirochetes plays an important role in the development of periodontal disease. The aim of this study was to characterize biofilm formation by Fusobacterium nucleatum and Capnocytophaga ochracea. Coaggregation between F. nucleatum and Capnocytophaga species was determined by visual assay. Biofilm formation was assessed by crystal violet staining. Enhancement of biofilm formation by F. nucleatum via soluble factor of C. ochracea was evaluated by addition of culture supernatant and a two-compartment separated co-culture system. Production of autoinducer-2 by the tested organisms was evaluated using Vibrio harveyi BB170. F. nucleatum strains coaggregated with C. ochracea ATCC 33596 or ONO-26 strains. Ethylenediamine tetraacetic acid, N-acetyl-d-galactosamine or lysine inhibited coaggregation. Heating or proteinase K treatment of F. nucleatum cells affected coaggregation, whereas the same treatment of C. ochracea cells did not. Co culture of F. nucleatum with C. ochracea in the same well resulted in a statistically significant increase in biofilm formation. Enhancement of F. nucleatum biofilm formation by a soluble component of C. ochracea was observed using the two-compartment co-culture system (P < 0.05) and confirmed by addition of culture supernatant of C. ochracea (P < 0.01). The present findings indicate that induction of coaggregation and intracellular interaction by release of a diffusible molecule by C. ochracea play a significant role in the formation of biofilm by F. nucleatum and C. ochracea. PMID- 22252102 TI - On the magnetic structure of PrMn2O5: a neutron diffraction study. AB - The long-range magnetic ordering of PrMn(2)O(5) has been studied on polycrystalline samples from neutron diffraction and specific heat measurements. The onset of antiferromagnetic ordering is observed at T(N) ~ 25 K. In the temperature interval 18 K < T < 25 K the magnetic structure is defined by the propagation vector k(1) = (1/2,0,0). Below 18 K, some additional magnetic satellites appear in the NPD patterns, which are indexed with k(2) = (0,0,1/2). Therefore, below 18 K the magnetic structure consists of two independent magnetic domains, defined by the propagation vectors k(1) and k(2). The magnetic structure of the k(1)-domain is given by the basis vectors (C(x),0,0) and (C(x)',0,0) for Mn(4h) and Mn(4f), respectively. In the k(2)-domain, the magnetic structure is defined by the basis vectors (0,0,G(z)) and (F(x)',G(y)',0) for Mn(4h) and Mn(4f), respectively. At T = 1.5 K, for the magnetic phase associated with k(1), the magnetic moments of the Mn atoms at the 4h and 4f sites are 1.82(7) and 1.81(6) MU(B), respectively; for the magnetic phase associated with k(2), the magnetic moments for the Mn(4h) and Mn(4f) atoms are 0.59(5) and 2.62(5) MU(B), respectively. PMID- 22252101 TI - Clinical significance of serum lipids in idiopathic pulmonary alveolar proteinosis. AB - BACKGROUND: It is well known that pulmonary alveolar proteinosis(PAP) is characterised by accumulation of surfactant lipids and proteins within airspaces. However, few previous data describe the serum lipid levels associated with PAP. MATERIALS AND METHODS: We retrospectively reviewed 25 patients with idiopathic PAP(iPAP). The serum lipid levels of patients with idiopathic PAP were compared with those of the healthy volunteers. In patients and healthy subjects, the LDL C/HDL-C ratios were 2.94 +/- 1.21 and 1.60 +/- 0.70, respectively (p < 0.001), HDL-C were 1.11 +/- 0.27 and 1.71 +/- 0.71 respectively (p < 0.001). The values of LDL-C correlated significantly with those of PaO2 and PA-aO2 (r = -0.685, p = 0.003, and r = 0.688, p = 0.003, respectively). The values of LDL-C/HDL-C ratios also correlated with PaO2 levels and PA-aO2 levels (r = -0.698, p = 0.003, and r = 0.653, p = 0.006, respectively). 11 and 13 patients experienced respectively a decline in TC and LDL-C levels following whole lung lavage(WLL), the median decline was 0.71 mmol/L(p < 0.009) and 0.47 mmol/L(p < 0.003), respectively. CONCLUSIONS: the serum lipid levels, especially the levels of LDL-C and LDL-C/HDL C, may reflect the severity of the disease in PAP patients, and predict the therapeutic effect of WLL. PMID- 22252103 TI - Increases of CRF in the amygdala are responsible for reinstatement of methamphetamine-seeking behavior induced by footshock. AB - Recent evidence suggests the involvement of corticotropin-releasing factor (CRF) in drug abuse. Here, we evaluated whether CRF modulates the reinstatement of methamphetamine (METH)-seeking behavior induced by stress using a drug-self administration paradigm in rats. Rats were trained to lever-press for intravenous METH (0.02 mg/infusion) accompanied by light and tone (drug-associated cues) and then underwent extinction training (saline substituted for METH without cues). Under the extinction condition, the inhibitory effects of a CRF receptor antagonist on the stress-induced reinstatement of METH-seeking behavior were assessed. Anxiety-like behaviors during METH withdrawal in METH self-administered rats were also evaluated. The non-selective CRF receptor antagonist alpha-helical CRF(9-41) attenuated METH-seeking behavior induced by footshock stress. CRF levels both in the amygdala and in plasma were significantly increased on day 10 of withdrawal after METH self-administration. However, plasma corticosterone concentrations were unchanged during the withdrawal. In addition, METH-seeking behavior was not affected by an inhibitor of corticosterone synthesis, metyrapone. In the elevated plus maze test, METH self-administered rats showed a decrease in the duration of time spent in the open arms on day 10 of withdrawal. The increased CRF levels in the amygdala may, at least in part, contribute to the footshock-induced reinstatement of METH-seeking behavior and the increase in anxiety-like behavior. The present findings indicate that CRF receptor antagonists would be useful as a therapeutic agent for METH-dependence. PMID- 22252104 TI - Lipid, lipoprotein and apolipoprotein profiles in European adolescents and its associations with gender, biological maturity and body fat--the HELENA Study. AB - BACKGROUND/OBJECTIVES: To provide a detailed lipid profile of a European adolescent population considering age, gender, biological maturity, body mass index (BMI), fat mass (FM) and percentage body fat (BF). SUBJECTS/METHODS: Within Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA), a cross sectional study was conducted to determine fasting serum concentrations of lipids, lipoproteins and apolipoproteins in 1076 adolescents aged 12.5-17.49 years from ten European centres. RESULTS: All serum lipid concentrations were significantly higher in girls than in boys. In boys, age was negatively correlated with high-density lipoprotein (HDL)-cholesterol and total cholesterol (TC), and positively associated with triacylglycerides (TAG) (P < 0.01) whereas no significant associations were observed in girls. Biological maturity was negatively associated with TC, HDL-, low-density lipoprotein (LDL)- and non-HDL cholesterol in boys (all P<0.05) and negatively correlated with HDL-cholesterol in girls (P<0.05). BMI, FM and BF were significantly correlated with HDL cholesterol, LDL-cholesterol, non-HDL cholesterol, apolipoprotein (apo) A1, apoB and TAG in both boys and girls. CONCLUSIONS: The lipid profile in adolescents is strongly determined by gender. Biological maturity, FM and percentage BF contribute to the variance in lipid concentrations and should be considered in future evaluations of lipid status. PMID- 22252105 TI - Percentile curves for skinfold thickness in 7- to 14-year-old children and adolescents from Jena, Germany. AB - OBJECTIVE: To present age- and sex-specific percentile curves for triceps and subscapular skinfold thickness, and to investigate long-term changes in skinfold thickness in children. SUBJECTS/METHODS: A cross-sectional study of children and adolescents was conducted in Jena/Germany in 2005/2006. The sample consisted of 2132 children (1018 girls and 1114 boys) aged 7-14 years and equated to the anthropometric characteristics of the German sample included in the reference values for body mass index (BMI). Height, weight and triceps and subscapular skinfold measurements were obtained using standardized methods. Smoothed percentile curves for triceps and subscapular skinfold thickness were derived by the LMS method. Data were compared with historical data of Jena schoolchildren from 1975. RESULTS: In both sexes, skinfold thickness increased between 7 and 14 years of age in a sex-specific pattern, with generally higher median values for triceps and subscapular skinfold in girls than boys. A comparison with skinfold thickness measured in Jena schoolchildren three decades ago showed a significant increase in subcutaneous fat. The changes in the lower range (below the tenth percentile) of the distribution exceed those in the upper range (above the 90th percentile) for both triceps and subscapular skinfold in both sexes. Furthermore, this gain in subcutaneous fat mainly occurred in underweight and normal-weight subjects, whereas skinfold thickness remained nearly unchanged in overweight subjects. CONCLUSIONS: The up-to-date percentile curves for skinfold thickness provide a basis for monitoring of individuals and evaluation of long-term trends in German children and adolescents. The changes in skinfold thickness indicate an unfavourable increase in adiposity, as well as an unfavourable change in the relationship between BMI and body fat in children and adolescents over time. PMID- 22252106 TI - Is a single bioelectrical impedance equation valid for children of wide ranges of age, pubertal status and nutritional status? Evidence from the 4-component model. AB - BACKGROUND/OBJECTIVES: Bioelectrical impedance analysis (BIA) is widely used to predict body composition in paediatric research and clinical practice. Many equations have been published, but provide inconsistent predictions. AIMS: To test whether a single equation for lean mass (LM) estimation from BIA is appropriate across wide ranges of age, pubertal status and nutritional status, by testing whether specific groups differ in the slope or intercept of the equation. SUBJECTS/METHODS: In 547 healthy individuals aged 4-24 years (240 males), we collected data on body mass (BM) and height (HT), and lean mass (LM) using the 4 component model. Impedance (Z) was measured using TANITA BC418MA instrumentation. LM was regressed on HT(2)/Z. Multiple regression analysis was conducted to investigate whether groups based on gender, age, pubertal status or nutritional status differed in the association of LM with HT(2)/Z. RESULTS: BM ranged from 5 to 128 kg. HT(2)/Z was a strong predictor of LM (r (2)=0.953, s.e.e.=2.9 kg). There was little evidence of a sex difference in this relationship, however, children aged 4-7 years and 16-19 years differed significantly from other age groups in regression slopes and intercepts. Similar variability was encountered for pubertal stage, but not for nutritional status. CONCLUSIONS: No single BIA equation applies across the age range 4-24 years. At certain ages or pubertal stages, the slope and intercept of the equation relating LM to HT(2)/Z alters. Failure to address such age effects is likely to result in poor accuracy of BIA (errors of several kg) for longitudinal studies of change in body composition. PMID- 22252107 TI - Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial. AB - BACKGROUND/OBJECTIVES: Observational studies indicate that sugar-sweetened soft drinks (SSSD) may promote obesity, among other factors, owing to low-satiating effects. The effect of energy in drinks on appetite is still unclear. We examined the effect of two isocaloric, but macronutrient, different beverages (SSSD versus semi-skimmed milk) and two non-energy-containing beverages (aspartame-sweetened soft drink (ASSD) and water) on appetite, appetite-regulating hormones and energy intake (EI). SUBJECTS/METHODS: In all, 24 obese individuals were included in a crossover trial. Each subject was served either 500 ml of SSSD (regular cola: 900 kJ), semi-skimmed milk (950 kJ), ASSD (diet cola: 7.5 kJ), or water. Subjective appetite scores, ghrelin, GLP-1, and GIP concentrations were measured at baseline and continuously 4-h post intake. Ad libitum EI was measured 4 h after intake of the test drinks. RESULTS: Milk induced greater subjective fullness and less hunger than regular cola (P<0.05). Also, milk led to 31% higher GLP-1 (95% CI: 20, 44; P<0.01) and 45% higher GIP (95% CI: 23, 72; P<0.01) concentrations compared with SSSD. Ghrelin was equally 20% lower after milk and SSSD compared with water. The total EI (ad libitum EI+EI from the drink) was higher after the energy-containing drinks compared with diet cola and water (P<0.01). CONCLUSIONS: Milk increased appetite scores and GLP-1 and GIP responses compared with SSSD. The energy containing beverages were not compensated by decreased EI at the following meal, emphasizing the risk of generating a positive energy balance by consuming energy containing beverages. Furthermore, there were no indications of ASSD increased appetite or EI compared with water. PMID- 22252108 TI - Environmental and individual determinants of core and non-core food and drink intake in preschool-aged children in the United Kingdom. AB - BACKGROUND/OBJECTIVES: Strategies to achieve healthier diets for children are likely to benefit from an understanding of the determinants. We examined environmental and individual predictors of children's intake of 'core' foods (fruit and vegetables) and 'non-core' foods (snacks and sweetened beverages). Predictors included parental intake, home availability, parental feeding styles (Encouragement and Monitoring) and children's food preferences. Based on research with older children, we expected intake of both food types to be associated with maternal intake, core foods to be more associated with children's preferences and non-core food intake more with the home environment. SUBJECTS/METHODS: Primary caregivers (n=434) of children (2-5 years) from preschools and Children's Centres in London, UK, completed a self-report survey in 2008. RESULTS: Multiple regression analyses indicated children's fruit intake was associated with maternal fruit intake (B=0.29; P=0.000), children's liking for fruit (B=0.81; P=0.000) and a Monitoring style of parental feeding (B=0.13; P=0.021). Children's vegetable intake was similarly associated with maternal intake (B=0.39; P=0.000), children's liking for vegetables (B=0.77; P=0.000), Encouragement (B=0.19; P=0.021) and Monitoring (B=0.11; P=0.029). Non-core snack intake was associated with maternal intake (B=0.25; P=0.029), Monitoring (B=-0.16; P=0.010), home availability (B=0.10; P=0.022) and television viewing (TV) (B=0.28; P=0.012). Non core drink intake was associated with maternal intake (B=0.32; P=0.000) and TV (B=0.20; P=0.019). CONCLUSIONS: Results indicate commonalities and differences in the predictors of core and non-core food intake, with only maternal intake being important across all types. Effective interventions to improve young children's diets may need to call on different strategies for different foods. PMID- 22252109 TI - Cost analysis of neonatal and pediatric parenteral nutrition in Europe: a multi country study. AB - OBJECTIVES: Parenteral nutrition (PN) is critical in neonatal and pediatric care for patients unable to tolerate enteral feeding. This study assessed the total costs of compounding PN therapy for neonates, infants and children. METHODS: Face to-face and telephone interviews were conducted in 12 hospitals across four European countries (Belgium, France, Germany and UK) to collect information on resources utilized to compound PN, including nutrients, staff time, equipment cost and supplies. A bottom-up cost model was constructed to assess total costs of PN therapy by assigning monetary values to the resource utilization using published list prices and interview data. RESULTS: A total of 49,922 PN bags per year were used to treat 4295 neonatal and pediatric patients among these hospitals. The daily total costs of one compounded PN bag for neonates in the 12 hospitals across the four countries equalled euro 55.16 (Belgium euro 53.26, France euro 46.23, Germany euro 64.05, UK L 37.43/?[euro]42.86). Overall, nutrients accounted for 25% of total costs, supplies 18%, wages 54% and equipment 3%. Average costs per bag for infants <2 year were euro 84.52 (euro 74.65 in Belgium, euro 83.84 in France, euro 92.70 in Germany and L 52.63/euro 60.26 in the UK), and for children 2-18 years euro 118.02 (euro 93.85 in Belgium, euro 121.35 in France, euro 124.54 in Germany and L 69.49/euro 79.56 in the UK), of which 63% is attributable to nutrients and 28% to wages. CONCLUSION: The data indicated that PN costs differ among countries and a major proportion was due to staff time (L 1=euro 1.144959). PMID- 22252110 TI - Selective guest recognition by a self-assembled paramagnetic cage complex. AB - A cubic cage complex assembled from twelve bis-bidentate ligands and eight Co(II) ions provides a cavity that selectively recognises and binds coumarin in MeCN solution. The cage portals are large enough to allow guest exchange, but small enough to provide a kinetic trap; the cage paramagnetism facilitates detailed NMR analysis. PMID- 22252112 TI - Comparison of diode laser-assisted surgery and conventional surgery in the management of hereditary ankyloglossia in siblings: a case report with scientific review. AB - Laser-assisted surgery is common nowadays and most of the oral soft tissue surgical procedures are done with lasers. Among the commonly available lasers today, the diode laser is the one frequently used one in dentistry. Bleeding control, visibility, and better tissue manipulation are some of the advantages of the laser. This article addresses the management of hereditary ankyloglossia using the diode laser and conventional surgery in siblings. PMID- 22252113 TI - Matrix metalloproteinase-9 expression in the Seoul-type keratoprosthesis implanted corneas with concurrent cultivated autologous oral mucosal epithelial cell transplantation. PMID- 22252114 TI - Porcine circovirus diseases: a review of PMWS. AB - This article is a review on post-weaning multisystemic wasting syndrome (PMWS), the first described disease among the porcine circovirus diseases (PCVD). Post weaning multisystemic wasting syndrome has, since its appearance in Canada in 1991, been seen in all major pig producing countries. To diagnose PMWS at herd level typical clinical appearance consisting of wasting and increased mortality must be combined with finding at autopsy of diseased pigs, where typical microscopic findings in the lymphatic tissue must be present. Post-weaning multisystemic wasting syndrome significantly increases the mortality and reduces the daily weight gain in weaner pig and/or in finishing pigs. Post-weaning multisystemic wasting syndrome can be transmitted by pig-to-pig contact and some studies point at airborne transmission as a possibility. Studies in Europe have shown several risk factors that either increase or decrease the risk for a pig herd to be affected by PMWS. At the pig level, studies have shown the importance of maternal immunity as protection for subsequent development of PMWS. To control PMWS, good production management and control of other diseases are crucial. Since 2004, commercial vaccines against Porcine Circo Virus type 2 have been coming on the market and many studies have shown great benefits of these to control PMWS. Today, sow vaccines as well as piglet vaccines are available in most countries. An extensive meta-analysis of many of the vaccines has shown a comparable good efficacy of the vaccines in significantly reducing mortality and increasing weight gain of the pigs. PMID- 22252115 TI - Lack of EGFR mutations benefiting gefitinib treatment in adenocarcinoma of esophagogastric junction. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) inhibitor, gefitinib, has been reported to successfully treat advanced non-small cell lung cancer patients with genetic mutations in EGFR. The aim of this study was to investigate the existence of EGFR mutations in carcinoma of esophagogastric junction, and also to explore the possibility of treating carcinoma of esophagogastric junction using gefitinib. METHODS: From Aug. 2009 to Jun. 2010, 65 patients with carcinoma of esophagogastric junction underwent surgical resection. The tumor tissue and corresponding blood specimens were collected from all cases. The DNA was extracted and PCR amplification was accomplished based on designed primers for exons 18, 19, 20, and 21. EGFR exons 18, 19, 20 and 21 of both cancer cell and white blood cell were finally successfully sequenced. RESULTS: In exon 20, a variant from CAG to CAA at codon 787 (2361G-> A) was identified in 19 patients, which was a genomic variation of EGFR since it was found in both cancer tissue and white blood cells. This EGFR alteration was a synonymous single nucleotide polymorphism (SNP) since CAA and CAG were encoding the same amino-acid of Glutamine (Q787Q, NCBI database 162093G > A, SNP ID: rs10251977). No genetic alteration was found in exons 18, 19 or 21. CONCLUSIONS: Adenocarcinoma of esophagogastric junction rarely presents EGFR mutation, especially gefitinib associated mutations such as L858R, or delE746-A750. This means that the gefitinib-based gene target therapy should not be recommended for treating carcinoma of esophagogastric junction. PMID- 22252116 TI - Circadian rhythms and tumor growth. AB - Hormone secretion, metabolism, and the cell cycle are under rhythmic control. Lack of rhythmic control has been predicted to lead to uncontrolled proliferation and cancer. Consistent with this prediction are findings that circadian disruption by dim light at night or chronic jet lag accelerates tumor growth in desynchronized animals. Circadian controlled factors such as insulin/IGF-1, glucocorticoids, catecholamines, and melatonin have be implicated in controlling tumor growth in the desynchronized animals. Recent attention has focused on the signaling pathways activated by the circadian controlled factors because these pathways hold the potential for the development of novel strategies for cancer prevention and treatment. PMID- 22252117 TI - Membrane proteomic analysis comparing squamous cell lung cancer tissue and tumour adjacent normal tissue. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is one of the predominant histological subtypes of lung cancer. Detecting lung cancer at an early stage is essential for successful therapy and increasing survival. There are still no satisfactory biomarkers for the early detection of lung cancer. In this study, tumour tissue paired with tumour adjacent normal bronchial epithelial tissue was obtained from patients with squamous cell lung carcinoma without metastasis. The proteins extracted from the cell membrane were separated by two-dimensional polyacrylamide gel electrophoresis (2-DE) and were analysed with the Image Master two-dimensional platinum software. Twenty-five significantly different protein spots were selected and identified with matrix-assisted laser desorption/ionisation time-of flight mass spectrometry (MALDI-TOF MS). A total of 19 proteins were successfully identified. Twelve proteins were up-regulated, and seven proteins were down regulated in the cancerous tissue compared with the tumour-adjacent normal tissue. One up-regulated protein and one down-regulated protein in squamous cell lung carcinoma were verified by Western blot analysis and RT-PCR; the results were consistent with the 2-DE analysis. In conclusion, membrane proteomics identified a number of candidate biomarker proteins that were differentially expressed between squamous cell lung cancer tissue and adjacent normal tissue. These biomarker candidates have the potential to elucidate the underlying pathogenesis of squamous cell lung cancer. PMID- 22252119 TI - Nitric oxide, peroxynitrite, S-nitrosothiols and thiols are unlikely to exert their effects on recombinant cyclooxygenase-1 and cyclooxygenase-2 activity in vitro by modifying cysteine moieties. PMID- 22252120 TI - Direct 4D parametric imaging for linearized models of reversibly binding PET tracers using generalized AB-EM reconstruction. AB - Due to high noise levels in the voxel kinetics, development of reliable parametric imaging algorithms remains one of most active areas in dynamic brain PET imaging, which in the vast majority of cases involves receptor/transporter studies with reversibly binding tracers. As such, the focus of this work has been to develop a novel direct 4D parametric image reconstruction scheme for such tracers. Based on a relative equilibrium (RE) graphical analysis formulation (Zhou et al 2009b Neuroimage 44 661-70), we developed a closed-form 4D EM algorithm to directly reconstruct distribution volume (DV) parametric images within a plasma input model, as well as DV ratio (DVR) images within a reference tissue model scheme (wherein an initial reconstruction was used to estimate the reference tissue time-activity curves). A particular challenge with the direct 4D EM formulation is that the intercept parameters in graphical (linearized) analysis of reversible tracers (e.g. Logan or RE analysis) are commonly negative (unlike for irreversible tracers, e.g. using Patlak analysis). Subsequently, we focused our attention on the AB-EM algorithm, derived by Byrne (1998, Inverse Problems 14 1455-67) to allow inclusion of prior information about the lower (A) and upper (B) bounds for image values. We then generalized this algorithm to the 4D EM framework, thus allowing negative intercept parameters. Furthermore, our 4D AB-EM algorithm incorporated and emphasized the use of spatially varying lower bounds to achieve enhanced performance. As validation, the means of parameters estimated from 55 human (11)C-raclopride dynamic PET studies were used for extensive simulations using a mathematical brain phantom. Images were reconstructed using conventional indirect as well as proposed direct parametric imaging methods. Noise versus bias quantitative measurements were performed in various regions of the brain. Direct 4D EM reconstruction resulted in notable qualitative and quantitative accuracy improvements (over 35% noise reduction, with matched bias, in both plasma and reference-tissue input models). Similar improvements were also observed in the coefficient of variation of the estimated DV and DVR values even for relatively low uptake cortical regions, suggesting the enhanced ability for robust parameter estimation. The method was also tested on a 90 min (11)C-raclopride patient study performed on the high-resolution research tomograph wherein the proposed method was shown across a variety of regions to outperform the conventional method in the sense that for a given DVR value, improved noise levels were observed. PMID- 22252121 TI - Regulation of HGF-mediated cell proliferation and invasion through NF-kappaB, JunB, and MMP-9 cascades in stomach cancer cells. AB - Blocking of activator protein-1 activity leads to suppression of growth factor induced transformation. However, the role of individual components of the Jun family in this process is unclear. Over-expression of JunB has been reported to be associated with neoplastic transformation and regulation of Matrix metalloproteinase-9 (MMP-9) expression. Using cDNA microarray, we found that JunB might be one of target genes up-regulated by hepatocyte growth factor (HGF). Therefore, we tried to investigate the role of JunB in HGF-medicated cell proliferation and cell invasion in human gastric cancer cells, NUGC3 and MKN28. We verified that HGF increased JunB in time and dose-dependent manners. The JunB levels were decreased by the treatment with an NF-kappaB inhibitor, pyrrolidine dithiocarbamate. Down-regulation of JunB by transfecting cells with JunB-short hairpin RNAs (shRNA) inhibited MMP-9 up-regulation induced by HGF. Furthermore, transfection with JunB-shRNA repressed HGF-mediated increases in cell proliferation and cell invasion. These data suggest that JunB might be regulated through an NF-kappaB pathway and up-regulation of JunB induced by HGF might play an important role in the regulation of cell proliferation and cell invasion through MMP-9 expression. In conclusion, these results may contribute to the JunB associated malignant phenotype of gastric cancers by regulating MMP-9, and serve as a novel therapeutic target for stomach cancer therapy in the future. PMID- 22252122 TI - The role of renal water channels in health and disease. AB - Seven members of the aquaporin (AQP) family are expressed in different regions of the kidney. AQP1-4 are localized in plasma membranes of renal epithelial cells and are intimately involved in water reabsorption by the kidney. AQP7 is also localized in the plasma membrane and may facilitate glycerol transport. AQP6 and AQP11 are localized within the cell, with AQP6 involved in anion transport and AQP11 water transport. Mutations in AQP2 can result in diabetes insipidus, whereas mutations in other AQPs have not yet been shown to be disease-associated. Genetic polymorphisms may contribute to the susceptibility to defects in urine concentrating mechanisms associated with some diseases. Most of the AQPs are subject to transcriptional regulation and post-translational modifications by a range of biological modifiers. As a result a number of chronic kidney and systemic diseases produce changes in the abundance of AQPs. The more recent developments in this field are reviewed. PMID- 22252123 TI - Field response of aboveground non-target arthropod community to transgenic Bt Cry1Ab rice plant residues in postharvest seasons. AB - Risk assessments of ecological effects of transgenic rice expressing lepidoptera Cry proteins from Bacillus thuringiensis (Bt) on non-target arthropods have primarily focused on rice plants during cropping season, whereas few studies have investigated the effects in postharvest periods. Harvested rice fallow fields provide a critical over-wintering habitat for arthropods in the Chinese rice ecosystems, particularly in the southern region of the country. During 2006-08, two independent field trials were conducted in Chongqing, China to investigate the effects of transgenic Cry1Ab rice residues on non-target arthropod communities. In each trial, pitfall traps were used to sample arthropods in field plots planted with one non-Bt variety and two Bt rice lines expressing the Cry1Ab protein. Aboveground arthropods in the trial plots during the postharvest season were abundant, while community densities varied significantly between the two trials. A total of 52,386 individual insects and spiders, representing 93 families, was captured in the two trials. Predominant arthropods sampled were detritivores, which accounted for 91.9% of the total captures. Other arthropods sampled included predators (4.2%), herbivores (3.2%), and parasitoids (0.7%). In general, there were no significant differences among non-Bt and Bt rice plots in all arthropod community-specific parameters for both trials, suggesting no adverse impact of the Bt rice plant residues on the aboveground non-target arthropod communities during the postharvest season. The results of this study provide additional evidence that Bt rice is safe to non-target arthropod communities in the Chinese rice ecosystems. PMID- 22252118 TI - Base excision repair and cancer. AB - Base excision repair is the system used from bacteria to man to remove the tens of thousands of endogenous DNA damages produced daily in each human cell. Base excision repair is required for normal mammalian development and defects have been associated with neurological disorders and cancer. In this paper we provide an overview of short patch base excision repair in humans and summarize current knowledge of defects in base excision repair in mouse models and functional studies on short patch base excision repair germ line polymorphisms and their relationship to cancer. The biallelic germ line mutations that result in MUTYH associated colon cancer are also discussed. PMID- 22252124 TI - Polymorphisms in the immunoregulatory genes are associated with hematopoietic recovery and increased susceptibility to bacterial infections in patients with thalassaemia major undergoing matched related hematopoietic stem cell transplantation. AB - In this study, the impact of polymorphisms in the genes of proinflammatory (IL beta, TNF-alpha, IL-6, IFN-gamma), anti-inflammatory (transforming growth factor [TGF]-beta, IL-10, IL-Ra), and other immunoregulatory factors (FcgammaRIIa, NOS3) along with the conventional risk factors on the rate of hematopoietic recovery and first episodes of bacterial, viral, or invasive fungal infections in 102 patients with beta-thalassaemia major who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with relatively uniform protocols at our center from June 1995 to June 2004 with a minimum follow-up of at least 2 years were studied retrospectively for 180 days after hematopoietic stem cell transplantation (HSCT). Our data show that (1) donor IL-1RN*2/2 (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.17-5.09; P = .018) and FCgammaRIIA +4481G/G genotypes (HR, 3.1; 95% CI, 1.56-6.31; P = .001) increased the incidence of bacterial infection; (2) fungal infection was increased in recipients with whose donors had IFN-gamma +874T/T genotype (HR, 3.8; 95% CI, 1.08-13.62; P = .037); (3) time to neutrophil recovery was shorter in splenectomized patients (HR, 3.1; 95% CI, 1.70-5.64; P < .001), donors without IL-10 -1082A, -819T, and 592A haplotype (HR, 1.6; 95% CI, 1.02-2.39; P = .039), and recipients with IFN gamma +874A/A genotype (HR, 1.6; 95% CI, 1.05-2.56; P = .029); and (4) time to platelet recovery was shorter in patients with IL-10 -1082A/A genotype (HR, 1.8; 95% CI, 1.14-2.68; P = .010) and with donors having TNF-alpha -308G/G genotypes (HR, 1.8; 95% CI, 1.06-2.93; P = .028). These data suggest that outcome after allogeneic stem cell transplantation could be affected by many factors. The mechanisms by which they bring about such impact needs further evaluation. PMID- 22252126 TI - Torque teno sus virus in pigs: an emerging pathogen? AB - The newly established family Anelloviridae includes a number of viruses infecting humans (Torque teno viruses) and other animal species. The ones infecting domestic swine and wild boar are nowadays named Torque teno sus viruses (TTSuV), which are small circular single-stranded DNA viruses highly prevalent in the pig population. So far, two genetically distinct TTSuV species are infecting swine. Both TTSuVs appear to efficiently spread by vertical and horizontal transmission routes; in fact, foetuses may be infected and the prevalence and viral loads increase by age of the animals. Detailed immunological studies on TTSuVs are still lacking, but it seems that there are no efficient immunological responses limiting viraemia. These viruses are currently receiving more attention due to the latest results on disease association. Torque teno sus viruses have been circulating unnoticed in pigs for a long time, and even considered non-pathogenic by themselves; there is increasing evidence that points to influence the development of some diseases or even affect their outcome. Such link has been mainly established with porcine circovirus diseases. PMID- 22252125 TI - Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. AB - Although allogeneic hematopoietic cell transplantation (HCT) has proven curative potential for myelodysplastic syndrome, relapse after HCT remains a problem. Pretransplantation cytoreduction with induction chemotherapy (IC) has been used to reduce relapse rates but is associated with significant toxicity and mortality. Hypomethylating agents may achieve cytoreduction with limited toxicity; however, data on the effect of pre-HCT hypomethylation on post-HCT outcomes are limited. We retrospectively reviewed results in 68 patients who underwent allogeneic HCT for myelodysplastic syndrome or acute myeloid leukemia transformed from MDS. Thirty-five patients had received cytoreduction with azacitidine before HCT with either a high-dose (40%) or a reduced-intensity (60%) conditioning regimen, and 33 had undergone IC before HCT with high-dose conditioning. The estimated 1-year overall survival (OS) was 57% in the azacitidine group and 36% in the IC group. The risk of post-HCT mortality (hazard ratio, 0.68; 95% confidence interval, 0.35-1.30), nonrelapse mortality (hazard ratio, 0.99; 95% confidence interval, 0.41-2.34), and relapse (hazard ratio, 0.34; 95% confidence interval, 0.41-2.34) were lower in the azacitidine group compared to the IC group, but only the hazard for relapse was significantly lower. After adjustment for cytogenetic risk, International Prognostic Scoring System, and donor, the rates of post-HCT relapse for the 2 cohorts were similar. Although the current study was retrospective and nonrandomized and needs to be interpreted in this context, the results add to the growing evidence that pre-HCT therapy with azacitidine is associated with less toxicity than IC and may allow for similar post-HCT outcomes. PMID- 22252127 TI - Pigment dispersing hormone modulates spontaneous electrical activity of the cerebroid ganglion and synchronizes electroretinogram circadian rhythm in crayfish Procambarus clarkii. AB - In crayfish, one very well-studied circadian rhythm is that of electroretinogram (ERG) amplitude. The cerebroid ganglion has been considered a plausible site for the circadian pacemaker of this rhythm and for the retinular photoreceptors, as the corresponding effectors. The pigment dispersing hormone (PDH) appears to synchronize ERG rhythm, but its characterization as a synchronizer cue remains incomplete. The main purposes of this work were a) to determine whether PDH acts on the cerebroid ganglion, and b) to complete its characterization as a non photic synchronizer. Here we show that PDH increases the number of the spontaneous potentials of the cerebroid ganglion, reaching 149.92+/-6.42% of the activity recorded in the controls, and that daily application of PDH for 15 consecutive days adjusts the ERG circadian rhythm period to 24.0+/-0.2h and the end of the activity period of the rhythm coincides with the injection of the hormone. In this work, we hypothesized that in crayfish, PDH transmits the "day" signal to the ERG circadian system and acts upon both the presumptive circadian pacemaker and the corresponding effectors to reinforce the synchronization of the system. PMID- 22252128 TI - A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. AB - Surface-exposed calreticulin (ecto-CRT) and secreted ATP are crucial damage associated molecular patterns (DAMPs) for immunogenic apoptosis. Inducers of immunogenic apoptosis rely on an endoplasmic reticulum (ER)-based (reactive oxygen species (ROS)-regulated) pathway for ecto-CRT induction, but the ATP secretion pathway is unknown. We found that after photodynamic therapy (PDT), which generates ROS-mediated ER stress, dying cancer cells undergo immunogenic apoptosis characterized by phenotypic maturation (CD80(high), CD83(high), CD86(high), MHC-II(high)) and functional stimulation (NO(high), IL-10(absent), IL 1beta(high)) of dendritic cells as well as induction of a protective antitumour immune response. Intriguingly, early after PDT the cancer cells displayed ecto CRT and secreted ATP before exhibiting biochemical signatures of apoptosis, through overlapping PERK-orchestrated pathways that require a functional secretory pathway and phosphoinositide 3-kinase (PI3K)-mediated plasma membrane/extracellular trafficking. Interestingly, eIF2alpha phosphorylation and caspase-8 signalling are dispensable for this ecto-CRT exposure. We also identified LRP1/CD91 as the surface docking site for ecto-CRT and found that depletion of PERK, PI3K p110alpha and LRP1 but not caspase-8 reduced the immunogenicity of the cancer cells. These results unravel a novel PERK-dependent subroutine for the early and simultaneous emission of two critical DAMPs following ROS-mediated ER stress. PMID- 22252129 TI - Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism. AB - Oxygen influences behaviour in many organisms, with low levels (hypoxia) having devastating consequences for neuron survival. How neurons respond physiologically to counter the effects of hypoxia is not fully understood. Here, we show that hypoxia regulates the trafficking of the glutamate receptor GLR-1 in C. elegans neurons. Either hypoxia or mutations in egl-9, a prolyl hydroxylase cellular oxygen sensor, result in the internalization of GLR-1, the reduction of glutamate activated currents, and the depression of GLR-1-mediated behaviours. Surprisingly, hypoxia-inducible factor (HIF)-1, the canonical substrate of EGL-9, is not required for this effect. Instead, EGL-9 interacts with the Mint orthologue LIN-10, a mediator of GLR-1 membrane recycling, to promote LIN-10 subcellular localization in an oxygen-dependent manner. The observed effects of hypoxia and egl-9 mutations require the activity of the proline-directed CDK-5 kinase and the CDK-5 phosphorylation sites on LIN-10, suggesting that EGL-9 and CDK-5 compete in an oxygen-dependent manner to regulate LIN-10 activity and thus GLR-1 trafficking. Our findings demonstrate a novel mechanism by which neurons sense and respond to hypoxia. PMID- 22252130 TI - Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly. AB - Respiratory chain (RC) complexes are organized into supercomplexes forming 'respirasomes'. The mechanism underlying the interdependence of individual complexes is still unclear. Here, we show in human patient cells that the presence of a truncated COX1 subunit leads to destabilization of complex IV (CIV) and other RC complexes. Surprisingly, the truncated COX1 protein is integrated into subcomplexes, the holocomplex and even into supercomplexes, which however are all unstable. Depletion of the m-AAA protease AFG3L2 increases stability of the truncated COX1 and other mitochondrially encoded proteins, whereas overexpression of wild-type AFG3L2 decreases their stability. Both full-length and truncated COX1 proteins physically interact with AFG3L2. Expression of a dominant negative AFG3L2 variant also promotes stabilization of CIV proteins as well as the assembled complex and rescues the severe phenotype in heteroplasmic cells. Our data indicate that the mechanism underlying pathogenesis in these patients is the rapid clearance of unstable respiratory complexes by quality control pathways, rather than their impaired assembly. PMID- 22252132 TI - Enlightening the impact of immunogenic cell death in photodynamic cancer therapy. PMID- 22252131 TI - Structure of a novel phosphotyrosine-binding domain in Hakai that targets E cadherin. AB - Phosphotyrosine-binding domains, typified by the SH2 (Src homology 2) and PTB domains, are critical upstream components of signal transduction pathways. The E3 ubiquitin ligase Hakai targets tyrosine-phosphorylated E-cadherin via an uncharacterized domain. In this study, the crystal structure of Hakai (amino acids 106-206) revealed that it forms an atypical, zinc-coordinated homodimer by utilizing residues from the phosphotyrosine-binding domain of two Hakai monomers. Hakai dimerization allows the formation of a phosphotyrosine-binding pocket that recognizes specific phosphorylated tyrosines and flanking acidic amino acids of Src substrates, such as E-cadherin, cortactin and DOK1. NMR and mutational analysis identified the Hakai residues required for target binding within the binding pocket, now named the HYB domain. ZNF645 also possesses a HYB domain but demonstrates different target specificities. The HYB domain is structurally different from other phosphotyrosine-binding domains and is a potential drug target due to its novel structural features. PMID- 22252133 TI - Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning. AB - Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABA(A) receptor Cl(-) channels. Although Kcc2 may have a morphogenic role in synapse development, Kcc2 disruption neither changed synapse density nor spine morphology. In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl( )](i) roughly two-fold. The reduced Cl(-) gradient nearly abolished GABA-induced hyperpolarization in PCs, but in GCs it merely affected excitability by membrane depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, whereas baseline performance, short-term gain-decrease learning and gain consolidation remained intact. These functions, however, were affected by disruption of Kcc2 in PCs. GC excitability plays a previously unknown, but specific role in consolidation of phase learning. PMID- 22252134 TI - An end-to-end examination of geometric accuracy of IGRT using a new digital accelerator equipped with onboard imaging system. AB - The Varian's new digital linear accelerator (LINAC), TrueBeam STx, is equipped with a high dose rate flattening filter free (FFF) mode (6 MV and 10 MV), a high definition multileaf collimator (2.5 mm leaf width), as well as onboard imaging capabilities. A series of end-to-end phantom tests were performed, TrueBeam-based image guided radiation therapy (IGRT), to determine the geometric accuracy of the image-guided setup and dose delivery process for all beam modalities delivered using intensity modulated radiation therapy (IMRT) and RapidArc. In these tests, an anthropomorphic phantom with a Ball Cube II insert and the analysis software (FilmQA (3cognition)) were used to evaluate the accuracy of TrueBeam image-guided setup and dose delivery. Laser cut EBT2 films with 0.15 mm accuracy were embedded into the phantom. The phantom with the film inserted was first scanned with a GE Discovery-ST CT scanner, and the images were then imported to the planning system. Plans with steep dose fall off surrounding hypothetical targets of different sizes were created using RapidArc and IMRT with FFF and WFF (with flattening filter) beams. Four RapidArc plans (6 MV and 10 MV FFF) and five IMRT plans (6 MV and 10 MV FFF; 6 MV, 10 MV and 15 MV WFF) were studied. The RapidArc plans with 6 MV FFF were planned with target diameters of 1 cm (0.52 cc), 2 cm (4.2 cc) and 3 cm (14.1 cc), and all other plans with a target diameter of 3 cm. Both onboard planar and volumetric imaging procedures were used for phantom setup and target localization. The IMRT and RapidArc plans were then delivered, and the film measurements were compared with the original treatment plans using a gamma criteria of 3%/1 mm and 3%/2 mm. The shifts required in order to align the film measured dose with the calculated dose distributions was attributed to be the targeting error. Targeting accuracy of image-guided treatment using TrueBeam was found to be within 1 mm. For irradiation of the 3 cm target, the gammas (3%, 1 mm) were found to be above 90% in all plan deliveries. For irradiations of smaller targets (2 cm and 1 cm), similar accuracy was achieved for 6 MV and 10 MV beams. Slightly degraded accuracy was observed for irradiations with higher energy beam (15 MV). In general, gammas (3%, 2 mm) were found to be above 97% for all the plans. Our end-to-end tests showed an excellent relative dosimetric agreement and sub-millimeter targeting accuracy for 6 MV and 10 MV beams, using both FFF and WFF delivery methods. However, increased deviations in spatial and dosimetric accuracy were found when treating lesions smaller than 2 cm or with 15 MV beam. PMID- 22252135 TI - Two versatile shuttle vectors for Thermus thermophilus-Escherichia coli containing multiple cloning sites, lacZalpha gene and kanamycin or hygromycin resistance marker. AB - Two versatile shuttle vectors for Thermus thermophilus and Escherichia coli were developed on the basis of the T. thermophilus cryptic plasmid pTT8 and E. coli vector pUC13. These shuttle vectors, pTRK1T and pTRH1T, carry a gene encoding a protein homologous to replication protein derived from pTT8, a replicon for E. coli, new multiple cloning sites and a lacZalpha gene from E. coli vector pUC13, and also have a gene encoding a thermostable protein that confers resistance to kanamycin or hygromycin, which can be used as a selection marker in T. thermophilus. These shuttle vectors are useful to develop enzymes and proteins of biotechnological interest. We also constructed a plasmid, pUC13T, which carries the same multiple cloning sites of pTRK1T and pTRH1T. These vectors should facilitate cloning procedures both in E. coli and T. thermophilus. PMID- 22252136 TI - Fitness of the pMV158 replicon in Streptococcus pneumoniae. AB - Promiscuous, rolling-circle replication plasmid pMV158 determines tetracycline resistance to its host and can be mobilized by conjugation. Plasmid pLS1 is a deletion derivative of pMV158 that has lost its conjugative mobilization ability. Both plasmids replicate efficiently and are stably inherited in Streptococcus pneumoniae. We have analyzed the effect of pMV158 and pLS1 carriage on the bacterial growth rate. Whereas the parental plasmid does not significantly modify the cell doubling time, pLS1 slows down the growth of the bacterial host by 8-9%. The bases of the differential burden caused by pMV158 and pLS1 carriage are not yet understood. The negligible cost of the pMV158 parental natural plasmid on the host might explain the prevalence of small, multicopy, rolling-circle replication plasmids, even though they lack any selectable trait. PMID- 22252137 TI - The segregation of Escherichia coli minichromosomes constructed in vivo by recombineering. AB - Circularized regions of the chromosome containing the origin of replication, oriC, can be maintained as autonomous minichromosomes, oriC plasmids. We show that oriC plasmids containing precise, pre-determined segments of the chromosome can be generated by a simple in vivo recombineering technique. We generated two such plasmids carrying fluorescent markers. These were transferred to a recipient strain with a different fluorescent marker near the chromosomal copy of oriC. Thus the fates of the oriC plasmid and chromosomal origins could be followed independently in living cells by fluorescence microscopy. In contrast to a previous report, we show that there is a strong tendency of oriC plasmid copies to accumulate at the cell center as a single or double focus at the plane of cell division. This is not simply due to exclusion from the nucleoid space but rather appears to be a specific recognition and retention of the plasmid by some central located cell site. PMID- 22252138 TI - Design of liquid-crystalline gold nanoparticles by click chemistry. AB - Mesomorphic alkyne-based first- and second-generation dendrons were grafted onto gold nanoparticles carrying azide groups under click reaction conditions. The nanoparticles decorated with the dendrons displayed liquid-crystalline properties and good thermal stability. PMID- 22252139 TI - Diagnosis of hypersplenism with the epinephrine stimulation test - 23 years of experience at a tertiary care hospital. AB - PRINCIPLES: Hypersplenism can be defined by thrombocytopenia and/or neutropenia resulting from blood cell sequestration in an enlarged spleen. In multimorbid patients the differential diagnosis of cytopenia is challenging and currently there is no established test for diagnosing hypersplenism. METHODS: The epinephrine stimulation test (EST) measures changes in platelets, neutrophil counts and spleen size following a subcutaneous epinephrine injection. We retrospectively analysed the results of EST in 228 patients. RESULTS: Increases in neutrophils and platelets after epinephrine injection were significantly greater in patients with enlarged than in patients with normal size spleens. Using cutoffs of low, intermediate and high confidence EST was positive in 69.8% vs. 41.3% (low confidence), 49.6% vs. 17.4% (intermediate confidence) and 38.8% vs. 10.9% (high confidence) in patients with enlarged vs. normal size spleens. Changes in platelet and neutrophil counts correlated with each other and with changes in spleen size, confirming cell release from the spleen during EST. When stratified according to the underlying diagnosis, patients with liver disease had the strongest response to EST, patients with malignant haematological diseases the weakest. In addition the response to EST was significantly related to changes in platelet and neutrophil counts after splenectomy, confirming the validity of our test. No serious side effects occurred during EST. CONCLUSION: When used in a large patient cohort, EST is a safe and simple diagnostic test. In this exploratory study EST is of value in evaluating patients with cytopenia and a positive EST argues strongly for hypersplenism. Future studies should prospectively evaluate EST for the management of patients with splenomegaly. PMID- 22252140 TI - A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. AB - Drug candidate and toxicity screening processes currently rely on results from early-stage in vitro cell-based assays expected to faithfully represent essential aspects of in vivo pharmacology and toxicology. Several in vitro designs are optimized for high throughput to benefit screening efficiencies, allowing the entire libraries of potential pharmacologically relevant or possible toxin molecules to be screened for different types of cell signals relevant to tissue damage or to therapeutic goals. Creative approaches to multiplexed cell-based assay designs that select specific cell types, signaling pathways and reporters are routine. However, substantial percentages of new chemical and biological entities (NCEs/NBEs) that fail late-stage human drug testing, or receive regulatory "black box" warnings, or that are removed from the market for safety reasons after regulatory approvals all provide strong evidence that in vitro cell based assays and subsequent preclinical in vivo studies do not yet provide sufficient pharmacological and toxicity data or reliable predictive capacity for understanding drug candidate performance in vivo. Without a reliable translational assay tool kit for pharmacology and toxicology, the drug development process is costly and inefficient in taking initial in vitro cell based screens to in vivo testing and subsequent clinical approvals. Commonly employed methods of in vitro testing, including dissociated, organotypic, organ/explant, and 3-D cultures, are reviewed here with specific focus on retaining cell and molecular interactions and physiological parameters that determine cell phenotypes and their corresponding responses to bioactive agents. Distinct advantages and performance challenges for these models pertinent to cell based assay and their predictive capabilities required for accurate correlations to in vivo mechanisms of drug toxicity are compared. PMID- 22252141 TI - One world, one health: the threat of emerging and re-emerging viral infections of pigs. PMID- 22252143 TI - The nuclear receptor signalling scaffold: insights from full-length structures. PMID- 22252144 TI - The potential for Cerenkov luminescence imaging of alpha-emitting radionuclides. AB - Targeted alpha-emitting drugs are promising for cancer therapy, but cannot be effectively imaged by conventional techniques. Cerenkov luminescence imaging (CLI) has previously been shown capable of imaging beta(+)- and beta(-)-emitting radionuclides in vivo and could have the potential to image alpha-emitters. Cerenkov light production from alpha-emitters is through Compton scattering and from farther down the decay chain. This causes the Cerenkov production to vary in time and depend on sample geometry, complicating the interpretation of CLI images. We used the simulation toolkit Geant4 to predict the Cerenkov light output from five alpha-emitting radionuclides that have therapeutic potential: (225)Ac, (230)U, (213)Bi, (212)Bi and (212)At. We found that (225)Ac, (213)Bi and (212)Bi produced an order of magnitude more Cerenkov light than (18)F. However, the light from (225)Ac is delayed from the initial decay, possibly decreasing the correlation of the drug and light source. This indicates that CLI will not be helpful in the development of some alpha-emitting drugs. PMID- 22252145 TI - Lumbar spine and total-body dual-energy X-ray absorptiometry in children with severe neurological impairment and intellectual disability: a pilot study of artefacts and disrupting factors. AB - BACKGROUND: Children with severe neurological impairment and intellectual disability (ID) are susceptible for developing low bone mineral density (BMD) and fractures. BMD is generally measured with dual-energy X-ray absorptiometry (DXA). OBJECTIVE: To describe the occurrence of factors that may influence the feasibility of DXA and the accuracy of DXA outcome in children with severe neurological impairment and ID. MATERIALS AND METHODS: Based on literature and expert opinion, a list of disrupting factors was developed. Occurrence of these factors was assessed in 27 children who underwent DXA measurement. RESULTS: Disrupting factors that occurred most frequently were movement during measurement (82%), aberrant body composition (67%), small length for age (56%) and scoliosis (37%). The number of disrupting factors per child was mean 5.3 (range 1-8). No correlation was found between DXA outcomes and the number of disrupting factors. CONCLUSION: Factors that may negatively influence the accuracy of DXA outcome are frequently present in children with severe neurological impairment and ID. No systematic deviation of DXA outcome in coherence with the amount of disrupting factors was found, but physicians should be aware of the possible influence of disrupting factors on the accuracy of DXA. PMID- 22252146 TI - Preliminary evaluation of growth and conformation traits of local goats and Nubians upgraded by a black Boer line in Taiwan. AB - The goal of this research, conducted in the most southern part of Taiwan, was to create a new genotype: the "Hengchun Black Goat" (HB). Nubian (NU) goats were first crossed with a local breed, the Taiwan native (TN), then the F1 females were crossed with the imported black Boer (BO) bucks. The upgraded genotypes were then compared with the parental breeds and Kinmen (KM), another local breed, for growth traits and body conformation. The study concerned 1,136 kids born between 2005 and 2007. The analysed traits were body weight (BW), average daily gain and three linear measurements, namely height at withers, body length and chest girth. The results indicated that environmental factors, sex, birth and rearing type, dam parity and birth year had significant effects from birth to 6 months of age. The same differences persisted to 1 year. At 6 months of age, the least square means of BW were 16.2, 19.2, 25.1, 32.0, 23.9, 23.8, 23.0 and 23.9 kg, for KM, TN, NU, 1/2BO, 3/4BO, 7/8BO, BO and HB, respectively. These first results also indicate that the growth performances of the newly created line, Hengchun Black, were equivalent to those of Boer goats. PMID- 22252147 TI - Non-communicable health risks during mass gatherings. AB - Mass gatherings (MGs) have been associated with high rates of morbidity and mortality from non-communicable diseases, accidents, and terrorist attacks, thus posing complex public health challenges. We assessed the health risks and public health responses to MGs to identify an evidence-based framework for public health interventions. Human stampedes and heat-related illnesses are the leading causes of mortality. Minor traumatic injuries and medical complaints are the main contributors to morbidity and, particularly, the need for on-site medical care. Infrastructure, crowd density and mood, weather, age, and sex determine the risks to health. Many predictive models for deployment of medical resources are proposed, but none have been validated. We identified the risks for mortality and morbidity during MGs, most efficient public health interventions, and need for robust research into health risks for non-communicable diseases during MGs. PMID- 22252148 TI - Research agenda for mass gatherings: a call to action. AB - Public health research is essential for the development of effective policies and planning to address health security and risks associated with mass gatherings (MGs). Crucial research topics related to MGs and their effects on global health security are discussed in this review. The research agenda for MGs consists of a framework of five major public health research directions that address issues related to reducing the risk of public health emergencies during MGs; restricting the occurrence of non-communicable and communicable diseases; minimisation of the effect of public health events associated with MGs; optimisation of the medical services and treatment of diseases during MGs; and development and application of modern public health measures. Implementation of the proposed research topics would be expected to provide benefits over the medium to long term in planning for MGs. PMID- 22252149 TI - Infectious disease surveillance and modelling across geographic frontiers and scientific specialties. AB - Infectious disease surveillance for mass gatherings (MGs) can be directed locally and globally; however, epidemic intelligence from these two levels is not well integrated. Modelling activities related to MGs have historically focused on crowd behaviours around MG focal points and their relation to the safety of attendees. The integration of developments in internet-based global infectious disease surveillance, transportation modelling of populations travelling to and from MGs, mobile phone technology for surveillance during MGs, metapopulation epidemic modelling, and crowd behaviour modelling is important for progress in MG health. Integration of surveillance across geographic frontiers and modelling across scientific specialties could produce the first real-time risk monitoring and assessment platform that could strengthen awareness of global infectious disease threats before, during, and immediately after MGs. An integrated platform of this kind could help identify infectious disease threats of international concern at the earliest stages possible; provide insights into which diseases are most likely to spread into the MG; help with anticipatory surveillance at the MG; enable mathematical modelling to predict the spread of infectious diseases to and from MGs; simulate the effect of public health interventions aimed at different local and global levels; serve as a foundation for scientific research and innovation in MG health; and strengthen engagement between the scientific community and stakeholders at local, national, and global levels. PMID- 22252150 TI - Crowd and environmental management during mass gatherings. AB - Crowds are a feature of large cities, occurring not only at mass gatherings but also at routine events such as the journey to work. To address extreme crowding, various computer models for crowd movement have been developed in the past decade, and we review these and show how they can be used to identify health and safety issues. State-of-the-art models that simulate the spread of epidemics operate on a population level, but the collection of fine-scale data might enable the development of models for epidemics that operate on a microscopic scale, similar to models for crowd movement. We provide an example of such simulations, showing how an individual-based crowd model can mirror aggregate susceptible infected-recovered models that have been the main models for epidemics so far. PMID- 22252151 TI - The rate of HIV testing is increasing among men who have sex with men in China. AB - OBJECTIVES: HIV infection is spreading relatively quickly among men who have sex with men (MSM) in China. Accurate knowledge of HIV status is of high importance for public health prevention. METHODS: We conducted a systematic review of literature published in either English or Chinese to collate available HIV testing data among MSM in China. Linear regression and Spearman's rank correlation were used to study factors associated with HIV testing rates. RESULTS: Fifty-five eligible articles were identified in this review. The proportion of MSM who had ever been tested for HIV has significantly increased, from 10.8% in 2002 to 51.2% in 2009. In comparison, reported rates of HIV testing in the past 12 months have also significantly increased, from 11.0% in 2003 to 43.7% in 2009. CONCLUSIONS: Chinese MSM have relatively low HIV testing rates compared with MSM in other settings. It is important to continue to promote HIV testing among MSM in China. PMID- 22252152 TI - Endocrine carcinoma of the stomach: clinicopathological analysis of 27 surgically treated cases in a single institute. AB - BACKGROUND: Gastric endocrine carcinoma (EC) is an uncommon tumor of the stomach and the clinical features are not well known. Additionally, the classification and staging systems of this tumor are not yet unified worldwide. In this study, we reviewed 27 patients with gastric EC to evaluate the clinicopathological characteristics of this tumor. METHODS: We retrospectively reviewed 27 patients with gastric EC among 6466 patients who had undergone gastrectomy between 1986 and 2008 at our institute. Clinicopathological features including immunohistochemistry of Ki-67 were investigated to evaluate the malignant potential of the tumor. Furthermore, survivals were compared between the 7th edition of the International Union Against Cancer (UICC)-TNM (7th TNM) classification for gastric cancer (GC) and the new TNM classification for foregut neuroendocrine tumors (NET). RESULTS: The median survival of the patients was 19.0 months. The 5-year survival rate was 100% in pathological stage (pStage) I, 40% in pStage II, 38% in pStage III, and 11% in pStage IV according to the 7th TNM classification for GC. Survivals by stage showed great difference between the 7th TNM classification for GC and the new TNM classification for foregut NET, but each system correlated with survival. The Ki-67 labeling index was more than 20% in most of the patients. Univariate analysis revealed that maximum tumor diameter, tumor depth, lymph node metastasis, lymphatic invasion, pStage, and curability had significant correlations with survival. CONCLUSION: Early detection and curative operations are essential for improving the prognosis of gastric EC. However, some adjuvant chemotherapies are required for advanced-stage tumors. Classification and staging systems may need to be unified worldwide for further analysis. PMID- 22252154 TI - Patient heterogeneity and allocation bias: how should they be reported in clinical trials of chemotherapy for advanced gastric cancer? PMID- 22252153 TI - Descriptive epidemiology of gastric adenocarcinoma in the state of Texas by ethnicity: Hispanic versus White non-Hispanic. AB - BACKGROUND: We aimed to evaluate the clinicopathological and demographic characteristics of gastric adenocarcinoma in Hispanics and compare these trends with those found in non-Hispanic Whites in Texas. METHODS: Records of patients with gastric adenocarcinoma found in the Texas Cancer Registry from 1995 to 2006 were reviewed. Four ethnic-geographic groups were formed: Hispanics residing in El Paso County (a county on the Texas-Mexico border), White non-Hispanics in El Paso County, Hispanics from the remaining counties of Texas combined, and White non-Hispanics from the remaining counties of Texas combined. Adjusted prevalence ratios (PRs) for the outcome of late stage at diagnosis were calculated. RESULTS: Of 9949 patients, 561 patients were El Paso County residents, of whom 83% were Hispanics. Among the four ethnic-geographic groups, the age-adjusted incidence was the highest in Hispanics in El Paso County (15.5 cases/100000). Tumor pathobiology varied by ethnicity. White non-Hispanics were more likely than Hispanics to have a proximal tumor and less likely to have a poorly differentiated or undifferentiated tumor. In El Paso County, patients in each of the eight age groups under 75 years compared to patients aged >=85 years were significantly more likely to be at late stage (adjusted PRs 1.44-1.71). CONCLUSION: The incidence of gastric adenocarcinoma is higher in Hispanics than in Whites in both El Paso County and the remaining portion of Texas. Hispanics have a higher grade of gastric adenocarcinoma. The prevalence of late stage at the time of diagnosis is higher in younger patients than in older patients. PMID- 22252155 TI - Magnifying endoscopy with narrow-band imaging helps determine the management of gastric adenomas. AB - BACKGROUND: There are no clear clinical criteria for the management of gastric lesions diagnosed as adenomas (Vienna classification category 3) by pre-treatment biopsy. In the present study, we examined the feasibility of magnifying endoscopy with narrow-band imaging (ME-NBI) in discriminating early gastric cancers (Vienna classification category 4 or 5) from adenomas in lesions diagnosed as adenomas by pre-treatment biopsy. METHODS: This was a single-center cross-sectional retrospective study at a tertiary referral center. One hundred thirty-seven consecutive cases of gastric lesions diagnosed as adenomas in pre-treatment forceps biopsy were examined with conventional non-magnifying endoscopy under white light, non-magnifying chromoendoscopy, and ME-NBI. We investigated the association between the final pathological diagnoses (carcinoma or adenoma) and the following factors: lesion size (mm), color (red or white), macroscopic type (depressed or others), presence of ulceration, and positive ME-NBI finding. The presence of an irregular microvascular pattern or an irregular microsurface pattern with a demarcation line between the lesion and the surrounding area was regarded as a positive ME-NBI finding. RESULTS: Lesion size was significantly larger in carcinomas than adenomas (P = 0.005). Depressed lesion (P = 0.011), red color (P < 0.001), and positive ME-NBI finding (P < 0.001) were significant predictive factors for carcinoma. Multivariate logistic regression confirmed that red color (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.26-7.34, P = 0.14) and a positive ME-NBI finding (OR 13.68, 95% CI 5.69-32.88, P < 0.001) were independent predictive factors for carcinomas. A positive ME-NBI finding was the strongest predictive factor. CONCLUSIONS: ME-NBI is useful in planning the management of lesions diagnosed as adenomas by pre-treatment forceps biopsy. PMID- 22252156 TI - Efficacy of weekly paclitaxel in patients with advanced gastric cancer refractory to docetaxel-based chemotherapy. AB - BACKGROUND: Only partial cross-resistance between docetaxel and paclitaxel has been demonstrated in breast and ovarian cancers. Whether weekly paclitaxel is effective in patients with advanced gastric cancer refractory to docetaxel-based chemotherapy remains unclear, and we aimed to clarify the efficacy and safety of weekly paclitaxel in such patients. METHODS: Patients who had received docetaxel based regimens were assigned to the prior-docetaxel group, and those who had never received docetaxel were designated as the non-docetaxel group. Paclitaxel at 80 mg/m(2) was administered by intravenous infusion in all patients, and this was repeated weekly for 3 weeks out of 4. RESULTS: Between April 2006 and June 2011, 65 patients were studied: 26 in the prior-docetaxel group and 39 patients were non-docetaxel group. The median age, gender, performance status, histological type, history of gastrectomy, and the locations and numbers of metastatic sites did not differ significantly between the two groups. In the prior-docetaxel group, the response rate (RR) was 14.2% (3/21) among patients with measurable lesions, median progression-free survival (PFS) was 79 days [95% confidence interval (CI), 47-135 days], and overall survival (OS) was 123 days (95% CI, 90-215 days) from the initiation of paclitaxel treatment. In the non docetaxel group, the RR was 11.5% (3/26) among patients with measurable lesions, PFS was 82 days (95% CI, 52-106 days), and OS was 143 days (95% CI, 121-178 days). The efficacy of weekly paclitaxel thus appeared to be similar in the two groups. CONCLUSIONS: Weekly paclitaxel was modestly active in patients with gastric cancer refractory to docetaxel-based chemotherapy. PMID- 22252157 TI - Vitamin A and gastric cancer risk. PMID- 22252158 TI - Decreased number and reduced NKG2D expression of Vdelta1 gammadelta T cells are involved in the impaired function of Vdelta1 gammadelta T cells in the tissue of gastric cancer. AB - BACKGROUND: In cancer patients, impaired function of immune cells--such as CD8(+) T cells, NK cells, and dendritic cells--reportedly results in tumor progression. Although gammadelta T cells also play a critical role in tumor defense, their function remains unclear in cancer patients. METHODS: The frequency and function of gammadelta T cells in peripheral blood, normal gastric mucosa, and cancer tissue were evaluated by multicolor flow cytometry. We also determined NKG2D expression on gammadelta T cells in gastric cancer patients. RESULTS: The frequency of Vdelta1 gammadelta T cells in gastric cancer tissue is significantly lower than in normal gastric mucosa; however, differences in the frequencies of Vdelta2 and Vgamma9 gammadelta T cells between normal gastric mucosa and gastric cancer tissue were not statistically significant. The Vdelta1 gammadelta T cells from gastric cancer tissue produce significantly less IFN-gamma than those from normal gastric mucosa do. Expression of NKG2D on Vdelta1 gammadelta T cells from gastric cancer tissue was significantly lower than in normal gastric mucosa. We also found a significant correlation between NKG2D expression and IFN-gamma production of Vdelta1 gammadelta T cells in gastric cancer tissue. CONCLUSION: Vdelta1 gammadelta T cells show decreased frequency and impaired function in gastric cancer tissue, for which decreased NKG2D expression might be one of the mechanisms. Modalities specifically targeting NKG2D in Vdelta1 gammadelta T cells may provide a breakthrough treatment for gastric cancer patients. PMID- 22252159 TI - Effect of ageing on the murine venous circulation. AB - The effect of ageing on the morphology of veins, venous valves and arteries was investigated in male wild-type mice using an adapted procedure with injection of a silicone polymer Microfil((r)) that preserves morphology of the vasculature. Throughout the hind limb the arterial, but not the venous, lumen area and wall thickness were significantly greater in 24-month as compared to 10-week-old C57BL/6 mice. Venous valves were most frequently located at the sapheno-femoral vein junction in the lower extremities, and appeared thicker at the base supported by structurally intact collagen fibers, and thinner towards the proximal end of the valve leaflet, with less organized collagen. Overall, valves were less supported by structurally intact collagen at 24 months as compared to 10 weeks. Endothelial expression of CD31, endothelial protein C receptor or von Willebrand factor (VWF) was not affected by age, while thrombomodulin expression was lower in aged versus young arteries. At both ages, expression of VWF was lower at venous valves versus veins. Evaluation of the blood coagulation profile revealed that aged mice had shortened prothrombin time, elevated plasma levels of factor (F)VII, FVIII and VWF and increased neutrophil and platelet counts. Thus, our data indicate that in mice with ageing, venous valves become more fragile, in association with a procoagulant and inflammatory blood phenotype. Taken together, we found that the procoagulant state in ageing, is accompanied by mild vascular changes. PMID- 22252160 TI - A partially crosslinked bicontinuous cubic phase exhibiting a temperature range of more than 100 degrees C. AB - A new methodology of partial crosslinking is presented for stabilizing the bicontinuous cubic phase without losing its dynamic nature. It was applied to a mixture of 1,2-bis[4'-(9''-decenyloxy)benzoyl]hydrazine with a bi-functional linker, remarkably stabilizing the phase in comparison with the neat compound having no C=C bond at the end of the alkyl tail. PMID- 22252161 TI - Growth of zeolite crystals with graphene oxide nanosheets. AB - Growth of silicalite with graphene oxide (GO) nanosheets occurred via attachment of GO onto the silicalite surface, and entrapment of GO nanosheets inside single crystals. Electrically conductive composites were produced by calcination in nitrogen whereas silicalite crystals with slit-like mesopores of sizes 20-25 A were obtained after GO burn-off. PMID- 22252162 TI - Violence in Canadian amateur hockey: the experience of referees in Ontario. AB - OBJECTIVE: To determine the perceptions and roles of referees about violence and injury in hockey games. DESIGN: Questionnaire. SETTING: Web-based survey. PARTICIPANTS: We contacted referees across Canada from various leagues and all levels of play, with the majority of respondents from Ontario (92%). MAIN OUTCOME MEASURES: We gathered demographic information anonymously and posed questions on aggression and experience in hockey games. RESULTS: The majority of referees (n = 632) indicated that violence is a serious concern to both players and referees at all levels of hockey. More than 90% of referees responded that they were the recipients of aggression and anger (92.1%, 95% confidence interval, 90.0-94.2), 55% had been involved in hockey games where aggressive behavior resulted in the referee losing control of the game, and 71% said that this increased aggression leads to injury. Referees' opinions are that the coach is the most responsible for managing on-ice safety (63%). To improve hockey safety, referees suggest education and more rigorous enforcement of discipline for all participants. CONCLUSIONS: Referees are important for hockey safety and need to be appropriately supported. Referees believe that increased aggression can lead to injury and that rules need to be enforced more diligently. Referees recommend that increased education about safety is needed to guide parents, coaches, and players to make hockey safer. PMID- 22252163 TI - Time-to-subsequent head injury from sports and recreation activities. AB - OBJECTIVE: To provide population-based risk estimates for sustaining subsequent head injuries (HIs), which occur in sports and recreation (SR). DESIGN: Population-based, retrospective, cross-sectional study. SETTING: Retrospective review of data from 2 tertiary care and 3 community care emergency departments (EDs) in Edmonton, Alberta, Canada. PATIENTS: Individuals younger than 36 years presenting to an ED with an SR-related injury between April 1, 1997, and March 31, 2008. There were 9246 subsequent ED records identified for 8958 patients in the main analysis. MAIN OUTCOME MEASURES: Clinically diagnosed HI occurring in SR activities after an index presentation, and the number of days between ED presentations for diagnosed SR-HIs. RESULTS: Individuals with 1 and 2 previous SR related HIs were 2.62 [95% confidence interval (CI), 2.23-3.07] and 5.94 times, respectively, more likely (95% CI, 3.43-10.29) to sustain a subsequent HI than those without a previous HI. The median time-to first HI was 758 days from an initial injury and decreased to 613 days and 303 days for those at risk of second and third SR-related HIs (P < 0.0001). Individuals aged 7 to 13 years were 4.29 times more likely (95% CI, 2.65-6.92) to sustain an HI when presenting with a subsequent SR injury, compared with those aged 30 to 35 years. CONCLUSIONS: The odds of sustaining a subsequent HI substantially increase with each successive HI. Time between SR-related HIs shortens as the number of HIs increases. Initial HI may be a key marker to institute high-risk injury prevention measures directed at young persons who present to EDs. PMID- 22252165 TI - Macroinvertebrate community response to repeated short-term pulses of the insecticide imidacloprid. AB - Small streams in agricultural landscape can experience short and repeated pulses of fluctuating pesticide concentrations. A single pesticide pulse may not have adverse effects on macrozoobenthos species but repeated pulses may have, especially if the organisms have not yet fully recovered when the second pesticide pulse occurs. Against this background, a comprehensive indoor stream mesocosm study was carried out in order to evaluate the cumulative effects of repeated insecticide pulses on a macrozoobenthos community. Weekly 12h pulses of 12 MUg/L of the insecticide imidacloprid were set 3 times in 4 stream mesocosms in 2 series, one in spring and one in summer. Another 4 mesocosms served as controls. Prior to each pulse series, the mesocosms were stocked with macroinvertebrates from an uncontaminated reference stream using straw bags as attraction devices. The straw bag method proved suitable for establishing a functional macroinvertebrate community in the stream mesocosms. The caddisfly species Neureclipsis sp. reacted immediately and most sensitively after a single imidacloprid pulse whilst insect larvae such as ephemerids and dipteran larvae were negatively affected only after repeated imidacloprid pulses. Effects on insect larvae were more pronounced in the summer series most likely due to increased temperature. Abundance was a less sensitive endpoint than sublethal endpoints such as emergence. The results of the study underline that pulse effects are driven by a number of variables like pulse height, pulse duration, number of pulses, time in between pulses and by the species and live stage specific ability of temperature dependent detoxification which all should be taken into account in the risk assessment of pesticides. PMID- 22252166 TI - Specific ion effects on the electrochemical properties of cytochrome c. AB - The range of salts used as supporting electrolytes in electrochemical studies of redox proteins and enzymes varies widely, with the choice of an electrolyte relying on the assumption that the electrolyte used does not affect the electrochemical properties of the proteins and enzymes under investigation. Examination of the electrochemical properties of the redox protein cytochrome c (cyt c) at a 4,4'-bipyridyl modified gold electrode demonstrates that both the redox potential (E(o')) and the faradaic current are influenced by the nature of the electrolyte used, in a manner explained primarily by Hofmeister effects. The faradaic peak currents display an atypical trend on switching from kosmotropic to chaotropic anions, with a maximum current observed in the presence of Cl(-). For a series of cations, the peak current increased in the sequence: Li(+) (0.34 MUA) < guanidinium(+) (0.36 MUA) < Na(+) (0.37 MUA) < K(+) (0.38 MUA) < Cs(+) (0.40 MUA) and for anions it decreased in the sequence: Cl(-) (0.37 MUA) > Br(-) (0.35 MUA) > ClO(4)(-) (0.35 MUA) > SCN(-) (0.31 MUA) > F(-) (0.30 MUA). E(o') decreased by a total of 24 mV across the series F(-) > Cl(-) > Br(-) > ClO(4)(-) > SCN(-) whereas no specific ion effect on E(o') was observed for cations. Factorisation of E(o') into its enthalpic and entropic components showed that while no specific trends were observed, large changes in DeltaH(o') and DeltaS(o') occurred with individual ions. The effect of anions on the faradaic peak current can be qualitatively explained by considering Collins' empirical rule of 'matching water affinities'. The effect of cations cannot be explained by this rule. However, both anion and cation effects can be understood by taking into account the cooperative action of electrostatic and ion dispersion forces. The results demonstrate that the choice of a supporting electrolyte in electrochemical investigations of redox proteins is important and emphasize that care needs to be taken in the determination and comparison of E(o'), DeltaH(o') and DeltaS(o') in different solutions. PMID- 22252167 TI - Characterization of RNA aptamers directed against the nucleocapsid protein of Rift Valley fever virus. AB - Nucleocapsid protein (N) is an essential RNA binding protein in many RNA viruses. During replication, N protein encapsidates viral genomic and antigenomic RNA, but not viral mRNA or other cellular RNAs. To discriminate between different species of RNA in a host cell, it is likely that N interacts with specific sequences and/or secondary structures on its target RNA. In this study, we explore the RNA binding properties of N using both natural and artificially selected RNAs as ligands. We found that N binds to RNAs that resemble the terminal panhandle structures of RVFV genomic and antigenomic RNA. Furthermore, we used SELEX to isolate RNA aptamers that bound N with high affinity and determined that N specifically recognizes and binds to GAUU and pyrimidine/guanine motifs. Interestingly, BLAST analysis revealed the presence of these motifs within the coding region of the viral genome, suggesting that N may interact with non terminal viral RNA sequences during replication. Finally, the aptamer RNAs were used to construct a sensitive fluorescence based sensor of N binding with potential applications for drug screening and imaging methodologies. PMID- 22252168 TI - Susceptibility of avian influenza viruses of the N6 subtype to the neuraminidase inhibitor oseltamivir. AB - Avian influenza viruses are a source of genetic material that can be transmitted to humans through direct introduction or reassortment. Although there is a wealth of information concerning global monitoring for antiviral resistance among human viruses of the N1 and N2 neuraminidase (NA) subtypes, information concerning avian viruses of these and other NA subtypes is limited. We undertook a surveillance study to investigate the antiviral susceptibility of avian influenza N6 NA viruses, the predominant subtype among wild waterfowl. We evaluated 73 viruses from North American ducks and shorebirds for susceptibility to the NA inhibitor oseltamivir in a fluorescence-based NA enzyme inhibition assay. Most (90%) had mean IC(50) values ranging from <0.01 to 5.0nM; 10% were from 5.1 to 50.0nM; and none were >50.0nM. Susceptibility to oseltamivir remained stable among all isolates collected over approximately three decades (P?0.74). Two isolates with I222V NA substitution had moderately reduced susceptibility to oseltamivir in vitro (IC(50), 30.0 and 40.0nM). One field sample was a mixed population containing an avian paramyxovirus (APMV) and H4N6 influenza virus, as revealed by electron microscopy and hemagglutination inhibition assays with a panel of anti-APMV antisera. This highlights the importance of awareness and careful examination of non-influenza pathogens in field samples from avian sources. This study showed that oseltamivir-resistant N6 NA avian influenza viruses are rare, and must be tested both phenotypically and genotypically to confirm resistance. PMID- 22252170 TI - A Rare Case of Gastrointestinal Stromal Tumour in Pregnancy Presenting with Upper Gastrointestinal Bleeding. PMID- 22252171 TI - Congenital syphilis in Switzerland: gone, forgotten, on the return. AB - INTRODUCTION: Acquired syphilis has re-emerged in many Western European countries. In contrast to international guidelines, screening for syphilis in pregnancy is not generally recommended in Switzerland. There has been an increase in the incidence of laboratory syphilis notifications in recent years, regardless of gender and age. METHODS: We conducted a retrospective study, evaluating the total numbers of pregnant women with positive syphilis serology (Treponema pallidum Particle Agglutination assay, TPPA) from 2000 to 2009, and evaluated the clinical management and outcome of their offspring. In addition, we sought to determine cases of infectious syphilis (primary, secondary, and early latent syphilis) reported to the Swiss Federal Office of Public Health in women of childbearing age, which has previously been shown to precede changes in the incidence of congenital syphilis within a population. RESULTS: Out of 13,833 women who gave birth at our institution, positive syphilis serology was found in 9 pregnant women during the 10 years studied. A total of 6 pregnant women were diagnosed having syphilis infection during pregnancy. Regarding their offspring, 8 of the 9 newborns were tested serologically. One neonate experienced congenital syphilis because the adequately treated mother developed re-infection after treatment. Within the Swiss population, infectious syphilis cases in women of childbearing age increased substantially from 2006 to 2009. CONCLUSIONS: The epidemiologic data suggest that congenital syphilis could become a medical problem in Switzerland due to the rise of infectious syphilis cases in women of childbearing age that have been shown to be followed by changes in the congenital syphilis incidence. The persistence of congenital syphilis in Switzerland along with this rise of infectious syphilis in women of childbearing age suggests a potential for improvement of prenatal care and syphilis control programmes. PMID- 22252172 TI - Optimising multistage dairy cattle breeding schemes including genomic selection using decorrelated or optimum selection indices. AB - BACKGROUND: The prediction of the outcomes from multistage breeding schemes is especially important for the introduction of genomic selection in dairy cattle. Decorrelated selection indices can be used for the optimisation of such breeding schemes. However, they decrease the accuracy of estimated breeding values and, therefore, the genetic gain to an unforeseeable extent and have not been applied to breeding schemes with different generation intervals and selection intensities in each selection path. METHODS: A grid search was applied in order to identify optimum breeding plans to maximise the genetic gain per year in a multistage, multipath dairy cattle breeding program. In this program, different values of the accuracy of estimated genomic breeding values and of their costs per individual were applied, whereby the total breeding costs were restricted. Both decorrelated indices and optimum selection indices were used together with fast multidimensional integration algorithms to produce results. RESULTS: In comparison to optimum indices, the genetic gain with decorrelated indices was up to 40% less and the proportion of individuals undergoing genomic selection was different. Additionally, the interaction between selection paths was counter intuitive and difficult to interpret. Independent of using decorrelated or optimum selection indices, genomic selection replaced traditional progeny testing when maximising the genetic gain per year, as long as the accuracy of estimated genomic breeding values was >= 0.45. Overall breeding costs were mainly generated in the path "dam-sire". Selecting males was still the main source of genetic gain per year. CONCLUSION: Decorrelated selection indices should not be used because of misleading results and the availability of accurate and fast algorithms for exact multidimensional integration. Genomic selection is the method of choice when maximising the genetic gain per year but genotyping females may not allow for a reduction in overall breeding costs. Furthermore, the economic justification of genotyping females remains questionable. PMID- 22252174 TI - Neuroblastoma: the challenge remains. PMID- 22252173 TI - Estrogen and progesterone play pivotal roles in endothelial progenitor cell proliferation. AB - BACKGROUND: It has been previously suggested that angiogenesis occurs during the menstrual cycle. Moreover, a rise in uterine blood flow is largely maintained by vasodilatation and substantial increases in angiogenesis. It is known that estradiol (E2) and progesterone (P4) are involved in angiogenesis. Recently, endothelial progenitor cells (EPCs) were found to be involved in neovascularization; however, their roles in uterine neovascularization have not been well characterized. We hypothesized that E2- or P4-mediated EPC proliferation plays important roles in uterine neovascularization during the menstrual cycle. METHODS: The number of EPCs in peripheral blood from subjects in the menstrual phase (n=12), follicular phase (n=8), and luteal phase (n=16), was measured using flow cytometry. Peripheral blood mononuclear cells (PBMCs) were cultured for seven days with or without 17beta-estradiol (E2beta) or P4, followed by assessment of EPC proliferation based upon the uptake of acetylated low density lipoprotein (LDL) and lectin. The expression of estrogen receptor (ER) or progesterone receptor (PR) in EPCs was also evaluated using real-time PCR. RESULTS: E2beta and P4 significantly increased the proliferation of EPCs derived from the peripheral blood of subjects in menstrual phase, but not subjects in the luteal phase. In addition, the expression level of ERalpha was markedly higher than ERbeta in EPCs derived from women in menstrual phase. CONCLUSIONS: EPC proliferation is induced during the menstrual phase and proliferation can be affected by estrogen through ERalpha activation. PMID- 22252175 TI - Singapore cancer trends in the last decade. AB - In this review, we examine the trends in cancer incidence, mortality and survival in the last decade, using published data from the Singapore Cancer Registry in the period 1998 to 2009. While overall cancer incidences have remained stable, overall cancer mortality rates have declined for both genders. Thus, it is not surprising that there was an improvement in cancer survival. A steady decrease in lung cancer among males and females was observed, thereby leading to a drop in its cancer ranking. In the last five years, the most frequently occurring cancer was colorectal cancer among the male population and breast cancer among females. Survival for both cancers remained relatively optimistic. There is good reason to pay special attention to colorectal cancer due to its high frequency of occurrence among the Singapore population and because it is amenable to early detection via screening. PMID- 22252176 TI - Ethical dilemmas in the care of cancer patients near the end of life. AB - By definition, an ethical dilemma involves the need to choose from among two or more morally acceptable options or between equally unacceptable courses of action, when one choice prevents selection of the other. Advances in medicine, increasing economic stress, rise of patient self-determination and differing values between healthcare workers and patients are among the many factors contributing to the frequency and complexity of ethical issues in healthcare. In the cancer patient near the end of life, common ethical dilemmas include those dealing with artificial nutrition and hydration, truth-telling and disagreements over management plans. It would stand the clinician in good stead to be aware of these issues and have an approach toward dealing with such problems. In addition, organisations have a responsibility to ensure that systems are in place to minimise its occurrence and ensure that staff are supported through the process of resolving dilemmas and conflicts that may arise. PMID- 22252177 TI - Willem Einthoven (1860-1927): father of electrocardiography. PMID- 22252178 TI - Neuroblastoma: experience from National University Health System, Singapore (1987 2008). AB - INTRODUCTION: Neuroblastoma is the most common extracranial solid tumour in childhood. We report our experience at National University Health System (NUHS), Singapore. METHODS: We performed a retrospective chart review of 43 patients diagnosed with neuroblastoma, who were seen and treated at the Department of Paediatrics, NUHS from November 1987 to November 2008. RESULTS: The median age of the patients at diagnosis was 1.9 (range 0.1-20.2) years. The majority (70.1%) of primary tumours were of abdominal and/or adrenal origin. According to the International Neuroblastoma Staging System, six (14.0%) patients were in stages 1 and 2, 11 (25.6%) in stage 3, 19 (44.2%) in stage 4, and seven (16.2%) in stage 4s. Therapy for all patients included surgery and/or chemotherapy and/or radiation therapy. Patients with stage 4 disease also underwent autologous stem cell transplant. The median follow-up for the cohort was 2.5 (range 0.4-21.0) years. At the time of analysis, 29 (67.4%) patients were alive. The two- and five year overall survival for the cohort was 65.0% (95% confidence interval [CI] 51.0%-80.0%) and 62.0% (95% CI 45.0%-79.0%), respectively. The five-year overall survival rates according to risk status were 100.0% for low-risk, 75.0% for intermediate risk and 28.2% for high-risk neuroblastoma. CONCLUSION: The prognosis for those with advanced stage neuroblastoma remains poor. A collaborative effort, with an emphasis on research in detecting biologic characteristics of aggressive disease and tailoring therapy, needs to be strengthened in order to further our understanding of this disease. PMID- 22252179 TI - Predominance of G to A codon 12 mutation K-ras gene in Dukes' B colorectal cancer. AB - INTRODUCTION: K-ras gene mutations in codons 12 and 13 are one of the earliest events in colon carcinogenesis. METHODS: DNA was extracted from 25 mg of tumour tissue (n = 70) that were taken from tumour mass and pairs with normal epithelial tissue distant from the tumour of colorectal cancer patients. Exon 1 and exon 2 of the K-ras gene were amplified. Hotspot mutations were detected using polymerase chain reaction-based single-strand conformation polymorphism method and confirmed by direct DNA sequencing analysis. RESULTS: Mutations were identified in 14 out of the 70 (20%) colorectal carcinoma tissues. Single-base transition from GGT to GAT (glycine to aspartate) in codon 12 was detected in nine samples, while three samples presented with GGC to GAC transition in codon 13. Patients with large adenoma had a 12-fold higher likelihood of K-ras mutations (odds ratios [OR] 12.31; 95% confidence intervals [CI] 1.81-83.76). Tumours located at the left colon were more likely to present with K-ras mutations (OR 4.54; 95% CI 0.96-21.54). CONCLUSION: Our study showed a high frequency of G to A transition of codon 12 mutation of the K-ras gene, with significant correlation with tumour size and tumour location. PMID- 22252180 TI - Value of alpha-foetoprotein for screening of recurrence in hepatocellular carcinoma post resection. AB - INTRODUCTION: The aim of this study was to establish the value of alpha foetoprotein (AFP) for the screening of recurrences in hepatocellular carcinoma (HCC) in patients who have undergone curative hepatic resection. METHODS: 72 HCC patients who had curative resection/liver transplant in 2000-2006 were monitored for recurrence by evaluating the three- or six-monthly AFP and computed tomography images. Patients without recurrence were followed up for a mean duration of 7.27 years. RESULTS: Out of the 72 patients, 34 (47.2%) suffered from HCC recurrence. 65.4% of recurrent cases had AFP values showing an upward trend. Patients with recurrence had higher AFP values than those without at last follow up (119.45 MUg/L vs. 3.1 MUg/L, p < 0.001). AFP at recurrence was independent of gender, race, history of alcohol consumption and hepatitis C or cirrhosis status. Patient with hepatitis B or those with tumours larger than 5 cm had higher AFP values. The best cut-off AFP indicative of HCC recurrence was 5.45 MUg/L (sensitivity 84.4%; specificity 77.1%). High preoperative AFP was associated with high AFP at recurrence (correlation coefficient 0.553, p = 0.01). CONCLUSION: AFP alone is an inadequate screening test for HCC recurrence since only about two thirds of patients showed upward AFP trend on recurrence. Our study found a relatively low cut-off point for detection of recurrence (5.54 MUg/L). Patients with high preoperative AFP tended to have high AFP on recurrence. Imaging is recommended for patients with AFP levels > 5.45 MUg/L, especially when AFP shows a rising trend. PMID- 22252181 TI - Psychometric properties of the Malay version of the Breast Module (BR23). AB - INTRODUCTION: The Breast Module (BR23) is increasingly being used worldwide in breast cancer research. This study evaluates the appropriateness of the translated version (i.e. BR23-Malay version) as a useful tool for the Malaysian population who could understand Malay, and examines the reliability and validity of the BR23-Malay version. METHODS: This was a prospective study involving 68 Malaysian women who could understand Malay very well. They answered the BR23 Malay version at two evaluation points--three and ten weeks following surgery for breast cancer. Internal consistency, test-retest intraclass correlation coefficients (ICC), effect size index, sensitivity and discriminity of the scale were calculated. RESULTS: Internal consistencies were acceptable for the functional domains (0.87 for body image; 0.84 for sexual functioning) and symptomatology domains (0.82 for systemic therapy side effect; 0.82 for breast symptoms; 0.70 for arm symptoms). Test-retest ICC ranged from 0.26 to 1.00. Sensitivity of the scale was observed in all domains except sexual functioning. CONCLUSION: The Malay version of BR23 is a suitable tool to measure the functional and symptomatology domains of women diagnosed with breast cancer. PMID- 22252182 TI - Diagnostic accuracy of ultrasonography-guided core needle biopsy for breast lesions. AB - INTRODUCTION: This study aimed to assess the diagnostic accuracy of ultrasonography (US)-guided core needle biopsy (CNB) for breast lesions. METHODS: We performed US-guided CNB of 733 lesions in 674 women from January 2003 to December 2005. Surgical excision was performed on 331 lesions. We compared the histopathologic findings of the CNB specimens with those of surgical specimens or with patients' long-term follow-up images. We also calculated the agreement, underestimation, sensitivity and false-negative rates. RESULTS: The CNB results showed 334 breast cancers (46%), 28 high-risk lesions (5%) and 367 benign lesions (50%). Four (1%) lesions were categorised as inconclusive. The final diagnosis was breast cancer in 348 lesions. The kappa measure of agreement between the US guided CNB results and surgical excision findings or follow-up results was 0.861 (p-value < 0.001). The underestimation rate was 40% (10 out of 25) for atypical ductal hyperplasia and 47% (14 out of 30) for ductal carcinoma in situ (DCIS). The CNB false negative rate and sensitivity for malignant lesions was 4% (14 out of 348) and 96% (334 out of 348), respectively. CONCLUSION: US-guided CNB is an accurate diagnostic alternative to surgical biopsy in patients with breast lesions detected via US, although the high underestimation rates in DCIS and high risk lesions are still a concern. PMID- 22252184 TI - Attitudes and role orientations on doctor-patient fit and patient satisfaction in cancer care. AB - INTRODUCTION: Findings in the area of patient-physician relationship are riddled with inconsistencies. Although patient-centredness has been found to have special relevance in chronic illnesses, no study in the Southeast Asian region has so far examined role orientation and its implication for patient-centred outcomes in the cancer context. This study aimed to examine role orientation in cancer patients and their physicians, doctor-patient fit and how this congruence relates to patient satisfaction. METHODS: The participants were 80 cancer patients and 12 physicians from a single academic medical centre. All participants completed the Patient-Practitioner Orientation Scale, while only the patient participants completed the self-administered Patient Satisfaction Questionnaire. RESULTS: The cancer patients and their oncologists were found to be patient-centred and thus showed a high doctor-patient fit. Our findings also support the hypothesis that patient-centredness (overall mean = 4.66 +/- 0.585) and patient-physician congruence (overall mean = 4.95 +/- 0.088) are significantly associated (t(90) = 1.75, p = 0.084) with patient satisfaction (r = 0.56, p < 0.01). CONCLUSION: To our knowledge, this study is the first in the Southeast Asian context to examine congruence using role orientations of cancer patients and their oncologists as well as the resultant patient satisfaction in an actual clinical setting. The finding that strong doctor-patient fit is linked to higher patient satisfaction is unexpected and differs from the results of other studies from the USA. Further studies are required in order to examine how this may be influenced by differences in socio-cultural norms and expectations. PMID- 22252183 TI - Reversal of Hartmann's procedure: experience in an Asian population. AB - INTRODUCTION: With improvements in surgical techniques, instrumentation and perioperative care, Hartmann's procedure is now less frequently performed. Restoration of intestinal continuity after Hartmann's procedure has traditionally been viewed to be technically demanding and associated with significant morbidity and mortality. This is a study of outcomes after the reversal of Hartmann's procedure in an Asian population. METHODS: A prospectively collected database showed that 255 patients had undergone Hartmann's procedure from October 1989 to October 2005. Patients who subsequently underwent Hartmann's reversal were identified and their records reviewed retrospectively. RESULTS: Hartmann's reversal was attempted in 49 patients. The most common indication for Hartmann's procedure was colorectal carcinoma (49.0%). The median interval between resection and reversal was 23 weeks. Reversal was successful in 46 (93.9%) patients, with 79.6% experiencing no intraoperative complications. Failure of reversal was significantly associated with prior radiotherapy to the pelvis (p-value = 0.007). Anastomotic leak rates and re-bleeding rates were both 0.0%. 79.6% of patients made an uneventful recovery with no postoperative complications. There was no significant increase in the complication rate in older patients or patients with higher American Society of Anesthesiologists status. The overall incidence of 30 day morbidity and mortality was 20.4% and 0.0%, respectively. CONCLUSION: In our population, Hartmann's procedure is more commonly performed for colorectal cancer rather than for diverticular disease, resulting in lower rates of stoma reversal. Hartmann's reversal could be performed with acceptable morbidity and minimal mortality, although prior radiotherapy and shorter rectal stump may pose challenges during reversal surgery. PMID- 22252185 TI - An update on imatinib mesylate therapy in chronic myeloid leukaemia patients in a teaching hospital in Malaysia. AB - INTRODUCTION: The introduction of imatinib mesylate in 1998 has changed the management of chronic myeloid leukaemia. It is now the first-line therapy for newly diagnosed chronic myeloid leukaemia patients worldwide. However, its long term survival benefit still needs to be established in clinical setting among Asian patients. METHODS: All chronic myeloid leukaemia patients in the chronic phase who were on imatinib mesylate therapy were retrospectively reviewed. Data was collected through a review of case notes, which was then processed, managed and analysed. RESULTS: A total of 44 patients were included in the study. The cumulative rates of complete haematological response, major cytogenetic response and major molecular response were 93.2%, 75.0% and 34.2%, respectively. The overall survival and event-free survival at five years were 86.0% and 84.9%, respectively. 31.8% of the patients developed anaemia, 29.5% neutropenia and 27.3% thrombocytopenia. A total of 43.2% of patients developed non-haematological side effects. Higher dosage (> 600 mg) and smaller body size (< 60 kg) were risk factors for haematological side effects. Patients with major cytogenetic response and absence of thrombocytopenia had better survival. CONCLUSION: The majority of our chronic myeloid leukaemia patients did well with imatinib therapy. The adverse effects in our patients were tolerable, and no patient had to stop treatment permanently. PMID- 22252186 TI - The use of midazolam and haloperidol in cancer patients at the end of life. AB - INTRODUCTION: This study aimed to describe the patterns of sedative use among terminally ill cancer patients who were referred to a hospital-based specialist palliative care service for symptom management. It also aimed to examine whether sedative use among terminally ill cancer patients during the last two days of life had any impact on their survival. METHODS: A retrospective review of case notes was carried out for patients with a diagnosis of terminal cancer, who died in a 95-bedded oncology ward between September 2006 and September 2007. Data was collected on patient characteristics, duration of palliative care, indications and doses of sedatives used at 48 hours and 24 hours before death. RESULTS: A total of 238 patients died while receiving specialist palliative care, 132 of whom (55.5%) were female. At 48 hours and 24 hours before death, 22.6% and 24.8% of patients, respectively, were on sedatives like midazolam, haloperidol or both. The median dose of midazolam was 5 mg/day while the haloperidol dose at 48 hours and 24 hours before death was 3 mg/day and 4 mg/day, respectively. The indications for midazolam were anxiety, breathlessness and stiffness, while those for haloperidol were confusion agitation and nausea. Survival analysis showed no significant difference in survival between patients who were on sedatives and those who were not. The p-value for log-rank test was 0.78. CONCLUSION: The results showed that the doses and overall frequency of sedative use in this patient population tended to be low and that usage of sedatives had no deleterious influence on survival. PMID- 22252187 TI - Clinics in diagnostic imaging (137). AB - A 45-year-old woman presented with generalised body itch, dark-coloured urine and pale stools for six day. Ultrasonography, endoscopic retrograde cholangiopancreatography and computed tomography revealed dilated intrahepatic ducts with stricture at the proximal common bile duct. The gallbladder was replaced by a large heterogeneous mass invading the liver and common bile duct. She underwent gallbladder resection, right hemihepatectomy, Whipple procedure, portal vein resection and reconstruction. Histopathology revealed diffusely infiltrating adenocarcinoma of the gallbladder. The patient made satisfactory postoperative recovery. The imaging features of gallbladder carcinoma are discussed. PMID- 22252190 TI - An unusual course of the thoracic duct in relation to the vertebral vessels. AB - A variation in the course of the thoracic duct was found in the cervical portion of a male cadaver during routine dissection of the head and neck region for undergraduate students. The thoracic duct, while arching laterally above the clavicle, was coursing posterior to the vertebral vein but anterior to the vertebral artery; it normally passes anterior to both the vertebral vein and artery. To the best of our knowledge, this variation in relation to the vertebral vein has not yet been reported. In addition, after coursing posterior to the vertebral vein, the thoracic duct divided into two branches that drained separately, one at the angle between the internal jugular vein and subclavian vein, and the other into the subclavian vein. Knowledge of these variations is essential in order to prevent injury to the thoracic duct while performing surgeries at the root of the neck. PMID- 22252192 TI - Intracranial hypertension with delayed puberty: a rare presentation of juvenile onset systemic lupus erythematosus. AB - An adolescent boy presented with headache, bilateral papilloedema, growth retardation and absent secondary sexual characteristics. The diagnosis of intracranial hypertension was confirmed by increased intracranial pressure and normal neuroimaging of the brain except for partial empty sella and prominent perioptic cerebrospinal fluid (CSF) spaces. Evaluation showed an erythrocyte sedimentation rate of 150 mm/hr, positive antinuclear antibody, anti-dsDNA and antiribosomal P protein. Renal biopsy revealed diffuse segmental proliferative lupus nephritis (LN) class IV-S (A), which confirmed the diagnosis of systemic lupus erythematosus (SLE). Treatment of LN with intravenous pulse methylprednisolone and cyclophosphamide normalised the patient's CSF pressure and symptoms. In cases of intracranial hypertension, SLE must be considered. Growth retardation and absence of secondary sexual characteristics could coexist and may be presenting features of SLE. These manifestations point to advanced grades of LN, which could be asymptomatic and may be missed without a renal biopsy. PMID- 22252191 TI - Psoriasiform dermatitis in a case of newly diagnosed locally advanced pyriform sinus tumour: Bazex syndrome revisited. AB - Acrokeratosis paraneoplastica of Bazex is a rare but important paraneoplastic dermatosis, usually manifesting as psoriasiform rashes over the acral sites. It often precedes diagnosis of the associated malignancy, usually that of upper aerodigestive tract squamous cell carcinoma. We present the case of a patient with a newly diagnosed pyriform sinus tumour and associated acrokeratosis paraneoplastica. To the best of our knowledge, this is the first reported case in the local literature. PMID- 22252193 TI - Graded balloon dilatation as a prerequisite to Amplatzer device closure of perforated interatrial septal aneurysm. AB - This case report describes a modification in the technique of atrial septal device closure in a patient with atrial septal defect (ASD) with associated atrial septum aneurysm and significant left-to-right shunt through multiple perforations. Graded balloon dilatation of the aneurysm was performed in this patient, as a preamble to successful deployment of a single large Amplatzer atrial septal occluder, closing the ASD completely and entrapping the aneurysm as a whole. PMID- 22252194 TI - Paradoxical emboli from left superior vena cava causing recurrent brain abscess. AB - Persistent left superior vena cava is a rare but well-recognised condition. We describe a case of persistent left superior vena cava draining directly into the left atrium, with a fixed anatomical right-to-left shunt and paradoxical embolic events causing recurrent brain abscess. Surgical ligation was curative. PMID- 22252196 TI - Splenic rupture in a patient with pelvic abscess and sepsis. AB - A 49-year-old man underwent appendicectomy through a Lanz incision for necrotic appendicitis. He subsequently developed pelvic abscess in the postoperative period, which was drained under computed tomography (CT) guidance. The bacteriology of pus swabs taken during appendicectomy and abscess drainage revealed coliforms. Six days after appendicectomy, the patient had an acute collapse due to rupture of the spleen, which was treated by splenectomy. CT of the abdomen at the time of abscess drainage had confirmed a normal spleen. Histopathological examination of the spleen revealed nonspecific acute splenitis- red pulp congested and infiltrated with neutrophils complicated by rupture. We postulate the abdominal source of sepsis and associated inflammatory response as the cause for the splenic pathology and rupture. PMID- 22252195 TI - Successful maternal-foetal outcome using nitric oxide and sildenafil in pulmonary hypertension with atrial septal defect and HIV infection. AB - Pulmonary hypertension associated with pregnancy carries a poor prognosis. We describe successful maternal-foetal outcome for a 30-year-old woman who was found to have severe pulmonary hypertension, human immunodeficiency virus (HIV) and an atrial septal defect. Prior to delivery, she was managed with subcutaneous enoxaparine, sildenafil, nitric oxide, careful maintenance of a euvolemic status and antiretroviral therapy. She was planned for an elective Caesarean section to reduce the risk of maternal-foetal HIV transmission, but went into labour in the coronary care unit. During delivery, antibiotic prophylaxis was given, although there was insufficient time for intravenous zidovudine. Peripartum, the patient was continued on nitric oxide and subcutaneous enoxaparine. She was eventually weaned off the nitric oxide and recovered well. PMID- 22252197 TI - Actinomyces turicensis infection mimicking ovarian tumour. AB - This case report explores an unusual presentation of a commensal organism, Actinomyces, which mimicked a presentation of ovarian cancer. A 73-year-old woman presented to a tertiary level hospital with persistent left iliac fossa abdominal pain, anorexia and fever lasting over one week, with a three-month history of bright rectal bleeding. Imaging was suggestive of malignancy. Fine needle aspiration of an enlarged lymph node was non-diagnostic. Blood cultures taken at presentation became positive after two days for Gram-positive rods, which were most likely Actinomyces. The patient was treated with penicillin 1.8 g four hourly with rapid improvement. Actinomycosis is frequently misdiagnosed as malignancy initially due to its relatively indolent course. Lesions often resolve with antibiotics, without the need for surgical intervention. PMID- 22252198 TI - Unzipping carbon nanotubes into nanoribbons upon oxidation: a first-principles study. AB - First-principles calculations are performed to investigate the unzipping mechanism of carbon nanotubes (CNTs) into narrow graphene nanoribbons (GNRs) upon oxidation. By treating possible adsorptive structures, we found that, upon further oxidation, epoxy pairs tear the CNT up with an initial energy barrier of 0.59 eV (armchair) and 0.60 eV (zigzag), and the following steps of unzipping CNT become much easier because of the stress induced by the carbonyl pair. However, for zigzag CNTS, the unzipped edge structures of nanoribbons cannot be controlled, because of the similar stability of different oxidation process, which means zigzag CNTs should be avoided in producing high-quality GNRs. PMID- 22252199 TI - Napyradiomycin A1, an inhibitor of mitochondrial complexes I and II. PMID- 22252200 TI - Catechoserine, a new catecholate-type inhibitor of tumor cell invasion from Streptomyces sp. PMID- 22252201 TI - Two new botcinin derivatives encountered in the studies of secondary metabolites from the marine-derived fungus Botryotinia sp. SF-5275. PMID- 22252202 TI - Identification, synthesis and characterization of a novel antimicrobial peptide HKPLP derived from Hippocampus kuda Bleeker. AB - A novel gene encoding 55 amino-acid residues has been identified from the brooding pouch cDNA library of Hippocampus kuda Bleeker. The deduced amino-acid sequence is highly homologous to several pleurocidin-like peptides from the winter flounder and comprises a signal peptide, a pro-peptide and a mature peptide. The glycine-rich mature peptide, designated HKPLP, contains 24 amino acid residues and has been synthesized by solid-phase peptide synthesis. The purified HKPLP exhibits antimicrobial activity against several Gram-positive and Gram-negative bacterial strains at low concentrations (MIC 1.5-7.5 MUM). Thermal stability assay data show good heat stability. CD spectroscopy experiments indicate that the dominant contents are anti-parallel and parallel sheets, which may have beta-sheet or beta-strand motif. It is inferred that HKPLP participates in the host defense during egg fertilization and embryo development as an antimicrobial peptide in brooding pouch. PMID- 22252203 TI - Segmental testicular infarction: report of seven new cases and literature review. AB - Segmental testicular infarction is a relatively rare acute or subacute condition which is infrequently thought of in the differential diagnosis for testicular pain. However, missing or misdiagnosing this entity on clinical evaluation and/or imaging has significant implications for patients as they may undergo unnecessary surgery for suspected testicular torsion or tumor. Knowledge and recognition of the features of segmental testicular infarction on ultrasound and MRI will aid in the diagnosis of this disease early in the patient's course. The common imaging features of segmental testicular infarction and the clinical literature are reviewed, with an emphasis on ultrasound, utilizing seven recent cases from three institutions. PMID- 22252205 TI - Commentary: Immunologic response to oral polio vaccine in human immunodeficiency virus-infected and uninfected Zimbabwean children. PMID- 22252204 TI - Maternal vitamin D status and child morbidity, anemia, and growth in human immunodeficiency virus-exposed children in Tanzania. AB - BACKGROUND: Vitamin D may help prevent adverse pediatric outcomes, including infectious diseases and growth failure, based on its role in immune and metabolic functions. We examined the association of maternal vitamin D status and pediatric health outcomes in children born to human immunodeficiency virus (HIV)-infected women. METHODS: Vitamin D status was determined in 884 HIV-infected pregnant women at 12 to 27 weeks of gestation in a trial of vitamin supplementation (not excluding vitamin D) in Tanzania. Information on child morbidities, anemia and hypochromic microcytosis, and anthropometry was recorded through monthly clinic visits. Generalized estimating equations and Cox proportional hazards models were used to assess the relationships of outcomes with maternal vitamin D status. RESULTS: A total of 39% of women had low vitamin D levels (<32 ng/mL). Children born to women with low vitamin D status were 1.11 times more likely to report cough during follow-up (relative risk [RR], 1.11; 95% confidence interval [CI], 1.02-1.21). No significant associations were noted for other respiratory symptoms, diarrhea, or anemia outcomes. Low maternal vitamin D status was associated with significantly increased risk of stunting (height-for-age z score, <-2; RR, 1.29; 95% CI, 1.05-1.59) and being underweight (weight-for-age z score, <-2; RR, 1.33; 95% CI, 1.03-1.71). CONCLUSIONS: Maternal vitamin D status may be important for preventing respiratory infections and ensuring optimal growth in HIV-exposed children. PMID- 22252206 TI - Efficacy of a pentavalent human-bovine reassortant rotavirus vaccine against rotavirus gastroenteritis among American Indian children. AB - BACKGROUND: Before the widespread use of rotavirus vaccines, rotavirus was a leading cause of gastroenteritis among children. Navajo and White Mountain Apache children suffer a disproportionate burden of severe rotavirus disease compared with the general U.S. population. METHODS: We enrolled Navajo and White Mountain Apache infants in a multicenter, double-blind, placebo-controlled trial of pentavalent human-bovine reassortant rotavirus vaccine (PRV). Subjects received 3 doses of vaccine or placebo at 4 to 10 week intervals, with the first dose given between 6 and 12 weeks of age. Gastroenteritis episodes were identified by active surveillance. Disease severity was determined by a standardized scoring system. RESULTS: There were 509 and 494 randomized children who received vaccine and placebo, respectively. Among placebo recipients, the incidence of rotavirus gastroenteritis was 34.2 episodes/100 child-years (95% confidence interval [95% CI]: 25.8-38.9) versus 8.1 episodes/100 child-years (95% CI: 5.4-12.5) in the vaccine group. The percentage of rotavirus episodes caused by serotypes G1, G2, and G3 was 72.3%, 23.4%, and 2.1%, respectively. There were no severe rotavirus episodes among vaccinees and 4 among placebo recipients. PRV was 77.1% (95% CI: 59.7-87.6), 89.5% (95% CI: 65.9-97.9), and 82.9% (95% CI: 61.1-93.6) effective against G1-G4 rotavirus disease, severe and moderate rotavirus disease combined, and outpatient visits for rotavirus disease, respectively. The risk of adverse events was similar for the vaccine and placebo groups. CONCLUSIONS: PRV was highly effective in preventing rotavirus disease and related health care utilization in these American Indian infants. Vaccine efficacy and immunogenicity were similar to the overall study population enrolled in the multicenter trial. PMID- 22252207 TI - A 2-month-old with bacteremia and gastroenteritis. PMID- 22252208 TI - Primary osteomyelitis of the clavicle in the newborn period. PMID- 22252209 TI - Antibiotic susceptibility of Kingella kingae isolates from children with skeletal system infections. PMID- 22252210 TI - CARESS: The Canadian Registry of Palivizumab. PMID- 22252212 TI - Health care-associated methicillin-resistant Staphylococcus aureus colonization in children attending day care centers in Singapore. PMID- 22252214 TI - Attitudes of pediatricians and primary health center physicians in India concerning routine immunization, barriers to vaccination, and missed opportunities to vaccinate. AB - BACKGROUND: India has some of the lowest immunization rates in the world. The objective of this study was to determine the attitudes and practices of pediatricians and physicians working in primary health centers (PHCs) regarding routine immunization and identify correlates of missed opportunities to vaccinate children. We focused on Uttar Pradesh and Bihar, which has faced some of the greatest challenges to achieving high routine immunization coverage. METHODS: A sample of pediatricians from Uttar Pradesh and Bihar was selected from the national membership of the Indian Academy of Pediatrics to participate in either a phone or mail survey. For the sampling frame, the PHCs within selected blocks were enumerated to provide a list from which individuals could be randomly sampled. In all, 614 PHCs in Uttar Pradesh and 159 PHCs were selected for in person surveys. RESULTS: The response rate for pediatricians was 47% (238/505) and 93% for PHC physicians (719/773). The greatest barrier to vaccinating children with routine immunizations, reported by both pediatricians (95.7%) and PHC physicians (95.1%), was parents' lack of awareness of their importance. Correlates of missing an opportunity to vaccinate for PHC physicians included holding other health care workers responsible for vaccination. PHC physicians were 50% to 70% less likely to vaccinate a child themselves if they thought another type of health care worker was responsible. CONCLUSIONS: Future interventions to increase vaccination coverage should address parental knowledge about the importance of vaccines. Understanding and addressing factors associated with missed opportunities to vaccinate may help improve vaccine coverage in Uttar Pradesh and Bihar. PMID- 22252215 TI - Antiviral treatment of influenza in children. AB - Influenza causes substantial morbidity in children in the United States each year. The 2009 influenza A (H1N1) pandemic disproportionately affected the pediatric population and resulted in a substantially increased number of hospitalizations and deaths among children. Early influenza antiviral treatment reduces the duration of illness, frequency of complications, antibiotic use, and health care utilization costs attributable to influenza. A comprehensive strategy to reduce influenza-associated hospitalizations and deaths among children should include empiric antiviral treatment for suspected or confirmed influenza of any severity in children who are hospitalized; who have severe, complicated, or progressive illness; or who are at high risk for influenza complications. Here, we summarize data on the burden of influenza among children in the United States, the indications for influenza antiviral treatment among children, the available evidence for influenza antiviral treatment, and antiviral treatment considerations, including resistance and adverse events. PMID- 22252216 TI - Antiretroviral therapy prescribing in hospitalized HIV clinic patients. AB - OBJECTIVES: Antiretroviral therapy (ART) medication prescribing errors in hospitalized patients still remain common. This study aimed to examine the initial prescribing of antiretroviral drug regimens for HIV clinic patients admitted to an urban academic teaching hospital. METHODS: A retrospective chart review of all patients with a discharge diagnosis of HIV or AIDS was performed. Only patients actively managed by the hospital out-patient HIV clinic at the time of discharge were included in the final analysis. We compared the ART initially prescribed during hospitalization with the clinic records. Medication errors were separated by type and the prescriber's area of specialty was noted. RESULTS: From 1 January 2009 to 31 December 2009, 90 admissions in 62 patients were included in the final analysis. In 47 of those admissions, the patient had an initial regimen considered to be incorrectly prescribed; in 17 of these 47 admissions, the patient was not prescribed any ART, and in the remainder the errors were related to drug omissions, incorrect frequency/dose, and prescription of the wrong drug. The majority of admissions were by an internal medicine or non-infectious disease (ID) specialist. Average time to ART initiation was comparable among all prescribers. No statistically significant correlation was found between the number of admissions per patient or the prescriber's area of specialty and the percentage of incorrect regimens ordered. CONCLUSION: Hospital HIV medication management still remains an area of focus because of the complexity of regimens, poor medication reconciliation and limited non-HIV/ID specialist knowledge. PMID- 22252217 TI - Effect of atorvastatin on erectile functions in comparison with regular tadalafil use. A prospective single-blind study. AB - OBJECTIVES: Erectile dysfunction (ED) is a common problem for elderly males. Higher serum lipid levels have important role in the pathogenesis, and in this prospective randomized trial, it is aimed to identify the effect of atorvastatin on erectile functions in comparison with regular tadalafil use. MATERIALS AND METHODS: 120 patients with a minimum 3-months history of moderate-to-severe ED were involved. The patients were randomized to receive atorvastatin 10 mg/day, tadalafil 20 mg 3 times/week or no medication. Baseline serum testosterone, lipid levels IEEF and NPT test were performed and repeated after 3 months of treatment, and the 3 groups were compared. RESULTS: Mean age of the whole population was 56 years (31-70). The 3 groups were well balanced for the baseline characteristics. Mean improvement of IIEF score was significantly higher in tadalafil group compared to atorvastatin (P = 0.01) and control group (P = 0.0001). Also atorvastatin showed significantly better improvement compared to control group (P = 0.001). Positive NPT test results in tadalafil group was significantly higher than atorvastatin group (25/40 (62.5%) vs. 16/41 (39%), P = 0.003) and compared to control group (25/40 (62.5%) vs. 3/39 (7.6%), P = 0.0001). At the same time, the difference between group 1 and group 3 was statistically significant (P = 0.001). CONCLUSION: Tadalafil 20 mg three times/week shows better results than 10 mg atorvastatin daily. Atorvastatin alone seems to improve EF compared to not using any medication, and this significance is more prominent in patients with supranormal serum lipid levels. Further studies with subgroups of different serum lipid levels should be conducted. PMID- 22252219 TI - A heptamethine cyanine-based colorimetric and ratiometric fluorescent chemosensor for the selective detection of Ag+ in an aqueous medium. AB - A highly selective and sensitive ratiometric fluorescent chemosensor for Ag(+) in aqueous solution was developed, in a linear range of 0.6 * 10(-7) to 50 * 10(-7) mol L(-1), based on a A-Ag(+)-A binding mode with a heptamethine cyanine motif containing one adenine moiety. PMID- 22252220 TI - Asymmetric oxidative Lewis base catalysis-unifying iminium and enamine organocatalysis with oxidations. AB - Enantioselective oxidative domino reactions of allylic alcohols to functionalized aldehydes have been developed. The one pot domino oxidation-iminium activation represents a convenient strategy for the enantioselective addition of malonates to allylic alcohols and the asymmetric formation of formyl cyclopropanes. PMID- 22252218 TI - Impact of asymptomatic prostatitis on re-operations due to urethral stricture or bladder neck contracture developed after TUR-P. AB - PURPOSE: To evaluate the relationship between pathologically proven prostatic inflammation (PI) and re-operation rates due to urethral stricture (US) or bladder neck contracture (BNC) after transurethral resection of prostate (TUR-P). MATERIALS AND METHODS: We have retrospectively reviewed the data of 917 consecutive TUR-P cases. Eligible patients (n = 276) were grouped with respect to presence of PI on TUR-P pathology; Group1: PI (+) (n = 67, 24.3%), and Group2: PI (-) (n = 209, 75.7%). The "re-operation" was defined as internal urethrotomy or bladder neck resection performed for BNC or US. Groups were compared with respect to descriptive data and need for re-operation. Logistic regression analysis was performed to estimate the independent risk factors for the development of BNC and US. P values under 0.05 were considered significant. RESULTS: Of the patients, 38 (13.8%) needed re-operation while 238 (86.2%) did not. The re-operation rate in Group1 was significantly higher than Group2 (29.8 vs. 8.6%, P < 0.001). In logistic regression analysis, duration of initial TUR-P and PI were found to be independent risk factors for development of BNC or US after TUR-P. CONCLUSIONS: Prostatic inflammation on TUR-P pathology is an independent variable affecting the development of US or BNC. Our results should be supported by prospective studies including higher number of patients. PMID- 22252221 TI - A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels. AB - Ultrasound contrast agents inside a microvessel, when driven by ultrasound, oscillate and induce mechanical stresses on the vessel wall. These mechanical stresses can produce beneficial therapeutic effects but also induce vessel rupture if the stresses are too high. Therefore, it is important to use sufficiently low pressure amplitudes to avoid rupturing the vessels while still inducing the desired therapeutic effects. In this work, we developed a comprehensive three-dimensional model of a confined microbubble inside a vessel while considering the bubble shell properties, blood viscosity, vessel wall curvature and the mechanical properties of the vessel wall. Two bubble models with the assumption of a spherical symmetric bubble and a simple asymmetrical bubble were simulated. This work was validated with previous experimental results and enabled us to evaluate the microbubbles' behaviour and the resulting mechanical stresses induced on the vessel walls. In this study, the fluid shear and circumferential stresses were evaluated as indicators of the mechanical stresses. The effects of acoustical parameters, vessel viscoelasticity and rigidity, vessel/bubble size and off-centre bubbles on bubble behaviour and stresses on the vessel were investigated. The fluid shear and circumferential stresses acting on the vessel varied with time and location. As the frequency changed, the microbubble oscillated with the highest amplitude at its resonance frequency which was different from the resonance frequency of an unbound bubble. The bubble resonance frequency increased as the rigidity of a flexible vessel increased. The fluid shear and circumferential stresses peaked at frequencies above the bubble's resonance frequency. The more rigid the vessels were, the more damped the bubble oscillations. The synergistic effect of acoustic frequency and vessel elasticity had also been investigated since the circumferential stress showed either an increasing trend or a decreasing one versus the vessel rigidity at different acoustic frequencies. When the acoustic pressure was increased from 52 to 680 kPa, the maximum bubble radius increase by 2.5 fold, and the maximum shear and circumferential stress increased by 15.7 and 18.3 fold, respectively. The shear stress was largest when the acoustic frequency was higher (3.25 MHz) and the ratio of the vessel radius to the bubble radius was lower. The circumferential stress was largest when the bubble wall was closer to the vessel wall. An oscillating off-centre bubble forms a mushroom shape with the most damping on the points closest to the vessel wall. PMID- 22252222 TI - Blood cadmium and moderate-to-severe glomerular dysfunction in Korean adults: analysis of KNHANES 2005-2008 data. AB - PURPOSE: The objective of this study was to evaluate the association between blood cadmium (Cd) and moderate-to-severe glomerular dysfunction in a Korean population using a representative sample. METHODS: A cross-sectional study was used to evaluate the association between blood Cd and glomerular dysfunction. Based on the Korean National Health and Nutrition Examination Survey (2005-2008), individual blood Cd was measured in 2,992 adults, aged between 20 and 65. RESULTS: After adjusting for survey years, age, sociodemographic factors, and health behaviors, the odds ratio for moderate-to-severe glomerular dysfunction (<60 mL/min per 1.73 m(2)) was 1.97 (95% CI: 1.28-3.07) when comparing the highest with the lowest blood Cd quartile in Korean women. However, in Korean men, there was no association between blood Cd and moderate-to-severe glomerular dysfunction. CONCLUSIONS: These findings support the consideration of Cd as a risk factor for glomerular dysfunction in the female population. Furthermore, environmental heavy metal monitoring and an institutional strategy should be implemented to reduce Cd exposure in the general population. PMID- 22252224 TI - Functional importance of GLP-1 receptor species and expression levels in cell lines. AB - Of the mammalian species, only the GLP-1 receptors of rat and human origin have been described and characterized. Here, we report the cloning of the homologous GLP-1 receptors from mouse, rabbit, pig, cynomolgus monkey and chimp. The GLP-1 receptor is highly conserved across species, thus underlining the physiological importance of the peptide hormone and its receptor across a wide range of mammals. We expressed the receptors by stable transfection of BHK cells, both in cell lines with high expression levels of the cloned receptors, as well as in cell lines with lower expression levels, more comparable to endogenous expression of these receptors. High expression levels of cloned GLP-1 receptors markedly increased the potency of GLP-1 and other high affinity ligands, whereas the K(d) values were not affected. For a low affinity ligand like the ago-allosteric modulator Compound 2, expression levels of the human GLP-1 receptor were important for maximal efficacy as well as potency. The two natural metabolites of GLP-1, GLP-1(9-37) and GLP-1(9-36)amide were agonists when tested on a cell line with high expression of the recombinant human GLP-1 receptor, whereas they behaved as (low potent) antagonists on a cell line that expressed the receptor endogenously, as well as cells expressing a moderate level of the recombinant human GLP-1 receptor. The amide form was a more potent agonist than the free acid from. In conclusion, receptor expression level is an important parametre for selecting cell lines with cloned GLP-1 receptors for functional characterization of physiological and pharmaceutical ligands. PMID- 22252225 TI - High-precision imaging of an encapsulated Lindqvist ion and correlation of its structure and symmetry with quantum chemical calculations. AB - Low-voltage aberration-corrected transmission electron microscopy (AC-TEM) of discrete Lindqvist [W(6)O(19)](2-) polyoxometalate ions inserted from an ethanolic solution of [NBu(4)](2)[W(6)O(19)] into double walled carbon nanotubes (DWNTs) allows a higher precision structural study to be performed than previously reported. W atom column separations within the constituent W(6) tungsten cage can now be visualized with sufficient clarity that reliable correlation with structural predictions from density functional theory (DFT) can be achieved. Calculations performed on [W(6)O(19)](2-) anions encapsulated in carbon nanotubes show good agreement with measured separations between pairs of W(2) atom columns imaged within equatorial WO(6) polyhedral pairs and also single W atom positions located within individual axial WO(6) octahedra. Structural data from the tilted chiral encapsulating DWNT were also determined simultaneously with the anion structural measurements, allowing the influence of the conformation of the encapsulating tubule to be included in the DFT calculation and compared against that of other candidate encapsulating nanotubes. Additional DFT calculations performed using Li(+) cations as a model for the [NBu(4)](+) counterions indicate that the latter may help to induce charge transfer between the DWNT and the [W(6)O(19)](2-) ion and this may help to constrain the motion of the ion in situ. PMID- 22252223 TI - Coastal seawater bacteria harbor a large reservoir of plasmid-mediated quinolone resistance determinants in Jiaozhou Bay, China. AB - Diversity and prevalence of plasmid-mediated quinolone resistance determinants were investigated in environmental bacteria isolated from surface seawater of Jiaozhou Bay, China. Five qnr gene alleles were identified in 34 isolates by PCR amplification, including qnrA3 gene in a Shewanella algae isolate, qnrB9 gene in a Citrobacter freundii isolate, qnrD gene in 22 Proteus vulgaris isolates, qnrS1 gene in 1 Enterobacter sp. and 4 Klebsiella spp. isolates, and qnrS2 gene in 1 Pseudomonas sp. and 4 Pseudoalteromonas sp. isolates. The qnrC, aac(6')-Ib-cr, and qepA genes could not be detected in this study. The 22 qnrD-positive Proteus vulgaris isolates could be differentiated into four genotypes based on ERIC-PCR assay. The qnrS1 and qnrD genes could be transferred to Escherichia coli J53 Azi(R) or E. coli TOP10 recipient strains using conjugation or transformation methods. Among the 34 qnr-positive isolates, 30 had a single point mutation in the QRDRs of GyrA protein (Ala67Ser, Ser83Ile, or Ser83Thr), indicating that cooperation of chromosome- and plasmid-mediated resistance contributed to the spread and evolution of quinolone resistance in this coastal bay. Eighty-five percent of the isolates were also found to be resistant to ampicillin, and bla(CMY), bla(OXY), bla(SHV), and bla(TEM) genes were detected in five isolates that also harbored the qnrB9 or qnrS1 gene. Our current study is the first identification of qnrS2 gene in Pseudoalteromonas and Pseudomonas strains, and qnrD gene in Proteus vulgaris strains. High prevalence of diverse qnr genes in Jiaozhou Bay indicates that coastal seawater may serve as an important reservoir, natural source, and dissemination vehicle of quinolone resistance determinants. PMID- 22252227 TI - Structure determination of neutral MgO clusters--hexagonal nanotubes and cages. AB - Structural information for neutral magnesium oxide clusters has been obtained by a comparison of their experimental vibrational spectra with predictions from theory. (MgO)(n) clusters with n = 3-16 have been studied in the gas phase with a tunable IR-UV two-color ionization scheme and size-selective infrared spectra have been measured. These IR spectra are compared to the calculated spectra of the global minimum structures predicted by a hybrid ab initio genetic algorithm. The comparison shows clear evidence that clusters of the composition (MgO)(3k) (k = 1-5) form hexagonal tubes, which confirm previous theoretical predictions. For the intermediate sizes (n? 3k) cage-like structures containing hexagonal (MgO)(3) rings are identified. Except for the cubic (MgO)(4) no evidence for bulk like structures is found. PMID- 22252226 TI - Ischemic preconditioning reduces endoplasmic reticulum stress and upregulates hypoxia inducible factor-1alpha in ischemic kidney: the role of nitric oxide. AB - BACKGROUND: Although recent studies indicate that renal ischemic preconditioning (IPC) protects the kidney from ischemia-reperfusion (I/R) injury, the precise protective mechanism remains unclear. In the current study, we investigated whether early IPC could upregulate hypoxia inducible transcription factor-1alpha (HIF-1alpha) expression and could reduce endoplasmic reticulum (ER) stress after renal I/R and whether pharmacological inhibition of nitric oxide (NO) production would abolish these protective effects. METHODS: Kidneys of Wistar rats were subjected to 60 min of warm ischemia followed by 120 min of reperfusion (I/R group), or to 2 preceding cycles of 5 min ischemia and 5 min reperfusion (IPC group), or to intravenously injection of NG-nitro-L-arginine methylester (L-NAME, 5 mg/kg) 5 min before IPC (L-NAME+IPC group). The results of these experimental groups were compared to those of a sham-operated group. Sodium reabsorption rate, creatinine clearance, plasma lactate dehydrogenase (LDH) activity, tissues concentrations of malonedialdehyde (MDA), HIF-1alpha and nitrite/nitrate were determined. In addition, Western blot analyses were performed to identify the amounts of Akt, endothelial nitric oxide synthase (eNOS) and ER stress parameters. RESULTS: IPC decreased cytolysis, lipid peroxidation and improved renal function. Parallelly, IPC enhanced Akt phosphorylation, eNOS, nitrite/nitrate and HIF-1alpha levels as compared to I/R group. Moreover, our results showed that IPC increased the relative amounts of glucose-regulated protein 78 (GRP78) and decreased those of RNA activated protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 4 (ATF4) and TNF-receptor associated factor 2 (TRAF2) as judged to I/R group. However, pre treatment with L NAME abolished these beneficial effects of IPC against renal I/R insults. CONCLUSION: These findings suggest that early IPC protects kidney against renal I/R injury via reducing oxidative and ER stresses. These effects are associated with phosphorylation of Akt, eNOS activation and NO production contributing thus to HIF-1alpha stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application. PMID- 22252229 TI - Diagnostic and therapeutic challenges. PMID- 22252228 TI - Regulator of complement activation (RCA) group 2 gene cluster in zebrafish: identification, expression, and evolution. AB - The activation of the complement system is tightly regulated by a group of plasma and cell membrane-associated proteins for host cell protection. In humans, these regulatory protein genes are clustered in a region named the regulator of complement activation (RCA) gene locus and can be categorized into two groups. The group 1 gene cluster has been reported in zebrafish, but information regarding the RCA locus remains scarce in fish. Here we identified two closely linked RCA group 2 genes in zebrafish, ZRC1 and ZRC2, which had all the features characteristic of known RCA group 2 genes. Both ZRC1 and ZRC2 were closely linked to the PFKFB1 gene and located 17 Mkb downstream of the PFKFB2 gene; in contrast, RCA group 2 genes are closely linked to PFKFB2 in frogs, chickens, and humans. However, both the direction of the RCA group 2 genes relative to PFKFB2 and the order of the RCA group 2 gene-encoded proteins in zebrafish were comparable to those in frogs, chickens, and humans. ZRC1 and ZRC2 shared 71.1% identity to each other, implicating that they might have originated by gene duplication after the split of the fish/mammalian common ancestor. Moreover, ZRC1 and ZRC2 encoded a membrane-associated protein and a soluble protein, respectively, and displayed different expression patterns, suggesting that functional divergence has already occurred. This is the first report showing the presence of the RCA group 2 cluster as well as the membrane-associated complement regulatory protein in zebrafish, providing a better understanding of the origin and evolution of RCA proteins. PMID- 22252232 TI - Effect of intravitreal triamcinolone injection during vitrectomy for idiopathic epiretinal membrane. AB - PURPOSE: To investigate the effect of intravitreal triamcinolone injections as an adjuvant of vitrectomy for idiopathic epiretinal membrane. METHODS: This study included 58 eyes of 58 patients who were diagnosed as having idiopathic epiretinal membrane and who underwent vitrectomy and membrane peeling. They were divided into 2 groups: 27 eyes in the injected group that received triamcinolone injection during the surgical procedure and 31 eyes in the control group that did not receive injection. The best-corrected visual acuity, foveal thickness, and complications were compared between the two groups. RESULTS: Average visual acuity of the injected group improved from 0.70 logarithm of the minimal angle of resolution (logMAR) (Snellen equivalent, 20/100; range, 20/25-20/200) at baseline to 0.59 logMAR (20/80; range, 20/40-20/200) at 1 month and 0.55 logMAR (20/70; range, 20/30-20/200) at 3 months. Foveal thickness reduced from 456.9 MUm (range, 307-740 MUm) to 387.9 MUm (range, 238-584 MUm) at 1 month and 336.4 MUm (range, 225-529 MUm) at 3 months, respectively. In the control group, average visual acuity improved from 0.63 logMAR (20/80; range, 20/40-20/300) to 0.48 logMAR (20/60; range, 20/25-20/125) and 0.43 logMAR (20/50; range, 20/25-20/160) at 1 month and 3 months, respectively. Foveal thickness reduced from 467.1 MUm (range, 328-621 MUm) to 376.1 MUm (range, 271-429 MUm) and 375.1 MUm (range, 236-475 MUm) at 1 month and 3 months, respectively. There were no significant differences in the visual acuity, foveal thickness, and any complications between the two groups during follow-up. CONCLUSION: Intravitreal injection of triamcinolone combined with vitrectomy for idiopathic epiretinal membrane did not affect postoperative foveal thickness and functional recovery. PMID- 22252233 TI - In vitro genotoxic perspective of Tamiflu. AB - The aim of this study was to investigate the genotoxic and/or cytotoxic effects of Tamiflu, commercial form of the oseltamivir antiviral and most frequently prescribed for the treatment of influenza infections, on cultured human peripheral lymphocytes by using sister chromatid exchange (SCE), chromosomal aberration (CA), and cytokinesis-blocked micronucleus (CBMN) assays. Cells were treated with 0.5, 1, 2 MUg/mL oseltamivir, the Tamiflu capsule ingredient, for 24 or 48 h in the absence or presence of an exogenous metabolic activation system (S9 mix). The test chemical did not demonstrate any genotoxic effect dose dependently but it showed a weak cytotoxicity on cells in this study. On the other hand, some concentrations of Tamiflu (2 MUg/mL without S9 mix for 48 h and 1 MUg/mL with S9 mix) induced SCE and also decreased significantly the proliferation index (PI) (48 h period) and the nuclear division index (NDI) (24 h period) (P < 0.05) in the absence of S9 mix. Considering the results, Tamiflu did not induce significant increases of CA or micronucleated cells in vitro in cultured peripheral blood lymphocytes under the treatment conditions used but weak SCE induction was observed. On the other hand, the weak cytotoxic effects observed disappeared in the cultures treated in presence of the S9 mix. PMID- 22252234 TI - Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner. AB - Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles located in the surrounding stroma. It is a pathological feature observed in certain tumors, referred to as neurotropic malignancies, that severely limits the ability to establish local control of disease and results in pain, recurrent growth, and distant metastases. Despite the importance of PNI as a prognostic indicator, its biological mechanisms are poorly understood. The semaphorins and their receptors, the plexins, compose a family of proteins originally shown to be important in nerve cell adhesion, axon migration, and proper central nervous system development. Emerging evidence has demonstrated that these factors are expressed in tissues outside of the nervous system and represent a widespread signal transduction system that is involved in the regulation of motility and adhesion in different cell types. We believe that the plexins and semaphorins, which are strongly expressed in both axons and many carcinomas, play a role in PNI. In this study, we show that plexin-B1 is overexpressed in tissues and cell lines from neurotropic malignancies and is attracted to nerves that express its ligand, semaphorin 4D, in a Rho/Rho kinase-dependent manner. We also demonstrate that nerves are attracted to tumors through this same system of proteins, suggesting that both plexin-B1 and semaphorin 4D are important in the promotion of PNI. PMID- 22252236 TI - Preserved acetazolamide reactivity in lacunar patients with severe white-matter lesions: 15O-labeled gas and H2O positron emission tomography studies. AB - Limited evidence exists on the relationships between severity of white-matter lesions (WMLs) and cerebral hemodynamics in patients without major cerebral artery disease. To examine changes of cerebral blood flow (CBF), oxygen metabolism, and vascular reserve capacity associated with severity of WML in patients with lacunar stroke, we used a positron emission tomography (PET). Eighteen lacunar patients were divided into two groups according to the severity of WMLs, assessed by Fazekas classification; grades 0 to 1 as mild WML group and grades 2 to 3 as severe WML group. Rapid dual autoradiography was performed with (15)O-labeled gas-PET followed by (15)O-labeled water-PET with acetazolamide (ACZ) challenge. Compared with the mild WML group, the severe WML group showed lower CBF (20.6+/-4.4 versus 29.9+/-8.2 mL/100 g per minute, P=0.008), higher oxygen extraction fraction (OEF) (55.2+/-7.4 versus 46.7+/-5.3%, P=0.013), and lower cerebral metabolic rate of oxygen (CMRO(2)) (1.95+/-0.41 versus 2.44+/-0.42 mL/100 g per minute, P=0.025) in the centrum semiovale. There were no significant differences in the ACZ reactivity between the two groups (48.6+/-22.6% versus 42.5+/-17.2%, P=0.524). Lacunar patients with severe WMLs exhibited reduced CBF and CMRO(2), and increased OEF in the centrum semiovale. The ACZ reactivity was preserved in both patients with severe and mild WMLs in each site of the brain. PMID- 22252235 TI - Neurological diseases in relation to the blood-brain barrier. AB - Disruption of the blood-brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity. PMID- 22252237 TI - Characterizing brain oxygen metabolism in patients with multiple sclerosis with T2-relaxation-under-spin-tagging MRI. AB - In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO(2)), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P<0.0001) and decreased CMRO(2) (P=0.003) in MS patients (mean+/-s.d.: 65.9%+/-5.1% and 138.8+/ 35.4 MUmol per 100 g per minute) as compared with healthy control subjects (60.2%+/-4.0% and 180.2+/-24.8 MUmol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n=30); on the contrary, there was a significant negative correlation between CMRO(2) and EDSS and between CMRO(2) and lesion load (n=12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease. PMID- 22252240 TI - Prevention of 1-palmitoyl lysophosphatidylcholine-induced inflammation by polyunsaturated acyl lysophosphatidylcholine. AB - OBJECTIVE: The aim of this study was to examine the inflammation induced by saturated acyl lysophosphatidylcholine (LPC) in vivo and to investigate whether it could be attenuated by the action of polyunsaturated acyl lysophosphatidylcholines (LPCs), which are known as anti-inflammatory lipid mediators. METHODS: First, saturated acyl LPC was administered intraperitoneally (i.p.) to mice and the inflammatory profile was extensively characterized. Subsequently, the preventive effect of polyunsaturated acyl LPCs, i.p. administered 30 min after saturated acyl LPC, was evaluated by measuring indices of inflammation such as leukocyte migration, plasma leakage, and eicosanoid or cytokine formation by light microscopy, Evans blue dye as indicator, and enzyme linked immunosorbent assay, respectively. RESULTS: Saturated acyl LPCs as LPC16:0 (100 mg/kg, i.p.) proved to be an effective inflammation inducer which causes a significant increase in plasma leakage, leukocyte migration into peritoneum and elevation of pro-inflammatory mediators. Interestingly, LPC20:4 and LPC22:6 (50 and 150 MUg/kg) significantly nullified LPC16:0-induced inflammation. The anti inflammatory effects of LPC20:4 and LPC22:6 were related to down-regulation of leukocyte extravasation, plasma leakage, and formation of pro-inflammatory mediators (IL-5, IL-6, NO, 12-HETE and PGE(2)) stimulated by LPC16:0, and up regulation of anti-inflammatory mediators (IL-4 and IL-10). CONCLUSION: These results indicated that the pro-inflammatory activity of saturated acyl LPCs could be antagonized by the actions of polyunsaturated acyl LPCs, anti-inflammatory lipid mediators. PMID- 22252241 TI - Proper theoretical analysis of the oxygen wash-in kinetics of circle breathing systems. AB - OBJECTIVE: To correctly define the theoretical treatment of oxygen wash-in kinetics in circle breathing systems and reevaluate previously published results for the rate of change of oxygen concentration in a large animal circle breathing system. STUDY DESIGN: Theoretical analysis of previously published data. ANIMALS: None. METHODS: Previously published data for the rate of change of oxygen concentration in a large animal circle breathing system with two reservoir bag sizes (40 and 20 L) at three different flow rates (3, 6, and 10 L minute(-1)) were obtained from the original publication, via digital extraction, and analyzed to determine system time constants. The results of this analysis were compared to those originally reported and the level of mathematical agreement between experiment and theory was quantified. RESULTS: Theoretical time constants for the system with 40 L reservoir bag with flow rates of 3, 6, and 10 L minute(-1) were 16.4, 8.2, and 4.9 minutes, respectively. Experimentally derived time constants for this system with flow rates of 3, 6, and 10 L minute(-1) were 18.1, 9.2, and 5.4 minutes, respectively. Percent differences between experimental and theoretical time constants for this system with flow rates of 3, 6, and 10 L minute(-1) were 10.4, 12.2, and 10.2%, respectively. For the system with a 20 L reservoir bag and 6 L minute(-1) flow rate, the theoretical and experimentally derived time constants were 5.5 and 5.6 minutes, respectively, with a 1.8% difference. The average relative deviations between theory and experiment for the system at 6 L minute(-1) flow with a 40 or 20 L reservoir bag were 1.3% and 3.0%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Proper theoretical analysis of experimentally obtained data for the wash-in kinetics of oxygen into a large animal circle breathing system leads to improved mathematical agreement between theory and experiment when compared to the originally published results. Application of this method should allow more accurate prediction of the rate of change of oxygen concentration in anesthetic circuits. PMID- 22252239 TI - Stem cell therapy for cerebral ischemia: from basic science to clinical applications. AB - Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future. PMID- 22252238 TI - Frontiers in optical imaging of cerebral blood flow and metabolism. AB - In vivo optical imaging of cerebral blood flow (CBF) and metabolism did not exist 50 years ago. While point optical fluorescence and absorption measurements of cellular metabolism and hemoglobin concentrations had already been introduced by then, point blood flow measurements appeared only 40 years ago. The advent of digital cameras has significantly advanced two-dimensional optical imaging of neuronal, metabolic, vascular, and hemodynamic signals. More recently, advanced laser sources have enabled a variety of novel three-dimensional high-spatial resolution imaging approaches. Combined, as we discuss here, these methods are permitting a multifaceted investigation of the local regulation of CBF and metabolism with unprecedented spatial and temporal resolution. Through multimodal combination of these optical techniques with genetic methods of encoding optical reporter and actuator proteins, the future is bright for solving the mysteries of neurometabolic and neurovascular coupling and translating them to clinical utility. PMID- 22252242 TI - Suppression of zinc finger protein 467 alleviates osteoporosis through promoting differentiation of adipose derived stem cells to osteoblasts. AB - Osteoblast and adipocyte are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. In this study, a comparative analysis of gene expression profiling using cDNA microarray and realtime-PCR indicated that Zinc finger protein 467 (Zfp467) involved in adipocyte and osteoblast differentiation of cultured adipose derived stem cells (ADSCs). Our results showed that RNA interference for Zfp467 in ADSCs inhibited adipocyte formation and stimulated osteoblast commitment. The mRNA levels of osteogenic and adipogenic markers in ADSCs were regulated by si-Zfp467. Zfp467 RNAi in ADSCs could restore bone function and structure in an ovariectomized (OVX)-induced osteoporotic mouse model. Thus Zfp467 play an important role in ADSCs differentiation to adipocyte and osteoblast. This has relevance to therapeutic interventions in osteoporosis, including si-Zfp467-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering. PMID- 22252245 TI - Imaging in arthritis: quantifying effects of therapeutic intervention using MRI and molecular imaging. AB - Modern imaging techniques are becoming increasingly important in assessing the course of arthritis and in permitting measurement of response to treatment as part of the follow-up of patients. They include ultrasonography (US), MRI, PET/CT, and biofluorescence. In patients with rheumatoid arthritis, clinical evaluation is significantly less sensitive than either US or MRI in detecting synovitis. As a result, imaging is a useful alternative to achieving proper assessment of disease activity. The different areas in which the new imaging techniques could help practicing rheumatologists and internal physicians include the following: early and differential diagnosis of arthritis, evaluation of disease activity, prognosis, assessment of treatment efficacy, assessment of remission, and evaluation of subclinical disease. MRI is probably the best imaging method to study disease activity in RA, because it can study all the joints with similar efficacy, has been sufficiently standardised, and yields data on inflammation that can be quantified. Different methods, developed to score synovitis activity, are increasingly used in clinical trials. The main application of PET/CT in rheumatology is the diagnosis and follow-up of large vessel vasculitis. More recently, also RA disease activity has been evaluated, allowing a panoramic view of the patient. Molecular imaging studies molecular and cellular processes in intact living organisms in a non-invasive fashion. In fluorescence, dyes, that emit light upon excitation by a light source and are read by a camera, can be used to show inflamed areas where neoangiogenesis, vasodilatation, and increased vessel permeability are present. These dyes can be coupled with different compounds including antibodies and drugs. PMID- 22252244 TI - Functional chromaffin cell plasticity in response to stress: focus on nicotinic, gap junction, and voltage-gated Ca2+ channels. AB - An increase in circulating catecholamines constitutes one of the mechanisms whereby human body responds to stress. In response to chronic stressful situations, the adrenal medullary tissue exhibits crucial morphological and functional changes that are consistent with an improvement of chromaffin cell stimulus-secretion coupling efficiency. Stimulus-secretion coupling encompasses multiple intracellular (chromaffin cell excitability, Ca(2+) signaling, exocytosis, endocytosis) and intercellular pathways (splanchnic nerve-mediated synaptic transmission, paracrine and endocrine communication, gap junctional coupling), each of them being potentially subjected to functional remodeling upon stress. This review focuses on three chromaffin cell incontrovertible actors, the cholinergic nicotinic receptors and the voltage-dependent T-type Ca(2+) channels that are directly involved in Ca(2+)-dependent events controlling catecholamine secretion and electrical activity, and the gap junctional communication involved in the modulation of catecholamine secretion. We show here that these three actors react differently to various stressors, sometimes independently, sometimes in concert or in opposition. PMID- 22252246 TI - Consequences of dose heterogeneity on the biological efficiency of 103Pd permanent breast seed implants. AB - Brachytherapy is associated with highly heterogeneous spatial dose distributions. This heterogeneity is usually ignored when estimating the biological effective dose (BED). In addition, the heterogeneities of the medium including the tissue heterogeneity (TH) and the interseed attenuation (ISA) are also contributing to the heterogeneity of the dose distribution, but they are both ignored in Task Group 43 (TG43)-based protocols. This study investigates the effect of dose heterogeneity, TH and ISA on metrics that are commonly used to quantify biological efficiency in brachytherapy. The special case of 29 breast cancer patients treated with permanent (103)Pd seed implant is considered here. BED is compared to equivalent uniform BED (EUBED) capable of considering the spatial heterogeneity of the dose distribution. The effects of TH and ISA on biological efficiency of treatments are taken into account by comparing TG43 with Monte Carlo (MC) dose calculations for each patient. The effect of clonogenic repopulation is also considered. The analysis is performed for different sets of (alpha/beta, alpha) ratios of (2, 0.3), (4, 0.27) and (10, 0.3) [Gy, Gy(-1)] covering the whole range of reported alpha/beta values in the literature. BED is sometimes larger and sometimes smaller than EUBED(TG43) indicating that the effect of the dose heterogeneity is not similar among patients. The effect of the dose heterogeneity can be characterized by using the D(99) dose metric. For each set of the radiobiological parameters considered, a D(99) threshold is found over which dose heterogeneity will cause an overestimation of the biological efficiencies while the inverse happens for smaller D(99) values. EUBED(MC) is always larger than EUBED(TG43) indicating that by neglecting TH and ISA in TG43 based dosimetry algorithms, the biological efficiencies may be underestimated by about 10 Gy. Overall, by going from BED to the more accurate EUBED(MC) there is a gain of about 9.6 to 13 Gy on the biological efficiency. The efficiency gain is about 10.8 to 14 Gy when the repopulation is considered. Dose heterogeneity does not have a constant impact on the biological efficiencies and may under- or overestimate the efficacy in different patients. However, the combined effect of neglecting dose heterogeneity, TH and ISA results in underestimation of the biological efficiencies in permanent breast seed implants. PMID- 22252247 TI - Treadmill training regulates beta-catenin signaling through phosphorylation of GSK-3beta in lumbar vertebrae of ovariectomized rats. AB - Postmenopausal osteoporosis is associated with high level of adipogenesis within the bone marrow at the expense of osteoblast population. The mechanical effect on beta-catenin through phosphorylation of glycogen synthase kinase-3beta (GSK 3beta) is critical for inhibition of adipogenesis in mesenchymal stem cells in vitro. In present study, we hypothesized that treadmill training could regulate the beta-catenin signaling through phosphorylation of GSK-3beta in the lumbar vertebrae of ovariectomized (OVX) rats. 3-month-old female Sprague-Dawley rats were divided randomly into the following four groups: (a) Sham, (b) OVX, (c) OVX exercised (EX), and (d) OVX estrogen replacement (E(2)). At the end of the experiment, the serum levels of estradiol (E(2)) and luteinizing hormone (LH), the ultimate lumbar vertebra strength, as well as the protein expression for peroxisome proliferators-activated receptor gamma (PPARgamma), beta-catenin, P GSK-3beta, and osterix (Osx) in lumbar vertebrae were analyzed. Moreover, the protein expression for beta-catenin and P-GSK-3beta were also examined in the uterus. The EX group had lower protein level of PPARgamma, higher ultimate lumbar vertebral strength, and higher protein levels of beta-catenin, and P-GSK-3beta in lumbar vertebral bodies compared with sedentary OVX group. The effects of EX treatment on the protein levels of beta-catenin and P-GSK-3beta in bones were not reproducible in the uterus. Moreover, exercise treatment produced no estrogenic effect as evidenced by serum level of LH. In conclusion, this study suggested that treadmill training could activate the GSK-3beta/beta-catenin signaling and inhibit the production of PPARgamma in lumbar vertebrae of OVX rats, which may contribute to the prevention of bone loss in OVX rats. PMID- 22252248 TI - Acclimatisation in trekkers with and without recent exposure to high altitude. AB - In mountaineers, recent altitude exposure has been shown to improve climbing performance and clinical outcomes during re-exposure to high altitude. However, the timing of previous altitude exposure has not been clearly reported and previous findings might be driven by individuals who were still acclimatised at the time of re-exposure. Our goal was to determine whether recent altitude exposure would confer an advantage even in individuals who had de-acclimatised for >= 1 week before being re-exposure. Low-altitude natives kept a daily trekking log throughout 7- to 8-day trek from Lukla (2,840 m) to Gokyo Ri (5,360 m). Trekkers with recent altitude exposure (re-acclimatisers, RA; n = 20) walked 20% faster (p < 0.01), reported lower acute mountain sickness scores (9 +/- 8 vs. 15 +/- 13; p = 0.02), and used less medication to treat headache (p < 0.05) compared to trekkers with no recent altitude exposure (initial acclimatisers, IA; n = 30). On Gokyo Ri, S(p)O(2) was significantly higher in RA than IA trekkers (85 +/- 6 vs. 78 +/- 6; p = 0.01). These data indicate improved functional outcomes and physiological compensation for hypoxia in RA. However, even after de acclimatisation for 7-30 days, it is possible that RA trekkers began the trek in a more acclimatised state than IA trekkers. RA trekkers might represent a self selected group that has previously tolerated altitude well and has therefore opted to return. Some findings might also reflect improved psychological altitude tolerance in RA. A direct comparison of the functional and physiological responses to hypoxia throughout an initial and re-acclimatisation to high altitude is needed. PMID- 22252249 TI - Disputing the claims for physiological fitness and health adaptations from purposeful training using off-road vehicles. PMID- 22252250 TI - The incidence of knee arthroplasty for primary osteoarthritis grows rapidly among baby boomers: a population-based study in Finland. AB - OBJECTIVE: Total knee arthroplasty (TKA) is a commonly used treatment for severe primary knee osteoarthritis (OA) that is refractory to conservative treatment. Despite the presumed increase in the use of this treatment modality in younger patients, there are few published data concerning this. The aim of our study was to examine the changes in the age- and sex-standardized incidence of TKA and unicondylar knee arthroplasty (UKA) in Finland during 1980-2006 and to identify factors that might affect the incidence during this period. METHODS: We obtained data on UKAs and TKAs from the Finnish Arthroplasty Registry and population data from Statistics Finland to analyze the incidence of UKAs and TKAs in Finland for the period 1980-2006. The effects of sex, age group, and hospital volume on the incidence of these procedures were also evaluated. RESULTS: The annual cumulative incidence of UKAs and TKAs has increased rapidly from 1980 to 2006 among 30-59 year-old inhabitants of Finland. For UKAs, the incidence increased from 0.2 per 100,000 inhabitants to 10 per 100,000, and for TKAs, the incidence increased from 0.5 per 100,000 to 65 per 100,000. The incidence remained higher among women during the entire study period. Most of the increase occurred among patients ages 50-59 years. The incidence grew more rapidly in low-volume and intermediate volume hospitals. CONCLUSION: We demonstrated a rapid increase in the incidence of arthroplasty among patients with primary knee OA in Finland, especially in those ages 50-59 years. There was no single explanatory factor behind this finding, although some of the growth might be due to the increased incidence noted in low- and intermediate-volume hospitals. PMID- 22252251 TI - Development of a drug assay system with hepatitis C virus genome derived from a patient with acute hepatitis C. AB - We developed a new cell culture drug assay system (AH1R), in which genome-length hepatitis C virus (HCV) RNA (AH1 strain of genotype 1b derived from a patient with acute hepatitis C) efficiently replicates. By comparing the AH1R system with the OR6 assay system that we developed previously (O strain of genotype 1b derived from an HCV-positive blood donor), we demonstrated that the anti-HCV profiles of reagents including interferon-gamma and cyclosporine A significantly differed between these assay systems. Furthermore, we found unexpectedly that rolipram, an anti-inflammatory drug, showed anti-HCV activity in the AH1R assay but not in the OR6 assay, suggesting that the anti-HCV activity of rolipram differs depending on the HCV strain. Taken together, these results suggest that the AH1R assay system is useful for the objective evaluation of anti-HCV reagents and for the discovery of different classes of anti-HCV reagents. PMID- 22252253 TI - Controlling the macrocycle size by the stoichiometry of the applied template ion. AB - Reaction of 4-tert-butyl-2,6-diformylphenol with (1R,2R)- or (1S,2S)-1,2 diaminocyclohexane in the presence of 1 equivalent of Zn(2+) ions leads to selective formation of a chiral 2+2 macrocycle. Application of 0.5 equivalent of Zn(2+) ions under the same conditions leads to selective formation of a chiral 3+3 macrocycle, which forms a cavitand-shaped trinuclear double-decker complex with Zn(II). PMID- 22252252 TI - Genetic characterization of subtype H1 avian influenza viruses isolated from live poultry markets in Zhejiang Province, China, in 2011. AB - Nine avian influenza A viruses (AIVs), H1N2 (n = 2) and H1N3 (n = 7), were isolated from domestic ducks in live poultry markets in Zhejiang Province, Eastern China, in 2011. All viruses were characterized by whole genome sequencing with subsequent phylogenetic analysis and genetic comparison. Phylogenetic analysis of all eight viral genes showed that the viruses clustered in the Eurasian lineage of influenza A viruses. The hemagglutinin cleavage site of all viruses displayed features of a monobasic cleavage site. Although there was no evidence of re-assortment in subtype H1 AIVs among the avian species and mammalian hosts in this study, continued surveillance is needed considering the important role of the domestic duck in the dissemination and re-assortment of AIVs. PMID- 22252254 TI - Rhodium-catalyzed 1,3-acyloxy migration and subsequent intramolecular [4+2] cycloaddition of vinylallene and unactivated alkyne. AB - A Rh-catalyzed 1,3-acyloxy migration of propargyl ester followed by intramolecular [4+2] cycloaddition of vinylallene and unactivated alkyne was developed. This tandem reaction provides access to bicyclic compounds containing a highly functionalized isotoluene or cyclohexenone structural motif, while only aromatic compounds were observed in related transition metal-catalyzed cycloadditions. PMID- 22252256 TI - Lifetime cancer risks in individuals with germline PTEN mutations. AB - PURPOSE: Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN hamartoma tumor syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion. EXPERIMENTAL DESIGN: A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype-phenotype analyses were carried out. RESULTS: Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 19.8-32.0], thyroid (51.1, 38.1-67.1), endometrium (42.9, 28.1-62.8), colorectum (10.3, 5.6-17.4), kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1-15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 71.4%-99.1%), 35.2% (19.7%-50.7%), 28.2% (17.1%-39.3%), 9.0% (3.8%-14.1%), 33.6% (10.4%-56.9%), and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, whereas colorectal cancer was associated with nonsense mutations. CONCLUSION: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations. The genotype phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations. PMID- 22252258 TI - Genetic variations in epigenetic genes are predictors of recurrence in stage I or II non-small cell lung cancer patients. AB - PURPOSE: Early-stage non-small cell lung cancer (NSCLC) is potentially curable, however, many patients develop recurrent disease. Therefore, identification of biomarkers that can be used to predict patient's risk of recurrence and survival is critical. Genetic polymorphisms or single-nucleotide polymorphisms (SNP) of DNA- and histone-modifying genes, particularly those of O(6)-methylguanine DNA methyltransferase (MGMT), have been linked to an increased risk of lung cancer as well as treatment outcomes in other tumors. EXPERIMENTAL DESIGN: We assessed the association of 165 SNPs in selected epigenetic enzyme genes, DNA methyltransferases, and methyl-CpG-binding proteins with cancer recurrence in 467 patients with stage I or II NSCLC treated with either surgery alone (N = 340) or surgery plus (neo)-adjuvant chemotherapy (N = 127). RESULTS: We found several SNPs to be strongly correlated with tumor recurrence. We identified 10 SNPs that correlated with the outcome in patients treated with surgery alone but not in patients treated with surgery and adjuvant chemotherapy, which suggested that the addition of platinum-based chemotherapy could reverse the high genetic risk of recurrence. We also identified 10 SNPs that predicted the risk of recurrence in patients treated with surgery plus adjuvant chemotherapy but not in patients treated with surgery alone. The cumulative effect of these SNPs significantly predicted outcomes with P-values of 10(-9) and 10(-6), respectively. CONCLUSIONS: The first set of genotypes may be used as novel predictive biomarkers to identify patients with stage I NSCLC, who could benefit from adjuvant chemotherapy, and the second set of SNPs might predict response to adjuvant chemotherapy. PMID- 22252259 TI - Issues associated with the case report entitled "hypertensive urgency associated with Xenadrine EFX use". PMID- 22252257 TI - Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. AB - PURPOSE: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). EXPERIMENTAL DESIGN: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3-4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. RESULTS: Overall, 17% of EACs were HER2 positive (i.e., IHC3(+) or IHC2(+) with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio >=2) and expression (kappa = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1-2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (P(interaction) = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35-0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. CONCLUSIONS: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. PMID- 22252261 TI - Pharmacists and collaborative drug therapy management in New York State. PMID- 22252263 TI - Bioconjugated silicon quantum dots from one-step green synthesis. AB - Biofunctionalized silicon quantum dots were prepared through a one step strategy avoiding the use of chemical precursors. UV-Vis spectroscopy, Raman spectroscopy and HAADF-STEM prove oligonucleotide conjugation to the surface of silicon nanoparticle with an average size of 4 nm. The nanoparticle size results from the size-quenching effect during in situ conjugation. Photoemissive properties, conjugation efficiency and stability of these pure colloids were studied and demonstrate the bio-application potential, e.g. for nucleic acid vector delivery with semiconducting, biocompatible nanoparticles. PMID- 22252264 TI - Biodiscovery of new Australian thraustochytrids for production of biodiesel and long-chain omega-3 oils. AB - Heterotrophic growth of thraustochytrids has potential in co-producing a feedstock for biodiesel and long-chain (LC, >=C(20)) omega-3 oils. Biodiscovery of thraustochytrids from Tasmania (temperate) and Queensland (tropical), Australia, covered a biogeographic range of habitats including fresh, brackish, and marine waters. A total of 36 thraustochytrid strains were isolated and separated into eight chemotaxonomic groups (A-H) based on fatty acid (FA) and sterol composition which clustered closely with four different genera obtained by 18S rDNA molecular identification. Differences in the relative proportions (%FA) of long-chain C(20), C(22), omega-3, and omega-6 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid (DHA), docosapentaenoic acid, arachidonic acid, eicosapentaenoic acid (EPA), and saturated FA, as well as the presence of odd-chain PUFA (OC-PUFA) were the major factors influencing the separation of these groups. OC-PUFA were detected in temperate strains of groups A, B, and C (Schizochytrium and Thraustochytrium). Group D (Ulkenia) had high omega-3 LC-PUFA (53% total fatty acids (TFA)) and EPA up to 11.2% TFA. Strains from groups E and F (Aurantiochytrium) contained DHA levels of 50-61% TFA after 7 days of growth in basal medium at 20 degrees C. Groups G and H (Aurantiochytrium) strains had high levels of 15:0 (20-30% TFA) and the sum of saturated FA was in the range of 32 51%. beta,beta-Carotene, canthaxanthin, and astaxanthin were identified in selected strains. Phylogenetic and chemotaxonomic groupings demonstrated similar patterns for the majority of strains. Our results demonstrate the potential of these new Australian thraustochytrids for the production of biodiesel in addition to omega-3 LC-PUFA-rich oils. PMID- 22252265 TI - Comparison and characterization of alpha-amylase inducers in Aspergillus nidulans based on nuclear localization of AmyR. AB - AmyR, a fungal transcriptional activator responsible for induction of amylolytic genes in Aspergillus nidulans, localizes to the nucleus in response to the physiological inducer isomaltose. Maltose, kojibiose, and D: -glucose were also found to trigger the nuclear localization of GFP-AmyR. Isomaltose- and kojibiose triggered nuclear localization was not inhibited by the glucosidase inhibitor, castanospermine, while maltose-triggered localization was inhibited. Thus, maltose itself does not appear to be an direct inducer, but its degraded or transglycosylated product does. Non-metabolizable D: -glucose analogues were also able to trigger the nuclear localization, implying that these sugars, except maltose, directly function as the inducers of AmyR nuclear entry. The inducing activity of D: -glucose was 4 orders-of-magnitude weaker compared with isomaltose. Although D: -glucose has the ability to induce alpha-amylase production, this activity would generally be masked by CreA-dependent carbon catabolite repression. Significant induction of alpha-amylase by D: -glucose was observed in creA-defective A. nidulans. PMID- 22252266 TI - Controlled synthesis of Mn2O3 nanowires by hydrothermal method and their bactericidal and cytotoxic impact: a promising future material. AB - Mn2O3 nanowires with diameter ~70 nm were synthesized by a simple hydrothermal method using Mn(II) nitrate as precursor. X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy (TEM), and energy dispersive X-ray spectroscopy techniques were employed to study structural features and chemical composition of the synthesized nanowires. A biological evaluation of the antimicrobial activity and cytotoxicity of Mn2O3 nanowires was carried out using Escherichia coli and mouse myoblast C2C12 cells as model organism and cell lines, respectively. The antibacterial activity and the acting mechanism of Mn2O3 nanowires were investigated by using growth inhibition studies and analyzing the morphology of the bacterial cells following the treatment with nanowires. These results suggest that the pH is critical factor affecting the morphology and production of the Mn2O3 nanowires. Method developed in the present study provided optimum production of Mn2O3 nanowires at pH ~ 9. The Mn2O3 nanowires showed significant antibacterial activity against the E. coli strain, and the lowest concentration of Mn2O3 nanowires solution inhibiting the growth of E. coli was found to be 12.5 MUg/ml. TEM analysis demonstrated that the exposure of the selected microbial strains to the nanowires led to disruption of the cell membranes and leakage of the internal contents. Furthermore, the cytotoxicity results showed that the inhibition of C2C12 increases with the increase in concentration of Mn2O3 nanowires. Our results for the first time highlight the cytotoxic and bactericidal potential of Mn2O3 nanowires which can be utilized for various biomedical applications. PMID- 22252267 TI - Early diagnosis and treatment of postoperative endoscopic recurrence of Crohn's disease: partial benefit by infliximab--a pilot study. AB - BACKGROUND: Current data indicate that infliximab-given immediately after surgery may be very effective in preventing postsurgical recurrence of Crohn's disease. However, it is unknown whether a similar benefit would result from early diagnosis and treatment, rather than prevention of endoscopic recurrence. AIMS: The primary outcome of this study was to clarify whether infliximab, given after diagnosis of postoperative endoscopic recurrence of Crohn's diseases (Rutgeerts score >= 2) can induce endoscopic remission (score <2) at 54 weeks. The secondary outcomes were improvement in the endoscopic score and clinical recurrence at 54 weeks. METHODS: In this prospective open label multicenter pilot study 43 patients with ileocolonic Crohn's disease subjected to curative surgery underwent colonoscopy 6 months after surgery. Patients with endoscopic recurrence (Rutgeerts score >=2) were treated with either mesalamine 800 mg tid or infliximab 5 mg/kg bw on a maintenance basis. Colonoscopy was performed after 54 weeks of therapy. RESULTS: A total of 24/43 patients were diagnosed with endoscopic recurrence at 6 months. Thirteen were treated with infliximab and 11 with mesalamine. None of the 11 mesalamine-treated patients had endoscopic remission at 54 weeks. Two had clinical recurrence at 8 and 9 months. Fifty-four percent of patients treated with infliximab had endoscopic remission at 54 weeks (P = 0.01) while 69% had an improvement in the endoscopic score. None had clinical recurrence. CONCLUSIONS: Treatment of postsurgical endoscopic lesions by infliximab appears superior to mesalamine. However, a sizeable proportion of patients did not fully benefit from this strategy. PMID- 22252268 TI - Evaluation of Seeplex(r) STD6 ACE Detection kit for the diagnosis of six bacterial sexually transmitted infections. AB - Traditionally, the diagnosis of bacterial sexually transmitted infection (STI) has been dependent on the isolation of the causative pathogens by culturing endocervical or urethral swab specimens on selective media. While such procedures typically provide excellent diagnostic accuracy, they are often time-consuming and expensive. A multiplex polymerase chain reaction (PCR) assay, based on a semi automated detection system, was evaluated for the detection of six STI causative organisms. The Seeplex((r)) STD6 ACE (auto-capillary electrophoresis) Detection assay employed six pairs of dual priming oligonucleotide (DPOTM) primers specifically targeted to unique genes of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Ureaplasma urealyticum, Mycoplasma hominis, and Trichomonas vaginalis. A total of 739 specimens (304 cervical swabs and 435 urine samples) collected for 4 months were tested, and results were compared to those obtained with a combined monoplex PCR. The concordance between the multiplex PCR and monoplex PCR assay was 100% for both sensitivity and specificity. We also tested for the presence of two pathogenic bacteria (C. trachomatis and N. gonorrhoeae) and compared the results obtained with the multiplex PCR and BD ProbeTec duplex strand displacement amplification (SDA). The results of the multiplex PCR and duplex SDA were 99.7% concordant for C. trachomatis and 100% concordant for N. gonorrhoeae. The multiplex PCR assay using the Seeplex((r)) STD6 ACE Detection kit proved to be a novel cost-effective and fast diagnostic tool with high sensitivity and specificity for the simultaneous detection of six STI pathogens. PMID- 22252269 TI - Combined in silico modeling and metabolomics analysis to characterize fed-batch CHO cell culture. AB - The increasing demand for recombinant therapeutic proteins highlights the need to constantly improve the efficiency and yield of these biopharmaceutical products from mammalian cells, which is fully achievable only through proper understanding of cellular functioning. Towards this end, the current study exploited a combined metabolomics and in silico modeling approach to gain a deeper insight into the cellular mechanisms of Chinese hamster ovary (CHO) fed-batch cultures. Initially, extracellular and intracellular metabolite profiling analysis shortlisted key metabolites associated with cell growth limitation within the energy, glutathione, and glycerophospholipid pathways that have distinct changes at the exponential-stationary transition phase of the cultures. In addition, biomass compositional analysis newly revealed different amino acid content in the CHO cells from other mammalian cells, indicating the significance of accurate protein composition data in metabolite balancing across required nutrient assimilation, metabolic utilization, and cell growth. Subsequent in silico modeling of CHO cells characterized internal metabolic behaviors attaining physiological changes during growth and non-growth phases, thereby allowing us to explore relevant pathways to growth limitation and identify major growth-limiting factors including the oxidative stress and depletion of lipid metabolites. Such key information on growth-related mechanisms derived from the current approach can potentially guide the development of new strategies to enhance CHO culture performance. PMID- 22252270 TI - Orientation and depth of surfactant protein B C-terminal helix in lung surfactant bilayers. AB - SP-B(CTERM) is a cationic amphipathic helical peptide and functional fragment composed of residues 63 to 78 of surfactant protein B (SP-B). Static oriented and magic angle spinning solid state NMR, along with molecular dynamics simulation was used to investigate its structure, orientation, and depth in lipid bilayers of several compositions, namely POPC, DPPC, DPPC/POPC/POPG, and bovine lung surfactant extract (BLES). In all lipid environments the peptide was oriented parallel to the membrane surface. While maintaining this approximately planar orientation, SP-B(CTERM) exhibited a flexible topology controlled by subtle variations in lipid composition. SP-B(CTERM)-induced lipid realignment and/or conformational changes at the level of the head group were observed using (31)P solid-state NMR spectroscopy. Measurements of the depth of SP-B(CTERM) indicated the peptide center positions ~8A more deeply than the phosphate headgroups, a topology that may allow the peptide to promote functional lipid structures without causing micellization upon compression. PMID- 22252271 TI - [CorBene: a new model for collaborative care of patients with congestive heart failure]. AB - Congestive heart failure (CHF) is one of the most common medical disorders. The prognosis tends to be unfavorable and the quality of care needs further improvement. The aim of the CorBene project is to improve the health-related quality of life and the prognosis in patients in all stages of CHF and to reduce the hospitalization rate. For this purpose a modern collaborative treatment program involving all relevant health care professionals was developed. The key feature is the close collaboration between family physicians, practicing cardiologists, hospitals and rehabilitation facilities. The CorBene model was launched in Cologne and then spread to North-Rhine/Westphalia and to Saarland. Currently, there is the possibility to offer it in all German states. Preliminary analyses confirm an optimal, guideline-based therapy of CHF. PMID- 22252272 TI - [The Swiss approach for cardiac rehabilitation]. AB - Structured cardiac rehabilitation goes back to the late 1960s also in Switzerland and in the beginning was only available in rehabilitation clinics. In 1972 the first ambulatory rehabilitation programs became available to patients in Zurich and Bern. In the following years, in addition to the increasing number of rehabilitation centers for inpatients, more and more ambulatory rehabilitation programs were developed, especially in the larger Midlands population area in German and French-speaking Switzerland. In 1985 the Swiss Working Group of Cardiac Rehabilitation (SAKR) was initiated as an official working group of the Swiss Society of Cardiology and one of its first tasks was to establish a list of the institutions for cardiac rehabilitation in Switzerland. At that time there were 42 rehabilitation programs for a population of approx. 6.5 million, 21 for inpatients and 21 ambulatory; however, 90% of the patients were in inpatient programs. In 1992 the SAKR group defined the quality criteria which were to be applied for official recognition of institutions for cardiac rehabilitation in Switzerland. Due to these criteria, plus the fact that an increasing number of rehabilitation clinics in the mountains had been closed down, the number of inpatient rehabilitation centers decreased from 21 to 11 between 1989 and 2011, whereas the number of ambulatory programs increased from 21 to 51. The ambulatory rehabilitation centers are partially organized by local medical groups; however, most have integrated their activities into the local hospitals. The trend shows a developing preference for ambulatory rehabilitation. More and more elderly, polymorbid patients, however, will still need care in inpatient programs. PMID- 22252273 TI - Mono- and dinuclear ruthenium(II) 1,6,7,12-tetraazaperylene complexes. AB - We report the synthesis of free 1,6,7,12-tetraazaperylene (tape). Tape was obtained from 1,1'-bis-2,7-naphthyridine by potassium promoted cyclization followed by oxidation with air. Mono- and dinuclear ruthenium(II) 1,6,7,12 tetraazaperylene complexes of the general formulas [Ru(L-L)(2)(tape)](PF(6))(2), [1](PF(6))(2)-[5](PF(6))(2), and [{Ru(L-L)(2)}(2)(MU-tape)](PF(6))(4), [6](PF(6))(4)-[10](PF(6))(4), with{L-L = phen, bpy, dmbpy (4,4'-dimethyl-2,2' bipyridine), dtbbpy (4,4'-ditertbutyl-2,2'-bipyridine) and tmbpy (4,4'5,5' tetramethyl-2,2'-bipyridine)}, respectively, were synthesized. The X-ray structures of tape.2CHCl(3) and the mononuclear complexes [Ru(bpy)(2)(tape)](PF(6))(2).0.5CH(3)CN.0.5toluene, [Ru(dmbpy)(2)(tape)](PF(6))(2).2toluene and [Ru(dtbbpy)(2)(tape)](PF(6))(2).3acetone.0.5H(2)O were solved. The UV-vis absorption spectra and the electrochemical behavior of the ruthenium(ii) tape complexes were explored and compared with the data of the analogous dibenzoeilatin (dbneil), 2,2'-bipyrimidine (bpym) and tetrapyrido[3,2-a:2',3' c:3'',2''-h:2''',3'''-j]phenazin (tpphz) species. PMID- 22252274 TI - Identification of older patients at risk of unplanned readmission after discharge from the emergency department - comparison of two screening tools. AB - STUDY HYPOTHESIS: The Identification of Senior At Risk (ISAR) and the Triage Risk Stratification Tool (TRST) are the two most studied screening tools to detect high-risk patients for unplanned readmission after an emergency department (ED) visit. Since their performance was unclear among ED-patients over 75 years, we evaluated their capacities to predict readmission at 1, 3, 6 and 12 months as well as their usefulness in avoiding unnecessary further comprehensive geriatric assessment (CGA) in negative screened patients. METHODS: Historical cohort study with systematic routine data collection of functional status, comorbid conditions and readmission rate of patients released home after an ED-visit between 2007 and 2009 at the Geneva University Hospitals. RESULTS: 345 patients were included (mean age 84y; 63% female). Readmission rates were 25%, 38%, 49%, and 60% at 1, 3, 6, and 12 months, respectively. Positive ISAR (>=2/6) and TRST (>=2/5) predicted modestly unplanned readmission at each time point (AUC range: 0.607 0.664). Prediction of readmission with ISAR or TRST was not modified after adjustment for variables significantly associated with readmission (being male, having poor functional or comorbid scores). In case of negative ISAR or TRST, their high negative predictive values (NPV) would safely allow avoiding 64 useless CGA (ISAR <2: 7/64 readmissions at 1 month). CONCLUSIONS: Both ISAR and TRST tools predicted modestly unplanned readmission after an ED-visit among patients over 75 years. Nevertheless, due to their low specificity and high NPV these screening tools are useful to select elderly ED-patients who can safely return home without any further CGA. PMID- 22252276 TI - Gelatin-layered and multi-sized porous beta-tricalcium phosphate for tissue engineering scaffold. AB - The multi-sized porous beta-tricalcium phosphate scaffolds were fabricated by freeze drying followed by slurry coating using a multi-sized porous sponge as a template. Then, gelatin was dip coated on the multi-sized porous beta-tricalcium phosphate scaffolds under vacuum. The mechanical and biological properties of the fabricated scaffolds were evaluated and compared to the uniformly sized porous scaffolds and scaffolds that were not coated by gelatin. The compressive strength was tested by a universal testing machine, and the cell viability and differentiation behavior were measured using a cell counting kit and alkaline phosphatase activity using the MC3T3-E1 cells. In comparison, the gelatin-coated multi-sized porous beta-tricalcium phosphate scaffold showed enhanced compressive strength. After 14 days, the multi-sized pores were shown to affect cell differentiation, and gelatin coatings were shown to affect the cell viability and differentiation. The results of this study demonstrated that the multi-sized porous beta-tricalcium phosphate scaffold coated by gelatin enhanced the mechanical and biological strengths. PMID- 22252277 TI - Palladium-catalyzed allylic C-H amination of alkenes with N fluorodibenzenesulfonimide: water plays an important role. AB - A new palladium-catalyzed highly regioselective allylic C-H amination of alkenes with NFSI in the presence of a catalytic amount of water was developed and successfully expanded to Selectfluor-mediated palladium-catalyzed aminations of alkenes with N-tosylcarbamates in water at room temperature. PMID- 22252275 TI - A neuronal death model: overexpression of neuronal intermediate filament protein peripherin in PC12 cells. AB - BACKGROUND: Abnormal accumulation of neuronal intermediate filament (IF) is a pathological indicator of some neurodegenerative disorders. However, the underlying neuropathological mechanisms of neuronal IF accumulation remain unclear. A stable clone established from PC12 cells overexpressing a GFP Peripherin fusion protein (pEGFP-Peripherin) was constructed for determining the pathway involved in neurodegeneration by biochemical, cell biology, and electronic microscopy approaches. In addition, pharmacological approaches to preventing neuronal death were also examined. RESULTS: Results of this study showed that TUNEL positive reaction could be detected in pEGFP-Peripherin cells. Swollen mitochondria and endoplasmic reticulum (ER) were seen by electron microscopy in pEGFP-Peripherin cells on day 8 of nerve growth factor (NGF) treatment. Peripherin overexpression not only led to the formation of neuronal IF aggregate but also causes aberrant neuronal IF phosphorylation and mislocation. Western blots showed that calpain, caspase-12, caspase-9, and caspase-3 activity was upregulated. Furthermore, treatment with calpain inhibitor significantly inhibited cell death. CONCLUSIONS: These results suggested that the cytoplasmic neuronal IF aggregate caused by peripherin overexpression may induce aberrant neuronal IF phosphorylation and mislocation subsequently trapped and indirectly damaged mitochondria and ER. We suggested that the activation of calpain, caspase 12, caspase-9, and caspase-3 were correlated to the dysfunction of the ER and mitochondria in our pEGFP-Peripherin cell model. The present study suggested that pEGFP-Peripherin cell clones could be a neuronal death model for future studies in neuronal IFs aggregate associated neurodegeneration. PMID- 22252278 TI - Outcome after ipsilateral breast tumor recurrence in patients who receive accelerated partial breast irradiation. AB - BACKGROUND: The objective of this study was to examine clinical outcomes and patterns of failure in patients with early stage breast cancer who developed an ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) using accelerated partial breast irradiation (APBI). METHODS: In total, 1440 patients (1449 tumors) with early stage breast cancer who underwent BCT were treated with the MammoSite device to deliver APBI (34 Gray [Gy] in 3.4-Gy fractions). One thousand two hundred fifty-five patients (87%) had invasive breast cancer (IBC) (median tumor size, 10 mm), and 194 patients (13%) had ductal carcinoma in situ (DCIS) (median tumor size, 8 mm). The median follow-up was 60 months. RESULTS: Fifty patients (3.5%) developed an IBTR for a 5-year actuarial rate of 3.61% (3.65% for IBC and 3.36% for DCIS). It was determined that 36 recurrences (72%) represented new primary cancers, and 14 recurrences (28%) represented recurrences of the index lesion. Of the 32 recurrences with known histology, 78% were IBC, and 22% were DCIS. After IBTR, 28 of 38 patients (74%) underwent salvage mastectomy, and 9 of 38 patients (26%) had a second attempt at BCT. Adjuvant therapies included tamoxifen in 8 patients (16%) and systemic chemotherapy in 6 patients (12%). The 3-year rates of disease-free survival, cause-specific survival, and overall survival after IBTR were 58.7%, 92.1%, and 80.5%, respectively. CONCLUSIONS: With 5 years of follow-up, APBI produced clinical outcomes and patterns of failure comparable to those achieved with whole breast irradiation. Patients who developed an IBTR after APBI had excellent 3 year survival outcomes after salvage treatments. PMID- 22252279 TI - Predictors of intra-community variation in air quality. AB - Air quality has emerged as a key determinant of important health outcomes in children and adults. This study aims to identify factors that influence local, within-community air quality, and to build a model for traffic-related air pollution (TRP).We utilized concentrations of NO(2), NO, and total oxides of nitrogen (NO(x)), which were measured at 942 locations in 12 southern California communities. For each location, population density, elevation, land-use, and several indicators of traffic were calculated. A spatial random effects model was used to study the relationship of these predictors to each TRP.Variation in TRP was strongly correlated with traffic on nearby freeways and other major roads, and also with population density and elevation. After accounting for traffic, categories of land-use were not associated with the pollutants. Traffic had a larger relative impact in small urban (low regional pollution) communities than in large urban (high regional pollution) communities. For example, our best fitting model explained 70% of the variation in NO(x) in large urban areas and 76% in small urban areas. Compared with living at least 1,500 m from a freeway, living within 250 m of a freeway was associated with up to a 41% increase in TRP in a large urban area, and up to a 75% increase in small urban areas.Thus, traffic strongly affects local air quality in large and small urban areas, which has implications for exposure assessment and estimation of health risks. PMID- 22252280 TI - Applying GIS and fine-resolution digital terrain models to assess three dimensional population distribution under traffic impacts. AB - Pollution exhibits significant variations horizontally and vertically within cities; therefore, the size and three-dimensional (3D) spatial distribution of population are significant determinants of urban health. This paper presents a novel methodology, 3D digital geography (3DIG) methodology, for investigating 3D spatial distributions of population in close proximity to traffic, thus the potential highly exposed population under traffic impacts. 3DIG applies geographic information system and fine-resolution (5 m) digital terrain models to obtain the number of building floors in residential zones of the Taipei metropolis; the vertical distribution of population at different floors was estimated based on demographic data in each census tract. In addition, population within 5, 10, 20, 50, and 100 m from the roadways was estimated. Field validation indicated that model results were reliable and accurate; the final population estimation differs only by 0.88% from the demographic database. The results showed that among the total 6.5 million Taipei residents, 0.8 (12.3%), 1.5 (22.9%), 2.3 (34.9), and 2.7 (41.1%) million residents live on the first or second floor within 5, 10, 20, and 50 m, respectively, of municipal roads. There are 22 census tracts with more than half of their residents living on the first or second floor within 5 m of municipal roads. In addition, half of the towns in Taipei city and county with >13.9% and 12.1% of residents live on the first and second floors within 5 m of municipal roads, respectively. These findings highlight the huge number of Taipei residents in close proximity to traffic and have significant implications for exposure assessment and environmental epidemiological studies. This study demonstrates that 3DIG is a versatile methodology for various research and policy planning in which 3D spatial population distribution is the central focus. PMID- 22252281 TI - Identification of potential biomarkers of exposure to di(isononyl)cyclohexane-1,2 dicarboxylate (DINCH), an alternative for phthalate plasticizers. AB - Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) is used as an alternative for some phthalate plasticizers. In rats, DINCH mostly eliminates in feces as cyclohexane-1,2-dicarboxylic acid (CHDA), mono isononyl ester (MINCH) or in urine as CHDA. However, CHDA is not a specific biomarker of DINCH and measuring MINCH in feces is impractical. To identify additional potential biomarkers, we administered DINCH (500 mg/kg body weight) in a single subcutaneous (SC) or oral dose to four adult female Sprague-Dawley rats. We collected 24-h urine samples before dosing (to be used as controls) and 24-h and 48-h after dosing, and serum at necropsy after 48 h. We positively identified and accurately quantified CHDA and cyclohexane-1,2-dicarboxylic [corrected] acid, mono hydroxyisononyl ester (MHNCH) using authentic standards. Moreover, we tentatively identified MINCH and 12 oxidative metabolites, including 4 cyclohexane ring oxidation products, based on their mass spectrometric-fragmentation patterns. CHDA and MHNCH levels were higher in the urine collected 24 h after oral than SC administration. By contrast, 48-h after dosing, CHDA urinary levels were similar regardless of the exposure route. We detected all but two of the urine metabolites also in serum. Levels of CHDA and MHNCH in serum were lower than in the two post-dose urine collections. Our results suggest that several urinary oxidative metabolites, specifically CHDA, mono oxoisononyl ester and MHNCH may be used as specific biomarkers of DINCH exposure in humans. PMID- 22252282 TI - The suggested algorithm for the management of "body packers". PMID- 22252283 TI - Fatigue and sleep disorders in multiple sclerosis: is obstructive sleep apnea a link? PMID- 22252284 TI - Gender and age influence the effects of slow-wave sleep on respiration in patients with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is influenced by sleep architecture with rapid eye movement (REM) sleep having the most adverse influence, especially in women. There is little data defining the influence of slow-wave sleep (SWS) on OSA. We wished to study the influence of SWS on OSA and identify differences attributable to gender and/or age, if any. METHODS: Retrospective study of polysomnography (PSG) records of adult patients referred for diagnostic PSG. Records were excluded if they underwent split night or positive airway pressure titration studies, had <180 min of total sleep time (TST) and/or <40% sleep efficiency, or had SWS <5 min and/or <1% of TST. The apnea-hypopnea index (AHI) recorded during SWS was compared with that measured during other non-rapid eye movement (NREM) sleep and during REM sleep. The REM-SWS difference in AHI was measured, and compared between genders. RESULTS: Records from 239 patients were included. The mean AHI in all subjects was 17.7 +/- 22.6. The SWS AHI was 6.8 +/- 18.9, compared to the REM AHI of 24.9 +/- 25.8, and NREM AHI of 15.8 +/- 22.8. Females had significantly higher SWS by percentage, and lower NREM AHI (P < 0.0001) and SWS AHI (P = 0.03). Among patients with OSA (AHI >=5), the difference between REM AHI and SWS AHI was greater in women than in men (34.2 +/- 27.4 vs. 21.6 +/- 26.0, P = 0.006). CONCLUSIONS: The upper airway appears to be less susceptible to OSA during SWS than during REM and other NREM sleep. This may be related to phase-specific influences on both dynamic upper airway control as well as loop gain. Gender and age appear to modify this effect. PMID- 22252285 TI - Shape persistence delivers lock-and-key chloride binding in triazolophanes. AB - Triazolophanes have recently surfaced as a new class of shape-persistent macrocycles that bind anions. Bearing only triazole- and phenyl-derived CH hydrogen bond donors, these receptors have shown extraordinary Cl(-) binding strengths (>10(6) M(-1), CH(2)Cl(2)). The attributes of the triazolophane that are responsible are presented herein alongside recent literature accounts that have utilized similar strategies in new and exciting supramolecular systems. This review describes how triazolophanes leverage the structural pre-organization characteristic of spherands to take advantage of non-traditional hydrogen bonds originating from extrinsic CH donors. PMID- 22252286 TI - Distally based sural fasciomusculocutaneous flap for treatment of wounds of the distal third of the leg and ankle with exposed internal hardware. AB - Soft tissue reconstruction of the distal third of the lower limb with exposure of the internal hardware is a challenging problem with several potential complications, such as exposure of the fracture line, fracture instability and bacterial contamination. The treatment of these lesions usually consists of substitution of the internal hardware with external fixation devices and further flap coverage. We propose a different reconstructive approach, characterized by harvesting a sural fasciomusculocutaneous flap on the exposed internal hardware once a sterile ground has been obtained. Four patients were retrospectively analyzed. Soft tissue reconstruction was achieved in all cases. In one case hardware removal was necessary for complete healing. The sural fasciomusculocutaneous flap is a safe alternative to other pedicled and free flaps. Moreover, it allows direct coverage of internal fixators, thus completing the reconstruction in less time. This flap fits best to the morphology of the wound and internal hardware, leaving the main vascular trunk of the leg intact and at the same time providing a reliable vascular supply. PMID- 22252287 TI - Freedom of choice--always beneficial? PMID- 22252288 TI - Ultrafast hydrogen sensing through hybrids of semiconducting single-walled carbon nanotubes and tin oxide nanocrystals. AB - We report an ultrafast and sensitive hydrogen (H(2)) sensing platform using semiconducting single-walled carbon nanotubes (SWCNTs) decorated with tin oxide (SnO(2)) nanocrystals (NCs). The hybrid SnO(2) NC-SWCNT platform shows a response time of 2-3 seconds to 1% H(2) under room temperature and can fully recover within a few minutes in air. PMID- 22252289 TI - Treatment of intracranial atherosclerotic disease with a balloon-expandable paclitaxel eluting stent: procedural safety, efficacy and mid-term patency. AB - PURPOSE: Procedural safety and high rates of in-stent recurrent stenotic lesions (ISR) remain a concern in the endovascular treatment of intracranial atherosclerotic disease (ICAD). In the present study technical feasibility, safety and efficacy of the paclitaxel eluting balloon-expandable coronary stent Coroflex((r)) Please was assessed in the treatment of ICAD. METHODS: A total of 95 patients (79 male; median age 68 years) with 106 intracranial atherosclerotic stenotic lesions underwent endovascular treatment using Coroflex((r)) Please stents (B. Braun, Melsungen, Germany). Location and degree of target stenoses before and after treatment and at follow-up and adverse clinical sequelae of treatment were registered. Post-procedural medication included 100 mg acetylsalicylic acid (ASA) and 75 mg clopidogrel for 1 year. Angiographic follow up was scheduled for 6, 12, 26 and 52 weeks after the treatment. RESULTS: The lesion locations were as follows: internal carotid artery (ICA) petrous (n = 44, 42%), ICA cavernous (n = 43, 41%), ICA paraclinoid (n = 4, 4%), intradural vertebral artery (VA; n = 11, 10%) and basilar artery (BA; n = 4, 4%). Of the lesions seven could not be treated due to difficult anatomy and stent stiffness (7% technical failure rate). The combined post-interventional neurological morbidity and mortality rate, including stroke, intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) and carotid cavernous fistula (CCF) was n = 4 (3.7%) within and n = 1 (0.9%) at and beyond 30 days, respectively. Angiographic and clinical follow-up examinations were carried out for 78 (78%) of the lesions (mean 16.1 months, maximum 48 months). Asymptomatic recurrent stenosis was seen in 3 out of 78 (3.8%) lesions and there was 1 case of late stent thrombosis (0.9%). CONCLUSIONS: Treatment of ICAD using drug-eluting coronary stents is safe and effective but technical failure due to stent stiffness remains a problem. Application of the more flexible, newest generation thin-strut stents, however, shows promising results. PMID- 22252290 TI - One-year monitoring of core biomarker and digestive enzyme responses in transplanted zebra mussels (Dreissena polymorpha). AB - A 12-month active biomonitoring study was performed in 2008-2009 on the Vesle river basin (Champagne-Ardenne, France) using the freshwater mussel Dreissena polymorpha as a sentinel species; allochthonous mussels originating from a reference site (Commercy) were exposed at four sites (Bouy, Sept-Saulx, Fismes, Ardre) within the Vesle river basin. Selected core biomarkers (acetylcholinesterase (AChE) activity, glutathione-S transferase (GST) activity, metallothionein concentration), along with digestive enzyme activities (amylase, endocellulase) and energy reserve concentrations (glycogen, lipids), were monitored throughout the study in exposed mussels. At the Fismes and Ardre sites (downstream basin), metallic and organic contamination levels were low but still high enough to elicit AChE and GST activity induction in exposed mussels (chemical stress); besides, chemical pollutants had no apparent deleterious effects on mussel condition. At the Bouy and Sept-Saulx sites (upstream basin), mussels obviously suffered from adverse food conditions which seriously impaired individual physiological state and survival (nutritional stress); food scarcity had however no apparent effects on core biomarker responses. Digestive enzyme activities responded to both chemical and nutritional stresses, the increase in energy outputs (general adaptation syndrome-downstream sites) or the decrease in energy inputs (food scarcity-upstream sites) leading to mid- or long-term induction of digestive carbohydrase activities in exposed mussels (energy optimizing strategy). Complex regulation patterns of these activities require nevertheless the use of a multi-marker approach to allow data interpretation. Besides, their sensitivity to natural confounding environmental factors remains to be precised. PMID- 22252291 TI - The individual and population effects of tetracycline on Daphnia magna in multigenerational exposure. AB - Multigenerational exposure of Daphnia magna to tetracycline was carried out through four consecutive generations. The effects of tetracycline on the survival, reproduction and growth of D. magna were assessed over a period of 21 days per generation. The evaluated endpoints were overall fecundity (total mean neonates per female over 21 days), time to first reproduction, longevity, molting number and somatic growth, such as body weight and body length. Using the results obtained for reproduction and survival rates, the intrinsic population growth rate (PGR) was calculated and compared throughout the generations. Reproductive impairment was observed in all generations and magnified with increasing generation number. The value of no observed effect concentration on D. magna also markedly decreased with increasing generation number. This subsequently resulted in a reduction of the PGR value. In addition, the PGR value was decreased with increasing exposure concentration, decreasing by about 30 and 60% at 0.1 and 5.0 mg/L tetracycline, respectively. On the other hands, somatic growth increased with increasing generation number, because the remaining input energy from the reduced reproduction was mainly used for body maintenance. As a result, the somatic growth and reproduction showed reversed trends on continuous exposure of tetracycline to four generations. In conclusion, multigenerational exposure of tetracycline can induce overall responses on reproduction and the somatic growth of D. magna. Moreover, the PGR value of D. magna exposed to tetracycline was reduced with increasing generation number; thereby, inhibiting the long term propagation of D. magna. PMID- 22252292 TI - Venous air embolism in consecutive balloon kyphoplasties visualised on CT imaging. AB - OBJECTIVE: We noted a large amount of intravenous gas during balloon kyphoplasty on CT imaging. Formal assessment to understand the extent, possible causes and implications was undertaken. MATERIALS AND METHODS: Ten consecutive cases of balloon kyphoplasty were performed under general anaesthesia in the prone position, on a single vertebral level using a two-step technique under combined fluoroscopic and CT guidance. CT of the affected vertebra was performed before, after, and intermittently during the procedure. In 2 cases delayed CT was carried out in the supine position. RESULTS: Gas was seen on CT imaging, but not on conventional fluoroscopy. The gas is most likely to be air introduced during the procedure and was seen in the epidural and paravertebral venous plexus, posterior intercostal veins, renal veins, IVC and azygos vein. The average measured volume of gas seen on the post-procedure CT imaging was 1.07 mL, range 0.16-3.97 mL. There was no correlation of the measured amount of gas to the procedure duration or location, the use of a curette or the injected cement volume. Delayed CT in the supine position no longer showed air in the local venous system. CONCLUSIONS: Balloon kyphoplasty is associated with the fluoroscopically invisible introduction of air into the vertebral and paravertebral veins and deep systemic veins and is likely to be much more extensive than identified on CT imaging. There is potential for serious air embolism in kyphoplasty and if there is a sudden deterioration in patient condition during the procedure the possibility of this complication needs to be considered. PMID- 22252293 TI - Quince (Cydonia oblonga Miller) peel polyphenols modulate LPS-induced inflammation in human THP-1-derived macrophages through NF-kappaB, p38MAPK and Akt inhibition. AB - Chronic inflammation is a hallmark of several pathologies, such as rheumatoid arthritis, gastritis, inflammatory bowel disease, atherosclerosis and cancer. A wide range of anti-inflammatory chemicals have been used to treat such diseases while presenting high toxicity and numerous side effects. Here, we report the anti-inflammatory effect of a non-toxic, cost-effective natural agent, polyphenolic extract from the Tunisian quince Cydonia oblonga Miller. Lipopolysaccharide (LPS) treatment of human THP-1-derived macrophages induced the secretion of high levels of the pro-inflammatory cytokine TNF-alpha and the chemokine IL-8, which was inhibited by quince peel polyphenolic extract in a dose dependent manner. Concomitantly, quince polyphenols enhanced the level of the anti-inflammatory cytokine IL-10 secreted by LPS-treated macrophages. We further demonstrated that the unexpected increase in IL-6 secretion that occurred when quince polyphenols were associated with LPS treatment was partially responsible for the polyphenols-mediated inhibition of TNF-alpha secretion. Biochemical analysis showed that quince polyphenols extract inhibited the LPS-mediated activation of three major cellular pro-inflammatory effectors, nuclear factor kappa B (NF-kappaB), p38MAPK and Akt. Overall, our data indicate that quince peel polyphenolic extract induces a potent anti-inflammatory effect that may prove useful for the treatment of inflammatory diseases and that a quince-rich regimen may help to prevent and improve the treatment of such diseases. PMID- 22252294 TI - Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues. AB - Notch pathway regulates vessel development and maturation. Dll4, a high-affinity ligand for Notch, is expressed predominantly in the arterial endothelium and is induced by hypoxia among other factors. Inhibition of Dll4 has paradoxical effects of reducing the maturation and perfusion in newly forming vessels while increasing the density of vessels. We hypothesized that partial and/or intermittent inhibition of Dll4 may lead to increased vascular response and still allow vascular maturation to occur. Thus tissue perfusion can be restored rapidly, allowing quicker recovery from ischemia or tissue injury. Our studies in two different models (hindlimb ischemia and skin flap) show that inhibition of Dll4 at low dose allows faster recovery from vascular and tissue injury. This opens a new possibility for Dll4 blockade's therapeutic application in promoting recovery from vascular injury and restoring blood supply to ischemic tissues. PMID- 22252295 TI - Properties and functions of KATP during mouse perinatal development. AB - BACKGROUND: Prevailing data suggest that ATP-sensitive potassium channels (K(ATP)) contribute to a surprising resistance to hypoxia in mammalian embryos, thus we aimed to characterize the developmental changes of K(ATP) channels in murine fetal ventricular cardiomyocytes. METHODS: Patch clamp was applied to investigate the functions of K(ATP). RT-PCR, Western blot were used to further characterize the molecular properties of K(ATP) channels. RESULTS: Similar K(ATP) current density was detected in ventricular cardiomyocytes of late development stage (LDS) and early development stage (EDS). Molecular-biological study revealed the upregulation of Kir6.1/SUR2A in membrane and Kir6.2 remained constant during development. Kir6.1, Kir6.2, and SUR1 were detectable in the mitochondria without marked difference between EDS and LDS. Acute hypoxia ischemia led to cessation of APs in 62.5% of tested EDS cells and no APs cessation was observed in LDS cells. SarcK(ATP) blocker glibenclamide rescued 47% of EDS cells but converted 42.8% of LDS cells to APs cessations under hypoxia ischemic condition. MitoK(ATP) blocker 5-HD did not significantly influence the response to acute hypoxia-ischemia at either EDS or LDS. In summary, sarcK(ATP) played distinct functional roles under acute hypoxia-ischemic condition in EDS and LDS fetal ventricular cardiomyocytes, with developmental changes in sarcK(ATP) subunits. MitoK(ATP) were not significantly involved in the response of fetal cardiomyocytes to acute hypoxia-ischemia and no developmental changes of K(ATP) subunits were found in mitochondria. PMID- 22252296 TI - Stat3 induces oncogenic Skp2 expression in human cervical carcinoma cells. AB - Dysregulated Skp2 function promotes cell proliferation, which is consistent with observations of Skp2 over-expression in many types of human cancers, including cervical carcinoma (CC). However, the molecular mechanisms underlying elevated Skp2 expression have not been fully explored. Interleukin-6 (IL-6) induced Stat3 activation is viewed as crucial for multiple tumor growth and metastasis. Here, we demonstrate that Skp2 is a direct transcriptional target of Stat3 in the human cervical carcinoma cells. Our data show that IL-6 administration or transfection of a constitutively activated Stat3 in HeLa cells activates Skp2 mRNA transcription. Using luciferase reporter and ChIP assays, we show that Stat3 binds to the promoter region of Skp2 and promotes its activity through recruiting P300. As a result of the increase of Skp2 expression, endogenous p27 protein levels are markedly decreased. Thus, our results suggest a previously unknown Stat3-Skp2 molecular network controlling cervical carcinoma development. PMID- 22252298 TI - Antioxidants, like coenzyme Q10, selenite, and curcumin, inhibited osteoclast differentiation by suppressing reactive oxygen species generation. AB - Coenzyme Q10 (CoQ10), selenium, and curcumin are known to be powerful antioxidants. Osteoclasts are capable of resorbing mineralized bone and excessive bone resorption by osteoclasts causes bone loss-related diseases. During osteoclast differentiation, the reactive oxygen species (ROS) acts as a secondary messenger on signal pathways. In this study, we investigated whether antioxidants can inhibit RANKL-induced osteoclastogenesis through suppression of ROS generation and compared the relative inhibitory activities of CoQ10, sodium selenite, and curcumin on osteoclast differentiation. We found that antioxidants markedly inhibited the formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells in both bone marrow-derived monocytes (BMMs) and RAW 264.7 cells. Antioxidants scavenged intracellular ROS generation within osteoclast precursors during RANKL-stimulated osteoclastogenesis. These also acted to significantly suppress the gene expression of NFATc1, TRAP, and osteoclast-associated immunoglobulin-like receptor (OSCAR), which are genetic markers of osteoclast differentiation in a dose-dependent manner. These antioxidants also suppressed ROS-induced IkappaBalpha signaling pathways for osteoclastogenesis. Specially, curcumin displayed the highest inhibitory effect on osteoclast differentiation when concentrations were held constant. Together, CoQ10, selenite, and curcumin act as inhibitors of RANKL-induced NFATc1 which is a downstream event of NF-kappaB signal pathway through suppression of ROS generation, thereby suggesting their potential usefulness for the treatment of bone disease associated with excessive bone resorption. PMID- 22252297 TI - Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation. AB - Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-gamma and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17 promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN--induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models. PMID- 22252299 TI - Peroxydisulfate activation by [RuII(tpy)(pic)(H2O)]+. Kinetic, mechanistic and anti-microbial activity studies. AB - The oxidation of [Ru(II)(tpy)(pic)H(2)O](+) (tpy = 2,2',6',2''-terpyridine; pic( ) = picolinate) by peroxidisulfate (S(2)O(8)(2-)) as precursor oxidant has been investigated kinetically by UV-VIS, IR and EPR spectroscopy. The overall oxidation of Ru(II)- to Ru(IV)-species takes place in a consecutive manner involving oxidation of [Ru(II)(tpy)(pic)H(2)O](+) to [Ru(III)(tpy)(pic)(OH)](+), and its further oxidation of to the ultimate product [Ru(IV)(tpy)(pic)(O)](+) complex. The time course of the reaction was followed as a function of [S(2)O(8)(2-)], ionic strength (I) and temperature. Kinetic data and activation parameters are interpreted in terms of an outer-sphere electron transfer mechanism. Anti-microbial activity of Ru(II)(tpy)(pic)H(2)O](+) complex by inhibiting the growth of Escherichia coli DH5alpha in presence of peroxydisulfate has been explored, and the results of the biological studies have been discussed in terms of the [Ru(IV)(tpy)(pic)(O)](+) mediated cleavage of chromosomal DNA of the bacteria. PMID- 22252301 TI - Optical sensing nanostructures for porous silicon rugate filters. AB - Porous silicon rugate filters [PSRFs] and combination PSRFs [C-PSRFs] are emerging as interesting sensing materials due to their specific nanostructures and superior optical properties. In this work, we present a systematic study of the PSRF fabrication and its nanostructure/optical characterization. Various PSRF chips were produced with resonance peaks that are adjustable from visible region to near-infrared region by simply increasing the periods of sine currents in a programmed electrochemical etching method. A regression analysis revealed a perfect linear correlation between the resonant peak wavelength and the period of etching current. By coupling the sine currents with several different periods, C PSRFs were produced with defined multiple resonance peaks located at desired positions. A scanning electron microscope and a microfiber spectrophotometer were employed to analyze their physical structure and feature spectra, respectively. The sensing properties of C-PSRFs were investigated in an ethanol vapor, where the red shifts of the C-PSRF peaks had a good linear relationship with a certain concentration of ethanol vapor. As the concentration increased, the slope of the regression line also increased. The C-PSRF sensors indicated the high sensitivity, quick response, perfect durability, reproducibility, and versatility in other organic gas sensing. PMID- 22252302 TI - Impact of preoperative radiotherapy on survival in locally advanced rectal cancer: an observational population-based study from the South of Switzerland. AB - Preoperative radiotherapy (RT) followed by surgery is widely accepted in the treatment of locally advanced rectal cancer (LARC). This study aimed to estimate at the population-based level the impact of preoperative RT on overall survival (OS) and cancer-specific survival (CSS) in LARCs diagnosed in Southern Switzerland between 1996 and 2007. All patients with LARC were selected from the Ticino Cancer Registry database. Patients were categorized according to the first administered treatment: preoperative radiotherapy (RT) followed by surgery (RT+) versus surgery (RT-). Clinical-pathological characteristics and 5-year OS and CSS were analysed. Among 384 patients with LARC, 54% underwent preoperative RT, occurring more frequently in the mid-distal part of the rectum compared with the RT- group (74.8 vs. 29.8%, respectively). Both 5-year OS and CSS significantly improved in RT+ patients (OS: 68 vs. 54%, respectively; CSS: 71 vs. 63%, respectively). The adjusted hazard ratio for all death was equal to 0.66 (95% confidence interval: 0.46; 0.97); similarly, the hazard ratio for cancer-specific death was 0.63 (95% confidence interval: 0.39; 0.99). These observational population-based results, after controlling for most important diagnostic and clinical prognostic factors, confirm the benefit of preoperative RT of LARC, even if the magnitude seems greater than expected in clinical trials results. Additional studies are needed, particularly with regard to the possible effect of standardized staging procedure and multidisciplinary discussion on patient outcome. PMID- 22252300 TI - Fine scale analysis of gene expression in Drosophila melanogaster gonads reveals Programmed cell death 4 promotes the differentiation of female germline stem cells. AB - BACKGROUND: Germline stem cells (GSCs) are present in the gonads of Drosophila females and males, and their proper maintenance, as well as their correct differentiation, is essential for fertility and fecundity. The molecular characterization of factors involved in maintenance and differentiation is a major goal both in Drosophila and stem cell research. While genetic studies have identified many of these key factors, the use of genome-wide expression studies holds the potential to greatly increase our knowledge of these pathways. RESULTS: Here we report a genome-wide expression study that uses laser cutting microdissection to isolate germline stem cells, somatic niche cells, and early differentiating germ cells from female and male gonads. Analysis of this data, in association with two previously published genome-wide GSC data sets, revealed sets of candidate genes as putatively expressed in specific cell populations. Investigation of one of these genes, CG10990 the Drosophila ortholog of mammalian Programmed cell death 4 (Pdcd4), reveals expression in female and male germline stem cells and early differentiating daughter cells. Functional analysis demonstrates that while it is not essential for oogenesis or spermatogenesis, it does function to promote the differentiation of GSCs in females. Furthermore, in females, Pdcd4 genetically interacts with the key differentiation gene bag of marbles (bam) and the stem cell renewal factor eIF4A, suggesting a possible pathway for its function in differentiation. CONCLUSIONS: We propose that Pdcd4 promotes the differentiation of GSC daughter cells by relieving the eIF4A mediated inhibition of Bam. PMID- 22252303 TI - Impact of lifestyle factors on preneoplastic changes in prophylactic oophorectomies of BRCA mutation carriers. AB - BRCA mutation carriers are at high risk of developing ovarian cancer. Ovarian malignancies are usually identified at an advanced stage with poor prognosis, attributed to inadequate options of early detection. Because of its risk-reducing effect of nearly 96%, prophylactic salpingo-oophorectomy is still the leading option for risk-reduction in women with a positive BRCA mutation status. The presence of ovarian cancer precursor lesions, such as epithelial inclusion cysts (EICs) or cortical invaginations (CIs), has previously been discussed in several studies with diverse conclusions. We retrospectively investigated a large and consistent population (n=94) of BRCA mutation carriers for the presence of potential preneoplastic and neoplastic changes. We also examined the role of specific lifestyle factors. Ninety-four women with disease-associated germline BRCA1 or BRCA2 mutations were included in this retrospective study. All women had undergone genetic counseling and prophylactic salpingo-oophorectomy, which was performed at a mean age of 43.33 years (range 27-66). Histological slides of both ovaries were reviewed by an independent pathologist. Data concerning lifestyle factors were collected from medical files and questionnaires. Two malignant lesions (2.1%), one bilateral serous papillary adenocarcinoma of the epithelial surface and one adenocarcinoma of the peritoneum with involvement of the left adnexa, and one lesion (1.1%) with obvious malignant potential, one mucinous borderline tumor of the right ovary, have been identified. We registered a high prevalence of CIs (30; 31.9%) and EICs (44; 46.8%) in prophylactically removed ovaries of BRCA mutation carriers. A significant correlation (P=0.002) was found with regard to the presence of EICs in women with increased BMI. Concerning the regular consumption of alcohol as a risk factor for premalignant lesions, in particular CIs, a statistically insignificant trend (P=0.083) was noted. Overweight women seem to be at risk of developing more cortical invaginations than women of normal weight. To improve the final outcome of the disease, women at increased risk of ovarian cancer should be appropriately informed of potential increased risk factors. PMID- 22252304 TI - Ideomotor silence: the case of complete paralysis and brain-computer interfaces (BCI). AB - The paper presents some speculations on the loss of voluntary responses and operant learning in long-term paralysis in human patients and curarized rats. Based on a reformulation of the ideomotor thinking hypothesis already described in the 19th century, we present evidence that instrumentally learned responses and intentional cognitive processes extinguish as a consequence of long-term complete paralysis in patients with amyotrophic lateral sclerosis (ALS). Preliminary data collected with ALS patients during extended and complete paralysis suggest semantic classical conditioning of brain activity as the only remaining communication possibility in those states. PMID- 22252305 TI - The impact of task rules on distracter processing: automatic categorization of irrelevant stimuli. AB - The goal of the study was to investigate whether task rules are automatically applied to irrelevant distracters. In three experiments, subjects categorized target words which were superimposed on distracter pictures. The categorization rule was arbitrary and the distracters were not relevant at any point during the experiment. We found congruency effects for distracters that belonged to the task relevant categories, but were never presented as target words. Responses were faster when target and distracter belonged to the same category, i.e., were mapped to the same response, than when they were mapped to different responses. Since the distracters were never responded to in the course of the experiment, interference caused by retrieval of S-R episodes cannot explain the results. Instead, we propose that even arbitrary categorization rules are applied to all suitable stimuli, including distracters. Results are taken as evidence that a currently relevant task rule enhances processing of target-related information thereby increasing interference by task related, but currently irrelevant information. PMID- 22252306 TI - Biogenesis, functions and fate of plant microRNAs. AB - microRNAs (miRNAs), a recently discovered class of small RNAs, are endogenously transcribed non-coding RNAs that are known to control diverse developmental processes and defense responses. They regulate these pathways by fine-tuning the levels of transcripts to which they bind and cause their cleavage or translation repression. Several studies on the processing of miRNA precursors have shed light on the essential structural features for precise release of miRNA duplexes. The identification of a protein that degrade single stranded small RNA has provided us with some understanding of how miRNA flux is maintained in plants. This review focuses on the genome organization, biogenesis, miRNA activity, and the fate of miRNAs. PMID- 22252307 TI - Time to incorporate time in cost-effectiveness analysis. AB - Cost-effectiveness analysis as a means to evaluate medical innovations has become well accepted in the UK and several other Western countries. An important assumption underlying this method is that costs and effects are constant over time. In reality, however, and especially in the short run, variations in costs and effects are likely to occur. These variations can lead to considerable deviations from the outcome of a conventional economic evaluation, which in turn may lead to serious implementation problems at a local level. Taking time into account explicitly in economic evaluations in health care may enhance their utility for both societal and local decision making, and may ultimately smooth the adoption of new and basically cost-effective health care technologies. PMID- 22252308 TI - Longitudinal predictive ability of mapping models: examining post-intervention EQ 5D utilities derived from baseline MHAQ data in rheumatoid arthritis patients. AB - OBJECTIVES: The purpose of this methodological study was to to provide insight into the under-addressed issue of the longitudinal predictive ability of mapping models. Post-intervention predicted and reported utilities were compared, and the effect of disease severity on the observed differences was examined. METHODS: A cohort of 120 rheumatoid arthritis (RA) patients (60.0% female, mean age 59.0) embarking on therapy with biological agents completed the Modified Health Assessment Questionnaire (MHAQ) and the EQ-5D at baseline, and at 3, 6 and 12 months post-intervention. OLS regression produced a mapping equation to estimate post-intervention EQ-5D utilities from baseline MHAQ data. Predicted and reported utilities were compared with t test, and the prediction error was modeled, using fixed effects, in terms of covariates such as age, gender, time, disease duration, treatment, RF, DAS28 score, predicted and reported EQ-5D. RESULTS: The OLS model (RMSE = 0.207, R(2) = 45.2%) consistently underestimated future utilities, with a mean prediction error of 6.5%. Mean absolute differences between reported and predicted EQ-5D utilities at 3, 6 and 12 months exceeded the typically reported MID of the EQ-5D (0.03). According to the fixed-effects model, time, lower predicted EQ-5D and higher DAS28 scores had a significant impact on prediction errors, which appeared increasingly negative for lower reported EQ-5D scores, i.e., predicted utilities tended to be lower than reported ones in more severe health states. CONCLUSIONS: This study builds upon existing research having demonstrated the potential usefulness of mapping disease-specific instruments onto utility measures. The specific issue of longitudinal validity is addressed, as mapping models derived from baseline patients need to be validated on post-therapy samples. The underestimation of post-treatment utilities in the present study, at least in more severe patients, warrants further research before it is prudent to conduct cost-utility analyses in the context of RA by means of the MHAQ alone. PMID- 22252309 TI - Structural origin of energetic heterogeneity in ionic liquids. AB - How structural features observed computationally are connected to excitation wavelength dependent kinetics observed experimentally remains an unanswered question in the field of ionic liquids. Using molecular dynamics simulation methods and approximated models that simplify the electrostatic interactions in ionic liquids, we discovered that on the timescale shorter than the relaxation time of the photochemical process, the energetic heterogeneity in terms of distribution of excitation energies is the consequence of the structure heterogeneity formed by local arrangement of ions around the solute probe. PMID- 22252311 TI - How to manage children and young adults with myeloproliferative neoplasms. AB - On the basis of my personal clinical and research experience and validated by the current literature, my approach to the management of pediatric (age <18 years) and young patients (age <40 years) with classic myeloproliferative neoplasms is presented by focusing on diagnosis, patient communication, risk stratification and therapy. The WHO-2008 diagnostic criteria are recommended, even though in children suspected with essential thrombocythemia (ET), a specific set of diagnostic features may be required. Patient communication includes information on natural history, genetic abnormalities and counseling in all women of child bearing age. The main challenge in children and young adults with ET and polycythemia vera (PV) is to avoid recurrence of major thrombosis by selecting those patients who ultimately can benefit from cytotoxic and antithrombotic therapy without increasing the incidence of drug-induced side effects. In asymptomatic low-risk patients no therapy is prescribed while in high-risk low dose aspirin, hydroxyurea and interferon-alpha are my first line drugs. My first decision when considering treatment of a young patient with primary myelofibrosis (PMF) or post-PV or post ET-myelofibrosis, is whether he/she qualifies for bone marrow allotransplantation. In the remaining young PMF patients palliative therapy or experimental drugs are considered. PMID- 22252310 TI - New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). AB - Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN. PMID- 22252312 TI - A robust zirconium N-heterocyclic carbene complex for the living and highly stereoselective ring-opening polymerization of rac-lactide. AB - A readily accessible and robust Zr-NHC complex was found to polymerize rac lactide in a highly controlled, living and stereoselective manner to afford heterotactic PLA. PMID- 22252313 TI - Loss of cadherin-binding proteins beta-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis. AB - Arrhythmic right ventricular cardiomyopathy (ARVC) is a hereditary heart muscle disease that causes sudden cardiac death (SCD) in young people. Almost half of ARVC patients have a mutation in genes encoding cell adhesion proteins of the desmosome, including plakoglobin (JUP). We previously reported that cardiac tissue-specific plakoglobin (PG) knockout (PG CKO) mice have no apparent conduction abnormality and survive longer than expected. Importantly, the PG homolog, beta-catenin (CTNNB1), showed increased association with the gap junction protein connexin43 (Cx43) in PG CKO hearts. To determine whether beta catenin is required to maintain cardiac conduction in the absence of PG, we generated mice lacking both PG and beta-catenin specifically in the heart (i.e., double knockout [DKO]). The DKO mice exhibited cardiomyopathy, fibrous tissue replacement, and conduction abnormalities resulting in SCD. Loss of the cadherin linker proteins resulted in dissolution of the intercalated disc (ICD) structure. Moreover, Cx43-containing gap junction plaques were reduced at the ICD, consistent with the arrhythmogenicity of the DKO hearts. Finally, ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous lethal ventricular arrhythmia in the DKO mice. In conclusion, these studies demonstrate that the N-cadherin-binding partners, PG and beta-catenin, are indispensable for maintaining mechanoelectrical coupling in the heart. PMID- 22252314 TI - A quantitative high-throughput in vitro splicing assay identifies inhibitors of spliceosome catalysis. AB - Despite intensive research, there are very few reagents with which to modulate and dissect the mRNA splicing pathway. Here, we describe a novel approach to identify such tools, based on detection of the exon junction complex (EJC), a unique molecular signature that splicing leaves on mRNAs. We developed a high throughput, splicing-dependent EJC immunoprecipitation (EJIPT) assay to quantitate mRNAs spliced from biotin-tagged pre-mRNAs in cell extracts, using antibodies to EJC components Y14 and eukaryotic translation initiation factor 4aIII (eIF4AIII). Deploying EJIPT we performed high-throughput screening (HTS) in conjunction with secondary assays to identify splicing inhibitors. We describe the identification of 1,4-naphthoquinones and 1,4-heterocyclic quinones with known anticancer activity as potent and selective splicing inhibitors. Interestingly, and unlike previously described small molecules, most of which target early steps, our inhibitors represented by the benzothiazole-4,7-dione, BN82685, block the second of two trans-esterification reactions in splicing, preventing the release of intron lariat and ligation of exons. We show that BN82685 inhibits activated spliceosomes' elaborate structural rearrangements that are required for second-step catalysis, allowing definition of spliceosomes stalled in midcatalysis. EJIPT provides a platform for characterization and discovery of splicing and EJC modulators. PMID- 22252315 TI - T-cell protein tyrosine phosphatase regulates bone resorption and whole-body insulin sensitivity through its expression in osteoblasts. AB - Insulin signaling in osteoblasts contributes to whole-body glucose homeostasis in the mouse and in humans by increasing the activity of osteocalcin. The osteoblast insulin signaling cascade is negatively regulated by ESP, a tyrosine phosphatase dephosphorylating the insulin receptor. Esp is one of many tyrosine phosphatases expressed in osteoblasts, and this observation suggests that other protein tyrosine phosphatases (PTPs) may contribute to the attenuation of insulin receptor phosphorylation in this cell type. In this study, we sought to identify an additional PTP(s) that, like ESP, would function in the osteoblast to regulate insulin signaling and thus affect activity of the insulin-sensitizing hormone osteocalcin. For that purpose, we used as criteria expression in osteoblasts, regulation by isoproterenol, and ability to trap the insulin receptor in a substrate-trapping assay. Here we show that the T-cell protein tyrosine phosphatase (TC-PTP) regulates insulin receptor phosphorylation in the osteoblast, thus compromising bone resorption and bioactivity of osteocalcin. Accordingly, osteoblast-specific deletion of TC-PTP promotes insulin sensitivity in an osteocalcin-dependent manner. This study increases the number of genes involved in the bone regulation of glucose homeostasis. PMID- 22252316 TI - Dynamic loss of H2B ubiquitylation without corresponding changes in H3K4 trimethylation during myogenic differentiation. AB - Ubiquitylation of H2B on lysine 120 (H2Bub) is associated with active transcriptional elongation. H2Bub has been implicated in histone cross talk and is generally regarded to be a prerequisite for trimethylation of histone 3 lysine 4 (H3K4me3) and H3K79 in both yeast and mammalian cells. We performed a genome wide analysis of epigenetic marks during muscle differentiation, and strikingly, we observed a near-complete loss of H2Bub in the differentiated state. We examined the basis for global loss of this mark and found that the H2B ubiquitin E3 ligase, RNF20, was depleted from chromatin in differentiated myotubes, indicating that recruitment of this protein to genes substantially decreases upon differentiation. Remarkably, during the course of myogenic differentiation, we observed retention and acquisition of H3K4 trimethylation on a large number of genes in the absence of detectable H2Bub. The Set1 H3K4 trimethylase complex was efficiently recruited to a subset of genes in myotubes in the absence of detectable H2Bub, accounting in part for H3K4 trimethylation in myotubes. Our studies suggest that H3K4me3 deposition in the absence of detectable H2Bub in myotubes is mediated via Set1 and, perhaps, MLL complexes, whose recruitment does not require H2Bub. Thus, muscle cells represent a novel setting in which to explore mechanisms that regulate histone cross talk. PMID- 22252317 TI - Contribution of a TANK-binding kinase 1-interferon (IFN) regulatory factor 7 pathway to IFN-gamma-induced gene expression. AB - Signal transducers and activators of transcription (STATs) and interferon regulatory factors (IRFs) share common target genes. Here we show that the Irf7 gene is regulated by transcription factors STAT1 and IRF9 in response to the type II interferon (IFN) IFN-gamma. IRF7 cooperated with STAT1 and IRF1 to stimulate the expression of a subset of IFN-gamma-induced STAT1 target genes. IRF7-mediated control of the Gbp2 gene required the presence and basal activity of the S/T kinase TANK-binding kinase 1 (TBK1), whereas the binding of IRF7 to the Gbp2 promoter did not. Analysis of RNA polymerase II (Pol II) recruitment to the Gbp2 promoter revealed a role for IRF7 at later stages of the IFN-gamma response. In support of the role of IRF7 in establishing an effective antibacterial response, IFN-gamma-pretreated Irf7(-/-) macrophages showed an increased bacterial burden after infection with Listeria monocytogenes. Our data thus describe a biologically relevant basal activity of TBK1 and identify IRF7 as a novel player in the IFN-gamma response. PMID- 22252318 TI - Evidence providing new insights into TOB-promoted deadenylation and supporting a link between TOB's deadenylation-enhancing and antiproliferative activities. AB - The mammalian TOB1 and TOB2 proteins have emerged as key players in repressing cell proliferation. Accumulating evidence indicates that TOBs regulate mRNA deadenylation. A recruitment model was proposed in which TOBs promote deadenylation by recruiting CAF1-CCR4 deadenylase complex to the 3' end of mRNAs by simultaneously binding CAF1 and PABP. However, the exact molecular mechanism underlying TOB-promoted deadenylation remains unclear. It is also unclear whether TOBs' antiproliferative and deadenylation-promoting activities are connected. Here, we combine biochemical analyses with a functional assay directly monitoring deadenylation and mRNA decay to characterize the effects of tethering TOBs or their mutant derivatives to mRNAs. The results provide direct evidence supporting the recruitment model and reveal a link between TOBs' antiproliferative and deadenylation-promoting activities. We also find that TOBs' actions in deadenylation are independent of the phosphorylation state of three serines known to regulate antiproliferative actions, suggesting that TOBs arrest cell growth through at least two different mechanisms. TOB1 and TOB2 were interchangeable in the properties tested here, indicating considerable functional redundancy between the two proteins. We propose that their multiple modes of modulating mRNA turnover and arresting cell growth permit the TOB proteins to coordinate their diverse roles in controlling cell growth and differentiation. PMID- 22252319 TI - Paf1 restricts Gcn4 occupancy and antisense transcription at the ARG1 promoter. AB - The conserved Paf1 complex negatively regulates the expression of numerous genes, yet the mechanisms by which it represses gene expression are not well understood. In this study, we use the ARG1 gene as a model to investigate the repressive functions of the Paf1 complex in Saccharomyces cerevisiae. Our results indicate that Paf1 mediates repression of the ARG1 gene independently of the gene-specific repressor, ArgR/Mcm1. Rather, by promoting histone H2B lysine 123 ubiquitylation, Paf1 represses the ARG1 gene by negatively affecting Gcn4 occupancy at the promoter. Consistent with this observation, Gcn5 and its acetylation sites on histone H3 are required for full ARG1 derepression in paf1Delta cells, and the repressive effect of Paf1 is largely maintained when the ARG1 promoter directs transcription of a heterologous coding region. Derepression of the ARG1 gene in paf1Delta cells is accompanied by small changes in nucleosome occupancy, although these changes are subtle in comparison to those that accompany gene activation through amino acid starvation. Additionally, conditions that stimulate ARG1 transcription, including PAF1 deletion, lead to increased antisense transcription across the ARG1 promoter. This promoter-associated antisense transcription positively correlates with ARG1 sense transcription. Finally, our results indicate that Paf1 represses other genes through mechanisms similar to those used at the ARG1 gene. PMID- 22252320 TI - snRNA 3' end formation requires heterodimeric association of integrator subunits. AB - The Integrator Complex is a group of proteins responsible for the endonucleolytic cleavage of primary small nuclear RNA (snRNA) transcripts within the nucleus. Integrator subunits 9 and 11 (IntS9/11) are thought to contain the catalytic activity based on their high sequence similarity to CPSF100 and CPSF73, which have been shown to be components of both the poly(A)(+) and histone pre-mRNA cleavage complex. Here we demonstrate that the specific heterodimeric interaction between IntS9 and IntS11 is mediated by a discrete domain present at the extreme C terminus of IntS9 and within the C terminus of IntS11, adjacent to the predicted active site of this endonuclease. This domain is highly conserved within IntS11 but conspicuously absent in CPSF73. Using a cell-based complementation assay that measures Integrator activity, we determined that the IntS9 interaction domain within IntS11 is required for its ability to restore snRNA 3' end processing after RNA interference (RNAi)-mediated depletion of IntS11. Moreover, overexpression of these interaction domains alone elicits snRNA misprocessing through a dominant-negative titration of endogenous Integrator subunits. These data collectively explain the mechanism by which the IntS11/9 and, by analogy, the CPSF73/100 heterodimeric cleavage factors distinguish themselves from each other and demonstrate that the heterodimeric interaction is functionally required for snRNA 3' end formation. PMID- 22252321 TI - Sam50 functions in mitochondrial intermembrane space bridging and biogenesis of respiratory complexes. AB - Mitochondria possess an outer membrane (OMM) and an inner membrane (IMM), which folds into invaginations called cristae. Lipid composition, membrane potential, and proteins in the IMM influence organization of cristae. Here we show an essential role of the OMM protein Sam50 in the maintenance of the structure of cristae. Sam50 is a part of the sorting and assembly machinery (SAM) necessary for the assembly of beta-barrel proteins in the OMM. We provide evidence that the SAM components exist in a large protein complex together with the IMM proteins mitofilin and CHCHD3, which we term the mitochondrial intermembrane space bridging (MIB) complex. Interactions between OMM and IMM components of the MIB complex are crucial for the preservation of cristae. After destabilization of the MIB complex, we observed deficiency in the assembly of respiratory chain complexes. Long-term depletion of Sam50 influences the amounts of proteins from all large respiratory complexes that contain mitochondrially encoded subunits, pointing to a connection between the structural integrity of cristae, assembly of respiratory complexes, and/or the maintenance of mitochondrial DNA (mtDNA). PMID- 22252322 TI - Dcp2 decapping protein modulates mRNA stability of the critical interferon regulatory factor (IRF) IRF-7. AB - The mammalian Dcp2 mRNA-decapping protein functions primarily on a subset of mRNAs in a transcript-specific manner. Here we show that Dcp2 is an important modulator of genes involved in the type I interferon (IFN) response, which is the initial line of antiviral innate immune response elicited by a viral challenge. Mouse embryonic fibroblast cells with reduced Dcp2 levels (Dcp2(beta/beta)) contained significantly elevated levels of mRNAs encoding proteins involved in the type I IFN response. In particular, analysis of a key type I IFN transcription factor, IFN regulatory factor 7 (IRF-7), revealed an increase in both IRF-7 mRNA and protein in Dcp2(beta/beta) cells. Importantly, the increase in IRF-7 mRNA within the background of reduced Dcp2 levels was attributed to a stabilization of the IRF-7 mRNA, suggesting that Dcp2 normally modulates IRF-7 mRNA stability. Moreover, Dcp2 expression was also induced upon viral infection, consistent with a role in attenuating the antiviral response by promoting IRF-7 mRNA degradation. The induction of Dcp2 levels following a viral challenge and the specificity of Dcp2 in targeting the decay of IRF-7 mRNA suggest that Dcp2 may negatively contribute to the innate immune response in a negative feedback mechanism to restore normal homeostasis following viral infection. PMID- 22252323 TI - Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. AB - VPS4B, an AAA ATPase (ATPase associated with various cellular activities), participates in vesicular trafficking and autophagosome maturation in mammalian cells. In solid tumors, hypoxia is a common feature and an indicator of poor treatment outcome. Our studies demonstrate that exogenous or endogenous (assessed with anchorage-independent three-dimensional multicellular spheroid culture) hypoxia induces VPS4B downregulation by the ubiquitin-proteasome system. Inhibition of VPS4B function by short hairpin VPS4B (sh-VPS4B) or expression of dominant negative VPS4B(E235Q) promotes anchorage-independent breast cancer cell growth and resistance to gefitinib, U0126, and genotoxicity. Biochemically, hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation and altered intracellular compartmentalization, is observed in cells with compromised VPS4B. Furthermore, enhanced FOS/JUN induction and AP-1 promoter activation are noted in EGF-treated cells with VPS4B knockdown. However, VPS4B depletion does not affect EGFRvIII stability or its associated signaling. An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. Together, our findings highlight a potentially critical role of VPS4B downregulation or chronic-hypoxia-induced VPS4B degradation in promoting tumor progression, unveiling a nongenomic mechanism for EGFR overproduction in human breast cancer. PMID- 22252324 TI - Liquid chromatography-tandem mass spectrometry or automated immunoassays: what are the future trends in therapeutic drug monitoring? PMID- 22252325 TI - Use of circulating microRNAs to diagnose acute myocardial infarction. AB - BACKGROUND: Rapid and correct diagnosis of acute myocardial infarction (MI) has an important impact on patient treatment and prognosis. We compared the diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) and cardiac enriched microRNAs (miRNAs) in patients with MI. METHODS: Circulating concentrations of cardiac-enriched miR-208b and miR-499 were measured by quantitative PCR in a case-control study of 510 MI patients referred for primary mechanical reperfusion and 87 healthy controls. RESULTS: miRNA-208b and miR-499 were highly increased in MI patients (>10(5)-fold, P < 0.001) and nearly undetectable in healthy controls. Patients with ST-elevation MI (n= 397) had higher miRNA concentrations than patients with non-ST-elevation MI (n = 113) (P < 0.001). Both miRNAs correlated with peak concentrations of creatine kinase and cTnT (P < 10(-9)). miRNAs and hs-cTnT were already detectable in the plasma 1 h after onset of chest pain. In patients who presented <3 h after onset of pain, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients (P= 0.78). Overall, miR-499 and hs-cTnT provided comparable diagnostic value with areas under the ROC curves of 0.97. The reclassification index of miR-499 to a clinical model including several risk factors and hs-cTnT was not significant (P = 0.15). CONCLUSION: Circulating miRNAs are powerful markers of acute MI. Their usefulness in the establishment of a rapid and accurate diagnosis of acute MI remains to be determined in unselected populations of patients with acute chest pain. PMID- 22252326 TI - Enhancement of myocardial and vascular function after phosphodiesterase-5 inhibition in a rat model. AB - BACKGROUND: Recent studies have shown the potential of PDE-5 inhibition on acute and chronic heart failure. Nevertheless it remained unclear, how far load reducing properties and direct effects on myocardial contractility are responsible for these observations. In the present study, we investigated the effects of vardenafil on myocardial contractility and vascular function in a dose response study. METHODS: We performed left ventricular pressure-volume analysis in young adult rats by using a Millar microtip conductance catheter. Pressure volume loops were recorded before and after intravenous injection of vardenafil (3, 10, 30, 100, 300 MUg/kg, n = 6/group). RESULTS: Treatment with vardenafil resulted in a significant (p < 0.05) increase in the load-independent cardiac contractility parameters reaching its maximum at the dose of 100MUg/kg (ESPVR: 2.15 +/- 0.15 vs. 3.29 +/- 0.26 mm Hg/MUL; PRSW: 93.28 +/- 4.04 vs. 134.90 +/- 6.27 mm Hg; peak positive dP/dt/EDV: 38.73 +/- 7.97 vs. 53.02 +/- 3.74 mm Hg.s 1.uL-1; before versus after 100 MUg/kg vardenafil). Results of the in vitro organ bath experiments showed an augmented vasorelaxation of precontracted aortic rings after vardenafil treatment. CONCLUSION: Our data supports the hypothesis that the usage of vardenafil as "inodilators" could have beneficial effects in heart failure patients. PMID- 22252327 TI - The mediastinoscopy and the future in nonsmall-cell lung cancer staging. PMID- 22252328 TI - Aortic intramural hematoma presenting as paraplegia progressed into segmental aortic dissection. AB - Intramural hematoma (IMH) is a newly defined disease entity and the optimal management is still controversial as the disease shows varied clinical course. We present a case of type B IMH, initially presenting with paraplegia progressing to segmental aortic dissection (SAD) which the formed dissection displayed as a segmental distribution pattern. To our knowledge, it may become a new progression pattern of IMH progression. The SAD was successfully treated with both thoracic and abdominal endovascular aortic repair (TEVAR plus EVAR). In 1-year follow-up, the patient recovered almost completely with moderately neurological deficit and the blood pressure is in control. PMID- 22252329 TI - Intrapericardial bronchogenic cyst adherent to the ascending aorta. AB - Bronchogenic cysts arise from an abnormal budding of the ventral diverticulum of the foregut or the tracheobronchial tree during embryogenesis. Pericardial location of these cysts is very rare. We describe a case of a young asymptomatic woman with an intrapericardial cystic mass compressing the right heart. Because of severe adhesions of the mass to the ascending aorta and to the right coronary artery, these structures were injured during surgical resection requiring the replacement of the ascending aorta and a coronary artery by-pass graft. Only the histopathologic findings provided the final diagnosis. PMID- 22252330 TI - Aortopulmonary window associated with interrupted aortic arch: report of surgical repair of eight cases and review of literature. AB - BACKGROUND: Patients with combined aortopulmonary window (APW) and interrupted aortic arch (IAA) malformations are rarely seen. We reviewed cases with such association with emphasis on surgical management and long-term outcome. METHODS: 109 patients with IAA and 25 patients with APW were operated upon between 1981 and 2011. The clinical records, operation and follow-up data were analyzed. Long term outcome was completed with the help of either outpatient data or inquiring. Related literature was investigated. RESULTS: Combined APW/IAA was found in 8 cases: 7.3% (8/109) of those with IAA diagnosis and 32% (8/25) with APW. All APWs were proximal. 7 patients had interruption type A. A ventricular septal defect (VSD) was associated in one case only. Median age at surgery was 10 days. The two first patients were operated upon without cardio-pulmonary bypass (CPB) and one died during operation. The other six underwent single stage approach under CPB with no death: overall early mortality of 12.5% (1/8). APW was closed with one or two patches; aortic arch was reconstructed either directly (extended end-to-side anastomosis) or by patch augmentation. There was no late death and no reoperation during mean follow-up of 118 months (range 1-360 months). Six patients were in functional NYHA class I, the remainder in class II. The cumulative APW/IAA incidence from literature varies between 4.9% (56/1105) and 22.2% (42/189). Early mortality reaches 15.1% (8/53) (95% CI: 6.8% - 27.6%). CONCLUSION: Neonatal repair with thorough mobilization of the aortic arch and extended end-to-side anastomosis or use of patch augmentation carries potential for the best early and late outcome for combined APW/IAA malformation. PMID- 22252332 TI - Clinical impact of intraoperative detection of carcinoembryonic antigen mRNA in pleural lavage specimens from nonsmall cell lung cancer patients. AB - BACKGROUND: The prospective trial of intraoperative detection of carcinoembryonic antigen mRNA (mCEA) in pleural lavage in patients undergoing resection for nonsmall cell lung cancers (NSCLCs) was undertaken to analyze clinical applicability. METHODS: From January 2006 to August 2008, cytology and mCEA analysis with pleural lavage were performed for 383 patients undergoing resection of NSCLCs. The pleural cavity was washed with 100 mL of physiological saline, and recovered lavage fluid was divided into two portions, one for pleural lavage cytology and the other for determination of mCEA expression by the transcription reverse transcription concerted reaction method. RESULTS: One hundred and nineteen (31%) cases were mCEA-positive. Positive mCEA results were observed frequently for adenocarcinoma patients and were recognized as a suggestive prognostic factor by stepwise regression analyses (p = 0.0472). The overall 4 year survival rate was 56% in the mCEA-positive group and 81% in the negative cases (p = 0.003). Of 71 cases suffering recurrence, it occurred frequently in mCEA-positive group (p = 0.035). CONCLUSION: Intraoperative mCEA analysis may be a reliable indicator for assessing short-term prognosis and likelihood of early recurrence. PMID- 22252333 TI - Probing inhibitory effects of nanocrystalline cellulose: inhibition versus surface charge. AB - NCC derived from different biomass sources was probed for its plausible cytotoxicity by electric cell-substrate impedance sensing (ECIS). Two different cell lines, Spodoptera frugiperda Sf9 insect cells and Chinese hamster lung fibroblast V79, were exposed to NCC and their spreading and viability were monitored and quantified by ECIS. Based on the 50%-inhibition concentration (ECIS(50)), none of the NCC produced was judged to have any significant cytotoxicity on these two cell lines. However, NCC derived from flax exhibited the most pronounced inhibition on Sf9 compared to hemp and cellulose powder. NCCs from flax and hemp pre-treated with pectate lyase were also less inhibitory than NCCs prepared from untreated flax and hemp. Results also suggested a correlation between the inhibitory effect and the carboxylic acid contents on the NCC. PMID- 22252334 TI - Embryonic development and metabolic costs in Gulf killifish Fundulus grandis exposed to varying environmental salinities. AB - The Gulf killifish (Fundulus grandis) is a euryhaline fish found in coastal marsh along the entire of Gulf of Mexico and southern Atlantic of coast of the United States. The objective of this study was to investigate the effects of salinity on embryogenesis in the Gulf killifish. Four recirculation systems at salinities of 0.4, 7, 15, and 30 g/L were maintained at a static temperature with flow-through trays, containing embryos (n = 39) placed in triplicate into each system. Throughout embryogenesis, the rate of development, ammonia and urea excretion, and heart rate were monitored. Percent hatch was recorded, and morphological parameters were measured for larvae at hatch. As salinity was increased, the rate of embryogenesis decreased. Salinity significantly affected percent hatch with an 80.0% +/- 2.6% for 7 g/L and 39.1 +/- 4.3, 45.4 +/- 4.5, and 36.3% +/- 12.0% for 0.4, 15, and 30 g/L, respectively. Salinity and stage of development significantly affected production of ammonia and urea. As salinity increased, the dominate metabolite end product changed from urea to ammonia. However, the 15 g/L salinity treatment had the two highest levels of urea recorded. Heart rate was unaffected by salinity but increased throughout embryogenesis and remained constant once embryos reached stages where hatching has been recorded. While mean total length was not affected by salinity, embryos incubated in 30 g/L produced larvae with significantly thicker body depth at hatch. The 0.4, 7, and 15 g/L salinity treatments all had similar mean hours to hatch. The 30 g/L treatment resulted in a significantly longer mean time to hatch and smaller body cavity area at hatch. PMID- 22252335 TI - Cytochrome P4501A mRNA and protein induction in striped bass (Morone saxatilis). AB - The striped bass (Morone saxatilis) supports a valuable recreational fishery and is among the most important piscivorous fish of the San Francisco Estuary. This species has suffered a significant decline in numbers over the past decades, and there is indication that contaminants are important contributors. Polycyclic aromatic hydrocarbons (PAHs) and polyhalogenated aromatic hydrocarbons (PHAHs) including PCBs and dioxins are widespread in the estuary, they typically bioaccumulate through trophic levels, reaching highest levels in top predators and are known to affect the fish health and development. The aim of this study was to investigate the dynamics of cytochrome P4501A (Cyp1a) induction simultaneously at different levels of biological organization (RNA transcription and protein synthesis) as a biomarker of exposure to PAHs and PHAHs. We utilized beta-naphthoflavone (BNF) as a model PAH to induce Cyp1a responses in juvenile striped bass in both dose-response and time-response assessments and determined Cyp1a mRNA and protein levels. Significant responses were measured in both systems at 10 mg BetaNuF kg-1, a concentration used for time-response studies. Messenger RNA levels peaked at 6 h post-injection, while protein levels increased progressively with time, significantly peaking at 96 h post-injection; both remaining elevated throughout the duration of the test (8 days). Our data suggest that rapid induction of gene transcription following exposure and subsequent cumulative protein synthesis could provide a useful means of identifying temporal variants in exposure to Cyp1a inducers in Morone saxatilis. The potential application of this combined Cyp1a gene and protein biomarker in this species for field studies is discussed. PMID- 22252336 TI - Affinity isolation and mass spectral analysis of 1,10-phenanthroline (OP) stimulated UV-damaged-DNA binding proteins expressed in zebrafish (Danio rerio) embryos. AB - Our earlier studies indicated the high expression of a UV-damaged-DNA binding activity in zebrafish (Danio rerio) embryos at 12 h postfertilization (hpf). Two 30- to 35-kDa polypeptides homologous to the N-terminal lipovitellin 1 (Lv1) domain of the 150-kDa zebrafish vitellogenin 1 (zfVg1) were identified as the damage recognition factors in zebrafish extracts, and the metal-chelating agent 1,10-phenanthroline (OP) was found to inhibit the embryonic UV-damaged-DNA binding activity. This study further explored the DNA damage-sensing components in 12 hpf zebrafish extracts. UV-damaged-DNA binding proteins were enriched from zebrafish extracts by isoelectrofocusing. Both OP-sensitive and OP-stimulated, UV damaged-DNA binding activities were detected in fractionated zebrafish extracts. Two-dimensional gel electrophoresis of proteins captured by an immobilized oligonucleotide carrying a UV-induced (6-4)photoproduct (6-4PP) revealed a 25-kDa polypeptide as the major 6-4PP-binding factor in an OP-stimulated fraction. Three 25-kDa factors that bound weakly to 6-4PPs were also isolated. The four polypeptides having pIs between 7.0 and 7.3 were unreactive to an anti-zfVg1 antibody targeting the Lv1 domain. Mass spectral analysis showed the appearance of amino acid sequences LPIIVTTYAK and IPEITMSK in all 25-kDa polypeptides and sequences exactly matching those contained in the four factors exist only in the C-terminal Lv2 domain of zfVg1, reflecting the origination of these factors from enzymatic cleavage of the Lv2 domain at slightly different positions. The OP stimulated fraction produced a much stronger UV-dependent DNA incision activity in the presence than in the absence of OP, suggesting the association of these factors with DNA damage repair under metal-deficient conditions. PMID- 22252337 TI - Characterization and virus susceptibility of a skin cell line from red-spotted grouper (Epinephelus akaara). AB - A red-spotted grouper Epinephelus akaara skin (RGS) cell line was established and characterized. RGS cells had a normal diploid chromosome number of 2n = 48, the morphology of which was fibroblastic-like in 3 days and epithelial-like over 5 after 16 passages. The cells multiplied well in Dulbecco's modified Eagle's medium supplemented with 10% of fetal bovine serum at 25 degrees C. Susceptibilities of RGS and grass carp ovary (GCO) cells to two viruses were tested, and the results showed that the titer of an iridovirus Rana grylio virus (RGV) in RGS cells was 103.5 TCID50 ml-1, which was much higher than a rhabdovirus spring viremia of carp virus (SVCV) in the cells (100.5 TCID50 ml-1). The titers of RGV and SVCV in GCO were 106.0 TCID50 ml-1 and 108.0 TCID50 ml-1, respectively, which were higher than those in RGS cells. The data may imply that RGS cells could be selectively resistible to some viruses during infection. RT PCR analysis of RGV-infected RGS cells showed that RGV could replicate in RGS cells. Further study of virus replications in RGS cells was conducted by electron microscopy and immunofluorescence microscopy has shown that virus particles scattered in the cytoplasm and virus protein appeared in both the cytoplasm and nucleus. The results suggested that RGS cells could be used as a potential in vitro model to study the cutaneous barrier function against virus infection. PMID- 22252338 TI - Effect of heating system using a geothermal heat pump on the production performance and housing environment of broiler chickens. AB - A geothermal heat pump (GHP) is a potential heat source for the economic heating of broiler houses with optimum production performance. An investigation was conducted to evaluate the effect of a heating system using a GHP on production performance and housing environment of broiler chickens. A comparative analysis was also performed between the GHP system and a conventional heating system that used diesel for fuel. In total, 34,000 one-day-old straight run broiler chicks were assigned to 2 broiler houses with 5 replicates in each (3,400 birds/replicate pen) for 35 d. Oxygen(,) CO(2), and NH(3) concentrations in the broiler house, energy consumption and cost of heating, and production performance of broilers were evaluated. Results showed that the final BW gain significantly (P < 0.05) increased when chicks were reared in the GHP broiler house compared with that of chicks reared in the conventional broiler house (1.73 vs. 1.62 kg/bird). The heating system did not affect the mortality of chicks during the first 4 wk of the experimental period, but the mortality markedly increased in the conventional broiler house during the last wk of the experiment. Oxygen content in the broiler house during the experimental period was not affected by the heating system, but the CO(2) and NH(3) contents significantly increased (P < 0.05) in the conventional broiler house compared with those in the GHP house. Fuel consumption was significantly reduced (P < 0.05) and electricity consumption significantly increased (P < 0.05) in the GHP house compared with the consumption in the conventional house during the experiment. The total energy cost of heating the GHP house was significantly lower (P < 0.05) compared with that of the conventional house. It is concluded that a GHP system could increase the production performance of broiler chicks due to increased inside air quality of the broiler house. The GHP system had lower CO(2) and NH(3) emissions with lower energy cost than the conventional heating system for broiler chickens. PMID- 22252339 TI - Persistent Salmonella Enteritidis environmental contamination on layer farms in the context of an implemented national control program with obligatory vaccination. AB - The aim of this study was to closely examine the Salmonella enterica serovar Enteritidis environmental contamination on persistently positive layer farms in Belgium during successive laying cycles. All of the farms were required to vaccinate their layers under the national control program for Salmonella. Seven farms with previous or current Salmonella Enteritidis contamination were monitored during different stages of the laying period and after cleaning and disinfection (CD). Environmental samples, including from the equipment and vermin, were taken in the henhouse and egg-collecting area. Dilutions were performed to define the degree of Salmonella Enteritidis contamination. Eggshells, egg contents, and ceca were also tested for Salmonella. At the end of the first sampled laying period, 41.6% of the environmental samples were contaminated with Salmonella Enteritidis. After CD, the prevalence dropped to 11.4%. On average, the prevalence in the second laying period increased again: 17.8, 18.4, and 22.3% at the onset, middle, and end of the lay period, respectively. After CD before the third laying period, the prevalence decreased to 6.6% and stabilized at the onset of lay (6.3%). During lay, as well as after CD, a wide variety of contaminated environmental samples were found; for example, in the henhouse, in the egg-collecting area, on mobile equipment and in or on vermin. In the henhouse during laying, the most recurrent and highly contaminated sites were the overshoes, floor, manure belt, and hen feces. The egg-collecting area had a significantly higher number of contaminated samples compared with that of the henhouse. For both sites, the floor appeared to be the most suitable sampling site to estimate the Salmonella Enteritidis status of the farms. Eggshell and egg content contamination varied between 0.18 and 1.8% and between 0.04 and 0.4%, respectively. In total, 2.2% of the analyzed ceca contained Salmonella Enteritidis. This study revealed that Salmonella Enteritidis is present in the environment of persistently Salmonella Enteritidis-contaminated layer farms, demonstrated that in many cases Salmonella Enteritidis contamination was not eliminated after CD, and identified the egg-collecting area as a critical point on most farms. PMID- 22252340 TI - Effects of a premolt calcium and low-energy molt program on laying hen performance, egg quality, and economics. AB - The objectives of this study were to evaluate and compare the effects of production, physiology, egg quality, and economics of laying hens housed in a cage system when offered a calcium premolt treatment and low-energy molt diets versus a traditional feed withdrawal (FW) treatment during and after molt. In total, 981 Hy-Line W-36 laying hens (85 wk of age) housed 3 per cage were used. Six treatments were compared in a 2 * 3 factorial design with 2 calcium premolt treatments (fine and coarse) and 3 molt diets (FW, soybean hulls, and wheat middlings). The coarse Ca was a 50:50 mix of fine (0.14-mm mean diameter) and coarse (2.27-mm mean diameter) CaCO(3), whereas the fine Ca was an all-fine CaCO(3). Both diets were formulated to contain 4.6% Ca, such that only the particle size of the CaCO(3) differed. Production parameters in experiment 1 included egg production, egg weight and mass, specific gravity, Haugh units, egg components, feed consumption and utilization, and BW. Physiological parameters in experiment 2 included ovary and oviduct weights, femur- and humerus-ash percentages, heterophil to lymphocyte ratios, plasma Ca and inorganic P concentrations, and alkaline phosphatase activity. Data were analyzed by ANOVA and P < 0.05 was significant. The fine-Ca premolt treatment was more effective than the coarse-Ca treatment at decreasing egg production during molt and increasing it postmolt, regardless of the molt diet. The FW molt diet resulted in the greatest decrease in production, but the soybean hulls diet resulted in lower production and ovary and oviduct weights during molt compared with those of the wheat middlings molt diet. Therefore, a fine-Ca premolt treatment and a low energy molt diet, particularly soybean hulls, can be useful alternatives to a FW molt. PMID- 22252341 TI - Aerial perches and free-range laying hens: the effect of access to aerial perches and of individual bird parameters on keel bone injuries in commercial free-range laying hens. AB - The aim of this trial was to determine the effect of aerial perches on keel bone injuries and tibia bone characteristics in free-range laying hens. The relationship between keel bone injuries and individual bird parameters, such as weight, girth, wing:girth ratio, feather coverage, and tibia bone characteristics, was also assessed. Five commercial free-range houses, each containing between 7,000 and 8,000 birds, were used. The houses and range areas were divided in half; in half of the house, birds had access to aerial perches (P) and in the other half, they did not (NP). On 13 occasions between 17 and 70 wk of age, 20 birds per treatment were randomly selected from the slatted area and palpated for keel bone injury. At 72 wk of age, 30 birds per treatment in each of 4 houses were selected at random, weighed, and then euthanized. Girth and wing area and feather coverage were measured. The keel and left tibia bones were removed and keel bones were scored for injury. Tibia bones were weighed and diameter, length, breaking strength, and ash content recorded. Results indicated that access to aerial perches did not affect tibia bone measures (P > 0.05). Average palpated keel bone score increased with age of the hens (P < 0.001) but was not significantly affected by perch treatment (P > 0.05). There was a significant interaction between treatment and farm on keel bone injuries measured at dissection (P < 0.05), with the probability of birds having high keel-damage scores increasing in the perched treatment in some farms but not others. In general, as the keel bone injury score measured at dissection increased, the breaking strength (P < 0.001) and ash content (P < 0.05) of the tibia bone decreased. It is suggested that individual variation in bone strength contributes to differences in susceptibility to keel injury. No relationship existed between keel-injury score measured at dissection and individual parameters, such as weight, girth, or wing:girth ratio (P > 0.05), although feather coverage tended to decline with increasing keel damage (P < 0.06). PMID- 22252342 TI - Effect of sequential feeding on nitrogen excretion, productivity, and meat quality of broiler chickens. AB - The aim of this trial was to investigate the effect of a 24-h cycle sequential feeding program on nitrogen excretion, incidence of foot pad lesions, productive performance, quality traits, and chemical composition of broiler chicken breast meat. In total, 1,320 one-day-old male Cobb 700 chicks were split into 2 groups of 6 replicates each. From 1 to 10 d of age, all of the chickens received the same prestarter diet (ME 3,058 kcal/kg; CP 226 g/kg). The control group (CON) received 1 of 3 diets for 24-h cycles: starter (ME 3,162 kcal/kg; CP 205 g/kg), grower (ME 3,224 kcal/kg; CP 192 g/kg), and finisher diets (ME 3,242 kcal/kg; CP 184 g/kg) from d 11 to 18, 19 to 38, and 39 to 44 of age, respectively. The sequential feeding group (SF) received the same diets as the CON birds for half of the day, and then low-protein and isoenergetic diets for the remaining half of the day. Birds submitted to the SF program showed better utilization of dietary nitrogen compared with the CON birds (45.0 vs. 46.1% of N excreted/N ingested, respectively; P < 0.05), and consequently the SF birds had lower nitrogen excretion compared with the CON birds (24.8 vs. 25.9 N g/kg of BW, respectively; P < 0.01). The SF birds exhibited a significantly lower incidence (7 vs. 13%) of foot pad lesions and consumed 70 g of feed/bird more than the CON birds. The SF birds also had a significantly higher feed conversion rate compared with that of the CON birds (1.84 vs. 1.78, respectively). The SF breast meat exhibited a significantly lower ultimate pH, a higher cook loss, and a lower lipid content compared with the values found for the CON group. The SF approach in poultry husbandry had positive repercussions on environmental and animal welfare aspects, but adversely affected feed efficiency, and altered some meat traits (mainly pH and cook loss). PMID- 22252343 TI - Liver enzymes in White Leghorns selected for the sheep red blood cell immune response. AB - Liver enzymes are essential to xenobiotic metabolism. Expression of these enzymes is dependent upon factors such as age and sex. The objective of this study was to determine basal liver enzyme levels in male and female White Leghorn chickens to provide reference values for future studies. Chickens from 2 lines divergently selected for 35 generations for high antibody and low antibody immune response to SRBC were used. Six male and 6 female chickens from each line were killed at each of 4, 8, 12, and 20 wk of age. Livers were collected and used for enzyme analyses. Liver tissue was analyzed for quinone reductase, glutathione-S transferase, and cytochrome P450 3A4 activity. All data were analyzed using ANOVA. There were no consistent differences in enzyme activity between high- and low-antibody lines at any age. Cytochrome P450 3A4 activity was substantially greater in 4- and 8-wk than in 12- and 20-wk-old chickens (P < 0.001). This study provides insights into enzyme activities of liver enzymes; however, except for cytochrome P450 3A4, no clear trends across ages were observed. PMID- 22252344 TI - Analysis of genetic divergence between closely related lines of chickens. AB - The aim of the present study was to characterize genetic diversity within and differentiation between 5 closely related lines of Japanese-native chickens, the Nagoya breed, based on microsatellite polymorphisms. For 5 Nagoya lines, the mean number of alleles per locus, the observed heterozygosity, the expected heterozygosity, and the inbreeding coefficient within a line ranged from 2.35 to 2.85, from 0.385 to 0.507 (average = 0.438), from 0.404 to 0.480 (average = 0.433), and from -0.056 to 0.074, respectively. These results indicated that Nagoya lines have moderate levels of genetic diversity and no severe inbreeding signatures. Genetic differentiations between pairs of lines (pairwise F(ST)) ranged from 0.0224 to 0.2500. The lowest differentiation was found between 2 lines that were divided into distinct lines about 10 years ago. Genetic clustering analyses, the neighbor-joining tree constructed from genetic distances of the proportion of shared alleles and the Bayesian model-based clustering, were carried out based on multilocus genotypes of individuals. The results suggested that Nagoya lines were genetically distinct from commercial gene pools (broilers and white- and brown-egg layers) and that the Nagoya breed is a unique genetic resource. The results from the present study have the potential to contribute to future breeding and management of lines of the Nagoya breed. PMID- 22252345 TI - Acute hypersensitive-like injury in specific-pathogen-free chickens after infection with very virulent infectious bursal disease virus. AB - Very virulent infectious bursal disease virus (vvIBDV) can cause systemic inflammatory syndromes and acute death in specific-pathogen-free chickens within 72 h. However, the subtle mechanism of these severe inflammatory responses has been unsatisfactorily resolved until now. This study determined the kinetics of mast cells, tryptase, eosinophilic major basic protein, and eotaxin expression in specific-pathogen-free chickens after vvIBDV infection. Results showed that mast cell population, tryptase activity, major basic protein, and eotaxin expression were increased markedly in the vvIBDV-infected animals compared with the controls, with a significant difference in the bursa. Acute inflammatory lesions and high mortality were observed in vvIBDV-infected chickens. These observations implicate activated mast cells and eosinophils as important participants in vvIBDV-induced acute inflammatory lesions through mediators released in a short timeframe. PMID- 22252346 TI - The role of heat shock protein 70 in resistance to Salmonella enteritidis in broiler chickens subjected to neonatal feed restriction and thermal stress. AB - Environmental stressors may influence chicken performance and susceptibility to pathogens, such as Salmonella enteritidis. This study was conducted to determine the effects of heat shock protein (Hsp)70 expression on resistance to Salmonella enteritidis infection in broiler chickens subjected to heat exposure. Chicks were divided into 3 feeding regimens: ad libitum feeding (control); 60% feed restriction on d 4, 5, and 6 (FR60); and 60% feed restriction on d 4, 5, and 6 plus 1,500 mg/kg of quercetin (FR60Q). On d 35, all of the chickens were individually inoculated with 1 mL of Salmonella enteritidis (1.5 * 10(8) cfu/bird) and exposed to an ambient temperature of 37 +/- 1 degrees C and 70% RH for 3 h/d. The FR60 and FR60Q chickens had significantly lower Salmonella enteritidis colonization and lower Hsp70 expression than that of the control chickens following the heat exposure period. The least colonization was observed in the FR60Q group (1.38 log(10) cfu/g in the spleen and 1.96 log(10) cfu/g in the cecal content) and the highest was in the control group (2.1 log(10) cfu/g in the spleen and 4.42 log(10) cfu/g in the cecal content). It appears that neonatal feed restriction can enhance resistance to Salmonella enteritidis colonization in heat-stressed broiler chicks, and the underlying mechanism could be associated with the lower expression of Hsp70. PMID- 22252347 TI - Differences in the early response of hatchlings of different chicken breeding lines to Salmonella enterica serovar Enteritidis infection. AB - Poultry products are the major source of food-borne Salmonella infection in humans. Broiler lines selected to be more resistant to Salmonella could reduce the transfer of Salmonella to humans. To investigate differences in the susceptibility of newly hatched chicks to oral infection with Salmonella enterica serovar Enteritidis, 3 commercial broiler lines (A, B, and C) were infected immediately after hatch and compared to healthy controls at 0.33, 1, and 2 d postinfection. Weight, bacteriological examination, and the jejunal influx of CD4, CD8, TCRalphabeta, TCRgammadelta, and KUL01 (macrophages and dendritic cells) cells that are positive was investigated. In addition, the jejunal transcriptional response was analyzed using whole-genome chicken cDNA arrays. Salmonella colony-forming unit counts from cecal content and liver revealed that Salmonella enterica entered the body at 0.33 d postinfection. Broiler line A appeared most susceptible to intestinal colonization and the systemic spread of Salmonella. In addition, the Salmonella-induced jejunal influx of macrophages in this line showed a clear increase in time, which is in contrast to lines B and C. On the other hand, all lines showed a peak of CD4(+) cells at 1 d postinfection when infected chicks were compared to control chicks. The transcriptional response of line A clearly differed from the responses in lines B and C. Functional analysis indicated that the majority of the differentially expressed genes at 0.33 d postinfection in line A were involved in cell-cycle functions, whereas at 2 d postinfection the majority of the differentially expressed genes could be assigned to inflammatory disorder, differentiation and proliferation of (T) lymphocytes. These data indicate that hatchlings of different broiler lines differ in their systemic spread of Salmonella and suggest that intestinal barrier functions, as well as immunological responses, may be the underlying factors. We hypothesize that the differences between genetic chicken lines divergent in their response to Salmonella infection at a young age include developmental differences of the gut. PMID- 22252348 TI - Combined effects of aflatoxin B1 and corticosterone treatment on selected performance indices and liver histopathology in Japanese quail. AB - Animal feed may be contaminated with different mycotoxins, with aflatoxin B(1) (AFB(1)) being a very common and toxic compound. Considering that birds normally have to cope with different stressful situations at the same time, the present study aims to evaluate the effects of feed contamination with AFB(1) in combination with corticosterone treatment in drinking water (a model to induce physiological stress in birds) on selected performance indices: BW, feed conversion, egg production, and macroscopic and microscopic liver alterations. At 5 wk of age, quails were randomly assigned to 1 of 6 dietary treatment groups that resulted from the combination of the presence or absence of corticosterone in drinking water (5 mg/L) with the presence or absence of AFB(1) contamination (0, 100, or 500 MUg/kg). The animals remained in these treatments from 5 to 11 wk of age. There were 6 replicates per treatment, each containing 2 males and 2 females. Contamination with 100 MUg of AFB(1) per kilogram of feed induced no changes in BW, feed conversion, and egg production parameters. Quail fed with 500 MUg of AFB(1) per kilogram of feed showed significant decreases in BW and feed consumption compared with their control counterparts. Corticosterone in combination with 500 MUg of AFB(1) per kilogram of feed intensified the negative effects observed on BW and feed consumption and also had negative effects on feed conversion rate and egg production parameters, suggesting that the adverse effects of contamination with AFB(1) are intensified in situations of chronic stress. Quail treated with 500 ug of AFB(1) per kilogram showed hepatocytes with degree 1 and 2 lesions, and all quail treated with 500 ug of AFB(1) per kilogram of feed in combination with corticosterone showed degree 2 liver lesions (i.e., hepatocytes with fatty macro and microvacuoles and necrosis). This result is also consistent with the hypothesis that chronic stress exacerbates the effect of AFB(1) contamination. In conclusion, this study suggests that the negative effects of AFB(1) contamination are increased when overlapped with chronic stressful stimulation. PMID- 22252349 TI - Evaluation of in vitro and in vivo adhesion and immunomodulatory effect of Lactobacillus species strains isolated from chickens. AB - This study aimed to characterize the in vitro and in vivo adhesion and immunomodulatory effect of Lactobacillus strains isolated from chickens. Lactobacillus samples isolated from 65-wk-old birds were identified by PCR; their adhesion was evaluated in vitro via basement membrane-type cell matrix and in vivo through carboxyfluorescein succinimidyl amino ester staining inoculation in 1-d-old birds and duodenum, jejunum, ileum, and cecum collections at 1, 4, 12, and 24 h after inoculation. The 5 best adhesive samples at the in vitro test formed a pool for total IgA and IgG measurement in sera and intestinal fluid. The birds were divided into groups by inoculation scheme: group 1 was treated with a pool of Lactobacillus spp. at 2-d-old and challenged 1 d later with Salmonella Enteritidis and then treated again with a pool of Lactobacillus spp. at 4 d of age; group 2 was treated with a pool of Lactobacillus spp. at 2 and 4 d of age; group 3 was challenged with Salmonella Enteritidis at 3 d of age; and group 4 was a negative control. Collections were taken at 7, 14, 21, 28, and 35 d after the first inoculation. The results suggest that basement membrane matrix use represents an important technique for triage of samples for subsequent in vivo evaluation and that carboxyfluorescein succinimidyl amino ester staining is efficient for identifying this bacterial characteristic. The Lactobacillus treated groups (1 and 2) presented the highest IgA concentrations at the end of the experiment (12,054.6 and 10,568.4 ng/mL, respectively). The group 2 IgG values in intestinal fluid exceeded those of the other 3 groups (P < 0.05), peaking at 6.419 ng/mL. In most serum collections, the Lactobacillus-treated groups (1 and 2) did not differ significantly in IgG concentrations (P > 0.05), whereas group 3 presented the highest concentration of this antibody. It is concluded that there was greater adhesion of strains in the cecum and an important correlation between in vitro and in vivo results. These results also suggest the immunomodulatory action of Lactobacillus spp. in the chicken. PMID- 22252350 TI - The embryo lethality of Escherichia coli isolates and its relationship to the presence of virulence-associated genes. AB - The aims of this study were to determine if the chicken embryo lethality assay and the presence of 9 virulence-associated genes of Escherichia coli were correlated and to discover which virulence genes contributed most to embryo lethality. We examined 58 E. coli strains isolated from visceral organs of chickens with colibacillosis for the presence of 9 virulence genes (fimC, tsh, fyuA, irp2, iucD, cvi/cva, iss, astA, and vat) by PCR. The gene FimC (type I fimbriae) was detected with the highest prevalence in 93.1% of the isolates, followed by iucD (67.24%), iss (58.62%), tsh (34.48%), cvi/cva (34.48%), fyuA (32.76%), astA (31.0%), irp2 (27.59%), and vat (17.24%). The embryo mortality ranged from 5 to 100%; however, most of the isolates were moderately or highly virulent. High positive correlations were observed between the presence of virulence genes and chicken embryo lethality. In addition, presence of the iucD (aerobactin) gene was the trait that best contributed to embryo mortality by using the multivariate model. These results suggest that expression frequency of these 9 virulence genes is associated with embryo mortality, and the gene that best predicted embryo mortality was iucD. PMID- 22252351 TI - Meta-analysis of the relationship of mycotoxins with biochemical and hematological parameters in broilers. AB - A meta-analysis was carried out to study the association of mycotoxins with hematological and biochemical profiles in broilers. Ninety-eight articles published between 1980 and 2009 were used in the database, totaling 37,371 broilers. The information was selected from the Materials and Methods and Results sections in the selected articles and then tabulated in a database. Meta-analysis followed 3 sequential analyses: graphic, correlation, and variance-covariance. Mycotoxins reduced (P < 0.05) the hematocrit (-5%), hemoglobin (-15%), leukocytes (-25%), heterophils (-2%), lymphocytes (-2%), uric acid (-31%), creatine kinase ( 27%), creatinine (-23%), triglycerides (-39%), albumin (-17%), globulin (-1%), total cholesterol (-14%), calcium (-5%), and inorganic phosphorus (-12%). Mycotoxins also altered (P < 0.05) the concentrations of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. A quadratic effect was observed on the relationship between the concentration of aflatoxin in diets and the serum concentration of alkaline phosphatase, gamma-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase. The total protein concentration in blood was 18% lower (P < 0.05) in broilers challenged by aflatoxins compared with that of the unchallenged ones. The inclusion of antimycotoxin additives in diets with aflatoxins altered (P < 0.05) some variables (uric acid, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) in relation to the group that received diets with the mycotoxin and without the additive. The meta analysis performed in this study allowed us to address and quantify systematically the relationship of mycotoxins with alterations in hematologic and biochemical profiles in broilers. PMID- 22252352 TI - Comprehensive analysis of commercially available mouse antichicken monoclonal antibodies for cross-reactivity with peripheral blood leukocytes from commercial turkeys. AB - In the United States, turkey production contributes approximately $14.4 billion to the US economy; however, the number of reagents specifically developed to study the immune system of this economically important species is limited. To compensate for this, laboratories focused on the turkey system have each empirically tested various chicken-specific reagents for cross-reactivity with turkeys. The result is a patchwork of reports using different genetic lines and different ages, and in many cases, leading to inconsistent conclusions about the cross-reactivity of the reagents tested. In the current study, we investigated a large panel of commercially available monoclonal antibodies specific for chicken leukocyte markers for their ability to specifically recognize the turkey homolog of their respective ligand using 2 different genetic lines of commercial turkeys. The results of these studies identify 8 chicken-specific monoclonal antibodies (F21-21, F21-2, CT4, EP96, 3-298, AV7, c264, and AV6) as demonstrating strong evidence for cross-reactivity with turkey peripheral blood mononuclear cells from both commercial lines, 3 of which (F21-2, EP96, and c264), to our knowledge, have not previously been reported. In addition, characterization of the anti-CD8alpha monoclonal antibody 3-298 provides evidence that turkeys, like chickens, have a relatively high percentage of CD4CD8 double-positive T-cells in circulation and have at least 5 alleles of the CD8alpha gene. Collectively, the results from these experiments strengthen our understanding of the turkey immune system, its relative level of conservation with the chicken system, and adds to the list of reagents that can be reliably used to assess immune responses in commercial turkeys. PMID- 22252353 TI - Effects of prebiotic, protein level, and stocking density on performance, immunity, and stress indicators of broilers. AB - An experiment was conducted to determine the effects of period on the performance, immunity, and some stress indicators of broilers fed 2 levels of protein and stocked at a normal or high stocking density. Experimental treatments consisted of a 2 * 2 * 2 factorial arrangement with 2 levels of prebiotic (with or without prebiotic), 2 levels of dietary CP [NRC-recommended or low CP level (85% of NRC-recommended level)], and 2 levels of stocking density (10 birds/m(2) as the normal density or 16 birds/m(2) as the high density), for a total of 8 treatments. Each treatment had 5 replicates (cages). Birds were reared in 3 tiered battery cages with wire floors in an open-sided housing system under natural tropical conditions. Housing and general management practices were similar for all treatment groups. Starter and finisher diets in mash form were fed from 1 to 21 d and 22 to 42 d of age, respectively. Supplementation with a prebiotic had no significant effect on performance, immunity, and stress indicators (blood glucose, cholesterol, corticosterone, and heterophil:lymphocyte ratio). Protein level significantly influenced broiler performance but did not affect immunity or stress indicators (except for cholesterol level). The normal stocking density resulted in better FCR and also higher antibody titer against Newcastle disease compared with the high stocking density. However, density had no significant effect on blood levels of glucose, cholesterol, corticosterone, and the heterophil:lymphocyte ratio. Significant interactions between protein level and stocking density were observed for BW gain and final BW. The results indicated that, under the conditions of this experiment, dietary addition of a prebiotic had no significant effect on the performance, immunity, and stress indicators of broilers. PMID- 22252354 TI - Supplementation of guanidinoacetic acid to broiler diets: effects on performance, carcass characteristics, meat quality, and energy metabolism. AB - Creatine, (CREA) a central constituent in energy metabolism, is obtained from dietary animal protein or de novo synthesis from guanidinoacetic acid (GAA). Especially in all-vegetable diets, supplemental CREA or GAA may restore the CREA availability in tissues, and hence, improve performance. In this study, 768 one-d old male Ross 308 broilers were assigned to 1 of 4 diets: negative control, all vegetable corn-soybean-based; negative control supplemented with either 0.6 or 1.2 g of GAA per kilogram of feed; and positive control (60, 30, and 30 g/kg of fish meal in the starter, grower, and finisher diets, respectively). Each treatment was replicated in 6 pens of 32 birds each. At the end of the grower period (d 26), 2 birds per pen were euthanized for metabolic measurements. Four broilers per pen were selected at slaughter age (d 39) to determine carcass characteristics and meat quality. Compared with the negative control, GAA supplementation resulted in an improved gain:feed ratio (P < 0.05) and ADG (P < 0.05; + 2.7 and + 2.2% for GAA at 0.6 and 1.2 g/kg, respectively) throughout the entire period. Breast meat yield was higher for the GAA diets compared with that of the negative control birds (P < 0.05; 30.6 vs. 29.4%) and was comparable with that of the positive control birds (30.2%). With regard to meat quality, lower ultimate pH values, higher cooking and press fluid losses, and higher color L* values were observed for the GAA diets compared with those of the negative control diet (P < 0.05). These effects were small, however. The GAA and CREA levels in breast meat were lower and higher, respectively, in GAA-fed birds compared with those of the control birds (P < 0.01). The diets did not affect plasma metabolic traits, except that plasma insulin-like growth factor I concentrations were almost twice as high in animals fed 1.2 g/kg of GAA compared with those of all other treatments. The GAA included in all-vegetable diets improved animal performance for the whole rearing period and increased breast meat yield. PMID- 22252355 TI - Effects of wheat inclusion and xylanase supplementation of the diet on productive performance, nutrient retention, and endogenous intestinal enzyme activity of laying hens. AB - An experiment was conducted to study the effects of inclusion of a wheat cultivar (high in nonstarch polysaccharides) and xylanase supplementation of the diet on productive performance, pH of the gastrointestinal tract, nutrient retention, and intestinal enzyme activity of Hy-Line W-36 laying hens from 25 to 47 wk of age. The experiment was completely randomized with 8 treatments arranged factorially with 4 levels of wheat (0, 23, 46, and 69%) that corresponded to a dietary arabinoxylan content of 3.0, 3.3, 3.6, and 3.9%, with or without xylanase supplementation. Each treatment was replicated 5 times. For the entire experimental period, egg weight (P < 0.05) and egg mass (P < 0.01) were reduced and the feed conversion ratio was hindered (P < 0.05) with increased levels of wheat in the diet, but ADFI and egg production were not affected. Xylanase supplementation improved egg production (P < 0.05), egg mass (P < 0.01), and the feed conversion ratio (P < 0.01). Diet did not affect egg quality at any age, except for shell thickness at 47 wk that was improved with xylanase supplementation (P < 0.05). Digesta pH of the different organs of the gastrointestinal tract was not affected by wheat inclusion or xylanase supplementation. Ileal viscosity increased (P < 0.001) with wheat inclusion and decreased (P < 0.001) with xylanase supplementation at all ages. Fat digestibility (P < 0.001) decreased with increased levels of wheat but AME(n) content of the diets (P < 0.05) and nitrogen retention were not affected. Wheat inclusion increased (P < 0.001) amylase (33 wk), lipase (33 wk), and aminopeptidase (47 wk) activity in the duodenum as well as lipase activity in the jejunum at 47 wk of age. However, xylanase supplementation did not affect the activity of any of the enzymes studied. It is concluded that most of the negative effects of wheat inclusion in the diet were reduced or even disappeared with xylanase supplementation. Wheat with a high nonstarch polysaccharide content (Pishtaz cultivar) can be used at levels of up to 69% in laying-hen diets without negatively affecting bird performance, provided that feeds are supplemented with xylanase. PMID- 22252356 TI - Dietary influence of digestible lysine concentration on Cobb 500 hen broiler breeder reproductive performance. AB - A study was conducted to examine the reproductive parameters of Cobb 500 broiler breeder hens fed 2 different types of diets varying in digestible lysine concentration. In total, 240 Cobb 500 broiler breeder pullets were placed in individual cages and given experimental diets from 35 to 45 wk of age. Treatments 1 and 2 were diets formulated using only commercially available feed ingredients and consisted of digestible lysine intakes of 1,200 (IDL) and 1,010 mg/hen per day (ID). Treatments 3 and 4 consisted of semipurified diets with the inclusion of l-glutamic acid to maintain isonitrogenous conditions with digestible lysine intakes of 1,010 (SPL) and 600 mg/hen per day (SP). Hens fed the SPL and SP diets had lower hen-day egg production than hens fed the ID diet, with hens receiving the IDL diet yielding intermediate values. Hens fed the SP diet had the lowest (P < 0.05) egg weight, but no differences were observed among dietary treatments for egg specific gravity. Fertility and hatchability of eggs set were lowest (P < 0.05) for hens fed the SPL dietary treatment. No differences were observed for early and middle embryonic mortality, contaminated, or pipped eggs. Late embryonic mortality was observed to be higher (P < 0.05) in hens fed the SP diet. A decrease in the daily intake of digestible lysine appeared to improve broiler breeder reproductive performance when hens were fed a semipurified diet. In contrast, the same effect was not observed when hens were fed a standard industry type diet that contained less lysine. PMID- 22252357 TI - beta-Cryptoxanthin biofortified maize (Zea mays) increases beta-cryptoxanthin concentration and enhances the color of chicken egg yolk. AB - The laying hen has a natural ability to deposit carotenoids into its egg yolks, especially the xanthophyll carotenoid lutein that is used commercially as an egg colorant. Can this ability to deposit carotenoids be used to enrich egg yolk provitamin A value? After a 10-d carotenoid depletion period in hens (n = 24), the effects of a 20-d intervention with high-beta-cryptoxanthin, high-beta carotene, or typical yellow maize on color and carotenoid profile were compared with the effects of a white maize diet (n = 6/treatment). Eggs were collected every other day and yolks were analyzed by using a portable colorimeter to define the color space and by using an HPLC to determine the carotenoid profile. The high-beta-cryptoxanthin and yellow maize increased beta-cryptoxanthin in the yolk (0.55 +/- 0.08 to 4.20 +/- 0.56 nmol/g and 0.55 +/- 0.08 to 1.06 +/- 0.12 nmol/g, respectively; P < 0.001). Provitamin A equivalents increased in eggs from hens fed high-beta-cryptoxanthin maize (P < 0.001) but not the high-beta-carotene maize. The color (L*, a*, and b*) assessment of the yolks showed an increase in the high-beta-cryptoxanthin treatment for the red-green a* scale (P < 0.001) and a decrease for the light-dark L* scale (P < 0.001). No appreciable change was noted in the yellow-blue b* scale for the high-beta-cryptoxanthin treatment; but significant changes were noted for the yellow (P = 0.002) and high-beta-carotene maize (P = 0.005) treatments, which were most evident at the end of the washout period with white maize. beta-Cryptoxanthin-biofortified maize is a potential vehicle to elevate provitamin A equivalents and to enhance the color of yolks. This could lead to a human health benefit if widely adopted. PMID- 22252358 TI - Ileal digestibility of amino acids for zero-tannin faba bean (Vicia faba L.) fed to broiler chicks. AB - An experiment was conducted to determine the apparent ileal digestibility (AID) of amino acids (AA) in zero-tannin faba beans (ZFB; Vicia faba L.) fed to broiler chicks. In total, 120 broiler chicks were divided into 24 groups of 5 birds that were balanced for BW and fed 1 of 3 diets in a completely randomized design (8 groups/diet) from d 14 to 21 of age. The diets were a soybean meal-cornstarch based basal diet or the basal diet with soybean meal and cornstarch replaced by 50% of either conventional (tannin-containing) faba beans (CFB) or ZFB. The CFB were fed for comparison with ZFB. All of the 3 diets contained chromic oxide (0.3%) as an indigestible marker, and nutrient digestibilities were determined by the difference method. On d 21, the birds were killed by cervical dislocation and contents of the lower-half of the ileum were obtained for determination of apparent AA digestibility. The CFB and ZFB were similar in CP, AA, neutral detergent fiber, and acid detergent fiber contents. The ZFB did not contain tannins, whereas the CFB contained 0.82% tannins. The ZFB had greater (P < 0.05) AID for all AA (except Met) compared with that of the CFB by an average of 12.6 percentage points. The 2 faba-bean types were similar in AID of Met. The results show that the ZFB evaluated in the current study had greater AID of AA than CFB, and hence, it may be a better source of protein for broiler chicks than CFB. PMID- 22252360 TI - Elucidation of colonization time and prevalence of thermophilic Campylobacter species during turkey rearing using multiplex polymerase chain reaction. AB - Two turkey flocks (male and female) and the environment of their house were investigated for the presence of thermophilic Campylobacter. Sample DNA was extracted directly from fecal material and environmental samples. Bacterial identification was done using a modified Campylobacter species specific multiplex PCR. The times needed for colonization and prevalence in male and female turkeys were determined independently. All environmental samples collected before restocking were negative in the PCR analysis, showing a good hygiene and biosecurity system. The first positive PCR results were obtained in drinking water samples at 6 d of age. Colonization occurred between the second and third week of age, starting in female birds and then followed by the males. Campylobacter jejuni was detected by multiplex PCR at first; later on, Campylobacter coli and mixtures of both were seen. After the 9 wk of age, the colonization of the flocks was completed. Great attention should be given to drinking water as a supposed source of Campylobacter contamination. Multiplex PCR proved to be a rapid, sensitive, and cheap tool for the diagnosis of Campylobacter contamination. PMID- 22252359 TI - Yolk sac carbohydrate levels and gene expression of key gluconeogenic and glycogenic enzymes during chick embryonic development. AB - Glycogen and glucose concentrations (mg/g of tissue) and amounts (mg) were determined in the yolks of fertile eggs on the day of set and in the yolk sac (YS) and liver of broiler chick embryos between 11 and 21 embryonic days of age (E). On the day of set, the yolk contained 50 mg of glucose (0.31% of yolk) but did not contain glycogen. During incubation, the amount of glucose in the YS increased from 20 mg on E11 to 60 mg on E19. A parallel increase in YS and liver glycogen concentrations (mg/g) during the last week of incubation implied a similar capacity for glycogen synthesis per gram of tissue. However, due to its larger size, the YS capacity for glycogen storage far exceeded that of the liver, which stored less than 12 mg of glycogen up to E19, as compared with more than 200 mg in the YS. Between E19 and 21, liver and YS glycogen amounts decreased by 10 mg and 100 mg, respectively. These results indicated that the YS is a glycogenic and perhaps gluconeogenic organ. We therefore evaluated the gene expression of glycogen synthase and glycogen phosphorylase as well as gluconeogenic enzymes (fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase) in the YS membrane and liver by real time reverse-transcription PCR. Although the YS membrane and liver displayed different patterns of mRNA abundance, the high abundance of fructose 1,6 bisphosphatase mRNA in the YS membrane between E11 and 15, and the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, supported the postulated gluconeogenic abilities of the YS membrane and indicated its role in providing glucose to the embryo. Thus, glucose is probably synthesized in the YS, stored in the form of glycogen, and toward hatch, the YS may have the potential to transfer 10 times more glycogen-derived glucose to the embryo as compared with the liver. As such, the YS may play a major role in the synthesis and storage of glucose and its supply to the chick embryo toward hatch. PMID- 22252361 TI - Comparison of gizzard activity between chickens from genetic D+ and D- lines selected for divergent digestion efficiency. AB - Gizzard motility was compared between chickens from D(+) (high digestion efficiency) and D(-) (low digestion efficiency) genetic lines selected for divergent digestion efficiency, using strain gauge transducers. Motility was recorded continuously during 24 h in 6 birds per line. Two stimuli, a meal distribution after a feed-deprivation period and lighting after a dark period, were tested during the recording period. A functional test with intravenous injection of serotonin performed at the end of the recording day often resulted in a sharp reduction in gizzard motility, without a significant difference between lines. Compared with D(+) birds, gizzard activity in D(-) birds remained high during fasting or dark periods (P < 0.0006), which reduced the effects of stimuli in D(-) birds. So, coordination between bird activity and gizzard motility tended to be reduced in D(-) compared with D(+) birds (P = 0.0018). This coordination was observed to be positively correlated (P = 0.011) with the relative weight (g/kg of BW) of the stomach (gizzard + proventriculus). This experiment pointed out differences in gizzard motility between D(+) and D(-) chicken lines in terms of response to environmental stimuli, characterized by a failure in the gizzard relaxation process in D(-) birds during rest periods. PMID- 22252362 TI - Effect of holding temperature, shackling, sex, and age on broiler breast meat quality. AB - Antemortem holding temperature and flapping can affect broiler pectoralis major (referred to as p. major) meat quality. The influence of environmental temperature 12 to 14 h before processing and antemortem handling on p. major functional properties and color was tested at multiple processing ages in a 3 * 2 * 5 factorial design study. At 28, 35, 42, 49, and 56 d of age, mixed-sex broilers were crated and held in one of 3 target temperature treatments: heat (30 degrees C), thermoneutral (21 degrees C), or cool (7 degrees C). Following feed withdrawal, birds were transported to a processing facility where either a long (120 s) or short (<10 s) shackling treatment was imposed. Sex was determined at processing. Lightness, redness, and yellowness values were measured at deboning [4.50 to 8.25 h postmortem (PM)] and at 24 h PM. Ultimate pH was measured at 24 h PM. Drip loss, cook loss, and Allo-Kramer shear force were determined at 72 h PM. Ultimate pH was highest in the cool treatment, with no difference between heat and thermoneutral treatments (5.97 vs. 5.87 and 5.90, respectively; P = 0.0004). Ultimate pH correlated negatively with drip loss (r = -0.47; P < 0.0001). Drip loss was lowest in the cool treatment, with no difference between the heat and thermoneutral treatments (2.06 vs. 2.24 and 2.19%, respectively; P = 0.007). The p. major from broilers in the heat treatment had higher Allo-Kramer shear force values than those in both the thermoneutral and cool treatments (4.64 kg/g vs. 4.21 and 4.21 kg/g, respectively; P = 0.023). With the exception of 49 d, broilers subjected to the long shackling treatment had higher redness values at deboning than broilers subjected to the short shackling treatment; by 24 h PM only the 28-d broilers subjected to the long shackling treatment had higher redness values. Higher hue angles at deboning and 24 h PM were observed in the short treatment compared with the long treatment (65.58 vs. 57.46 and 68.48 vs. 63.31, respectively; P < 0.0001), indicating that p. major from long-shackled broilers were redder in appearance. Ultimate pH was lower in female broilers than in male broilers (5.87 vs. 5.96, respectively; P < 0.0001) and subsequent drip loss was higher in females compared with males (2.34 vs. 1.99%, respectively; P < 0.0001). Although temperature and handling before slaughter affected p. major color and texture traits, the differences may not be large enough to have commercial significance. Differences in p. major quality attributable to sex of the bird may have greater commercial significance than previously reported. PMID- 22252363 TI - Poultry offal meal in chicken: traceability using the technique of carbon (13C/12C)- and nitrogen (15N/14N)-stable isotopes. AB - Studies on the detection of animal by-products in poultry meat are rare and practically nonexistent in chicken meat. With the development of the technique of stable isotopes for traceability purposes and the certification of broiler diet patterns, it has been necessary to know the behavior of the isotopic signature of different tissues in birds, in case of a potential replacement of a diet containing animal ingredients with a strictly vegetable one and vice versa. Thus, this study, carried out at the Sao Paulo State University, Botucatu Campus, Brazil, aimed to evaluate meat from the breast, thigh, drumstick, and wings to trace the presence of poultry offal meal (OM) in broiler feed using the analysis of stable isotopes of carbon ((13)C/(12)C) and nitrogen ((15)N/(14)N) by mass spectrometry. In total, 720 one-d-old chicks were distributed into 6 groups: vegetable diet (VD) from 1 to 42 d; 8% poultry offal meal (OM) diet from 1 to 42 d; VD from 1 to 21 d and 8% OM diet from 22 to 42 d; VD from 1 to 35 d and 8% OM diet from 36 to 42 d; 8% OM diet from 1 to 21 d and VD from 22 to 42 d; and 8% OM diet from 1 to 35 d and VD from 36 to 42 d. Through the analysis of C and N, it is possible to trace the use of OM in broiler feeding when this ingredient is part of the feeding throughout the breeding phase or when it substitutes a strictly VD even up to 35 d. When an OM diet is substituted by a VD, the animal ingredient has to be part of the feeding for 21 d or longer to be detected by this method. PMID- 22252364 TI - Breed effect between Mos rooster (Galician indigenous breed) and Sasso T-44 line and finishing feed effect of commercial fodder or corn. AB - The aim of this research was to study the Mos rooster breed growth performance, carcass, and meat quality. The breed effect (Mos vs. Sasso T-44) and finishing feed in the last month (fodder vs. corn) on animal growth, carcass characteristics, meat quality, and fatty and amino acid profiles were studied using a randomized block design with initial weight as covariance. In total, 80 roosters (n = 30 of Sasso T-44 line and n = 50 of Mos breed) were used. They were separated by breed and allocated to 2 feeding treatment groups (concentrate and corn). Each feeding treatment group consisted of 15 and 25 roosters, for Sasso T 44 line and Mos breed, respectively. Finishing feeding did not affect growth parameters in the 2 genotypes of rooster tested (P > 0.05). Nonetheless, the comparison between both types of roosters led to significant differences in growth parameters (P < 0.05). Regarding carcass characteristics, no significant influences of finishing feeding treatment (P > 0.05) were found, and as expected, carcass weight clearly differed between genotypes due to the lower growth rate of Mos roosters. However, drumstick, thigh, and wing percentages were greater in the Mos breed than in the hybrid line. In color instrumental traits, roosters feeding with corn showed breast meat with significantly (P < 0.001) higher a* and b* values than those of cocks feeding with commercial fodder. Values of shear force were less than 2 kg for both genotypes, thus it can be classified as very tender meat. Finishing with corn significantly increased (P < 0.001) the polyunsaturated fatty acid content in the breast; the Mos breed had a polyunsaturated to saturated fatty acid ratio of 0.73. The amino acid profile of the indigenous breed was not similar to that of the commercial strain. Finishing feeding treatment had a greater influence than breed effect on amino acid profile. PMID- 22252365 TI - Small bird programs: effect of phase-feeding, strain, sex, and debone time on meat quality of broilers. AB - Phase-feeding (PF) has been effective in maintaining broiler growth while reducing production cost, but the effect on different broiler strains grown in a small-bird production scenario has not been assessed. The objective of this study was to evaluate 3 commercial broiler strains typically used in a small-bird production scenario to assess the effect of various debone times and PF on yield and meat quality. Birds (n = 1,080) were fed either diets with average industry nutrient levels or diets with phased levels of amino acids. In total, 540 birds were commercially processed at 40 and 42 d of age. Breast fillets were harvested at 2, 4, and 6 h postmortem (PM). Muscle pH was measured at the time of debone and fillet dimensions, instrumental color (L*, a*, and b*), and pH were measured at 24 h PM. Fillets were cooked to 76 degrees C and cook loss was calculated, followed by Meullenet-Owens Razor shear (MORS) analysis. Phase-feeding, strain, and sex had little effect on fillet yield, but deboning at 2 h PM resulted in a higher fillet yield compared with that of later debone times. Strain, sex, and debone hour had significant effects on fillet dimensions, with strain A producing longer and wider fillets than strains B and C. Males had larger fillets than females (longer and wider), whereas deboning early resulted in significantly thicker fillets compared with those of later deboning. There were no differences in fillet dimensions due to PF, however, uniformity was improved. The PF treatment did not affect pH, color, cook loss, or MORS energy. Deboning at 2 h PM resulted in higher MORS energy, indicating decreased tenderness in 2 of the strains, whereas in one strain, tenderness was not affect by debone time. Results of this study suggest PF does not adversely affect yield or meat quality of broilers in small-bird programs but strain, sex, and debone time can affect quality. Results also suggest that strain can effect tenderness of breast fillets when deboned prerigor. PMID- 22252366 TI - Effects of dietary oregano essential oil and vitamin E on the lipid oxidation stability of cooked chicken breast meat. AB - The antioxidant effect of oregano essential oil and vitamin E was evaluated in cooked chicken breast meat. In total, 480 broilers were randomly assigned to 6 treatments and 4 replications. Broilers were raised with a corn-soybean meal diet including either crude soybean oil or acidulated soybean oil soapstock, each supplemented with vitamin E at 10 or 100 mg or oregano essential oil at 100 mg/kg of feed. At 42 d, broilers were slaughtered and their breast meat was prepared into strips (1.5 * 10 cm) or patties (150 g). Fatty acid composition of the muscle was determined. For lipid oxidation stability, both meat strips and patties were cooked to an internal temperature of 74 degrees C and malonaldehyde contents were assessed during 0, 3, 6, and 9 d of storage at 4 degrees C. Each storage day had 4 replications per treatment. The meat lipid oxidative stability was estimated by content of malonaldehyde values. Results showed that feed consumption, weight gain, and feed conversion were not affected by the dietary oils or antioxidants, except for the mortality in acidulated soybean oil soapstock with the 10-mg vitamin E treatment. The fatty acid composition of the meat was similar between the 2 diets given the same antioxidant supplement. The oxidation stability of meat lipids in both types of meats showed a significant (P < 0.05) interaction between oils, antioxidants, and storage time. In the crude soybean oil oil diet, the malonaldehyde value in the 10-mg vitamin E treatment was the highest, followed by oregano essential oil, and then the 100-mg vitamin E treatment at 9 d of storage, whereas the value of oregano essential oil in the acidulated soybean oil soapstock diet was the highest, followed by the 10-mg vitamin E, and then the 100-mg vitamin E treatment during the 9 d of storage. In conclusion, the dietary oils and antioxidants used can be included in broiler diets without negative effects on their productivity. The antioxidant effect of vitamin E was higher with a higher supplementation level, regardless of the oil treatment, whereas the antioxidant effect of oregano essential oil was better in crude soybean oil than in the acidulated soybean oil soapstock diet. PMID- 22252367 TI - Pathogenic and multidrug-resistant Escherichia fergusonii from broiler chicken. AB - An Escherichia spp. isolate, ECD-227, was previously identified from the broiler chicken as a phylogenetically divergent and multidrug-resistant Escherichia coli possessing numerous virulence genes. In this study, whole genome sequencing and comparative genome analysis was used to further characterize this isolate. The presence of known and putative antibiotic resistance and virulence open reading frames were determined by comparison to pathogenic (E. coli O157:H7 TW14359, APEC O1:K1:H7, and UPEC UTI89) and nonpathogenic species (E. coli K-12 MG1655 and Escherichia fergusonii ATCC 35469). The assembled genome size of 4.87 Mb was sequenced to 18-fold depth of coverage and predicted to contain 4,376 open reading frames. Phylogenetic analysis of 537 open reading frames present across 110 enteric bacterial species identifies ECD-227 to be E. fergusonii. The genome of ECD-227 contains 5 plasmids showing similarity to known E. coli and Salmonella enterica plasmids. The presence of virulence and antibiotic resistance genes were identified and localized to the chromosome and plasmids. The mutation in gyrA (S83L) involved in fluoroquinolone resistance was identified. The Salmonella-like plasmids harbor antibiotic resistance genes on a class I integron (aadA, qacEDelta-sul1, aac3-VI, and sulI) as well as numerous virulence genes (iucABCD, sitABCD, cib, traT). In addition to the genome analysis, the virulence of ECD-227 was evaluated in a 1-d-old chick model. In the virulence assay, ECD-227 was found to induce 18 to 30% mortality in 1-d-old chicks after 24 h and 48 h of infection, respectively. This study documents an avian multidrug-resistant and virulent E. fergusonii. The existence of several resistance genes to multiple classes of antibiotics indicates that infection caused by ECD-227 would be difficult to treat using antimicrobials currently available for poultry. PMID- 22252368 TI - The use of sodium bicarbonate for marination of broiler breast meat. AB - This study aimed to evaluate marination performances and the effect on meat quality traits of sodium bicarbonate, used alone or in combination with sodium chloride, when compared with sodium trypolyphosphate by using advanced analytical tools, including low-field nuclear magnetic resonance and differential scanning calorimetry. In total, 140 samples (cylindrical shape of 1 * 4 cm size) were obtained from a batch of 24-h postmortem broiler breast meat (Ross 708, females, 47 d old). Six of the groups were used for subsequent marination treatments, whereas the last group was kept as a nonmarinated control. Samples were subjected to vacuum tumbling in a special equipped laboratory rotary evaporator with a 12% (wt/wt) water:meat ratio using 6 marinade solutions: 7.7% (wt/wt) NaCl (S); 2.3% (wt/wt) Na(4)O(7)P(2) (P); 2.3% (wt/wt) NaHCO(3) (B); S and P; S and B; S, P, and B. Samples marinated with bicarbonate alone or in combination (B, SB, and SPB) significantly increased (P < 0.05) the meat pH by approximately 0.7 units compared with that of the control, whereas phosphate alone or in combination with salt increased (P < 0.05) the pH by 0.2 units. The combination containing all of the ingredients (SPB) produced the highest marinade performances; however, SB was able to guarantee a better marinade uptake and water retention ability with respect to that of SP. According to low-field nuclear magnetic resonance, the combined use of B and P with S determined a remarkable increase in proportion of entrapped water into the myofibrillar spaces, while the extramyofibrillar water fraction was not modified. Moreover, water gain following marination does not correspond to an increase in the freezable water amount, as detected by differential scanning calorimetry. In conclusion, B is a very promising marinating agent, and it can be exploited to develop processed poultry products with no added phosphates to match the request to avoid the nutritional drawbacks recently indicated with the use of phosphates. PMID- 22252369 TI - Synthesis of N-heterocyclic carbene rhenium(I) carbonyl complexes. AB - Reaction of aminophosphinimine [RHN(CH(2))(2)N[double bond, length as m dash]PPh(3)] (R = H, Et) with Re(2)(CO)(10) provided the NH-functionalized carbene rhenium complex [Re(2)(CNHCH(2)CH(2)NR)(CO)(9)] (3a, R = H, 3b, R = Et). Treatment of 3 with Br(2) provided the mono nuclear [Re(CNHCH(2)CH(2)NR)(CO)(4)Br] (1, R = H, 2, R = Et). However, NH-functionalized carbene complexes 1-3 did not undergo N-alkylation with alkyl halides to yield the N-substituted NHC complexes. The direct ligand substitution of [Re(CO)(5)Br] with a carbene donor was employed to prepare [Re(IMes(2))(CO)(4)Br] (6a, IMes(2) = 1,3-di-mesitylimidazol-2-ylidene; 6b, IMes(2) = 1,3-dimesityl-4,5 dihydroimidazol-2-ylidene). Analyses of spectroscopic and crystal data of 6a and 6b show similar corresponding data among these complexes, suggesting the saturated and unsaturated NHCs have similar bonding with Re(I) metal centers. Reduction of 6a and 6b with LiEt(3)BH yielded the corresponding hydrido complexes 7a-b [ReH(CO)(4)(IMes(2))], but not 1 and 2. Ligand substitution of 1, 6a and 6b toward 2,2'-bipyridine (bipy) was investigated. Crystal structures of 1, 3a-b, 6a b and 7b were determined for characterization and comparison. PMID- 22252370 TI - Evolutionary dynamics of protein domain architecture in plants. AB - BACKGROUND: Protein domains are the structural, functional and evolutionary units of the protein. Protein domain architectures are the linear arrangements of domain(s) in individual proteins. Although the evolutionary history of protein domain architecture has been extensively studied in microorganisms, the evolutionary dynamics of domain architecture in the plant kingdom remains largely undefined. To address this question, we analyzed the lineage-based protein domain architecture content in 14 completed green plant genomes. RESULTS: Our analyses show that all 14 plant genomes maintain similar distributions of species specific, single-domain, and multi-domain architectures. Approximately 65% of plant domain architectures are universally present in all plant lineages, while the remaining architectures are lineage-specific. Clear examples are seen of both the loss and gain of specific protein architectures in higher plants. There has been a dynamic, lineage-wise expansion of domain architectures during plant evolution. The data suggest that this expansion can be largely explained by changes in nuclear ploidy resulting from rounds of whole genome duplications. Indeed, there has been a decrease in the number of unique domain architectures when the genomes were normalized into a presumed ancestral genome that has not undergone whole genome duplications. CONCLUSIONS: Our data show the conservation of universal domain architectures in all available plant genomes, indicating the presence of an evolutionarily conserved, core set of protein components. However, the occurrence of lineage-specific domain architectures indicates that domain architecture diversity has been maintained beyond these core components in plant genomes. Although several features of genome-wide domain architecture content are conserved in plants, the data clearly demonstrate lineage-wise, progressive changes and expansions of individual protein domain architectures, reinforcing the notion that plant genomes have undergone dynamic evolution. PMID- 22252373 TI - Indocyanine green fluorescence-navigated sentinel node biopsy showed higher sensitivity than the radioisotope or blue dye method, which may help to reduce false-negative cases in skin cancer. AB - BACKGROUND AND OBJECTIVES: Although sentinel lymph node (SLN) biopsy using radioisotope (RI) and blue dye (BD) achieved a high detection rate, approximately 5% of melanomas with negative SLNs develop nodal metastasis. We tested a new lymphatic navigation method using indocyanine green fluorescence imaging (ICG-FI) to detect such "occult" SLNs. METHODS: Thirty-four skin cancer patients received SLN biopsy with the following three methods: RI (99Tc-tin colloid), BD (2% patent blue), and ICG (0.5% indocyanine green). Lymph nodes detected by any of the three methods were counted as SLNs. RESULTS: ICG-FI detected more SLNs in 8 out of the 34 cases (24%). The average numbers of SLNs detected by ICG-FI, RI, and BD were 2.18, 1.76, and 1.73, respectively. Interestingly, ICG-FI not only detected more SLNs in one basin (ICG-FI: 1.64, RI: 1.50, and BD: 1.51 SLNs per basin), but also detected additional SLNs in other basins (ICG-FI: 1.32, RI: 1.18, and BD: 1.15 basins per case). CONCLUSION: ICG-FI detected SLNs more efficiently than did the conventional methods, and these "occult" SLNs may offer an explanation for some false-negative cases. We recommend using ICG-FI in addition to a conventional method to reduce the risk of overlooking these "occult" SLNs. PMID- 22252374 TI - Total knee arthroplasty on the rise in younger patients: are we sure that past performance will guarantee future success? PMID- 22252372 TI - Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. AB - PURPOSE: Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer's disease (AD). The aim of this study was to test the feasibility of using PET imaging with (18)F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC). METHODS: In this study, 46 subjects (20 men and 26 women, mean age of 69.0 +/- 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean +/- SD of radioactivity injected, 259 +/- 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region. RESULTS: The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1 Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55-0.98) and a specificity of 38.1% (95% CI 0.18-0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894). CONCLUSION: These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools. PMID- 22252375 TI - TiN nanoparticles: small size-selected fabrication and their quantum size effect. AB - Size-selected TiN nanoclusters in the range of 4 to 20 nm have been produced by an ionized cluster beam, which combines a glow-discharge sputtering with an inert gas condensation technique. With this method, by controlling the experimental conditions, it was possible to produce nanoparticles with a high control in size. The size distribution of TiN nanoparticles was determined before deposition by mass spectroscopy and confirmed by atomic force microscopy. The size distribution was also analyzed using a high-resolution transmission electron micrograph. The photoluminescence [PL] spectra of TiN nanoparticles at different sizes were also experimentally investigated. We reported, for the first time, the strong visible luminescence of TiN nanoparticles on Si (111) wafer due to the reduced size. We also discussed the PL intensity as a function of the nanoparticle size distribution. PMID- 22252376 TI - Brain structure and function in borderline personality disorder. AB - The spotlight on borderline personality disorder (BPD) has been growing in recent years, with the number of papers discussing potential causes and triggers of the disorder rapidly on the increase. Also on the increase, though still lacking sufficient numbers to produce well-supported hypotheses, are studies employing neuroimaging techniques as investigative tools in BPD. In this review, we investigate the current state and findings of neuroimaging studies in BPD, focusing in particular, on the studies examining structural, functional, and neurometabolic abnormalities in the disorder. Some suspected trends in the data are highlighted, including reductions in the hippocampi and amygdalae of BPD patients compared to healthy controls, exaggerated amygdala activity in BPD patients when confronted with emotion-related stimulus, and negative correlations between increases in left amygdalar creatine and reductions in amygdalar volume, reductions in absolute N-acetylaspartate concentration in the dorsolateral prefrontal cortex of BPD patients, and increases in glutamate concentration in the anterior cingulate cortices of BPD patients. We also discuss the limitations of some of the current studies including hindrances due to sample effects and techniques used and the potential of future neuroimaging research in BPD. PMID- 22252377 TI - [Complex surgical care of a defect in the pelvis after repeated curatively intended resections of a rare sacral chordoma with initially inadequate resection and multiple episodes of recurrent tumor growth]. PMID- 22252378 TI - Polymorphism of DNA sequences of cryptochrome genes is not associated with the photoperiodic flowering of wild soybean along a latitudinal cline. AB - Both cultivated soybean and its wild relative Glycine soja exhibit strong photoperiodic sensitivity at different latitudes. Recent studies have demonstrated that the blue light-absorbing cryptochrome gene, CRY1a, is involved in the photoperiodic flowering of soybeans. However, no sequence variation was found in the cDNA among cultivars at different latitudinal clines. In the present study, we examined whether positive selection due to polymorphisms in the cryptochrome genes of G. soja occurs. Partial DNA sequences, mainly exons, of cryptochrome genes CRY1a-1d and CRY2a-2c were analyzed for 18 accessions in the Japanese archipelago. The neutral evolutionary pattern of the polymorphisms for all cryptochrome genes except for CRY1a was summarized using Tajima's D test and low nucleotide diversity was shown for all genes. Although CRY1a did not show neutral evolution, balancing selection was recognized in the intron while not in the exon. No geographical pattern of polymorphisms was observed in the cryptochrome genes. These results reject the possibility of cryptochrome genes being involved in the photoperiodic flowering of wild soybeans along a latitudinal cline. PMID- 22252380 TI - Re: Clinical guidelines and payer policies on fusion for the treatment of chronic low back pain. PMID- 22252379 TI - Phenylephrine protects cardiomyocytes from starvation-induced apoptosis by increasing glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is known to be a "housekeeping" protein; studies in non-cardiomyocytic cells have shown that GAPDH plays pro apoptotic role by translocating from cytoplasm to the nucleus or to the mitochondria. However, the cardiovascular roles of GAPDH are unknown. We observed that phenylephrine (PE) (100 uM) protected against serum and glucose starvation induced apoptosis in neonatal rat cardiac myocytes as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and mitochondrial membrane potential depolarization. GAPDH glycolysis activity was positively correlated with the antiapoptotic action of PE. GAPDH activity inhibition blunted PE-induced protection of the mitochondrial membrane potential and cardiomyocytes. PE-induced Bcl-2 protein increase, Bax mitochondrial decrease and inhibition of cytochrome C release and Caspase 3 activation, as well as ROS production were blunted by GAPDH activity inhibition. Moreover, GAPDH overexpression provided protection against starvation-induced cardiomyocyte apoptosis in vitro and ischemia-induced cardiac infarction in vivo. Inhibition of Akt prevented PE-induced GAPDH activity increase and cardiomyocytes protection. In conclusion, the present study provides the first direct evidence of an antiapoptotic role of GAPDH in PE-induced cardiomyocytes protection; GAPDH activity elevation mainly affects the mitochondria-induced apoptosis. PMID- 22252383 TI - Aquatic ecotoxicity assessment of a new natural formicide. AB - BACKGROUND, AIM AND SCOPE: Agrochemicals could reach aquatic ecosystems and damage ecosystem functionality. Natural formicide could be an alternative to use in comparison with the more toxic formicides available on the market. Thus, the objective of this study was to assess the ecotoxicity of the new natural formicide Macex(r) with a battery of classical aquatic ecotoxicity tests. MATERIAL AND METHODS: Bacteria (Aliivibrio fischeri), algae (Pseudokirchneriella subcapitata), hydra (Hydra attenuata), daphnids (Daphnia magna), and fish (Danio rerio) tests were performed in accordance with international standardized methodologies. RESULTS: In the range of formicide concentrations tested (0.03 to 2.0 g L(-1)) EC(50) values varied from 0.49 to >2.0 g L(-1), with P. subcapitata being the most sensitive species and H. attenuata and D. rerio the most tolerant species to this product in aqueous solutions. CONCLUSIONS: This new formicide preparation can be classed as a product of low toxicity compared to the aquatic ecotoxicity of the most common commercialized formicides. PMID- 22252384 TI - Evaluation of bactericidal efficacy of silver ions on Escherichia coli for drinking water disinfection. AB - PURPOSE: The purpose of this study is the development of a suitable process for the disinfection of drinking water by evaluating bactericidal efficacy of silver ions from silver electrodes. METHODS: A prototype of a silver ioniser with silver electrodes and control unit has been fabricated. Silver ions from silver electrodes in water samples were estimated with an atomic absorption spectrophotometer. A fresh culture of Escherichia coli (1.75 * 10(3) c.f.u./ml) was exposed to 1, 2, 5, 10 and 20 ppb of silver ions in 100 ml of autoclaved tap water for 60 min. The effect of different pH and temperatures on bactericidal efficacy was observed at constant silver ion concentration (5 ppb) and contact time of 30 min. RESULTS: The maximum bactericidal activity (100%) was observed at 20 ppb of silver ion concentration indicating total disinfection after 20 min while minimum bactericidal activity (25%) was observed after 10 min at 01 ppb of silver ions. Likewise, 100% bactericidal activity was noticed with 2, 5 and 10 ppb of silver ions after 60, 50 and 40 min, respectively. Bactericidal activity at pH 5, 6, 7, 8 and 9 was observed at 79.9%, 79.8%, 80.5%, 100% and 100%, respectively, whereas it was 80.4%, 88.3%, 100%, 100% and 100% at 10 degrees C, 20 degrees C, 30 degrees C, 40 degrees C and 50 degrees C, respectively. CONCLUSION: The findings of this study revealed that very low concentrations of silver ions at pH 8-9 and temperature >20 degrees C have bactericidal efficacy for total disinfection of drinking water. Silver ionisation is suitable for water disinfection and an appropriate alternative to chlorination which forms carcinogenic disinfection by-products. PMID- 22252385 TI - Microbial fuel cells in power generation and extended applications. AB - Microbial fuel cells (MFCs) have been progressing at an amazing speed in the past few years, with higher power density but lower cost being continuously achieved. However, most of the studies to date have been conducted at laboratory scale, and many technological and economic barriers remain to be overcome prior to large scale application of the MFC technique. In recent years, China has been playing an increasingly important role in this field, and has contributed considerably to moving MFCs forward toward large-scale implementations for both power generation and extended applications. Nevertheless, the development of MFCs is still in its infancy, the power density needs to be further improved, the cost reduced and a better understanding gained on the underlying mechanisms of electron generation and flow. All these warrant further investigations at both laboratory and pilot levels, and more cooperation of scientists and engineers from different disciplines and countries. In this review, we highlight the progress achieved to date in MFC technology, especially in China, and discuss the challenges and future opportunities. PMID- 22252386 TI - Nonheme iron-oxo and -superoxo reactivities: O2 binding and spin inversion probability matter. AB - DFT calculated barriers for C-H activation of 1,4-cyclohexadiene by nonheme iron(IV)-oxo and iron(III)-superoxo species show that the experimental trends can be explained if the spin inversion probability of the TMC iron(IV)-oxo is assumed to be poor. Also, the TMC iron(III)-superoxo reaction proceeds with an endothermic O(2)-binding energy followed by an intrinsically reactive quintet state. PMID- 22252387 TI - Bistability in feedback circuits as a byproduct of evolution of evolvability. AB - Noisy bistable dynamics in gene regulation can underlie stochastic switching and is demonstrated to be beneficial under fluctuating environments. It is not known, however, if fluctuating selection alone can result in bistable dynamics. Using a stochastic model of simple feedback networks, we apply fluctuating selection on gene expression and run in silico evolutionary simulations. We find that independent of the specific nature of the environment-fitness relationship, the main outcome of fluctuating selection is the evolution of increased evolvability in the network; system parameters evolve toward a nonlinear regime where phenotypic diversity is increased and small changes in genotype cause large changes in expression level. In the presence of noise, the evolution of increased nonlinearity results in the emergence and maintenance of bistability. Our results provide the first direct evidence that bistability and stochastic switching in a gene regulatory network can emerge as a mechanism to cope with fluctuating environments. They strongly suggest that such emergence occurs as a byproduct of evolution of evolvability and exploitation of noise by evolution. PMID- 22252390 TI - Radiation therapy at the end of life in patients with incurable nonsmall cell lung cancer. AB - BACKGROUND: Receipt of chemotherapy at the end of life (EOL) is considered an indicator of poor quality of care for medical oncology. The objective of this study was to characterize the use of radiotherapy (RT) in patients with nonsmall cell lung cancer (NSCLC) during the same period. METHODS: Treatment characteristics of patients with incurable NSCLC who received RT at the EOL, defined as within 14 days of death, were analyzed from the National Comprehensive Cancer Network NSCLC Outcomes Database. RESULTS: Among 1098 patients who died, 10% had received EOL RT. Patients who did and did not receive EOL RT were similar in terms of sex, race, comorbid disease, and Eastern Cooperative Oncology Group performance status. On multivariable logistic regression analysis, independent predictors of receiving EOL RT included stage IV disease (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.09-3.83) or multiorgan involvement (OR, 1.75; 95% CI, 1.08-2.84) at diagnosis, age <65 years at diagnosis (OR, 1.85; 95% CI, 1.21 2.83), and treating institution (OR, 1.24-5.94; P = .02). Nearly 50% of EOL RT recipients did not complete it, most commonly because of death or patient preference. CONCLUSIONS: In general, EOL RT was received infrequently, was delivered more commonly to younger patients with more advanced disease, and often was not completed as planned. There also was considerable variation in its use among National Comprehensive Cancer Network institutions. Next steps include expanding this research to other cancers and settings and investigating the clinical benefit of such treatment. PMID- 22252388 TI - Differential network biology. AB - Protein and genetic interaction maps can reveal the overall physical and functional landscape of a biological system. To date, these interaction maps have typically been generated under a single condition, even though biological systems undergo differential change that is dependent on environment, tissue type, disease state, development or speciation. Several recent interaction mapping studies have demonstrated the power of differential analysis for elucidating fundamental biological responses, revealing that the architecture of an interactome can be massively re-wired during a cellular or adaptive response. Here, we review the technological developments and experimental designs that have enabled differential network mapping at very large scales and highlight biological insight that has been derived from this type of analysis. We argue that differential network mapping, which allows for the interrogation of previously unexplored interaction spaces, will become a standard mode of network analysis in the future, just as differential gene expression and protein phosphorylation studies are already pervasive in genomic and proteomic analysis. PMID- 22252389 TI - Widespread translational control contributes to the regulation of Arabidopsis photomorphogenesis. AB - Environmental 'light' has a vital role in regulating plant growth and development. Transcriptomic profiling has been widely used to examine how light regulates mRNA levels on a genome-wide scale, but the global role of translational regulation in the response to light is unknown. Through a transcriptomic comparison of steady-state and polysome-bound mRNAs, we reveal a clear impact of translational control on thousands of genes, in addition to transcriptomic changes, during photomorphogenesis. Genes encoding ribosomal protein are preferentially regulated at the translational level, which possibly contributes to the enhanced translation efficiency. We also reveal that mRNAs regulated at the translational level share characteristics of longer half-lives and shorter cDNA length, and that transcripts with a cis-element, TAGGGTTT, in their 5' untranslated region have higher translatability. We report a previously neglected aspect of gene expression regulation during Arabidopsis photomorphogenesis. The identities and molecular signatures associated with mRNAs regulated at the translational level also offer new directions for mechanistic studies of light-triggered translational enhancement in Arabidopsis. PMID- 22252391 TI - Telmisartan exerts renoprotective actions via peroxisome proliferator-activated receptor-gamma/hepatocyte growth factor pathway independent of angiotensin II type 1 receptor blockade. AB - Angiotensin (Ang) II type 1 receptor blockers have demonstrated beneficial effects beyond blood pressure control in the treatment of chronic kidney disease. There is clinical evidence that telmisartan is more effective than losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, because it is a partial agonist of peroxisome-proliferator activated receptor-gamma (PPARgamma), as well as an Ang II type 1 receptor blocker (AMADEO Study [A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy]). In this study, we examined the role of PPARgamma activation in the renal protective actions of telmisartan using Ang II type 1 receptor-deficient mice. Renal injury was induced in Ang II type 1 receptor-deficient mice by producing unilateral ureteral obstruction, which exhibited severe renal interstitial fibrosis and inflammation. In these mice, telmisartan prevented hydronephrosis induced by unilateral ureteral obstruction more strongly than did losartan. Importantly, the prevention of renal atrophy and fibrosis by telmisartan was significantly attenuated by GW9662, a PPARgamma antagonist. Interestingly, the downstream effector of PPARgamma activation by telmisartan is hepatocyte growth factor (HGF), a well-known antifibrotic factor, because renal HGF expression was significantly increased by telmisartan, and a neutralizing antibody against HGF diminished the renal protective action of telmisartan. These beneficial changes by telmisartan were associated with a decrease in the expression of transforming growth factor-beta1 and other proinflammatory and profibrotic cytokine genes through PPARgamma/HGF activation. Our findings provide evidence of organ protective actions of telmisartan through the PPARgamma/HGF pathway, independent of Ang II type 1 receptor blockade. Further development of the next generation of Ang II type 1 receptor blockers with added organ protective actions, such as PPARgamma activation, might provide new beneficial drugs to treat renal and cardiovascular diseases. PMID- 22252392 TI - Upper normal blood pressures predict incident atrial fibrillation in healthy middle-aged men: a 35-year follow-up study. AB - Hypertension is the most prevalent risk factor for incident atrial fibrillation (AF). Recently, even high normal blood pressures (BPs) have been established as predictive of AF in women. We aimed to study the long-term impact of upper normal BP on incident AF in a population-based study of middle-aged men. From 1972 to 1975, 2014 healthy Norwegian men were included in a prospective cardiovascular survey and underwent a comprehensive clinical examination including standardized BP measurements. During up to 35 years of follow-up, 270 men were documented with AF by scrutinizing all hospital discharges. Risk estimations for incident AF were analyzed in quartiles of BP using multivariate adjusted Cox proportional hazards. Men with baseline systolic BP >=140 mm Hg and upper normal BP 128 to 138 mm Hg had 1.60-fold (95% CI 1.15-2.21) and 1.50-fold (1.10-2.03) risk of AF, respectively, compared with men with BP <128 mm Hg. Baseline diastolic BP >=80 mm Hg increased the risk of incident AF 1.79-fold (95% CI 1.28-2.59) compared with diastolic BP <80 mm Hg. When adjusting for the occurrence of diabetes mellitus or cardiovascular diseases before an AF event, the results still maintained significance. Additional analyses, on average 7 years after baseline, including men still healthy, showed that sustained upper normal systolic BP remained a significant predictor of subsequent AF. In conclusion, upper normal blood pressures are long-term predictors of incident AF in initially healthy middle aged men. PMID- 22252393 TI - Inducible nitric oxide synthase inhibition as a target for the treatment of vascular dysfunction in hypertension. PMID- 22252394 TI - Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. AB - Primary hyperaldosteronism, one cause of which is aldosterone-producing adenomas (APAs), may account for <=5% to 10% of cases of essential hypertension. Germline mutations have been identified in 2 rare familial forms of primary hyperaldosteronism, but it has been reported recently that somatic mutations of the KCNJ5 gene, which encodes a potassium channel, are present in some sporadic nonsyndromic APAs. To address this further we screened 2 large collections of sporadic APAs from the United Kingdom and Australia (totalling 73) and found somatic mutations in the selectivity filter of KCNJ5 in 41% (95% CI: 31% to 53%) of the APAs (30 of 73). These included the previously noted nonsynonymous mutations, G151R and L158R, and an unreported 3-base deletion, delI157, in the region of the selectivity filter. APAs containing a somatic KCNJ5 mutation were significantly larger than those without (1.61 cm [95% CI: 1.39-1.83 cm] versus 1.04 cm [95% CI: 0.91-1.17 cm]; P<0.0001) but with substantial overlap in size between genotypes. The APAs carrying a mutation, but not those without, also consistently lacked a postural aldosterone response, suggesting a physiologically distinct subtype. Hence, somatic KCNJ5 mutations are not restricted to large APAs (>2 cm), and their frequency in our unselected series suggests they are common and could be important in the molecular pathogenesis of many sporadic cases of APA. PMID- 22252395 TI - Pseudoresistant hypertension attributed to white-coat effect. PMID- 22252397 TI - Resistance training, blood pressure, and meta-analyses. PMID- 22252396 TI - Significance of white-coat hypertension in older persons with isolated systolic hypertension: a meta-analysis using the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes population. AB - The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (>=90 mm Hg) or by daytime ABP (>=85 mm Hg), a history of cardiovascular disease, and persons <18 years of age, the present analysis totaled 7295 persons, of whom 1593 had isolated systolic hypertension. During a median follow-up of 10.6 years, there was a total of 655 fatal and nonfatal cardiovascular events. The analyses were stratified by treatment status. In untreated subjects, those with white-coat hypertension (CBP >=140/<90 mm Hg and ABP <135/<85 mm Hg) and subjects with normal BP (CBP <140/<90 mm Hg and ABP <135/<85 mm Hg) were at similar risk (adjusted hazard rate: 1.17 [95% CI: 0.87-1.57]; P=0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79 1.53]; P=0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00; [95% CI: 1.43-2.79]; P<0.0001) and treated subjects with normal BP (adjusted hazard rate: 1.98 [95% CI: 1.49-2.62]; P<0.0001) were at higher risk as compared with untreated normotensive subjects. In conclusion, subjects with sustained hypertension who have their ABP normalized on antihypertensive therapy but with residual white coat effect by CBP measurement have an entity that we have termed, "treated normalized hypertension." Therefore, one should be cautious in applying the term "white-coat hypertension" to persons receiving antihypertensive treatment. PMID- 22252398 TI - Abnormal intracellular calcium homeostasis in sympathetic neurons from young prehypertensive rats. AB - Hypertension is associated with cardiac noradrenergic hyperactivity, although it is not clear whether this precedes or follows the development of hypertension itself. We hypothesized that Ca(2+) homeostasis in postganglionic sympathetic neurons is impaired in spontaneously hypertensive rats (SHRs) and may occur before the development of hypertension. The depolarization-induced rise in intracellular free calcium concentration ([Ca(2+)](i); measured using fura-2 acetoxymethyl ester) was significantly larger in cultured sympathetic neurons from prehypertensive SHRs than in age matched normotensive Wistar-Kyoto rats. The decay of the [Ca(2+)](i) transient was also faster in SHRs. The endoplasmic reticulum Ca(2+) content and caffeine-induced [Ca(2+)](i) amplitude were significantly greater in the young SHRs. Lower protein levels of phospholamban and more copies of ryanodine receptor mRNA were also observed in the young SHRs. Depleting the endoplasmic reticulum Ca(2+) store did not alter the difference of the evoked [Ca(2+)](i) transient and decay time between young SHRs and Wistar Kyoto rats. However, removing mitochondrial Ca(2+) buffering abolished these differences. A lower mitochondrial membrane potential was also observed in young SHR sympathetic neurons. This resulted in impaired mitochondrial Ca(2+) uptake and release, which might partly be responsible for the increased [Ca(2+)](i) transient and faster decay in SHR sympathetic neurons. This Ca(2+) phenotype seen in early development in cardiac stellate and superior cervical ganglion neurons may contribute to the sympathetic hyperresponsiveness that precedes the onset of hypertension. PMID- 22252399 TI - Role of K(+) channels in the pathophysiology of primary aldosteronism. PMID- 22252400 TI - Above which blood pressure level does the risk of atrial fibrillation increase? PMID- 22252401 TI - Tempol prevents altered K(+) channel regulation of afferent arteriolar tone in diabetic rat kidney. AB - Experiments were performed to test the hypothesis that oxidative stress underlies the enhanced tonic dilator impact of inward-rectifier K(+) channels on renal afferent arterioles of rats with streptozotocin-induced diabetes mellitus. Sham and diabetic rats were left untreated or provided Tempol in their drinking water for 26+/-1 days, after which afferent arteriolar lumen diameter and its responsiveness to K(+) channel blockade were measured using the in vitro blood perfused juxtamedullary nephron technique. Afferent diameter averaged 19.4+/-0.8 MUm in sham rats and 24.4+/-0.8 MUm in diabetic rats (P<0.05). The decrease in diameter evoked by Ba(2+) (inward-rectifier K(+) channel blocker) was 3 times greater in diabetic rats than in sham rats. Glibenclamide (K(ATP) channel blocker) and tertiapin-Q (Kir1.1/Kir3.x channel blocker) decreased afferent diameter in diabetic rats but had no effect on arterioles from sham rats. Chronic Tempol treatment prevented diabetes mellitus-induced increases in both renal vascular dihydroethidium staining and baseline afferent arteriolar diameter. Moreover, Tempol prevented the exaggeration of afferent arteriolar responses to Ba(2+), tertiapin-Q, and glibenclamide otherwise evident in diabetic rats. Preglomerular microvascular smooth muscle cells expressed mRNA encoding Kir1.1, Kir2.1, and Kir6.1. Neither diabetes mellitus nor Tempol altered Kir1.1, Kir2.1, Kir6.1, or SUR2B protein levels in renal cortical microvessels. To the extent that the effects of Tempol reflect its antioxidant actions, our observations indicate that oxidative stress contributes to the exaggerated impact of Kir1.1, Kir2.1, and K(ATP) channels on afferent arteriolar tone during diabetes mellitus and that this phenomenon involves posttranslational modulation of channel function. PMID- 22252402 TI - Ferruccio Ritossa's scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal. AB - The pioneering discovery of the heat shock response by the Italian scientist Ferruccio Ritossa reached maturity this year, 2012. It was 50 years ago that Professor Ritossa, through an extraordinary combination of serendipity, curiosity, knowledge and inspiration, published the first observation that cells could mount very strong transcriptional activity when exposed to elevated temperatures, which was coined the heat shock response. This discovery led to the identification of heat shock proteins, which impact many areas of current biology and medicine, and has created a new avenue for more exciting discoveries. In recognition of the discovery of the heat shock response, Cell Stress Society International (CSSI) awarded Professor Ritossa with the CSSI medallion in October 2010 in Dozza, Italy. This article is based on a session of the Fifth CSSI Congress held in Quebec commemorating Professor Ritossa and his discovery. PMID- 22252403 TI - Development of a process for efficient use of CO2 from flue gases in the production of photosynthetic microorganisms. AB - A new methodology to use efficiently flue gases as CO(2) source in the production of photosynthetic microorganisms is proposed. The CO(2) is absorbed in an aqueous phase that is then regenerated by microalgae. Carbonated solutions could absorb up to 80% of the CO(2) from diluted gas reaching total inorganic carbon (TIC) concentrations up to 2.0 g/L. The pH of the solution was maintained at 8.0-10.0 by the bicarbonate/carbonate buffer, so it is compatible with biological regeneration. The absorption process was modeled and the kinetic parameters were determined. Anabaena sp. demonstrated to tolerate pH (8.0-10.0) and TIC (up to 2.0 g/L) conditions imposed by the absorption step. Experiments of regeneration of the liquid phase demonstrated the feasibility of the overall process, converting CO(2) into organic matter. The developed process avoids heating to regenerate the liquid whereas maximizing the efficiency of CO(2) use, which is relevant to achieve the commercial production of biofuels from microalgae. PMID- 22252404 TI - Therapeutic potential of selenium and tellurium compounds: opportunities yet unrealised. AB - Despite being disparaged for their malodorous and toxic demeanour, compounds of selenium, a bio-essential element, and tellurium, offer possibilities as therapeutic agents. Herein, their potential use as drugs, for example, as anti viral, anti-microbial, anti-inflammatory agents, etc., will be surveyed along with a summary of the established biological functions of selenium. The natural biological functions of tellurium remain to be discovered. PMID- 22252405 TI - Recent development in in situ NMR study on heterogeneous catalysis: mechanisms of light alkane functionalisation. AB - In situ NMR studies of C(1)-C(5) light alkane activation and functionalisation in heterogeneous catalytic systems are overviewed. The results obtained from the NMR technique, particularly those quantitative ones, provide unique information on the activation of alkane molecules and the nature of relevant intermediates, leading to better understanding reaction mechanisms and designing catalysts. PMID- 22252406 TI - UPDG: utilities package for data analysis of pooled DNA GWAS. AB - BACKGROUND: Despite being a well-established strategy for cost reduction in disease gene mapping, pooled DNA association study is much less popular than the individual DNA approach. This situation is especially true for pooled DNA genomewide association study (GWAS), for which very few computer resources have been developed for its data analysis. This motivates the development of UPDG (Utilities package for data analysis of Pooled DNA GWAS). RESULTS: UPDG represents a generalized framework for data analysis of pooled DNA GWAS with the integration of Unix/Linux shell operations, Perl programs and R scripts. With the input of raw intensity data from GWAS, UPDG performs the following tasks in a stepwise manner: raw data manipulation, correction for allelic preferential amplification, normalization, nested analysis of variance for genetic association testing, and summarization of analysis results. Detailed instructions, procedures and commands are provided in the comprehensive user manual describing the whole process from preliminary preparation of software installation to final outcome acquisition. An example dataset (input files and sample output files) is also included in the package so that users can easily familiarize themselves with the data file formats, working procedures and expected output. Therefore, UPDG is especially useful for users with some computer knowledge, but without a sophisticated programming background. CONCLUSIONS: UPDG provides a free, simple and platform-independent one-stop service to scientists working on pooled DNA GWAS data analysis, but with less advanced programming knowledge. It is our vision and mission to reduce the hindrance for performing data analysis of pooled DNA GWAS through our contribution of UPDG. More importantly, we hope to promote the popularity of pooled DNA GWAS, which is a very useful research strategy. PMID- 22252407 TI - Altered human CYP3A4 activity caused by Antley-Bixler syndrome-related variants of NADPH-cytochrome P450 oxidoreductase measured in a robust in vitro system. AB - NADPH-cytochrome P450 oxidoreductase (CYPOR) variants have been described in patients with perturbed steroidogenesis and sexual differentiation, related to Antley-Bixler syndrome (ABS). It is important to determine the effect of these variants on CYP3A4, the major drug-metabolizing cytochrome P450 (P450) in humans. In this study, 12 CYPOR_ABS variants were separately coexpressed with CYP3A4 in a robust in vitro system to evaluate the effects of these variants on CYP3A4 activity in a milieu that recapitulates the stoichiometry of the mammalian systems. Full-length CYPOR variants were coexpressed with CYP3A4, resulting in relative expression levels comparable to those found in hepatic tissue. Dibenzylfluorescein (DBF), a CYP3A-specific reporter substrate (Biopharm Drug Dispos 24:375-384, 2003), was used to compare the variants and wild-type (WT) CYPOR activities with that of human liver microsomes. CYP3A4, combined with WT CYPOR, demonstrated kinetic parameters (k(cat) and K(m)) equal to those for pooled human liver microsomes. CYPOR variants Y181D, Y459H, V492E, L565P, and R616X all demonstrated maximal loss of CYP3A4 catalytic efficiency, whereas R457H and G539R retained ~10 and 30% activities, respectively. Conversely, variants P228L, M263V, A287P, and G413S each showed WT-like capacity (k(cat)/K(m)), with the A287P variant being formerly reported to exhibit substantially lower catalytic efficiency. In addition, Q153R exhibited 60% of WT CYPOR capacity to support the DBF O-debenzylation reaction, contradicting increased catalytic efficiency (k(cat)/K(m)) relative to that for the WT, reported previously. Our data indicate the importance of use of simulated, validated in vitro systems, employing full-length proteins with appropriate stoichiometric incorporation of protein partners, when pharmacogenetic predictions are to be made for P450 mediated biotransformation. PMID- 22252408 TI - Lights out: impact of the August 2003 power outage on mortality in New York, NY. AB - BACKGROUND: Little is known about how power outages affect health. We investigated mortality effects of the largest US blackout to date, 14-15 August 2003 in New York, NY. METHODS: We estimated mortality risk in New York, NY, using a generalized linear model with data from 1987-2005. We incorporated possible confounders, including weather and long-term and seasonal mortality trends. RESULTS: During the blackout, mortality increased for accidental deaths (122% [95% confidence interval = 28%-287%]) and nonaccidental (ie, disease-related) deaths (25% [12%-41%]), resulting in approximately 90 excess deaths. Increased mortality was not from deaths being advanced by a few days; rather, mortality risk remained slightly elevated through August 2003. CONCLUSIONS: To our knowledge, this is the first analysis of power outages and nonaccidental mortality. Understanding the impact of power outages on human health is relevant, given that increased energy demand and climate change are likely to put added strain on power grids. PMID- 22252409 TI - Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, or acetaminophen and risk of ovarian cancer. AB - BACKGROUND: Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) and acetaminophen all have biologic effects that might reduce the risk of ovarian cancer. However, epidemiologic data on this question are mixed. METHODS: A population-based, case-control study in western Pennsylvania, eastern Ohio, and western New York State included 902 women with incident epithelial ovarian cancer who were diagnosed between February 2003 and November 2008 as well as 1802 matched controls. Regular use (at least 2 tablets per week for 6 months or more) of aspirin, NA-NSAIDs, and acetaminophen before the reference date (9 months before interview date) was assessed by in-person interview. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The OR for aspirin use was 0.81 (95% CI = 0.63-1.03). Decreased risks were found among women who used aspirin continuously (0.71 [0.54-0.94]) or at a low-standardized daily dose (0.72 [0.53-0.97]), who used aspirin for the prevention of cardiovascular disease (0.72 [0.57-0.97]), who used aspirin more recently, or who used selective cyclooxygenase-2 inhibitors (0.60 [0.39-0.94]). No associations were observed among women using nonselective NA-NSAIDs or acetaminophen. CONCLUSIONS: Risk reductions of ovarian cancer were observed with use of aspirin or selective cyclooxygenase-2 inhibitors. However, the results should be interpreted with caution due to the inherent study limitations and biases. PMID- 22252411 TI - The morphological findings of malleus and incus in a case of Marfan's syndrome. AB - In Marfan's syndrome, which is a connective tissue disorder of hereditary origin, collagenous tissue development and bone synthesis are generally altered in addition to the occurrence of many systemic deformities. External ear, stapes, and vestibular aqueduct pathologies are reported as some of the otological deformities. However, the malleus and incus pathologies of the ear are not reported in any study. In the morphometric measurements carried out, the distance between the malleus head and manubrium was found to be 9.8 mm. When similar measurements were carried out for the incus, the distance between the upper part of the incus body and tip of the long process was found to be 6.9 mm. All of these measurements were detected to be greater than in normal people. It can be concluded from this study that in Marfan's syndrome, in addition to the musculoskeletal alterations particularly in bone synthesis, the ossicular chain in the middle ear is also affected. PMID- 22252410 TI - Impact of colon cancer screening on family history phenotype. AB - BACKGROUND: If effective cancer screening is more common in people with a family history of cancer, the relationship between family history and cancer incidence may become distorted. METHODS: To assess the impact of screening on the association between colorectal cancer family history and risk of colorectal cancer, we developed a model to simulate screening patterns in those with and without a family history. RESULTS: The introduction of screening reduces the apparent risk of colorectal cancer associated with family history in subsequent generations. This reduction becomes more pronounced as the difference in the uptake of screening between those with a family history and those without becomes larger. CONCLUSION: A result of effective screening is that observed family history of colorectal cancer may no longer match inherited risk, and observed family history may fail to be a strong risk factor. This may have implications for exposure-disease relationships if screening is differentially associated with the exposure. PMID- 22252412 TI - Microbiological diagnosis of spinal tuberculosis. AB - PURPOSE: The purpose of this study was to review the clinical features and diagnosis of spinal tuberculosis cases reported in the literature. METHODS: A medical literature search in the Medline Pubmed database was undertaken to review tuberculosis spinal infection and extra-pulmonary tuberculosis diagnosis improvement. We introduced the following search items and boolean operators: "spinal infection", "spinal tuberculosis infection", "microbiological diagnosis of spinal tuberculosis" and "spinal tuberculosis PCR." Single cases or series without microbiological diagnosis were rejected. Manuscript language was restricted to Spanish, French, and English versions. RESULTS AND CONCLUSIONS: Spinal tuberculosis is more common in developing countries and is probably underdiagnosed. Delayed diagnosis is characteristic; it worsens the prognosis and increases morbidity. The microbiological diagnosis is crucial for several reasons. Despite surgical treatment, medical treatment with anti-tuberculous drugs is always necessary. A total of 20-40% of the spinal tuberculosis patients show another locus of infection. Pulmonary location can become a public health problem. Previously treated patients for other tuberculosis locations, incomplete treatments, or poor adherence can change the M. tuberculosis sensitivity pattern. Drug resistance test becomes a major need in the microbiology laboratory. PCR diagnostic techniques advance the diagnosis and increase the sensitivity and specificity rate. PMID- 22252413 TI - Percutaneous pinning of three- or four-part fractures of the proximal humerus in elderly patients in poor general condition: MIROS(r) versus traditional pinning. AB - PURPOSE: Elderly subjects often have fractures of the proximal humerus, which may be difficult to manage in patients in poor general condition. The MIROS is a new percutaneous pinning device allowing correction of angular displacement and stable fixation of fracture fragments. We evaluated the results of percutaneous fixation of three- or four-part fractures of the proximal humerus of patients in the American Society of Anesthesiologists physical status three or four treated either with MIROS or traditional percutaneous pinning (TPP). METHODS: A total of 31 patients treated with MIROS and 27 undergoing TPP were enrolled in the study. Pre-operatively anteroposterior and transthoracic or axillary radiographs were obtained in all cases and computed tomography scans in patients with the most complex fractures. Follow-up evaluations were carried out at three, six, 12 and 16 weeks, and six months, one year and two years postoperatively, using the Constant Score (CS) and subjective shoulder value (SSV) methods. RESULTS: Of the 58 patients, 52 could be evaluated at all follow-ups. In both three- or four-part fractures there were significantly higher CS and SSV scores in the MIROS compared to the TPP group at all the late follow-ups. Lower rates of deep infection, pin tract infection and pin mobilisation were found in the MIROS group (p < 0.001). In both groups there was a significant association between the final result (CS) and either the type of fracture or complications (p < 0.001). CONCLUSIONS: The MIROS resulted in better clinical results and less complications than TPP in elderly patients. This method, however, may not be indicated for younger patients in good general condition. PMID- 22252414 TI - Computer-assisted surgery as indication of choice: total knee arthroplasty in case of retained hardware or extra-articular deformity. AB - PURPOSE: The use of traditional cutting guides during knee arthroplasty in some cases could be extremely difficult, if not impossible, because of angular deformities, IM sclerosis, long-stemmed hip implants, or hardware within the femoral canal that cannot be removed. In these difficult cases navigation assisted knee arthroplasty should be considered as an effective and appealing option. METHODS: We present 14 cases in which ideal mechanical and prosthetic alignment was achieved with different image-free, computer-assisted navigation systems, because of an extra-articular deformity (group A, nine patients) or because of a retained implant or hardware (group B, five patients). RESULTS: After a mean follow-up of 28 months (range 12-53 months), the average knee score increased overall from a mean of 33 points (range 12-63) to 78 points (range 63 90). The average functional score improved from a mean of 32 points (range 10-65) to 72 points (range 40-90). The postoperative mechanical axis ranged between 3 degrees of varus and 3 degrees of valgus. There was an implant revision in one patient who had a traumatic rupture of medial collateral ligament, which occurred 27 months after the index procedure. CONCLUSIONS: Based on our results we think that the navigation-assisted technique provides an alternative approach to the traditional instrumentation for treating these difficult patients in an effective and less invasive manner. PMID- 22252415 TI - Sperm nucleus decondensation, hyaluronic acid (HA) binding and oocyte activation capacity: different markers of sperm immaturity? Case reports. PMID- 22252416 TI - Conformational stability studies of a stapled hexa-beta3-peptide library. AB - A library of 14-helical hexa beta(3)-peptides was synthesized in order to determine the influence of sequence variation as well as staple size and location on conformational stability. From this study we show that appropriately stapled hexa-beta(3)-peptides can allow for a number of variations without significant perturbation of the 14-helix. PMID- 22252417 TI - Testing for sexually transmitted infections in a population-based sexual health survey: development of an acceptable ethical approach. AB - Population-based research is enhanced by biological measures, but biological sampling raises complex ethical issues. The third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) will estimate the population prevalence of five sexually transmitted infections (STIs) (Chlamydia trachomatis, Neisseria gonorrhoeae, human papillomavirus (HPV), HIV and Mycoplasma genitalium) in a probability sample aged 16-44 years. The present work describes the development of an ethical approach to urine testing for STIs, including the process of reaching consensus on whether to return results. The following issues were considered: (1) testing for some STIs that are treatable and for which appropriate settings to obtain free testing and advice are widely available (Natsal-3 provides all respondents with STI and healthcare access information), (2) limits on test accuracy and timeliness imposed by survey conditions and sample type, (3) testing for some STIs with unknown clinical and public health implications, (4) how a uniform approach is easier to explain and understand, (5) practical difficulties in returning results and cost efficiency, such as enabling wider STI testing by not returning results. The agreed approach, to perform voluntary anonymous testing with specific consent for five STIs without returning results, was approved by stakeholders and a research ethics committee. Overall, this was acceptable to respondents in developmental piloting; 61% (68 of 111) of respondents agreed to provide a sample. The experiences reported here may inform the ethical decision making of researchers, research ethics committees and funders considering population-based biological sampling. PMID- 22252418 TI - A survey of the perspectives of patients who are seriously ill regarding end-of life decisions in some medical institutions of Korea, China and Japan. AB - PURPOSE: The debate about the end-of-life care decision is becoming a serious ethical and legal concern in the Far-Eastern countries of Korea, China and Japan. However, the issues regarding end-of-life care will reflect the cultural background, current medical practices and socioeconomic conditions of the countries, which are different from Western countries and between each other. Understanding the genuine thoughts of patients who are critically ill is the first step in confronting the issues, and a comparative descriptive study of these perspectives was conducted by collaboration between researchers in all three countries. METHODS: Surveys using self-reporting paper questionnaire forms were conducted from December 2008 to April 2009 in Korea (six hospitals in two regions), China (five hospitals in four regions) and Japan (nine hospitals in one region). The subjects were patients who were critically ill who had been diagnosed as having cancer. A total of 235 participants (Korea, 91; China, 62; Japan, 52) were eventually recruited and statistically analysed. RESULTS: Most respondents had sometimes or often thought of their own death, mostly fear of 'separation from loved ones'. They wanted to hear the news regarding their own condition directly and frankly from the physician. A quarter of them preferred making end-of-life care decisions by themselves, while many respondents favoured a 'joint decision' with their family members. The most favoured proxy decision maker was the spouse, followed by the children. Most admitted the necessity of 'advance directives' and agreed with artificial ventilation withdrawal in irreversible conditions. The most common reason was 'artificial prolongation of life is unnecessary'. Most respondents agreed with the concept of active euthanasia; however, significant differences were sometimes observed in the responses according to variables such as patient's country of origin, age, gender and education level. CONCLUSION: Patients in Far-Eastern countries gave various responses regarding end-of-life care decisions. Although familial input is still influential, most patients think of themselves as the major decision maker and accept the necessity of advance directives with Westernization of the society. Artificial ventilation withdrawal and even active euthanasia may be acceptable to them. PMID- 22252419 TI - Carboxymethylcellulose-gelatin-superoxidase dismutase electrode for amperometric superoxide radical sensing. AB - A novel, highly sensitive superoxide dismutase biosensor for the direct and simultaneous determination of superoxide radicals was developed by immobilization of superoxide dismutase within carboxymethylcellulose-gelatin on a Pt electrode surface. The parameters affecting the performance of the biosensor were investigated. The response of the CMC-G-SOD biosensor was proportional to O (2) (.-) concentration and the detection limit was 1.25 * 10(-3) mM with a correlation coefficient of 0.9994. The developed biosensor exhibited high analytical performance with wider linear range, high sensitivity and low response time. The biosensor retained 89.8% of its sensitivity after use for 80 days. The support system enhanced the immobilization of superoxide dismutase and promoted the electron transfer of superoxide dismutase minimizing its fouling effect. The biosensor was quite effective not only in detecting O (2) (.-) , but also in determining the antioxidant properties of acetylsalicylic acid-based drugs and the anti-radical activity of healthy and cancerous human brain tissues. PMID- 22252420 TI - Effects of some inhibitors on the growth and lipid accumulation of oleaginous yeast Rhodosporidium toruloides and preparation of biodiesel by enzymatic transesterification of the lipid. AB - Microbial lipid produced using yeast fermentation with inexpensive carbon sources such as lignocellulosic hydrolyzate can be an alternative feedstock for biodiesel production. Several inhibitors that can be generated during acid hydrolysis of lignocellulose were added solely or together into the culture medium to study their individual inhibitory actions and their synergistic effects on the growth and lipid accumulation of oleaginous yeast Rhodosporidium toruloides. When the inhibitors were present in isolation in the medium, to obtain a high cell biomass accumulation, the concentrations of formic acid, acetic acid, furfural and vanillin should be lower than 2, 5, 0.5 and 1.5 g/L, respectively. However, the synergistic effects of these compounds could dramatically decrease the minimum critical inhibitory concentrations leading to significant growth and lipid production inhibitions. Unlike the above-cited inhibitors, sodium lignosulphonate had no negative influence on biomass accumulation when its concentration was in the range of 0.5-2.0 g/L; in effect, it was found to facilitate cell growth and sugar-to-lipid conversion. The fatty acid compositional profile of the yeast lipid was in the compositional range of various plant oils and animal tallow. Finally, the crude yeast lipid from bagasse hydrolyzate could be well converted into fatty acid methyl ester (FAME, biodiesel) by enzymatic transesterification in a tert-butanol system with biodiesel yield of 67.2% and lipid-to-biodiesel conversion of 88.4%. PMID- 22252421 TI - Optimization of biological sulfide removal in a CSTR bioreactor. AB - In this study, biological sulfide removal from natural gas in a continuous bioreactor is investigated for estimation of the optimal operational parameters. According to the carried out reactions, sulfide can be converted to elemental sulfur, sulfate, thiosulfate, and polysulfide, of which elemental sulfur is the desired product. A mathematical model is developed and was used for investigation of the effect of various parameters on elemental sulfur selectivity. The results of the simulation show that elemental sulfur selectivity is a function of dissolved oxygen, sulfide load, pH, and concentration of bacteria. Optimal parameter values are calculated for maximum elemental sulfur selectivity by using genetic algorithm as an adaptive heuristic search. In the optimal conditions, 87.76% of sulfide loaded to the bioreactor is converted to elemental sulfur. PMID- 22252422 TI - A convenient approach to synthesizing peptide C-terminal N-alkyl amides. AB - Peptide C-terminal N-alkyl amides have gained more attention over the past decade due to their biological properties, including improved pharmacokinetic and pharmacodynamic profiles. However, the synthesis of this type of peptide on solid phase by current available methods can be challenging. Here we report a convenient method to synthesize peptide C-terminal N-alkyl amides using the well known Fukuyama N-alkylation reaction on a standard resin commonly used for the synthesis of peptide C-terminal primary amides, the peptide amide linker polyethylene glycol-polystyrene (PAL-PEG-PS) resin. The alkylation and oNBS deprotection were conducted under basic conditions and were therefore compatible with this acid labile resin. The alkylation reaction was very efficient on this resin with a number of different alkyl iodides or bromides, and the synthesis of model enkephalin N-alkyl amide analogs using this method gave consistently high yields and purities, demonstrating the applicability of this methodology. The synthesis of N-alkyl amides was more difficult on a Rink amide resin, especially the coupling of the first amino acid to the N-alkyl amine, resulting in lower yields for loading the first amino acid onto the resin. This method can be widely applied in the synthesis of peptide N-alkyl amides. PMID- 22252423 TI - The silkmoth eggshell as a natural amyloid shield for the safe development of insect oocyte and embryo: insights from studies of silkmoth chorion protein peptide-analogues of the B family. AB - Silkmoth chorion is the major component of the silkmoth eggshell. The proteins that constitute more than 95% of its dry mass have remarkable mechanical and physicochemical properties forming a protective natural shield for the oocyte and the developing embryo from a wide range of environmental hazards. Peptide analogues of the central conservative domain of the two major families of silkmoth chorion proteins, the A's and the B's, form amyloid fibrils under a variety of conditions, which prompted us to propose, 10 years ago, that silkmoth chorion is an amyloid with protective properties. Following our finding, a number of studies verified the existence of several functional amyloids. In this study, we designed, synthesized and studied two peptide-analogues of the central conservative domain of the B family of silkmoth chorion proteins, and we present experimental results, which show: (a) that the amyloidogenic properties of silkmoth chorion peptides are encoded into the tandemly repeating hexapeptides comprising the central domain of silkmoth chorion proteins, confirming our previous findings from peptide analogues of the A family of chorion proteins, and, (b) they suggest how silkmoth chorion proteins of the B family self-assemble in vivo, for the formation of the helicoidal architecture of silkmoth chorion. PMID- 22252424 TI - Sol and gel states in peptide hydrogels visualized by Gd(III)-enhanced magnetic resonance imaging. AB - The hydrogels assembled from a pair of self-repulsive but mutually attractive decapeptides are visualized by magnetic resonance imaging (MRI). It is found that in the absence of Gd(III)-chelate, gelation has little effect on MRI signal intensity. In the presence of Gd(III)-chelate, gelation leads to significant changes in water relaxation and MR signal intensity. The sol to gel transition is best visualized by T2-weighted imaging using large echo time with the sol producing a bright spot and the gel producing a dark spot. MRI studies point to high local Gd(III)-chelate concentration. Small-angle X-ray scattering study indicates that this local enrichment of Gd(III)-chelate has two contributing processes: first, the aggregation of peptides into fibers; second, within peptide fibers, Gd(III)-chelate further aggregate into clusters. This work demonstrates that the status of peptide-based hydrogels can be visualized by MRI with the aid of covalently linked Gd(III)-chelates. This result has implications for monitoring peptide scaffolds in vivo. PMID- 22252425 TI - Chain length effects on helix-hairpin distribution in short peptides with Aib DAla and Aib-Aib segments. AB - The Aib-D Ala dipeptide segment has a tendency to form both type-I'/III' and type I/III beta-turns. The occurrence of prime turns facilitates the formation of beta hairpin conformations, while type-I/III turns can nucleate helix formation. The octapeptide Boc-Leu-Phe-Val-Aib-DAla-Leu-Phe-Val-OMe (1) has been previously shown to form a beta-hairpin in the crystalline state and in solution. The effects of sequence truncation have been examined using the model peptides Boc Phe-Val-Aib-Xxx-Leu-Phe-NHMe (2, 6), Boc-Val-Aib-Xxx-Leu-NHMe (3, 7), and Boc-Aib Xxx-NHMe (4, 8), where Xxx=DAla, Aib. For peptides with central Aib-Aib segments, Boc-Phe-Val-Aib-Aib-Leu-Phe-NHMe (6), Boc-Val-Aib-Aib-Leu-NHMe (7), and Boc-Aib Aib-NHMe (8) helical conformations have been established by NMR studies in both hydrogen bonding (CD3OH) and non-hydrogen bonding (CDCl3) solvents. In contrast, the corresponding hexapeptide Boc-Phe-Val-Aib-DAla-Leu-Phe-Val-NHMe (2) favors helical conformations in CDCl3 and beta-hairpin conformations in CD3 OH. The beta turn conformations (type-I'/III) stabilized by intramolecular 4->1 hydrogen bonds are observed for the peptide Boc-Aib-D Ala-NHMe (4) and Boc-Aib-Aib-NHMe (8) in crystals. The tetrapeptide Boc-Val-Aib-Aib-Leu-NHMe (7) adopts an incipient 3(10) helical conformation stabilized by three 4->1 hydrogen bonds. The peptide Boc-Val Aib-DAla-Leu-NHMe (3) adopts a novel alpha-turn conformation, stabilized by three intramolecular hydrogen bonds (two 4->1 and one 5->1). The Aib-DAla segment adopts a type-I' beta-turn conformation. The observation of an NOE between Val (1) NH<->HNCH3 (5) in CD3OH suggests, that the solid state conformation is maintained in methanol solutions. PMID- 22252426 TI - Enhanced cellular uptake and metabolic stability of lipo-oligoarginine peptides. AB - Developing efficient cellular delivery vectors is crucial for designing novel therapeutic agents to enhance their plasma membrane permeability and metabolic stability in cells. Previously, we engineered cell penetrating peptide vectors named as "lipo-oligoarginine peptides" (LOAPs) by conjugating a proper combination of fatty acid and oligoarginine that translocated into cell easily without adverse effect on cell viability. In the present study, we report a systemic evaluation of cellular uptake and metabolic stability of LOAPs in Jurkat cells by introducing different combination of D-Arg residues in the peptide backbone. The cellular uptake and intracellular fate, cell viability, and metabolic stability and proteolytic degradation patterns of various LOAPs consisted of different combination of L- and D-Arg sequences were confirmed by flow cytometry, cytotoxicity assay, and analytical RP-HPLC with MALDI-TOF mass. All investigated LOAPs penetrated the cell efficiently with low cellular toxicity. The LOAPs having D-Arg residues at their N-termini seemed to have better metabolic stability than the LOAPs having C-terminal D-Arg residues. The metabolic degradation patterns were similar among all investigated LOAPs. The major hydrolytic site was between lauroyl group and beta-Ala residue. Without the lipid chain, the oligoarginine peptide was pumped out ofcells easily. The results presented in this study suggest that structurally modified LOAPs could be used as a novel CPP design toward improved therapeutic application. PMID- 22252428 TI - GIRK2 expression in dopamine neurons of the substantia nigra and ventral tegmental area. AB - G-protein-regulated inward-rectifier potassium channel 2 (GIRK2) is reported to be expressed only within certain dopamine neurons of the substantia nigra (SN), although very limited data are available in humans. We examined the localization of GIRK2 in the SN and adjacent ventral tegmental area (VTA) of humans and mice by using either neuromelanin pigment or immunolabeling with tyrosine hydroxylase (TH) or calbindin. GIRK2 immunoreactivity was found in nearly every human pigmented neuron or mouse TH-immunoreactive neuron in both the SN and VTA, although considerable variability in the intensity of GIRK2 staining was observed. The relative intensity of GIRK2 immunoreactivity in TH-immunoreactive neurons was determined; in both species nearly all SN TH-immunoreactive neurons had strong GIRK2 immunoreactivity compared with only 50-60% of VTA neurons. Most paranigral VTA neurons also contained calbindin immunoreactivity, and approximately 25% of these and nearby VTA neurons also had strong GIRK2 immunoreactivity. These data show that high amounts of GIRK2 protein are found in most SN neurons as well as in a proportion of nearby VTA neurons. The single previous human study may have been compromised by the fixation method used and the postmortem delay of their controls, whereas other studies suggesting that GIRK2 is located only in limited neuronal groups within the SN have erroneously included VTA regions as part of the SN. In particular, the dorsal layer of dopamine neurons directly underneath the red nucleus is considered a VTA region in humans but is commonly considered the dorsal tier of the SN in laboratory species. PMID- 22252430 TI - Chemical compositions and sources of atmospheric PM10 in heating, non-heating and sand periods at a coal-based city in northeastern China. AB - Mass concentrations and chemical components (18 elements, 9 ions, organic carbon [OC] and elemental carbon [EC]) in atmospheric PM(10) were measured at five sites in Fushun during heating, non-heating and sand periods in 2006-2007. PM(10) mass concentrations varied from 62.0 to 226.3 MUg m(-3), with 21% of the total samples' mass concentrations exceeding the Chinese national secondary standard value of 150 MUg m(-3), mainly concentrated in heating and sand periods. Crustal elements, trace elements, water-soluble ions, OC and EC represented 20-47%, 2-9%, 13-34%, 15-34% and 13-25% of the particulate matter mass concentrations, respectively. OC and crustal elements exhibited the highest mass percentages, at 27-34% and 30-47% during heating and sand period. Local agricultural residuals burning may contribute to EC and ion concentrations, as shown by ion temporal variation and OC and EC correlation analysis. Heavy metals (Cr, Ni, Zn, Cu and Mn) from coal combustion and industrial processes should be paid attention to in heating and sand periods. The anion/cation ratios exhibited their highest values for the background site with the influence of stationary sources on its upper wind direction during the sand period. Secondary organic carbon were 1.6-21.7, 1.5-23.0, 0.4-17.0, 0.2-33.0 and 0.2-21.1 MUg m(-3), accounting for 20-77%, 44 88%, 4-77%, 8-69% and 4-73% of OC for the five sampling sites ZQ, DZ, XH, WH and SK, respectively. From the temporal and spatial variation analysis of major species, coal combustion, agricultural residual burning and industrial emission including dust re-suspended from raw material storage piles were important sources for atmospheric PM(10) in Fushun at heating, non-heating and sand periods, respectively. It was confirmed by principal component analysis that coal combustion, vehicle emission, industrial activities, soil dust, cement and construction dust and biomass burning were the main sources for PM(10) in this coal-based city. PMID- 22252429 TI - Analytic lymph node number establishes staging accuracy by occult tumor burden in colorectal cancer. AB - BACKGROUND AND OBJECTIVES: Recurrence in lymph node-negative (pN0) colorectal cancer suggests the presence of undetected occult metastases. Occult tumor burden in nodes estimated by GUCY2C RT-qPCR predicts risk of disease recurrence. This study explored the impact of the number of nodes analyzed by RT-qPCR (analytic) on the prognostic utility of occult tumor burden. METHODS: Lymph nodes (range: 2 159) from 282 prospectively enrolled pN0 colorectal cancer patients, followed for a median of 24 months (range: 2-63), were analyzed by GUCY2C RT-qPCR. Prognostic risk categorization defined using occult tumor burden was the primary outcome measure. Association of prognostic variables and risk category were defined by multivariable polytomous and semi-parametric polytomous logistic regression. RESULTS: Occult tumor burden stratified this pN0 cohort into categories of low (60%; recurrence rate (RR) = 2.3% [95% CI 0.1-4.5%]), intermediate (31%; RR = 33.3% [23.7-44.1%]), and high (9%; RR = 68.0% [46.5-85.1%], P < 0.001) risk of recurrence. Beyond race and T stage, the number of analytic nodes was an independent marker of risk category (P < 0.001). When >12 nodes were analyzed, occult tumor burden almost completely resolved prognostic risk classification of pN0 patients. CONCLUSIONS: The prognostic utility of occult tumor burden assessed by GUCY2C RT-qPCR is dependent on the number of analytic lymph nodes. PMID- 22252431 TI - Comparative incidence patterns and trends of gonadal and extragonadal germ cell tumors in England, 1979 to 2003. AB - BACKGROUND: It is believed that gonadal and extragonadal germ cell tumors (GCTs) arise from primordial germ cells and may have similar etiopathogenesis. Unlike testicular GCTs, there has been limited comprehensive population-based analysis of ovarian and extragonadal GCTs. METHODS: All malignant GCTs and all central nervous system (CNS) GCTs with benign and uncertain behavior that were registered in England in the age group 0 to 84 years from 1979 to 2003 were included in the current study. Incidence rates were calculated and adjusted to the world standard population. RESULTS: There were 33,364 GCTs (92.5% testes, 3.9% ovary, 3.2% extragonadal) in individuals aged 0 to 84 years. The CNS was the most common extragonadal site. An initial peak in incidence at ages 0 to 4 years of nongerminomas was observed at all sites except ovary. Second incidence peaks between ages 10 to 39 years that were more marked among males also were observed at all sites. The ages at these incidence peaks varied by site and were 10 to 14 years (CNS), 15 to 19 years (ovary), 25 to 29 years (other extragonadal sites), and 30 to 34 years (testes). A statistically significant increase in incidence over time was observed in germinomas (testes, CNS) and nongerminomas (testes, ovary). CONCLUSIONS: The age-incidence patterns observed suggested a common initiation of GCTs in embryonic/fetal life with variable rates of tumor progression as a result of subsequent events that may be site specific. The authors concluded that future genetic studies should consider GCTs from all sites to enable a better understanding of their etiology. PMID- 22252432 TI - Three-dimensional reconstruction of paracentesis approach in transjugular intrahepatic portosystemic shunt. AB - To establish a digital transjugular intrahepatic portosystemic shunt (TIPS) model and provide morphological data for radiological diagnosis and interventional radiology to reduce portal vein pressure, 400 serial sectional images from the internal jugular vein superior margin to the lower edge of the liver were chosen from the Chinese Visible Human dataset. Surface and volume reconstructions were performed using 3D-DOCTOR 3.5 software on an ordinary personal computer. Volume and surface renderings were employed to perform data segmentation and image edge detection for reconstruction of the internal jugular vein, brachiocephalic vein, superior vena cava, heart, inferior vena cava, hepatic vein, and portal vein for computerized 3D reconstruction of the TIPS pathway and construction of a 3D visible model of different structures along it. The model can also display pathway and distribution characteristics and interactively show the spatial structural relationships between intrahepatic venous lines from any position and angle, plus complete data acquisition for any range and angle for 3D reconstruction with stereopsis and measurements using any visualization platform. The digital reconstruction of the TIPS pathway correctly reflected the complicated anatomic structural characteristics and spatial adjacency relationships between intrahepatic venous lines, providing a reference 3D morphology for image diagnostics and interventional TIPS therapy. PMID- 22252433 TI - The peroneus quartus muscle: clinical correlation with evolutionary importance. AB - The peroneus quartus (PQ) is an accessory muscle of the peroneal/lateral compartment of the leg. The muscle has often been implicated as a cause of pain in the lateral ankle region, and subluxation or attrition of the peroneal tendons. The present study was aimed at observing the prevalence and morphology of this muscle in human cadavers. Ninety-two embalmed lower limbs were dissected for this study. The PQ muscle was found in 21% of the limbs. In all these limbs it originated from the lower part of the lateral surface of the fibula, the undersurface of peroneus brevis and the posterior intermuscular septum. In the majority of limbs, insertion was on the retrotrochlear eminence of the calcaneus. Taking into account the possibility of this muscle being a cause of lateral ankle pathology, the present study attempts to correlate the findings with the anatomy of the surrounding region. The frequent occurrence of this muscle in humans is suggestive of a progressive evolutionary change to evert the foot in order to assume a bipedal gait. PMID- 22252434 TI - The impact of age on the physical and cellular properties of the human limbal stem cell niche. AB - The limbal niche in the corneoscleral junction of the eye, habitat of the limbal epithelial stem cells (LESC), facilitates corneal epithelial regeneration by providing physical support and chemical signalling. Anatomical structures within the limbus, namely, limbal epithelial crypts and focal stromal projections, are believed to function as a putative niche for LESCs. In this study, the impact of age on the topography of this niche was investigated. Also, the relationship between niche topography and limbal epithelial cell phenotype was assessed. Ex vivo imaging of the limbus in cadaveric tissue of donors aged from infancy to 90 years was carried out using electron and confocal microscopy. The data suggested that the area occupied by the crypts was sharply reduced after the age of 60 years. The niche microstructures also became smoother with donor age. The phenotypic assessment of cultured limbal epithelial cells harvested from donors of different ages showed that the levels of putative stem cell markers as well as telomerase activity and telomere length remained unchanged, regardless of niche topography. However, the colony forming efficiency of the cultures was significantly reduced with age (p < 0.05). This is the first comprehensive study of the effect of age on the structural and phenotypic characteristics of the human limbal niche. The results have a significant biological value as they suggest a correlation of limbal architecture with decline of re-epithelialisation rate in older patients. Overall, the data also suggest that LESCs harvested from younger donors may be more suitable for cultured LESC therapy production. PMID- 22252435 TI - Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress. AB - Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, gamma-rays or H2O2 as compared to their younger counterparts. In response to gamma-rays and H2O2, the levels of Bcl-2 and both forms of survivin were up-regulated in old cells, but not in their corresponding young ones. This repression of survivin and phospho-survivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer. PMID- 22252436 TI - Limitations to exercise in female centenarians: evidence that muscular efficiency tempers the impact of failing lungs. AB - Centenarians are an outstanding model of successful aging, with genetics and healthy lifestyle certainly being key factors responsible for their longevity. Exercise capacity has been identified to play an important role in healthy aging, but a comprehensive assessment of the limitations to maximal exercise in this population is lacking. Following, health histories, lung function, and anthropometric measures, eight female centenarians (98-102 years old) and eight young females (18-22 years old) performed a series of graded maximal exercise tests on a cycle ergometer that facilitated absolute and relative work rate comparisons. Centenarians revealed a dramatically attenuated lung function, as measured by spirometry (forced expiratory volume in 1 s (FEV1/forced vital capacity (FVC), 55 +/- 10%) compared to the young (FEV1/FVC, 77 +/- 5%). During exercise, although the centenarians relied heavily on respiratory rate which yielded ~50% higher dead space/tidal volume, minute ventilation was similar to that of the young at all but maximal exercise, and alveolar PO2 was maintained in both groups. In contrast, peak WR and VO2 were significantly reduced in the centenarians (33 +/- 4 vs 179 +/- 24 W; 7.5 +/- 1.2 vs 39.6 +/- 3.5 ml min(-1) kg(-1)). Arterial PO2 of the centenarians fell steadily from the normal range of both groups to yield a large A-a gradient (57 +/- 6 mmHg). Metabolic cost of a given absolute work rate was consistently lower, ~46% less than the young at maximal effort. Centenarians have significant limitations to gas exchange across the lungs during exercise, but this limited oxygen transport is tempered by improved skeletal muscle mechanical efficiency that may play a vital role in maintaining physical function and therefore longevity in this population. PMID- 22252438 TI - Non-aggregational aromatic oligoamide macrocycles. AB - Attaching peripheral amide groups to the backbone of cyclic aromatic oligoamides 1 leads to new macrocycles 2 that show drastically changed behavior including modest yields of formation and no tendency to aggregate while maintaining a rigid backbone and a defined, guest-binding internal cavity. PMID- 22252440 TI - Minimally invasive approach for the management of the leaking tracheoesophageal puncture. AB - OBJECTIVES/HYPOTHESIS: An enlarging tracheoesophageal puncture (TEP) site after total laryngectomy is associated with substantial functional, hygienic, and potentially life-threatening problems. The enlarged TEP is challenging to manage. TEP injection (TEP-I) for control of the enlarged puncture site may be beneficial in avoiding surgery. Our study reviewed the clinical outcomes of patients at a single institution with enlarged TEP treated by office-based TEP-I. STUDY DESIGN: Retrospective study. METHODS: Chart review of eight patients who had an enlarged TEP with leakage around the prosthesis treated with TEP-I after attempted customization of voice prostheses. Patient demographics and treatments were reviewed, and injection efficacy was evaluated by the duration of leakage resolution. RESULTS: Eight patients underwent 20 TEP-I procedures. The average duration of leak resolution after each injection was 174.5 days. There were no complications. Six patients required custom modifications of the voice prosthesis to control TEP leakage after TEP-I, and all patients resumed their baseline speech and swallowing function. There was a trend toward an increase in number of injections among patients with N+ disease, disease recurrence, a history of irradiation and secondary TEP. No patients required surgical closure of the TEP. CONCLUSIONS: Office-based TEP-I is a safe and effective treatment option for patients with an enlarged TEP site who have failed more conservative measures. A history of irradiation, disease recurrence, secondary TEP, and high-volume neck disease were predictive of multiple injections. Further study is warranted to accurately identify patients who may benefit from TEP-I to control leakage around the TEP. PMID- 22252437 TI - The role of the T cell in age-related inflammation. AB - Ageing is accompanied by alterations to T-cell immunity and also by a low-grade chronic inflammatory state termed inflammaging. The significance of these phenomena is highlighted by their being predictors of earlier mortality. We have recently published that the proinflammatory cytokine TNFalpha is a strong inducer of CD4(+) T-cell senescence and T-cell differentiation, adding to the growing body of literature implicating proinflammatory molecules in mediating these critical age-related T-cell alterations. Moreover, the inflammatory process is also being increasingly implicated in the pathogenesis of many common and severe age-related diseases, including cancer, cardiovascular diseases and type 2 diabetes. Furthermore, major age-related risk factors for poor health, such as obesity, stress and smoking, are also associated with an upregulation in systemic inflammatory markers. We propose the idea that the ensuing inflammatory response to influenza infection propagates cardiovascular diseases and constitutes a major cause of influenza-related mortality. While inflammation is not a negative phenomenon per se, this age-related dysregulation of inflammatory responses may play crucial roles driving age-related pathologies, T-cell immunosenescence and CMV reactivation, thereby underpinning key features of the ageing process. PMID- 22252439 TI - A long-lived luminescent probe to sensitively detect arylamine N acetyltransferase (NAT) activity of cells. AB - Arylamine N-acetyltransferase (NAT) is an important phase II metabolizing enzyme that influences drug efficacy and adverse effects. Here, we report a long-lived luminescent lanthanide complex as a probe for NAT, employing an intraligand photoinduced electron transfer strategy. The probe shows approximately 100-fold increase of luminescence upon N-acetylation catalyzed by NAT, with relatively high specificity for NAT2 over NAT1. It is the first NAT probe that is suitable for sensitive, homogeneous, and rapid detection of NAT activity of recombinant enzyme or cell lysate, and is expected to be useful for drug discovery and clinical diagnosis. PMID- 22252441 TI - Metabolic profiling reveals growth related FAME productivity and quality of Chlorella sorokiniana with different inoculum sizes. AB - Inoculum size strongly affects cell growth and lipid accumulation of microalgae, one of the most potential biodiesel feedstock, however, the metabolic mechanism(s) of the lipid biosynthesis upon inoculum size has not been fully explored yet. The effects of inoculum size on cell growth, lipid accumulation, and metabolic changes of a green microalga Chlorella sorokiniana were investigated. In our experimental range of inoculum size, the productivity and the cetane number (CN) of fatty acid methyl esters (FAME) increased with increasing initial cell density, and the inoculum of 1 * 10(7) cells mL(-1) processed much higher productivity (up to 2.02-fold) and CN (up to 1.19-fold) of the FAME than the others. A significant correlation between the metabolic profile and quantity and quality of lipid production was revealed by partial least squares to latent structures (PLS) analysis, and 15 key metabolites were identified. Most of those metabolites were involved in the photosynthetically fixed carbon metabolism. Furthermore, light intensity as one of the vital limitation factors for the high inoculum size cultivation was evaluated by illumination assay and the results revealed that increasing light intensity could improve the polyunsaturated fatty acids composition and lipid accumulation of C. sorokiniana. The lipid productivity of the culture was improved by 71.21% with the light intensity of 110 umol m(-2) s(-1), compared to that under the irradiance of 65 umol m(-2) s(-1). PMID- 22252442 TI - Development and mapping of SNP assays in allotetraploid cotton. AB - A narrow germplasm base and a complex allotetraploid genome have made the discovery of single nucleotide polymorphism (SNP) markers difficult in cotton (Gossypium hirsutum). To generate sequence for SNP discovery, we conducted a genome reduction experiment (EcoRI, BafI double digest, followed by adapter ligation, biotin-streptavidin purification, and agarose gel separation) on two accessions of G. hirsutum and two accessions of G. barbadense. From the genome reduction experiment, a total of 2.04 million genomic sequence reads were assembled into contigs with an N(50) of 508 bp and analyzed for SNPs. A previously generated assembly of expressed sequence tags (ESTs) provided an additional source for SNP discovery. Using highly conservative parameters (minimum coverage of 8* at each SNP and 20% minor allele frequency), a total of 11,834 and 1,679 non-genic SNPs were identified between accessions of G. hirsutum and G. barbadense in genome reduction assemblies, respectively. An additional 4,327 genic SNPs were also identified between accessions of G. hirsutum in the EST assembly. KBioscience KASPar assays were designed for a portion of the intra specific G. hirsutum SNPs. From 704 non-genic and 348 genic markers developed, a total of 367 (267 non-genic, 100 genic) mapped in a segregating F(2) population (Acala Maxxa * TX2094) using the Fluidigm EP1 system. A G. hirsutum genetic linkage map of 1,688 cM was constructed based entirely on these new SNP markers. Of the genic-based SNPs, we were able to identify within which genome ('A' or 'D') each SNP resided using diploid species sequence data. Genetic maps generated by these newly identified markers are being used to locate quantitative, economically important regions within the cotton genome. PMID- 22252443 TI - Chemometric modeling and two-dimensional fluorescence analysis of bioprocess with a new strain of Klebsiella pneumoniae to convert residual glycerol into 1,3 propanediol. AB - The goal of this study was to show that the metabolism of Klebsiella pneumoniae under different aeration strategies could be monitored and predicted by the application of chemometric models and fluorescence spectroscopy. Multi-wavelength fluorescence was applied to the on-line monitoring of process parameters for K. pneumoniae cultivations. Differences observed in spectra collected under aerobiosis and anaerobiosis can be explained by the different metabolic states of the cells. To predict process variables such as biomass, glycerol, and 1,3 propanediol (1,3-PD), chemometric models were developed on the basis of the acquired fluorescence spectra, which were measured continuously. Although glycerol and 1,3-PD are not fluorescent compounds, the results showed that this technique could be successfully applied to the on-line monitoring of variables in order to understand the process and thus improve 1,3-PD production. The root mean square errors of predictions were 0.78 units, 10 g/L, and 2.6 g/L for optical density, glycerol, and 1,3-PD, respectively. PMID- 22252444 TI - Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements. AB - Nearly 30% of currently approved recombinant therapeutic proteins are produced in Escherichia coli. Due to its well-characterized genetics, rapid growth and high yield production, E. coli has been a preferred choice and a workhorse for expression of non-glycosylated proteins in the biotech industry. There is a wealth of knowledge and comprehensive tools for E. coli systems, such as expression vectors, production strains, protein folding and fermentation technologies, that are well tailored for industrial applications. Advancement of the systems continues to meet the current industry needs, which are best illustrated by the recent drug approval of E. coli produced antibody fragments and Fc-fusion proteins by the FDA. Even more, recent progress in expression of complex proteins such as full-length aglycosylated antibodies, novel strain engineering, bacterial N-glycosylation and cell-free systems further suggests that complex proteins and humanized glycoproteins may be produced in E. coli in large quantities. This review summarizes the current technology used for commercial production of recombinant therapeutics in E. coli and recent advances that can potentially expand the use of this system toward more sophisticated protein therapeutics. PMID- 22252445 TI - Minimal polyketide pathway expression in an actinorhodin cluster-deleted and regulation-stimulated Streptomyces coelicolor. AB - Along with traditional random mutagenesis-driven strain improvement, cloning and heterologous expression of Streptomyces secondary metabolite gene clusters have become an attractive complementary approach to increase its production titer, of which regulation is typically under tight control via complex multiple regulatory networks present in a metabolite low-producing wild-type strain. In this study, we generated a polyketide non-producing strain by deleting the entire actinorhodin cluster from the chromosome of a previously generated S. coelicolor mutant strain, which was shown to stimulate actinorhodin biosynthesis through deletion of two antibiotic downregulators as well as a polyketide precursor flux downregulator (Kim et al. in Appl Environ Microbiol 77:1872-1877, 2011). Using this engineered S. coelicolor mutant strain as a surrogate host, a model minimal polyketide pathway for aloesaponarin II, an actinorhodin shunt product, was cloned in a high-copy conjugative plasmid, followed by functional pathway expression and quantitative metabolite analysis. Aloesaponarin II production was detected only in the presence of a pathway-specific regulatory gene, actII-ORF4, and its production level was the highest in the actinorhodin cluster-deleted and downregulator-deleted mutant strain, implying that this engineered polyketide pathway-free and regulation-optimized S. coelicolor mutant strain could be used as a general surrogate host for efficient expression of indigenous or foreign polyketide pathways derived from diverse actinomycetes in nature. PMID- 22252447 TI - Diffuse unilateral pediatric arteriopathy: successful treatment with repeated angioplasty. AB - We report a three-year-old girl exhibiting severe long-segment stenoses and occlusions with diffuse arterial involvement of the upper and lower extremities on the right side. The obstructive lesions, which caused atrophy of the right limb and chronic ulceration of the foot, were treated successfully with repeated percutaneous transluminal angioplasty. Obstructive peripheral arterial disease can cause growth retardation of the involved extremity, which can be salvaged by repeated endovascular therapy even in a small growing child. PMID- 22252448 TI - Suprachoroidal electrotransfer: a nonviral gene delivery method to transfect the choroid and the retina without detaching the retina. AB - Photoreceptors and retinal pigment epithelial cells (RPE) targeting remains challenging in ocular gene therapy. Viral gene transfer, the only method having reached clinical evaluation, still raises safety concerns when administered via subretinal injections. We have developed a novel transfection method in the adult rat, called suprachoroidal electrotransfer (ET), combining the administration of nonviral plasmid DNA into the suprachoroidal space with the application of an electrical field. Optimization of injection, electrical parameters and external electrodes geometry using a reporter plasmid, resulted in a large area of transfected tissues. Not only choroidal cells but also RPE, and potentially photoreceptors, were efficiently transduced for at least a month when using a cytomegalovirus (CMV) promoter. No ocular complications were recorded by angiographic, electroretinographic, and histological analyses, demonstrating that under selected conditions the procedure is devoid of side effects on the retina or the vasculature integrity. Moreover, a significant inhibition of laser induced choroidal neovascularization (CNV) was achieved 15 days after transfection of a soluble vascular endothelial growth factor receptor-1 (sFlt-1)-encoding plasmid. This is the first nonviral gene transfer technique that is efficient for RPE targeting without inducing retinal detachment. This novel minimally invasive nonviral gene therapy method may open new prospects for human retinal therapies. PMID- 22252446 TI - Drug design for ever, from hype to hope. AB - In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data. PMID- 22252449 TI - Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. AB - alpha-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently reduced by an average of 80%. Treated animals showed knockdown of Z-AAT in liver and serum with concomitant increased serum M-AAT as determined by allele-specific enzyme-linked immunosorbent assays (ELISAs). In addition, decreased globular accumulation of misfolded Z-AAT in hepatocytes and a reduction in inflammatory infiltrates in the liver was observed. Results from microarray studies demonstrate that endogenous miRNAs were minimally affected by this treatment. These data suggests that miRNA mediated knockdown does not saturate the miRNA pathway as has been seen with viral vector expression of short hairpin RNAs (shRNAs). This safe dual-therapy approach can be applied to other disorders such as amyotrophic lateral sclerosis, Huntington disease, cerebral ataxia, and optic atrophies. PMID- 22252450 TI - Intranasal delivery of HMGB1 siRNA confers target gene knockdown and robust neuroprotection in the postischemic brain. AB - Noninvasive intranasal drug administration has been noted to allow direct delivery of drugs to the brain. In the present study, the therapeutic efficacy of intranasal small interfering RNA (siRNA) delivery was investigated in the postischemic rat brain. Fluorescein isothiocyanate (FITC)-labeled control siRNA was delivered intranasally in normal adult rats using e-PAM-R, a biodegradable PAMAM dendrimer, as gene carrier. Florescence-tagged siRNA was found in the cytoplasm and processes of neurons and of glial cells in many brain regions, including the hypothalamus, amygdala, cerebral cortex, and striatum, in 1 hour after infusion, and the FITC-fluorescence was continuously detected for at least 12 hours. When siRNA for high mobility group box 1 (HMGB1), which functions as an endogenous danger molecule and aggravates inflammation, was delivered intranasally, the target gene was significantly depleted in many brain regions, including the prefrontal cortex and striatum. More importantly, intranasal delivery of HMGB1 siRNA markedly suppressed infarct volume in the postischemic rat brain (maximal reduction to 42.8 +/- 5.6% at 48 hours after 60 minutes middle cerebral artery occlusion (MCAO)) and this protective effect was manifested by recoveries from neurological and behavioral deficits. These results indicate that the intranasal delivery of HMGB1 siRNA offers an efficient means of gene knockdown-mediated therapy in the ischemic brain. PMID- 22252452 TI - Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease. AB - In the gut of patients with Crohn's disease (CD), high Smad7 blocks the immune suppressive activity of transforming growth factor (TGF)-beta1, thereby contributing to amplify inflammatory signals. In vivo in mice, knockdown of Smad7 with a Smad7 antisense oligonucleotide (GED0301) attenuates experimental colitis. Here, we provide results of a phase 1 clinical, open-label, dose-escalation study of GED0301 in patients with active, steroid-dependent/resistant CD, aimed at assessing the safety and tolerability of the drug. Patients were allocated to three treatment groups receiving oral GED0301 once daily for 7 days at doses of 40, 80, or 160 mg. A total of 15 patients were enrolled. No serious adverse event was registered. GED0301 was well tolerated and no patient dropped out during the study. Twenty-five adverse events were documented in 11 patients, the majority of whom were judged to be of mild intensity and unrelated to treatment. GED0301 treatment reduced the percentage of inflammatory cytokine-expressing CCR9 positive T cells in the blood. The study shows for the first time that GED0301 is safe and well tolerated in patients with active CD. PMID- 22252451 TI - Action and reaction: the biological response to siRNA and its delivery vehicles. AB - RNA interference (RNAi)-based therapeutics have significant potential for the treatment of human disease. Safe and effective delivery of RNA to target tissues remains a major barrier to realizing its clinical potential. Several factors can affect the in vivo performance of short interfering RNA (siRNA) delivery formulations, including siRNA sequence, structure, chemical modification, and delivery formulation. This review provides an introduction to the principles underlying the pharmacokinetics and pharmacodynamics of systemically administered siRNA and its delivery formulations, including the factors that lead to its degradation, clearance, and tissue uptake, as well as its potential for immunogenicity, toxicity, and off-target effects within the body. PMID- 22252454 TI - Estimation of linkage disequilibrium in four US pig breeds. AB - BACKGROUND: The success of marker assisted selection depends on the amount of linkage disequilibrium (LD) across the genome. To implement marker assisted selection in the swine breeding industry, information about extent and degree of LD is essential. The objective of this study is to estimate LD in four US breeds of pigs (Duroc, Hampshire, Landrace, and Yorkshire) and subsequently calculate persistence of phase among them using a 60 k SNP panel. In addition, we report LD when using only a fraction of the available markers, to estimate persistence of LD over distance. RESULTS: Average r2 between adjacent SNP across all chromosomes was 0.36 for Landrace, 0.39 for Yorkshire, 0.44 for Hampshire and 0.46 for Duroc. For markers 1 Mb apart, r2 ranged from 0.15 for Landrace to 0.20 for Hampshire. Reducing the marker panel to 10% of its original density, average r2 ranged between 0.20 for Landrace to 0.25 for Duroc. We also estimated persistence of phase as a measure of prediction reliability of markers in one breed by those in another and found that markers less than 10 kb apart could be predicted with a maximal accuracy of 0.92 for Landrace with Yorkshire. CONCLUSIONS: Our estimates of LD, although in good agreement with previous reports, are more comprehensive and based on a larger panel of markers. Our estimates also confirmed earlier findings reporting higher LD in pigs than in American Holstein cattle, especially at increasing marker distances (> 1 Mb). High average LD (r2 > 0.4) between adjacent SNP found in this study is an important precursor for the implementation of marker assisted selection within a livestock species.Results of this study are relevant to the US purebred pig industry and critical for the design of programs of whole genome marker assisted evaluation and selection. In addition, results indicate that a more cost efficient implementation of marker assisted selection using low density panels with genotype imputation, would be feasible for these breeds. PMID- 22252453 TI - Retroviral integrations in gene therapy trials. AB - gamma-Retroviral and lentiviral vectors allow the permanent integration of a therapeutic transgene in target cells and have provided in the last decade a delivery platform for several successful gene therapy (GT) clinical approaches. However, the occurrence of adverse events due to insertional mutagenesis in GT treated patients poses a strong challenge to the scientific community to identify the mechanisms at the basis of vector-driven genotoxicity. Along the last decade, the study of retroviral integration sites became a fundamental tool to monitor vector-host interaction in patients overtime. This review is aimed at critically revising the data derived from insertional profiling, with a particular focus on the evidences collected from GT clinical trials. We discuss the controversies and open issues associated to the interpretation of integration site analysis during patient's follow up, with an update on the latest results derived from the use of high-throughput technologies. Finally, we provide a perspective on the future technical development and on the application of these studies to address broader biological questions, from basic virology to human hematopoiesis. PMID- 22252455 TI - Externally sensitized deprotection of PPG-masked carbonyls as a spatial proximity probe in photoamplified detection of binding events. AB - Externally sensitized electron-transfer fragmentation in dithiane PPG (photoremovable protecting group)-protected carbonyls is adopted for detection and amplification of molecular recognition events. The new methodology allows for detection of as low as 50 attomoles of avidin utilizing an imager based on a low sensitivity mass-produced consumer CCD camera. Numeric modelling is carried out to demonstrate the intrinsic limitations of 2D amplification on surfaces and the advantages of unconstrained amplification in a compartmentalized volume of spatially addressable 3D solutions. PMID- 22252457 TI - Comment on "binding free energies of inhibitors to iron porphyrin complex as a model for cytochrome P450". PMID- 22252456 TI - Genomics of mature and immature olfactory sensory neurons. AB - The continuous replacement of neurons in the olfactory epithelium provides an advantageous model for investigating neuronal differentiation and maturation. By calculating the relative enrichment of every mRNA detected in samples of mature mouse olfactory sensory neurons (OSNs), immature OSNs, and the residual population of neighboring cell types, and then comparing these ratios against the known expression patterns of >300 genes, enrichment criteria that accurately predicted the OSN expression patterns of nearly all genes were determined. We identified 847 immature OSN-specific and 691 mature OSN-specific genes. The control of gene expression by chromatin modification and transcription factors, and neurite growth, protein transport, RNA processing, cholesterol biosynthesis, and apoptosis via death domain receptors, were overrepresented biological processes in immature OSNs. Ion transport (ion channels), presynaptic functions, and cilia-specific processes were overrepresented in mature OSNs. Processes overrepresented among the genes expressed by all OSNs were protein and ion transport, ER overload response, protein catabolism, and the electron transport chain. To more accurately represent gradations in mRNA abundance and identify all genes expressed in each cell type, classification methods were used to produce probabilities of expression in each cell type for every gene. These probabilities, which identified 9,300 genes expressed in OSNs, were 96% accurate at identifying genes expressed in OSNs and 86% accurate at discriminating genes specific to mature and immature OSNs. This OSN gene database not only predicts the genes responsible for the major biological processes active in OSNs, but also identifies thousands of never before studied genes that support OSN phenotypes. PMID- 22252459 TI - The challenge of evaluating health effects of organic food; operationalisation of a dynamic concept of health. AB - The health benefits of consuming organically produced foods compared with conventional foods are unclear. Important obstacles to drawing clear conclusions in this field of research are (1) the lack of a clear operational definition of health and (2) the inability to distinguish between different levels of health using valid biomarkers. In this paper, some shortcomings of the current definition of health are outlined and the relevance of integrating a more dynamic and functional component is emphasised, which is reflected by the ability to adapt. The state of health could then be determined by challenging an individual with some form of stressor and by subsequent quantification and evaluation of the coherence in recovery of various physiological processes and parameters. A set of relevant parameters includes the activity of the immune system and the activity of the autonomous nervous system. A good recovery towards homeostasis is suggested to reflect a qualitatively good state of health. Furthermore, it would enable objective evaluation of health-optimising strategies, including the consumption of organically produced foods that aim to strengthen health. PMID- 22252460 TI - A multifunctional pipette. AB - Microfluidics has emerged as a powerful laboratory toolbox for biologists, allowing manipulation and analysis of processes at a cellular and sub-cellular level, through utilization of microfabricated features at size-scales relevant to that of a single cell. In the majority of microfluidic devices, sample processing and analysis occur within closed microchannels, imposing restrictions on sample preparation and use. We present an optimized non-contact open-volume microfluidic tool to overcome these and other restrictions, through the use of a hydrodynamically confined microflow pipette, serving as a multifunctional solution handling and dispensing tool. The geometries of the tool have been optimised for use in optical microscopy, with integrated solution reservoirs to reduce reagent use, contamination risks and cleaning requirements. Device performance was characterised using both epifluorescence and total internal reflection fluorescence (TIRF) microscopy, resulting in ~200 ms and ~130 ms exchange times at ~100 nm and ~30 MUm distances to the surface respectively. PMID- 22252461 TI - Vascular tortuosity: a mathematical modeling perspective. AB - Although vascular tortuosity is a ubiquitous phenomenon, almost no mathematical models exist to describe its shape. Given that the shape of tortuous vessel curves seems fairly uniform across orders of magnitude of vessel size and across vast differences in anatomic substrata, it is hypothesized that the shape of tortuosity is not purely random but rather is governed by physical principles. We present a mathematical model of tortuosity based on optimality principles, and show how this model can potentially be used to distinguish physiologic tortuosity from abnormal tortuosity which may exist in disease states. Using the calculus of variations, a model of tortuosity has been developed which minimizes average curvature per unit length. The model is tested against curves in normal vessels and in diseased vessels in a case of Fabry's disease. It is found that the theoretical model provides a good fit for normal vessel tortuosity. This suggests that blood vessels obey optimality principles, and curve in such a way as to minimize average curvature. The model may also be able to distinguish physiologic tortuosity from abnormal tortuosity found in disease states. PMID- 22252462 TI - Cancer burden in Africa and opportunities for prevention. AB - Cancer is an emerging public health problem in Africa. About 715,000 new cancer cases and 542,000 cancer deaths occurred in 2008 on the continent, with these numbers expected to double in the next 20 years simply because of the aging and growth of the population. Furthermore, cancers such as lung, female breast, and prostate cancers are diagnosed at much higher frequencies than in the past because of changes in lifestyle factors and detection practices associated with urbanization and economic development. Breast cancer in women and prostate cancer in men have now become the most commonly diagnosed cancers in many Sub-Saharan African countries, replacing cervical and liver cancers. In most African countries, cancer control programs and the provision of early detection and treatment services are limited despite this increasing burden. This paper reviews the current patterns of cancer in Africa and the opportunities for reducing the burden through the application of resource level interventions, including implementation of vaccinations for liver and cervical cancers, tobacco control policies for smoking-related cancers, and low-tech early detection methods for cervical cancer, as well as pain relief at the palliative stage of cancer. PMID- 22252464 TI - The oncology of otology. AB - OBJECTIVES/HYPOTHESIS: To describe the population of patients with malignancy affecting the ear canal and temporal bone. STUDY DESIGN: Retrospective review. METHODS: The charts of 157 patients with temporal bone cancer were reviewed for clinical outcomes. RESULTS: Between 1999 and 2009, 157 patients underwent temporal bone surgery for cancer involving the ear canal (n = 25), external ear with ear canal involvement (n = 26), periauricular skin (n = 40), parotid gland (n = 40), temporal bone (n = 13), and lateral skull base (n = 13). All surgeries involved one or more otologic approaches: mastoidectomy (28.0%), lateral temporal bone resection (TBR) (59.2%), subtotal TBR (2.5%), total TBR (3.2%), transtemporal approach (TTA) to the jugular foramen (8.2%), TTA to the middle fossa (5.7%), and TTA to the infratemporal fossa (3.2%). Cancers of the cartilaginous ear canal were managed with wide local excision of canal skin and cartilage in nine patients (5.7%). A combination of approaches was performed in 32 patients (20.4%). The 5-year overall survival rate was 58.0%. Patients whose disease was limited to the ear canal had significantly better overall survival than did patients who had skull base primaries (P = .02989), periauricular skin cancer (P = .00138), or temporal bone tumors (P = .02598). Patients with parotid tumors also had better overall survival than did those with periauricular skin tumors (P = .02357). CONCLUSIONS: Otologic surgery plays an important role in managing cancers that involve the ear canal, temporal bone, or lateral skull base. The specialty of otologic oncology is emerging as a defined area of practice. PMID- 22252465 TI - Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis. AB - Alemtuzumab is an anti-CD52 monoclonal antibody with remarkable efficacy in relapsing multiple sclerosis (MS). In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia as IV. Oncology guidelines recommend alemtuzumab subcutaneous (SC) over IV. There is no report of alemtuzumab SC in MS. We report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events. SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events. PMID- 22252463 TI - Reduced DICER1 elicits an interferon response in endometrial cancer cells. AB - DICER1 is essential for the generation of mature miRNAs and other short noncoding RNAs. Several lines of investigation implicate DICER1 as a tumor suppressor. Reduced DICER1 levels and changes in miRNA abundance have been associated with aggressive tumor phenotypes. The global effects of reduced DICER1 on mRNA transcript abundance in tumor cells remain largely unknown. We used short hairpin RNA to stably knock down DICER1 in endometrial cancer cell lines to begin to determine how reduced DICER1 activity contributes to tumor phenotypes. DICER1 knockdown did not affect cell proliferation but caused enhanced cell migration and growth in soft agar. miRNA and mRNA profiling in KLE cells revealed overall decreases in miRNA levels and changes in the relative abundance of many mRNAs. One of the most striking changes in mRNA levels was the upregulation of IFN stimulated genes (ISG), the majority of which lack known miRNA target sequences. IFNbeta, a key upstream regulator of the IFN response, was significantly increased in DICER1 knockdowns in the AN3CA, Ishikawa, and KLE endometrial cancer cell lines and in the normal endometrial cell line EM-E6/E7/TERT. IFNbeta secreted in media from KLE and EM-E6/E7/TERT shDcr cells was sufficient to activate an IFN response in HT29 cells. The reduced miRNA processing in DICER1 knockdowns was associated with increases in pre-miRNAs in the cytoplasm. Our findings suggest that elevated pre-miRNA levels trigger the IFN response to double-stranded RNA. We thus report a novel effect of reduced DICER1 function in cancer cells. PMID- 22252466 TI - No proinflammatory signature in CD34+ hematopoietic progenitor cells in multiple sclerosis patients. AB - Autologous hematopoietic stem cell transplantation (aHSCT) has been used as a therapeutic approach in multiple sclerosis (MS). However, it is still unclear if the immune system that emerges from autologous CD34+ hematopoietic progenitor cells (HPC) of MS patients is pre-conditioned to re-develop the proinflammatory phenotype. The objective of this article is to compare the whole genome gene and microRNA expression signature in CD34+ HPC of MS patients and healthy donors (HD). CD34+ HPC were isolated from peripheral blood of eight MS patients and five HD and analyzed by whole genome gene expression and microRNA expression microarray. Among the differentially expressed genes (DEGs) only TNNT1 reached statistical significance (logFC=3.1, p<0.01). The microRNA expression was not significantly different between MS patients and HD. We did not find significant alterations of gene expression or microRNA profiles in CD34+ HPCs of MS patients. Our results support the use of aHSCT for treatment of MS. PMID- 22252467 TI - Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis. AB - BACKGROUND: The complex pathogenesis of multiple sclerosis, combined with an unpredictable prognosis, requires identification of disease-specific diagnostic and prognostic biomarkers. OBJECTIVE: To determine whether inflammatory proteins, such as neurofilament light chain, myelin oligodendrocyte glycoprotein and myelin basic protein, and neurodegenerative proteins, such as tau and glial fibrillary acidic protein, can serve as biomarkers for predicting the clinical subtype and prognosis of MS. METHODS: Cerebrospinal fluid and serum samples were collected from patients with a diagnosis of clinically isolated syndrome (n = 46), relapsing-remitting MS (n = 67) or primary-progressive MS (n = 22) along with controls having other non-inflammatory neurological disease (n = 22). Western blot analyses were performed for the listed proteins. Protein levels were compared among different clinical subtypes using one-way analysis of variance analysis. The k-nearest neighbour algorithm was further used to assess the predictive use of these proteins for clinical subtype classification. RESULTS: The results showed that each of tau, GFAP, MOG and NFL protein concentrations differed significantly (p < 0.001) in multiple sclerosis clinical subtypes compared with the controls. Levels of the proteins also differed between the multiple sclerosis clinical subtypes, which may be associated with the underlying disease process. Classification studies revealed that these proteins might be useful for identifying multiple sclerosis clinical subtypes. CONCLUSIONS: We showed that select biomarkers may have potential in identifying multiple sclerosis clinical subtypes. We also showed that the predictive value of the prognosis increased when using a combination of the proteins versus using them individually. PMID- 22252468 TI - P4 activation by group 3 metal arene complexes. AB - The direct P(4) activation using group 3 metal complexes was achieved for the first time under mild conditions. Two P(n)-containing products, P(8)(4-) and P(7)(3-), were isolated and characterized for scandium; however, P(7)(3-) was the sole product for yttrium. PMID- 22252469 TI - Fabrication of nanofibers through a unique morphological transformation of poly(lactic acid) particles in water. AB - Poly(lactic acid) (PLA) particles dispersed in water were transformed into nanofibers by simply heating above the glass transition temperatures of the hydrated PLAs. PMID- 22252470 TI - Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. AB - AIMS/HYPOTHESIS: We sought to evaluate if the cellular localisation and molecular species of diacylglycerol (DAG) were related to insulin sensitivity in human skeletal muscle. METHODS: Healthy sedentary obese controls (Ob; n = 6; mean+/-SEM age 39.5 +/- 2.3 years; mean +/- SEM BMI 33.3 +/- 1.4 kg/m(2)), individuals with type 2 diabetes (T2D; n = 6; age 44 +/- 1.8 years; BMI 30.1 +/- 2.3 kg/m(2)), and lean endurance-trained athletes (Ath; n = 10; age 35.4 +/- 3.1 years; BMI 23.3 +/ 0.8 kg/m(2)) were studied. Insulin sensitivity was determined using an IVGTT. Muscle biopsy specimens were taken after an overnight fast, fractionated using ultracentrifugation, and DAG species measured using liquid chromatography/MS/MS. RESULTS: Total muscle DAG concentration was higher in the Ob (mean +/- SEM 13.3 +/- 1.0 pmol/MUg protein) and T2D (15.2 +/- 1.0 pmol/MUg protein) groups than the Ath group (10.0 +/- 0.78 pmol/MUg protein, p = 0.002). The majority (76-86%) DAG was localised in the membrane fraction for all groups, but was lowest in the Ath group (Ob, 86.2 +/- 0.98%; T2D, 84.2 +/- 1.2%; Ath, 75.9 +/- 2.7%; p = 0.008). There were no differences in cytoplasmic DAG species (p > 0.12). Membrane DAG species C18:0/C20:4, Di-C16:0 and Di-C18:0 were significantly more abundant in the T2D group. Cytosolic DAG species were negatively related to activation of protein kinase C (PKC)epsilon but not PKCtheta, whereas membrane DAG species were positively related to activation of PKCepsilon, but not PKCtheta. Only total membrane DAG (r = -0.624, p = 0.003) and Di-C18:0 (r = -0.595, p = 0.004) correlated with insulin sensitivity. Disaturated DAG species were significantly lower in the Ath group (p = 0.001), and significantly related to insulin sensitivity (r = -0.642, p = 0.002). CONCLUSIONS/INTERPRETATION: These data indicate that both cellular localisation and composition of DAG influence the relationship to insulin sensitivity. Our results suggest that only saturated DAG in skeletal muscle membranes are related to insulin resistance in humans. PMID- 22252471 TI - Mice expressing a human K(ATP) channel mutation have altered channel ATP sensitivity but no cardiac abnormalities. AB - AIMS/HYPOTHESIS: Patients with severe gain-of-function mutations in the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, have neonatal diabetes, muscle hypotonia and mental and motor developmental delay-a condition known as iDEND syndrome. However, despite the fact that Kir6.2 forms the pore of the cardiac K(ATP) channel, patients show no obvious cardiac symptoms. The aim of this project was to use a mouse model of iDEND syndrome to determine whether iDEND mutations affect cardiac function and cardiac K(ATP) channel ATP sensitivity. METHODS: We performed patch-clamp and in vivo cine-MRI studies on mice in which the most common iDEND mutation (Kir6.2-V59M) was targeted to cardiac muscle using Cre-lox technology (m-V59M mice). RESULTS: Patch-clamp studies of isolated cardiac myocytes revealed a markedly reduced K(ATP) channel sensitivity to MgATP inhibition in m-V59M mice (IC(50) 62 MUmol/l compared with 13 MUmol/l for littermate controls). In vivo cine-MRI revealed there were no gross morphological differences and no differences in heart rate, end diastolic volume, end systolic volume, stroke volume, ejection fraction, cardiac output or wall thickening between m-V59M and control hearts, either under resting conditions or under dobutamine stress. CONCLUSIONS/INTERPRETATION: The common iDEND mutation Kir6.2-V59M decreases ATP block of cardiac K(ATP) channels but was without obvious effect on heart function, suggesting that metabolic changes fail to open the mutated channel to an extent that affects function (at least in the absence of ischaemia). This may have implications for the choice of sulfonylurea used to treat neonatal diabetes. PMID- 22252472 TI - Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling. AB - AIMS/HYPOTHESIS: Knowledge of number, size and content of insulin secretory granules is pivotal for understanding the physiology of pancreatic beta cells. Here we re-evaluated key structural features of rat beta cells, including insulin granule size, number and distribution as well as cell size. METHODS: Electron micrographs of rat beta cells fixed either chemically or by high-pressure freezing were compared using a high-content analysis approach. These data were used to develop three-dimensional in silico beta cell models, the slicing of which would reproduce the experimental datasets. RESULTS: As previously reported, chemically fixed insulin secretory granules appeared as hollow spheres with a mean diameter of ~350 nm. Remarkably, most granules fixed by high-pressure freezing lacked the characteristic halo between the dense core and the limiting membrane and were smaller than their chemically fixed counterparts. Based on our analyses, we conclude that the mean diameter of rat insulin secretory granules is 243 nm, corresponding to a surface area of 0.19 MUm(2). Rat beta cells have a mean volume of 763 MUm(3) and contain 5,000-6,000 granules. CONCLUSIONS/INTERPRETATION: A major reason for the lower mean granule number/rat beta cell relative to previous accounts is a reduced estimation of the mean beta cell volume. These findings imply that each granule contains about twofold more insulin, while its exocytosis increases membrane capacitance about twofold less than assumed previously. Our integrated approach defines new standards for quantitative image analysis of beta cells and could be applied to other cellular systems. PMID- 22252473 TI - Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes. AB - AIMS/HYPOTHESIS: The aim of this study was to use lipidomics to determine if the lipid composition of apolipoprotein-B-containing lipoproteins is modified by dyslipidaemia in type 2 diabetes and if any of the identified changes potentially have biological relevance in the pathophysiology of type 2 diabetes. METHODS: VLDL and LDL from normolipidaemic and dyslipidaemic type 2 diabetic women and controls were isolated and quantified with HPLC and mass spectrometry. A detailed molecular characterisation of VLDL triacylglycerols (TAG) was also performed using the novel ozone-induced dissociation method, which allowed us to distinguish vaccenic acid (C18:1 n-7) from oleic acid (C18:1 n-9) in specific TAG species. RESULTS: Lipid class composition was very similar in VLDL and LDL from normolipidaemic type 2 diabetic and control participants. By contrast, dyslipidaemia was associated with significant changes in both lipid classes (e.g. increased diacylglycerols) and lipid species (e.g. increased C16:1 and C20:3 in phosphatidylcholine and cholesteryl ester and increased C16:0 [palmitic acid] and vaccenic acid in TAG). Levels of palmitic acid in VLDL and LDL TAG correlated with insulin resistance, and VLDL TAG enriched in palmitic acid promoted increased secretion of proinflammatory mediators from human smooth muscle cells. CONCLUSIONS: We showed that dyslipidaemia is associated with major changes in both lipid class and lipid species composition in VLDL and LDL from women with type 2 diabetes. In addition, we identified specific molecular lipid species that both correlate with clinical variables and are proinflammatory. Our study thus shows the potential of advanced lipidomic methods to further understand the pathophysiology of type 2 diabetes. PMID- 22252475 TI - Do safer sex self-efficacy, attitudes toward condoms, and HIV transmission risk beliefs differ among men who have sex with men, heterosexual men, and women living with HIV? AB - To understand sexual decision-making processes among people living with HIV, we compared safer sex self-efficacy, condom attitudes, sexual beliefs, and rates of unprotected anal or vaginal intercourse with at-risk partners (UAVI-AR) in the past 3 months among 476 people living with HIV: 185 men who have sex with men (MSM), 130 heterosexual men, and 161 heterosexual women. Participants were enrolled in SafeTalk, a randomized, controlled trial of a safer sex intervention. We found 15% of MSM, 9% of heterosexual men, and 12% of heterosexual women engaged in UAVI-AR. Groups did not differ in self-efficacy or sexual attitudes/beliefs. However, the associations between these variables and UAVI-AR varied within groups: greater self-efficacy predicted less UAVI-AR for MSM and women, whereas more positive condom attitudes--but not self-efficacy--predicted less UAVI-AR for heterosexual men. These results suggest HIV prevention programs should tailor materials to different subgroups. PMID- 22252476 TI - A commentary on the role of sexually explicit media (SEM) in the transmission and prevention of HIV among men who have sex with men (MSM). AB - Although research has been conducted over the last half century to test the hypothesis that pornography, or sexually explicit media (SEM), influences behavior, information regarding usage and its effect on men who have sex with men (MSM) is limited. It is important for researchers studying online risk factors for HIV to consider the relationship between SEM consumption and risky sexual behavior, particularly given the exponential increase in SEM exposure as a result of the near-compulsory use of the Internet. In this commentary, we review findings regarding this relationship from studies of international and heterosexual populations. We then suggest future directions for research regarding MSM in the United States and practical applications of such research if the results from other populations extend to them. Research suggests there might be ways to use SEM to create innovative approaches to online HIV prevention, particularly among such at-risk populations as youth and MSM of lower socio economic statuses. PMID- 22252477 TI - Engineering novel Lec1 glycosylation mutants in CHO-DUKX cells: molecular insights and effector modulation of N-acetylglucosaminyltransferase I. AB - Many secreted or cell surface proteins are post-translationally modified by carbohydrate chains which are a primary source of heterogeneity. The Lec1 mutant, which is defective in Golgi N-acetylglucosaminyltransferase I (GnTI) activity, produces relatively homogeneous Man(5) GlcNAc(2) glycan modifications, and is widely used for various applications. To facilitate the investigation of GnTI, its Man5 glycan endproduct, and the impact of Man5 on effector function, the present study has established several novel Lec1 mutants in dhfr(-) CHO-DUKX cells through chemical mutagenesis and lectin selection. A total of nine clonal lines exhibiting the Lec1-phenotype are characterized, six of which harbor non sense mutations leading to a truncated GnTI, and three (R415K, D291N, and P138L) of which are novel loss-of-function sense mutations. Analysis of the rabbit GnTI structure (Unligil et al., 2000) indicates that D291 is the proposed catalytic base and R415 is a crucial residue in forming the substrate binding pocket, whereas P138 is key to maintaining two beta strands in proximity to the substrate binding pocket. Computational modeling reveals that the oligomannose glycan backbone of a glycoprotein (the acceptor substrate) fits nicely into the unoccupied channel of the substrate binding pocket partly through hydrogen bonding with R415 and D291. This finding is consistent with the ordered sequential Bi Bi kinetic mechanism suggested for GnTI, in which binding of UDP GlcNAc (the donor substrate)/Mn(2+) induces conformational changes that promote acceptor binding. When an anti-human CD20 antibody protein is stably expressed in one CHO-DUKX-Lec1 line, it is confirmed that N-glycans are predominantly Man(5) GlcNAc(2) and they do not contain an alpha1,6-fucose linked to the innermost GlcNAc. Furthermore, this Man(5) GlcNAc(2) modified antibody exhibits a significantly increased ADCC activity than the wild-type protein, while displaying a lower CDC activity. The data support the hypothesis that modulating GnTI activity can influence antibody effector functions for proteins with an IgG1 immunoglobulin Fc domain. PMID- 22252478 TI - The relationship between arterial stiffness and increase in blood pressure during exercise in normotensive persons. AB - BACKGROUND: Arterial stiffness is increased in hypertension, even at an earlier stage. The blood pressure (BP) response to exercise reflects the future risk of developing hypertension. We investigated the relationship between the pulse wave velocity (PWV) and the BP response to exercise to evaluate whether arterial stiffness is increased in normotensive persons with higher exercise BPs. METHODS: The participants of the study were adults with normal BP (SBP < 120 mmHg and DBP < 80 mmHg) without history of clinical cardiovascular diseases, who had undergone health screening. Treadmill exercise tests were done by modified Bruce protocol, and brachial-ankle PWV (baPWV) was measured. RESULTS: The participants were 2156 men and women (69 : 31%) with mean age of 52 +/- 5 years. The baPWV correlated significantly to variables such as age, sex, baseline SBP and DBP, pulse pressure, maximal oxygen consumption (VO(2max)), SBP at stage 1, at stage 2 and peak exercise and hemoglobin A1c (HbA1c). In multiple regression model, SBP at stage 1 had a significant association with baPWV after an adjustment with age, sex, VO(2max) and SBP at rest, current smoking and HbA1c. For every 10 mmHg increase in exercise SBP, baPWV increased by 18 +/- 0.3 cm/s (P < 0.001). CONCLUSION: In normotensive individuals, increased arterial stiffness, as reflected by baPWV, is accompanied by higher SBP at the early stage of treadmill exercise test. This finding suggests that arterial stiffening processes are present even in the normotensive setting and are correlated with BP changes during exercise. PMID- 22252479 TI - Compensatory remodeling of coronary microvasculature maintains shear stress in porcine left-ventricular hypertrophy. AB - BACKGROUND: Hypertension-induced left-ventricular hypertrophy (LVH) is generally accompanied with coronary neovascularization. The extent of vascular growth or rarefaction depends on many factors (e.g. age, duration of hypertension, degree of hypertrophy). Here, we hypothesize that there is a compensatory vascular growth that maintains uniform wall shear stress (WSS) in perfusion arterioles (diameters of 8-60 MUm) in LVH of young porcine. METHOD: To test this hypothesis, we investigated LVH in young porcine after 5 weeks of supravalvular aortic stenosis (3 months of age). The morphometry (diameters, lengths, number and connectivity of vessels) of the entire left circumflex (LCx) arterial tree was determined and a hemodynamic network analysis was used to calculate the distribution of pressure, flow and WSS throughout the tree in the control and LVH groups. RESULTS: It was found that the number of vessels and the weight of left ventricle (LV) in hypertrophy increased 1.5 and 1.2 times, respectively, and the length of the LCx main trunk increased by 3 cm (36% increase), as compared with those in control group. There were similar myocardial blood flows of 0.87 +/- 0.24 and 0.94 +/- 0.38 ml/min per g in control and LVH hearts, respectively. The compensatory remodeling in early LVH restores WSS in the smaller perfusion arterioles, but not in the larger epicardial branches. CONCLUSION: The present findings quantify the structural and functional remodeling in the entire LCx arterial tree in response to LVH, which reflect heterogeneity in vascular morphometry and hemodynamics from small to large vessels. These conclusions enhance our understanding of compensatory vascular remodeling in LVH of pediatric heart. PMID- 22252480 TI - Relationship between blood pressure, cholesterolemia and serum apolipoprotein B in a large population sample: the Brisighella Heart Study. AB - OBJECTIVE: The objective is to evaluate the relationship between cholesterolemia, serum apolipoprotein B (apoB) level and blood pressure in a large sample of general population. METHODS: The Brisighella Heart Study (BHS) is a prospective, population-based longitudinal epidemiological investigation. For this study, we analysed the data sampled in the 2008 BHS population survey, excluding those participants treated with antihypertensive and/or lipid lowering drugs (N: 2473). RESULTS: In a sex, BMI, smoking habit, physical activity level and serum creatinine adjusted model, low-density lipoprotein-cholesterol (LDL-C) appears to be significantly related to SBP (P < 0.001), DBP (P = 0.026), and pulse pressure (PP) (P < 0.001). In individuals aged less than 52 years, LDL-C was significantly associated to SBP and DBP (P < 0.001), but not PP. In the same model, apoB appears to be mildly but significantly related to SBP (P < 0.001), DBP (P < 0.001), and PP (P < 0.001). In individuals aged less than 52 years, apoB was significantly associated to SBP (P < 0.001), DBP (P < 0.001), and PP (P < 0.001). In individuals aged 52 or more, nor LDL-C neither apoB were significantly associated to blood pressure. Including in the same model LDL-C and apoB, apoB excluded the predicting role of LDL-C as it regards the blood pressure either in the whole population sample and in the younger individuals. CONCLUSION: On the basis of our observation, either serum LDL-C and apoB are significantly related to the blood pressure level in a large sample of individuals untreated with antihypertensive and lipid-lowering drugs. This association is stronger in younger individuals than in elderly. ApoB seems to be a stronger predictor of either SBP, DBP and PP than LDL-C. PMID- 22252481 TI - Renal sympathetic activation from long-term low-dose angiotensin II infusion in rabbits. AB - OBJECTIVE: Activation of renal sympathetic nerve activity (RSNA) has not been observed during long-term infusion of angiotensin II (AngII) which results in marked hypertension, despite activation of hypothalamic autonomic regions. We examined whether the function of central pathways influencing sympathetic activity is altered in conscious rabbits given a low dose of AngII that produces a modest hypertension and, therefore, limited secondary complications. METHODS: Rabbits received AngII (20-30 ng/kg per min, subcutaneously) or sham treatment for 3 months at which time they were implanted with a renal sympathetic nerve electrode and the responses to airjet stress, baroreflexes and hypoxia were examined. RESULTS: AngII infusion for 3 months increased mean arterial pressure by 16% and RSNA by 43%. Increases in RSNA during airjet stress and hypoxia (10% O2) were 35 and 65% greater in AngII-treated rabbits than sham controls, respectively. Tachycardic responses were also enhanced. Baroreflexes were shifted to the right and upward in the AngII animals but baroreflex gain was similar in the two groups, indicating near complete resetting. Greater neuronal Fos-related antigen immunoreactivity was found in the vascular organ of the lamina terminalis, paraventricular and supraoptic hypothalamic nuclei in AngII-treated rabbits compared with sham. CONCLUSION: Our results suggest that low-dose AngII treatment results in marked sympathetic activation at rest and during stress and hypoxia, due to activation of specific hypothalamic pathways. These mechanisms may contribute to sympathetic activation in conditions associated with chronic activation of the renin-angiotensin system such as obesity or renovascular disease. PMID- 22252482 TI - Blood pressure and medication changes following adrenalectomy for unilateral primary aldosteronism: a follow-up study. AB - OBJECTIVE: Adrenalectomy for unilateral primary aldosteronism cures hypertension in less than 50% of patients, but improvement is observed in most of the remaining ones. Our goal was to quantify the blood pressure (BP) decrease adjusted for medication changes following adrenalectomy and to identify preoperative predictors of this outcome. METHODS: We analyzed simultaneous changes in BP and medication by reviewing the records of 156 consecutive patients who had undergone adrenalectomy for unilateral primary aldosteronism in one center between 2001 and 2009 for whom postoperative follow-up data were available. RESULTS: Median [interquartile range] baseline SBP was 149 [135-160] mmHg on drugs from two [1-3] different classes. After adrenalectomy, SBP decreased by 21 [5-31] mmHg and the number of drug classes administered, by one [0-2]. The decrease in SBP, adjusted for the change in the number of drug classes, was 26 [14-36] mmHg. Each drug class dropped after surgery was equivalent to a 5 mmHg SBP decrease. Patients with higher preoperative BP or serum sodium levels experienced a greater BP decrease after adrenalectomy. Adrenalectomy cured hypertension in 68 (44%) patients. Hypertension was less likely to be cured in patients with a longer history of hypertension, higher preoperative BP levels, larger number of drug classes, or lower urinary aldosterone levels. CONCLUSION: Although patients with severe hypertension are likely to derive considerable benefits from adrenalectomy in terms of BP or treatment reduction, they should be warned that hypertension cure is unlikely. PMID- 22252483 TI - A procedure to validate and correct the 13C chemical shift calibration of RNA datasets. AB - Chemical shifts reflect the structural environment of a certain nucleus and can be used to extract structural and dynamic information. Proper calibration is indispensable to extract such information from chemical shifts. Whereas a variety of procedures exist to verify the chemical shift calibration for proteins, no such procedure is available for RNAs to date. We present here a procedure to analyze and correct the calibration of (13)C NMR data of RNAs. Our procedure uses five (13)C chemical shifts as a reference, each of them found in a narrow shift range in most datasets deposited in the Biological Magnetic Resonance Bank. In 49 datasets we could evaluate the (13)C calibration and detect errors or inconsistencies in RNA (13)C chemical shifts based on these chemical shift reference values. More than half of the datasets (27 out of those 49) were found to be improperly referenced or contained inconsistencies. This large inconsistency rate possibly explains that no clear structure-(13)C chemical shift relationship has emerged for RNA so far. We were able to recalibrate or correct 17 datasets resulting in 39 usable (13)C datasets. 6 new datasets from our lab were used to verify our method increasing the database to 45 usable datasets. We can now search for structure-chemical shift relationships with this improved list of (13)C chemical shift data. This is demonstrated by a clear relationship between ribose (13)C shifts and the sugar pucker, which can be used to predict a C2'- or C3'-endo conformation of the ribose with high accuracy. The improved quality of the chemical shift data allows statistical analysis with the potential to facilitate assignment procedures, and the extraction of restraints for structure calculations of RNA. PMID- 22252484 TI - Combinatorial triple-selective labeling as a tool to assist membrane protein backbone resonance assignment. AB - Obtaining NMR assignments for slowly tumbling molecules such as detergent solubilized membrane proteins is often compromised by low sensitivity as well as spectral overlap. Both problems can be addressed by amino-acid specific isotope labeling in conjunction with (15)N-(1)H correlation experiments. In this work an extended combinatorial selective in vitro labeling scheme is proposed that seeks to reduce the number of samples required for assignment. Including three different species of amino acids in each sample, (15)N, 1-(13)C, and fully (13)C/(15)N labeled, permits identification of more amino acid types and sequential pairs than would be possible with previously published combinatorial methods. The new protocol involves recording of up to five 2D triple-resonance experiments to distinguish the various isotopomeric dipeptide species. The pattern of backbone NH cross peaks in this series of spectra adds a new dimension to the combinatorial grid, which otherwise mostly relies on comparison of [(15)N, (1)H]-HSQC and possibly 2D HN(CO) spectra of samples with different labeled amino acid compositions. Application to two alpha-helical membrane proteins shows that using no more than three samples information can be accumulated such that backbone assignments can be completed solely based on 3D HNCA/HN(CO)CA experiments. Alternatively, in the case of severe signal overlap in certain regions of the standard suite of triple-resonance spectra acquired on uniformly labeled protein, or missing signals due to a lack of efficiency of 3D experiments, the remaining gaps can be filled. PMID- 22252485 TI - Temporal and spatial expression of high-mobility group box 1 in surgically injured rat vocal folds. AB - OBJECTIVES/HYPOTHESIS: High-mobility group box 1 (HMGB1) protein has been identified as a principal instigator of injury-induced inflammation in many organ systems. Physiologically, HMGB1 binds to chromatin in cell nucleus. Upon injury, cells release HMGB1 to extracellular milieu, triggering a destructive inflammatory response. Neutralizing or removing HMGB1 has been shown to control inflammation. Unfortunately, the role of HMGB1 in laryngeal inflammation and healing has yet to be defined. The purpose of this study was to determine spatial and temporal patterns of HMGB1 expression in surgically injured rat vocal folds up to 2 weeks after injury. STUDY DESIGN: Prospective animal study. METHODS: Bilateral vocal fold injury was performed on 70 Sprague-Dawley rats. An additional 14 rats served as uninjured controls. Animals were sacrificed at 1 day, 3 days, 5 days, 1 week, and 2 weeks following surgery. Immunohistochemistry staining and enzyme-linked immunosorbent assay (ELISA) were performed to determine the spatial distribution and temporal expression, respectively, of HMGB1 in vocal fold tissue. Hematoxylin-and-eosin staining for cell counting was performed to evaluate cell infiltration. RESULTS: Cell number peaked significantly 5 days after injury. HMGB1 was positively stained in the nuclear, cytoplasmic, and extracellular compartments from days 1 to 7 after injury, whereas a strict nuclear staining was observed in uninjured controls and week 2 animals. Staining results were corroborated by ELISA. CONCLUSIONS: Spatial and temporal changes of HMGB1 expression were shown in injured vocal fold tissue, indicating this protein may be one of the principal drivers of inflammation and healing response to surgical injury in the larynx. PMID- 22252486 TI - Hox collinearity - a new perspective. AB - Hox collinearity is a spectacular phenomenon that has excited life scientists since its discovery in 1978. Two mechanisms have been proposed to explain the spatially sequential pattern of Hox gene expression in animal embryonic development: interactions among Hox genes, or the progressive opening of chromatin in the Hox clusters, from 3' to 5'. A review of the evidence across different species and developmental stages points to the universal involvement of trans-acting factors and cell-cell interactions. The evidence focuses attention on interactions between Hox genes and on the vertebrate somitogenesis clock. These novel conclusions open new perspectives for the field. PMID- 22252487 TI - A possible role of Reproductive Homeobox 6 in primordial germ cell differentiation. AB - Rhox6 is one of the Reproductive Homeobox genes on the X chromosome (Rhox) that is expressed in the placenta and the post-migratory primordial germ cells (PGCs) in the nascent gonad. Despite its novel expression pattern, the significance of Rhox6 expression in the differentiation of these cell types remains unknown. To investigate the role that Rhox6 plays in PGCs, cDNA encoding Rhox6 and short hairpin (sh) RNA directed against Rhox6 transcripts were introduced by unique expression vectors into a genetically engineered mouse embryonic stem cell (ESC) line. This ESC line expresses enhanced green fluorescent protein (EGFP) under the Oct3/4 promoter, thereby allowing us to monitor the presence of undifferentiated ESCs and PGCs in culture in real time. This ESC line was used to isolate clones that stably expressed Rhox6 cDNA, shRNA against Rhox6 transcripts, or controls. Quantitative RT-PCR results validated that overexpression had been achieved, as well as knockdown of Rhox6 transcripts in these ESC clones. However, these clones exhibited a normal appearance of undifferentiated ESCs and expressed EGFP. Next, these ESC clones were induced to differentiate into PGCs by generating embryoid bodies (EBs) in culture medium without leukemia inhibitory factor. Detection of EGFP expression by fluorescence microscopy and germ cell markers by RT-PCR validated the differentiation of PGCs in EBs. The Rhox6 transgene had little, if any, effect on EGFP expression in EBs, whereas Rhox6 knockdown significantly decreased EGFP expression in EBs. Thus, it is suggested with these results that Rhox6 is necessary for determination of the germ cell lineage. PMID- 22252488 TI - XIer2 is required for convergent extension movements during Xenopus development. AB - Immediate early response 2 (Ier2) is a downstream target of fibroblast growth factor (FGF) signaling. In zebrafish, Ier2 is involved in left-right asymmetry establishment and in convergent extension movements. We isolated the Xenopus ier2 gene based on sequence similarity searches using multiple vertebrate species. Xenopus Ier2 has high homology in the N-terminal region to other vertebrate Ier2 proteins, and Xier2 transcripts were observed from oocytes through larval stages. Except for the maternal expression of xier2, the expression of this gene in the marginal region at gastrulation and in somites and the notochord at later stages is similar to the expression pattern of zebrafish ier2. XIer2 knockdown using antisense morpholinos resulted in defects of convergent extension leading to severe neural tube defects; overexpression of Ier2 showed similar, albeit milder phenotypes. Assays in animal cap explants likewise showed inhibition of elongation after blocking XIer2 expression. These results indicate that Xenopus Ier2 is essential for the execution of convergent extension movements during early Xenopus development. PMID- 22252489 TI - The RNA-binding protein Xp54nrb isolated from a Ca2+-dependent screen is expressed in neural structures during Xenopus laevis development. AB - In amphibian embryos, calcium (Ca(2+)) signalling is a necessary and sufficient event to induce neural fate. Transient elevations of [Ca(2+)]i are recorded in neural tissue precursor cells in whole embryos during gastrulation. Using a subtractive cDNA library between control ectoderm (animal caps) and ectoderm induced toward a neural fate by Ca(2+) release, we have isolated several Ca(2+) induced target genes. Among the isolated genes, Xp54nrb encodes a protein which exhibits the RRM domains characteristic of RNA binding proteins, and is implicated in pre-mRNA splicing steps. Here we show that the Xp54nrb transcripts are expressed throughout early developmental stages, specifically in the neural and sensorial territories and that Xp54nrb could be involved in anterior neural patterning. PMID- 22252490 TI - Tgm2/Gh, Gbx1 and TGF-beta are involved in retinoic acid-induced transdifferentiation from epidermis to mucosal epithelium. AB - We previously demonstrated that retinoic acid (RA) induces epidermis to transdifferentiate to mucosal epithelium with goblet cells in chick embryonic cultured skin. To characterize the molecular mechanism of this transdifferentiation process, we used rat embryonic cultured skin and immunohistochemistry to confirm that RA-induced epidermal transdifferentiation accompanies the expression of markers of esophagus epithelium. Because Gbx1, TG2/Gh (transglutaminase2) and TGF-beta2 are reported individually to be induced by RA in cultures of chick embryonic skin, mouse epidermal cells and human hair follicles respectively, here, we investigated whether cooperative interplay of Gbx1, TG2/Gh and TGF-beta2 is required for the transdifferentiation of epidermal cells to mucosal cells. We have shown that expression of Gbx1, TG2/Gh and TGF beta proteins were all upregulated in RA-induced transdifferentiated skin and that the former two were expressed in the epidermis, while TGF-beta was expressed in the dermis. Inhibitors of the TGF-beta signal pathway partially inhibited transdifferentiation. Overexpression of both hTG2/Gh and mGbx1 together in the epidermis by electroporation resulted in cuboidal cells in the upper cell layers of the epidermis without keratinized layers, although epidermal keratinization was observed in skin by overexpression of either of them. Labeling DNA with BrdU indicated that RA directly transdifferentiated transient amplifying epidermal cells, not stem cells, to mucosal cells. This study showed that coexpression of TG/2 and Gbx1 in the epidermis was required for esophagus-like mucosal transdifferentiation, and that increase in TGF-beta2 expression by RA in the dermis was essential to induce transdifferentiation through epithelial mesenchymal interaction. PMID- 22252491 TI - The drumstick gene acts cell-non-autonomously and triggers specification of the small intestine in the Drosophila hindgut. AB - An odd family gene drumstick (drm) encodes a zinc finger protein, and is necessary for the development of the small intestine, an anterior domain of the ectodermal hindgut of Drosophila melanogaster. However, mechanisms that specify the small intestine, as well as gene regulatory pathways leading to transcriptional activation of drm, are still unclear. We found that drm is expressed in two different tissues abutting the anterior end of the hindgut primordium, that is, the posterior-most region of the midgut (endoderm) and basal portion of the Malpighian tubules. A small intestine marker gene, unpaired (upd), begins to be expressed at the anterior-most region of the hindgut primordium that abuts the basal portion of Malpighian tubules, and the upd-positive region expands, resulting in a short tube during stages 11-13. The small intestine develops in both of the mutant embryos, serpent (srp) and Kruppel (Kr), that lack the drm-positive midgut or Malpighian tubules, respectively, while it fails to develop in the Kr srp double-mutant embryos that lack both of the drm-positive tissues. These results demonstrate that drm expressed in the abutting tissues cell-non-autonomously induces development of the small intestine in the hindgut primordium, probably by deploying some extracellular signaling factor. drm expression in the posterior gut region disappears and the small intestine fails to form in tailless (tll) mutant embryos, whereas over-expression of tll causes expansion of drm expression throughout the midgut, inducing a longer small intestine. These results indicate that drm is activated under the control of tll and triggers development of the small intestine cell-non-autonomously through some extracellular signaling. PMID- 22252492 TI - Multiple effects of the cellular prion protein on tooth development. AB - The role of the prion protein (PrP) in transmissible spongiform encephalopathies has been the focus of intense investigation. However, less is known about the physiological function of normal cellular PrP (PrP(C)). In adult human teeth, PrP(C) has been identified in odontoblasts, cementoblasts and epithelial remnants of Malassez. In this study, we have localized PrP(C) in developing human and mouse teeth, and investigated the function of PrP using a PrP-knockout (Prnp(0/0) ) mouse model. PrP(C) was detected in developing human and mouse ameloblasts and odontoblasts. In vitro, undifferentiated dental mesenchymal cells from embryonic day 18 (E18) Prnp(0/0) mouse molars proliferated much more rapidly compared to age-matched, wild-type (wt) mouse molar dental mesenchymal cells. Histochemistry and immunohistochemical analyses showed a subtle but measurable phenotype, with the absence of PrP resulting in earlier initiation of both dentin and enamel formation. Consistent with this finding, laser microdissected odontoblasts from newborn Prnp(0/0) mouse incisors had a reduced proliferation rate, as measured by the expression of proliferating cell nuclear antigen (PCNA), and increased type 1 collagen mRNA expression. Dentin microhardness of the fully erupted molars was reduced and incisal enamel mineralization was delayed in Prnp(0/0) compared to age-matched wt mouse teeth. Taken together, these results suggest that PrP(C) affects multiple processes involved in tooth formation, through regulating the differentiation of ameloblasts and odontoblasts. PMID- 22252493 TI - ADAM17 overexpression promotes angiogenesis by increasing blood vessel sprouting and pericyte number during brain microvessel development. AB - The angiogenic process is precisely regulated by different molecular mechanisms, with a balance between stimulatory and inhibitory factors in embryonic development. Transmembrane proteins of the ADAM (a disintegrin and metalloprotease) family play a critical role in embryogenesis and are involved in protein ectodomain shedding, as well as cell-cell and cell-matrix interactions. In the present study, we found that ADAM17 is expressed spatiotemporally in the tectal layers during chicken embryonic development. To investigate the effect of ADAM17 overexpression on angiogenesis, chicken ADAM17 plasmids were transfected into the developing tectum in vivo by electroporation. Results showed that overexpression of ADAM17 induces morphological changes of brain microvessels, such as an increase in diameter, of capillary sprouting from radial microvessels and an increase in the number of pericytes, but not of endothelial cells. Our data suggest that overexpression of ADAM17 in the developing tectum promotes angiogenesis by increasing the number of pericytes and capillary sprouting in the radial vessels. PMID- 22252494 TI - A non-enzymatic microsurgical dissection technique of mouse embryonic tissues for gene expression profiling applications. AB - With the increased use of gene expression profiling to identify molecular regulators of cellular and developmental mechanisms, developmental biologists face a new challenge in dissecting tissues without cross-contamination or change in RNA profile, and with intact RNA integrity. We have developed a technique that overcomes these problems. We took the dissection of rudimentary mouse embryonic mammary glands as an example, as these structures are particularly difficult to separate from their contiguous ectoderm and strongly adhering mesenchyme. Contrary to conventional enzymatic tissue-separation methods, we blocked transcriptional activity prior to dissection and protected RNA from degradation during dissection, by the use of RNAlater. While RNAlater dehydrates specimens so severely that it interferes with visibility and clean dissection of organs or tissues, we established rehydration conditions that in fact facilitated tissue separation and shortened dissection time to about 10 minutes. The extracted RNA had an excellent quality, rendering it perfectly suitable for transcriptional profiling. Visual inspection of separated tissues and tissue specific gene expression analysis by microarray and RT-PCR confirmed that the tissues were separated with minimal or no cross-contamination. We show that this dissection method can be applied to a broad variety of organs, and that the tissue is still amenable to protein detection. In conclusion, this is a rapid, cheap and effective non-enzymatic tissue separation method which greatly facilitates the exploration of molecular mechanisms in organ formation. PMID- 22252495 TI - Effect of the transformer-2 gene of Anastrepha on the somatic sexual development of Drosophila. AB - The transformer-2 gene is involved in sex determination in tephritid flies (Tephritidae). It is required for the auto-regulation of the transformer gene (the memory device for sex determination in these insects) and for the female specific splicing of doublesex pre-mRNA, the last gene in the sex determination gene cascade. The present manuscript addressed the question of the functional conservation of the tephritid Anastrepha Tra2 protein to direct sexual development in Drosophila (Drosophilidae). To express this protein in Drosophila, the GAL4-UAS system was used. The Anastrepha Tra2 protein supplies tra-2 function in Drosophila: this protein would form a complex with the endogenous Drosophila Tra protein to promote the female-specific splicing of the Drosophila doublesex pre-mRNA. The feminisation produced by the Anastrepha Tra2 protein was, however, partial. PMID- 22252496 TI - Hypoxia-inducible factor 1 controls the expression of the uncoordinated-5-B receptor, but not of netrin-1, in first trimester human placenta. AB - Uncoordinated-5 homologs 1-4 (UNC5H1-4) transmembrane netrin receptors are reported to control a number of cellular processes, including axonal guidance, angiogenesis and cell proliferation. These receptors are known as "dependence receptors" because they are able to induce apoptosis in the absence of their ligand, netrin. We have recently reported the localization of netrin-1 and its uncoordinated-5-B (UNC5B) receptor in both villous and extravillous cytotrophoblasts in the human placenta. However, the roles that netrin-1 and UNC5B play in the development of the placenta, as well as the regulation of their expression during the early stages of placental development, remain unexplored. Placental explants were used to demonstrate a proliferative effect of netrin-1 on cytotrophoblasts, as assessed by Ki67 staining. Primary cytotrophoblasts collected at different gestational ages during the first trimester of pregnancy indicated that netrin-1 mRNA expression decreased after 6 weeks of gestation (wg), whereas UNC5B expression increased gradually up to 13-14 wg. The BeWo cell line was used to evaluate the effect of hypoxia on the expression of netrin-1 and UNC5B. Primary cytotrophoblast and BeWo cells cultured under hypoxic conditions exhibited a decrease in the expression of UNC5B both at the mRNA and protein levels; in contrast, hypoxia induced no change in the levels of netrin-1. When hypoxia-inducible factor 1alpha (HIF-1alpha) was knocked down by siRNA, we found a significant increase in UNC5B expression, indicating that the HIF-1 pathway is involved in hypoxia-induced UNC5B transcriptional down-regulation. Altogether, these results demonstrate the role of netrin-1 as a new mitogenic factor for cytotrophoblastic cells, report the pattern of expression of netrin-1 and its receptor, UNC5B, in the human placenta during the first trimester of pregnancy, and bring insights into the direct control of the expression of UNC5B by HIF-1. PMID- 22252497 TI - Cloning and developmental expression of zebrafish pdzrn3. AB - Pdzrn3, a member of the PDZRN/SEMCAP/LNX protein family containing a RING finger and two PDZ domains, has been implicated in myoblast and osteoblast differentiation. However, its spatio-temporal expression pattern during embryonic development has not been defined. Here, we describe the cloning and expression pattern of pdzrn3 during zebrafish development. We found that in addition to being expressed in several mesodermal structures, this gene displays specific expression in the central nervous system including rhombomere 1, ventral retina, thalamus and motor neurons, indicating a novel function during neural development. In particular, the absence of expression of pdzrn3 in the ventral retina of noi mutant fish suggests a possible role for this gene in regulating fasciculation and/or navigation of retinal ganglion cell axons. PMID- 22252498 TI - Genome-wide gene expression analysis in mouse embryonic stem cells. AB - Embryonic stem cell studies have generated great interest, due to their ability to form a wide variety of matured cells. However, there remains a poor understanding of mechanisms regulating the cell state of embryonic stem cells (ESCs) and of the genes they express during early differentiation. Gene expression analysis may be a valuable tool to elucidate either the molecular pathways involved in self-renewal and pluripotency, or early differentiation and to identify potential molecular therapy targets. The aim of this study was to characterize at the molecular level the undifferentiated mouse ESC state and the early development towards embryoid bodies. To attempt this issue, we performed CodeLink Mouse Uniset I 20K bioarrays in a well-characterized mouse ESC line, MES3, 3- and 7 day-old embryoid bodies and we compared our findings with those in adult tissue cells. Gene expression results were subsequently validated in a commercial stem cell line, CGR8 (ATCC). Significance Analysis of Microarrays (SAM) was used to identify statistically significant changes in microarray data. We identified 3664 genes expressed at significantly greater levels in MES3 stem cells than in adult tissue cells, which included 611 with 3-fold higher gene expression levels versus the adult cells. We also investigated the gene expression profile during early embryoid body formation, identifying 2040 and 2243 genes that were up-regulated in 3- and 7- day-old embryoid bodies, respectively. Our gene expression results in MES3 cells were partially confirmed in CGR8 cells, showing numerous genes that are expressed in both mouse stem cells. In conclusion, our results suggest that commonly expressed genes may be strong candidates for involvement in the maintenance of a pluripotent and undifferentiated phenotype and in early development. PMID- 22252499 TI - Ccbe1 expression marks the cardiac and lymphatic progenitor lineages during early stages of mouse development. AB - The mammalian heart is a complex organ composed of diverse components and various cell types. Heart organogenesis requires the contribution of distinct pools of heart progenitors positioned in separate embryonic regions and subject to particular developmental signals. Moreover, these embryonic heart lineages have different transcriptional profiles expressing specific genes which activate pathways involved in heart lineage specification. Understanding the molecular control of heart organogenesis has major implications for treating congenital and adult heart diseases since specific heart lineages have been associated with particular human cardiovascular malformations. Collagen and calcium-binding EGF like domain 1 (Ccbe1) was identified in our laboratory using an Affymetrix GeneChip system approach to identify the transcriptome of chick heart/hemangioblast precursor cells. Here, we present a detailed and systematic analysis of the expression of Ccbe1 during early mouse development using whole mount in situ hybridization (WISH), immunohistochemistry and histological techniques. Ccbe1 mRNA was initially detected in the early cardiac progenitors of the two bilateral cardiogenic fields (E7.0) and in the cardiogenic mesoderm (E7.5 to E8.0). Ccbe1 mRNA was then persistently detected in the pericardium and transiently expressed in the myocardial tissue of the primitive heart tube (E8.25), being later expressed in the proepicardium. By E9.5, the Ccbe1 and Prox1 proteins were found to be expressed in common regions, including the septum transversum and in the proximity of the anterior cardinal vein. Here, it is shown that Ccbe1 is expressed in the FHF, SHF and proepicardium during heart organogenesis (E7.0 to E8.75). Later in development, Ccbe1 expression is localized in the septum transversum and in the vicinity of the anterior cardinal vein, embryonic structures related to hepatic and lymphatic development, respectively. PMID- 22252500 TI - Two novel naphthalene glucosides and an anthraquinone isolated from Rumex dentatus and their antiproliferation activities in four cell lines. AB - An ethyl acetate extract of the roots of Rumex dentatus L. was investigated. Three compounds were identified by their spectroscopic data as chrysophanol (1), 6-methyl-7-acetyl-1, 8-dihydroxy-3-methoxy naphthalene-1-O-beta-D(L)-glucoside (2) and 6-methyl-7-acetyl-1, 8-dihydroxy naphthalene-1-O-beta-D(L)-glucoside (3) were found in the plant for the first time. Compounds 2 and 3 are novel compounds. Their antiproliferation activities were tested by the MTT assay in four cell lines (breast cancer MCF-7, gastric cancer 7901, melanoma A375 and oophoroma SKOV-3). PMID- 22252501 TI - Effect of efavirenz on UDP-glucuronosyltransferase 1A1, 1A4, 1A6, and 1A9 activities in human liver microsomes. AB - Efavirenz is a non-nucleoside reverse transcriptase inhibitor used for the treatment of human immunodeficiency virus type 1 infections. Drug interactions of efavirenz have been reported due to in vitro inhibition of CYP2C9, CYP2C19, CYP3A4, and UDP-glucuronosyltransferase 2B7 (UGT2B7) and in vivo CYP3A4 induction. The inhibitory potentials of efavirenz on the enzyme activities of four major UDP-glucuronosyltransferases (UGTs), 1A1, 1A4, 1A6, and 1A9, in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Efavirenz potently inhibited UGT1A4-mediated trifluoperazine N glucuronidation and UGT1A9-mediated propofol glucuronidation, with K(i) values of 2.0 and 9.4 MUM, respectively. [I]/K(i) ratios of efavirenz for trifluoperazine N glucuronidation and propofol glucuronidation were 6.5 and 1.37, respectively. Efavirenz also moderately inhibited UGT1A1-mediated 17beta-estradiol 3 glucuronidation, with a K(i) value of 40.3 MUM, but did not inhibit UGT1A6 mediated 1-naphthol glucuronidation. Those in vitro results suggest that efavirenz should be examined for potential pharmacokinetic drug interactions in vivo due to strong inhibition of UGT1A4 and UGT1A9. PMID- 22252502 TI - Phytochemical study and anti-inflammatory, antidiabetic and free radical scavenger evaluations of Krameria pauciflora methanol extract. AB - The plant Krameria pauciflora MOC et. Sesse ex DC. is used as an anti inflammatory and antidiabetic in traditional medicine. The aim of this study was to evaluate the in vivo anti-inflammatory and antidiabetic effects of a methanol extract from the roots of K. pauciflora. Dichloromethane and ethyl acetate extracts obtained by partitioning the methanol extract were also evaluated. Complete methanol and dichloromethane extracts showed anti-inflammatory effects at 3 mg/kg. An anti-inflammatory effect similar to indomethacin (10 mg/kg) was observed when the methanol and dichloromethane extracts, which contain a cycloartane-type triterpene and an sterol, were administered orally at several doses (3, 10, 30 and 100 mg/kg), whereas no anti-inflammatory effect was observed at any dose for the ethyl acetate extract, which contains catechin-type flavonoids. The antidiabetic effect of each extract was also determined. An antihyperglycaemic effect was observed in diabetic rats, but no effect in normoglycaemic animals was observed when the methanol extract was administrated at 30 mg/kg. All of the extracts exhibited radical scavenger activity. Additionally, constituents from all of the extracts were identified by NMR. This article supports the use of K. pauciflora as an anti-inflammatory because it exhibits a similar effect to indomethacin. However, its antidiabetic effect is not completely clear, although it could be useful for preventing diabetic complications. PMID- 22252503 TI - Novel benzothiazole, benzimidazole and benzoxazole derivatives as potential antitumor agents: synthesis and preliminary in vitro biological evaluation. AB - In a previous hit-to-lead research program targeting anticancer agents, two promising lead compounds, 1a and 1b, were found. However, the poor solubility of 1a and 1b made difficult further in vivo studies. To solve this problem, a lead optimization was conducted through introducing N-methyl-piperazine groups at the 2-position and 6-position. To our delight, the optimized analogue 1d showed comparable antiproliferative activity in vitro with better solubility, compared with 1a. Based on this result, the replacement of the benzothiazole scaffold with benzimidazole and benzoxazole moieties afforded 1f and 1g, whose activities were fundamentally retained. In the preliminary in vitro biological evaluation, the immunofluorescence staining of HCT116 cells indicated that 1d, 1f and 1g led to cytosolic vacuolization which was not induced by 1a at low micromolecular concentrations. These results suggest that these optimized compounds might potentially constitute a novel class of anticancer agents, which merit further studies. PMID- 22252504 TI - Design, synthesis and antifibrotic activities of carbohydrate-modified 1 (substituted aryl)-5-trifluoromethyl-2(1H) pyridones. AB - Pirfenidone, a pyridone compound, is an effective and novel antifibrotic agent. In this article, we describe the design, synthesis and activity evaluation of novel antifibrotic agents, 1-(substituted aryl)-5-trifluoromethyl-2(1H) pyridones modified with carbohydrate. Most of the title compounds exhibited comparable or better inhibitory activity than fluorofenidone. Notably, compound 19a demonstrated the highest cell-based inhibitory activity against NIH 3T3 (IC(50) = 0.17 mM). PMID- 22252505 TI - Effective degree household network disease model. AB - An ordinary differential equation (ODE) epidemiological model for the spread of a disease that confers immunity, such as influenza, is introduced incorporating both network topology and households. Since most individuals of a susceptible population are members of a household, including the household structure as an aspect of the contact network in the population is of significant interest. Epidemic curves derived from the model are compared with those from stochastic simulations, and shown to be in excellent agreement. Expressions for disease threshold parameters of the ODE model are derived analytically and interpreted in terms of the household structure. It is shown that the inclusion of households can slow down or speed up the disease dynamics, depending on the variance of the inter-household degree distribution. This model illustrates how households (clusters) can affect disease dynamics in a complicated way. PMID- 22252506 TI - Estimating the fitness effect of an insertion sequence. AB - Since its discovery, mobile DNA has fascinated researchers. In particular, many researchers have debated why insertion sequences persist in prokaryote genomes and populations. While some authors think that insertion sequences persist only because of occasional beneficial effects they have on their hosts, others argue that horizontal gene transfer is strong enough to overcome their generally detrimental effects. In this study, we model the long-term fate of a prokaryote cell population, of which a small proportion of cells has been infected with one insertion sequence per cell. Based on our model and the distribution of IS5, an insertion sequence for which sufficient data is available in 525 fully sequenced proteobacterial genomes, we show that the fitness cost of insertion sequences is so small that they are effectively neutral or only slightly detrimental. We also show that an insertion sequence infection can persist and reach the empirically observed distribution if the rate of horizontal gene transfer is at least as large as the fitness cost, and that this rate is well within the rates of horizontal gene transfer observed in nature. In addition, we show that the time needed to reach the observed prevalence of IS5 is unrealistically long for the fitness cost and horizontal gene transfer rate that we computed. Occasional beneficial effects may thus have played an important role in the fast spreading of insertion sequences like IS5. PMID- 22252507 TI - Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. AB - Heterogeneity of embryological origins is a hallmark of vascular smooth muscle cells (SMCs) and may influence the development of vascular disease. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin specific SMC subtypes remains elusive. Here we describe a chemically defined protocol in which hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated toward SMCs (>80% MYH11(+) and ACTA2(+)), which displayed contractile ability in response to vasoconstrictors and invested perivascular regions in vivo. Derived SMC subtypes recapitulated the unique proliferative and secretory responses to cytokines previously documented in studies using aortic SMCs of distinct origins. Notably, this system predicted increased extracellular matrix degradation by SMCs derived from lateral plate mesoderm, which was confirmed using rat aortic SMCs from corresponding origins. This differentiation approach will have broad applications in modeling origin-dependent disease susceptibility and in developing bioengineered vascular grafts for regenerative medicine. PMID- 22252508 TI - Three-dimensional reconstruction of protein networks provides insight into human genetic disease. AB - To better understand the molecular mechanisms and genetic basis of human disease, we systematically examine relationships between 3,949 genes, 62,663 mutations and 3,453 associated disorders by generating a three-dimensional, structurally resolved human interactome. This network consists of 4,222 high-quality binary protein-protein interactions with their atomic-resolution interfaces. We find that in-frame mutations (missense point mutations and in-frame insertions and deletions) are enriched on the interaction interfaces of proteins associated with the corresponding disorders, and that the disease specificity for different mutations of the same gene can be explained by their location within an interface. We also predict 292 candidate genes for 694 unknown disease-to-gene associations with proposed molecular mechanism hypotheses. This work indicates that knowledge of how in-frame disease mutations alter specific interactions is critical to understanding pathogenesis. Structurally resolved interaction networks should be valuable tools for interpreting the wealth of data being generated by large-scale structural genomics and disease association studies. PMID- 22252509 TI - Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. AB - Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety. PMID- 22252510 TI - Photoactivatable fluorophores and techniques for biological imaging applications. AB - Photoactivatable fluorophores (PAFs) are powerful imaging probes for tracking molecular and cellular dynamics with high spatiotemporal resolution in biological systems. Recent developments in biological microscopy have raised new demands for engineering new PAFs with improved properties, such as high two photon excitation efficiency, reversibility, cellular delivery and targeting. Here we review the history and some of the recent developments in this area, emphasizing our efforts in developing a new class of caged coumarins and related imaging methods for studying dynamic cell-cell communication through gap junction channels, and in extending the application of these caged coumarins to new areas including spatiotemporal control of microRNA activity in vivo. PMID- 22252511 TI - Effect of shading on yield, sugar content, phenolic acids and antioxidant property of coffee beans (Coffea Arabica L. cv. Catimor) harvested from north eastern Thailand. AB - BACKGROUND: Environmental conditions, including shading, generally influence the physical and chemical qualities of coffee beans. The present study assessed the changes in some phenolic compounds, antioxidant activity and agronomic characters of coffee beans (Coffea arabica L. cv. Catimor) as affected by different shading conditions including full sun, three artificial shading conditions using a saran covering (50% shade, 60% shade, and 70% shade) and lychee shade. RESULTS: Bean weight and bean size increased significantly (P < 0.05) when the shade level was progressively increased. The coffee beans grown under lychee shade exhibited superior bean yield, 1000-bean weight, total phenolic content and antioxidant activity compared to all other beans. Chlorogenic acid was the most predominant phenolic acid in all samples studied, being the highest in the beans grown under lychee shade, followed by 60% shade, 70% shade, 50% shade and full sun, respectively. In contrast, bean grown under full sun had the highest amount of vanillic acid and caffeic acid. CONCLUSIONS: Antioxidant activity was highly positively associated with chlorogenic acid content. The content of total sugar (fructose, glucose and sucrose) was found highest in coffee beans grown in 60% shade, with fructose the predominant sugar. Under climatic conditions similar to this experiment, it is advisable that growers provide shade to the coffee crop to reduce heat from direct sunlight and promote yield as well as obtain good quality coffee beans. PMID- 22252512 TI - Preventing spontaneous genetic rearrangements in the transgene cassettes of adenovirus vectors. AB - First-generation, E1/E3-deleted adenoviral vectors with diverse transgenes are produced routinely in laboratories worldwide for development of novel prophylactics and therapies for a variety of applications, including candidate vaccines against important infectious diseases, such as HIV/AIDS, tuberculosis, and malaria. Here, we show, for two different transgenes (both encoding malarial antigens) inserted at the E1 locus, that rare viruses containing a transgene inactivating mutation exhibit a selective growth advantage during propagation in E1-complementing HEK293 cells, such that they rapidly become the major or sole species in the viral population. For one of these transgenes, we demonstrate that viral yield and cytopathic effect are enhanced by repression of transgene expression in the producer cell line, using the tetracycline repressor system. In addition to these transgene-inactivating mutations, one of which occurred during propagation of the pre-viral genomic clone in bacteria, and the other after viral reconstitution in HEK293 cells, we describe two other types of mutation, a small deletion and a gross rearranging duplication, in one of the transgenes studied. These were of uncertain origin, and the effects on transgene expression and viral growth were not fully characterized. We demonstrate that, together with minor protocol modifications, repression of transgene expression in HEK293 cells during viral propagation enables production of a genetically stable chimpanzee adenovirus vector expressing a malarial antigen which had previously been impossible to derive. These results have important implications for basic and pre clinical studies using adenoviral vectors and for derivation of adenoviral vector products destined for large-scale amplification during biomanufacture. PMID- 22252518 TI - Cytoarchitecture, areas, and neuron numbers of the Etruscan shrew cortex. AB - The Etruscan shrew, Suncus etruscus, is one of the smallest mammals. Etruscan shrews can recognize prey shape with amazing speed and accuracy, based on whisker mediated tactile cues. Because of its small size, quantitative analysis of the Etruscan shrew cortex is more tractable than in other animals. To quantitatively assess the anatomy of the Etruscan shrew's brain, we sectioned brains and applied Nissl staining and NeuN (neuronal nuclei) antibody staining. On the basis of these stains, we estimated the number of neurons of 10 cortical hemispheres by using Stereoinvestigator and Neurolucida (MBF Bioscience) software. On average, the neuron number per hemisphere was found to be ~1 million. We also measured cortical surface area and found an average of 11.1 mm2 (n = 7) and an average volume of 5.3 mm3 (n = 10) per hemisphere. We identified 13 cortical regions by cytoarchitectonic boundaries in coronal, sagittal, and tangential sections processed for Nissl substance, myelin, cytochrome oxidase, ionic zinc, neurofilaments, and vesicular glutamate transporter 2 (VGluT2). The Etruscan shrew is a highly tactile animal with a large somatosensory cortex, which contains a barrel field, but the barrels are much less clearly defined than in rodents. The anatomically derived cortical partitioning scheme roughly corresponds to physiologically derived maps of neocortical sensory areas. PMID- 22252519 TI - A 3D mammalian cell separator biochip. AB - The dissimilar cytoskeletal architecture in diverse cell types induces a difference in their deformability that presents a viable approach to separate cells in a non-invasive manner. We report on the design and fabrication of a robust and scalable device capable of separating a heterogeneous population of cells with variable degree of deformability into enriched populations with deformability above a certain threshold. The three dimensional device was fabricated in fused silica by femtosecond laser direct writing combined with selective chemical etching. The separator device was evaluated using promyelocytic HL60 cells. Using flow rates as large as 167 MUL min(-1), throughputs of up to 2800 cells min(-1) were achieved at the device output. A fluorescence-activated cell sorting (FACS) viability analysis on the cells revealed 81% of the population maintain cellular integrity after passage through the device. PMID- 22252520 TI - A simple height-independent equation for estimating glomerular filtration rate in children. AB - BACKGROUND: The chronic kidney disease (CKD) classification system for children is similar to the CKD classification system for adults, using estimated glomerular filtration rate (eGFR) combined with fixed cut-off values of 60, 30, and 15 ml/min/1.73 m(2) for CKD stages III, IV, and V, respectively. To estimate GFR in children, eGFR-equations are used that require serum creatinine (Scr), but also height information, which is normally not available in clinical laboratory databases. METHODS: This retrospective study is based on data from two different databases, one that has previously been used to develop the Flanders Metadata equation for children and one database including 353 children who underwent (51)Cr-EDTA GFR, serum creatinine, height, and weight measurements. RESULTS: A height-independent eGFR equation based on the concept of a population-normalized Scr, presented before for adults, is extended to children: eGFR = 107.3/(Scr/Q), with Q the median Scr for healthy children of a particular age. This equation is validated against direct measurements of GFR, and against the updated Schwartz and Flanders Metadata equation. CONCLUSIONS: The new simple height-independent equation performs very well and should make (mass) screening of kidney function in children easier. PMID- 22252521 TI - Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children's Oncology Group. AB - BACKGROUND: There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials. METHODS: Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG 9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS). RESULTS: A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10-year EFS and OS in patients <10, 10 to 17, and >=18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients >=18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049). CONCLUSIONS: In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation. PMID- 22252522 TI - Diagnostic and prognostic utility of methylation and protein expression patterns of myopodin in colon cancer. AB - Myopodin is an actin-binding protein believed to play a tumor suppressor role in several solid neoplasias. We evaluated the potential differential myopodin methylation and expression and their clinical relevance in colon cancer. The epigenetic silencing of myopodin by hypermethylation was tested in colon cancer cells (n = 5) before and after azacitidine treatment. Myopodin methylation status was evaluated by methylation-specific PCR in colon cancer cells and colorectal tissues (n = 210) grouped in a training set (n = 62) and two independent validation series (n = 100 and n = 48) collected at independent clinical settings. Myopodin expression patterns were analyzed by immunohistochemistry on tissue arrays. Myopodin hypermethylation correlated with gene and protein expression loss, being increased in vitro by azacitidine. Myopodin was frequently methylated in colon cancer cells (four out of five). Methylation rates were 90.3%, 70.0%, and 47.8% in the training and validation sets, respectively. Myopodin methylation rendered a diagnostic accuracy of 83.9% (p < 0.0005). Cytoplasmic myopodin expression was significantly higher in non-neoplastic biopsies compared to colon tumors (p < 0.0005). Loss of myopodin expression correlated with increasing tumor stage (p = 0.011), methylation (p = 0.005), and poor overall survival (p = 0.003). In the first validation set (n = 100), myopodin methylation predicted disease-free (p = 0.046) and overall survival (p = 0.031). In the second validation cohort, myopodin methylation and protein expression patterns predicted disease-specific (p = 0.012 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.043, respectively). Thus, myopodin was revealed to be epigenetically modified in colon cancer. The diagnostic and prognostic clinical utility of myopodin methylation and expression patterns suggest considering their assessment for the clinical management of colon cancer patients. PMID- 22252523 TI - Antiproliferative effects of selective cyclooxygenase-2 inhibitor modulated by nimotuzumab in estrogen-dependent breast cancer cells. AB - Breast cancer is the most common malignancy in women, and many breast cancer patients fail conventional treatment strategies of chemotherapy, radiation, and antiestrogen therapy. Research into the molecular pathways and biomarkers involved in the development of breast cancer should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of breast cancer and exist tight crosstalk with estrogen receptor (ER) pathway. Combination of EGFR and COX-2 inhibitors, therefore, could be an effective strategy for reducing cell growth in estrogen-dependent breast cancer. In order to verify the effects of EGFR and COX-2 inhibitors, breast cancer cells MCF-7 and SKBR-3 were characterized for receptors status and then treated with respective inhibitors (nimotuzumab and celecoxib) alone and in combination. Both cell lines were sensitive to celecoxib, but not to nimotuzumab. However, combination of two drugs demonstrated synergistic effects on cell killing. Moreover, association of two drugs resulted in SKBR-3 cells, a further G0/G1 phase arrest than one drug alone. Downregulation of p-EGFR, p-Akt, p-mTOR, and amplified in breast cancer 1 (AIB1) were observed in both cell lines, and upregulation of E-cadherin was only found in MCF-7, after treatment with single agent or in combination. These studies suggest that nimotuzumab and celecoxib exert synergistic antiproliferation effects in breast cancer, which partly correlates with ER status. Due to Akt/mTOR, EMT and AIB1 pathways participate in this process, therefore, E cadherin and AIB1 may be considered as possible biomarkers to predict response in ER-positive breast cancer cells treated with EGFR and COX-2 inhibitors. PMID- 22252526 TI - Low workload as a trigger of sick leave: results from a Swedish case-crossover study. AB - OBJECTIVES: To investigate if exposure to an unusually low workload when ill can trigger taking sick leave. METHODS: A case-crossover design was applied to 546 sick-leave spells obtained from a cohort of 1430 employees within six Swedish workplaces. New sick-leave spells were reported from the workplaces during 3 to 12 months follow-up. Exposure was assessed in structured participant interviews at sick leave. Case and control periods from the same individual were sampled according to the matched-pair and usual-frequency approaches. Results are presented as odds ratios with surrounding 95% confidence intervals. RESULTS: The odds ratio of sick leave on a day with an unusually low workload was 2.57 (confidence interval, 1.07-6.16). CONCLUSIONS: Becoming ill on a day with a lower workload than usual can trigger the decision to take sick leave. PMID- 22252525 TI - PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. AB - P21-activated protein kinase1 (PAK1), a main downstream effector of small Rho GTPases, Rac1, and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Despite its importance, the molecular mechanisms of PAK1 that contributed to colorectal carcinogenesis remain unclear. Our immunohistochemistry showed that PAK1 expression was increased with colorectal cancer (CRC) progression through the adenoma to carcinoma sequence. Furthermore, our results suggested a relationship between PAK1 nuclear localization and the Dukes staging. In the present study, we showed that PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition, and increased apoptosis in vivo and in vitro. In addition, PAK1 knock-down downregulated c-Jun amino terminal kinases (JNK) activity and the levels of cyclinD1, CDK4/6. Inhibition of the JNK activity by chemical inhibitor (SP600125) significantly reduced the effects of PAK1 on CRC proliferation via accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In conclusion, our results demonstrate that knockdown of PAK1 could enhance the chemosensitivity of CRCs to 5-fluorouracil through G1 arrest. The mechanism by which PAK1 induced cancer growth might involve activation of JNK as well as downregulation of PTEN. Targeting PAK1 may represent a novel treatment strategy for developing novel chemotherapeutic agents. PMID- 22252524 TI - Synergistic effect of SCF and G-CSF on stem-like properties in prostate cancer cell lines. AB - Bone marrow metastases are formed in the late phases of prostate cancer disease. Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are present in the microenvironment of the bone marrow and play a vital role in cell biology therein. The present study was to investigate the influence of SCF and G CSF on stem-like properties in prostate cancer cell lines. Upon stimulation with SCF or G-CSF, higher levels of CD117, ABCG2, and CD44 were observed in PC-3 and DU145 cells examined by flow cytometry. Simultaneously, the expressions of Oct3/4 and Nanog were upregulated. Moreover, quantitative real-time PCR verified that the increased Nanog under the stimulations was mostly derived from NANOGP8. In parallel with the increasing expressions of these proteins, higher colony and sphere formation efficiencies were seen in these cells in response to the cytokine stimulations. Furthermore, a synergistic effect of SCF and G-CSF on colony and sphere formations and ABCG2 expression was disclosed. Our results indicate a favorable bone marrow niche for prostate cancer cells where higher levels of cell stemness are maintained at least partly by the cytokines SCF and G CSF. PMID- 22252527 TI - The effect of occupational and workplace gender composition on sickness absence. AB - OBJECTIVES: To examine whether gender composition of the occupation or the workplace is associated with sickness absence, whether the gender composition accounts for the observed female excess in sickness absence, and whether gender composition explains variation in sickness absence rates between occupations and workplaces. METHODS: Random effects models conducted among Helsinki employees (N = 36,395). RESULTS: Women and men working in women-dominated occupations and workplaces had more short-term (1 to 3 days') sickness absence. Gender composition of the occupation and the workplace partly explained gender differences in short-term but not in intermediate (4 to 14 days') and long-term (>2 weeks') absence. Gender composition also explained variation in short-term sickness absence among occupations and workplaces, but this was partly accounted for by social class, income, and job contract type. CONCLUSIONS: The results are consistent with the assumption that short-term sickness absence reflects cultures and norms shaping sickness absence behavior. PMID- 22252528 TI - Impact of a work-focused intervention on the productivity and symptoms of employees with depression. AB - OBJECTIVE: To test a new program's effectiveness in reducing depression's work burden. METHODS: A brief telephonic program to improve work functioning was tested in an early-stage randomized controlled trial involving 79 Maine State Government employees who were screened in for depression and at-work limitations (treatment group = 59; usual care group = 27). Group differences in baseline to follow-up change scores on the Work Limitations Questionnaire (WLQ), WLQ Absence Module, and Patient Health Questionnaire (PHQ)-9 depression severity scale were tested with analysis of covariance. RESULTS: Although there were no baseline group differences (P >= 0.05), by follow-up, the treatment group had significantly better scores on every outcome and differences in the longitudinal changes were all statistically significant (P = 0.0.27 to 0.0001). CONCLUSIONS: The new program was superior to usual care. The estimated productivity cost savings is $6041.70 per participant annually. PMID- 22252529 TI - Vacuum-assisted closure for managing neck abscesses involving the mediastinum. AB - A 57-year-old immunocompetent male patient with a deep neck abscess involving the mediastinum was referred to us following unsuccessful treatment at his local hospital with medical therapy and ultrasound-guided aspiration. After initial evaluation and resuscitation, a contrast-enhanced computed tomography (CT) scan was performed, and the patient was transferred for surgical drainage. A vacuum assisted closure (VAC) device was used as a surgical drain to help prevent reaccumulation of the purulent collections. A repeat CT scan on day 3 confirmed the absence of residual pus in the mediastinum and in the neck spaces, and the VAC device was removed. Perfect healing of the deep tissues with successful mediastinal toilette was observed. The patient resumed oral meals on postoperative day 10, and 2 days later he was discharged. A 1-month follow-up CT again demonstrated the complete healing and absence of the neck abscess. This case illustrates the possibility of avoiding more extensive and life-threatening procedures, such as open thoracotomy, in the treatment of neck abscesses extending into the mediastinum, and highlights the utility of VAC in the management of deep neck abscesses. PMID- 22252530 TI - Comparative proteomic profiling of mammalian cell lysates using phosphopeptide microarrays. AB - A library of 176 human phosphotyrosine-containing peptides was used to establish cell lysate binding profiles in a two colour microarray format. The resulting hits led to the pull-down and identification of biomarkers associated with cancer states. PMID- 22252531 TI - ICB3E induces iNOS expression by ROS-dependent JNK and ERK activation for apoptosis of leukemic cells. AB - The role of c-Jun N terminal Kinase (JNK) has been well documented in various cellular stresses where it leads to cell death. Similarly, extracellular signal regulated kinase (ERK) which was identified as a signalling molecule for survival pathway has been shown recently to be involved in apoptosis also. Recently we reported that ICB3E, a synthetic analogue of Piper betle leaf-derived apoptosis inducing agent hydroxychavicol (HCH), possesses anti-chronic myeloid leukemia (CML) acitivity in vitro and in vivo without insight on mechanism of action. Here we report that ICB3E is three to four times more potent than HCH in inducing apoptosis of leukemic cells without having appreciable effects on normal human peripheral blood mononuclear cells, mouse fibroblast cell line NIH3T3 and monkey kidney epithelial cell line Vero. ICB3E causes early accumulation of mitochondria derived reactive oxygen species (ROS) in K562 cells. Unlike HCH, ICB3E treatment caused ROS dependent activation of both JNK, ERK and induced the expression of iNOS leading to generation of nitric oxide (NO). This causes cleavage of caspase 9, 3 and PARP leading to apoptosis. Lack of cleavage of caspase 8 and inability of blocking chimera antibody to DR5 or neutralizing antibody to Fas to reverse ICB3E-mediated apoptosis suggest the involvement of only intrinsic pathway. Our data reveal a novel ROS-dependent JNK/ERK-mediated iNOS activation pathway which leads to NO mediated cell death by ICB3E. PMID- 22252532 TI - Generation of a cholesterol-independent, non-GS NS0 cell line through chemical treatment and application for high titer antibody production. AB - NS0 cells require exogenous cholesterol for growth. The non-glutamine synthetase (GS) cholesterol-dependent NS0 host was treated with 5-azacytidine (5azaC), a demethylation drug, and adapted to grow in cholesterol-free, chemically defined medium. Within 7 weeks, a stable, cholesterol-independent NS0 host (NS0.CF) was obtained. The new NS0.CF host, as well as the original cholesterol auxotroph host, was transfected with the same mAb expression plasmid, and the top producing clone from both hosts were compared side-by-side in the enhanced platform fed batch cultures using chemically defined media. The NS0.CF derived clone significantly out-performed the cholesterol-dependent clone, with titer reaching 4.5 g/L versus 3.0 g/L, respectively, mainly due to higher specific productivity, while key product quality attributes remained comparable. This work demonstrated an effective and rapid approach to generate a cholesterol-independent NS0 host, and its application in recombinant protein production. PMID- 22252533 TI - Facile synthesis of silicon nanoparticles inserted into graphene sheets as improved anode materials for lithium-ion batteries. AB - Silicon nanoparticles have been successfully inserted into graphene sheets via a novel method combining freeze-drying and thermal reduction. The as-obtained Si/graphene nanocomposite exhibits remarkably enhanced cycling performance and rate performance compared with bare Si nanoparticles for lithium-ion batteries. PMID- 22252535 TI - The effect of continuous positive airway pressure on middle ear pressure. AB - OBJECTIVES/HYPOTHESIS: While continuous positive airway pressure (CPAP) is commonly used for obstructive sleep apnea treatment, its effect on middle ear pressure is unknown. The purpose of this study was to measure the effect of CPAP on middle ear pressure and describe the correlation between CPAP levels and middle ear pressures. STUDY DESIGN: Retrospective review of normal tympanometry values and a prospective cohort evaluation of subjects' tympanometric values while using CPAP at distinct pressure levels. METHODS: A total of 3,066 tympanograms were evaluated to determine the normal range of middle ear pressures. Ten subjects with no known history of eustachian tube dysfunction or obstructive sleep apnea had standard tympanometry measurements while wearing a CPAP device. Measurements were taken at baseline and with CPAP air pressures of 0, 5, 10, and 15 cm H(2)O. RESULTS: The percentage of normal control patients with middle ear pressures above 40 daPa was 0.03%. In the study population, prior to a swallowing maneuver to open the eustachian tube, average middle ear pressures were 21.67 daPa, 22.63 daPa, 20.42, daPa, and 21.58 daPa with CPAP pressures of 0, 5, 10, and 15 cm H(2) 0, respectively. After swallowing, average middle ear air pressures were 18.83 daPa, 46.75 daPa, 82.17 daPa, and 129.17 daPa with CPAP pressures of 0, 5, 10, and 15 cm H(2)0, respectively. The postswallow Pearson correlation coefficient correlating CPAP and middle ear pressures was 0.783 (P < 0.001). CONCLUSIONS: Middle ear air pressure is directly proportional to CPAP air pressure in subjects with normal eustachian tube function. Middle ear pressure reaches supraphysiologic levels at even minimal CPAP levels. Although further investigation is necessary, there may be otologic implications for patients who are chronically CPAP dependent. These findings may also influence the perioperative practice of otologic and skull base surgeons. PMID- 22252534 TI - School performance and hospital admission due to unipolar depression: a three generational study of social causation and social selection. AB - PURPOSE: Both "social causation" and "social selection" offer plausible explanations for an association between education and mental health. We aimed to explore these processes in unipolar depression, with a specific focus on school performance and family tradition of education. METHOD: Grandchildren (N = 28,089, 49% female, aged 13-47 years in 2002) of a cohort born in Uppsala, Sweden, in 1915-1929 were studied in national registers. We obtained data on final grade point average (GPA) in compulsory school, hospitalizations for unipolar depression, grandparental/parental education and other parental social characteristics. Hospitalization in adolescence and adulthood were studied separately, as were hospitalization for depression with or without a lifetime externalizing disorder. RESULTS: Low compulsory school GPA (1-2 SD or >2 SD below average vs. average GPA) was associated with increased rate of adolescent hospitalization for unipolar depression, both with externalizing comorbidity [hazard ratio (HR) point estimates of 66-80] and without (HR point estimates of 4 6). By contrast, low GPA was only associated with first-time hospitalization in adulthood for the subgroup with externalizing comorbidity (HR point estimates of 4-6). These associations were largely independent of family education and social characteristics. Overall, low parental/grandparental education was not related to increased rates of hospitalization. CONCLUSION: The association between school performance and hospitalization for depression depended on adolescent hospitalization or externalizing comorbidity, suggesting that disorders with an early onset are decisive. Contrary to the social patterning of many health outcomes, low grandparental/parental education did not appear to increase the rate of hospitalization for unipolar depression in the offspring. PMID- 22252536 TI - n-Hexyl laurate and fourteen related fatty acid esters: new secretory compounds from the julid millipede, Anaulaciulus sp. AB - A total of fifteen saturated fatty acid esters were newly identified from the secretions of an unidentified Anaulaciulus sp. (Julida: Julidae). The fatty acid components of the esters were composed of normal chain acids (from C(10) to C(14)) and of branched chain acids (from iso-C(12) to iso-C(15) and anteiso C(15)). The alcohol moieties were all composed of normal chain alcohols varying from n-butanol to n-octanol. The most abundant component found in the total esters was n-hexyl laurate (64.7%). Novel compounds identified from the millipede secretion extracts include six branched iso- and anteiso-fatty esters, an odd numbered C(11)-fatty acid ester, a C(13)-fatty acid ester, and a C(7)-alcohol ester, all of which were previously undescribed natural products. In addition, a characteristic mixture of benzoquinones, such as 2-methyl-1,4-benzoquinone, 2 methoxy-3-methyl-1,4-benzoquinone, 2,3-dimethoxy-1,4-benzoquinone, 2-methoxy-6 methyl-1,4-benzoquinone, and 2,3-dimethoxy-5-methyl-1,4-benzoquinone were identified from the secretions, together with trace amounts of 1,4-benzoquinone. PMID- 22252537 TI - Bimodal distribution of motility and cell fate in Dictyostelium discoideum. AB - Pre-starvation amoebae of Dictyostelium discoideum exhibit random movements. Starved cells aggregate by directed movements (chemotaxis) towards cyclic AMP and differentiate into live spores or dead stalk cells. Many differences between presumptive spore and stalk cells precede differentiation. We have examined whether cell motility-related factors are also among them. Cell speeds and localisation of motility-related signalling molecules were monitored by live cell imaging and immunostaining (a) in nutrient medium during growth, (b) immediately following transfer to starvation medium and (c) in nutrient medium that was re introduced after a brief period of starvation. Cells moved randomly under all three conditions but mean speeds increased following transfer from nutrient medium to starvation medium; the transition occurred within 15 min. The distribution of speeds in starvation medium was bimodal: about 20% of the cells moved significantly faster than the remaining 80%. The motility-related molecules F-actin, PTEN and PI3 kinase were distributed differently in slow and fast cells. Among starved cells, the calcium content of slower cells was lower than that of the faster cells. All differences reverted within 15 min after restoration of the nutrient medium. The slow/fast distinction was missing in Polysphondylium pallidum, a cellular slime mould that lacks the presumptive stalk and spore cell classes, and in the trishanku (triA(-)) mutant of D. discoideum, in which the classes exist but are unstable. The transition from growth to starvation triggers a spontaneous and reversible switch in the distribution of D. discoideum cell speeds. Cells whose calcium content is relatively low (known to be presumptive spore cells) move slower than those whose calcium levels are higher (known to be presumptive stalk cells). Slow and fast cells show different distributions of motility-related proteins. The switch is indicative of a bistable mechanism underlying cell motility. PMID- 22252539 TI - Decreased neoblast progeny and increased cell death during starvation-induced planarian degrowth. AB - The development of a complex multicellular organism requires a careful coordination of growth, cell division, cell differentiation and cell death. All these processes must be under intricate and coordinated control, as they have to be integrated across all tissues. Freshwater planarians are especially plastic, in that they constantly replace somatic tissues from a pool of adult somatic stem cells and continuously undergo growth and degrowth as adult animals in response to nutrient availability. During these processes they appear to maintain perfect scale of tissues and organs. These life history traits make them an ideal model system to study growth and degrowth. We have studied the unique planarian process of degrowth. When food is not available, planarians are able to degrow to a minimum size, without any signs of adverse physiological outcomes. For example they maintain full regenerative capacity. Our current knowledge of how this is regulated at the molecular and cellular level is very limited. Planarian degrowth has been reported to result from a decrease in cell number rather than a decrease in cell size. Thus one obvious explanation for degrowth would be a decrease in stem cell proliferation. However evidence in the literature suggests this is not the case. We show that planarians maintain normal basal mitotic rates during degrowth but that the number of stem cell progeny decreases during starvation and degrowth. These observations are reversed upon feeding, indicating that they are dependent on nutritional status. An increase in cell death is also observed during degrowth, which is not rapidly reversed upon feeding. We conclude that degrowth is a result of cell death decreasing cell numbers and that the dynamics of neoblast self-renewal and differentiation adapt to nutrient conditions to allow maintenance of the neoblast population during the period of starvation. PMID- 22252538 TI - An insulin-like peptide regulates size and adult stem cells in planarians. AB - Animal growth depends on nutritional intake during development. In many animals, nutritional status is uncoupled from moderation of adult stature after adult size is achieved. However, some long-lived animals continue to regulate adult size and fertility in a nutrition-dependent manner. For example, the regenerating flatworm Schmidtea mediterranea becomes smaller, or degrows, during periods of starvation. These animals provide an opportunity to readily observe adult stem cell population dynamics in response to nutritional cues. We explored the role of insulin signaling in S. mediterranea. We disrupted insulin signaling via RNA interference and showed that animals, despite eating, degrew similarly to starved animals. Utilizing in situ hybridization and immunofluorescence, we assessed cellular changes in proliferative populations including the planarian adult stem cell population (neoblasts) and the germline. Both impaired insulin signaling and nutritional deprivation correlated with decreased neoblast proliferation. Additionally, insulin signaling played a role in supporting spermatogenesis that was distinct from the effects of starvation. In sum, we have demonstrated that insulin signaling is responsible for regulation of adult animal size and tissue homeostasis in an organism with plastic adult size. Importantly, insulin signaling continued to affect stem cell and germline populations in a mature organism. Furthermore, we have shown that adult organisms can differentially regulate specific cell populations as a result of environmental challenges. PMID- 22252540 TI - The planarian neoblast: the rambling history of its origin and some current black boxes. AB - First described by Randolph in 1897, the nature and main features of planarian neoblasts have a long rambling history. While their morphologically undifferentiated features have long been recognized, their origin and actual role during regeneration have been highly debated. Here I summarize the main stages of this rambling history: 1) undifferentiated, wandering cells of uncertain origin with a main, albeit undefined, role in regeneration (1890-1940s); 2) quiescent, undifferentiated cells whose main function is to build the blastema during regeneration, an idea which culminated in the 'neoblast theory' of the French School (1940-1960); 3) neoblasts as temporal, undifferentiated cells arising by dedifferentiation from differentiated cells (the 'cell dedifferentiation theory'; 1960-1980s); 4) a new paradigm, starting in the late 1970s-early 1980s, that brought together the role of neoblasts as the main cell for regeneration, with its more important role as somatic stem cells for the daily wear and tear of tissues and as the source of germ cells; and 5) more recent developments that culminate in the report of rescuing lethally irradiated planarians by injection of single neoblasts, which makes of neoblasts an unrivaled toti-, pluripotent somatic stem cell system in the Animal Kingdom. I finally discuss some "black boxes" regarding neoblasts which still baffle us, namely their phylogenetic and ontogenetic origins, their role in body size control, how their pool is regulated during growth and degrowth, the logic of their proliferative control, and some 'old' long-sought missing tools. PMID- 22252542 TI - Comparing cost aspects of coronary artery bypass graft surgery with coronary artery stenting. AB - Randomized trials have compared revascularization of coronary artery disease by coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI). CABG is an expensive treatment. However, it manages to improve quality of life, restore general well being, and alleviate symptoms of patients. Coronary stents have improved the safety and durability of PCI. Nonetheless, stenting remains limited by a relatively high in-stent restenosis and thrombosis rate. The costs and cost-effectiveness for these different treatment modalities are relevant issues because cardiovascular disease and its management are prime targets for cost reduction initiatives. There is a debate as to which is the optimal treatment strategy as well as to the cost-effectiveness comparing CABG and PCI. This review provides an overview of cost-effectiveness of CABG compared with PCI. PCI has high costs due to the need for subsequent revascularization procedures, with absence of mortality and survival benefit compared with CABG. Despite the relative lower initial costs of PCI in the first year, PCI is not a cost-effective intervention in comparison with CABG. However, the studies undertaken to date have predominantly been short term and provide a very limited evidence base by which to assess the cost-effectiveness of modern clinical practice. It seems that in longer term, the benefits of CABG may exceed those of stenting and the difference in net cost may be in favour of CABG as the risk of repeat revascularization still increases with PCI regardless of the use of DES. However, to date no long-term data are available in cost-effectiveness between CABG and PCI. The 5-year outcome of the ongoing SYNTAX trial is essential and might therefore provide new insights into the comparison of cost-effectiveness between CABG and DES PCI. PMID- 22252544 TI - Visible light-induced oxidative coupling reaction: easy access to Mannich-type products. AB - An efficient methodology for the functionalization of sp(3) C-H bond adjacent to nitrogen has been developed utilizing visible light-induced photoredox catalysis. Through optimization of solvent and light source, the reaction can be rapidly achieved to provide the desired product under mild reaction conditions. PMID- 22252543 TI - Impact of pr-10a overexpression on the cryopreservation success of Solanum tuberosum suspension cultures. AB - Although many genes are supposed to be a part of plant cell tolerance mechanisms against osmotic or salt stress, their influence on tolerance towards stress during cryopreservation procedures has rarely been investigated. For instance, the overexpression of the pathogenesis-related gene 10a (pr-10a) leads to improved osmotic tolerance in a transgenic cell culture of Solanum tuberosum cv. Desiree. In this study, a cryopreservation method, consisting of osmotic pretreatment, cryoprotection with DMSO and controlled-rate freezing, was used to characterize the relation between cryopreservation success and pr-10a expression in suspension cultures of S. tuberosum wild-type cells and cells overexpressing pathogenesis-related protein 10a (Pr-10a). By varying the sorbitol concentration, thus modifying the strength of the osmotic stress during the pretreatment phase, it can be shown that the wild type can successfully be cryopreserved only in a relatively narrow range of sorbitol concentrations, while the pr-10a overexpression leads to an enhanced cryopreservation success over the whole range of applied sorbitol concentrations. Together with transcription data we show that the pr-10a overexpression causes an enhanced osmotic tolerance, which in turn leads to enhanced cryopreservability, but also indicates a role of pr-10a in signal transduction. An increased cryopreservability of the transgenic cell line occurs for pretreatments longer than 24 h. Since both genotypes, characterized by distinct baseline levels of expression, exhibited similar patterns of expression induction, the induction of pr-10a appears to be a key step in the stress signal transduction of plant cells under osmotic stress. PMID- 22252545 TI - Theory-based predictors of follow-up exercise behavior after a supervised exercise intervention in older breast cancer survivors. AB - PURPOSE: Supervised exercise interventions can elicit numerous positive health outcomes in older breast cancer survivors. However, to maintain these benefits, regular exercise needs to be maintained long after the supervised program. This may be difficult, as in this transitional period (i.e., time period immediately following a supervised exercise program), breast cancer survivors are in the absence of on-site direct supervision from a trained exercise specialist. The purpose of the present study was to identify key determinants of regular exercise participation during a 6-month follow-up period after a 12-month supervised exercise program among women aged 65+ years who had completed adjuvant treatment for breast cancer. METHODS: At the conclusion of a supervised exercise program and 6 months later, 69 breast cancer survivors completed surveys examining their exercise behavior and key constructs from the Transtheoretical Model. RESULTS: After adjusting for weight status and physical activity at the transition point, breast cancer survivors with higher self-efficacy at the point of transition were more likely to be active 6 months after leaving the supervised exercise program (odds ratio [95% confidence interval, 1.10 [1.01-1.18]). Similarly, breast cancer survivors with higher behavioral processes of change use at the point of transition were more likely to be active (odds ratio [95% confidence interval], 1.13 [1.02-1.26]). CONCLUSION: These findings suggest that self-efficacy and the behavioral processes of change, in particular, play an important role in exercise participation during the transition from a supervised to a home-based program among older breast cancer survivors. PMID- 22252546 TI - Interviews with patients with advanced cancer--another step towards an international cancer pain classification system. AB - PURPOSE: Patients' involvement in the development of assessment tools is recommended, and the European Palliative Care Research Collaborative has adhered to this when developing a shared language for cancer pain, an international assessment and classification system. Study objectives were to investigate how patients ranked the relevance of several previously identified pain domains, to investigate patients' perception of the pain experience and to disclose additional, relevant pain domains for cancer pain classification to those identified in the literature. METHODS: Semistructured interviews with advanced cancer patients treated with opioids were performed and analysed verbatim. Patients scored the relevance of predefined pain domains on an 11-point Numerical Rating Scale. RESULTS: Thirty-three Norwegian and Austrian patients were included (16 females and 17 males); the mean age was 63 years, and the mean Karnofsky performance score was 65. The ranking of domains was as follows etiology (mean Numerical Rating Scale score, 8.5), duration (8.0), intensity (7.4), coping (7.1), physical (5.9) and psychological functioning (5.8). Sleep was identified as a new candidate domain to include in the system. The patients emphasised consequences of having pain, for example, poor physical functioning and psychological distress. CONCLUSIONS: Previously identified pain domains were confirmed to be relevant to the patients; however, the ranking differed from the experts' ranking. Sleep disturbances may be added as a domain in a future classification system. PMID- 22252547 TI - Physical compatibility of binary and ternary mixtures of morphine and methadone with other drugs for parenteral administration in palliative care. AB - The parenteral administration of combinations of drugs is often necessary in palliative medicine, particularly in the terminal stage of life, when patients are no longer able to take medication orally. The use of infusers to administer continuous subcutaneous infusions is a well-established practice in the palliative care setting and enables several drugs to be given simultaneously, avoiding the need for repeated administrations and the effects of peaks and troughs in the doses of medication. The method is also appreciated by patients and caregivers in the home care setting because the devices and infusion sites are easy to manage. Despite their frequent use, however, the mixtures of drugs adopted in clinical practice are sometimes not supported by reliable data concerning their chemical and physical compatibility. The present study investigates the chemical compatibility of binary mixtures (morphine with ketorolac) and the physical compatibility of binary (morphine or methadone with ketorolac) or ternary mixtures (morphine with ketorolac and/or haloperidol, and/or dexamethasone, and/or metoclopramide, and/or hyoscine butylbromide) with a view to reducing the aleatory nature of the empirical use of such combinations, thereby increasing their safety and clinical appropriateness. PMID- 22252549 TI - Carmustine infusion reactions are more common with rapid administration. AB - PURPOSE: Carmustine is a nitrosurea alkylating agent predominantly used at Peter MacCallum Cancer Centre as part of the autologous stem cell transplant induction regimens Stanford BCNU and BEAM. Acute infusion reactions were anecdotally reported to be higher than the reported rates of 10%, and it was suggested that the rate of infusion being employed was excessive. Some references suggest maximum infusion rates of 3 mg/m(2)/min for carmustine, a rate which is exceeded in the 2-h infusions used for Stanford BCNU, but not with BEAM. METHODS: A retrospective audit was conducted in 64 patients (57 Stanford BCNU, 7 BEAM) who had received these regimens between January 2009 and November 2010. RESULTS: Rates of infusion reaction to carmustine were higher than literature values, with reactions in Stanford BCNU (94.7%) being significantly higher than for BEAM (28.6%; P = 0.0003). These findings have resulted in a change of administration of carmustine in Stanford BCNU from 2 to 3 h. Further studies plan to compare the incidence of infusion reactions before and after the change in administration rates. CONCLUSION: Patients receiving rapid infusion of carmustine in the Stanford BCNU regimen for stem cell conditioning have a high rate of infusion reaction. A maximum rate of 3 mg/m(2)/min is recommended. PMID- 22252548 TI - Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: a systematic review and meta-analysis. AB - BACKGROUND: Variable febrile neutropenia (FN) rates reported with adjuvant TC (taxotere(r), cyclophosphamide) and FEC-D (5-flurouracil, epirubicin, cyclophosphamide, docetaxel) outside of clinical trials have precluded definitive recommendations for primary G-CSF (granulocyte colony-stimulating factor) prophylaxis in most jurisdictions. A systematic review and meta-analysis was conducted to assess: (a) FN rates associated with TC and FEC-D without primary G CSF prophylaxis outside of clinical trial settings, and (b) the potential impact of G-CSF prophylaxis on FN prevention. METHODS: A MEDLINE search was conducted and major conference abstracts were reviewed up to June 15th 2011 to identify all relevant English-language studies. Random- and fixed-effects meta-analysis models were performed. RESULTS: Nine hundred two patients treated with TC and 1342 with FEC-D from 13 to 9 studies, respectively, were included. The pooled random effects meta-analysis estimates of FN rates for TC and FEC-D without G-CSF were 29% (95% CI 24-35%) and 31% (95% CI 27-35%), with a 76% (RR = 0.24, 95% CI 0.14 0.41) and 63% (RR = 0.37, 95% CI 0.11-1.24) relative risk reduction with G-CSF, respectively. CONCLUSION: In routine clinical practice, TC and FEC-D without G CSF are associated with FN rates exceeding the 20% threshold for which primary G CSF prophylaxis is commonly recommended, and are considerably higher than those reported in pivotal clinical trials. PMID- 22252550 TI - ABL1 regulates spindle orientation in adherent cells and mammalian skin. AB - Despite the growing evidence for the regulated spindle orientation in mammals, a systematic approach for identifying the responsible genes in mammalian cells has not been established. Here we perform a kinase-targeting RNAi screen in HeLa cells and identify ABL1 as a novel regulator of spindle orientation. Knockdown of ABL1 causes the cortical accumulation of Leu-Gly-Asn repeat-enriched-protein (LGN), an evolutionarily conserved regulator of spindle orientation. This results in the LGN-dependent spindle rotation and spindle misorientation. In vivo inactivation of ABL1 by a pharmacological inhibitor or by ablation of the abl1 gene causes spindle misorientation and LGN mislocalization in mouse epidermis. Furthermore, ABL1 directly phosphorylates NuMA, a binding partner of LGN, on tyrosine 1774. This phosphorylation maintains the cortical localization of NuMA during metaphase, and ensures the LGN/NuMA-dependent spindle orientation control. This study provides a novel approach to identify genes regulating spindle orientation in mammals and uncovers new signalling pathways for this mechanism. PMID- 22252551 TI - Evidence for the late formation of hydrous asteroids from young meteoritic carbonates. AB - The accretion of small bodies in the Solar System is a fundamental process that was followed by planet formation. Chronological information of meteorites can constrain when asteroids formed. Secondary carbonates show extremely old (53)Mn (53)Cr radiometric ages, indicating that some hydrous asteroids accreted rapidly. However, previous studies have failed to define accurate Mn/Cr ratios; hence, these old ages could be artefacts. Here we develop a new method for accurate Mn/Cr determination, and report a reliable age of 4,563.4+0.4/-0.5 million years ago for carbonates in carbonaceous chondrites. We find that these carbonates have identical ages, which are younger than those previously estimated. This result suggests the late onset of aqueous activities in the Solar System. The young carbonate age cannot be explained if the parent asteroid accreted within 3 million years after the birth of the Solar System. Thus, we conclude that hydrous asteroids accreted later than differentiated and metamorphosed asteroids. PMID- 22252552 TI - Electrically driven photon antibunching from a single molecule at room temperature. AB - Single-photon emitters have been considered for applications in quantum information processing, quantum cryptography and metrology. For the sake of integration and to provide an electron photon interface, it is of great interest to stimulate single-photon emission by electrical excitation as demonstrated for quantum dots. Because of low exciton binding energies, it has so far not been possible to detect sub-Poissonian photon statistics of electrically driven quantum dots at room temperature. However, organic molecules possess exciton binding energies on the order of 1eV, thereby facilitating the development of an electrically driven single-photon source at room temperature in a solid-state matrix. Here we demonstrate electroluminescence of single, electrically driven molecules at room temperature. By careful choice of the molecular emitter, as well as fabrication of a specially designed organic light-emitting diode structure, we were able to achieve stable single-molecule emission and detect sub Poissonian photon statistics. PMID- 22252553 TI - Observation of the inverse spin Hall effect in silicon. AB - The spin-orbit interaction in a solid couples the spin of an electron to its momentum. This coupling gives rise to mutual conversion between spin and charge currents: the direct and inverse spin Hall effects. The spin Hall effects have been observed in metals and semiconductors. However, the spin/charge conversion has not been realized in one of the most fundamental semiconductors, silicon, where accessing the spin Hall effects has been believed to be difficult because of its very weak spin-orbit interaction. Here we report observation of the inverse spin Hall effect in silicon at room temperature. The spin/charge current conversion efficiency, the spin Hall angle, is obtained as 0.0001 for a p-type silicon film. In spite of the small spin Hall angle, we found a clear electric voltage due to the inverse spin Hall effect in the p-Si film, demonstrating that silicon can be used as a spin-current detector. PMID- 22252554 TI - c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. AB - Interleukin-6 (IL-6) and c-Src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-Src stimulates IL-6 expression through the STAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-Src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-Src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-Src, IL 6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions. PMID- 22252555 TI - A cobalt complex redox shuttle for dye-sensitized solar cells with high open circuit potentials. AB - Dye-sensitized solar cells are a promising alternative to traditional inorganic semiconductor-based solar cells. Here we report an open-circuit voltage of over 1,000 mV in mesoscopic dye-sensitized solar cells incorporating a molecularly engineered cobalt complex as redox mediator. Cobalt complexes have negligible absorption in the visible region of the solar spectrum, and their redox properties can be tuned in a controlled fashion by selecting suitable donor/acceptor substituents on the ligand. This approach offers an attractive alternate to the traditional I(3)(-)/I(-) redox shuttle used in dye-sensitized solar cells. A cobalt complex using tridendate ligands [Co(bpy pz)(2)](3+/2+)(PF(6))(3/2) as redox mediator in combination with a cyclopentadithiophene-bridged donor-acceptor dye (Y123), adsorbed on TiO(2), yielded a power conversion efficiency of over 10% at 100 mW cm(-2). This result indicates that the molecularly engineered cobalt redox shuttle is a legitimate alternative to the commonly used I(3)(-)/I(-) redox shuttle. PMID- 22252556 TI - Propagation stability of self-reconstructing Bessel beams enables contrast enhanced imaging in thick media. AB - Laser beams that can self-reconstruct their initial beam profile even in the presence of massive phase perturbations are able to propagate deeper into inhomogeneous media. This ability has crucial advantages for light sheet-based microscopy in thick media, such as cell clusters, embryos, skin or brain tissue or plants, as well as scattering synthetic materials. A ring system around the central intensity maximum of a Bessel beam enables its self-reconstruction, but at the same time illuminates out-of-focus regions and deteriorates image contrast. Here we present a detection method that minimizes the negative effect of the ring system. The beam's propagation stability along one straight line enables the use of a confocal line principle, resulting in a significant increase in image contrast. The axial resolution could be improved by nearly 100% relative to the standard light-sheet techniques using scanned Gaussian beams, while demonstrating self-reconstruction also for high propagation depths. PMID- 22252557 TI - ELL facilitates RNA polymerase II pause site entry and release. AB - Transcription is a multi-stage process that coordinates several steps within the transcription cycle including chromatin reorganization, RNA polymerase II recruitment, initiation, promoter clearance and elongation. Recent advances have identified the super elongation complex, containing the eleven-nineteen lysine rich leukaemia (ELL) protein, as a key regulator of transcriptional elongation. Here we show that ELL has a diverse and kinetically distinct role before its assembly into the super elongation complex by stabilizing Pol II recruitment/initiation and entry into the pause site. Loss of ELL destabilizes the pre-initiation complexes and results in disruption of early elongation and promoter proximal chromatin structure before recruitment of AFF4 and other super elongation complex components. These changes result in significantly reduced transcriptional activation of rapidly induced genes. Thus, ELL has an early and essential role during rapid high-amplitude gene expression that is required for both Pol II pause site entry and release. PMID- 22252558 TI - Tight finite-key analysis for quantum cryptography. AB - Despite enormous theoretical and experimental progress in quantum cryptography, the security of most current implementations of quantum key distribution is still not rigorously established. One significant problem is that the security of the final key strongly depends on the number, M, of signals exchanged between the legitimate parties. Yet, existing security proofs are often only valid asymptotically, for unrealistically large values of M. Another challenge is that most security proofs are very sensitive to small differences between the physical devices used by the protocol and the theoretical model used to describe them. Here we show that these gaps between theory and experiment can be simultaneously overcome by using a recently developed proof technique based on the uncertainty relation for smooth entropies. PMID- 22252560 TI - The fable of Babel and building a foundation for quality. PMID- 22252561 TI - Dutch statistics on lung cancer: sobering experience for a new approach. PMID- 22252562 TI - Preliminary report of late recurrences, at 5 years or more, after stereotactic body radiation therapy for non-small cell lung cancer. AB - INTRODUCTION: Long-term outcomes remain unknown after stereotactic body radiation therapy (SBRT). We observed a few patients who developed disease progression late, at 5 years or more, after SBRT. In this report, we describe the characteristics of those patients with late recurrence after SBRT. METHODS: We retrospectively reviewed patients who underwent SBRT for non-small cell lung cancer with histological confirmation between January 1999 and December 2005 at our institution. During this period, 48 Gy of SBRT in four fractions at the isocenter was prescribed for all patients. RESULTS: In total, 66 patients were eligible. With a median follow-up period of 35.9 months, the 5-year overall survival and disease-free survival rates were 44.6% (95% confidence interval, 33.5-59.5%) and 33.8% (95% confidence interval, 23.6-48.4%), respectively. Of the patients, 16 survived without disease progression for 5 years or more after SBRT. Of these, four patients developed late recurrence at 76, 101, 108, and 109 months after SBRT. Three of the patients were females with adenocarcinomas; the other was a male with squamous cell carcinoma. The initial sites of recurrence were local in two patients, distant in one, and simultaneously local and distant in one. A total of two patients with local recurrence alone were still alive at 138 months after SBRT. CONCLUSIONS: The rate of late recurrence was not negligible in long-term survivors after SBRT. Our experiences indicate that long-term follow-up is needed after SBRT for non-small cell lung cancer. PMID- 22252563 TI - Rapidly progressive diffuse cystic lesions as a radiological hallmark of lung adenocarcinoma. PMID- 22252564 TI - Complete regression of a non-small cell lung cancer choroidal metastasis with intravitreal bevacizumab. PMID- 22252565 TI - An updated meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. PMID- 22252566 TI - Systematic prevention of bubble formation and accumulation for long-term culture of pancreatic islet cells in microfluidic device. AB - Reliable long-term cell culture in microfluidic system is limited by air bubble formation and accumulation. In this study, we developed a bubble removal system capable of both trapping and discharging air bubbles in a consistent and reliable manner. Combined with PDMS (Polydimethylsiloxane) hydrophilic surface treatment and vacuum filling, a microfluidic perifusion system equipped with the bubble trap was successfully applied for long-term culture of mouse pancreatic islets with no bubble formation and no flow interruption. In addition to demonstrating normal cell viability and islet morphology, post-cultured islets exhibited normal insulin secretion kinetics, intracellular calcium signaling, and changes in mitochondrial potentials in response to glucose challenge. This design could be easily adapted by other microfluidic systems due to its simple design, ease of fabrication, and portability. PMID- 22252567 TI - Indigenous and immigrant populations' use and experience of community pharmacies in New Zealand. AB - We sought to identify what services indigenous (Maori) and immigrant populations use pharmacies for, and how long pharmacy staff spend interacting with them, as longer interactions are associated with better quality care. We review literature on counseling in pharmacy, and interaction length as an indicator of counseling quality. 1,086 interactions were discretely observed in 36 pharmacies in 5 cities around New Zealand. Maori or Pacific people, along with men, were more likely to treat pharmacies as prescription 'depots', being less likely to buy over-the counter or pharmacist only medicines (ORs: 0.25-0.72). However, the influence of demographic factors on interaction length was small (|B|s < 7.7 s). The weak effect of ethnicity on interaction length suggests that pharmacies are providing advice of relatively consistent quality to different population groups. Possible barriers to use of pharmacies for primary healthcare, including over-the-counter medicines in Maori and Pacific people are discussed. PMID- 22252568 TI - Doppler ultrasound and D-dimer: friend or foe? AB - The diagnosis of venous thromboembolism has evolved considerably with the development of standardized diagnostic algorithms that include clinical probability assessment, D-dimer measurement and the use of non-invasive imaging modalities such as compression ultrasonography and computed tomography angiography. The implementation of these strategies aims to improve resource allocation and patient outcome. The judicious use of these diagnostic tools requires a thorough knowledge of the appropriate clinical setting in which every test and strategy is efficient and can be used safely. For this purpose, D-dimer measurement and compression ultrasonography are complementary: the former is mainly used to exclude VTE in selected patients, while the latter is used to confirm the presence of an underlying DVT. This review provides an appraisal of the features and use of D-dimer and compression ultrasonography in the context of suspected venous thromboembolism. PMID- 22252569 TI - FSAP, a new player in inflammation? AB - Factor VII-activating protease (FSAP) is a serine protease in plasma that has a role in coagulation and fibrinolysis. FVII could be activated by purified FSAP in a tissue factor independent manner and pro-urokinase has been demonstrated to be a substrate for purified FSAP in-vitro. However, the physiological role of FSAP in haemostasis remains unclear. More recently FSAP is suggested to be involved in inflammation. It modulates vascular permeability directly and indirectly by the generation of bradykinin. Furthermore, FSAP is activated by dead cells induced by the inflammatory response and subsequently removes nucleosomes from apoptotic cells. FSAP activation can be detected in sepsis patients as well. However, whether FSAP activation upon inflammation is beneficial or detrimental remains an open question. In this review the structure, activation mechanisms and the possible role of FSAP in inflammation are discussed. PMID- 22252570 TI - Botulinum toxin in the treatment of facial synkinesis and hyperkinesis. AB - OBJECTIVES/HYPOTHESIS: Facial synkinesis and hyperkinesis commonly impair the outcome of facial nerve palsy. Botulinum toxin type A has shown positive results in the treatment of these symptoms. Our experience is reported in this article. STUDY DESIGN: Prospective study. METHODS: Forty-one patients affected by facial synkinesis and hyperkinesis due to facial palsy were treated. The etiology of the facial palsy was: 28 Bell's palsy cases, nine iatrogenic cases (seven acoustic neuroma surgeries, one tympano-jugular glomus tumor removal, and one middle ear surgery), three herpes zoster virus cases, and one case of Melkersson-Rosenthal syndrome. Botulinum toxin type A was used in the treatment. Clinical evaluation was obtained through the Sunnybrook Grading Scale and an author's modification of this method purposely designed for evaluation of hyperkinesis. Further evaluation through a self-administered synkinesis questionnaire was also performed. RESULTS: All patients showed some improvement of synkinesis and hyperkinesis after treatment. The mean values of the data obtained, regardless of the method of evaluation, gave statistically significant results. Correlation between objective and subjective evaluation methods was also statistically positive. CONCLUSIONS: This work stresses the importance of considering synkinesis and hyperkinesis separately because they are different conditions. These two symptoms showed improvement after botulinum toxin treatment, but only hyperkinesis showed a positive correlation when objective and subjective evaluations were performed. This treatment is effective in the management of facial synkinesis and hyperkinesis due to facial palsy, thus improving quality of life. It is a safe, minimally invasive treatment that can be repeated. PMID- 22252571 TI - Aberrant DNA methylation of tumor-related genes in oral rinse: a noninvasive method for detection of oral squamous cell carcinoma. AB - BACKGROUND: The early detection of oral squamous cell carcinoma (OSCC) is important, and a screening test with high sensitivity and specificity is urgently needed. Therefore, in this study, the authors investigated the methylation status of tumor-related genes with the objective of establishing a noninvasive method for the detection of OSCC. METHODS: Oral rinse samples were obtained from 34 patients with OSCC and from 24 healthy individuals (controls). The methylation status of 13 genes was determined by using methylation-specific polymerase chain reaction analysis and was quantified using a microchip electrophoresis system. Promoter methylation in each participant was screened by receiver operating characteristic analysis, and the utility of each gene's methylation status, alone and in combination with other genes, was evaluated as a tool for oral cancer detection. RESULTS: Eight of the 13 genes had significantly higher levels of DNA methylation in samples from patients with OSCC than in controls. The genes E cadherin (ECAD), transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains 2 (TMEFF2), retinoic acid receptor beta (RARbeta), and O 6 methylguanine DNA methyltransferase (MGMT) had high sensitivity (>75%) and specificity for the detection of oral cancer. OSCC was detected with 100% sensitivity and 87.5% specificity using a combination of ECAD, TMEFF2, RARbeta, and MGMT and with 97.1% sensitivity and 91.7% specificity using a combination of ECAD, TMEFF2, and MGMT. CONCLUSIONS: The aberrant methylation of a combination of marker genes present in oral rinse samples was used to detect OSCC with >90% sensitivity and specificity. The detection of methylated marker genes from oral rinse samples has great potential for the noninvasive detection of OSCC. PMID- 22252572 TI - Hydrodynamic and kinetic study of cellulase production by Trichoderma reesei with pellet morphology. AB - Numerical simulations and experimental validation were performed to understand the effects of hydrodynamics on pellet formation and cellulase production by filamentous T. reesei. The constructed model combined a steady-state multiple reference frame (MRF) approach describing mechanical mixing, oxygen mass transfer, and non-Newtonian flow field with a transient sliding mesh approach and kinetics of oxygen consumption, pellet formation, and enzyme production. The model was experimentally validated at various agitation speeds in a two-impeller Rushton turbine fermentor. Results from simulation and experimentation showed that higher agitation speeds led to increases in the pellet diameter and the proportion of pelletized (vs. filamentous) forms of the biomass. It also led to increase in dissolved oxygen mass transfer rate in shear-thinning fluid and cellulase productivity. The extent of these increases varied considerably among agitation speeds. Pellet formation and morphology were presumably affected within a viscosity-dependent shear-rate range. Cellulase activity and cell viability were shown to be sensitive to impeller shear. A maximum cellulase activity of 3.5 IU/mL was obtained at 400 rpm, representing a twofold increase over that at 100 rpm. PMID- 22252573 TI - Modified hemi-Lothrop procedure for supraorbital ethmoid lesion access. AB - The supraorbital ethmoid (SOE) cell is an accessory ethmoid cell in the frontal area that extends into and pneumatizes superolaterally along the orbital plate of the frontal bone. The outflow pathway of the SOE cell can become obstructed, leading to an SOE mucocele. Given their lateral location, SOE lesions are traditionally treated through external approaches, although some authors have advocated treatment through standard endoscopic routes. We present a case of a large, supraorbital ethmoid mucocele treated with a novel modified hemi-Lothrop procedure (MHLP). This technique provides the benefit of an angulated approach to increase lateral visualization and bimanual, binostril instrumentation through a superior septectomy window. PMID- 22252574 TI - Pot evaluation of synthetic nanosiderite for the prevention of iron chlorosis. AB - BACKGROUND: Iron chlorosis is a problem that affects crops grown on calcareous soils. In this work, we assessed the effectiveness of nanosized siderite (FeCO3) to prevent iron chlorosis, the underlying hypothesis being that the oxidation products of siderite in soil are poorly crystalline, and hence plant-available, iron oxides. RESULTS: Nanosized siderite was prepared by mixing FeSO4 and K2CO3 solutions, either pure or doped with phosphate (siderite SID and SIDP, respectively). The average specific surface area was ~140 m2 g-1 for SID and ~220 m2 g-1 for SIDP. Experimental oxidation in a calcite suspension yielded goethite for SID and a mixture of lepidocrocite and goethite for SIDP. Two pot experiments in which a SID or SIDP suspension was applied to a calcareous soil at a rate of ~2 g Fe kg-1 showed nanosiderite to prevent iron chlorosis in chickpea. In a pot experiment with five successive crops, one initial application of ~0.7 g Fe kg-1 soil in the form of SID or SIDP was as effective as FeEDDHA in preventing Fe chlorosis. The residual effect of nanosiderite when applied to the first crop alone clearly exceeded that of FeEDDHA. CONCLUSION: Nanosiderite suspensions applied at rates of ~0.7 g Fe kg-1 soil were highly effective in preventing iron chlorosis and have a great residual effect. PMID- 22252575 TI - Letter from the editor. PMID- 22252576 TI - Improving frontline treatment for chronic myeloid leukemia: emerging evidence for use of nilotinib and dasatinib. AB - The approval of imatinib in 2001 changed the landscape of chronic myeloid leukemia (CML) management, becoming the standard of care and improving the survival rates of patients. With the prevalent use of imatinib worldwide, it was observed that up to one-third of patients are resistant to or intolerant of imatinib therapy, fueling the search for safer and more effective agents. The newer and more potent tyrosine kinase inhibitors nilotinib and dasatinib were first indicated for the treatment of imatinib-resistant/-intolerant patients, for whom these agents are both safe and efficacious. More recent clinical studies have examined nilotinib and dasatinib in the frontline setting in newly diagnosed patients. Data reported from the phase III ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study and the DASISION (Dasatinib versus Imatinib in Patients with Newly Diagnosed Chronic-phase CML) trial support the use of nilotinib and dasatinib as potential new standards for frontline care of newly diagnosed patients with CML in chronic phase. Furthermore, both agents have received regulatory approval for use as frontline agents. These agents have demonstrated significantly superior efficacy compared with imatinib, as measured by complete cytogenetic response and major molecular response rates. In addition, progression to advanced disease was significantly lower for nilotinib, and a trend toward lower progression was observed with dasatinib. Although both nilotinib and dasatinib are generally well tolerated in the frontline setting, they have different safety profiles that may affect their selection as treatment. Understanding the efficacy, safety profiles, and patterns of resistance to various BCR-ABL1 mutations of these newer agents, as well as implementing management strategies to treat adverse events, will help physicians to provide the best therapy options for their patients with CML. PMID- 22252577 TI - The relevance of BRCA genetics to prostate cancer pathogenesis and treatment. AB - The breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are cellular proteins involved in DNA repair. They are normally expressed in the breast, ovaries, prostate, and other tissues. Their germline mutation is the cause of hereditary breast-ovarian cancer syndromes. BRCA mutation carriers are also susceptible to other cancers, notably prostate cancer. In this article, we review the role of BRCA genes in the pathogenesis and clinical course of prostate cancer. We also discuss the molecular mechanisms of action and the therapeutic implications of BRCA germline mutations. PMID- 22252578 TI - Gaucher disease: hematologic and oncologic implications. PMID- 22252579 TI - Maintenance therapy in the treatment of sarcoma. PMID- 22252580 TI - Blinatumomab: a novel agent to treat minimal residual disease in patients with acute lymphoblastic leukemia. PMID- 22252581 TI - Cancer vaccines. PMID- 22252582 TI - Hematuria--a rare presentation of Hodgkin lymphoma. PMID- 22252584 TI - Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae. AB - Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non-neoplastic gastric specimens using quantitative methylation-specific PCR in patients with GC (n = 207) and their age- and gender matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy-based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation levels in MOS remained increased in patients with past H. pylori infection compared to H. pylori-negative subjects (p < 0.001). Methylation levels in MOS in non-neoplastic gastric mucosae increased in the presence of GC, regardless of H. pylori infection status (p < 0.01). Methylation levels in all genes but DCC decreased significantly in GC specimens compared to neoplastic gastric mucosae (p < 0.01); however, methylation levels in GC tissues were not correlated with those in their background gastric mucosae. Hypomethylation of MOS in GC tissues was associated with tumour invasion, nodal metastasis, and undifferentiated histology (p < 0.05). To summarize, among the candidate genes, DNA methylation of MOS may reflect the duration of H. pylori exposure and may be a marker for the development of GC. PMID- 22252585 TI - Applying microdroplets as sensors for label-free detection of chemical reactions. AB - Despite its tremendous high-throughput screening capabilities, widespread applications of droplet-based microfluidics are still limited by the poor availability of appropriate analytical assays. Here we report on a novel sensor method that exploits the osmosis-driven change in droplet size as a quantitative and label-free marker for reactions inside the droplets. We present an analysis of the underlying mechanism and apply the method for monitoring metabolic activity at a single-cell level. PMID- 22252586 TI - Right- and left-handedness of 2(1) symmetrical herringbone assemblies of benzene. AB - A universal method to determine handedness of 2(1) helical assemblies composed of planar aromatic molecules is proposed and demonstrated by taking P2(1)/c and Pbca crystals of benzene, the simplest aromatic molecule, as examples. PMID- 22252587 TI - Breast cancer screening: successes and challenges. PMID- 22252588 TI - [Malignant skin diseases in organ transplant patients]. PMID- 22252590 TI - [Pain disorders in traumatized individuals - neurophysiology and clinical presentation]. AB - This overview portrays the salient physiological mechanisms being involved in the clinical manifestation of chronic pain in traumatized patients. A "hypermnesia hyperarousal-model" is purported to support the neurophysiologic plausibility of the trauma-pain-relationship. We discuss seven characteristic clinical pain entities which alone or in combination can be found in patients with a previous psychological trauma. PMID- 22252591 TI - [Intraoperative neurophysiological monitoring improves outcome in neurosurgery]. AB - Intraoperative Neurophysiological Mo-nitoring (IONM) identifies eloquent areas or nerves fibers during neurosurgical interventions and monitors their function. For several interventions IONM has become mandatory in neurosurgery. IONM increases patient safety during surgery as the risk of neurological deficits is reduced. Safer surgery reduces the time needed for the intervention and thereby reduces risk. IONM contributes to complete resection of tumors, which in turn prolongs patients' survival. Complicated surgical interventions associated with an elevated risk of neurological deficits have only become possible due to IONM. IONM comprises a variety of procedures that are selected for a particular intervention. With appropriate selection of the procedures IONM has been shown to improve neurological and functional outcome after neurosurgical interventions. PMID- 22252592 TI - [How to Read a Chest-X-ray?]. AB - Only a standartized, systematic approach allows a complete review of a chest x ray and the collection of all relevant informations. In detail, alterations of the following structures should be sought: soft tissue, bones, pleura, mediastinum, lung, heart, pulmonary circulation and hili. Technical factors and the position of the patient should also be considered. PMID- 22252593 TI - [New biomarkers in prostate cancer]. AB - Prostate cancer (PCa) is one of the most common solid cancers and one of the most important causes of morbidity and mortality worldwide in men. So far, several efforts have been devoted to identify prostate cancer biomarkers, which allow a discrimination between indolent and clinically significant diseases, however with scarce results. The prostate-specific antigen (PSA) still remains the marker of choice for PCa diagnosis, prognosis, and "active surveillance". Thus, a sensitive and specific independent indicator, easy to screen in blood or urine is still not available. This review will provide a new insight into the role of previous (i.e. PSA) and new biomarkers, to use separately or in combination for prostate cancer screening and early detection programs. PMID- 22252594 TI - [Diagnosis in incidental eosinophilia findings]. PMID- 22252595 TI - [Life-threatening complication of schizophrenia]. AB - The Wernicke Encephalopathy (WE) as a result of a (sub)acute thiamine deficiency remains, unfortunately, still under-diagnosed, especially among non-alcoholics. It should be considered in each occurrence of delirium as well as in any ocular motor disorder and ataxia, in particular if there is a history of weight loss with or without gastrointestinal symptoms. In cases with suspected WE an immediate intravenous substitution of 3*200 mg/d is recommended. PMID- 22252596 TI - [In the diagnosis of arterial hypertension, 24-hour blood pressure monitoring is the most accurate method]. PMID- 22252597 TI - [ABCD2 score is inexact for assessing the risk of a stroke in a patient with transient ischemic attacks]. PMID- 22252599 TI - [CME-EKG 36. Fabry disease]. PMID- 22252603 TI - Interplay between hydrophilic and hydrophobic interactions in the self-assembly of a gemini amphiphilic pseudopeptide: from nano-spheres to hydrogels. AB - The formation of soluble nano-spheres or stable hydrogels through the self assembling of a simple gemini amphiphilic pseudopeptide can be controlled by the tuning of the hydrophilic/hydrophobic interactions in aqueous medium. PMID- 22252604 TI - Association between bone mineral density and hearing loss in osteogenesis imperfecta. AB - OBJECTIVES/HYPOTHESIS: Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, predominantly characterized by bone fragility. In half of the patients, progressive hearing loss develops, which is associated with abnormal bony changes involving the middle ear ossicles and stapes footplate. In the present study, we investigated whether the development of hearing loss in OI may be related to the overall aberrant bone quality. STUDY DESIGN: Observational study. METHODS: Following audiologic evaluation, 56 adult OI patients were classified as presenting normal hearing or conductive/mixed or pure sensorineural hearing loss. Areal bone mineral density (BMD) (aBMD) was measured using lumbar spine (LS) and whole body (WB) dual X-ray absorptiometry. By means of peripheral computed tomography, volumetric BMD (vBMD) and morphometric bone parameters were determined at distal and proximal radius, providing separate results for trabecular and cortical bone. The obtained bone parameters were compared between normal-hearing OI patients and those with either conductive/mixed or pure sensorineural hearing loss. RESULTS: Z scores demonstrated decreased LS aBMD, WB aBMD, and trabecular vBMD in OI adults compared to the healthy population. Patients with conductive/mixed hearing loss had lower trabecular vBMD compared to those with normal hearing or pure sensorineural loss at both whole-group and between-relatives comparisons. CONCLUSIONS: It is hypothesized that OI patients with lower BMD might be more susceptible to accumulating microfractures, which may interfere with the bone remodeling inhibition pathways in the temporal bone and, therefore, contribute to stapes footplate fixation and a conductive hearing loss component. PMID- 22252605 TI - Reversible aberration of neurogenesis targeting late-stage progenitor cells in the hippocampal dentate gyrus of rat offspring after maternal exposure to acrylamide. AB - We have recently shown that maternal exposure to acrylamide (AA) impaired neurogenesis in rat offspring measured by the increase in interneurons producing reelin, a molecule regulating migration and correct positioning of developing neurons, in the hippocampal dentate gyrus. To clarify the cellular target of AA on hippocampal neurogenesis and its reversibility after maternal exposure, pregnant Sprague-Dawley rats were given drinking water containing AA at 0, 4, 20, 100 ppm on day 10 of pregnancy through day 21 after delivery on weaning. Male offspring were examined immunohistochemically on postnatal day (PND) 21 and PND 77. For comparison, male pups of direct AA-injection control during lactation (50 mg/kg body weight, intraperitoneally, 3 times/week) were also examined. On PND 21, maternal AA-exposure decreased progenitor cell proliferation in the subgranular zone (SGZ) from 20 ppm accompanied with increased density of reelin producing interneurons and NeuN-expressing mature neurons within the hilus at 100 ppm, similar to the direct AA-injection control. In the SGZ examined at 100 ppm, cellular populations immunoexpressing doublecortin or dihydropyrimidinase-like 3, suggesting postmitotic immature granule cells, were decreased. On PND 77, the SGZ cell proliferation and reelin-producing interneuron density recovered, while the hilar mature neurons sustained to increase from 20 ppm, similar to the direct AA injection control. Thus, developmental exposure to AA reversibly affects hippocampal neurogenesis targeting the proliferation of type-3 progenitor cells resulting in a decrease in immature granule cells in rats. A sustained increase in hilar mature neurons could be the signature of the developmental effect of AA. PMID- 22252602 TI - Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target. AB - Castrate-resistant prostate cancer (CRPC) and neuroendocrine carcinoma of the prostate are invariably fatal diseases for which only palliative therapies exist. As part of a prostate tumor sequencing program, a patient tumor was analyzed using Illumina genome sequencing and a matched renal capsule tumor xenograft was generated. Both tumor and xenograft had a homozygous 9p21 deletion spanning the MTAP, CDKN2, and ARF genes. It is rare for this deletion to occur in primary prostate tumors, yet approximately 10% express decreased levels of methylthioadenosine phosphorylase (MTAP) mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it seems that this deletion is more common in CRPC than in primary prostate cancer. We show for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient-derived neuroendocrine xenograft growth while protecting the host from 6-thioguanine toxicity. This therapeutic approach can be applied to other MTAP-deficient human cancers as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology. PMID- 22252606 TI - Design of a fuzzy-based decision support system for coronary heart disease diagnosis. AB - In the present paper, a fuzzy rule-based system (FRBS) is designed to serve as a decision support system for Coronary heart disease (CHD) diagnosis that not only considers the decision accuracy of the rules but also their transparency at the same time. To achieve the two above mentioned objectives, we apply a multi objective genetic algorithm to optimize both the accuracy and transparency of the FRBS. In addition and to help assess the certainty and the importance of each rule by the physician, an extended format of fuzzy rules that incorporates the degree of decision certainty and importance or support of each rule at the consequent part of the rules is introduced. Furthermore, a new way for employing Ensemble Classifiers Strategy (ECS) method is proposed to enhance the classification ability of the FRBS. The results show that the generated rules are humanly understandable while their accuracy compared favorably with other benchmark classification methods. In addition, the produced FRBS is able to identify the uncertainty cases so that the physician can give a special consideration to deal with them and this will result in a better management of efforts and tasks. Furthermore, employing ECS has specifically improved the ability of FRBS to detect patients with CHD which is desirable feature for any CHD diagnosis system. PMID- 22252607 TI - Pleiotropic increases in free non-polar lipid, glycolipid and phospholipid contents in waxy bread wheat (Triticum aestivum L.) grain. AB - BACKGROUND: Diethyl ether-extractable free lipid (FL), non-polar or neutral lipid (NL), glycolipid (GL) and phospholipid (PL) contents and water-saturated 1 butanol (WSB)-extractable non-starch lipid (NSL)-monogalactosyldiglyceride (MGDG), digalactosyldiglyceride (DGDG) and phosphatidylcholine (PC)-contents in bread wheat (Triticum aestivum L.) grain were evaluated to elucidate the possible influence of the Wx-D1 gene on the lipid composition. RESULTS: Waxy near-isogenic lines with a non-functional Wx-D1d allele showed consistently increased NL, GL and PL contents among FL and MGDG, DGDG and PC contents among NSL compared with non-waxy near-isogenic lines with a functional Wx-D1a allele throughout three growing/harvest seasons. However, the proportion of NL, GL and PL among FL was not influenced by the non-waxy/waxy state of the endosperm. The nearly non functional Wx-D1f allele influenced the FL and NL contents in a similar manner to the non-functional allele across two seasons, while the partly functional Wx-D1g allele only affected the NL content. CONCLUSION: The Wx-D1 locus has pleiotropic effects on the diethyl ether-extractable FL, NL, GL and PL contents and WSB extractable MGDG, DGDG and PC contents of bread wheat grain. The non-functional Wx-D1d allele causes an increase in the levels of these lipids. PMID- 22252608 TI - Confinement effects in the hydrogen adsorption on paddle wheel containing metal organic frameworks. AB - The confinement effects upon hydrogen adsorption in Cu(II)-paddle wheel containing metal-organic frameworks (MOFs) were evaluated and rationalized in terms of the structural properties (cavity types and pore diameters) of PCN-12, HKUST-1, MOF-505, NOTT-103 and NOTT-112. First-principles calculations were employed to identify the strongest adsorption positions at the paddle wheel inorganic building unit (IBU). The adsorption centres due to confinement were located through analysis of 3D occupancy maps obtained from the hydrogen trajectories computed via molecular dynamics simulations. It was found that the confinement enhances the adsorption on the weakest adsorption centres around the IBU in regions close to the narrowest windows and promotes the formation of new adsorption regions into the small cavities. Our results indicate that at low pressure, the high H(2) uptake in these materials is partly due to the presence of small cavities (5.3-8.5 A) or narrow windows where the long-range contribution to the adsorption becomes important. Conversely, confinement effects in cavities with diameters >12 A were not observed. PMID- 22252609 TI - Modified microslicing technique for auricular cartilage to reduce curling. PMID- 22252610 TI - Insular thyroid cancer: a population-level analysis of patient characteristics and predictors of survival. AB - BACKGROUND: Insular thyroid cancer (ITC) is an uncommon, poorly differentiated thyroid malignancy. To date, there have been no population-level studies of the characteristics and outcomes of patients with ITC. METHODS: The authors used the Surveillance, Epidemiology, and End Results (SEER) database from 1999 to 2007 to compare the characteristics and prognosis of patients who had ITC with those of patients who had well differentiated thyroid cancer (WDTC) and anaplastic thyroid cancer (ATC). Data analyses were performed using chi-square tests, analyses of variance, log-rank tests, and multivariate regression. RESULTS: There were 114 patients with ITC, 497 patients with ATC, and 34,021 patients with WDTC. The mean age of patients with ITC was 62.1 years versus 48.1 years for patients with WDTC and 69.5 years for patients with ATC (P < .001). The mean ITC tumor size was 5.9 cm versus 2.0 cm for WDTC and 6.4 cm for ATC (P < .001). Distant metastasis occurred in 31% of patients with ITC versus 4.5% of patients with WDTC and 59.1% of patients with ATC (P < .001). Insular histology was associated independently with compromised survival in the overall study sample (hazard ratio [HR], 2.1; P = .001). The 5-year disease-specific survival rate was 72.6%, 97.2%, and 9.1% for patients with ITC, WDTC, and ATC, respectively (P < .001). After adjustment, radioiodine therapy (HR, 0.15; 95% confidence interval, 0.04-0.5) and distant metastasis (HR, 15.3; 95% confidence interval, 3.7-62.2) were associated independently with ITC survival. The mortality rate was 7.1%, 12%, and 54.3% for patients with localized, regional, and distant stage ITC, respectively (P < .001). For patients who had ITC with distant metastasis, thyroidectomy and radioiodine therapy independently improved survival. CONCLUSIONS: ITC is rare and aggressive. The current results indicated that its treatment should include total thyroidectomy and high-dose radioiodine for all patients and neck dissections for patients with lymph node disease. Early diagnosis and close surveillance are essential in the management of patients with ITC. PMID- 22252611 TI - Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. AB - While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT. PMID- 22252612 TI - The pheromones of laying workers in two honeybee sister species: Apis cerana and Apis mellifera. AB - When a honeybee colony loses its queen, workers activate their ovaries and begin to lay eggs. This is accompanied by a shift in their pheromonal bouquet, which becomes more queen like. Workers of the Asian hive bee Apis cerana show unusually high levels of ovary activation and this can be interpreted as evidence for a recent evolutionary arms race between queens and workers over worker reproduction in this species. To further explore this, we compared the rate of pheromonal bouquet change between two honeybee sister species of Apis cerana and Apis mellifera under queenright and queenless conditions. We show that in both species, the pheromonal components HOB, 9-ODA, HVA, 9-HDA, 10-HDAA and 10-HDA have significantly higher amounts in laying workers than in non-laying workers. In the queenright colonies of A. mellifera and A. cerana, the ratios (9-ODA)/(9 ODA + 9-HDA + 10-HDAA + 10-HDA) are not significantly different between the two species, but in queenless A. cerana colonies the ratio is significant higher than in A. mellifera, suggesting that in A. cerana, the workers' pheromonal bouquet is dominated by the queen compound, 9-ODA. The amount of 9-ODA in laying A. cerana workers increased by over 585% compared with the non-laying workers, that is 6.75 times higher than in A. mellifera where laying workers only had 86% more 9-ODA compared with non-laying workers. PMID- 22252614 TI - Letter from the editor. Can you name the six US airports named after US presidents? PMID- 22252613 TI - A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. AB - BACKGROUND: High-dose chemotherapy combined with autologous stem-cell transplantation (ASCT) is the standard therapy for refractory/relapsed aggressive lymphoma. In the era of rituximab-containing frontline regimens, it is becoming more challenging to salvage patients in this setting, and novel approaches are required. This is a randomized study evaluating the safety and efficacy of standard-dose ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy (Z-BEAM) and ASCT in refractory/relapsed aggressive lymphoma. METHODS: Forty-three patients with CD20(+) -aggressive lymphoma were randomized to a treatment arm (Z-BEAM, n = 22) or control arm (BEAM alone, n = 21). Ibritumomab tiuxetan was given at 0.4 mCi/kg on day -14 before ASCT. RESULTS: Patient characteristics, engraftment kinetics, and toxicity profile were similar between the 2 groups. Two-year progression-free survival (PFS) for all patients was 48% (95% confidence interval, 32%-64%): 59% and 37% after Z-BEAM and BEAM alone, respectively (P = .2). Multivariate analysis identified advanced age (hazard ratio [HR], 8.3; P = .001), high-risk disease (relapse within 12 months of diagnosis and/or secondary International Prognostic Index >2; HR, 2.8; P = .04), positive positron emission tomography-computed tomography pretransplant (HR, 2.4; P = .07), and BEAM alone (HR, 2.8; P = .03) as poor prognostic factors. Intermediate-risk patients with 1 or 2 risk factors had better PFS with Z-BEAM compared with BEAM: 69% and 29%, respectively (P = .07). Two-year overall survival was 91% and 62% after Z-BEAM and BEAM, respectively (P = .05). Similar prognostic factors determined survival. The HR for BEAM alone in the multivariate analysis was 8.1 (P = .01). CONCLUSIONS: Standard-dose ibritumomab tiuxetan combined with BEAM high-dose chemotherapy is safe and possibly more effective than BEAM alone as a conditioning regimen for ASCT in the era of rituximab containing chemotherapy regimens. PMID- 22252615 TI - Pulmonary toxicities of tyrosine kinase inhibitors. AB - The incidence of pulmonary toxicities with the use of tyrosine kinase inhibitors (TKIs) is not very high; however, various case reports and studies continue to show significant variability in the incidence of these adverse events, ranging from 0.2% to 10.9%. Gefitinib and erlotinib are orally active, small-molecule inhibitors of the epidermal growth factor receptor tyrosine kinase that are mainly used to treat non-small cell lung cancer. Imatinib is an inhibitor of BCR ABL tyrosine kinase that is used to treat various leukemias, gastrointestinal stromal tumors, and other cancers. In this article, we review data to identify the very rare but fatal pulmonary toxicities (mostly interstitial lung disease) caused by these drugs. PMID- 22252616 TI - A phase I trial of vatalanib (PTK/ZK) in combination with bevacizumab in patients with refractory and/or advanced malignancies. AB - BACKGROUND: Vatalanib is an orally active, small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR). Bevacizumab is also an angiogenesis inhibitor, but it possesses a different mechanism of action. This phase I study was conducted to determine the dose-limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of vatalanib and bevacizumab. PATIENTS AND METHODS: Treatment cycles were 4 weeks in length. Patients received oral vatalanib once or twice daily continuously. Bevacizumab was administered intravenously starting on day 15 of cycle 1, and dosing was repeated at 2-week intervals in patients with at least stable disease for 4 cycles. After 4 cycles, only patients with a partial or complete response continued treatment with the combination of vatalanib and bevacizumab. Patients with stable disease were allowed to continue single-agent vatalanib from cycle 5 until disease progression or intolerable toxicity. RESULTS: A total of 27 patients received 93 cycles of treatment. Dose escalation was difficult due to enhanced toxicities (primarily proteinuria and hypertension) with the regimen that required numerous dose modifications. Interruption of vatalanib and bevacizumab dosing due to proteinuria occurred in 4 patients enrolled at dose level 3, with 1 of these patients developing grade 3 nephrotic range proteinuria. As a result, further dose escalation with the combination regimen was abandoned. CONCLUSIONS: Further development of bevacizumab and oral VEGF tyrosine kinase inhibitor combination regimens is questionable due to the additive toxicities that occur; future investigations should proceed with caution. PMID- 22252617 TI - JAK2 inhibitors in myelofibrosis. PMID- 22252618 TI - Diet and exercise in breast cancer. PMID- 22252619 TI - Advances in the treatment of neuroblastoma. PMID- 22252620 TI - Cyclic and chronic neutropenia: an update on diagnosis and treatment. PMID- 22252621 TI - Effectiveness of dasatinib in relapsed CNS, Ph+ ALL that is refractory to radiochemotherapy plus imatinib: a case report. PMID- 22252622 TI - Which tyrosine kinase inhibitor, if any? PMID- 22252623 TI - Neuroinflammation and cognitive dysfunction in chronic disease and aging. PMID- 22252624 TI - Proteoglycans: gene cloning. AB - Aggrecan is a large proteoglycan that plays roles in numerous tissues during vertebrate development and adult life. The 6,327-nt chick aggrecan coding sequence had been determined from overlapping clones, but a full-length cDNA, needed for use in transgenic expression studies, had not been constructed. The strategy employed to do so was to generate two overlapping cDNA subfragments that shared a unique restriction site in the overlap and then join them at that site. These subfragments were obtained and cloned into the TOPO-TA vector pCR2.1. Digestion of the two constructs with the shared-site enzyme, XbaI, produced vector/5'-cDNA and 3'-cDNA fragments with XbaI-ends; these were ligated to produce the final full-length cDNA. PMID- 22252625 TI - Proteoglycan: site mapping and site-directed mutagenesis. AB - Identification of proteoglycan chain modification sites cannot yet be reliably predicted from primary amino acid sequence data. A number of studies have shown that serine is the predominant amino acid that is modified and it is frequently flanked by a C-terminal glycine and proximal N-terminal acidic amino acids; however, not all simple Ser-Gly motifs constitute a modification site. Here we present a rapid method for cloning small, defined segments of putative proteoglycan attachment sites and expressing them as a mini-reporter protein in an insect tissue culture system that is expandable to high throughput analysis. Reporter proteins with attached proteoglycans can be readily discerned from their unmodified form, by a simple gel-shift assay and Western blot detection for an epitope tag engineered into the reporter. Unmodified proteins are generated as a reference standard by treating cells with dsRNA to knock down the endogenous polypeptide xylose transferase, which is responsible for initiating proteoglycan site attachment. Examination of proteoglycan attachment by different metazoan organisms can be studied in the same cell line by cotransfecting a polypeptide xylose transferase expression plasmid and reporter construct from human, mouse, frog, or worm, for example. Reporter proteins engineer with point mutations can be rapidly generated with this system to pinpoint the exact residue that is glycosylated, to verify the mapping data. PMID- 22252626 TI - Mapping of the Wnt/beta-catenin/TCF response elements in the human versican promoter. AB - Versican, a chondroitin sulfate proteoglycan, is one of the main components of the extracellular matrix and is considered to be crucial to several key cellular processes involved in development and disease. There is differential temporal and spatial expression of versican by multiple cell types and in different developmental and pathological timeframes. In order to fully appreciate the functional roles of versican as it relates to changing patterns of expression in development and disease, an in-depth knowledge of versican's biosynthetic processing is necessary. We have recently shown that beta-catenin/T-cell factor (TCF) complex formation at the versican promoter site is essential for activation of versican transcription. The transcriptional activator beta-catenin is the key mediator of the canonical Wnt signaling pathway. However, beta-catenin does not itself bind DNA and thus functions via interaction with TCF/Lymphoid-enhancing factor (LEF) transcription factors. These proteins contain a high-mobility group (HMG) box that binds DNA in a sequence-specific manner. Thus, in the case of active Wnt signaling, beta-catenin activates, in cooperation with proteins of the TCF/LEF family, the expression of a wide variety of target genes. The goal of this chapter is to describe the techniques used to elucidate the transcriptional control of versican by the beta-catenin/TCF response elements in its promoter site and to demonstrate how this signaling may be assayed experimentally. These approaches provide insight into the transcriptional regulation of the versican gene and provide the basis for the identification of novel Wnt/beta-catenin/TCF regulated genes that are part of the signaling machinery regulating early embryogenesis, neoplasia, and cardiovascular remodeling. PMID- 22252627 TI - Gene silencing in mouse embryonic stem cells. AB - Embryonic stem cells (ESCs) are promising tools for regenerative medicine as well as for biotechnological research. However, to exploit ESCs for clinical purposes, a better understanding of the molecular mechanisms that control the pluripotency and differentiation of ESCs is required. Several extrinsic signaling pathways contribute to the maintenance of pluripotency, as well as induction of differentiation, in ESCs. However, the mechanisms that regulate extrinsic signaling in ESCs are largely unknown. Heparan sulfate (HS) is present ubiquitously as a component of cell surface proteoglycans and is known to play crucial roles in the regulation of several signaling pathways. We have validated that RNA interference (RNAi) is a useful method for the functional analysis of some target genes in mouse ESCs (mESCs). Indeed, we have investigated the functions of HS in mESCs by using RNAi and have demonstrated that HS on mESCs is involved in regulating signaling pathways that are important for the maintenance of mESCs. In this chapter, we describe detailed methods for the gene silencing of proteoglycan-related genes in mESCs by RNAi. PMID- 22252628 TI - A novel strategy for a splice-variant selective gene ablation: the example of the versican V0/V2 knockout. AB - The complete knockout of genes that give rise to alternative splice products can often provide only an integral view of the dominant function(s) of all the isoforms they encode. If one of these isoforms is indispensable for life, a constitutive and complete inactivation may even preclude any in vivo studies of later expressed splice-variants in mice. To explore function of the tissue restricted versican V2 isoform during central nervous system maturation, for instance, we had to circumvent the early embryonic lethality of the complete knockout by employing a novel splice-variant-specific gene ablation approach. For this purpose, we introduced a preterm translational stop codon preceded by an ER retention signal (KDEL) into the alternatively spliced exon 7 of the VCAN gene. This way the synthesis of the V2- and the V0-forms of the proteoglycan was entirely abolished in the mutant mice, most likely mediated by a KDEL-promoted intracellular degradation of the mutant fragment and by a nonsense-mediated decay mechanism. The expression of the vitally important V1-isoform and the smallest V3 variant remained, however, unaffected. Here we provide the details of our targeting strategy, the screening procedure, the generation of isoform-specific antibodies, and the transcript analysis and we supply the experimental protocols for the biochemical and immunohistological examinations of the mutant mouse strain Vcan(tm1.1Dzim). PMID- 22252629 TI - Detection of neurocan in cerebrospinal fluid. AB - Cerebrospinal fluid (CFS) is the most easily accessible component of the human central nervous system and has been successfully used for the analysis of disease associated molecular imbalances, particularly for extracellular matrix components. Alterations in the presence of the nervous system-associated chondroitin sulfate proteoglycan neurocan had been reported from active multiple sclerosis lesions. Neurocan could be detected as a component of human CFS after enrichment of proteoglycans by anion exchange chromatography from pooled liquor as well as individual 300 MUL samples by Western blot. However, a general alteration in neurocan levels in CFS sample with high immunoglobulin content could not be demonstrated. To further reduce the sample size, the development of a PG capturing assay based on polybrene-coated 96-well plates was initiated. This approach could be an interesting alternative option for the analysis of PGs in biological fluid and tissue samples. PMID- 22252630 TI - Glycosaminoglycan chain analysis and characterization (glycosylation/epimerization). AB - Glycosaminoglycans (GAGs) including chondroitin sulfate (CS), dermatan sulfate (DS), and heparan sulfate/heparin (HS/Hep) are linear polysaccharides and involved in the regulation of various biological events through interaction with functional proteins. GAGs are modified by sulfation at various positions of each saccharide residue and the epimerization of uronic acid residues during the chain's biosynthesis, resulting in enormous structural diversity. This structural diversity is the basis for the wide range of biological activities of GAGs. Thus, the structural analysis of GAGs is key to understanding their biological functions. This chapter describes detailed instructions for the extraction and structural analysis of GAGs from cultured cells and tissues using a combination of GAG-degrading enzymes and high-performance liquid chromatography. PMID- 22252631 TI - Characterization of glycosaminoglycans by tandem vibrational microspectroscopy and multivariate data analysis. AB - Vibrational spectroscopies (VS), INFRARED SPECTROSCOPY and RAMAN SPECTROSCOPY, are well-established techniques for exploring the chemical composition of samples. VS are based on the molecular vibrations and give a spectral signature also called "molecular fingerprint" characteristic of the studied material. Recent advances in these techniques have rendered them faster, more sensitive, and easier to use. This chapter describes their application to characterize the main glycosaminoglycans-without any sample destruction or degradation. Nowadays, the use of multivariate statistical analysis for analyzing spectral data allows to extract rapidly the discriminant spectral information from large data sets. The combination of VS and this type of data analysis is also discussed in this chapter. PMID- 22252633 TI - Brain chondroitin/dermatan sulfate, from cerebral tissue to fine structure: extraction, preparation, and fully automated chip-electrospray mass spectrometric analysis. AB - Chondroitin sulfate (CS) and dermatan sulfate (DS) glycosaminoglycans (GAGs) are covalently linked to proteins, building up a wide range of proteoglycans, with a prevalent expression in the extracellular matrix (ECM). In mammalian tissues, these GAG species are often found as hybrid CS/DS chains. Their structural diversity during chain elongation is produced by variability of sulfation in the repeating disaccharide units. In central nervous system, a large proportion of the ECM is composed of proteoglycans; therefore, CS/DS play a significant role in the functional diversity of neurons, brain development, and some brain diseases. A requirement for collecting consistent data on brain proteoglycan glycosylation is the development of adequate protocols for CS/DS extraction and detailed compositional and structure analysis. This chapter will present a strategy, which combines biochemical tools for brain CS/DS extraction, purification, and fractionation, with a modern analytical platform based on chip-nanoelectrospray multistage mass spectrometry (MS) able to provide information on the essential structural elements such as epimerization, chain length, sulfate content, and sulfation sites. PMID- 22252632 TI - Glycosaminoglycans: oligosaccharide analysis by liquid chromatography, capillary electrophoresis, and specific labeling. AB - Glycosaminoglycans (GAGs) are a class of biopolymers that include chondrotin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, heparin, and heparan sulfate. The GAGs are linear polysaccharides that are microheterogeneous in composition and polydisperse in size. Because they have the most complex structures, this article is aimed at describing a step-by-step procedure for processing and analyzing heparin and heparan sulfate-derived oligosaccharides, although the basic protocols and procedures apply equally well to other members of the GAG family. The methods described in this manuscript include the preparation of oligosaccharides through enzymatic depolymerization, size fractionation by preparative scale size-exclusion chromatography (SEC), and disaccharide isomer analysis by reverse-phase ion-pair high-performance liquid chromatography (RPIP-HPLC) and capillary electrophoresis (CE). PMID- 22252634 TI - Use of neutrons reveals the dynamics of cell surface glycosaminoglycans. AB - Cell surface glycosaminoglycans (GAG), such as heparan sulfate (HS) and heparin, are key multifunctional cell regulators, which are involved in numerous molecular events associated with tumor growth, metastasis, pathogen attachment, and immune response. GAG dynamically bind and regulate the activities of many signaling proteins such as growth factors, chemokines, and cytokines. GAG-binding interactions with proteins rely on the coupling between the geometry, flexibility, and rigidity of the polysaccharide chain. Understanding GAG dynamics at the molecular level can therefore provide fundamental insights into GAG function in a cellular context. Elastic incoherent neutron scattering is a powerful tool for the exploration of fast molecular motions in biological macromolecules. Recently, the technique was used to evaluate HS flexibility and rigidity on different timescales between the picosecond (ps) and the nanosecond (ns). Here, neutron spectroscopy experimental procedures are presented, with emphasis on the practical details necessary to prepare samples, run neutron scattering experiments, and extract the dynamics parameters from the data. PMID- 22252635 TI - Following protein-glycosaminoglycan polysaccharide interactions with differential scanning fluorimetry. AB - Studies of the structural changes invoked in proteins by the binding of the glycosaminoglycan (GAG) polysaccharide portion of proteoglycans are of increasing importance to research in a wide range of fields, from biochemistry and molecular biology to biotechnology and medicine. One important aspect is the degree of stabilisation or destabilisation induced in a protein by the binding of these anionic materials, and this can affect enzyme activity, the stability of complexes, folding and the formation of aggregates, including those in neurodegenerative processes. A simple method, able to determine the effect of interactions with GAG polysaccharides on protein stability is described, based on the propensity of a fluorescent dye-SyproTM Orange-to present differentiable fluorescence emission spectra following contact with exposed core amino acid residues. The method requires only commonly available and inexpensive equipment and is suitable for a multi-well format, allowing multiple readings to be made simultaneously. PMID- 22252637 TI - Serglycin: the master of the mast cell. AB - Serglycin is a proteoglycan composed of a relatively small (~17 kDa) core protein to which sulfated glycosaminoglycans of either heparin, heparan sulfate or chondroitin sulfate types are attached. Serglycin is expressed in many cell types, including in particular cells of hematopoietic origin. To study the function of serglycin, we have used a serglycin knockout mouse strain. A striking finding was that the mast cell population was severely affected by the absence of serglycin, as evidenced by distorted granule morphology and defective staining with cationic dyes. Moreover, the absence of serglycin caused a dramatic effect on the ability of mast cells to store a number of granule compounds, including several mast cell-specific proteases as well as biogenic amines. Hence, serglycin has a major function in maintaining mast cell secretory granule homeostasis. PMID- 22252636 TI - In vivo scintigraphic imaging of proteoglycans. AB - In this chapter, we present the methods developed in our lab for the scintigraphic imaging and direct quantitative evaluation of proteoglycan (PG) distribution in vivo. These methods relate to (1) the synthesis and radiolabeling of the NTP 15-5 with (99m)Tc, (2) preclinical scintigraphic imaging using laboratory animals, and (3) quantitative analysis of scintigraphic images. PMID- 22252638 TI - Analysis of aggrecan catabolism by immunoblotting and immunohistochemistry. AB - Aggrecan is essential for the normal function of articular cartilage and intervertebral disc, where it provides the ability for the tissues to withstand compressive loading. This property depends on both the high charge density endowed by its numerous chondroitin sulfate and keratan sulfate chains and its ability to form large molecular aggregates via interaction with hyaluronan. Degradation of aggrecan via the action of proteases takes place throughout life and the degradation products accumulate in the tissue and impair its function. Such degradation is exacerbated in degenerative or inflammatory joint disorders. The use of antibodies recognizing the various regions of aggrecan and the neoepitopes generated upon proteolytic cleavage has shown that matrix metalloproteinases and aggrecanases, members of the ADAMTS family, are responsible for aggrecan degradation, both throughout life and in disease. By using immunoblotting techniques, it is possible to determine the extent of aggrecan degradation and to identify the degradation products that have accumulated in the tissue, and immunohistochemistry allows the location of the aggrecan degradation to be established. PMID- 22252639 TI - Heparan sulfate proteoglycans as multifunctional cell regulators: cell surface receptors. AB - Proteoglycans are macromolecules expressed on the cell surfaces and in the extracellular matrix of most animal tissues (Annu Rev Biochem 68:729-777, 1999; Int Rev Cell Mol Biol 276:105-159, 2009). Heparan sulfate proteoglycans (HSPGs) are essential for animal development and homeostasis, and are involved in various pathological processes. The functions of HSPGs are largely exerted through interaction of the heparan sulfate (HS) side chains with different types of ligands, including diverse molecules such as cytokines, enzymes, and pathogens. One of the important roles of cell surface HSPGs is to mediate cytokine-induced cell signaling through interaction with growth factors (GFs) and their cognate receptors. A selective dependence of GFs for different structural features of HS has been demonstrated by applying cell models that are mutated variously in HS structure due to deficiency in enzymes involved in the biosynthesis of HS chains. PMID- 22252641 TI - Lumican promotes corneal epithelial wound healing. AB - Lumican regulates collagenous matrix assembly as a keratan sulfate proteoglycan in the cornea and is also present in the connective tissues of other organs and embryonic corneal stroma as a glycoprotein. In normal unwounded cornea, lumican is expressed by stromal keratocytes. Interestingly, injured mouse corneal epithelium ectopically and transiently expresses lumican during the early phase of wound healing, suggesting a potential lumican functionality unrelated to regulation of collagen fibrillogenesis, e.g., modulation of epithelial cell adhesion or migration. Healing of a corneal epithelial injury in lumican knockout (Lum(-/-)) mice was significantly delayed compared with Lum(+/-) mice. Addition of purified lumican to cultured medium promoted re-epithelialization and enhanced cell proliferation of wild-type mouse corneal epithelial cells in an organ culture. Therefore, administration of lumican may be beneficial for treating epithelial defects in the cornea and other tissues. PMID- 22252640 TI - Models for studies of proteoglycans in kidney pathophysiology. AB - Proteoglycans (PGs) impact many aspects of kidney health and disease. Models that permit genetic dissection of PG core protein and glycosaminoglycan (GAG) function have been instrumental to understanding their roles in the kidney. Matrix associated PGs do not serve critical structural roles in the organ, nor do they contribute significantly to the glomerular barrier under normal conditions, but their abnormal expression influences fibrosis, inflammation, and progression of kidney disease. Most core proteins are dispensable for nephrogenesis (glypican-3 being an exception) and for maintenance of function in adult life, but their loss alters susceptibility to experimental kidney injury. In contrast, kidney development is exquisitely sensitive to GAG expression and fine structure as evidenced by the severe phenotypes of mutants for genes involved in GAG biosynthesis. This article reviews PG expression in normal kidney and the abnormalities caused by their disruption in mice and man. PMID- 22252642 TI - Shedding of cell membrane-bound proteoglycans. AB - Membrane-bound proteoglycans function primarily as coreceptors for many glycosaminoglycan (GAG)-binding ligands at the cell surface. The majority of membrane-bound proteoglycans can also function as soluble autocrine or paracrine effectors as their extracellular domains, replete with all GAG chains, are enzymatically cleaved and released from the cell surface by ectodomain shedding. In particular, the ectodomain shedding of syndecans, a major family of cell surface heparan sulfate proteoglycans, is an important posttranslational mechanism that modulates diverse pathophysiological processes. Syndecan shedding is a tightly controlled process that regulates the onset, progression, and resolution of various infectious and noninfectious inflammatory diseases. This review describes methods to induce and measure the shedding of cell membrane bound proteoglycans, focusing on syndecan shedding as a prototypic example. PMID- 22252643 TI - Modulatory effects of proteoglycans on proteinase activities. AB - Proteoglycans (PGs), composed of a core protein and one or more covalently attached sulfated glycosaminoglycan (GAG) chains, interact with a wide range of bioactive molecules, such as growth factors and chemokines, to regulate cell behaviors in normal and pathological processes. Additionally, PGs, through their compositional diversity, play a broad variety of roles as modulators of proteinase activities. Interactions of proteinases with other molecules on the plasma membrane anchor and activate them at a specific location on the cell surface. These interactions with macromolecules other than their own protein substrates or inhibitors result in changes in their activity and/or may have important biological effects. Thus, GAG chains induce conformational changes upon their binding to peptides or proteins. This behavior may be related to the ability of GAGs to act as modulators for some proteins (1) by acting as crucial structural elements by the control of proteinase activities, (2) by increasing the protein stability, (3) by permitting some binding to occur, exposing binding regions on the target protein, or (4) by acting as coreceptors for some inhibitors, playing important roles for the acceleration of proteinase inhibition. Understanding the modulatory effects exerted by PGs on proteinase activities is expected to lead to new insights in the understanding of some molecular systems present in pathological states, providing new targets for drug therapy. PMID- 22252645 TI - Proteoglycans and cartilage repair. AB - Repair of damaged articular cartilage in osteoarthritis (OA) is a clinical challenge. Because cartilage is an avascular and aneural tissue, normal mechanisms of tissue repair through recruitment of cells to the site of tissue destruction are not feasible. Proteoglycan (PG) depletion induced by the proinflammatory cytokine interleukin-1beta, a principal mediator in OA, is a major factor in the onset and progression of joint destruction. Current symptomatic treatments of OA by anti-inflammatory drugs do not alter the progression of the disease. Various therapeutic strategies have been developed to antagonize the effect of proinflammatory cytokines. However, relatively few studies were conducted to stimulate anabolic activity, in an attempt to enhance cartilage repair. To this aim, a nonviral gene transfer strategy of glycosyltransferases responsible for PG synthesis has been developed and tested for its capacity to promote cartilage PG synthesis and deposition. Transfection of chondrocytes or cartilage explants by the expression vector for the glycosyltransferase beta-1,3-glucuronosyltransferase-I (GlcAT-I) enhanced PG synthesis and deposition in the ECM by promoting the synthesis of chondroitin sulfate GAG chains of the cartilage matrix. This indicates that therapy mediated through GT gene delivery may constitute a new strategy for the treatment of OA. PMID- 22252644 TI - Proteoglycans and osteolysis. AB - Osteolysis is a complex mechanism resulting from an exacerbated activity of osteoclasts associated or not with a dysregulation of osteoblast metabolism leading to bone loss. This bone defect is not compensated by bone apposition or by apposition of bone matrix with poor mechanical quality. Osteolytic process is regulated by mechanical constraints, by polypeptides including cytokines and hormones, and by extracellular matrix components such as proteoglycans (PGs) and glycosaminoglycans (GAGs). Several studies revealed that GAGs may influence osteoclastogenesis, but data are very controversial: some studies showed a repressive effect of GAGs on osteoclastic differentiation, whereas others described a stimulatory effect. The controversy also affects osteoblasts which appear sometimes inhibited by polysaccharides and sometimes stimulated by these compounds. Furthermore, long-term treatment with heparin leads to the development of osteoporosis fueling the controversy. After a brief description of the principal osteoclastogenesis assays, the present chapter summarizes the main data published on the effect of PGs/GAGs on bone cells and their functional incidence on osteolysis. PMID- 22252646 TI - Vecuronium was safely used in a patient with Engelmann's disease without muscle weakness. PMID- 22252647 TI - Increasing the detection speed of an all-electronic real-time biosensor. AB - Biosensor response time, which depends sensitively on the transport of biomolecules to the sensor surface, is a critical concern for future biosensor applications. We have fabricated carbon nanotube field-effect transistor biosensors and quantified protein binding rates onto these nanoelectronic sensors. Using this experimental platform we test the effectiveness of a protein repellent coating designed to enhance protein flux to the all-electronic real time biosensor. We observe a 2.5-fold increase in the initial protein flux to the sensor when upstream binding sites are blocked. Mass transport modelling is used to calculate the maximal flux enhancement that is possible with this strategy. Our results demonstrate a new methodology for characterizing nanoelectronic biosensor performance, and demonstrate a mass transport optimization strategy that is applicable to a wide range of microfluidic based biosensors. PMID- 22252649 TI - Debottlenecking recombinant protein production in Bacillus megaterium under large scale conditions--targeted precursor feeding designed from metabolomics. AB - In the present work the impact of large production scale was investigated for Bacillus megaterium expressing green fluorescent protein (GFP). Specifically designed scale-down studies, mimicking the intermittent and continuous nutrient supply of large- and small-scale processes, were carried out for this purpose. The recombinant strain revealed a 40% reduced GFP yield for the large-scale conditions. In line with extended carbon loss via formation of acetate and carbon dioxide, this indicated obvious limitations in the underlying metabolism of B. megaterium under the large-scale conditions. Quantitative analysis of intracellular amino acids via validated fast filtration protocols revealed that their level strongly differed between the two scenarios. During cultivation in large-scale set-up, the availability of most amino acids, serving as key building blocks of the recombinant protein, was substantially reduced. This was most pronounced for tryptophan, aspartate, histidine, glutamine, and lysine. In contrast alanine was increased, probably related to a bottleneck at the level of pyruvate which also triggered acetate overflow metabolism. The pre-cursor quantifications could then be exploited to verify the presumed bottlenecks and improve recombinant protein production under large-scale conditions. Addition of only 5 mM tryptophan, aspartate, histidine, glutamine, and lysine to the feed solution increased the GFP yield by 100%. This rational concept of driving the lab scale productivity of recombinant microorganisms under suboptimal feeding conditions emulating large scale can easily be extended to other processes and production hosts. PMID- 22252650 TI - Camptothecin induces apoptosis in cancer cells via microRNA-125b-mediated mitochondrial pathways. AB - Camptothecin (CPT) is an effective chemotherapeutic agent for treatment of patients with cancer. The mechanisms underlying CPT-mediated responses in cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug sensitivity. However, the interaction between camptothecin and miRNA has not been previously explored. In this study, we verified that miR 125b was down-regulated in CPT-induced apoptosis in cancer cells and that ectopic expression of miR-125b partially restored cell viability and inhibited cell apoptosis that was induced by CPT. In addition, we demonstrated that CPT induced apoptosis in cancer cells by miR-125b-mediated mitochondrial pathways via targeting to the 3'-untranslated (UTR) regions of Bak1, Mcl1, and p53. A significant increase in Bak1, Mcl1, and p53 protein levels was detected in response to the treatments of CPT. It is noteworthy that the expression levels of Bak1, Mcl1, and p53 increased in a time-dependent manner and negatively correlated with miR-125b expression. It is noteworthy that we revealed that miR 125b directly targeted the 3'UTR regions of multiple genes in a CPT-induced mitochondrial pathway. In addition, most targets of miR-125b were proapoptotic genes, whereas some of the targets were antiapoptotic genes. We hypothesized that miR-125b may mediate the activity of chemotherapeutic agents to induce apoptosis by regulating multiple targets. This is the first report to show that camptothecin induces cancer cell apoptosis via miRNA-mediated mitochondrial pathways. The results suggest that suppression of miR-125b may be a novel approach for the treatment of cancer. PMID- 22252651 TI - Discovery of 2-aminobuta-1,3-enynes in asymmetric organocascade catalysis: construction of drug-like spirocyclic cyclohexanes having five to six contiguous stereocenters. AB - We present herein for the first time the asymmetric synthesis of drug-like spiranes through reflexive-Michael reaction by using 2-aminobuta-1,3-enyne catalysis under mild conditions. PMID- 22252652 TI - Implementation of ethics grand rounds in an otolaryngology department. AB - OBJECTIVES/HYPOTHESIS: To create a case-based curriculum designed to teach and discuss the tenets of clinical medical ethics within an otolaryngology department. STUDY DESIGN: Survey-based study in a single-institution, academic otolaryngology department. METHODS: Case-based departmental ethics grand rounds were implemented on a quarterly basis within an academic department of otolaryngology. One-hour sessions were designed to use challenging cases volunteered by clinicians within the department to create a forum for discussion and education about clinical medical ethics. A four-question satisfaction survey was administered to participating clinicians to measure the impact of the program. RESULTS: Five grand rounds were held over 16 months from 2009 to 2011, with four to six cases presented per session. Sessions were well attended and received, with broad coverage of topics and lively discussions. The mean survey score was 18 (median, 19; standard deviation, 2) out of a maximum possible score of 20. When asked if the sessions helped to advance their skills and comfort within the field of medical ethics, 100% of respondents agreed or strongly agreed. A total of 86% of respondents agreed or strongly agreed that the sessions would change how they practiced medicine in a way that would benefit their patients. CONCLUSIONS: It is feasible to successfully implement case-based ethics grand rounds within an otolaryngology department. Participants demonstrated a gratifying level of approval, and a stated desire to implement the principles learned within their clinical practice. PMID- 22252653 TI - Letter to the Editor regarding "GC-MS with ethyl chloroformate derivatization for comprehensive analysis of metabolites in serum and its application to human uremia". PMID- 22252654 TI - Use of pneumatic nebulization and laser ablation-inductively coupled plasma-mass spectrometry to study the distribution and bioavailability of an intraperitoneally administered Pt-containing chemotherapeutic drug. AB - Quadrupole-based inductively coupled-mass spectrometry (ICP-MS) with pneumatic nebulization as a means of sample introduction was employed for quantification of platinum in blood and tissue samples of rats with peritoneal carcinomatosis, receiving intraperitoneal treatment with the Pt-containing chemotherapeutic drug oxaliplatin, and in the perfusate solution used for this purpose. The Pt levels were measured for various treatment conditions, i.e., with and without supporting treatment with the drug bevacizumab and at two different temperatures. Limits of detection obtained for platinum in blood and tissue samples were 0.3 and 2.0 pg g(-1) respectively. Evaluation of drug penetration into the tumor, under different conditions of treatment, was carried out via laser ablation-ICP-MS. Quantitative mapping of the Pt distribution in tissue sections of rat was attempted relying on gelatin standards. The results show an influence of the temperature at which the treatment is carried out, while supporting administration of the drug bevacizumab did not seem to affect the results. PMID- 22252655 TI - Quantification of femtomolar concentrations of the CYP3A substrate midazolam and its main metabolite 1'-hydroxymidazolam in human plasma using ultra performance liquid chromatography coupled to tandem mass spectrometry. AB - The benzodiazepine midazolam is a probe drug used to phenotype cytochrome P450 3A activity. In this situation, effective sedative concentrations are neither needed nor desired, and in fact the use of very low doses is advantageous. We therefore developed and validated an assay for the femtomolar quantification of midazolam and 1'-hydroxymidazolam in human plasma. Plasma (0.25 mL) and 96-well-based solid phase extraction were used for sample preparation. Extraction recoveries ranged between 75 and 92% for both analytes. Extracts were chromatographed within 2 min on a Waters BEH C18 1.7 MUm UPLC(r) column with a fast gradient consisting of formic acid, ammonia, and acetonitrile. Midazolam and 1'-hydroxymidazolam were quantified using deuterium- and (13)C-labeled internal standards and positive electrospray tandem mass spectrometry in the multiple reaction monitoring mode, which yielded lower limits of quantification of 50 fg/mL (154 fmol/L) and 250 fg/mL (733 fmol/L) and a corresponding precision of <20%. The calibrated concentration ranges were linear for midazolam (0.05-250 pg/mL) and 1' hydroxymidazolam (0.25-125 pg/mL), with correlation coefficients of >0.99. Within batch and batch-to-batch precision in the calibrated ranges for both analytes were <14% and <12%. No ion suppression was detectable, and plasma matrix effects were minimized to <15% (<25%) for midazolam (1'-hydroxymidazolam). The assay was successfully applied to assess the kinetics of midazolam in two human volunteers after the administration of single oral microgram doses (1-100 MUg). This ultrasensitive assay allowed us to quantify the kinetics of midazolam and 1' hydroxymidazolam for at least 10 h, even after the administration of only 1 MUg of midazolam. PMID- 22252656 TI - Capillary ion electrophoresis-capacitively coupled contactless conductivity detection of inorganic cations in human saliva on a polyvinyl alcohol-coated capillary. AB - Capillary ion electrophoresis-capacitively coupled contactless conductivity detection (CIE-C4D) with a polyvinyl alcohol chemically coated capillary (PVA capillary) was used to analyze inorganic cations (Na(+), K(+), NH(4)(+), Mg(2+), and Ca(2+)) commonly found in human saliva. The PVA capillary, which was made by our laboratory, minimized electro-osmotic flow in the wide pH range of the background electrolyte (BGE), and the PVA layer adsorbed to capillary wall did not affect the conductimetric background level. In this study, we determined an optimized BGE of 30 mM lactic acid/histidine plus 3 mM 18-crown-6 for the CIE-C4D system using the PVA capillary, which could simultaneously improve the separation of Mg(2+) and Ca(2+) from Na(+) and that of K(+) from NH(4)(+). This system obtained highly reproducible separation of cations in human saliva samples within 8 min at 20 kV without deprotonation. The quantifiability of cations in human saliva samples on the CIE-C4D system was demonstrated through identification by ion chromatography with satisfactory results. PMID- 22252657 TI - Letter from the editor. PMID- 22252658 TI - Pancreatic cancer: the role of molecular markers in diagnosis and management. AB - Despite an annual incidence of just 40,000 new cases per year, pancreatic adenocarcinoma (PAC) remains the fourth most common cause of cancer-related mortality in the United States, a fact indicative of the considerable diagnostic and therapeutic challenges posed by this malignancy. The availability of increasingly sophisticated molecular techniques over the last decade has intensified the search for biomarkers not only to predict outcome and response to therapy in established pancreatic malignancy but also to identify premalignant pancreatic lesions in at-risk individuals. A wealth of information regarding the complex sequence of genetic abnormalities in PAC has been gained from recent in depth molecular analyses, and lately the role of epigenetic alterations in the development and maintenance of pancreatic carcinogenesis has been more clearly described. In addition, advances in serum proteomic methods and the collection of circulating tumor cells offer hope for the development of noninvasive techniques for biomarker discovery. At present, we are awaiting the development and validation of robust biomarkers suitable for clinical application in this disease. Herein, we discuss the current status of molecular markers in the diagnosis and management of PAC and review potential clinical applications thereof. PMID- 22252659 TI - Primary cytoreductive surgery for advanced ovarian cancer: is it the past, present, or future? AB - Ovarian cancer accounts for more deaths in the United States than all other gynecologic malignancies combined. This is largely due to the fact that no effective screening test has been identified thus far to facilitate early detection. As a result, two-thirds of women continue to be diagnosed with advanced stage III or IV disease. Historically, the standard of care has consisted of primary cytoreductive surgery-with an operative goal of achieving an optimal result with minimal residual disease-followed by adjuvant, platinum-based chemotherapy. However, data suggesting comparable efficacy of neoadjuvant chemotherapy and interval debulking has recently challenged this conventional dogma. The current decision-making on how to initially treat women with newly diagnosed advanced ovarian cancer has become increasingly controversial. This article focuses on whether primary cytoreductive surgery should remain the preferred method of management, or whether it is time for it to be superseded by neoadjuvant chemotherapy. PMID- 22252660 TI - Ponatinib: targeting the T315I mutation in chronic myelogenous leukemia. PMID- 22252661 TI - Chuvash polycythemia: diagnosis and management. PMID- 22252663 TI - Targeted treatment in sarcoma patients. PMID- 22252664 TI - Diagnosis and treatment of atypical hemolytic uremic syndrome. PMID- 22252665 TI - Epithelial-mesenchymal transition in cancer progression. PMID- 22252666 TI - Granulocytic sarcoma 12 years following allogeneic marrow transplant for AML. PMID- 22252667 TI - Relapsed AML post-allogeneic hematopoietic stem cell transplantation. PMID- 22252668 TI - A case of concomitant T-cell large granular lymphocyte leukemia and plasma cell myeloma. PMID- 22252669 TI - A case of concomitant T-cell large granular lymphocytic leukemia and plasma cell myeloma. PMID- 22252670 TI - Meta-analysis of endoscopic versus sublabial pituitary surgery. AB - OBJECTIVES/HYPOTHESIS: To determine whether the endoscopic or sublabial transseptal transsphenoidal approach for pituitary surgery has superior outcomes or decreased complication rates. STUDY DESIGN: Retrospective meta-analysis of literature. METHODS: A MEDLINE search was conducted identifying all relevant literature in the English language from 1998 through 2010. Studies explicitly identifying pure sublabial or completely endoscopic approaches were included. Meta-analysis comparing the two techniques was performed for multiple outcome measures utilizing a random effects approach. RESULTS: A total of 21 endoscopic studies (n = 2,335) and 17 sublabial studies (n = 2,565) met inclusion criteria. Analysis revealed significantly superior rates of gross tumor resection (79% vs. 65%, P < .0001), as well as lower rates of cerebral spinal fluid leak (5% vs. 7%, P < .01), septal perforation (0% vs. 5%), and postoperative epistaxis (1% vs. 4%, P < .0001) for the endoscopic approach compared to the sublabial approach. There was no difference between the two techniques in the incidence of meningitis, diabetes insipidus, or resolution of hormonal abnormality. Hospital stay (P = .01) was shorter for endoscopic surgery compared to sublabial surgery, and there was no significant difference in terms of length of operation. CONCLUSIONS: The sublabial transsphenoidal approach has been the gold standard for pituitary surgery for many years. However, meta-analysis of the recent literature demonstrates superior outcomes and decreased postoperative complications with the endoscopic approach, potentially justifying a shift toward endoscopic pituitary surgery. PMID- 22252671 TI - In reference to The comparison of various ventilation modes and the association of risk factors with CO2 retention during suspension laryngoscopy. PMID- 22252673 TI - Medium from mesangial cells incubated with aggregated IgA1 from IgA nephropathy patients reduces podocyte adhesion through activation of the renin angiotensin system. AB - BACKGROUND: Podocyte injury plays an important role in glomerulosclerosis in IgA nephropathy (IgAN), and detachment from the glomerular basement membrane is the main cause of podocyte damage. In a previous study we found that medium from mesangial cells incubated with aggregated IgA1 (aIgA1) isolated from IgAN patients decreased podocyte adhesive capacity. However, the underlying mechanism remains unclear. MATERIALS AND METHODS: Podocytes were incubated in medium from mesangial cells incubated with aIgA1 isolated from IgAN patients, enalaprilat (10 5 M) and chymostatin (20 MUM), or with enalaprilat and chymostatin separately. Podocyte adhesive capacity was evaluated by cell counting and hexosaminidase assay. Expression of the renin angiotensin system was measured by real-time PCR, Western blot analysis and ELISA. RESULTS: Angiotensinogen, renin and angiotensin II type 1 and 2 receptors mRNA and protein expression, angiotensin-converting enzyme activity, and angiotensin II levels increased in podocyte lysates and conditioned culture media on exposure to mesangial medium containing aIgA1 from IgAN patients (P <0.05). Enalaprilat or chymostatin partly improved the reduced adhesive capacity of podocytes compared to cells exposed to mesangial medium (P <0.05), but it was still lower than for podocytes exposed to mesangial medium containing aIgA1 from healthy controls (P <0.05). CONCLUSION: Our findings indicate that activation of the renin angiotensin system in podocytes is partly involved in downregulation of adhesive capacity in podocytes by mesangial medium in IgA nephropathy. PMID- 22252674 TI - Anxiety in children with hearing aids or cochlear implants compared to normally hearing controls. AB - OBJECTIVES/HYPOTHESIS: The objectives of this study were to examine the levels of anxiety in hearing-impaired children with hearing aids or cochlear implants compared to normally hearing children, and to identify individual variables that were associated with differences in the level of anxiety. STUDY DESIGN: Large retrospective cohort study. METHODS: Self-reports and parent-reports concerning general anxiety, social anxiety, and generalized anxiety disorder were used. The study group (mean age, 11.8 years) consisted of three age-matched subgroups: 32 children with cochlear implants, 51 children with conventional hearing aids, and 127 children without hearing loss. RESULTS: Levels of anxiety in children with cochlear implants and normally hearing children were similar. Early implantation was associated with lower levels of general and social anxiety. Remarkably, children with conventional hearing aids had higher levels of social anxiety, and their parents also reported more generalized anxiety disorder. CONCLUSIONS: The outcomes demonstrate that in their level of anxiety, children with cochlear implants might be more comparable to normally hearing children than to children with hearing aids. This positive finding can be the consequence of audiological factors or other aspects of the cochlear implant rehabilitation program. PMID- 22252672 TI - Routine clinical use of the one-step nucleic acid amplification assay for detection of sentinel lymph node metastases in breast cancer patients: results of a multicenter study in Japan. AB - BACKGROUND: The objective of this study was to confirm, by means of a multicenter study conducted in Japan, the reliability and usefulness of the one-step nucleic acid amplification (OSNA) assay in routine clinical use for sentinel lymph node biopsy (SLNB) of breast cancer patients. METHODS: Patients with Tis-T2N0M0 breast cancer who underwent SLNB before systemic chemotherapy comprised the study cohort. A whole sentinel lymph node (SLN) was examined intraoperatively with the OSNA assay except for a 1-mm-thick, central slice of the lymph node, which underwent pathologic examination after the operation. For patients who underwent axillary dissection, non-SLNs were examined with routine pathologic examination. RESULTS: In total, 417 SLNBs from 413 patients were analyzed. SLN metastases were detected with greater sensitivity by the OSNA assay than by pathologic examination (22.5% vs 15.8%; P < .001), as expected from the difference in size of the specimens examined. Patients who had SLN metastases assessed with the OSNA assay proved to harbor non-SLN metastases with an overall risk ratio of 33.7%. The risk of non-SLN metastasis was significantly lower for patients who had positive SLNs assessed as OSNA+ than for those who had SLNs assessed as OSNA++ (17.6% vs 44%; P = .012). CONCLUSIONS: The OSNA assay can be used for routine clinical SLNB, and its assessment for volume of metastasis may be a powerful predictive factor for non-SLN metastasis. Further studies with more patients are needed to confirm the usefulness of this assay for selection in the clinical setting of patients who do not need axillary dissection. PMID- 22252675 TI - Erythropoietin biosimilars currently available in hematology-oncology. AB - The discovery of epoietin (EPO) and the cloning of its gene facilitated the understanding of the mechanism of control behind red blood cell formation. This cloning was followed by the commercial development of recombinant human EPO (rHuEPO). The use of erythropoiesis-stimulating agents (ESAs) (epoietin, ESA, EPO) is important for the treatment of anemia in patients with chronic renal failure and cancer patients with chemotherapy-induced anemia. After several years of discussions, debates and questions, ESA, intravenous iron and blood transfusions seem to have finally found their respective indications in the treatment of anemia in cancer patients receiving chemotherapy. Now, a new question arises: What is the role of ESA biosimilars? PMID- 22252676 TI - A population-based study of therapy and survival for patients with head and neck cancer treated in the community. AB - BACKGROUND: The objective of this study was to examine patterns of care and survival in a population-based sample of patients with head and neck cancer (HNC) who were treated in the community or in hospitals that had residency training programs. METHODS: Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program were used to sample 1317 patients aged >=20 years with invasive squamous HNC who were diagnosed during 2004 and who had vital status available through 2008. RESULTS: Treatment and survival were influenced by tumor site and disease stage. Patients who had stage I/II cancer of the oral cavity generally underwent surgery; patients with stage III oral cavity disease underwent surgery and received radiation; and patients with stage IV oral cavity disease underwent surgery and received chemoradiation. Patients with early stage cancer of the oropharynx either underwent surgery or received radiation and chemotherapy, and patients with late/unstaged oropharyngeal disease primarily received radiation and chemotherapy. Patients with early stage cancer of the larynx mainly received radiation alone, and patients with late stage laryngeal disease generally received chemoradiation. Cisplatin-based regimens were used most frequently. Overall, taxanes were used in 32% of regimens, and cetuximab was used in <3% of regimens. Patients aged >=50 years, those with a Charlson comorbidity score >=1, those with stage IV disease, and those with cancer located in the oral cavity or larynx had poorer survival. Although facilities with residency training programs treated more black patients and more patients with late stage disease, when adjusted for other factors, survival rates were similar to those reported in facilities with no such programs. CONCLUSIONS: Therapy generally followed accepted standards for 2004. Findings in particular tumor sites and stages may reflect the variability that still exists for the treatment of HNC. The use of taxanes and cetuximab is expected to increase based on new evidence of benefit. Reducing treatment-related toxicities and long-term functional deficits will be critical and especially important with the increase in human papillomavirus-related cancers. In addition, further attempts to improve survival for older patients are needed. PMID- 22252677 TI - Racial variation in umbilical cord blood sex steroid hormones and the insulin like growth factor axis in African-American and white female neonates. AB - PURPOSE: To evaluate whether there is racial variation in venous umbilical cord blood concentrations of sex steroid hormones and the insulin-like growth factor (IGF) axis between female African-American and white neonates. METHODS: Maternal and birth characteristics and venous umbilical cord blood samples were collected from 77 African-American and 41 white full-term uncomplicated births at two urban hospitals in 2004 and 2005. Cord blood was measured for testosterone, dehydroespiandrosterone-sulfate, estradiol, and sex steroid hormone-binding globulin (SHBG) by immunoassay. IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) were measured by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed for the hormones. RESULTS: African-American neonates weighed less at birth (3,228 g vs. 3,424 g, p < 0.004) than whites. Birth weight was positively correlated with IGF-1, IGFBP-3, and the molar ratio of IGF-1 to IGFBP-3, but inversely correlated with the molar ratio of IGF-2 to IGFBP-3. Adjusted models showed higher testosterone (1.82 ng/ml vs. 1.47 ng/ml, p = 0.006) and the molar ratio of testosterone to SHBG (0.42 vs. 0.30, p = 0.03) in African American compared to white female neonates. IGF-1, IGF-2, and IGFBP-3 were lower in African-American compared to white female neonates, but only the difference for IGF-2 remained significant (496.5 ng/ml vs. 539.2 ng/ml, p = 0.04). CONCLUSION: We provide evidence of racial variation in cord blood testosterone and testosterone to SHBG in African-American compared to white female neonates, and higher IGF-2 in white compared to African-American female neonates. Findings suggest plausible explanations for a prenatal influence on subsequent breast cancer risk and mortality. Further work is needed to confirm these observations. PMID- 22252685 TI - In situ exposure to non-directional beacons for air traffic control. AB - In situ electromagnetic field exposure of workers and the general public due to non-directional beacons (NDB) for air traffic control is assessed and characterized. For occupational exposure, the maximal measured electric field value is 881.6 V/m and the maximal magnetic field value is 9.1 A/m. The maximum electric fields exceed the International Commission on Non-Ionizing Radiation Protection (ICNIRP) reference levels at all seven NDB sites, and the magnetic fields at two of the seven NDB sites (occupational exposure). Recommendations and compliance distances for workers and the general public are provided. PMID- 22252686 TI - Posterior pharyngeal flap for velopharyngeal insufficiency patients: a new technique for flap inset. AB - OBJECTIVES/HYPOTHESIS: To describe a modification of the originally described superiorly based pharyngeal flap as a secondary operation to correct velopharyngeal insufficiency (VPI) in patients with nonsyndromic repaired cleft palate. STUDY DESIGN: Prospective clinical trial at university medical center. METHODS: Twenty-six patients with VPI after cleft palate repair underwent a modified posterior pharyngeal flap procedure. Patients with submucous cleft palate or associated with syndromic VPI or Pierre Robin sequence were excluded from the study. Flap was harvested high up in the nasopharynx and inserted into the soft palate through a transverse full-thickness palatal incision. Lateral pharyngeal ports were determined by 45-degree nasoendoscopy. Speech assessment was done preoperatively and 3 months postoperatively. The flap integrity and lateral pharyngeal ports were evaluated with postoperative nasoendoscopy. RESULTS: Postoperative speech assessment showed significant improvement in the overall velopharyngeal function, nasal emission, resonance, and articulation defects. The pattern of velopharyngeal closure was circular in 15 patients, coronal in six patients, and sagittal in five patients. Eighteen patients received medium to wide flap, five patients had narrow flap, and three patients had near obstructing flap. Velopharyngeal function was normal or borderline insufficiency in 24 patients (92%). Partial flap dehiscence was seen in two patients and was considered as failure despite the significant improvement in their preoperative VPI. CONCLUSIONS: The minimal complication and ease of flap design with precise flap inset make this modified superior flap technique easily applicable with a high success rate for patients with VPI after cleft palate repair. PMID- 22252687 TI - Friction coefficients for mechanically damaged bovine articular cartilage. AB - We used a pin-on-disc tribometer to measure the friction coefficient of both pristine and mechanically damaged cartilage samples in the presence of different lubricant solutions. The experimental set up maximizes the lubrication mechanism due to interstitial fluid pressurization. In phosphate buffer solution (PBS), the measured friction coefficient increases with the level of damage. The main result is that when poly(ethylene oxide) (PEO) or hyaluronic acid (HA) are dissolved in PBS, or when synovial fluid (SF) is used as lubricant, the friction coefficients measured for damaged cartilage samples are only slightly larger than those obtained for pristine cartilage samples, indicating that the surface damage is in part alleviated by the presence of the various lubricants. Among the lubricants considered, 100 mg/mL of 100,000 Da MW PEO in PBS appears to be as effective as SF. We attempted to discriminate the lubrication mechanism enhanced by the various compounds. The lubricants viscosity was measured at shear rates comparable to those employed in the friction experiments, and a quartz crystal microbalance with dissipation monitoring was used to study the adsorption of PEO, HA, and SF components on collagen type II adlayers pre-formed on hydroxyapatite. Under the shear rates considered the viscosity of SF is slightly larger than that of PBS, but lower than that of lubricant formulations containing HA or PEO. Neither PEO nor HA showed strong adsorption on collagen adlayers, while evidence of adsorption was found for SF. Combined, these results suggest that synovial fluid is likely to enhance boundary lubrication. It is possible that all three formulations enhance lubrication via the interstitial fluid pressurization mechanism, maximized by the experimental set up adopted in our friction tests. PMID- 22252688 TI - Magnetic resonance imaging surveillance following vestibular schwannoma resection. AB - OBJECTIVES/HYPOTHESIS: To describe the incidence, pattern, and course of postoperative enhancement within the operative bed using serial gadolinium enhanced magnetic resonance imaging (MRI) following vestibular schwannoma (VS) resection and to identify clinical and radiologic variables associated with recurrence. STUDY DESIGN: Retrospective cohort study. METHODS: All patients who underwent microsurgical resection of VS between January 2000 and January 2010 at a single tertiary referral center were reviewed. Postoperative enhancement patterns were characterized on serial MRI studies. Clinical follow-up and outcomes were recorded. RESULTS: During the last 10 years, 350 patients underwent microsurgical VS resection, and of these, 203 patients met study criteria (mean radiologic follow-up, 3.5 years). A total of 144 patients underwent gross total resection (GTR), 32 received near-total resection (NTR), and the remaining 27 underwent subtotal resection (STR); 98.5% of patients demonstrated enhancement within the operative bed following resection (58.5% linear, 41.5% nodular). Stable enhancement patterns were seen in 24.5% of patients, regression in 66.0%, and resolution in only 3.5% of patients on the most recent postoperative MRI. Twelve patients recurred a mean of 3.0 years following surgery. The average maximum linear diameter growth rate among recurrent tumors was 2.3 mm per year. Those receiving STR were more than nine times more likely to experience recurrence compared to those undergoing NTR or GTR (P < .001). Nodular enhancement on the initial postoperative MRI was associated with a 16-fold increased risk for future recurrence compared to those with linear patterns (P = .008). Among those with nodular enhancement on baseline postoperative MRI, a maximum linear diameter of >= 15 mm or volume of >= 0.4 cm(3) was associated with an approximate five-fold increased risk for future growth (P < .02). CONCLUSIONS: Persistent nonspecific radiologic enhancement within the postoperative field is common, making the diagnosis of tumor recurrence challenging. Factors including completeness of resection and baseline postoperative MRI findings provide valuable information regarding risk for recurrence, which may assist the clinician in determining an appropriate postoperative MRI surveillance schedule. Future studies using standardized terminology and consistent study metrics are needed to further refine surveillance recommendations. PMID- 22252689 TI - Neonatal intracranial hemangiopericytoma: a 7-year follow-up. PMID- 22252690 TI - A C-di-GMP-proflavine-hemin supramolecular complex has peroxidase activity- implication for a simple colorimetric detection. AB - Herein, we demonstrate that the bacterial signaling molecule, c-di-GMP, can enhance the peroxidation of hemin when proflavine is present. The c-di-GMP proflavine-hemin nucleotidezyme can oxidize the colorless compound 2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonic acid), ABTS, to the colored radical cation ABTS(+) and hence provides simple colorimetric detection of c-di-GMP at low micromolar concentrations. PMID- 22252691 TI - Why are the chosen pulse oximeters so expensive? PMID- 22252693 TI - Lifeblood responds to criticisms in Welfare's personal view article. PMID- 22252695 TI - Are we going over the top with VTE prophylaxis tick boxes? PMID- 22252694 TI - Guideline development group was not in the pocket of pharma. PMID- 22252696 TI - Why does the BMJ support donations of pulse oximeters when they have no effect? PMID- 22252697 TI - Doctors taking a pulse using their mobile phone can spread MRSA. PMID- 22252698 TI - Smart doctors playing stupid? PMID- 22252699 TI - Bring back nylon string vests. PMID- 22252701 TI - Brisk and prolonged daily walking is needed to outpace the Grim Reaper. PMID- 22252702 TI - Arthroprosthetic cobaltism associated with metal on metal hip implants. PMID- 22252703 TI - Anticipatory palliative care allows people to die with dignity. PMID- 22252704 TI - Preparation is the key to death being our friend. PMID- 22252705 TI - Scientists are urged to oppose new US legislation that will put studies behind a pay wall. PMID- 22252706 TI - Airlines should be legally required to warn travellers about malaria. PMID- 22252707 TI - Scotland introduces record of ethnicity on death certificates. PMID- 22252708 TI - Doctor approved detention of unconscious man three hours before he died, court hears. PMID- 22252709 TI - Only women with symptoms need to have their breast implants removed, says government. PMID- 22252711 TI - Electrode screening by ionic liquids. AB - In this work we are concerned with the short-range screening provided by the ionic liquid dimethylimidazolium chloride near a charged wall. We study the free energy profiles (or potentials of mean force) for charged and neutral solutes as a function of distance from a charged wall. Four different wall charge densities are used in addition to a wall with zero charge. The highest magnitude of the charge densities is +/-1 e nm(-2) which is close to the maximum limit of charge densities accessible in experiments, while the intermediate charges +/-0.5 e nm( 2) are in the range of densities typically used in most of the experimental studies. Positively and negatively charged solutes of approximately the size of a BF ion and a Cl(-) ion are used as probes. We find that the ionic liquid provides excellent electrostatic screening at a distance of 1-2 nm. The free energy profiles show minima which are due to layering in the ionic liquid near the electrodes. This indicates that the solute ions tend to displace ionic liquid ions in the layers when approaching the electrode. The important role of non electrostatic forces is demonstrated by the oscillations in the free energy profiles of uncharged solutes as a function of distance from the wall. PMID- 22252710 TI - Sendai virus vector-mediated brain-derived neurotrophic factor expression ameliorates memory deficits and synaptic degeneration in a transgenic mouse model of Alzheimer's disease. AB - Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain. PMID- 22252712 TI - Mice with a D190N mutation in the gene encoding rhodopsin: a model for human autosomal-dominant retinitis pigmentosa. AB - Rhodopsin is the G protein-coupled receptor in charge of initiating signal transduction in rod photoreceptor cells upon the arrival of the photon. D190N (Rho(D190n)), a missense mutation in rhodopsin, causes autosomal-dominant retinitis pigmentosa (adRP) in humans. Affected patients present hyperfluorescent retinal rings and progressive rod photoreceptor degeneration. Studies in humans cannot reveal the molecular processes causing the earliest stages of the condition, thus necessitating the creation of an appropriate animal model. A knock-in mouse model with the D190N mutation was engineered to study the pathogenesis of the disease. Electrophysiological and histological findings in the mouse were similar to those observed in human patients, and the hyperfluorescence pattern was analogous to that seen in humans, confirming that the D190N mouse is an accurate model for the study of adRP. PMID- 22252713 TI - Genipin attenuates sepsis by inhibiting Toll-like receptor signaling. AB - The pathogenesis of sepsis is characterized by overwhelming inflammatory responses that lead to tissue damage and organ failure. Toll-like receptor (TLR) signaling is crucial for induction of hyperinflammatory responses and tissue injury during sepsis. Genipin, an aglycon of geniposide, has antiinflammatory and antimicrobial activities. The purpose of this study was to test the hypothesis that genipin reduces multiple organ dysfunction and mortality during sepsis through inhibition of TLR signaling. Male ICR were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia by lipopolysaccharide (LPS). Various doses of genipin (1, 2.5 and 5 mg/kg) or a vehicle were administered intravenously immediately after CLP or intraperitoneally after LPS treatment. In another set of survival tests, mice were treated with 2.5 mg/kg of genipin 0 and 24 h after CLP. Genipin was found to improve survival and to attenuate multiple organ dysfunction. Genipin attenuated production of proinflammatory cytokines and release of high-mobility group box 1 (HMGB1). Genipin prevented TLR2 and TLR4, myeloid differentiation factor 88 and the Toll/interleukin-1 receptor domain containing adaptor protein, inducing interferon-beta overexpression. Phosphorylation of mitogen-activated protein kinases and interferon regulatory factor 3 and translocation of nuclear factor (NF)-kappaB were prevented by genipin. Moreover, genipin attenuated increases in serum tumor necrosis factor alpha and HMGB1 in LPS-induced endotoxemia. Pam3CSK4- and LPS-mediated production of nitrites and proinflammatory cytokines was suppressed by genipin in RAW264.7 cells. Genipin attenuated mortality and organ injuries during sepsis through interference with TLR signaling. Therefore, genipin might be useful as a potential therapeutic agent for treatment of sepsis. PMID- 22252714 TI - Preserving the B-cell compartment favors operational tolerance in human renal transplantation. AB - Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-cell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT. PMID- 22252715 TI - Squamous cell carcinoma metastatic to neck from an unknown primary: the potential impact of modern pathologic evaluation on perceived incidence of human papillomavirus-positive oropharyngeal carcinoma prior to 1970. AB - OBJECTIVES/HYPOTHESIS: From the 1950s through the 1960s, an unknown number of oropharyngeal squamous cell carcinomas (SCCs) presented with metastases to cervical lymph nodes from an unknown primary (SCCUP) and were not recognized as oropharyngeal in origin. At present, pathologic evaluation of SCCUP for human papillomavirus (HPV) improves discovery of occult oropharyngeal SCC and may partially explain increased incidence of HPV-positive oropharyngeal SCC. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective study of 13 cases of SCCUP diagnosed from 1956 to 1969 was performed. The probability of these cases of metastatic SCC to originate from the oropharynx was assessed by characterizing their morphology (keratinizing vs. nonkeratinizing) and HPV status by in situ hybridization and p16 immunostaining. RESULTS: Two cases of nonkeratinizing SCC positive for HPV by in situ hybridization and p16 immunohistochemistry were identified. These cases were most likely of oropharyngeal origin. CONCLUSIONS: These two cases can be added to the other 15 cases of HPV-positive primary oropharyngeal SCC identified in our department from 1956 to 1969. When determining the incidence of HPV-positive oropharyngeal SCC before the 1970s, a correction factor of about +13% (2/15) accounting for modern pathologic workup of SCCUP during the last couple of decades may be appropriate. PMID- 22252716 TI - Portraying disease: Sorolla's Sad Legacy. AB - In 1899, the Spanish painter Joaquin Sorolla represented, in a large canvas, a group of children probably with sequels of poliomyelitis bathing at Valencia's beach. The title of this painting was Sad Legacy. This work contributed to the international diffusion of Sorolla's artistic creation. We briefly report some facts regarding the painter and his work referring to those portraits of children and especially of sick children. PMID- 22252717 TI - Permeability of the arachnoid and pia mater. The role of ion channels in the leptomeningeal physiology. AB - PURPOSE: The purpose of this paper is to study the ionic permeability of the leptomeninges related to the effect of ouabain (sodium-potassium-ATPase inhibitor) and amiloride (epithelial sodium channel (ENaC) inhibitor) on the tissue, as well as identify the presence of ion channels. METHODS: Cranial leptomeningeal samples from 26 adult sheep were isolated. Electrophysiological measurements were performed with Ussing system and transmembrane resistance values (R(TM) in Omega*cm(2)) obtained over time. Experiments were conducted with the application of ouabain 10(-3) M or amiloride 10(-5) M at the arachnoidal and pial sides. Immunohistochemical studies of leptomeningeal tissue were prepared with alpha-1 sodium-potassium-ATPase (ATP1A1), beta-ENaC, and delta-ENaC subunit antibodies. RESULTS: The application of ouabain at the arachnoidal side raised the transmembrane resistance statistically significantly and thus decreased its ionic permeability. The addition of ouabain at the pial side led also to a significant but less profound increment in transmembrane resistance. The addition of amiloride at the arachnoidal or pial side did not produce any statistical significant change in the R(TM) from controls (p > 0.05). Immunohistochemistry confirmed the presence of the ATP1A1 and beta- and delta-ENaC subunits at the leptomeninges. CONCLUSIONS: In summary, leptomeningeal tissue possesses sodium potassium-ATPase and ENaC ion channels. The application of ouabain alters the ionic permeability of the leptomeninges thus reflecting the role of sodium potassium-ATPase. Amiloride application did not alter the ionic permeability of leptomeninges possibly due to localization of ENaC channels towards the subarachnoid space, away from the experimental application sites. The above properties of the tissue could potentially be related to cerebrospinal fluid turnover at this interface. PMID- 22252718 TI - Blinking--an unusual presentation of obstructive hydrocephalus relieved by endoscopic third ventriculostomy. PMID- 22252719 TI - Systematic review and meta-analysis of the risk factors for sudden sensorineural hearing loss in adults. AB - OBJECTIVES/HYPOTHESIS: To review the medical literature evidence of potential risk factors for sudden sensorineural hearing loss (SSNHL) in the adult general population. STUDY DESIGN: Systematic review of prospective and retrospective studies; meta-analysis of case-controlled studies. METHODS: Three researchers independently reviewed MEDLINE (January 1, 1950-November 30, 2010), Embase (January 1, 1980-November 30, 2010), and Evidence-Based Medicine Reviews databases in addition to conducting a manual reference search. Randomized controlled trials, prospective cohort studies, consecutive/nonconsecutive case series, and retrospective reviews in which a clear definition of SSNHL was stated were included in the study. Researchers individually extracted data regarding patient information and the presumed risk factors. Discrepancies were resolved by mutual consensus. RESULTS: Twenty-two articles met the inclusion criteria. Cardiovascular risk factors (smoking, increased alcohol consumption) appeared to be associated with a higher risk of developing SSNHL. A low level of serum folate may also be implicated as a risk factor. Factor V Leiden and MTHFR gene polymorphisms were found to occur more frequently in patients with SSNHL in several studies, suggesting these inherited prothrombophilic mutations could be independent risk factors of SSNHL. CONCLUSIONS: Acquired and inherited cardiovascular risk factors appeared to be associated with an increased risk of developing SSNHL. PMID- 22252720 TI - Cortical sensitivity to contrast polarity and orientation of faces is modulated by temporal-nasal hemifield asymmetry. AB - Behavioral studies demonstrate that the efficiency of detection of faces is dependent on configural and contrast polarity information characteristic to human faces. Stimulus inversion or contrast polarity reversal can disrupt this process. We investigated whether a face-sensitive event-related potential component, the N170, is modulated by the orientation and contrast polarity of highly degraded schematic face-like patterns (Experiment 1) in the same manner as it is for face photographs (Experiment 2). Inversion and/or contrast reversal delayed and enhanced the N170 for both kinds of stimuli, suggesting that a white oval with three black squares is sufficient to elicit face-sensitive cortical responses. In Experiment 3 we further tested whether the extrageniculate visual pathways modulate early cortical responses to faces. We found that the N170 responses to configural and contrast information are modulated by temporal-nasal visual field asymmetry under monocular viewing conditions, suggesting the involvement of subcortical, extrageniculate visual pathways in face detection. These results are consistent with the idea that an ontogenetically early and primitive bias to orient towards face-like patterns with relevant configural and contrast information influences the early stages of cortical face processing. PMID- 22252721 TI - Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy. AB - BACKGROUND: For limited-stage diffuse large B-cell lymphoma (DLBCL), treatment decisions are often influenced by toxicity profiles. One strategy that minimizes chemotherapy-induced toxicities is abbreviated chemotherapy plus consolidation involved-field radiotherapy (IFRT). Involved-node radiotherapy (INRT) is a new concept to DLBCL, aimed to reduce radiotherapy-induced toxicities. We retrospectively review the long-term outcomes of limited-stage DLBCL treated with abbreviated systemic therapy and radiotherapy focusing on field size: IFRT versus INRT. METHODS: The British Columbia Cancer Agency Lymphoid Cancer Database was used to identify patients diagnosed with limited-stage DLBCL (stage I/II, without B-symptoms; bulk < 10 cm) from 1981 to 2007. Patients were prescribed 3 cycles of chemotherapy plus IFRT (1981-1996) or INRT<=5 cm (1996-2007), defined as INRT to the prechemotherapy involved nodes with margins <= 5 cm. RESULTS: A total of 288 patients were identified: 56% were aged >60 years, 34% had stage II disease, 55% had extranodal disease, 19% had elevated lactate dehydrogenase levels, and 15% received rituximab. The two radiotherapy groups were IFRT (138 patients; 48%) and INRT<=5cm (150 patients; 52%); median follow-up was 117 and 89 months, respectively. Distant relapse was the most common site of failure in both groups. After INRT<=5 cm, marginal recurrence was infrequent (2%). Time to progression (P = .823), progression-free survival (P = .575), and overall survival (P = .417) were not significantly different between the radiotherapy cohorts. Radiotherapy field size was not a significant prognostic factor on multivariate analyses. CONCLUSIONS: This research is the first known body of work to apply the concept of INRT to limited-stage DLBCL. Reducing the field size from IFRT to INRT<=5 cm maintains a low marginal recurrence risk with no impact on overall outcome. PMID- 22252722 TI - Thermoresponsive semicrystalline poly(epsilon-caprolactone) networks: exploiting cross-linking with cinnamoyl moieties to design polymers with tunable shape memory. AB - The overall goal of this study was to synthesize semicrystalline poly(epsilon caprolactone) (PCL) copolymer networks with stimuli-responsive shape memory behavior. Herein, we investigate the influence of a cinnamoyl moiety to design shape memory polymer networks with tunable transition temperatures. The effect of various copolymer architectures (random or ABA triblock), the molecular weight of the crystalline domains, PCL diol, (M(w) 1250 or 2000 g mol(-1)) and its composition in the triblock (50 or 80 mol %) were also investigated. The polymer microstructures were confirmed by NMR, DSC, WAXS and UV-vis spectroscopic techniques. The thermal and mechanical properties and the cross-linking density of the networks were characterized by DSC, tensile testing and solvent swelling, respectively. Detailed thermomechanical investigations conducted using DMA showed that shape memory behavior was obtained only in the ABA triblock copolymers. The best shape memory fixity, R(f) of ~99% and shape recovery, R(r) of ~99% was obtained when PCL diol with M(w) 2000 g mol(-1) was incorporated in the triblock copolymer at a concentration of 50 mol %. The series of triblock copolymers with PCL at 50 mol % also showed mechanical properties with tunable shape memory transition temperatures, ranging from 54 degrees C to close to body temperature. Our work establishes a general design concept for inducing a shape memory effect into any semicrystalline polyester network. More specifically, it can be applied to systems which have the highest transition temperature closest to the application temperature. An advantage of our novel copolymers is their ability to be cross-linked with UV radiation without any initiator or chemical cross-linker. Possible applications are envisioned in the area of endovascular treatment of ischemic stroke and cerebrovascular aneurysms, and for femoral stents. PMID- 22252723 TI - Freedom of choice of specialist physicians is important to Swiss resident: a cross-sectional study. AB - QUESTION UNDER STUDY: To assess how important the possibility to choose specialist physicians is for Swiss residents and to determine which variables are associated with this opinion. METHODS: This cross-sectional study used data from the 2007 Swiss population-based health survey and included 13,642 non institutionalised adults who responded to the telephone and paper questionnaires. The dependent variable included answers to the question "How important is it for you to be able to choose the specialist you would like to visit?" Independent variables included socio-demographics, health and past year healthcare use measures. Crude and adjusted logistic regressions for the importance of being able to choose specialist physicians were performed, accounting for the survey design. RESULTS: 45% of participants found it very important to be able to choose the specialist physician they wanted to visit. The answers "rather important", "rather not important" and "not important" were reported by 28%, 20% and 7% of respondents. Women, individuals in middle/high executive position, those with an ordinary insurance scheme, those reporting >=2 chronic conditions or poorer subjective health, or those who had had >=2 outpatient visits in the preceding year were more likely to find this choice very important. CONCLUSIONS: In 2007, almost half of all Swiss residents found it very important to be able to choose his/her specialist physician. The further development of physician networks or other chronic disease management initiatives in Switzerland, towards integrated care, need to pay attention to the freedom of choice of specialist physicians that Swiss residents value. Future surveys should provide information on access and consultations with specialist physicians. PMID- 22252724 TI - Regeneration of mastoid air cells using polycaprolactone/beta-tricalcium phosphate biocomposites: an experimental study. AB - OBJECTIVES/HYPOTHESIS: The study aimed to regenerate pneumatic air cells in guinea pig bulla using three-dimenisonal (3D) biocomposite scaffolds consisting of polycaprolactone/beta-tricalcium phosphate (PCL/beta-TCP). STUDY DESIGN: Prospective controlled study in experimental animals. METHODS: PCL/beta-TCP composites were implanted into the bulla with mucosa preservation in group A (n = 10). PCL/beta-TCP composites coated with collagen were implanted in group B (n = 10). After 12 weeks, the bullae were extracted and evaluated by micro-computed tomography (micro-CT) and were processed for histological analyses. RESULTS: In group A, micro-CT showed a well-maintained honeycomb appearance of micropores without obstruction. Regeneration of the mucosa was noted inside the pores of the 3D scaffold. However, partial obstruction of the micropores with new bone formation was evident in group B. CONCLUSIONS: Group A showed more satisfactory mucosal regeneration into the micropores. Our results indicate that the 3D scaffold may be amenable for use during mastoidectomy. Further studies for gas exchange in the regenerated mucosa are necessary. PMID- 22252725 TI - Protective effects of Salvianolic acid B on Schwann cells apoptosis induced by high glucose. AB - Diabetic peripheral neuropathy (DPN) is one of the most common and debilitating microvascular complications of diabetes, and there is no effective therapy for the prevention or treatment of DPN. Oxidative stress triggers several pathways of injury and may be the unifying factor of hyperglycemia. The aim of this study was to investigate protective effect of Salvianolic acid B (Sal B) on the high glucose (HG)-induced oxidative stress-induced mitochondrial pathway activation and Schwann cells (SCs) apoptosis in vitro. We found that Sal B inhibited the HG induced oxidative stress by reducing ROS and 8-hydroxy-2-deoxy Guanosine (8-OHdG) production, and mitochondrial depolarization and apoptosis in SCs in a dose dependent manner. Furthermore, Sal B down-regulated the HG-mediated Bax expression and AIF nuclear translocation and the release of cytochrome c, but up regulated the HG-induced BcL-2 expression in SCs. In addition, Sal B attenuated the HG-induced activation of caspase 3 and 9 and minimized the cleavage of PARP in SCs. Our results indicated that Sal B antagonized the HG-induced oxidative stress, activation of the mitochondrial pathway and apoptosis in SCs. PMID- 22252726 TI - Cholesterol, GM1, and autism. AB - Disruption of cholesterol metabolism has been hypothesized to contribute to dementia, possibly due to its role in maintaining membrane fluidity as well as the integrity of lipid rafts. Previously, we reported an apparent inverse relationship between membrane cholesterol levels and those of GM1, another lipid that can be found in rafts. This paper describes the observation that red blood cell (RBC) membranes isolated from blood drawn from children diagnosed with autism have on the average significantly less cholesterol and significantly more GM1 than RBC membranes isolated from blood obtained from control children. While cholesterol in the circulation does not cross the blood brain barrier, a generalized defect in its synthesis could affect its concentration in the central nervous system and that, coupled with a change in ganglioside expression, could contribute to development of the behaviors associated with autism. PMID- 22252727 TI - Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat. AB - Both dopamine (DA) and melatonin (MLT) are abundant neuromodulators located in vertebrate retina. The retinal DA deficiency and variations in MLT levels have been linked to Parkinson's disease (PD). No studies have investigated the ipsilateral and contralateral DA and MLT in retina and their relationships in 6 hydroxydopamine (6-OHDA) induced hemiparkinsonian rats. We established PD rat model by unilateral injection of 6-OHDA into the right substantia nigra and the right medial forebrain bundle. Eye tissue was collected and the levels of MLT and DA were measured twice daily at 10:00 and 22:00. The concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic (DOPAC) and homovanillic acid (HVA), as well as MLT were determined by HPLC. The results show that DA levels in the eye contralateral to the side of a unilateral intracerebral 6-OHDA lesion significantly decreased (P < 0.001). Both the ratios of DOPAC/DA and HVA/DA were increased in comparison with the vehicle groups after 3 weeks post-lesion. The concentrations of MLT at 10:00 and 22:00 in both eyes were distinctly increased compared with the vehicle groups (P < 0.05). The change of DA and its metabolites, as well as MLT appeared to correlate well with the rotation behavior of rats. These findings suggest that rats receive a unilateral intracerebral injection of 6-OHDA that mainly causes the contralateral eye destruction of DA containing neurons. Increased retinal MLT level probably is associated with the progression of PD. PMID- 22252734 TI - Hypertrophied tonsils impair velopharyngeal function after palatoplasty. AB - OBJECTIVES/HYPOTHESIS: When tonsillar hypertrophy obstructing the airway is encountered in a child with a repaired cleft palate and velopharyngeal insufficiency, the surgeon may opt for tonsillectomy to relieve the airway obstruction, with possible effects on velopharyngeal closure. The aim of this study was to assess the impact of hypertrophied tonsils on velopharyngeal function in children with repaired cleft palate and to measure the effect of tonsillectomy on velopharyngeal closure and speech resonance. STUDY DESIGN: Case series. METHODS: Twelve children with repaired cleft palate and tonsillar hypertrophy underwent tonsillectomy to relieve airway obstruction. Preoperative and postoperative evaluation of velopharyngeal function was performed. Auditory perceptual assessment of speech and nasalance scores were measured, and velopharyngeal closure was evaluated by flexible nasopharyngoscopy. RESULTS: Preoperative impairment of velopharyngeal function was detected. However, significant postoperative improvement of speech parameters (hypernasality, nasal emission of air, and weak pressure consonants measured with auditory perceptual assessment) was achieved, and the overall postoperative nasalance score was improved significantly for nasal and oral sentences. Reduction of velopharyngeal gap size was detected after removal of hypertrophied tonsils. Although the improvement of velopharyngeal closure was not significant, three cases demonstrated complete postoperative closure with no gap. CONCLUSIONS: Hypertrophied tonsils may impair velopharyngeal function in children with repaired cleft palate, and tonsillectomy is beneficial for such patients as it can improve the velopharyngeal closure and speech resonance. Secondary corrective surgery may be avoided in some cases after tonsillectomy. PMID- 22252735 TI - Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells. AB - Daunorubicin (as well as other anthracyclines) is known to be toxic to heart cells and other cells in organism thus limiting its applicability in human cancer therapy. To investigate possible mechanisms of daunorubicin cytotoxicity, we used stem cell lines derived from adult rabbit skeletal muscle. Recently, we have shown that daunorubicin induces apoptotic cell death in our cell model system and distinctly influences the activity of MAP kinases. Here, we demonstrate that two widely accepted antagonistic signalling pathways namely proapoptotic JNK and prosurvival PI3K/AKT participate in apoptosis. Using the Western blot method, we observed the activation of JNK and phosphorylation of its direct target c-Jun along with inactivation of AKT and its direct target GSK in the course of programmed cell death. By means of small-molecule kinase inhibitors and transfection of cells with the genes of the components of these pathways, c-Jun and AKT, we confirm that JNK signalling pathway is proapoptotic, whereas AKT is antiapoptotic in daunorubicin-induced muscle cells. These findings could contribute to new approaches which will result in less toxicity and fewer side effects that are currently associated with the use of daunorubicin in cancer therapies. PMID- 22252728 TI - Predicting survival of patients with hypocellular myelodysplastic syndrome: development of a disease-specific prognostic score system. AB - BACKGROUND: Although most patients with myelodysplastic syndrome (MDS) exhibit bone marrow hypercellularity, a subset of them present with a hypocellular bone marrow. Specific factors associated with poor prognosis have not been investigated in patients with hypocellular MDS. METHODS: The authors studied a cohort of 253 patients with hypocellular MDS diagnosed at The University of Texas MD Anderson Cancer Center between 1993 and 2007 and a cohort of 1725 patients with hyper-/normocellular MDS diagnosed during the same time period. RESULTS: Patients with hypocellular MDS presented more frequently with thrombocytopenia (P < .019), neutropenia (P < .001), low serum beta-2 microglobulin (P < .001), increased transfusion dependency (P < .001), and intermediate-2/high-risk disease (57% vs 42%, P = .02) compared with patients with hyper-/normocellular MDS. However, no difference in overall survival was observed between the 2 groups (P = .28). Multivariate analysis identified poor performance status (Eastern Cooperative Oncology Group >=2), low hemoglobin (<10 g/dL), unfavorable cytogenetics (-7/7q or complex), increased bone marrow blasts (>=5%), and high serum lactate dehydrogenase (>600 IU/L) as adverse independent factors for survival. CONCLUSIONS: A new prognostic model based on these factors was built that segregated patients into 3 distinct risk categories independent of International Prognostic Scoring System (IPSS) score. This model is independent from the IPSS, further refines IPSS-based prognostication, and may be used to develop of risk-adapted therapeutic approaches for patients with hypocellular MDS. PMID- 22252736 TI - Assessing the structure-activity relationships of fluorotelomer unsaturated acids and aldehydes with glutathione. Reactivity of glutathione with fluorotelomer unsaturated acids and aldehydes. AB - Fluorotelomer alcohols (FTOHs) have been shown to degrade via abiotic and biotic mechanisms to perfluorocarboxylates (PFCAs) which are environmentally persistent and bioaccumulate in humans and wildlife depending on their chain length. Fluorotelomer unsaturated aldehydes (FTUALs) and acids (FTUCAs) are intermediate metabolites that form from the degradation of FTOHs. Their potential for toxicity is not yet defined and may be more significant compared to PFCAs. Past studies have shown that these intermediates form adducts with glutathione (GSH). The purpose of this study was to further assess the reactivity of these intermediate compounds. In vitro experiments were carried out in an aqueous buffer system (pH 7.4) where FTUCAs and FTUALs of varying chain lengths were reacted with GSH. To quantify the reactivity of FTUCAs and FTUALs, unreacted free GSH was derivatized with 5,5'-dithiobis(2-nitrobenzoic acid), its absorbance measured at 412 nm, and the percentage of unconjugated free GSH evaluated over time. EC50 values were obtained for the reactions of GSH with acrolein and methyl methacrylate to assess the accuracy of the method, as well as for acrylic acid, FTUCAs, and FTUALs. The results of this study indicated that alpha,beta-unsaturated aldehydes are comparatively the most reactive and reaction with GSH may be influenced by the length of the fluorinated tail. This is the first study to examine the relationship of FTUCAs and FTUALs with biological nucleophiles by quantifying their intrinsic reactivity. PMID- 22252737 TI - Genome-scale metabolic representation of Amycolatopsis balhimycina. AB - Infection caused by methicillin-resistant Staphylococcus aureus (MRSA) is an increasing societal problem. Typically, glycopeptide antibiotics are used in the treatment of these infections. The most comprehensively studied glycopeptide antibiotic biosynthetic pathway is that of balhimycin biosynthesis in Amycolatopsis balhimycina. The balhimycin yield obtained by A. balhimycina is, however, low and there is therefore a need to improve balhimycin production. In this study, we performed genome sequencing, assembly and annotation analysis of A. balhimycina and further used these annotated data to reconstruct a genome scale metabolic model for the organism. Here we generated an almost complete A. balhimycina genome sequence comprising 10,562,587 base pairs assembled into 2,153 contigs. The high GC-genome (~ 69%) includes 8,585 open reading frames (ORFs). We used our integrative toolbox called SEQTOR for functional annotation and then integrated annotated data with biochemical and physiological information available for this organism to reconstruct a genome-scale metabolic model of A. balhimycina. The resulting metabolic model contains 583 ORFs as protein encoding genes (7% of the predicted 8,585 ORFs), 407 EC numbers, 647 metabolites and 1,363 metabolic reactions. During the analysis of the metabolic model, linear, quadratic and evolutionary programming algorithms using flux balance analysis (FBA), minimization of metabolic adjustment (MOMA), and OptGene, respectively were applied as well as phenotypic behavior and improved balhimycin production were simulated. The A. balhimycina model shows a good agreement between in silico data and experimental data and also identifies key reactions associated with increased balhimycin production. The reconstruction of the genome-scale metabolic model of A. balhimycina serves as a basis for physiological characterization. The model allows a rational design of engineering strategies for increasing balhimycin production in A. balhimycina and glycopeptide production in general. PMID- 22252738 TI - Number representation is influenced by numerical processing level: an ERP study. AB - The same numerical magnitude can be manifested in different physical notations. However, how the numbers with distinct notations are mentally represented is still unclear. Here, we hypothesized that how the number is mentally represented is influenced by the numerical processing level of the tasks. If the task only needed a low-level processing, the representation would be dependent on the surface forms of the numbers, exhibiting a numerical notation-dependent effect. By contrast, if the task required a deeper magnitude processing, the processing would utilize an abstract numerical format whose effects are notation independent. To test this hypothesis, we manipulated the notation type and the numerical processing level of the tasks. An ERP component N270 was taken to index the mismatch between the internal representation and the probed number. The results showed that N270 was enhanced when the magnitude was mismatched between two numbers. More importantly, under the task requiring a low-level processing (e.g., magnitude comparison), compared with the same notations, the latency of N270 difference wave was delayed by different notations, exhibiting a notation dependent effect. However, in the task involving a deeper processing (e.g., magnitude addition), the N270 latencies were earlier for probes having distinct notations (Mandarin or Arabic number) than for probes having the same notations as in the addition operation (Mahjong). Moreover, no difference was found on N270 latencies between the two distinct notations but with similar degree of familiarity. Taken together, these results support our hypothesis that the numerical processing level affects the number representation. PMID- 22252739 TI - Synthesis and aggregation properties of a novel enzymatically resistant nucleoamino acid. AB - In this work, we describe the synthesis, evaluation of some biological properties, such as DNA- and RNA-binding ability and in sero stability, as well as the supramolecular assembly of a novel nucleoamino acid based on L-spinacine. More particularly, a thymine-containing L-spinacine derivative was synthesized in liquid phase by a simple peptide-coupling procedure. Subsequently, nucleic acid and Cu(2+)-binding ability, as well as self-assembly properties of the novel nucleoamino acid, were investigated by spectroscopy (CD and UV) and laser light scattering which furnished interesting information on the assembly of supramolecular networks based on the peptidyl nucleoside analog. Finally, nucleoamino acid enzymatic stability was studied and a half life of about 7 days was found in the presence of fresh human serum. PMID- 22252740 TI - Hennebert's sign in superior semicircular canal dehiscence syndrome: a video case report. AB - Superior semicircular canal dehiscence (SSCD) syndrome has been called the great otologic mimicker because its presentation overlaps with otosclerosis, Meniere's disease, perilymphatic fistula, and patulous eustachian tube. A valuable examination finding that can help distinguish SSCD syndrome from other pathologic conditions is the presence of Hennebert's sign, in which pressure changes in the external auditory canal evoke stereotyped eye movements that align in the plane of the dehiscent semicircular canal. This video case report demonstrates Hennebert's sign associated with SSCD syndrome and discusses its pathophysiological basis. PMID- 22252741 TI - Gene networking and inflammatory pathway analysis in a JMJD3 knockdown human monocytic cell line. AB - JMJD3, a Jumonji C family histone demethylase, is induced by transcription factor, nuclear factor-kappa B (NF-kappaB), in response to various stimuli. JMJD3 is crucial for erasing histone-3 lysine-27 trimethylation (H3K27me3), a modification associated with transcriptional repression and is responsible for the activation of a diverse set of genes. Here, we identify the genes in human leukaemia monocyte (THP-1) human monocytic cells that are significantly affected by the stable knockdown (kd) of JMJD3. Global gene expression levels were detected in stable JMJD3 knockdown THP-1 cells and in tumor necrosis factor-alpha (TNF-alpha)-stimulated JMJD3-kd THP-1 cells by using a 12-plex NimbleGen human whole genome array. In addition, datasets were analysed by using Ingenuity Pathway Analysis. Stable knockdown of JMJD3 in THP-1 cells affected particularly in expression levels and in downstream effects on inflammatory signalling pathways. JMJD3 attenuation down-regulates various key genes in NF-kappaB, chemokine and CD40 signalling, and mostly affects inflammatory disease response molecules. In addition, chromatin immunoprecipitation revealed that JMJD3-kd could inhibit several NF-kappaB-regulated inflammatory genes by recruiting repressive histone-3 lysine-27 trimethylation to their promoters. Moreover, this study significantly highlights the connexion of NF-kappaB with JMJD3, which suggests an epigenetic regulation in different signalling pathways. Finally, this study establishes novel JMJD3 targets through Ingenuity Pathway Analysis. PMID- 22252743 TI - Intense photoluminescence from ceria-based nanoscale lamellar hybrid. AB - Nanosheets, which are ultrathin inorganic crystals, have the potential to exhibit unique surface states and quantum effects. These nanosheets can be further manipulated to form lamellar structures for the fabrication of advanced hybrid nanomaterials. Here we report that conventionally nonluminescent ceria yields intense UV photoluminescence with an internal quantum yield (QY) of 59% when self organized into a nanosheet lamellar architecture with dodecyl sulfate (DS) bilayers. The origin of luminescence exist at the organic/inorganic interfaces, where surface Ce(3+) ions of ceria nanosheet layers graft with DS anions to activate radiative 5d -> 4f transition. PMID- 22252744 TI - Altered microtubule dynamics in Mecp2-deficient astrocytes. AB - Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the gene MECP2 encoding the methyl-CpG binding protein 2. This genetic disease affects predominantly girls and is characterized by a period of normal development that lasts for 8-18 months, followed by neurologic regression affecting both motor and mental abilities. Previous studies performed on brains from RTT subjects and Mecp2-deficient mice showed striking changes in neuronal maturation and dendritic arborization. Recently, we showed that expression of stathmin-like 2 (STMN2) was significantly reduced in fibroblasts from RTT patients, and similar results were obtained in the cerebellum of Mecp2-deficient mice. Because assembly and dynamics of microtubules are known to be modulated by STMN2, we studied microtubule dynamics in brain cells from Mecp2-deficient mice. We observed that Mecp2 deficiency affects microtubule dynamics in astrocytes from Mecp2-deficient mice. Our data reinforce the fact that the loss of Mecp2 in astrocytes may influence the onset and progression of RTT. These results imply that Mecp2 has a stabilizing role in microtubule dynamics and that Mecp2 deficiency, which is associated with STMN2 down-regulation, could lead to impaired microtubule stability, hence explaining the dendritic abnormalities observed in RTT brains. PMID- 22252745 TI - Laparoscopic conversion of failed gastric banding to Roux-en-Y gastric bypass: short-term follow-up and technical considerations. AB - BACKGROUND: The most common bariatric procedure in Australia is laparoscopic adjustable gastric banding (LAGB). Although successful, there is a substantial long-term complication and failure rate. Band removal and conversion to Roux-en-Y gastric bypass (RYGB) can be an effective treatment for complicated or failed bands. There is increasing evidence supporting good weight loss and resolution of band-related complications after conversion. METHODS: A prospective database of all bariatric procedures is maintained. Patients having revision of LAGB to RYGB between December 2007 and April 2011 were included in this study. Indications for surgery, operative details, morbidity and mortality, weight loss data, and post operative symptoms were recorded. RESULTS: Eighty-two patients were included. Indications for surgery were inadequate weight loss (n = 42), adverse symptoms (reflux = 8, dysphagia = 2), and band complications (band erosion = 7, band sepsis = 1, band slip = 11, esophageal dilatation = 11). Seventy-eight percent of procedures were completed in a single stage and 96.3% laparoscopically. There was no 30-day mortality. Total morbidity was 46.3% (minor complications = 32.9%, major complications = 13.4%). Median BMI was 43 kg/m(2) pre-RYGB and 34 kg/m(2) after 12 months. All patients with adverse band-related symptoms had resolution. CONCLUSIONS: LAGB has a considerable complication and failure rate. Conversion of these patients to RYGB results in further weight loss and resolution of adverse symptoms. This is a challenging procedure, but can usually be performed in a single stage with acceptable morbidity and mortality. These patients should be treated in high-volume, subspecialty bariatric units. PMID- 22252746 TI - Shared medical appointments for bariatric surgery follow-up: a patient satisfaction questionnaire. AB - BACKGROUND: Shared medical appointments (SMAs) are group clinics where practitioners see several patients, with common health needs, at once. There is a great financial strain on the National Health Service (NHS) to provide bariatric surgery. The aim of this study was to review patient satisfaction with the SMA that is the default means of following up patients after bariatric surgery at one particular NHS trust. METHODS: A patient-validated questionnaire was designed and handed out at the end of the SMAs. Patients who attended an SMA earlier in 2011 were also retrospectively sent questionnaires via post. RESULTS: A total of 47 patients completed the questionnaire from seven different SMAs covering the period from January to July 2011. All patients underwent laparoscopic adjustable gastric banding. After attending an SMA, patients gave an overall mean satisfaction rating of 4.13 +/- 0.163 (on a scale of 1 to 5, 1 = very poor and 5 = excellent) which represented an increase (p < 0.01) compared to preconceptions before the clinic (3.59 +/- 0.175). A cost analysis estimated a yearly saving of L4,617 or 65.1% made by the SMAs compared to 1:1 appointments. CONCLUSIONS: The bariatric surgery SMA demonstrates high levels of patient satisfaction and is cost-effective. PMID- 22252748 TI - Cryoglobulinemic glomerulonephritis--lessons from animal models. AB - In humans cryoglobulinemic glomerulonephritis (CGGN) may develop in the course of systemic cryoglobulinemia (CG) and is often associated with hepatitis C virus infection. It is believed that the glomerular injury in CG results from the deposition of immune complexes, but exact sequence of events in this process is unknown. Experimental models of CGGN provide an important tool to study pathogenesis of this type injury. This review describes two mouse models of CGGN and their use in understanding the role of various molecules involved in regulation of inflammatory and fibrosis pathways, such as complement components, Fc receptors, growth factors, and others; as well as illustrates their role in testing novel approaches of treatment in this type of renal injury. PMID- 22252749 TI - Cathepsin E (EC 3.4.23.34)--a review. AB - Cathepsin E belongs to the third class of enzymes - hydrolases, a subclass of peptide bond hydrolases and a sub-subclass of endopeptidases with aspartic catalytic sites. Cathepsin E is an endopeptidase with substrate specificity similar to that of cathepsin D. In a human organism, cathepsin E occurs in: erythrocytes, thymus, dendritic cells, epithelial M cells, microglia cells, Langerhans cells, lymphocytes, epithelium of gastrointestinal tract, urinary bladder, lungs, osteoclasts, spleen and lymphatic nodes. In human cells, loci of the gene of pre-procathepsin E are located on chromosome 1 in the region 1231-32. The catalytic site of cathepsin E is two residues of aspartic acid - Asp96 and Asn281, occurring in amino acid triads with sequences DTG96-98 and DTG281-283. To date, no particular role of cathepsin E in the metabolism of proteins in normal tissues has been found. However, it is known that there are many documented pathological conditions in which overexpression of cathepsin E occurs. PMID- 22252750 TI - Bone as a source of organism vitality and regeneration. AB - The most important features that determine the vital role of bone include: a) a continuous supply of calcium, which is indispensible for every cell of the entire organism at all times, and b) the delivery of circulating blood cells and some adult stem cells to keep the body vigorous, ready for self-reparation, and continuously rebuilding throughout life. These functions of bones are no less important than protecting the body cavities, serving as mechanical levers connected to the muscles, and determining the shape and dimensions of the entire organism. The aim of this review was to address some basic cellular and molecular knowledge to better understand the complex interactions of bone structural components. The apprehension of osteoblast differentiation and its local regulation has substantially increased in recent years. It has been suggested that osteocytes, cells within the bone matrix, act as regulatory mechanosensors. Therefore immobility as well as limited activity has a dramatic effect on bone structure and influences a broad spectrum of bone physiology-related functions as well as the functions of many other organs. Lifelong bone rebuilding is modulated through several pathways, including the Wnt pathway that regulates bone formation and resorption. In the adult skeleton, bone is continuously renewed in response to a variety of stimuli, such as the specific process of remodeling dependent on RANK/ /RANKL/OPG interactions. Better understanding of bone biology provides opportunities for the development of more effective prevention and treatment modalities for a variety of bone diseases, including new approaches to adult stem cell-based therapies. PMID- 22252751 TI - Digital pathology in personalized cancer therapy. AB - The development of small molecule inhibitors of growth factor receptors, and the discovery of somatic mutations of the tyrosine kinase domain, have resulted in new paradigms for cancer therapy. Digital microscopy is an important tool for surgical pathologists. The achievements in the digital pathology field have modified the workflow of pathomorphology labs, enhanced the pathologist's role in diagnostics, and increased their contribution to personalized targeted medicine. Digital image analysis is now available in a variety of platforms to improve quantification performance of diagnostic pathology. We here describe the state of digital microscopy as it applies to the field of quantitative immunohistochemistry of biomarkers related to the clinical personalized targeted therapy of breast cancer, non-small lung cancer and colorectal cancer: HER-2, EGFR, KRAS and BRAF genes. The information is derived from the experience of the authors and a review of the literature. PMID- 22252752 TI - The role of tumor cells in the modification of T lymphocytes activity--the expression of the early CD69+, CD71+ and the late CD25+, CD26+, HLA/DR+ activation markers on T CD4+ and CD8+ cells in squamous cell laryngeal carcinoma. Part I. AB - The role of interactions between tumor cells and autologous immunocompetent cells, the impact on the modulation of the activity of T CD4(+) and CD8(+) lymphocytes, as well as the influence on the regulation and determination of antitumor cellular immune response in patients with head and neck squamous cell carcinomas (HNSCC) is not completely clear. The aim of this study was to analyze early and late activation antigens expression on T cells subpopulations modified under the influence of the presence of cancer cells to investigate the regulatory mechanisms of the local cellular immune response in carcinoma of the larynx. Cytofluorymetric analysis of the early (CD69(+), CD71(+)) and late activation markers (CD25(+) (high), CD26(+), HLA/DR(+)) expression on T CD3(+)CD4(+) and CD3(+)CD8(+) cells subpopulations in mixed cellular cultures of freshly isolated tumor cells (MLTMC) and non-cancerous normal epithelial cells (MLNCC) with immunocompetent cells was performed in 55 cases of squamous cell laryngeal carcinoma. The whole peripheral blood concentrations of IL-10 and IFN-gamma in 21 h and 72 h of experiments were also measured by ELISA. The relationships between the activation markers expression depending on the type of cells used in co cultures, as well as the level of secreted cytokines, were investigated. Our work has revealed a statistically significant dependence of cytofluorymetric results on the presence of TMC or NCC in mixed cellular cultures. Increased expression of CD69(+), CD71(+) and CD25(+) (high), CD26(+), HLA/DR(+) antigens on T CD3(+)CD4(+) and CD3(+)CD8(+) cells was higher in MLTMC cultures, in comparison with MLNCC. We demonstrated negative significant relationships of IFN-gamma and IL-10 secretion with regard to CD4(+)CD69(+), CD8(+)CD69(+), CD4(+)CD71(+), CD8(+)CD71(+) antigens expression in 21 h of experiments without mitogenic stimulation. Furthermore, this study revealed negative significant relationships of IFN-g secretion with regard to CD4(+)HLA/DR(+) and CD8(+)HLA/DR(+) as well as between IL-10 concentration and CD4(+)HLA/DR(+) in trials without PHA stimulation. Our findings have confirmed a key role for tumor cells in determining the function of T cells involved in the immunological processes and impact of neoplastic cells on modulating the activity of T CD4(+) and CD8(+) lymphocytes in laryngeal carcinoma. PMID- 22252753 TI - Prognostic value of the immunological phenomena and relationship with clinicopathological characteristics of the tumor--the expression of the early CD69+, CD71+ and the late CD25+, CD26+, HLA/DR+ activation markers on T CD4+ and CD8+ lymphocytes in squamous cell laryngeal carcinoma. Part II. AB - One of the most important challenges in contemporary oncology is to find objective biomarkers of tumor aggressiveness, which help to identify more invasive phenotypes of the carcinoma. The purpose of this study was to investigate the relationships between the early and the late activation markers expression on T CD4(+) and CD8(+) cells subpopulations and certain clinicopathological characteristics of the neoplastic infiltration in order to determine their role as biomarkers for tumor behavior in squamous cell laryngeal carcinoma. Analysis of the early (CD69(+), CD71(+)) and the late activation antigens (CD25(+) (high), CD26(+), HLA/DR(+)) expression on T CD4+ and CD8(+) lymphocytes by cytofluorymetry in 55 patients treated for squamous cell laryngeal carcinoma was performed. Clinicomorphological analysis on the basis of TNM criteria and tumor front grading, which included tumor-related features and adjacent stroma-related characteristics of the peripheral edge of infiltration was carried out. The relationships between the activation markers expression and parameters of tumor aggressiveness were investigated. Our work revealed statistically significant differences in the expression of the studied activation markers on T cells with regard to certain clinicomorphological features. The expressions of CD69(+) and CD71(+) antigens on T CD3(+)CD4(+) and CD3(+)CD8(+) cells as well as CD4(+)HLA/DR(+) markers were higher for pT3 and pT4 tumors, in comparison with pT2 carcinomas. Moreover, tumors with the smallest number of TFG points were characterized by significantly lower values of the average expression of CD3(+)CD69(+) and CD3(+)CD71(+) as well as CD4(+)HLA/DR(+) markers on T lymphocytes. In addition, more aggressive and deeply infiltrating laryngeal carcinomas were most often characterized by significantly higher values of the average expression of CD69(+) and CD71(+) antigens on CD8(+) as well as HLA/DR(+) markers on CD4(+). Our study confirmed the implication of the early and the late activation antigens expression on CD4(+) and CD8(+) T lymphocytes in clinicomorphological parameters of the tumor, especially TFG total score and depth of invasion, and their importance as indicators of the invasive phenotype of laryngeal carcinoma. PMID- 22252754 TI - Distribution and chemical coding pattern of the cocaine- and amphetamine regulated transcript (CART) immunoreactivity in the preoptic area of the pig. AB - This study provides a detailed description of cocaine-and amphetamine-regulated transcript (CART) distribution and the co-localization pattern of CART and gonadotropin releasing hormone (GnRH), somatostatin (SOM), neuropeptide Y (NPY), cholecystokinin (CCK), and substance P (SP) in the preoptic area (POA) of the domestic pig. The POA displays a low density of immunoreactive cells and rich immunoreactivity for CART in fibers. CART-immunoreactive (CART-IR) cell bodies were single and faintly stained, and located in the medial preoptic area (MPA) and the periventricular region of the POA. A high density of immunoreactive fibers was observed in the periventricular preoptic nucleus (PPN); a high to moderate density of fibers was observed in the MPA; but in the dorso-medial region of the MPA the highest density of fibers in the whole POA was observed. The lateral preoptic area (LPA) exhibited a less dense concentration of CART immunoreactive fibers than the MPA. The median preoptic nucleus (MPN) showed moderate to low expression of staining fibers. In the present study, dual labeling immunohistochemistry was used to show that CART-IR cell bodies do not contain any GnRH and SP. CART-positive fibers were identified in close apposition with GnRH neurons. This suggests that CART may influence GnRH secretion. Double staining revealed that CART-IR structures do not co-express any of the substances we studied, but a very small population of CART-IR fibers also contain SOM, CCK or SP. PMID- 22252755 TI - No correlation between pinopode formation and LIF and MMP2 expression in endometrium during implantation window. AB - Implantation depends on two factors - embryo and endometrium. The period of maximal endometrial receptivity is a poorly understood phenomenon. We decided to look at three possible markers of implantation: pinopodes, leukemia inhibitory factor, and matrix metalloproteinase 2 and their correlations. We included in the study 23 idiopathic infertility patients and 21 patients with recurrent spontaneous abortions of unknown etiology. Twenty one fertile patients were also recruited. A biopsy was used for endometrial dating according to the Noyes and Hertig criteria, and assessed for the presence of pinopodes via a scanning electron microscope. Endometria were examined in Real Time-Polymerase Chain Reaction cycles for the mRNA expression of leukemia inhibitory factor (LIF) and matrix metalloproteinase 2 (MMP2). No difference was found in the stage of pinopodes development, nor in the coverage of endometrial surface between the studied groups. The expression level for LIF mRNA was lower in control patients compared to idiopathic infertility and recurrent miscarriage patients. No difference was detected in the expression of MMP2 between all studied groups. No correlation was found between pinopodes development stage and LIF and MMP2 expressions in endometrium. Of the studied factors, LIF and pinopodes show the most promise as potential markers of endometrial receptivity. However, the results achieved suggest that these markers are independent of each other. PMID- 22252756 TI - Localization of substance P, calcitonin gene related peptide and galanin in the nerve fibers of porcine cystic ovaries. AB - In a previous study, we showed that both the noradrenergic and cholinergic component of ovarian innervation is markedly changed in porcine cystic ovaries. The present study is aimed at elucidating the distribution pattern of substance P (SP), calcitonin gene related peptide CGRP- and/or galanin (GAL)-containing nerve fibers within porcine cystic ovaries. The status polycysticus was induced by dexamethasone phosphate disodium salt i.m. injections performed from the 7(th) until the 21(st) day of the first studied estrous cycle. During the same period of time, gilts of the control group received saline. All animals were slaughtered on the expected 11(th) day of the second studied estrous cycle, and their ovaries were collected. When compared to control gonad, a distinct difference in the distribution pattern and the density of SP-, CGRP- and/or GAL-immunoreactive (GAL IR) nerve fibers was observed. Thus, unlike in the control gonad, SP- and/or CGRP IR perivascular nerve fibers were found to supply medullar blood vessels of polycystic ovary. Furthermore, the number of GAL-IR nerve fibers contributing to the ground plexus in polycystic ovaries was higher than that observed in the control gonads. Thus, as may be judged from the profound changes in the distribution pattern of differently chemically coded afferent terminals within polycystic gonads, it appears possible that neuropeptides released from these terminals may take part in the etiopathogenesis of this disorder. PMID- 22252757 TI - The prognostic significance of the immunohistochemical expression of P53 and BCL 2 in endometrial cancer. AB - The objective of this study was to verify the frequency of P53 and BCL-2 immunohistochemical expression in 98 patients with endometrial carcinoma, and to correlate it with clinical stage and patient survival. A significant difference was found regarding the frequency of P53 expression when comparing type I and II tumors (23.7% and 54.5%, respectively; p = 0.006). A positive correlation was observed between P53 immunoexpression and patient survival in type I and II tumors (p = 0.009 and p = 0.036, respectively). BCL-2 expression was significantly more frequent in early clinical stages in both types of endometrial cancer (p < 0.001 and 0.002) and correlated with a decrease in overall survival in type I endometrial cancer (p = 0.014). Thus, the prognostic value of these biomarkers in endometrial cancer needs to be further investigated. PMID- 22252758 TI - Enhanced expression of Fas Ligand (FasL) in the lower airways of patients with fibrotic interstitial lung diseases (ILDs). AB - The exact role of FasL, and particularly its soluble and membrane-bound forms, in the development of chronic ILDs and lung fibrosis has not been extensively explored. We aimed at analyzing membrane-bound FasL expression on alveolar macrophages (AM) and lymphocytes (AL) as well as soluble FasL (sFasL) levels in bronchoalveolar lavage (BAL) from ILDs patients, incl. pulmonary sarcoidosis (PS), hypersensitivity pneumonitis (HP), silicosis, asbestosis, idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), and healthy subjects (n = 89, 12, 7, 8, 23, 6, 17, respectively). In IPF, significantly increased percentage of AM FasL(+) and CD8(+)FasL(+) cells as well as sFasL levels in BAL were found. Increased sFasL levels were also observed in HP. NSIP and asbestosis were characterized by higher AM FasL(+) relative number; CD8(+)FasL(+) population was expanded in asbestosis only. There was a significant decline in AL FasL(+) percentage in PS and HP. Vital capacity was negatively correlated with sFasL levels, AM FasL(+) and CD8(+)FasL(+) cell relative count. CD4(+)FasL(+) and CD8(+)FasL(+) percentage strongly correlated with BAL neutrophilia, an unfavorable prognostic factor in lung fibrosis. The concurrent comparative BAL analysis of FasL expression indicates that FasL(+) AM and AL (mainly Tc cells) comprise an important element of the fibrotic process, mostly in IPF. FasL might play a crucial role in other fibrosis-complicated ILDs, like NSIP and asbestosis. PMID- 22252759 TI - Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus. AB - Impaired function of regulatory T-cells (Treg) leads to a failure in immune tolerance and triggers autoimmunity. We analyzed whether the deficiency in Treg in systemic lupus erythematosus (SLE) is accompanied by an increase in effector T cell responses. We studied the frequencies of IL-17A (Th17) and IFNg (Th1) producing CD4(+) T-cells by flow cytometric detection of intracellular cytokines in PMA/ionomycin stimulated blood lymphocytes from seven patients with active SLE, eight with SLE in remission, and 11 healthy controls. Circulating Treg were evaluated as CD4(+)CD25(+) lymphocytes expressing FoxP3. There was no difference in the percentage of Treg cells between the groups, but their absolute counts were decreased in active SLE (5 [1-7] cells/MUL) compared to inactive SLE (11 [6 15]; p = 0.05) and healthy controls (16 [10-20]; p < 0.01). Both the frequency and numbers of Th1 cells were decreased in SLE compared to controls. No difference was observed in the number of Th17 cells, which resulted in a decreased Th1/Th17 ratio. In parallel, a higher Treg/Th17 ratio in healthy controls (2.2 [1.8-3.6]) compared to active SLE (1.1 [1.0-2.1]; p < 0.05) was observed. There was a correlation between the number of Treg cells and disease activity status (SLEDAI, r = -0.59). SLE patients in the active phase of the disease are characterized by a deficiency in Treg cells and decreased Treg/Th17 ratio. This suggests that the imbalance between major T-cells subsets might be responsible for an increased proinflammatory response in the exacerbation of SLE. PMID- 22252760 TI - The levels of sMUC-1 in patients with multiple myeloma. AB - Mucins have been shown to be aberrantly overexpressed in various diseases including cystic fibrosis, asthma, and cancer. Recent studies have uncovered the roles of these mucins in the pathogenesis of cancer. The presence of MUC-1 has also been detected on the cell surface of multiple myeloma (MM) cells in peripheral blood and showed direct correlation with tumor mass. In this study, we evaluated the levels of soluble MUC-1 (sMUC-1) in 50 new MM patients and correlated this with the levels of sMUC-1 after treatment. High levels of sMUC-1 were found in 20/50 (40%) MM patients, and in 2/50 (4%) healthy individuals (p = 0.001). According to the ISS, we found significant differences of mean sMUC-1 levels between the first stage of the disease (0.63 +/- +/- 0.26) and the third (0.93 +/- 0.24; p = 0.03), but not with the second stage (0.80 +/- 0.22; p = 0.08). Our study confirmed the correlation between elevated sMUC-1 and high elevated lactate dehydrogenase (p = 0.03) and the level of IgG in groups of patients with MM IgG at every stage of disease (p = 0.001). We showed for the first time that levels of sMUC-1 after treatment, in a group of patients with initially elevated levels of MUC-1, were statistically lower than in a group of patients with initially lower levels of sMUC-1 (21% vs. 42,6%; p = 0.05). At 37 months median of follow-up, we found a statistically significant difference between patients with normal versus elevated sMUC-1 in terms of progression-free survival (median 12 months vs. 8.1 months; p = 0.03). PMID- 22252761 TI - Videostroboscopic and morphological aspects of voice disturbances in patients with larynx atrophy and coexisting hypopharynx cancer. AB - Vocal folds play a crucial role in voice production. The physiological vibrations of vocal folds depend on the unchanged multilayered structure of the vocal folds mucosa. Morphological changes of mucosa are the cause of voice quality disorders dysphonia. The aim of this study was to determine the morphological base of dysphonia in patients with vocal folds atrophy. A group of 24 patients with larynx atrophy confirmed by endoscopic (VLS) and stroboscopic (VLSS) examination of the larynx was included in the study. The morphological assessment of the larynx mucosa was carried out with the use of the transmission electron microscopy (TEM). Ultramorphological examinations revealed changes in the epithelium, basal membrane and lamina propria of the vocal folds mucosa. An increased number of collagenous fibers, fibroblasts with signs of vacuolar degeneration inflammatory cells and a decreased number of blood vessels and pericytes were observed. Morphological changes found in the epithelium, basal membrane and lamina propria of the vocal folds mucosa were the cause of disorders of vocal folds vibrations registered in the stroboscopic examination of the larynx (VLSS). PMID- 22252762 TI - The effect of ursolic and oleanolic acids on human skin fibroblast cells. AB - In this article, we look at how ursolic and oleanolic acids can be used for the purpose of quality control of natural products used in dermatocosmetology as well as of various other therapeutic preparations. Ursolic acid (UA) and oleanolic acid (OA) are pentacyclic triterpenes and they are constituents of many medicinal herbs. In this study, we analyzed the cytotoxic and anti-proliferative activity of OA and UA against normal human skin fibroblasts (HSF). Additionally, the scavenging activity of free radicals of both acids was analyzed. The sensitivity of cells to OA and UA activity was determined using a standard spectrophotometric (MTT) assay. The free radical scavenging activity of OA and UA was measured using the DPPH* test. The F-actin cytoskeletal proteins organization was analyzed using TRITC-phalloidine fluorescent staining. The cytotoxic activity of the analyzed acids was determined using Neutral Red (NR) uptake assay. Of the two isomeric compounds, UA showed a higher cytotoxic activity against HSF cells than did OA. Our investigations showed that OA, in view of its non-toxic nature, may be used as a supplementary factor for dermal preparations. PMID- 22252763 TI - Control of active B and L cathepsins in tissues of colorectal cancer using cystatins isolated from chicken egg proteins: in vitro studies. AB - The activity of cysteine peptidases (cathepsins B and L) was estimated in homogenates of tissues sampled during surgery from 60 patients operated due to colorectal tumors. The results were compared to those obtained using tissues in which histopathology disclosed no tumorous cells, obtained from 20 patients of the same group, treated as a control. Activity of the enzymes was inhibited using cysteine peptidase inhibitors isolated from chicken egg proteins. Application of the inhibitors was found to inhibit activity of the enzymes which play a key role in tumor development. It is suggested that in future the inhibitors may provide a component of new generation drugs in the so-called inhibitor therapy. PMID- 22252764 TI - Testis morphology in rats chronically treated with letrozole, an aromatase inhibitor. AB - The aim of this study was to investigate the influence of the long-term treatment of rats with letrozole on the testis morphology. The pharmacologically induced estrogen deficiency caused statistically significant decreases of both intratesticular and serum levels of estradiol, and morphological changes in the seminiferous epithelium and in the interstitial tissue of the testes. Six months of treatment resulted in the sloughing of premature germ cells of the seminiferous epithelium into the tubular lumen and in intraepithelial vacuolization. Multinucleated giant cells composed of premature germ cells, conglomerates of various cell nuclei and cell debris as well as irregularities and infoldings of the tubular basement membrane were also seen. Moreover, deep invaginations of the lamina propria with myoid cells were observed. Cells in the interstitial tissue showed changes similar to that observed in aging processes. The cytoplasm of LH-R-positive Leydig cells was loaded with lipofuscin granules. The number of lipofuscin-loaded cells was significantly increased in the interstitial tissue of testis in letrozole-treated rats. The results indicate the direct influence of estrogens on seminiferous tubules and the interstitial tissue morphology. PMID- 22252765 TI - Di(n-butyl) phthalate has no effect on the rat prepubertal testis despite its estrogenic activity in vitro. AB - The aim of this study was to assess the impact of di(n-butyl) phthalate (DBP) on the rat's prepubertal testis. Male Wistar rats were given daily subcutaneous injections with DBP (20 or 200 MUg) or a vehicle from the 5th to the 15th postnatal day (pd). On the 16(th) pd, the rats were euthanized, and the testes were dissected, weighed, and paraffin embedded. The blood was collected to determine the serum levels of testosterone (T), estradiol (E) and FSH. The following parameters were assessed in the testis sections: diameter and length of seminiferous tubules (st), numbers of spermatogonia A + intermediate + B (A/In/B), preleptotene spermatocytes (PL), leptotene + zygotene + pachytene spermatocytes (L/Z/PA) and Sertoli cells per testis, percentage of st containing gonocytes or pachytene spermatocytes or lumen. An estrogenicity in vitro test was performed by means of a transgenic yeast strain expressing human estrogen receptor alpha. At both doses, DBP had no influence on testis and seminal vesicle weight, st diameter and length, number of germ and Sertoli cells per testis, percentage of st containing gonocytes or pachytene spermatocytes or lumen. DBP did not change E, T or FSH serum levels. The in vitro yeast screen showed that DBP was a weak estrogenic compound, approximately six to seven orders of magnitude less potent than 17beta-estradiol. In conclusion, exposure of a rat to DBP in doses 100 or 1,000-fold higher than a Tolerable Daily Intake for humans had no effect on its testicular development. PMID- 22252766 TI - Distribution and chemical coding pattern of somatostatin immunoreactivity in the dorsal striatum of the guinea pig. AB - The present study provides a detailed description of somatostatin (SOM) distribution and the colocalization pattern of SOM, neuropeptide Y (NPY) and nitric oxide synthase (NOS) in the dorsal striatum (caudate-putamen complex) of the guinea pig. Within the dorsal striatum, SOM is found in a population of medium-sized aspiny interneurons. We found that 97% of all SOM-IR neurons expressed NPY simultaneously, while 98% of all NPY-ergic perikarya was simultaneously SOM-IR. On the other hand, while 98% of all SOM-IR cells were simultaneously NOS-IR, only 91% of all NOS-containing neurons exhibited SOM immunoreactivity. Irrespective of their chemical coding, both types of SOM-IR neurons were scattered throughout the dorsal striatum, sometimes in the form of small, loosely arranged clusters of 2-4 cells. While SOM-IR and NPY-IR nerve fibers were present in all of the studied regions, they were more numerous in the ventro-medial part of the studied structure, with the exception of its caudal portion, where SOM-IR and NPY-IR fibers additionally formed a dense network in the part corresponding to the caudate nucleus. A low expression of staining for NOS-IR fibers was seen throughout the entire dorsal striatum. In some fibers, SOM and NPY were co-expressed. Fibers expressing both SOM and NOS were not found. PMID- 22252767 TI - Evaluation of peritoneal tissue by means of differential scanning calorimetry (DSC). AB - Abdominal surgeries alter the integrity of the peritoneal layer and cause imbalances among immunological, inflammatory and angiogenic mechanisms within the tissue. During laparoscopic procedures a protective function of the peritoneal layer can be disturbed by the gas used to create a pneumoperitoneum. The aim of this study was to characterize peritoneal tissue by means of differential scanning calorimetry (DSC) as a reference for future investigations on the influence of surgical procedures on the physicochemical state of the peritoneum. Thirty-seven patients participated in the study. Patients were divided into three groups according to the type of surgery: group H - patients who underwent hernia repair; group Ch - patients who underwent laparoscopic cholecystectomy; and group C - patients operated due to rectal cancer. It was observed that onset temperature (T(o)), denaturation temperature (T(m)) and change of enthalpy (DeltaH) during thermal denaturation of peritoneal collagen in were significantly different for these three groups of patients. The mean values of onset temperature (T(o)) and denaturation temperature (T(m)) in group H were significantly lower, while DH in this group was significantly higher than in the two other groups (Ch and C). This preliminary study does not answer whether the differences in collagen denaturation found in peritoneal tissue from different groups of patients resulted from a different inherent state of the tissue, or from surgical procedures. However, the results suggest that DSC is an appropriate method to study subtle changes in the physicochemical condition of the peritoneum using small samples obtained during surgical procedures. PMID- 22252768 TI - Interaction of PC-3 cells with fibronectin adsorbed on sulfonated polystyrene surfaces. AB - The ability of cancer cells to invade neighboring tissues is crucial for cell dissemination and tumor metastasis. It is generally assumed that cell adhesion to extracellular matrix proteins is an important stage of cancer progression. Hence, adhesion of cancer cells under in vitro conditions to proteins adsorbed on a substratum surface has been studied to provide a better understanding of cell protein interaction mechanisms. A protein, adsorbed in an appropriate conformation on a substratum surface, creates a biologically active layer that regulates such cell functions as adhesion, spreading, proliferation and migration. In our study, we examined the interaction of PC-3 cells under in vitro conditions with fibronectin adsorbed on sulfonated polystyrene surfaces of a defined chemical composition and topography. We investigated cell adhesion to fibronectin and cell spreading. Using automatic, sequential microscopic image registration, we are the first to present observations of the dynamics of PC-3 cell spreading and the cell shape during this process. Our results show that cell adhesion and the shape of spreading cells strongly depend on the time interaction with fibronectin. The analysis of images of cytoskeletal protein distribution in the cell region near the cell-substratum interface revealed that induction of a signal cascade took place, which led to the reorganization of the cytoskeletal proteins and the activation of focal adhesion kinase (FAK). PMID- 22252769 TI - SOCS3 and SOCS5 mRNA expressions may predict initial steroid response in nephrotic syndrome children. AB - Suppressors of Cytokine Signaling (SOCS) inhibit Signal Transducers and Activators of Transcription (STATs) phosphorylation by binding and inhibiting Janus Kinases (JaKs). The aim of the present study was to evaluate the influence of glucocorticosteroids on the JaK/STAT signaling pathway in the leukocytes of nephrotic syndrome (NS) patients. The study group was composed of 34 steroid sensitive NS (SSNS) children and 20 steroid resistant NS (SRNS) subjects. Gene expression was assessed by real-time PCR using pre-designed human JaK/STAT PCR array. Protein expression was evaluated using ELISA assay (plasma concentration) and immunofluorescence (in situ protein expression). In SSNS children, the initial increased expression of JaK1, JaK2, JaK3, STAT1, STAT2, STAT6, TYK2, SOCS1, SOCS2, SOCS3, SOCS4 and SOCS5 was reduced back to the control limits. Similarly, in SRNS patients the increased levels of almost all mRNA expressions for the abovementioned genes were decreased, with the exceptions of SOCS3 and SOCS5 expressions. These mRNA expressions were still significantly increased and correlated with early unfavorable course of nephrotic syndrome in children. Plasma levels of SOCS3, SOCS5, IL-6 and IL-20 were significantly increased in SRNS subjects after six weeks of steroids medication compared to SSNS and control participants. We conclude that SOCS3 and SOCS5 increased mRNA expressions might predict initial resistance to steroids in NS patients. PMID- 22252770 TI - Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer. AB - The K-ras gene is frequently mutated in colorectal cancer and has been associated with tumor initiation and progression; approximately 90% of the activating mutations are found in codons 12 and 13 of exon 1 and just under 5% in codon 61 located in exon 2. These mutations determine single aminoacidic substitutions in the GTPase pocket leading to a block of the GTP hydrolytic activity of the K-ras p21 protein, and therefore to its constitutive activation. Point mutations in sites of the K-ras gene, other than codons 12, 13 and 61, and other types of genetic alterations, may occur in a minority of cases, such as in the less frequent cases of double mutations in the K-ras gene. However, all mutations in this gene, even those which occur in non-canonical sites or double mutations, are relevant oncogenic alterations in colorectal cancer and may underlie K-ras pathway hyperactivation. In the present study, we report the case of a patient with colorectal cancer presenting a concurrent point mutation in exons 1 and 2 of the K-ras gene, a GGT to TGT substitution (Glycine to Cysteine) at codon 12, and a GAC to AAC substitution (Aspartic Acid to Asparagine) at codon 57. In addition, we found in the same patient's sample a silent polymorphism at codon 11 (Ala11Ala) of exon 1. PMID- 22252771 TI - BOX-PCR is an adequate tool for typing of clinical Pseudomonas aeruginosa isolates. AB - In this study, the BOX-PCR fingerprinting technique was evaluated for the discrimination of clinical Pseudomonas aeruginosa isolates. All isolates were typeable and nearly half showed unique banding patterns. According to our results, BOX-PCR fingerprinting is applicable for typing of Pseudomonas aeruginosa isolates and can be considered a useful complementary tool for epidemiological studies of members of this genus. PMID- 22252772 TI - Impact of a region wide antimicrobial stewardship guideline on urinary tract infection prescription patterns. AB - BACKGROUND: Fluoroquinolones are frequently prescribed for non complicated urinary tract infection treatments and have a negative ecological impact. We aimed to substitute them by antibiotics with narrower activity spectrum in order to preserve fluoroquinolone activity in complicated hospital infections. OBJECTIVE: To assess the impact of a multi-modal approach that combines the dispatching of antibiotic prescription guidelines and voluntary attendance at educational sessions on general practitioners' (GP) antibiotic prescription habits. SETTING: This study was led in Franche-Comte, a French eastern region, where GPs were given a guideline recommending a restricted use of fluoroquinolones for urinary tract infections. METHOD: Segmented regression analysis of interrupted time series was used to assess changes in antibiotic prescription. MAIN OUTCOME MEASURE: The antibiotic prescription data of nitrofurantoin, fosfomycin-trometamol and fluoroquinolones for women aged 15-65 years were obtained from the regional agency of health insurance. RESULTS: Twenty months after intervention, the number of nitrofurantoin and fosfomycintrometamol prescriptions increased by 36.8% (95% CI: 30.6-42.2) and 28.5% (95% CI: 22.9 35.4), respectively, while that of norfloxacin decreased by 9.1% (95% CI: -15.3 to -3.5). CONCLUSION: This study suggests that the dispatch of the guideline on urinary tract infection had a moderate impact on antibiotic prescriptions. PMID- 22252773 TI - Acceptance and importance of clinical pharmacists' LIMM-based recommendations. AB - OBJECTIVE: The objective of this study was to evaluate the quality of the clinical pharmacy service in a Swedish hospital according to the Lund Integrated Medicine Management (LIMM) model, in terms of the acceptance and clinical significance of the recommendations made by clinical pharmacists. METHOD: The clinical significance of the recommendations made by clinical pharmacists was assessed for a random sample of inpatients receiving the clinical pharmacy service in 2007. Two independent physicians retrospectively ranked the recommendations emerging from errors in the patients' current medication list and actual drug-related problems according to Hatoum, with rankings ranging between 1 (adverse significance) and 6 (extremely significant). RESULTS: The random sample comprised 132 patients (out of 800 receiving the service). The clinical significance of 197 recommendations was assessed. The physicians accepted and implemented 178 (90%) of the clinical pharmacists' recommendations. Most of these recommendations, 170 (83%), were ranked 3 (somewhat significant) or higher. CONCLUSION: This study provides further evidence of the quality of the LIMM model and confirms that the inclusion of clinical pharmacists in a multi-professional team can improve drug therapy for inpatients. The very high level of acceptance by the physicians of the pharmacists' recommendations further demonstrates the effectiveness of the process. PMID- 22252774 TI - Fitness to practise in pharmacy: a study of impairment in professional practice. AB - OBJECTIVE: To explore the opinions and knowledge of Australian pharmacists about impairment in the profession, and their awareness of new legislation regarding impairment and mandatory reporting. SETTING: Pharmacy practice in Australia. METHOD: Pharmacists' opinions and knowledge were explored using a purposively designed, de-identified survey distributed by an intermediate mailing house to randomly selected pharmacists registered with the Pharmacy Board. Descriptive statistics and thematic analyses were conducted on the data. KEY OUTCOME MEASURES: This being an explorative study, we analysed various items using standard statistical methods and qualitative thematic analysis for responses to open-ended questions. RESULTS: Responses from 370 registered pharmacists were obtained. Of these, nearly 60% were not confident in their knowledge of legislation relating to impairment. The vast majority stated they would consider reporting an impaired colleague in principle, but only after consulting the colleague. Older pharmacists demonstrated increased awareness of new legislation; this was accompanied however, by a marked decrease in confidence regarding knowledge about impairment. Thematic analysis of the qualitative data revealed four main themes: (1) perception of impairment and support systems available (2) stigma related to implications of impairment and whistle-blowing (3) factors affecting reporting of impairment and (4) management of impairment. CONCLUSION: Australian pharmacists in this study recognised the importance of the issue of impairment, but appeared to lack confidence and/or awareness of legislative requirements regarding impairment in the profession. There is a need for educative programs and accessible, profession-specific rehabilitative programs to be instigated for management of impairment in the profession of pharmacy in Australia. PMID- 22252775 TI - Augmenting advance care planning in poor prognosis cancer with a video decision aid: a preintervention-postintervention study. AB - BACKGROUND: The authors tested whether an educational video on the goals of care in advanced cancer (life-prolonging care, basic care, or comfort care) helped patients understand these goals and had an impact on their preferences for resuscitation. METHODS: A survey of 80 patients with advanced cancer was conducted before and after they viewed an educational video. The outcomes of interest included changes in goals of care preference and knowledge and consistency of preferences with code status. RESULTS: Before viewing the video, 10 patients (13%) preferred life-prolonging care, 24 patients (30%) preferred basic care, 29 patients (36%) preferred comfort care, and 17 patients (21%) were unsure. Preferences did not change after the video, when 9 patients (11%) chose life-prolonging care, 28 patients (35%) chose basic care, 29 patients (36%) chose comfort care, and, 14 patients (18%) were unsure (P = .28). Compared with baseline, after the video presentation, more patients did not want cardiopulmonary resuscitation (CPR) (71% vs 62%; P = .03) or ventilation (80% vs 67%; P = .008). Knowledge about goals of care and likelihood of resuscitation increased after the video (P < .001). Of the patients who did not want CPR or ventilation after the video augmentation, only 4 patients (5%) had a documented do-not-resuscitate order in their medical record (kappa statistic, -0.01; 95% confidence interval, -0.06 to 0.04). Acceptability of the video was high. CONCLUSIONS: Patients with advanced cancer did not change care preferences after viewing the video, but fewer wanted CPR or ventilation. Documented code status was inconsistent with patient preferences. Patients were more knowledgeable after the video, reported that the video was acceptable, and said they would recommend it to others. The current results indicated that this type of video may enable patients to visualize "goals of care," enriching patient understanding of worsening health states and better informing decision making. PMID- 22252776 TI - Ex vivo expansion of hematopoietic stem cells: mission accomplished? AB - A small number of hematopoietic stem cells (HSCs) with self-renewal and multi lineage repopulation capacity maintain hematopoiesis during the lifetime of an individual. Moreover, HSCs and their potential exist in excess as one individual can share its HSCs with another leading to creation of a genetically identical hematopoietic system. For over half a century this property of HSCs has been utilised by successful allogeneic clinical HSC transplantation for treatment of patients with inherited or acquired genetic and neoplastic diseases of the hematopoietic and immune system. There are now more than twenty thousand allogeneic HSC transplants per year worldwide [1]. However, although more than 17.5 million potential HSC donors are registered and additional 500,000 cord bloods are stored for potential allogeneic HSC transplantation [2], timely availability of appropriately human leukocyte antigen (HLA)-compatible HSCs with sufficient quality for patients still poses a problem in the field. Even if a donor is available, toxicity of the procedure could be reduced by increasing HSC numbers in transplants. One way to solve these issues would be by generation of quality-controlled, off the shelf HSC products via in vitro HSC expansion, a "holy grail" procedure many have been hunting for. Here, we discuss accumulating knowledge on signalling pathways involved in HSC maintenance as well as recent achievements to apply the findings to ex vivo HSC expansion for clinical use. Although the specific issue concerns only highly specialised medicine today, newly generated knowledge will be critical for the whole field of stem cell transplantation and regenerative medicine in the future. PMID- 22252777 TI - Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas. AB - BACKGROUND: Metastatic propensity of soft tissue sarcoma (STS) is heterogeneous and may be determined by gene expression patterns that do not correlate well with morphology. The authors have reported gene expression patterns that distinguish 2 broad classes of clear cell renal carcinoma (ccRCC-gene set), and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA-gene set) and aggressive fibromatosis (AF-gene set); however, clinical follow-up data were not available for these samples. METHODS: In the current study, gene expression patterns in 73 samples of high-grade STS were examined using spotted cDNA microarray slides that contained ~16,000 unique UniGene clusters. Approximately 50% of the genes present in the ccRCC-, OVCA-, and AF-gene sets were also represented in the data from this chip set, and these were combined to form a composite gene set of 278 probes. RESULTS: Hierarchical clustering using this composite gene set suggested the existence of subsets of the STS samples. Analysis revealed differences in the time to development of metastatic disease between the clusters defined by the first branch point of the clustering dendrogram (P = .005), and also among the 4 different clusters defined by the second branch points (P = .001). CONCLUSIONS: This approach suggests the existence of >2 subsets of high-grade pleomorphic STS, each with distinct clinical behavior. A composite gene set such as that described here may be useful to stratify STS in clinical trials, and may be of practical utility in patient management. PMID- 22252778 TI - Predicting prosthetic use in elderly patients after major lower limb amputation. AB - BACKGROUND: The main determinants of prosthetic use known from literature apply to the younger patient with lower limb amputation. Studies aimed at identifying determinants of outcome of lower limb amputation in elderly patients with multimorbidity that rehabilitate in skilled nursing facilities (SNFs) are scarce. OBJECTIVES: To predict prosthetic use and physical mobility in geriatric patients admitted to SNFs for rehabilitation after lower limb amputation and the impact of multimorbidity. STUDY DESIGN: Prospective design. METHODS: Univariate and multivariate logistic and linear regression analyses were used to identify determinants that were independently related to prosthetic use and the timed-up and-go test (TUG test). RESULTS: Of 55 eligible patients, 38 had complete assessments on admission and at discharge. Fifty per cent was provided with a prosthesis. Multimorbidity was present in 53% of the patients. Being able to ambulate independently, and having a transtibial amputation (rather than a higher level of amputation), without phantom pain determined prosthetic use (R(2)=56%), while cognitive abilities, low amputation level, and pre-operative functional abilities were independently associated with the TUG test (R(2)=82%). CONCLUSIONS: Elderly patients referred to an SNF for prosthetic training have a high probability of using a prosthesis when having an independent ambulation after transtibial amputation, without phantom pain. These patients should be considered for prosthetic training. PMID- 22252779 TI - Micro-CT visualization of the cricothyroid joint cavity in cadavers. AB - OBJECTIVES/HYPOTHESIS: To directly visualize the cricothyroid joint (CTJ) cavity of the human cadaver and to correlate the appearance of the CTJ cavity to its fibrous capsule. STUDY DESIGN: Prospective. METHODS: Twenty-five cadavers (nine females and 16 males; age range, 67-95 years) were used for gross anatomy, micro computed tomography (CT) arthrography, histology, E12 sheet plastination, and magnetic resonance imaging examinations. The cadavers were donated for the purposes of teaching and research under the Human Tissues Act. RESULTS: Using micro-CT arthrography with intra-articular filling and sheet plastination technique, this study demonstrated that the dimension of the CTJ cavity was much larger than that of the articular surfaces, particularly at the superior and anterior aspects of the joint. Connective tissue fibers were regularly orientated and significantly strengthened in the posterior and inferior aspects of the CTJ capsule. Such fibrous configuration appeared to enhance the strength of the capsule itself rather than to shorten the distance between the articular surfaces. The size of the direct contact area of the opposing articular surfaces varied significantly between the sides of the same subject and among individuals. CONCLUSIONS: This study supports the general view that the cricoid cartilage rotates in a visor-like fashion on the inferior cornu of the thyroid cartilage. However, the pivot for the CTJ rotation appears wobbly. The wobbly pivot may increase the joint mobility as the rotation allows the horizontal and vertical gliding movements of the CTJ. PMID- 22252780 TI - Laryngeal mask airway versus endotracheal tube in pediatric adenotonsillectomy. AB - OBJECTIVES/HYPOTHESIS: Evaluation of safety and postoperative outcomes of the laryngeal mask airway (LMA) during pediatric tonsil surgery compared to use of the endotracheal tube (ETT). STUDY DESIGN: Randomized controlled trial. METHODS: A population-based sample of 117 patients ages 2 to 18 years requiring adenotonsillectomy, adenoidectomy, or tonsillectomy was studied. Evaluation forms covering 36 safety, surgery duration, and patient comfort variables were given to the surgeon, anesthesiologist, and phase I and phase II recovery nurses to collect data on the intra- and postoperative course. A phone survey was conducted 24 hours after surgery. RESULTS: At the alpha level following Bonferroni correction, LMA showed less coughing or gagging during the anesthesia phase for all surgeries combined (48% for ETT vs. 20% for LMA; chi(2) = 10.153, P = .002), and for ETT nontonsillectomy vs. LMA nontonsillectomy (48% for ETT vs. 3% for LMA; chi(2) = 15.196, P = .000), spontaneous ventilation was used more often in the LMA group when comparing all surgeries (chi(2) = 19.493, P = .000), and when comparing ETT tonsillectomy and LMA tonsillectomy (chi(2) = 11.131, P = .000). CONCLUSIONS: Use of the LMA during pediatric tonsil surgery does not appear to have any major disadvantages compared to use of the ETT. In fact, analysis of safety, comfort, complications, and postoperative problems suggests that LMA may be superior for some outcome variables such as coughing and gagging. Use of spontaneous ventilation is more common among LMA patients, although the significance of this finding is uncertain. PMID- 22252781 TI - Bacterial chemotaxis toward a NAPL source within a pore-scale microfluidic chamber. AB - Chemotaxis toward chemical pollutants provides a mechanism for bacteria to migrate to locations of high contamination, which may improve the effectiveness of bioremediation. A microfluidic device was designed to mimic the dissolution of an organic-phase contaminant from a single pore into a larger macropore representing a preferred pathway for microorganisms that are carried along by groundwater flow. The glass windows of the microfluidic device allowed direct image analysis of bacterial distributions within the vicinity of the organic contaminant. Concentrations of chemotactic bacteria P. putida F1 near the organic/aqueous interface were 25% greater than those of a nonchemotactic mutant in the vicinity of toluene for a fluid velocity of 0.5 m/d. For E. coli responding to phenol, the bacterial concentrations were 60% greater than the controls, also at a velocity of 0.5 m/d. Velocities in the macropore were varied over a range from 0.5 to 10 m/d, the lower end of which is typical of groundwater velocities. The accumulation of chemotactic bacteria near the NAPL chemoattractant source decreased as the fluid velocity increased. Good agreement between computer-based simulations, generated using reasonable values of the model parameters, and the experimental data for P. putida strains confirmed the contribution due to chemotaxis. The experimental data for E. coli required a larger chemotactic sensitivity coefficient than that for P. putida, which was consistent with parameter values reported in the literature. PMID- 22252782 TI - Not just another face in the crowd: society's perceptions of facial paralysis. AB - OBJECTIVES/HYPOTHESIS: There is a paucity of data showing the perception penalty caused by facial paralysis. Our objective was to measure society's perception of facial paralysis on the characteristic of beauty. We hypothesized that patients with paralysis would be considered by society as less attractive than normals, a difference amplified by smiling. STUDY DESIGN: Randomized controlled experiment. METHODS: Forty subjects viewed photographs of normal and paralyzed faces. They rated attractiveness, identified paralysis if present, its severity, and the feature most affected. RESULTS: There were significant differences in attractiveness scores for normal and paralyzed faces (Wilcoxon rank sum test, z = 16.912; P < .001). A mixed effects regression model was used to explain differences in the scores. The fixed portion of the model shows paralyzed faces were 1 standard deviation less attractive than normal faces. Smiling increased attractiveness for normals (constant, 5.9; smile effect, 0.735; P < .001). The smile * paralysis interaction term was -0.892; P < .001, but not significantly different from the smile term (chi(2) (1) = 0.87; P = .352). The random effects model showed an intersubject rating variability of 1.32. CONCLUSIONS: The attractiveness penalty imposed by facial paralysis is significant, with paralyzed faces considered markedly less attractive than normals. However, the ratings did not change significantly when patients smiled, despite the increased asymmetry that occurs through smiling. Observers were moderately good at identifying the presence of facial paralysis, but less good at distinguishing side of involvement. These results have important implications for patient counseling and management of facial paralysis patients in an evidence-based manner. PMID- 22252783 TI - Transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. AB - Various acute and chronic brain diseases result in disturbed expression of the glial glutamate transporters, GLAST/EAAT-1 and GLT-1/EAAT-2, and subsequent secondary neuronal cell death. The idea that glutamate-induced brain damage can be prevented by restoring glutamate homeostasis in the injured brain, focussed previous efforts on identifying the network controlling astrocytic glutamate transport. Since most of this work was performed with rat astrocytes, we now sought to compare the transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. Reporter gene assay demonstrated that the human GLAST/EAAT-1 promoter comprises the 2.3 kb region immediately flanking the 5'-end of the human GLAST/EAAT-1 gene. Cloning of the previously unknown promoter of rat GLAST/EAAT-1 gene demonstrated maximal reporter gene activity with a sequence comprising the 1.5 kb region flanking the 5'-end of the gene as well as non-coding exon 1, and intron 1-2. Although the promoter regions from both species lacked sequence homology, they contained numerous identical consensus motifs. In human promoter constructs, dbcAMP, PACAP, EGF, and TGFalpha, which represent potent stimulators of endogenous GLAST/EAAT-1 expression, only further increased reporter gene activity in the presence of the GLAST/EAAT-1 3'-UTR. By contrast, the rat GLAST/EAAT-1 3'-UTR only mediated the stimulatory increases of dbcAMP. Moreover, the GLAST/EAAT-1 3'-UTR repressed constitutive GLAST/EAAT-1 expression in man, but enhanced GLAST/EAAT-1 transcription in rat. Together, our findings suggest the existence of close functional similarities of the GLAST/EAAT-1 promoter regions in man and rat and further point to a species-specific function of the GLAST/EAAT-1 3'-UTR in constitutive and regulated GLAST/EAAT-1 expression. PMID- 22252784 TI - Mouse delta opioid receptors are located on presynaptic afferents to hippocampal pyramidal cells. AB - Delta opioid receptors participate in the control of chronic pain and emotional responses. Recent data have also identified their implication in drug-context associations pointing to a modulatory role on hippocampal activity. We used fluorescent knock-in mice that express a functional delta opioid receptor fused at its carboxy terminus with the green fluorescent protein in place of the native receptor to investigate the receptor neuroanatomical distribution in this structure. Fine mapping of the pyramidal layer was performed in hippocampal acute brain slices and organotypic cultures using fluorescence confocal imaging, co localization with pre- and postsynaptic markers and correlative light-electron microscopy. The different approaches concurred to identify delta opioid receptors on presynaptic afferents to glutamatergic principal cells. In the latter, only scarce receptors were detected that were confined within the Golgi or vesicular intracellular compartments with no receptor present at the cell surface. In the mouse hippocampus, expression of functional delta opioid receptors is therefore mostly associated with interneurons emphasizing a presynaptic modulatory effect on the pyramidal cell firing rate. PMID- 22252785 TI - The microtubule-associated protein 1A (MAP1A) is an early molecular target of soluble Abeta-peptide. AB - A progressive accumulation of amyloid beta-protein (Abeta) is widely recognized as a pathological hallmark of Alzheimer's disease (AD). Substantial progress has been made toward understanding the neurodegenerative cascade initiated by small soluble species of Abeta and recent evidence supports the notion that microtubule rearrangements may be proximate to neuritic degeneration and deficits in episodic declarative memory. Here, we examined primary cortical neurons for changes in markers associated with synaptic function following exposure to sublethal concentrations of non-aggregated Abeta-peptide. This data show that soluble Abeta species at a sublethal concentration induce degradation of the microtubule associated protein 1A (MAP1A) without concurrently affecting dendritic marker MAP2 and/or the pre-synaptic marker synaptophysin. In addition, MAP1A was found to highly co-localize with the postsynaptic density-95 (PSD-95) protein, proposing that microtubule perturbations might be central for the Abeta-induced neuronal dysfunctions as PSD-95 plays a key role in synaptic plasticity. In conclusion, this study suggests that disruption of MAP1A could be a very early manifestation of Abeta-mediated synaptic dysfunction-one that presages the clinical onset of AD by years. Moreover, our data support the notion of microtubule-stabilizing agents as effective AD drugs. PMID- 22252786 TI - Effect of oxytocin on neuroblastoma cell viability and growth. AB - Oxytocin, released in response to different physiological stimuli, could play a key role in reducing stress reaction. It was suggested that it has protective effect against inflammation and consequences of oxidative stress. Mechanisms how oxytocin effects mediated in the brain tissue are unclear. In this study, oxytocin effect on cell growth and neuronal viability was examined. Human neuroblastoma (SH-SY5Y and SK-N-SH) and glioblastoma (U87MG) cells were exposed to different concentrations of oxytocin for 12-96 h. Potential protective effect of oxytocin treatment was investigated after exposing cells to oxidative stress using hydrogen peroxide (50 mM, 2 h) or 6-hydroxydopamine (25 MUM, 24 h). Cell proliferation was measured by cell counting and cell viability was examined by MTT assay. Protein expression of selected neurotrophic factors was measured as an additional parameter. Oxytocin (1 MUM) significantly increased cell number in all three cell types. Viability of SH-SY5Y cells was increased in the presence of oxytocin without significant effect of dose (0.01-1 MUM). Cell death induced by hydrogen peroxide was not prevented by incubation with oxytocin. Oxytocin pretreatment blunted neurotoxin 6-OHDA reduction of cell viability in SH-SY5Y cells. Oxytocin (1 MUM, 12 h) elevated amount of total proteins without increasing levels of brain-derived neurotrophic factor and neurotrophic growth factor. In conclusion, oxytocin increases growth and viability of neuroblastoma and glioblastoma cells without activation of neurotrophic factors. Oxytocin does not have protective effect in oxidative stress; however, it might be important for neuroprotection to dopaminergic neurons. Its proliferative effect might be important in native cell life, euplastic processes, and tumor progression. PMID- 22252788 TI - Motor vehicle traffic and cardiovascular mortality in male adults. AB - OBJECTIVE: To assess the association between indicators of exposure to motor vehicle-related air pollution and cardiovascular mortality in male adults. METHODS: Information on roads and traffic volume for the year 2007 in the city of Sao Paulo, Southeastern Brazil, was obtained from the local Traffic Engineering Division. Data on mortality from cardiovascular diseases among men aged >40 years in 2005 were obtained from the mortality database of the city of Sao Paulo. Socioeconomic data from the 2000 Population Census and information on location of health care units were also collected. Exposure was assessed by road density and traffic volume for each geographic unit (administrative districts). Spatial regression (alpha= 5%) between these indicators of exposure and standardized mortality rates from cardiovascular diseases were estimated. The models were adjusted for socioeconomic variables, number of health care units in the districts and spatial autocorrelation. RESULTS: It was found a modest correlation between road density and traffic volume (r2 = 0.28). The central districts had the highest road densities. The spatial regression model of road density showed an association with mortality from cardiovascular diseases (p = 0.017). No association was found in the model of traffic volume. The socioeconomic variable was statistically significant in both models of road and traffic volume. CONCLUSIONS: The association between mortality from cardiovascular diseases and road density is consistent with literature data. Further individual-level epidemiological studies should be performed using more accurate methods for the assessment of exposure. PMID- 22252787 TI - Respiratory diseases and associated factors: population-based study in Sao Paulo, 2008-2009. AB - OBJECTIVE: To assess the prevalence of acute bronchitis, rhinitis, and sinusitis among children and adolescents and identify associated factors. METHODS: This is a population-based, cross-sectional study. A household survey was conducted with 1,185 children and adolescents from the city of Sao Paulo (Southeastern Brazil), from 2008 to 2009. The participants were selected by means of probability sampling, stratified by sex and age, and by two-stage cluster sampling. For the adjusted analysis, multiple Poisson regression was used. RESULTS: Of the respondents, 7.3% reported acute bronchitis, 22.6% rhinitis and 15.3% sinusitis. After the adjusted analysis, the following characteristics were associated with self;reported acute bronchitis: age 0 to 4 years (PR=17.86; 95%CI: 3.65;90.91), 5 to 9 years (PR=37.04; 95%CI: 8.13;166.67), 10 to 14 years (PR=20,83; 95%CI: 4.93;90.91), allergy (PR=3.12; 95%CI: 1.70;5.73), black and mixed-ethnicity (black and white) skin color (PR=2.29; 95%CI: 1.21;4.35), and living in a household with 1 to 3 rooms (PR=1.85; 95%CI: 1.17;2.94). As to self-reported rhinitis, the following characteristics were associated: age 10 to 14 years (PR=2.77; 95%CI: 1.60;4.78), 15 to 19 years (PR=2.58; 95%CI: 1.52;4.39), allergy (PR=4.32; 95%CI: 2.79;6.70), asthma (PR=2.30; 95%CI: 1.30;4.10) and living in flats (PR=1.70; 95%CI: 1.06;2.73). Concerning self-reported sinusitis, the following characteristics were associated: age 5 to 9 years (PR=2.44; 95%CI: 1.09;5.43), 10 to 14 years (PR=2.99; 95%CI: 1.36;6.58), 15 to 19 years (PR=3.62; 95%CI: 1.68;7.81), allergy (PR=2.23 (95%CI: 1.41;3.52) and obesity (PR=4.42; 95%CI: 1.56;12.50). CONCLUSIONS: Respiratory diseases were more prevalent in population groups with defined characteristics, such as age group, self-reported diseases, type of household and obesity. PMID- 22252789 TI - Evaluation of innovative strategies in the organization of Primary Health Care. AB - OBJECTIVE: To compare the performance of Primary Care Units according to the implementation of new arrangements and strategies in primary care and mental health. METHODOLOGICAL PROCEDURES: Evaluative research with triangulation of methods and theoretical framework of critical hermeneutics, carried out at six Primary Care Units of the two most populous health districts of the city of Campinas (Southeastern Brazil) in 2007. The Primary Care Units were analyzed according to clinical resolution, articulation between the primary care and mental health networks and implementation of health promotion strategies. Two groups were defined by cluster analysis: one with higher and another one with lower degree of implementation of the actions. The groups were compared based on the improvement in clinical follow-up, given by the occurrence of cerebral vascular accident; evaluation of dispensation of psychiatric medicines; focal groups with workers, users and community health agents; and interviews with users and relatives. Inclusive and participatory research strategies were employed. ANALYSIS OF RESULTS: There were no pure models, but a mosaic of organizational proposals. Positive advances were identified in the group with higher implementation of innovative strategies in relation to better integration of the community agents in the Units' teams; to the workers' and agents' perception of improvement in the assistance; and to the facility for referrals and assistance of mental health cases. The difficulties identified in both groups were: communication among the levels of care and within the teams, in the implementation of matrix support, and incipient health promotion actions. CONCLUSIONS: The development and implementation of mechanisms to fix professionals in Primary Care in large cities are necessary. The community health agents are fundamental to perform the territorial work proposed by the Family Health Strategy, using mechanisms to integrate the community health agents into the healthcare teams in order to counterbalance the tendency to isolation. The researched arrangements proved to be potent to produce this integration. PMID- 22252790 TI - Effect of the Family Health Strategy on surveillance of infant mortality. AB - OBJECTIVE: To evaluate the effect of the Family Health Strategy on infant mortality surveillance. METHODS: An ecologic study was performed with a multiple group design, and the unit of analysis was municipalities in Bahia state (Northeastern Brazil) in 2008. The 3,947 deaths analyzed were obtained from the Mortality Information System, and the minimum acceptable level for death investigation was 25%. Logistic regression models were used for bivariate and multivariate analysis and adjusted for sociodemographic and service organization variables. RESULTS: In 48.9% of the municipalities at least one infant death was investigated, and 35.5% of municipalities achieved the minimum target for investigation. In the bivariate model, the investigation of at least one infant death was statistically associated with more populous municipalities, higher Human Development Indices, existence of Investigation Committee and obstetric beds in the municipality; there were no associations with Family Health Strategy coverage and existence of a designated person in the municipality. In multivariate models, the investigation of at least one infant death was statistically associated with population size (OR = 4.02) and presence of obstetric beds (OR = 2.68). Achieving the minimum target was associated only with the existence of obstetric beds in the municipality (OR = 1.76). CONCLUSIONS: The investigation rate for deaths of children less than one year of age was less than the level agreed upon in Bahia in 2008. There was no association between coverage of the Family Health Strategy and death investigations, which suggests that Infant Mortality Surveillance is at an incipient stage, especially in regards to decentralization to local primary care teams. PMID- 22252791 TI - Tuberculosis and latent tuberculosis in prison inmates. AB - OBJECTIVE: To estimate the prevalences of tuberculosis and latent tuberculosis in inmates. METHODS: Observational study was carried out with inmates of a prison and a jail in the State of Sao Paulo, Southeastern Brazil, between March and December of 2008. Questionnaires were used to collect sociodemographic and epidemiological data. Tuberculin skin testing was administered (PPD-RT23-2TU/0.1 mL), and the following laboratory tests were also performed: sputum smear examination, sputum culture, identification of strains isolated and drug susceptibility testing. The variables were compared using Pearson's chi-square (Chi2) association test, Fisher's exact test and the proportion test. RESULTS: Of the 2,435 inmates interviewed, 2,237 (91.9%) agreed to submit to tuberculin skin testing and of these, 73.0% had positive reactions. The prevalence of tuberculosis was 830.6 per 100,000 inmates. The coefficients of prevalence were 1,029.5/100,000 for inmates of the prison and 525.7/100,000 for inmates of the jail. The sociodemographic characteristics of the inmates in the two groups studied were similar; most of the inmates were young and single with little schooling. The epidemiological characteristics differed between the prison units, with the number of cases of previous tuberculosis and of previous contact with the disease greater in the prison and coughing, expectoration and smoking more common in the jail. Among the 20 Mycobacterium tuberculosis strains identified, 95.0% were sensitive to anti-tuberculosis drugs, and 5.0% were resistant to streptomycin. CONCLUSIONS: The prevalences of tuberculosis and latent tuberculosis were higher in the incarcerated population than in the general population, and they were also higher in the prison than in the jail. PMID- 22252792 TI - In vivo waveguide elastography of white matter tracts in the human brain. AB - White matter is composed primarily of myelinated axons which form fibrous, organized structures and can act as waveguides for the anisotropic propagation of sound. The evaluation of their elastic properties requires both knowledge of the orientation of these waveguides in space, as well as knowledge of the waves propagating along and through them. Here, we present waveguide elastography for the evaluation of the elastic properties of white matter tracts in the human brain, in vivo, using a fusion of diffusion tensor imaging, magnetic resonance elastography, spatial-spectral filtering, a Helmholtz decomposition, and anisotropic inversions, and apply this method to evaluate the material parameters of the corticospinal tracts of five healthy human volunteers. We begin with an Orthotropic inversion model and demonstrate that redundancies in the solution for the nine elastic coefficients indicate that the corticospinal tracts can be approximated by a Hexagonal model (transverse isotropy) comprised of five elastic coefficients representative of a medium with fibers aligned parallel to a central axis, and provides longitudinal and transverse wave velocities on the order of 5.7 m/s and 2.1 m/s, respectively. This method is intended as a new modality to assess white matter structure and health by means of the evaluation of the anisotropic elasticity tensor of nerve fibers. PMID- 22252793 TI - The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: a pooled analysis of 12 randomised controlled trials. AB - PURPOSE: Plant sterols (PS) are well known for their low-density lipoprotein cholesterol-lowering effect. Until recently, they were believed to have little or no impact on blood triglycerides (TG). However, studies taken individually were possibly lacking statistical power to detect modest TG decreases. This study was performed to quantify the TG-lowering effect of PS by pooling individual subject data from 12 randomised controlled trials that investigated the effects of PS on blood lipids. METHODS: The main outcome variable was the control-adjusted PS effect on relative (%) and absolute (mmol/L) changes in TG. The relative and absolute changes in high-density lipoprotein cholesterol (HDL-C) were also assessed. Differences in changes of serum lipid concentrations between PS and control treatments were estimated by an ANCOVA using a random effect model which included PS intake (active or control), study and predefined subject characteristics. RESULTS: The twelve randomised controlled trials included in total 935 hypercholesterolaemic subjects not preselected based on their baseline TG concentrations. In most studies, the PS dose ranged between 1.6 and 2.5 g/day. PS intake significantly lowered serum TG by 6.0% (95% CI: -10.7, -1.2) or 0.12 mmol/L (95% CI: -0.20, -0.04). No significant interaction was observed between PS intake and baseline TG concentrations on relative changes, but, on absolute changes, interaction was significant with larger TG decreases observed with higher TG concentrations at baseline. No effects were observed on HDL-C concentrations. CONCLUSIONS: These results show that PS exert a modest TG lowering effect which is dependent on baseline concentrations. PMID- 22252794 TI - Radiological pitfalls with laryngopharyngeal injectables. AB - The aim of this report was to describe the computed tomography features of injected carboxymethylcellulose and how it can be mistaken for tumor recurrence. Carboxymethylcellulose is a low-density injectable indicated for short-term vocal fold augmentation. When used in patients with head and neck cancer, differentiating this agent from a neoplastic recurrence can be difficult on imaging. The imaging findings of five patients who received carboxymethylcellulose augmentation are presented to illustrate a potential pitfall of image interpretation. When injectable carboxymethylcellulose is used in cancer patients, knowledge of the injection sites, material used, and procedural history can avoid misinterpretation of monitory imaging. PMID- 22252796 TI - Switching from enoxaparin to dabigatran etexilate: pharmacokinetics, pharmacodynamics, and safety profile. AB - PURPOSE: Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and pharmacodynamic (PD) parameters and safety profile of dabigatran. METHODS: Enoxaparin 40 mg was administered subcutaneously once daily for 3 days followed by a single dose of dabigatran etexilate 220 mg (test treatment) on day 4 in an open-label, two-way cross-over trial in healthy volunteers. Dabigatran plasma levels were measured using a validated high performance liquid chromatography tandem mass spectrometry method. Anticoagulant activity was measured using a number of clotting tests, including prothrombinase induced clotting time (PiCT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). RESULTS: PK, PD, and safety data were available for 23 subjects for each treatment. The adjusted geometric mean test/reference ratio of area under the concentration-time curve for total dabigatran was 84% (90% confidence interval 67.2-105.0%) and 86% (67.0 110.0%) for maximum plasma concentration. The PiCT test/reference ratio, which represents the activity of enoxaparin and dabigatran, was elevated by approximately 15% for peak maximum effect ratio to baseline and total area under the effect curve (AUEC0-48) activity, suggesting that some anticoagulant activity of enoxaparin was still present. Enoxaparin pre-treatment increased the AUEC0-48 of activated partial thromboplastin time by approximately 14%. All other dabigatran-related PD markers were unaffected. Tolerability was good, with only mild and reversible adverse events during the treatment. CONCLUSION: Prior administration of enoxaparin did not meaningfully affect the PK or PD properties of dabigatran, and the switch from enoxaparin to dabigatran etexilate was well tolerated among the study subjects. These data support the safety of switching patients from enoxaparin to dabigatran etexilate. PMID- 22252797 TI - NDM-4 metallo-beta-lactamase with increased carbapenemase activity from Escherichia coli. AB - A clinical Escherichia coli isolate resistant to all beta-lactams, including carbapenems, expressed a novel metallo-beta-lactamase (MBL), NDM-4, differing from NDM-1 by a single amino acid substitution (Met154Leu). NDM-4 possessed increased hydrolytic activity toward carbapenems and several cephalosporins compared to that of NDM-1. This amino acid substitution was not located in the known active sites of NDM-1, indicating that remote amino acid substitutions might also play a role in the extended activity of this MBL. PMID- 22252798 TI - Population pharmacokinetics of telavancin in healthy subjects and patients with infections. AB - A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of >= 75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function. PMID- 22252799 TI - Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function. AB - This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL(CR)s) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL(CR)s of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL(CR)s of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC(tau)) was computed as dose/CL. The probability of achieving an AUC(tau)/MIC ratio of >= 219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC(tau)/MIC ratio of >= 219 for MIC values as high as 2 mg/liter. For patients with CL(CR)s of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC0-24 (AUC from 0 to 24 h) and AUC24-48 intervals for MICs of <= 1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC0-24 and AUC24-48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate. PMID- 22252800 TI - Tolerability and safety of primaquine in Papua New Guinean children 1 to 10 years of age. AB - Primaquine is currently the only drug available for radical cure of Plasmodium vivax and P. ovale liver infection stages, but limited safety data exist for children <10 years of age. Detailed daily assessments of side effects in glucose 6-phosphate dehydrogenase (G6PD)-normal children treated with 14 days of primaquine plus chloroquine (3 days; n = 252) or artesunate (7 days; n = 141) (0.5 mg/kg of body weight) showed that both treatments are well tolerated, do not lead to reductions in hemoglobin levels, and can thus safely be used in children 1 to 10 years of age. PMID- 22252801 TI - NagZ-dependent and NagZ-independent mechanisms for beta-lactamase expression in Stenotrophomonas maltophilia. AB - beta-N-Acetylglucosaminidase (NagZ), encoded by the nagZ gene, is a critical enzyme for basal-level ampC derepression (ampC expression in the absence of beta lactam challenge) in ampD and dacB mutants of Pseudomonas aeruginosa. Three mutants with a phenotype of basal-level L1 and L2 beta-lactamase derepression in Stenotrophomonas maltophilia have been reported, including KJDeltaDI (ampD(I) mutant), KJDeltamrcA (mrcA mutant), and KJDeltaDIDeltamrcA (ampD(I) and mrcA double mutant). In this study, nagZ of S. maltophilia was characterized, and its roles in basal-level beta-lactamase derepression, induced beta-lactamase activities, and beta-lactam resistance of KJDeltaDI, KJDeltamrcA, and KJDeltaDIDeltamrcA were evaluated. Expression of the nagZ gene was constitutive and not regulated by AmpR, AmpD(I), AmpN, AmpG, PBP1a, and NagZ. Introduction of DeltanagZ into KJDeltaDI nearly abolished basal-level derepressed beta-lactamase activity; conversely, introduction of DeltanagZ into KJDeltamrcA did not affect it. At least two activator ligands (ALs) are thus considered responsible for beta lactamase expression in the S. maltophilia system, specifically, the NagZ dependent (AL1) and NagZ-independent (AL2) ligands responsible for the basal level derepressed beta-lactamase activities of KJDeltaDI and KJDeltamrcA, respectively. The contributions of AL1 and AL2 to the induced beta-lactamase activities may vary with the types of beta-lactams. nagZ inactivation did not affect aztreonam-, cefoxitin-, and carbenicillin-induced beta-lactamase activities, but it attenuated cefuroxime- and piperacillin-induced beta-lactamase activities. Introduction of DeltanagZ into KJ, KJDeltaDI, KJDeltamrcA, and KJDeltaDIDeltamrcA did not significantly change the MICs of the beta-lactams tested except that the MICs of cefuroxime and piperacillin moderately decreased in strains KJDeltaZ and KJDeltaDIDeltaZ (nagZ mutants). PMID- 22252802 TI - S279 point mutations in Candida albicans Sterol 14-alpha demethylase (CYP51) reduce in vitro inhibition by fluconazole. AB - The effects of S279F and S279Y point mutations in Candida albicans CYP51 (CaCYP51) on protein activity and on substrate (lanosterol) and azole antifungal binding were investigated. Both S279F and S279Y mutants bound lanosterol with 2 fold increased affinities (K(s), 7.1 and 8.0 MUM, respectively) compared to the wild-type CaCYP51 protein (K(s), 13.5 MUM). The S279F and S279Y mutants and the wild-type CaCYP51 protein bound fluconazole, voriconazole, and itraconazole tightly, producing typical type II binding spectra. However, the S279F and S279Y mutants had 4- to 5-fold lower affinities for fluconazole, 3.5-fold lower affinities for voriconazole, and 3.5- to 4-fold lower affinities for itraconazole than the wild-type CaCYP51 protein. The S279F and S279Y mutants gave 2.3- and 2.8 fold higher 50% inhibitory concentrations (IC50s) for fluconazole in a CYP51 reconstitution assay than the wild-type protein did. The increased fluconazole resistance conferred by the S279F and S279Y point mutations appeared to be mediated through a combination of a higher affinity for substrate and a lower affinity for fluconazole. In addition, lanosterol displaced fluconazole from the S279F and S279Y mutants but not from the wild-type protein. Molecular modeling of the wild-type protein indicated that the oxygen atom of S507 interacts with the second triazole ring of fluconazole, assisting in orientating fluconazole so that a more favorable binding conformation to heme is achieved. In contrast, in the two S279 mutant proteins, this S507-fluconazole interaction is absent, providing an explanation for the higher K(d) values observed. PMID- 22252803 TI - The natural antimicrobial peptide subtilosin acts synergistically with glycerol monolaurate, lauric arginate, and epsilon-poly-L-lysine against bacterial vaginosis-associated pathogens but not human lactobacilli. AB - Subtilosin is a cyclical antimicrobial peptide produced by Bacillus amyloliquefaciens that has antimicrobial activity against the bacterial vaginosis associated human pathogen Gardnerella vaginalis. The ability of subtilosin to inhibit G. vaginalis alone and in combination with the natural antimicrobial agents glycerol monolaurate (Lauricidin), lauric arginate, and epsilon-poly-L lysine was tested using a checkerboard approach. Subtilosin was found to act synergistically with all of the chosen antimicrobials. These promising results indicate that lower concentrations of subtilosin in combination with other compounds could effectively be used to inhibit growth of the pathogen, thereby decreasing the risk of developed antimicrobial resistance. This is the first report on the effects of subtilosin combined with other natural antimicrobials against G. vaginalis. PMID- 22252804 TI - Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. AB - Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4 g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P < 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P < 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivax and multidrug-resistant P. falciparum malaria are endemic. PMID- 22252805 TI - Preexposure prophylaxis with albumin-conjugated C34 peptide HIV-1 fusion inhibitor in SCID-hu Thy/Liv mice. AB - PC-1505 is a C34 peptide derived from the heptad repeat 2 region of HIV-1 gp41 conjugated to human serum albumin for sustained in vivo activity. One single preexposure dose of PC-1505 reduced viral RNA in HIV-1-infected SCID-hu Thy/Liv mice by 3.3 log10 and protected T cells from virus-mediated depletion. In contrast, a single preexposure dose of Truvada reduced viral RNA by only 0.8 log10 and was substantially less effective in preventing T cell depletion. PMID- 22252806 TI - Role of rifampin against Propionibacterium acnes biofilm in vitro and in an experimental foreign-body infection model. AB - Propionibacterium acnes is an important cause of orthopedic-implant-associated infections, for which the optimal treatment has not yet been determined. We investigated the activity of rifampin, alone and in combination, against planktonic and biofilm P. acnes in vitro and in a foreign-body infection model. The MIC and the minimal bactericidal concentration (MBC) were 0.007 and 4 MUg/ml for rifampin, 1 and 4 MUg/ml for daptomycin, 1 and 8 MUg/ml for vancomycin, 1 and 2 MUg/ml for levofloxacin, 0.03 and 16 MUg/ml for penicillin G, 0.125 and 512 MUg/ml for clindamycin, and 0.25 and 32 MUg/ml for ceftriaxone. The P. acnes minimal biofilm eradication concentration (MBEC) was 16 MUg/ml for rifampin; 32 MUg/ml for penicillin G; 64 MUg/ml for daptomycin and ceftriaxone; and >=128 MUg/ml for levofloxacin, vancomycin, and clindamycin. In the animal model, implants were infected by injection of 109 CFU P. acnes in cages. Antimicrobial activity on P. acnes was investigated in the cage fluid (planktonic form) and on explanted cages (biofilm form). The cure rates were 4% for daptomycin, 17% for vancomycin, 0% for levofloxacin, and 36% for rifampin. Rifampin cured 63% of the infected cages in combination with daptomycin, 46% with vancomycin, and 25% with levofloxacin. While all tested antimicrobials showed good activity against planktonic P. acnes, for eradication of biofilms, rifampin was needed. In combination with rifampin, daptomycin showed higher cure rates than with vancomycin in this foreign-body infection model. PMID- 22252807 TI - Azole resistance by loss of function of the sterol Delta5,6-desaturase gene (ERG3) in Candida albicans does not necessarily decrease virulence. AB - The inactivation of ERG3, a gene encoding sterol Delta5,6-desaturase (essential for ergosterol biosynthesis), is a known mechanism of in vitro resistance to azole antifungal drugs in the human pathogen Candida albicans. ERG3 inactivation typically results in loss of filamentation and attenuated virulence in animal models of disseminated candidiasis. In this work, we identified a C. albicans clinical isolate (VSY2) with high-level resistance to azole drugs in vitro and an absence of ergosterol but normal filamentation. Sequencing of ERG3 in VSY2 revealed a double base deletion leading to a premature stop codon and thus a nonfunctional enzyme. The reversion of the double base deletion in the mutant allele (erg3-1) restored ergosterol biosynthesis and full fluconazole susceptibility in VSY2, confirming that ERG3 inactivation was the mechanism of azole resistance. Additionally, the replacement of both ERG3 alleles by erg3-1 in the wild-type strain SC5314 led to the absence of ergosterol and to fluconazole resistance without affecting filamentation. In a mouse model of disseminated candidiasis, the clinical ERG3 mutant VSY2 produced kidney fungal burdens and mouse survival comparable to those obtained with the wild-type control. Interestingly, while VSY2 was resistant to fluconazole both in vitro and in vivo, the ERG3-derived mutant of SC5314 was resistant only in vitro and was less virulent than the wild type. This suggests that VSY2 compensated for the in vivo fitness defect of ERG3 inactivation by a still unknown mechanism(s). Taken together, our results provide evidence that contrary to previous reports inactivation of ERG3 does not necessarily affect filamentation and virulence. PMID- 22252808 TI - Case-control study comparing de novo and daptomycin-exposed daptomycin nonsusceptible Enterococcus infections. AB - Understanding factors associated with de novo daptomycin-nonsusceptible Enterococcus (DNSE) infections will aid in better understanding the mechanisms of daptomycin nonsusceptibility. We conducted a case-control study to compare patients with DNSE infections who were daptomycin treatment naive (n = 9) and those with DNSE infections who had exposure to daptomycin (n = 13). Less frequent exposure to antimicrobials, increased susceptibility to nitrofurantoin and gentamicin, and shorter duration of hospitalization were associated with de novo DNSE infection, suggesting a potential community reservoir. PMID- 22252809 TI - In vitro and in vivo antimalarial activities of T-2307, a novel arylamidine. AB - T-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated the in vitro and in vivo antimalarial activity of T-2307. The 50% inhibitory concentrations (IC50s) of T-2307 against Plasmodium falciparum FCR-3 and K-1 strains were 0.47 and 0.17 MUM, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibited in vitro and in vivo antimalarial activity. PMID- 22252810 TI - MupB, a new high-level mupirocin resistance mechanism in Staphylococcus aureus. AB - Mupirocin is a topical antibiotic used for the treatment of skin infections and the eradication of methicillin-resistant Staphylococcus aureus carriage. It inhibits bacterial protein synthesis by interfering with isoleucyl-tRNA synthetase activity. High-level mupirocin resistance (MIC of >= 512 MUg/ml) is mediated by the expression of mupA (ileS2), which encodes an alternate isoleucyl tRNA synthetase. In this study, we describe high-level mupirocin resistance mediated by a novel locus, mupB. The mupB gene (3,102 bp) shares 65.5% sequence identity with mupA but only 45.5% identity with ileS. The deduced MupB protein shares 58.1% identity (72.3% similarity) and 25.4% identity (41.8% similarity) with MupA and IleS, respectively. Despite this limited homology, MupB contains conserved motifs found in class I tRNA synthetases. Attempts to transfer high level mupirocin resistance via conjugation or transformation (using plasmid extracts from an mupB-containing strain) were unsuccessful. However, by cloning the mupB gene into a shuttle vector, it was possible to transfer the resistance phenotype to susceptible S. aureus by electroporation, proving that mupB was responsible for the high-level mupirocin resistance. Further studies need to be done to determine the prevalence of mupB and to understand risk factors and outcomes associated with resistance mediated by this gene. PMID- 22252811 TI - pJIE137 carrying blaCTX-M-62 is closely related to p271A carrying blaNDM-1. AB - Complete sequencing of pJIE137 revealed a backbone closely related to p271A, encoding a novel RepA protein but with a similar organization and up to ~70% nucleotide identity to IncN plasmids. A region in pJIE137 resembling the IncN CUP regulon is mostly missing from p271A, presumably due to recombination. The class 1 In/Tn and ISEcp1-bla(CTX-M-62) transposition unit in pJIE137 and a putative transposon carrying bla(NDM-1) in p271A are inserted in different locations in the plasmid backbone. PMID- 22252813 TI - In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010. AB - This study examines in vitro antimicrobial resistance data from Escherichia coli isolates obtained from urine samples of U.S. outpatients between 2000 and 2010 using The Surveillance Network (TSN). Antimicrobial susceptibility results (n = 12,253,679) showed the greatest increases in E. coli resistance from 2000 to 2010 for ciprofloxacin (3% to 17.1%) and trimethoprim-sulfamethoxazole (TMP-SMX) (17.9% to 24.2%), whereas nitrofurantoin (0.8% to 1.6%) and ceftriaxone (0.2% to 2.3%) showed minimal change. From 2000 to 2010, the antimicrobial resistance of urinary E. coli isolates to ciprofloxacin and TMP-SMX among outpatients increased substantially. PMID- 22252814 TI - Community-associated Escherichia coli harboring CTX-M beta-lactamases from urine cultures from pediatric patients. PMID- 22252812 TI - Structural and inhibition studies of the RNase H function of xenotropic murine leukemia virus-related virus reverse transcriptase. AB - RNase H inhibitors (RNHIs) have gained attention as potential HIV-1 therapeutics. Although several RNHIs have been studied in the context of HIV-1 reverse transcriptase (RT) RNase H, there is no information on inhibitors that might affect the RNase H activity of other RTs. We performed biochemical, virological, crystallographic, and molecular modeling studies to compare the RNase H function and inhibition profiles of the gammaretroviral xenotropic murine leukemia virus related virus (XMRV) and Moloney murine leukemia virus (MoMLV) RTs to those of HIV-1 RT. The RNase H activity of XMRV RT is significantly lower than that of HIV 1 RT and comparable to that of MoMLV RT. XMRV and MoMLV, but not HIV-1 RT, had optimal RNase H activities in the presence of Mn2+ and not Mg2+. Using hydroxyl radical footprinting assays, we demonstrated that the distance between the polymerase and RNase H domains in the MoMLV and XMRV RTs is longer than that in the HIV-1 RT by ~3.4 A. We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with 50% inhibitory concentrations ranging from ~0.8 to 0.02 MUM. Two acylhydrazones effective against HIV-1 RT RNase H were less potent against the XMRV enzyme. We also solved the crystal structure of an XMRV RNase H fragment at high resolution (1.5 A) and determined the molecular details of the XMRV RNase H active site, thus providing a framework that would be useful for the design of antivirals that target RNase H. PMID- 22252815 TI - Klebsiella pneumoniae ST258 producing KPC-3 identified in italy carries novel plasmids and OmpK36/OmpK35 porin variants. AB - A carbapenemase-resistant Klebsiella pneumoniae strain, clone ST258 producing KPC 3, was fully characterized. The entire plasmid content was investigated, thereby identifying plasmids of the IncFII(k) (two of them similar to pKPQIL and pKPN3, respectively), IncX, and ColE types, carrying a formidable set of resistance genes against toxic compounds, metals, and antimicrobial drugs and a novel iron(III) uptake system. PMID- 22252816 TI - Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. AB - Klebsiella pneumoniae producing Klebsiella pneumoniae carbapenemase (KPC) has been associated with serious infections and high mortality. The optimal antimicrobial therapy for infection due to KPC-producing K. pneumoniae is not well established. We conducted a retrospective cohort study to evaluate the clinical outcome of patients with bacteremia caused by KPC-producing K. pneumoniae. A total of 41 unique patients with blood cultures growing KPC producing K. pneumoniae were identified at two medical centers in the United States. Most of the infections were hospital acquired (32; 78%), while the rest of the cases were health care associated (9; 22%). The overall 28-day crude mortality rate was 39.0% (16/41). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (odds ratio, 0.07 [95% confidence interval, 0.009 to 0.71], P = 0.02). The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (P = 0.01). The most commonly used combinations were colistin polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despite in vitro susceptibility, patients who received monotherapy with colistin-polymyxin B or tigecycline had a higher mortality of 66.7% (8/12). The use of combination therapy for definitive therapy appears to be associated with improved survival in bacteremia due to KPC-producing K. pneumoniae. PMID- 22252817 TI - A genomewide screen in Schizosaccharomyces pombe for genes affecting the sensitivity of antifungal drugs that target ergosterol biosynthesis. AB - We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that target ergosterol biosynthesis using a Schizosaccharomyces pombe gene deletion library consisting of 3,004 nonessential haploid deletion mutants. We identified 109 mutants that were hypersensitive and 11 mutants that were resistant to these antifungals. Proteins whose absence rendered cells sensitive to these antifungals were classified into various functional categories, including ergosterol biosynthesis, membrane trafficking, histone acetylation and deacetylation, ubiquitination, signal transduction, ribosome biosynthesis and assembly, regulation of transcription and translation, cell wall organization and biogenesis, mitochondrion function, amino acid metabolism, nucleic acid metabolism, lipid metabolism, meiosis, and other functions. Also, proteins whose absence rendered cells resistant to these antifungals were classified into functional categories including mitochondrion function, ubiquitination, membrane trafficking, cell polarity, chromatin remodeling, and some unknown functions. Furthermore, the 109 sensitive mutants were tested for sensitivity to micafungin, another antifungal drug that inhibits (1,3)-beta-D-glucan synthase, and 57 hypersensitive mutants were identified, suggesting that these mutants were defective in cell wall integrity. Altogether, our findings in fission yeast have shed light on molecular pathways associated with the cellular response to ergosterol biosynthesis inhibitors and may provide useful information for developing strategies aimed at sensitizing cells to these drugs. PMID- 22252818 TI - Antimicrobial and anticoagulant activities of N-chlorotaurine, N,N-dichloro-2,2 dimethyltaurine, and N-monochloro-2,2-dimethyltaurine in human blood. AB - The aim of this study was to determine the potential application of N chlorotaurine (NCT), N,N-dichloro-2,2-dimethyltaurine (NVC-422), and N-monochloro 2,2-dimethyltaurine (NVC-612) as catheter lock solutions for the prevention of catheter blockage and catheter-related bloodstream infections by testing their anticoagulant and broad-spectrum antimicrobial activities in human blood. NCT, NVC-422, NVC-612, and control compounds were serially diluted in fresh human blood to evaluate the effects on prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, and direct thrombin inhibition. Quantitative killing assays against pathogens, including methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans, were performed in the presence of heparin and human blood. NCT and NVC-612 (1.38 mM each) and 1.02 mM NVC-422 prolonged prothrombin time (Quick value, 17 to 30%), activated partial thromboplastin time 3- to 4-fold to 76 to 125 s, and thrombin time 2- to 4-fold to 34 to 68 s. Fibrinogen decreased from 258 to 283 mg/dl (range of controls) to <40 mg/dl. No direct thrombin inhibition was observed by NVC-422 or NVC-612. Heparin did not influence the bactericidal activity of NCT. The microbicidal activities of NCT, NVC-422, and NVC-612 were maintained in diluted human blood. NCT, NVC-612, and NVC-422 have broad-spectrum antimicrobial activity in blood and anticoagulant activity targeting both intrinsic and extrinsic pathways of the coagulation system. These properties support their application as catheter lock solutions. PMID- 22252819 TI - Population pharmacokinetics of metronidazole evaluated using scavenged samples from preterm infants. AB - Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were <= 32 weeks of gestational age at birth and <120 postnatal days. A 5 center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 * (weight/1.5) * (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 * (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations. PMID- 22252820 TI - Differential use of CCR5 by HIV-1 clinical isolates resistant to small-molecule CCR5 antagonists. AB - How HIV-1 resistant to small-molecule CCR5 antagonists uses the coreceptor for entry has been studied in a limited number of isolates. We characterized dependence on the N terminus (NT) and the second extracellular loop (ECL2) of CCR5 of three vicriviroc (VCV)-resistant clinical isolates broadly cross resistant to other CCR5 antagonists. Pseudoviruses were constructed to assess CCR5 use by VCV-sensitive and -resistant envelopes of subtype B and C viruses. We determined the extent of entry inhibition by monoclonal antibodies (MAbs) directed against the NT and ECL2 in the presence and absence of VCV and the capacity of these pseudoviruses to use CCR5 mutants that contained scanning alanine substitutions in the CCR5 NT and ECL2 domains. Sensitive and resistant viruses were completely and competitively inhibited by the ECL2-specific MAb 2D7, whereas the NT-specific MAb CTC5 led to partial noncompetitive inhibition. VCV resistant clones showed greater sensitivity to 2D7 than VCV-sensitive clones, but in the presence of saturating VCV concentrations, the 2D7 susceptibilities of two VCV-resistant viruses were similar to that of VCV-sensitive virus. The entry of VCV-sensitive and -resistant isolates was impaired to differing degrees by alanine mutations in CCR5; substitutions in NT had the greatest effect on viral entry. HIV-1 clinical isolates broadly resistant to CCR5 antagonists demonstrated significant heterogeneity in their use of CCR5. This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry. PMID- 22252821 TI - Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope active antibiotics. AB - The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics. PMID- 22252822 TI - Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria. AB - Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series. PMID- 22252823 TI - Ketoamide resistance and hepatitis C virus fitness in val55 variants of the NS3 serine protease. AB - Drug-resistant viral variants are a major issue in the use of direct-acting antiviral agents in chronic hepatitis C. Ketoamides are potent inhibitors of the NS3 protease, with V55A identified as mutation associated with resistance to boceprevir. Underlying molecular mechanisms are only partially understood. We applied a comprehensive sequence analysis to characterize the natural variability at Val55 within dominant worldwide patient strains. A residue-interaction network and molecular dynamics simulation were applied to identify mechanisms for ketoamide resistance and viral fitness in Val55 variants. An infectious H77S.3 cell culture system was used for variant phenotype characterization. We measured antiviral 50% effective concentration (EC50) and fold changes, as well as RNA replication and infectious virus yields from viral RNAs containing variants. Val55 was found highly conserved throughout all hepatitis C virus (HCV) genotypes. The conservative V55A and V55I variants were identified from HCV genotype 1a strains with no variants in genotype 1b. Topology measures from a residue-interaction network of the protease structure suggest a potential Val55 key role for modulation of molecular changes in the protease ligand-binding site. Molecular dynamics showed variants with constricted binding pockets and a loss of H-bonded interactions upon boceprevir binding to the variant proteases. These effects might explain low-level boceprevir resistance in the V55A variant, as well as the Val55 variant, reduced RNA replication capacity. Higher structural flexibility was found in the wild-type protease, whereas variants showed lower flexibility. Reduced structural flexibility could impact the Val55 variant's ability to adapt for NS3 domain-domain interaction and might explain the virus yield drop observed in variant strains. PMID- 22252824 TI - In vivo impact of Met221 substitution in GOB metallo-beta-lactamase. AB - Metallo-beta-lactamases (MbetaLs) represent one of the main mechanisms of bacterial resistance against beta-lactam antibiotics. The elucidation of their mechanism has been limited mostly by the structural diversity among their active sites. All MbetaLs structurally characterized so far present a Cys or a Ser residue at position 221, which is critical for catalysis. GOB lactamases stand as an exception within this picture, possessing a Met residue in this location. We studied different mutants in this position, and we show that Met221 is essential for protein stability, most likely due to its involvement in a hydrophobic core. In contrast to other known MbetaLs, residue 221 is not involved in metal binding or in catalysis in GOB enzymes, further highlighting the structural diversity of MbetaLs. We also demonstrate the usefulness of protein periplasmic profiles to assess the contribution of protein stability to antibiotic resistance. PMID- 22252825 TI - Pharmacokinetics of and short-term virologic response to low-dose 400-milligram once-daily raltegravir maintenance therapy. AB - Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC0-12) was 15.6 mg/liter-h and the minimum plasma drug concentration (C(trough)) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC0-24 was 33.6 mg/liter-h and the C(trough) was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC0 24 was 18.6 mg/liter-h and the C(trough) was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC0-24 for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC0-24 and those on raltegravir at 400 mg QD had a similar AUC0-24. More patients had a C(trough) of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C(trough) values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C(trough) and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed. PMID- 22252826 TI - PXR variants and artemisinin use in Vietnamese subjects: frequency distribution and impact on the interindividual variability of CYP3A induction by artemisinin. AB - Artemisinins induce drug metabolism through the activation of the pregnane X receptor (PXR) in vitro. Here, we report the resequencing and genotyping of PXR variants in 75 Vietnamese individuals previously characterized for CYP3A enzyme activity after artemisinin exposure. We identified a total of 31 PXR variants, including 5 novel single nucleotide polymorphisms (SNPs), and we identified significantly different allele frequencies relative to other ethnic groups. A trend of significance was observed between the level of CYP3A4 induction by artemisinin and two PXR variants, the 8118C->T (Y328Y) and 10719A->G variants. PMID- 22252827 TI - A semimechanistic pharmacokinetic-enzyme turnover model for rifampin autoinduction in adult tuberculosis patients. AB - The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters . h-1 at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction. PMID- 22252828 TI - SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. AB - SQ109, a 1,2-diamine related to ethambutol, is currently in clinical trials for the treatment of tuberculosis, but its mode of action remains unclear. Here, we demonstrate that SQ109 disrupts cell wall assembly, as evidenced by macromolecular incorporation assays and ultrastructural analyses. SQ109 interferes with the assembly of mycolic acids into the cell wall core of Mycobacterium tuberculosis, as bacilli exposed to SQ109 show immediate inhibition of trehalose dimycolate (TDM) production and fail to attach mycolates to the cell wall arabinogalactan. These effects were not due to inhibition of mycolate synthesis, since total mycolate levels were unaffected, but instead resulted in the accumulation of trehalose monomycolate (TMM), the precursor of TDM and cell wall mycolates. In vitro assays using purified enzymes showed that this was not due to inhibition of the secreted Ag85 mycolyltransferases. We were unable to achieve spontaneous generation of SQ109-resistant mutants; however, analogs of this compound that resulted in similar shutdown of TDM synthesis with concomitant TMM accumulation were used to spontaneously generate resistant mutants that were also cross-resistant to SQ109. Whole-genome sequencing of these mutants showed that these all had mutations in the essential mmpL3 gene, which encodes a transmembrane transporter. Our results suggest that MmpL3 is the target of SQ109 and that MmpL3 is a transporter of mycobacterial TMM. PMID- 22252829 TI - Attenuation-based dual-fluorescent-protein reporter for screening translation inhibitors. AB - A reporter construct was created on the basis of the transcription attenuator region of the Escherichia coli tryptophan operon. Dual-fluorescent-protein genes for red fluorescent protein and cerulean fluorescent protein were used as a sensor and internal control of gene expression. The sequence of the attenuator was modified to avoid tryptophan sensitivity while preserving sensitivity to ribosome stalling. Antimicrobial compounds which cause translation arrest at the stage of elongation induce the reporter both in liquid culture and on an agar plate. This reporter could be used for high-throughput screening of translation inhibitors. PMID- 22252830 TI - Prospective observational study comparing three different treatment regimes in patients with Clostridium difficile infection. AB - In a hospital-based, prospective cohort study, the effects of the three standard treatment regimens for mild Clostridium difficile infection (CDI), oral (p.o.) metronidazole at 500 mg three times/day, intravenous (i.v.) metronidazole at 500 mg three times/day, and oral (p.o.) vancomycin at 250 mg four times/day, were compared with respect to the risk of occurrence of complications, sequelae, and all-cause death within 30 days after the date of starting treatment. Differences in the incidence of these outcomes were tested by chi2 or Fisher's exact tests. A Poisson regression model was performed to control for possible confounding effects of sex, age, and severity of comorbidity categorized according to the Charlson comorbidity index. The highest mortality was observed in the metronidazole i.v. group, with a mortality rate 38.1% (16/42) compared to mortality rates of 7.4% (9/121) in the metronidazole p.o. group and 9.5% (4/42) in the vancomycin p.o. group (P < 0.001). After adjustment for possible effects of sex, age (> 65 years), and severity of comorbidity, the relative risk of a 30 day fatal outcome for patients receiving metronidazole i.v. was 4.3 (95% confidence interval [CI] = 1.92 to 10; P < 0.0001) compared to patients treated with metronidazole p.o. and 4.0 (95% CI = 1.31 to 5.0; P < 0.015) compared to patients treated with vancomycin p.o. There were no significant differences in the risk of complications between the three treatment groups. This study generates the hypothesis that treatment with i.v. metronidazole is inferior to the oral alternatives metronidazole and vancomycin. PMID- 22252831 TI - Mutation analysis of mycobacterial rpoB genes and rifampin resistance using recombinant Mycobacterium smegmatis. AB - Rifampin is a major drug used to treat leprosy and tuberculosis. The rifampin resistance of Mycobacterium leprae and Mycobacterium tuberculosis results from a mutation in the rpoB gene, encoding the beta subunit of RNA polymerase. A method for the molecular determination of rifampin resistance in these two mycobacteria would be clinically valuable, but the relationship between the mutations and susceptibility to rifampin must be clarified before its use. Analyses of mutations responsible for rifampin resistance using clinical isolates present some limitations. Each clinical isolate has its own genetic variations in some loci other than rpoB, which might affect rifampin susceptibility. For this study, we constructed recombinant strains of Mycobacterium smegmatis carrying the M. leprae or M. tuberculosis rpoB gene with or without mutation and disrupted their own rpoB genes on the chromosome. The rifampin and rifabutin susceptibilities of the recombinant bacteria were measured to examine the influence of the mutations. The results confirmed that several mutations detected in clinical isolates of these two pathogenic mycobacteria can confer rifampin resistance, but they also suggested that some mutations detected in M. leprae isolates or rifampin resistant M. tuberculosis isolates are not involved in rifampin resistance. PMID- 22252832 TI - In reference to balloon catheter technology in rhinology: reviewing the evidence. PMID- 22252833 TI - Self-assembly of DNA on a gapped carbon nanotube. AB - We perform molecular dynamics simulations to analyze the wrapping process of a single-stranded (ss) DNA around a gapped CNT immersed in a bath of water. We observe the formation of a stable molecular junction with the ssDNA adopting a helical or circular conformation around one CNT electrode and a linear conformation around the opposite electrode. We find that DNA undergoes several conformational changes during equilibration of the self-assembled molecular junction. This process would allow a higher yield of successful CNT-DNA interconnections, which constitutes a novel structure of interest in chemical and biological sensing at the single-molecule level. PMID- 22252834 TI - Tetraethylorthosilicate as molecular precursor to the formation of amorphous silica networks. A DFT-SCRF study of the base catalyzed hydrolysis. AB - Quantum chemical calculations using density functional theory have been carried out to investigate two chemical pathways for the last step of the hydrolysis of tetraethylorthosilicate (TEOS) in basic catalyzed environment. The two models that are introduced in this study depend on the number of water molecules involved at the base catalyzed hydrolysis. Solution equilibrium geometries of the molecules involved in the transition states, reactants and product complexes of the two chemical pathways were fully optimized at B3LYP level of theory with the standard 6-31+G(d) basis set, modeling solvent effects using a polarizable continuum solvation model (PCM). Both models predict relative low activation energies. However, the model with two water molecules seems to be more adequate to describe the basic hydrolysis. A natural bond orbital (NBO) analysis seems to show that the proton transfer from water to ethoxy group would occur through a large hyperconjugative interaction, LP(O) -> sigma*(O-H), which is related to the nonbonding oxygen lone pair orbital from ethoxy group with the vicinal sigma*(O H) anti bonding orbital O-H of a water molecule. PMID- 22252835 TI - Anion recognition based on halogen bonding: a case study of macrocyclic imidazoliophane receptors. AB - The structures and properties of noncovalent interactions involving three imidazoliophane receptors 1-3 and halide anions have been investigated by means of density functional theory calculations. To account for the influence of the solvent environment, the implicit polarized continuum model was also employed. For the halogenated cyclophane receptors 1 and 2, the halide ions are held by a bidentate array of halogen bonds (C-Br/C-I...X(-)), while multiple hydrogen bonding interactions (C-H...X(-)) are present in the complexes of the nonhalogenated macrocyclic receptor 3. To accommodate the negatively charged guest anions, the structures of 1 and 2 fully reorganize into a calix-like shape, while both the imidazole and benzene rings in 3 tend to point towards the anions and thus rotate to form a cage-like shape. In both the gas phase and aqueous solution, the binding affinities of the anions for halogen-bonding receptors 1 and 2 become stronger than those for hydrogen-bonding receptor 3. The results reported here should prove to be of great value in the design and synthesis of effective and selective anion receptors based on halogen bonding. PMID- 22252836 TI - Vector correlations in the F + HO -> HF + O reaction and its isotopic variant. AB - The F + H(D)O -> HF(DF) + O reactions have been studied using quasi-classical trajectory (QCT) calculation method, based on the three different potential energy surfaces (PESs) of Gomez-Carrasco et al. (J Chem Phys 2004, 121:4605; J Chem Phys 2005, 123:114310; Chem Phys Lett 2007, 435:188). Facilitated with the analysis of the QCT results, the pictures for product scattering and product polarizations have been presented to investigate the vector correlations in the two reactions, with effects of isotope substitution and electronic state as well as collision energy being revealed at a chemical stereodynamical level. PMID- 22252837 TI - Herpes simplex virus type 1 induces nuclear accumulation of hyperphosphorylated tau in neuronal cells. AB - Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that remains latent in host neurons. Viral DNA replication is a highly structured process in which the redistribution of nuclear proteins plays an important role. Although tau is most widely known as a microtubule-associated protein found in a hyperphosphorylated state in the brains of patients with Alzheimer's disease (AD), this protein has also been detected at other sites such as the nucleolus. Here, we establish that HSV-1 infection gives rise to an increase in tau phosphorylation and that hyperphosphorylated tau accumulates in the nucleus, forming defined structures in HSV-1-infected neuronal cells reminiscent of the common sites of viral DNA replication. When tau expression in human neuroblastoma cells was specifically inhibited using an adenoviral vector expressing a short hairpin RNA to tau, viral DNA replication was not affected, indicating that tau is not required for HSV-1 growth in neuronal cells. Given that HSV-1 is considered a risk factor for AD, our results suggest a new way in which to understand the relationships between HSV-1 infection and the pathogenic mechanisms leading to AD. PMID- 22252838 TI - Prenatal stress effects on emotion regulation differ by genotype and sex in prepubertal rats. AB - Behavioral effects of different prenatal stress (PNS) schedules were examined in prepubertal "depressive/anxious-like" WKY and control Wistar rats. Pregnant dams received 1 hr daily restraint stress on gestational days 14-20 or on 7 randomly scheduled days, or remained undisturbed. Offspring were tested during postnatal days 29-35 in social play, forced swim-test, open field, and novelty tests. PNS induced an increase in anxiety-like behaviors in WKY, particularly in females, while seemingly reducing depressive-like behavior in the swim test. However, very high post-stress corticosterone levels were found, suggesting that the reductions in swim-test immobility reflect an extremely over-responsive HPA axis, rather than normalization in stress reactivity leading to a less depressive-like profile. In Wistar, PNS produced weight loss, hyperactivity and risk taking behavior, especially in males. The results support the importance of the environment during gestation and its interaction with sex and genetics on long term anxiety and depressive like behaviors. PMID- 22252839 TI - Nonlinear laser scanning microscopy of human vocal folds. AB - OBJECTIVES/HYPOTHESIS: The purpose of this work was to apply nonlinear laser scanning microscopy (NLSM) for visualizing the morphology of extracellular matrix proteins within human vocal folds. This technique may potentially assist clinicians in making rapid diagnoses of vocal fold tissue disease or damage. Microstructural characterization based on NLSM provides valuable information for better understanding molecular mechanisms and tissue structure. STUDY DESIGN: Experimental, ex vivo human vocal fold. METHODS: A custom-built multimodal nonlinear laser scanning microscope was used to scan fibrillar proteins in three 4% formaldehyde-fixed cadaveric samples. Collagen and elastin, key extracellular matrix proteins in the vocal fold lamina propria, were imaged by two nonlinear microscopy modalities: second harmonic generation (SHG) and two-photon fluorescence (TPF), respectively. An experimental protocol was introduced to characterize the geometrical properties of the imaged fibrous proteins. RESULTS: NLSM revealed the biomorphology of the human vocal fold fibrous proteins. No photobleaching was observed for the incident laser power of ~60 mW before the excitation objective. Types I and III fibrillar collagen were imaged without label in the tissue by intrinsic SHG. Imaging while rotating the incident laser light-polarization direction confirmed a helical shape for the collagen fibers. The amplitude, periodicity, and overall orientation were then computed for the helically distributed collagen network. The elastin network was simultaneously imaged via TPF and found to have a basket-like structure. In some regions, particularly close to the epithelium, colocalization of both extracellular matrix components were observed. CONCLUSIONS: A benchmark study is presented for quantitative real-time, ex vivo, NLSM imaging of the extracellular macromolecules in human vocal fold lamina propria. The results are promising for clinical applications. PMID- 22252840 TI - Genetic susceptibility to otitis media in childhood. AB - Otitis media (OM) is a common disease in early childhood characterized by inflammation of the middle ear cavity. Heritability studies suggest that there is a substantial genetic component (40%-70%) to the risk of recurrent acute OM, defined as three or more episodes in 6 months or four or more episodes in a year, or chronic OM with effusion (COME), defined as middle ear fluid for >= 3 months. To date, only a handful of the regions/genes underlying this genetic susceptibility have been identified. These include several regions of linkage on chromosome 3p25, 10q22, 10q26, 17q12, and 19q13 identified by two genome-wide linkage scans, which appear to harbor susceptibility loci. Fine mapping of these regions has yet to identify the causative genes. Several candidate genes studies have also been reported, with candidates selected on the basis of a plausible biological role in OM or through OM mouse models. Reviewed in this article, these studies have identified positive association at 21 genes, including FBXO11, TLR4, and TNF, with association at five of these replicated in independent populations. However, these studies have been based on small sample sizes, and it is only recently that well-powered OM cohorts suitable for genome-wide association studies (GWAS) have become available. Results from such GWAS will identify novel genes involved in this complex disease. Identification of the genes that contribute to OM susceptibility in childhood will provide important insights into the biological complexity of this disease that could ultimately contribute to improved preventative and therapeutic strategies to reduce the incidence of this disease. PMID- 22252841 TI - Glucose/O2 biofuel cell based on enzymes, redox mediators, and multiple-walled carbon nanotubes deposited by AC-electrophoresis then stabilized by electropolymerized polypyrrole. AB - In this study, we developed an automated strategy to manufacture an enzyme BFC powered by glucose/O(2). The bioanode consists of GOx enzyme and PQQ redox mediator adsorbed over night on MWCNTs then deposited by means of AC electrophoresis at 30 Hz and 160 V(p-p) and, finally stabilized by electropolymerized polypyrrole. The biocathode is constructed from LAc enzyme and ABTS redox mediator adsorbed over night on MWCNTs, then electrophoretically deposited under AC-electric field at 30 Hz and 160 V(p-p) and, finally stabilized by electrodeposited polypyrrole. The BFC was studied under air in phosphate buffer solution pH 7.4 containing 10 mM glucose and in human serum with 5 mM glucose addition at the physiological temperature of 37 degrees C. Under these conditions, the maximum power density reaches 1.1 uW . mm(-2) at a cell voltage of 0.167 V in buffer solution and 0.69 uW . mm(-2) at cell voltage of 0.151 V in human serum. Such automated BFCs have a great potential to be optimized, miniaturized to micro and nanoscale devices suitable for in vivo studies. PMID- 22252843 TI - Improved health of hospitality workers after a Swiss cantonal smoking ban. AB - QUESTIONS UNDER STUDY: Hospitality workers are a population particularly at risk from the noxious effects of environmental tobacco smoke (ETS). The Canton of Vaud, Switzerland banned smoking in public places in September 2009. This prospective study addresses the impact of the ban on the health of hospitality workers. METHODS: ETS exposure was evaluated using a passive sampling device that measures airborne nicotine; lung function was assessed by spirometry; health related quality of life, ETS exposure symptoms and satisfaction were measured by questionnaire. RESULTS: 105 participants (smokers and non-smokers) were recruited initially and 66 were followed up after one year. ETS exposure was significantly lower after the ban. Hospitality workers had lower pre-ban forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) values than expected. FEV1 remained stable after the ban, with a near-significant increase in the subgroup of asthmatics only. FVC increased at one year follow-up from 90.42% to 93.05% (p = 0.02) in the entire cohort; women, non-smokers and older participants gained the greatest benefit. The health survey showed an increase in physical wellbeing after the ban, the greatest benefit being observed in non-smokers. ETS exposure symptoms were less frequent after the ban, especially red and irritated eyes and sneezing. The new law was judged useful and satisfactory by the vast majority of employees, including smokers. CONCLUSION: The recent cantonal ban on smoking in public places brought about an improvement in lung function, physical well-being and ETS symptoms of hospitality workers, including smokers. PMID- 22252842 TI - HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ. AB - BACKGROUND: HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. METHODS: A HER 2/neu dendritic cell vaccine was administered to 27 patients with HER-2/neu overexpressing DCIS. The HER-2/neu vaccine was administered before surgical resection, and pre- and postvaccination analysis was conducted to assess clinical results. RESULTS: At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, whereas among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing estrogen receptor (ER)(neg) with ER(pos) DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER(neg) subjects compared with 5.9% in ER(pos) subjects. Sustained HER-2/neu expression was found in 10% of ER(neg) subjects compared with 47.1% in ER(pos) subjects (P = .04). Postvaccination phenotypes were significantly different between ER(pos) and ER(neg) subjects (P = .01), with 7 of 16 (43.8%) initially presenting with ER(pos) HER-2/neu(pos) luminal B phenotype finishing with the ER(pos) HER 2/neu(neg) luminal A phenotype, and 3 of 6 (50%) with the ER(neg) HER-2/neu(pos) phenotype changing to the ER(neg) HER-2/neu(neg) phenotype. CONCLUSIONS: Results suggest that vaccination against HER-2/neu is safe and well tolerated and induces decline and/or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor-associated antigens and pathways. PMID- 22252844 TI - Validation of some pathophysiological mechanisms of the CKD progression theory and outcome prediction in IgA nephropathy. AB - BACKGROUND: The "remnant kidney" chronic kidney disease (CKD) progression theory based on hemodynamic, proteinuric and inflammatory mechanisms consequent to nephron loss has not been confirmed in a human disease. The aim of this study was to evaluate whether some of these mechanisms are present in IgA nephropathy (IgAN) and predict functional outcome. METHODS: In 132 IgAN patients (68 untreated, 64 angiotensin-converting enzyme inhibitor [ACEi]-treated) fractional excretion of IgG (FEIgG) and alpha1-microglobulin, proteinuria/day and beta-NAG excretion were divided by percentage of nonglobally sclerotic glomeruli ("surviving glomeruli" [SG]) to assess the effective glomerular loss and tubular load of proteins in surviving nephrons. Proteinuric markers were compared between 4 SG groups: group 1: <=50%; group 2: >50% and <80%; group 3: >=80% and <100%; and group 4: 100%. The outcome prediction (estimated glomerular filtration rate [eGFR] improvement and stability, progression) was assessed comparing low- and high-risk groups for each marker. RESULTS: Proteinuric markers showed increasing values in parallel with reduction of percentages of SG (p<0.0001). FEIgG/SG, 40 fold higher in patients with SG <=50% vs. SG=100% (0.00040 +/- 0.00039 vs. 0.00001 +/- 0.00002, p<0.0001), was the most powerful outcome predictor: in ACEi untreated patients, FEIgG/SG less or greater than 0.00010 predicted eGFR improvement and stability (88% vs. 12%, p<0.0001) and end-stage renal disease (ESRD) + eGFR reduction >=50% (2% vs. 87.5%, p<0.0001); ACEi treatment reduced ESRD+eGFR reduction >=50%: 36% vs. 87.5% (p=0.002). In patients with FEIgG/SG <0.00010 the eGFR increase is significantly higher in ACEi-treated for >=70 months versus ACEi-untreated with follow up >=70 months (+35% +/- 23% vs. +13% +/ 8%, p=0.004). CONCLUSIONS: In IgAN, progressive nephron loss is associated with an increase of proteinuric markers of glomerular and tubular damage. FEIgG/SG is the best outcome predictor. These data represent the first validation in a human disease of some pathophysiological mechanisms of CKD progression theory. PMID- 22252845 TI - Vitamin D status in dark-skinned patients undergoing hemodialysis in a continually sunny country. AB - BACKGROUND: Vitamin D (vitD) insufficiency is common in end-stage renal disease. Seasonal and ethnic differences in vitD status have been reported previously. We hypothesized that vitD status in Afro-Caribbean patients on hemodialysis (HD) living in a country with a constant sunny climate would be better than that in African-American HD patients living in countries with a winter season. METHOD: A cross-sectional study was conducted in 152 Afro-Caribbean HD patients in a dialysis center located in Guadeloupe. We evaluated the prevalence of vitD insufficiency, defined as serum 25-hydroxyvitamin D (25(OH)D) levels below 30 ng/mL, compared with those results previously reported in African-American HD patients (88%). RESULTS: Prevalence of vitD insufficiency was 60% and thus lower than that in the African-American patients considered as the reference population (p<0.001). In our diabetic patients, this prevalence was 72.4%. Globally, 9.2% of patients had 25(OH)D below 15 ng/mL. Alfacalcidol therapy was prescribed in 29%. Mean 25(OH)D levels were higher in treated than in untreated patients (32 vs. 27 ng/mL; p=0.009). Patients with vitD insufficiency had dyslipidemia and diabetes more frequently. No significant differences were found between patients with and without vitD insufficiency for serum calcium, phosphorus and parathyroid hormone (PTH). In untreated patients, no significant correlation was found between 25(OH)D and PTH levels. CONCLUSION: Prevalence of vitD insufficiency in Afro Caribbean HD patients was lower than that previously reported in African Americans undergoing HD in the United States. This finding may be due to the constantly sunny weather with a high intensity of UVB radiation in Guadeloupe. PMID- 22252846 TI - Reversible acute encephalopathy with mutism, induced by calcineurin inhibitors after renal transplantation. AB - The incidence of neurotoxicity from calcineurin inhibitors varies by the organ transplanted. Akinetic mutism is characterized by the inability to perform voluntary movements and express language, without alterations in mental status. This process has been reported in neurotoxicity due to high serum levels of calcineurin inhibitors, but in rare cases, it presents as a form of tacrolimus toxicity after renal transplantation, despite normal serum levels. We report a clinical case of a renal transplant patient in whom reversible acute encephalopathy and akinetic mutism developed. Brain lesions appeared on magnetic resonance imaging, and the condition resolved after the drug was withdrawn. PMID- 22252847 TI - Effect of administration route on the renal safety of contrast agents: a meta analysis of randomized controlled trials. AB - BACKGROUND: The objective of this study was to examine the association between administration route and relative renal safety of contrast agents. METHODS: We searched all published articles indexed in Embase, Medline and the Cochrane Central Register of Controlled Trials, from January 1980 to November 2010, to identify relevant studies. Of the 1,047 initially identified studies, 11 randomized controlled trials (RCTs) including 2,210 patients with intra-arterial route and 7 RCTs including 919 patients with intravenous route were finally analyzed. RESULTS: With regard to intra-arterial route, our meta-analysis showed that iodixanol significantly decreased the risk of contrast-induced acute kidney injury (CI-AKI) when compared with a pool of low-osmolar contrast media (LOCM; risk ratio [RR] = 0.68; 95% confidence interval [95% CI], 0.50-0.92; Z=2.47; p=0.01), with no significant heterogeneity between individual studies (p=0.14, I2=32.4%). However, iodixanol was not associated with a reduction in CI-AKI compared with the LOCM pooled together (RR=0.75; 95% CI, 0.44-1.26; Z=1.10; p=0.27) with intravenous application, again with no significant heterogeneity between individual studies (p=0.40, I2=3.6%). CONCLUSIONS: Our meta-analysis suggests that administration route may affect the renal safety of contrast agents. Specifically, iodixanol may be a better choice for patients in the interventional cardiology setting. PMID- 22252848 TI - Psychiatric issues in cosmetic plastic surgery. AB - The objective of cosmetic surgery is increased patient self-esteem and confidence. Most patients undergoing a procedure report these results post operatively. The success of any procedure is measured in patient satisfaction. In order to optimize patient satisfaction, literature suggests careful pre-operative patient preparation including a discussion of the risks, benefits, limitations and expected results for each procedure undertaken. As a general rule, the patients that are motivated to surgery by a desire to align their outward appearance to their body-image tend to be the most satisfied. There are some psychiatric conditions that can prevent a patient from being satisfied without regard aesthetic success. The most common examples are minimal defect/Body Dysmorphic Disorder, the patient in crisis, the multiple revision patient, and loss of identity. This paper will familiarize the audience with these conditions, symptoms and related illnesses. Case examples are described and then explored in terms of the conditions presented. A discussion of the patient's motivation for surgery, goals pertaining to specific attributes, as well as an evaluation of the patient's understanding of the risks, benefits, and limitations of the procedure can help the physician determine if a patient is capable of being satisfied with a cosmetic plastic surgery procedure. Plastic surgeons can screen patients suffering from these conditions relatively easily, as psychiatry is an integral part of medical school education. If a psychiatric referral is required, then the psychiatrist needs to be aware of the nuances of each of these conditions. PMID- 22252849 TI - Position of the hyoid and larynx in people with muscle tension dysphonia. AB - OBJECTIVES/HYPOTHESIS: To determine whether radiographic measures of hyoid position, laryngeal position, and hyolaryngeal space during phonation were different for people with primary muscle tension dysphonia (MTD) as compared to control participants without voice disorders. STUDY DESIGN: Prospective, quasi experimental research design. METHODS: Twenty participants, 10 with primary MTD and 10 without voice disorders who were age and sex matched were studied radiographically while producing phonation. Lateral x-ray images were obtained for each participant during three tasks: resting state, sustained phonation, and a swallow-hold maneuver. Vertical positions of the hyoid and larynx were measured on a Cartesian coordinate system and were normalized to reflect change from rest during phonation. RESULTS: Normalized, vertical hyoid, and laryngeal positions during phonation were significantly higher for people with MTD than for control participants. Normalized hyolaryngeal space during phonation did not show differences between groups. A low to moderate significant correlation for radiographically measured hyoid and laryngeal position and the total score from a subjective laryngeal palpatory scale were evidenced, but no relationship was evidenced for radiographic laryngeal position and the laryngeal position subscore of the palpatory examination. CONCLUSIONS: Objective determinants of physiology are critical for the differential diagnosis of MTD and its effective treatment. Radiographic findings from this study indicate that hyoid and laryngeal positions during phonation are higher in people with primary MTD as compared to people without voice disorders. PMID- 22252850 TI - DREAM--a novel approach for robust, ultrafast, multislice B1 mapping. AB - A novel multislice B1-mapping method dubbed dual refocusing echo acquisition mode is proposed, able to cover the whole transmit coil volume in only one second, which is more than an order of magnitude faster than established approaches. The dual refocusing echo acquisition mode technique employs a stimulated echo acquisition mode (STEAM) preparation sequence followed by a tailored single-shot gradient echo sequence, measuring simultaneously the stimulated echo and the free induction decay as gradient-recalled echoes, and determining the actual flip angle of the STEAM preparation radiofrequency pulses from the ratio of the two measured signals. Due to an elaborated timing scheme, the method is insensitive against susceptibility/chemical shift effects and can deliver a B0 phase map and a transceive phase map for free. The approach has only a weak T1 and T2 dependence and moreover, causes only a low specific absorption rate (SAR) burden. The accuracy of the method with respect to systematic and statistical errors is investigated both, theoretically and in experiments on phantoms. In addition, the performance of the approach is demonstrated in vivo in B1-mapping and radiofrequency shimming experiments on the abdomen, the legs, and the head on an eight-channel parallel transmit 3 T MRI system. PMID- 22252851 TI - Single-stage anterior debridement and fusion with autografting and internal fixation for pyogenic lumbar spondylodiscitis. AB - INTRODUCTION: Patients with pyogenic lumbar spondylodiscitis can be successfully treated by non-operative methods. However, the typical operation for this condition includes debridement of the infected site, bone grafting and internal fixation to stabilize the spine. Single-stage anterior debridement and fusion with autografting and internal fixation of one spinal segment were performed on nine patients with pyogenic lumbar spondylodiscitis. This operative procedure is rarely documented for pyogenic lumbar spondylodiscitis. AIM: To evaluate the safety and effectiveness of single-stage anterior debridement, autografting and internal fixation of one spinal segment for pyogenic lumbar spondylodiscitis. RESULTS: At the final follow-up, seven out of the nine patients were pain free. Two patients had mild, intermittent back pain (Visual Analogue Scale rating of 1 2), which represented an improvement from their preoperative pain. All nine patients had no clinical, laboratory or radiological evidence of recurrence of infection. Moreover, all the patients showed solid bony fusion. CONCLUSION: Based on the limited population studied, it suggested that this technique may be a safe and effective operative procedure for appropriate pyogenic lumbar spondylodiscitis in patients. PMID- 22252852 TI - All-pedicle-screw versus hybrid hook-screw instrumentation for posterior spinal correction surgery in adolescent idiopathic scoliosis: a curve flexibility matched-pair study. AB - INTRODUCTION: Comparisons of all-pedicle-screw (PS) and hybrid hook-screw (HS) instrumentation for the treatment of adolescent idiopathic scoliosis (AIS) have produced conflicting results. The aim of this study was to compare all-pedicle screw and hybrid hook-screw instrumentation for the treatment of AIS using a matched-pair study design in which preoperative flexibility was matched. METHODS: In this retrospective study conducted at one medical center, 21 all-pedicle screw/hybrid hook-screw pairs of Lenke type I AIS patients matched for age, height, weight, body mass index, sex, and preoperative curve flexibility who had been treated at our institution from January 2000 to October 2006 were selected. Postoperative and 2-year postoperative coronal curve correction, postoperative kyphosis, blood transfusion needs, operation time, and hospital cost were measured and analyzed statistically. RESULTS: The PS group compared with the HS group had better postoperative correction (P = 0.0231) and 2-year coronal curve correction (P = 0.016). While statistically significant (P = 0.0073), the postoperative Cobb angle was only 3 degrees less in the PS group, Maintenance of correction after 2 years was better in the PS group (P = 0.0016). The PS group had less blood loss (P < 0.0001) and shorter operation time (P < 0.0001), but the hospital cost for the PS group was higher (P < 0.0001). CONCLUSIONS: All-pedicle screw and hybrid hook-screw instrumentations are comparable with regard to curve correction, but all-pedicle screw instrumentation reduces blood loss during surgery and shortens the operation time, which may help shorten healing time. PMID- 22252855 TI - Genetic characterization of vocal fold lesions: leukoplakia and carcinoma. AB - OBJECTIVES/HYPOTHESIS: Malignant transformation of laryngeal keratosis has been reported in a substantial subset of patients, yet reliable criteria for predicting patients most at risk have yet to be determined. Current methods for determining dysplasia ratings are susceptible to errors in biopsy sampling and interpretation. An understanding of the genetic underpinnings of the progression of vocal fold tumorigenesis may contribute to the creation of reliable and predictive diagnostic criteria. We hypothesized that genetic expression markers distinguish patients with keratotic noncancerous vocal fold lesions from invasive carcinoma. STUDY DESIGN: Observational cross-sectional study. METHODS: Real-time polymerase chain reaction (RT-PCR) was used to compare expression of 84 cancer pathway genes of patients following histologic diagnosis of nondysplastic keratotic epithelium (ND) (n = 7), dysplastic keratotic epithelium (DYS) (n = 3), and invasive carcinoma (CA) (n = 7). All patients had a clinical diagnosis of leukoplakia, and biopsies were obtained from true vocal fold tissue. RESULTS: Four genes (IGF-1, EPDR1, MMP-2, S100A4) were significantly upregulated in DYS over the ND group. Seven genes were significantly upregulated in CA over the DYS group, and 31 genes were significantly upregulated in CA over the ND group (P < .02). The expression of matrix metalloproteinases (MMP-1, MMP-2, MMP-9) was found to statistically differentiate the groups (P < .02) and suggested disease progression associated with extracellular matrix degradation and angiogenesis promotion. CONCLUSIONS: With these preliminary array data, we demonstrate the feasibility of using RT-PCR to identify distinct genetic expression between diagnostic groups. Characterization of genetic changes marking the progression of vocal fold tumorigenesis may lead to robust diagnostic criteria in the future. PMID- 22252853 TI - Plasma phospholipid fatty acid and ex vivo neutrophil responses are differentially altered in dogs fed fish- and linseed-oil containing diets at the same n-6:n-3 fatty acid ratio. AB - The effect of diets containing either 18-carbon n-3 fatty acids (FA) or 20/22 carbon n-3 FA on canine plasma and neutrophil membrane fatty acid composition, superoxide and leukotriene B4 and B5 production when fed at the same n-6:n-3 fatty acid ratio was investigated. Four groups of ten dogs each were fed a low fat basal diet supplemented with safflower oil (SFO), beef tallow (BTO), linseed oil (LSO), or Menhaden fish oil (MHO) for 28 days. Dietary fat provided 40.8% of energy and the n-6:n-3 of the diets were ~100:1, 9.7:1, 0.38:1, and 0.34:1 for the SFO, BTO, LSO and MHO groups, respectively. The MHO and LSO groups had increased incorporation of EPA and DPA in both the plasma and neutrophil membranes compared to the BTO and SFO groups. DHA was observed in the MHO but not in the LSO group. Neutrophils from the MHO diet fed dogs had less LTB4 and greater LTB5 than the other three groups. The LSO group also showed a reduction in LTB4 and greater LTB5 production compared to the SFO and BTO groups. Both LSO and MHO groups had lower superoxide production compared to the SFO and BTO groups. Diets containing 18 or 20/22 carbon n-3 FA fed at the same n-6:n-3 resulted in differential incorporation of long chain n-3 FA into neutrophil membranes. Thus, fatty acid type and chain length individually affect neutrophil membrane structure and function and these effects exist independent of dietary total n-6:total n-3 FA ratios. PMID- 22252856 TI - Small adsorbate-assisted shape control of Pd and Pt nanocrystals. AB - The shape control of noble metal nanocrystals is crucial to their optical properties and catalysis applications. In this Progress Report, the recent progress of shape-controlled synthesis of Pd and Pt nanostructures assisted by small adsorbates is summarized. The use of small strong adsorbates (e.g., I(-) , CO, amines) makes it possible to fabricate Pd and Pt nanostructures with not only well-defined surface structure but also morphologies that have not been achieved by other synthetic strategies. The roles of small adsorbates in shape control of Pd and Pt nanocrystals are discussed in the Report. Also presented in the Report are unique optical and catalytic properties of several Pd and Pt nanostructures (e.g., ultrathin Pd nanosheets, concave Pt octapod, concave Pd tetrahedra), as well as their bioapplications, to demonstrate the power of using small strong adsorbates in the shape control of Pt and Pd nanostructures. PMID- 22252857 TI - Asthma deaths: we need to identify risk factors early and construct at-risk asthma registers. PMID- 22252858 TI - Monitoring buried jejunum free flaps with a sentinel: a retrospective study of 20 cases. AB - OBJECTIVES/HYPOTHESIS: The free jejunum transfer has become a widely used reconstruction option after total laryngopharyngectomy. The aim of this study was to evaluate the effectiveness of using an exteriorized jejunal segment for flap monitoring. STUDY DESIGN: Case series. METHODS: Twenty patients with tumors involving the pharynx, larynx, or cervical esophagus were subjected to total laryngopharyngectomy and neck dissection. The resulting esophageal defect was reconstructed with a free jejunal flap based on a major branch of the superior mesenteric artery and vein. After completion of anastomoses with the recipient vessels, the flap was divided into two segments of common vascular supply. The smaller segment was exteriorized in the cervical region for direct monitoring of serosal color, temperature, peristalsis, and bleeding during the postoperative period. This sentinel was resected once the viability of the flap was judged appropriate. RESULTS: Of the 20 patients who had free jejunum transfers for pharyngoesophageal reconstruction, 14 had an uneventful postoperative course, and six needed re-exploration due to signs of arterial insufficiency in the sentinel segment. On re-exploration, four flaps were found to have arterial thrombosis and two had no abnormality at the anastomotic site. One of the flaps that developed thrombosis was subsequently lost. CONCLUSIONS: Monitoring of buried free jejunal flap with a sentinel is an effective method of assessing flap viability after total laryngopharyngectomy and guides re-exploration in cases of anastomotic complications. PMID- 22252859 TI - Protective effects of quercetine on the neuronal injury in frontal cortex after chronic toluene exposure. AB - The aim of this study was designed to evaluate the possible protective effects of quercetine (QE) on the neuronal injury in the frontal cortex after chronic toluene exposure in rats. The rats were randomly allotted into one of the three experimental groups, namely, groups A (control), B (toluene treated) and C (toluene-treated with QE), where each group contains 10 animals. Control group received 1 ml of normal saline solution, and toluene treatment was performed by the inhalation of 3000 ppm toluene in an 8-h/day and 6-day/week order for 12 weeks. The rats in QE-treated group was given QE (15 mg/kg body weight) once a day intraperitoneally for 12 weeks, starting just after toluene exposure. Tissue samples were obtained for histopathological investigation. To date, no histopathological changes of neurodegeneration in the frontal cortex after chronic toluene exposure in rats by QE treatment have been reported. In this study, the morphology of neurons in the QE treatment group was well protected. Chronic toluene exposure caused severe degenerative changes, shrunken cytoplasm and extensively dark picnotic nuclei in neurons of the frontal cortex. We conclude that QE therapy causes morphologic improvement in neurodegeneration of frontal cortex after chronic toluene exposure in rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment on neurodegeneration after chronic toluene exposure in rats. PMID- 22252860 TI - Protective effect of curcumin on acute lung injury induced by intestinal ischaemia/reperfusion. AB - The aim of this study is to evaluate the role of curcumin on acute lung injury induced by intestinal ischaemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into 3 groups: sham, I/R, and I/R + curcumin; each group contains 10 animals. Sham group animals underwent laparotomy without I/R injury. After I/R groups animals underwent laparotomy, 1 h of superior mesenteric artery ligation were followed by 1 h of reperfusion. In the curcumin group, 3 days before I/R, curcumin (100 mg/kg) was administered by gastric gavage. All animals were killed at the end of reperfusion and lung tissue samples were obtained for biochemical and histopathological investigation in all groups. To date, no more biochemical and histopathological changes on intestinal I/R injury in rats by curcumin treatment have been reported. Curcumin treatment significantly decreased the elevated tissue malondialdehyde levels and increased reduced superoxide dismutase, and glutathione peroxidase enzyme activities in lung tissue samples. Intestinal I/R caused severe histopathological injury including oedema, haemorrhage, increased thickness of the alveolar wall, and infiltration of inflammatory cells into alveolar spaces. Curcumin treatment significantly attenuated the severity of intestinal I/R injury. Furthermore, there is a significant reduction in the activity of inducible nitric oxide synthase and increase in the expression of surfactant protein D in lung tissue of acute lung injury induced by intestinal I/R with curcumin therapy. It was concluded that curcumin treatment may have beneficial effects in acute lung injury, and therefore has potential for clinical use. PMID- 22252861 TI - Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults. AB - OBJECTIVES/HYPOTHESIS: Over half of chronic rhinosinusitis with nasal polyps (CRSwNP) patients in China show noneosinophilic inflammation. The aim of this study was to compare the clinical characteristics of eosinophilic and noneosinophilic CRSwNP and to identify the predictors of eosinophilic CRSwNP. STUDY DESIGN: A retrospective study. METHODS: There were 155 CRSwNP patients enrolled in the Tongji cohort. Eosinophilic CRSwNP was diagnosed according to our previously published histologic criterion. The demographic and clinical features were compared between eosinophilic and noneosinophilic CRSwNP. Factors associated with eosinophilic CRSwNP were determined with regression analysis, and optimal cutoff points of the predictors were determined by a receiver operating characteristic curve. The optimal cutoff points of the predictors were validated in an independent group of 35 CRSwNP patients referred to as the Taizhou cohort. RESULTS: A male preponderance, a higher prevalence of smoking and atopy, and higher peripheral blood eosinophil absolute count and percentage and blood IgE levels were found in eosinophilic CRSwNP compared with noneosinophilic CRSwNP. Peripheral eosinophil absolute count and percentage were independently and significantly associated with eosinophilic CRSwNP. An absolute blood eosinophil count >= 0.215 * 10(9) /L yielded a sensitivity of 74.2% and a specificity of 86.5%, and a blood eosinophil percentage >= 3.05% yielded a sensitivity of 80.3% and a specificity of 75.3% for the diagnosis of eosinophilic CRSwNP in the Tongji cohort. The validation study in the Taizhou cohort revealed a lower sensitivity and specificity. CONCLUSIONS: Eosinophilic and noneosinophilic CRSwNP displayed significant differences in certain clinical features. Peripheral blood eosinophil count could distinguish eosinophilic and noneosinophilic CRSwNP in Chinese adults. PMID- 22252862 TI - When FESS fails: the inflammatory load hypothesis in refractory chronic rhinosinusitis. AB - Through recent advances in research, our understanding of chronic rhinosinusitis (CRS) has evolved to consider it as an inflammatory condition of the mucosa brought about by multiple factors. However, surgical management is still ruled by the classical concepts of functional endoscopic sinus surgery (FESS), which emphasizes the importance of ostial obstruction and sinus ventilation. These concepts fail to provide sufficient explanation for the presence of a subset of patients with refractory CRS who fail to respond to conventional FESS. Recent outcome studies have shown that high-grade mucosal inflammation often results in a poor outcome and that this patient group may show improved results with more radical surgery. This review examines the "inflammatory load hypothesis" as a possible explanation. We hypothesize that the grade of the inflammation is the most important predictor of long-term outcomes. Surgery, therefore, has a significant role not only in reestablishing ventilation, but also with removing the inflammatory load in the affected sinuses. We suspect that in these severely diseased patients, a more radical removal of local proinflammatory factors during surgery may improve patient outcomes. PMID- 22252863 TI - Intestinally secreted C-type lectin Reg3b attenuates salmonellosis but not listeriosis in mice. AB - The Reg3 protein family, including the human member designated pancreatitis associated protein (PAP), consists of secreted proteins that contain a C-type lectin domain involved in carbohydrate binding. They are expressed by intestinal epithelial cells. Colonization of germ-free mice and intestinal infection with pathogens increase the expression of Reg3g and Reg3b in the murine ileum. Reg3g is directly bactericidal for gram-positive bacteria, but the exact role of Reg3b in bacterial infections is unknown. To investigate the possible protective role of Reg3b in intestinal infection, Reg3b knockout (Reg3b(-/-)) mice and wild-type (WT) mice were orally infected with gram-negative Salmonella enteritidis or gram positive Listeria monocytogenes. At day 2 after oral Listeria infection and at day 4 after oral Salmonella infection, mice were sacrificed to collect intestinal and other tissues for pathogen quantification. Protein expression of Reg3b and Reg3g was determined in intestinal mucosal scrapings of infected and noninfected mice. In addition, ex vivo binding of ileal mucosal Reg3b to Listeria and Salmonella was investigated. Whereas recovery of Salmonella or Listeria from feces of Reg3b(-/-) mice did not differ from that from feces of WT mice, significantly higher numbers of viable Salmonella, but not Listeria, bacteria were recovered from the colon, mesenteric lymph nodes, spleen, and liver of the Reg3b(-/-) mice than from those of WT mice. Mucosal Reg3b binds to both bacterial pathogens and may interfere with their mode of action. Reg3b plays a protective role against intestinal translocation of the gram-negative bacterium S. enteritidis in mice but not against the gram-positive bacterium L. monocytogenes. PMID- 22252864 TI - Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region. AB - Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic to regions of Southeast Asia and Northern Australia. Both humans and a range of other animal species are susceptible to melioidosis, and the production of a group 3 polysaccharide capsule in B. pseudomallei is essential for virulence. B. pseudomallei capsular polysaccharide (CPS) I comprises unbranched manno-heptopyranose residues and is encoded by a 34.5-kb locus on chromosome 1. Despite the importance of this locus, the role of all of the genes within this region is unclear. We inactivated 18 of these genes and analyzed their phenotype using Western blotting and immunofluorescence staining. Furthermore, by combining this approach with bioinformatic analysis, we were able to develop a model for CPS I biosynthesis and export. We report that inactivating gmhA, wcbJ, and wcbN in B. pseudomallei K96243 retains the immunogenic integrity of the polysaccharide despite causing attenuation in the BALB/c murine infection model. Mice immunized with the B. pseudomallei K96243 mutants lacking a functional copy of either gmhA or wcbJ were afforded significant levels of protection against a wild-type B. pseudomallei K96243 challenge. PMID- 22252865 TI - Vaccination of BALB/c mice with an avirulent Mycoplasma pneumoniae P30 mutant results in disease exacerbation upon challenge with a virulent strain. AB - Mycoplasma pneumoniae is a significant human respiratory pathogen that causes high morbidity worldwide. No vaccine to prevent M. pneumoniae infection currently exists, since the mechanisms of pathogenesis are poorly understood. To this end, we constructed a P30 cytadhesin mutant (P-130) with a drastically reduced capacity for binding to erythrocytes and an inability to glide on glass substrates. This mutant was determined to be avirulent and cannot survive in the lungs of BALB/c mice. We also ascertained that the previously identified P30 gliding motility mutant II-3R is avirulent and also cannot be recovered from the lungs of mice after infection. Mutant P130 was then assessed for its efficacy as a live attenuated vaccine candidate in mice after challenge with wild-type M. pneumoniae. After vaccination with the P-130 P30 mutant, mice showed evidence of exacerbated disease upon subsequent challenge with the wild-type strain PI1428, which appears to be driven by a Th17 response and corresponding eosinophilia. Our results are in accordance with other reports of vaccine-induced disease exacerbation in rodents and emphasize the need to better understand the basic mechanisms of M. pneumoniae pathogenesis. PMID- 22252866 TI - Evaluation of Salmonella enterica type III secretion system effector proteins as carriers for heterologous vaccine antigens. AB - Live attenuated strains of Salmonella enterica have a high potential as carriers of recombinant vaccines. The type III secretion system (T3SS)-dependent translocation of S. enterica can be deployed for delivery of heterologous antigens to antigen-presenting cells. Here we investigated the efficacy of various effector proteins of the Salmonella pathogenicity island (SPI2)-encoded T3SS for the translocation of model antigens and elicitation of immune responses. The SPI2 T3SS effector proteins SifA, SteC, SseL, SseJ, and SseF share an endosomal membrane-associated subcellular localization after translocation. We observed that all effector proteins could be used to translocate fusion proteins with the model antigens ovalbumin and listeriolysin into the cytosol of host cells. Under in vitro conditions, fusion proteins with SseJ and SteC stimulated T cell responses that were superior to those triggered by fusion proteins with SseF. However, in mice vaccinated with Salmonella carrier strains, only fusion proteins based on SseJ or SifA elicited potent T-cell responses. These data demonstrate that the selection of an optimal SPI2 effector protein for T3SS mediated translocation is a critical parameter for the rational design of effective Salmonella-based recombinant vaccines. PMID- 22252867 TI - Interplay between Candida albicans and the mammalian innate host defense. AB - Candida albicans is both the most common fungal commensal microorganism in healthy individuals and the major fungal pathogen causing high mortality in at risk populations, especially immunocompromised patients. In this review, we summarize the interplay between the host innate system and C. albicans, ranging from how the host recognizes, responds, and clears C. albicans infection to how C. albicans evades, dampens, and escapes from host innate immunity. PMID- 22252868 TI - Hypoxia-mediated impairment of the mitochondrial respiratory chain inhibits the bactericidal activity of macrophages. AB - In infected tissues oxygen tensions are low. As innate immune cells have to operate under these conditions, we analyzed the ability of macrophages (Mphi) to kill Escherichia coli or Staphylococcus aureus in a hypoxic microenvironment. Oxygen restriction did not promote intracellular bacterial growth but did impair the bactericidal activity of the host cells against both pathogens. This correlated with a decreased production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates. Experiments with phagocyte NADPH oxidase (PHOX) and inducible NO synthase (NOS2) double-deficient Mphi revealed that in E. coli- or S. aureus-infected cells the reduced antibacterial activity during hypoxia was either entirely or partially independent of the diminished PHOX and NOS2 activity. Hypoxia impaired the mitochondrial activity of infected Mphi. Inhibition of the mitochondrial respiratory chain activity during normoxia (using rotenone or antimycin A) completely or partially mimicked the defective antibacterial activity observed in hypoxic E. coli- or S. aureus-infected wild type Mphi, respectively. Accordingly, inhibition of the respiratory chain of S. aureus-infected, normoxic PHOX(-/-) NOS2(-/-) Mphi further raised the bacterial burden of the cells, which reached the level measured in hypoxic PHOX(-/-) NOS2( /-) Mphi cultures. Our data demonstrate that the reduced killing of S. aureus or E. coli during hypoxia is not simply due to a lack of PHOX and NOS2 activity but partially or completely results from an impaired mitochondrial antibacterial effector function. Since pharmacological inhibition of the respiratory chain raised the generation of ROI but nevertheless phenocopied the effect of hypoxia, ROI can be excluded as the mechanism underlying the antimicrobial activity of mitochondria. PMID- 22252869 TI - Identification of the cellular receptor of Clostridium spiroforme toxin. AB - Clostridium spiroforme produces the binary actin-ADP-ribosylating toxin CST (C. spiroforme toxin), which has been proposed to be responsible for diarrhea, enterocolitis, and eventually death, especially in rabbits. Here we report on the recombinant production of the enzyme component (CSTa) and the binding component (CSTb) of C. spiroforme toxin in Bacillus megaterium. By using the recombinant toxin components, we show that CST enters target cells via the lipolysis stimulated lipoprotein receptor (LSR), which has been recently identified as the host cell receptor of the binary toxins Clostridium difficile transferase (CDT) and Clostridium perfringens iota toxin. Microscopic studies revealed that CST, but not the related Clostridium botulinum C2 toxin, colocalized with LSR during toxin uptake and traffic to endosomal compartments. Our findings indicate that CST shares LSR with C. difficile CDT and C. perfringens iota toxin as a host cell surface receptor. PMID- 22252870 TI - Polymorphisms in the lcrV gene of Yersinia enterocolitica and their effect on plague protective immunity. AB - Current efforts to develop plague vaccines focus on LcrV, a polypeptide that resides at the tip of type III secretion needles. LcrV-specific antibodies block Yersinia pestis type III injection of Yop effectors into host immune cells, thereby enabling phagocytes to kill the invading pathogen. Earlier work reported that antibodies against Y. pestis LcrV cannot block type III injection by Yersinia enterocolitica strains and suggested that lcrV polymorphisms may provide for escape from LcrV-mediated plague immunity. We show here that polyclonal or monoclonal antibodies raised against Y. pestis KIM D27 LcrV (LcrV(D27)) bind LcrV from Y. enterocolitica O:9 strain W22703 (LcrV(W22703)) or O:8 strain WA-314 (LcrV(WA-314)) but are otherwise unable to block type III injection by Y. enterocolitica strains. Replacing the lcrV gene on the pCD1 virulence plasmid of Y. pestis KIM D27 with either lcrV(W22703) or lcrV(WA-314) does not affect the ability of plague bacteria to secrete proteins via the type III pathway, to inject Yops into macrophages, or to cause lethal plague infections in mice. LcrV(D27)-specific antibodies blocked type III injection by Y. pestis expressing lcrV(W22703) or lcrV(WA-314) and protected mice against intravenous lethal plague challenge with these strains. Thus, although antibodies raised against LcrV(D27) are unable to block the type III injection of Y. enterocolitica strains, expression of lcrV(W22703) or lcrV(WA-314) in Y. pestis did not allow these strains to escape LcrV-mediated plague protective immunity in the intravenous challenge model. PMID- 22252871 TI - Molecular characterizations of cytolethal distending toxin produced by Providencia alcalifaciens strains isolated from patients with diarrhea. AB - Cytolethal distending toxins (CDTs), which block eukaryotic cell proliferation by acting as inhibitory cyclomodulins, are produced by diverse groups of Gram negative bacteria. Active CDT is composed of three polypeptides--CdtA, CdtB, and CdtC--encoded by the genes cdtA, cdtB, and cdtC, respectively. We developed a PCR restriction fragment length polymorphism assay for the detection and differentiation of five alleles of cdtB (Cdt-I through Cdt-V) in Escherichia coli and used the assay to investigate the prevalence and characteristic of CDT producing E. coli in children with diarrhea (A. Hinenoya et al., Microbiol. Immunol. 53:206-215, 2009). In these assays, two untypable cdtB genes were detected and the organisms harboring the cdtB gene were identified as Providencia alcalifaciens (strains AH-31 and AS-1). Nucleotide sequence analysis of the cdt gene cluster revealed that the cdtA, cdtB, and cdtC genes of P. alcalifaciens are of 750, 810, and 549 bp, respectively. To understand the possible horizontal transfer of the cdt genes among closely related species, the presence of cdt genes was screened in various Providencia spp. by colony hybridization assay, and the cdt gene cluster was found in only limited strains of P. alcalifaciens. Genome walking revealed that the cdt gene cluster of P. alcalifaciens is located adjacent to a putative transposase gene, suggesting the locus might be horizontally transferable. Interestingly, the CDT of P. alcalifaciens (PaCDT) showed some homology with the CDT of Shigella boydii. Whereas filter-sterilized lysates of strains AH-31 and AS-1 showed distention of CHO but not of HeLa cells, E. coli CDT-I exhibited distention of both cells. This activity of PaCDT was confirmed by generating recombinant PaCDT protein, which could also be neutralized by rabbit anti-PaCdtB antibody. Furthermore, recombinant PaCDT was found to induce G(2)/M cell cycle arrest and phosphorylation of host histone H2AX, a sensitive marker of DNA double-strand breaks. To our knowledge, this is the first report showing that certain clinical P. alcalifaciens strains could produce variants of the CDTs compared. PMID- 22252872 TI - Analysis of cell cycle and replication of mouse macrophages after in vivo and in vitro Cryptococcus neoformans infection using laser scanning cytometry. AB - We investigated the outcome of the interaction of Cryptococcus neoformans with murine macrophages using laser scanning cytometry (LSC). Previous results in our lab had shown that phagocytosis of C. neoformans promoted cell cycle progression. LSC allowed us to simultaneously measure the phagocytic index, macrophage DNA content, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation such that it was possible to study host cell division as a function of phagocytosis. LSC proved to be a robust, reliable, and high-throughput method for quantifying phagocytosis. Phagocytosis of C. neoformans promoted cell cycle progression, but infected macrophages were significantly less likely to complete mitosis. Hence, we report a new cytotoxic effect associated with intracellular C. neoformans residence that manifested itself in impaired cell cycle completion as a consequence of a block in the G(2)/M stage of the mitotic cell cycle. Cell cycle arrest was not due to increased cell membrane permeability or DNA damage. We investigated alveolar macrophage replication in vivo and demonstrated that these cells are capable of low levels of cell division in the presence or absence of C. neoformans infection. In summary, we simultaneously studied phagocytosis, the cell cycle state of the host cell and pathogen-mediated cytotoxicity, and our results demonstrate a new cytotoxic effect of C. neoformans infection on murine macrophages: fungus-induced cell cycle arrest. Finally, we provide evidence for alveolar macrophage proliferation in vivo. PMID- 22252873 TI - Interleukin-17 drives pulmonary eosinophilia following repeated exposure to Aspergillus fumigatus conidia. AB - Previous research in our laboratory has demonstrated that repeated intranasal exposure to Aspergillus fumigatus conidia in C57BL/6 mice results in a chronic pulmonary inflammatory response that reaches its maximal level after four challenges. The inflammatory response is characterized by eosinophilia, goblet cell metaplasia, and T helper T(H)2 cytokine production, which is accompanied by sustained interleukin-17 (IL-17) expression that persists even after the T(H)2 response has begun to resolve. T(H)17 cells could develop in mice deficient in gamma interferon (IFN-gamma), IL-4, or IL-10. In the lungs of IL-17 knockout mice repeatedly challenged with A. fumigatus conidia, inflammation was attenuated (with the most significant decrease occurring in eosinophils), conidial clearance was enhanced, and the early transient peak of CD4(+) CD25(+) FoxP3(+) cells blunted. IL-17 appeared to play only a minor role in eosinophil differentiation in the bone marrow but a central role in eosinophil extravasation from the blood into the lungs. These observations point to an expanded role for IL-17 in driving T(H)2-type inflammation to repeated inhalation of fungal conidia. PMID- 22252874 TI - Plasmodium yoelii macrophage migration inhibitory factor is necessary for efficient liver-stage development. AB - Mammalian macrophage migration inhibitory factor (MIF) is a multifaceted cytokine involved in both extracellular and intracellular functions. Malaria parasites express a MIF homologue that might modulate host immune responses against blood stage parasites, but the potential importance of MIF against other life cycle stages remains unstudied. In this study, we characterized the MIF homologue of Plasmodium yoelii throughout the life cycle, with emphasis on preerythrocytic stages. P. yoelii MIF (Py-MIF) was expressed in blood-stage parasites and detected at low levels in mosquito salivary gland sporozoites. MIF expression was strong throughout liver-stage development and localized to the cytoplasm of the parasite, with no evidence of release into the host hepatocyte. To examine the importance of Py-MIF for liver-stage development, we generated a Py-mif knockout parasite (P. yoelii Deltamif). P. yoelii Deltamif parasites grew normally as asexual erythrocytic-stage parasites and showed normal infection of mosquitoes. In contrast, the P. yoelii Deltamif strain was attenuated during the liver stage. Mice infected with P. yoelii Deltamif sporozoites either did not develop blood stage parasitemia or exhibited a delay in the onset of blood-stage patency. Furthermore, P. yoelii Deltamif parasites exhibited growth retardation in vivo. Combined, the data indicate that Plasmodium MIF is important for liver-stage development of P. yoelii, during which it is likely to play an intrinsic role in parasite development rather than modulating host immune responses to infection. PMID- 22252875 TI - Infection with Anaplasma phagocytophilum activates the phosphatidylinositol 3 Kinase/Akt and NF-kappaB survival pathways in neutrophil granulocytes. AB - Anaplasma phagocytophilum, a Gram-negative, obligate intracellular bacterium infects primarily neutrophil granulocytes. Infection with A. phagocytophilum leads to inhibition of neutrophil apoptosis and consequently contributes to the longevity of the host cells. Previous studies demonstrated that the infection inhibits the executionary apoptotic machinery in neutrophils. However, little attempt has been made to explore which survival signals are modulated by the pathogen. The aim of the present study was to clarify whether the phosphatidylinositol 3-kinase (PI3K)/Akt and NF-kappaB signaling pathways, which are considered as important survival pathways in neutrophils, are involved in A. phagocytophilum-induced apoptosis delay. Our data show that infection of neutrophils with A. phagocytophilum activates the PI3K/Akt pathway and suggest that this pathway, which in turn maintains the expression of the antiapoptotic protein Mcl-1, contributes to the infection-induced apoptosis delay. In addition, the PI3K/Akt pathway is involved in the activation of NF-kappaB in A. phagocytophilum-infected neutrophils. Activation of NF-kappaB leads to the release of interleukin-8 (IL-8) from infected neutrophils, which, in an autocrine manner, delays neutrophil apoptosis. In addition, enhanced expression of the antiapoptotic protein cIAP2 was observed in A. phagocytophilum-infected neutrophils. Taken together, the data indicate that upstream of the apoptotic cascade, signaling via the PI3K/Akt pathway plays a major role for apoptosis delay in A. phagocytophilum-infected neutrophils. PMID- 22252876 TI - Plasmodium falciparum malaria in the Peruvian Amazon, a region of low transmission, is associated with immunologic memory. AB - The development of clinical immunity to Plasmodium falciparum malaria is thought to require years of parasite exposure, a delay often attributed to difficulties in developing protective antibody levels. In this study, we evaluated several P. falciparum vaccine candidate antigens, including apical membrane antigen 1 (AMA 1), circumsporozoite protein (CSP), erythrocyte binding antigen 175 (EBA-175), and the 19-kDa region of merozoite surface protein 1 (MSP1(19)). After observing a more robust antibody response to MSP1(19), we evaluated the magnitude and longevity of IgG responses specific to this antigen in Peruvian adults and children before, during, and after P. falciparum infection. In this low transmission region, even one reported prior infection was sufficient to produce a positive anti-MSP1(19) IgG response for >5 months in the absence of reinfection. We also observed an expansion of the total plasmablast (CD19(+) CD27(+) CD38(high)) population in the majority of individuals shortly after infection and detected MSP1-specific memory B cells in a subset of individuals at various postinfection time points. This evidence supports our hypothesis that effective antimalaria humoral immunity can develop in low-transmission regions. PMID- 22252877 TI - A hybrid multistage protein vaccine induces protective immunity against murine malaria. AB - We have previously reported the design and expression of chimeric recombinant proteins as an effective platform to deliver malaria vaccines. The erythrocytic and exoerythrocytic protein chimeras described included autologous T helper epitopes genetically linked to defined B cell epitopes. Proof-of-principle studies using vaccine constructs based on the Plasmodium yoelii circumsporozoite protein (CSP) and P. yoelii merozoite surface protein-1 (MSP-1) showed encouraging results when tested individually in this mouse malaria model. To evaluate the potential synergistic or additive effect of combining these chimeric antigens, we constructed a synthetic gene encoding a hybrid protein that combined both polypeptides in a single immunogen. The multistage vaccine was expressed in soluble form in Escherichia coli at high yield. Here we report that the multistage protein induced robust immune responses to individual components, with no evidence of vaccine interference. Passive immunization using purified IgG from rabbits immunized with the hybrid protein conferred more robust protection against the experimental challenge with P. yoelii sporozoites than passive immunization with purified IgG from rabbits immunized with the individual proteins. High antibody titers and high frequencies of CD4(+)- and CD8(+) specific cytokine-secreting T cells were elicited by vaccination. T cells were multifunctional and able to simultaneously produce interleukin-2 (IL-2), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). The mechanism of vaccine-induced protection involved neutralizing antibodies and effector CD4(+) T cells and resulted in the control of hyperparasitemia and protection against malarial anemia. These data support our strategy of using an array of autologous T helper epitopes to maximize the response to multistage malaria vaccines. PMID- 22252878 TI - Correlating levels of type III secretion and secreted proteins with fecal shedding of Escherichia coli O157:H7 in cattle. AB - The locus of enterocyte effacement (LEE) of Escherichia coli O157:H7 (O157) encodes a type III secretion system (T3SS) for secreting LEE-encoded and non-LEE encoded virulence proteins that promote the adherence of O157 to intestinal epithelial cells and the persistence of this food-borne human pathogen in bovine intestines. In this study, we compared hha sepB and hha mutants of O157 for LEE transcription, T3SS activity, adherence to HEp-2 cells, persistence in bovine intestines, and the ability to induce changes in the expression of proinflammatory cytokines. LEE transcription was upregulated in the hha sepB and hha mutant strains compared to that in the wild-type strain, but the secretion of virulence proteins in the hha sepB mutant was severely compromised. This reduced secretion resulted in reduced adherence of the hha sepB mutant to Hep-2 cells, correlating with a significantly shorter duration and lower magnitude of fecal shedding in feces of weaned (n = 4 per group) calves inoculated with this mutant strain. The levels of LEE transcription, T3SS activity, and adherence to HEp-2 cells were much lower in the wild-type strain than in the hha mutant, but no significant differences were observed in the duration or the magnitude of fecal shedding in calves inoculated with these strains. Examination of the rectoanal junction (RAJ) tissues from three groups of calves showed no adherent O157 bacteria and similar proinflammatory cytokine gene expression, irrespective of the inoculated strain, with the exception that interleukin-1beta was upregulated in calves inoculated with the hha sepB mutant. These results indicate that the T3SS is essential for intestinal colonization and prolonged shedding, but increased secretion of virulence proteins did not enhance the duration and magnitude of fecal shedding of O157 in cattle or have any significant impact on the cytokine gene expression in RAJ tissue compared with that in small intestinal tissue from the same calves. PMID- 22252879 TI - Nonhuman primate model of pertussis. AB - Pertussis is a highly contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis. Despite nearly universal vaccine coverage, pertussis rates in the United States have been rising steadily over the last 20 years. Our failure to comprehend and counteract this important public health concern is due in large part to gaps in our knowledge of the disease and the mechanisms of vaccine-mediated protection. Important questions about pertussis pathogenesis and mechanisms of vaccine effectiveness remain unanswered due to the lack of an animal model that replicates the full spectrum of human disease. Because current animal models do not meet these needs, we set out to develop a nonhuman primate model of pertussis. We inoculated rhesus macaques and olive baboons with wild-type B. pertussis strains and evaluated animals for clinical disease. We found that only 25% of rhesus macaques developed pertussis. In contrast, 100% of inoculated baboons developed clinical pertussis. A strong anamnestic response was observed when convalescent baboons were infected 6 months following recovery from a primary infection. Our results demonstrate that the baboon provides an excellent model of clinical pertussis that will allow researchers to investigate pertussis pathogenesis and disease progression, evaluate currently licensed vaccines, and develop improved vaccines and therapeutics. PMID- 22252880 TI - Post genomic decade--the epigenome and exposome challenges. AB - Sequencing the human genome was the big challenge of the last decade. Ten years later, the large amount of DNA sequences accumulated in our databases allows us to look at genome variations between humans. The level of complexity of these variations is much higher than previously expected. It goes from changes in the nucleotidic sequence, such as single nucleotide polymorphisms (SNPs) or copy number variations (CNVs), to modifications in DNA transcription or methylation. Indeed, epigenetics, with chromatin modifications and underlying crosstalk between DNA methylation, histone tails acetylation and non coding RNAs, as microRNAs, all participate to this non-encoded gene expression regulation. Understanding the extent of genomic diversity between humans and linking it to phenotypes and diseases, unravelling the environmental exposures that may be detrimental for our health is the next challenge of the geneticists. The decrypting of the epigenome and the exposome is now on its way. PMID- 22252881 TI - BESSICC, a COSMO-RS based tool for in silico solvent screening of biocatalyzed reactions. AB - Many enzymatic reactions are near-equilibrium reactions. This often limits final yield and hence application of biocatalyzed processes in the industrial production. The most widely applied strategy to overcome this issue is solvent selection. It must be underlined that measuring the equilibrium position experimentally is a difficult and time-consuming procedure and any tool for predicting the solvent effect on the reaction equilibrium can be very valuable. The present work reports on the development of BESSICC, an algorithm to calculate the effect of medium composition on biocatalyzed reactions equilibrium. It is based on COSMO-RS calculation of activity coefficients of all the species in the reaction mixture and minimization of Gibbs free energy of the reaction. Starting from one single experimental measurement of the equilibrium position for a given biocatalyzed reaction it can predict the yield of the reaction in any other solvent or solvent mixture. Predictions are accurate, the errors of prediction are in average below 25% for the esterification of dodecanoic acid with menthol and below 65% for esterification of 1-dodecanoic acid with 1-dodecanol. The best predictions show an error well below 5%. PMID- 22252882 TI - Ipsilateral breast tumor recurrence (IBTR) in patients with operable breast cancer who undergo breast-conserving treatment after receiving neoadjuvant chemotherapy: risk factors of IBTR and validation of the MD Anderson Prognostic Index. AB - BACKGROUND: There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast-conserving surgery plus radiotherapy (breast-conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors. METHODS: The authors collected data from 375 patients who underwent BCT and received NAC and analyzed the risk of IBTR associated with undergoing BCT after NAC. The usefulness of the MD Anderson Prognostic Index (MDAPI) for IBTR also was validated using the current data set. RESULTS: The median follow-up was 47.8 months, and the 4-year IBTR-free survival rate was 95.6%. Multivariate analysis demonstrated that estrogen receptor (ER) status and multifocality of the residual tumor were associated significantly with IBTR-free survival. In addition, patients who had ER-positive and human epidermal growth factor 2 (HER2) negative tumors did not develop IBTR during the observation period. Although prognostic stratification according to MDAPI was relatively good for the prediction of IBTR in the study patients, the IBTR rate in the high-risk group was not very high and was lower than that in the intermediate-risk group. Multivariate analyses demonstrated that IBTR was an independent predictive factor for overall survival. CONCLUSIONS: ER status and multifocality of the residual tumor after NAC were independent predictors of IBTR after BCT. The MDAPI was barely adaptable to the study patients in terms of predicting IBTR. Patients with ER-positive and HER2-negative tumors had a favorable prognosis, whereas patients who developed IBTR after NAC had significantly worse overall survival. The authors propose a new IBTR prognostic index using the 2 factors that were identified as predictive of IBTR: ER status and multifocality of the residual tumor. PMID- 22252883 TI - The unconditioned stimulus pre-exposure effect in preweanling rats in taste aversion learning: role of the training context and injection cues. AB - The unconditioned stimulus pre-exposure effect (US-PE) refers to the interference paradigm in which acquisition of the conditioned response is retarded due to prior experience with the US. Most studies analyzing the psychological mechanisms underlying this effect have been conducted with adult rats. The most widely accepted hypothesis explains this effect as a contextual blocking effect. Contextual cues associated with the US block the conditioned stimulus (CS)-US association during conditioning. The modulatory role of a context devoid of distinctive olfactory attributes is not observable until approximately PD23 in rats, including modulation of interference paradigms such as latent inhibition or extinction. In this study, we analyzed US-PE in preweanling rats along with the role of the training context in this effect in terms of conditioned taste aversion preparation. Pre-exposure to LiCl before conditioning retarded the acquisition of taste aversion. The US-PE was observed in preweanling rats when, during pre-exposure, subjects were exposed to the conditioning context, and this effect was not attenuated either by the administration of the US in a familiar environment (Experiment 1a), or by the presence of an alternative, more salient context during pre-exposure (Experiment 1b). Additionally, the US-PE was still observed when the route by which the US was administered was changed between the pre-exposure and conditioning phases (Experiment 2a) as well as when the injection cues were removed during conditioning (Experiment 2b). These experiments show a strong US-PE in preweanling rats and fail to support the contextual blocking hypothesis, at least in this stage of ontogeny. PMID- 22252885 TI - IgG4-related disease presenting as recurrent mastoiditis. PMID- 22252884 TI - Current treatment options for metastatic head and neck cancer. AB - Head and neck squamous cell carcinoma is now the 8th most common cancer affecting men in the United States largely due to a rising epidemic of oropharynx cancer (tonsil and tongue base) associated with the human papillomavirus (HPV). The median overall survival for recurrent or metastatic head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, cetuximab, constitute the backbone of treatment for patients with R/M HNSCC. Platinum doublets studied in phase III trials include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/pemetrexed. Platinum chemotherapy in combination with 5-fluorouracil and cetuximab has resulted in the longest median overall survival. Combination platinum regimens increase response rates and toxicity but not survival and should be reserved for patients who are symptomatic from their disease for whom the benefit of a partial response may be worth the cost of increased treatment-related side effects. For many patients who are asymptomatic with a low disease burden, single agent regimens are appropriate to balance treatment with side effects. Drugs commonly used as single agents in the treatment of R/M HNSCC include docetaxel, paclitaxel, cetuximab, capecitabine, pemetrexed, and methotrexate. Best supportive care alone is often appropriate for poor performance status patients. Palliative radiation therapy is beneficial for treating symptomatic metastatic sites. Aggressive symptom management is imperative for all patients and often should include referral to experts in palliative care and pain management. New therapies currently under investigation include mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors. Given the poor prognosis for most patients with R/M HNSCC, enrollment in clinical trials investigating novel approaches to therapy should be encouraged. PMID- 22252886 TI - Cobaltocenium-containing block copolymers: ring-opening metathesis polymerization, self-assembly and precursors for template synthesis of inorganic nanoparticles. AB - Side-chain cobaltocenium-containing block copolymers are prepared by ring-opening metathesis polymerization (ROMP). These block copolymers include one cobaltocenium-containing block, with the second block being either a nonmetal containing segment or a cobaltocenium-containing segment with different counterions. These block copolymers are self-assembled into spherical core/shell micelles in solutions. A template strategy is used to prepare cobalt (II or III) containing nanoparticles by treating the self-assembled micelles via UV/ozonolysis and pyrolysis. Characterization by X-ray photon spectroscopy and X ray diffraction indicates that these nanoparticles consist of different oxidants of cobalt, depending on the chemical compositions of block copolymers. PMID- 22252887 TI - Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. AB - There is increasing evidence that a variety of cancers arise from transformation of normal stem cells to cancer stem cells (CSCs). CSCs are thought to sustain cancer progression, invasion, metastasis, and recurrence after therapy. Reports suggest that CSCs are highly resistant to conventional therapy. Emerging evidences show that the chemoresistance of CSCs are in part due to the activation of B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), a stem cell factor, and a polycomb group family member. BMI1 is reported to regulate the proliferation activity of normal, stem, and progenitor cells. BMI1 plays a role in cell cycle, cell immortalization, and senescence. Numerous studies demonstrate that BMI1, which is upregulated in a variety of cancers, has a positive correlation with clinical grade/stage and poor prognosis. Although evidences are in support of the role of BMI1 as a factor in chemoresistance displayed by CSCs, its mechanism of action is not fully understood. In this review, we provide summary of evidences (with mechanism of action established) suggesting the significance of BMI1 in chemoresistance and recurrence of CSCs. PMID- 22252888 TI - Locus coeruleus dysfunction: a feature of essential or senile tremor? PMID- 22252889 TI - Can imaging separate multiple system atrophy from Parkinson's disease? PMID- 22252890 TI - Dreaming in dementia--REM sleep behavior disorder and synucleinopathy. PMID- 22252891 TI - Toward a redefinition of Parkinson's disease. PMID- 22252892 TI - Functional connectivity in human and monkey brain: new insights for understanding movement disorders? PMID- 22252893 TI - Progressive ataxia with palatal tremor due to gluten sensitivity. PMID- 22252894 TI - The new Bradykinesia Akinesia Incoordination (BRAIN) test: preliminary data from an online test of upper limb movement. PMID- 22252895 TI - Graphene oxide-templated synthesis of ultrathin or tadpole-shaped au nanowires with alternating hcp and fcc domains. AB - Ultrathin Au nanowires (AuNWs) and tadpole-shaped nanowires are synthesized on graphene oxide (GO) sheet templates. For the first time, 1.6 nm-diameter AuNWs are shown to contain hexagonal close-packed (hcp) crystal domains, and the tadpole-shaped nanowires exhibit alternating sets of hcp and face-centered cubic (fcc) structures, associated with variation in wire thickness. PMID- 22252897 TI - Early experience of radio frequency coblation in the management of intranasal and sinus tumors. AB - The purpose of this study was to evaluate the safety and efficacy of the use of radiofrequency coblation for endoscopic resection of intranasal and sinus tumors. A review was conducted of 15 adult patients with intranasal and or sinus tumors endoscopically treated with radio frequency coblation between November 2008 and November 2010 at St. John's Hospital at Livingston, a tertiary referral center that covers otolaryngology services for the southeast of Scotland. Fifteen patients with intranasal and sinus tumors were treated with transnasal endoscopic resection using radiofrequency coblation. The tumors included inverted papilloma (seven), paraganglioma (one), glomangiopericytoma (one), capillary hemangioma (one), hemangiopericytoma (one), juvenile angiofibroma (one), juvenile ossifying fibroma (one), oncocytic adenoma (one), and transitional cell carcinoma (one). We found that radiofrequency coblation is a useful and safe tool associated with minimal blood loss (<200 mL to 600 mL) in the resection of these tumors, and the average operating time was 1.67 hours. Radio frequency is a rapidly evolving technique and in the future will have an increasing role to play in the endoscopic resection of intranasal and sinus tumors. PMID- 22252896 TI - Chemical correction of pre-mRNA splicing defects associated with sequestration of muscleblind-like 1 protein by expanded r(CAG)-containing transcripts. AB - Recently, it was reported that expanded r(CAG) triplet repeats (r(CAG)(exp)) associated with untreatable neurological diseases cause pre-mRNA mis-splicing likely due to sequestration of muscleblind-like 1 (MBNL1) splicing factor. Bioactive small molecules that bind the 5'CAG/3'GAC motif found in r(CAG)(exp) hairpin structure were identified by using RNA binding studies and virtual screening/chemical similarity searching. Specifically, a benzylguanidine containing small molecule was found to improve pre-mRNA alternative splicing of MBNL1-sensitive exons in cells expressing the toxic r(CAG)(exp). The compound was identified by first studying the binding of RNA 1 * 1 nucleotide internal loops to small molecules known to have affinity for nucleic acids. Those studies identified 4',6-diamidino-2-phenylindole (DAPI) as a specific binder to RNAs with the 5'CAG/3'GAC motif. DAPI was then used as a query molecule in a shape- and chemistry alignment-based virtual screen to identify compounds with improved properties, which identified 4-guanidinophenyl 4-guanidinobenzoate, a small molecule that improves pre-mRNA splicing defects associated with the r(CAG)(exp) MBNL1 complex. This compound may facilitate the development of therapeutics to treat diseases caused by r(CAG)(exp) and could serve as a useful chemical tool to dissect the mechanisms of r(CAG)(exp) toxicity. The approach used in these studies, defining the small RNA motifs that bind small molecules with known affinity for nucleic acids and then using virtual screening to optimize them for bioactivity, may be generally applicable for designing small molecules that target other RNAs in the human genomic sequence. PMID- 22252898 TI - Activation of group III metabotropic glutamate receptors by endogenous glutamate protects against glutamate-mediated excitotoxicity in the hippocampus in vivo. AB - Perfusion of 4-aminopyridine (4-AP) by microdialysis in the hippocampus produces intense epileptiform behavioral and electrical activity and neurodegeneration, resulting from a stimulated release of glutamate from nerve endings. In contrast, accumulation of extracellular glutamate by blockade of its transport in vivo in anesthetized rats is innocuous, and studies in vitro in brain slices suggest that under these conditions glutamate may activate presynaptic group III metabotropic glutamate receptors (mGluRs) and inhibit its own release. Therefore, using microdialysis, EEG recording, and histological evaluation, we studied the effect of increased endogenous extracellular glutamate by blockade of its transport with pyrrolidine dicarboxylic acid (PDC) on the excitotoxic action of 4-AP in the hippocampus of awake rats. We found that up to a 20-fold increase in extracellular glutamate during >90 min with PDC does not induce any sign of excitotoxicity. On the contrary, this glutamate increase notably protected against the 4-AP-induced seizures and neurodegeneration, and, remarkably, this protection was dependent on the time of perfusion with PDC and thus on the duration of extracellular glutamate accumulation. To test whether this protective action was mediated by the activation of group III mGluRs, we used specific antagonists of these receptors and found that they clearly prevented the protective effect of PDC, without affecting the accumulation of extracellular glutamate. We conclude that the spillover of the excess extracellular glutamate activates presynaptic group III mGluRs and inhibits the stimulatory effect of 4 AP on its release, thus preventing the activation of postsynaptic N-methyl-D aspartate receptors and its deleterious consequences. PMID- 22252899 TI - Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations. AB - Mutations in the Aristaless-related homeobox gene (ARX) are associated with a wide variety of neurologic disorders including lissencephaly, hydrocephaly, West syndrome, Partington syndrome, and X-linked intellectual disability with or without epilepsy. A genotype-phenotype correlation exists for ARX mutations; however, the molecular basis for this association has not been investigated. To begin understanding the molecular basis for ARX mutations, we tested the DNA binding sequence preference and transcriptional repression activity for Arx, deletion mutants and mutants associated with various neurologic disorders. We found DNA binding preferences of Arx are influenced by the amino acid sequences adjacent to the homeodomain. Mutations in the homeodomain show a loss of DNA binding activity, while the T333N and P353R homeodomain mutants still possess DNA binding activities, although less than the wild type. Transcription repression activity, the primary function of ARX, is reduced in all mutants except the L343Q, which has no DNA binding activity and does not functionally repress Arx targets. These data indicate that mutations in the homeodomain result in not only a loss of DNA binding activity but also loss of transcriptional repression activity. Our results provide novel insights into the pathogenesis of ARX-related disorders and possible directions to pursue potential therapeutic interventions. PMID- 22252900 TI - Transforming growth factor beta3 for the prevention of vocal fold scarring. AB - OBJECTIVES/HYPOTHESIS: Vocal fold scarring poses a therapeutic challenge. It causes hoarseness and decreases the quality of life. Transforming growth factor beta3 (TGFbeta3) is highly expressed in fetal wounds that heal without scarring, and administration of TGFbeta3 has been reported to prevent scarring of the skin and the buccal mucosa. Thus TGFbeta3 is considered to be a key molecule in scar free healing. This study aimed to examine the ability of TGFbeta3 to prevent vocal fold scarring, with particular attention paid to the distribution of extracellular matrices and functional outcomes. STUDY DESIGN: Prospective study using an animal model. METHODS: Ten beagles were used in this study; 500 MUL of TGFbeta3 (0.5 MUg/mL: 5 beagles) or saline (5 beagles) was injected into the vocal fold lamina propria. Fifteen minutes after injection, vocal folds were injured by stripping off the entire layer of the lamina propria. Six months after surgery, animals were euthanized and the larynges were harvested. Vibratory and histologic examinations were performed. RESULTS: The administration of TGFbeta3 suppressed granulation-tissue formation and scarring. TGFbeta3-treated vocal folds showed significantly better vibratory properties, resembling normal vocal folds. Histologic analysis revealed favorable restoration of elastin and hyaluronic acid in the lamina propria. The distribution of collagen was well organized, and collagen deposition was less dense in TGFbeta3-treated vocal folds compared to sham-treated vocal folds. CONCLUSIONS: Administration of TGFbeta3 before injury significantly suppressed scar formation and induced favorable restoration of extracellular matrices in the vocal fold lamina propria, resulting in much improved phonatory function. PMID- 22252901 TI - Intracoronary versus intravenous high-dose bolus plus maintenance administration of tirofiban in patients undergoing primary percutaneous coronary intervention for acute ST elevation myocardial infarction. AB - We aimed to examine whether intracoronary high-dose bolus of tirofiban plus maintenance would result in improved clinical outcome in STEMI patients undergoing primary PCI in this pilot trial. A total of 56 patients were enrolled to receive either intracoronary high-dose bolus plus maintenance (n = 34) or intravenous high-dose bolus plus maintenance (n = 22) of tirofiban. Pre and post intervention TIMI flow grades, myocardial blush grades, peak CKMB and troponin levels, time to peak CKMB and troponin, time to 50% ST resolution and major composite adverse cardiac event rates at 30 days were recorded. Although incidence of major adverse cardiac events was not different, post intervention TIMI flow and TIMI blush grades, peak CKMB and troponin levels, and time to peak CKMB and time to peak troponin were significantly different, favoring intracoronary strategy. In conclusion, this regimen improved myocardial reperfusion and coronary flow, and reduced myocardial necrosis, but failed to improve clinical outcomes at 30 days. PMID- 22252902 TI - Macro-scale topology optimization for controlling internal shear stress in a porous scaffold bioreactor. AB - Shear stress is an important physical factor that regulates proliferation, migration, and morphogenesis. In particular, the homeostasis of blood vessels is dependent on shear stress. To mimic this process ex vivo, efforts have been made to seed scaffolds with vascular and other cell types in the presence of growth factors and under pulsatile flow conditions. However, the resulting bioreactors lack information on shear stress and flow distributions within the scaffold. Consequently, it is difficult to interpret the effects of shear stress on cell function. Such knowledge would enable researchers to improve upon cell culture protocols. Recent work has focused on optimizing the microstructural parameters of the scaffold to fine tune the shear stress. In this study, we have adopted a different approach whereby flows are redirected throughout the bioreactor along channels patterned in the porous scaffold to yield shear stress distributions that are optimized for uniformity centered on a target value. A topology optimization algorithm coupled to computational fluid dynamics simulations was devised to this end. The channel topology in the porous scaffold was varied using a combination of genetic algorithm and fuzzy logic. The method is validated by experiments using magnetic resonance imaging readouts of the flow field. PMID- 22252903 TI - Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients. AB - BACKGROUND: High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. The authors retrospectively reviewed glucarpidase use in pediatric cancer patients at their institution and evaluated whether subsequent resumption of HDMTX was tolerated. METHODS: Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed. RESULTS: Of 1141 patients who received 4909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dose was 51.6 U/kg (range, 13 65.6 U/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 MUM (range, 1.3-590.6 MUM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244-763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66 268 hours) for the next HDMTX course, and 72 hours (range, 42-116 hours) for subsequent courses. The median peak serum creatinine level during these HDMTX courses was 2.2 mg/dL (range, 0.8-9.6 mg/dL), 0.8 mg/dL (range, 0.4-1.6 mg/dL), and 0.6 mg/dL (range, 0.4-0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients, and no patient died as a result of methotrexate toxicity. CONCLUSIONS: The current results indicated that it is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury. PMID- 22252904 TI - Adenotonsillar hypertrophy: correlation between obstruction types and cardiopulmonary complications. AB - OBJECTIVES/HYPOTHESIS: To evaluate the association of upper airway obstruction (UAO) type and cardiopulmonary complications in children. The effect of obstruction type on quality of life and severity of obstructive symptoms were also investigated. STUDY DESIGN: Cross-sectional study. METHODS: A Brodsky scale and adenoid-nasopharynx ratio (ANR) were used to categorize tonsil and adenoid size, respectively. The patients were divided into four groups according to obstruction type: adenoid hypertrophy only (ANR >= 0.63, tonsil grade 1 or 2), adenoid and tonsil hypertrophy (ANR >= 0.63, tonsil grade 3 or 4), tonsillar hypertrophy only (ANR < 0.63, tonsil grade 3 or 4), and normal (ANR < 0.63, tonsil grade 1 or 2). Mean pulmonary artery pressure (MPAP), tricuspid annular plane systolic excursion (TAPSE), and right ventricle myocardial performance index (RVMPI) were evaluated for each patient. The obstructive sleep apnea questionnaire (OSA-18) and Brouilette symptom score questionnaire were completed by each child's parents. RESULTS: MPAP was higher in patients with adenoid hypertrophy and adenoid and tonsil hypertrophy in comparison with the normal group. The P values were .079 and .055, respectively, when comparing TAPSE and RVMPI measurents in adenoid and tonsil hypertrophy and normal patients. A significant correlation was found between ANR and MPAP, RVMP, and TAPSE. The patients in the adenoid and tonsil hypertrophy group had the highest Brouilette symptom and OSA-18 scores. CONCLUSIONS: Patients with adenoid and tonsil hypertrophy are at a higher risk for cardiopulmonary complications, poorer quality of life, and more severe UAO symptoms and should have priority for surgical treatment to prevent cardiopulmonary complications. PMID- 22252905 TI - A review of epidemiological studies on neuropsychological effects of air pollution. AB - The aim of the present review is to provide an update of the epidemiological evidence of the effects of air pollution on neuropsychological development and impairment, as well as of the evidence on individual susceptibility to these effects. Animal studies have shown deposition of ultrafine particles containing metals in olfactory bulb and frontal cortical and subcortical areas, and overexpression of inflammatory responses, white matter lesions and vascular pathology in these areas that could be the basis for functional and structural brain effects. Several observational studies in the general population have observed cognitive deficits and behavioural impairment in children and the elderly. These effects, however, are not conclusive given the limited number of studies, their small size and their methodological constraints. PMID- 22252906 TI - Isolation of hemoglobin from bovine erythrocytes by controlled hemolysis in the membrane bioreactor. AB - In this work, we describe an optimized procedure based on gradual hemolysis for the isolation of hemoglobin derived from bovine slaughterhouse erythrocytes in a membrane bioreactor. The membrane bioreactor system that provided high yields of hemoglobin (mainly oxyhemoglobin derivate) and its separation from the empty erythrocyte membranes (ghosts) was designed at a pilot scale. Ten different concentrations of hypotonic media were assessed from the aspect of the extent of hemolysis, hematocrit values of the erythrocyte suspensions, cell swelling, and membrane deformations induced by decreased salt concentration. Effective gradual osmotic hemolysis with an extent of hemolysis of 88% was performed using 35 mM Na phosphate/NaCl buffer of pH 7.2-7.4. Under these conditions most of the cell membranes presented the appearance of the normal ghosts under phase contrast microscope. The hemoglobin purity of >80% was confirmed by SDS-PAGE. Kinetic studies showed that maximal concentration of hemoglobin was reached after 40 min, but the process cycle at which recovery of 83% was achieved lasted for 90 min. The dynamics of both steps, (1) transport through the membrane of erythrocytes during process of hemolysis and (2) transport through the reactor filters, were evaluated. PMID- 22252907 TI - Endoscopic axillo-breast approach for benign neck mass excision. AB - OBJECTIVES/HYPOTHESIS: Benign neck masses are usually found in younger patients, who are more likely to be concerned about postoperative scars. Until recently, a direct approach through a transcervical incision along the mass has been accepted as a standard surgical procedure for the benign neck mass. However, this conventional transcervical approach leaves a visible scar on the neck, regardless of the size of the incision. We assumed that an endoscopic gasless axillo-breast (A-B) approach might be a good alternative method for excision of benign neck masses. The aim of this study was to determine the safety and feasibility of a gasless A-B approach for the excision of benign neck masses by comparing it to the conventional open approach. STUDY DESIGN: Case series. METHODS: We prospectively compared the outcomes of endoscopic removal of benign neck lesions with the outcomes of conventional open surgery. RESULTS: Most patients in the endoscopy group were women, and the mean age was younger than in the open group. Although operative time was longer and amount of drainage was larger in the endoscopy group, there was no statistically significant difference in duration of drainage, hospitalization period, complication rate, and pain score. Endoscopically treated patients were more satisfied with the cosmetic outcome of the surgery than patients in the conventional open group. CONCLUSIONS: Endoscopic excision via an A-B approach without gas insufflation could be a good substitute for conventional transcervical excision in selected cases of benign neck lesion. PMID- 22252908 TI - Microwave-assisted hydrogel synthesis: a new method for crosslinking polymers in aqueous solutions. AB - It has been found that hydrogels may be formed by microwave irradiation of aqueous solutions containing appropriate combinations of polymers. This new method of hydrogel synthesis yields sterile hydrogels without the use of monomers, eliminating the need for the removal of unreacted species from the final product. Results for two particularly successful combinations, poly(vinyl alcohol) with either poly(acrylic acid) or poly(methylvinylether-alt-maleic anhydride), are presented. Irradiation using temperatures of 100-150 degrees C was found to yield hydrogels with large equilibrium swelling degrees of 500-1000 g g(-1) . Material leached from both types of hydrogel shows little cytotoxicity towards HT29 cells. PMID- 22252909 TI - Double-blind controlled trial of venlafaxine for treatment of adults with attention deficit/hyperactivity disorder. AB - BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is one of the most common mental disorders beginning in childhood that may continue to adulthood. The purpose of this study was to evaluate the possible therapeutic effect of venlafaxine in adults with ADHD. METHODS: In a double-blind setting, drug-naive adults with a diagnosis of ADHD based on DSM-IV-TR criteria were randomly selected to receive either venlafaxine (up to 225 mg/day) or a placebo for 6 weeks. The Conners Adult ADHD Rating Scale self-report screening version was administered before and during the treatment at 2-week intervals to measure the therapeutic effects. RESULTS: The mean age (SD) of patients was 30.5 (8.1) years. Eleven out of 20 patients receiving venlafaxine and 13 out of 21 patients receiving the placebo were male. The two groups were not significantly different in terms of age, educational level, weight, or blood pressure. Significant decrease was observed in both subscales (inattentive, hyperactive/impulsive), total ADHD symptoms score, and ADHD index in both the venlafaxine and the placebo groups. Seventy-five percent of treatment group versus 20% of placebo group met treatment response criteria when defined as a 25% drop in total ADHD score (p = 0.001). No serious adverse effects were reported during the trial. CONCLUSIONS: In this double-blind trial, the symptoms of adult ADHD decreased after a 6-week trial of either venlafaxine or a placebo with no significant difference. However, a significant treatment response defined as a 25% drop in ADHD index (measured by a self-report scale) was achieved by venlafaxine. The interpretation of these results is limited by the short duration of follow-up in this study. PMID- 22252910 TI - Build/couple/pair strategy for the synthesis of stereochemically diverse macrolactams via head-to-tail cyclization. AB - A build/couple/pair (B/C/P) strategy was employed to generate a library of 7936 stereochemically diverse 12-membered macrolactams. All 8 stereoisomers of a common linear amine precursor were elaborated to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds were further diversified via capping of two amine functionalities on SynPhase Lanterns. Reagents used for solid-phase diversification were selected using a sparse matrix design strategy with the aim of maximizing coverage of chemical space while adhering to a preset range of physicochemical properties. PMID- 22252911 TI - Fine wettability control created by a photochemical combination method for inkjet printing on self-assembled monolayers. AB - Wettability tuning for organic solvents is demonstrated with the "combination method", a reversal of the conventional "cleavage method". Several advantages are inherent to this method: for example, the syntheses are simple, various surface active groups can be used, and the reaction proceeds with a low-energy light source. The image shows the result after UV irradiation through a patterning mask. PMID- 22252913 TI - Juvenile immunotoxicology. AB - Developmental immunotoxicity (DIT) testing is centered around the concern that exposure to immunotoxicants early in development may result in enhanced susceptibility of, or unique or more persistent effects on, the immune system, in comparison to adult exposure. Developmental immunotoxicity has been the focus of numerous workshops and reviews for at least fifteen years. Most of these earlier activities have focused on both environmental chemicals and pharmaceuticals and have concluded that the best approach to DIT is to address the possible impacts of exposure during all of the critical windows of development. This article will emphasize the critical role played by exposure during the juvenile stage of development. This article will also highlight several key issues that distinguish DIT testing of pharmaceuticals. Representatives from the pharmaceutical, biotechnology, academic, and regulatory sectors (both FDA and EMA) were brought together during a two-day workshop in May 2010 to consider the current state of the science of DIT as it pertains to the testing of pharmaceuticals. It is important to emphasize at the onset that there are currently no regulatory guidelines for either drugs or nondrug chemicals specifically focused on assessment of DIT, although some general guidelines are included in both developmental and reproductive toxicity and general immunotoxicology guidance documents. PMID- 22252912 TI - Ultrastructural evaluation of semen to assess effects of exposure to toxicants. AB - Conventional light microscopic evaluation of a semen ejaculate does not fully utilize potential indicators of functional impairment in sperm organelles. The technique described here facilitates critical evaluation of morphological features of spermatozoal organelles at an ultrastructural level and helps identify vulnerable targets. Compared with a battery of sperm function assays employed in andrology clinics, this relatively less expensive technique efficiently uses semen as biopsy material and thus serves as a comprehensive means to assess the impact of toxicants on the male reproductive system. PMID- 22252914 TI - Determination of counter-ions in synthetic peptides by ion chromatography, capillary isotachophoresis and capillary electrophoresis. AB - The utility of three various analytical techniques [ion chromatography (IC), capillary electrophoresis (CE) and isotachophoresis (ITP)] was tested in the determination of counter-ions in synthetic peptides. The analyzed ions were acetates, trifluoroacetates and chlorides. IC provided the best results; CE, except limit of detection and limit of quantification, exhibited the comparable results. ITP was classified as the less useful because of the problem with the determination of the chloride ions. Nevertheless, all the three techniques were able to analyze trifluoroacetates and acetates ions with satisfactory results. Except analytical methods, three procedures using hydrochloric acid (HCl) (at two different concentrations) and acetic acid as sample solvents processed by lyophilization were tested. It has been found that the lyophilization not only by HCl but also by acetic acid is a simple and cheap procedure for removal of toxic trifluoroacetic counter-ions from peptides on satisfactory levels. PMID- 22252915 TI - Nimodipine accelerates reinnervation of denervated rat thyroarytenoid muscle following nerve-muscle pedicle implantation. AB - OBJECTIVES/HYPOTHESIS: To determine whether nimodipine, an L-type voltage operated calcium channel antagonist that is an accelerator of axonal regeneration following peripheral nerve injury, can expedite reinnervation of denervated rat thyroarytenoid (TA) muscle following nerve-muscle pedicle (NMP) flap implantation. STUDY DESIGN: A quantitative histologic and physiologic assessment of the TA muscle following NMP flap implantation, with or without nimodipine treatment. METHODS: Using 72 Wistar rats, we performed a transection on the left recurrent laryngeal nerve, followed by NMP flap implantation. Thirty-six animals received nimodipine treatment (NIMO [+] group), and the remaining 36 animals received no nimodipine treatment (NIMO [-] group). As a control, 18 animals were subjected only to transection of the left recurrent laryngeal nerve. We performed a histologic assessment for muscle area, axon, nerve terminals (NTs), and acetylcholine receptors (AchRs) in the TA muscle and electromyography at 2, 4, and 10 weeks after surgery. RESULTS: Muscle area, ratio of the number of NTs to that of AchRs (NT/AchR ratio), and evoked action potential in the TA muscle were significantly greater in the NIMO (+) group than in the NIMO (-) group (P < .05) at 4 weeks. At 10 weeks, the NT/AchR ratio was significantly greater in the NIMO (+) group than in the NIMO (-) group (P < .05). CONCLUSIONS: We found that nimodipine accelerated reinnervation of the denervated TA muscle following NMP flap implantation. PMID- 22252916 TI - Palladium-catalyzed intermolecular coupling of 2-silylaryl bromides with alkynes: synthesis of benzosiloles and heteroarene-fused siloles by catalytic cleavage of the C(sp3)-Si bond. PMID- 22252917 TI - Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from Ts65Dn mice. AB - Overexpression of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A), encoded by a gene located in the Down syndrome (DS) critical region, is considered a major contributor to developmental abnormalities in DS. DYRK1A regulates numerous genes involved in neuronal commitment, differentiation, maturation, and apoptosis. Because alterations of neurogenesis could lead to impaired brain development and mental retardation in individuals with DS, pharmacological normalization of DYRK1A activity has been postulated as DS therapy. We tested the effect of harmine, a specific DYRK1A inhibitor, on the development of neuronal progenitor cells (NPCs) isolated from the periventricular zone of newborn mice with segmental trisomy 16 (Ts65Dn mice), a mouse model for DS that overexpresses Dyrk1A by 1.5-fold. Trisomy did not affect the ability of NPCs to expand in culture. Twenty-four hours after stimulation of migration and neuronal differentiation, NPCs showed increased expression of Dyrk1A, particularly in the trisomic cultures. After 7 days, NPCs developed into a heterogeneous population of differentiating neurons and astrocytes that expressed Dyrk1A in the nuclei. In comparison with disomic cells, NPCs with trisomy showed premature neuronal differentiation and enhanced gamma-aminobutyric acid (GABA) ergic differentiation, but astrocyte development was unchanged. Harmine prevented premature neuronal maturation of trisomic NPCs but not acceleration of GABA-ergic development. In control NPCs, harmine treatment caused altered neuronal development of NPCs, similar to that in trisomic NPCs with Dyrk1A overexpression. This study suggests that pharmacological normalization of DYRK1A activity may have a potential role in DS therapy. PMID- 22252919 TI - Hepatitis B infection: current concepts and future challenges. AB - Chronic hepatitis B (CHB) is a global health problem affecting more than 350 million people worldwide. Chronic carriage of HBV is related to the age when the infection occurs; the younger the age the higher the chronicity rate. Knowledge of the natural history of CHB is important for the management of the disease. The goal of hepatitis B treatment is to prevent cirrhosis, liver decompensation and hepatocellular carcinoma. In clinical practice, treatment response is determined by the suppression of serum HBV DNA levels. However, current antiviral therapies are usually unable to achieve sustained off-treatment responses and eradicate the infection. Impairment of immune responses including defective innate non cytolytic antiviral function together with exhausted T cells and the tolerogenic liver environment may all contribute to the poor clinical response. A more comprehensive understanding of the immunological phases of CHB, potential triggers of liver flares and molecular mechanisms underlying viral persistence and immunopathology will help to tailor future therapeutic strategies. A synergistic approach of boosting the immune response of the host by specific immunotherapeutic interventions and effective viral load suppression will be needed to promote sustained viral clearance in chronic infection. PMID- 22252920 TI - Cervical metastasis of germ cell tumors: evaluation, management, complications, and outcomes. AB - OBJECTIVES/HYPOTHESIS: Head and neck surgeons can be involved in the management of germ cell tumor (GCT) metastatic to the neck from initial diagnosis through postchemotherapy management of residual neck masses. This article reports on 34 consecutive patients with GCT metastatic to the neck. STUDY DESIGN: Retrospective chart review. METHODS: A single-institution retrospective chart review of 34 consecutive patients with GCT metastatic to the neck who underwent postchemotherapy neck surgery between 1991 and 2009 was performed. RESULTS: Seventy-four percent of patients had a neck mass at initial diagnosis, with 50% of patients having a neck mass as the presenting symptom leading to a diagnosis of GCT. Of the 37 neck procedures, positive nodes were found in 22. No significant relationship between preoperative tumor markers and neck pathology (P = .35) was identified. No patients had neck recurrence. No patients had permanent nerve injury or chyle leak. As a secondary end point, survival analysis related to cervical pathology showed that viable tumor in the neck predicted disease specific survival (P = .01). Five- and 10-year disease-specific survival was 82.3% (median, 52-month follow-up). CONCLUSIONS: Operative management for patients with metastatic GCT to the neck can achieve long-term durable cervical control with limited complications. PMID- 22252921 TI - Cosmetics and function: quality-of-life changes after rhinoplasty surgery. AB - OBJECTIVES/HYPOTHESIS: To measure patient quality of life after rhinoplasty in regard to nose appearance and function with use of the modern structural and functional surgical approach. STUDY DESIGN: Retrospective chart review at a tertiary referral center. METHODS: We performed a retrospective chart review with prospective follow-up. All patients with rhinoplasty in the past 5 years by the senior author were identified. Patients who simultaneously underwent additional nasal surgery were excluded. McNemar test was used to compare preoperative and postoperative clinical evaluations. Paired t tests were used to evaluate questionnaire scores preoperatively and postoperatively from the nasal obstruction symptom evaluation and rhinoplasty outcome evaluation. Two-group t tests were used for comparative analysis after dividing patients into two groups on the basis of dorsal reduction, osteotomies, open versus closed approach, and revisions. RESULTS: Among 370 patients invited, 126 participated and 113 provided completed questionnaires. Analysis of preoperative and postoperative nasal obstruction symptom evaluation scores showed a median difference of -40 (quartiles, -25 and -60), indicating improvement (P < .01). Preoperative and postoperative rhinoplasty outcome evaluation scores showed a median difference of 29.2 (quartiles, 12 and 50), also indicating improvement (P < .01). Difference in improvement in scores was not significant when groups were divided on the basis of dorsal reduction, osteotomies, and open versus closed approach or whether rhinoplasty was primary versus revision. CONCLUSIONS: Modern rhinoplasty techniques that depend on a strong structural framework of grafts compared with the traditional reduction rhinoplasty techniques significantly improve patient quality of life in regard to nose function and appearance. PMID- 22252922 TI - Continuum heterogeneous biofilm model--a simple and accurate method for effectiveness factor determination. AB - We present a novel analytical approach to describe biofilm processes considering continuum variation of both biofilm density and substrate effective diffusivity. A simple perturbation and matching technique was used to quantify biofilm activity using the steady-state diffusion-reaction equation with continuum variable substrate effective diffusivity and biofilm density, along the coordinate normal to the biofilm surface. The procedure allows prediction of an effectiveness factor, eta, defined as the ratio between the observed rate of substrate utilization (reaction rate with diffusion resistance) and the rate of substrate utilization without diffusion limitation. Main assumptions are that (i) the biofilm is a continuum, (ii) substrate is transferred by diffusion only and is consumed only by microorganisms at a rate according to Monod kinetics, (iii) biofilm density and substrate effective diffusivity change in the x direction, (iv) the substrate concentration above the biofilm surface is known, and (v) the substratum is impermeable. With this approach one can evaluate, in a fast and efficient way, the effect of different parameters that characterize a heterogeneous biofilm and the kinetics of the rate of substrate consumption on the behavior of the biological system. Based on a comparison of eta profiles the activity of a homogeneous biofilm could be as much as 47.8% higher than that of a heterogeneous biofilm, under the given conditions. A comparison of eta values estimated for first order kinetics and eta values obtained by numerical techniques showed a maximum deviation of 1.75% in a narrow range of modified Thiele modulus values. When external mass transfer resistance, is also considered, a global effectiveness factor, eta(0) , can be calculated. The main advantage of the approach lies in the analytical expression for the calculation of the intrinsic effectiveness factor eta and its implementation in a computer program. For the test cases studied convergence was achieved quickly after four or five iterations. Therefore, the simulation and scale-up of heterogeneous biofilm reactors can be easily carried out. PMID- 22252923 TI - Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. AB - Enzyme replacement therapy (ERT) for Pompe disease using recombinant acid alpha glucosidase (rhGAA) has resulted in increased survival although the clinical response is variable. Cross-reactive immunological material (CRIM)-negative status has been recognized as a poor prognostic factor. CRIM-negative patients make no GAA protein and develop sustained high antibody titers to ERT that render the treatment ineffective. Antibody titers are generally low for the majority of CRIM-positive patients and there is typically a better clinical outcome. Because immunomodulation has been found to be most effective in CRIM-negative patients prior to, or shortly after, initiation of ERT, knowledge of CRIM status is important before ERT is begun. We have analyzed 243 patients with infantile Pompe disease using a Western blot method for determining CRIM status and using cultured skin fibroblasts. Sixty-one out of 243 (25.1%) patients tested from various ethnic backgrounds were found to be CRIM-negative. We then correlated the CRIM results with GAA gene mutations where available (52 CRIM-negative and 88 CRIM-positive patients). We found that, in most cases, CRIM status can be predicted from GAA mutations, potentially circumventing the need for invasive skin biopsy and time wasted in culturing cells in the future. Continued studies in this area will help to increase the power of GAA gene mutations in predicting CRIM status as well as possibly identifying CRIM-positive patients who are at risk for developing high antibody titers. PMID- 22252924 TI - Use of high-gradient magnetic fishing for reducing proteolysis during fermentation. AB - Proteolysis during fermentation may have a severe impact on the yield and quality of a secreted product. In the current study, we demonstrate the use of high gradient magnetic fishing (HGMF) as an efficient alternative to the more conventional methods of preventing proteolytic degradation. Bacitracin-linked magnetic affinity adsorbents were employed directly in a fermenter during Bacillus licheniformis cultivation to remove trace amounts of unwanted proteases. The constructed magnetic adsorbents had excellent, highly specific binding characteristics in the fermentation broth (K(d) = 1.94 micromolar; Q(max) = 222.8 mg/g), which obeyed the Langmuir isotherm and had rapid binding kinetics (equilibrium in <300 s). When applied directly in shake-flask cultures or in a 1 L fermenter and then removed by HGMF, the degradation of the model protein bovine serum albumin was stopped. The adsorbents could be recycled and reused during the same fermentation to remove freshly produced proteases, extending the life of the model protein in the fermenter. HGMF may provide an efficient method of stabilizing heterologous proteins produced in cultivation processes. PMID- 22252925 TI - Hepatitis C virus co-infection and sexual risk behaviour are associated with a high homocysteine serum level in HIV-infected patients. AB - BACKGROUND AND AIMS: A better understanding of the relationship of homocysteine with cardiovascular risk factors is needed. The objectives of this study were to assess the serum level of homocysteine in HIV-infected patients and to analyse the possible association of increased levels of the amino acid with cardiovascular risk factors, demographic and clinical characteristics of participants. METHODS: Cross-sectional study carried out as a supplementary task to the usual controls necessary in HIV-infected patients in the outpatient clinic of the Hospital General of Castellon, Spain. For two consecutive visits the demographic, clinical and HIV-related characteristics and blood analyses results were obtained for each participant. Homocysteine serum level was documented and the possible association of the amino acid with all the other study variables was assessed with a multiple linear regression analysis. RESULTS: A total of 145 patients were included. The mean homocysteine serum level of all participants was 11.9 +/- 5.9 umol/L. A total of 54 patients (37%) presented homocysteine serum levels higher than the upper limit of normal. An association was found between higher homocysteine serum level and the following variables: family history of early coronary disease (P = 0.027), sexual HIV risk behaviour (P = 0.016), hepatitis C virus co-infection (P = 0.002), higher height (P = 0.002), higher diastolic blood pressure (P = 0.049), lower serum level of folic acid (P <0.001), and lower serum level of vitamin B12 (P = <0.001). CONCLUSION: In the HIV population, increased homocysteine serum level is associated with sexual risk behaviour and hepatitis C virus coinfection. PMID- 22252926 TI - Four-year outcomes of palatal implants for primary snoring treatment: a prospective longitudinal study. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to evaluate the long-term effectiveness of palatal implants as the treatment of primary snoring. STUDY DESIGN: Prospective longitudinal cohort study. METHODS: This study compared snoring outcomes before and after soft palate implantation for patients diagnosed with primary snoring (no sleep apnea). Snoring severity was obtained by the subjects' sleep partners on a 10-point Likert scale. A paired Student t test compared the mean scale values preoperatively at week 52 and at the current 4 year follow-up. Body mass index for each patient was also compared to evaluate for any significant confounders. RESULTS: Data were obtained from 23 patients out of 26 who were followed for the full study term. The follow-up time was on average 4 years following palatal implantation. A statistically (P < .016) and clinically significant improvement in the snoring scale was noted when comparing snoring severity between the preoperative and 4-year period and between the 52 week and 4-year scores. Although statistically significant improvement was found between the preoperative period and 52 weeks, there was a clinical deterioration in snoring scale scores between 52 weeks and 4 years. The mean (standard deviation) preoperative score was 9.5 (0.5), mean week-52 score was 5.0 (1.6), and mean 4-year score was 7.0 (1.8). Body mass index did not change through the observation interval. CONCLUSIONS: Soft palate implantation is a possible surgical technique with which to attempt to achieve subjective improvement of primary snoring severity. Subjective improvement, however, deteriorates significantly over time, and is only minimally sustained at 4 years postoperatively. This study provides new information on long-term palatal implant effectiveness. PMID- 22252929 TI - What makes our field unique? PMID- 22252931 TI - Differential management of scaphocephaly. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to review the outcomes of scaphocephaly management. We hypothesized that differential treatment of scaphocephaly based on age at correction and degree of severity yields consistently satisfying results while reducing the operative morbidity. STUDY DESIGN: Retrospective patient record review. METHODS: Three cranial vault remodeling procedures with varying levels of aggressiveness (limited-access, partial, and total cranial-vault remodeling) were performed on patients with scaphocephaly from 1995 to 2010. More-aggressive procedures were performed on older patients and patients having more-severe deformities. Patient records were reviewed for age, weight, blood loss, and length of hospital stay, and cephalic indices (CIs) were calculated from computed tomography scans and clinical photographs. RESULTS: Fifty-one patients underwent surgery for scaphocephaly during the study period. The average estimated blood volume fraction lost was 0.41. The average length of hospital stay was 4.49 days. Pre- and postoperative CIs were calculable for 36 patients. The average preoperative CI was 68.7. The average postoperative CI was 79.3, for an average operative change of 15%. The three procedures had statistically different values for average length of stay. A trend was suggested for estimated blood loss and volume fraction lost. There was no statistically significant difference in CI outcomes. CONCLUSIONS: This study supports the concept of a proportionate response in the management of scaphocephaly. Less-aggressive procedures do not yield less-desirable results when properly selected to match the clinical situation of the individual patient. PMID- 22252927 TI - Phase 2 results from Radiation Therapy Oncology Group Study 0537: a phase 2/3 study comparing acupuncture-like transcutaneous electrical nerve stimulation versus pilocarpine in treating early radiation-induced xerostomia. AB - BACKGROUND: In this phase 2 component of a multi-institutional, phase 2/3, randomized trial, the authors assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. METHODS: Patients with cancer of the head and neck who were 3 to 24 months from completing radiotherapy with or without chemotherapy (RT +/- C) and who were experiencing xerostomia symptoms with basal whole saliva production >=0.1 mL per minute and were without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 sessions over 12 weeks) using a proprietary electrical stimulation unit. The primary study objective was to assess the feasibility of ALTENS treatment. Patients were considered compliant if 19 of 24 ALTENS sessions were delivered, and the targeted compliance rate was 85%. Secondary objectives measured treatment-related toxicities and the effect of ALTENS on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). RESULTS: Of 48 accrued patients, 47 were evaluable. The median age was 60 years, 84% of patients were men, 70% completed RT +/- C for >12 months, and 21% had previously received pilocarpine. Thirty-four patients completed all 24 ALTENS sessions, 9 patients completed 20 to 23 sessions, and 1 patient completed 19 sessions, representing a 94% total compliance rate. Six-month XeQOLS scores were available for 35 patients and indicated that 30 patients (86%) achieved a positive treatment response with a mean +/- standard deviation reduction of 35.9% +/- 36.1%. Five patients developed grade 1 or 2 gastrointestinal toxicity, and 1 had a grade 1 pain event. CONCLUSIONS: The current results indicated that ALTENS treatment for radiation-induced xerostomia can be delivered uniformly in a cooperative, multicenter setting and produces possible beneficial treatment response. Given these results, the phase 3 component of this study was initiated. PMID- 22252932 TI - Nanoparticulate TiO2(B): an anode for lithium-ion batteries. PMID- 22252933 TI - Comparison of speech parameters and olfaction using different tracheotomy speaking valves. AB - BACKGROUND: The objective of this work was to obtain a controlled subjective and objective in vivo clinical comparison of the Passy-Muir, Shiley, and Ball speaking valves. METHODS: Ten patients free of laryngeal pathology but dependent on tracheotomy for respiration were tested with each of the speaking valves. Olfaction was assessed for each patient using the University of Pennsylvania Smell Identification Test (UPSIT). Acoustic and perceptual analyses included subjective assessments, noninstrumental objective assessments (including maximum phonation time, and S:Z ratio), and instrumental objective assessments (including fundamental frequency:maximum phonation range, vocal intensity, perturbation, naturalness, and turbulence). Oxygen saturation was assessed by pulse oximetry. RESULTS: There was a highly significant statistical difference in olfaction and speech naturalness, in favor of the Ball valve (The Airway Company, Forest Hill, MD). The Ball valve's speech parameters were generally better than with the Passy Muir and Shiley valves, including maximum phonation, S:Z ratio, jitter, noise, and turbulence, although the differences were not statistically significant. There were no differences among the valves in oxygen saturation levels. CONCLUSION: This study illustrates that olfaction and certain speech parameters, most noticeably speech naturalness, are significantly improved with the Ball valve as compared to the Passy-Muir and Shiley valves. PMID- 22252935 TI - Evaluation of COMU as a coupling reagent for in situ neutralization Boc solid phase peptide synthesis. AB - Benzotriazole-based coupling reagents have dominated the last two decades of solid phase peptide synthesis. However, a growing interest in synthesizing complex peptides has stimulated the search for more efficient and low-cost coupling reagents, such as COMU which has been introduced as a nonexplosive alternative to the classic benzotriazole coupling reagents. Here, we present a comparative study of the coupling efficiency of COMU with the benzotriazole-based HBTU and HCTU for use in in situ neutralization Boc-SPPS. Difficult sequences, such as ACP(65-74), Jung-Redeman 10-mer, and HIV-1 PR(81-99), were used as model target peptides on polystyrene-based resins, as well as polyethylene glycol-based resins. Coupling yields obtained using fast in situ Boc-SPPS cycles were determined with the quantitative ninhydrin test as well as via LC-MS analysis of the crude cleavage products. Our results demonstrate that COMU coupling efficiency was less effective compared to HBTU and HCTU with HCTU >= HBTU > COMU, when polystyrene-based resins were employed. However, when the PEG resin was employed in combination with a safety catch amide (SCAL) linker, more comparable yields were observed for the three coupling reagents with the same ranking HCTU >= HBTU > COMU. PMID- 22252934 TI - Palliative care in advanced cancer patients: how and when? AB - Cancer patients develop severe physical and psychological symptoms as a result of their disease and treatment. Their families commonly suffer great emotional distress as a result of caregiving. Early palliative care access can improve symptom control and quality of life and reduce the cost of care. Preliminary results show that early palliative care access can also extend survival. Unfortunately, only a minority of cancer centers in the U.S. have the two most important resources for palliative care delivery: outpatient palliative care centers and inpatient palliative care units. In this article, we use a case presentation to discuss the impact of early palliative care access in light of the currently available evidence, and we recommend ways to improve early access to palliative care through education and research. PMID- 22252937 TI - High-temperature gating of solid-state nanopores with thermo-responsive macromolecular nanoactuators in ionic liquids. AB - Stimuli-responsive nanofluidic systems in room temperature ionic liquids (RTILs). The nanofluidic device can withstand high temperatures up to 200 degrees C, in which conventional water-based smart materials and nanodevices are invalid. The smart nanopores can be "irreversibly" turned off above the transition temperature of ca. 120-150 degrees C, actuated by the conformational change of the chemically-modified polymer brushes. PMID- 22252936 TI - Osteoclastogenesis is negatively regulated by D-serine produced by osteoblasts. AB - We have shown the functional expression by chondrocytes of serine racemase (SR) which is responsible for the synthesis of D-serine (Ser) from L-Ser in cartilage. In this study, we evaluated the possible functional expression of SR by bone forming osteoblasts and bone-resorbing osteoclasts. Expression of SR mRNA was seen in osteoblasts localized at the cancellous bone surface in neonatal rat tibial sections and in cultured rat calvarial osteoblasts endowed to release D Ser into extracellular medium, but not in cultured osteoclasts differentiated from murine bone marrow progenitor cells. Sustained exposure to D-Ser failed to significantly affect alkaline phosphatase activity and Ca(2+) accumulation in cultured osteoblasts, but significantly inhibited differentiation and maturation in a concentration-dependent manner at a concentration range of 0.1-1 mM without affecting cellular survival in cultured osteoclasts. By contrast, L-Ser promoted osteoclastic differentiation in a manner sensitive to the inhibition by D-Ser. Matured osteoclasts expressed mRNA for the amino acid transporter B(0,+) (ATB(0,+) ) and the system alanine, serine, and cysteine amino acid transporter-2 (ASCT2), which are individually capable of similarly incorporating extracellular L- and D-Ser. Knockdown of these transporters by siRNA prevented both the promotion by L-Ser and the inhibition by D-Ser of osteoclastic differentiation in pre-osteoclastic RAW264.7 cells. These results suggest that D-Ser may play a pivotal role in osteoclastogenesis through a mechanism related to the incorporation mediated by both ATB(0,+) and ASCT2 of serine enantiomers in osteoclasts after the synthesis and subsequent release from adjacent osteoblasts. PMID- 22252938 TI - The prevalence of depressive symptoms among the older in China: a meta-analysis. AB - BACKGROUND: This study aims to find the status and prevalence of depressive symptoms among the population aged 60 years and above in China. METHODS: We conducted a meta-analysis of cross-sectional studies in older population. Epidemiological studies on depressive symptoms published in Chinese journals were identified manually and online by using the Chinese Biological Medical Literature Database, Chongqing VIP database for Chinese Technical Periodicals, and Chinese National Knowledge Infrastructure database. Studies published in English journals were identified using Medlars Online. RESULTS: A total of 32 eligible studies were included in this review. The analysis showed that the pooled prevalence (with 95% confidence interval) of depressive symptoms for the seniors in China was 22.7% (confidence interval: 19.4-26.4%). The prevalence of depressive symptoms among the older was a little higher in women (24.2%) than in men (19.4%), in rural (29.2%) than urban (20.5%) areas, and in western (30.5%) than eastern (19.5%) areas. In addition, the prevalence of depressive symptoms decreased with increasing levels of education. However, it did not increase gradually with age. CONCLUSIONS: The prevalence of depressive symptoms among the older in China was a little high, and it was varied by gender, age, area, and education level. PMID- 22252939 TI - Glucose ingestion acutely lowers pulsatile LH and basal testosterone secretion in men. AB - Chronic hyperglycemia inhibits the male gonadal axis. The present analyses test the hypothesis that acute glucose ingestion also suppresses LH and testosterone (T) secretion and blunts the LH-T dose-response function. The design comprised a prospectively randomized crossover comparison of LH and T secretion after glucose vs. water ingestion in a Clinical Translational Research Center. The participants were healthy men (n = 57) aged 19-78 yr with body mass index (BMI) of 20-39 kg/m(2). The main outcome measurements were deconvolution and LH-T dose-response analyses of 10-min data. LH-T responses were regressed on glucose, insulin, leptin, adiponectin, age, BMI, and CT-estimated abdominal visceral fat. During the first 120 min after glucose ingestion, for each unit decrease in LH concentrations, T concentrations decreased by 86 (27-144) ng/dl (r = 0.853, P < 0.001). Based upon deconvolution analysis, glucose compared with water ingestion reduced 1) basal (nonpulsatile; P < 0.001) and total (P < 0.001) T secretion without affecting pulsatile T output and 2) pulsatile (P = 0.043) but not basal LH secretion. By multivariate analysis, pulsatile LH secretion positively predicted basal T secretion after glucose ingestion (r = 0.374, P = 0.0042). In addition, the glucose-induced fall in pulsatile LH secretion was exacerbated by higher fasting insulin concentrations (P = 0.054) and attenuated by higher adiponectin levels (P = 0.0037). There were no detectable changes in the analytically estimated LH-T dose-response curves (P > 0.30). In conclusion, glucose ingestion suppresses pulsatile LH and basal T secretion acutely in healthy men. Suppression is influenced by age, glucose, adiponectin, and insulin concentrations. PMID- 22252940 TI - Selective estrogen receptor modulator promotes weight loss in ovariectomized female rhesus monkeys (Macaca mulatta) by decreasing food intake and increasing activity. AB - The effect of hormone replacement therapy (HRT) on body weight in postmenopausal women is controversial, with studies reporting an increase, a decrease, and no change in body weight. To examine estrogen receptor actions on body weight, we investigated the effects of treatment with a selective estrogen receptor modulator (SERM) on body weight, food intake, and activity and metabolic rate in a nonhuman primate model. Eighteen ovariectomized female rhesus monkeys were treated with a nonsteroidal SERM (GSK232802A, 5 mg/kg po) for 3 mo. GSK232802A decreased lutenizing hormone (P < 0.0001) and follicle-stimulating hormone levels (P < 0.0001), consistent with the estrogenic action of the compound. GSK232802A treatment produced a small but sustained weight loss (4.6 +/- 1.0%, P < 0.0001) and reduced adiposity (P < 0.0001), which was due at least in part to a suppression of food intake (3.6 +/- 3.7%, P < 0.0001). Physical activity increased during the 3rd mo of treatment (P = 0.04). Baseline activity level and the change in activity due to treatment were correlated, with the most sedentary individuals exhibiting increased physical activity during the 1st mo of treatment (P = 0.02). Metabolic rate did not change (P = 0.58). These results indicate that GSK232802A treatment reduces body weight and adiposity in ovariectomized nonhuman primates by suppressing food intake and increasing activity, particularly in the most sedentary individuals. These findings suggest that SERM treatment may counteract weight gain in postmenopausal women. PMID- 22252941 TI - Increased expression of miR-325-3p by urocortin 2 and its involvement in stress induced suppression of LH secretion in rat pituitary. AB - Urocortin 2 (Ucn2) is a member of the corticotropin releasing factor (CRF) peptide family, which binds to CRF type 2 receptor. We previously reported on expression of Ucn2 in proopiomelanocortin cells of rat pituitary and its inhibitory action on LH secretion. We also demonstrated that Ucn2 is involved in the mechanism underlying immobilization-induced suppression of LH secretion; the details remain unclear. Here, we found that Ucn2 increased the expression of miR 325-3p, one of three microRNAs with predicted sequence for binding to LH beta subunit 3'-untranslated region (3'-UTR) in monolayer cultured rat anterior pituitary cells, and that miR-325-3p was expressed in LH cells of the anterior pituitary. Immobilization also increased miR-325-3p expression in the anterior pituitary, and its increase was blocked by pretreatment with anti-Ucn2 IgG. Overexpression of miR-325-3p in cultured pituitary cells significantly suppressed intracellular contents and secretion of LH, while miR-325-3p knockdown blocked Ucn2-induced suppression of intracellular contents and secretion of LH. Coexpression of miR-325-3p with LH beta-subunit 3'-UTR-fused luciferase vector significantly suppressed luciferase activity compared with that of mock transfectants. These results suggest that miR-325-3p is involved in immobilization-induced suppression of LH translation and secretion and that Ucn2 plays a role in the increase in miR-325-3p expression. PMID- 22252943 TI - Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes. AB - The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/?) and obese diabetic (db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1alpha and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction. PMID- 22252942 TI - Testosterone increases the muscle protein synthesis rate but does not affect very low-density lipoprotein metabolism in obese premenopausal women. AB - Men and women with hyperandrogenemia have a more proatherogenic plasma lipid profile [e.g., greater triglyceride (TG) and total and low-density lipoprotein cholesterol and lower high-density lipoprotein-cholesterol concentrations] than healthy premenopausal women. Furthermore, castration of male rats markedly reduces testosterone availability below normal and decreases plasma TG concentration, and testosterone replacement reverses this effect. Testosterone is, therefore, thought to be an important regulator of plasma lipid homeostasis. However, little is known about the effect of testosterone on plasma TG concentration and kinetics. Furthermore, testosterone is a potent skeletal muscle protein anabolic agent in men, but its effect on muscle protein turnover in women is unknown. We measured plasma lipid concentrations, hepatic very low density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 secretion rates, and the muscle protein fractional synthesis rate in 10 obese women before and after trandermal testosterone (1.25 g of 1% AndroGel daily) treatment for 3 wk. Serum total and free testosterone concentrations increased (P < 0.05) by approximately sevenfold in response to testosterone treatment, reaching concentrations that are comparable to those in women with hyperandrogenemia, but lower than the normal range for eugonadal men. Except for a small (~10%) decrease in plasma high density lipoprotein particle and cholesterol concentrations (P < 0.04), testosterone therapy had no effect on plasma lipid concentrations, lipoprotein particle sizes, and hepatic VLDL-TG and VLDL-apolipoprotein B-100 secretion rates (all P > 0.05); the muscle protein fractional synthesis rate, however, increased by ~45% (P < 0.001). We conclude that testosterone is a potent skeletal muscle protein anabolic agent, but not an important regulator of plasma lipid homeostasis in obese women. PMID- 22252944 TI - Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. AB - Amenorrhea is common in young athletes and is associated with low fat mass. However, hormonal factors that link decreased fat mass with altered gonadotropin pulsatility and amenorrhea are unclear. Low levels of leptin (an adipokine) and increased ghrelin (an orexigenic hormone that increases as fat mass decreases) impact gonadotropin pulsatility. Studies have not examined luteinizing hormone (LH) secretory dynamics in relation to leptin or ghrelin secretory dynamics in adolescent and young adult athletes. We hypothesized that 1) young amenorrheic athletes (AA) would have lower LH and leptin and higher ghrelin secretion than eumenorrheic athletes (EA) and nonathletes and 2) higher ghrelin and lower leptin would be associated with lower LH secretion. This was a cross-sectional study. We examined ghrelin and leptin secretory patterns (over 8 h, from 11 PM to 7 AM) in relation to LH secretory patterns in AA, EA, and nonathletes aged 14-21 yr. Ghrelin and leptin were assessed every 20 min and LH every 10 min. Groups did not differ for age, bone age, or BMI. However, fat mass was lower in AA than in EA and nonathletes. AA had lower LH and higher ghrelin pulsatile secretion and AUC than nonathletes and lower leptin pulsatile secretion and AUC than EA and nonathletes. Percent body fat was associated positively with LH and leptin secretion and inversely with ghrelin. In a regression model, ghrelin and leptin secretory parameters were associated independently with LH secretory parameters. We conclude that higher ghrelin and lower leptin secretion in AA related to lower fat mass may contribute to altered LH pulsatility and amenorrhea. PMID- 22252945 TI - Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function. AB - Male obesity is associated with reduced sperm motility and morphology and increased sperm DNA damage and oxidative stress; however, the reversibility of these phenotypes has never been studied. Therefore, the aim of this study was to assess the reversibility of obesity and its associated sperm physiology and function in mice in response to weight loss through diet and exercise. C57BL6 male mice (n = 40) were fed either a control diet (CD; 6% fat) or a high-fat diet (HFD; 21% fat) for 10 wk before allocation to either diet and/or swimming exercise interventions for 8 wk. Diet alone reduced adiposity (1.6-fold) and serum cholesterol levels (1.7-fold, P < 0.05), while exercise alone did not alter these, but exercise plus diet also improved glucose tolerance (1.3-fold, P < 0.05). Diet and/or exercise improved sperm motility (1.2-fold) and morphology (1.1-fold, P < 0.05), and reduced sperm DNA damage (1.5-fold), reactive oxygen species (1.1-fold), and mitochondrial membrane potential (1.2-fold, P < 0.05) and increased sperm binding (1.4-fold) (P < 0.05). Sperm parameters were highly correlated with measures of glycemia, insulin action, and serum cholesterol (all P < 0.05) regardless of adiposity or intervention, suggesting a link between systemic metabolic status and sperm function. This is the first study to show that the abnormal sperm physiology resulting from obesity can be reversed through diet and exercise, even in the presence of ongoing obesity, suggesting that diet and lifestyle interventions could be a combined approach to target subfertility in overweight and obese men. PMID- 22252946 TI - Differential in-gel electrophoresis (DIGE) analysis of CHO cells under hyperosmotic pressure: osmoprotective effect of glycine betaine addition. AB - The use of glycine betaine combined with hyperosmolality is known to be an efficient means for achieving high protein production in recombinant Chinese hamster ovary (rCHO) cells. In order to understand the intracellular events and identify the key factors in rCHO cells cultivated with glycine betaine under hyperosmotic conditions, two-dimensional differential in-gel electrophoresis (2D DIGE) followed by mass spectrometric analysis was applied. Differentially expressed 19 protein spots were selected and 16 different kinds of proteins were successfully identified. The identified proteins were associated with cellular metabolism (PEPCK, GAPDH, and PK), cellular architecture (beta-tubulin and beta actin), protein folding (GRP78 and OSP94), mRNA processing (Rbm34, ACF, and IPMK), and protein secretion (gamma-COP). 2D-Western blot analysis of beta tubulin, GAPDH, Peroxidoxin-1, and GRP78 confirmed the proteomic findings. The proteins identified from this study, which are related to cell growth and antibody production, can be applied to cell engineering for maximizing the efficacy of the use of glycine betaine combined with hyperosmolality in rCHO cells. PMID- 22252947 TI - Incidence of laryngospasm and bronchospasm in pediatric adenotonsillectomy. AB - OBJECTIVES/HYPOTHESIS: To evaluate and describe airway complications in pediatric adenotonsillectomy. STUDY DESIGN: Retrospective case-control study. METHODS: A chart review of patients that underwent adenotonsillectomy between 2006 and 2010 was performed. Perioperative complications, patient characteristics, and surgeon and anesthesia technique were recorded. RESULTS: A total of 682 charts were reviewed. Eleven cases (1.6%) of laryngospasm were identified: one was preoperative, seven occurred in the operating room postextubation, and three occurred in the recovery area. Four patients were given succinylcholine, one was reintubated, and the other cases were managed conservatively. Mean age of patients with laryngospasm was 5.87 years (standard deviation [SD], 4.01; 1.9 15.8 years). There were 12 cases (1.8%) of bronchospasm; all were treated with nebulized albuterol. Mean age of patients with bronchospasm was 5.81 years (SD, 4.17; 1.8-14.1 years). Overall, 22 patients required antiemetics (3.3%), 19 required albuterol (2.9%), and five required racemic epinephrine (0.8%). Compared to the children without airway complications, there was no difference in age, weight, American Society of Anesthesiologists status, length of surgery, need for admission, and anesthesia technique in those that had laryngospasm. Patients with bronchospasm, compared to the patients without complications, had faster surgeries (P < .05), were more likely to have underlying asthma (P < .05), and were more likely to be admitted (P < .05). There were no unexpected admissions or other morbidities. CONCLUSIONS: The rates of laryngospasm (1.6%) and bronchospasm (1.8%) are significantly lower than reported in the literature, reflecting refinements in modern anesthesia/surgical technique. Knowledge of at-risk patients can facilitate planning to potentially reduce the incidence of perioperative airway complications during adenotonsillectomy. PMID- 22252948 TI - Editorial. The importance of an evidence-based approach. PMID- 22252949 TI - Agomelatine and the brave old world of narrative-based medicine. PMID- 22252950 TI - Comment on risk assessment: predicting violence. PMID- 22252952 TI - Mortality gap between people with schizophrenia or bipolar disorder and the general population persists in England. PMID- 22252955 TI - Glycopeptidolipids: immuno-modulators in greasy mycobacterial cell envelope. AB - Species of opportunistic mycobacteria are the major causative agent for disseminating pulmonary infections in immuno-compromised individuals. These naturally resistant strains recruit a unique type of glycolipid known as glycopeptidolipids (GPLs), noncovalently attached to the outer surface of their thick lipid rich cell envelope. Species specific GPLs constitute the chemical determinants of most nontuberculous mycobacterial serotypes, and their absence from the cell surface confers altered colony morphology, hydrophobicity, and inability to grow as biofilms. The objective of this review is to present a comprehensive account and highlight the renewed interest on this much neglected group of pleiotropic molecules with respect to their structural diversity and biosynthesis. In addition, the role of GPLs in mycobacterial survival, both intracellular and in the environment is also discussed. It also explores the possibility of identifying new targets for intervening Mycobacterium avium complex-related infections. These antigenic molecules have been considered to play a pivotal role in immune suppression and can also induce various cytokine mediated innate immune responses, the molecular mechanism of which remains obscure. PMID- 22252956 TI - Clinical trial of regeneration of aged vocal folds with growth factor therapy. AB - OBJECTIVES/HYPOTHESIS: Aged vocal folds are characterized by atrophy of the mucosa, which causes mucosal wave deficiency and glottal insufficiency. This clinical trial examined the regenerative effects and safety considerations of basic fibroblast growth factor (bFGF) on restoration of aged vocal folds. STUDY DESIGN: Institutional review board-approved human clinical trial. METHODS: Ten patients (6 men and 4 women; mean age, 70.1 years) were recruited in the trial. Ten micrograms of bFGF was injected into each treated vocal fold. Injection was performed unilaterally or bilaterally according to each patient's need and repeated up to seven times if necessary. Patient follow-up continued for at least 6 months. The effectiveness of the treatment was assessed by stroboscopic, acoustic, and aerodynamic measurements. RESULTS: All patients showed improvement of voice. Significant improvements in maximum phonation time, mean flow rate, jitter, shimmer, and noise-to-harmonic ratio lasted for at least 1 year. No allergic or long-term adverse effects were noted. CONCLUSIONS: This clinical trial suggests that bFGF may be effective and safe as a regenerative agent for aged vocal folds. PMID- 22252957 TI - Sonographic findings in a fatal case of transient myeloproliferative disorder. AB - Transient myeloproliferative disorder is a unique disease in infants with Down syndrome that typically resolves spontaneously. In this report, we present a fatal case of transient myeloproliferative disorder with unusual sonographic findings including adrenal gland enlargement and thickening of the corpus callosum. PMID- 22252958 TI - beta-Cyclodextrin-platinum nanoparticles/graphene nanohybrids: enhanced sensitivity for electrochemical detection of naphthol isomers. AB - Naphthol isomers, including alpha-naphthol (alpha-NAP) and beta-naphthol (beta NAP), are used widely in various fields and are harmful to the environment and human health. The qualitative and quantitative determination of naphthol isomers is therefore of great significance. Herein, beta-cyclodextrin (beta-CD)-platinum nanoparticles (Pt NPs)/graphene nanosheets (GNs) nanohybrids (beta-CD-PtNPs/GNs) were prepared for the first time using a simple wet chemical method and characterized by atomic force microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and electrochemical methods, and then applied successfully in the ultrasensitive electrochemical detection of naphthol isomers. The results show that the oxidation peak currents of naphthol isomers obtained at the glassy carbon (GC) electrode modified with beta-CD-PtNPs/GNs are much higher than those at the beta-CD/GNs/GC, PtNPs/GNs/GC, GNs/GC, and bare GC electrodes. Additionally, compared with other electrochemical sensors developed previously, the proposed electrode results in improved detection limits of about one order of magnitude for alpha-NAP (0.23 nM) and three orders of magnitude for beta -NAP (0.37 nM). PMID- 22252959 TI - Ultrastructure of the larval eye of the scorpionfly Panorpa dubia (Mecoptera: Panorpidae) with implications for the evolutionary origin of holometabolous larvae. AB - The evolutionary origin of holometabolous larvae is a long-standing and controversial issue. The Mecoptera are unique in Holometabola for their larvae possessing a pair of compound eyes instead of stemmata. The ultrastructure of the larval eyes of the scorpionfly Panorpa dubia Chou and Wang, 1981 was investigated using transmission electron microscopy. Each ommatidium possesses a cornea, a tetrapartite eucone crystalline cone, eight retinula cells, two primary pigment cells, and an undetermined number of secondary pigment cells. The rhabdomeres of the eight retinula cells form a centrally-fused, tiered rhabdom of four distal and four proximal retinula cells. The rhabdomeres of the four distal retinula cells extend distally into a funnel shape around the basal surface of the crystalline cone. Based on the similarity of the larval eyes of Panorpidae to the eyes of the hemimetabolous insects and the difference from the stemmata of the holometabolous larvae, the evolutionary origin of the holometabolous larvae is briefly discussed. PMID- 22252960 TI - Changing paradigms in frontal sinus cerebrospinal fluid leak repair. AB - BACKGROUND: Frontal sinus cerebrospinal fluid (CSF) leaks have traditionally been repaired via open procedures (eg, osteoplastic flap or cranialization). Advancements in instrumentation, technique, and experience have improved the feasibility of repairing frontal sinus skull-base defects using an endoscopic approach. This study describes endoscopic closure of frontal sinus CSF leaks focusing on management, surgical technique, and outcomes. METHODS: Prospective evaluation of patients with skull-base defects involving the frontal sinus was performed. Demographics, size of skull-base defect, length involving the posterior table, successful closure, frontal sinus patency, and complications were recorded. RESULTS: Over 3.5 years, 37 patients (average age 46 years) were treated for CSF leaks involving the frontal sinus by a single otolaryngologist. Etiologies included spontaneous (13), tumor (13), and trauma (11). Average defect size (length vs width) was 16.9 mm * 10.7 mm and average length involving the posterior table was 6.9 mm (range, 1-30 mm). Success rate on first attempt was 91.9% (34/37), but improved to 97.3% on subsequent endoscopic revision. One patient required a cranialization. The average follow-up was 48 weeks. The nasoseptal flap was used for reconstruction in 27 patients. A Draf III procedure (ie, bilateral resection of the frontal sinus floor) was required in 14 subjects. Three patients were referred as a result of unsuccessful closure following cranializations; their CSF leaks were successfully repaired using endoscopic approaches. Two individuals required a subsequent endoscopic frontal sinus procedure, but have maintained long-term patency following revision. CONCLUSION: Frontal sinus CSF leaks were successfully closed in 97.3% of individuals. Our data supports the routine use of endoscopic repair in the treatment algorithm for frontal sinus skull-base defects. PMID- 22252961 TI - Assessing disease severity in Pompe disease: the roles of a urinary glucose tetrasaccharide biomarker and imaging techniques. AB - Defining disease severity in patients with Pompe disease is important for prognosis and monitoring the response to therapies. Current approaches include qualitative and quantitative assessments of the disease burden, and clinical measures of the impact of the disease on affected systems. The aims of this manuscript were to review a noninvasive urinary glucose tetrasaccharide biomarker of glycogen storage, and to discuss advances in imaging techniques for determining the disease burden in Pompe disease. The glucose tetrasaccharide, Glcalpha1-6Glcalpha1-4Glcalpha1-4Glc (Glc(4) ), is a glycogen-derived limit dextrin that correlates with the extent of glycogen accumulation in skeletal muscle. As such, it is more useful than traditional biomarkers of tissue damage, such as CK and AST, for monitoring the response to enzyme replacement therapy in patients with Pompe disease. Glc(4) is also useful as an adjunctive diagnostic test for Pompe disease when performed in conjunction with acid alpha-glucosidase activity measurements. Review of clinical records of 208 patients evaluated for Pompe disease by this approach showed Glc(4) had 94% sensitivity and 84% specificity for Pompe disease. We propose Glc(4) is useful as an overall measure of disease burden, but does not provide information on the location and distribution of excess glycogen accumulation. In this manuscript we also review magnetic resonance spectroscopy and imaging techniques as alternative, noninvasive tools for quantifying glycogen and detailing changes, such as fibrofatty muscle degeneration, in specific muscle groups in Pompe disease. These techniques show promise as a means of monitoring disease progression and the response to treatment in Pompe disease. (c) 2012 Wiley Periodicals, Inc. PMID- 22252962 TI - Preoperative imaging and surgical margins in maxillectomy patients. AB - BACKGROUND: High rates of positive surgical margins are reported after a maxillectomy. A large part of tumors that are preoperatively considered "operable" can thus not be resected with tumor-free margins. METHODS: This was a retrospective study on medical files of 69 patients that underwent maxillectomy as primary treatment for a squamous cell carcinoma. RESULTS: More than one third (39%) of all resections performed is incomplete, with dorsal or dorsocranial positive surgical margins in two thirds. Correlation of tumor extension on preoperative imaging to surgical margins status revealed that dorsal and cranial tumor extension were significant prognostic factors for tumor positive surgical margins (p = .006 and p = .031, respectively). Positive margins were associated with a 2-fold increased risk of death (hazard ratio, 2.4; 95% confidence interval, 1.2-4.9). CONCLUSION: Cranial or dorsal tumor extension on preoperative imaging was a significant risk factor for positive surgical margins after maxillectomy with significant negative influence on overall survival. PMID- 22252963 TI - A cost-effectiveness analysis of positron emission tomography-computed tomography surveillance versus up-front neck dissection for management of the neck for N2 disease after chemoradiotherapy. AB - OBJECTIVES/HYPOTHESIS: To study the cost effectiveness of positron emission tomography-computerized tomography (PET-CT) scanning in the management of the neck after chemoradiotherapy (CRT). STUDY DESIGN: Cost effectiveness and decision analysis model. METHODS: A cost-effectiveness analysis comparing up-front neck dissection to serial PET-CT imaging in a hypothetical clinical scenario of debate. A patient with an oropharygeal cancer with pretreatment N2 disease having a complete response was considered. Standardized costs were obtained using national databases. A literature review in PubMed was performed to obtain information on incidence, probabilities, and range for various clinical events in the algorithm. RESULTS: PET-CT strategy costs an average of $14,492 per patient. Neck dissection had a 0.6% greater efficacy in controlling neck disease with a $22,433 incremental cost. CONCLUSIONS: Our results strongly support the use of PET-CT imaging as the more cost-effective strategy for surveillance of neck after completion of definitive CRT compared to up-front neck dissection. PMID- 22252964 TI - Suicidal thoughts and behaviors in older adults in rural China: a preliminary study. AB - BACKGROUND: One purpose of this study was to examine the feasibility of conducting epidemiological survey on suicidal thoughts and behaviors (hereafter "suicidal thoughts/behaviors"; i.e., any suicidal ideation, serious ideation, planning, and attempts) among older adults in rural China. Another purpose was to investigate among older people in rural China the prevalence of suicidal thoughts/behaviors, as well as their sociodemographic and clinical correlates. METHODS: A randomly selected sample of 263 subjects, 50 years or older, was recruited in a remote rural area of Southwestern China (Mianyang Region, Sichuan Province) and interviewed using structured instruments. Basic sociodemographic and clinical data were collected. RESULTS: There was no refusal among approached subjects, and subjects were willing to answer questions on suicidal thoughts/behaviors. The lifetime prevalence of suicidal ideation, serious ideation, planning, and attempt was 28.9% (23.4%-34.4%), 19.7% (14.9%-24.6%), 11.4% (7.5%-15.3%), and 5.3% (2.6%-8.1%), respectively. The corresponding 12 month prevalence was 8.8% (5.3%-12.2%), 5.3% (2.6%-8.1%), 2.7% (0.7%-4.6%), and 0%, respectively. The 2-week prevalence was 3.4% (1.2%-5.6%), 2.3% (0.5%-4.1%), 2.3% (0.5%-4.1%), and 0%, respectively. Correlates of suicidal thoughts/behaviors of this group are similar to findings from other community studies, such as female gender, unmarried status, major medical conditions, insomnia, financial difficulties and lower education, depressive symptoms, recent stressful life events, greater life dissatisfaction. CONCLUSIONS: Our findings suggest that larger scale epidemiological survey of suicidal thoughts/behaviors on older adults in rural China would be feasible. Suicidal thoughts/behaviors are common among older people in rural China, as seen in this preliminary study, which points to the need for further larger scale investigations. PMID- 22252965 TI - Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. AB - The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, and the acquisition of new genetic aberrations or non genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCI and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDC were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridization (aCGH) and Sequenom MassARRAY (Oncocarta v 1.0 panel). Fluorescence in situ hybridization and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively. Although the genomic profiles of matched DCI and IDCs were similar, in three of 13 matched pairs amplification of distinct loci (ie 1q41, 2q24.2, 6q22.31, 7q11.21, 8q21.2 and 9p13.3) was either restricted to, or more prevalent in, the modal population of cancer cells of one of the components. Sequenom MassARRAY identified PIK3CA mutations restricted to the DCIS component in two cases, and in a third case the frequency of the PIK3CA mutant allele reduced from 49% in the DCIS to 25% in the IDC component. Despite the genomic similarities between synchronous DCIS and IDC, our data provide strong circumstantial evidence to suggest that in some cases the progression from DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations. PMID- 22252967 TI - The granule size distribution in an anammox-based granular sludge reactor affects the conversion--implications for modeling. AB - Mathematical models are useful tools to optimize the performance of granular sludge reactors. In these models, typically a uniform granule size is assumed for the whole reactor, even though in reality the granules follow a size distribution and the granule size as such affects the process performance. This study assesses the effect of the granule size distribution on the performance of a granular sludge reactor in which autotrophic nitrogen removal is realized through one stage partial nitritation-anammox. A comparison is made between different approaches to deal with particle size distributions in one-dimensional biofilm models, from the use of a single characteristic diameter to applying a multiple compartment model. The results show a clear impact on the conversion efficiency of the way in which particle size distribution is modeled, resulting from the effect of the granule size on the competition between nitrite oxidizing and anammox bacteria and from the interaction between granules of different sizes in terms of the exchange of solutes. Whereas the use of a uniform granule size is sufficient in case only the overall reactor behavior needs to be assessed, taking into account the detailed granule size distribution is required to study the solute exchange between particles of different sizes. For the latter purpose, the application of the widespread software package Aquasim is limited and the development of dedicated software applications is required. PMID- 22252966 TI - Associations among physical activity, body mass index, and health-related quality of life by race/ethnicity in a diverse sample of breast cancer survivors. AB - BACKGROUND: Health-related quality of life (HRQOL), body mass index (BMI), and physical activity (PA) levels have all been associated with prognosis following breast cancer and may explain partially the higher mortality for breast cancer in certain racial/ethnic subgroups. In this study, associations between PA, BMI, and HRQOL by race were examined in a sample of breast cancer survivors. METHODS: Measures of PA, BMI, and HRQOL as well as demographic and medical characteristics of women (N = 3013, 13% nonwhite) who participated in the Women's Healthy Eating and Living Study were assessed at baseline. Analysis of covariance was used to examine the relationship between PA and obesity with HRQOL outcomes. Statistical tests were 2-sided. RESULTS: African American women were less likely to meet guidelines for PA and more likely to be obese than women from other ethnic groups (P < .05). In adjusted models, women who met guidelines for PA reported significantly higher physical health composite (point differences ranged from 10.5 to 21.2 points, all P < .05) and vitality (point differences ranged from 9.9 to 16.5 points, all P < .05) scores than those who did not, regardless of race/ethnicity. Associations between obesity and HRQOL were mixed with fewer associations for Asian American and African American women and stronger associations for whites. CONCLUSIONS: Breast cancer survivors from racially and ethnically diverse populations have lower levels of PA and higher rates of obesity that are generally associated with poorer HRQOL. Culturally sensitive PA and weight loss interventions may improve these lifestyle characteristics and result in improved HRQOL. PMID- 22252968 TI - Detection of intracochlear damage during cochlear implant electrode insertion using extracochlear measurements in the gerbil. AB - OBJECTIVES/HYPOTHESIS: An intraoperative monitoring algorithm during cochlear implant electrode insertion could be used to detect trauma and guide electrode placement relative to surviving hair cells. The aim of this report was to assess the feasibility of using extracochlear recording sites to monitor acoustically evoked responses from surviving hair cells and neural elements during implantation in an animal model. STUDY DESIGN: Animal experiments. METHODS: The normal-hearing gerbil was used. Two recording methods, one using a lock-in amplifier and another using Fourier analysis of recorded signals, were used to obtain frequency-specific information about the responses to tones. Amplitude and threshold determinations were made at the round window and at three extracochlear sites. To induce intracochlear damage, a platinum-iridium wire was inserted through the round window. The wire was advanced, and changes in the potentials were correlated with cochlear contact. Anatomic integrity was assessed using cochlea whole mount preparations. RESULTS: In general, the lock-in amplifier showed greater sensitivity and lower thresholds at higher frequencies relative to the Fourier method. Also, the lock-in amplifier was more resistant to masking effects. Both systems were able to detect loss of cochlear potentials secondary to intracochlear trauma. Histologic damage was seen in all cases and corresponded to electrophysiologic changes. CONCLUSIONS: Impact of electrodes on cochlear structures affecting cochlear performance could be detected from several extracochlear sites. The lock-in amplifier demonstrated greater sensitivity and resistance to noise when compared to the fast Fourier transform recording paradigm. The latter showed greater flexibility of detecting and separating hair cell and neural potentials. PMID- 22252969 TI - Rapid and stereochemically flexible synthesis of polypropionates: super-silyl governed aldol cascades. PMID- 22252970 TI - Endonasal endoscopic exposure of the internal carotid artery: an anatomical study. AB - OBJECTIVES/HYPOTHESIS: The aim of this work was to define the anatomical landmarks, limitations, and difficulties of obtaining internal carotid artery (ICA) exposure via endonasal endoscopic approaches (EEA). STUDY DESIGN: Cadaveric descriptive study. METHODS: The ICA was dissected via EEA in 10 cadaveric specimens (20 sides) prepared with intravascular injections of colored silicone. We carried the ICA dissection from the cavernous to the distal parapharyngeal segments through a transpterygoid corridor. RESULTS: The transpterygoid approach provided adequate exposure of the lacerum and horizontal petrous ICA. Additional exposure of the ICA and the infrapetrous area required resection of the eustachian tube (ET) and the fibrocartilaginous tissue of the foramen lacerum after a medial maxillectomy and resection of the pterygoid plates. The main anatomical landmarks to the corresponding ICA segment include: the vidian nerve that points to the lacerum and horizontal segments, the mandibular nerve (V3) that heralds the petrous segment, the foramen ovale and the ET that signal toward the carotid canal, and the posterior trunk of the mandibular nerve (V3) and the ET that mark the parapharyngeal segment. CONCLUSIONS: EEAs provide access to the ICA from its cavernous to the distal parapharyngeal segments. A stepwise approach is critical to its exposure and control. Surgeons must be aware of its frequently tortuous three-dimensional course and the intimate relation of the vessel to the carotid canal and the cartilage of the foramen lacerum. PMID- 22252972 TI - Controlled synthesis of uniform and monodisperse upconversion core/mesoporous silica shell nanocomposites for bimodal imaging. AB - Here we report the design and controlled synthesis of monodisperse and precisely size-controllable UCNP@mSiO(2) nanocomposites smaller than 50 nm by directly coating a mesoporous silica shell (mSiO(2)) on upconversion nanocrystals NaYF(4):Tm/Yb/Gd (UCNPs), which can be used as near-infrared fluorescence and magnetic resonance imaging (MRI) agents and a platform for drug delivery as well. Some key steps such as transferring hydrophobic UCNPs to the water phase by using cetyltrimethylammonium bromide (CTAB), removal of the excess amount of CTAB, and temperature-controlled ultrasonication treatment should be adopted and carefully monitored to obtain uniform upconversion core/mesoporous silica shell nanocomposites. The excellent performance of the core-shell-structured nanocomposite in near-infrared fluorescence and magnetic resonance imaging was also demonstrated. PMID- 22252971 TI - Biological effects of the plant-derived polyphenol resveratrol in human articular cartilage and chondrosarcoma cells. AB - The natural phytoestrogen resveratrol (RSV) may have therapeutic potential for arthritic conditions. RSV is chondroprotective for articular cartilage in rabbit models for arthritis, but its biological effects on human articular cartilage and chondrosarcoma cells are unknown. Effects of RSV on human articular cartilage homeostasis were studied by assessing production of matrix-degrading enzymes (MMP 13, ADAMTS4, and ADAMTS5), as well as proteoglycan production and synthesis. The counteractions of RSV against catabolic factors (e.g., FGF-2 or IL-1beta) were examined by in vitro and ex vivo using monolayer, three-dimensional alginate beads and cartilage explants cultures, respectively. RSV improves cell viability of articular chondrocytes and effectively antagonizes cartilage-degrading protease production that was initiated by catabolic and/or anti-anabolic cytokines in human articular chondrocytes. RSV significantly also enhances BMP7 promoted proteoglycan synthesis as assessed by (35) S-sulfate incorporation. Protein-DNA interaction arrays suggest that RSV inhibits the activation of transcription factors involved in inflammation and cartilage catabolic signaling pathways, including direct downstream regulators of MAPK (e.g., AP-1, PEA3) and NFkappaB. RSV selectively compromises survival of human chondrosarcoma cells, but not primary articular chondrocytes, revealing cell-specific activity of RSV on non-tumorigenic versus tumor-derived cells. We propose that RSV exerts its chondroprotective functions, in part, by deactivating p53-induced apoptosis in human primary chondrocytes, but not human chondrosarcoma. Our findings suggest that RSV has potential as a unique biologic treatment for both prevention and treatment of cartilage degenerative diseases. PMID- 22252973 TI - Two- and three-dimensional sonographic diagnosis of fetal intra-abdominal umbilical vein varix: a case report. AB - Fetal intra-abdominal umbilical vein varix is a rare condition characterized by focal dilatation of the umbilical vein of the fetus. We report a case of fetal intra-abdominal umbilical vein varix associated with additional sonographic abnormalities and detected at 31 weeks' gestation. Several follow-up sonographic examinations were performed, and the prenatal findings were confirmed on postnatal ultrasound. The diagnosis was facilitated by the use of three dimensional power Doppler sonography. PMID- 22252974 TI - Saccular cysts: a current review of characteristics and management. AB - OBJECTIVES/HYPOTHESIS: To review a large cohort of adult saccular cyst patients and update current management of saccular cysts. STUDY DESIGN: Retrospective review of treatment of adult patients with saccular cysts. METHODS: Medical records were reviewed of all adult patients with saccular cysts identified between July 1, 2005 and August 31, 2009 at a tertiary care voice center. RESULTS: Sixteen patients were identified. All complained of dysphonia. Saccular cysts were predominantly left-sided (62.5%). The majority were anterior (85.7%); 14.3% were combined anterior/lateral. There were no isolated lateral saccular cysts. Surgical intervention was performed in 13 patients (81%); 100% were endoscopic. No patient required an external approach. Two patients recurred (15%), both within 2 months, and were managed conservatively. CONCLUSIONS: Saccular cyst is uncommonly encountered but can cause debilitating or even life threatening symptoms. Over time, management of these lesions has changed dramatically. With current, improved endoscopic techniques, most saccular cysts can be managed endoscopically with great success rates, often without the need for an external approach. PMID- 22252975 TI - The recombinant kringle domain of urokinase plasminogen activator inhibits VEGF165-induced angiogenesis of HUVECs by suppressing VEGFR2 dimerization and subsequent signal transduction. AB - The recombinant kringle domain (UK1) of urokinase plasminogen activator was previously reported to exert antiangiogenic activity against Vascular Endothelial Growth Factor (VEGF)-induced angiogenesis in both in vitro and in vivo models. In this study, we explored the molecular signaling mechanisms involved in the antiangiogenic activity of UK1 by examining VEGF signaling proteins. VEGF165 stimulates the phosphorylation of VEGF signaling molecules, and pretreatment with UK1 blocked VEGF-induced signal transduction associated with proliferation, survival, and migration. UK1 also suppressed VEGF165-induced activation of MMP-2. Moreover, UK1 suppressed the phosphorylation and activation of VEGFR2 in VEGF stimulated human umbilical cord vein endothelial cells (HUVECs) by blocking the dimerization of VEGFR2. Overall, our findings suggest that UK1 inhibits VEGF induced proliferation, migration, and matrix metalloproteinase activity of HUVECs by suppressing VEGFR2 dimerization and subsequent angiogenic signals. PMID- 22252976 TI - New perspectives on collagen fibers in the squid mantle. AB - The squid mantle is a complex structure which, in conjunction with a highly sensitive sensory system, provides squid with a wide variety of highly controlled movements. This article presents a model describing systems of collagen fibers that give the mantle its shape and mechanical properties. The validity of the model is verified by comparing predicted optimal fiber angles to actual fiber angles seen in squid mantle. The model predicts optimal configurations for multiple fiber systems. It is found that the tunic fibers (outer collagen layers) provide optimal jetting characteristics when oriented at 31 degrees , which matches empirical data from previous studies. The model also predicted that a set of intramuscular fibers (IM-1) are oriented relative to the longitudinal axis to provide optimal energy storage capacity within the limiting physical bounds of the collagen fibers themselves. In addition, reasons for deviations from the predicted values are analyzed. This study illustrates how the squid's reinforcing collagen fibers are aligned to provide several locomotory advantages and demonstrates how this complex biological process can be accurately modeled with several simplifying assumptions. PMID- 22252977 TI - Cost analysis of office-based and operating room procedures in rhinology. AB - BACKGROUND: Analyses of office-based procedures in laryngology and otology have shown them to be safe and satisfying for patients, with substantial savings of time and money for patients and physicians. The objectives of this study were to compare the billable charges and reimbursement for rhinologic procedures performed in the office with charges for procedures performed in an ambulatory surgery center operating room (OR). METHODS: A retrospective, matched-pair cost analysis was performed. Patients who underwent office-based procedures between 2006 and 2011 were matched by Current Procedural Terminology(r) (CPT) code with patients who underwent similar procedures in the OR. Twenty-nine matched pairs were included. Charges for surgery, anesthesia, and facility usage were analyzed. Because surgery charges may be influenced by contracts with insurance providers, both the total billed charges and total allowed charges were analyzed using paired t tests. When a single office-based procedure was compared with multiple procedures performed during the same operation in the OR, anesthesia and facility charges were scaled to allow for more accurate comparison. RESULTS: Mean total charges for office-based procedures were significantly less than for OR procedures ($2,737.17 vs $7,329.69, p < 0.001). Mean allowed charges for office based procedures were significantly less than for OR procedures ($762.08 vs $5,835.09, p < 0.001). Mean scaled charges for office-based procedures were also significantly less than mean scaled charges for OR procedures ($762.08 vs $4,089.33, p < 0.001). Office procedures were reimbursed at similar or higher rates than were OR procedures. CONCLUSION: In appropriate patients, performing simple rhinologic procedures in the office rather than in the OR offers significant cost savings without impacting physician reimbursement. PMID- 22252978 TI - Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. AB - Age-related memory loss is considered to commence at middle-age and coincides with reduced adult hippocampal neurogenesis and neurotrophin levels. Consistent physical activity at midlife may preserve brain-derived neurotrophic factor (BDNF) levels, new cell genesis, and learning. In the present study, 9-month-old female C57Bl/6J mice were housed with or without a running wheel and injected with bromodeoxyuridine (BrdU) to label newborn cells. Morris water maze learning, open field activity and rotarod behavior were tested 1 and 6 months after exercise onset. Here we show that long-term running improved retention of spatial memory and modestly enhanced rotarod performance at 15 months of age. Both hippocampal neurogenesis and mature BDNF peptide levels were elevated after long term running. Thus, regular exercise from the onset and during middle-age may maintain brain function. PMID- 22252979 TI - In reference to Cost analysis of asymmetric sensorineural hearing loss investigations. PMID- 22252980 TI - Mortality and causes of death in older patients with schizophrenia. AB - OBJECTIVE: The aim of this study was to evaluate mortality and causes of death in older patients with schizophrenia in comparison with the general population. The mortality of patients experiencing relapse was also compared with those in remission. METHODS: The study sample consists of patients (n = 9461) over 65 years by the first of January 1999, with schizophrenia or schizoaffective disorder (ICD-8, ICD-9: 295, ICD-10: F20, F25) as the main register diagnosis during the period 1969-1998. The sample was collected from nationwide registers in Finland and followed up between 1999 and 2008. RESULTS: Overall Standard Mortality Ratio (SMR) of the older schizophrenia patients was 2.69 [95% confidence interval, 2.62-2.76]. For natural causes of death, overall SMR was 2.58 (2.51-2.65; n = 5301), and for unnatural causes of death, it was 11.04 (9.75 12.47; n = 262). The most common causes of death matched those in the general population. Of patients who died during follow-up, 31% (1709/5596) had at least one psychiatric hospitalization within 5 years before follow-up. The SMR for this group was higher (3.92; 3.73-4.11) than in those patients (2.37; 2.29-2.44) with no such treatment during that time. CONCLUSION: All-cause mortality of older patients with schizophrenia was almost threefold that of general population. They died for similar reasons to the general population; however, deaths for unnatural causes were especially common (accidents and suicides). Those patients still experiencing relapses in older age have an increased risk of death compared with those with schizophrenia in remission. PMID- 22252981 TI - Comorbid predictors of poor response to chemoradiotherapy for laryngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: To investigate whether a correlation exists between medical comorbidities and disease control following primary therapy of laryngeal squamous cell carcinoma. STUDY DESIGN: Retrospective medical record review. METHODS: A retrospective chart review was performed on patients diagnosed with laryngeal carcinoma between 1997 and 2011. The Adult Comorbidity Evaluation 27 (ACE 27) index was used to evaluate severity of comorbid health. Ten-year disease free survival rates and median disease-free intervals were calculated, and significant associations between disease recurrence and comorbid factors were determined using the log-rank test. Independent significant risk factors for disease recurrence were determined with the Cox proportional hazard regression model. RESULTS: Of the 181 patients identified, 121 were treated nonsurgically with either primary radiotherapy (XRT) (49%) or chemoradiotherapy (CRT) (51%). Sixty patients (50%) experienced recurrence of their disease. The 10-year disease free survival rate was 23.8%, and the median disease-free survival was 58 months (95% confidence interval, 12-108 months). Factors observed to be significantly associated with recurrence within 10 years after treatment were renal disease (P < .01), pulmonary disease (P < .01), malnutrition (P < .01), T size (P < .01), stage (P = .02), and ACE 27 Index (P < .01). Independent significant risk factors for recurrence were malnutrition (P < .01), T stage (P = .01), and ACE 27 (P < .01). Adjusted hazard ratios were 1.43 for T stage, 2.58 for ACE 27, and 2.15 for malnutrition. CONCLUSIONS: The results of this study demonstrate that there is a significant association between increased comorbidity and recurrent disease in laryngeal carcinoma treated with XRT/CRT. The consideration of comorbid health in primary treatment planning may improve the success and survival of patients with laryngeal squamous cell carcinoma. PMID- 22252982 TI - Solid-state vitrification of crystalline griseofulvin by mechanical milling. AB - The thermodynamic, dynamic, and structural changes of crystalline griseofulvin upon high-energy ball milling at room temperature have been studied. The investigations have been performed by differential scanning calorimetry (DSC), dielectric relaxation spectroscopy, and powder X-ray diffraction. The results indicate that this compound undergoes a direct crystal-to-glass transformation upon milling, whereas no glass transition can be clearly detected upon heating because of the exceptional sub-glass transition temperature (T(g) ) recrystallization of the milled sample. This intrinsic difficulty for characterizing the glassy state has been overcome using three independent strategies: (i) comparison of the evolutions upon milling of both the crystalline powder and the quenched liquid, (ii) use of fast DSC to delay the recrystallization event, and (iii) search for dielectric beta relaxations typical of glasses in the milled compound. PMID- 22252983 TI - Transformative binding and release of gold guests from a self-assembled Cu8L4 tube. PMID- 22252984 TI - Scientific discovery as a combinatorial optimisation problem: how best to navigate the landscape of possible experiments? AB - A considerable number of areas of bioscience, including gene and drug discovery, metabolic engineering for the biotechnological improvement of organisms, and the processes of natural and directed evolution, are best viewed in terms of a 'landscape' representing a large search space of possible solutions or experiments populated by a considerably smaller number of actual solutions that then emerge. This is what makes these problems 'hard', but as such these are to be seen as combinatorial optimisation problems that are best attacked by heuristic methods known from that field. Such landscapes, which may also represent or include multiple objectives, are effectively modelled in silico, with modern active learning algorithms such as those based on Darwinian evolution providing guidance, using existing knowledge, as to what is the 'best' experiment to do next. An awareness, and the application, of these methods can thereby enhance the scientific discovery process considerably. This analysis fits comfortably with an emerging epistemology that sees scientific reasoning, the search for solutions, and scientific discovery as Bayesian processes. PMID- 22252985 TI - Hexafluoroisopropanol induces self-assembly of beta-amyloid peptides into highly ordered nanostructures. AB - Deposition of insoluble fibrillar aggregates of beta-amyloid (Abeta) peptides in the brain is a hallmark of Alzheimer's disease. Apart from forming fibrils, these peptides also exist as soluble aggregates. Fibrillar and a variety of nonfibrillar aggregates of Abeta have also been obtained in vitro. Hexafluoroisopropanol (HFIP) has been widely used to dissolve Abeta and other amyloidogenic peptides. In this study, we show that the dissolution of Abeta40, 42, and 43 in HFIP followed by drying results in highly ordered aggregates. Although alpha-helical conformation is observed, it is not stable for prolonged periods. Drying after prolonged incubation of Abeta40, 42, and 43 peptides in HFIP leads to structural transition from alpha-helical to beta-conformation. The peptides form short fibrous aggregates that further assemble giving rise to highly ordered ring-like structures. Abeta16-22, a highly amyloidogenic peptide stretch from Abeta, also formed very similar rings when dissolved in HFIP and dried. HFIP could not induce alpha-helical conformation in Abeta16-22, and rings were obtained from freshly dissolved peptide. The rings formed by Abeta40, 42, 43, and Abeta16-22 are composed of the peptides in beta-conformation and cause enhancement in thioflavin T fluorescence, suggesting that the molecular architecture of these structures is amyloid-like. Our results clearly indicate that dissolution of Abeta40, 42 and 43 and the amyloidogenic fragment Abeta16-22 in HFIP results in the formation of annular amyloid-like structures. PMID- 22252986 TI - GABAergic contributions to gating, timing, and phase precession of hippocampal neuronal activity during theta oscillations. AB - Successful spatial exploration requires gating, storage, and retrieval of spatial memories in the correct order. The hippocampus is known to play an important role in the temporal organization of spatial information. Temporally ordered spatial memories are encoded and retrieved by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta oscillations paced by intra- and extrahippocampal areas. Much is known about the anatomical, physiological, and molecular characteristics as well as the connectivity and synaptic properties of various cell types in the hippocampal microcircuits, but how these detailed properties of individual neurons give rise to temporal organization of spatial memories remains unclear. We present a model of the hippocampal CA1 microcircuit based on observed biophysical properties of pyramidal cells and six types of inhibitory interneurons: axo-axonic, basket, bistratistified, neurogliaform, ivy, and oriens lacunosum-moleculare cells. The model simulates a virtual rat running on a linear track. Excitatory transient inputs come from the entorhinal cortex (EC) and the CA3 Schaffer collaterals and impinge on both the pyramidal cells and inhibitory interneurons, whereas inhibitory inputs from the medial septum impinge only on the inhibitory interneurons. Dopamine operates as a gate-keeper modulating the spatial memory flow to the PC distal dendrites in a frequency-dependent manner. A mechanism for spike-timing-dependent plasticity in distal and proximal PC dendrites consisting of three calcium detectors, which responds to the instantaneous calcium level and its time course in the dendrite, is used to model the plasticity effects. The model simulates the timing of firing of different hippocampal cell types relative to theta oscillations, and proposes functional roles for the different classes of the hippocampal and septal inhibitory interneurons in the correct ordering of spatial memories as well as in the generation and maintenance of theta phase precession of pyramidal cells (place cells) in CA1. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical computations in the hippocampus and medial septum. PMID- 22252987 TI - Involvements of the ABC protein ABCF2 and alpha-actinin-4 in regulation of cell volume and anion channels in human epithelial cells. AB - After osmotic swelling, cell volume is regulated by a process called regulatory volume decrease (RVD). Although actin cytoskeletons are known to play a regulatory role in RVD, it is not clear how actin-binding proteins are involved in the RVD process. In the present study, an involvement of an actin-binding protein, alpha-actinin-4 (ACTN4), in RVD was examined in human epithelial HEK293T cells. Overexpression of ACTN4 significantly facilitated RVD, whereas siRNA mediated downregulation of endogenous ACTN4 suppressed RVD. When the cells were subjected to hypotonic stress, the content of ACTN4 increased in a 100,000 * g pellet, which was sensitive to cytochalasin D pretreatment. Protein overlay assays revealed that ABCF2, a cytosolic member of the ABC transporter superfamily, is a binding partner of ACTN4. The ACTN4-ABCF2 interaction was markedly enhanced by hypotonic stimulation and required the NH(2) -terminal region of ABCF2. Overexpression of ABCF2 suppressed RVD, whereas downregulation of ABCF2 facilitated RVD. We then tested whether ABCF2 has a suppressive effect on the activity of volume-sensitive outwardly rectifying anion channel (VSOR), which is known to mediate Cl(-) efflux involved in RVD, because another ABC transporter member, CFTR, was shown to suppress VSOR activity. Whole-cell VSOR currents were largely reduced by overexpression of ABCF2 and markedly enhanced by siRNA-mediated depletion of ABCF2. Thus, the present study indicates that ACTN4 acts as an enhancer of RVD, whereas ABCF2 acts as a suppressor of VSOR and RVD, and suggests that a swelling-induced interaction between ACTN4 and ABCF2 prevents ABCF2 from suppressing VSOR activity in the human epithelial cells. PMID- 22252988 TI - Current dysphonia trends in patients over the age of 65: is vocal atrophy becoming more prevalent? AB - OBJECTIVES/HYPOTHESIS: The current trends in geriatric voice referrals including the number of patients over the age of 65 years seen per year, the common diagnostic patterns, and specifically the number of patients with vocal atrophy were assessed. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective chart review of all patients seen at the Emory Voice Center for otolaryngologic complaints between the years of 2004 and 2009 was performed. RESULTS: Of the 6,360 patients seen over a 6-year period, 21% were over the age of 65 years. Fifty-eight percent of patients over the age of 65 years had vocal complaints, with the most common diagnoses being vocal atrophy (25%), neurologic vocal dysfunction (23%), and vocal fold immobility (19.2%). Of those patients diagnosed with vocal atrophy, the majority opted for voice therapy (57%), followed by reassurance (39%), and injection laryngoplasty (6%). There was a statistically significant improvement in mean pretherapy and post-therapy voice-related quality of life (VRQOL) score. CONCLUSIONS: As the number of people in the over 65-year old age bracket increases, so do the number of geriatric referrals. Although diagnostic trends remain the same, vocal atrophy is becoming more prevalent, with a large number of patients seeking intervention. This will likely result in an increased need for health resources in the future. PMID- 22252989 TI - Infantile Pompe disease on ERT: update on clinical presentation, musculoskeletal management, and exercise considerations. AB - Enzyme replacement therapy (ERT) with alglucosidase alpha, approved by the FDA in 2006, has expanded possibilities for individuals with Pompe disease (glycogen storage disease type II, GSDII, or acid maltase deficiency). Children with infantile Pompe disease are surviving beyond infancy, some achieving independent walking and functional levels never before possible. Individuals with late-onset Pompe disease are experiencing motor and respiratory improvement and/or stabilization with slower progression of impairments. A new phenotype is emerging for those with infantile Pompe disease treated with ERT. This new phenotype appears to be distinct from the late-onset phenotype rather than a shift from infantile to late-onset phenotype that might be expected from a simple diminution of symptoms with ERT. Questions arise regarding the etiology of the distinct distribution of weakness in this new phenotype, with increasing questions regarding exercise and musculoskeletal management. Answers require an increased understanding of the muscle pathology in Pompe disease, how that muscle pathology may be impacted by ERT, and the potential impact of, and need for, other clinical interventions. This article reviews the current state of knowledge regarding the pathology of muscle involvement in Pompe disease and the potential change in muscle pathology with ERT; the newly emerging musculoskeletal and gross motor phenotype of infantile Pompe disease treated with ERT; updated recommendations regarding musculoskeletal management in Pompe disease, particularly in children now surviving longer with residual weakness impacting development and integrity of the musculoskeletal system; and the potential impact and role of exercise in infantile Pompe survivors treated with ERT. PMID- 22252990 TI - Topographic cues of nano-scale height direct neuronal growth pattern. AB - We study the role of nano-scale cues in controlling neuronal growth. We use photolithography to fabricate substrates with repeatable line-pattern ridges of nano-scale heights. We find that neuronal processes, which are of micron size, have strong interactions with ridges even as low as 10 nm. The interaction between the neuronal process and the ridge leads to a deflection of growth direction and a preferred alignment with the ridges. The interaction strength clearly depends on the ridges' height. For 25 nm ridges approximately half of the neuronal processes are modified, while at 100 nm the majority of neurites change their original growth direction post interaction. In addition, the effect on growth correlates with the incoming angle between the neuronal process and the ridge. We underline the adhesion as a key mechanism in directing neuronal growth. Our study highlights the sensitivity of growing neurites to nano-scale cues thus opens a new avenue of research for pre-designed neuronal growth and circuitry. PMID- 22252991 TI - Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method. AB - BACKGROUND: Several promising molecular-targeted drugs are used for advanced renal cancers. However, complete remission is rarely achieved, because none of the drugs targets a key molecule that is specific to the cancer, or is associated with "oncogene addiction" (dependence on one or a few oncogenes for cell survival) of renal cancer. Recently, an anaplastic lymphoma kinase (ALK) fusion, vinculin-ALK, has been reported in pediatric renal cell carcinoma (RCC) cases who have a history of sickle cell trait. In this context, ALK inhibitor therapy would constitute a therapeutic advance, as has previously been demonstrated with lung cancer, inflammatory myofibroblastic tumors, and anaplastic large cell lymphomas. METHODS: Anti-ALK immunohistochemistry was used to screen 355 tumor tissues, using the intercalated antibody-enhanced polymer (iAEP) method. The cohort consisted of 255 clear cell RCCs, 32 papillary RCCs, 34 chromophobe RCCs, 6 collecting duct carcinomas, 10 unclassified RCCs, 6 sarcomatoid RCCs, and 12 other tumors. RESULTS: Two patients (36- and 53-year-old females) were positive for ALK as determined by iAEP immunohistochemistry. Using 5'- rapid amplification of complementary DNA ends, we detected TPM3-ALK and EML4-ALK in these tumors. The results of this study were confirmed by fluorescence in situ hybridization assays. The 2 ALK-positive RCCs were unclassified (mixed features of papillary, mucinous cribriform, and solid patterns with rhabdoid cells) and papillary subtype. They comprised 2.3% of non-clear cell RCCs (2 of 88) and 3.7% of non clear cell and nonchromophobe RCCs (2 of 54). CONCLUSIONS: The results of this study indicate that ALK fusions also exist in adult RCC cases without uncommon backgrounds. These findings confirm the potential of ALK inhibitor therapy for selected cases of RCC. PMID- 22252992 TI - Assessments of growth conditions on the production of cyanophycin by recombinant Escherichia coli strains expressing cyanophycin synthetase gene. AB - The synthesis of cyanophycin, a biodegradable polymer, is directed by cyanophycin synthetase. Polymerase chain reaction (PCR) cloned the gene cphA coding for cyanophycin synthetase from Synechocystis sp. PCC 6803 into pET-21b followed by transformation into two Escherichia coli hosts. The culture conditions for cyanophycin production were investigated, and the molecular weight and compositions of purified cyanophycin were analyzed. The results showed that E. coli BL21-CodonPlus(DE3)-RIL could produce 120 mg cyanophycin per gram dry cell weight in terrific medium. The purified cyanophycin consisted of insoluble and soluble forms at pH 7. The insoluble form had a higher molecular weight (20-32 kDa) than the soluble form (14-25 kDa). Both forms are composed of three major amino acids, aspartic acid, arginine, and lysine, and the insoluble form showed a higher arginine/lysine molar ratio (4.61 +/- 0.31) than the soluble form (0.89 +/ 0.05). In addition, the nitrogen sources could affect the yields of insoluble and soluble forms of cyanophycin. The medium containing additional lysine could enhance the proportion of the soluble form, but had little effect on the lysine and arginine percentages of both soluble and insoluble forms. The medium containing additional arginine slightly decreased the proportion of soluble form and altered its amino acid composition, with a minimal effect on the lysine and arginine percentages in the insoluble form. PMID- 22252993 TI - The effects of rearing light level and duration differences on the optic nerve, brain, and associated structures in developing zebrafish larvae: a light and transmission electron microscope study. AB - The ultrastructure of the optic nerve, brain, and some associated structures of larval zebrafish, grown under three different light regimens were studied. Fish grown under cyclic light (control), constant dark (CD), and constant light (CL) were studied for 4 and 8 days postfertilization (dpf). We also studied the control and CD fish at 15 dpf. The brains of the control and CL fish were larger at 4 dpf than at 8 dpf. In all 4 dpf fish, the brain occupied the entire expanse between the two retinas and the optic nerve extended the shortest distance between the retina and the brain. The 15 dpf zebrafish had the smallest brain size. Groups of skeletal muscle cells associated with the optic nerves became visible in all older larvae. In the 15 dpf larvae, bulges and dilations in the optic nerve occurred as it reached the brain and optic chiasms occurred proximal to the brain. Electron microscopy yielded information about myelinated and unmyelinated axons in the optic nerve, the dimensions of neurotubules, neurofilaments, and myofilaments, including a unique variation in actin myofilaments, and a confirmation of reported myosin myofilament changes (but with dimensions). We also describe the ultrastructure of a sheath-like structure that is confluent over the optic nerve and the brain, which has not been described before in zebrafish. Also presented are images of associated fibroblasts, epithelial cells lining the mouth, cartilage plates, blood vessels, nerve bundles, and skeletal muscle cells, most of which have not been previously described in the literature. PMID- 22252994 TI - Histology and histochemistry of the gekkotan notochord and their bearing on the development of notochordal cartilage. AB - The persistence of the notochord into the skeletally mature life stage is characteristic of gekkotans, but is otherwise of rare occurrence among amniotes. The taxonomic diversity of Gekkota affords the opportunity to investigate the structure and development of this phylogenetically ancestral component of the skeleton, and to determine its basic characteristics. The gekkotan notochord spans almost the entire postcranial long axis and is characterized by a moniliform morphology with regularly alternating zones of chordoid and chondroid tissue. Chordoid tissue persists in the region of intervertebral articulations and occupies the cavitations that lie between the centra of the amphicoelous vertebrae. Chondroid tissue is restricted to zones in which the diameter of the notochord is reduced, corresponding to mid-vertebral locations. In the tail, these zones of chondroid tissue are associated with the autotomic fracture planes. Chondroid tissue first manifests during late embryogenesis, appears to differentiate from pre-existing chordoid tissue, and has the histological and histochemical characteristics of cartilage. Our observations lend support to the hypothesis that cartilage can be derived directly from notochordal tissue, and suggest that the latter may be an evolutionary and developmental precursor to chordate cartilage. The persistence of chordoid tissue in the intervertebral regions of amphicoelous vertebrae is consistent with a suite of paedomorphic traits exhibited by gekkotans and suggests that the typical hydrostatic nature of notochordal tissue may play a role in mechanically governing patterns of displacement between adjacent amphicoelous vertebrae that lack extensive centrum to-centrum contact. PMID- 22252995 TI - Oscillations in sensorimotor cortex in movement disorders: an electrocorticography study. AB - Movement disorders of basal ganglia origin may arise from abnormalities in synchronized oscillatory activity in a network that includes the basal ganglia, thalamus and motor cortices. In humans, much has been learned from the study of basal ganglia local field potentials recorded from temporarily externalized deep brain stimulator electrodes. These studies have led to the theory that Parkinson's disease has characteristic alterations in the beta frequency band (13 30 Hz) in the basal ganglia-thalamocortical network. However, different disorders have rarely been compared using recordings in the same structure under the same behavioural conditions, limiting straightforward assessment of current hypotheses. To address this, we utilized subdural electrocorticography to study cortical oscillations in the three most common movement disorders: Parkinson's disease, primary dystonia and essential tremor. We recorded local field potentials from the arm area of primary motor and sensory cortices in 31 subjects using strip electrodes placed temporarily during routine surgery for deep brain stimulator placement. We show that: (i) primary motor cortex broadband gamma power is increased in Parkinson's disease compared with the other conditions, both at rest and during a movement task; (ii) primary motor cortex high beta (20 30 Hz) power is increased in Parkinson's disease during the 'stop' phase of a movement task; (iii) the alpha-beta peaks in the motor and sensory cortical power spectra occur at higher frequencies in Parkinson's disease than in the other two disorders; and (iv) patients with dystonia have impaired movement-related beta band desynchronization in primary motor and sensory cortices. The findings support the emerging hypothesis that disease states reflect abnormalities in synchronized oscillatory activity. This is the first study of sensorimotor cortex local field potentials in the three most common movement disorders. PMID- 22252996 TI - Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. AB - Huntington's disease is caused by expression of a mutant form of Huntingtin protein containing an expanded polyglutamine repeat. One possible treatment for Huntington's disease may be to reduce expression of mutant Huntingtin in the brain via RNA interference. Unless the therapeutic molecule is designed to be allele-specific, both wild-type and mutant protein will be suppressed by an RNA interference treatment. A key question is whether suppression of wild-type as well as mutant Huntingtin in targeted brain regions can be tolerated and result in a net benefit to patients with Huntington's disease. Whether Huntingtin performs essential functions in the adult brain is unclear. Here, we tested the hypothesis that the adult primate brain can tolerate moderately reduced levels of wild-type Huntingtin protein for an extended period of time. A serotype 2 adeno associated viral vector encoding for a short hairpin RNA targeting rhesus huntingtin messenger RNA (active vector) was bilaterally injected into the striatum of four adult rhesus monkeys. Four additional animals received a comparable vector encoding a scrambled control short hairpin RNA (control vector). General health and motor behaviour were monitored for 6 months. Upon termination, brain tissues were sampled and assessed blindly for (i) huntingtin messenger RNA knockdown; (ii) Huntingtin protein expression; and (iii) neuropathological changes. Reduction in wild-type huntingtin messenger RNA levels averaging ~30% was measured in the striatum of active vector recipients 6 months post-injection. A widespread reduction in Huntingtin protein levels was also observed by immunohistochemistry in these animals, with an average protein reduction of ~45% relative to controls measured by western blot analysis in the putamen of active vector recipients. As with control vector recipients, no adverse effects were observed behaviourally, and no neurodegeneration was found on histological examination of active vector recipients. Our results suggest that long-term partial suppression of wild-type Huntingtin may be safe, and thus if a comparable level of suppression of mutant Huntingtin is beneficial, then partial suppression of both wild-type and mutant Huntingtin may result in a net benefit in patients with heterozygous Huntington's disease. PMID- 22252997 TI - The blood-brain barrier hypothesis in drug resistant epilepsy. PMID- 22252998 TI - Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. AB - Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to alpha-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis. PMID- 22252999 TI - The infusion drain: an approach to treatment of intranasal abscesses. PMID- 22253000 TI - Mixed colloidal suspensions of reduced graphene oxide and layered metal oxide nanosheets: useful precursors for the porous nanocomposites and hybrid films of graphene/metal oxide. AB - Homogeneously mixed colloidal suspensions of reduced graphene oxide, or RGO, and layered manganate nanosheets have been synthesized by a simple addition of the exfoliated colloid of RGO into that of layered MnO(2). The obtained mixed colloidal suspensions with the RGO/MnO(2) ratio of <=0.3 show good colloidal stability without any phase separation and a negatively charged state with a zeta (zeta) potential of -30 to -40 mV. The flocculation of these mixed colloidal suspensions with lithium cations yields porous nanocomposites of Li/RGO-layered MnO(2) with high electrochemical activity and a markedly expanded surface area of around 70-100 m(2) g(-1). Relative to the Li/RGO and Li/layered MnO(2) nanocomposites (~116 and ~167 F g(-1)), the obtained Li/RGO-layered MnO(2) nanocomposites deliver a larger capacitance of approximately 210 F g(-1) with good cyclability of around 95-97 % up to the 1000th cycle, thus indicating the positive effect of hybridization on the electrode performances of RGO and lithium manganate. Also, an electrophoretic deposition of the mixed colloidal suspensions makes it possible to easily fabricate uniform hybrid films composed of graphene and manganese oxide. The obtained films show a distinct electrochemical activity and a homogeneous distribution of RGO and MnO(2). The present experimental findings clearly demonstrate that the utilization of the mixed colloidal suspensions as precursors provides a facile and universal methodology to synthesize various types of graphene/metal oxide hybrid materials. PMID- 22253001 TI - Exposure to different sources of second-hand smoke during pregnancy and its effect on urinary cotinine and tobacco-specific nitrosamine (NNAL) concentrations. AB - BACKGROUND: To date, no research exists on the role that different sources of exposure to second-hand smoke (SHS) have on 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) and nicotine uptake, assessed via urinary 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanol (NNAL) and cotinine concentrations of non-smoking pregnant women, nor the differences in NNAL concentrations among pregnant women who quit smoking in comparison to those who do not. METHODS: As part of the 'Rhea' mother childbirth cohort in Crete, Greece, 1317 mother-child pairs were followed-up until delivery, while among a subsample, maternal urine was assessed for its NNAL (n=117) and cotinine concentrations (n=377). RESULTS: Pregnant women who continued to smoke during pregnancy were found to have geometric mean urinary NNAL concentrations of 0.612 pmol/ml, in comparison to the 0.100 pmol/ml of ex smokers and 0.0795 pmol/ml of non-smokers exposed to SHS. Exposure to SHS in the home was associated with a 4.40 ng/ml increase in urinary cotinine levels, while reported exposure to SHS in cars was associated with an even higher (8.73 ng/ml) increase in cotinine concentrations and was strongly related to NNAL concentrations. Exposure to SHS in the workplace and in public places was also shown to increase cotinine and NNAL concentrations. The NNAL:cotinine ratio was found to be higher among pregnant women who were exposed to SHS but did not smoke (p<0.001). CONCLUSIONS: Using cotinine levels as an indicator of NNK, exposure due to SHS during pregnancy leads to an underestimation of exposure to NNK uptake. Moreover, each source of exposure contributed to the increase in cotinine levels, indicating the importance of avoiding SHS exposure from any source. PMID- 22253002 TI - Effect of smoking on use of antibacterials: a 9-year follow-up study of 24 000 working-aged Finns. AB - BACKGROUND: Previous studies indicate an association between tobacco smoking and infectious diseases. However, large population-based follow-up studies including both accurate measurements of smoking behaviour and confounders and a reliable register-based follow-up of infections are lacking. OBJECTIVE: To examine the effect of smoking on use of antibacterials as an indicator of infections among working-aged population. METHODS: The participants of the population-based Health and Social Support Study (24,283 working-aged Finns) were followed up for 9 years. Information on smoking behaviour and confounders was obtained from a questionnaire in 1998. Number of antibacterial purchases was obtained from the National-Drug-Prescription-Register. The association between smoking and use of antibacterials was analysed using multinomial regression models. RESULTS: A graded association between lifetime smoking as measured by pack-years and use of antibacterials was found. Compared with never-smokers, the age-adjusted OR for multiple use of antibacterials among smokers with 12 or more pack-years was 2.32 (95% CI 1.91 to 2.82) in women and 1.45 (95% CI 1.23 to 1.71) in men. The associations remained after adjustment for the following confounding factors: use of alcohol, body mass index, physical activity, socioeconomic status, hard physical work, life satisfaction, disability pension and dyspnoea. CONCLUSIONS: Smoking is associated with increased use of antibacterials. Infectious periods experienced by patients should be used as an opportunity to encourage smoking cessation. PMID- 22253003 TI - The impact of changes in tobacco control funding on healthcare expenditures in California, 2012-2016. AB - OBJECTIVE: This study presents estimates of the impact of changes in California tobacco control funding on healthcare expenditures for 2012-2016 under four funding scenarios. METHODS: Smoking prevalence is projected using a cointegrated time series regression model. Smoking-attributable healthcare expenditures are estimated with econometric models that use a prevalence-based annual cost approach and an excess cost methodology. RESULTS: If tobacco control spending in California remains at the current level of 5 cents per pack (base case), smoking prevalence will increase from 12.2% in 2011 to 12.7% in 2016. If funding is cut in half, smoking prevalence will increase to 12.9% in 2016 and smoking attributable healthcare expenditures will be $307 million higher over this time period than in the base case. If the tobacco tax is increased by $1.00 per pack with 20 cents per pack allocated to tobacco control, smoking prevalence will fall to 10.4% in 2016 and healthcare expenditures between 2012 and 2016 will be $3.3 billion less than in the base case. If funding is increased to the Centers for Disease Control and Prevention recommended level, smoking prevalence will fall to 10.6% in 2016 and there will be savings in healthcare expenditures of $4.7 billion compared to the base case due to the large reduction in heavy smoking prevalence. CONCLUSIONS: California's highly successful tobacco control program will become less effective over time because inflation is eroding the 5 cents per pack currently allocated to tobacco control activities. More aggressive action needs to be taken to reduce smoking prevalence and healthcare expenditures in the future. PMID- 22253004 TI - Subjective memory complaints in general practice predicts future dementia: a 4 year follow-up study. AB - OBJECTIVE: Many older patients in general practice have subjective memory complaints (SMC); however, not all share this information with their general practitioner (GP). The association between SMC and future cognitive decline or dementia is not clear, especially in a general practice population. The aim of this study was to determine the risk for receiving a subsequent hospital-based dementia diagnosis on the basis of patients' reports of SMC in a primary care setting. METHODS: Prospective cohort survey with 4-year register-based follow-up in general practice. All 17 practices with a total of 24 GPs working in the inner district of Copenhagen municipality, Denmark. A total of 40 865 patients were listed, and 2934 were 65 years or older. Cox proportional hazard models were used to examine the influence of risk factors for hospital-based dementia diagnosis. RESULTS: A total of 758 non-nursing home residents aged 65 years and older consulted their GP in October and November 2002, and, when asked, 177 (24%) reported memory problems, and 50 (6.6%) received a hospital-based dementia diagnosis within the 4-years follow-up. SMC had an adjusted Hazard Ratio (HR) of 2.27 for subsequent dementia diagnosis. Other statistical significant covariates were Mini Mental State Examination < 24 (HR 3.97), age (HR 2.73 for 75-84 years and HR 3.75 for 85+ years) and receiving home care (HR 3.24) CONCLUSIONS: This study indicates that the presence of SMC in an older general practice population is a significant independent predictor for subsequent hospital-based dementia diagnosis. Thus, the GP could consider inquiring for memory complaints to identify vulnerable older patients. PMID- 22253005 TI - Deforming materials with light: photoresponsive materials muscle in on the action. PMID- 22253006 TI - Facial vein aneurysm associated with sialadenitis. AB - A 20 year-old man presented with pain and swelling of the left submandibular area. Neck sonography revealed enlargement of the submandibular gland, coarsening of its echotexture with a few calculi and a multiloculated cystic lesion. Doppler sonography revealed venous flow within the cystic lesion and aneurysmal dilatation of the adjacent facial vein. CT angiography confirmed the facial vein aneurysm. We hypothesize that inflammation of the gland had weakened the wall of the adjacent facial vein, causing aneurysmal dilatation. PMID- 22253007 TI - Feasibility and acute healing of vocal fold microflap incisions in a rabbit model. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the feasibility of performing mucosal elevation of a vocal fold microflap in a rabbit model and to measure the acute healing of rabbit microflap incisions compared to control vocal folds. STUDY DESIGN: Prospective animal study. METHODS: Ten New Zealand white rabbits were used in this study. All rabbits received a 3-mm incision through the epithelium of one vocal fold using a sickle knife and mucosal elevation through this incision using a microlaryngeal fine-angled spatula. The contralateral vocal fold was left intact to serve as an internal control. Student t tests were used to investigate differences in epithelial thickness, immunohistochemical staining of CD45, and inflammatory and profibrotic gene expression between vocal folds undergoing microflap and control. RESULTS: Exposure of the rabbit larynx was achieved, allowing for the identification of a surgical plane and the creation of a microflap and elevation of the vocal fold mucosa. Hematoxylin-and-eosin staining revealed no significant differences in epithelial thickness, immunohistochemistry for CD45 showed no significant differences in CD45-positive cells, and quantitative polymerase chain reaction revealed no significant differences in interleukin-1beta, transforming growth factor beta-1, or cyclooxygenase-2 gene expression between vocal folds undergoing microflap and control. CONCLUSIONS: We demonstrate the feasibility of vocal fold microflap surgery in a rabbit model. With the advantage of greater access to primers and antibodies for molecular biologic studies, the application of the microflap technique in a small-animal model such as rabbit has broad implications for future experimental investigations in laryngology. PMID- 22253008 TI - Histopathological analysis of a 15-year user of an auditory brainstem implant. AB - Auditory brainstem implants (ABIs) can provide highly beneficial hearing sensations to individuals deafened by bilateral vestibular schwannomas (neurofibromatosis type 2). Relatively little is known about the status of stimulated neurons after long-term ABI use. Direct examination of the cochlear nuclear complex (CN) of one 5-year ABI user indicated no deleterious effect. Recently, we examined the brainstem of a patient who used his ABI daily for 15 years with excellent performance. There was good preservation of CN cell size, morphology, and packing density, a very favorable sign considering that a number of infants are now receiving ABIs. PMID- 22253009 TI - Synthesis, evaluation and molecular modeling of cyclic tetrapeptide histone deacetylase inhibitors as anticancer agents. AB - Histone deacetylase inhibitors (HDACIs) are a promising class of anticancer agents. To examine whether a slight change in the recognition domain could alter their inhibitory activity, we synthesized a series of cyclo(-L-Am7(S2Py)-Aib-L Phe(n-Me)-D-Pro)derivatives and evaluated their HDAC inhibitory and anticancer activities. The peptides exhibited potent HDAC inhibitory activity and inhibited three human cancer cell lines with IC50 in the micromolar range. Docking and molecular dynamics simulation were conducted to explore the interaction mechanisms of class I and II HDACs with these inhibitors. It revealed that the zinc ion in the active site coordinated five atoms of HDACs and the sulfur atom of the inhibitor. The metal binding domains of these compounds interacted with HDAC2, and the surface recognition domains of these compounds interacted with HDAC4 through hydrogen bonding. The hydrophobic interactions also provided favorable contributions to stabilize the complexes. The results obtained from this study would be helpful for us to design some novel cyclic tetrapeptides that may act as potent HDACIs. PMID- 22253010 TI - Toward deconstructing the phenotype of late-onset Pompe disease. AB - Pompe disease (glycogen storage disease type 2 or acid maltase deficiency) is a rare autosomal recessive lysosomal storage disorder. Since the advent of ERT a lot has been learned about the phenotypic spectrum especially in the late onset patients. We describe in detail 44 patients diagnosed with late-onset Pompe disease (LOPD) at our neuromuscular department from 1985 to 2011 and compare them to patients with LOPD in the literature of the past 40 years. Study of the Munich LOPD group revealed varying musculoskeletal and cardio-cerebrovascular manifestation patterns. Several of these symptom patterns commonly appeared in conjunction with one another, highlighting the multisystem involvement of this condition. Common symptom patterns include: (i) Classic limb girdle and diaphragmatic weakness, (ii) rigid spine syndrome (RSS), scoliosis, and low body mass, and (iii) several cardio-cerebrovascular manifestation patterns. The most common presentation, limb girdle and diaphragmatic weakness, appeared in 78% (34/44) of our patients and over 80% of those in the literature. Sixteen percent (7/44) of our patients presented with rigid spine, scoliosis, and low body mass. Although scoliosis had a reported frequency of 33% in the general LOPD patient population, the literature only occasionally reported low body mass and RSS. Importantly, a multisystem extramuscular finding accompanied by cardio cerebrovascular manifestations was found in 29% (13/44) of our LOPD patients; the literature showed an increasing prevalence of this latter finding. By examining the phenotype of patients with confirmed LOPD, we found a more subtle clinical multisystem involvement in LOPD. Whether patients presenting with the different symptom patterns respond differently to enzyme replacement therapy remains a key question for future research. (c) 2012 Wiley Periodicals, Inc. PMID- 22253011 TI - Malignant triton tumors--complete surgical resection and adjuvant radiotherapy associated with improved survival. AB - BACKGROUND: Malignant triton tumors (MTT) are a rare form of peripheral nerve sheath tumors that follows a particularly aggressive course. Given its rarity, only case reports and small series of patients have been published. METHODS: A Pubmed search was conducted (1966-2009) using the terms "triton tumor," "rhabdomyosarcoma," and "malignant peripheral nerve sheath tumor." The reference lists of retrieved articles were searched. Cases were included when the diagnosis was clear, the patient underwent surgery, and follow-up data were available. Univariate and multivariate analyses were conducted for predictors of positive resection margin, local recurrence/progression, development of metastases, and mortality. RESULTS: A total of 124 cases were included. The overall 5-year survival was 14% and the median time to death was 13 months. The overall local recurrence/progression rate was 50% and the median time to recurrence/progression was 6 months. On multivariate Cox proportional hazards analysis, positive margin status (HR 2.2, P = 0.01), local recurrence/progression (HR 3.1, P = 0.003), and development of metastases (HR 2.6, P = 0.003) were associated with mortality. Adjuvant radiotherapy was associated with improved survival (HR 0.4, P = 0.005). CONCLUSION: Complete surgical resection and adjuvant radiotherapy should be the cornerstones of treatment for MTT. PMID- 22253014 TI - Dual-function of alcohols in gold-mediated selective coupling of amines and alcohols. AB - Oxidative coupling of alcohols (methanol and ethanol) and dimethylamine on atomic oxygen-activated Au(111) occurs entirely on the surface to form the corresponding amides when the alkoxy of the alcohol and the amide derived from the amine are co adsorbed. For effective oxygen-assisted coupling the formation of the amide requires excess methanol. Mechanistic studies reveal that molecularly adsorbed methanol removes excess adsorbed atomic oxygen efficiently, precluding either secondary oxidation or oxidative dehydrogenation of dimethylamide to the imine. The adsorbed amide then can react with the aldehyde produced by beta-hydride elimination from the alkoxy to form the hemiaminal, the reactive intermediate leading to coupling. The selectivity for formamide production can be increased to nearly 100 % in excess methanol. PMID- 22253012 TI - JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a severe disease of the central nervous system (CNS), caused by infection with the Polyomavirus JC virus (JCV). Because there are no known treatments or prognostic factors, we performed a long-term study focusing mainly on cerebrospinal fluid (CSF) samples from PML patients to describe the virological features akin to the different forms of the disease. Twenty-eight PML patients were enrolled: 10 HIV-1+ patients with classical PML (CPML), 9 HIV-1+ patients with slowly progressing or stable neurological symptoms (benign PML), 3 HIV-1+ asymptomatic patients, and 6 HIV-1 negative patients. CSF, urine, and blood samples were collected at the enrollment (baseline) and every 6 months afterwards when possible. The JCV DNA and HIV-1 RNA loads were determined, and the JCV strains were characterized. At baseline, the mean CSF JCV load was log 6.0 +/- 1.2 copies/ml for CPML patients, log 4.0 +/- 1.0 copies/ml for benign PML patients, log 4.2 +/- 0.5 copies/ml for asymptomatic PML patients, and log 5.8 +/- 1.3 copies/ml for HIV-1-negative PML patients (CPML vs. benign: P < 0.01; CPML vs. asymptomatic: P < 0.05; HIV-1 negative vs. benign: P < 0.01). Organization of the JCV transcriptional control region (TCR) showed unusual archetype structures in two long-term survival patients; the NF1 sequence was found most commonly, whereas the Sp1 binding site was the most common for both CPML patients and HIV-1 negative patients. Our results suggest that the JCV load in the CSF and the organization of the TCR should be considered as indicators of PML clinical outcome. PMID- 22253013 TI - Microbiome complexity and Staphylococcus aureus in chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to compare microbiological culture-based and culture-independent (16S rRNA gene sequencing) methodologies for pathogen identification in chronic rhinosinusitis (CRS) patients. We hypothesized that bacterial culture and DNA sequencing would yield largely concurrent results, although sequencing would detect greater bacterial diversity, and the sinonasal microbiomes of CRS patients would differ in composition and diversity compared with non-CRS controls. STUDY DESIGN: Cross-sectional observational study. METHODS: Middle meatus swabs from CRS patients collected during endoscopic sinus surgery were analyzed by both clinical culture and broad range analysis of 16S rRNA gene pyrosequences. RESULTS: A total of 21 swab samples from 15 CRS patients and five non-CRS controls were analyzed. One CRS patient was also swabbed 3 weeks postoperatively due to evidence of purulence during a clinical visit. All subjects had positive bacterial cultures, with a mean of 2.8 isolates per subject. The most prevalent cultivars were coagulase negative staphylococci (15/20 specimens, 75%), Staphylococcus aureus (10/20, 50%), and Propionibacterium acnes (6/20, 30%). Among 57,407 pyrosequences generated, the most prevalent were from coagulase-negative staphylococci (21/21 specimens, 100%), Corynebacterium spp (18/21, 85.7%), P acnes (16/21, 76.2%), and S aureus (14/21, 66.7%). Bacterial diversity correlated with recent antibiotic use, asthma, prior sinus surgery, and relative abundance of S aureus. CONCLUSIONS: DNA pyrosequencing revealed greater biodiversity than culture, although in most cases culture results represented a subset of the abundant DNA sequence types. CRS patients were characterized by altered microbial composition (P = .02) and greater abundance of S aureus (P = .03). PMID- 22253015 TI - Role of amino acid hydrophobicity, aromaticity, and molecular volume on IAPP(20 29) amyloid self-assembly. AB - Aromatic amino acids strongly promote cross-beta amyloid formation; whether the amyloidogenicity of aromatic residues is due to high hydrophobicity and beta sheet propensity or formation of stabilizing pi-pi interactions has been debated. To clarify the role of aromatic residues on amyloid formation, the islet amyloid polypeptide 20-29 fragment [IAPP(20-29)], which contains a single aromatic residue (Phe 23), was adopted as a model. The side chain of residue 23 does not self-associate in cross-beta fibrils of IAPP(20-29) (Nielsen et al., Angew Chem Int Ed 2009;48:2118-2121), allowing investigation of the amyloidogenicity of aromatic amino acids in a context where direct pi-pi interactions do not occur. We prepared variants of IAPP(20-29) in which Tyr, Leu, Phe, pentafluorophenylalanine (F5-Phe), Trp, cyclohexylalanine (Cha), alpha naphthylalanine (1-Nap), or beta-naphthylalanine (2-Nap) (in order of increasing peptide hydrophobicity) were incorporated at position 23 (SNNXGAILSS-NH2), and the kinetic and thermodynamic effects of these mutations on cross-beta self assembly were assessed. The Tyr, Leu, and Trp 23 variants failed to readily self assemble at concentrations up to 1.5 mM, while the Cha 23 mutant fibrillized with attenuated kinetics and similar thermodynamic stability relative to the wild-type Phe 23 peptide. Conversely, the F5-Phe, 1-Nap, and 2-Nap 23 variants self assembled at enhanced rates, forming fibrils with greater thermodynamic stability than the wild-type peptide. These results indicate that the high amyloidogenicity of aromatic amino acids is a function of hydrophobicity, beta-sheet propensity, and planar geometry and not the ability to form stabilizing or directing pi-pi bonds. PMID- 22253016 TI - Protecting the oral mucosa in patients with oral tongue squamous cell carcinoma treated postoperatively with intensity-modulated radiotherapy: a randomized study. AB - OBJECTIVES/HYPOTHESIS: Is the severity of acute oral mucositis in patients who receive postoperative intensity-modulated radiotherapy (PO-IMRT) for oral tongue squamous cell carcinoma (SCC) reduced by sparing the oral mucosa outside of the planning target volume (PTV)? STUDY DESIGN: Prospective, randomized trial. METHODS: Forty-eight patients with oral tongue SCC who received PO-IMRT at our institution were randomized to two groups: the oral-sparing (OR-SP) group and oral-unsparing (OR-USP) group. For the OR-SP group (n = 24), the oral mucosa outside of the PTV was spared. Furthermore, the mucosa including the bilateral cheeks, upper lip, and lower lip was defined as the united site and given <32 Gy. For the OR-USP group (n = 24), none of the oral mucosa was protected. The severity of clinical acute mucositis in each patient was assessed weekly during PO-IMRT until completely healed. Oral mucositis was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Dosimetry and therapeutic measures related to acute mucositis between the two groups were compared. RESULTS: During PO-IMRT, no patient experienced grade 4+ acute mucositis in any oral site. Compared to the OR-USP group, there was less grade 2 and 3 mucositis in the united site of the OR-SP group (0% and 25% vs. 45.8% and 54.2%, respectively; P = .000). Also, the mean dose to the united site was significantly lower with OR-SP compared to OR-USP (41.8 +/- 7.4 Gy vs. 58.8 +/- 2.2 Gy; P = .000). The OR-SP group was associated with significant reductions in the use of analgesics (P = .043) and intravenous antibiotics (P = .039). No recurrences were detected in the vicinity of the spared oral mucosa (the united site) during a median follow-up time of 30 months. CONCLUSIONS: OR-SP PO-IMRT for patients with oral tongue SCC resulted in a significant decrease in the severity of acute mucositis and improved quality of life. The sparing of the oral mucosa outside of the PTV is safe and does not compromise oncologic outcomes. PMID- 22253017 TI - Trends in the consumption of attention deficit hyperactivity disorder medications in Castilla y Leon (Spain): changes in the consumption pattern following the introduction of extended release methylphenidate. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is the most diagnosed behavioural disorder in children and adolescents; prevalence has been estimated around 5%. Studies have shown an increase in the use of ADHD medications during the last years. The aim of the present study was to learn the pattern and the evolution of ADHD medication consumption in Castilla y Leon (Spain). METHOD: Consumption data for the period 1992-2009 were obtained from databases containing information upon consumption and cost of medications dispensed by pharmacies at the expense of the Spanish National Health System. The data were expressed in defined daily doses (DDDs) per 1000 inhabitants per day (DDD/1000 inhabitants/day). A model to forecast consumption was built. RESULTS: Attention deficit hyperactivity disorder medication consumption increased in Castilla y Leon from 0.1 DDD/1000 inhabitants/day in 1992 to 1.5 DDD/1000 inhabitants/day in 2009; expected consumption will reach 2.5 DDD/1000 inhabitants/day by 2013. The drugs accounting for this increase were mainly made up of methylphenidate preparations (1.4 DDD/1000 inhabitants/day in 2009). From 1992 to 1999, there was a slight reduction in methylphenidate use; following amphetamine withdrawal, the consumption of stimulants began to increase, and figures showed a sharp rise after marketing of extended-release formulations in 2003. CONCLUSIONS: There has been an enormous increase in ADHD medication consumption in Castilla y Leon in the last few years; increase rocketed when extended-release methylphenidate was marketed. A rapid increase in the consumption is a warning on possible overdiagnosis and inappropriate prescription. PMID- 22253018 TI - Complex activities of the human Bloom's syndrome helicase are encoded in a core region comprising the RecA and Zn-binding domains. AB - Bloom's syndrome DNA helicase (BLM), a member of the RecQ family, is a key player in homologous recombination (HR)-based error-free DNA repair processes. During HR, BLM exerts various biochemical activities including single-stranded (ss) DNA translocation, separation and annealing of complementary DNA strands, disruption of complex DNA structures (e.g. displacement loops) and contributes to quality control of HR via clearance of Rad51 nucleoprotein filaments. We performed a quantitative mechanistic analysis of truncated BLM constructs that are shorter than the previously identified minimal functional module. Surprisingly, we found that a BLM construct comprising only the two conserved RecA domains and the Zn(2+)-binding domain (residues 642-1077) can efficiently perform all mentioned HR-related activities. The results demonstrate that the Zn(2+)-binding domain is necessary for functional interaction with DNA. We show that the extensions of this core, including the winged-helix domain and the strand separation hairpin identified therein in other RecQ-family helicases, are not required for mechanochemical activity per se and may instead play modulatory roles and mediate protein-protein interactions. PMID- 22253019 TI - mRNA knockdown by single strand RNA is improved by chemical modifications. AB - While RNAi has traditionally relied on RNA duplexes, early evaluation of siRNAs demonstrated activity of the guide strand in the absence of the passenger strand. However, these single strands lacked the activity of duplex RNAs. Here, we report the systematic use of chemical modifications to optimize single-strand RNA (ssRNA)-mediated mRNA knockdown. We identify that 2'F ribose modifications coupled with 5'-end phosphorylation vastly improves ssRNA activity both in vitro and in vivo. The impact of specific chemical modifications on ssRNA activity implies an Ago-mediated mechanism but the hallmark mRNA cleavage sites were not observed which suggests ssRNA may operate through a mechanism beyond conventional Ago2 slicer activity. While currently less potent than duplex siRNAs, with additional chemical optimization and alternative routes of delivery, chemically modified ssRNAs could represent a powerful RNAi platform. PMID- 22253020 TI - Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. AB - BACKGROUND: This study sought to evaluate patient-reported health-related quality of life following proton therapy for prostate cancer in men <= 60 years old. METHODS: Between August 2006 and January 2010, 262 hormone-naive men <= 60 years old were treated with definitive proton therapy for prostate cancer. Before treatment and every 6 months after treatment, patients filled out the Expanded Prostate Index Composite (EPIC) and the International Index of Erectile Function (IIEF) questionnaires. Potency was defined as successful sexual intercourse in the prior month or an EPIC sexual summary (SS) score >= 60. RESULTS: Median follow-up was 24 months; 90% of men completed follow-up EPIC forms within the last year. For EPIC urinary, bowel, and hormone subscales, the average decline from baseline to 2 years was <=5 points, except for bowel function (5.2 points). SS scores declined 12.6 points after 2 years. Potency rates declined by 11% from baseline at 2 years, but 94% of men were potent with a baseline IIEF > 21, body mass index < 30, and no history of diabetes. At 2 years after treatment, only 1.8% of men required a pad for urge incontinence. On multivariate analysis, factors associated with a significant decline in SS score were mean penile bulb dose >=40 cobalt Gy equivalents (P = .012) and radiation dose >= 80 cobalt Gy equivalents (P = .017); only diabetes was significantly associated with impotence (P = .015). CONCLUSIONS: Young men undergoing proton therapy for treatment of prostate cancer have excellent outcomes with respect to erectile dysfunction, urinary incontinence, and other health-related quality of life parameters during the first 2 years after treatment. Longer follow-up is needed to confirm these findings. PMID- 22253021 TI - Barnacle bonding: morphology of attachment of Xenobalanus globicipitis to its host Tursiops truncatus. AB - Xenobalanus globicipitis, a unique type of small pseudo-stalked barnacle occurs on the appendages of cetaceans, including the common bottlenose dolphin Tursiops truncatus. In this study, we examined attachment structures of X. globicipitis and modifications to the skin of T. truncatus in areas of attachment compared to skin nearby an attachment site. Barnacles and their six calcareous footplates were measured for their length and width. There was a positive correlation of barnacle width and length to footplate width and length. The thickness of the stratum corneum increased significantly in areas of attachment compared to skin nearby a footplate. The mitotic stratum germinativum at the base of the dermal papillae did not change significantly in areas of attachment compared to skin nearby a footplate. The stratum germinativum lining the lateral walls of the dermal papillae was significantly thicker in areas of skin nearby a footplate compared to in areas of attachment. Skin of T. truncatus nearby a footplate, displayed dermal papillae extending from the dermis and pointing roughly perpendicular to the epidermal stratum corneum. At sites of X. globicipitis attachment, the dermal papillae were forced to extend laterally, parallel to the stratum corneum, and the dermal papillae length to width ratio at an attachment site was significantly higher than on skin near an attachment site. Our results show that attachment of X. globicipitis through production of footplates organized into calcareous rings, leads to a thickened stratum corneum of the epidermis, a thinner lateral mitotic stratum germinativum and displaced structures of the upper dermis. These resulting modifications to the epidermis and dermis of the host may add to securing barnacle attachment to its host. PMID- 22253022 TI - Comparative pharmacokinetics of prim-O-glucosylcimifugin and cimifugin by liquid chromatography-mass spectrometry after oral administration of Radix Saposhnikoviae extract, cimifugin monomer solution and prim-O-glucosylcimifugin monomer solution to rats. AB - A sensitive and reliable liquid chromatography-mass spectrometry method has been developed and validated for simultaneous determination of cimifugin and prim-O glucosylcimifugin in rat plasma after oral administration of Radix Saposhnikoviae (RS) extract, prim-O-glucosylcimifugin monomer solution and cimifugin monomer solution. Plasma samples were pretreated by protein precipitation with acetonitrile containing the internal standards puerarin and daidzein. LC separation was achieved on a Zorbax SB-C(18) column (150 * 4.6 mm i.d., 5 um) with 0.1% formic acid in water and methanol by isocratic elution. The detection was carried out in select-ion-monitoring mode with a positive electrospray ionization interface. The fully validated method was successfully applied to the pharmacokinetic study of the analytes in rats. A bimodal phenomenon appeared in the concentration-time curve of prim-O-glucosylcimifugin and cimifugin after oral administration of RS extract. Prim-O-glucosylcimifugin mainly transformed to cimifugin when it was absorbed into blood. Both absorption and elimination of cimifugin after oral administration of RS were longer than after administration of single cimifugin. The pharmacokinetic parameters (AUC(0-t) , AUC(0-infinity) and t(1/2) ) of prim-O-glucosylcimifugin and cimifugin by giving cimifugin monomer solution, prim-O-glucosylcimifugin monomer solution and RS extract had significant differences (P < 0.05). PMID- 22253023 TI - National prevalence of gout derived from administrative health data in Aotearoa New Zealand. AB - OBJECTIVE: Previous small studies in Aotearoa New Zealand have indicated a high prevalence of gout. This study sought to determine the prevalence of gout in the entire Aotearoa New Zealand population using national-level health data sets. METHODS: We used hospitalization and drug dispensing claims for allopurinol and colchicine for the entire Aotearoa New Zealand population from the Aotearoa New Zealand Health Tracker (ANZHT) to estimate the prevalence of gout in 2009, stratified by age, gender, ethnicity and socio-economic status (n = 4 295 296). RESULTS: were compared with those obtained from an independent large primary care data set (HealthStat, n = 555 313). Results. The all-ages crude prevalence of diagnosed gout in the ANZHT population was 2.69%. A similar prevalence of 2.89% was observed in the HealthStat population standardized to the ANZHT population for age, gender, ethnicity and deprivation. Analysis of the ANZHT population showed that gout was more common in Maori and Pacific people [relative risk (RR) 3.11 and 3.59, respectively], in males (RR 3.58), in those living in the most socio-economically deprived areas (RR 1.41) and in those aged >65 years (RR >40) (P-value for all <0.0001). The prevalence of gout in elderly Maori and Pacific men was particularly high at >25%. CONCLUSION: Applying algorithms to national administrative data sets provides a readily available method for estimating the prevalence of a chronic condition such as gout, where diagnosis and drug treatment are relatively specific for this disease. We have demonstrated high gout prevalence in the entire Aotearoa New Zealand population, particularly among Maori and Pacific people. PMID- 22253024 TI - Expression of Toll-like receptors and their detection of nuclear self-antigen leading to immune activation in JSLE. AB - OBJECTIVES: Toll-like receptors (TLRs) essential in the functioning of the immune system have been implicated in the development of autoimmunity. TLR3, 7, 8 and 9 are capable of recognizing nucleic autoantigens typical of SLE. Their expression correlates positively with disease activity in adult-onset SLE. This study aimed to determine the role of TLRs in JSLE and whether apoptotic neutrophils are a source of nuclear autoantigen being detected through TLR3, 7, 8 and 9, leading to an inflammatory response. METHODS: TLR3, 7, 8 and 9 mRNA and protein expression were measured in peripheral blood mononuclear cells (PBMCs) in JSLE patients compared with JIA and non-inflammatory controls. Activation of the TLRs by JSLE serum-induced apoptotic neutrophils was detected by measuring IFN-alpha mRNA and protein expression, and confirmed using myeloid differentiation factor 88 (MyD88) and TIR domain-containing adapter-inducing IFN-beta (TRIF) inhibitors. RESULTS: JSLE patients have increased TLR3, 8 and 9 mRNA and protein expression compared with controls (P < 0.05). Incubation of PBMCs with apoptotic neutrophils demonstrated a dose-response relationship for IFN-alpha mRNA expression. Inhibition of TLR signalling by blocking MyD88 and TRIF signalling decreased IFN alpha mRNA expression in PBMCs incubated with apoptotic neutrophils (P < 0.05). CONCLUSIONS: This study demonstrated significantly increased TLR expression in JSLE compared with controls. Our data indicate that apoptotic neutrophils trigger TLR activation through their presentation of autoantigens. The role of TLRs in this inflammatory response was demonstrated by a dose-response relationship to apoptotic neutrophil concentration and confirmed by a decrease in IFN-alpha production after inhibition of TLR signalling. PMID- 22253025 TI - Anti-TNF-alpha therapy may not improve arterial stiffness in patients with AS: a 24-week follow-up. AB - OBJECTIVE: The availability of new-generation drugs has provided significant success reflected by disease activity markers and clinical status in AS, but controversial reports necessitate further assessment of associated increased risk of cardiovascular burden that might persist. Hence this prospective clinical study evaluated the effectiveness of a 24-week anti-TNF-alpha therapy on vascular stiffness [pulse wave velocity (PWV)] in AS. METHODS: A total of 28 active AS patients (21 males, 7 females) were enrolled before the start of biologic therapy. Demographic and clinical characteristics were recorded. Arterial stiffness was assessed using PWV. Patients were evaluated before and 24 weeks after anti-TNF-alpha therapy. RESULTS: The mean disease duration was 8.4 (4.9) years. After 24 weeks of anti-TNF-alpha therapy, despite significant improvements in patients' symptoms and clinical activity parameters, including BASDAI score [4.9 (0.9) vs 1.9 (0.5), P = 0.0001], ESR [35.5 (23.1) vs 13.8 (9.2) mm/h, P = 0.0001) and CRP level [2.1 (1.6) vs 0.4 (0.3) ng/dl, P = 0.0001], no significant change was seen in arterial stiffness parameters [7.9 (1.3) vs 7.7 (1.3) m/s, P = 0.412]. Significant correlation was determined between arterial stiffness and age, systolic blood pressure and high-density lipoprotein cholesterol levels. CONCLUSION: Despite significant improvement in markers of disease activity, anti TNF-alpha therapy does not seem to improve arterial stiffness, a significant AS associated cardiovascular burden. Thus, when treating AS, significant end-points other than DASs should also be considered, and any hidden threat like arterial stiffness should be addressed further. PMID- 22253026 TI - Fas-associated death domain protein and adenosine partnership: fad in RA. AB - Inflammation is the principal hallmark of RA. Different pathways are implicated in the production of pro-inflammatory cytokines, the bona fide mediators of this inflammation. Among them are the TNF pathway and the IL-1 receptor/Toll-like receptor (IL-1R/TLR4) pathway. One of the potential negative regulators of IL 1R/TLR4 signalling is the Fas-associated death domain protein (FADD), which is the pivotal adaptor of the apoptotic signal mediated by death receptors of the TNF family. FADD can sequester myeloid differentiation primary response gene 88 (MyD88), the common adaptor of most TLRs, and hence hinder the activation of nuclear factor kappaB (NF-kappaB), the downstream transcription factor. We recently described a new regulatory mechanism of FADD expression, via the shedding of microvesicles, mediated by adenosine receptors. Interestingly, adenosine is found in high concentrations in the joints of RA patients and has been largely reported as a regulator of inflammation. This review discusses the possible link that could exist between the adenosine-dependent regulation of FADD in the inflammatory context of RA and the potential role of FADD as a therapeutic target in the treatment of RA. We will see that the modulation of FADD expression may be a double-edged sword by increasing apoptosis and at the same time limiting NF-kappaB activation. PMID- 22253027 TI - The role of Doppler ultrasound in rheumatic diseases. AB - The use of Doppler techniques, including power, colour and spectral Doppler, has greatly increased in rheumatology in recent years. This is due to the ability of Doppler US (DUS) to detect pathological vascularization within joints and periarticular soft tissues, thereby demonstrating the presence of active inflammation, which has been reported to be correlated with the local neo angiogenesis. In synovitis, DUS showed a high correlation with histological and MRI findings, thus it is considered a valid tool to detect pathological synovial vascularization. Moreover, it is more sensitive than clinical examination in detecting active joint inflammation and in the evaluation of response to treatment. In addition, DUS may be considered as a reference imaging modality in the assessment of enthesitis, MRI being not sensitive and histology not feasible. Moreover, it has been demonstrated to be able to detect changes in asymptomatic enthesis. In conclusion, DUS is a useful and sensitive tool in the evaluation and monitoring of active inflammation. Its widespread use in clinical rheumatological practice is recommended. The aim of this article is to review the current literature about the role of DUS in rheumatic diseases, analysing its validity, reliability and feasibility. PMID- 22253028 TI - Increased serum COMP predicts mortality in SSc: results from a longitudinal study of interstitial lung disease. AB - OBJECTIVES: COMP is a regulator of assembly and maintenance of the fibrillar collagen I and II networks. Serum COMP reflects skin fibrosis in SSc. The purpose of this study was to examine whether serum COMP reflects fibrotic lung involvement in SSc patients and to study if serum COMP predicts mortality. METHODS: Three overlapping cohorts of 244 SSc patients were studied. Two hundred and eighteen patients were included to study survival, 80 patients to study longitudinal changes of pulmonary function tests and 64 to study pulmonary involvement assessed by high-resolution CT (HRCT). Serum COMP was measured by ELISA. Skin involvement was assessed with the modified Rodnan skin score (mRSS). Data about survival were obtained from the central population registry. RESULTS: Serum COMP measured within 5 years after the first non-Raynaud's manifestation was a predictor of death, and crude mortality increased by 6% for each COMP unit elevation. Serum COMP levels >15 U/l were associated with a 3.13-fold (95% CI 1.73, 5.64; P < 0.001) increased risk of death. During the first year of follow up serum COMP and vital capacity (VC) changed inversely (r(s) = -0.32; P = 0.005), but there were no correlations between baseline serum COMP and concurrent findings by spirometry or HRCT. CONCLUSION: Serum COMP early in disease is a predictor of mortality in SSc patients. Serum COMP changes in parallel with lung fibrosis as measured by VC, but the release from fibrotic skin possibly obscures the influx from the lungs and therefore serum COMP seems to have little utility as a marker of lung fibrosis. PMID- 22253029 TI - Does joint position affect US findings in inflammatory arthritis? AB - OBJECTIVE: Musculoskeletal US is being increasingly used for the assessment of synovitis, although questions remain about its reliability. One potential factor affecting reliability is the lack of consensus of image acquisition methods such as using different joint positions. This may have an implication on the reproducibility of studies that use US as an outcome measure. The aim of this study was to determine whether a change in joint position might significantly alter the quantification of US-detected synovitis in patients with inflammatory arthritis (IA). METHODS: IA patients with clinically swollen wrists, MCP and/or knee joints were recruited. These joints were assessed quantitatively for the presence of synovitis when they were placed in different positions. RESULTS: Seventy-five patients with IA were assessed. The greatest grey scale (GS) and power Doppler (PD) scores for the MCP joints were found in the flat (0 degrees ) position (91 and 100% of cases, respectively) compared with other positions (P < 0.001). Similar results were found in the wrist joints. The greatest GS and PD scores for the knee joint were found in 30 degrees flexion [100 and 95.6% of cases, respectively, compared with other positions (P < 0.001)]. The inter- and intra-reader reliability was good to excellent. CONCLUSION: The position in which a joint is scanned for synovitis appears to significantly influence the US assessment of synovitis. Our study suggests that the standardized scanning of the hand joints in a flat position and the knees in a 30 degrees position are associated with the highest GS and PD scores. PMID- 22253030 TI - Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics. AB - OBJECTIVE: To investigate whether the incidence of secondary hypogammaglobulinaemia in patients with RA following rituximab was related to patterns of B-cell return and relapse. METHODS: CD19(+) B-cell and serum immunoglobulin (sIg) determinations were done every 2 or 3 months in 137 consecutive patients treated with one or more courses of rituximab-based B-cell depletion therapy. The pattern of B-cell return, either concordant or discordant with relapse, was also recorded. RESULTS: There were 119 responders. Before treatment, three patients had low IgM and four had low IgG. After the first cycle, low IgM or IgG was present in 9.2% (11/119) and 11.8% (14/119) of the patients, respectively, increasing to 38.8% (8/18) and 22.2% (4/18) after five cycles. The mean percent maximum sIg decrease/cycle was relatively constant. The CD19(+) B-cell count at repopulation was not correlated with immunoglobulin (Ig) levels after each cycle. Patients discordant for B-cell return and relapse developed significantly lower serum IgM and more low IgM episodes than concordant patients (P < 0.05). CONCLUSION: Patients with lower baseline sIg levels tended to develop persistent IgM and IgG hypogammaglobulinaemia, resulting from an accumulation of incremental decreases after repeat cycles. This was not due to lower numbers of returning B cells in those developing low sIgs. The association of low IgM in patients with a discordant pattern of relapse suggests that underlying defects in B cells relating to survival and maturation into Ig secreting cells, as well as attrition of IgG plasma cells may be contributing to low sIg levels in some patients. PMID- 22253031 TI - Foot drop developing during infliximab therapy for inflammatory bowel disease. PMID- 22253032 TI - Biomarkers and boundaries to break. PMID- 22253033 TI - Gluten sensitivity in Meniere's disease. AB - OBJECTIVES/HYPOTHESIS: Wheat is one of the most common food allergens found in patients with Meniere's disease (MD). Gluten from wheat has been identified to have a etiopathogenetic role in celiac disease, IgE hypersensitivity to wheat disease, and recently to gluten sensitivity. The aim of this study was to verify the incidence of gliadin prick test response in patients affected by MD. STUDY DESIGN: Prospective individual case-control study. METHODS: There were 58 adult patients with definite MD, 25 healthy volunteers, and 25 patients with grass pollen rhinoconjunctivitis tested with skin prick test to gliadin. RESULTS: A total of 33 MD patients (56.9%) proved to be sensitive to gliadin, eight of whom were positive to prick test after 20 minutes, 13 after 6 hours, 11 after 12 hours, and one after 24 hours. CONCLUSIONS: This is the first report of gliadin skin test response in MD. Further studies are needed to define the relationship between immune response to wheat proteins and MD symptoms. PMID- 22253034 TI - Intranasal drug-induced fungal rhinopharyngitis. AB - BACKGROUND: Intranasal drug abuse has long been recognized as an etiology of sinonasal pathology. However, the intranasal use of prescription and nonprescription drugs has surpassed the use of illicit drugs, and the pattern of presentation and required therapeutic intervention appears to be different. We report on our experience with these patients, along with a successful treatment algorithm for this disease process. METHODS: Retrospective chart review of 9 consecutive patients who presented with rhinopharyngitis and a history of intranasal opioid and/or acetaminophen abuse, from 2007 to 2010, at a tertiary referral center. RESULTS: Nine patients were found to have abused intranasal hydrocodone/acetaminophen, oxycodone/aceta-minophen, or acetaminophen and were diagnosed with rhinopharyngitis. Sinonasal pain and odynophagia were the most common chief complaints and 8 of 9 patients reported previous antibiotic failures. On endoscopy, all patients exhibited a thick, white, exudative process involving the nasal septum and lateral nasal mucosa. Five of 9 exhibited large septal perforations. Seven of 9 exhibited white, exudative pharyngitis. Seven of 9 patients had identifiable fungal organisms on culture, including 5 with species of Candida and 3 with Aspergillus. Two patients grew Staphylococcus aureus. Five patients were compliant with follow up. All 5 showed significant improvement in symptoms and examination, following treatment with oral and topical antifungal therapy and nasal irrigations. CONCLUSION: Intranasal opioid and acetaminophen abuse is often associated with the development of fungal rhinopharyngitis. Recognizing that this process is primarily fungal in origin is paramount to successful treatment, as most patients respond well to antifungal therapy when compliant with treatment. PMID- 22253035 TI - ATP-independent formation of hydrocarbons catalyzed by isolated nitrogenase cofactors. PMID- 22253036 TI - Case-control study of risk factors for spasmodic dysphonia: A comparison with other voice disorders. AB - OBJECTIVES/HYPOTHESIS: This epidemiology study examined risk factors uniquely associated with spasmodic dysphonia (SD). STUDY DESIGN: Case-control. METHODS: A questionnaire was administered to 150 patients with SD (with and without coexisting vocal tremor) and 136 patients with other structural, neurological, and functional voice disorders (excluding SD and vocal tremor). Questions included personal and family medical histories, environmental exposures, trauma, illnesses, voice use habits, and the Short Form 36. RESULTS: Several factors were uniquely associated with SD (alpha = .05), including: 1) a personal history of cervical dystonia, sinus and throat illnesses, mumps, rubella, dust exposure, and frequent volunteer voice use, 2) a family history of voice disorders, 3) an immediate family history of vocal tremor and meningitis, and 4) an extended family history of head and neck tremor, ocular disease, and meningitis. Vocal tremor coexisted with SD in 29% of cases. Measles and mumps vaccines were protective for SD. CONCLUSIONS: SD is likely multifactorial and associated with several endogenous and exogenous factors. Certain viral exposures, voice use patterns, and familial neurological conditions may contribute to the onset of SD later in life. PMID- 22253037 TI - Characterization of small RNAs in Xenopus tropicalis gastrulae. AB - Here, we report and characterize deep sequencing data and bioinformatics analysis of small RNAs from Xenopus tropicalis gastrula. A total of 17,553,124 reads with perfect match to the genome derived from 2,616,053 unique sequences were identified. Seventy-seven percent of theses sequences were not found in previous reports from X. tropicalis oocytes and somatic tissues. Bioinformatics analyses indicate that a large fraction of the small RNAs are PIWI-interacting RNAs. Up to 23.9% of small RNAs mapped to transposable elements and 27% to genic regions. Most of abundant transposable derived small RNAs are found in oocyte and gastrula libraries, suggesting that transposon needs to be silenced also during early development. Additionally, miRNAs were identified and many of them are not present in oocytes, suggesting that miRNA expression is stage specific. To the best of our knowledge, this is the first high throughput data release and bioinformatics characterization of small RNAs during Xenopus development. PMID- 22253038 TI - Cognitive and adaptive functioning of children with infantile Pompe disease treated with enzyme replacement therapy: long-term follow-up. AB - This report documents the long-term cognitive and adaptive outcome of children with infantile Pompe disease. Specifically, we describe the cognitive and adaptive functioning of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who have received enzyme replacement therapy (Myozyme(r)) for an average of 6 years, 8 months and 4 years, 1. 5 months, respectively. Multiple assessments of cognitive functioning were completed over time by means of individualized intelligence (IQ) testing. Adaptive functioning was measured by means of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Consistent with our earlier findings regarding infants treated with ERT, children with classic infantile Pompe disease (ages 4 years, 11 months to 8 years, 11 months) were functioning at the lower end of the average range in comparison to their typical peers on their most recent IQ test. There was no evidence of a decline in their cognitive abilities over time. In contrast, the two children with atypical infantile Pompe disease (ages 5 years, 4 months and 5 years, 11 months) obtained above average IQ scores and demonstrated significant gains in IQ over time. For all children where adaptive functioning was assessed, their overall level of adaptive functioning on the VABS-II was lower than their Full Scale IQ scores on cognitive testing. Motor function appears to be an important factor impacting on reduced adaptive behavior. The implication of these findings on our understanding of a possible relationship between CNS status in children with Pompe and their adaptive and cognitive function is discussed. PMID- 22253039 TI - Conformational dynamics of capping protein and interaction partners: simulation studies. AB - Capping protein (CP) is important for the regulation of actin polymerization. CP binds to the barbed end of the actin filament and prevents actin polymerization. This interaction is modulated through competitive binding by regulatory proteins such as myotrophin (V-1) and the capping protein interacting (CPI) motif from CARMIL. The binding site of myotrophin overlaps with the region of CP that binds to the barbed end of actin filament, whereas CPI binds at a distant site. The binding of CPI to the myotrophin-CP complex dissociates myotrophin from CP. Detailed multicopy molecular dynamics simulations suggest that the binding of CPI shifts the conformational equilibria of CP away from states that favor myotrophin binding. This shift is underpinned by allosteric effects where CPI inhibits CP through suppression of flexibility and disruption of concerted motions that appear to mediate myotrophin binding. Accompanying these effects are changes in electrostatic interactions, notably those involving residue K142beta, which appears to play a critical role in regulating flexibility. In addition, accessibility of the site on CP for binding the key hydrophobic residue W8 of myotrophin is modulated by CPI. These results provide insights into the modulation of CP by CPI and myotrophin and indicate the mechanism by which CPI drives the dissociation of the myotrophin-CP complex. PMID- 22253040 TI - Zinc-catalyzed depolymerization of artificial polyethers. AB - Recycling polymers: In the present study, the efficient zinc-catalyzed depolymerization of a variety of artificial polyethers has been investigated. Chloroesters were obtained as the depolymerization products, which are suitable precursors for new polymers. By using straightforward zinc salts, extraordinary catalyst activities and selectivities were feasible (see scheme). PMID- 22253041 TI - "First-principles" kinetic Monte Carlo simulations revisited: CO oxidation over RuO2 (110). AB - First principles-based kinetic Monte Carlo (kMC) simulations are performed for the CO oxidation on RuO(2) (110) under steady-state reaction conditions. The simulations include a set of elementary reaction steps with activation energies taken from three different ab initio density functional theory studies. Critical comparison of the simulation results reveals that already small variations in the activation energies lead to distinctly different reaction scenarios on the surface, even to the point where the dominating elementary reaction step is substituted by another one. For a critical assessment of the chosen energy parameters, it is not sufficient to compare kMC simulations only to experimental turnover frequency (TOF) as a function of the reactant feed ratio. More appropriate benchmarks for kMC simulations are the actual distribution of reactants on the catalyst's surface during steady-state reaction, as determined by in situ infrared spectroscopy and in situ scanning tunneling microscopy, and the temperature dependence of TOF in the from of Arrhenius plots. PMID- 22253042 TI - Wet air as an alternative to traditional water irrigation during caloric vestibular testing. AB - OBJECTIVES/HYPOTHESIS: To evaluate whether caloric vestibular testing by wet air (WAI) is better than by dry air (DAI) in comparison to the gold standard using water (WAT). STUDY DESIGN: Prospective study, comparison with reference standard. METHODS: Fifty volunteers with normal ear and balance function were enrolled in a prospective study. After side-specific warm and cold DAI, WAI, and WAT experimental nystagmuses were recorded using video-oculography. Peak slow nystagmus phase velocity (SPV) data at test culmination and the subjective tolerance of the methods were analyzed by visual analog scale. RESULTS: The three methods differed significantly with respect to warm versus cold stimulation and stimulus side, with one exception. In the case of cold stimulation on the left side, SPV values did not differ between DAI and WAI. The intraclass correlation coefficients (ICCs) of WAT versus WAI were indicative of a medium to high agreement with the SPV data for all four individual irrigations. The ICCs of the WAT/DAI comparison were usually smaller. Generally, smaller individual differences were shown in Bland-Altman plots comparing WAI and WAT than plots comparing DAI and WAT. WAI had better subjective tolerability than WAT. CONCLUSIONS: WAI is an alternative caloric test method for anxious subjects oversensitive to WAT and probably for patients with suspected pathological ear canal and tympanic membrane findings. PMID- 22253045 TI - Regulation of murine sinonasal cilia function by microbial secreted factors. AB - BACKGROUND: Chronic rhinosinusitis is a multifactorial disease resulting in impaired mucociliary clearance. Recent literature suggests that different bacterial species are associated with varied disease severity. We examined the immediate effect of microbial secreted factors on sinonasal ciliary function. METHODS: Murine primary sinonasal cultures were established in an air-liquid interface (ALI). Bacterial supernatants were isolated from H. influenza, S. pneumoniae, S. aureus, and P. aeruginosa cultures, as well as co-cultures of H. influenza/S. pneumoniae and S. aureus/P. aeruginosa. Controlling for pH and osmolarity, supernatants were administered at 50% concentration to the apical surface of the ALI culture. Basal ciliary beat frequency (CBF) was recorded for 20 minutes, at 5-minute intervals. Control groups were treated with culture broth. At minimum, experiments were performed in triplicate. Stimulated CBF was recorded after mechanical stimulation via short bursts of pressurized air (55 mmHg). RESULTS: All supernatants reduced basal CBF. S. pneumoniae and P. aeruginosa caused significant reduction in CBF at all time points, with the largest decrease of -46.3 +/- 1.6% (p < 0.001) for S. pneumoniae and -27.1 +/- 2.8% (p < 0.001) for P. aeruginosa. S. aureus caused the basal CBF to decline by 33.0 +/- 2.8% (p < 0.001) at 5 minutes, which reversed by 20 minutes. Overall, H. influenza yielded the least change in CBF (-20.0 +/- 2.8%, p < 0.002). Co cultures (H. influenza/S. pneumoniae and S. aureus/P. aeruginosa) resulted in delayed CBF reduction compared with monocultures. P. aeruginosa also blunted stimulated CBF (p < 0.02). CONCLUSION: Results demonstrated acute decreases in murine sinonasal CBF after exposure to bacterial supernatants. Moreover, P. aeruginosa resulted in diminished ciliary stimulation capacity. PMID- 22253047 TI - Lateral oropharyngeal wall and supraglottic airway collapse associated with failure in sleep apnea surgery. AB - OBJECTIVES/HYPOTHESIS: To identify patterns of airway collapse during preoperative drug-induced sleep endoscopy (DISE) as predictors of surgical failure following multilevel airway surgery for patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). STUDY DESIGN: Retrospective clinical chart review. METHODS: Medical records of patients who underwent site-specific surgical modification of the upper airway for treatment of OSHAS were reviewed. Patients were included in this study if they had a preoperative airway evaluation with DISE as well as preoperative and postoperative polysomnography. Airway obstruction on DISE was described according to airway level, severity, and axis of collapse. Severe airway obstruction was defined as >75% collapse on endoscopy. Surgical success was described as a postoperative apnea-hypopnea index (AHI) of <20 and a >50% decrease in preoperative AHI. RESULTS: A total of 34 patients were included in this study. The overall surgical success rate was 56%. Surgical success (n = 19) and surgical failure (n = 15) patients were similar with regard to age, gender, body mass index, preoperative AHI, Friedman stage, adenotonsillar grades, and surgical management. DISE findings in the surgical failure group demonstrated greater incidence of severe lateral oropharyngeal wall collapse (73.3% vs. 36.8%, P = .037) and severe supraglottic collapse (93.3% vs. 63.2%, P = .046) as compared to the surgical success group. CONCLUSIONS: The presence of severe lateral pharyngeal wall and/or supraglottic collapse on preoperative DISE is associated with OSAHS surgical failure. The identification of this failure prone collapse pattern may be useful in preoperative patient counseling as well as in directing an individualized and customized approach to the treatment of OSHAS. PMID- 22253048 TI - Microglial zinc uptake via zinc transporters induces ATP release and the activation of microglia. AB - Previously, we demonstrated that extracellular zinc plays a key role in transient global ischemia-induced microglial activation through sequential activation of NADPH oxidase and poly(ADP-ribose) polymerase (PARP)-1. However, it remains unclear how zinc causes the sequential activation of microglia. Here, we examined whether transporter-mediated zinc uptake is necessary for microglial activation. Administration of zinc to microglia activated them through reactive oxygen species (ROS) generation and poly(ADP-ribose) (PAR) formation, which were suppressed by intracellular zinc chelation with 25 MUM TPEN (N,N,N',N'-tetrakis(2 pyridylmethyl)ethylenediamine) or 2 MUM BAPTA-AM (1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid-acetoxymethyl ester). The (65)Zn uptake by microglia was temperature- and dose-dependent, and it was blocked by metal cations, but not by L-type calcium channel blockers nifedipine and nimodipine. Expression of Zrt Irt-like protein (ZIP)1, a plasma membrane-type zinc transporter, was detected in microglia, and nickel, a relatively sensitive substrate/inhibitor of ZIP1, showed cis- and trans-inhibitory effects on the (65)Zn uptake. Exposure of microglia to zinc increased the extracellular ATP concentration, which was suppressed by intracellular zinc chelation and inhibition of hemichannels. mRNA expression of several types of P2 receptors was detected in microglia, and periodate-oxidized ATP, a selective P2*7 receptor antagonist, attenuated the zinc-induced microglial activation via NADPH oxidase and PARP-1. Exogenous ATP and 2'(3')-O-(4-benzoyl benzoyl) ATP also caused microglial activation through ROS generation and PAR formation. These findings demonstrate that ZIP1-mediated uptake of zinc induces ATP release and autocrine/paracrine activation of P2X(7) receptors, and then activates microglia, suggesting that zinc transporter-mediated uptake of zinc is a trigger for microglial activation via the NADPH oxidase and PARP-1 pathway. (c) 2011 Wiley-Liss, Inc. PMID- 22253049 TI - The new era of Pompe disease: advances in the detection, understanding of the phenotypic spectrum, pathophysiology, and management. AB - Pompe disease is an autosomal recessive neuromuscular disorder marked by progressive muscle weakness due to lysosomal buildup of glycogen. Presentation is described as a spectrum, varying by age of onset, organ involvement, and degree of myopathy. Given the phenotypic variability, Pompe disease is broadly classified into an infantile form and a late onset (juvenile, childhood, adult onset) form. Prior to the advent of enzyme replacement therapy (ERT) with alglucosidase alfa and approval for human use in 2006, the natural history was limited due to death before age 2 years for infantile onset cases and significant morbidity and early mortality for late onset Pompe disease (LOPD). ERT with alglucosidase alfa redefined the once fatal outcome in infantile Pompe, establishing an emergent phenotype. Treatment in late onset patients resulted in improved outcomes, enhancing understanding of the phenotype, presentation, and extent of organ involvement. This Issue of the Seminars seeks to enumerate the recent advancements in the field of Pompe disease, including newborn screening, novel therapeutic targets, new insights in the pathophysiology including role of autophagy, and impacts of long-term disease burden and CNS glycogen accumulation on cognition in infantile survivors. It also addresses immunological challenges and the critical role of immunomodulation in ERT treatment outcome. Other topics discussed include the role of biomarkers in monitoring disease progression and treatment responses, the role of genotype in defining phenotype and treatment response, better insights into the clinical presentations in LOPD and finally the importance of a multidisciplinary approach to care with the role of physical therapy as an example. Many gaps in our scientific understanding of this disease still remain; however, we hope the next decade will bring new knowledge and therapies to the horizon. PMID- 22253050 TI - Development of Xenopus resource centers: the National Xenopus Resource and the European Xenopus Resource Center. AB - Xenopus is an essential vertebrate model system for biomedical research that has contributed to important discoveries in many disciplines, including cell biology, molecular biology, physiology, developmental biology, and neurobiology. However, unlike other model systems no central repository/stock center for Xenopus had been established until recently. Similar to mouse, zebrafish, and fly communities, which have established stock centers, Xenopus researchers need to maintain and distribute rapidly growing numbers of inbred, mutant, and transgenic frog strains, along with DNA and protein resources, and individual laboratories struggle to accomplish this efficiently. In the last 5 years, two resource centers were founded to address this need: the European Xenopus Resource Center (EXRC) at the University of Portsmouth in England, and the National Xenopus Resource (NXR) at the Marine Biological Laboratory in Woods Hole, MA. These two centers work together to provide resources and support to the Xenopus research community. The EXRC and NXR serve as stock centers and acquire, produce, maintain and distribute mutant, inbred and transgenic Xenopus laevis and Xenopus tropicalis lines. Independently, the EXRC is a repository for Xenopus cDNAs, fosmids, and antibodies; it also provides oocytes and wild-type frogs within the United Kingdom. The NXR will complement these services by providing research training and promoting intellectual interchange through hosting mini-courses and workshops and offering space for researchers to perform short-term projects at the Marine Biological Laboratory. Together the EXRC and NXR will enable researchers to improve productivity by providing resources and expertise to all levels, from graduate students to experienced PIs. These two centers will also enable investigators that use other animal systems to take advantage of Xenopus' unique experimental features to complement their studies. PMID- 22253052 TI - Seven years of experience with high-intensity focused ultrasound for prostate cancer: advantages and limitations. AB - BACKGROUND: The aim of this study was to evaluate oncologic outcomes and adverse events for patients with prostate cancer after treatment by high-intensity focused ultrasound (HIFU). METHODS: Between February 2004 and August 2010, patients with prostate cancer who underwent HIFU treatment were reviewed about oncologic outcomes and complications. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) nadir plus 1.2 ng/ml. Kaplan-Meier analysis was performed to evaluate BCR- and disease progression-free survival according to risk stratification. Predictors for BCR and disease progression were identified using the Cox-proportional hazard method. RESULTS: The overall BCR rate was 59.5%, and median time to BCR was 13.8 months. The 5-year BCR-free survival rates of the low-, intermediate-, and high-risk groups were 66.3, 40.2, and 21.0% (P = 0.001), respectively, and the 5-year disease progression-free survival rates were 73.5, 46.0, and 29.2%, respectively (P = 0.008). Multivariate analysis showed that risk stratification, PSA nadir, and time to PSA nadir were significant predictors of BCR and disease progression. In the first 3 months post-op, 11 patients (8.7%) had complications. There were no patients who required blood transfusions or who had wound problems, stroke, deep vein thrombosis, or bowel dysfunction. CONCLUSIONS: HIFU treatment does not provide effective oncologic outcomes even in low risk patients with prostate cancer as well as in the intermediate or high risk groups. Therefore, patients selected to undergo HIFU treatment for prostate cancer must be very carefully chosen. On the other hand, HIFU treatment for prostate cancer had a very low rate of complications. PMID- 22253051 TI - Pro-apoptotic gene knockdown mediated by nanocomplexed siRNA reduces radiation damage in primary salivary gland cultures. AB - A critical issue in the management of head and neck tumors is radioprotection of the salivary glands. We have investigated whether siRNA-mediated gene knock down of pro-apoptotic mediators can reduce radiation-induced cellular apoptosis in salivary gland cells in vitro. We used novel, pH-responsive nanoparticles to deliver functionally active siRNAs into cultures of salivary gland cells. The nanoparticle molecules are comprised of cationic micelles that electrostatically interact with the siRNA, protecting it from nuclease attack, and also include pH responsive endosomolytic constituents that promote release of the siRNA into the target cell cytoplasm. Transfection controls with Cy3-tagged siRNA/nanoparticle complexes showed efficiently internalized siRNAs in more than 70% of the submandibular gland cells. We found that introduction of siRNAs specifically targeting the Pkcdelta or Bax genes significantly blocked the induction of these pro-apoptotic proteins that normally occurs after radiation in cultured salivary gland cells. Furthermore, the level of cell death from subsequent radiation, as measured by caspase-3, TUNEL, and mitochondrial disruption assays, was significantly decreased. Thus, we have successfully demonstrated that the siRNA/nanoparticle-mediated knock down of pro-apoptotic genes can prevent radiation-induced damage in submandibular gland primary cell cultures. PMID- 22253053 TI - Reversibly shape-shifting organic optical waveguides: formation of organic nanorings, nanotubes, and nanosheets. PMID- 22253054 TI - Comparison of conventional continuous positive airway pressure to continuous positive airway pressure titration performed with sleep endoscopy. AB - OBJECTIVES/HYPOTHESIS: To evaluate the effect and obtain a pressure value of continuous positive airway pressure (CPAP) under direct visualization using drug induced sleep endoscopy (DISE) and compare the pressure values with values obtained using conventional CPAP. STUDY DESIGN: Prospective, double-blinded, cohort study. METHODS: Sixteen patients with obstructive sleep apnea syndrome (OSAS) were included in the study. Each patient underwent polysomnographic evaluation. After diagnosis of OSAS, patients underwent conventional CPAP titration. Patients were then taken to the operating theatre and put under sedation, where CPAP titration with nasendoscopy was performed (DISE CPAP). RESULTS: There were no statistically significant differences between the two techniques regarding pressure levels that decreased apneas in conventional CPAP and provided sufficient opening during DISE CPAP. CONCLUSIONS: Results with conventional CPAP titration and endoscopy-assisted CPAP titration showed no statistically significant difference. Endoscopy-assisted CPAP is a cheaper and less time consuming alternative to conventional CPAP and has similar results. PMID- 22253055 TI - Ginsenoside Rg3 inhibits endothelial progenitor cell differentiation through attenuation of VEGF-dependent Akt/eNOS signaling. AB - Endothelial progenitor cells (EPCs) play a critical role both in vascular repair after cell transplantation for ischemic diseases and in the growth of early tumors by intervening with the angiogenic switch during tumor progression. This paper reports on the effect of ginsenoside Rg3 in EPCs as a candidate angiogenesis inhibitor for in vitro functional assays. CD34+ cells were isolated from human cord blood and the study investigated whether or not ginsenoside Rg3 regulated EPC bioactivities including cell proliferation, differentiation, migration and tube formation. Although ginsenoside Rg3 did not affect the ex vivo expansion of CD34 and/or KDR (VEGFR2) stem/progenitor cells, treatment with ginsenoside Rg3 led to a significant decrease in CD34-expressing cells, specifically the absolute number of expanded CD34+ cells. Importantly, a significantly decreased number of EPC colony-forming units among human cord blood derived CD34+ cells was observed, implying that ginsenoside Rg3 inhibited EPC differentiation, in particular, the commitment to primitive EPC colonies (the early stage of EPC differentiation). Moreover, treatment of CD34-derived EPCs with ginsenoside Rg3 resulted in the attenuation of VEGF-dependent Akt/eNOS signaling as well as the inhibition of migration and tube formation. In conclusion, this study provides in vitro evidence for ginsenoside Rg3 as a potential therapeutic molecule, specifically as an angiogenesis inhibitor that functions by attenuating EPC bioactivities. PMID- 22253056 TI - Evaluation of the ethmoid skull-base height prior to endoscopic sinus surgery: a preoperative computed tomography evaluation technique. AB - INTRODUCTION: Iatrogenic ethmoid skull base (ESB) injury during endoscopic sinus surgery (ESS) is a potentially devastating complication. The height of the ESB can vary substantially and should be assessed during preoperative evaluation of the sinus computed tomography (CT) scan. METHODS: The objective of this study is to describe an objective preoperative CT evaluation technique to assist the surgeon in defining the height of the ESB prior to performing ESS. RESULTS: We propose a technique which measures the height of the ESB from a single horizontal mid-orbital line located on a standardized coronal sinus CT image at the level of the anterior ethmoid artery canal. CONCLUSIONS: Utilization of an objective preoperative CT measurement technique may quantify identification of a low ESB and optimize surgical awareness of this potentially dangerous anatomic skull base variation. PMID- 22253058 TI - Dose-response assessment of naphthalene-induced genotoxicity and glutathione detoxication in human TK6 lymphoblasts. AB - The dose-response relationship for the induction of micronuclei (MN) and the impact of glutathione (GSH) detoxication on naphthalene-induced cytotoxicity and genotoxicity were investigated in human TK6 cells. TK6 cells were exposed to 10 concentrations ranging from 0.0625 to 30MUM naphthalene in the presence of beta naphthoflavone- and phenobarbital (betaNP/PB)-induced rat liver S9 with a nicotinamide adenine dinucleotide phosphate-generating system. Three approaches were used to identify a no-observed-effect level (NOEL) for naphthalene-induced genotoxicity: (1) laboratory criteria of >= twofold increase over the concurrent solvent controls (NOEL = 10MUM), (2) ANOVA with Bonferroni correction (NOEL = 2.5MUM), and (3) the benchmark dose approach (BMCL(10) = 3.35MUM). The NOEL and point of departure micronucleus frequency for naphthalene-induced MN are between the tested naphthalene concentrations of 2.5-10.0MUM in this experimental system. Supplementation of the exposure system with physiological relevant concentrations of 5mM GSH eliminated naphthalene-induced cytotoxicity and genotoxicity; no increased cytotoxicity or genotoxicity was observed at concentrations of up to 500MUM naphthalene in the presence of GSH compared with 2.5-10.0MUM in the absence of GSH. Naphthalene bioactivation by betaNP/PB-induced rat liver S9 exhibits a nonlinear dose-response for the induction of MN in TK6 cells with a NOEL of 2.5-10MUM that in the presence of GSH is shifted upward greater than 50- to 200-fold. These data demonstrate a nonlinear dose-response for naphthalene induced genotoxicity that is eliminated by GSH, and both observations should be considered when assessing human risk from naphthalene exposures. PMID- 22253059 TI - Voids and necks in liquid ammonia and their roles in diffusion of ions of varying size. AB - Voids in a medium are defined as the regions that are located outside an appropriately defined occupied space associated with molecules. Dynamical properties like diffusion can be related to the structure and distribution of voids present in the medium. This work deals with an analysis of voids and diffusion in liquid ammonia. The analysis of voids is done by the construction of Voronoi polyhedra and Delaunay tessellation. We have performed a series of molecular dynamics simulations of monovalent cations and anions of varying size in liquid ammonia at two different temperatures of 210 and 240 K to investigate the effects of ion size on the diffusion of ions and roles of voids in determining the observed diffusion behavior. It is found that with the increase of ion size, the diffusion coefficients first increase and then pass through a maximum similar to the behavior observed earlier for diffusion in water. The observed results are explained in terms of passage through voids and necks that are present in liquid ammonia. PMID- 22253057 TI - Increased sensitivity to testicular toxicity of transplacental benzo[a]pyrene exposure in male glutamate cysteine ligase modifier subunit knockout (Gclm-/-) mice. AB - Polycyclic aromatic hydrocarbons (PAHs), like benzo[a]pyrene (BaP), are ubiquitous environmental pollutants formed by the incomplete combustion of organic materials. The tripeptide glutathione (GSH) is a major antioxidant and is important in detoxification of PAH metabolites. Mice null for the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations. We investigated the effects of Gclm deletion alone on male fertility and spermatogenesis and its effect on the sensitivity of male embryos to the transplacental testicular toxicity of BaP. Gclm-/- males had dramatically decreased testicular and epididymal GCL enzymatic activity and total GSH concentrations compared with Gclm+/+ littermates. Ratios of reduced to oxidized GSH were significantly increased in Gclm-/- testes. GSH reductase enzymatic activity was increased in Gclm-/- epididymides. We observed no changes in fertility, testicular weights, testicular sperm head counts, or testicular histology and subtle changes in cauda epididymal sperm counts, motility, and morphology in Gclm-/- compared with Gclm+/+ males. Prenatal exposure to BaP from gestational day 7 to 16 was dose dependently associated with significantly decreased testicular and epididymal weights, testicular and epididymal sperm counts, and with vacuolated seminiferous tubules at 10 weeks of age. Gclm-/- males exposed prenatally to BaP had greater decreases in testicular weights, testicular sperm head counts, epididymal sperm counts, and epididymal sperm motility than Gclm+/+ littermates. These results show no effects of Gclm deletion alone on male fertility and testicular spermatogenesis and subtle epididymal effects but support increased sensitivity of Gclm-/- males to the transplacental testicular toxicity of BaP. PMID- 22253060 TI - Endoscopic skull base reconstruction of large dural defects: a systematic review of published evidence. AB - OBJECTIVES/HYPOTHESIS: Systematically review the outcomes of endoscopic endonasal techniques to reconstruct large skull base defects (ESBR). Such surgical innovation is likely to be reported in case series, retrospective cohorts, or case-control studies rather than higher level evidence. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Embase (1980-December 7, 2010) and MEDLINE (1950-November 14, 2010) were searched using a search strategy designed to include any publication on endoscopic endonasal reconstruction of the skull base. A title search selected those articles relevant to the clinical or basic science of an endoscopic approach. A subsequent abstract search selected articles of any defect other than simple cerebrospinal fluid (CSF) fistula, sella only, meningoceles, or simple case reports. The articles selected were subject to full text review to extract data on perioperative outcomes for ESBR. Surgical technique was used for subgroup analysis. RESULTS: There were 4,770 articles selected initially, and full-text analysis produced 38 studies with extractable data regarding ESBR. Of these articles, 12 described a vascularized reconstruction, 17 described free graft, and nine were mixed reconstructions. Three had mixed data in clearly defined patient groups that could be used for meta-analysis. The overall CSF leak rate was 11.5% (70/609). This was represented as a 15.6% leak rate (51/326) for free grafts and a 6.7% leak rate (19/283) for the vascularized reconstructions (chi(2) = 11.88, P = .001). CONCLUSIONS: Current evidence suggests that ESBR with vascularized tissue is associated with a lower rate of CSF leaks compared to free tissue graft and is similar to reported closure rates in open surgical repair. PMID- 22253063 TI - First isolation of disubstituted cis-5,6-dihydro-1,10-phenanthrolines. Lipase mediated resolution of cis- and trans-phenoxy alcohol isomers and assignment of absolute stereochemistry via CD and NMR spectroscopy. AB - 5,6-Dihydro-1,10-phenanthrolines can display axial and central chirality. In conjunction with the ligating properties of the diimino moiety, this class of compounds is of great interest to applications in supramolecular chemistry. We report the first preparation of cis-5,6-dihydro-1,10-phenanthroline derivatives by reacting triphenyl borate with the corresponding epoxide precursor. We found that solvent and temperature choice determined the stereoselectivity of the epoxide opening giving rise to the cis (14:1 dr) or trans (99:1 dr) product. Racemates of each stereoisomeric mixture, cis- and trans-phenoxy alcohol, were separated via highly enantioselective transesterifications with lipase PSCI from Burkholderia cepacia (97% ee, E > 200). Stereochemical assignments were carried out using CD and X-ray analyses in conjunction with NMR studies of alpha-methoxy alpha-(trifluoromethyl)phenylacetic acid and alpha-methoxyphenylacetic acid esters. PMID- 22253064 TI - Maintenance of redox state and pancreatic beta-cell function: role of leptin and adiponectin. AB - Whereas oxidative stress is linked to cellular damage, reactive oxygen species (ROS) are also believed to be involved in the propagation of signaling pathways. Studies on the role of ROS in pancreatic beta-cell physiology, in contrast to pathophysiology, have not yet been reported. In this study we investigate the importance of maintaining cellular redox state on pancreatic beta-cell function and viability, and the effects of leptin and adiponectin on this balance. Experiments were conducted on RINm and MIN6 pancreatic beta-cells. Leptin (1-100 ng/ml) and adiponectin (1-100 nM) increased ROS accumulation, as was determined by DCFDA fluorescence. Using specific inhibitors, we found that the increase in ROS levels was mediated by NADPH oxidase (Nox), but not by AMP kinase (AMPK) or phosphatidyl inositol 3 kinase (PI3K). Leptin and adiponectin increased beta-cell number as detected by the XTT method, but did not affect apoptosis, indicating that the increased cell number results from increased proliferation. The adipokines-induced increase in viability is ROS dependent as this effect was abolished by N-acetyl-L-cysteine (NAC) or PEG-catalase. In addition, insulin secretion was found to be regulated by alterations in redox state, but not by adipokines. Finally, the effects of the various treatments on activity and mRNA expression of several antioxidant enzymes were determined. Both leptin and adiponectin reduced mRNA levels of superoxide dismutase (SOD)1. Adiponectin also decreased SOD activity and increased catalase and glutathione peroxidase (GPx) activities in the presence of H2O2. The results of this study show that leptin and adiponectin, by inducing a physiological increase in ROS levels, may be positive regulators of beta-cell mass. PMID- 22253065 TI - Cell analysis in cerebrospinal fluid (CSF) using Sysmex(r) hematology analyzers XT-4000i and XE-5000: evaluation with CSF controls of the Joint German Society for Clinical Chemistry and Laboratory Medicine (DGKL). AB - In cerebrospinal fluid (CSF) analysis, hematology analyzers (HAs) Sysmex(r) XT 4000i and XE-5000, equipped with flow cytometry (FCM), were used to count cells and differentiate leukocytes into mononuclear and polymorphonuclear cells (MNCs, PMCs) applying body fluid mode. FCM was evaluated with 20 DGKL CSF controls containing viable human leukocytes and erythrocytes. HA values were compared with reference values by Passing/Bablok regression analysis to reveal conformity. Conformity of white blood cells (WBCs) was obtained with native leukocytes, counted in calibrated Fuchs-Rosenthal chamber as reference; red blood cell counts proved inaccurate. CV <40% with WBC counts <20 per MUL impairs accuracy. Reference WBC differentiation was assayed using FACS Canto IITM and FC-500 SN with anti-CD45, anti-CD14, anti-CD16, anti-CD16/56 [Becton Dickinson (BD); Beckman Coulter (BC)]. BD FACS lysing solution(r)-no-wash-procedure was applied. BC pretreatment with Versalyse lysing solution was not recommended. MNCs (lymphocytes + monocytes) were significantly lower (~14%) on both HAs; PMCs (granulocytes or sum of neutrophils + eosinophils + basophils: range 1-86 M/L) were significantly higher (~2.2-fold). WBC HA differentiation is not reliable because MNC/PMC differentiation yielded lower and higher values than FACS-FCM references, respectively. This is attributed to incorrect discrimination of leukocytes with rounded/nonrounded nuclei; adding leukocytes with nonrounded nuclei to too low HA MNCs (about 40% not-activated) yielded P/B conformity; subtraction of leukocytes with nonrounded nuclei from elevated HA PMCs showed conformity (about 85% activated). Nucleus/activation state of leukocytes was assessed using microhistology. Sysmex XT-4000i and XE-5000 HAs systems are inappropriate for complete CSF cell analysis. PMID- 22253066 TI - Dysphagia in severe anorexia nervosa: a case report. AB - OBJECTIVE: The purpose of this case report is to increase awareness among clinicians that oropharyngeal dysphagia occurs in patients with severe anorexia nervosa, placing them at risk for aspiration and impeding nutritional rehabilitation. METHOD: We describe a patient with severe anorexia nervosa who manifested symptoms of dysphagia, with resultant aspiration pneumonia, at the time of her admission for medical stabilization. RESULTS: The speech pathology team administered dysphagia therapy, using neuromuscular electrical stimulation (NMES) in conjunction with swallowing therapy. Following the course of dysphagia treatment intervention, the patient was able to tolerate an oral diet with improved swallowing function and no ongoing aspiration. DISCUSSION: Patients with severe anorexia nervosa should be screened for possible dysphagia. NMES in the treatment of dysphagia in patients with anorexia nervosa may reduce the need for enteral feeds and prolonged hospitalization. PMID- 22253067 TI - Importance of normohydration for the long-term survival of haemodialysis patients. AB - BACKGROUND: Fluid overload and hypertension are among the most important risk factors for haemodialysis (HD) patients. The aim of this study was to analyse the impact of fluid overload for the survival of HD patients by using a selected reference population from Tassin. METHODS: A positively selected HD population (n = 50) from Tassin (Lyon-France) was used as a reference for fluid status and all cause mortality. This population was compared to one dialysis centre from Giessen (Germany) which was separated into a non-hyperhydrated (n = 123) and a hyperhydrated (n = 35) patient group. The hydration status (DeltaHS) of all patients was objectively measured with whole-body bioimpedance spectroscopy in 2003. All-cause mortality was analysed after a 6.5-year follow-up. RESULTS: Most of the reference patients from Tassin were normohydrated (DeltaHS = 0.25 +/- 1.15 L) at the start of the HD session. The hydration status of the Tassin patients was not different to the non-hyperhydrated Giessen patients (DeltaHS = 0.8 +/- 1.1 L) but significantly lower than in the hyperhydrated Giessen group (DeltaHS = 3.5 +/- 1.2 L). Multivariate adjusted all-cause mortality was significantly increased in the hyperhydrated patient group (hazard ratio = 3.41)- no difference in mortality could be observed between the Tassin and the non-hyperhydrated group from Giessen-even considering the fact that Tassin patients presented a significantly lower blood pressure. CONCLUSIONS: Fluid overload has a very high predictive value for all-cause mortality and seems to be one of the major killers in the HD population. Patients might strongly benefit from active management of fluid overload. PMID- 22253068 TI - Altitude and the risk of cardiovascular events in incident US dialysis patients. AB - BACKGROUND: Altitude is associated with all-cause mortality in US dialysis patients, but its association with cardiovascular outcomes has not been assessed. We hypothesized that higher altitude would be associated with lower rates of cardiovascular events due to an altered physiological response of dialysis patients to altitude induced hypoxia. METHODS: We studied 984,265 patients who initiated dialysis from 1995 to 2006. Patients were stratified by the mean elevation of their residential zip codes and were followed from the start of dialysis to the occurrence of several validated cardiovascular endpoints: myocardial infarction, stroke, cardiovascular death and a composite of these end points. Incidence rate ratios across altitude strata were estimated using proportional hazards regression. RESULTS: All outcomes occurred less frequently among patients living at higher altitude compared with patients living at or near sea level, and the association appeared monotonic for all outcomes except for stroke, which was most incident in the 250-1999 ft group. Compared with otherwise similar patients residing at or near sea level, patients living at >= 6000 ft had 31% [95% confidence interval (CI): 21-41%] lower rates of myocardial infarction, 27% (95% CI: 15-37%) lower rates of stroke and 19% (95% CI: 14-24%) lower rates of cardiovascular death. Additional adjustment for biometric information did not materially change these findings. Effect modification between race and altitude was only consistently significant for Native Americans. Altitude did not significantly alter the rates of non-cardiovascular death. CONCLUSION: We conclude that dialysis patients at higher altitude experience lower rates of cardiovascular events compared to otherwise similar patients at lower altitude. PMID- 22253069 TI - Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction. AB - BACKGROUND: We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD). METHODS: Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD. RESULTS: In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD 0 was diagnosed based on clinical criteria. CONCLUSIONS: In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD. PMID- 22253070 TI - Inverted papilloma of the nasal cavity and paranasal sinuses: a Korean multicenter study. AB - OBJECTIVES/HYPOTHESIS: The study group for sinonasal tumors at the Korean Rhinologic Society analyzed the results of the Korean multicenter experience for sinonasal inverted papilloma (IP) surgeries. STUDY DESIGN: Multicenter cohort study and retrospective analysis. METHODS: In total, 939 patients diagnosed with sinonasal IP treated between 1998 and 2007 at 17 university hospitals were enrolled. Demographic data and information about previous surgeries, the origin and involved site of the tumor, the surgical approach, follow-up duration, recurrence, and the presence of malignancy were collected. There were 361 patients whose follow-up was <12 months who were excluded, and 578 patients were included for recurrence analysis. RESULTS: The mean follow-up duration for recurrence analysis was 41.0 months, and 15.7% (91/578) had recurrences, with a mean time to recurrence of 32.6 months. However, the group whose follow-up was longer than 3 years had a higher chance of tumor recurrence. Patients whose IPs involved the frontal sinus or the medial wall of the maxillary sinus had higher recurrence rates. There was no significant difference in recurrence rates according to stage or surgical approach. In the T3 stage of Krouse, the T3-A stage of Furuta, and group B of the Citardi staging system, the endoscopic approach alone resulted in higher recurrence rates. CONCLUSIONS: Generally, there were no significant differences in recurrence rates according to clinical stage or surgical approach. Given the rate of delayed recurrence, follow-up of >3 years is required. Moreover, surgeons should always consider combined approaches to reduce the chances of recurrence. PMID- 22253071 TI - Dual effects of phloretin on aflatoxin B1 metabolism: activation and detoxification of aflatoxin B1. AB - Typically, chemopreventive agents involve either induction of phase II detoxifying enzymes and/or inhibition of cytochrome P450 enzymes (CYPs) that are required for the activation of procarcinogens. In this study, we investigated the protective effects of phloretin against aflatoxin B1 (AFB1) activation to the ultimate carcinogenic intermediate, AFB(1)-8, 9-epoxide (AFBO), and its subsequent detoxification. Phloretin markedly inhibited formation of the epoxide with human liver microsomes in a dose-dependent manner. Phloretin also inhibited the activities of nifedipine oxidation and ethoxyresorufin O-deethylase (EROD) in human liver microsomes. These data show that phloretin strongly inhibits CYP1A2 and CYP3A4 activities, which are involved in the activation of AFB1. Phloretin increased glutathione S-transferase (GST) activity of alpha mouse liver 12 (AML 12) cells in a dose-dependent manner. GST activity toward AFBO in cell lysates treated with 20 MUM phloretin was 23-fold that of untreated control cell lysates. The expression of GSTA3, GSTA4, GSTM1, GSTP1 and GSTT1 was induced by phloretin in a dose-dependent manner in AML 12 cells. GSTP1, GSTM1, and GSTT1 were able to significantly increase the conjugation of AFBO with glutathione. Concurrently, induction of the GST isozyme genes was partially associated with the Nrf2/ARE pathway. Taken together, the results demonstrate that phloretin has a strong chemopreventive effect against AFB1 through its inhibitory effect on CYP1A2, CYP3A4, and its inductive effect on GST activity. PMID- 22253072 TI - Synthesis of functionalized benzo[b]thiophenes by the intramolecular copper catalyzed carbomagnesiation of alkynyl(aryl)thioethers. PMID- 22253073 TI - Eustachian tube balloon dilation surgery. AB - BACKGROUND: Eustachian tube dysfunction (ETD) is a common condition without an effective, accepted treatment. Balloon dilation Eustachian tuboplasty (BDET) has been recently proposed for the management of ETD. Previous studies of Eustachian tube function and treatment have not included a validated assessment of patient symptoms. We report for the first time the outcomes of BDET using a validated disease-specific symptom score, the 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7). METHODS: Consecutive patients undergoing BDET were prospectively enrolled from an otolaryngology practice at a tertiary care medical center. Inclusion criteria were adults with a diagnosis of ETD based on symptoms and abnormal tympanogram. Patients with craniofacial abnormalities or active infection were excluded from study. Primary outcome measures included the ETDQ-7 score, tympanometry, and otoscopic appearance. Secondary measures included the 22 item Sinonasal Outcome Test (SNOT-22) score. RESULTS: Twenty-two consecutive patients underwent 35 BDET procedures. Significant postoperative improvement was seen in tympanometry and otoscopic appearance (p < 0.001). ETDQ-7 scores at 3 weeks, 6 weeks, 12 weeks, and 6 months postoperatively were significantly improved over baseline (p < 0.001). ETDQ-7 scores showed fair correlation with SNOT-22 scores (r > 0.65). ETDQ-7 change scores demonstrated good responsiveness and sensitivity to clinical change following BDET. CONCLUSION: BDET is an effective surgical intervention for the treatment of ETD in adults. Postoperative improvements were observed using objective and subjective measures. The ETDQ-7 is a valid, disease-specific instrument for the assessment of treatment outcomes and may be applied for clinical use in patients with ETD. Further study is necessary to determine long-term effectiveness. PMID- 22253075 TI - Chemically modified fullerene derivatives as photosensitizers in photodynamic therapy: a first-principles study. AB - The first-principles density functional theory (DFT) and its time-dependent approach (TD-DFT) are used to characterize the electronic structures and optical spectra properties of five chemically modified fullerenes. It is revealed that the metal fullerene derivatives possess not only stronger absorption bands in visible light regions than organically modified fullerene but also the large energy gaps (DeltaE(S-T) > 0.98 eV) between the singlet ground state and the triplet state, which imply their significant aspect of potential candidates as a photosensitizer. We have found that a new metal-containing bisfullerene complexes (Pt(C(60) )(2) ), with the extended conjugated pi-electrons, much degenerate orbitals and a uniform electrostatic potential surface, behave more pre-eminent photosensitizing properties than other examined fullerene derivatives. PMID- 22253074 TI - Cyr61 increases matrix metalloproteinase-3 expression and cell motility in human oral squamous cell carcinoma cells. AB - Oral squamous cell carcinoma (OSCC) has a striking tendency to migrate and metastasize. Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth and differentiation. However, the effects of Cyr61 on human OSCC cells are largely unknown. In this study, we found that Cyr61 increased the migration and the expression of matrix metalloproteinases-3 (MMP)-3 in human OSCC cells. alphavbeta5 or alpha6beta1 monoclonal antibody (mAb), focal adhesion kinase (FAK) inhibitor, and mitogen-activated protein kinase (MEK) inhibitors (PD98059 and U0126) inhibited the Cyr61-induced increase of the migration and MMP-3 up regulation of OSCC cells. Cyr61 stimulation increased the phosphorylation of FAK, MEK, and extracellular signal-regulated kinase (ERK). In addition, NF-kappaB inhibitors suppressed the cell migration and MMP-3 expression enhanced by Cyr61. Moreover, Cyr61 increased NF-kappaB luciferase activity and binding of p65 to the NF-kappaB element on the MMP-3 promoter. Taken together, our results indicate that Cyr61 enhances the migration of OSCC cells by increasing MMP-3 expression through the alphavbeta3 or alpha6beta1 integrin receptor, FAK, MEK, ERK, and NF kappaB signal transduction pathway. PMID- 22253076 TI - Reversible control of electrochemical properties using thermally-responsive polymer electrolytes. AB - A thermally responsive copolymer is designed to modulate the properties of an electrolyte solution. The copolymer is prepared using pNIPAM, which governs the thermal properties, and acrylic acid, which provides the electrolyte ions. As the polymer undergoes a thermally activated phase transition, the local environment around the acid groups is reversibly switched, decreasing ion concentration and conductivity. The responsive electrolyte is used to control the activity of redox electrodes with temperature. PMID- 22253077 TI - Toward wearable sensors: fluorescent attoreactor mats as optically encoded cross reactive sensor arrays. PMID- 22253078 TI - Flow cytometric characterization of "early" and "late differentiated" T-cells including PR3-specific cells in granulomatosis with polyangiitis (Wegener's). PMID- 22253079 TI - Developmental patterns and family predictors of adolescent weight concerns: a replication and extension. AB - OBJECTIVE: We examined how weight concerns changed across adolescence and whether within-person changes in parent-adolescent relationships were longitudinally linked to within-person changes in adolescent weight concerns. METHOD: Participants were mothers, fathers, and the two eldest adolescent siblings from 201 families. Adolescents rated their weight concerns on five occasions across 7 years. Parents rated their acceptance of and conflict with their adolescents, and adolescents rated their depressive symptoms, a year prior to each weight concern measurement. RESULTS: Although girls' weight concerns increased from early to late adolescence and then leveled off, boys' weight concerns remained relatively unchanged. Moreover, controlling for adolescents' depressive symptoms, when mothers reported less acceptance of and fathers reported more conflict with their adolescents than usual, adolescents reported more weight concerns than usual in the following year. DISCUSSION: Findings highlight the vulnerability of adolescents and the role of both mothers and fathers in the etiology of weight related problems. PMID- 22253081 TI - [Restless legs syndrome - a review]. AB - Restless legs syndrome (RLS) is a common disorder with a prevalence between 10 20% in Iceland. There are two forms of RLS, idiopathic and secondary. Symptom onset of RLS before the age of 45 suggests an idiopathic form with no known underlying cause but inheritance. Symptom onset after age of 45 indicates a secondary form with an underlying cause without inheritance. Causes for secondary forms are for example: iron depletion, uraemia and polyneuropathy. Symptoms of RLS are uncomfortable and unpleasant deep sensations in the legs that are felt at rest, accompanied by an urge to move the legs, typically just before sleep. Accompanying RLS is a sleep disturbance that can lead to daytime somnolence, decreased quality of life, poor concentration, memory problems, depression and decreased energy. Dopamine agonists are currently the first line treatment for RLS. KEYWORDS: restless legs, periodic limb movements, sleep disturbance, dopamine agonists. PMID- 22253080 TI - [Endocarditis in Iceland 2000-2009, a national survey incidence, microbiology and prognosis]. AB - INTRODUCTION: The objective of this study was to analyze the incidence, clinical features, microbiology and prognosis of patients with infective endocarditis (IE) in Iceland, and to compare the results with a previous study made in Iceland 1976 85. MATERIAL AND METHODS: A retrospective study including all patients diagnosed with IE in Iceland 2000-2009. Information was obtained from medical records. RESULTS: A total of 88 cases (71% men, mean age 59 years) were diagnosed and the incidence of IE was calculated 2.97/100.000 person-years. The mitral valve was infected in 35 patients (40%), aortic in 27 (31%) and tricuspid in 9 (10%). In 19 cases a prosthetic valve was infected (22%), one early (<<60 days from procedure) and 18 late. Sixteen patients were intravenous drug users. The most common causative organisms were streptococcus (33%), staphylococcus (25%) and enterococcus (16%). Surgical intervention was performed in 16 cases (18%). One and five year survival was 77% and 57% respectively. CONCLUSION: The incidence of IE in Iceland is still low compared to other countries. The clinical profile of the disease has changed since 1976-85, patients with prosthetic heart valves and intravenous drug users were more prominent than before. The microbiological spectrum has not changed much, streptococcus is still the most common pathogen, contrary to what is seen in other industrial countries where S. aureus is more frequent. Death rate is lower than before and one year survival good compared to other reports. PMID- 22253082 TI - [The outcomes of coronary artery bypass and aortic valve replacement in elderly patients]. AB - OBJECTIVE: To study the outcome of open heart surgery in an increasing population of elderly patients in Iceland. MATERIAL AND METHODS: A retrospective study of patients (n=876) that underwent coronary artery bypass (CABG) or aortic valve replacement (AVR) for aortic stenosis in Iceland 2002-2006. Complication rates, operative mortality and long-term survival were compared between patients older (n=221, 25%) and younger (n=655, 75%) than 75 years. Long-term survival of the older group was compared to an age and sex matched reference population. RESULTS: Older patients had a higher incidence of atrial fibrillation (57% vs. 37%, p<0.001), stroke (5% vs. 1%, p=0.009) and operative mortality (9% vs. 2%, p<0.001) following CABG. Length of ICU stay was similar but total length of stay was one day longer in the older cohort. Following AVR, older patients had a higher incidence of atrial fibrillation (90% vs. 71%, p=0.006), ARDS (19% vs. 7%, p=0.04), myocardial infarction (21% vs. 8%, p=0.05) and operative mortality (11% vs. 2%, p=0.04). The ICU stay was a day longer and the total length of stay was about four days longer in the older cohort. A total of 75% of the older patients were alive five years after CABG, compared to 74% of the reference population (p=0.87). Similar numbers for AVR were 65% for the patients compared to 74% in the reference population (p=0.06). CONCLUSION: The rate of complications, operative mortality and length of hospital stay is higher in patients older than 75 years compared to younger patients. Survival of the older group of patients indicates good long-term results after open heart surgery for this patient cohort. PMID- 22253083 TI - [Relationship between pre-adoptive risk factors and psychopathological difficulties of internationally adopted children in Iceland]. AB - OBJECTIVE: In recent years a number of children have been adopted to Iceland. The aim of our study was to evaluate which factors may affect their mental and behavioural health. MATERIALS AND METHODS: Information was collected on the health of internationally adopted children in Iceland as well as on pre-adoptive risk factors. This was done using a survey developed by Dr. Dana Johnson from the International Adoption Project at the University of Minnesota in the United States. Other questionnaires include the Child Behavior Checklist (CBCL), Strenghts and Difficulties Questionnaires (SDQ), Attention Deficit/Hyper activity Rating Scale (ADHD-RS-IV) and Austism Spectrum Screening Questionaire (ASSQ). For the comparative analysis data from the general population was used. RESULTS: Children adopted after 18 months of age and who have been institutionalised for 18 months or more showed higher risk for ADHD symptoms and behavioral and emotional problems than the general population. In addition, those who were subject to severe emotional neglect had significantly higher scores on CBCL, SDQ and ADHD-RS. A trend was seen between risk factors and scores on ASSQ. Children adopted before 12 months of age scored within the normal range on all questionnaires. CONCLUSION: These results suggest that children adopted after 18 months of age are at risk of psychopathological difficulties. These results emphasize the importance of early adoption and of minimizing the time spent in an institution. PMID- 22253084 TI - [Health care in rural areas during budget cuts]. PMID- 22253085 TI - [High sensitivity cardiac troponin T - friend or foe?]. PMID- 22253086 TI - Predicting death in patients with acetaminophen-induced acute liver failure: the King's College Hospital model is on the SOFA, not the mat. PMID- 22253087 TI - Assessment of glycosaminoglycan concentration changes in the intervertebral disc via chemical exchange saturation transfer. AB - In this study, it is shown that the chemical exchange saturation transfer (CEST) method for hydroxyl protons can be used to detect changes in glycosaminoglycan (GAG) concentration in the intervertebral disc. The method, termed gagCEST, was demonstrated ex vivo by correlating the CEST effect with the fixed charge density (FCD) of the nucleus pulposus (NP), as well as by correlating tissue CEST images with their corresponding (23)Na images. Incubation of five NP samples with trypsin produced samples with varying GAG content (n = 19). A good correlation was found between the -OH CEST effect and FCD, as well as with the N-acetyl signal amplitude. gagCEST images in vitro further illustrated the amount of detail obtainable from this contrast mechanism when compared with conventional imaging. The large concentration of GAG and the relatively long T(1) of water in NP make the method sensitive, in particular, for the assessment of GAG depletion in this tissue. It is the loss of GAG in NP that indicates the early stage of disc degeneration. PMID- 22253088 TI - Metabolic consequences of treatment with AKT inhibitor perifosine in breast cancer cells. AB - Activation of the PI3K/Akt pathway is associated with the development of numerous human cancers. As a result, many emerging therapies target this pathway. Previous studies have shown that targeting the PI3K/Akt pathway at the level of PI3K is associated with a drop in phosphocholine (PCho) and a reduction in hyperpolarized lactate production. However, the consequences of targeting downstream of PI3K at the level of Akt have not been investigated. Perifosine is an anticancer alkylphospholipid used in clinical trials. It acts by inhibiting phosphorylation of Akt and has been shown to inhibit CTP-phosphocholine cytidyltransferase (CT). The goal of this study was to identify the MRS-detectable metabolic consequences of treatment with perifosine in MCF-7 breast cancer cells. We found that perifosine treatment led to a 51 +/- 5% drop in PCho from 30 +/- 5 to 15 +/- 1 fmol/cell and a comparable drop in de novo synthesized PCho. This was associated with a drop in choline kinase (ChoK) activity and ChoKalpha expression. CT inhibition could not be ruled out but likely did not contribute to the change in PCho. We also found that intracellular lactate levels decreased from 2.7 +/- 0.5 to 1.5 +/- 0.3 fmol/cell and extracellular lactate levels dropped by a similar extent. These findings were consistent with a drop in lactate dehydrogenase expression and associated with a drop in activity of the hypoxia inducible factor (HIF)-1alpha. The drops in PCho and lactate production following perifosine treatment are therefore mediated downstream of Akt by the drop in HIF-1alpha, which serves as the transcription factor for both ChoK and lactate dehydrogenase. The metabolic changes were confirmed in a second breast cancer cell line, MDA-MB 231. Taken together, these findings indicate that PCho and lactate can serve as noninvasive metabolic biomarkers for monitoring the effects of inhibitors that target the PI3K/Akt pathway, independent of the step that leads to inhibition of HIF-1alpha. PMID- 22253090 TI - 3 Tesla turbo-FLASH magnetic resonance imaging of deglutition. AB - OBJECTIVES/HYPOTHESIS: In this article we describe a methodology for obtaining high-quality dynamic magnetic resonance imaging (MRI) sequences of the swallow sequence in healthy volunteers. The study includes comparison to previous work done in our lab using a 1.5 Tesla (T) magnet. STUDY DESIGN: Case series. METHODS: Three healthy volunteers underwent turbo-fast low angle shot MRI at 3T while swallowing liquid boluses delivered via intravenous tubing to the oral cavity. Imaging was performed in the sagittal and axial planes. RESULTS: Imaging provided by this sequence provided high temporal resolution, with the ability to depict deglutition in the axial and sagittal planes. Comparison with imaging at 1.5 T demonstrated benefits in temporal resolution and signal-to-noise. Anatomic information provided differed from comparative videofluoroscopy. CONCLUSIONS: MRI of swallowing using the described technique is reliable and provides a unique evaluation of the swallowing sequence. PMID- 22253092 TI - An epigenetic integrator: new insights into genome regulation, environmental stress responses and developmental controls by histone deacetylase 6. AB - Histone acetylation ranks with DNA methylation as one of major epigenetic modifications in eukaryotes. Deacetylation of histone N-terminal tails is intimately correlated with gene silencing and heterochromatin formation. In Arabidopsis, histone deacetylase 6 (HDA6) is a well-studied histone deacetylase that functions in gene silencing. Recently, it has been reported that HDA6 cooperates with DNA methylation on its direct target locus in the gene silencing mechanism. HDA6 has the multifaceted role in regulation of genome maintenance, development and environmental stress responses in plants. Elucidation of HDA6 function provides important information for understanding of epigenetic regulation in plants. In this review, we highlight recent progress in elucidating the HDA6-mediated gene silencing mechanisms and deciphering the biological function of HDA6. PMID- 22253091 TI - Well-defined, reversible boronate crosslinked nanocarriers for targeted drug delivery in response to acidic pH values and cis-diols. PMID- 22253093 TI - Endoscopic skull base surgery and its impact on sinonasal-related quality of life. AB - BACKGROUND: Endoscopic skull base surgery (ESBS) is considered a minimally invasive surgical modality with less morbidity and patient discomfort. Quality-of life (QOL) assessments provide a patient-reported estimate of well-being that may be clinically relevant. Although the sinonasal tract is integral to ESBS, the change in sinonasal-related QOL with ESBS has not been well studied. The aim of this study was to prospectively assess QOL before and after ESBS using validated outcome measures. METHODS: Consecutive adult patients undergoing ESBS for anterior skull base lesions were prospectively enrolled from a tertiary referral center. Each patient was asked to complete the 22-item Sinonasal Outcome Test (SNOT-22) and the Anterior Skull Base Questionnaire (ASBQ) preoperatively, and again at 3 weeks, 6 weeks, 12 weeks, 6 months, and 1 year postoperatively. RESULTS: Eighty-five patients were included for study, 44.7% of whom underwent ESBS for nonpituitary pathology. Mean SNOT-22 scores transiently worsened in the early postoperative period, and significantly improved at 1 year after surgery (p < 0.01). Gross-total tumor resection and use of autologous grafting materials were associated with improved SNOT-22 scores at later time points (p < 0.05). Type of reconstruction, tumor pathology, and functionality did not affect QOL scores. Correlation between SNOT-22 and ASBQ scores was good at all time points (r < -0.50). Cerebrospinal fluid leak and other complications were uncommon. CONCLUSION: ESBS does not have a detrimental long-term effect and is associated with ultimate improvement in sinonasal-related QOL. Short-term impairments of sinonasal-related QOL are predictable and self-limited. Prospective assessment using sinonasal-related and site-specific QOL instruments provide complementary information about ESBS outcomes. PMID- 22253094 TI - Robust large dimension terahertz cloaking. AB - A large scale homogenous invisibility cloak functioning at terahertz frequencies is reported. The terahertz invisibility device features a large concealed volume, low loss, and broad bandwidth. In particular, it is capable of hiding objects with a dimension nearly an order of magnitude larger than that of its lithographic counterpart, but without involving complex and time-consuming cleanroom processing. PMID- 22253095 TI - The cytoprotective effect of butin against oxidative stress is mediated by the up regulation of manganese superoxide dismutase expression through a PI3K/Akt/Nrf2 dependent pathway. AB - Butin (7,3',4'-trihydroxydihydroflavone), a flavonoid with antioxidant activity, was recently reported to protect cells against H2O2-induced apoptosis, oxidative DNA damage and oxidative mitochondrial dysfunction. The objective of the present study was to elucidate the mechanism by which butin protects mitochondria. The antioxidant function of manganese superoxide dismutase (Mn SOD) is important in preventing oxidative stress. While exposure to H2O2 reduced the expression of Mn SOD in Chinese hamster lung fibroblast (V79-4), the addition of butin restored Mn SOD expression at both the mRNA and protein levels, resulting in increased Mn SOD activity. The transcription factor NF-E2-related factor 2 (Nrf2) regulates Mn SOD gene expression by binding to the antioxidant responsive element (ARE). Butin enhanced the nuclear translocation and ARE-binding activity of Nrf2, which was decreased by H2O2. The siRNA-mediated knockdown of Nrf2 attenuated butin-induced Mn SOD expression and activity. Further, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) contributed to the ARE-driven Mn SOD expression. Butin activated PI3K/Akt and exposure to either LY294002 (a PI3K inhibitor), Akt inhibitor IV (an Akt-specific inhibitor), or Akt siRNA suppressed the butin-induced activation of Nrf2, resulting in decreased Mn SOD expression and activity. Finally, the cytoprotective effect of butin against H2O2-induced cell damage was suppressed by the siRNA-mediated knockdown of Mn SOD. These studies demonstrate that butin attenuates oxidative stress by activating Nrf2 mediated Mn SOD induction via the PI3K/Akt signaling pathway. PMID- 22253096 TI - Does the overvaluation of shape and weight predict initial symptom severity or treatment outcome among patients with binge eating disorder? AB - OBJECTIVE: To examine whether overvaluation of shape and weight is associated with initial symptom severity or treatment outcome among patients with binge eating disorder (BED). METHOD: Patients with BED (n = 116) completed assessments at baseline and treatment termination, including the Eating Disorder Examination (EDE) and self-report measures of eating-related cognitions and behaviors, depression, and self-esteem. Clinical overvaluation was determined by EDE. RESULTS: The clinical overvaluation group demonstrated significantly higher pre treatment scores on measures of depression, behavioral and cognitive aspects of binge eating, and eating-related psychopathology, and lower self-esteem scores than individuals without overvaluation. At treatment termination, patients with overvaluation continued to display elevated scores on measures of binge eating severity at a trend level. DISCUSSION: Overvaluation of shape and weight was associated with symptom severity in patients with BED, but additional research is needed to determine whether this construct holds clinically useful predictive validity for treatment outcome. PMID- 22253097 TI - Monocillin II inhibits human breast cancer growth partially by inhibiting MAPK pathways and CDK2 Thr160 phosphorylation. AB - Twenty-two beta-resorcylic acid lactones (RALs) were evaluated for cytotoxicity against human breast cancer cells to find their structure-activity relationship (SAR). Monocillin II, a trans-enone RAL without epoxy and conjugated dienone, was found to have higher activity in inhibiting tumor cell growth in both in vitro experiment and in vivo nude xenografted mice model than its analogue radicicol, an anticancer lead compound. We demonstrated for the first time that monocillin II could arrest breast cancer cell cycle in G1 phase, which might partially be the result of its inhibition effect on the phosphorylation of the Thr160 residue of cyclin dependent kinase 2 (CDK2), a key enzyme in cell-cycle regulation. Moreover, monocillin II exhibited inhibition of heat shock protein 90 (Hsp90) and depleted its target proteins, Raf-1 and A-Raf, which are involved in Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway. Remarkably, we found that monocillin II could inhibit activation of MAPKs including ERK, JNK and p38, which might be involved in the inactivation of CDK2. These results suggest that monocillin II has potential therapeutic benefits in breast cancer prevention and intervention. PMID- 22253098 TI - Chemical constituents and some biological activities of plants from the genus Ceriops. AB - In this review, the literature data on phytochemical and biological investigations of the genus Ceriops are compiled. The Ceriops species are mangrove plants widely distributed along the sea coasts of Africa, Madagascar, South Asia, and South Pacific islands. To date, 43 diterpenes and 29 triterpenes have been reported from the embryos, fruits, hypocotyls, roots, stems, and twigs of C. tagal and C. decandra. Diterpenoids and triterpenoids are the main constituents of this genus. The isolated terpenes showed an enormous structural diversity and exhibited various biological properties, such as antitumor, antibacterial, and larvicidal activities. PMID- 22253099 TI - Antimicrobial efficacy of Achillea ligustica All. (Asteraceae) essential oils against reference and isolated oral microorganisms. AB - The aim of this study was to verify the effectiveness of Achillea ligustica essential oils against several oral microorganisms in comparison with a commercial essential oil-containing mouthrinse (Listerine((r))) and clove oil (containing 89% eugenol). The inhibition efficacy of A. ligustica essential oils alone and in combination with Listerine((r)) was evaluated by the micro-dilution method. The most susceptible microorganisms were Bacillus cereus, Streptococcus pyogenes, and Candida albicans. The efficacy was similar to that of the clove oil. The antiseptic mouthwash Listerine((r)) did not exert a strong inhibition on microbial strains tested, whereas its effectiveness increased significantly when essential oil was added. The study provides additional evidence for the in vitro inhibitory activity of A. ligustica essential oils on several pathogens, suggesting their usefulness in mouthrinse formulations as an adjunct to mechanical oral hygiene regimens. Essential oil-containing mouthrinses can be beneficial, safe components of daily oral health routines, representing an efficient and without side effect alternative to prevent and control oral infections. PMID- 22253100 TI - New insights into the characterization of 'insoluble black HCN polymers'. AB - The data presented here provide a novel contribution to the understanding of the structural features of HCN polymers and could be useful in further development of models for prebiotic chemistry. The interpretation of spectroscopic and analytical data, along with previous results reported by other authors, allowed us to propose a mechanism for the aqueous polymerization of HCN from its primary and simplest isolated oligomer, the diaminomaleonitrile (DAMN) tetramer. We suggest that 'insoluble black HCN polymers' are formed by an unsaturated complex matrix, which retains a significant amount of H(2) O and important bioorganic compounds or their precursors. This polymeric matrix can be formed by various motifs of imidazoles and cyclic amides, among others. The robust formation of HCN polymers assayed under several conditions seems to explain the plausible ubiquity of these complex substances in space. PMID- 22253101 TI - Synthesis and structure-activity relationships of antifungal crassinervic acid analogs. AB - A series of analogs of the natural antifungal compound crassinervic acid, a constituent of Piper crassinervium, were synthesized to gain insight into the most relevant structural features affecting the activity of the parent molecule. Most compounds were prepared by aldol reaction of methyl 3-acetyl-4 hydroxybenzoate with a series of ketones, followed by reduction, hydrolysis, and oxidation. The antifungal activities of crassinervic acid and its analogs was assessed against Cladosporium cladosporioides by using the method of bioautography. The bioassay results allowed us to depict structure?activity relationships for this class of compounds. PMID- 22253102 TI - One-pot synthesis of new (1,3-thiazolo[5,4-b]pyridin-2-yl)benzenediols and their antiproliferative activities against human cancer cell lines. AB - A one-pot synthesis of new 4-(1,3-thiazolo[5,4-b]pyridin-2-yl)benzene-1,3-diols has been described. The compounds were prepared by the reaction of sulfinylbis[(2,4-dihydroxyphenyl)methanethione] derivatives, with various substituents in the aryl rings, with 2-chloropyridin-3-amines. Their structures were deduced from IR and, (1) H- and (13) C-NMR spectroscopic, mass spectrometric, and elemental analyses. The antiproliferative properties of some of the products against human cancer cell lines were comparable to those of cisplatin. Structure-activity analysis showed that the presence of hydrophobic substituents in both heterocyclic fused and phenyl rings of the compounds improves their biological effects. Further, an additional OH group in the resorcinol moiety reduced the antiproliferative activity. PMID- 22253103 TI - Haemolytic activity and immunological adjuvant effect of a new steroidal saponin from Allium ampeloprasum var. porrum. AB - A new steroidal saponin was isolated from the bulbs of Allium ampeloprasum L. var. porrum. On the basis of chemical evidence, comprehensive spectroscopic analyses, and comparison with known compounds, its structure was established as (3beta,5alpha,6beta,25R)-3-{(O-beta-D-glucopyranosyl-(1->3)-beta-D-glucopyranosyl (1->2)-O-[O-beta-D-glucopyranosyl-(1->3)]-O-beta-D-glucopyranosyl-(1->4)-beta-D galactopyranosyl)oxy}-6-hydroxyspirostan-2-one (1). Results of the present study indicated that 1 exhibited haemolytic activity in the in vitro assays, and immunological adjuvant activity on the cellular immune response against ovalbumin antigen. PMID- 22253104 TI - Antioxidant phenolic compounds from the stems of Entada phaseoloides. AB - The EtOH extract of the stems of Entada phaseoloides displayed potent antioxidant activity when assessed by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2' azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging, reducing power, beta-carotene-bleaching, and superoxide radical-scavenging analyses. Fractionation of the EtOH extracts showed that the AcOEt fraction is the most active, followed by the H(2) O fraction, while BuOH fraction was least active. Further activity-guided fractionation studies on the active fractions resulted in the isolation of 22 compounds. The identities of these compounds were established based on extensive spectroscopic studies. Furthermore, the antioxidant activities of the isolated compounds were evaluated by using the above-mentioned five assays. The results demonstrated that the EtOH extract of E. phaseoloides stems exhibits an excellent antioxidant activity and thus presents a great potential as a source of natural antioxidants. PMID- 22253105 TI - Chemodiversity of nonacosan-10-ol and n-alkanes in the needle wax of Pinus heldreichii. AB - This is the first report of individual variability and population diversity of the contents of nonacosan-10-ol and n-alkanes in the needle cuticular waxes of Bosnian pines originated from Montenegro, regarded as Pinus heldreichii var. leucodermis, and from Serbia, regarded as P. heldreichii var. pancici. The amount of nonacosan-10-ol varied individually from 27.4 to 73.2% (55.5% in average), but differences between the four investigated populations were not statistically confirmed. The size of the n-alkanes ranged from C(18) to C(33). The most abundant n-alkanes were C(23), C(27), and C(25) (12.2, 11.2, and 10.8% in average, resp.). The carbon preference index (CPI) of the n-alkanes ranged from 0.8 to 3.1 (1.6 in average), while the average chain length (ACL) ranged from 20.9 to 26.5 (24.4 in average). Long-chain and mid-chain n-alkanes prevailed (49.6 and 37.9% in average, resp.). It was also found that the populations of P. heldreichii var. leucodermis had predominantly a narrower range of n-alkanes (C(18)-C(31)) than the trees of the variety pancici (C(18)-C(33)). Differences between the varieties were also significant for most of the other characteristics of the n-alkane pattern (e.g., most abundant n-alkanes, CPI, ACL, and relative proportion of short-, mid-, and long-chain n-alkanes). The principle component and cluster analyses of eleven n-alkanes confirmed the significant diversity of these two varieties. PMID- 22253107 TI - A new benzoylphloroglucinol derivative with an adamantyl skeleton and other constituents from Garcinia multiflora: effects on neutrophil pro-inflammatory responses. AB - A novel benzoylphloroglucinol derivative, garcimultiflorone D (1), with an unusual adamantyl-caged skeleton was isolated from the fruits of Garcinia multiflora, together with four known compounds. The structure of 1 was determined through extensive 1D/2D-NMR and mass-spectrometric analyses. Garcimultiflorone D (1) exhibited inhibitory activities with IC(50) values of 7.21+/-1.07 and 6.01+/ 0.37 MUg/ml against fMLP/CB-induced superoxide anion generation and elastase release, respectively. PMID- 22253106 TI - Biologically active bergenin derivatives from Bergenia stracheyi. AB - New bergenin derivatives, bergecins A and B (1 and 2, resp.), have been isolated from the AcOEt-soluble fraction of Bergenia stracheyi, along with bergenin (3), and their structures were elucidated on the basis of (1) H- and (13) C-NMR spectra, and by COSY, HMQC, and HMBC experiments. Compound 2 showed potent inhibitory potential against the enzyme lipoxygenase, while 1 was moderately active. On the other hand, both compounds exhibited significant antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay. PMID- 22253108 TI - Chemotaxonomy of Serbian Teucrium species inferred from essential oil chemical composition: the case of Teucrium scordium L. ssp. scordioides. AB - The volatile constituents of Teucrium scordium L. ssp. scordioides, T. polium, and T. montanum, obtained by hydrodistillation, were investigated by GC-FID and GC/MS analyses. A total of 296 constituents were identified, representing 89.8 98.4% of the oil compositions. The oils of T. polium and T. montanum consisted mainly of sesquiterpenes (64.3 and 72.7%, resp.), with germacrene D (4; 31.0%) and delta-cadinene (10; 8.1%) as the main constituents, respectively. In contrast, the monoterpene menthofuran (1; 11.9%) predominated in the oil of T. scordium ssp. scordioides, and this clearly distinguished this species from the other Teucrium taxa investigated up to date. The chemistry of the volatiles of eight Teucrium taxa from Serbia and Montenegro were compared using multivariate statistical analysis, and this provided chemotaxonomically important conclusions. PMID- 22253109 TI - Phenolic compounds from the branches of Eucalyptus maideni. AB - Three new phenolic compounds, eucalmaidin F (1), (3S)-5-guaiacyl-3 hydroxypentanoic acid (2), and 8-beta-C-glucopyranosyl-5,7-dihydroxy-2 isobutylchromone (3), were isolated from the branches of E. maideni, together with 30 known compounds, including four phenylpropanoids, three lignans, four phloroglucinol glucosides, five dihydroflavonoids, seven simple phenolic compounds, six terpenoids, and glycerol. The new structures were established by spectroscopic studies (MS, and 1D- and 2D-NMR), chemical degradation, and modified Mosher's method. Compounds 3, guaiacylglycerol, 3-hydroxy-1-(4 hydroxyphenyl)propan-1-one, caffeic acid, (2E)-3-(4-hydroxyphenyl)prop-2-enoic acid, (7'S,8R,8'R)-lyoniresinol, (+)-lyoresinol 3alpha-O-alpha-L rhamnopyranoside, garcimangosone, phlorocetophenone 2'-glucopyranoside, (+) taxifolin 3alpha-O-alpha-L-rhamnopyranoside, (+)-aromadendrin, (+)-taxifolin, resveratrol, piceatannol, 3,4,5-trihydroxyphenol. Tachiaside, gallic acid, macrocapals A und G, and oleuropeic acid were evaluated for their cytotoxicities against five human cancer cell lines. Resveratrol, piceatannol, gallic acid, and macrocapal G exhibited moderate inhibitory effects on human myeloid heukemia HL 60 cell, with IC(50) values of 22.05, 22.05, 7.75, and 31.93 MUM, respectively; and only macrocapal G showed inhibitory effect on hepatocellular carcinoma SMMC 7721 cell, with an IC(50) value of 26.75 MUM. PMID- 22253110 TI - Inhibitory effects of terpenoids from the fermented broth of the ascomycete Stilbohypoxylon elaeicola YMJ173 on nitric oxide production in RAW264.7 macrophages. AB - A series of six isopimarane-type diterpene glycosides, along with an eremophilane type sesquiterpene, i.e., elaeicolasides A-C (1-3, resp.), 16-(alpha-D mannopyranosyloxy)isopimar-7-en-19-oic acid (4), hymatoxin K (5), hymatoxin L (6), and elaeicolalactone (7), were isolated from the AcOEt extract of the fermented broth of Stilbohypoxylon elaeicola YMJ173. Among these, 1-3 and 7 are new compounds based on their spectroscopic data and sugar composition analysis. The effects of 1-7 on the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells were evaluated. All these compounds inhibited NO production, detected as nitrite in the culture medium, in activated macrophages without any cytotoxicity at a concentration of 100 MUM. Among these compounds, 2 showed a significant activity with the average maximum inhibition (E(max)) and median inhibitory concentration (IC(50)) values of 93.3+/-0.5% and 79.3+/-0.4 MUM, respectively. PMID- 22253111 TI - Chemical variation of essential oil constituents of Ocimum gratissimum L. from Benin, and impact on antimicrobial properties and toxicity against Artemia salina leach. AB - To determine the period of harvest that optimizes the antimicrobial activities of the essential oil of Ocimum gratissimum L. from Benin, aerial plant parts were collected at two vegetative stages (pre- and full-flowering) and three sampling times (7 am, 1 pm, and 7 pm). Extraction by hydrodistillation yielded between 0.65 and 0.78% of essential oils. Characterization of the oils by GC-FID and GC/MS analysis revealed the presence of monoterpenes (87.26-93.81%), sesquiterpenes (5.57-11.34%), and aliphatic compounds (0.15-0.18%), with p-cymene (1; 28.08-53.82%), thymol (2; 3.32-29.13%), gamma-terpinene (3; 1.11-10.91%), alpha-thujene (4; 3.37-10.77%), and beta-myrcene (5; 4.24-8.28%) as major components. Two chemotypes were observed, i.e., a p-cymene/thymol and a p-cymene chemotype, for plants harvested at 7 am for the former and at 1 pm or 7 pm for the latter, respectively. The oils were fungicidal against Candida albicans, with the sample from full-flowering plants collected at 7 am being the most active (MIC = 0.06+/-0.00 mg/ml). The chemical variation of the oils also influenced the antimicrobial effect against Staphylococcus aureus; the most active oil was obtained from plants at the pre-flowering stage collected at 7 am (MIC=0.24+/ 0.01 mg/ml). Escherichia coli was insensitive to the chemical variation of the oils (MICs of ca. 0.48+/-0.02 mg/ml for all oils). Moreover, the essential oils showed low toxicity against Artemia salina Leach larvae, with LC(50) values in the range of 43-146 MUg/ml. This is the first study of the interaction between the daytime of collection and vegetative stage of the plants and the antimicrobial properties and toxicity of the essential oil of O. gratissimum from Benin. PMID- 22253112 TI - Essential oils in the ranunculaceae family: chemical composition of hydrodistilled oils from Consolida regalis, Delphinium elatum, Nigella hispanica, and N. nigellastrum seeds. AB - In this study, we analyzed the chemical composition of volatile oils hydrodistilled from seeds of Consolida regalis, Delphinium elatum, Nigella hispanica, and N. nigellastrum using GC and GC/MS. In C. regalis, octadecenoic (77.79%) and hexadecanoic acid (8.34%) were the main constituents. Similarly, the oils from D. elatum and N. hispanica seeds consisted chiefly of octadecadienoic (42.83 and 35.58%, resp.), hexadecanoic (23.87 and 28.59%, resp.), and octadecenoic acid (21.67 and 19.76%, resp.). Contrastingly, the monoterpene hydrocarbons alpha-pinene (34.67%) and beta-pinene (36.42%) were the main components of N. nigellastrum essential oil. Our results confirm the presence of essential oils in the family Ranunculaceae and suggest chemotaxonomical relationships within the representatives of the genera Consolida, Delphinium, and Nigella. In addition, the presence of various bioactive constituents such as linoleic acid, (-)-beta-pinene, squalene, or carotol in seeds of D. elatum, N. hispanica, and N. nigellastrum indicates a possible industrial use of these plants. PMID- 22253113 TI - Synthesis and antidiabetic activity of 5,7-dihydroxyflavonoids and analogs. AB - In a study to evaluate the structural elements essential for the antidiabetic activity of flavonoids, we synthesized two series of flavonoids, 5,7 dihydroxyflavanones and 5,7-dihydroxyflavones. In a screening for potential antidiabetic activity, most of the flavonoids showed a remarkable in vitro activity, and compounds 1f, 2d, and 3c were significantly more effective than the positive control, metformin. The biological activity was mainly affected by structural modification at the ring B moiety of the flavonoid skeleton. The results suggest that 5,7-dihydroxyflavonoids can be considered as promising candidates in the development of new antidiabetic lead compounds. PMID- 22253114 TI - Studies of the activity of peroxidase-like DNAzyme by modifying 3'- or 5'-end of aptamers. AB - In the presence of hemin and under appropriate conditions, some modalities of G quadruplexes can form a peroxidase-like DNAzyme that has been widely used in biology. Structure-function studies on the DNAzyme revealed that its catalytic ability may be dependent on the unimolecular parallel G-quadruplex. In this report, we present the preliminary investigation on the relationship between the structure and function of DNAzymes through a terminal oligo modification in G quadruplex sequences by adding different lengths of oligo-dT to the 3'- or 5'-end of the aptamers. The results suggested that adding dT(n) to the 5'-end of the DNA sequence of the enzyme improved the ability of hemin to bind with DNA, but the addition of dT(n) to the 3'-end decreased the binding ability of hemin for DNA. The increased stability of the assembled DNAzyme would lead to more favorable binding between the enzyme and substrate (H(2) O(2)), facilitating higher peroxidase activity; on the contrary, with lower stability of the DNAzyme complex, we observed reduced peroxidase activity. PMID- 22253116 TI - Ultrasound presentation of Pallister-Killian syndrome with a prominent sacral appendage. PMID- 22253117 TI - Standard hepatic vein reconstruction with patch plasty using the native portal vein in adult living donor liver transplantation. AB - An outflow obstruction of the hepatic vein is a critical complication after living donor liver transplantation (LDLT) and occasionally leads to hepatic failure. Here we introduce a simple method for preventing outflow obstructions by patch plasty in adult LDLT. Between September 2001 and May 2010, 468 adult LDLT procedures were performed at Kyoto University Hospital. We harvested each recipient's portal vein (PV) from the extirpated liver for a patch. We intended to re-form several orifices of the hepatic veins into a single, large orifice. The patch was attached to the anterior wall of the re-formed orifice on the bench. After we put in the liver graft, the procedure for the hepatic vein anastomosis to the inferior vena cava was simple enough that the warm ischemia time was reduced. Three of the 468 cases were diagnosed with an outflow obstruction. All 3 cases underwent hepatic vein reconstruction without patch plasty. In contrast, none of the 159 cases that underwent LDLT with patch plasty suffered from an outflow obstruction, regardless of the liver graft type. The procedure for hepatic vein plasty using a patch from the native PV is simple and elegant and results in excellent outcomes. We propose this as the standard procedure for hepatic vein reconstruction in adult LDLT. PMID- 22253118 TI - A cross-sectional study of the change in mastoid geometry with age in children without a history of otitis media. AB - OBJECTIVES/HYPOTHESIS: This study assessed the normal growth and development of mastoid air-cell system (MACS) geometry from infancy through adolescence. STUDY DESIGN: Cross-sectional study. METHODS: This cross-sectional study evaluated the change with age in MACS volume, surface area, and surface area/volume ratio in 36 (72 ears) individuals aged 1.6 to 18 years with no history of middle ear disease. The three MACS parameters were reconstructed using computed tomography (CT) scans judged by a radiologist to be normal. Linear regression was used to determine the relationship between the left and right values of each parameter, and between those parameters and age for male and female subjects. RESULTS: For all three MACS parameters, the right and left values were highly correlated. MACS volume and surface area for male and female subjects showed an increase between 1 and 18 years. The surface area/volume ratio for males was independent of age but showed a shallow increase for females. When averaged across all ages, the ratio was similar to those previously reported. CONCLUSIONS: The growth trajectory for MACS volume observed in this study was not consistent with other cross-sectional studies employing planimetry or CT of normal subjects that reported inconsistent results. Because of its potential role as a susceptibility factor for otitis media and other otologic problems, it is important to describe the growth and development of MACS geometry. Additional well-controlled studies of this phenomenon are needed to clarify which of the growth trajectories actually describe the growth process for the three parameters of interest. PMID- 22253119 TI - Maps for the world of genomic medicine: the 2011 CSHL Personal Genomes meeting. AB - The fourth Personal Genomes meeting was held at Cold Spring Harbor Laboratory, New York, from 30 September to 2 October and provided an exciting collection of science built on recent significant milestones in individual human genome sequencing, from the first personal genomes to thousands of human genomes sequenced. As ultra-high throughput sequencing platforms enable the production of more and more individual genomes, a growing number of scientists, physicians, and clinical geneticists are actively exploring the promise and the implications of these new data. Personal Genomes brought many of these pioneers together with nearly 200 scientists, physicians, ethicists, and others to discuss the progress and opportunities around the sequencing and medical interpretation of individual genome sequences. PMID- 22253120 TI - [Newborn at the limit of viability. Part 1: Ethical dilemmas, international recommendations]. AB - Immense scientific and technological progress in perinatal medicine during the 1990s enabled to save extremely immature newborns. The fact faced doctors with new challenges and ethical problems regarding especially infants born at the limit of viability (22-26 weeks of gestation). The aim of this study is an attempt to answer the question concerning the mode of operation in the delivery room and/or NICU towards this group of infants. Decisions may concern undertaking resuscitation, limiting medical procedures and the use of palliative care. Materials for preparation of this paper included international recommendations developed by teams of specialists (part 1), as well as Polish recommendations (part 2). The first part presents world epidemiological data regarding survival rate and long-term developmental assessment of extremely low gestational age infants, indicating difficulties in interpretation of some of the research. We also emphasized the discrepancies in precise evaluation of gestational age, which is of great significance for qualifying the newborn into the group unable to survive or at the limit of viability. For better assessment of the research, recommendations developed by FIGO Committee in 1994 are presented: "Ethical aspects in management of newborn infants at the threshold of viability." In the discussion part we presented differences between world recommendations regarding newborns at the limit of viability, emphasizing the need to define the "grey zone" (gestational age at which there is doubt about the newborns' viability and development and, as a result, the possibility of making "good" therapeutic decisions is limited). In summary it has been emphasized that at the current state of knowledge decisions cannot be based solely on gestational age and estimated body weight, but other factors improving or worsening the prognosis should be taken into consideration as well. Finally the situation in Poland is discussed, indicating problems regarding this group of newborns. It is also emphasized that a Team for Ethical Recommendations in Perinatology, appointed in 2009, developed recommendations which are discussed in the second part of the paper. PMID- 22253121 TI - [Newborn at the limit of viability. Part 2: Recommendations regarding treatment of mother and newborn at the limit of viability considering ethical aspects]. AB - The first Polish recommendations regarding the treatment of mothers and infants born at the limit of viability are the result of 1,5 years of work by the Team for Ethical Recommendations in Perinatology, consisting not only of gynecologists obstetricians and neonatologists, but also geneticists, psychologists, ethics specialists, philosophers and lawyers. Their development was based on similar standards already existing in other European countries, as well as in Australia, Canada and the USA. The recommendations were accepted by the National Consultant for Neonatology, Polish Gynecological Society, Polish Perinatal Medicine Society and Polish Pediatric Society. The Recommendations indicate ethical problems and presented transfer of information among the members of the treatment team as well as between the team and the parents of extremely immature newborns. The necessity of informing parents about their infant's chances for survival has been emphasized, as well as the need to hear their opinions and expectations. A Prenatal Consultation Card and Newborn Treatment Card have been attached to the recommendations, as a tool for presenting decisions and parents' opinions. Problems concerning accurate determination of gestational age and biological maturity of the foetus have also been discussed. Furthermore, on the basis of international research, morbidity and mortality data on infants born at the limit of viability have been presented. The paper also presents recommendations concerning: in utero transport, cesarean section and undertaking resuscitation as opposed to palliative care in newborns depending on their gestational age. It has been emphasized that gestational age cannot be the only criteria in the course of making decisions. Individual pre- and post-natal factors influencing the prognosis should also be taken into account. Recommendations allow both for the situation when the gestational age is precisely determined and when it is uncertain. Attention has been drawn to the need of long-term assessment of development in this group of children. The procedure in case of the infants' death has also been discussed. PMID- 22253122 TI - [Does the spectrum of peri-intraventricular haemorrhages in preterm infants change over the years? Comparison of two cohorts treated in 1998-2002 and 2005 2009]. AB - AIM OF STUDY: Analysis of prevalence and degree of intraventricular haemorrhages in preterm infants treated at the Institute of Mother and Child in Warsaw between 2005-2009.The results were compared with a similar analysis conducted between 1998-2002 in an effort to find an answer to the question regarding definite changes or trends of changes in this pathology over time. MATERIAL AND METHODS: The studied population comprised 350 infants born at 22-34 weeks of gestation, hospitalised between 2005-2009. These infants were compared with 354 infants treated between 1998 and 2002. Haemorrhages was diagnosed on the basis of repeated ultrasounds performed in a standard manner, through the fontanelle, according to classic rules. MR imaging was performed as required. The extent of haemorrhage was classified in stages 1 to 4. In deceased infants the stage of haemorrhage was verified on the basis of autopsy results. RESULTS: The investigations carried out between 2005 and 2009 showed haemorrhages in 174 infants (49.7%). Extensive stage 3 haemorrhages were diagnosed in 45 infants (12.9%),and grade 4 in 35 infants (10,0%). 40 infants (11,4%) died during hospitalization. Autopsy was conducted in 26 deceased infants (65%); in 18 cases (69%) the diagnosis was confirmed and in no case was the diagnosis regarding the extent of haemorrhage changed. Studies carried out in the period 1998-2002 revealed haemmorhages in 248 infants (70%), including stage 3 in 67 infants (19%), and stage 4 in 34 infants (10%). 93 infants died during hospitalisation. Prevalence of all types of peri- intraventricular haemorrhages (PVH/IVH) is currently significantly lower, but the prevalence of extensive haemorrhages of grade 4 has not decreased. The number of deaths has decreased by half, although at present more infants with grade 4 haemorrhages survive. Comparison of prevalence of (PVH/IVH) of all grades in both cohorts of infants born up to 34 weeks of gestation in different periods, i.e. 1998-2002 and 2005-2009, shows a statistically significant decrease. However, the comparison of prevalence of extensive IVH of grade 4, does not show a statistically significant decrease. The percentage of women with threatened pregnancy who recieved corticotheraphy was 64.2%. This is still definitely too low. CONCLUSIONS: 1. Statistically significant decrease in the prevalence and the severity of peri-intraventricular haemorrhage in the analysis carried out between 2005 and 2009 is a positive conclusion. A negative finding is the fact that the incidence of IV degree intraventricular haemorrhage, does not show a falling trend. 2. A fall in the number of deaths in the population of premature infants born in our Department can be the result of significantly improved medical care in the compared groups. 3. In both cohorts still insufficient percentage of pregnant women receiving prenatal corticosteroids in cases of high risk pregnancy, could be linked with unsatisfactory prophylactie perinatal care. This could lead to lack of improvement in the incidence of IV degree intraventricular haemorrhage. 4. The existing data base in Poland on the incidence of PVH/IVH in the risk group, is insufficient for comparison with European Union Countries data in the EuroNeoNet. The significance of this pathology on individual, social and economic levels, creates a need to carry out periodical analysis, at regional level, concerning its incidence, causes and effects. PMID- 22253123 TI - [What is the impact of fetal magnetic resonance imaging (MRI) on prenatal diagnosis of cerebral anomalies]. AB - Fetal magnetic resonance imaging (MRI) is an adjunct to sonography (US), often necessary when cerebral abnormality is suspected. With use of fast sequences, such as T2 HASTE or SSFSE, gradient-echo T1- weighted images and diffusion weighted imaging, it is possible to obtain images of fetal brain in three planes without mother's sedation. Diagnosing brain anomalies using MRI requires good knowledge of normal anatomy depending on gestational age: phases of neuronal migration, sulcation and gyration, myelination in particular. The main indications to perform MRI are as follows : ventricular dilatation, midline and posterior fossa abnormalities, microcephaly (in search for migrational disorders), cerebral location of tuberous sclerosis which is suspected when cardiac tumours are detected. MRI allows to confirm US diagnosis and to answer the question whether the abnormality is isolated or complex. This enables not only to establish the diagnosis but also the prognosis. This method plays an important role in the work of the interdisciplinary team managing the pregnancies with a suspicion of congenital anomalies. Prenatal MRI is a great progress in diagnosing brain anomalies and has become indispensable in modern perinatology in the last decades. The situation of mother and child after the anomaly had been detected requires discussion and care of the interdisciplinary team consisting of an obstetrician, neonatologist, radiologist, geneticist, pathologist, psychologist and paediatric neurologist. PMID- 22253124 TI - [Predictive value of magnetic resonance imaging (MRI) in cases of acquired brain injury in neonates]. AB - Magnetic resonance (MRI) is at present the most accurate method of brain imaging in neonates, but it is not always and not everywhere available. This examination is commonly used in neonates born on time but it does not replace transfontanel sonography (US) in routine care in case of preterm babies. In the last years there have been more and more publications dealing with the prognostic value of MRI in both these groups of newborns. In this study the predictive value of MRI was analysed on the basis of own material and literature. The indications for MRI in case of term and preterm neonates were established. PMID- 22253125 TI - [Surgical treatment of neonates with very low (VLBW) or extremely low (ELBW) birth weight]. AB - Progress in perinatology and neonatal intensive care led to surgical treatment of premature infants born with low (<1500 g) and extremely low (<1000 g) birth weight. AIM: Evaluation of surgical treatment in the group of neonates with very low birth weight (<1500 g) and extremely low birth weight (<1000 g). MATERIAL AND METHODS: In the years 2000-2009 in the Department of Paediatric Surgery in the Institute of Mother and Child, 617 neonates underwent surgical treatment, 101 of them (16%) were born with very low or extremely low birth weight. In the analyzed group the birth weight ranged from 450 g to 1500 g (mean 952 g), gestational age ranged from 23 weeks to 32 weeks (mean 27 weeks). Fifty four patients (53%) were operated with the weight <1000 g. Indications for surgery were of two categories: pathologies related to prematurity and congenital defects. The extend of surgical intervention is presented. Additional pathologies influencing prognosis such as respiratory distress syndrome, haemodynamic ductus arteriosus, intraventricular haemorrhagia, multiple congenital defects and genetic disorders were also taken into consideration. Mortality in the entire group of patients was evaluated in relation to the birth weight, gestational age, reasons for surgical treatment and additional risk factors. RESULTS: Pathologies related to prematurity were indications for surgical treatment in 70 patients: perforation of the bowel in the course of necrotizing enterocolitis - NEC (28 patients), spontaneous intestinal perforation - SIP (32), gastric perforation - GP (4), meconium obstruction - MO (3) posthemorrhagic hydrocephalus - PH (3). In the remaining 31 neonates the following congenital defects were operated: inguinal hernia (10 patients), oesophageal atresia (8), anal atresia (2), torsion of the bowel (2), bowel atresia (3), hernia of the umbilical cord (3), ruptured omphalocele (1), myelomeningocele (2). In the entire group of 101 premature infants, 99 patients (98%) had respiratory distress syndrome, 56 (56%) required the closure of ductus arteriosus , in 55 patients (55%) intraventricular haemorrhage from II to IV degree was confirmed. In total thirty patients died. Twenty one of them were ELBW neonates. None of the patients died during the operation or within the first postoperative day. Mortality rate in the group with the weight <1000 g was 38%, in the group with the weight 1000 g-1500 g it was 19%. Highest mortality was observed in the patients with oesophageal atresia (62%) In this group the biggest number of additional anomalies or other genetic disorders was found. Twenty infants died (31%) in the group of 64 neonates with perforations. Mortality rate in the groups with the weight <1000 g and 1000 g-1500 g it was 34% and 26% respectively. Our results confirmed the significant difference between mortality in NEC - 65% and in SIP - 19.5% . The remaining 5 deaths were related both to extreme multiorgan prematurity and severe congenital defects. CONCLUSION: The most frequent indications for surgery in premature neonates (VLBW and ELBW) are acquired pathologies which are related to premature multiorgan insufficiency: perforations in the course of ischaemic or inflamatory changes in the bowel (NEC, SIP), intestinal obstruction related to functional insufficiency of alimentary tract (MO) and posthaemorrhagic hydrocephalus. Congenital anomalies constitute 30% of indications for surgical treatment in this group of patients. Neonates born with low or extremely low birth weight are in the group of patients with the highest intraoperative risk. There is herefore a need to create well equipped, interdisciplinary centres employing paediatric surgeons, anaesthesiologists and neonatologists experienced in treatment of extremely premature neonates. PMID- 22253126 TI - [Own experience in the treatment of infantile haemangiomas with propranolol - preliminary results]. AB - BACKGROUND: Infantile haemangiomas are the most common vascular tumours in children. Since 2008 the application of propranolol has been a promising therapy in the management of haemangiomas. AIM OF THE STUDY: Analysis of the patients with infantile haemangiomas treated with propranolol. MATERIAL AND METHODS: Between June 2009 and December 2010 in Department of Pediatric Surgery and Oncology Medical University of Lodz, 35 children with infantile haemangiomas (29 females and 6 males) were treated with propranolol. Therapy was initiated in age of 2-15 months (mean 4.5). All infantile haemangiomas were in a proliferative phase. In 27 children lesions were located in the head and neck, 2 of them were located in the orbital region and 3 penetrated into the orbit. In 5 children haemangiomas were located in the trunk, with 3 in the perineum and 3 in limbs. In 2 children the PHACE Syndrome was diagnosed. In one of these cases exploratory laparatomy revealed jejunal haemangiomatosis. The indication for propranolol application was impairment of physiological functions in 23 cases, cosmetic defect in 8 and ulceration in 4. The duration of treatment was 4 to 12 months (mean 7.5-months). The change of haemangioma volume, density and colour were evaluated. Reduction of " haemangioma volume was assessed as very good response, 1/3 as good response, and 1/4 as poor. RESULTS: In 7 patients therapy has been finished. In all cases decrease in density, volume and fading was observed. Very good result was achieved in 27 patients, good in 5, poor in 3. Recurrence of haemangioma appeared in two patients after termination of treatment. A spectacularly good result was achieved in the child with PHACE syndrome and in one with jejunal haemangiomatosis. CONCLUSIONS: Propranolol therapy is safe and effective in children with infantile proliferating haemangiomas. It can be the treatment of choice in cases with impairment of physiological functions or severe cosmetic defect. Election and therapy of the children should be carried out in highly reference centres. PMID- 22253127 TI - [Neonatal behavioural assessment of pre-term and full-term infants as experienced by parents]. AB - AIM: The analysis of similarities and differences of parental experience of observing preterm versus full term babies assessed with the Neonatal Behavioural Assessment Scale (NBAS). MATERIAL AND METHOD: 95 pairs of parents participated in the study, including 33 mothers and fathers of babies born before 29th gestational week, 31 - between 29th and 34th week and 31 - at term. All infants were assessed with the NBAS in the first month of life (or corrected age) in the presence of both parents. Semi-structured clinical interviews were conducted with each parental pair and the qualitative analysis of the obtained co-constructed narratives was carried out. RESULTS: Seven common categories of parental experience related to the NBAS were empirically discerned in all groups of parents. There were also two categories of experience related to the NBAS that were different in the group of parents of preterm versus full term babies. Apart from that, three specific categories characteristic of the parental narratives in the two preterm groups were identified: parental tendency to compare NBAS assessment with medical examination, hope for having the child's health confirmed and parental tendency to compare preterm with full term babies. CONCLUSIONS: Mothers and fathers of preterm vs full term babies experience the observation of NBAS assessment differently. Parents of preterm babies are extremely sensitive to any information regarding their child. Therefore specialists should pay a special attention to the process of communicating with the family. Effective support of any family in the perinatal period requires special appreciation of the individual parental needs. PMID- 22253128 TI - Allosteric binding of halide anions by a new dimeric interpenetrated coordination cage. PMID- 22253129 TI - Interrater agreement of nasal endoscopy for chronic rhinosinusitis. AB - BACKGROUND: Nasal endoscopy is a routine, important diagnostic tool in the evaluation of chronic rhinosinusitis (CRS). Although the procedure is ideally "objective," the subjective nature of endoscopy interpretation and lack of standardization are potential limitations. The goal of this study was to examine the interrater agreement of various categories of nasal endoscopy findings in patients undergoing evaluation for CRS. METHODS: Fourteen patients (28 sides) with CRS underwent clinical evaluation, SNOT-22, sinus computed tomography (CT), and digital video nasal endoscopy. Five academic rhinologists blindly reviewed the endoscopies for structural anatomic issues, inflammatory rhinosinusitis findings, and atypical lesions. Statistical comparison of the endoscopy interpretations was performed using the unweighted Fleiss' kappa statistic (K(f) ). RESULTS: The mean Lund-Mackay CT scan score was 7.8 (standard deviation [SD] 4.9) and the mean SNOT-22 score was 35.8 (SD 22.7). Significant variability was noted among the raters with respect to the various categories of nasal endoscopy findings. The overall levels of interrater agreement for the various categories were as follows: "almost perfect" for atypical lesions (K(f) = 0.912); "substantial" for nasal polyps (K(f) = 0.693); "moderate" for nasal discharge (K(f) = 0.422) and mucosal inflammatory changes of the middle turbinate (K(f) = 0.413); and "fair" for edema of the middle meatus (K(f) = 0.214), obstruction by nasal septum deviation (K(f) = 0.240), and obstruction by the middle turbinate (K(f) = 0.276). CONCLUSION: Significant variability was noted in the interrater agreement for nasal endoscopy findings in this study, with relatively limited agreement on some of the key findings of the procedure. Additional investigation and standardization of nasal endoscopy interpretation is required to improve the clinical utility of the procedure. PMID- 22253130 TI - High-temperature solid-state dye-sensitized solar cells based on organic ionic plastic crystal electrolytes. AB - Organic ionic plastic crystal, 1-ethyl-1-methyl pyrrolidinium iodide (P(12) I), is employed as the solid-state electrolytes for dye-sensitized solar cells. The fabricated solid-state devices show an overall power conversion efficiency of ~5.8% under AM 1.5 radiation (50 mW/cm(2) ) and excellent long-term stability at 80 degrees C. PMID- 22253132 TI - Effect of stationary magnetic field strengths of 150 and 200 mT on reactive oxygen species production in soybean. AB - Our previous investigation reported the beneficial effect of pre-sowing magnetic treatment for improving germination parameters and biomass accumulation in soybean. In this study, soybean seeds treated with static magnetic fields of 150 and 200 mT for 1 h were evaluated for reactive oxygen species (ROS) and activity of antioxidant enzymes. Superoxide and hydroxyl radicals were measured in embryos and hypocotyls of germinating seeds by electron paramagnetic resonance spectroscopy and kinetics of superoxide production; hydrogen peroxide and antioxidant activities were estimated spectrophotometrically. Magnetic field treatment resulted in enhanced production of ROS mediated by cell wall peroxidase while ascorbic acid content, superoxide dismutase and ascorbate peroxidase activity decreased in the hypocotyl of germinating seeds. An increase in the cytosolic peroxidase activity indicated that this antioxidant enzyme had a vital role in scavenging the increased H(2)O(2) produced in seedlings from the magnetically treated seeds. Hence, these studies contribute to our first report on the biochemical basis of enhanced germination and seedling growth in magnetically treated seeds of soybean in relation to increased production of ROS. PMID- 22253131 TI - Arachidonate 5 lipoxygenase expression in papillary thyroid carcinoma promotes invasion via MMP-9 induction. AB - Arachidonate 5-lipoxygenase (ALOX5) expression and activity has been implicated in tumor pathogenesis, yet its role in papillary thyroid carcinoma (PTC) has not been characterized. ALOX5 protein and mRNA were upregulated in PTC compared to matched, normal thyroid tissue, and ALOX5 expression correlated with invasive tumor histopathology. Evidence suggests that PTC invasion is mediated through the induction of matrix metalloproteinases (MMPs) that can degrade and remodel the extracellular matrix (ECM). A correlation between MMP-9 and ALOX5 protein expression was established by immunohistochemical analysis of PTC and normal thyroid tissues using a tissue array. Transfection of ALOX5 into a PTC cell line (BCPAP) increased MMP-9 secretion and cell invasion across an ECM barrier. The ALOX5 product, 5(S)-hydroxyeicosatetraenoic acid also increased MMP-9 protein expression by BCPAP in a dose-dependent manner. Inhibitors of MMP-9 and ALOX5 reversed ALOX5-enhanced invasion. Here we describe a new role for ALOX5 as a mediator of invasion via MMP-9 induction; this ALOX5/MMP9 pathway represents a new avenue in the search for functional biomarkers and/or potential therapeutic targets for aggressive PTC. PMID- 22253133 TI - Lipid diffusion within black lipid membranes measured with dual-focus fluorescence correlation spectroscopy. AB - We present an overview of the application of dual-focus fluorescence correlation spectroscopy (2f-FCS) for the measurement of diffusion coefficients within free standing lipid membranes. The first part gives a detailed theoretical analysis of the expected performance of 2f-FCS, in particular about the sensitivity of the method with regard to precise focus position and to aberrations caused by refractive index mismatch or cover slide thickness deviation. After describing the experimental details of the 2f-FCS setup and the preparation of free-standing black lipid membranes (BLMs), we apply the method to study the diffusion of lipids within BLMs as a function of lipid composition and of ion valency and ionic strength of the surrounding buffer. PMID- 22253134 TI - Evaluating the interaction between the therapy and the treatment in clinical trials by the propensity score weighting method. AB - In clinical trials for antihypertensive drugs, a combination therapy trial and a monotherapy trial are often conducted simultaneously. In this situation, it can be a clinical concern to know the difference of the safety or efficacy of the new drug between the two therapies, in other words, to investigate the interaction between the therapy (monotherapy or combination therapy) and the treatment (test or control). However, because patients are often registered in either of these trials on the basis of their background characteristics, specific patients may be selected to participate in the monotherapy trial or combination therapy trial and not chosen at random, whereas the treatment is assigned randomly in each trial after registration. If this fact is not considered, the statistical analysis of the interaction may be biased. In this paper, we aim to evaluate the interaction between the two aforementioned factors by adjusting for covariates that may affect registration in the two trials. For this purpose, we apply the propensity score weighting method to suit the problem. The propensity score in this case is decomposed into the usual propensity score for the registration and the assignment probability for the random treatment assignment on the basis of their two-stage structure. We also discuss the augmented estimator known as the doubly robust estimator. In addition, we apply this method to data of a clinical trial for an antihypertensive drug that was conducted in Japan and conduct a simulation study to evaluate the performance of our proposed method. PMID- 22253135 TI - The interactome of LIM domain proteins: the contributions of LIM domain proteins to heart failure and heart development. AB - LIM domain proteins all contain at least one double zinc-finger motif. They belong to a large family and here we review those expressed mainly in mammalian hearts, but particularly in cardiomyocytes. These proteins contain between one and five LIM domains and usually these proteins contain other domains that have specific functions such as actin-binding, kinases and nuclear translocation motifs. While several recent reviews have summarised the importance of individual LIM domain proteins, this is the first review of its kind to cover all LIMs associated with the heart. Here we examine 33 LIM proteins (including three that bind to, but do not themselves contain, LIM domains) that are implicated in either the development of the heart, heart disorders and failure, or both. Our analysis is consistent with the view that cardiac LIM domain proteins form multiple extensive networks of multi-protein complexes within the myocardium. This multiplicity of binding partners probably protects the heart as it is challenged to maintain cardiac output, until the imbalance reaches a turning point that results in failure. We believe that the complexity of LIM interactions is properly described by the term LIM interactome. PMID- 22253138 TI - Brainstem-vermis and brainstem-tentorium angles allow accurate categorization of fetal upward rotation of cerebellar vermis. AB - OBJECTIVE: To evaluate the role of the brainstem-vermis (BV) and brainstem tentorium (BT) angles in the differential diagnosis of upward rotation of the fetal cerebellar vermis. METHODS: The BV and BT angles were measured retrospectively on median sonographic views of the brain in 31 fetuses at 19-28 weeks' gestation with upward rotation of the cerebellar vermis due to Blake's pouch cyst (n = 12), Dandy-Walker malformation (n = 12) and cerebellar vermian hypoplasia (n = 7). Eighty normal fetuses at 20-24 weeks were included as controls. RESULTS: In the control group, BV and BT angles were 9.1 +/- 3.5 degrees (range, 4-17 degrees ) and 29.3 +/- 5.8 degrees (range, 21-44 degrees ), respectively. The BV angle was significantly increased in each of the three subgroups of anomalies: Blake's pouch cyst (23 +/- 2.8 degrees ; range, 19-26 degrees ), vermian hypoplasia (34.9 +/- 5.4 degrees ; range, 24-40 degrees ) and Dandy-Walker malformation (63.5 +/- 17.6 degrees ; range, 45-112 degrees ), the angle increasing with increasing severity of the condition. The BT angle had a similar pattern but there was overlap among the different groups. CONCLUSION: The BV angle and, to a lesser degree, the BT angle are simple and reproducible measurements that provide valuable additional information for the categorization of upward rotation of the fetal cerebellar vermis. From mid gestation, a BV angle > 45 degrees is strongly suggestive of a Dandy-Walker malformation, while a measurement < 30 degrees favors the diagnosis of a Blake's pouch cyst. PMID- 22253139 TI - Working towards a risk prediction model for neural tube defects. AB - BACKGROUND: Several risk factors have been consistently associated with neural tube defects (NTDs). However, the predictive ability of these risk factors in combination has not been evaluated. METHODS: To assess the predictive ability of established risk factors for NTDs, we built predictive models using data from the National Birth Defects Prevention Study, which is a large, population-based study of nonsyndromic birth defects. Cases with spina bifida or anencephaly, or both (n = 1239), and controls (n = 8494) were randomly divided into separate training (75% of cases and controls) and validation (remaining 25%) samples. Multivariable logistic regression models were constructed with the training samples. The predictive ability of these models was evaluated in the validation samples by assessing the area under the receiver operator characteristic curves. An ordinal predictive risk index was also constructed and evaluated. In addition, the ability of classification and regression tree (CART) analysis to identify subgroups of women at increased risk for NTDs in offspring was evaluated. RESULTS: The predictive ability of the multivariable models was poor (area under the receiver operating curve: 0.55 for spina bifida only, 0.59 for anencephaly only, and 0.56 for anencephaly and spina bifida combined). The predictive abilities of the ordinal risk indexes and CART models were also low. CONCLUSION: Current established risk factors for NTDs are insufficient for population-level prediction of a women's risk for having affected offspring. Identification of genetic risk factors and novel nongenetic risk factors will be critical to establishing models, with good predictive ability, for NTDs. PMID- 22253140 TI - How does growth temperature affect cadmium toxicity measured on different life history traits in the soil nematode Caenorhabditis elegans? AB - Environmental factors, in particular temperature, have been shown to affect the toxicity of chemicals. In the present study the authors exposed the nematode Caenorhabditis elegans to five concentrations of Cd (2, 4, 6, 8, and 10 mg Cd/L agar) at four constant temperatures (11, 15, 18, and 21 degrees C) and monitored survival and reproduction on a daily basis. Data were incorporated in a population matrix model to determine the population growth rate (PGR). An additional experiment at 15 and 20 degrees C and 0, 1, 5, and 10 mg Cd/L was performed to include growth measurements in order to relate changes in reproduction to resource allocations between investments in growth and reproduction. The impacts of Cd on PGR increased with increasing temperature, shifting the median effective concentration (EC50) for PGR from 11.6 +/- 5.4 and 9.2 +/- 1.3 at 11 degrees C and 15 degrees C, to 2.1 +/- 0.1 and 1.7 +/- 0.4 at 18 degrees C and 21 degrees C. Cadmium and temperature decreased growth rates, but Cd also increased maturation times and decreased final body size. It is hypothesized that Cd toxicity leads to a decrease in nutrient assimilation and that this "chemical anorexia" is more severe at high temperatures, where energy demands for growth and reproduction are the highest. PMID- 22253141 TI - A nanoscale force probe for gauging intermolecular interactions. PMID- 22253142 TI - Hierarchical priors for bias parameters in Bayesian sensitivity analysis for unmeasured confounding. AB - Recent years have witnessed new innovation in Bayesian techniques to adjust for unmeasured confounding. A challenge with existing methods is that the user is often required to elicit prior distributions for high-dimensional parameters that model competing bias scenarios. This can render the methods unwieldy. In this paper, we propose a novel methodology to adjust for unmeasured confounding that derives default priors for bias parameters for observational studies with binary covariates. The confounding effects of measured and unmeasured variables are treated as exchangeable within a Bayesian framework. We model the joint distribution of covariates by using a log-linear model with pairwise interaction terms. Hierarchical priors constrain the magnitude and direction of bias parameters. An appealing property of the method is that the conditional distribution of the unmeasured confounder follows a logistic model, giving a simple equivalence with previously proposed methods. We apply the method in a data example from pharmacoepidemiology and explore the impact of different priors for bias parameters on the analysis results. PMID- 22253143 TI - Comments on 'Efficiency loss because of varying cluster size in cluster randomized trials is smaller than literature suggests'. PMID- 22253145 TI - Comparison of low-frequency spectra between aromatic and nonaromatic cation based ionic liquids using femtosecond Raman-induced Kerr effect spectroscopy. AB - In this minireview, the features of low-frequency spectra within the frequency range 0-200 cm(-1) for aromatic and nonaromatic cation based ionic liquids obtained by femtosecond Raman-induced Kerr effect spectroscopy are reviewed. For aromatic cation based ionic liquids, the aromatic group of the cations is largely responsible for the spectral line shape due to their larger polarizability anisotropy volume and more polarizable nature than nonaromatic cations. The low frequency Kerr spectra are also compared with the bulk properties of the ionic liquids. The differences in the relationship of the first moment of the low frequency spectrum band and the bulk properties between the aromatic and nonaromatic cation based ionic liquids with respect to the natures of constituent ions and microscopic aspects are discussed. For aromatic cation based ionic liquids, the ionic region is more pronounced than the nonpolar region in their low-frequency Kerr spectra. In contrast, the ionic and nonpolar regions of nonaromatic cation based ionic liquids are likely to be captured due to the weaker signal of the cationic region. Also, the low-frequency Kerr spectra of the nonaromatic analogues are influenced by their weaker segregation as compared to aromatic cation based ionic liquids. PMID- 22253146 TI - Does conjugation help exciton dissociation? a study on poly(p-phenylene)s in planar heterojunctions with C60 or TNF. AB - Internal photocurrent quantum yields near 100% can be obtained from the separation of loosely bound geminate pairs when sufficiently large electric fields are applied to organic heterojunctions. The fields needed for complete electron-hole dissociation decrease to those prevailing in organic solar cells under operating conditions when well-conjugated polymers are employed. PMID- 22253147 TI - Safe injection practice (Safe-1 program). PMID- 22253148 TI - Challenges in scaling up of special care newborn units--lessons from India. AB - Neonatal mortality rate in India is high and stagnant. Special Care Newborn Units (SCNUs) are being set up to provide quality level II newborn care services in district hospitals of several districts to meet this challenge. The units are located in some of the remotest districts where the burden of neonatal deaths and accessibility to special care is a concern. A recently concluded evaluation of these units indicates that it is possible to provide quality level II newborn care in district hospitals. However, there are critical constraints such as availability and skills of human resources, maintenance of equipment and bed occupancy. It is not the SCNU alone but an active network of SCNU (level II care), neonatal stabilization units (level I care) and newborn care corners can impact neonatal mortality rate reduction higher. Number of beds is also not sufficient to cater to the increasing demand of such services. Available number of nurses is a problem in many such units. An effective and sustainable system to maintain and repair the equipment is essential. Scaling up these units would require squarely addressing these issues. PMID- 22253149 TI - Treatment challenges in co-infected HIV and TB children. PMID- 22253150 TI - Diagnosis of ventilator associated pneumonia: is there a simple solution? PMID- 22253151 TI - The challenge of improving neonatal mortality in India, key to global achievement of MDG 4. PMID- 22253152 TI - Carbon baby syndrome (universal acquired melanosis). PMID- 22253153 TI - Bullous congenital ichthyosiform erythroderma. PMID- 22253154 TI - Azathioprine hypersensitivity presenting as sweet syndrome in a child with ulcerative colitis. AB - Sweet syndrome is a cutaneous lesion characterized by tender, red inflammatory nodules or papules. We describe a pediatric case of Sweet syndrome presenting 10 days after treatment with azathioprine. As azathioprine is widely used in children with inflammatory bowel disease, clinicians should be aware of this unusual adverse reaction. PMID- 22253155 TI - H1N1 infection in children with hematological malignancies. AB - In the recent pandemic of H1N1 infection, pediatric patients with haematological malignancies were considered high risk for severe illness. There is paucity of data regarding course of H1N1 infection in this subgroup. We describe H1N1 infection in 3 children with acute leukemia. All three patients presented with neutropenic fever; 2 had probable fungal pneumonia based on chest imaging and galactomanan estimation. Diagnosis of H1N1 infection was delayed in all 3 patients as it was not suspected initially. One patient died despite treatment. H1NI infection may coexist with other infections in febrile neutropenia. PMID- 22253144 TI - Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. AB - Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 * 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 * 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 * 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID- 22253156 TI - Intramedullary spinal cord abscess masquerading as spinal tumor. AB - We report a 5-year-old girl who presented with acute onset paraparesis with differential loss of sensation. Magnetic resonance imaging of spine revealed exophytic intramedullary mass lesion from T12 to L1. Peroperatively, the diagnosis was confirmed as abscess. The patient recovered following decompression and antibiotic treatment. PMID- 22253157 TI - Disseminated strongyloidiasis in a immunocompromised host. AB - Strongyloidiasis in an immunocompromised patient has the potential to be life threatening. We describe a boy who was on steroids for acute demyelinating myelitis and receiving antibiotics for E. coli UTI and meningitis. He developed anasarca, malabsorption, malnutrition and left ventricular failure. Duodenal biopsy revealed abundant rhabditiform larvae of Strongyloides stercoralis. The diagnosis went unsuspected and proved fatal. This emphasizes the need to have a high index of suspicion and early intervention for S. stercoralis in immunosuppressed persons who present with refractory gastrointestinal symptoms. PMID- 22253158 TI - Spontaneous pneumomediastinum in H1N1 infection. AB - Spontaneous pneumomediastinum is an uncommon pediatric emergency which usually occurs secondary to bronchial asthma in children. We report a case of spontaneous pneumomediastinum in a 7 year child following Swine Flu (H1N1) infection. PMID- 22253159 TI - Partial extensively drug resistance (XDR) tuberculosis in children. AB - Emergence of resistance to two most potent first line anti-TB drugs i.e. isoniazid and rifampicin (multidrug resistant TB MDR TB) is well known, but, the second line drugs used to treat MDR-TB are also showing resistance to the same strain of Mycobacteria (extensively drug resistance TB, XDR-TB). We report 3 children with partial XDR TB. Two responded to treatment while one was lost to follow-up. PMID- 22253161 TI - Neurodevelopmental outcome following whole body cooling for perinatal asphyxia. AB - This follow-up study conducted on children who underwent therapeutic cooling for hypoxic ischemic encephalopathy, showed normal neurodevelopmental outcome with normal milestones and normal developmental quotient in a minimum of 60% of children at 18-24 months of age. This study shows comparable neurodevelopmental outcome in infants who underwent cooling in a resource poor setting, when compared with existing literature. PMID- 22253160 TI - Zinc deficiency amongst adolescents in Delhi. AB - A cross sectional study was conducted in 260 adolescent schoolchildren (114 males) in the age group of 11-18 years to estimate the prevalence of zinc deficiency in the National Capital Territory of Delhi. Serum zinc was estimated using Inductively coupled plasma mass spectrometer. Overall, 49.4% children (50.8% males, 48.2% females) were found to have a deficient zinc nutriture. PMID- 22253162 TI - Violence-related behaviors and self-inflicted injuries among 15-18 year old Iranian adolescents. AB - In this population-based cross-sectional study, we determined the prevalence of intentional injuries and associated factors among 1201 adolescents in Tehran, Iran. Overall, 63.9% of adolescents had at least one intentional injury behavior which was significantly higher in males. Gender preference for males by parents, very high or very low supervision, waterpipe smoking, and alcohol consumption were significantly associated with injuries in females. In addition, poor wealth index, parental punishment and smoking were incriminating factors in males. PMID- 22253163 TI - Etiology of acute bacterial meningitis in hospitalized children in western Uttar Pradesh. AB - We retrospectively studied clinical and etiological profile of acute bacterial meningitis in hospitalized children for two consecutive years at a pediatric hospital in western Uttar Pradesh. Etiological diagnosis could be made in 30 (44.8%) out of 67 cases with either culture or latex agglutination test. Pneumococcus was the commonest pathogen found in 17 (25.4%) cases. The overall mortality was 10.5%. PMID- 22253164 TI - Tetanus in pediatric patients--predictors affecting mortality and role of immunoglobulin. AB - Analysis of pediatric tetanus cases was carried out to study the predictors of mortality and role of tetanus immunoglobulin (TIG). Shorter incubation period, onset time and autonomic dysfunction were significantly associated with mortality and may be used to stratify patients requiring intensive care. TIG may not have independent role in decreasing mortality in sick patients. PMID- 22253165 TI - Clinical spectrum of category C swine flu in Indian children. PMID- 22253166 TI - Cervical spine injury--a rare cause of torticollis. PMID- 22253167 TI - Screening for heart disease at birth. PMID- 22253168 TI - Persistent thrombocytopenia due to Scrub Typhus. PMID- 22253169 TI - Retracted nipples. PMID- 22253170 TI - Avascular necrosis of hip following combined protein C and protein S deficiency. PMID- 22253172 TI - Great debate on the complex systems approach to cognitive science. PMID- 22253173 TI - Is cognitive science usefully cast as complexity science? AB - Readers of TopiCS are invited to join a debate about the utility of ideas and methods of complexity science. The topics of debate include empirical instances of qualitative change in cognitive activity and whether this empirical work demonstrates sufficiently the empirical flags of complexity. In addition, new phenomena discovered by complexity scientists, and motivated by complexity theory, call into question some basic assumptions of conventional cognitive science such as stable equilibria and homogeneous variance. The articles and commentaries that appear in this issue also illustrate a new debate style format for topiCS. PMID- 22253174 TI - Pragmatic choice in conversation. AB - How do people decide what to say in context? Many theories of pragmatics assume that people have specialized knowledge that drives them to utter certain words in different situations. But these theories are mostly unable to explain both the regularity and variability in people's speech behaviors. Our purpose in this article is to advance a view of pragmatics based on complexity theory, which specifically explains the pragmatic choices speakers make in conversations. The concept of self-organized criticality sheds light on how a history of utterances and subtle details of a situation surrounding a conversation may directly specify language behavior. Under this view, pragmatic choice in discourse does not reflect the output of any dedicated pragmatic module but arises from a complex coordination or coupling between speakers and their varying communicative tasks. PMID- 22253175 TI - Learning from the body about the mind. AB - In some areas of cognitive science we are confronted with ultrafast cognition, exquisite context sensitivity, and scale-free variation in measured cognitive activities. To move forward, we suggest a need to embrace this complexity, equipping cognitive science with tools and concepts used in the study of complex dynamical systems. The science of movement coordination has benefited already from this change, successfully circumventing analogous paradoxes by treating human activities as phenomena of self-organization. Therein, action and cognition are seen to be emergent in ultrafast symmetry breaking across the brain and body; exquisitely constituted of the otherwise trivial details of history, context, and environment; and exhibiting the characteristic scale-free signature of self organization. PMID- 22253176 TI - Complexity and extended phenomenological-cognitive systems. AB - The complex systems approach to cognitive science invites a new understanding of extended cognitive systems. According to this understanding, extended cognitive systems are heterogenous, composed of brain, body, and niche, non-linearly coupled to one another. This view of cognitive systems, as non-linearly coupled brain-body-niche systems, promises conceptual and methodological advances. In this article we focus on two of these. First, the fundamental interdependence among brain, body, and niche makes it possible to explain extended cognition without invoking representations or computation. Second, cognition and conscious experience can be understood as a single phenomenon, eliminating fruitless philosophical discussion of qualia and the so-called hard problem of consciousness. What we call "extended phenomenological-cognitive systems" are relational and dynamical entities, with interactions among heterogeneous parts at multiple spatial and temporal scales. PMID- 22253177 TI - Multifractal dynamics in the emergence of cognitive structure. AB - The complex-systems approach to cognitive science seeks to move beyond the formalism of information exchange and to situate cognition within the broader formalism of energy flow. Changes in cognitive performance exhibit a fractal (i.e., power-law) relationship between size and time scale. These fractal fluctuations reflect the flow of energy at all scales governing cognition. Information transfer, as traditionally understood in the cognitive sciences, may be a subset of this multiscale energy flow. The cognitive system exhibits not just a single power-law relationship between fluctuation size and time scale but actually exhibits many power-law relationships, whether over time or space. This change in fractal scaling, that is, multifractality, provides new insights into changes in energy flow through the cognitive system. We survey recent findings demonstrating the role of multifractality in (a) understanding atypical developmental outcomes, and (b) predicting cognitive change. We propose that multifractality provides insights into energy flows driving the emergence of cognitive structure. PMID- 22253178 TI - Self-organization takes time too. AB - Four articles in this issue of topiCS (volume 4, issue 1) argue against a computational approach in cognitive science in favor of a dynamical approach. I concur that the computational approach faces some considerable explanatory challenges. Yet the dynamicists' proposal that cognition is self-organized seems to only go so far in addressing these challenges. Take, for instance, the hypothesis that cognitive behavior emerges when brain and body (re-)configure to satisfy task and environmental constraints. It is known that for certain systems of constraints, no procedure can exist (whether modular, local, centralized, or self-organized) that reliably finds the right configuration in a realistic amount of time. Hence, the dynamical approach still faces the challenge of explaining how self-organized constraint satisfaction can be achieved by human brains and bodies in real time. In this commentary, I propose a methodology that dynamicists can use to try to address this challenge. PMID- 22253179 TI - The complex systems approach: rhetoric or revolution. AB - The complex systems approach (CSA) to characterizing cognitive function is purported to underlie a conceptual and methodological revolution by its proponents. I examine one central claim from each of the contributed papers and argue that the provided examples do not justify calls for radical change in how we do cognitive science. Instead, I note how currently available approaches in ''standard'' cognitive science are adequate (or even more appropriate) for understanding the CSA provided examples. PMID- 22253180 TI - Commentary: why I am not a dynamicist. AB - The dynamical systems approach in cognitive science offers a potentially useful perspective on both brain and behavior. Indeed, the importation of formal tools from dynamical systems research has already paid off for our field in many ways. However, like some other theoretical perspectives in cognitive science, the dynamical systems approach comes in both moderate or pragmatic and "fundamentalist" varieties (Jones & Love, 2011). In the latter form, dynamical systems theory can rise to some stirring rhetorical heights. However, as argued here, it also triggers a number of serious and specific reservations. PMID- 22253181 TI - Useful theories make predictions. AB - Stephen and Van Orden (this issue) propose that there is a complex system approach to cognitive science, and collectively the authors of the papers presented in this issue believe that this approach provides the means to drive a revolution in the science of the mind. Unfortunately, however illuminating, this explanation is absent and hyperbole is all too extensive. In contrast, I argue (1) that dynamic systems theory is not new to cognitive science and does not provide a basis for a revolution, (2) it is not necessary to reject cognitive science in order to explain the constraints imposed by the body and the environment, (3) it is not necessary, as Silberstein and Chemero (this issue) appear to do, to reject cognitive science in order to explain consciousness, and (4) our understanding of pragmatics is not advanced by Gibbs and Van Orden's (this issue) "self-organized criticality".? Any debate about the future of cognitive science could usefully focus on predictive adequacy. Unfortunately, this is not the approach taken by the authors of this issue. PMID- 22253182 TI - Abstract concepts require concrete models: why cognitive scientists have not yet embraced nonlinearly coupled, dynamical, self-organized critical, synergistic, scale-free, exquisitely context-sensitive, interaction-dominant, multifractal, interdependent brain-body-niche systems. AB - After more than 15 years of study, the 1/f noise or complex-systems approach to cognitive science has delivered promises of progress, colorful verbiage, and statistical analyses of phenomena whose relevance for cognition remains unclear. What the complex-systems approach has arguably failed to deliver are concrete insights about how people perceive, think, decide, and act. Without formal models that implement the proposed abstract concepts, the complex-systems approach to cognitive science runs the danger of becoming a philosophical exercise in futility. The complex-systems approach can be informative and innovative, but only if it is implemented as a formal model that allows concrete prediction, falsification, and comparison against more traditional approaches. PMID- 22253184 TI - Perceptual inference through global lexical similarity. AB - The literature contains a disconnect between accounts of how humans learn lexical semantic representations for words. Theories generally propose that lexical semantics are learned either through perceptual experience or through exposure to regularities in language. We propose here a model to integrate these two information sources. Specifically, the model uses the global structure of memory to exploit the redundancy between language and perception in order to generate inferred perceptual representations for words with which the model has no perceptual experience. We test the model on a variety of different datasets from grounded cognition experiments and demonstrate that this diverse set of results can be explained as perceptual simulation (cf. Barsalou, Simmons, Barbey, & Wilson, 2003) within a global memory model. PMID- 22253185 TI - Understanding human navigation using network analysis. AB - We have considered a simple word game called the word-morph. After making our participants play a stipulated number of word-morph games, we have analyzed the experimental data. We have given a detailed analysis of the learning involved in solving this word game. We propose that people are inclined to learn landmarks when they are asked to navigate from a source to a destination. We note that these landmarks are nodes that have high closeness-centrality ranking. PMID- 22253186 TI - Criterion setting and the dynamics of recognition memory. AB - Models of recognition memory have traditionally struggled with the puzzle of criterion setting, a problem that is particularly acute in cases in which items for study and test are of widely varying types, with differing degrees of baseline familiarity and experience (e.g., words vs. random dot patterns). We present a dynamic model of the recognition process that addresses the criterion setting problem and produces joint predictions for choice and reaction time. In this model, recognition decisions are based not on the absolute value of familiarity, but on how familiarity changes over time as features are sampled from the test item. Decisions are the outcome of a race between two parallel accumulators: one that accumulates positive changes in familiarity (leading to an ''old'' decision) and another that accumulates negative changes (leading to a ''new'' decision). Simulations with this model make realistic predictions for recognition performance and latency regardless of the baseline familiarity of study and test items. PMID- 22253187 TI - Inferring expertise in knowledge and prediction ranking tasks. AB - We apply a cognitive modeling approach to the problem of measuring expertise on rank ordering problems. In these problems, people must order a set of items in terms of a given criterion (e.g., ordering American holidays through the calendar year). Using a cognitive model of behavior on this problem that allows for individual differences in knowledge, we are able to infer people's expertise directly from the rankings they provide. We show that our model-based measure of expertise outperforms self-report measures, taken both before and after completing the ordering of items, in terms of correlation with the actual accuracy of the answers. These results apply to six general knowledge tasks, like ordering American holidays, and two prediction tasks, involving sporting and television competitions. Based on these results, we discuss the potential and limitations of using cognitive models in assessing expertise. PMID- 22253188 TI - Bacterial microcolonies exist within the sphenoid bone in chronic rhinosinusitis and healthy controls. AB - BACKGROUND: Some patients with chronic rhinosinusitis (CRS) exhibit thickening of the sinus bones that has been termed osteitis. The histopathology and microbiology of these changes have not been fully described. The aim of this study was to look for the presence of bacteria and immune cells within samples of bone from patients with and without CRS and correlate these findings to radiological findings. METHODS: Bone on the anterior face of the sphenoid was examined radiologically and histologically in 8 patients with CRS with nasal polyposis, 8 patients with CRS without polyposis, and 6 control patients with pituitary adenomas and normal sinuses. Bone thickness and density were measured by computed tomography (CT) scanning. Bone samples were collected intraoperatively and 20 tissue sections were analyzed for each patient. Bacteria were identified by Giemsa and Gram stains. Immune cells were identified by conventional histology and immunohistochemistry. RESULTS: Small colonies of bacteria were identified within the bone in 3 of 16 CRS patients and 2 of 6 control subjects (p = 0.6). Isolated immune cells were identified within the bone in 3 of 16 CRS patients and 2 of 6 control subjects (p = 0.6) but both bacteria and immune cells occurred together in only 1 case. The presence of bacteria or immune cells within bone samples did not correlate with either bone thickness or bone density. CONCLUSION: This study describes the presence of bacteria and immune cells within a minority of CRS patients and normal controls. The bacterial microcolonies identified do not appear to be the cause of the bone changes seen in many CRS patients. PMID- 22253189 TI - Age-dependent magnetosensitivity of heart muscle hydration. AB - The reason for hyper magnetosensitivity of young animals compared to older ones remains unclear. It has been suggested that age-induced tissue dehydration (decreased water content) could be a basis for the aging-related decrease in the organism's magnetosensitivity. To test this hypothesis, the effect of a 0.2 T static magnetic field (SMF) exposure on heart muscle hydration in three age groups of rats (young, adult, and older) was studied, with and without ouabain poisoning. The SMF exposure resulted in heart muscle dehydration of young (21%) and adult (6.2%) rats but had no effect on older animals. In young animals without ouabin poisoning, SMF exposure caused dehydration of the heart muscle while in the ouabain-poisoned animals it led to hydration (29.6%). These hydration effects were more pronounced in young animals than in adult and older animals. The increased hydration (5.7%) of heart muscles in older animals was evoked by providing distilled water for seven days, which elevated (by 12%) the SMF-induced heart muscle hydration effect. These results suggest that the hyper magnetosensitivity of the young heart muscle and the lower sensitivity of older animals are due to initial high (83.5%) and low (75.3%) tissue hydration levels, respectively. Therefore, the age-induced decrease in the magnetosensitivity of heart muscle is likely to be a result of Na(+)/K(+) pump dysfunction. PMID- 22253190 TI - Use of fenofibrate during the first trimester of unplanned pregnancy in a patient with hypertriglyceridemia. AB - OBJECTIVE: To describe a successful pregnancy in a patient who used fenofibrate during the first trimester. CASE SUMMARY: A 30-year-old female with a history of polycystic ovarian syndrome was referred to our department for evaluation of hypertriglyceridemia, and fenofibrate treatment was initiated. After 1 year of therapy, a gynecologic visit for menstrual cycle abnormalities revealed an unplanned pregnancy at 8 weeks of gestation (dating from the first day of the last menstrual period). Fenofibrate was discontinued and the pregnancy was continued despite the potential risks involved with the use of fibrates during early pregnancy. Fetal ultrasound performed routinely during each trimester showed normal fetal growth with no malformation. The patient delivered a healthy male infant at 36 weeks of gestation. No congenital malformation was recorded. The baby was healthy on pediatrician examination at 1 year. DISCUSSION: Fibrates have good efficacy in lowering fasting triglyceride (TG) levels as well as postprandial TG and TG-rich lipoprotein remnant particles. Previous reports showed that fibrates have been administered cautiously in pregnant women after embryogenesis if their use is necessary; however, in our case, the embryo had been exposed to fenofibrate from the beginning of fertilization. Nevertheless, fenofibrate did not cause significant damage, such as external, skeletal, and visceral abnormalities, to the developing embryo. CONCLUSIONS: In this case, no harmful effects on fetal development were observed after exposure to fenofibrate during organogenesis. PMID- 22253191 TI - Adverse drug reaction deaths reported in United States vital statistics, 1999 2006. AB - BACKGROUND: Adverse drug reactions (ADRs) are an important source of morbidity and mortality during medical care. OBJECTIVE: To examine the trends in mortality related to ADRs reported through the US vital statistics system since January 1999. METHODS: Demographic characteristics of people reported as dying as a result of ADRs from 1999 to 2006 were evaluated. The National Mortality Statistics database was queried for International Classification of Diseases, Tenth Revision, codes Y40-Y59, which are specific for deaths due to adverse effects of drugs in therapeutic use. The data were subgrouped based on demographic factors to identify important trends. Crude rates were calculated based on incidents per 100,000 population. Odds ratios and 95% confidence intervals for subgroups were calculated by logistical regression. RESULTS: During the 8-year study period 2,313,902,748 person years were evaluated and 2341 ADR related deaths were identified. Annual rates ranged from 0.08/100,000 to 0.12/100,000, and rates increased significantly over time at a rate of 0.0058 per year. ADR deaths were significantly more likely in persons older than 55 years. The risk was greatest in those aged 75 years or older (OR 6.96, 95% CI 6.30 to 7.69). ADR deaths were higher among men than women. Rates varied by race and ethnicity and were highest among blacks (OR 1.38, 95% CI 1.23 to 1.54). Geographically, rates varied widely between states. Based on urbanization, rates were highest in extremely rural (non-core) areas (OR 2.05, 95% CI 1.76 to 2.38). The most common drug classes associated with death were anticoagulants, opioids, and immunosuppressants. CONCLUSIONS: ADR death rates have a clear association with age, race, and urbanization subgroups. Older individuals, males, blacks, and individuals residing in extremely rural areas experienced higher ADR death rates; these findings warrant further study to develop prevention strategies. PMID- 22253192 TI - Comparison between transvaginal sonography, saline contrast sonovaginography and magnetic resonance imaging in the diagnosis of posterior deep infiltrating endometriosis. AB - OBJECTIVE: To compare clinical evaluation, transvaginal sonography (TVS), saline contrast sonovaginography (SCSV) and magnetic resonance imaging (MRI) in the diagnosis of posterior deep pelvic endometriosis (DPE). METHODS: Women suspected of having posterior DPE on the basis of subjective symptoms and clinical evaluation underwent digital vaginal and rectal examination, TVS, SCSV and MRI. Laparoscopy was performed and specimens were sent for histological examination. Sensitivity, specificity, positive and negative predictive value, as well as positive and negative likelihood ratios were analyzed for each diagnostic method. RESULTS: Fifty-four out of 102 women suspected of having posterior DPE underwent laparoscopic surgery. Among these, in 46 (85.2%) cases DPE was confirmed at laparoscopic and histological examination. SCSV correctly identified 43 (93.5%) cases, presenting higher accuracy than did the other procedures. SCSV and MRI were more accurate in diagnosing and discriminating between the different locations of endometriotic lesions, with respective sensitivities of 94.7 and 73.1% for vaginal fornix, 88.9 and 66.7% for the uterosacral ligaments and 80.6 and 83.3% for involvement of the rectovaginal septum. The specificity of SCSV and MRI, respectively, was 97.1 and 94.3% for vaginal fornix, 95.6 and 95.6% for uterosacral ligaments and 100 and 77.8% for involvement of the rectovaginal septum. In the diagnosis of rectal endometriosis, we found a sensitivity of 66.7% for both techniques and specificity of 93.8% for SCSV and 95.8% for MRI. CONCLUSION: TVS should be used as the first-line diagnostic technique and SCSV and/or MRI as second-line methods in the diagnosis of posterior DPE. PMID- 22253193 TI - Comprehensive surface-based morphometry reveals the association of fracture risk and bone geometry. AB - Surface-based morphometry method is advantageous in its objectivity and increased capability in detecting focal morphological changes, but has not been applied in bone-related research. Orthopedics research in human has confirmed the association of the bone geometry in proximal femur and its fracture. In this study, surface-based morphometry is used to test the hypothesis that there is relationship between bone geometry and fracture risk of the proximal sesamoid bone (PSB) in forelimbs of Thoroughbred racehorses. The PSB surfaces were extracted from CT images of nonfractured forelegs (i.e., right foreleg in this study) of 6 racehorses with fractures in the contralateral (i.e., left) foreleg, and the right forelegs of 6 matched controls. Significant differences were detected at the abaxial margin of the medial PSB base which was found to be up to 3.5 mm more prominent in the fracture-group compared to the control-group. This study demonstrated a successful application of computational morphometry in bone. The detected anatomical differences may lead to a larger moment arm generated via the medial branch of the suspensory apparatus, increasing pressure on the sesamoid surface, and thus potentially predisposing to fracture. Findings from this pilot study not only increase the likelihood of accurate PSB fracture risk assessment, but also shed light on investigating the influence of sports and exercise on human athletes. PMID- 22253194 TI - Planar four-coordinate boron: a single, flat boron atom as a ligand for four metals. PMID- 22253196 TI - Agreement between self-report and prescription data in medical records for pregnant women. AB - BACKGROUND Clinical teratology studies often rely on patient reports of medication use in pregnancy with or without other sources of information. Electronic medical records (EMRs), administrative databases, pharmacy dispensing records, drug registries, and patients' self-reports are all widely used sources of information to assess potential teratogenic effect of medications. The objective of this study was to assess comparability of self-reported and prescription medication data in EMRs for the most common therapeutic classes. METHODS The study population included 404 pregnant women prospectively recruited from five prenatal care clinics affiliated with the University of New Mexico. Self-reported information on prescription medications taken since the last menstrual period (LMP) was obtained by semistructured interviews in either English or Spanish. For validation purposes, EMRs were reviewed to abstract information on medications prescribed between the LMP and the date of the interview. Agreement was estimated by calculating a kappa (kappa) coefficient, sensitivity, and specificity. RESULTS In this sample of socially-disadvantaged (i.e., 67.9% high school education or less, 48.5% no health insurance), predominantly Latina (80.4%) pregnant women, antibiotics and antidiabetic agents were the most prevalent therapeutic classes. The agreement between the two sources substantially varied by therapeutic class, with the highest level of agreement seen among antidiabetic and thyroid medications (kappa >=0.8) and the lowest among opioid analgesics (kappa = 0.35). CONCLUSIONS Results indicate a high concordance between self-report and prescription data for therapeutic classes used chronically, while poor agreement was observed for medications used intermittently, on an 'as needed" basis, or in short courses. PMID- 22253195 TI - Transcriptional hallmarks of Noonan syndrome and Noonan-like syndrome with loose anagen hair. AB - Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is genetically heterogeneous, being caused by germline mutations affecting various genes implicated in the RAS signaling network. This network transduces extracellular signals into intracellular biochemical and transcriptional responses controlling cell proliferation, differentiation, metabolism, and senescence. To explore the transcriptional consequences of NS causing mutations, we performed global mRNA expression profiling on peripheral blood mononuclear cells obtained from 23 NS patients carrying heterozygous mutations in PTPN11 or SOS1. Gene expression profiling was also resolved in five subjects with Noonan-like syndrome with loose anagen hair (NS/LAH), a condition clinically related to NS and caused by an invariant mutation in SHOC2. Robust transcriptional signatures were found to specifically discriminate each of the three mutation groups from 21 age- and sex-matched controls. Despite the only partial overlap in terms of gene composition, the three signatures showed a notable concordance in terms of biological processes and regulatory circuits affected. These data establish expression profiling of peripheral blood mononuclear cells as a powerful tool to appreciate differential perturbations driven by germline mutations of transducers involved in RAS signaling and to dissect molecular mechanisms underlying NS and other RASopathies. PMID- 22253197 TI - Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. AB - Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target. PMID- 22253198 TI - Expression of antioxidant molecules after peripheral nerve injury and regeneration. AB - Oxidative stress is considered to be one of the main causes of neural damage after injury. However, little is known about the changes in mRNA expression of antioxidant molecules that occur after injury and regeneration of the peripheral nerve. In the present study, the rat median nerve was transected, and transcriptional changes were studied at day 6 and day 12 after injury in both the proximal and the distal stumps, in the absence or presence of microsurgical repair. The expression profiles of the following genes were investigated: three metallothionein isoforms (MT-1, MT-2, and MT-3), the main antioxidant enzymes (catalase, superoxide dismutase, and glutathione-S-transferase), and the marker of cellular damage poly(ADP-ribose) polymerase-1 (PARP-1). The results showed that, in the proximal nerve stump, MT-3 mRNA expression was significantly and markedly up-regulated in the absence of surgical repair, whereas MT-1 and MT-2 showed significant down-regulation. In the distal nerve portion, mRNA expression of all MT isoforms decreased significantly in the absence of microsurgical reconstruction, whereas, after repair, MT-3 mRNA expression alone was up regulated. Expression of all the antioxidant enzymes decreased significantly after repair in the proximal nerve portion, but a significant general increase in their mRNA expression was revealed in the distal nerve stump. PARP-1 expression was significantly up-regulated in the proximal nerve portion without repair but dramatically reduced after reconstruction. In contrast, PARP-1 expression increased markedly in the distal stump after surgical repair. Taken together, these findings indicate that antioxidant molecules are differentially modulated and might, therefore, play an important role in peripheral nerve injury and regeneration. PMID- 22253199 TI - Effect of a dexamethasone Sinu-FoamTM middle meatal spacer on endoscopic sinus surgery outcomes: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Off-label drug eluting middle-meatal spacers have shown promising results for improving clinical outcomes following endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS). This study evaluates a dexamethasone Sinu FoamTM spacer following ESS for CRS without nasal polyposis (CRSsNP). METHODS: Patients with CRSsNP (n = 36) were enrolled into a double-blind, placebo controlled trial and randomized into either a treatment arm (dexamethasone Sinu FoamTM mixture; n = 18) or placebo arm (Sinu-FoamTM alone; n = 18). Therapeutic outcomes were evaluated at 1 week, 4 weeks, and 3 months using sinonasal endoscopy and graded using the Lund-Kennedy scoring system. Postoperative care included nasal saline irrigations and a short course of systemic steroids. RESULTS: All patients completed the study follow-up period. Both study arms experienced significant improvement in endoscopic grading over the study duration (p < 0.001). There was no difference in average endoscopic scores between the treatment and placebo groups at 1 week, 4 weeks, and 3 months (all p > 0.489). CONCLUSION: This study demonstrated that an off-label drug-eluting middle-meatal spacer of dexamethasone and Sinu-FoamTM does not improve endoscopic outcomes in the early postoperative period following ESS when combined with postoperative saline irrigations and a short course of systemic steroids. PMID- 22253200 TI - Development of the maternal anal canal during pregnancy and the postpartum period: a longitudinal and functional ultrasound study. AB - OBJECTIVES: Normal anatomical and physiological development of the maternal anal canal during and after pregnancy has been documented scarcely. We aimed to study the position and volume of the anal canal, during and after pregnancy, in women without previous delivery. METHODS: This was a longitudinal study in which transvaginal three-dimensional ultrasound was used to measure anatomical structures in the anal canal during rest and squeeze in 23 nulliparous women. The total anal canal volume (ACV), anorectal curvature (ARC), anovaginal angle (AVA) and anal canal length were determined at 18, 28 and 36 weeks of pregnancy and at 3 months postpartum. RESULTS: Total ACV at rest increased from a mean of 10.17 cm(3) at 18 weeks to 12.37 cm(3) and 12.21 cm(3) at 28 and 36 weeks, respectively (P = 0.001 and P = 0.010 vs. first measurement). For anal canal length, the corresponding mean measurements were 3.91 cm, 4.07 cm (P = 0.13) and 4.21 cm (P = 0.017). Postpartum, the mean total ACV was 10.86 cm(3) and length was 3.90 cm (P = 0.10 and P = 0.70 vs. first measurement). No significant changes were observed in ARC and AVA during or after pregnancy. Compared to at-rest status, the anal length significantly increased on voluntary squeeze (P = 0.007, 0.007, 0.022 and 0.004 at the four time points), while no differences in total ACV were observed. In mid-pregnancy AVA significantly increased during squeeze (P = 0.006 and 0.002 at weeks 18 and 28, respectively). CONCLUSION: Anal canal length and total ACV increase during pregnancy in women without previous delivery. Voluntary squeezing elongates the anal canal and increases the angle formed with respect to the direction of the vagina. During postpartum involution, the characteristics of the anal canal revert to those observed at 18 weeks of pregnancy. PMID- 22253201 TI - Probing the electronic state of a single coronene molecule by the emission from proximate fluorophores. AB - We measured electronic transitions of the 2D graphene-type molecule hexa-peri hexabenzocoronene (HBC) at the single-molecule level. The large intersystem crossing rate and long triplet state lifetime in the range of seconds are prohibitive for direct single-molecule observation. By covalently coupling fluorescent acceptor molecules (perylenecarboximide, PMI) to HBC, efficient singlet energy transfer gives rise to strong PMI fluorescence. Confocal single molecule fluorescence microscopy with two excitation colours matching the HBC and PMI transition frequencies, respectively, was conducted. Single HBC-6PMI molecules were readily observed via the PMI emission. It was found that after selective excitation of the HBC the PMI emission is interrupted by dark intervals whose length of several seconds is in agreement with the triplet state lifetime of HBC. Accordingly, the presence/absence of PMI emission permits to read out the spin state of a single HBC molecule. Moreover, due to spectral overlap, the HBC triplet state acts as an energy acceptor for PMI in the excited singlet state, thus leading to efficient singlet-triplet annihilation (STA) during its lifetime. Hence, intersystem crossing into the HBC triplet state serves as a collective fluorescence switch for individual multichromophores. PMID- 22253202 TI - Catechol-O-methyltransferase polymorphisms do not play a significant role in pain perception in male Chinese Han population. AB - Polymorphisms in the human catechol-O-methyltransferase (COMT) gene have been widely studied for their role in pain and analgesia. In this study, sensitivity to potassium iontophoresis, visual analog scale measurements for fixed twofold pain threshold stimulation and pain threshold changes induced by transcutaneous electrical acupoint stimulation (TEAS) were assessed in a population of healthy Chinese males. These results were correlated with the alleles of six single nucleotide polymorphisms (SNP) or diplotypes of common haplotypes designated as low pain sensitive, average pain sensitive, and high pain sensitive in the COMT gene of these subjects. Our results reveal that the alleles of each SNP are not significantly correlated with pain perception except for the rs4633 allele in the 2 Hz TEAS session (P < 0.05). In addition, the six diplotypes of COMT haplotypes, which cover 92.5% of the Chinese population, are also not correlated with pain perception. Moreover, there were no significant differences in pain threshold changes induced by 2 and 100 Hz TEAS among the diplotypes of each SNP or the various haplotypes. These results suggest that COMT activity do not play a significant role in pain perception and TEAS-induced analgesia in the Chinese Han male population. PMID- 22253203 TI - Use of gentamicin-collagen sponges in closure of sternal wounds in cardiothoracic surgery to reduce wound infections. AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Are antibiotic implants like gentamicin collagen implants useful in preventing sternal wound infections (SWIs)? Altogether, more than 484 papers were found using the reported search; of these, 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that most randomized controlled trials (RCTs) have been performed with gentamicin collagen sponges for sternal closure. Two out of four RCTs showed a significant benefit of the implant in a reduction in superficial and deep SWIs in routine and emergency cardiac surgery. One RCT showed a significant reduction in superficial infections in 2005, a follow-up trial by the same group in 2009 showed a reduction in deep infections as well. Another group has shown a reduction in deep and superficial SWI with gentamicin implant, in an RCT on 800 patients, however have not published details of the complete trial. The third trial on 542 patients showed no benefit of the implant, but was not adequately powered. However, the most recent multicentre RCT conducted on 1052 patients showed no benefit of gentamicin-collagen sponges in elective surgery (coronary artery bypass grafting and/or valve surgery) in high-risk patients with diabetes, obesity or both. Concerns were raised that gentamicin sponges dipped in saline 1-2 s prior to application may have lost the gentamicin into the saline, thereby reducing their efficacy and that some surgeons may have been unfamiliar with wound closure with sponges. However, these were robustly refuted by the authors. One RCT showed that gentamicin sponges may cause increased sternal rebleeding if used in double layers. Coagulase-negative staphylococci were predominantly isolated from infected wounds in all the trials except the one from USA, where infections were polymicrobial. Gentamicin resistance among common pathogens causing SWIs can vary from 15 to 80%. Gentamicin-collagen is unlikely to reduce SWIs in high-risk patients and polymicrobial infections. PMID- 22253204 TI - Double-structured LiMn(0.85)Fe(0.15)PO4 coordinated with LiFePO4 for rechargeable lithium batteries. PMID- 22253205 TI - Minocycline protects oligodendroglial precursor cells against injury caused by oxygen-glucose deprivation. AB - Ischemic brain injury is widely modeled in vitro with paradigms of oxygen-glucose deprivation (OGD), which leads to cell death. The prevention and attenuation of brain injury by the tetracycline antibiotic minocycline has been attributed largely to suppression of microglial activation, but its benefits in oligodendrocyte cells have not been well characterized. Using primary cultures of rat oligodendroglial precursor cells (OPC) exposed to OGD, we investigated the direct effects of minocycline on the survival, proliferation, and maturation of oligodendroglial lineage cells. OGD for 2 hr caused a decrease in the total number of OPC and the amount of proliferating progenitors by 50%, which was attenuated by inclusion of minocycline. The reduced numbers of immature oligodendroglial cells at 72 hr and of mature oligodendrocytes at 120 hr after OGD were partially restored by minocycline. In OPC, OGD caused an increase of reactive oxygen species (ROS) and production of TUNEL-positive cell numbers, which was abolished by minocycline. Minocycline preferentially increased the expression of superoxide dismutase under OGD but not in control OPC. Minocycline also prevented the OGD-induced downregulation of the transcription factors Sox10 and Olig2 and of myelin-specific genes 2'3' cyclic nucleotide phosphodiesterase (CNP) and myelin basic protein (MBP) in response to OGD. These studies demonstrate direct protective actions of minocycline on oligodendroglial-lineage cells, suggesting potential benefit in white matter injury involving OGD. PMID- 22253206 TI - Acquisition of polychlorinated biphenyls (PCBs) by Pacific chinook salmon: an exploration of various exposure scenarios. AB - In 2011, as part of an update to its state water quality standards (WQS) for protection of human health, the State of Oregon adopted a fish consumption rate of 175 g/day for freshwater and estuarine finfish and shellfish, including anadromous species. WQS for the protection of human health whose derivation is based in part on anadromous fish, create the expectation that implementation of these WQS will lead to lower contaminant levels in returning adult fish. Whether this expectation can be met is likely a function of where and when such fish are exposed. Various exposure scenarios have been advanced to explain acquisition of bioaccumulative contaminants by Pacific salmonids. This study examined 16 different scenarios with bioenergetics and toxicokinetic models to identify those where WQS might be effective in reducing polychlorinated biphenyls (PCBs)--a representative bioaccumulative contaminant--in returning adult Fall chinook salmon, a representative salmonid. Model estimates of tissue concentrations and body burdens in juveniles and adults were corroborated with observations reported in the literature. Model results suggest that WQS may effect limited (< approximately 2 *) reductions in PCB levels in adults who were resident in a confined marine water body or who transited a highly contaminated estuary as out migrating juveniles. In all other scenarios examined, WQS would have little effect on PCB levels in returning adults. Although the results of any modeling study must be interpreted with caution and are not necessarily applicable to all salmonid species, they do suggest that the ability of WQS to meet the expectation of reducing contaminant loadings in anadromous species is limited. PMID- 22253207 TI - A comparative study of mouse nasal septal and turbinal epithelium for in vitro cell cultures. AB - BACKGROUND: The small number of epithelial cells that can be isolated from mouse respiratory tract has limited its application to study of the airway. Our purpose in this work was to compare the potential of mouse nasal septal and turbinal epithelium for serving as a cell source for in vitro cell cultures. METHODS: The distribution of ciliated epithelial cells in the mouse nasal cavity, and the surface area of the respiratory epithelium in the mouse nasal septum and turbinate were determined by beta-tubulin IV immunohistochemistry. Ciliated epithelial cell density of native mouse nasal septum and turbinate, and the morphology of cultured mouse nasal septal and turbinal epithelial cells were examined by scanning electron microscopy (SEM) and beta-tubulin IV and zona occludens (ZO)-1 dual-label fluorescent cytochemistry, respectively. Cilia reactivity to exogenous stimuli (adenosine triphosphate or benzalkonium chloride) in cultured nasal septal and turbinal epithelial cells was studied using high speed digital microscopy. RESULTS: The ciliated epithelial cell density of native nasal epithelium, the morphology and cell yield of in vitro cultured epithelial cells, and cilia reactivity to exogenous stimuli of mouse turbinate are comparable to that of the nasal septum. However, the respiratory epithelium surface area of mouse turbinate is significantly larger than that of the nasal septum. CONCLUSION: Mouse turbinate may also serve as an ideal source of in vitro epithelial cell cultures. Both nasal septum and turbinate should be harvested to optimize animal use in the establishment of primary murine respiratory epithelial cultures. PMID- 22253208 TI - Intermolecular weak interactions in HTeXH dimers (X=O, S, Se, Te): hydrogen bonds, chalcogen-chalcogen contacts and chiral discrimination. AB - A theoretical study of the HTeXH (X=O, S, Se and Te) monomers and homodimers was carried out by means of second-order Moller-Plesset perturbation theory (MP2) computational methods. In the case of monomers, the isomerization energy from HTeXH to H(2) Te=X and H(2) X=Te (X=O, S, Se, and Te) and the rotational transition-state barriers were obtained. Due to the chiral nature of these compounds, homo and heterochiral dimers were found. The electron density of the complexes was characterized with the atoms-in-molecules (AIM) methodology, finding a large variety of interactions. The charge transfer within the dimers was analyzed by means of natural bond orbitals (NBO). The density functional theory-symmetry adapted perturbation theory (DFT-SAPT) method was used to compute the components of the interaction energies. Hydrogen bonds and chalcogen chalcogen interactions were characterized and their influence analyzed concerning the stability and chiral discrimination of the dimers. PMID- 22253209 TI - Synthesis of block copolymers by combination of atom transfer radical polymerization and visible light-induced free radical promoted cationic polymerization. AB - A new synthetic approach for the preparation of block copolymers by mechanistic transformation from atom transfer radical polymerization (ATRP) to visible light induced free radical promoted cationic polymerization is described. A series of halide end-functionalized polystyrenes with different molecular weights synthesized by ATRP were utilized as macro-coinitiators in dimanganese decacarbonyl [Mn(2) (CO)(10) ] mediated free radical promoted cationic photopolymerization of cyclohexene oxide or isobutyl vinyl ether. Precursor polymers and corresponding block copolymers were characterized by spectral, chromatographic, and thermal analyses. PMID- 22253210 TI - Ultrastructural characteristics of spermatogenesis in Pallas's mastiff bat, Molossus molossus (Chiroptera: Molossidae). AB - Despite the large number of species, their wide distribution, and unique reproductive characteristics, Neotropical bats have been poorly studied, and important aspects of the reproduction of these animals have not been elucidated. We made an ultrastructural analysis of spermatogenesis in Molossus molossus (Molossidae). The process of spermatogonial differentiation is similar to that found in other bats and is also relatively similar to that of Primates, with three main spermatogonia types: A(d), A(p), and B. Meiotic divisions proceed similarly to those of most mammals, and spermiogenesis is clearly divided into 12 steps, in the middle of the range known for bats (9-16 steps). Formation of the acrosome is similar to that known from other mammals; however, the ultrastructure of spermatozoa was found to have unique characteristics, including many wavy acrosomal projections on its surface, which seems to be specific for the family Molossidae. Comparing the ultrastructure of the spermatozoon of M. molossus with other bats already study, we observed that three characters vary: morphology of the outer dense fibers, of the perforatorium, and of the spermatozoon head. The great similarity of morphological characters between M. molossus and Platyrrhinus lineatus suggests that M. molossus is more closely related to the Phyllostomidae than to the Rhinolophidae and the Vespertilionidae. PMID- 22253212 TI - Advanced fluorescence technologies help to resolve long-standing questions about microbial vitality. AB - Advances in fundamental physical and optical principles applied to novel fluorescence methods are currently resulting in rapid progress in cell biology and physiology. Instrumentation devised in pioneering laboratories is becoming commercially available, and study findings are now becoming accessible. The first results have concerned mainly higher eukaryotic cells but many more developments can be expected, especially in microbiology. Until now, some important problems of cell physiology have been difficult to investigate due to interactions between probes and cells, excretion of probes from cells and the inability to make in situ observations deep within the cell, within tissues and structures. These technologies will enable microbiologists to address these topics. This Review aims at introducing the limits of current physiology evaluation techniques, the principles of new fluorescence technologies and examples of their use in this field of research for evaluating the physiological state of cells in model media, biofilms or tissue environments. Perspectives on new imaging technologies, such as super-resolution imaging and non-linear highly sensitive Raman microscopy, are also discussed. This review also serves as a reference to those wishing to explore how fluorescence technologies can be used to understand basic cell physiology in microbial systems. PMID- 22253211 TI - Multivariate analysis of anxiety disorders yields further evidence of linkage to chromosomes 4q21 and 7p in panic disorder families. AB - Replication has been difficult to achieve in linkage studies of psychiatric disease. Linkage studies of panic disorder have indicated regions of interest on chromosomes 1q, 2p, 2q, 3, 7, 9, 11, 12q13, 12q23, and 15. Few regions have been implicated in more than one study. We examine two samples, the Iowa (IA) and the Columba panic disorder families. We use the fuzzy-clustering method presented by Kaabi et al. [Kaabi et al. (2006); Am J Hum Genet 78: 543-553] to summarize liability to panic disorder, agoraphobia, simple phobia, and social phobia. Kaabi et al. applied this method to the Yale panic disorder linkage families and found evidence of linkage to chromosomes 4q21, 4q32, 7p, and 8. When we apply the same method to the IA families, we obtain overlapping evidence of linkage to chromosomes 4q21 and 7p. Additionally, we find evidence of linkage on chromosomes 1, 5, 6, 16, and 22. The Columbia (CO) data does not indicate linkage to any of the Kaabi et al. peaks, instead implicating chromosomes 2 and 22q11 (2 Mb from COMT). There is some evidence of overlapping linkage between the IA and CO datasets on chromosomes 1 and 14. While use of fuzzy clustering has not produced complete concordance across datasets, it has produced more than previously seen in analyses of panic disorder proper. We conclude that chromosomes 4q21 and 7p should be considered strong candidate regions for panic and fear-associated anxiety disorder loci. More generally, this suggests that analyses including multiple aspects of psychopathology may lead to greater consistency across datasets. PMID- 22253213 TI - Motor performance of young dystrophic mdx mice treated with long-circulating prednisolone liposomes. AB - For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3-6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-beta and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases. PMID- 22253214 TI - Facile access to chiral ketones through metal-free oxidative C-C bond cleavage of aldehydes by O2. PMID- 22253215 TI - Supercapacitors based on c-type cytochromes using conductive nanostructured networks of living bacteria. AB - Supercapacitors have attracted interest in energy storage because they have the potential to complement or replace batteries. Here, we report that c-type cytochromes, naturally immersed in a living, electrically conductive microbial biofilm, greatly enhance the device capacitance by over two orders of magnitude. We employ genetic engineering, protein unfolding and Nernstian modeling for in vivo demonstration of charge storage capacity of c-type cytochromes and perform electrochemical impedance spectroscopy, cyclic voltammetry and charge-discharge cycling to confirm the pseudocapacitive, redox nature of biofilm capacitance. The biofilms also show low self-discharge and good charge/discharge reversibility. The superior electrochemical performance of the biofilm is related to its high abundance of cytochromes, providing large electron storage capacity, its nanostructured network with metallic-like conductivity, and its porous architecture with hydrous nature, offering prospects for future low cost and environmentally sustainable energy storage devices. PMID- 22253216 TI - Examining the safety of prednisolone acetate 1% nasal spray for treatment of nasal polyposis. AB - BACKGROUND: Topical intranasal corticosteroid sprays are a mainstay of treatment for nasal polyposis. Newer treatment strategies for refractory polypoid disease include "off label" topical steroids such as prednisolone acetate. This study investigates the safety of intranasal prednisolone acetate; evaluating its effect on serum cortisol and adrenocorticotropin hormone (ACTH) levels. METHODS: This retrospective study included adult patients with refractory nasal polyposis, who had not taken oral steroids for 3 months prior to entry into the study. Patients applied 2 sprays of 1% prednisolone acetate delivered via a 15-mL standardized spray bottle twice daily. Morning serum cortisol and ACTH levels were collected prior to treatment and 6 to 8 weeks posttreatment. Pretreatment and posttreatment values were compared. RESULTS: Nine patients were included in this study. The average serum cortisol and ACTH levels prior to treatment was 12.09 MUg/dL (95% confidence interval [CI], 6.94-17.24) and 12.33 ng/L (95% CI, 8.97-15.70), respectively. After 6 to 8 weeks of treatment, the average serum cortisol and ACTH levels were 11.76 MUg/dL (95% CI, 9.51-14.00) and 13.22 ng/L (95% CI, 10.68 15.77), respectively. There was no statistically significant difference between pretreatment and posttreatment values for cortisol (p = 0.89) or ACTH (p = 0.63). CONCLUSION: Intranasal delivery of prednisolone acetate, at the specified dose, does not result in suppression of the adrenal axis. It can be considered as a safe alternative for management of aggressive nasal polyposis refractory to traditional treatment strategies. PMID- 22253217 TI - Photonics of a conjugated organometallic Pt-Ir polymer and its model compounds exhibiting hybrid CT excited states. AB - Trans- dichlorobis(tri-n-butylphosphine)platinum(II) reacts with bis(2- phenylpyridinato)-(5,5'-diethynyl-2,2'-bipyridine)iridium(III) hexafluorophosphate to form the luminescent conjugated polymer poly[trans-[(5,5' ethynyl-2,2'-bipyridine)bis(2- phenylpyridinato)-iridium(III)]bis(tri-n butylphosphine)platinum(II)] hexafluorophosphate ([Pt]-[Ir])n. Gel permeation chromatography indicates a degree of polymerization of 9 inferring the presence of an oligomer. Comparison of the absorption and emission band positions and their temperature dependence, emission quantum yields, and lifetimes with those for models containing only the [Pt] or the [Ir] units indicates hybrid excited states including features from both chromophores. PMID- 22253218 TI - How to define, find and classify side effects in psychotherapy: from unwanted events to adverse treatment reactions. AB - OBJECTIVE: Empirical research on the negative effects of psychotherapy is insufficient, partly because there is a lack of theoretical concept on how to define, classify and assess psychotherapy side effects. This paper proposes a model for the definition, classification and assessment of psychotherapy side effects. METHOD: Definitions are provided for 'unwanted events', 'treatment emergent reactions', 'adverse treatment reactions', 'malpractice reactions', 'treatment non-response', 'deterioration of illness', 'therapeutic risks' and 'contraindications'. We describe processes analysing the causality of negative events and the correctness of treatment. RESULT: A procedural model on how to find, classify and evaluate negative events is described, the unwanted event to adverse treatment reaction (UE-ATR) checklist. CONCLUSION: Recognition of adverse treatment effects is a characteristic of good therapists and treatments. Psychotherapists should be sensitive for negative effects. This can help improve the quality of treatment. The UE-ATR checklist can be used in psychotherapy trials, quality assurance, clinical practice and training of psychotherapists. PMID- 22253219 TI - Newborn screening for Pompe disease: an update, 2011. AB - There is mounting evidence in support of universal newborn screening for Pompe disease. Early treatment of children with infantile Pompe disease, prior to clinical diagnosis, is clearly of benefit in prolonging survival and improving cardiac and motor function. Several testing methods applicable to newborn screening using dried blood spots have been described and several are currently being tested in pilot screening programs. Although challenges remain, particularly in identification of the best strategy for follow-up and management of later onset Pompe disease, these challenges can surely be overcome as they have been with other disorders added to the newborn screening panel. It is anticipated that the results of the several pilot programs currently ongoing or in the planning stages in the United States will provide the data necessary to recommend universal newborn screening for Pompe disease for all infants. PMID- 22253221 TI - Tailoring silicalite-1 crystal morphology with molecular modifiers. AB - Modified point of view: a bio-inspired approach was used to tailor silicalite-1 crystallization. Growth modifiers (ZGMs) with molecular recognition for binding to specific crystal faces produced drastic changes in zeolite crystal morphology. This facile approach offers an efficient method for tuning zeolite properties. PMID- 22253220 TI - ID2: A negative transcription factor regulating oligodendroglia differentiation. AB - Remyelination of the central nervous system in multiple sclerosis patients is often incomplete. Remyelination depends on normal oligodendrogenesis and the differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). Inhibitor of DNA binding (ID), a transcription factor, is thought to inhibit oligodendrogenesis and the differentiation of OPC. This Mini Review aims to reveal the roles of and mechanisms used by IDs (mainly ID2) in this process. An interaction between ID2 and retinoblastoma tumor suppressor is responsible for the cell cycle transition from G1 to S. The translocation of ID2 between the nucleus and cytoplasm is regulated by E47 and OLIG. An interaction between ID2 and OLIG mediates the inhibitory effects of bone morphogenic proteins and G protein-coupled receptor 17 on oligodendroglia differentiation. ID2 expression is regulated by Wnt and histone deacetylases during the differentiation of OPC. ID4, another member of the ID family, functions similarly to ID2 in regulating the differentiation of OPC. The main difference is that ID4 is essential for oligodendrogenesis, whereas ID2 is nonessential. This could have important implications for demyelinating diseases, and interfering with these pathways might represent a viable therapeutic approach for these diseases. PMID- 22253222 TI - A volitional help sheet to reduce binge drinking in students: a randomized exploratory trial. AB - AIMS: This study tested the ability of a volitional help sheet (VHS) to decrease binge drinking in UK students. METHODS: Fifty-six participants were randomly allocated to one of three conditions: control, active control or VHS as part of a questionnaire-based study. RESULTS: There were significant decreases in units of alcohol consumed and self-reported binge drinking frequency in the VHS condition, but not in either of the control conditions. CONCLUSIONS: The findings support use of the VHS to help people to reduce their alcohol consumption and binge drinking. PMID- 22253223 TI - Cation-pi interactions between a free-base porphyrin and an ionic liquid: a computational study. AB - A cation-pi stacking structure consisting of a free-base porphyrin (FBP) and 1 butyl-3-methylimidazolium (BMIM(+)) cation is demonstrated by both ab initio theory and polarizable force field. The isolated FBP-BMIM(+) complex forms a face to-face alignment, and the polarizable force-field-optimized complex reproduces that by ab initio theory reasonably well. Molecular dynamics simulation finds that the stacking structure is slightly altered for the FBP dissolved in the bulk ionic liquid (IL) due to the complexity of the solution structure. In the bulk IL, the FBP is sandwiched between two BMIM(+) cations stacking on both sides of the FBP ring plane with a slipped-parallel alignment. Furthermore, the FBP BMIM(+) stacking structure is found to be more stable than the BMIM(+)-PF(6)(-) ion pair in the IL. PMID- 22253224 TI - Long-term results after primary frontal sinus surgery. AB - BACKGROUND: The objectives of this study were to evaluate the long-term frontal ostium patency rate and symptom improvement in patients undergoing primary endoscopic frontal sinusotomy (Draf 2A) and to assess the impact of patient factors, disease factors, and frontal ostium size on surgical outcomes. METHODS: Retrospective chart review was used. Endoscopic assessment of frontal ostium patency and patient-reported symptoms were prospectively collected on patients who underwent primary frontal sinusotomy between January 2003 and December 2009. RESULTS: A total of 109 patients underwent primary endoscopic surgery on 210 frontal sinuses over the study period. The overall patency rate was 92%. Complete resolution of symptoms was noted in 85 patients (78%). Stenosis of the frontal sinus ostium correlated significantly with persistence of symptoms, infection, or polyp recurrence (p = 0.0066), and frontal ostium size (p < 0.03). No significant correlation could be found between the presence of eosinophilic mucin, asthma, polyposis, and smoking on patency or resolution of symptoms. CONCLUSION: To our knowledge, this is the largest study of primary endoscopic frontal sinus surgery in the literature. The technical and subjective measures of success are high. Frontal ostium size correlates with risk of stenosis of the frontal sinus. Patients with a stenosed frontal ostium and residual frontal sinus disease are more likely to be symptomatic or have endoscopic evidence of polyp recurrence or endoscopic evidence of persistent infection. Asthma, eosinophilic mucin chronic rhinosinusitis (EMCRS), allergy, and smoking do not appear to affect outcomes. PMID- 22253225 TI - Routes to the tonoplast: the sorting of tonoplast transporters in Arabidopsis mesophyll protoplasts. AB - Vacuoles perform a multitude of functions in plant cells, including the storage of amino acids and sugars. Tonoplast-localized transporters catalyze the import and release of these molecules. The mechanisms determining the targeting of these transporters to the tonoplast are largely unknown. Using the paralogous Arabidopsis thaliana inositol transporters INT1 (tonoplast) and INT4 (plasma membrane), we performed domain swapping and mutational analyses and identified a C-terminal di-leucine motif responsible for the sorting of higher plant INT1-type transporters to the tonoplast in Arabidopsis mesophyll protoplasts. We demonstrate that this motif can reroute other proteins, such as INT4, SUCROSE TRANSPORTER2 (SUC2), or SWEET1, to the tonoplast and that the position of the motif relative to the transmembrane helix is critical. Rerouted INT4 is functionally active in the tonoplast and complements the growth phenotype of an int1 mutant. In Arabidopsis plants defective in the beta-subunit of the AP-3 adaptor complex, INT1 is correctly localized to the tonoplast, while sorting of the vacuolar sucrose transporter SUC4 is blocked in cis-Golgi stacks. Moreover, we demonstrate that both INT1 and SUC4 trafficking to the tonoplast is sensitive to brefeldin A. Our data show that plants possess at least two different Golgi dependent targeting mechanisms for newly synthesized transporters to the tonoplast. PMID- 22253226 TI - Leaf-induced gibberellin signaling is essential for internode elongation, cambial activity, and fiber differentiation in tobacco stems. AB - The gibberellins (GAs) are a group of endogenous compounds that promote the growth of most plant organs, including stem internodes. We show that in tobacco (Nicotiana tabacum) the presence of leaves is essential for the accumulation of bioactive GAs and their immediate precursors in the stem and consequently for normal stem elongation, cambial proliferation, and xylem fiber differentiation. These processes do not occur in the absence of maturing leaves but can be restored by application of C(19)-GAs, identifying the presence of leaves as a requirement for GA signaling in stems and revealing the fundamental role of GAs in secondary growth regulation. The use of reporter genes for GA activity and GA directed DELLA protein degradation in Arabidopsis thaliana confirms the presence of a mobile signal from leaves to the stem that induces GA signaling. PMID- 22253227 TI - A new type of compartment, defined by plant-specific Atg8-interacting proteins, is induced upon exposure of Arabidopsis plants to carbon starvation. AB - Atg8 is a central protein in bulk starvation-induced autophagy, but it is also specifically associated with multiple protein targets under various physiological conditions to regulate their selective turnover by the autophagy machinery. Here, we describe two new closely related Arabidopsis thaliana Atg8-interacting proteins (ATI1 and ATI2) that are unique to plants. We show that under favorable growth conditions, ATI1 and ATI2 are partially associated with the endoplasmic reticulum (ER) membrane network, whereas upon exposure to carbon starvation, they become mainly associated with newly identified spherical compartments that dynamically move along the ER network. These compartments are morphologically distinct from previously reported spindle-shaped ER bodies and, in contrast to them, do not contain ER-lumenal markers possessing a C-terminal HDEL sequence. Organelle and autophagosome-specific markers show that the bodies containing ATI1 are distinct from Golgi, mitochondria, peroxisomes, and classical autophagosomes. The final destination of the ATI1 bodies is the central vacuole, indicating that they may operate in selective turnover of specific proteins. ATI1 and ATI2 gene expression is elevated during late seed maturation and desiccation. We further demonstrate that ATI1 overexpression or suppression of both ATI1 and ATI2, respectively, stimulate or inhibit seed germination in the presence of the germination-inhibiting hormone abscisic acid. PMID- 22253228 TI - Rhizobial and fungal symbioses show different requirements for calmodulin binding to calcium calmodulin-dependent protein kinase in Lotus japonicus. AB - Ca(2+)/calmodulin (CaM)-dependent protein kinase (CCaMK) is a key regulator of root nodule and arbuscular mycorrhizal symbioses and is believed to be a decoder for Ca(2+) signals induced by microbial symbionts. However, it is unclear how CCaMK is activated by these microbes. Here, we investigated in vivo activation of CCaMK in symbiotic signaling, focusing mainly on the significance of and epistatic relationships among functional domains of CCaMK. Loss-of-function mutations in EF-hand motifs revealed the critical importance of the third EF hand for CCaMK activation to promote infection of endosymbionts. However, a gain-of function mutation (T265D) in the kinase domain compensated for these loss-of function mutations in the EF hands. Mutation of the CaM binding domain abolished CaM binding and suppressed CCaMK(T265D) activity in rhizobial infection, but not in mycorrhization, indicating that the requirement for CaM binding to CCaMK differs between root nodule and arbuscular mycorrhizal symbioses. Homology modeling and mutagenesis studies showed that the hydrogen bond network including Thr265 has an important role in the regulation of CCaMK. Based on these genetic, biochemical, and structural studies, we propose an activation mechanism of CCaMK in which root nodule and arbuscular mycorrhizal symbioses are distinguished by differential regulation of CCaMK by CaM binding. PMID- 22253229 TI - p53 inhibits angiogenesis by inducing the production of Arresten. AB - Several types of collagen contain cryptic antiangiogenic noncollagenous domains that are released upon proteolysis of extracellular matrix (ECM). Among those is Arresten, a collagen-derived antiangiogenic factor (CDAF) that is processed from alpha1 collagen IV. However, the conditions under which Arresten is released from collagen IV in vivo or whether the protein functions in tumor suppressor pathways remain unknown. Here, we show that p53 induces the expression of alpha1 collagen IV and release of Arresten-containing fragments from the ECM. Comparison of the transcriptional activation of COL4A1 with other CDAF-containing genes revealed that COL4A1 is a major antiangiogenic gene induced by p53 in human adenocarinoma cells. p53 directly activated transcription of the COL4A1 gene by binding to an enhancer region 26 kbp downstream of its 3' end. p53 also stabilized the expression of full-length alpha1 collagen IV by upregulation of alpha(II) prolyl hydroxylase and increased the release of Arresten in the ECM through a matrix metalloproteinase (MMP)-dependent mechanism. The resulting upregulation of alpha1 collagen IV and production of Arresten by the tumor cells significantly inhibited angiogenesis and limited tumor growth in vivo. Furthermore, we show that immunostaining of Arresten correlated with p53 status in human prostate cancer specimens. Our findings, therefore, link the production of Arresten to the p53 tumor suppressor pathway and show a novel mechanism through which p53 can inhibit angiogenesis. PMID- 22253231 TI - Human T(H)17 immune cells specific for the tumor antigen MAGE-A3 convert to IFN gamma-secreting cells as they differentiate into effector T cells in vivo. AB - The role of T(H)17 cells in cancer is being investigated, but the existence of tumor antigen-specific T(H)17 cells has yet to be ascertained. Here, we report the first description of a spontaneous T(H)17 (IL-17(+)) response to the important tumor antigen MAGE-A3, which occurred concurrently with a T(H)1 (IFN gamma(+)) response in a lung cancer patient. MAGE-A3-specific interleukin (IL) 17(+) T cells were mainly CCR7(+) central memory T cells, whereas IFN-gamma(+) cells were enriched for CCR7(-) effector memory T cells. An assessment of the fine specificity of antigen recognition by these T cells indicated that the CCR6(+)CCR4(+) and CCR6(+)CXCR3(+) fractions contained the same T(H)17/T(H)1 population at early and late differentiation stages, respectively, whereas the CCR6(-)CXCR3(+) fraction contained a distinct T(H)1 population. These findings are important because they suggest a differentiation model in which tumor antigen specific CD4(+) T cells that are primed under T(H)17 polarizing conditions will progressively convert into IFN-gamma-secreting cells in vivo as they differentiate into effector T cells that can effectively attack tumors. PMID- 22253230 TI - Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB mediated transcriptional upregulation of Twist1. AB - Proinflammatory cytokines produced in the tumor microenvironment facilitate tumor development and metastatic progression. In particular, TNF-alpha promotes cancer invasion and angiogenesis associated with epithelial-mesenchymal transition (EMT); however, the mechanisms underlying its induction of EMT in cancer cells remain unclear. Here we show that EMT and cancer stemness properties induced by chronic treatment with TNF-alpha are mediated by the upregulation of the transcriptional repressor Twist1. Exposure to TNF-alpha rapidly induced Twist1 mRNA and protein expression in normal breast epithelial and breast cancer cells. Both IKK-beta and NF-kappaB p65 were required for TNF-alpha-induced expression of Twist1, suggesting the involvement of canonical NF-kappaB signaling. In support of this likelihood, we defined a functional NF-kappaB-binding site in the Twist1 promoter, and overexpression of p65 was sufficient to induce transcriptional upregulation of Twist1 along with EMT in mammary epithelial cells. Conversely, suppressing Twist1 expression abrogated p65-induced cell migration, invasion, EMT, and stemness properties, establishing that Twist1 is required for NF-kappaB to induce these aggressive phenotypes in breast cancer cells. Taken together, our results establish a signaling axis through which the tumor microenvironment elicits Twist1 expression to promote cancer metastasis. We suggest that targeting NF-kappaB-mediated Twist1 upregulation may offer an effective a therapeutic strategy for breast cancer treatment. PMID- 22253232 TI - KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A. AB - Transcriptional regulation by p53 is thought to play a role in its ability to suppress tumorigenesis. However, there remain gaps in understanding about how p53 regulates transcription and how disrupting this function may promote cancer. Here we report a role in these processes for the kidney cancer-related gene KR-POK (ZBTB7C), a POZ domain and Kruppel-like zinc finger transcription factor that we found to physically interact with p53. Murine embryonic fibroblasts isolated from genetically deficient mice (Kr-pok(-/-) MEFs) exhibited a proliferative defect relative to wild-type mouse embryonic fibroblasts (MEF). The zinc finger domain of Kr-pok interacted directly with the DNA binding and oligomerization domains of p53. This interaction was essential for Kr-pok to bind the distal promoter region of the CDKN1A gene, an important p53 target gene encoding the cell-cycle regulator p21WAF1, and to inhibit p53-mediated transcriptional activation of CDKN1A. Kr-pok also interacted with the transcriptional corepressors NCoR and BCoR, acting to repress histone H3 and H4 deacetylation at the proximal promoter region of the CDKN1A gene. Importantly, Kr-pok(-/-) MEFs displayed an enhancement in CDKN1A transactivation by p53 during the DNA damage response, without any parallel changes in transcription of either the p53 or Kr-pok genes themselves. Furthermore, Kr-pok promoted cell proliferation in vitro and in vivo, and its expression was increased in more than 50% of the malignant human kidney cancer cases analyzed. Together, our findings define KR-POK as a transcriptional repressor with a pro-oncogenic role that relies upon binding to p53 and inhibition of its transactivation function. PMID- 22253234 TI - The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease. AB - Pompe disease is a lysosomal storage disorder caused by deficiency in the enzyme acid alpha-glucosidase (GAA). Pompe disease is characterized by the accumulation of glycogen, predominantly in muscle tissue, leading to progressive muscle weakness, loss of motor, respiratory, and, in the infantile-onset form, cardiac function. Disease progression is highly variable depending on phenotype, but premature death due to respiratory complications occurs in most patients. Beginning in 2006, approved alglucosidase alfa enzyme replacement therapies [recombinant human (rh) GAA] have been available to treat Pompe patients. Treatment of classic infantile-onset patients, who manifest the severest form of the disease, with alglucosidase alfa (Myozyme(r)) has led to extended survival and an evolving understanding of the pathophysiology and course of the disease. Moreover, such treatment has brought to light the role of the immune response in abrogating the efficacy of rhGAA in classic infantile-onset patients with severe genetic mutations. Thus, optimization of treatment for such patients includes development and utilization of strategies to prevent or eliminate immune responses, including modulating the immune system (prophylactic and therapeutic immune tolerance induction regimens) and engineering the enzyme to be less immunogenic and more effective. Future research is also critical for evaluating and mitigating novel disease-associated pathologies uncovered by prolonged survival of infantile-onset patients including development of novel therapeutics, and for protein design strategies to increase delivery of enzyme replacement therapy to critical target tissues. Such efforts would be greatly bolstered by further development of predictive animal models and biomarkers to facilitate clinical trials and patient management. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. PMID- 22253233 TI - Combat experiences, pre-deployment training, and outcome of exposure therapy for post-traumatic stress disorder in Operation Enduring Freedom/Operation Iraqi Freedom veterans. AB - The association between exposure to multiple potentially traumatic events (PTEs) and subsequent increased risk of post-traumatic stress disorder (PTSD) is well established. However, less is known about the relation between exposure to numerous PTEs, as is typical with military service, and treatment outcome. Furthermore, there has been little research examining military specific protective factors, such as pre-deployment preparedness, on PTSD treatment response. The current study investigated combat exposure and potential moderators of treatment outcome for exposure therapy in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with PTSD. One hundred and eleven OEF/OIF veterans diagnosed with PTSD participated in 8 weeks of exposure therapy. Results indicated that increased combat exposure was associated with a reduced rate of change in PTSD symptoms but not depression symptoms. These findings were consistent across two measures of combat exposure. There was preliminary support for the moderating effect of pre-deployment preparedness on the association between combat exposure and treatment response. Together, these findings suggest that increased combat exposure is associated with poor treatment response in veterans with PTSD; however, this can be reduced by elevated pre-deployment preparedness. PMID- 22253236 TI - Physics at the high-energy frontier: the Large Hadron Collider project. PMID- 22253235 TI - What rhinologists and allergists should know about the medico-legal implications of corticosteroid use: a review of the literature. AB - BACKGROUND: Corticosteroids are a mainstay of treatment in the management of sinonasal inflammatory disease. Despite their common use, many practitioners are not well versed in their potential complications or the medico-legal ramifications of their use. The objectives of this review were to outline the existing data of the medico-legal implications of oral steroids. METHODS: An OVID database search of the terms "corticosteroids OR adrenal cortex hormones" AND "medico-legal OR malpractice OR jurisprudence OR expert testimony OR informed consent" was performed. This search was then narrowed to English language articles and the titles and abstracts were searched for relevance. RESULTS: The OVID search identified 178 articles. This search was then narrowed, resulting in 9 articles that were relevant and included in the current review. Five articles involved database reviews of litigation associated with medications. Steroids were found to be a common medication associated with litigation and the cost of the litigation involving steroid use can be very high. Common themes associated with the litigation include poor communication and lack of informed consent regarding steroid use. Several additional articles addressed single cases and many addressed lawsuit prevention. CONCLUSION: Lawsuits associated with steroids are disproportionately costly and most of the allegations stem from a lack of informed consent over the use of steroids. Open dialogue with patients is the key to informed consent. Ideally, clinicians should discuss the rationale for steroid use, and the risks, expected benefits, and alternatives of the steroid therapy. Document this discussion and consider providing educational material for the patient to read and review. PMID- 22253237 TI - The Standard Model. AB - The Standard Model is the theory used to describe the interactions between fundamental particles and fundamental forces. It is remarkably successful at predicting the outcome of particle physics experiments. However, the theory has not yet been completely verified. In particular, one of the most vital constituents, the Higgs boson, has not yet been observed. This paper describes the Standard Model, the experimental tests of the theory that have led to its acceptance and its shortcomings. PMID- 22253238 TI - Outstanding questions: physics beyond the Standard Model. AB - The Standard Model of particle physics agrees very well with experiment, but many important questions remain unanswered, among them are the following. What is the origin of particle masses and are they due to a Higgs boson? How does one understand the number of species of matter particles and how do they mix? What is the origin of the difference between matter and antimatter, and is it related to the origin of the matter in the Universe? What is the nature of the astrophysical dark matter? How does one unify the fundamental interactions? How does one quantize gravity? In this article, I introduce these questions and discuss how they may be addressed by experiments at the Large Hadron Collider, with particular attention to the search for the Higgs boson and supersymmetry. PMID- 22253239 TI - The Large Hadron Collider. AB - The construction of the Large Hadron Collider (LHC) has been a massive endeavour spanning almost 30 years from conception to commissioning. Building the machine with the highest possible energy (7 TeV) in the existing large electron-positron (LEP) collider tunnel of 27 km circumference and with a tunnel diameter of only 3.8 m has required considerable innovation. The first was the development of a two-in-one magnet, where the two rings are integrated into a single magnetic structure. This compact two-in-one structure was essential for the LHC owing to the limited space available in the existing LEP collider tunnel and the cost. The second was a bold move to the use of superfluid helium cooling on a massive scale, which was imposed by the need to achieve a high (8.3 T) magnetic field using an affordable Nb-Ti superconductor. PMID- 22253240 TI - Large Hadron Collider commissioning and first operation. AB - A history of the commissioning and the very successful early operation of the Large Hadron Collider (LHC) is described. The accident that interrupted the first commissioning, its repair and the enhanced protection system put in place are fully described. The LHC beam commissioning and operational performance are reviewed for the period from 2010 to mid-2011. Preliminary plans for operation and future upgrades for the LHC are given for the short and medium term. PMID- 22253241 TI - Physics requirements for the design of the ATLAS and CMS experiments at the Large Hadron Collider. AB - The ATLAS and CMS experiments at the CERN Large Hadron Collider are discovery experiments. Thus, the aim was to make them sensitive to the widest possible range of new physics. New physics is likely to reveal itself in addressing questions such as: how do particles acquire mass; what is the particle responsible for dark matter; what is the path towards unification; do we live in a world with more space-time dimensions than the familiar four? The detection of the Higgs boson, conjectured to give mass to particles, was chosen as a benchmark to test the performance of the proposed experiment designs. Higgs production is one of the most demanding hypothesized processes in terms of required detector resolution and background discrimination. ATLAS and CMS feature full coverage, 4pi-detectors to measure precisely the energies, directions and identity of all the particles produced in proton-proton collisions. Realizing this goal has required the collaborative efforts of enormous teams of people from around the world. PMID- 22253242 TI - Characteristics of the ATLAS and CMS detectors. AB - The goal for the detection of new physics processes in particle collisions at Large Hadron Collider energies, combined with the broad spectrum of possibilities for how the physics might be manifest, leads to detectors of unprecedented scope and size for particle physics experiments at colliders. The resulting two detectors, ATLAS (A Toroidal LHC ApparatuS) and CMS (compact muon spectrometer), must search for the new physics processes within very complex events arising from the very high-energy collisions. The two experiments share many basic design features-in particular, the need for very selective triggering to weed out the bulk of the uninteresting events; the order in which detector types are arrayed in order to provide maximum information about each event; and the very large angular coverage required to constrain the energy carried by any non-interacting particles. However, within these basic constraints, the detectors are quite different given the different emphases placed on issues such as resolution and background rejection. Both common features and the distinct differences will be presented. PMID- 22253243 TI - Flavour physics and the Large Hadron Collider beauty experiment. AB - An exciting new era in flavour physics has just begun with the start of the Large Hadron Collider (LHC). The LHCb (where b stands for beauty) experiment, designed specifically to search for new phenomena in quantum loop processes and to provide a deeper understanding of matter-antimatter asymmetries at the most fundamental level, is producing many new and exciting results. It gives me great pleasure to describe a selected few of the results here-in particular, the search for rare B(0)(s)-->MU+ MU- decays and the measurement of the B(0)(s) charge-conjugation parity-violating phase, both of which offer high potential for the discovery of new physics at and beyond the LHC energy frontier in the very near future. PMID- 22253244 TI - Heavy-ion physics with the ALICE experiment at the CERN Large Hadron Collider. AB - After close to 20 years of preparation, the dedicated heavy-ion experiment A Large Ion Collider Experiment (ALICE) took first data at the CERN Large Hadron Collider (LHC) accelerator with proton collisions at the end of 2009 and with lead nuclei at the end of 2010. After a short introduction into the physics of ultra-relativistic heavy-ion collisions, this article recalls the main design choices made for the detector and summarizes the initial operation and performance of ALICE. Physics results from this first year of operation concentrate on characterizing the global properties of typical, average collisions, both in proton-proton (pp) and nucleus-nucleus reactions, in the new energy regime of the LHC. The pp results differ, to a varying degree, from most quantum chromodynamics-inspired phenomenological models and provide the input needed to fine tune their parameters. First results from Pb-Pb are broadly consistent with expectations based on lower energy data, indicating that high density matter created at the LHC, while much hotter and larger, still behaves like a very strongly interacting, almost perfect liquid. PMID- 22253245 TI - Early physics results. AB - For the past year, experiments at the Large Hadron Collider (LHC) have started exploring physics at the high-energy frontier. Thanks to the superb turn-on of the LHC, a rich harvest of initial physics results have already been obtained by the two general-purpose experiments A Toroidal LHC Apparatus (ATLAS) and the Compact Muon Solenoid (CMS), which are the subject of this report. The initial data have allowed a test, at the highest collision energies ever reached in a laboratory, of the Standard Model (SM) of elementary particles, and to make early searches Beyond the Standard Model (BSM). Significant results have already been obtained in the search for the Higgs boson, which would establish the postulated electro-weak symmetry breaking mechanism in the SM, as well as for BSM physics such as Supersymmetry (SUSY), heavy new particles, quark compositeness and others. The important, and successful, SM physics measurements are giving confidence that the experiments are in good shape for their journey into the uncharted territory of new physics anticipated at the LHC. PMID- 22253246 TI - The data acquisition and reduction challenge at the Large Hadron Collider. AB - The Large Hadron Collider detectors are technological marvels-which resemble, in functionality, three-dimensional digital cameras with 100 Mpixels-capable of observing proton-proton (pp) collisions at the crossing rate of 40 MHz. Data handling limitations at the recording end imply the selection of only one pp event out of each 10(5). The readout and processing of this huge amount of information, along with the selection of the best approximately 200 events every second, is carried out by a trigger and data acquisition system, supplemented by a sophisticated control and monitor system. This paper presents an overview of the challenges that the development of these systems has presented over the past 15 years. It concludes with a short historical perspective, some lessons learnt and a few thoughts on the future. PMID- 22253247 TI - The Large Hadron Collider and Grid computing. AB - We present a brief history of the beginnings, development and achievements of the worldwide Large Hadron Collider Computing Grid (wLCG). The wLCG is a huge international endeavour, which is itself embedded within, and directly influences, a much broader computing and information technology landscape. It is often impossible to identify true cause and effect, and they may appear very different from the different perspectives (e.g. information technology industry or academic researcher). This account is no different. It represents a personal view of the developments over the last two decades and is therefore inevitably biased towards those things in which the author has been personally involved. PMID- 22253248 TI - The Large Hadron Collider project: organizational and financial matters (of physics at the terascale). AB - In this paper, I present a view of organizational and financial matters relevant for the successful construction and operation of the experimental set-ups at the Large Hadron Collider of CERN, the European Laboratory for Particle Physics in Geneva. Construction of these experiments was particularly challenging: new detector technologies had to be developed; experimental set-ups that are larger and more complex than ever before had to be constructed; and larger collaborations than ever before had to be organized. Fundamental to the success were: the 'reference' provided by CERN, peer review, signed memoranda of understanding, well-organized resources review boards as an interface to the national funding agencies and collegial, but solidly organized, experimental collaborations. PMID- 22253249 TI - The future of the Large Hadron Collider and CERN. AB - This paper presents the Large Hadron Collider (LHC) and its current scientific programme and outlines options for high-energy colliders at the energy frontier for the years to come. The immediate plans include the exploitation of the LHC at its design luminosity and energy, as well as upgrades to the LHC and its injectors. This may be followed by a linear electron-positron collider, based on the technology being developed by the Compact Linear Collider and the International Linear Collider collaborations, or by a high-energy electron-proton machine. This contribution describes the past, present and future directions, all of which have a unique value to add to experimental particle physics, and concludes by outlining key messages for the way forward. PMID- 22253250 TI - The Large Hadron Collider: lessons learned and summary. AB - The Large Hadron Collider (LHC) machine and detectors are now working superbly. There are good reasons to hope and expect that the new domain that the LHC is already exploring, operating at 7 TeV with a luminosity of 10(33) cm(-2) s(-1), or the much bigger domain that will be opened up as the luminosity increases to over 10(34) and the energy to 14 TeV, will provide clues that will usher in a new era in particle physics. The arguments that new phenomena will be found in the energy range that will be explored by the LHC have become stronger since they were first seriously analysed in 1984, although their essence has changed little. I will review the evolution of these arguments in a historical context, the development of the LHC project since 1984, and the outlook in the light of reports on the performance of the machine and detectors presented at this meeting. PMID- 22253251 TI - Reaction dynamics: rules change with molecular size. PMID- 22253252 TI - Platelet-rich plasma or hyaluronate in the management of osteochondral lesions of the talus. AB - BACKGROUND: Nonoperative options for osteochondral lesions (OCLs) of the talar dome are limited, and currently, there is a lack of scientific evidence to guide management. PURPOSE: To evaluate the short-term efficacy and safety of platelet rich plasma (PRP) compared with hyaluronic acid (HA) in reducing pain and disability caused by OCLs of the ankle. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Thirty-two patients aged 18 to 60 years were allocated to a treatment by intra-articular injections of either HA (group 1) or PRP (plasma rich in growth factors [PRGF] technique, group 2) for OCLs of the talus. Thirty OCLs, 15 per arm, received 3 consecutive intra-articular therapeutic injections and were followed for 28 weeks. The efficacy of the injections in reducing pain and improving function was assessed at each visit using the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale (AHFS); a visual analog scale (VAS) for pain, stiffness, and function; and the subjective global function score. RESULTS: The majority of patients were men (n = 23; 79%). The AHFS score improved from 66 and 68 to 78 and 92 in groups 1 and 2, respectively, from baseline to week 28 (P < .0001), favoring PRP (P < .05). Mean VAS scores (1 = asymptomatic, 10 = severe symptoms) decreased for pain (group 1: 5.6 to 3.1; group 2: 4.1 to 0.9), stiffness (group 1: 5.1 to 2.9; group 2: 5.0 to 0.8), and function (group 1: 5.8 to 3.5; group 2: 4.7 to 0.8) from baseline to week 28 (P < .0001), favoring PRP (P < .05 for stiffness, P < .01 for function, P > .05 for pain). Subjective global function scores, reported on a scale from 0 to 100 (with 100 representing healthy, preinjury function) improved from 56 and 58 at baseline to 73 and 91 by week 28 for groups 1 and 2, respectively (P < .01 in favor of PRP). CONCLUSION: Osteochondral lesions of the ankle treated with intra-articular injections of PRP and HA resulted in a decrease in pain scores and an increase in function for at least 6 months, with minimal adverse events. Platelet-rich plasma treatment led to a significantly better outcome than HA. PMID- 22253253 TI - Plant bioreactors - the taste of sweet success. AB - Thaumatins are intensely sweet proteins (3000 times sweeter than the same weight of sucrose) that are found in the arils of the tropical perennial plant Thaumatococcus daniellii Benth and are produced commercially by aqueous extraction from the fruits. The proteins are widely used as sweeteners and flavor enhancers in the food industry, and the European Food Safety Association (EFSA) has recently confirmed that their use as feed additive (1 to 5 mg/kg complete feed) is safe for all animal species. Given the large market for sweeteners and flavor enhancers, thaumatins could become increasingly important in the food and feed additives sector. In this issue of Biotechnology Journal, a study examines the production of thaumatin in tobacco hairy root cultures. PMID- 22253255 TI - Caesarean section under local anaesthesia: back to basics. AB - Caesarean section under local anaesthesia (CSLA) was performed on a patient with a diagnosis of gravida 2 para 1 living 1, with eight months amenorrhea and uncontrolled, refractory, complicated eclampsia with intrauterine fetal demise and a previous lower segment Caesarean section. As she was at very high risk (ASA Grade III) for main stream anaesthesia, i.e. general/regional, lidocaine (0.5%) was used. CSLA should not be seen as a primitive/retrograde step. Instead, it should be considered to be a life-saving procedure, especially for women in rural India. Anaesthetists are not dispensable but with them on standby one can avoid mainstream anaesthesia complications in high-risk patients. PMID- 22253254 TI - Autophagy and mitochondria in Pompe disease: nothing is so new as what has long been forgotten. AB - Macroautophagy (often referred to as autophagy) is an evolutionarily conserved intracellular system by which macromolecules and organelles are delivered to lysosomes for degradation and recycling. Autophagy is robustly induced in response to starvation in order to generate nutrients and energy through the lysosomal degradation of cytoplasmic components. Constitutive, basal autophagy serves as a quality control mechanism for the elimination of aggregated proteins and worn-out or damaged organelles, such as mitochondria. Research during the last decade has made it clear that malfunctioning or failure of this system is associated with a wide range of human pathologies and age-related diseases. Our recent data provide strong evidence for the role of autophagy in the pathogenesis of Pompe disease, a lysosomal glycogen storage disease caused by deficiency of acid alpha-glucosidase (GAA). Large pools of autophagic debris in skeletal muscle cells can be seen in both our GAA knockout model and patients with Pompe disease. In this review, we will focus on these recent data, and comment on the not so recent observations pointing to the involvement of autophagy in skeletal muscle damage in Pompe disease. PMID- 22253256 TI - The TGB1 movement protein of Potato virus X reorganizes actin and endomembranes into the X-body, a viral replication factory. AB - Potato virus X (PVX) requires three virally encoded proteins, the triple gene block (TGB), for movement between cells. TGB1 is a multifunctional protein that suppresses host gene silencing and moves from cell to cell through plasmodesmata, while TGB2 and TGB3 are membrane-spanning proteins associated with endoplasmic reticulum-derived granular vesicles. Here, we show that TGB1 organizes the PVX "X body," a virally induced inclusion structure, by remodeling host actin and endomembranes (endoplasmic reticulum and Golgi). Within the X-body, TGB1 forms helically arranged aggregates surrounded by a reservoir of the recruited host endomembranes. The TGB2/3 proteins reside in granular vesicles within this reservoir, in the same region as nonencapsidated viral RNA, while encapsidated virions accumulate at the outer (cytoplasmic) face of the X-body, which comprises a highly organized virus "factory." TGB1 is both necessary and sufficient to remodel host actin and endomembranes and to recruit TGB2/3 to the X-body, thus emerging as the central orchestrator of the X-body. Our results indicate that the actin/endomembrane-reorganizing properties of TGB1 function to compartmentalize the viral gene products of PVX infection. PMID- 22253257 TI - On the discordance of metabolomics with proteomics and transcriptomics: coping with increasing complexity in logic, chemistry, and network interactions scientific correspondence. PMID- 22253258 TI - The genotype-phenotype correlation in Pompe disease. AB - Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that is caused by acid alpha-glucosidase (GAA) deficiency and is due to pathogenic sequence variations in the corresponding GAA gene. The correlation between genotypes and phenotypes is strict, in that patients with the most severe phenotype, classic infantile Pompe disease, have two pathogenic mutations, one in each GAA allele, that prevent the formation of GAA or totally obliterates its function. All patients with less progressive phenotypes have at least one sequence variation that allows normal or low level synthesis of GAA leading to the formation of analytically measurable, low level GAA activity in most cases. There is an overall trend of finding higher GAA enzyme levels in patients with onset of symptoms in adulthood when compared to patients who show clinical manifestations in early childhood, aged 0-5 years, with a rapidly progressive course, but who lack the severe characteristics of classic infantile Pompe disease. However, several cases have been reported of adult-onset disease with very low GAA activity, which in all those cases corresponds with the GAA genotype. The clinical diversity observed within a large group of patients with functionally the same GAA genotype and the same c.-32-13C > T haplotype demonstrates that modifying factors can have a substantial effect on the clinical course of Pompe disease, disturbing the GAA genotype-phenotype correlation. The present day challenge is to identify these factors and explore them as therapeutic targets. PMID- 22253259 TI - Dispositional mindfulness and the attenuation of neural responses to emotional stimuli. AB - Considerable research has disclosed how cognitive reappraisals and the modulation of emotional responses promote successful emotion regulation. Less research has examined how the early processing of emotion-relevant stimuli may create divergent emotional response consequences. Mindfulness--a receptive, non evaluative form of attention--is theorized to foster emotion regulation, and the present study examined whether individual differences in mindfulness would modulate neural responses associated with the early processing of affective stimuli. Focus was on the late positive potential (LPP) of the event-related brain potential to visual stimuli varying in emotional valence and arousal. This study first found, replicating past research, that high arousal images, particularly of an unpleasant type, elicited larger LPP responses. Second, the study found that more mindful individuals showed lower LPP responses to high arousal unpleasant images, even after controlling for trait attentional control. Conversely, two traits contrasting with mindfulness--neuroticism and negative affectivity--were associated with higher LPP responses to high arousal unpleasant images. Finally, mindfulness was also associated with lower LPP responses to motivationally salient pleasant images (erotica). These findings suggest that mindfulness modulates neural responses in an early phase of affective processing, and contribute to understanding how this quality of attention may promote healthy emotional functioning. PMID- 22253260 TI - A sweet spot in the FGFR signal transduction pathway. AB - The hexosamine biosynthetic pathway, whose end product is UDP-N acetylglucosamine (UDP-GlcNAc), lies at the base of cellular glycosylation pathways, including glycosylation of lipids, formation of heparin sulfated proteoglycans, and N- and O-linked glycosylation of proteins. Forward genetic studies in Drosophila have revealed that mutations in genes encoding different enzymes of the hexosamine biosynthetic pathway result in reduction of UDP-GlcNAc to different extents, with a consequent disruption of distinct glycosylation pathways and developmental processes. A maternal and zygotic loss-of-function screen has identified mutations in nesthocker (nst), which encodes an enzyme in the hexosamine biosynthetic pathway. Embryos lacking maternal and zygotic nst gene products show defective O-GlcNAcylation of a fibroblast growth factor receptor (FGFR)-specific adaptor protein, which impairs FGFR-dependent migration of mesodermal and tracheal cells. PMID- 22253261 TI - LRRK2 and human disease: a complicated question or a question of complexes? AB - Leucine-rich repeat kinase 2 (LRRK2) is linked to various diseases, including Parkinson's disease, cancer, and leprosy. Data from LRRK2 knockout mice has highlighted a possible role for LRRK2 in regulating signaling pathways that are linked to the pathogenesis of Crohn's disease. Here, we examine how LRRK2's role as a signaling hub in the cell could lead to diverse pathologies. PMID- 22253262 TI - Interleukin-11 links oxidative stress and compensatory proliferation. AB - Apoptotic cells can stimulate the compensatory proliferation of surrounding cells to maintain tissue homeostasis. Although oxidative stress is associated with apoptosis and necrosis, whether it contributes to compensatory proliferation is unknown. Here, we showed that interleukin-11 (IL-11), a member of the IL-6 family of proinflammatory cytokines, was produced by cells in an oxidative stress dependent manner. IL-11 production depended on the activation in dying cells of extracellular signal-regulated kinase 2, which in turn caused the phosphorylation and accumulation of the transcription factor Fra-1 by preventing its proteasome dependent degradation. Fra-1 was subsequently recruited to the Il11 promoter and activated gene transcription. Upon acute liver injury in mice, IL-11 was mainly produced by hepatocytes in response to reactive oxygen species that were presumably released from dying hepatocytes. IL-11 that was secreted by the dying cells then induced the phosphorylation of the transcription factor STAT3 in adjacent healthy hepatocytes, which resulted in their compensatory proliferation. Furthermore, an IL-11 receptor (IL-11R) agonist enhanced the proliferation of hepatocytes and ameliorated oxidative stress upon acetaminophen-induced liver injury. Conversely, the effects of acetaminophen were exacerbated in mice deficient in the IL-11R alpha subunit. Together, these results suggest that IL-11 provides a functional link between oxidative stress and compensatory proliferation. PMID- 22253264 TI - Systemic lidocaine does not attenuate hepatic dysfunction after liver surgery in rats. AB - BACKGROUND: Lidocaine has been shown to attenuate ischemia-reperfusion (I/R) injury in the heart, lung, and brain, potentially due to modulation of inflammatory responses and apoptotic signaling pathways. Because hepatic I/R injury after liver surgery still poses a significant risk for postoperative liver dysfunction or even failure, we investigated whether systemic lidocaine would also positively affect hepatocellular damage and overall liver function after hepatic I/R injury. In addition the potential underlying mechanisms of action were studied. METHODS: A standardized rat model of 70% I/R injury was used to assess the effects of systemic lidocaine on hepatocellular damage after 60 minutes of ischemia and subsequent reperfusion. To better mimic the clinical situation, we combined 45 minutes of ischemia with partial hepatectomy in a second model. Systemic lidocaine was administered continuously, starting 30 minutes before the ischemic insult until 20 minutes of reperfusion. Hepatocellular function was assessed using different variables of liver synthesis, cellular integrity, and metabolism. Inflammation was evaluated by measuring leukocyte influx and apoptosis detected using TUNEL staining and a caspase-3 assay. RESULTS: In both models, I/R injury resulted in a significant increase in biochemical and histological hepatocellular damage with comparable values in control and lidocaine-treated animals. Postoperative liver function was significantly impaired secondary to ischemia, yet no significant differences between control and lidocaine groups could be observed. Likewise, there was no significant difference between control and lidocaine-treated animals with respect to I/R injury-induced leukocyte influx, as a marker for inflammatory response. CONCLUSION: Systemic lidocaine in therapeutic concentrations neither attenuated hepatocellular damage nor improved postoperative liver function after hepatic I/R injury. PMID- 22253265 TI - The analgesic activity of intrathecal tianeptine, an atypical antidepressant, in a rat model of inflammatory pain. AB - BACKGROUND: Tianeptine is an atypical antidepressant that exhibits structural similarities to the tricyclic antidepressants but has distinct neurochemical properties. We evaluated the antinociceptive activity of tianeptine and its mechanism of action regarding serotonergic and adrenergic transmission at the spinal level. METHODS: The effects of intrathecally administered tianeptine and DUP-697 (a cyclooxygenase-2 inhibitor) were examined on flinching behavior evoked by intraplantar formalin injection, and their interaction was characterized using isobolographic analysis. Dihydroergocristine, prazosin, or yohimbine-which are serotonergic, alpha-1, and alpha-2 adrenergic receptor antagonists, respectively were intrathecally administered 10 minutes before tianeptine to investigate its mechanism of action. RESULTS: Intrathecally administered tianeptine and DUP-697 reduced the flinching response evoked by formalin injection during phases 1 and 2 in an additive fashion. Prazosin and yohimbine attenuated the antinociceptive effect of intrathecal tianeptine during both phases of the formalin test. Dihydroergocristine reversed the antinociception of tianeptine during phase 2, but not during phase 1. CONCLUSIONS: Intrathecally administered tianeptine effectively relieved inflammatory pain in rats. The serotonergic system is related to the activity of tianeptine for facilitated pain at the spinal level. Adrenergic transmission is also involved in tianeptine-induced analgesia for both facilitated and acute pain. The combination of tianeptine and cyclooxygenase-2 inhibitor may provide additional benefits for the management of inflammatory pain. PMID- 22253263 TI - Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. AB - Plexins are cell surface receptors that bind to semaphorins and transduce signals that regulate neuronal development, immune responses, and other processes. Signaling through plexins has been proposed to rely on specific guanosine triphosphatase (GTPase)-activating protein (GAP) activity for R-Ras and M-Ras. Activation of this GAP activity of plexins appears to require simultaneous binding of semaphorin to the plexin extracellular domain and of the Rho GTPases Rac1 or Rnd1 to the cytoplasmic region. However, GAP activity of plexins has eluded detection in several recent studies. We show that the purified cytoplasmic region of plexin uses a noncanonical catalytic mechanism to act as a GAP for Rap, but not for R-Ras or M-Ras. The RapGAP activity of plexins was autoinhibited and was activated by induced dimerization. Biochemical and crystallographic analyses demonstrated that binding of Rho GTPases did not directly contribute to activation of plexin RapGAP activity. Semaphorin stimulated the RapGAP activity of full-length plexin in cells, which was required for plexin-mediated neuronal growth cone collapse. Together, these findings define a pathway for plexin signaling and provide insights into the mechanism for semaphorin-induced activation of plexins. PMID- 22253266 TI - Angiotensin converting enzyme inhibitors are not associated with respiratory complications or mortality after noncardiac surgery. AB - BACKGROUND: General use of angiotensin-converting enzyme inhibitors (ACEIs) is associated with upper-airway complications such as cough, angioedema, and bronchospasm; furthermore, preoperative use is associated with increased morbidity or mortality. Our primary goal in this study was thus to evaluate the association of ACEI therapy with perioperative respiratory morbidity in adult noncardiac surgical patients. Our secondary goals were to evaluate the association between preoperative use of ACEI and 30-day mortality, as well as to a composite outcome of in-hospital morbidity and mortality in adult noncardiac surgical patients having general anesthesia. METHODS: We evaluated 79,228 patients (9905 ACEI users [13] and 66,620 [87%] non-ACEI users) who had noncardiac surgery at the Cleveland Clinic between 2005 and 2009. Propensity matching successfully paired 9028 ACEI users (91% of 9905 patients) with 9028 controls. Matched intraoperative ACEI users and non-ACEI users were compared on intraoperative and postoperative respiratory morbidity composites as well as individual complications, 30-day mortality, and a composite of in-hospital morbidity and mortality. RESULTS: The association between ACEI use and respiratory morbidity composites was not statistically significant intraoperatively (OR: 1.09 [97.5% CI: 0.91, 1.31], ACEI versus non-ACEI; P = 0.28) or postoperatively (OR: 0.97 [97.5% CI: 0.81, 1.16], ACEI versus non-ACEI; P = 0.69). Within the propensity-matched subset, ACEI usage was not associated with either 30-day mortality (OR: 0.93 [95% CI: 0.73, 1.19], ACEI versus non ACEI; P = 0.56) or the composite of in-hospital morbidity and mortality (OR: 1.06 [95% CI: 0.97, 1.15], ACEI versus non-ACEI; P = 0.22). We also observed that the ACEI and the non-ACEI groups were descriptively similar (standardized differences <0.03) on multiple time periods of intraoperative hemodynamic characteristics, vasopressor use, and colloid and crystalloid infusions. CONCLUSIONS: We did not find any association between use of ACEIs and intraoperative or postoperative upper-airway complications. Furthermore, ACEI use was not associated with in hospital complications or increased 30-day mortality. PMID- 22253268 TI - Intravenous dextrose administration reduces postoperative antiemetic rescue treatment requirements and postanesthesia care unit length of stay. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) remains the most common postoperative complication, and causes decreased patient satisfaction, prolonged postoperative hospital stays, and unanticipated admission. There are limited data that indicate that dextrose may reduce nausea and vomiting. In this trial, we attempted to determine whether the rate of PONV can be decreased by postoperative administration of IV dextrose bolus. METHODS: To test the effect of postoperative dextrose administration on PONV rates, we conducted a double-blind, randomized, placebo-controlled trial. We enrolled 62 nondiabetic, ASA class I or II nonsmoking outpatients scheduled for gynecologic laparoscopic and hysteroscopic procedures. Patients were randomized into 2 groups: the treatment group received dextrose 5% in Ringer lactate solution, and the control (placebo) group received Ringer lactate solution given immediately after surgery. All patients underwent a standardized general anesthesia and received 1 dose of antiemetic a half hour before emergence from anesthesia. PONV scores, antiemetic rescue medications, narcotic consumption, and discharge time were recorded in the postanesthesia care unit (PACU) in half-hour intervals. RESULTS: The 2 groups were similar with regard to age, weight, anxiety scores, prior PONV, non per os status, presurgical glucose, anesthetic duration, intraoperative narcotic use, and total weight-based fluid volume received. Postoperative nausea scores were not significantly different in the dextrose group compared with the control group (P > 0.05) after Bonferroni correction for repeated measurements over time. However, patients who received dextrose 5% in Ringer lactate solution consumed less rescue antiemetic medications (ratio mean difference, 0.56; 95% confidence interval, 0.39-0.82; P = 0.02), and had a shorter length of stay in the PACU (ratio mean difference, 0.80; 95% confidence interval, 0.66-0.97; P = 0.03) compared with patients in the control group. CONCLUSION: In this trial, postanesthesia IV dextrose administration resulted in improved PONV management as defined by reductions in antiemetic rescue medication requirements and PACU length of stay that are worthy of further study. In light of its ease, low risk, and benefit to patient care and satisfaction, this therapeutic modality could be considered. PMID- 22253267 TI - Brain monitoring with electroencephalography and the electroencephalogram-derived bispectral index during cardiac surgery. AB - Cardiac surgery presents particular challenges for the anesthesiologist. In addition to standard and advanced monitors typically used during cardiac surgery, anesthesiologists may consider monitoring the brain with raw or processed electroencephalography (EEG). There is strong evidence that a protocol incorporating the processed EEG bispectral index (BIS) decreases the incidence intraoperative awareness in comparison with standard practice. However, there is conflicting evidence that incorporating the BIS into cardiac anesthesia practice improves "fast-tracking," decreases anesthetic drug use, or detects cerebral ischemia. Recent research, including many cardiac surgical patients, shows that a protocol based on BIS monitoring is not superior to a protocol based on end-tidal anesthetic concentration monitoring in preventing awareness. There has been a resurgence of interest in the anesthesia literature in limited montage EEG monitoring, including nonproprietary processed indices. This has been accompanied by research showing that with structured training, anesthesiologists can glean useful information from the raw EEG trace. In this review, we discuss both the hypothesized benefits and limitations of BIS and frontal channel EEG monitoring in the cardiac surgical population. PMID- 22253269 TI - Is a neutral head position safer than 45-degree neck rotation during ultrasound guided internal jugular vein cannulation? Results of a randomized controlled clinical trial. AB - BACKGROUND: The optimal degree of neck rotation during internal jugular vein (IJV) cannulation remains undetermined because previous studies suggested using sonography, but without puncturing the vein. We assessed whether a neutral position (NP) of the head (0 degrees) during ultrasound-guided cannulation of the IJV was safer than rotating the neck to 45 degrees head turned. The effect of these 2 positions during ultrasound-guided cannulation on major complications was the primary outcome. Overall complications, venous access time, and perception of difficulty during the procedure were also evaluated. METHODS: A prospective, randomized, controlled, nonblinded study was conducted in a tertiary neurosurgical hospital. Patients undergoing major elective neurosurgical procedures requiring a central venous line were randomly allocated to 2 groups; ultrasound-guided cannulation of the IJV was then performed using an out-of-plane orientation. RESULTS: One thousand four hundred twenty-four patients were evaluated, but 92 were excluded; 670 were allocated to the head turned group and 662 to the NP group. Cannulation was 100% successful. Demographic data were similar in the 2 groups except for IJV positions. There were only 10 major complications: 6 in the 0-degree NP group and 4 in the 45-degree head turned group. The frequency of these complications was not different between the 2 groups. The overall complication rate was 13%, and was higher in women, in patients with ASA physical status >=II, and in patients with a smaller diameter vein, or when the vein was located deeper and lateral or in the anterolateral position. An increased venous access time was associated with an increased rate of overall complications. The perception of difficulty performing the procedure with the head placed in the 2 positions was not statistically different in either group. CONCLUSION: A head NP was as safe as a 45-degree neck rotation during ultrasound-guided IJV cannulation with regard to both major and minor complications, and venous access time was similar. Ultrasound guidance helps determine optimal head rotation for IJV cannulation. PMID- 22253270 TI - A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. AB - BACKGROUND: A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. METHODS: A phase I, single-center, double-blind, placebo and active controlled, randomized, single dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. RESULTS: A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 MUg/mL; gamma: 1.6, 8.6; k(e0): 0.14, 0.053 min(-1); I(MAX): 39, 19, and MOAA/S IC(50): 0.4, 0.08 MUg/mL; gamma: 1.4, 3.4; k(e0): 0.25, 0.050 min(-1) for remimazolam and midazolam, respectively. Simulations to obtain >70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%-74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at >2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%-91%) of the treated population after this loading/maintenance dose regimen. CONCLUSIONS: Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65-90 kg). PMID- 22253271 TI - Partner's presence during initiation of epidural labor analgesia does not decrease maternal stress: a prospective randomized controlled trial. AB - BACKGROUND: Epidural analgesia reduces pain and anxiety during childbirth. In this randomized controlled trial, we sought to determine whether partner presence during the initiation of epidural analgesia reduces stress of both the mother and her partner and their perception of maternal pain. METHODS: Healthy, nulliparous women who were accompanied by their partners and requested neuraxial analgesia were enrolled into the study. The study took place in the Labor and Delivery Unit of a large tertiary hospital in Israel. Upon request for epidural analgesia, both partners were assessed for baseline anxiety (numerical rating scale, 0 to 10), systolic blood pressure, heart rate, estimated contraction pain of parturient (verbal rating scale for pain, 0 to 10), and salivary amylase. After measurements, couples were randomized into 1 of 2 groups: "partner in" and "partner out." Immediately after epidural catheter insertion, anxiety, arterial blood pressure, heart rate, and salivary amylase were measured again in both partners. Both partners were asked to complete the State Anxiety Inventory questionnaire measuring current anxiety. The parturient was asked to rate the pain of epidural catheter insertion. The primary outcome measurement was parturient and partner anxiety as assessed by the numerical rating scale. RESULTS: Eighty-four couples were randomized (partner in 41, partner out 42, protocol violation 1). At baseline there was no difference in self-reported anxiety of parturients between the partner-in and partner-out groups (median interquartile range 7.5 [6.0 to 9.0] versus 7.0 [3.5 to 8.5]; P = 0.26, difference in medians = -1.0; 95% confidence interval [CI] of difference -2.0 to 1.0). After epidural catheter insertion, parturients in the partner-in group had a higher level of anxiety than those in the partner-out group (8.0 [7.0 to 10.0] versus 7.0 [5.0 to 9.0]; P = 0.03, difference in medians -1.0; 95% CI of difference -2.0 to 0.0). Pain scores during epidural catheter placement were higher in partner-in than in partner-out groups (7.0 [4.0 to 8.0] versus 4.0 [3.0 to 6.0]; P = 0.004, difference in medians = -2.0; 95% CI of difference -3.0 to 1.0). CONCLUSION: Partner presence during epidural catheter insertion for labor analgesia did not decrease anxiety levels. To the contrary, anxiety and pain of epidural catheter placement were greater if the partner remained in the room. PMID- 22253272 TI - The effects of electroacupuncture at the ST36 (Zusanli) acupoint on cancer pain and transient receptor potential vanilloid subfamily 1 expression in Walker 256 tumor-bearing rats. AB - BACKGROUND: Several studies have addressed the expression of transient receptor potential vanilloid subfamily 1(TRPV1) playing an important role in the generation of cancer pain. Electroacupuncture (EA) is an effective method of acupuncture shown to attenuate different kinds of pain such as inflammatory, neuropathic, and cancer. In this study, we investigated the effect of EA on cancer pain caused by intraplantar injection of Walker 256 carcinoma cells and cancer-driven TRPV1 expression in the dorsal root ganglions (DRGs). METHODS: Rats were randomly divided into 4 groups: the nontumor cell inoculation group (normal control, n = 8); Walker 256 carcinoma cell inoculation group (tumor control, n = 8); sham point electrical stimulation treatment with Walker 256 carcinoma cell inoculation group (SES, n = 8); EA treatment with Walker 256 carcinoma cell inoculation group (EA, n = 8). The time courses of thermal, mechanical sensitivity, and spontaneous nocifensive behavior were determined. In addition, TRPV1 expression in DRGs was observed by quantitative real-time polymerase chain reaction and Western blotting. RESULTS: Injection of cancer cells decreased the paw withdrawal threshold, increased spontaneous nocifensive behavior, and induced significant thermal hyperalgesia that was attenuated by EA at the ST36 acupoint (2 Hz, 0.3 ms, <=1 mA). TRPV1 mRNA and protein in DRGs were upregulated in the cancer pain model, and EA at ST36 acupoint counteracted the cancer-driven upregulation of TRPV1 expression in the corresponding DRGs. CONCLUSIONS: EA at ST36 could attenuate cancer-induced pain, at least in part, through suppressing TRPV1 mRNA and protein upregulation in the DRGs. PMID- 22253273 TI - The Friday of rage of the Egyptian revolution: a unique role for anesthesiologists. PMID- 22253274 TI - Perioperative fluid management strategies in major surgery: a stratified meta analysis. AB - BACKGROUND: Both "liberal" and "goal-directed" (GD) therapy use a large amount of perioperative fluid, but they appear to have very different effects on perioperative outcomes. We sought to determine whether one fluid management strategy was superior to the others. METHODS: We selected randomized controlled trials (RCTs) on the use of GD or restrictive versus liberal fluid therapy (LVR) in major adult surgery from MEDLINE, EMBASE, PubMed (1951 to April 2011), and Cochrane controlled trials register without language restrictions. Indirect comparison between the GD and LVR strata was performed. RESULTS: A total of 3861 patients from 23 GD RCTs (median sample size = 90, interquartile range [IQR] 57 to 109) and 1160 patients from 12 LVR RCTs (median sample size = 80, IQR36 to 151) were considered. Both liberal and GD therapy used more fluid compared to their respective comparative arm, but their effects on outcomes were very different. Patients in the liberal group of the LVR stratum had a higher risk of pneumonia (risk ratio [RR] 2.2, 95% confidence interval [CI] 1.0 to 4.5), pulmonary edema (RR 3.8, 95% CI 1.1 to 13), and a longer hospital stay than those in the restrictive group (mean difference [MD] 2 days, 95% CI 0.5 to 3.4). Using GD therapy also resulted in a lower risk of pneumonia (RR 0.7, 95% CI 0.6 to 0.9) and renal complications (0.7, 95% CI 0.5 to 0.9), and a shorter length of hospital stay (MD 2 days, 95% CI 1 to 3) compared to not using GD therapy. Liberal fluid therapy was associated with an increased length of hospital stay (4 days, 95% CI 3.4 to 4.4), time to first bowel movement (2 days, 95% CI 1.3 to 2.3), and risk of pneumonia (RR ratio 3, 95% CI 1.8 to 4.8) compared to GD therapy. CONCLUSION: Perioperative outcomes favored a GD therapy rather than liberal fluid therapy without hemodynamic goals. Whether GD therapy is superior to a restrictive fluid strategy remains uncertain. PMID- 22253276 TI - Two-dimensional transesophageal echocardiographic imaging of the tricuspid valve. PMID- 22253275 TI - Delayed treatment with lidocaine reduces mouse microglial cell injury and cytokine production after stimulation with lipopolysaccharide and interferon gamma. AB - BACKGROUND: Neuroinflammation is an important pathological process for almost all acquired neurological diseases. Microglial cells play a critical role in neuroinflammation. We determined whether lidocaine, a local anesthetic with anti inflammatory property, protected microglial cells and attenuated cytokine production from activated microglial cells. METHODS: Mouse microglial cultures were incubated with or without 1 MUg/mL lipopolysaccharide and 10 U/mL interferon gamma (IFNgamma) for 24 hours in the presence or absence of lidocaine for 1 hour started at 2, 3, or 4 hours after the onset of lipopolysaccharide and IFNgamma stimulation. Lactate dehydrogenase release and cytokine production were determined after the cells were stimulated by lipopolysaccharide and IFNgamma for 24 hours. RESULTS: Lidocaine dose-dependently reduced lipopolysaccharide and IFNgamma-induced microglial cell injury as measured by lactate dehydrogenase release. This effect was apparent with lidocaine at 2 MUg/mL (30.3% +/- 5.8% and 23.1% +/- 9.7%, respectively, for stimulation alone and the stimulation in the presence of lidocaine, n = 18, P = 0.025). Lidocaine applied at 2, 3, or 4 hours after the onset of lipopolysaccharide and IFNgamma stimulation reduced the cell injury. This lidocaine effect was not affected by the mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate. Similar to lidocaine, QX314, a permanently charged lidocaine analog that usually does not permeate through the plasma membrane, reduced lipopolysaccharide and IFNgamma-induced microglial cell injury. QX314 also attenuated the stimulation-induced interleukin-1beta production. CONCLUSIONS: Delayed treatment with lidocaine protects microglial cells and reduces cytokine production from these cells. These effects may involve action site(s) on the cell surface. PMID- 22253277 TI - The Anesthesia Patient Safety Foundation at 25: a pioneering success in safety, 25th anniversary provokes reflection, anticipation. AB - The Anesthesia Patient Safety Foundation (APSF) was created in 1985. Its founders coined the term "patient safety" in its modern public usage and created the very first patient safety organization, igniting a movement that is now universal in all of health care. Driven by the vision "that no patient shall be harmed by anesthesia," the APSF has worked tirelessly for more than a quarter century to promote safety education and communication through its widely read Newsletter, its programs, and its presentations. The APSF's extensive research grant program has supported a great many projects leading to key safety improvements and, in particular, was central in the development of high-fidelity mannequin simulation as a research and teaching tool. With its pioneering collaboration, the APSF is unique in incorporating the talents and resources of anesthesia professionals of all types, safety scientists, pharmaceutical and equipment manufacturers, regulators, liability insurance companies, and also surgeons. Specific alerts, campaigns, discussions, and projects have targeted a host of safety issues and dangers over the years, starting with minimal intraoperative monitoring in 1986 and all the way up to beach-chair position cerebral perfusion pressure, operating room medication errors, and the extremely popular DVD on operating room fire safety in 2010; the list is long and expansive. The APSF has served as a model and inspiration for subsequent patient safety organizations and has been recognized nationally as having a dramatic positive impact on the safety of anesthesia care. Recognizing that the work is not over, that systems, organizations, and equipment still at times fail, that basic preventable human errors still do sometimes occur, and that "production pressure" in anesthesia practice threatens past safety gains, the APSF is firmly committed and continues to work hard both on established tenets and new patient safety principles. PMID- 22253278 TI - Diagnosing coeliac disease. PMID- 22253279 TI - Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. AB - OBJECTIVE: To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.5-6 years and their ability to swallow the mini tablets. METHODS: 60 children aged 0.5-6 years (10 subjects per year of life) were enrolled in our prospective, open random, two-way cross-over exploratory pilot study. The children were administered either an uncoated drug-free mini tablet 2 mm in diameter with a beverage of their choice or 3 ml of glucose syrup 15% followed by the other formulation. Deglutition was visually assessed for the two different dosage forms using a predefined criteria list. RESULTS: The study hypothesis was that children would accept the liquid formulation better than the solid mini-tablets. Surprisingly, the authors found that the acceptance of the mini-tablets, defined as immediate swallowing or chewing first with subsequent swallowing, was higher or at least equal to that of the syrup. Very young children (6-12 months) were fully capable of swallowing the mini-tablets and may even accept them better than the sweet liquid formulation. Some children aged between 2 and 4 years chewed the tablets before swallowing, but still accepted them quite well. The acceptance rate of the mini-tablets in the different age groups was much higher than expected. CONCLUSIONS: Uncoated mini-tablets seem to be a very promising alternative to liquid formulations and could be used at an earlier age in paediatric drug therapy than previously anticipated. PMID- 22253280 TI - BamView: visualizing and interpretation of next-generation sequencing read alignments. AB - So-called next-generation sequencing (NGS) has provided the ability to sequence on a massive scale at low cost, enabling biologists to perform powerful experiments and gain insight into biological processes. BamView has been developed to visualize and analyse sequence reads from NGS platforms, which have been aligned to a reference sequence. It is a desktop application for browsing the aligned or mapped reads [Ruffalo, M, LaFramboise, T, Koyuturk, M. Comparative analysis of algorithms for next-generation sequencing read alignment. Bioinformatics 2011;27:2790-6] at different levels of magnification, from nucleotide level, where the base qualities can be seen, to genome or chromosome level where overall coverage is shown. To enable in-depth investigation of NGS data, various views are provided that can be configured to highlight interesting aspects of the data. Multiple read alignment files can be overlaid to compare results from different experiments, and filters can be applied to facilitate the interpretation of the aligned reads. As well as being a standalone application it can be used as an integrated part of the Artemis genome browser, BamView allows the user to study NGS data in the context of the sequence and annotation of the reference genome. Single nucleotide polymorphism (SNP) density and candidate SNP sites can be highlighted and investigated, and read-pair information can be used to discover large structural insertions and deletions. The application will also calculate simple analyses of the read mapping, including reporting the read counts and reads per kilobase per million mapped reads (RPKM) for genes selected by the user. AVAILABILITY: BamView and Artemis are freely available software. These can be downloaded from their home pages: http://bamview.sourceforge.net/; http://www.sanger.ac.uk/resources/software/artemis/. Requirements: Java 1.6 or higher. PMID- 22253282 TI - JNK-induced apoptosis, compensatory growth, and cancer stem cells. AB - Overwhelming are a set of key stress-responsive kinases that mediate cell apoptosis, which is an important process for tumor suppression. However, JNKs have also been implicated in the malignant transformation and tumorigenesis of cells. This review attempts to reconcile these 2 contradictory functions of JNKs with recent discoveries on the role of JNKs in compensatory growth of neighboring cells and stem cells, which may provide new mechanistic understanding about the role of JNKs in the regulation of cancer stem cells and the pathogenesis of cancers. PMID- 22253283 TI - Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer. AB - Cancer cells frequently exhibit deregulation of coregulatory molecules to drive the process of growth and metastasis. One such group of ubiquitously expressed coregulators is the metastasis-associated protein (MTA) family, a critical component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA1 occupies a special place in cancer biology because of its dual corepressor or coactivator nature and widespread overexpression in human cancers. Here, we highlight recent advances in our understanding of the vital roles of MTA1 on transformation, epithelial-mesenchymal transition, and the functions of key cancer-relevant molecules such as a nexus of multiple oncogenes and tumor suppressors. In addition to its paramount role in oncogenesis, we reveal several new physiologic functions of MTA1 related to DNA damage, inflammatory responses, and infection, in which MTA1 functions as a permissive "gate keeper" for cancer causing parasites. Further, these discoveries unraveled the versatile multidimensional modes of action of MTA1, which are independent of the NuRD complex and/or transcription. Given the emerging roles of MTA1 in DNA repair, inflammation, and parasitism, we discuss the possibility of MTA1-targeted therapy for use not only in combating cancer but also in other inflammation and pathogen driven pathologic conditions. PMID- 22253286 TI - alpha-Lipoic acid, diabetic neuropathy, and Nathan's prophecy. AB - Both oral and intravenous administration of alpha-lipoic acid (ALA) has been investigated as add-on treatment for diabetic peripheral neuropathy. The recent Neurological Assessment of Thioctic Acid in Diabetic Neuropathy (NATHAN) 1 trial has shown that 4-year oral ALA administration is of some value in achieving a clinically meaningful improvement and a slight delay in the progression of neuropathic deficits among patients with mild/moderate diabetic peripheral neuropathy. Despite these promising results, important questions remain to be answered, mainly appropriate patient selection and optimal treatment duration. Moreover, a cost-benefit analysis would be useful. PMID- 22253285 TI - The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells. AB - AIMS: Mitofusin-2 (Mfn2) expression is dysregulated in vascular proliferative disorders and its overexpression attenuates the proliferation of vascular smooth muscle cells (VSMCs) and neointimal lesion development after balloon angioplasty. We sought to gain insight into the mechanisms that control Mfn2 expression in VSMCs. METHODS AND RESULTS: We cloned and characterized 2 kb of the 5'-flanking region of the human Mfn2 gene. Its TATA-less promoter contains a CpG island. In keeping with this, 5'-rapid amplification of cDNA ends revealed six transcriptional start sites (TSSs), of which TSS2 and TSS5 were the most frequently used. The strong CpG island was found to be non-methylated under conditions characterized by large differences in Mfn2 gene expression. The proximal Mfn2 promoter contains six putative Sp1 motifs. Sp1 binds to the Mfn2 promoter and its overexpression activates the Mfn2 promoter in VSMCs. Chemical inhibition of Sp1 reduced Mfn2 expression, and Sp1 silencing reduced transcriptional activity of the Mfn2 promoter. In keeping with this view, Sp1 and Mfn2 mRNA levels were down-regulated in the aorta early after an atherogenic diet in apolipoprotein E-knockout mice or in VSMCs cultured in the presence of low serum. CONCLUSION: Sp1 is a key factor in maintaining basal Mfn2 transcription in VSMCs. Given the anti-proliferative actions of Mfn2, Sp1-induced Mfn2 transcription may represent a mechanism for prevention of VSMC proliferation and neointimal lesion and development. PMID- 22253287 TI - Endothelial nitric oxide synthase gene variants and coronary heart disease. PMID- 22253288 TI - Ankle-brachial index as an indicator of arterial stiffness. PMID- 22253289 TI - Generalization procedures in training interventionists for individuals with developmental disabilities. AB - The literature pertaining to training staff, parents, and peers to implement interventions for individuals with developmental disabilities was reviewed for training procedures that incorporated strategies to promote generalization. The search engines for the Journal of Applied Behavior Analysis and Pubmed(c) were used to find relevant studies. Studies met the inclusion criteria if they sufficiently operationalized their training procedure, took data on individual trainees' performance, and used a single-subject experimental design. The training procedures were coded for generalization procedures as per Stokes and Baer. Of the 54 studies, 46 considered used procedures to promote generalization. The most prevalent generalization procedures were use of common stimuli, followed by using sufficient exemplars and mediated generalization. Studies demonstrated empirical support for these procedures producing generalized use of newly acquired direct-care skills. The remaining generalization procedures cited in Stokes and Baer were absent or far less prevalent. Future research should explore the use of these procedures and their effectiveness as a technology to bring about generalized responding of interventionists' skills. PMID- 22253290 TI - IMA: an R package for high-throughput analysis of Illumina's 450K Infinium methylation data. AB - The Illumina Infinium HumanMethylation450 BeadChip is a newly designed high density microarray for quantifying the methylation level of over 450 000 CpG sites within human genome. Illumina Methylation Analyzer (IMA) is a computational package designed to automate the pipeline for exploratory analysis and summarization of site-level and region-level methylation changes in epigenetic studies utilizing the 450K DNA methylation microarray. The pipeline loads the data from Illumina platform and provides user-customized functions commonly required to perform exploratory methylation analysis for individual sites as well as annotated regions. AVAILABILITY: IMA is implemented in the R language and is freely available from http://www.rforge.net/IMA. PMID- 22253291 TI - ReLA, a local alignment search tool for the identification of distal and proximal gene regulatory regions and their conserved transcription factor binding sites. AB - MOTIVATION: The prediction and annotation of the genomic regions involved in gene expression has been largely explored. Most of the energy has been devoted to the development of approaches that detect transcription start sites, leaving the identification of regulatory regions and their functional transcription factor binding sites (TFBSs) largely unexplored and with important quantitative and qualitative methodological gaps. RESULTS: We have developed ReLA (for REgulatory region Local Alignment tool), a unique tool optimized with the Smith-Waterman algorithm that allows local searches of conserved TFBS clusters and the detection of regulatory regions proximal to genes and enhancer regions. ReLA's performance shows specificities of 81 and 50% when tested on experimentally validated proximal regulatory regions and enhancers, respectively. PMID- 22253292 TI - CODEX: exploration of semantic changes between ontology versions. AB - Life science ontologies substantially change over time to meet the requirements of their users and to include the newest domain knowledge. Thus, an important task is to know what has been modified between two versions of an ontology (diff). This diff should contain all performed changes as compact and understandable as possible. We present CODEX (Complex Ontology Diff Explorer), a tool that allows determining semantic changes between two versions of an ontology, which users can interactively analyze in multiple ways. PMID- 22253293 TI - SNP calling using genotype model selection on high-throughput sequencing data. AB - MOTIVATION: A review of the available single nucleotide polymorphism (SNP) calling procedures for Illumina high-throughput sequencing (HTS) platform data reveals that most rely mainly on base-calling and mapping qualities as sources of error when calling SNPs. Thus, errors not involved in base-calling or alignment, such as those in genomic sample preparation, are not accounted for. RESULTS: A novel method of consensus and SNP calling, Genotype Model Selection (GeMS), is given which accounts for the errors that occur during the preparation of the genomic sample. Simulations and real data analyses indicate that GeMS has the best performance balance of sensitivity and positive predictive value among the tested SNP callers. AVAILABILITY: The GeMS package can be downloaded from https://sites.google.com/a/bioinformatics.ucr.edu/xinping-cui/home/software or http://computationalbioenergy.org/software.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22253294 TI - Qualitative exploration of psychological factors associated with spinal cord stimulation outcome. AB - BACKGROUND AND AIM: Spinal cord stimulation (SCS) is a last resort treatment for chronic pain consisting of an implantable pulse generator connected to leads placed in the epidural space of the spinal cord. Effective in reducing chronic pain, however, efficacy has been found to decrease over time. Psychological factors affecting outcome of SCS have been investigated through quantitative methods, but these have failed to provide confident predictors. We aimed to investigate via a qualitative approach, the experience of SCS following 1 year of therapy. METHODS: Thirteen chronic non-cancer pain participants were interviewed. All participants had been trialled with SCS. The majority had gone on to full implantation with varying degrees of pain relief. Thematic analysis was employed to analyse the data from the interviews. RESULTS: Interviews resulted in findings that previous quantitative studies had failed to uncover. Two emergent core themes surfaced: 'coping with pain' and 'SCS treatment'. The effect of emotion upon coping was recurrent. Participants divided the SCS experience into information provision, independence and unexpected experiences. CONCLUSION: The findings provide context for the patients' experience of SCS. This research suggests that improved preparation prior to SCS including information provision, CBT and contact with expert patients may be of value. PMID- 22253295 TI - Associations between genes in the one-carbon metabolism pathway and advanced colorectal adenoma risk in individuals with low folate intake. AB - BACKGROUND: Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer. METHODS: We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels. RESULTS: Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 * 10(-5)]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 * 10(-5)). CONCLUSIONS AND IMPACT: Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk. PMID- 22253296 TI - Vitamin D and calcium supplementation and one-year change in mammographic density in the women's health initiative calcium and vitamin D trial. AB - BACKGROUND: Calcium and vitamin D may be inversely related to breast cancer risk, in part by affecting mammographic density. However, results from previous, mostly cross-sectional studies have been mixed, and there have been few randomized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density. METHODS: We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Women's Health Initiative hormone therapy (HT) and calcium and vitamin D (CaD) trials. Women were randomized to receive 1,000 mg/d of elemental calcium carbonate plus 400 IU/d of vitamin D(3) or placebo. RESULTS: After approximately one year, mammographic density decreased 2% in the CaD supplementation group and increased 1% in the placebo group (ratio of means = 0.97; 95% CI = 0.81-1.17). Results suggested potential interaction by HT use (P = 0.08). Among women randomized to HT placebo, the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 (95% CI = 0.61-1.11) vs. 1.16 (95% CI = 0.92-1.45) in women randomized to active HT. In sensitivity analyses limited to women taking >= 80% of study supplements, ratios were 0.67 (95% CI = 0.41-1.07) in women not assigned to HT and 1.07 (95% CI = 0.79-1.47) women assigned to HT. CONCLUSIONS: We observed no overall effect of vitamin D and calcium supplementation on mammographic density after one year. IMPACT: Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study. PMID- 22253297 TI - Common variation in Nemo-like kinase is associated with risk of ovarian cancer. AB - BACKGROUND: Overexpression of mitotic kinases has been associated with prognosis, histologic grade, and clinical stage in ovarian cancer, but the relationship between inherited variation in these genes and ovarian cancer risk has not been well defined. METHODS: We measured associations between 397 single nucleotide polymorphisms (SNPs) from 67 mitotic kinases and invasive epithelial ovarian cancer risk in two case-control studies (n = 671 cases; n = 939 controls). Thirty six candidate SNPs (P < 0.05) were assessed in a replication analysis consisting of three additional studies (n = 1,094 cases; n = 829 controls). RESULTS: In initial analysis, thirty-six SNPs were suggestive of association with risk of serous ovarian cancer, all subtypes of ovarian cancer, or both (P < 0.05). Replication analyses suggested an association between rs2125846 in the Nemo-like kinase (NLK) gene and ovarian cancer (serous OR = 1.36, 95% CI: 1.11-1.67, P = 1.77 * 10(-3); all subtypes OR = 1.30, 95% CI: 1.08-1.56, P = 2.97 * 10(-3)). Furthermore, rs2125846 was associated with risk in the combined discovery and replication sets (serous OR = 1.33, 95% CI: 1.15-1.54; all subtypes OR = 1.27, 95% CI: 1.12-1.45). CONCLUSIONS: Variation in NLK may be associated with risk of invasive epithelial ovarian cancer. Further studies are needed to confirm and understand the biologic relationship between this mitotic kinase and ovarian cancer risk. IMPACT: An association between SNPs in NLK and ovarian cancer may provide biologic insight into the development of this disease. PMID- 22253298 TI - Nitrosamines and heme iron and risk of prostate cancer in the European prospective investigation into cancer and nutrition. AB - BACKGROUND: The evidence about nitrosamines and heme iron intake and cancer risk is limited, despite the biologic plausibility of the hypothesis that these factors might increase cancer risk. We investigated the association between dietary nitrosamines and heme iron and the risk of prostate cancer among participants of European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Data on food consumption and complete follow-up for cancer occurrence was available for 139,005 men, recruited in 8 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, and study center, and adjusted for total energy intake, smoking status, marital status, dairy products, educational level, and body mass index. RESULTS: After a mean follow-up of 10 years, 4,606 participants were diagnosed with first incident prostate cancer. There was no overall association between prostate cancer risk and nitrosamines exposure (preformed and endogenous) or heme iron intake (HR for a doubling of intake: 1.00; 95% CI: 0.98-1.03 for N Nitrosodimethlyamine, 0.95; 95% CI: 0.88-1.03 for endogenous Nitrosocompounds, and 1.00; 95 CI: 0.97-1.03 for heme iron). CONCLUSIONS AND IMPACT: Our findings do not support an effect of nitrosamines (endogenous and exogenous) and heme iron intake on prostate cancer risk. PMID- 22253300 TI - Commentary: The evolution of methods to assess the effects of treatments, illustrated by the development of treatments for diphtheria, 1825-1918. PMID- 22253301 TI - Inter-generational influences on age at onset of puberty: Hong Kong's 'Children of 1997' birth cohort. AB - BACKGROUND: Early puberty often occurs in migrants from less to more economically developed locations, particularly among girls, perhaps because of mismatched inter-generational conditions. However, migrants may differ from their host population in many ways. OBJECTIVE: In an ethnically homogenous Chinese population in a developed environment, we examined the association of mother's growth environment (proxied by migration status) with age at onset of puberty. We assessed differences by sex and whether associations were independent of intra uterine growth. METHODS: We used interval-censored survival analyses in 3832 boys and 3279 girls (follow-up rate of 92%) from the 'Children of 1997' birth cohort, comprising 88% of births in Hong Kong in April and May 1997, to examine the adjusted association of mother's migration status (born and raised in mainland China or in comparatively more developed Hong Kong), with clinically assessed age at onset of puberty (Tanner stage II for breast/genital and pubic hair development). RESULTS: Children with mothers from a less developed environment had earlier onset of breast/genital [time ratio (TR) 0.987, 95% confidence intervals (CIs) 0.980-0.993] and pubic hair (TR 0.993, 95% CI 0.986-1.000) development, independent of birth size for gestational age and socio-economic position, possibly with a more marked association in girls. CONCLUSION: Mismatch of growth conditions between mothers and children was associated with younger age at onset of puberty. Given the association of early puberty with chronic diseases, inter-generational influences may be relevant to the emerging epidemics of these diseases in rapidly developing populations where age of puberty is declining sharply. PMID- 22253302 TI - Commentary: Dr Choksy's dilemma. PMID- 22253303 TI - What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. AB - BACKGROUND: Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P <= 5 * 10(-8) are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance. METHODS: We defined as 'borderline' associations those with P > 5 * 10(-8) and P <= 1 * 10(-7). The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P <= 5 * 10(-8) with inclusion of additional data from subsequent GWA studies. RESULTS: Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P <= 5 * 10(-8) for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P < 10(-8). If the seven associations that did not reach P <= 5 * 10(-8) when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 10(-6) [corresponding false-discovery rate 19% (95% CI 7 39%)]. CONCLUSION: A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold. PMID- 22253304 TI - Increasing prevalence of HIV and syphilis but decreasing rate of self-reported unprotected anal intercourse among men who had sex with men in Harbin, China: results of five consecutive surveys from 2006 to 2010. AB - BACKGROUND: To monitor the prevalence of HIV and syphilis as well as behaviours, a sentinel site for men who have sex with men was established in Harbin in 2002. With additional funding, the sentinel surveillance evolved into annual cross sectional surveys since 2006. METHODS: Behavioural and serological data collected in five consecutive cross-sectional surveys were analysed. SPSS 13.0 was applied to compare prevalence of HIV and syphilis as well as behavioural variables over time by demographic variables, bivariate and multivariate analysis. RESULTS: The prevalence of HIV and syphilis increased from 1.0% in 2006 to 7.5% in 2010 and from 9.2% in 2006 to 22.4% in 2009, respectively, whereas the rate of unprotected anal intercourse decreased from 61.3% in 2006 to 47.1% in 2010. Syphilis positivity and HIV infection are independently associated with each other across years. The rate of unprotected anal sex remains high although it has decreased over the years. CONCLUSION: Findings support an increasing prevalence of HIV and syphilis among men who have sex with men in Harbin. Targeted behavioural intervention and syphilis treatment are urgently needed to prevent the epidemic from growing. PMID- 22253299 TI - Environmental chemical exposures and human epigenetics. AB - Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes. PMID- 22253305 TI - Commentary: The epigenotype--a dynamic network view of development. PMID- 22253306 TI - Commentary: 'The epigenotype' by C.H. Waddington. PMID- 22253307 TI - Betel quid chewing in rural Bangladesh: prevalence, predictors and relationship to blood pressure. AB - BACKGROUND: Betel quid is chewed by 600 million people worldwide and it has been linked to obesity and cardiovascular disease. The purpose of our study was to examine the prevalence and predictors of betel quid chewing in a rural area of Bangladesh, and determine its effects on body mass index (BMI) and blood pressure. METHODS: In this population-based prospective study, we analysed data on 19 934 Bangladeshi adults. Linear and multivariate logistic regression was used to determine the socio-demographic predictors of betel quid chewing and the effect of betel quid on change in BMI and on systolic and diastolic blood pressure, pulse pressure, arterial pressure, overweight or obesity, and hypertension. RESULTS: At baseline, betel quid was chewed by 33.2% of the cohort (35.5% of men, 31.6% of women). In a subsample in which we collected methods of use, 17.5% chewed it without tobacco and 82.5% chewed it with tobacco. In multivariate analysis, betel quid chewing was associated with female sex, older age, tobacco smoking and lower socio-economic status, as measured by fewer years of formal education and not owning land. Betel quid was chewed more times per day among women and older persons. At follow-up, persons who chewed betel quid without tobacco had higher systolic blood pressure, diastolic blood pressure and arterial pressure in comparison with never users. After controlling for other explanatory variables, chewing betel quid without tobacco was associated with general hypertension [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.04 2.10] and systolic hypertension (OR 1.55, 95% CI 1.01-2.37). We did not observe associations of betel quid chewing with BMI or overweight. CONCLUSIONS: Betel quid chewing is likely contributing to high blood pressure in Bangladesh, particularly among women. PMID- 22253309 TI - Humans and models: converging 'truths'. PMID- 22253308 TI - Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California. AB - BACKGROUND: The incidence and prevalence of autism have dramatically increased over the last 20 years. Decomposition of autism incidence rates into age, period and cohort effects disentangle underlying domains of causal factors linked to time trends. We estimate an age-period-cohort effect model for autism diagnostic incidence overall and by level of functioning. METHODS: Data are drawn from sequential cohorts of all 6 501 262 individuals born in California from 1992 to 2003. Autism diagnoses from 1994 to 2005 were ascertained from the California Department of Development Services Client Development and Evaluation Report. RESULTS: Compared with those born in 1992, each successively younger cohort has significantly higher odds of an autism diagnosis than the previous cohort, controlling for age and period effects. For example, individuals born in 2003 have 16.6 times the odds of an autism diagnosis compared with those born in 1992 [95% confidence interval (CI) 7.8-35.3]. The cohort effect observed in these data is stronger for high than for low-functioning children with an autism diagnosis. DISCUSSION: Autism incidence in California exhibits a robust and linear positive cohort effect that is stronger among high-functioning children with an autism diagnosis. This finding indicates that the primary drivers of the increases in autism diagnoses must be factors that: (i) have increased linearly year-to-year; (ii) aggregate in birth cohorts; and (iii) are stronger among children with higher levels of functioning. PMID- 22253310 TI - Cohort profile: the Lothian Birth Cohorts of 1921 and 1936. AB - This cohort profile describes the origins, tracing, recruitment, testing and follow-up of the University of Edinburgh-based Lothian Birth Cohorts of 1921 (LBC1921; N = 550) and 1936 (LBC1936; N = 1091). The participants undertook a general intelligence test at age 11 years and were recruited for these cohorts at mean ages of 79 (LBC1921) and 70 (LBC1936). The LBC1921 have been examined at mean ages of 79, 83, 87 and 90 years. The LBC1936 have been examined at mean ages of 70 and 73 years, and are being seen at 76 years. Both samples have an emphasis on the ageing of cognitive functions as outcomes. As they have childhood intelligence test scores, the cohorts' data have been used to search for determinants of lifetime cognitive changes, and also cognitive change within old age. The cohorts' outcomes also include a range of physical and psycho-social aspects of well-being in old age. Both cohorts have a wide range of variables: genome-wide genotyping, demographics, psycho-social and lifestyle factors, cognitive functions, medical history and examination, and biomarkers (from blood and urine). The LBC1936 participants also have a detailed structural magnetic resonance imaging (MRI) brain scan. A range of scientific findings is described, to illustrate the possible uses of the cohorts. PMID- 22253311 TI - Ageing, physical activity and mortality--a 42-year follow-up study. AB - BACKGROUND: Physical activity (PA) is inversely associated with mortality in the general population. We wanted to quantify the association of self-reported PA with mortality from all causes, ischaemic heart disease (IHD) and stroke, and compare it with other known risk factors in different age segments. METHODS: The Bergen Clinical Blood Pressure Survey examined a sample of 6811 Norwegian men and women in 1965-71 with follow-up until 2005-07. Cox proportional hazard regression ratio (HR) and population attributable fraction (PAF) were calculated for the old (>65), middle-aged (45-64) and young adults (22-44), respectively. We minimized confounding and bias by progressive comprehensive adjustments and subgroup analyses (excluding early follow-up deaths, participants with self-reported disease and participants with changes in their PA-level prior baseline due to disease). RESULTS: The HR [95% confidence interval (CI)] associated with a high PA-level was 0.63(0.56-0.71), 0.66(0.52-0.83) and 0.66(0.47-0.93) for mortality from all causes, IHD and stroke, respectively (reference: no participation in any of the listed activities, adjusted for age and gender). PAF (95% CI) of no/low activity (reference: any activity) was consistent across all age groups, varying from 7.3% (3.4-11.4) in the young adults to 9.1% (3.6-15.3) in the old. PAF of smoking and high s-cholesterol declined with increasing age [smoking from 19.9% (15.3-24.7) to 1.5% (-1.3 to 6.2) and s-cholesterol from 11.5% (5.6-17.5) to 9.5% (-18.1 to -0.7)], whereas PAF of hypertension increased from 5.3% (2.1-9.1) to 18.9% (8.3-28.4). CONCLUSION: The relative importance of traditional risk factors varies between the age groups, but physical activity is a major health promoting factor across all age segments and should be encouraged particularly in an ageing population. PMID- 22253312 TI - The value of twins in epigenetic epidemiology. AB - During past decades, twin studies have played an important role in genetic epidemiology studies of complex traits. The strength of twin studies lies in the ability to disentangle genetic and environmental factors that contribute to a phenotype, by comparing genetically identical monozygotic twins to dizygotic twins, who share on average 50% of genetic variants. Twin studies now offer the opportunity to study epigenetic variation across the genome with two aims. First, twin studies can improve our understanding of the factors regulating epigenetic variability by assessing the heritability of epigenetic variants. Secondly, the use of twins in epigenetic research is increasingly recognized as an important approach to help unravel the complexities associated with human development and disease. The strategic use of identical twins discordant for complex disease has revealed the importance of linking epigenetic disruption to the disease associated risk in humans. Lastly, we also discuss the possibility that epigenetic effects on disease may in part explain some of the missing heritability in genome-wide association studies. The study of human epigenetic factors in twins can inform the role of genetics, as well as in utero and postnatal environments to the establishment, maintenance and functional consequences of human epigenome variation. PMID- 22253313 TI - Moderate alcohol intake during pregnancy and risk of fetal death. AB - BACKGROUND: Controversies still exist regarding the existence of a 'safe' level of alcohol intake during pregnancy. The aim of this study was to assess the risk of fetal death (spontaneous abortion and stillbirth) according to maternal alcohol consumption in a large Danish pregnancy cohort. METHODS: A cohort study carried out within the framework of the Danish National Birth Cohort. A total of the 92 719 participants enrolled in the Danish National Birth Cohort who provided information about lifestyle during first trimester of pregnancy were included in the study. Information about average weekly consumption of alcohol during pregnancy, smoking, coffee drinking, occupational status and reproductive history were obtained by means of computer-assisted telephone interviews. Pregnancy outcomes (spontaneous abortion, stillbirth, live birth and other pregnancy outcome) and gestational age at end of pregnancy were obtained through register linkage with the Civil Registration System and the National Discharge Registry. Data were analysed using Cox regression models, taking the varying gestational age at recruitment and time-dependent co-variables into account. RESULTS: Fifty five per cent of the participants abstained from alcohol drinking during pregnancy and only 2.2% reported four or more drinks per week. The adjusted hazard ratios for fetal death in first trimester were 1.66 [95% confidence interval (CI) 1.43-1.92] and 2.82 (95% CI 2.27-3.49) for women who reported 2 31/2; drinks per week and 4 or more drinks per week, respectively, and 1.57 (95% CI 1.30-1.90) and 1.73 (95% CI 1.24-2.41) for fetal death during pregnancy weeks 13-16. No increased risk was found for fetal death after 16 weeks of pregnancy. CONCLUSIONS: Even low amounts of alcohol consumption during early pregnancy increased the risk of spontaneous abortion substantially. The results indicate that the fetus is particularly susceptible to alcohol exposure early in pregnancy. PMID- 22253314 TI - Where science meets policy: comparing longitudinal and cross-sectional designs to address diarrhoeal disease burden in the developing world. AB - BACKGROUND: Longitudinal studies are considered preferable to cross-sectional studies for informing public health policy. However, when resources are limited, the trade-off between an accurate cross-section of the population and an understanding of the temporal variation should be optimized. When risk factors vary more across space at a fixed moment in time than at a fixed location across time, cross-sectional studies will tend to give more precise estimates of risk factor effects and thus may be a better source of data for policy judgments. METHODS: We conducted a diarrhoeal disease surveillance of 5616 individuals within 19 Ecuadorian villages. This data set was used to mimic cross-sectional and longitudinal studies by restricting focus to a single week and a single village, respectively. We compared the variability in risk factor effect estimates produced from each type of study. RESULTS: For household risk factors, the effect estimates produced by the longitudinal studies were more variable than their cross-sectional counterparts, which can be explained by greater spatial than temporal variability in the risk factor distribution. For example, the effect estimate of improved sanitation was almost twice as variable in longitudinal studies. CONCLUSIONS: In our study, cross-sectional designs yielded more consistent evaluations of diarrhoea disease risk factors when those factors varied more between villages than over time. Cross-sectional studies can provide information that is representative across large geographic regions and therefore can provide insight for local, regional and national policy decisions. The value of the cross-sectional study should be reconsidered in the public health community. PMID- 22253315 TI - Cohort profile: the health survey for England. AB - To monitor the health of the public in England, UK, the Central Health Monitoring Unit within the UK Department of Health commissioned an annual health examination survey, which became known as the Health Survey for England (HSE). The first survey was completed in 1991. The HSE covers all of England and is a nationally representative sample of those residing at private residential addresses. Each survey year consists of a new sample of private residential addresses and people. The HSE collects detailed information on mental and physical health, health related behaviour, and objective physical and biological measures in relation to demographic and socio-economic characteristics of people aged 16 years and over at private residential addresses. There are two parts to the HSE; an interviewer visit, to conduct an interview and measure height and weight, then a nurse visit, to carry out further measurements and take biological samples. Since 1994, survey participants aged 16 years and over have been asked for consent to follow-up through linkage to mortality and cancer registration data, and from 2003, to the Hospital Episode Statistics database, thus converting annual cross-sectional survey data into a longitudinal study. Annual survey data (1994-2009) are available through the UK Data Archive. PMID- 22253317 TI - Cohort profile: growing up in New Zealand. PMID- 22253316 TI - Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. AB - BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene smoking interaction; and 16 published studies from non-European ancestry. RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association. PMID- 22253318 TI - Cohort Profile: TwinsUK and healthy ageing twin study. AB - The UK's largest registry of adult twins, or TwinsUK Registry, started in 1992 and encompasses about 12000 volunteer twins from all over the United Kingdom. More than 70% of the registered twins have filled at least one detailed health questionnaire and about half of them undergone a baseline comprehensive assessment and two follow-up clinical evaluations. The most recent follow-up visit, known as Healthy Ageing Twin Study (HATS), involved 3125 female twins aged >40 years with at least one previous clinical assessment to enable inspection of longitudinal changes in ageing traits and their genetic and environmental components. The study benefits from several state-of-the-art OMICs studies including genome-wide association, next-generation genome and transcriptome sequencing, and epigenetic and metabolomic profiles. This makes our cohort as one of the most deeply phenotyped and genotyped in the world. Several collaborative projects in the field of epidemiology of complex disorders are ongoing in our cohort and interested researchers are encouraged to get in contact for future collaborations. PMID- 22253319 TI - Competing risks in epidemiology: possibilities and pitfalls. AB - BACKGROUND: In studies of all-cause mortality, the fundamental epidemiological concepts of rate and risk are connected through a well-defined one-to-one relation. An important consequence of this relation is that regression models such as the proportional hazards model that are defined through the hazard (the rate) immediately dictate how the covariates relate to the survival function (the risk). METHODS: This introductory paper reviews the concepts of rate and risk and their one-to-one relation in all-cause mortality studies and introduces the analogous concepts of rate and risk in the context of competing risks, the cause specific hazard and the cause-specific cumulative incidence function. RESULTS: The key feature of competing risks is that the one-to-one correspondence between cause-specific hazard and cumulative incidence, between rate and risk, is lost. This fact has two important implications. First, the naive Kaplan-Meier that takes the competing events as censored observations, is biased. Secondly, the way in which covariates are associated with the cause-specific hazards may not coincide with the way these covariates are associated with the cumulative incidence. An example with relapse and non-relapse mortality as competing risks in a stem cell transplantation study is used for illustration. CONCLUSION: The two implications of the loss of one-to-one correspondence between cause-specific hazard and cumulative incidence should be kept in mind when deciding on how to make inference in a competing risks situation. PMID- 22253320 TI - Socio-economic status is associated with epigenetic differences in the pSoBid cohort. AB - BACKGROUND: Epigenetic programming and epigenetic mechanisms driven by environmental factors are thought to play an important role in human health and ageing. Global DNA methylation has been postulated as an epigenetic marker for epidemiological studies as it is reflective of changes in gene expression linked to disease. How epigenetic mechanisms are affected by psychological, sociological and biological determinants of health still remains unclear. The aim of this study was to investigate the relationship between socio-economic and lifestyle factors and epigenetic status, as measured by global DNA methylation content, in the pSoBid cohort, which is characterized by an extreme socio-economic and health gradient. METHODS: DNA was extracted from peripheral blood leukocytes using the Maxwell(r) 16 System and Maxwell(r) 16 Blood DNA Purification kit (Promega, UK). Global DNA methylation was assessed using MethylampTM Global DNA Methylation Quantification Ultra kit (Epigentek, USA). Associations between global DNA methylation and socio-economic and lifestyle factors were investigated in linear regression models. RESULTS: Global DNA hypomethylation was observed in the most socio-economically deprived subjects. Job status demonstrated a similar relationship, with manual workers having 24% lower DNA methylation content than non-manual. Additionally, associations were found between global DNA methylation content and biomarkers of cardiovascular disease (CVD) and inflammation, including fibrinogen and interleukin-6 (IL-6), after adjustment for socio economic factors. CONCLUSIONS: This study has indicated an association between epigenetic status and socio-economic status (SES). This relationship has direct implications for population health and is reflected in further associations between global DNA methylation content and emerging biomarkers of CVD. PMID- 22253321 TI - Recommendations for presenting analyses of effect modification and interaction. AB - Authors often do not give sufficient information to draw conclusions about the size and statistical significance of interaction on the additive and multiplicative scales. To improve this, we provide four steps, template tables and examples. We distinguish two cases: when the causal effect of intervening on one exposure, across strata of another factor, is of interest ('effect modification'); and when the causal effect of intervening on two exposures is of interest ('interaction'). Assume we study whether X modifies the effect of A on D, where A, X and D are dichotomous. We propose presenting: (i) relative risks (RRs), odds ratios (ORs) or risk differences (RDs) for each (A, X) stratum with a single reference category taken as the stratum with the lowest risk of D; (ii) RRs, ORs or RDs for A within strata of X; (iii) interaction measures on additive and multiplicative scales; (iv) the A-D confounders adjusted for. Assume we study the interaction between A and B on D, where A, B and D are dichotomous. Steps (i) and (iii) are similar to presenting effect modification. (ii) Present RRs, ORs or RDs for A within strata of B and for B within strata of A. (iv) List the A-D and B-D confounders adjusted for. These four pieces of information will provide a reader the information needed to assess effect modification or interaction. The presentation can be further enriched when exposures have multiple categories. Our proposal hopefully encourages researchers to present effect modification and interaction analyses in as informative a manner as possible. PMID- 22253322 TI - Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. AB - BACKGROUND AND METHOD: Increased plasma clot density and prolonged lysis times are associated with cardiovascular disease. In this study, we employed a functional proteomics approach to identify novel clot components which may influence clot phenotypes. RESULTS: Analysis of perfused, solubilised plasma clots identified inflammatory proteins, including complement C3, as novel clot components. Analysis of paired plasma and serum samples confirmed concentration dependent incorporation of C3 into clots. Surface plasmon resonance indicated high-affinity binding interactions between C3 and fibrinogen and fibrin. Turbidimetric clotting and lysis assays indicated C3 impaired fibrinolysis in a concentration-dependent manner, both in vitro and ex vivo. CONCLUSION: These data indicate functional interactions between complement C3 and fibrin leading to prolonged fibrinolysis. These interactions are physiologically relevant in the context of protection following injury and suggest a mechanistic link between increased plasma C3 concentration and acute cardiovascular thrombotic events. PMID- 22253323 TI - Effects of a group-based exercise and self-regulatory intervention on obese adolescents' physical activity, social cognitions, body composition and strength: a randomized feasibility study. AB - This feasibility study assessed the effects of an exercise plus group-based self regulatory skills intervention on obese youths' physical activity, social cognitions, body composition and strength. Forty-three obese youth (male = 13, BMI > 95th percentile; 10-16 yrs) completed this 12-week intervention. Assessments were taken at baseline, week 6, 13 and 12 weeks post-intervention (week 24). Although no attention control group (i.e. exercise only) was included in this study, participants engaged in significantly more self-reported physical activity at weeks 13 and 24 as compared to baseline. Social cognitions, body composition and strength were also positively impacted suggesting this intervention technique may be feasible for treating obese adolescents. PMID- 22253324 TI - Investigating mothers' decisions about their child's sun-protective behaviour using the Theory of Planned Behaviour. AB - This study tested the utility of the Theory of Planned Behaviour (TPB) to predict mothers' decisions to ensure their child engages in sun-protective behaviours. Mothers (N = 162) of children aged four or five years completed standard TPB items (attitude, subjective norm, perceived behavioural control, intention) and additional variables of role construction, mothers' own sun safe behaviour, planning and past behaviour. One week later, participants (N = 116) reported their behaviour. Results found support for the TPB constructs, role construction, past behaviour and the mediating role of planning. These findings can inform strategies to prevent skin cancer. PMID- 22253325 TI - The role of context stability and behavioural stability in the mere measurement effect: an examination across six behaviours. AB - Asking about intentions and behaviour may alter future reports of health behaviours due to the stability of the behaviours (behavioural stability hypothesis), or changes in performance context (context stability hypothesis). Two studies (Ns = 116, 177) confirmed the distinction between stable and unstable behaviours and explored context stability for six health-related behaviours. Study 3 used a longitudinal intervention design in which the intervention group (N time 1 = 292, N time 2 = 149) reported their intentions and past-behaviours at time 1 while the non-intervention group (N = 118) did not. The context stability hypothesis was supported. PMID- 22253326 TI - Parenting styles and alcohol consumption among Brazilian adolescents. AB - AIM: This study evaluates the correlation between alcohol consumption in adolescence and parenting styles of socialization among Brazilian adolescents. The sample was composed of 273 adolescents, 58% whom were males. Instruments were: 1) Sociodemographic Questionnaire; 2) Demand and Responsiveness Scales; 3) Drug Use Screening Inventory (DUSI). Study analyses employed multiple correspondence analysis and logistic regression. RESULTS: Maternal, but not paternal, authoritative and authoritarian parenting styles were directly related to adolescent alcohol intake. CONCLUSIONS: The style that mothers use to interact with their children may influence uptake of high-risk behaviors. PMID- 22253327 TI - The relationship of coping strategies, social support, and attachment style with posttraumatic growth in cancer survivors. AB - This cross-sectional study investigated attachment style, coping strategies, social support, and posttraumatic growth (PTG) in 54 cancer survivors. Secure attachment was significantly associated with active coping, positive reframing, and religion, and these were all associated with PTG. Insecure types of attachment and social support variables were unrelated to PTG. Regression analysis suggests that positive reframing and religion as coping strategies may mediate the relationship between secure attachment and PTG. PMID- 22253328 TI - The romantic experiences of adolescents with a visible difference: exploring concerns, protective factors and support needs. AB - Injuries or conditions that affect appearance can increase adolescents' risk of psychosocial and interpersonal difficulties and may also impact on romantic relationships - an important aspect of adolescent development. A mixed method online approach explored the romantic experiences of 40 adolescents with a variety of visible differences. Young people identified appearance-related romantic concerns that cause distress, and impede the development and enjoyment of romantic relations. In contrast, some shared positive experiences and evidence of attitudes and behaviours that appear to protect against these concerns. Adolescents requested online peer support specific to their appearance-related needs. These findings can inform intervention development. PMID- 22253329 TI - Social correlates of distress following hematopoietic stem cell transplantation: exploring the role of loneliness and cognitive processing. AB - This study investigated whether loneliness and cognitive processing explain the influence of negative (social constraints) and positive (emotional support) relationship qualities on cancer survivors' distress. Participants were 195 cancer survivors who had undergone hematopoietic stem cell transplantation. Path analysis supported the hypothesis that loneliness and cognitive processing would mediate the association between social constraints and distress. Only loneliness mediated the association between emotional support and distress - an indirect effect significant only when support came from family and friends rather than a partner. Findings suggest that addressing social constraints may enhance cancer survivors' adjustment. PMID- 22253330 TI - Exploring the interaction of patient activation and message design variables: message frame and presentation mode influence on the walking behavior of patients with type 2 diabetes. AB - Examining interpersonal (physician-patient) communication strategies for promoting walking exercise to patients with type 2 diabetes assigned to primary care clinics, the study evaluated two message design variables--frame and presentation mode--as influencers of communication and adoption success. The single-site, four-week, prospective intervention study followed a 2*3 factorial, non-equivalent comparison group quasi-experimental design. Results showed frame was significantly related to steps walked; however, when including patient activation as an interaction, frame was non-significant. The model including patient activation interactions, however, detected significant mode effects on behavior. Results provide evidence that statistics are most effectively used with activated patients. PMID- 22253332 TI - Assessing risk for ventricular tachyarrhythmias and sudden cardiac death: is there a role for cardiac MRI? PMID- 22253333 TI - Low-flow low-gradient aortic stenosis: in search of optimal risk stratification. PMID- 22253334 TI - The detection of myocardial fibrosis: an opportunity to reduce cardiovascular risk in patients with diabetes mellitus? PMID- 22253335 TI - Assessment of skin microvascular function and dysfunction with laser speckle contrast imaging. PMID- 22253336 TI - Three-dimensional transesophageal echocardiography enhances multimodal imaging of a successful repair of a case with scimitar syndrome. PMID- 22253338 TI - Thoracic duct and cisterna chyli: evaluation with multidetector row CT. AB - OBJECTIVES: The aim of this study was to evaluate the normal anatomy of the thoracic duct and cisterna chyli obtained by axial and multiplanar reformation (MPR) images of 1 mm slice thickness using multidetector row CT (MDCT). METHODS: We evaluated the ability of MDCT to examine the normal anatomy of the thoracic duct and cisterna chyli. The axial and coronal images of thoracoabdominal MDCT images obtained in 50 patients (20 females and 30 males; mean age, 63.5 years; range, 32-81 years) were reviewed between January and October 2005. We excluded patients with malignant neoplasms, inflammation or vascular diseases (e.g. aortic aneurysm, aortic dissection) and those with a history of thoracoabdominal surgery. The thoracic duct was divided into three anatomical sections: the upper, middle and lower. We evaluated the degree of visualisation and the maximum size of the thoracic duct. We also evaluated the degree of visualisation, maximum size, configuration and location of the cisterna chyli. RESULTS: Visualisation of the thoracic duct and cisterna chyli was almost 100% on axial and coronal images. The lower section of the thoracic duct was most clearly visualised among the three sections. There was little difference in the maximum size of the thoracic duct among the three sections. The cisterna chyli was most frequently located at the Th12 or L1 level, and the most common type was the "straight thin tube type". CONCLUSION: Axial and MPR images of 1 mm slice thickness using MDCT can clearly depict the thoracic duct and cisterna chyli. PMID- 22253339 TI - Imaging features of paediatric haemophilic pseudotumour of the maxillary bone: report of three cases and review of the literature. AB - OBJECTIVES: Haemophilic pseudotumour (HP) is an extremely rare lesion. The purpose of this study was to describe the CT and MRI features of maxillary bone HPs and introduce the key points to differentiate HP from the mimicking entities in the region. METHODS: We retrospectively reviewed three paediatric patients with histology-proven HPs arising from the maxillary bone. All three patients underwent CT and/or MRI. Combined with six previously reported cases in the literature, the imaging features were comprehensively analysed. RESULTS: All HPs showed a well-demarcated, multilobulated expansile osteolytic lesion in the maxillary bone. On non-enhanced CT, HPs appeared of mixed density relative to grey matter. The lesions appeared to have markedly heterogeneous signal intensity on both T(1) and T(2) weighted images, with septa-like enhancement following the administration of contrast material, which corresponded to blood products in various stages of evolution. The lesions caused cortical thinning and even focal disappearance and multiple bone septa were identified within the involved maxillary bone. Some HPs were associated with radiated periosteal proliferation, which can easily be misdiagnosed as a malignant bone tumour. CONCLUSION: A high index of suspicion for HP and a familiarity with imaging findings may help to accurately diagnose this rare entity. PMID- 22253340 TI - Visualisation of liver tumours using hand-held real-time strain imaging: results of animal experiments. AB - OBJECTIVE: Surgical resection is the only curative option for colorectal hepatic metastases. Intra-operative localisation of these metastases during hepatic resection is performed by intra-operative B-mode imaging and palpation. Because liver metastases are stiffer than normal tissues, elastography may be a useful complement to B-mode imaging. This paper reports quantitative measures of the image quality attained during intra-operative real-time elastographic visualisation of liver metastasis. METHODS: VX2 tumours were implanted in the liver of eight rabbits and were scanned in vivo. Measurements of the tumour dimensions obtained via elastography were compared with those obtained using B mode imaging and with gross pathology. RESULTS: Measurements of tumour diameters were similar when obtained by intra-operative elastography and pathological measurement methods (mean difference+/-standard deviation, 0.1+/-0.9 mm). The contrast between tumours and normal tissues was significantly higher (p<0.05) in elastograms (26+/-10 dB contrast) than in sonograms (1+/-1 dB contrast). Sensitivity and specificity for detecting tumours using intra-operative elastography were 100% and 88%, respectively, and positive and negative predictive values were 89% and 100%, respectively. In two cases elastograms were able to detect a tumour that was ambiguous in B-mode images. CONCLUSION: Combined hand-held B-mode/strain imaging may provide additional information that is relevant for detection of liver metastases that may be missed by standard B-mode imaging alone, such as small and/or isoechoic tumours. PMID- 22253341 TI - Neuroimaging of isolated and non-isolated third nerve palsies. AB - A variety of aetiologies may cause third nerve palsy (TNP), and some manifestations may herald neurological emergencies. This article describes and illustrates various diseases that lead to TNP. PMID- 22253342 TI - Prostatic cancer surveillance following whole-gland high-intensity focused ultrasound: comparison of MRI and prostate-specific antigen for detection of residual or recurrent disease. AB - OBJECTIVE: This retrospective study compares dynamic contrast-enhanced (DCE) MRI with the serial prostate-specific antigen (PSA) measurement for detection of residual disease following whole-gland high-intensity focused ultrasound (HIFU) therapy of prostate cancer. METHODS: Patients in whom post-HIFU DCE-MRI was followed within 3 months by ultrasound-guided transrectal biopsy were selected from a local database. 26 patients met the study inclusion criteria. Serial PSA levels following HIFU and post-HIFU follow-up MRI were retrieved for each patient. Three radiologists unaware of other investigative results independently assessed post-HIFU MRI studies for the presence of cancer, scoring on a four point scale (1, no disease; 2, probably no disease; 3, probably residual disease; and 4, residual disease). Sensitivity, specificity and receiver operating characteristic (ROC) analysis were performed for each reader, post-HIFU PSA nadir and pre-biopsy PSA level thresholds of >0.2 and >0.5 ng ml(-1). RESULTS: The sensitivity of DCE-MRI for detection of residual disease for the three readers ranged between 73% and 87%, and the specificity between 73% and 82%. There was good agreement between readers (kappa = 0.69-0.77). The sensitivity and specificity of PSA thresholds was 60-87% and 73-100%, respectively. The area under the ROC curve was greatest for pre-biopsy PSA (0.95). CONCLUSION: DCE-MRI performed following whole-gland HIFU has similar sensitivity and specificity and ROC performance to serial PSA measurements for detection of residual or recurrent disease. PMID- 22253343 TI - Comparison of clinical, tumour-related and dosimetric factors in grade 0-1, grade 2 and grade 3 radiation pneumonitis after stereotactic body radiotherapy for lung tumours. AB - OBJECTIVE: The aim of this study was to investigate significant clinical, tumour related and dosimetric factors among patients with grade 0-1, grade 2 and grade 3 radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) for lung tumours. METHODS: Patients (n=128) with a total of 133 lung tumours treated with SBRT of 50 Gy in 5 fractions were analysed. RP was graded according to the Common Terminology Criteria for Adverse Events v.3.0. Significant factors were identified by univariate and multivariate analyses. Threshold dose-volume histograms (DVHs) were constructed to identify the incidence of RP. RESULTS: The median follow-up period was 12 months (range, 6-45 months). In univariate analyses, gender, operability, forced expiratory volume in 1 s (FEV1), internal target volume, lung volumes treated with doses >5-30 Gy (V5-30) and mean lung dose were significant factors differentiating between grade 0-1 and grade 2 RP, and V15-30 were significant factors differentiating between grade 2 and grade 3. However, no factors were significant between grade 0-1 and grade 3 RP. Multivariate analysis showed that female gender, high FEV1 and high V15 were significant factors differentiating between grade 0-1 and grade 2 RP. Threshold DVH curves were created based on <=5% and <=15% risk of grade 2 RP among patients with grade 0-2 RP. CONCLUSIONS: Grade 0-2 RP was dose-volume dependent, and female gender and high FEV1 were significant predictive clinical factors for grade 2 RP among patients with grade 0-2 RP. However, incidences of V15-30 in grade 3 RP were significantly lower than those in grade 2 RP, and no significant clinical or tumour-related factors were found. Further studies are needed to identify the mechanism underlying the development of grade 3 RP after SBRT for lung tumours. PMID- 22253344 TI - Predictive factors for radiation pneumonitis in oesophageal cancer patients treated with chemoradiotherapy without prophylactic nodal irradiation. AB - OBJECTIVE: The objective of this study was to identify clinical and dosimetric factors for the development of radiation pneumonitis (RP) among patients with oesophageal cancer treated with three-dimensional radiotherapy without prophylactic nodal irradiation. METHODS: 125 patients with oesophageal cancer had undergone dose-volume histogram (DVH) metrics and received chemoradiotherapy (CRT). Several clinical and dosimetric factors with regard to the lung were evaluated as predictive factors for the development of symptomatic RP. RESULTS: 26 patients (20.8%) developed symptomatic RP classified as greater than or equal to Grade 2. By univariate analysis, body weight loss, tumour length, Stage IV, response to treatment and all DVH parameters proved to be significant factors for the development of RP (p < 0.05). By multivariate analysis, Stage IV and all dosimetric factors were independent predictive factors for the development of symptomatic RP (p < 0.05). Recursive partitioning analysis indicated that V10 values of 24.8% or more and Stage IV were associated with higher development of RP (odds ratio 6.53). CONCLUSIONS: Our study demonstrated that severe RP was also developed in patients treated with the minimal radiation field. Stage IV and the dosimetric factors were identified as independent predictive factors for symptomatic RP in oesophageal cancer patients treated with CRT without prophylactic nodal irradiation. PMID- 22253345 TI - Patient-reported complications from fiducial marker implantation for prostate image-guided radiotherapy. AB - OBJECTIVES: To report on complications from transrectal ultrasound-guided insertion of fiducial markers for prostate image-guided radiotherapy. METHODS: 234 patients who underwent transrectal fiducial marker insertion for prostate cancer image-guided radiotherapy were assessed retrospectively by questionnaire with regard to the duration and severity of eight symptoms experienced following the procedure. Pain during the implantation procedure was assessed according to the Wong-Baker faces pain scale. RESULTS: Of 234 patients, 32% had at least one new symptom after the procedure. The commonest new symptom following the procedure was urinary frequency affecting 16% of patients who had not been troubled by frequency beforehand. Haematuria, rectal bleeding, dysuria and haematospermia affected 9-13% of patients, mostly at Grade 1 or 2. Pain, obstruction, and fever and shivers affected 3-4% of patients. Grade 3 rectal bleeding, haematuria, fever and shivers, and urinary frequency affected 0.5-1.5% of patients. Only one patient had a Grade 4 complication (i.e. fever and shivers). Overall, 9% of patients had symptoms lasting more than 2 weeks. The commonest symptoms that lasted more than 2 weeks were frequency, dysuria, obstructive symptoms and rectal bleeding. Mean pain score during the procedure was 1.1 (range 0-5). CONCLUSION: Transrectal ultrasound-guided fiducial marker insertion for image-guided radiotherapy is well tolerated in the majority of prostate cancer patients. Most symptoms were Grade 1 or 2 in severity. Symptoms in the majority of patients last under 2 weeks. The most serious complication was sepsis in our study. PMID- 22253346 TI - Dose reduction and image quality in CT angiography for cerebral aneurysm with various tube potentials and current settings. AB - OBJECTIVES: The purpose of this study is to investigate the image quality on both axial and three-dimensional CT angiograms of the brain at various tube potentials and currents, and to propose the use of descriptors for evaluating the image quality of three-dimensional CT angiograms using entropy analysis. METHODS: A head phantom was used as a target object. Axial CT and three-dimensional CT angiograms were obtained at various effective milliampere-second values (49-350 mAs) and tube potentials (80-140 kVp) with a 64-row detector CT scanner. Lens doses were measured using a planar silicon pin-photodiode system. The signal-to noise ratio (SNR) and streak artefacts on the axial CT angiograms were evaluated and the image quality of the three-dimensional CT angiograms was assessed using entropy analysis. RESULTS: Lens doses increased with tube potential and effective milliampere-seconds. From the evaluation of SNR and streak artefacts on axial CT angiograms, we found that the image quality was improved by setting the tube potential at 100 kVp. However, there was little visual difference in the image quality for 100 kVp between 252 (effective value recommended by the manufacturer) and 350 mAs (maximum effective value). In the entropy analysis of the image quality of three-dimensional CT angiograms, the mutual information (information gain) per lens dose was largest at 80 kVp and 252 mAs. CONCLUSION: Our results suggested that the suitable tube potentials for axial CT and three-dimensional CT angiograms were 100 and 80 kVp, respectively, and the effective milliampere second value recommended by the manufacturer was appropriate. PMID- 22253347 TI - Pancreatic endocrine neoplasms: a current update on genetics and imaging. AB - Pancreatic endocrine neoplasms are rare pancreatic tumours that may occur sporadically or as part of inherited syndromes such as multiple endocrine neoplasia-1 syndrome, von Recklinghausen disease, von Hippel-Lindau syndrome and tuberous sclerosis complex. Recent advances in the genetics and pathology of hereditary syndromes have provided valuable insights into the pathophysiology and biology of sporadic pancreatic endocrine neoplasms. Evolving molecular data on the biology of these neoplasms have the potential for diagnostic, therapeutic and prognostic use. PMID- 22253348 TI - Sonography in pathologies of scalp and hair. AB - Disorders of the scalp often result in severe cosmetic interference with quality of life, creating the need for optimal medical surveillance. We tested the latest generation of ultrasound machines in patients with scalp pathology and prepared a cross-sectional library encompassing a wide assortment of conditions. Normative data on the sonographic anatomy of scalp and human hair, and important methodological considerations, are also included. PMID- 22253349 TI - Use of a digitally reconstructed radiograph-based computer simulation for the optimisation of chest radiographic techniques for computed radiography imaging systems. AB - OBJECTIVES: The purpose of this study was to derive an optimum radiographic technique for computed radiography (CR) chest imaging using a digitally reconstructed radiograph computer simulator. The simulator is capable of producing CR chest radiographs of adults with various tube potentials, receptor doses and scatter rejection. METHODS: Four experienced image evaluators graded images of average and obese adult patients at different potentials (average sized, n=50; obese, n=20), receptor doses (n=10) and scatter rejection techniques (average-sized, n=20; obese, n=20). The quality of the images was evaluated using visually graded analysis. The influence of rib contrast was also assessed. RESULTS: For average-sized patients, image quality improved when tube potential was reduced compared with the reference (102 kVp). No scatter rejection was indicated. For obese patients, it has been shown that an antiscatter grid is indicated, and should be used in conjunction with as low a tube potential as possible (while allowing exposure times <20 ms). It is also possible to reduce receptor air kerma by 50% without adversely influencing image quality. Rib contrast did not interfere at any tube potential. CONCLUSIONS: A virtual clinical trial has been performed with simulated chest CR images. Results indicate that low tube potentials (<102 kVp) are optimal for average and obese adults, the former acquired without scatter rejection, the latter with an anti-scatter grid. Lower receptor (and therefore patient doses) than those used clinically are possible while maintaining adequate image quality. PMID- 22253350 TI - Intensity-modulated radiotherapy for nasopharyngeal carcinoma: improvement of the therapeutic ratio with helical tomotherapy vs segmental multileaf collimator based techniques. AB - OBJECTIVES: The aim of the study was to compare differences in dosimetric, clinical and quality-of-life end points among patients treated with helical tomotherapy (HT) and segmental multileaf collimator (SMLC)-based intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma. METHODS: From June 2005 to August 2009, 30 consecutive patients were treated with IMRT for nasopharyngeal carcinoma to a dose of 70 Gy. 14 patients (47%) were treated using HT and 16 (53%) were treated using SMLC-based IMRT. 28 patients (93%) received concurrent chemotherapy. The patients were evenly balanced between the two radiotherapy groups with respect to clinical and pathological characteristics. Median follow-up was 30 months (range, 6-62 months). RESULTS: The 2-year estimates of overall survival, local-regional control and progression-free survival were 81%, 87% and 82%, respectively. There were no significant differences in any of these end points with respect to IMRT technique (p>0.05 for all). Dosimetric analysis revealed that patients treated by HT had significantly improved salivary sparing with respect to mean dose (27.3 vs 34.1 Gy, p=0.03) and volume receiving greater than or equal to 30 Gy (31.7% vs 47.3%, p=0.01) to the contralateral (spared) parotid gland. The incidence of Grade 3+ late xerostomia was 13 and 7% among patients treated with SMLC-based IMRT and HT, respectively (p=0.62). The corresponding proportion of patients who subjectively reported "too little" or "no" saliva at final follow-up was 38% and 7%, respectively (p=0.04). CONCLUSION: The superior dosimetric outcome observed with HT appeared to translate into moderately improved clinical outcomes with respect to salivary sparing. Prospective trials are needed to validate this gain in the therapeutic ratio. PMID- 22253351 TI - Miscellaneous tumour-like lesions of the ovary: cross-sectional imaging review. AB - Miscellaneous tumour-like ovarian lesions are histobiologically diverse, and are often mistaken for the more common ovarian cancers, leading to aggressive management. Knowledge of characteristic clinical, laboratory and imaging findings of these select non-neoplastic ovarian entities allows correct diagnoses and permits optimal management. PMID- 22253352 TI - Burnout in therapy radiographers in the UK. AB - The 2007 UK National Radiotherapy Advisory Group report indicated that the number and type of staff available is one of the "rate-limiting" steps in improving productivity in radiotherapy departments. Retaining well-trained, satisfied staff is key to meeting the objectives of the report; burnout is an important factor linked to satisfaction and attrition. The results of a survey measuring burnout in a sample of radiotherapists (therapy radiographers) are presented and considered against norms for the health sector and burnout in therapists from Canada and the USA. Case study methodology was used studying six radiotherapy departments selected because of close geographical proximity and differing vacancy rates for radiotherapists. An anonymous survey of radiotherapists used the Maslach Burnout Inventory (MBI) and other workforce-related measures (e.g. job satisfaction scales, measures of professional plateau, intentions to leave, job characteristics and demographic data); the results of the burnout questionnaire alone are presented in this paper. A total of 97 completed questionnaires were returned (representing a 28% response rate). The average score for emotional exhaustion was higher than the MBI norms, with 38% of respondents reporting emotional exhaustion (an element of burnout). The data presented support and validated a previous qualitative study, and highlighted key areas of concern requiring further study. A correlation between burnout and job dissatisfaction and intention to leave was identified; managers may want to consider encouraging role extension and good leadership qualities in treatment unit leaders to minimise the potential for burnout. PMID- 22253354 TI - Is there a role for free breathing non-contrast steady-state free precession renal MRA imaging for assessing live donors? A preliminary study. AB - OBJECTIVE: Accurate pre-operative evaluation of renal vascular anatomy is essential for successful renal harvest in live donor transplantation. Non contrast renal MR angiographic (MRA) techniques are potentially well suited to the screening of donors; however, their restricted imaging field of view (FOV) has previously been an important limitation. We sought to assess whether the addition of a large FOV balanced fast field echo (BFFE) steady-state free precession (SSFP) sequence to non-contrast SSFP MRA could overcome this problem. Comparison with contrast-enhanced MRA (CE MRA) and findings at surgery were performed. METHODS: 22 potential renal donors each underwent SSFP and CE MRA. 11 out of 22 potential donors subsequently underwent a donor nephrectomy. RESULTS: All images were diagnostic. Both SSFP MRA and CE MRA identified an equal number of arteries. Surgery confirmed two accessory renal arteries, both demonstrated with both imaging techniques. A third accessory vessel was identified with both techniques on a kidney contralateral to the donated organ. 6 out of 11 procured kidneys demonstrated early branch arteries at surgery, 5 out of 6 of which had been depicted on both SSFP and CE MRA. The median grading of image quality for main renal arteries was slightly better for CE MRA (p=0.048), but for accessory vessels it was better for SSFP MRA. CONCLUSION: This pilot study indicates that by combining free-breathing SSFP MRA with large-FOV bFFE images, an accurate depiction of renal vascular anatomy without the need for intravenous contrast administration can be obtained, as compared with surgical findings and CE MRA. PMID- 22253353 TI - Coronary CT angiography: current status and continuing challenges. AB - Coronary CT angiography has been increasingly used in the diagnosis of coronary artery disease owing to rapid technological developments, which are reflected in the improved spatial and temporal resolution of the images. High diagnostic accuracy has been achieved with multislice CT scanners (64 slice and higher), and in selected patients coronary CT angiography is regarded as a reliable alternative to invasive coronary angiography. With high-quality coronary CT imaging increasingly being performed, patients can benefit from an imaging modality that provides a rapid and accurate diagnosis while avoiding an invasive procedure. Despite the tremendous contributions of coronary CT angiography to cardiac imaging, study results reported in the literature should be interpreted with caution as there are some limitations existing within the study design or related to patient risk factors. In addition, some attention must be given to the potential health risks associated with the ionising radiation received during cardiac CT examinations. Radiation dose associated with coronary CT angiography has raised serious concerns in the literature, as the risk of developing malignancy is not negligible. Various dose-saving strategies have been implemented, with some of the strategies resulting in significant dose reduction. The aim of this review is to present an overview of the role of coronary CT angiography on cardiac imaging, with focus on coronary artery disease in terms of the diagnostic and prognostic value of coronary CT angiography. Various approaches for dose reduction commonly recommended in the literature are discussed. Limitations of coronary CT angiography are identified. Finally, future directions and challenges with the use of coronary CT angiography are highlighted. PMID- 22253355 TI - The effect of adaptive iterative dose reduction on image quality in 320-detector row CT coronary angiography. AB - OBJECTIVE: To evaluate the effect of adaptive iterative dose reduction (AIDR) on image noise and image quality as compared with standard filtered back projection (FBP) in 320-detector row CT coronary angiography (CTCA). METHODS: 50 patients (14 females, mean age 68 +/- 9 years) who underwent CTCA (100 kV or 120 kV, 400 580 mA) within a single heartbeat were enrolled. Studies were reconstructed with FBP and subsequently AIDR. Image noise, vessel contrast and contrast-to-noise ratio (CNR) in the coronary arteries were evaluated. Overall image quality for coronary arteries was assessed using a five-point scale (1, non-diagnostic; 5, excellent). RESULTS: All the examinations were performed in a single heartbeat. Image noise in the aorta was significantly lower in data sets reconstructed with AIDR than in those reconstructed with FBP (21.4 +/- 3.1 HU vs 36.9 +/- 4.5 HU; p<0.001). No significant differences were observed between FBP and AIDR for the mean vessel contrast (HU) in the proximal coronary arteries. Consequently, CNRs in the proximal coronary arteries were higher in the AIDR group than in the FBP group (p<0.001). The mean image quality score was improved by AIDR (3.75 +/- 0.38 vs 4.24 +/- 0.38; p<0.001). CONCLUSION: The use of AIDR reduces image noise and improves image quality in 320-detector row CTCA. PMID- 22253356 TI - Outcomes after stent implantation for the treatment of congenital and postoperative pulmonary vein stenosis in children. AB - BACKGROUND: Pulmonary vein stenosis (PVS) is a rare condition that can lead to worsening pulmonary hypertension and cardiac failure in children, and it is frequently lethal. Surgical and transcatheter approaches are acutely successful but restenosis is common and rapid. METHODS AND RESULTS: We reviewed outcomes among patients who underwent transcatheter pulmonary vein stent implantation for congenital or postoperative PVS at <18 years of age. A total of 74 pulmonary veins were stented with bare metal, drug-eluting, or covered stents in 47 patients. Primary diagnoses included PVS associated with anomalous venous return in 51%, PVS associated with other congenital cardiovascular defects in 36%, and congenital ("de novo") PVS in 13% of patients. Median age at the time of pulmonary vein stent implantation was 1.4 years. During a median cross-sectional follow-up of 3.1 years, 21 patients died. Estimated survival was 62+/-8% at 1 year and 50+/-8% at 5 years after pulmonary vein stent implantation. Stent placement acutely relieved focal obstruction in all veins. Of the 54 stents reexamined with catheterization, 32 underwent reintervention. Freedom from reintervention was 62+/-7% at 6 months and 42+/-7% at 1 year. Stent occlusion was documented in 9 cases and significant in-stent stenosis in 17 cases. Stent implantation diameter >=7 mm was associated with longer freedom from reintervention (hazard ratio, 0.32; P=0.015) and from significant in-stent stenosis (hazard ratio, 0.14; P=0.002). Major acute complications occurred in 5 cases. CONCLUSIONS: Transcatheter stent implantation can acutely relieve PVS in children, but reintervention is common. Larger stent lumen size at implantation is associated with longer stent patency and a lower risk of reintervention. PMID- 22253357 TI - Composition of target lesions by near-infrared spectroscopy in patients with acute coronary syndrome versus stable angina. AB - BACKGROUND: Whereas acute coronary syndromes (ACS) typically develop from the rupture of lipid core plaque (LCP), lesions causing stable angina are believed to be composed of fibrocalcific plaque. In this study, intracoronary near-infrared spectroscopy (NIRS) was used to determine the frequency of LCP at target and remote sites in patients with ACS versus those with stable angina. METHODS AND RESULTS: The study was performed in patients having >=1 target lesion identified by invasive angiography who also underwent NIRS before intervention. LCP was defined as a 2-mm segment on the NIRS block chemogram having a strong positive reading indicated by a bright-yellow color. Patients with ACS and those with stable angina were compared for the frequency of LCP at target and remote sites. Among 60 patients (46.7% with ACS) undergoing invasive angiography and NIRS, 68 target lesions were identified. Although target lesions in patients with ACS were more frequently composed of LCP than targets in patients with stable angina (84.4% versus 52.8%, P=0.004), approximately one half of target lesions in patients with stable angina contained LCP. LCPs anatomically remote from the target lesion were frequent in patients with ACS and less common in patients with stable angina (73.3% versus 17.6%, P=0.002). CONCLUSIONS: Target lesions responsible for ACS were frequently composed of LCP; in addition, LCPs often were found in remote, nontarget areas. Both target and remote LCPs were more common in patients with ACS than in those with stable angina. Approximately one half of target lesions in stable patients were also composed of LCP. PMID- 22253358 TI - Late positive remodeling and late lumen gain contribute to vascular restoration by a non-drug eluting bioresorbable scaffold: a four-year intravascular ultrasound study in normal porcine coronary arteries. AB - BACKGROUND: The interplay between mechanical dilatation, resorption, and arterial response following implantation of bioresorbable scaffolds is still poorly understood. METHODS AND RESULTS: Long-term geometric changes in porcine coronary arteries in relation to gradual degradation of bioresorbable scaffolds were assessed in comparison with bare metal stents (BMS). Intravascular ultrasound (IVUS)-derived lumen, outer stent/scaffold, and reference vessel areas were evaluated in 94 polymer scaffolds and 46 BMS at 5 days and 3, 6, 12, 18, 24, and 55 months, in addition to polymer scaffold radial crush strength and molecular weight (M(W)) at 3, 6, and 12 months. BMS outer stent area and lumen area remained constant through 55 months (P=0.05, but within 1 standard deviation of 100%, and P=0.58, respectively), while significant increases were exhibited by polymer-scaffolded vessels with the maximum late lumen gain at 24 months, paralleled by the outer scaffold area increase, and then remaining at that increased level at 55 months (P<0.01). By 12 months polymer scaffolds experienced significant reductions in radial strength and M(W), while the animals underwent the largest weight gain. At 3 months and beyond, the patency ratio (lumen area/reference vessel area) of BMS remained constant (0.71 to 0.85, P=0.49). In contrast, that of polymer scaffolds increased and approached 1 (P=0.13). CONCLUSIONS: Bioresorbable polymer scaffolds allow restoration of the treated segment's ability to remodel outward to achieve level lumen transition between reference vessel and scaffold-treated regions, a process mediated by animal growth and scaffold degradation. This also introduces a challenge to standard analyses of IVUS outcomes relying on constant stent diameters over time. PMID- 22253359 TI - Bare metal stent thrombosis and in-stent neoatherosclerosis. AB - BACKGROUND: Very late stent thrombosis (VLST) was reported to occur even in patients with bare metal stent (BMS) implantation, although the annual incidence of VLST after BMS was much lower than that after drug-eluting stent implantation. Pathophysiologic mechanisms of VLST after BMS implantation remain largely unknown. METHODS AND RESULTS: From September 2002 to February 2010, we identified 102 patients with definite stent thrombosis (ST) of BMS and 42 control patients with acute coronary syndrome (ACS) unrelated to ST who underwent thrombus aspiration with histopathologic evaluation. There were 40 patients with early ST (EST, within 30 days), 20 patients with late ST (LST, between 31-365 days), and 42 patients with VLST (>1 year). Evidence for fragments of atherosclerotic plaques, such as foamy macrophages, cholesterol crystals, and thin fibrous cap, was more commonly seen in patients with EST (23%) and VLST (31%), whereas these findings were rarely observed in patients with LST (10%). Atherosclerotic fragments were predominantly seen in patients who had EST within 7 days or VLST beyond 3 years. The aspirated thrombi harvested from patients with ST and those with ACS were histologically indistinguishable from each other. Eosinophils were very rarely observed. Plasma level of total cholesterol and triglyceride were significantly higher in VLST cases with atherosclerotic fragments as compared with those without. CONCLUSIONS: Fragments of atherosclerotic plaque were highly prevalent in patients with VLST beyond 3 years. Disruption of in-stent neoatherosclerosis could play an important role in the pathogenesis of VLST of BMS occurring beyond 3 years after implantation. PMID- 22253361 TI - Maternal attachment representations and initiation and duration of breastfeeding. AB - Despite the evidence that there are considerable benefits of breastfeeding, there are still gaps in understanding why many women have difficulties initiating and maintaining breastfeeding. In this prospective longitudinal study, the factors affecting the initiation and duration of breastfeeding were expanded to include attachment representations, which are known to influence health behaviors as well as one's ability to cope with stressful situations. Participants (n = 460) completed attachment and depression questionnaires during a prenatal clinic appointment, and in the postpartum period, mothers reported on their mood and breastfeeding behaviors. Consistent with attachment theory and previous research, women with attachment approach orientations were more likely to breastfeed, breastfeed longer, and continue breastfeeding when they experienced initial difficulties. The results of this study demonstrate that it is important to look beyond demographics to understand breastfeeding initiation and duration and provide further evidence that attachment representations influence health decisions. PMID- 22253360 TI - Cellular localization and biochemical analysis of mammalian CDC50A, a glycosylated beta-subunit for P4 ATPases. AB - CDC50 proteins are beta-subunits for P4 ATPases, which upon heterodimerization form a functional phospholipid translocation complex. Emerging evidence in mouse models and men links mutations in P4 ATPase genes with human disease. This study analyzed the tissue distribution and cellular localization of CDC50A, the most abundant and ubiquitously expressed CDC50 homologue in the mouse. The authors have raised antibodies that detect mouse and human CDC50A and studied CDC50A localization and glycosylation status in mouse liver cells. CDC50A is a terminal glycosylated glycoprotein and is expressed in hepatocytes and liver sinusoidal endothelial cells, where it resides in detergent-resistant membranes. In pancreas and stomach, CDC50A localized to secretory vesicles, whereas in the kidney, CDC50A localized to the apical region of proximal convoluted tubules of the cortex. In WIF-B9 cells, CDC50A partially costains with the trans-Golgi network. Data suggest that CDC50A is present as a fully glycosylated protein in vivo, which presumes interaction with distinct P4 ATPases. PMID- 22253362 TI - Author response: incident open-angle glaucoma and ocular perfusion pressure. PMID- 22253363 TI - Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. AB - CONTEXT: Between 1980 and 1999, the prevalence of adult obesity (body mass index [BMI] >=30) increased in the United States and the distribution of BMI changed. More recent data suggested a slowing or leveling off of these trends. OBJECTIVE: To estimate the prevalence of adult obesity from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) and compare adult obesity and the distribution of BMI with data from 1999-2008. DESIGN, SETTING, AND PARTICIPANTS: NHANES includes measured heights and weights for 5926 adult men and women from a nationally representative sample of the civilian noninstitutionalized US population in 2009-2010 and for 22,847 men and women in 1999-2008. MAIN OUTCOME MEASURES: The prevalence of obesity and mean BMI. RESULTS: In 2009-2010 the age adjusted mean BMI was 28.7 (95% CI, 28.3-29.1) for men and also 28.7 (95% CI, 28.4-29.0) for women. Median BMI was 27.8 (interquartile range [IQR], 24.7-31.7) for men and 27.3 (IQR, 23.3-32.7) for women. The age-adjusted prevalence of obesity was 35.5% (95% CI, 31.9%-39.2%) among adult men and 35.8% (95% CI, 34.0% 37.7%) among adult women. Over the 12-year period from 1999 through 2010, obesity showed no significant increase among women overall (age- and race-adjusted annual change in odds ratio [AOR], 1.01; 95% CI, 1.00-1.03; P = .07), but increases were statistically significant for non-Hispanic black women (P = .04) and Mexican American women (P = .046). For men, there was a significant linear trend (AOR, 1.04; 95% CI, 1.02-1.06; P < .001) over the 12-year period. For both men and women, the most recent 2 years (2009-2010) did not differ significantly (P = .08 for men and P = .24 for women) from the previous 6 years (2003-2008). Trends in BMI were similar to obesity trends. CONCLUSION: In 2009-2010, the prevalence of obesity was 35.5% among adult men and 35.8% among adult women, with no significant change compared with 2003-2008. PMID- 22253364 TI - Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. AB - CONTEXT: The prevalence of childhood obesity increased in the 1980s and 1990s but there were no significant changes in prevalence between 1999-2000 and 2007-2008 in the United States. OBJECTIVES: To present the most recent estimates of obesity prevalence in US children and adolescents for 2009-2010 and to investigate trends in obesity prevalence and body mass index (BMI) among children and adolescents between 1999-2000 and 2009-2010. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional analyses of a representative sample (N = 4111) of the US child and adolescent population (birth through 19 years of age) with measured heights and weights from the National Health and Nutrition Examination Survey 2009-2010. MAIN OUTCOME MEASURES: Prevalence of high weight-for-recumbent length (>=95th percentile on the growth charts) among infants and toddlers from birth to 2 years of age and obesity (BMI >=95th percentile of the BMI-for-age growth charts) among children and adolescents aged 2 through 19 years. Analyses of trends in obesity by sex and race/ethnicity, and analyses of trends in BMI within sex-specific age groups for 6 survey periods (1999-2000, 2001-2002, 2003-2004, 2005-2006, 2007 2008, and 2009-2010) over 12 years. RESULTS: In 2009-2010, 9.7% (95% CI, 7.6% 12.3%) of infants and toddlers had a high weight-for-recumbent length and 16.9% (95% CI, 15.4%-18.4%) of children and adolescents from 2 through 19 years of age were obese. There was no difference in obesity prevalence among males (P = .62) or females (P = .65) between 2007-2008 and 2009-2010. However, trend analyses over a 12-year period indicated a significant increase in obesity prevalence between 1999-2000 and 2009-2010 in males aged 2 through 19 years (odds ratio, 1.05; 95% CI, 1.01-1.10) but not in females (odds ratio, 1.02; 95% CI, 0.98-1.07) per 2-year survey cycle. There was a significant increase in BMI among adolescent males aged 12 through 19 years (P = .04) but not among any other age group or among females. CONCLUSION: In 2009-2010, the prevalence of obesity in children and adolescents was 16.9%; this was not changed compared with 2007-2008. PMID- 22253366 TI - Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. PMID- 22253367 TI - Population health, outcomes research, and prevention: example of the American Heart Association 2020 goals. PMID- 22253368 TI - Universal access to a percutaneous coronary intervention hospital: is it feasible or desirable? PMID- 22253369 TI - High risk percutaneous coronary intervention and intra-aortic balloon pumps: when is the safety net needed? PMID- 22253370 TI - Linking the National Cardiovascular Data Registry CathPCI Registry with Medicare claims data: validation of a longitudinal cohort of elderly patients undergoing cardiac catheterization. AB - BACKGROUND: The National Cardiovascular Data Registry CathPCI Registry was recently linked with longitudinal Centers for Medicare & Medicaid (CMS) claims data. The degree to which this linked cohort is representative of the overall CathPCI Registry and CMS PCI populations is unknown. METHODS AND RESULTS: CathPCI Registry records were linked to CMS inpatient claims using indirect identifiers. We examined the degree to which hospitals and patients in the linked cohort are representative of the elderly (>=65 years) CathPCI Registry and CMS populations. From 2004 to 2006, 1492 hospitals filed CMS PCI claims and 663 contributed CathPCI Registry data. Of these hospitals, 643 (97%) were linked across data sources. Compared with all CMS PCI hospitals, the linked data set contained fewer governmental, northeastern, southern, and low-volume (<200 beds) sites. Among CMS beneficiaries, 993,351 PCI procedures were performed, including 398,508 (40.1%) at centers in the linked database. Of these, 341,916 (86%) were linked to CathPCI Registry records. Linked and unlinked CMS patients had similar demographic and clinical features. In the CathPCI Registry database, 477,456 elderly patients underwent PCI, with 359,077 (75%) linked to CMS claims. Linked and unlinked National Cardiovascular Data Registry patients were similar, except for less commercial or health maintenance organization insurance in the linked cohort. CONCLUSIONS: By using deterministic matching strategies, a large and representative cohort with detailed clinical data from the CathPCI Registry and longitudinal follow-up from CMS claims has been created. PMID- 22253372 TI - Spiral shapes in heart and shells: when form and function do matter. PMID- 22253373 TI - Reparative surgery of the pulmonary autograft: experience with Ross reoperations. AB - OBJECTIVE: Autograft valve and root pathology is the leading cause of Ross procedure failure. To define risk and outcome of autograft valve/root repair at reoperation, a 17-year experience was analysed. METHODS: One hundred and thirty two consecutive late survivors underwent cross-sectional clinical and echocardiographic examination on average 10.8 +/- 14.7 years (range 0.4-17) after Ross procedure. Study endpoints were hospital and late morbidity, freedom from autograft reoperation, freedom from root/valve replacement and functional outcome after valve/root repair. RESULTS: Twenty-seven (20%) patients underwent 33 cardiac reoperations, the first on average 7.7 +/- 4.5 years (range 0.08-16.2) after Ross operation. Nineteen had undergone root replacement, 5 inclusion cylinder and 3 subcoronary grafting. Indication was root pathology in 17 (63%) patients and isolated valve in 10. Surgery consisted in valve repair/sparing in 17 patients and valve/root replacement in 10, with no hospital mortality. Freedom from any autograft valve/root reoperation was 74 +/- 5% at 15 years. No patient with valve/root replacement required second reoperation. Instead, 6/17 (35%) patients having autograft valve repair/sparing and followed for 4.2 +/- 2.9 years (range 0.3-10.8) required re-repair/AVR, while 11 present mild AI or less. Freedom from autograft valve/root replacement was 83 +/- 5% at 15 years. At multivariate analysis, predictors of reoperation were age at Ross (P = 0.002) and use of root technique (P = 0.049). Failure of autograft valve repair/sparing was associated with isolated valve pathology (P = 0.014) and earlier reoperation (P = 0.002). Pre-repair autograft insufficiency was significant at univariate analysis only (P = 0.01). CONCLUSIONS: Autograft reoperation carries negligible hospital risk. Pulmonary valve sparing or repair is feasible in half of patients with Ross failure. Concomitant root remodelling and absence of preoperative severe valve dysfunction predict successful and durable repair. PMID- 22253374 TI - Electrophysiological efficacy of Epicor high-intensity focused ultrasound. AB - OBJECTIVES: Clinical success of atrial fibrillation (AF) ablation depends on persistent blocking of electrical conduction across the ablation lines. Epicor high-intensity focused ultrasound (HIFU) ablation has been credited with a variable clinical efficacy. The aim of this work is to ascertain the electrophysiological (EP) efficacy of such lesions, by assessing pulmonary vein isolation (PVI) after open chest HIFU ablation, in the clinical setting. METHODS: Ten consecutive mitral patients (mean age: 57+/-10 years) with paroxysmal AF undergoing concomitant ablation with the Epicor ablation system (St. Jude Inc.(r), Minneapolis, MN, USA) were enrolled for EP assessment. During surgery, pairs of additional temporary wires were positioned on the right PVs (RPVs) and on the roof of the left atrium (RLA), before epicardial ablation. Exit block (no capture during PV pacing) of RPV and of RLA was assessed before, after ablating and immediately after closure of the chest, in order to check the correct positioning of the wires. EP assessment was repeated before discharge and at 3 weeks. RESULTS: Baseline RPV pacing threshold (PT) was 3.5+/-2 mA (range 1.5-8), of RLA 1.73+/-1.1 mA (range 0.7-4.3 mA). PVI was not reached any time after HIFU ablation. At the pre-discharge EP study, the absence of isolation was observed in all cases. At 3 weeks, the PTs were 6.8+/-5.8 mA on RPV (range 2-16) and 6.4+/ 5.3 mA (range 1-19) on RLA. All patients were discharged in sinus rhythm. CONCLUSIONS: PVI was not achieved after Epicor HIFU ablations, up to 3 weeks after surgery. PMID- 22253375 TI - Exciting view on coronary arteries in children with hypoplastic left heart syndrome: finding new answers helps asking better questions. PMID- 22253376 TI - The cover. The philosopher. PMID- 22253378 TI - Studies probe self-referral for imaging. PMID- 22253377 TI - Research yields new insights into mechanisms and treatment of pain. PMID- 22253379 TI - Poisonings top crashes for injury-related deaths. PMID- 22253384 TI - Same-day discharge after percutaneous coronary intervention. PMID- 22253385 TI - Same-day discharge after percutaneous coronary intervention. PMID- 22253386 TI - Mandatory HPV vaccination. PMID- 22253387 TI - Mandatory HPV vaccination. PMID- 22253388 TI - Mandatory HPV vaccination. PMID- 22253389 TI - Screening for osteoporosis in men receiving androgen deprivation therapy. PMID- 22253390 TI - Is universal pediatric lipid screening justified? PMID- 22253391 TI - Plain packaging of tobacco products in Australia: a novel regulation faces legal challenge. PMID- 22253392 TI - A piece of my mind. Lessons in elder care. PMID- 22253393 TI - Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. AB - CONTEXT: Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5 to 7 days prior to surgery to minimize bleeding. OBJECTIVE: To evaluate the use of cangrelor, an intravenous, reversible P2Y(12) platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG) surgery. DESIGN, SETTING, AND PATIENTS: Prospective, randomized, double-blind, placebo-controlled, multicenter trial, involving 210 patients with an acute coronary syndrome (ACS) or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n = 11) conducted between January 2009 and April 2011. Interventions Thienopyridines were stopped and patients were administered cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery. MAIN OUTCOME MEASURES: The primary efficacy end point was platelet reactivity (measured in P2Y(12) reaction units [PRUs]), assessed daily. The main safety end point was excessive CABG surgery-related bleeding. RESULTS: The dose of cangrelor determined in 10 patients in the open label stage was 0.75 MUg/kg per minute. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary end point, PRU <240; 98.8% (83 of 84) vs 19.0% (16 of 84); relative risk [RR], 5.2 [95% CI, 3.3-8.1] P < .001). Excessive CABG surgery-related bleeding occurred in 11.8% (12 of 102) vs 10.4% (10 of 96) in the cangrelor and placebo groups, respectively (RR, 1.1 [95% CI, 0.5-2.5] P = .763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor. CONCLUSIONS: Among patients who discontinue thienopyridine therapy prior to cardiac surgery, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00767507. PMID- 22253395 TI - Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. AB - CONTEXT: Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. OBJECTIVE: To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). MAIN OUTCOME MEASURES: The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. RESULTS: Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). CONCLUSION: In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology. PMID- 22253396 TI - Symptomatic in-hospital deep vein thrombosis and pulmonary embolism following hip and knee arthroplasty among patients receiving recommended prophylaxis: a systematic review. AB - CONTEXT: Symptomatic venous thromboembolism (VTE) after total or partial knee arthroplasty (TPKA) and after total or partial hip arthroplasty (TPHA) are proposed patient safety indicators, but its incidence prior to discharge is not defined. OBJECTIVE: To establish a literature-based estimate of symptomatic VTE event rates prior to hospital discharge in patients undergoing TPHA or TPKA. DATA SOURCES: Search of MEDLINE, EMBASE, and the Cochrane Library (1996 to 2011), supplemented by relevant articles. STUDY SELECTION: Reports of incidence of symptomatic postoperative pulmonary embolism or deep vein thrombosis (DVT) before hospital discharge in patients who received VTE prophylaxis with either a low molecular-weight heparin or a subcutaneous factor Xa inhibitor or oral direct inhibitor of factors Xa or IIa. DATA EXTRACTION AND SYNTHESIS: Meta-analysis of randomized clinical trials and observational studies that reported rates of postoperative symptomatic VTE in patients who received recommended VTE prophylaxis after undergoing TPHA or TPKA. Data were independently extracted by 2 analysts, and pooled incidence rates of VTE, DVT, and pulmonary embolism were estimated using random-effects models. RESULTS: The analysis included 44,844 cases provided by 47 studies. The pooled rates of symptomatic postoperative VTE before hospital discharge were 1.09% (95% CI, 0.85%-1.33%) for patients undergoing TPKA and 0.53% (95% CI, 0.35%-0.70%) for those undergoing TPHA. The pooled rates of symptomatic DVT were 0.63% (95% CI, 0.47%-0.78%) for knee arthroplasty and 0.26% (95% CI, 0.14%-0.37%) for hip arthroplasty. The pooled rates for pulmonary embolism were 0.27% (95% CI, 0.16%-0.38%) for knee arthroplasty and 0.14% (95% CI, 0.07%-0.21%) for hip arthroplasty. There was significant heterogeneity for the pooled incidence rates of symptomatic postoperative VTE in TPKA studies but less heterogeneity for DVT and pulmonary embolism in TPKA studies and for VTE, DVT, and pulmonary embolism in TPHA studies. CONCLUSION: Using current VTE prophylaxis, approximately 1 in 100 patients undergoing TPKA and approximately 1 in 200 patients undergoing TPHA develops symptomatic VTE prior to hospital discharge. PMID- 22253394 TI - Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. AB - CONTEXT: Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age. OBJECTIVE: To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age. DESIGN, SETTING, AND PARTICIPANTS: Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years. MAIN OUTCOME MEASURES: Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness. RESULTS: The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89). CONCLUSION: Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years. PMID- 22253397 TI - Neuroprotection for premature infants?: another perspective on caffeine. PMID- 22253398 TI - Estimating the incidence of symptomatic postoperative venous thromboembolism: the importance of perspective. PMID- 22253399 TI - JAMA patient page. Liver transplantation. PMID- 22253400 TI - Confirmatory testing in primary aldosteronism: extensive medication switching is not needed in all patients. AB - OBJECTIVE: Confirmatory testing of suspected primary aldosteronism (PA) requires an extensive medication switch that can be difficult for patients with severe complicated hypertension and/or refractory hypokalemia. For this reason, we investigated the effect of chronic antihypertensive medication on confirmatory testing results. To allow the results to be interpreted, the reproducibility of confirmatory testing was also evaluated. DESIGN AND METHODS: The study enrolled 114 individuals with suspected PA who underwent two confirmatory tests. The patients were divided into two groups. In Group A, both tests were performed on the guidelines-recommended therapy, i.e. not interfering with the renin angiotensin-aldosterone system. In Group B, the first test was performed on chronic therapy with the exclusion of thiazides, loop diuretics, and aldosterone antagonists; and the second test was performed on guidelines-recommended therapy. Saline infusion, preceded by oral sodium loading, was used to suppress aldosterone secretion. RESULTS: Agreement in the interpretation of the two confirmatory tests was observed in 84 and 66% of patients in Groups A and B respectively. For all 20 individuals in Group A who ever had end-test serum aldosterone levels >=240 pmol/l, aldosterone was concordantly nonsuppressible during the other test. Similarly, for all 16 individuals in Group B who had end test serum aldosterone levels >=240 pmol/l on modified chronic therapy, aldosterone remained nonsuppressible with guidelines-recommended therapy. CONCLUSION: Confirmatory testing performed while the patient is on chronic therapy without diuretics and aldosterone antagonists can confirm the diagnosis of PA, provided serum aldosterone remains markedly elevated at the end of saline infusion. PMID- 22253401 TI - Comment on Rogers et al. "Acute response of plasma markers of bone turnover to a single bout of resistance training or plyometrics". PMID- 22253403 TI - Does skeletal muscle fiber branching play a role in the inability of old EDL dystrophic muscle to resist large passive stretches? PMID- 22253405 TI - Classification of patients with acute heart failure syndromes in the emergency department. PMID- 22253406 TI - Heart failure prognostic models: why bother? PMID- 22253407 TI - Interventions to enhance adherence to medications in patients with heart failure: a systematic review. PMID- 22253408 TI - Mitochondrial A3243G mutation with manifestation of acute dilated cardiomyopathy. PMID- 22253409 TI - Letter by Pohjoismaki regarding article, "Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease". PMID- 22253412 TI - Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer. AB - PURPOSE: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). EXPERIMENTAL DESIGN: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. RESULTS: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%-100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median K(trans) values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median K(trans) values that decreased during therapy. CONCLUSIONS: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure. PMID- 22253411 TI - Subcellular structures and function of myocytes impaired during heart failure are restored by cardiac resynchronization therapy. AB - RATIONALE: Cardiac resynchronization therapy (CRT) is an established treatment for patients with chronic heart failure. However, CRT-associated structural and functional remodeling at cellular and subcellular levels is only partly understood. OBJECTIVE: To investigate the effects of CRT on subcellular structures and protein distributions associated with excitation-contraction coupling of ventricular cardiomyocytes. METHODS AND RESULTS: Our studies revealed remodeling of the transverse tubular system (t-system) and the spatial association of ryanodine receptor (RyR) clusters in a canine model of dyssynchronous heart failure (DHF). We did not find this remodeling in a synchronous heart failure model based on atrial tachypacing. Remodeling in DHF ranged from minor alterations in anterior left ventricular myocytes to nearly complete loss of the t-system and dissociation of RyRs from sarcolemmal structures in lateral cells. After CRT, we found a remarkable and almost complete reverse remodeling of these structures despite persistent left ventricular dysfunction. Studies of whole-cell Ca(2+) transients showed that the structural remodeling and restoration were accompanied with remodeling and restoration of Ca(2+) signaling. CONCLUSIONS: DHF is associated with regional remodeling of the t-system. Myocytes undergo substantial structural and functional restoration after only 3 weeks of CRT. The finding suggests that t-system status can provide an early marker of the success of this therapy. The results could also guide us to an understanding of the loss and remodeling of proteins associated with the t system. The steep relationship between free Ca(2+) and contraction suggests that some restoration of Ca(2+) release units will have a disproportionately large effect on contractility. PMID- 22253413 TI - Here, there be dragons: charting autophagy-related alterations in human tumors. AB - Macroautophagy (or autophagy) is a catabolic cellular process that is both homeostatic and stress adaptive. Normal cells rely on basal levels of autophagy to maintain cellular integrity (via turnover of long-lived proteins and damaged organelles) and increased levels of autophagy to buoy cell survival during various metabolic stresses (via nutrient and energy provision through lysosomal degradation of cytoplasmic components). Autophagy can function in both tumor suppression and tumor progression, and is under investigation in clinical trials as a novel target for anticancer therapy. However, its role in cancer pathogenesis has yet to be fully explored. In particular, it remains unknown whether in vitro observations will be applicable to human cancer patients. Another outstanding question is whether there exists tumor-specific selection for alterations in autophagy function. In this review, we survey reported mutations in autophagy genes and key autophagy regulators identified in human tumor samples and summarize the literature regarding expression levels of autophagy genes and proteins in various cancer tissues. Although it is too early to draw inferences from this collection of in vivo studies of autophagy-related alterations in human cancers, their results highlight the challenges that must be overcome before we can accurately assess the scope of autophagy's predicted role in tumorigenesis. PMID- 22253414 TI - Antiapolipoprotein A-1 IgG chronotropic effects require nongenomic action of aldosterone on L-type calcium channels. AB - Autoantibodies to apolipoprotein A-1 (antiapoA-1 IgG) have been shown to be associated with higher resting heart rate and morbidity in myocardial infarction patients and to behave as a chronotropic agent in the presence of aldosterone on isolated neonatal rat ventricular cardiomyocytes (NRVC). We aimed at identifying the pathways accounting for this aldosterone-dependent antiapoA-1 IgG-positive chronotropic effect on NRVC. The rate of regular spontaneous contractions was determined on NRVC in the presence of different steroid hormones and antagonists. AntiapoA-1 IgG chronotropic response was maximal within 20 min and observed only in aldosterone-pretreated cells but not in those exposed to other steroids. The positive antiapoA-1 IgG chronotropic effect was already significant after 5 min aldosterone preincubation, was dependent on 3-kinase and protein kinase A activities, was not inhibited by actinomycin D, and was fully abrogated by eplerenone (but not by spironolactone), demonstrating the dependence on a nongenomic action of aldosterone elicited through the mineralocorticoid receptor (MR). Under oxidative conditions (but not under normal redox state), corticosterone mimicked the permissive action of aldosterone on the antiapoA-1 IgG chronotropic response. Pharmacological and patch-clamp studies identified L type calcium channels as crucial effectors of antiapoA-1 IgG chronotropic action, involving two converging pathways that increase the channel activity. The first one involves the rapid, nongenomic activation of the phosphatidylinositol 3 kinase enzyme by MR, and the second one requires a constitutive basal protein kinase A activity. In conclusion, our results indicate that, on NRVC, the aldosterone-dependent chronotropic effects of antiapoA-1 IgG involve the nongenomic activation of L-type calcium channels. PMID- 22253415 TI - Brown fat lipoatrophy and increased visceral adiposity through a concerted adipocytokines overexpression induces vascular insulin resistance and dysfunction. AB - In this study, we analyzed the role played by concerted expression of adipocytokines associated with brown fat lipoatrophy and increased visceral adiposity on triggering vascular insulin resistance and dysfunction in brown adipose tissue (BAT) insulin receptor knockout (BATIRKO) mice. In addition, we assessed whether vascular insulin resistance may aggravate vascular damage. The 52-wk-old, but not 33-wk-old, BATIRKO mice had a significant decrease of BAT mass associated with a significant increase of visceral white adipose tissue (WAT) mass, without changes in body weight. Brown fat lipoatrophy and increased visceral adiposity enhanced the concerted expression of adipocytokines (TNF alpha, leptin, and plasminogen activator inhibitor 1) and nuclear factor-kappaB binding activity in BAT and visceral WAT, mainly in the gonadal depot, and aorta. Although those mice showed insulin sensitivity in the liver and skeletal muscle, insulin signaling in WAT (gonadal depot) and aorta was markedly impaired. Treatment with anti-TNF-alpha antibody impaired the inflammatory activity in visceral adipose tissue, attenuated insulin resistance in WAT and aorta and induced glucose tolerance. Finally, 52-wk-old BATIRKO mice showed vascular dysfunction, macrophage infiltration, oxidative stress, and a significant increase of gene markers of endothelial activation and inflammation, the latter effect being totally reverted by anti-TNF-alpha antibody treatment. Our results suggest that brown fat lipoatrophy and increased visceral adiposity through the concerted overexpression of cytoadipokines induces nuclear factor-kappaB-mediated inflammatory signaling, vascular insulin resistance, and vascular dysfunction. Inhibition of inflammatory activity by anti-TNF-alpha antibody treatment attenuates vascular insulin resistance and impairs gene expression of vascular dysfunction markers. PMID- 22253416 TI - Uncovering novel reproductive defects in neurokinin B receptor null mice: closing the gap between mice and men. AB - Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3(-/-) mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, and fertility. Tacr3( /-) mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3(-/-) males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3(-/-) females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3(-/-) females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3(-/-) females achieved fertility when mated. However, Tacr3(-/-) females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release. PMID- 22253417 TI - Angiotensin II-dependent transcriptional activation of human steroidogenic acute regulatory protein gene by a 25-kDa cAMP-responsive element modulator protein isoform and Yin Yang 1. AB - Transcriptional activation of the steroidogenic acute regulatory protein (STAR) gene is a critical component in the angiotensin II (Ang II)-dependent increase in aldosterone biosynthesis in the adrenal gland. The purpose of this study was to define the molecular mechanisms that mediate the Ang II-dependent increase in STARD1 gene (STAR) expression in H295R human adrenocortical cells. Mutational analysis of the STAR proximal promoter revealed that a nonconsensus cAMP responsive element located at -78 bp relative to the transcription start site ( 78CRE) is required for the Ang II-stimulated STAR reporter gene activity. DNA immunoaffinity chromatography identified a 25-kDa cAMP-responsive element modulator isoform and Yin Yang 1 (YY1) as -78CRE DNA-binding proteins, and Ang II treatment of H295R cells increased expression of that 25-kDa CREM isoform. Small interfering RNA silencing of CREM and YY1 attenuated the Ang II-dependent increases in STAR reporter gene activity and STAR mRNA levels. Conversely, overexpression of CREM and YY1 in COS-1 cells resulted in transactivation of STAR reporter gene activity. Chromatin immunoprecipitation analysis demonstrated recruitment of CREM and YY1 to the STAR promoter along with increased association of the coactivator cAMP response element-binding protein-binding protein (CBP) and increased phosphorylated RNA polymerase II after Ang II treatment. Together our data reveal that the Ang II-stimulated increase in STAR expression in H295R cells requires 25 kDa CREM and YY1. The recruitment of these transcription factors to the STAR proximal promoter results in association of CBP and activation of RNA polymerase II leading to increased STAR transcription. PMID- 22253418 TI - Activation of southern white rhinoceros (Ceratotherium simum simum) estrogen receptors by phytoestrogens: potential role in the reproductive failure of captive-born females? AB - The captive southern white rhinoceros (SWR; Ceratotherium simum simum) population serves as an important genetic reservoir critical to the conservation of this vulnerable species. Unfortunately, captive populations are declining due to the poor reproductive success of captive-born females. Captive female SWR exhibit reproductive problems suggested to result from continual ovarian follicular activity and prolonged exposure to endogenous estrogen. However, we investigated the potential role of exogenous dietary phytoestrogens in the reproductive failure of SWR by cloning and characterizing in vitro phytoestrogen binding and activation of recombinant SWR estrogen receptors (ESR). We compared those characteristics with recombinant greater one-horned rhinoceros (GOHR; Rhinoceros unicornis) ESR, a species that receives similar captive diets yet reproduces relatively well. Our results indicate that phytoestrogens bind rhino ESR in a manner similar to other vertebrate species, but there are no differences found in phytoestrogen binding affinity of SWR ESR compared with GOHR ESR. However, species-specific differences in ESR activation by phytoestrogens were detected. The phytoestrogen coumestrol stimulated greater maximal activation of SWR ESR1 than GOHR ESR1. SWR ESR2 were also more sensitive to phytoestrogens and were activated to a greater extent by both coumestrol and daidzein. The concentrations in which significant differences in ESR activation occurred (10(-7) to 10(-5) m) are consistent with circulating concentrations measured in other vertebrate species. Taken together, these findings suggest that phytoestrogens potentially pose a risk to the reproductive health of captive SWR. However, additional studies are needed to further clarify the physiological role of dietary phytoestrogens in the reduced fertility of this species. PMID- 22253419 TI - Peroxisome proliferator-activated receptors-alpha and -gamma, and cAMP-mediated pathways, control retinol-binding protein-4 gene expression in brown adipose tissue. AB - Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor (PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPARgamma and PPARalpha induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPARalpha-null brown adipocytes or in the presence of inhibitors of PPARgamma and PPARalpha. PPARgamma and norepinephrine can also induce the RBP4 gene in white adipocytes, and overexpression of PPARalpha confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPARalpha, and PPARgamma. This is mediated by a PPAR-responsive element capable of binding PPARalpha and PPARgamma and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPARgamma-coactivator-1 alpha, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPARgamma- and PPARalpha-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPARgamma coactivator-1-alpha coactivation of PPAR signaling. PMID- 22253420 TI - Early postnatal hyperalimentation impairs renal function via SOCS-3 mediated renal postreceptor leptin resistance. AB - Early postnatal hyperalimentation has long-term implications for obesity and developing renal disease. Suppressor of cytokine signaling (SOCS) 3 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and ERK1/2 and thereby plays a pivotal role in mediating leptin resistance. In addition, SOCS-3 is induced by both leptin and inflammatory cytokines. However, little is known about the intrinsic-renal leptin synthesis and function. Therefore, this study aimed to elucidate the implications of early postnatal hyperalimentation on renal function and on the intrinsic-renal leptin signaling. Early postnatal hyperalimentation in Wistar rats during lactation was induced by litter size reduction at birth (LSR) either to LSR10 or LSR6, compared with home cage control male rats. Assessment of renal function at postnatal day 70 revealed decreased glomerular filtration rate and proteinuria after LSR6. In line with this impairment of renal function, renal inflammation and expression as well as deposition of extracellular matrix molecules, such as collagen I, were increased. Furthermore, renal expression of leptin and IL-6 was up-regulated subsequent to LSR6. Interestingly, the phosphorylation of Stat3 and ERK1/2 in the kidney, however, was decreased after LSR6, indicating postreceptor leptin resistance. In accordance, neuropeptide Y (NPY) gene expression was down-regulated; moreover, SOCS-3 protein expression, a mediator of postreceptor leptin resistance, was strongly elevated and colocalized with NPY. Thus, our findings not only demonstrate impaired renal function and profibrotic processes but also provide compelling evidence of a SOCS-3-mediated intrinsic renal leptin resistance and concomitant up-regulated NPY expression as an underlying mechanism. PMID- 22253421 TI - Phylogenetic comparisons implicate sex hormone-binding globulin in "masculinization" of the female spotted hyena (Crocuta crocuta). AB - Exposures to sex steroids during fetal development are thought to contribute to the unique urogenital anatomy and social dominance of the female spotted hyena: overt phenotypes not shared by other hyenids (i.e. striped hyena, brown hyena, and aardwolf). Because both androgens and estrogens influence development of genitalia and behavior, and because plasma SHBG regulates their access to tissues, we compared the Shbg gene sequences, structures, and steroid-binding properties in the four extant hyenids. We found the hyenid Shbg genes (>95% identical) and mature protein sequences (98% identical) are highly conserved. As in other mammals, the hyenid SHBG all bind 5alpha-dihydrotestosterone with high affinity (K(d) = 0.62-1.47 nm), but they also bind estrone and dehydroepiandrosterone with similarly high affinity, and this unusual property was attributed to specific amino acids within their SHBG steroid-binding sites. Phylogenetic comparisons also indicated that the spotted hyena SHBG precursor uniquely lacks two leucine residues and has a L15W substitution within its secretion signal polypeptide, the reduced size and hydrophobicity of which markedly decreases the production of SHBG and may therefore explain why serum SHBG concentrations in male and female spotted hyenas are approximately five times lower than in other hyenids. This is important because low plasma SHBG concentrations in spotted hyenas will increase exposure to biologically active androgens and estrogen as well as to their precursors (dehydroepiandrosterone and estrone), which may contribute to the masculinized external genitalia of female spotted hyenas and to female social dominance over males. PMID- 22253422 TI - Molecular characterization and biological function of neuroendocrine regulatory peptide-3 in the rat. AB - Neuroendocrine regulatory peptide (NERP)-3, derived from the neurosecretory protein VGF (non-aconymic), is a new biologically active peptide identified through peptidomic analysis of the peptides secreted by an endocrine cell line. Using a specific antibody recognizing the C-terminal region of NERP-3, immunoreactive (ir)-NERP-3 was identified in acid extracts of rat brain and gut as a 30-residue NERP-3 with N-terminal pyroglutamylation. Assessed by radioimmunoassay, ir-NERP-3 was more abundant in the brain, including the posterior pituitary (PP), than in the gut. Immunohistochemistry demonstrated that ir-NERP-3 was significantly increased in the suprachiasmatic nucleus, the magnocellular division of the paraventricular nucleus, and the external layer of the median eminence, but not in the supraoptic nucleus, after dehydration. The immunoreactivity was, however, markedly decreased in all of these locations after chronic salt loading. Intracerebroventricular administration of NERP-3 in conscious rats induced Fos expression in a subset of arginine vasopressin (AVP) containing neurons in the supraoptic nucleus and the magnocellular division of the paraventricular nucleus. On in vitro isolated rat PP preparations, NERP-3 caused a significant AVP release in a dose-related manner, suggesting that NERP-3 in the PP could be an autocrine activator of AVP release. Taken together, the present results suggest that NERP-3 in the hypothalamo-neurohypophyseal system may be involved in the regulation of body fluid balance. PMID- 22253423 TI - Improved insulin sensitivity after long-term treatment with AT1 blockers is not associated with PPARgamma target gene regulation. AB - In both cell culture experiments and in vivo studies, a number of angiotensin II type 1 (AT(1)) receptor antagonists activated the peroxisome proliferator activated receptor-gamma (PPARgamma). This mechanism has been discussed to be, at least in part, responsible for the improvement in glucose metabolism observed in animal studies and clinical trials. To investigate whether the PPARgamma dependent mechanism may represent a valid target for chronic therapy, spontaneously hypertensive rats (SHR) were fed either with a cafeteria diet (CD) or standard chow. CD-fed SHR were simultaneously treated with either telmisartan (TEL; 8 mg/kg(body weight). d) or candesartan (CAND; 10 mg/kg(body weight). d) for 3 months because TEL, but not CAND, has been demonstrated to be a strong activator of PPARgamma. After 3 months, chow- and CD-fed controls were hypertensive, whereas TEL and CAND treatment resulted in normalized blood pressures in SHR. Body weight and the amount of abdominal fat (determined by magnetic resonance imaging) were higher in CD- than in chow-fed SHR. After TEL or CAND, body weight, abdominal fat quantity, and adipocyte size returned to normal. In glucose tolerance tests, the glucose responses were comparable in the TEL- and CAND-treated SHR and obese controls, whereas the insulin response was almost halved by AT(1) blockade. Expression of PPARgamma target genes aP2, FAT CD36, FASn, and PEPCK remained unaltered at the protein level in visceral fat after TEL and CAND compared with the CD-fed controls. Because the expression of examined PPARgamma target genes was not affected, we concluded that improved insulin sensitivity after long-term treatment with AT(1) blockers was not related to a PPARgamma-dependent mechanism. PMID- 22253424 TI - Disruption of the murine Glp2r impairs Paneth cell function and increases susceptibility to small bowel enteritis. AB - Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytoprotective responses in the gastrointestinal mucosa and ameliorates experimental small and large bowel gut injury. Nevertheless, the essential physiological role(s) of the endogenous GLP-2R remain poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response to mucosal injury, and host-bacterial interactions in Glp2r(-/-) and littermate control Glp2r(+/+) mice. Glp2r(-/-) mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r(-/-) mice failed to up regulate intestinal epithelial c-fos expression in response to acute GLP-2 administration and do not exhibit changes in small bowel conductance or small or large bowel growth after administration of GLP-2R agonists. The crypt and villus compartment and the numbers and localization of Paneth, enteroendocrine, and goblet cells were comparable in Glp2r(+/+) vs. Glp2r(-/-) mice. Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r(-/-) mice exhibited significantly increased morbidity and mortality and increased bacterial translocation after induction of enteritis with indomethacin and enhanced mucosal injury in response to irinotecan. Moreover, bacterial colonization of the small bowel was significantly increased, expression of Paneth cell antimicrobial gene products was reduced, and mucosal bactericidal activity was impaired in Glp2r(-/ ) mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r(-/-) mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel. PMID- 22253425 TI - Antiapoptotic actions of exendin-4 against hypoxia and cytokines are augmented by CREB. AB - Islets isolated from cadaveric donor pancreas are functionally viable and can be transplanted in diabetic patients to reduce insulin requirements. This therapeutic approach is less efficient because a significant portion of functional islets is lost due to oxidative stress, inflammation, and hypoxia. Exendin-4, a glucagon-like peptide-1 receptor agonist, is known to improve islet survival through activation of the transcription factor, cAMP response element binding protein (CREB). However, isolated human islets are exposed to several stresses known to down-regulate CREB. The objective of the present study was to determine whether the cytoprotective actions of exendin-4 in human islets can be augmented by increasing the levels of CREB. Simulation of ischemia/reperfusion injury and exposure to hypoxic conditions in cultured human islets resulted in decreased CREB activation and induction of apoptosis. Islets were transduced with adenoviral CREB followed by exposure to exendin-4 as a strategy for improving their survival. This combination increased the levels of several proteins needed for beta-cell survival and function, including insulin receptor substrate-2, Bcl 2, and baculoviral IAP repeat-containing 3, and suppressed the expression of proapoptotic and inflammatory genes. A combination of CREB and exendin-4 exerted enhanced antiapoptotic action in cultured islets against hypoxia and cytokines. More significantly, transplantation of human islets transduced with adenoviral CREB and treated with exendin-4 showed improved glycemic control over a 30-d period in diabetic athymic nude mice. These observations have significant implications in the therapeutic potential of exendin-4 and CREB in the islet transplantation setting as well as in preserving beta-cell mass of diabetic patients. PMID- 22253426 TI - Expression and regulation of human fetal-specific CYP3A7 in mice. AB - CYP3A7 is the predominant cytochrome P450 (CYP) expressed in human fetal liver, accounting for 30-50% of the total CYP in fetal liver and 87-100% of total fetal hepatic CYP3A content. However, the lack of a rodent model limits the investigation of CYP3A7 regulation and function. Hence, double-transgenic mice expressing human pregnane X receptor (PXR) and CYP3A4/7 (Tg3A4/7-hPXR) were used to investigate the regulation and function of CYP3A7. Expression of CYP3A7 was monitored in mice that ranged in age from 14.5-d-old embryos to 8.5-d-old newborns; expression of CYP3A7 mRNA was increased before birth in the embryos and decreased after birth in the newborns. This is consistent with the observed developmental regulation of CYP3A7 protein levels and CYP3A7-mediated dehydroepiandrosterone 16alpha-hydroxylase activities. This developmental flux is also in agreement with previous studies that have investigated the expression of CYP3A7 in developing human liver. The regulation of CYP3A7 was further studied using hepatoblasts from the Tg3A4/7-hPXR mice. Glucocorticoids, including dexamethasone, cortisol, corticosterone, and cortisone all induced the expression of CYP3A7 mRNA, whereas rifampicin, an activator of PXR and an inducer of CYP3A4 in adult liver, had no effect on CYP3A7 expression. Cell-based promoter luciferase and chromatin immunoprecipitation assays further confirmed glucocorticoid receptor-mediated control of the CYP3A7 promoter. These findings indicate that CYP3A7 is developmentally regulated in mouse liver primarily by glucocorticoids through the glucocorticoid receptor. The Tg3A4/7-hPXR mouse model could therefore potentially serve as a tool for investigating CYP3A7 regulation and function. PMID- 22253427 TI - Minireview: Epigenetics of obesity and diabetes in humans. AB - Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation. PMID- 22253428 TI - Physiological responses to acute psychological stress are reduced by the PPARgamma agonist rosiglitazone. AB - Physiological reactions to psychological stress are positively associated with several important chronic conditions including cardiovascular and neurodegenerative diseases and are linked to increased mortality. As such, the identification of cellular and molecular pathways that act to reduce stress responding may represent important targets for therapeutic intervention. Here we report that acute treatment with the peroxisome-proliferator activated receptor gamma (PPARgamma) agonist rosiglitazone (RSG) blunts systemic responses to acute psychological stress in rats. Rats that had previously received oral RSG for 5 d exhibited a 40% reduction in the initial heart rate response to an acute restraint stress, compared with vehicle-treated controls, suggesting that increased PPARgamma signaling blunts the acute autonomic response to stress. Rats previously treated with RSG likewise had a blunted hormonal response to this stressor, exhibiting a 30% reduction in peak corticosterone levels compared with controls. Moreover, stress-induced expression of c-Fos, a marker of early neuronal activation, was similarly reduced in the paraventricular hypothalamus, a key site for brain stress integration, facilitating both autonomic and hypothalamic-pituitary-adrenocortical responses to stress. Taken as a whole, these data suggest that PPARgamma stimulation potently inhibits physiological responses to psychological stress, prescribing a novel role for PPARgamma signaling in the regulation of brain stress integration. PMID- 22253429 TI - Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU). AB - Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy. PMID- 22253430 TI - Quantitative measurement of full-length and C-terminal proteolyzed RBP4 in serum of normal and insulin-resistant humans using a novel mass spectrometry immunoassay. AB - Serum retinol-binding protein 4 (RBP4) levels are increased in insulin-resistant humans and correlate with severity of insulin resistance in metabolic syndrome. Quantitative Western blotting (qWestern) has been the most accurate method for serum RBP4 measurements, but qWestern is technically complex and labor intensive. The lack of a reliable, high-throughput method for RBP4 measurements has resulted in variability in findings in insulin-resistant humans. Many commonly used ELISAs have limited dynamic range. Neither the current ELISAs nor qWestern distinguish among full-length and carboxyl terminus proteolyzed forms of circulating RBP4 that are altered in different medical conditions. Here, we report the development of a novel quantitative mass spectrometry immunoaffinity assay (qMSIA) to measure full-length and proteolyzed forms of RBP4. qMSIA and qWestern of RBP4 were performed in identical serum aliquots from insulin-sensitive/normoglycemic or insulin-resistant humans with impaired glucose tolerance or type 2 diabetes. Total RBP4 qMSIA measurements were highly similar to qWestern and correlated equally well with clinical severity of insulin resistance (assessed by clamp glucose disposal rate, r = -0.74), hemoglobin A1c (r = 0.63), triglyceride/high density lipoprotein (r = 0.55), waist/hip (r = 0.61), and systolic blood pressure (r = 0.53, all P < 0.001). Proteolyzed forms of RBP4 accounted for up to 50% of total RBP4 in insulin-resistant subjects, and des(Leu)-RBP4 (cleavage of last leucine) correlated highly with insulin resistance (assessed by glucose disposal rate, r = -0.69). In multiple regression analysis, insulin resistance but not glomerular filtration rate was the strongest, independent predictor of serum RBP4 levels. Thus, qMSIA provides a novel tool for accurately measuring serum RBP4 levels as a biomarker for severity of insulin resistance and risk for type 2 diabetes and metabolic syndrome. PMID- 22253431 TI - Thyroid hormone receptors control developmental maturation of the middle ear and the size of the ossicular bones. AB - Thyroid hormone is critical for auditory development and has well-known actions in the inner ear. However, less is known of thyroid hormone functions in the middle ear, which contains the ossicles (malleus, incus, stapes) that relay mechanical sound vibrations from the outer ear to the inner ear. During the later stages of middle ear development, prior to the onset of hearing, middle ear cavitation occurs, involving clearance of mesenchyme from the middle ear cavity while the immature cartilaginous ossicles attain appropriate size and ossify. Using in situ hybridization, we detected expression of Thra and Thrb genes encoding thyroid hormone receptors alpha1 and beta (TRalpha1 and TRbeta, respectively) in the immature ossicles, surrounding mesenchyme and tympanic membrane in the mouse. Thra(+/PV) mice that express a dominant-negative TRalpha1 protein exhibited deafness with elevated auditory thresholds and a range of middle ear abnormalities including chronic persistence of mesenchyme in the middle ear into adulthood, markedly enlarged ossicles, and delayed ossification of the ossicles. Congenitally hypothyroid Tshr(-/-) mice and TR-deficient Thra1( /-);Thrb(-/-) mice displayed similar abnormalities. These findings demonstrate that middle ear maturation is TR dependent and suggest that the middle ear is a sensitive target for thyroid hormone in development. PMID- 22253432 TI - Minireview: Epigenetic programming of diabetes and obesity: animal models. AB - A growing body of evidence suggests that the intrauterine (IU) environment has a significant and lasting effect on the long-term health of the growing fetus and the development of metabolic disease in later life as put forth in the fetal origins of disease hypothesis. Metabolic diseases have been associated with alterations in the epigenome that occur without changes in the DNA sequence, such as cytosine methylation of DNA, histone posttranslational modifications, and micro-RNA. Animal models of epigenetic modifications secondary to an altered IU milieu are an invaluable tool to study the mechanisms that determine the development of metabolic diseases, such as diabetes and obesity. Rodent and nonlitter bearing animals are good models for the study of disease, because they have similar embryology, anatomy, and physiology to humans. Thus, it is feasible to monitor and modify the IU environment of animal models in order to gain insight into the molecular basis of human metabolic disease pathogenesis. In this review, the database of PubMed was searched for articles published between 1999 and 2011. Key words included epigenetic modifications, IU growth retardation, small for gestational age, animal models, metabolic disease, and obesity. The inclusion criteria used to select studies included animal models of epigenetic modifications during fetal and neonatal development associated with adult metabolic syndrome. Experimental manipulations included: changes in the nutritional status of the pregnant female (calorie-restricted, high-fat, or low protein diets during pregnancy), as well as the father; interference with placenta function, or uterine blood flow, environmental toxin exposure during pregnancy, as well as dietary modifications during the neonatal (lactation) as well as pubertal period. This review article is focused solely on studies in animal models that demonstrate epigenetic changes that are correlated with manifestation of metabolic disease, including diabetes and/or obesity. PMID- 22253433 TI - miR-30 family members negatively regulate osteoblast differentiation. AB - miRNAs are endogenously expressed 18- to 25-nucleotide RNAs that regulate gene expression through translational repression by binding to a target mRNA. Recently, it has been indicated that miRNAs are closely related to osteogenesis. Our previous data suggested that miR-30 family members might be important regulators during the biomineralization process. However, whether and how they modulate osteogenic differentiation have not been explored. In this study, we demonstrated that miR-30 family members negatively regulate BMP-2-induced osteoblast differentiation by targeting Smad1 and Runx2. Evidentially, overexpression of miR-30 family members led to a decrease of alkaline phosphatase activity, whereas knockdown of them increased the activity. Then bioinformatic analysis identified potential target sites of the miR-30 family located in the 3' untranslated regions of Smad1 and Runx2. Western blot analysis and quantitative RT-PCR assays demonstrated that miR-30 family members inhibit Smad1 gene expression on the basis of repressing its translation. Furthermore, dual luciferase reporter assays confirmed that Smad1 is a direct target of miR-30 family members. Rescue experiments that overexpress Smad1 and Runx2 significantly eliminated the inhibitory effect of miR-30 on osteogenic differentiation and provided strong evidence that miR-30 mediates the inhibition of osteogenesis by targeting Smad1 and Runx2. Also, the inhibitory effects of the miR-30 family were validated in mouse bone marrow mesenchymal stem cells. Therefore, our study uncovered that miR-30 family members are key negative regulators of BMP-2 mediated osteogenic differentiation. PMID- 22253434 TI - Kinetic equivalence of transmembrane pH and electrical potential differences in ATP synthesis. AB - ATP synthase is the key player of Mitchell's chemiosmotic theory, converting the energy of transmembrane proton flow into the high energy bond between ADP and phosphate. The proton motive force that drives this reaction consists of two components, the pH difference (DeltapH) across the membrane and transmembrane electrical potential (Deltapsi). The two are considered thermodynamically equivalent, but kinetic equivalence in the actual ATP synthesis is not warranted, and previous experimental results vary. Here, we show that with the thermophilic Bacillus PS3 ATP synthase that lacks an inhibitory domain of the epsilon subunit, DeltapH imposed by acid-base transition and Deltapsi produced by valinomycin mediated K(+) diffusion potential contribute equally to the rate of ATP synthesis within the experimental range examined (DeltapH -0.3 to 2.2, Deltapsi -30 to 140 mV, pH around the catalytic domain 8.0). Either DeltapH or Deltapsi alone can drive synthesis, even when the other slightly opposes. Deltapsi was estimated from the Nernst equation, which appeared valid down to 1 mm K(+) inside the proteoliposomes, due to careful removal of K(+) from the lipid. PMID- 22253435 TI - Mutual information analysis reveals coevolving residues in Tat that compensate for two distinct functions in HIV-1 gene expression. AB - Viral genomes are continually subjected to mutations, and functionally deleterious ones can be rescued by reversion or additional mutations that restore fitness. The error prone nature of HIV-1 replication has resulted in highly diverse viral sequences, and it is not clear how viral proteins such as Tat, which plays a critical role in viral gene expression and replication, retain their complex functions. Although several important amino acid positions in Tat are conserved, we hypothesized that it may also harbor functionally important residues that may not be individually conserved yet appear as correlated pairs, whose analysis could yield new mechanistic insights into Tat function and evolution. To identify such sites, we combined mutual information analysis and experimentation to identify coevolving positions and found that residues 35 and 39 are strongly correlated. Mutation of either residue of this pair into amino acids that appear in numerous viral isolates yields a defective virus; however, simultaneous introduction of both mutations into the heterologous Tat sequence restores gene expression close to wild-type Tat. Furthermore, in contrast to most coevolving protein residues that contribute to the same function, structural modeling and biochemical studies showed that these two residues contribute to two mechanistically distinct steps in gene expression: binding P-TEFb and promoting P TEFb phosphorylation of the C-terminal domain in RNAPII. Moreover, Tat variants that mimic HIV-1 subtypes B or C at sites 35 and 39 have evolved orthogonal strengths of P-TEFb binding versus RNAPII phosphorylation, suggesting that subtypes have evolved alternate transcriptional strategies to achieve similar gene expression levels. PMID- 22253436 TI - Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). AB - Mammalian cells maintain iron homeostasis by sensing changes in bioavailable iron levels and promoting adaptive responses. FBXL5 is a subunit of an E3 ubiquitin ligase complex that mediates the stability of iron regulatory protein 2, an important posttranscriptional regulator of several genes involved in iron metabolism. The stability of FBXL5 is regulated in an iron- and oxygen-responsive manner, contingent upon the presence of its N-terminal domain. Here we present the atomic structure of the FBXL5 N terminus, a hemerythrin-like alpha-helical bundle fold not previously observed in mammalian proteins. The core of this domain employs an unusual assortment of amino acids necessary for the assembly and sensing properties of its diiron center. These regulatory features govern the accessibility of a mapped sequence required for proteasomal degradation of FBXL5. Detailed molecular and structural characterization of the ligand-responsive hemerythrin domain provides insights into the mechanisms by which FBXL5 serves as a unique mammalian metabolic sensor. PMID- 22253437 TI - Unusual N-terminal alphaalphabetaalphabetabetaalpha fold of PilQ from Thermus thermophilus mediates ring formation and is essential for piliation. AB - DNA translocators of natural transformation systems are complex systems critical for the uptake of free DNA and provide a powerful mechanism for adaptation to changing environmental conditions. In natural transformation machineries, outer membrane secretins are suggested to form a multimeric pore for the uptake of external DNA. Recently, we reported on a novel structure of the DNA translocator secretin complex, PilQ, in Thermus thermophilus HB27 comprising a stable cone and cup structure and six ring structures with a large central channel. Here, we report on structural and functional analyses of a set of N-terminal PilQ deletion derivatives in T. thermophilus HB27. We identified 136 N-terminal residues exhibiting an unusual alphaalphabetaalphabetabetaalpha fold as a ring-building domain. Deletion of this domain had a dramatic effect on twitching motility, adhesion, and piliation but did not abolish natural transformation. These findings provide clear evidence that the pilus structures of T. thermophilus are not essential for natural transformation. The truncated complex was not affected in inner and outer membrane association, indicating that the 136 N-terminal residues are not essential for membrane targeting. Analyses of complex formation of the truncated PilQ monomers revealed that the region downstream of residue 136 is required for multimerization, and the region downstream of residue 207 is essential for monomer stability. Possible implications of our findings for the mechanism of DNA uptake are discussed. PMID- 22253438 TI - Biosynthesis, localization, and macromolecular arrangement of the Plasmodium falciparum translocon of exported proteins (PTEX). AB - To survive within its host erythrocyte, Plasmodium falciparum must export hundreds of proteins across both its parasite plasma membrane and surrounding parasitophorous vacuole membrane, most of which are likely to use a protein complex known as PTEX (Plasmodium translocon of exported proteins). PTEX is a putative protein trafficking machinery responsible for the export of hundreds of proteins across the parasitophorous vacuole membrane and into the human host cell. Five proteins are known to comprise the PTEX complex, and in this study, three of the major stoichiometric components are investigated including HSP101 (a AAA(+) ATPase), a protein of no known function termed PTEX150, and the apparent membrane component EXP2. We show that these proteins are synthesized in the preceding schizont stage (PTEX150 and HSP101) or even earlier in the life cycle (EXP2), and before invasion these components reside within the dense granules of invasive merozoites. From these apical organelles, the protein complex is released into the host cell where it resides with little turnover in the parasitophorous vacuole membrane for most of the remainder of the following cell cycle. At this membrane, PTEX is arranged in a stable macromolecular complex of >1230 kDa that includes an ~600-kDa apparently homo-oligomeric complex of EXP2 that can be separated from the remainder of the PTEX complex using non-ionic detergents. Two different biochemical methods undertaken here suggest that PTEX components associate as EXP2-PTEX150-HSP101, with EXP2 associating with the vacuolar membrane. Collectively, these data support the hypothesis that EXP2 oligomerizes and potentially forms the putative membrane-spanning pore to which the remainder of the PTEX complex is attached. PMID- 22253439 TI - Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions. AB - Cationic antimicrobial peptides (CAPs) occur as important innate immunity agents in many organisms, including humans, and offer a viable alternative to conventional antibiotics, as they physically disrupt the bacterial membranes, leading to membrane lysis and eventually cell death. In this work, we studied the biophysical and microbiological characteristics of designed CAPs varying in hydrophobicity levels and charge distributions by a variety of biophysical and biochemical approaches, including in-tandem atomic force microscopy, attenuated total reflection-FTIR, CD spectroscopy, and SDS-PAGE. Peptide structural properties were correlated with their membrane-disruptive abilities and antimicrobial activities. In bacterial lipid model membranes, a time-dependent increase in aggregated beta-strand-type structure in CAPs with relatively high hydrophobicity (such as KKKKKKALFALWLAFLA-NH(2)) was essentially absent in CAPs with lower hydrophobicity (such as KKKKKKAAFAAWAAFAA-NH(2)). Redistribution of positive charges by placing three Lys residues at both termini while maintaining identical sequences minimized self-aggregation above the dimer level. Peptides containing four Leu residues were destructive to mammalian model membranes, whereas those with corresponding Ala residues were not. This finding was mirrored in hemolysis studies in human erythrocytes, where Ala-only peptides displayed virtually no hemolysis up to 320 MUM, but the four-Leu peptides induced 40-80% hemolysis at the same concentration range. All peptides studied displayed strong antimicrobial activity against Pseudomonas aeruginosa (minimum inhibitory concentrations of 4-32 MUM). The overall findings suggest optimum routes to balancing peptide hydrophobicity and charge distribution that allow efficient penetration and disruption of the bacterial membranes without damage to mammalian (host) membranes. PMID- 22253440 TI - Z-Phe-Ala-diazomethylketone (PADK) disrupts and remodels early oligomer states of the Alzheimer disease Abeta42 protein. AB - The oligomerization of the amyloid-beta protein (Abeta) is an important event in Alzheimer disease (AD) pathology. Developing small molecules that disrupt formation of early oligomeric states of Abeta and thereby reduce the effective amount of toxic oligomers is a promising therapeutic strategy for AD. Here, mass spectrometry and ion mobility spectrometry were used to investigate the effects of a small molecule, Z-Phe-Ala-diazomethylketone (PADK), on the Abeta42 form of the protein. The mass spectrum of a mixture of PADK and Abeta42 clearly shows that PADK binds directly to Abeta42 monomers and small oligomers. Ion mobility results indicate that PADK not only inhibits the formation of Abeta42 dodecamers, but also removes preformed Abeta42 dodecamers from the solution. Electron microscopy images show that PADK inhibits Abeta42 fibril formation in the solution. These results are consistent with a previous study that found that PADK has protective effects in an AD transgenic mouse model. The study of PADK and Abeta42 provides an example of small molecule therapeutic development for AD and other amyloid diseases. PMID- 22253441 TI - Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition induces neurotoxicity via dysregulation of glutamate/calcium signaling and hyperexcitability. AB - Aberrant glutamate and calcium signalings are neurotoxic to specific neuronal populations. Calcium/calmodulin-dependent kinase II (CaMKII), a multifunctional serine/threonine protein kinase in neurons, is believed to regulate neurotransmission and synaptic plasticity in response to calcium signaling produced by neuronal activity. Importantly, several CaMKII substrates control neuronal structure, excitability, and plasticity. Here, we demonstrate that CaMKII inhibition for >4 h using small molecule and peptide inhibitors induces apoptosis in cultured cortical neurons. The neuronal death produced by prolonged CaMKII inhibition is associated with an increase in TUNEL staining and caspase-3 cleavage and is blocked with the translation inhibitor cycloheximide. Thus, this neurotoxicity is consistent with apoptotic mechanisms, a conclusion that is further supported by dysregulated calcium signaling with CaMKII inhibition. CaMKII inhibitory peptides also enhance the number of action potentials generated by a ramp depolarization, suggesting increased neuronal excitability with a loss of CaMKII activity. Extracellular glutamate concentrations are augmented with prolonged inhibition of CaMKII. Enzymatic buffering of extracellular glutamate and antagonism of the NMDA subtype of glutamate receptors prevent the calcium dysregulation and neurotoxicity associated with prolonged CaMKII inhibition. However, in the absence of CaMKII inhibition, elevated glutamate levels do not induce neurotoxicity, suggesting that a combination of CaMKII inhibition and elevated extracellular glutamate levels results in neuronal death. In sum, the loss of CaMKII observed with multiple pathological states in the central nervous system, including epilepsy, brain trauma, and ischemia, likely exacerbates programmed cell death by sensitizing vulnerable neuronal populations to excitotoxic glutamate signaling and inducing an excitotoxic insult itself. PMID- 22253442 TI - Solution structure of homology region (HR) domain of type II secretion system. AB - The type II secretion system of Gram-negative bacteria is important for bacterial pathogenesis and survival; it is composed of 12 mostly multimeric core proteins, which build a sophisticated secretion machine spanning both bacterial membranes. OutC is the core component of the inner membrane subcomplex thought to be involved in both recognition of substrate and interaction with the outer membrane secretin OutD. Here, we report the solution structure of the HR domain of OutC and explore its interaction with the secretin. The HR domain adopts a beta sandwich-like fold consisting of two beta-sheets each composed of three anti parallel beta-strands. This structure is strikingly similar to the periplasmic region of PilP, an inner membrane lipoprotein from the type IV pilus system highlighting the common evolutionary origin of these two systems and showing that all the core components of the type II secretion system have a structural or sequence ortholog within the type IV pili system. The HR domain is shown to interact with the N0 domain of the secretin. The importance of this interaction is explored in the context of the functional secretion system. PMID- 22253443 TI - Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. AB - miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133(+) cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR 124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2. PMID- 22253444 TI - Apoptotic DNA degradation into oligonucleosomal fragments, but not apoptotic nuclear morphology, relies on a cytosolic pool of DFF40/CAD endonuclease. AB - Apoptotic cell death is characterized by nuclear fragmentation and oligonucleosomal DNA degradation, mediated by the caspase-dependent specific activation of DFF40/CAD endonuclease. Here, we describe how, upon apoptotic stimuli, SK-N-AS human neuroblastoma-derived cells show apoptotic nuclear morphology without displaying concomitant internucleosomal DNA fragmentation. Cytotoxicity afforded after staurosporine treatment is comparable with that obtained in SH-SY5Y cells, which exhibit a complete apoptotic phenotype. SK-N-AS cell death is a caspase-dependent process that can be impaired by the pan-caspase inhibitor q-VD-OPh. The endogenous inhibitor of DFF40/CAD, ICAD, is correctly processed, and dff40/cad cDNA sequence does not reveal mutations altering its amino acid composition. Biochemical approaches show that both SH-SY5Y and SK-N-AS resting cells express comparable levels of DFF40/CAD. However, the endonuclease is poorly expressed in the cytosolic fraction of healthy SK-N-AS cells. Despite this differential subcellular distribution of DFF40/CAD, we find no differences in the subcellular localization of both pro-caspase-3 and ICAD between the analyzed cell lines. After staurosporine treatment, the preferential processing of ICAD in the cytosolic fraction allows the translocation of DFF40/CAD from this fraction to a chromatin-enriched one. Therefore, the low levels of cytosolic DFF40/CAD detected in SK-N-AS cells determine the absence of DNA laddering after staurosporine treatment. In these cells DFF40/CAD cytosolic levels can be restored by the overexpression of their own endonuclease, which is sufficient to make them proficient at degrading their chromatin into oligonucleosome-size fragments after staurosporine treatment. Altogether, the cytosolic levels of DFF40/CAD are determinants in achieving a complete apoptotic phenotype, including oligonucleosomal DNA degradation. PMID- 22253445 TI - Phosphatidylinositol 4-kinase IIIbeta is required for severe acute respiratory syndrome coronavirus spike-mediated cell entry. AB - Phosphatidylinositol kinases (PI kinases) play an important role in the life cycle of several viruses after infection. Using gene knockdown technology, we demonstrate that phosphatidylinositol 4-kinase IIIbeta (PI4KB) is required for cellular entry by pseudoviruses bearing the severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein and that the cell entry mediated by SARS-CoV spike protein is strongly inhibited by knockdown of PI4KB. Consistent with this observation, pharmacological inhibitors of PI4KB blocked entry of SARS pseudovirions. Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. We further demonstrate that PI4KB does not affect virus entry at the SARS-CoV S-ACE2 binding interface or at the stage of virus internalization but rather at or before virus fusion. Taken together, these results indicate a new function for PI4KB and suggest a new drug target for preventing SARS-CoV infection. PMID- 22253446 TI - Phosphorylation of calcineurin B-like (CBL) calcium sensor proteins by their CBL interacting protein kinases (CIPKs) is required for full activity of CBL-CIPK complexes toward their target proteins. AB - Calcineurin B-like proteins (CBLs) represent a family of calcium sensor proteins that interact with a group of serine/threonine kinases designated as CBL interacting protein kinases (CIPKs). CBL-CIPK complexes are crucially involved in relaying plant responses to many environmental signals and in regulating ion fluxes. However, the biochemical characterization of CBL-CIPK complexes has so far been hampered by low activities of recombinant CIPKs. Here, we report on an efficient wheat germ extract-based in vitro transcription/translation protocol that yields active full-length wild-type CIPK proteins. We identified a conserved serine residue within the C terminus of CBLs as being phosphorylated by their interacting CIPKs. Remarkably, our studies revealed that CIPK-dependent CBL phosphorylation is strictly dependent on CBL-CIPK interaction via the CIPK NAF domain. The phosphorylation status of CBLs does not appear to influence the stability, localization, or CIPK interaction of these calcium sensor proteins in general. However, proper phosphorylation of CBL1 is absolutely required for the in vivo activation of the AKT1 K(+) channel by CBL1-CIPK23 and CBL9-CIPK23 complexes in oocytes. Moreover, we show that by combining CBL1, CIPK23, and AKT1, we can faithfully reconstitute CBL-dependent enhancement of phosphorylation of target proteins by CIPKs in vitro. In addition, we report that phosphorylation of CBL1 by CIPK23 is also required for the CBL1-dependent enhancement of CIPK23 activity toward its substrate. Together, these data identify a novel general regulatory mechanism of CBL-CIPK complexes in that CBL phosphorylation at their flexible C terminus likely provokes conformational changes that enhance specificity and activity of CBL-CIPK complexes toward their target proteins. PMID- 22253447 TI - Molecular determinants of proteolytic disassembly of the reovirus outer capsid. AB - Following attachment and internalization, mammalian reoviruses undergo intracellular proteolytic disassembly followed by viral penetration into the cytoplasm. The initiating event in reovirus disassembly is the cathepsin-mediated proteolytic degradation of viral outer capsid protein sigma3. A single tyrosine to-histidine mutation at amino acid 354 (Y354H) of strain type 3 Dearing (T3D) sigma3 enhances reovirus disassembly and confers resistance to protease inhibitors such as E64. The sigma3 amino acid sequence of strain type 3 Abney (T3A) differs from that of T3D at eight positions including Y354H. However, T3A displays disassembly kinetics and protease sensitivity comparable with T3D. We hypothesize that one or more additional sigma3 polymorphisms suppress the Y354H phenotype and restore T3D disassembly characteristics. To test this hypothesis, we engineered a panel of reovirus variants with T3A sigma3 polymorphisms introduced individually into T3D-sigma3Y354H. We evaluated E64 resistance and in vitro cathepsin L susceptibility of these viruses and found that one containing a glycine-to-glutamate substitution at position 198 (G198E) displayed disassembly kinetics and E64 sensitivity similar to those properties of T3A and T3D. Additionally, viruses containing changes at positions 233 and 347 (S233L and I347T) developed de novo compensatory mutations at position 198, strengthening the conclusion that residue 198 is a key determinant of sigma3 proteolytic susceptibility. Variants with Y354H in sigma3 lost infectivity more rapidly than T3A or T3D following heat treatment, an effect abrogated by G198E. These results identify a regulatory network of residues that control sigma3 cleavage and capsid stability, thus providing insight into the regulation of nonenveloped virus disassembly. PMID- 22253448 TI - Role of runt-related transcription factor 3 (RUNX3) in transcription regulation of natural cytotoxicity receptor 1 (NCR1/NKp46), an activating natural killer (NK) cell receptor. AB - Natural cytotoxicity receptor 1 (NCR1), also known as NKp46, is a natural killer (NK) lymphocyte-activating receptor. It is involved in major aspects of NK immune function and shows a high degree of lineage specificity in blood and bone marrow. The nature of its NK-restricted expression is not well understood. In this study, we confirm that human NCR1 NK-specific expression is achieved at the mRNA level. We found two key cis-regulatory elements in the immediate vicinity upstream of the gene. One element acts as an essential promoter, whereas the other acts as a tissue-dependent enhancer/repressor. This latter regulatory element contains a runt related-transcription factor (RUNX) recognition motif that preferentially binds RUNX3. Interfering with RUNX proteins using a dominant negative form results in decreased Ncr1 expression. RUNX3 overexpression had the opposite effect. These findings shed light on the role of RUNX3 in the control of an important NK-activating receptor. PMID- 22253449 TI - Regulation of bone and cartilage development by network between BMP signalling and transcription factors. AB - Bone morphogenetic protein(s) (BMP) are very powerful cytokines that induce bone and cartilage formation. BMP also stimulate osteoblast and chondrocyte differentiation. During bone and cartilage development, BMP regulates the expression and/or the function of several transcription factors through activation of Smad signalling. Genetic studies revealed that Runx2, Osterix and Sox9, all of which function downstream of BMP, play essential roles in bone and/or cartilage development. In addition, two other transcription factors, Msx2 and Dlx5, which interact with BMP signalling, are involved in bone and cartilage development. The importance of these transcription factors in bone and cartilage development has been supported by biochemical and cell biological studies. Interestingly, BMP is regulated by several negative feedback systems that appear necessary for fine-tuning of bone and cartilage development induced by BMP. Thus, BMP harmoniously regulates bone and cartilage development by forming network with several transcription factors. PMID- 22253450 TI - Left ventricular non-compaction: dreaming of the perfect diagnostic tool. PMID- 22253451 TI - Current studies of diabetic cardiomyopathy and the advancement of our knowledge: time to learn from history, guidelines, ... and other disciplines? PMID- 22253452 TI - Circulating microRNAs to identify human heart failure. PMID- 22253454 TI - Heart failure and socioeconomic status: accumulating evidence of inequality. AB - AIMS: Socioeconomic status (SES) is a powerful predictor of incident coronary disease and adverse cardiovascular outcomes. Understanding the impact of SES on heart failure (HF) development and subsequent outcomes may help to develop effective and equitable prevention, detection, and treatment strategies METHODS AND RESULTS: A systematic literature review of electronic databases including PubMed, EMBASE, CINAHL, and the Cochrane Library, restricted to human subjects, was carried out. The principal outcomes were incidence, prevalence, hospitalizations, mortality, and treatment of HF. Socioeconomic measures included education, occupation, employment relations, social class, income, housing characteristics, and composite and area level indicators. Additional studies were identified from bibliographies of relevant articles and reviews. Twenty-eight studies were identified. Lower SES was associated with increased incidence of HF, either in the community or presenting to hospital. The adjusted risk of developing HF was increased by ~30-50% in most reports. Readmission rates following hospitalization were likewise greater in more deprived patients. Although fewer studies examined mortality, lower SES was associated with poorer survival. Evidence defining the equity of medical treatment of patients with HF was scarce and conflicting. CONCLUSIONS: Socioeconomic deprivation is a powerful independent predictor of HF development and adverse outcomes. However, the precise mechanisms accounting for this risk remain elusive. Heart failure represents the endpoint of numerous different pathophysiological processes and 'chains of events', each modifiable throughout the disease trajectories. The interaction between SES and HF is accordingly complex. Disentangling the many and varied life course processes is challenging. A better understanding of these issues may help attenuate the health inequalities so clearly evident among patients with HF. PMID- 22253453 TI - Targeting myocardial substrate metabolism in heart failure: potential for new therapies. AB - The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area. PMID- 22253455 TI - Ten-year prognosis of heart failure in the community: follow-up data from the Echocardiographic Heart of England Screening (ECHOES) study. AB - AIMS: This study investigates the 10-year survival in the ECHOES (Echocardiographic Heart of England Screening) study and examines factors associated with prognosis. METHODS AND RESULTS: A prospective study was carried out to investigate 10-year survival in those with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD). The mean age of participants in ECHOES was 64, and 50% were male. Records of all 6162 screened participants were flagged, and deaths up to 25 February 2009 were coded. Causes of death were categorized according to diagnosis on death certificate. Kaplan-Meier curves and log rank tests were used to compare survival times of participants with HF and LVSD in different diagnostic groups. A Cox proportional hazards regression model was used to identify variables associated with risk of death. A total of 2062 of the 6162 (33.5%) participants had died at the census date in February 2009. Of these deaths, 902 (43.7%) were due to cardiovascular disease, including 263 (12.8%) due to HF. Ten-year survival was 75% for participants without HF, 26.7% for those with HF, 37.6% for those with LVSD, and 27.4% for those with HF and LVSD. Multiple-cause HF had a 10-year survival of 11.6%. Multiple variables including diabetes, valvular disease, diuretic use, and a previous label of HF, as well as lifestyle factors such as smoking and obesity, were associated with increased risk of death. CONCLUSIONS: Patients with HF and LVSD have a poor prognosis. However, the mortality rates of all-cause, all-stage HF as measured in the ECHOES cohort are around half those reported for patients diagnosed for the first time with HF during hospital admission. PMID- 22253456 TI - Long-term severe diabetes only leads to mild cardiac diastolic dysfunction in Zucker diabetic fatty rats. AB - AIMS: Type 2 diabetes mellitus (DM) leads to cardiac dysfunction irrespective of hypertension and coronary artery disease; this is called diabetic cardiomyopathy. Here, we investigated the severity of diabetic cardiomyopathy and myocardial remodelling in aged Zucker diabetic fatty (ZDF) rats. METHODS AND RESULTS: Body weight, blood glucose and glycated haemoglobin (Hb(A1c)) levels, and urinary albumin excretion were monitored regularly in ZDF rats (n = 19) and control littermates (n = 19) up to age 45 weeks. ZDF rats were severely diabetic during the entire study period and demonstrated decreased body and heart weights at sacrifice. Left ventricular (LV) function was determined using magnetic resonance imaging (MRI) at age 44 weeks and revealed similar LV ejection fraction and cardiac output index in control and ZDF rats, indicating preserved systolic function. LV pressure characteristics assessed at age 45 weeks showed significant, but mild elevations of LV end-diastolic pressure (+45%) and relaxation time constant Tau (+54%) in ZDF rats, indicating diastolic dysfunction. Histological analyses revealed a significantly increased LV collagen content (+50%), but no cardiomyocyte hypertrophy in ZDF rats. CONCLUSION: The present study clearly shows that long term, severe DM in 45-week-old ZDF rats resulted in relatively mild impairment of diastolic LV function, whereas systolic function was well preserved. These data do not support the notion that diabetes per se is a critical factor in the induction of a clinically relevant degree of cardiac dysfunction. Co-morbidities such as hypertension and coronary artery disease probably have larger impacts on myocardial function in diabetic individuals. PMID- 22253457 TI - A selective follow-up study on a public health survey. AB - BACKGROUND: The non-response rates in surveys are increasing which is problematic as it means that a progressively smaller proportion of the population represents the majority, and it is uncertain how health survey results are affected. This follow-up was performed on the non-responders to the postal questionnaire in the public health survey Life and Health, conducted in Orebro County Council, Sweden, where large differences in response rates had been found between different socio demographic groups and geographical areas. The main objective was to analyse non response bias regarding self-rated health. METHODS: This follow-up study was conducted as a census to all non-responders in the area that had the lowest response rate and, in one other geographical area used as a control. It was carried out by telephone interviews, 49.3% (580 individuals) answered the follow up. The outcome variable was self-rated health, a main variable in public health surveys. Differences in response patterns between responders and initial non responders were approximated by prevalences with confidence intervals and adjusted odds ratios. RESULTS: Poor health was more common in the initial non response group than among the responders, even with consideration given to sex, age, country of birth and education. However, good health was equally common among responders and initial non-responders. CONCLUSIONS: Public health surveys can be biased due to certain groups being under-represented or not represented at all. For this reason, in repeated public health surveys, we recommend selective follow-ups of such groups at regular intervals. PMID- 22253458 TI - Syncope and profound bradycardia associated with intrauterine contraceptive procedures. AB - There has been recent interest in this Journal concerning the occurrence of profound bradycardia with impaired consciousness during insertion of intrauterine contraceptive devices or systems. Questions have been raised regarding the requirement for medication for reversal of the condition, the role of the nurse practitioner in the light of this, and the effects upon sexual and reproductive health care service delivery. We present three cases where this condition affected patients under our care and suggest that although very infrequent, it is important. Medication for treatment and staff trained to administer it should always be available. PMID- 22253459 TI - Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision. AB - PURPOSE: Prediction of patients at highest risk for ipsilateral breast tumor recurrence (IBTR) after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The aim of our study was to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center to predict for risk of IBTR in patients with DCIS from our institution. PATIENTS AND METHODS: We retrospectively identified 794 patients with a diagnosis of DCIS who had undergone local excision from 1990 through 2007 at the MD Anderson Cancer Center (MDACC). Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients who had complete data. RESULTS: There was a marked difference with respect to tumor grade, prevalence of necrosis, initial presentation, final margins, and receipt of endocrine therapy between the two cohorts. The biggest difference was that more patients received radiation in the MDACC cohort (75% at MDACC v 49% at MSKCC; P < .001). Follow-up time in the MDACC cohort was longer than in the MSKCC cohort (median 7.1 years v 5.6 years), and the recurrence rate was lower in the MDACC cohort (7.9% v 11%). The median 5-year probability of recurrence was 5%, and the median 10-year probability of recurrence was 7%. The nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated imperfect calibration and discrimination, with a concordance index of 0.63. CONCLUSION: Predictive models for IBTR in patients with DCIS who were treated with local excision are imperfect. Our current ability to accurately predict recurrence on the basis of clinical parameters alone is limited. PMID- 22253460 TI - Meta-analysis of psychosocial interventions to reduce pain in patients with cancer. AB - PURPOSE: Pain is one of the most common, burdensome, and feared symptoms experienced by patients with cancer. American Pain Society standards for pain management in cancer recommend both pharmacologic and psychosocial approaches. To obtain a current, stable, and comprehensive estimate of the effect of psychosocial interventions on pain-an important clinical topic-we conducted a meta-analysis of randomized controlled studies among adult patients with cancer published between 1966 and 2010. METHODS: Three pairs of raters independently reviewed 1,681 abstracts, with a systematic process for reconciling disagreement, yielding 42 papers, of which 37 had sufficient data for meta-analysis. Studies were assessed for quality using a modified seven-item Physiotherapy Evidence Database (PEDro) coding scheme. Pain severity and interference were primary outcome measures. RESULTS: Study participants (N = 4,199) were primarily women (66%) and white (72%). The weighted averaged effect size across studies for pain severity (38 comparisons) was 0.34 (95% CI, 0.23 to 0.46; P < .001), and the effect size for pain interference (four comparisons) was 0.40 (95% CI, 0.21 to 0.60; P < .001). Studies that monitored whether treatment was delivered as intended had larger effects than those that did not (P = .04). CONCLUSION: Psychosocial interventions had medium-size effects on both pain severity and interference. These robust findings support the systematic implementation of quality-controlled psychosocial interventions as part of a multimodal approach to the management of pain in patients with cancer. PMID- 22253461 TI - How many therapeutic options are there for recurrent or metastatic salivary duct carcinoma? PMID- 22253462 TI - Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. AB - PURPOSE: Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and "virtual" biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment. PATIENTS AND METHODS: Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined. RESULTS: CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean +/- standard deviation = 1,589 +/- 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with >= 50 CTCs/7.5 mL of blood and 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM. CONCLUSION: Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology. PMID- 22253463 TI - Metabolic-morphologic discordant solitary skeletal muscle metastasis on [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography scan in synchronous lung and esophageal cancer: a lesson. PMID- 22253464 TI - Like raising a child. PMID- 22253465 TI - Selecting individualized treatment for patients with ductal carcinoma in situ of the breast: the search continues. PMID- 22253466 TI - Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. AB - PURPOSE: Clinical trials have shown that adding bevacizumab to cytotoxic chemotherapy improves survival for patients with colorectal cancer, although its effectiveness in the Medicare population is uncertain. PATIENTS AND METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) -Medicare linked database, we identified 2,526 patients with stage IV colorectal cancer diagnosed between 2002 and 2007 who received first-line combination chemotherapy with a fluoropyrimidine and either irinotecan (33%) or oxaliplatin (67%). Thirty-six percent of patients received bevacizumab with first-line therapy. The primary outcome was overall survival. Secondary outcomes were bevacizumab-associated toxicities, including the incidence of stroke, myocardial infarction, and GI perforation. RESULTS: In the primary cohort inclusive of patients diagnosed between 2002 and 2007, bevacizumab with combination chemotherapy was associated with improved overall survival (adjusted hazard ratio [HR], 0.85; 95% CI, 0.78 to 0.93), although the effect was more modest when restricted to years 2004 to 2007 (HR, 0.93; 95% CI, 0.84 to 1.02). The observed survival advantage of bevacizumab was more apparent with irinotecan-based chemotherapy (HR, 0.80; 95% CI, 0.66 to 0.97) than with oxaliplatin-based chemotherapy (HR, 0.96; 95% CI, 0.86 to 1.07). Combination chemotherapy with bevacizumab, versus combination chemotherapy without bevacizumab, was associated with increased risk of stroke (4.9% v 2.5%, respectively; P < .01) and GI perforation (2.3% v 1.0%, respectively; P < .01). Cardiac events and venous thrombosis were not increased with bevacizumab. CONCLUSION: The addition of bevacizumab to cytotoxic combination chemotherapy was associated with small improvement in overall survival as well as increased risk of stroke and perforation, but not cardiac events, among Medicare beneficiaries with stage IV colorectal cancer. PMID- 22253467 TI - Recommendations for clinical trials of off-label drugs used to treat advanced stage cancer. AB - PURPOSE: To provide recommendations to trialists and sponsors that guide the design and implementation of prospective postapproval clinical trials for oncology drugs used outside US Food and Drug Administration-labeled indications for treatment of late-stage cancers. METHODS: A meeting was hosted by the Center for Medical Technology Policy in Baltimore, MD, on November 12, 2009. Discussions during the meeting and key informant interviews were conducted before and after this stakeholder meeting. Peer review by multidisciplinary stakeholders was followed by a public comment period. Input was received from patient advocacy groups, medical oncologists, pharmaceutical companies, the US Food and Drug Administration, Centers for Medicare and Medicaid Services, the National Cancer Institute, foreign government agencies involved in health technology assessment, public and private payers, drug compendia, clinical research entities, statisticians, academics, and the American Society of Clinical Oncology. RESULTS: To address the needs of patients and their clinical providers, compendia, payers, and policy makers, recommendations are proposed to guide the design of future prospective trials for off-label use of oncology drugs across four areas: trial design and data analysis, patient and site recruitment, comparators, and outcomes. CONCLUSION: The US Food and Drug Administration provides guidance to the pharmaceutical industry and others designing randomized clinical trials for regulatory approval. However, a gap exists for postregulatory decision makers, including patients, prescribers, and payers, because regulatory trials do not answer the questions most relevant to them. Therefore, guidance is needed for trials performed in the postapproval environment for these postapproval decision makers. PMID- 22253468 TI - Registries and randomized trials in assessing the effects of bevacizumab in colorectal cancer: is there a common theme? PMID- 22253469 TI - Circulating invariant natural killer T-cell numbers predict outcome in head and neck squamous cell carcinoma: updated analysis with 10-year follow-up. PMID- 22253470 TI - Off-label use of oncology drugs: the need for more data and then some. PMID- 22253471 TI - Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata. AB - Many cell surface proteins in mammalian cells are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The predominant form of mammalian GPI contains 1-alkyl-2-acyl phosphatidylinositol (PI), which is generated by lipid remodeling from diacyl PI. The conversion of diacyl PI to 1-alkyl-2-acyl PI occurs in the ER at the third intermediate in the GPI biosynthetic pathway. This lipid remodeling requires the alkyl-phospholipid biosynthetic pathway in peroxisome. Indeed, cells defective in dihydroxyacetone phosphate acyltransferase (DHAP-AT) or alkyl-DHAP synthase express only the diacyl form of GPI-anchored proteins. A defect in the alkyl-phospholipid biosynthetic pathway causes a peroxisomal disorder, rhizomelic chondrodysplasia punctata (RCDP), and defective biogenesis of peroxisomes causes Zellweger syndrome, both of which are lethal genetic diseases with multiple clinical phenotypes such as psychomotor defects, mental retardation, and skeletal abnormalities. Here, we report that GPI lipid remodeling is defective in cells from patients with Zellweger syndrome having mutations in the peroxisomal biogenesis factors PEX5, PEX16, and PEX19 and in cells from patients with RCDP types 1, 2, and 3 caused by mutations in PEX7, DHAP AT, and alkyl-DHAP synthase, respectively. Absence of the 1-alkyl-2-acyl form of GPI-anchored proteins might account for some of the complex phenotypes of these two major peroxisomal disorders. PMID- 22253472 TI - MicroRNAs control neurobehavioral development and function in zebrafish. AB - microRNAs (miRNAs) have emerged as regulators of a broad spectrum of neurodevelopmental processes, including brain morphogenesis, neuronal differentiation, and survival. While the role of miRNAs in establishing and maintaining the developing nervous system is widely appreciated, the developmental neurobehavioral role of miRNAs has yet to be defined. Here we show that transient disruption of brain morphogenesis by ethanol exposure results in behavioral hyperactivity in larval zebrafish challenged with changes in lighting conditions. Aberrations in swimming activity persist in juveniles that were developmentally exposed to ethanol. During early neurogenesis, multiple gene expression profiling studies revealed widespread changes in mRNA and miRNA abundance in ethanol-exposed embryos. Consistent with a role for miRNAs in neurobehavioral development, target prediction analyses identified multiple miRNAs misexpressed in the ethanol-exposed cohorts that were also predicted to target inversely expressed transcripts known to influence brain morphogenesis. In vivo knockdown of miR-9/9* or miR-153c persistently phenocopied the effect of ethanol on larval and juvenile swimming behavior. Structural analyses performed on adults showed that repression of miR-153c during development impacts craniofacial skeletal development. Together, these data support an integral role for miRNAs in the establishment of vertebrate neurobehavioral and skeletal systems. PMID- 22253473 TI - Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. AB - Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease (AD); however, the relationship between NFTs and disease progression remains controversial. Analyses of tau animal models suggest that phenotypes coincide with accumulation of soluble aggregated tau species but not the accumulation of NFTs. The pathological role of prefilamentous tau aggregates, e.g., tau oligomeric intermediates, is poorly understood, in part because of methodological challenges. Here, we engineered a novel tau oligomer-specific antibody, T22, and used it to elucidate the temporal course and biochemical features of oligomers during NFT development in AD brain. We found that tau oligomers in human AD brain samples were 4-fold higher than those in the controls. We also revealed the role of oligomeric tau conformers in pretangles, neuritic plaques, and neuropil threads in the frontal cortex tissue from AD brains; this analysis uncovers a consistent code that governs tau oligomerization with regard to degree of neuronal cytopathology. These data are the first to characterize the role of tau oligomers in the natural history of NFTs, and they highlight the suitability of tau oligomers as therapeutic targets in AD and related tauopathies. PMID- 22253474 TI - alpha-Actinin-2 deficiency results in sarcomeric defects in zebrafish that cannot be rescued by alpha-actinin-3 revealing functional differences between sarcomeric isoforms. AB - alpha-Actinins are actin-binding proteins that can be broadly divided into Ca(2+) sensitive cytoskeletal and Ca(2+)-insensitive sarcomeric isoforms. To date, little is known about functional differences between the isoforms due to their indistinguishable activities in most in vitro assays. To identify functional differences in vivo between sarcomeric isoforms, we employed computational and molecular approaches to characterize the zebrafish (Danio rerio) genome, which contains orthologoues of each human alpha-actinin gene, including duplicated copies of actn3. Each isoform exhibits a distinct and unique pattern of gene expression as assessed by mRNA in situ hybridization, largely sharing similar expression profiles as seen in humans. The spatial conservation of expression of these genes from lower invertebrates to humans suggests that regulation and subsequent functions of these genes are conserved during evolution. Morpholino based knockdown of the sarcomeric isoform, actn2, leads to skeletal muscle, cardiac, and ocular defects evident over the first week of development. Remarkably, despite the high degree of sequence conservation between actn2 and actn3, the phenotypes of alpha-actinin-2 deficient zebrafish can be rescued by overexpression of alpha-actinin-2 but not by alpha-actinin-3 mRNAs from zebrafish or human. These data provide functional evidence that the primary sequences of alpha-actinin-2 and alpha-actinin-3 evolved differences to optimize their functions. PMID- 22253475 TI - A single amino acid determines the toxicity of Ginkgo biloba extracts. AB - Ginkgo biloba extracts are currently used for a wide range of health-related conditions. Some of the medical benefits of these extracts are controversial, but their lack of toxicity in humans is not in doubt. These extracts are, however, highly toxic to insects. Their active components (ginkgolides and bilobalide) have structures similar to the convulsant picrotoxin, a GABA(A) receptor antagonist, so their lack of toxicity in mammals is puzzling. Here, we show that the different compositions of insect and vertebrate GABA receptor pores are responsible for the differing toxicities. Insect GABA receptors contain Ala at their 2' position in the pore. Substitution with Val, which is the equivalent residue in vertebrate GABA(A) receptor alpha-subunits, decreases ginkgolide potency by up to 10,000-fold. The reverse mutation in vertebrate GABA(A) alpha1 subunits increased the sensitivity of alpha1beta2 and alpha1beta2gamma2 receptors to ginkgolides. Mutant cycle analysis demonstrates a strong interaction between the ginkgolides and the 2' residue, a result supported by in silico docking of compounds into a model of the pore. We conclude that the insecticidal activity of G. biloba extracts can be attributed to their effects at insect GABA receptors, and the presence of a Val at the 2' position in vertebrate GABA(A) receptors explains why these compounds are not similarly toxic to humans. PMID- 22253476 TI - Nonmuscle myosin IIA facilitates vesicle trafficking for MG53-mediated cell membrane repair. AB - Repair of injury to the plasma membrane is an essential mechanism for maintenance of cellular homeostasis and integrity that involves coordinated movement of intracellular vesicles to membrane injury sites to facilitate patch formation. We have previously identified MG53 as an essential component of the cell membrane repair machinery. In order for MG53 and intracellular vesicles to translocate to membrane injury sites, motor proteins must be involved. Here, we show that nonmuscle myosin type IIA (NM-IIA) interacts with MG53 to regulate vesicle trafficking during cell membrane repair. In cells that are deficient for NM-IIA expression, MG53 cannot translocate to acute injury sites, whereas rescue of NM IIA expression in these cells can restore MG53-mediated membrane repair. Compromised cell membrane repair is observed in cells with RNAi-mediated knockdown of NM-IIA expression, or following pharmacological alteration of NM-IIA motor function. Together, our data reveal NM-IIA as a key cytoskeleton motor protein that facilitates vesicle trafficking during MG53-mediated cell membrane repair. PMID- 22253477 TI - Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. AB - Self-resolving inflammatory exudates and lipid mediator metabolomics recently uncovered a new family of potent anti-inflammatory and proresolving mediators biosynthesized by macrophages (MPhis), denoted maresins. Here we determined that maresin 1 (MaR1) produced by human MPhis from endogenous docosahexaenoic acid (DHA) matched synthetic 7R,14S-dihydroxydocosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid. The MaR1 alcohol groups and Z/E geometry of conjugated double bonds were matched using isomers prepared by total organic synthesis. MaR1's potent defining actions were confirmed with synthetic MaR1, i.e., limiting polymorphonuclear neutrophil (PMN) infiltration in murine peritonitis (ng/mouse range) as well as enhancing human macrophage uptake of apoptotic PMNs. At 1 nM, MaR1 was slightly more potent than resolvin D1 in stimulating human MPhi efferocytosis, an action not shared by leukotriene B(4). MaR1 also accelerated surgical regeneration in planaria, increasing the rate of head reappearance. On injury of planaria, MaR1 was biosynthesized from deuterium-labeled (d(5))-DHA that was blocked with lipoxygenase (LOX) inhibitor. MaR1 dose-dependently inhibited TRPV1 currents in neurons, blocked capsaicin (100 nM)-induced inward currents (IC(50) 0.49+/-0.02 nM), and reduced both inflammation- and chemotherapy-induced neuropathic pain in mice. These results demonstrate the potent actions of MaR1 in regulating inflammation resolution, tissue regeneration, and pain resolution. These findings suggest that chemical signals are shared in resolution cellular trafficking, a key process in tissue regeneration. Moreover, immunoresolvents of the innate immune response, such as MaR1, offer new opportunities for assessing MPhis and their local DHA metabolome in the return to tissue homeostasis. PMID- 22253478 TI - 5-Lipoxygenase-dependent apoptosis of human lymphocytes in the International Space Station: data from the ROALD experiment. AB - The functional adaptation of the immune system to the surrounding environment is also a fundamental issue in space. It has been suggested that a decreased number of lymphocytes might be a cause of immunosuppression, possibly due to the induction of apoptosis. Early activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of the apoptotic program. The goal of the role of apoptosis in lymphocyte depression (ROALD) experiment, flown on the International Space Station as part of the BIO-4 mission of the European Space Agency, was to ascertain the induction of apoptosis in human lymphocytes under authentic microgravity, and to elucidate the possible involvement of 5-LOX. Our results demonstrate that exposure of human lymphocytes to microgravity for 48 h onboard the ISS remarkably increased apoptotic hallmarks such as DNA fragmentation (~3 fold compared to ground-based controls) and cleaved-poly (ADP-ribose) polymerase (PARP) protein expression (~3-fold), as well as mRNA levels of apoptosis-related markers such as p53 (~3-fold) and calpain (~4-fold); these changes were paralleled by an early increase of 5-LOX activity (~2-fold). Our findings provide a molecular background for the immune dysfunction observed in astronauts during space missions, and reveal potential new markers to monitor health status of ISS crew members. PMID- 22253479 TI - Neuronal cGMP kinase I is essential for stimulation of duodenal bicarbonate secretion by luminal acid. AB - Brief contact of the duodenal mucosa with luminal acid elicits a long-lasting bicarbonate (HCO(3)(-)) secretory response, which is believed to be the primary protective mechanism against mucosal damage. Here, we show that cGMP-dependent protein kinase type I-knockout (cGKI(-/-)) mice are unable to respond to a physiological H(+) stimulus with a HCO(3)(-) secretory response and spontaneously develop duodenal ulcerations. Smooth muscle-selective cGKI knock-in rescued the motility disturbance but not the defective HCO(3)(-) secretion. Proton-induced HCO(3)(-) secretion was not attenuated by selective inactivation of the cGKI gene in interstitial cells of Cajal or in enterocytes, but was abolished by inactivation of cGKI in neurons (ncGKI(-/-)). cGKI was expressed in the brainstem nucleus tractus solitarius that connects the afferent with the efferent N. vagus. Accordingly, truncation of the subdiaphragmal N. vagus significantly diminished proton-induced HCO(3)(-) secretion in wild-type mice, whereas stimulation of the subdiaphragmal N. vagus elicited a similar HCO(3)(-) secretory response in cGKI( /-), ncGKI(-/-) and wild-type mice. These findings show that protection of the duodenum from acid injury requires neuronal cGKI. PMID- 22253480 TI - New insights into the role of the glutamic acid of the E-box motif in group B Streptococcus pilus 2a assembly. AB - Group B Streptococcus pili are covalently linked structures assembled via a sortase-catalyzed transpeptidation mechanism involving specific residues and motifs. A sequence element containing a conserved glutamic acid, called the E box, has been described to be involved in pilus formation. Although it is known that the glutamic acid is involved in stabilizing the internal isopeptide bonds, its role in pilus assembly still needs to be investigated. Using site-specific mutagenesis and complementation studies of knockout strains, we found that the E box glutamic residue of the backbone and the major ancillary proteins is essential for pilus protein polymerization. NMR analysis revealed that the mutation of this residue seriously affected the folding of the protein. By contrast, the mutation of the lysine involved in the same isopeptide bond did not engender a structural destabilization, and the native fold was preserved. Moreover, molecular dynamics simulations on the E-box-containing domain of the backbone protein showed that the E-box glutamic acid is necessary to maintain the appropriate dryness of the domain core and that its mutation favors an unfolded state. The data provide the first direct evidence that the E-box has an additional and key role in maintaining the correct protein fold independently of isopeptide bond formation. PMID- 22253482 TI - Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. AB - BACKGROUND: Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. OBJECTIVE: Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. METHODS: ApoE(-/-)/TLR4(mut) mice and ApoE(-/-)/TLR4 wild-type mice (ApoE(-/-)/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE(-/-)) strain with TLR4-mutant (TLR4(mut)) mice, which were fed with high fat, high-cholesterol (HFHC) diet to induce obesity. RESULTS: ApoE(-/-)/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE(-/-)/TLR4(mut) mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE(-/-)/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE(-/ )/TLR4(mut) mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-kappaB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice. CONCLUSIONS: These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1. PMID- 22253483 TI - The impact of the economy and recessions on the marketplace demand for ophthalmologists (an American Ophthalmological Society thesis). AB - PURPOSE: To develop a help-wanted index (HWI) to measure trends in marketplace demand for ophthalmologists, to identify the economic drivers of demand, and to determine the impact of economic recessions on the ophthalmology job market. METHODS: Review of physician recruitment advertisements appearing in the journals Ophthalmology, American Journal of Ophthalmology, and Archives of Ophthalmology from January 1980 through June 2006. RESULTS: Over the 26-year study period a consistent increase in the demand for subspecialists (31% of HWI in 1980 to 80% in 2005) was noted. There was also an increase in the demand for academic ophthalmologists. The need for academic ophthalmologists seems to be correlated with national research expenditure and stock market gains (P = .00191), whereas demand for private practice ophthalmologists seems to be correlated with the national economic well-being, as measured by gross domestic product (GDP) (P < .001). Residency applicants (P = .0128) and fellowship applicants (P = .0198) respond to marketplace demand. During the recessions, the demand for ophthalmologists fell 2 to 3 years after the economic downturn. CONCLUSIONS: Over a 26-year period, HWI data suggest an increased need for subspecialists and academic ophthalmologists. The ophthalmic community has been quick to respond to marketplace demand. National research expenditure, stock market gains, GDP, and discretionary health care expenditure have been associated with the ophthalmology job market. These factors tend to decline with economic recessions. Historically, the demand for ophthalmologists has declined 2 to 3 years following a recession, which may mean lower demand in the near future, given the recent recession. PMID- 22253484 TI - Anterior segment alterations and comparative aqueous humor proteomics in the buphthalmic rabbit (an American Ophthalmological Society thesis). AB - PURPOSE: To use an integrated proteohistologic approach to gain insight into the anterior segment alterations in the buphthalmic rabbit. METHODS: Eyes from 2- and 5-year-old buphthalmic and normal rabbits (n=20) were studied histologically. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) of aqueous humor (AH) was used to determine differential protein expression between animal groups. Western blot and immunohistochemistry were performed on selected differentially expressed proteins identified by LC-MS/MS. RESULTS: The buphthalmic rabbits manifested a mild clinical phenotype with typical angle anomalies that appeared progressive by histology. Significantly thickened Descemet's membrane (DM) and anterior lens capsule in all buphthalmic rabbits showed increased fibronectin and collagen-IV immunolabeling. LC-MS/MS applying stringent filtering criteria revealed significant differential expression of several AH proteins in these rabbits. The protein of interest in the 2-year-old group was histidine-rich glycoprotein, and those in the 5-year-old group included alpha-2-HS-glycoprotein, clusterin, apolipoprotein E, interphotoreceptor retinoid-binding protein, transthyretin, cochlin, gelsolin, haptoglobin, hemopexin, and beta-2 microglobulin. The proteomic data for selected proteins was validated by Western blot and immunohistochemistry. A wide range of functional groups were affected by the altered AH proteins. These included extracellular matrix modulation, regulation of apoptosis, oxidative stress, and protein transport. CONCLUSIONS: Multiple anterior segment alterations were histologically identified in the buphthalmic rabbits that showed progressive changes with age. The differentially expressed AH proteins in these rabbits suggest a multifunctional role for AH in modulating pathologic changes in DM, anterior lens capsule, and the angular meshwork in these animals. PMID- 22253486 TI - Cosmetic outcome of posterior approach ptosis surgery (an American Ophthalmological Society thesis). AB - PURPOSE: To test the hypothesis that posterior approach ptosis surgery, with or without blepharoplasty, can improve the cosmetic appearance of the eyelid. METHODS: In a retrospective, observational, consecutive case cohort study, 261 patients who had posterior approach upper eyelid ptosis surgery with or without concurrent blepharoplasty performed by one surgeon, between 1997 and 2009, were reviewed. Patients were included if they had symmetric eyelid position within 1.5 mm at 3 months after surgery. Outcome measures were subjective grading of eyelid margin contour, millimeters of tarsal platform show (TPS), and millimeters of eyebrow fat span (BFS). Paired preoperative and postoperative standardized photographs were viewed in masked fashion by three experts. RESULTS: One hundred and forty patients (55 men, 85 women, mean age 70 years, range 20-93) who underwent 233 posterior approach procedures for correction of upper eyelid ptosis had postoperative eyelid symmetry within 1.5 mm. Concurrent blepharoplasty was performed in 67 cases. Eyelid contour scores were significantly improved following surgery (P=.009). Ptosis surgery, without blepharoplasty, decreased the TPS, from 6.1+/-2.5 mm to 4.8+/-2.0 mm (P<.001). Patients who underwent concurrent blepharoplasty had a statistically insignificant increase of TPS from 4.0+/-3.5 mm to 4.3+/-3.6 mm, had a decrease of BFS from 20.8+/-6.3 mm to 17.7+/ 6.4 mm (P=.001), and showed similar BFS symmetry postoperatively, compared to patients who had ptosis surgery only. CONCLUSIONS: posterior approach surgery alone was often successful in controlling TPS: it shortened the TPS. Blepharoplasty combined with posterior approach ptosis surgery tended to lengthen the TPS and shorten the BFS. PMID- 22253487 TI - The role of thyroid eye disease and other factors in the overcorrection of hypotropia following unilateral adjustable suture recession of the inferior rectus (an American Ophthalmological Society thesis). AB - PURPOSE: Overcorrection of hypotropia subsequent to adjustable suture surgery following inferior rectus recession is undesirable, often resulting in persistent diplopia and reoperation. I hypothesized that overcorrection shift after suture adjustment may be unique to thyroid eye disease, and the use of a nonabsorbable suture may reduce the occurrence of overcorrection. METHODS: A retrospective chart review of adult patients who had undergone eye muscle surgery with an adjustable suture technique was performed. Overcorrection shifts that occurred between the time of suture adjustment and 2 months postoperatively were examined. Descriptive statistics, linear regression, Anderson-Darling tests, generalized Pareto distributions, odds ratios, and Fisher tests were performed for two overcorrection shift thresholds (>2 and >5 prism diopters [PD]). RESULTS: Seventy seven patients were found: 34 had thyroid eye disease and inferior rectus recession, 30 had no thyroid eye disease and inferior rectus recession, and 13 patients had thyroid eye disease and medial rectus recession. Eighteen cases exceeded the 2 PD threshold, and 12 exceeded the 5 PD threshold. Statistical analyses indicated that overcorrection was associated with thyroid eye disease (P=6.7E-06), inferior rectus surgery (P=6.7E-06), and absorbable sutures (>2 PD: OR=3.7, 95% CI=0.4-35.0, P=0.19; and >5 PD: OR=6.0, 95% CI=1.1-33.5, P=0.041). CONCLUSIONS: After unilateral muscle recession for hypotropia, overcorrection shifts are associated with thyroid eye disease, surgery of the inferior rectus, and use of absorbable sutures. Surgeons performing unilateral inferior rectus recession on adjustable suture in the setting of thyroid eye disease should consider using a nonabsorbable suture to reduce the incidence of postoperative overcorrection. PMID- 22253485 TI - The influence of genetics on response to treatment with ranibizumab (Lucentis) for age-related macular degeneration: the Lucentis Genotype Study (an American Ophthalmological Society thesis). AB - PURPOSE: Age-related macular degeneration (AMD) has a complex etiology arising from genetic and environmental influences. This past decade have seen several genes associated with the disease. Variants in five genes have been confirmed to play a major role. The objective of this study was to evaluate whether genes influence treatment response to ranibizumab for neovascular AMD. The hypothesis was that an individual's genetic variation will determine treatment response. METHODS: The study was a two-site prospective open-label observational study of patients newly diagnosed with exudative (neovascular) AMD receiving intravitreal ranibizumab therapy. Treatment-naive patients were enrolled at presentation and received monthly "as needed" therapy. Clinical data was collected monthly and DNA extracted. Genotyping was performed using the Illumina (San Diego, California) 660-Quad single-nucleotide polymorphism (SNP) chip. Regression analyses were performed to identify SNPs associated with treatment-response end points. RESULTS: Sixty-five patients were enrolled. No serious adverse events were recorded. The primary outcome measure was change in ETDRS visual acuity at 12 months. A SNP in the CFH gene was found to be associated with less improvement in visual acuity while receiving ranibizumab therapy. The C3 gene, among others, was associated with reduced thickening and improved retinal architecture. VEGFA, FLT1, and CFH were associated with requiring fewer ranibizumab injections over the 12-month study. CONCLUSIONS: This study is one of the first prospective pharmacogenetic study of intravitreal ranibizumab. Although preliminary, the results identify a number of putative genetic variants, which will be further examined by replication and functional studies to elucidate the complete pharmacogenetic architecture of therapy for AMD. PMID- 22253488 TI - Wavefront-guided laser in situ keratomileusis (Lasik) versus wavefront-guided photorefractive keratectomy (Prk): a prospective randomized eye-to-eye comparison (an American Ophthalmological Society thesis). AB - PURPOSE: To compare the safety and efficacy of wavefront-guided laser in situ keratomileusis (LASIK) vs photorefractive keratectomy (PRK) in a prospective randomized clinical trial. METHODS: A cohort of 68 eyes of 34 patients with -0.75 to -8.13 diopters (D) of myopia (spherical equivalent) were randomized to receive either wavefront-guided PRK or LASIK in the fellow eye using the VISX CustomVue laser. Patients were evaluated at 1 day, 1 week, and months 1, 3, 6, and 12. RESULTS: At 1 month, uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), 5% and 25% contrast sensitivity, induction of higher-order aberrations (HOAs), and subjective symptoms of vision clarity, vision fluctuation, ghosting, and overall self-assessment of vision were worse (P<0.05) in the PRK group. By 3 months, these differences had resolved (P>0.05). At 1 year, mean spherical equivalent was reduced 94% to -0.27 +/- 0.31 D in the LASIK group and reduced 96% to -0.17 +/- 0.41 D in the PRK group. At 1 year, 91% of eyes were within +/-0.50 D and 97 % were within +/-1.0 D in the PRK group. At 1 year, 88% of eyes were within +/-0.50 D and 97% were within +/-1.0 D in the LASIK group. At 1 year, 97% of eyes in the PRK group and 94% of eyes in the LASIK group achieved an UCVA of 20/20 or better (P=0.72). Refractive stability was achieved in both PRK and LASIK groups after 1 month. There were no intraoperative or postoperative flap complications in the LASIK group. There were no instances of corneal haze in the PRK group. CONCLUSIONS: Wavefront-guided LASIK and PRK are safe and effective at reducing myopia. At 1 month postoperatively, LASIK demonstrates an advantage over PRK in UCVA, BSCVA, low-contrast acuity, induction of total HOAs, and several subjective symptoms. At postoperative month 3, these differences between PRK and LASIK results had resolved. PMID- 22253489 TI - Comparison of through-focus image quality across five presbyopia-correcting intraocular lenses (an American Ophthalmological Society thesis). AB - PURPOSE: To assess through-focus polychromatic image sharpness of five US Food and Drug Administration-approved presbyopia-correcting intraocular lenses (IOLs) through a range of object vergences and pupil diameters utilizing an image sharpness algorithm. METHODS: A 1951 US Air Force resolution target was imaged through a Crystalens AO (AO) (Bausch & Lomb Surgical, Aliso Viejo, California), Crystalens HD (HD) (Bausch & Lomb Surgical, Aliso Viejo, California), aspheric ReSTOR +4.0 (R4) (Alcon Laboratories, Fort Worth, Texas), aspheric ReSTOR +3.0 (R3) (Alcon Laboratories, Fort Worth, Texas), and Tecnis Multifocal Acrylic (TMF) (Abbott Medical Optics, Irvine, California) IOL in an anatomically and optically accurate model eye and captured digitally for each combination of pupil diameter and object vergence. The sharpness of each digital image was objectively scored using a two-dimensional gradient function. RESULTS: The AO lens had the best distance image sharpness for all pupil diameters, followed by the HD. With a 5-mm pupil, the R4 lens achieved distance image quality similar to the HD, but inferior to the AO. The R3 successfully moved the near focal point farther from the patient compared to the R4, but did not improve image sharpness at intermediate distances and showed worse distance and near image sharpness. Consistent with apodization, the ReSTOR IOLs displayed better distance and poorer near image sharpness as pupil diameter increased. The TMF lens showed consistent distance and near image sharpness across pupil diameters and exhibited the best near image sharpness for all pupil diameters. CONCLUSIONS: Differing IOL design strategies to increase depth of field are associated with quantifiable differences in image sharpness at varying vergences and pupil sizes. An objective comparison of the imaging properties of specific presbyopia-correcting IOLs, in conjunction with patients' pupil sizes, can be useful in selecting the most appropriate IOL for each patient. PMID- 22253490 TI - The decompensated monofixation syndrome (an American Ophthalmological Society thesis). AB - PURPOSE: To describe the clinical features and response to treatment of patients with decompensated monofixation syndrome (MFS) and to propose a hypothesis for a decompensation mechanism in such patients. METHODS: Fourteen adults with MFS who had been symptomatically stable for a mean duration of 25 years developed diplopia in the absence of neurologic or orbital disease. After retrospective chart review, they underwent detailed orthoptic testing. Results from this cross sectional analysis were compared with similar data from 16 control subjects with stable MFS. RESULTS: Compared to stable MFS patients, decompensated subjects had significantly poorer horizontal fusional amplitudes but greater torsional fusional amplitudes; they were also more likely to have a small vertical strabismus and to have received initial treatment later. Stable subjects, however, also had subnormal horizontal as well as torsional fusional amplitudes. There was no difference between groups with respect to refractive error, amblyopia, type or prior treatment of strabismus, stereoacuity, or angle of deviation. After treatment, all patients regained monofixational alignment, but up to one-third had continued diplopia. Symptoms recurred in two patients whose treatment was initially successful. CONCLUSIONS: Patients with MFS lose fusional amplitudes over time. In some cases this results in development of sensory torsion with secondary decompensation and diplopia. The rate of decompensation averages 7% per year from ages 20 to 70. Treatment for decompensation offers excellent motor results, but sensory symptoms may persist and recurrent symptoms may develop. Monitoring and maintenance of fusional vergence amplitudes should be part of the routine care for patients with MFS. PMID- 22253491 TI - Individual differences in neurocognitive aging of the medial temporal lobe. AB - A wide spectrum of outcomes in the cognitive effects of aging is routinely observed in studies of the elderly. Individual differences in neurocognitive aging are also a characteristic of other species, such as rodents and non-human primates. In particular, investigations at behavioral, brain systems, cellular and molecular levels of analysis have provided much information on the basis for individual differences in neurocognitive aging among healthy outbred rats. These findings are likely to be relevant to an understanding of the effects of aging on the brain, apart from neurodegenerative conditions, such as Alzheimer's disease, which do not naturally occur in rodents. Here we review and integrate those findings in a model supporting the concept that certain features of cognitive decline are caused by distributed alterations in the medial temporal lobe, which alter the information processing functions of the hippocampal formation. An additional emerging concept from this research is that preserved abilities at older ages may depend on adaptive changes in the hippocampal system that distinguish successful aging. PMID- 22253492 TI - Spatial learning and psychomotor performance of C57BL/6 mice: age sensitivity and reliability of individual differences. AB - Two tests often used in aging research, the elevated path test and the Morris water maze test, were examined for their application to the study of brain aging in a large sample of C57BL/6JNia mice. Specifically, these studies assessed: (1) sensitivity to age and the degree of interrelatedness among different behavioral measures derived from these tests, (2) the effect of age on variation in the measurements, and (3) the reliability of individual differences in performance on the tests. Both tests detected age-related deficits in group performance that occurred independently of each other. However, analysis of data obtained on the Morris water maze test revealed three relatively independent components of cognitive performance. Performance in initial acquisition of spatial learning in the Morris maze was not highly correlated with performance during reversal learning (when mice were required to learn a new spatial location), whereas performance in both of those phases was independent of spatial performance assessed during a single probe trial administered at the end of acquisition training. Moreover, impaired performance during initial acquisition could be detected at an earlier age than impairments in reversal learning. There were modest but significant age-related increases in the variance of both elevated path test scores and in several measures of learning in the Morris maze test. Analysis of test scores of mice across repeated testing sessions confirmed reliability of the measurements obtained for cognitive and psychomotor function. Power calculations confirmed that there are sufficiently large age-related differences in elevated path test performance, relative to within age variability, to render this test useful for studies into the ability of an intervention to prevent or reverse age-related deficits in psychomotor performance. Power calculations indicated a need for larger sample sizes for detection of intervention effects on cognitive components of the Morris water maze test, at least when implemented at the ages tested in this study. Variability among old mice in both tests, including each of the various independent measures in the Morris maze, may be useful for elucidating the biological bases of different aspects of dysfunctional brain aging. PMID- 22253493 TI - Relationships among cognitive function, fine motor speed and age in the rhesus monkey. AB - Declines in fine motor skills and cognitive function are well known features of human aging. Yet, the relationship between age-related impairments in motor and cognitive function remains unclear. Rhesus monkeys, like humans, show marked decline in cognitive and fine motor function with age and are excellent models to investigate potential interactions between age-related declines in cognitive and motor functioning. We investigated the relationships among cognition, motor function and age in 30 male and female rhesus monkeys, 5-28 years of age, tested on a battery of cognitive tasks [acquisition of the delayed non-matching-to sample (DNMS), DNMS-120s, DNMS-600s, acquisition of delayed recognition span test (DRST), spatial-DRST and object-DRST] and a fine motor task (Lifesaver test). Global cognitive ability, as assessed by the cognitive performance index (CPI), was impaired with age in both sexes, while age-related motor slowing was found only in males. After age was controlled for, half the variance in CPI was predicted by motor speed, with better cognitive ability associated with slower motor skills. Analyses at the level of each cognitive task revealed that motor speed and age predicted the rate of acquisition of the DNMS. This relationship was robust in males and absent in females. Motor speed was not a significant predictor of any other cognitive variable. We conclude that the relationship between cognition and motor function (1) may be limited to non-spatial tasks; (2) exists independently of age; (3) may reflect different contributions of the fronto-striatal system; (4) may be particularly evident in males. PMID- 22253494 TI - Profiling psychomotor and cognitive aging in four-way cross mice. AB - In part due to their genetic uniformity and stable characteristics, inbred rodents or their F1 progeny are frequently used to study brain aging. However, it is recognized that focus on a single genotype could lead to generalizations about brain aging that might not apply to the species as a whole, or to the human population. As a potential alternative to uniform genotypes, genetically heterogeneous (HET) mice, produced by a four-way cross, were tested in the current study to determine if they exhibit age-related declines in cognitive and psychomotor function similar to other rodent models of brain aging. Young (4 months) and older (23 months) CB6F1 * C3D2F1 mice were administered a variety of tests for cognitive, psychomotor, and sensory/reflexive capacities. Spontaneous locomotion, rearing, and ability to turn in an alley all decreased with age, as did behavioral measures sensitive to muscle strength, balance, and motor coordination. Although no effect of age was found for either startle response amplitude or reaction time to shock stimuli, the old mice reacted with less force to low intensity auditory stimuli. When tested on a spatial swim maze task, the old mice learned less efficiently, exhibited poorer retention after a 66-h delay, and demonstrated greater difficulty learning a new spatial location. In addition, the older mice were less able to learn the platform location when it was identified by a local visual cue. Because there was a significant correlation between spatial and cued discrimination performance in the old mice, it is possible that age-related spatial maze learning deficits could involve visual or motor impairments. Variation among individuals increased with age for most tests of psychomotor function, as well as for spatial swim performance, suggesting that four-way cross mice may be appropriate models of individualized brain aging. However, the analysis of spatial maze learning deficits in older CB6F1 * C3D2F1 mice may have limited applicability in the study of brain aging, because of a confounding with visually cued performance deficits. PMID- 22253495 TI - Age-related disruptions of circadian rhythm and memory in the senescence accelerated mouse (SAMP8). AB - Common complaints of the elderly involve impaired cognitive abilities, such as loss of memory and inability to attend. Although much research has been devoted to these cognitive impairments, other factors such as disrupted sleep patterns and increased daytime drowsiness may contribute indirectly to impaired cognitive abilities. Disrupted sleep-wake cycles may be the result of age-related changes to the internal (circadian) clock. In this article, we review recent research on aging and circadian rhythms with a focus on the senescence-accelerated mouse (SAM) as a model of aging. We explore some of the neurobiological mechanisms that appear to be responsible for our aging clock, and consider implications of this work for age-related changes in cognition. PMID- 22253497 TI - Age editorial. PMID- 22253496 TI - Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia. AB - Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer's disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD. PMID- 22253499 TI - Dietary differences between centenarians residing in communities and in skilled nursing facilities: the Georgia Centenarian Study. AB - The purpose of this study was to examine the dietary habits among centenarians residing in community settings (n=105) and in skilled nursing facilities (n=139). The sample was a population-based multi-ethnic sample of adults aged 98 years and older (N=244) from northern Georgia in the US. Compared to centenarians in skilled nursing facilities, those residing in the community were more than twice as likely to be able to eat without help and to receive most of their nourishment from typical foods, but they had a lower frequency of intake of all of the food groups examined, including dairy, meat, poultry and fish, eggs, green vegetables, orange/yellow vegetables, citrus fruit or juice, non-citrus fruit or juice, and oral liquid supplements. A food summary score was created (the sum of the meeting recommendations for five food groups). In multiple regression analyses, the food summary scores were positively associated with residing in a nursing facility and negatively associated with eating without help and receiving most nourishment from typical foods. These data suggest that centenarians residing in communities may have limited access to foods that are known to provide nutrients essential to health and well-being. Also, centenarians who are able to eat without help and/or who eat mainly typical foods may have inadequate intakes of recommended food groups. Given the essential role of foods and nutrition to health and well-being throughout life, these findings require further exploration through the detailed dietary analyses of centenarians living in various settings. PMID- 22253498 TI - Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study. AB - Centenarians represent a rare phenotype appearing in roughly 10-20 per 100,000 persons in most industrialized countries but as high as 40-50 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58 fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90 years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity. PMID- 22253500 TI - Personality and longevity: findings from the Georgia Centenarian Study. AB - Centenarians are thought of as unique and exceptional survivors. This study evaluated specific personality traits and configurations of traits among participants of the Georgia Centenarian Study. Two hundred and eighty five centenarians and their nominated proxies participated in this study. Self ratings and proxy informant ratings were obtained for different traits and facets of the Big-5 personality typology. Results suggested that centenarians overall had low levels of Neuroticism, but high levels of Extraversion, Competence, and Trust. When compared to centenarian self ratings, proxies provided significantly higher ratings for Neuroticism, Hostility, and Vulnerability, but lower ratings for Competence and Trust. Among Centenarians, the personality configuration of low Neuroticism, high Competence, and high Extraversion traits is over-represented relative to chance. The results confirm that centenarians show several unique single traits, but that a special combination of traits (i.e., low levels of Neuroticism, high Competence, and high Extraversion) are also notable in this group of exceptional survivors. PMID- 22253501 TI - Do personality characteristics predict longevity? Findings from the Tokyo Centenarian Study. AB - To explore whether personality influences longevity we examined the personality characteristics of centenarians. We developed a new method that compares an actual personality test score for centenarians with a predicted test score for a 100-year-old, calculated from younger controls. The participants consisted of 70 cognitively intact Japanese centenarians aged 100-106 years and 1812 elderly people aged 60-84 years, all residents of Tokyo. The NEO five factor inventory (NEO-FFI) was used to assess the "big five" personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness. The results showed higher openness in both male and female centenarians, and higher conscientiousness and extraversion in female centenarians, as compared to controls. These results suggest that high scores in the specific personality traits conscientiousness, extraversion, and openness, are associated with longevity. We speculate that these personality traits contribute to longevity through health-related behavior, stress reduction, and adaptation to the challenging problems of the "oldest old". PMID- 22253502 TI - Planned progress for health. PMID- 22253503 TI - Reverse pharmacology for antimalarial plants goes global. PMID- 22253504 TI - Observational therapeutics: Scope, challenges, and organization. AB - The importance of Observational Therapeutics in the progress of medicine has been neglected in the current era of the hierarchal position imparted to Randomized Controlled Trials (RCTs) for new drug discovery and practice of evidence-based medicine. There is a need to reflect on the reason for many new drugs being withdrawn during post marketing surveillance. There are several examples in literature where drug-discovery has originated initially from keen clinical and / or laboratory observations. The roots of these discoveries have often been from observations made by practitioners of traditional medicine including Ayurveda. The present article draws attention to the scope and challenges for observational therapeutics. There is an urgent need for the meticulous planning for a systematic organization of developing observational therapeutics, with a full understanding of its strengths and limitations. PMID- 22253505 TI - Practices at an AYUSH health camp for asthma in Pendra, Chhattisgarh. AB - Chhattisgarh has abundant herbal resources and a parallel AYUSH public health system. AYUSH health camps are conducted regularly in rural areas of the State by public and social sectors. The study aims to advocate the gravity of policy issues involved in AYUSH practices at health camps. A cross-sectional study was conducted in Pendra block of Bilaspur district, Chhattisgarh. Random sample of 600 people attending the camp were interviewed. A semi-structured questionnaire was used to collect data on disease complaints and established risk factors for asthma. Pearson's Chi-square test was used to calculate odds ratio (OR) with 95% confidence interval (CI). Analysis suggests that there was a significant decrease in reported asthmatic attacks (OR 6.68, 95% CI 4.05-11.01) among those who attended the camp. Established risk factors of asthma that were identified as prevalent in the community were using wood and biomass as fuel (OR 2.61, 95% CI 1.30-5.24) and damp walls (OR 1.88, CI 0.9-3.93). Practices at AYUSH health camps conducted by the public and nonpublic sectors need to be documented and reported. People have faith in traditional medicine, and the remedies and practices need to be further explicated and validated in context to health care-seeking practices. The importance of formulation of guidelines by the government for conducting AYUSH health camps is indicated. PMID- 22253506 TI - Puttur kattu (bandage) - A traditional bone setting practice in south India. AB - Traditional bone setting practices are quite popular in India and nearly 6000 traditional bone setting Vaidyas (Practisioners) are practicing the same in our country. Puttur kattu is a traditional way of bone setting practice, invented accidentally by K. Kesava Raju in 1881. Now, the fourth generation of his family is practicing this bone setting practice in hospitals at Puttur, Andhra Pradesh, with 200-300 patients per day. A prospective study was undertaken to analyze the techniques in diagnosis, way of management, medicine preparation, plants used and way of applications by traditional bone setter (TBS) Vaidyas, with special reference to Puttur. We also tried to understand the reasons which make lots of people go to Puttur for getting treatment, means of contact for treatment, pathology of fracture and outcome of some treated cases through this study. 54% of the studied patients came to Puttur TBS on the advice of old patients. It is observed that more educated people are patronizing this therapy and 23% patients of the observed cases took discharge from modern hospital voluntarily to receive Puttur kattu treatment. 80% patients believed that this therapy with home remedy would fasten the healing process. 44% patients opted for this therapy due to fear of pain, heavy plaster of Paris bandage, prolonged period of immobilization, surgery and amputation. 71% patients of the followed cases were satisfied with the treatment of TBS of Puttur with minimum complications. The authors also attempted to put forth the legacy of the tradition, the way of management and the plant used for bone setting by the Puttur bone setting Vaidyas. PMID- 22253507 TI - Contribution of world health organization in the global acceptance of Ayurveda. AB - Amongst the mandates of United Nations, health of mankind is the thrust area of UN through World Health Organization (WHO). Planning and execution of policies for mainstreaming of traditional medicines (TRM) of respective countries along with conventional system of medicine (allopathy), first in the country of origin followed by the international arena, is the priority agenda of operations of WHO. Within Indian context, WHO accorded prime focus to Ayurveda in its activities related to TRM.Sponsorship and encouragement of studies substantiating parameters of standardization, safety and efficacy of herbal medicines of Ayurveda are under chief consideration of WHO. In this review, several guidelines of WHO are summarized. Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH), Central Council of Research in Ayurveda and Siddha and numerous other collaborative centers of WHO in India are assigned with several Appraisal Project Work (APW) and Direct Financial Cooperation (DFC) projects that will strengthen Ayurveda as evidence-based medicine for its global acceptance. Implementation of pharmacovigilance program in Ayurveda, publication of documents for rational use and initiatives to prepare consumer guidelines for appropriate use of Ayurvedic medicines are some other contributions of WHO toward advancement of Ayurveda at national as well as global level. Here, we suggest further exploration, interaction and interpretation of traditional knowledge in the light of contemporary core sciences and biomedical sciences that can pave the way for accreditation of Ayurveda worldwide as an established system of medicine. PMID- 22253508 TI - Evaluation of the effect of conventionally prepared swarna makshika bhasma on different bio-chemical parameters in experimental animals. AB - Swarna makshika (chalcopyrite) bhasma (SMB) has been used for different therapeutic purposes since long in Ayurveda. The present study is conducted to evaluate the effect of conventionally prepared SMB on different bio-chemical parameters in experimental animals, for providing scientific data base for its logical use in clinical practice. The genuine SMB was prepared by following classical techniques of shodhana and marana most commonly used by different Ayurvedic drug manufacturers. Shodhana was done by roasting raw swarna makshika with lemon juice for three days and marana was performed by 11 putas. The experimental animals (rats) were divided into two groups. SMB mixed with diluted honey was administered orally in therapeutic dose to Group SMB and diluted honey only was administered to vehicle control Group, for 30 days. The blood samples were collected twice, after 15 days and after 30 days of drug administration and different biochemical investigations were done. Biochemical parameters were chosen based on references from Ayurvedic classics and contemporary medicine. It was observed that Hb% was found significantly increased and LDL and VLDL were found significantly decreased in Group SMB when compared with vehicle control group. This experimental data will help the clinician for the logical use of SMB in different disease conditions with findings like low Hb% and high LDL, VLDL levels. PMID- 22253509 TI - Evaluation of immunomodulatory activity of "Shirishavaleha"-An Ayurvedic compound formulation in albino rats. AB - The immunomodulatory activity of Shirishavaleha prepared from two different parts of Shirisha (Albizia lebbeck Benth), i.e., Twak (Bark) and Sara (Heartwood) as main ingredients was evaluated for humoral antibody formation and cell-mediated immunity in established experimental models. The study used Wistar rats of either sex weighing 200 +/- 40 g, while the test drug was administered orally at a dose of 1.8 g/kg. Hemagglutination titer and body weight were recorded to assess effects on humoral immunity; immunological paw edema was assessed for cell mediated immunity. Shirishavaleha prepared from heartwood shows significant enhancement in antibody formation, attenuation of body weight changes, and suppression of immunological paw edema, while Shirishavaleha prepared from bark shows weak immunomodulatory activity. The study therefore concludes that Shirishavaleha prepared from heartwood has significant immunomodulatory activity. PMID- 22253510 TI - Effectiveness, safety, and standard of service delivery: A patient-based survey at a pancha karma therapy unit in a secondary care Ayurvedic hospital. AB - Pancha karma is a modality of treatments commonly used in Ayurvedic hospitals. It has elaborate textual reference of its usage in various clinical conditions forming the basis of its extensive use in Ayurvedic clinical practice. Unfortunately, despite its unquestionable popularity and usage among Ayurvedic physicians and patients, it has not been evaluated rigorously on scientific parameters to identify its effectiveness, safety, and procedural standards. Considering the patient's opinion as an important determinant in this perspective, this study aims at identifying the patient's (actual recipients of pancha karma therapy) perception toward the effectiveness, safety, and standard of service delivery concerning pancha karma through a structured survey at a pre identified pancha karma therapy unit in a secondary care Ayurvedic hospital. Majority of the survey respondents considered these therapies as safe and effective (88%). Ninety-four percent respondents have expressed their satisfaction to the standard of services provided to them at the pancha karma unit of the hospital concerned. PMID- 22253511 TI - Dr. Sharadini dahanukar. PMID- 22253512 TI - Dr. Ashok DB Vaidya. PMID- 22253514 TI - Future events. PMID- 22253513 TI - "Science means learning to say-I don't know": An interview with Dr. Ashok D.B. Vaidya. AB - Dr. Ashok D.B. Vaidya, the stalwart in the fields of Experimental Pharmacology, Clinical Pharmacology, and Reverse Pharmacology turns 75 on Nov, 27, 2011. A former Clinical Research Head of CIBA Geigy Research Centre, his name has been synonymous with the concept of the Golden Triangle for resurgence of Ayurveda and its reinterpretation in modern scientific terms. At a time when most fields are populated by intellectual dwarfs and unethical operators, he stands like a giant a scientist, a philosopher, and an ardent fighter for ethical values. In this free-wheeling interview with Ravindra R.Pandharinath, he discusses the milestones in his life, his inspirations, and dreams for the confluence of modern science, modern medicine, and Ayurveda as the new health care model for the 21st century. PMID- 22253515 TI - Current treatment options and response rates in children with chronic hepatitis C. AB - Vertical transmission has become the most common mode of transmission of hepatitis C virus (HCV) in children. The rate of perinatal transmission from an HCV-infected mother to her child ranges from 2% to 5% and the prevalence of HCV in children in developed countries ranges between 0.1% and 0.4%. Spontaneous viral clearance seems to be dependent on the genotype and has been reported between 2.4%-25%. For chronically infected patients, treatment with recombinant polyethylene glycol (PEG)-interferon alpha-2b and daily ribavirin has now been approved as standard treatment for children 2-17 years of age. In five large prospective studies, a total of 318 children and adolescents aged 3-17 years were treated either with subcutaneous PEG-interferon alpha-2b at a dose of 1-1.5 MUg/kg or 60 MUg/m2 once a week in combination with oral ribavirin (15 mg/kg per day) or PEG-interferon alpha-2a with ribavirin. Subjects with genotype 1 and 4 received the medication for 48 wk and individuals with genotype 2 and 3 mainly for 24 wk. Overall sustained viral response (SVR) was achieved in 193/318 (60.7%) of treated patients. Stratified for genotype; 120/234 (51%) with genotype 1, 68/73 (93%) with genotype 2/3, and 6/11 (55%) with genotype 4 showed SVR. Relapse rate was between 7.7% and 17%. Overall, treatment was well tolerated; however, notable side effects were present in approximately 20%. According to recent experiences in the treatment of chronic hepatitis C in children and adolescents, a combination of PEG-interferon alpha with ribavirin has been found to be well tolerated and highly efficacious, particularly in individuals with genotype 2/3. Thus, this treatment can be recommended as standard of care until more effective treatment options will become available for genotype 1 patients. PMID- 22253516 TI - Role of genetics in the diagnosis and prognosis of Crohn's disease. AB - Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians. PMID- 22253517 TI - Immune mechanisms of Concanavalin A model of autoimmune hepatitis. AB - As a chronic inflammatory disease of the liver, the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated, with prognosis and diagnosis remaining unsatisfied. Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation. It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure. The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice, which closely mimics the pathogenesis mechanisms and pathological changes of patients, and is regarded as the best experimental model for AIH research so far. In this paper we elucidated the pathogenic mechanisms of AIH and the evolution of relative animal models. We go on to further focus on Con A induced liver injury from the point of immunological mechanisms and the change of cytokine levels. Finally, we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development. PMID- 22253518 TI - Suppression of esophageal cancer cell growth using curcumin, (-)-epigallocatechin 3-gallate and lovastatin. AB - AIM: To determine the effects of curcumin, (-)-epigallocatechin-3-gallate (EGCG), lovastatin, and their combinations on inhibition of esophageal cancer. METHODS: Esophageal cancer TE-8 and SKGT-4 cell lines were subjected to cell viability methyl thiazolyl tetrazolium and tumor cell invasion assays in vitro and tumor formation and growth in nude mouse xenografts with or without curcumin, EGCG and lovastatin treatment. Gene expression was detected using immunohistochemistry and Western blotting in tumor cell lines, tumor xenografts and human esophageal cancer tissues, respectively. RESULTS: These drugs individually or in combinations significantly reduced the viability and invasion capacity of esophageal cancer cells in vitro. Molecularly, these three agents reduced the expression of phosphorylated extracellular-signal-regulated kinases (Erk1/2), c Jun and cyclooxygenase-2 (COX-2), but activated caspase 3 in esophageal cancer cells. The nude mouse xenograft assay showed that EGCG and the combinations of curcumin, EGCG and lovastatin suppressed esophageal cancer cell growth and reduced the expression of Ki67, phosphorylated Erk1/2 and COX-2. The expression of phosphorylated Erk1/2 and COX-2 in esophageal cancer tissue specimens was also analyzed using immunohistochemistry. The data demonstrated that 77 of 156 (49.4%) tumors expressed phosphorylated Erk1/2 and that 121 of 156 (77.6%) esophageal cancers expressed COX-2 protein. In particular, phosphorylated Erk1/2 was expressed in 23 of 50 (46%) cases of esophageal squamous cell carcinoma (SCC) and in 54 of 106 (50.9%) cases of adenocarcinoma, while COX-2 was expressed in 39 of 50 (78%) esophageal SCC and in 82 of 106 (77.4%) esophageal adenocarcinoma. CONCLUSION: The combinations of curcumin, EGCG and lovastatin were able to suppress esophageal cancer cell growth in vitro and in nude mouse xenografts, these drugs also inhibited phosphorylated Erk1/2, c-Jun and COX-2 expression. PMID- 22253519 TI - Characterization of gastric cancer models from different cell lines orthotopically constructed using improved implantation techniques. AB - AIM: To develop orthotopic gastric cancer mouse models from different cell lines and characterize the tumor features to assist further in preclinical trials and clinical treatment strategies. METHODS: Human gastric cancer SGC-7901 and BGC-823 cell suspensions were injected subcutaneously into nude mice to develop solid tumors, and tumor tissue pieces were then implanted under the serous coat of the stomach. An autopsy was performed on all animals of the SGC-7901 and BGC-823 models to observe the primary tumor growth and metastases using pathological and immunohistochemical methods. RESULTS: Both models showed large tumors in situ resulting in pressure and infiltration of the adjacent organs. The gastric cavity became smaller, along with stenosis of the cardia or pylorus. There were biological and statistical differences between the two models. The metastasis rate in involved organs (lymph nodes, kidney, spleen, testis) was significantly higher in the BGC-823 model compared to the SGC-7901 model (P < 0.05 or P < 0.01). The median survival of the BGC-823 model was shorter than that of SGC-7901 (23 d vs 84 d, P < 0.05). Histopathologically, the primary tumor and metastatic lesions of the two models showed obvious atypia and mucus in the cytoplasm. Compared with the SGC-7901 model, BGC-823 appeared more poorly differentiated (absence of adenoid structure), had a smaller volume, and richer capillary structure. Immunohistochemical staining revealed cytokeratin 20 and epithelial membrane antigen expression was positive in the SGC-7901 tumors, while negative in BGC-823 ones. CONCLUSION: Models using the SGC-7901 and BGC-823 cell lines were established which could function in gastric cancer research on carcinogenesis mechanism and drug discovery. The two models showed different tumor behavior and the latter was more malignant than the former. PMID- 22253520 TI - B1a lymphocytes in the rectal mucosa of ulcerative colitis patients. AB - AIM: To assess B1a cell expression in the rectal mucosa of ulcerative colitis (UC) patients in comparison with healthy controls. METHODS: Rectal mucosa biopsies were collected from 15 UC patients and 17 healthy controls. CD5(+) B cells were analysed by three colour flow cytometry from rectal mucosal samples after mechanical disaggregation by Medimachine((r)). Immunohistochemical analysis of B and T lymphocytes was also performed. Correlations between, on the one hand, rectal B1a cell concentrations and, on the other, erythrocyte sedimentation rate and C-reactive protein levels and clinical, endoscopic and histological disease activity indices were evaluated. RESULTS: Rectal B-lymphocyte (CD19(+)/CD45(+)) rate and concentration were higher in UC patients compared with those in healthy controls (47.85% +/- 3.12% vs 26.10% +/- 3.40%, P = 0.001 and 501 +/- 91 cells/mm(2) vs 117 +/- 18 cells/mm(2), P < 0.001); Rectal B1a cell density (CD5(+)CD19(+)) was higher in UC patients than in healthy controls (85 +/- 15 cells/mm(2) vs 31 +/- 6.7 cells/mm(2), P = 0.009). Rectal B1a cell (CD5/CD19(+)) rate correlated inversely with endoscopic classification (Rs = -0.637, P < 0.05). CONCLUSION: B1a lymphocytes seem to be involved in the pathogenesis of UC, however, the role they play in its early phases and in disease activity, have yet to be defined. PMID- 22253521 TI - Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology. AB - AIM: To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). METHODS: 120 cases of primary gastric carcinomas and 45 matched lymph node metastases from patients with full clinicopathological features were mounted onto multiple-punch and single-punch tissue microarrays, respectively, and examined for HER2 overexpression and gene amplification by IHC and CISH. RESULTS: Twenty-four tumors (20%) expressed HER2 immunohistochemically. An IHC score of >= 2+ was observed in 20 tumors (16.6%). HER2 amplification was detected by CISH in 19 tumors (15.8%) and in their matched lymph node metastases. A high concordance rate was found between HER2 positivity (as detected by IHC) and HER2 gene amplification (as detected by CISH), since 19 of the 20 IHC positive cases were amplified (95%). All amplified cases had 2+ or 3+ IHC results. Amplification was associated with intestinal phenotype (P < 0.05). No association with grading, staging or survival was found. CONCLUSION: In gastric cancer, HER2 amplification is the main mechanism for HER2 protein overexpression and is preserved in lymph node metastases. PMID- 22253522 TI - Protective effect of alcohol consumption for fatty liver but not metabolic syndrome. AB - AIM: To investigate the effect of alcohol on the metabolic syndrome (MS) and fatty liver in Japanese men and women. METHODS: A cross-sectional study was conducted in a medical health checkup program at a general hospital. This study involved 18 571 Japanese men and women, 18-88 years of age, with a mean body mass index of 22.6 kg/m(2). A standardized questionnaire was administered. The total amount of alcohol consumed per week was calculated, and categorized into four grades. Fatty liver was examined by ultrasound modified criteria of the revised National Cholesterol Education Program Adult Treatment Panel III and the new International Diabetes Federation. RESULTS: The prevalence of fatty liver decreased in men and women with light to moderate alcohol consumption, whereas the prevalence of MS was not so changed. The prevalence of fatty liver of any grade in men was lower than that in those with no or minimal alcohol consumption. In women with light to moderate alcohol consumption, prevalence of fatty liver was lower than that in women with no or minimal alcohol consumption. By logistic regression analysis, the odds ratio (OR) for MS in women with light alcohol consumption was decreased to < 1.0, but this change was not clear in men. The OR for fatty liver was clearly < 1.0 in men with any level of alcohol consumption and in women with light to moderate consumption. CONCLUSION: Light to moderate alcohol consumption has a favorable effect for fatty liver, but not for MS in Japanese men and women. PMID- 22253523 TI - 18F-fluoro-2-deoxyglucose uptake on PET CT and glucose transporter 1 expression in colorectal adenocarcinoma. AB - AIM: To evaluate the correlation between the level of (18)F-fluoro-2-deoxyglucose ((18)F-FDG) uptake and glucose transporter 1 (GLUT1) expression in colorectal adenocarcinoma (CRA). METHODS: Forty four patients with resected CRA and preoperative (18)F-FDG positron emission tomography - computed tomography data were investigated in this study. Comparison of maximum standardized uptake value (SUVmax) of the lesion was made with GLUT1 expression by immunohistochemistry and various clinicopathologic factors including tumor volume, invasion depth, gross finding, and lymph node metastasis. RESULTS: SUVmax was 14.45 +/- 7.0 in negative GLUT1 expression cases, 15.51 +/- 5.7 in weak GLUT1 expression cases, and 16.52 +/- 6.8 in strong GLUT1 expression cases, and there was no correlation between between GLUT1 expression and SUVmax. SUVmax was significantly correlated with tumor volume (P < 0.001). However, there was no significant differences in SUVmax and GLUT1 expression among other clinicopathologic factors. CONCLUSION: GLUT1 expression does not correlates significantly with (18)F-FDG uptake in CRA. (18)F FDG uptake was increased with tumor volume, which is statistically significant. PMID- 22253524 TI - Prognostic relevance of circulating CK19 mRNA in advanced malignant biliary tract diseases. AB - AIM: To determine the role of circulating tumor cells (CTCs) in prediction of the overall survival of patients with advanced malignant biliary tract obstruction. METHODS: We investigated the prognostic value of CTCs by examining two markers, cytokeratin (CK) 19 and human telomerase reverse transcriptase (hTERT) mRNA, in 40 patients diagnosed with advanced malignant biliary tract diseases. Quantitative real-time reverse transcription polymerase chain reaction was used to detect CK19 and hTERT mRNA in the peripheral blood of these patients. Overall survival was analyzed using the Kaplan-Meier method and Cox regression modeling. RESULTS: Positive CK19 and hTERT mRNA expression was detected in 45% and 60%, respectively, of the 40 patients. Univariable analysis indicated that positive CK19 mRNA expression was significantly associated with worse overall survival (P = 0.009). Multivariable analysis determined that positive CK19 mRNA expression, patient's age and serum bilirubin were each independently associated with overall survival. CONCLUSION: CK19 mRNA expression levels in peripheral blood appear to provide a valuable marker to predict the overall survival of patients with advanced malignant biliary tract obstruction. PMID- 22253525 TI - Quality of life and psychological outcome of donors after living donor liver transplantation. AB - AIM: To investigate the health related quality of life (HRQoL) and psychological outcome of donors after living donor liver transplantation. METHODS: Participants were 92 consecutive liver transplant donors who underwent hepatectomy without middle hepatic vein at West China Hospital of Sichuan University between January 2007 and September 2010. HRQoL was measured using the Chinese version of the Medical Outcomes Study Short Form-36 (SF-36), and psychological symptoms were measured using the Symptom Checklist-90-Revised (SCL-90-R). Data collected from donors were compared to previously published data from the general population. Clinical and demographic data were collected from medical records and questionnaires. RESULTS: The general health score of the SF-36 was significantly lower in females (59.78 +/- 12.25) than in males (75.83 +/- 22.09). Donors more than 40 years old scored higher in social functioning (85.71 +/- 14.59) and mental health (82.61 +/- 20.00) than those younger than 40 (75.00 +/- 12.13, 68.89 +/- 12.98; social functioning and mental health, respectively). Donors who had surgery more than two years prior to the study scored highest in physical functioning (P = 0.001) and bodily pain (P = 0.042) while those less than one year from surgery scored lowest. The health of the liver recipient significantly influenced the general health (P = 0.042), social functioning (P = 0.010), and role-emotional (P = 0.028) of donors. Donors with full-time employment scored highest in role-physical (P = 0.005), vitality (P = 0.001), social functioning (P = 0.016), mental health (P < 0.001), the physical component summary scale (P < 0.001), and the mental component summary scale (MCS) (P < 0.001). Psychological measures indicated that donors were healthier than the general population in obsessive-compulsive behavior, interpersonal sensitivity, phobic anxiety, and paranoid ideation. The MCS of the SF-36 was significantly correlated with most symptom scores of the SCL-90-R. CONCLUSION: HRQoL and psychological outcome were favorable in living liver transplant donors after donation. Specifically, gender, age, time since operation, recipient health condition, and employment after donation, influenced postoperative quality of life. PMID- 22253526 TI - Central nervous system vasculitis and polyneuropathy as first manifestations of hepatitis C. AB - Sensory or motor peripheral neuropathy may be observed in a significant proportion of hepatitis C virus (HCV)-infected patients. However, central nervous system (CNS) involvement is uncommon, especially in cryoglobulin-negative subjects. We describe a case of peripheral neuropathy combined with an ischemic CNS event as primary manifestations of chronic HCV infection without cryoglobulinemia. Significant improvement was observed after antiviral therapy. We discuss the spectrum of neurological manifestations of HCV infection and review the literature. PMID- 22253527 TI - Concurrent systemic AA amyloidosis can discriminate primary sclerosing cholangitis from IgG4-associated cholangitis. AB - Chronic hepatobiliary inflammatory diseases are not widely acknowledged as underlying disorders of systemic AA amyloidosis, except epidemic schistosomiasis. Among them, primary sclerosing cholangitis (PSC) might initiate amyloid A protein deposition in diverse tissues, giving rise to systemic amyloidosis, due to a progressive and unresolved inflammatory process, and its possible association with inflammatory bowel diseases. Nevertheless, only one such case has been reported in the literature to date. We report a 69-year-old Japanese woman with cirrhosis who was diagnosed with PSC complicated with systemic AA amyloidosis, without any evidence of other inflammatory disorders. As a result of cholestasis in conjunction with biliary strictures and increased serum IgG4, the presence of IgG4(+) plasma cells was examined systemically, resulting in unexpected documentation of Congo-red-positive amyloid deposits, but not IgG4(+) plasma cells, in the liver, stomach and salivary glands. Elevated serum IgG4 is the hallmark of IgG4-related disease, including IgG4-associated cholangitis, but it has also been demonstrated in certain patients with PSC. Amyloid A deposits in multiple organs associated with an indolent clinical course that progresses over many years might have a diagnostic value in discriminating PSC from IgG4 associated cholangitis. PMID- 22253529 TI - Nutritional requirements for the improvement of growth and sporulation of several strains of Monascus purpureus on solid state cultivation. AB - This paper describes the nutritional requirements for the improvement of growth and sporulation of several strains of Monascus purpureus on solid state cultivation. The findings revealed that glucose enhanced growth of all M. purpureus strains tested but inhibited the sporulation rate. On the other hand, sucrose induced sporulation but inhibited production of cell mass. A combination of glucose and sucrose greatly enhanced sporulation and cell mass production of M. purpureus. Although growth and sporulation rate were related to the ratio of carbon to nitrogen (C/N ratio), the types and concentrations of carbon and nitrogen sources also greatly influenced the growth kinetics. Among the media tested, Hiroi-PDA medium was the most preferred medium for all M. purpureus strains tested for the enhancement of radial growth rate, sporulation, and cell production. Hence, Hiroi-PDA could be suggested as the generic basal medium for the cultivation of M. purpureus. However, individual medium optimization is required for significant enhancement in growth and sporulation of each strain of M. purpureus. PMID- 22253528 TI - Novel immunotherapeutic strategies of gastric cancer treatment. AB - Gastric cancer (GC) is the fourth most common cancer and the second most frequent cause of cancer-related deaths, accounting for 10.4% of cancer deaths worldwide. Despite the improvements, estimated cure rates for patients with advanced stages remain poor, and in the metastatic setting, chemotherapy is the mainstay of palliative therapy and results in objective response rates (ORRs) of only 20-40% and median overall survivals (OS) of 8-10 months. Therefore, many investigators believe that the potential for making significant progress lies in understanding and exploiting the molecular biology of these tumors to investigate new therapeutic strategies to combat GC, such as specific immunotherapy. In this paper, we analyze the different approaches used for immune-based (especially dendritic and T cells) therapies to gastric cancer treatment and discuss the results obtained in preclinical models as in clinical trials. PMID- 22253530 TI - The hamster model for identification of specific antigens of Taenia solium tapeworms. AB - Humans acquire taeniasis by ingesting pork meat infected with Taenia solium cysticerci, which are the only definitive hosts of the adult stage (tapeworm) and responsible for transmitting the human and porcine cysticercosis. Hence, detection of human tapeworm carriers is a key element in the development of viable strategies to control the disease. This paper presents the identification of specific antigens using sera from hamsters infected with T. solium tapeworms analyzed by western blot assay with crude extracts (CEs) and excretion-secretion antigens (E/S Ag) obtained from T. solium cysticerci and tapeworms and extracts from other helminthes as controls. The hamster sera infected with T. solium tapeworms recognized specific bands of 72, 48, 36, and 24 kDa, in percentages of 81, 81, 90, and 88%, respectively, using the T. solium tapeworms E/S Ag. The antigens recognized by these hamster sera could be candidates to improve diagnosis of human T. solium taeniasis. PMID- 22253532 TI - ColorPhylo: A Color Code to Accurately Display Taxonomic Classifications. AB - Color may be very useful to visualise complex data. As far as taxonomy is concerned, color may help observing various species' characteristics in correlation with classification. However, choosing the number of subclasses to display is often a complex task: on the one hand, assigning a limited number of colors to taxa of interest hides the structure imbedded in the subtrees of the taxonomy; on the other hand, differentiating a high number of taxa by giving them specific colors, without considering the underlying taxonomy, may lead to unreadable results since relationships between displayed taxa would not be supported by the color code. In the present paper, an automatic color coding scheme is proposed to visualise the levels of taxonomic relationships displayed as overlay on any kind of data plot. To achieve this goal, a dimensionality reduction method allows displaying taxonomic "distances" onto a Euclidean two dimensional space. The resulting map is projected onto a 2D color space (the Hue, Saturation, Brightness colorimetric space with brightness set to 1). Proximity in the taxonomic classification corresponds to proximity on the map and is therefore materialised by color proximity. As a result, each species is related to a color code showing its position in the taxonomic tree. The so called ColorPhylo displays taxonomic relationships intuitively and can be combined with any biological result. A Matlab version of ColorPhylo is available at http://sy.lespi.free.fr/ColorPhylo-homepage.html. Meanwhile, an ad-hoc distance in case of taxonomy with unknown edge lengths is proposed. PMID- 22253533 TI - Factors affecting synonymous codon usage bias in chloroplast genome of oncidium gower ramsey. AB - Oncidium Gower Ramsey is a fascinating and important ornamental flower in floral industry. In this research, the complete nucleotide sequence of the chloroplast genome in Oncidium Gower Ramsey was studied, then analyzed using Codonw software. Correspondence analysis and method of effective number of codon as Nc-plot were conducted to analyze synonymous codon usage. According to the corresponding analysis, codon bias in the chloroplast genome of Oncidium Gower Ramsey is related to their gene length, mutation bias, gene hydropathy level of each protein, gene function and selection or gene expression only subtly affect codon usage. This study will provide insights into the molecular evolution study and high-level transgene expression. PMID- 22253531 TI - Protective role of cytotoxic T lymphocytes in filovirus hemorrhagic fever. AB - Infection with many emerging viruses, such as the hemorrhagic fever disease caused by the filoviruses, Marburg (MARV), and Ebola virus (EBOV), leaves the host with a short timeframe in which to mouse a protective immune response. In lethal cases, uncontrolled viral replication and virus-induced immune dysregulation are too severe to overcome, and mortality is generally associated with a lack of notable immune responses. Vaccination studies in animals have demonstrated an association of IgG and neutralizing antibody responses against the protective glycoprotein antigen with survival from lethal challenge. More recently, studies in animal models of filovirus hemorrhagic fever have established that induction of a strong filovirus-specific cytotoxic T lymphocyte (CTL) response can facilitate complete viral clearance. In this review, we describe assays used to discover CTL responses after vaccination or live filovirus infection in both animal models and human clinical trials. Unfortunately, little data regarding CTL responses have been collected from infected human survivors, primarily due to the low frequency of disease and the inability to perform these studies in the field. Advancements in assays and technologies may allow these studies to occur during future outbreaks. PMID- 22253534 TI - Evolution of antifreeze protein genes in the diatom genus fragilariopsis: evidence for horizontal gene transfer, gene duplication and episodic diversifying selection. AB - Hypotheses about horizontal transfer of antifreeze protein genes to ice-living diatoms were addressed using two different statistical methods available in the program Prunier. The role of diversifying selection in driving the differentiation of a set of antifreeze protein genes in the diatom genus Fragilariopsis was also investigated. Four horizontal gene transfer events were identified. Two of these took place between two major eukaryote lineages, that is from the diatom Chaetoceros neogracile to the copepod Stephos longipes and from a basidiomycete clade to a monophyletic group, consisting of the diatom species Fragilariopsis curta and Fragilariopsis cylindrus. The remaining two events included transfers from an ascomycete lineage to the proteobacterium Stigmatella aurantiaca and from the proteobacterium Polaribacter irgensii to a group composed of 4 proteobacterium species. After the Fragilariopsis lineage acquired the antifreeze protein gene from the basidiomycetes, it duplicated and went through episodic evolution, characterized by strong positive selection acting on short segments of the branches in the tree. This selection pattern suggests that the paralogs differentiated functionally over relatively short time periods. Taken together, the results obtained here indicate that the group of antifreeze protein genes considered here have a complex evolutionary history. PMID- 22253535 TI - Glycemic control and anti-osteopathic effect of propolis in diabetic rats. AB - The aim of the study was to explore the possibility that propolis can control diabetes mellitus and prevent diabetic osteopathy in rats. The study compared 60 streptozotocin (STZ)-induced diabetic rats, with ten nondiabetic rats used as a negative control. The experimental design comprised seven groups (n = 10 rats per group): (1) nondiabetic, used as a negative control; (2) nontreated, used as a positive control; (3) treated with insulin alone; (4) treated with a single dose of propolis alone; (5) treated with a double dose of propolis; (6) treated with insulin and a single dose of propolis; and (7) treated with insulin and a double dose of propolis. After 6 weeks of treatment, the rats were sacrificed. Ratios of femur ash to femur weight and of femur weight to body weight (FW/BW) were calculated and calcium (Ca), phosphorus (P), and magnesium (Mg) concentrations in femur ash were estimated and analyzed. Fasting blood glucose (FBG), plasma insulin and glucagon, serum thiobarbituric acid reactive substances (TBARS), plasma parathyroid hormone (PTH), and calcitonin levels were also estimated and analyzed. There was significant reduction in FBG in all diabetic treated rats. Similarly, higher plasma insulin levels were observed in diabetic rats treated with propolis and insulin than in nontreated diabetic rats, although plasma insulin was not comparatively higher in diabetic rats treated with insulin alone. Serum TBARS was significantly lower in the propolis treated rats than the diabetic nontreated rats. No differences in PTH and calcitonin levels were observed among treatment groups. The FW/BW ratio was significantly higher in diabetic treated groups than in control groups. Furthermore, diabetic rats treated with propolis and insulin had significantly higher Ca, P, and Mg concentrations in femoral ash than nontreated diabetic rats and diabetic rats treated with insulin alone. In conclusion, propolis has a remarkable effect on glucose homeostasis and bone mineralization. PMID- 22253536 TI - Resistance training associated with the administration of anabolic-androgenic steroids improves insulin sensitivity in ovariectomized rats. AB - The aim of the present study was to investigate the effects of anabolic androgenic steroids and resistance training (RT) on insulin sensitivity in ovariectomized rats. Adult female Wistar rats were divided into ten experimental groups (n = 5 animals per group): (1) sedentary (Sed-Intact); (2) sedentary ovariectomized (Sed-Ovx); (3) sedentary nandrolone (Sed-Intact-ND); (4) sedentary ovariectomized plus nandrolone (Sed-Ovx-ND); (5) trained (TR-Intact); (6) trained nandrolone (TR-Intact-ND); (7) trained ovariectomized (TR-Ovx); (8) trained ovariectomized plus nandrolone; (9) trained sham; and (10) trained ovariectomized plus sham. Four sessions of RT were used, during which the animals climbed a 1.1 m vertical ladder with weights attached to their tails. The sessions were performed once every 3 days, with between four and nine climbs and with eight to twelve dynamic movements per climb. To test the sensitivity of insulin in the pancreas, glucose and insulin tolerance tests were performed. For insulin sensitivity, there was a statistically significant interaction for the TR-Ovx group, which presented higher sensitivity than the Sed-Intact, Sed-Ovx, and TR Intact groups. Sed-Intact-ND and TR-Intact-ND groups exhibited higher values of insulin sensitivity than the Sed-Intact group. Except for the TR-Intact group, sensitivity was greater in trained groups than in the Sed-Intact group. There was higher insulin sensitivity in the TR-Intact-ND group than in the Sed-Intact and Sed-Intact-ND groups (P < 0.05). In conclusion, ovariectomy and short-term RT alone induced no change on insulin action. Administration of nandrolone decanoate improved insulin action, mainly when it was associated with RT. PMID- 22253537 TI - Comparison of demographic and clinical characteristics influencing health-related quality of life in patients with diabetic foot ulcers and those without foot ulcers. AB - BACKGROUND: A number of studies have demonstrated that health-related quality of life (HRQoL) is negatively affected by diabetic foot ulcers. The aim of this study was to compare HRQoL in diabetic patients with and without foot ulcers and to determine demographic and clinical factors influencing HRQoL. METHODS: There were no variables affecting HRQoL except for gender in diabetic patients without foot ulcers. Demographic and clinical variables were recorded and HRQoL was evaluated using the Short Form 36 (SF-36) survey for all participants. The summary physical component score (PCS) and mental component score (MCS) and eight domains of HRQoL were compared in the two groups. Linear regression analysis was also used to investigate sociodemographic and clinical characteristics as predictors of quality of life as measured by SF-36. RESULTS: The overall score, PCS, and MCS, were significantly higher in patients without diabetic foot ulcers. Except for gender, none of the variables affected HRQoL in diabetic patients without foot ulcers. Male gender had a higher score in all domains of quality of life than female gender in diabetic patients without foot ulcers. Living alone, a low educational level, and having at least one complication were all associated with a lower HRQoL score in patients with foot ulcers. High-grade ulcers determined by Wagner's classification and poor glycemic control as measured by HbA(1C) predicted HRQoL impairment in patients with diabetic foot ulcers. CONCLUSION: Because Wagner's grade was one of the strongest variables associated with HRQoL, this scale is recommended for monitoring of patients with diabetic foot ulcers in order to prevent continuing deterioration of HRQoL by treatment of foot ulcers at an earlier stage. PMID- 22253538 TI - Association of patient-rated severity with other outcomes in patients with painful diabetic peripheral neuropathy. AB - OBJECTIVE: To evaluate the association of patient-reported severity of painful diabetic peripheral neuropathy (pDPN) with other outcomes in a European population of patients using the Adelphi Disease Specific Programme for pDPN (DSP III, 2008). METHODS: The severity of patients' pDPN (mild, moderate, or severe) was rated independently by both patients and physicians. Relationships were evaluated between patient-reported pDPN severity and other patient-reported outcomes including pain, sleep, function, and work productivity. Physicians rated the severity of patients' pDPN (1 = mild, 2 = moderate, 3 = severe) and sleep interference. RESULTS: Patient-reported data were available from 634 individuals (56.2% male, mean age 63 years) from France, Germany, Italy, and the UK, of whom only 22.2% reported that they were currently employed. pDPN severity was rated as mild, moderate, and severe by 22.2%, 60.9%, and 16.9% of the patients, respectively. There was a significant association between patient-rated and physician-rated pDPN severity (P < 0.0001), although there were discrepancies in agreement (kappa = 0.37, 95% confidence interval [CI] 0.31, 0.43; weighted kappa = 0.43, 95% CI 0.37, 0.48) among physician and patient ratings in a substantial proportion of patients across severity categories. Higher pDPN severity was associated with greater interference of daily function including sleep (P < 0.0001 for all pairwise comparisons). Among employed patients, percent of pDPN related impairment while at work (presenteeism) and overall work impairment increased with greater pDPN severity, resulting in indirect costs that increased significantly with pDPN severity; $8266, $15,449, and $24,300 for mild, moderate, and severe pDPN, respectively (overall P < 0.001). CONCLUSION: Severity of patient-rated pDPN was significantly associated with outcomes, including function and productivity; poorer function and lower productivity were reported at higher pDPN severity levels. Moreover, physicians rated pDPN severity different from patients in a substantial proportion of patients. PMID- 22253539 TI - Effect of Ramadan fasting on metabolic markers, body composition, and dietary intake in Emiratis of Ajman (UAE) with metabolic syndrome. AB - BACKGROUND/AIM: The aim of the study was to evaluate the effect of Ramadan fasting on metabolic markers, body composition and dietary intake in native Emiratis of Ajman, UAE with the metabolic syndrome (MS). DESIGN: 19 patients (14 Female, 5 Male) aged 37.1 +/- 12.5 years, were encouraged healthy lifestyle changes during fasting and data was collected 1 week before and in the fourth week of Ramadan. RESULTS: No patients experienced complications or increased symptoms of hypoglycemia during Ramadan. Total energy consumption remained similar. Meal frequency decreased (3.2 +/- 0.5 vs 2.1 +/- 0.4 meals/day). Protein intake decreased 12% (P = 0.04) but fat intake increased 23% (P = 0.03). Body weight (103.9 +/- 29.8 vs 102.1 +/- 29.0 kg, P = 0.001) and waist circumference (123 +/- 14 vs 119 +/- 17 cm, P = 0.001) decreased. Forty percent of patients increased their physical activity due to increased praying hours. Fasting P glucose (6.3 +/- 1.7 vs 6.8 +/- 2.0 mmol/L, P = 0.024) and B-HbA(1c) concentrations 6.3 +/- 0.9 vs 6.5% +/- 0.9%, P = 0.003) increased but P-insulin concentration, HOMA-IR index and lipid concentrations remained unchanged. CONCLUSION: The present study investigated the effect of Ramadan fasting on dietary intake, metabolic parameters and body composition showing that the energy consumption per day did not decrease, although the fat intake increased. However, the patients lost weight and reduced their waist circumference. Ramadan fasting has also elicited small but significant increases in Glucose and HbA(1c) after 4 weeks. PMID- 22253540 TI - Arab Teens Lifestyle Study (ATLS): objectives, design, methodology and implications. AB - BACKGROUND: There is a lack of comparable data on physical activity, sedentary behavior, and dietary habits among Arab adolescents, which limits our understanding and interpretation of the relationship between obesity and lifestyle parameters. Therefore, we initiated the Arab Teens Lifestyle Study (ATLS). The ATLS is a multicenter collaborative project for assessing lifestyle habits of Arab adolescents. The objectives of the ATLS project were to investigate the prevalence rates for overweight and obesity, physical activity, sedentary activity and dietary habits among Arab adolescents, and to examine the interrelationships between these lifestyle variables. This paper reports on the objectives, design, methodology, and implications of the ATLS. DESIGN/METHODS: The ATLS is a school-based cross-sectional study involving 9182 randomly selected secondary-school students (14-19 years) from major Arab cities, using a multistage stratified sampling technique. The participating Arab cities included Riyadh, Jeddah, and Al-Khobar (Saudi Arabia), Bahrain, Dubai (United Arab Emirates), Kuwait, Amman (Jordan), Mosel (Iraq), Muscat (Oman), Tunisia (Tunisia) and Kenitra (Morocco). Measured variables included anthropometric measurements, physical activity, sedentary behavior, sleep duration, and dietary habits. DISCUSSION: The ATLS project will provide a unique opportunity to collect and analyze important lifestyle information from Arab adolescents using standardized procedures. This is the first time a collaborative Arab project will simultaneously assess broad lifestyle variables in a large sample of adolescents from numerous urbanized Arab regions. This joint research project will supply us with comprehensive and recent data on physical activity/inactivity and eating habits of Arab adolescents relative to obesity. Such invaluable lifestyle-related data are crucial for developing public health policies and regional strategies for health promotion and disease prevention. PMID- 22253542 TI - Josef Jadassohn (1863-1936), Felix Lewandowsky (1879-1921), and their syndrome. AB - Josef Jadassohn (1863-1936) and his assistant, Felix Lewandowsky (1879-1921), were eminent German dermatologists who had several dermatology conditions linked eponymously. One such condition is Jadassohn-Lewandowsky syndrome, which is a type of pachyonychia congenita - a disease that is characterized by severe thickening of the nail due to massive nail hyperkeratosis. This report describes Jadassohn-Lewandowsky syndrome and the men behind this disease. PMID- 22253541 TI - Filament formation associated with spirochetal infection: a comparative approach to Morgellons disease. AB - Bovine digital dermatitis is an emerging infectious disease that causes lameness, decreased milk production, and weight loss in livestock. Proliferative stages of bovine digital dermatitis demonstrate keratin filament formation in skin above the hooves in affected animals. The multifactorial etiology of digital dermatitis is not well understood, but spirochetes and other coinfecting microorganisms have been implicated in the pathogenesis of this veterinary illness. Morgellons disease is an emerging human dermopathy characterized by the presence of filamentous fibers of undetermined composition, both in lesions and subdermally. While the etiology of Morgellons disease is unknown, there is serological and clinical evidence linking this phenomenon to Lyme borreliosis and coinfecting tick-borne agents. Although the microscopy of Morgellons filaments has been described in the medical literature, the structure and pathogenesis of these fibers is poorly understood. In contrast, most microscopy of digital dermatitis has focused on associated pathogens and histology rather than the morphology of late-stage filamentous fibers. Clinical, laboratory, and microscopic characteristics of these two diseases are compared. PMID- 22253543 TI - Cytotoxicity patterns of arsenic trioxide exposure on HaCaT keratinocytes. AB - BACKGROUND: Arsenic is a ubiquitous environmental toxicant, and abnormalities of the skin are the most common outcomes of long-term, low-dose, chronic arsenic exposure. If the balance between keratinocyte proliferation, differentiation, and death is perturbed, pathologic changes of the epidermis may result, including psoriasis, atopic dermatitis, and certain forms of ichthyosis. Therefore, research investigations using in vitro human epidermal cells could help elucidate cellular and molecular processes in keratinocytes affected by arsenic. Data from such investigations could also provide the basis for developing cosmetic intervention for skin diseases caused by arsenic. METHODS: The viability of HaCaT keratinocyte cultures with or without prior exposure to low-dose arsenic trioxide was compared for varying concentrations of arsenic trioxide over a time course of 14 days because in untreated control cultures, approximately 2 weeks is required to complete cell differentiation. Long-term cultures were established by culturing HaCaT cells on collagen IV, and cells were subsequently exposed to 0 parts per million (ppm), 1 ppm, 5 ppm, 7.5 ppm, 10 ppm, and 15 ppm of arsenic trioxide. The percentages of viable cells as well as DNA damage after exposure were determined on Day 2, Day 5, Day 8, and Day 14. RESULTS: Using both statistical and visual analytics approaches for data analysis, we have observed a biphasic response at a 5 ppm dose with cell viability peaking on Day 8 in both chronic and acute exposures. Further, a low dose of 1 ppm arsenic trioxide enhanced HaCaT keratinocyte proliferation, whereas doses above 7.5 ppm inhibited growth. CONCLUSION: The time course profiling of arsenic trioxide cytotoxicity using long-term HaCaT keratinocyte cultures presents an approach to modeling the human epidermal cellular responses to varying doses of arsenic trioxide treatment or exposure. A low dose of arsenic trioxide appears to aid cell growth but concomitantly disrupts the DNA transcription process. PMID- 22253544 TI - The use of concentrated heat after insect bites/stings as an alternative to reduce swelling, pain, and pruritus: an open cohort-study at German beaches and bathing-lakes. AB - BACKGROUND: Swelling, pain, and pruritus are the most relevant symptoms after insect bites/stings. Glucocorticoids and antihistamines are well established in insect sting treatment. Bite Away((r)) is a CE-certified medical device of class 2A (noninvasive device intended for administration to the body, which exchanges energy with the patient in a therapeutic manner) to reduce swelling, pruritus, and pain after insect bites/stings via non-invasive administration of concentrated heat to the skin. We therefore performed a prospective, non interventional, single-arm cohort study with 146 volunteers using the visual analog scale (VAS) for insect bites/stings to study the reduction of swelling, pruritus, and pain. Demographic data, time from insect sting to treatment, number and duration of administrations of concentrated heat, relevant symptoms, and the development of a VAS score of swelling, pruritus, and pain on baseline, after 2, 5, and 10 minutes after administration, were registered. RESULTS: In total 146 subjects with a mean age of 29.4 +/- 20.7 years (range 2-81) were enrolled in the study. Ninety-three (63.7%) of the subjects were stung by wasps, 33 (22.6%) of the subjects were bitten by mosquitoes, and eight suffered bee stings (5.3%). VAS score swelling decreased with statistical significance after the use of Bite Away((r)) from 4 before treatment to 2 and 1 after 2-5 and 10 minutes, respectively. VAS pain score was 6 before treatment, 2 after 2 minutes, 1 after 5 minutes, and 0 after 10 minutes (median). VAS pruritus score was only available for 52 (35.2%) of the patients. The score decreased from 5 before treatment, to 2 after 2 minutes, and 0 after 5 and 10 minutes. CONCLUSIONS: Locally administrated concentrated heat leads to fast amelioration of symptoms. Usually an absence of symptoms is noticeable 10 minutes after administration. Pain reduction is the dominant effect. Compared with alternatives of pruritus and pain treatment after insect bites/stings, Bite Away((r)) seems to be the fastest treatment option available. PMID- 22253545 TI - A comparison of the efficacy, safety, and longevity of two different hyaluronic acid dermal fillers in the treatment of severe nasolabial folds: a multicenter, prospective, randomized, controlled, single-blind, within-subject study. AB - BACKGROUND: Commercially available hyaluronic acid (HA)-based fillers have distinct physicochemical properties related to their specific manufacturing technology, including HA concentration, cross-linking percentage, and particle size. These factors may determine treatment effectiveness, safety, and longevity; however, this requires confirmation in the clinic. METHODS: To compare the efficacy, safety, and longevity of two distinct HA-based dermal fillers in the correction of severe nasolabial folds (NLFs), a 24 mg/mL smooth gel (Juvederm ULTRA PLUSTM [JUP]) and a 20 mg/mL particulate gel (Perlane((r)) [PER]) were injected in a total of 80 normal, healthy subjects using a split face design and were followed for 12 months in this prospective, randomized, controlled, multicenter study. RESULTS: Both fillers achieved a clinically relevant NLF correction (one point or more improvement, based on a validated NLF severity scale). However, JUP displayed greater longevity, with this correction maintained in a significantly larger percentage of NLFs after 6 months (physician's evaluation) or 9 months (subject's evaluation) and thereafter for the remainder of the study (70% vs 45%; P = 0.0002 and 62.5% vs 46.3%; P = 0.01 at month 12, based on physician and subject assessments, respectively). At month 12, 71.4% of the subjects nominated a preference for the NLF injected with JUP (P < 0.0001). Both treatments were well tolerated. CONCLUSION: These results suggest that different physicochemical properties of HA-based fillers, associated with distinct manufacturing technologies, may influence treatment longevity in the correction of volume deficits. This may relate to a differential resistance to hyaluronidase and/or free radical degradation as previously documented in vitro. PMID- 22253546 TI - Integrated control of hypertension by olmesartan medoxomil and hydrochlorothiazide and rationale for combination. AB - Hypertension affects nearly one-third of all individuals in the US, yet one-half of all treated patients achieve blood pressure (BP) controlled to recommended goals. The percentage of patients with uncontrolled BP is likely to be much higher when considering the number of patients who are not even aware of their hypertensive state. Elevated BP is associated with increased risks of cardiovascular events and end-organ damage. Antihypertensive monotherapy is not always sufficient to achieve BP goals, and thus more aggressive treatment regimens need to be considered. Antihypertensive combination therapy, which may improve tolerability, offers the benefit of targeting different mechanisms of action. Numerous outcomes studies support the use of a renin-angiotensin system inhibitor as a first-line choice in antihypertensive therapy. This review discusses the benefits of combination therapy with the angiotensin type II receptor blocker olmesartan medoxomil (OM) paired with the thiazide diuretic hydrochlorothiazide (HCTZ). The pharmacokinetic properties of OM will be reviewed in addition to efficacy studies that support OM + HCTZ combination therapy over other possible antihypertensive combinations. Finally, a rationale for choosing HCTZ over another diuretic, chlorthalidone, will also be discussed based on pharmacokinetic differences, clinical concerns, and trends in use. PMID- 22253547 TI - Recent trends in the characteristics and prognosis of patients hospitalized with acute heart failure. AB - BACKGROUND: Despite the magnitude and impact of heart failure (HF) in the United States, relatively little data are available that describe the prognosis associated with acute HF, especially from the perspective of a population-based investigation. The purpose of this nonconcurrent prospective study was to describe the overall, and changing trends therein, prognosis of 4228 patients discharged from all eleven greater Worcester (MA) medical centers after a documented episode of acute HF and factors associated with an increased risk of dying after hospital discharge. METHODS: The study population consisted of residents of the Worcester metropolitan area discharged after being hospitalized for acute HF at all greater Worcester medical centers during 1995 (n = 1783) and 2000 (n = 2445). RESULTS: The 3-month (20% versus 18%), 1-year (41% versus 38%), and 5-year (84% versus 82%) death rates were lower in patients discharged from all metropolitan Worcester hospitals in 2000 versus 1995, respectively. Improving long-term survival rates for patients discharged in 2000 as compared with 1995 were magnified after controlling for several confounding demographic and clinical factors of prognostic importance. A number of potentially modifiable demographic, medical history, and clinical factors were associated with an increased risk of dying during the first year after hospital discharge for acute HF. CONCLUSION: The results of this community-wide observational study suggest improving trends in the long-term prognosis after acute HF. Despite these encouraging trends, the long-term prognosis for patients with acute HF remains poor, and several at-risk groups can be identified for early intervention and increased monitoring efforts. PMID- 22253548 TI - Incidence and risk factors of suicide reattempts within 1 year after psychiatric hospital discharge in mood disorder patients. AB - BACKGROUND: The incidence and risk factors of suicide reattempts within 1 year after psychiatric hospital discharge in mood disorder patients remain uninvestigated in Thailand. OBJECTIVE: To determine incidence and risk factors of suicide reattempts within 1 year after psychiatric hospital discharge in mood disorder patients. METHODS: A retrospective cohort study was conducted by reviewing medical charts at Suanprung Psychiatric Hospital, Chiang Mai, Thailand. Mood disorder patients, diagnosed with the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes F31.x, F32.x, and F33.x, who were admitted owing to suicide attempts between October 2006 and May 2009 were eligible. The influence of sociodemographic and clinical risk factors on suicide reattempts was investigated using Cox's proportional hazards regression analysis. RESULTS: Of 235 eligible mood disorder patients, 36 (15.3%) reattempted suicide (median 109.5 days, range 1-322), seven (3.0%) completed suicide (median 90 days, range 5-185), and 192 (84.2%) neither reattempted nor completed suicide during follow-up. Of all nonfatal suicide reattempts, 14 patients (38.9%) did so within 90 days. Among suicide completers, one (14.3%) did so 5 days after discharge, and four (57.1%) did so within 90 days. The following three risk factors explained 73.3% of the probability of suicide reattempts: over two previous suicide attempts before the index admission (adjusted hazard ratio [HR] 2.48; 95% confidence interval [CI] 1.07-5.76), being concomitantly prescribed typical and atypical antipsychotics (adjusted HR 4.79; 95% CI 1.39-16.52) and antidepressants, and taking a selective serotonin reuptake inhibitor alone (adjusted HR 5.08; 95% CI 1.14-22.75) or concomitantly with norepinephrine and/or serotonin reuptake inhibitors (adjusted HR 6.18; 95% CI 1.13-33.65). CONCLUSION: Approximately 40% of suicide reattempts in mood disorder patients occurred within 90 days after psychiatric hospital discharge. For mood disorders and when there have been over two previous suicide attempts, prescribed antipsychotics or antidepressants may help predict suicide reattempts. PMID- 22253549 TI - Chronic obstructive pulmonary disease prevalence in Lebanon: a cross-sectional descriptive study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) continues to increase worldwide. The objective of this study was to determine the prevalence of COPD in Lebanese adults. METHODS: A cross-sectional study was carried out using a multistage cluster sample from all over Lebanon. Residents aged 40 years and over were enrolled. Subjects underwent baseline spirometry and answered a questionnaire. After an albuterol + ipratropium bromide bronchodilator, a posttest was performed. RESULTS: Of 2201 individuals, only 33.3% had never smoked. The prevalence of COPD by the Global Initiative for Chronic Obstructive Lung Disease definition, was 9.7% (95% confidence interval [CI]: 8.5%-10.9%). According to the 5% lower limit of normal definition of COPD, the prevalence was 12.5% (95% CI: 11.2%-13.9%). A total of 20.2% were already diagnosed by a physician. No differences in symptoms across stages of COPD were found, but there was a significant trend for a higher number of visits to the emergency room and to the doctor (P < 0.001), and a higher number of hospitalizations (P < 0.001). Older individuals had an increased risk of COPD (adjusted odds ratio [OR(a)] = 1.05); so did "ever" cigarette smokers (OR(a) = 4.88) and water-pipe smokers (OR(a) = 2.53). CONCLUSION: This is the first epidemiological study in Lebanon that determined COPD prevalence and the link with water-pipe smoking. PMID- 22253550 TI - Safety and efficacy of lenalidomide in relapsed or refractory multiple myeloma. AB - Lenalidomide is an oral immunomodulatory drug that has helped improve outcomes in multiple myeloma (MM) patients. Combination lenalidomide and dexamethasone (Len+Dex) has been shown to increase response rates and prolong survival compared with dexamethasone alone in patients with relapsed or refractory MM (RRMM). Clinical benefit may be greatest when Len+Dex is given at first relapse, and continued treatment appears to provide greater depth of response and improved survival outcomes. The most common adverse events associated with Len+Dex are cytopenias, which are predictable and manageable. Len+Dex is associated with an increased risk of venous thromboembolism, which necessitates adequate prophylaxis. The risk of second primary malignancies does not appear to be increased in patients with RRMM treated with lenalidomide-based therapy. Here we review the safety and efficacy of Len+Dex in RRMM, and provide an overview of data from Spain on the use of Len+Dex in RRMM. PMID- 22253551 TI - Survival of patients with squamous cell malignancies of the upper urinary tract. AB - BACKGROUND: Carcinomas of the renal pelvis and ureter are rare diseases, accounting for only about 1% of all urogenital malignancies. Previous reports suggest that squamous cell histology is associated with inferior survival. We present the largest population based analysis to date of survival in patients with upper urinary tract malignancies. METHODS: We analyzed the Surveillance, Epidemiology and End Results database for cancer specific survival rates in patients with renal pelvis and ureteral malignancies who were diagnosed between 1973 and 2003 in the SEER catchment geographic areas. The primary exposure of interest was the underlying histology, squamous cell versus transitional cell differentiation. We performed descriptive statistics, non parametric survival analysis, and cox proportional hazard analysis. RESULTS: We identified 13,213 eligible patients, 7,716 renal pelvis and 5,497 ureteral carcinomas. Among this cohort, 179 patients had squamous cell carcinoma (SCC), 12,395 had transitional cell carcinoma (TCC), including 121 papillary, and 619 had other histologies. Overall, patients with SCC histology fared worse. The median overall survival time was 10 months for SCC and 63 months for TCC. The cox analysis revealed a HR 3.7 (95% CI 3.0-4.5) for SCC when compared to TCC and corrected for decade of diagnosis, age, gender, prior treatment, and race. The difference between the two groups was entirely attributable to survival differences in patients with loco regional disease. However, when stratified by lymph node involvement this difference disappeared for patients with locally involved lymph nodes (P = 0.84) and for patients with clear lymph nodes (P = 0.92). CONCLUSIONS: SCCs of the upper urinary tract present at a higher clinical stage and appear to represent more aggressive disease when compared to other histologies. However, when appropriately staged according to lymph node status, the survival of TCC and SCC of the upper urinary tract is identical when compared stage by stage. PMID- 22253552 TI - Aflibercept in the treatment of metastatic colorectal cancer. AB - Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept. PMID- 22253553 TI - Emerging Pharmacotherapy for Relapsed or Refractory Hodgkin's Lymphoma: Focus on Brentuximab Vedotin. AB - Hodgkins' lymphoma (HL) which has relapsed post or is refractory to autologous bone marrow transplant presents an ongoing treatment challenge. Development of monoclonal antibodies (mAb) for the treatment of HL has aimed to replicate the success of mAb therapy in the treatment on Non Hodgkins Lymphoma. The identification of CD30 as a potential target for treatment has led to the development of a new antibody-drug conjugate, brentuximab vedotin (SGN-35), which conjugates monomethyl auristatin E to an anti-CD30 antibody to deliver targeted toxicity to the malignant Reed Sternberg cells of HL. This review describes CD30 as an antibody target, and focuses on the antibody-drug conjugate brentuximab vedotin, including current knowledge of the mechanism of action, preclinical, clinical and pharmacokinetic data available for Brentuximab Vedotin. PMID- 22253554 TI - Safety and efficacy of everolimus in adult patients with neuroendocrine tumors. AB - Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors. PMID- 22253555 TI - Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. AB - The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically diverse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors. PMID- 22253556 TI - Clinical Efficacy of TroVax in the Treatment of Progressive Castration-resistant Prostate Cancer. AB - With approximately 240,890 new cases expected in 2011, prostate cancer remains the leading cause of non-melanoma cancer deaths in men. Immunotherapies using viral vector-based delivery systems targeting tumor-specific antigens are being studied. Viral vector-based delivery systems present tumor-targeted antigens (TAAs) to the immune system while breaking self-tolerance. Modified vaccinia ankara has been combined with the oncofetal antigen 5T4 to create TroVax for the treatment of castration-resistant prostate cancer (CRPC). The 5T4 antigen is highly expressed in a large number of carcinomas, including prostate cancer, but is rarely expressed in healthy tissue. TroVax has been demonstrated to be safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies in colorectal, renal cell, and prostate cancer. With minimal side effects and the ability to produce a strong immunogenic response, TroVax (MVA-5T4) is a viable addition to the treatment of prostate cancer. PMID- 22253557 TI - Relationship between antithyroid antibody and pregnancy outcome following in vitro fertilization and embryo transfer. AB - OBJECTIVE: To investigate the impact of antithyroid antibody on pregnancy outcome following the in vitro fertilization and embryo transfer (IVF-ET). METHODS: A total of 90 patients (156 cycles) positive for antithyroid antibody (ATA+ group) and 676 infertile women (1062 cycles) negative for antithyroid antibody (ATA- group) undergoing IVF/ICSI from August 2009 to August 2010 were retrospectively analyzed. RESULTS: There was no significant difference in the days of ovarian stimulation, total gonadotropin dose, serum E2 level of HCG day and number of oocytes retrieved between the two groups. The fertilization rate, implantation rate and pregnancy rate following IVF-ET were significantly lower in women with antithyroid antibody than in control group (64.3% vs 74.6%, 17.8% vs 27.1% and 33.3% vs 46.7%, respectively), but the abortion rate was significantly higher in patients with antithyroid antibody (26.9% vs 11.8%). CONCLUSION: Patients with antithyroid antibody showed significantly lower fertilization rate, implantation rate and pregnancy rate and higher risk for abortion following IVF-ET when compared with those without antithyroid antibody. Thus, the presence of antithyroid antibody is detrimental for the pregnancy outcome following IVF-ET. PMID- 22253558 TI - Potential impact of the financial crisis on outpatient hospital visits due to otorhinolaryngologic disorders in Crete, Greece. AB - The public health effect of financial crises has been emphasized in previous studies. In addition, a series of otorhinolaryngologic disorders and manifestations has been related to psychological factors in the literature. Such conditions include temporomandibular joint disorders, laryngopharyngeal reflux, chronic tinnitus, and vertigo. Focusing on the outpatient database records of a large hospital in Crete, Greece, the objective of this retrospective study was to explore possible occurrence variations within the prementioned otorhinolaryngologic morbidity which may be potentially attributed to increased levels of socioeconomic stress. Results revealed that although the total number of visits between two periods - before and after the beginning of the financial crisis in Greece - was comparable, a significant increase in the diagnosis of two disorders, namely vertigo and tinnitus was found. In addition, a trend toward increased rate of diagnosis for reflux and temporomandibular joint disorders was noted. Potential implications of these findings are discussed. In conclusion, health care providers in this as well as in other countries facing similar socio economic conditions should be aware of potential changes in the epidemiologic figures regarding specific medical conditions. PMID- 22253559 TI - Effects of two fluoride varnishes and one fluoride/chlorhexidine varnish on Streptococcus mutans and Streptococcus sobrinus biofilm formation in vitro. AB - AIMS: The aim of this study was to evaluate and to compare the effect of two fluoride varnishes and one fluoride/chlorhexidine varnish on Streptococcus mutans and Streptococcus sobrinus biofilm formation, in vitro. STUDY DESIGN: Standard acrylic discs were prepared and divided into groups based on the varnish applied to the disc surface: Fluor Protector, Bifluoride 12, and Fluor Protector + Cervitec (1:1). Untreated discs served as controls. In the study groups, biofilms of S. mutans and S. sobrinus were formed over 24 h, 48 h, and 5 days. The fluoride concentrations in the monospecies biofilms and viable counts of S. mutans and S. sobrinus were investigated. RESULTS: In all study groups, a statistically significant increase in the viable number of S. mutans and S. sobrinus cells was observed between 24 h and 5 days. In both monospecies biofilms, the greatest antibacterial efficacy was detected in the Fluor Protector and Fluor Protector + Cervitec groups at 24 h. For all groups, the amount of fluoride released was highest during the first 24 h, followed by a significant decrease over the next 4 days. A negative correlation was detected between fluoride concentration and antibacterial effect in those groups with biofilms containing both species. Despite the release of high levels of fluoride, the greatest number of viable S. mutans and S. sobrinus cells was detected in the Bifluoride 12 group. STATISTICS: The data were analyzed using GraphPad Prism software (ver. 3). CONCLUSIONS: The Fluor Protector + Cervitec varnish exerted prolonged antibacterial effects on S. mutans and S. sobrinus biofilms compared to the other varnishes tested. PMID- 22253560 TI - Oral and maxillofacial considerations in Gardner's Syndrome. AB - Gardner's Syndrome is a variant of familial adenomatosis polyposis (FAP) with a triad consisting of polyps of the colon, multiple osteomas and surface tumors of soft and hard tissue. The intestinal polyps have a %100 risk of undergoing malignant transformation, therefore early identification of this disease is very important. There are several symptoms of Gardner's syndrome in the oral and maxillofacial surgery, which can be discovered during routine dental examination. We report a case of a 25-year old male patient with Gardner's syndrome who has not any intestinal polyps but osteomas in the mandible and jaw deformalities. PMID- 22253561 TI - What questions do people ask on a human papillomavirus website? A comparative analysis of public and private questions. AB - OBJECTIVE: In 2004, we launched the question and answer (Q&A) section on a human papillomavirus (HPV) website (www.hpvkorea.org) that provides ample and regularly updated information about HPV. The purpose of this study is to collect data pertaining to questions posed on this website about HPV and its related diseases and analyze the type of questions and frequency before and after introduction of HPV vaccine in Korea. Using these results, we intend to determine the clinical and practical implications for doctors treating HPV and for HPV website providers. METHOD: Data were collected from March 2004 to July 2011. This study analyzed all the questions that were asked on the website during this period. The questions were categorized into 2 groups, according to whether they were asked publicly or privately. The 10 categories for classification were determined on the basis of the contents of the questions by 4 researchers with medical degrees (Ph.D.) related to HPV research. The frequency of the questions was separately determined for the public and private question formats. Also, we compared the type of questions and frequency before and after introduction of HPV vaccine in Korea and evaluated the changes in the 2 groups over the 2 periods studied. RESULTS: Of the 3,062 subjects who visited the HPV website, 2,330 subjects asked public questions and 732 asked private questions. The most frequent question was "I have been infected with HPV, and I want to know about the treatment options for HPV infection and cervical dysplasia" (n = 1156, 37.8%), and the second most common question was "What are the transmission routes of HPV?" (n = 684, 22.3%). The third most common question was "How long does it take for HPV infection to spontaneously remit?" (n = 481, 15.7%).Of the 2,330 public questions, the most common question types pertained to the treatment of HPV and cervical dysplasia, HPV transmission, HPV remission, and risk of cervical cancer (in that order). Of the 732 private questions, the most frequent question types pertained to the HPV transmission, treatment of HPV and cervical dysplasia, genital warts, and HPV & pregnancy (in that order). The type and frequency of public and private questions showed statistical differences between the 2 groups (p < 0.001). CONCLUSION: Our results show that when people consult an internet site about HPV, they actually want to seek about "treatment of HPV and cervical dysplasia", "HPV transmission", "HPV remission", "genital warts", and "risk of cervical cancer" (in this order). Also, our results showed that "genital warts" and "HPV & pregnancy" may have been considered embarrassing topics. Thus, these findings can be used to make informed recommendations for future clinical or internet-based communications with patients and the general public. PMID- 22253562 TI - Rapid detection of rpoB mutations in rifampin resistant M. tuberculosis from sputum samples by denaturing gradient gel electrophoresis. AB - OBJECTIVE: To establish a rapid detection method for identifying rpoB mutations associated with rifampin (RIF) resistance in sputum specimens. METHODS: We detected rpoB mutations directly in 90 sputum specimens collected from suspected tuberculosis patients using PCR-based denaturing gradient gel electrophoresis (DGGE) and compared these results with those obtained by rpoB sequencing and conventional drug susceptibility testing. RESULTS: The positive detection rate of Mycobacterium tuberculosis (M. tuberculosis) was 52.2% by Acid-Fast Bacilli staining and 72.2% by conventional mycobacterial culture. In contrast, the positive rate was significantly higher (93.3%) by PCR-based detection of the rpoB gene in the same specimens. Furthermore, 75% of the tested specimens presented abnormal patterns compared with the wild-type pattern (standard H37Rv strain) analysed by DGGE. A total of 12 different patterns, representing 12 different rpoB mutations, were observed in the 63 abnormal patterns. The match rate of rpoB mutations detected by DGGE reached 96.9% when compared to DNA sequencing. CONCLUSION: Our findings indicate that PCR-based DGGE is a rapid and reliable bio technique for direct detection of rpoB mutations associated with RIF resistance in the sputum of suspected tuberculosis patients. PMID- 22253563 TI - Inhaled nitric oxide therapy fails to improve outcome in experimental severe influenza. AB - In vitro, nitric oxide (NO) has been shown to have antimicrobial activity against a wide range of viruses, including influenza A virus. Therefore, we hypothesized that inhaled nitric oxide (iNO) would increase survival in vivo by reducing the viral load in C57Bl/6 mice infected with a lethal dose of influenza A/WSN/33 (H1N1; WSN/33) virus. NO was delivered to influenza-infected mice either continuously or intermittently at 80 or 160 ppm, respectively, using both prophylactic and post-infection treatment strategies. Murine survival and weight loss were assessed, and lung viral load was quantified via plaque assay. Here, we report that iNO administered prophylactically or post-influenza infection failed to improve survival of infected mice. No difference in lung viral load was observed between experimental groups. Although NO has antiviral activity against influenza A virus in vitro, iNO therapy provided no apparent benefit when used for treatment of influenza A virus infection in vivo. PMID- 22253565 TI - Contrasting cellularity and fatty acid composition in fat depots from Alentejana and Barrosa bovine breeds fed high and low forage diets. AB - During the finishing phase of bovines, large amounts of subcutaneous and visceral fats are deposited leading to production inefficiencies with major impact on meat quality. A better understanding of the cellularity features of the main fat depots could provide strategies for adipose tissue manipulation. This study assessed the effect of feeding diets with distinct forage to concentrate ratios on the cellularity of two fat depots of beef cattle and their implications on the fatty acid profile. Thus, two phylogenetically distant Portuguese bovine breeds, Alentejana and Barrosa, were selected. The results did not show differences in subcutaneous fat deposition nor in visceral fat depots partitioning. Plasma adipokines concentration failed to show a consistent relationship with fatness, as leptin remained constant in all experimental groups, whereas interleukin-6 was influenced by breed. Fat depot seems to determine the area and number of adipocytes, with larger adipocytes and a lower number of cells in subcutaneous fat than in mesenteric fat. Neither breed nor diet influenced adipocytes area and number. The contents of total fatty acids, partial sums of fatty acids and conjugated linoleic acid isomeric profile were affected by breed and fat depot. The incorporation of saturated fatty acids (SFA), trans fatty acids, polyunsaturated fatty acids (PUFA) and branched chain fatty acids (BCFA) was higher in mesenteric fat depot, whereas subcutaneous fat depot had greater percentages of monounsaturated fatty acids (MUFA). In addition, SFA and MUFA proportions seem to be breed-related. In spite of the less relevant role of diet, the percentages of PUFA and BCFA were influenced by this factor. Under these experimental conditions, the effect of fat depot on cellularity and fatty acid composition prevails over breed or diet, as reinforced by the principal component analysis. PMID- 22253564 TI - TGFbeta signaling and cardiovascular diseases. AB - Transforming growth factor beta (TGFbeta) family members are involved in a wide range of diverse functions and play key roles in embryogenesis, development and tissue homeostasis. Perturbation of TGFbeta signaling may lead to vascular and other diseases. In vitro studies have provided evidence that TGFbeta family members have a wide range of diverse effects on vascular cells, which are highly dependent on cellular context. Consistent with these observations genetic studies in mice and humans showed that TGFbeta family members have ambiguous effects on the function of the cardiovascular system. In this review we discuss the recent advances on TGFbeta signaling in (cardio)vascular diseases, and describe the value of TGFbeta signaling as both a disease marker and therapeutic target for (cardio)vascular diseases. PMID- 22253566 TI - The pro-inflammatory role of TGFbeta1: a paradox? AB - TGFbeta1 was initially identified as a potent chemotactic cytokine to initiate inflammation, but the autoimmune phenotype seen in TGFbeta1 knockout mice reversed the dogma of TGFbeta1 being a pro-inflammatory cytokine to predominantly an immune suppressor. The discovery of the role of TGFbeta1 in Th17 cell activation once again revealed the pro-inflammatory effect of TGFbeta1. We developed K5.TGFbeta1 mice with latent human TGFbeta1 overexpression targeted to epidermal keratinocytes by keratin 5. These transgenic mice developed significant skin inflammation. Further studies revealed that inflammation severity correlated with switching TGFbeta1 transgene expression on and off, and genome wide expression profiling revealed striking similarities between K5.TGFbeta1 skin and human psoriasis, a Th1/Th17-associated inflammatory skin disease. Our recent study reveals that treatments alleviating inflammatory skin phenotypes in this mouse model reduced Th17 cells, and antibodies against IL-17 also lessen the inflammatory phenotype. Examination of inflammatory cytokines/chemokines affected by TGFbeta1 revealed predominantly Th1-, Th17-related cytokines in K5.TGFbeta1 skin. However, the finding that K5.TGFbeta1 mice also express Th2-associated inflammatory cytokines under certain pathological conditions raises the possibility that deregulated TGFbeta signaling is involved in more than one inflammatory disease. Furthermore, activation of both Th1/Th17 cells and regulatory T cells (Tregs) by TGFbeta1 reversely regulated by IL-6 highlights the dual role of TGFbeta1 in regulating inflammation, a dynamic, context and organ specific process. This review focuses on the role of TGFbeta1 in inflammatory skin diseases. PMID- 22253567 TI - Simvastatin modulates remodeling of Kv4.3 expression in rat hypertrophied cardiomyocytes. AB - OBJECTIVES: Hypertrophy has been shown to be associated with arrhythmias which can be caused by abnormal remodeling of the Kv4-family of transient potassium channels. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) have recently been shown to exert pleiotropic protective effects in cardiovascular diseases, including anti-arrhythmias. It is hypothesized that remodeling of Kv4.3 occurs in rat hypertrophied cardiomyocytes and is regulated by simvastatin. METHODS: Male Sprague-Dawley rats and neonatal rat ventricular myocytes (NRVMs) underwent abdominal aortic banding (AAB) for 7 weeks and angiotensin II (AngII) treatment, respectively, to induce cardiac hypertrophy. Kv4.3 expression by NRVMs and myocardium (subepicardial and subendocardial) in the left ventricle was measured. The transient outward potassium current (I(to)) of NRVMs was recorded using a whole-cell patch-clamp method. RESULTS: Expression of the Kv4.3 transcript and protein was significantly reduced in myocardium (subepicardial and subendocardial) in the left ventricle and in NRVMs. Simvastatin partially prevented the reduction of Kv4.3 expression in NRVMs and subepicardial myocardium but not in the subendocardial myocardium. Hypertrophied NRVMs exhibited a significant reduction in the I(to) current and this effect was partially reversed by simvastatin. CONCLUSIONS: Simvastatin alleviated the reduction of Kv4.3 expression, I(to) currents in hypertrophied NRVMs and alleviated the reduced Kv4.3 expression in subepicardial myocardium from the hypertrophied left ventricle. It can be speculated that among the pleiotropic effects of simvastatin, the anti-arrhythmia effect is partly mediated by its effect on Kv4.3. PMID- 22253568 TI - Interleukin-22 ameliorates cerulein-induced pancreatitis in mice by inhibiting the autophagic pathway. AB - Pancreatitis occurs when digestive enzymes are activated in the pancreas. Severe pancreatitis has a 10-30% mortality rate. No specific treatments for pancreatitis exist now. Here, we discovered that interleukin-22 (IL-22) may have therapeutic potential in treating acute and chronic pancreatitis. Wild-type and IL-22 knockout mice were equally susceptible to cerulein-induced acute and chronic pancreatitis, whereas liver-specific IL-22 transgenic mice were completely resistant to cerulein-induced elevation of serum digestive enzymes, pancreatic necrosis and apoptosis, and inflammatory cell infiltration. Treatment of wild type mice with recombinant IL-22 or adenovirus IL-22 markedly attenuated the severity of cerulein-induced acute and chronic pancreatitis. Mechanistically, we show that the protective effect of IL-22 on pancreatitis was mediated via the induction of Bcl-2 and Bcl-X(L), which bind to Beclin-1 and subsequently inhibit autophagosome formation to ameliorate pancreatitis. In conclusion, IL-22 ameliorates cerulein-induced pancreatitis by inhibiting the autophagic pathway. IL-22 could be a promising therapeutic drug to treat pancreatitis. PMID- 22253571 TI - Functional clustering drives encoding improvement in a developing brain network during awake visual learning. AB - Sensory experience drives dramatic structural and functional plasticity in developing neurons. However, for single-neuron plasticity to optimally improve whole-network encoding of sensory information, changes must be coordinated between neurons to ensure a full range of stimuli is efficiently represented. Using two-photon calcium imaging to monitor evoked activity in over 100 neurons simultaneously, we investigate network-level changes in the developing Xenopus laevis tectum during visual training with motion stimuli. Training causes stimulus-specific changes in neuronal responses and interactions, resulting in improved population encoding. This plasticity is spatially structured, increasing tuning curve similarity and interactions among nearby neurons, and decreasing interactions among distant neurons. Training does not improve encoding by single clusters of similarly responding neurons, but improves encoding across clusters, indicating coordinated plasticity across the network. NMDA receptor blockade prevents coordinated plasticity, reduces clustering, and abolishes whole-network encoding improvement. We conclude that NMDA receptors support experience dependent network self-organization, allowing efficient population coding of a diverse range of stimuli. PMID- 22253572 TI - A modular library of small molecule signals regulates social behaviors in Caenorhabditis elegans. AB - The nematode C. elegans is an important model for the study of social behaviors. Recent investigations have shown that a family of small molecule signals, the ascarosides, controls population density sensing and mating behavior. However, despite extensive studies of C. elegans aggregation behaviors, no intraspecific signals promoting attraction or aggregation of wild-type hermaphrodites have been identified. Using comparative metabolomics, we show that the known ascarosides are accompanied by a series of derivatives featuring a tryptophan-derived indole moiety. Behavioral assays demonstrate that these indole ascarosides serve as potent intraspecific attraction and aggregation signals for hermaphrodites, in contrast to ascarosides lacking the indole group, which are repulsive. Hermaphrodite attraction to indole ascarosides depends on the ASK amphid sensory neurons. Downstream of the ASK sensory neuron, the interneuron AIA is required for mediating attraction to indole ascarosides instead of the RMG interneurons, which previous studies have shown to integrate attraction and aggregation signals from ASK and other sensory neurons. The role of the RMG interneuron in mediating aggregation and attraction is thought to depend on the neuropeptide Y-like receptor NPR-1, because solitary and social C. elegans strains are distinguished by different npr-1 variants. We show that indole ascarosides promote attraction and aggregation in both solitary and social C. elegans strains. The identification of indole ascarosides as aggregation signals reveals unexpected complexity of social signaling in C. elegans, which appears to be based on a modular library of ascarosides integrating building blocks derived from lipid beta-oxidation and amino-acid metabolism. Variation of modules results in strongly altered signaling content, as addition of a tryptophan-derived indole unit to repellent ascarosides produces strongly attractive indole ascarosides. Our findings show that the library of ascarosides represents a highly developed chemical language integrating different neurophysiological pathways to mediate social communication in C. elegans. PMID- 22253573 TI - USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. AB - The seven transmembrane protein Smoothened (Smo) is a critical component of the Hedgehog (Hh) signaling pathway and is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hh stimulation. However, it is not clear how Hh regulates Smo accumulation on the cell surface or how Hh regulates the intracellular trafficking of Smo. In addition, little is known about whether ubiquitination is involved in Smo regulation. In this study, we demonstrate that Smo is multi-monoubiquitinated and that Smo ubiquitination is inhibited by Hh and by phosphorylation. Using an in vivo RNAi screen, we identified ubiquitin-specific protease 8 (USP8) as a deubiquitinase that down regulates Smo ubiquitination. Inactivation of USP8 increases Smo ubiquitination and attenuates Hh-induced Smo accumulation, leading to decreased Hh signaling activity. Moreover, overexpression of USP8 prevents Smo ubiquitination and elevates Smo accumulation, leading to increased Hh signaling activity. Mechanistically, we show that Hh promotes the interaction of USP8 with Smo aa625 753, which covers the three PKA and CK1 phosphorylation clusters. Finally, USP8 promotes the accumulation of Smo at the cell surface and prevents localization to the early endosomes, presumably by deubiquitinating Smo. Our studies identify USP8 as a positive regulator in Hh signaling by down-regulating Smo ubiquitination and thereby mediating Smo intracellular trafficking. PMID- 22253575 TI - New signaling chemicals spur worms to seek company. PMID- 22253574 TI - Hedgehog-regulated ubiquitination controls smoothened trafficking and cell surface expression in Drosophila. AB - Hedgehog transduces signal by promoting cell surface expression of the seven transmembrane protein Smoothened (Smo) in Drosophila, but the underlying mechanism remains unknown. Here we demonstrate that Smo is downregulated by ubiquitin-mediated endocytosis and degradation, and that Hh increases Smo cell surface expression by inhibiting its ubiquitination. We find that Smo is ubiquitinated at multiple Lysine residues including those in its autoinhibitory domain (SAID), leading to endocytosis and degradation of Smo by both lysosome- and proteasome-dependent mechanisms. Hh inhibits Smo ubiquitination via PKA/CK1 mediated phosphorylation of SAID, leading to Smo cell surface accumulation. Inactivation of the ubiquitin activating enzyme Uba1 or perturbation of multiple components of the endocytic machinery leads to Smo accumulation and Hh pathway activation. In addition, we find that the non-visual beta-arrestin Kurtz (Krz) interacts with Smo and acts in parallel with ubiquitination to downregulate Smo. Finally, we show that Smo ubiquitination is counteracted by the deubiquitinating enzyme UBPY/USP8. Gain and loss of UBPY lead to reciprocal changes in Smo cell surface expression. Taken together, our results suggest that ubiquitination plays a key role in the downregulation of Smo to keep Hh pathway activity off in the absence of the ligand, and that Hh-induced phosphorylation promotes Smo cell surface accumulation by inhibiting its ubiquitination, which contributes to Hh pathway activation. PMID- 22253576 TI - The inadequate treatment of pain: collateral damage from the war on drugs. AB - Jason Nickerson and Amir Attaran examine the vast inequities in medical pain relief around the world and argue that the global control of licit narcotics be shifted from the International Narcotic Control Board to WHO. PMID- 22253577 TI - Trends in compulsory licensing of pharmaceuticals since the Doha Declaration: a database analysis. AB - BACKGROUND: It is now a decade since the World Trade Organization (WTO) adopted the "Declaration on the TRIPS Agreement and Public Health" at its 4th Ministerial Conference in Doha. Many anticipated that these actions would lead nations to claim compulsory licenses (CLs) for pharmaceutical products with greater regularity. A CL is the use of a patented innovation that has been licensed by a state without the permission of the patent title holder. Skeptics doubted that many CLs would occur, given political pressure against CL activity and continued health system weakness in poor countries. The subsequent decade has seen little systematic assessment of the Doha Declaration's impact. METHODS AND FINDINGS: We assembled a database of all episodes in which a CL was publically entertained or announced by a WTO member state since 1995. Broad searches of CL activity were conducted using media, academic, and legal databases, yielding 34 potential CL episodes in 26 countries. Country- and product-specific searches were used to verify government participation, resulting in a final database of 24 verified CLs in 17 nations. We coded CL episodes in terms of outcome, national income, and disease group over three distinct periods of CL activity. Most CL episodes occurred between 2003 and 2005, involved drugs for HIV/AIDS, and occurred in upper-middle-income countries (UMICs). Aside from HIV/AIDS, few CL episodes involved communicable disease, and none occurred in least-developed or low-income countries. CONCLUSIONS: Given skepticism about the Doha Declaration's likely impact, we note the relatively high occurrence of CLs, yet CL activity has diminished markedly since 2006. While UMICs have high CL activity and strong incentives to use CLs compared to other countries, we note considerable countervailing pressures against CL use even in UMICs. We conclude that there is a low probability of continued CL activity. We highlight the need for further systematic evaluation of global health governance actions. Please see later in the article for the Editors' Summary. PMID- 22253578 TI - Long-term survival in a large cohort of patients with venous thrombosis: incidence and predictors. AB - BACKGROUND: Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis. METHODS AND FINDINGS: 4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well. 736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0-24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0-5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7-4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0-6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories. CONCLUSIONS: Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients. Please see later in the article for the Editors' Summary. PMID- 22253580 TI - Parsimonious higher-order hidden Markov models for improved array-CGH analysis with applications to Arabidopsis thaliana. AB - Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions C24 and Col-0 of the model plant Arabidopsis thaliana. We compare these models against first-order HMMs and other existing methods using a reference of known deletions and sequence deviations. We find that parsimonious higher-order HMMs clearly improve the identification of these polymorphisms. Moreover, we perform a functional analysis of identified polymorphisms revealing novel details of genomic differences between C24 and Col 0. Additional model evaluations are done on widely considered Array-CGH data of human cell lines indicating that parsimonious HMMs are also well-suited for the analysis of non-plant specific data. All these results indicate that parsimonious higher-order HMMs are useful for Array-CGH analyses. An implementation of parsimonious higher-order HMMs is available as part of the open source Java library Jstacs (www.jstacs.de/index.php/PHHMM). PMID- 22253579 TI - What will it take to eliminate pediatric HIV? Reaching WHO target rates of mother to-child HIV transmission in Zimbabwe: a model-based analysis. AB - BACKGROUND: The World Health Organization (WHO) has called for the "virtual elimination" of pediatric HIV: a mother-to-child HIV transmission (MTCT) risk of less than 5%. We investigated uptake of prevention of MTCT (PMTCT) services, infant feeding recommendations, and specific drug regimens necessary to achieve this goal in Zimbabwe. METHODS AND FINDINGS: We used a computer model to simulate a cohort of HIV-infected, pregnant/breastfeeding women (mean age, 24 y; mean CD4, 451/ul; breastfeeding duration, 12 mo). Three PMTCT regimens were evaluated: (1) single-dose nevirapine (sdNVP), (2) WHO 2010 guidelines' "Option A" (zidovudine in pregnancy, infant nevirapine throughout breastfeeding for women without advanced disease, lifelong combination antiretroviral therapy for women with advanced disease), and (3) WHO "Option B" (pregnancy/breastfeeding-limited combination antiretroviral drug regimens without advanced disease; lifelong antiretroviral therapy with advanced disease). We examined four levels of PMTCT uptake (proportion of pregnant women accessing and adhering to PMTCT services): reported rates in 2008 and 2009 (36% and 56%, respectively) and target goals in 2008 and 2009 (80% and 95%, respectively). The primary model outcome was MTCT risk at weaning. The 2008 sdNVP-based National PMTCT Program led to a projected 12-mo MTCT risk of 20.3%. Improved uptake in 2009 reduced projected risk to 18.0%. If sdNVP were replaced by more effective regimens, with 2009 (56%) uptake, estimated MTCT risk would be 14.4% (Option A) or 13.4% (Option B). Even with 95% uptake of Option A or B, projected transmission risks (6.1%-7.7%) would exceed the WHO goal of less than 5%. Only if the lowest published transmission risks were used for each drug regimen, or breastfeeding duration were shortened, would MTCT risks at 95% uptake fall below 5%. CONCLUSIONS: Implementation of the WHO PMTCT guidelines must be accompanied by efforts to improve access to PMTCT services, retain women in care, and support medication adherence throughout pregnancy and breastfeeding, to approach the "virtual elimination" of pediatric HIV in Zimbabwe. Please see later in the article for the Editors' Summary. PMID- 22253581 TI - Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations. AB - Cholesteryl ester transfer protein (CETP) transports cholesteryl esters, triglycerides, and phospholipids between different lipoprotein fractions in blood plasma. The inhibition of CETP has been shown to be a sound strategy to prevent and treat the development of coronary heart disease. We employed molecular dynamics simulations to unravel the mechanisms associated with the CETP-mediated lipid exchange. To this end we used both atomistic and coarse-grained models whose results were consistent with each other. We found CETP to bind to the surface of high density lipoprotein (HDL) -like lipid droplets through its charged and tryptophan residues. Upon binding, CETP rapidly (in about 10 ns) induced the formation of a small hydrophobic patch to the phospholipid surface of the droplet, opening a route from the core of the lipid droplet to the binding pocket of CETP. This was followed by a conformational change of helix X of CETP to an open state, in which we found the accessibility of cholesteryl esters to the C-terminal tunnel opening of CETP to increase. Furthermore, in the absence of helix X, cholesteryl esters rapidly diffused into CETP through the C-terminal opening. The results provide compelling evidence that helix X acts as a lid which conducts lipid exchange by alternating the open and closed states. The findings have potential for the design of novel molecular agents to inhibit the activity of CETP. PMID- 22253582 TI - Global analysis of small molecule binding to related protein targets. AB - We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity. PMID- 22253583 TI - A dynamic view of domain-motif interactions. AB - Many protein-protein interactions are mediated by domain-motif interaction, where a domain in one protein binds a short linear motif in its interacting partner. Such interactions are often involved in key cellular processes, necessitating their tight regulation. A common strategy of the cell to control protein function and interaction is by post-translational modifications of specific residues, especially phosphorylation. Indeed, there are motifs, such as SH2-binding motifs, in which motif phosphorylation is required for the domain-motif interaction. On the contrary, there are other examples where motif phosphorylation prevents the domain-motif interaction. Here we present a large-scale integrative analysis of experimental human data of domain-motif interactions and phosphorylation events, demonstrating an intriguing coupling between the two. We report such coupling for SH3, PDZ, SH2 and WW domains, where residue phosphorylation within or next to the motif is implied to be associated with switching on or off domain binding. For domains that require motif phosphorylation for binding, such as SH2 domains, we found coupled phosphorylation events other than the ones required for domain binding. Furthermore, we show that phosphorylation might function as a double switch, concurrently enabling interaction of the motif with one domain and disabling interaction with another domain. Evolutionary analysis shows that co evolution of the motif and the proximal residues capable of phosphorylation predominates over other evolutionary scenarios, in which the motif appeared before the potentially phosphorylated residue, or vice versa. Our findings provide strengthening evidence for coupled interaction-regulation units, defined by a domain-binding motif and a phosphorylated residue. PMID- 22253584 TI - Adjusting phenotypes by noise control. AB - Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system; for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks. PMID- 22253585 TI - Network model of immune responses reveals key effectors to single and co infection dynamics by a respiratory bacterium and a gastrointestinal helminth. AB - Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations. PMID- 22253586 TI - Maximization of learning speed in the motor cortex due to neuronal redundancy. AB - Many redundancies play functional roles in motor control and motor learning. For example, kinematic and muscle redundancies contribute to stabilizing posture and impedance control, respectively. Another redundancy is the number of neurons themselves; there are overwhelmingly more neurons than muscles, and many combinations of neural activation can generate identical muscle activity. The functional roles of this neuronal redundancy remains unknown. Analysis of a redundant neural network model makes it possible to investigate these functional roles while varying the number of model neurons and holding constant the number of output units. Our analysis reveals that learning speed reaches its maximum value if and only if the model includes sufficient neuronal redundancy. This analytical result does not depend on whether the distribution of the preferred direction is uniform or a skewed bimodal, both of which have been reported in neurophysiological studies. Neuronal redundancy maximizes learning speed, even if the neural network model includes recurrent connections, a nonlinear activation function, or nonlinear muscle units. Furthermore, our results do not rely on the shape of the generalization function. The results of this study suggest that one of the functional roles of neuronal redundancy is to maximize learning speed. PMID- 22253587 TI - Kinetic rate constant prediction supports the conformational selection mechanism of protein binding. AB - The prediction of protein-protein kinetic rate constants provides a fundamental test of our understanding of molecular recognition, and will play an important role in the modeling of complex biological systems. In this paper, a feature selection and regression algorithm is applied to mine a large set of molecular descriptors and construct simple models for association and dissociation rate constants using empirical data. Using separate test data for validation, the predicted rate constants can be combined to calculate binding affinity with accuracy matching that of state of the art empirical free energy functions. The models show that the rate of association is linearly related to the proportion of unbound proteins in the bound conformational ensemble relative to the unbound conformational ensemble, indicating that the binding partners must adopt a geometry near to that of the bound prior to binding. Mirroring the conformational selection and population shift mechanism of protein binding, the models provide a strong separate line of evidence for the preponderance of this mechanism in protein-protein binding, complementing structural and theoretical studies. PMID- 22253588 TI - Residual structures, conformational fluctuations, and electrostatic interactions in the synergistic folding of two intrinsically disordered proteins. AB - To understand the interplay of residual structures and conformational fluctuations in the interaction of intrinsically disordered proteins (IDPs), we first combined implicit solvent and replica exchange sampling to calculate atomistic disordered ensembles of the nuclear co-activator binding domain (NCBD) of transcription coactivator CBP and the activation domain of the p160 steroid receptor coactivator ACTR. The calculated ensembles are in quantitative agreement with NMR-derived residue helicity and recapitulate the experimental observation that, while free ACTR largely lacks residual secondary structures, free NCBD is a molten globule with a helical content similar to that in the folded complex. Detailed conformational analysis reveals that free NCBD has an inherent ability to substantially sample all the helix configurations that have been previously observed either unbound or in complexes. Intriguingly, further high-temperature unbinding and unfolding simulations in implicit and explicit solvents emphasize the importance of conformational fluctuations in synergistic folding of NCBD with ACTR. A balance between preformed elements and conformational fluctuations appears necessary to allow NCBD to interact with different targets and fold into alternative conformations. Together with previous topology-based modeling and existing experimental data, the current simulations strongly support an "extended conformational selection" synergistic folding mechanism that involves a key intermediate state stabilized by interaction between the C-terminal helices of NCBD and ACTR. In addition, the atomistic simulations reveal the role of long range as well as short-range electrostatic interactions in cooperating with readily fluctuating residual structures, which might enhance the encounter rate and promote efficient folding upon encounter for facile binding and folding interactions of IDPs. Thus, the current study not only provides a consistent mechanistic understanding of the NCBD/ACTR interaction, but also helps establish a multi-scale molecular modeling framework for understanding the structure, interaction, and regulation of IDPs in general. PMID- 22253590 TI - The Vibrio cholerae colonization factor GbpA possesses a modular structure that governs binding to different host surfaces. AB - Vibrio cholerae is a bacterial pathogen that colonizes the chitinous exoskeleton of zooplankton as well as the human gastrointestinal tract. Colonization of these different niches involves an N-acetylglucosamine binding protein (GbpA) that has been reported to mediate bacterial attachment to both marine chitin and mammalian intestinal mucin through an unknown molecular mechanism. We report structural studies that reveal that GbpA possesses an unusual, elongated, four-domain structure, with domains 1 and 4 showing structural homology to chitin binding domains. A glycan screen revealed that GbpA binds to GlcNAc oligosaccharides. Structure-guided GbpA truncation mutants show that domains 1 and 4 of GbpA interact with chitin in vitro, whereas in vivo complementation studies reveal that domain 1 is also crucial for mucin binding and intestinal colonization. Bacterial binding studies show that domains 2 and 3 bind to the V. cholerae surface. Finally, mouse virulence assays show that only the first three domains of GbpA are required for colonization. These results explain how GbpA provides structural/functional modular interactions between V. cholerae, intestinal epithelium and chitinous exoskeletons. PMID- 22253591 TI - Sequence divergent RXLR effectors share a structural fold conserved across plant pathogenic oomycete species. PMID- 22253592 TI - Two distinct coagulase-dependent barriers protect Staphylococcus aureus from neutrophils in a three dimensional in vitro infection model. AB - Staphylococcus aureus is a pyogenic abscess-forming facultative pathogenic microorganism expressing a large set of virulence-associated factors. Among these, secreted proteins with binding capacity to plasma proteins (e.g. fibrinogen binding proteins Eap and Emp) and prothrombin activators such as Coagulase (Coa) and vWbp are involved in abscess formation. By using a three dimensional collagen gel (3D-CoG) supplemented with fibrinogen (Fib) we studied the growth behavior of S. aureus strain Newman and a set of mutants as well as their interaction with mouse neutrophils by real-time confocal microscopy. In 3D CoG/Fib, S. aureus forms microcolonies which are surrounded by an inner pseudocapsule and an extended outer dense microcolony-associated meshwork (MAM) containing fibrin. Coa is involved in formation of the pseudocapsule whereas MAM formation depends on vWbp. Moreover, agr-dependent dispersal of late stage microcolonies could be observed. Furthermore, we demonstrate that the pseudocapsule and the MAM act as mechanical barriers against neutrophils attracted to the microcolony. The thrombin inhibitor argatroban is able to prevent formation of both pseudocapsule and MAM and supports access of neutrophils to staphylococci. Taken together, this model can simulate specific stages of S. aureus abscess formation by temporal dissection of bacterial growth and recruitment of immune cells. It can complement established animal infection models in the development of new treatment options. PMID- 22253593 TI - The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. AB - Survival of bacterial infection is the result of complex host-pathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Previously, we demonstrated that Drosophila mutants lacking the circadian regulatory proteins Timeless (Tim) and Period (Per) are sensitive to infection by S. pneumoniae. Sensitivity to infection can be mediated either by changes in resistance (control of microbial load) or tolerance (endurance of the pathogenic effects of infection). Here we show that Tim regulates resistance against both S. pneumoniae and S. marcescens. We set out to characterize and identify the underlying mechanism of resistance that is circadian-regulated. Using S. pneumoniae, we found that resistance oscillates daily in adult wild-type flies and that these oscillations are absent in Tim mutants. Drosophila have at least three main resistance mechanisms to kill high levels of bacteria in their hemolymph: melanization, antimicrobial peptides, and phagocytosis. We found that melanization is not circadian-regulated. We further found that basal levels of AMP gene expression exhibit time-of-day oscillations but that these are Tim independent; moreover, infection-induced AMP gene expression is not circadian regulated. We then show that phagocytosis is circadian-regulated. Wild-type flies exhibit up-regulated phagocytic activity at night; Tim mutants have normal phagocytic activity during the day but lack this night-time peak. Tim appears to regulate an upstream event in phagocytosis, such as bacterial recognition or activation of phagocytic hemocytes. Interestingly, inhibition of phagocytosis in wild type flies results in survival kinetics similar to Tim mutants after infection with S. pneumoniae. Taken together, these results suggest that loss of circadian oscillation of a specific immune function (phagocytosis) can have significant effects on long-term survival of infection. PMID- 22253594 TI - Nonsex genes in the mating type locus of Candida albicans play roles in a/alpha biofilm formation, including impermeability and fluconazole resistance. AB - The mating type locus (MTL) of Candida albicans contains the mating type genes and has, therefore, been assumed to play an exclusive role in the mating process. In mating-incompetent a/alpha cells, two of the mating type genes, MTLa1 and MTLalpha2, encode components of the a1-alpha2 corepressor that suppresses mating and switching. But the MTL locus of C. albicans also contains three apparently unrelated "nonsex" genes (NSGs), PIK, PAP and OBP, the first two essential for growth. Since it had been previously demonstrated that deleting either the a/alpha copy of the entire MTL locus, or either MTLa1 or MTLalpha2, affected virulence, we hypothesized that the NSGs in the MTL locus may also play a role in pathogenesis. Here by mutational analysis, it is demonstrated that both the mating type and nonsex genes in the MTL locus play roles in a/alpha biofilm formation, and that OBP is essential for impermeability and fluconazole resistance. PMID- 22253595 TI - The RBP-Jkappa binding sites within the RTA promoter regulate KSHV latent infection and cell proliferation. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is tightly linked to at least two lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). However, the development of KSHV-mediated lymphoproliferative disease is not fully understood. Here, we generated two recombinant KSHV viruses deleted for the first RBP-Jkappa binding site (RTA(1st)) and all three RBP-Jkappa binding sites (RTA(all)) within the RTA promoter. Our results showed that RTA(1st) and RTA(all) recombinant viruses possess increased viral latency and a decreased capability for lytic replication in HEK 293 cells, enhancing colony formation and proliferation of infected cells. Furthermore, recombinant RTA(1st) and RTA(all) viruses showed greater infectivity in human peripheral blood mononuclear cells (PBMCs) relative to wt KSHV. Interestingly, KSHV BAC36 wt, RTA(1st) and RTA(all) recombinant viruses infected both T and B cells and all three viruses efficiently infected T and B cells in a time dependent manner early after infection. Also, the capability of both RTA(1st) and RTA(all) recombinant viruses to infect CD19+ B cells was significantly enhanced. Surprisingly, RTA(1st) and RTA(all) recombinant viruses showed greater infectivity for CD3+ T cells up to 7 days. Furthermore, studies in Telomerase immortalized human umbilical vein endothelial (TIVE) cells infected with KSHV corroborated our data that RTA(1st) and RTA(all) recombinant viruses have enhanced ability to persist in latently infected cells with increased proliferation. These recombinant viruses now provide a model to explore early stages of primary infection in human PBMCs and development of KSHV-associated lymphoproliferative diseases. PMID- 22253596 TI - Mechanisms of NK cell-macrophage Bacillus anthracis crosstalk: a balance between stimulation by spores and differential disruption by toxins. AB - NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-gamma production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-gamma production by NK cells in response to B. anthracis spores was: i) contact dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-gamma production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-gamma secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-gamma secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms. PMID- 22253597 TI - The bZIP transcription factor Rca1p is a central regulator of a novel CO2 sensing pathway in yeast. AB - Like many organisms the fungal pathogen Candida albicans senses changes in the environmental CO(2) concentration. This response involves two major proteins: adenylyl cyclase and carbonic anhydrase (CA). Here, we demonstrate that CA expression is tightly controlled by the availability of CO(2) and identify the bZIP transcription factor Rca1p as the first CO(2) regulator of CA expression in yeast. We show that Rca1p upregulates CA expression during contact with mammalian phagocytes and demonstrate that serine 124 is critical for Rca1p signaling, which occurs independently of adenylyl cyclase. ChIP-chip analysis and the identification of Rca1p orthologs in the model yeast Saccharomyces cerevisiae (Cst6p) point to the broad significance of this novel pathway in fungi. By using advanced microscopy we visualize for the first time the impact of CO(2) build-up on gene expression in entire fungal populations with an exceptional level of detail. Our results present the bZIP protein Rca1p as the first fungal regulator of carbonic anhydrase, and reveal the existence of an adenylyl cyclase independent CO(2) sensing pathway in yeast. Rca1p appears to regulate cellular metabolism in response to CO(2) availability in environments as diverse as the phagosome, yeast communities or liquid culture. PMID- 22253598 TI - Human Herpesvirus 8 (HHV8) sequentially shapes the NK cell repertoire during the course of asymptomatic infection and Kaposi sarcoma. AB - The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells. PMID- 22253599 TI - Two-drug antimicrobial chemotherapy: a mathematical model and experiments with Mycobacterium marinum. AB - Multi-drug therapy is the standard-of-care treatment for tuberculosis. Despite this, virtually all studies of the pharmacodynamics (PD) of mycobacterial drugs employed for the design of treatment protocols are restricted to single agents. In this report, mathematical models and in vitro experiments with Mycobacterium marinum and five antimycobacterial drugs are used to quantitatively evaluate the pharmaco-, population and evolutionary dynamics of two-drug antimicrobial chemotherapy regimes. Time kill experiments with single and pairs of antibiotics are used to estimate the parameters and evaluate the fit of Hill-function-based PD models. While Hill functions provide excellent fits for the PD of each single antibiotic studied, rifampin, amikacin, clarithromycin, streptomycin and moxifloxacin, two-drug Hill functions with a unique interaction parameter cannot account for the PD of any of the 10 pairs of these drugs. If we assume two antibiotic-concentration dependent functions for the interaction parameter, one for sub-MIC and one for supra-MIC drug concentrations, the modified biphasic Hill function provides a reasonably good fit for the PD of all 10 pairs of antibiotics studied. Monte Carlo simulations of antibiotic treatment based on the experimentally-determined PD functions are used to evaluate the potential microbiological efficacy (rate of clearance) and evolutionary consequences (likelihood of generating multi-drug resistance) of these different drug combinations as well as their sensitivity to different forms of non-adherence to therapy. These two-drug treatment simulations predict varying outcomes for the different pairs of antibiotics with respect to the aforementioned measures of efficacy. In summary, Hill functions with biphasic drug-drug interaction terms provide accurate analogs for the PD of pairs of antibiotics and M. marinum. The models, experimental protocols and computer simulations used in this study can be applied to evaluate the potential microbiological and evolutionary efficacy of two-drug therapy for any bactericidal antibiotics and bacteria that can be cultured in vitro. PMID- 22253600 TI - Genomic ancestry of North Africans supports back-to-Africa migrations. AB - North African populations are distinct from sub-Saharan Africans based on cultural, linguistic, and phenotypic attributes; however, the time and the extent of genetic divergence between populations north and south of the Sahara remain poorly understood. Here, we interrogate the multilayered history of North Africa by characterizing the effect of hypothesized migrations from the Near East, Europe, and sub-Saharan Africa on current genetic diversity. We present dense, genome-wide SNP genotyping array data (730,000 sites) from seven North African populations, spanning from Egypt to Morocco, and one Spanish population. We identify a gradient of likely autochthonous Maghrebi ancestry that increases from east to west across northern Africa; this ancestry is likely derived from "back to-Africa" gene flow more than 12,000 years ago (ya), prior to the Holocene. The indigenous North African ancestry is more frequent in populations with historical Berber ethnicity. In most North African populations we also see substantial shared ancestry with the Near East, and to a lesser extent sub-Saharan Africa and Europe. To estimate the time of migration from sub-Saharan populations into North Africa, we implement a maximum likelihood dating method based on the distribution of migrant tracts. In order to first identify migrant tracts, we assign local ancestry to haplotypes using a novel, principal component-based analysis of three ancestral populations. We estimate that a migration of western African origin into Morocco began about 40 generations ago (approximately 1,200 ya); a migration of individuals with Nilotic ancestry into Egypt occurred about 25 generations ago (approximately 750 ya). Our genomic data reveal an extraordinarily complex history of migrations, involving at least five ancestral populations, into North Africa. PMID- 22253601 TI - The Drosophila melanogaster seminal fluid protease "seminase" regulates proteolytic and post-mating reproductive processes. AB - Proteases and protease inhibitors have been identified in the ejaculates of animal taxa ranging from invertebrates to mammals and form a major protein class among Drosophila melanogaster seminal fluid proteins (SFPs). Other than a single protease cascade in mammals that regulates seminal clot liquefaction, no proteolytic cascades (i.e. pathways with at least two proteases acting in sequence) have been identified in seminal fluids. In Drosophila, SFPs are transferred to females during mating and, together with sperm, are necessary for the many post-mating responses elicited in females. Though several SFPs are proteolytically cleaved either during or after mating, virtually nothing is known about the proteases involved in these cleavage events or the physiological consequences of proteolytic activity in the seminal fluid on the female. Here, we present evidence that a protease cascade acts in the seminal fluid of Drosophila during and after mating. Using RNAi to knock down expression of the SFP CG10586, a predicted serine protease, we show that it acts upstream of the SFP CG11864, a predicted astacin protease, to process SFPs involved in ovulation and sperm entry into storage. We also show that knockdown of CG10586 leads to lower levels of egg laying, higher rates of sexual receptivity to subsequent males, and abnormal sperm usage patterns, processes that are independent of CG11864. The long-term phenotypes of females mated to CG10586 knockdown males are similar to those of females that fail to store sex peptide, an important elicitor of long-term post mating responses, and indicate a role for CG10586 in regulating sex peptide. These results point to an important role for proteolysis among insect SFPs and suggest that protease cascades may be a mechanism for precise temporal regulation of multiple post-mating responses in females. PMID- 22253602 TI - Adaptive evolution of the lactose utilization network in experimentally evolved populations of Escherichia coli. AB - Adaptation to novel environments is often associated with changes in gene regulation. Nevertheless, few studies have been able both to identify the genetic basis of changes in regulation and to demonstrate why these changes are beneficial. To this end, we have focused on understanding both how and why the lactose utilization network has evolved in replicate populations of Escherichia coli. We found that lac operon regulation became strikingly variable, including changes in the mode of environmental response (bimodal, graded, and constitutive), sensitivity to inducer concentration, and maximum expression level. In addition, some classes of regulatory change were enriched in specific selective environments. Sequencing of evolved clones, combined with reconstruction of individual mutations in the ancestral background, identified mutations within the lac operon that recapitulate many of the evolved regulatory changes. These mutations conferred fitness benefits in environments containing lactose, indicating that the regulatory changes are adaptive. The same mutations conferred different fitness effects when present in an evolved clone, indicating that interactions between the lac operon and other evolved mutations also contribute to fitness. Similarly, changes in lac regulation not explained by lac operon mutations also point to important interactions with other evolved mutations. Together these results underline how dynamic regulatory interactions can be, in this case evolving through mutations both within and external to the canonical lactose utilization network. PMID- 22253604 TI - An siRNA screen in pancreatic beta cells reveals a role for Gpr27 in insulin production. AB - The prevalence of type 2 diabetes in the United States is projected to double or triple by 2050. We reasoned that the genes that modulate insulin production might be new targets for diabetes therapeutics. Therefore, we developed an siRNA screening system to identify genes important for the activity of the insulin promoter in beta cells. We created a subclone of the MIN6 mouse pancreatic beta cell line that expresses destabilized GFP under the control of a 362 base pair fragment of the human insulin promoter and the mCherry red fluorescent protein under the control of the constitutively active rous sarcoma virus promoter. The ratio of the GFP to mCherry fluorescence of a cell indicates its insulin promoter activity. As G protein coupled receptors (GPCRs) have emerged as novel targets for diabetes therapies, we used this cell line to screen an siRNA library targeting all known mouse GPCRs. We identified several known GPCR regulators of insulin secretion as regulators of the insulin promoter. One of the top positive regulators was Gpr27, an orphan GPCR with no known role in beta cell function. We show that knockdown of Gpr27 reduces endogenous mouse insulin promoter activity and glucose stimulated insulin secretion. Furthermore, we show that Pdx1 is important for Gpr27's effect on the insulin promoter and insulin secretion. Finally, the over-expression of Gpr27 in 293T cells increases inositol phosphate levels, while knockdown of Gpr27 in MIN6 cells reduces inositol phosphate levels, suggesting this orphan GPCR might couple to Gq/11. In summary, we demonstrate a MIN6-based siRNA screening system that allows rapid identification of novel positive and negative regulators of the insulin promoter. Using this system, we identify Gpr27 as a positive regulator of insulin production. PMID- 22253603 TI - A gene regulatory network for root epidermis cell differentiation in Arabidopsis. AB - The root epidermis of Arabidopsis provides an exceptional model for studying the molecular basis of cell fate and differentiation. To obtain a systems-level view of root epidermal cell differentiation, we used a genome-wide transcriptome approach to define and organize a large set of genes into a transcriptional regulatory network. Using cell fate mutants that produce only one of the two epidermal cell types, together with fluorescence-activated cell-sorting to preferentially analyze the root epidermis transcriptome, we identified 1,582 genes differentially expressed in the root-hair or non-hair cell types, including a set of 208 "core" root epidermal genes. The organization of the core genes into a network was accomplished by using 17 distinct root epidermis mutants and 2 hormone treatments to perturb the system and assess the effects on each gene's transcript accumulation. In addition, temporal gene expression information from a developmental time series dataset and predicted gene associations derived from a Bayesian modeling approach were used to aid the positioning of genes within the network. Further, a detailed functional analysis of likely bHLH regulatory genes within the network, including MYC1, bHLH54, bHLH66, and bHLH82, showed that three distinct subfamilies of bHLH proteins participate in root epidermis development in a stage-specific manner. The integration of genetic, genomic, and computational analyses provides a new view of the composition, architecture, and logic of the root epidermal transcriptional network, and it demonstrates the utility of a comprehensive systems approach for dissecting a complex regulatory network. PMID- 22253605 TI - Cdc5-dependent asymmetric localization of bfa1 fine-tunes timely mitotic exit. AB - In budding yeast, the major regulator of the mitotic exit network (MEN) is Tem1, a GTPase, which is inhibited by the GTPase-activating protein (GAP), Bfa1/Bub2. Asymmetric Bfa1 localization to the bud-directed spindle pole body (SPB) during metaphase also controls mitotic exit, but the molecular mechanism and function of this localization are not well understood, particularly in unperturbed cells. We identified four novel Cdc5 target residues within the Bfa1 C-terminus: (452)S, (453)S, (454)S, and (559)S. A Bfa1 mutant in which all of these residues had been changed to alanine (Bfa1(4A)) persisted on both SPBs at anaphase and was hypo phosphorylated, despite retaining its GAP activity for Tem1. A Bfa1 phospho mimetic mutant in which all of these residues were switched to aspartate (Bfa1(4D)) always localized asymmetrically to the SPB. These observations demonstrate that asymmetric localization of Bfa1 is tightly linked to its Cdc5 dependent phosphorylation, but not to its GAP activity. Consistent with this, in kinase-defective cdc5-2 cells Bfa1 was not phosphorylated and localized to both SPBs, whereas Bfa1(4D) was asymmetrically localized. BFA1(4A) cells progressed through anaphase normally but displayed delayed mitotic exit in unperturbed cell cycles, while BFA1(4D) cells underwent mitotic exit with the same kinetics as wild-type cells. We suggest that Cdc5 induces the asymmetric distribution of Bfa1 to the bud-directed SPB independently of Bfa1 GAP activity at anaphase and that Bfa1 asymmetry fine-tunes the timing of MEN activation in unperturbed cell cycles. PMID- 22253606 TI - A high density SNP array for the domestic horse and extant Perissodactyla: utility for association mapping, genetic diversity, and phylogeny studies. AB - An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of ~43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50-100 kb and reached background levels within 1-2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of ~750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species. PMID- 22253607 TI - Genetic evidence for an indispensable role of somatic embryogenesis receptor kinases in brassinosteroid signaling. AB - The Arabidopsis thaliana somatic embryogenesis receptor kinases (SERKs) consist of five members, SERK1 to SERK5, of the leucine-rich repeat receptor-like kinase subfamily II (LRR-RLK II). SERK3 was named BRI1-Associated Receptor Kinase 1 (BAK1) due to its direct interaction with the brassinosteroid (BR) receptor BRI1 in vivo, while SERK4 has also been designated as BAK1-Like 1 (BKK1) for its functionally redundant role with BAK1. Here we provide genetic and biochemical evidence to demonstrate that SERKs are absolutely required for early steps in BR signaling. Overexpression of four of the five SERKs-SERK1, SERK2, SERK3/BAK1, and SERK4/BKK1-suppressed the phenotypes of an intermediate BRI1 mutant, bri1-5. Overexpression of the kinase-dead versions of these four genes in the bri1-5 background, on the other hand, resulted in typical dominant negative phenotypes, resembling those of null BRI1 mutants. We isolated and generated single, double, triple, and quadruple mutants and analyzed their phenotypes in detail. While the quadruple mutant is embryo-lethal, the serk1 bak1 bkk1 triple null mutant exhibits an extreme de-etiolated phenotype similar to a null bri1 mutant. While overexpression of BRI1 can drastically increase hypocotyl growth of wild-type plants, overexpression of BRI1 does not alter hypocotyl growth of the serk1 bak1 bkk1 triple mutant. Biochemical analysis indicated that the phosphorylation level of BRI1 in serk1 bak1 bkk1 is incapable of sensing exogenously applied BR. As a result, the unphosphorylated level of BES1 has lost its sensitivity to the BR treatment in the triple mutant, indicating that the BR signaling pathway has been completely abolished in the triple mutant. These data clearly demonstrate that SERKs are essential to the early events of BR signaling. PMID- 22253608 TI - Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance. AB - The cytoplasmic polyadenylation element binding protein CPEB1 (CPEB) regulates germ cell development, synaptic plasticity, and cellular senescence. A microarray analysis of mRNAs regulated by CPEB unexpectedly showed that several encoded proteins are involved in insulin signaling. An investigation of Cpeb1 knockout mice revealed that the expression of two particular negative regulators of insulin action, PTEN and Stat3, were aberrantly increased. Insulin signaling to Akt was attenuated in livers of CPEB-deficient mice, suggesting that they might be defective in regulating glucose homeostasis. Indeed, when the Cpeb1 knockout mice were fed a high-fat diet, their livers became insulin-resistant. Analysis of HepG2 cells, a human liver cell line, depleted of CPEB demonstrated that this protein directly regulates the translation of PTEN and Stat3 mRNAs. Our results show that CPEB regulated translation is a key process involved in insulin signaling. PMID- 22253609 TI - Parallel mapping and simultaneous sequencing reveals deletions in BCAN and FAM83H associated with discrete inherited disorders in a domestic dog breed. AB - The domestic dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10-14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (P(raw) 1.9*10(-14); P(genome) = 1.0*10(-5)) and chromosome 13 (P(raw) 1.2*10(-17); P(genome) = 1.0*10(-5)), respectively. We resequenced both the EF and CKCSID disease associated regions in just five dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic dog to study the genetic basis of more than one disease simultaneously in a single breed and to identify multiple novel candidate genes in parallel. PMID- 22253610 TI - A half-century of inspiration: an interview with Hamilton Smith. Interview by Jane Gitschier. PMID- 22253612 TI - Genome engineering in Vibrio cholerae: a feasible approach to address biological issues. AB - Although bacteria with multipartite genomes are prevalent, our knowledge of the mechanisms maintaining their genome is very limited, and much remains to be learned about the structural and functional interrelationships of multiple chromosomes. Owing to its bi-chromosomal genome architecture and its importance in public health, Vibrio cholerae, the causative agent of cholera, has become a preferred model to study bacteria with multipartite genomes. However, most in vivo studies in V. cholerae have been hampered by its genome architecture, as it is difficult to give phenotypes to a specific chromosome. This difficulty was surmounted using a unique and powerful strategy based on massive rearrangement of prokaryotic genomes. We developed a site-specific recombination-based engineering tool, which allows targeted, oriented, and reciprocal DNA exchanges. Using this genetic tool, we obtained a panel of V. cholerae mutants with various genome configurations: one with a single chromosome, one with two chromosomes of equal size, and one with both chromosomes controlled by identical origins. We used these synthetic strains to address several biological questions--the specific case of the essentiality of Dam methylation in V. cholerae and the general question concerning bacteria carrying circular chromosomes--by looking at the effect of chromosome size on topological issues. In this article, we show that Dam, RctB, and ParA2/ParB2 are strictly essential for chrII origin maintenance, and we formally demonstrate that the formation of chromosome dimers increases exponentially with chromosome size. PMID- 22253611 TI - Calpains mediate integrin attachment complex maintenance of adult muscle in Caenorhabditis elegans. AB - Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC 112/MIG-2/Kindlin-2, were recently identified as negative regulators of muscle protein degradation and as having decreased mRNA levels in response to spaceflight. Integrin complexes transmit force between the inside and outside of muscle cells and signal changes in muscle size in response to force and, perhaps, disuse. We therefore investigated the effects of acute decreases in expression of the genes encoding these multi-protein complexes. We find that in fully developed adult Caenorhabditis elegans muscle, RNAi against genes encoding core, and peripheral, members of these complexes induces protein degradation, myofibrillar and mitochondrial dystrophies, and a movement defect. Genetic disruption of Z line- or M-line-specific complex members is sufficient to induce these defects. We confirmed that defects occur in temperature-sensitive mutants for two of the genes: unc-52, which encodes the extra-cellular ligand Perlecan, and unc-112, which encodes the intracellular component Kindlin-2. These results demonstrate that integrin containing attachment complexes, as a whole, are required for proper maintenance of adult muscle. These defects, and collapse of arrayed attachment complexes into ball like structures, are blocked when DIM-1 levels are reduced. Degradation is also blocked by RNAi or drugs targeting calpains, implying that disruption of integrin containing complexes results in calpain activation. In wild-type animals, either during development or in adults, RNAi against calpain genes results in integrin muscle attachment disruptions and consequent sub-cellular defects. These results demonstrate that calpains are required for proper assembly and maintenance of integrin attachment complexes. Taken together our data provide in vivo evidence that a calpain-based molecular repair mechanism exists for dealing with attachment complex disruption in adult muscle. Since C. elegans lacks satellite cells, this mechanism is intrinsic to the muscles and raises the question if such a mechanism also exists in higher metazoans. PMID- 22253614 TI - Relation of adiponectin to glucose tolerance status, adiposity, and cardiovascular risk factor load. AB - OBJECTIVE: Adiponectin has anti-atherogenic and anti-inflammatory properties. We investigated the influence of adiponectin on glucose tolerance status, adiposity and cardiovascular risk factors (CVRFs). DESIGN AND PATIENTS: Study consisted of 107 subjects: 55 with normal glucose tolerance (NGT) and 52 with impaired glucose regulation (IGR) who were divided into two groups: 24 subjects with impaired fasting glucose (IFG Group) and 28 patients with type 2 diabetes mellitus (DM Group). In additional analysis, study participants were divided into two groups, according to CVRFs: low and high risk. MEASUREMENTS: Patients were evaluated for glucose, HbA1C, insulin, lipids, CRP, HOMA-IR and adiponectin. RESULTS: Adiponectin was significantly higher in NGT group than in IFG (P = 0.003) and DM (P = 0.01) groups. Adiponectin was significantly, positively associated with HDL and inversely associated with glucose, HbA1c, ALT, AST, TG, HOMA-IR. Patients with higher CVRFs load have lesser adiponectin compared to patients with low cardiovascular risk P < 0.0001). Adiponectin was inversely associated with the number of risk factors (r = -0.430, P = 0.0001). CONCLUSIONS: Circulating adiponectin was significantly lower in subjects with different degree of IGR compared to subjects with normal glucose homeostasis. Adiponectin was significantly lower in high risk group than low risk group and decreased concurrently with increased number of CVRFs. PMID- 22253613 TI - Osmolarity and glucose differentially regulate aldose reductase activity in cultured mouse podocytes. AB - Podocyte injury is associated with progression of many renal diseases, including diabetic nephropathy. In this study we examined whether aldose reductase (AR), the enzyme implicated in diabetic complications in different tissues, is modulated by high glucose and osmolarity in podocyte cells. AR mRNA, protein expression, and activity were measured in mouse podocytes cultured in both normal and high glucose and osmolarity for 6 hours to 5 days. Hyperosmolarity acutely stimulated AR expression and activity, with subsequent increase of AR expression but decrease of activity. High glucose also elevated AR protein level; however, this was not accompanied by respective enzyme activation. Furthermore, high glucose appeared to counteract the osmolarity-dependent activation of AR. In conclusion, in podocytes AR is modulated by high glucose and increased osmolarity in a different manner. Posttranslational events may affect AR activity independent of enzyme protein amount. Activation of AR in podocytes may be implicated in diabetic podocytopathy. PMID- 22253616 TI - POPcorn: An Online Resource Providing Access to Distributed and Diverse Maize Project Data. AB - The purpose of the online resource presented here, POPcorn (Project Portal for corn), is to enhance accessibility of maize genetic and genomic resources for plant biologists. Currently, many online locations are difficult to find, some are best searched independently, and individual project websites often degrade over time-sometimes disappearing entirely. The POPcorn site makes available (1) a centralized, web-accessible resource to search and browse descriptions of ongoing maize genomics projects, (2) a single, stand-alone tool that uses web Services and minimal data warehousing to search for sequence matches in online resources of diverse offsite projects, and (3) a set of tools that enables researchers to migrate their data to the long-term model organism database for maize genetic and genomic information: MaizeGDB. Examples demonstrating POPcorn's utility are provided herein. PMID- 22253617 TI - Identification of Regional Lymph Node Involvement of Colorectal Cancer by Serum SELDI Proteomic Patterns. AB - Background. To explore the application of serum proteomic patterns for the preoperative detection of regional lymph node involvement of colorectal cancer (CRC). Methods. Serum samples were applied to immobilized metal affinity capture ProteinChip to generate mass spectra by Surface-Enhanced Laser Desorption/ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS). Proteomic spectra of serum samples from 70 node-positive CRC patients and 75 age- and gender-matched node-negative CRC patients were employed as a training set, and a classification tree was generated by using Biomarker Pattern Software package. The validity of the classification tree was then challenged with a blind test set including another 65 CRC patients. Results. The software identified an average of 46 mass peaks/spectrum and 5 of the identified peaks at m/z 3,104, 3,781, 5,867, 7,970, and 9,290 were used to construct the classification tree. The classification tree separated effectively node-positive CRC patients from node negative CRC patients, achieving a sensitivity of 94.29% and a specificity of 100.00%. The blind test challenged the model independently with a sensitivity of 91.43% a specificity of 96.67%. Conclusions. The results indicate that SELDI-TOF MS can correctly distinguish node-positive CRC patients from node-negative ones and show great potential for preoperative screening for regional lymph node involvement of CRC. PMID- 22253618 TI - Investigation of Bacteremia due to Aeromonas Species and Comparison with That due to Enterobacteria in Patients with Liver Cirrhosis. AB - Background. The role of Aeromonas species (sp.) in bacteremia in Japanese patients with liver cirrhosis is poorly understood. Aim. To establish the importance of Aeromonas sp. as a cause of bacteremia in patients with liver cirrhosis. Methods. Clinical and serological features and short-term prognosis were retrospectively investigated and compared in Japanese patients with bacteremia due to Aeromonas sp. (n = 11) and due to enterobacteria (E. coli, Klebsiella sp., and Enterobacter sp.) (n = 84). Results. There were no significant differences in patients' clinical background, renal dysfunction, or short-term mortality rate between the two groups. However, in the Aeromonas group, the model for end-stage liver disease (MELD) score and Child-Pugh score were significantly higher than in the enterobacteria group. Conclusion. These results indicate that the severity of liver dysfunction in Aeromonas-induced bacteremia is greater than that in enterobacteria-induced bacteremia in Japanese patients with liver cirrhosis. PMID- 22253615 TI - Cellular dysfunction in diabetes as maladaptive response to mitochondrial oxidative stress. AB - Oxidative stress has been implicated in diabetes long-term complications. In this paper, we summarize the growing evidence suggesting that hyperglycemia-induced overproduction of superoxide by mitochondrial electron transport chain triggers a maladaptive response by affecting several metabolic and signaling pathways involved in the pathophysiology of cellular dysfunction and diabetic complications. In particular, it is our goal to describe physiological mechanisms underlying the mitochondrial free radical production and regulation to explain the oxidative stress derived from a high intracellular glucose concentration and the resulting maladaptive response that leads to a cellular dysfunction and pathological state. Finally, we outline potential therapies for diabetes focused to the prevention of mitochondrial oxidative damage. PMID- 22253619 TI - Laparoscopic surgery for recurrent Crohn's disease. AB - In spite of the recent improvements in drug therapy, surgery still represents the most frequent treatment for Crohn's disease (CD) complications. Laparoscopy has been widely applied over the last twenty years in colorectal surgery and was associated with lower postoperative pain, shorter hospitalization, faster return to daily activities, and better cosmetic results. Laparoscopy experienced a slower diffusion in inflammatory bowel disease surgery than in oncologic colorectal surgery, but proved to be safe and effective, and is currently considered the gold standard for the treatment of primary uncomplicated ileocolic CD. Indications for laparoscopy in CD have recently been widened to embrace more complicated or recurrent CD. This paper reviews the available data on the subset of recurrent CD patients. The reported results indicate that laparoscopy may be safely applied even in selected recurrent CD cases in hands of IBD surgeons with broad laparoscopic experience. PMID- 22253620 TI - Capsule Endoscopy in Patients with Cardiac Pacemakers and Implantable Cardioverter Defibrillators: (Re)evaluation of the Current State in Germany, Austria, and Switzerland 2010. AB - Background and Aims. The study was a repeated evaluation of the experience of capsule endoscopy (CE) in patients with cardiac pacemaker or implantable cardioverter defibrillator (ICD). Patients and Methods. A standardized questionnaire was sent by the manufactors Given Imaging and Olympus to all centers in Germany, Austria, and Switzerland providing capsule endoscopy service. The questionnaire covers the number of examined patients, monitoring during CE, check of the electric implants before and after CE, occurrence of arrhythmia, quality of CE video, complications, indication of CE, and type of institution. Results. Overall 580 questionnaires were sent to the users. 26/5% (Germany/Austria + Switzerland) of the questionnaires were sent back anonymously to the authors. 114 centers (82 hospitals, 11 surgeries, 21 without specification) replied. In 58 centers (51%), patients with cardiac pacemaker (n = 300) and ICDs (n = 80) underwent uneventful capsule endoscopy. The predominant indication (patients with CP 97%, patients with ICD 100%) was mid gastrointestinal bleeding. Conclusion. The results of our inquiry show that in spite of formal contraindication CE is increasingly applied in bleeding patients with cardiac pacemakers/ICDs and seems to be safe even in a large cohort. PMID- 22253621 TI - Swallowable wireless capsule endoscopy: progress and technical challenges. AB - Wireless capsule endoscopy (WCE) offers a feasible noninvasive way to detect the whole gastrointestinal (GI) tract and revolutionizes the diagnosis technology. However, compared with wired endoscopies, the limited working time, the low frame rate, and the low image resolution limit the wider application. The progress of this new technology is reviewed in this paper, and the evolution tendencies are analyzed to be high image resolution, high frame rate, and long working time. Unfortunately, the power supply of capsule endoscope (CE) is the bottleneck. Wireless power transmission (WPT) is the promising solution to this problem, but is also the technical challenge. Active CE is another tendency and will be the next geneion of the WCE. Nevertheless, it will not come true shortly, unless the practical locomotion mechanism of the active CE in GI tract is achieved. The locomotion mechanism is the other technical challenge, besides the challenge of WPT. The progress about the WPT and the active capsule technology is reviewed. PMID- 22253622 TI - Changes Related to Age in Natural and Acquired Systemic Self-IgG Responses in Malaria. AB - Background. Absence of acquired protective immunity in endemic areas children leads to higher susceptibility to severe malaria. To investigate the involvement of regulatory process related to self-reactivity, we evaluated potent changes in auto-antibody reactivity profiles in children and older subjects living in malaria-endemic zones comparatively to none-exposed healthy controls. Methods. Analysis of IgG self-reactive footprints was performed using Western blotting against healthy brain antigens. Plasmas of 102 malaria exposed individuals (MEIs) from endemic zone, with or without cerebral malaria (CM) were compared to plasmas from non-endemic controls (NECs). Using linear discriminant and principal component analysis, immune footprints were compared by counting the number, the presence or absence of reactive bands. We identified the most discriminant bands with respect to age and clinical status. Results. A higher number of bands were recognized by IgG auto-antibodies in MEI than in NEC. Characteristic changes in systemic self-IgG-reactive repertoire were found with antigenic bands that discriminate Plasmodium falciparum infections with or without CM according to age. 8 antigenic bands distributed in MEI compared with NEC were identified while 6 other antigenic bands were distributed within MEI according to the age and clinical status. Such distortion might be due to evolutionary processes leading to pathogenic/protective events. PMID- 22253624 TI - Application of the new classification on patients with a disorder of sex development in indonesia. AB - Disorder of sex development (DSD) patients in Indonesia most often do not receive a proper diagnostic evaluation and treatment. This study intended to categorize 88 Indonesian patients in accordance with the new consensus DSD algorithm. Diagnostic evaluation including clinical, hormonal, genetic, imaging, surgical, and histological parameters was performed. Fifty-three patients were raised as males, and 34 as females. Of 22 patients with 46, XX DSD, 15 had congenital adrenal hyperplasia, while in one patient, an ovarian Leydig cell tumor was found. In all 58 46, XY DSD patients, 29 were suspected of a disorder of androgen action (12 with an androgen receptor mutation), and in 9, gonadal dysgenesis was found and, in 20, severe hypospadias e.c.i. Implementation of the current consensus statement in a resource-poor environment is very difficult. The aim of the diagnostic workup in developing countries should be to end up with an evidence-based diagnosis. This is essential to improve treatment and thereby to improve the patients' quality of life. PMID- 22253623 TI - Acute Exposure to Microcystin-Producing Cyanobacterium Microcystis aeruginosa Alters Adult Zebrafish (Danio rerio) Swimming Performance Parameters. AB - Microcystins (MCs) are toxins produced by cyanobacteria (blue-green algae), primarily Microcystis aeruginosa, forming water blooms worldwide. When an organism is exposed to environmental perturbations, alterations in normal behavioral patterns occur. Behavioral repertoire represents the consequence of a diversity of physiological and biochemical alterations. In this study, we assessed behavioral patterns and whole-body cortisol levels of adult zebrafish (Danio rerio) exposed to cell culture of the microcystin-producing cyanobacterium M. aeruginosa (MC-LR, strain RST9501). MC-LR exposure (100 MUg/L) decreased by 63% the distance traveled and increased threefold the immobility time when compared to the control group. Interestingly, no significant alterations in the number of line crossings were found at the same MC-LR concentration and time of exposure. When animals were exposed to 50 and 100 MUg/L, MC-LR promoted a significant increase (around 93%) in the time spent in the bottom portion of the tank, suggesting an anxiogenic effect. The results also showed that none of the MC-LR concentrations tested promoted significant alterations in absolute turn angle, path efficiency, social behavior, or whole-body cortisol level. These findings indicate that behavior is susceptible to MC-LR exposure and provide evidence for a better understanding of the ecological consequences of toxic algal blooms. PMID- 22253625 TI - Dietary restriction promotes vessel maturation in a mouse astrocytoma. AB - Mature vasculature contains an endothelial cell lining with a surrounding sheath of pericytes/vascular smooth muscle cells (VSMCs). Tumor vessels are immature and lack a pericyte sheath. Colocalization of vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor beta (PDGF Rbeta) reduces pericyte ensheathment of tumor vessels. We found that a 30% dietary restriction (DR) enhanced vessel maturation in the mouse CT-2A astrocytoma. DR reduced microvessel density and VEGF expression in the astrocytoma, while increasing recruitment of pericytes, positive for alpha-smooth muscle actin (alpha-SMA). Moreover, DR reduced colocalization of VEGF-R2 and PDGF Rbeta, but did not reduce total PDGF-Rbeta expression. These findings suggest that DR promoted vessel normalization by preventing VEGF-induced inhibition of the PDGF signaling axis in pericytes. DR appears to shift the tumor vasculature from a leaky immature state to a more mature state. We suggest that vessel normalization could improve delivery of therapeutic drugs to brain tumors. PMID- 22253626 TI - Impact of histopathological diagnosis with ancillary immunohistochemical studies on lung cancer subtypes incidence and survival: a population-based study. AB - PURPOSE: The aim of this study was to assess the impact of immunohistochemical- (IHC-) studies on incidence and survival of lung cancer histotypes. PATIENTS AND METHODS: Lung cancers occurred in southern Switzerland between 1996 and 2010 were selected by the Ticino Cancer Registry and categorised into adenocarcinoma (AC), squamous-cell-carcinoma (SqCC), small-cell-carcinoma (SmCC), and large-cell carcinoma/non-small-cell lung cancer (LCC/NSCLC). Incidence rates, annual percentage-change (APC), and two-year overall survival (OS) (follow-up: 31.12.2010) were performed. RESULTS: 2467 cases were selected: 997 (40.4%) AC; 522 (21.2%) LCC/NSCLC, 378 (15.3%) SmCC, and 570 (23.1%) SqCC. Trend-analysis showed significant increase in AC (APC: 4.6; 95% CI: 3.1; 6.0) and decrease of LCC/NSCLC, with significant joinpoint in 2003 (APC: -14.7; 95% CI: -21.6; -7.1). Improved OS and decreased OS were detected in SqCC and LCC/NSCLC, respectively. CONCLUSIONS: This study highlights that diagnosis with ancillary immunohistochemical studies will change incidence and survival of precisely defined lung cancer subtypes. It calls attention to the need for cautious interpretation of studies and clinical trials, where the diagnosis was based on histology unaccompanied by IHC studies, and to the need of standardised diagnostic procedures. PMID- 22253627 TI - Colorectal carcinoma: why is there a lower incidence in Nigerians when compared to Caucasians? AB - Carcinoma of the colon and rectum is the 2nd commonest cancer in the United States; the leading cancer being lung cancer. It has been estimated that 130,200 new cases of colorectal cancer will be diagnosed annually while 56,300 sufferers will die from the disease (Murphy et al., 2000). In developing countries especially West Africa, the rate has not yet reached such magnitude. This suggests that there may be factors either anthropomorphic or environmental which may be responsible for this. The paper acknowledges the reduced incidence of colorectal cancer in native West Africans living in Africa and endeavours to highlight the various factors that produce this observation in medical literature. A diligent search through available literature on the aetiology, epidemiology and comparative anthropology of colorectal cancer was done. Internet search using PubMed, British Library Online and Google Scholar was also utilized. The rarity of adenomatous polyposis syndromes in the native West African contributes to the reduced incidence of colorectal cancer. Cancer prevention and cancer-protective factors are deemed to lie in the starchy, high-fiber, spicy, peppery foodstuff low in animal protein which many West African nations consume. PMID- 22253628 TI - The effect of exposed glass fibers and particles of bioactive glass on the surface wettability of composite implants. AB - Measurement of the wettability of a material is a predictive index of cytocompatibility. This study was designed to evaluate the effect of exposed E glass fibers and bioactive glass (BAG) particles on the surface wettability behavior of composite implants. Two different groups were investigated: (a) fiber reinforced composites (FRCs) with different fiber orientations and (b) polymer composites with different wt. % of BAG particles. Photopolymerized and heat postpolymerized composite substrates were made for both groups. The surface wettability, topography, and roughness were analyzed. Equilibrium contact angles were measured using the sessile drop method. Three liquids were used as a probe for surface free energy (SFE) calculations. SFE values were calculated from contact angles obtained on smooth surfaces. The surface with transverse distribution of fibers showed higher (P < 0.001) polar (gamma(P)) and total SFE (gamma(TOT)) components (16.9 and 51.04 mJ/m(2), resp.) than the surface with in plane distribution of fibers (13.77 and 48.27 mJ/m(2), resp.). The increase in BAG particle wt. % increased the polar (gamma(P)) value, while the dispersive (gamma(D)) value decreased. Postpolymerization by heat treatment improved the SFE components on all the surfaces investigated (P < 0.001). Composites containing E glass fibers and BAG particles are hydrophilic materials that show good wettability characteristics. PMID- 22253630 TI - Pearls and pitfalls in cochlear implantation. PMID- 22253629 TI - The role of lipid rafts in cancer cell adhesion and migration. AB - Lipid rafts are cholesterol-enriched microdomains of the cell membrane and possess a highly dynamic nature. They have been involved in various cellular functions including the regulation of cell adhesion and membrane signaling through proteins within lipid rafts. The dynamic features of the cancer cell surface may modulate the malignant phenotype of cancer, including adhesion disorders and aggressive phenotypes of migration and invasion. Recently, it was demonstrated that lipid rafts play critical roles in cancer cell adhesion and migration. This article summarizes the important roles of lipid rafts in cancer cell adhesion and migration, with a focus on the current state of knowledge. This article will improve the understanding of cancer progression and lead to the development of novel targets for cancer therapy. PMID- 22253631 TI - Safety of ovarian tissue autotransplantation for cancer patients. AB - Cancer treatments can induce premature ovarian failure in almost half of young women suffering from invasive neoplasia. Cryopreservation of ovarian cortex and subsequent autotransplantation of frozen-thawed tissue have emerged as promising alternatives to conventional fertility preservation technologies. However, human ovarian tissue is generally harvested before the administration of gonadotoxic treatment and could be contaminated with malignant cells. The safety of autotransplantation of ovarian cortex remains a major concern for fertility preservation units worldwide. This paper discusses the main tools for detecting disseminated cancer cells currently available, their limitations, and clinical relevance. PMID- 22253633 TI - Ligament tissue engineering and its potential role in anterior cruciate ligament reconstruction. AB - Tissue engineering is an emerging discipline that combines the principle of science and engineering. It offers an unlimited source of natural tissue substitutes and by using appropriate cells, biomimetic scaffolds, and advanced bioreactors, it is possible that tissue engineering could be implemented in the repair and regeneration of tissue such as bone, cartilage, tendon, and ligament. Whilst repair and regeneration of ligament tissue has been demonstrated in animal studies, further research is needed to improve the biomechanical properties of the engineered ligament if it is to play an important part in the future of human ligament reconstruction surgery. We evaluate the current literature on ligament tissue engineering and its role in anterior cruciate ligament reconstruction. PMID- 22253632 TI - Multiple approaches for individualized fertility protective therapy in cancer patients. AB - In the last decade, fertility preservation has risen as a major field of interest, creating new interactions between oncologists and gynecologists. Various options, such as cryopreservation of ovarian tissue, have been developed and are currently routinely proposed in many centers. However, many of the options remain experimental and should be offered to patients only after adequate counseling. This paper addresses the efficiency and the potential of the different fertility preservation approaches. PMID- 22253634 TI - Immunity to visceral leishmaniasis. PMID- 22253635 TI - Induced Sputum Substance P in Children with Difficult-to-Treat Bronchial Asthma and Gastroesophageal Reflux: Effect of Esomeprazole Therapy. AB - Objectives. To assess the induced sputum substance P (ISSP) levels in children having difficult-to-treat asthma (DA) with and without gastroesophageal reflux (GER). We aimed also to evaluate the association of GER with childhood DA, relationship of GER severity with childhood asthma control test (C-ACT), FEV(1), peak expiratory flow (PEF) variability, and ISSP. Finally, we tried to evaluate esomeprazole treatment effect on C-ACT and FEV(1) in children with DA. Methods. Spirometry, C-ACT, upper gastrointestinal endoscopy, and ISSP measurement were done for children with DA compared to healthy controls. Results. ISSP was high in DA with higher levels in the group having associated GER. In the latter group, ISSP and C-ACT improved significantly after esomeprazole treatment while FEV(1) and PEF variability did not improve. Reflux severity was positively correlated with ISSP and negatively correlated with FEV(1). Conclusions. GER was found in 49% of our patients with childhood DA. Very high ISSP levels in children with DA may be used as a marker for presence of GERD. Esomeprazole therapy improved asthma symptoms but did not improve lung function. PMID- 22253636 TI - Anti-Malassezia-Specific IgE Antibodies Production in Japanese Patients with Head and Neck Atopic Dermatitis: Relationship between the Level of Specific IgE Antibody and the Colonization Frequency of Cutaneous Malassezia Species and Clinical Severity. AB - Atopic dermatitis of the head and neck (HNAD) is recognized as a separate condition. Malassezia, the predominant skin microbiota fungus, is considered to exacerbate atopic dermatitis (AD), especially HNAD. In the present study, we investigated the relationships between the levels of specific IgE antibodies, colonization frequency of eight predominant Malassezia species, and clinical severity in 61 patients with HNAD (26 mild, 24 moderate, and 11 severe cases). As clinical severity increased, the levels of specific IgE antibodies against eight Malassezia species also increased. Species diversity of the Malassezia microbiota in scale samples from patients was analyzed by nested PCR using species-specific primers. The clinical severity of HNAD was correlated with the total level of specific IgE antibodies against Malassezia species and the number of Malassezia species detected. PMID- 22253637 TI - Human excretion of bisphenol A: blood, urine, and sweat (BUS) study. AB - BACKGROUND: Bisphenol A (BPA) is an ubiquitous chemical contaminant that has recently been associated with adverse effects on human health. There is incomplete understanding of BPA toxicokinetics, and there are no established interventions to eliminate this compound from the human body. Using 20 study participants, this study was designed to assess the relative concentration of BPA in three body fluids-blood, urine, and sweat-and to determine whether induced sweating may be a therapeutic intervention with potential to facilitate elimination of this compound. METHODS: Blood, urine, and sweat were collected from 20 individuals (10 healthy participants and 10 participants with assorted health problems) and analyzed for various environmental toxicants including BPA. RESULTS: BPA was found to differing degrees in each of blood, urine, and sweat. In 16 of 20 participants, BPA was identified in sweat, even in some individuals with no BPA detected in their serum or urine samples. CONCLUSIONS: Biomonitoring of BPA through blood and/or urine testing may underestimate the total body burden of this potential toxicant. Sweat analysis should be considered as an additional method for monitoring bioaccumulation of BPA in humans. Induced sweating appears to be a potential method for elimination of BPA. PMID- 22253639 TI - The changing trends in live birth statistics in Korea, 1970 to 2010. AB - Although Korean population has been growing steadily during the past four decades, the nation is rapidly becoming an aging society because of its declining birth rate combined with an increasing life expectancy. In addition, Korea has one of the lowest fertility rates in the world due to fewer married couples, advanced maternal age, and falling birth rate. The prevalence of low birth weight infants and multiple births has been increased compared with the decrease in the birth rate. Moreover, the number of congenital anomalies is expected to increase due to the advanced maternal age. In addition, the number of interracial children is expected to increase due to the rise in the number of international marriages. However, the maternal education level is high, single-mother birth rate is low, and the gender imbalance has lessened. The number of overweight babies has been decreased, as more pregnant women are receiving adequate prenatal care. Compared to the Asian average birth weight, the average birth weight is the highest in Asia. Moreover, the rate of low birth weight infants is low, and infant mortality is similarly low across Asia. Using birth data from Statistics Korea and studies of birth outcomes in Korea and abroad, this study aimed to assess the changes in maternal and infant characteristics associated with birth outcomes during the past four decades and identify necessary information infrastructures to study countermeasures the decrease in birth rate and increase in low birth weight infants in Korea. PMID- 22253638 TI - A review of the diagnosis and treatment of Ochratoxin A inhalational exposure associated with human illness and kidney disease including focal segmental glomerulosclerosis. AB - Ochratoxin A (OTA) exposure via ingestion and inhalation has been described in the literature to cause kidney disease in both animals and humans. This paper reviews Ochratoxin A and its relationship to human health and kidney disease with a focus on a possible association with focal segmental glomerulosclerosis (FSGS) in humans. Prevention and treatment strategies for OTA-induced illness are also discussed, including cholestyramine, a bile-acid-binding resin used as a sequestrant to reduce the enterohepatic recirculation of OTA. PMID- 22253640 TI - Secular trends of body sizes in Korean children and adolescents: from 1965 to 2010. AB - An anthropometric survey is one of the most important approaches to use when evaluating the health status of children. Secular trends in body sizes, such as height, weight, head circumference, chest circumference, and body mass index showed significant changes over 40 years in Korea. A series of periodic surveys were conducted in 1967, 1975, 1985, 1997, and 2005 by the Korean Pediatric Society and Ministry of Health and Welfare. The quality of data from school health examinations and the Korea National Health and Nutrition Examination Survey has improved, so we can use them now as resources for anthropometric analysis. The final height differences between 1965 and 1997 were 4.5 cm both in boys (168.9 cm in 1965; 173.4 cm in 1997) and girls (155.9 cm in 1965; 160.4 cm in 1997). The differences between 1997 and 2005 were 0.9 cm in boys (174.3cm in 2005) and 0.8 cm in girls (161.2 cm in 2005). There was no difference in final height measurements between 2005 and 2010. An increase in body size at earlier teen ages was pronounced during these decades compared to the previous generation; however, little change has been identified more recently. Body size has been increasing, and obesity has become more prevalent. Systems that gather data should be updated in order to cope with these secular trends. In an upcoming era of secular trends that would be in a slow transition, several surveys that include body measurements should be prepared to meet future needs. PMID- 22253641 TI - Changes in the neonatal and infant mortality rate and the causes of death in Korea. AB - Neonatal mortality rate (NMR) or infant mortality rate (IMR) are the rate of deaths per 1,000 live births at which babies of either less than four weeks or of one year of age die, respectively. The NMR and IMR are commonly accepted as a measure of the general health and wellbeing of a population. Korea's NMR and IMR fell significantly between 1993 and 2009 from 6.6 and 9.9 to 1.7 and 3.2, respectively. Common causes of infantile death in 2008 had decreased compared with those in 1996 such as other disorders originating in the perinatal period, congenital malformation of the heart, bacterial sepsis of newborns, disorders related to length of gestation and fetal growth, intra-uterine hypoxia, birth asphyxia. However, some other causes are on the increase, such as respiratory distress of newborn, other respiratory conditions originating in the perinatal period, other congenital malformation, diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism. In this study, we provide basic data about changes of NMR and IMR and the causes of neonatal and infantile death from 1983 to 2009 in Korea. PMID- 22253642 TI - Effect of respiratory syncytial virus infection on regulated on activation, normal T-cells expressed and secreted production in a murine model of asthma. AB - PURPOSE: Synthesis of regulated on activation, normal T-cells expressed and secreted (RANTES) in the airway has previously been shown to be elevated after respiratory syncytial virus (RSV) infection. However, since few studies have examined whether RSV-infected asthma patients express a higher level of RANTES than do normal individuals, we used a murine model of asthma to address this question. METHODS: We prepared Dermatophagoides farinae-sensitized mice as an asthma model, and then infected them with RSV and analyzed the changes in airway responsiveness and the cell populations and cytokine levels of bronchoalveolar lavage fluid. RESULTS: RANTES synthesis increased in response to RSV infection in both control mice and in asthma model (D. farinae) mice. However, there was no significant difference in the amount of RANTES produced following RSV infection between control and D. farinae mice. RSV infection affected neither interferon gammasynthesis nor airway responsiveness in either control or D. farinae mice. CONCLUSION: RSV infection did not induce more RANTES in a murine model of asthma than in control mice. PMID- 22253643 TI - Validation study of the Dinamap ProCare 200 upper arm blood pressure monitor in children and adolescents. AB - PURPOSE: To validate the Dinamap ProCare 200 blood pressure (BP) monitor against a mercury sphygmomanometer in children 7 to 18 years old in accordance with the 2010 International Protocol of European Society of Hypertension (ESH-IP2) and the British Hypertension Society (BHS) protocol. METHODS: Forty-five children were recruited for the study. A validation procedure was performed following the protocol based on the ESH-IP2 and BHS protocols for children and adolescents. Each subject underwent 7 sequential BP measurements alternatively with a mercury sphygmomanometer and the test device by trained nurses. The results were analyzed according to the validation criteria of ESH-IP2. RESULTS: The mean (+/-SD) difference in the absolute BP values between test device and mercury sphygmomanometer readings was 1.85+/-1.65 mmHg for systolic BP (SBP) and 4.41+/ 3.53 mmHg for diastolic BP (DBP). These results fulfilled the Association for the Advancement of Medical Instrumentation criterion of a mean+/-SD below 5+/-8 mmHg for both SBP and DBP. The percentages of test device-observer mercury sphygmomanometer BP differences within 5, 10, and 15 mmHg were 96%, 100%, and 100% for SBP, and 69%, 92%, and 100% for DBP, respectively, in the part 1 analysis; both SBP and DBP passed the part 1 criteria. In the part 2 analysis, SBP passed the criteria but DBP failed. CONCLUSION: Although the Dinamap ProCare 200 BP monitor failed an adapted ESH-IP2, SBP passed. When comparing BP readings measured by oscillometers and mercury sphygmomanometers, one has to consider the differences between them, particularly in DBP, because DBP can be underestimated. PMID- 22253644 TI - Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A. AB - Familial hyperkalemic periodic paralysis (HYPP) is an autosomaldominant channelopathy characterized by transient and recurrent episodes of paralysis with concomitant hyperkalemia. Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clinically unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been reported. The patient did not respond to acetazolamide, but showed a marked improvement in paralytic symptoms upon treatment with hydrochlorothiazide. The findings in this case indicate that a de novo mutation needs to be considered when an isolated family member is found to have a HYPP phenotype. PMID- 22253645 TI - Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations. AB - Primary hypokalemic periodic paralysis (HOKPP) is an autosomal dominant disorder manifesting as recurrent periodic flaccid paralysis and concomitant hypokalemia. HOKPP is divided into type 1 and type 2 based on the causative gene. Although 2 different ion channels have been identified as the molecular genetic cause of HOKPP, the clinical manifestations between the 2 groups are similar. We report the cases of 2 patients with HOKPP who both presented with typical clinical manifestations, but with mutations in 2 different genes (CACNA1Sp.Arg528His and SCN4A p.Arg672His). Despite the similar clinical manifestations, there were differences in the response to acetazolamide treatment between certain genotypes of SCN4A mutations and CACNA1S mutations. We identified p.Arg672His in the SCN4A gene of patient 2 immediately after the first attack through a molecular genetic testing strategy. Molecular genetic diagnosis is important for genetic counseling and selecting preventive treatment. PMID- 22253646 TI - 55-week treatment of mice with the unani and ayurvedic medicine pomegranate flower ameliorates ageing-associated insulin resistance and skin abnormalities. AB - PPARs play a pivotal role in regulating lipid and glucose homeostasis and are involved in diverse biological activities in skin. Pomegranate flower (PGF, an antidiabetic therapy in Unani and Ayurvedic medicines) has been previously demonstrated to activate both PPARalpha/gamma. Here, we found that treatment of mice with the diet containing PGF powder over 55 weeks attenuated ageing-induced abnormal increases in the homeostasis model assessment of insulin resistance, glucose concentrations during oral glucose tolerance test, and adipose insulin resistance index. The diet tended to decrease the excessive peri-ovary fat mass. It, however, increased the thinned subcutaneous fat thickness. In addition, the diet restored decreases in skin water content, epidermis thickness, and collagen density in corium. Thus, our results demonstrate that long-term treatment with the Unani and Ayurvedic therapy ameliorates ageing-induced insulin resistance, which is associated with reversal of ageing-induced fat redistribution. Further, PGF attenuates ageing-mediated undesirable skin abnormalities. PMID- 22253647 TI - Vinegar-Baked Radix Bupleuri Regulates Lipid Disorders via a Pathway Dependent on Peroxisome-Proliferator-Activated Receptor-alpha in High-Fat-Diet-Induced Obese Rats. AB - The aim of this study was to investigate the antiobesity and antihyperlipidemic effects of vinegar-baked Radix Bupleuri (VBRB) on high-fat diet- (HFD-) induced obese rats. After being fed HFD for two weeks, rats were dosed orally with VBRB or fenofibrate, once daily for further twelve weeks. VBRB (1.0 g kg(-1) per day) produced effects similar to fenofibrate (100 mg kg(-1)) in reducing body weight (BW) gain, visceral fat-pad weights, plasma lipid levels, as well as hepatic TG and cholesterol content of HFD-fed rats. VBRB also lowered hepatic lipid droplet accumulation and the size of epididymal adipocytes in HFD-fed rats. VBRB and fenofibrate reversed the HFD-induced downregulation of hepatic peroxisome proliferator-activated receptor (PPAR)alpha. HFD-induced reductions in the hepatic levels of acyl-CoA oxidase (ACO) and cytochrome P450 isoform 4A1 (CYP4A1) proteins were reversed by VBRB and fenofibrate. The elevated expression of hepatic sterol regulatory element binding proteins (SREBPs) in HFD-fed rats was lowered by VBRB and fenofibrate. The results of this study show that VBRB suppresses BW gain and body fat accumulation by increasing fatty acid oxidation, an effect which is likely mediated via upregulation of PPARalpha and downregulation of SREBP expression in the liver of HFD-fed rats. PMID- 22253648 TI - New Perspectives of "omics" Applications in Melanoma Research. AB - BACKGROUND: Oncoproteomics is the study of proteins and their interactions in a cancer cell by proteomic technologies and has the potential to revolutionize clinical practice, including cancer diagnosis. Recent technological advances in the analysis of the human genome have opened the door to improving our primitive understanding of the gene expression patterns in cancer. The examination of the phenotypic and (epi) genetic changes in cutaneous melanoma has identified several genes deemed central to the development and progression of melanoma. METHODS: A review of the literature was performed to determine the role of epigenetic modifications in human melanoma. The role of array-based high-throughput gene expression analysis in understanding the specific genes involved as well as the pathways and the comparative gene expression patterns of primary and metastatic melanoma. The development and clinical application of selective pharmacologic agents are also discussed. RESULTS: We identified several articles that have extensively studied the role of epigenetics in melanoma, further elucidating the complex processes involved in gene regulation and expression. Other studies utilizing gene microarray analysis and other whole genome approaches reveal a wide array of genes and expression patterns in human melanoma. Several genes have been identified as potential prognostic markers of tumor progression and overall clinical outcome. CONCLUSIONS: High-throughput gene expression analysis has had a major impact in melanoma research. Several gene expression platforms have provided insight into the gene expression patterns in melanoma. Such data will provide foundations for the future development of prognostic markers and improved targeted therapies for patients with melanoma. PMID- 22253649 TI - Prediction of bodyweight and energy expenditure using point pressure and foot acceleration measurements. AB - Bodyweight (BW) is an essential outcome measure for weight management and is also a major predictor in the estimation of daily energy expenditure (EE). Many individuals, particularly those who are overweight, tend to underreport their BW, posing a challenge for monitors that track physical activity and estimate EE. The ability to automatically estimate BW can potentially increase the practicality and accuracy of these monitoring systems. This paper investigates the feasibility of automatically estimating BW and using this BW to estimate energy expenditure with a footwear-based, multisensor activity monitor. The SmartShoe device uses small pressure sensors embedded in key weight support locations of the insole and a heel-mounted 3D accelerometer. Bodyweight estimates for 9 subjects are computed from pressure sensor measurements when an automatic classification algorithm recognizes a standing posture. We compared the accuracy of EE prediction using estimated BW compared to that of using the measured BW. The results show that point pressure measurement is capable of providing rough estimates of body weight (root-mean squared error of 10.52 kg) which in turn provide a sufficient replacement of manually-entered bodyweight for the purpose of EE prediction (root mean squared error of 0.7456 METs vs. 0.6972 METs). Advances in the pressure sensor technology should enable better accuracy of body weight estimation and further improvement in accuracy of EE prediction using automatic BW estimates. PMID- 22253650 TI - Conformational Differences Unfold a Wide Range of Enterotoxigenic Abilities Exhibited by rNSP4 Peptides from Different Rotavirus Strains. AB - NSP4 has been recognized as the rotavirus-encoded enterotoxin. However, a few studies failed to support its diarrheagenic activity. As recombinant NSP4 (rNSP4) peptides of different lengths were used in the limited number of studies, a comparison of relative diarrheagenic potential of NSP4 from different strains could not be possible. To better understand the diarrheagenic potential of NSP4 from different strains, in this report we have evaluated the enterotoxigenic activity of the deletion mutant DeltaN72 that lacks the N-terminal 72 residues and the biologically relevant DeltaN112 peptide which when derived from SA11 rotavirus strain were previously shown to be highly diarrheagenic in newborn mice. Detailed comparative analysis of biochemical and biophysical properties and diarrheagenic activity of the recombinant DeltaN72 peptides from seventeen different strains under identical conditions revealed wide differences among themselves in their resistance to trypsin cleavage, thioflavin T (ThT) binding, multimerization and conformation without any correlation with their diarrhea inducing abilities. These results support our previously proposed concept for the requirement of a unique conformation for optimal biological functions conferred by cooperation between the N- and C-terminal regions of the cytoplasmic tail. PMID- 22253651 TI - Silencing of ORFs C2 and C4 of Tomato Yellow Leaf Curl Virus Engenders Resistant or Tolerant Plants. AB - The IL-60 system is a transient universal vector system for expression and silencing in plants [1]. This vector has been derived from Tomato yellow leaf curl virus (TYLCV). The viral intergenic region (IR) is a non-coding short (314 b) sequence separating the viral sense-oriented genes from the complementary oriented genes. IR carries the viral origin of replication as well as a promoter at each end. Placing a gene segment between two IRs at opposite orientations followed by trans-activation of the construct by the plasmid IL-60-BS, caused silencing of the pertinent gene as indicated by the silencing of the endogenous gene PDS.. The viral genes C2 and C4 are implicated as having a role in viral directed silencing suppression. The silencing of C2 and C4 intervened with the virus ability to counter-react to viral silencing by the host plant, thus engendering resistance or tolerance. PMID- 22253652 TI - Influenza A(H1N1) Oseltamivir Resistant Viruses in the Netherlands During the Winter 2007/2008. AB - BACKGROUND: Antiviral susceptibility surveillance in the Netherlands was intensified after the first reports about the emergence of influenza A(H1N1) oseltamivir resistant viruses in Norway in January, 2008. METHODS: Within the existing influenza surveillance an additional questionnaire study was performed to retrospectively assess possible risk factors and establish clinical outcome of all patients with influenza virus A(H1N1) positive specimens. To discriminate resistant and sensitive viruses, fifty percent inhibitory concentrations for the neuramidase inhibitors oseltamivir and zanamivir were determined in a neuraminidase inhibition assay. Mutations previously associated with resistance to neuramidase inhibitors and M2 blockers (amantadine and rimantadine) were searched for by nucleotide sequencing of neuraminidase and M2 genes respectively. RESULTS: Among 171 patients infected with A(H1N1) viruses an overall prevalence of oseltamivir resistance of 27% (95% CI: 20-34%) was found. None of influenza A(H1N1) oseltamivir resistant viruses tested was resistant against amantadine or zanamivir. Patient characteristics, underlying conditions, influenza vaccination, symptoms, complications, and exposure to oseltamivir and other antivirals did not differ significantly between patients infected with resistant and sensitive A(H1N1) viruses. CONCLUSION: In 2007/2008 a large proportion of influenza A(H1N1) viruses resistant to oseltamivir was detected. There were no clinical differences between patients infected with resistant and sensitive A(H1N1) viruses. Continuous monitoring of the antiviral drug sensitivity profile of influenza viruses is justified, preferably using the existing sentinel surveillance, however, complemented with data from the more severe end of the clinical spectrum. In order to act timely on emergencies of public health importance we suggest setting up a surveillance system that can guarantee rapid access to the latter. PMID- 22253653 TI - Cerebral Blood Volume Measurements - Gd_DTPA vs. VASO - and Their Relationship with Cerebral Blood Flow in Activated Human Visual Cortex. AB - Measurements of task-induced changes in cerebral blood volume (CBV) have been demonstrated using VAscular Space Occupancy (VASO) techniques (noninvasive and newly developed) and a contrast agent-based (Gd- DTPA) method (invasive but well established) with functional magnetic resonance imaging (fMRI). We compared the two methods in determining CBV changes during multi-frequency visual stimulation (4 and 8 Hz). Specifically, we aimed to assess the impact of repetition time (TR) on CBV changes determination using VASO. With additional measurements of cerebral blood flow (CBF), the flow-volume coupling relationship (alpha value) and cerebral metabolic rate of oxygen were further determined. The results showed that i) using VASO, short TR (2s) caused overestimation of CBV changes, while long TR (6s) generated consistent CBV results, by comparison to the GD-DTPA method; ii) overestimation of CBV changes caused underestimated CMRO(2) changes, but did not alter the frequency-related pattern, i.e., CMRO(2) changes at 4 Hz were greater than those at 8 Hz regardless of the TR; and iii) the tasked-induced CBF-CBV coupling was stimulus frequency-dependent, i.e., alpha = 0.35-0.38 at 4 Hz and alpha = 0.51-0.53 at 8 Hz. Our data demonstrated that, with carefully chosen TRs, CBV measurements can be achieved non-invasively with VASO techniques. PMID- 22253654 TI - Quantitative MRI of cerebral arterial blood volume. AB - Baseline cerebral arterial blood volume (CBV(a)) and its change are important for potential diagnosis of vascular dysfunctions, the determination of functional reactivity, and the interpretation of BOLD fMRI. To quantitative measure baseline CBV(a) non-invasively, we developed arterial spin labeling methods with magnetization transfer (MT) or bipolar gradients by utilizing differential MT or diffusion properties of tissue vs. arteries. Cortical CBV(a) of isoflurane anesthetized rats was 0.6 - 1.4 ml/100 g. During 15-s forepaw stimulation, CBV(a) change was dominant, while venous blood volume change was minimal. This indicates that the venous CBV increase may be ignored for BOLD quantification for a stimulation duration of less than 15 s. By incorporating BOLD fMRI with varied MT effects in a cat visual cortical layer model, the highest DeltaCBV(a) was observed at layer 4, while the highest BOLD signal was detected at the surface of the cortex, indicating that CBV(a) change is highly specific to neural activity. The CBV(a) MRI techniques provide quantified maps, thus, may be valuable tools for routine determination of vessel viability and function, as well as the identification of vascular dysfunction. PMID- 22253655 TI - Neuroimaging of non-human primates. PMID- 22253656 TI - MRI of perfusion-diffusion mismatch in non-human primate (baboon) stroke: a preliminary report. AB - The goal of this study was to develop a clinically relevant non-human primate (baboon) stroke model and multi-parametric MRI protocols on a clinical scanner with long-term goals to better model human stroke and facilitate clinical translations of novel therapeutic strategies. Baboons were chosen because of their relatively large brain volume and that they are evolutionarily close to humans. Middle cerebral artery occlusion (MCAO) was induced using a minimally invasive endovascular approach to guide an inflatable balloon catheter into the MCA and followed by permanently or transiently inflate the balloon. Using multimodal MRI, including perfusion and diffusion imaging, the spatiotemporal dynamic evolution of the ischemic lesions in permanent and transient occlusion experiments in baboons were investigated. Perfusion-diffusion mismatch, which approximates the ischemic penumbra, was detected. In the permanent MCAO group (n = 2), the mean infarct volume was 29 ml (17% of total brain volume) whereas in the transient MCAO group (n = 2, 60 or 90 min of occlusion), the mean infarct volume was 15 ml (9% of total brain volume). Substantial perfusion-diffusion mismatch tissue (~50%) was salvaged by reperfusion compared to permanent MCAO. This baboon stroke model has the potential to become a translational platform to better design clinical studies, guide clinical diagnosis and improve treatment time windows in patients. PMID- 22253657 TI - Dynamic Diffusion Magnetic Resonance Imaging of Infarct Formation and Peri infarct Spreading Depression after Middle Cerebral Artery Occlusion (MCAO) in macacca fasicularis. AB - Dynamic diffusion MRI was used to visualize hyperacute stroke formation in the brain of a cynomolgus macaque. Under fluoroscopic guidance, a microcatheter was placed into the middle cerebral artery (MCA). The animal was immediately transferred to a 1.5T clinical scanner. Dynamic T2-weighted imaging during bolus injection of Oxygen-17 enriched water through the microcatheter mapped out the territory perfused by the MCA segment. Serial diffusion measurements were made using diffusion-weighted echo-planar imaging, with a temporal resolution of 15 seconds, during injection of a glue embolus into the microcatheter. The apparent diffusion coefficient declined within the lesion core. A wave of transient diffusion decline spread through peripheral uninvolved brain immediately following stroke induction. The propagation speed and pattern is consistent with spreading peri-infarct depolarizations (PID). The detection of PIDs following embolic stroke in a higher nonhuman primate brain supports the hypothesis that spreading depressions may occur following occlusive stroke in humans. PMID- 22253658 TI - Methods for fine scale functional imaging of tactile motion in human and nonhuman primates. AB - In the visual and auditory systems specialized neural pathways use motion cues to track object motion and self-motion, and use differential motion cues for figure ground segregation. To examine the neural circuits that encode motion in the somatosensory system, we have developed neuroimaging methods to study motion processing in human and nonhuman primates. We have implemented stimulus presentation paradigms to examine neural encoding of apparent motion percepts. These paradigms are designed to be compatible with fMRI, optical imaging, and electrophysiological methods, thereby permitting direct comparison of data derived across neurofunctional scales. An additional motivation for using a common tactile motion stimulation paradigm is to bridge two disparate bodies of work, that derived from neuroimaging studies in humans and another from neuroimaging, neurophysiological and neuroanatomical studies in monkeys. Here, we demonstrate that such an approach through the use of optical imaging and 9.4 Tesla fMRI experiments in monkeys, and 7 Tesla fMRI experiments in humans is effective in revealing neural regions activated by tactile motion stimuli. These methods span spatial scales capable of detecting 100 MUm sized domains to those that would reveal global whole brain circuits. Armed with such capabilities, our long-term goals are to identify directionally selective areas and directionally se-lective functional domains and understand the global pathways within which they reside. Such knowledge would have great impact on our thinking regarding not only tactile motion processing, but also general strategies underlying somatosensory cortical processing. PMID- 22253659 TI - Comparison of in vivo and ex vivo diffusion tensor imaging in rhesus macaques at short and long diffusion times. AB - Diffusion tensor imaging (DTI) is widely used to non-invasively study neural tissue micro-structure. While DTI tractography of large nerve fibers is well accepted, visualization of smaller fibers and resolution of branching fibers is challenging. Sensitivity of DTI to diffusion anisotropy can be further enhanced using long diffusion time that can provide a more accurate representation of the tissue micro-structure. We previously reported that ex vivo fixed brain DTI at long t(diff) (192 ms) showed improved sensitivity to fiber tracking compared to short t(diff) (48 ms) in 4% formalin-fixed non-human primate (NHP) brains. This study further tested the hypothesis that DTI at longer diffusion time improves DTI fiber tracking in the in vivo NHP brains on a clinical 3 Tesla MRI scanner. Compared to fixed brains, the in vivo ADC was larger by a factor of 5. Also, the white-matter FA was 28% higher in the in vivo study as compared to our ex vivo experiments. Compared to short t(diff), long t(diff) increased white-matter FA by 6.0+/-0.5%, diffusion was more anisotropic, tensor orientations along major fiber tracts were more coherent, and tracked fibers were about 10.1+/-2.9% longer in the corpus callosum and 7.3+/-2.8% longer along the cortico-spinal tract. The overall improvements in tractography were, however, less pronounced in the in vivo brain than in fixed brains. Nonetheless, these in vivo findings reinforce that DTI tractography at long diffusion time improves tracking of smaller fibers in regions of low fractional anisotropy. PMID- 22253660 TI - Tracking development of the corpus callosum in fetal and early postnatal baboons using magnetic resonance imaging. AB - Although the maturation of the corpus callosum (CC) can serve as a sensitive marker for normative antenatal and postnatal brain development, little is known about its development across this critical period. While high-resolution magnetic resonance imaging can provide an opportunity to examine normative brain development in humans, concerns remain over the exposure of developing fetuses to non-essential imaging. Nonhuman primates can provide a valuable model for normative brain maturation. Baboons share several important developmental characteristics with humans, including a highly orchestrated pattern of cerebral development. Developmental changes in total CC area and its subdivisions were examined across the antenatal (weeks 17 - 26 of 28 weeks total gestation) and early postnatal (to week 32) period in baboons (Papio hamadryas anubis). Thirteen fetal and sixteen infant baboons were studied using high-resolution MRI. During the period of primary gyrification, the total area of the CC increased by a magnitude of five. By postnatal week 32, the total CC area attained only 51% of the average adult area. CC subdivisions showed non-uniform increases in area, throughout development. The splenium showed the most maturation by postnatal week 32, attaining 55% of the average adult value. The subdivisions of the genu and anterior midbody showed the least maturation by postnatal week 32, attaining 50% and 49% of the average adult area. Thus, the CC of baboons shows continued growth past the postnatal period. These age-related changes in the developing baboon CC are consistent with the developmental course in humans. PMID- 22253661 TI - Atlas-guided segmentation of vervet monkey brain MRI. AB - The vervet monkey is an important nonhuman primate model that allows the study of isolated environmental factors in a controlled environment. Analysis of monkey MRI often suffers from lower quality images compared with human MRI because clinical equipment is typically used to image the smaller monkey brain and higher spatial resolution is required. This, together with the anatomical differences of the monkey brains, complicates the use of neuroimage analysis pipelines tuned for human MRI analysis. In this paper we developed an open source image analysis framework based on the tools available within the 3D Slicer software to support a biological study that investigates the effect of chronic ethanol exposure on brain morphometry in a longitudinally followed population of male vervets. We first developed a computerized atlas of vervet monkey brain MRI, which was used to encode the typical appearance of the individual brain structures in MRI and their spatial distribution. The atlas was then used as a spatial prior during automatic segmentation to process two longitudinal scans per subject. Our evaluation confirms the consistency and reliability of the automatic segmentation. The comparison of atlas construction strategies reveals that the use of a population-specific atlas leads to improved accuracy of the segmentation for subcortical brain structures. The contribution of this work is twofold. First, we describe an image processing workflow specifically tuned towards the analysis of vervet MRI that consists solely of the open source software tools. Second, we develop a digital atlas of vervet monkey brain MRIs to enable similar studies that rely on the vervet model. PMID- 22253662 TI - A frameless stereotaxic MRI technique for macaque neuroscience studies. AB - MRI has achieved widespread use for preplanning neuroscience procedures for non human primate studies. However, orienting imaging studies in stereotaxic space has relied primarily on using a stereotaxic frame or co-registering fiducial markers with the neuroimaging. In this study, we present a simple approach in which the MRI dataset is aligned to the bony landmarks that define the Frankfurt stereotaxic baseline plane, without the need for a stereotaxic frame or additional external fiducials. To facilitate localizing the bony landmarks (infraorbital margin, external bony auditory meatus) on the MRI scans additional imaging landmarks (mid ocular plane, temporomandibular joint) are discussed that provide supplementary and readily visible points of reference. The frameless MRI stereotaxic technique was evaluated in 8 rhesus macaque monkeys using 3D fast gradient echo MRI images with 0.7mm isotropic resolution. 1) Difference in stereotaxic coordinates of fiducial markers was compared between a traditional stereotaxic frame and the frameless MRI technique (n=2). 2) Differences in stereotaxic coordinates for cerebral regions were compared between the frameless MRI technique and MRI obtained with the animal positioned in a MRI-compatible stereotaxic frame (n=4). 3) The frameless MRI technique was further refined to prescribe electrode penetrations within a dural recording chamber in stereotaxic coordinates relative to the electrode microdrive. Differences in MRI coordinates were compared with the electrode microdrive (n=3). Mean localization of fiducial markers differed by 1.6 +/- 0.6 mm between the frameless MRI technique and a traditional stereotaxic frame. Between the frameless technique and an MRI compatible stereotaxic frame, localization of cerebral anatomy differed by 2.8 +/ 2.2 mm with the primary source of error being a pitch-up rotation in the sagittal plane. This localization difference was reduced to 0.5 +/- 0.6 mm when this rotation was removed. Frameless MRI coordinates for electrode tracts within the dural recording chamber were within 0.5mm +/- 0.2 mm of the electrode microdrive readings. This simple technique provides the ability to accurately plan surgery and neurophysiological recordings in an individual animal, and to define the location of cerebral anatomy and electrode or injection tracts using publically available software, and without the need for dedicated MRI-compatible localization hardware. The reduced need for deep anesthesia (a necessity with traditional stereotaxic frames) makes the technique more amenable for functional MRI studies. Since each animal provides the bony landmarks to define their own stereotaxic space, this technique is readily applicable to other species. PMID- 22253663 TI - Imaging Stroke Evolution after Middle Cerebral Artery Occlusion in Non-human Primates. AB - This article reviews imaging approaches applied to the study of stroke in nonhuman primates. We briefly survey the various surgical and minimally invasive experimental stroke models in nonhuman primates, followed by a summary of studies using computed tomography, positron emission tomography and magnetic resonance imaging and spectroscopy to monitor stroke from the hyperacute phase (within minutes of the onset of cerebral ischemia) to the chronic phase (1 month and beyond). PMID- 22253664 TI - The role of neuroimaging in the latent period of blunt traumatic cerebrovascular injury. AB - INTRODUCTION: Blunt cerebrovascular injury (BCVI) is found in 1-2.7% of all blunt trauma when appropriate screening criteria are employed. A significant number of patients with BCVI have a latent, or asymptomatic period, in which therapeutic intervention based on the appropriate use of angiographic imaging may decrease the risk of an ischemic stroke. METHODS: Case report and review of literature. RESULTS: A 42 year old woman suffered a fall off a motorcycle and was neurologically intact in the emergency room. Fractures involving the transverse foramen of cervical vertebrae were found on non-contrast Computed Tomography (CT) but screening for BCVI with angiographic imaging not performed. She subsequently suffered an ischemic stroke resulting in significant disability. Published studies that address the use of screening criteria for BCVI and subsequent management are reviewed. CONCLUSION: BCVI results in significant morbidity and mortality attributable to ischemic stroke. There is often a latent period between BCVI and occurrence of ischemic stroke. Specific risk factors can be used to identify patients requiring screening with catheter or CT angiography. Treatment with antithrombotic agents is the mainstay of treatment of BCVI and may reduce the rate of ischemic stroke. Identification and treatment of asymptomatic BCVI in blunt trauma patients may prevent ischemic stroke in a predominantly young population. PMID- 22253665 TI - Time-dependent cortical activation in voluntary muscle contraction. AB - This study was to characterize dynamic source strength changes estimated from high-density scalp electroencephalogram (EEG) at different phases of a submaximal voluntary muscle contraction. Eight healthy volunteers performed isometric handgrip contractions of the right arm at 20% maximal intensity. Signals of the handgrip force, electromyography (EMG) from the finger flexor and extensor muscles and 64-channel EEG were acquired simultaneously. Sources of the EEG were analyzed at 19 time points across preparation, execution and sustaining phases of the handgrip. A 3-layer boundary element model (BEM) based on the MNI (Montreal Neurological Institute) brain MRI was used to overlay the sources. A distributed current density model, LORETA L1 norm method was applied to the data that had been processed by independent component analysis (ICA). Statistical analysis based on a mixed-effects polynomial regression model showed a significant and consistent time-dependent non-linear source strength change pattern in different phases of the handgrip. The source strength increased at the preparation phase, peaked at the force onset time and decreased in the sustaining phase. There was no significant difference in the changing pattern of the source strength among Brodmann's areas 1, 2, 3, 4, and 6. These results show, for the first time, a high time resolution increasing-and-decreasing pattern of activation among the sensorimotor regions with the highest activity occurs at the muscle activity onset. The similarity in the source strength time courses among the cortical centers examined suggests a synchronized parallel function in controlling the motor activity. PMID- 22253666 TI - Trends in the Treatment of Anemia Using Recombinant Human Erythropoietin in Patients with HIV Infection. AB - BACKGROUND: Treating anemia with erythropoietin (EPO) to hemoglobin (Hb) endpoints >11 g/dL may increase risk of serious adverse cardiovascular events. METHODS: We used medical records data (1996-2003 from the Adolescent Spectrum of HIV Disease Project [ASD] and 1996-2006 from the HIV Outpatient Study [HOPS]) to describe EPO prescription patterns for mildly, moderately, or severely anemic HIV infected patients. We calculated proportions prescribed EPO and treated to Hb>12 g/dL, and tested for trends over time. We calculated median hemoglobin at first EPO prescription, and described temporal changes using linear regression. RESULTS: Among 37,395 patients in ASD and 7,005 patients in HOPS, EPO prescription increased over time for moderately anemic patients; for patients with severe anemia, EPO prescription increased only among ASD patients. Hb at EPO prescription decreased over time in ASD patients (median=8.5 g/dL), but not in HOPS patients (median 9.5 g/dL). Percentage of EPO-treated patients with post treatment Hb>12 g/dL was 18.3% in ASD and stable, and was 56.7% in HOPS and increased over time (p = 0.03). CONCLUSIONS: Through 2006, EPO prescription increased over time for patients with moderate or severe anemia. Many patients treated with EPO had post-treatment Hb>12 g/dL. Based on 2011 FDA recommendations, changes in previous prescription practices will be needed. PMID- 22253667 TI - Readiness in HIV Treatment Adherence: A Matter of Confidence. An Exploratory Study. AB - Adherence to treatment is recognized as the essence of a successful HIV combination therapy. Optimal adherence implies a readiness to begin the treatment on the part of the patient. A better understanding of the "readiness phenomenon" will become an asset for optimizing HIV treatment. However, few studies have focused on understanding the process underlying the choice to adhere. The aim of this study is to understand the readiness process that leads to adhering to the HIV treatment, from both patient and professional perspectives. Twenty-seven in depth interviews, with a qualitative exploratory design, were the source of our data. Participants were recruited in two hospitals in Paris. Throughout the data collection process, analysed data were supplied to all participants and the research team, thus allowing for shared constructions. Four themes, interrelated with a constitutive pattern, emerged from the data we collected. Being ready to begin and adhere to treatment is a matter of confidence in oneself, as well as in relatives, in the treatment and in the health professional team. These themes are not constant and unvarying; instead, they constitute a picture moving across time and life events. Results of this study show that adherence that goes beyond "complying with" the medical instructions, but depends on how much of an active role the patient plays in the choice to adhere. PMID- 22253668 TI - Correlates of HIV Infection Among Sexually Active Adults in Kenya: A National Population-Based Survey. AB - OBJECTIVE: To identify factors associated with prevalent HIV in a national HIV survey in Kenya. METHODS: The Kenya AIDS Indicator Survey was a nationally representative population-based sero-survey that examined demographic and behavioral factors and serologic testing for HIV, HSV-2 and syphilis in adults aged 15-64 years. We analyzed questionnaire and blood testing data to identify significant correlates of HIV infection among sexually active adults. RESULTS: Of 10,957 eligible women and 8,883 men, we interviewed 10,239 (93%) women and 7,731 (87%) men. We collected blood specimens from 9,049 women and 6,804 men of which 6,447 women and 5,112 men were sexually active during the 12 months prior to the survey. HIV prevalence among sexually active adults was 7.4%. Factors independently associated with HIV among women were region (Nyanza vs Nairobi: adjusted OR [AOR] 1.6, 95%CI 1.1-2.3), number of lifetime sex partners (6-9 vs 0 1 partners: AOR 3.0, 95%CI 1.6-5.9), HSV-2 (AOR 6.5, 95%CI 4.9-8.8), marital status (widowed vs never married: AOR 2.7, 95%CI 1.5-4.8) and consistent condom use with last sex partner (AOR 2.3, 95%CI 1.6-3.4). Among men, correlates of HIV infection were 30-to-39-year-old age group (AOR 5.2, 95%CI 2.6-10.5), number of lifetime sex partners (10+ vs 0-1 partners, AOR 3.5, 95%CI 1.4-9.0), HSV-2 (AOR 4.7, 95%CI 3.2-6.8), syphilis (AOR 2.4, 95%CI 1.4-4.0), consistent condom use with last sex partner (AOR 2.1, 95% CI 1.5-3.1) and lack of circumcision (AOR 4.0, 95%CI 2.8 - 5.5). CONCLUSION: Kenya's heterogeneous epidemic will require regional and gender-specific prevention approaches. PMID- 22253669 TI - Neuro-cognitive mechanisms of conscious and unconscious visual perception: From a plethora of phenomena to general principles. AB - Psychological and neuroscience approaches have promoted much progress in elucidating the cognitive and neural mechanisms that underlie phenomenal visual awareness during the last decades. In this article, we provide an overview of the latest research investigating important phenomena in conscious and unconscious vision. We identify general principles to characterize conscious and unconscious visual perception, which may serve as important building blocks for a unified model to explain the plethora of findings. We argue that in particular the integration of principles from both conscious and unconscious vision is advantageous and provides critical constraints for developing adequate theoretical models. Based on the principles identified in our review, we outline essential components of a unified model of conscious and unconscious visual perception. We propose that awareness refers to consolidated visual representations, which are accessible to the entire brain and therefore globally available. However, visual awareness not only depends on consolidation within the visual system, but is additionally the result of a post-sensory gating process, which is mediated by higher-level cognitive control mechanisms. We further propose that amplification of visual representations by attentional sensitization is not exclusive to the domain of conscious perception, but also applies to visual stimuli, which remain unconscious. Conscious and unconscious processing modes are highly interdependent with influences in both directions. We therefore argue that exactly this interdependence renders a unified model of conscious and unconscious visual perception valuable. Computational modeling jointly with focused experimental research could lead to a better understanding of the plethora of empirical phenomena in consciousness research. PMID- 22253670 TI - Roles of contour and surface processing in microgenesis of object perception and visual consciousness. AB - Developments in visual neuroscience and neural-network modeling indicate the existence of separate pathways for the processing of form and surface attributes of a visual object. In line with prior theoretical proposals, it is assumed that the processing of form can be explicit or conscious only as or after the surface property such as color is filled in. In conjunction with extant psychophysical findings, these developments point to interesting distinctions between nonconscious and conscious processing of these attributes, specifically in relation to distinguishable temporal dynamics. At nonconscious levels form processing proceeds faster than surface processing, whereas in contrast, at conscious levels form processing proceeds slower than surface processing. I mplications of separate form and surface processing for current and future psychophysical and neuroscientific research, particularly that relating cortical oscillations to conjunctions of surface and form features, and for cognitive science and philosophy of mind and consciousness are discussed. PMID- 22253671 TI - Follow the sign! Top-down contingent attentional capture of masked arrow cues. AB - Arrow cues and other overlearned spatial symbols automatically orient attention according to their spatial meaning. This renders them similar to exogenous cues that occur at stimulus location. Exogenous cues trigger shifts of attention even when they are presented subliminally. Here, we investigate to what extent the mechanisms underlying the orienting of attention by exogenous cues and by arrow cues are comparable by analyzing the effects of visible and masked arrow cues on attention. In Experiment 1, we presented arrow cues with overall 50% validity. Visible cues, but not masked cues, lead to shifts of attention. In Experiment 2, the arrow cues had an overall validity of 80%. Now both visible and masked arrows lead to shifts of attention. This is in line with findings that subliminal exogenous cues capture attention only in a top-down contingent manner, that is, when the cues fit the observer's intentions. PMID- 22253672 TI - Good vibrations, bad vibrations: Oscillatory brain activity in the attentional blink. AB - The attentional blink (AB) is a deficit in reporting the second (T2) of two targets (T1, T2) when presented in close temporal succession and within a stream of distractor stimuli. The AB has received a great deal of attention in the past two decades because it allows to study the mechanisms that influence the rate and depth of information processing in various setups and therefore provides an elegant way to study correlates of conscious perception in supra-threshold stimuli. Recently evidence has accumulated suggesting that oscillatory signals play a significant role in temporally coordinating information between brain areas. This review focuses on studies looking into oscillatory brain activity in the AB. The results of these studies indicate that the AB is related to modulations in oscillatory brain activity in the theta, alpha, beta, and gamma frequency bands. These modulations are sometimes restricted to a circumscribed brain area but more frequently include several brain regions. They occur before targets are presented as well as after the presentation of the targets. We will argue that the complexity of the findings supports the idea that the AB is not the result of a processing impairment in one particular process or brain area, but the consequence of a dynamic interplay between several processes and/or parts of a neural network. PMID- 22253674 TI - Dos and don'ts in response priming research. AB - Response priming is a well-understood but sparsely employed paradigm in cognitive science. The method is powerful and well-suited for exploring early visuomotor processing in a wide range of tasks and research fields. Moreover, response priming can be dissociated from visual awareness, possibly because it is based on the first sweep of feedforward processing of primes and targets. This makes it a theoretically interesting device for separating conscious and unconscious vision. We discuss the major opportunities of the paradigm and give specific recommendations (e.g., tracing the time-course of priming in parametric experiments). Also, we point out typical confounds, design flaws, and data processing artifacts. PMID- 22253675 TI - The effects of spatial and temporal cueing on metacontrast masking. AB - We studied the effects of selective attention on metacontrast masking with 3 different cueing experiments. Experiments 1 and 2 compared central symbolic and peripheral spatial cues. For symbolic cues, we observed small attentional costs, that is, reduced visibility when the target appeared at an unexpected location, and attentional costs as well as benefits for peripheral cues. All these effects occurred exclusively at the late, ascending branch of the U-shaped metacontrast masking function, although the possibility exists that cueing effects at the early branch were obscured by a ceiling effect due to almost perfect visibility at short stimulus onset asynchronies (SOAs). In Experiment 3, we presented temporal cues that indicated when the target was likely to appear, not where. Here, we also observed cueing effects in the form of higher visibility when the target appeared at the expected point in time compared to when it appeared too early. However, these effects were not restricted to the late branch of the masking function, but enhanced visibility over the complete range of the masking function. Given these results we discuss a common effect for different types of spatial selective attention on metacontrast masking involving neural subsystems that are different from those involved in temporal attention. PMID- 22253673 TI - Top-down contingent feature-specific orienting with and without awareness of the visual input. AB - In the present article, the role of endogenous feature-specific orienting for conscious and unconscious vision is reviewed. We start with an overview of orienting. We proceed with a review of masking research, and the definition of the criteria of experimental protocols that demonstrate endogenous and exogenous orienting, respectively. Against this background of criteria, we assess studies of unconscious orienting and come to the conclusion that so far studies of unconscious orienting demonstrated endogenous feature-specific orienting. The review closes with a discussion of the role of unconscious orienting in action control. PMID- 22253676 TI - Cognitive and affective judgements of syncopated musical themes. AB - This study investigated cognitive and emotional effects of syncopation, a feature of musical rhythm that produces expectancy violations in the listener by emphasising weak temporal locations and de-emphasising strong locations in metric structure. Stimuli consisting of pairs of unsyncopated and syncopated musical phrases were rated by 35 musicians for perceived complexity, enjoyment, happiness, arousal, and tension. Overall, syncopated patterns were more enjoyed, and rated as happier, than unsyncopated patterns, while differences in perceived tension were unreliable. Complexity and arousal ratings were asymmetric by serial order, increasing when patterns moved from unsyncopated to syncopated, but not significantly changing when order was reversed. These results suggest that syncopation influences emotional valence (positively), and that while syncopated rhythms are objectively more complex than unsyncopated rhythms, this difference is more salient when complexity increases than when it decreases. It is proposed that composers and improvisers may exploit this asymmetry in perceived complexity by favoring formal structures that progress from rhythmically simple to complex, as can be observed in the initial sections of musical forms such as theme and variations. PMID- 22253688 TI - Density-independent mortality and increasing plant diversity are associated with differentiation of Taraxacum officinale into r- and K-strategists. AB - BACKGROUND: Differential selection between clones of apomictic species may result in ecological differentiation without mutation and recombination, thus offering a simple system to study adaptation and life-history evolution in plants. METHODOLOGY/PRINCIPAL FINDINGS: We caused density-independent mortality by weeding to colonizer populations of the largely apomictic Taraxacum officinale (Asteraceae) over a 5-year period in a grassland biodiversity experiment (Jena Experiment). We compared the offspring of colonizer populations with resident populations deliberately sown into similar communities. Plants raised from cuttings and seeds of colonizer and resident populations were grown under uniform conditions. Offspring from colonizer populations had higher reproductive output, which was in general agreement with predictions of r-selection theory. Offspring from resident populations had higher root and leaf biomass, fewer flower heads and higher individual seed mass as predicted under K-selection. Plants grown from cuttings and seeds differed to some degree in the strength, but not in the direction, of their response to the r- vs. K-selection regime. More diverse communities appeared to exert stronger K-selection on resident populations in plants grown from cuttings, while we did not find significant effects of increasing species richness on plants grown from seeds. CONCLUSIONS/SIGNIFICANCE: Differentiation into r- and K-strategists suggests that clones with characteristics of r-strategists were selected in regularly weeded plots through rapid colonization, while increasing plant diversity favoured the selection of clones with characteristics of K-strategists in resident populations. Our results show that different selection pressures may result in a rapid genetic differentiation within a largely apomictic species. Even under the assumption that colonizer and resident populations, respectively, happened to be r- vs. K selected already at the start of the experiment, our results still indicate that the association of these strategies with the corresponding selection regimes was maintained during the 5-year experimental period. PMID- 22253686 TI - HCV 6a prevalence in Guangdong province had the origin from Vietnam and recent dissemination to other regions of China: phylogeographic analyses. AB - BACKGROUND: Recently in China, HCV 6a infection has shown a fast increase among patients and blood donors, possibly due to IDU linked transmission. METHODOLOGY/FINDINGS: We recruited 210 drug users in Shanwei city, Guangdong province. Among them, HCV RNA was detected in 150 (71.4%), both E1 and NS5B genes were sequenced in 136, and 6a genotyped in 70. Of the 6a sequences, most were grouped into three clusters while 23% represent emerging strains. For coalescent analysis, additional 6a sequences were determined among 21 blood donors from Vietnam, 22 donors from 12 provinces of China, and 36 IDUs from Liuzhou City in Guangxi Province. Phylogeographic analyses indicated that Vietnam could be the origin of 6a in China. The Guangxi Province, which borders Vietnam, could be the first region to accept 6a for circulation. Migration from Yunnan, which also borders Vietnam, might be equally important, but it was only detected among IDUs in limited regions. From Guangxi, 6a could have further spread to Guangdong, Yunnan, Hainan, and Hubei provinces. However, evidence showed that only in Guangdong has 6a become a local epidemic, making Guangdong the second source region to disseminate 6a to the other 12 provinces. With a rate of 2.737*10-3 (95% CI: 1.792*10-3 to 3.745*10-3), a Bayesian Skyline Plot was portrayed. It revealed an exponential 6a growth during 1994-1998, while before and after 1994 1998 slow 6a growths were maintained. Concurrently, 1994-1998 corresponded to a period when contaminated blood transfusion was common, which caused many people being infected with HIV and HCV, until the Chinese government outlawed the use of paid blood donations in 1998. CONCLUSIONS/SIGNIFICANCE: With an origin from Vietnam, 6a has become a local epidemic in Guangdong Province, where an increasing prevalence has subsequently led to 6a spread to many other regions of China. PMID- 22253687 TI - Different domains of the RNA polymerase of infectious bursal disease virus contribute to virulence. AB - BACKGROUND: Infectious bursal disease virus (IBDV) is a pathogen of worldwide significance to the poultry industry. IBDV has a bi-segmented double-stranded RNA genome. Segments A and B encode the capsid, ribonucleoprotein and non-structural proteins, or the virus polymerase (RdRp), respectively. Since the late eighties, very virulent (vv) IBDV strains have emerged in Europe inducing up to 60% mortality. Although some progress has been made in understanding the molecular biology of IBDV, the molecular basis for the pathogenicity of vvIBDV is still not fully understood. METHODOLOGY, PRINCIPAL FINDINGS: Strain 88180 belongs to a lineage of pathogenic IBDV phylogenetically related to vvIBDV. By reverse genetics, we rescued a molecular clone (mc88180), as pathogenic as its parent strain. To study the molecular basis for 88180 pathogenicity, we constructed and characterized in vivo reassortant or mosaic recombinant viruses derived from the 88180 and the attenuated Cu-1 IBDV strains. The reassortant virus rescued from segments A of 88180 (A88) and B of Cu-1 (BCU1) was milder than mc88180 showing that segment B is involved in 88180 pathogenicity. Next, the exchange of different regions of BCU1 with their counterparts in B88 in association with A88 did not fully restore a virulence equivalent to mc88180. This demonstrated that several regions if not the whole B88 are essential for the in vivo pathogenicity of 88180. CONCLUSION, SIGNIFICANCE: The present results show that different domains of the RdRp, are essential for the in vivo pathogenicity of IBDV, independently of the replication efficiency of the mosaic viruses. PMID- 22253689 TI - Poor cognitive flexibility in eating disorders: examining the evidence using the Wisconsin Card Sorting Task. AB - BACKGROUND: People with eating disorders (ED) frequently present with inflexible behaviours, including eating related issues which contribute to the maintenance of the illness. Small scale studies point to difficulties with cognitive set shifting as a basis. Using larger scale studies will lend robustness to these data. METHODOLOGY/PRINCIPAL FINDINGS: 542 participants were included in the dataset as follows: Anorexia Nervosa (AN) n = 171; Bulimia Nervosa (BN) n = 82; Recovered AN n = 90; Healthy controls (HC): n = 199. All completed the Wisconsin Card Sorting Task (WCST), an assessment that integrates multiple measurement of several executive processes concerned with problem solving and cognitive flexibility. The AN and BN groups performed poorly in most domains of the WCST. Recovered AN participants showed a better performance than currently ill participants; however, the number of preservative errors was higher than for HC participants. CONCLUSIONS/SIGNIFICANCE: There is a growing interest in the diagnostic and treatment implications of cognitive flexibility in eating disorders. This large dataset supports previous smaller scale studies and a systematic review which indicate poor cognitive flexibility in people with ED. PMID- 22253690 TI - Modeling of molecular interaction between apoptin, BCR-Abl and CrkL--an alternative approach to conventional rational drug design. AB - In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the newly found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous leukaemia (CML). It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth and survival. Therefore, the oncogenic effect of Bcr-Abl could be inhibited by the interaction of small molecules with these domains. Apoptin is a viral protein with well-documented cancer-selective cytotoxicity. Apoptin attributes such as SH2-like sequence similarity with CrkL SH2 domain, unique SH3 domain binding sequence, presence of proline-rich segments, and its nuclear affinity render the molecule capable of interaction with Bcr-Abl. Despite almost two decades of research, the mode of apoptin's action remains elusive because 3D structure of apoptin is unavailable. We performed in silico three-dimensional modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl. We also biochemically validated some of the interactions that were first predicted in silico. This structure-property relationship of apoptin may help in unlocking its cancer-selective toxic properties. Moreover, such models will guide us in developing of a new class of potent apoptin-like molecules with greater selectivity and potency. PMID- 22253691 TI - An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma. AB - In severe asthma, bronchodilator- and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G-protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain- and loss-of-function approaches, the precise role of RGS proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR) mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma. PMID- 22253693 TI - A meta-analysis of seaweed impacts on seagrasses: generalities and knowledge gaps. AB - Seagrasses are important habitat-formers and ecosystem engineers that are under threat from bloom-forming seaweeds. These seaweeds have been suggested to outcompete the seagrasses, particularly when facilitated by eutrophication, causing regime shifts where green meadows and clear waters are replaced with unstable sediments, turbid waters, hypoxia, and poor habitat conditions for fishes and invertebrates. Understanding the situations under which seaweeds impact seagrasses on local patch scales can help proactive management and prevent losses at greater scales. Here, we provide a quantitative review of available published manipulative experiments (all conducted at the patch-scale), to test which attributes of seaweeds and seagrasses (e.g., their abundances, sizes, morphology, taxonomy, attachment type, or origin) influence impacts. Weighted and unweighted meta-analyses (Hedges d metric) of 59 experiments showed generally high variability in attribute-impact relationships. Our main significant findings were that (a) abundant seaweeds had stronger negative impacts on seagrasses than sparse seaweeds, (b) unattached and epiphytic seaweeds had stronger impacts than 'rooted' seaweeds, and (c) small seagrass species were more susceptible than larger species. Findings (a) and (c) were rather intuitive. It was more surprising that 'rooted' seaweeds had comparatively small impacts, particularly given that this category included the infamous invasive Caulerpa species. This result may reflect that seaweed biomass and/or shading and metabolic by-products like anoxia and sulphides could be lower for rooted seaweeds. In conclusion, our results represent simple and robust first-order generalities about seaweed impacts on seagrasses. This review also documented a limited number of primary studies. We therefore identified major knowledge gaps that need to be addressed before general predictive models on seaweed-seagrass interactions can be build, in order to effectively protect seagrass habitats from detrimental competition from seaweeds. PMID- 22253692 TI - Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. AB - Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes. PMID- 22253694 TI - Investigating meta-approaches for reconstructing gene networks in a mammalian cellular context. AB - The output of state-of-the-art reverse-engineering methods for biological networks is often based on the fitting of a mathematical model to the data. Typically, different datasets do not give single consistent network predictions but rather an ensemble of inconsistent networks inferred under the same reverse engineering method that are only consistent with the specific experimentally measured data. Here, we focus on an alternative approach for combining the information contained within such an ensemble of inconsistent gene networks called meta-analysis, to make more accurate predictions and to estimate the reliability of these predictions. We review two existing meta-analysis approaches; the Fisher transformation combined coefficient test (FTCCT) and Fisher's inverse combined probability test (FICPT); and compare their performance with five well-known methods, ARACNe, Context Likelihood or Relatedness network (CLR), Maximum Relevance Minimum Redundancy (MRNET), Relevance Network (RN) and Bayesian Network (BN). We conducted in-depth numerical ensemble simulations and demonstrated for biological expression data that the meta-analysis approaches consistently outperformed the best gene regulatory network inference (GRNI) methods in the literature. Furthermore, the meta-analysis approaches have a low computational complexity. We conclude that the meta-analysis approaches are a powerful tool for integrating different datasets to give more accurate and reliable predictions for biological networks. PMID- 22253695 TI - A "crossomics" study analysing variability of different components in peripheral blood of healthy caucasoid individuals. AB - BACKGROUND: Different immunotherapy approaches for the treatment of cancer and autoimmune diseases are being developed and tested in clinical studies worldwide. Their resulting complex experimental data should be properly evaluated, therefore reliable normal healthy control baseline values are indispensable. METHODOLOGY/PRINCIPAL FINDINGS: To assess intra- and inter-individual variability of various biomarkers, peripheral blood of 16 age and gender equilibrated healthy volunteers was sampled on 3 different days within a period of one month. Complex "crossomics" analyses of plasma metabolite profiles, antibody concentrations and lymphocyte subset counts as well as whole genome expression profiling in CD4+T and NK cells were performed. Some of the observed age, gender and BMI dependences are in agreement with the existing knowledge, like negative correlation between sex hormone levels and age or BMI related increase in lipids and soluble sugars. Thus we can assume that the distribution of all 39.743 analysed markers is well representing the normal Caucasoid population. All lymphocyte subsets, 20% of metabolites and less than 10% of genes, were identified as highly variable in our dataset. CONCLUSIONS/SIGNIFICANCE: Our study shows that the intra-individual variability was at least two-fold lower compared to the inter-individual one at all investigated levels, showing the importance of personalised medicine approach from yet another perspective. PMID- 22253696 TI - Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. AB - BACKGROUND: Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages. METHODOLOGY AND PRINCIPAL FINDINGS: We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue. CONCLUSIONS AND SIGNIFICANCE: We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes. PMID- 22253697 TI - Principal-oscillation-pattern analysis of gene expression. AB - Principal-oscillation-pattern (POP) analysis is a multivariate and systematic technique for identifying the dynamic characteristics of a system from time series data. In this study, we demonstrate the first application of POP analysis to genome-wide time-series gene-expression data. We use POP analysis to infer oscillation patterns in gene expression. Typically, a genomic system matrix cannot be directly estimated because the number of genes is usually much larger than the number of time points in a genomic study. Thus, we first identify the POPs of the eigen-genomic system that consists of the first few significant eigengenes obtained by singular value decomposition. By using the linear relationship between eigengenes and genes, we then infer the POPs of the genes. Both simulation data and real-world data are used in this study to demonstrate the applicability of POP analysis to genomic data. We show that POP analysis not only compares favorably with experiments and existing computational methods, but that it also provides complementary information relative to other approaches. PMID- 22253698 TI - Comparative effectiveness research: an empirical study of trials registered in ClinicalTrials.gov. AB - BACKGROUND: The $1.1 billion investment in comparative effectiveness research will reshape the evidence-base supporting decisions about treatment effectiveness, safety, and cost. Defining the current prevalence and characteristics of comparative effectiveness (CE) research will enable future assessments of the impact of this program. METHODS: We conducted an observational study of clinical trials addressing priority research topics defined by the Institute of Medicine and conducted in the US between 2007 and 2010. Trials were identified in ClinicalTrials.gov. Main outcome measures were the prevalence of comparative effectiveness research, nature of comparators selected, funding sources, and impact of these factors on results. RESULTS: 231 (22.3%; 95% CI 19.8%-24.9%) studies were CE studies and 804 (77.7%; 95% CI, 75.1%-80.2%) were non-CE studies, with 379 (36.6%; 95% CI, 33.7%-39.6%) employing a placebo control and 425 (41.1%; 95% CI, 38.1%-44.1%) no control. The most common treatments examined in CE studies were drug interventions (37.2%), behavioral interventions (28.6%), and procedures (15.6%). Study findings were favorable for the experimental treatment in 34.8% of CE studies and greater than twice as many (78.6%) non-CE studies (P<0.001). CE studies were more likely to receive government funding (P = 0.003) and less likely to receive industry funding (P = 0.01), with 71.8% of CE studies primarily funded by a noncommercial source. The types of interventions studied differed based on funding source, with 95.4% of industry trials studying a drug or device. In addition, industry-funded CE studies were associated with the fewest pediatric subjects (P<0.001), the largest anticipated sample size (P<0.001), and the shortest study duration (P<0.001). CONCLUSIONS: In this sample of studies examining high priority areas for CE research, less than a quarter are CE studies and the majority is supported by government and nonprofits. The low prevalence of CE research exists across CE studies with a broad array of interventions and characteristics. PMID- 22253699 TI - DNA barcoding for community ecology--how to tackle a hyperdiverse, mostly undescribed Melanesian fauna. AB - BACKGROUND: Trigonopterus weevils are widely distributed throughout Melanesia and hyperdiverse in New Guinea. They are a dominant feature in natural forests, with narrow altitudinal zonation. Their use in community ecology has been precluded by the "taxonomic impediment". METHODOLOGY/PRINCIPAL FINDINGS: We sampled >6,500 specimens from seven areas across New Guinea; 1,002 specimens assigned to 270 morphospecies were DNA sequenced. Objective clustering of a refined dataset (excluding nine cryptic species) at 3% threshold revealed 324 genetic clusters (DNA group count relative to number of morphospecies = 20.0% overestimation of species diversity, or 120.0% agreement) and 85.6% taxonomic accuracy (the proportion of DNA groups that "perfectly" agree with morphology-based species hypotheses). Agreement and accuracy were best at an 8% threshold. GMYC analysis revealed 328 entities (21.5% overestimation) with 227 perfect GMYC entities (84.1% taxonomic accuracy). Both methods outperform the parataxonomist (19% underestimation; 31.6% taxonomic accuracy). The number of species found in more than one sampling area was highest in the Eastern Highlands and Huon (Sorensen similarity index 0.07, 4 shared species); 1/3 of all areas had no species overlap. Success rates of DNA barcoding methods were lowest when species showed a pronounced geographical structure. In general, Trigonopterus show high alpha and beta-diversity across New Guinea. CONCLUSIONS/SIGNIFICANCE: DNA barcoding is an excellent tool for biodiversity surveys but success rates might drop when closer localities are included. Hyperdiverse Trigonopterus are a useful taxon for evaluating forest remnants in Melanesia, allowing finer-grained analyses than would be possible with vertebrate taxa commonly used to date. Our protocol should help establish other groups of hyperdiverse fauna as target taxa for community ecology. Sequencing delivers objective data on taxa of incredible diversity but mostly without a solid taxonomic foundation and should help pave the road for the eventual formal naming of new species. PMID- 22253700 TI - AU-rich element-mediated mRNA decay can occur independently of the miRNA machinery in mouse embryonic fibroblasts and Drosophila S2-cells. AB - AU-rich elements (AREs) are regulatory sequences located in the 3' untranslated region of many short-lived mRNAs. AREs are recognized by ARE-binding proteins and cause rapid mRNA degradation. Recent reports claimed that the function of AREs may be--at least in part--relayed through the miRNA pathway. We have revisited this hypothesis using dicer knock-out mouse embryonic fibroblasts and cultured Drosophila cells. In contrast to the published results, we find no evidence for a general requirement of the miRNA pathway in the function of AREs. Endogenous ier3 mRNA, which is known to contain a functional ARE, was degraded rapidly at indistinguishable rates in wild type and dicer knock-out mouse embryonic fibroblasts. In cultured Drosophila cells, both ARE-containing GFP reporter mRNAs and the endogenous cecA1 mRNA were resistant to depletion of the mi/siRNA factors dcr-1, dcr-2, ago1 and ago2. Furthermore, the Drosophila miRNA originally proposed to recognize AU-rich elements, miR-289, is not detectably expressed in flies or cultured S2 cells. Even our attempts to overexpress this miRNA from its genomic hairpin sequence failed. Thus, this sequence cannot serve as link between the miRNA and the AU-rich element mediated silencing pathways. Taken together, our studies in mammalian and Drosophila cells strongly argue that AREs can function independently of miRNAs. PMID- 22253701 TI - Liganded thyroid hormone receptor inhibits phorbol 12-O-tetradecanoate-13-acetate induced enhancer activity via firefly luciferase cDNA. AB - Thyroid hormone receptor (TR) belongs to the nuclear hormone receptor (NHR) superfamily and regulates the transcription of its target genes in a thyroid hormone (T3)-dependent manner. While the detail of transcriptional activation by T3 (positive regulation) has been clarified, the mechanism of T3-dependent repression (negative regulation) remains to be determined. In addition to naturally occurring negative regulations typically found for the thyrotropin beta gene, T3-bound TR (T3/TR) is known to cause artificial negative regulation in reporter assays with cultured cells. For example, T3/TR inhibits the transcriptional activity of the reporter plasmids harboring AP-1 site derived from pUC/pBR322-related plasmid (pUC/AP-1). Artificial negative regulation has also been suggested in the reporter assay with firefly luciferase (FFL) gene. However, identification of the DNA sequence of the FFL gene using deletion analysis was not performed because negative regulation was evaluated by measuring the enzymatic activity of FFL protein. Thus, there remains the possibility that the inhibition by T3 is mediated via a DNA sequence other than FFL cDNA, for instance, pUC/AP-1 site in plasmid backbone. To investigate the function of FFL cDNA as a transcriptional regulatory sequence, we generated pBL-FFL-CAT5 by ligating FFL cDNA in the 5' upstream region to heterologous thymidine kinase promoter in pBL-CAT5, a chloramphenicol acetyl transferase (CAT)-based reporter gene, which lacks pUC/AP-1 site. In kidney-derived CV1 and choriocarcinoma derived JEG3 cells, pBL-FFL-CAT5, but not pBL-CAT5, was strongly activated by a protein kinase C activator, phorbol 12-O-tetradecanoate-13-acetate (TPA). TPA induced activity of pBL-FFL-CAT5 was negatively regulated by T3/TR. Mutation of nt. 626/640 in FFL cDNA attenuated the TPA-induced activation and concomitantly abolished the T3-dependent repression. Our data demonstrate that FFL cDNA sequence mediates the TPA-induced transcriptional activity, which is inhibited by T3/TR. PMID- 22253702 TI - Clinical and pathological heterogeneity of cervical intraepithelial neoplasia grade 3. AB - OBJECTIVE: Cervical intraepithelial neoplasia grade 3 (CIN3), the immediate cervical cancer precursor, is a target of cervical cancer prevention. However, less than half of CIN3s will progress to cancer. Routine treatment of all CIN3s and the majority of CIN2s may lead to overtreatment of many lesions that would not progress. To improve our understanding of CIN3 natural history, we performed a detailed characterization of CIN3 heterogeneity in a large referral population in the US. METHODS: We examined 309 CIN3 cases in the SUCCEED, a large population based study of women with abnormal cervical cancer screening results. Histology information for 12 individual loop electrosurgical excision procedure (LEEP) segments was evaluated for each woman. We performed case-case comparisons of CIN3s to analyze determinants of heterogeneity and screening test performance. RESULTS: CIN3 cases varied substantially by size (1-10 LEEP segments) and by presentation with concomitant CIN2 and CIN1. All grades of CINs were equally distributed over the cervical surface. In half of the women, CIN3 lesions were found as multiple distinct lesions on the cervix. Women with large and solitary CIN3 lesions were more likely to be older, have longer sexual activity span, and have fewer multiple high risk HPV infections. Screening frequency, but not HPV16 positivity, was an important predictor of CIN3 size. Large CIN3 lesions were also characterized by high-grade clinical test results. CONCLUSIONS: We demonstrate substantial heterogeneity in clinical and pathological presentation of CIN3 in a US population. Time since sexual debut and participation in screening were predictors of CIN3 size. We did not observe a preferential site of CIN3 on the cervical surface that could serve as a target for cervical biopsy. Cervical cancer screening procedures were more likely to detect larger CIN3s, suggesting that CIN3s detected by multiple independent diagnostic tests may represent cases with increased risk of invasion. PMID- 22253703 TI - Brain phenotype of transgenic mice overexpressing cystathionine beta-synthase. AB - BACKGROUND: The cystathionine beta-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have studied the neural consequences of CBS overexpression in a transgenic mouse line (60.4P102D1) expressing the human CBS gene under the control of its endogenous regulatory regions. These mice displayed a ~2-fold increase in total CBS proteins in different brain areas and a ~1.3-fold increase in CBS activity in the cerebellum and the hippocampus. No major disturbance of SAA metabolism was observed, and the transgenic mice showed normal behavior in the rotarod and passive avoidance tests. However, we found that hippocampal synaptic plasticity is facilitated in the 60.4P102D1 line. CONCLUSION/SIGNIFICANCE: We demonstrate that CBS overexpression has functional consequences on hippocampal neuronal networks. These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS. PMID- 22253704 TI - Dynamic ligand modulation of EPO receptor pools, and dysregulation by polycythemia-associated EPOR alleles. AB - Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1) High- Mr EPOR forms become obviously expressed only when EPO is limited. 2) EPOR 68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3) Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size). 4) In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts) to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products). Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects). New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via which mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism. PMID- 22253705 TI - NMR studies on structure and dynamics of the monomeric derivative of BS-RNase: new insights for 3D domain swapping. AB - Three-dimensional domain swapping is a common phenomenon in pancreatic-like ribonucleases. In the aggregated state, these proteins acquire new biological functions, including selective cytotoxicity against tumour cells. RNase A is able to dislocate both N- and C-termini, but usually this process requires denaturing conditions. In contrast, bovine seminal ribonuclease (BS-RNase), which is a homo dimeric protein sharing 80% of sequence identity with RNase A, occurs natively as a mixture of swapped and unswapped isoforms. The presence of two disulfides bridging the subunits, indeed, ensures a dimeric structure also to the unswapped molecule. In vitro, the two BS-RNase isoforms interconvert under physiological conditions. Since the tendency to swap is often related to the instability of the monomeric proteins, in these paper we have analysed in detail the stability in solution of the monomeric derivative of BS-RNase (mBS) by a combination of NMR studies and Molecular Dynamics Simulations. The refinement of NMR structure and relaxation data indicate a close similarity with RNase A, without any evidence of aggregation or partial opening. The high compactness of mBS structure is confirmed also by H/D exchange, urea denaturation, and TEMPOL mapping of the protein surface. The present extensive structural and dynamic investigation of (monomeric) mBS did not show any experimental evidence that could explain the known differences in swapping between BS-RNase and RNase A. Hence, we conclude that the swapping in BS-RNase must be influenced by the distinct features of the dimers, suggesting a prominent role for the interchain disulfide bridges. PMID- 22253706 TI - A temporal-omic study of Propionibacterium freudenreichii CIRM-BIA1 adaptation strategies in conditions mimicking cheese ripening in the cold. AB - Propionibacterium freudenreichii is used as a ripening culture in Swiss cheese manufacture. It grows when cheeses are ripened in a warm room (about 24 degrees C). Cheeses with an acceptable eye formation level are transferred to a cold room (about 4 degrees C), inducing a marked slowdown of propionic fermentation, but P. freudenreichii remains active in the cold. To investigate the P. freudenreichii strategies of adaptation and survival in the cold, we performed the first global gene expression profile for this species. The time-course transcriptomic response of P. freudenreichii CIRM-BIA1(T) strain was analyzed at five times of incubation, during growth at 30 degrees C then for 9 days at 4 degrees C, under conditions preventing nutrient starvation. Gene expression was also confirmed by RT-qPCR for 28 genes. In addition, proteomic experiments were carried out and the main metabolites were quantified. Microarray analysis revealed that 565 genes (25% of the protein-coding sequences of P. freudenreichii genome) were differentially expressed during transition from 30 degrees C to 4 degrees C (P<0.05 and |fold change|>1). At 4 degrees C, a general slowing down was observed for genes implicated in the cell machinery. On the contrary, P. freudenreichii CIRM-BIA1(T) strain over-expressed genes involved in lactate, alanine and serine conversion to pyruvate, in gluconeogenesis, and in glycogen synthesis. Interestingly, the expression of different genes involved in the formation of important cheese flavor compounds, remained unchanged at 4 degrees C. This could explain the contribution of P. freudenreichii to cheese ripening even in the cold. In conclusion, P. freudenreichii remains metabolically active at 4 degrees C and induces pathways to maintain its long-term survival. PMID- 22253707 TI - Evidence for a grooming claw in a North American adapiform primate: implications for anthropoid origins. AB - Among fossil primates, the Eocene adapiforms have been suggested as the closest relatives of living anthropoids (monkeys, apes, and humans). Central to this argument is the form of the second pedal digit. Extant strepsirrhines and tarsiers possess a grooming claw on this digit, while most anthropoids have a nail. While controversial, the possible presence of a nail in certain European adapiforms has been considered evidence for anthropoid affinities. Skeletons preserved well enough to test this idea have been lacking for North American adapiforms. Here, we document and quantitatively analyze, for the first time, a dentally associated skeleton of Notharctus tenebrosus from the early Eocene of Wyoming that preserves the complete bones of digit II in semi-articulation. Utilizing twelve shape variables, we compare the distal phalanges of Notharctus tenebrosus to those of extant primates that bear nails (n = 21), tegulae (n = 4), and grooming claws (n = 10), and those of non-primates that bear claws (n = 7). Quantitative analyses demonstrate that Notharctus tenebrosus possessed a grooming claw with a surprisingly well-developed apical tuft on its second pedal digit. The presence of a wide apical tuft on the pedal digit II of Notharctus tenebrosus may reflect intermediate morphology between a typical grooming claw and a nail, which is consistent with the recent hypothesis that loss of a grooming claw occurred in a clade containing adapiforms (e.g. Darwinius masillae) and anthropoids. However, a cladistic analysis including newly documented morphologies and thorough representation of characters acknowledged to have states constituting strepsirrhine, haplorhine, and anthropoid synapomorphies groups Notharctus tenebrosus and Darwinius masillae with extant strepsirrhines rather than haplorhines suggesting that the form of pedal digit II reflects substantial homoplasy during the course of early primate evolution. PMID- 22253708 TI - Remarkable rates of lightning strike mortality in Malawi. AB - Livingstone's second mission site on the shore of Lake Malawi suffers very high rates of consequential lightning strikes. Comprehensive interviewing of victims and their relatives in seven Traditional Authorities in Nkhata Bay District, Malawi revealed that the annual rate of consequential strikes was 419/million, more than six times higher than that in other developing countries; the rate of deaths from lightning was 84/million/year, 5.4 times greater than the highest ever recorded. These remarkable figures reveal that lightning constitutes a significant stochastic source of mortality with potential life history consequences, but it should not deflect attention away from the more prominent causes of mortality in this rural area. PMID- 22253709 TI - Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects. AB - Polyunsaturated fatty acids (PUFA) have shown efficacy in the treatment of bipolar disorder, however their specific role in treating the illness is unclear. Serum PUFA and dietary intakes of PUFA associate with suicidal behavior in epidemiological studies. The objective of this study was to assess serum n-3 and n-6 PUFA levels in bipolar subjects and determine possible associations with suicidal risk, including suicidal history and relevant personality factors that have been associated with suicidality. We studied 27 bipolar subjects using the NEO-PI to assess the big five personality factors, structured interviews to verify diagnosis and assess suicidal history, and lipomics to quantify n-3 and n 6 PUFA in serum. We found positive associations between personality factors and ratios of n-3 PUFA, suggesting that conversion of short chain to long chain n-3s and the activity of enzymes in this pathway may associate with measures of personality. Thus, ratios of docosahexaenoic acid (DHA) to alpha linolenic acid (ALA) and the activity of fatty acid desaturase 2 (FADS2) involved in the conversion of ALA to DHA were positively associated with openness factor scores. Ratios of eicosapentaenoic acid (EPA) to ALA and ratios of EPA to DHA were positively associated with agreeableness factor scores. Finally, serum concentrations of the n-6, arachidonic acid (AA), were significantly lower in subjects with a history of suicide attempt compared to non-attempters. The data suggest that specific lipid profiles, which are controlled by an interaction between diet and genetics, correlate with suicidal history and personality factors related to suicidal risk. This study provides preliminary data for future studies to determine whether manipulation of PUFA profiles (through diet or supplementation) can affect personality measures and disease outcome in bipolar subjects and supports the need for further investigations into individualized specific modulations of lipid profiles to add adjunctive value to treatment paradigms. PMID- 22253710 TI - Effects of Astragalus polysaccharide on immune responses of porcine PBMC stimulated with PRRSV or CSFV. AB - BACKGROUND: Astragalus polysaccharide (APS) has been used as an immunomodulator that can enhance immune responses, whereas the immunomodulatory effects of APS on porcine peripheral blood mononuclear cells (PBMCs) exposed to porcine reproductive and respiratory syndrome virus (PRRSV) and classical swine fever virus (CSFV) have not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: Porcine PBMCs were cultured in complete RPMI media in the presence of the R98-strain of PRRSV (5*10(4) TCID(50)/ml) or C-strain of CSFV (10(3) TCID(50)/ml) with or without APS. The expression of mRNA for CD28, cytotoxic T-lymphocyte antigen 4 (CTLA-4), transforming growth factor-beta (TGF-beta), interleukin 2 (IL-2) and IL 10 was assayed by TaqMan real-time RT-PCR. The expression of mRNA for CD28 and CTLA-4 increased at 24 h after stimulation of PBMCs with CSFV and the increased production of CTLA-4 was confirmed by western blot analysis, whereas the increases were inhibited by the addition of APS. In addition, APS alone upregulated IL-2 and TGF-beta mRNA expression in PBMCs and the addition of APS had the capacity to prevent a further increase in IL-2 mRNA expression in PBMCs during CSFV or PRRSV infection, but had no effect on TGF-beta mRNA expression. The production of tumor necrosis factor-alpha (TNF-alpha) increased at 12 h after stimulation with PRRSV or CSFV, but not with PRRSV plus APS or CSFV plus APS, whereas the addition of APS to PBMCs infected with PRRSV or CSFV promoted IL-10 mRNA expression. CONCLUSIONS: We suggested that APS had immunomodulatory effects on cells exposed to PRRSV or CSFV. It might be that APS via different mechanisms affects the activities of immune cells during either PRRSV or CSFV infection. This possibility warrants further studies to evaluate whether APS would be an effective adjuvant in vaccines against PRRSV or CSFV. PMID- 22253711 TI - Modulation of the pentose phosphate pathway induces endodermal differentiation in embryonic stem cells. AB - Embryonic stem (ES) cells can differentiate in vitro into a variety of cell types. Efforts to produce endodermal cell derivatives, including lung, liver and pancreas, have been met with modest success. Understanding how the endoderm originates from ES cells is the first step to generate specific cell types for therapeutic purposes. Recently, it has been demonstrated that inhibition of Myc or mTOR induces endodermal differentiation. Both Myc and mTOR are known to be activators of the Pentose Phosphate Pathway (PPP). We found that, differentely from wild type (wt), ES cells unable to produce pentose sugars through PPP differentiate into endodermal precursors in cell culture conditions generally non permissive to generate them. The same effect was observed when wt ES cells were differentiated in presence of chemical inhibitors of the PPP. These data highlight a new role for metabolism. Indeed, to our knowledge, it is the first time that modulation of a metabolic pathway is described to be crucial in determining ES cell fate. PMID- 22253712 TI - Breastfeeding and infant temperament at age three months. AB - BACKGROUND & METHODS: To examine the relationship between breastfeeding and maternally-rated infant temperament at age 3 months, 316 infants in the prospective Cambridge Baby Growth Study, UK had infant temperament assessed at age 3 months by mothers using the Revised Infant Behavior Questionnaire, which produces scores for three main dimensions of temperament derived from 14 subscales. Infant temperament scores were related to mode of infant milk feeding at age 3 months (breast only; formula milk only; or mixed) with adjustment for infant's age at assessment and an index of deprivation. RESULTS: Infant temperament dimension scores differed across the three infant feeding groups, but appeared to be comparable between exclusive breast-fed and mixed-fed infants. Compared to formula milk-fed infants, exclusive breast-fed and mixed-fed infants were rated as having lower impulsivity and positive responses to stimulation (adjusted mean [95% CI] "Surgency/Extraversion" in formula-fed vs. mixed-fed vs. breast-fed groups: 4.3 [4.2-4.5] vs. 4.0 [3.8-4.1] vs. 4.0 [3.9-4.1]; p heterogeneity = 0.0006), lower ability to regulate their own emotions ("Orienting/Regulation": 5.1 [5.0-5.2], vs. 4.9 [4.8-5.1] vs. 4.9 [4.8-5.0]; p = 0.01), and higher emotional instability ("Negative affectivity": 2.8 [2.6-2.9] vs. 3.0 [2.8-3.1] vs. 3.0 [2.9-3.1]; p = 0.03). CONCLUSIONS: Breast and mixed-fed infants were rated by their mothers as having more challenging temperaments in all three dimensions; particular subscales included greater distress, less smiling, laughing, and vocalisation, and lower soothability. Increased awareness of the behavioural dynamics of breastfeeding, a better expectation of normal infant temperament and support to cope with difficult infant temperament could potentially help to promote successful breastfeeding. PMID- 22253713 TI - Long-term survival of hydrated resting eggs from Brachionus plicatilis. AB - BACKGROUND: Several organisms display dormancy and developmental arrest at embryonic stages. Long-term survival in the dormant form is usually associated with desiccation, orthodox plant seeds and Artemia cysts being well documented examples. Several aquatic invertebrates display dormancy during embryonic development and survive for tens or even hundreds of years in a hydrated form, raising the question of whether survival in the non-desiccated form of embryonic development depends on pathways similar to those occurring in desiccation tolerant forms. METHODOLOGY/PRINCIPAL FINDINGS: To address this question, Illumina short read sequencing was used to generate transcription profiles from the resting and amictic eggs of an aquatic invertebrate, the rotifer, Brachionus plicatilis. These two types of egg have very different life histories, with the dormant or diapausing resting eggs, the result of the sexual cycle and amictic eggs, the non-dormant products of the asexual cycle. Significant transcriptional differences were found between the two types of egg, with amictic eggs rich in genes involved in the morphological development into a juvenile rotifer. In contrast, representatives of classical "stress" proteins: a small heat shock protein, ferritin and Late Embryogenesis Abundant (LEA) proteins were identified in resting eggs. More importantly however, was the identification of transcripts for messenger ribonucleoprotein particles which stabilise RNA. These inhibit translation and provide a valuable source of useful RNAs which can be rapidly activated on the exit from dormancy. Apoptotic genes were also present. Although apoptosis is inconsistent with maintenance of prolonged dormancy, an altered apoptotic pathway has been proposed for Artemia, and this may be the case with the rotifer. CONCLUSIONS: These data represent the first transcriptional profiling of molecular processes associated with dormancy in a non-desiccated form and indicate important similarities in the molecular pathways activated in resting eggs compared with desiccated dormant forms, specifically plant seeds and Artemia. PMID- 22253714 TI - GABAergic gene expression in postmortem hippocampus from alcoholics and cocaine addicts; corresponding findings in alcohol-naive P and NP rats. AB - BACKGROUND: By performing identical studies in humans and rats, we attempted to distinguish vulnerability factors for addiction from neurobiological effects of chronic drug exposure. We focused on the GABAergic system within the hippocampus, a brain region that is a constituent of the memory/conditioning neuronal circuitry of addiction that is considered to be important in drug reinforcement behaviors in animals and craving and relapse in humans. METHODOLOGY: Using RNA Seq we quantified mRNA transcripts in postmortem total hippocampus from alcoholics, cocaine addicts and controls and also from alcohol-naive, alcohol preferring (P) and non-preferring (NP) rats selectively bred for extremes of alcohol-seeking behavior that also show a general addictive tendency. A pathway targeted analysis of 25 GABAergic genes encoding proteins implicated in GABA synthesis, metabolism, synaptic transmission and re-uptake was undertaken. PRINCIPAL FINDINGS: Directionally consistent and biologically plausible overlapping and specific changes were detected: 14/25 of the human genes and 12/25 of the rat genes showed nominally significant differences in gene expression (global p values: 9*10-14, 7*10-11 respectively). Principal FDR corrected findings were that GABBR1 was down-regulated in alcoholics, cocaine addicts and P rats with congruent findings in NSF, implicated in GABAB signaling efficacy, potentially resulting in increased synaptic GABA. GABRG2, encoding the gamma2 subunit required for postsynaptic clustering of GABAA receptors together with GPHN, encoding the associated scaffolding protein gephryin, were both down regulated in alcoholics and cocaine addicts but were both up-regulated in P rats. There were also expression changes specific to cocaine addicts (GAD1, GAD2), alcoholics (GABRA2) and P rats (ABAT, GABRG3). CONCLUSIONS/SIGNIFICANCE: Our study confirms the involvement of the GABAergic system in alcoholism but also reveals a hippocampal GABA input in cocaine addiction. Congruent findings in human addicts and P rats provide clues to predisposing factors for alcohol and drug addiction. Finally, the results of this study have therapeutic implications. PMID- 22253715 TI - Impact of IL28B-related single nucleotide polymorphisms on liver histopathology in chronic hepatitis C genotype 2 and 3. AB - BACKGROUND AND AIMS: Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naive patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory. METHODS: Three hundred and thirty nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology. RESULTS: IL28B CC(rs12979860) genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CC(rs12979860) genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients. CONCLUSION: This study shows that the CC(rs12979860) SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection. PMID- 22253716 TI - Bmp7 functions via a polarity mechanism to promote cloacal septation. AB - BACKGROUND: During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse. CONCLUSION/SIGNIFICANCE: Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations. PMID- 22253717 TI - ORAI1 genetic polymorphisms associated with the susceptibility of atopic dermatitis in Japanese and Taiwanese populations. AB - Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD. PMID- 22253718 TI - Leptin reduces the expression and increases the phosphorylation of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4 in muscle of ob/ob mice. AB - Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P = 0.004) in the leptin treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4. PMID- 22253719 TI - Perturbation dynamics of the rumen microbiota in response to exogenous butyrate. AB - The capacity of the rumen microbiota to produce volatile fatty acids (VFAs) has important implications in animal well-being and production. We investigated temporal changes of the rumen microbiota in response to butyrate infusion using pyrosequencing of the 16S rRNA gene. Twenty one phyla were identified in the rumen microbiota of dairy cows. The rumen microbiota harbored 54.5+/-6.1 genera (mean +/- SD) and 127.3+/-4.4 operational taxonomic units (OTUs), respectively. However, the core microbiome comprised of 26 genera and 82 OTUs. Butyrate infusion altered molar percentages of 3 major VFAs. Butyrate perturbation had a profound impact on the rumen microbial composition. A 72 h-infusion led to a significant change in the numbers of sequence reads derived from 4 phyla, including 2 most abundant phyla, Bacteroidetes and Firmicutes. As many as 19 genera and 43 OTUs were significantly impacted by butyrate infusion. Elevated butyrate levels in the rumen seemingly had a stimulating effect on butyrate producing bacteria populations. The resilience of the rumen microbial ecosystem was evident as the abundance of the microorganisms returned to their pre disturbed status after infusion withdrawal. Our findings provide insight into perturbation dynamics of the rumen microbial ecosystem and should guide efforts in formulating optimal uses of probiotic bacteria treating human diseases. PMID- 22253720 TI - Can tropical insects stand the heat? A case study with the brown planthopper Nilaparvata lugens (Stal). AB - The brown planthopper Nilaparvata lugens (Stal) is the most serious pest of rice across the world, especially in tropical climates. N. lugens nymphs and adults were exposed to high temperatures to determine their critical thermal maximum (CT(max)), heat coma temperature (HCT) and upper lethal temperature (ULT). Thermal tolerance values differed between developmental stages: nymphs were consistently less heat tolerant than adults. The mean (+/- SE) CT(max) of nymphs and adult females and males were 34.9+/-0.3, 37.0+/-0.2 and 37.4+/-0.2 degrees C respectively, and for the HCT were 37.7+/-0.3, 43.5+/-0.4 and 42.0+/-0.4 degrees C. The ULT50 values (+/- SE) for nymphs and adults were 41.8+/-0.1 and 42.5+/-0.1 degrees C respectively. The results indicate that nymphs of N. lugens are currently living at temperatures close to their upper thermal limits. Climate warming in tropical regions and occasional extreme high temperature events are likely to become important limiting factors affecting the survival and distribution of N. lugens. PMID- 22253721 TI - Genome-wide high-resolution aCGH analysis of gestational choriocarcinomas. AB - Eleven samples of DNA from choriocarcinomas were studied by high resolution CGH array 244 K. They were studied after histopathological confirmation of the diagnosis, of the androgenic etiology and after a microsatellite marker analysis confirming the absence of contamination of tumor DNA from maternal DNA. Three cell lines, BeWo, JAR, JEG were also studied by this high resolution pangenomic technique. According to aCGH analysis, the de novo choriocarcinomas exhibited simple chromosomal rearrangements or normal profiles. The cell lines showed various and complex chromosomal aberrations. 23 Minimal Critical Regions were defined that allowed us to list the genes that were potentially implicated. Among them, unusually high numbers of microRNA clusters and imprinted genes were observed. PMID- 22253722 TI - Generation of long insert pairs using a Cre-LoxP Inverse PCR approach. AB - Large insert mate pair reads have a major impact on the overall success of de novo assembly and the discovery of inherited and acquired structural variants. The positional information of mate pair reads generally improves genome assembly by resolving repeat elements and/or ordering contigs. Currently available methods for building such libraries have one or more of limitations, such as relatively small insert size; unable to distinguish the junction of two ends; and/or low throughput. We developed a new approach, Cre-LoxP Inverse PCR Paired-End (CLIP PE), which exploits the advantages of (1) Cre-LoxP recombination system to efficiently circularize large DNA fragments, (2) inverse PCR to enrich for the desired products that contain both ends of the large DNA fragments, and (3) the use of restriction enzymes to introduce a recognizable junction site between ligated fragment ends and to improve the self-ligation efficiency. We have successfully created CLIP-PE libraries up to 22 kb that are rich in informative read pairs and low in small fragment background. These libraries have demonstrated the ability to improve genome assemblies. The CLIP-PE methodology can be implemented with existing and future next-generation sequencing platforms. PMID- 22253723 TI - Active and passive immunization protects against lethal, extreme drug resistant Acinetobacter baumannii infection. AB - Extreme-drug-resistant (XDR) Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. New methods to prevent and treat such infections are a critical unmet medical need. To conduct a rational vaccine discovery program, OmpA was identified as the primary target of humoral immune response after intravenous infection by A. baumannii in mice. OmpA was >99% conserved at the amino acid level across clinical isolates harvested between 1951 and 2009 from cerebrospinal fluid, blood, lung, and wound infections, including carbapenem resistant isolates, and was >=89% conserved among other sequenced strains, but had minimal homology to the human proteome. Vaccination of diabetic mice with recombinant OmpA (rOmpA) with aluminum hydroxide adjuvant markedly improved survival and reduced tissue bacterial burden in mice infected intravenously. Vaccination induced high titers of anti-OmpA antibodies, the levels of which correlated with survival in mice. Passive transfer with immune sera recapitulated protection. Immune sera did not enhance complement-mediated killing but did enhance opsonophagocytic killing of A. baumannii. These results define active and passive immunization strategies to prevent and treat highly lethal, XDR A. baumannii infections. PMID- 22253724 TI - Molecular genetic features of polyploidization and aneuploidization reveal unique patterns for genome duplication in diploid Malus. AB - Polyploidization results in genome duplication and is an important step in evolution and speciation. The Malus genome confirmed that this genus was derived through auto-polyploidization, yet the genetic and meiotic mechanisms for polyploidization, particularly for aneuploidization, are unclear in this genus or other woody perennials. In fact the contribution of aneuploidization remains poorly understood throughout Plantae. We add to this knowledge by characterization of eupolyploidization and aneuploidization in 27,542 F1 seedlings from seven diploid Malus populations using cytology and microsatellite markers. We provide the first evidence that aneuploidy exceeds eupolyploidy in the diploid crosses, suggesting aneuploidization is a leading cause of genome duplication. Gametes from diploid Malus had a unique combinational pattern; ova preserved euploidy exclusively, while spermatozoa presented both euploidy and aneuploidy. All non-reduced gametes were genetically heterozygous, indicating first-division restitution was the exclusive mode for Malus eupolyploidization and aneuploidization. Chromosome segregation pattern among aneuploids was non uniform, however, certain chromosomes were associated for aneuploidization. This study is the first to provide molecular evidence for the contribution of heterozygous non-reduced gametes to fitness in polyploids and aneuploids. Aneuploidization can increase, while eupolyploidization may decrease genetic diversity in their newly established populations. Auto-triploidization is important for speciation in the extant Malus. The features of Malus polyploidization confer genetic stability and diversity, and present heterozygosity, heterosis and adaptability for evolutionary selection. A protocol using co-dominant markers was proposed for accelerating apple triploid breeding program. A path was postulated for evolution of numerically odd basic chromosomes. The model for Malus derivation was considerably revised. Impacts of aneuploidization on speciation and evolution, and potential applications of aneuploids and polyploids in breeding and genetics for other species were evaluated in depth. This study greatly improves our understanding of evolution, speciation, and adaptation of the Malus genus, and provides strategies to exploit polyploidization in other species. PMID- 22253725 TI - Establishing human lacrimal gland cultures with secretory function. AB - PURPOSE: Dry eye syndrome is a multifactorial chronic disabling disease mainly caused by the functional disruptions in the lacrimal gland. The treatment involves palliation like ocular surface lubrication and rehydration. Cell therapy involving replacement of the gland is a promising alternative for providing long term relief to patients. This study aimed to establish functionally competent lacrimal gland cultures in-vitro and explore the presence of stem cells in the native gland and the established in-vitro cultures. METHODS: Fresh human lacrimal gland from patients undergoing exenteration was harvested for cultures after IRB approval. The freshly isolated cells were evaluated by flow cytometry for expression of stem cell markers ABCG2, high ALDH1 levels and c-kit. Cultures were established on Matrigel, collagen and HAM and the cultured cells evaluated for the presence of stem cell markers and differentiating markers of epithelial (E cadherin, EpCAM), mesenchymal (Vimentin, CD90) and myofibroblastic (alpha-SMA, S 100) origin by flow cytometry and immunocytochemistry. The conditioned media was tested for secretory proteins (scIgA, lactoferrin, lysozyme) post carbachol (100 uM) stimulation by ELISA. RESULTS: Native human lacrimal gland expressed ABCG2 (mean+/-SEM: 3.1+/-0.61%), high ALDH1 (3.8+/-1.26%) and c-kit (6.7+/-2.0%). Lacrimal gland cultures formed a monolayer, in order of preference on Matrigel, collagen and HAM within 15-20 days, containing a heterogeneous population of stem like and differentiated cells. The epithelial cells formed 'spherules' with duct like connections, suggestive of ductal origin. The levels of scIgA (47.43 to 61.56 ng/ml), lysozyme (24.36 to 144.74 ng/ml) and lactoferrin (32.45 to 40.31 ng/ml) in the conditioned media were significantly higher than the negative controls (p<0.05 for all comparisons). CONCLUSION: The study reports the novel finding of establishing functionally competent human lacrimal gland cultures in vitro. It also provides preliminary data on the presence of stem cells and duct like cells in the fresh and in-vitro cultured human lacrimal gland. These significant findings could pave way for cell therapy in future. PMID- 22253726 TI - Comparative analysis of reproductive traits in black-chinned tilapia females from various coastal marine, estuarine and freshwater ecosystems. AB - The black-chinned tilapia Sarotherodon melanotheron is a marine teleost characterised by an extreme euryhalinity. However, beyond a certain threshold at very high salinity, the species exhibits impaired growth and precocious reproduction. In this study, the relationships between reproductive parameters, environmental salinity and condition factor were investigated in wild populations of this species that were sampled in two consecutive years (2003 and 2004) from three locations in Senegal with different salinities: Guiers lake (freshwater, 0 psu), Hann bay (seawater, 37 psu) and Saloum estuary (hypersaline water, 66-127 psu). The highest absolute fecundity and spawning weight were recorded in seawater by comparison to either freshwater or hypersaline water whereas the poorest condition factors were observed in the most saline sampling site. These results reflect higher resource allocation to the reproduction due to the lowest costs of adaptation to salinity in seawater (the natural environment of this species) rather than differences in food resources at sites and/or efficiency at foraging and prey availability. Fecundities, oocyte size as well as spawning weight were consistent from year to year. However, the relative fecundity in the Saloum estuary varied significantly between the dry and rainy raisons with higher values in the wet season, which seems to reflect seasonal variations in environmental salinity. Such a reproductive tactic of producing large amounts of eggs in the rainy season when the salinity in the estuary was lower, would give the fry a better chance at survival and therefore assures a high larval recruitment. An inverse correlation was found between relative fecundity and oocyte size at the two extreme salinity locations, indicating that S. melanotheron has different reproductive strategies in these ecosystems. The adaptive significance of these two reproductive modes is discussed in regard to the heavy osmotic constraint imposed by extreme salinities and high inter specific competition. PMID- 22253727 TI - Mutation in SUMO E3 ligase, SIZ1, disrupts the mature female gametophyte in Arabidopsis. AB - Female gametophyte is the multicellular haploid structure that can produce embryo and endosperm after fertilization, which has become an attractive model system for investigating molecular mechanisms in nuclei migration, cell specification, cell-to-cell communication and many other processes. Previous reports found that the small ubiquitin-like modifier (SUMO) E3 ligase, SIZ1, participated in many processes depending on particular target substrates and suppression of salicylic acid (SA) accumulation. Here, we report that SIZ1 mediates the reproductive process. SIZ1 showed enhanced expression in female organs, but was not detected in the anther or pollen. A defect in the siz1-2 maternal source resulted in reduced seed-set regardless of high SA concentration within the plant. Moreover, aniline blue staining and scanning electron microscopy revealed that funicular and micropylar pollen tube guidance was arrested in siz1-2 plants. Some of the embryo sacs of ovules in siz1-2 were also disrupted quickly after stage FG7. There was no significant affects of the siz1-2 mutation on expression of genes involved in female gametophyte development- or pollen tube guidance in ovaries. Together, our results suggest that SIZ1 sustains the stability and normal function of the mature female gametophyte which is necessary for pollen tube guidance. PMID- 22253729 TI - A technique for measuring petal gloss, with examples from the Namaqualand flora. AB - The degree of floral gloss varies between species. However, little is known about this distinctive floral trait, even though it could be a key feature of floral biotic and abiotic interactions. One reason for the absence of knowledge is the lack of a simple, repeatable method of gloss measurement that can be used in the field to study floral gloss. A protocol is described for measuring gloss in petal samples collected in the field, using a glossmeter. Repeatability of the technique is assessed. We demonstrate a simple yet highly accurate and repeatable method that can easily be implemented in the field. We also highlight the huge variety of glossiness found within flowers and between species in a sample of spring-blooming flowers collected in Namaqualand, South Africa. We discuss the potential uses of this method and its applications for furthering studies in plant-pollinator interactions. We also discuss the potential functions of gloss in flowers. PMID- 22253728 TI - Rapid plant identification using species- and group-specific primers targeting chloroplast DNA. AB - Plant identification is challenging when no morphologically assignable parts are available. There is a lack of broadly applicable methods for identifying plants in this situation, for example when roots grow in mixture and for decayed or semi digested plant material. These difficulties have also impeded the progress made in ecological disciplines such as soil- and trophic ecology. Here, a PCR-based approach is presented which allows identifying a variety of plant taxa commonly occurring in Central European agricultural land. Based on the trnT-F cpDNA region, PCR assays were developed to identify two plant families (Poaceae and Apiaceae), the genera Trifolium and Plantago, and nine plant species: Achillea millefolium, Fagopyrum esculentum, Lolium perenne, Lupinus angustifolius, Phaseolus coccineus, Sinapis alba, Taraxacum officinale, Triticum aestivum, and Zea mays. These assays allowed identification of plants based on size-specific amplicons ranging from 116 bp to 381 bp. Their specificity and sensitivity was consistently high, enabling the detection of small amounts of plant DNA, for example, in decaying plant material and in the intestine or faeces of herbivores. To increase the efficacy of identifying plant species from large number of samples, specific primers were combined in multiplex PCRs, allowing screening for multiple species within a single reaction. The molecular assays outlined here will be applicable manifold, such as for root- and leaf litter identification, botanical trace evidence, and the analysis of herbivory. PMID- 22253730 TI - Mutation of Rubie, a novel long non-coding RNA located upstream of Bmp4, causes vestibular malformation in mice. AB - BACKGROUND: The vestibular apparatus of the vertebrate inner ear uses three fluid filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified. METHODOLOGY/PRINCIPAL FINDINGS: We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears. CONCLUSIONS/SIGNIFICANCE: Based on these results and previous studies showing that Bmp4 is essential for proper vestibular development, we propose that Rubie is the gene mutated in Ecl mice, that it is involved in regulating inner ear expression of Bmp4, and that aberrant Bmp4 expression contributes to the Ecl phenotype. PMID- 22253731 TI - Zoonotic viruses associated with illegally imported wildlife products. AB - The global trade in wildlife has historically contributed to the emergence and spread of infectious diseases. The United States is the world's largest importer of wildlife and wildlife products, yet minimal pathogen surveillance has precluded assessment of the health risks posed by this practice. This report details the findings of a pilot project to establish surveillance methodology for zoonotic agents in confiscated wildlife products. Initial findings from samples collected at several international airports identified parts originating from nonhuman primate (NHP) and rodent species, including baboon, chimpanzee, mangabey, guenon, green monkey, cane rat and rat. Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples. These results are the first demonstration that illegal bushmeat importation into the United States could act as a conduit for pathogen spread, and suggest that implementation of disease surveillance of the wildlife trade will help facilitate prevention of disease emergence. PMID- 22253732 TI - Identification of gene networks and pathways associated with Guillain-Barre syndrome. AB - BACKGROUND: The underlying change of gene network expression of Guillain-Barre syndrome (GBS) remains elusive. We sought to identify GBS-associated gene networks and signaling pathways by analyzing the transcriptional profile of leukocytes in the patients with GBS. METHODS AND FINDINGS: Quantitative global gene expression microarray analysis of peripheral blood leukocytes was performed on 7 patients with GBS and 7 healthy controls. Gene expression profiles were compared between patients and controls after standardization. The set of genes that significantly correlated with GBS was further analyzed by Ingenuity Pathways Analyses. 256 genes and 18 gene networks were significantly associated with GBS (fold change >=2, P<0.05). FOS, PTGS2, HMGB2 and MMP9 are the top four of 246 significantly up-regulated genes. The most significant disease and altered biological function genes associated with GBS were those involved in inflammatory response, infectious disease, and respiratory disease. Cell death, cellular development and cellular movement were the top significant molecular and cellular functions involved in GBS. Hematological system development and function, immune cell trafficking and organismal survival were the most significant GBS-associated function in physiological development and system category. Several hub genes, such as MMP9, PTGS2 and CREB1 were identified in the associated gene networks. Canonical pathway analysis showed that GnRH, corticotrophin-releasing hormone and ERK/MAPK signaling were the most significant pathways in the up-regulated gene set in GBS. CONCLUSIONS: This study reveals the gene networks and canonical pathways associated with GBS. These data provide not only networks between the genes for understanding the pathogenic properties of GBS but also map significant pathways for the future development of novel therapeutic strategies. PMID- 22253733 TI - SARS coronavirus 3b accessory protein modulates transcriptional activity of RUNX1b. AB - BACKGROUND: The causative agent of severe acute respiratory syndrome, SARS coronavirus (SARS-CoV) genome encodes several unique group specific accessory proteins with unknown functions. Among them, accessory protein 3b (also known as ORF4) was lately identified as one of the viral interferon antagonist. Recently our lab uncovered a new role for 3b in upregulation of AP-1 transcriptional activity and its downstream genes. Thus, we believe that 3b might play an important role in SARS-CoV pathogenesis and therefore is of considerable interest. The current study aims at identifying novel host cellular interactors of the 3b protein. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using yeast two hybrid and co-immunoprecipitation techniques, we have identified a host transcription factor RUNX1b (Runt related transcription factor, isoform b) as a novel interacting partner for SARS-CoV 3b protein. Chromatin immunoprecipitaion (ChIP) and reporter gene assays in 3b expressing jurkat cells showed recruitment of 3b on the RUNX1 binding element that led to an increase in RUNX1b transactivation potential on the IL2 promoter. Kinase assay and pharmacological inhibitor treatment implied that 3b also affect RUNX1b transcriptional activity by regulating its ERK dependent phosphorylation levels. Additionally, mRNA levels of MIP-1alpha, a RUNX1b target gene upregulated in SARS-CoV infected monocyte derived dendritic cells, were found to be elevated in 3b expressing U937 monocyte cells. CONCLUSIONS/SIGNIFICANCE: These results unveil a novel interaction of SARS CoV 3b with the host factor, RUNX1b, and speculate its physiological relevance in upregulating cytokines and chemokine levels in state of SARS virus infection. PMID- 22253734 TI - Capsules from pathogenic and non-pathogenic Cryptococcus spp. manifest significant differences in structure and ability to protect against phagocytic cells. AB - Capsule production is common among bacterial species, but relatively rare in eukaryotic microorganisms. Members of the fungal Cryptococcus genus are known to produce capsules, which are major determinants of virulence in the highly pathogenic species Cryptococcus neoformans and Cryptococcus gattii. Although the lack of virulence of many species of the Cryptococcus genus can be explained solely by the lack of mammalian thermotolerance, it is uncertain whether the capsules from these organisms are comparable to those of the pathogenic cryptococci. In this study, we compared the characteristic of the capsule from the non-pathogenic environmental yeast Cryptococcus liquefaciens with that of C. neoformans. Microscopic observations revealed that C. liquefaciens has a capsule visible in India ink preparations that was also efficiently labeled by three antibodies generated to specific C. neoformans capsular antigens. Capsular polysaccharides of C. liquefaciens were incorporated onto the cell surface of acapsular C. neoformans mutant cells. Polysaccharide composition determinations in combination with confocal microscopy revealed that C. liquefaciens capsule consisted of mannose, xylose, glucose, glucuronic acid, galactose and N acetylglucosamine. Physical chemical analysis of the C. liquefaciens polysaccharides in comparison with C. neoformans samples revealed significant differences in viscosity, elastic properties and macromolecular structure parameters of polysaccharide solutions such as rigidity, effective diameter, zeta potential and molecular mass, which nevertheless appeared to be characteristics of linear polysaccharides that also comprise capsular polysaccharide of C. neoformans. The environmental yeast, however, showed enhanced susceptibility to the antimicrobial activity of the environmental phagocytes, suggesting that the C. liquefaciens capsular components are insufficient in protecting yeast cells against killing by amoeba. These results suggest that capsular structures in pathogenic Cryptococcus species and environmental species share similar features, but also manifest significant difference that could influence their potential to virulence. PMID- 22253736 TI - Stable photosymbiotic relationship under CO2-induced acidification in the acoel worm Symsagittifera roscoffensis. AB - As a consequence of anthropogenic CO2 emissions, oceans are becoming more acidic, a phenomenon known as ocean acidification. Many marine species predicted to be sensitive to this stressor are photosymbiotic, including corals and foraminifera. However, the direct impact of ocean acidification on the relationship between the photosynthetic and nonphotosynthetic organism remains unclear and is complicated by other physiological processes known to be sensitive to ocean acidification (e.g. calcification and feeding). We have studied the impact of extreme pH decrease/pCO2 increase on the complete life cycle of the photosymbiotic, non calcifying and pure autotrophic acoel worm, Symsagittifera roscoffensis. Our results show that this species is resistant to high pCO2 with no negative or even positive effects on fitness (survival, growth, fertility) and/or photosymbiotic relationship till pCO2 up to 54 K uatm. Some sub-lethal bleaching is only observed at pCO2 up to 270 K uatm when seawater is saturated by CO2. This indicates that photosymbiosis can be resistant to high pCO2. If such a finding would be confirmed in other photosymbiotic species, we could then hypothesize that negative impact of high pCO2 observed on other photosymbiotic species such as corals and foraminifera could occur through indirect impacts at other levels (calcification, feeding). PMID- 22253735 TI - Lack of effective anti-apoptotic activities restricts growth of Parachlamydiaceae in insect cells. AB - The fundamental role of programmed cell death in host defense is highlighted by the multitude of anti-apoptotic strategies evolved by various microbes, including the well-known obligate intracellular bacterial pathogens Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. As inhibition of apoptosis is assumed to be essential for a successful infection of humans by these chlamydiae, we analyzed the anti-apoptotic capacity of close relatives that occur as symbionts of amoebae and might represent emerging pathogens. While Simkania negevensis was able to efficiently replicate within insect cells, which served as model for metazoan-derived host cells, the Parachlamydiaceae (Parachlamydia acanthamoebae and Protochlamydia amoebophila) displayed limited intracellular growth, yet these bacteria induced typical features of apoptotic cell death, including formation of apoptotic bodies, nuclear condensation, internucleosomal DNA fragmentation, and effector caspase activity. Induction of apoptosis was dependent on bacterial activity, but not bacterial de novo protein synthesis, and was detectable already at very early stages of infection. Experimental inhibition of host cell death greatly enhanced parachlamydial replication, suggesting that lack of potent anti apoptotic activities in Parachlamydiaceae may represent an important factor compromising their ability to successfully infect non-protozoan hosts. These findings highlight the importance of the evolution of anti-apoptotic traits for the success of chlamydiae as pathogens of humans and animals. PMID- 22253737 TI - Native environment modulates leaf size and response to simulated foliar shade across wild tomato species. AB - The laminae of leaves optimize photosynthetic rates by serving as a platform for both light capture and gas exchange, while minimizing water losses associated with thermoregulation and transpiration. Many have speculated that plants maximize photosynthetic output and minimize associated costs through leaf size, complexity, and shape, but a unifying theory linking the plethora of observed leaf forms with the environment remains elusive. Additionally, the leaf itself is a plastic structure, responsive to its surroundings, further complicating the relationship. Despite extensive knowledge of the genetic mechanisms underlying angiosperm leaf development, little is known about how phenotypic plasticity and selective pressures converge to create the diversity of leaf shapes and sizes across lineages. Here, we use wild tomato accessions, collected from locales with diverse levels of foliar shade, temperature, and precipitation, as a model to assay the extent of shade avoidance in leaf traits and the degree to which these leaf traits correlate with environmental factors. We find that leaf size is correlated with measures of foliar shade across the wild tomato species sampled and that leaf size and serration correlate in a species-dependent fashion with temperature and precipitation. We use far-red induced changes in leaf length as a proxy measure of the shade avoidance response, and find that shade avoidance in leaves negatively correlates with the level of foliar shade recorded at the point of origin of an accession. The direction and magnitude of these correlations varies across the leaf series, suggesting that heterochronic and/or ontogenic programs are a mechanism by which selective pressures can alter leaf size and form. This study highlights the value of wild tomato accessions for studies of both morphological and light-regulated development of compound leaves, and promises to be useful in the future identification of genes regulating potentially adaptive plastic leaf traits. PMID- 22253738 TI - Modulating activity of vancomycin and daptomycin on the expression of autolysis cell-wall turnover and membrane charge genes in hVISA and VISA strains. AB - Glycopeptides are still the gold standard to treat MRSA (Methicillin Resistant Staphylococcus aureus) infections, but their widespread use has led to vancomycin reduced susceptibility [heterogeneous Vancomycin-Intermediate-Staphylococcus aureus (hVISA) and Vancomycin-Intermediate-Staphylococcus aureus (VISA)], in which different genetic loci (regulatory, autolytic, cell-wall turnover and cell envelope positive charge genes) are involved. In addition, reduced susceptibility to vancomycin can influence the development of resistance to daptomycin. Although the phenotypic and molecular changes of hVISA/VISA have been the focus of different papers, the molecular mechanisms responsible for these different phenotypes and for the vancomycin and daptomycin cross-resistance are not clearly understood. The aim of our study was to investigate, by real time RT-PCR, the relative quantitative expression of genes involved in autolysis (atl-lytM), cell wall turnover (sceD), membrane charges (mprF-dltA) and regulatory mechanisms (agr locus-graRS-walKR), in hVISA and VISA cultured with or without vancomycin and daptomycin, in order to better understand the molecular basis of vancomycin reduced susceptibility and the modulating activity of vancomycin and daptomycin on the expression of genes implicated in their reduced susceptibility mechanisms. Our results show that hVISA and VISA present common features that distinguish them from Vancomycin-Susceptible Staphylococcus aureus (VSSA), responsible for the intermediate glycopeptide resistance i.e. an increased cell-wall turnover, an increased positive cell-wall charge responsible for a repulsion mechanism towards vancomycin and daptomycin, and reduced agr-functionality. Indeed, VISA emerges from hVISA when VISA acquires a reduced autolysis caused by a down-regulation of autolysin genes, atl/lytM, and a reduction of the net negative cell-envelope charge via dltA over-expression. Vancomycin and daptomycin, acting in a similar manner in hVISA and VISA, can influence their cross-resistance mechanisms promoting VISA behavior in hVISA and enhancing the cell-wall pathways responsible for the intermediate vancomycin resistance in VISA. Daptomycin can also induce a charge repulsion mechanism both in hVISA and VISA increasing the activity of the mprF. PMID- 22253739 TI - Macrophages homing to metastatic lymph nodes can be monitored with ultrasensitive ferromagnetic iron-oxide nanocubes and a 1.5T clinical MR scanner. AB - BACKGROUND: Due to the ability of macrophages to specifically home to tumors, their potential use as a delivery vehicle for cancer therapeutics has been suggested. Tracking the delivery and engraftment of macrophages into human tumors with a 1.5T clinical MR scanner requires the development of sensitive contrast agents for cell labeling. Therefore, this study aimed to determine whether intravenously injected macrophages could target a primary tumor as well as metastatic LNs, and whether these cells could be detected in vivo by MRI. METHODOLOGY: Peritoneal macrophages were obtained from BALB/c nude mice. The viability, phagocytotic capacity and migratory activity of the macrophages were assessed. MR imaging was performed using a clinical 1.5 T MR scanner and we estimated the T2* of the labeled macrophages. Metastatic lymph nodes were produced in BALB/c nude mice. We administrated 2*106 macrophages labeled with 50 ug Fe/mL FIONs intravenously into the mice. In the 3D T2* GRE MR images obtained one day after the injection of the labeled macrophages or FION solution, the percentages of pixels in the tumors or LNs below the minimum normalized SI (signal intensity) threshold were summated and reported as the black pixel count (%) for the FION hypointensity. Tumors in the main tumor model as well as the brachial, axillary and inguinal lymph nodes in the metastatic LN models were removed and stained. For all statistical analyses, single-group data were assessed using t test or the Mann-Whitney test. Repeated measurements analysis of variance (ANOVA) with Tukey-Kramer post hoc comparisons were performed for multiple comparisons. CONCLUSIONS: The FION-labeled macrophages, which could be non-invasively monitored using a 1.5T clinical MR scanner, targeted both the main tumors and LN metastases. Overall, the results of this study suggest that the use of macrophages may have many future applications in the clinic for vectorizing therapeutic agents toward main tumors as well as LN metastases. PMID- 22253740 TI - Genetic interactions between chromosomes 11 and 18 contribute to airway hyperresponsiveness in mice. AB - We used two-dimensional quantitative trait locus analysis to identify interacting genetic loci that contribute to the native airway constrictor hyperresponsiveness to methacholine that characterizes A/J mice, relative to C57BL/6J mice. We quantified airway responsiveness to intravenous methacholine boluses in eighty eight (C57BL/6J X A/J) F2 and twenty-seven (A/J X C57BL/6J) F2 mice as well as ten A/J mice and six C57BL/6J mice; all studies were performed in male mice. Mice were genotyped at 384 SNP markers, and from these data two-QTL analyses disclosed one pair of interacting loci on chromosomes 11 and 18; the homozygous A/J genotype at each locus constituted the genetic interaction linked to the hyperresponsive A/J phenotype. Bioinformatic network analysis of potential interactions among proteins encoded by genes in the linked regions disclosed two high priority subnetworks--Myl7, Rock1, Limk2; and Npc1, Npc1l1. Evidence in the literature supports the possibility that either or both networks could contribute to the regulation of airway constrictor responsiveness. Together, these results should stimulate evaluation of the genetic contribution of these networks in the regulation of airway responsiveness in humans. PMID- 22253741 TI - Prevalence of obesity and the relationship between the body mass index and body fat: cross-sectional, population-based data. AB - BACKGROUND: Anthropometric measures such as the body mass index (BMI) and waist circumference are widely used as convenient indices of adiposity, yet there are limitations in their estimates of body fat. We aimed to determine the prevalence of obesity using criteria based on the BMI and waist circumference, and to examine the relationship between the BMI and body fat. METHODOLOGY/PRINCIPAL FINDINGS: This population-based, cross-sectional study was conducted as part of the Geelong Osteoporosis Study. A random sample of 1,467 men and 1,076 women aged 20-96 years was assessed 2001-2008. Overweight and obesity were identified according to BMI (overweight 25.0-29.9 kg/m2; obesity >=30.0 kg/m2) and waist circumference (overweight men 94.0-101.9 cm; women 80.0-87.9 cm; obesity men >=102.0 cm, women >=88.0 cm); body fat mass was assessed using dual energy X-ray absorptiometry; height and weight were measured and lifestyle factors documented by self-report. According to the BMI, 45.1% (95%CI 42.4-47.9) of men and 30.2% (95%CI 27.4-33.0) of women were overweight and a further 20.2% (95%CI 18.0-22.4) of men and 28.6% (95%CI 25.8-31.3) of women were obese. Using waist circumference, 27.5% (95%CI 25.1-30.0) of men and 23.3% (95%CI 20.8-25.9) of women were overweight, and 29.3% (95%CI 26.9-31.7) of men and 44.1% (95%CI 41.2 47.1) of women, obese. Both criteria indicate that approximately 60% of the population exceeded recommended thresholds for healthy body habitus. There was no consistent pattern apparent between BMI and energy intake. Compared with women, BMI overestimated adiposity in men, whose excess weight was largely attributable to muscular body builds and greater bone mass. BMI also underestimated adiposity in the elderly. Regression models including gender, age and BMI explained 0.825 of the variance in percent body fat. CONCLUSIONS/SIGNIFICANCE: As the BMI does not account for differences in body composition, we suggest that gender- and age specific thresholds should be considered when the BMI is used to indicate adiposity. PMID- 22253742 TI - Wind-driven roof turbines: a novel way to improve ventilation for TB infection control in health facilities. AB - OBJECTIVE: Tuberculosis transmission in healthcare facilities contributes significantly to the TB epidemic, particularly in high HIV settings. Although improving ventilation may reduce transmission, there is a lack of evidence to support low-cost practical interventions. We assessed the efficacy of wind-driven roof turbines to achieve recommended ventilation rates, compared to current recommended practices for natural ventilation (opening windows), in primary care clinic rooms in Khayelitsha, South Africa. METHODS: Room ventilation was assessed (CO2 gas tracer technique) in 4 rooms where roof turbines and air-intake grates were installed, across three scenarios: turbine, grate and window closed, only window open, and only turbine and grate open, with concurrent wind speed measurement. 332 measurements were conducted over 24 months. FINDINGS: For all 4 rooms combined, median air changes per hour (ACH) increased with wind speed quartiles across all scenarios. Higher median ACH were recorded with open roof turbines and grates, compared to open windows across all wind speed quartiles. Ventilation with open turbine and grate exceeded WHO-recommended levels (60 Litres/second/patient) for 95% or more of measurements in 3 of the 4 rooms; 47% in the remaining room, where wind speeds were lower and a smaller diameter turbine was installed. CONCLUSION: High room ventilation rates, meeting recommended thresholds, may be achieved using wind-driven roof turbines and grates, even at low wind speeds. Roof turbines and air-intake grates are not easily closed by staff, allowing continued ventilation through colder periods. This simple, low-cost technology represents an important addition to our tools for TB infection control. PMID- 22253743 TI - Stimulus and network dynamics collide in a ratiometric model of the antennal lobe macroglomerular complex. AB - Time is considered to be an important encoding dimension in olfaction, as neural populations generate odour-specific spatiotemporal responses to constant stimuli. However, during pheromone mediated anemotactic search insects must discriminate specific ratios of blend components from rapidly time varying input. The dynamics intrinsic to olfactory processing and those of naturalistic stimuli can therefore potentially collide, thereby confounding ratiometric information. In this paper we use a computational model of the macroglomerular complex of the insect antennal lobe to study the impact on ratiometric information of this potential collision between network and stimulus dynamics. We show that the model exhibits two different dynamical regimes depending upon the connectivity pattern between inhibitory interneurons (that we refer to as fixed point attractor and limit cycle attractor), which both generate ratio-specific trajectories in the projection neuron output population that are reminiscent of temporal patterning and periodic hyperpolarisation observed in olfactory antennal lobe neurons. We compare the performance of the two corresponding population codes for reporting ratiometric blend information to higher centres of the insect brain. Our key finding is that whilst the dynamically rich limit cycle attractor spatiotemporal code is faster and more efficient in transmitting blend information under certain conditions it is also more prone to interference between network and stimulus dynamics, thus degrading ratiometric information under naturalistic input conditions. Our results suggest that rich intrinsically generated network dynamics can provide a powerful means of encoding multidimensional stimuli with high accuracy and efficiency, but only when isolated from stimulus dynamics. This interference between temporal dynamics of the stimulus and temporal patterns of neural activity constitutes a real challenge that must be successfully solved by the nervous system when faced with naturalistic input. PMID- 22253744 TI - Inscuteable regulates the Pins-Mud spindle orientation pathway. AB - During asymmetric cell division, alignment of the mitotic spindle with the cell polarity axis ensures that the cleavage furrow separates fate determinants into distinct daughter cells. The protein Inscuteable (Insc) is thought to link cell polarity and spindle positioning in diverse systems by binding the polarity protein Bazooka (Baz; aka Par-3) and the spindle orienting protein Partner of Inscuteable (Pins; mPins or LGN in mammals). Here we investigate the mechanism of spindle orientation by the Insc-Pins complex. Previously, we defined two Pins spindle orientation pathways: a complex with Mushroom body defect (Mud; NuMA in mammals) is required for full activity, whereas binding to Discs large (Dlg) is sufficient for partial activity. In the current study, we have examined the role of Inscuteable in mediating downstream Pins-mediated spindle orientation pathways. We find that the Insc-Pins complex requires Galphai for partial activity and that the complex specifically recruits Dlg but not Mud. In vitro competition experiments revealed that Insc and Mud compete for binding to the Pins TPR motifs, while Dlg can form a ternary complex with Insc-Pins. Our results suggest that Insc does not passively couple polarity and spindle orientation but preferentially inhibits the Mud pathway, while allowing the Dlg pathway to remain active. Insc-regulated complex assembly may ensure that the spindle is attached to the cortex (via Dlg) before activation of spindle pulling forces by Dynein/Dynactin (via Mud). PMID- 22253745 TI - Measures of association for identifying microRNA-mRNA pairs of biological interest. AB - MicroRNAs are a class of small non-protein coding RNAs that play an important role in the regulation of gene expression. Most studies on the identification of microRNA-mRNA pairs utilize the correlation coefficient as a measure of association. The use of correlation coefficient is appropriate if the expression data are available for several conditions and, for a given condition, both microRNA and mRNA expression profiles are obtained from the same set of individuals. However, there are many instances where one of the requirements is not satisfied. Therefore, there is a need for new measures of association to identify the microRNA-mRNA pairs of interest and we present two such measures. The first measure requires expression data for multiple conditions but, for a given condition, the microRNA and mRNA expression may be obtained from different individuals. The new measure, unlike the correlation coefficient, is suitable for analyzing large data sets which are obtained by combining several independent studies on microRNAs and mRNAs. Our second measure is able to handle expression data that correspond to just two conditions but, for a given condition, the microRNA and mRNA expression must be obtained from the same set of individuals. This measure, unlike the correlation coefficient, is appropriate for analyzing data sets with a small number of conditions. We apply our new measures of association to multiple myeloma data sets, which cannot be analyzed using the correlation coefficient, and identify several microRNA-mRNA pairs involved in apoptosis and cell proliferation. PMID- 22253746 TI - An MMP13-selective inhibitor delays primary tumor growth and the onset of tumor associated osteolytic lesions in experimental models of breast cancer. AB - We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2 methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis. PMID- 22253747 TI - Evidence for diffuse central retinal edema in vivo in diabetic male Sprague Dawley rats. AB - BACKGROUND: Investigations into the mechanism of diffuse retinal edema in diabetic subjects have been limited by a lack of animal models and techniques that co-localized retinal thickness and hydration in vivo. In this study we test the hypothesis that a previously reported supernormal central retinal thickness on MRI measured in experimental diabetic retinopathy in vivo represents a persistent and diffuse edema. METHODOLOGY/PRINCIPAL FINDINGS: In diabetic and age matched control rats, and in rats experiencing dilutional hyponatremia (as a positive edema control), whole central retinal thickness, intraretinal water content and apparent diffusion coefficients (ADC, 'water mobility') were measured in vivo using quantitative MRI methods. Glycated hemoglobin and retinal thickness ex vivo (histology) were also measured in control and diabetic groups. In the dilutional hyponatremia model, central retinal thickness and water content were supernormal by quantitative MRI, and intraretinal water mobility profiles changed in a manner consistent with intracellular edema. Groups of diabetic (2, 3, 4, 6, and 9 mo of diabetes), and age-matched controls were then investigated with MRI and all diabetic rats showed supernormal whole central retinal thickness. In a separate study in 4 mo diabetic rats (and controls), MRI retinal thickness and water content metrics were significantly greater than normal, and ADC was subnormal in the outer retina; the increase in retinal thickness was not detected histologically on sections of fixed and dehydrated retinas from these rats. CONCLUSIONS/SIGNIFICANCE: Diabetic male Sprague Dawley rats demonstrate a persistent and diffuse retinal edema in vivo, providing, for the first time, an important model for investigating its pathogenesis and treatment. These studies also validate MRI as a powerful approach for investigating mechanisms of diabetic retinal edema in future experimental and clinical investigations. PMID- 22253748 TI - The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. AB - GNAQ mutations at codon 209 have been recently identified in approximately 50% of uveal melanomas (UM) and are reported to be oncogenic through activating the MAPK/Erk1/2 pathway. Protein kinase C (PKC) is a component of signaling from GNAQ to Erk1/2. Inhibition of PKC might regulate GNAQ mutation-induced Erk1/2 activation, resulting in growth inhibition of UM cells carrying GNAQ mutations. UM cells carrying wild type or mutant GNAQ were treated with the PKC inhibitor enzastaurin. Effects on proliferation, apoptosis, and signaling events were evaluated. Enzastaurin downregulated the expression of several PKC isoforms including PKCbetaII PKCtheta, PKCepsilon and/or their phosphorylation in GNAQ mutated cells. Downregulation of these PKC isoforms in GNAQ mutated cells by shRNA resulted in reduced viability. Enzastaurin exhibited greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis. Enzastaurin-induced G1 arrest was associated with inhibition of Erk1/2 phosphorylation, downregulation of cyclin D1, and accumulation of cyclin dependent kinase inhibitor p27(Kip1). Furthermore, enzastaurin reduced the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells. Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27(Kip1) accumulation and/or inhibition of enzastaurin-induced survivin and Bcl 2 upregulation. PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis. Inhibition of the PKC pathway provides a basis for clinical investigation in patients with UM. PMID- 22253749 TI - Uterine dysfunction in biglycan and decorin deficient mice leads to dystocia during parturition. AB - Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, we assessed wild type, biglycan, decorin and double knockout pregnancies for timing of birth and uterine function. Uteri were harvested at embryonic days 12, 15 and 18. Nonpregnant uterine samples of the same genotypes were assessed for tissue failure rate and spontaneous and oxytocin-induced contractility. We discovered that biglycan/decorin mixed double-knockout dams displayed dystocia, were at increased risk of delayed labor onset, and showed increased tissue failure in a predominantly decorin-dependent manner. In vitro spontaneous uterine contractile amplitude and oxytocin-induced contractile force were decreased in all biglycan and decorin knockout genotypes compared to wild-type. Notably, we found no significant compensation between biglycan and decorin using quantitative real time PCR or immunohistochemistry. We conclude that the biglycan/decorin mixed double knockout mouse is a model of dystocia and delayed labor onset. Moreover, decorin is necessary for uterine function in a dose-dependent manner, while biglycan exhibits partial compensatory mechanisms in vivo. Thus, this model is poised for use as a model for testing novel targets for preventive or therapeutic manipulation of uterine dysfunction. PMID- 22253750 TI - Association analysis of 94 candidate genes and schizophrenia-related endophenotypes. AB - While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis. PMID- 22253751 TI - An educational and physical program to reduce headache, neck/shoulder pain in a working community: a cluster-randomized controlled trial. AB - BACKGROUND: Noninvasive physical management is often prescribed for headache and neck pain. Systematic reviews, however, indicate that the evidence of its efficacy is limited. Our aim was to evaluate the effectiveness of a workplace educational and physical program in reducing headache and neck/shoulder pain. METHODOLOGY/PRINCIPAL FINDINGS: Cluster-randomized controlled trial. All municipal workers of the City of Turin, Italy, were invited to participate. Those who agreed were randomly assigned, according to their departments, to the intervention group (IG) or to the control group and were given diaries for the daily recording of pain episodes for 1 month (baseline). Subsequently, only the IG (119 departments, 923 workers) began the physical and educational program, whereas the control group (117 departments, 990 workers) did not receive any intervention. All participants were again given diaries for the daily recording of pain episodes after 6 months of intervention. The primary outcome was the change in the frequency of headache (expressed as the proportion of subjects with a >=50% reduction of frequency; responder rate); among the secondary outcomes there were the absolute reduction of the number of days per month with headache and neck/shoulder pain. Differences between the two groups were evaluated using mixed-effect regression models. The IG showed a higher responder rate [risk ratio, 95% confidence interval (CI)] for headache (1.58; 1.28 to 1.92) and for neck/shoulder pain (1.53; 1.27 to 1.82), and a larger reduction of the days per month (95% CI) with headache (-1.72; -2.40 to -1.04) and with neck/shoulder pain (-2.51; -3.56 to -1.47). CONCLUSIONS: The program effectively reduced headache and neck/shoulder pain in a large working community and appears to be easily transferable to primary-care settings. Further trials are needed to investigate the program effectiveness in a clinical setting, for highly selected patients suffering from specific headache types. TRIAL REGISTRATION: ClinicalTrials.gov NCT00551980. PMID- 22253752 TI - Spatial modeling of vesicle transport and the cytoskeleton: the challenge of hitting the right road. AB - The membrane trafficking machinery provides a transport and sorting system for many cellular proteins. We propose a mechanistic agent-based computer simulation to integrate and test the hypothesis of vesicle transport embedded into a detailed model cell. The method tracks both the number and location of the vesicles. Thus both the stochastic properties due to the low numbers and the spatial aspects are preserved. The underlying molecular interactions that control the vesicle actions are included in a multi-scale manner based on the model of Heinrich and Rapoport (2005). By adding motor proteins we can improve the recycling process of SNAREs and model cell polarization. Our model also predicts that coat molecules should have a high turnover at the compartment membranes, while the turnover of motor proteins has to be slow. The modular structure of the underlying model keeps it tractable despite the overall complexity of the vesicle system. We apply our model to receptor-mediated endocytosis and show how a polarized cytoskeleton structure leads to polarized distributions in the plasma membrane both of SNAREs and the Ste2p receptor in yeast. In addition, we can couple signal transduction and membrane trafficking steps in one simulation, which enables analyzing the effect of receptor-mediated endocytosis on signaling. PMID- 22253753 TI - Intestinal absorption and first-pass metabolism of polyphenol compounds in rat and their transport dynamics in Caco-2 cells. AB - BACKGROUND: Polyphenols, a group of complex naturally occurring compounds, are widely distributed throughout the plant kingdom and are therefore readily consumed by humans. The relationship between their chemical structure and intestinal absorption, transport, and first-pass metabolism remains unresolved, however. METHODS: Here, we investigated the intestinal absorption and first-pass metabolism of four polyphenol compounds, apigenin, resveratrol, emodin and chrysophanol, using the in vitro Caco-2 cell monolayer model system and in situ intestinal perfusion and in vivo pharmacokinetic studies in rats, so as to better understand the relationship between the chemical structure and biological fate of the dietary polyphenols. CONCLUSION: After oral administration, emodin and chrysophanol exhibited different absorptive and metabolic behaviours compared to apigenin and resveratrol. The differences in their chemical structures presumably resulted in differing affinities for drug-metabolizing enzymes, such as glucuronidase and sulphatase, and transporters, such as MRP2, SGLT1, and P glycoprotein, which are found in intestinal epithelial cells. PMID- 22253754 TI - Dual effect of beta-amyloid on alpha7 and alpha4beta2 nicotinic receptors controlling the release of glutamate, aspartate and GABA in rat hippocampus. AB - BACKGROUND: We previously showed that beta-amyloid (Abeta), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Abeta (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, alpha4beta2 and alpha7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. METHODOLOGY/FINDINGS: WE USED A DUAL APPROACH: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Abeta considered (10 uM in vivo and 100 nM in vitro). In vivo administration of 100 nM Abeta (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Abeta and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (alpha7 and alpha4beta2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Abeta concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Abeta concentrations (1 nM and 100 pM) selectively acted on alpha7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA. CONCLUSIONS/SIGNIFICANCE: The results reinforce the concept that Abeta has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used. PMID- 22253755 TI - Application of high-resolution DNA melting for genotyping in lepidopteran non model species: Ostrinia furnacalis (Crambidae). AB - Development of an ideal marker system facilitates a better understanding of the genetic diversity in lepidopteran non-model organisms, which have abundant species, but relatively limited genomic resources. Single nucleotide polymorphisms (SNPs) discovered within single-copy genes have proved to be desired markers, but SNP genotyping by current techniques remain laborious and expensive. High resolution melting (HRM) curve analysis represents a simple, rapid and inexpensive genotyping method that is primarily confined to clinical and diagnostic studies. In this study, we evaluated the potential of HRM analysis for SNP genotyping in the lepidopteran non-model species Ostrinia furnacalis (Crambidae). Small amplicon and unlabeled probe assays were developed for the SNPs, which were identified in 30 females of O. furnacalis from 3 different populations by our direct sequencing. Both assays were then applied to genotype 90 unknown female DNA by prior mixing with known wild-type DNA. The genotyping results were compared with those that were obtained using bi-directional sequencing analysis. Our results demonstrated the efficiency and reliability of the HRM assays. HRM has the potential to provide simple, cost-effective genotyping assays and facilitates genotyping studies in any non-model lepidopteran species of interest. PMID- 22253756 TI - Reduction of mitoferrin results in abnormal development and extended lifespan in Caenorhabditis elegans. AB - Iron is essential for organisms. It is mainly utilized in mitochondria for biosynthesis of iron-sulfur clusters, hemes and other cofactors. Mitoferrin 1 and mitoferrin 2, two homologues proteins belonging to the mitochondrial solute carrier family, are required for iron delivery into mitochondria. Mitoferrin 1 is highly expressed in developing erythrocytes which consume a large amount of iron during hemoglobinization. Mitoferrin 2 is ubiquitously expressed, whose functions are less known. Zebrafish with mitoferrin 1 mutation show profound hypochromic anaemia and erythroid maturation arrests, and yeast with defects in MRS3/4, the counterparts of mitoferrin 1/2, has low mitochondrial iron levels and grows poorly by iron depletion. Mitoferrin 1 expression is up-regulated in yeast and mouse models of Fiedreich's ataxia disease and in human cell culture models of Parkinson disease, suggesting its involvement in the pathogenesis of diseases with mitochondrial iron accumulation. In this study we found that reduced mitoferrin levels in C. elegans by RNAi treatment causes pleiotropic phenotypes such as small body size, reduced fecundity, slow movement and increased sensitivity to paraquat. Despite these abnormities, lifespan was increased by 50% to 80% in N2 wild type strain, and in further studies using the RNAi sensitive strain eri-1, more than doubled lifespan was observed. The pathways or mechanisms responsible for the lifespan extension and other phenotypes of mitoferrin RNAi worms are worth further study, which may contribute to our understanding of aging mechanisms and the pathogenesis of iron disorder related diseases. PMID- 22253757 TI - A new approach for assessment of mental architecture: repeated tagging. AB - A new approach to the study of a relatively neglected property of mental architecture-whether and when the already-processed elements are separated from the to-be-processed elements-is proposed. The process of numerical proportion discrimination between two sets of elements defined either by color or by orientation can be described as sampling with or without replacement (characterized by binomial or hypergeometric probability distributions respectively) depending on the possibility to tag an element once or repeatedly. All empirical psychometric functions were approximated by a theoretical model showing that the ability to keep track of the already tagged elements is not an inflexible part of the mental architecture but rather an individually variable strategy which also depends on conspicuity of perceptual attributes. Strong evidence is provided that in a considerable number of trials, observers tagged the same element repeatedly which can only be done serially at two separate time moments. PMID- 22253758 TI - Brain training game improves executive functions and processing speed in the elderly: a randomized controlled trial. AB - BACKGROUND: The beneficial effects of brain training games are expected to transfer to other cognitive functions, but these beneficial effects are poorly understood. Here we investigate the impact of the brain training game (Brain Age) on cognitive functions in the elderly. METHODS AND RESULTS: Thirty-two elderly volunteers were recruited through an advertisement in the local newspaper and randomly assigned to either of two game groups (Brain Age, Tetris). This study was completed by 14 of the 16 members in the Brain Age group and 14 of the 16 members in the Tetris group. To maximize the benefit of the interventions, all participants were non-gamers who reported playing less than one hour of video games per week over the past 2 years. Participants in both the Brain Age and the Tetris groups played their game for about 15 minutes per day, at least 5 days per week, for 4 weeks. Each group played for a total of about 20 days. Measures of the cognitive functions were conducted before and after training. Measures of the cognitive functions fell into four categories (global cognitive status, executive functions, attention, and processing speed). Results showed that the effects of the brain training game were transferred to executive functions and to processing speed. However, the brain training game showed no transfer effect on any global cognitive status nor attention. CONCLUSIONS: Our results showed that playing Brain Age for 4 weeks could lead to improve cognitive functions (executive functions and processing speed) in the elderly. This result indicated that there is a possibility which the elderly could improve executive functions and processing speed in short term training. The results need replication in large samples. Long-term effects and relevance for every-day functioning remain uncertain as yet. TRIAL REGISTRATION: UMIN Clinical Trial Registry 000002825. PMID- 22253759 TI - CD14 deficiency impacts glucose homeostasis in mice through altered adrenal tone. AB - The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS), may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis. PMID- 22253760 TI - SDS can be utilized as an amyloid inducer: a case study on diverse proteins. AB - Sodium dodecyl sulphate (SDS), an anionic surfactant that mimics some characteristics of biological membrane has also been found to induce aggregation in proteins. The present study was carried out on 25 diverse proteins using circular dichroism, fluorescence spectroscopy, dye binding assay and electron microscopy. It was found that an appropriate molar ratio of protein to SDS readily induced amyloid formation in all proteins at a pH below two units of their respective isoelectric points (pI) while no aggregation was observed at a pH above two units of pI. We also observed that electrostatic interactions play a leading role in the induction of amyloid. This study can be used to design or hypothesize a molecule or drug, which may counter act the factor responsible for amyloid formation. PMID- 22253761 TI - Broad phylogenomic sampling and the sister lineage of land plants. AB - The tremendous diversity of land plants all descended from a single charophyte green alga that colonized the land somewhere between 430 and 470 million years ago. Six orders of charophyte green algae, in addition to embryophytes, comprise the Streptophyta s.l. Previous studies have focused on reconstructing the phylogeny of organisms tied to this key colonization event, but wildly conflicting results have sparked a contentious debate over which lineage gave rise to land plants. The dominant view has been that 'stoneworts,' or Charales, are the sister lineage, but an alternative hypothesis supports the Zygnematales (often referred to as "pond scum") as the sister lineage. In this paper, we provide a well-supported, 160-nuclear-gene phylogenomic analysis supporting the Zygnematales as the closest living relative to land plants. Our study makes two key contributions to the field: 1) the use of an unbiased method to collect a large set of orthologs from deeply diverging species and 2) the use of these data in determining the sister lineage to land plants. We anticipate this updated phylogeny not only will hugely impact lesson plans in introductory biology courses, but also will provide a solid phylogenetic tree for future green-lineage research, whether it be related to plants or green algae. PMID- 22253762 TI - You look familiar: how Malaysian Chinese recognize faces. AB - East Asian and white Western observers employ different eye movement strategies for a variety of visual processing tasks, including face processing. Recent eye tracking studies on face recognition found that East Asians tend to integrate information holistically by focusing on the nose while white Westerners perceive faces featurally by moving between the eyes and mouth. The current study examines the eye movement strategy that Malaysian Chinese participants employ when recognizing East Asian, white Western, and African faces. Rather than adopting the Eastern or Western fixation pattern, Malaysian Chinese participants use a mixed strategy by focusing on the eyes and nose more than the mouth. The combination of Eastern and Western strategies proved advantageous in participants' ability to recognize East Asian and white Western faces, suggesting that individuals learn to use fixation patterns that are optimized for recognizing the faces with which they are more familiar. PMID- 22253763 TI - Predicted disappearance of Cephalantheropsis obcordata in Luofu Mountain due to changes in rainfall patterns. AB - BACKGROUND: In the past century, the global average temperature has increased by approximately 0.74 degrees C and extreme weather events have become prevalent. Recent studies have shown that species have shifted from high-elevation areas to low ones because the rise in temperature has increased rainfall. These outcomes challenge the existing hypothesis about the responses of species to climate change. METHODOLOGY/PRINCIPAL FINDINGS: With the use of data on the biological characteristics and reproductive behavior of Cephalantheropsis obcordata in Luofu Mountain, Guangdong, China, trends in the population size of the species were predicted based on several factors. The response of C. obcordata to climate change was verified by integrating it with analytical findings on meteorological data and an artificially simulated environment of water change. The results showed that C. obcordata can grow only in waterlogged streams. The species can produce fruit with many seeds by insect pollination; however, very few seeds can burgeon to become seedlings, with most of those seedlings not maturing into the sexually reproductive phase, and grass plants will die after reproduction. The current population's age pyramid is kettle-shaped; it has a Deevey type I survival curve; and its net reproductive rate, intrinsic rate of increase, as well as finite rate of increase are all very low. The population used in the artificial simulation perished due to seasonal drought. CONCLUSIONS: The change in rainfall patterns caused by climate warming has altered the water environment of C. obcordata in Luofu Mountain, thereby restricting seed burgeoning as well as seedling growth and shortening the life span of the plant. The growth rate of the C. obcordata population is in descending order, and models of population trend predict that the population in Luofu Mountain will disappear in 23 years. PMID- 22253764 TI - Network structure and city size. AB - Network structure varies across cities. This variation may yield important knowledge about how the internal structure of the city affects its performance. This paper systematically compares a set of surface transportation network structure variables (connectivity, hierarchy, circuity, treeness, entropy, accessibility) across the 50 largest metropolitan areas in the United States. A set of scaling parameters are discovered to show how network size and structure vary with city size. These results suggest that larger cities are physically more inter-connected. Hypotheses are presented as to why this might obtain. This paper then consistently measures and ranks access to jobs across 50 US metropolitan areas. It uses that accessibility measure, along with network structure variables and city size to help explain journey-to-work time and auto mode share in those cities. A 1 percent increase in accessibility reduces average metropolitan commute times by about 90 seconds each way. A 1 percent increase in network connectivity reduces commute time by 0.1 percent. A 1 percent increase in accessibility results in a 0.0575 percent drop in auto mode share, while a 1 percent increase in treeness reduces auto mode share by 0.061 percent. Use of accessibility and network structure measures is important for planning and evaluating the performance of network investments and land use changes. PMID- 22253765 TI - Distinct expression/function of potassium and chloride channels contributes to the diverse volume regulation in cortical astrocytes of GFAP/EGFP mice. AB - Recently, we have identified two astrocytic subpopulations in the cortex of GFAP EGFP mice, in which the astrocytes are visualized by the enhanced green fluorescent protein (EGFP) under the control of the human glial fibrillary acidic protein (GFAP) promotor. These astrocytic subpopulations, termed high response- (HR-) and low response- (LR-) astrocytes, differed in the extent of their swelling during oxygen-glucose deprivation (OGD). In the present study we focused on identifying the ion channels or transporters that might underlie the different capabilities of these two astrocytic subpopulations to regulate their volume during OGD. Using three-dimensional confocal morphometry, which enables quantification of the total astrocytic volume, the effects of selected inhibitors of K+ and Cl- channels/transporters or glutamate transporters on astrocyte volume changes were determined during 20 minute-OGD in situ. The inhibition of volume regulated anion channels (VRACs) and two-pore domain potassium channels (K(2P)) highlighted their distinct contributions to volume regulation in HR-/LR astrocytes. While the inhibition of VRACs or K(2P) channels revealed their contribution to the swelling of HR-astrocytes, in LR-astrocytes they were both involved in anion/K+ effluxes. Additionally, the inhibition of Na+-K+-Cl- co transporters in HR-astrocytes led to a reduction of cell swelling, but it had no effect on LR-astrocyte volume. Moreover, employing real-time single-cell quantitative polymerase chain reaction (PCR), we characterized the expression profiles of EGFP-positive astrocytes with a focus on those ion channels and transporters participating in astrocyte swelling and volume regulation. The PCR data revealed the existence of two astrocytic subpopulations markedly differing in their gene expression levels for inwardly rectifying K+ channels (Kir4.1), K(2P) channels (TREK-1 and TWIK-1) and Cl- channels (ClC2). Thus, we propose that the diverse volume changes displayed by cortical astrocytes during OGD mainly result from their distinct expression patterns of ClC2 and K(2P) channels. PMID- 22253766 TI - HSPG-deficient zebrafish uncovers dental aspect of multiple osteochondromas. AB - Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2-/- fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2-/- fish. Histological analysis reveals that ext2-/- fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2-/- fish have a single tooth at the end of the 5(th) pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2-/- teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2+/- adults. The tooth morphology in ext2-/- was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems. PMID- 22253768 TI - Color-to-grayscale: does the method matter in image recognition? AB - In image recognition it is often assumed the method used to convert color images to grayscale has little impact on recognition performance. We compare thirteen different grayscale algorithms with four types of image descriptors and demonstrate that this assumption is wrong: not all color-to-grayscale algorithms work equally well, even when using descriptors that are robust to changes in illumination. These methods are tested using a modern descriptor-based image recognition framework, on face, object, and texture datasets, with relatively few training instances. We identify a simple method that generally works best for face and object recognition, and two that work well for recognizing textures. PMID- 22253767 TI - Regulation of asymmetrical cytokinesis by cAMP during meiosis I in mouse oocytes. AB - Mammalian oocytes undergo an asymmetrical first meiotic division, extruding half of their chromosomes in a small polar body to preserve maternal resources for embryonic development. To divide asymmetrically, mammalian oocytes relocate chromosomes from the center of the cell to the cortex, but little is known about the underlying mechanisms. Here, we show that upon the elevation of intracellular cAMP level, mouse oocytes produced two daughter cells with similar sizes. This symmetrical cell division could be rescued by the inhibition of PKA, a cAMP dependent protein kinase. Live cell imaging revealed that a symmetrically localized cleavage furrow resulted in symmetrical cell division. Detailed analyses demonstrated that symmetrically localized cleavage furrows were caused by the inappropriate central positioning of chromosome clusters at anaphase onset, indicating that chromosome cluster migration was impaired. Notably, high intracellular cAMP reduced myosin II activity, and the microinjection of phospho myosin II antibody into the oocytes impeded chromosome migration and promoted symmetrical cell division. Our results support the hypothesis that cAMP plays a role in regulating asymmetrical cell division by modulating myosin II activity during mouse oocyte meiosis I, providing a novel insight into the regulation of female gamete formation in mammals. PMID- 22253769 TI - Changes in humpback whale song occurrence in response to an acoustic source 200 km away. AB - The effect of underwater anthropogenic sound on marine mammals is of increasing concern. Here we show that humpback whale (Megaptera novaeangliae) song in the Stellwagen Bank National Marine Sanctuary (SBNMS) was reduced, concurrent with transmissions of an Ocean Acoustic Waveguide Remote Sensing (OAWRS) experiment approximately 200 km away. We detected the OAWRS experiment in SBNMS during an 11 day period in autumn 2006. We compared the occurrence of song for 11 days before, during and after the experiment with song over the same 33 calendar days in two later years. Using a quasi-Poisson generalized linear model (GLM), we demonstrate a significant difference in the number of minutes with detected song between periods and years. The lack of humpback whale song during the OAWRS experiment was the most substantial signal in the data. Our findings demonstrate the greatest published distance over which anthropogenic sound has been shown to affect vocalizing baleen whales, and the first time that active acoustic fisheries technology has been shown to have this effect. The suitability of Ocean Acoustic Waveguide Remote Sensing technology for in-situ, long term monitoring of marine ecosystems should be considered, bearing in mind its possible effects on non-target species, in particular protected species. PMID- 22253770 TI - Sexual risk behaviours and sexual abuse in persons with severe mental illness in Uganda: a qualitative study. AB - Persons with severe mental illness (SMI) engage in risky sexual behaviours and have high prevalence of HIV in high-income countries. Little is known about sexual behaviours and HIV risk among persons with SMI in sub-Saharan Africa. In this qualitative study we explored how SMI may influence sexual risk behaviours and sexual health risks in Uganda. Individual semi-structured interviews were conducted with 7 male and 13 female psychiatric patients aged 18-49 years. Participants were interviewed in hospital when clinically stable and capable of giving informed consent. Interview transcripts were analysed using manifest content analysis, generating the categories: (1) casual sex during illness episodes, (2) rape by non-partners, (3) exploitation by partners, (4) non monogamous partners, and (5) sexual inactivity. Our findings suggest that SMI exacerbated sexual vulnerability in the women interviewed, by contributing to casual sex, to exploitative and non-monogamous sexual relationships, and to sexual assault by non-partners. No link could be established between SMI and increased sexual risk behaviours in the men interviewed, due to a small sample of men, and given that men's accounts showed little variability. Our findings also suggest that SMI caused sexual inactivity due to decreased sexual desire, and in men, due to difficulties forming an intimate relationship. Overall, our study highlights how SMI and gender inequality can contribute to the shaping of sexual risk behaviours and sexual health risks, including HIV risk, among persons with SMI in this Ugandan setting. PMID- 22253771 TI - Postnatal changes in the expression pattern of the imprinted signalling protein XLalphas underlie the changing phenotype of deficient mice. AB - The alternatively spliced trimeric G-protein subunit XLalphas, which is involved in cAMP signalling, is encoded by the Gnasxl transcript of the imprinted Gnas locus. XLalphas deficient mice show neonatal feeding problems, leanness, inertia and a high mortality rate. Mutants that survive to weaning age develop into healthy and fertile adults, which remain lean despite elevated food intake. The adult metabolic phenotype can be attributed to increased energy expenditure, which appears to be caused by elevated sympathetic nervous system activity. To better understand the changing phenotype of Gnasxl deficient mice, we compared XLalphas expression in neonatal versus adult tissues, analysed its co localisation with neural markers and characterised changes in the nutrient sensing mTOR1-S6K pathway in the hypothalamus. Using a newly generated conditional Gnasxl lacZ gene trap line and immunohistochemistry we identified various types of muscle, including smooth muscle cells of blood vessels, as the major peripheral sites of expression in neonates. Expression in all muscle tissues was silenced in adults. While Gnasxl expression in the central nervous system was also developmentally silenced in some midbrain nuclei, it was upregulated in the preoptic area, the medial amygdala, several hypothalamic nuclei (e.g. arcuate, dorsomedial, lateral and paraventricular nuclei) and the nucleus of the solitary tract. Furthermore, expression was detected in the ventral medulla as well as in motoneurons and a subset of sympathetic preganglionic neurons of the spinal cord. In the arcuate nucleus of Gnasxl deficient mice we found reduced activity of the nutrient sensing mTOR1-S6K signalling pathway, which concurs with their metabolic status. The expression in these brain regions and the hypermetabolic phenotype of adult Gnasxl-deficient mice imply an inhibitory function of XLalphas in energy expenditure and sympathetic outflow. By contrast, the neonatal phenotype of mutant mice appears to be due to a transient role of XLalphas in muscle tissues. PMID- 22253772 TI - Eccentric exercise facilitates mesenchymal stem cell appearance in skeletal muscle. AB - Eccentric, or lengthening, contractions result in injury and subsequently stimulate the activation and proliferation of satellite stem cells which are important for skeletal muscle regeneration. The discovery of alternative myogenic progenitors in skeletal muscle raises the question as to whether stem cells other than satellite cells accumulate in muscle in response to exercise and contribute to post-exercise repair and/or growth. In this study, stem cell antigen-1 (Sca-1) positive, non-hematopoetic (CD45-) cells were evaluated in wild type (WT) and alpha7 integrin transgenic (alpha7Tg) mouse muscle, which is resistant to injury yet liable to strain, 24 hr following a single bout of eccentric exercise. Sca 1+CD45- stem cells were increased 2-fold in WT muscle post-exercise. The alpha7 integrin regulated the presence of Sca-1+ cells, with expansion occurring in alpha7Tg muscle and minimal cells present in muscle lacking the alpha7 integrin. Sca-1+CD45- cells isolated from alpha7Tg muscle following exercise were characterized as mesenchymal-like stem cells (mMSCs), predominantly pericytes. In vitro multiaxial strain upregulated mMSC stem cells markers in the presence of laminin, but not gelatin, identifying a potential mechanistic basis for the accumulation of these cells in muscle following exercise. Transplantation of DiI labeled mMSCs into WT muscle increased Pax7+ cells and facilitated formation of eMHC+DiI- fibers. This study provides the first demonstration that mMSCs rapidly appear in skeletal muscle in an alpha7 integrin dependent manner post-exercise, revealing an early event that may be necessary for effective repair and/or growth following exercise. The results from this study also support a role for the alpha7 integrin and/or mMSCs in molecular- and cellular-based therapeutic strategies that can effectively combat disuse muscle atrophy. PMID- 22253773 TI - Deconstruction of the (paleo)polyploid grapevine genome based on the analysis of transposition events involving NBS resistance genes. AB - Plants have followed a reticulate type of evolution and taxa have frequently merged via allopolyploidization. A polyploid structure of sequenced genomes has often been proposed, but the chromosomes belonging to putative component genomes are difficult to identify. The 19 grapevine chromosomes are evolutionary stable structures: their homologous triplets have strongly conserved gene order, interrupted by rare translocations. The aim of this study is to examine how the grapevine nucleotide-binding site (NBS)-encoding resistance (NBS-R) genes have evolved in the genomic context and to understand mechanisms for the genome evolution. We show that, in grapevine, i) helitrons have significantly contributed to transposition of NBS-R genes, and ii) NBS-R gene cluster similarity indicates the existence of two groups of chromosomes (named as Va and Vc) that may have evolved independently. Chromosome triplets consist of two Va and one Vc chromosomes, as expected from the tetraploid and diploid conditions of the two component genomes. The hexaploid state could have been derived from either allopolyploidy or the separation of the Va and Vc component genomes in the same nucleus before fusion, as known for Rosaceae species. Time estimation indicates that grapevine component genomes may have fused about 60 mya, having had at least 40-60 mya to evolve independently. Chromosome number variation in the Vitaceae and related families, and the gap between the time of eudicot radiation and the age of Vitaceae fossils, are accounted for by our hypothesis. PMID- 22253774 TI - CTNNB1 signaling in sertoli cells downregulates spermatogonial stem cell activity via WNT4. AB - Constitutive activation of the WNT signaling effector CTNNB1 (beta-catenin) in the Sertoli cells of the Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) mouse model results in progressive germ cell loss and sterility. In this study, we sought to determine if this phenotype could be due to a loss of spermatogonial stem cell (SSC) activity. Reciprocal SSC transplants between Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) and wild-type mice showed that SSC activity is lost in Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) testes over time, whereas the mutant testes could not support colonization by wild-type SSCs. Microarray analyses performed on cultured Sertoli cells showed that CTNNB1 induces the expression of genes associated with the female sex determination pathway, which was also found to occur in Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) testes. One CTNNB1 target gene encoded the secreted signaling molecule WNT4. We therefore tested the effects of WNT4 on SSC-enriched germ cell cultures, and found that WNT4 induced cell death and reduced SSC activity without affecting cell cycle. Conversely, conditional inactivation of Wnt4 in the Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) model rescued spermatogenesis and male fertility, indicating that WNT4 is the major effector downstream of CTNNB1 responsible for germ cell loss. Furthermore, WNT4 was found to signal via the CTNNB1 pathway in Sertoli cells, suggesting a self-reinforcing positive feedback loop. Collectively, these data indicate for the first time that ectopic activation of a signaling cascade in the stem cell niche depletes SSC activity through a paracrine factor. These findings may provide insight into the pathogenesis of male infertility, as well as embryonic gonadal development. PMID- 22253775 TI - Transcription factor STOX1A promotes mitotic entry by binding to the CCNB1 promotor. AB - BACKGROUND: In this study we investigated the involvement of the transcription factor STOX1A in the regulation of the cell cycle. METHODOLOGY/PRINCIPAL FINDINGS: We found that several major cell cycle regulatory genes were differentially expressed upon STOX1A stimulation and knockdown in the neuroblastoma cell line SH-SY5Y. This includes STOX1A dependent differential regulation of cyclin B1 expression, a cyclin which is known to regulate mitotic entry during the cell cycle. The differential regulation of cyclin B1 expression by STOX1A is direct as shown with chromatin immunoprecipitation. Results furthermore suggest that mitotic entry is enhanced through the direct upregulation of cyclin B1 expression effectuated by STOX1A. CONCLUSIONS: In conclusion we hereby show that STOX1A is directly involved in the regulation of the cell cycle. PMID- 22253776 TI - Autoluminescent Mycobacterium tuberculosis for rapid, real-time, non-invasive assessment of drug and vaccine efficacy. AB - Preclinical efforts to discover and develop new drugs and vaccines for tuberculosis are hampered by the reliance on colony-forming unit (CFU) counts as primary outcomes for in vivo efficacy studies and the slow growth of Mycobacterium tuberculosis. The utility of bioluminescent M. tuberculosis reporter strains for real-time in vitro and ex vivo assessment of drug and vaccine activity has been demonstrated but a simple, non-invasive, real-time surrogate marker to replace CFU counts for real-time evaluation of drug and vaccine efficacy in vivo has not been described. We describe the development of a fully virulent and stable autoluminescent strain of M. tuberculosis and proof-of concept experiments demonstrating its utility for in vivo bioluminescence imaging to assess the efficacy of new drugs and vaccines for tuberculosis in a mouse model. Relative light unit (RLU) counts paralleled CFU counts during the active phase of bacterial growth, with a lower limit of detection of approximately 10(6) CFU in live, anesthetized mice. Experiments distinguishing active from inactive anti-tuberculosis drugs and bacteriostatic drug effects from bactericidal effects were completed in less than 5 days. The ability of a recombinant BCG vaccine to limit bacterial growth was demonstrated within 3 weeks. Use of this autoluminescent reporter strain has the potential to drastically reduce the time, effort, animals and costs consumed in the evaluation of drug activity in vitro and the in vivo assessment of drug and vaccine efficacy. PMID- 22253777 TI - Health related quality of life among patients with tuberculosis and HIV in Thailand. AB - INTRODUCTION: Health utilities of tuberculosis (TB) patients may be diminished by side effects from medication, prolonged treatment duration, physical effects of the disease itself, and social stigma attached to the disease. METHODS: We collected health utility data from Thai patients who were on TB treatment or had been successfully treated for TB for the purpose of economic modeling. Structured questionnaire and EuroQol (EQ-5D) and EuroQol visual analog scale (EQ-VAS) instruments were used as data collection tools. We compared utility of patients with two co-morbidities calculated using multiplicative model (U(CAL)) with the direct measures and fitted Tobit regression models to examine factors predictive of health utility and to assess difference in health utilities of patients in various medical conditions. RESULTS: Of 222 patients analyzed, 138 (62%) were male; median age at enrollment was 40 years (interquartile range [IQR], 35-47). Median monthly household income was 6,000 Baht (187 US$; IQR, 4,000-15,000 Baht [125-469 US$]). Concordance correlation coefficient between utilities measured using EQ-5D and EQ-VAS (U(EQ-5D) and U(VAS), respectively) was 0.6. U(CAL) for HIV-infected TB patients was statistically different from the measured U(EQ-5D) (p-value<0.01) and U(VAS) (p-value<0.01). In tobit regression analysis, factors independently predictive of U(EQ-5D) included age and monthly household income. Patients aged >=40 years old rated U(EQ-5D) significantly lower than younger persons. Higher U(EQ-5D) was significantly associated with higher monthly household income in a dose response fashion. The median U(EQ-5D) was highest among patients who had been successfully treated for TB and lowest among multi drug resistant TB (MDR-TB) patients who were on treatment. CONCLUSIONS: U(CAL) of patients with two co-morbidities overestimated the measured utilities, warranting further research of how best to estimate utilities of patients with such conditions. TB and MDR-TB treatments impacted on patients' self perceived health status. This effect diminished after successful treatment. PMID- 22253778 TI - Incidence and correlates of HIV-1 RNA detection in the breast milk of women receiving HAART for the prevention of HIV-1 transmission. AB - BACKGROUND: The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission. METHODS: Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2-5 days during 1 month postpartum for measurements of cell associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection. RESULTS: Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97-1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log(10) copies/ml (range 2.0-3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/10(6) cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8-44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5-56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54-1.7). CONCLUSIONS: The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA. PMID- 22253779 TI - Impact of the genome wide supported NRGN gene on anterior cingulate morphology in schizophrenia. AB - BACKGROUND: The rs12807809 single-nucleotide polymorphism in NRGN is a genetic risk variant with genome-wide significance for schizophrenia. The frequency of the T allele of rs12807809 is higher in individuals with schizophrenia than in those without the disorder. Reduced immunoreactivity of NRGN, which is expressed exclusively in the brain, has been observed in Brodmann areas (BA) 9 and 32 of the prefrontal cortex in postmortem brains from patients with schizophrenia compared with those in controls. METHODS: Genotype effects of rs12807809 were investigated on gray matter (GM) and white matter (WM) volumes using magnetic resonance imaging (MRI) with a voxel-based morphometry (VBM) technique in a sample of 99 Japanese patients with schizophrenia and 263 healthy controls. RESULTS: Although significant genotype-diagnosis interaction either on GM or WM volume was not observed, there was a trend of genotype-diagnosis interaction on GM volume in the left anterior cingulate cortex (ACC). Thus, the effects of NRGN genotype on GM volume of patients with schizophrenia and healthy controls were separately investigated. In patients with schizophrenia, carriers of the risk T allele had a smaller GM volume in the left ACC (BA32) than did carriers of the non-risk C allele. Significant genotype effect on other regions of the GM or WM was not observed for either the patients or controls. CONCLUSIONS: Our findings suggest that the genome-wide associated genetic risk variant in the NRGN gene may be related to a small GM volume in the ACC in the left hemisphere in patients with schizophrenia. PMID- 22253780 TI - HCV infection among Saudi population: high prevalence of genotype 4 and increased viral clearance rate. AB - HCV is a major etiological agent of liver disease with a high rate of chronic evolution. The virus possesses 6 genotypes with many subtypes. The rate of spontaneous clearance among HCV infected individuals denotes a genetic determinant factor. The current study was designed in order to estimate the rate of HCV infection and ratio of virus clearance among a group of infected patients in Saudi Arabia from 2008 to 2011. It was additionally designed to determine the genotypes of the HCV in persistently infected patients. HCV seroprevalence was conducted on a total of 15,323 individuals. Seropositive individuals were tested by Cobas AmpliPrep/Cobas TaqMan HCV assay to determine the ratio of persistently infected patients to those who showed spontaneous viral clearance. HCV genotyping on random samples from persistently infected patients were conducted based on the differences in the 5'untranslated region (5'UTR). Anti-HCV antibodies were detected in 7.3% of the totally examined sera. A high percentage of the HCV infected individuals experienced virus clearance (48.4%). HCV genotyping revealed the presence of genotypes 1 and 4, the latter represented 97.6% of the tested strains. Evidences of the widespread of the HCV genotype 4 and a high rate of HCV virus clearance were found in Saudi Arabia. PMID- 22253781 TI - Association of coagulation activation with clinical complications in sickle cell disease. AB - BACKGROUND: The contribution of hypercoagulability to the pathophysiology of sickle cell disease (SCD) remains poorly defined. We sought to evaluate the association of markers of coagulation and platelet activation with specific clinical complications and laboratory variables in patients with SCD. DESIGN AND METHODS: Plasma markers of coagulation activation (D-dimer and TAT), platelet activation (soluble CD40 ligand), microparticle-associated tissue factor (MPTF) procoagulant activity and other laboratory variables were obtained in a cohort of patients with SCD. Tricuspid regurgitant jet velocity was determined by Doppler echocardiography and the presence/history of clinical complications was ascertained at the time of evaluation, combined with a detailed review of the medical records. RESULTS: No significant differences in the levels of D-dimer, TAT, soluble CD40 ligand, and MPTF procoagulant activity were observed between patients in the SS/SD/Sbeta0 thalassemia and SC/Sbeta+ thalassemia groups. Both TAT and D-dimer were significantly correlated with measures of hemolysis (lactate dehydrogenase, indirect bilirubin and hemoglobin) and soluble vascular cell adhesion molecule-1. In patients in the SS/SD/Sbeta0 thalassemia group, D-dimer was associated with a history of stroke (p = 0.049), TAT was associated with a history of retinopathy (p = 0.0176), and CD40 ligand was associated with the frequency of pain episodes (p = 0.039). In multivariate analyses, D-dimer was associated with reticulocyte count, lactate dehydrogenase, NT-proBNP and history of stroke; soluble CD40 ligand was associated with WBC count and platelet count; and MPTF procoagulant activity was associated with hemoglobin and history of acute chest syndrome. CONCLUSIONS: This study supports the association of coagulation activation with hemolysis in SCD. The association of D-dimer with a history of stroke suggests that coagulation activation may contribute to the pathophysiology of stroke in clinically severe forms of SCD. More research is needed to evaluate the contribution of coagulation and platelet activation to clinical complications in SCD. PMID- 22253782 TI - Development of a model system to identify differences in spring and winter oat. AB - Our long-term goal is to develop a Swedish winter oat (Avena sativa). To identify molecular differences that correlate with winter hardiness, a winter oat model comprising of both non-hardy spring lines and winter hardy lines is needed. To achieve this, we selected 294 oat breeding lines, originating from various Russian, German, and American winter oat breeding programs and tested them in the field in south- and western Sweden. By assaying for winter survival and agricultural properties during four consecutive seasons, we identified 14 breeding lines of different origins that not only survived the winter but also were agronomically better than the rest. Laboratory tests including electrolytic leakage, controlled crown freezing assay, expression analysis of the AsVrn1 gene and monitoring of flowering time suggested that the American lines had the highest freezing tolerance, although the German lines performed better in the field. Finally, six lines constituting the two most freezing tolerant lines, two intermediate lines and two spring cultivars were chosen to build a winter oat model system. Metabolic profiling of non-acclimated and cold acclimated leaf tissue samples isolated from the six selected lines revealed differential expression patterns of 245 metabolites including several sugars, amino acids, organic acids and 181 hitherto unknown metabolites. The expression patterns of 107 metabolites showed significant interactions with either a cultivar or a time point. Further identification, characterisation and validation of these metabolites will lead to an increased understanding of the cold acclimation process in oats. Furthermore, by using the winter oat model system, differential sequencing of crown mRNA populations would lead to identification of various biomarkers to facilitate winter oat breeding. PMID- 22253783 TI - The role of gamma-tubulin in centrosomal microtubule organization. AB - As part of a multi-subunit ring complex, gamma-tubulin has been shown to promote microtubule nucleation both in vitro and in vivo, and the structural properties of the complex suggest that it also seals the minus ends of the polymers with a conical cap. Cells depleted of gamma-tubulin, however, still display many microtubules that participate in mitotic spindle assembly, suggesting that gamma tubulin is not absolutely required for microtubule nucleation in vivo, and raising questions about the function of the minus end cap. Here, we assessed the role of gamma-tubulin in centrosomal microtubule organisation using three dimensional reconstructions of gamma-tubulin-depleted C. elegans embryos. We found that microtubule minus-end capping and the PCM component SPD-5 are both essential for the proper placement of microtubules in the centrosome. Our results further suggest that gamma-tubulin and SPD-5 limit microtubule polymerization within the centrosome core, and we propose a model for how abnormal microtubule organization at the centrosome could indirectly affect centriole structure and daughter centriole replication. PMID- 22253784 TI - Emergence of good conduct, scaling and zipf laws in human behavioral sequences in an online world. AB - We study behavioral action sequences of players in a massive multiplayer online game. In their virtual life players use eight basic actions which allow them to interact with each other. These actions are communication, trade, establishing or breaking friendships and enmities, attack, and punishment. We measure the probabilities for these actions conditional on previous taken and received actions and find a dramatic increase of negative behavior immediately after receiving negative actions. Similarly, positive behavior is intensified by receiving positive actions. We observe a tendency towards antipersistence in communication sequences. Classifying actions as positive (good) and negative (bad) allows us to define binary 'world lines' of lives of individuals. Positive and negative actions are persistent and occur in clusters, indicated by large scaling exponents alpha ~ 0.87 of the mean square displacement of the world lines. For all eight action types we find strong signs for high levels of repetitiveness, especially for negative actions. We partition behavioral sequences into segments of length n (behavioral 'words' and 'motifs') and study their statistical properties. We find two approximate power laws in the word ranking distribution, one with an exponent of kappa ~ -1 for the ranks up to 100, and another with a lower exponent for higher ranks. The Shannon n-tuple redundancy yields large values and increases in terms of word length, further underscoring the non-trivial statistical properties of behavioral sequences. On the collective, societal level the timeseries of particular actions per day can be understood by a simple mean-reverting log-normal model. PMID- 22253785 TI - Ecological guild evolution and the discovery of the world's smallest vertebrate. AB - Living vertebrates vary drastically in body size, yet few taxa reach the extremely minute size of some frogs and teleost fish. Here we describe two new species of diminutive terrestrial frogs from the megadiverse hotspot island of New Guinea, one of which represents the smallest known vertebrate species, attaining an average body size of only 7.7 mm. Both new species are members of the recently described genus Paedophryne, the four species of which are all among the ten smallest known frog species, making Paedophryne the most diminutive genus of anurans. This discovery highlights intriguing ecological similarities among the numerous independent origins of diminutive anurans, suggesting that minute frogs are not mere oddities, but represent a previously unrecognized ecological guild. PMID- 22253786 TI - Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. AB - Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting. PMID- 22253787 TI - Evolution of susceptibility to ingested double-stranded RNAs in Caenorhabditis nematodes. AB - BACKGROUND: The nematode Caenorhabditis elegans is able to take up external double-stranded RNAs (dsRNAs) and mount an RNA interference response, leading to the inactivation of specific gene expression. The uptake of ingested dsRNAs into intestinal cells has been shown to require the SID-2 transmembrane protein in C. elegans. By contrast, C. briggsae was shown to be naturally insensitive to ingested dsRNAs, yet could be rendered sensitive by transgenesis with the C. elegans sid-2 gene. Here we aimed to elucidate the evolution of the susceptibility to external RNAi in the Caenorhabditis genus. PRINCIPAL FINDINGS: We study the sensitivity of many new species of Caenorhabditis to ingested dsRNAs matching a conserved actin gene sequence from the nematode Oscheius tipulae. We find ample variation in the Caenorhabditis genus in the ability to mount an RNAi response. We map this sensitivity onto a phylogenetic tree, and show that sensitivity or insensitivity have evolved convergently several times. We uncover several evolutionary losses in sensitivity, which may have occurred through distinct mechanisms. We could render C. remanei and C. briggsae sensitive to ingested dsRNAs by transgenesis of the Cel-sid-2 gene. We thus provide tools for RNA interference studies in these species. We also show that transgenesis by injection is possible in many Caenorhabditis species. CONCLUSIONS: The ability of animals to take up dsRNAs or to respond to them by gene inactivation is under rapid evolution in the Caenorhabditis genus. This study provides a framework and tools to use RNA interference and transgenesis in various Caenorhabditis species for further comparative and evolutionary studies. PMID- 22253788 TI - Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations. AB - The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone. PMID- 22253789 TI - S100A9 is a biliary protein marker of disease activity in primary sclerosing cholangitis. AB - BACKGROUND AND AIMS: Bile analysis has the potential to serve as a surrogate marker for inflammatory and neoplastic disorders of the biliary epithelium and may provide insight into biliary pathophysiology and possible diagnostic markers. We aimed to identify biliary protein markers of patients with primary sclerosing cholangitis (PSC) by a proteomic approach. METHODS: Bile duct-derived bile samples were collected from PSC patients (n = 45) or patients with choledocholithiasis (n = 24, the control group). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to analyse the proteins, 2-D-gel patterns were compared by densitometry, and brush cytology specimens were analysed by RT-PCR. RESULTS: A reference bile-duct bile proteome was established in the control group without signs of inflammation or maligancy comprising a total of 379 non-redundant biliary proteins; 21% were of unknown function and 24% had been previously described in serum. In PSC patients, the biliary S100A9 expression was elevated 95-fold (p<0.005), serum protein expression was decreased, and pancreatic enzyme expression was unchanged compared to controls. The S100A9 expression was 2-fold higher in PSC patients with high disease activity than in those with low activity (p<0.05). The brush cytology specimens from the PSC patients with high disease activity showed marked inflammatory activity and leukocyte infiltration compared to the patients with low activity, which correlated with S100A9 mRNA expression (p<0.05). CONCLUSIONS: The bile-duct bile proteome is complex and its analysis might enhance the understanding of cholestatic liver disease. Biliary S100A9 levels may be a useful marker for PSC activity, and its implication in inflammation and carcinogenesis warrants further investigation. PMID- 22253790 TI - Arbuscular mycorrhizas reduce nitrogen loss via leaching. AB - The capacity of mycorrhizal and non-mycorrhizal root systems to reduce nitrate (NO3-) and ammonium (NH4+) loss from soils via leaching was investigated in a microcosm-based study. A mycorrhiza defective tomato mutant and its mycorrhizal wildtype progenitor were used in this experiment in order to avoid the indirect effects of establishing non-mycorrhizal control treatments on soil nitrogen cycling and the wider soil biota. Mycorrhizal root systems dramatically reduced nitrate loss (almost 40 times less) via leaching, compared to their non mycorrhizal counterparts, following a pulse application of ammonium nitrate to experimental microcosms. The capacity of AM to reduce nutrient loss via leaching has received relatively little attention, but as demonstrated here, can be significant. Taken together, these data highlight the need to consider the potential benefits of AM beyond improvements in plant nutrition alone. PMID- 22253791 TI - Genetic evidence of tiger population structure and migration within an isolated and fragmented landscape in Northwest India. AB - BACKGROUND: Majority of the tiger habitat in Indian subcontinent lies within high human density landscapes and is highly sensitive to surrounding pressures. These forests are unable to sustain healthy tiger populations within a tiger-hostile matrix, despite considerable conservation efforts. Ranthambore Tiger Reserve (RTR) in Northwest India is one such isolated forest which is rapidly losing its links with other tiger territories in the Central Indian landscape. Non-invasive genetic sampling for individual identification is a potent technique to understand the relationships between threatened tiger populations in degraded habitats. This study is an attempt to establish tiger movement across a fragmented landscape between RTR and its neighboring forests, Kuno-Palpur Wildlife Sanctuary (KPWLS) and Madhav National Park (MNP) based on non-invasively obtained genetic data. METHODS: Data from twelve microsatellite loci was used to define population structure and also to identify first generation migrants and admixed individuals in the above forests. RESULTS: Population structure was consistent with the Central Indian landscape and we could determine significant gene flow between RTR and MNP. We could identify individuals of admixed ancestry in both these forests, as well as first generation migrants from RTR to KPWLS and MNP. CONCLUSIONS: Our results indicate reproductive mixing between animals of RTR and MNP in the recent past and migration of animals even today, despite fragmentation and poaching risk, from RTR towards MNP. Substantial conservation efforts should be made to maintain connectivity between these two subpopulations and also higher protection status should be conferred on Madhav National Park. PMID- 22253792 TI - Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty. AB - Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed. OBJECTIVE: To evaluate the outcome of brain MRI in girls referred with early signs of puberty in relation to age at presentation as well as clinical and biochemical parameters. METHOD: A single-center study of 229 consecutive girls with early or precocious puberty who had brain imaging performed. We evaluated medical history, clinical and biochemical factors, and four groups were defined based on the outcome of their MRI. RESULTS: Thirteen out of 208 (6.3%) girls with precocious puberty, but no other sign of CNS symptoms, had a pathological brain MRI. Importantly, all 13 girls were above 6 years of age, and 6 girls were even 8-9 years old. Twenty girls (9.6%) had incidental findings on brain MRI. Furthermore, 21 girls had known CNS pathology at time of evaluation. Basal LH was significantly higher in girls with newly diagnosed CNS pathology compared to girls with a non-pathological MRI (p = 0.025); no cut of value was found as values overlapped. CONCLUSION: A high frequency of 6-8 year old girls with precocious puberty in our study had a pathological brain MRI, which could not be predicted from any clinical nor biochemical parameters. Thus, we believe that girls with precocious pubertal development of central origin before 8 years of age should continue to be examined by a brain MRI. PMID- 22253793 TI - Retinal Muller glia initiate innate response to infectious stimuli via toll-like receptor signaling. AB - Ocular surgeries and trauma predispose the eye to develop infectious endophthalmitis, which often leads to vision loss. The mechanisms of initiation of innate defense in this disease are not well understood but are presumed to involve retinal glial cells. We hypothesize that retinal Muller glia can recognize and respond to invading pathogens via TLRs, which are key regulators of the innate immune system. Using the mouse retinal sections, human retinal Muller cell line (MIO-M1), and primary mouse retinal Muller cells, we show that they express known human TLR1-10, adaptor molecules MyD88, TRIF, TRAM, and TRAF6, and co-receptors MD2 and CD14. Consistent with the gene expression, protein levels were also detected for the TLRs. Moreover, stimulation of the Muller glia with TLR 2, 3, 4, 5, 7 and 9 agonists resulted in an increased TLR expression as assayed by Western blot and flow cytometry. Furthermore, TLR agonists or live pathogen (S. aureus, P. aeruginosa, & C. albicans)-challenged Muller glia produced significantly higher levels of inflammatory mediators (TNF-alpha, IL 1beta, IL-6 and IL-8), concomitantly with the activation of NF-kappaB, p38 and Erk signaling. This data suggests that Muller glia directly contributes to retinal innate defense by recognizing microbial patterns under infectious conditions; such as those in endophthalmitis. PMID- 22253794 TI - Amyloid-mediated sequestration of essential proteins contributes to mutant huntingtin toxicity in yeast. AB - BACKGROUND: Polyglutamine expansion is responsible for several neurodegenerative disorders, among which Huntington disease is the most well-known. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq1 protein ([PIN+]), which has a glutamine/asparagine-rich domain. PRINCIPAL FINDINGS: Here, we showed that aggregation and toxicity of mutant htt depended on [PIN+] only quantitatively: the presence of [PIN+] elevated the toxicity and the levels of htt detergent-insoluble polymers. In cells lacking [PIN+], toxicity of mutant htt was due to the polymerization and inactivation of the essential glutamine/asparagine-rich Sup35 protein and related inactivation of another essential protein, Sup45, most probably via its sequestration into Sup35 aggregates. However, inhibition of growth of [PIN+] cells depended on Sup35/Sup45 depletion only partially, suggesting that there are other sources of mutant htt toxicity in yeast. CONCLUSIONS: The obtained data suggest that induced polymerization of essential glutamine/asparagine-rich proteins and related sequestration of other proteins which interact with these polymers represent an essential source of htt toxicity. PMID- 22253795 TI - Acanthamoeba polyphaga-enhanced growth of Mycobacterium smegmatis. AB - BACKGROUND: Mycobacterium smegmatis is a rapidly-growing mycobacterium causing rare opportunistic infections in human patients. It is present in soil and water environments where free-living amoeba also reside, but data regarding M. smegmatis-amoeba relationships have been contradictory from mycobacteria destruction to mycobacteria survival. METHODOLOGY/PRINCIPAL FINDINGS: Using optic and electron microscopy and culture-based microbial enumeration we investigated the ability of M. smegmatis mc(2) 155, M. smegmatis ATCC 19420(T) and M. smegmatis ATCC 27204 organisms to survive into Acanthamoeba polyphaga trophozoites and cysts. We observed that M. smegmatis mycobacteria penetrated and survived in A. polyphaga trophozoites over five-day co-culture resulting in amoeba lysis and the release of viable M. smegmatis mycobacteria without amoebal cyst formation. We further observed that amoeba-co-culture, and lysed amoeba and supernatant and pellet, significantly increased five-day growth of the three tested M. smegmatis strains, including a four-fold increase in intra-amoebal growth. CONCLUSIONS/SIGNIFICANCE: Amoebal co-culture increases the growth of M. smegmatis resulting in amoeba killing by replicating M. smegmatis mycobacteria. This amoeba-M. smegmatis co-culture system illustrates an unusual paradigm in the mycobacteria-amoeba interactions as mycobacteria have been mainly regarded as amoeba-resistant organisms. Using these model organisms, this co-culture system could be used as a simple and rapid model to probe mycobacterial factors implicated in the intracellular growth of mycobacteria. PMID- 22253796 TI - The contribution of 17beta-hydroxysteroid dehydrogenase type 1 to the estradiol estrone ratio in estrogen-sensitive breast cancer cells. AB - Estrone and estradiol are both estrogens with estrone being the less potent form and estradiol being the most potent estrogen. The binding of the latter to cellular regulatory elements stimulates the proliferation of breast cancer cells. A high ratio of estradiol/estrone is related to increased cell proliferation, and is of great importance to understanding of breast cancer mechanisms. 17beta hydroxysteroid dehydrogenase type 1 and type 2 play important roles in the activation of estrone and inactivation of estradiol. Breast cancer cells T47D, MCF-7, BT 20, and JEG 3 as control cells, were chosen to evaluate the contribution of these two enzymes to the ratio. Twenty four hours after addition of different concentrations of estrone and estradiol, the ratio stabilized to around 9/1 in breast cancer cell lines with high expression of type 1 (T47D, BT 20, and JEG 3), whereas it approached 1/5 in cells with low expression of type 1 (MCF-7). The estradiol/estrone concentration ratio was modified to 9/1 in MCF-7 and HEK-293 cells over-expressing type 1. In T47D and BT 20, this ratio was decreased from 9/1 to nearly 1/5 (19/81 and 17/83 respectively) after type 1 knockdown by specific siRNAs. Type 2 is mainly involved in the conversion of estradiol into estrone. This ratio was decreased from 9/1 to 7/3 after over expression of type 2 in MCF-7 cells already over-expressing type 1. The ratio was further decreased by the addition of the oxidative cofactor, NAD, to the cell culture to facilitate the estradiol to estrone conversion catalyzed by type 2. These results demonstrate that the estradiol/estrone ratio is controlled by both type 1 and type 2 with an additional contribution by NAD, although type 1 is the first determining factor in the cellular environment compared with type 2 and cofactors. Moreover, kinetic studies were carried out in intact cells as a new approach, using HEK-293 cells over-expressing type 1 and T47D breast cancer cells. PMID- 22253797 TI - Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols. AB - BACKGROUND: Polyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee or wine. Epidemiological, clinical and animal studies support a role of polyphenols in the prevention of various diseases, such as cardiovascular diseases, cancers or neurodegenerative diseases. Recent findings suggest that polyphenols could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. However, the impact of polyphenol on the expression of microRNA, small non-coding RNAs, has not yet been studied. The aim of this study was to investigate the impact of dietary supplementation with polyphenols at nutritional doses on miRNA expression in the livers of apolipoprotein E-deficient mice (apoE-/-) jointly with mRNA expression profiling. METHODOLOGY/PRINCIPAL FINDINGS: Using microarrays, we measured the global miRNA expression in the livers of wild-type (C57B6/J) mice or apoE-/- mice fed diets supplemented with one of nine different polyphenols or a control diet. This analysis revealed that knock-out of the apoE gene induced significant modulation in the expression of miRNA. Moreover, changes in miRNA expression were observed after polyphenol supplementation, and five miRNAs (mmu-miR-291b-5p, mmu-miR-296-5p, mmu-miR-30c-1*, mmu-miR-467b* and mmu miR-374*) were identified as being commonly modulated by these polyphenols. We also observed that these polyphenols counteracted the modulation of miRNA expression induced by apoE mutation. Pathway analyses on these five miRNA-target genes revealed common pathways, some of which were also identified from a pathway analysis on mRNA profiles. CONCLUSION: This in vivo study demonstrated for the first time that polyphenols at nutritional doses modulate the expression of miRNA in the liver. Even if structurally different, all polyphenols induced a similar miRNA expression profile. Common pathways were identified from both miRNA-target and mRNA analysis, revealing cellular functions that could be regulated by polyphenols at both the miRNA and mRNA level. PMID- 22253798 TI - "One-size-fits-all"? Optimizing treatment duration for bacterial infections. AB - Historically, antibiotic treatment guidelines have aimed to maximize treatment efficacy and minimize toxicity, but have not considered the evolution of antibiotic resistance. Optimizing the duration and dosing of treatment to minimize the duration of symptomatic infection and selection pressure for resistance simultaneously has the potential to extend the useful therapeutic life of these valuable life-saving drugs without compromising the interests of individual patients.Here, using mathematical models, we explore the theoretical basis for shorter durations of treatment courses, including a range of ecological dynamics of bacteria that cause infections or colonize hosts as commensals. We find that immunity is an important mediating factor in determining the need for long duration of treatment. When immunity to infection is expected, shorter durations that reduce the selection for resistance without interfering with successful clinical outcome are likely to be supported. Adjusting drug treatment strategies to account for the impact of the differences in the ecological niche occupied by commensal flora relative to invasive bacteria could be effective in delaying the spread of bacterial resistance. PMID- 22253799 TI - An investigation into the determining factors of zoo visitor attendances in UK zoos. AB - The debate as to which animals are most beneficial to keep in zoos in terms of financial and conservative value is readily disputed; however, demographic factors have also been shown to relate to visitor numbers on an international level. The main aims of this research were: (1) To observe the distribution and location of zoos across the UK, (2) to develop a way of calculating zoo popularity in terms of the species kept within a collection and (3) to investigate the factors related to visitor numbers regarding admission costs, popularity of the collection in terms of the species kept and local demographic factors. Zoo visitor numbers were positively correlated with generated popularity ratings for zoos based on the species kept within a collection and admission prices (Pearson correlation: n = 34, r = 0.268, P = 0.126 and n = 34, r = -0.430, P = 0.011). Animal collections are aggregated around large cities and tourist regions, particularly coastal areas. No relationship between demographic variables and visitor numbers was found (Pearson correlation: n = 34, r = 0.268, P = 0.126), which suggests that the popularity of a zoo's collection relative to the types and numbers of species kept is more indicative of a collection's visitor numbers than its surrounding demographic figures. Zoos should incorporate generating high popularity scores as part of their collection planning strategies, to ensure that they thrive in the future, not only as tourist attractions but also as major conservation organizations. PMID- 22253800 TI - Cretaceous small scavengers: feeding traces in tetrapod bones from Patagonia, Argentina. AB - Ecological relationships among fossil vertebrate groups are interpreted based on evidence of modification features and paleopathologies on fossil bones. Here we describe an ichnological assemblage composed of trace fossils on reptile bones, mainly sphenodontids, crocodyliforms and maniraptoran theropods. They all come from La Buitrera, an early Late Cretaceous locality in the Candeleros Formation of northwestern Patagonia, Argentina. This locality is significant because of the abundance of small to medium-sized vertebrates. The abundant ichnological record includes traces on bones, most of them attributable to tetrapods. These latter traces include tooth marks that provde evidence of feeding activities made during the sub-aerial exposure of tetrapod carcasses. Other traces are attributable to arthropods or roots. The totality of evidence provides an uncommon insight into paleoecological aspects of a Late Cretaceous southern ecosystem. PMID- 22253801 TI - Mapping genetic diversity of cherimoya (Annona cherimola Mill.): application of spatial analysis for conservation and use of plant genetic resources. AB - There is a growing call for inventories that evaluate geographic patterns in diversity of plant genetic resources maintained on farm and in species' natural populations in order to enhance their use and conservation. Such evaluations are relevant for useful tropical and subtropical tree species, as many of these species are still undomesticated, or in incipient stages of domestication and local populations can offer yet-unknown traits of high value to further domestication. For many outcrossing species, such as most trees, inbreeding depression can be an issue, and genetic diversity is important to sustain local production. Diversity is also crucial for species to adapt to environmental changes. This paper explores the possibilities of incorporating molecular marker data into Geographic Information Systems (GIS) to allow visualization and better understanding of spatial patterns of genetic diversity as a key input to optimize conservation and use of plant genetic resources, based on a case study of cherimoya (Annona cherimola Mill.), a Neotropical fruit tree species. We present spatial analyses to (1) improve the understanding of spatial distribution of genetic diversity of cherimoya natural stands and cultivated trees in Ecuador, Bolivia and Peru based on microsatellite molecular markers (SSRs); and (2) formulate optimal conservation strategies by revealing priority areas for in situ conservation, and identifying existing diversity gaps in ex situ collections. We found high levels of allelic richness, locally common alleles and expected heterozygosity in cherimoya's putative centre of origin, southern Ecuador and northern Peru, whereas levels of diversity in southern Peru and especially in Bolivia were significantly lower. The application of GIS on a large microsatellite dataset allows a more detailed prioritization of areas for in situ conservation and targeted collection across the Andean distribution range of cherimoya than previous studies could do, i.e. at province and department level in Ecuador and Peru, respectively. PMID- 22253802 TI - Expression of a neuroendocrine gene signature in gastric tumor cells from CEA 424 SV40 large T antigen-transgenic mice depends on SV40 large T antigen. AB - BACKGROUND: A large fraction of murine tumors induced by transgenic expression of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine phenotype. It is unclear whether SV40 TAg induces the neuroendocrine phenotype by preferential transformation of progenitor cells committed to the neuroendocrine lineage or by transcriptional activation of neuroendocrine genes. METHODOLOGY/PRINCIPAL FINDINGS: To address this question we analyzed CEA424-SV40 TAg-transgenic mice that develop spontaneous tumors in the antral stomach region. Immunohistology revealed expression of the neuroendocrine marker chromogranin A in tumor cells. By ELISA an 18-fold higher level of serotonin could be detected in the blood of tumor-bearing mice in comparison to nontransgenic littermates. Transcriptome analyses of antral tumors combined with gene set enrichment analysis showed significant enrichment of genes considered relevant for human neuroendocrine tumor biology. This neuroendocrine gene signature was also expressed in 424GC, a cell line derived from a CEA424-SV40 TAg tumor, indicating that the tumor cells exhibit a similar neuroendocrine phenotype also in vitro. Treatment of 424GC cells with SV40 TAg-specific siRNA downregulated expression of the neuroendocrine gene signature. CONCLUSIONS/SIGNIFICANCE: SV40 TAg thus appears to directly induce a neuroendocrine gene signature in gastric carcinomas of CEA424-SV40 TAg transgenic mice. This might explain the high incidence of neuroendocrine tumors in other murine SV40 TAg tumor models. Since the oncogenic effect of SV40 TAg is caused by inactivation of the tumor suppressor proteins p53 and RB1 and loss of function of these proteins is commonly observed in human neuroendocrine tumors, a similar mechanism might cause neuroendocrine phenotypes in human tumors. PMID- 22253803 TI - Transcriptome-based differentiation of closely-related Miscanthus lines. AB - BACKGROUND: Distinguishing between individuals is critical to those conducting animal/plant breeding, food safety/quality research, diagnostic and clinical testing, and evolutionary biology studies. Classical genetic identification studies are based on marker polymorphisms, but polymorphism-based techniques are time and labor intensive and often cannot distinguish between closely related individuals. Illumina sequencing technologies provide the detailed sequence data required for rapid and efficient differentiation of related species, lines/cultivars, and individuals in a cost-effective manner. Here we describe the use of Illumina high-throughput exome sequencing, coupled with SNP mapping, as a rapid means of distinguishing between related cultivars of the lignocellulosic bioenergy crop giant miscanthus (Miscanthus * giganteus). We provide the first exome sequence database for Miscanthus species complete with Gene Ontology (GO) functional annotations. RESULTS: A SNP comparative analysis of rhizome-derived cDNA sequences was successfully utilized to distinguish three Miscanthus * giganteus cultivars from each other and from other Miscanthus species. Moreover, the resulting phylogenetic tree generated from SNP frequency data parallels the known breeding history of the plants examined. Some of the giant miscanthus plants exhibit considerable sequence divergence. CONCLUSIONS: Here we describe an analysis of Miscanthus in which high-throughput exome sequencing was utilized to differentiate between closely related genotypes despite the current lack of a reference genome sequence. We functionally annotated the exome sequences and provide resources to support Miscanthus systems biology. In addition, we demonstrate the use of the commercial high-performance cloud computing to do computational GO annotation. PMID- 22253804 TI - Regulation of the Na,K-ATPase gamma-subunit FXYD2 by Runx1 and Ret signaling in normal and injured non-peptidergic nociceptive sensory neurons. AB - Dorsal root ganglia (DRGs) contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury. PMID- 22253805 TI - Matrix metalloproteinase-1 and -9 in human placenta during spontaneous vaginal delivery and caesarean sectioning in preterm pregnancy. AB - Preterm birth is a major public health problem in terms of loss of life, long term and short term disabilities worldwide. The process of parturition (both term and preterm) involves intensive remodelling of the extracellular matrix (ECM) in the placenta and fetal membranes by matrix metalloproteinases (MMPs). Our previous studies show reduced docosahexaenoic acid (DHA) in women delivering preterm. Further omega 3 fatty acids are reported to regulate MMP levels. This study was undertaken to examine the placental levels of MMPs and their association with placental DHA levels in women delivering preterm. The levels of MMP-1 and MMP-9 in 74 women delivering preterm (52 by spontaneous vaginal delivery and 22 by caesarean sectioning) and 75 women delivering at term (59 by spontaneous vaginal delivery and 16 by caesarean sectioning) were determined by enzyme-linked immunosorbent assay (ELISA) and their association with placental DHA was studied. Placental MMP-1 levels were higher (p<0.05) in women delivering preterm (both by spontaneous vaginal delivery and caesarean sectioning) as compared to those delivering at term. In contrast, placental MMP-9 levels in preterm pregnancies was higher (p<0.05) in women with spontaneous vaginal delivery while lower (p<0.05) in women delivering by caesarean sectioning. Low placental DHA was associated with higher placental MMP-9 levels. Our study suggests a differential effect of mode of delivery on the levels of MMPs from placenta. Further this study suggests a negative association of DHA and the levels of MMP-9 in human placenta although the mechanisms need further study. PMID- 22253806 TI - The role of the multiple banded antigen of Ureaplasma parvum in intra-amniotic infection: major virulence factor or decoy? AB - The multiple banded antigen (MBA) is a predicted virulence factor of Ureaplasma species. Antigenic variation of the MBA is a potential mechanism by which ureaplasmas avoid immune recognition and cause chronic infections of the upper genital tract of pregnant women. We tested whether the MBA is involved in the pathogenesis of intra-amniotic infection and chorioamnionitis by injecting virulent or avirulent-derived ureaplasma clones (expressing single MBA variants) into the amniotic fluid of pregnant sheep. At 55 days of gestation pregnant ewes (n = 20) received intra-amniotic injections of virulent-derived or avirulent derived U. parvum serovar 6 strains (2*104 CFU), or 10B medium (n = 5). Amniotic fluid was collected every two weeks post-infection and fetal tissues were collected at the time of surgical delivery of the fetus (140 days of gestation). Whilst chronic colonisation was established in the amniotic fluid of animals infected with avirulent-derived and virulent-derived ureaplasmas, the severity of chorioamnionitis and fetal inflammation was not different between these groups (p>0.05). MBA size variants (32-170 kDa) were generated in vivo in amniotic fluid samples from both the avirulent and virulent groups, whereas in vitro antibody selection experiments led to the emergence of MBA-negative escape variants in both strains. Anti-ureaplasma IgG antibodies were detected in the maternal serum of animals from the avirulent (40%) and virulent (55%) groups, and these antibodies correlated with increased IL-1beta, IL-6 and IL-8 expression in chorioamnion tissue (p<0.05). We demonstrate that ureaplasmas are capable of MBA phase variation in vitro; however, ureaplasmas undergo MBA size variation in vivo, to potentially prevent eradication by the immune response. Size variation of the MBA did not correlate with the severity of chorioamnionitis. Nonetheless, the correlation between a maternal humoral response and the expression of chorioamnion cytokines is a novel finding. This host response may be important in the pathogenesis of inflammation-mediated adverse pregnancy outcomes. PMID- 22253807 TI - Hemodynamic responses evoked by neuronal stimulation via channelrhodopsin-2 can be independent of intracortical glutamatergic synaptic transmission. AB - Maintenance of neuronal function depends on the delivery of oxygen and glucose through changes in blood flow that are linked to the level of ongoing neuronal and glial activity, yet the underlying mechanisms remain unclear. Using transgenic mice expressing the light-activated cation channel channelrhodopsin-2 in deep layer pyramidal neurons, we report that changes in intrinsic optical signals and blood flow can be evoked by activation of a subset of channelrhodopsin-2-expressing neurons in the sensorimotor cortex. We have combined imaging and pharmacology to examine the importance of glutamatergic synaptic transmission in this form of neurovascular coupling. Blockade of ionotropic glutamate receptors with the antagonists CNQX and MK801 significantly reduced forepaw-evoked hemodynamic responses, yet resulted in no significant reduction of channelrhodopsin-evoked hemodynamic responses, suggesting that stimulus-dependent coupling of neuronal activity to blood flow can be independent of local excitatory synaptic transmission. Together, these results indicate that channelrhodopsin-2 activation of sensorimotor excitatory neurons produces changes in intrinsic optical signals and blood flow that can occur under conditions where synaptic activation of neurons or other cells through ionotropic glutamate receptors would be blocked. PMID- 22253808 TI - Evidence that putrescine modulates the higher plant photosynthetic proton circuit. AB - The light reactions of photosynthesis store energy in the form of an electrochemical gradient of protons, or proton motive force (pmf), comprised of electrical (Deltapsi) and osmotic (DeltapH) components. Both components can drive the synthesis of ATP at the chloroplast ATP synthase, but the DeltapH component also plays a key role in regulating photosynthesis, down-regulating the efficiency of light capture by photosynthetic antennae via the q(E) mechanism, and governing electron transfer at the cytochrome b(6)f complex. Differential partitioning of pmf into DeltapH and Deltapsi has been observed under environmental stresses and proposed as a mechanism for fine-tuning photosynthetic regulation, but the mechanism of this tuning is unknown. We show here that putrescine can alter the partitioning of pmf both in vivo (in Arabidopsis mutant lines and in Nicotiana wild type) and in vitro, suggesting that the endogenous titer of weak bases such as putrescine represents an unrecognized mechanism for regulating photosynthetic responses to the environment. PMID- 22253809 TI - CD1 gene polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (chi2 = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD. PMID- 22253810 TI - Glycoprotein hyposialylation gives rise to a nephrotic-like syndrome that is prevented by sialic acid administration in GNE V572L point-mutant mice. AB - Mutations in the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetyl-mannosamine kinase, result in distal myopathy with rimmed vacuoles (DMRV)/hereditary inclusion body myopathy (HIBM) in humans. Sialic acid is an acidic monosaccharide that modifies non-reducing terminal carbohydrate chains on glycoproteins and glycolipids, and it plays an important role in cellular adhesions and interactions. In this study, we generated mice with a V572L point mutation in the GNE kinase domain. Unexpectedly, these mutant mice had no apparent myopathies or motor dysfunctions. However, they had a short lifespan and exhibited renal impairment with massive albuminuria. Histological analysis showed enlarged glomeruli with mesangial matrix deposition, leading to glomerulosclerosis and abnormal podocyte foot process morphologies in the kidneys. Glycan analysis using several lectins revealed glomerular epithelial cell hyposialylation, particularly the hyposialylation of podocalyxin, which is one of important molecules for the glomerular filtration barrier. Administering Neu5Ac to the mutant mice from embryonic stages significantly suppressed the albuminuria and renal pathology, and partially recovered the glomerular glycoprotein sialylation. These findings suggest that the nephrotic-like syndrome observed in these mutant mice resulted from impaired glomerular filtration due to the hyposialylation of podocyte glycoproteins, including podocalyxin. Furthermore, it was possible to prevent the nephrotic-like disease in these mice by beginning Neu5Ac treatment during gestation. PMID- 22253811 TI - Curing of plasmid pXO1 from Bacillus anthracis using plasmid incompatibility. AB - The large plasmid pXO1 encoding the anthrax toxin is important for the virulence of Bacillus anthracis. It is essential to cure pXO1 from B. anthracis to evaluate its role in the pathogenesis of anthrax infection. Because conventional methods for curing plasmids (e.g., curing agents or growth at elevated temperatures) can induce mutations in the host chromosomal DNA, we developed a specific and reliable method to eliminate pXO1 from B. anthracis using plasmid incompatibility. Three putative replication origins of pXO1 were inserted into a temperature-sensitive plasmid to generate three incompatible plasmids. One of the three plasmids successfully eliminated the large plasmid pXO1 from B. anthracis vaccine strain A16R and wild type strain A16. These findings provided additional information about the replication/partitioning of pXO1 and demonstrated that introducing a small incompatible plasmid can generate plasmid-cured strains of B. anthracis without inducing spontaneous mutations in the host chromosome. PMID- 22253812 TI - DNA barcoding Bromeliaceae: achievements and pitfalls. AB - BACKGROUND: DNA barcoding has been successfully established in animals as a tool for organismal identification and taxonomic clarification. Slower nucleotide substitution rates in plant genomes have made the selection of a DNA barcode for land plants a much more difficult task. The Plant Working Group of the Consortium for the Barcode of Life (CBOL) recommended the two-marker combination rbcL/matK as a pragmatic solution to a complex trade-off between universality, sequence quality, discrimination, and cost. METHODOLOGY/PRINCIPAL FINDINGS: It is expected that a system based on any one, or a small number of plastid genes will fail within certain taxonomic groups with low amounts of plastid variation, while performing well in others. We tested the effectiveness of the proposed CBOL Plant Working Group barcoding markers for land plants in identifying 46 bromeliad species, a group rich in endemic species from the endangered Brazilian Atlantic Rainforest. Although we obtained high quality sequences with the suggested primers, species discrimination in our data set was only 43.48%. Addition of a third marker, trnH-psbA, did not show significant improvement. This species identification failure in Bromeliaceaecould also be seen in the analysis of the GenBank's matK data set. Bromeliaceae's sequence divergence was almost three times lower than the observed for Asteraceae and Orchidaceae. This low variation rate also resulted in poorly resolved tree topologies. Among the three Bromeliaceae subfamilies sampled, Tillandsioideae was the only one recovered as a monophyletic group with high bootstrap value (98.6%). Species paraphyly was a common feature in our sampling. CONCLUSIONS/SIGNIFICANCE: Our results show that although DNA barcoding is an important tool for biodiversity assessment, it tends to fail in taxonomy complicated and recently diverged plant groups, such as Bromeliaceae. Additional research might be needed to develop markers capable to discriminate species in these complex botanical groups. PMID- 22253813 TI - Granulocyte-colony stimulating factor (G-CSF) improves motor recovery in the rat impactor model for spinal cord injury. AB - Granulocyte-colony stimulating factor (G-CSF) improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. Previously we have employed the mouse hemisection SCI model and studied motor function after subcutaneous or transgenic delivery of the protein. To further broaden confidence in animal efficacy data we sought to determine efficacy in a different model and a different species. Here we investigated the effects of G-CSF in Wistar rats using the New York University Impactor. In this model, corroborating our previous data, rats treated subcutaneously with G-CSF over 2 weeks show significant improvement of motor function. PMID- 22253815 TI - Targeting RNA polymerase primary sigma70 as a therapeutic strategy against methicillin-resistant Staphylococcus aureus by antisense peptide nucleic acid. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) causes threatening infection-related mortality worldwide. Currently, spread of multi-drug resistance (MDR) MRSA limits therapeutic options and requires new approaches to "druggable" target discovery, as well as development of novel MRSA-active antibiotics. RNA polymerase primary sigma70 (encoded by gene rpoD) is a highly conserved prokaryotic factor essential for transcription initiation in exponentially growing cells of diverse S. aureus, implying potential for antisense inhibition. METHODOLOGY/PRINCIPAL FINDINGS: By synthesizing a serial of cell penetrating peptide conjugated peptide nucleic acids (PPNAs) based on software predicted parameters and further design optimization, we identified a target sequence (234 to 243 nt) within rpoD mRNA conserved region 3.0 being more sensitive to antisense inhibition. A (KFF)3K peptide conjugated 10-mer complementary PNA (PPNA2332) was developed for potent micromolar-range growth inhibitory effects against four pathogenic S. aureus strains with different resistance phenotypes, including clinical vancomycin-intermediate resistance S. aureus and MDR-MRSA isolates. PPNA2332 showed bacteriocidal antisense effect at 3.2 fold of MIC value against MRSA/VISA Mu50, and its sequence specificity was demonstrated in that PPNA with scrambled PNA sequence (Scr PPNA2332) exhibited no growth inhibitory effect at higher concentrations. Also, PPNA2332 specifically interferes with rpoD mRNA, inhibiting translation of its protein product sigma70 in a concentration dependent manner. Full decay of mRNA and suppressed expression of sigma70 were observed for 40 uM or 12.5 uM PPNA2332 treatment, respectively, but not for 40 uM Scr PPNA2332 treatment in pure culture of MRSA/VISA Mu50 strain. PPNA2332 (>=1 uM) essentially cleared lethal MRSA/VISA Mu50 infection in epithelial cell cultures, and eliminated viable bacterial cells in a time- and concentration- dependent manner, without showing any apparent toxicity at 10 uM. CONCLUSIONS: The present result suggested that RNAP primary sigma70 is a very promising candidate target for developing novel antisense antibiotic to treat severe MRSA infections. PMID- 22253814 TI - A multi-cohort study of polymorphisms in the GH/IGF axis and physical capability: the HALCyon programme. AB - BACKGROUND: Low muscle mass and function have been associated with poorer indicators of physical capability in older people, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF) axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability. METHODS: As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UK cohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2), rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previously been robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-study genotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance. RESULTS: Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 was associated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82-0.98, p-value = 0.01, n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms and physical capability traits. CONCLUSION: Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults. PMID- 22253816 TI - The outcome of renal ischemia-reperfusion injury is unchanged in AMPK-beta1 deficient mice. AB - AIM: Activation of the master energy-regulator AMP-activated protein kinase (AMPK) in the heart reduces the severity of ischemia-reperfusion injury (IRI) but the role of AMPK in renal IRI is not known. The aim of this study was to determine whether activation of AMPK by acute renal ischemia influences the severity of renal IRI. METHODS: AMPK expression and activation and the severity of renal IRI was studied in mice lacking the AMPK beta1 subunit and compared to wild type (WT) mice. RESULTS: Basal expression of activated AMPK, phosphorylayed at alphaThr172, was markedly reduced by 96% in AMPK-beta1-/- mice. Acute renal ischaemia caused a 3.2-fold increase in alpha1-AMPK activity and a 2.5-fold increase in alpha2-AMPK activity (P<0.001) that was associated with an increase in AMPK phosphorylation of the AMPK-alpha subunit at Thr172 and Ser485, and increased inhibitory phosphorylation of the AMPK substrate acetyl-CoA carboxylase. After acute renal ischemia AMPK activity was reduced by 66% in AMPK beta1-/- mice compared with WT. There was no difference, however, in the severity of renal IRI at 24-hours between AMPK-beta1-/- and WT mice, as measured by serum urea and creatinine and histological injury score. In the heart, macrophage migration inhibitory factor (MIF) released during IRI contributes to AMPK activation and protects from injury. In the kidney, however, no difference in AMPK activation by acute ischemia was observed between MIF-/- and WT mice. Compared with the heart, expression of the MIF receptor CD74 was found to be reduced in the kidney. CONCLUSION: The failure of AMPK activation to influence the outcome of IRI in the kidney contrasts with what is reported in the heart. This difference might be due to a lack of effect of MIF on AMPK activation and lower CD74 expression in the kidney. PMID- 22253817 TI - Long-range autocorrelations of CpG islands in the human genome. AB - In this paper, we use a statistical estimator developed in astrophysics to study the distribution and organization of features of the human genome. Using the human reference sequence we quantify the global distribution of CpG islands (CGI) in each chromosome and demonstrate that the organization of the CGI across a chromosome is non-random, exhibits surprisingly long range correlations (10 Mb) and varies significantly among chromosomes. These correlations of CGI summarize functional properties of the genome that are not captured when considering variation in any particular separate (and local) feature. The demonstration of the proposed methods to quantify the organization of CGI in the human genome forms the basis of future studies. The most illuminating of these will assess the potential impact on phenotypic variation of inter-individual variation in the organization of the functional features of the genome within and among chromosomes, and among individuals for particular chromosomes. PMID- 22253818 TI - Transcriptional repression by a bZIP protein regulates Dictyostelium prespore differentiation. AB - In response to the signaling polyketide DIF-1 DimB directly activates transcription of the ecmB gene in pstB cells; a subset of the prestalk cells that are the precursors of the basal disc. We show that the promoter of pspA, a prespore-specific gene, also contains a DimB binding site. Mutation of this site causes ectopic expression in the prestalk region and ChIP analysis shows that DIF 1 induces binding of DimB to the pspA promoter. DIF-1 represses pspA gene expression in a suspension cell assay but this repression is abrogated in a dimB null strain. These results suggest a coupled control mechanism, whereby the same DIF-DimB signaling pathway that directly activates ecmB gene expression directly represses pspA gene expression. PMID- 22253819 TI - Mechanism and function of Drosophila capa GPCR: a desiccation stress-responsive receptor with functional homology to human neuromedinU receptor. AB - The capa peptide receptor, capaR (CG14575), is a G-protein coupled receptor (GPCR) for the D. melanogaster capa neuropeptides, Drm-capa-1 and -2 (capa-1 and 2). To date, the capa peptide family constitutes the only known nitridergic peptides in insects, so the mechanisms and physiological function of ligand receptor signalling of this peptide family are of interest. Capa peptide induces calcium signaling via capaR with EC50 values for capa-1 = 3.06 nM and capa-2 = 4.32 nM. capaR undergoes rapid desensitization, with internalization via a b arrestin-2 mediated mechanism but is rapidly re-sensitized in the absence of capa 1. Drosophila capa peptides have a C-terminal -FPRXamide motif and insect PRXamide peptides are evolutionarily related to vertebrate peptide neuromedinU (NMU). Potential agonist effects of human NMU-25 and the insect -PRLamides [Drosophila pyrokinins Drm-PK-1 (capa-3), Drm-PK-2 and hugin-gamma [hugg]] against capaR were investigated. NMU-25, but not hugg nor Drm-PK-2, increases intracellular calcium ([Ca2+]i) levels via capaR. In vivo, NMU-25 increases [Ca2+]i and fluid transport by the Drosophila Malpighian (renal) tubule. Ectopic expression of human NMU receptor 2 in tubules of transgenic flies results in increased [Ca2+]i and fluid transport. Finally, anti-porcine NMU-8 staining of larval CNS shows that the most highly immunoreactive cells are capa-producing neurons. These structural and functional data suggest that vertebrate NMU is a putative functional homolog of Drm-capa-1 and -2. capaR is almost exclusively expressed in tubule principal cells; cell-specific targeted capaR RNAi significantly reduces capa-1 stimulated [Ca2+]i and fluid transport. Adult capaR RNAi transgenic flies also display resistance to desiccation. Thus, capaR acts in the key fluid-transporting tissue to regulate responses to desiccation stress in the fly. PMID- 22253820 TI - Novel nonphosphorylated peptides with conserved sequences selectively bind to Grb7 SH2 domain with affinity comparable to its phosphorylated ligand. AB - The Grb7 (growth factor receptor-bound 7) protein, a member of the Grb7 protein family, is found to be highly expressed in such metastatic tumors as breast cancer, esophageal cancer, liver cancer, etc. The src-homology 2 (SH2) domain in the C-terminus is reported to be mainly involved in Grb7 signaling pathways. Using the random peptide library, we identified a series of Grb7 SH2 domain binding nonphosphorylated peptides in the yeast two-hybrid system. These peptides have a conserved GIPT/K/N sequence at the N-terminus and G/WD/IP at the C terminus, and the region between the N-and C-terminus contains fifteen amino acids enriched with serines, threonines and prolines. The association between the nonphosphorylated peptides and the Grb7 SH2 domain occurred in vitro and ex vivo. When competing for binding to the Grb7 SH2 domain in a complex, one synthesized nonphosphorylated ligand, containing the twenty-two amino acid-motif sequence, showed at least comparable affinity to the phosphorylated ligand of ErbB3 in vitro, and its overexpression inhibited the proliferation of SK-BR-3 cells. Such nonphosphorylated peptides may be useful for rational design of drugs targeted against cancers that express high levels of Grb7 protein. PMID- 22253821 TI - Armadillo 1.1: an original workflow platform for designing and conducting phylogenetic analysis and simulations. AB - In this paper we introduce Armadillo v1.1, a novel workflow platform dedicated to designing and conducting phylogenetic studies, including comprehensive simulations. A number of important phylogenetic and general bioinformatics tools have been included in the first software release. As Armadillo is an open-source project, it allows scientists to develop their own modules as well as to integrate existing computer applications. Using our workflow platform, different complex phylogenetic tasks can be modeled and presented in a single workflow without any prior knowledge of programming techniques. The first version of Armadillo was successfully used by professors of bioinformatics at Universite du Quebec a Montreal during graduate computational biology courses taught in 2010 11. The program and its source code are freely available at: . PMID- 22253822 TI - Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. AB - The persistence of symptoms in Lyme disease patients following antibiotic therapy, and their causes, continue to be a matter of intense controversy. The studies presented here explore antibiotic efficacy using nonhuman primates. Rhesus macaques were infected with B. burgdorferi and a portion received aggressive antibiotic therapy 4-6 months later. Multiple methods were utilized for detection of residual organisms, including the feeding of lab-reared ticks on monkeys (xenodiagnosis), culture, immunofluorescence and PCR. Antibody responses to the B. burgdorferi-specific C6 diagnostic peptide were measured longitudinally and declined in all treated animals. B. burgdorferi antigen, DNA and RNA were detected in the tissues of treated animals. Finally, small numbers of intact spirochetes were recovered by xenodiagnosis from treated monkeys. These results demonstrate that B. burgdorferi can withstand antibiotic treatment, administered post-dissemination, in a primate host. Though B. burgdorferi is not known to possess resistance mechanisms and is susceptible to the standard antibiotics (doxycycline, ceftriaxone) in vitro, it appears to become tolerant post dissemination in the primate host. This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post-treatment. PMID- 22253823 TI - Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta adrenergic receptors: a novel target for intervention. AB - Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and beta-adrenergic receptors (beta-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the alpha7nAChR and alpha4nAChR, along with significant inductions of p-CREB and p ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the alpha7nAChR antagonist alpha-BTX or the beta-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing beta adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by beta blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy. PMID- 22253824 TI - Localization of nucleoporin Tpr to the nuclear pore complex is essential for Tpr mediated regulation of the export of unspliced RNA. AB - Nucleoporin Tpr is a component of the nuclear pore complex (NPC) that localizes exclusively to intranuclear filaments. Tpr functions as a scaffolding element in the nuclear phase of the NPC and plays a role in mitotic spindle checkpoint signalling. Export of intron-containing mRNA in Mason Pfizer Monkey Virus is regulated by direct interaction of cellular proteins with the cis-acting Constitutive Transport Element (CTE). In mammalian cells, the transport of Gag/Pol-CTE reporter construct is not very efficient, suggesting a regulatory mechanism to retain this unspliced RNA. Here we report that the knockdown of Tpr in mammalian cells leads to a drastic enhancement in the levels of Gag proteins (p24) in the cytoplasm, which is rescued by siRNA resistant Tpr. Tpr's role in the retention of unspliced RNA is independent of the functions of Sam68 and Tap/Nxf1 proteins, which are reported to promote CTE dependent export. Further, we investigated the possible role for nucleoporins that are known to function in nucleocytoplasmic transport in modulating unspliced RNA export. Results show that depletion of Nup153, a nucleoporin required for NPC anchoring of Tpr, plays a role in regulating the export, while depletion of other FG repeat-containing nucleoporins did not alter the unspliced RNA export. Results suggest that Tpr and Nup153 both regulate the export of unspliced RNA and they are most likely functioning through the same pathway. Importantly, we find that localization of Tpr to the NPC is necessary for Tpr mediated regulation of unspliced RNA export. Collectively, the data indicates that perinuclear localization of Tpr at the nucleopore complex is crucial for regulating intron containing mRNA export by directly or indirectly participating in the processing and degradation of aberrant mRNA transcripts. PMID- 22253825 TI - Bone marrow-infiltrating human neuroblastoma cells express high levels of calprotectin and HLA-G proteins. AB - Metastases in the bone marrow (BM) are grim prognostic factors in patients with neuroblastoma (NB). In spite of extensive analysis of primary tumor cells from high- and low-risk NB patients, a characterization of freshly isolated BM infiltrating metastatic NB cells is still lacking. Our aim was to identify proteins specifically expressed by metastatic NB cells, that may be relevant for prognostic and therapeutic purposes. Sixty-six Italian children over 18 months of age, diagnosed with stage 4 NB, were included in the study. Metastatic NB cells were freshly isolated from patients' BM by positive immunomagnetic bead manipulation using anti-GD2 monoclonal antibody. Gene expression profiles were compared with those obtained from archived NB primary tumors from patients with 5 y-follow-up. After validation by RT-qPCR, expression/secretion of the proteins encoded by the up-regulated genes in the BM-infiltrating NB cells was evaluated by flow cytometry and ELISA. Compared to primary tumor cells, BM-infiltrating NB cells down-modulated the expression of CX3CL1, AGT, ATP1A2 mRNAs, whereas they up regulated several genes commonly expressed by various lineages of BM resident cells. BM-infiltrating NB cells expressed indeed the proteins encoded by the top ranked genes, S100A8 and A9 (calprotectin), CD177 and CD3, and secreted the CXCL7 chemokine. BM-infiltrating NB cells also expressed CD271 and HLA-G. We have identified proteins specifically expressed by BM-infiltrating NB cells. Among them, calprotectin, a potent inflammatory protein, and HLA-G, endowed with tolerogenic properties facilitating tumor escape from host immune response, may represent novel biomarkers and/or targets for therapeutic intervention in high risk NB patients. PMID- 22253826 TI - Defining the sister rat mammary tumor cell lines HH-16 cl.2/1 and HH-16.cl.4 as an in vitro cell model for Erbb2. AB - Cancer cell lines have been shown to be reliable tools in genetic studies of breast cancer, and the characterization of these lines indicates that they are good models for studying the biological mechanisms underlying this disease. Here, we describe the molecular cytogenetic/genetic characterization of two sister rat mammary tumor cell lines, HH-16 cl.2/1 and HH-16.cl.4, for the first time. Molecular cytogenetic analysis using rat and mouse chromosome paint probes and BAC/PAC clones allowed the characterization of clonal chromosome rearrangements; moreover, this strategy assisted in revealing detected breakpoint regions and complex chromosome rearrangements. This comprehensive cytogenetic analysis revealed an increase in the number of copies of the Mycn and Erbb2 genes in the investigated cell lines. To analyze its possible correlation with expression changes, relative RNA expression was assessed by real-time reverse transcription quantitative PCR and RNA FISH. Erbb2 was found to be overexpressed in HH-16.cl.4, but not in the sister cell line HH-16 cl.2/1, even though these lines share the same initial genetic environment. Moreover, the relative expression of Erbb2 decreased after global genome demethylation in the HH-16.cl.4 cell line. As these cell lines are commercially available and have been used in previous studies, the present detailed characterization improves their value as an in vitro cell model. We believe that the development of appropriate in vitro cell models for breast cancer is of crucial importance for revealing the genetic and cellular pathways underlying this neoplasy and for employing them as experimental tools to assist in the generation of new biotherapies. PMID- 22253827 TI - Unique properties of eukaryote-type actin and profilin horizontally transferred to cyanobacteria. AB - A eukaryote-type actin and its binding protein profilin encoded on a genomic island in the cyanobacterium Microcystis aeruginosa PCC 7806 co-localize to form a hollow, spherical enclosure occupying a considerable intracellular space as shown by in vivo fluorescence microscopy. Biochemical and biophysical characterization reveals key differences between these proteins and their eukaryotic homologs. Small-angle X-ray scattering shows that the actin assembles into elongated, filamentous polymers which can be visualized microscopically with fluorescent phalloidin. Whereas rabbit actin forms thin cylindrical filaments about 100 um in length, cyanobacterial actin polymers resemble a ribbon, arrest polymerization at 5-10 um and tend to form irregular multi-strand assemblies. While eukaryotic profilin is a specific actin monomer binding protein, cyanobacterial profilin shows the unprecedented property of decorating actin filaments. Electron micrographs show that cyanobacterial profilin stimulates actin filament bundling and stabilizes their lateral alignment into heteropolymeric sheets from which the observed hollow enclosure may be formed. We hypothesize that adaptation to the confined space of a bacterial cell devoid of binding proteins usually regulating actin polymerization in eukaryotes has driven the co-evolution of cyanobacterial actin and profilin, giving rise to an intracellular entity. PMID- 22253828 TI - A functional variant in ERAP1 predisposes to multiple sclerosis. AB - The ERAP1 gene encodes an aminopeptidase involved in antigen processing. A functional polymorphism in the gene (rs30187, Arg528Lys) associates with susceptibility to ankylosying spondylitis (AS), whereas a SNP in the interacting ERAP2 gene increases susceptibility to another inflammatory autoimmune disorder, Crohn's disease (CD). We analysed rs30187 in 572 Italian patients with CD and in 517 subjects suffering from multiple sclerosis (MS); for each cohort, an independent sex- and age-matched control group was genotyped. The frequency of the 528Arg allele was significantly higher in both disease cohorts compared to the respective control population (for CD, OR = 1.20 95%CI: 1.01-1.43, p = 0.036; for RRMS, OR = 1.26; 95%CI: 1.04-1.51, p = 0.01). Meta-analysis with the Wellcome Trust Cases Control Consortium GWAS data confirmed the association with MS (p(meta) = 0.005), but not with CD. In AS, the rs30187 variant has a predisposing effect only in an HLA-B27 allelic background. It remains to be evaluated whether interaction between ERAP1 and distinct HLA class I alleles also affects the predisposition to MS, and explains the failure to provide definitive evidence for a role of rs30187 in CD. Results herein support the emerging concept that a subset of master-regulatory genes underlay the pathogenesis of autoimmunity. PMID- 22253829 TI - Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: "in vivo" evidence from FAP mice models. AB - BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disease caused by the extracellular deposition of mutant transthyretin (TTR), with special involvement of the peripheral nervous system (PNS). Currently, hepatic transplantation is considered the most efficient therapy to halt the progression of clinical symptoms in FAP since more than 95% of TTR is produced by the liver. However, less invasive and more reliable therapeutic approaches have been proposed for FAP therapy, namely based on drugs acting as inhibitors of amyloid formation or as amyloid disruptors. We have recently reported that epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, is able to inhibit TTR aggregation and fibril formation, "in vitro" and in a cellular system, and is also able to disrupt pre-formed amyloid fibrils "in vitro". METHODOLOGY AND PRINCIPAL FINDINGS: In the present study, we assessed the effect of EGCG subchronic administration on TTR amyloidogenesis "in vivo", using well characterized animal models for FAP. Semiquantitative immunohistochemistry (SQ-IHC) and Western blot analysis of mice tissues after treatment demonstrated that EGCG inhibits TTR toxic aggregates deposition in about 50% along the gastrointestinal tract (GI) and peripheral nervous system (PNS). Moreover EGCG treatment considerably lowered levels of several biomarkers associated with non fibrillar TTR deposition, namely endoplasmic reticulum (ER)-stress, protein oxidation and apoptosis markers. Treatment of old FAP mice with EGCG resulted not only in the decrease of non-fibrillar TTR deposition but also in disaggregation of amyloid deposits. Consistently, matrix metalloproteinase (MMP)-9 and serum amyloid P component (SAP), both markers of amyloid deposition, were also found reduced in treated old FAP mice. CONCLUSIONS AND SIGNIFICANCE: The dual effect of EGCG both as TTR aggregation inhibitor and amyloid fibril disruptor together with the high tolerability and low toxicity of EGCG in humans, point towards the potential use of this compound, or optimized derivatives, in the treatment of TTR related amyloidoses. PMID- 22253830 TI - Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. AB - Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase 3 family, is activated by oxidative stress. The death-signaling pathway mediated by ASK1 is inhibited by DJ-1, which is linked to recessively inherited Parkinson's disease (PD). Considering that DJ-1 deficiency exacerbates the toxicity of the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), we sought to investigate the direct role and mechanism of ASK1 in MPTP-induced dopamine neuron toxicity. In the present study, we found that MPTP administration to wild-type mice activates ASK1 in the midbrain. In ASK1 null mice, MPTP-induced motor impairment was less profound, and striatal dopamine content and nigral dopamine neuron counts were relatively preserved compared to wild-type littermates. Further, microglia and astrocyte activation seen in wild-type mice challenged with MPTP was markedly attenuated in ASK-/- mice. These data suggest that ASK1 is a key player in MPTP-induced glial activation linking oxidative stress with neuroinflammation, two well recognized pathogenetic factors in PD. These findings demonstrate that ASK1 is an important effector of MPTP-induced toxicity and suggest that inhibiting this kinase is a plausible therapeutic strategy for protecting dopamine neurons in PD. PMID- 22253831 TI - Expression of extracellular matrix components is disrupted in the immature and adult estrogen receptor beta-null mouse ovary. AB - Within the ovary, Estrogen Receptor beta (ERbeta) is localized to the granulosa cells of growing follicles. 17beta-estradiol (E2) acting via ERbeta augments the actions of follicle stimulating hormone in granulosa cells, leading to granulosa cell differentiation and formation of a preovulatory follicle. Adult ERbeta-null females are subfertile and possess ovaries with reduced numbers of growing follicles and corpora lutea. Because the majority of E2 production by granulosa cells occurs once puberty is reached, a role for ERbeta in the ovary prior to puberty has not been well examined. We now provide evidence that lack of ERbeta disrupts gene expression as early as post-natal day (PND) 13, and in particular, we identify a number of genes of the extracellular matrix (ECM) that are significantly higher in ERbeta-null follicles than in wildtype (WT) follicles. Considerable changes occur to the ECM occur during normal folliculogenesis to allow for the dramatic growth, cellular differentiation, and reorganization of the follicle from the primary to preovulatory stage. Using quantitative PCR and immunofluorescence, we now show that several ECM genes are aberrantly overexpressed in ERbeta-null follicles. We find that Collagen11a1, a protein highly expressed in cartilage, is significantly higher in ERbeta-null follicles than WT follicles as early as PND 13, and this heightened expression continues through PND 23-29 into adulthood. Similarly, Nidogen 2, a highly conserved basement membrane glycoprotein, is elevated in ERbeta-null follicles at PND 13 into adulthood, and is elevated specifically in the ERbeta-null focimatrix, a basal lamina-like matrix located between granulosa cells. Focimatrix laminin and Collagen IV expression were also higher in ERbeta-null ovaries than in WT ovaries at various ages. Our findings suggest two novel observations: a) that ERbeta regulates granulosa cell gene expression ovary prior to puberty, and b) that ERbeta regulates expression of ECM components in the mouse ovary. PMID- 22253832 TI - Molecular phylogeny and evolution of parabasalia with improved taxon sampling and new protein markers of actin and elongation factor-1alpha. AB - BACKGROUND: Inferring the evolutionary history of phylogenetically isolated, deep branching groups of taxa-in particular determining the root-is often extraordinarily difficult because their close relatives are unavailable as suitable outgroups. One of these taxonomic groups is the phylum Parabasalia, which comprises morphologically diverse species of flagellated protists of ecological, medical, and evolutionary significance. Indeed, previous molecular phylogenetic analyses of members of this phylum have yielded conflicting and possibly erroneous inferences. Furthermore, many species of Parabasalia are symbionts in the gut of termites and cockroaches or parasites and therefore formidably difficult to cultivate, rendering available data insufficient. Increasing the numbers of examined taxa and informative characters (e.g., genes) is likely to produce more reliable inferences. PRINCIPAL FINDINGS: Actin and elongation factor-1alpha genes were identified newly from 22 species of termite gut symbionts through careful manipulations and seven cultured species, which covered major lineages of Parabasalia. Their protein sequences were concatenated and analyzed with sequences of previously and newly identified glyceraldehyde-3 phosphate dehydrogenase and the small-subunit rRNA gene. This concatenated dataset provided more robust phylogenetic relationships among major groups of Parabasalia and a more plausible new root position than those previously reported. CONCLUSIONS/SIGNIFICANCE: We conclude that increasing the number of sampled taxa as well as the addition of new sequences greatly improves the accuracy and robustness of the phylogenetic inference. A morphologically simple cell is likely the ancient form in Parabasalia as opposed to a cell with elaborate flagellar and cytoskeletal structures, which was defined as most basal in previous inferences. Nevertheless, the evolution of Parabasalia is complex owing to several independent multiplication and simplification events in these structures. Therefore, systematics based solely on morphology does not reflect the evolutionary history of parabasalids. PMID- 22253833 TI - Human Vav1 expression in hematopoietic and cancer cell lines is regulated by c Myb and by CpG methylation. AB - Vav1 is a signal transducer protein that functions as a guanine nucleotide exchange factor for the Rho/Rac GTPases in the hematopoietic system where it is exclusively expressed. Recently, Vav1 was shown to be involved in several human malignancies including neuroblastoma, lung cancer, and pancreatic ductal adenocarcinoma (PDA). Although some factors that affect vav1 expression are known, neither the physiological nor pathological regulation of vav1 expression is completely understood. We demonstrate herein that mutations in putative transcription factor binding sites at the vav1 promoter affect its transcription in cells of different histological origin. Among these sites is a consensus site for c-Myb, a hematopoietic-specific transcription factor that is also found in Vav1-expressing lung cancer cell lines. Depletion of c-Myb using siRNA led to a dramatic reduction in vav1 expression in these cells. Consistent with this, co transfection of c-Myb activated transcription of a vav1 promoter-luciferase reporter gene construct in lung cancer cells devoid of Vav1 expression. Together, these results indicate that c-Myb is involved in vav1 expression in lung cancer cells. We also explored the methylation status of the vav1 promoter. Bisulfite sequencing revealed that the vav1 promoter was completely unmethylated in human lymphocytes, but methylated to various degrees in tissues that do not normally express vav1. The vav1 promoter does not contain CpG islands in proximity to the transcription start site; however, we demonstrated that methylation of a CpG dinucleotide at a consensus Sp1 binding site in the vav1 promoter interferes with protein binding in vitro. Our data identify two regulatory mechanisms for vav1 expression: binding of c-Myb and CpG methylation of 5' regulatory sequences. Mutation of other putative transcription factor binding sites suggests that additional factors regulate vav1 expression as well. PMID- 22253835 TI - Prediction of glioblastoma multiform response to bevacizumab treatment using multi-parametric MRI. AB - Glioblastoma multiform (GBM) is a highly malignant brain tumor. Bevacizumab is a recent therapy for stopping tumor growth and even shrinking tumor through inhibition of vascular development (angiogenesis). This paper presents a non invasive approach based on image analysis of multi-parametric magnetic resonance images (MRI) to predict response of GBM to this treatment. The resulting prediction system has potential to be used by physicians to optimize treatment plans of the GBM patients. The proposed method applies signal decomposition and histogram analysis methods to extract statistical features from Gd-enhanced regions of tumor that quantify its microstructural characteristics. MRI studies of 12 patients at multiple time points before and up to four months after treatment are used in this work. Changes in the Gd-enhancement as well as necrosis and edema after treatment are used to evaluate the response. Leave-one out cross validation method is applied to evaluate prediction quality of the models. Predictive models developed in this work have large regression coefficients (maximum R2 = 0.95) indicating their capability to predict response to therapy. PMID- 22253834 TI - Evidence for a common toolbox based on necrotrophy in a fungal lineage spanning necrotrophs, biotrophs, endophytes, host generalists and specialists. AB - The Sclerotiniaceae (Ascomycotina, Leotiomycetes) is a relatively recently evolved lineage of necrotrophic host generalists, and necrotrophic or biotrophic host specialists, some latent or symptomless. We hypothesized that they inherited a basic toolbox of genes for plant symbiosis from their common ancestor. Maintenance and evolutionary diversification of symbiosis could require selection on toolbox genes or on timing and magnitude of gene expression. The genes studied were chosen because their products have been previously investigated as pathogenicity factors in the Sclerotiniaceae. They encode proteins associated with cell wall degradation: acid protease 1 (acp1), aspartyl protease (asps), and polygalacturonases (pg1, pg3, pg5, pg6), and the oxalic acid (OA) pathway: a zinc finger transcription factor (pac1), and oxaloacetate acetylhydrolase (oah), catalyst in OA production, essential for full symptom production in Sclerotinia sclerotiorum. Site-specific likelihood analyses provided evidence for purifying selection in all 8 pathogenicity-related genes. Consistent with an evolutionary arms race model, positive selection was detected in 5 of 8 genes. Only generalists produced large, proliferating disease lesions on excised Arabidopsis thaliana leaves and oxalic acid by 72 hours in vitro. In planta expression of oah was 10-300 times greater among the necrotrophic host generalists than necrotrophic and biotrophic host specialists; pac1 was not differentially expressed. Ability to amplify 6/8 pathogenicity related genes and produce oxalic acid in all genera are consistent with the common toolbox hypothesis for this gene sample. That our data did not distinguish biotrophs from necrotrophs is consistent with 1) a common toolbox based on necrotrophy and 2) the most conservative interpretation of the 3-locus housekeeping gene phylogeny--a baseline of necrotrophy from which forms of biotrophy emerged at least twice. Early oah overexpression likely expands the host range of necrotrophic generalists in the Sclerotiniaceae, while specialists and biotrophs deploy oah, or other as-yet-unknown toolbox genes, differently. PMID- 22253836 TI - Discovery of T cell antigens by high-throughput screening of synthetic minigene libraries. AB - The identification of novel T cell antigens is central to basic and translational research in autoimmunity, tumor immunology, transplant immunology, and vaccine design for infectious disease. However, current methods for T cell antigen discovery are low throughput, and fail to explore a wide range of potential antigen-receptor interactions. To overcome these limitations, we developed a method in which programmable microarrays are used to cost-effectively synthesize complex libraries of thousands of minigenes that collectively encode the content of hundreds of candidate protein targets. Minigene-derived mRNA are transfected into autologous antigen presenting cells and used to challenge complex populations of purified peripheral blood CD8+ T cells in multiplex, parallel ELISPOT assays. In this proof-of-concept study, we apply synthetic minigene screening to identify two novel pancreatic islet autoantigens targeted in a patient with Type I Diabetes. To our knowledge, this is the first successful screen of a highly complex, synthetic minigene library for identification of a T cell antigen. In principle, responses against the full protein complement of any tissue or pathogen can be assayed by this approach, suggesting that further optimization of synthetic libraries holds promise for high throughput antigen discovery. PMID- 22253837 TI - Basin-scale control on the phytoplankton biomass in Lake Victoria, Africa. AB - The relative bio-optical variability within Lake Victoria was analyzed through the spatio-temporal decomposition of a 1997-2004 dataset of remotely-sensed reflectance ratios in the visible spectral range. Results show a regular seasonal pattern with a phase shift (around 2 months) between the south and north parts of the lake. Interannual trends suggested a teleconnection between the lake dynamics and El-Nino phenomena. Both seasonal and interannual patterns were associated to conditions of light limitation for phytoplankton growth and basin-scale hydrodynamics on phytoplankton access to light. Phytoplankton blooms developed during the periods of lake surface warming and water column stability. The temporal shift apparent in the bio-optical seasonal cycles was related to the differential cooling of the lake surface by southeastern monsoon winds. North south differences in the exposure to trade winds are supported by the orography of the Eastern Great Rift Valley. The result is that surface layer warming begins in the northern part of the lake while the formation of cool and dense water continues in the southern part. The resulting buoyancy field is sufficient to induce a lake-wide convective circulation and the tilting of the isotherms along the north-south axis. Once surface warming spreads over the whole lake, the phytoplankton bloom dynamics are subjected to the internal seiche derived from the relaxation of thermocline tilting. In 1997-98, El-Nino phenomenon weakened the monsoon wind flow which led to an increase in water column stability and a higher phytoplankton optical signal throughout the lake. This suggests that phytoplankton response to expected climate scenarios will be opposite to that proposed for nutrient-limited great lakes. The present analysis of remotely sensed bio-optical properties in combination with environmental data provides a novel basin-scale framework for research and management strategies in Lake Victoria. PMID- 22253838 TI - Multidimensional characterization and differentiation of neurons in the anteroventral cochlear nucleus. AB - Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies. PMID- 22253839 TI - Sickness absence due to otoaudiological diagnoses and risk of disability pension: a nationwide Swedish prospective cohort study. AB - BACKGROUND: Hearing difficulties are a large public health problem. Knowledge is scarce regarding risk of disability pension among people who have been sickness absent due to these difficulties. METHODS: A cohort including all 4,687,756 individuals living in Sweden in 2005, aged 20-64, and not on disability or old age pension, was followed through 2009. Incidence rate ratios (RR) of disability pension with 95% confidence intervals (CI) were estimated using Cox proportional hazard models. RESULTS: In multivariable models, individuals who had a sick-leave spell due to otoaudiological diagnoses in 2005 had a 1.52-fold (95% CI: 1.43 1.62) increased risk of being granted a disability pension compared to individuals on sick leave due to other diagnoses. Hearing and tinnitus sick-leave diagnoses were associated with risk of disability pension: RR 3.38, 95% CI: 3.04 3.75, and 3.30, 95% CI: 2.95-3.68, respectively. No association was observed between sick leave due to vertigo diagnoses and disability pension whereas otological diagnoses and no sick leave were inversely associated with risk of disability pension compared to non-otoaudiological sick-leave diagnoses. Sick leave due to otoaudiological diagnoses was positively associated with risk of disability pension due to otoaudiological diagnoses and sick leave due to a tinnitus diagnosis was also associated with risk of disability pension due to mental diagnoses. The risk of disability pension among individuals with hearing or tinnitus sick-leave diagnoses was highest in the age group 35-44. Moreover, men had a slightly higher risk. CONCLUSION: This large cohort study suggests an increased risk of disability pension among those with sickness absence due to otoaudiological diagnoses, particularly hearing and tinnitus diagnoses, compared to those with sickness absence due to non-otoaudiological diagnoses. PMID- 22253840 TI - Highly parallel and short-acting amplification with locus-specific primers to detect single nucleotide polymorphisms by the DigiTag2 assay. AB - The DigiTag2 assay enables analysis of a set of 96 SNPs using Kapa 2GFast HotStart DNA polymerase with a new protocol that has a total running time of about 7 hours, which is 6 hours shorter than the previous protocol. Quality parameters (conversion rate, call rate, reproducibility and concordance) were at the same levels as when genotype calls were acquired using the previous protocol. Multiplex PCR with 192 pairs of locus-specific primers was available for target preparation in the DigiTag2 assay without the optimization of reaction conditions, and quality parameters had the same levels as those acquired with 96 plex PCR. The locus-specific primers were able to achieve sufficient (concentration of target amplicon >=5 nM) and specific (concentration of unexpected amplicons <2 nM) amplification within 2 hours, were also able to achieve detectable amplifications even when working in a 96-plex or 192-plex form. The improved DigiTag2 assay will be an efficient platform for screening an intermediate number of SNPs (tens to hundreds of sites) in the replication analysis after genome-wide association study. Moreover, highly parallel and short acting amplification with locus-specific primers may thus facilitate widespread application to other PCR-based assays. PMID- 22253841 TI - Stable extracellular RNA fragments of Mycobacterium tuberculosis induce early apoptosis in human monocytes via a caspase-8 dependent mechanism. AB - The molecular basis of pathogen-induced host cell apoptosis is well characterized for a number of microorganisms. Mycobacterium tuberculosis is known to induce apoptosis and it was shown that live but not heat killed M. tuberculosis stimulates this biological pathway in monocytes. The dependence of this activity on live bacilli led us to hypothesize that products released or secreted by M. tuberculosis are the primary apoptotic factors for human monocytes. Thus, the culture filtrate of in vitro grown M. tuberculosis strain H37Rv was fractioned by conventional chromatography and the apoptosis-inducing activity of individual fractions was measured on human monocytes. The tests employed included measurement of cell membrane damage, caspase activation, and cytokine release. Small molecular weight RNAs of M. tuberculosis were recognized as the predominant apoptosis inducing factors. The RNA was comprised primarily of tRNA and rRNA fragments that stably accumulate in the culture filtrate during early log-phase growth. The RNA fragments signaled through a caspase-8 dependent, caspase-1 and TNF-alpha independent pathway that ultimately compromised the human monocytes' ability to control M. tuberculosis infection. These studies provide the first report of bacterial RNA inducing apoptosis. They also provide a foundation to pursue pathways for secretion or release of nucleic acids from M. tuberculosis and the impact of secreted RNA fragments on pathogenesis. PMID- 22253842 TI - Nanomechanics and sodium permeability of endothelial surface layer modulated by hawthorn extract WS 1442. AB - The endothelial glycocalyx (eGC) plays a pivotal role in the physiology of the vasculature. By binding plasma proteins, the eGC forms the endothelial surface layer (ESL) which acts as an interface between bloodstream and endothelial cell surface. The functions of the eGC include mechanosensing of blood flow induced shear stress and thus flow dependent vasodilation. There are indications that levels of plasma sodium concentrations in the upper range of normal and beyond impair flow dependent regulation of blood pressure and may therefore increase the risk for hypertension. Substances, therefore, that prevent sodium induced endothelial dysfunction may be attractive for the treatment of cardiovascular disease. By means of combined atomic force-epifluorescence microscopy we studied the impact of the hawthorn (Crataegus spp.) extract WS 1442, a herbal therapeutic with unknown mechanism of action, on the mechanics of the ESL of ex vivo murine aortae. Furthermore, we measured the impact of WS 1442 on the sodium permeability of endothelial EA.hy 926 cell monolayer. The data show that (i) the ESL contributes by about 11% to the total endothelial barrier resistance for sodium and (ii) WS 1442 strengthens the ESL resistance for sodium up to about 45%. This mechanism may explain some of the vasoprotective actions of this herbal therapeutic. PMID- 22253843 TI - Amplification by PCR artificially reduces the proportion of the rare biosphere in microbial communities. AB - The microbial world has been shown to hold an unimaginable diversity. The use of rRNA genes and PCR amplification to assess microbial community structure and diversity present biases that need to be analyzed in order to understand the risks involved in those estimates. Herein, we show that PCR amplification of specific sequence targets within a community depends on the fractions that those sequences represent to the total DNA template. Using quantitative, real-time, multiplex PCR and specific Taqman probes, the amplification of 16S rRNA genes from four bacterial species within a laboratory community were monitored. Results indicate that the relative amplification efficiency for each bacterial species is a nonlinear function of the fraction that each of those taxa represent within a community or multispecies DNA template. Consequently, the low-proportion taxa in a community are under-represented during PCR-based surveys and a large number of sequences might need to be processed to detect some of the bacterial taxa within the 'rare biosphere'. The structure of microbial communities from PCR-based surveys is clearly biased against low abundant taxa which are required to decipher the complete extent of microbial diversity in nature. PMID- 22253844 TI - Wnt4 participates in the formation of vertebrate neuromuscular junction. AB - Neuromuscular junction (NMJ) formation requires the highly coordinated communication of several reciprocal signaling processes between motoneurons and their muscle targets. Identification of the early, spatially restricted cues in target recognition at the NMJ is still poorly documented, especially in mammals. Wnt signaling is one of the key pathways regulating synaptic connectivity. Here, we report that Wnt4 contributes to the formation of vertebrate NMJ in vivo. Results from a microarray screen and quantitative RT-PCR demonstrate that Wnt4 expression is regulated during muscle cell differentiation in vitro and muscle development in vivo, being highly expressed when the first synaptic contacts are formed and subsequently downregulated. Analysis of the mouse Wnt4-/- NMJ phenotype reveals profound innervation defects including motor axons overgrowing and bypassing AChR aggregates with 30% of AChR clusters being unapposed by nerve terminals. In addition, loss of Wnt4 function results in a 35% decrease of the number of prepatterned AChR clusters while Wnt4 overexpression in cultured myotubes increases the number of AChR clusters demonstrating that Wnt4 directly affects postsynaptic differentiation. In contrast, muscle structure and the localization of several synaptic proteins including acetylcholinesterase, MuSK and rapsyn are not perturbed in the Wnt4 mutant. Finally, we identify MuSK as a Wnt4 receptor. Wnt4 not only interacts with MuSK ectodomain but also mediates MuSK activation. Taken together our data reveal a new role for Wnt4 in mammalian NMJ formation that could be mediated by MuSK, a key receptor in synaptogenesis. PMID- 22253845 TI - Negotiating left-hand and right-hand bends: a motorcycle simulator study to investigate experiential and behaviour differences across rider groups. AB - Why do motorcyclists crash on bends? To address this question we examined the riding styles of three groups of motorcyclists on a motorcycle simulator. Novice, experienced and advanced motorcyclists navigated a series of combined left and right bends while their speed and lane position were recorded. Each rider encountered an unexpected hazard on both a left- and right-hand bend section. Upon seeing the hazards, all riders decreased their speed before steering to avoid the hazard. Experienced riders tended to follow more of a racing line through the bends, which resulted in them having to make the most severe changes to their position to avoid a collision. Advanced riders adopted the safest road positions, choosing a position which offered greater visibility through the bends. As a result, they did not need to alter their road position in response to the hazard. Novice riders adopted similar road positions to experienced riders on the left-hand bends, but their road positions were more similar to advanced riders on right-hand bends, suggesting that they were more aware of the risks associated with right bends. Novice riders also adopted a safer position on post hazard bends whilst the experienced riders failed to alter their behaviour even though they had performed the greatest evasive manoeuvre in response to the hazards. Advanced riders did not need to alter their position as their approach to the bends was already optimal. The results suggest that non-advanced riders were more likely to choose an inappropriate lane position than an inappropriate speed when entering a bend. Furthermore, the findings support the theory that expertise is achieved as a result of relearning, with advanced training overriding 'bad habits' gained through experience alone. PMID- 22253846 TI - Analysis of medaka sox9 orthologue reveals a conserved role in germ cell maintenance. AB - The sex determining gene is divergent among different animal species. However, sox9 is up-regulated in the male gonads in a number of species in which it is the essential regulator of testis determination. It is therefore often discussed that the sex determining gene-sox9 axis functions in several vertebrates. In our current study, we show that sox9b in the medaka (Oryzias latipes) is one of the orthologues of mammalian Sox9 at syntenic and expression levels. Medaka sox9b affects the organization of extracellular matrices, which represents a conserved role of sox9, but does not directly regulate testis determination. We made this determination via gene expression and phenotype analyses of medaka with different copy numbers of sox9b. Sox9b is involved in promoting cellular associations and is indispensible for the proper proliferation and survival of germ cells in both female and male medaka gonads. Medaka mutants that lack sox9b function exhibit a seemingly paradoxical phenotype of sex reversal to male. This is explained by a reduction in the germ cell number associated with aberrant extracellular matrices. Together with its identified roles in other vertebrate gonads, a testis determining role for Sox9 in mammals is likely to have been neofunctionalized and appended to its conserved role in germ cell maintenance. PMID- 22253847 TI - Sequence analysis of the IL28A/IL28B inverted gene duplication that contains polymorphisms associated with treatment response in hepatitis C patients. AB - Several SNPs located in or around the IL28B gene are associated with response of patients infected with Hepatitis C virus to treatment with pegylated interferon alpha +/- ribavirin or with spontaneous clearance of the virus. The results of such studies are so compelling that future treatment approaches are likely to involve clinical decisions being made on the basis of a patient's genotype. Since IL28B is a paralogue of IL28A with greater than 95% sequence identity, it is possible that without genotyping assay specificity, sequences in IL28A may contribute to genotype identification, and potentially confound treatment decisions. This study aimed to 1) examine DNA sequences in IL28B surrounding each of the reported associated SNPs and the corresponding regions in IL28A; and 2) develop a robust assay for rs12979860, the most 'cosmopolitan' SNP most strongly associated with treatment response across all global populations studied to date. Bioinformatic analysis of genomic regions surrounding IL28A and IL28B demonstrated that 3 SNPs were unique to IL28B, whereas the remaining 6 SNP regions shared >93% identity between IL28A and IL28B. Using a panel of DNA samples, PCR amplification followed by Sanger sequencing was used to examine IL28B SNPs and the corresponding regions in IL28A. For the overlapping SNPs, all 6 in IL28B were confirmed to be polymorphic whereas the corresponding positions in IL28A were monomorphic. Based upon IL28A and IL28B sequence data, a specific TaqMan(r) assay was developed for SNP rs12979860 that was 100% concordant to the sequence-derived genotypes. Analysis using a commercial assay identified one discordant result which led to a change in their genotype-calling algorithm. Where future treatment decisions are made upon the results of genotyping assays, it is very important that results are concordant with data from a sequence-based format. This is especially so in situations where designing specific PCR primers is a challenge. PMID- 22253848 TI - Global phylogeography with mixed-marker analysis reveals male-mediated dispersal in the endangered scalloped hammerhead shark (Sphyrna lewini). AB - BACKGROUND: The scalloped hammerhead shark, Sphyrna lewini, is a large endangered predator with a circumglobal distribution, observed in the open ocean but linked ontogenetically to coastal embayments for parturition and juvenile development. A previous survey of maternal (mtDNA) markers demonstrated strong genetic partitioning overall (global Phi(ST) = 0.749) and significant population separations across oceans and between discontinuous continental coastlines. METHODOLOGY/PRINCIPAL FINDINGS: We surveyed the same global range with increased sample coverage (N = 403) and 13 microsatellite loci to assess the male contribution to dispersal and population structure. Biparentally inherited microsatellites reveal low or absent genetic structure across ocean basins and global genetic differentiation (F(ST) = 0.035) over an order of magnitude lower than the corresponding measures for maternal mtDNA lineages (Phi(ST) = 0.749). Nuclear allelic richness and heterozygosity are high throughout the Indo-Pacific, while genetic structure is low. In contrast, allelic diversity is low while population structure is higher for populations at the ends of the range in the West Atlantic and East Pacific. CONCLUSIONS/SIGNIFICANCE: These data are consistent with the proposed Indo-Pacific center of origin for S. lewini, and indicate that females are philopatric or adhere to coastal habitats while males facilitate gene flow across oceanic expanses. This study includes the largest sampling effort and the most molecular loci ever used to survey the complete range of a large oceanic predator, and findings emphasize the importance of incorporating mixed-marker analysis into stock assessments of threatened and endangered shark species. PMID- 22253849 TI - Development of a DNA barcoding system for seagrasses: successful but not simple. AB - Seagrasses, a unique group of submerged flowering plants, profoundly influence the physical, chemical and biological environments of coastal waters through their high primary productivity and nutrient recycling ability. They provide habitat for aquatic life, alter water flow, stabilize the ground and mitigate the impact of nutrient pollution. at the coast region. Although on a global scale seagrasses represent less than 0.1% of the angiosperm taxa, the taxonomical ambiguity in delineating seagrass species is high. Thus, the taxonomy of several genera is unsolved. While seagrasses are capable of performing both, sexual and asexual reproduction, vegetative reproduction is common and sexual progenies are always short lived and epimeral in nature. This makes species differentiation often difficult, especially for non-taxonomists since the flower as a distinct morphological trait is missing. Our goal is to develop a DNA barcoding system assisting also non-taxonomists to identify regional seagrass species. The results will be corroborated by publicly available sequence data. The main focus is on the 14 described seagrass species of India, supplemented with seagrasses from temperate regions. According to the recommendations of the Consortium for the Barcoding of Life (CBOL) rbcL and matK were used in this study. After optimization of the DNA extraction method from preserved seagrass material, the respective sequences were amplified from all species analyzed. Tree- and character-based approaches demonstrate that the rbcL sequence fragment is capable of resolving up to family and genus level. Only matK sequences were reliable in resolving species and partially the ecotype level. Additionally, a plastidic gene spacer was included in the analysis to confirm the identification level. Although the analysis of these three loci solved several nodes, a few complexes remained unsolved, even when constructing a combined tree for all three loci. Our approaches contribute to the understanding of the morphological plasticity of seagrasses versus genetic differentiation. PMID- 22253850 TI - Stress hormones receptors in the amygdala mediate the effects of stress on the consolidation, but not the retrieval, of a non aversive spatial task. AB - This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress) impaired consolidation and retrieval, but not acquisition, of the task. Non habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side), a glucocorticoid receptor (GR) antagonist, or propranolol (0.75 ug/side), a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA), prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 ug/side) microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i) GR and beta-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii) the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas), and (iii) the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive). PMID- 22253851 TI - Rod and cone pathway signalling is altered in the P2X7 receptor knock out mouse. AB - The P2X7 receptor (P2X7-R) is expressed in the retina and brain and has been implicated in neurodegenerative diseases. However, whether it is expressed by neurons and plays a role as a neurotransmitter receptor has been the subject of controversy. In this study, we first show that the novel vesicular transporter for ATP, VNUT, is expressed in the retina, verifying the presence of the molecular machinery for ATP to act as neurotransmitter at P2X7-Rs. Secondly we show the presence of P2X7-R mRNA and protein in the retina and cortex and absence of the full length variant 1 of the receptor in the P2X7-R knock out (P2X7-KO) mouse. The role of the P2X7-R in neuronal function of the retina was assessed by comparing the electroretinogram response of P2X7-KO with WT mice. The rod photoreceptor response was found to be similar, while both rod and cone pathway post-photoreceptor responses were significantly larger in P2X7-KO mice. This suggests that activation of P2X7-Rs modulates output of second order retinal neurons. In line with this finding, P2X7-Rs were found in the outer plexiform layer and on inner retinal cell classes, including horizontal, amacrine and ganglion cells. The receptor co-localized with conventional synapses in the IPL and was expressed on amacrine cells post-synaptic to rod bipolar ribbon synapses. In view of the changes in visual function in the P2X7-KO mouse and the immunocytochemical location of the receptor in the normal retina, it is likely the P2X7-R provides excitatory input to photoreceptor terminals or to inhibitory cells that shape both the rod and cone pathway response. PMID- 22253852 TI - Social determinants of long lasting insecticidal hammock use among the Ra-glai ethnic minority in Vietnam: implications for forest malaria control. AB - BACKGROUND: Long-lasting insecticidal hammocks (LLIHs) are being evaluated as an additional malaria prevention tool in settings where standard control strategies have a limited impact. This is the case among the Ra-glai ethnic minority communities of Ninh Thuan, one of the forested and mountainous provinces of Central Vietnam where malaria morbidity persist due to the sylvatic nature of the main malaria vector An. dirus and the dependence of the population on the forest for subsistence--as is the case for many impoverished ethnic minorities in Southeast Asia. METHODS: A social science study was carried out ancillary to a community-based cluster randomized trial on the effectiveness of LLIHs to control forest malaria. The social science research strategy consisted of a mixed methods study triangulating qualitative data from focused ethnography and quantitative data collected during a malariometric cross-sectional survey on a random sample of 2,045 study participants. RESULTS: To meet work requirements during the labor intensive malaria transmission and rainy season, Ra-glai slash and burn farmers combine living in government supported villages along the road with a second home at their fields located in the forest. LLIH use was evaluated in both locations. During daytime, LLIH use at village level was reported by 69.3% of all respondents, and in forest fields this was 73.2%. In the evening, 54.1% used the LLIHs in the villages, while at the fields this was 20.7%. At night, LLIH use was minimal, regardless of the location (village 4.4%; forest 6.4%). DISCUSSION: Despite the free distribution of insecticide-treated nets (ITNs) and LLIHs, around half the local population remains largely unprotected when sleeping in their forest plot huts. In order to tackle forest malaria more effectively, control policies should explicitly target forest fields where ethnic minority farmers are more vulnerable to malaria. PMID- 22253853 TI - Sharpin contributes to TNFalpha dependent NFkappaB activation and anti-apoptotic signalling in hepatocytes. AB - TNFalpha stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFkappaB activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains. Sharpin-deficiency sensitized hepatocytes to induction of apoptosis by TNFalpha even in the absence of transcriptional inhibition. TNFalpha induced activation of NFkappaB was strongly reduced in hepatocytes from Sharpin deficient mice, due to reduced and delayed phosphorylation and degradation of IkappaBalpha. Injection of TNFalpha-inducing lipopolysaccharides led to strongly exacerbated liver damage and premature death in Sharpin-deficient mice. Our findings point to an essential role of Sharpin in linear ubiquitin chain formation, NFkappaB activation, and protection of the liver against inflammatory damaging signals. PMID- 22253854 TI - Crucial ignored parameters on nanotoxicology: the importance of toxicity assay modifications and "cell vision". AB - Until now, the results of nanotoxicology research have shown that the interactions between nanoparticles (NPs) and cells are remarkably complex. In order to get a deep understanding of the NP-cell interactions, scientists have focused on the physicochemical effects. However, there are still considerable debates about the regulation of nanomaterials and the reported results are usually in contradictions. Here, we are going to introduce the potential key reasons for these conflicts. In this case, modification of conventional in vitro toxicity assays, is one of the crucial ignored matter in nanotoxicological sciences. More specifically, the conventional methods neglect important factors such as the sedimentation of NPs and absorption of proteins and other essential biomolecules onto the surface of NPs. Another ignored matter in nanotoxicological sciences is the effect of cell "vision" (i.e., cell type). In order to show the effects of these ignored subjects, we probed the effect of superparamagnetic iron oxide NPs (SPIONs), with various surface chemistries, on various cell lines. We found thatthe modification of conventional toxicity assays and the consideration of the "cell vision" concept are crucial matters to obtain reliable, and reproducible nanotoxicology data. These new concepts offer a suitable way to obtain a deep understanding on the cell-NP interactions. In addition, by consideration of these ignored factors, the conflict of future toxicological reports would be significantly decreased. PMID- 22253855 TI - Visual lateralization in wild striped dolphins (Stenella coeruleoalba) in response to stimuli with different degrees of familiarity. AB - BACKGROUND: Apart from findings on both functional and motor asymmetries in captive aquatic mammals, only few studies have focused on lateralized behaviour of these species in the wild. METHODOLOGY/PRINCIPAL FINDINGS: In this study we focused on lateralized visual behaviour by presenting wild striped dolphins with objects of different degrees of familiarity (fish, ball, toy). Surveys were conducted in the Gulf of Taranto, the northern Ionian Sea portion delimited by the Italian regions of Calabria, Basilicata and Apulia. After sighting striped dolphins from a research vessel, different stimuli were presented in a random order by a telescopic bar connected to the prow of the boat. The preferential use of the right/left monocular viewing during inspection of the stimuli was analysed. CONCLUSION: Results clearly showed a monocular viewing preference with respect to the type of the stimulus employed. Due to the complete decussation of the optical nerves in dolphin brain our results reflected a different specialization of brain hemispheres for visual scanning processes confirming that in this species different stimuli evoked different patterns of eye use. A preferential use of the right eye (left hemisphere) during visual inspection of unfamiliar targets was observed supporting the hypothesis that, in dolphins, the organization of the functional neural structures which reflected cerebral asymmetries for visual object recognition could have been subjected to a deviation from the evolutionary line of most terrestrial vertebrates. PMID- 22253856 TI - Accommodating ontologies to biological reality--top-level categories of cumulative-constitutively organized material entities. AB - BACKGROUND: The Basic Formal Ontology (BFO) is a top-level formal foundational ontology for the biomedical domain. It has been developed with the purpose to serve as an ontologically consistent template for top-level categories of application oriented and domain reference ontologies within the Open Biological and Biomedical Ontologies Foundry (OBO). BFO is important for enabling OBO ontologies to facilitate in reliably communicating and managing data and metadata within and across biomedical databases. Following its intended single inheritance policy, BFO's three top-level categories of material entity (i.e. 'object', 'fiat object part', 'object aggregate') must be exhaustive and mutually disjoint. We have shown elsewhere that for accommodating all types of constitutively organized material entities, BFO must be extended by additional categories of material entity. METHODOLOGY/PRINCIPAL FINDINGS: Unfortunately, most biomedical material entities are cumulative-constitutively organized. We show that even the extended BFO does not exhaustively cover cumulative-constitutively organized material entities. We provide examples from biology and everyday life that demonstrate the necessity for 'portion of matter' as another material building block. This implies the necessity for further extending BFO by 'portion of matter' as well as three additional categories that possess portions of matter as aggregate components. These extensions are necessary if the basic assumption that all parts that share the same granularity level exhaustively sum to the whole should also apply to cumulative-constitutively organized material entities. By suggesting a notion of granular representation we provide a way to maintain the single inheritance principle when dealing with cumulative-constitutively organized material entities. CONCLUSIONS/SIGNIFICANCE: We suggest to extend BFO to incorporate additional categories of material entity and to rearrange its top level material entity taxonomy. With these additions and the notion of granular representation, BFO would exhaustively cover all top-level types of material entities that application oriented ontologies may use as templates, while still maintaining the single inheritance principle. PMID- 22253857 TI - Histone H2A (H2A.X and H2A.Z) variants in molluscs: molecular characterization and potential implications for chromatin dynamics. AB - Histone variants are used by the cell to build specialized nucleosomes, replacing canonical histones and generating functionally specialized chromatin domains. Among many other processes, the specialization imparted by histone H2A (H2A.X and H2A.Z) variants to the nucleosome core particle constitutes the earliest response to DNA damage in the cell. Consequently, chromatin-based genotoxicity tests have been developed in those cases where enough information pertaining chromatin structure and dynamics is available (i.e., human and mouse). However, detailed chromatin knowledge is almost absent in most organisms, specially protostome animals. Molluscs (which represent sentinel organisms for the study of pollution) are not an exception to this lack of knowledge. In the present work we first identified the existence of functionally differentiated histone H2A.X and H2A.Z variants in the mussel Mytilus galloprovincialis (MgH2A.X and MgH2A.Z), a marine organism widely used in biomonitoring programs. Our results support the functional specialization of these variants based on: a) their active expression in different tissues, as revealed by the isolation of native MgH2A.X and MgH2A.Z proteins in gonad and hepatopancreas; b) the evolutionary conservation of different residues encompassing functional relevance; and c) their ability to confer specialization to nucleosomes, as revealed by nucleosome reconstitution experiments using recombinant MgH2A.X and MgH2A.Z histones. Given the seminal role of these variants in maintaining genomic integrity and regulating gene expression, their preliminary characterization opens up new potential applications for the future development of chromatin-based genotoxicity tests in pollution biomonitoring programs. PMID- 22253858 TI - A modified RMCE-compatible Rosa26 locus for the expression of transgenes from exogenous promoters. AB - Generation of gain-of-function transgenic mice by targeting the Rosa26 locus has been established as an alternative to classical transgenic mice produced by pronuclear microinjection. However, targeting transgenes to the endogenous Rosa26 promoter results in moderate ubiquitous expression and is not suitable for high expression levels. Therefore, we now generated a modified Rosa26 (modRosa26) locus that combines efficient targeted transgenesis using recombinase-mediated cassette exchange (RMCE) by Flipase (Flp-RMCE) or Cre recombinase (Cre-RMCE) with transgene expression from exogenous promoters. We silenced the endogenous Rosa26 promoter and characterized several ubiquitous (pCAG, EF1alpha and CMV) and tissue specific (VeCad, alphaSMA) promoters in the modRosa26 locus in vivo. We demonstrate that the ubiquitous pCAG promoter in the modRosa26 locus now offers high transgene expression. While tissue-specific promoters were all active in their cognate tissues they additionally led to rare ectopic expression. To achieve high expression levels in a tissue-specific manner, we therefore combined Flp-RMCE for rapid ES cell targeting, the pCAG promoter for high transgene levels and Cre/LoxP conditional transgene activation using well-characterized Cre lines. Using this approach we generated a Cre/LoxP-inducible reporter mouse line with high EGFP expression levels that enables cell tracing in live cells. A second reporter line expressing luciferase permits efficient monitoring of Cre activity in live animals. Thus, targeting the modRosa26 locus by RMCE minimizes the effort required to target ES cells and generates a tool for the use exogenous promoters in combination with single-copy transgenes for predictable expression in mice. PMID- 22253859 TI - Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury. AB - Secondary damage following primary spinal cord injury extends pathology beyond the site of initial trauma, and effective management is imperative for maximizing anatomical and functional recovery. Bisperoxovanadium compounds have proven neuroprotective effects in several central nervous system injury/disease models, however, no mechanism has been linked to such neuroprotection from bisperoxovanadium treatment following spinal trauma. The goal of this study was to assess acute bisperoxovanadium treatment effects on neuroprotection and functional recovery following cervical unilateral contusive spinal cord injury, and investigate a potential mechanism of the compound's action. Two experimental groups of rats were established to 1) assess twice-daily 7 day treatment of the compound, potassium bisperoxo (picolinato) vanadium, on long-term recovery of skilled forelimb activity using a novel food manipulation test, and neuroprotection 6 weeks following injury and 2) elucidate an acute mechanistic link for the action of the drug post-injury. Immunofluorescence and Western blotting were performed to assess cellular signaling 1 day following SCI, and histochemistry and forelimb functional analysis were utilized to assess neuroprotection and recovery 6 weeks after injury. Bisperoxovanadium promoted significant neuroprotection through reduced motorneuron death, increased tissue sparing, and minimized cavity formation in rats. Enhanced forelimb functional ability during a treat-eating assessment was also observed. Additionally, bisperoxovanadium significantly enhanced downstream Akt and mammalian target of rapamycin signaling and reduced autophagic activity, suggesting inhibition of the phosphatase and tensin homologue deleted on chromosome ten as a potential mechanism of bisperoxovanadium action following traumatic spinal cord injury. Overall, this study demonstrates the efficacy of a clinically applicable pharmacological therapy for rapid initiation of neuroprotection post-spinal cord injury, and sheds light on the signaling involved in its action. PMID- 22253860 TI - Multiple pathway-based genetic variations associated with tobacco related multiple primary neoplasms. AB - BACKGROUND: In order to elucidate a combination of genetic alterations that drive tobacco carcinogenesis we have explored a unique model system and analytical method for an unbiased qualitative and quantitative assessment of gene-gene and gene-environment interactions. The objective of this case control study was to assess genetic predisposition in a biologically enriched clinical model system of tobacco related cancers (TRC), occurring as Multiple Primary Neoplasms (MPN). METHODS: Genotyping of 21 candidate Single Nucleotide Polymorphisms (SNP) from major metabolic pathways was performed in a cohort of 151 MPN cases and 210 cancer-free controls. Statistical analysis using logistic regression and Multifactor Dimensionality Reduction (MDR) analysis was performed for studying higher order interactions among various SNPs and tobacco habit. RESULTS: Increased risk association was observed for patients with at least one TRC in the upper aero digestive tract (UADT) for variations in SULT1A1 Arg213His, mEH Tyr113His, hOGG1 Ser326Cys, XRCC1 Arg280His and BRCA2 Asn372His. Gene-environment interactions were assessed using MDR analysis. The overall best model by MDR was tobacco habit/p53(Arg/Arg)/XRCC1(Arg399His)/mEH(Tyr113His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This model also showed significant association using logistic regression analysis. CONCLUSION: This is the first Indian study on a multipathway based approach to study genetic susceptibility to cancer in tobacco associated MPN. This approach could assist in planning additional studies for comprehensive understanding of tobacco carcinogenesis. PMID- 22253861 TI - Mood induction in depressive patients: a comparative multidimensional approach. AB - Anhedonia, reduced positive affect and enhanced negative affect are integral characteristics of major depressive disorder (MDD). Emotion dysregulation, e.g. in terms of different emotion processing deficits, has consistently been reported. The aim of the present study was to investigate mood changes in depressive patients using a multidimensional approach for the measurement of emotional reactivity to mood induction procedures. Experimentally, mood states can be altered using various mood induction procedures. The present study aimed at validating two different positive mood induction procedures in patients with MDD and investigating which procedure is more effective and applicable in detecting dysfunctions in MDD. The first procedure relied on the presentation of happy vs. neutral faces, while the second used funny vs. neutral cartoons. Emotional reactivity was assessed in 16 depressed and 16 healthy subjects using self-report measures, measurements of electrodermal activity and standardized analyses of facial responses. Positive mood induction was successful in both procedures according to subjective ratings in patients and controls. In the cartoon condition, however, a discrepancy between reduced facial activity and concurrently enhanced autonomous reactivity was found in patients. Relying on a multidimensional assessment technique, a more comprehensive estimate of dysfunctions in emotional reactivity in MDD was available than by self-report measures alone and this was unsheathed especially by the mood induction procedure relying on cartoons. The divergent facial and autonomic responses in the presence of unaffected subjective reactivity suggest an underlying deficit in the patients' ability to express the felt arousal to funny cartoons. Our results encourage the application of both procedures in functional imaging studies for investigating the neural substrates of emotion dysregulation in MDD patients. Mood induction via cartoons appears to be superior to mood induction via faces and autobiographical material in uncovering specific emotional dysfunctions in MDD. PMID- 22253862 TI - Effect of vaccines and antivirals during the major 2009 A(H1N1) pandemic wave in Norway--and the influence of vaccination timing. AB - To evaluate the impact of mass vaccination with adjuvanted vaccines (eventually 40% population coverage) and antivirals during the 2009 influenza pandemic in Norway, we fitted an age-structured SEIR model using data on vaccinations and sales of antivirals in 2009/10 in Norway to Norwegian ILI surveillance data from 5 October 2009 to 4 January 2010. We estimate a clinical attack rate of approximately 30% (28.7-29.8%), with highest disease rates among children 0-14 years (43-44%). Vaccination started in week 43 and came too late to have a strong influence on the pandemic in Norway. Our results indicate that the countermeasures prevented approximately 11-12% of potential cases relative to an unmitigated pandemic. Vaccination was found responsible for roughly 3 in 4 of the avoided infections. An estimated 50% reduction in the clinical attack rate would have resulted from vaccination alone, had the campaign started 6 weeks earlier. Had vaccination been prioritized for children first, the intervention should have commenced approximately 5 weeks earlier in order to achieve the same 50% reduction. In comparison, we estimate that a non-adjuvanted vaccination program should have started 8 weeks earlier to lower the clinical attack rate by 50%. In conclusion, vaccination timing was a critical factor in relation to the spread of the 2009 A(H1N1) influenza. Our results also corroborate the central role of children for the transmission of A(H1N1) pandemic influenza. PMID- 22253863 TI - RFID tracking of sublethal effects of two neonicotinoid insecticides on the foraging behavior of Apis mellifera. AB - The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15-6 ng/bee) and clothianidin (0.05-2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of >=0.5 ng/bee (clothianidin) and >=1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides. PMID- 22253864 TI - Characterization of a novel association between two trypanosome-specific proteins and 5S rRNA. AB - P34 and P37 are two previously identified RNA binding proteins in the flagellate protozoan Trypanosoma brucei. RNA interference studies have determined that the proteins are essential and are involved in ribosome biogenesis. Here, we show that these proteins interact in vitro with the 5S rRNA with nearly identical binding characteristics in the absence of other cellular factors. The T. brucei 5S rRNA has a complex secondary structure and presents four accessible loops (A to D) for interactions with RNA-binding proteins. In other eukaryotes, loop C is bound by the L5 ribosomal protein and loop A mainly by TFIIIA. The binding of P34 and P37 to T. brucei 5S rRNA involves the LoopA region of the RNA, but these proteins also protect the L5 binding site located on LoopC. PMID- 22253865 TI - Interactive marine spatial planning: siting tidal energy arrays around the Mull of Kintyre. AB - The rapid development of the offshore renewable energy sector has led to an increased requirement for Marine Spatial Planning (MSP) and, increasingly, this is carried out in the context of the 'ecosystem approach' (EA) to management. We demonstrate a novel method to facilitate implementation of the EA. Using a real time interactive mapping device (touch-table) and stakeholder workshops we gathered data and facilitated negotiation of spatial trade-offs at a potential site for tidal renewable energy off the Mull of Kintyre (Scotland). Conflicts between the interests of tidal energy developers and commercial and recreational users of the area were identified, and use preferences and concerns of stakeholders were highlighted. Social, cultural and spatial issues associated with conversion of common pool to private resource were also revealed. The method identified important gaps in existing spatial data and helped to fill these through interactive user inputs. The workshops developed a degree of consensus between conflicting users on the best areas for potential development suggesting that this approach should be adopted during MSP. PMID- 22253866 TI - A2BR adenosine receptor modulates sweet taste in circumvallate taste buds. AB - In response to taste stimulation, taste buds release ATP, which activates ionotropic ATP receptors (P2X2/P2X3) on taste nerves as well as metabotropic (P2Y) purinergic receptors on taste bud cells. The action of the extracellular ATP is terminated by ectonucleotidases, ultimately generating adenosine, which itself can activate one or more G-protein coupled adenosine receptors: A1, A2A, A2B, and A3. Here we investigated the expression of adenosine receptors in mouse taste buds at both the nucleotide and protein expression levels. Of the adenosine receptors, only A2B receptor (A2BR) is expressed specifically in taste epithelia. Further, A2BR is expressed abundantly only in a subset of taste bud cells of posterior (circumvallate, foliate), but not anterior (fungiform, palate) taste fields in mice. Analysis of double-labeled tissue indicates that A2BR occurs on Type II taste bud cells that also express Galpha14, which is present only in sweet-sensitive taste cells of the foliate and circumvallate papillae. Glossopharyngeal nerve recordings from A2BR knockout mice show significantly reduced responses to both sucrose and synthetic sweeteners, but normal responses to tastants representing other qualities. Thus, our study identified a novel regulator of sweet taste, the A2BR, which functions to potentiate sweet responses in posterior lingual taste fields. PMID- 22253867 TI - Late replication domains in polytene and non-polytene cells of Drosophila melanogaster. AB - In D. melanogaster polytene chromosomes, intercalary heterochromatin (IH) appears as large dense bands scattered in euchromatin and comprises clusters of repressed genes. IH displays distinctly low gene density, indicative of their particular regulation. Genes embedded in IH replicate late in the S phase and become underreplicated. We asked whether localization and organization of these late replicating domains is conserved in a distinct cell type. Using published comprehensive genome-wide chromatin annotation datasets (modENCODE and others), we compared IH organization in salivary gland cells and in a Kc cell line. We first established the borders of 60 IH regions on a molecular map, these regions containing underreplicated material and encompassing ~12% of Drosophila genome. We showed that in Kc cells repressed chromatin constituted 97% of the sequences that corresponded to IH bands. This chromatin is depleted for ORC-2 binding and largely replicates late. Differences in replication timing between the cell types analyzed are local and affect only sub-regions but never whole IH bands. As a rule such differentially replicating sub-regions display open chromatin organization, which apparently results from cell-type specific gene expression of underlying genes. We conclude that repressed chromatin organization of IH is generally conserved in polytene and non-polytene cells. Yet, IH domains do not function as transcription- and replication-regulatory units, because differences in transcription and replication between cell types are not domain-wide, rather they are restricted to small "islands" embedded in these domains. IH regions can thus be defined as a special class of domains with low gene density, which have narrow temporal expression patterns, and so displaying relatively conserved organization. PMID- 22253869 TI - Evidence of allomaternal nursing across one-male units in the Yunnan snub-nosed monkey (Rhinopithecus Bieti). AB - BACKGROUND: Allomaternal nursing, common in several species of social mammals, also has been reported in nonhuman primates. However, the function of this behavior in enhancing infant survivorship remains poorly understood. METHODOLOGY AND PRINCIPAL FINDINGS: The study was conducted on a free-ranging group of the Yunnan snub-nosed monkey (Rhinopithecus bieti) in the Baimaxueshan Natural Reserve. Direct observation and ad libitum sampling were used to record allocare behavior during a 20 month field study. R. bieti exhibits a multilevel social organization in which a large single troop, consisting of over 100 individuals, is divided into many one-male units (OMUs: 6~41). These OMUs coordinate their daily activities, and feed, forage, travel, and rest together. Here we report on one case of infant temporary adoption in which an adult female from one OMU engaged in allomaternal nursing and cared for an infant from a different OMU of the same troop. This event began when the mother and her five-month-old infant were found to became separated accidentally. The victim infant was observed staying in another OMU. Over the next several days we observed a lactating female in the new OMU to care for and nurse both her infant and the immigrant infant, who also was tolerated by and cared for by the harem male. CONCLUSIONS AND SIGNIFICANCE: Our findings suggest that lactating primate females are primed to care for young infants and, that the misdirected parental care hypothesis may offer the strongest explanation for allomaternal nursing in R. bieti. PMID- 22253868 TI - OsTIR1 and OsAFB2 downregulation via OsmiR393 overexpression leads to more tillers, early flowering and less tolerance to salt and drought in rice. AB - The microRNA miR393 has been shown to play a role in plant development and in the stress response by targeting mRNAs that code for the auxin receptors in Arabidopsis. In this study, we verified that two rice auxin receptor gene homologs (OsTIR1 and OsAFB2) could be targeted by OsmiR393 (Os for Oryza sativa). Two new phenotypes (increased tillers and early flowering) and two previously observed phenotypes (reduced tolerance to salt and drought and hyposensitivity to auxin) were observed in the OsmiR393-overexpressing rice plants. The OsmiR393 overexpressing rice demonstrated hyposensitivity to synthetic auxin-analog treatments. These data indicated that the phenotypes of OsmiR393-overexpressing rice may be caused through hyposensitivity to the auxin signal by reduced expression of two auxin receptor genes (OsTIR1 and OsAFB2). The expression of an auxin transporter (OsAUX1) and a tillering inhibitor (OsTB1) were downregulated by overexpression of OsmiR393, which suggested that a gene chain from OsmiR393 to rice tillering may be from OsTIR1 and OsAFB2 to OsAUX1, which affected the transportation of auxin, then to OsTB1, which finally controlled tillering. The positive phenotypes (increased tillers and early flowering) and negative phenotypes (reduced tolerance to salt and hyposensitivity to auxin) of OsmiR393 overexpressing rice present a dilemma for molecular breeding. PMID- 22253870 TI - BRCAness profile of sporadic ovarian cancer predicts disease recurrence. AB - BACKGROUND: The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes. OBJECTIVE: To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival. MATERIALS AND METHODS: Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan Meier method, Cox proportional hazard model, and cumulative incidence function. RESULTS: High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03). CONCLUSIONS: Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance. PMID- 22253871 TI - Is evolution of blind mole rats determined by climate oscillations? AB - The concept of climate variability facilitating adaptive radiation supported by the "Court Jester" hypothesis is disputed by the "Red Queen" one, but the prevalence of one or the other might be scale-dependent. We report on a detailed, comprehensive phylo-geographic study on the ~4 kb mtDNA sequence in underground blind mole rats of the family Spalacidae (or subfamily Spalacinae) from the East Mediterranean steppes. Our study aimed at testing the presence of periodicities in branching patterns on a constructed phylogenetic tree and at searching for congruence between branching events, tectonic history and paleoclimates. In contrast to the strong support for the majority of the branching events on the tree, the absence of support in a few instances indicates that network-like evolution could exist in spalacids. In our tree, robust support was given, in concordance with paleontological data, for the separation of spalacids from muroid rodents during the first half of the Miocene when open, grass-dominated habitats were established. Marine barriers formed between Anatolia and the Balkans could have facilitated the separation of the lineage "Spalax" from the lineage "Nannospalax" and of the clade "leucodon" from the clade "xanthodon". The separation of the clade "ehrenbergi" occurred during the late stages of the tectonically induced uplift of the Anatolian high plateaus and mountains, whereas the separation of the clade "vasvarii" took place when the rapidly uplifting Taurus mountain range prevented the Mediterranean rainfalls from reaching the Central Anatolian Plateau. The separation of Spalax antiquus and S. graecus occurred when the southeastern Carpathians were uplifted. Despite the role played by tectonic events, branching events that show periodicity corresponding to 400 kyr and 100-kyr eccentricity bands illuminate the important role of orbital fluctuations on adaptive radiation in spalacids. At the given scale, our results supports the "Court Jester" hypothesis over the "Red Queen" one. PMID- 22253872 TI - CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model. AB - INTRODUCTION: Organ-specific composition of extracellular matrix proteins (ECM) is a determinant of metastatic host organ involvement. The chemokine CXCL12 and its receptor CXCR4 play important roles in the colonization of human breast cancer cells to their metastatic target organs. In this study, we investigated the effects of chemokine stimulation on adhesion and migration of different human breast cancer cell lines in vivo and in vitro with particular focus on the liver as a major metastatic site in breast cancer. METHODS: Time lapse microscopy, in vitro adhesion and migration assays were performed under CXCL12 stimulation. Activation of small GTPases showed chemokine receptor signalling dependence from ECM components. The initial events of hepatic colonisation of MDA-MB-231 and MDA MB-468 cells were investigated by intravital microscopy of the liver in a rat model and under shRNA inhibition of CXCR4. RESULTS: In vitro, stimulation with CXCL12 induced increased chemotactic cell motility (p<0.05). This effect was dependent on adhesive substrates (type I collagen, fibronectin and laminin) and induced different responses in small GTPases, such as RhoA and Rac-1 activation, and changes in cell morphology. In addition, binding to various ECM components caused redistribution of chemokine receptors at tumour cell surfaces. In vivo, blocking CXCR4 decreased extravasation of highly metastatic MDA-MB-231 cells (p<0.05), but initial cell adhesion within the liver sinusoids was not affected. In contrast, the less metastatic MDA-MB-468 cells showed reduced cell adhesion but similar migration within the hepatic microcirculation. CONCLUSION: Chemokine induced extravasation of breast cancer cells along specific ECM components appears to be an important regulator but not a rate-limiting factor of their metastatic organ colonization. PMID- 22253873 TI - Novel protocol for the chemical synthesis of crustacean hyperglycemic hormone analogues--an efficient experimental tool for studying their functions. AB - The crustacean Hyperglycemic Hormone (cHH) is present in many decapods in different isoforms, whose specific biological functions are still poorly understood. Here we report on the first chemical synthesis of three distinct isoforms of the cHH of Astacus leptodactylus carried out by solid phase peptide synthesis coupled to native chemical ligation. The synthetic 72 amino acid long peptide amides, containing L- or D-Phe3 and (Glp1, D-Phe3) were tested for their biological activity by means of homologous in vivo bioassays. The hyperglycemic activity of the D-isoforms was significantly higher than that of the L-isoform, while the presence of the N-terminal Glp residue had no influence on the peptide activity. The results show that the presence of D-Phe3 modifies the cHH functionality, contributing to the diversification of the hormone pool. PMID- 22253874 TI - Robust metabolic responses to varied carbon sources in natural and laboratory strains of Saccharomyces cerevisiae. AB - Understanding factors that regulate the metabolism and growth of an organism is of fundamental biologic interest. This study compared the influence of two different carbon substrates, dextrose and galactose, on the metabolic and growth rates of the yeast Saccharomyces cerevisiae. Yeast metabolic and growth rates varied widely depending on the metabolic substrate supplied. The metabolic and growth rates of a yeast strain maintained under long-term laboratory conditions was compared to strain isolated from natural condition when grown on different substrates. Previous studies had determined that there are numerous genetic differences between these two strains. However, the overall metabolic and growth rates of a wild isolate of yeast was very similar to that of a strain that had been maintained under laboratory conditions for many decades. This indicates that, at in least this case, metabolism and growth appear to be well buffered against genetic differences. Metabolic rate and cell number did not co-vary in a simple linear manner. When grown in either dextrose or galactose, both strains showed a growth pattern in which the number of cells continued to increase well after the metabolic rate began a sharp decline. Previous studied have reported that O2 consumption in S. cerevisiae grown in reduced dextrose levels were elevated compared to higher levels. Low dextrose levels have been proposed to induce caloric restriction and increase life span in yeast. However, there was no evidence that reduced levels of dextrose increased metabolic rates, measured by either O2 consumption or CO2 production, in the strains used in this study. PMID- 22253875 TI - Influence of antipsychotic drugs on human endogenous retrovirus (HERV) transcription in brain cells. AB - Human endogenous retroviruses (HERVs) have been associated with various neurological and neuropsychiatric disorders. Transcripts and proteins of at least three HERV groups, HERV-W, ERV9 and HERV-K(HML-2) have been detected repeatedly in brain samples or cerebrospinal fluid of patients with schizophrenia suggesting that alterations in HERV activity may play a role in etiopathogenesis. Current therapies otherwise include neuroleptics and/or antidepressants that may induce epigenetic alterations and thus influence HERV expression. To investigate the effects of these drugs on HERV transcriptional activity, HERV expression profiles of a broad range of human brain cell lines treated with valproic acid (VPA), haloperidol, risperidone, and clozapine were analyzed using a retrovirus-specific microarray and qRT-PCR. Investigation of 52 HERV subgroups revealed upregulation of several class I and class II HERV elements by VPA in a dose-dependent manner. The strongest effect was observed on HERV-W and ERV9 groups in the human glioblastoma cell lines SK-N-SH and SK-N-MC, respectively. The transcript level of HERV-K(HML-2) elements was not influenced. Transcription of HERV-W, ERV9 and HERV-K(HML-2) taxa was further quantified in postmortem brain samples of patients with schizophrenia, bipolar disorders and a healthy control group with regard to their medication. Patients with schizophrenia showed a significantly higher HERV W transcription associated with VPA treatment. However in case of ERV9, enhanced transcript levels could not be explained solely by VPA treatment, since a slight increase was also found in untreated patients compared to healthy controls. HERV K(HML-2) elements appeared to be upregulated in some patients with bipolar disorders independent from medication. In conclusion, these results suggest that antipsychotic medication may contribute to increased expression of distinct HERV taxa in patients with neuropsychiatric diseases. PMID- 22253876 TI - Molecular mechanisms of fiber differential development between G. barbadense and G. hirsutum revealed by genetical genomics. AB - Cotton fiber qualities including length, strength and fineness are known to be controlled by genes affecting cell elongation and secondary cell wall (SCW) biosynthesis, but the molecular mechanisms that govern development of fiber traits are largely unknown. Here, we evaluated an interspecific backcrossed population from G. barbadense cv. Hai7124 and G. hirsutum acc. TM-1 for fiber characteristics in four-year environments under field conditions, and detected 12 quantitative trait loci (QTL) and QTL-by-environment interactions by multi-QTL joint analysis. Further analysis of fiber growth and gene expression between TM-1 and Hai7124 showed greater differences at 10 and 25 days post-anthesis (DPA). In this two period important for fiber performances, we integrated genome-wide expression profiling with linkage analysis using the same genetic materials and identified in total 916 expression QTL (eQTL) significantly (P<0.05) affecting the expression of 394 differential genes. Many positional cis-/trans-acting eQTL and eQTL hotspots were detected across the genome. By comparative mapping of eQTL and fiber QTL, a dataset of candidate genes affecting fiber qualities was generated. Real-time quantitative RT-PCR (qRT-PCR) analysis confirmed the major differential genes regulating fiber cell elongation or SCW synthesis. These data collectively support molecular mechanism for G. hirsutum and G. barbadense through differential gene regulation causing difference of fiber qualities. The down-regulated expression of abscisic acid (ABA) and ethylene signaling pathway genes and high-level and long-term expression of positive regulators including auxin and cell wall enzyme genes for fiber cell elongation at the fiber developmental transition stage may account for superior fiber qualities. PMID- 22253877 TI - Metagenomic analysis of the bioremediation of diesel-contaminated Canadian high arctic soils. AB - As human activity in the Arctic increases, so does the risk of hydrocarbon pollution events. On site bioremediation of contaminated soil is the only feasible clean up solution in these remote areas, but degradation rates vary widely between bioremediation treatments. Most previous studies have focused on the feasibility of on site clean-up and very little attention has been given to the microbial and functional communities involved and their ecology. Here, we ask the question: which microorganisms and functional genes are abundant and active during hydrocarbon degradation at cold temperature? To answer this question, we sequenced the soil metagenome of an ongoing bioremediation project in Alert, Canada through a time course. We also used reverse-transcriptase real-time PCR (RT-qPCR) to quantify the expression of several hydrocarbon-degrading genes. Pseudomonas species appeared as the most abundant organisms in Alert soils right after contamination with diesel and excavation (t = 0) and one month after the start of the bioremediation treatment (t = 1m), when degradation rates were at their highest, but decreased after one year (t = 1y), when residual soil hydrocarbons were almost depleted. This trend was also reflected in hydrocarbon degrading genes, which were mainly affiliated with Gammaproteobacteria at t = 0 and t = 1m and with Alphaproteobacteria and Actinobacteria at t = 1y. RT-qPCR assays confirmed that Pseudomonas and Rhodococcus species actively expressed hydrocarbon degradation genes in Arctic biopile soils. Taken together, these results indicated that biopile treatment leads to major shifts in soil microbial communities, favoring aerobic bacteria that can degrade hydrocarbons. PMID- 22253878 TI - Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia. AB - PURPOSE: The hypoxic microenvironment of glioblastoma multiforme (GBM) is thought to increase resistance to cancer therapies. Recent evidence suggests that hypoxia induces protein phosphatase 2A (PP2A), a regulator of cell cycle and cell death. The effects of PP2A on GBM tumor cell proliferation and survival during hypoxic conditions have not been studied. EXPERIMENTAL DESIGN: Expression of PP2A subunits and HIF-alpha proteins was measured in 65 high-grade astrocytoma and 18 non-neoplastic surgical brain specimens by western blotting. PP2A activity was measured by an immunoprecipitation assay. For in vitro experiments, GBM-derived tumor stem cell-like cells (TSCs) were exposed to severe hypoxia produced by either CoCl2 or 1% O2. PP2A activity was inhibited either by okadaic acid or by shRNA depletion of the PP2A C subunit. Effects of PP2A activity on cell cycle progression and cell survival during hypoxic conditions were assessed using flow cytometry. RESULTS: In our patient cohort, PP2A activity was positively correlated with HIF-1? protein expression (P = 0.002). Patients with PP2A activity levels above 160 pMP had significantly worse survival compared to patients with levels below this threshold (P = 0.002). PP2A activity was an independent predictor of survival on multivariable analysis (P = 0.009). In our in vitro experiments, we confirmed that severe hypoxia induces PP2A activity in TSCs 6 hours after onset of exposure. PP2A activity mediated G1/S phase growth inhibition and reduced cellular ATP consumption in hypoxic TSCs. Conversely, inhibition of PP2A activity led to increased cell proliferation, exhaustion of intracellular ATP, and accelerated P53-independent cell death of hypoxic TSCs. CONCLUSIONS: Our results suggest that PP2A activity predicts poor survival in GBM. PP2A appears to reduce the metabolic demand of hypoxic TSCs and enhances tumor cell survival. Modulation of PP2A may be a potential target for cancer therapy. PMID- 22253879 TI - Inhibition of firefly luciferase by general anesthetics: effect on in vitro and in vivo bioluminescence imaging. AB - Bioluminescence imaging is routinely performed in anesthetized mice. Often isoflurane anesthesia is used because of its ease of use and fast induction/recovery. However, general anesthetics have been described as important inhibitors of the luciferase enzyme reaction. AIM: To investigate frequently used mouse anesthetics for their direct effect on the luciferase reaction, both in vitro and in vivo. MATERIALS AND METHODS: isoflurane, sevoflurane, desflurane, ketamine, xylazine, medetomidine, pentobarbital and avertin were tested in vitro on luciferase-expressing intact cells, and for non-volatile anesthetics on intact cells and cell lysates. In vivo, isoflurane was compared to unanesthetized animals and different anesthetics. Differences in maximal photon emission and time-to-peak photon emission were analyzed. RESULTS: All volatile anesthetics showed a clear inhibitory effect on the luciferase activity of 50% at physiological concentrations. Avertin had a stronger inhibitory effect of 80%. For ketamine and xylazine, increased photon emission was observed in intact cells, but this was not present in cell lysate assays, and was most likely due to cell toxicity and increased cell membrane permeability. In vivo, the highest signal intensities were measured in unanesthetized mice and pentobarbital anesthetized mice, followed by avertin. Isoflurane and ketamine/medetomidine anesthetized mice showed the lowest photon emission (40% of unanesthetized), with significantly longer time-to-peak than unanesthetized, pentobarbital or avertin anesthetized mice. We conclude that, although strong inhibitory effects of anesthetics are present in vitro, their effect on in vivo BLI quantification is mainly due to their hemodynamic effects on mice and only to a lesser extent due to the direct inhibitory effect. PMID- 22253880 TI - Rescue of dystrophic skeletal muscle by PGC-1alpha involves a fast to slow fiber type shift in the mdx mouse. AB - Increased utrophin expression is known to reduce pathology in dystrophin deficient skeletal muscles. Transgenic over-expression of PGC-1alpha has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1alpha signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1alpha in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1alpha. PGC-1alpha over expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1alpha over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1alpha pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1alpha pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle. PMID- 22253881 TI - Introduced predator elicits deficient brood defence behaviour in a crater lake fish. AB - Introduced species represent one of the most serious global threats to biodiversity. In this field-based study, we assessed behavioural responses of brood tending cichlid fish to an invasive predator of their offspring. This was achieved by comparing parental defence responses of the endangered arrow cichlid (Amphilophus zaliosus), a fish species endemic to the crater lake Apoyo in Nicaragua, towards the bigmouth sleeper (Gobiomorus dormitor), a formidable predator of cichlid fry, and all other potential fish predators of offspring. The bigmouth sleeper was recently introduced into Apoyo but naturally co-exists with cichlids in a few other Nicaraguan lakes. Arrow cichlid parents allowed bigmouth sleepers to advance much closer to their fry than other predators before initiating aggressive brood defence behaviours. Interestingly, parents of a very closely related species, A. sagittae, which has coevolved with bigmouth sleepers in crater lake Xiloa, reacted to approaching bigmouth sleepers at comparable distances as to other predators of cichlid fry. These results provide a novel demonstration of the specific mechanism (i.e. naive parental behaviour) by which invasive predators may negatively affect species that lack the adequate behavioural repertoire. PMID- 22253882 TI - The RNA binding protein Csx1 promotes sexual differentiation in Schizosaccharomyces pombe. AB - Sexual differentiation is a highly regulated process in the fission yeast Schizosaccharomyces pombe and is triggered by nutrient depletion, mainly nitrogen source. One of the key regulatory proteins in fission yeast sexual differentiation is the transcription factor Ste11. Ste11 regulates the transcription of many genes required for the initial steps of conjugation and meiosis, and its deficiency leads to sterility. Ste11 activity is mainly regulated at two levels: phosphorylation and abundance of its mRNA. Csx1 is an RNA binding protein that we have previously described to bind and regulate the turnover rate of the mRNA encoding the transcription factor Atf1 in the presence of oxidative stress. We have observed that Csx1-deficient cells have defects in sexual differentiation and are partially sterile. We investigated how Csx1 is regulating this process in S. pombe. Csx1 associates with ste11+ mRNA and cells lacking Csx1 are sterile with a reduced amount of ste11+ mRNA. Overexpression of ste11+ mRNA completely rescues the mating deficiencies of csx1Delta cells. Here, we present a novel mechanism of ste11+ mRNA positive regulation through the activity of Csx1, an RNA binding protein that also have key functions in the response to oxidative stress in fission yeast. This finding opens interesting question about the possible coordination of sexual differentiation and oxidative stress response in eukaryotes and the role of RNA binding proteins in the adaptation to environmental signals. PMID- 22253883 TI - Preserved morphology and physiology of excitatory synapses in profilin1-deficient mice. AB - Profilins are important regulators of actin dynamics and have been implicated in activity-dependent morphological changes of dendritic spines and synaptic plasticity. Recently, defective presynaptic excitability and neurotransmitter release of glutamatergic synapses were described for profilin2-deficient mice. Both dendritic spine morphology and synaptic plasticity were fully preserved in these mutants, bringing forward the hypothesis that profilin1 is mainly involved in postsynaptic mechanisms, complementary to the presynaptic role of profilin2. To test the hypothesis and to elucidate the synaptic function of profilin1, we here specifically deleted profilin1 in neurons of the adult forebrain by using conditional knockout mice on a CaMKII-cre-expressing background. Analysis of Golgi-stained hippocampal pyramidal cells and electron micrographs from the CA1 stratum radiatum revealed normal synapse density, spine morphology, and synapse ultrastructure in the absence of profilin1. Moreover, electrophysiological recordings showed that basal synaptic transmission, presynaptic physiology, as well as postsynaptic plasticity were unchanged in profilin1 mutants. Hence, loss of profilin1 had no adverse effects on the morphology and function of excitatory synapses. Our data are in agreement with two different scenarios: i) profilins are not relevant for actin regulation in postsynaptic structures, activity dependent morphological changes of dendritic spines, and synaptic plasticity or ii) profilin1 and profilin2 have overlapping functions particularly in the postsynaptic compartment. Future analysis of double mutant mice will ultimately unravel whether profilins are relevant for dendritic spine morphology and synaptic plasticity. PMID- 22253884 TI - Polar invasion and translocation of Neisseria meningitidis and Streptococcus suis in a novel human model of the blood-cerebrospinal fluid barrier. AB - Acute bacterial meningitis is a life-threatening disease in humans. Discussed as entry sites for pathogens into the brain are the blood-brain and the blood cerebrospinal fluid barrier (BCSFB). Although human brain microvascular endothelial cells (HBMEC) constitute a well established human in vitro model for the blood-brain barrier, until now no reliable human system presenting the BCSFB has been developed. Here, we describe for the first time a functional human BCSFB model based on human choroid plexus papilloma cells (HIBCPP), which display typical hallmarks of a BCSFB as the expression of junctional proteins and formation of tight junctions, a high electrical resistance and minimal levels of macromolecular flux when grown on transwell filters. Importantly, when challenged with the zoonotic pathogen Streptococcus suis or the human pathogenic bacterium Neisseria meningitidis the HIBCPP show polar bacterial invasion only from the physiologically relevant basolateral side. Meningococcal invasion is attenuated by the presence of a capsule and translocated N. meningitidis form microcolonies on the apical side of HIBCPP opposite of sites of entry. As a functionally relevant human model of the BCSFB the HIBCPP offer a wide range of options for analysis of disease-related mechanisms at the choroid plexus epithelium, especially involving human pathogens. PMID- 22253885 TI - HIV-1 promotes renal tubular epithelial cell protein synthesis: role of mTOR pathway. AB - Tubular cell HIV-infection has been reported to manifest in the form of cellular hypertrophy and apoptosis. In the present study, we evaluated the role of mammalian target of rapamycin (mTOR) pathway in the HIV induction of tubular cell protein synthesis. Mouse proximal tubular epithelial cells (MPTECs) were transduced with either gag/pol-deleted NL4-3 (HIV/MPTEC) or empty vector (Vector/MPTEC). HIV/MPTEC showed enhanced DNA synthesis when compared with Vector/MPTECs by BRDU labeling studies. HIV/MPTECs also showed enhanced production of beta-laminin and fibronection in addition to increased protein content per cell. In in vivo studies, renal cortical sections from HIV transgenic mice and HIVAN patients showed enhanced tubular cell phosphorylation of mTOR. Analysis of mTOR revealed increased expression of phospho (p)-mTOR in HIV/MPTECs when compared to vector/MPTECs. Further downstream analysis of mTOR pathway revealed enhanced phosphorylation of p70S6 kinase and associated diminished phosphorylation of eEF2 (eukaryotic translation elongation factor 2) in HIV/MPTECs; moreover, HIV/MPTECs displayed enhanced phosphorylation of eIF4B (eukaryotic translation initiation factor 4B) and 4EBP-1 (eukaryotic 4E binding protein). To confirm our hypothesis, we evaluated the effect of rapamycin on HIV induced tubular cell downstream signaling. Rapamycin not only attenuated phosphorylation of p70S6 kinase and associated down stream signaling in HIV/MPTECs but also inhibited HIV-1 induced tubular cell protein synthesis. These findings suggest that mTOR pathway is activated in HIV-induced enhanced tubular cell protein synthesis and contributes to tubular cell hypertrophy. PMID- 22253886 TI - Cell wall antibiotics provoke accumulation of anchored mCherry in the cross wall of Staphylococcus aureus. AB - A fluorescence microscopy method to directly follow the localization of defined proteins in Staphylococcus was hampered by the unstable fluorescence of fluorescent proteins. Here, we constructed plasmid (pCX) encoded red fluorescence (RF) mCherry (mCh) hybrids, namely mCh-cyto (no signal peptide and no sorting sequence), mCh-sec (with signal peptide), and mCh-cw (with signal peptide and cell wall sorting sequence). The S. aureus clones targeted mCh-fusion proteins into the cytosol, the supernatant and the cell envelope respectively; in all cases mCherry exhibited bright fluorescence. In staphylococci two types of signal peptides (SP) can be distinguished: the +YSIRK motif SP(lip) and the -YSIRK motif SP(sasF). mCh-hybrids supplied with the +YSIRK motif SP(lip) were always expressed higher than those with -YSIRK motif SP(sasF). To study the location of the anchoring process and also the influence of SP type, mCh-cw was supplied on the one hand with +YSIRK motif (mCh-cw1) and the other hand with -YSIRK motif (mCh-cw2). MCh-cw1 preferentially localized at the cross wall, while mCh-cw2 preferentially localized at the peripheral wall. Interestingly, when treated with sub-lethal concentrations of penicillin or moenomycin, both mCh-cw1 and mCh-cw2 were concentrated at the cross wall. The shift from the peripheral wall to the cross wall required Sortase A (SrtA), as in the srtA mutant this effect was blunted. The effect is most likely due to antibiotic mediated increase of free anchoring sites (Lipid II) at the cross wall, the substrate of SrtA, leading to a preferential incorporation of anchored proteins at the cross wall. PMID- 22253887 TI - Elevation in body temperature to fever range enhances and prolongs subsequent responsiveness of macrophages to endotoxin challenge. AB - Macrophages are often considered the sentries in innate immunity, sounding early immunological alarms, a function which speeds the response to infection. Compared to the large volume of studies on regulation of macrophage function by pathogens or cytokines, relatively little attention has been devoted to the role of physical parameters such as temperature. Given that temperature is elevated during fever, a long-recognized cardinal feature of inflammation, it is possible that macrophage function is responsive to thermal signals. To explore this idea, we used LPS to model an aseptic endotoxin-induced inflammatory response in BALB/c mice and found that raising mouse body temperature by mild external heat treatment significantly enhances subsequent LPS-induced release of TNF-alpha into the peritoneal fluid. It also reprograms macrophages, resulting in sustained subsequent responsiveness to LPS, i.e., this treatment reduces "endotoxin tolerance" in vitro and in vivo. At the molecular level, elevating body temperature of mice results in a increase in LPS-induced downstream signaling including enhanced phosphorylation of IKK and IkappaB, NF-kappaB nuclear translocation and binding to the TNF-alpha promoter in macrophages upon secondary stimulation. Mild heat treatment also induces expression of HSP70 and use of HSP70 inhibitors (KNK437 or Pifithrin-u) largely abrogates the ability of the thermal treatment to enhance TNF-alpha, suggesting that the induction of HSP70 is important for mediation of thermal effects on macrophage function. Collectively, these results support the idea that there has been integration between the evolution of body temperature regulation and macrophage function that could help to explain the known survival benefits of fever in organisms following infection. PMID- 22253888 TI - Coexistence via resource partitioning fails to generate an increase in community function. AB - Classic ecological theory suggests that resource partitioning facilitates the coexistence of species by reducing inter-specific competition. A byproduct of this process is an increase in overall community function, because a greater spectrum of resources can be used. In contrast, coexistence facilitated by neutral mechanisms is not expected to increase function. We studied coexistence in laboratory microcosms of the bactivorous ciliates Paramecium aurelia and Colpidium striatum to understand the relationship between function and coexistence mechanism. We quantified population and community-level function (biomass and oxygen consumption), competitive interactions, and resource partitioning. The two ciliates partitioned their bacterial resource along a size axis, with the larger ciliate consuming larger bacteria than the smaller ciliate. Despite this, there was no gain in function at the community level for either biomass or oxygen consumption, and competitive effects were symmetrical within and between species. Because other potential coexistence mechanisms can be ruled out, it is likely that inter-specific interference competition diminished the expected gain in function generated by resource partitioning, leading to a system that appeared competitively neutral even when structured by niche partitioning. We also analyzed several previous studies where two species of protists coexisted and found that the two-species communities showed a broad range of biomass levels relative to the single-species states. PMID- 22253889 TI - DNA display selection of peptide ligands for a full-length human G protein coupled receptor on CHO-K1 cells. AB - The G protein-coupled receptors (GPCRs), which form the largest group of transmembrane proteins involved in signal transduction, are major targets of currently available drugs. Thus, the search for cognate and surrogate peptide ligands for GPCRs is of both basic and therapeutic interest. Here we describe the application of an in vitro DNA display technology to screening libraries of peptide ligands for full-length GPCRs expressed on whole cells. We used human angiotensin II (Ang II) type-1 receptor (hAT1R) as a model GPCR. Under improved selection conditions using hAT1R-expressing Chinese hamster ovary (CHO)-K1 cells as bait, we confirmed that Ang II gene could be enriched more than 10,000-fold after four rounds of selection. Further, we successfully selected diverse Ang II like peptides from randomized peptide libraries. The results provide more precise information on the sequence-function relationships of hAT1R ligands than can be obtained by conventional alanine-scanning mutagenesis. Completely in vitro DNA display can overcome the limitations of current display technologies and is expected to prove widely useful for screening diverse libraries of mutant peptide and protein ligands for receptors that can be expressed functionally on the surface of CHO-K1 cells. PMID- 22253890 TI - Associations of insulin and insulin-like growth factors with physical performance in old age in the Boyd Orr and Caerphilly studies. AB - OBJECTIVE: Insulin and the insulin-like growth factor (IGF) system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age. METHODS: Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63-86 years. We examined prospective associations of insulin, IGF-I, IGF II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men); and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women). RESULTS: In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD) increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: -0.2%, 3.2%; p = 0.08), but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08), although associations were attenuated after controlling for body mass index (BMI) and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02), but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance. CONCLUSIONS: There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings. PMID- 22253891 TI - Involvement of autophagy in cardiac remodeling in transgenic mice with cardiac specific over-expression of human programmed cell death 5. AB - Programmed cell death 5 (PDCD5) is a cytosolic protein suppressing growth of multiple types of cancer cells through activating p53. We hypothesized that PDCD5 plays an essential role in cardiac remodeling and function. PDCD5 was significantly up-regulated in the hearts from mice subjected to angiotensin II treatment or transverse aortic constriction. Thus, we generated transgenic mice over-expressing human PDCD5 under the control of alpha myosin heavy chain promoter to examine the role of PDCD5 in cardiac remodeling. Transgenic founder died spontaneously displayed enlarged heart. The high PDCD5 over-expressing line (10-fold) showed reduced survival rate, increase in heart weight normalized to body weight. Real-Time RT-PCR analysis revealed fetal gene program was up regulated. Echocardiography and histopathological examination showed characteristics of dilated cardiomyopathy and heart failure in transgenic mice. Western blot and immunohistochemistry analysis showed autophagy was dramatically increased in transgenic mice as compared to WT littermates control mice, while apoptosis remained unchanged. The enhanced autophagy in high over-expressing line was associated with significant increase in p53 activity and its downstream target damage-regulated autophagy modulator expression. The low over-expressing line (3.5-fold) appeared normal, but was more susceptible to angiotensin II induced cardiac hypertrophy. This study is the first providing evidence that PDCD5 plays an important role in cardiac remodeling. PMID- 22253892 TI - Neuroretinal rim area and body mass index. AB - PURPOSE: To examine associations between neuroretinal rim area, pressure related factors and anthropometric parameters in a population-based setting. METHODS: The population-based cross-sectional Beijing Eye Study 2006 included 3251 subjects with an age of 45+ years. The participants underwent a detailed ophthalmic examination. Exclusion criteria for our study were high myopia of more than -8 diopters and angle-closure glaucoma. RESULTS: The study included 2917 subjects with a mean age of 59.8+/-9.8 years (range: 45-89 years). Mean neuroretinal rim area was 1.97+/-0.38 mm2, mean intraocular pressure 15.6+/-3.0 mmHg, mean diastolic blood pressure 79.0+/-5.9 mm Hg, mean systolic blood pressure 133.5+/ 11.1 mmHg, and mean body mass index was 25.5+/-3.7. In univariate analysis, neuroretinal rim area was significantly associated with optic disc size, open angle glaucoma, refractive error, age and gender. After adjustment for these parameters in a multivariate analysis, a larger neuroretinal rim area was significantly correlated with a higher body mass index (P<0.001), in addition to be associated with a lower intraocular pressure (P = 0.004), lower mean blood pressure (P = 0.02), and higher ocular perfusion pressure. CONCLUSIONS: In a general population, neuroretinal rim as equivalent of the optic nerve fibers is related to a higher body mass index, after adjustment for disc area, refractive error, age, gender, open-angle glaucoma, intraocular pressure, blood pressure and ocular perfusion pressure. Since body mass index is associated with cerebrospinal fluid pressure, the latter may be associated with neuroretinal rim area. It may serve as an indirect hint for an association between cerebrospinal fluid pressure and glaucoma. PMID- 22253893 TI - Ecoregional analysis of nearshore sea-surface temperature in the North Pacific. AB - The quantification and description of sea surface temperature (SST) is critically important because it can influence the distribution, migration, and invasion of marine species; furthermore, SSTs are expected to be affected by climate change. To better understand present temperature regimes, we assembled a 29-year nearshore time series of mean monthly SSTs along the North Pacific coastline using remotely-sensed satellite data collected with the Advanced Very High Resolution Radiometer (AVHRR) instrument. We then used the dataset to describe nearshore (<20 km offshore) SST patterns of 16 North Pacific ecoregions delineated by the Marine Ecoregions of the World (MEOW) hierarchical schema. Annual mean temperature varied from 3.8 degrees C along the Kamchatka ecoregion to 24.8 degrees C in the Cortezian ecoregion. There are smaller annual ranges and less variability in SST in the Northeast Pacific relative to the Northwest Pacific. Within the 16 ecoregions, 31-94% of the variance in SST is explained by the annual cycle, with the annual cycle explaining the least variation in the Northern California ecoregion and the most variation in the Yellow Sea ecoregion. Clustering on mean monthly SSTs of each ecoregion showed a clear break between the ecoregions within the Warm and Cold Temperate provinces of the MEOW schema, though several of the ecoregions contained within the provinces did not show a significant difference in mean seasonal temperature patterns. Comparison of these temperature patterns shared some similarities and differences with previous biogeographic classifications and the Large Marine Ecosystems (LMEs). Finally, we provide a web link to the processed data for use by other researchers. PMID- 22253894 TI - Surface modifications by field induced diffusion. AB - By applying a voltage pulse to a scanning tunneling microscope tip the surface under the tip will be modified. We have in this paper taken a closer look at the model of electric field induced surface diffusion of adatoms including the van der Waals force as a contribution in formations of a mound on a surface. The dipole moment of an adatom is the sum of the surface induced dipole moment (which is constant) and the dipole moment due to electric field polarisation which depends on the strength and polarity of the electric field. The electric field is analytically modelled by a point charge over an infinite conducting flat surface. From this we calculate the force that cause adatoms to migrate. The calculated force is small for voltage used, typical 1 pN, but due to thermal vibration adatoms are hopping on the surface and even a small net force can be significant in the drift of adatoms. In this way we obtain a novel formula for a polarity dependent threshold voltage for mound formation on the surface for positive tip. Knowing the voltage of the pulse we then can calculate the radius of the formed mound. A threshold electric field for mound formation of about 2 V/nm is calculated. In addition, we found that van der Waals force is of importance for shorter distances and its contribution to the radial force on the adatoms has to be considered for distances smaller than 1.5 nm for commonly used voltages. PMID- 22253895 TI - Supplementation of male pheromone on rock substrates attracts female rock lizards to the territories of males: a field experiment. AB - BACKGROUND: Many animals produce elaborated sexual signals to attract mates, among them are common chemical sexual signals (pheromones) with an attracting function. Lizards produce chemical secretions for scent marking that may have a role in sexual selection. In the laboratory, female rock lizards (Iberolacerta cyreni) prefer the scent of males with more ergosterol in their femoral secretions. However, it is not known whether the scent-marks of male rock lizards may actually attract females to male territories in the field. METHODOLOGY/PRINCIPAL FINDINGS: In the field, we added ergosterol to rocks inside the territories of male lizards, and found that this manipulation resulted in increased relative densities of females in these territories. Furthermore, a higher number of females were observed associated to males in manipulated plots, which probably increased mating opportunities for males in these areas. CONCLUSIONS/SIGNIFICANCE: These and previous laboratory results suggest that female rock lizards may select to settle in home ranges based on the characteristics of scent-marks from conspecific males. Therefore, male rock lizards might attract more females and obtain more matings by increasing the proportion of ergosterol when scent-marking their territories. However, previous studies suggest that the allocation of ergosterol to secretions may be costly and only high quality males could afford it, thus, allowing the evolution of scent marks as an honest sexual display. PMID- 22253896 TI - NMR derived model of GTPase effector domain (GED) self association: relevance to dynamin assembly. AB - Self-association of dynamin to form spiral structures around lipidic vesicles during endocytosis is largely mediated by its 'coiled coil' GTPase Effector Domain (GED), which, in vitro, self-associates into huge helical assemblies. Residue-level structural characterizations of these assemblies and understanding the process of association have remained a challenge. It is also impossible to get folded monomers in the solution phase. In this context, we have developed here a strategy to probe the self-association of GED by first dissociating the assembly using Dimethyl Sulfoxide (DMSO) and then systematically monitoring the refolding into helix and concomitant re-association using NMR spectroscopy, as DMSO concentration is progressively reduced. The short segment, Arg109 - Met116, acts as the nucleation site for helix formation and self-association. Hydrophobic and complementary charge interactions on the surfaces drive self-association, as the helices elongate in both the directions resulting in an antiparallel stack. A small N-terminal segment remains floppy in the assembly. Following these and other published results on inter-domain interactions, we have proposed a plausible mode of dynamin self assembly. PMID- 22253898 TI - "Hot hand" on strike: bowling data indicates correlation to recent past results, not causality. AB - Recently, the "hot hand" phenomenon regained interest due to the availability and accessibility of large scale data sets from the world of sports. In support of common wisdom and in contrast to the original conclusions of the seminal paper about this phenomenon by Gilovich, Vallone and Tversky in 1985, solid evidences were supplied in favor of the existence of this phenomenon in different kinds of data. This came after almost three decades of ongoing debates whether the "hot hand" phenomenon in sport is real or just a mis-perception of human subjects of completely random patterns present in reality. However, although this phenomenon was shown to exist in different sports data including basketball free throws and bowling strike rates, a somehow deeper question remained unanswered: are these non random patterns results of causal, short term, feedback mechanisms or simply time fluctuations of athletes performance. In this paper, we analyze large amounts of data from the Professional Bowling Association(PBA). We studied the results of the top 100 players in terms of the number of available records (summed into more than 450,000 frames). By using permutation approach and dividing the analysis into different aggregation levels we were able to supply evidence for the existence of the "hot hand" phenomenon in the data, in agreement with previous studies. Moreover, by using this approach, we were able to demonstrate that there are, indeed, significant fluctuations from game to game for the same player but there is no clustering of successes (strikes) and failures (non strikes) within each game. Thus we were lead to the conclusion that bowling results show correlation to recent past results but they are not influenced by them in a causal manner. PMID- 22253897 TI - Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. AB - The testicular dysgenesis syndrome (TDS) hypothesis proposes that maldevelopment of the testis, irrespective of cause, leads to malfunction of the somatic (Leydig, Sertoli) cells and consequent downstream TDS disorders. Studies in rats exposed in utero to di(n-butyl) phthalate (DBP) have strongly supported the TDS concept, but so far no direct evidence has been produced that links dysgenesis per se to somatic cell dysfunction, in particular to androgen production/action during the 'masculinization programming window' (MPW; e15.5-e18.5). Normal reproductive tract development and anogenital distance (AGD) are programmed within the MPW, and TDS disorders arise because of deficiencies in this programming. However, DBP-induced focal testicular dysgenesis (Leydig cell aggregation, ectopic Sertoli cells, malformed seminiferous cords) is not evident until after the MPW. Therefore, we used AGD as a read-out of androgen exposure in the MPW, and investigated if this measure was related to objectively quantified dysgenesis (Leydig cell aggregation) at e21.5 in male fetuses exposed to vehicle, DBP (500 or 750 mg/kg/day) or the synthetic glucocorticoid dexamethasone (Dex; alone or plus DBP-500) from e15.5-e18.5 (MPW), e13.5-e20.5 or e19.5-e20.5 (late window). Dysgenesis was found only in animals exposed to DBP during the MPW, and was negatively correlated (R2 = -0.5) with AGD at e21.5 and at postnatal day 8, irrespective of treatment period. Dysgenesis was also negatively correlated (R2 = -0.5) with intratesticular testosterone (ITT) at e21.5, but only when treatments in short windows (MPW, late window) were excluded; the same was true for correlation between AGD and ITT. We conclude that AGD, reflecting Leydig cell function solely within the MPW, is strongly related to focal dysgenesis. Our results point to this occurring because of a common early mechanism, targeted by DBP that determines both dysgenesis and early (during the MPW) fetal Leydig cell dysfunction. The findings provide strong validation of the TDS hypothesis. PMID- 22253899 TI - Cell hierarchy and lineage commitment in the bovine mammary gland. AB - The bovine mammary gland is a favorable organ for studying mammary cell hierarchy due to its robust milk-production capabilities that reflect the adaptation of its cell populations to extensive expansion and differentiation. It also shares basic characteristics with the human breast, and identification of its cell composition may broaden our understanding of the diversity in cell hierarchy among mammals. Here, Lin- epithelial cells were sorted according to expression of CD24 and CD49f into four populations: CD24(med)CD49f(pos) (putative stem cells, puStm), CD24(neg)CD49f(pos) (Basal), CD24(high)CD49f(neg) (putative progenitors, puPgt) and CD24(med)CD49f(neg) (luminal, Lum). These populations maintained differential gene expression of lineage markers and markers of stem cells and luminal progenitors. Of note was the high expression of Stat5a in the puPgt cells, and of Notch1, Delta1, Jagged1 and Hey1 in the puStm and Basal populations. Cultured puStm and Basal cells formed lineage-restricted basal or luminal clones and after re-sorting, colonies that preserved a duct-like alignment of epithelial layers. In contrast, puPgt and Lum cells generated only luminal clones and unorganized colonies. Under non-adherent culture conditions, the puPgt and puStm populations generated significantly more floating colonies. The increase in cell number during culture provides a measure of propagation potential, which was highest for the puStm cells. Taken together, these analyses position puStm cells at the top of the cell hierarchy and denote the presence of both bi-potent and luminally restricted progenitors. In addition, a population of differentiated luminal cells was marked. Finally, combining ALDH activity with cell-surface marker analyses defined a small subpopulation that is potentially stem cell-enriched. PMID- 22253900 TI - Information transmission in cercal giant interneurons is unaffected by axonal conduction noise. AB - What are the fundamental constraints on the precision and accuracy with which nervous systems can process information? One constraint must reflect the intrinsic "noisiness" of the mechanisms that transmit information between nerve cells. Most neurons transmit information through the probabilistic generation and propagation of spikes along axons, and recent modeling studies suggest that noise from spike propagation might pose a significant constraint on the rate at which information could be transmitted between neurons. However, the magnitude and functional significance of this noise source in actual cells remains poorly understood. We measured variability in conduction time along the axons of identified neurons in the cercal sensory system of the cricket Acheta domesticus, and used information theory to calculate the effects of this variability on sensory coding. We found that the variability in spike propagation speed is not large enough to constrain the accuracy of neural encoding in this system. PMID- 22253901 TI - Candida albicans isolates from the gut of critically ill patients respond to phosphate limitation by expressing filaments and a lethal phenotype. AB - Candida albicans is an opportunistic pathogen that proliferates in the intestinal tract of critically ill patients where it continues to be a major cause of infectious-related mortality. The precise cues that shift intestinal C. albicans from its ubiquitous indolent colonizing yeast form to an invasive and lethal filamentous form remain unknown. We have previously shown that severe phosphate depletion develops in the intestinal tract during extreme physiologic stress and plays a major role in shifting intestinal Pseudomonas aeruginosa to express a lethal phenotype via conserved phosphosensory-phosphoregulatory systems. Here we studied whether phosphate dependent virulence expression could be similarly demonstrated for C. albicans. C. albicans isolates from the stool of critically ill patients and laboratory prototype strains (SC5314, BWP17, SN152) were evaluated for morphotype transformation and lethality against C. elegans and mice during exposure to phosphate limitation. Isolates ICU1 and ICU12 were able to filament and kill C. elegans in a phosphate dependent manner. In a mouse model of intestinal phosphate depletion (30% hepatectomy), direct intestinal inoculation of C. albicans caused mortality that was prevented by oral phosphate supplementation. Prototype strains displayed limited responses to phosphate limitation; however, the pho4Delta mutant displayed extensive filamentation during low phosphate conditions compared to its isogenic parent strain SN152, suggesting that mutation in the transcriptional factor Pho4p may sensitize C. albicans to phosphate limitation. Extensive filamentation was also observed in strain ICU12 suggesting that this strain is also sensitized to phosphate limitation. Analysis of the sequence of PHO4 in strain ICU12, its transcriptional response to phosphate limitation, and phosphatase assays confirmed that ICU12 demonstrates a profound response to phosphate limitation. The emergence of strains of C. albicans with marked responsiveness to phosphate limitation may represent a fitness adaptation to the complex and nutrient scarce environment typical of the gut of a critically ill patient. PMID- 22253902 TI - Region specific and worldwide distribution of collagen-binding M proteins with PARF motifs among human pathogenic streptococcal isolates. AB - Some of the variety of Streptococcus pyogenes and Streptococcus dysgalactiae ssp. equisimilis (SDSE) M proteins act as collagen-binding adhesins that facilitate acute infection. Moreover, their potential to trigger collagen autoimmunity has been implicated in the pathogenesis of acute rheumatic fever and attributed to a collagen-binding motif called PARF (peptide associated with rheumatic fever). For the first time we determine the rate of clinical isolates with collagen-binding M proteins that use a PARF motif (A/T/E)XYLXX(L/F)N in a defined geographic region, Vellore in South India. In this region both, incidence of streptococcal infections and prevalence of acute rheumatic fever are high. M proteins with PARF motif conferred collagen-binding activity to 3.9% of 153 S. pyogenes and 10.6% of 255 SDSE clinical isolates from Vellore. The PARF motif occurred in three S. pyogenes and 22 SDSE M protein types. In one of the S. pyogenes and five of the SDSE M proteins that contained the motif, collagen-binding was impaired, due to influences of other parts of the M protein molecule. The accumulated data on the collagen binding activity of certain M protein types allowed a reanalysis of published worldwide emm-typing data with the aim to estimate the rates of isolates that bind collagen via PARF. The results indicate that M proteins, which bind collagen via a PARF motif, are epidemiologically relevant in human infections, not only in Vellore. It is imperative to include the most relevant collagen-binding M types in vaccines. But when designing M protein based vaccines it should be considered that collagen binding motifs within the vaccine antigen remain potential risk factors. PMID- 22253903 TI - Interleukin-1 inhibition and fatigue in primary Sjogren's syndrome--a double blind, randomised clinical trial. AB - OBJECTIVES: Fatigue is a major cause of disability in primary Sjogren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue. METHODS: Twenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4. RESULTS: There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group. CONCLUSIONS: This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS. TRIAL REGISTRATION: ClinicalTrials.gov NCT00683345. PMID- 22253904 TI - The effect of p38 mitogen-activated protein kinase activation on inflammatory liver damage following hemorrhagic shock in rats. AB - Hemorrhagic shock is a frequent cause of liver failure and often leads to a fatal outcome. Several studies have revealed that p38 MAPK is a key mediator in hemorrhagic damage of the primary organs through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. However, the precise role of these factors in liver damage following hemorrhagic shock is unclear. In this study, we used FR167653, a specific inhibitor of p38 MAPK phosphorylation, to examine the role of p38 MAPK in liver damage occurring up to 5 hours after a hemorrhagic episode in a rat model. Activation of p38 MAPK in the liver as well as an increase in hepatic mRNA expression and serum concentrations of TNF-alpha and IL-1beta occurred during the early phase after hemorrhage. Increased serum levels of hepatic enzymes, as well as histological damage and activated neutrophil accumulation in the liver, were observed in the late phase following hemorrhagic shock. FR167653 inhibited the inflammation-related hepatic injury following hemorrhagic shock. Bacterial lipopolysaccharide (LPS) derived from the gut appeared to have little effects on the hepatic damage. These results demonstrate that p38 MAPK activation is induced by hepatic ischemia during hemorrhagic shock and plays an important role both in the hepatic expression of proinflammatory cytokines and in the development of inflammation-related liver damage. PMID- 22253905 TI - Hepatocyte proliferation/growth arrest balance in the liver of mice during E. multilocularis infection: a coordinated 3-stage course. AB - BACKGROUND: Alveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection. METHODOLOGY/PRINCIPAL FINDINGS: Using Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45beta, Gadd45gamma, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2-60) and middle (day60-180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45beta, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45gamma gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180-360), p53, p21 and Gadd45gamma gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time. CONCLUSIONS: Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals. PMID- 22253906 TI - Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat. AB - BACKGROUND: Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. METHODS: Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1beta, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-alpha) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. RESULTS: Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. CONCLUSION: AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality. PMID- 22253907 TI - Biophysical factors affecting the distribution of demersal fish around the head of a Submarine Canyon off the Bonney Coast, South Australia. AB - We sampled the demersal fish community of the Bonney Canyon, South Australia at depths (100-1,500 m) and locations that are poorly known. Seventy-eight species of demersal fish were obtained from 12 depth-stratified trawls along, and to either side, of the central canyon axis. Distributional patterns in species richness and biomass were highly correlated. Three fish assemblage groupings, characterised by small suites of species with narrow depth distributions, were identified on the shelf, upper slope and mid slope. The assemblage groupings were largely explained by depth (rhow = 0.78). Compared to the depth gradient, canyon related effects are weak or occur at spatial or temporal scales not sampled in this study. A conceptual physical model displayed features consistent with the depth zonational patterns in fish, and also indicated that canyon upwelling can occur. The depth zonation of the fish assemblage was associated with the depth distribution of water masses in the area. Notably, the mid-slope community (1,000 m) coincided with a layer of Antarctic Intermediate Water, the upper slope community (500 m) resided within the core of the Flinders Current, and the shelf community was located in a well-mixed layer of surface water (<450 m depth). PMID- 22253908 TI - Modeling of miRNA and drug action in the EGFR signaling pathway. AB - MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer. PMID- 22253909 TI - c-MET protects breast cancer cells from apoptosis induced by sodium butyrate. AB - Sodium butyrate (NaBu) is regarded as a potential reagent for cancer therapy. In this study, a specific breast cancer cell population that is resistant NaBu treatment was identified. These cells possess cancer stem cell characters, such as the capability of sphere formation in vitro and high tumor incident rate (85%) in mouse model. Forty percent of the NaBu resistant cells express the cancer stem cells marker, the CD133, whereas only 10% intact cells present the CD133 antigen. Furthermore, the endogenous expressing c-MET contributes to the survival of cancer stem cell population from the treatment of NaBu. The CD133+ group also presents a higher level of c-MET. A combination treatment of MET siRNA and NaBu efficiently prohibited the breast cancer progression, and the incident rate of the tumor decrease to 18%. This study may help to develop a new and alternative strategy for breast cancer therapy. PMID- 22253911 TI - Immunological evaluation of lipopeptide group A streptococcus (GAS) vaccine: structure-activity relationship. AB - Streptococcus pyogenes (group A streptococcus, GAS) is a Gram-positive bacterial pathogen responsible for a wide variety of diseases. To date, GAS vaccine development has focused primarily on the M-protein. The M-protein is highly variable at the amino (N)-terminus (determining serotype) but is conserved at the carboxyl (C)-terminus. Previously a 29 amino acid peptide (named J14) from the conserved region of the M-protein was identified as a potential vaccine candidate. J14 was capable of eliciting protective antibodies that recognized many GAS serotypes when co-administered with immuno-stimulants. This minimal epitope however showed no immunogenicity when administered alone. In an attempt overcome this immunological non-responsiveness, we developed a self-adjuvanting vaccine candidate composed of three components: the B-cell epitope (J14), a universal helper T-cell epitope (P25) and a lipid moiety consisting of lipoamino acids (Laas) which target Toll-like receptor 2 (TLR2). Immunological evaluation in B10.BR (H-2k) mice demonstrated that the epitope attachment to the point of lipid moiety, and the length of the Laa alkyl chain have a profound effect on vaccine immunogenicity after intranasal administration. It was demonstrated that a vaccine featuring C-terminal lipid moiety containing alkyl chains of 16 carbons, with P25 located at the N-terminus, and J14 attached to the side chain of a central lysine residue was capable of inducing optimal antibody response. These findings have considerable relevance to the development of a broad spectrum J14-based GAS vaccine and in particular provided a rational basis for peptide vaccine design based on this self-adjuvanting lipopeptide technology. PMID- 22253910 TI - Identifying mechanisms by which Escherichia coli O157:H7 subverts interferon gamma mediated signal transducer and activator of transcription-1 activation. AB - Enterohemorrhagic Escherichia coli serotype O157:H7 is a food borne enteric bacterial pathogen that causes significant morbidity and mortality in both developing and industrialized nations. E. coli O157:H7 infection of host epithelial cells inhibits the interferon gamma pro-inflammatory signaling pathway, which is important for host defense against microbial pathogens, through the inhibition of Stat-1 tyrosine phosphorylation. The aim of this study was to determine which bacterial factors are involved in the inhibition of Stat-1 tyrosine phosphorylation. Human epithelial cells were challenged with either live bacteria or bacterial-derived culture supernatants, stimulated with interferon gamma, and epithelial cell protein extracts were then analyzed by immunoblotting. The results show that Stat-1 tyrosine phosphorylation was inhibited by E. coli O157:H7 secreted proteins. Using sequential anion exchange and size exclusion chromatography, YodA was identified, but not confirmed to mediate subversion of the Stat-1 signaling pathway using isogenic mutants. We conclude that E. coli O157:H7 subverts Stat-1 tyrosine phosphorylation in response to interferon-gamma through a still as yet unidentified secreted bacterial protein. PMID- 22253912 TI - Crystal structure of a human single domain antibody dimer formed through V(H) V(H) non-covalent interactions. AB - Single-domain antibodies (sdAbs) derived from human V(H) are considered to be less soluble and prone to aggregate which makes it difficult to determine the crystal structures. In this study, we isolated and characterized two anti-human epidermal growth factor receptor-2 (HER2) sdAbs, Gr3 and Gr6, from a synthetic human V(H) phage display library. Size exclusion chromatography and surface plasmon resonance analyses demonstrated that Gr3 is a monomer, but that Gr6 is a strict dimer. To understand this different molecular behavior, we solved the crystal structure of Gr6 to 1.6 A resolution. The crystal structure revealed that the homodimer assembly of Gr6 closely mimics the V(H)-V(L) heterodimer of immunoglobulin variable domains and the dimerization interface is dominated by hydrophobic interactions. PMID- 22253913 TI - Herpesvirus glycoproteins undergo multiple antigenic changes before membrane fusion. AB - Herpesvirus entry is a complicated process involving multiple virion glycoproteins and culminating in membrane fusion. Glycoprotein conformation changes are likely to play key roles. Studies of recombinant glycoproteins have revealed some structural features of the virion fusion machinery. However, how the virion glycoproteins change during infection remains unclear. Here using conformation-specific monoclonal antibodies we show in situ that each component of the Murid Herpesvirus-4 (MuHV-4) entry machinery--gB, gH/gL and gp150--changes in antigenicity before tegument protein release begins. Further changes then occurred upon actual membrane fusion. Thus virions revealed their final fusogenic form only in late endosomes. The substantial antigenic differences between this form and that of extracellular virions suggested that antibodies have only a limited opportunity to block virion membrane fusion. PMID- 22253914 TI - Increasing dietary fat elicits similar changes in fat oxidation and markers of muscle oxidative capacity in lean and obese humans. AB - In lean humans, increasing dietary fat intake causes an increase in whole-body fat oxidation and changes in genes that regulate fat oxidation in skeletal muscle, but whether this occurs in obese humans is not known. We compared changes in whole-body fat oxidation and markers of muscle oxidative capacity differ in lean (LN) and obese (OB) adults exposed to a 2-day high-fat (HF) diet. Ten LN (BMI = 22.5+/-2.5 kg/m2, age = 30+/-8 yrs) and nine OB (BMI = 35.9+/-4.93 kg/m2, 38+/-5 yrs, Mean+/-SD) were studied in a room calorimeter for 24hr while consuming isocaloric low-fat (LF, 20% of energy) and HF (50% of energy) diets. A muscle biopsy was obtained the next morning following an overnight fast. 24h respiratory quotient (RQ) did not significantly differ between groups (LN: 0.91+/ 0.01; OB: 0.92+/-0.01) during LF, and similarly decreased during HF in LN (0.86+/ 0.01) and OB (0.85+/-0.01). The expression of pyruvate dehydrogenase kinase 4 (PDK4) and the fatty acid transporter CD36 increased in both LN and OB during HF. No other changes in mRNA or protein were observed. However, in both LN and OB, the amounts of acetylated peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC1-alpha) significantly decreased and phosphorylated 5-AMP activated protein kinase (AMPK) significantly increased. In response to an isoenergetic increase in dietary fat, whole-body fat oxidation similarly increases in LN and OB, in association with a shift towards oxidative metabolism in skeletal muscle, suggesting that the ability to adapt to an acute increase in dietary fat is not impaired in obesity. PMID- 22253915 TI - Effects of light, food availability and temperature stress on the function of photosystem II and photosystem I of coral symbionts. AB - BACKGROUND: Reef corals are heterotrophic coelenterates that achieve high productivity through their photosynthetic dinoflagellate symbionts. Excessive seawater temperature destabilises this symbiosis and causes corals to "bleach," lowering their photosynthetic capacity. Bleaching poses a serious threat to the persistence of coral reefs on a global scale. Despite expanding research on the causes of bleaching, the mechanisms remain a subject of debate. METHODOLOGY/PRINCIPAL FINDINGS: This study determined how light and food availability modulate the effects of temperature stress on photosynthesis in two reef coral species. We quantified the activities of Photosystem II, Photosystem I and whole chain electron transport under combinations of normal and stressful growth temperatures, moderate and high light levels and the presence or absence of feeding of the coral hosts. Our results show that PS1 function is comparatively robust against temperature stress in both species, whereas PS2 and whole chain electron transport are susceptible to temperature stress. In the symbiotic dinoflagellates of Stylophora pistillata the contents of chlorophyll and major photosynthetic complexes were primarily affected by food availability. In Turbinaria reniformis growth temperature was the dominant influence on the contents of the photosynthetic complexes. In both species feeding the host significantly protected photosynthetic function from high temperature stress. CONCLUSIONS/SIGNIFICANCE: Our findings support the photoinhibition model of coral bleaching and demonstrate that PS1 is not a major site for thermal damage during bleaching events. Feeding mitigates bleaching in two scleractinian corals, so that reef responses to temperature stresses will likely be influenced by the coinciding availabilities of prey for the host. PMID- 22253916 TI - Ejaculate economics: testing the effects of male sexual history on the trade-off between sperm and immune function in Australian crickets. AB - Trade-offs between investment into male sexual traits and immune function provide the foundation for some of the most prominent models of sexual selection. Post copulatory sexual selection on the male ejaculate is intense, and therefore trade offs should occur between investment into the ejaculate and the immune system. Examples of such trade-offs exist, including that between sperm quality and immunity in the Australian cricket, Teleogryllus oceanicus. Here, we explore the dynamics of this trade-off, examining the effects that increased levels of sexual interaction have on the viability of a male's sperm across time, and the concomitant effects on immune function. Males were assigned to a treatment, whereby they cohabited with females that were sexually immature, sexually mature but incapable of copulation, or sexually mature and capable of copulation. Sperm viability of each male was then assessed at two time points: six and 13 days into the treatment, and immune function at day 13. Sperm viability decreased across the time points, but only for males exposed to treatment classes involving sexually mature females. This decrease was similar in magnitude across both sexually mature classes, indicating that costs to the expression of high sperm viability are incurred largely through levels of pre-copulatory investment. Males exposed to immature females produced sperm of low viability at both time points. Although we confirmed a weak negative association between sperm viability and lytic activity (a measure of immune response to bacterial infection) at day 13, this relationship was not altered across the mating treatment. Our results highlight that sperm viability is a labile trait, costly to produce, and subject to strategic allocation in these crickets. PMID- 22253917 TI - High prevalence of Clostridium difficile colonization among nursing home residents in Hesse, Germany. AB - Clostridium difficile is the most common cause of antibiotic-associated diarrhoea in hospitals and other healthcare facilities. The elderly are particularly susceptible and at increased risk for adverse outcome as a result of C. difficile infection. The aim of this study was to determine the prevalence of C. difficile colonization among residents of nursing homes in Hesse and to compare it with the prevalence in the general population living outside long-term care facilities (LTCF). We assessed possible risk factors for C. difficile colonization and determined the genotype of circulating strains. C. difficile was isolated from 11/240 (4.6%) nursing home residents and 2/249 (0.8%) individuals living outside LTCF (p = 0.02). Ten of 11 (90.9%) isolates from nursing homes and one of two isolates from the population outside LTCF were toxigenic. The prevalence of C. difficile colonization varied from 0% to 10% between different nursing homes. Facilities with known actual or recent CDI cases were more likely to have colonized residents than facilities without known CDI cases. C. difficile PCR ribotypes 014 and 001 were the most prevalent genotypes and accounted for 30% and 20% of toxigenic isolates in nursing homes, respectively. Interestingly, no individuals carried the epidemic strain PCR-ribotype 027. Our results suggest that residents of nursing homes in Germany are at high risk for colonization by virulent C. difficile strains. The high prevalence of C. difficile colonization in nursing homes underscores the importance of good adherence to standard infection control precautions even in the absence of a diagnosed infection. They also emphasize the need for specific programs to increase the awareness of healthcare professionals in LTCF for CDI. PMID- 22253919 TI - Factors influencing Chinese male's willingness to undergo circumcision: a cross sectional study in western China. AB - BACKGROUND: Male circumcision (MC) has been shown to reduce the risk of female to male transmission of HIV. The goal of this survey was to explore the acceptability of MC among the Chinese and to identify factors associated with circumcision preference. METHODS: A cross-sectional survey was conducted between September 2009 and December 2010. We interviewed 2,219 male community participants, from three high HIV prevalence provinces in western China. A structured questionnaire was used to collect data on MC knowledge, willingness to accept MC, reasons to accept or refuse MC, and sexual behaviors and health. For those who refused MC, a health education intervention providing information on the benefits of circumcision was conducted. We used multiple logistic regression models to identify factors associated with the acceptability of MC. RESULTS: Of the respondents (n = 2,219), 44.6% (989/2,219) reported they would accept MC for the following reasons: promotion of female partners' hygiene (60.3%), redundant foreskin (59.4%), prevention of penile cancer (50.2%), enhanced sexual pleasure (41.4%), and protection against HIV and STDs (34.2%). The multivariable logistic regression showed that five factors were associated with MC willingness: long foreskin (OR = 15.98), residing in Xinjiang province (OR = 3.69), being younger than 25 (OR = 1.60), knowing hazards of redundant foreskin (OR = 1.78), and having a friend who underwent circumcision (OR = 1.36). CONCLUSION: The acceptability of male circumcision was high among the general population in China. Our study elucidates the factors associated with circumcision preference and suggests that more health education campaigns about positive health effects are necessary to increase the MC rate in China. PMID- 22253918 TI - Up-regulation of Mcl-1 and Bak by coronavirus infection of human, avian and animal cells modulates apoptosis and viral replication. AB - Virus-induced apoptosis and viral mechanisms that regulate this cell death program are key issues in understanding virus-host interactions and viral pathogenesis. Like many other human and animal viruses, coronavirus infection of mammalian cells induces apoptosis. In this study, the global gene expression profiles are first determined in IBV-infected Vero cells at 24 hours post infection by Affymetrix array, using avian coronavirus infectious bronchitis virus (IBV) as a model system. It reveals an up-regulation at the transcriptional level of both pro-apoptotic Bak and pro-survival myeloid cell leukemia-1 (Mcl-1). These results were further confirmed both in vivo and in vitro, in IBV-infected embryonated chicken eggs, chicken fibroblast cells and mammalian cells at transcriptional and translational levels, respectively. Interestingly, the onset of apoptosis occurred earlier in IBV-infected mammalian cells silenced with short interfering RNA targeting Mcl-1 (siMcl-1), and was delayed in cells silenced with siBak. IBV progeny production and release were increased in infected Mcl-1 knockdown cells compared to similarly infected control cells, while the contrary was observed in infected Bak knockdown cells. Furthermore, IBV infection-induced up-regulation of GADD153 regulated the expression of Mcl-1. Inhibition of the mitogen-activated protein/extracellular signal-regulated kinase (MEK/ERK) and phosphoinositide 3-kinase (PI3K/Akt) signaling pathways by chemical inhibitors and knockdown of GADD153 by siRNA demonstrated the involvement of ER-stress response in regulation of IBV-induced Mcl-1 expression. These results illustrate the sophisticated regulatory strategies evolved by a coronavirus to modulate both virus-induced apoptosis and viral replication during its replication cycle. PMID- 22253920 TI - p63 expression defines a lethal subset of muscle-invasive bladder cancers. AB - BACKGROUND: p63 is a member of the p53 family that has been implicated in maintenance of epithelial stem cell compartments. Previous studies demonstrated that p63 is downregulated in muscle-invasive bladder cancers, but the relationship between p63 expression and survival is not clear. METHODOLOGY/PRINCIPAL FINDINGS: We used real-time PCR to characterize p63 expression and several genes implicated in epithelial-to-mesenchymal transition (EMT) in human bladder cancer cell lines (n = 15) and primary tumors (n = 101). We correlated tumor marker expression with stage, disease-specific (DSS), and overall survival (OS). Expression of E-cadherin and p63 correlated directly with one another and inversely with expression of the mesenchymal markers Zeb-1, Zeb 2, and vimentin. Non-muscle-invasive (Ta and T1) bladder cancers uniformly expressed high levels of E-cadherin and p63 and low levels of the mesenchymal markers. Interestingly, a subset of muscle-invasive (T2-T4) tumors maintained high levels of E-cadherin and p63 expression. As expected, there was a strongly significant correlation between EMT marker expression and muscle invasion (p<0.0001). However, OS was shorter in patients with muscle-invasive tumors that retained p63 (p = 0.007). CONCLUSIONS/SIGNIFICANCE: Our data confirm that molecular markers of EMT are elevated in muscle-invasive bladder cancers, but interestingly, retention of the "epithelial" marker p63 in muscle-invasive tumors is associated with a worse outcome. PMID- 22253921 TI - Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma--a pilot study. AB - BACKGROUND: To date, no biomarkers with reasonable sensitivity and specificity for the early detection of malignant mesothelioma have been described. The use of microRNAs (miRNAs) as minimally-invasive biomarkers has opened new opportunities for the diagnosis of cancer, primarily because they exhibit tumor-specific expression profiles and have been commonly observed in blood of both cancer patients and healthy controls. The aim of this pilot study was to identify miRNAs in the cellular fraction of human peripheral blood as potential novel biomarkers for the detection of malignant mesothelioma. METHODOLOGY/PRINCIPAL FINDINGS: Using oligonucleotide microarrays for biomarker identification the miRNA levels in the cellular fraction of human peripheral blood of mesothelioma patients and asbestos-exposed controls were analyzed. Using a threefold expression change in combination with a significance level of p<0.05, miR-103 was identified as a potential biomarker for malignant mesothelioma. Quantitative real-time PCR (qRT PCR) was used for validation of miR-103 in 23 malignant mesothelioma patients, 17 asbestos-exposed controls, and 25 controls from the general population. For discrimination of mesothelioma patients from asbestos-exposed controls a sensitivity of 83% and a specificity of 71% were calculated, and for discrimination of mesothelioma patients from the general population a sensitivity of 78% and a specificity of 76%. CONCLUSIONS/SIGNIFICANCE: The results of this pilot study show that miR-103 is characterized by a promising sensitivity and specificity and might be a potential minimally-invasive biomarker for the diagnosis of mesothelioma. In addition, our results support the concept of using the cellular fraction of human blood for biomarker discovery. However, for early detection of malignant mesothelioma the feasibility of miR-103 alone or in combination with other biomarkers needs to be analyzed in a prospective study. PMID- 22253922 TI - Cell-to-cell heterogeneity in cortical tension specifies curvature of contact surfaces in Caenorhabditis elegans embryos. AB - In the two-cell stage embryos of Caenorhabditis elegans, the contact surface of the two blastomeres forms a curve that bulges from the AB blastomere to the P1 blastomere. This curve is a consequence of the high intracellular hydrostatic pressure of AB compared with that of P1. However, the higher pressure in AB is intriguing because AB has a larger volume than P1. In soap bubbles, which are a widely used model of cell shape, a larger bubble has lower pressure than a smaller bubble. Here, we reveal that the higher pressure in AB is mediated by its higher cortical tension. The cell fusion experiments confirmed that the curvature of the contact surface is related to the pressure difference between the cells. Chemical and genetic interferences showed that the pressure difference is mediated by actomyosin. Fluorescence imaging indicated that non-muscle myosin is enriched in the AB cortex. The cell killing experiments provided evidence that AB but not P1 is responsible for the pressure difference. Computer simulation clarified that the cell-to-cell heterogeneity of cortical tensions is indispensable for explaining the pressure difference. This study demonstrates that heterogeneity in surface tension results in significant deviations of cell behavior compared to simple soap bubble models, and thus must be taken into consideration in understanding cell shape within embryos. PMID- 22253923 TI - Two-stage clustering (TSC): a pipeline for selecting operational taxonomic units for the high-throughput sequencing of PCR amplicons. AB - Clustering 16S/18S rRNA amplicon sequences into operational taxonomic units (OTUs) is a critical step for the bioinformatic analysis of microbial diversity. Here, we report a pipeline for selecting OTUs with a relatively low computational demand and a high degree of accuracy. This pipeline is referred to as two-stage clustering (TSC) because it divides tags into two groups according to their abundance and clusters them sequentially. The more abundant group is clustered using a hierarchical algorithm similar to that in ESPRIT, which has a high degree of accuracy but is computationally costly for large datasets. The rarer group, which includes the majority of tags, is then heuristically clustered to improve efficiency. To further improve the computational efficiency and accuracy, two preclustering steps are implemented. To maintain clustering accuracy, all tags are grouped into an OTU depending on their pairwise Needleman-Wunsch distance. This method not only improved the computational efficiency but also mitigated the spurious OTU estimation from 'noise' sequences. In addition, OTUs clustered using TSC showed comparable or improved performance in beta-diversity comparisons compared to existing OTU selection methods. This study suggests that the distribution of sequencing datasets is a useful property for improving the computational efficiency and increasing the clustering accuracy of the high throughput sequencing of PCR amplicons. The software and user guide are freely available at http://hwzhoulab.smu.edu.cn/paperdata/. PMID- 22253924 TI - Decrease in pneumococcal co-colonization following vaccination with the seven valent pneumococcal conjugate vaccine. AB - Understanding the epidemiology of pneumococcal co-colonization is important for monitoring vaccine effectiveness and the occurrence of horizontal gene transfer between pneumococcal strains. In this study we aimed to evaluate the impact of the seven-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal co colonization among Portuguese children. Nasopharyngeal samples from children up to 6 years old yielding a pneumococcal culture were clustered into three groups: pre-vaccine era (n = 173), unvaccinated children of the vaccine era (n = 169), and fully vaccinated children (4 doses; n = 150). Co-colonization, serotype identification, and relative serotype abundance were detected by analysis of DNA of the total bacterial growth of the primary culture plate using the plyNCR-RFLP method and a molecular serotyping microarray-based strategy. The plyNCR-RFLP method detected an overall co-colonization rate of 20.1%. Microarray analysis confirmed the plyNCR-RFLP results. Vaccination status was the only factor found to be significantly associated with co-colonization: co-colonization rates were significantly lower (p = 0.004; Fisher's exact test) among fully vaccinated children (8.0%) than among children from the pre-PCV7 era (17.3%) or unvaccinated children of the PCV7 era (18.3%). In the PCV7 era there were significantly less non-vaccine type (NVT) co-colonization events than would be expected based on the NVT distribution observed in the pre-PCV7 era (p = 0.024). In conclusion, vaccination with PCV7 resulted in a lower co-colonization rate due to an asymmetric distribution between NVTs found in single and co-colonized samples. We propose that some NVTs prevalent in the PCV7 era are more competitive than others, hampering their co-existence in the same niche. This result may have important implications since a decrease in co-colonization events is expected to translate in decreased opportunities for horizontal gene transfer, hindering pneumococcal evolution events such as acquisition of antibiotic resistance determinants or capsular switch. This might represent a novel potential benefit of conjugate vaccines. PMID- 22253926 TI - Abnormal white matter integrity in adolescents with internet addiction disorder: a tract-based spatial statistics study. AB - BACKGROUND: Internet addiction disorder (IAD) is currently becoming a serious mental health issue around the globe. Previous studies regarding IAD were mainly focused on associated psychological examinations. However, there are few studies on brain structure and function about IAD. In this study, we used diffusion tensor imaging (DTI) to investigate white matter integrity in adolescents with IAD. METHODOLOGY/PRINCIPAL FINDINGS: Seventeen IAD subjects and sixteen healthy controls without IAD participated in this study. Whole brain voxel-wise analysis of fractional anisotropy (FA) was performed by tract-based spatial statistics (TBSS) to localize abnormal white matter regions between groups. TBSS demonstrated that IAD had significantly lower FA than controls throughout the brain, including the orbito-frontal white matter, corpus callosum, cingulum, inferior fronto-occipital fasciculus, and corona radiation, internal and external capsules, while exhibiting no areas of higher FA. Volume-of-interest (VOI) analysis was used to detect changes of diffusivity indices in the regions showing FA abnormalities. In most VOIs, FA reductions were caused by an increase in radial diffusivity while no changes in axial diffusivity. Correlation analysis was performed to assess the relationship between FA and behavioral measures within the IAD group. Significantly negative correlations were found between FA values in the left genu of the corpus callosum and the Screen for Child Anxiety Related Emotional Disorders, and between FA values in the left external capsule and the Young's Internet addiction scale. CONCLUSIONS: Our findings suggest that IAD demonstrated widespread reductions of FA in major white matter pathways and such abnormal white matter structure may be linked to some behavioral impairments. In addition, white matter integrity may serve as a potential new treatment target and FA may be as a qualified biomarker to understand the underlying neural mechanisms of injury or to assess the effectiveness of specific early interventions in IAD. PMID- 22253925 TI - Targeting sialic acid dependent and independent pathways of invasion in Plasmodium falciparum. AB - The pathology of malaria is a consequence of the parasitaemia which develops through the cyclical asexual replication of parasites in a patient's red blood cells. Multiple parasite ligand-erythrocyte receptor interactions must occur for successful Plasmodium invasion of the human red cell. Two major malaria ligand families have been implicated in these variable ligand-receptor interactions used by Plasmodium falciparum to invade human red cells: the micronemal proteins from the Erythrocyte Binding Ligands (EBL) family and the rhoptry proteins from the Reticulocyte binding Homolog (PfRH) family. Ligands from the EBL family largely govern the sialic acid (SA) dependent pathways of invasion and the RH family ligands (except for RH1) mediate SA independent invasion. In an attempt to dissect out the invasion inhibitory effects of antibodies against ligands from both pathways, we have used EBA-175 and RH5 as model members of each pathway. Mice were immunized with either region II of EBA-175 produced in Pichia pastoris or full-length RH5 produced by the wheat germ cell-free system, or a combination of the two antigens to look for synergistic inhibitory effects of the induced antibodies. Sera obtained from these immunizations were tested for native antigen recognition and for efficacy in invasion inhibition assays. Results obtained show promise for the potential use of such hybrid vaccines to induce antibodies that can block multiple parasite ligand-red cell receptor interactions and thus inhibit parasite invasion. PMID- 22253927 TI - Tissue-specific function of Period3 in circadian rhythmicity. AB - The mammalian circadian system is composed of multiple central and peripheral clocks that are temporally coordinated to synchronize physiology and behavior with environmental cycles. Mammals have three homologs of the circadian Period gene (Per1, 2, 3). While numerous studies have demonstrated that Per1 and Per2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the suprachiasmatic nuclei (SCN), the function of Per3 has been elusive. In the current study, we investigated the role of Per3 in circadian timekeeping in central and peripheral oscillators by analyzing PER2::LUCIFERASE expression in tissues explanted from C57BL/6J wild-type and Per3-/- mice. We observed shortening of the periods in some tissues from Per3-/- mice compared to wild-types. Importantly, the periods were not altered in other tissues, including the SCN, in Per3-/- mice. We also found that Per3-dependent shortening of endogenous periods resulted in advanced phases of those tissues, demonstrating that the in vitro phenotype is also present in vivo. Our data demonstrate that Per3 is important for endogenous timekeeping in specific tissues and those tissue specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3-/- mice. Taken together, our studies demonstrate that Per3 is a key player in the mammalian circadian system. PMID- 22253928 TI - Henipavirus neutralising antibodies in an isolated island population of African fruit bats. AB - Isolated islands provide valuable opportunities to study the persistence of viruses in wildlife populations, including population size thresholds such as the critical community size. The straw-coloured fruit bat, Eidolon helvum, has been identified as a reservoir for henipaviruses (serological evidence) and Lagos bat virus (LBV; virus isolation and serological evidence) in continental Africa. Here, we sampled from a remote population of E. helvum annobonensis fruit bats on Annobon island in the Gulf of Guinea to investigate whether antibodies to these viruses also exist in this isolated subspecies. Henipavirus serological analyses (Luminex multiplexed binding and inhibition assays, virus neutralisation tests and western blots) and lyssavirus serological analyses (LBV: modified Fluorescent Antibody Virus Neutralisation test, LBV and Mokola virus: lentivirus pseudovirus neutralisation assay) were undertaken on 73 and 70 samples respectively. Given the isolation of fruit bats on Annobon and their lack of connectivity with other populations, it was expected that the population size on the island would be too small to allow persistence of viruses that are thought to cause acute and immunising infections. However, the presence of antibodies against henipaviruses was detected using the Luminex binding assay and confirmed using alternative assays. Neutralising antibodies to LBV were detected in one bat using both assays. We demonstrate clear evidence for exposure of multiple individuals to henipaviruses in this remote population of E. helvum annobonensis fruit bats on Annobon island. The situation is less clear for LBV. Seroprevalences to henipaviruses and LBV in Annobon are notably different to those in E. helvum in continental locations studied using the same sampling techniques and assays. Whilst cross-sectional serological studies in wildlife populations cannot provide details on viral dynamics within populations, valuable information on the presence or absence of viruses may be obtained and utilised for informing future studies. PMID- 22253929 TI - Electrical stimulation influences satellite cell proliferation and apoptosis in unloading-induced muscle atrophy in mice. AB - Muscle atrophy caused by disuse is accompanied by adverse physiological and functional consequences. Satellite cells are the primary source of skeletal muscle regeneration. Satellite cell dysfunction, as a result of impaired proliferative potential and/or increased apoptosis, is thought to be one of the causes contributing to the decreased muscle regeneration capacity in atrophy. We have previously shown that electrical stimulation improved satellite cell dysfunction. Here we test whether electrical stimulation can also enhance satellite cell proliferative potential as well as suppress apoptotic cell death in disuse-induced muscle atrophy. Eight-week-old male BALB/c mice were subjected to a 14-day hindlimb unloading procedure. During that period, one limb (HU-ES) received electrical stimulation (frequency: 20 Hz; duration: 3 h, twice daily) while the contralateral limb served as control (HU). Immunohistochemistry and western blotting techniques were used to characterize specific proteins in cell proliferation and apoptosis. The HU-ES soleus muscles showed significant improvement in muscle mass, cross-sectional area, and peak tetanic force relative to the HU limb (p<0.05). The satellite cell proliferative activity as detected within the BrdU+/Pax7+ population was significantly higher (p<0.05). The apoptotic myonuclei (detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) and the apoptotic satellite cells (detected by cleaved Poly [ADP-ribose] polymerase co-labeled with Pax7) were reduced (p<0.05) in the HU-ES limb. Furthermore the apoptosis-inducing factor and cleaved caspase-3 were down-regulated while the anti-apoptotic Bcl-2 protein was up-regulated (p<0.05), in the HU-ES limb. These findings suggest that the electrical stimulation paradigm provides an effective stimulus to rescue the loss of myonuclei and satellite cells in disuse muscle atrophy, thus maintaining a viable satellite cell pool for subsequent muscle regeneration. Optimization of stimulation parameters may enhance the outcome of the intervention. PMID- 22253930 TI - Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. AB - While Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from WASP15 transgenic (Tg) mice overexpressing the WASP N-terminal region (exons 1-5). Upon LPS stimulation, WASP15 Tg BMDM cell lines produce lower levels of inflammatory cytokines, such as TNF-alpha, IL-6, and IL-12p40 than the wild-type BMDM cell line. In addition, the production of nitric oxide by WASP15 Tg BMDM cells in response to LPS and IFN-gamma was significantly impaired. Furthermore, we uncovered that the WASP N-terminal domain associates with the Src homology (SH) 3 domain of Bruton's tyrosine kinase (Btk). Overexpression of the WASP N-terminal domain diminishes the extent of tyrosine phosphorylation of endogenous WASP in WASP15 Tg BMDM cells, possibly by interfering with the specific binding between endogenous WASP and Btk during LPS signaling. These observations strongly suggest that the interaction between WASP N-terminal domain and Btk plays important roles in the LPS signaling cascade in innate immunity. PMID- 22253931 TI - A whole cell assay to measure caspase-6 activity by detecting cleavage of lamin A/C. AB - Caspase-6 is a cysteinyl protease implicated in neurodegenerative conditions including Alzheimer's and Huntington's disease making it an attractive target for therapeutic intervention. A greater understanding of the role of caspase-6 in disease has been hampered by a lack of suitable cellular assays capable of specifically detecting caspase-6 activity in an intact cell environment. This is mainly due to the use of commercially available peptide substrates and inhibitors which lack the required specificity to facilitate development of this type of assay. We report here a 384-well whole-cell chemiluminescent ELISA assay that monitors the proteolytic degradation of endogenously expressed lamin A/C during the early stages of caspase-dependent apoptosis. The specificity of lamin A/C proteolysis by caspase-6 was demonstrated against recombinant caspase family members and further confirmed in genetic deletion studies. In the assay, plasma membrane integrity remained intact as assessed by release of lactate dehydrogenase from the intracellular environment and the exclusion of cell impermeable peptide inhibitors, despite the induction of an apoptotic state. The method described here is a robust tool to support drug discovery efforts targeting caspase-6 and is the first reported to specifically monitor endogenous caspase-6 activity in a cellular context. PMID- 22253932 TI - Lysosome-membrane fusion mediated superoxide production in hyperglycaemia-induced endothelial dysfunction. AB - Lysosomal exocytosis and fusion to cellular membrane is critical in the oxidative stress formation of endothelium under apoptotic stimulus. We investigated the role therein of it in hyperglycaemia-induced endothelial dysfunction. The lysosome-membrane fusion was shown by the expression of lamp1, the lysosomal membrane marker, on cellular membrane and the transportation of lysosomal symbolic enzymes into cultural medium. We also examined the ceramide production, lipid rafts (LRs) clustering, colocalization of gp91(phox), a NADPH oxidase subunit (NOX) to LRs clusters, superoxide (O2.-) formation and nitric oxide (NO) content in human umbilical vein endothelial cells (HUVEC) and the endothelium dependent NO-mediated vasodilation in isolated rat aorta. As compared to normal glucose (5.6 mmol/l, Ctrl) incubation, high glucose (22 mmol/l, HG) exposure facilitated the lysosome-membrane fusion in HUVEC shown by significantly increased quantity of lamp1 protein on cellular membrane and enhanced activity of lysosomal symbolized enzymes in cultural medium. HG incubation also elicited ceramide generation, LRs clustering and gp91(phox) colocalization to LRs clusters which were proved to mediate the HG induced O2.- formation and NO depletion in HUVEC. Functionally, the endothelium-dependent NO-mediated vasodilation in aorta was blunted substantially after HG incubation. Moreover, the HG-induced effect including ceramide production, LRs clustering, gp91(phox) colocalization to LRs clusters, O2.- formation and endothelial dysfunction could be blocked significantly by the inhibition of lysosome-membrane fusion. We propose that hyperglycaemia-induced endothelial impairment is closely related to the lysosome membrane fusion and the following LRs clustering, LRs-NOX platforms formation and O2.- production. PMID- 22253933 TI - Induction of VMAT-1 and TPH-1 expression induces vesicular accumulation of serotonin and protects cells and tissue from cooling/rewarming injury. AB - DDT1 MF-2 hamster ductus deferens cells are resistant to hypothermia due to serotonin secretion from secretory vesicles and subsequent cystathionine beta synthase (CBS) mediated formation of H2S. We investigated whether the mechanism promoting resistance to hypothermia may be translationally induced in cells vulnerable to cold storage. Thus, VMAT-1 (vesicular monoamino transferase) and TPH-1 (tryptophan hydroxylase) were co-transfected in rat aortic smooth muscle cells (SMAC) and kidney tissue to create a serotonin-vesicular phenotype (named VTSMAC and VTkidney, respectively). Effects on hypothermic damage were assessed. VTSMAC showed a vesicular phenotype and an 8-fold increase in serotonin content and 5-fold increase in its release upon cooling. Cooled VTSMAC produced up to 10 fold higher concentrations of H2S, and were protected from hypothermia, as shown by a 50% reduction of caspase 3/7 activity and 4 times higher survival compared to SMAC. Hypothermic resistance was abolished by the inhibition of CBS activity or blockade of serotonin re-uptake. In VTkidney slices, expression of CBS was 3 fold increased in cold preserved kidney tissue, with two-fold increase in H2S concentration. While cooling induced substantial damage to empty vector transfected kidney as shown by caspase 3/7 activity and loss of FABP1, VTkidney was fully protected and comparable to non-cooled control. Thus, transfection of VMAT-1 and TPH-1 induced vesicular storage of serotonin which is triggered release upon cooling and has protective effects against hypothermia. The vesicular serotonergic phenotype protects against hypothermic damage through re uptake of serotonin inducing CBS mediated H2S production both in cells and kidney slices. PMID- 22253934 TI - Diagnostic accuracy of molecular amplification tests for human African trypanosomiasis--systematic review. AB - BACKGROUND: A range of molecular amplification techniques have been developed for the diagnosis of Human African Trypanosomiasis (HAT); however, careful evaluation of these tests must precede implementation to ensure their high clinical accuracy. Here, we investigated the diagnostic accuracy of molecular amplification tests for HAT, the quality of articles and reasons for variation in accuracy. METHODOLOGY: Data from studies assessing diagnostic molecular amplification tests were extracted and pooled to calculate accuracy. Articles were included if they reported sensitivity and specificity or data whereby values could be calculated. Study quality was assessed using QUADAS and selected studies were analysed using the bivariate random effects model. RESULTS: 16 articles evaluating molecular amplification tests fulfilled the inclusion criteria: PCR (n = 12), NASBA (n = 2), LAMP (n = 1) and a study comparing PCR and NASBA (n = 1). Fourteen articles, including 19 different studies were included in the meta analysis. Summary sensitivity for PCR on blood was 99.0% (95% CI 92.8 to 99.9) and the specificity was 97.7% (95% CI 93.0 to 99.3). Differences in study design and readout method did not significantly change estimates although use of satellite DNA as a target significantly lowers specificity. Sensitivity and specificity of PCR on CSF for staging varied from 87.6% to 100%, and 55.6% to 82.9% respectively. CONCLUSION: Here, PCR seems to have sufficient accuracy to replace microscopy where facilities allow, although this conclusion is based on multiple reference standards and a patient population that was not always representative. Future studies should, therefore, include patients for which PCR may become the test of choice and consider well designed diagnostic accuracy studies to provide extra evidence on the value of PCR in practice. Another use of PCR for control of disease could be to screen samples collected from rural areas and test in reference laboratories, to spot epidemics quickly and direct resources appropriately. PMID- 22253935 TI - Early diagnosis, treatment and follow-up of cystic echinococcosis in remote rural areas in Patagonia: impact of ultrasound training of non-specialists. AB - Cystic echinococcosis (CE) is a chronic, complex and neglected disease caused by the larval stage of Echinococcus granulosus. The effects of this neglect have a stronger impact in remote rural areas whose inhabitants have no chances of being diagnosed and treated properly without leaving their jobs and travelling long distances, sometimes taking days to reach the closest referral center. BACKGROUND: In 1980 our group set up a control program in endemic regions with CE in rural sections of Rio Negro, Argentina. Since 1997, we have used abdominopelvic ultrasound (US) as a screening method of CE in school children and determined an algorithm of treatment. OBJECTIVES: To describe the training system of general practitioners in early diagnosis and treatment of CE and to evaluate the impact of the implementation of the field program. MATERIALS AND METHODS: In 2000, to overcome the shortage of radiologists in the area, we set up a short training course on Focused Assessment with Sonography for Echinococcosis (FASE) for general practitioners with no previous experience with US. After the course, the trainees were able to carry out autonomous ultrasound surveys under the supervision of the course faculty. From 2000 to 2008, trainees carried out 22,793 ultrasound scans in children from 6 to 14 years of age, and diagnosed 87 (0.4%) new cases of CE. Forty-nine (56.4%) were treated with albendazole, 29 (33.3%) were monitored expectantly and 9 (10.3%) were treated with surgery. DISCUSSION: The introduction of a FASE course for general practitioners allowed for the screening of CE in a large population of individuals in remote endemic areas with persistent levels of transmission, thus overcoming the barrier of the great distance from tertiary care facilities. The ability of local practitioners to screen for CE using US saved the local residents costly travel time and missed work and proved to be an efficacious and least expensive intervention tool for both the community and health care system. PMID- 22253936 TI - A systematically improved high quality genome and transcriptome of the human blood fluke Schistosoma mansoni. AB - Schistosomiasis is one of the most prevalent parasitic diseases, affecting millions of people in developing countries. Amongst the human-infective species, Schistosoma mansoni is also the most commonly used in the laboratory and here we present the systematic improvement of its draft genome. We used Sanger capillary and deep-coverage Illumina sequencing from clonal worms to upgrade the highly fragmented draft 380 Mb genome to one with only 885 scaffolds and more than 81% of the bases organised into chromosomes. We have also used transcriptome sequencing (RNA-seq) from four time points in the parasite's life cycle to refine gene predictions and profile their expression. More than 45% of predicted genes have been extensively modified and the total number has been reduced from 11,807 to 10,852. Using the new version of the genome, we identified trans-splicing events occurring in at least 11% of genes and identified clear cases where it is used to resolve polycistronic transcripts. We have produced a high-resolution map of temporal changes in expression for 9,535 genes, covering an unprecedented dynamic range for this organism. All of these data have been consolidated into a searchable format within the GeneDB (www.genedb.org) and SchistoDB (www.schistodb.net) databases. With further transcriptional profiling and genome sequencing increasingly accessible, the upgraded genome will form a fundamental dataset to underpin further advances in schistosome research. PMID- 22253937 TI - Sero-epidemiology as a tool to screen populations for exposure to Mycobacterium ulcerans. AB - BACKGROUND: Previous analyses of sera from a limited number of Ghanaian Buruli ulcer (BU) patients, their household contacts, individuals living in BU non endemic regions as well as European controls have indicated that antibody responses to the M. ulcerans 18 kDa small heat shock protein (shsp) reflect exposure to this pathogen. Here, we have investigated to what extent inhabitants of regions in Ghana regarded as non-endemic for BU develop anti-18 kDa shsp antibody titers. METHODOLOGY/PRINCIPAL FINDINGS: For this purpose we determined anti-18 kDa shsp IgG titers in sera collected from healthy inhabitants of the BU endemic Densu River Valley and the Volta Region, which was so far regarded as BU non-endemic. Significantly more sera from the Densu River Valley contained anti 18 kDa shsp IgG (32% versus 12%, respectively). However, some sera from the Volta Region also showed high titers. When interviewing these sero-responders, it was revealed that the person with the highest titer had a chronic wound, which was clinically diagnosed and laboratory reconfirmed as active BU. After identification of this BU index case, further BU cases were clinically diagnosed by the Volta Region local health authorities and laboratory reconfirmed. Interestingly, there was neither a difference in sero-prevalence nor in IS2404 PCR positivity of environmental samples between BU endemic and non-endemic communities located in the Densu River Valley. CONCLUSIONS: These data indicate that the intensity of exposure to M. ulcerans in endemic and non-endemic communities along the Densu River is comparable and that currently unknown host and/or pathogen factors may determine how frequently exposure is leading to clinical disease. While even high serum titers of anti-18 kDa shsp IgG do not indicate active disease, sero-epidemiological studies can be used to identify new BU endemic areas. PMID- 22253938 TI - Orientia tsutsugamushi in human scrub typhus eschars shows tropism for dendritic cells and monocytes rather than endothelium. AB - Scrub typhus is a common and underdiagnosed cause of febrile illness in Southeast Asia, caused by infection with Orientia tsutsugamushi. Inoculation of the organism at a cutaneous mite bite site commonly results in formation of a localized pathological skin reaction termed an eschar. The site of development of the obligate intracellular bacteria within the eschar and the mechanisms of dissemination to cause systemic infection are unclear. Previous postmortem and in vitro reports demonstrated infection of endothelial cells, but recent pathophysiological investigations of typhus patients using surrogate markers of endothelial cell and leucocyte activation indicated a more prevalent host leucocyte than endothelial cell response in vivo. We therefore examined eschar skin biopsies from patients with scrub typhus to determine and characterize the phenotypes of host cells in vivo with intracellular infection by O. tsutsugamushi, using histology, immunohistochemistry, double immunofluorescence confocal laser scanning microscopy and electron microscopy. Immunophenotyping of host leucocytes infected with O. tsutsugamushi showed a tropism for host monocytes and dendritic cells, which were spatially related to different histological zones of the eschar. Infected leucocyte subsets were characterized by expression of HLADR+, with an "inflammatory" monocyte phenotype of CD14/LSP 1/CD68 positive or dendritic cell phenotype of CD1a/DCSIGN/S100/FXIIIa and CD163 positive staining, or occasional CD3 positive T-cells. Endothelial cell infection was rare, and histology did not indicate a widespread inflammatory vasculitis as the cause of the eschar. Infection of dendritic cells and activated inflammatory monocytes offers a potential route for dissemination of O. tsutsugamushi from the initial eschar site. This newly described cellular tropism for O. tsutsugamushi may influence its interaction with local host immune responses. PMID- 22253939 TI - A field trial of alternative targeted screening strategies for Chagas disease in Arequipa, Peru. AB - BACKGROUND: Chagas disease is endemic in the rural areas of southern Peru and a growing urban problem in the regional capital of Arequipa, population ~860,000. It is unclear how to implement cost-effective screening programs across a large urban and periurban environment. METHODS: We compared four alternative screening strategies in 18 periurban communities, testing individuals in houses with 1) infected vectors; 2) high vector densities; 3) low vector densities; and 4) no vectors. Vector data were obtained from routine Ministry of Health insecticide application campaigns. We performed ring case detection (radius of 15 m) around seropositive individuals, and collected data on costs of implementation for each strategy. RESULTS: Infection was detected in 21 of 923 (2.28%) participants. Cases had lived more time on average in rural places than non-cases (7.20 years versus 3.31 years, respectively). Significant risk factors on univariate logistic regression for infection were age (OR 1.02; p = 0.041), time lived in a rural location (OR 1.04; p = 0.022), and time lived in an infested area (OR 1.04; p = 0.008). No multivariate model with these variables fit the data better than a simple model including only the time lived in an area with triatomine bugs. There was no significant difference in prevalence across the screening strategies; however a self-assessment of disease risk may have biased participation, inflating prevalence among residents of houses where no infestation was detected. Testing houses with infected-vectors was least expensive. Ring case detection yielded four secondary cases in only one community, possibly due to vector-borne transmission in this community, apparently absent in the others. CONCLUSIONS: Targeted screening for urban Chagas disease is promising in areas with ongoing vector-borne transmission; however, these pockets of epidemic transmission remain difficult to detect a priori. The flexibility to adapt to the epidemiology that emerges during screening is key to an efficient case detection intervention. In heterogeneous urban environments, self-assessments of risk and simple residence history questionnaires may be useful to identify those at highest risk for Chagas disease to guide diagnostic efforts. PMID- 22253940 TI - Renal hyperfiltration related to diabetes mellitus and obesity in human disease. AB - High intraglomerular pressure is associated with renal hyperfiltration, leading to the initiation and progression of kidney disease in experimental models of diabetes mellitus (DM). In humans, hyperfiltration is observed in patients with type 1 and type 2 DM, and is also seen in patients with pre-diabetic conditions, such as the metabolic syndrome. From a mechanistic perspective, both vascular and tubular factors likely contribute to the pathogenesis of hyperfiltration. Until now, human studies have primarily focused on the use of medications that inhibit the renin angiotensin system to reduce efferent vasoconstriction and thereby improve hyperfiltration. More recent advances in the development of investigational adenosine antagonists and inhibitors of sodium glucose co transport may help to elucidate tubular factors that contribute to afferent vasodilatation. In this review, we summarize available data from experimental and human studies of type 1 and type 2 DM and obesity to provide an overview of factors that contribute to the hyperfiltration state. We have focused on the renin angiotensin system, cyclooxygenase-2 system, nitric oxide, protein kinase C and endothelin as vascular determinants of hyperfiltration. We also discuss relevant tubular factors, since experimental models have suggested that inhibition of sodium-glucose cotransport may be renoprotective. PMID- 22253943 TI - Cyanotic changes of the toes. PMID- 22253941 TI - Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy. AB - Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication. PMID- 22253942 TI - Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment? AB - Redox balance is fundamentally important for physiological homeostasis. Pathological factors that disturb this dedicated balance may result in oxidative stress, leading to the development or aggravation of a variety of diseases, including diabetes mellitus, cardiovascular diseases, metabolic syndrome as well as inflammation, aging and cancer. Thus, the capacity of endogenous free radical clearance can be of patho-physiological importance; in this regard, the major reactive oxygen species defense machinery, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system needs to be precisely modulated in response to pathological alterations. While oxidative stress is among the early events that lead to the development of insulin resistance, the activation of Nrf2 scavenging capacity leads to insulin sensitization. Furthermore, Nrf2 is evidently involved in regulating lipid metabolism. Here we summarize recent findings that link the Nrf2 system to metabolic homeostasis and insulin action and present our view that Nrf2 may serve as a novel drug target for diabetes and its complications. PMID- 22253944 TI - Muslims and the medical research: past, present, future. PMID- 22253946 TI - Medical rehabilitation of leprosy patients discharged home in abia and ebonyi States of Nigeria. AB - OBJECTIVES: To examine the extent to which medical coverage is available to discharged leprosy patients in communities. Evidence has shown that after care services, follow-up visits and national disease prevention programs are important components of medical rehabilitation to leprosy patients discharged home after treatment. Denying them accessibility to these services could expose them to multiple disabilities as well as several disease conditions including HIV/AIDS. These adverse health conditions could be averted if health workers extend healthcare services to discharged leprosy patients. This study was conducted to examine the extent to which discharged leprosy patients have access to healthcare services in the communities. METHODS: All 33 leprosy patients who were fully treated with multi-drug therapy (MDT) and discharged home in the two leprosy settlements in Abia and Ebonyi States of Nigeria were included in this study. The list of discharged leprosy patients studied and their addresses were provided by the leprosy settlements where they were treated. Also, snowball-sampling method was used to identify some of the leprosy patients whose addresses were difficult to locate in the communities. Instruments for data collection were questionnaire, interview guide and checklist. These were administered because respondents were essentially those with no formal education. Analysis of data was done quantitatively and qualitatively. RESULTS: Findings showed that 20 (60.6%) of discharged patients did not receive health programs like HIV/AIDS prevention or family planning. Also, follow-up visits and after-care services were poor. About 14 (42.4%) of the patients live in dirty and overcrowded houses. On the whole, discharged patients were poorly medically rehabilitated (mean score: 4.7+/-1.1 out of total score of 7). CONCLUSION: Denying discharged leprosy patients opportunity of accessing health care services could increase prevalence of infectious diseases including HIV/AIDS among them. There is need to extend national prevention programs, follow-up visits, after-care services and free treatment to discharged patients in the communities. PMID- 22253947 TI - Active-passive Immunization Effectiveness Against Hepatitis B Virus in Children Born to HBsAg Positive Mothers in Amol, North of Iran. AB - OBJECTIVES: HBV infection is a contagious disease that may transmit vertically from mothers to their neonates or horizontally by blood products and body secretions. Over 50% of Iranian carriers have contracted the infection perinatally, making this the most likely route of transmission of HBV in Iran. This study assesses the serologic markers of HBV in children born to HBsAg positive mothers who received HBIG and 3 doses of HBV vaccine. METHODS: To evaluate the effectiveness of vaccination against HBV, a study was conducted on 95 Children, born to hepatitis B surface antigen (HBsAg)-positive mothers, who had received Hepatitis B Immune Globulin and HBV vaccines during 2004-2008. All children were tested for the presence of HBsAg, anti-HBs and anti-HB core antigen (anti-HBc). RESULTS: Among an estimated 30000 pregnant women during the five year study, about 130 (0.42%) were HBV carriers. Ninety-five children from these mothers were enrolled in this study. Only one child (1.1%) was HBsAg positive, while 88.4% of children were Anti-HBs Positive. Eleven children (11.6%) were exposed to HBV as shown by the presence of anti-HBc. A significant difference was observed between the children's age and Anti-HBs (p=0.0001). CONCLUSION: Passive active immunoprophylaxis of high risk babies was highly efficacious in preventing perinatal transmission of the HBV carrier state. Also, evaluation of serologic markers in HBV infected people is important for designing the strategies for disease control. PMID- 22253945 TI - Gastrointestinal and Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) confer a gastrointestinal (GI) side effect profile and concerns regarding adverse cardiovascular effects have emerged associated with considerable morbidity and mortality. NSAIDs are highly effective in treating pain and inflammation, but it is well recognized that these agents are associated with substantial gastrointestinal toxicity. Cyclo-oxygenase-2 inhibitors may also reduce the risk for gastrointestinal events, although they may increase cardiovascular adverse events. The selection of an appropriate analgesic or anti-inflammatory agent with or without gastroprotective therapy should be individualized. PMID- 22253948 TI - The effect of amantadine on clomipramine induced sexual dysfunction in male rats. AB - OBJECTIVE: Several studies have reported that Clomipramine has the ability to suppress male rat sexual behavior. Literature indicates that the activation of brain D(2) receptors causes facilitation of penile erection, and a number of reports have indicated dopamine's involvement in sexual function. Hence this study was undertaken to investigate the effect of Amantadine, a dopamine agonists on the Clomipramine induced sexual dysfunction. METHODS: The study subjects involved a total of 48 males and 48 females, 4 months old Sprague-Dawley albino rats, all housed in a group of six males and females separately in plexi glass cages in an acclimatized colony room (25+/-0.5(0)C) maintained on a 12/12 hr light/dark cycle. The male rats were randomly divided into four groups of 12 male rats each. Group I served as controls. Group II, III, and IV were treated with Amantadine (9 mg/kg body weight, p.o) 30 min, prior to the treatment with 13.5 mg/kg, 27 mg/Kg and 54 mg/Kg bodyweight p.o of Clomipramine respectively for 60 days. The control group received vehicle 1 ml / kg p.o. The sexual behavior of the male rats was observed to determine the following parameters: mount latency, intromission latency, ejaculation latency, post ejaculatory pause, and intromission frequency. As well as the sexual behavior; serum testosterone and histopathology of the testes were also investigated in this study. RESULTS: The results indicate that Amantadine in all aspects failed to antagonize Clomipramine induced sexual dysfunction in male rats. Even the sexual competence of male rats treated with 1/2 therapeutic dose (TD) of Clomipramine failed to regain their sexual competence in the presence of Amantadine. Testicular damage and decline in testosterone levels continued in the presence of Amantadine. CONCLUSION: Overall, the results suggest that Amantadine could not be a safe antidote to antagonize Clomipramine induced sexual dysfunction. PMID- 22253949 TI - Profile difference between male and female psychiatric patients seeking certificate of disability. AB - OBJECTIVE: Neuropsychiatric disorders are one of the major contributors to the global burden of disease and disability. Issue of disability in psychiatric disorders has been studied across multiple studies in India. However, there are no reports on the profile and nature of disability among those seeking disability certificates. The current study aims at understanding the socio-clinical profile of patients seeking disability certificate in a tertiary care hospital in India. METHODS: The study was carried out in the Department of Psychiatry of a tertiary care multispecialty teaching hospital. A chart review of the records of the patients referred for disability evaluation over a one year period was conducted. The disability was assessed using IDEAS. In between group comparisons were carried out for male and female subjects for different socio-demographic variables, IDEAS total score and individuals item score using independent sample t test (parametric test) and Mann Whitney-U test (non parametric test). Additionally, Spearman's rank order correlation was calculated to establish the level of correlation between total IDEAS score and score on individual items of the scale. RESULTS: The subjects were diagnosed to have been suffering from mental retardation 107 (61.8%), schizophrenia 54 (31.2%), dementia 5 (2.9%), bipolar affective disorder 4 (2.3%) and obsessive compulsive disorder 3 (1.7%) as per ICD-10. Male and female subjects differed significantly on the global IDEAS score. The total score was significantly higher for male subjects compared to female subjects. The difference was statistically significant for "self care" and interpersonal activities items of the scale with male subjects having higher disability scores. CONCLUSIONS: The current study provides some important insights into profile of disability certificate seeking individuals in India. PMID- 22253950 TI - Non allergic rhinitis: prevalence, clinical profile and knowledge gaps in literature. AB - OBJECTIVES: Although Nasal symptoms induced by Non-allergic rhinitis| (NAR) are a cause of wide spread morbidity; the disease is trivialized. There is a lack of Epidemiological studies on the prevalence of non-allergic rhinitis. In spite of being one of the commonest conditions presenting to the General practitioner and otolaryngologists, the clinical profile, diagnosis, and management outcomes are unknown. The objectives of the study were to examine the prevalence and clinical profile of non-allergic rhinitis in Oman. Secondary objective was to identify Knowledge gaps in literature with the aim of directing future research. METHODS: A cross sectional study of 610 consecutive adult patients presenting to the Ear, Nose and Throat clinic at Sultan Qaboos University Hospital is presented in this paper. The diagnosis of NAR was mainly based on step wise fashion; including a thorough clinical history and exclusion of other causes of rhinitis; all consecutive patients diagnosed with rhinitis (n=113) had a detailed history, nasal endoscopy, nasal smears, CT scans and an antihistamine response trial. The prevalence of NAR with its clinical profile was subsequently determined. Primary research articles and meta-analysis evaluated for the knowledge gap study were identified through MEDLINE search of English language literature published between 2000-2011. RESULTS: A total of 610 consecutive patients were studied. The overall prevalence of rhinitis was 18.5% (n=113). The prevalence of NAR was 7.5% (n=46). Cases of allergic rhinitis (5.7%; n=35), Chronic rhinosinusitis (1.8%; n=11), and miscellaneous causes (3.4%; n=21) were excluded. Among the rhinitis population (n=113), the prevalence of NAR was 57% (n=46). The major presenting symptoms included nasal obstruction (93%; n=43), postnasal drainage (78%; n=36), and rhinorrhea (62%; n=29). For the knowledge gap study; 115 Medline titles were reviewed, four systematic reviews, and 34 research papers were reviewed. The text of two recent otolaryngology text books was also reviewed, and the main results of the study revealed the prevalence of NAR had not previously been studied in Oman. Although the recent text now clearly defines NAR, there is scant literature on the prevalence, diagnosis and management outcomes of NAR in the literature. CONCLUSION: The study found that more than half of rhinitis patients suffered from NAR. There are no specific diagnostic tests for NAR; a thorough case history is the best diagnostic tool to date. A substantial knowledge gap exists in literature with relations to pathogenesis, clinical and laboratory diagnosis, as well as in reference to medical and surgical outcomes. Larger studies are required and management outcomes need to be studied. PMID- 22253951 TI - A comparison of serum cystatin C and creatinine with glomerular filtration rate in Indian patients with chronic kidney disease. AB - OBJECTIVES: There is no literature available on the performance of cystatin C in Chronic Kidney Disease (CKD) patients of Indian population based on age group. Hence, this study is aimed to compare the diagnostic performance of serum cystatin C and creatinine with measured glomerular filtration rate (GFR) and estimated GFR (eGFR) in subjects of Indian origin. METHODS: The study was carried out at Tiruchirappalli, South India during the period of September 2010 to march 2011. One hundred and six CKD patients (82 males, 24 females) were enrolled and categorized into three groups based on age. The eGFR was calculated using Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. Serum cystatin C was measured with a particle-enhanced nephelometric immunoassay (PENIA) method. GFR was measured using (99m)T(C) - diethylene triamine penta aceticacid (DTPA) renal scan method. RESULTS: Serum cystatin C showed significant correlation with measured GFR in all the three groups (r=-0.9735, r=-0.8975 and r=-0.7994 respectively) than serum creatinine (r=-0.7380, r=-0.6852 and r=-0.5127 respectively). CONCLUSION: Serum cystatin C showed a high correlation with measured GFR in young and older patients with CKD than creatinine. Thus, cystatin C is a good alternative marker to creatinine in CKD patients. PMID- 22253952 TI - Osteoarthritis among women in bahrain: a public health audit. AB - OBJECTIVE: This study aims to train students on public health survey; correlate risk factors of osteoarthritis and to identify modifiable risk factors. METHODS: Osteoarthritis survey was carried out among 420 Bahraini women, above 40 years of age, diagnosed of osteoarthritis, attending ministry of health facilities. RESULTS: Most cases in the study were from the age group of 50-59 years with a mean age of 57. Osteoarthritis: of major joints alone was 74%; of generalized was 21% and of small joints of hands and feet alone was 5%. Within major osteoarthritis: 48% were knees alone; 51% were knee and hip and 2% were hip alone. Combinations of co-morbidities were found among 43%. History of diagnosed: diabetes in 10%, hypertension among 13% and hypercholesterolemia in 5% of cases. Half of the cases in the study were obese and 30% were overweight. Osteoarthritis of the Knee and the combination of the osteoarthritis of knee and hip was highest among obese followed by overweight cases. Menopause was found among 68%of patients. Patients on medication accounted for 85% and 75% were on Physiotherapy. Half of the sample had family history of osteoarthritis. While over 90% were less educated with odds ratio for being housewives at 3.085. The multivariate analysis of ordinal regression returned pseudo R(2) of 30% for the model with the following significant variables: age, BMI, menopause status, exercise, chronic morbidities and family history of osteoarthritis. CONCLUSION: Overall, the proportion of major osteoarthritis of the weight bearing joints is very high. The modifiable risk factors identified from this study are sedentary lifestyle, obesity and overweight, as well as chronic morbidities. PMID- 22253953 TI - Effect of thrombolytic therapy on the incidence of early left ventricular infarct expansion in acute anterior myocardial infarction. AB - OBJECTIVES: To determine the incidence of early left ventricular infarct expansion within five days after first anterior ST-segment elevation myocardial infarction and the effect of early thrombolytic therapy on the incidence of early infarct expansion compared with late thrombolytic therapy. METHODS: In a prospective study of 101 patients (75males and 26 females), with the first attack of acute anterior myocardial infarction, their ages ranged from 40-80 years (mean age: 61.07+/-10.78) who had been admitted to the Coronary Care Unit of Hawler Teaching Hospital for the period from July 2007 through to September 2009. Those who received alteplase <=3 hours of acute myocardial infarction were labelled as group-I (49 patients) and those who received alteplase >3-12 hours were labelled as group-II (52 patients). RESULTS: The incidence of early left ventricular infarct expansion was diagnosed by 2D-echocardiography and was found to be 17.8%. Group I patients had a lower incidence of early left ventricular infarct expansion (8.16%) compared with group-II (26.92%; p=0.014). Patients with early left ventricular infarct expansion had a higher frequency rate of left ventricular systolic dysfunction (94.44%) compared to patients without early left ventricular infarct expansion (8.43%; p<0.001). There was a significant difference in the incidence of in-hospital mortality between the patients who developed early left ventricular infarct expansion (11.1%) compared with patients without early left ventricular infarct expansion (1.2%; p=0.025). CONCLUSION: Early reperfusion therapy in acute anterior myocardial infarction can decrease the incidence of early left ventricular infarct expansion, preserve left ventricular systolic function and decrease in-hospital mortality. PMID- 22253954 TI - Traumatic panniculitis of the right thigh: a case report. AB - Panniculitis is a group of diseases whose hallmark is inflammation of the subcutaneous adipose tissue that may be challenging both for the clinician and the dermatopathologist. It can occur in any fatty tissue (cutaneous or visceral) and is often diagnosed on the basis of a deep skin biopsy. Though mesenteric panniculitis is a common entity, and often associated with intra-abdominal inflammatory conditions, cutaneous panniculitis is a rare entity and can be mistaken for other skin and subcuteneous lesions. We present a patient with traumatic panniculitis. PMID- 22253955 TI - Ischemic stroke secondary to aortic dissection following rifle butt recoil chest injury: a case report. AB - Ischemic stroke secondary to aortic dissection is not uncommon. We present a patient with left hemiplegia secondary to Stanford type A aortic dissection extending to the supra-aortic vessels, which was precipitated by rifle butt recoil chest injury. The diagnosis of aortic dissection was delayed due to various factors. Finally, the patient underwent successful Bentall procedure with complete resolution of symptoms. This case emphasizes the need for caution in the use of firearms for recreation and to take precautions in preventing such incidents. In addition, this case illustrates the need for prompt cardiovascular physical examination in patients presenting with stroke. PMID- 22253956 TI - A Rare Case of Pericentric Inversion, Inv (21) (p12;q22) in Repeated Pregnancy Loss: A Case Report. AB - Pericentric inversions are among the most frequent chromosomal rearrangements with a frequency of 1-2%. There is no phenotypic effect in the majority of pericentric inversion heterozygote carriers, when it is a balanced rearrangement. However, miscarriages, infertility and/or chromosomally unbalanced offspring can be observed in carriers of a pericentric inversion. This is a case of pericentric inversion of one chromosome 21: inv (21) (p12; q22) in repeated pregnancy loss. A couple was referred for cytogenetic examination due to idiopathic miscarriages. The proband proved to be a carrier of chromosomal inversion and her partner's karyotype was found to be normal. The karyotype of the proband is 46, xx, inv (21) (p12; q22). This abnormal karyotype is reported as a probable reason of miscarriage in the investigated couple. The risk of further miscarriages and the risk of a progeny with abnormal karyotype are rather high. Therefore, amniocenthesis for finding the chromosomal abnormality as a prenatal diagnosis are proposed for the patient if future pregnancy does not lead to miscarriage. PMID- 22253957 TI - Fetomaternal transfusion as a cause of severe fetal anemia causing early neonatal death: a case report. AB - Fetomaternal hemorrhage refers to the entry of fetal blood into the maternal circulation before or during delivery. Very small amount of fetal red cells are normally detectable in all pregnancies. Massive fetomaternal bleed is very rare and even rarer is the resultant severe anemia causing early neonatal death, despite an uneventful normal pregnancy until the end. Antenatal fetomaternal hemorrhage is a pathological condition with a wide spectrum of clinical variation. Secondary to the resultant anemia, fetomaternal hemorrhage may have devastating consequences for the fetus such as neurologic injury, stillbirth, or neonatal death. The Presentation is frequently without an evident precipitating factor. Recognition may become apparent only after injury has occurred, if at all. The most common antenatal presentation is decreased fetal activity and a heightened index of suspicion is warranted in cases of persistent maternal perception of decreased fetal movements. PMID- 22253958 TI - Uterus didelphys with obstructed right hemivagina, ipsilateral renal agenesis and right pyocolpos: a case report. AB - Uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA Syndrome) is a rare congenital anomaly of the female genital tract. Uterus didelphys occurs when the midline fusion of the mullerian ducts is arrested, either completely or incompletely. Women with didelphic uterus may be asymptomatic and unaware of having a double uterus. They may present with complaints of dysmenorrhoea and dyspareunia. A 25 year old woman attending the infertility clinic at Nizwa regional referral hospital presented with history of dysmenorrhoea and foul vaginal discharge with right cystic pelvic mass. She was diagnosed as a case of double uterus with obstructed right hemivagina and right pyocolpos with ipsilateral renal agenesis after routine ultrasonography in the clinic followed by MRI. Excision of the right vaginal septum with drainage of 200 ml of purulent discharge was performed. She was relieved of her symptoms and conceived promptly after the surgical excision of the partial vaginal septum. PMID- 22253959 TI - Knowledge, attitudes and awareness of community pharmacists towards the use of herbal medicines in muscat region. AB - OBJECTIVE: This study aims to investigate the knowledge and attitudes among pharmacists in Oman towards the specific use and knowledge of herbal drugs. METHODS: The study was conducted on 100 pharmacists employed in Oman. The data was collected using two self- administered questionnaire containing 7 and 11 closed ended questions in each, respectively. RESULTS: The mean age of pharmacists was 32.6 (SD=5.6) years. The majority of pharmacists were interested in herbal information and their herbal information mainly comes from their previous classes during college. Most of them have belief on the effectiveness of herbal products. Pharmacists were more knowledgeable on specific therapeutic indications of herbal products rather than on other areas such as drug- herb interaction or side effects. CONCLUSION: In summary, Pharmacists need to be informed on the therapeutic indications, drug interactions, dose, active constituent and precautions of herbal products. Concerned bodies must also provide them with regular continuing education programs apart from putting their effects to incorporate relevant topics in herbal medicine in pharmacy curriculum. PMID- 22253960 TI - Role of water soluble contrast agents in assigning patients to a non-operative course in adhesive small bowel obstruction. AB - OBJECTIVES: Adhesive small bowel obstruction (SBO) is a common surgical emergency. It is estimated that at least 60% of SBO are due to post-operative adhesions. Water soluble contrast agents (gastrografin) have been used to identify patients who might be treated non-operatively. This study aims to determine the role of gastrografin in adhesive intestinal obstruction patients. METHODS: In this prospective study, 27 patients admitted between 1(st) August 2004 and 1(st) July 2006 with clinical signs suggestive of postoperative adhesive SBO met the inclusion criteria. After intravenous hydration, nasogastric tube insertion and complete suctioning of the gastric fluid, 100 ml of gastrograsfin was given and plain abdominal radiography was taken 6 hours and 24 hours if the contrast is not seen in the colon. Those in whom the contrast reached the colon in 24 hours were considered to have partial SBO and started oral intake. If gastrografin failed to reach the colon in 24 hours and the patient did not improve in the following 24 hours, laparotomy was performed. RESULTS: Conservative treatment was successful in 31 cases (91%) and 3 (9%) required operation. Patients treated conservatively had short hospital stay (mean=4 days) and tolerated oral feeding with no morbidity or mortality. CONCLUSION: Oral gastrografin helps in the management of patients with postoperative adhesive SBO. PMID- 22253961 TI - An unusual cause of hemoptysis in a young female. PMID- 22253962 TI - ST Analysis of the Fetal ECG, as an Adjunct to Fetal Heart Rate Monitoring in Labour: A Review. PMID- 22253963 TI - Why nutrients? PMID- 22253964 TI - The amelioration of olfactory acuity upon sexual maturation might affect food preferences. AB - Upon sexual maturation, olfactory acuity in women ameliorates and starts oscillating across the cycle. During ovulation, mean olfactory threshold is 30 times lower than during bleeding. Interestingly, menstruated women undergo maleodorant trimethylaminuria. We argued that olfactory amelioration during ovulation might concur to a mating strategy, whereas olfactory impairment during bleeding might protect women against self-refusal. Testosterone and its 17beta estradiol derivative might be responsible for the synchronization of these menstrual events. Furthermore, we posed the question whether olfactory detection amelioration upon sexual maturation might provoke a change in food preferences, for instance a reduction in fish consumption. A preliminary survey in Italy provided encouraging results: 15-44 year-old women have lower fish consumption than 3-14 year-old girls. Surprisingly, men exhibited the same behaviour, so new olfactory tests as well as testosterone measurements are under way. PMID- 22253965 TI - Effects of mate tea intake on ex vivo LDL peroxidation induced by three different pathways. AB - Yerba mate (Ilex paraguariensis) is a native South America plant widely consumed as different beverages. Yerba mate leaves contains high concentrations of polyphenols that are responsible for its high in vitro and in vivo antioxidant activity. The in vivo antioxidant properties vis a vis LDL particles has not yet been studied for mate tea, the roasted yerba mate product. The aim of this study was to evaluate the antioxidant activity of mate tea ingestion ex vivo on human LDL. Fasting peripheral venous blood samples of healthy women were taken in three different times: before drinking the tea, one hour later and after one week (7 days) of daily consumption of mate tea. The isolated LDL was oxidized by three different pathways [copper (CuSO4), lipoxygenase and peroxynitrite (SIN-1)]. Conjugated dienes and structural modifications on LDL were evaluated. Ingestion of mate tea increased LDL resistance towards ex vivo copper oxidation, but did not alter the peroxidation pattern when SIN-1 or lipoxygenase were used as oxidants. PMID- 22253966 TI - Selenium in camel--a review. AB - Requirements for trace minerals in camels, particularly selenium, are not well known. Selenium supplementation using a pharmaceutical form or commercial mineral mixture is common practice in camels to address the cardiomyopathy often attributed to selenium deficiency. This supplementation is often empirical and based on estimated needs for cattle. Nowadays the use of selenium in animal foodstuffs is commonplace and further investigation of its metabolism (ingestion, dynamic of storage-destocking, excretion) in camels is warranted. The present review aimed to synthesize all the experimental research (comparative selenium status in cow and camel, response to different levels of supplementation at different physiological stages, excretion maternal transfer, experimental toxicosis) and field observations (deficiency, supplementation practices) undertaken in camels. The results underline the particularity of the unique metabolic profile of the camel and lead to practical recommendations for supplementation in camels, highlighting its relative sensitivity to excess Se intake at lower levels than in cattle. The maximal tolerable dose is 8 mg and the recommended doses range from 2 to 4 mg. PMID- 22253968 TI - Animal nutrition and lipids in animal products and their contribution to human intake and health. AB - Few EU countries meet targets for saturated fatty acid (SFA) intake. Dairy products usually represent the single largest source of SFA, yet evidence indicates that milk has cardioprotective properties. Options for replacing some of the SFA in milk fat with cis-monounsaturated fatty acids (MUFA) through alteration of the cow's diet are examined. Also, few people achieve minimum recommended intakes (~450-500 mg/d) of the long chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Enrichment of EPA+DHA in poultry meat via bird nutrition is described and how this would impact on habitual intake is discussed. PMID- 22253967 TI - Dietary calcium and dairy modulation of oxidative stress and mortality in aP2 agouti and wild-type mice. AB - Oxidative and inflammatory stress have been implicated as major contributors to the aging process. Dietary Ca reduced both factors in short-term interventions, while milk exerted a greater effect than supplemental Ca. In this work, we examined the effects of life-long supplemental and dairy calcium on lifespan and life-span related biomarkers in aP2-agouti transgenic (model of diet-induced obesity) and wild-type mice fed obesigenic diets until their death. These data demonstrate that dairy Ca exerts sustained effects resulting in attenuated adiposity, protection against age-related muscle loss and reduction of oxidative and inflammatory stress in both mouse strains. Although these effects did not alter maximum lifespan, they did suppress early mortality in wild-type mice, but not in aP2-agouti transgenic mice. PMID- 22253969 TI - Dairy-rich diets augment fat loss on an energy-restricted diet: a multicenter trial. AB - A 12-week randomized controlled multi-center clinical trial was conducted in 106 overweight and obese adults. Diets were designed to produce a 2,093 kJ/day energy deficit with either low calcium (LC; ~600 mg/day), high calcium (HC; ~1,400 mg/day), or high dairy (HD; three dairy servings, diet totaling ~1,400 mg/day). Ninety-three subjects completed the trial, and 68 met all a priori weekly compliance criteria. Both HC and HD contained comparable levels of calcium, but HC was only ~30% as effective as HD in suppressing 1,25-(OH)(2)D and exerted no significant effects on weight loss or body composition compared to LC. In the group that met compliance criteria, HD resulted in ~two-fold augmentation of fat loss compared to LC and HC (HD: -4.43 +/- 0.53 kg; LC: -2.69 +/- 0.0.53 kg; HC: 2.23 +/- 0.73 kg, p < 0.025); assessment of all completers and an intent-to-treat analysis produced similar trends. HD augmentated central (trunk) fat loss (HD: 2.38 +/- 0.30 kg; HC: -1.42 +/- 0.30 kg; LC: -1.36 +/- 0.42 kg, p < 0.05) and waist circumference (HD: -7.65 +/- 0.75 cm; LC: -4.92 +/- 0.74 cm; LC: -4.95 +/- 1.05 cm, p < 0.025). Similar effects were noted among all subjects completing the study and in an intent-to-treat analysis. These data indicate that dairy-rich diets augment weight loss by targeting the fat compartment during energy restriction. PMID- 22253971 TI - Development of rabbit meat products fortified with n-3 polyunsaturated fatty acids. AB - Rabbit meat is a highly digestible, tasty, low-calorie food, often recommended by nutritionists over other meats. Currently research in the rabbit sector is interested in developing feeding strategies aiming to further increase the nutritional value of rabbit meat as a "functional food" by including n-3 polyunsaturated fatty acids (n-3 PUFA), conjugated linoleic acid (CLA), vitamins and antioxidants in rabbit diets and assessing their effects on both raw and stored/processed meat quality properties. Our recent studies indicate that the dietary inclusion from 3 to 6% of linseed might be considered as a way to achieve the enrichment of the meat with alpha-linolenic acid and to guarantee satisfactory product stability during further processing and storage. Considering that 6% dietary linseed corresponds to a n-3 PUFA content of 8.5% of the total fatty acids and a lipid content of 4.7 g/100 g of leg meat, a content of 396 mg n 3 PUFA/100g meat can be estimated, which represents about 19% of the recommended daily allowance (RDA) for n-3 PUFA. PMID- 22253970 TI - Monitoring healthy metabolic trajectories with nutritional metabonomics. AB - Metabonomics is a well established analytical approach for the analysis of physiological regulatory processes via the metabolic profiling of biofluids and tissues in living organisms. Its potential is fully exploited in the field of "nutrimetabonomics" that aims at assessing the metabolic effects of active ingredients and foods in individuals. Yet, one of the greatest challenges in nutrition research is to decipher the critical interactions between mammalian organisms and environmental factors, including the gut microbiota. "Nutrimetabonomics" is today foreseen as a powerful approach for future nutritional programs tailored at health maintenance and disease prevention. PMID- 22253972 TI - Functional genomics of allergen gene families in fruits. AB - Fruit consumption is encouraged for health reasons; however, fruits may harbour a series of allergenic proteins that may cause discomfort or even represent serious threats to certain individuals. Thus, the identification and characterization of allergens in fruits requires novel approaches involving genomic and proteomic tools. Since avoidance of fruits also negatively affects the quality of patients' lives, biotechnological interventions are ongoing to produce low allergenic fruits by down regulating specific genes. In this respect, the control of proteins associated with allergenicity could be achieved by fine tuning the spatial and temporal expression of the relevant genes. PMID- 22253974 TI - NMR-based multi parametric quality control of fruit juices: SGF profiling. AB - With SGF ProfilingTM we introduce an NMR-based screening method for the quality control of fruit juices. This method has been developed in a joint effort by Bruker BioSpin GmbH and SGF International e.V. The system is fully automated with respect to sample transfer, measurement, data analysis and reporting and is set up on an Avance 400 MHz flow-injection NMR spectrometer. For each fruit juice a multitude of parameters related to quality and authenticity are evaluated simultaneously from a single data set acquired within a few minutes. This multimarker/multi-aspect NMR screening approach features low cost-per-sample and is highly competitive with conventional and targeted fruit juice quality control methods. PMID- 22253973 TI - Activation of hepatic lipase expression by oleic acid: possible involvement of USF1. AB - Polyunsaturated fatty acids affect gene expression mainly through peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element binding proteins (SREBPs), but how monounsaturated fatty acids affect gene expression is poorly understood. In HepG2 cells, oleate supplementation has been shown to increase secretion of hepatic lipase (HL). We hypothesized that oleate affects HL gene expression at the transcriptional level. To test this, we studied the effect of oleate on HL promoter activity using HepG2 cells and the proximal HL promoter region (700 bp). Oleate increased HL expression and promoter activity 1.3-2.1 fold and reduced SREBP activity by 50%. Downregulation of SREBP activity by incubation with cholesterol+25-hydroxycholesterol had no effect on HL promoter activity. Overexpression of SREBP2, but not SREBP1, reduced HL promoter activity, which was effected mainly through the USF1 binding site at -307/-312. Oleate increased the nuclear abundance of USF1 protein 2.7 +/- 0.6 fold, while USF1 levels were reduced by SREBP2 overexpression. We conclude that oleate increases HL gene expression via USF1. USF1 may be an additional fatty acid sensor in liver cells. PMID- 22253975 TI - Hypocholesterolemic effects of nutraceuticals produced from the red microalga Porphyridium sp in rats. AB - Red microalgae contain functional sulfated polysaccharides (containing dietary fibers), polyunsaturated fatty acids, zeaxanthin, vitamins, minerals, and proteins. Studies in rat models support the therapeutic properties of algal biomass and isolated polysaccharides. Algal products incorporated into rat diets were found to significantly improve total serum cholesterol, serum triglycerides, hepatic cholesterol levels, HDL/LDL ratios and increased fecal excretion of neutral sterols and bile acids. Morphological and metabolic changes were induced by consumption of algal products. These results suggest that red microalgae can be used as potent hypocholesterolemic agents, and they support the potential use of red microalgae as novel nutraceuticals. PMID- 22253976 TI - Seedless fruit production by hormonal regulation of fruit set. AB - Seed and fruit development are intimately related processes controlled by internal signals and environmental cues. The absence of seeds is usually appreciated by consumers and producers because it increases fruit quality and fruit shelf-life. One method to produce seedless fruit is to develop plants able to produce fruits independently from pollination and fertilization of the ovules. The onset of fruit growth is under the control of phytohormones. Recent genomic studies have greatly contributed to elucidate the role of phytohormones in regulating fruit initiation, providing at the same time genetic methods for introducing seedlessness in horticultural plants. PMID- 22253978 TI - Pediatric obesity: looking into treatment. AB - Prevalence of pediatric obesity continues to rise worldwide. Increasing the number of health care practitioners as well as pediatricians with expertise in obesity treatment is necessary. Because many obese patients suffer obesity associated cardiovascular, metabolic and other health complications that could increase the severity of obesity, it is fundamental not only to identify the child prone to obesity as early as possible, but to recognize, treat and monitor obesity-related diseases during adolescence. This short review outlines the treatment of pediatric obesity that may have applications in the primary care setting. It examines current information on eating behavior, sedentary behavior, and details studies of multidisciplinary, behavior-based, obesity treatment programs. We also report the less common and more aggressive forms of treatment, such as medication and bariatric surgery. We emphasize that health care providers have the potential to improve outcomes by performing early identification, helping families create the best possible home environment, and by providing structured guidance to obese children and their families. PMID- 22253977 TI - Dietary supplementation with conjugated linoleic acid plus n-3 polyunsaturated fatty acid increases food intake and brown adipose tissue in rats. AB - The effect of supplementation with 1% conjugated linoleic acid and 1% n-3 long chain polyunsaturated fatty acids (CLA/n-3) was assessed in rats. Food intake increased with no difference in body weights. White adipose tissue weights were reduced whereas brown adipose tissue and uncoupling protein-1 expression were increased. Plasma adiponectin, triglyceride and cholesterol levels were reduced while leptin, ghrelin and liver weight and lipid content were unchanged. Hypothalamic gene expression measurements revealed increased expression of orexigenic and decreased expression of anorexigenic signals. Thus, CLA/n-3 increases food intake without affecting body weight potentially through increasing BAT size and up-regulating UCP-1 in rats. PMID- 22253979 TI - Development and optimization of a fluorescent differential display PCR system for analyzing the stress response in Lactobacillus sakei strains. AB - Lactobacillus sakei is widely used as starter in the production process of Italian fermented sausages and its growth and survival are affected by various factors. We studied the differential expression of genome in response to different stresses by the fluorescent differential display (FDD) technique. This study resulted in the development and optimization of an innovative technique, with a high level of reproducibility and quality, which allows the identification of gene expression changes associated with different microbial behaviours under different growth conditions. PMID- 22253980 TI - Bovine colostrum supplementation during running training increases intestinal permeability. AB - Endurance exercise training can increase intestinal permeability which may contribute to the development of gastrointestinal symptoms in some athletes. Bovine colostrum (BC) supplementation reduces intestinal permeability induced by non-steroidal anti-inflammatory drugs. This study aimed to determine whether BC could also reduce intestinal permeability induced by endurance exercise. Thirty healthy adult males (25.0 +/- 4.7 yr; mean +/- SD) completed eight weeks of running three times per week for 45 minutes at their lactate threshold while consuming 60 g/day of BC, whey protein (WP) or control (CON). Intestinal permeability was assessed at baseline and after eight weeks by measuring the ratio of urinary lactulose (L) and rhamnose (R) excretion. After eight weeks the L/R ratio increased significantly more in volunteers consuming BC (251 +/- 140%) compared with WP (21 +/- 35%, P < 0.05) and CON (-7 +/- 13%, P < 0.02). The increase in intestinal permeability with BC may have been due to BC inducing greater leakiness of tight junctions between enterocytes or by increasing macromolecular transport as it does in neonatal gut. Further research should investigate the potential for BC to increase intestinal macromolecular transport in adults. PMID- 22253981 TI - A tool for sheep product quality: custom microarrays from public databases. AB - Milk and dairy products are an essential food and an economic resource in many countries. Milk component synthesis and secretion by the mammary gland involve expression of a large number of genes whose nutritional regulation remains poorly defined. The purpose of this study was to gain an understanding of the genomic influence on milk quality and synthesis by comparing two sheep breeds with different milking attitude (Sarda and Gentile di Puglia) using sheep-specific microarray technology. From sheep ESTs deposited at NCBI, we have generated the first annotated microarray developed for sheep with a coverage of most of the genome. PMID- 22253982 TI - Traceability of plant diet contents in raw cow milk samples. AB - The use of molecular marker in the dairy sector is gaining large acceptance as a reliable diagnostic approach for food authenticity and traceability. Using a PCR approach, the rbcL marker, a chloroplast-based gene, was selected to amplify plant DNA fragments in raw cow milk samples collected from stock farms or bought on the Italian market. rbcL-specific DNA fragments could be found in total milk, as well as in the skimmed and the cream fractions. When the PCR amplified fragments were sent to sequence, the nucleotide composition of the chromatogram reflected the multiple contents of the polyphytic diet. PMID- 22253983 TI - Whey protein ingestion activates mTOR-dependent signalling after resistance exercise in young men: a double-blinded randomized controlled trial. AB - The effect of resistance exercise with the ingestion of supplementary protein on the activation of the mTOR cascade, in human skeletal muscle has not been fully elucidated. In this study, the impact of a single bout of resistance exercise, immediately followed by a single dose of whey protein isolate (WPI) or placebo supplement, on the activation of mTOR signalling was analyzed. Young untrained men completed a maximal single-legged knee extension exercise bout and were randomized to ingest either WPI supplement (n = 7) or the placebo (n = 7). Muscle biopsies were taken from the vastus lateralis before, and 2, 4 and 24 h post exercise. WPI or placebo ingestion consumed immediately post-exercise had no impact on the phosphorylation of Akt (Ser473). However, WPI significantly enhanced phosphorylation of mTOR (Ser2448), 4E-BP1 (Thr(37/46)) and p70(S6K) (Thr389) at 2 h post-exercise. This study demonstrates that a single dose of WPI, when consumed in modest quantities, taken immediately after resistance exercise elicits an acute and transient activation of translation initiation within the exercised skeletal muscle. PMID- 22253984 TI - Immunogenicity characterization of two ancient wheat alpha-gliadin peptides related to coeliac disease. AB - The immunogenic potential of alpha-gliadin protein from two ancient wheats was studied with reference to coeliac disease. To this aim we investigated Graziella Ra(r) and Kamut(r) (the latter is considered an ancient relative of modern durum wheat) in comparison to four durum wheat accessions (Senatore Cappelli, Flaminio, Grazia and Svevo). ELISA and Western Blot analyses - carried out by two monoclonal antibodies raised against the alpha-gliadin peptides p31-49 (LGQQQPFPQQPYPQPQPF) and p56-75 (LQLQPFPQPQLPYPQPQLPY) containing a core region (underlined) reported to be toxic for coeliac patients - always showed an antibody-antigen positive reaction. For all accessions, an alpha-gliadin gene has also been cloned and sequenced. Deduced amino acid sequences constantly showed the toxic motifs. In conclusion, we strongly recommend that coeliac patients should avoid consuming Graziella Ra(r) or Kamut(r). In fact their alpha-gliadin not only is as toxic as one of the other wheat accessions, but also occurs in greater amount, which is in line with the higher level of proteins in ancient wheats when compared to modern varieties. PMID- 22253985 TI - Comparison among different gilthead sea bream (Sparus aurata) farming systems: activity of intestinal and hepatic enzymes and 13C-NMR analysis of lipids. AB - In order to evaluate differences in general health and nutritional values of gilthead sea bream (Sparus aurata), the effects of semi-intensive, land-based tanks and sea-cages intensive rearing systems were investigated, and results compared with captured wild fish. The physiological state was determined by measuring the activity of three different intestinal digestive enzymes: alkaline phosphatase (ALP), leucine aminopeptidase (LAP) and maltase; and the activity of the hepatic ALP. Also, the hepatic content in protein, cholesterol, and lipid were assessed. 13C-NMR analysis for qualitative and quantitative characterization of the lipid fraction extracted from fish muscles for semi-intensive and land based tanks intensive systems was performed. The lipid fraction composition showed small but significant differences in the monounsaturated/saturated fatty acid ratio, with the semi-intensive characterized by higher monounsaturated and lower saturated fatty acid content with respect to land based tanks intensive rearing system. PMID- 22253987 TI - Soft fruit traceability in food matrices using real-time PCR. AB - Food product authentication provides a means of monitoring and identifying products for consumer protection and regulatory compliance. There is a scarcity of analytical methods for confirming the identity of fruit pulp in products containing Soft Fruit. In the present work we have developed a very sensible qualitative and quantitative method to determine the presence of berry DNAs in different food matrices. To our knowledge, this is the first study that shows the applicability, to Soft Fruit traceability, of melting curve analysis and multiplexed fluorescent probes, in a Real-Time PCR platform. This methodology aims to protect the consumer from label misrepresentation. PMID- 22253986 TI - Comparison of milk fat globule membrane (MFGM) proteins of Chianina and Holstein cattle breed milk samples through proteomics methods. AB - Identification of proteins involved in milk production is important to understand the biology of lactation. Many studies have advanced the understanding of mammary function and milk secretion, but the critical molecular mechanisms implicated in milk fat secretion is still incomplete. Milk fat globules are secreted from the apical surface of the mammary cells, surrounded by a thin membrane bilayer, the milk fat globule membrane (MFGM), formed by proteins which have been suggested to be cholesterolemia-lowering factors, inhibitors of cancer cell growth, vitamin binders, bactericidal, suppressors of multiple sclerosis. Using a proteomic approach, we compared MFGM from milk samples of individuals belonging to two different cattle breeds, Chianina and Holstein, representative of selection for milk and meat traits, respectively. We were able to isolate some of the major MFGM proteins in the examined samples and to identify differences between the protein fractions of the two breeds. We detected differences in the amount of proteins linked to mammary gland development and lipid droplets formation, as well as host defence mechanisms. We have shown that proteomics is a suitable, unbiased method for the study of milk fractions proteins and a powerful tool in nutritional genomics. PMID- 22253988 TI - NMR-metabolic methodology in the study of GM foods. AB - The 1H-NMR methodology used in the study of genetically modified (GM) foods is discussed. Transgenic lettuce (Lactuca sativa cv "Luxor") over-expressing the ArabidopsisKNAT1 gene is presented as a case study. Twenty-two water-soluble metabolites (amino acids, organic acids, sugars) present in leaves of conventional and GM lettuce were monitored by NMR and quantified at two developmental stages. The NMR spectra did not reveal any difference in metabolite composition between the GM lettuce and the wild type counterpart. Statistical analyses of metabolite variables highlighted metabolism variation as a function of leaf development as well as the transgene. A main effect of the transgene was in altering sugar metabolism. PMID- 22253989 TI - The gluten-free diet: safety and nutritional quality. AB - The prevalence of celiac disease (CD), an autoimmune enteropathy, characterized by chronic inflammation of the intestinal mucosa, atrophy of intestinal villi and several clinical manifestations has increased in recent years. Subjects affected by CD cannot tolerate gluten protein, a mixture of storage proteins contained in several cereals (wheat, rye, barley and derivatives). Gluten free-diet remains the cornerstone treatment for celiac patients. Therefore the absence of gluten in natural and processed foods represents a key aspect of food safety of the gluten free diet. A promising area is the use of minor or pseudo-cereals such as amaranth, buckwheat, quinoa, sorghum and teff. The paper is focused on the new definition of gluten-free products in food label, the nutritional properties of the gluten-free cereals and their use to prevent nutritional deficiencies of celiac subjects. PMID- 22253991 TI - Regiospecific profiles of fatty acids in triacylglycerols and phospholipids from Adzuki beans (Vigna angularis). AB - Regiospecific distributions of fatty acids (FA) of triacylglycerols (TAG) and phospholipids (PL) isolated from five cultivars of adzuki beans (Vigna angularis) were investigated. The lipids comprised mainly PL (72.2-73.4 wt-%) and TAG (20.6 21.9 wt-%), whilst other components were detected in minor proportions (0.1-3.4 wt-%). The principal profiles of the FA distribution in the TAG and PL were evident in the beans among the five cultivars: unsaturated FA were predominantly distributed in the sn-2 position, whilst saturated FA primarily occupied the sn-1 or the sn-3 position in the these lipids. The results would be useful information to both producers and consumers for manufacturing traditional adzuki confectionaries such as wagashi in Japan. PMID- 22253990 TI - Epidemiologic studies of isoflavones & mammographic density. AB - Isoflavones, phytoestrogens in soy beans with estrogen-like properties, have been examined for their cancer protective effects. Mammographic density is a strong predictor of breast cancer. This review summarizes studies that have examined the association between isoflavones and breast density. Observational investigations in Hawaii and Singapore suggest slightly lower breast density among women of Asian descent with regular soy intake, but two larger studies from Japan and Singapore did not observe a protective effect. The findings from seven randomized trials with primarily Caucasian women indicate that soy or isoflavones do not modify mammographic density. Soy foods and isoflavone supplements within a nutritional range do not appear to modify breast cancer risk as assessed by mammographic density. PMID- 22253992 TI - Risk factors for overweight and obesity among Thai adults: results of the National Thai Food Consumption Survey. AB - We evaluated the associations between overweight and obesity and socio-economic status (SES), behavioral factors, and dietary intake in Thai adults. A nationally representative sample of 6,445 Thais adults (18-70 years) was surveyed during 2004-2005. Information including demographics, SES characteristics, dietary intake, and anthropometrics were obtained. Overall, 35.0% of men, and 44.9% of women were overweight or obese (BMI >= 23 kg/m2) using the Asian cut-points. Regression models demonstrated that age was positively associated with being overweight in both genders. In gender-stratified analyses, male respondents who were older, lived in urban areas, had higher annual household income, and did not smoke were more likely to be classified as overweight and obese. Women who were older, had higher education, were not in a marriage-like relationship and were in semi-professional occupation were at greater risk for being overweight and obese. High carbohydrate and protein intake were found to be positively associated with BMI whereas the frequent use of dairy foods was found to be negatively associated with BMI among men. The present study found that SES factors are associated with being classified as overweight and obese in Thai adults, but associations were different between genders. Health promotion strategies regarding obesity and its related co-morbidity are necessary. PMID- 22253994 TI - Calcium: a nutrient deserving a special issue. AB - Interest in calcium has continued since the 1980s when its role in promoting bone growth and retention was established in clinical trials of children and postmenopausal women. The human nutrition functions now attributed to calcium have expanded beyond bone health to include other conditions such as body weight maintenance. While most efforts have been focused on the findings that dietary intakes are low, there are emerging data on safety concerns of excess amounts. This Special Issue on calcium nutrition, spanning the lifecycle from critically ill neonates through to older adults, has been written by some of the leading researchers in this field. PMID- 22253993 TI - Effects of beta-alanine on muscle carnosine and exercise performance: a review of the current literature. AB - Muscle carnosine has been reported to serve as a physiological buffer, possess antioxidant properties, influence enzyme regulation, and affect sarcoplasmic reticulum calcium regulation. Beta-alanine (beta-ALA) is a non-essential amino acid. beta-ALA supplementation (e.g., 2-6 grams/day) has been shown to increase carnosine concentrations in skeletal muscle by 20-80%. Several studies have reported that beta-ALA supplementation can increase high-intensity intermittent exercise performance and/or training adaptations. Although the specific mechanism remains to be determined, the ergogenicity of beta-ALA has been most commonly attributed to an increased muscle buffering capacity. More recently, researchers have investigated the effects of co-ingesting beta-ALA with creatine monohydrate to determine whether there may be synergistic and/or additive benefits. This paper overviews the theoretical rationale and potential ergogenic value of beta ALA supplementation with or without creatine as well as provides future research recommendations. PMID- 22253995 TI - Flavan-3-ol compounds from wine wastes with in vitro and in vivo antioxidant activity. AB - It has been suggested that the dietary intake of antioxidant supplements could be a useful strategy to reduce the incidence of diseases associated with oxidative stress. The aim of present work is to study the possibility to obtain compounds with antioxidant activity from wine wastes using water as solvent. Results have shown that it is possible to obtain flavan-3-ol compounds from wine wastes both from V. vinifera (cv. Cabernet Sauvignon and Merlot) and V. labrusca (cv. Bordo and Isabella) species. The main phenolic compounds found in the extracts were catechin and epicatechin, followed by procyanidin B3, procyanidin B1, procyanidin B2, gallic acid, epigallocatechin, and procyanidin B4. All flavan-3-ol extracts showed significant in vitro and in vivo activities. It was found that the extracts were able to prevent lipid and protein oxidative damage in the cerebral cortex, cerebellum and hippocampus tissues of rats. Although further studies are necessary, these flavan-3-ol extracts show potential to be used to reduce the incidence of degenerative diseases associated with oxidative stress. PMID- 22253997 TI - Osteoporosis prevention--a worthy and achievable strategy. PMID- 22253996 TI - Effect of the glycemic index of carbohydrates on Acne vulgaris. AB - Acne vulgaris may be improved by dietary factors that increase insulin sensitivity. We hypothesized that a low-glycemic index diet would improve facial acne severity and insulin sensitivity. Fifty-eight adolescent males (mean age +/- standard deviation 16.5 +/- 1.0 y and body mass index 23.1 +/- 3.5 kg/m(2)) were alternately allocated to high or low glycemic index diets. Severity of inflammatory lesions on the face, insulin sensitivity (homeostasis modeling assessment of insulin resistance), androgens and insulin-like growth factor-1 and its binding proteins were assessed at baseline and at eight weeks, a period corresponding to the school term. Forty-three subjects (n = 23 low glycemic index and n = 20 high glycemic index) completed the study. Diets differed significantly in glycemic index (mean +/- standard error of the mean, low glycemic index 51 +/- 1 vs. high glycemic index 61 +/- 2, p = 0.0002), but not in macronutrient distribution or fiber content. Facial acne improved on both diets (low glycemic index -26 +/- 6%, p = 0.0004 and high glycemic index -16 +/- 7%, p = 0.01), but differences between diets did not reach significance. Change in insulin sensitivity was not different between diets (low glycemic index 0.2 +/- 0.1 and high glycemic index 0.1 +/- 0.1, p = 0.60) and did not correlate with change in acne severity (Pearson correlation r = -0.196, p = 0.244). Longer time frames, greater reductions in glycemic load or/and weight loss may be necessary to detect improvements in acne among adolescent boys. PMID- 22253998 TI - Trends in body fat, body mass index and physical fitness among male and female college students. AB - There have been many publications in recent years reporting on the quantity of physical activity among college students using indirect indicators such as steps walked per day or time spent on physical activities. The purpose of this study was to describe the trends of physical fitness related to BMI and body fat among university students between 1996 and 2008. The results showed a significant decline in the average fitness levels measured as an estimation of VO(2max) for male and female students (p < 0.001 for both sexes). The linear trend for BMI by years was not significant for both sexes (p for males = 0.772, p for females = 0.253). On average, in the last 13 years, % body fat was increasing 0.513%/year for males and 0.654%/year for females. There is a significant indirect correlation between the student's VO(2max) levels and % body fat, r = -0.489; p < 0.001 for males; and r = -0.416, p < 0.001 for females. Approximately 23.9% of the variance in the VO(2max) levels in males and 17.3% in females can be explained by the variance in % body fat. The results support recent findings that physical fitness among college students is declining and body fatness is increasing. PMID- 22253999 TI - Bone health nutrition issues in aging. AB - Bone health is an important issue in aging. Calcium and vitamin D currently have the most focus in published research on nutrition and bone health in aging, although evidence from published research is not conclusive. A systematic review was conducted to determine the impact of dietary and supplemental interventions focused on calcium and vitamin D over the past 10 years. Using key words to search, and search limits (aging population, English), 62 papers were found related to diet, nutrition, and bone; and 157 were found related to calcium and bone. Our review found a positive effect on bone health for supplements; food based interventions; and educational strategies. Although there may be a publishing bias related to non-significant findings not being published, our results suggest the effectiveness of food based and educational interventions with less economic impact to the individual, as well as less risk of physiological side effects occurring. PMID- 22254001 TI - Monitoring the affordability of healthy eating: a case study of 10 years of the Illawarra Healthy Food Basket. AB - Healthy food baskets have been used around the world for a variety of purposes, including: examining the difference in cost between healthy and unhealthy food; mapping the availability of healthy foods in different locations; calculating the minimum cost of an adequate diet for social policy planning; developing educational material on low cost eating and examining trends on food costs over time. In Australia, the Illawarra Healthy Food Basket was developed in 2000 to monitor trends in the affordability of healthy food compared to average weekly wages and social welfare benefits for the unemployed. It consists of 57 items selected to meet the nutritional requirements of a reference family of five. Bi annual costing from 2000-2009 has shown that the basket costs have increased by 38.4% in the 10-year period, but that affordability has remained relatively constant at around 30% of average household incomes. PMID- 22254002 TI - The serum metabolite response to diet intervention with probiotic acidified milk in irritable bowel syndrome patients is indistinguishable from that of non probiotic acidified milk by 1H NMR-based metabonomic analysis. AB - The effects of a probiotic acidified milk product on the blood serum metabolite profile of patients suffering from Irritable Bowel Syndrome (IBS) compared to a non-probiotic acidified milk product was investigated using (1)H NMR metabonomics. For eight weeks, IBS patients consumed 0.4 L per day of a probiotic fermented milk product or non-probiotic acidified milk. Both diets resulted in elevated levels of blood serum L-lactate and 3-hydroxybutyrate. Our results showed identical effects of acidified milk consumption independent of probiotic addition. A similar result was previously obtained in a questionnaire-based evaluation of symptom relief. A specific probiotic effect is thus absent both in the patient subjective symptom evaluations and at the blood serum metabolite level. However, there was no correspondence between symptom relief and metabolite response on the patient level. PMID- 22254003 TI - Early exposure to soy isoflavones and effects on reproductive health: a review of human and animal studies. AB - Soy isoflavones are phytoestrogens with potential hormonal activity due to their similar chemical structure to 17-beta-estradiol. The increasing availability of soy isoflavones throughout the food supply and through use of supplements has prompted extensive research on biological benefits to humans in chronic disease prevention and health maintenance. While much of this research has focused on adult populations, infants fed soy protein based infant formulas are exposed to substantial levels of soy isoflavones, even when compared to adult populations that consume a higher quantity of soy-based foods. Infant exposure, through soy formula, primarily occurs from birth to one year of life, a stage of development that is particularly sensitive to dietary and environmental compounds. This has led investigators to study the potential hormonal effects of soy isoflavones on later reproductive health outcomes. Such studies have included minimal human data with the large majority of studies using animal models. This review discusses key aspects of the current human and animal studies and identifies critical areas to be investigated as there is no clear consensus in this research field. PMID- 22254000 TI - Polyphenols and human health: prevention of disease and mechanisms of action. AB - Polyphenols are found ubiquitously in plants and their regular consumption has been associated with a reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD) and neurodegenerative disorders. Rather than exerting direct antioxidant effects, the mechanisms by which polyphenols express these beneficial properties appear to involve their interaction with cellular signaling pathways and related machinery that mediate cell function under both normal and pathological conditions. We illustrate that their interactions with two such pathways, the MAP kinase (ERK, JNK, p38) and PI3 kinase/Akt signaling cascades, allow them to impact upon normal and abnormal cell function, thus influencing the cellular processes involved in the initiation and progression of cancer, CVD and neurodegeneration. For example, their ability to activate ERK in neurons leads to a promotion of neuronal survival and cognitive enhancements, both of which influence the progression of Alzheimer's disease, whilst ERK activation by polyphenols in vascular endothelial cells influences nitric oxide production, blood pressure and ultimately CVD risk. The main focus of this review is to provide an overview of the role that polyphenols play in the prevention of cancer, cardiovascular disease and neurodegeneration. We present epidemiological data, human intervention study findings, as well as animal and in vitro studies in support of these actions and in each case we consider how their actions at the cellular level may underpin their physiological effects. PMID- 22254004 TI - Nutrition-related practices and attitudes of Kansas skipped-generation(s) caregivers and their grandchildren. AB - Despite growing numbers, the nutrition practices and attitudes of skipped generation(s) kinship caregivers regarding feeding the dependent children in their care have not been examined. In this qualitative study, transcriptions of semi-structured interviews with 19 female and four male skipped-generation(s) Kansas caregivers (ages 47 to 80, 92% non-Hispanic whites, 83% female, 78% grandparents and 22% great-aunt or great-grandparent caregivers; caring for a range of one to four children, ages three to 18, for an average of nine years) were content analyzed for how their nutrition-related practices and attitudes had changed since parenting the first time. Sub-themes regarding practices included: being more nutrition and food safety conscious now, and shifting their child feeding style. The children seemed to be adversely affected by an on-the-go lifestyle and the use of more electronics. Caregivers described their sources for child feeding advice as being based mostly on information from their mothers, physicians, and their past parenting experiences. Sub-themes for attitudes included opinions that nutrition and safe food handling are important and that nutritious food is expensive. They preferred printed or video nutrition education materials and wanted to receive information through organizations they trusted. This population could benefit from education on: infant, child, adolescent, and sports nutrition; feeding "picky eaters"; healthful recipes, "fast foods" and packaged foods; quick, inexpensive meals and snacks low in fat, sugar, and salt; limiting sedentary time; family meals; using food thermometers; and intergenerational gardening and cooking. PMID- 22254005 TI - Long-chain omega-3 polyunsaturated fatty acids may be beneficial for reducing obesity-a review. AB - Current recommendations for counteracting obesity advocate the consumption of a healthy diet and participation in regular physical activity, but many individuals have difficulty complying with these recommendations. Studies in rodents and humans have indicated that long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation which might facilitate nutrient delivery to skeletal muscle and changes in gene expression which shift metabolism toward increased accretion of lean tissue, enhanced fat oxidation and energy expenditure and reduced fat deposition. While LC n-3 PUFA supplementation has been shown to reduce obesity in rodents, evidence in humans is limited. Epidemiological associations between LC n-3 PUFA intakes and obesity are inconclusive but small cross-sectional studies have demonstrated inverse relationships between markers of LC n-3 PUFA status and markers of obesity. Human intervention trials indicate potential benefits of LC n-3 PUFA supplementation, especially when combined with energy-restricted diets or exercise, but more well-controlled and long-term trials are needed to confirm these effects and identify mechanisms of action. PMID- 22254006 TI - Chemistry and biochemistry of dietary polyphenols. AB - Polyphenols are the biggest group of phytochemicals, and many of them have been found in plant-based foods. Polyphenol-rich diets have been linked to many health benefits. This paper is intended to review the chemistry and biochemistry of polyphenols as related to classification, extraction, separation and analytical methods, their occurrence and biosynthesis in plants, and the biological activities and implications in human health. The discussions are focused on important and most recent advances in the above aspects, and challenges are identified for future research. PMID- 22254007 TI - Dietary advanced glycation end products and aging. AB - Advanced glycation end products (AGEs) are a heterogeneous, complex group of compounds that are formed when reducing sugar reacts in a non-enzymatic way with amino acids in proteins and other macromolecules. This occurs both exogenously (in food) and endogenously (in humans) with greater concentrations found in older adults. While higher AGEs occur in both healthy older adults and those with chronic diseases, research is progressing to both quantify AGEs in food and in people, and to identify mechanisms that would explain why some human tissues are damaged, and others are not. In the last twenty years, there has been increased evidence that AGEs could be implicated in the development of chronic degenerative diseases of aging, such as cardiovascular disease, Alzheimer's disease and with complications of diabetes mellitus. Results of several studies in animal models and humans show that the restriction of dietary AGEs has positive effects on wound healing, insulin resistance and cardiovascular diseases. Recently, the effect of restriction in AGEs intake has been reported to increase the lifespan in animal models. This paper will summarize the work that has been published for both food AGEs and in vivo AGEs and their relation with aging, as well as provide suggestions for future research. PMID- 22254008 TI - Effects of dietary fiber and its components on metabolic health. AB - Dietary fiber and whole grains contain a unique blend of bioactive components including resistant starches, vitamins, minerals, phytochemicals and antioxidants. As a result, research regarding their potential health benefits has received considerable attention in the last several decades. Epidemiological and clinical studies demonstrate that intake of dietary fiber and whole grain is inversely related to obesity, type two diabetes, cancer and cardiovascular disease (CVD). Defining dietary fiber is a divergent process and is dependent on both nutrition and analytical concepts. The most common and accepted definition is based on nutritional physiology. Generally speaking, dietary fiber is the edible parts of plants, or similar carbohydrates, that are resistant to digestion and absorption in the small intestine. Dietary fiber can be separated into many different fractions. Recent research has begun to isolate these components and determine if increasing their levels in a diet is beneficial to human health. These fractions include arabinoxylan, inulin, pectin, bran, cellulose, beta glucan and resistant starch. The study of these components may give us a better understanding of how and why dietary fiber may decrease the risk for certain diseases. The mechanisms behind the reported effects of dietary fiber on metabolic health are not well established. It is speculated to be a result of changes in intestinal viscosity, nutrient absorption, rate of passage, production of short chain fatty acids and production of gut hormones. Given the inconsistencies reported between studies this review will examine the most up to date data concerning dietary fiber and its effects on metabolic health. PMID- 22254009 TI - Vitamin enhanced waters and polyphenol rich beverages analyzed for antioxidant capacity and antioxidants/calorie. AB - The purpose of this study was to analyze polyphenol rich beverages (vitamin enhanced waters (VEWs), fruit juices and berry juices) to determine free polyphenol concentrations and free polyphenols per Calorie based on a serving size. The Folin-Ciocalteu reagent was used in a colorimetric assay based on a catechin standard. Fruit and berry juices contained, on average, more than eight times the concentration of free polyphenols when compared to VEWs. When Calories per serving were taken into consideration, fruit and berry juices contained more than twice the free polyphenols per Calorie. PMID- 22254010 TI - Food intake of Kansans over 80 years of age attending congregate meal sites. AB - As the population of the United States continues to age, it has become increasingly more important to recognize the food intake and eating habits of older adults. The objective of this study was to describe the food group intake, factors predicting food group intake, and the food choices of community-dwelling Kansans, 80 years of age and older who participate in congregate meal programs. Participants completed a short questionnaire querying demographic information, current health status, and dietary supplement use. Participants (n = 113) were then followed up via telephone to complete two 24-hour diet recalls. Data were analyzed to determine adequacy of food group intake and mean intake. Regression analyses were used to determine factors predicting intake and frequency analysis established food typically consumed. Female participants were significantly more likely to consume more fruit servings than males. Intake was low for all five of the food groups, especially dairy. Chronic health conditions and dietary supplement use were consistently predictive factors of the amount of each food group consumed. PMID- 22254011 TI - Assessment of information to substantiate a health claim on the prevention of prostate cancer by lignans. AB - Lignans and their in vivo metabolites, especially enterolactone (ENL), have attracted substantial interest as potential chemopreventive agents for prostate cancer. Preclinical and clinical interventions performed with lignan-rich flaxseed that use surrogate biomarkers as endpoints suggest that lignans may attenuate prostate carcinogenesis in individuals with increased risk or with diagnosed cancer. No unequivocal prostate cancer risk reduction has been found for lignans in epidemiological studies, suggesting that lignan concentrations found in populations consuming a regular non-supplemented diet are not chemopreventive in prostate cancer. Presumably, the main obstacles in assessing the efficacy of food lignans is limited knowledge of the serum and tissue lignan concentrations required for the putative prevention. Further clinical studies performed with the purified compounds are required to substantiate a health claim. PMID- 22254012 TI - Dietary phospholipids and intestinal cholesterol absorption. AB - Experiments carried out with cultured cells and in experimental animals have consistently shown that phospholipids (PLs) can inhibit intestinal cholesterol absorption. Limited evidence from clinical studies suggests that dietary PL supplementation has a similar effect in man. A number of biological mechanisms have been proposed in order to explain how PL in the gut lumen is able to affect cholesterol uptake by the gut mucosa. Further research is however required to establish whether the ability of PLs to inhibit cholesterol absorption is of therapeutic benefit. PMID- 22254014 TI - Production of hesperetin glycosides by Xanthomonas campestris and cyclodextrin glucanotransferase and their anti-allergic activities. AB - The production of hesperetin glycosides was investigated using glycosylation with Xanthomonas campestris and cyclodextrin glucanotransferase (CGTase). X. campestris glucosylated hesperetin to its 3'-, 5-, and 7-O-glucosides, and CGTase converted hesperetin glucosides into the corresponding maltosides. The resulting 7-O-glucoside and 7-O-maltoside of hesperetin showed inhibitory effects on IgE antibody production and on O2- generation from rat neutrophils. PMID- 22254013 TI - Oiling the brain: a review of randomized controlled trials of omega-3 fatty acids in psychopathology across the lifespan. AB - Around one in four people suffer from mental illness at some stage in their lifetime. There is increasing awareness of the importance of nutrition, particularly omega-3 polyunsaturated fatty acids (n-3 PUFA), for optimal brain development and function. Hence in recent decades, researchers have explored effects of n-3 PUFA on mental health problems over the lifespan, from developmental disorders in childhood, to depression, aggression, and schizophrenia in adulthood, and cognitive decline, dementia and Alzheimer's disease in late adulthood. This review provides an updated overview of the published and the registered clinical trials that investigate effects of n-3 PUFA supplementation on mental health and behavior, highlighting methodological differences and issues. PMID- 22254015 TI - Vaccenic and elaidic acid modify plasma and splenocyte membrane phospholipids and mitogen-stimulated cytokine production in obese insulin resistant JCR: LA-cp rats. AB - This study assessed the long-term effects of dietary vaccenic acid (VA) and elaidic acid (EA) on plasma and splenocyte phospholipid (PL) composition and related changes in inflammation and splenocyte phenotypes and cytokine responses in obese/insulin resistant JCR:LA-cp rats. Relative to lean control (Ctl), obese Ctl rats had higher serum haptoglobin and impaired T-cell-stimulated cytokine responses. VA and EA diets improved T-cell-stimulated cytokine production; but, only VA normalized serum haptoglobin. However, EA- and VA-fed rats had enhanced LPS-stimulated cytokine responses. The changes elicited by VA were likely due changes in essential fatty acid composition in PL; whereas EA-induced changes may due to direct incorporation into membrane PL. PMID- 22254016 TI - Do pregnant women and those at risk of developing post-natal depression consume lower amounts of long chain omega-3 polyunsaturated fatty acids? AB - The aims were to compare intakes of long chain omega-3 polyunsaturated fatty acid (LC n-3 PUFA) in pregnant and non-pregnant women in Australia and to compare these intakes to the Australian National Nutrition Survey of 1995 (NNS95) [1] and to determine if the LC n-3 PUFA intakes differed in women who may be 'at risk' compared with women 'not at risk' of developing post-natal depression (PND). A validated LC n-3 PUFA food frequency questionnaire and pregnant women's Edinburgh Postnatal Depression Scale (EPDS) scores were used. LC n-3 PUFA intakes were comparable to the NNS95 but did not differ due to pregnancy or whether or not a woman is at risk of developing PND. PMID- 22254017 TI - Antioxidant properties and neuroprotective capacity of strawberry tree fruit (Arbutus unedo). AB - Berries contain significant amounts of phytochemicals, including polyphenols, which are reported to reduce cancer risk, coronary heart disease and other degenerative diseases. These effects are mainly attributed to the antioxidant capacity of polyphenols found in berries. Strawberry tree (Arbutus unedo) berries are used in folk medicine but seldom eaten as fresh fruits. Their phenolic profile and antioxidant capacity reveal a high potential, but they are not well characterized as a "health promoting food". The aim of this study was to assess the antioxidant properties of the edible strawberry tree fruit in vitro and in a neurodegeneration cell model. Raspberry (Rubus idaeus), a well documented health promoting fruit, was used as a control for comparison purposes. A. unedo yielded a similar content in polyphenols and a slightly lower value of total antioxidant capacity in comparison to R. idaeus. Although the chemically-measured antioxidant activity was similar between both fruits, R. idaeus increased neuroblastoma survival in a neurodegeneration cell model by 36.6% whereas A. unedo extracts caused no effect on neuroblastoma viability. These results clearly demonstrate that a promising level of chemically-determined antioxidant activity of a plant extract is not necessarily correlated with biological significance, as assessed by the effect of A. unedo fruit in a neurodegeneration cell model. PMID- 22254018 TI - Continuous feedings of fortified human milk lead to nutrient losses of fat, calcium and phosphorous. AB - Substantial losses of nutrients may occur during tube (gavage) feeding of fortified human milk. Our objective was to compare the losses of key macronutrients and minerals based on method of fortification and gavage feeding method. We used clinically available gavage feeding systems and measured pre- and post-feeding (end-point) nutrient content of calcium (Ca), phosphorus (Phos), protein, and fat. Comparisons were made between continuous, gravity bolus, and 30 minute infusion pump feeding systems, as well as human milk fortified with donor human milk-based and bovine milk-based human milk fortifier using an in vitro model. Feeding method was significantly associated with fat and Ca losses, with increased losses in continuous feeds. Fat losses in continuous feeds were substantial, with 40 +/- 3 % of initial fat lost during the feeding process. After correction for feeding method, human milk fortified with donor milk-based fortifier was associated with significantly less loss of Ca (8 +/- 4% vs. 28 +/- 4%, p< 0.001), Phos (3 +/- 4% vs. 24 +/- 4%, p < 0.001), and fat (17 +/- 2% vs. 25 +/- 2%, p = 0.001) than human milk fortified with a bovine milk-based fortifier (Mean +/- SEM). PMID- 22254020 TI - 1H NMR fingerprinting of soybean extracts, with emphasis on identification and quantification of isoflavones. AB - 1H NMR spectra were recorded of methanolic extracts of seven soybean varieties (Glycine max.), cultivated using traditional and organic farming techniques. It was possible to identify signals belonging to the groups of amino acids, carbohydrates, organic acids and aromatic substances in the spectra. In the aromatic zone, the isoflavone signals were of particular interest: genistein, daidzein, genistin, daidzin, malonylgenistin, acetylgenistin, malonyldaidzin signals were assigned and these compounds were quantified, resulting in accordance with published data, and further demonstrating the potential of the NMR technique in food science. PMID- 22254021 TI - Streptococcus mutans, caries and simulation models. AB - Dental caries and dental plaque are among the most common diseases worldwide, and are caused by a mixture of microorganisms and food debris. Specific types of acid producing bacteria, especially Streptococcus mutans, colonize the dental surface and cause damage to the hard tooth structure in the presence of fermentable carbohydrates e.g., sucrose and fructose. This paper reviews the link between S. mutans and caries, as well as different simulation models that are available for studying caries. These models offer a valuable approach to study cariogenicity of different substrates as well as colonization of S. mutans. PMID- 22254019 TI - Potential health-modulating effects of isoflavones and metabolites via activation of PPAR and AhR. AB - Isoflavones have multiple actions on cell functions. The most prominent one is the activation of estrogen receptors. Other functions are often overlooked, but are equally important and explain the beneficial health effects of isoflavones. Isoflavones are potent dual PPARalpha/gamma agonists and exert anti-inflammatory activity, which may contribute to the prevention of metabolic syndrome, atherosclerosis and various other inflammatory diseases. Some isoflavones are potent aryl hydrocarbon receptor (AhR) agonists and induce cell cycle arrest, chemoprevention and modulate xenobiotic metabolism. This review discusses effects mediated by the activation of AhR and PPARs and casts a light on the concerted action of isoflavones. PMID- 22254022 TI - Vitamin B12 in health and disease. AB - Vitamin B(12) is essential for DNA synthesis and for cellular energy production.This review aims to outline the metabolism of vitamin B(12), and to evaluate the causes and consequences of sub-clinical vitamin B(12) deficiency. Vitamin B(12) deficiency is common, mainly due to limited dietary intake of animal foods or malabsorption of the vitamin. Vegetarians are at risk of vitamin B(12) deficiency as are other groups with low intakes of animal foods or those with restrictive dietary patterns. Malabsorption of vitamin B(12) is most commonly seen in the elderly, secondary to gastric achlorhydria. The symptoms of sub-clinical deficiency are subtle and often not recognized. The long-term consequences of sub-clinical deficiency are not fully known but may include adverse effects on pregnancy outcomes, vascular, cognitive, bone and eye health. PMID- 22254024 TI - The effect of antioxidant supplementation on fatigue during exercise: potential role for NAD+(H). AB - This study compared serum pyridine levels (NAD(+)/NADH) in trained (n = 6) and untrained (n = 7) subjects after continuous progressive exercise at 50%, 70% then 95% of physical work capacity until fatigue (TTF) after consuming a placebo or antioxidant (AO) cocktail (Lactaway((c))). An increase of 17% in TTF was observed in AO as compared to placebo (p = 0.032). This was accompanied by a significant increase in serum NAD(+) levels (p = 0.037) in the AO supplemented group post exercise. The increases in NAD(+) and improved endurance reflect lower oxidative stress-induced suppression of aerobic respiration. PMID- 22254025 TI - Pilot-scale production and viability analysis of freeze-dried probiotic bacteria using different protective agents. AB - The functional food industry requires an improvement of probiotic strain stability during storage, especially when they are stored at room temperature. In this study, the viability of freeze-dried Lactobacillus rhamnosus IMC 501((r)) and Lactobacillus paracasei IMC 502((r)) using different protective agents (i.e., glycerine, mannitol, sorbitol, inulin, dextrin, Crystalean((r))) was determined and compared with semi skimmed milk (SSM) control. No significant differences were observed between the tested protectants and the control (SSM) during storage at refrigerated conditions. During storage at room temperature, only glycerine was found to stabilize viability better than other tested substances. PMID- 22254026 TI - Comparative effects of R- and S-equol and implication of transactivation functions (AF-1 and AF-2) in estrogen receptor-induced transcriptional activity. AB - Equol, one of the main metabolites of daidzein, is a chiral compound with pleiotropic effects on cellular signaling. This property may induce activation/inhibition of the estrogen receptors (ER) a or b, and therefore, explain the beneficial/deleterious effects of equol on estrogen-dependent diseases. With its asymmetric centre at position C-3, equol can exist in two enantiomeric forms (R- and S-equol). To elucidate the yet unclear mechanisms of ER activation/inhibition by equol, we performed a comprehensive analysis of ERa and ERb transactivation by racemic equol, as well as by enantiomerically pure forms. Racemic equol was prepared by catalytic hydrogenation from daidzein and separated into enantiomers by chiral HPLC. The configuration assignment was performed by optical rotatory power measurements. The ER-induced transactivation by R- and S-equol (0.1-10 uM) and 17b-estradiol (E2, 10 nM) was studied using transient transfections of ERalpha and ERbeta in CHO, HepG2 and HeLa cell lines. R- and S-equol induce ER transactivation in an opposite fashion according to the cellular context. R-equol and S-equol are more potent in inducing ERalpha in an AF-2 and AF-1 permissive cell line, respectively. Involvement of ERalpha transactivation functions (AF-1 and AF-2) in these effects has been examined. Both AF-1 and AF-2 are involved in racemic equol, R-equol and S-equol induced ERalpha transcriptional activity. These results could be of interest to find a specific ligand modulating ER transactivation and could contribute to explaining the diversity of equol actions in vivo. PMID- 22254027 TI - Omega-3 fatty acids and inflammatory processes. AB - Long chain fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by, or at least associated with, changes in fatty acid composition of cell membranes. Changes in these compositions can modify membrane fluidity, cell signaling leading to altered gene expression, and the pattern of lipid mediator production. Cell involved in the inflammatory response are typically rich in the n-6 fatty acid arachidonic acid, but the contents of arachidonic acid and of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be altered through oral administration of EPA and DHA. Eicosanoids produced from arachidonic acid have roles in inflammation. EPA also gives rise to eicosanoids and these often have differing properties from those of arachidonic acid-derived eicosanoids. EPA and DHA give rise to newly discovered resolvins which are anti-inflammatory and inflammation resolving. Increased membrane content of EPA and DHA (and decreased arachidonic acid content) results in a changed pattern of production of eicosanoids and resolvins. Changing the fatty acid composition of cells involved in the inflammatory response also affects production of peptide mediators of inflammation (adhesion molecules, cytokines etc.). Thus, the fatty acid composition of cells involved in the inflammatory response influences their function; the contents of arachidonic acid, EPA and DHA appear to be especially important. The anti-inflammatory effects of marine n-3 PUFAs suggest that they may be useful as therapeutic agents in disorders with an inflammatory component. PMID- 22254028 TI - Omega-3 Index and sudden cardiac death. AB - Sudden cardiac death (SCD) is an unresolved health issue, and responsible for 15% of all deaths in Western countries. Epidemiologic evidence, as well as evidence from clinical trials, indicates that increasing intake and high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect from SCD and other major adverse cardiac events. Levels of EPA+DHA are best assessed by the Omega-3 Index, representing the red cell fatty acid content of EPA+DHA. Work is in progress that will further define the value of the Omega-3 Index as a risk factor for SCD, other cardiac events, and as target for treatment with EPA+DHA. PMID- 22254031 TI - Vitamin D and cardiovascular disease. AB - Vitamin D insufficiency/deficiency has been observed worldwide at all stages of life. It has been characterized as a public health problem, since low concentrations of this vitamin have been linked to the pathogenesis of several chronic diseases. Several studies have suggested that vitamin D is involved in cardiovascular diseases and have provided evidence that it has a role in reducing cardiovascular disease risk. It may be involved in regulation of gene expression through the presence of vitamin D receptors in various cells, regulation of blood pressure (through renin-angiotensin system), and modulation of cell growth and proliferation including vascular smooth muscle cells and cardiomyocytes. Identifying correct mechanisms and relationships between vitamin D and such diseases could be important in relation to patient care and healthcare policies. PMID- 22254029 TI - Vitamin D status during pregnancy and aspects of offspring health. AB - Low maternal vitamin D levels during pregnancy have been linked to various health outcomes in the offspring, ranging from periconceptional effects to diseases of adult onset. Maternal and infant cord 25(OH)D levels are highly correlated. Here, we review the available evidence for these adverse health effects. Most of the evidence has arisen from observational epidemiological studies, but randomized controlled trials are now underway. The evidence to date supports that women should be monitored and treated for vitamin D deficiency during pregnancy but optimal and upper limit serum 25(OH)D levels during pregnancy are not known. PMID- 22254030 TI - Nonclassical vitamin D action. AB - It is becoming increasingly clear that vitamin D has a broad range of actions in the human body. Besides its well-known effects on calcium/phosphate homeostasis, vitamin D influences muscle function, cardiovascular homeostasis, nervous function, and the immune response. Vitamin D deficiency/insufficiency has been associated with muscle weakness and a high incidence of various chronic diseases such as cardiovascular disease, cancer, multiple sclerosis, and type 1 and 2 diabetes. Most importantly, low vitamin D status has been found to be an independent predictor of all-cause mortality. Several recent randomized controlled trials support the assumption that vitamin D can improve muscle strength, glucose homeostasis, and cardiovascular risk markers. In addition, vitamin D may reduce cancer incidence and elevated blood pressure. Since the prevalence of vitamin D deficiency/insufficiency is high throughout the world, there is a need to improve vitamin D status in the general adult population. However, the currently recommended daily vitamin D intake of 5-15 ug is too low to achieve an adequate vitamin D status in individuals with only modest skin synthesis. Thus, there is a need to recommend a vitamin D intake that is effective for achieving adequate circulating 25-hydroxyvitamin D concentrations (>75 nmol/L). PMID- 22254032 TI - Capturing the data: nutrition risk screening of adults in hospital. AB - This study aims to explore limitations with the Malnutrition Screening Tool in identifying malnutrition risk, in a cohort of 3,033 adult Australian medical and surgical hospital inpatients. Seventy-two percent of patients were screened; illness and medical care limited access to others. Malnutrition risk (16.5%; n = 501) was found in all age groups with a trend to higher risk in medical wards; 10% (n = 300) of patients with communication barriers were excluded. Systematic screening increased dietitians' referrals by 39%. Further research is required to enable screening of all patients, including those with communication issues with an easy to use valid tool. PMID- 22254034 TI - Calcium absorption in infants and small children: methods of determination and recent findings. AB - Determining calcium bioavailability is important in establishing dietary calcium requirements. In infants and small children, previously conducted mass balance studies have largely been replaced by stable isotope-based studies. The ability to assess calcium absorption using a relatively short 24-hour urine collection without the need for multiple blood samples or fecal collections is a major advantage to this technique. The results of these studies have demonstrated relatively small differences in calcium absorption efficiency between human milk and currently available cow milk-based infant formulas. In older children with a calcium intake typical of Western diets, calcium absorption is adequate to meet bone mineral accretion requirements. PMID- 22254033 TI - Beneficial effects of probiotic and food borne yeasts on human health. AB - Besides being important in the fermentation of foods and beverages, yeasts have shown numerous beneficial effects on human health. Among these, probiotic effects are the most well known health effects including prevention and treatment of intestinal diseases and immunomodulatory effects. Other beneficial functions of yeasts are improvement of bioavailability of minerals through the hydrolysis of phytate, folate biofortification and detoxification of mycotoxins due to surface binding to the yeast cell wall. PMID- 22254036 TI - The relationship between ultraviolet radiation exposure and vitamin D status. AB - This paper reviews the main factors influencing the synthesis of vitamin D, with particular focus on ultraviolet radiation exposure. On the global level, the main source of vitamin D is the sun. The effect of solar radiation on vitamin D synthesis depends to some extent on the initial vitamin D levels. At moderate to high latitudes, diet becomes an increasingly important source of vitamin D due to decreased solar intensity and cold temperatures, which discourage skin exposure. During the mid-winter season, these factors result in decreased solar radiation exposure, hindering extensively the synthesis of vitamin D in these populations. PMID- 22254037 TI - Effects of vegetarian nutrition-A nutrition ecological perspective. AB - Although vegetarian nutrition is a complex issue, the multidimensionality and interrelatedness of its effects are rarely explored. This article aims to demonstrate the complexity of vegetarian nutrition by means of the nutrition ecological modeling technique NutriMod. The integrative qualitative cause-effect model, which is based on scientific literature, provides a comprehensive picture of vegetarian nutrition. The nutrition ecological perspective offers a basis for the assessment of the effects of worldwide developments concerning shifts in diets and the effects of vegetarian nutrition on global problems like climate change. Furthermore, new research areas on the complexity of vegetarian nutrition can be identified. PMID- 22254039 TI - Beliefs and attitudes toward vegetarian lifestyle across generations. AB - The objective of the study was to examine whether reasons to adopt vegetarian lifestyle differ significantly among generations. Using a Food Frequency Questionnaire (FFQ), we identified that 4% of the participants were vegans, 25% lacto-ovo-vegetarians, 4% pesco-vegetarians and 67% non-vegetarian. Younger people significantly agreed more with the moral reason and with the environmental reason. People ages 41-60 significantly agreed more with the health reason. There are significant differences across generations as to why people choose to live a vegetarian lifestyle. PMID- 22254038 TI - Is excess calcium harmful to health? AB - Most current guidelines recommend that older adults and the elderly strive for a total calcium intake (diet and supplements) of 1,000 to 1,300 mg/day to prevent osteoporosis and fractures. Traditionally, calcium supplements have been considered safe, effective and well tolerated, but their safety has recently been questioned due to potential adverse effects on vascular disease which may increase mortality. For example, the findings from a meta-analysis of randomized controlled trials (currently published in abstract form only) revealed that the use of calcium supplements was associated with an ~30% increased risk of myocardial infarction. If high levels of calcium are harmful to health, this may alter current public health recommendations with regard to the use of calcium supplements for preventing osteoporosis. In this review, we provide an overview of the latest information from human observational and prospective studies, randomized controlled trials and meta-analyses related to the effects of calcium supplementation on vascular disease and related risk factors, including blood pressure, lipid and lipoprotein levels and vascular calcification. PMID- 22254040 TI - Vitamin A-not for your eyes only: requirement for heart formation begins early in embryogenesis. AB - Vitamin A insufficiency has profound adverse effects on embryonic development. Major advances in understanding the role of vitamin A in vertebrate heart formation have been made since the discovery that the vitamin A active form, all trans-retinoic acid, regulates many genes, including developmental genes. Among the experimental models used, the vitamin A-deficient avian embryo has been an important tool to study the function of vitamin A during early heart formation. A cluster of retinoic acid-regulated developmental genes have been identified that participate in building the heart. In the absence of retinoic acid the embryonic heart develops abnormally leading to embryolethality. PMID- 22254042 TI - Long-chain omega-3 oils-an update on sustainable sources. AB - Seafood is currently the best and generally a safe source of long-chain (LC, (>=C(20)) omega-3 oils amongst the common food groups. LC omega-3 oils are also obtained in lower amounts per serve from red meat, egg and selected other foods. As global population increases the opportunities to increase seafood harvest are limited, therefore new alternate sources are required. Emerging sources include microalgae and under-utilized resources such as Southern Ocean krill. Prospects for new land plant sources of these unique and health-benefiting oils are also particularly promising, offering hope for alternate and sustainable supplies of these key oils, with resulting health, social, economic and environmental benefits. PMID- 22254041 TI - When food meets man: the contribution of epigenetics to health. AB - Post-translational modifications of chromatin contribute to the epigenetic control of gene transcription. The response to food intake and individual nutrients also includes epigenetic events. Bile acids are necessary for lipid digestion and absorption, and more recently have emerged as signaling molecules. Their synthesis is transcriptionally regulated also in relation to the fasted-to fed cycle, and interestingly, the underlying mechanisms include chromatin remodeling at promoters of key genes involved in their metabolism. Several compounds present in nutrients affect gene transcription through epigenetic mechanisms and recent studies demonstrate that, beyond the well known anti-cancer properties, they beneficially affect energy metabolism. PMID- 22254043 TI - Postprandial energy metabolism in the regulation of body weight: is there a mechanistic role for dietary calcium? AB - There has been much interest in the mechanisms by which calcium may attenuate weight gain or accelerate body fat loss. This review focuses on postprandial energy metabolism and indicates that dietary calcium increases whole body fat oxidation after single and multiple meals. There is, as yet, no conclusive evidence for a greater diet induced thermogenesis, an increased lipolysis or suppression of key lipogenic enzyme systems. There is however convincing evidence that higher calcium intakes promote a modest energy loss through increased fecal fat excretion. Overall, there is a role for dietary calcium in human energy metabolism. Future studies need to define threshold intakes for metabolic and gastrointestinal outcomes. PMID- 22254044 TI - Are new generations of female college-student populations meeting calcium requirements: comparison of American and Croatian female students. AB - We compared calcium (Ca) sources and intake, as well as multivitamin/mineral supplement use between female students with nutrition/health background and those from general-student-populations. 314 participants 18-37 y, including 57 African Americans and 54 Caucasian-Americans recruited from Nutrition and/or other Health Sciences departments (NHS), and 100 African-American and 103 Croatian women representing general-student-population (GSP), completed food frequency questionnaire assessing their usual Ca intake and supplement use. NHS populations met recommendations and consumed significantly more Ca, particularly from dairy sources, and were more likely to take supplements than GSP groups, suggesting that health education may influence Ca intake. PMID- 22254045 TI - The role of functional foods, nutraceuticals, and food supplements in intestinal health. AB - New eating habits, actual trends in production and consumption have a health, environmental and social impact. The European Union is fighting diseases characteristic of a modern age, such as obesity, osteoporosis, cancer, diabetes, allergies and dental problems. Developed countries are also faced with problems relating to aging populations, high energy foods, and unbalanced diets. The potential of nutraceuticals/functional foods/food supplements in mitigating health problems, especially in the gastrointestinal (GI) tract, is discussed. Certain members of gut microflora (e.g., probiotic/protective strains) play a role in the host health due to its involvement in nutritional, immunologic and physiological functions. The potential mechanisms by which nutraceuticals/functional foods/food supplements may alter a host's health are also highlighted in this paper. The establishment of novel functional cell models of the GI and analytical tools that allow tests in controlled experiments are highly desired for gut research. PMID- 22254046 TI - Micronutrients, N-acetyl cysteine, probiotics and prebiotics, a review of effectiveness in reducing HIV progression. AB - Low serum concentrations of micronutrients, intestinal abnormalities, and an inflammatory state have been associated with HIV progression. These may be ameliorated by micronutrients, N-acetyl cysteine, probiotics, and prebiotics. This review aims to integrate the evidence from clinical trials of these interventions on the progression of HIV. Vitamin B, C, E, and folic acid have been shown to delay the progression of HIV. Supplementation with selenium, N acetyl cysteine, probiotics, and prebiotics has considerable potential, but the evidence needs to be further substantiated. Vitamin A, iron, and zinc have been associated with adverse effects and caution is warranted for their use. PMID- 22254047 TI - Health benefits of nut consumption. AB - Nuts (tree nuts and peanuts) are nutrient dense foods with complex matrices rich in unsaturated fatty and other bioactive compounds: high-quality vegetable protein, fiber, minerals, tocopherols, phytosterols, and phenolic compounds. By virtue of their unique composition, nuts are likely to beneficially impact health outcomes. Epidemiologic studies have associated nut consumption with a reduced incidence of coronary heart disease and gallstones in both genders and diabetes in women. Limited evidence also suggests beneficial effects on hypertension, cancer, and inflammation. Interventional studies consistently show that nut intake has a cholesterol-lowering effect, even in the context of healthy diets, and there is emerging evidence of beneficial effects on oxidative stress, inflammation, and vascular reactivity. Blood pressure, visceral adiposity and the metabolic syndrome also appear to be positively influenced by nut consumption. Thus it is clear that nuts have a beneficial impact on many cardiovascular risk factors. Contrary to expectations, epidemiologic studies and clinical trials suggest that regular nut consumption is unlikely to contribute to obesity and may even help in weight loss. Safety concerns are limited to the infrequent occurrence of nut allergy in children. In conclusion, nuts are nutrient rich foods with wide-ranging cardiovascular and metabolic benefits, which can be readily incorporated into healthy diets. PMID- 22254048 TI - Short-term effect of prebiotics administration on stool characteristics and serum cytokines dynamics in very young children with acute diarrhea. AB - We investigated the effect of a mixture of long-chain fructo-oligosaccharides, galacto-oligosaccharides and acidic oligosaccharides on the number and consistency of stools and on immune system biomarkers in 104 supplemented and non supplemented subjects (aged 9-24 months) with acute diarrhea. Interleukin-1 (IL 1), IL-1RA, IL-6, IL-8, IL-10, TNF-alpha and sIL-2R cytokine levels were determined. The significant decrease in number of stools and increase in stool consistency in the supplemented group was of little clinical relevance. The only significant change in pro- and anti-inflammatory cytokines was decreased TNF alpha levels in the supplemented group. Prebiotic supplementation during acute diarrhea episodes did not influence the clinical course. PMID- 22254049 TI - Vitamin D and bone health: potential mechanisms. AB - Osteoporosis is associated with increased morbidity, mortality and significant economic and health costs. Vitamin D is a secosteriod hormone essential for calcium absorption and bone mineralization which is positively associated with bone mineral density [BMD]. It is well-established that prolonged and severe vitamin D deficiency leads to rickets in children and osteomalacia in adults. Sub optimal vitamin D status has been reported in many populations but it is a particular concern in older people; thus there is clearly a need for effective strategies to optimise bone health. A number of recent studies have suggested that the role of vitamin D in preventing fractures may be via its mediating effects on muscle function (a defect in muscle function is one of the classical signs of rickets) and inflammation. Studies have demonstrated that vitamin D supplementation can improve muscle strength which in turn contributes to a decrease in incidence of falls, one of the largest contributors to fracture incidence. Osteoporosis is often considered to be an inflammatory condition and pro-inflammatory cytokines have been associated with increased bone metabolism. The immunoregulatory mechanisms of vitamin D may thus modulate the effect of these cytokines on bone health and subsequent fracture risk. Vitamin D, therefore, may influence fracture risk via a number of different mechanisms. PMID- 22254050 TI - Lipophilic compound-mediated gene expression and implication for intervention in reactive oxygen species (ROS)-related diseases: mini-review. AB - In addition to exhibiting antioxidant properties, conjugated linoleic acid (CLA) and vitamin E may modulate gene expression of endogenous antioxidant enzymes. Depending on cellular microenvironments, such modulation reflects either antioxidant or prooxidant outcomes. Although epidemiological/experimental studies have indicated that CLA and vitamin E have health promoting properties, recent findings from clinical trials have been inconclusive. Discrepancies between the results found from prospective studies and recent clinical trials might be attributed to concentration-dependent cellular microenvironment alterations. We give a perspective of possible molecular mechanisms of actions of these lipophilic compounds and their implications for interventions of reactive oxygen species (ROS)-related diseases. PMID- 22254051 TI - Dietary polyphenols and obesity. AB - The prevalence of overweight and obesity and their associated metabolic disorders are considered a major threat to the public's health. While several diet and exercise programs are available for weight loss and prevention of weight regain, progress is often slow and disappointing. Recently, natural bioactive phytochemicals present in foods have been discovered for their potential health benefit effects on the prevention of chronic disorders such as cancer, cardiovascular disease, inflammatory and metabolic diseases including obesity. Polyphenols are a class of naturally-occurring phytochemicals, of which some such as catechins, anthocynines, resveratrol and curcumin have been shown to modulate physiological and molecular pathways that are involved in energy metabolism, adiposity, and obesity. The potential in vivo, beneficial effects of these polyphenols on adiposity and obesity as complementary agents in the up-regulation of energy expenditure have emerged by investigating these compounds in cell cultures, animal models of obesity and in some human clinical and epidemiological studies. In this brief review, the efficacy of the above-named polyphenols and their potential efficacy to modulate obesity and some associated disorders are discussed. PMID- 22254053 TI - Human milk banking-facts and issues to resolve. AB - The number of human milk banks is increasing worldwide. Although the beneficial effects of feeding premature infants with their mother's milk are well documented, less is known about the effects of feeding these infants with pasteurized donor milk. We propose a randomized trial comparing the effects of a 100% human milk-based diet (human milk supplemented with a human milk-derived fortifier) and a diet (partially) based on bovine milk. In theory, human milk has a beneficial effect on various aspects of human physiology, most of which become apparent after infancy. We therefore propose an extensive follow-up program that takes this aspect into consideration. Other issues concerning the practice of human milk banks need to be addressed as well as optimization of the feeding strategies for preterm infants. PMID- 22254052 TI - Fractional absorption of active absorbable algal calcium (AAACa) and calcium carbonate measured by a dual stable-isotope method. AB - With the use of stable isotopes, this study aimed to compare the bioavailability of active absorbable algal calcium (AAACa), obtained from oyster shell powder heated to a high temperature, with an additional heated seaweed component (Heated Algal Ingredient, HAI), with that of calcium carbonate. In 10 postmenopausal women volunteers aged 59 to 77 years (mean +/- S.D., 67 +/- 5.3), the fractional calcium absorption of AAACa and CaCO(3) was measured by a dual stable isotope method. (44)Ca-enriched CaCO(3) and AAACa were administered in all subjects one month apart. After a fixed-menu breakfast and pre-test urine collection (Urine 0), (42)Ca-enriched CaCl(2) was intravenously injected, followed by oral administration of (44)Ca-enriched CaCO(3) without carrier 15 minutes later, and complete urine collection for the next 24 hours (Urine 24). The fractional calcium absorption was calculated as the ratio of Augmentation of (44)Ca from Urine 0 to Urine 24/ augmentation of (42)Ca from Urine 0 to Urine 24. Differences and changes of (44)Ca and (42)Ca were corrected by comparing each with (43)Ca. Fractional absorption of AAACa (mean +/- S.D., 23.1 +/- 6.4), was distinctly and significantly higher than that of CaCO(3 )(14.7 +/- 6.4; p = 0.0060 by paired t test). The mean fractional absorption was approximately 1.57-times higher for AAACa than for CaCO(3). The serum 25(OH) vitamin D level was low (mean +/- S.D., 14.2 +/- 4.95 ng/ml), as is common in this age group in Japan. Among the parameters of the bone and mineral metabolism measured, none displayed a significant correlation with the fractional absorption of CaCO(3) and AAACa. Higher fractional absorption of AAACa compared with CaCO(3) supports previous reports on the more beneficial effect of AAACa than CaCO(3) for osteoporosis. PMID- 22254054 TI - Nutritional status of Flemish vegetarians compared with non-vegetarians: a matched samples study. AB - The present study compares the nutritional status of vegetarian (V) with non vegetarian (NV) subjects. A three-day food record and a health questionnaire were completed by 106 V and 106 NV matched for following characteristics: sex, age, BMI, physical activity, tobacco use and alcohol consumption. Total energy intake was not significantly different (men: V: 2,346 +/- 685 kcal/d; NV: 2,628 +/- 632 kcal/d; p = 0.078; women: V: 1,991 +/- 539 kcal/d; NV: 1,973 +/- 592 kcal/d; p = 0.849). Macronutrients intake differed significantly between the V and NV subjects for protein (men: V:12.7 +/- 2.3 E%; NV:15.3 +/- 4.5 E%; p = 0.003; women: V: 13.2 +/- 2.3 E%; NV:16.0 +/- 4.0 E%; p < 0.001), fat (men: V: 29.3 +/- 8.4 E%; NV: 33.8 +/- 5.3 E%; p = 0.010; women: V: 29.7 +/- 6.9 E%; NV: 34.7 +/- 9.0 E%; p < 0.001), and carbohydrate (men: V: 55.3 +/- 10.1 E%; NV: 47.4 +/- 6.9 E%; p < 0.001; women: V: 55.1 +/- 7.6 E%; NV: 47.2 +/- 8.2 E%; p < 0.001). The intake of most minerals was significantly different between the V and the NV subjects. V had a lower sodium intake, higher calcium, zinc, and iron intake compared to the NV subjects. Our results clearly indicate that a vegetarian diet can be adequate to sustain the nutritional demands to at least the same degree as that of omnivores. The intakes of the V subjects were closer to the recommendations for a healthy diet when compared to a group of well matched NV subjects. PMID- 22254055 TI - Alcohol, athletic performance and recovery. AB - Alcohol consumption within elite sport has been continually reported both anecdotally within the media and quantitatively in the literature. The detrimental effects of alcohol on human physiology have been well documented, adversely influencing neural function, metabolism, cardiovascular physiology, thermoregulation and skeletal muscle myopathy. Remarkably, the downstream effects of alcohol consumption on exercise performance and recovery, has received less attention and as such is not well understood. The focus of this review is to identify the acute effects of alcohol on exercise performance and give a brief insight into explanatory factors. PMID- 22254057 TI - A food frequency questionnaire for the assessment of calcium, vitamin D and vitamin K: a pilot validation study. AB - The study objective was to validate a food frequency questionnaire (FFQ) to assess calcium, vitamin D and vitamin K intakes in overweight and obese postmenopausal community-dwelling women. The FFQ was validated against intakes derived from a 5-day diet record (5DDR) that also included assessment of supplement intake. Strong correlations between methods were observed for all nutrients (r = 0.63, 0.89, 0.54 for calcium, vitamin D and vitamin K, respectively) and cross-classification analyses demonstrated no major misclassification of participants into intake quartiles. Bland-Altman analysis showed that the FFQ overestimated intakes for calcium, by 576 mg/day (95% CI, 668 to 1,821 mg/day), for vitamin D by 75 IU/day (95% CI, -359 to 510 IU/day), and for vitamin K by 167 mcg/day (95% CI, -233 to 568 mcg/day). This pilot study showed promising validation evidence for the use of this FFQ, which focuses on calcium, vitamin D and vitamin K intakes in postmenopausal women, as a screening tool in clinical and research settings. PMID- 22254056 TI - Effect of long-chain polyunsaturated fatty acid supplementation on neurodevelopmental outcome in full-term infants. AB - It takes more than 20 years before the human brain obtains its complex, adult configuration. Most dramatic developmental changes occur prenatally and early postnatally. During development, long-chain polyunsaturated fatty acids (LCPUFA) such as doxosahexaenoic acid (DHA) and arachidonic acid (AA) are accreted in the brain. Since breastfeeding is associated with a better developmental outcome than formula feeding, and human milk in contrast to traditional standard formula contains LCPUFA, the question arose whether LCPUFA supplementation of infant formula may promote the neurodevelopmental outcome. The current paper reviews the evidence available in full-term infants. It concludes that postnatal supplementation of formula with LCPUFA is associated with a beneficial effect on short-term neurodevelopmental outcome. However, no evidence is available that LCPUFA supplementation enhances neurodevelopmental outcome in full-term infants beyond the age of four months. Nevertheless, it should be realized that very limited information is available on the effect of LCPUFA supplementation on neurodevelopmental outcome at school age or later. It is conceivable that effects of LCPUFA supplementation first emerge or re-emerge at school age when more complex neural functions are expressed. PMID- 22254058 TI - Bioavailability of coffee chlorogenic acids and green tea flavan-3-ols. AB - This paper reviews recent human studies on the bioavailability of chlorogenic acids in coffee and green tea flavan-3-ols in which the identification of metabolites, catabolites and parent compounds in plasma, urine and ileal fluid was based on mass spectrometric methodology. Both the chlorogenic acids and the flavan-3-ols are absorbed in the small intestine and appear in the circulatory system predominantly as glucuronide, sulfate and methylated metabolites. Even when absorption occurs in the small intestine, feeding studies with ileostomists reveal that substantial amounts of the parent compounds and some of their metabolites appear in ileal fluid indicating that in volunteers with a functioning colon these compounds will pass to the large intestine where they are subjected to the action of the colonic microflora. A diversity of colonic-derived catabolites are absorbed into the bloodstream and pass through the body prior to excretion in urine. There is growing evidence that these compounds, which were little investigated until recently, are produced in quantity in the colon and form a key part of the bioavailability equation of flavonoids and related compounds that occur in fruits, vegetables and beverages. Recent evidence indicates that some colon-derived phenolic acids have in vitro anti-inflammatory activity. PMID- 22254059 TI - Changes in intakes of total and added sugar and their contribution to energy intake in the U.S. AB - This study was designed to document changes in total sugar intake and intake of added sugars, in the context of total energy intake and intake of nutrient categories, between the 1970s and the 1990s, and to identify major food sources contributing to those changes in intake. Data from the NHANES I and III were analyzed to obtain nationally representative information on food consumption for the civilian, non-institutionalized population of the U.S. from 1971 to 1994. In the past three decades, in addition to the increase in mean intakes of total energy, total sugar, added sugars, significant increases in the total intake of carbohydrates and the proportion of carbohydrates to the total energy intake were observed. The contribution of sugars to total carbohydrate intake decreased in both 1-18 y and 19+ y age subgroups, and the contribution of added sugars to the total energy intake did not change. Soft drinks/fluid milk/sugars and cakes, pastries, and pies remained the major food sources for intake of total sugar, total carbohydrates, and total energy during the past three decades. Carbonated soft drinks were the most significant sugar source across the entire three decades. Changes in sugar consumption over the past three decades may be a useful specific area of investigation in examining the effect of dietary patterns on chronic diseases. PMID- 22254061 TI - Flavonoids: antioxidants against atherosclerosis. AB - Oxidative stress results from an imbalance between excessive formation of reactive oxygen species (ROS) and/or reactive nitrogen species and limited antioxidant defences. Endothelium and nitric oxide (NO) are key regulators of vascular health. NO bioavailability is modulated by ROS that degrade NO, uncouple NO synthase, and inhibit synthesis. Cardiovascular risk conditions contribute to oxidative stress, causing an imbalance between NO and ROS, with a relative decrease in NO bioavailability. Dietary flavonoids represent a range of polyphenolic compounds naturally occurring in plant foods. Flavonoids are potentially involved in cardiovascular prevention mainly by decreasing oxidative stress and increasing NO bioavailability. PMID- 22254060 TI - The role of soy in vegetarian diets. AB - Soyfoods have long been prized among vegetarians for both their high protein content and versatility. Soybeans differ markedly in macronutrient content from other legumes, being much higher in fat and protein, and lower in carbohydrate. In recent years however, soyfoods and specific soybean constituents, especially isoflavones, have been the subject of an impressive amount of research. Nearly 2,000 soy-related papers are published annually. This research has focused primarily on the benefits that soyfoods may provide independent of their nutrient content. There is particular interest in the role that soyfoods have in reducing risk of heart disease, osteoporosis and certain forms of cancer. However, the estrogen-like effects of isoflavones observed in animal studies have also raised concerns about potential harmful effects of soyfood consumption. This review addresses questions related to soy and chronic disease risk, provides recommendations for optimal intakes, and discusses potential contraindications. As reviewed, the evidence indicates that, with the exception of those individuals allergic to soy protein, soyfoods can play a beneficial role in the diets of vegetarians. Concerns about adverse effects are not supported by the clinical or epidemiologic literature. Based on the soy intake associated with health benefits in the epidemiologic studies and the benefits noted in clinical trials, optimal adult soy intake would appear to be between two and four servings per day. PMID- 22254063 TI - Reexamination of a meta-analysis of the effect of antioxidant supplementation on mortality and health in randomized trials. AB - A recent meta-analysis of selected randomized clinical trials (RCTs), in which population groups of differing ages and health status were supplemented with various doses of beta-carotene, vitamin A, and/or vitamin E, found that these interventions increased all-cause mortality. However, this meta-analysis did not consider the rationale of the constituent RCTs for antioxidant supplementation, none of which included mortality as a primary outcome. As the rationale for these trials was to test the hypothesis of a potential benefit of antioxidant supplementation, an alternative approach to a systematic evaluation of these RCTs would be to evaluate this outcome relative to the putative risk of greater total mortality. Thus, we examined these data based on the primary outcome of the 66 RCTs included in the meta-analysis via a decision analysis to identify whether the results provided a positive (i.e., benefit), null or negative (i.e., harm) outcome. Our evaluation indicated that of these RCTs, 24 had a positive outcome, 39 had a null outcome, and 3 had a negative outcome. We further categorized these interventions as primary (risk reduction in healthy populations) or secondary (slowing pathogenesis or preventing recurrent events and/or cause-specific mortality) prevention or therapeutic (treatment to improve quality of life, limit complications, and/or provide rehabilitation) studies, and determined positive outcomes in 8 of 20 primary prevention studies, 10 of 34 secondary prevention studies, and 6 out of 16 therapeutic studies. Seven of the eight RCTs with a positive outcome in primary prevention included participants in a population where malnutrition is frequently described. These results suggest that analyses of potential risks from antioxidant supplementation should be placed in the context of a benefit/risk ratio. PMID- 22254062 TI - The role of phytonutrients in skin health. AB - Photodamage is known to occur in skin with exposure to sunlight, specifically ultraviolet (UV) radiation. Such damage includes inflammation, oxidative stress, breakdown of the extracellular matrix, and development of cancer in the skin. Sun exposure is considered to be one of the most important risk factors for both nonmelanoma and melanoma skin cancers. Many phytonutrients have shown promise as photoprotectants in clinical, animal and cell culture studies. In part, the actions of these phytonutrients are thought to be through their actions as antioxidants. In regard to skin health, phytonutrients of interest include vitamin E, certain flavonoids, and the carotenoids, beta-carotene, lycopene and lutein. PMID- 22254064 TI - Calcium intake and body composition in African-American children and adolescents at risk for overweight and obesity. AB - This study examined the role of calcium intake on body composition in 186 African American adolescents at risk for overweight and obesity. The average weight of 89.8 kg +/- 23.6 (SD) had a mean BMI z score of 2.2. Females with a calcium intake of <314 mg/day had higher percent fat mass compared to those with the highest calcium intakes that were >=634 mg/day. Compared to those with a low calcium intake (<365 mg/day), those with the highest calcium intake of >701 mg/day had higher intake of thiamin, folate, cobalamin, vitamin D, phosphorus, iron, zinc. PMID- 22254065 TI - Long-chain polyunsaturated fatty acids in inborn errors of metabolism. AB - The treatment of children with inborn errors of metabolism (IEM) is mainly based on restricted dietary intake of protein-containing foods. However, dietary protein restriction may not only reduce amino acid intake, but may be associated with low intake of polyunsaturated fatty acids as well. This review focuses on the consequences of dietary restriction in IEM on the bioavailability of long chain polyunsaturated fatty acids (LCPUFAs) and on the attempts to ameliorate these consequences. We were able to identify during a literature search 10 observational studies investigating LCPUFA status in patients with IEM and six randomized controlled trials (RCTs) reporting effect of LCPUFA supplementation to the diet of children with IEM. Decreased LCPUFA status, in particular decreased docosahexaenoic acid (DHA) status, has been found in patients suffering from IEM based on the evidence of observational studies. LCPUFA supplementation effectively improves DHA status without detectable adverse reactions. Further research should focus on functional outcomes of LCPUFA supplementation in children with IEM. PMID- 22254066 TI - Prevention of fractures in older people with calcium and vitamin D. AB - The greatest cause of fracture in older people is osteoporosis which contributes to increased morbidity and mortality in older people. A number of meta-analyses have been performed assessing the effectiveness of calcium supplementation alone, vitamin D supplementation alone and the combined therapy on bone loss and fracture reduction in older people. The results of these meta-analyses indicate that vitamin D supplementation alone is unlikely to reduce fracture risk, calcium supplementation alone has a modest effect in reducing total fracture risk, but compliance with calcium supplements is poor in the long term. The combination of calcium supplementation with vitamin D supplementation, particularly in those at risk of marginal and low vitamin D status reduces total fractures, including hip fractures. Therefore older people would be recommended to consume adequate dietary calcium (>1100 mg/day) together with maintaining adequate vitamin D status (>60 nmol/L 25(OH)D) to reduce risk of fracture. It is a challenge to consume sufficient dietary calcium from dietary sources, but the increasing range of calcium fortified foods could assist in increasing the dietary calcium intake of older people. In addition to the usual dairy based food sources, vitamin D supplements are likely to be required for older people with reduced mobility and access to sunlight. PMID- 22254067 TI - Bone density testing: an under-utilised and under-researched health education tool for osteoporosis prevention? AB - Feedback of fracture risk based on bone mineral density (BMD) is an under explored potential osteoporosis education intervention. We performed a randomised controlled trial of either an osteoporosis information leaflet or small group education (the Osteoporosis Prevention and Self-Management Course (OPSMC)), combined with individualised fracture risk feedback in premenopausal women over two years. Women with a mean T-score at spine and hip of <0 were informed they were at higher risk of fracture in later life and those with T-score >= 0 were informed they were not. Women receiving feedback of high fracture risk had a greater increase in femoral neck, but not lumbar spine, BMD compared to the low risk group (1.6% p.a. vs. 0.7% p.a., p = 0.0001). Participation in the OPSMC had no greater effect on BMD than receiving the leaflet. Femoral neck BMD change was associated with starting calcium supplements (1.3% p.a., 95% CI +0.49, +2.17) and self-reported physical activity change (0.7% p.a., 95% CI +0.22, +1.22). Mother's report of increasing their children's calcium intake was associated with receiving the OPSMC (OR 2.3, 95% CI 1.4, 3.8) and feedback of high fracture risk (OR 2.0, 95% CI 1.2, 3.3). Fracture risk feedback based on BMD could potentially make an important contribution to osteoporosis prevention but confirmation of long-term benefits and cost effectiveness is needed before implementation can be recommended. PMID- 22254068 TI - Evolution of the calcium paradigm: the relation between vitamin D, serum calcium and calcium absorption. AB - Osteoporosis is the index disease for calcium deficiency, just as rickets/osteomalacia is the index disease for vitamin D deficiency, but there is considerable overlap between them. The common explanation for this overlap is that hypovitaminosis D causes malabsorption of calcium which then causes secondary hyperparathyroidism and is effectively the same thing as calcium deficiency. This paradigm is incorrect. Hypovitaminosis D causes secondary hyperparathyroidism at serum calcidiol levels lower than 60 nmol/L long before it causes malabsorption of calcium because serum calcitriol (which controls calcium absorption) is maintained until serum calcidiol falls below 20 nmol/L. This secondary hyperparathyroidism, probably due to loss of a "calcaemic" action of vitamin D on bone first described in 1957, destroys bone and explains why vitamin D insufficiency is a risk factor for osteoporosis. Vitamin D thus plays a central role in the maintenance of the serum (ionised) calcium, which is more important to the organism than the preservation of the skeleton. Bone is sacrificed when absorbed dietary calcium does not match excretion through the skin, kidneys and bowel which is why calcium deficiency causes osteoporosis in experimental animals and, by implication, in humans. PMID- 22254069 TI - Independent and combined effects of exercise and vitamin D on muscle morphology, function and falls in the elderly. AB - Regular exercise, particularly progressive resistance training (PRT), is recognized as one of the most effective strategies to prevent age-related muscle loss (sarcopenia), but its effects on muscle function are mixed. However, emerging data indicates that high velocity PRT (fast concentric muscle contractions) is more effective for improving functional outcomes than traditional PRT. In terms of falls prevention, high-challenging balance training programs appear to be most effective. There is also compelling evidence that supplemental vitamin D is an effective therapeutic option for falls prevention. The findings from a recent meta-analysis revealed that supplemental vitamin D at a dose of at least 700-1,000 IU/d or an achieved serum 25(OH)D level of at least 60 nmol/L was associated with reduced falls risk among older individuals. Based on these findings, it is possible that the combination of exercise and vitamin D could have a synergistic effect on muscle morphology and function, particularly since both interventions have been shown to have beneficial effects on type II "fast twitch" muscle fibers and systemic inflammation, which have both been linked to losses in muscle mass and function. Unfortunately however, the findings from the limited number of factorial 2 * 2 design RCTs indicate that additional vitamin D does not enhance the effects of exercise on measures of muscle morphology, function or falls risk. However, none of these trials were adequately powered to detect a "synergistic" effect between the two treatment strategies, but it is likely that if an exercise-by-vitamin D interaction does exist, it may be limited to situations when vitamin D deficiency/insufficiency is corrected. Further targeted research in "high risk" groups is still needed to address this question, and evaluate whether there is a threshold level of serum 25(OH)D to maximize the effects of exercise on muscle and falls risk. PMID- 22254070 TI - Annual feedback is an effective tool for a sustained increase in calcium intake among older women. AB - We aimed to optimize calcium intake among the 2,000+ older women taking part in the Vital D study. Calcium supplementation was not included in the study protocol. Our hypothesis was that annual feedback of calcium intake and informing women of strategies to improve calcium intake can lead to a sustained increase in the proportion of women who consume adequate levels of the mineral. Calcium intake was assessed on an annual basis using a validated short food frequency questionnaire (FFQ). Supplemental calcium intake was added to the dietary estimate. Participants and their nominated doctor were sent a letter that the participant's estimated daily calcium intake was adequate or inadequate based on a cutoff threshold of 800 mg/day. General brief statements outlining the importance of an adequate calcium intake and bone health were included in all letters. At baseline, the median daily consumption of calcium was 980 mg/day and 67 percent of 1,951 participants had calcium intake of at least 800 mg per day. Of the 644 older women advised of an inadequate calcium intake at baseline (<800 mg/day), 386 (60%) had increased their intake by at least 100 mg/day when re assessed twelve months later. This desirable change was sustained at 24 months after baseline with almost half of these women (303/644) consuming over 800 mg calcium per day. This study devised an efficient method to provide feedback on calcium intake to over 2,000 older women. The improvements were modest but significant and most apparent in those with a low intake at baseline. The decreased proportion of these women with an inadequate intake of calcium 12- and 24-months later, suggests this might be a practical, low cost strategy to maintain an adequate calcium intake among older women. PMID- 22254071 TI - Experimental evidence for the effects of calcium and vitamin D on bone: a review. AB - Animal models fed low calcium diets demonstrate a negative calcium balance and gross bone loss while the combination of calcium deficiency and oophorectomy enhances overall bone loss. Following oophorectomy the dietary calcium intake required to remain in balance increases some 5 fold, estimated to be approximately 1.3% dietary calcium. In the context of vitamin D and dietary calcium depletion, osteomalacia occurs only when low dietary calcium levels are combined with low vitamin D levels and osteoporosis occurs with either a low level of dietary calcium with adequate vitamin D status or when vitamin D status is low in the presence of adequate dietary calcium intake. Maximum bone architecture and strength is only achieved when an adequate vitamin D status is combined with sufficient dietary calcium to achieve a positive calcium balance. This anabolic effect occurs without a change to intestinal calcium absorption, suggesting dietary calcium and vitamin D have activities in addition to promoting a positive calcium balance. Each of the major bone cell types, osteoblasts, osteoclasts and osteocytes are capable of metabolizing 25 hydroxyvitamin D (25D) to 1,25 dihydroxyvitamin D (1,25D) to elicit biological activities including reduction of bone resorption by osteoclasts and to enhance maturation and mineralization by osteoblasts and osteocytes. Each of these activities is consistent with the actions of adequate circulating levels of 25D observed in vivo. PMID- 22254072 TI - Calcium intake in elderly Australian women is inadequate. AB - The role of calcium in the prevention of bone loss in later life has been well established but little data exist on the adequacy of calcium intakes in elderly Australian women. The aim of this study was to compare the dietary intake including calcium of elderly Australian women with the Australian dietary recommendation, and to investigate the prevalence of calcium supplement use in this population. Community-dwelling women aged 70-80 years were randomly recruited using the Electoral Roll for a 2-year protein intervention study in Western Australia. Dietary intake was assessed at baseline by a 3-day weighed food record and analysed for energy, calcium and other nutrients. A total of 218 women were included in the analysis. Mean energy intake was 7,140 +/- 1,518 kJ/day and protein provided 19 +/- 4% of energy. Mean dietary calcium intake was 852 +/- 298 mg/day, which is below Australian recommendations. Less than one quarter of women reported taking calcium supplements and only 3% reported taking vitamin D supplements. Calcium supplements by average provided calcium 122 +/- 427 mg/day and when this was taken into account, total calcium intake increased to 955 +/- 504 mg/day, which remained 13% lower than the Estimated Average Requirement (EAR, 1,100 mg/day) for women of this age group. The women taking calcium supplements had a higher calcium intake (1501 +/- 573 mg) compared with the women on diet alone (813 +/- 347 mg). The results of this study indicate that the majority of elderly women were not meeting their calcium requirements from diet alone. In order to achieve the recommended dietary calcium intake, better strategies for promoting increased calcium, from both diet and calcium supplements appears to be needed. PMID- 22254073 TI - Components of an anticancer diet: dietary recommendations, restrictions and supplements of the Bill Henderson Protocol. AB - The use of complementary and alternative medicines including dietary supplements, herbals and special diets to prevent or treat disease continues to be popular. The following paper provides a description of an alternative dietary approach to the self-management and treatment of cancer, the Bill Henderson Protocol (BHP). This diet encourages daily intake of raw foods, a combination of cottage cheese and flaxseed oil and a number of supplements. Some foods and food groups are restricted (e.g., gluten, meat, dairy). Early background theory that contributed to the protocol's development is presented as is a summary of relevant evidence concerning the anti-cancer fighting properties of the individual components. Supplement intake is considered in relation to daily recommended intakes. Challenges and risks to protocol adherence are discussed. As with many complementary and alternative interventions, clear evidence of this dietary protocol's safety and efficacy is lacking. Consumers of this protocol may require guidance on the ability of this protocol to meet their individual nutritional needs. PMID- 22254075 TI - Higher diet quality does not predict lower Medicare costs but does predict number of claims in mid-aged Australian women. AB - Optimal dietary quality, indicated by higher diet quality index scores, reflects greater adherence to National dietary recommendations and is also associated with lower morbidity and mortality from chronic disease. Whether this is reflected in lower health care cost over time has rarely been examined. The aim of this study was to examine whether higher diet quality, as measured by the Australian Recommended Food Score (ARFS), was associated with lower health care costs within the mid-aged cohort of the Australian Longitudinal Study on Women's Health. We found that there was a statistically significant association between five year cumulative costs and ARFS, but in the opposite direction to that predicted, with those in the highest quintiles of ARFS having higher health care costs. However the number of Medicare claims over the six year period (2002-2007) was lower for those in the highest compared with the lowest quintile, p = 0.002. There is a need to monitor both costs and claims over time to examine health care usage in the longer term in order to determine whether savings are eventually obtained for those with the dietary patterns that adhere more closely to National recommendations. PMID- 22254074 TI - Vitamin A metabolism and adipose tissue biology. AB - In recent years, the importance of vitamin A in adipose tissue biology, obesity and type II diabetes has become apparent. This review focuses on recent developments within the area of vitamin A and adipose tissue biology. Adipose tissue has an active vitamin A metabolism as it not only stores vitamin A but retinol is also converted to its active metabolite retinoic acid. Several mouse models point to a relationship between vitamin A metabolism and the development of adiposity. Similarly, in vitro studies provide new molecular mechanisms for the function of different forms of vitamin A and retinol- or retinoic acid binding proteins in adipose tissue. PMID- 22254076 TI - Folate status of reproductive age women and neural tube defect risk: the effect of long-term folic acid supplementation at doses of 140 ug and 400 ug per day. AB - Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 MUg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate >=906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 ug/day and 140 ug/day (dose designed to mimic the average daily folic acid intake received from New Zealand's proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 ug (n = 49), 400 ug (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate <906 nmol/L decreased to 18% and 35% in the 400 ug and 140 ug groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate <906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs. PMID- 22254077 TI - Effect of lactobacilli on paracellular permeability in the gut. AB - Paracellular permeability is determined by the complex structures of junctions that are located between the epithelial cells. Already in 1996, it was shown that the human probiotic strain Lactobacillus plantarum 299v and the rat-originating strain Lactobacillus reuteri R2LC could reduce this permeability in a methotrexate-induced colitis model in the rat. Subsequently, many animal models and cell culture systems have shown indications that lactobacilli are able to counteract increased paracellular permeability evoked by cytokines, chemicals, infections, or stress. There have been few human studies focusing on the effect of lactobacilli on intestinal paracellular permeability but recently it has been shown that they could influence the tight junctions. More precisely, short-term administration of L. plantarum WCSF1 to healthy volunteers increased the relocation of occludin and ZO-1 into the tight junction area between duodenal epithelial cells. PMID- 22254078 TI - Folate production by probiotic bacteria. AB - Probiotic bacteria, mostly belonging to the genera Lactobacillus and Bifidobacterium, confer a number of health benefits to the host, including vitamin production. With the aim to produce folate-enriched fermented products and/or develop probiotic supplements that accomplish folate biosynthesis in vivo within the colon, bifidobacteria and lactobacilli have been extensively studied for their capability to produce this vitamin. On the basis of physiological studies and genome analysis, wild-type lactobacilli cannot synthesize folate, generally require it for growth, and provide a negative contribution to folate levels in fermented dairy products. Lactobacillus plantarum constitutes an exception among lactobacilli, since it is capable of folate production in presence of para-aminobenzoic acid (pABA) and deserves to be used in animal trials to validate its ability to produce the vitamin in vivo. On the other hand, several folate-producing strains have been selected within the genus Bifidobacterium, with a great variability in the extent of vitamin released in the medium. Most of them belong to the species B. adolescentis and B. pseudocatenulatum, but few folate producing strains are found in the other species as well. Rats fed a probiotic formulation of folate-producing bifidobacteria exhibited increased plasma folate level, confirming that the vitamin is produced in vivo and absorbed. In a human trial, the same supplement raised folate concentration in feces. The use of folate-producing probiotic strains can be regarded as a new perspective in the specific use of probiotics. They could more efficiently confer protection against inflammation and cancer, both exerting the beneficial effects of probiotics and preventing the folate deficiency that is associated with premalignant changes in the colonic epithelia. PMID- 22254079 TI - A retrospective investigation of thiamin and energy intakes following an outbreak of beriberi in The Gambia. AB - In the early part of the rainy season in 1988, an outbreak of beriberi occurred in free-living adults in a relatively small area in the North Bank region of The Gambia. In 1995 we selected two compounds in a village called Chilla situated within the affected district to retrospectively examine dietary factors potentially contributing to the outbreak. There had previously been cases of beriberi in one compound (BBC) but not in the other (NBC). We measured energy and thiamin intakes for four days on six occasions during the year. We calculated energy and thiamin intakes of people living in the two compounds and foods were collected for thiamin analysis through the year. Thiamin:Energy ratios only met international recommendations in the immediate post-harvest season when energy and thiamin intakes were highest and then fell through the year. In the rainy season when food was short and labour was heaviest, energy intakes were lower in the NBC but thiamin:energy ratios were lower in BBC. Records of rainfall in 1988 collected near the village indicated that the amount in August was twice the average. We suggest the heavy rainfall may have increased farm workload and reduced income from outside-village work activity. The lower energy intakes in the NBC may have forced adults to rest thus sparing thiamin demands and delaying onset of beriberi. In contrast, the higher energy intake of adults in the BBC may have enabled them to continue working, thus increasing demands for thiamin and inducing the earlier onset of beriberi. PMID- 22254080 TI - Serum fatty acid reference ranges: percentiles from a New Zealand national nutrition survey. AB - Serum fatty acids are increasingly used in cross-sectional surveys and cohort studies as biomarkers of dietary fat intake; however, it is currently difficult to judge whether an individual has low or high fatty acid status, or whether the distribution of fatty acids of a group of people is low or high due to a lack of appropriate reference values. In the absence of interpretive criteria, the distribution of serum fatty acids from a suitable reference population can be used as an alternative. We describe the distribution of the fatty acid composition of the three most commonly reported lipid classes in serum; cholesterol ester, phospholipid and triacylgycerol. Results for each serum lipid class are presented as means (SD) and percentiles (5, 10, 25, 50, 75, 90, and 95) of serum fatty acids in non-fasting blood samples collected from a population based cross-sectional survey of New Zealand adults (n = 2793). These serum fatty acid reference ranges are applicable and relevant to Australia, United Kingdom, and United States as well as other countries where fat intakes are similar to New Zealand. PMID- 22254081 TI - Risk assessment to underpin food regulatory decisions: an example of public health nutritional epidemiology. AB - The approach used by food regulation agencies to examine the literature and forecast the impact of possible food regulations has many similar features to the approach used in nutritional epidemiological research. We outline the Risk Analysis Framework described by FAO/WHO, in which there is formal progression from identification of the nutrient or food chemical of interest, through to describing its effect on health and then assessing whether there is a risk to the population based on dietary exposure estimates. We then discuss some important considerations for the dietary modeling component of the Framework, including several methodological issues that also exist in research nutritional epidemiology. Finally, we give several case studies that illustrate how the different methodological components are used together to inform decisions about how to manage the regulatory problem. PMID- 22254082 TI - Hydroxytyrosol protects against oxidative DNA damage in human breast cells. AB - Over recent years, several studies have related olive oil ingestion to a low incidence of several diseases, including breast cancer. Hydroxytyrosol and tyrosol are two of the major phenols present in virgin olive oils. Despite the fact that they have been linked to cancer prevention, there is no evidence that clarifies their effect in human breast tumor and non-tumor cells. In the present work, we present hydroxytyrosol and tyrosol's effects in human breast cell lines. Our results show that hydroxytyrosol acts as a more efficient free radical scavenger than tyrosol, but both fail to affect cell proliferation rates, cell cycle profile or cell apoptosis in human mammary epithelial cells (MCF10A) or breast cancer cells (MDA-MB-231 and MCF7). We found that hydroxytyrosol decreases the intracellular reactive oxygen species (ROS) level in MCF10A cells but not in MCF7 or MDA-MB-231 cells while very high amounts of tyrosol is needed to decrease the ROS level in MCF10A cells. Interestingly, hydroxytyrosol prevents oxidative DNA damage in the three breast cell lines. Therefore, our data suggest that simple phenol hydroxytyrosol could contribute to a lower incidence of breast cancer in populations that consume virgin olive oil due to its antioxidant activity and its protection against oxidative DNA damage in mammary cells. PMID- 22254083 TI - Regulation of inflammation by short chain fatty acids. AB - The short chain fatty acids (SCFAs) acetate (C(2)), propionate (C(3)) and butyrate (C(4)) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, SCFAs modulate different processes in the gastrointestinal (GI) tract such as electrolyte and water absorption. These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-alpha, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2). The ability of leukocytes to migrate to the foci of inflammation and to destroy microbial pathogens also seems to be affected by the SCFAs. In this review, the latest research that describes how SCFAs regulate the inflammatory process is presented. The effects of these fatty acids on isolated cells (leukocytes, endothelial and intestinal epithelial cells) and, particularly, on the recruitment and activation of leukocytes are discussed. Therapeutic application of these fatty acids for the treatment of inflammatory pathologies is also highlighted. PMID- 22254084 TI - Effect of micronutrient and probiotic fortified yogurt on immune-function of anti retroviral therapy naive HIV patients. AB - BACKGROUND: Micronutrient supplementation has been shown to reduce the progression of HIV but does not have an effect on the intestinal barrier or the intestinal microbiota of HIV patients. Studies have suggested that probiotics could potentially complement micronutrients in preserving the immune-function of HIV patients. OBJECTIVE: Assess the impact of micronutrient supplemented probiotic yogurt on the immune function of HIV patients. DESIGN: We performed a randomized, double blind, controlled trial with CD4 count as primary outcome among HIV patients naive to anti-retroviral treatment. Secondary outcomes included hematological parameters, incidence of diarrhea and clinical symptoms. A total of 112 HIV patients were randomized to receive a micronutrient fortified yogurt with (n = 55) or without additional probiotic Lactobacillus rhamnosus GR-1 (n = 57) for four weeks. RESULTS: An average decline in CD4 count of -70 cells/MUL (95% CI: -154 to -15) was observed in the micronutrient, probiotic group versus a decrease of -63 cells/MUL (95% CI: -157 to -30) in the micronutrient control group (p = 0.9). Additional probiotic supplementation was well tolerated and not associated with adverse events. No difference between groups was detected in incidence of diarrhea or clinical symptoms. An improvement of hemoglobin levels was observed for all subjects, based upon a mean difference from baseline of 1.4 g/L (SD = 6) (p = 0.02). CONCLUSION: The addition of probiotics to a micronutrient fortified yogurt was well tolerated by HIV patients but was not associated with a further increase in CD4 count after one month. PMID- 22254085 TI - Apical localization of zinc transporter ZnT4 in human airway epithelial cells and its loss in a murine model of allergic airway inflammation. AB - The apical cytoplasm of airway epithelium (AE) contains abundant labile zinc (Zn) ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG)-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm. This observation was consistent with the starry sky Zinquin fluorescence staining of labile Zn ions confined to the same region. The vesicular Zn transporter ZnT4 was likewise prominent in both the apical and basal parts of the epithelium both in rodent and human AE, although the apical pools were more obvious. Expression of ZnT4 mRNA was unaffected by changes in the extracellular Zn concentration. However, levels increased 3-fold during growth of cells in air liquid interface cultures and decreased sharply in the presence of retinoic acid. When comparing nasal versus bronchial human AE cells, there were significant positive correlations between levels of ZnT4 from the same subject, suggesting that nasal brushings may allow monitoring of airway Zn transporter expression. Finally, there were marked losses of both basally-located ZnT4 protein and labile Zn in the bronchial epithelium of mice with allergic airway inflammation. This study is the first to describe co-localization of zinc vesicles with the specific zinc transporter ZnT4 in airway epithelium and loss of ZnT4 protein in inflamed airways. Direct evidence that ZnT4 regulates Zn levels in the epithelium still needs to be provided. We speculate that ZnT4 is an important regulator of zinc ion accumulation in secretory apical vesicles and that the loss of labile Zn and ZnT4 in airway inflammation contributes to AE vulnerability in diseases such as asthma. PMID- 22254086 TI - Differential mammary gland development in FVB and C57Bl/6 mice: implications for breast cancer research. AB - A growing body of research suggests a linkage between pubertal mammary gland development and environmental factors such as diet as modifiers of long term breast cancer risk. Much of this research is dependent upon mouse models, which may vary between studies. However, effects may be strain dependent and further modified by diet, which has not been previously examined. Therefore, the objective of the present study was to determine whether mammary gland development differs between FVB and C57Bl/6 strains on diets containing either n-6 or n-3 polyunsaturated fats. Developmental measures related to onset of puberty and mammary gland development differed between strains. Mice fed the n-3 polyunsaturated fatty acids (PUFA) diet were shown to have lower numbers of terminal end buds, a marker of mammary gland development. This study helps to further clarify differences in development and dietary response between FVB and C57Bl/6 mice in order to more appropriately relate mammary gland research to human populations. PMID- 22254087 TI - Caffeinated coffee, decaffeinated coffee and endometrial cancer risk: a prospective cohort study among US postmenopausal women. AB - There is plausible biological evidence as well as epidemiologic evidence to suggest coffee consumption may lower endometrial cancer risk. We evaluated the associations between self-reported total coffee, caffeinated coffee and decaffeinated coffee, and endometrial cancer risk using the Women's Health Initiative Observational Study Research Materials obtained from the National Heart, Lung, and Blood Institute Biological Specimen and Data Repository Coordinating Center. Our primary analyses included 45,696 women and 427 incident endometrial cancer cases, diagnosed over a total of 342,927 person-years of follow-up. We used Cox-proportional hazard models to evaluate coffee consumption and endometrial cancer risk. Overall, we did not find an association between coffee consumption and endometrial cancer risk. Compared to non-daily drinkers (none or <1 cup/day), the multivariable adjusted hazard ratios for women who drank >=4 cups/day were 0.86 (95% confidence interval (CI) 0.63, 1.18) for total coffee, 0.89 (95% CI 0.63, 1.27) for caffeinated coffee, and 0.51 (95% CI 0.25, 1.03) for decaf coffee. In subgroup analyses by body mass index (BMI) there were no associations among normal-weight and overweight women for total coffee and caffeinated coffee. However among obese women, compared to the referent group (none or <1 cup/day), the hazard ratios for women who drank >=2 cups/day were: 0.72 (95% CI 0.50, 1.04) for total coffee and 0.66 (95% CI 0.45, 0.97) for caffeinated coffee. Hazard ratios for women who drank >=2 cups/day for decaffeinated coffee drinkers were 0.67 (0.43-1.06), 0.93 (0.55-1.58) and 0.80 (0.49-1.30) for normal, overweight and obese women, respectively. Our study suggests that caffeinated coffee consumption may be associated with lower endometrial cancer risk among obese postmenopausal women, but the association with decaffeinated coffee remains unclear. PMID- 22254088 TI - Higher urinary sodium, a proxy for intake, is associated with increased calcium excretion and lower hip bone density in healthy young women with lower calcium intakes. AB - We assessed 24-h urinary sodium (Na) and its relationship with urinary calcium (Ca) and areal bone mineral density (aBMD) at the whole body, lumbar spine and total hip in a cross-sectional study. 102 healthy non-obese women completed timed 24-h urine collections which were analyzed for Na and Ca. Dietary intakes were estimated using a validated food frequency questionnaire. Participants were grouped as those with lower vs. higher calcium intake by median split (506 mg/1000 kcal). Dietary Na intake correlated with 24-h urinary loss. Urinary Na correlated positively with urinary Ca for all participants (r = 0.29, p < 0.01) and among those with lower (r = 0.37, p < 0.01) but not higher calcium intakes (r = 0.19, p = 0.19). Urinary Na was inversely associated with hip aBMD for all participants (r = -0.21, p = 0.04) and among women with lower (r = -0.36, p < 0.01) but not higher (r = -0.05, p = 0.71) calcium intakes. Urinary Na also entered a regression equation for hip aBMD in women with lower Ca intakes, contributing 5.9% to explained variance. In conclusion, 24-h urinary Na (a proxy for intake) is associated with higher urinary Ca loss in young women and may affect aBMD, particularly in those with lower calcium intakes. PMID- 22254091 TI - Misreporting of energy intake in the 2007 Australian Children's Survey: identification, characteristics and impact of misreporters. AB - Misreporting of energy intake (EI) is a common problem in national surveys. The aim of this study was to identify misreporters using a variety of criteria, examine the impact of misreporting on the association between EI and weight status, and to define the characteristics of misreporters in the 2007 Australian Children's Survey. Data from the 2007 Australian Children's Survey which included 4800 children aged 2-16 years were used to examine the extent of misreporting based on EI, physical activity level (PAL), age, gender, height and weight status. Three options for identifying misreporters using the Goldberg cut-offs were explored as was direct comparison of EI to energy expenditure (TEE) in a subset of children. Linear regression was used to determine the impact of misreporting on the association between EI and weight status. The prevalence of under-reporting among all children varied from 5.0% to 6.7%, and over-reporting from 1.6% to 3.0% depending on the option used. Direct comparison of EI to TEE revealed similar results. Regression analysis showed that excluding misreporters provided the best model to examine cross-sectional associations between EI and BMI. Characteristics associated with under-reporting included older age, female, higher BMI, higher PAL, living in an urban location, lower parental education level and feeling unwell on the survey day. Over-reporting was more common among children with a lower BMI and lower PAL. In conclusion, misreporting of EI is present among various subgroups of the 2007 Australian Children's Survey. The impact of misreporting on the association between EI and body weight should be recognised by users of this survey. PMID- 22254090 TI - Hepatic oxidative stress in fructose-induced fatty liver is not caused by sulfur amino acid insufficiency. AB - Fructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreased sulfur amino acid intake is known to cause oxidative stress. Studies were designed to test whether oxidative stress in fructose-sweetened liquid-induced fatty liver is caused by decreased ad libitum solid food intake with associated inadequate sulfur amino acid intake. C57BL6 mice were grouped as: control (ad libitum water), fructose (ad libitum 30% fructose-sweetened liquid), glucose (ad libitum 30% glucose-sweetened water) and pair-fed (ad libitum water and sulfur amino acid intake same as the fructose group). Hepatic and plasma thiol-disulfide antioxidant status were analyzed after five weeks. Fructose- and glucose-fed mice developed fatty liver. The mitochondrial antioxidant protein, thioredoxin-2, displayed decreased abundance in the liver of fructose and glucose-fed mice compared to controls. Glutathione/glutathione disulfide redox potential (E(h)GSSG) and abundance of the cytoplasmic antioxidant protein, peroxiredoxin-2, were similar among groups. We conclude that both fructose and glucose-sweetened liquid consumption results in fatty liver and upregulated thioredoxin-2 expression, consistent with mitochondrial oxidative stress; however, inadequate sulfur amino acid intake was not the cause of this oxidative stress. PMID- 22254089 TI - Chemopreventive activity of vitamin E in breast cancer: a focus on gamma- and delta-tocopherol. AB - Vitamin E consists of eight different variants: alpha-, beta-, gamma-, and delta tocopherols (saturated phytyl tail) and alpha-, beta-, gamma-, and delta tocotrienols (unsaturated phytyl tail). Cancer prevention studies with vitamin E have primarily utilized the variant alpha-tocopherol. To no avail, a majority of these studies focused on variant alpha-tocopherol with inconsistent results. However, gamma-tocopherol, and more recently delta-tocopherol, have shown greater ability to reduce inflammation, cell proliferation, and tumor burden. Recent results have shown that gamma-enriched mixed tocopherols inhibit the development of mammary hyperplasia and tumorigenesis in animal models. In this review, we discuss the possible differences between the variant forms, molecular targets, and cancer-preventive effects of tocopherols. We recommend that a gamma-enriched mixture, gamma- and delta-tocopherol, but not alpha-tocopherol, are promising agents for breast cancer prevention and warrant further investigation. PMID- 22254092 TI - Dietary acid-base balance in adolescent sprint athletes: a follow-up study. AB - Sprinters are advised to include additional protein sources in their diet. Basal metabolism and vigorous physical activities generate hydrogen ions that need to be buffered. The present follow-up study estimates the dietary potential renal acid load (PRAL) and net endogenous acid production (NEAP) in adolescent sprint athletes. Seven-day food diaries and anthropometrics of 60 adolescent sprint athletes (mean age at start 14.7 +/- 1.9 years) were collected every six months over a three year period. Comparisons were made between athletes with a negative (PRAL(-)) versus positive PRAL (PRAL(+)). For the entire sample, mean PRAL values of up to 6 mEq/day were slightly positive despite a relatively high protein intake of around 1.5 g/kg. The NEAP ranging between 42 and 46 mEq/day remained stable during the study period. Athletes with a PRAL(-) (-8 to -10 mEq/day) consumed significantly more fruit and fruit juice than athletes with a PRAL(+) (+9 to 14 mEq/day). Athletes with a PRAL(+) did not consume more meat, fish and poultry than athletes with a PRAL(-). Grains and dairy products were only discriminative between the two groups on one measurement occasion. Lowering the PRAL can be obtained by increasing the consumption of potatoes, fruits, vegetables and vegetable soup. PMID- 22254093 TI - Metabolomics as a powerful tool for molecular quality assessment of the fish Sparus aurata. AB - The molecular profiles of perchloric acid solutions extracted from the flesh of Sparus aurata fish specimens, produced according to different aquaculture systems, have been investigated. The (1)H-NMR spectra of aqueous extracts are indicative of differences in the metabolite content of fish reared under different conditions that are already distinguishable at their capture, and substantially maintain the same differences in their molecular profiles after sixteen days of storage under ice. The fish metabolic profiles are studied by top down chemometric analysis. The results of this exploratory investigation show that the fish metabolome accurately reflects the rearing conditions. The level of many metabolites co-vary with the rearing conditions and a few metabolites are quantified including glycogen (stress indicator), histidine, alanine and glycine which all display significant changes dependent on the aquaculture system and on the storage times. PMID- 22254094 TI - Inhibition of rotavirus infectivity by a neoglycolipid receptor mimetic. AB - Group A rotaviruses are a major cause of diarrhea in the young of many mammalian species. In rotavirus infected piglets mortality can be as high as 60%. Previous research in this laboratory has identified a porcine intestinal GM(3) ganglioside receptor that is required for sialic acid-dependent rotavirus recognition of host cells. In addition, we previously demonstrated exogenously added GM(3) can competitively inhibit porcine rotavirus binding and infectivity of host cells in vitro. Sialyllactose, the carbohydrate moiety of GM(3), is approximately 3 orders of magnitude less effective than GM(3) at inhibiting rotavirus binding to cells. Furthermore, production of therapeutic quantities of GM(3) ganglioside for use as an oral carbomimetic in swine is cost prohibitive. In an effort to circumvent these problems, a sialyllactose-containing neoglycolipid was synthesized and evaluated for its ability to inhibit rotavirus binding and infectivity of host cells. Sialyllactose was coupled to dipalmitoylphosphatidylethanolamine (PE) by reductive amination and the product (SLPE) purified by HPLC. Characterization of the product showed a single primulin (lipid) and resorcinol (sialic acid) positive band by thin layer chromatography and quantification of phosphate and sialic acid yielded a 1:1 molar ratio. Mass spectroscopy confirmed a molecular weight coinciding with SLPE. Concentration-dependent binding of rotavirus to SLPE was demonstrated using a thin-layer overlay assay. Using concentrations comparable to GM(3), SLPE was also shown to inhibit rotavirus binding to host cells by 80%. Furthermore, SLPE was shown to decrease rotavirus infection of host cells by over 90%. Finally, preliminary results of in vivo animal challenge studies using newborn piglets in their natural environment, demonstrated SLPE afforded complete protection from rotavirus disease. The efficacy of SLPE in inhibiting rotavirus binding and infection in vitro and in vivo, coupled with its relatively low-cost, large-scale production capabilities make SLPE a promising candidate for further exploration as a possible prophylactic or therapeutic nutriceutical for combating rotavirus disease in animals. Most importantly, the results presented here provide proof of concept that the nutriceutical approach of providing natural or synthetic dietary receptor mimetics for protection against gastrointestinal virus infectious disease in all species is plausible. PMID- 22254095 TI - Probiotics in inflammatory bowel diseases and associated conditions. AB - A complex set of interactions between the human genes encoding innate protective functions and immune defenses and the environment of the intestinal mucosa with its microbiota is currently considered key to the pathogenesis of the chronic inflammatory bowel diseases (IBD). Probiotics offer a method to potentially alter the intestinal microbiome exogenously or may provide an option to deliver microbial metabolic products to alter the chronicity of intestinal mucosal inflammation characterizing IBD. At present, there is little evidence for the benefit of currently used probiotic microbes in Crohn's disease or associated conditions affecting extra-intestinal organs. However, clinical practice guidelines are now including a probiotic as an option for recurrent and relapsing antibiotic sensitive pouchitis and the use of probiotics in mild ulcerative colitis is provocative and suggests potential for benefit in select patients but concerns remain about proof from trials. PMID- 22254096 TI - Iodine deficiency in pregnancy: the effect on neurodevelopment in the child. AB - Iodine is an integral part of the thyroid hormones, thyroxine (T(4)) and tri iodothyronine (T(3)), necessary for normal growth and development. An adequate supply of cerebral T(3), generated in the fetal brain from maternal free T(4) (fT(4)), is needed by the fetus for thyroid hormone dependent neurodevelopment, which begins in the second half of the first trimester of pregnancy. Around the beginning of the second trimester the fetal thyroid also begins to produce hormones but the reserves of the fetal gland are low, thus maternal thyroid hormones contribute to total fetal thyroid hormone concentrations until birth. In order for pregnant women to produce enough thyroid hormones to meet both her own and her baby's requirements, a 50% increase in iodine intake is recommended. A lack of iodine in the diet may result in the mother becoming iodine deficient, and subsequently the fetus. In iodine deficiency, hypothyroxinemia (i.e., low maternal fT(4)) results in damage to the developing brain, which is further aggravated by hypothyroidism in the fetus. The most serious consequence of iodine deficiency is cretinism, characterised by profound mental retardation. There is unequivocal evidence that severe iodine deficiency in pregnancy impairs brain development in the child. However, only two intervention trials have assessed neurodevelopment in children of moderately iodine deficient mothers finding improved neurodevelopment in children of mothers supplemented earlier rather than later in pregnancy; both studies were not randomised and were uncontrolled. Thus, there is a need for well-designed trials to determine the effect of iodine supplementation in moderate to mildly iodine deficient pregnant women on neurodevelopment in the child. PMID- 22254097 TI - Aging and longevity: why knowing the difference is important to nutrition research. AB - Life expectancies after the age of 70 and the number of individuals living with age-related chronic conditions that affect daily activities continue to increase. Age-specific nutritional recommendations may help to decrease the incidence or severity of age-related debilitating chronic disorders. However, research in this area has seen limited success in identifying nutrition-related mechanisms that underlie the functional loss and chronic conditions that occur as a function of time. We believe that the limited success in establishing age-specific nutrition recommendations for the older population reflects, at least in part, research designs that fail to consider the evolutionary and biological bases of aging and longevity. Longevity has evolved as a by-product of genes selected for their contribution in helping the organism survive to the age of reproduction. As such, the principle of genetic determinism provides an appropriate underlying theory for research designs evaluating nutritional factors involved with life span. Aging is not a product of evolution and reflects stochastic and/or random events that most likely begin during the early, reproductively-active years. The genetic determinism model by which young (normal, control) are compared to old (abnormal, experimental) groups will not be effective in identifying underlying mechanisms and nutritional factors that impact aging. The purpose of this commentary is to briefly discuss the difference between aging and longevity and why knowing the difference is important to nutrition research and to establishing the most precise nutritional recommendations possible for the older population. PMID- 22254098 TI - Iron, meat and health. AB - This article is a summary of the publication "Iron and Health" by the Scientific Advisory Committee on Nutrition (SACN) to the U.K. Government (2010), which reviews the dietary intake of iron and the impact of different dietary patterns on the nutritional and health status of the U.K. population. It concludes that several uncertainties make it difficult to determine dose-response relationships or to confidently characterize the risks associated with iron deficiency or excess. The publication makes several recommendations concerning iron intakes from food, including meat, and from supplements, as well as recommendations for further research. PMID- 22254099 TI - Antioxidant activity of a Mediterranean food product: "fig syrup". AB - In this work, the efficacy of fig syrup, a Mediterranean fig derivative, as a nutraceutical supplement, was demonstrated. Fig syrup is a fruit concentrate used as a common ingredient in the preparation of typical foods, and particularly in cakes. In vitro assays were performed to determine the amount of nutraceutical ingredients, such as phenolic compounds (3.92 mg equivalent of gallic acid per g) and flavonoids (0.35 mg equivalent of catechin per g), while HPLC analyses provided specific information about the composition of antioxidants in the syrup. Furthermore, total antioxidant activity, scavenging properties against DPPH and peroxyl radicals, and the anticholinesterase activity, clearly showed the efficacy of the syrup in preventing damage induced by free radicals and, thus, the applicability of this food derivative as a nutraceutical supplement. PMID- 22254100 TI - Perceived barriers to application of glycaemic index: valid concerns or lost in translation? AB - The term glycaemic-index (GI) originally appeared in the literature in the early 1980s. GI categorizes carbohydrate according to glycaemic effect postprandially. Since its inception, GI has obtained and maintained interest of academics and clinicians globally. Upon review of GI literature, it becomes clear that the clinical utility of GI is a source of controversy. Can and should GI be applied clinically? There are academics and clinicians on both sides of the argument. Certainly, this controversy has been a stimulus for the evolution of GI methodology and application research, but may also negatively impact clinicians' perception of GI if misunderstood. This article reviews two assessments of GI that are often listed as barriers to application; the GI concept is (1) too complex and (2) too difficult for clients to apply. The literature reviewed does not support the majority of purported barriers, but does indicate that there is a call from clinicians for more and improved GI education tools and clinician GI education. The literature indicates that the Registered Dietitian (RD) can play a key role in GI knowledge translation; from research to application. Research is warranted to assess GI education tool and knowledge needs of clinicians and the clients they serve. PMID- 22254101 TI - Starches, sugars and obesity. AB - The rising prevalence of obesity, not only in adults but also in children and adolescents, is one of the most important public health problems in developed and developing countries. As one possible way to tackle obesity, a great interest has been stimulated in understanding the relationship between different types of dietary carbohydrate and appetite regulation, body weight and body composition. The present article reviews the conclusions from recent reviews and meta-analyses on the effects of different starches and sugars on body weight management and metabolic disturbances, and provides an update of the most recent studies on this topic. From the literature reviewed in this paper, potential beneficial effects of intake of starchy foods, especially those containing slowly-digestible and resistant starches, and potential detrimental effects of high intakes of fructose become apparent. This supports the intake of whole grains, legumes and vegetables, which contain more appropriate sources of carbohydrates associated with reduced risk of cardiovascular and other chronic diseases, rather than foods rich in sugars, especially in the form of sugar-sweetened beverages. PMID- 22254102 TI - Folic acid food fortification-its history, effect, concerns, and future directions. AB - Periconceptional intake of folic acid is known to reduce a woman's risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs. PMID- 22254104 TI - The nutrition transition in Africa: can it be steered into a more positive direction? AB - The objective of this narrative review is to examine the nutrition transition and its consequences when populations in Africa modernize as a result of socio economic development, urbanization, and acculturation. The focus is on the changes in dietary patterns and nutrient intakes during the nutrition transition, the determinants and consequences of these changes as well as possible new approaches in public health nutrition policies, interventions and research needed to steer the nutrition transition into a more positive direction in Africa. The review indicates that non-communicable, nutrition-related diseases have emerged in sub-Saharan Africa at a faster rate and at a lower economic level than in industrialized countries, before the battle against under-nutrition has been won. There is a putative epigenetic link between under- and over-nutrition, explaining the double burden of nutrition-related diseases in Africa. It is concluded that it is possible to steer the nutrition transition into a more positive direction, provided that some basic principles in planning public health promotion strategies, policies and interventions are followed. It is suggested that sub Saharan African countries join forces to study the nutrition transition and implemented interventions on epidemiological, clinical and molecular (genetic) level for better prevention of both under- and over-nutrition. PMID- 22254103 TI - Vitamin A in reproduction and development. AB - The requirement for vitamin A in reproduction was first recognized in the early 1900's, and its importance in the eyes of developing embryos was realized shortly after. A greater understanding of the large number of developmental processes that require vitamin A emerged first from nutritional deficiency studies in rat embryos, and later from genetic studies in mice. It is now generally believed that all-trans retinoic acid (RA) is the form of vitamin A that supports both male and female reproduction as well as embryonic development. This conclusion is based on the ability to reverse most reproductive and developmental blocks found in vitamin A deficiency induced either by nutritional or genetic means with RA, and the ability to recapitulate the majority of embryonic defects in retinoic acid receptor compound null mutants. The activity of the catabolic CYP26 enzymes in determining what tissues have access to RA has emerged as a key regulatory mechanism, and helps to explain why exogenous RA can rescue many vitamin A deficiency defects. In severely vitamin A-deficient (VAD) female rats, reproduction fails prior to implantation, whereas in VAD pregnant rats given small amounts of carotene or supported on limiting quantities of RA early in organogenesis, embryos form but show a collection of defects called the vitamin A deficiency syndrome or late vitamin A deficiency. Vitamin A is also essential for the maintenance of the male genital tract and spermatogenesis. Recent studies show that vitamin A participates in a signaling mechanism to initiate meiosis in the female gonad during embryogenesis, and in the male gonad postnatally. Both nutritional and genetic approaches are being used to elucidate the vitamin A dependent pathways upon which these processes depend. PMID- 22254106 TI - Human folate bioavailability. AB - The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate. PMID- 22254107 TI - The Australian paradox: a substantial decline in sugars intake over the same timeframe that overweight and obesity have increased. AB - Ecological research from the USA has demonstrated a positive relationship between sugars consumption and prevalence of obesity; however, the relationship in other nations is not well described. The aim of this study was to analyze the trends in obesity and sugar consumption in Australia over the past 30 years and to compare and contrast obesity trends and sugar consumption patterns in Australia with the UK and USA. Data on consumption of sugar in Australia, the UK and USA were obtained from the Food and Agriculture Organization for the years 1980-2003. The prevalence of obesity has increased 3 fold in Australians since 1980. In Australia, the UK and USA, per capita consumption of refined sucrose decreased by 23%, 10% and 20% respectively from 1980 to 2003. When all sources of nutritive sweeteners, including high fructose corn syrups, were considered, per capita consumption decreased in Australia (-16%) and the UK (-5%), but increased in the USA (+23%). In Australia, there was a reduction in sales of nutritively sweetened beverages by 64 million liters from 2002 to 2006 and a reduction in percentage of children consuming sugar-sweetened beverages between 1995 and 2007. The findings confirm an "Australian Paradox"--a substantial decline in refined sugars intake over the same timeframe that obesity has increased. The implication is that efforts to reduce sugar intake may reduce consumption but may not reduce the prevalence of obesity. PMID- 22254108 TI - Variation in fatty acid distribution of different acyl lipids in rice (Oryza sativa L.) brans. AB - The lipids extracted from rice brans were classified by thin-layer chromatography into eight fractions, and their fatty acid (FA) compositions were investigated among five different Japanese cultivars. The lipids of these rice brans comprised mainly triacylglycerols (TAG; 84.9-86.0 wt%), free FA (4.2-4.6 wt%), and phospholipids (PL; 6.5-6.7 wt%), whilst other components were also detected in minor proportions (0.2-2.1 wt%). The PL components included phosphatidyl choline (43.3-46.8 wt%) phosphatidyl ethanolamine (25.0-27.3 wt%) and phosphatidyl inositol (20.2-23.2 wt%). Comparison of the different cultivars showed, with a few exceptions, no substantial difference (P > 0.05) in FA distribution. FA distribution of TAG among the five cultivars was characterized as: unsaturated FA predominantly concentrated at the sn-2 position and saturated FA primarily occupying the sn-1 or sn-3 position in these lipids. These results suggest that the rice bran lipids may be well incorporated into our daily diet to improve nutritional value of the Japanese diet. PMID- 22254105 TI - Perspectives on immunoglobulins in colostrum and milk. AB - Immunoglobulins form an important component of the immunological activity found in milk and colostrum. They are central to the immunological link that occurs when the mother transfers passive immunity to the offspring. The mechanism of transfer varies among mammalian species. Cattle provide a readily available immune rich colostrum and milk in large quantities, making those secretions important potential sources of immune products that may benefit humans. Immune milk is a term used to describe a range of products of the bovine mammary gland that have been tested against several human diseases. The use of colostrum or milk as a source of immunoglobulins, whether intended for the neonate of the species producing the secretion or for a different species, can be viewed in the context of the types of immunoglobulins in the secretion, the mechanisms by which the immunoglobulins are secreted, and the mechanisms by which the neonate or adult consuming the milk then gains immunological benefit. The stability of immunoglobulins as they undergo processing in the milk, or undergo digestion in the intestine, is an additional consideration for evaluating the value of milk immunoglobulins. This review summarizes the fundamental knowledge of immunoglobulins found in colostrum, milk, and immune milk. PMID- 22254109 TI - Breakfast and snacks: associations with cognitive failures, minor injuries, accidents and stress. AB - One strategy for examining effects of nutrients on cognitive function is to initially investigate foods that contain many different nutrients. If effects are demonstrated with these foods then further studies can address the role of specific nutrients. Breakfast foods (e.g., cereals, dairy products and fruit) provide many important nutrients and consumption of breakfast has been shown to be associated with beneficial effects on cognitive function. Isolating effects of specific constituents of breakfast has proved more difficult and it is still unclear what impact breakfast has on real-life performance. The present study provided initial information on associations between breakfast consumption and cognitive failures and accidents. A second aim was to examine associations between consumption of snacks which are often perceived as being unhealthy (chocolate, crisps and biscuits). A sample of over 800 nurses took part in the study. The results showed that frequency of breakfast consumption (varied breakfasts: 62% cereal) was associated with lower stress, fewer cognitive failures, injuries and accidents at work. In contrast, snacking on crisps, chocolate and biscuits was associated with higher stress, more cognitive failures and more injuries outside of work. Further research requires intervention studies to provide a clearer profile of causality and underlying mechanisms. PMID- 22254111 TI - Dehydration influences mood and cognition: a plausible hypothesis? AB - The hypothesis was considered that a low fluid intake disrupts cognition and mood. Most research has been carried out on young fit adults, who typically have exercised, often in heat. The results of these studies are inconsistent, preventing any conclusion. Even if the findings had been consistent, confounding variables such as fatigue and increased temperature make it unwise to extrapolate these findings. Thus in young adults there is little evidence that under normal living conditions dehydration disrupts cognition, although this may simply reflect a lack of relevant evidence. There remains the possibility that particular populations are at high risk of dehydration. It is known that renal function declines in many older individuals and thirst mechanisms become less effective. Although there are a few reports that more dehydrated older adults perform cognitive tasks less well, the body of information is limited and there have been little attempt to improve functioning by increasing hydration status. Although children are another potentially vulnerable group that have also been subject to little study, they are the group that has produced the only consistent findings in this area. Four intervention studies have found improved performance in children aged 7 to 9 years. In these studies children, eating and drinking as normal, have been tested on occasions when they have and not have consumed a drink. After a drink both memory and attention have been found to be improved. PMID- 22254110 TI - Docosahexaenoic acid (DHA): an ancient nutrient for the modern human brain. AB - Modern humans have evolved with a staple source of preformed docosahexaenoic acid (DHA) in the diet. An important turning point in human evolution was the discovery of high-quality, easily digested nutrients from coastal seafood and inland freshwater sources. Multi-generational exploitation of seafood by shore based dwellers coincided with the rapid expansion of grey matter in the cerebral cortex, which characterizes the modern human brain. The DHA molecule has unique structural properties that appear to provide optimal conditions for a wide range of cell membrane functions. This has particular implications for grey matter, which is membrane-rich tissue. An important metabolic role for DHA has recently been identified as the precursor for resolvins and protectins. The rudimentary source of DHA is marine algae; therefore it is found concentrated in fish and marine oils. Unlike the photosynthetic cells in algae and higher plants, mammalian cells lack the specific enzymes required for the de novo synthesis of alpha-linolenic acid (ALA), the precursor for all omega-3 fatty acid syntheses. Endogenous synthesis of DHA from ALA in humans is much lower and more limited than previously assumed. The excessive consumption of omega-6 fatty acids in the modern Western diet further displaces DHA from membrane phospholipids. An emerging body of research is exploring a unique role for DHA in neurodevelopment and the prevention of neuropsychiatric and neurodegenerative disorders. DHA is increasingly being added back into the food supply as fish oil or algal oil supplementation. PMID- 22254113 TI - Use of probiotics as prophylaxis for postoperative infections. AB - Postoperative bacterial infections are common despite prophylactic administration of antibiotics. The wide-spread use of antibiotics in patients has contributed to the emergence of multiresistant bacteria. A restricted use of antibiotics must be followed in most clinical situations. In surgical patients there are several reasons for an altered microbial flora in the gut in combination with an altered barrier function leading to an enhanced inflammatory response to surgery. Several experimental and clinical studies have shown that probiotics (mainly lactobacilli) may reduce the number of potentially pathogenia bacteria (PPM) and restore a deranged barrier function. It is therefore of interest to test if these abilities of probiotics can be utilized in preoperative prophylaxis. These factors may be corrected by perioperative administration of probiotics in addition to antibiotics. Fourteen randomized clinical trials have been presented in which the effect of such regimens has been tested. It seems that in patients undergoing liver transplantation or elective surgery in the upper gastrointestinal tract prophylactic administration of different probiotic strains in combination with different fibers results in a three-fold reduction in postoperative infections. In parallel there seems to be a reduction in postoperative inflammation, although that has not been studied in a systematic way. The use of similar concepts in colorectal surgery has not been successful in reducing postoperative infections. Reasons for this difference are not obvious. It may be that higher doses of probiotics with longer duration are needed to influence microbiota in the lower gastrointestinal tract or that immune function in colorectal patients may not be as important as in transplantation or surgery in the upper gastrointestinal tract. The favorable results for the use of prophylactic probiotics in some settings warrant further controlled studies to elucidate potential mechanisms, impact on gut microbiota and influence on clinical management. The use of probiotics must be better delineated in relation to type of bacteria, dose and length of administration. PMID- 22254112 TI - Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract. AB - Dietary proteins elicit a wide range of nutritional and biological functions. Beyond their nutritional role as the source of amino acids for protein synthesis, they are instrumental in the regulation of food intake, glucose and lipid metabolism, blood pressure, bone metabolism and immune function. The interaction of dietary proteins and their products of digestion with the regulatory functions of the gastrointestinal (GI) tract plays a dominant role in determining the physiological properties of proteins. The site of interaction is widespread, from the oral cavity to the colon. The characteristics of proteins that influence their interaction with the GI tract in a source-dependent manner include their physico-chemical properties, their amino acid composition and sequence, their bioactive peptides, their digestion kinetics and also the non-protein bioactive components conjugated with them. Within the GI tract, these products affect several regulatory functions by interacting with receptors releasing hormones, affecting stomach emptying and GI transport and absorption, transmitting neural signals to the brain, and modifying the microflora. This review discusses the interaction of dietary proteins during digestion and absorption with the physiological and metabolic functions of the GI tract, and illustrates the importance of this interaction in the regulation of amino acid, glucose, lipid metabolism, and food intake. PMID- 22254116 TI - Food intake and dietary glycaemic index in free-living adults with and without type 2 diabetes mellitus. AB - A recent Cochrane review concluded that low glycaemic index (GI) diets are beneficial in glycaemic control for patients with type 2 diabetes mellitus (T2DM). There are limited UK data regarding the dietary GI in free-living adults with and without T2DM. We measured the energy and macronutrient intake and the dietary GI in a group (n = 19) of individuals with diet controlled T2DM and a group (n = 19) without diabetes, matched for age, BMI and gender. Subjects completed a three-day weighed dietary record. Patients with T2DM consumed more daily portions of wholegrains (2.3 vs. 1.1, P = 0.003), more dietary fibre (32.1 vs. 20.9 g, P < 0.001) and had a lower diet GI (53.5 vs. 57.7, P = 0.009) than subjects without T2DM. Both groups had elevated fat and salt intake and low fruit and vegetable intake, relative to current UK recommendations. CONCLUSIONS: Patients with T2DM may already consume a lower GI diet than the general population but further efforts are needed to reduce dietary GI and achieve other nutrient targets. PMID- 22254114 TI - Lactobacillus adhesion to mucus. AB - Mucus provides protective functions in the gastrointestinal tract and plays an important role in the adhesion of microorganisms to host surfaces. Mucin glycoproteins polymerize, forming a framework to which certain microbial populations can adhere, including probiotic Lactobacillus species. Numerous mechanisms for adhesion to mucus have been discovered in lactobacilli, including partially characterized mucus binding proteins. These mechanisms vary in importance with the in vitro models studied, which could significantly affect the perceived probiotic potential of the organisms. Understanding the nature of mucus microbe interactions could be the key to elucidating the mechanisms of probiotic adhesion within the host. PMID- 22254117 TI - Reducing sodium in foods: the effect on flavor. AB - Sodium is an essential micronutrient and, via salt taste, appetitive. High consumption of sodium is, however, related to negative health effects such as hypertension, cardiovascular diseases and stroke. In industrialized countries, about 75% of sodium in the diet comes from manufactured foods and foods eaten away from home. Reducing sodium in processed foods will be, however, challenging due to sodium's specific functionality in terms of flavor and associated palatability of foods (i.e., increase of saltiness, reduction of bitterness, enhancement of sweetness and other congruent flavors). The current review discusses the sensory role of sodium in food, determinants of salt taste perception and a variety of strategies, such as sodium replacers (i.e., potassium salts) and gradual reduction of sodium, to decrease sodium in processed foods while maintaining palatability. PMID- 22254115 TI - Gut microbiota and inflammation. AB - Systemic and local inflammation in relation to the resident microbiota of the human gastro-intestinal (GI) tract and administration of probiotics are the main themes of the present review. The dominating taxa of the human GI tract and their potential for aggravating or suppressing inflammation are described. The review focuses on human trials with probiotics and does not include in vitro studies and animal experimental models. The applications of probiotics considered are systemic immune-modulation, the metabolic syndrome, liver injury, inflammatory bowel disease, colorectal cancer and radiation-induced enteritis. When the major genomic differences between different types of probiotics are taken into account, it is to be expected that the human body can respond differently to the different species and strains of probiotics. This fact is often neglected in discussions of the outcome of clinical trials with probiotics. PMID- 22254118 TI - The effect of Spirulina platensis versus soybean on insulin resistance in HIV infected patients: a randomized pilot study. AB - HIV-infected patients develop abnormalities of glucose metabolism due to the virus and antiretroviral drugs. Spirulina and soybean are nutritional supplements that are cheap, accessible in our community and affect glucose metabolism. We carried out a randomized study to assess the effect of Spirulina platensis versus soybean as a food supplement on HIV/HAART-associated insulin resistance (IR) in 33 insulin-resistant HIV-infected patients. The study lasted for two months at the National Obesity Centre of Cameroon. Insulin resistance was measured using the short insulin tolerance test. Physical activity and diet did not change over the study duration. On-treatment analysis was used to analyze data. The Mann Whitney U test, the Students T test and the Chi square test were used as appropriate. Curve gradients were analyzed using ANCOVA. Seventeen subjects were randomized to spirulina and 16 to soybean. Each received 19 g of supplement daily. The follow up rate was 65% vs. 100% for spirulina and soybean groups, respectively, and both groups were comparable at baseline. After eight weeks, insulin sensitivity (IS) increased by 224.7% vs. 60% in the spirulina and soybean groups respectively (p < 0.001). One hundred per cent vs. 69% of subjects on spirulina versus soybean, respectively, improved their IS (p = 0.049) with a 1.45 (1.05-2.02) chance of improving insulin sensitivity on spirulina. This pilot study suggests that insulin sensitivity in HIV patients improves more when spirulina rather than soybean is used as a nutritional supplement. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01141777. PMID- 22254119 TI - Consumption of milk-protein combined with green tea modulates diet-induced thermogenesis. AB - Green tea and protein separately are able to increase diet-induced thermogenesis. Although their effects on long-term weight-maintenance were present separately, they were not additive. Therefore, the effect of milk-protein (MP) in combination with green tea on diet-induced thermogenesis (DIT) was examined in 18 subjects (aged 18-60 years; BMI: 23.0 +/- 2.1 kg/m(2)). They participated in an experiment with a randomized, 6 arms, crossover design, where energy expenditure and respiratory quotient (RQ) were measured. Green tea (GT)vs. placebo (PL) capsules were either given in combination with water or with breakfasts containing milk protein in two different dosages: 15 g (15 MP) (energy% P/C/F: 15/47/38; 1.7 MJ/500 mL), and 3.5 g (3.5 MP) (energy% P/C/F: 41/59/0; 146.4 kJ/100 mL). After measuring resting energy expenditure (REE) for 30 min, diet-induced energy expenditure was measured for another 3.5 h after the intervention. There was an overall significant difference observed between conditions (p < 0.001). Post-hoc, areas under the curve (AUCs) for diet-induced energy expenditure were significantly different (P <= 0.001) for GT + water (41.11 [91.72] kJ.3.5 h) vs. PL + water (10.86 [28.13] kJ.3.5 h), GT + 3.5 MP (10.14 [54.59] kJ.3.5 h) and PL + 3.5 MP (12.03 [34.09] kJ.3.5 h), but not between GT + 3.5 MP, PL + 3.5 MP and PL + water, indicating that MP inhibited DIT following GT. DIT after GT + 15 MP (167.69 [141.56] kJ.3.5 h) and PL + 15 MP (168.99 [186.56] kJ.3.5 h) was significantly increased vs. PL + water (P < 0.001), but these were not different from each other indicating that 15 g MP stimulated DIT, but inhibited the GT effect on DIT. No significant differences in RQ were seen between conditions for baseline and post-treatment. In conclusion, consumption of milk-protein inhibits the effect of green tea on DIT. PMID- 22254122 TI - Canadian initiatives to prevent hypertension by reducing dietary sodium. AB - Hypertension is the leading risk for premature death in the world. High dietary sodium is an important contributor to increased blood pressure and is strongly associated with other important diseases (e.g., gastric cancer, calcium containing kidney stones, osteoporosis, asthma and obesity). The average dietary sodium intake in Canada is approximately 3400 mg/day. It is estimated that 30% of hypertension, more than 10% of cardiovascular events and 1.4 billion dollars/year in health care expenses are caused by this high level of intake in Canada. Since 2006, Canada has had a focused and evolving effort to reduce dietary sodium based on actions from Non Governmental Organizations (NGO), and Federal and Provincial/Territorial Government actions. NGOs initiated Canadian sodium reduction programs by developing a policy statement outlining the health issue and calling for governmental, NGO and industry action, developing and disseminating an extensive health care professional education program including resources for patient education, developing a public awareness campaign through extensive media releases and publications in the lay press. The Federal Government responded by striking a Intersectoral Sodium Work Group to develop recommendations on how to implement Canada's dietary reference intake values for dietary sodium and by developing timelines and targets for foods to be reduced in sodium, assessing key research gaps with funding for targeted dietary sodium based research, developing plans for public education and for conducting evaluation of the program to reduce dietary sodium. While food regulation is a Federal Government responsibility Provincial and Territorial governments indicated reducing dietary sodium needed to be a priority. Federal and Provincial Ministers of Health have endorsed a target to reduce the average consumption of sodium to 2300 mg/day by 2016 and the Deputy Ministers of Health have tasked a joint committee to review the recommendations of the Sodium Work Group and report back to them. PMID- 22254121 TI - Metabolic agents that enhance ATP can improve cognitive functioning: a review of the evidence for glucose, oxygen, pyruvate, creatine, and L-carnitine. AB - Over the past four or five decades, there has been increasing interest in the neurochemical regulation of cognition. This field received considerable attention in the 1980s, with the identification of possible cognition enhancing agents or "smart drugs". Even though many of the optimistic claims for some agents have proven premature, evidence suggests that several metabolic agents may prove to be effective in improving and preserving cognitive performance and may lead to better cognitive aging through the lifespan. Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. There are a number of agents with the potential to improve metabolic activity. Research is now beginning to identify these various agents and delineate their potential usefulness for improving cognition in health and disease. This review provides a brief overview of the metabolic agents glucose, oxygen, pyruvate, creatine, and L-carnitine and their beneficial effects on cognitive function. These agents are directly responsible for generating ATP (adenosine triphosphate) the main cellular currency of energy. The brain is the most metabolically active organ in the body and as such is particularly vulnerable to disruption of energy resources. Therefore interventions that sustain adenosine triphosphate (ATP) levels may have importance for improving neuronal dysfunction and loss. Moreover, recently, it has been observed that environmental conditions and diet can affect transgenerational gene expression via epigenetic mechanisms. Metabolic agents might play a role in regulation of nutritional epigenetic effects. In summary, the reviewed metabolic agents represent a promising strategy for improving cognitive function and possibly slowing or preventing cognitive decline. PMID- 22254123 TI - Bioactive peptides from muscle sources: meat and fish. AB - Bioactive peptides have been identified in a range of foods, including plant, milk and muscle, e.g., beef, chicken, pork and fish muscle proteins. Bioactive peptides from food proteins offer major potential for incorporation into functional foods and nutraceuticals. The aim of this paper is to present an outline of the bioactive peptides identified in the muscle protein of meat to date, with a focus on muscle protein from domestic animals and fish. The majority of research on bioactives from meat sources has focused on angiotensin-1 converting enzyme (ACE) inhibitory and antioxidant peptides. PMID- 22254124 TI - Effects of dietary glutamine supplementation on the body composition and protein status of early-weaned mice inoculated with Mycobacterium bovis Bacillus Calmette Guerin. AB - Glutamine, one of the most abundant amino acids found in maternal milk, favors protein anabolism. Early-weaned babies are deprived of this source of glutamine, in a period during which endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress, mainly during infections. The objective of this study was to verify the effects of dietary glutamine supplementation on the body composition and visceral protein status of early-weaned mice inoculated with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Mice were weaned early on their 14th day of life and seperated into two groups, one of which was fed a glutamine-free diet (n = 16) and the other a glutamine-supplemented diet (40 g/kg diet) (n = 16). At 21 days of age, some mice were intraperitoneally injected with BCG. Euthanasia was performed at the 28th day of age. BCG inoculation significantly reduced body weight (P < 0.001), lean mass (P = 0.002), water (P = 0.006), protein (P = 0.007) and lipid content (P = 0.001) in the carcass. Dietary glutamine supplementation resulted in a significant increase in serum IGF-1 (P = 0.019) and albumin (P = 0.025) concentration, muscle protein concentration (P = 0.035) and lipid content (P = 0.002) in the carcass. In conclusion, dietary glutamine supplementation had a positive influence on visceral protein status but did not affect body composition in early-weaned mice inoculated with BCG. PMID- 22254125 TI - Deficiency in the 15 kDa selenoprotein inhibits human colon cancer cell growth. AB - Selenium is an essential micronutrient for humans and animals, and is thought to provide protection against some forms of cancer. These protective effects appear to be mediated, at least in part, through selenium-containing proteins (selenoproteins). Recent studies in a mouse colon cancer cell line have shown that the 15 kDa selenoprotein (Sep15) may also play a role in promoting colon cancer. The current study investigated whether the effects of reversing the cancer phenotype observed when Sep15 was removed in mouse colon cancer cells, were recapitulated in HCT116 and HT29 human colorectal carcinoma cells. Targeted down-regulation of Sep15 using RNAi technology in these human colon cancer cell lines resulted in similarly decreased growth under anchorage-dependent and anchorage-independent conditions. However, the magnitude of reduction in cell growth was much less than in the mouse colon cancer cell line investigated previously. Furthermore, changes in cell cycle distribution were observed, indicating a delayed release of Sep15 deficient cells from the G(0)/G(1) phase after synchronization. The potential mechanism by which human colon cancer cells lacking Sep15 revert their cancer phenotype will need to be explored further. PMID- 22254127 TI - Approach to the pretransplant evaluation of the living kidney donor. AB - Evaluation of the potential kidney donor is a complex activity that differs substantially from other types of preoperative assessments. The well being of the donor, who derives no medical benefit from this surgery, must be assured in both the short term and long term, and the potential adverse consequences to the recipient must be determined as well. The criteria that must be met for a person to donate a kidney are rigorous and include medical, social, psychosocial, ethical, and legal issues. Donor evaluation can be divided into assessments to protect the health and safety of the donor and assessments to protect the health and safety of the recipient. This article provides an approach to evaluating a donor, focusing on the complex issues that an evaluator is faced with. A careful assessment of risks and benefits to both the donor and recipient can lead to favorable outcomes. PMID- 22254126 TI - Antioxidant and antiradical activities of Manihot esculenta Crantz (Euphorbiaceae) leaves and other selected tropical green vegetables investigated on lipoperoxidation and phorbol-12-myristate-13-acetate (PMA) activated monocytes. AB - Abelmoschus esculentus (Malvaceae), Hibiscus acetosella (Malvaceae), Manihot esculenta Crantz (Euphorbiaceae) and Pteridium aquilinum (Dennstaedtiaceae) leaves are currently consumed as vegetables by migrants from sub-Saharan Africa living in Western Europe and by the people in the origin countries, where these plants are also used in the folk medicine. Manihot leaves are also eaten in Latin America and some Asian countries. This work investigated the capacity of aqueous extracts prepared from those vegetables to inhibit the peroxidation of a linoleic acid emulsion. Short chain, volatile C-compounds as markers of advanced lipid peroxidation were measured by gas chromatography by following the ethylene production. The generation of lipid hydroperoxides, was monitored by spectroscopy using N-N'-dimethyl-p-phenylene-diamine (DMPD). The formation of intermediate peroxyl, and other free radicals, at the initiation of the lipid peroxidation was investigated by electron spin resonance, using alpha-(4-pyridyl-1-oxide)-N-tert butylnitrone as spin trap agent. The ability of the extracts to decrease the cellular production of reactive oxygen species (ROS) in "inflammation like" conditions was studied by fluorescence technique using 2',7'-dichlorofluorescine diacetate as fluorogenic probe, in a cell model of human monocytes (HL-60 cells) activated with phorbol ester. Overall the extracts displayed efficient concentration-dependent inhibitory effects. Their total polyphenol and flavonoid content was determined by classic colorimetric methods. An HPLC-UV/DAD analysis has clearly identified the presence of some polyphenolic compounds, which explains at least partially the inhibitions observed in our models. The role of these plants in the folk medicine by sub-Saharan peoples as well as in the prevention of oxidative stress and ROS related diseases requires further consideration. PMID- 22254128 TI - Inflammatory and angiogenic protein detection in the human vitreous: cytometric bead assay. AB - Introduction. To evaluate clinical feasibility and reproducibility of cytometric bead assay (CBA) in nondiluted vitreous samples of patients with age-related macular degeneration (ARMD), diabetic macular edema (DME), and central retinal vein occlusion (CRVO). Methods. Twelve patients from a single clinics day qualified for intravitreal injections (ARMD n = 6, DME n = 3, CRVO n = 3) and underwent a combination treatment including a single-site 23 gauge core vitrectomy which yielded a volume of 0.6 mL undiluted vitreous per patient. Interleukin-6 (IL-6), vascular endothelial growth factor isoform A (VEGF-A), and monocyte chemo-attractant protein-1 (MCP-1) were assessed directly from 0.3 mL at the same day (fresh samples). To assess the reproducibility 0.3 ml were frozen for 60 days at -80 degrees , on which the CBA was repeated (frozen samples). Results. In the fresh samples IL-6 was highest in CRVO (median IL-6 55.8 pg/mL) > DME (50.6) > ARMD (3.1). Highest VEGF was measured in CRVO (447.4) > DME (3.9) > ARMD (2.0). MCP-1 was highest in CRVO (595.7) > AMD (530.8) > DME (178). The CBA reproducibility after frozen storage was examined to be most accurate for MCP1 (P = 0.91) > VEGF (P = 0.68) > IL-6 (P = 0.49). Conclusions. CBA is an innovative, fast determining, and reliable technology to analyze proteins in fluids, like the undiluted vitreous, which is important to better understand ocular pathophysiology and pharmacology. There is no influence of intermittent storage at -80 degrees for the reproducibility of the CBA. PMID- 22254129 TI - Spectral Domain OCT: An Aid to Diagnosis and Surgical Planning of Retinal Detachments. AB - Regmatogenous retinal detachments need prompt intervention particularly when macula is on. Unfortunately this is not always easy to ascertain clinically and the chronicity of the event is often muddled in patient's histories. Developments in optical coherence tomography (OCT) have allowed high-resolution axial scans which have enabled the characterisation of retinal changes in retinal detachments. In this paper, we show the changes in retinal morphology observed by spectral domain OCT and how this can be used to plan appropriate surgical intervention. PMID- 22254130 TI - Complications of corneal collagen cross-linking. AB - Cross-linking of corneal collagen (CXL) is a promising approach for the treatment of keratoconus and secondary ectasia. Several long-term and short-term complications of CXL have been studied and documented. The possibility of a secondary infection after the procedure exists because the patient is subjected to epithelial debridement and the application of a soft contact lens. Formation of temporary corneal haze, permanent scars, endothelial damage, treatment failure, sterile infiltrates, and herpes reactivation are the other reported complications of this procedure. Cross-linking is a low-invasive procedure with low complication and failure rate but it may have direct or primary complications due to incorrect technique application or incorrect patient's inclusion and indirect or secondary complications related to therapeutic soft contact lens, patient's poor hygiene, and undiagnosed concomitant ocular surface diseases. PMID- 22254132 TI - Skin diseases-related enzymes: mechanisms and clinical applications. PMID- 22254131 TI - Lipid disorders in elderly hypertensive patients. AB - Lipid disorders are a common clinical challenge in the western countries. In patients with dyslipemia (total cholesterol > 200 mg/dl, HDL cholesterol < 35 mg/dl, LDL cholesterol > 130 mg/dl and triglycerides > 150 mg/dl) it is mandatory to normalize blood pressure (<130/80 mmHg) as well to reduce LDL-C values to normal levels by using drugs to inhibit of endogenous and exogenous cholesterol, to decrease triglycerides, and increases HDL-C up to normal range. It is also essential to maintain for this purpose suitable dietetic measures (reduction of unsatured fats and salt intakes-<2.5 g/daily) and without interruption, to support pharmacologic treatment in most of the patients. PMID- 22254133 TI - Selected Papers from ENZITEC 2010. PMID- 22254135 TI - Local context influence, activity space, and foodscape exposure in two canadian metropolitan settings: is daily mobility exposure associated with overweight? AB - It has become increasingly common to attribute part of the obesity epidemic to changes in the environment. Identification of a clear and obvious role for contextual risk factors has not yet been demonstrated. The objectives of this study were to explain differences in local overweight risk in two different urban settings and to explore sex-specific associations with estimated mobility patterns. Overweight was modeled within a multilevel framework using built environmental and socioeconomic contextual indicators and individual-level estimates of activity space exposure to fast-food restaurants (or exposure to visited places). Significant variations in local levels in overweight risk were observed. Physical and socioeconomic contexts explained more area-level differences in overweight among men than among women and among inhabitants of Montreal than among inhabitants of Quebec City. Estimated activity space exposure to fast-food outlets was significantly associated with overweight for men in Montreal. Local-level analyses are required to improve our understanding of contextual influences on obesity, including multiple influences in people's daily geographies. PMID- 22254134 TI - Vitamin d deficiency in obese children and its relationship to insulin resistance and adipokines. AB - Low-serum concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with insulin resistance in adults. Less data are available in pediatric populations. Serum 25(OH)D serum concentrations were assessed in 125 obese and 31 nonobese children (age 11.9 +/- 2.7 y, range 6-16 y, 49% male) living in Bonn, Germany. The relationship between 25(OH)D, measured by liquid chromatography-tandem mass spectrometry, and measures of insulin sensitivity and adipokines adiponectin and resistin were analyzed. Seventy-six % of subjects were 25(OH)D deficient (<20 ng/mL). Higher insulin, homeostasis model assessment-insulin resistance (HOMA-IR r = -0.269, P = 0.023), and hemoglobin A1c (HbA(1c)) as well as lower quantitative insulin-sensitivity check index (QUICKI r = 0.264, P = 0.030) values were found in obese children with lower 25(OH)D concentrations even after adjustment for gender, age, and body mass index. Furthermore, 25(OH)D correlated significantly with adiponectin, but not with resistin. Our results suggest that hypovitaminosis D is a risk factor for developing insulin resistance independent of adiposity. PMID- 22254136 TI - Malnutrition in patients with acute stroke. AB - Stroke is a devastating event that carries a potential for long-term disability. Malnutrition is frequently observed in patients with stroke, and dysphagia contributes to malnutrition risk. During both the acute phase of stroke and rehabilitation, specific nutritional interventions in the context of a multidisciplinary team effort can enhance the recovery of neurocognitive function. Early identification and management of malnutrition with dietary modifications or specific therapeutic strategies to ensure adequate nutritional intake should receive more attention, since poor nutritional status appears to exacerbate brain damage and to contribute to adverse outcome. The main purpose of nutritional intervention should be the prevention or treatment of complications resulting from energy-protein deficit. This paper reviews the evaluation and management of malnutrition and the use of specialized nutrition support in patients with stroke. Emphasis is given to enteral tube and oral feeding and to strategies to wean from tube feeding. PMID- 22254137 TI - Validation of hepascore as a predictor of liver fibrosis in patients with chronic hepatitis C infection. AB - Introduction. Liver biopsy is an invasive determinator for hepatic fibrosis. Serum biomarkers can probably be used as an alternative to liver biopsy in assessment of the degree of fibrosis in patients with chronic Hepatitis C. Method. Eighty patients with chronic Hepatitis C were included in the study using simple nonrandom sampeling metod. After fulfillment of liver biopsy, the patients were categorized according to the METAVIR Scoring system. The Hepascore algorithm is computed based on age, sex, and the serum levels of total bilirubin, delta glutamyl transferase, alpha2-Macroglobulin, and hyaluronic acid. The spearman and ROC tests were used. Results. According to the liver biopsy results, 12, 25, 20, 7 and 16 patients had F0, F1, F2, F3, and F4, respectively. With regard to the 0.34 cut-off point Hepascore had 67%, 56%, 64%, and 56% sensitivity, specificity, respectively, positive prediction value (PPV), and negative prediction value (NPV), respectively, for diagnosis of significant fibrosis. For a Hepascore cut off point 0.61, sensitivity, specificity, respectively, PPV and NPB 82%, 86%, 70%, and 92% in diagnosis of severe fibrosis. For a Hepascore cut-off point 0.84, sensitivity, specificity, PPV and NPB were respectively 100%, 97%, 89%, and 100% for diagnosis of cirrhosis. Conclusion. Hepascore has a high value in diagnosis of the level of fibrosis, particularly cirrhosis. Therefore, it can be used for primary screening of patients to determine the need for liver biopsy. PMID- 22254138 TI - Rheolytic Thrombectomy with or without Adjunctive Indwelling Pharmacolysis in Patients Presenting with Acute Pulmonary Embolism Presenting with Right Heart Strain and/or Pulseless Electrical Activity. AB - Purpose. To evaluate the safety and efficacy of the Possis rheolytic thrombectomy with or without indwelling catheter-directed pharmacolysis for the treatment of massive pulmonary embolus in patients presenting with right heart strain and/or a pulseless electrical activity (PEA). Materials and Methods. Retrospective review of patients undergoing pulmonary pharmacolysis was performed (07/2004-06/2009). Pre- and posttreatment Miller index scoring weres calculated and compared. Patients were evaluated for tPA doses, ICU stay, hospital stay, and survival by Kaplan-Meier analysis. Results. 11 patients with massive PE were found, with 10/11 presenting with a Miller score of >17 (range: 16-27, mean: 23.2). CTPA and/or echocardiographic evidence of right heart strain was found in 10/11 patients. 3 (27%) patients presented with a PEA event. Two (18%) patients had a contraindication to pharmacolysis and were treated with mechanical thrombectomy alone. The intraprocedural mortality was 9% (n = 1/11). Of the 10 patients who survived the initial treatment, 7 patients underwent standard mechanical thrombectomy initially, while 5 received power pulse spray mechanical thrombectomy. Eight of these 10 patients underwent adjunctive indwelling catheter directed thrombolysis. The mean catheter-directed infusion duration was 18 hours (range of 12-26 hours). The average intraprocedural, infusion, and total doses of tPA were 7 mg, 19.7 mg, and 26.7 mg, respectively. There was a 91% (10/11) technical success rate. The failure was the single mortality. Average reduction in Miller score was 9.5 or 41% (P = 0.009), obstructive index of 6.4 or 47% (P = 0.03), and perfusion index of 2.7 or 28% (P = 0.05). Average ICU and hospital stay were 7.4 days (range 2-27 days) and 21.3 days (range 6-60 days), respectively. Intent to treat survival was 90% at 6, 12, and 18 months. Conclusion. Rheolytic thrombectomy with or without adjunctive catheter-directed thrombolysis provides a safe and effective method for treatment of acute PE in patients who present with right heart strain and/or a PEA event. PMID- 22254139 TI - The severity of Fatty liver disease relating to metabolic abnormalities independently predicts coronary calcification. AB - Background. Nonalcoholic fatty liver disease (NAFLD) is one of the metabolic disorders presented in liver. The relationship between severity of NAFLD and coronary atherosclerotic burden remains largely unknown. Methods and Materials. We analyzed subjects undergoing coronary calcium score evaluation by computed tomography (MDCT) and fatty liver assessment using abdominal ultrasonography. Framingham risk score (FRS) and metabolic risk score (MRS) were obtained in all subjects. A graded, semiquantitative score was established to quantify the severity of NAFLD. Multivariate logistic regression analysis was used to depict the association between NAFLD and calcium score. Results. Of all, 342 participants (female: 22.5%, mean age: 48.7 +/- 7.0 years) met the sufficient information rendering detailed analysis. The severity of NAFLD was positively associated with MRS (X(2) = 6.12, trend P < 0.001) and FRS (X(2) = 5.88, trend P < 0.001). After multivariable adjustment for clinical variables and life styles, the existence of moderate to severe NAFLD was independently associated with abnormal calcium score (P < 0.05). Conclusion. The severity of NAFLD correlated well with metabolic abnormality and was independently predict coronary calcification beyond clinical factors. Our data suggests that NAFLD based on ultrasonogram could positively reflect the burden of coronary calcification. PMID- 22254141 TI - Neuroendocrine Liver Metastases and Orthotopic Liver Transplantation: The US Experience. AB - Liver transplantation remains a controversial therapy for Neuroendocrine liver metastases (NLM), with coflicting suvival data reported. The aim was to assess the evolution of outcomes for patients transplanted for NLM in the US, both before and after the introduction of the MELD scoring system in 2002. The UNOS/OPTN database was reviewed to identify patients diagnosed with NLM who subsequently underwent a liver transplantation from 1988 to March 2011 (n = 184); Patient survival was determined using Kaplan-Meier methods and log-rank tests, and cox regression analysis was performed, using SPSS 15.0 (SPSS, Inc, Chicago, IL). The overall NLM patient survivals in the pre-MELD era were 79.5%, 61.4%, and 49.2% at 1, 3, and 5 years, respectively. After the introduction of the MELD score, NET/NLM patients had improved overall patient survivals at 1, 3, and 5 years of 84.7%, 65%, and 57.8%. Patients transplanted after 2002 had an improved survival outcome. Notably, the overall patient survival for NET is not significantly different when compared to the outcomes of patients transplanted for HCC, in the current era. This progress acknowleges the significant improvement in outcomes for NLM patients after liver transplantation and the potential for further gain in the survival of otherwise nonsurgical, terminal patients. PMID- 22254142 TI - Multiple pregnancy after gonadotropin-intrauterine insemination: an unavoidable event? AB - Objective. Determine which factors predict multiple pregnancy in gonadotropin intrauterine insemination cycles so that cancellation criteria might be developed. Study Design. Retrospective chart review of all patients undergoing gonadotropin-intrauterine insemination over a continuous 36 month period. Results. No factors examined were able to predict the occurrence of multiple pregnancy. Conclusion. Multiple pregnancy is an unavoidable complication of gonadotropin-intrauterine insemination treatment. PMID- 22254140 TI - Pediatric stroke: a review. AB - Stroke is relatively rare in children, but can lead to significant morbidity and mortality. Understanding that children with strokes present differently than adults and often present with unique risk factors will optimize outcomes in children. Despite an increased incidence of pediatric stroke, there is often a delay in diagnosis, and cases may still remain under- or misdiagnosed. Clinical presentation will vary based on the child's age, and children will have risk factors for stroke that are less common than in adults. Management strategies in children are extrapolated primarily from adult studies, but with different considerations regarding short-term anticoagulation and guarded recommendations regarding thrombolytics. Although most recommendations for management are extrapolated from adult populations, they still remain useful, in conjunction with pediatric-specific considerations. PMID- 22254143 TI - Screening for Intimate Partner Violence against Women in Healthcare Sweden: Prevalence and Determinants. AB - We assessed the extent to which healthcare providers at a large healthcare facility in Sweden screen for intimate partner violence against women and the determinants of such screening. Data on frequency of screening, readiness to screen on many dimensions (using the Domestic Violence Healthcare Provider Survey Scale), demographic and occupational characteristics were administered electronically to 217 healthcare providers. We found that only 50% of participants had during the past 3 month screened for IPV at least once, and screening activity was marked with inequalities in measured individual characteristics. Participants of female gender and of doctor/nurse occupation were more likely to screen than male and midwife peers, respectively. Healthcare providers who perceived high efficacy in handling IPV issues, low fears of offending clients, professional preparedness, and with availability of support networks for IPV victims were more likely to screen for IPV. Implications of these findings for interventions are discussed. PMID- 22254145 TI - Modelling tauopathies in Drosophila: insights from the fruit fly. AB - Drosophila melanogaster is an experimentally tractable model organism that has been used successfully to model aspects of many human neurodegenerative diseases. Drosophila models of tauopathy have provided valuable insights into tau-mediated mechanisms of neuronal dysfunction and death. Here we review the findings from Drosophila models of tauopathy reported over the past ten years and discuss how they have furthered our understanding of the pathogenesis of tauopathies. We also discuss the multitude of technical advantages that Drosophila offers, which make it highly attractive as a model for such studies. PMID- 22254146 TI - Leptin: a novel therapeutic target in Alzheimer's disease? AB - It is well established that the hormone leptin circulates in the plasma in amounts proportional to body fat content and it regulates food intake and body weight via its actions in the hypothalamus. However, numerous studies have shown that leptin receptors are widely expressed throughout the CNS and evidence is growing that leptin plays a role in modulating a variety of neuronal processes. In particular, recent studies have highlighted a potential cognitive enhancing role for leptin as it regulates diverse aspects of hippocampal synaptic function that are thought to underlie learning and memory processes including glutamate receptor trafficking, dendritic morphology, and activity-dependent synaptic plasticity. Characterisation of the novel actions of leptin in limbic brain regions is providing valuable insights into leptin's role in higher cognitive functions in health and disease. PMID- 22254148 TI - Prognostic factors for thyroid carcinoma originating from follicular cells. PMID- 22254147 TI - Autoimmune thyroid disorders. PMID- 22254149 TI - Inflammation and Parkinson's disease. PMID- 22254144 TI - Alzheimer's Disease: APP, Gamma Secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and Their Relationships with Herpes Simplex, C. Pneumoniae, Other Suspect Pathogens, and the Immune System. AB - Alzheimer's disease susceptibility genes, APP and gamma-secretase, are involved in the herpes simplex life cycle, and that of other suspect pathogens (C. pneumoniae, H. pylori, C. neoformans, B. burgdorferri, P. gingivalis) or immune defence. Such pathogens promote beta-amyloid deposition and tau phosphorylation and may thus be causative agents, whose effects are conditioned by genes. The antimicrobial effects of beta-amyloid, the localisation of APP/gamma-secretase in immunocompetent dendritic cells, and gamma secretase cleavage of numerous pathogen receptors suggest that this network is concerned with pathogen disposal, effects which may be abrogated by the presence of beta-amyloid autoantibodies in the elderly. These autoantibodies, as well as those to nerve growth factor and tau, also observed in Alzheimer's disease, may well be antibodies to pathogens, due to homology between human autoantigens and pathogen proteins. NGF or tau antibodies promote beta-amyloid deposition, neurofibrillary tangles, or cholinergic neuronal loss, and, with other autoantibodies, such as anti-ATPase, are potential agents of destruction, whose formation is dictated by sequence homology between pathogen and human proteins, and thus by pathogen strain and human genes. Pathogen elimination in the ageing population and removal of culpable autoantibodies might reduce the incidence and offer hope for a cure in this affliction. PMID- 22254150 TI - Critical aspects of clinical trial design for novel cell and gene therapies. AB - Neural cell transplantation and gene therapy have attracted considerable interest as promising therapeutic alternatives for patients with Parkinson's disease (PD). Preclinical and open-label studies have suggested that grafted fetal neural tissue or viral vector gene transfer can achieve considerable biochemical and clinical improvements, whereas subsequent double-blind, placebo-controlled protocols have produced rather more modest and variable results. Detailed evaluation of these discordant findings has highlighted several crucial issues such as patient selection criteria, details surrounding transplantation or gene therapy methodologies, as well as the study designs themselves that ought to be carefully considered in the planning phases of future clinical trials. Beyond the provision of symptomatic efficacy and safety data, it also remains to be identified whether the possibilities offered by stem cell and gene therapy technological advances might translate to meaningful neuroprotection and/or disease-modifying effects or alleviate the nonmotor aspects of PD and thus offer additional benefits beyond those achieved through conventional pharmacotherapy or deep brain stimulation (DBS). PMID- 22254152 TI - Potential Infectious Etiology of Behcet's Disease. AB - Behcet's disease is a multisystem inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. The cause of Behcet's disease remains unknown, but epidemiologic findings suggest that an autoimmune process is triggered by an environmental agent in a genetically predisposed individual. An infectious agent could operate through molecular mimicry, and subsequently the disease could be perpetuated by an abnormal immune response to an autoantigen in the absence of ongoing infection. Potentia bacterial are Saccharomyces cerevisiae, mycobacteria, Borrelia burgdorferi, Helicobacter pylori, Escherichia coli, Staphylococcus aureus, and Mycoplasma fermentans, but the most commonly investigated microorganism is Streptococcus sanguinis. The relationship between streptococcal infections and Behcet's disease is suggested by clinical observations that an unhygienic oral condition is frequently noted in the oral cavity of Behcet's disease patients. Several viral agents, including herpes simplex virus-1, hepatitis C virus, parvovirus B19, cytomegalovirus, Epstein-Barr virus and varicella zoster virus, may also have some role. PMID- 22254151 TI - The neuroprotective disease-modifying potential of psychotropics in Parkinson's disease. AB - Neuroprotective treatments in Parkinson's disease (PD) have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, alpha synuclein, reactive oxygen species (ROS), reactive nitrogen species (RNS), apoptosis, inflammation, and trophic factors including GDNF and BDNF. PMID- 22254154 TI - Prospect of cell therapy for Parkinson's disease. AB - The hallmark of Parkinson's disease is on-going degeneration of dopaminergic neurons in the substantia nigra, which may be due to various etiologies. Various approaches to alleviate symptoms are available, such as life-long pharmacological intervention, deep brain stimulation, and transplantation of dopaminergic neuron containing fetal tissue. However, each of these approaches has a disadvantage. Several studies have shown that various kinds of stem cells, induced pluripotent stem cells, and other cells can differentiate into dopaminergic neurons and may be promising for treating Parkinson's disease in the future. Therefore, this review addresses those cells in terms of their prospects in cell therapy for Parkinson's disease. In addition, the need for safety and efficacy studies, various cell delivery modes and sites, and possible side effects will be discussed. PMID- 22254153 TI - Induced pluripotent stem cells and personalized medicine: current progress and future perspectives. AB - Generation of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. iPSCs can self-renew and can differentiate into many cell types, offering a potentially unlimited source of cells for targeted differentiation into somatic effector cells. Hence, iPSCs are likely to be invaluable for therapeutic applications and disease-related research. In this review, we summarize the recent progress of iPSC generation that has been made with an emphasis on both basic and clinical applications including disease modeling, drug toxicity screening/drug discovery and cell replacement therapy. PMID- 22254155 TI - Laminar flow activation of ERK5 leads to cytoprotective effect via CHIP-mediated p53 ubiquitination in endothelial cells. AB - Atherosclerosis is readily observed in areas where disturbed flow is formed, while the atheroprotective region is found in areas with steady laminar flow (L flow). It has been established that L-flow protects endothelial cells against endothelial dysfunction, including apoptosis and inflammation. It has also been reported that extracellular signal-regulated kinase 5 (ERK5) regulated endothelial integrity and protected endothelial cells from vascular dysfunction and disease under L-flow. However, the molecular mechanism by which L-flow induced ERK5 activation inhibits endothelial apoptosis has not yet been determined. Transcription factor p53 is a major pro-apoptotic factor which contributes to apoptosis in various cell types. In this study, we found that 15 deoxy-Delta(12,14)-prostaglandin J(2) induced p53 expression and that endothelial apoptosis was reduced under the L-flow condition. This anti-apoptotic response was reversed by the biochemical inhibition of ERK5 activation. It was also found that activation of ERK5 protected endothelial apoptosis in a C terminus of Hsc70 interacting protein (CHIP) ubiquitin ligase-dependent manner. Moreover, molecular interaction between ERK5-CHIP and p53 ubiquitination were addressed with a CHIP ubiquitin ligase activity assay. Taken together, our data suggest that the ERK5 CHIP signal module elicited by L-flow plays an important role in the anti apoptotic mechanism in endothelial cells. PMID- 22254156 TI - Morphological evidences in circumvallate papilla and von Ebners' gland development in mice. AB - In rodents, the circumvallate papilla (CVP), with its underlying minor salivary gland, the von Ebners' gland (VEG), is located on the dorsal surface of the posterior tongue. Detailed morphological processes to form the proper structure of CVP and VEG have not been properly elucidated. In particular, the specific localization patterns of taste buds in CVP and the branching formation of VEG have not yet been elucidated. To understand the developmental mechanisms underlying CVP and VEG formation, detailed histological observations of CVP and VEG were examined using a three-dimensional computer-aided reconstruction method with serial histological sections and pan-Cytokeratins immunostainings. In addition, to define the developmental processes in CVP and VEG formation, we examined nerve innervations and cell proliferation using microinjections of AM1 43 and immunostainings with various markers, including phosphoinositide 3-kinase, Ki-67, PGP9.5, and Ulex europaeus agglutinin 1 (UEA1). Results revealed specific morphogenesis of CVP and VEG with nerve innervations patterns, evaluated by the coincided localization patterns of AM1-43 and UEA1. Based on these morphological and immunohistochemical results, we suggest that nerve innervations and cell proliferations play important roles in the positioning of taste buds in CVP and branching morphogenesis of VEG in tongue development. PMID- 22254158 TI - Different expressions of AQP1, AQP4, eNOS, and VEGF proteins in ischemic versus non-ischemic cerebropathy in rats: potential roles of AQP1 and eNOS in hydrocephalic and vasogenic edema formation. AB - In this study, expressions of aquaporin (AQP) 1, AQP4, endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor in blood-cerebrospinal fluid (CSF) barrier and blood-brain barrier (BBB) are examined in rat choroid plexus and peri-infarcted hippocampal formation (HF) following systemic hyponatremia (SH) and permanent middle cerebral artery occlusion (pMCAO). These events are thought to cause the development of hydrocephalic and vasogenic edemas. The importance of CSF overproduction and intact blood-CSF barrier during hydrocephalic edema formation is demonstrated by the high expression of AQP1 (329.86+/-10.2%, n=4 , P<0.01) and trapped plasma immunoglobulin G (IgG) in choroid plexus epithelium after 24 hours of SH. However, the increased eNOS expression in peri-infarcted HF (130+/-3%, n=4, P<0.01) and extravasation of plasma IgG into the extravascular compartment after 24 hours of pMCAO suggest that increased microvascular permeability, probably due to elevated levels of nitric oxide, leads to development of vasogenic brain edema via BBB breakdown. Based on these findings, the authors suggest that modulation of different protein expression, dependent on the type of brain edema, is required for primary (pMCAO) and secondary (SH) brain injuries to attenuate brain edema and neuronal degeneration. PMID- 22254157 TI - Histological and immunohistochemical studies on the epididymal duct in the dromedary camel (Camelus dromedarius). AB - This study was conducted to underscore the spatial distribution of some biologically active proteins within the epididymal duct in the dromedary camel. Paraffin-embedded sections from different regions of epididymis were stained by conventional histological techniques and by immunohistochemistry. A battery of primary antibodies against six proteins (S100, alpha smooth muscle actin [alpha SMA], connexin-43 [Cx43], galactosyltransferase [GalTase], angiotensin converting enzyme [ACE], and vascular endothelial growth factor [VEGF]) were used. The epididymal epithelium consisted of five cell populations: principal, basal, apical, dark, and halo cells. The histochemical findings indicated the absence of binding sites for VEGF and Cx43. The principal cells (PCs) showed variable immunoreactivity (IR) for ACE, S100, and GalTase throughout the whole length of the duct. The apical surfaces of most PCs (at the caput) and some PCs (at the corpus) exhibited intense ACE-IR, whereas those at the cauda displayed alternating negative and strong immunostaining. Similarly, moderate S100-IR was found in cytoplasm and nuclei of all PCs at the caput, few PCs at the corpus, and several PCs alternating with negative PCs at the cauda. In contrast, only some PCs showed weak to strong GalTase-IR in different regions. Apart from negative to weak positive S100-IR, basal cells failed to show IR for all other proteins. Apical cells displayed strong IR for ACE, S100, and GalTase with some regional differences. The peritubular and vascular smooth muscle cells revealed strong alpha-SMA-IR in all regions. In conclusion, the spatial distribution of different proteins in camel epididymis showed similarities and differences to other mammalian species. The region-specific topographic distribution of different proteins and cell types might indicate that the caput and cauda are metabolically more active than that of the corpus. PMID- 22254159 TI - The use of Stronger Neo-Minophagen C, a glycyrrhizin-containing preparation, in robust neuroprotection in the postischemic brain. AB - Stronger Neo-Minophagen C (SNMC) is a glycyrrhizin-containing preparation that is approved in Japan for the treatment of chronic hepatic diseases and is marketed in Japan, China, Korea, Taiwan, and India. Glycyrrhizin, a triterpene present in the roots and rhizomes of licorice (Glycyrrhiza glabra) has been shown to have anti-inflammatory, anti-oxidative, and anti-viral effects. In the present study, we demonstrated the marked neuroprotective effects of SNMC in the postischemic rat brain after middle cerebral artery occlusion (MCAO). We used 1 ml/kg of SNMC, which is within the dose range used for the treatment of patients with chronic hepatic disease. The administration of SNMC intravenously at 30 minutes before or 30 minutes and 3 hours after MCAO (60 minutes) reduces mean infarct volumes to 27.0+/-4.2%, 37.1+/-12.4%, and 67.8+/-5.8% of that of untreated controls, respectively. This neuroprotective effect is accompanied by improvements in motor impairment and neurological deficits. The administration of SNMC is shown to suppress microglia activation and neutrophil infiltration in the postischemic brain. In addition, SNMC suppresses lipopolysaccharide-induced nitrite production and proinflammatory cytokine induction in a microglia cell line, BV2. This indicates that the neuroprotective effect of SNMC might be due, at least in part, to an anti-inflammatiory effect. Interestingly, SNMC shows significantly higher neuroprotective potency compared to an equivalent dose of pure glycyrrhizin, in terms of reducing infarct volume and improving neurological deficits. Together these results indicate that SNMC, a glycyrrhizin-containing preparation developed for chronic liver disease, has a marked neuroprotective function in the postischemic brain via its anti-inflammatory effects. PMID- 22254160 TI - Morphological and functional evaluation of an animal model for the retinal degeneration induced by N-methyl-N-nitrosourea. AB - The retinal degeneration (RD) is a general cause of blindness. To study its pathophysiology and evaluate the effects of new therapeutic agents before clinical trials, it is essential to establish reliable and stable animal models. This study evaluated a RD animal model in which blindness was induced by N-methyl N-nitrosourea (MNU), a potent retinotoxin leading to apoptosis of photoreceptors. MNU was applied to the Sprague-Dawley rats by a single intraperitoneal injection in different doses (40, 50, and 60 mg/kg). The retinal functions were examined at 1 week after MNU injection by electroretinogram (ERG). Afterwards, each retina was examined by hematoxylin and eosin stain and immunohistochemistry with anti glial fibrillary acidic protein antibody. Upon MNU injection of 40, 50 and 60 mg/kg, the ERG amplitude of a-waves showed significant reductions of 7, 26, and 44%, respectively, when compared to that of normal a-waves. The b-wave amplitudes were about 89, 65, and 58% of normal b-waves in the response to scotopic light stimulus. At 1 week, 2 weeks, and 4 weeks after MNU injection (50 mg/kg), all scotopic ERG components decreased progressively. In addition, degeneration of retinal neurons was observed in a time- and dose-dependent manner after MNU injection. Taken together, functional reduction following RD induced by MNU correlates with morphological changes. Thus, this RD rat model may be a useful model to study its pathophysiology and to evaluate the effects of new therapeutic agents before clinical trials. PMID- 22254161 TI - A simple technique for morphological measurement of cerebral arterial circle variations using public domain software (Osiris). AB - This article describes a straightforward method to measure the dimensions and identify morphological variations in the cerebral arterial circle using the general-purpose software program Osiris. This user-friendly and portable program displays, manipulates, and analyzes medical digital images, and it has the capability to determine morphometric properties of selected blood vessels (or other anatomical structures) in humans and animals. To ascertain morphometric variations in the cerebral arterial circle, 132 brains of recently deceased fetuses, infants, and adults were dissected. The dissection procedure was first digitized, and then the dimensions were measured with Osiris software. Measurements of each vessel's length and external diameters were used to identify and classify morphological variations in the cerebral arterial circle. The most commonly observed anatomical variations were uni- and bilateral hypoplasia of the posterior communicating artery. This study demonstrates that public domain software can be used to measure and classify cerebral arterial circle vessels. This method could be extended to examine other anatomical regions or to study other animals. Additionally, knowledge of variations within the circle could be applied clinically to enhance diagnostic and treatment specificity. PMID- 22254162 TI - Increase in concentration of soluble HLA-G in high-quality embryos after intracytoplasmic sperm injection. AB - Non-invasive methods are normally preferred to conventional invasive methods when selecting suitable embryos to improve pregnancy rates after assisted reproduction techniques. One of the most recognized non-invasive methods is to examine the supernatants of embryo culture media. Soluble human leukocyte antigen, class I, G (sHLA-G) antigen is a non-classical class I molecule that has been widely considered as a marker of pregnancy failure or implantation success. In the current study of some Iranian patients, we examined the concentration of sHLA-G at different time points after intracytoplasmic sperm injection and compared the rates to the morphology and quality of the selected embryos. We showed that the concentration of sHLA-G increases over time in high-quality embryos. We conclude that there is a positive relationship between morphology, quality, and sHLA-G concentration. We suggest that this relationship can be used to increase the chance of a successful pregnancy. PMID- 22254163 TI - In vivo structural imaging of the cornea by polarization-resolved second harmonic microscopy. AB - The transparency and mechanical strength of the cornea are related to the highly organized three-dimensional distribution of collagen fibrils. It is of great interest to develop specific and contrasted in vivo imaging tools to probe these collagenous structures, which is not available yet. Second Harmonic Generation (SHG) microscopy is a unique tool to reveal fibrillar collagen within unstained tissues, but backward SHG images of cornea fail to reveal any spatial features due to the nanometric diameter of stromal collagen fibrils. To overcome this limitation, we performed polarization-resolved SHG imaging, which is highly sensitive to the sub-micrometer distribution of anisotropic structures. Using advanced data processing, we successfully retrieved the orientation of the collagenous fibrils at each depth of human corneas, even in backward SHG homogenous images. Quantitative information was also obtained about the submicrometer heterogeneities of the fibrillar collagen distribution by measuring the SHG anisotropy. All these results were consistent with numerical simulation of the polarization-resolved SHG response of cornea. Finally, we performed in vivo SHG imaging of rat corneas and achieved structural imaging of corneal stroma without any labeling. Epi-detected polarization-resolved SHG imaging should extend to other organs and become a new diagnosis tool for collagen remodeling. PMID- 22254164 TI - Non-contact photoacoustic tomography and ultrasonography for tissue imaging. AB - The detection of ultrasound in photoacoustic tomography (PAT) and ultrasonography (US) usually relies on ultrasonic transducers in contact with the biological tissue. This is a major drawback for important potential applications such as surgery and small animal imaging. Here we report the use of remote optical detection, as used in industrial laser-ultrasonics, to detect ultrasound in biological tissues. This strategy enables non-contact implementation of PAT and US without exceeding laser exposure safety limits. The method uses suitably shaped laser pulses and a confocal Fabry-Perot interferometer in differential configuration to reach quantum-limited sensitivity. Endogenous and exogenous inclusions exhibiting optical and acoustic contrasts were detected ex vivo in chicken breast and calf brain specimens. Inclusions down to 0.5 mm in size were detected at depths well exceeding 1 cm. The method could significantly expand the scope of applications of PAT and US in biomedical imaging. PMID- 22254165 TI - Perturbative forward solver software for small localized fluorophores in tissue. AB - In this paper a forward solver software for the time domain and the CW domain based on the Born approximation for simulating the effect of small localized fluorophores embedded in a non-fluorescent biological tissue is proposed. The fluorescence emission is treated with a mathematical model that describes the migration of photons from the source to the fluorophore and of emitted fluorescent photons from the fluorophore to the detector for all those geometries for which Green's functions are available. Subroutines written in FORTRAN that can be used for calculating the fluorescent signal for the infinite medium and for the slab are provided with a linked file. With these subroutines, quantities such as reflectance, transmittance, and fluence rate can be calculated. PMID- 22254166 TI - Extending vaterite microviscometry to ex vivo blood vessels by serial calibration. AB - The endothelial glycocalyx layer is a ~2 um thick glycosaminoglycan rich pericellular matrix expressed on the luminal surface of vascular endothelial cells, which has implications in vessel mechanics and mechanotransduction. Despite its role in vascular physiology, no direct measurement has of yet been made of vessel glycocalyx material properties. Vaterite microviscometry is a laser tweezers based microrheological method, which has been previously utilized to measure the viscosity of linear and complex fluids under flow. This form of microrheology has until now relied on complete recollection of the forward scattered light. Here we present a novel method to extend vaterite microviscometry to relatively thick samples. We validate our method and its assumptions and measure the apparent viscosity as a function of distance from the vascular endothelium. We observe a differential response in conditions designed to preserve the EGL in comparison to those designed to collapse it. PMID- 22254167 TI - Snapshot hyperspectral retinal camera with the Image Mapping Spectrometer (IMS). AB - We present a snapshot hyperspectral retinal camera with the Image Mapping Spectrometer (IMS) for eye imaging applications. The resulting system is capable of simultaneously acquiring 48 spectral channel images in the range 470 nm-650 nm with frame rate at 5.2 fps. The spatial sampling of each measured spectral scene is 350 * 350 pixels. The advantages of this snapshot device are elimination of the eye motion artifacts and pixel misregistration problems in traditional scanning-based hyperspectral retinal cameras, and real-time imaging of oxygen saturation dynamics with sub-second temporal resolution. The spectral imaging performance is demonstrated in a human retinal imaging experiment in vivo. The absorption spectral signatures of oxy-hemoglobin and macular pigments were successfully acquired by using this device. PMID- 22254168 TI - Optical coherence tomography-based freeze-drying microscopy. AB - A new type of freeze-drying microscope based upon time-domain optical coherence tomography is presented here (OCT-FDM). The microscope allows for real-time, in situ 3D imaging of pharmaceutical formulations in vials relevant for manufacturing processes with a lateral resolution of <7 MUm and an axial resolution of <5 MUm. Correlation of volumetric structural imaging with product temperature measured during the freeze-drying cycle allowed investigation of structural changes in the product and determination of the temperature at which the freeze-dried cake collapses. This critical temperature is the most important parameter in designing freeze-drying processes of pharmaceutical products. PMID- 22254169 TI - Independent component analysis of broadband near-infrared spectroscopy data acquired on adult human head. AB - The goal of this study was to investigate the ability of independent component analysis in the time-spectral domain to isolate physiological sources of functional near infrared spectroscopy signals. We apply independent component analysis to the broadband fNIRS data acquired on the human forehead at 650 different wavelengths between 700 nm and 950 nm. To induce cerebral oxygenation changes we use the breath holding paradigm. We found one major independent component during baseline and two major components during exercise. Each independent component corresponds to one oxy-hemoglobin and one deoxy-hemoglobin time courses. The corresponding characteristic spectra of changes in optical absorption suggested that one component represented vasodilation of cerebral arterioles while the delayed component represented the washout of deoxyhemoglobin either in cerebral capillaries and venules or in extra cerebral tissue. We found that both broadband and isolated wavelength data can produce similar independent components. PMID- 22254170 TI - Optical imaging of metabolism in HER2 overexpressing breast cancer cells. AB - The optical redox ratio (fluorescence intensity of NADH divided by that of FAD), was acquired for a panel of breast cancer cell lines to investigate how overexpression of human epidermal growth factor receptor 2 (HER2) affects tumor cell metabolism, and how tumor metabolism may be altered in response to clinically used HER2-targeted therapies. Confocal fluorescence microscopy was used to acquire NADH and FAD auto-fluorescent images. The optical redox ratio was highest in cells overexpressing HER2 and lowest in triple negative breast cancer (TNBC) cells, which lack HER2, progesterone receptor, and estrogen receptor (ER). The redox ratio in ER-positive/HER2-negative cells was higher than what was seen in TNBC cells, but lower than that in HER2 overexpressing cells. Importantly, inhibition of HER2 using trastuzumab significantly reduced the redox ratio in HER2 overexpressing cells. Furthermore, the combinatorial inhibition of HER2 and ER decreased the redox ratio in ER+/HER2+ breast cancer cells to a greater extent than inhibition of either receptor alone. Interestingly, trastuzumab had little impact upon the redox ratio in a cell line selected for acquired resistance to trastuzumab. Taken together, these data indicate that the optical redox ratio measures changes in tumor metabolism that reflect the oncogenic effects of HER2 activity within the cell, as well as the response of the cell to therapeutic inhibition of HER2. Therefore, optical redox imaging holds the promise of measuring response and resistance to receptor-targeted breast cancer therapies in real time, which could potentially impact clinical decisions and improve patient outcome. PMID- 22254171 TI - Automated choroidal segmentation of 1060 nm OCT in healthy and pathologic eyes using a statistical model. AB - A two stage statistical model based on texture and shape for fully automatic choroidal segmentation of normal and pathologic eyes obtained by a 1060 nm optical coherence tomography (OCT) system is developed. A novel dynamic programming approach is implemented to determine location of the retinal pigment epithelium/ Bruch's membrane /choriocapillaris (RBC) boundary. The choroid-sclera interface (CSI) is segmented using a statistical model. The algorithm is robust even in presence of speckle noise, low signal (thick choroid), retinal pigment epithelium (RPE) detachments and atrophy, drusen, shadowing and other artifacts. Evaluation against a set of 871 manually segmented cross-sectional scans from 12 eyes achieves an average error rate of 13%, computed per tomogram as a ratio of incorrectly classified pixels and the total layer surface. For the first time a fully automatic choroidal segmentation algorithm is successfully applied to a wide range of clinical volumetric OCT data. PMID- 22254172 TI - Phase-sensitive imaging of the outer retina using optical coherence tomography and adaptive optics. AB - The cone photoreceptor's outer segment (OS) experiences changes in optical path length, both in response to visible stimuli and as a matter of its daily course of renewal and shedding. These changes are of interest, to quantify function in healthy cells and assess dysfunction in diseased ones. While optical coherence tomography (OCT), combined with adaptive optics (AO), has permitted unprecedented three-dimensional resolution in the living retina, it has not generally been able to measure these OS dynamics, whose scale is smaller than OCT's axial resolution of a few microns. A possible solution is to take advantage of the phase information encoded in the OCT signal. Phase-sensitive implementations of spectral-domain optical coherence tomography (SD-OCT) have been demonstrated, capable of resolving sample axial displacements much smaller than the imaging wavelength, but these have been limited to ex vivo samples. In this paper we present a novel technique for retrieving phase information from OCT volumes of the outer retina. The key component of our technique is quantification of phase differences within the retina. We provide a quantitative analysis of such phase information and show that-when combined with appropriate methods for filtering and unwrapping-it can improve the sensitivity to OS length change by more than an order of magnitude, down to 45 nm, slightly thicker than a single OS disc. We further show that phase sensitivity drops off with retinal eccentricity, and that the best location for phase imaging is close to the fovea. We apply the technique to the measurement of sub-resolution changes in the OS over matters of hours. Using custom software for registration and tracking, these microscopic changes are monitored in hundreds of cones over time. In two subjects, the OS was found to have average elongation rates of 150 nm/hr, values which agree with our previous findings. PMID- 22254173 TI - Optoacoustic monitoring of cerebral venous blood oxygenation through extracerebral blood. AB - There is strong clinical evidence that controlling cerebral venous oxygenation (oxyhemoglobin saturation) is critically important for patients with severe traumatic brain injury as well as for patients undergoing cardiac surgery. However, the only available method for cerebral venous blood oxygenation monitoring is invasive and requires catheterization of the internal jugular vein. We designed and built a novel optoacoustic monitor of cerebral venous oxygenation as measured in the superior sagittal sinus (SSS), the large midline cerebral vein. To the best of our knowledge, optical monitoring of cerebral venous blood oxygenation through overlying extracerebral blood is reported for the first time in this paper. The system was capable of detecting SSS signals in vivo at 700, 800, and 1064 nm through the thick (5-6 mm) sheep skull containing the circulating blood. The high (submillimeter) in-depth resolution of the system provided identification of the SSS peaks in the optoacoustic signals. The SSS peak amplitude closely followed the actual SSS blood oxygenation measured invasively using catheterization, blood sampling, and "gold standard" CO Oximetry. Our data indicate the system may provide accurate measurement of the SSS blood oxygenation in patients with extracerebral blood over the SSS. PMID- 22254174 TI - Semi-empirical model of the effect of scattering on single fiber fluorescence intensity measured on a turbid medium. AB - Quantitative determination of fluorophore content from fluorescence measurements in turbid media, such as tissue, is complicated by the influence of scattering properties on the collected signal. This study utilizes a Monte Carlo model to characterize the relationship between the fluorescence intensity collected by a single fiber optic probe (F(SF)) and the scattering properties. Simulations investigate a wide range of biologically relevant scattering properties specified independently at excitation (lambda(x)) and emission (lambda(m)) wavelengths, including reduced scattering coefficients in the range MU'(s)(lambda(x)) ? [0.1 - 8]mm(-1) and MU'(s)(lambda(m)) ? [0.25 - 1] * MU'(s)(lambda(x)). Investigated scattering phase functions (P(theta)) include both Henyey-Greenstein and Modified Henyey-Greenstein forms, and a wide range of fiber diameters (d(f) ? [0.2 - 1.0] mm) was simulated. A semi-empirical model is developed to estimate the collected F(SF) as the product of an effective sampling volume, and the effective excitation fluence and the effective escape probability within the effective sampling volume. The model accurately estimates F(SF) intensities (r=0.999) over the investigated range of MU'(s)(lambda(x)) and MU'(s)(lambda(m)), is insensitive to the form of the P(theta), and provides novel insight into a dimensionless relationship linking F(SF) measured by different d(f). PMID- 22254175 TI - Measurement of the traction force of biological cells by digital holography. AB - The traction force produced by biological cells has been visualized as distortions in flexible substrata. We have utilized quantitative phase microscopy by digital holography (DH-QPM) to study the wrinkling of a silicone rubber film by motile fibroblasts. Surface deformation and the cellular traction force have been measured from phase profiles in a direct and straightforward manner. DH-QPM is shown to provide highly efficient and versatile means for quantitatively analyzing cellular motility. PMID- 22254176 TI - Tensor total variation approach to optical coherence tomography reconstruction for improved visualization of retinal microvasculature. AB - A novel optical coherence tomography (OCT) reconstruction approach is introduced for improved visualization of inner-retina capillaries in retinal OCT tomograms. The proposed method utilizes a minimization framework based on a tensor total variation (TTV) energy functional, to enforce capillary structural characteristics in the spatial domain. By accounting for structure tensor characteristics, the TTV reconstruction method allows for contrast enhancement of capillary structural characteristics. The novel TTV method was tested on high resolution OCT images acquired in-vivo from the foveal region of the retina of a healthy human subject. Experimental results demonstrate significant contrast and visibility enhancement of the inner retina capillaries in the retinal OCT tomograms, achieved by use of the TTV reconstruction method. Therefore, the TTV method has a strong potential for improved disease progression analysis based on the study of disease-induced changes in the inner retina vasculature. PMID- 22254177 TI - Scanning thin-sheet laser imaging microscopy (sTSLIM) with structured illumination and HiLo background rejection. AB - We report replacement of one side of a static illumination, dual sided, thin sheet laser imaging microscope (TSLIM) with an intensity modulated laser scanner in order to implement structured illumination (SI) and HiLo image demodulation techniques for background rejection. The new system is equipped with one static and one scanned light-sheet and is called a scanning thin-sheet laser imaging microscope (sTSLIM). It is an optimized version of a light-sheet fluorescent microscope that is designed to image large specimens (<15 mm in diameter). In this paper we describe the hardware and software modifications to TSLIM that allow for static and uniform light-sheet illumination with SI and HiLo image demodulation. The static light-sheet has a thickness of 3.2 um; whereas, the scanned side has a light-sheet thickness of 4.2 um. The scanned side images specimens with subcellular resolution (<1 um lateral and <4 um axial resolution) with a size up to 15 mm. SI and HiLo produce superior contrast compared to both the uniform static and scanned light-sheets. HiLo contrast was greater than SI and is faster and more robust than SI because as it produces images in two-thirds of the time and exhibits fewer intensity streaking artifacts. PMID- 22254178 TI - Fluorescence-guided optical coherence tomography imaging for colon cancer screening: a preliminary mouse study. AB - A new concept for cancer screening has been preliminarily investigated. A cancer targeting agent loaded with a near-infrared (NIR) dye was topically applied on the tissue to highlight cancer-suspect locations and guide optical coherence tomography (OCT) imaging, which was used to further investigate tissue morphology at the micron scale. A pilot study on ApcMin mice has been performed to preliminarily test this new cancer screening approach. As a cancer-targeting agent, poly(epsilon-caprolactone) microparticles (PCLMPs), labeled with a NIR dye and functionalized with an RGD (argenine-glycine-aspartic acid) peptide, were used. This agent recognizes the alpha(nu)beta(3) integrin receptor (ABIR), which is over-expressed by epithelial cancer cells. The contrast agent was administered topically in vivo in mouse colon. After incubation, the animals were sacrificed and fluorescence-guided high resolution optical coherence tomography (OCT) imaging was used to visualize colon morphology. The preliminary results show preferential staining of the abnormal tissue, as indicated by both microscopy and laser-induced fluorescence imaging, and OCT's capability to differentiate between normal mucosal areas, early dysplasia, and adenocarcinoma. Although very preliminary, the results of this study suggest that fluorescence-guided OCT imaging might be a suitable approach for cancer screening. If successful, this approach could be used by clinicians to more reliably diagnose early stage cancers in vivo. PMID- 22254179 TI - A hematoma detector-a practical application of instrumental motion as signal in near infra-red imaging. AB - In this paper we discuss results based on using instrumental motion as a signal rather than treating it as noise in Near Infra-Red (NIR) imaging. As a practical application to demonstrate this approach we show the design of a novel NIR hematoma detection device. The proposed device is based on a simplified single source configuration with a dual separation detector array and uses motion as a signal for detecting changes in blood volume in the dural regions of the head. The rapid triage of hematomas in the emergency room will lead to improved use of more sophisticated/expensive imaging facilities such as CT/MRI units. We present simulation results demonstrating the viability of such a device and initial phantom results from a proof of principle device. The results demonstrate excellent localization of inclusions as well as good quantitative comparisons. PMID- 22254180 TI - Improving signal-to-noise ratio of structured light microscopy based on photon reassignment. AB - In this paper, we report a method for 3D visualization of a biological specimen utilizing a structured light wide-field microscopic imaging system. This method improves on existing structured light imaging modalities by reassigning fluorescence photons generated from off-focal plane excitation, improving in focus signal strength. Utilizing a maximum likelihood approach, we identify the most likely fluorophore distribution in 3D that will produce the observed image stacks under structured and uniform illumination using an iterative maximization algorithm. Our results show the optical sectioning capability of tissue specimens while mostly preserving image stack photon count, which is usually not achievable with other existing structured light imaging methods. PMID- 22254181 TI - Boosted classification trees result in minor to modest improvement in the accuracy in classifying cardiovascular outcomes compared to conventional classification trees. AB - PURPOSE: Classification trees are increasingly being used to classifying patients according to the presence or absence of a disease or health outcome. A limitation of classification trees is their limited predictive accuracy. In the data-mining and machine learning literature, boosting has been developed to improve classification. Boosting with classification trees iteratively grows classification trees in a sequence of reweighted datasets. In a given iteration, subjects that were misclassified in the previous iteration are weighted more highly than subjects that were correctly classified. Classifications from each of the classification trees in the sequence are combined through a weighted majority vote to produce a final classification. The authors' objective was to examine whether boosting improved the accuracy of classification trees for predicting outcomes in cardiovascular patients. METHODS: We examined the utility of boosting classification trees for classifying 30-day mortality outcomes in patients hospitalized with either acute myocardial infarction or congestive heart failure. RESULTS: Improvements in the misclassification rate using boosted classification trees were at best minor compared to when conventional classification trees were used. Minor to modest improvements to sensitivity were observed, with only a negligible reduction in specificity. For predicting cardiovascular mortality, boosted classification trees had high specificity, but low sensitivity. CONCLUSIONS: Gains in predictive accuracy for predicting cardiovascular outcomes were less impressive than gains in performance observed in the data mining literature. PMID- 22254182 TI - Control of eotaxin-1 expression and release by resveratrol and its metabolites in culture human pulmonary artery endothelial cells. AB - Population studies suggest that moderate red wine intake correlates with reduced risk of cardiovascular disease (CVD); cardioprotection may attribute to consumption of red wine polyphenol resveratrol. Since inflammation plays a key role in CVD, we investigated modulation of inflammation by resveratrol and its metabolites by determining the expression and release of chemokine, eotaxin-1, in cultured human pulmonary artery endothelial cells (HPAEC) treated with proinflammatory cytokines IL-13 and TNF-alpha. Up-regulation of eotaxin-1 gene expression by IL-13 or TNF-alpha was confirmed by RT-PCR, by reporter assays using eotaxin-1 gene promoter constructs, and by the changes in transcriptional factors STAT6 and NF-kappaB. Exposure to resveratrol suppressed IL-13 and TNF alpha induced eotaxin-1 gene expression as well as attenuated the eotaxin-1 promoter activity, in coordination with inhibition of expression of JAK-1, reduction in phosphorylated-STAT6 and decreased p65 subunit of NF-kappaB. In addition, quantitative determination of eotaxin-1 release using enzyme-linked immunosorbent assay (ELISA) showed increased eotaxin-1 release in response to treatment by IL-13 and TNF-alpha, which was effectively inhibited by resveratrol. Whether resveratrol metabolites affected eotaxin-1 was also tested; piceatannol showed potency similar to resveratrol. We propose that control of eotaxin-1 expression and release by proinflammatory cytokines in HPAEC may be considered as an in vitro model for screening and discovering polyphenols with anti inflammatory activities and cardioprotective potentials. PMID- 22254183 TI - Quantitative angiography in South Asians reveals differences in vessel size and coronary artery disease severity compared to Caucasians. AB - South Asians are one of the highest risk ethnic groups for development of coronary artery disease (CAD) mortality and morbidity. Previous studies have investigated whether South Asians exhibit differences in angiographic coronary artery disease compared to Caucasians, with inconsistent results. We conducted a retrospective observational study comparing South Asians undergoing cardiac catheterization at a tertiary care institution with Caucasians who underwent catheterization at the same time and location to assess whether South Asians demonstrated smaller coronary artery size and/or increased angiographic coronary artery disease. Demographic and laboratory data were retrospectively abstracted. Quantitative coronary angiographic analysis of all three coronary arteries was performed using the edge-detection method. South Asian patients were younger (57 versus 64 years, p=0.004) and showed higher prevalences of diabetes, dyslipidemia, and acute coronary syndrome compared with Caucasians (40% versus 16%, p=0.004; 65% versus 46%, p=0.04; and 37% versus 10%, p<0.001; respectively). South Asians exhibited smaller normalized proximal LAD luminal diameters (1.56 versus 1.72 mm/m(2), p=0.04) when compared to Caucasians. South Asians also displayed more severe CAD as determined by both increased mean percent stenosis in the proximal LAD and RCA segments (22.7% versus 11.1%, p=0.004; and 24.5% versus 13.9%, p=0.0001, respectively) as well as a higher number of patients with multiple diseased vessel segments. South Asians demonstrated more severe CAD compared to Caucasians undergoing cardiac catheterization as evidenced by smaller proximal LAD luminal diameters, higher mean percent stenosis per vessel, and more patients with multivessel disease. Further study is warranted to better define factors important in the development of CAD and inform risk stratification in this high-risk population. PMID- 22254184 TI - Cardioprotection by resveratrol: a review of effects/targets in cultured cells and animal tissues. AB - The most widespread form of cardiovascular disease (CVD) in the western world today is atherosclerosis (AS), notably of the major arteries. Despite decades of laboratory, animal, and clinical investigation providing multiple leads and intervention strategies that have resulted in a progressive decline in CVD related mortality rates, the etiology of AS is incomplete; hence, the need for management and prevention remains imperative. AS is initiated by endothelial cell (EC) injury whereas its progression is promoted by EC interaction with cells that are recruited to the injured endothelium, and additionally, bioactive cytokines and chemokines elaborated by the intercellular interplay. A primary research interest of our laboratory has been the mechanisms that underlie the "French paradox" - an epidemiological association of the co-existence of risk factors with low CVD incidence/mortality rates postulated to attribute to low-to-moderate consumption of red wine and grape-derived polyphenol resveratrol. This review summarizes effects and targets of resveratrol in cultured human aortic and pulmonary aortic endothelial cells (HAEC and HPAEC) and animal tissues, with focus on the resveratrol target protein RTP, N-ribosyldihydro nicotinamide:quinone oxidoreductase (NQO2). PMID- 22254186 TI - Acute exercise with whole-body vibration decreases wave reflection and leg arterial stiffness. AB - AIM: Whole-body vibration exercise (WBV) acutely decreases brachial-ankle pulse wave velocity (baPWV), an index of systemic arterial stiffness. However, the effect of WBV on segmental PWV and aortic hemodynamics is unknown. We examined the acute effects of WBV on arterial function. METHODS: Fifteen young men performed ten 1-min sets of static squat with WBV (40 Hz, 1 mm, 5.37 G) and without WBV (no-WBV). Brachial and aortic blood pressure (BP), heart rate (HR), augmentation index (AIx), baPWV, carotid-femoral PWV (cfPWV), and femoral-ankle (faPWV), were recorded before and 5, 15, and 30 min after both trials. RESULTS: Brachial and aortic SBP (P < 0.01), and HR (P < 0.01) were increased only at 5 min after both exercise trials. AIx was elevated through the recovery after no WBV while decreased at 15 and 30 min after WBV exercise. FaPWV was decreased (P < 0.01) at 5 min after both trials, but returned to baseline at 15 min after no-WBV exercise and was maintained decreased at 15 and 30 min after WBV exercise. There were no significant changes in brachial and aortic diastolic BP, cfPWV and baPWV after both trials. CONCLUSIONS: Our findings indicate that regardless of WBV, static squat causes a small transient increase in hemodynamic responses during early recovery. WBV counteracts the increase in AIx induced by static squat and reduces wave reflection magnitude through a local effect on arterial stiffness. PMID- 22254185 TI - Plasma neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (a-MSH) levels in patients with or without hypertension and/or obesity: a pilot study. AB - AIM: Obesity frequently co-exists with hypertension (HTN). Hypothalamus neuropeptides such as neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (a-MSH) interact with leptin, an anorexic peptide produced mainly by adipose tissue and are involved in the regulation of appetite, energy balance and sympathetic nervous system (SNS) activity, possibly contributing to blood pressure (BP) elevation. We compared plasma NPY and a-MSH levels between patients with or without hypertension and/or obesity and the differences in these neuropeptides between patients with or without pathological heart echo findings, aiming to investigate the possible role of these peptides in obesity induced HTN. PATIENTS AND METHODS: 160 non-diabetic, treatment-naive individuals were randomly recruited from our outpatient clinics. Study population was divided into 6 groups, according to body mass index-BMI (OB=obese, OW=overweight, NW=normal weight) and blood pressure. Waist circumference (WC) and heart rate (HR) were also recorded. A heart echo was performed and plasma NPY and a-MSH levels were measured for all participants. RESULTS: Plasma NPY levels and HR were higher in OW and OB hypertensives compared with NW hypertensives. OW and OB hypertensives had also higher NPY concentrations compared with OW and OB normotensives, respectively. However, in NW patients, plasma NPY concentrations did not differ between hypertensives and normotensives. Patients with central obesity (COB) had also higher NPY levels compared with patients without COB, a difference also observed in hypertensives but not in normotensive patients. Furthermore, plasma NPY concentrations were significantly correlated with BMI, WC, HR, systolic and diastolic BP. Patients with left ventricle hypertrophy had higher plasma NPY levels compared with those with normal findings, but this was not seen in hypertensives. The majority of these differences were also observed in male and female patient populations. In contrast, plasma a-MSH levels were similar in all study groups. CONCLUSIONS: These results suggest that NPY may be involved in obesity-related HTN, possibly via increased SNS activity. Further investigation is needed to elucidate the role of both NPY and a-MSH in obesity-related HTN. PMID- 22254187 TI - Characterization of macro-and microvascular function and structure in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Diabetes mellitus (DM) leads to accelerated progression of arteriosclerosis with an increased risk of coronary events in comparison to non diabetic patients with coronary artery disease (CAD). The precise and early detection of DM-induced vascular alterations is crucial to identify patients with high risk for cardiovascular complications. Thus, we aimed at simultaneously characterizing functional, physicomechanical, and structural vascular alterations in diabetic patients using a non-invasive approach. RESEARCH DESIGN AND METHODS: In CAD patients with and without type 2 diabetes mellitus (n=50), we non invasively measured flow-mediated dilation (FMD) of the brachial artery as a marker for endothelial function, fractional diameter changes (FDC) as a marker for physicomechanical properties, intima-media thickness (IMT) as a marker for structural properties, and forearm blood flow (FBF) as a marker for microvascular function. RESULTS: DM was associated with reduced FMD (2.5+/-0.2 vs 4.8+/-0.4%; p<=0.001) indicating impaired macrovascular endothelial function. In parallel, reduced FDC (0.024+/-0.002 vs 0.034+/-0.004; p<=0.05) and increased IMT (0.38+/ 0.01 vs 0.31+/-0.01mm; p<=0.001) indicated increased stiffness and enhanced structural alterations. Furthermore, reduced forearm blood flow during reactive hyperemia (10.7+/-1.0 vs. 15.3+/-1.4mL/min*100mL; p<=0.05) was found indicating microvascular dysfunction. Plasma glucose and HbA(1c) correlated with FMD (glucose: r=-0.32; HbA(1c): r=-0.45), IMT (glucose: r=0.54; HbA(1c): r=0.48) and FBF (glucose: r=-0.30) suggesting diabetes-specific effects on vascular properties. CONCLUSION: In patients with CAD, DM leads to functional and structural vascular alterations of the peripheral vasculature which are determined by the control of the disease underlining the relevance of a strict control of the DM to prevent accelerated atherosclerosis. PMID- 22254188 TI - Periodontitis and coronary artery disease: a questioned association between periodontal and vascular plaques. AB - Periodontitis is a bacterially-induced, localized chronic inflammatory disease destroying both the connective tissue and the supporting bone of the teeth. In the general population, severe forms of the disease demonstrate a prevalence of almost 5%, whereas initial epidemiological evidence suggests an association between periodontitis and coronary artery disease (CAD). Both the infectious nature of periodontitis and the yet etiologically unconfirmed infectious hypothesis of CAD, question their potential association. Ephemeral bacteremia, systemic inflammation and immune-pathological reactions constitute a triad of mechanisms supporting a cross-talk between periodontal and vascular damage. To which extent each of these periodontitis-mediated components contribute to vascular damage still remains uncertain. More than twenty years from the initial epidemiological association, the positive weight of evidence remains still alive but rather debated, because of both the presence of many uncontrolled confounding factors and the different assessment of periodontal disease. From the clinical point of view, advising periodontal prevention or treatment targeting on the prevention of CAD it is unjustified. By contrast, oral hygiene including periodontal health might contribute to the overall well-being and healthy lifestyle and hence as might at least partially contribute to cardiovascular prevention. PMID- 22254190 TI - The launch of American Journal of Cardiovascular Disease. PMID- 22254189 TI - Relation of components of the metabolic syndrome to left ventricular geometry in hispanic and non-hispanic black adults. AB - BACKGROUND: Left ventricular (LV) hypertrophy is an independent predictor of increased cardiovascular morbidity and mortality. It remains unclear whether components of the metabolic syndrome are associated with LV hypertrophy. METHODS AND RESULTS: Accordingly, we analyzed echocardiograms in 192 consecutive ambulatory patients referred for echocardiography from October to December 2004. Patients were excluded if they had atrial fibrillation, significant valvular heart disease or failed to cooperate for echocardiogram. Of these, 126 (66%) patients met Adult Treatment Panel (ATP) III diagnostic criteria for the metabolic syndrome. 29% had any 3 metabolic syndrome components, 18% had any 4 metabolic syndrome components and 17% had all 5 metabolic syndrome components. In analyses of variance adjusted for age and sex, LV mass and LV mass adjusted to its allometric relation to height(2.7) (LV mass/height(2.7)) were higher in patients with metabolic syndrome compared to those without metabolic syndrome (237 g [228-239 95%CI] vs. 224 g [206-239 95%CI] p=0.005 and 62 g/m(2.7) [59-65 95%CI] vs. 56 g/m(2.7) [52-60 95%CI] p=0.014, respectively). The prevalence of LV hypertrophy using prognostically-validated gender-specific partition values for LV mass/height(2.7) was significantly higher in metabolic syndrome patients than in those without metabolic syndrome (81 v. 58%, p<0.001). There was a step-wise increase in LV mass/height(2.7) in those with no metabolic syndrome components to those with increasing number of metabolic syndrome components (Figure, p<0.001). In this study of high-risk patients, the significant independent predictors of LV hypertrophy were only high blood pressure (OR=3.2, p=0.008) and increased waist circumference (OR=2.8, p=0.006) with no interaction between blood pressure and waist circumference. CONCLUSION: Metabolic syndrome is associated with higher LV mass and prevalence of LV hypertrophy. Increasing number of metabolic syndrome components is associated with step-wise increases in LV mass. Identification of LV hypertrophy in metabolic syndrome patients may provide an additional prognostic tool to further risk-stratify these patients. PMID- 22254191 TI - Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy? AB - Cardiac fibrosis is known to alter cardiac conduction and promote reentry. Recent evidence indicates that fibrosis characterized by increased interstitial collagen accumulation and increased myofibroblast proliferation also promotes enhanced automaticity and early afterdepolarizations (EADs) causing triggered activity. Fibrosis then becomes an effective therapeutic target for the management of lethal cardiac arrhythmias. While oxidative stress with hydrogen peroxide (H(2)O(2)) is shown to readily promote EADs and triggered activity in isolated rat and rabbit ventricular myocytes however, this same stress fails to cause EADs in well-coupled, non-fibrotic hearts due to source-to-sink mismatches arising from cell-to-cell coupling. The triggered activity in the aged fibrotic hearts causes focal ventricular tachycardia (VT) that degenerates within seconds to ventricular fibrillation (VF) after the emergence of spatially discordant action potential duration alternans leading to wavebreak, reentry and VF. Computer simulations in 2D tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or very severe) fibrosis promoted EADs and TA. Human studies have shown that myocardial fibrosis was an independent predictor for arrhythmias including sustained VT and VF. A variety of drug classes including, torsemide, a loop diuretic, that inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules and the inhibitors of the renin-angiotensin-aldosterone system (RAAS), the mineralocorticoid receptors and endothelin receptors reduce cardiac fibrosis with reduction of myocardial stiffness and improved ventricular function. It is hoped that in the near future effective antifibrotic drug regimen would be developed to reduce the risk of fibrosis related VT and VF. PMID- 22254192 TI - Point-of-care screening for left ventricular hypertrophy and concentric geometry using hand-held cardiac ultrasound in hypertensive patients. AB - BACKGROUND: The introduction of the hand-held cardiac ultrasound (HCU) may potentially increase detection of LV hypertrophy in hypertensive patients. However, whether point-of-care screening for LV hypertrophy and concentric LV geometry by HCU in hypertensive patients is feasible and comparable to that of standard state-of-the-art echocardiography (SE) evaluation remains to be elucidated. METHODS AND RESULTS: Accordingly, one hundred consecutive patients (66 female, mean age=58+/-13 years, 32% African-American, mean body mass index=31+/-8 kg/m(2)) with the diagnosis of hypertension underwent both HCU and SE examinations in tandem. A cardiology fellow-in-training performed the HCU exam while a cardiac sonographer performed the SE. 37% of hypertensive patients had electrocardiographic LV hypertrophy by Sokolow-Lyon or Cornell voltage criteria. Mean LV mass was 210+/-42 g with the HCU and 209+/-40 g with SE. Mean relative wall thickness was 0.45+/-0.05 by the HCUD and 0.44+/-0.05 by SE. There was excellent correlation between LV mass and relative wall thickness measurements by HCU and SE (r=0.985, SEE=6.8 g and r=0.762, SEE=0.33, respectively, both p<0.001). The prevalence of LV hypertrophy using prognostically-validated partition values for LV mass/height(2.7) of 46.7 and 49.2 g/m(2.7) in women and men, respectively was 76% by HCU and 78% by SE (p=NS), with excellent agreement (92%, kappa=0.774, p<0.001). Agreement for detection of concentric LV geometry (relative wall thickness>0.43) was also excellent (88%, kappa =0.756, p<0.001). Agreement for LV hypertrophy and concentric geometry detection between the cardiology fellow-in-training and sonographer was excellent (kappa =0.786, p<0.001). CONCLUSION: Point-of-care screening for LV hypertrophy and concentric LV geometry by HCU is feasible and correlates very well with that of SE. HCU may allow for immediate point-of-care assessment and treatment of cardiac target organ damage in hypertensive patients. PMID- 22254193 TI - GRK2 and beta-arrestins in cardiovascular disease: Something old, something new. AB - Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by phosphorylation of the agonist-bound receptor by the family of G-protein coupled receptor kinases (GRKs) followed by betaarrestin binding, which uncouples the phosphorylated receptor and G protein and subsequently targets the receptor for internalization. As the receptor betaarrestin complex enters the cell, betaarrestins serve as ligand-regulated scaffolds that recruit a host of intracellular proteins and signal transducers, thus promoting their own wave of signal transduction independently of G-proteins. A large number of preclinical studies in small and large animals over the past several years have pinpointed specific pathophysiologic roles played by these two families of receptor-regulating proteins in various cardiovascular diseases, directly implicating them in disease pathology and suggesting them as potential therapeutic targets. The present review gives an account of what is currently known about the benefits of cardiac GRK2 inhibition for cardiovascular disease treatment, and also discusses the exciting new therapeutic possibilities emerging from uncovering the physiological roles of adrenal GRK2 and of betaarrestin mediated signaling in vivo in the cardiovascular system. PMID- 22254194 TI - Heme oxygenase-1 in inflammation and cardiovascular disease. AB - Cardiovascular disease accounts for 1 of every 2.9 deaths in the United States, thus the burden of the disease remains high. Given the high mortality and escalating healthcare cost for the disease, it is of urgent need to treat cardiovascular disease effectively. Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to generate carbon monoxide, biliverdin, and iron. These reaction products of HO-1 have potent anti-inflammatory and anti-oxidative functions. Although HO-1 is expressed at low levels in most tissues under normal basal conditions, it is highly inducible in response to various pathophysiological stresses. Numerous studies have indicated that HO-1 induction is an adaptive defense mechanism to protect cells and tissues against injury in many disease settings. This review highlights the role of HO-1 in inflammation and several cardiovascular diseases-atherosclerosis, myocardial infarction, graft survival after heart transplantation, and abdominal aortic aneurysm. Given that inflammation and oxidative stress are associated with development of cardiovascular disease and that HO-1 has anti-inflammatory and anti-oxidative properties, HO-1 is emerging as a great potential therapeutic target for treating cardiovascular disease. PMID- 22254195 TI - CHADS(2) score is predictive of left atrial thrombus on precardioversion transesophageal echocardiography in atrial fibrillation. AB - OBJECTIVE: The goals of this study were to determine: 1) if the CHADS(2) score correlates with left atrial (LA) or left atrial appendage (LAA) thrombus on pre cardioversion transesophageal echocardiography (TEE) in nonvalvular atrial fibrillation (NVAF); and 2) what, if any, components of the CHADS(2) score are most important in predicting LA/LAA thrombus. BACKGROUND: It is unknown if CHADS(2) score, a marker of thromboembolic risk in NVAF, accurately predicts LA/LAA thrombus on pre-cardioversion TEE. METHODS: We retrospectively studied patients undergoing precardioversion TEE for NVAF at a tertiary hospital. TEE reports were reviewed for presence of LA/LAA thrombus. Using medical records and an ICD-9 coding database, a CHADS(2) score was derived, and the association between CHADS(2) and thrombus was evaluated with Mantel-Haenszel Chi-Square. The relation between the singular components of CHADS(2) and thrombus were analyzed using Pearson's Chi-Square. RESULTS: In 643 consecutive patients undergoing pre cardioversion TEE, LA/LAA thrombus was identified in 46 (7.2 %). A strong association was present between CHADS(2)score and LA/LAA thrombus (p = 0.0005). No thrombi were identified in patients with CHADS(2) = 0. Among 46 patients with thrombus, all (100%) had CHF. Of the singular components, CHF was the only factor independently associated with thrombus (p < 0.0001). CONCLUSIONS: In non-valvular atrial fibrillation, CHADS(2) is strongly associated with LA thrombus on TEE. Our findings suggest pre-cardioversion TEE may be unnecessary if the CHADS(2) score = 0. Of the components of the CHADS(2) score, CHF was the only independently associated risk factor which correlated with LA/LAA thrombus. PMID- 22254196 TI - Influence of myocardial ischemia on outcomes in patients with systolic versus non systolic heart failure. AB - BACKGROUND: Heart failure (HF) is a leading cause of adult hospitalization, morbidity, and mortality. We evaluated the influence of myocardial ischemia and left ventricular ejection fraction (LVEF) on outcomes in patients who were hospitalized with new onset HF. METHODS: We prospectively recruited 201 consecutive patients hospitalized for a first episode of HF from 17 medical centers across Europe and North America. All patients received gated single photon emission computed tomographic testing with standardized study interpretations by trained core laboratory investigators. Predefined data from routine care were collected and aggregated. Computerized scoring was performed at the core laboratory and participants with a summed difference score >=4 were defined as having myocardial ischemia. Participants were categorized as having systolic heart failure (SHF) (LVEF<40%) or nonsystolic heart failure (NS-HF) (LVEF>=40%). A proportional hazards model was used to assess the impact of clinical predictors on the outcomes of mortality, cardiac rehospitalization and a combined outcome within 2 years of study enrollment. RESULTS: 180 patients (mean age was 65.5 +/- 14.6 years and 57.2% male) fulfilled study criteria and were included. Myocardial ischemia was present in 45 (41.2%) patients with SHF and 19 (27.5%) patients with NS-HF (p <0.01). During the follow-up period, 11.1% (n=20) died and 42.2% (n=76) experienced a recurrent hospitalization. Patients with NS HF and ischemia had the highest (73.7%) event rate compared with the other cohorts (multivariate OR=3.29, 95% CI 1.69-6.42, p=0.001). CONCLUSIONS: In new onset HF, those with NS-HF and myocardial ischemia are at the highest risk for poor outcomes. PMID- 22254197 TI - Echocardiographic findings and abnormalities in HIV-infected patients: results from a large, prospective, multicenter HIV-heart study. AB - AIMS: The aim of the current study was to assess cardiac structure and function as well as cardiac abnormalities in a large patient-population based multicenter study of HIV-infected subjects. MATERIALS AND METHODS: We enrolled 803 HIV positive adults (83.4% men, mean age: 44.2 +/- 10.3 yrs) in this prospective, cross-sectional cohort study. The study protocol included a standardized documentation of patient history, medical treatment and clinical examination. All subjects underwent a standardized transthoracic echocardiographic examination protocol including Doppler and tissue Doppler imaging. RESULTS: Echocardiographic measurements revealed a structural dilatation of the left ventricle in 10.1% of all HIV-infected subjects. Interventricular septum and posterior wall thickness were increased in 18.0% and 11.1%, respectively, with elevated muscle mass in 14.3% male and 19.4% female patients. Of all participants 13.5% exhibited a pathologic contraction characteristic of one or more myocardial segments. Prevalence of systolic and diastolic dysfunction was 34.3% and 48.0%, respectively. However, severe forms of ventricular dysfunction were rare. CONCLUSIONS: In conclusion our results demonstrate the relevance of echocardiography in this patient-population in the era of antiretroviral therapy. Above all, left ventricular wall thickness and function should be controlled regularly in HIV-infected subjects. (ClinicalTrials.gov number, NCT01119729). PMID- 22254198 TI - Pathogenesis of aortic stenosis: not just a matter of wear and tear. AB - Aortic valve stenosis (AS) is the commonest form of valvular heart disease in the Western world. Its prevalence increases exponentially with age and it is present in 2-7% of all patients over 65 years of age. In view of the considerable cardiovascular morbidity and mortality associated not only with AS, but even its earlier stage, aortic sclerosis, many investigations have been directed towards better understanding of its pathogenesis, with the ultimate objective of developing strategies to retard its progression. Although risk factors and downstream mediators appear similar for AS and atherosclerosis (older age, male sex, hypertension, smoking, hypercholesterolemia, and diabetes, as many as 50% of patients with AS do not have clinically significant atherosclerosis. On the basis both of recent experimental evidence and clinical trials, it appears that atherogenesis is not pivotal to the pathogenesis of AS. On the other hand, there is increasing evidence of active involvement of aortic valve fibroblasts with resultant increased production of reactive oxygen species, active pro inflammatory and pro-fibrotic processes culminating in calcification. We also discuss the evidence of involvement of the nitric oxide system in the pathogenesis of AS. The renin-angiotensin system has also emerged as a major player in the pathogenesis of AS. Histologically, there is increased ACE expression and elevated angiotensin II levels in stenotic valves, while we have just demonstrated amelioration of AS with the use of ACE inhibitors in an animal model. We further discuss intervention studies aimed at retarding AS progression, including recent failures of statins to retard progression of AS in large randomized clinical studies. Finally, we discuss the special case of bicuspid aortic valve, including its genetics and unique associated features. PMID- 22254200 TI - Anatomo-functional characterization of interatrial septum for catheter-based interventions. AB - Secundum Atrial septal defect (ASD) and Patent foramen ovale (PFO) is becoming the most popular field of interest for catheter-based interventions. While there is a common agreement about the management of ASD patients, there is no complete agreement on which is the best management of PFO patients. In PFO patients, the real challenge for the clinician, beside secondary prevention of recurrent stroke, is to understand which the higher risk patients to refer for treatment are and which is the proper device to use. In this setting, the anatomo functional characterization of interatrial septum seems to be of paramount importance for both ASD and PFO, not only for the device selection but also for therapeutic decision-making. In the present review the author overviews the main anatomic a functional characteristics of interatrial septum, obtained with the current available diagnostic tools, such as transcranial Doppler, transthoracic and transesophageal echocardiography and intracardiac echocardiography, and discusses the impact of such characteristics on catheter based closure. PMID- 22254199 TI - Hyaluronan regulation of vascular integrity. AB - Vascular integrity or the maintenance of blood vessel continuity is a fundamental process regulated, in part, by the endothelial glycocalyx and cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including atherosclerosis, ischemia/reperfusion, tumor angiogenesis, cancer metastasis, diabetes, sepsis and acute lung injury. The glycosaminoglycan, hyaluronan (HA), maintains vascular integrity through endothelial glycocalyx modulation, caveolin-enriched microdomain regulation and interaction with endothelial HA binding proteins. Certain disease states increase hyaluronidase activity and reactive oxygen species (ROS) generation which break down high molecular weight HA to low molecular weight fragments causing damage to the endothelial glycocalyx. Further, these HA fragments can activate specific HA binding proteins upregulated in vascular disease to promote actin cytoskeletal reorganization and inhibition of endothelial cell-cell contacts. This review focuses on the crucial role of HA in vascular integrity and how HA degradation promotes vascular barrier disruption. PMID- 22254201 TI - Emerging concept of anti-hypertensive therapy based on ambulatory blood pressure profile in chronic kidney disease. AB - Presently hypertensive patients with chronic kidney disease (CKD) particularly diabetic nephropathy are increasing in number, and cardiovascular and renal complications are the most common cause of death in these patients. The control of blood pressure (BP) is an important issue in cardiovascular and renal protection in hypertensive patients with CKD. Although hypertension is usually diagnosed based on measurements of BP recorded during a visit to a physician, that is, office BP, several studies have shown that target organ damage and prognosis are more closely associated with ambulatory BP than with office BP. It should be important to achieve the target absolute BP levels in hypertensive patients obtained either by office or home measurements or by ambulatory recordings for the cardiovascular and renal protection. Noninvasive techniques for measuring ambulatory BP have allowed BP to be monitored during both day and night. Additionally, ambulatory BP monitoring can provide information on circadian BP variation and short-term BP variability, which is suggested to be associated with cardiovascular and renal morbidity and mortality. This review will briefly summarize the emerging concept of anti-hypertensive therapy based on ambulatory BP profile in hypertensive patients with CKD. PMID- 22254202 TI - Inflammasomes in cardiovascular diseases. AB - NOD-like receptors (NLRs) constitute a recently identified family of macromolecules that participate in regulation of innate immune responses. To date, 23 members of the NLR family are identified in humans. Diverse NLRs are stimulated by a broad range of pathogen- or danger-associated molecular patterns, and collectively function as intracellular pattern recognition receptors (PRRs). The most studied inflammasomes are NLRP1 and NLRP3 that process inactive pro caspase-1 to its active form, allowing the cleavage and subsequent activation of pro-IL-1beta and pro-IL-18, and initiation of inflammatory responses. Three models, based upon extracellular ATP/K(+) flux, lysosomal release of cathepsin, and reactive oxygen species, have been proposed to be involved in signaling activation of NLRs and downstream events. In this review, I discuss the current state of knowledge related to the roles of NLRs and inflammasomes in the development of cardiovascular diseases. PMID- 22254203 TI - Antithrombotic therapy in patients with acute coronary syndromes: a balance between protection from ischemic events and risk of bleeding. AB - Platelet activation plays a primary role in the pathogenesis of acute coronary syndromes (ACS); thus, anti-thrombotic therapy with aspirin and clopidogrel represents the mainstay of treatment in those patients. However, low clopidogrel response has become a contemporary issue in interventional cardiology, increasing the risk of ischemic events and significantly worsening short- and long-term prognosis after coronary stenting. Alternative approaches to overcome this phenomenon have been investigated as well as increase in the loading and maintenance clopidogrel doses, reloading patients already on chronic therapy, use of newer and more effective antiplatelet agents. Otherwise a more aggressive antiplatelet treatment may lead to possible increase in bleeding complications. A strategy of an individualized antiplatelet therapy according to point-of-care platelet function tests may represent the optimal approach to balance both ischemic and hemorrhagic risk. PMID- 22254204 TI - Early and late improvement of global and regional left ventricular function after transcatheter aortic valve implantation in patients with severe aortic stenosis: an echocardiographic study. AB - The recent development of transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) treatment offers a viable option for high-risk patient categories. Our aim is to evaluate whether 2D strain and strain rate can detect subtle improvement in global and regional LV systolic function immediately after TAVI. 2D conventional and 2D strain (speckle analysis) echocardiography was performed before, at discharge and after three months in thirty three patients with severe AS. After TAVI, we assessed by conventional echocardiography an immediate reduction of transaortic peak pressure gradient (p<0.0001), of mean pressure gradient (p<0.0001) and a concomitant increase in aortic valve area (AVA: 1.08+/-0.31 cm(2)/m(2); p<0.0001). 2D longitudinal systolic strain showed a significant improvement in all patients, both at septal and lateral level, as early as 72 h after procedure (septal: -14.2+/-5.1 vs -16.7+/-3.7%, p<0.001; lateral: -9.4+/-3.9 vs -13.1+/-4.5%, p<0.001; respectively) and continued at 3 months follow-up (septal: -18.1+/-4.6%, p<0.0001; lateral: -14.8+/-4.4%, p<0.0001; respectively). Conventional echocardiography after TAVI proved a significant reduction of LV end-systolic volume and of LV mass with a mild improvement of LV ejection fraction (EF) (51.2+/-11.8 vs 52.9+/-6.4%; p<0.02) only after three months. 2D strain seems to be able to detect subtle changes in LV systolic function occurring early and late after TAVI in severe AS, while all conventional echo parameters seem to be less effective for this purpose. Further investigations are needed to prove the real prognostic impact of these echocardiographic findings. PMID- 22254207 TI - Valvular leak after transcatheter aortic valve implantation: a clinician update on epidemiology, pathophysiology and clinical implications. AB - During trascatheter aortic valve implantation (TAVI) the native valve is not removed but crushed. Thus, a slight prosthesis insufficiency is not uncommon and has been reported in about 70% of patients for both available types of percutaneous valves. However, the definition of clinically "significant" valve regurgitation is not fully established yet. In most cases, aortic insufficiency is mild and clinical acceptable, however, severe insufficiency can occur. Paravalvular insufficiency is usually prevalent, and it may be the consequence of prosthesis/patient mismatch due to an undersizing of the implanted device or to an incomplete expansion of the prosthesis stent frame, or also to incorrect site of prosthesis implantation. Thus, an accurate assessment of the aortic valve annulus before TAVI is mandatory in order to select the optimal size of the valve. The presence of large calcium burden or bicuspid valve as well as the correct implantation of the device are other key determinants of final valve insufficiency. When severe regurgitation is present, an integration of hemodynamic, angiographic, transthoracic and TEE data is necessary to tailor the best clinical decision on a per-patient basis. PMID- 22254205 TI - Cardioproteomics: advancing the discovery of signaling mechanisms involved in cardiovascular diseases. AB - Cardioproteomics (Cardiovascular proteomics) is fast becoming an indispensible technique in deciphering changes in signaling pathways that occur in cardiovascular diseases (CVDs). The quality and availability of the instruments and bioinformatics software used for cardioproteomics continues to improve, and these techniques are now available to most cardiovascular researchers either directly or indirectly via university core centers. The heart and aorta are specialized tissues which present unique challenges to investigate. Currently, the diverse range of proteomic techniques available for cardiovascular research makes the choice of the best method or best combination of methods for the disease parameter(s) being investigated as important as the equipment used. This review focuses on proteomic techniques and their applications which have advanced our understanding of the signaling mechanisms involved in CVDs at the levels of protein complex/protein-protein interaction, post-translational modifications and signaling induced protein changes. PMID- 22254206 TI - Role of taurine in the vasculature: an overview of experimental and human studies. AB - Taurine is a sulfur-containing amino acid-like endogenous compound found in substantial amounts in mammalian tissues. It exerts a diverse array of biological effects, including cardiovascular regulation, antioxidation, modulation of ion transport, membrane stabilization, osmoregulation, modulation of neurotransmission, bile acid conjugation, hypolipidemia, antiplatelet activity and modulation of fetal development. This brief review summarizes the role of taurine in the vasculature and modulation of blood pressure, based on experimental and human studies. Oral supplementation of taurine induces antihypertensive effects in various animal models of hypertension. These effects of taurine have been shown to be both centrally and peripherally mediated. Consistent with this, taurine produces endothelium-dependent and independent relaxant effects in isolated vascular tissue preparations. Oral administration of taurine also ameliorates impairment of vascular reactivity, intimal thickening, arteriosclerosis, endothelial apoptosis, oxidative stress and inflammation, associated primarily with diabetes and, to a lesser extent with obesity, hypertension and nicotine-induced vascular adverse events. In rat aortic vascular smooth muscle cells (VSMCs), taurine acts as an antiproliferative and antioxidant agent. In endothelial cells, taurine inhibits apoptosis, inflammation, oxidative stress and cell death while increasing NO generation. Oral taurine in hypertensive human patients alleviates the symptoms of hypertension and also reverses arterial stiffness and brachial artery reactivity in type 1 diabetic patients. However, despite these favorable findings, there is a need to further establish certain aspects of the reported results and also consider addressing unresolved related issues. In addition, the molecular mechanism (s) involved in the vascular effects of taurine is largely unknown and requires further investigations. Elucidation of the mechanisms through which taurine affects the vasculature could facilitate the development of therapeutic and/or diet-based strategies to reduce the burdens of vascular diseases. PMID- 22254208 TI - Profound influence of LDL oxidative status and monocyte co-cultures on baboon endothelial activation. AB - OBJECTIVE: To investigate how increased LDL levels interact with endothelial cells by using well-defined LDL preparations to limit experimental biases caused by heterogeneity of LDL preparations. METHODS: We pooled LDL from multiple subjects and prepared several types of LDL from a single source. Then we observed their effects on cultured endothelial cells with and without monocyte co-culture. RESULTS: Native and minimally oxidized LDL did not cause significant cell death under most circumstances, and did not up-regulate cellular adhesion molecule (CAM) expression. Native LDL did result in significant increases of MCP-1 release in five of eight subjects. However, extensively oxidized LDL caused a significant amount of cell death and dramatically decreased MCP-1 secretion. Minimally oxidized LDL elicited a mixed response pattern, with a great deal of variation among subjects. When endothelial cells were co-cultured with monocytes and treated with native LDL, significant up-regulation of CAMs was detected after 24 hours of exposure. Up-regulation was not seen in any treatment group that contained either native LDL or monocytes only, indicating a synergistic effect of LDL and monocytes on endothelial cells. Incubation of cultured monocytes with native LDL also resulted in TNF-alpha and IL-1beta release in a dosage- and time dependent manner. Neutralization of both TNF-alpha and IL-1beta by 10 MUg/mL polyclonal antibodies inhibited the up-regulation of CAMs. CONCLUSION: Our results suggest that varying extents of oxidative modification of LDL lead to fundamentally different cytological effects and that native LDL exhibits greater endothelial activation capacity when it interactively cooperates with monocytes. PMID- 22254209 TI - Higher fasting glucose levels are associated with reduced circulating angiogenic cell migratory capacity among healthy individuals. AB - BACKGROUND: Chronic or severe acute elevations in plasma glucose are associated with decreases in the number and function of circulating angiogenic cells (CACs). However, less is known about whether fasting plasma glucose levels (FPG) within the normal or pre-diabetic range among healthy individuals are associated with decreased CAC function. Establishing this relationship is an important step in developing a line of research that may ultimately lead to preventative lifestyle interventions intended to maximize endogenous CAC function and reduce cardiometabolic disease risk. OBJECTIVES: 1) To examine whether increases in FPG are associated with decreases in CAC migration among healthy individuals with FPG levels below the threshold for hyperglycemia, and 2) to contrast effect of FPG on CAC migration toward a pro-angiogenic stimulus (vascular endothelial growth factor; VEGF) with effect on intrinsic cell migratory capacity (i.e., random migration with no stimulus). METHODS: 28 men and women ranging from 20-57 years of age and free of cardiovascular disease participated in a pilot study, involving a fasting blood draw for FPG and isolation of peripheral blood mononuclear cells. CAC migration toward VEGF and random cell migration (control) were assessed in vitro. VEGF-induced migration that was normalized to control migration, representing the VEGF-response component of chemotaxis independent of motility, was calculated to determine whether any impairment in migration to VEGF was due to lower specific response to VEGF or to lower non-specific migratory capacity. RESULTS: Increased levels of FPG were associated in a dose-response fashion with a significantly lower random migration under control conditions (CTRL: r= -.408, p=.031), no differences in migration to VEGF (r= -.039, p=.842) and a borderline association with VEGF-induced migration normalized to control migration (VEGF/CTRL: r=.349, p=.069). The relationship between FPG and random migration under control conditions remained significant when controlling for gender and body mass index (p's<.05), and became borderline significant when controlling for age (p=.062). CONCLUSIONS: Among healthy individuals, higher fasting glucose levels, despite falling below the diabetic range, are associated with decreased random CAC migration. These findings suggest a need for further studies investigating the effects of lifestyle or dietary interventions on glucose regulation and CAC function. PMID- 22254211 TI - Patent foramen ovale as a preferential mechanism for increasing the likelihood of brain tumor metastasis. AB - Metastases are the most common tumors of the central nervous system which may lie dormant behind the brain blood- barrier sheltering from chemiotherapeutic drugs, and whose presence usually indicates a poor prognosis. Development of brain metastases includes the intravasation of the cancer cells through the tumor blood vessels, their circulation within the venous system, passing through the pulmonary filter thus reaching the systemic circulation. Patent foramen ovale (PFO) is a natural communication between the right and left atrium with a prevalence of about 25% in the general population. It may predispose to a right to-left shunt by-passing the pulmonary filter. Recent literature suggests that the presence of a permanent shunt, large shunt, atrial septal aneurysm and/or venous valve remnants, all increase the risk of paradoxical embolism in PFO patients. The hypothesis that cancer cells may reach the brain circulation through a significant PFO, might open up new fields in brain metastases pathophysiology and prevention. PMID- 22254210 TI - SDF-1alpha and CXCR4 as therapeutic targets in cardiovascular disease. AB - SDF-1alpha/CXCR4 signaling is important for endogenous processes, including organogenesis and hematopoeisis, as well as in response to tissue injury. The secretion of SDF-1alpha acts as a chemoattractant to facilitate the homing of circulating CXCR4 positive cells as well as other stem cells to the site of injury for the initiation organ regeneration and repair. In the case of cardiovascular disease, and particularly myocardial infarction, this signaling axis is implicated in many of these processes, and has an additional role in providing trophic support for cells and utilizing paracrine mechanisms to enhance cell survival, promote angiogenesis, and stimulate differentiation. Current research is focused on elucidating these complex events, and so far have produced promising results that have led to the development of cell therapies that can more effectively repair cardiac tissue following ischemic injury than currently used treatments. Despite these advancements, much remains to be discovered so that in the future, new treatments will be better able to regenerate tissue and recover function. PMID- 22254212 TI - Tachycardic vs. pharmacologic stress myocardial perfusion imaging: differential implications in multi-vessel ischemia. AB - BACKGROUND: In patients unable to exercise, potential methods of induction of reversible myocardial ischemia include physiological heart rate acceleration via pacing or dobutamine infusion and asymmetric coronary vasodilatation using dipyridamole. Although their bases for induction of ischemia are widely disparate, no direct comparison of these techniques has previously been reported. METHODS: We performed a randomised, paired comparison of dipyridamole and pacing myocardial perfusion imaging (MPI) in 28 patients in whom exercise stress imaging was precluded, comparing the detection, localisation and quantitation of ischemia. RESULTS: Reversible myocardial ischemia was detected in 21 patients, concordantly in 13 (p = 0.042). There was a high degree of concordance (p < 0.0001) regarding locations of sites of ischemia. While there was a good correlation (r = 0.74, p < 0.0001) between size of total ischemic zones with dipyridamole and pacing, the magnitude of ischemia tended to be greater with dipyridamole (mean percentage of left ventricular myocardium +/- SD, 9.4 +/- 11.0% vs. 7.0 +/- 9.0%, p = 0.091). Furthermore, this difference resulted from accentuation of the primary ischemic zone with dipyridamole in patients with multi-vessel ischemia (mean +/- SD, 28.1 +/- 21.1% vs. 18.7 +/- 16.1%, p = 0.046). CONCLUSIONS: Despite major differences in mechanism(s) of induction of ischemia, dipyridamole and pacing produce similar results regarding detection, localisation and severity of ischemia. However, dipyridamole accentuates ischemia in primary (vs. secondary) ischemic zones, consistent with known induction of coronary "steal". This should be taken into account in interpretation of scan results. PMID- 22254213 TI - Pathogenesis of aortic sclerosis: association with low BMI, tissue nitric oxide resistance, but not systemic inflammatory activation. AB - Aortic sclerosis (ASc) represents the earliest stage of development of aortic valve thickening, and may eventually progress to aortic valve stenosis (AS). ASc is associated with intra-valvular inflammatory activation, and potentially with attenuation of the anti-inflammatory effect of nitric oxide (NO). We have shown that ASc occurs less frequently in obese individuals, in whom systemic inflammatory activity is generally increased. We explored these relationships further by stratifying a population of 253 ageing individuals according to BMI. Increasing BMI was associated with increased hs-CRP concentrations (r=0.43; p<0.001). However, presence/absence of ASc did not significantly modify this relationship. Furthermore, increasing BMI was independent of tissue responsiveness to NO, as measured via inhibition of platelet aggregation by the NO donor sodium nitroprusside. Therefore the association of low BMI with increased risk of ASc appears to interact neither with systemic inflammatory activation in such individuals, nor with any "paradoxical" occurrence of NO resistance. PMID- 22254215 TI - C-kit-positive cardiac stem cells and myocardial regeneration. AB - Two distinct subpopulations of endogenous cardiac stem cells (CSCs) are identified in the adult heart; myogenic CSCs (mCSCs), which are characterized by the presence of c-kit receptor, reside in the myocyte niche surrounded by matured cardiomyocytes, whereas vasculogenic CSCs (vCSCs), which express c-kit as well as KDR, are stored in the vascular niche found in the vessel wall. They both possess the fundamental properties of stem cells: self -renewing, clonogenic, and multipotent. While mCSCs preferentially differentiate into myocyte lineage in vitro, vCSCs tend to commit to vascular endothelial or smooth muscle lineages upon stimulation. Intramyocardial injection of human mCSCs to the region bordering infarct of immunosuppressed animals induces cardiac regeneration involving intensive muscle and vessel formation. On the other hand, the administration of human vCSCs near the critical stenosis created in the dog coronary artery results in the formation of large conductive vessels, i.e. "biological coronary bypass", coupled with the improved tissue perfusion. A clinical trial utilizing autologous c-kit-positive CSCs on patients with chronic ischemic heart failure was launched recently. Upon coronary artery bypass graft (CABG) surgery, a small portion of the right atrial appendage was obtained and used for isolation and expansion of CSCs. Intracoronary CSC implantation was performed 4 months after the surgery, and the symptom and the cardiac function were followed. Although the study is still ongoing, no adverse event due to cell infusion has been reported in any of the cell-treated patients, and the initial outcome is very promising. Disease-based customized cell therapy employing various combinations of autologous mCSCs and vCSCs would become available in the near future. PMID- 22254214 TI - Aldosterone and aldosterone antagonists in cardiac disease: what is known, what is new. AB - Experimental and clinical studies indicate that exposure to high aldosterone concentrations causes cardiac damage independent of the blood pressure level. In recent years, it has become clear that the effects of aldosterone on the heart are mediated by actions on a variety of cell types and intracellular mechanisms that contribute to regulation of specific tissue responses, leading to hypertrophy and fibrosis. Most cardiac effects of aldosterone are mediated by activation of mineralocorticoid receptors that are detected in cardiac myocytes and fibroblasts. Clinical evidence of the unfavorable cardiac effects of aldosterone has been established in landmark studies that have tested the benefits of aldosterone antagonists in patients with heart failure and decreased ejection fraction. However, evidence of benefits of aldosterone antagonists occurring independent of the renal effects of these agents is not limited to patients with systolic heart failure. In this article, we briefly summarize the current knowledge on the effects of aldosterone antagonists on cardiac protection and highlight the most recent findings that have been obtained in different cardiac conditions with use of these drugs. PMID- 22254216 TI - Long-term results of the amplatzer cribriform occluder for patent foramen ovale with associated atrial septal aneurysm: impact on occlusion rate and left atrial functional remodelling. AB - BACKGROUND: Treatment of patients with concomitant patent foramen ovale (PFO) and atrial septal aneurysm (ASA) poses a number of challenges; while some authors have suggested the off-label use of the Amplatzer Cribriform Occluder in such anatomy, the long-term outcomes of this strategy is unknown. Our study aimed to assess the long-term impact on closure rate, left atrial functional remodelling, and clinical outcomes of off-label implantation of Amplatzer ASD Cribriform Occluder in patients with PFO and ASA. METHODS: We prospectively enrolled 160 consecutive patients with previous stroke (mean age 36 +/- 9.5 years, 109 females), significant PFO and ASA. All patients were treated with Amplatzer Cribriform Occluder to ensure the most complete possible coverage of the ASA. Residual shunt and LA passive and active emptying, LA conduit function, and LA ejection fraction were computed before and after 6 months from the procedure and then yearly. All patients underwent successful transcatheter closure (mean ratio device/diameter of interatrial septum = 0.74). RESULTS: Incomplete ASA coverage during intraprocedural intracardiac echocardiography was observed in 71 patients. During mean follow-up of 3.6 +/- 1.8 years, when compared to patients with complete coverage, there were no differences in LA functional parameters and complete occlusion achieved in 150/160 patients (93.7%). No new cerebral ischemic events, aortic erosions or device thrombosis were recorded during the follow-up. CONCLUSIONS: THE USE OF THE AMPLATZER ASD CRIBRIFORM TO TREAT PFO AND ASSOCIATED ASA SEEMS SAFE AND EFFECTIVE: relatively small Occluder devices are probably effective enough to promote left atrial functional remodelling. PMID- 22254218 TI - Asymptomatic. PMID- 22254217 TI - Recent concepts for the roles of progenitor/stem cell niche in heart repair. AB - Progenitor/stem cell (PSC) has shown great promise for generation in failing heart. Advances in PSC biology have greatly enhanced our understanding of how PSC self-renewal, migration, maintenance of stemness, and cell-fate commitment depend on the balance of complex signals in their microenvironment. Endogenous PSC exists within structural and functional units known as PSC niches, which play important roles in directing PSC behavior. Recent years have witnessed great progress in our understanding of the PSC niche in cardiovascular biology. PSC based therapy could lead to successful cardiac regeneration or repair. Realizing the potential of therapeutic strategies is based on 1) differentiation of the PSC into all of the cellular constituents of the heart; 2) release of paracrine/ autocrine factors from the PSC; 3) fusion of the PSC with the existing constituents of the heart; and 4) stimulation of endogenous repair (regeneration of PSC niches). Importantly, cardiac PSC niches contain supporting cells and these cell-cell interactions have crucial regulatory roles in PSC based therapy. These findings have important implications for heart development, bioengineering, and furthermore elucidate a broader dimension of PSC control within the niche toward cardiomyocyte phenotype. PMID- 22254219 TI - Successful management of peri-implantitis with a regenerative approach: a consecutive series of 51 treated implants with 3- to 7.5-year follow-up. AB - The results of a case series of 51 consecutively treated, peri-implantitis affected implants in 38 patients with follow-up measurements from 3 to 7.5 years are presented. Each implant displayed bleeding on probing, probing depths >= 6 mm, and bone loss >= 4 mm prior to surgery. A successful regenerative approach including surface decontamination, use of enamel matrix derivative, a combination of platelet-derived growth factor with anorganic bovine bone or mineralized freeze-dried bone, and coverage with a collagen membrane or a subepithelial connective tissue graft was employed in all cases. Patients were divided into two groups. Group 1 included patients in which the greatest defect depth was visible on radiographs; group 2 included patients in which the greatest loss of bone was on the facial or oral aspect of the implant. Bone level changes in patients in group 2 were determined by probe sounding under local anesthesia. Probing depth reductions at 3 to 7.5 years of follow-up were 5.4 and 5.1 mm in groups 1 and 2, respectively. Concomitant bone level gain was 3.75 mm in group 1 and 3.0 mm in group 2. No implant in either group lost bone throughout the duration of the study. The results to date with this regenerative approach for the treatment of peri-implantitis appear to be encouraging. PMID- 22254220 TI - Healing of gingival recession following orthodontic treatment: a 30-year case report. AB - This case report describes the healing of gingival recessions on mandibular incisors resulting from orthodontic treatment of a deep bite malocclusion at a 30 year follow-up observation. The marked improvement in the severe recessions was a consequence of the elimination of the direct trauma, orthodontic intrusion of the affected teeth, and subsequent creeping attachment over time. No periodontal treatment was performed before or after orthodontic treatment. PMID- 22254221 TI - Gingival papilla dimensions in anterosuperior regions adjacent to single-tooth implants. AB - This study compared the dimensions of gingival papillae in anterosuperior areas presenting at natural teeth (teeth sites) or single-tooth implants adjacent to natural teeth (implant-tooth sites) by analyzing determined distances. A total of 45 teeth and 46 implant-tooth sites were carefully selected. Clinical evaluation consisted of visual and quantitative analyses with millimeter grids on radiographs. Implant-tooth sites showed a smaller gingival papilla dimension than tooth sites (P < .01). Both evaluated distances (contact point to bone crest and between the roots of adjacent teeth or implant platform to root of adjacent tooth) in all groups significantly influenced the presence/absence of gingival papillae (P < .01). PMID- 22254222 TI - Immediate loading of four or six implants in completely edentulous patients. AB - In this retrospective study, 44 patients received screw-retained full-arch acrylic resin provisional prostheses connected on 4 or 6 implants in the mandible or maxilla, respectively. With a mean follow-up of 17.6 months, 3 of 205 implants were lost and replaced successfully. Cosmetic fractures were shown in six patients; one abutment loosening, one abutment fracture, and one implant fracture were also observed. Prosthetic fracture was shown in one patient. Marginal bone loss reached two to five threads on 13 implants (6.4%). The results confirmed that immediate loading of 4 mandibular or 6 maxillary implants with an acrylic resin prosthesis for full-arch rehabilitation is a reliable technique in the short- and midterm. PMID- 22254223 TI - Immediate provisionalization of dental implants placed in fresh extraction sockets using a flapless technique. AB - The aim of this clinical study was to evaluate the 24-month clinical outcomes of immediate provisionalization of dental implants placed in fresh extraction sockets using a flapless technique. Fifteen patients were included under strict inclusion and exclusion criteria. All patients required one or two teeth to be extracted for lesions with a hopeless prognosis in the maxillary monoradicular or first premolar region. Twenty implants were placed immediately after tooth extraction, and immediate provisionalization was performed. Sixteen implants had a diameter of 5 mm, and four implants had a diameter of 3.80 mm, all with a 13-mm length. After 24 months of follow-up, a cumulative survival rate of 100% was reported for all implants. Modified Bleeding Index (mBI), modified Plaque Index (mPI), probing depth (PD), marginal gingiva level (MGL), and keratinized mucosa (KM) remained stable for up to 24 months. Mean MGL at 24 months was 0.22 +/- 0.15 mm; no significant changes occurred in MGL between baseline and 24 months. Mean KM remained stable from baseline to 24 months. At 24 months, a mean bone loss of 0.83 +/- 0.52 mm was measured. The results of this study indicate that flapless surgery for immediately provisionalized implants placed in fresh extraction sockets provides soft tissue and marginal bone maintenance for up to 24 months of follow-up. PMID- 22254224 TI - Immediate restoration of nonsubmerged titanium implants with a sandblasted and acid-etched surface: five-year results of a prospective case series study using clinical and radiographic data. AB - The aim of this study was to evaluate the survival and success rates of immediately restored implants with sandblasted, large-grit, acid-etched (SLA) surfaces over a period of 5 years. Twenty patients (mean age, 47.3 years) received a total of 21 SLA wide-neck implants in healed mandibular first molar sites after initial periodontal treatment. To be included in the study, the implants had to demonstrate primary stability with an insertion torque value of 35 Ncm. A provisional restoration was fabricated chairside and placed on the day of surgery. Definitive cemented restorations were inserted 8 weeks after surgery. Community Periodontal Index of Treatment Needs (CPITN) indices and the radiographic distance between the implant shoulder and the first visible bone implant contact (DIB) were measured and compared over the study period. The initial mean CPITN was 3.24, and decreased over the study period to 1.43. At the postoperative radiographic examination, the mean DIB was 1.41 mm for the 21 implants, indicating that part of the machined neck of the implants was placed slightly below the osseous crest. The mean DIB value increased to 1.99 mm at the 5-year examination. This increase proved to be statistically significant (P < .0001). Between the baseline and 5-year examinations, the mean bone crest level loss was 0.58 mm. Success and survival rates of the 21 implants after 5 years of function were 100%. This 5-year study confirms that immediate restoration of mandibular molar wide-neck implants with good primary stability, as noted by insertion torque values of at least 35 Ncm, is a safe and predictable procedure. PMID- 22254225 TI - Efficacy of micronized acellular dermal graft for use in interproximal papillae regeneration. AB - The aim of this study was to evaluate interdental papillary reconstruction based on a micronized acellular dermal matrix allograft technique. Thirty-eight papillae in 12 patients with esthetic complaints of insufficient papillae were evaluated. Decreased gingival recession values were found postoperatively (P < .001). Chi-square analysis showed significantly higher postoperative Papilla Index values (chi-square = 43, P < .001), further supported by positive symmetry statistical analysis values (positive kappa and weighted kappa values). This procedure shows promise as a method for papillary reconstruction. PMID- 22254226 TI - The negative effect of combining rhBMP-2 and Bio-Oss on bone formation for maxillary sinus augmentation. AB - Sinus augmentation with various bone graft materials may be required in the posterior maxilla. This study compared bone formation in a lateral window sinus augmentation with recombinant human bone morphogenetic protein 2/acellular collagen sponge (rhBMP-2/ACS) combined with Bio-Oss or Bio-Oss graft alone. Patients were assigned to treatment with either rhBMP-2/ACS + Bio-Oss or Bio-Oss alone. After a healing period, bone cores were harvested. Histologic specimens demonstrated that new bone formation was less in those who received rhBMP-2/ACS + Bio-Oss than those with Bio-Oss alone. This study indicated that the addition of rhBMP-2/ACS to Bio-Oss has a negative effect on bone formation. PMID- 22254227 TI - Analysis of the shapes of maxillary central incisors in a Caucasian population. AB - The purpose of this study was to objectively define and quantify triangular, square, and square/tapered maxillary central incisors. In this study, the shape of maxillary central incisor crowns was investigated in 100 healthy individuals. The results showed that when the contact surface/crown length ratio is less than 43%, the tooth is triangular in shape; when the ratio is more than 57%, the tooth is square in shape; and when the ratio is between 43% and 57%, the tooth is defined as square/tapered. Since it has been shown that the morphologic characteristics of the gingiva and periodontium are partly related to the shape of the teeth, a means of truly defining the shapes of the incisors is now available. This is significant in predicting esthetics, bone volume, and susceptibility to recession, pocketing in the natural dentition, and ridge shrinkage for prosthetic tooth replacement. PMID- 22254228 TI - A new flapless technique for crown lengthening after orthodontic extrusion. AB - Orthodontic extrusion (OE), which is performed in many different clinical situations to move a tooth or its periodontal tissues coronally, is often associated with supracrestal fiberotomy and root planing (OEFRP) or followed by surgical crown lengthening. The OEFRP procedure must be carried out every 2 weeks during the entire extrusive orthodontic phase, and precise control of the technique itself can be quite difficult, especially when this approach is to be performed on a limited portion of the root perimeter in teeth affected by angular defects. The aim of this study was to show a new nonsurgical crown-lengthening technique, performed shortly after the completion of OE, to simultaneously achieve proper hard and soft tissue architecture. Three different illustrative situations (periodontal pocket, root fracture, and root perforation) are described. PMID- 22254229 TI - Periodontal plastic surgery for management of cleft alveolar ridge: a case report. AB - Cleft lips, alveoli, and palates are the most common congenital malformations of the head and neck region, all of which often can be managed successfully when presented at a young age. It is a common belief that clefts in the alveolar ridge should be treated with the help of bone grafting materials. This could be the best option when the cleft is to be treated in early age, when the patient is still developing and has high regenerative potential. However, in adults, the literature supports the fact that bone grafting in alveolar clefts has a higher chance for failure. The present case report exemplifies a periodontal plastic surgical procedure involving a combination of connective tissue and free gingival grafting to restore the form and function of a cleft alveolar ridge in an adult patient. PMID- 22254230 TI - Split-mouth comparison of a coronally advanced flap with or without enamel matrix derivative for coverage of multiple gingival recession defects: 6- and 24-month follow-up. AB - The aim of this study was to evaluate whether the use of enamel matrix derivative (EMD) improves clinical results of the coronally advanced flap (CAF) procedure in the treatment of multiple gingival recession defects. Ten patients presenting at least two adjacent buccal gingival recession defects affecting symmetric teeth on both sides of the maxilla were included in this study. Each set of multiple recession defects was assigned randomly to the test or control group. A bilateral simultaneous CAF procedure with vertical releasing incisions, with the adjunct of EMD for test sites, was performed. Clinical measurements (recession length, keratinized tissue, probing depth, and clinical attachment level) were assessed at baseline and 6 and 24 months after surgery by a blinded examiner. At the 6 month evaluation, both treatment procedures displayed good results with significant root coverage gain (CAF, 80.7% +/- 20%; CAF + EMD, 82.8% +/- 14%). A similar amount of relapse was noted at the 24-month evaluation when compared with the 6-month results (CAF, 71.0% +/- 22%; CAF + EMD, 74.8% +/- 16%). The use of EMD does not seem to significantly improve the results of the CAF procedure for root coverage in treatment of multiple recessions. PMID- 22254231 TI - Histomorphometric analysis of newly formed bone after bilateral maxillary sinus augmentation using two different osteoconductive materials and internal collagen membrane. AB - Deproteinized bovine bone mineral (DBBM) and human freeze-dried bone allograft (FDBA) were compared in five patients undergoing bilateral maxillary sinus floor augmentation using DBBM on one side and FDBA on the contralateral side. After 9 months, core biopsy specimens were harvested. Mean newly formed bone values were 31.8% and 27.2% at FDBA and DBBM sites, respectively (P = .451); mean residual graft particle values were 21.5% and 24.2%, respectively (P = .619); and mean connective tissue values were 46.7% and 48.6%, respectively (P = .566). Within the limits of the present study, it is suggested that both graft materials are equally suitable for sinus augmentation. PMID- 22254232 TI - Bruxism elicited by inferior alveolar nerve injury: a case report. AB - The aim of this case report is to describe the history of a patient who received an injury to the right inferior alveolar nerve after placement of a dental implant, with bruxism noted afterward. The symptoms were managed by the use of an occlusal appliance worn at night and occasionally during the day, associated with increased awareness of parafunction during the day to reduce muscle pain and fatigue. Paresthesia of the teeth, gingiva, and lower lip persisted but were reduced during appliance use. PMID- 22254233 TI - Soft tissue integration of a porcine collagen membrane: an experimental study in pigs. AB - Autogenous soft tissue augmentation procedures around natural teeth and dental implants are performed daily by clinicians. However, patient morbidity is often associated with the second surgical site; hence, research is moving toward an era where matrices may substitute autogenous grafts. The aim of this study was to assess the soft tissue response to a collagen matrix in an animal model. Nine pigs were included in this study. Each animal received four collagen matrices, two for each mandible. Three cohorts were included in the study: group A, where the matrix was applied as an onlay on a partial-thickness flap; group B, where the matrix was inserted under a partial-thickness flap; and group C, where the matrix was inserted in an inverted position under a full-thickness flap. Sacrifice occurred at 7, 15, and 30 days postoperatively for histologic assessment. The collagen matrix was seen in place for the first 2 weeks, and it was completely replaced by healthy connective tissue within 30 days in the inlay cohorts. No inflammatory adverse reactions were noticed in any specimen, resulting in optimal integration of the device. This study showed an optimal integration within 30 days postoperative of the placement of experimental collagen matrix in the soft tissues of an animal model. Its proven safety in this model provides an optimal starting point for further research projects considering its clinical applications. PMID- 22254234 TI - Metal-air batteries: from oxygen reduction electrochemistry to cathode catalysts. AB - Because of the remarkably high theoretical energy output, metal-air batteries represent one class of promising power sources for applications in next generation electronics, electrified transportation and energy storage of smart grids. The most prominent feature of a metal-air battery is the combination of a metal anode with high energy density and an air electrode with open structure to draw cathode active materials (i.e., oxygen) from air. In this critical review, we present the fundamentals and recent advances related to the fields of metal air batteries, with a focus on the electrochemistry and materials chemistry of air electrodes. The battery electrochemistry and catalytic mechanism of oxygen reduction reactions are discussed on the basis of aqueous and organic electrolytes. Four groups of extensively studied catalysts for the cathode oxygen reduction/evolution are selectively surveyed from materials chemistry to electrode properties and battery application: Pt and Pt-based alloys (e.g., PtAu nanoparticles), carbonaceous materials (e.g., graphene nanosheets), transition metal oxides (e.g., Mn-based spinels and perovskites), and inorganic-organic composites (e.g., metal macrocycle derivatives). The design and optimization of air-electrode structure are also outlined. Furthermore, remarks on the challenges and perspectives of research directions are proposed for further development of metal-air batteries (219 references). PMID- 22254236 TI - Improved quantification of CSF bilirubin in the presence of hemoglobin using least squares curve-fitting. AB - Subarachnoid hemorrhage (SAH) is a dangerous neurological event with a very short time window for early diagnosis. Clinical diagnoses performed in a lab seek to quantify bilirubin in cerebrospinal fluid (CSF) as a biomarker for SAHs; however laboratory assays suffer from lengthy protocols, interference from hemoglobin, and the availability of expertise. Substantial improvements in the determination of bilirubin concentration in the presence of hemoglobin in CSF are demonstrated in this work. Concentration estimates within 15% for bilirubin in the range of 0.2 to 1.6 mg /dl were determined for CSF samples containing fresh hemoglobin concentrations ranging from 0.05 to 0.25 g/dl. To demonstrate extensibility of the system with respect to more complete mock SAH samples, sample sets with one additional species of both hemoglobin and bilirubin, methemoglobin and alpha bilirubin, respectively, were tested and yielded results within 25% of actual values, as measured by standard chemical assays of preparations prior to mixing. PMID- 22254237 TI - CMOS direct time interval measurement of long-lived luminescence lifetimes. AB - We describe a Complementary Metal-Oxide Semiconductor (CMOS) Direct Time Interval Measurement (DTIM) Integrated Circuit (IC) to detect the decay (fall) time of the luminescence emission when analyte-sensitive luminophores are excited with an optical pulse. The CMOS DTIM IC includes 14 * 14 phototransistor array, transimpedance amplifier, regulated gain amplifier, fall time detector, and time to-digital convertor. We examined the DTIM system to measure the emission lifetime of oxygen-sensitive luminophores tris(4,7-diphenyl-1, 10-phenanthroline) ruthenium(II) ([Ru(dpp)(3)](2+)) encapsulated in sol-gel derived xerogel thin films. The DTIM system fabricated using TSMC 0.35 MUm process functions to detect lifetimes from 4 MUs to 14.4 MUs but can be tuned to detect longer lifetimes. The system provides 8-bit digital output proportional to lifetimes and consumes 4.5 mW of power with 3.3 V DC supply. The CMOS system provides a useful platform for the development of reliable, robust, and miniaturized optical chemical sensors. PMID- 22254238 TI - CMOS integrated avalanche photodiodes and frequency-mixing optical sensor front end for portable NIR spectroscopy instruments. AB - This paper presents the design and measurement results of two avalanche photodiode structures (APDs) and a novel frequency-mixing transimpedance amplifier (TIA), which are key building blocks towards a monolithically integrated optical sensor front end for near-infrared (NIR) spectroscopy applications. Two different APD structures are fabricated in an unmodified 0.18 ?im CMOS process, one with a shallow trench isolation (STI) guard ring and the other with a P-well guard ring. The APDs are characterized in linear mode. The STI bounded APD demonstrates better performance and exhibits 3.78 A/W responsivity at a wavelength of 690 nm and bias voltage of 10.55 V. The frequency mixing TIA (FM-TIA) employs a T-feedback network incorporating gate-controlled transistors for resistance modulation, enabling the simultaneous down-conversion and amplification of the high frequency modulated photodiode (PD) current. The TIA achieves 92 dS Omega conversion gain with 0.5 V modulating voltage. The measured IIP(3) is 10.6/M. The amplifier together with the 50 Omega output buffer draws 23 mA from a1.8 V power supply. PMID- 22254239 TI - Inclusion mechanical property estimation using tactile images, finite element method, and artificial neural network. AB - In this paper, we developed a methodology for estimating three parameters of tissue inclusion: size, depth, and Young's modulus from the tactile data obtained at the tissue surface with the tactile sensation imaging system. The estimation method consists of the forward algorithm using finite element method, and inversion algorithm using artificial neural network. The forward algorithm is designed to comprehensively predict the tactile data based on the mechanical properties of the tissue inclusion. This forward information is used to develop an inversion algorithm that will be used to extract the size, depth, and Young's modulus of a tissue inclusion from the tactile image. The proposed method is then validated with custom made tissue phantoms with matching elasticities of typical human breast tissues. The experimental results showed that the proposed estimation method estimates the size, depth, and Young's modulus of tissue inclusions with root mean squared errors of 1.25 mm, 2.09 mm, and 28.65 kPa, respectively. PMID- 22254240 TI - Development of an optoelectronic sensor for the investigation of photoplethysmographic signals from the anterior fontanel of the newborn. AB - There is a need for more reliable, non-invasive and alternative measurement sites for the monitoring of arterial blood oxygen saturation in critically ill newborns at times of peripheral compromise. The anterior fontanelle, a unique anatomical feature of the newborn, has been presented as an alternative site for the estimation of oxygen saturation. A multi-wavelength non-invasive optoelectronic sensor has been designed and developed for the investigation of photoplethysmographic (PPG) signals and blood oxygen saturation values from the fontanelle. In vivo thermal tests of the optical sensor show that under normal operating conditions the heating at the skin surface was negligible (<0.1 degrees C). Good quality PPGs with large amplitudes and high signal to noise ratio were recorded at all three (red, infrared and green) wavelengths prior to clinical measurements. PMID- 22254241 TI - Development of cell culture monitoring system and novel non-contact pH measurement. AB - This paper describes a cell culture monitoring system for regenerative medicine. To realize this monitoring system, a new culture vessel and a removable measurement unit were proposed. The measurement unit was installed in the culture vessel and it was used to measure important cell culture parameters (e.g., temperature, CO(2) level, and pH). Thus, the status of the culture could be monitored. In addition, we developed a novel noninvasive method based on spectrophotometry for measuring pH. This method is a non-contact method that permits noninvasive and contamination-free pH measurement. The spectroscopic pH measurements agreed well with pH measurements using an electrode. The error was within 0.02; thus, the new pH measurement method is sufficiently accurate for cell culture. This new system is expected to contribute to advances in tissue engineering and regenerative medicine. PMID- 22254242 TI - Using photonic crystal enhanced fluorescence on quartz substrates to improve the sensitivity of DNA microarrays. AB - Gene expression analysis of low abundance genes remains difficult when DNA microarrays are performed on standard glass substrates. However, we have shown that by using photonic crystals (PC) made on quartz substrates, the fluorescence intensity of Cyanine-5 (Cy5) labeled microarray spots is greatly enhanced. In a 1 color microarray experiment studying gene expression of soybean cotyledon tissue, an average signal enhancement factor of 17.8* was observed on the PC. Furthermore, twice as many genes were detectable on these PCs as compared to glass. By improving the sensitivity of this fluorescent assay, low expression genes that were undetectable on glass were quantified on the PC. PMID- 22254243 TI - Analysis of integrated optofluidic lab-on-a-chip fluorescence biosensor based on transmittance of light through a fluidic gap. AB - Sensitivity analysis is an important aspect to be looked into while designing lab on-a-chip systems. In this paper we will be showing with appropriate design that the best sensitivity of the fluorescence biosensor is achieved for an optimal width of fluidic gap, corresponding to a particular mode spot size. We will be also showing that the sensitivity of the biosensor is affected by efficiency of light coupling, which is influenced by changes in the width of fluidic gap, refractive index of the fluid and higher order modes. PMID- 22254244 TI - Fluorescence-based system for measurement of electrophysiological changes in stretched cultured cardiomyocytes. AB - Acute or sustained stretch of cardiac tissue is known to play a key role in arrhythmogenesis. Using a fluorescence approach, we designed a system measuring calcium transients and transmembrane potential changes in monolayers of cultured cardiomyocytes under uniaxial elongation and electrical stimulation. Cardiac myocytes are seeded on a rectangular PDMS template held and stretched by a motorized linear guide system. Electrical stimulation is performed with two parallel carbon electrodes supplied by amplified pulses from a digital-to-analog converter. The cells are stained with either voltage- or calcium-sensitive dye (di-4-ANEPPS and Fluo-4 AM respectively). The two available excitation light sources are both current-controlled LED arrays (lambda = 523 +/- 45 nm for di-4 ANEPPS and lambda = 505 +/- 15 nm for Fluo-4 AM). The filtered emitted fluorescence (lambda > 610 nm for di-4-ANEPPS and lambda = 535 +/- 25 nm for Fluo 4 AM) is transduced to current with a photodiode, converted to amplified voltage signals and digitized. The design and preliminary validation results are presented. PMID- 22254245 TI - High speed low noise multiplexed three color absorbance photometry. AB - Multispectral photometry is often required to distinguish samples in flow injection analysis and flow cytometry; however, the cost of multiple light detectors, filters, and optical paths contribute to the high cost of multicolor and spectral detection systems. This paper describes frequency division multiplexing (FDM), a simple approach for performing multi-wavelength absorbance photometry with a single light detector and a single interrogation window. In previous efforts, modulation frequencies were <10 KHz, resulting in a detector bandwidth of <20 Hz. This paper presents a high frequency FDM circuit which can increase the oscillation frequencies to several 100 KHz, improving the detection bandwidth by a factor of 10 while still maintaining low cost. Light from 3 different LED sources are encoded into unique frequency channels, passed through the detection cell, and later demodulated using phase-sensitive electronics. Electronic multiplexing couples all light sources into a single optical train without spectral filters. Theory and high frequency considerations are demonstrated. Simultaneous three color absorbance detection is demonstrated in solutions and in flowing droplet microreactors. This technique can potentially reduce the cost of multicolor photometry by replacing expensive optical components with low-cost electronics. PMID- 22254246 TI - Noise and range considerations for close-range radar sensing of life signs underwater. AB - Close-range underwater sensing of motion-based life signs can be performed with low power Doppler radar and ultrasound techniques. Corresponding noise and range performance trade-offs are examined here, with regard to choice of frequency and technology. The frequency range examined includes part of the UHF and microwave spectrum. Underwater detection of motion by radar in freshwater and saltwater are demonstrated. Radar measurements exhibited reduced susceptibility to noise as compared to ultrasound. While higher frequency radar exhibited better signal to noise ratio, propagation was superior for lower frequencies. Radar detection of motion through saltwater was also demonstrated at restricted ranges (1-2 cm) with low power transmission (10 dBm). The results facilitate the establishment of guidelines for optimal choice in technology for the underwater measurement motion based life signs, with respect to trade offs involving range and noise. PMID- 22254247 TI - Lung water assessment in isolated lung perfusion model via reactance monitoring. AB - The aim of this work was to build up a new monitoring technique for the lung preservation. The medical aside problem is to measure the integrity and functionality of the lung tissue, specifically at cellular preservation level in order to improve the survival time until it is grafted. The Impedance monitoring technique for diagnosis edema development is the key in this new technique. The hypothesis was that lung edema formation is highly correlated with the reactance changes so that a rat lung perfusion model was considered as a good model to produce edema in vitro. To prove that pulmonary edema can be induced increasing the venous pressure and the perfusion time, the reactance and hemodynamic parameters were recorder in 16 pulmonary blocks of Wistar rats as methodology. Results showed statistical changes in each pulmonary block weight as a consequence to apply 7.5 +/- 1.2 and 10.2 +/- 1.7 mmHg venous pressure (multiple samples, Anova, p<0.05). These edema weights were correlated with the reactance changes giving 0.6 (p<0.05, Pearson). Also, data analysis showed significant differences in reactance with the time of perfusion at 16, 30, and 50 min when venous pressure level were intermittent switched from 7.5 to 10.2 mmHg. The conclusion was this preliminary evidence sustains that reactance measurement is a good technique for monitoring the lung edema level in rats. However, more research should be continuing in bigger animal models in order to prove the validity and application of this monitoring technique in human lungs. PMID- 22254248 TI - Soft magnetic material based localized magnetic stimulation to cultured neuronal cells and modulation of network activities. AB - Magnetic stimulation is able to modulate the neuronal network activity using the non-invasive magnetically induced current. However, it is unknown how stimulation modulates the neuronal network activity. Therefore, we considered that precise stimulation and evaluation of the modulation of network activities in the vicinity of stimulated sites is required. Here, to establish precisely magnetic stimulation, we developed a Mu-metal that has high magnetic permeability soft magnetic material based localized magnetic stimulation (LMS) system with micro fabricated dual cell-culture chambers. And, combining this device with a microelectrode array (MEA) permitted the evaluation of the stimulus effects at the stimulated and non-stimulated sites. Here, the dual cell-culture chambers were arranged in a concentric circle manner. Between the inner and outer chambers, 4, 8 and 12 connecting microfluid channels were fabricated using polydimethylsiloxane (PDMS). Rat cortical neurons were separately cultured in outer and inner chambers. Through the micro-conduits, functional synaptic connections were formed. Mu-metal was aligned along the outer circle, which allowed us of focal magnetic stimulation to the cells in the outer chamber. Applying low frequency magnetic field to the Mu-metal, induced currents were generated and the electrical activity of the cells in the outer chamber was modified depending on the stimulation intensity. Following the modified activity in the outer circles, the cells in the inner chamber also showed slightly depressed activity patterns. These results suggested that our system would be promising for highly regulated neural stimulation. PMID- 22254249 TI - Novel flexible dry PU/TiN-multipin electrodes: first application in EEG measurements. AB - Dry biosignal electrodes for electro-encephalography (EEG) are an essential step for realization of ubiquitous EEG monitoring and brain computer interface technologies. We propose a novel electrode design with a specific shape for hair layer interfusion and reliable skin contact. An electrically conductive Titanium Nitride (TiN) thin layer is deposited on a polyurethane substrate using a multiphase DC magnetron sputtering technique. In the current paper we describe the development and manufacturing of the electrode. Furthermore, we perform comparative EEG measurements with conventional Ag/AgCl electrodes in a 6-channel setup. Our results are promising, as the primary shape of the EEG is preserved in the signals of both electrodes sets, according to recordings of spontaneous EEG and visual evoked potentials. The variance of both signals is in the same order of magnitude. The Wilcoxon-Mann-Whitney two-sample rank-sum test revealed no significant differences for 25 of the 28 compared signal episodes. Hence, our novel electrodes show equivalent signal quality compared to conventional Ag/AgCl electrodes. PMID- 22254250 TI - Performance of dry electrode with bristle in recording EEG rhythms across brain state changes. AB - In this paper we evaluate the physiological performance of a silver-silver chloride dry electrode with bristle (B-Electrode) in recording EEG data. For this purpose, we compare the performance of the bristle electrode in recording EEG data with the standard wet gold-plated cup electrode (G-Electrode) using two different brain state change tasks including resting condition with eyes-closed and performing mathematical task with eyes-open. Using a 2 channel recording device, eyes-closed command data were collected from each of 6 participants for a period of 20 sec and the same procedure was applied for the mathematical calculation task. These data were used for statistical and classification analyse. Although, B-electrode has shown a slightly higher performance compared with G-electrode in both tasks, but analyse did not reveal any significant differences between both electrodes in all six subjects tested. PMID- 22254251 TI - An adaptive algorithm for real-time electrode calibration. AB - Continuous brain monitoring based on EEG recorded from surface electrodes is believed to have potentials in wearable medical devices. In such devices capacitive electrodes are attractive compared to conventional electrodes because there is no need for skin preparation and conductive gels, and because of diminished motion artifacts. However, there are technical challenges connected to the practical application of capacitive electrodes. The electrode capacitance, which has significant impact on the signal measured, will vary between channels and will be time varying. Therefore calibration of the electrode array is an important preprocessing step before the signal processing. This paper proposes an algorithm for blindly estimating the parameters of the analog signal acquisition paths, including the capacitances of the electrodes. The algorithm continuously estimates the parameters, based on the measured EEG signals, and compensates for variations in the analog signal paths. Simulations show that the algorithm can estimate the parameters, and track changes of the electrodes capacitance in real time. PMID- 22254252 TI - Signal source localization with tetrodes: experimental verification. AB - Multi-sensor electrodes for extracellular recording of neuronal action potentials have significantly increased the signal-to-noise ratio (SNR) in neurophysiological experiments, ultimately leading to a more accurate interpretation of scientific data. Apart from improving SNR, we hypothesize that these electrodes can be used to estimate the location of underlying neuronal signal sources, and perhaps other parameters such as the size and shape of neurons whose activities are being recorded. This study introduces the multiple signal classification (MUSIC) algorithm to the problem of neuron localization and presents the first experimental demonstration of signal source localization using commercially available 4-sensor electrodes (tetrodes). PMID- 22254253 TI - Interdigitated electrodes based on impedance biosensor for sensing peptide LL-37. AB - An antimicrobial peptide, LL-37, is found in an innate defense system of humans. Patients who suffer urinary tract infection (UTI) will generate LL-37 and which is released into urine. LL-37 can be used as an indicator for the diagnosis of UTI. We have designed a biosensor with an interdigitated electrode on a printed circuit board (PCB). The surface of the electrode was modified with 3 mercaptopropionic acid and immobilized with anti-LL37 antibody to improve the specificity of the biosensor. By de-embedding jig impedance, the impedance associated with the change of LL-37 concentration was calculated. The sensitivity of this biosensor for LL-37 in a urine sample can reach 50 MUg/mL. PMID- 22254254 TI - Model based user interface design for predicting lung cancer treatment outcomes. AB - We have developed a web-based tool to predict lung cancer patient's survival probability using previously developed survivability prediction software architecture. Four statistical models are included in this version, three for non small cell lung cancer and one for limited-stage small cell lung cancer. To make the software tool more accessible and convenient for doctors and patients in a clinical setting, user interfaces are developed using a model based approach. Inputs common to prediction models are placed in interface which appears first, model specific inputs later. This design approach reduced both number of entries per interface and average number of interfaces a user needs to navigate. PMID- 22254255 TI - A comparison of non-symmetric entropy-based classification trees and support vector machine for cardiovascular risk stratification. AB - Classification tree-based risk stratification models generate easily interpretable classification rules. This feature makes classification tree-based models appealing for use in a clinical setting, provided that they have comparable accuracy to other methods. In this paper, we present and evaluate the performance of a non-symmetric entropy-based classification tree algorithm. The algorithm is designed to accommodate class imbalance found in many medical datasets. We evaluate the performance of this algorithm, and compare it to that of SVM-based classifiers, when applied to 4219 non-ST elevation acute coronary syndrome patients. We generated SVM-based classifiers using three different strategies for handling class imbalance: cost-sensitive SVM learning, synthetic minority oversampling (SMOTE), and random majority undersampling. We used both linear and radial basis kernel-based SVMs. Our classification tree models outperformed SVM-based classifiers generated using each of the three techniques. On average, the classification tree models yielded a 14% improvement in G-score and a 21% improvement in F-score relative to the linear SVM classifiers with the best performance. Similarly, our classification tree models yielded a 12% improvement in G-score and a 21% improvement in the F-score over the best RBF kernel-based SVM classifiers. PMID- 22254256 TI - Simplification of an erythropoiesis model for design of anemia management protocols in end stage renal disease. AB - Many end stage renal disease (ESRD) patients suffer from anemia due to insufficient endogenous production of erythropoietin (EPO). The discovery of recombinant human EPO (rHuEPO) over 30 years ago has shifted the treatment of anemia for patients on dialysis from blood transfusions to rHuEPO therapy. Many anemia management protocols (AMPs) used by clinicians comprise a set of experience-based rules for weekly-to-monthly titration of rHuEPO doses based on hemoglobin (Hgb) measurements. In order to facilitate the design of an AMP based on formal control design methods, we present a physiologically-relevant erythropoiesis model, and show that its nonlinear dynamics can be approximated using a static nonlinearity, a step that greatly simplifies AMP design. We demonstrate applicability of our results using clinical data. PMID- 22254257 TI - In silico analysis of nuclei in glioblastoma using large-scale microscopy images improves prediction of treatment response. AB - In this paper, we present a complete and novel workflow for quantitative nuclear feature analysis of glioblastoma using high-throughput whole-slide microscopy image processing as it relates to treatment response and patient survival. With a complete suite of computer algorithms, large numbers of micro-anatomical structures, in this case nuclei, are analyzed and represented efficiently from whole-slide digitized images with numerical features. With regard to endpoints of treatment response, the computerized analysis presents a better discrimination than traditional neuropathologic review. As a result, this analysis method shows potential to facilitate a better understanding of disease progression and patients' response to therapy for glioblastoma. PMID- 22254258 TI - Comparison of survival predictions for rats with hemorrhagic shocks using an artificial neural network and support vector machine. AB - Hemorrhagic shock is the cause of one third of deaths resulting from injury in the world. Early diagnosis of hemorrhagic shock makes it possible for physicians to treat patients successfully. The objective of this study was to select an optimal survival prediction model using physiological parameters from rats during our hemorrhagic experiment. These physiological parameters were used for the training and testing of survival prediction models using an artificial neural network (ANN) and support vector machine (SVM). To avoid over-fitting, we chose the optimal survival prediction model according to performance measured by a 5 fold cross validation method. We selected an ANN with three hidden neurons and one hidden layer and an SVM with Gaussian kernel function as a trained survival prediction model. For the ANN model, the sensitivity, specificity, and accuracy of survival prediction were 97.8 +/- 3.3 %, 96.3 +/- 2.7 %, and 96.8 +/- 1.7 %, respectively. For the SVM model, the sensitivity, specificity, and accuracy were 97.5 +/- 2.9 %, 99.3 +/- 1.1 %, and 98.5 +/- 1.2 %, respectively. SVM was preferable to ANN for the survival prediction. PMID- 22254259 TI - In vivo dynamic imaging, in silico modeling and global sensitivity analysis for the study and the diagnosis of epithelial neoplasia. AB - We present a method for detecting and studying neoplasia-specific functional and structural features through the combination of in vivo dynamic imaging, in silico modeling and global sensitivity analysis. We particularly present the case of cervical epithelium interacting with acetic acid solution, which is employed as an optical biomarker. The in vivo measured dynamic scattering characteristics are strongly correlated with the output of the biomarker's pharmacokinetic model that we have developed. Model global sensitivity analysis has shown that the measured/modeled bio-optical processes can be used for probing, in vivo, the number of neoplastic layers, the extracellular pH, the intracellular buffering efficiency and the size of the extracellular space. PMID- 22254260 TI - Severe sepsis mortality prediction with relevance vector machines. AB - Sepsis is a transversal pathology and one of the main causes of death at the Intensive Care Unit (ICU). It has in fact become the tenth most common cause of death in western societies. Its mortality rates can reach up to 45.7% for septic shock, its most acute manifestation. For these reasons, the prediction of the mortality caused by sepsis is an open and relevant medical research challenge. This problem requires prediction methods that are robust and accurate, but also readily interpretable. This is paramount if they are to be used in the demanding context of real-time decision making at the ICU. In this brief paper, such a method is presented. It is based on a variant of the well-known support vector machine (SVM) model and provides an automated ranking of relevance of the mortality predictors. The reported results show that it outperforms in terms of accuracy alternative techniques currently in use, while simultaneously assessing the relative impact of individual pathology indicators. PMID- 22254261 TI - Multi-scale modeling of glycosylation modulation dynamics in cardiac electrical signaling. AB - The cardiac action potential (AP) is produced by the orchestrated functions of ion channel dynamics. The coordinated functions can be simulated by computational cardiac cell models, which could not only overcome the practical and ethical limitations in physical experiments but also provide predictive insights on the underlying mechanisms. This investigation is aimed at modeling the variations of cardiac electrical signaling due to changes in glycosylation of a voltage-gated K+ channel, hERG, responsible for late phase 2 and phase 3 of the human ventricular AP. The voltage-dependence of hERG channels steady-state activation and inactivation under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich and N-Glycanase treated, demonstrated that reduced glycosylation modulates hERG channel gating. Here, the proposed multi scale computer model incorporates the measured changes in hERG channel gating observed under conditions of reduced glycosylation, and further predicts the electrical behaviors of cardiac cells and tissues (cable/ring). The multi-scale modeling results show that reduced glycosylation would act to shorten the repolarization period of cardiac APs, and distort the AP propagation in cardiac tissues. This multi-scale modeling investigation reveals novel mechanisms of hERG channel modulation by regulated glycosylation that also impact cardiac myocyte and tissue functions. It can potentially lead to new pharmaceutical treatments and drug designs for long QT syndrome and cardiac arrhythmia. PMID- 22254262 TI - Biological and physical methods for risk estimation in interventional radiology: a detrimental effect approach. AB - Interventional radiologists and staff members are frequently exposed to the effects of direct and scattered radiation, which undergo in deterministic effects (radiodermitis, aged skin, cataracts, telangiectasia in nasal region, vasocellular epitelioms, hands depilation) and/or stochastic ones (cancer incidence). A methodology has been proposed for estimating the radiation risk or detriment from a group of six exposed interventional radiologists of the Hospital Universitario La Fe (Valencia, Spain), which had developed general exposition symptoms attributable to deterministic effects of ionizing radiation. Equivalent doses have been periodically registered using termoluminiscence dosimeters (TLD's) and wrist dosimeters, H(p)(10) and H(p)(0.07), respectively, and estimated through the observation of translocations in lymphocytes of peripheral blood (biological methods), by extrapolating the yield of translocations to their respective dose-effect curves. The software RADRISK has been applied for estimating radiation risks in these occupational radiation exposures. The minimum and maximum average excess ratio for skin cancer has been, using wrist physical doses, of [1.03 * 10(-3), 5.06 * 10(-2)], concluding that there is not an increased risk of skin cancer incidence. The minimum and maximum average excess ratio for leukemia has been, using TLD physical doses, of [7.84 * 10(-2), 3.36 * 10(-1)], and using biological doses, of [1.40 * 10(-1), 1.51], which is considerably higher than incidence rates, showing an excess radio-induced risk of leukemia in the group under study. Finally, the maximum radiological detriment in the group, evaluated as the total number of radio-induced cancers using physical dosimetry, has been of 2.18 per 1000 person-year (skin and leukemia), and using biological dosimetry of 9.20 per 1000 PY (leukemia). As a conclusion, this study has provided an assessment of the non-deterministic effects (rate of radio induced cancer incidence) attributable to the group under study due to their professional activity. PMID- 22254263 TI - Locating of the required key-variables to be employed in a ventilation management decision support system. AB - The aim of the paper is to identify the key physiological variables and ventilator settings involved in ventilation management, and required for an appropriate Clinical Decision Support System (CDSS). Based on the results of a questionnaire designed for the purpose of the research, 70 hours of physiological and ventilation data were recorded. Recorded data were classified by clinicians into three major lung pathologies and were further statistically analyzed for identifying strong relationships between monitored and controlled ventilator parameters. Correlation analysis was evaluated by Intensive Care Unit (ICU) clinicians. Based on the evaluators' majority voting the number and type of participating variables in a CDSS was drastically decreased. The number and type of monitored variables ranged from a single one to six, depending on the patient's lung pathology, and the controlled ventilator setting. Evaluation results were successfully applied to Neural Network models for providing suggestions on Tidal Volume and the Fraction of inspired Oxygen. PMID- 22254264 TI - Measurement error robustness of a closed-loop minimal sampling method for HIV therapy switching. AB - We test the robustness of a closed-loop treatment scheduling method to realistic HIV viral load measurement error. The purpose of the algorithm is to allow the accurate detection of an induced viral load minimum with a reduced number of samples. Therapy must be switched at or near the viral-load minimum to achieve optimal therapeutic benefit; therapeutic benefit decreases logarithmically with increased viral load at the switching time. The performance of the algorithm is characterized using a number of metrics. These include the number of samples saved vs. fixed-rate sampling, the risk-reduction achieved vs. the risk-reduction possible with frequent sampling, and the difference between the switching time vs. the theoretical optimal switching time. The algorithm is applied to simulated patient data generated from a family of data-driven patient models and corrupted by experimentally confirmed levels of log-normal noise. PMID- 22254265 TI - Modeling the effects of bivalirudin in cardiac surgical patients. AB - Bivalirudin is direct thrombin inhibitor used in patients with heparin-induced thrombocytopenia. A pharmacokinetic and--dynamic model that predicts the partial thromboplastin time (PTT) based on the past infusion rates of bivalirudin following dose adjustment would be useful to guide optimal therapy. In this retrospective study we randomized 132 patients to a derivation and a validation cohort, and tested two models. The first model is a single-state linear model; the other incorporates a non-linear element to account for renal elimination of bivalirudin. Both models predicted PTT changes equally well with root-mean squared errors of 15 to 16 seconds (Pearson correlation coefficients for both were 0.67). Intra- and inter-individual variability of response to bivalirudin was significant. Although a high percentage of patients had moderate to severe renal dysfunction at one point during the bivalirudin infusion, the non-linear model that incorporates variable renal clearance of drug did not perform better than the linear model. This finding persisted even in the subgroup analysis of patients with moderate and low estimated glomerular filtration rates. PMID- 22254267 TI - 6 and 15 MeV photon spectra reconstruction using an unfolding depth dose gradient methodology. AB - An accurate knowledge of the spectral distribution emission is essential for precise dose calculations in radiotherapy treatment planning. Reconstruction of photon spectra emitted by medical accelerators from measured depth dose distributions in a water cube is an important tool for commissioning a Monte Carlo treatment planning system. However, the reconstruction problem is an inverse radiation transport function which is poorly conditioned and its solution may become unstable due to small perturbations in the input data. In this paper we present a more stable spectral reconstruction method which can be used to provide an independent confirmation of source models for a given machine without any prior knowledge of the spectral distribution. This technique involves measuring the depth dose curve in a water phantom and applying an unfolding method using Monte Carlo simulated depth dose gradient curves for consecutives mono-energetic beams. We illustrate this theory to calculate a 6 and a 15 MeV photon beam emitted from an Elekta Precise radiotherapy unit using the gradient of depth dose curves in a cube-shaped water tank. PMID- 22254266 TI - Training data selection method for prediction of anticancer drug effects using a genetic algorithm with local search. AB - Here, we propose a training data selection method using a Support Vector Machine (SVM) to predict the effects of anticancer drugs. Conventionally, SVM is used for distinguishing between several types of data. However, in the method proposed here, the SVM is used to distinguish areas with only one or two types of data. The proposed method treats training data selection as an optimization problem and involves application of a genetic algorithm (GA). Moreover, GA with local search was applied to find the solution as the target problem was difficult to find. The composition method of GA for proposed method was examined. To determine its effectiveness, the proposed method was applied to an artificial anticancer drug data set. The verification results showed that the proposed method can be used to create a verifiable and predictable discriminant function by training data selection. PMID- 22254268 TI - Sequential versus concurrent computation of complex model systems for medical decision support. AB - Medical Decision Support Systems employ mathematical models to optimize therapy settings. The mathematical models are used to predict patient reactions towards alteration in the therapy regime. This prediction should not be limited to one detail but should feature a broad picture. A previously proposed framework is able to dynamically combine submodels of three model families (respiratory mechanics, gas exchange and cardiovascular dynamics) to form a complex, interacting model system. When concurrent computation of the combined submodels is employed, tests exhibited high computing costs. Therefore, a sequential computing approach is introduced. Thereby, direct interaction between the submodels is not applicable as all submodels are computed individually. To simulate submodel interaction, interface signals that are normally present in the concurrent approach were precalculated using reduced models of respiratory mechanics and cardiovascular dynamics. Evaluation of the new approach showed that results feature a discrepancy lower than 2.5% compared to the results computed by the concurrent approach. Simulation error could be decreased to 2% by improving the precalculation of the interface signals. Computing costs have been decreased by a factor of 17. PMID- 22254269 TI - A study on prediction methods for a cardiovascular strong-coupling simulation. AB - We investigated numerical methods for predictors in a multiscale cardiovascular simulation model. The proposed method predicts initial approximations for the iterative convergence calculations of the strong coupling method using the smoothing spline to remove errors from values of past timesteps and using the linear and second-order extrapolation. The new coupling algorithm was used for coupling a left ventricular finite element model to a myocardial excitation contraction model. We performed experiments with different values for the smoothing parameter lambda and with linear and second-order extrapolations. lambda = 1 with the linear extrapolation gave the best results. It reduced computation time by 91% compared to the strong coupling method. With the use of the smoothing spline, distance between the initial approximation and converged solution reduced by 62%, while the average number of iterations reduced by 32%. The smoothing spline can be used to improve the accuracy of predictors and reduce the number of iterations needed for the computation of the convergence procedure. PMID- 22254270 TI - Analysis of cell cycle dynamics using probabilistic cell cycle models. AB - In this study, we develop asynchronous probabilistic cell cycle models to quantitatively assess the effect of ionizing radiation on a human colon cancer cell line. We use both synchronous and asynchronous cell populations and follow treated cells for up to 2 cell cycle times. The model outputs quantify the changes in cell cycle dynamics following ionizing radiation treatment, principally in the duration of both Gi and G(2)/M phases. PMID- 22254271 TI - Agent based modeling of blood coagulation system: implementation using a GPU based high speed framework. AB - The coagulation and fibrinolytic systems are complex, inter-connected biological systems with major physiological roles. The complex, nonlinear multi-point relationships between the molecular and cellular constituents of two systems render a comprehensive and simultaneous study of the system at the microscopic and macroscopic level a significant challenge. We have created an Agent Based Modeling and Simulation (ABMS) approach for simulating these complex interactions. As the scale of agents increase, the time complexity and cost of the resulting simulations presents a significant challenge. As such, in this paper, we also present a high-speed framework for the coagulation simulation utilizing the computing power of graphics processing units (GPU). For comparison, we also implemented the simulations in NetLogo, Repast, and a direct C version. As our experiments demonstrate, the computational speed of the GPU implementation of the million-level scale of agents is over 10 times faster versus the C version, over 100 times faster versus the Repast version and over 300 times faster versus the NetLogo simulation. PMID- 22254272 TI - Regulatory network analysis acceleration with reconfigurable hardware. AB - In medical research it is of great importance to be able to quickly obtain answers to inquiries about system response to different stimuli. Modeling the dynamics of biological regulatory networks is a promising approach to achieve this goal, but existing modeling approaches suffer from complexity issues and become inefficient with large networks. In order to improve the efficiency, we propose the implementation of models of regulatory networks in hardware, which allows for highly parallel simulation of these networks. We find that our FPGA implementation of an example model of peripheral naive T cell differentiation provides five orders of magnitude speedup when compared to software simulation. PMID- 22254273 TI - Example-based support vector machine for drug concentration analysis. AB - Machine learning has been largely applied to analyze data in various domains, but it is still new to personalized medicine, especially dose individualization. In this paper, we focus on the prediction of drug concentrations using Support Vector Machines (S VM) and the analysis of the influence of each feature to the prediction results. Our study shows that SVM-based approaches achieve similar prediction results compared with pharmacokinetic model. The two proposed example based SVM methods demonstrate that the individual features help to increase the accuracy in the predictions of drug concentration with a reduced library of training data. PMID- 22254274 TI - Parameter fitting using multiple datasets in cardiac action potential modeling. AB - A multiple dataset model fitting approach for improving parameter reliability in action potential modeling is presented. A robust generic cardiac ionic model employing membrane currents based on two-gate Hodgkin-Huxley kinetics is described. Its generic nature allows it to accurately reproduce action potential waveforms in heterogeneous cardiac tissue by optimizing parameters governing ion channel kinetics and magnitudes. The model allows a user-defined number of voltage and time-dependent ion currents to be incorporated, in order to reproduce and predict multiple action potential waveforms recorded in intact cardiac myocyte. In total 12 N(c)+2 parameters were optimized using a curvilinear gradient method, where N(c) is the user-specified number of time-dependent currents. Given appropriate experimental datasets, many of the known physiological membrane currents could be effectively reconstructed. Also, the optimized models were able to predict additional experimental action potential recordings that were not used in the optimization process. PMID- 22254275 TI - A framework for mapping between "living" muscle model parameters and systems biology data for muscle tissue. AB - Striated muscle represents a unique type of actuator in that it depends on living tissue. Models of muscle have historically focused on the role of actuator, using properties that do not adapt over time. This paper extends the foundation of Hill based muscle models by considering muscle as a tissue composed of well-mixed composite materials (at the level of fascicle), and identifies three specific classes of protein families that occupy functional space functional space: excitation -> activation; mechanical attachment/transmission, and myo-energy supply. Typically parameters describing nonlinear muscle properties have been estimated either directly or based on anthropometry and fiber composition. Here we develop a framework for augmenting such estimation through mapping to the up/down-regulation of specific proteins and their transcripts. While useful for establishing a framework for "living" muscle models that can evolve, it also provides an attractive approach for helping interpret high-throughput systems biology data, especially muscle tissue biopsies from studies that target interventional tasks and/or myo-disorders. PMID- 22254276 TI - Nonlinear solution for radiation boundary condition of heat transfer process in human eye. AB - In this paper we propose a new method based on finite element method for solving radiation boundary condition of heat equation inside the human eye and other applications. Using this method, we can solve heat equation inside human eye without need to model radiation boundary condition to a robin boundary condition. Using finite element method we can obtain a nonlinear equation, and finally we use nonlinear algorithm to solve it. The human eye is modeled as a composition of several homogeneous regions. The Ritz method in the finite element method is used for solving heat differential equation. Applying the boundary conditions, the heat radiation condition and the robin condition on the cornea surface of the eye and on the outer part of sclera are used, respectively. Simulation results of solving nonlinear boundary condition show the accuracy of the proposed method. PMID- 22254277 TI - Discrete interference modeling via boolean algebra. AB - Two types of boolean functions are considered, the locus function of n variables, and the interval function of nu = n - 1 variables. A 1-1 mapping is given that takes elements (cells) of the interval function to antidual pairs of elements in the locus function, and vice versa. A set of nu binary codewords representing the intervals are defined and used to generate the codewords of all genomic regions. Next a diallelic three-point system is reviewed in the light of boolean functions, which leads to redefining complete interference by a logic function. Together with the upper bound of noninterference already defined by a boolean function, it confines the region of interference. Extensions of these two functions to any finite number of nu are straightforward, but have been also made in terms of variables taken from the inclusion-exclusion principle (expressing "at least" and "exactly equal to" a decimal integer). Two coefficients of coincidence for systems with more than three loci are defined and discussed, one using the average of several individual coefficients and the other taking as coefficient a real number between zero and one. Finally, by way of a malfunction of the mod-2 addition, it is shown that a four-point system may produce two different functions, one of which exhibiting loss of a class of odd recombinants. PMID- 22254278 TI - Estimating brain microvascular blood flows from partial two-photon microscopy data by computation with a circuit model. AB - The cortical microvasculature plays a key role in cortical tissue health by transporting important molecules via blood. Disruptions to blood flow in the microvasculature due to events such as stroke can thus induce damage to the cortex. Recent developments in two-photon microscopy have enabled in vivo imaging of anesthetized rat cortex in three dimensions. The microscopy data provide information about the geometry of the cortical microvasculature, length and diameter of the vessels in the imaged microvasculature network, and blood flow through a subset of those vessels. We demonstrate a model that achieves three goals. First, given a network of interconnected vessels and flow measurements on a subset of those vessels, we can estimate the flows in the remaining vessels. Second, we can determine which and how many vessels should have blood flow measurements taken to provide sufficient information to predict the unmeasured flows. Finally, the model enables us to predict effects of blockages in one or more vessels, indicating which vessels are most important to overall flow in the network. PMID- 22254279 TI - Mechanical forces mediate localized topological change in epithelia. AB - Regulation of cell growth and proliferation has a fundamental role in tissue development, organogenesis, and disease progression. Conserved distribution of the number of sides of cells with a mean value of six was found in a variety of proliferating epithelia. Previous studies have shown that clones of proliferating cells bounded by quiescent cells have fewer sides than normal epithelia. However, the mechanisms for mediating such localized topological change remain poorly understood. In this study, we use a two-dimensional vertex model with consideration of mechanical forces to investigate how differential proliferation and forces can influence cell shape and tissue morphogenesis, and how they may lead to distorted topological change. We find that differential proliferation alone is insufficient to affect the topology of boundary proliferating cells. Rather, increased surface tension on the boundary, in addition to differential proliferation, can significantly decrease the average number of cell sides. Our results are consistent with experimental observations. We conclude that mechanical forces in addition to localized differential proliferation are required to produce the distorted topological change which significantly impacts the overall cell shape and tissue morphogenesis. PMID- 22254280 TI - Mathematical, numerical and experimental study in the human aorta with coexisting models of bicuspid aortic stenosis and coarctation of the aorta. AB - Coarctation of the aorta is an obstruction of the aorta and is usually associated with other concomitant cardiovascular abnormalities especially with bicuspid aortic valve stenosis. The objectives of this study are, (1) to investigate the effects of coarctation on the hemodynamics in the aorta to gain a better understanding of the cause of certain post-surgical coarctation problems, (2) to develop and introduce a new lumped parameter model, mainly based on non-invasive data, allowing the description of the interaction between left ventricle, coarctation of the aorta, aortic valve stenosis, and the arterial system. PMID- 22254281 TI - Endothelial cell culture model of carotid artery atherosclerosis. AB - Atherosclerotic lesions form non-randomly at locations in bends and bifurcations where the local flow can be classified as 'disturbed flow' and is associated with low shear stress oscillatory or reciprocating flow. Endothelial cells in vivo are constantly exposed to mechanical stimulation due to hemodynamic loading in the form of pulsatile pressure, cyclic stretch and shear stress to maintain phenotype and control function. In conditions like atherosclerosis, the pressure and strain loading remains the same whereas the local fluid flow behavior and shear stress are altered. Common in vitro models of atherosclerosis focus primarily on shear stress without accounting for pressure and strain loading. To overcome this limitation, we used our microfluidic Endothelial Cell Culture Model (ECCM) to achieve accurate replication of pressure, strain and shear stress waveforms associated with both normal flow seen in straight sections of arteries and disturbed flow seen atherosclerosis lesion susceptible regions. We specifically recreated mechanical stresses associated with the proximal internal carotid which is a major risk factor for stroke. Cells cultured using both conditions show distinct differences in alignment and cytoskeletal organization. In summary we recreated pressure, stretch and shear stress loading seen in straight sections and in the proximal internal carotid in a cell culture compatible platform. PMID- 22254282 TI - A cycle-averaged model of hypoplastic left heart syndrome (HLHS). AB - This paper is concerned with computational modeling of a severe congenital defect called Hypoplastic left heart syndrome (HLHS) that is the most common cardiac malformation with the highest likelihood of deaths in newborns. A lumped parameter model of the HLHS circulation has been developed to study the hemodynamic variables in the various sections of the cardio-pulmonary circulation system. We applied a short-term, cycle-averaging operation to the differential equations of the HLHS model to obtain the cycle-averaged model. Study has been carried out to analyze the variation of blood flow rate in different parts due to parameter changes. Results show that the developed model, could bring a good insight into understanding of the HLHS disease. PMID- 22254283 TI - Computer simulation and experimental analysis of LDL transport in the arteries. AB - Atherosclerosis develops from oxidized low-density lipoprotein molecules (LDL). When oxidized LDL evolves in plaque formations within an artery wall, a series of reactions occur to repair the damage to the artery wall caused by oxidized LDL. Macrophages accumulate inside arterial intima, they started to collect oxidized LDL and form foam cells. Smooth muscle cells accumulate in the atherosclerotic arterial intima, where they proliferate and secrete extracellular matrix to form a fibrous cap. In this study, experimental model of LDL transport on the isolated blood vessel from rabbit on high fat diet after 8 weeks is simulated numerically by using a specific model and histological data. The 3D blood flow is governed by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow by the convection-diffusion equation. LDL transport in lumen of the vessel is described by Kedem-Katchalsky equations. The inflammatory process is solved using three additional reaction-diffusion partial differential equations. Matching of histological rabbit data is performed using 3D histological image reconstruction and 3D deformation of elastic body. Computed concentrations of labeled LDL of 5.2 % and macrophages distribution of 4.2% inside the media are found to be in good agreement with experimental results. This simulation study provides a useful tool for understanding and prediction of LDL transport through the arterial wall and evolution of atherosclerotic plaques. PMID- 22254284 TI - Variation of wave speed determined by the PU-loop with proximity to a reflection site. AB - Wave speed is directly related to arterial distensibility and is widely used by clinicians to assess arterial stiffness. The PU-loop method for determining wave speed is based on the water hammer equation for flow in flexible tubes and artery using the method of characteristics. This technique determines wave speed using simultaneous measurements of pressure and velocity at a single point. The method shows that during the early part of systole, the relationship between pressure and velocity is generally linear, and the initial slope of the PU-loop is proportional to wave speed. In this work, we designed an in-vitro experiment to investigate the effect of proximity to a reflection site on the wave speed determined by the PU-loop through varying the distance between the measurement and reflection sites. Measurements were made in a flexible tube with a reflection site at the distal end formed by joining the tube to another tube with a different diameter and material properties. Six different flexible tubes were used to generate both positive and negative reflection coefficients of different magnitudes. We found that the wave speed determined by the PU-loop did not change when the measurement site was far from the reflection site but did change as the distance to the reflection site decreased. The calculated wave speed increased with positive reflections and decreased with negative reflections. The magnitude of the change in wave speed at a fixed distance from the reflection site increased with increasing the value of the reflection coefficient. PMID- 22254285 TI - Arterial diameter measurement using high resolution ultrasonography: in vitro validation. AB - Simultaneous measurement of pressure and diameter in blood vessels or vascular prosthesis is of great importance in cardiovascular research. Knowledge of diameter changes as response to intravascular pressure is the basis to estimate the biomechanical properties of blood vessel. In this work a new method to quantify arterial diameter based in high resolution ultrasonography is proposed. Measurements on an arterial phantom placed on a cardiovascular simulator were performed. The results were compared to sonomicrometry measurements considered as gold standard technique. The obtained results indicate that the new method ensure an optimal diameter quantification. This method presents two main advantages respect to sonomicrometry: is noninvasive and the vessel wall strain can be measured directly. PMID- 22254286 TI - Gender-related differences in the excess pressure component of central aortic pressure waveform of healthy young. AB - Gender-related difference in cardiovascular diseases is one of the most investigated and still unsolved issues. Finding an explanation to this topic might have important implications for the understanding of the differences between men and women in diseases and possibly lead to the development of gender specific strategies for its management. Recent studies have proposed that the capacitive or reservoir function of the aorta and large elastic arteries plays a major role in determining the pulse wave morphology. The pressure waveform can be explained in terms of a reservoir pressure related to arterial compliance and an "excess" or wave-related pressure associated with traveling waves. Gender differences in the ascending aorta pressure waveform reservoir and excess components are to be characterized. The aim of this study was to evaluate, by means of a mathematical approach, gender-related differences in the central aortic pressure waveform components. Central aortic pressure waveform was non invasively obtained in 22 healthy subjects (Age: 20 years old; 11 female). Males and females showed differences in the level and time to maximal excess pressure component, but no gender-related differences were found in the reservoir one. PMID- 22254287 TI - Pulse wave velocity normal levels in a Uruguayan population: differences between 'adjusted' and measured values vary depending on age and the calculation algorithm used. AB - Carotid-femoral pulse wave velocity (PWV) has emerged as the gold standard for non-invasive evaluation of aortic stiffness. However, the absence of standardized methodologies of study and lack of normal and references values have limited wider implementation of PWV in clinical practice. In this work normal PWV levels were determined in a Uruguayan population and the obtained values were analyzed taking into account data from other populations. The differences between the 'real' PWV levels and the PWV calculated using different wave detection algorithms and path lengths were assessed, and compared the taking into account the changes in PWV with aging. RESULTS: The Uruguayan population showed a rate of PWV increase comparable to that reported previously in non-hypertensive European subjects, although overall, PWV values were approximately 2 m/s higher in the Uruguayan population. The different approaches used to calculate the PWV showed differences in their availability to follow aging-variations in 'adjusted' (or 'real') PWV. PMID- 22254288 TI - Using nanosecond pulse near-field sensing technology for non-contact cardiovascular parameters measurement. AB - Clinically arterial stiffness has shown that it is the most important cause of cardiovascular complications and also an independent risk factor to several cardiovascular diseases. In routine, there are many preferable non-invasive methods, including pressure-sensitive transducers, applanation tonometry, Doppler ultrasound and MRI, to get insight of cardiovascular condition. However, the operation of traditional monitors is relied on professionals' experience, and also the sensing probes needed to exert pressure to the user directly. The measurement procedure is short-term and easy to cause discomfort. To improve the issues of these measuring techniques, the non-contact and non-invasive measuring method will become an important innovation. In this paper, the novel nanosecond pulse near-field sensing (NPNS) based screening technology, which includes radio frequency (RF) pulse transmission and a flat antenna connected to transceiver of miniature radar, is proposed to monitor cardiovascular activity. A dedicated analysis software is also provided to calculate cardiovascular parameters, including PWV, average systolic time, reflection index (RI), heart and heart rate variability (HRV), for clinical applications. To evaluate the performance, the proposed method was applied on aortic pulse measurement at the body site of chest. As a result, it shows 0.92 correlations with the measurement result from commercial product, and performs the capability of continuously long-term monitoring in real-time. PMID- 22254289 TI - Wave speed and intensity in the canine aorta: analysis with and without the Windkessel-wave system. AB - The Windkessel model, coupled with the wave propagation theory, was applied to data measured in the ascending aorta of 11 anaesthetised dogs during total aortic occlusion at the thoracic and diaphragm levels. Wave speed and wave intensity were calculated using the measured pressure (P) and velocity (U), and separately using the pressure due to the wave (P(ex)) and U in the aorta approximately 1 cm distal to the aortic valve. Results show that wave speed, determined using the PU loop method, is higher during thoracic than in diaphragm occlusion (p<0.001). On average wave speed calculated using P (c) is higher than that determined using P(ex) (c(WK)) in both occlusion sites (p<0.001). During aortic occlusion at the thoracic level, the intensity of backward waves was almost negligible using the Windkessel-wave system. Backward waves were observed during the occlusion at the diaphragm level, but their magnitude is lower compared to that determined with P. The Windkessel-wave system seems to reduce the magnitude of reflected waves during total aorta occlusion, notably if the occlusion sites are close to the ascending aorta. PMID- 22254290 TI - Assessment of cardiac function during mechanical circulatory support: the quest for a suitable clinical index. AB - A new index to assess left ventricular (LV) function in patients implanted with continuous flow left-ventricular assist devices (LVADs) is proposed. Derived from the pump flow signal, this index is defined as the coefficient (k) of the semilogarithmic relationship between "pseudo-ejection" fraction (pEF) and the volume discharged by the pump in diastole, (V d). pEF is defined as the ratio of the "pseudo-stroke volume" (pSV) to V d. The pseudo-stroke volume is the difference between V d and the volume discharged by the pump in systole (V s), both obtained by integrating pump flow with respect to time in a cardiac cycle. k was compared in-vivo with others two indices: the LV pressure-based index, M(TP), and the pump flow-based index, I(Q). M(TP) is the slope of the linear regression between the "triple-product" and end-diastolic pressure, EDP. The triple-product, TP = LV SP.dP/dt(max). HR, is the product of LV systolic pressure, maximum time derivative of LV pressure, and heart rate. I(Q) is the slope of the linear regression between maximum time-derivative of pump flow, dQ/dt(max), and pump flow peak-to-peak amplitude variation, Q(P2P). To test the response of k to contractile state changes, contractility was altered through pharmacological interventions. The absolute value of k decreased from 1.354 +/- 0.25 (baseline) to 0.685 +/- 0.21 after esmolol infusion. The proposed index is sensitive to changes in inotropic state, and has the potential to be used clinically to assess contractile function of patients implanted with VAD. PMID- 22254291 TI - Preprocessing of fluoresced transmembrane potential signals for cardiac optical mapping. AB - Fluorescence imaging of transmembrane voltage-sensitive dyes is used to study electrical activation in cardiac tissue. However, fluorescence signals typically have a low signal to noise ratio that can be contaminated with motion artifacts. We describe an alternative processing approach for fluoresced transmembrane potentials (fTmps) using the wavelet multiresolution analysis. We show that fTmp signals can be decomposed and reconstructed to form three sub-signals that contain signal noise (noise signal), the early depolarization phase of the action potential (rTmp signal), and motion artifact (rMA signal). Discrete wavelet transform is used with coiflet 4 scaling and wavelet functions for fTmp decomposition and reconstruction of these sub-signals. Our results show that this type of analysis can be used to remove baseline drift, reduce noise, and reveal wavefronts. It streamlines the preprocessing of fTmps for subsequent measurement of activation times and conduction velocities. The approach is promising for studying wave fronts without aggressive mechanical tissue constraint or electromechanical uncoupling agents, and it is particularly useful for single camera systems that do not provide for ratiometric imaging. PMID- 22254292 TI - Relating spatial heterogeneities to rotor formation in studying human ventricular fibrillation. AB - Ventricular fibrillation (VF) occurs due to disorganized electrical activity in the ventricles. This leads to rapid uncoordinated contractions of the ventricles and sudden cardiac death if not treated within minutes of its occurrence. The mechanism of VF initiation and maintenance is still elusive, however the mother rotor and multiple wavelet theories attempt to explain the mechanism behind this lethal arrhythmia. In mother rotor theory, VF is believed to be maintained by high frequency periodic sources called rotors that could be tracked using the phase progression along and through the myocardium using spatio-temporal electrical mapping of the heart. There are exiting works including our previous works that have related the formation of these rotors to anatomical and physiological heterogeneities observed in the myocardium. In this study we performed an correlation exercise of the locations of rotors with scar boundary maps and dominant frequency maps and elucidated this relation using human VF data acquired from isolated human hearts. The results suggest that in 14 rotors over 6 human hearts that we studied, all rotors co-localized to boundary zones of scar and low-high dominant frequency locations. The mean variance of the dominant frequency over the spatial location of the rotor was found to be 0.55 with average minimum of 4.15 Hz to a maximum of 5.71 Hz. This results in human VF data strongly suggest that boundary zones of healthy-non-healthy tissues and low-high frequency boundaries form a favorite substrate for rotor formation. PMID- 22254293 TI - Characteristics of inverse-computed epicardial electrograms of Brugada syndrome patients. AB - Brugada syndrome (BrS) causes sudden death in patients with structurally normal hearts. Manifestation of BrS in the ECG is dynamic and most patients do not show unequivocal signs of the syndrome during ECG screening. Electrograms (EGMs) of BrS patients show conduction delay and fractionation at the right ventricular outflow tract area (RVOT) and thus could be used for diagnosis, but their recording requires an invasive procedure. We have obtained 67-lead body surface potential mapping recordings (BSPM) of 6 BrS patients and 6 controls and computed their EGMs by solving the inverse problem of electrocardiography by using Tikhonov's regularization method. Inverse-computed EGMs presented similar activation times and durations in controls and BrS patients for apex and septum. However, RVOT EGMs showed a later activation in BrS patients than in controls (58 +/- 7 vs. 39 +/- 5 ms, p<0.01) and EGMs were longer (122 +/- 22 vs. 85 +/- 8 ms, p<0.01). Inverse-computed EGMs of BrS patients showed abnormalities consistent with those observed in electrophysiological studies and could be used for a non invasive diagnosis and characterization of Brugada syndrome. PMID- 22254294 TI - Measuring defibrillator surface potentials for simulation verification. AB - Though implantable cardioverter defibrillators (ICDs) are increasing in use in both adults and children, little progress has been devoted to optimizing device and electrode placement. To facilitate effective ICD placement, especially in pediatric cases, we have developed a predictive model that evaluates the efficacy of a delivered shock. We have also developed an experimental validation approach based on measurements from clinical cases. The approach involves obtaining body surface potential maps of ICD discharges during implantation surgery using a limited lead selection and body surface estimation algorithm. Comparison of the simulated and measured potentials yielded very similar patterns and a typical correlation greater than 0.93, suggesting that the predictive simulation generates realistic potential values. This validation approach provides confidence in application of the simulation pipeline and offers areas to focus future improvements. PMID- 22254295 TI - Cathether contact geometry affects lesion formation in radio-frequency cardiac catheter ablation. AB - One factor which may be important for determining proper lesion creation in an atrial ablation procedure is catheter-endocardial contact. Little information is available that relates geometric contact, depth and angle, to ablation lesion formation. We present an electrothermal computer model of ablation that calculates lesion volume and temperature development over time. The Pennes bioheat equation was coupled to a quasistatic electrical problem. This method simulates importantly, not just catheter penetration depth, but also several different incident catheter angles as may occur in practise. Results show that for deeply penetrating tips, greater catheter angles reduce the rate of temperature buildup, allowing for larger lesions to form before temperatures become dangerous. It was also found that greater penetration may not lead to greater transmurality in lesion formation. We conclude that catheter contact angle plays a significant role in lesion formation, and the time course must be considered. This is clinically relevant because it makes proper identification and prediction of geometric contact variables a necessity in order to improve ablation efficacy and safety. PMID- 22254296 TI - Topology and conduction in the inferior right atrial isthmus measured in rabbit hearts. AB - The inferior right atrial isthmus consisting of the terminal crest, the network of pectinate muscles, and the vestibule shows very complex anatomical structure. It is seen as potential substrate for atrial flutter. In this work we present results from an electro-anatomical characterization of this region based on Cardiac Near Field recordings taken from five preparations of rabbit atrium. Pectinate muscles in the region of interest were divided into three segments: central as well as proximal and distal with respect to the terminal crest. Electrograms measured in these segments showed differences in the degree of fractionation, i.e. the numbers of distinct local activation events, indicating heterogeneities in microstructure. From 249 recording sites 63.9% showed no fractionation, 26.9% showed two activation events, and 9.2% were highly fractionated. The proximal starting sequence of activation in a series of adjacent pectinate muscles is not sorted but rather seems to be arbitrary. The same applies to the arrival sequence of activation close to the vestibule. In the network of pectinate muscles on average one proximal segment branches into two central strands and two central strands merge into one distal stem. PMID- 22254297 TI - Predicting refibrillation from pre-shock waveforms in optimizing cardiac resuscitation. AB - Ventricular fibrillation (VF) is a lethal cardiac arrhythmia that if untreated within minutes of its occurrence will lead to sudden cardiac death. Defibrillation using electric shocks is the only choice of treatment to restore the heart to normal rhythm especially in out-of-the-hospital VF incidents. Refibrillation (i.e., recurrence of VF) is a common and significant problem in cardiac resuscitation as it negatively impacts the survival rates. In such refibrillation cases administration of anti-arrhythmic drugs could improve the shock outcomes or prevent refibrillation. In cases of prolonged VF, cardio pulmonary resuscitation (CPR) prior to the shocks have been shown to improve the survival rates. The proposed work using wavelet analysis of the pre-shock VF electrograms attempts to predict the shock outcomes as successful, refibrillation, and unsuccessful categories. This feedback in real-time would be of immense assistance to the Emergency Medical Services (EMS) personnel in choosing the right combination of therapies (i.e., shock, CPR, pharmacology interventions) in improving the shock outcomes. Using a real-word database of 34 pre-shock VF electrograms obtained from Toronto area EMS personnel, the proposed method achieved classification accuracies of 76.5% and 75% for a two level binary classification of the three groups. PMID- 22254298 TI - Ventricular fibrillation threshold of rapid short pulses. AB - The risk of VF (ventricular fibrillation) from continuous AC utility (50/60 Hz) power has been well quantified and is reflected in accepted standards. Similarly, the required charge for a single pulse delivered during the T-wave of the ECG is also quantified. However, there are no studies that deal with the VF risk of a train of multiple short pulses such as those used in electric fences and conducted electrical weapons (CEWs). We studied 5 swine with an electrode placed through the anterior chest such that the tip was 10 mm from the epicardium. A return electrode was attached remotely to the lower abdomen. Five-second trains of 100 MUs pulses at rates of 10-70 PPS (pulses per second) were delivered with gradually increasing charges until VF was induced. The VF threshold was also determined for 60 Hz AC current. As expected, the VF charge threshold decreased with increasing rates. For pulse rates between 10-30 PPS, the aggregate current (= charge * pulse rate) was constant at the VF threshold. The VF threshold in terms of AC RMS current was 7.4 +/- 1.9 times the aggregate current VF threshold for the rapid short pulses. These results may have utility for setting safety standards for electric fences and for CEWs such as TASER(r) CEWs. This also allows for the risk assessment of CEWs by comparison to international electrical safety standards. The output of these weapons appears to be well below the VF risk limits as set by these standards. PMID- 22254299 TI - Cardiac alternans annihilation by distributed mechano-electric feedback (MEF). AB - The presence of the electrical alternans induces, through the mechanism of the excitation-contraction coupling, an alternation in the heart muscle contractile activity. In this work, we demonstrate the cardiac alternans annihilation by applied mechanical perturbation. In particular, we address annihilation of alternans in realistic heart size tissue by considering ionic currents suggested by Luo-Rudy-1 (LR1) model, in which the control algorithm involves a combined electrical boundary pacing control and a spatially distributed calcium based control which perturbs the calcium in the cells. Complimentary to this, we also address a novel mechanism of alternans annihilation which uses a Nash Panfilov model coupled with the stress equilibrium equations. The coupled model includes an additional variable to represent the active stress which defines the mechanical properties of the tissue. PMID- 22254300 TI - Modeling cardiac pacemaker malfunctions with the Virtual Heart Model. AB - Implantable cardiac devices such as artificial pacemakers deliver therapies according to the timing information from the heart. Such devices work under the assumptions of perfect sensing, which are: (a) the pacemaker leads remain in place, and (b) the pacing therapy in one chamber (e.g. atrium) is insulated from the other chambers (e.g. ventricles). But there are common cases which violate these assumptions and the mechanisms for imperfect sensing cannot be captured by a simple signal generator. In this paper we use the Penn Virtual Heart Model (VHM) to investigate the spatial and temporal aspects of the electrical conduction system of the heart in a closed-loop with a pacemaker model. We utilize the spatial properties of the heart to model the sensing mechanism, and use clinical cases to show the validity of our sensing model. Such closed-loop evaluation of the pacemaker operation allows for functional testing of pacemaker software, the development of new algorithms for rhythm therapy and also serves as a tool for incoming cardiac electrophysiology fellows. PMID- 22254301 TI - A toolkit for forward/inverse problems in electrocardiography within the SCIRun problem solving environment. AB - Computational modeling in electrocardiography often requires the examination of cardiac forward and inverse problems in order to non-invasively analyze physiological events that are otherwise inaccessible or unethical to explore. The study of these models can be performed in the open-source SCIRun problem solving environment developed at the Center for Integrative Biomedical Computing (CIBC). A new toolkit within SCIRun provides researchers with essential frameworks for constructing and manipulating electrocardiographic forward and inverse models in a highly efficient and interactive way. The toolkit contains sample networks, tutorials and documentation which direct users through SCIRun-specific approaches in the assembly and execution of these specific problems. PMID- 22254302 TI - Ventricular fibrillation risk estimation for conducted electrical weapons: critical convolutions. AB - The TASER(r) Conducted Electrical Weapon (CEW) is used by law enforcement agencies about 900 times per day worldwide and has been shown to reduce suspect and officer injuries by about 65%. However, since a CEW delivers rapid electrical pulses through injected probes, the risk of inducing ventricular fibrillation (VF) has been considered. Animal studies have shown that the tip of the probe must come within a few millimeters of the surface of the heart for the CEW to induce VF in a typical animal application. Early calculations of the CEW VF risk in humans used sophisticated 3-D chest models to determine the size of the probe landing areas that had cardiac tissue within a given distance of the inner surface of the ribs. This produced a distribution of area (cm(2)) vs. mm of depth. Echocardiography was then used to determine the shortest distance from the skin surface to the cardiac surface. This produced a population distribution of skin-to-heart (STH) distances. These 2 distributions were then convolved to arrive at a probability of inducing VF for a typical human CEW application. With 900, 000 probe-mode field uses to date, epidemiological results have shown that these initial VF risk estimates were significant overestimates. We present model refinements that take into account the gender and body-mass-index (BMI) of the target demographics and produce VF risk estimates concordant with the epidemiological results. The risk of VF is estimated at 0.4 per million uses with males. PMID- 22254303 TI - Design of an embedded PID controller applied to blood pressure control. AB - Some diseases, such as hypertension, require a close control of the patient's blood pressure. This is even more critical when that patient is going through--or has just underwent--a surgical procedure In such situations, reducing blood pressure to normal levels is of paramount importance. Usually, this demanding and time consuming monitoring is done manually by clinical personnel and are subject to mistakes and inconsistent practices. In this paper, we propose a solution to the manual monitoring through the design and implementation of an embedded PID controller to handle blood pressure, integrated to an automated monitoring system to assist in detecting anomalies and to optimize the process of patient care. PMID- 22254304 TI - Effects of radiotherapy fractionation on breast stromal activity. AB - We study the dynamics of tumor cell progression as growth factors and ionizing radiation (IR) combine to modify cellular microenvironments. Breast tumor growth depends on the behavior of cancer cells in their microenvironment, and both components are affected by IR fractionation parameters. TGF-beta1 promotes differentiation of fibroblasts to myofibroblasts, which stiffens the extracellular matrix (ECM) and promotes malignant cell phenotypes. IR generates reactive oxygen species (ROS) that damages and inactivates cells thus controlling proliferation. The effects of TGF-beta1 and IR at various fraction sizes on ECM stiffness and fibroblast differenation are studied using MRC-5 fibroblasts in 3-D collagen cultures. PMID- 22254305 TI - Non-linear stress-strain measurements of ex vivo produced oral mucosal equivalent (EVPOME) compared to normal oral mucosal and skin tissue. AB - Stress-strain curves of oral mucosal tissues were measured using direct mechanical testing. Measurements were conducted on both natural oral mucosal tissues and engineered devices, specifically a clinically developed ex vivo produced oral mucosal equivalent (EVPOME). As seeded cells proliferate on EVPOME devices, they produce a keratinized protective upper layer which fills in surface irregularities. These transformations can further alter stress-strain parameters as cells in EVPOME differentiate, more similar to natural oral mucosal tissues in contrast to an unseeded scaffold. In addition to tissue devices grown under normal conditions (37 degrees C), EVPOMEs were also produced at 43 degrees C. These thermally stressed specimens model possible failure mechanisms. Results from a mechanical deformation system capable of accurate measurements on small (approximately 1.0-1.5 cm(2)) cylindrical tissue samples are presented. Deformations are produced by lowering a circular piston, with a radius smaller than the sample radius, onto the center of the sample. Resulting force is measured with a precision electronic balance. Cultured EVPOME was less stiff than AlloDerm(r), but similar to native porcine buccal tissue. Porcine skin and porcine palate tissues were even less stiff. Thermally stressed EVPOME was less stiff than normally cultured EVPOME as expected because stressed keratin cells were damaged reducing the structural integrity of the tissue. PMID- 22254306 TI - MEMS-assisted spatially homogeneous endothelialization of a high length-to-depth aspect ratio microvascular network. AB - The endothelialization of an engineered microvascular network is constrained by the mass transport of the endothelial cells through high length-to-depth (l/d) aspect ratio microchannels. This paper presents a deformable, reentrant microvascular scaffold as a microelectromechanical systems (MEMS)-assisted approach for spatially homogeneous endothelial cell seeding of high l/d (>200) aspect ratio microvasculature. Nickel electroplating and micromolding were employed for the fabrication of the polydimethylsiloxane (PDMS) reentrant microvascular scaffold. A 'stretch--seed--seal' ('3S') operation was implemented for uniform incorporation of endothelial cells on the luminal surface of the elastomeric constructs. Confocal microscopy was utilized to establish the uniformity of endothelialization and to demonstrate the feasibility of this strategy. PMID- 22254307 TI - The electric field system of a macular ion channel plaque. AB - Recent empirical neuroscience evidence increasingly supports an active role for the endogenous electromagnetic (EM) field system of brain tissue. These results undermine the long-held view that the field system is a causally inert byproduct of action potential and synapse electrochemical activity. The dominant originating mechanism for the endogenous EM field remains undetermined. The new observations make the isolation of an unambiguous original EM field source a matter of some urgency. As part of the process of elaboration of the field systems produced by coherent transmembrane filamentary currents (the most plausible original mechanism), this paper looks at the contribution by a localized density of cooperating ion channels in the form of the macular synaptic plaque engaged in conducting a post-synaptic current. The method uses the volume conduction formalism driven by filamentary currents that stand in for ion channels. Not surprisingly, the result is a pulsing dipole. Despite its extreme material abstraction, the result forms one of the basic mechanisms for future models capable of revealing whole-neuron and network-level endogenous EM field system. PMID- 22254308 TI - A wearable stimulation bandage for electrotherapy studies in a rat ischemic wound model. AB - The clinical efficacy of electro-therapy in the treatment of chronic wounds is currently debated, and a in-vivo evaluation of stimulation parameters will provide the statistical evidence needed to direct clinical guidelines. A low cost, wearable electrical stimulation bandage has been developed for use with an established rat ischemic wound model. The bandage consists of a user-programmable stimulator PCB and a plastic bandage with two hydrogel electrodes. The battery powered bandage may be used for up to seven days between dressing changes, and the stimulator may be reused. The microcontroller-based stimulator uses a boost converter circuit to generate pulses up to 90 V from a 3 V coin cell battery. Consistent operation of the boost converter over the wide input and output voltage ranges is achieved using voltage feedforward and soft-start techniques implemented in firmware. The bandages are laser-cut to shape, and electrical traces are applied using stencils and conductive nickel paint. Both the PCB and electrical traces are encapsulated to protect the animal. The device has been successfully demonstrated using the rat ischemic wound model for a period of seven days, and clinical experiments are ongoing. PMID- 22254309 TI - Microdosimetry applied to nanosecond pulsed electric fields: a comparison on a single cell between real and ideal waveforms. AB - A microdosimetric analysis using ideal and real pulses was carried out in this paper. To perform this goal, authors employed an algorithm developed recently for nsPEF based on Laplace's equation and able to take into account cell compartment dispersivity. A comparison between biphasic real and ideal waveforms was carried out. The ideal pulse induced the highest pore density efficiency, hence evidencing that a device optimization to avoid waveform degradation and losses has a fundamental impact on the performances of the delivered pulses at the single cell level. PMID- 22254310 TI - A thermal stereoscope for surface reconstruction of the diabetic foot. AB - We have constructed a thermal stereoscope utilizing three digital SLR cameras and an infrared camera for rapid surface reconstruction of diabetic foot geometry and temperature distribution. A structured light pattern is projected on to the foot to provide approximately 2500 reconstructed points. The reconstructed point cloud is then fitted to a finite element model, producing root mean squared errors of less than 0.4 mm. PMID- 22254311 TI - Heating properties of a new hyperthermia system for deep tumors without contact. AB - In this paper, heating properties of the proposed hyperthermia system for non invasive treatment of deep tumors are discussed. Our heating system is composed of a large size resonant cavity applicator. In this heating method, a human body is placed between the two inner electrodes. It is heated by electromagnetic fields stimulated in the cavity without contact between the surface of the human body and the applicator. First, we presented the experimental results of heating a cylindrical agar phantom and a cylindrical fat-agar phantom using the proposed system. From the thermal images of the heated phantoms, the center of the agar was locally heated to maximum temperature. Second, we presented the experimental results of heating a mini pig. In the heating experiment, temperature measurements were performed by using fiber-optical thermometers inserted in four locations inside the mini pig. From the results, the deepest region of the liver was heated to the highest temperature 43.3 degrees C. PMID- 22254312 TI - Theoretical and experimental study on RF tumor ablation with internally cooled electrodes: when does the roll-off occur? AB - The Cool-tip is one of the most widely employed electrodes in radiofrequency (RF) ablation (RFA) of hepatic tumors. This electrode creates reliable geometry and coagulation zones. Despite the advantages of this electrode, during the ablation is produced a phenomenon called roll-off in which impedance increases, energy deposition completely stops and the lesion size cannot be increased. Consequently, the thermal lesion size is smaller and the tumors which can be ablated are smaller too. In this research we studied theoretical and experimentally the electrical-thermal performance of the Cool-tip electrode during RFA of hepatic tissue. Mainly, we were interested in the occurrence of the roll-off and its relationship with the tissue temperatures around the electrode. The theoretical model included the vaporization of the tissue and the variation of the thermal and electrical conductivities with temperature. The model was solved numerically using COMSOL Multiphysics software. For the experimental part we conducted a study in ex vivo liver tissue. The experimental and theoretical results showed that the roll-off is totally related when temperatures around 100 degrees C surrounds the tissue close to the center of the Cool-tip. The knowledge of this fact brings a powerful tool to analyze alternative methods or techniques to avoid the roll-off. PMID- 22254313 TI - Ablation of demineralized dentin using a mid-infrared tunable nanosecond pulsed laser at 6 MUm wavelength range for selective excavation of carious dentin. AB - In dental clinic, some lasers have already realized the optical drilling of dental hard tissue. However, conventional lasers lack the ability to discriminate and excavate carious tissue only, and still depend on the dentist's ability. The objective of this study is to develop a selective excavation of carious dentin by using the laser ablation with 6 MUm wavelength range. Bovine dentin demineralized with lactic acid solution was used as a carious dentin model. A mid-infrared tunable pulsed laser was obtained by difference-frequency generation technique. The wavelength was tuned around the absorption bands called amide 1 and amide 2. In the wavelength range from 5.75 to 6.60 MUm, the difference of ablation depth between demineralized and normal dentin was observed. The wavelength at 6.02 MUm and the average power density of 15 W/cm(2), demineralized dentin was removed selectively with less-invasive effect on normal dentin. The wavelength at 6.42 MUm required the increase of average power density, but also showed the possibility of selective ablation. In the near future, development of compact laser device will open the minimal invasive laser treatment to the dental clinic. PMID- 22254314 TI - Electrical-thermal-structural coupling simulation for electrosurgery simulators. AB - An electrosurgery is a fundamental operation that utilizes Joule heat generated by the passage of a radiofrequency current. Surgical simulators are demanded for training of the electrosurgical skill with fewer complications. However, foregoing simulators have never implemented a series of physics phenomena in electrosurgery. The aim of this study is to construct a surgical simulator with a unified physics-based modeling of whole processes of electrosurgery. In this paper, we developed an electrosurgical cutting simulation system with consideration of a series of physical phases: electrical, thermal, and structural phases. Especially, the structural change based on the vaporization and mechanical rupture is modeled. The experiments using porcine livers compared the simulated temperature change with the measured one in electrosurgical cutting, and the effectiveness of the proposed model was found. In addition, the rate controlling step for real-time electrosurgery simulation was examined. PMID- 22254315 TI - Integrated heaters for temperature control in disposable bioassay cartridges for use with portable, battery-operated instruments. AB - Two methods for heating fluids in microliter- to milliliter-scale reaction chambers in disposable bioassay cartridges are analyzed and compared. Inductive heating requires no electrical contact between the energy source and the cartridge and uses a very inexpensive component in the cartridge. Resistive heating with a surface mount component requires electrical interconnection, but is generally conducive to low-cost off-the-shelf components. Typical power consumption for both inductive heating and resistive heating is consistent with battery-powered operation. A finite element model for heating an injection-molded plastic cartridge with a surface-mount resistor has been developed and validated through experiments on a 40 mm * 10 mm * 7.5 mm injection molded polystyrene cartridge with embedded 1 kOmega surface-mount resistors. A model of frequency dependent heat generation in a novel inductive heating device is also presented. PMID- 22254316 TI - A new heating method with dielectric bolus using resonant cavity applicator for brain tumors. AB - In this paper, we discuss a new method of controlling heating location in the proposed resonant cavity applicator. A dielectric bolus was used to non invasively treat brain tumors. We have already confirmed that our heating system using resonant cavity is useful to non-invasively heat brain tumors. In order to heat tumors occurring at various locations, it is necessary to control the heating area with our heating system. First, we presented the proposed heating method and a phantom model to calculate temperature distributions. The results of temperature distributions were discussed. Second, a 3-D human head model constructed from 2-D MRI images was presented. The results of specific absorption rate distributions were discussed. From these results, it was found that the proposed heating method was useful to non-invasively treat brain tumors. PMID- 22254317 TI - Electromagnetic analysis of an RF rectangular resonant cavity applicator for hyperthermic treatment using whole-body voxel human model of Japanese adult male. AB - The numerical whole-body voxel human model (numerical model) developed by National Institute of Information and Communications Technology (NICT) was assumed and hyperthemic treatment using radio-frequency wave was investigated. We assumed 51 different human tissues and organs with 2-mm spatial resolution in the numerical model, inserted it into the resonant cavity applicator, and Maxwell's equations were solved by FDTD method with variable mesh. We obtained the realistic energy patterns for a deep-seated tumor as compared to those obtained in our previous studies. PMID- 22254318 TI - Potential of gallium-based leads for cardiac rhythm management devices. AB - We propose the use of gallium (Ga), a metal that is liquid at physiological temperatures, or one of its alloys, for use as the conducting material in the leads of implantable pacemakers or cardioverter defibrillators. It is proposed that a liquid conductor will make these leads more pliable and thus less susceptible to fracture in situ. As an initial step towards utilizing liquid gallium in leads, the biocompatibility of Ga was investigated via cytotoxicity, hemocompatibility, and intracutaneous injection testing. Unipolar pacing Ga prototypes were fabricated by adapting existing pacemaker leads. The electrical impedance and pulse transmission ability of these leads were examined. Ga was well tolerated both in vitro and in vivo. Additionally, the Ga prototypes conductors behaved as low magnitude resistances that did not distort pulses as generated by conventional pacemakers. These results indicate that Ga is an appropriate material for implantable cardiac stimulators and will be a focus of our liquid metal prototypes. PMID- 22254320 TI - Novel short-duration heating balloon dilatation with uniform temperature distribution: the heating conditions to suppress neo-intimal hyperplasia. AB - We investigate the relation between the influences on smooth muscle cells and the chronic performances of our novel short-duration heating balloon dilatation to reveal the heating conditions which can suppress the neo-intimal hyperplasia after our heating dilatations. The temperature of prototype balloon catheter surface was measured during short-duration heating balloon dilatation ex vivo. There existed 2 degrees C temperature variations in the long direction of prototype balloon catheter at a maximum. The neo-intimal hyperplasia occupancy rate after our short-duration heating dilatations were measured in vivo porcine study. The neo-intimal hyperplasia was suppressed most at 75 degrees C in balloon peak temperature in vivo. The estimated dead rate of smooth muscle cells at this condition was about 13% by the Arrhenius equation. We think that the suppression of neo-intimal hyperplasia was obtained after our short-duration heating dilatation due to the proper decrease of smooth muscle cells by heating and no thermal damages to the adventitia and surrounding tissues. PMID- 22254319 TI - Evaluation of a newly designed endoscope for observing inner wall of large arteries for the use of endovascular intervention. AB - A prototype endoscope for observing inner wall of large arteries was specially designed and evaluated through in vitro and in vivo tests. The purpose of this endoscope is to visualize the inner wall of large arteries, e.g., an aorta, without blocking off the blood stream aiming for the use of an assistive technique for endovascular interventions such as stent-graft placement for aortic aneurysm. The technique newly introduced for this purpose was the use of intermittent high-pressure saline jet synchronized to heart beat (diastolic phase). In the previous studies using commercially available bronchoscopes, we confirmed the validity of the system utilizing this technique [1, 2]. Based on these findings, in this study, we have specially designed a new endoscope with two channels, one for saline discharge and the other for forceps, and evaluated its performance through in vitro and in vivo tests. From the results of in vitro tests using a mock circulation system, it was confirmed that the newly designed endoscope was capable of visualizing a target installed on an inner surface of the mock system. Also confirmed through in vivo tests using swine was that we could observe bifurcation in descending aorta, e.g., left renal artery, without stopping off the blood stream. PMID- 22254321 TI - Confidence-based classification with dynamic conformal prediction and its applications in biomedicine. AB - Computer-aided decision support systems enable physicians to make more accurate clinical decisions and can significantly improve the quality of care provided to patients. However, prediction of classification confidence as the degree of reliability on the resulting predictions is a much needed step in clinical decision making. A recently developed technique called conformal prediction utilizes the similarity between a new sample and the training samples in order to form confidence measures for predictions. However, the conventional conformal prediction method suffers from shortcomings such as high computational complexity that prevent its use in real-time applications. This paper introduces an alternative approach to the conventional confidence prediction that addresses some of this and other disadvantages. Both real clinical and non-clinical datasets are employed to test and validate the capabilities of the proposed approach. PMID- 22254322 TI - Detection and classification of hypovolaemia during anaesthesia. AB - In recent years, there has been a rapid growth in patient monitoring and medical data analysis using decision support systems, smart alarm monitoring, expert systems and many other computer aided protocols. The main goal of this study was to enhance the developed diagnostic alarm system for detecting critical events during anaesthesia. The proposed diagnostic alarm system is called Fuzzy logic monitoring system-2 (FLMS-2). The performance of the system was validated through a series of off-line tests. When detecting hypovolaemia a substantial level of agreement was observed between FLMS-2 and the human expert and it is shown that system has a better performance with sensitivity of 94%, specificity of 90% and predictability of 72%. PMID- 22254323 TI - Development of a dental implant mobility measurement system using an inductive sensor. AB - Estimation of dental implant stability is an important factor for diagnosis of implant treatment. In this study, we have developed a new system for measuring dental implant mobility. Movement of the implant was measured by an inductive sensor and an amplification adaptor was developed to multiply movement of the implant. Impulse response signal of the implant was acquired and power spectrum analysis was applied for the signal. Various implant-tissue interfacial conditions were simulated in an in vitro experiment and average peak frequency of the power spectrum was calculated for each condition. Artificial implantation model of acryl was fabricated and holes of different levels of depth and diameter were drilled. Two types of impression materials were used to fix the dental implant into the hole. The peak frequency showed linear relationship (P value<0.01) with the depth and the diameter of the hole. Differentiability of the system was evaluated by ANOVA test. PMID- 22254324 TI - Semi-supervised event detection using higher order statistics for multidimensional time series accelerometer data. AB - In this study, we target to automatically detect stereotypical behavioral patterns (stereotypy) and self-injurious behaviors (SIB) of Autistic children which can lead to critical damages or wounds as they tend to repeatedly harm oneself. Our custom designed accelerometer based wearable sensors are placed at wrists, ankles and upper body to detect stereotypy and SIB. The analysis was done on four children diagnosed with ASD who showed repeated behaviors that involve part of the body such as flapping arms, body rocking and self-injurious behaviors such as punching their face, or hitting their legs. Our goal of detecting novel events relies on the fact that the limitation of training data and variability in the possible combination of signals and events also make it impossible to design a single algorithm to understand all events in natural setting. Therefore, a semi supervised method to discover and track unknown events in a multidimensional sensor data rises as a very important topic in classification and detection problems. In this paper, we show how the Higher Order Statistics (HOS) features can be used to design dictionaries and to detect novel events in a multichannel time series data. We explain our methods to detect novel events in a multidimensional time series data and combine the proposed semi-supervised learning method to improve the adaptability of the system while maintaining comparable detection accuracy as the supervised method. We, compare our results to the supervised methods that we have previously developed and show that although semi-supervised method do not achieve better performance compared to supervised methods, it can efficiently find new events and anomalies in multidimensional time series data with similar performance of the supervised method. We show that our proposed method achieves recall rate of 93.3% compared to 94.1% for the supervised method studied earlier. PMID- 22254325 TI - Direction sensitive fall detection using a triaxial accelerometer and a barometric pressure sensor. AB - Falling is one of the leading causes of serious health decline or injury-related deaths in the elderly. For survivors of a fall, the resulting health expenses can be a devastating burden, largely because of the long recovery time and potential comorbidities that ensue. The detection of a fall is, therefore, important in care of the elderly for decreasing the reaction time by the care-givers especially for those in care who are particularly frail or living alone. Recent advances in motion-sensor technology have enabled wearable sensors to be used efficiently for pervasive care of the elderly. In addition to fall detection, it is also important to determine the direction of a fall, which could help in the location of joint weakness or post-fall fracture. This work uses a waist-worn sensor, encompassing a 3D accelerometer and a barometric pressure sensor, for reliable fall detection and the determination of the direction of a fall. Also assessed is an efficient analysis framework suitable for on-node implementation using a low-power micro-controller that involves both feature extraction and fall detection. A detailed laboratory analysis is presented validating the practical application of the system. PMID- 22254326 TI - Rotary blood pump control using integrated inlet pressure sensor. AB - Due to improved reliability and reduced risk of thromboembolic events, continuous flow left ventricular assist devices are being used more commonly as a long term treatment for end-stage heart failure. As more and more patients with these devices are leaving the hospital, a reliable control system is needed that can adjust pump support in response to changes in physiologic demand. An inlet pressure sensor has been developed that can be integrated with existing assist devices. A control system has been designed to adjust pump speed based on peak-to peak changes in inlet pressure. The inlet pressure sensor and control system have been tested with the HeartMate II axial flow blood pump using a mock circulatory loop and an active left ventricle model. The closed loop control system increased total systemic flow and reduced ventricular load following a change in preload as compared to fixed speed control. The increase in systemic flow occurred under all operating conditions, and maximum unloading occurred in the case of reduced ventricular contractility. PMID- 22254327 TI - Improved blood glucose estimation through multi-sensor fusion. AB - Continuous glucose monitoring systems are an integral component of diabetes management. Efforts to improve the accuracy and robustness of these systems are at the forefront of diabetes research. Towards this goal, a multi-sensor approach was evaluated in hospitalized patients. In this paper, we report on a multi sensor fusion algorithm to combine glucose sensor measurements in a retrospective fashion. The results demonstrate the algorithm's ability to improve the accuracy and robustness of the blood glucose estimation with current glucose sensor technology. PMID- 22254328 TI - Breathing sensor selection during movement. AB - A pressure sensor array placed below a mattress can be used to estimate the breathing effort signal unobtrusively. When multiple breathing effort sensor outputs are available, there is sometimes a need to choose the sensor with the best approximation of the actual breathing effort. Previous work with pressure sensor arrays placed on top of or under mattresses used for respiration rate and breathing signal estimation have used either the amplitude or the power spectrum to choose the most representative sensor. These methods are both useful when the subject is still; however, pressure sensor signals also contain movement. We propose and test a spectral ratio method for selection in the presence of movement. The spectral ratio method is good at finding strong breathing signals and at discriminating movement signals from strong breathing signals. This method provides a mean correlation to respiration bands that is 4% higher than the next best method during small movements and 14% higher during larger movements. PMID- 22254329 TI - A new virtual environment for testing and hardware implementation of closed-loop control algorithms in the artificial pancreas. AB - This article presents a new simulation tool for designing and testing blood glucose control algorithms in patients with type 1 diabetes. The control algorithms can be designed and implemented either with textual or graphical programming languages or by importing them from several frameworks. Realistic scenarios and protocols can be customized and built through graphical user interfaces, where several outcomes are available to evaluate control performance. Sophisticated models of the glucose-insulin system, as well as representative models of the instrumentation, have been included. Unlike existing systems, this simulation tool allows integrating the control algorithms into an electronic control unit, thus reusing the entire code in a straightforward way. PMID- 22254330 TI - Uncertainty analysis in the simulation of X-ray spectra in the diagnostic range using the MCNP5 code. AB - An accurate knowledge of the photonic spectra emitted by X-ray tubes in radiodiagnostics is essential to better estimate the imparted dose to patients and to improve the image quality obtained with these devices. In this work, several X-ray spectra have been simulated using the MCNP5 code to simulate X-ray production in a commercial device. To validate the Monte Carlo results, simulated spectra have been compared to those extracted from the IPEM 78 database. The uncertainty associated to some geometrical features of the tube and its effect on the simulated spectra has been analyzed using the Noether-Wilks formula. This analysis has been focused on the thickness of collimators, filters, shielding and barrel shutter. Furthermore, results show that the uncertainty due to geometrical parameters (0.98% in terms of Root Mean Squared) is higher than the statistical uncertainty associated to the MCNP5 calculations. PMID- 22254331 TI - Distance estimation from acceleration for quantitative evaluation of Parkinson tremor. AB - The purpose of this paper is to assess Parkinson tremor estimating actual distance amplitude. We propose a practical, useful and simple method for evaluating Parkinson tremor with distance value. We measured resting tremor of 7 Parkinson Disease (PD) patients with triaxial accelerometer. Resting tremor of participants was diagnosed by Unified Parkinson's Disease Rating Scale (UPDRS) by neurologist. First, we segmented acceleration signal during 7 seconds from recorded data. To estimate a displacement of tremor, we performed double integration from the acceleration. Prior to double integration, moving average method was used to reduce an error of integral constant. After estimation of displacement, we calculated tremor distance during 1s from segmented signal using Euclidean distance. We evaluated the distance values compared with UPDRS. Averaged moving distance during 1 second corresponding to UPDRS 1 was 11.52 mm, that of UPDRS 2 was 33.58 mm and tremor distance of UPDRS 3 was 382.22 mm. Estimated moving distance during 1s was proportional to clinical rating scale- UPDRS. PMID- 22254332 TI - Development of a fully automated closed loop artificial pancreas control system with dual pump delivery of insulin and glucagon. AB - Patients with diabetes have difficulty controlling their blood sugar and suffer from acute effects of hypoglycemia and long-term effects of hyperglycemia, which include disease of the eyes, kidneys and nerves/feet. In this paper, we describe a new system that is used to automatically control blood sugar in people with diabetes through the fully automated measurement of blood glucose levels and the delivery of insulin and glucagon via the subcutaneous route. When a patient's blood sugar goes too high, insulin is given to the patient to bring his/her blood sugar back to a normal level. To prevent a patient's blood sugar from going too low, the patient is given a hormone called glucagon which raises the patient's blood sugar. While other groups have described methods for automatically delivering insulin and glucagon, many of these systems still require human interaction to enter the venous blood sugar levels into the control system. This paper describes the development of a fully automated closed-loop dual sensor bi hormonal artificial pancreas system that does not require human interaction. The system described in this paper is comprised of two sensors for measuring glucose, two pumps for independent delivery of insulin and glucagon, and a laptop computer running a custom software application that controls the sensor acquisition and insulin and glucagon delivery based on the glucose values recorded. Two control algorithms are designed into the software: (1) an algorithm that delivers insulin and glucagon according to their proportional and derivative errors and proportional and derivative gains and (2) an adaptive algorithm that adjusts the gain factors based on the patient's current insulin sensitivity as determined using a mathematical model. Results from this work may ultimately lead to development of a portable, easy to use, artificial pancreas device that can enable far better glycemic control in patients with diabetes. PMID- 22254333 TI - Multi-GPU accelerated three-dimensional FDTD method for electromagnetic simulation. AB - Numerical simulation with a numerical human model using the finite-difference time domain (FDTD) method has recently been performed in a number of fields in biomedical engineering. To improve the method's calculation speed and realize large-scale computing with the numerical human model, we adapt three-dimensional FDTD code to a multi-GPU environment using Compute Unified Device Architecture (CUDA). In this study, we used NVIDIA Tesla C2070 as GPGPU boards. The performance of multi-GPU is evaluated in comparison with that of a single GPU and vector supercomputer. The calculation speed with four GPUs was approximately 3.5 times faster than with a single GPU, and was slightly (approx. 1.3 times) slower than with the supercomputer. Calculation speed of the three-dimensional FDTD method using GPUs can significantly improve with an expanding number of GPUs. PMID- 22254334 TI - Basic concepts of optical measuring of bone thickness with IR-beam. AB - This paper describes a new concept for measuring bone thickness via optically analyzing of hard tissue. In many surgical disciplines effecting bone treatment, like oral and maxillofacial surgery or otolaryngology, the knowledge of existing bone material is very important in order not to hurt anatomically sensitive structures. The existing bone material can be determined preoperatively using imaging procedures. However, the surgeon has no information about the residual bone thickness during the intervention. As a consequence of this, the distance between the tip of his instrument and sensitive structures is also unknown. Therefore, it would be very useful, if the bone thickness could be measured concurrently to the bone ablation. In this work, bone was irradiated with IR Light and the reflection was detected. It would be examined, if there was an interrelation between bone thickness and reflection and how it could be measured. The results of the experiments show, that by means of this method it is possible to detect different bone thicknesses for a bone thickness < 1 mm. PMID- 22254335 TI - Feasibility of implementing stereotactic body radiation therapy using a non commercial volumetric modulated arc therapy treatment planning system for early stage lung cancer. AB - Nearly 25% of patients diagnosed with early-stage non-small cell lung carcinomas (NSCLC) are medically inoperable. For these patients, the radial stereotactic body radiation therapy (SBRT), planned and delivered with intensity modulated radiation therapy (IMRT) techniques, offers the only curative option. However, IMRT-SBRT has three significant deficiencies: an elevated beam-on time (MU); a reduced MU-to-cGy coefficient; and a prolonged delivery time. To address these issues, we have developed our in-house version of volumetric modulated arc therapy (VMAT). In this preliminary study, we compared VMAT-SBRT with IMRT-SBRT in terms of optimization, dosimetry, and delivery. Our goal was to investigate the feasibility of replacing the exiting IMRT-SBRT with VMAT-SBRT as a safe and viable alternative radiation modality for early-stage NSCLC. PMID- 22254336 TI - Three-dimensional reconstruction of transcranial ultrasound images obtained through the temporal bone window using a helmet-mounted mechanical beam-steering device. AB - Transcranial sonography has been an increasingly widespread diagnostic tool for the diagnosis of neural diseases like Parkinson's disease. However, the utilization of modern 3D ultrasound techniques has been hampered by the acoustical barrier of the skull bones. We report the development of and preliminary results from an ultrasound helmet which uses mechanical beam-steering to allow 3-D reconstruction of deep brain structures such as the substantia nigra. PMID- 22254337 TI - A multi-radar wireless system for respiratory gating and accurate tumor tracking in lung cancer radiotherapy. AB - Respiratory gating and tumor tracking are two promising motion-adaptive lung cancer treatments, minimizing incidence and severity of normal tissues and precisely delivering radiation dose to the tumor. Accurate respiration measurement is important in respiratory-gated radiotherapy. Conventional gating techniques are either invasive to the body or bring insufficient accuracy and discomfort to the patients. In this paper, we present an accurate noncontact means of measuring respiration for the use in gated lung cancer radiotherapy. We also present an accurate tumor tracking technique for dynamical beam tracking radiotherapy. Two 2.4 GHz miniature radars were used to monitor the chest wall and abdominal movements simultaneously to get high resolution and enhanced parameter identification. Ray tracing technique was used to investigate the impact of antenna size in clinical practice. It is shown that our multiple radar system can reliably measure respiration signals for respiratory gating and accurate tumor tracking in motion-adaptive lung cancer radiotherapy. PMID- 22254338 TI - Vibro-acoustography and B-mode integration for 3D imaging. AB - Tridimensional representation of vibro-acoustography images based on the topology acquired by B-mode acquisitions is proposed for the evaluation of bone and implant surfaces. A tridimensional evaluation of the implant coverage used in a total hip arthroplasty procedure was performed to show the feasibility of this approach. A vibro-acoustography image of the uncovered area of the implant was acquired and represented in planar representation. However, tridimensional representation of the exposed surface area is necessary for proper evaluation of the stability of the implant. Hence, the topologies of the implant and the bone region around it were determined by acquiring 280 B-mode images. The B-scan images were processed in order to reconstruct the tridimensional surface of the objects. Finally, the vibro-acoustography image and the B-mode-based surface were aligned for the tridimensional visualization. The B-mode tridimensional representation of the bone and implant was improved by the enhancement of contrast and resolution provided by the vibro-acoustography image. The final tridimensional image presented a resolution of 0.25 mm. The topological correction based on B-mode slices allowed an accurate evaluation of the surface area. PMID- 22254339 TI - Feasibility evaluation of a motion detection system with face images for stereotactic radiosurgery. AB - In stereotactic radiosurgery we can irradiate a targeted volume precisely with a narrow high-energy x-ray beam, and thus the motion of a targeted area may cause side effects to normal organs. This paper describes our motion detection system with three USB cameras. To reduce the effect of change in illuminance in a tracking area we used an infrared light and USB cameras that were sensitive to the infrared light. The motion detection of a patient was performed by tracking his/her ears and nose with three USB cameras, where pattern matching between a predefined template image for each view and acquired images was done by an exhaustive search method with a general-purpose computing on a graphics processing unit (GPGPU). The results of the experiments showed that the measurement accuracy of our system was less than 0.7 mm, amounting to less than half of that of our previous system. PMID- 22254340 TI - A computational approach to understanding gastrointestinal motility in health and disease. AB - Gastrointestinal (GI) motility disorders are not well understood, resulting in patient management that typically controls symptoms. Patients suffer from reduced quality of life and incur large costs from chronic GI disorders. It is imperative to elucidate underlying mechanisms causing GI motility disorders that, in turn, can facilitate development of treatment such as drug therapeutics. To this end, we seek to use multi-scale computational models to better understand GI motility in health and disease. An initial computational framework was established to study genetic perturbation in causing a phenotypical change at the GI tissue level. Computer models describing a couple of genetic perturbations were developed and examined in the multi-scale framework. Preliminary findings suggest alterations to phenotype that may adversely affect GI motility. However, much work remains, given the tissue complexity and uncertainties in our knowledge of the GI organs. A future direction will be to incorporate multi-scale mechanical models in the current framework. PMID- 22254341 TI - Petascale computation performance of lightweight multiscale cardiac models using hybrid programming models. AB - Future multiscale and multiphysics models must use the power of high performance computing (HPC) systems to enable research into human disease, translational medical science, and treatment. Previously we showed that computationally efficient multiscale models will require the use of sophisticated hybrid programming models, mixing distributed message passing processes (e.g. the message passing interface (MPI)) with multithreading (e.g. OpenMP, POSIX pthreads). The objective of this work is to compare the performance of such hybrid programming models when applied to the simulation of a lightweight multiscale cardiac model. Our results show that the hybrid models do not perform favourably when compared to an implementation using only MPI which is in contrast to our results using complex physiological models. Thus, with regards to lightweight multiscale cardiac models, the user may not need to increase programming complexity by using a hybrid programming approach. However, considering that model complexity will increase as well as the HPC system size in both node count and number of cores per node, it is still foreseeable that we will achieve faster than real time multiscale cardiac simulations on these systems using hybrid programming models. PMID- 22254342 TI - A finite element approach for modeling micro-structural discontinuities in the heart. AB - The presence of connective tissue as well as interstitial clefts forms a natural barrier to the electrical propagation in the heart. At a microscopic scale, such uncoupling structures change the pattern of the electrical conduction from uniform towards complex and may play a role in the genesis of cardiac arrhythmias. The anatomical diversity of conduction structures and their topology at a microscopic size scale is overwhelming for experimental techniques. Mathematical models have been often employed to study the behavior of the electrical propagation at a sub-cellular level. However, very fine and computationally expensive meshes are required to capture all microscopic details found in the cardiac tissue. In this work, we present a numerical technique based on the finite element method which allows to reproduce the effects of microscopic conduction barriers caused by the presence of uncoupling structures without actually resolving these structures in a high resolution mesh, thereby reducing the computational costs significantly. PMID- 22254343 TI - TumorML: Concept and requirements of an in silico cancer modelling markup language. AB - This paper describes the initial groundwork carried out as part of the European Commission funded Transatlantic Tumor Model Repositories project, to develop a new markup language for computational cancer modelling, TumorML. In this paper we describe the motivations for such a language, arguing that current state-of-the art biomodelling languages are not suited to the cancer modelling domain. We go on to describe the work that needs to be done to develop TumorML, the conceptual design, and a description of what existing markup languages will be used to compose the language specification. PMID- 22254344 TI - Modeling of the nervous system: from molecular dynamics and synaptic modulation to neuron spiking activity. AB - The brain is a perfect example of an integrated multi-scale system, as the complex interactions taking place at the molecular level regulate neuronal activity that further modifies the function of millions of neurons connected by trillions of synapses, ultimately giving rise to complex function and behavior at the system level. Likewise, the spatial complexity is accompanied by a complex temporal integration of events taking place at the microsecond scale leading to slower changes occurring at the second, minute and hour scales. In the present study we illustrate our approach to model and simulate the spatio-temporal complexity of the nervous system by developing a multi-scale model integrating synaptic models into the neuronal and ultimately network levels. We apply this approach to a concrete example and demonstrate how changes at the level of kinetic parameters of a receptor model are translated into significant changes in the firing of a pyramidal neuron. These results illustrate the abilities of our modeling approach and support its direct application to the evaluation of the effects of drugs, from functional target to integrated system. PMID- 22254345 TI - Towards multiscale systems modeling of endocardial to mesenchymal transition. AB - Cell behavior during endocardial to mesenchymal transition (EMT) was simulated using the cellular Potts formalism in Compucell 3D. The processes of loss of endocardial cohesion and invasion into the extracellular matrix (ECM) were stimulated by changing surface energy parameters. The simulations match in vitro results which suggest that endocardial motility on the surface of collagen gel can be induced separately from 3D invasion of the gel, via Notch signaling in the absence of BMP2. A principle by which the rate of mitosis would regulate the monolayer was demonstrated; suggesting a route for Vascular Endothelial Growth Factor (VEGF) control of EMT. A conceptual model of the system of protein interactions during EMT was assembled from multiple studies. A route for subcellular models to be formalized as Systems Biology Markup Language (SBML) differential equations is indicated. Scale linking would be achieved through Compucell 3D periodically integrating the SBML models for each cell during a simulation run, and updating parameters for protein concentrations assigned to individual cells. The surface energy parameters for the cells would be recalculated at each step from their simulated protein concentrations. Such scale linking opens up the potential for complexity to be gradually introduced, while maintaining experimental validation. PMID- 22254346 TI - Automatic classification of pathological gait patterns using ground reaction forces and machine learning algorithms. AB - An automated gait classification method is developed in this study, which can be applied to analysis and to classify pathological gait patterns using 3D ground reaction force (GRFs) data. The study involved the discrimination of gait patterns of healthy, cerebral palsy (CP) and multiple sclerosis subjects. The acquired 3D GRFs data were categorized into three groups. Two different algorithms were used to extract the gait features; the GRFs parameters and the discrete wavelet transform (DWT), respectively. Nearest neighbor classifier (NNC) and artificial neural networks (ANN) were also investigated for the classification of gait features in this study. Furthermore, different feature sets were formed using a combination of the 3D GRFs components (mediolateral, anterioposterior, and vertical) and their various impacts on the acquired results were evaluated. The best leave-one-out (LOO) classification accuracy 85% was achieved. The results showed some improvement through the application of a features selection algorithm based on M-shaped value of vertical force and the statistical test ANOVA of mediolateral and anterioposterior forces. The optimal feature set of six features enhanced the accuracy to 95%. This work can provide an automated gait classification tool that may be useful to the clinician in the diagnosis and identification of pathological gait impairments. PMID- 22254347 TI - FBG in PVC foils for monitoring the knee joint movement during the rehabilitation process. AB - This paper presents a sensing electronic-free wearable solution for monitoring the body kinematics. The measuring of the knee movements, flexion and extension, with the corresponding joint acting as the rotation axis is shown as working principle. The proposed sensing system is based on a single optical Fiber-Bragg Grating (FBG) with a resonance wavelength of 1547.76 nm. The optical fiber with the FBG is placed inside a new polymeric foil composed by three flexible layers which facilitates its placement in the anatomic parts under investigation while maintaining full sensing capabilities. The way the device is placed in the specific body part to be measured enables the clear detection of the movements in respect to the joint. The proposed solution was tested using a prototype that was built to evaluate the device under different condition tests and also to assess the system's consistency. The designed and fabricated system demonstrates clear advantages in medical fields like physical therapy applications as optical fiber is not affected by electromagnetic interference nor does the system needs complex and expensive electronic systems and mechanical parts. Another advantage is the possibility to measure, record and evaluate specific mechanical parameters of the limbs' motion. Patients with bone, muscular and joint related health conditions, as well as athletes, are within the most important end-user applications. PMID- 22254348 TI - Clinical Gait assessment of older adults using open platform tools. AB - Gait impairment is associated with increased falls risk. The gait of 321 community dwelling elderly adults was assessed using the TRIL Gait Analysis Platform (GAP), which was specially designed for ease of use in a research clinic setting by non-experts. The GAP featured body-worn kinematic sensors, a pressure sensitive electronic walkway, and two orthogonally mounted web cameras, and was developed using open platform tools. This flexible platform was applied to objectively measure gait parameters in different gait assessments. The results from the 6 meter walk assessment are presented here. In this assessment, participants were categorized by clinical falls history as 'fallers' or 'non fallers'. Temporal and spatial gait parameters were examined. Significant differences in spatial parameters were observed when fallers and non-fallers were compared. Temporal parameters were found to differ, though not significantly. PMID- 22254349 TI - Reliability of quantitative TUG measures of mobility for use in falls risk assessment. AB - Recent advances in body-worn sensor technology have increased the scope for harnessing quantitative information from the timed-up-and-go test (TUG), well beyond simply the time taken to perform the test. Previous research has shown that the quantitative TUG method can differentiate fallers from non-fallers with greater success than the manually timed TUG or the Berg Balance Test. In order to advance this paradigm of falls risk estimation it is necessary to investigate the robustness of the quantitative TUG variables. This study investigated the inter session and intra-session reliability of 44 quantitative TUG variables measured from the shanks and lower back of 33 study participants aged between 55-65 yrs. For intra-session reliability, 25 variables demonstrated excellent reliability (ICC>0.75), and 12 demonstrated "fair to good reliability" with ICCs between 0.4 and 0.75. Analysis of test-retest reliability resulted in ICC > 0.75 for 18 out of 44 variables, with 20 variables showing fair to good reliability. Turn time parameters demonstrated poor reliability. We conclude that this is a reliable instrument that may be used as part of a long-term falls risk assessment, with further work required to improve certain turn parameters. PMID- 22254350 TI - Variability of hand tremor in rest and in posture--a pilot study. AB - Previous, studies have demonstrated variability in the frequency and amplitude in tremor between subjects and between trials in both healthy individuals and those with disease states. However, to date, few studies have examined the composition of tremor. Efficacy of treatment for tremor using techniques such as Botulinum neurotoxin type A (BoNT A) injection may benefit from a better understanding of tremor variability, but more importantly, tremor composition. In the present study, we evaluated tremor variability and composition in 8 participants with either essential tremor or Parkinson disease tremor using kinematic recording methods. Our preliminary findings suggest that while individual patients may have more intra-trial and intra-task variability, overall, task effect was significant only for amplitude of tremor. Composition of tremor varied among patients and the data suggest that tremor composition is complex involving multiple muscle groups. These results may support the value of kinematic assessment methods and the improved understanding of tremor composition in the management of tremor. PMID- 22254351 TI - Classification of lying position using load cells under the bed. AB - Individuals who suffer from acid reflux at night, who snore chronically, or who have sleep apnea are frequently encouraged to sleep in a particular lying position. Side sleeping decreases the frequency and severity of obstructive respiratory events (e.g. apnea and hypopnea) in patients with positional sleep apnea. It has been suggested that individuals with Gastroesophageal Reflux Disease sleep on their left sides in order to help minimize symptoms. In this paper, we present a method of predicting the position of an individual lying on the bed using load cells placed under each of the bed supports. Our results suggest that load cells utilized in this manner could be successfully implemented into a system that tracks or helps train individuals to sleep in a particular lying position. PMID- 22254352 TI - Multiplexed, rapid point of care platform to quantify allergen-specific IgE. AB - Variation of probe immobilization on microarrays hinders the ability to make high quality, assertive and statistically relevant conclusions needed in the healthcare setting. To address this problem, we have developed a calibrated, compact, inexpensive, multiplexed, dual modality point-of-care detection platform that calibrates and correlates surface probe density measured label-free to captured labeled secondary antibody, is independent of chip-to-chip variability, and improves upon existing diagnostic technology. We have identified four major technological advantages of our proposed platform: the capability to perform single spot analysis based on the fluorophore used for detection, a 10-fold gain in fluorescence signal due to optimized substrate, a calibrated, quantitative method that uses the combined fluorescent and label-free modalities to accurately measure the density of probe and bound target for a variety of systems, and a compact measurement platform offering reliable and rapid results at the doctor's office. Already, we have formulated over a 90% linear correlation between the amount of probe bound to surface and the resulting fluorescence of captured target for IgG, beta-lactoglobulin, Ara h 1 peanut allergen, and Phl 5a Timothy grass allergen. PMID- 22254353 TI - Optical microplates for photonic high throughput screening of algal photosynthesis and biofuel production. AB - Biological systems respond not only to chemical stimuli (drugs, proteins) but also to physical stimuli (light, heat, stress). Though there are many high throughput tools for screening chemical stimuli, no such tool exists for screening of physical stimuli. This paper presents a novel instrument for photonic high throughput screening of photosynthesis, a light-driven bioprocess. The optical microplate has a footprint identical to a standard 96 well plate, and it provides temporal and intensity control of light in each individual well. Intensity control provides 128 dimming levels (7-bit resolution), with maximum intensity 120 mE/cm(2). Temporal modulation, used for studying dynamics and regulation of photosynthesis, can be as low as 10 MUs. We used photonic screening for high throughput studies of algal growth rates and photosynthetic efficiency, using the model organism Dunaliella tertiolecta, a lipid producing algae of interest in biofuel production. Due to the ability to conduct 96 studies in parallel, experiments that would require 2 years using conventional tools can be completed in 1 week. This instrument opens up novel high throughput protocols for photobiology and the growing field of phenomics. PMID- 22254354 TI - Validation of a device for fluorescence sensing of rare circulating cells with diffusive light in an optical flow phantom model. AB - Detection and quantification of rare circulating cells in biological tissues is an important problem and has many applications in biomedical research. Current methods normally involve extraction of blood samples and counting of cells ex vivo, or the use of microscopy-based fluorescence in vivo flow cytometry. The goal of this work is to develop an instrument for non-invasively enumerating very rare circulating cells in small animals with diffuse light with several orders of magnitude sensitivity improvement versus current approaches. In this work, we describe the design of our system and show that single, fluorescent microspheres can be detected in limb-mimicking optical flow phantoms with varying optical properties chosen to simulate in vivo conditions. Further, we demonstrate single cell counting capabilities using fluorescently (Vybrant-DiD) labeled Jurkat and Multiple Myeloma cells. Ongoing work includes in vivo testing and characterization of our system in mice. PMID- 22254355 TI - Detection of tip-enhanced fluorescence from loop-mediated isothermal amplification of hepatitis B virus by two-photon microscopy. AB - Tip-enhanced fluorescence of localized DNA replication by loop-mediated isothermal amplification (LAMP) is a potential way to observe real-time biological reaction confined in nanometer scale. We successfully coated Bst polymerase on the apex (~100 nm) of an atomic force microscope (AFM) tip and performed localized LAMP reaction of hepatitis B virus (HBV). By using this tip based reaction, the replicated HBV DNA can be directly imaged to be 400~500 nm spots by using two-photon excitation fluorescence microscopy. PMID- 22254356 TI - Robust video-oculography for non-invasive autonomic nerve quantification. AB - A relationship between autonomic nerves activity and depression or Alzheimer's disease has been reported. The quantification of autonomic nerves is expected to serve as a tool for quantifying the of severity of the disease or for early detection. Video-oculography is known as a non-invasive and reliable procedure of measurement of pupil response and is used in clinical practice. However, measuring the transition of pupil areas accurately is often difficult due to eyelid overlap, effects of blinking, eyelashes etc. Current video-oculography only performs thresholding to split pupil area and backgrounds and therefore sometimes has difficult in measuring accurate transitions of pupil reflex. In this study, we developed a robust and accurate method to measure the transition of pupil size. The proposed method introduces an interpolation process using an active contour model and ellipse estimation with selection of reliable contour points and attains robust measurement of pupil area against the abovementioned difficulties. We confirmed our method achieved an extraction accuracy of 98.3 % in precision and 98.9% in recall in average on the tested a total of 8,518 image frames from 30 movies. PMID- 22254357 TI - A 1MUm diameter tip fiber-based surface plasmon resonance system for single unit optical neural recording. AB - A gold-deposited optical fiber sensor system based on surface plasmon resonance (SPR) was developed for optical measurement of neuronal activity. To enhance the sensitivity of localized SPR and to make a precise and safe contact with the cellular membrane, we designed a tapered optical probe of 1 MUm diameter at the tip of the fiber. By wet etching and gold evaporating processes, pencil-shaped optical probes were successfully fabricated. The SPR system with the sharp optical probe was integrated with a conventional patch clamping system to realize a simultaneous optical and electrical recording on a single neuron. Although the shape of optical signal is not clear due to tiny change of intrinsic optical properties on the neuron, optical and electrical signals were simultaneously changed by capsaicin stimulation. Furthermore, our designed fiber probe can be applicable to localized optical stimulation as well as in vivo optical neuroprosthetic devices. PMID- 22254358 TI - Passive monitoring using a combination of focused and phased array radiometry: a simulation study. AB - Aim of this simulation study is to use the focusing properties of a conductive ellipsoidal reflector in conjunction with directive phased microwave antenna configurations in order to achieve brain passive monitoring with microwave radiometry. One of the main modules of the proposed setup which ensures the necessary beamforming and focusing on the body and brain areas of interest is a symmetrical axis ellipsoidal conductive wall cavity. The proposed system operates in an entirely non-invasive contactless manner providing temperature and/or conductivity variations monitoring and is designed to also provide hyperthermia treatment. In the present paper, the effect of the use of patch antennas as receiving antennas on the system's focusing properties and specifically the use of phased array setups to achieve scanning of the areas under measurement is investigated. Extensive simulations to compute the electric field distributions inside the whole ellipsoidal reflector and inside two types of human head models were carried out using single and two element microstrip patch antennas. The results show that clear focusing (creation of "hot spots") inside the head models is achieved at 1.53GHz. In the case of the two element antennas, the "hot spot" performs a linear scan around the brain area of interest while the phase difference of the two microstrip patch antennas significantly affects the way the scanning inside the head model is achieved. In the near future, phased array antennas with multiband and more elements will be used in order to enhance the system scanning properties toward the acquisition of tomography images without the need of subject movement. PMID- 22254359 TI - Time-domain ultra-wideband synthetic imager (TUSI) in silicon. AB - This paper introduces a silicon-based imaging array for remote measurements of complex permittivity of tissue. Using a coherent pulsed measurement approach, this time-frequency resolved technique recovers the three dimensional mapping of electrical properties of the subject in the microwave/millimeter-wave frequency spectrum. Some of the major challenges in the design of the system are described. Initial measurement results from the prototype high-resolution transmitter fabricated in a 0.13 MUm SiGe process are described. The transmitter achieves pulse widths suitable for millimeter-level accuracy imaging. PMID- 22254360 TI - Flexible sensor for blood pressure measurement. AB - A new approach for the design and fabrication of a highly flexible blood pressure sensor is introduced in this paper. The goal is to measure the pressure within an aneurysm sac for post-endovascular aneurysms repair (EVAR) surveillance. Biocompatible polydimethylsiloxane (PDMS) membranes with embedded aligned carbon nanotubes (CNTs) are used to build the conductive elements of the pressure sensitive capacitor and the inductor for telemetry. Inductive coupling will be used to measure the internal capacitive variations. Fabricated test sensors validate the approach and demonstrate that CNTs/PDMS technology can be used to build highly flexible pressure sensors. PMID- 22254361 TI - Pulse arrival time estimation from the impedance plethysmogram obtained with a handheld device. AB - This paper describes a novel method to estimate pulse arrival time (PAT) from the electrocardiogram (ECG) and the impedance plethysmogram (TPG) obtained by using a compact and easy-to-use handheld device with only four electrodes. A proof-of concept has been carried out where PAT values obtained with the proposed device have been compared to PAT values measured between the ECG and the photoplethysmogram (PPG) during three experiments of paced respiration to induce controlled PAT changes. The results show that both methods yield equivalent PAT values in within +/- 7 ms (95 % confidence interval), which is less than typical deviations reported for common PAT measurements. PMID- 22254362 TI - A vapor pressure thermometer for use in muscle microcalorimetry. AB - Measurement of the energy consumption of isolated cardiac trabeculae requires highly sensitive temperature sensors. In this paper we describe and characterize an initial prototype of a vapor pressure thermometer being designed and built for application to muscle microcalorimetry. The device exploits the change in vapor pressure with temperature of a solvent and the change in pressure with volume of a gas. The sensor achieves a sensitivity of 86 MUm/K and a resolution of 3.6 MUK. Predictions from a finite element model of the expected displacement compare favorably with the tests performed. PMID- 22254363 TI - Shape visualization method of flexible colonoscopy using non visual sensor network for monitoring of operation. AB - 3D Visualization method of shape of flexible colonoscopy in simulated computing environment is proposed. Signals from sensor network are used to calculate the orientation of the body of each sensor. Position of each sensor is estimated from the orientation using assumption of forward kinematics in robotics. This data are then interpolated with curve fitting method to give natural impression of shape to surgeon who are watching monitor. The resulting simulated curve shows that motion of shape of colonoscopy can be simulated at it is. PMID- 22254364 TI - X-ray coherent diffraction imaging of cellulose fibrils in situ. AB - Cellulose is the most abundant renewable source of organic molecules on earth[1]. As fossil fuel reserves become depleted, the use of cellulose as a feed stock for fuels and chemicals is being aggressively explored. Cellulose is a linear polymer of glucose that packs tightly into crystalline fibrils that make up a substantial proportion of plant cell walls. Extraction of the cellulose chains from these fibrils in a chemically benign process has proven to be a substantial challenge [2]. Monitoring the deconstruction of the fibrils in response to physical and chemical treatments would expedite the development of efficient processing methods. As a step towards achieving that goal, we here describe Bragg-coherent diffraction imaging (CDI) as an approach to producing images of cellulose fibrils in situ within vascular bundles from maize. PMID- 22254365 TI - An improved real-time cine Late Gadolinium Enhancement (LGE) imaging method at 3T. AB - A real-time Late Gadolinium Enhancement (LGE) MRI technique (free breathing and non-gated) is presented for detection of myocardial scars. Conventional LGE imaging methods currently in use are applied in conjunction with breath-hold and, thus, are difficult to use in patients with cardiac disease and may lead to motion artifacts. Additionally, conventional techniques involve ECG gating, which is problematic in patients with arrhythmias requiring multiple breath holds and use of arrhythmia rejection techniques. Finally, conventional LGE techniques require accurate estimates for the inversion time in order to null the normal myocardium, revealing the location of the scar with high contrast. Real-time LGE imaging obviates these difficulties and can, in principle, acquire cine images to assess wall motion over several heart phases as part of the same scan. To date, the main limitation of real-time LGE imaging has been long acquisition window and low temporal resolution. These limitations lead to temporal blurring of wall motion and possible overestimation of infarct size. The goal of this study was to increase the temporal resolution of real-time, cine LGE imaging, providing the possibility for better visualization of the wall motion and more accurate assessment of myocardial viability. PMID- 22254366 TI - Orthogonal CSPAMM (OCSPAMM) MR tagging for imaging ventricular wall motion. AB - Tagged magnetic resonance imaging (MRI) has the ability to directly and non invasively alter tissue magnetization and produce tags on the deforming tissue [1], [2]. Since its development, the Spatial Modulation of Magnetization (SPAMM) [2] tagging pulse sequence has been widely available and is the most commonly used technique for producing sinusoidal tag patterns. However, SPAMM suffers from tag fading which occurs in the later phases of the cardiac cycle. Complementary SPAMM (CSPAMM) was introduced to solve this problem by acquiring and subtracting two SPAMM images [3]. The drawback of CSPAMM is that it results in doubling of the acquisition time. In this paper, we propose a novel pulse sequence, termed Orthogonal CSPAMM (OCSAPMM), which results in the same acquisition time as SPAMM for 2D deformation estimation while keeping the advantages of CSPAMM. Different from CSPAMM, in OCSPAMM the second tagging pulse orientation is rotated 90 degrees relative to the first one so that motion information can be obtained simultaneously in two directions. A cardiac motion phantom, which independently models cardiac wall thickening and rotation in the human heart was used to show the effectiveness of the proposed pulse sequence. PMID- 22254367 TI - A theoretical study for the inverse design of an ellipsoidal phased-array breast coil. AB - Magnetic resonance imaging (MRI) is widely used in human breast cancer detection, and the advancement of the radio-frequency (RF) phased-array technology promises to further improve the diagnostic image quality. In this paper, an inverse design method is presented for the theoretical design of an ellipsoidal RF phased array coil for human breast MRI. The target field technique was used to analytically express the relationship between the current density and the magnetic field within a predefined region; the streamline function technique was subsequently utilized to find the coil winding patterns. Based on a spherical coordinate system, the method is extended from the conventional cylindrical shape to the more tailored ellipsoidal geometry, a linearly polarization field used as an example. The theoretical analysis and the preliminary results presented demonstrate the flexibility of the proposed method. PMID- 22254368 TI - A comparison study of different RF shields for an 8-element transceive small animal array at 9.4T. AB - In this study, three types of radio-frequency shields are studied and compared in the context of ultra-high field small-animal magnetic resonance imaging. It has been demonstrated that the coil penetration depth and mutual coupling between the coils depend heavily on the type of shield employed. The results were used to guide the design of a 9.4T 8-element transceive small animal array, which provides high overall coil penetration. PMID- 22254369 TI - Analysis of RF transmit performance for a 7T dual row multichannel MRI loop array. AB - We present a numerical investigation of the RF fields generated inside a human head by single and dual-row loop arrays. For a uniform circular polarization (CP) mode excitation, a dual-row array has no advantage for human brain excitation. Significant improvement of B(1)+ homogeneity with a simultaneous increase of coverage in the axial direction can be obtained by using a dual-row array together with a static RF shim: that is, excitation of both rows separately in CP mode, while providing the upper row elements with a +90 degrees phase shift relative to axially adjacent lower row elements. For this case the excitation efficiency over the entire brain remains practically unaffected, and the improved B(1)+ coverage results in a relatively smaller amount of power delivered to brain. To keep the mean B(1)+ across the brain equal to its value in a uniform CP excitation mode, a larger transmit power level is required. This results in a moderate increase of peak SAR(10 g). The location of peak SAR(10 g) moves from the brain (uniform CP mode location) to the nose skin. The performance of dual row arrays in transmit SENSE operation will be explored in future investigations. PMID- 22254370 TI - Highly adaptive RF excitation scheme based on conformal resonant CRLH metamaterial ring antennas for 7-Tesla traveling-wave magnetic resonance imaging. AB - We propose an adaptive RF antenna system for the excitation (and manipulation) of the fundamental circular waveguide mode (TE(11)) in the context of high-field (7T) traveling-wave magnetic resonance imaging (MRI). The system consists of <> composite right-/left-handed (CRLH) meta-material ring antennas that fully conforms to the inner surface of the MRI bore. The specific use of CRLH metamaterials is motivated by its inherent dispersion engineering capabilities, which is needed when designing resonant ring structures for virtually any predefined diameter operating at the given Larmor frequency (i.e. 298 MHz). Each functional group of the RF antenna system consists of a pair of subsequently spaced and correspondingly fed CRLH ring antennas, allowing for the unidirectional excitation of propagating, circularly polarized B(1) mode fields. The same functional group is also capable to simultaneously mold an incoming, counter-propagating mode. Given these functionalities we are proposing now a compound scheme (i.e. periodically arranged multiple antenna pairs)--termed as "MetaBore"--that is apt to provide a tailored RF power distribution as well as full wave reflection compensation virtually at any desired location along the bore. PMID- 22254371 TI - Affine optical flow combined with multiscale image analysis for motion estimation of the arterial wall from B-mode ultrasound. AB - This paper investigated the performance of affine optical flow (AFOF) in motion tracking of the arterial wall from B-mode ultrasound images and the effect of its combination with multiscale image analysis on the accuracy of the process. Multiscale AFOF (MAFOF) exploits the information obtained with AFOF from the approximation sub-images at different spatial resolution levels of the images, obtained using a 2D discrete wavelet transform. Both AFOF and MAFOF were evaluated through their application to synthetic image sequences of the common carotid artery. Multiscale image analysis increased the accuracy in motion tracking, with MAFOF yielding average displacement error reductions of 9% with respect to AFOF. The methods were also effectively applied to real ultrasound image sequences of the carotid artery. The results showed that MAFOF could be considered as a reliable estimator for arterial wall motion from B-mode ultrasound images. PMID- 22254372 TI - Two-dimensional flow study in a stenotic artery phantom using ultrasonic particle image velocimetry. AB - Blood flow dynamics has an important role in atherosclerosis initiation, progression, plaque rupture and thrombosis, and it is important to investigate the flow characteristics in the context of a mild stenotic artery. In this paper, tissue-equivalent ultrasound phantoms of artery stenosis were fabricated, and ultrasonic particle image velocimetry (EchoPIV) method was applied for two dimensional flow study. A flow circuit was established and steady flow was provided by the gear pump. Flow at the inlet and the stenosis region were researched with EchoPIV method and ultrasound Doppler technique. The detailed 2D two-component velocity vectors were determined with EchoPIV method, and the measuring accuracy outweighs that of Ultrasound Doppler by comparing to the theoretical values of Poiseuille flow. PMID- 22254373 TI - In-vivo Pulse Wave Imaging for arterial stiffness measurement under normal and pathological conditions. AB - Numerous studies have identified arterial stiffening as a strong indicator of cardiovascular pathologies such as hypertension and abdominal aortic aneurysm (AAA). Pulse Wave Imaging (PWI) is a novel, noninvasive ultrasound-based method to quantify regional arterial stiffness by measuring the velocity of the pulse wave that propagates along arterial walls after each left ventricular contraction. The PWI method employs 1D cross-correlation speckle tracking to compute axial incremental displacements, then tracks the position of the displacement wave in the anterior wall of the vessel to estimate pulse wave velocity (PWV). PWI has been validated on straight tube aortic phantoms and aortas of healthy humans as well as normal and AAA murine models. This paper presents and compares preliminary PWI results from normal, hypertensive, and AAA human subjects. PWV was computed in select cases from each subject category. The measured PWV values in hypertensive (N = 5) and AAA (N = 2) subjects were found to be significantly higher than in normal subjects (N = 8). In all subjects, the spatio-temporal profile and waveform morphologies of the pulse wave were generated from the displacement data for visualization and qualitative evaluation of the pulse wave propagation. While the waveforms were found to maintain roughly the same shape in normal subjects, those in the AAA and most hypertensive cases changed drastically along the imaged aortic segment, suggesting non-uniform wall mechanical properties. PMID- 22254374 TI - Automated detection of the carotid artery wall in longitudinal B-mode images using active contours initialized by the Hough transform. AB - In this paper, a fully automatic active-contour-based segmentation method is presented, for detecting the carotid artery wall in longitudinal B-mode ultrasound images. A Hough-transform-based methodology is used for the definition of the initial snake, followed by a gradient vector flow (GVF) snake deformation for the final contour detection. The GVF snake is based on the calculation of the image edge map and the calculation of GVF field which guides its deformation for the estimation of the real arterial wall boundaries. In twenty cases there was no significant difference between the automated segmentation and the manual diameter measurements. The sensitivity, specificity and accuracy were 0.97, 0.99 and 0.98, respectively, for both diastolic and systolic cases. In conclusion, the proposed methodology provides an accurate and reliable way to segment ultrasound images of the carotid artery. PMID- 22254375 TI - Carotid automated ultrasound double line extraction system (CADLES) via Edge Flow. AB - This paper presents a completely user-independent algorithm, that automatically extracts the far (distal) double line (lumen-intima and media-adventitia) in the carotid artery using an Edge Flow technique (a class of AtheroEdgeTM systems) based on directional probability maps using the attributes of intensity and texture. The extracted double line translates into a measure of the intima-media thickness (IMT), a validated marker for the progression of atherosclerosis. The Carotid Automated Double Line Extraction System based on Edge-Flow (CADLES-EF) is characterized and validated by comparing the output of the algorithm with two other completely automatic techniques (CALEXia and CULEXsa) published by the same authors. Validation was performed on a multi-institutional database of 300 longitudinal B-mode carotid images with normal and pathologic arteries. CADLES-EF showed an intima-media thickness (IMT) bias of 0.043 +/- 0.097 mm in comparison to CALEXia and CULEXsa that showed 0.134 +/- 0.0.88 mm and 0.74 +/- 0.092 mm, respectively. The system's Figure of Merit (FoM) showed an improvement when compared to previous automated methods: CALEXia and CULEXsa, leading to values of 84.7%, 91.5%, while our new approach, CADLES-EF performed the best with 94.8%. PMID- 22254376 TI - Assessment of the cerebral venous system from the transcondylar ultrasound window using virtual navigator technology and MRI. AB - The Chronic Cerebro-Spinal Venous Insufficiency, recently described as a possible role in Multiple Sclerosis pathogenesis, is diagnosed and classified with Echo Color Doppler (ECD) examination of the extra- and intra-cranial veins. As to the intracranial examination, the presence of reflux in the deep cerebral veins (DCVs) or in the dural sinuses is inspected, with a new insonation approach, i.e. the transcondylar window. This work describes a procedure for the co-registration of anatomical Proton Density-weighted Magnetic Resonance Images (MRI) with the intracranial ECD obtained through the transcondylar window. The procedure, preliminarily tested on 10 volunteers, allowed to assess what are the DCVs visible from this new insonation approach and their position relative to the surrounding brain tissues. PMID- 22254377 TI - Influence of parallel spring-loaded exoskeleton on ankle muscle-tendon dynamics during simulated human hopping. AB - Robotic assistance for rehabilitation and enhancement of human locomotion has become a major goal of biomedical engineers in recent years. While significant progress to this end has been made in the fields of neural interfacing and control systems, little has been done to examine the effects of mechanical assistance on the biomechanics of underlying muscle-tendon systems. Here, we model the effects of mechanical assistance via a passive spring acting in parallel with the triceps surae-Achilles tendon complex during cyclic hopping in humans. We examine system dynamics over a range of biological muscle activation and exoskeleton spring stiffness. We find that, in most cases, uniform cyclic mechanical power production of the coupled system is achieved. Furthermore, unassisted power production can be reproduced throughout parameter space by trading off decreases in muscle activation with increases in ankle exoskeleton spring stiffness. In addition, we show that as mechanical assistance increases the biological muscle-tendon unit becomes less 'tuned' resulting in higher mechanical power output from active components of muscle despite large reductions in required force output. PMID- 22254378 TI - Simulation of a slope adapting ankle prosthesis provided by semi-active damping. AB - Modern passive prosthetic foot/ankles cannot adapt to variations in ground slope. The lack of active adaptation significantly compromises an amputee's balance and stability on uneven terrains. To address this deficit, this paper proposes an ankle prosthesis that uses semi-active damping as a mechanism to provide active slope adaptation. The conceptual ankle prosthesis consists of a modulated damper in series with a spring foot that allows the foot to conform to the angle of the surface in the sagittal plane. In support of this approach, biomechanics data is presented showing unilateral transtibial amputees stepping on a wedge with their daily-use passive prosthesis. Based on this data, a simulation of the ankle prosthesis with semi-active damping is developed. The model shows the kinematic adaptation of the prosthesis to sudden changes in ground slope. The results show the potential of an ankle prosthesis with semi-active damping to actively adapt to the ground slope at each step. PMID- 22254379 TI - Design of a fully-passive transfemoral prosthesis prototype. AB - In this study, we present the mechanical design of a prototype of a fully-passive transfemoral prosthesis for normal walking. The conceptual working principle at the basis of the design is inspired by the power flow in human gait, with the main purpose of realizing an energy efficient device. The mechanism is based on three elements, which are responsible of the energetic coupling between the knee and ankle joints. The design parameters of the prototype are determined according to the human body and the natural gait characteristics, in order to mimic the dynamic behavior of a healthy leg. Hereby, we present the construction details of the prototype, which realizes the working principle of the conceptual mechanism. PMID- 22254380 TI - Semi-automatic customization of internal fracture fixation plates. AB - A new method for customization of fixation plates for repairing bone fractures is proposed. Digital models of plates are typically available as CAD models that contain smooth analytic geometry representations including NURBS. With the existing pre-operative planning solutions, these models are converted to polygonal meshes and adapted manually to the patient's bone geometry by the user. Based on the deformed model, physical bending is then performed by the surgeon in operating room. With the proposed approach, CAD models are semi-automatically adapted using NURBS to generate customized plates that conform to the desired region of the bone surface of patients. This enables an efficient and accurate approach that is also computationally suitable for interactive planning applications. Moreover, the patient-specific customized plates can then be produced directly from the adapted CAD models with a standard CNC machine before surgery. This may dramatically reduce time spent in OR, improve precision of the procedure and as a result improve the patient's outcome. PMID- 22254381 TI - A dynamic 3D foot reconstruction system. AB - Foot problems are varied and range from simple disorders through to complex diseases and joint deformities. Wherever possible, the use of insoles, or orthoses, is preferred over surgery. Current insole design techniques are based on static measurements of the foot, despite the fact that orthoses are prevalently used in dynamic conditions while walking or running. This paper presents the design and implementation of a structured-light prototype system providing dense three dimensional (3D) measurements of the foot in motion, and its use to show that foot measurements in dynamic conditions differ significantly from their static counterparts. The input to the system is a video sequence of a foot during a single step; the output is a 3D reconstruction of the plantar surface of the foot for each frame of the input. Engineering and clinical tests were carried out for the validation of the system. The accuracy of the system was found to be 0.34 mm with planar test objects. In tests with real feet, the system proved repeatable, with reconstruction differences between trials one week apart averaging 2.44 mm (static case) and 2.81 mm (dynamic case). Furthermore, a study was performed to compare the effective length of the foot between static and dynamic reconstructions using the 4D system. Results showed an average increase of 9 mm for the dynamic case. This increase is substantial for orthotics design, cannot be captured by a static system, and its subject-specific measurement is crucial for the design of effective foot orthoses. PMID- 22254382 TI - Optimal trajectory planning for a constrained functional electrical stimulation based human walking. AB - In contrast to the muscle recruitment during voluntary walking, only a limited number of muscles are activated during functional electrical stimulation (FES) based walking. This implies that a trajectory designed or recorded from the normal human walking data may not be the best choice for tracking control. Another major challenge during FES-based walking is the rapid onset of muscle fatigue. Two methods to reduce fatigue during FES-based walking are employing an orthosis and minimizing muscle activations. To deal with these aforementioned challenges, this paper presents firstly a dynamic model representing FES-elicited walking constrained by an orthosis and a walker. Secondly, this paper deals with the design of optimal stimulation and force profiles (instead of gait trajectories from able-bodied humans) that minimize muscle activations via FES and arm reaction forces from the walker. Ten walking steps are simulated to show the feasibility of the walking model and optimization algorithm. PMID- 22254383 TI - Restoration of stance phase knee flexion during walking after spinal cord injury using a variable impedance orthosis. AB - A hybrid neuroprosthesis (HNP) combines lower extremity bracing with functional neuromuscular stimulation (FNS) to restore walking function and enhance the efficiency of ambulation. This report details the development of a novel HNP containing a variable impedance knee mechanism (VIKM) capable of supporting the knee against collapse while allowing controlled stance phase knee flexion. The design of a closed loop, finite state controller for coordination of VIKM activity with FNS-driven gait is presented. The controller is verified in testing during able bodied gait. The improved functionality provided by this system has the potential to delay the onset of fatigue and to expand FNS driven gait to allow walking over uneven terrains and down stairs. PMID- 22254384 TI - Self-adjusting, isostatic exoskeleton for the human knee joint. AB - A knee-joint exoskeleton design that can apply programmable torques to the articulation and that self-adjusts to its physiological movements is described. Self-adjustment means that the articular torque is automatically produced around the rotational axis of the joint. The requirements are first discussed and the conditions under which the system tracks the spatial relative movements of the limbs are given. If these conditions are met, the torque applied to the joint takes into account the possible relative movements of the limbs without introducing constraints. A prototype was built to demonstrate the applicability of these principles and preliminary tests were carried out to validate the design. PMID- 22254385 TI - Repeatability analysis of rollover recognition in changing myoelectric electrode condition. AB - Bone cancer metastasis patients feel severe pain while performing rollover movement. We have been developing a robotic trunk orthosis to support the rollover movement in bed for bone cancer metastasis patients. In this support system, the myoelectric signal is used to recognize the start timing of the rollover movement. However, the characteristics of the myoelectric signal can change easily from long-term use and due to electrode misalignment. In this paper, the effects of long-term use and electrode misalignment in rollover movement were analyzed. It was found that continuous usage of less than 18 hours was suitable. In addition, the electrode was needed to be attached around the ASIS from 0 to 23 (deg) to obtain a large potential and quick response signal. PMID- 22254386 TI - Experimental evaluation of a portable powered ankle-foot orthosis. AB - Ankle-foot orthoses (AFOs) ameliorate the impact of impairments to the lower limb neuromuscular motor system that affect gait. Emerging technologies provide a vision for fully powered, untethered AFOs. The portable powered AFO (PPAFO) provides both plantarflexor and dorsiflexor torque assistance via a bi directional pneumatic rotary actuator. The system uses a portable pneumatic power source (bottle of compressed CO(2)) and embedded electronics to control foot motion during level walking. Experimental data were collected to demonstrate functionality from two subjects with bilateral impairments to the lower legs. These data demonstrated the PPAFO's ability to provide functional assistance during gait. The stringent design requirements of light weight, small size, high efficiency and low noise make the creation of daily wear assist devices challenging; but once such devices appear, they will present new opportunities for clinical treatment of gait abnormalities. PMID- 22254387 TI - Proportional EMG control for upper-limb powered exoskeletons. AB - Electromyography (EMG) has been frequently proposed as the driving signal for controlling powered exoskeletons. Lot of effort has been spent to design accurate algorithms for muscular torque estimation, while very few studies attempted to understand to what extent an accurate torque estimate is indeed necessary to provide effective movement assistance through powered exoskeletons. In this study, we focus on the latter aspect by using a simple and "low-accuracy" torque estimate, an EMG-proportional control, to provide assistance through an elbow exoskeleton. Preliminary results show that subjects adapt almost instantaneously to the assistance provided by the exoskeleton and can reduce their effort while keeping full control of the movement. PMID- 22254388 TI - Strip-driven devices for the spatial motion guidance of human joints. AB - Orthoses and exoskeletons need devices that can replicate the natural spatial motion of human joints. These devices should be simple and should have a high accuracy, in order not to constrain and load the joints unnaturally. In this study, strip-driven devices are proposed to guide the spatial joint motion. Classic planar devices are generalized to obtain rolling without slipping between two ruled surfaces. The special case of spherical motion is presented and analysed in details. The influence of several design parameters on the kinematic and static behaviour of these devices is also presented. PMID- 22254389 TI - Advancements in electrode design and laser techniques for fabricating micro electrode arrays as part of a retinal prosthesis. AB - Retinal micro-electrode arrays (MEAs) for a visual prosthesis were fabricated by laser structuring of platinum (Pt) foil and liquid silicone rubber. A new design was created using a folding technique to create a multi-layered array from a single Pt sheet. This method allowed a reduction in both the electrode pitch, and the overall width of the array, while maintaining coplanar connection points for more stable interconnections to other components of the system. The design also included a section which could be rolled to create a cylindrical segment in order to minimise the size of the exit in the sclera after implantation. A picosecond mode-locked 532 nm laser system was investigated as a replacement for the nanosecond Q-switched 1064 nm laser currently in use. Trials showed that the ps system could produce high quality electrode tracks with a minimum pitch of 30 MUm, less than 40% the pitch achievable with the ns laser. A method was investigated for the cutting of Pt foils without damaging the underlying silicone by laser machining to a depth just below the thickness of the foil. Initial samples showed promise with full penetration of the foil only occurring at cross points of the laser paths. The ps laser was also used to create roughened surfaces, in order to increase the electrochemical surface area of the electrodes. Surfaces were imaged using a scanning electron microscope, and compared to surfaces roughened with the ns laser. The ps laser was seen to offer a reduction in feature size, as well as an increase in control over the appearance of the electrode surface. PMID- 22254390 TI - Mechanical characterization of neural electrodes based on PDMS-parylene C-PDMS sandwiched system. AB - Manufacturing of neural electrodes based on metal foil and silicone rubber using a laser is a simple and promising method. A handicap of such electrode arrays is the mechanical robustness of the thin metal tracks that connect the electrode sites with the interconnection pads. Embedding of structured parylene C foil in silicone rubber turned out to be an interesting method to increase the robustness. Test samples with 12.5 MUm thick platinum tracks and a 15 MUm thick embedded and RIE-structured parylene C foil showed more than 800 % higher ultimate strength until breakage of the tracks. Different structured parylene C foil showed increasing robustness with increasing hole-spacing. PMID- 22254391 TI - Chronic intracortical implantation of saccharose-coated flexible shaft electrodes into the cortex of rats. AB - Within this study, polyimide based shaft electrodes were fabricated and dip coated in molten saccharose to stiffen them for insertion into the brain tissue. These electrodes were then implanted successfully into the cortex of whistar rats and the insertion force during implantation was recorded. Electrochemical impedance spectroscopy was performed immediately after implantation and in regular time intervals up to 201 days after implantation to monitor the tissue response to the implanted electrodes. Depending on the measured electrode pairs and the rats, the impedance spectra behaved different over time. Either they showed a constant decrease in impedance at 1 kHz, or they showed an initial decrease to increase again later. Furthermore, physiological signal recording was performed by stimulating the rats with acoustic signals and simultaneously recording the response on the different electrode sites. Multi-unit activity was detected until 37 days after implantation with an averaged signal-to-noise ratio of 2 to 4. PMID- 22254392 TI - An experimental approach towards the development of an in vitro cortical-thalamic co-culture model. AB - In this paper, we propose an experimental approach to develop an in vitro dissociated cortical-thalamic co-culture model using a dual compartment neurofluidic device. The device has two compartments separated by 10 MUm wide and 3 MUm high microchannels. The microchannels provide a physical isolation of neurons allowing only neurites to grow between the compartments. Long-term viable co-culture was maintained in the compartmented device, neurite growth through the microchannels was verified using immunofluorescence staining, and electrophysiological recordings from the co-culture system was investigated. Preliminary analysis of spontaneous activities from the co-culture shows a distinctively different firing pattern associated with cultures of individual cell types and further analysis is proposed for a deeper understanding of the dynamics involved in the network connectivity in such a co-culture system. PMID- 22254393 TI - Reconfigurable fault-tolerant multielectrode array for dependable monitoring of the human brain. AB - We introduce a fault-tolerant strategy to improve the dependability of a multi electrode array (MEA), an issue of considerable concern. We propose an interstitial redundancy approach with local reconfiguration. Here spare modules are placed at interstitial sites and can replace neighboring primary modules when they develop faults. We evaluate the performance of such a system under different faults to characterize MEA dependability as a function of redundancy. The results demonstrate that a considerable improvement in MEA dependability can be achieved with a well designed increase in redundancy. PMID- 22254394 TI - Micro-reaction chamber electrodes for neural stimulation and recording. AB - Biocompatible electrodes with smaller geometric area are preferred to improve the selectivity of the neural recording and stimulation applications. We introduce the concept of a micro-reaction chamber (MURC) in which a volume within the electrode back plane is used to confine and sequester the electrochemical reactions used for charge passage. The URC electrode design helps decrease impedance and improves the charge storage capacity without altering the geometry of the active site. Here we demonstrate that MURC electrodes fabricated from 50 MUm diameter microwire have significantly improved charge storage capacity and lowered impedance at physiologically relevant frequencies in phosphate buffered saline solution compared with other designs. PMID- 22254395 TI - Development of an implantable microstimulation system for chronic DBS in rodents. AB - High frequency deep brain stimulation (DBS) of certain basal ganglia nuclei (e.g. subthalamic nucleus, STN) has emerged as a powerful neuromodulatory approach in the treatment of late stage Parkinson's disease patients. However, the underlying mechanisms of action are not fully understood. We have therefore established an implantable DBS device for small laboratory animals (e.g. rats) that allows the reliable and safe application of continuous DBS for at least 3 weeks. We could further show that miniaturized monopolar electrodes comprising activated iridium are suitable for continuous stimulation of small brain structures like the STN without inducing severe insertion or stimulation related injuries. PMID- 22254396 TI - The translational value of the MPTP non-human primate model of Parkinsonism for deep brain stimulation research. AB - Deep brain stimulation (DBS) has been applied in more than 70000 patients worldwide during the last two decades. The main target is the subthalamic nucleus (STN) for the treatment of motor complications in late stage Parkinson's disease (PD). Positive results in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated non-human primates have set the grounds for its successful translation to PD patients. Since then, this model has allowed gaining significant insights in the underlying mechanisms of action of DBS and is currently being used for the development of new stimulation techniques. Altogether, this underpins the high potential of this preclinical model for future translation of DBS research in PD. PMID- 22254398 TI - Advancing neuromodulation using a dynamic control framework. AB - The current state of neuromodulation can be cast in a classical dynamic control framework such that the nervous system is the classical "plant", the neural stimulator is the controller, tools to collect clinical data are the sensors, and the physician's judgment is the state estimator. This framework characterizes the types of opportunities available to advance neuromodulation. In particular, technology can potentially address two dominant factors limiting the performance of the control system: "observability," the ability to observe the state of the system from output measurements, and "controllability," the ability to drive the system to a desired state using control actuation. Improving sensors and actuation methods are necessary to address these factors. Equally important is improving state estimation by understanding the neural processes underlying diseases. Development of enabling technology to utilize control theory principles facilitates investigations into improving intervention as well as research into the dynamic properties of the nervous system and mechanisms of action of therapies. In this paper, we provide an overview of the control system framework for neuromodulation, its practical challenges, and investigational devices applying this framework for limited applications. To help motivate future efforts, we describe our chronically implantable, low-power neural stimulation system, which integrates sensing, actuation, and state estimation. This research system has been implanted and used in an ovine to address novel research questions. PMID- 22254399 TI - Improving postural stability via computational modeling approach to deep brain stimulation programming. AB - Bilateral subthalamic (STN) deep brain stimulation (DBS) is generally effective in improving the cardinal motor signs of advanced Parkinson's disease (PD). However, in many cases postural instability is refractory to STN DBS. The goal of this project was to determine if postural instability could be improved with STN DBS by avoiding current spread to the non-motor territories of the STN. Stimulation parameters that maximized activation of a theoretically defined target region were determined via patient-specific computer models created in Cicerone. Postural stability was assessed under three conditions: Off DBS, Clinical DBS, and Model DBS. Clinical settings were the patients' DBS settings determined via traditional clinical practice and were considered optimized and stable for at least 6 months prior to study enrollment. Blinded and randomized evaluations were performed in five patients. Postural sway was significantly less during Model DBS compared to Clinical DBS. These results support the hypothesis that minimizing spread of current to non-motor territories of the STN can improve PD related instability with DBS. PMID- 22254400 TI - Emerging techniques for elucidating mechanism of action of deep brain stimulation. AB - Deep brain stimulation (DBS) within the basal ganglia complex is an effective neurosurgical approach for treating symptoms of Parkinson's disease (PD), Essential Tremor, Dystonia, Depression, Obssessive Compulsive Disorder, and Tourette's Syndrome, among others. Elucidating DBS mechanism has become a critical clinical and research goal in stereotactic and functional neurosurgery and in neural engineering. Along with electro-physiological and microdialysis techniques, two additional powerful technologies, notably functional Magnetic Resonance Imaging (fMRI) and in vivo neurochemical monitoring have recently been used to investigate DBS-mediated activation of basal ganglia network circuitry. For this purpose, we have previously developed WINCS (Wireless Instantaneous Neurotransmitter Concentration Sensor System), which is an MRI-compatible wireless monitoring device to obtain chemically resolved neurotransmitter measurements at implanted microsensors in a large mammalian model (pig) as well as in human patients. This device supports an array of electrochemical measurements that includes fast-scan cyclic voltammetry (FSCV) for real-time simultaneous in vivo monitoring of dopamine and adenosine release at carbon-fiber microelectrodes as well as fixed potential amperometry for monitoring of glutamate at enzyme-linked biosensors. In addition, we have utilized fMRI to investigate subthalamic nucleus (STN) DBS activation in the pig with 3Tesla MR scanner. We demonstrate the activation of specific basal ganglia circuitry during STN DBS using both fMRI and FSCV in the pig model. Our results suggest that fMRI and electrochemistry are important emerging techniques for use in elucidating mechanism of action of DBS. PMID- 22254401 TI - Correlation of heart rate variability and circadian markers in humans. AB - The frequency of adverse cardiovascular events is greater in the morning compared to its 24-hour average. A circadian variation in the regulation of the cardiovascular system could contribute to this increased cardiovascular risk in the morning. Indeed, circadian rhythms have been shown for a wide array of physiological processes. Using an ultradian sleep-wake cycle (USW) procedure, we sought to determine how heart rate (HR) and heart rate variability (HRV) correlate with the well-characterized circadian rhythms of cortisol and melatonin secretion. Specific HRV components, namely the low frequency (LF) power, high frequency (HF) power, and the LF:HF ratio can be used as markers of the autonomic modulation of the heart. Cross-correlation between HRV parameters and hormonal rhythms demonstrated that mean RR interval is significantly phase-advanced relative to salivary cortisol and urinary 6-sulfatoxy-melatonin (UaMt6s). Parasympathetic modulation of the heart (HF power) was phase-advanced relative to cortisol, but was in-phase with UaMt6s levels. Maximal correlation of the sympathovagal balance (the LF:HF ratio) had no significant lag compared to cortisol secretion and UaMt6s excretion. The protective effect of the parasympathetic nervous system at night, combined with the putative risk associated with the sympathetic nervous system peaking in the morning, could be associated with the increased cardiovascular risk observed in the morning hours. PMID- 22254402 TI - Heart rate variability effect on the myocyte action potential duration restitution: insights from switched systems theory. AB - The physiological heart rate presents a stochastic behavior known as heart rate variability (HRV). In this framework the influence of HRV on the action potential duration (APD) of the atrial myocyte is analyzed in a computer model. We have found that introducing HRV into the myocyte action potential model decreases the APD of the extra beat S2 in an S1-S2 protocol compared to constant heart rate. A possible theoretical explanation for this is also presented and is derived from switched systems theory. It is suggested to consider the myocyte action potential phase 4 and phase 2 as two operation modes of a switching system and analyze the stability of switching between them. Since random switching is known to have a stabilization effect on a switching system, this might explain why HRV has a stabilization effect on the myocyte APD restitution. Implications of this finding include reduced system stability for conditions with low HRV. A possible application for this phenomenon regards artificial pacemakers, where a preset added HRV is predicted to reduce susceptibility to arrhythmias. PMID- 22254403 TI - Consideration on step duration to assess open-loop static characteristics of the carotid sinus baroreflex in rats. AB - The carotid sinus baroreflex is one of the most important negative feedback systems to stabilize arterial pressure. Although static characteristics of the carotid sinus baroreflex can be assessed by using a stepwise input protocol under baroreflex open-loop conditions, the step duration has been determined empirically. In the present study, we examined the effects of different time windows (5-10, 15-20, 25-30, 35-40, 45-50, and 55-60 s) on the static characteristics estimated by using a 60-s stepwise input protocol in 10 anesthetized rats. Based on the results, we compared the static characteristics between actual 60-s and 20-s stepwise input protocols. Most of the parameters of the static characteristics did not differ significantly between the 60-s and 20-s stepwise input protocols, suggesting that the open-loop baroreflex static characteristics can be estimated by using a stepwise input with the step duration as short as 20 s in normal rats. PMID- 22254404 TI - Changes in blood volume pulse during exercise recovery in activity-based therapy for spinal cord injury. AB - This paper presents the results of cardiovascular changes that occur during a novel rehabilitation strategy called activity based therapy (ABT). Blood volume pulse (BVP) signals were measured during functional electrical stimulation (FES) induced cycling in adults with spinal cord injury (SCI) persons and results were compared to a passive cycling task and able-bodied controls performing normal cycling. BVP signals were compared during three conditions, a baseline pre exercise condition, 5 minutes after exercise and after 30-minutes rest following exercise. Exercise recovery was evaluated using normalized inner products values in BVP signals. The results showed that FES-induced cycling in SCI participants resulted in a significantly greater peripheral resistance level and longer time to recover from exercise compared with passive cycling and normal cycling in able bodied controls. PMID- 22254405 TI - Artificial baroreflex system restores volume tolerance in the absence of native baroreflex. AB - The arterial baroreflex stabilizes arterial pressure by modulating the mechanical properties of cardiovascular system. We previously demonstrated that the baroreflex impairment makes the circulatory system extremely sensitive to volume overload and predisposes to pulmonary edema irrespective of left ventricular systolic function. To overcome the volume intolerance, we developed an artificial baroreflex system by directly stimulating the carotid sinus nerves in response to changes in arterial pressure. The artificial baroreflex system precisely reproduced the native arterial pressure response and restored physiological volume buffering function. We conclude that the artificial baroreflex system would be an attractive tool in preventing pulmonary edema in patients with impaired baroreflex function. PMID- 22254406 TI - A systematic approach to local stability analysis of cardiovascular baroreflex. AB - This paper presents a novel systematic approach to the stability analysis of the cardiovascular (CV) baroreflex. The proposed approach determines the equilibrium state and the system stability in its neighbourhood with computational efficiency, once the parameters of the CV baroreflex model are specified for an individual. We first propose a linearization-based analytical method for determining the equilibrium state of the CV baroreflex. We then present a Lyapunov-based systematic approach to analyze the system stability in the neighbourhood of the equilibrium state. The results of simulation experiments suggest that the performance of the proposed approach is encouraging: it was able to accurately determine the equilibrium state and quantify the stability of the CV baroreflex. The proposed approach is also powerful in exploring the relationship between the CV baroreflex stability and its parameter configurations. PMID- 22254407 TI - Comparison of continuous and discrete stochastic ion channel models. AB - The stochastic behaviour of ion channels can be described by a discrete model or by an approximate continuous approach. While the discrete approach is exact, it is also less computationally efficient, and so the continuous model is often the method of choice since it allows for incorporation into a multiscale environment. However, in recent years the accuracy of the stochastic continuous approach for calculating statistics of certain quantities in the Hodgkin-Huxley model has come into question. In this paper, we show that by correct formulation of the continuous model, the first two moments in the number of open sodium and potassium channels in the Hodgkin-Huxley model, calculated under voltage clamp conditions using the continuous approach are in good agreement with those obtained from the discrete model. PMID- 22254408 TI - 3-D Modeling of nitric oxide emission and vasodilation induced by CA3 hippocampal neurons. AB - The modeling of the spread, diffusion, and decay of chemicals in the brain is a complex problem that is made difficult by the fact that the structures that produce chemicals (synapses etc.) may be very small in comparison to their radii of chemical influence. In this article, we concentrate on modeling a simple instance of this problem; that of a proficiently diffusing molecule that may cause changes in smooth muscle contractions over relatively large areas. An optimized diffusion system was developed to study the diffusion of neuronal nitric oxide. Our diffusion system allows us to model the spread of nitric oxide from all areas of neurons, including the soma and dendritic processes. In addition, our system allows us to model tiny diffusing structures without sacrificing large-scale granularity. To study the effect of NO-producing neurons on vasodilation, we simulate systems of 1 and 2 neurons. We show that it is possible for nitric oxide emitted from neurons to be involved in regulating blood flow. PMID- 22254409 TI - Prediction of mean arterial blood pressure with linear stochastic models. AB - A model-based approach that integrates known portion of the cardiovascular system and unknown portion through a parameter estimation to predict evolution of the mean arterial pressure is considered. The unknown portion corresponds to the neural portion that acts like a controller that takes corrective actions to regulate the arterial blood pressure at a constant level. The input to the neural part is the arterial pressure and output is the sympathetic nerve activity. In this model, heart rate is considered a proxy for sympathetic nerve activity. The neural portion is modeled as a linear discrete-time system with random coefficients. The performance of the model is tested on a case study of acute hypotensive episodes (AHEs) on PhysioNet data. TPRs and FPRs improve as more data becomes available during estimation period. PMID- 22254410 TI - A feedback control model for cortisol secretion. AB - Existing mathematical models for cortisol secretion do not describe the entire cortisol secretion process, from the neural firing of corticotropin releasing hormone (CRH) in the hypothalamus to cortisol concentration in the plasma. In this paper, we lay the groundwork to construct a more comprehensive model, relating CRH, Adrenocorticotropic hormone (ACTH), and cortisol. We start with an existing mathematical model for cortisol secretion, and combine it with a simplified neural firing model that describes CRH and ACTH release. This simplified neural firing model is obtained using the extended FitzHugh-Nagumo (FHN) model, which includes a time-varying spiking threshold [3]. A key feature of our model is the presence of a feedback loop from cortisol secretion to ACTH secretion. PMID- 22254411 TI - 3D tracking of mating events in wild swarms of the malaria mosquito Anopheles gambiae. AB - We describe an automated tracking system that allows us to reconstruct the 3D kinematics of individual mosquitoes in swarms of Anopheles gambiae. The inputs to the tracking system are video streams recorded from a stereo camera system. The tracker uses a two-pass procedure to automatically localize and track mosquitoes within the swarm. A human-in-the-loop step verifies the estimates and connects broken tracks. The tracker performance is illustrated using footage of mating events filmed in Mali in August 2010. PMID- 22254412 TI - GPGPU accelerated cardiac arrhythmia simulations. AB - Computational modeling of cardiac electrophysiology is a powerful tool for studying arrhythmia mechanisms. In particular, cardiac models are useful for gaining insights into experimental studies, and in the foreseeable future they will be used by clinicians to improve therapy for the patients suffering from complex arrhythmias. Such models are highly intricate, both in their geometric structure and in the equations that represent myocyte electrophysiology. For these models to be useful in a clinical setting, cost-effective solutions for solving the models in real time must be developed. In this work, we hypothesized that low-cost GPGPU-based hardware systems can be used to accelerate arrhythmia simulations. We ported a two dimensional monodomain cardiac model and executed it on various GPGPU platforms. Electrical activity was simulated during point stimulation and rotor activity. Our GPGPU implementations provided significant speedups over the CPU implementation: 18X for point stimulation and 12X for rotor activity. We found that the number of threads that could be launched concurrently was a critical factor in optimizing the GPGPU implementations. PMID- 22254413 TI - Electrochemotherapy of solid tumors--preclinical and clinical experience. AB - Electrochemotherapy consists of administration of the chemotherapeutic drug followed by application of electric pulses to the tumor, in order to facilitate the drug uptake into the cells. Only two chemotherapeutics are currently used in electrochemotherapy, bleomycin and cisplatin, which both have hampered transport through the plasma membrane without electroporation of tumors. Based on extensive preclinical studies, elaborating on parameters for effective tumor treatment and elucidating the mechanisms of this therapy, electrochemotherapy is now in clinical use. It is in standard treatment of melanoma cutaneous metastases in Europe. However it is effective also for cutaneous metastases of other tumor types. Currently the technology is being developed also for treatment of bigger, deep seated tumors. With long needle electrodes and new electric pulse generators, clinical trials are on-going for treatment of liver metastases, bone metastases and soft tissue sarcomas. PMID- 22254414 TI - Intracellular electroporation site distributions: modeling examples for nsPEF and IRE pulse waveforms. AB - We illustrate expected electroporation (EP) responses to two classes of large electric field pulses by employing systems models, one of a cell in vitro and the other of multiple cells in vivo. The first pulse class involves "nsPEF" (nanosecond pulsed electric fields). The durations are less than a microsecond, but the magnitudes are extremely large, often 10 kV/cm or more, and all of the pores remain small. The second class involves "IRE" (irreversible electroporation). Durations are many microseconds to several milliseconds, but with magnitudes smaller than 10 kV/cm, and a wide range of pore sizes evolves. A key feature of both pulse classes is non-thermal cell killing by multiple pulses without delivering external drugs or genes. For small pulses the models respond passively (no pore creation) providing negative controls. For larger pulses transient aqueous pore populations evolve. These greatly increase local membrane conductance temporarily, causing rapid redistribution of fields near and within cells. This complex electrical behavior is generally not revealed by experiments reporting biological end points resulting from cumulative ionic and molecular transport through cell membranes. The underlying, heterogeneous pore population distributions are also not obtained from typical experiments. Further, traditional EP applications involving molecular delivery are usually assumed to create pores solely in the outer, plasma membrane (PM). In contrast, our examples support the occurrence of intracellular EP by both nsPEF and IRE, but with different intracellular spatial distributions of EP sites. PMID- 22254415 TI - Electroporation based gene therapy--from the bench to the bedside. AB - A critical aspect of gene transfer is effective delivery of the transgene to the appropriate target. Electrically mediated delivery (electroporation) of plasmid DNA has been accepted as a viable approach to achieve effective delivery. One promising area is delivering plasmid DNA to skin. Gene transfer to the skin with electroporation is currently being evaluated for its potential for inducing angiogenesis for wound healing and for delivering DNA vaccines to the skin. Experiments utilizing a plasmid encoding for vascular endothelial growth factor has demonstrated how wound healing could be accelerated. In another study, delivery of a plasmid encoding Hepatitis B surface antigen have demonstrated that high antibody titers can be induced after two applications (prime/boost). Our laboratory has also examined the use of electroporation to delivery plasmid DNA encoding various cytokines as a potential therapy for melanoma. The plasmid is injected directly into the tumor followed by the administration of electroporation. Extensive preclinical work provided the rationale for a Phase I proof of concept first in human trial in patients with accessible cutaneous melanoma metastases. Biopsies of treated lesions showed significant necrosis of melanoma cells within the tumor as well as IL-12 expression. Lymphocytic infiltrate was observed in biopsies from patients in several cohorts. Clinical evidence of responses in untreated lesions suggested there was a systemic response following therapy was observed. Since this trial several other clinical studies utilizing electroporation to deliver plasmid DNA have been initiated. It is clear that this delivery approach has tremendous potential to facilitate the translation of gene transfer protocols from the bench to the bedside. PMID- 22254416 TI - Electrical conductivity changes during irreversible electroporation treatment of brain cancer. AB - Irreversible electroporation (IRE) is a new minimally invasive technique to kill tumors and other undesirable tissue in a non-thermal manner. During an IRE treatment, a series of short and intense electric pulses are delivered to the region of interest to destabilize the cell membranes in the tissue and achieve spontaneous cell death. The alteration of the cellular membrane results in a dramatic increase in electrical conductivity during IRE as in other electroporation-based-therapies. In this study, we performed the planning and execution of an IRE brain cancer treatment using MRI reconstructions of the tumor and a multichannel array that served as a stereotactic fiducial and electrode guide. Using the tumor reconstructions within our numerical simulations, we developed equations relating the increase in tumor conductivity to calculated currents and volumes of tumor treated with IRE. We also correlated the experimental current measured during the procedure to an increase in tumor conductivity ranging between 3.42-3.67 times the baseline conductivity, confirming the physical phenomenon that has been detected in other tissues undergoing similar electroporation-based treatments. PMID- 22254417 TI - Mitochondrial membrane permeabilization with nanosecond electric pulses. AB - Ultra-short, high-field electric pulses permeabilize plasma and intracellular membranes. We report here nanosecond pulse-induced permeabilization of mitochondrial membranes in living cells. Using four independent methods based on fluorescent dyes--JC-1, rhodamine 123, tetramethyl rhodamine ethyl ester, and cobalt-quenched calcein--we show that as few as five, 4 ns, 10 MV/m pulses delivered at 1 kHz cause an increase of the inner mitochondrial membrane permeability and an associated loss of mitochondrial membrane potential. The most likely interpretation of these results is a pulse-induced permeabilization of the inner mitochondrial membrane. PMID- 22254418 TI - Planar lipid bilayers: observing pore creation and extinction. AB - From an electrical point of view a planar lipid bilayer can be considered as a non-perfect capacitor; it can be presented as an ideal capacitor in parallel with resistor. In this study the whole measuring system including planar lipid bilayer was modeled by an equivalent electric circuit in Spiceopus software. Such a model gives additional information of experimentally obtained results. In this way we analyze measurements of transmembrane voltage that appears on planar lipid bilayer as consequence of linear rising current. Small voltage drops were obtained before the planar lipid bilayer breakdown. The model showed that effective current on planar lipid bilayer is actually much smaller than the current applied with current generator and should be used in calculations of a conductance related to voltage drops. PMID- 22254419 TI - Variable-arrival-time reaching with the brain-machine interface: performance comparison on empirically-derived movements. AB - Patients with paralysis will one day rely on clinically-available brain-machine interfaces (BMI) to facilitate activities of daily living. As such, the ability to generate dexterous reaching movements remains a prime target of BMI algorithms research. The Bayesian approach to BMI algorithms requires a statistical model to describe reaching movements. To date, available models have either required fixed targets or fixed arrival times, neither of which can be assumed under natural operating conditions. Recently, we described a generative reach model, GPFD-RSE, that simultaneously breaks both restrictions. This method combines the reach state equation (RSE) with General Purpose Filter Design (GPFD). In the following paper, we further compare GPFD-RSE against standard methods in simulated open loop decoding using empirically-derived movements, as an adjunct to the idealized movements tested previously. Our results indicate that GPFD-RSE continues to outperform standard methods when reconstructing more realistic arm movements in simulation. PMID- 22254420 TI - Emerging technology for advancing the treatment of epilepsy using a dynamic control framework. AB - We briefly describe a dynamic control system framework for neuromodulation for epilepsy, with an emphasis on its practical challenges and the preliminary validation of key prototype technologies in a chronic animal model. The current state of neuromodulation can be viewed as a classical dynamic control framework such that the nervous system is the classical "plant", the neural stimulator is the controller/actuator, clinical observation, patient diaries and/or measured bio-markers are the sensor, and clinical judgment applied to these sensor inputs forms the state estimator. Technology can potentially address two main factors contributing to the performance limitations of existing systems: "observability," the ability to observe the state of the system from output measurements, and "controllability," the ability to drive the system to a desired state. In addition to improving sensors and actuator performance, methods and tools to better understand disease state dynamics and state estimation are also critical for improving therapy outcomes. We describe our preliminary validation of key "observability" and "controllability" technology blocks using an implanted research tool in an epilepsy disease model. This model allows for testing the key emerging technologies in a representative neural network of therapeutic importance. In the future, we believe these technologies might enable both first principles understanding of neural network behavior for optimizing therapy design, and provide a practical pathway towards clinical translation. PMID- 22254421 TI - Using point process models to describe rhythmic spiking in the subthalamic nucleus of Parkinson's patients. AB - Neurological disease is often associated with changes in firing activity in specific brain areas. Accurate statistical models of neural spiking can provide insight into the mechanisms by which the disease develops and clinical symptoms manifest. Point process theory provides a powerful framework for constructing, fitting, and evaluating the quality of neural spiking models. We illustrate an application of point process modeling to the problem of characterizing abnormal oscillatory firing patterns of neurons in the subthalamic nucleus (STN) of patients with Parkinson's disease (PD). We characterize the firing properties of these neurons by constructing conditional intensity models using spline basis functions that relate the spiking of each neuron to movement variables and the neuron's past firing history, both at short and long time scales. By calculating maximum likelihood estimators for all of the parameters and their significance levels, we are able to describe the relative propensity of aberrant STN spiking in terms of factors associated with voluntary movements, with intrinsic properties of the neurons, and factors that may be related to dysregulated network dynamics. PMID- 22254422 TI - Millimeter-scale epileptiform spike patterns and their relationship to seizures. AB - Advances in neural electrode technology are enabling brain recordings with increasingly fine spatial and temporal resolution. We explore spatio-temporal (ST) patterns of local field potential spikes using a new high-density active electrode array with 500 MUm resolution. We record subdural micro electrocorticographic (MUECoG) signals in vivo from a feline model of acute neocortical epileptiform spikes and seizures induced with local administration of the GABA antagonist, picrotoxin. We employ a clustering algorithm to separate 2 dimensional (2-D) spike patterns to isolate distinct classes of spikes unique to the interictal and ictal states. Our findings indicate that the 2-D patterns can be used to distinguish seizures from non-seizure state. We find two statistically significant ST patterns that uniquely characterize ictal epochs. We conclude that millimeter-scale ST spike dynamics contain useful information about ictal state. This finding may be important to understanding mechanisms underlying local circuit activity during seizure generation. Further work will investigate whether patterns we identify can increase our understanding of seizure dynamics and their underlying mechanisms and inform new electrical stimulation protocols for seizure termination. PMID- 22254423 TI - Anodal transcranial direct current stimulation relieves the unilateral bias of a rat model of Parkinson's disease. AB - The unilaterally lesioned rat model of Parkinson's disease which fails to orient to the food stimuli presented on the contralateral side of its preferential side of body could be induced by the injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). We employed transcranial direct current stimulation (tDCS, current intensity: 80 MUA, and 40 MUA; anodal electrode area: 3.14 mm(2); stimulation time: 30 minutes) over the M1 area to relieve the ipsilateral bias in the rat model. A corridor test was set to count the ipsilateral bias of the rats. In this experiment, 30 Sprague-Dawley rats (80 MUA: n = 8, 40 MUA: n = 8, sham: n = 7, healthy control: n = 7) were chosen for the corridor test and the tDCS session. The lesioned rats exhibited increased ipsilateral bias 4 weeks after the lesion surgery (P < 0.01), and the anodal tDCS with the active electrode on the lesioned side relieved the ipsilateral bias significantly (P < 0.01) immediately after the surgery and the improvement lasted for nearly 1 day. The rats in the group of 80 MUA exhibited more significant changes than the 40 MUA group after one day. After all the experiments, the histological process showed no neurotrauma led by the tDCS. In conclusion, the modulatory function of the cortical excitability of the tDCS may awaken the compensatory mechanisms and the response mechanisms which modulate the loss of the brain function. Further studies should be done to provide more evidence about the assumption. PMID- 22254424 TI - Assessment of sleep quality in powernapping. AB - The purpose of this study is to assess the Sleep Quality (SQ) in powernapping. The contributed factors for SQ assessment are time of Sleep Onset (SO), Sleep Length (SL), Sleep Depth (SD), and detection of sleep events (K-complex (KC) and Sleep Spindle (SS)). Data from daytime nap for 10 subjects, 2 days each, including EEG and ECG were recorded. The SD and sleep events were analyzed by applying spectral analysis. The SO time was detected by a combination of signal spectral analysis, Slow Rolling Eye Movement (SREM) detection, Heart Rate Variability (HRV) analysis and EEG segmentation using both Autocorrelation Function (ACF), and Crosscorrelation Function (CCF) methods. The EEG derivation FP1-FP2 filtered in a narrow band and used as an alternative to EOG for SREM detection. The ACF and CCF segmentation methods were also applied for detection of sleep events. The ACF method detects segment boundaries based on single channel analysis, while the CCF includes spatial variation from multiple EEG derivation. The results indicate that SREM detection using EEG is possible and can be used as input together with power spectral analysis to enhance SO detection. Both segmentation methods could detect SO as a segment boundary. Additionally they were able to contribute to detection of KC and SS events. The CCF method was more sensitive to spatial EEG changes and the exact segment boundaries varied slightly between the two methods. The HRV analysis revealed, that low and very low frequency variations in the heart rate was highly correlated with the EEG changes during both SO and variations in SD. Analyzing the relationship between the sleep events and SD showed a negative correlation between the Delta and Sigma activity. Analyzing the subjective measurement (SM) showed that there were a positive correlation between the SL and rated SQ. This preliminary study showed that the factors contributing to the overall SQ during powernapping can be assessed markedly better using a fusion of multiple methods. Future studies will include measures of individual performance before and after powernapping and investigate its relation to the assessed SQ. PMID- 22254425 TI - Obstructive sleep apnea prediction during wakefulness. AB - In this paper, a novel technique based on signal processing of breath sounds during wakefulness for prediction of obstructive sleep apnea (OSA) is proposed. We recorded tracheal breath sounds of 35 people with various severity of OSA and 17 non-apneic individuals; the breath sounds were recorded in supine and upright positions during both nose and mouth breathing at medium flow rate. Power spectrum, Kurtosis and Katz fractal dimension of the recorded signals in every posture and breathing maneuver were calculated. We used one-way ANOVA to select the features with most significant differences between the groups followed by the Maximum Relevancy Minimum Redundancy (mRMR) method to reduce the number of characteristic features to three, and investigated the separability of the groups based on the three selected features. The results are encouraging for classification of patients using the selected features. Once being verified on a larger population, the proposed method offers a fast, simple and non-invasive screening tool for prediction of OSA during wakefulness. PMID- 22254426 TI - Toward a taxonomy of autonomic sleep patterns with electrodermal activity. AB - This paper presents a first version of a taxonomy of automatic sleep patterns found with the Affectiva QTM Sensor, a wireless, logging biosensor that measures skin conductance, skin temperature, and motion comfortably from the wrist. Several studies have examined electrodermal activity (EDA) during sleep, but they focused on an analysis of EDA for only a small number of nights. We quantitatively analyzed EDA during sleep in three study situations: (1) Comparing EDA with polysomnography (PSG) from seven subjects in a sleep lab, (2) Characterizing multiple nights of EDA in a sleep lab, in a hospital and at home from 24 subjects, and (3) Gathering long-term EDA (30-60 nights) patterns from three subjects during home sleep. After gathering this rich corpus of data, we characterized inter- and intra-individual differences of EDA features and the relation of EDA peaks to subjective sleep quality. Here we present results from the three studies in an effort to begin to characterize autonomic patterns found in natural sleep. PMID- 22254427 TI - Visual ERP P3 amplitude and latency in standalone and embedded visual processing task. AB - Event-related potentials (ERPs) of a visual processing task are compared with and without a simultaneous external working memory load. Ten adults participated the same measurement session on three separate days. Results for visual ERP P3 amplitude and reaction time (RT) are presented for both task conditions. Both the reaction time of the visual task and the respective P3 latency increased during high memory load. It was also found that P3 amplitude and reaction time correlated only under the high memory load condition. The results indicate that visual P3 to a simple processing task is affected by external working memory load. PMID- 22254428 TI - A methodology to improve estimation of stimulus-evoked hemodynamic response from fNIRS measurements. AB - Functional near-infrared spectroscopy (fNIRS) is a non-invasive optical neuroimaging method used to investigate functional activity of the cerebral cortex evoked by cognitive, visual, auditory and motor tasks, detecting regional changes of oxy- and deoxy-hemoglobin concentration. Accurate estimation of the stimulus-evoked hemodynamic response (HR) from fNIRS signals in order to quantitatively investigate cognitive functions requires to cope with several noise components. Some of them appear as random disturbances (typically tackled through averaging techniques), while others are due to physiological sources, such as heart beat, respiration, vasomotor waves, and are particularly challenging to be dealt with because they lie in the same frequency band of HR. In this work we present a new two-steps methodology for the HR estimation from fNIRS data. The first step is a pre-processing stage where physiological trends in fNIRS data are reduced by exploiting a mathematical model identified from the signal of a reference channel. In the second step, the pre-processed data of the other channels are filtered with a recently presented non-parametric Bayesian approach (Scarpa et al., Optics Express, 2010). The presented method for HR estimation is compared with widely used methods: conventional averaging, band pass filtering and principal component analysis (PCA). Results on simulated data reveal the ability of the proposed method to improve the accuracy of the estimates of the functional hemodynamic response, as well as the estimate of peak amplitude and latency. Encouraging preliminary results in a representative real data set showing an improvement of contrast to noise ratio are also reported. PMID- 22254429 TI - An auditory Go/No-Go study of event-related potentials in children with fetal alcohol spectrum disorders. AB - In this study event-related potentials (ERPs) were used to investigate the effects of prenatal alcohol exposure on response inhibition identified during task performance. ERPs were recorded during a auditory Go/No Go task in two groups of children with mean age of 12.8 years (11 years to 14.7 years): one diagnosed with fetal alcohol syndrome (FAS) or partial FAS (FAS/PFAS; n = 12) and a control group of children of same age whose mothers abstained from alcohol or drank minimally during pregnancy (n = 11). The children were instructed to push a button in response to the Go stimulus and not to press the button when the No Go stimulus were heard. Task performance accuracy did not differ between the two groups, however differences were observed in the ERP components: P2, N2, and P3. The P2 amplitude were larger for Go trials in both groups. The FAS/PFAS group showed slower N2 response to Go trials, suggesting a less efficient early classification of the stimulus. P3 showed larger amplitudes to No-Go vs. Go in both groups. The study has provided new evidence for inhibition deficits in FAS/PFAS subjects identified by ERPs. PMID- 22254430 TI - Power independent EMG based gesture recognition for robotics. AB - A novel method for detecting muscle contraction is presented. This method is further developed for identifying four different gestures to facilitate a hand gesture controlled robot system. It is achieved based on surface Electromyograph (EMG) measurements of groups of arm muscles. The cross-information is preserved through a simultaneous processing of EMG channels using a recent multivariate extension of Empirical Mode Decomposition (EMD). Next, phase synchrony measures are employed to make the system robust to different power levels due to electrode placements and impedances. The multiple pairwise muscle synchronies are used as features of a discrete gesture space comprising four gestures (flexion, extension, pronation, supination). Simulations on real-time robot control illustrate the enhanced accuracy and robustness of the proposed methodology. PMID- 22254431 TI - Artifact removal for intracranial pressure monitoring signals: a robust solution with signal decomposition. AB - Intracranial Pressure (ICP) monitoring signal collected in Neuro Intensive Care Units often contains large amount of artifacts. The artifacts not only directly lead to false alarms in automatic Intracranial Hypertension (IH) alert systems, and they also severely contaminate the characteristics of the underlying signal, which makes accurate forecasting of impending IH impossible. Therefore, in this paper, we propose a novel solution to effectively remove artifacts from ICP monitoring signals. The proposed method effectively detects artifacts by decomposing the ICP monitoring signal with Empirical Mode Decomposition (EMD) method. An iterative filtering method is also proposed to extract artifacts from the decomposed components of ICP signals. The proposed filter is robust. That is, the parameters of the iterative filter are estimated with robust statistics, which ensures the performance of the proposed filter will not be unduly affected by artifacts. The detected artifacts are then imputed based on the Auto Regressive Moving Average (ARMA) model to preserve the original characteristics of the ICP signal. The effectiveness of the proposed artifact removal method is experimentally justified based on the ICP monitoring signals of 59 patients. PMID- 22254433 TI - Comparison between EEMD, wavelet and FIR denoising: influence on event detection in impedance cardiography. AB - During thoracic impedance signal acquisition, noise is inherently introduced and hence, denoising is required to allow for accurate event detection. This paper investigates the effectiveness of Ensemble Emperical Mode Decomposition to filter random noise. The performance of the EEMD method is compared with an optimal FIR filter and wavelet denoising. The IMF selection for signal reconstruction in the EEMD denoising method is optimized using a sequential search. Denoising performance was evaluated by the SNR and the accuracy in event detection after filtering. When all criteria are taken into account, wavelet seems to outperform both EEMD and FIR denoising. PMID- 22254432 TI - Towards a suitable time-scale representation of cardio-respiratory signals through Empirical Mode Decomposition algorithms: a simulation and validation tool. AB - To what extent is Empirical Mode Decomposition (EMD) able to differentiate the embedded components of a cardio-respiratory (CR) signal? We intend to answer this question by providing a tool which compares the performances of the original EMD algorithm with those of a noise-assisted version (CEEMD) on simulated CR signals, depending on the frequency and amplitude ratios between their respiratory and cardiac components. A statistical Bland & Altman test checks the matching of stroke volumes calculated from the extracted cardiac signal and those from the simulated one. CEEMD turns out to be better than EMD by yielding to reliable multiscale representation of simulated CR signals on a wider domain of frequency and amplitude ratios. PMID- 22254434 TI - Multivariate multiscale entropy for brain consciousness analysis. AB - The recently introduced multiscale entropy (MSE) method accounts for long range correlations over multiple time scales and can therefore reveal the complexity of biological signals. The existing MSE algorithm deals with scalar time series whereas multivariate time series are common in experimental and biological systems. To that cause, in this paper the MSE method is extended to the multivariate case. This allows us to gain a greater insight into the complexity of the underlying signal generating system, producing multifaceted and more robust estimates than standard single channel MSE. Simulations on both synthetic data and brain consciousness analysis support the approach. PMID- 22254435 TI - Analysis of local field potential signals: a systems approach. AB - Efficient methods for Local Field Potential (LFP) signal analysis amenable to interpretation are becoming increasingly relevant. LFP signals are believed, in part, to reflect neural action potential activity, and LFP frequency modulations are linked to spiking events. Furthermore, LFP signals are increasingly accessible in human brain regions previously unreachable due to a proliferation of deep brain stimulation implantation procedures. Traditional LFP analysis involves computing power spectra densities (PSDs) of these signals, which captures power at various frequencies in the signal. However, PSDs are second order statistics and may not capture non-trivial temporal dependencies that exist in the raw data. In this paper, we propose an LFP analysis method that is useful for describing unique features of temporal dependencies in LFP signals. This method is based on autoregressive (AR) modeling and draws from the systems identification sub-field of systems and control. Specifically, we have built and analysed AR models of LFP activity, and have demonstrated statistically significant differences in temporal dependencies between diseased globus pallidus tissue and control regions in two dystonia patients receiving deep brain stimulation implantation. Differences in the PSDs of LFP signals between these two groups were not statistically significant. PMID- 22254437 TI - Circadian rest-activity rhythm for maintenance of body shape. AB - A recently developed wearable device has gained attention in the area of self discipline for the prevention of lifestyle-related diseases. The present study aimed to clarify the relationship between circadian rhythm and body shape change using actigraphy. Using a body shape vector, we classified 24 women in their 40s and 50s into 3 groups with different body shape changes. A circadian rhythm experiment was conducted on weekdays for 1 week with 24 healthy women. Amounts of activity of the non-dominant wrist and trunk, subjective evaluation of sleep quality, and subjective state of activity were surveyed. In order to maintain a constant body shape throughout life, a less sedentary lifestyle with more trunk movement during the day, getting adequate sleep at night, and having a varied sleep-wake cycle may be important factors. PMID- 22254436 TI - Hearing level equalized otoacoustic emissions acquired by swept-tones: intensity characteristics. AB - Otoacoustic emissions (OAE), which are acoustic responses produced by the cochlea, can be recorded with a microphone in the ear canal to give diagnostic information regarding cochlear functioning. Recently, the researchers developed a novel stimulus for the acquisition of OAE using a hearing-level equalized (HL(eq)) swept-tone signal. The objective of this study was to observe OAE characteristics at a multitude of intensities to track the changes in temporal and spectral morphology. An increase in high-frequency emissions was found as stimulation intensity decreased. Furthermore, it was found that hearing level equalized swept-tone OAEs (HL(eq) sTEAOE) can be acquired at very low intensities, which is not typical under current acquisition modalities. This may result in clinical improvements by providing a fast and cheap method for contributing to the detection of auditory thresholds. PMID- 22254438 TI - A data-driven modeling approach to stochastic computation for low-energy biomedical devices. AB - Low-power devices that can detect clinically relevant correlations in physiologically-complex patient signals can enable systems capable of closed-loop response (e.g., controlled actuation of therapeutic stimulators, continuous recording of disease states, etc.). In ultra-low-power platforms, however, hardware error sources are becoming increasingly limiting. In this paper, we present how data-driven methods, which allow us to accurately model physiological signals, also allow us to effectively model and overcome prominent hardware error sources with nearly no additional overhead. Two applications, EEG-based seizure detection and ECG-based arrhythmia-beat classification, are synthesized to a logic-gate implementation, and two prominent error sources are introduced: (1) SRAM bit-cell errors and (2) logic-gate switching errors ('stuck-at' faults). Using patient data from the CHB-MIT and MIT-BIH databases, performance similar to error-free hardware is achieved even for very high fault rates (up to 0.5 for SRAMs and 7 * 10(-2) for logic) that cause computational bit error rates as high as 50%. PMID- 22254439 TI - Auditory evoked responses to binaural beat illusion: stimulus generation and the derivation of the Binaural Interaction Component (BIC). AB - Electrophysiological indices of auditory binaural beats illusions are studied using late latency evoked responses. Binaural beats are generated by continuous monaural FM tones with slightly different ascending and descending frequencies lasting about 25 ms presented at 1 sec intervals. Frequency changes are carefully adjusted to avoid any creation of abrupt waveform changes. Binaural Interaction Component (BIC) analysis is used to separate the neural responses due to binaural involvement. The results show that the transient auditory evoked responses can be obtained from the auditory illusion of binaural beats. PMID- 22254440 TI - Extraction of deep brain stimulation (DBS) source in SEEG using EMD and ICA. AB - In the context of drug resistant partial epilepsy, intra-cerebral electrical stimulation (Deep Brain Stimulation) constitutes one of the means of investigation to locate epileptic volume. This exogenous source can then activate the underlying epileptic networks and generate an electrophysiological reaction. The purpose of this work is to estimate and eliminate the overlapping electrical stimulation signal in order to subsequently explore the provoked underlying electrical activity. We propose here several methods to tackle this problem, using two different approaches based on different assumptions: BSS approach based on Independent Component Analysis (ICA) and non parametric decomposition - empirical modes decomposition (EMD) algorithms. PMID- 22254441 TI - Patient specific cardiovascular risk assessment and treatment decision support based on multiscale modelling and medical guidelines. AB - In this work we present an enhanced medical workflow and a decision support system for atherosclerotic risk assessment and treatment, that is based both on existing medical guidelines and on patient specific multiscale data. The medical expert that uses the system is able to apply both existing medical guidelines as well as to take into account additional information for the patient by inspecting the 3D geometry of an arterial segment or the arterial tree, model the blood flow in the patient specific arterial model and predict the progression of the plaque. Moreover, the user is able to apply plaque characterization techniques in Intravascular Ultrasound images (IVUS) and Tomography Images (CT). The combination of the medical guidelines with the patient specific multiscale data provides a detailed view in the patient status for risk assessment and treatment suggestion. PMID- 22254442 TI - Uruguay eHealth initiative: preliminary studies regarding an integrated approach to evaluate vascular age and preclinical atherosclerosis (CUiiDARTE project). AB - In this work we present an initiative to develop a national (Uruguayan) program to evaluate vascular age and to detect pre-clinical atherosclerosis using: gold standard technologies; complimentary and integrative approaches to asses arterial functional and structural indexes; data bases systems to process, analyze and determine normal and reference values and to identify the most sensitive markers of vascular changes for different ages. We evaluated, in a Uruguayan population complementary structural and functional vascular parameters that associate aging related changes and are considered markers of sub-clinical atherosclerosis. Traditional CV risk factors were assessed. The subjects (n=281) were submitted to non-invasive vascular studies to evaluate: 1) Common carotid artery (CCA) intima media thickness and diameter waveforms, 2) CCA stiffness, 3) aortic stiffness (pulse wave velocity) and 4) peripheral and central pressure pulse wave derived parameters. Age groups: 21-30, 31-40, 41-50, 51-60, and 61-70 years-old. Age related profiles were obtained for the different vascular parameters, and their utility to assess vascular changes in young, middle-aged and old subjects was evaluated. The work has the strength of being the first that uses, in Latin America an integrative approach to characterize vascular aging-related changes. PMID- 22254443 TI - ZigBee-based wireless multi-sensor system for physical activity assessment. AB - Physical activity (PA) is important for assessing human exposure to the environment. This paper presents a ZigBee-based Wireless wearable multi-sensor Integrated Measurement System (WIMS) for in-situ PA measurement. Two accelerometers, a piezoelectric displacement sensor, and an ultraviolet (UV) sensor have been used for the physical activity assessment. Detailed analysis was performed for the hardware design and embedded program control, enabling efficient data sampling and transmission, compact design, and extended battery life to meet requirements for PA assessment under free-living conditions. Preliminary testing of the WIMS has demonstrated the functionality of the design, while performance comparison of the WIMS with a wired version on an electromagnetic shaker has demonstrated the signal validity. PMID- 22254444 TI - Diagnostic grade wireless ECG monitoring. AB - In remote monitoring of Electrocardiogram (ECG), it is very important to ensure that the diagnostic integrity of signals is not compromised by sensing artifacts and channel errors. It is also important for the sensors to be extremely power efficient to enable wearable form factors and long battery life. We present an application of Compressive Sensing (CS) as an error mitigation scheme at the application layer for wearable, wireless sensors in diagnostic grade remote monitoring of ECG. In our previous work, we described an approach to mitigate errors due to packet losses by projecting ECG data to a random space and recovering a faithful representation using sparse reconstruction methods. Our contributions in this work are twofold. First, we present an efficient hardware implementation of random projection at the sensor. Second, we validate the diagnostic integrity of the reconstructed ECG after packet loss mitigation. We validate our approach on MIT and AHA databases comprising more than 250,000 normal and abnormal beats using EC57 protocols adopted by the Food and Drug Administration (FDA). We show that sensitivity and positive predictivity of a state-of-the-art ECG arrhythmia classifier is essentially invariant under CS based packet loss mitigation for both normal and abnormal beats even at high packet loss rates. In contrast, the performance degrades significantly in the absence of any error mitigation scheme, particularly for abnormal beats such as Ventricular Ectopic Beats (VEB). PMID- 22254445 TI - PERCEPT: indoor navigation for the blind and visually impaired. AB - In order to enhance the perception of indoor and unfamiliar environments for the blind and visually-impaired, we introduce the PERCEPT system that supports a number of unique features such as: a) Low deployment and maintenance cost; b) Scalability, i.e. we can deploy the system in very large buildings; c) An on demand system that does not overwhelm the user, as it offers small amounts of information on demand; and d) Portability and ease-of-use, i.e., the custom handheld device carried by the user is compact and instructions are received audibly. PMID- 22254446 TI - Scalable patients tracking framework for mass casualty incidents. AB - We introduce a system that tracks patients in a Mass Casualty Incident (MCI) using active RFID triage tags and mobile anchor points (DM-tracks) carried by the paramedics. The system does not involve any fixed deployment of the localization devices while maintaining a low cost triage tag. The localization accuracy is comparable to GPS systems without incurring the cost of providing a GPS based device to every patient in the disaster scene. PMID- 22254447 TI - CHRONIOUS: a wearable platform for monitoring and management of patients with chronic disease. AB - The CHRONIOUS system has been developed based on an open architecture design that consists of a set of subsystems which interact in order to provide all the needed services to the chronic disease patients. An advanced multi-parametric expert system is being implemented that fuses information effectively from various sources using intelligent techniques. Data are collected by sensors of a body network controlling vital signals while additional tools record dietary habits and plans, drug intake, environmental and biochemical parameters and activity data. The CHRONIOUS platform provides guidelines and standards for the future generations of "chronic disease management systems" and facilitates sophisticated monitoring tools. In addition, an ontological information retrieval system is being delivered satisfying the necessities for up-to-date clinical information of Chronic Obstructive pulmonary disease (COPD) and Chronic Kidney Disease (CKD). Moreover, support tools are being embedded in the system, such as the Mental Tools for the monitoring of patient mental health status. The integrated platform provides real-time patient monitoring and supervision, both indoors and outdoors and represents a generic platform for the management of various chronic diseases. PMID- 22254448 TI - Biometric and mobile gait analysis for early diagnosis and therapy monitoring in Parkinson's disease. AB - Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Early diagnosis and effective therapy monitoring is an important prerequisite to treat patients and reduce health care costs. Objective and non invasive assessment strategies are an urgent need in order to achieve this goal. In this study we apply a mobile, lightweight and easy applicable sensor based gait analysis system to measure gait patterns in PD and to distinguish mild and severe impairment of gait. Examinations of 16 healthy controls, 14 PD patients in an early stage, and 13 PD patients in an intermediate stage were included. Subjects performed standardized gait tests while wearing sport shoes equipped with inertial sensors (gyroscopes and accelerometers). Signals were recorded wirelessly, features were extracted, and distinct subpopulations classified using different classification algorithms. The presented system is able to classify patients and controls (for early diagnosis) with a sensitivity of 88% and a specificity of 86%. In addition it is possible to distinguish mild from severe gait impairment (for therapy monitoring) with 100% sensitivity and 100% specificity. This system may be able to objectively classify PD gait patterns providing important and complementary information for patients, caregivers and therapists. PMID- 22254449 TI - Fusion of risk assessment models with application to coronary artery disease patients. AB - Several risk score models are available in literature to predict death/myocardial infarction event for coronary artery disease (CAD) patients, within a short period of time. However, the choice of the most adequate model is not straightforward since there might not be a consensus about the best model to use in clinical practice Moreover, individually, these models present some weaknesses, such as the inability to deal with missing information. This work addresses these problems, proposing a Bayesian classifier strategy enabling the simultaneous use of several models (models' fusion). Thus, a higher number of risk factors can be used in the common model, while it can deal with missing information. The validation of the strategy is carried out through the combination of three current risk score models (GRACE, TIMI, PURSUIT). Results were obtained based on a dataset that comprises 460 consecutive patients admitted to the Cardiology Department of Santa Cruz Hospital, Lisbon, from 1999 to 2001. A comparison with the voting scheme, which considers exclusively the outputs of models to combine (models output combination) is also carried out. The proposed Bayesian approach had very satisfactory results, confirming the potential of its application to the clinical practice. PMID- 22254450 TI - Cardiac status assessment with a multi-signal device for improved home-based congestive heart failure management. AB - State-of-the-Art disease management for Congestive Heart Failure (CHF) patients is still based on easy-to-acquire measures such as heart rate (HR), weight and blood pressure (BP). However, these measures respond late to changes of the patient health status and provide limited information to personalize and adapt medication therapy. This paper describes our concept called "Cardiac Status Assessment" we have been investigating within the European project "HeartCycle" towards next-generation home-based disease management of CHF. In our concept we analyze non-invasive surrogate measures of the cardio-vascular function in particular systolic time intervals and pulse wave characteristics to estimate Cardiac Output (CO) and Systemic Vascular Resistance (SVR) both are established clinical measures. We discuss the underlying concept, a developed measurement system and first results. PMID- 22254451 TI - Personalized behavior change support for disease prevention. AB - Healthy lifestyle is essential in prevention of chronic diseases. However, people need motivation and support to achieve and to maintain behavior changes. Moreover, effective behavior change support should be personalized to individual's unique characteristics, needs and context. This paper presents a blueprint of an ICT system, which is able to provide holistic, dynamic support for healthy behaviors, engaging also various co-producers in the health journey of a person. Three main concepts in the system are Virtual Individual, which maintains the user's personal profile, PGS-Mall, which collects various health and well-being services into one place, and HealthGuides, which support healthy choices in everyday life and coordinate the interactions between the user, the system, and other co-producers of health. PMID- 22254452 TI - Risk assessment and patient stratification using implantable medical devices. The funding for personal health programs. AB - Chronic diseases are currently recognized as one of the leading causes of mortality and morbidity worldwide. On top of this, these diseases represent a major burden for the healthcare systems in terms of costs and resources, which is driving them to define and adopt novel programs for prevention and chronic disease management. Still, many aspects of the processes of care and follow up of these patients remain unsolved and there is yet uncertainty on how technology can provide an added value to the current processes of care. This paper addresses the importance of the adoption of strategies for the anticipation to acute events within the disease management programs and suggests a holistic approach to embrace the healthcare organizations in the design development and implementation of the new personal health systems. PMID- 22254453 TI - Novel approaches for medication compliance and effectiveness analysis and support in cardiovascular disease patients. AB - HeartCycle is an integrated project aiming to provide a disease management solution for cardiovascular disease patients, by developing technologies, algorithms to interpret data and services to facilitate the remote management of patients at home. In this paper an overview of part of the algorithmic work package, oriented at motivating the patients to be compliant to treatment regimes and to adopt a beneficial lifestyle, will be given. A concept allowing further education of the patient on the effect of medication on their vital signs, as well as the prediction of medication effect and a possible way to check compliance using vital signs measurements will be presented. PMID- 22254454 TI - Towards closed-loop personal health systems in cardiology: the HeartCycle approach. AB - HeartCycle is a large-scale EU integrated project aiming to provide a complete disease management solution for cardiovascular disease patients, with emphasis on Heart Failure (HF) and Coronary Artery Disease (CAD) patients. The project develops innovative technologies and services to facilitate remote management of patients at home and motivate them to be compliant to treatment regimes and to adopt a beneficial lifestyle. HeartCycle aims to develop a personalised care system, integrating care at home with professional care in the hospital embedding health delivery feedback loops both at the professional and patient levels. In this paper, we present the three major systems that HeartCycle consists of, namely, the Heart Failure Management system, the Guided Exercise system, and the Assessment system. For each of these systems we summarise the current research and development efforts conducted, as well as the challenges faced towards their embodiment in actual healthcare delivery. PMID- 22254455 TI - Validation of a preterm infant cardiovascular system model under baroreflex control with heart rate and blood pressure data. AB - In this paper we present an autonomic cardiovascular model of a preterm infant of 28 weeks of gestation with a birth weight of 1000 g and a closed ductus arteriosus by the end of the first week, that is capable of describing the complex interactions between heart rate, blood pressure and respiration. The hemodynamic model consists of a pulsatile heart and several vascular compartments, and is regulated by a baroreflex control system. The model is relatively simple to allow for a mathematical analysis of the dynamics but sufficiently complex to provide a realistic representation of the underlying physiology. The model provides (beat-to-beat) values of R-R interval and blood pressure that resemble realistic signals of preterm infants. The model is validated with experimental data obtained in preterm infants. PMID- 22254456 TI - A simulation framework for estimating wall stress distribution of abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) rupture is believed to occur when the mechanical stress acting on the wall exceeds the strength of the wall tissue. In endovascular aneurysm repair, a stent-graft in a catheter is released at the aneurysm site to form a new blood vessel and protect the weakened AAA wall from the pulsatile pressure and, hence, possible rupture. In this paper, we propose a framework to estimate the wall stress distribution of non-stented/stented AAA based on fluid-structure interaction, which is utilized in a surgical simulation system (IRAS). The 3D geometric model of AAA is reconstructed from computed tomography angiographic (CTA) images. Based on our experiments, a combined logarithm and polynomial strain energy equation is applied to model the elastic properties of arterial wall. The blood flow is modeled as laminar, incompressible, and non-Newtonian flow by applying Navier-Stokes equation. The obtained pressure of blood flow is applied as load on the AAA meshes with and without stent-graft and the wall stress distribution is calculated by fluid structure interaction (FSI) solver equipped in ANSYS. Experiments demonstrate that our analytical results are consistent with clinical observations. PMID- 22254457 TI - Balloon type elasticity sensing for left ventricle of small laboratory animal. AB - This paper describes an elasticity sensing system for left ventricle of small laboratory animal. We first show the basic concept of the proposed method, where a ring shaped specimen is dilated by a balloon type probe using a pressure based control, and the elasticity of the specimen is estimated by using the stress and strain information. We introduce a dual cylinder model for approximating the strengths of the specimen's material and the balloon. Based on this model, we can derive Young's modulus of the specimen. After explaining the developed experimental system, we show a couple of experimental results using rats and mice, where HFPEF (Heart Failure Preserved Ejection Fraction) group can be distinguished from a normal group. PMID- 22254458 TI - Continuum model of light response in the retina. AB - A continuum model is presented of the retinal ON cone pathway to simulate the effects of light stimulation, motivated to provide validation of retinal response to electrical stimulation from vision implants. The model embodies four cell types involved in the direct pathway of light from cones to retinal ganglion cells. Center and surround mechanisms were incorporated through lateral inhibition via horizontal cells and convergence of inputs at the level of bipolar cells. Simulations were performed to investigate the network response to large and small spots of light. The results indicate the presence of surround suppression is correlated to spot size, consistent with experimental findings. PMID- 22254459 TI - Parameter exploration of staircase-shape extracellular stimulation for targeted stimulation of myelinated axon. AB - Spatio-temporal dynamics of a mathematical model of myelinated axon in response to staircase-shape extracellular electrical stimulation, which was developed for selective nerve stimulation, is investigated by the computer simulation. It is shown that the response is classified into four types: subthreshold response, cathodic excitation, anodal block and anodal break excitation. Based on the simulation results, simple diagrams representing the response characteristics of the axon are constructed as functions of stimulation parameters and distance between the axon and electrode. The diagram would be useful for determining simulation parameters for dynamic targeted stimulation of myelinated axon. PMID- 22254460 TI - Evaluation of a resectable ultrasound liver phantom for testing of surgical navigation systems. AB - A formerly developed ultrasound liver phantom for testing of surgical navigation systems and liver resection trainings was evaluated experimentally. The phantom was scanned with CT and the dataset was analyzed with existing segmentation techniques. A virtual 3D model was generated on the basis of the segmentation; it was later used for phantom registration in a surgical assistance navigation system. Within an experiment, ten test persons have tried to touch three tumor models hidden in the phantom with the tip of a resection instrument. In 67% of overall 30 touch trials it was a successful touch at the first go. It means that the developed liver phantom is appropriate for testing of surgical navigation systems, as well as for computer assisted liver resection trainings. PMID- 22254461 TI - Preliminary design of a SIMO fuzzy controller for steering microparticles inside blood vessels by using a magnetic resonance imaging system. AB - In this paper, a Single-Input-Multiple-Output (SIMO) fuzzy controller is designed to drive an upgraded clinical real-time Magnetic Resonance Imaging (MRI) system to provide steering forces for an aggregation of ferromagnetic microparticles in the human cardiovascular system according to a pre-set pathway. This kind of endovascular navigation is considered as an important procedure of the catheter based method for medical treatments against diseases such as some particular types of cancers. The validity of the fuzzy controller has been tested by preliminary simulation results. PMID- 22254462 TI - Design of multiple sequence alignment algorithms on parallel, distributed memory supercomputers. AB - The challenge of comparing two or more genomes that have undergone recombination and substantial amounts of segmental loss and gain has recently been addressed for small numbers of genomes. However, datasets of hundreds of genomes are now common and their sizes will only increase in the future. Multiple sequence alignment of hundreds of genomes remains an intractable problem due to quadratic increases in compute time and memory footprint. To date, most alignment algorithms are designed for commodity clusters without parallelism. Hence, we propose the design of a multiple sequence alignment algorithm on massively parallel, distributed memory supercomputers to enable research into comparative genomics on large data sets. Following the methodology of the sequential progressiveMauve algorithm, we design data structures including sequences and sorted k-mer lists on the IBM Blue Gene/P supercomputer (BG/P). Preliminary results show that we can reduce the memory footprint so that we can potentially align over 250 bacterial genomes on a single BG/P compute node. We verify our results on a dataset of E.coli, Shigella and S.pneumoniae genomes. Our implementation returns results matching those of the original algorithm but in 1/2 the time and with 1/4 the memory footprint for scaffold building. In this study, we have laid the basis for multiple sequence alignment of large-scale datasets on a massively parallel, distributed memory supercomputer, thus enabling comparison of hundreds instead of a few genome sequences within reasonable time. PMID- 22254463 TI - ABS: Sequence alignment by scanning. AB - Sequence alignment is an essential tool in almost any computational biology research. It processes large database sequences and considered to be high consumers of computation time. Heuristic algorithms are used to get approximate but fast results. We introduce fast alignment algorithm, called 'Alignment By Scanning' (ABS), to provide an approximate alignment of two DNA sequences. We compare our algorithm with the well-known alignment algorithms, the 'FASTA' (which is heuristic) and the 'Needleman-Wunsch' (which is optimal). The proposed algorithm achieves up to 76% enhancement in alignment score when it is compared with the FASTA Algorithm. The evaluations are conducted using different lengths of DNA sequences. PMID- 22254464 TI - Analyzing mRNA and microRNA co-expression profiles to identify pathways and their potential regulators in ER+ and ER- breast tumors. AB - Transcription factors and microRNAs are both considered pivotal regulators of gene expression. Numerous computational methods have been developed to predict their targets. These methods, although powerful, provide a static snapshot of how genes may be regulated by transcription factors and microRNAs. We propose a method that combines these prediction data with co-expression analysis and a supervised learning algorithm to determine the main regulators in different pathways of ER+ and ER- tumors. PMID- 22254465 TI - Gene expression analysis with integrated fuzzy C-means and pathway analysis. AB - A workflow for associating fuzzy clusters to biological pathways has been implemented as a Java-based software tool. Its software implementation is comprised of a correlation-based fuzzy c-means algorithm and an enrichment test on Kyoto Encyclopedia of Genes and Genomes' pathways. We applied this workflow to gene expression in classification of lung cancer cell types and achieved satisfactory results. The software could aid in the validation of results of fuzzy clustering algorithms and the exploration of un-annotated associations between genes and gene ontology categories. PMID- 22254466 TI - A general CellML simulation code generator using ODE solving scheme description. AB - To cope with the complexity of the biological function simulation models, model representation with description language is becoming popular. However, simulation software itself becomes complex in these environment, thus, it is difficult to modify target computation resources or numerical calculation methods or simulation conditions. Typical biological function simulation software consists of 1) model equation, 2) boundary conditions and 3) ODE solving scheme. Introducing the description model file such as CellML is useful for generalizing the first point and partly second point, however, third point is difficult to handle. We introduce a simulation software generation system which use markup language based description of ODE solving scheme together with cell model description file. By using this software, we can easily generate biological simulation program code with different ODE solving schemes. To show the efficiency of our system, experimental results of several simulation models with different ODE scheme and different computation resources are shown. PMID- 22254467 TI - Prediction of protein subcellular localization based on variable-length motifs detection and dissimilarity based classification. AB - Predict the function of unknown proteins is one of the principal goals in computational biology. The subcellular localization of a protein allows further understanding its structure and molecular function. Numerous prediction techniques have been developed, usually focusing on global information of the protein. But, predictions can be done through the identification of functional sub-sequence patterns known as motifs. For motifs discovery problem, many methods requires a predefined fixed window size in advance and aligned sequences. To confront these problems we proposed a method based on variable length motifs characterization and detection using the continuous wavelet transform (CWT) and a dissimilarity space representation. For analyzing the motifs results generated by our approach, we divide the entire dataset into training (60%) and validation (40%). A Support Vector Machine (SVM) classifier is used as predictor for validation set. The highest Sn = 82.58% and Sp = 92.86%, across 10-fold cross validation, is obtained for endosome proteins. Average results Sn = 74% and Sp = 75.58% are comparable to current state of the art. For data sets whose identity is low (< 40%), the motifs characterization and localization based on CWT shows a good performance and the interpretability of the subsequences in each subcellular localization. PMID- 22254468 TI - Evaluating feature selection strategies for high dimensional, small sample size datasets. AB - In this work, we analyze and evaluate different strategies for comparing Feature Selection (FS) schemes on High Dimensional (HD) biomedical datasets (e.g. gene and protein expression studies) with a small sample size (SSS). Additionally, we define a new feature, Robustness, specifically for comparing the ability of an FS scheme to be invariant to changes in its training data. While classifier accuracy has been the de facto method for evaluating FS schemes, on account of the curse of dimensionality problem, it might not always be the appropriate measure for HD/SSS datasets. SSS lends the dataset a higher probability of containing data that is not representative of the true distribution of the whole population. However, an ideal FS scheme must be robust enough to produce the same results each time there are changes to the training data. In this study, we employed the robustness performance measure in conjunction with classifier accuracy (measured via the K-Nearest Neighbor and Random Forest classifiers) to quantitatively compare five different FS schemes (T-test, F-test, Kolmogorov-Smirnov Test, Wilks Lambda Test and Wilcoxon Rand Sum Test) on 5 HD/SSS gene and protein expression datasets corresponding to ovarian cancer, lung cancer, bone lesions, celiac disease, and coronary heart disease. Of the five FS schemes compared, the Wilcoxon Rand Sum Test was found to outperform other FS schemes in terms of classification accuracy and robustness. Our results suggest that both classifier accuracy and robustness should be considered when deciding on the appropriate FS scheme for HD/SSS datasets. PMID- 22254469 TI - Beat to beat wavelet variability in atrial fibrillation. AB - Atrial fibrillation (AF) is a complex phenomenon, related with a multitude of factors, including the electrical properties of the atrial substrate. The purpose of this work is to present a method that highlights electrocardiographic differences between normal subjects and patients with paroxysmal AF episodes (PAF), potentially related with substrate differences. Vectorcardiography recordings are considered and, for each lead (X-Y-Z), on a beat by beat basis, a steady window before QRS, corresponding to the atrial activity, is analysed via continuous wavelet transform. Wavelet-based parameters are calculated and compared between the normal and AF group, with the beat to beat variation of wavelet energy as the most important feature showing a significantly higher variability in the AF group. PMID- 22254470 TI - A spline framework for ECG analysis. AB - In this effort we introduce a spline framework for ECG waveform analysis, with initial application to the ECG delineation (segmentation) problem. The framework comprises knot initialization, spline interpolant, error metric, and knot location optimization to parametrically represent the waveform for analysis, classification, or compression. Choice of these constituents is driven by the application of the framework. For our initial application of ECG delineation, we use the framework to identify characteristic points corresponding to waveform onset and offset times, peak values, and junction points. These are represented mathematically as critical points and points of inflection, which serve as knot locations for linear or cubic Hermite interpolants in the framework. Preliminary tests on a limited but diverse set of morphologies from the European ST-T database indicate that the framework obtains knot locations corresponding to characteristic points, and the resultant interpolated waveform represents the original signal well with low mean squared error. PMID- 22254471 TI - Excitation specificity of repolarization parameters. AB - The excitation specificity of QT dynamic parameters was tested on three groups of subjects: healthy subjects; non-medicated hypertensive subjects with metabolic syndrome; and subjects with essential hypertension. Four different excitations of RR were used: bicycling exercise; tilt with breathing 0.1 and 0.33 Hz; and deep breathing. Linear dynamic feedback model of QT/RR coupling was supposed at the analysis and next repolarization parameters were tested: QTc; gain of QT/RR coupling for slow and fast RR variability; time constant of QT adaptation; and random QT variability. RESULTS: Dynamic repolarization parameters statistically significantly depend on the type of RR excitation. The gain of QT/RR coupling for slow RR variability, the time constant of QT adaptation and QTc are maximal at RR excitation given by the bicycling exercise. The frequency of breathing, i.e. corresponding vagal modulation has no effect on repolarization parameters. The measurements with deep breathing, without any other slow excitation of heart rate, has low signal-to-noise ratio of analyzed data and resulting QT parameters are inaccurate. CONCLUSION: The use of heart rate excitation and all measurements conditions should be defined for the exact analysis of the repolarization dynamic parameters. PMID- 22254472 TI - Algorithm for quantitative 3 dimensional analysis of ECG signals improves myocardial diagnosis over cardiologists in diabetic patients. AB - Acute myocardial infarction (AMI) diagnosis in type II diabetes (DM2) patients is difficult and ECG findings are often non-diagnostic or inconclusive. We developed computer algorithms to process standard 12-lead ECG input data for quantitative 3 dimensional (3D) analysis (my3KGTM), and hypothesized that use of the my3KGTM's array of over 100 3D-based AMI diagnostic markers may improve diagnostic accuracy for AMI in DM2 patients. METHODS: We identified 155 consecutive DM2 patients age >25 yrs with chest discomfort or shortness of breath who were evaluated at an urban emergency department (130 patients (pts)) or the cardiac catheterization laboratory (25 pts) for possible AMI. The first digital 12-lead ECG for each patient, obtained within 30 min of presentation, was evaluated by (1) 2 blinded expert cardiologists, and (2) my3KGTM. In each case, the ECG was classified as either likely AMI or likely non-AMI. "Gold standard" was the final clinical diagnosis. Statistical analysis was McNemar's test with continuity correction. RESULTS: The 155 DM2 patients were 50% male, mean age 56.8 +/- 12.0 yrs; 44 pts had a final clinical diagnosis of AMI (17 ST Elevation Myocardial Infarctions (STEMI), 27 Non-ST Elevation Myocardial Infarctions (NSTEMI)) and 111 had no AMI. CONCLUSIONS: Relative to standard 12L ECG read by cardiologists, quantitative 3D ECG analysis showed significant and substantial gains in sensitivity for AMI diagnosis in DM2 patients, without loss in specificity. Sensitivity gains were particularly high in patients exhibiting NSTEMI, the most common form of AMI in DM2. PMID- 22254473 TI - Wavelet-based features for characterizing ventricular arrhythmias in optimizing treatment options. AB - Ventricular arrhythmias arise from abnormal electrical activity of the lower chambers (ventricles) of the heart. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the two major subclasses of ventricular arrhythmias. While VT has treatment options that can be performed in catheterization labs, VF is a lethal cardiac arrhythmia, often when detected the patient receives an implantable defibrillator which restores the normal heart rhythm by the application of electric shocks whenever VF is detected. The classification of these two subclasses are important in making a decision on the therapy performed. As in the case of all real world process the boundary between VT and VF is ill defined which might lead to many of the patients experiencing arrhythmias in the overlap zone (that might be predominately VT) to receive shocks by the an implantable defibrillator. There may also be a small population of patients who could be treated with anti-arrhythmic drugs or catheterization procedure if they can be diagnosed to suffer from predominately VT after objectively analyzing their intracardiac electrogram data obtained from implantable defibrillator. The proposed work attempts to arrive at a quantifiable way to scale the ventricular arrhythmias into VT, VF, and the overlap zone arrhythmias as VT-VF candidates using features extracted from the wavelet analysis of surface electrograms. This might eventually lead to an objective way of analyzing arrhythmias in the overlap zone and computing their degree of affinity towards VT or VF. A database of 24 human ventricular arrhythmia tracings obtained from the MIT-BIH arrhythmia database was analyzed and wavelet-based features that demonstrated discrimination between the VT, VF, and VT-VF groups were extracted. An overall accuracy of 75% in classifying the ventricular arrhythmias into 3 groups was achieved. PMID- 22254474 TI - A vectorcardiogram-based classification system for the detection of Myocardial infarction. AB - Myocardial infarction (MI), generally known as a heart attack, is one of the top leading causes of mortality in the world. In clinical diagnosis, cardiologists generally utilize 12-lead ECG system to classify patients into MI symptoms: 1. ST segment elevation, 2. ST segment depression or T wave inversion. However unstable ischemic syndromes have rapidly changing supply versus demand characteristics that is one of the several limitations of 12-lead ECG system for MI detection. In addition, the ECG sensor placements of 12-lead system is not easily donned and doffed for tele-healthcare monitoring at home. Vectorcardiogram (VCG) system in clinic is another type of diagnosis plot which represents the magnitude and direction of the electrical potential in the form of a vector loop during cardiac electric activity. The VCG system can easily acquire three ECG waves from X, Y, Z directions to composite vector signal in space and the VCG signals can be transferred to 12-lead ECG signal through Dower transformation and vice versa. Hence, this study attempts to develop a VCG-based classification system for the detection of Myocardial infarction. In the experiment results, the proposed system can select the proper ECG features based on cardiologist's knowledge and proposed principal moments of QRS complex. The classification performance of MI detection can be reached to 99.89% of sensitivity, 92.51% of specificity, 95.35% of positive predictive value, and 96.96% overall accuracy with maximum-likelihood classifier (MLC). PMID- 22254475 TI - Baseline wander estimation and removal by quadratic variation reduction. AB - The baseline wander is a low frequency additive noise partially overlapping the band of ECG signal. This makes its removal difficult without affecting the ECG. In this work we propose a novel approach to baseline wander estimation and removal based on the notion of quadratic variation. The quadratic variation is a suitable index of variability for vectors and sampled functions. We derive an algorithm for baseline estimation solving a constrained convex optimization problem. The computational complexity of the algorithm is linear in the size of the ECG record to detrend, making it suitable for realtime applications. Simulation results confirm the effectiveness of the approach and highlight its ability to remove baseline wander. Eventually, the proposed algorithm is not limited to ECG signals, but can be effectively applied whenever baseline estimation and removal are needed, such as EEG records. PMID- 22254476 TI - Denoising and harmonic artifacts rejection for ECG P-waves by quadratic variation reduction. AB - Atrial fibrillation (AF) is a common cardiac arrhythmia related to irregular atrial contractions. Several studies have shown that the analysis of P-waves extracted from ECG signals is helpful in understanding the predisposing factors to AF. However, P-waves are usually highly corrupted by noise and harmonic artifacts and this makes quite difficult their analysis. Recently we proposed a novel algorithm for denoising P-waves based on the notion of quadratic variation reduction. It is quite good in denoising P-waves affected by noise, but its effectiveness reduces when it is used in filtering out harmonic artifacts, like power-line interference. In this paper we propose an algorithm that overcomes this limitation and extends our previous method allowing it to both denoise and reject harmonic artifacts. Simulation results confirm the effectiveness of the approach and highlight its ability to remove both noise and artifacts. The algorithm has reduced computational complexity and this makes it suitable for real-time applications. PMID- 22254477 TI - Use of genetic algorithm for selection of regularization parameters in multiple constraint inverse ECG problem. AB - Tikhonov regularization is one of the most widely used regularization approaches in literature to overcome the ill-posedness of the inverse electrocardiography problem. However, the resulting solutions are biased towards the constraint used for regularization. One alternative to obtain improved results is to employ multiple constraints in the cost function. This approach has been shown to produce better results; however finding appropriate regularization parameters is a serious limitation of the method. In this study, we propose estimating multiple regularization parameters using a genetic algorithm based approach. Applicability of the approach is demonstrated here using two and three constraints. The results show that GA based multiple constraints approach improves the Tikhonov regularization solutions. PMID- 22254478 TI - Home-based mobile cardio-pulmonary rehabilitation consultant system. AB - Cardiovascular diseases are the most popular cause of death in the world recently. For postoperatives, cardiac rehabilitation is still asked to maintain at home (phase II) to improve cardiac function. However, only one third of outpatients do the exercise regularly, reflecting the difficulty for home-based healthcare: lacking of monitoring and motivation. Hence, a cardio-pulmonary rehabilitation system was proposed in this research to improve rehabilitation efficiency for better prognosis. The proposed system was built on mobile phone and receiving electrocardiograph (ECG) signal from a wireless ECG holter via Bluetooth connection. Apart from heart rate (HR) monitor, an ECG derived respiration (EDR) technique is also included to provide respiration rate (RR). Both HR and RR are the most important vital signs during exercise but only used one physiological signal recorder in this system. In clinical test, there were 15 subjects affording Bruce Task (treadmill) to simulate rehabilitation procedure. Correlation between this system and commercial product (Custo-Med) was up to 98% in HR and 81% in RR. Considering the prevention of sudden heart attack, an arrhythmia detection expert system and healthcare server at the backend were also integrated to this system for comprehensive cardio-pulmonary monitoring whenever and wherever doing the exercise. PMID- 22254479 TI - Predicting the optimal position and direction of a ubiquitous ECG using a multi scale model of cardiac electrophysiology. AB - In this study, we determined the optimal position and direction of a one-channel bipolar electrocardiogram (ECG), used ubiquitously in healthcare. To do this, we developed a three-dimensional (3D) electrophysiological model of the heart coupled with a torso model that can generate a virtual body surface potential map (BSPM). Finite element models of the atria and ventricles incorporated the electrophysiological dynamics of atrial and ventricular myocytes, respectively. The torso model, in which the electric wave pattern on the cardiac tissue is reflected onto the body surface, was implemented using a boundary element method. Using the model, we derived the optimal positions of two electrodes, 5 cm apart, of the bipolar ubiquitous ECG (U-ECG) for detecting the P, R, and T waves. This model can be used as a simulation tool to design U-ECG device for use for various arrhythmia and normal patients. PMID- 22254480 TI - Numerical simulation of motion-induced dynamic noise in a ubiquitous ECG application. AB - Wearable ubiquitous biomedical applications, such as ECG monitors, can generate dynamic noise as a person moves. However, the source of this noise is not clear. We postulated that the dynamic ECG noise has two causes: the change in displacement of the heart during motion and the change in the electrical impedance of the skin-gel interface due to motion-induced deformation of the skin gel interface. Using a three-dimensional electrophysiological heart model coupled with a torso model, dynamic noise was simulated, while the displacement of the heart was changed in the vertical and horizontal directions, independently and while the skin-gel interface was deformed during motion. To determine the deformation rate of the skin and sol-gel layers, motion-induced deformation of the two layers was simulated using a three-dimensional finite element method. PMID- 22254481 TI - Breath gas analysis for estimating physiological processes using anesthetic monitoring as a prototypic example. AB - Analysis of exhaled trace gases is a novel methodology for gaining continuous and non-invasive information on the clinical state of an individual. This paper serves to explore some potential applications of breath gas analysis in anesthesia, describing a monitoring scheme for target site concentrations and cardiac output via physiological modeling and real-time breath profiles of the anesthetic agent. The rationale given here is mainly simulation-based, however, the underlying concepts are directly applicable to a routine clinical setting. PMID- 22254482 TI - Robust online adaptive neural network control for the regulation of treadmill exercises. AB - The paper proposes a robust online adaptive neural network control scheme for an automated treadmill system. The proposed control scheme is based on Feedback Error Learning Approach (FELA), by using which the plant Jacobian calculation problem is avoided. Modification of the learning algorithm is proposed to solve the overtraining issue, guaranteeing to system stability and system convergence. As an adaptive neural network controller can adapt itself to deal with system uncertainties and external disturbances, this scheme is very suitable for treadmill exercise regulation when the model of the exerciser is unknown or inaccurate. In this study, exercise intensity (measured by heart rate) is regulated by simultaneously manipulating both treadmill speed and gradient in order to achieve fast tracking for which a single input multi output (SIMO) adaptive neural network controller has been designed. Real-time experiment result confirms that robust performance for nonlinear multivariable system under model uncertainties and unknown external disturbances can indeed be achieved. PMID- 22254483 TI - A convenient pulmonary volume and flow detection system. AB - The pulmonary function test (PFT) is a widely used test in patients or for those who are at risk of respiratory dysfunction. In this study, we aimed to develop a more convenient system, namely, the impedance pulmonary function measurement system (IPFS), for overcoming the restrictions posed by the prevalent spirometric PFT. IPFS employs tetra polar electrodes that can measure pulmonary function using the subjects' hands alone. The impedance measured by IPFS extracts AC values of pulmonary impedance from DC values of body impedance in respiration. This system yields changes in the impedance of volume and flow. In order to verify IPFS, we compared the continuous waveforms obtained from the PFT module and developed IPFS using Pearson linear correlation coefficients (p < 0.01) for volume and flow. Further, we evaluated the potential application of IPFS for detecting pulmonary functions such as volume (FEV(1)/FVC Ratio) and flow (PEF), and compared the measured parameters between IPFS and spirometric PFT. Our results demonstrate that the measurements obtained using IPFS reflect pulmonary function parameters. PMID- 22254484 TI - Inverse modeling supports quantification of pressure and time depending effects in ARDS patients. AB - The application of respiratory mechanics models combined with standardized ventilation maneuvers enable investigations of patients' lung mechanics at the bedside in order to optimize ventilation therapy. Therefore, the underlying dynamic effects of respiratory mechanics (viscoelasticity, inhomogeneity and recruitment) are uncovered by applying various ventilation maneuvers and subsequently captured by the corresponding model via parameter identification methods. Data sets of patients undergoing quasi-static and dynamic ventilation patterns are available along with a hierarchical model structure for parameter identification and simulation purposes. The applicability of the basic 1(st) order model (FOM) of respiratory mechanics for various flow rates proved to be critical and patient dependent, since distinctive time-depending effects could not be considered. To improve this, a 2(nd) order model (SOM), individualized using data of a SCASS maneuver (Static Compliance Automated Single Step), enables successful simulations of respiratory mechanics in dynamic and quasi-static conditions. Pressure dependent effects such as static recruitment, can be captured by Hickling's nonlinear compliance model. This research illustrates the applicability of various models of respiratory mechanics within the model hierarchy in various circumstances and the ability to distinguish between dynamic and static effects. PMID- 22254485 TI - Effectiveness of interval training compared with endurance training in cardiac rehabilitation. AB - Anaerobic endurance training (AET) can improve sympathomimetic hyperactivity, and anaerobic interval training (AIT) is recommended for patients who cannot exercise due to exertional breathlessness and leg fatigue. However, the difference in sympathetic nerve activation (SNA) and parasympathetic nerve activation (PNA) during AIT and AET is unclear. The aim of this study is to investigate the differences between endurance and interval trainings. We studied three patients (63-73 years) assigned to AIT which exercise/pause phase is 60/120 seconds (AIT120) and AET of 10 minutes duration. Systolic blood pressure, heart rate (HR), and rate pressure product (as an index of SNA) and oxygen uptake, tidal volume, respiratory rate, and minute ventilation were measured. As a result, these parameters in AET were increased compared with those of AIT120 among the subjects. While, high frequency component of frequency distribution in HR (HF) in AET was decrease compared with that in AIT120 among subject. We concluded that AIT inhibited SNA more effectively compared with AET and AIT may be safe for cardiac rehabilitation. PMID- 22254486 TI - Effect of deep breathing on extracted oxygen and cerebral hemoglobin levels. AB - This study examines the relationship between oxygen expired and functional near infrared spectroscopy (fNIRS) measured hemoglobin levels in the brain. Analysis of these two signals during normal versus deep breathing provides insight into the dynamics of cerebral physiology. Intersubject variation suggests the existence of two distinct groups with respect to oxygen extraction and hemoglobin levels. PMID- 22254487 TI - Effect of inflow on computational fluid dynamic simulation of cerebral bifurcation aneurysms. AB - Morphological characteristics associated with cerebral aneurysm formation can be used to assess aneurysm rupture. This study investigated hemodynamic effects resulting from change in the parent artery diameter of bifurcation type aneurysm. Computational fluid dynamic (CFD) analysis was performed on middle cerebral artery (MCA) models with various parent artery diameters. Calculations were performed with steady flow rate (125 +/- 12.5 ml/min) at the parent artery inlet. Energy loss (EL) was calculated from pressure and kinetic energy obtained from flow velocity. The results indicate that the high wall shear stress (WSS) and EL occurs in model with the smallest parent vessel compared to the other models for all three inflows. Results also showed that 10% variation of inflow results in average of 23 +/- 2.9% changes in WSS and 25.5 +/- 0.5% changes in energy loss. These results demonstrated that for CFD analysis of MCA bifurcation type aneurysm, upstream parent vessel and inflow evaluation for individual patient is essential. PMID- 22254488 TI - Modeling the adaptive pathophysiology of essential hypertension. AB - This paper proposes an adaptive neuro-fuzzy model to study the pathophysiology of essential hypertension. Using diverse inputs such as risk factors, physical relations and medical interventions, and states that include both transient and resting states for key physiological variables (blood pressure, total peripheral resistance), it can roughly predict both real-time and long-term blood pressure change for a robust range of inputs. Although it was tuned using published population data, it can be applied to specific individuals to estimate the risks of hypertension with different life experience. PMID- 22254489 TI - Automation of an extracorporeal support system with adaptive fuzzy controllers. AB - For patients suffering from cardiogenic shock cardiopulmonary resuscitation may not be sufficient to restore normal heart function. However, their chances of survival may be increased with the use of an extracorporeal support system. With this system the patient's organs are perfused while being transported to the nearest hospital for proper treatment. In the automation of an extracorporeal support system the patient's vital signals are constantly monitored and proper adjustments are performed to improve organ perfusion. In this paper, an adaptive fuzzy controller is proposed that uses the knowledge and expertise of a perfusionist as a starting point and reference for regulation. Furthermore it is able to adapt to the patient's specific reactions by manipulating the rule base of the fuzzy controller. The performance of the adaptive fuzzy controller is tested with a simulation model of the cardiovascular system. PMID- 22254490 TI - Modeling of aquaporin 1-mediated transmural water transport and the resulting oncotic paradox. AB - The earliest observable prelesion event in atherosclerosis, macromolecular transport across the vessel wall, occurs via advection by transmural pressure driven water transport, characterized by the hydraulic conductivity (Lp), defined as the ratio of water flux to the transmural pressure difference. The discovery of the presence of aquaporin-1 (AQP) in aortic endothelial cells suggests a new possibility of water transport across the endothelial cell (EC), alongside the generally accepted paracellular route. In this study, we propose a new filtration theory to explain the experimentally observed pressure-dependent effect of AQP blocking on the Lp of rat aorta. However, given the isotonic lumen, this AQP mediated pure water inflow into the arterial subendothelial intima (SI) should set up an oncotic pressure gradient that opposes the AP-driven flow through the cell. How then could trans-AQP flow persist for many hours, as indicated by chemical blocking of AQP experiments? To resolve this paradox, we have extended our filtration theory to also include the mass transfer of oncatically active small solutes like albumin. This addition non-linearly couples the mass transfer, the fluid flow and the wall mechanics. We employ finite difference methods to simultaneously solve the filtration and mass-transfer problem as a long-time solution of an unsteady problem. Our results agree well with the experimental data and suggest that AQPs contribute about 30% to the phenomenological endothelial Lp. We have also found that, due to media filtration, at steady state, the albumin concentration in the SI is in fact higher than in the glycocalyx. This results in higher osmotic pressure in the SI, which drives the fluid flow into the SI from the luminal side of the EC and not the other way around. Controlling endothelial Lp, via AQP expression, might serve as a future therapeutic target to inhibit pre-atherosclerotic events. PMID- 22254491 TI - A multiple-input multiple-output system for modeling the cardiac dynamics. AB - We describe the dynamics of the cardiovascular system by finding the input-output relationships in the state space of a functional cardiac model, based on state equations and observability criteria of control theory. The unit step response of the multiple-input multiple-output system model illustrates the damping effect of the arterial wall to the pulsatility of the heart. Our results show that hypertensive patients exhibit a lower inertia of the blood flow. PMID- 22254492 TI - A PDA platform for offline processing and streaming of stimuli for cochlear implant research. AB - A PDA-based research platform has been developed for implementing novel speech processing strategies and conducting psychophysical experiments with cochlear implant (CI) research that do not necessarily require real-time processing. The developed interface streams stimuli pulses to a CI unit in an offline mode from a Personal Computer via PDA platform using Windows Sockets (WINSOCK). Front-end of the application is run in MATLAB where stimuli pulses are created. Winsock establishes a TCP/IP connection with the PDA and starts the transmission of stimuli data. Server application installed on the PDA reads the stimulation data and forwards it to the SDIO board in packets where it is forwarded to the cochlear implant unit and pulses are then played in realtime. Versatility and flexibility are the key characteristics of the platform for easy implementation and testing of a wide range of applications and experiments without advanced programming skills. PMID- 22254493 TI - Current steering and current focusing with a high-density intracochlear electrode array. AB - Creating high-resolution or high-density, intra-cochlear electrode arrays may significantly improve quality of hearing for cochlear implant recipients. Through focused activation of neural populations such arrays may better exploit the cochlea's frequency-to-place mapping, thereby improving sound perception. Contemporary electrode arrays approach high-density stimulation by employing multi-polar stimulation techniques such as current steering and current focusing. In our procedure we compared an advanced high-density array with contemporary arrays employing these strategies. We examined focused stimulation of auditory neurons using an activating function and a neural firing probability model that together enable a first-order estimation of an auditory nerve fiber's response to electrical stimulation. The results revealed that simple monopolar stimulation with a high-density array is more localized than current steering with a contemporary array and requires 25-30% less current. Current focusing with high density electrodes is more localized than current focusing with a contemporary array; however, a greater amount of current is required. This work illustrates that advanced high-density electrode arrays may provide a low-power, high resolution alternative to current steering with contemporary cochlear arrays. PMID- 22254494 TI - Responses of starburst amacrine cells to prosthetic stimulation of the retina. AB - Recent advances in the design and development of retinal implants have made these devices a promising therapeutic strategy for restoring sight to the blind. Over the last decade a plethora of studies have investigated the responses of the retinal ganglion cells (RGCs) to electrical stimulation under a variety of stimulus configurations. Similar to the RGCs, the amacrine cells also survive in large numbers following retinal neural degeneration. However, with the exception of two previous reports, where the responses of the amacrine cells were measured indirectly, these cells have thus far received little attention in the context of prosthetic stimulation. In this study we focused on the starburst amacrine cells (SACs), a particularly well-characterized amacrine cell among the approximately two-dozen types known to exist in the retina. Using whole-cell patch clamp recordings in the whole-mount rabbit retina, we investigated the temporal responses of the SACs following subretinal biphasic pulse stimulation. These cells responded to the stimuli with oscillatory membrane potentials that lasted for tens to hundreds of milliseconds, with the response amplitude increasing as a function of stimulus strength. Furthermore, the SAC responses originated primarily from the presynaptic inputs they receive, rather than through direct activation of these cells by the electrical stimuli. PMID- 22254495 TI - Selective co-stimulation of pudendal afferents enhances reflex bladder activation. AB - The loss of normal bladder function is common in persons with spinal cord injury (SCI) and negatively impacts their quality of life. Electrical stimulation of pudendal nerve afferents is a promising approach to restore control of bladder function. Pudendal afferent stimulation can generate reflex contraction of the bladder, but the resulting bladder voiding efficiency remains low. The objective of this work was t o evaluate selective co-stimulation of two branches of the pudendal nerve--the cranial urethral sensory nerve (CSN) and the dorsal nerve of the penis (DNP)--as a means to enhance reflex bladder activation and bladder voiding efficiency. In preclinical studies in anesthetized adult cats, co stimulation of CSN and DNP evoked larger bladder contractions than individual stimulation of either CSN or DNP. In a parallel clinical experiment involving a participant with chronic SCI, co-stimulation of the proximal and distal urethra also produced synergistic augmentation of reflex bladder activity, and thus improved voiding efficiency when compared to reflex distension-evoked voiding. Selective co-stimulation of pudendal afferents is efficacious and should be considered in the development of neural prosthetics for restoration of bladder function in persons with SCI. PMID- 22254496 TI - Vibrotactile feedback aids EMG control of object manipulation. AB - We have previously shown that augmentative vibrotactile feedback can improve performance of a virtual object manipulation task using the finger. Here we studied the effects of vibrotactile feedback using instead electromyographic (EMG) control of object manipulation in N=6 healthy participants. Results showed that users were able to increase performance on an object manipulation task via EMG control when given augmentative vibrotactile feedback. Performance showed a strong effect of learning, which indicates further promise for utilization of this method in prosthetic hand users. PMID- 22254497 TI - Sensory cortical re-mapping following upper-limb amputation and subsequent targeted reinnervation: a case report. AB - This case study demonstrates the ability of sensory cortical representations to remap following arm amputation and subsequent targeted reinnervation (TR). Previous human studies have demonstrated functional plasticity in the primary sensory cortex months or years after amputation of the upper arm, forearm, the hand or a single finger, or after subsequent replantation. Targeted reinnervation, a surgical procedure that re-routes inactive, residual sensorimotor nerves previously responsible for innervating the missing limb to alternative muscle groups and skin areas [1-3], has shown the ability to restore a subject's sensation in the reinnervated skin areas. Whether this new technique causes analogous cortical remapping in a similar timeframe as following hand replantation is still unknown. In order to answer this question, high-density electroencephalography was used to study whether the original sensory cortical territory was regained after TR. Before TR, we found that the cortical response to sensory electrical stimulation in the residual limb showed a diffuse bilateral pattern without a clear focus in either the time or spatial domain, Two years after TR, the sensory map of the reinnervated median nerve shifted back to a close-to-normal, predominantly contralateral pattern. The overall trend of TR induced sensory remapping is similar to previous reports related to hand replantation but occurs over a slower timeframe. This relatively slower progress after TR as compared to after hand replantation could be because TR is performed months or even years after amputation, while hand replantation was performed immediately after the injury. This work provides new evidence for long term plasticity in the human brain. PMID- 22254498 TI - Optimizing microstimulation using a reinforcement learning framework. AB - The ability to provide sensory feedback is desired to enhance the functionality of neuroprosthetics. Somatosensory feedback provides closed-loop control to the motor system, which is lacking in feedforward neuroprosthetics. In the case of existing somatosensory function, a template of the natural response can be used as a template of desired response elicited by electrical microstimulation. In the case of no initial training data, microstimulation parameters that produce responses close to the template must be selected in an online manner. We propose using reinforcement learning as a framework to balance the exploration of the parameter space and the continued selection of promising parameters for further stimulation. This approach avoids an explicit model of the neural response from stimulation. We explore a preliminary architecture--treating the task as a k armed bandit--using offline data recorded for natural touch and thalamic microstimulation, and we examine the methods efficiency in exploring the parameter space while concentrating on promising parameter forms. The best matching stimulation parameters, from k = 68 different forms, are selected by the reinforcement learning algorithm consistently after 334 realizations. PMID- 22254499 TI - 3D hybrid electrode structure as implantable interface for a vestibular neural prosthesis in humans. AB - Implantable interfaces are essential components of vestibular neural prostheses. They interface the biological system with electrical stimulation that is used to restore transfer of vestibular information. Regarding the anatomical situation special 3D structures are required. In this paper, the design and the manufacturing process of a novel 3D hybrid microelectrode structure as interface to the human vestibular system are described. Photolithography techniques, assembling technology and rapid prototyping are used for manufacturing. PMID- 22254500 TI - High frequency electric stimulation of retinal neurons elicits physiological signaling patterns. AB - The effectiveness of retinal prosthetics will depend on their ability to elicit patterns of neural activity that can be recognized by the visual cortex. While conventional short-duration pulses activate retinal neurons effectively, many nearby neurons are thought to respond similarly to a given pulse train--a situation that is non-physiological. Use of pulse trains delivered at rates > 1000 pulses per second (PPS) in cochlear prosthetics help to avoid phase-locked responses but have not been evaluated in the retina; here, we explored the response to trains of 2000 PPS. We found that ganglion cells respond robustly to these stimuli but that the properties of the response were highly sensitive to stimulus amplitude. At low amplitudes the response patterns were burst-like while at higher amplitudes elicited spikes had intervals that were more uniform. Because burst responses were insensitive to synaptic blockers, our results suggest that they arise from direct activation. This was surprising because previous studies indicated that burst responses arise only through indirect activation. Thus, our results suggest multiple mechanisms of burst creation may exist. Further, histograms of interspike intervals revealed that the response properties were different in different types of ganglion cells. While further testing is needed, the ability to create different patterns of activity in different types of ganglion cells raises the possibility that more natural spike patterns can be created. PMID- 22254501 TI - Physiological response of mouse retinal ganglion cells to electrical stimulation: effect of soma size. AB - An epiretinal prosthesis aims to restore functional vision by stimulating electrically the retinal ganglion cells (RGCs) in patients affected by photoreceptor degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). During retinal degeneration, photoreceptor death is followed by pronounced remodeling and rewiring of inner retinal cells. Despite these changes, a considerable population of RGCs remain receptive to prosthetic stimulation. To target selectively a localized subset of RGCs, an improved understanding of the anatomical and physiological properties of these cells is required. Additionally, potential alterations in electrical excitability produced by the retinal degeneration needs to be assessed. This study investigates the effect of RGC soma size on the threshold for action potential (spike) generation and its implications for the rescue of visual function. PMID- 22254502 TI - Laser-micromachined, chip-scaled ceramic carriers for implantable neurostimulators. AB - Hermetic encapsulation of long-term implantable devices using ceramics has been investigated over several decades. Our studies focus on the miniaturization of ceramic encapsulations for large numbers of stimulation channels. Laser patterning of screen printed platinum (Pt) paste on cofired ceramics has been shown to enable the construction of features comparable in size to classical screen printing. A novel technique for embedding Pt structures into the surface of Al(2)O(3) substrates is shown to produce features with a line width minimum of 20 MUm and a pitch of 40 MUm. Polishing the ceramic substrates enables flip-chip bonding of application specific integrated circuits (ASIC) using gold stud bumps. A new technique for fine tuning of an ASIC stimulator with stud bump bridges is described. The technique eliminates the need for wire bond loops and increases reliability and integration density of the system, which are major requirements used to construct a visual prosthesis or other implantable devices requiring miniaturization. The methods for laser-patterned Pt tracks in alumina for fine pitch structures are described. Feasibility studies for flip-chip bonding and stud bump bridges were undertaken and the results were found to be promising. PMID- 22254503 TI - Standard ERG equipment can be used to monitor functionality of retinal implants. AB - Identifying whether or not a retinal implant has malfunctioned after implantation is crucial for safety and efficacy testing in preclinical animal studies and clinical testing in human volunteers. Technical failure can lead to charge injection to areas other than the retina leading to a misjudgment of safety considerations or psychophysical results. This study assessed the feasibility of using standard ERG recordings for the detection of failure of a subretinal implant in-situ using a porcine model. Corneally recorded potentials were compared before and after introduction of damage to the implant leading to failure to deliver charges to the retina. The recorded signal decreased by up to 173% following induced damage to the implant. This shows that standard ERG equipment can be used to monitor if a malfunction occurred in animal testing and can also be applicable in clinical trials. PMID- 22254504 TI - Comparison of basal oscillatory rhythm of retinal activities in rd1 and rd10 mice. AB - Among the many animal models of retinitis pigmentosa (RP), the most extensively characterized animal is the rd1 mouse. Recent studies showed that the neurophysiological properties of rd1 retinas differ significantly from those of normal retina; the presence of an oscillatory rhythmic activity (~10 Hz) both in retinal ganglion cell (RGC) spikes and field potentials (slow wave component, SWC). However, lesser studies have been done regarding electrical characteristics of rd10 retina, carrying the mutation of same rod-PDE gene and showing a later onset degeneration of photoreceptors. Therefore, in this study, we compared the oscillatory rhythm in RGC spike and SWC between rd1 and rd10 mice in different postnatal ages to understand neural code used by two diseased retinas to communicate with the brain. Extracellular action potentials are recorded by 8 * 8 MEA from the RGC in the in vitro whole mount retina. 4 and 8 weeks in rd1 mice and 4, 10, 15, and 20 weeks in rd10 mice were used (n=3 for each postnatal age). From the raw waveform of retinal recording, RGC Spikes and SWC were isolated by using 200 Hz high-pass filter and 20 Hz low-pass filter, respectively. Fourier transform was performed for detection of oscillatory rhythm in RGC spikes and SWC. In rd1 mice, there is no statistical difference between the frequency of SWC and spike in 4 weeks [p>0.05; spike 9.3 +/- 0.9 Hz (n=40), SWC 9.3 +/- 1.5 Hz (n=25)] and 8 weeks [p>0.05; spike 10.0 +/- 1.3 Hz (n=87), SWC 10.9 +/- 1.7 Hz (n=25)]. While in rd10 mice there is no statistical differences among the SWC through 4 ~ 20 weeks, significant differences were observed between the frequency of RGC spike and SWC and also among RGC spikes [4 weeks (p<0.001): spike 5.5 +/- 1.3 Hz (n=59), SWC 10.8 +/- 3.1 Hz (n=14); 10 weeks (p<0.001): spike 6.8 +/- 3.8 Hz (n=79), SWC 10.3 +/- 2.6 Hz (n=25); 15 weeks (p<0.05): spike 3.9 +/- 0.7 Hz (n=33), SWC 9.9 +/- 1.2 Hz (n=25); 20 weeks (p<0.05): spike 4.4 +/- 1.2 Hz (n=53), SWC 9.8 +/- 1.2 Hz (n=25)]. PMID- 22254505 TI - Eye-surface conformable telemetric structure for polymer-based retinal prosthesis. AB - In this research, inductive telemetric structure for retinal prosthesis was developed based on Liquid Crystal Polymers. For power and data transmission into the polymer-based retinal implant which is conformable to eye surface, the designed coil was thermo-formed into convex shape. The geometric parameters of the coil were optimized using finite element method (FEM) simulations for maximizing coupling coefficient and quality factor. The electrical properties of fabricated coils were characterized and their power and data transmission performance was tested. The properties of deformed structure were compared to those of the planar structure. In vivo experiment were also conducted to confirm the functionality of telemetry system in implanted conditions as well as to estimate the influence of biological media upon link properties. PMID- 22254506 TI - Multi-command SSVEP-based BCI system via single flickering frequency half-field stimulation pattern. AB - This paper proposes a half-field steady state visual evoked potential (SSVEP) based brain-computer interface (BCI) system to enhance the number of limited commands obtained from the existing SSVEP-based BCI methods. With the theory of vision perception and the concept of the existing half-field SSVEP-based BCI system, we propose the new stimulation pattern that, by using only one frequency, four commands can be generated with the average classification accuracy of approximately 77%. By using only one frequency, eye fatigue can be reduced. Furthermore, this method can be efficiently used to further increase the number of commands for the existing SSVEP-based BCI system. PMID- 22254507 TI - New variable porosity flow diverter (VPOD) stent design for treatment of cerebrovascular aneurysms. AB - Using flow diverting Stents for intracranial aneurysm repair has been an area of recent active research. While current commercial flow diverting stents rely on a dense mesh of braided coils for flow diversion, our group has been developing a method to selectively occlude the aneurysm neck, without endangering nearby perforator vessels. In this paper, we present a new method of fabricating the low porosity patch, a key element of such asymmetric vascular stents (AVS). PMID- 22254508 TI - Neural network based classifier for cardio vascular diseases based on vascular aging. AB - Vascular Aging is a cardio vascular risk factor. Vascular aging and vascular disease go together. Cardio vascular diseases (CVDs) remain and will continue to be the leading cause of death in all countries. This rate is more, particularly in developing countries. This paper attempts to classify subjects tested as healthy or not based on the data obtained from the analysis of common carotid artery. The network taken for training and testing is a multilayer perceptron (MLP) with one hidden layer. Data obtained from the analysis has three parameters -diameter, distension and age of the subject under test. Subjects of varying age groups are taken for this. Network successfully classifies whether the person is 'healthy' or 'should meet the cardiologist for further treatment'. Since this is done at a very early stage, this will be a milestone in the treatment of cardio vascular diseases. Moreover, this uses data obtained from the analysis of ultrasound images of the carotid artery and therefore is a cost effective method. PMID- 22254509 TI - Surface EMG and heartbeat analysis preliminary results in surgical training: dry boxes and live tissue. AB - The training in the surgical practice is of paramount importance to prepare the residents in performing surgical procedures on human subject and to provide exercise on new techniques for experienced surgeons. Usually, these trainings are carried out on live animals or in virtual environments and dry boxes; the complexity of the exercises is identical in both of the case, but the pressure in operating with a living subject could change the attitude and the movements of the trainee. Until now, it has not been possible to analyze this stress in details together in the surgical animal training and dry boxes. In this work we propose an innovative portable system that can measure two physiological parameters, the heartbeat and the surface electromyography, during a session of training in both of the environment. The preliminary results, for one subject, show a bigger average power in the shoulder muscles during the living operation together with a higher but stable heartbeat rate. PMID- 22254510 TI - Progress on multimodal molecular / anatomical intravascular imaging of coronary vessels combining near infrared fluorescence and ultrasound. AB - The use of intravascular imaging modalities for the detection and assessment of atherosclerotic plaque is becoming increasingly useful. Current clinical invasive modalities assess the presence of plaque using anatomical information and include Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT). However, such modalities cannot take into account underlying functional biological information, which can however be revealed with the use of molecular imaging. Consequently, intravascular molecular imaging is emerging as a powerful approach. We have developed such a Near-Infrared Fluorescence (NIRF) imaging system and showcased, in both phantom and in-vivo (rabbit) experiments, its potential to successfully detect inflamed atherosclerotic plaques, using appropriate fluorescent probes. Here, we discuss some limitations of the current system and suggest the combined use of the NIRF and IVUS imaging systems as a means for more accurate assessment of atherosclerotic plaque. We include some results and models that showcase the potential power of this kind of hybrid imaging. PMID- 22254511 TI - Haptic interface protocol for FEM-based deformable model and effects on fineness of force feedback and perceived hardness. AB - The remote haptic collaboration system between operating and assistant surgeons causes both shift and step delays of force feedback, and then makes users feel coarse reaction forces and different hardness of the object. In this study, we propose a haptic interface protocol for finite-element-method based deformable objects, in order to achieve a high update rate of force calculation. The method exports the necessary information for calculation of reaction forces from the simulation loop to the haptic loop. The experimental results indicated that the proposed method improved the fineness of force feedback and subjective hardness significantly. PMID- 22254512 TI - Estimation of traversed distance in level walking using a single inertial measurement unit attached to the waist. AB - A method for estimating step length during level walking using a single inertial measurement unit is proposed. A combination of an optimally filtered direct and reverse integration technique and a velocity update technique for the initial velocity values identification was implemented to reduce the effects of the acceleration signals drift. The method takes advantage of the cyclic nature of gait. The inertial measurement unit was placed at waist level on the right side and the method was validated on eight subjects walking for 75 m while varying their speed. The traversed distance was estimated with an average error equal to 0.8% of the total walking distance. PMID- 22254514 TI - Animal-Assisted Therapy for persons with disabilities based on canine tail language interpretation via fuzzy emotional behavior model. AB - Animal-Assisted Therapy (AAT) is the science that employs the merit of human animal interaction to alleviate mental and physical problems of persons with disabilities. However, to achieve the goal of AAT for persons with severe disabilities (e.g. spinal cord injury and amyotrophic lateral sclerosis), real time animal language interpretation is needed. Since canine behaviors can be visually distinguished from its tail, this paper proposes the automatic real-time interpretation of canine tail language for human-canine interaction in the case of persons with severe disabilities. Canine tail language is captured via two 3 axis accelerometers. Directions and frequency are selected as our features of interests. New fuzzy rules and center of gravity (COG)-based defuzzification method are proposed in order to interpret the features into three canine emotional behaviors, i.e., agitate, happy, and scare as well as its blended emotional behaviors. The emotional behavior model is performed in the simulated dog. The average recognition rate in real dog is 93.75% accuracy. PMID- 22254513 TI - A method for selecting an efficient diagnostic protocol for classification of perceptive and cognitive impairments in neurological patients. AB - An important and unresolved problem in the assessment of perceptual and cognitive deficits in neurological patients is how to choose from the many existing behavioral tests, a subset that is sufficient for an appropriate diagnosis. This problem has to be dealt with in clinical trials, as well as in rehabilitation settings and often even at bedside in acute care hospitals. The need for efficient, cost effective and accurate diagnostic-evaluations, in the context of clinician time constraints and concerns for patients' fatigue in long testing sessions, make it imperative to select a set of tests that will provide the best classification of the patient's deficits. However, the small sample size of the patient population complicates the selection methodology and the potential accuracy of the classifier. We propose a method that allows for ordering tests based on having progressive increases in classification using cross-validation to assess the classification power of the chosen test set. This method applies forward linear regression to find an ordering of the tests with leave-one-out cross-validation to quantify, without biasing to the training set, the classification power of the chosen tests. PMID- 22254515 TI - Assessment and follow-up of muscle injuries in athletes by bioimpedance: preliminary results. AB - Mono-frequency (50 kHz) whole-body and segmental bioimpedance is measured before sport training in 14 high performance athletes. The athletes are classified in two groups according to the team sport: football and basketball. Bioelectrical impedance vector analysis (BIVA) method is used to obtain the individual whole body impedance and 6 segmental impedance vectors in the main muscular groups in the lower-limbs. The whole-body vector is analyzed in the tolerance ellipses of the reference population. Individual impedance vector components are standardized by the height H of the subject, (R/H and Xc/H) to obtain the impedance vector (Z/H) of each segment. The hypotheses of the study are: 1) Not all the sports have the same pattern of bioimpedance vector by muscle group. 2) In elite well trained athletes their muscle groups are symmetrical (right and left sides), thus each athlete is its own reference for future comparisons. 3) We expect a change in the two components of bioimpedance vector (R/H and Xc/H) in front of a muscle injury. In order to compare the differences between the complex Z/H vector (R/H, Xc/H) we use Hotelling's T2 test. Preliminary results show a significant difference (P < 0.05) in bioimpedance vectors between groups according to the team sport, and also between normal muscle condition and after muscle injury producing hyper-hydration. PMID- 22254516 TI - Magnetic stimulation for fracture consolidation--clinical study. AB - This paper presents a randomized clinical design for evaluating magnetic fields in the consolidation of femoral shaft fractures. The study involved the design and construction of 20 devices (stimulators and placebos) and the development of 3D computer models of stimulated patient's thighs. A total of 64 patients were included in the study. Follow up time was 8 weeks with 1 hour of stimulation a day. The electrical signals estimated in the computer models were magnetic field, current density and voltage for different frequencies and currents. The results revealed 83% consolidated cases, and 7% with nonunion within the stimulation group, and 72% of consolidated cases and 14% with non-union for the control group. The consolidation results of patients who received stimulation were superior in time and number, but were not statistically significant. The values of electrical variables estimated by the computational model were found to be within a range not harmful to the patient (MUA/m2, MUT, nV). PMID- 22254517 TI - Neural adaptation and perceptual learning using a portable real-time cochlear implant simulator in natural environments. AB - A portable real-time speech processor that implements an acoustic simulation model of a cochlear implant (CI) has been developed on the Apple iPhone / iPod Touch to permit testing and experimentation under extended exposure in real-world environments. This simulator allows for both a variable number of noise band channels and electrode insertion depth. Utilizing this portable CI simulator, we tested perceptual learning in normal hearing listeners by measuring word and sentence comprehension behaviorally before and after 2 weeks of exposure. To evaluate changes in neural activation related to adaptation to transformed speech, fMRI was also conducted. Differences in brain activation after training occurred in the inferior frontal gyrus and areas related to language processing. A 15-20% improvement in word and sentence comprehension of cochlear implant simulated speech was also observed. These results demonstrate the effectiveness of a portable CI simulator as a research tool and provide new information about the physiological changes that accompany perceptual learning of degraded auditory input. PMID- 22254518 TI - High frequency oscillations evoked by peripheral magnetic stimulation. AB - The analysis of somatosensory evoked potentials (SEP) and / or fields (SEF) is a well-established and important tool for investigating the functioning of the peripheral and central human nervous system. A standard technique to evoke SEPs / SEFs is the stimulation of the median nerve by using a bipolar electrical stimulus. We aim at an alternative stimulation technique enabling stimulation of deep nerve structures while reducing patient stress and error susceptibility. In the current study, we apply a commercial transcranial magnetic stimulation system for peripheral magnetic stimulation of the median nerve. We compare the results of simultaneously recorded EEG signals to prove applicability of our technique to evoke SEPs including low frequency components (LFC) as well as high frequency oscillations (HFO). Therefore, we compare amplitude, latency and time-frequency characteristics of the SEP of 14 healthy volunteers after electric and magnetic stimulation. Both low frequency components and high frequency oscillations were detected. The HFOs were superimposed onto the primary cortical response N20. Statistical analysis revealed significantly lower amplitudes and increased latencies for LFC and HFO components after magnetic stimulation. The differences indicate the inability of magnetic stimulation to elicit supramaximal responses. A psycho-perceptual evaluation showed that magnetic stimulation was less unpleasant for 12 out of the 14 volunteers. In conclusion, we showed that LFC and HFO components related to median nerve stimulation can be evoked by peripheral magnetic stimulation. PMID- 22254519 TI - Nerve block using a navigation system and ultrasound imaging for regional anesthesia. AB - During the last few years, regional anesthesia using ultrasound imaging has increased dramatically in both clinical and research areas. This method provides a direct noninvasive imaging of the targeted nerve and the tissue around it in real time. Furthermore, it allows anesthetists to observe the injected anesthetics for optimal distribution. However, there are still some major limitations to this method such as poor visibility of the standard needle tip and shaft, tricky location estimation of needle tip, and difficult needle alignment before and during insertion. This article presents the concept of a new application field of medical navigation for regional anesthesia using ultrasound imaging, to avoid the above-mentioned drawbacks. In addition, a laboratory experiment on a phantom to verify the effectiveness, safety, precision and handling of the navigation method in comparison with standard ultrasound-guided regional anesthesia is described. During the experiment ten test persons who have no experience in this field should touch a target in a phantom, avoiding contact with the simulated blood vessels and nerve. Each test person was asked to repeat the test five times with and without navigation assistance, respectively. Thereafter, a two-sample one-tailed paired t-test with a significance level of 1% was applied to statistically analyze the difference. The results show that navigation assistance significantly improves effectiveness, safety, precision and handling of ultrasound-guided regional anesthesia. PMID- 22254520 TI - Methods for assessment of effects of habitual exercise on the autonomic nervous function using plethysmogram. AB - The present paper has proposed two methods for obtaining the linear correlation of the baroreflex system without measurement of blood pressure. One is based on the pulse wave transit time which needs both the electrocardiogram and the photoplethysmogram. The other is based on the photoplethysmogram only. The results from the experiments showed that the effect of habitual exercise and the Valsalva maneuver can be verified quantitatively. The proposed methods are possible to be used for a test of the autonomic nervous function at home. PMID- 22254521 TI - ISO/IEEE 11073 PHD message generation toolkit to standardize healthcare device. AB - As senior population increases, various healthcare devices and services are developed such as fall detection device, home hypertension management service, and etc. However, to vitalize healthcare devices and services market, standardization for interoperability between device and service must precede. To achieve the standardization goal, the IEEE 11073 Personal Health Device (PHD) group has been standardized many healthcare devices, but until now there are few devices compatible with the PHD standard. One of main reasons is that it isn't easy for device manufactures to implement standard communication module by analyzing standard documents of over 600 pages. In this paper, we propose a standard message generation toolkit to easily standardize existing non-standard healthcare devices. The proposed toolkit generates standard PHD messages using inputted device information, and the generated messages are adapted to the device with the standard state machine file. For the experiments, we develop a reference H/W, and test the proposed toolkit with three healthcare devices: blood pressure, weighting scale, and glucose meter. The proposed toolkit has an advantage that even if the user doesn't know the standard in detail, the user can easily standardize the non-standard healthcare devices. PMID- 22254522 TI - An automated medication adherence tool. AB - Misuse of medications is a major cause of morbidity and mortality. The pervasiveness of non-adherence to medications is having significant health care implications, including costly and distressing hospitalization. This paper presents a new method for delivering medication instructions that incorporates all aspects of all medications in a regimen into one chronological schedule, rather than using an independent instruction set for each medication as is currently done. It is an automated tool that accepts as input only the name, dose, and frequency of each medication, and generates a chronological schedule that respects all medication constraints and contains the essential directions for use. The potential users of the system are health care environments in which a log of all of a patient's medications, including over-the-counter medications, resides in one place. PMID- 22254523 TI - A user centered design approach for patient interfaces to a diabetes IT platform. AB - Improving patient self-management can have a greater impact than improving any clinical treatment (WHO). We propose here a systematic and comprehensive user centered design approach for delivering a technological platform for diabetes disease management. The system was developed under the METABO research project framework, involving patients from 3 different clinical centers in Parma, Modena and Madrid. PMID- 22254524 TI - A chair-type interface for long-term and ambient vital sensing. AB - We investigate a novel type of interface that enables long-term vital sensing through noninvasive direct-contact vital sign detection and observation of body motion and feedback of health conditions through an illuminated display. Although various types of vital sign measuring equipment are currently commercially available, their complexity and inconvenient user interfaces coupled with human reluctance to continue long-term use discourage their daily use. Consequently, in this research we propose a method for involuntary measurement of vital signs of a user who is relaxing in a normal living environment. This study also investigates physical and physiological activity regarding body motion. In addition, a trend analysis is also performed with the help of past data automatically stored after each session. PMID- 22254525 TI - Rapid trend detection for an ambulatory monitoring system. AB - An algorithm for rapid trend detection of physiological parameter is introduced for ambulatory monitoring applications. Kalman prediction error of monitored parameter is used to estimate the physiological status and detect rapid change. With this algorithm, rapid trend during ambulatory monitoring can be found to predict disease exacerbation; and it is also applied to identify outliers of measurement due to poor signal quality to avoid false alarms. PMID- 22254526 TI - iHeartLift: a closed loop system with bio-feedback that uses music tempo variability to improve heart rate variability. AB - "Musica delenit bestiam feram" translates into "Music soothes the savage beast". There is a hidden truth in this ancient quip passed down from generations. Besides soothing the heart, it also incites the heart to a healthier level of heart rate variability (HRV). In this paper, an approach to use and test music and biofeedback to increase the heart rate variability for people facing daily stress is discussed. By determining the music tempo variability (MTV) of a piece of music and current heart rate variability, iHeartLift is able to compare the 2 trends and locate a musical piece that is suited to increase the user's heart rate variability to a healthier level. With biofeedback, the 2 trends are continuously compared in real-time and the musical piece is changed in accordance with the current comparisons. A study was conducted and it was generally found that HRV can be uplifted by music regardless of language and meaning of musical lyrics but with limitations to musical genre. PMID- 22254527 TI - Improving the drug dispensing process at the National Institute of respiratory diseases by applying the six sigma methodology. AB - The purpose of this work was to improve the drug dispensing process at the National Institute of Respiratory Diseases of Mexico by applying the six sigma methodology, identifying the non-value added activities as well as the areas of opportunity, in order to make proposals to ensure the supply of prescription drugs to the patient in a timely manner. Seven variables were defined and three indicators were generated, which were implemented in three clinical services of the Institute to measure the current performance of the drug distribution process. With the obtained results, a proposed set of eight improvements were subsequently implemented in a pilot program. PMID- 22254528 TI - A novel mainstream capnometer system for non-intubated pediatric patients requiring oxygen administration. AB - Capnometer has been widely used as a respiratory monitor. Stable carbon dioxide (CO(2)) monitoring of non-intubated patient is especially problematic due to the frequent occurrence of tube obstruction and it could be even more difficult when oxygen is being administered. Oxygen is often administered by an oxygen mask or oxygen nasal cannula; however there are some problems with these methods. For oxygen masks, it is necessary to provide high-flow oxygen to prevent rebreathing of exhaled CO(2), and as for oxygen nasal cannula, it is incapable of increasing the oxygen concentration and patient may feel uncomfortable during oxygen administration because it could dry nasal mucous. To solve these problems, we developed a novel mainstream capnometer system, which provides stable monitoring of exhaled CO(2) while administering oxygen. This capnometer system has a mask with an opening large enough to facilitate the observation of patient's nose and mouth and the procedures such as daily oral care. Furthermore, the outer rim of the mask is designed to effectively retain oxygen flow without causing rebreathing. PMID- 22254529 TI - DigiScope--unobtrusive collection and annotating of auscultations in real hospital environments. AB - Digital stethoscopes are medical devices that can collect, store and sometimes transmit acoustic auscultation signals in a digital format. These can then be replayed, sent to a colleague for a second opinion, studied in detail after an auscultation, used for training or, as we envision it, can be used as a cheap powerful tool for screening cardiac pathologies. In this work, we present the design, development and deployment of a prototype for collecting and annotating auscultation signals within real hospital environments. Our main objective is not only pave the way for future unobtrusive systems for cardiac pathology screening, but more immediately we aim to create a repository of annotated auscultation signals for biomedical signal processing and machine learning research. The presented prototype revolves around a digital stethoscope that can stream the collected audio signal to a nearby tablet PC. Interaction with this system is based on two models: a data collection model adequate for the uncontrolled hospital environments of both emergency room and primary care, and a data annotation model for offline metadata input. A specific data model was created for the repository. The prototype has been deployed and is currently being tested in two Hospitals, one in Portugal and one in Brazil. PMID- 22254530 TI - An alignment procedure for ambulatory measurements of lower limb kinematic using magneto-inertial sensors. AB - In this work, an alignment procedure of magneto-inertial units in the Special Orthogonal Space SO(3) is presented and discussed. The procedure, designed for ambulatory measurements of lower limb kinematic, is based on simple rotation movements around anatomical axes of hip joint and its accuracy is independent of the speed as well as the range of the movements. This is particularly important for movement analysis of subjects with motor impairments. Despite such procedure was designed for lower limb movement analysis, it can be applied to every anatomical compartment (e.g.: upper limb). PMID- 22254531 TI - Respiratory rate estimation using respiratory sinus arrhythmia from photoplethysmography. AB - Respiratory rate (RR) is an important measurement for ambulatory care and there is high interest in its detection using unobtrusive mobile devices. For this study, we investigated the estimation of RR from a photoplethysmography (PPG) signal that originated from a pulse oximeter sensor and had a sub-optimal sampling rate. We explored the possibility of estimating RR by extracting respiratory sinus arrhythmia (RSA) from the PPG-derived heart rate variability (HRV) measurement using real-time algorithms. Data from 29 children and 13 adults undergoing general anesthesia were analyzed. We compared the RSA power derived from electrocardiography (ECG) with PPG at the reference RR derived from capnography. The power of the PPG was significantly higher than that of the ECG (182.42 +/- 36.75 dB vs. 162.30 +/- 43.66 dB). Further, the mean RR error for PPG was lower than ECG. Both PPG and ECG RR estimation techniques were more powerful and reliable in cases of spontaneous ventilation than when pressure controlled ventilation was used. The analysis of cases containing artifacts in the PPG revealed a significant increase in RR error, a trend that was less pronounced for controlled ventilation. These results indicate that the estimation of RR from the sub-optimally sampled PPG signal is possible and more reliable than from the ECG. PMID- 22254532 TI - Gas pre-warming for improving performances of heated humidifiers in neonatal ventilation. AB - Adequate temperature and humidification of gas delivered must be performed during long term neonatal ventilation to avoid potential adverse health effects. Literature shows that performances of heated humidifiers are, at least in some cases, quite poor. In this study, a novel approach to gas conditioning, consisting of gas warming upstream the humidification chamber, is presented. Gas pre-warming, in combination with a control strategy based on a mathematical model taking into account a number of parameters, allows to significantly improve the heated humidifier performances. The theoretical model has been validated and experimental trials have been carried out in the whole volumetric flow-rate (Q) range of neonatal ventilation (lower than 10 L . min(-1)). Experimental results (temperature values ranging from 36 degrees C to 38 degrees C and relative humidity values from 90 % to 98 % in the whole range of Q) show values very close to the ideal thermo-hygrometric conditions. The proposed solution allows to avoid vapor condensation at low flow rates and decrease of relative humidity at high flow rates. PMID- 22254533 TI - A multi agent system model for evaluating quality service of Clinical Engineering Department. AB - Biomedical technology is strategically important to the operational effectiveness of healthcare facilities. As a consequence, clinical engineers have become an essential figure in hospital environment: their role in maintenance, support, evaluation, integration, assessment of new, advanced and complex technologies in point of view of patient safety and cost reduction is become inalienable. For this reason, nations have begun to establish Clinical Engineering Department, but, unfortunately, in a very diversified and fragmented way. So, a tool able to evaluate and improve the quality of current services is needed. Hence, this work builds a model that acts as a reference tool in order to assess the quality of an existing Clinical Engineering Department, underlining its defaulting aspects and suggesting improvements. PMID- 22254534 TI - A methodology aimed to guarantee technology continuity in health structures. AB - In healthcare the importance of clinical continuity is essential for both patients life and health organization activity. Since technology continuity is having more and more importance for the service continuity, a correct management of medical devices must be guided by criteria that ensure its safe, appropriate and economical use through a well planned purchase, appropriate preventive and corrective maintenance Indeed, the aim of health technology managers is to optimize the integration of external interventions assistance and internal technical service to guarantee an efficient and cost-effective maintenance system. This paper proposes an innovative carefully thought methodology which is aimed to provide technological and procedural actions which offer support to decision makers in technology management regarding the implementation of continuity in medical services and response to technology failures and emergency events. PMID- 22254535 TI - In vivo performance evaluation of the Innovamedica pneumatic ventricular assist device. AB - We evaluated the in vivo performance of the Innovamedica pneumatic ventricular assist device (VAD), a new prototype of a simple, low-cost device for hospital circulatory support programs. We implanted the Innovamedica VAD in 6 sheep (weighing 55 to 91 kg). The inflow cannula was placed in the left ventricle, and the outflow cannula was anastomosed to the descending thoracic aorta. After heparinization (3mg/kg), we initiated the pump and monitored its hemodynamic performance for 6 hours. In a subsequent study we implanted the device for left ventricular support in two sheep for a 30-day period. We evaluated device performance based on implantation procedure, hemodynamic performance, and hematological impact. We monitored hematological and biochemical variables, and we assessed hemolysis. In the short-term experiments, the pumps maintained a mean blood flow of 4.4 +/- 0.8 L/min. During support, mean arterial blood pressure was 76 +/- 15 mmHg. The overall average concentration of plasma free hemoglobin was 5.11 +/- 0.6 mg/dl compared with a baseline value of 4.52 +/- 0.7 mg/dl. In the 30 day trials, mean blood output was 4 l/min +/- 0.2, plasma free hemoglobin was 5.9 +/- 4 mg/dl for the 30 day period excluding the first 48 hours. Warfarin/Aspirin anticoagulation was used after the first 72 hours with an average INR of 2.9 for the entire test period. Post-mortem showed no blood clots or any significant tissue damage to brain, lungs or kidneys. The devices operated without any significant adverse events in all of the experiments. The Innovamedica VAD was easy to implant and de-air and was found to be effective, reliable and biocompatible. PMID- 22254536 TI - Intensive care unit availability indexed to patient complexity. AB - In this paper, a procedure to estimate a Clinical Unit availability is presented. Service availability depends on multiple resources, some of them redundant, to function properly. However, resource consumption varies according to patient's medical condition. The availability of an Intensive Care Unit (ICU) depends both on basic components (electricity, water) and on requirements set by patient complexity and quantity. We propose using Diagnosis Related Groups (DRG) as an estimator of patient complexity. Accumulated DRG (DRG(a)) represents the quantity/complexity combination that the ICU has to care for at any given moment. Our analysis allowed us to find the theoretical combination of patients that would collapse a clinical unit. This limit was deemed reasonable to expert advisors based on their experience at the ICU. The study was conducted for the adult ICU at the 'Clinica Universitaria de Concepcion', a teaching hospital in Concepcion, Chile. Data was collected during 4 months and analyzed using reliability theory. Overall reliability and availability results are consistent with incident reports at the Clinic. The procedure and recommendations for unit design and management are applicable to Clinical Units both at early planning stages or for currently working units. PMID- 22254537 TI - Biphasic transdermal iontophoretic drug delivery platform. AB - Transdermal iontophoresis is an active drug delivery method that has the potential to transform treatment of conditions such as acute pain that require a succession of on-demand metered-dose drug deliveries. However, current monophasic iontophoresis methods fail to meet these requirements due to their inability to halt the passive diffusion of active agents when therapy is not required. We have developed a biphasic iontophoretic system to overcome these limitations. The viability of this system was assessed in an in vitro porcine skin preparation using FeCl(2) (127 Daltons), a charged molecule which can undergo both active and passive transdermal diffusion. The transport properties of the system were modeled using a Fourier Transform-derived optimum estimate transfer function. Using this model, experimental results showed good correlation to predicted values for both cumulative dose (R(2)=0.912, n=10), and density dose (R(2)=0.802, n=10). Results also showed the ability to effectively deliver the compound during active periods while minimizing delivery during inactive periods. While preliminary, our results suggest biphasic iontophoresis is a viable means of delivering on-demand drug therapy while minimizing unwanted off-demand delivery. PMID- 22254538 TI - NIRS study of cerebral oxygenation and hemodynamics in neonate at birth. AB - To study the changes of cerebral oxygenation and hemodynamics in normal neonates at 2-5 min post-birth and understand the effects of pregnancy-induced hypertension (PIH) upon cerebral oxygenation and hemodynamics in newborn neonates. The near infrared spectroscopy (NIRS) was employed to measure the absolute quantity of brain tissue oxygen saturation (rSO2) in newborn neonates and the changes of concentrations of deoxyhemoglobin (Hb) and oxygenation hemoglobin (HbO2) with time relative to initial values to further obtain the changes of total hemoglobin (tHb) and cerebral perfusion (denoted by HbD). In normal neonates at 2-5 min post-birth, rSO2 increased while tHb remained relatively stable and HbD increased. In neonates born of PIH mothers at 3-5 min post-birth, the changes of tHb were markedly higher than those in the normal infants, p<0.05; at 2-5 min post-birth, the changes were markedly lower than the normal term infants. We concluded that NIRS can detect the changes of cerebral oxygenation and blood flow in a non-invasive and effective way. PMID- 22254539 TI - Design and accuracy evaluation of a new navigated drill system for computer assisted ENT-surgery. AB - In this article a new navigated drill system for computer assisted ear, nose and throat (ENT) surgery is presented. The navigated drill and the microscope probe are part of a surgical navigation system for ENT-surgery. In particular, the accuracy of the new navigated drill is compared to an existing navigated drill experimentally under conditions close to the surgical workflow. For the technical accuracy experiment, the new navigated drill in combination with the new microscope probe and a particular navigated measurement board have been integrated, together with the current navigated drill, in a navigation system by a special navigation software with measuring function, based on a standard ENT navigation software. The developed navigated measurement board provided the implementation of reproducible experiments and the direct accuracy comparison of the two navigated instruments under the same conditions. Thereby, N = 15 accuracy experiments are performed with both navigated drill systems with three possible tracker positions. The distance between the planned and the touched points were calculated and compared. The average distances from the planned points to the touched points with the new navigated drill is in the left tracker position 1.10 mm, in the middle tracker position 1.14 mm and in the right tracker position 1.59 mm. In comparison to the existing drill, the new navigated drill, measured with each tracker position, is 0.62 mm more accurate. PMID- 22254540 TI - Official measurement protocol and accuracy results for an optical surgical navigation system (NPU). AB - Image-guided surgical navigation is on the rise in many different areas of modern medicine and is already an established standard in some disciplines like ear nose and throat (ENT) or maxillofacial surgery. When evaluating surgical navigation systems the absolute accuracy of the device is of major concern to the surgeon. The following work presents two different ways of measuring the accuracy of surgical navigation systems using the example of the KARL STORZ Navigation Panel Unit (NPU). According to these protocols the FDA approval of the NPU navigation system was prepared. In a first series of experiments the accuracy under realistic surgical conditions is evaluated with a phantom of a human head, which is manufactured in rapid-prototyping processes. In another series of experiments a custom registration board is used, which provides means to evaluate the accuracy under optimal conditions and also allows further measurements regarding the registration error, that are not possible with the phantom. In the experiments an accuracy of 1.44 mm +/- 0.18 mm was measured in the surgical setup and 0.63 mm +/- 0.07 mm under ideal conditions. PMID- 22254541 TI - New approach for quantitative measurement of ultrasonic cavitation yields. AB - In this study, we propose the use of the bubble cloud ellipsoid volume as the quantitative evaluation parameter to monitor the ultrasonic cavitation yield. The bubble cloud ellipsoid volume was calculated by using the bubble cloud image and attenuation characteristics in bubble cloud. The usefulness of this parameter was verified by observing the change in the bubble cloud under various conditions. Under all sonication conditions, the bubble cloud volume was increased in proportion to the rise in sonication intensity (R(2): 0.9283, 0.8817, and 0.9439). On the basis of these results, we consider that the bubble cloud ellipsoid volume is a very useful evaluation parameter for quantitatively assessing the cavitation yield. Furthermore, this new approach may form the foundation of future studies on cavitation applications. PMID- 22254542 TI - Influence of ventilatory settings on indirect calorimetry in mechanically ventilated patients. AB - With the aim to assess metabolic monitor's suitability to the use in mechanically ventilated patients, a method, based on the comparison between the measurements performed by the monitor and the ventilator, is here described. In particular, the effects of positive end-expiratory pressure and oxygen inspiratory fraction (FiO(2)) on the metabolic measurements in presence of bias flow are investigated. In this study a metabolic monitor is used to estimate the energy expenditure of 10 mechanically ventilated cardiosurgical patients at different positive end expiratory pressure, FiO(2) and two different modes of ventilation, with bias flow. The influence of the ventilatory settings on the parameters measured by the monitor is here quantified: a slight decrease of respiratory quotient and a slight increase of resting energy expenditure are observed with the increase of FiO(2). This study shows a good agreement between the measurements of the two devices: FiO(2), expiratory volume (mean difference lower than 3%), and respiratory frequency (mean difference lower than 1%). This also demonstrates the capability of the metabolic monitor to reject the effect of the bias flow. PMID- 22254543 TI - A conceptual cognitive architecture for robots to learn behaviors from demonstrations in robotic aid area. AB - This paper proposes a conceptual hybrid cognitive architecture for cognitive robots to learn behaviors from demonstrations in robotic aid situations. Unlike the current cognitive architectures, this architecture puts concentration on the requirements of the safety, the interaction, and the non-centralized processing in robotic aid situations. Imitation learning technologies for cognitive robots have been integrated into this architecture for rapidly transferring the knowledge and skills between human teachers and robots. PMID- 22254544 TI - Algorithm for selecting appropriate transfer support equipment based on the physical ability of the user. AB - In the present paper, we propose an algorithm for selecting appropriate transfer support equipment based on the physical ability of the user. In addition, we describe the relationship between features of the human body and the physical burdens during standing. Although several care support devices have been developed, assistive robots are not yet popular because users do not know which devices are suitable for their needs or appropriate for their physical abilities. In the present study, we focus on a transfer support device and propose an algorithm for selecting transfer support equipment that will be suitable to the physical ability of the user. We investigated the relationship between standing support equipment and physical burdens during standing, which is one of transfer motions. In an experiment, we calculated and analyzed the knee and ankle joint moments and discussed the relationship between standing support equipment and the knee and ankle joint moments during standing. The results indicated a difference in the relation of standing support equipments appropriate to the user's physical ability. It was found effective to provide a railing to persons having low residual ability in the ankle joints and an up/down seat to persons having low residual ability in the knee joints. PMID- 22254545 TI - Trajectory planning of a robot for lower limb rehabilitation. AB - We introduce a method for lower-limb physical rehabilitation by means of a robot that applies preliminary defined forces to a patient's foot while moving it on a preliminary defined trajectory. We developed a special musculoskeletal model that takes into consideration the generated muscle forces of 27 musculotendon actuators and joint stiffness of the leg and allows the calculation of the motion trajectory of the robot and the forces that the robot needs to apply to the foot in each moment of the therapeutic exercise. Robotic treatment programs are customized for the individual patient by using a genetic algorithm (GA) that refers to the musculoskeletal model and calculates the parameters of the spline curves of the motion trajectory of the robot and forces acting on the foot. PMID- 22254546 TI - Direct interaction with an assistive robot for individuals with chronic stroke. AB - Many robotic systems have been developed to provide assistance to individuals with disabilities. Most of these systems require the individual to interact with the robot via a joystick or keypad, though some utilize techniques such as speech recognition or selection of objects with a laser pointer. In this paper, we describe a prototype system using a novel method of interaction with an assistive robot. A touch-sensitive skin enables the user to directly guide a robotic arm to a desired position. When the skin is released, the robot remains fixed in position. The target population for this system is individuals with hemiparesis due to chronic stroke. The system can be used as a substitute for the paretic arm and hand in bimanual tasks such as holding a jar while removing the lid. This paper describes the hardware and software of the prototype system, which includes a robotic arm, the touch-sensitive skin, a hook-style prehensor, and weight compensation and speech recognition software. PMID- 22254547 TI - Improving the ROM of wrist movements in stroke patients by means of a haptic wrist robot. AB - A 3 DoFs haptic wrist robot is used to measure and/or assist the movement of the wrist on three axes: flexion/extension (F/E), abduction/adduction (A/A), pronation/ supination (P/S). An assistance scheme based on the widely used progressive splinting therapy is proposed and its efficacy is tested within a group of nine chronic stroke patients, during a pilot study consisting of 2 sessions. Preliminary outcomes show that the technique is effective with the very distal part of wrist involving F/E and A/A but results in a reduced motor improvement for the P/S where proximal part of the arm is involved. PMID- 22254548 TI - Thoracic ROM measurement system with visual bio-feedback: system design and biofeedback evaluation. AB - Patients with diseases such as chronic obstructive pulmonary disease (COPD) need to improve their thorax mobility. Thoracic ROM is one of the simplest and most useful indexes to evaluate the respiratory function. In this paper, we have proposed the prototype of a simple thoracic ROM measurement system with real-time visual bio-feedback in the chest expansion test. In this system, the thoracic ROM is measured using a wire-type linear encoder whose wire is wrapped around the thorax. In this paper, firstly, the repeatability and reliability of measured thoracic ROM was confirmed as a first report of the developed prototype. Secondly, we analyzed the effect of the bio-feedback system on the respiratory function. The result of the experiment showed that it was easier to maintain a large and stable thoracic ROM during deep breathing by using the real-time visual biofeedback system of the thoracic ROM. PMID- 22254549 TI - Generation of complex motor patterns in american grasshopper via current controlled thoracic electrical interfacing. AB - Micro-air vehicles (MAVs) have attracted attention for their potential application to military applications, environmental sensing, and search and rescue missions. While progress is being made toward fabrication of a completely human-engineered MAV, another promising approach seeks to interface to, and take control of, an insect's nervous system. Cyborg insects take advantage of their innate exquisite loco-motor, navigation, and sensing abilities. Recently, several groups have demonstrated the feasibility of radio-controlled flight in the hawkmoth and beetle via electrical neural interfaces. Here, we report a method for eliciting the "jump" response in the American grasshopper (S. Americana). We found that stimulating the metathoracic T3 ganglion with constant-current square wave pulses with amplitude 186 +/- 40 MUA and frequency 190 +/- 13 Hz reproducibly evoked (>=95% success rate) the desired motor activity in N=3 test subjects. To the best of our knowledge, this is the first report of an insect cyborg with a synchronous neuromuscular system. PMID- 22254550 TI - Time-frequency analysis of human motion during rhythmic exercises. AB - Biomechanical signals due to human movements during exercise are represented in time-frequency domain using Wigner Distribution Function (WDF). Analysis based on WDF reveals instantaneous spectral and power changes during a rhythmic exercise. Investigations were carried out on 11 healthy subjects who performed 5 cycles of sun salutation, with a body-mounted Inertial Measurement Unit (IMU) as a motion sensor. Variance of Instantaneous Frequency (I.F) and Instantaneous Power (I.P) for performance analysis of the subject is estimated using one-way ANOVA model. Results reveal that joint Time-Frequency analysis of biomechanical signals during motion facilitates a better understanding of grace and consistency during rhythmic exercise. PMID- 22254551 TI - Throwing darts utilizes the interaction torque of the elbow joint. AB - Acquiring the skillful movements of experts is a difficult task in many fields. If we find quantitative indices of skillful movement, we can develop an adaptive training system using the indices. We focused on throwing darts in our previous study. It was found that optimization criteria of sum of squared joint torque changes over time was negatively correlated with subject's scores, suggesting that the experts optimally controlled the shoulder elevations and rotation around the elbow joint in terms of dynamics. In this study, we investigate the relationship between the skill level of subjects and their utilization joint torque components such as the muscular torque, interaction torque and gravity torque. It is shown found that the sum of squared joint torque components of the subjects correlates with their scores, suggesting that the subjects who can take higher scores utilize the interaction torque of the elbow joint without shoulder displacement. PMID- 22254552 TI - Arm motion analysis of stroke patients in activities of daily living tasks: a preliminary study. AB - Analyzing activities of daily living (ADL) for the development of practical upper limb rehabilitation robots is challenging in stroke patients. Basic ADL tasks using an upper limb are defined based on clinical assessment tools. The motions of 8 healthy participants and 8 stroke patients were recorded during defined ADL tasks, and then analyzed with respect to completion time, linearity of motion, and range of motion of the joints. Completion time and motion trajectories were significantly different between stroke subjects and healthy participants. For tasks involving the transfer of an object from a table to the user's mouth, wrist radial-ulnar deviation motions should be taken into account while designing robots for gross movements via elbow and shoulder joints. Our findings can be extended to the design of trajectories of rehabilitation robots as well as of simplified robots. PMID- 22254553 TI - Accuracy and repeatability of parameter estimation methods from ambulatory data for the wrist joint. AB - In this paper, as a preliminary study, we show that accuracy and repeatability in ambulatory measurements of wrist joint are related to movement conditions which are going to be used in a calibration procedure. We chose two representative in vivo, non-invasive calibration methods of the human upper limb, from those available in literature, to estimate joint parameters. Developing an analytical model of wrist joint we used sets of synthetic data each of which containing different number of samples, joint covariations and noise to estimate the repeatability and accuracy of the methods in estimation. Afterwards, we used our mechanical mock-up to examine single joint motions as well as the rotation of both joints (i.e. flexion-extension rotation and radial-ulnar deviation) on accuracy and repeatability by calculating the mean and standard deviation of the relative errors. Finally, we show that the accuracy of adapted method (its relative error was less than 7%) is better than the other method in estimating the joint parameters. PMID- 22254555 TI - Monkey models for brain-machine interfaces: the need for maintaining diversity. AB - Brain-machine interfaces (BMIs) aim to help disabled patients by translating neural signals from the brain into control signals for guiding prosthetic arms, computer cursors, and other assistive devices. Animal models are central to the development of these systems and have helped enable the successful translation of the first generation of BMIs. As we move toward next-generation systems, we face the question of which animal models will aid broader patient populations and achieve even higher performance, robustness, and functionality. We review here four general types of rhesus monkey models employed in BMI research, and describe two additional, complementary models. Given the physiological diversity of neurological injury and disease, we suggest a need to maintain the current diversity of animal models and to explore additional alternatives, as each mimic different aspects of injury or disease. PMID- 22254556 TI - A balance control model predicts how vestibular loss subjects benefit from a vibrotactile balance prosthesis. AB - A balance control model was applied to interpret how subjects with a severe vestibular loss (VL) used vibrotactile information from a balance prosthesis to enhance balance control. Experimental data were from 5 VL subjects standing with eyes closed and responding to continuous pseudorandom surface tilts of the stance platform. Results showed that vibrotactile feedback information reduced sway at frequencies below ~0.6 Hz, but vibrotactile feedback was less effective in reducing sway as stimulus amplitude increased. This experimental pattern was accurately predicted by the model, which was based on time-delayed sensory feedback control. The model predicted that changes to the vibrotactor activation scheme could improve performance of the prosthesis and demonstrated that further improvements might be possible if motor learning, acquired by practice and training, could increase VL subjects' reliance on the prosthesis. PMID- 22254557 TI - Designing vibrotactile balance feedback for desired body sway reductions. AB - Vibrotactile feedback about body position and velocity has been shown to be effective at reducing low frequency body sway (below about 0.5 Hz) in response to balance perturbations while standing. However, current devices cause an undesirable increase in high frequency body sway. In addition, unlike other sensory prostheses such as hearing aids, which are fine-tuned to the user, current vibrotactile balance prostheses largely employ a "one size fits all" approach, in that they use the same settings (i.e. parameter values) for all subjects. Rather than using a fixed design consisting of position and velocity feedback for all subjects, we propose a "custom design" approach that employs system identification methods to identify the feedback required to achieve a desired body sway frequency response for the subject. Our derivations and simulations show that in order to accomplish this objective, feedback consisting of a subject-specific filtered combination of body position, velocity and acceleration is required. Simulation results are provided to illustrate the results. PMID- 22254558 TI - Improving impaired balance function: real-time versus carry-over effects of prosthetic feedback. AB - This study investigated whether training with realtime prosthetic biofeedback (BF) of trunk sway induces a carry-over improvement in balance control once BF is removed. 12 healthy older adults and 7 uncompensated unilateral vestibular loss patients were tested. All participants performed a battery of 14 balance and gait tasks (pre-test) upon their initial lab visit during which trunk angular sway was measured at L1-3. They then received balance BF training on a subset of 7 tasks, three times per week, for two consecutive weeks. BF was provided using a multi modal biofeedback system with graded vibrotactile, auditory, and visual cues in relation to subject-specific angular displacement thresholds. Performance on the battery of the 14 balance and gait tasks (without BF) was re-assessed immediately after the 2 week training period, as well as 1 week later to examine BF carry over effects. Significant reductions in trunk angular displacement were observed with the real-time BF, compared to the pre-test trials. The effects of BF persisted when BF was removed immediately after the final training session. BF carry-over effects were less evident at one week post-training. This evidence supports the potential short-term effects of BF training in a limited number of tasks after the BF is removed in healthy elderly subjects and those with vestibular loss. However, the prospect for longer term (>1 week) effects of prosthetic training on balance control remains currently unknown. PMID- 22254559 TI - An integrated vestibular-cochlear prosthesis for restoring balance and hearing. AB - An integrated vestibular-cochlear implant can be rapidly prototyped and clinically tested by modifying an existing modern cochlear implant. The modifications include addition of gyroscope sensors and reallocation of several electrodes that are normally used for auditory nerve stimulation to the semicircular canals, while sharing the external DSP processor and the internal receiver/stimulator. This paper discusses the validation issues related to hardware and software design that arise in integrating electric hearing and balance onto a single device. The device's initially targeted population will be deaf individuals who also have vestibular impairment since there is a strong ethical justification for vestibular implantation along with minimal additional surgical risk. Because of widespread usage of ototoxic drugs and unique genetic mutations, the patient population with both impaired hearing and balance function is especially prevalent in Asian countries such as China and India. Should such an integrated vestibular-cochlear implant be verified, it could be used to restore balance or treat a wide array of vestibular disorders. PMID- 22254560 TI - Can an electro-tactile vestibular substitution system improve balance in patients with unilateral vestibular loss under altered somatosensory conditions from the foot and ankle? AB - This pilot study aimed at assessing the feasibility and the effectiveness of an electro Electro-tactile Vestibular Substitution System (EVSS) in patients with unilateral vestibular loss under normal and altered somatosensory conditions from the foot and ankle. Four unilateral vestibular-defective patients voluntarily participated in the experiment. They were asked to stand upright as still as possible with their eyes closed in two Normal and Altered foot and ankle sensory conditions. In the Normal condition, the postural task was executed on a firm support surface constituted by the force platform. In the Altered condition, a 2 cm thick foam support surface was placed under the participants' feet. These two foot and ankle sensory conditions were executed under two No EVSS and EVSS experimental conditions. The No EVSS condition served as a control condition. In the EVSS condition, participants executed the postural task using a biofeedback system whose underlying principle consisted of supplying them with additional information about their head orientation/motion with respect to gravitational vertical through electro-tactile stimulation of their tongue. Centre of foot pressure displacements (CoP) were recorded using the force platform. Results showed that, relative to the No EVSS condition, the EVSS condition decreased CoP displacements in both the Normal and the Altered foot and ankle sensory conditions. Interestingly, the stabilizing effect was more pronounced in the Altered than in the Normal foot and ankle sensory condition. These preliminary results suggest that patients with unilateral vestibular loss were able to take advantage to a head position-based electro-tactile tongue biofeedback to mitigate the postural perturbation induced by alteration of somatosensory input from the foot and the ankle. PMID- 22254561 TI - Development and validation of a clinic based balance assessment technology. AB - Falls in the elderly are a major problem worldwide, with enormous associated societal costs. Deficits in balance and postural control have long been associated with falls risk in elderly adults. The gold standard for quantitative assessment of human balance in a clinical setting is the force plate which is highly expensive, non-portable and requires specialized personnel to operate. The present study aims to evaluate the validity and reliability of a portable quantitative balance measurement technology compared to the forceplate. Two participants (1 male, 1 female) performed sixteen balance trials each (eight eyes open and eight eyes closed). Simultaneous data were recorded from a portable pressure sensor platform and a laboratory grade force platform. Standard centre of pressure (COP) metrics from both modalities were compared and high levels of agreement in terms of intraclass correlation coefficient (ICC), mean absolute error (MAE) and mean percentage error (MPE) were found. PMID- 22254562 TI - Improvement of hemocompatibility for hydrodynamic levitation centrifugal pump by optimizing step bearings. AB - We have developed a hydrodynamic levitation centrifugal blood pump with a semi open impeller for a mechanically circulatory assist. The impeller levitated with original hydrodynamic bearings without any complicated control and sensors. However, narrow bearing gap has the potential for causing hemolysis. The purpose of the study is to investigate the geometric configuration of the hydrodynamic step bearing to minimize hemolysis by expansion of the bearing gap. Firstly, we performed the numerical analysis of the step bearing based on Reynolds equation, and measured the actual hydrodynamic force of the step bearing. Secondly, the bearing gap measurement test and the hemolysis test were performed to the blood pumps, whose step length were 0 %, 33 % and 67 % of the vane length respectively. As a result, in the numerical analysis, the hydrodynamic force was the largest, when the step bearing was around 70 %. In the actual evaluation tests, the blood pump having step 67 % obtained the maximum bearing gap, and was able to improve the hemolysis, compared to those having step 0% and 33%. We confirmed that the numerical analysis of the step bearing worked effectively, and the blood pump having step 67 % was suitable configuration to minimize hemolysis, because it realized the largest bearing gap. PMID- 22254563 TI - Frank-starling control of a left ventricular assist device. AB - A physiological control system was developed for a rotary left ventricular assist device (LVAD) in which the target pump flow rate (LVADQ) was set as a function of left atrial pressure (LAP), mimicking the Frank-Starling mechanism. The control strategy was implemented using linear PID control and was evaluated in a pulsatile mock circulation loop using a prototyped centrifugal pump by varying pulmonary vascular resistance to alter venous return. The control strategy automatically varied pump speed (2460 to 1740 to 2700 RPM) in response to a decrease and subsequent increase in venous return. In contrast, a fixed-speed pump caused a simulated ventricular suction event during low venous return and higher ventricular volumes during high venous return. The preload sensitivity was increased from 0.011 L/min/mmHg in fixed speed mode to 0.47L/min/mmHg, a value similar to that of the native healthy heart. The sensitivity varied automatically to maintain the LAP and LVADQ within a predefined zone. This control strategy requires the implantation of a pressure sensor in the left atrium and a flow sensor around the outflow cannula of the LVAD. However, appropriate pressure sensor technology is not yet commercially available and so an alternative measure of preload such as pulsatility of pump signals should be investigated. PMID- 22254564 TI - The aortic valve dynamics role in the recovery treatments of patients with left ventricular assist devices. AB - This paper intends to define an optimal range for the pump speed of Rotary Left Ventricular Assist Devices (LVADs) that are used in bridge-to-recovery treatments. If the pump is operating within that optimal range, the aortic valve will be working properly (i.e. opening and closing) in each cardiac cycle. The proper operation of the aortic valve is a very important factor in helping the heart muscle recovers. The optimal range varies depending on the severity of the Heart Failure (HF) and the level of activity of the patient. A comparison is shown between the total flow produced as a result of operating the pump within the optimal range and the physiological demand of the patient. The comparison suggests that for cases of mild to moderate HF the flow produced is close to the physiological demand, but in severe cases the flow is significantly less than what the patient requires. Furthermore, our results suggest that data from the pump flow and the left ventricle volume signals can be used to test whether or not the aortic valve is experiencing permanent closure. Also an investigation of the aortic valve opening duration is presented for two cases: first, for mild HF case with varying Heart Rate (HR) and then for fixed HR and mild to severe HF cases. These Simulation results are obtained using a 6(th) order mathematical model of the cardiovascular-LVAD system. PMID- 22254565 TI - Noninvasive miniaturized mass-flow meter using a curved cannula for implantable axial flow blood pump. AB - Blood flow should be measured to monitor conditions of patients with implantable artificial hearts continuously and noninvasively. We have developed a noninvasive miniaturized mass-flow meter using a curved cannula for an axial flow blood pump. The mass-flow meter utilized centrifugal force generated by the mass-flow rate in the curved cannula. Two strain gauges served as sensors. Based on the numerical analysis, the first gauge, attached to the curved area, measured static pressure and centrifugal force, and the second, attached to the straight area, measured static pressure for static pressure compensation. The mass-flow rate was determined by the differences in output from the two gauges. To compensate for the inertia force under the pulsatile flow, a 0.75-Hz low-pass filter was added to the electrical circuit. In the evaluation tests, numerical analysis and an actual measurement test using bovine blood were performed to evaluate the measurement performances. As a result, in the numerical analysis, the relationship between the differential pressure caused by centrifugal force and the flow rate was verified. In the actual measurement test, measurement error was less than +/- 0.5 L/min, and the time delay was 0.12 s. We confirmed that the developed mass-flow meter was able to measure mass-flow rate continuously and noninvasively. PMID- 22254566 TI - A new index measured by cardiovascular magnetic resonance imaging to detect mechanical heart valve malfunction. AB - More than two thirds of valve replacement operations performed each year used mechanical heart valve. These valves are subject to complications such: pannus and/or thrombus formation. One other potential complication is a malfunction in one of the valve leaflets. It is then important to develop parameters that will allow a non-invasive diagnosis of such valve malfunction. In the present study, we evaluated under steady low flow (1-8 L/min) and pulsatile flow (3, 5 and 7 L/min) a bileafleat mechanical heart valve with normal function, 50% and 100% of one valve leaflet malfunction. Image analysis was performed using cardiovascular magnetic resonance imaging to evaluate transvalvular pressure gradients (TPG), effective orifice area and a new index given by central/lateral velocity ratio downstream of the valve. Our results showed that the flow upstream and downstream of the defective valve is highly influenced by malfunction severity. TPG did not allow differentiating valve malfunction at low flow under steady and pulsatile conditions. However the new index given by central/lateral ratio allowed differentiating the presence of valve malfunction using a single transverse velocity measurement. PMID- 22254567 TI - Template for preparation of papers for IEEE sponsored conferences & Symposia. AB - Rotary blood pumps which have contact-less suspension are small, durable and widely used for left ventricular assist devices (LVADs). In order to design a total artificial heart (TAH) with rotary blood pumps, two pumps one for each ventricle, are controlled independently. Some of the challenges for the development of a TAH includes the requirement of a small size and the anatomical fitting of inlets and outlets which should be arranged closely on the circumference in the same direction. And they should be combined into a unit. In this paper, a helical flow total artificial heart (HFTAH) combing two centrifugal pumps with helical inlet in face is proposed in order to achieve a smaller TAH. To examine the pump performance, a preliminary test model for left ventricle was built, the size of the pump was 69.0mm in diameter and 45.0mm height. The size of the impeller was 44.0mm in diameter and 23.0mm height including a 15.0mm-height hydrodynamic bearing. The pump was externally driven by a direct current motor. 5.0L/min flow rate against 100mmHg pressure difference was obtained, where the total power consumption was 5.0W, the system efficiency was 23% with a rotational speed of 2070rpm. In this system, maximum pressure head, flow rate and efficiency were 420mmHg, 15.0L/min and 26%, respectively. In acute animal experiments with three healthy adult goats, the total biventricular bypass assist system using the pumps was able to maintain the maximum aortic flow at approximately 5.0L/min, and the pulmonary arterial flow at approximately 4.6L/min, the mean aorta pressure was 105mmHg, and the mean pulmonary artery pressure was 51mmHg. The development of the control method is undergoing, and a driving system and the pump aiming at the chronic animal experiments will be developed. PMID- 22254568 TI - Reconstruction of multiple gastric electrical wave fronts using potential based inverse methods. AB - The ability to reconstruct gastric electrical activity (termed slow waves) non invasively from potential field measurements made on the torso surface would be a useful tool to aid in the clinical diagnosis of a number of gastric disorders. This is mathematically akin to the inverse problem of electrocardiography. To investigate this problem, an anatomically realistic torso model and an electrical stomach model were used to simulate potentials on the stomach and skin surfaces arising from normal gastric electrical activity. Gaussian noise was added to the torso potentials to represent experimental signal noise. The stomach potentials, activation profiles and gastric slow wave velocities were inversely reconstructed from the torso potentials, using the Tikhonov-Greensite inverse method with regularisation determined using an L-curve method. The inverse solutions were then compared with the known input solutions. The reconstructed solutions were able to represent the presence of multiple propagating wave fronts, determine average activation times to within 5 s and average velocities to within 1 mm/s. When more virtual body surface electrodes were used in the inverse calculations, the accuracy of the reconstructed activity improved. PMID- 22254569 TI - Permittivity estimation for breast cancer detection using particle swarm optimization algorithm. AB - In this paper, particle swarm optimization (PSO) algorithm is used to estimate the permittivities of the tissue layers at microwave frequency band. According to the literature, microwave radiometry (MWR) is potentially a promising cancer detection technique. In addition, breast cancer is an appropriate candidate of MWR due to the breast's exclusive physiology. Several algorithms have been evaluated for analyzing the measurement data and solving the inverse scattering problem in MWR, and different levels of accuracy have been reported. In this paper, the potential of PSO in solving this problem is demonstrated at 1-2.25 GHz. Two distinct algorithms are developed for the two considered scenarios. In the first scenario, we assume no a priori knowledge of the tissue under the test, whereas, in the second scenario, a priori knowledge is assumed. It is noteworthy that, there are only a few research articles studying PSO for permittivity estimation. However, since these studies underestimate the loss encountered by the test samples, the methods are not valid for body tissue case. Here, measurement-based loss coefficients, reported in the existing literature, are included in the calculations. It is shown that the algorithm converges relatively fast, and, distinguishes between different tissues with an acceptable accuracy. PMID- 22254570 TI - Comparison of system identification techniques in the analysis of a phantom for studying shaken-baby syndrome. AB - This article compares two techniques for estimating the parameters describing the motion of a phantom designed to investigate shaking baby syndrome. Parameters of a simple computational model and an impulse response function for a linear second order system were both fitted using kinematic measurements of the motion of an inverted jointed pendulum. From the two methods respectively, the rotational stiffness of the joint was calculated to be 1.396 kgm(2) s(-2) and 1.355 kgm(2) s(-2) and the damping coefficient was calculated to be 0.0142 kgm(2) s(-1) and 0.0133 kgm(2) s(-1). The parameter estimates were similar demonstrating that the two techniques were comparable. Identifying accurate parameters will allow more complex phantoms to be modeled, and will provide insight into the relationship between the shaking of the torso and the resultant head motion during shaken baby syndrome. PMID- 22254571 TI - Inverse modeling for heat conduction problem in human abdominal phantom. AB - Noninvasive methods for deep body temperature measurement are based on the principle of heat equilibrium between the thermal sensor and the target location theoretically. However, the measurement position is not able to be definitely determined. In this study, a 2-dimensional mathematical model was built based upon some assumptions for the physiological condition of the human abdomen phantom. We evaluated the feasibility in estimating the internal organs temperature distribution from the readings of the temperature sensors arranged on the skin surface. It is a typical inverse heat conduction problem (IHCP), and is usually mathematically ill-posed. In this study, by integrating some physical and physiological a-priori information, we invoked the quasi-linear (QL) method to reconstruct the internal temperature distribution. The solutions of this method were improved by increasing the accuracy of the sensors and adjusting their arrangement on the outer surface, and eventually reached the state of converging at the best state accurately. This study suggests that QL method is able to reconstruct the internal temperature distribution in this phantom and might be worthy of a further study in an anatomical based model. PMID- 22254573 TI - Tissue-based optimization of a sino-atrial node disc model. AB - A cardiac sino-atrial tissue model based on a simplified 2D disc geometry and a generic ionic model is described and optimized to fit intact-tissue microelectrode experimental recordings. Concentric regions were defined representing the central and peripheral sino-atrial node and the atrium, each with a unique set of ionic model parameters. Intracellular action potentials were recorded from the respective myocytes in an intact rabbit in vitro sino-atrial tissue preparation. The 2D disc geometry was described numerically using a modified version of the cable equation of electrical propagation. The cell specific model parameters at three nodes representing each region of the disc geometry were optimized, using a curvilinear gradient optimization algorithm, to generate action potentials waveforms that fitted the experimentally recorded waveforms. The optimized model was able to reproduce spontaneous sino-atrial node activation and atrial excitation and propagation. It offers an improved representation of the electrotonic interactions between heterogenous cell types and is able to reproduce the transition in action potential morphology between different regions. This tissue based optimization approach is a contribution to the development of realistic electro-anatomical cardiac models based on experimental data. PMID- 22254572 TI - Estimating parameters in genetic regulatory networks with SUM logic. AB - Many methods for inferring genetic regulatory networks have been proposed. However inferred networks can hardly be used to analyze the dynamics of genetic regulatory networks. Recently nonlinear differential equations are proposed to model genetic regulatory networks. Based on this kind of model, the stability of genetic regulatory networks has been intensively investigated. Because of difficulty in estimating parameters in nonlinear model, inference of genetic regulatory networks with nonlinear model has been paid little attention. In this paper, we present a method for estimating parameters in genetic regulatory networks with SUM regulatory logic. In this kind of genetic regulatory networks, a regulatory function for each gene is a linear combination of Hill form functions, which are nonlinear in parameters and in system states. To investigate the proposed method, the gene toggle switch network is used as an illustrative example. The simulation results show that the proposed method can accurately estimates parameters in genetic regulatory networks with SUM logic. PMID- 22254574 TI - Augmenting sensory-motor conflict promotes adaptation of postural behaviors in a virtual environment. AB - We present results from a series of studies that investigated how multimodal mismatches in a virtual environment modified postural response organization. Adaptation of motor commands to functional circumstances is driven directly by error signals. Thus, motor relearning should increase when performing in environments containing sensory mismatch. We hypothesized that kinematics of the response would be linked to specific characteristics of the sensory array. Sensory weighting was varied by: 1) rotating the visual field about the talo crural joint or the interaural axis, 2) adding stochastic vibrations at the sole of the foot, and 3) combining galvanic vestibular stimulation with rotations of the visual field. Results indicated that postural responses are shaped by the location of a sensory disturbance and also by the processing demands of the environmental array. Sensory-motor demands need to be structured when developing therapeutic interventions for patients with balance disorders. PMID- 22254575 TI - Incorporating virtual reality graphics with brain imaging for assessment of sport related concussions. AB - There is a growing concern that traditional neuropsychological (NP) testing tools are not sensitive to detecting residual brain dysfunctions in subjects suffering from mild traumatic brain injuries (MTBI). Moreover, most MTBI patients are asymptomatic based on anatomical brain imaging (CT, MRI), neurological examinations and patients' subjective reports within 10 days post-injury. Our ongoing research has documented that residual balance and visual-kinesthetic dysfunctions along with its underlying alterations of neural substrates may be detected in "asymptomatic subjects" by means of Virtual Reality (VR) graphics incorporated with brain imaging (EEG) techniques. PMID- 22254576 TI - Interactive rehabilitation and dynamical analysis of scalp EEG. AB - Electroencephalography (EEG) has been used for decades to measure the brain's electrical activity. Planning and performing a complex movement (e.g., reaching and grasping) requires the coordination of muscles by electrical activity that can be recorded with scalp EEG from relevant regions of the cortex. Prior studies, utilizing motion capture and kinematic measures, have shown that an augmented reality feedback system for rehabilitation of stroke patients can help patients develop new motor plans and perform reaching tasks more accurately. Historically, traditional signal analysis techniques have been utilized to quantify changes in EEG when subjects perform common, simple movements. These techniques have included measures of event-related potentials in the time and frequency domains (e.g., energy and coherence measures). In this study, a more advanced, nonlinear, analysis technique, mutual information (MI), is applied to the EEG to capture the dynamics of functional connections between brain sites. In particular, the cortical activity that results from the planning and execution of novel reach trajectories by normal subjects in an augmented reality system was quantified by using statistically significant MI interactions between brain sites over time. The results show that, during the preparation for as well as the execution of a reach, the functional connectivity of the brain changes in a consistent manner over time, in terms of both the number and strength of cortical connections. A similar analysis of EEG from stroke patients may provide new insights into the functional deficiencies developed in the brain after stroke, and contribute to evaluation, and possibly the design, of novel therapeutic schemes within the framework of rehabilitation and BMI (brain machine interface). PMID- 22254577 TI - Utilizing media arts principles for developing effective interactive neurorehabilitation systems. AB - This paper discusses how interactive neurorehabilitation systems can increase their effectiveness through systematic integration of media arts principles and practice. Media arts expertise can foster the development of complex yet intuitive extrinsic feedback displays that match the inherent complexity and intuitive nature of motor learning. Abstract, arts-based feedback displays can be powerful metaphors that provide re-contextualization, engagement and appropriate reward mechanisms for mature adults. Such virtual feedback displays must be seamlessly integrated with physical components to produce mixed reality training environments that promote active, generalizable learning. The proposed approaches are illustrated through examples from mixed reality rehabilitation systems developed by our team. PMID- 22254578 TI - Adaptive strategy for multi-user robotic rehabilitation games. AB - In this paper, we discuss a strategy for the adaptation of the "difficulty level" in games intended to include motor planning during robotic rehabilitation. We consider concurrently the motivation of the user and his/her performance in a Pong game. User motivation is classified in three levels (not motivated, well motivated and overloaded). User performance is measured as a combination of knowledge of results--achieved goals and score points in the game--and knowledge of performance--joint displacement, speed, aiming, user work, etc. Initial results of a pilot test with unimpaired healthy young volunteers are also presented showing a tendency for individualization of the parameter values. PMID- 22254579 TI - A computational framework for constructing interactive feedback for assisting motor learning. AB - New motion capture technologies are allowing detailed, precise and complete monitoring of movement through real-time kinematic analysis. However, a clinically relevant understanding of movement impairment through kinematic analysis requires the development of computational models that integrate clinical expertise in the weighing of the kinematic parameters. The resulting kinematics based measures of movement impairment would further need to be integrated with existing clinical measures of activity disability. This is a challenging process requiring computational solutions that can extract correlations within and between three diverse data sets: human driven assessment of body function, kinematic based assessment of movement impairment and human driven assessment of activity. We propose to identify and characterize different sensorimotor control strategies used by normal individuals and by hemiparetic stroke survivors acquiring a skilled motor task. We will use novel quantitative approaches to further our understanding of how human motor function is coupled to multiple and simultaneous modes of feedback. The experiments rely on a novel interactive tasks environment developed by our team in which subjects are provided with rich auditory and visual feedback of movement variables to drive motor learning. Our proposed research will result in a computational framework for applying virtual information to assist motor learning for complex tasks that require coupling of proprioception, vision audio and haptic cues. We shall use the framework to devise a computational tool to assist with therapy of stroke survivors. This tool will utilize extracted relationships in a pre-clinical setting to generate effective and customized rehabilitation strategies. PMID- 22254580 TI - Study of neurovascular and autonomic response in a divided attention test by means of EEG, ECG and NIRS signals. AB - We evaluated neurovascular and autonomic response to a Divided Attention task within a group of 16 healthy subjects, by means of Electroencephalography, Electrocardiography, functional Near Infrared Spectroscopy techniques, acquired simultaneously. We exctracted Alpha (8-13,5 Hz) and Beta (13,5-30 Hz) power rhythms with a spectral autoregressive residual model, and inter-beat-interval (RR series) and separated superficial (extracortical) and depth NIRS contribution. Cross Correlation Function at different time lags was then calculated between each signal and the task, modeled as a square wave and among couples of signals, in order to evaluate the sequence of activation of the different physiological districts involved and the common information shared. Results showed the presence of a cascade of responses and a strong influence by the block task on each signal, representative of the neurovascular coupling elicited by the cognitive cerebral activation. PMID- 22254581 TI - Robust EEG preprocessing for dependence-based condition discrimination. AB - This paper addresses the robustness of the filtering schemes in processing high resolution electroencephalogram (EEG) data in the context of discriminating two stimuli flickering at a given frequency. The raw data consists of recordings from a 128-channel HydroCell GSN where the subject was visually stimulated with two images flickering at 17.5 Hz, representing two distinct conditions, referred to as Face and Mock. These signals were then passed through a band pass filter to only capture the modulation at the flickering frequency, and a connectivity analysis was performed on the filtered signal using generalized measure of association, to observe if the network connectivity changes from one stimulus to the other. In this paper, we investigate the effect of the bandpass filter on the discriminability of the stimuli over different filter orders and quality factors. We observe that the network connectivity is stable over a significant range of parameter values of the filter, thus establishing the desired robustness. PMID- 22254582 TI - Modeling cortical source dynamics and interactions during seizure. AB - Mapping the dynamics and spatial topography of brain source processes critically involved in initiating and propagating seizure activity is critical for effective epilepsy diagnosis, intervention, and treatment. In this report we analyze neuronal dynamics before and during epileptic seizures using adaptive multivariate autoregressive (VAR) models applied to maximally-independent (ICA) sources of intracranial EEG (iEEG, ECoG) data recorded from subdural electrodes implanted in a human patient for evaluation of surgery for epilepsy. We visualize the spatial distribution of causal sources and sinks of ictal activity on the cortical surface (gyral and sulcal) using a novel combination of multivariate Granger-causal and graph-theoretic metrics combined with distributed source localization by Sparse Bayesian Learning applied to a multi-scale patch basis. This analysis reveals and visualizes distinct, seizure stage-dependent shifts in inter-component spatiotemporal dynamics and connectivity including the clinically identified epileptic foci. PMID- 22254583 TI - Cortical networks for rotational uncertainty effect in mental rotation task by partial directed coherence analysis of EEG. AB - Partial directed coherence (PDC) as a frequency-domain representation of Granger casuality (GC) could detect both strength and direction of cortical interactions by multivariate autoregressive (MVAR) model of electroencephalography (EEG). In the present study, we investigate the underlying neural networks mechanisms of "rotational uncertainty effect" during mental rotation (MR) task by PDC analysis of multichannel EEG signals before and after the visual stimuli presented, we found that (i) temporally the "rotational uncertainty effect" involved an activated network before the visual stimuli presented, which could also affect the cognitive process of MR later; (ii) the causality functional connectivity network indicated that the bi-directional frontal [symbol see text] parietal networks played critical roles in maintaining the readiness during the MR task. These findings suggest that functional networks of un-cued preparation before visual stimuli presented are worth to be paid more attention. And these networks provide crucial casuality information to understand the neural mechanism for "rotational uncertainty effect" in MR task. PMID- 22254584 TI - Graphic patterns of cortical functional connectivity of depressed patients on the basis of EEG measurements. AB - Considerable evidences have shown a decrease of neuronal activity in the left frontal lobe of depressed patients, but the underlying cortical network is still unclear. The present study intends to investigate the conscious-state brain network patterns in depressed patients compared with control individuals. Cortical functional connectivity is quantified by the partial directed coherence (PDC) analysis of multichannel EEG signals from 12 depressed patients and 12 healthy volunteers. The corresponding PDC matrices are first converted into unweighted graphs by applying a threshold to obtain the topographic property in degree (K(in)). A significantly larger K(in) in the left hemisphere is identified in depressed patients, while a symmetric pattern is found in the control group. Another two topographic measures, i.e., clustering coefficients (C) and characteristic path length (L), are obtained from the original weighted PDC digraphs. Compared with control individuals, significantly smaller C and L are revealed in the depression group, indicating a random network-like architecture due to affective disorder. This study thereby provides further support for the presence of a hemispheric asymmetry syndrome in the depressed patients. More importantly, we present evidence that depression is characterized by a loss of optimal small-world network characteristics in conscious state. PMID- 22254585 TI - Kalman filter-based time-varying cortical connectivity analysis of newborn EEG. AB - Multivariate Granger causality in the time-frequency domain as a representation of time-varying cortical connectivity in the brain has been investigated for the adult case. This is, however, not the case in newborns as the nature of the transient changes in the newborn EEG is different from that of adults. This paper aims to evaluate the performance of the time-varying versions of the two popular Granger causality measures, namely Partial Directed Coherence (PDC) and direct Directed Transfer Function (dDTF). The parameters of the time-varying AR, that models the inter-channel interactions, are estimated using Dual Extended Kalman Filter (DEKF) as it accounts for both non-stationarity and non-linearity behaviors of the EEG. Using simulated data, we show that fast changing cortical connectivity between channels can be measured more accurately using the time varying PDC. The performance of the time-varying PDC is also tested on a neonatal EEG exhibiting seizure. PMID- 22254586 TI - A two-stage cascade nonlinear dynamical model of single neurons for the separation and quantification of pre- and post-synaptic mechanisms of synaptic transmission. AB - Neurons receive pre-synaptic spike trains and transform them into post-synaptic spike trains. This spike train to spike train temporal transformation underlies all cognitive functions performed by neurons, e.g., learning and memory. The transformation is a highly nonlinear dynamical process that involves both pre- and post-synaptic mechanisms. The ability to separate and quantify the nonlinear dynamics of pre- and post-synaptic mechanism is needed to gain insights into this transformation. In this study, we developed a Volterra kernel based two-stage cascade model of synaptic transmission using synaptically-driven intracellular activities, to which broadband stimulation conditions were imposed. The first stage of the model represents the pre-synaptic mechanisms and describes the nonlinear dynamical transformation from pre-synaptic spike trains to transmitter vesicle release strengths. The vesicle release strengths were obtained from the intracellularly recorded excitatory post-synaptic currents (EPSCs). The second stage of the model represents the post-synaptic mechanisms and describes the nonlinear dynamical transformation from release strengths to excitatory post synaptic potentials (EPSPs). One application of this cascade model is to analyze the pre- and post-synaptic mechanism change induced by long-term potentiation (LTP). This future application is expected to shed new light on the expression locus of LTP. PMID- 22254587 TI - A state-space model of the burst suppression ratio. AB - Burst suppression is an electroencephalogram pattern observed in states of severely reduced brain activity, such as general anesthesia, hypothermia and anoxic brain injuries. The burst suppression ratio (BSR), defined as the fraction of EEG spent in suppression per epoch, is the standard quantitative measure used to characterize burst suppression. We present a state space model to compute a dynamic estimate of the BSR as the instantaneous probability of suppression. We estimate the model using an approximate EM algorithm and illustrate its application in the analysis of rodent burst suppression recordings under general anesthesia. Our approach removes the need to artificially average the ratio over long epochs and allows us to make formal statistical comparisons of burst activity at different time points. Our state-space model suggests a more principled way to analyze this key EEG feature that may offer more informative assessments of its associated brain state. PMID- 22254588 TI - A Bayesian framework for analyzing iEEG data from a rat model of epilepsy. AB - The early detection of epileptic seizures requires computing relevant statistics from multivariate data and defining a robust decision strategy as a function of these statistics that accurately detects the transition from the normal to the peri-ictal (problematic) state. We model the afflicted brain as a hidden Markov model (HMM) with two hidden clinical states (normal and peri-ictal). The output of the HMM is a statistic computed from multivariate neural measurements. A Bayesian framework is developed to analyze the a posteriori conditional probability of being in peri-ictal state given current and past output measurements. We apply this method to multichannel intracortical EEGs (iEEGs) from the thalamo-cortical ictal pathway in an epilepsy rat model. We first define the output statistic as the max singular value of a connectivity matrix computed on the EEG channels with spectral techniques Then, we estimate the HMM transition probabilities from this statistic and track the a posteriori probability of being in peri-ictal state (the "information state variable"). We show how the information state variable changes as a function of time and we predict a seizure when this variable becomes greater than 0.5. This Bayesian strategy significantly improves over chance level and heuristically-chosen threshold-based predictors. PMID- 22254589 TI - Assessing the impact of signal normalization: preliminary results on epileptic seizure detection. AB - Signal normalization is an essential part of patient independent algorithms, for example to correct for variations in signal amplitude from different parts of the body, prior to applying a fixed threshold for event detection. Multiple methods for providing the required normalization are available. This paper presents a systematic investigation into the effects of five different methods using epileptic seizure detection from the EEG as an illustration case. It is found that, whilst normalization is essential, four of the considered methods actually decrease the ability to detect seizures, counteracting the algorithm aim. For optimal detection performance the effects of the signal normalization illustrated here should be incorporated into future algorithm designs. PMID- 22254590 TI - An algorithm for detecting seizure termination in scalp EEG. AB - Little effort has been devoted to developing algorithms that can detect the cessation of seizure activity in scalp EEG. Such algorithms could facilitate clinical applications such as the estimation of seizure duration or the delivery of therapies designed to mitigate postictal period symptoms. In this paper, we present a method for detecting the termination of seizure activity. When tested on 133 seizures from a public database, our method detected the end of 132 seizures with a mean absolute error of 10.3 +/- 5.5 seconds of the time marked by an electroencephalographer. Furthermore, by pairing our seizure end detector with a previously published seizure onset detector, we could automatically estimate the duration of 85% of test seizures within a 15 second error margin. PMID- 22254591 TI - Online EEG channel weighting for detection of seizures in the neonate. AB - A framework for online dynamic channel weighting is developed for the task of EEG based neonatal seizure detection. The channel weights are computed on-the-fly by combining the up-to-now patient-specific history and the clinically-derived prior channel importance. These estimated time-varying weights are introduced within a Bayesian probabilistic framework to provide a channel-specific and thus patient adaptive seizure classification scheme. Validation results on one of the largest clinical datasets of neonatal seizures confirm the utility of the proposed channel weighting for the SVM-based detector recently developed by this research group. Exploiting the channel weighting, the precision-recall area can be drastically increased (up to 25%) for the most difficult patients, with the average increase from 81.0% to 84.42%. It is also shown that the increase in performance with channel weighting is proportional to the time the patient is observed. PMID- 22254592 TI - Multi-scale characteristics of resampled fetal heart rate pattern provide novel fetal developmental indices. AB - The increasing functional integrity of the organism during fetal maturation is connected with increasing complex internal coordination mediated by the autonomic nervous system. We hypothesize that time scales of complex and dynamic inter dependencies over more than one heart beat interval reflect the increasing complex adjustments within the fetal organism during its prenatal development. We investigated multi-scale complexity and time irreversibility from equidistantly resampled heart rate time series of 73 fetal magnetocardiographic recordings over the third trimester. We found scale dependent changes in complexity and time irreversibility. The functions obtained from equidistantly resampled heart rate time series showed qualitatively similar curves compared to those obtained from heart beat intervals series previously reported. Time scales of fetal heart rate characteristics may provide novel information for the identification of developmental disorders in prenatal diagnosis. PMID- 22254593 TI - Phase plane based identification of fetal heart rate patterns. AB - Using a phase plane analysis (PPA) of the spatial spread of trajectories of the fetal heart rate and its time-derivative we characterize the fetal heart rate patterns (fHRP) as defined by Nijhuis. For this purpose, we collect 22 fetal magnetocardiogram using a 151 SQUID system from 22 low-risk fetuses in gestational ages ranging from 30 to 37 weeks. Each study lasted for 30 minutes. After the attenuation of the maternal cardiac signals, we identify the R waves using an adaptive Hilbert transform approach and calculate the fetal heart rate. On these datasets, we apply the proposed approach and the traditionally used approaches such as standard deviation of the normal to normal intervals (SDNN) and root mean square of the successive difference (RMSSD). Heart rate patterns are scored by an expert using Nijhuis criteria and revealed A, B, and D patterns. A receiver operator characteristic (ROC) curve is used to assess the performance of the metric to differentiate the different patterns. Results showed that only PPA was able to differentiate all pairs of fHRP with high performance. PMID- 22254594 TI - Quantification of cardio-respiratory interactions in healthy children during night-time sleep using joint symbolic dynamics. AB - The aim of this paper was to study interactions between R-R intervals and respiratory phases in healthy children during night-time sleep using a novel technique based on joint symbolic dynamics. We investigated overnight polysomnography data of 40 healthy children. The R-R time series were extracted from electrocardiograms (ECG) and respiratory phases were obtained from abdominal sensors using the Hilbert transform. Both the series were transformed into ternary symbol vectors based on the changes between two successive R-R intervals or respiratory phases, respectively. Subsequently, words of length '2' were formed and the correspondence between words of the two series for each sleep stage was determined to quantify cardio-respiratory interaction. We found a significantly higher percentage of similarity in the joint symbolic dynamics of R R intervals and respiratory phases during slow-wave (SW) sleep compared to any other sleep stage. There was, however, no significant effect of age, gender or BMI on cardio-respiratory interaction. In conclusion, joint symbolic dynamics provides a novel efficient technique for the analysis of cardio-respiratory interaction. PMID- 22254595 TI - Improved entropy rate estimation in physiological data. AB - Calculating entropy rate in physiologic signals has proven very useful in many settings. Common entropy estimates for this purpose are sample entropy (SampEn) and its less robust elder cousin, approximate entropy (ApEn). Both approaches count matches within a tolerance r for templates of length m consecutive observations. When physiologic data records are long and well-behaved, both approaches work very well for a wide range of m and r. However, more attention to the details of the estimation algorithm is needed for short records and signals with anomalies. In addition, interpretation of the magnitude of these estimates is highly dependent on how r is chosen and precludes comparison across studies with even slightly different methodologies. In this paper, we summarize recent novel approaches to improve the accuracy of entropy estimation. An important (but not necessarily new) alternative to current approaches is to develop estimates that convert probabilities to densities by normalizing by the matching region volume. This approach leads to a novel concept introduced here of reporting entropy rate in equivalent Gaussian white noise units. Another approach is to allow r to vary so that a pre-specified number of matches are found, called the minimum numerator count, to ensure confident probability estimation. The approaches are illustrated using a simple example of detecting abnormal cardiac rhythms in heart rate records. PMID- 22254596 TI - Noninvasive organization analysis along consecutive episodes of paroxysmal atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Although its mechanisms are incompletely understood, electrophysiological and structural remodeling of the atria seem to play an important role in the arrhythmia transition from paroxysmal to persistent. However, the time course of the atrial remodeling along onward episodes of non induced paroxysmal AF has not been investigated yet. In this work, a non-invasive method, based on the regularity estimation of AF through sample entropy (SampEn), has been used to assess the organization evolution along onward episodes of paroxysmal AF. Given that AF organization has been associated to the number of existing wavelets wandering throughout the atrial tissue, SampEn could be considered as a concomitant estimator of atrial remodeling. The achieved results, in close agreement with previous findings obtained from invasive recordings, showed a progressive disorganization increase along onward episodes of AF for 63% of the analyzed patients and a stable AF organization degree in the remaining 37%. Additionally, a positive correlation between episode duration and SampEn was also noticed (R = 0.541, p < 0.01). As a consequence, it could be considered that atrial electrophysiological dynamics that occur along onward paroxysmal AF episodes are reflected and can be quantified from ECG recordings through non invasive organization estimation. PMID- 22254597 TI - Electropathological substrate detection of persistent atrial fibrillation--a novel method to analyze unipolar electrograms of noncontact mapping. AB - Radiofrequency catheter ablation as a curative method for atrial fibrillation (AF) has become increasingly popular. Patients with paroxysmal AF have been treated by catheter ablation with great success, but so far this treatment has been less effective for patients with persistent AF. Usually there are multiple triggers or substrates during persistent AF and their exact locations are unclear. On the other hand, the non-contact mapping system (Ensite 3000, St Jude Medical) producing thousands of virtual endocardial electrograms, has gradually become accepted as a powerful tool to use on patients before and after ablation. Effective mathematical tools to detect the substrates of AF from unipolar electrograms produced by the non-contact mapping are few, though many methods are available for performing this task with bipolar electrograms. In this work, we introduce for the first time a simple and efficient approach to automatically and systematically determine the substrate of persistent AF in order to guide catheter ablation via the non-contact mapping. PMID- 22254598 TI - Cardiovascular and respiratory regulation during sleep in patients with sleep apnea with and without hypertension. AB - Sleep is a physiological process with an internal program of a number of well defined sleep stages and intermediate wakefulness periods. The sleep stages do modulate the autonomous nervous system and thereby the sleep stages are accompanied by different regulation regimes for the cardiovascular and respiratory system. The differences in regulation can be distinguished by new analysis techniques on the recorded signals. In addition to normal sleep regulation some sleep disorders affect the cardiovascular and respiratory regulation. The most prevalent disorder linked to sleep and changes in the autonomous system is obstructive sleep apnea. In patients with obstructive sleep apnea marked short term changes in cardiovascular and respiratory regulation are observed during sleep. These abnormalities in regulation are further differentiated between the sleep stages. For long term changes obstructive sleep apnea is recognized as a major risk factor for arterial hypertension. Treatment of obstructive sleep apnea lowers blood pressure during the night and over time also lowers blood pressure during daytime. In this study we investigated 18 patients with sleep apnea and normal blood pressure, 10 patients with sleep apnea and arterial hypertension and 10 normal subjects as controls. Both patient groups were tested with cardiorespiratory polysomnography before and under CPAP therapy. The effects on cardiovascular and respiratory regulation during sleep and daytime are investigated in the three groups. PMID- 22254599 TI - Mapping sleep using coupled biological oscillations. AB - Sleep and wake state have different influences on a variety of recordable signals that make up the polysomnogram. Conventional sleep stages are dependent on analysis of electroencephalogram (EEG) waveforms. Non-EEG approaches can provide a different view of sleep. One such example is the electrocardiogram (ECG) derived sleep spectrogram, which computes the coupling and coherence of heart rate variability and respiratory tidal volume influences on the ECG R wave. Novel insights into sleep physiology and pathology are available through this technique. PMID- 22254600 TI - Sleep apnoea detection in children using PPG envelope-based dynamic features. AB - Photopletysmography signal has been developed for monitoring of Obstructive Sleep Apnoea, in particular, whenever an apneic episode occurs, that is reflected by decreases in the photopletysmography signal amplitude fluctuation. However, other physiological events such as artifacts and deep inspiratory gasp produce sympathetic activation, being unrelated to apnea. Thus, its high sensitivity can produce misdetections and overestimate apneic episodes. In this regard, a methodology for selecting a set of relevant non-stationary features to increase the specificity of the obstructive sleep apnea detector is discussed. A time evolving version of the standard linear multivariate decomposition is discussed to perform stochastic dimensionality reduction. As a result, performed outcomes of accuracy bring enough evidence that if using a subset of cepstral-based dynamic features, then patient classification accuracy is 83.3%. Therefore, photoplethysmography--based detection provides an adequate scheme for obstructive sleep apnea diagnosis. PMID- 22254601 TI - Monitoring ultradian changes in cardiorespiratory control in obstructive sleep apnea syndrome. AB - Spectral analysis of heart rate variability (HRV) is commonly employed to track changes in autonomic nervous system and respiratory activity during sleep. However, conventional HRV spectral indices can be seriously confounded by inter subject differences or intra-individual changes in ventilation and ventilatory pattern, especially in subjects with obstructive sleep apnea syndrome (OSAS). We highlight the approach we have undertaken to circumvent this problem by introducing "respiration-adjusted" spectral indices of HRV. Since fluctuations in sleep state also affect HRV considerably, we describe a method for combining the information derived from sleep staging and the information derived from cardiorespiratory measurements. We also introduce a new complementary index of autonomic function, BRS(PTT), based on measurements of heart period and pulse transit time. We demonstrate that this surrogate measure of baroreflex gain correlates well with the corresponding measures of baroreflex sensitivity based on noninvasive blood pressure measurements. Our experience to date suggests that BRS(PTT), along with respiration-adjusted spectral measures of HRV, are useful as clinical tools for assessing autonomic dysfunction in OSAS. PMID- 22254602 TI - Automatic detection of CAP on central and fronto-central EEG leads via Support Vector Machines. AB - The aim of this study is to implement a high-accuracy automatic detector of the Cyclic Alternating Pattern (CAP) during sleep. EEG data from four healthy subjects were used. Both the C4-A1 and the F4-C4 leads were analyzed for this study. Seven features were extracted from each of the two leads and two separate studies were performed for each set of descriptors. For both sets, a Support Vector Machine was trained and tested on the data with the Leave One Out cross validation method. The two final classifications obtained on the two sets were merged, by considering a CAP A phase scored only if it had been recognized both on the central and on the frontal lead. The length of the A phase was then determined by the result on the fronto-central lead. This method leads to encouraging results, with a classification sensitivity on the whole dataset equal to 73.82%, specificity equal to 85.93%, accuracy equal to 84,05% and Cohen's kappa equal to 0.50. PMID- 22254603 TI - CAP sleep in insomnia: new methodological aspects for sleep microstructure analysis. AB - This work aims to propose new methodologies for the quantitative characterization of insomnia. Sleep microstructure, as expressed by Cyclic Alternatic pattern (CAP) sleep, is studied and differences between normal sleepers and insomniacs are investigated. The dynamic in the structure of CAP activation events is studied by use of wavelet analysis and the content of events, i.e. EEG dynamics, is studied in terms of complexity analysis. Both in structure and content, features exhibiting statistically significant differences are proposed, opening new perspectives for the understanding and the quantitative characterization of sleep and its disorders. PMID- 22254604 TI - Classification between non-multiple fallers and multiple fallers using a triaxial accelerometry-based system. AB - Falls are a prominent problem facing older adults and a common cause of hospitalized injuries. Accurate falls-risk assessment and classification of falls risk levels will provide useful information for the prevention of future falls. This study presents a triaxial accelerometer (TA) based two-class classifier, which discriminates between multiple fallers and non-multiple fallers, using a directed-routine (DR) movement test. One-hundred-and-twenty-six features were extracted from the accelerometry signals, recorded during the DR tests using a waist mounted TA, from 68 subjects. A linear multiple regression model was employed to map a subset of these features to an estimate of the number of previous falls experienced in the preceding twelve months. A simple threshold is applied to this estimated number of falls to create a basic linear discriminant classifier to separate multiple from non-multiple fallers. The system attained an accuracy of 71% in classifying the exact number of falls experienced in the last 12 months and 97% in identifying multiple fallers. PMID- 22254605 TI - Characterization of maternal body movement during sleep before and after parturition. AB - The purpose of this study was to characterize the different features of body movements for females before and after parturition. Body movement signal was measured by a piezoelectric sensor board which was deployed on the abdominal position beneath a mattress during sleep to monitor pressure changes around abdominal area. Body movement epochs were detected by an innovative algorithm based on Hilbert transform. Data were collected from two healthy pregnant females during sleep for 7 weeks before parturition and 6 weeks after parturition. The pressure signal was used to determine the duration and time interval of maternal movements. Characteristics of the detected body movements before and after parturition were investigated through their proportion. The results showed that before and after parturition, the body movement which features as 0~1 min in interval and 0~6 sec in duration has significant difference statistically. It is considered that these differences are highly correlated with the prenatal activities. PMID- 22254606 TI - A wireless sensory feedback system for real-time gait modification. AB - Current rehabilitation technology and techniques have proven effective at modifying and correcting gait abnormalities. They are however limited to laboratory and clinical settings, under the supervision of a specialist. Conventional techniques for quantifying gait asymmetries can be combined with sensory feedback methods to provide an intuitive and inexpensive feedback system for extra-clinical rehabilitation. A wireless feedback system has been designed to collect gait information, process it in real-time, and provide corrective feedback to the user. The corrective feedback can be presented through visual, audible, or vibrotactile methods, or a combination thereof. Initial results have led to improvement in the sensory interface of the device to maximize the corrective influence on inexperienced subjects. These preliminary findings suggest that the wireless feedback device can influence the gait of the user, and effectively adapt to their personal feedback preferences. PMID- 22254607 TI - Analysis of time-series correlation between weighted lifestyle data and health data. AB - The time-series data analysis described here is based on the simple idea that the accumulation of the effects of lifestyle events, such as ingestion and exercise, could affect personal health with some delay. The delay may reflect complex bio reactions such as those of metabolism in a human body. In the analysis, the accumulation of the effects of lifestyle events is represented by a summation of daily lifestyle data whose time-series correlation to variations of health data is examined (healthcare-data-mining). The concept of weighting is introduced for the summation of daily lifestyle data. As a result, it is suggested that the nature of personal health could be represented by a weighting pattern characterized by a small number of parameters. PMID- 22254608 TI - Evaluation of a novel cardiac output index on healthy elderly, cardiovascular and heart failure patients during dynamic exercise. AB - We have recently proposed a novel CO index, namely pulse time reflection ratio (PTRR), which is extracted from photoplethysmogram and electrocardiogram and measurable from wearable devices, and proved that this index is potentially useful for dynamic CO monitoring in a preliminary study carried out on young, healthy subjects. In this study, we presented an evaluation of this technique against impedance cardiography on 64 subjects undergoing incremental maximal exercise testing, including 15 healthy elderly, 19 cardiovascular patients and 30 heart failure patients. Results showed significant intra-subject correlations (r) between PTRR and reference CO in all subjects (mean r: 0.93, p<0.05) and no significant differences on mean r among subject populations (one-way ANOVA, p=0.48). With further development and testing on mobile subjects, this technique can be applied for long-term CO monitoring at home or in other dynamic situations. PMID- 22254609 TI - An improved scheme of IPI-based entity identifier generation for securing body sensor networks. AB - Securing body sensor network (BSN) in an efficient manner is very important for preserving the privacy of medical data. Protecting data confidentiality, integrity and to authenticate the communicating nodes are basic requirements to secure BSN. The existing method to generate entity identifier (EI) from inter pulse intervals (IPIs) of heartbeats has its advantages in authenticating and identifying nodes, which however was found in this study that such generated EIs are not so resistant to attacks because of potential error patterns. This paper presents an improved scheme of IPI-based EI generation to eliminate the error patterns. The performance of randomness and node identification, i.e. false acceptance rate and false rejection rate, is experimentally evaluated. The results indicate that compared with the existing one, the new scheme is effective to eliminate the error patterns and thus more tolerant to attacks, while there is no compromise on the randomness level and identification performance. PMID- 22254610 TI - A collaborative awareness system for chronic disease medication adherence applied to HIV infection. AB - Electronic reminder systems have been available for decades, yet medication adherence remains poor. Most systems rely on simple alarms and do not address other determinants of health-related behavior. This paper describes a collaborative awareness system for chronic disease medication adherence that relies on patient self-reflection and clinician support. Visualizations of adherence performance, including estimated plasma concentration graphs and a dynamic, personalized, disease-state simulation, are available to the patient (cell phone and internet media display) and clinician (computer) in real-time. The clinician can send asynchronous video messages of advice and encouragement to the patient regularly. A pilot was conducted with four HIV positive patients for four weeks. Three patients who started with suboptimal adherence improved (93.0% to 99.1%, 83.0% to 96.3%, and 63.9% to 81.3%). One patient who started with optimal medication adherence (>95%) maintained this level. All four patients appreciated the rich feedback and wanted to continue using the system. PMID- 22254611 TI - A sensor network to iPhone interface separating continuous and sporadic processes in mobile telemedicine. AB - In this contribution, a new concept for interfacing sensor network nodes (motes) and smartphones is presented for the first time. In the last years, a variety of telemedicine applications on smartphones for data reception, display and transmission have been developed. However, it is not always practical or possible to have a smartphone application running continuously to accomplish these tasks. The presented system allows receiving and storing data continuously using a mote and visualizing or sending it on the go using the smartphone as user interface only when desired. Thus, the processes of data reception and storage run on a safe system consuming less energy and the smartphone's potential along with its battery are not demanded continuously. Both, system concept and realization with an Apple iPhone are presented. PMID- 22254612 TI - Mapping of multiple parameter m-health scenarios to mobile WiMAX QoS variables. AB - Multiparameter m-health scenarios with bandwidth demanding requirements will be one of key applications in future 4 G mobile communication systems. These applications will potentially require specific spectrum allocations with higher quality of service requirements. Furthermore, one of the key 4 G technologies targeting m-health will be medical applications based on WiMAX systems. Hence, it is timely to evaluate such multiple parametric m-health scenarios over mobile WiMAX networks. In this paper, we address the preliminary performance analysis of mobile WiMAX network for multiparametric telemedical scenarios. In particular, we map the medical QoS to typical WiMAX QoS parameters to optimise the performance of these parameters in typical m-health scenario. Preliminary performance analyses of the proposed multiparametric scenarios are evaluated to provide essential information for future medical QoS requirements and constraints in these telemedical network environments. PMID- 22254613 TI - Estimation of patient compliance in application of adherent mobile cardiac telemetry device. AB - In an in home usage outpatient setting, patient compliance is a key factor in determining the adoption and efficacy of treatment for any illness and is paramount for patient dependent medical technologies such as mobile patient monitoring systems. As a leader in the development of these technologies, Corventis has deployed its NUVANTTM Mobile Cardiac Telemetry System to thousands of patients around the world. The NUVANT system includes an externally worn adherent sensing device, the PiiX, whose proper application is critical to the on patient longevity and thus performance of the NUVANT system. Patient compliance in this context is a universal challenge for such patient-applied adherent devices. Understanding and tracking a problem is key to solving it and the integrated suite of vital sign sensors in the Corventis PiiX offers a unique opportunity for extracting patient application compliance information from the incoming health data. Analysis of data from 5000 randomly selected patients has shown that improper application of the PiiX is a factor in 2.3% of patients. However, no reduction in adherent device longevity or performance was observed. Such information is a valuable feedback metric for product design, instructions for use, packaging of medical technologies, level of customer support and replacement costs. PMID- 22254614 TI - Mobile health for drug dose optimisation. AB - Mobile health monitoring in the management of long term conditions has potential benefits for patient care, especially when coupled with active adjustment of medication dosage. We report studies of patient-led self-titration of oral glucose lowering medication (OGLM) and insulin in type 2 diabetes, and dose adjustments (including dose increases) in oral chemotherapy for metastatic colorectal or breast cancer. Monitoring compliance was high in each case, and the feasibility of patients self-titrating OGLM or insulin following an agreed treatment plan was demonstrated. Chemotherapy dose increases supported by detailed toxicity profiles collected by phone have also been demonstrated. PMID- 22254615 TI - Feasibility assessment of Doppler radar long-term physiological measurements. AB - In this paper we examine the feasibility of applying doppler radar technique for a long-term health monitoring. Doppler radar was used to detect and eliminate periods of significant motion. This technique was verified using a human study on 17 subjects, and it was determined that for 15 out of 17 subjects there was no significant motion for over 85% of the measurement interval in supine positions. Majority of subjects exhibited significantly less motion in supine position, which is promising for sleep monitoring, and monitoring of hospitalized patients. PMID- 22254616 TI - The era of micro and nano systems in the biomedical area: bridging the research and innovation gap. AB - The area of Micro and Nano systems (MNS) focuses on heterogeneous integration of technologies (e.g. electronics, mechanics and biotechnology) and implementation of multiple functionalities (e.g. sensing, processing, communication, energy and actuation) into small systems. A significant amount of MNS activities targets development and testing of systems enabling biomedicine and personal health solutions. Convergence of micro-nano-bio and Information & communication technologies is being leading to enabling innovative solutions e.g. for in-vitro testing and in vivo interaction with the human body for early diagnosis and minimally invasive therapy. Of particular interest are smart wearable systems such as smart textiles aiming at the full integration of sensors/actuators, energy sources, processing and communication within the clothes to enable non invasive personal health, lifestyle, safety and emergency applications. The paper presents on going major R&D activities on micro-nano-bio systems (MNBS) and wearable systems for pHealth under the European Union R&D Programs, Information and Communication Technologies (ICT) priority; it also identifies gaps and discusses key challenges for the future. PMID- 22254617 TI - Longitudinal monitoring of patients with Parkinson's disease via wearable sensor technology in the home setting. AB - Objective longitudinal monitoring of symptoms related motor fluctuations can provide valuable information for the clinical management of patients with Parkinson's disease. Current methods for long-term monitoring of motor fluctuations, such as patient diaries, are ineffective due to their time consuming and subjective nature. Researchers have shown that wearable sensors such as accelerometers can be used to gather objective information about a patient's motor symptoms. In this paper, we present preliminary results from our analysis on wearable sensor data gathered during longitudinal monitoring of 5 patients with PD. Our results indicate that it is possible to track longitudinal changes in motor symptoms by training a regression model based on Random Forests. PMID- 22254618 TI - Closing the loop for Deep Brain Stimulation implants enables personalized healthcare for Parkinson's disease patients. AB - DEEP brain stimulation implants have improved life quality for more than 70,000 patients world-wide with diseases like Parkinson's, essential tremor, or obsessive-compulsive disorder where pharmaceutical therapies alone could not offer sufficient relief. Still, optimization and monitoring relies heavily on regular clinical visits, putting a burden on patient's comfort and clinicians. Permanent monitoring and combination with other patient health signals could ultimately lead to a personalized closed-loop therapy with remote quality monitoring. This requires technological improvements on the DBS implants such as integration of recording capabilities for brain activity monitoring, active low power electronics, rechargeable battery technology, and body sensor networks for integration with e.g. gait, speech, and other vital information sensors on the patient's body and a link to a telemedicine platform using mobile technologies. PMID- 22254619 TI - Innovative self management system for guided cardiac rehabilitation. AB - This paper describes the design and development of a system for cardio rehabilitation of patients that suffered a myocardial infarction. The proposed solution focuses on exercise prescriptions and the encouragement of healthy behaviors. The innovative strategy of the design takes into account health promotion models to provide safe, assistive exercise training sessions, personalized feedbacks, and educational contents. PMID- 22254620 TI - An integrated advanced communication and coaching platform for enabling personalized management of chronic cardiovascular diseases. AB - Chronic cardiovascular diseases directly account for millions of deaths, billions of Euros and a big number of disabilities affecting the world's population. Even though primary and secondary prevention factors are well known, the awareness and the concern of citizens and patients is not big enough to cause a significant change in lifestyle that modifies the increasing trends. Patients and families, professionals and healthcare systems are not prepared to fight against this burden in an effective and aligned way. Some disease management programmes based on ICT solutions have and are currently being tested around the world but their relative impaction has been very limited. This paper proposes a new turn into Personal Health Systems applied to chronic disease management by increasing the capabilities for personalization, providing the patients with motivation and coaching support and enabling the work of the professionals with intelligent tools for strategic and clinical decision making based on the newest medical evidence. PMID- 22254621 TI - An ontology-based framework aiming to support personalized exercise prescription: application in cardiac rehabilitation. AB - Exercise constitutes an important intervention aiming to improve health and quality of life for several categories of patients. Personalized exercise prescription is a rather complicated issue, requiring several aspects to be taken into account, e.g. patient's medical history and response to exercise, medication treatment, personal preferences, etc. The present work proposes an ontology-based framework designed to facilitate healthcare professionals in personalized exercise prescription. The framework encapsulates the necessary domain knowledge and the appropriate inference logic, so as to generate exercise plan suggestions based on patient's profile. It also supports readjustments of a prescribed plan according to the patient's response with respect to goal achievement and changes in physical-medical status. An instantiation of the proposed framework for cardiac rehabilitation illustrates the virtue and the applicability of this work. PMID- 22254622 TI - On the interlimb coordination and synchronization during gait. AB - Human locomotion is based on the finely tuned coordination of the two legs. For this research, we studied the contribution of interlimb pathways for coordinating and synchronizing the legs' motion in the case where body weight is externally supported and vestibular feedback is limited. The experiments were conducted using a novel device intended for gait therapy: the MIT-Skywalker. The subject's body weight was supported by an underneath saddle-like seat, and a chest harness was used to provide stabilization of the torso. Two neurologically healthy individuals were asked to walk on the MIT-Skywalker, while one side of its split belt treadmill was unexpectedly dropped during the perturbed leg stance phase. Leg kinematics are reported as well as the effect of the timing of perturbation on the unperturbed leg. Presented here are the phase-response curves (PRCs) for both legs. We found that unilateral perturbations evoked responses at the contralateral limb, while the timing of the activation played a significant role in those responses. PMID- 22254623 TI - A multi-DOF robotic exoskeleton interface for hand motion assistance. AB - This paper outlines the design and development of a robotic exoskeleton based rehabilitation system. A portable direct-driven optimized hand exoskeleton system has been proposed. The optimization procedure primarily based on matching the exoskeleton and finger workspaces guided the system design. The selection of actuators for the proposed system has emerged as a result of experiments with users of different hand sizes. Using commercial sensors, various hand parameters, e.g. maximum and average force levels have been measured. The results of these experiments have been mapped directly to the mechanical design of the system. An under-actuated optimum mechanism has been analysed followed by the design and realization of the first prototype. The system provides both position and force feedback sensory information which can improve the outcomes of a professional rehabilitation exercise. PMID- 22254624 TI - Supinator Extender (SUE): a pneumatically actuated robot for forearm/wrist rehabilitation after stroke. AB - The robot described in this paper, SUE (Supinator Extender), adds forearm/wrist rehabilitation functionality to the UCI BONES exoskeleton robot and to the ArmeoSpring rehabilitation device. SUE is a 2-DOF serial chain that can measure and assist forearm supination-pronation and wrist flexion-extension. The large power to weight ratio of pneumatic actuators allows SUE to achieve the forces needed for rehabilitation therapy while remaining lightweight enough to be carried by BONES and ArmeoSpring. Each degree of freedom has a range of 90 degrees, and a nominal torque of 2 ft-lbs. The cylinders are mounted away from the patient's body on the lateral aspect of the arm. This is to prevent the danger of a collision and maximize the workspace of the arm robot. The rotation axis used for supination-pronation is a small bearing just below the subject's wrist. The flexion-extension motion is actuated by a cantilevered pneumatic cylinder, which allows the palm of the hand to remain open. Data are presented that demonstrate the ability of SUE to measure and cancel forearm/wrist passive tone, thereby extending the active range of motion for people with stroke. PMID- 22254625 TI - Treadmill motor current based anteroposterior force estimation using ground reaction force approximation depending on gait cycle. AB - We have been developing a new vehicle, "Tread-Walk 2 (TW-2)", which supports walking for the elderly. TW-2 is controlled by the natural walking movement. In our previous work, we tried to estimate the user's anteroposterior force from the motor current value without a force sensor in order to possible to have a more intuitive operability of TW-2. But, a user of this vehicle experienced some discomfort both when he started walking and when he stopped walking. This problem is caused by inaccurate estimation of the user's anteroposterior force at the heel contact and the toe off. The estimation of the user's anteroposterior force is greatly related to inaccurate estimation of the vertical component of the ground reaction force, which is approximated by the square waveform in the stance phase. In order to construct a control algorithm to improve the operability of TW 2, we accurately estimated the user's anteroposterior force. We therefore proposed the new method to approximate the vertical force in order to estimate the user's anteroposterior force accurately. This paper describes the new method to approximate the waveforms of the vertical forces as isosceles trapezoidal waves with a slope changed depending on the change of the walking velocity. By comparing the estimated anteroposterior force using the new method with the measured value using the force plate, for two young subjects whose physical characteristics were different, the waveform pattern of the estimated force was found to be similar to that of the measured force. This showed that the proposed method could possibly be useful for accurate estimation of anteroposterior force. PMID- 22254626 TI - Pelvis motion analysis for gait phase estimation toward leg-dependent body weight support at different walking speed. AB - Gait phase based body weight support can be an effective method for patients who possess different ability in each leg and who require different unloading forces between the affected and unaffected sides. To realize this concept, we proposed a gait phase estimation method from pelvic motion focusing on the feature of its quasi-periodic movement at constant walking speeds. In this study, we analyzed the relationship between the turning point of pelvic motion and the heel contact point at different walking speeds. The values of time lag were not constant at different walking speeds; rather they declined as walking speed increased. In addition, the results indicate that the turning points of lateral movement and vertical movement always occurred in advance of heel contact under 6.0 (km/h). Under this condition, the gait phase estimation method can be adopted if the time lag values at different walking speeds are prerecorded. PMID- 22254627 TI - Disturbance road adaptive driving control of power-assisted wheelchair using fuzzy inference. AB - This paper describes a novel driving control scheme of electric power-assisted wheelchairs for assistive driving on various large disturbance roads. The "electric power-assisted wheelchair" which assists the driving force by electric motors is expected to be widely used as a mobility support system for elderly people and disabled people; however, there are lots of large disturbance roads such as uphill roads and rough roads and operators need to row the hand-rims with the larger power load on such roads in order to obtain the enough driving velocity. For example the wheelchair might move backward on uphill roads due to the driving torque shortage. Therefore this study proposes a fuzzy algorithm based adaptive control scheme in order to realize the assistive driving without the operator's power load on large disturbance roads. The proposed fuzzy rules are designed from the driving distance information and the control parameters are inferred by the fuzzy algorithm. The assisted torque can be adjusted so that the enough distance and velocity are kept even on large disturbance roads. Driving experimental results are provided to verify the effectiveness of the proposed control system. PMID- 22254628 TI - Evaluation of modal analysis techniques using physical models to detect osseointegration of implants in transfemoral amputees. AB - Non-invasive vibration analysis has been used extensively to monitor the progression of dental implant healing and stabilization. It is now being considered as a method to monitor femoral implants in transfemoral amputees. This paper evaluates two modal analysis excitation methods and investigates their capabilities in detecting changes at the interface between the implant and the bone that occur during osseointegration. Excitation of bone-implant physical models with the electromagnetic shaker provided higher coherence values and a greater number of modes over the same frequency range when compared to the impact hammer. Differences were detected in the natural frequencies and fundamental mode shape of the model when the fit of the implant was altered in the bone. The ability to detect changes in the model dynamic properties demonstrates the potential of modal analysis in this application and warrants further investigation. PMID- 22254629 TI - Optimal tracking of a sEMG based force model for a prosthetic hand. AB - This paper presents a surface electromyographic (sEMG)-based, optimal control strategy for a prosthetic hand. System Identification (SI) is used to obtain the dynamic relation between the sEMG and the corresponding skeletal muscle force. The input sEMG signal is preprocessed using a Half-Gaussian filter and fed to a fusion-based Multiple Input Single Output (MISO) skeletal muscle force model. This MISO system model provides the estimated finger forces to be produced as input to the prosthetic hand. Optimal tracking method has been applied to track the estimated force profile of the Fusion based sEMG-force model. The simulation results show good agreement between reference force profile and the actual force. PMID- 22254630 TI - Decoding of individuated finger movements using surface EMG and input optimization applying a genetic algorithm. AB - In this paper we present surface electromyo-graphic (EMG) data collected from 16 channels on five unimpaired subjects and one transradial amputee performing 12 individual finger movements and a rest class. EMG were processed using a traditional Time Domain feature-set and classifiers: a Linear Discriminant Analysis (LDA) a k-Nearest Neighbors (k-NN) and Support Vector Machine (SVM). Using continuous datasets we show that it is possible to achieve an accuracy up to 80% across subjects. Thereafter possibilities to reduce the numbers of channels physically required, as well as the number of features have been investigated by means of a developed Genetic Algorithm (GA) that included a bonus system to reward eliminated features and channels. The classification was performed firstly on the full datasets and in later runs using the GA. The GA demonstrated high redundancy in the recorded 16 channel data as well as the insignificance of certain features. Although the GA optimization yielded to reduce 8 to 11 channels depending on the subject, such reduction had little to no effect on the classification accuracies. PMID- 22254631 TI - Biomechanical consideration based on the unrestrained gait measurement of trans femoral amputee with a prosthetic limb. AB - Trans-femoral amputees must regain moving pattern by refined rehabilitation program using loads applied on a prosthetic limb. On the other hand, understanding those loads is indispensable for biomechanical consideration of trans-femoral amputees. However, conventional prosthetic gait training systems cannot measure long continuous walking motions. In this paper, loads applied on trans-femoral prosthesis are measured by the prosthetic gait training system for the unrestrained gait measurement. As a result of the experiments, the patterns of moments about the medio-lateral axis are remarkably different among the six activities. Finally, the effectiveness of the developed prosthetic gait training system to analyze biomechanics in trans-femoral prosthesis is validated. PMID- 22254632 TI - Control of a myoelectric arm considering cooperated motion of elbow and shoulder joints. AB - In order to improve the quality of life of persons who lost their limb due to an accident or a sickness, many myoelectric artificial arms have been proposed. To control the motion of the elbow joint of the myoelectric arm, the EMG signals of the biceps brachii and the triceps brachii muscles are frequently used as input signals. However, since both muscles are the biarticular muscles between the shoulder joint and elbow joint, the amount of the EMG signals of these muscles are affected by the motion of the shoulder joint. In this paper, a control method for a myoelectric arm is proposed in order to cancel the influence of the shoulder joint motion on EMG signals is removed by using the neuro-fuzzy modifier in order to realize proper elbow motion. The effectiveness of the proposed method has been evaluated by performing experiments. PMID- 22254633 TI - Influence of the weight actions of the hand prosthesis on the performance of pattern recognition based myoelectric control: preliminary study. AB - In transradial amputees, the muscles in the residual forearm naturally employed by the unimpaired for flexing/extending the hand fingers, are the most appropriate targets, for multi-fingered prostheses control. However, once the prosthetic socket is manufactured and fitted on the residual forearm, the recorded EMG might not be originated only by the intention of performing finger movements, but also by the muscular activity needed to sustain the prosthesis itself. In this work, we preliminary show--on healthy subjects wearing a prosthetic socket emulator--that (i) variations in the weight of the prosthesis, and (ii) upper arm movements significantly influence the robustness of a traditional classifier based on k-nn algorithm. We show in simulated conditions that traditional pattern recognition systems do not allow the separation of the effects of the weight of the prosthesis because a surface recorded EMG pattern caused by the simple lifting or moving of the prosthesis is misclassified into a hand control movement. This suggests that a robust classifier should add to myoelectric signals, inertial transducers like multi-axes position, acceleration sensors or sensors able to monitor the interaction forces between the socket and the end-effector. PMID- 22254634 TI - Seizure prediction in epilepsy: from circadian concepts via probabilistic forecasting to statistical evaluation. AB - Seizure prediction performance is hampered by high numbers of false predictions. Here we present an approach to reduce the number of false predictions based on circadian concepts. Based on eight representative patients we demonstrate that this approach increases the performance considerably. The fraction of patients for whom we found a significant seizure prediction performance was increased from 25% to 38% by accounting for circadian dependencies. PMID- 22254635 TI - Hardware for seizure prediction: towards wearable devices to support epileptic people. AB - This paper presents the hardware developed for the EPILEPSIAE project (www.epilepsiae.eu), focused on epileptic seizure prediction. A portable low power acquisition system for EEG signals, called LTM-EU (Long Term Monitoring), with 64 channels and 2048 Hz sampling rate each and a safe (high isolation) PC interface on a PCIe bus specifically designed for this task, is described. The acquisition system, designed for a rapid commercialization, though used for research purposes, got the CE certification. The signal from the patient, on each channel, is amplified, converted in digital form and stored into a local flash memory (SD-MMC, 4 GB). Data are then formatted into a serial stream at 4 Mb/s and sent through a half-duplex RS485 link to the host where a specifically designed PCIe (BQPCIe) interface receive them and release the information to the OS (Windows or Linux). The amplifier runs with a couple of AA battery for more than 15 hours (300 mW). If a wireless link is established (Bluetooth), a bandwidth limited stream of data (or a subset of channels) is sent for monitoring purposes. The mission is to support the researchers of the consortium with a suitable hardware to have a real time seizure prediction system for algorithms tests. In the experimental phase all algorithms run on a portable PC, wire or wireless connected to the acquisition system. PMID- 22254636 TI - Probing cortical excitability using cross-frequency coupling in intracranial EEG recordings: a new method for seizure prediction. AB - The need of a reliable seizure prediction is motivated by the 50 million people in the world suffering from epilepsy, of whom 30% have no control on seizures with current pharmacological treatments. Seizure prediction research holds great promise for such patients, since an effective algorithm will enable the development of a closed-loop system that intervenes before the clinical onset of a seizure. As a step toward practical implementation of this technology, we present a new method based on a measure of brain excitability identified by couplings between low-frequency phases and high-frequency amplitudes of brain oscillations. The proposed method was applied to long-term intracranial recordings of 20 patients with partial epilepsy, for a total of 267 seizures and more than 3400-hour-long interictal activities. We found that our predictor was in 50% of cases better than chance, with an average sensitivity of 98.9% and false prediction rate of 1.84/hour. From these observations, we concluded that our method enables a new quantitative way to identify preictal states with a high risk of seizure generation. PMID- 22254637 TI - Optimized feature subsets for epileptic seizure prediction studies. AB - The reduction of the number of EEG features to give as inputs to epilepsy seizure predictors is a needed step towards the development of a transportable device for real-time warning. This paper presents a comparative study of three feature selection methods, based on Support Vector Machines. Minimum-Redundancy Maximum Relevance, Recursive Feature Elimination, Genetic Algorithms, show that, for three patients of the European Database on Epilepsy, the most important univariate features are related to spectral information and statistical moments. PMID- 22254638 TI - A low complexity seizure prediction algorithm. AB - A new low complexity seizure prediction algorithm is proposed. The algorithm achieves high sensitivity and low false positive rates in 10 out of 18 epileptic patients from the Freiburg database. Its primary achievement is two orders of magnitude computational complexity reduction. The reduced complexity makes an implantable medical device application realizable. In the subset of ten highly predictable patients average sensitivity is 96%, average specificity is 0.25 false positives per hour, and 13.5% of time is spent in false alarms. For all eighteen patients tested, the average sensitivity is 83%, the average specificity is 0.38 false positives per hour, and the amount of time spent in false alarms is 21.1%. This result may be compared with sensitivity of 97.5%, specificity of 0.27 false positives per hour, and 13% of time is spent in false alarms of prior results without complexity reduction. PMID- 22254639 TI - Probing for cortical excitability. AB - This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus via intracranial electroencephalography (iEEG). Stimuli consisted of 100 single bi-phasic pulses, delivered every 10 minutes. Neural excitability is estimated by extracting a feature from the iEEG responses to the stimuli, which we dub the mean phase variance (PV). We show that the mean PV increases with the rate of inter-ictal discharges in one patient. In another patient, we show that the mean PV changes with sleep and an epileptic seizure. The results demonstrate a proof-of-principal for the method to be applied in a seizure anticipation framework. PMID- 22254640 TI - A point process approach for analyzing gait variability dynamics. AB - We present a novel statistical paradigm for modeling and analysis of gait variability which captures the natural point process structure of gait intervals and allows for definition of new measures instantaneous mean and standard deviation. We validate our model using two existing data sets from physionet.org. Results show an excellent model fit and yield insights into the underlying statistical structure behind human gait. Statistical analyses further corroborate previous findings of increased variability in gait at different speeds, both self paced and metronome-paced, and reveal a significant increase in gait variability in Parkinson's subjects, as compared to young and elderly healthy subjects. These results indicate the validity of a point process approach to the analysis of gait, and the potential utility of incorporating instantaneous measures of gait into diagnostic or patient monitoring applications. PMID- 22254641 TI - Statistical analysis of gait maturation in children based on probability density functions. AB - Analysis of gait patterns in children is useful for the study of maturation of locomotor control. In this paper, we utilized the Parzen-window method to estimate the probability density functions (PDFs) of the stride interval for 50 children. With the estimated PDFs, the statistical measures, i.e., averaged stride interval (ASI), variation of stride interval (VSI), PDF skewness (SK), and PDF kurtosis (KU), were computed for the gait maturation in three age groups (aged 3-5 years, 6-8 years, and 10-14 years) of young children. The results indicated that the ASI and VSI values are significantly different between the three age groups. The VSI is decreased rapidly until 8 years of age, and then continues to be decreased at a slower rate. The SK values of the PDFs for all of the three age groups are positive, which shows a slight imbalance in the stride interval distribution within each age group. In addition, the decrease of the KU values of the PDFs is age-dependent, which suggests the effects of the musculo skeletal growth on the gait maturation in young children. PMID- 22254642 TI - Multivariate nonlinear regression analysis of trajectory tracking performance using force reflecting joystick in chronic stroke-induced hemiparesis. AB - Individualizing a neurorehabilitation training protocol requires understanding the performance of subjects with various capabilities under different task settings. We use multivariate regression to evaluate the performance of subjects with stroke-induced hemiparesis in trajectory tracking tasks using a force reflecting joystick. A nonlinear effect was consistently shown in both dimensions of force field strength and impairment level for selected kinematic performance measures, with greatest sensitivity at lower force fields. This suggests that the form of a force field may play a different "role" for subjects with various impairment levels, and confirms that to achieve optimized therapeutic benefit, it is necessary to personalize interfaces. PMID- 22254643 TI - Identification of nocturnal movements during sleep using the non-contact under mattress bed sensor. AB - This paper describes the calculation of statistical, spatial and spatiotemporal features from a novel non-contact technology for sleep monitoring, the Under Mattress Bed Sensor (UMBS). Data was collected from two relatively healthy adults with a possible sleep disorder in a clinical setting. Methods for the extraction of statistical data describing overall bed restlessness, a spatial description of movement (centre and spread of pressure) and a spatiotemporal description of each in-bed body movement over the entire sleeping episode are discussed using the pressure sensing grid. These provide a quantitative description of sleep and restlessness throughout the night. PMID- 22254644 TI - The frequency of saccades correlates to peak velocity in symmetrical disparity vergence. AB - A pure vergence stimulus requires the two eyes to turn equally inward or outward theoretically resulting in a pure symmetrical vergence response. However, saccades, a rapid conjugate eye movement, are frequently observed in vergence responses. This investigation sought to systematically quantify whether the occurrence of saccades within symmetrical vergence responses is correlated to vergence peak velocity. Eye movements are quantified using a limbus tracking system from three subjects. Symmetrical convergence and divergence 4 degrees step responses with an initial position located at far or near which are known to evoke different peak velocities are analyzed. Data are quantified via peak velocity. A saccade detecting algorithm is utilized to quantify the frequency of saccades in the transient portion (first second) of vergence responses. Near convergence responses are slower than far convergence and far divergence responses are slower compared to near divergence movements. The occurrence of saccades is negatively correlated to vergence peak velocity. When the velocity is slower, the number of saccades increases. This study suggests that the brain may initiate a saccade to facilitate a slow vergence movement, potentially to allow object recognition before binocular fusion. PMID- 22254645 TI - Vibrotactile stimulation of the upper leg: effects of location, stimulation method and habituation. AB - In this study vibrotactile stimulation of the upper leg and its usability for feedback was tested. Three experiments were performed on ten healthy subjects using pager motors. The first experiment was to test the perception of the vibration at different frequencies and at different locations of the upper leg. The second experiment tested the ability of subjects to estimate location and number of stimuli in an array. In addition it was evaluated whether simultaneous or sequential stimulation is better interpretable. Thirdly the habituation of the vibration was determined. The experiments showed that vibrotactile stimulation is well perceived and can be useful in providing feedback on the upper leg. Further experiments are needed to determine the effectiveness of vibrotactile stimulation for feedback in trans-femoral prostheses. PMID- 22254646 TI - Image-based estimation of ventricular fiber orientations for patient-specific simulations. AB - Patient-specific simulation of heart (dys)function aimed at personalizing cardiac therapy are hampered by the absence of in vivo imaging technology for clinically acquiring myocardial fiber orientations. In this research, we develop a methodology to predict ventricular fiber orientations of a patient heart, given the geometry of the heart and an atlas. We test the methodology by comparing the estimated fiber orientations with measured ones, and by quantifying the effect of the estimation error on outcomes of electrophysiological simulations, in normal and failing canine hearts. The new insights obtained from the project will pave the way for the development of patient-specific models of the heart that can aid physicians in personalized diagnosis and decisions regarding electrophysiological interventions. PMID- 22254647 TI - Experimental validation of alternating transillumination for imaging intramural wave propagation. AB - Current techniques to map intramural activation patterns in ex vivo cardiac tissue have limited spatial resolution. Here, we report on the experimental validation of a novel optical technique that was recently proposed to resolve the size and depth of intramural wave fronts using alternating transillumination (AT). AT was achieved by simultaneously mapping the epi- and endocardial surfaces with two synchronized CCD cameras and rapidly alternating LED illumination between both surfaces. Optical phantoms were made based on tissue optical properties measured using a hybrid optical spectrometer. Spherical fluorescent sources (Scarlet microspheres, Invitrogen, UK) of varying sizes were embedded at known depths in the phantoms. Coronary-perfused procine left ventricular slab preparations were stained with DI-4-ANBDQBS (n = 3) and paced at known intramural depths. In phantoms we were able to reliably estimate the depth of the center of fluorescent sources (9.6 +/- 5.4% error), as well as their transmural extent (15.7 +/- 11.5% error). In ventricular slabs we were able to localize the sites of origin of intramural excitation waves with a precision of +/- 1.6 mm. Transmural conduction velocities were, for the first time, measured optically from the surfaces and found to be 21.0 +/- 12.4 cm/s. In conclusion, alternating transillumination is a promising technique for reliable reconstruction of depth and expansion rate of intramural activation wave fronts in cardiac tissue. PMID- 22254648 TI - An optimization framework for inversely estimating myocardial transmembrane potentials and localizing ischemia. AB - By combining a static bidomain heart model with a torso conduction model, we studied the inverse electrocardiographic problem of computing the transmembrane potentials (TMPs) throughout the myocardium from a body-surface potential map, and then used the recovered potentials to localize myocardial ischemia. Our main contribution is solving the inverse problem within a constrained optimization framework, which is a generalization of previous methods for calculating transmembrane potentials. The framework offers ample flexibility for users to apply various physiologically-based constraints, and is well supported by mature algorithms and solvers developed by the optimization community. By avoiding the traditional inverse ECG approach of building the lead-field matrix, the framework greatly reduces computation cost and, by setting the associated forward problem as a constraint, the framework enables one to flexibly set individualized resolutions for each physical variable, a desirable feature for balancing model accuracy, ill-conditioning and computation tractability. Although the task of computing myocardial TMPs at an arbitrary time instance remains an open problem, we showed that it is possible to obtain TMPs with moderate accuracy during the ST segment by assuming all cardiac cells are at the plateau phase. Moreover, the calculated TMPs yielded a good estimate of ischemic regions, which was of more clinical interest than the voltage values themselves. We conducted finite element simulations of a phantom experiment over a 2D torso model with synthetic ischemic data. Preliminary results indicated that our approach is feasible and suitably accurate for the common case of transmural myocardial ischemia. PMID- 22254649 TI - Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the rabbit heart. AB - Ventricular arrhythmias represent one of leading causes for sudden cardiac death, a significant problem in public health. Noninvasive imaging of cardiac electric activities associated with ventricular arrhythmias plays an important role in better our understanding of the mechanisms and optimizing the treatment options. The present study aims to rigorously validate a novel three-dimensional (3-D) cardiac electrical imaging (3-DCEI) technique with the aid of 3-D intra-cardiac mapping during paced rhythm and ventricular tachycardia (VT) in the rabbit heart. Body surface potentials and intramural bipolar electrical recordings were simultaneously measured in a closed-chest condition in thirteen healthy rabbits. Single-site pacing and dual-site pacing were performed from ventricular walls and septum. VTs and premature ventricular complexes (PVCs) were induced by intravenous norepinephrine (NE). The non-invasively imaged activation sequence correlated well with invasively measured counterparts, with a correlation coefficient of 0.72 and a relative error of 0.30 averaged over all paced beats and NE-induced PVCs and VT beats. The averaged distance from imaged site of initial activation to measured site determined from intra-cardiac mapping was ~5mm. These promising results suggest that 3-DCEI is feasible to non-invasively localize the origins and image activation sequence of focal ventricular arrhythmias. PMID- 22254650 TI - Slowed propagation across the compacta-trabeculata interface: a consequence of fiber and sheet anisotropy. AB - Transmural myocardial activation is influenced by myocardial structure, including structural differences between the compacta (Cta) and the trabeculata (Tta), although this has not been fully explained. Hearts from rats were Langendorff perfused, stained with DI-4-ANEPPS, the apex was cut off and fluorescence acquired from the exposed short-axis surface. The hearts were stimulated at 160 ms cycle length at the anterior, lateral, posterior left ventricle (LV) and septal sub-epicardial sites. Conduction velocity perpendicular to the wave front orientation was measured in each pixel using a gradient-based approach. After optical mapping the cut surface was imaged using a light microscope and the extent of the Cta and Tta mapped and validated against 50 u, m isotropic MRI images. We used a 3D rat ventricle computational model, with architecture obtained from 200 u, m isotropic diffusion tensor MRI and kinetics from the modified Pandit model to determine the relative roles of fibers and sheets on propagation. We show in the experimental study that circumferential propagation around the LV cavity is fast in the Cta: 63.2+/-19.5 and is slower in the Tta: 32.7+/-11.0(*) (mean +/- s.d cms-1, * p < 0.01 by two sample t test). In the simulation study the pattern and velocity are not replicated in an isotropic model (I), are partially replicated in a simulation study including fiber anisotropy (A) and is more fully replicated in orthotropic (O) ventricles (fiber and sheet anisotropy), where the circumferential propagation velocity is, I: Cta: 54.2+/-3.9; Tta:54.3+/-3.9; A: Cta:43.6+/-3.2; Tta: 40.6+/-6.6; O: Cta: 63.2+/ 19.5; Tta: 32.7+/-11.9(*). We show that sheet orientation is important in understanding activation differences between Cta and Tta. PMID- 22254652 TI - Application of higher order cumulants to ECG signals for the cardiac health diagnosis. AB - Electrocardiogram (ECG) is the P-QRS-T wave which indicates the electrical activity of the heart. The subtle changes in the amplitude and duration of the ECG signal depict the cardiac abnormality. It is very difficult to decipher these minute changes by the naked eye. Hence, a computer-aided diagnosis system will help the physicians to monitor the cardiac health. The ECG is a nonlinear and non stationary signal. Hence, the hidden information in the ECG signal can be extracted using nonlinear method. In this paper, we have automatically classified normal and abnormal beats using higher order spectra (HOS) cumulants of wavelet packet decomposition (WPD). The abnormal beats are ventricular premature contractions (VPC) and Atrial premature contractions (APC). These HOS cumulant features of the WPD are subjected to principal component analysis (PCA) to reduce the number of features to five. Finally these features were fed to the support vector machine (SVM) with kernel functions for automatic classification. In our work, we have obtained the highest accuracy of 98.4% sensitivity and specificity of 98.9% and 98.0% respectively with radial basis function (RBF) kernel function and Meyer's wavelet (dmey) function. Our system is ready clinically to run on large amount of data sets. PMID- 22254651 TI - Electrophysiological models for the heterogeneous canine atria: computational platform for studying rapid atrial arrhythmias. AB - Heterogeneity in the electrical action potential (AP) properties can provide a substrate for atrial arrhythmias, especially at rapid pacing rates. In order to quantify such substrates, we develop a family of detailed AP models for canine atrial cells. An existing model for the canine right atrial (RA) myocyte was modified based on electrophysiological data from dog to create new models for the canine left atrium (LA), the interatrial Bachmann's bundle (BB), and the pulmonary vein (PV). The heterogeneous AP models were incorporated into a tissue strand model to simulate the AP propagation, and used to quantify conditions for conduction abnormalities (primarily, conduction block at rapid pacing rated) in the canine atria. PMID- 22254653 TI - HRV response of vegetative state patient with music therapy. AB - This case study centered on the effects of Music Therapy (MT) on vegetative state (VS) patients for a continuous 41-day experiment with electrocardiogram (ECG) recorded. Mahler's Second Symphony was used for this MT. There are various elements in Mahler's second symphony, with string, wind, drum, and even voice; providing the subject a strong and dynamic stimulation. There are some significant changes after 14-day stimulation: both standard deviation of all normal RR intervals (SDNN) and root mean square successive differences (RMSSD) in heart rate variability of the subject increased, indicating the activity of the cardiovascular system was enhanced. Although there's only one subject in this experiment, the results are still encouraging. PMID- 22254654 TI - Twin-peak effect in both cardiac response and tempo of popular music. AB - How the musical tempo affects the performance of heart rate variability (HRV) was studied in this work. By understanding the relationship between the HRV response and the music tempo with decreasing tempo from 140 to 70 beats per minute (bpm) periodically in six successive weeks. There were two groups in the experiment, one was listening drum loop music 3 minutes in the middle of experiment and the other was just rest for 20 minutes. After the processed the information from the objects, the distribution of difference of HRV response between before and after listening various tempo drum loop was similar to the distribution of modern popular music in tempo. Both distributions have the twin peaks about 70-85 and 110-125 bpm. PMID- 22254655 TI - Detection of cardiac arrest using a simplified frequency analysis of the impedance cardiogram recorded from defibrillator pads. AB - An algorithm based only on the impedance cardiogram (ICG) recorded through two defibrillation pads, using the strongest frequency component and amplitude, incorporated into a defibrillator could determine circulatory arrest and reduce delays in starting cardiopulmonary resuscitation (CPR). Frequency analysis of the ICG signal is carried out by integer filters on a sample by sample basis. They are simpler, lighter and more versatile when compared to the FFT. This alternative approach, although less accurate, is preferred due to the limited processing capacity of devices that could compromise real time usability of the FFT. These two techniques were compared across a data set comprising 13 cases of cardiac arrest and 6 normal controls. The best filters were refined on this training set and an algorithm for the detection of cardiac arrest was trained on a wider data set. The algorithm was finally tested on a validation set. The ICG was recorded in 132 cardiac arrest patients (53 training, 79 validation) and 97 controls (47 training, 50 validation): the diagnostic algorithm indicated cardiac arrest with a sensitivity of 81.1% (77.6-84.3) and specificity of 97.1% (96.7 97.4) for the validation set (95% confidence intervals). Automated defibrillators with integrated ICG analysis have the potential to improve emergency care by lay persons enabling more rapid and appropriate initiation of CPR and when combined with ECG analysis they could improve on the detection of cardiac arrest. PMID- 22254656 TI - Automatic sleep spindles detection--overview and development of a standard proposal assessment method. AB - Since the 1970s, various automatic sleep spindles procedures have been implemented and presented in the literature. Unfortunately, their results are not easily comparable because the databases, the assessment methods and the terminologies employed are often radically different. In this study, we propose a systematic assessment method for any automatic sleep spindles detection algorithm. We apply this assessment method to our own automatic detection process in order to illustrate and legitimate its use. We obtain a global sensitivity of 70.20%, for a false positive proportion (relative to the total number of visually scored sleep spindles) of only 26.44% (False positive rate = 1.38% and specificity = 98.62%). PMID- 22254657 TI - Induced gamma activity in EEG represents cognitive control during detecting emotional expressions. AB - Cognitive control of emotion plays an important role in maintaining emotional stability in people's daily life. However, the neural mechanism remains unclear. This study examined the induced gamma activity in response to emotional expressions which was associated with the cognitive regulation. Electroencephalogram (EEG) was recorded in fifteen normal subjects when detecting emotional expressions. The mean energy was estimated using time-frequency representations in two gamma bands, low gamma band (25-50 Hz) and high gamma band (50-70 Hz), and eight time windows from 0 to 800 ms after the stimulus onset. Two typical gamma activities were observed: (1) the early gamma activity in the 100 200 ms time window was attenuated along with the increased detection difficulty, reflecting the bottom-up attention regulation; (2) the late gamma activity after 400 ms post-stimulus was enhanced with the increased detection difficulty, reflecting the top-down cognitive control. The characteristics of the induced early gamma activity distinguished different mechanisms of attention regulation in the early stage for detecting the negative expression and detecting the positive one. Our study suggested the induced gamma activity was a useful tool to uncover the mechanism of cognitive control of emotion. PMID- 22254658 TI - Correcting for serial dependence in studies of respiratory dynamics. AB - Understanding the physiological impact of drug treatments on patients is important in assessing their performance and determining possible side effects. While this effect might be best determined in individual subjects, conventional methods assess treatment performance by averaging a physiological measure of interest before and after drug administration for n subjects. Summarizing large numbers of time-series observations in two means for each subject in this way results in significant information loss. Treatment effect can instead be analyzed in individual subjects. Because serial dependence of observations from the same animal must then be considered, methods that assume independence of observations, such as the t-test and z-test, cannot be used. We address this issue in the case of respiratory data collected from anesthetized rats that were injected with a dopamine agonist. In order to accurately assess treatment effect in time-series data, we begin by formulating a method of conditional likelihood maximization to estimate the parameters of a first-order autoregressive (AR) process. We show that treatment effect of a dopamine agonist can be determined while incorporating serial effect into the analysis. In addition, while maximum likelihood estimators of a large sample with independent observations may converge to an asymptotically normal distribution, this result of large sample theory may not hold when observations are serially dependent. In this case, a parametric bootstrap comparison can be used to approximate an appropriate measure of uncertainty. PMID- 22254659 TI - Analysis of the respiratory flow cycle morphology in chronic heart failure patients applying principal components analysis. AB - The study of flow cycle morphology provides new information about the breathing pattern. This study proposes the characterization of cycle morphology in chronic heart failure patients (CHF) patients, with periodic (PB) and non-periodic breathing (nPB) patterns, and healthy subjects. Principal component analysis is applied to extract a respiratory cycle model for each time segment defined by a 30-s moving window. To characterize morphology of the model waveform, a number of parameters are extracted whose significance is evaluated in terms of the following three classification problems: CHF patients with either PB or nPB, CHF patients versus healthy subjects, and nPB patients versus healthy subjects. 26 CHF patients (8 with PB and 18 with non-periodic breathing pattern (nPB)) and 35 healthy subjects are studied. The results show that a respiratory cycle compressed in time characterizes PB patients, i.e., shorter inspiratory and expiratory periods, and higher dispersion of the maximum inspiratory and expiratory flow value (accuracy of 87%). The maximal expiratory flow instant occurs earlier in CHF patients than in healthy subjects (accuracy of 87%), with a steeper slope between inspiration and expiration. It is also found that the standard deviation of the expiratory period, evaluated for each subject, is much lower in CHF patients than in healthy subjects. The maximal expiratory flow instant occurs earlier (accuracy of 84%) in nPB patients, when comparing subjects with similar respiratory pattern like nPB patients and healthy subjects. PMID- 22254660 TI - Distilling clinically interpretable information from data collected on next generation wearable sensors. AB - Medical electronic systems are generating ever larger data sets from a variety of sensors and devices. Such systems are also being packaged in wearable designs for easy and broad use. The large volume of data and the constraints of low-power, extended-duration, and wireless monitoring impose the need for on-chip processing to distill clinically relevant information from the raw data. The higher-level information, rather than the raw data, is what needs to be transmitted. We present one example of information processing for continuous, high-sampling-rate data collected from wearable and portable devices. A wearable cardiac and motion monitor designed by colleagues at MIT simultaneously records electrocardiogram (ECG) and 3-axis acceleration to onboard memory, in an ambulatory setting. The acceleration data is used to generate a continuous estimate of physical activity. Additionally, we use a Portapres continuous blood pressure monitor to concurrently record the arterial blood pressure (ABP) waveform. To help reduce noise, which is an increased challenge in ambulatory monitoring, we use both the ECG and ABP waveforms to generate a robust measure of heart rate from noisy data. We also generate an overall signal abnormality index to aid in the interpretation of the results. Two important cardiovascular quantities, namely cardiac output (CO) and total peripheral resistance (TPR), are then derived from this data over a sequence of physical activities. CO and TPR can be estimated (to within a scale factor) from heart rate, pulse pressure and mean arterial blood pressure, which in turn are directly obtained from the ECG and ABP signals. Data was collected on 10 healthy subjects. The derived quantities vary in a manner that is consistent with known physiology. Further work remains to correlate these values with the cardiac health state. PMID- 22254661 TI - Ensemble classification for robust discrimination of multi-channel, multi-class tongue-movement ear pressure signals. AB - In this paper we introduce a robust classification framework for tongue-movement ear pressure signals based around an ensemble voting methodology. The ensemble members are comprised of different combinations of sensor inputs i.e. two in-ear microphones and an acoustic gel sensor positioned under the chin of the individual and classification using three different base models. It is shown that by using all nine ensemble members when compared to the individual (base) models, the average misclassification rate can be reduced from 23% to 2.8% when using the majority voting strategy. The correct classification rate is improved from 76% to 92.4% when utilizing either the borda count or condorcet methods. This is achieved through a combination of rejection based on ambiguity in the ensemble and diversity in the misclassified instances across the ensemble members. PMID- 22254662 TI - Improved signal processing techniques for the analysis of high resolution serosal slow wave activity in the stomach. AB - High resolution electrical mapping of slow waves on the stomach serosa has improved our understanding of gastric electrical activity in normal and diseased states. In order to assess the signals acquired from high resolution mapping, a robust framework is required. Our framework is semi-automated and allows for rapid processing, analysis and interpretation of slow waves via qualitative and quantitative measures including isochronal activation time mapping, and velocity and amplitude mapping. Noise removal techniques were validated for raw recorded signals, where three filters were evaluated for baseline drift removal and three filters for removal of high frequency interference. For baseline drift removal, the Gaussian moving median filter was most effective, while for eliminating high frequency interference the Savitzky Golay filter was the most effective. Methods for assessing slow wave velocity and amplitude were investigated. To estimate slow wave velocity, a finite difference approach with interpolation and smoothing was used. To evaluate the slow wave amplitude and width, a peak and trough method based on Savitzky Golay derivative filters was used. Together, these methods constitute a significantly improved framework for analyzing gastric high resolution mapping data. PMID- 22254663 TI - A framework for the online analysis of multi-electrode gastric slow wave recordings. AB - High resolution mapping of electrical activity is becoming an important technique for analysing normal and dysrhythmic gastrointestinal (GI) slow wave activity. Several methods are used to extract meaningful information from the large quantities of data obtained, however, at present these methods can only be used offline. Thus, all analysis currently performed is retrospective and done after the recordings have finished. Limited information about the quality or characteristics of the data is therefore known while the experiments take place. Building on these offline analysis methods, an online implementation has been developed that identifies and displays slow wave activations working alongside an existing recording system. This online system was developed by adapting existing and novel signal processing techniques and linking these to a new user interface to present the extracted information. The system was tested using high resolution porcine data, and will be applied in future high resolution mapping studies allowing researchers to respond in real time to experimental observations. PMID- 22254664 TI - Analysis of nocturnal oxygen saturation recordings using kernel entropy to assist in sleep apnea-hypopnea diagnosis. AB - In this study, a new entropy measure known as kernel entropy (KerEnt), which quantifies the irregularity in a series, was applied to nocturnal oxygen saturation (SaO(2)) recordings. A total of 96 subjects suspected of suffering from sleep apnea-hypopnea syndrome (SAHS) took part in the study: 32 SAHS negative and 64 SAHS-positive subjects. Their SaO(2) signals were separately processed by means of KerEnt. Our results show that a higher degree of irregularity is associated to SAHS-positive subjects. Statistical analysis revealed significant differences between the KerEnt values of SAHS-negative and SAHS-positive groups. The diagnostic utility of this parameter was studied by means of receiver operating characteristic (ROC) analysis. A classification accuracy of 81.25% (81.25% sensitivity and 81.25% specificity) was achieved. Repeated apneas during sleep increase irregularity in SaO(2) data. This effect can be measured by KerEnt in order to detect SAHS. This non-linear measure can provide useful information for the development of alternative diagnostic techniques in order to reduce the demand for conventional polysomnography (PSG). PMID- 22254665 TI - Do anthropometric parameters change the characteristics of snoring sound? AB - Snoring sounds is commonly known to be associated with obstructive sleep apnea (OSA). There are many studies trying to distinguish between the snoring sounds of non-OSA and those of OSA patients. However, OSA is only one of the conditions that affect the structure of upper airway. In this study, we investigated the effect of anthropometric parameters on the snoring sounds. Since snoring sounds are non-Gaussian signals by nature, we derived its Higher Order Statistical (HOS) features and investigated the statistical significance of the anthropometric parameters on each of these features. Data were collected from 40 patients with different levels of OSA. Tracheal respiratory sounds collected by a microphone placed over suprasternal notch, were recorded simultaneously with full-night Polysomnography (PSG) data during sleep. The snoring segments were identified semi-automatically from respiratory sounds using an unsupervised snore detection algorithm. The bispectrum of each SS segment was estimated. We calculated two common HOS measures, Skewness and Kurtosis, plus a new feature called Projected Median Bifrequency (PMBF) from the SS segments. Then, we investigated the statistical relationship between these features and anthropometric parameters such as height, Body Mass Index (BMI), age, gender, and Apnea-Hypopnea Index (AHI). The result showed that gender, BMI, height, and AHI are the parameters that do change the characteristics of snoring sounds significantly. PMID- 22254666 TI - Synchronization of sacral skin blood flow oscillations in response to local heating. AB - Local heating causes an increase in skin blood flow by activating sensory axon reflex and metabolic nitric oxide controls. It has been observed that the remote skin area without temperature changes also shows a slightly increase in blood flow. The responsible mechanism of this indirect vasodilation remains unclear. We hypothesized that the remote skin area will have enhanced synchronization of blood flow oscillations (BFO), thus inducing a vasodilatory response. We studied BFO in two sites separated 10 cm of the sacral skin in 12 healthy people. Ensemble empirical mode decomposition method was used to decompose blood flow signals into a set of intrinsic mode functions (IMFs), and an IMF was selected to quantify each of myogenic, neurogenic, and metabolic modes of BFO. Then the instantaneous phase of the mode was calculated using the Hilbert transform. From the time series of phase difference between a pair of characteristic modes, we detected the epochs of phase synchronization and estimated the level of statistical significance using surrogate time series. The results showed that phase synchronization between neurogenic BFO was significantly higher in the period of the maximal vasodilation. We also observed a weak synchronization between myogenic BFO of the two skin sites. Our results suggested that synchronization of BFO may be associated with the changes in skin blood flow at the non-heated site. PMID- 22254667 TI - Matrix completion based ECG compression. AB - An innovative electrocardiogram compression algorithm is presented in this paper. The proposed method is based on matrix completion, a new paradigm in signal processing that seeks to recover a low-rank matrix based on a small number of observations. The low-rank matrix is obtained via normalization of electrocardiogram records. Using matrix completion, the ECG data matrix is recovered from a few number of entries, thereby yielding high compression ratios comparable to those obtained by existing compression techniques. The proposed scheme offers a low-complexity encoder, good tolerance to quantization noise, and good quality reconstruction. PMID- 22254668 TI - Low-complexity R-peak detection in ECG signals: a preliminary step towards ambulatory fetal monitoring. AB - Non-invasive fetal health monitoring during pregnancy has become increasingly important. Recent advances in signal processing technology have enabled fetal monitoring during pregnancy, using abdominal ECG recordings. Ubiquitous ambulatory monitoring for continuous fetal health measurement is however still unfeasible due to the computational complexity of noise robust solutions. In this paper an ECG R-peak detection algorithm for ambulatory R-peak detection is proposed, as part of a fetal ECG detection algorithm. The proposed algorithm is optimized to reduce computational complexity, while increasing the R-peak detection quality compared to existing R-peak detection schemes. Validation of the algorithm is performed on two manually annotated datasets, the MIT/BIH Arrhythmia database and an in-house abdominal database. Both R-peak detection quality and computational complexity are compared to state-of-the-art algorithms as described in the literature. With a detection error rate of 0.22% and 0.12% on the MIT/BIH Arrhythmia and in-house databases, respectively, the quality of the proposed algorithm is comparable to the best state-of-the-art algorithms, at a reduced computational complexity. PMID- 22254669 TI - Regularity analysis of spontaneous MEG activity in Attention Deficit/Hyperactivity Disorder. AB - The aim of this study was to analyze the magnetoencephalography (MEG) background activity in Attention-Deficit/Hyperactivity Disorder (ADHD) using a regularity measure: sample entropy (SampEn). Five minutes of recording were acquired with a 148-channel whole-head magnetometer in 14 ADHD patients and 14 control subjects. Our results showed that ADHD patients' MEGs were more regular than controls' recordings. Additionally, there were statistically significant differences (p < 0.01, Student's t-test with Bonferroni's correction) at the five analyzed brain areas: anterior, central, posterior, left lateral and right lateral. Using receiver operating characteristic (ROC) curves, the highest accuracy (82.14%) was achieved at posterior region, whereas the highest area under the ROC curves (0.8827) were reached at anterior and central brain regions. These results suggest the usefulness of SampEn to reveal an abnormal type of dynamics associated with ADHD. PMID- 22254670 TI - Use of electrical devices reveals our well being. AB - We want to objectivize the level of activity of elderly persons living independently at home. Most existing monitoring systems are intrusive and/or require a large number of sensors. We hope the "ubiquitous computing" concept could find an application in this context. We proposed to monitor the use of electrical appliances. We built a unique "activity indicator" which integrates all the activities of the person. This was assessed during 6 months within 12 flats occupied by single elderly persons. PMID- 22254671 TI - Towards a single sensor passive solution for automated fall detection. AB - Falling in the home is one of the major challenges to independent living among older adults. The associated costs, coupled with a rapidly growing elderly population, are placing a burden on healthcare systems worldwide that will swiftly become unbearable. To facilitate expeditious emergency care, we have developed an artificially intelligent camera-based system that automatically detects if a person within the field-of-view has fallen. The system addresses concerns raised in earlier work and the requirements of a widely deployable in home solution. The presented prototype utilizes a consumer-grade camera modified with a wide-angle lens. Machine learning techniques applied to carefully engineered features allow the system to classify falls at high accuracy while maintaining invariance to lighting, environment and the presence of multiple moving objects. This paper describes the system, outlines the algorithms used and presents empirical validation of its effectiveness. PMID- 22254672 TI - Smart homes to improve the quality of life for all. AB - A home is smart when, being aware of its own state and that of its users, is capable of controlling itself in order to support the user wishes and thus improving their quality of life. This holds both for users with special needs and for those with ordinary domestic needs. In this paper, we overview the Smart Homes for All project which represents the current state of the art with respect to software control and user interfaces in the smart homes arena. PMID- 22254673 TI - Modelling of distributed activity recognition in the home environment. AB - Distributed ambient and on-body sensor systems can provide a suitable basis for recognizing complex human activities in daily life. Moreover, distributed activity recognition systems have high prospects for handling processing and communication loads more effectively than centralized solutions. A key challenge is to construct distributed activity recognition systems that make efficient use of the resources available for the recognition task, considering scalability and dynamic system reconfiguration. In this work, we present an approach to distributed activity recognition by introducing an activity-event-detector (AED) concept. We show formally how to construct and use AED for distributed recognition systems based on directed acyclic graphs. We illustrate essential properties for system scalability and efficiency using AED graphs. Results from a home monitoring study targeted at monitoring daily life activities are presented to illustrate the AED-based model regarding applicability and reconfiguration. PMID- 22254674 TI - Ambient Assisted Living spaces validation by services and devices simulation. AB - The design of Ambient Assisted Living (AAL) products is a very demanding challenge. AAL products creation is a complex iterative process which must accomplish exhaustive prerequisites about accessibility and usability. In this process the early detection of errors is crucial to create cost-effective systems. Computer-assisted tools can suppose a vital help to usability designers in order to avoid design errors. Specifically computer simulation of products in AAL environments can be used in all the design phases to support the validation. In this paper, a computer simulation tool for supporting usability designers in the creation of innovative AAL products is presented. This application will benefit their work saving time and improving the final system functionality. PMID- 22254675 TI - Review of wireless sensors networks in health applications. AB - Wireless Sensor Networks (WSN) are becoming increasingly important for telemedicine applications, monitoring patients both in the clinical setting and at home. They reduce user discomfort, enhance mobility and reduce costs. WSN are also fundamental in Ambient Assisted Living (AAL) since these smart systems, which are tailored to users needs, collect information about users and their ambient in order to provide personalized feedback. Despite the growing use of wireless communications in the health domain and in AAL systems there is a lack of research literature reviewing trials of these technologies. This paper provides a systematic review of the use of WSN in the health domain, presenting current WSN implementations. It covers 126 papers, of which 26 are studies, classified according to inclusion criteria. There is presented a discussion about the recent research conducted in the field. PMID- 22254676 TI - A semi-supervised Hidden Markov model-based activity monitoring system. AB - Most existing human activity classification systems require a large training dataset to construct statistical models for each activity of interest. This may be impractical in many cases. In this paper, we proposed a semi-supervised HMM based activity monitoring system, that adapts the HMM for a specific subject from a general model in order to alleviate the requirement of a large training data set. In addition, using two triaxial accelerometers, our system not only identifies simple events such as sitting, standing and walking, but also recognizes the behavior or a more complex activity by temporally linking the events together. Experimental results demonstrate the feasibility of our proposed system. PMID- 22254677 TI - Towards mental stress detection using wearable physiological sensors. AB - Early mental stress detection can prevent many stress related health problems. This study aimed at using a wearable sensor system to measure physiological signals and detect mental stress. Three different stress conditions were presented to a healthy subject group. During the procedure, ECG, respiration, skin conductance, and EMG of the trapezius muscles were recorded. In total, 19 physiological features were calculated from these signals. After normalization of the feature values and analysis of correlations among these features, a subset of 9 features was selected for further analysis. Principal component analysis reduced these 9 features to 7 principal components (PCs). Using these PCs and different classifiers, a consistent classification accuracy between stress and non stress conditions of almost 80% was found. This suggests that a promising feature subset was found for future development of a personalized stress monitor. PMID- 22254678 TI - Wearable sensor platform and mobile application for use in cognitive behavioral therapy for drug addiction and PTSD. AB - We present a wearable sensor platform designed for monitoring and studying autonomic nervous system (ANS) activity for the purpose of mental health treatment and interventions. The mobile sensor system consists of a sensor band worn on the ankle that continuously monitors electrodermal activity (EDA), 3-axis acceleration, and temperature. A custom-designed ECG heart monitor worn on the chest is also used as an optional part of the system. The EDA signal from the ankle bands provides a measure sympathetic nervous system activity and used to detect arousal events. The optional ECG data can be used to improve the sensor classification algorithm and provide a measure of emotional "valence." Both types of sensor bands contain a Bluetooth radio that enables communication with the patient's mobile phone. When a specific arousal event is detected, the phone automatically presents therapeutic and empathetic messages to the patient in the tradition of Cognitive Behavioral Therapy (CBT). As an example of clinical use, we describe how the system is currently being used in an ongoing study for patients with drug-addiction and post-traumatic stress disorder (PTSD). PMID- 22254679 TI - A low-power multi-modal body sensor network with application to epileptic seizure monitoring. AB - Monitoring patients' physiological signals during their daily activities in the home environment is one of the challenge of the health care. New ultra-low-power wireless technologies could help to achieve this goal. In this paper we present a low-power, multi-modal, wearable sensor platform for the simultaneous recording of activity and physiological data. First we provide a description of the wearable sensor platform, and its characteristics with respect to power consumption. Second we present the preliminary results of the comparison between our sensors and a reference system, on healthy subjects, to test the reliability of the detected physiological (electrocardiogram and respiration) and electromyography signals. PMID- 22254680 TI - Assessment of Bradykinesia in Parkinson's disease patients through a multi parametric system. AB - The aim of this paper is to describe and present the results of the automatic detection and assessment of bradykinesia in motor disease patients using wireless, wearable accelerometers. The current work is related to a module of the PERFORM system, a FP7 project from the European Commission, that aims at providing an innovative and reliable tool, able to evaluate, monitor and manage patients suffering from Parkinson's disease. The assessment procedure was carried out through a developed C# library that detects the activities of the patient using an activity recognition algorithm and classifies the data using a Support Vector Machine trained with data coming from previous test phases. The accuracy between the output of the automatic detection and the evaluation of the clinician both expressed with the Unified Parkinson's disease Rating Scale, presents an average value of [68.3 +/- 8.9]%. A meta-analysis algorithm is used in order to improve the accuracy to an average value of [74.4 +/- 14.9]%. Future work will include a personalized training of the classifiers in order to achieve a higher level of accuracy. PMID- 22254681 TI - Evaluation of a radio based ADL interaction recognition system in a day hospital for old age psychiatry with healthy probands. AB - In this contribution the evaluation of a system called "Eventlogger" is presented, which is installed in a day hospital for old age psychiatry. The Eventlogger is a radio based module with an adjustable communication range, able to recognize interaction of the user with objects or with other people. It is intended to function as a monitoring tool for the users' activities. Due to the demographic change monitoring systems for elderly people become more important. In this paper the "simple activities of daily living" (sADL) is introduced as well as the evaluation for the recognition of sADL in a day hospital for old age psychiatry with healthy probands is presented. Together with the first approaches of post processing for better results it is shown that the system is now ready to be used with patients of the day hospital for old age psychiatry. PMID- 22254682 TI - A telerehabilitation platform for home-based automated therapy of arm function. AB - Constraint-Induced Movement Therapy (CI therapy) has been shown to be an effective approach for improving arm function in stroke survivors with mild to severe hemiparesis. Given the time-intensive nature of the intervention, and the inherent costs and travel required to receive in-clinic treatment, the accessibility and availability of CI therapy is limited. To facilitate home-based CI therapy, a telerehabilitation platform has been developed. It consists of a table-top workstation configured with a range of physical task devices (e.g. pegboard, object flipping, threading, vertical reaching). A desktop PC is used to acquire data from sensors embedded in the task devices; display visual instructions, stimuli, and feedback to the patient during tasks; and provide videoconferencing and remote connection capabilities so the therapist can interact with and monitor the patient during at-home therapy sessions. This system has potential to greatly expand access to CI therapy and make it a more realistic option for a larger number of stroke survivors with upper extremity impairment. PMID- 22254683 TI - Home-based system for stroke rehabilitation. AB - A system was developed for home-based stroke motor rehabilitation of the ankle. A study was conducted to test the hypothesis that moving while concentrating will lead to greater recovery than movement alone. Sixteen post-stroke subjects participated, one half in a tracking training group and the other have in a move group. The tracking training group tracked a target waveform by moving their ankle to control the tracking cursor while the move group moved their ankle approximately the same amount but without target following. Over four weeks subjects completed 3600 trials. The results showed that the Tracking group had more improvement in ankle dorsiflexion compared to the Move group. The remaining assessment criteria showed no significant differences between the groups. PMID- 22254684 TI - A low cost, adaptive mixed reality system for home-based stroke rehabilitation. AB - This paper presents a novel, low-cost, real-time adaptive multimedia environment for home-based upper extremity rehabilitation of stroke survivors. The primary goal of this system is to provide an interactive tool with which the stroke survivor can sustain gains achieved within the clinical phase of therapy and increase the opportunity for functional recovery. This home-based mediated system has low cost sensing, off the shelf components for the auditory and visual feedback, and remote monitoring capability. The system is designed to continue active learning by reducing dependency on real-time feedback and focusing on summary feedback after a single task and sequences of tasks. To increase system effectiveness through customization, we use data from the training strategy developed by the therapist at the clinic for each stroke survivor to drive automated system adaptation at the home. The adaptation includes changing training focus, selecting proper feedback coupling both in real-time and in summary, and constructing appropriate dialogues with the stroke survivor to promote more efficient use of the system. This system also allows the therapist to review participant's progress and adjust the training strategy weekly. PMID- 22254685 TI - Development and evaluation of low cost game-based balance rehabilitation tool using the Microsoft Kinect sensor. AB - The use of the commercial video games as rehabilitation tools, such as the Nintendo WiiFit, has recently gained much interest in the physical therapy arena. Motion tracking controllers such as the Nintendo Wiimote are not sensitive enough to accurately measure performance in all components of balance. Additionally, users can figure out how to "cheat" inaccurate trackers by performing minimal movement (e.g. wrist twisting a Wiimote instead of a full arm swing). Physical rehabilitation requires accurate and appropriate tracking and feedback of performance. To this end, we are developing applications that leverage recent advances in commercial video game technology to provide full-body control of animated virtual characters. A key component of our approach is the use of newly available low cost depth sensing camera technology that provides markerless full body tracking on a conventional PC. The aim of this research was to develop and assess an interactive game-based rehabilitation tool for balance training of adults with neurological injury. PMID- 22254686 TI - Long-term hand tele-rehabilitation on the PlayStation 3: benefits and challenges. AB - Rehabilitation interventions for the hand have shown benefits for children with Hemiplegia due to cerebral palsy or traumatic brain injury. Longer interventions are facilitated if training is provided in the patient's home, due to easier access to care and reduced impact on school or work activities. Providing remote rehabilitation over lengthy periods of time has however its own challenges. This paper presents two pediatric patients with hemiplegia, who practiced virtual hand rehabilitation games using a modified PlayStation 3 and 5DT sensing gloves. Despite severe initial hand spasticity, and occasional technology shortcomings, the subjects practiced for about 14 months, and 6 months, respectively. Game performance data for the second patient is presented. Follow-up evaluations 14 months from the removal of the PlayStation 3 from the home of the child with cerebral palsy showed that the patient had good retention in terms of grasp strength, hand function and bone health. Challenges of long-term home tele rehabilitation are also discussed. PMID- 22254687 TI - Usability testing of a mobile robotic system for in-home telerehabilitation. AB - Mobile robots designed to enhance telepresence in the support of telehealth services are being considered for numerous applications. TELEROBOT is a teleoperated mobile robotic platform equipped with videoconferencingcapabilities and designed to be used in a home environment to. In this study, learnability of the system's teleoperation interface and controls was evaluated with ten rehabilitation professionals during four training sessions in a laboratory environment and in an unknown home environment while performing the execution of a standardized evaluation protocol typically used in home care. Results show that the novice teleoperators' performances on two of the four metrics used (number of command and total time) improved significantly across training sessions (ANOVAS, p<0.05) and that performance in these metrics in the last training session reflected teleoperation abilities seen in the unknown home environment during navigation tasks (r=0,77 and 0,60). With only 4 hours of training, rehabilitation professionals were able learn to teleoperate successfully TELEROBOT. However teleoperation performances remained significantly less efficient then those of an expert. Under the home task condition (navigating the home environment from one point to the other as fast as possible) this translated to completion time between 350 seconds (best performance) and 850 seconds (worse performance). Improvements in other usability aspects of the system will be needed to meet the requirements of in-home telerehabilitation. PMID- 22254689 TI - A band-tunable, multichannel amplifier for neural recording with AP/LFP separation and dual-threshold adaptive AP detector. AB - This article presents a low-power low-noise neural recording system comprising a set of 4-channel amplifiers and a dual-threshold adaptive action potential detector. The front-end amplifier is optimized for power efficiency, noise, and silicon area. A balanced tunable pseudo-resistor is used to acquire local field potential (LFP) and action potential (AP) separately. The post-layout simulation results show that the system achieved input referred noise 4.7 MUVrms and noise efficiency factor (NEF) 2.79 with mid-band gain of 51.9 dB and power consumption of 5.22 MUW. The bandwidth is highly tunable in the range of 2.38 Hz-300 Hz for high-pass corner and 248 Hz-12.9 kHz for low-pass corner, which can acquire AP and LPF without out-band noise. The proposed dual-threshold adaptive AP detector can capture action potential precisely from background activity, thus data reduction can be realized by only processing these significant waveforms. The results show that the proposed low-power, low-noise biomedical system is suitable for implantable device applications. PMID- 22254688 TI - Cole parameter estimation from total right side electrical bioimpedance spectroscopy measurements--influence of the number of frequencies and the upper limit. AB - Applications based on measurements of Electrical Bioimpedance Spectrocopy (EBIS) analysis are proliferating. The most spread and known application of EBIS is the non-invasive assessment of body composition. Fitting to the Cole function to obtain the Cole parameters, R(0) and R(infinity), is the core of the EBIS analysis to obtain the body fluid distribution. An accurate estimation of the Cole parameters is essential for the Body Composition Assessment (BCA) and the estimation process depends on several factors. One of them is the upper frequency limit used for the estimation and the other is the number of measured frequencies in the measurement frequency range. Both of them impose requirements on the measurement hardware, influencing largely in the complexity of the bioimpedance spectrometer. In this work an analysis of the error obtained when estimating the Cole parameters with several frequency ranges and different number of frequencies has been performed. The study has been done on synthetic EBIS data obtained from experimental Total Right Side (TRS) measurements. The results suggest that accurate estimations of R(0) and R(infinity) for BCA measurements can be achieved using much narrower frequency ranges and quite fewer frequencies than electrical bioimpedance spectrometers commercially available nowadays do. PMID- 22254690 TI - Comparison of performance parameters for conventional and localized surface plasmon resonance graphene biosensors. AB - This paper investigates the enhancement of the sensitivity and adsorption efficiency of a localized surface plasmon resonance (LSPR) biosensor that includes a layer of graphene sheet on top of the gold layer. For this purpose, biomolecular interactions of biotin-streptavidin with the graphene layer on the gold thin film are monitored. The performance of the LSPR graphene biosensor is theoretically and numerically assessed in terms of sensitivity and adsorption efficiency under varying conditions, including the thickness of biomolecule layer, number of graphene layers and operating wavelength. Enhanced sensitivity and improved adsorption efficiency are obtained for the LSPR graphene biosensor in comparison with its conventional counterpart. It is found that the LSPR graphene biosensor has better sensitivity with lower operating wavelength and larger number of graphene layers. PMID- 22254691 TI - Effect of temperature changes on the performance of ionic strength biosensors based on hydrogels and pressure sensors. AB - Stimuli responsive hydrogels show a strong ability to change in volume with changes in selected environmental properties. This tendency of these hydrogels to change in volume is captured as pressure-change in confined cavities of pressure sensors. An array of pressure sensors on a single chip may carry hydrogels sensitive to multiple, selected metabolic markers and continuously monitor multiple vital parameters simultaneously. Currently, such sensors are capable of continuously monitoring pH, ionic strength, glucose levels and temperature in the sensor environment. In this paper, we report the effect of temperature changes on the performance of ionic strength sensor. A formulation of hydrogel that renders it sensitive to changes in ionic strength was UV polymerized in situ in piezoresistive pressure sensors with different membrane sizes. The sensor sensitivity, response time and stability are investigated as a function of temperature in vitro. The effect of temperature on these sensor characteristics is discussed. PMID- 22254692 TI - An ultra-low-power filtering technique for biomedical applications. AB - This paper describes an ultra-low-power filtering technique for biomedical applications designated as T-wave sensing in heart-activities detection systems. The topology is based on a source-follower-based Biquad operating in the sub threshold region. With the intrinsic advantages of simplicity and high linearity of the source-follower, ultra-low-cutoff filtering can be achieved, simultaneously with ultra low power and good linearity. An 8(th)-order 2.4-Hz lowpass filter design example optimized in a 0.35-MUm CMOS process was designed achieving over 85-dB dynamic range, 74-dB stopband attenuation and consuming only 0.36 nW at a 3-V supply. PMID- 22254693 TI - Efficient magnetic torque transduction in biological environments using tunable nanomechanical resonators. AB - Electromagnetic interactions with biological systems promise new possibilities in medical applications and synthetic biology. Creating a controlled action in biological systems requires an efficient transduction of the electromagnetic energy to thermal or mechanical biosignals. In this paper, we present the design and optimization for a nano-scale magnetic torque transducer based on a tunable nanomechanical resonator. Operating in the resonance regime allows the presented system to efficiently absorb a large amount of energy from the source. In addition, systems tuned on well separated resonance frequencies may operate simultaneously without any interference. We describe the theoretical model of the system and show the possibility of achieving the resonance in biological settings for a system with reasonable dimensions. PMID- 22254694 TI - Skin-electrode contact area in electrical bioimpedance spectroscopy. Influence in total body composition assessment. AB - Electrical Bioimpedance Spectroscopy (EBIS) has been widely used for assessment of total body composition and fluid distribution. (EBIS) measurements are commonly performed with electrolytic electrodes placed on the wrist and the ankle with a rather small skin-electrode contact area. The use of textile garments for EBI requires the integration of textrodes with a larger contact area surrounding the limbs in order to compensate the absence of electrolytic medium commonly present in traditional Ag/AgCl gel electrodes. Recently it has been shown that mismatch between the measurements electrodes might cause alterations on the EBIS measurements. When performing EBIS measurements with textrodes certain differences have been observed, especially at high frequencies, respect the same EBIS measurements using Ag/AgCl electrodes. In this work the influence of increasing the skin-electrode area on the estimation of body composition parameters has been studied performing experimental EBIS measurement. The results indicate that an increment on the area of the skin-electrode interface produced noticeable changes in the bioimpedance spectra as well as in the body composition parameters. Moreover, the area increment showed also an apparent reduction of electrode impedance mismatch effects. This influence must be taken into consideration when designing and testing textile-enable EBIS measurement systems. PMID- 22254695 TI - Assessing electrical impedance alterations in spinal muscular atrophy via the finite element method. AB - Electrical impedance myography (EIM) is a surface-based, non-invasive technique of evaluation of muscle health, involving the application of high frequency, low amplitude current to the skin over a muscle of interest. Results from a previous animal study suggest that the finite element method can relate disease-induced changes in electrical properties of the muscle to alterations in surface impedance measurements; however, whether such an approach will prove useful in human models is uncertain. Therefore, to further investigate this question, we have created a single finite element model of the human biceps muscle using data from one healthy subject and one with spinal muscular atrophy (SMA), each of whom had comparable age, limb girth, muscle size, and subcutaneous fat thickness. Since healthy human tissue was unavailable, permittivity and conductivity measurements were obtained from five healthy and five advanced amyotrophic lateral sclerosis rat gastrocnemius muscles immediately after sacrifice; their data were input into the human biceps model and the expected surface voltages calculated. We then compared the results of this model to the actual surface EIM data for both individuals. Although the actual resistance and reactance values varied and the peak values were displaced, the resulting maximum phase predicted by the model approximated that obtained with surface recordings. These results support that alterations in the primary characteristics of muscle impact the surface impedance measurements in meaningful and likely predictable ways. PMID- 22254696 TI - Heart rate, oxygen saturation, and skin conductance: a comparison study of acute pain in Brazilian newborns. AB - Heart rate variability (HRV), oxygen saturation variability (OSV) and skin conductance activity (SCA) are recognized physiological markers of acute pain. In order to verify which of them has the best correlation with psychophysical parameters of pain (intensity, reactivity, direction, regulation and slope), an observational prospective study was performed, including 41 healthy full term newborns. The measurements studied were the HRV, the OSV, and the following SCA variables: number of waves per second (NWps) and relative area under the curve of waves (AUC). The measurements were performed in periods labeled before, during, and after a heel prick. The variation measured for intensity between periods was significant for the NWps (p=0.001), AUC (p=0.03), HRV (p=0.001) and OSV (p=0.004). Also, the reactivity and direction were significant for all variables, except AUC. The regulation parameter was significant for the variables NWps (p<0.01), AUC (p<0.05), HRV (p<0.01) and OSV (p<0.01). The slope was statistically significant only for the OSV variable (p=0.000). We concluded that the responses of the SCA, HRV and OSV to painful events fit the psychophysical parameters of a physiological marker and serve as valuable measures for pain diagnostic working the use in accordance with the needs of the context. PMID- 22254697 TI - A miniaturized pressure sensor with inherent biofouling protection designed for in vivo applications. AB - The design, fabrication, and measurement results for a diaphragm-based single crystal silicon sensor element of size 820 MUm * 820 MUm * 500 MUm are presented. The sensor element is designed for in vivo applications with respect to size and measurement range. Moreover, it is optimized for longtime operation in the human body through a built-in protection preventing biofouling on the piezoresistors. The sensitivity is about 20 mV/V for a change from 500 to 1500 mbar absolute pressure. This result is comparable to conventional sized micromachined pressure sensors. The output signal is not found to be influenced by exposure to 60 degrees C for three hours, a normal temperature load for a typical sterilization process for medical devices (Ethylene Oxide Sterilization). The hysteresis is low; < 0.25% of full scale output signal. The sensor element withstands an overload pressure of 3000 mbar absolute pressure. Observed decrease in the output signal with temperatures and observed nonlinearity can easily be handled by traditional electronic compensation techniques. PMID- 22254698 TI - Design of a instrumentation module for monitoring ingestive behavior in laboratory studies. AB - The development of accurate and objective tools for monitoring of ingestive behavior (MIB) is one of the most important needs facing studies of obesity and eating disorders. This paper presents the design of an instrumentation module for non-invasive monitoring of food ingestion in laboratory studies. The system can capture signals from a variety of sensors that characterize ingestion process (such as acoustical and other swallowing sensors, strain sensor for chewing detection and self-report buttons). In addition to the sensors, the data collection system integrates time-synchronous video footage that can be used for annotation of subject's activity. Both data and video are simultaneously and synchronously acquired and stored by a LabVIEW-based interface specifically developed for this application. This instrumentation module improves a previously developed system by eliminating the post-processing stage of data synchronization and by reducing the risks of operator's error. PMID- 22254699 TI - Low cost electroencephalographic acquisition amplifier to serve as teaching and research tool. AB - We described the development and testing of a low cost, easily constructed electroencephalographic (EEG) acquisition amplifier for noninvasive Brain Computer Interface (BCI) education and research. The acquisition amplifier was constructed from newly available off-the-shelf integrated circuit components, and readily sends a 24-bit data stream via USB (Universal Serial Bus) to a computer platform. We demonstrate here the hardware's use in the analysis of a visually evoked P300 paradigm for a choose one-of-eight task. This clearly shows the applicability of this system as a low cost teaching and research tool. PMID- 22254700 TI - 2-Scale topography dry electrode for biopotential measurements. AB - The design and fabrication of a novel 2-scale topography dry electrode using macro and micro needles is presented. The macro needles enable biopotential measurements on hairy skin, the function of the micro needles is to decrease the electrode impedance even further by penetrating the outer skin layer. Also, a fast and reliable impedance characterization protocol is described. Based on this impedance measurement protocol, a comparison study is made between our dry electrode, 3 other commercial dry electrodes and a standard wet gel electrode. Promising results are already obtained with our electrodes which do not have skin piercing micro needles. For the proposed electrodes, three different conductive coatings (Ag/AgCl/Au) are compared. AgCl is found to be slightly better than Ag as coating material, while our Au coated electrodes have the highest impedance. PMID- 22254701 TI - An embedded reconfigurable architecture for patient-specific multi-paramater medical monitoring. AB - A robust medical monitoring device should be able to provide intelligent diagnosis based on accurate analysis of physiological parameters in real-time. At the same time, such device must be able to adapt to the characteristics of a specific patient and desired diagnostic needs, and continue to operate even in presence of unexpected artifacts and accidental errors. A reconfigurable architecture is proposed for real-time assessment of individual's health status based on development of a patient-specific health index and online analysis and fusion of multi-parameter physiological signals. This is achieved by static configuration of processing elements and communication blocks in the architecture based on the patient's diagnostic needs. The proposed architecture is prototyped as a single integrated device on an FPGA platform and is evaluated using multi parameter data from intensive care units (ICUs). Three representative test cases of concurrently analyzing Blood Pressure, Heart Rate, and Electrocardiogram (ECG) data from MIMIC database are presented. The results show the effectiveness of the proposed technique in eliminating false alarms caused by patient movements, monitor noise, or imperfections in the detection schemes. PMID- 22254702 TI - A work-loop calorimeter for measuring the force-length-heat relationship of working excised cardiac muscle fibers. AB - Isolated cardiac trabeculae are convenient specimens with which to study the properties of cardiac muscle under a variety of controlled conditions in vitro. We have developed an instrument for measuring the mechanical and energetic properties of continuously-superfused cardiac trabeculae. Our instrument is capable of dynamically transitioning between fixed-length, isometric and isotonic modes of control during the time-course of a muscle twitch, allowing us to impart force-length work-loops that mimic the behaviour of cardiac muscle in vivo. Simultaneously, sensitive temperature transducers quantify muscle heat production. The combination of these interventions and measurements yields unique insight into the energetic efficiency of living cardiac muscle. PMID- 22254703 TI - Towards unified electromagnetic tracking system assessment-static errors. AB - Recent advances in Image-Guided Surgery allows physicians to incorporate up-to date, high quality patient data in the surgical decision making, and sometimes to directly perform operations based on pre- or intra-operatively acquired patient images. Electromagnetic tracking is the fastest growing area within, where the position and orientation of tiny sensors can be determined with sub-millimeter accuracy in the field created by a generator. One of the major barriers to the wider spread of electromagnetic tracking solutions is their susceptibility to ferromagnetic materials and external electromagnetic sources. The research community has long been engaged with the topic to find engineering solutions to increase measurement reliability and accuracy. This article gives an overview of related experiments, and presents our recommendation towards a robust method to collect representative data about electromagnetic trackers. PMID- 22254704 TI - DC coupled Doppler radar physiological monitor. AB - One of the challenges in Doppler radar systems for physiological monitoring is a large DC offset in baseband outputs. Typically, AC coupling is used to eliminate this DC offset. Since the physiological signals of interest include frequency content near DC, it is not desirable to simply use AC coupling on the radar outputs. While AC coupling effectively removes DC offset, it also introduces a large time delay and distortion. This paper presents the first DC coupled IQ demodulator printed circuit board (PCB) design and measurements. The DC coupling is achieved by using a mixer with high LO to RF port isolation, resulting in a very low radar DC offset on the order of mV. The DC coupled signals from the PCB radar system were successfully detected with significant LNA gain without saturation. Compared to the AC coupled results, the DC coupled results show great advantages of less signal distortion and more accurate rate estimation. PMID- 22254705 TI - System-on-chip based Doppler radar occupancy sensor. AB - System-on-Chip (SoC) based Doppler radar occupancy sensor is developed through non contact detection of respiratory signals. The radio was developed using off the shelf low power RF CC2530 SoC chip by Texas Instruments. In order to save power, the transmitter sends signal intermittently at 2.405 GHz. Reflected pulses are demodulated, and the baseband signals are processed to recover periodic motion. The system was tested both with mechanical target and a human subject. In both cases Doppler radar detected periodic motion closely matched the actual motion, and it has been shown that an SoC based system can be used for subject detection. PMID- 22254706 TI - Cardio-respiratory and daily activity monitor based on FMCW Doppler radar embedded in a wheelchair. AB - Unobtrusive monitoring of the cardio-respiratory and daily activity for wheelchair users became nowadays an important challenge, considering population aging phenomena and the increasing of the elderly with chronic diseases that affect their motion capabilities. This work reports the utilization of FMCW (frequency modulated continuous wave) Doppler radar sensors embedded in a manual wheelchair to measure the cardiac and respiratory activities and the physical activity of the wheelchair user. Another radar sensor is included in the system in order to quantify the motor activity through the wheelchair traveled distance, when the user performs the manual operation of the wheelchair. A conditioning circuit including active filters and a microcontroller based primary processing module was designed and implemented to deliver the information through Bluetooth communication protocol to an Android OS tablet computer. The main capabilities of the software developed using Android SDK and Java were the signal processing of Doppler radar measurement channel signals, graphical user interface, data storage and Wi-Fi data synchronization with remote physiological and physical activity database. PMID- 22254707 TI - Effect of respiratory modulation on relationship between heart rate variability and motion sickness. AB - This study investigates the interplay among heart rate variability (HRV), respiration, and the severity of motion sickness (MS) in a realistic passive driving task. Although HRV is a commonly used metrically in physiological research or even believed to be a direct measure of sympathovagal activities, the results of MS-effected HRV remain mixed across studies. The goal of this study is to find the source of these contradicting results of HRV associated with MS. Experimental results of this study showed that the group trend of the low frequency (LF) component and the LF/HF ratio increased and high-frequency (HF) component decreased significantly as self-reported MS level increased (p<0.001), consistent with a perception-driven autonomic response of the cardiovascular system. However, in one of the subjects, the relationship was reversed when individuals intentionally adjust themselves (deep breathing) to relieve the discomfort of MS during the experiments. It appears that the correlations between HRV and MS level were higher when individuals made fewer adjustments (the number of deep breathing) during the passive driving experiments. PMID- 22254708 TI - Physiological variables and subjective symptoms by 60 Hz magnetic field in EHS and non-EHS persons. AB - Electromagnetic hypersensitivity (EHS) is a set of claims of adverse medical symptoms self attributed by exposure to electromagnetic field. In this study, we simultaneously investigated both physiological changes (heart rate, respiration rate, and heart rate variability) and subjective symptoms to determine the origin of EHS. Two volunteer groups (15 self-reported EHS and 16 non-EHS participants) were tested under both sham and real exposure to 12.5 MUT magnetic fields at 60 Hz that lasted a half an hour. The magnetic field exposure did not have any effect on physiological variables or subjective symptoms in either group. We conclude that the subjective symptoms did not result from exposure to 12.5 MUT magnetic field at 60 Hz. PMID- 22254709 TI - Short-term heart rate dynamics of women during labor. AB - We studied 10 minutes segments of heartbeat interval fluctuations from 18 young women in labor with normal outcome of pregnancy. Data of each studied case were classified into two distinct groups. One group involving segments where the uterine activity was observable (three or more contractions in ten minutes), and the other group of reference having segments with fewer uterine activity or not presenting contractions at all. For comparison, we also included segments collected during the last trimester of gestation prior to labor from a third group of women. Corresponding RR interval series were analyzed to estimate RR(mean), RMSSD, alpha(1), alpha(1(MAG)) and alpha(1(SIGN)) parameters. No significant differences among groups were identified in RMSSD, alpha(1) and alpha(1(MAG)) Nevertheless, alpha(1(SIGN)) did present significant differences in comparison with the last trimester results (p<0.007), revealing a subtle change in the temporal organization of maternal RR series during labor. Results of these parameters then suggest that during labor, despite preserving a concomitant non linear influence, the maternal short-term autonomic cardiac regulation behaves with less antagonism. PMID- 22254710 TI - The effect of electrocardiographic lead choice on RR time series. AB - Results of heart rate variability analysis depend on the quality of the initial RR time series that is measured only in one lead of the ECG. This work shows that RR time series can subtly change from lead to lead so the choice of the analyzed lead is another source of uncertainty. The standard deviation of the differences of two RR time series obtained from different leads can change from 0.5 ms to more than 20 ms depending on the amount of noise, the morphological changes of the QRS complexes, the strategies of fiducial point determination and the measured subject. This source of uncertainty is in healthy subjects greater than that associated to the sampling frequency of the ECG for sampling frequencies greater than 400 Hz. PMID- 22254711 TI - Cerebral near-infrared spectroscopy analysis in preterm infants with intraventricular hemorrhage. AB - Near-infrared spectroscopy (NIRS) for cerebral circulation monitoring has gained popularity in the neonatal intensive care setting, with studies showing the possibility of identifying preterm infants with intraventricular hemorrhage (IVH) by transfer function analysis of arterial blood pressure (BP) and NIRS measures. In this study, we examined a number of NIRS-derived measures in a cohort of preterm infants with IVH (n = 5) and without IVH (n = 12) within 1-3 hours after birth. The IVH infants were found to have significantly higher tissue oxygenation index (TOI), lower fractional tissue oxygen extraction (FTOE) and lower coherence between arterial BP and deoxygenated hemoglobin (HHb) in the very low frequency range (VLF, 0.02-0.04 Hz). Further studies with larger sample size are warranted for a more complete understanding of the clinical utility of these NIRS measures for early identification of IVH infants. PMID- 22254712 TI - A method for characterizing circadian changes in QT intervals of diabetic patients. AB - This paper proposes a method to characterize circadian changes in QT intervals for diabetic studies. Although properties of QT intervals for diabetic patients are extensively studied, their circadian changes are not fully understood. Recently, the traditional cosinor method has been utilized for a study examining the relationship between QT circadian changes and the insulin resistance of the diabetic patients. For better characterization of the circadian change in QT intervals of this kind, spline smoothing technique applied to a decimated data set of QT intervals is proposed. New indices named QT circadian transition time (QTCT) and QT circadian transition amplitude (QTCA) associated with the subjects' awakening process are defined to characterize diabetic patients' condition. The method is applied to ten normal and fifteen type 2 diabetic patients. The proposed indices showed significantly lower values for type 2 diabetic patients compared to the control subjects indicating their effectiveness for the characterization. PMID- 22254713 TI - Autonomic nervous system driven cardiomyocytes in vitro. AB - Rat superior cervical ganglia (SCG), which are sympathetic ganglia, neurons and ventricular myocytes (VMs) were co-cultured separately in a minichamber placed on a microelectrode-array (MEA) substrate. The minichamber was fabricated photolithographically and had 2 compartments, 16 microcompartments and 8 microconduits. The SCG neurons were seeded into one of the compartments and all of the microcompartments using a glass pipette controlled by a micromanipulator and a microinjector. The VMs were seeded into the other compartment. Three days after seeding of the VMs, the neurites of the SCG neurons had connected with the VMs via the microconduits. Electrical stimulations, trains of biphasic square pulses, were applied to the SCG neurons in the microcompartments using 16 electrodes. Evoked responses were observed in several electrodes while electrical stimulation was applied to the SCG neurons. According to the two-way analysis of variance (ANOVA), the beat rate after electrical stimulation was affected by the frequency and the number of the stimulation pulses. These results suggest that pulse number and the frequency of the electrical stimulation contribute to modulation of the beat rate of the cardiomyocytes. PMID- 22254714 TI - Oscillatory patterns of respiration: consequences for the stability and control of cardiac electrophysiology. AB - Periodic breathing patterns known as Central Sleep Apnea (CSA) are often observed in congestive heart failure. This phenomenon is associated with increased risk of sudden cardiac death, but the mechanism for that outcome has not been exposed. Endocardial electrograms were recorded during spontaneous episodes of CSR and PB in patients in conscious and unconscious states. Analysis exposed a regular bidirectional phase-walk in the relationship between respiration and arterial blood pressure. Recently developed signal processing techniques revealed that respiration also modulates cardiac repolarization properties at multiple simultaneous frequencies, and the effect was heterogeneous across measurement sites in both ventricles. These measurements offer unique evidence of the electro physiological manifestations of these breathing patterns. Analysis of phase relationships suggested a mechanism by which the behavior may predispose patients to cardiac arrhythmias. Such predisposition would be easily measured to direct treatment priorities and improve risk stratification. PMID- 22254715 TI - Effect of atrioventricular conduction on heart rate variability. AB - This paper discusses the effect of atrioventricular conduction time (AVCT) on the short-term Heart Rate Variability (HRV) by computing HRV parameters using intervals between the onsets of successive P waves (PP time series) for three groups: normal, arrhythmia and sudden cardiac death (SCD) patients. A very precise wavelet transform based ECG delineator was developed to detect PP, PR and RR time series. Mean PR variation in arrhythmia and SCD group was found to be significantly high as compared to the normal group. It was observed that when PR variations in arrhythmia and SCD cases crossed a certain threshold, RR variability no longer provided a very accurate estimate of HRV. In such cases, PP variability was able to provide a better assessment of HRV. PMID- 22254716 TI - Robust heart rate measurement with phonocardiogram by on-line template extraction and matching. AB - As health care becomes popular, daily monitoring of health-status related parameters, including the heart rate (HR), is getting more and more valued. An easy, comfortable and robust solution is therefore an important issue. Phonocardiogram (PCG) is a physiological signal reflecting the cardiovascular status. It could be recorded by microphone-equipped on-hand devices, like the smartphone, even without direct skin contact. However, high inter- and intra variance of PCG make its processing challenging. For PCG-based HR measurement, a robust method is still strongly required. In this paper, we propose a HR measurement algorithm on the processing of PCG that uses on-line template extraction and matching. Through several experiments where traditional methods cannot effectively handle, the robustness of our method is verified by its accurate HR measurement results. PMID- 22254717 TI - Effects of RF fields emitted from smart phones on cardio-respiratory parameters: a preliminary provocation study. AB - This paper describes an experimental setup for evaluating the physiological effects of radiofrequency (RF) emitted from a Wideband Code Division Multiple Access (WCDMA) module with a 24 dBm at 1950 MHz for specific absorption rate (SAR(1g)) of 1.57 W/kg. This provocation study was executed in a double-blind study of two volunteer groups of 10 self-reported electromagnetic hypersensitivity (EHS) and 10 non-EHS subjects under both sham and real exposures in a randomly assigned and counter-balanced order. In the preliminary results, WCDMA RF exposure of 30 min did not have any effects on physiological changes in either group. PMID- 22254718 TI - Multiscale analysis of acceleration and deceleration of the instantaneous heart rate using symbolic dynamics. AB - The multiscale analysis of physiologic time series such as the RR interval time series has revealed that the entropy differs according to the scale. Furthermore, healthy subjects show different characteristics on the different time scales compared to patients. Instead of calculating entropies of the time series, the sequence of acceleration and deceleration of the instantaneous heart rate may also be investigated by means of binary symbolic dynamics. This kind of analysis revealed that the healthy heartbeat series also contains numerous regular binary sequences indicating runs of acceleration or deceleration. Here, we investigate whether this approach yields new information when applied to multiple time scales. We investigate the occurrence of binary patterns of length 8 on different time scales of heart rate series from healthy subjects and patients with congestive heart failure (CHF). Healthy subjects and CHF patients show different occurrences of binary patterns. These occurrences change especially on scales 1 to 5. Healthy subjects show more pronounced changes than CHF patients. At larger scales only gradual changes were observed. In conclusion, the application of binary symbolic dynamics on different scales yields new information, in particular on small scales. PMID- 22254719 TI - Experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT1 receptor in the brainstem. AB - Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including the abnormal autonomic nervous system. We have demonstrated that the oxidative stress through AT(1) receptor in the brain activates sympathetic nervous system. The aim of the present study was to determine whether experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT(1) receptor in the cardiovascular center of the brainstem (rostral ventrolateral medulla; RVLM) or not. Experimental 'jet lag' was made to normotensive (Wister-Kyoto rat; WKY rat) and hypertensive rats (stroke-prone spontaneously hypertensive rats; SHRSP) by the exposure to a 12 hour phase advance for 5 days. In WKY, 'jet lag' increases blood pressure and the activity of sympathetic nervous system via oxidative stress through angiotensin II type 1 receptor in the RVLM for 2 days only, and the changes are improved at 3 day after the initiation of 'jet lag'. In SHRSP, 'jet lag' also increases blood pressure and the activity of sympathetic nervous system via oxidative stress through angiotensin II type 1 receptor in the RVLM, and the changes are greater compared to those in WKY, and are maintained for the period of 'jet lag'. These results suggest that experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT(1) receptor in the brain, especially in hypertension. PMID- 22254720 TI - Time-frequency heart rate variability characteristics of young adults during physical, mental and combined stress in laboratory environment. AB - The goal of this study was to evaluate the changes in heart rate variability (HRV) parameters due to a specific physical, mental or combined load. More specifically, the difference in effect between mental load and physical activity is studied. In addition, the effect of the combined physical and mental demand on the HRV parameters was examined and compared with the changes during the single task. In a laboratory environment, 28 subjects went through a protocol with different types of load (physical and/or mental), each followed by a period of rest. Continuous wavelet transformation was applied to create time series of instantaneous power and frequency in specified frequency bands (LF and HF). HF could distinguish the active conditions from the rest condition, meaning that HRV is sensitive to any change in mental or physical state. Differences in HRV parameters were observed between physical, mental and the combined load. In conclusion, we were able to distinguish between rest, physical and mental condition by combining different HRV characteristics. The addition of a mental load to a physical task had an extra effect on the HRV characteristics. PMID- 22254721 TI - Determining the effects of electrical stimulation on functional recovery of denervated rat gastrocnemius muscle using motor unit number estimation. AB - The use of electrical muscle stimulation to treat denervated muscle prior to delayed reinnervation has been widely debated. There is evidence showing both positive and negative results following different protocols of electrical stimulation. In this study we investigated the role electrical stimulation has on muscle reinnervation following immediate and delayed nerve repair using motor unit estimation techniques. Rat gastrocnemius muscle was denervated and repaired using the peroneal nerve either immediately or following three-months with and without electrical stimulation. Motor unit counts, average motor unit sizes, and maximum compound action potentials were measured three-months following peroneal nerve repair. Motor unit counts in animals that were denervated and stimulated were significantly higher than those that were denervated and not stimulated. Both average motor unit sizes and maximum compound action potentials showed no significant differences between denervated and denervated-stimulated animals. These results provide evidence that electrical stimulation prior to delayed nerve repair increases muscle receptivity to regenerating axons and may be a worthwhile treatment for peripheral nerve injuries. PMID- 22254723 TI - Fabrication of a prototype magnetic stimulator equipped with eccentric spiral coils. AB - The development of compact magnetic stimulators will enable us to treat some intractable neurological diseases at one's home. In this study, we propose eccentric spiral coils which induce sufficient eddy currents in the brain at lower driving currents for the stimulator circuit. Numerical simulations based on the finite element method showed the advantages of the proposed design. A prototype coil and driving circuit were fabricated. The coil generated a magnetic field of 1.41 T at the maximum output level of stimulator. PMID- 22254722 TI - Phase-based measures of cross-frequency coupling in brain electrical dynamics under general anesthesia. AB - The state of general anesthesia (GA) is associated with an increase in spectral power in scalp electroencephalogram (EEG) at frequencies below 40 Hz, including spectral peaks in the slow oscillation (SO, 0.1-1 Hz) and alpha (8-14 Hz) bands. Because conventional power spectral analyses are insensitive to possible cross frequency coupling, the relationships among the oscillations at different frequencies remain largely unexplored. Quantifying such coupling is essential for improving clinical monitoring of anesthesia and understanding the neuroscience of this brain state. We tested the usefulness of two measures of cross-frequency coupling: the bispectrum-derived SynchFastSlow, which is sensitive to phase-phase coupling in different frequency bands, and modulogram analysis of coupling between SO phase and alpha rhythm amplitude. SynchFastSlow, a metric that is used in clinical depth-of-anesthesia monitors, showed a robust correlation with the loss of consciousness at the induction of propofol GA, but this could be largely explained by power spectral changes without considering cross-frequency coupling. Modulogram analysis revealed two distinct modes of cross-frequency coupling under GA. The waking and two distinct states under GA could be discriminated by projecting in a two-dimensional phase space defined by the SynchFastSlow and the preferred SO phase of alpha activity. Our results show that a stereotyped pattern of phase-amplitude coupling accompanies multiple stages of anesthetic-induced unconsciousness. These findings suggest that modulogram analysis can improve EEG based monitoring of brain state under GA. PMID- 22254724 TI - On handling the layered structure of the skull in transcranial direct current stimulation models. AB - In a tDCS model study, the accuracy of isotropic and anisotropic single-layer approximations to the actual three-layered skull is evaluated. For both approximation models, the average difference in brain current density with respect to the layered skull model are shown to be small. We conclude that both approximations can be used to accurately compute the current density in the brain, provided that the radial conductivity in the model matches the effective radial conductivity of the three-layered skull. PMID- 22254725 TI - Transcranial magnetic stimulation coil with electronically switchable active and sham modes. AB - Blinded studies with transcranial magnetic stimulation (TMS) require a valid sham condition. A wide range of sham approaches have been implemented but they have various limitations including residual electric field in the brain, inadequate reproduction of auditory and cutaneous sensations, and/or need for electrical stimulation with scalp electrodes. We propose a quadrupole TMS coil configuration that can be electronically switched between active and sham modes. In active mode, the quadrupole coil has electric field characteristics similar to a conventional figure-8 coil. In sham mode, the quadrupole coil compared to the reverse-current sham figure-8 coil has 50% less electric field penetration depth, is 97% more focal, produces 35% less intense field in the brain, and induces scalp electric field characteristics closer to those of active TMS. PMID- 22254726 TI - Dorsolateral prefrontal cortex sensitivity to rTMS. AB - This paper presents the preliminary results of a study to determine dorsolateral prefrontal cortex sensitivity to rTMS stimulation presented at clinically accepted amplitudes, frequencies and locations. A specially developed EEG system with 10-20 electrode locations was used to record the short latency magnetically evoked potentials. Sixteen normal subjects were stimulated using 10 Hz for the left hemisphere and 1 Hz for the right. The evoked potentials recorded for left sided stimulation were significantly larger than for the right sided stimulation. Further, the stimulation energies, though within the range used clinically for the treatment of depression were insufficient to excite evoked potentials in several subjects. PMID- 22254727 TI - Statistical model applied to motor evoked potentials analysis. AB - Motor evoked potentials (MEPs) convey information regarding the functional integrity of the descending motor pathways. Absence of the MEP has been used as a neurophysiological marker to suggest cortico-spinal abnormalities in the operating room. Due to their high variability and sensitivity, detailed quantitative studies of MEPs are lacking. This paper applies a statistical method to characterize MEPs by estimating the number of motor units and single motor unit potential amplitudes. A clearly increasing trend of single motor unit potential amplitudes in the MEPs after each pulse of the stimulation pulse train is revealed by this method. This statistical method eliminates the effects of anesthesia, and provides an objective assessment of MEPs. Consequently this statistical method has high potential to be useful in future quantitative MEPs analysis. PMID- 22254728 TI - Plasticity associated changes in cortical somatosensory evoked potentials following spinal cord injury in rats. AB - Spinal cord injury (SCI) causes a number of physiological and neurological changes resulting in loss of sensorimotor function. Recent work has shown that the central nervous system is capable of plastic behaviors post-injury, including axonal regrowth and cortical remapping. Functional integrity of afferent sensory pathways can be quantified using cortical somatosensory evoked potentials (SSEPs) recorded upon peripheral limb stimulation. We implanted 15 rats with transcranial screw electrodes and recorded SSEPs from cortical regions corresponding to each limb before and after a mild or moderate contusion injury. We report a post injury increase in the mean amplitude of cortical SSEPs upon forelimb stimulation. SSEP amplitudes for mild and moderate SCI groups increased by 183% +/- 95% and 107% +/- 38% over baseline, respectively, while hindlimb SSEPs decreased by 58% +/- 14% and 79% +/- 4%. In addition, we report increased SSEP amplitude measured from the anatomically adjacent hindlimb region upon forelimb stimulation (increase of 90% +/- 19%). Our results show that previously allocated hindlimb cortical regions are now activated by forelimb stimulation, suggesting an expansion in the area of cortical forelimb representation into hindlimb regions after an injury. This result is indicative of adaptive plasticity in undamaged areas of the CNS following SCI. PMID- 22254729 TI - Innovative pattern reversal displays for visual electrophysiological studies. AB - Pattern Reversal (PR) stimulation is a frequently used tool in the evaluation of the visual pathway. The PR stimulus consists of a field of black and white segments (usually checks or bars) of constant luminance, which change phase (black to white and white to black) at a given reversal rate. The Pattern Electroretinogram (PERG) is a biological potential that is evoked from the retina upon viewing PR display. Likewise, the Pattern Visual Evoked Potential (PVEP) is a biological potential recorded from the occipital cortex when viewing a PR display. Typically, PR stimuli are presented on a Cathode Ray Tube (CRT) or Liquid Crystal Display (LCD) monitor. This paper presents three modalities to generate pattern reversal stimuli. The three methods are as follows: a display consisting of array of Light Emitting Diodes (LEDs), a display comprised of two miniature projectors, and a display utilizing a modified LCD display in conjunction with a variable polarizer. The proposed stimulators allow for the recording of PERG and PVEP waveforms at much higher rates than are capable with conventional stimulators. Additionally, all three of the alternative PR displays will be able to take advantage of advanced analysis techniques, such as the recently developed Continuous Loop Averaging Deconvolution (CLAD) algorithm. PMID- 22254730 TI - Effects of auditory selective attention on chirp evoked auditory steady state responses. AB - Auditory steady state responses (ASSRs) are frequently used to assess auditory function. Recently, the interest in effects of attention on ASSRs has increased. In this paper, we investigated for the first time possible effects of attention on AS-SRs evoked by amplitude modulated and frequency modulated chirps paradigms. Different paradigms were designed using chirps with low and high frequency content, and the stimulation was presented in a monaural and dichotic modality. A total of 10 young subjects participated in the study, they were instructed to ignore the stimuli and after a second repetition they had to detect a deviant stimulus. In the time domain analysis, we found enhanced amplitudes for the attended conditions. Furthermore, we noticed higher amplitudes values for the condition using frequency modulated low frequency chirps evoked by a monaural stimulation. The most difference between attended and unattended modality was exhibited at the dichotic case of the amplitude modulated condition using chirps with low frequency content. PMID- 22254731 TI - Instrumented toys for studying power and precision grasp forces in infants. AB - Currently the study of infants grasping development is purely clinical, based on functional scales or on the observation of the infant while playing; no quantitative variables are measured or known for diagnosis of eventually disturbed development. The aim of this work is to show the results of a longitudinal study achieved by using a "baby gym" composed by a set of instrumented toys, as a tool to measure and stimulate grasping actions, in infants from 4 to 9 months of life. The study has been carried out with 7 healthy infants and it was observed, during infants development, an increase of precision grasp and a reduction of power grasp with age. Moreover the forces applied for performing both precision and power grasp increase with age. The proposed devices represent a valid tool for continuous and quantitative measuring infants manual function and motor development, without being distressful for the infant and consequently it could be suitable for early intervention training during the first year of life. The same system, in fact, could be used with infants at high risk for developmental motor disorder in order to evaluate any potential difference from control healthy infants. PMID- 22254732 TI - HRV and EEG based indicators of stress in children with Asperger syndrome in audio-visual stimulus test. AB - Asperger syndrome (AS) is a neurobiological condition which is characterized by poor skills in social communication, and restricted and repetitive patterns of behavior and interests. We studied whether stress-related indices of heart rate variability (HRV) and electroencephalography (EEG) are different in children with AS than normal controls. We analyzed retrospectively the data of the test where audiovisual stimuli were used. We hypothesized that this test is a stressful situation for individuals with AS and they would have a greater reaction than control subjects. EEG and one-channel electrocardiography (ECG) were collected for children with diagnosis of AS (N = 20) and their age-matched controls (N = 21). HRV indices, frontal EEG asymmetry index and brain load index were calculated. HRV based indices revealed increased sympathetic activity during the test in children with AS. EEG based indices increased more in children with AS during the test compared to baseline. Thus, the children with AS seems to have a greater reaction to stressful situation. PMID- 22254734 TI - Computational modeling to evaluate helical electrode designs. AB - Finite element models of helical electrodes were utilized in conjunction with nerve fiber models to determine the efficacy of various changes in helical electrode design in improving nerve fiber recruitment. It was determined that an increase in the helical overlap angle does not facilitate recruitment of smaller diameter nerve fibers. The simulations led to some strategies that could potentially improve the electrode design. PMID- 22254733 TI - A computerized perimeter for assessing modality-specific visual field loss. AB - The characterization of visual field loss provides a valuable diagnostic metric for studying the effects of damage to the retina, optic nerve or visual cortex. We describe a tool, the Quadrant Vision Perimeter (QVp), to rapidly and accurately measure visual fields. In addition to measuring the location of visual deficits, the tool can assess modality-specific field loss (e.g., impaired detection of luminance, motion, depth and color) and severity of the deficit. We present validation and normalization for parameters of visual attributes, as well as exemplar comparisons of visual fields obtained automatically using QVp to standardized perimeters for three stroke patients. Patient visual fields are compared among visual features to assess modality-specific deficits, and over time, to measure fine changes in visual fields, due either to spontaneous recovery or visual degradation. PMID- 22254735 TI - Analysis of complexity based EEG features for the diagnosis of Alzheimer's disease. AB - As life expectancy increases, particularly in the developed world, so does the prevalence of Alzheimer's Disease (AD). AD is a neurodegenerative disorder characterized by neurofibrillary plaques and tangles in the brain that leads to neuronal death and dementia. Early diagnosis of AD is still a major unresolved health concern: several biomarkers are being investigated, among which the electroencephalogram (EEG) provides the only option for an electrophysiological information. In this study, EEG signals obtained from 161 subjects--79 with AD, and 82 age-matched controls (CN)--are analyzed using several nonlinear signal complexity measures. These measures include: Higuchi fractal dimension (HFD), spectral entropy (SE), spectral centroid (SC), spectral roll-off (SR), and zero crossing rate (ZCR). HFD is a quantitative measure of time series complexity derived from fractal theory. Among spectral measures, SE measures the level of disorder in the spectrum, SC is a measure of spectral shape, and SR is frequency sample below which a specified percent of the spectral magnitude distribution is contained. Lastly, ZCR is simply the rate at which the signal changes signs. A t test was first applied to determine those features that provide significant differences between the groups. Those features were then used to train a neural network. The classification accuracies ranged from 60-66%, suggesting they contain some discriminatory information; however, not enough to be clinically useful alone. Combining these features and training a support vector machine (SVM) resulted in a diagnostic accuracy of 78%, indicating that these feature carry complementary information. PMID- 22254736 TI - A modelling study on transmission of the central oscillator in tremor by a motor neuron pool. AB - In spite of decades of intense research, pathological tremors still constitute unknown disorders. This study addresses, based on a multi-scale model, the behavior of an entire pool of motor neurons in tremor, under the hypothesis that tremor is an oscillation of central origin commonly projected to all motor neurons that innervate a muscle. Our results show that under such conditions both paired discharges and enhanced motor neuron synchronization, two of the characteristic landmarks of tremor, emerge. Moreover, coherence and correlation analyses suggest that the central tremor oscillator is transmitted linearly by the motor neuron pool given that a small set (7 or 8) of motor neurons are sampled. PMID- 22254737 TI - Vibrotactile pattern perception as a method for the assessment of brain dysfunction. AB - An immediate need exists for a portable diagnostic device for the assessment of cortical function, and diagnosis of mTBI. This paper presents initial results using a vibrotactile acuity test for the objective and quantitative diagnosis of acute mTBI suspects. mTBI is hypothesized to involve derangement or damage to the underlying cortical network. In particular, fundamental building blocks of the cortex are changed in such a way as to limit the functional connectivity within and between cortical columns. Our approach is based on sensory illusions that are configured as a test of neural connectivity. Pilot clinical test data showed differences between a small healthy normal group and a concussion group using a sports concussion model. PMID- 22254738 TI - Development of intelligent model to determine favorable wheelchair tilt and recline angles for people with spinal cord injury. AB - Machine-learning techniques have found widespread applications in bioinformatics. Such techniques provide invaluable insight on understanding the complex biomedical mechanisms and predicting the optimal individualized intervention for patients. In our case, we are particularly interested in developing an individualized clinical guideline on wheelchair tilt and recline usage for people with spinal cord injury (SCI). The current clinical practice suggests uniform settings to all patients. However, our previous study revealed that the response of skin blood flow to wheelchair tilt and recline settings varied largely among patients. Our finding suggests that an individualized setting is needed for people with SCI to maximally utilize the residual neurological function to reduce pressure ulcer risk. In order to achieve this goal, we intend to develop an intelligent model to determine the favorable wheelchair usage to reduce pressure ulcers risk for wheelchair users with SCI. In this study, we use artificial neural networks (ANNs) to construct an intelligent model that can predict whether a given tilt and recline setting will be favorable to people with SCI based on neurological functions and SCI injury history. Our results indicate that the intelligent model significantly outperforms the traditional statistical approach in accurately classifying favorable wheelchair tilt and recline settings. To the best of our knowledge, this is the first study using intelligent models to predict the favorable wheelchair tilt and recline angles. Our methods demonstrate the feasibility of using ANN to develop individualized wheelchair tilt and recline guidance for people with SCI. PMID- 22254739 TI - Laser speckle imaging reveals multiple aspects of cerebral vascular responses to whole body mild hypothermia in rats. AB - In this paper, we present a novel method to study the effect of induced mild hypothermia on cerebral vascular responses. To measure cerebral vascular responses, a minimally invasive imaging method, temporal laser speckle imaging, was developed and adapted for induced-hypothermia rat model. Experiments were carried out in rats under anesthesia. Laser speckle images were acquired at different temperature points, normothermia (37 degrees Q and mild therapeutic hypothermia (34 degrees Q. We extracted multiple hemodynamic responses simultaneously from the images, including blood flow, vessel size and deoxy hemoglobin saturation. A wide-field view of the cerebral vascular response distribution was studied, which showed an inhomogeneous response map across the region of interest. A comparison between responses in arterioles and venules was carried out (blood flow decreased by 58 +/- 9 % vs. 27 +/- 8 %). The global decrease of blood flow, dilatation in arterioles and decrease of deoxy-hemoglobin saturation in veins at mild hypothermia suggests a beneficial role of circulatory and oxygenation changes in therapeutic hypothermia. The results reported provide a circulatory explanation for the hypothermia therapeutic effects and mechanism. PMID- 22254740 TI - Characterization of the tendon vibration reflex response in hemi-spastic stroke individuals. AB - The objective of our study was to assess the role of persistent inward currents, or PICs, on the excitability of motoneurons innervating spastic muscle in hemi spastic stroke individuals. This was accomplished by examining the effects of tonic vibration applied to the tendon of the biceps brachii muscle. The elicited TVR (tonic vibration reflex) provides a useful way to assess the degree of excitability of spinal neurons in spastic syndromes, and it has additional features that may signify the presence of PICs in spastic motoneurons. We applied sinusoidal stretches of varied duration to the biceps tendon of two hemi-spastic stroke individuals and one neurologically intact individual. We recorded the resulting TVR response from electromyographic(EMG) signals obtained from the biceps as well as force recorded at the wrist. The results of our preliminary study show that the initial rise of the TVR force response as well as the force magnitude are generally greater in spastic muscle, perhaps a marker of motoneuron excitability. Additionally, a shorter vibration duration was sufficient to evoke a response on the spastic side of our tested stroke subjects. However, the key marker of PICs--the decay of the force response as well as sustained after discharge did not exhibit clear differences. Our present data suggests that motoneurons innervating spastic muscle are more readily activated, and thus exhibit increased excitability, which could possibly be a function of greater depolarization, without a change in PIC magnitude. Our data does not rule out the possibility of subthreshold activation of the PIC resulting in enhanced motoneuron depolarization. PMID- 22254741 TI - Frequency interactions in human epileptic brain. AB - We have used two algorithms, wavelet phase coherence (WPC) and modulation index (MI) analysis to study frequency interactions in the human epileptic brain. Quantitative analyses were performed on intracranial electroencephalographic (iEEG) segments from three patients with neocortical epilepsy. Interelectrode coherence was measured using WPC and intraelectrode frequency interactions were analyzed using MI. WPC was performed on electrode pairings and the temporal evolution of phase couplings in the following frequency ranges: 1-4 Hz, 4-8 Hz, 8 13 Hz, 13-30 Hz and 30-100 Hz was studied. WPC was strongest in the 1-4 Hz frequency range during both seizure and non-seizure activities; however, WPC values varied minimally between electrode pairings. The 13-30 Hz band showed the lowest WPC values during seizure activity. MI analysis yielded two prominent patterns of frequency-specific activity, during seizure and non-seizure activities, which were present across all patients. PMID- 22254742 TI - Capturing the state transitions of seizure-like events using Hidden Markov models. AB - The purpose of this study was to investigate the number of states present in the progression of a seizure-like event (SLE). Of particular interest is to determine if there are more than two clearly defined states, as this would suggest that there is a distinct state preceding an SLE. Whole-intact hippocampus from C57/BL mice was used to model epileptiform activity induced by the perfusion of a low Mg(2+)/high K(+) solution while extracellular field potentials were recorded from CA3 pyramidal neurons. Hidden Markov models (HMM) were used to model the state transitions of the recorded SLEs by incorporating various features of the Hilbert transform into the training algorithm; specifically, 2- and 3-state HMMs were explored. Although the 2-state model was able to distinguish between SLE and nonSLE behavior, it provided no improvements compared to visual inspection alone. However, the 3-state model was able to capture two distinct nonSLE states that visual inspection failed to discriminate. Moreover, by developing an HMM based system a priori knowledge of the state transitions was not required making this an ideal platform for seizure prediction algorithms. PMID- 22254743 TI - Employing neuronal networks to investigate the pathophysiological basis of abnormal cortical oscillations in Alzheimer's disease. AB - This paper describes an investigation into the pathophysiological causes of abnormal cortical oscillations in Alzheimer's disease (AD) using two heterogeneous neuronal network models. The effect of excitatory circuit disruption on the beta band power (13-30 Hz) using a conductance-based network model of 200 neurons is assessed. Then, the neural correlates of abnormal cortical oscillations in different frequency bands based on a larger network model of 1000 neurons consisting of different types of cortical neurons is also analyzed. The results show that, despite the heterogeneity of the network models, the beta band power is significantly affected by excitatory neural and synaptic loss. Secondly, the results of modeling a functional impairment in the excitatory circuit shows that beta band power exhibits the most decrease compared with other bands. Previous biological experiments on different types of cultural excitatory neurons show that cortical neuronal death is mediated by dysfunctional ionic behavior that might specifically contribute to the pathogenesis of p-amyloid peptide (Ap)-induced neuronal death in AD. Our study also shows that beta band power was the first affected component when the modeled excitatory circuit begins to lose neurons and synapses. Alpha (8-12 Hz), gamma (30-50 Hz) and Full frequency (1-70 Hz) band power are affected in a later stage when more severe synaptic loss occurs. PMID- 22254744 TI - Absolute position calculation for a desktop mobile rehabilitation robot based on three optical mouse sensors. AB - ArmAssist is a wireless robot for post stroke upper limb rehabilitation. Knowing the position of the arm is essential for any rehabilitation device. In this paper, we describe a method based on an artificial landmark navigation system. The navigation system uses three optical mouse sensors. This enables the building of a cheap but reliable position sensor. Two of the sensors are the data source for odometry calculations, and the third optical mouse sensor takes very low resolution pictures of a custom designed mat. These pictures are processed by an optical symbol recognition algorithm which will estimate the orientation of the robot and recognize the landmarks placed on the mat. The data fusion strategy is described to detect the misclassifications of the landmarks in order to fuse only reliable information. The orientation given by the optical symbol recognition (OSR) algorithm is used to improve significantly the odometry and the recognition of the landmarks is used to reference the odometry to a absolute coordinate system. The system was tested using a 3D motion capture system. With the actual mat configuration, in a field of motion of 710 * 450 mm, the maximum error in position estimation was 49.61 mm with an average error of 36.70 +/- 22.50 mm. The average test duration was 36.5 seconds and the average path length was 4173 mm. PMID- 22254745 TI - An advanced rehabilitation robotic system for augmenting healthcare. AB - Emerging technologies such as rehabilitation robots (RehaBot) for retraining upper and lower limb functions have shown to carry tremendous potential to improve rehabilitation outcomes. Hstar Technologies is developing a revolutionary rehabilitation robot system enhancing healthcare quality for patients with neurological and muscular injuries or functional impairments. The design of RehaBot is a safe and robust system that can be run at a rehabilitation hospital under the direct monitoring and interactive supervision control and at a remote site via telepresence operation control. RehaBot has a wearable robotic structure design like exoskeleton, which employs a unique robotic actuation--Series Elastic Actuator. These electric actuators provide robotic structural compliance, safety, flexibility, and required strength for upper extremity dexterous manipulation rehabilitation training. RehaBot also features a novel non-treadmill paddle platform capable of haptics feedback locomotion rehabilitation training. In this paper, we concern mainly about the motor incomplete patient and rehabilitation applications. PMID- 22254746 TI - Improving the ROM of wrist movements in stroke patients by means of a haptic wrist robot. AB - A 3 DoFs haptic wrist robot is used to measure and/or assist the movement of the wrist on three axes: flexion/extension (F/E), abduction/adduction (A/A), pronation/ supination (P/S). An assistance scheme based on the widely used progressive splinting therapy is proposed and its efficacy is tested within a group of nine chronic stroke patients, during a pilot study consisting of 2 sessions. Preliminary outcomes show that the technique is effective with the very distal part of wrist involving F/E and A/A but results in a reduced motor improvement for the P/S where proximal part of the arm is involved. PMID- 22254747 TI - Offaxis neuromuscular training of knee injuries using an offaxis robotic elliptical trainer. AB - The goal of this study was to use an offaxis robotic elliptical trainer to improve off-axis neuromuscular control in people with knee injuries. Thirteen individuals with knee injuries participated in the study. Among them, 8 individuals participated in 18 sessions of pivoting offaxis intensity-adjustable neuromuscular control training (POINT) (3 sessions/week for 6 weeks including 3 evaluation sessions) to improve offaxis neuromuscular control, specifically dynamic lower limb stability in pivoting. 5 individuals served as controls who only participated in the three evaluations. Following POINT patients in the training group reduced pivoting instability (p=0.024), while the control group did not (p=0.118). Individuals in the training group were able to hop farther in a single leg hop for distance task, take shorter in 12 m hop time for time task, and reported reduced knee pain. The results suggest that subject-specific POINT utilizing the novel robotic elliptical trainer can be implemented as a rehabilitation protocol for patients with knee injuries to improve their lower limb functions and reduce knee symptoms. PMID- 22254748 TI - Improvement of gait & muscle strength with functional electrical stimulation in sub-acute & chronic stroke patients. AB - The main objective of this work was to evaluate and compare the effects of Functional Electrical Stimulation (FES) therapy in the walking ability and muscle strength studied by electromyography (EMG) analysis between subacute and chronic stroke patients. Eighteen consecutive hemiplegic patients suffering from foot drop were assigned either to subacute or chronic group. Patients of both groups' were treated according to conventional rehabilitation program combined with FES therapy for 12 weeks. At post-treatment, subacute subjects showed a mean increase in walking speed of 29.4% and chronic subjects of 17.1% and the physiological cost index (PCI), with a reduction of 73.1% in subacute subjects and 46.5 % in chronic subjects. Improvement was also found in cadence, step length, and mean absolute-value (MAV) and root-mean-square (RMS) of EMG signal of tibialis anterior (TA) muscle in both groups, but subacute subjects improved better compared with chronic subjects. Thus we suggested that an early intervention of FES therapy combined with conventional rehabilitation program (CRP) could significantly improve the gait and muscle strength in stroke survivors. PMID- 22254749 TI - Young's modulus measurement on pig trachea and bronchial airways. AB - Young's Modulus was measured on the trachea and first three generations of pig airways by compression. A simple and low-cost system for measuring the elastic properties of small bio-materials is presented. The force-displacement measurements have been undertaken on dissected cartilage and trachea mucosa from pig trachea and bronchial segments. Young's Modulus of trachea wall, 1.78 +/- 0.51 MPa, is found to be dominated by the trachea cartilage of value 1.74 +/- 0.85 MPa while the modulus for trachea mucosa was 0.15 +/- 0.03 MPa. The Young's Modulus of the airway wall from the first three generations of bronchi decreases from 1.35 +/- 0.17 to 0.35 +/- 0.10 MPa which is also found to be dominated by the airway cartilage. Airway mucosa is found to have similar Young's modulus of 0.036 +/- 0.005 MPa for the first three generations of bronchial airways. PMID- 22254750 TI - Evaluation of a wearable tele-echography robot system: FASTele in a vehicle using a mobile network. AB - This paper shows the focused assessment with sonography for trauma (FAST) performance of a wearable tele-echography robot system we have developed that we call "FASTele". FAST is a first-step way of assessing the injury severity of patients suffering from internal bleeding who may be some time away from hospital treatment. So far, we have only verified our system's effectiveness under constantly wired network conditions. To determine its FAST performance within an emergency vehicle, we extended it to a WiMAX mobile network and performed experiments on it. Experiment results showed that paramedics could attach the system to FAST areas on a patient's body on the basis of the attaching position and procedure. We also assessed echo images to confirm that the system is able to extract the echo images required for FAST under maximum vehicle acceleration. PMID- 22254751 TI - Design of a robotic tool for percutaneous instrument distal tip repositioning. AB - Manually performed image-guided percutaneous procedures are limited by targeting errors due to instrument misalignment, deflection and an inability to reposition the distal tip of the instrument after it has been percutaneously inserted. These limitations result in suboptimal instrument positioning that limits diagnosis and treatment for a variety of procedures as well as excessive procedure time and radiation dose (in the case of x-ray based imaging). Hence we are developing a robotic tool capable of repositioning the distal tip of a percutaneous instrument after a single insertion into the body. It is based on the concept of deploying a super-elastic pre-curved stylet from a concentric straight cannula. The proximal end of the cannula is attached to the distal end of a screw-spline that enables it to be translated and rotated with respect to the casing. Translation of the stylet relative to the cannula is achieved with a second threaded screw with a splined groove. The device is made of mostly plastic components and actuation is achieved using micro-stepper motors. Measurements of the maximum axial force for the cannula screw-spline and stylet screw were found to match those from design calculations. Evaluation of the mechanism positioning capability demonstrated sub millimeter and sub-degree translation and angular accuracy. We foresee this robotic tool having wide application across a range of procedures such as biopsy, thermal ablation and brachytherapy seed placement. PMID- 22254752 TI - Accuracy of navigated control concepts using an Er: Yag-laser for cavity preparation. AB - This paper describes a method for measuring the shape accuracy of a cylindrical hole which is created by means of an automatically power-controlled laser system using navigated control. In dental surgery, drills or mills are used for bone treatment. For most patients the use of these instruments is very inconvenient. Furthermore, the bone treatment with rotating instruments can lead to thermal necrosis. Using a laser system could be a good alternative for the patient. The utilization of a laser system could also facilitate bone treatment without any severe thermal damage. An optical navigation system can be used for a safer handling of a laser system. The position and the orientation of the laser handpiece relative to the patient can be calculated. Thereby, the laser can be automatically switched off, if the end of the laser beam does not hit the preoperative planned area. In order to measure the accuracy of such a laser system, we created several cavities in a phantom with a manually guided, automatically power-controlled laser. Afterwards, the deviation between the planned shape and the shape created by manually guided automatically power controlled laser treatment has been measured. The application of this system showed, that the required accuracy of <1 mm for dental implantology applications, could not be reached. PMID- 22254753 TI - Virtually transparent epidermal imagery for laparo-endoscopic single-site surgery. AB - This paper presents a novel design, and prototype implementation, of a virtually transparent epidermal imagery (VTEI) system for laparo-endoscopic single-site (LESS) surgery. The system uses a network of multiple, micro wireless cameras and multiview mosaicing technique to obtain a panoramic view of the surgery area. This view provides visual feedback to surgeons with large viewing angles and areas of interest so that the surgeons can improve the safety of surgical procedures by being better aware of where the surgical instruments are relative to tissue and organs. The prototype VTEI system also projects the generated panoramic view on the abdomen area to create a transparent display effect that mimics equivalent, but higher risk, open-cavity surgeries. PMID- 22254754 TI - Reconfigurable MRI-guided robotic surgical manipulator: prostate brachytherapy and neurosurgery applications. AB - This paper describes a modular design approach for robotic surgical manipulator under magnetic resonance imaging (MRI) guidance. The proposed manipulator provides 2 degree of freedom (DOF) Cartesian motion and 2-DOF pitch and yaw motion. Primarily built up with dielectric materials, it utilizes parallel mechanism and is compact in size to fit into the limited space of close-bore MRI scanner. It is ideal for needle based surgical procedures which usually require positioning and orientation control for accurate imaging plane alignment. Specifically, this mechanism is easily reconfigurable to over constrained manipulator structure which provides 2-DOF Cartesian motion by simple structure modification. This modular manipulator integrated with different end-effector modules is investigated for prostate brachytherapy and neurosurgery applications as preliminary evaluation. PMID- 22254756 TI - Sensors management in robotic neurosurgery: the ROBOCAST project. AB - Robot and computer-aided surgery platforms bring a variety of sensors into the operating room. These sensors generate information to be synchronized and merged for improving the accuracy and the safety of the surgical procedure for both patients and operators. In this paper, we present our work on the development of a sensor management architecture that is used is to gather and fuse data from localization systems, such as optical and electromagnetic trackers and ultrasound imaging devices. The architecture follows a modular client-server approach and was implemented within the EU-funded project ROBOCAST (FP7 ICT 215190). Furthermore it is based on very well-maintained open-source libraries such as OpenCV and Image-Guided Surgery Toolkit (IGSTK), which are supported from a worldwide community of developers and allow a significant reduction of software costs. We conducted experiments to evaluate the performance of the sensor manager module. We computed the response time needed for a client to receive tracking data or video images, and the time lag between synchronous acquisition with an optical tracker and ultrasound machine. Results showed a median delay of 1.9 ms for a client request of tracking data and about 40 ms for US images; these values are compatible with the data generation rate (20-30 Hz for tracking system and 25 fps for PAL video). Simultaneous acquisitions have been performed with an optical tracking system and US imaging device: data was aligned according to the timestamp associated with each sample and the delay was estimated with a cross correlation study. A median value of 230 ms delay was calculated showing that realtime 3D reconstruction is not feasible (an offline temporal calibration is needed), although a slow exploration is possible. In conclusion, as far as asleep patient neurosurgery is concerned, the proposed setup is indeed useful for registration error correction because the brain shift occurs with a time constant of few tens of minutes. PMID- 22254755 TI - Surgical assistance for instruments' power control based on navigation and neuromonitoring. AB - In order to prevent nerve injuries during ear-nose-throat (ENT) and skull base surgery, the method Navigated Control Functional is presented. Thereby, the power of active instruments is controlled based on position information, provided by a surgical navigation system, and nerve activity information, provided by a neurophysiologic monitoring system. Electrical stimulation is usually required for the extraction of distance information from neurophysiologic signals (e.g., Electromyography (EMG)). However, this article presents an experiment to investigate a possible relationship between EMG signals and the nerve-instrument distance without additional electrical stimulation. The EMG signals and position information were recorded intra-operatively during ear surgery. An off-line statistical analysis with Spearman's rank correlation coefficient was accomplished. The results show that there is occasionally some correlation at a statistically significant level of 5%. They highly depend on time range, the selected threshold value and time window. Moreover, all the observed correlations are positive against an expected negative correlation. PMID- 22254757 TI - Elastic properties and yield stress of fetal membranes. AB - This is a presentation of a biomechanics project from almost 30 years ago, that, despite the long delay, is both relevant today and may be interesting from a historical perspective. Premature rupture of the amniotic sac membranes enclosing the fetus is, as yet, a not fully understood process, but may related to the mechanical properties of those membranes. The late biomechanics pioneer Tom McMahon and I developed a method for testing the yield stress of fetal membranes and found it to be homogeneous throughout individual samples. The method was: 1. insensitive to initial stretch, 2. avoided damaging contact with the membrane during stress-testing, and 3. modeled the mechanical properties using a power-law relationship. Because the clinical samples were from normal deliveries, clinical correlation remains as an unfinished aim of this project. PMID- 22254758 TI - A chance-constrained approach to preoperative planning of robotics-assisted interventions. AB - In this paper, a planning strategy for robotics-assisted interventions is formulated in terms of uncertainty at the task level. The proposed formulation attempts to increase the chance of success by maximizing robustness with respect to the task uncertainty. It is assumed that the instrument tip pose has a Gaussian distribution in the vicinity of the desired task frame, and the planner is formulated as a chance-constrained programming problem in terms of the chance of collisions and joint limit violations based on the inverse kinematics of the arms. The proposed objective function addresses the robustness as well as the performance of the robotic arms. As an illustrative example, the planning strategy is implemented for LIMA harvesting in minimally invasive coronary artery bypass with the da Vinci robot. PMID- 22254759 TI - ECM versus ICP for point registration. AB - Iterative Closest Point (ICP) is a widely exploited method for point registration that is based on binary point-to-point assignments, whereas the Expectation Conditional Maximization (ECM) algorithm tries to solve the problem of point registration within the framework of maximum likelihood with point-to-cluster matching. In this paper, by fulfilling the implementation of both algorithms as well as conducting experiments in a scenario where dozens of model points must be registered with thousands of observation points on a pelvis model, we investigated and compared the performance (e.g. accuracy and robustness) of both ICP and ECM for point registration in cases without noise and with Gaussian white noise. The experiment results reveal that the ECM method is much less sensitive to initialization and is able to achieve more consistent estimations of the transformation parameters than the ICP algorithm, since the latter easily sinks into local minima and leads to quite different registration results with respect to different initializations. Both algorithms can reach the high registration accuracy at the same level, however, the ICP method usually requires an appropriate initialization to converge globally. In the presence of Gaussian white noise, it is observed in experiments that ECM is less efficient but more robust than ICP. PMID- 22254760 TI - Development of a StandAlone Surgical Haptic Arm. AB - When performing telesurgery with current commercially available Minimally Invasive Robotic Surgery (MIRS) systems, a surgeon cannot feel the tool interactions that are inherent in traditional laparoscopy. It is proposed that haptic feedback in the control of MIRS systems could improve the speed, safety and learning curve of robotic surgery. To test this hypothesis, a standalone surgical haptic arm (SASHA) capable of manipulating da Vinci tools has been designed and fabricated with the additional ability of providing information for haptic feedback. This arm was developed as a research platform for developing and evaluating approaches to telesurgery, including various haptic mappings between master and slave and evaluating the effects of latency. PMID- 22254761 TI - Conceptual design of a miniaturized hybrid local actuator for Minimally Invasive Robotic Surgery (MIRS) instruments. AB - The actuation mechanism of the tip of an endoscopic instrument is a major problem in designing miniature scale motorized instruments, especially when a high level of functionality and multi degrees of freedom (DOF) are concerned. We evaluated the different possible actuation methods for an endoscopic needle holder and proposed a new design of hybrid local-actuation, including a micro DC motor and a piezoelectric (PZT) actuator. The DC motor provided the long movement course required for opening-closing function of the gripper while the PZT guaranteed the high gripping force required for holding the needle. A compact serial configuration was considered for the actuators, producing an overall size of 10 mm in diameter and 39 mm in length, so that it could be implemented in the limited space available. The efficacy of the design was analyzed in a simulation study, using FEM and it was shown that the needle holder is capable to apply a sufficiently high gripping force of 22 N. PMID- 22254762 TI - Method, accuracy and limitation of computer interaction in the operating room by a navigated surgical instrument. AB - This article describes a new interaction device for surgical navigation systems- the so-called navigation mouse system. The idea is to use a tracked instrument of a surgical navigation system like a pointer to control the software. The new interaction system extends existing navigation systems with a microcontroller unit. The microcontroller-unit uses the existing communication line to extract the needed 3D-information of an instrument to calculate positions analogous to the PC mouse cursor and click events. These positions and events are used to manipulate the navigation system. In an experimental setup the reachable accuracy with the new mouse system is shown. PMID- 22254763 TI - Technical accuracy of an O-arm registered surgical navigator. AB - The objective of this study was to assess the accuracy of a commercial surgical navigator using optical tracking modality with automated registration between O arm images and the scanned object. Automated registration was enabled by using the spine navigation software of the navigator. The used phantom was designed by the authors of this paper. The surgical navigators and the O-arm are routinely used at Oulu University Hospital, Oulu, Finland. The distances measured with the surgical navigator from the fixed origin of the phantom were compared to the known phantom accuracy assessment coordinates. The error of the surgical navigator was the difference between measured and true values. The mean displacement error was 0.20 mm with a standard deviation of 0.14 mm. The results show that automated registration is very reliable for image guided surgery (IGS) and that the present accuracy assessment method can be used to periodically check surgical navigator accuracy using O-arm data. PMID- 22254764 TI - A robotics-based flat-panel ultrasound device for continuous intraoperative transcutaneous imaging. AB - Laparoscopic partial nephrectomy has become more and more popular in the last decade. Video laparoscopes remain the gold standard of intraoperative imaging during laparoscopic interventions. However, providing only superficial images of the target tissue. In contrast, ultrasound (US) imaging may offer crucial information of the interior of the target tissue that could improve surgical outcome. In this paper, we propose a new concept and prototype system to manipulate an US-probe during laparoscopic partial nephrectomies. Our primary goal was to provide the surgeon with US-images during the intervention in real time. The prototype system consists of three components: a conventional US machine, a manipulator to guide the US-probe, and a joystick console to control the manipulator. The results of our experiments show that the concept is feasible for US-imaging during laparoscopic partial nephrectomy. PMID- 22254765 TI - Active Tracking and Dynamic Dose Delivery for robotic couch in radiation therapy. AB - Precise and accurate dose delivery is critically important in external beam radiation therapy. In many cases target-volumes are stationary, but the problem arises when the tumors move significantly due to cardiac and respiratory motions. This is a case for tumors in lung, esophagus, pancreas, liver, prostate, breast, and other organs in thoracic and abdominal regions. In the article we have described the Active Tracking and Dynamic Dose Delivery (ATDD) technique for real time tumor motion compensation. In this approach, the robotic treatment table moves while delivering the radiation beam and compensates for breathing-induced tumor motion. Many parameters of the control system, such as patient mass or breathing pattern, are initially uncertain and may vary during the treatment. To solve these problems, feedforward adaptive control was adopted to minimize irradiation to healthy tissue and spare critical organs while ensuring prescribed radiation dose coverage to the target-volume. PMID- 22254766 TI - Development of a triage engine enabling behavior recognition and lethal arrhythmia detection for remote health care system. AB - For ubiquitous health care systems which continuously monitor a person's vital signs such as electrocardiogram (ECG), body surface temperature and three dimensional (3D) acceleration by wireless, it is important to accurately detect the occurrence of an abnormal event in the data and immediately inform a medical doctor of its detail. In this paper, we introduce a remote health care system, which is composed of a wireless vital sensor, multiple receivers and a triage engine installed in a desktop personal computer (PC). The middleware installed in the receiver, which was developed in C++, supports reliable data handling of vital data to the ethernet port. On the other hand, the human interface of the triage engine, which was developed in JAVA, shows graphics on his/her ECG data, 3D acceleration data, body surface temperature data and behavior status in the display of the desktop PC and sends an urgent e-mail containing the display data to a pre-registered medical doctor when it detects the occurrence of an abnormal event. In the triage engine, the lethal arrhythmia detection algorithm based on short time Fourier transform (STFT) analysis can achieve 100 % sensitivity and 99.99 % specificity, and the behavior recognition algorithm based on the combination of the nearest neighbor method and the Naive Bayes method can achieve more than 71 % classification accuracy. PMID- 22254767 TI - Eye-screen distance monitoring for computer use. AB - The extended period many people now spend looking at computer screens is thought to affect eyesight over the long term. In this paper we are concerned with developing and initial evaluation of a wireless camera-based tracking system providing quantitative assessment of computer screen interaction. The system utilizes a stereo camera system and wireless XBee based infrared markers and enables unobtrusive monitoring. Preliminary results indicate that the system is an excellent method of monitoring eye-screen distance. This type of system will enable future studies of eye-screen distance for computer users. PMID- 22254768 TI - Onboard tagging for smart medical devices. AB - Most medical devices are 'dumb:' their role is to acquire, display, and forward data. They make few if any operational decisions based on those data. Onboard tagging is a means whereby a device can embed information about itself, its data, and the sensibility of those data into its data stream. This diagnostic add-on offers a move toward 'smart' devices that will have the ability to affect changes in operational modes based on onboard contextual decision making, such as decisions to avoid needless wireless transmission of corrupt data. This paper presents a description of three types of onboard tags that relate to device hardware (type I tag), signal statistics (type II tag), and signal viability for the intended application (type III tag). A custom wireless pulse oximeter is presented as a use case to show how type II and III tags that convey photoplethysmogram (PPG) statistics and usability specifiers can be calculated and embedded into the data stream without degrading performance. PMID- 22254769 TI - Development of an integrated obesity management waist belt system composed of calorie tracking and waist circumference measuring module for long term monitoring. AB - A waist belt type simple device was designed to monitor the individuals who are obese and want to maintain their consumed calories and waist circumference changes. Relatively long term monitoring with this device could help them maintain their health conditions. This devised system is composed of calorie tracking and waist circumference module. This study suggests feasible and meaningful results. If users' data are collected largely with this developed system, we can reveal the relationship between obesity and daily life pattern. PMID- 22254770 TI - UWB-WBAN sensor node design. AB - In this paper, we discuss the hardware development of a UWB sensor node for wireless body area networks. A few unique UWB pulse generation techniques have been discussed. The sensor node transmits multiple pulses per bit to increase the average power of the transmitted signal in order to improve the bit-error rate (BER) performance. The multiple-pulse per bit technique is also used as the coding scheme to identify the individual sensor nodes when more than one sensor forms a network. The sensors nodes are able to transmit body signals up to 2 m with a BER lower than 10(-5). PMID- 22254771 TI - Radio Frequency Identification (RFID) in medical environment: Gaussian Derivative Frequency Modulation (GDFM) as a novel modulation technique with minimal interference properties. AB - Radio Frequency Identification (RFID) systems in healthcare facilitate the possibility of contact-free identification and tracking of patients, medical equipment and medication. Thereby, patient safety will be improved and costs as well as medication errors will be reduced considerably. However, the application of RFID and other wireless communication systems has the potential to cause harmful electromagnetic disturbances on sensitive medical devices. This risk mainly depends on the transmission power and the method of data communication. In this contribution we point out the reasons for such incidents and give proposals to overcome these problems. Therefore a novel modulation and transmission technique called Gaussian Derivative Frequency Modulation (GDFM) is developed. Moreover, we carry out measurements to show the inteference properties of different modulation schemes in comparison to our GDFM. PMID- 22254772 TI - Scalable customization of atrial fibrillation detection in cardiac monitoring devices: increasing detection accuracy through personalized monitoring in large patient populations. AB - To make it viable for remote monitoring to scale to large patient populations, the accuracy of detectors used to identify patient states of interests must improve. Patient-specific detectors hold the promise of higher accuracy than generic detectors, but the need to train these detectors individually for each patient using expert labeled data limits their scalability. We explore a solution to this challenge in the context of atrial fibrillation (AF) detection. Using patient recordings from the MIT-BIH AF database, we demonstrate the importance of patient specificity and present a scalable method of constructing a personalized detector based on active learning. Using a generic detector having a sensitivity of 76% and a specificity of 57% as its seed, our active learning approach constructs a detector with a sensitivity of 90% and specificity of 85%. This performance approaches that of a patient-specific detector, which has a sensitivity of 94% and specificity of 85%. By selectively choosing examples for training, the active learning approach reduces the amount of expert labeling needed by almost eight fold (compared to the patient-specific detector) while achieving accuracy within 99%. PMID- 22254773 TI - Towards wireless emotional valence detection from EEG. AB - Intelligent affective computers can have many medical and non-medical applications. However today's affective computers are limited in scope by their transferability to other application environments or that they monitor only one aspect of physiological emotion expression. Here, the use of a wireless EEG system, which can be implemented in a body area network, is used to investigate the potential of monitoring emotional valence in EEG, for application in real life situations. The results show 82% accuracy for automatic classification of positive, negative and neutral valence based on film clip viewing, using features containing information on both the frequency content of the EEG and how this changes over time. PMID- 22254774 TI - Improving the reliability of wireless body area networks. AB - In this paper we propose a highly reliable wireless body area network (WBAN) that provides increased throughput and avoids single points of failure. Such networks improve upon current WBANs by taking advantage of a new technology, Cooperative Network Coding (CNC). Using CNC in wireless body area network to support real time applications is an attractive solution to combat packet loss, reduce latency due to retransmissions, avoid single points of failure, and improve the probability of successful recovery of the information at the destination. In this paper, we have extended Cooperative Network Coding, from its original configuration (one-to-one) to many-to-many as in multiple-input-multiple-output (MIMO) systems. Cooperative Network Coding results in increased throughput and network reliability because of the cooperation of the nodes in transmitting coded combination packets across spatially distinct paths to the information sinks. PMID- 22254775 TI - A mixed signal ECG processing platform with an adaptive sampling ADC for portable monitoring applications. AB - This paper describes a mixed-signal ECG processing platform with an 12-bit ADC architecture that can adapt its sampling rate according to the input signals rate of change. This enables the sampling of ECG signals with significantly reduced data rate without loss of information. The presented adaptive sampling scheme reduces the ADC power consumption, enables the processing of ECG signals with lower power consumption, and reduces the power consumption of the radio while streaming the ECG signals. The test results show that running a CWT-based R peak detection algorithm using the adaptively sampled ECG signals consumes only 45.6 MUW and it leads to 36% less overall system power consumption. PMID- 22254776 TI - Battery friendly packet transmission scheme for body sensor networks. AB - For body sensor networks (BSN) nodes, extending battery lifetime is one of the key problems. In this paper, we address the problems of designing battery friendly packet transmission policies in order to maximize the lifetime of batteries for BSN nodes under certain delay and deadline constraints. We present local optimization scheme for slack time and evaluate it with respect to battery performance. The algorithm first simplifies the analytical battery model under the premise of ensuring battery model precision, and then distributes the available slack time between two adjacent tasks. The scheme was simulated for BSN nodes, and the results demonstrate a 79% reduction in the total charge consumption of six tasks in a BSN node along with the deadline constraint of 40 mins. PMID- 22254777 TI - Power allocation strategies to minimize energy consumption in wireless body area networks. AB - The wide scale deployment of wireless body area networks (WBANs) hinges on designing energy efficient communication protocols to support the reliable communication as well as to prolong the network lifetime. Cooperative communications, a relatively new idea in wireless communications, offers the benefits of multi-antenna systems, thereby improving the link reliability and boosting energy efficiency. In this short paper, the advantages of resorting to cooperative communications for WBANs in terms of minimized energy consumption are investigated. Adopting an energy model that encompasses energy consumptions in the transmitter and receiver circuits, and transmitting energy per bit, it is seen that cooperative transmission can improve energy efficiency of the wireless network. In particular, the problem of optimal power allocation is studied with the constraint of targeted outage probability. Two strategies of power allocation are considered: power allocation with and without posture state information. Using analysis and simulation-based results, two key points are demonstrated: (i) allocating power to the on-body sensors making use of the posture information can reduce the total energy consumption of the WBAN; and (ii) when the channel condition is good, it is better to recruit less relays for cooperation to enhance energy efficiency. PMID- 22254778 TI - RiBOMS: RFID-based object management system for home environments. AB - In this paper we introduce a RFID-based object management system, RiBOMS, for home environments. The system has an easy to use pictorial user interface aimed at older adults with associative memory impairments. The system technical correctness was successfully tested in a lab environment. PMID- 22254779 TI - A warning system based on the RFID technology for running-out of injection fluid. AB - For providing an automatic warning system of running-out of injection fluid, RFID technology is applied in this work to propose an infrastructure with low cost to help nurses and patient's company. Specially, a RFID tag is designed and attached on a bag of intravenous drip to demonstrate the benefits in the present system. The main idea of this system is that, tag is disabled when the bag is not empty because of the EM loading due to the liquid contained. The bag can be any kind in the current market and be without any electronic attachment or modification. LAN (Local Area Network) is also applied as a part of this infrastructure for data transmission. PMID- 22254780 TI - Continuous remote vital sign/environment monitoring for returning soldier adjustment assessment. AB - A three-stage study to develop and test an unobtrusive room sensor unit and subject data management system to discover correlation between sensor-based time series measurements of sleep quality and clinical assessments of combat veterans suffering from Post-traumatic Stress Disorder (PTSD) and mild Traumatic Brain Injury (TBI), is described. Experiments and results for testing sensitivity and robustness of the sensor unit and data management protocol are provided. The current sensitivity of remote vital sign monitoring system is below 20% and 10% for respiration and heart rates, respectively. PMID- 22254781 TI - Building smart sensor nodes according to IEEE 1451.3 standard. AB - A Body Sensor Network (BSN) application requires many software and hardware adaptations to support correctly data exchanges between different sensor node architectures. However, these customizations demand extra time, cost and components. This paper introduces a simple development process in order to customize off-the-shelf BSN sensor nodes according to Transducer Bus Interface Modules (TBIM) standard. IEEE 1451.3 offers technical solutions for interfacing multiple and physically separated transducer allowing self-identification, self configuration, plug and play and hot swapping capabilities. These are important requirements relating to most BSN applications. PMID- 22254782 TI - Interoperable and diligent body area networks over IEEE802.15.6 for real-time monitoring. AB - Currently, there are no standardization efforts to define interfaces and verify interoperability among implementations for body area networks (BANs) on IEEE802.15.6. A BAN consists of small and lightweight sensors, such as the ring type SpO2 sensor, and a coordinator that collects vital data from the sensors and transfers them to a backend system for real-time monitoring and analysis. It is important for sensors to be easy-to-use, light for wearing and that they are long lived using a small rechargeable battery. IEEE802.15.6 provides basic features for these sensors. We establish an industry-driven standardization association for healthcare/medical services on IEEE802.15.6. Industry standardization targets current and emerging small sensors, not those for fixed medical devices in hospitals, such as those in the ISO/IEEE11073 family, and deals with time-driven data. We propose a combination of various layers of power-saving functions for a sensor that satisfies the interfaces. We discuss these functions and evaluate them. As a feasibility study, we then test a false-alert system using a BAN configuration following the standard interfaces, though the standardizations and evaluations are still in progress along with the IEEE802.15.6 standardization activity. PMID- 22254783 TI - CARER: efficient dynamic sensing for continuous activity monitoring. AB - Advancement in wireless health sensor systems has triggered rapidly expanding research in continuous activity monitoring for chronic disease management or promotion and assessment of physical rehabilitation. Wireless motion sensing is increasingly important in treatments where remote collection of sensor measurements can provide an in-field objective evaluation of physical activity patterns. The well-known challenge of limited operating lifetime of energy constrained wireless health sensor systems continues to present a primary limitation for these applications. This paper introduces CARER, a software system that supports a novel algorithm that exploits knowledge of context and dynamically schedules sensor measurement episodes within an energy consumption budget while ensuring classification accuracy. The sensor selection algorithm in the CARER system is based on Partially Observable Markov Decision Process (POMDP). The parameters for the POMDP algorithm can be obtained through standard maximum likelihood estimation. Sensor data are also collected from multiple locations of the subjects body, providing estimation of an individual's daily activity patterns. PMID- 22254784 TI - Gait assessment in Parkinson's disease patients through a network of wearable accelerometers in unsupervised environments. AB - Parkinson's disease (PD) predominantly alters the motor performance of the affected individuals. In particular, the loss of dopaminergic neurons compromises the speed, the automaticity and fluidity of movements. As the disease evolves, PD patient's motion becomes slower and tremoric and the response to medication fluctuates along the day. In addition, the presence of involuntary movements deteriorates voluntary movement in advanced state of the disease. These changes in the motion can be detected by studying the variation of the signals recorded by accelerometers attached in the limbs and belt of the patients. The analysis of the most significant changes in these signals make possible to build an individualized motor profile of the disease, allowing doctors to personalize the medication intakes and consequently improving the response of the patient to the treatment. Several works have been done in a laboratory and supervised environments providing solid results; this work focused on the design of unsupervised method for the assessment of gait in PD patients. The development of a reliable quantitative tool for long-term monitoring of PD symptoms would allow the accurate detection of the clinical status during the different PD stages and the evaluation of motor complications. Besides, it would be very useful both for routine clinical care as well as for novel therapies testing. PMID- 22254785 TI - Low-power sensor module for long-term activity monitoring. AB - Wearable sensor modules are a promising approach to collecting data on functional motor activities, both for repeated and long-term assessments, as well as to investigate the transfer of therapy to activities of daily living at home, but have so far either had limited sensing capabilities, or were not laid out for long-term monitoring. This paper presents ReSense, a miniature sensor unit optimized for long-term monitoring of functional activity. Inertial MEMS sensors capture accelerations along six degrees of freedom and a barometric pressure sensor serves as a precise altimeter. Data is written to an integrated memory card. The realized module measures O25 * 10 mm, weighs 10 g and can record continuously for 27 h at 25 Hz and over 22 h at 100 Hz. The integrated power management system detects inactivity and extends the operating time by about a factor of two, as shown by initial 24 h recordings on five energetic healthy adults. The integrated barometric pressure sensor allowed to identify activities incorporating a change in altitude, such as going up/down stairs or riding an elevator. By taking into account data from the inertial sensors during the altitude changes, it becomes possible to distinguish between these two activities. PMID- 22254786 TI - Path-loss estimation of wireless channels in capsule endoscopy from X-ray CT images. AB - The paper describes an estimation method of path-loss for capsule endoscopy using wireless communications to send images from digestive tract. This method is based on the use of a set of X-ray computer tomography (CT) images of the patient. In order to evaluate this method, we conducted a measurement of received signal strength (RSS) by introducing a signal generator (SG) in esophagus and duodenum of a participant. As a result of comparisons, the method provides estimates on path-loss for the participant with estimation errors of less than 6 dB in 75% measurement positions. PMID- 22254787 TI - Long-term performance of a CE-approved telemetric intracranial pressure monitoring. AB - Telemetric intracranial pressure (ICP) monitoring has been a challenge throughout several decades. Major obstruction was to minimize zero drift of absolute pressure sensors. A new promising product demonstrating in-vitro excellent long term stability has been tested for its reliability in an animal model with a follow-up of up to 2 years. In "minipigs" sub-dural (Raumedic-STel(r), Helmbrechts Germany) and intraparenchymal (Raumedic-PTel(r)) telemetric ICP probes have been inserted. Standard ICP probes (Raumedic Neurovent P(r)) served as controls. In regular intervals of 3 months the telemetrically and conventionally measured ICP have been compared. For each control a new conventional ICP probe has been inserted frontally to the telemetric device in the generalized anesthetized minipigs, resulting in overall 38 comparisons. Bland Altman-plots, Chi2-tests and matched pair T-tests (significance level < 0.05) were used for data-analysis. The zero-shift was -1.7 +/- 7.6 mm Hg (limits of agreement: 4.4 +/- 1.9 mm Hg) and -3.0 +/- 6.0 mm Hg (limits of agreement: 3.6 +/ 2.6 mm Hg) in STel and PTel respectively meeting well the devices specification of +/- 2 mm Hg drift per year. The reliability of both telemetric probes has been proved as quite comparable (p=0.2). These new telemetric ICP probes demonstrate reliable data during at least the first 6 months after implantation. PMID- 22254788 TI - Wearable monitoring systems for psychological and physiological state assessment in a naturalistic environment. AB - Wearable monitoring systems based on Smart Fibers and Interactive Textile (SFIT) platforms combine imperceptible sensing and computing functions with an interactive communication network. The integration into clothes of bio-potential sensors for health monitoring provides daily physiological parameters through a continuous, personalized, self-made detection of vital signs and the tracking of behavioral indicators of the subject. SFIT platforms can be used unobtrusively into the routinely daily activity to perform remote monitoring of persons in different circumstances and situations: during controlled exercises and diagnostic procedures as a biofeedback tool, during the usual daily life, during sleep or even to monitor behavioral indexes and mood disorders. Treatment of stress may include also training in cognitive-behavioral skills. Moreover, physiological signs and behavioral monitoring based on a multivariable approach leads to an enhanced sensitivity and specificity of these systems for the prediction of critical events. This paper presents two applications: a platform used in the frame of PSYCHE project, based on textile platforms and portable sensing devices for the long term and short term acquisition of data from patients affected by mood disorders and a platform addressing healthy subjects, based on biofeedback methodology, designed for the training of professional drivers named Mental Bio. PMID- 22254789 TI - Neuroscience, virtual reality and neurorehabilitation: brain repair as a validation of brain theory. AB - This paper argues that basing cybertherapy approaches on a theoretical understanding of the brain has advantages. On one hand it provides for a rational approach towards therapy design while on the other allowing for a direct validation of brain theory in the clinic. As an example this paper discusses how the Distributed Adaptive Control architecture, a theory of mind, brain and action, has given rise to a new paradigm in neurorehabilitation called the Rehabilitation Gaming System (RGS) and to novel neuroprosthetic systems. The neuroprosthetic system considered is developed to replace the function of cerebellar micro-circuits, expresses core aspects of the learning systems of DAC and has been successfully tested in in-vivo experiments. The Virtual reality based rehabilitation paradigm of RGS has been validated in the treatment of acute and chronic stroke and has been shown to be more effective than existing methods. RGS provides a foundation for integrated at-home therapy systems that can operate largely autonomously when also augmented with appropriate physiological monitoring and diagnostic devices. These examples provide first steps towards a science based medicine. PMID- 22254790 TI - Finding physiological responses in vestibular evoked potentials. AB - Vestibular prostheses are regarded as a promising tool to restore lost sensation in patients with vestibular disorders. These prostheses often electrically stimulate the vestibular nerve and stimulation efficacy is evaluated by measuring the vestibulo-ocular reflex (VOR). However, eye movement recording as intuitive metric of vestibular functionality is difficult to obtain outside the laboratory environment, and hence not available as an error signal in a closed-loop prosthesis. Recently we investigated vestibular evoked potentials (VEPs) by stimulating and recording in the same semicircular canal of a guinea pig. Here we studied the correlation between VOR and one region of VEP. We further analyzed a second portion of VEP, where vestibular nerve activity should occur using rectified bin integration (RBI). To this end, stimulation artifact was significantly reduced by hardware and software approaches. We found a high VEP VOR correlation (R-squared=0.86), suggesting that VEP could substitute VOR as metric of vestibular function. Differences between below and above vestibular threshold stimulation were seen for the second portion of VEP. Further investigations are required to determine the specific parts of VEP that accurately represents vestibular function(s). PMID- 22254791 TI - Vestibular implants: the first steps in humans. AB - Currently there is no efficient treatment for patients with severe bilateral vestibular function impairment. Presence of oscillopsia is their main complaint. It has a significant negative impact on their quality of life. Recently it has been shown that angular vestibulo-ocular reflex can be partially restored in animals. In humans it is possible to elicit a nystagmic response by electric stimulation of ampullary parts of the vestibular nerve. Controlled eye movements can be generated by frequency and intensity modulation of the restored baseline firing rate of the vestibular nerve. During adaptation phase to the electric stimulus, patients experience nystagmus with associated inconveniences. By repetition of "on/off periods" the duration of the adaptation phase can be significantly decreased. Results show that permanent electric stimulation is necessary to maintain this "optimal" adaptation state. PMID- 22254792 TI - Ethical issues in the development of a vestibular prosthesis. AB - During the development of a neural prosthesis, various ethical aspects have to be considered. These range from the basic design of the prosthesis and manufacturing of the various components and the system using biocompatible materials to extensive in vitro and in vivo testing and investigations in the animal model, before taking the final step and going to human trials. As medical systems, neural prostheses have to be proven absolutely safe before considering any clinical study. In this work, the various steps accompanying the development are described taking the example of a vestibular prosthesis currently developed within the European project CLONS. PMID- 22254793 TI - Secret laws of the labyrinth. AB - This abstract presents new results on the structure and function of vestibular part of the inner ear of vertebrates with special emphasis on human behavior. First we summarize a mathematical analysis of motion of the endolymphatic fluid, justifying known approximated formulas for the cupula functioning based on a set of anatomical parameters. Some of these parameters can be estimated from the bony labyrinth, some others cannot be. We present original data issued from synchrotron microtomography (S MU CT) of five tetrapod species, allowing to compare bony and membranous labyrinths. We derive several simple and robust empirical laws connecting membranous parameters and bony parameters. Then, using published results on human labyrinths (Bradshaw et al. 2009), we deduce functional consequences for the human labyrinths. For instance we show that, contrarily to current belief, the kinematic sensitivity for yaw is larger than for pitch and roll. PMID- 22254794 TI - Non-linear Galilean vestibular receptive fields. AB - We present a set of formulas for the receptive fields of the vestibular neurons that are motivated by Galilean invariance. We show that these formulas explain non-trivial data in neurophysiology, and suggest new hypothesis to be tested in dynamical 3D conditions. Moreover our model offers a way for neuronal computing with 3D displacements, which is reputed to be hard, underlying the vestibular reflexes. This computation is presented in a Bayesian framework. The basis of the model is the necessity of living bodies to work invariantly in space-time, allied to the necessary discreteness of neuronal transmission. PMID- 22254795 TI - Vestibular prosthesis tested in rhesus monkeys. AB - We are studying the effectiveness of a semicircular canal prosthesis to improve postural control, perception of spatial orientation, and the VOR in rhesus monkeys with bilateral vestibular hypofunction. Balance is examined by measuring spontaneous sway of the body during quiet stance and postural responses evoked by head turns and rotation of the support surface; perception is measured with a task derived from the subjective visual vertical (SVV) test during static and dynamic rotation in the roll plane; and the angular VOR is measured during rotation about the roll, pitch, and yaw axes. After the normal responses are characterized, bilateral vestibular loss is induced with intratympanic gentamicin, and then multisite stimulating electrodes are chronically implanted into the ampullae of all three canals in one ear. The postural, perceptual, and VOR responses are then characterized in the ablated state, and then bilateral, chronic electrical stimulation is applied to the ampullary nerves using a prosthesis that senses angular head velocity in three-dimensions and uses this information to modulate the rate of current pulses provided by the implanted electrodes. We are currently characterizing two normal monkeys with these paradigms, and vestibular ablation and electrode implantation are planned for the near future. In one prior rhesus monkey tested with this approach, we found that a one-dimensional (posterior canal) prosthesis improved balance during head turns, perceived head orientation during roll tilts, and the VOR in the plane of the instrumented canal. We therefore predict that the more complete information provided by a three-dimensional prosthesis that modulates activity in bilaterally paired canals will exceed the benefits provided by the one-dimensional, unilateral approach used in our preliminary studies. PMID- 22254796 TI - Chronic cuff electrode recordings from walking Gottingen mini-pigs. AB - We present data from cuff electrode recordings from a mixed sensory-/motor nerve as expressed during walking in chronically implanted Gottingen mini-pigs. Our results show that it is possible to filter out residual electromyographic interference and that the energy content of the resulting electroneurographic (ENG) signals modulate clearly with gait. The approach may be used to detect heel strike from cuff electrode measurements to control the timing of stimulation in implantable foot drop correction systems. PMID- 22254797 TI - Compact wireless neural recording system for small animals using silicon-based probe arrays. AB - This paper reports on a compact, small-scale neural recording system combining state-of-art silicon-based probe arrays with a light-weight 32-channel wireless head stage. The system is equipped with two- and four-shaft, comb-shaped probe arrays connected to highly flexible ribbon cables enabling a reliable and controlled insertion of probe arrays through the intact dura mater into the medial prefrontal cortex and nucleus accumbens of rats. The in vivo experiments applied the 5-choice serial reaction time task (5-CSRTT) using freely behaving rats in order to understand the neural basis of sustained visual attention and impulsivity. The long-term stability of the system allowed local field potential (LFP) activity to be recorded without a significant decrement in signal quality for up to 28 weeks, and similarly, we were able to follow single unit activity for up to 4 weeks. PMID- 22254798 TI - Robust intraocular acquisition of the accommodation demand using eyeball movements. AB - The Artificial Accommodation System is a mechatronic lens implant that will restore the ability of the human eye to accommodate. Therefore, the accommodation demand has to be acquired. One possibility is to measure the vergence angle of the eyeballs in reference to an external field. Using the earth magnetic field as reference the proof of this measuring principle was possible. Still there are drawbacks like high responsivity to interferences and limitations of the measuring range. The new approach is to use the gravity field as reference and thus reduce the responsivity to interferences. The measuring range can be expanded by combining both sensing principles. PMID- 22254799 TI - Chronic behavior evaluation of a micro-machined neural implant with optimized design based on an experimentally derived model. AB - Understanding the mechanical interactions between implants and the surrounding tissue is known to have an important role for improving the bio-compatibility of such devices. Using a recently developed model, a particular micro-machined neural implant design aiming the reduction of insertion forces dependence on the insertion speed was optimized. Implantations with 10 and 100 MUm/s insertion speeds showed excellent agreement with the predicted behavior. Lesion size, gliosis (GFAP), inflammation (ED1) and neuronal cells density (NeuN) was evaluated after 6 week of chronic implantation showing no insertion speed dependence. PMID- 22254800 TI - Ensuring minimal humidity levels in hermetic implant housings. AB - The electronic circuitry of active implantable devices is commonly protected against the risk of water-induced corrosion by using gas-tight (hermetic) packages, preventing moisture from the host body to reach the electronics. However, when closing the package, one has to ensure that the packaged components do not contain moisture that could rise humidity inside the package to critical levels by outgassing. For our miniature metal/ceramic packages, we found a drying procedure of 120 degrees C at 180 mbar absolute pressure for one hour, followed by a dry helium purge sufficient to keep the relative humidity below 2.5% over a time span of 300 days at 80 degrees C, corresponding to over 15 years at 37 degrees C. The additional integration of a desiccant inside the package permits to keep the relative humidity below 0.1%, the detection limit of the integrated sensor. This sensor was selected based on an evaluation of 17 commercially available humidity sensors. PMID- 22254801 TI - A 32-channel fully implantable wireless neurosensor for simultaneous recording from two cortical regions. AB - We present a fully implantable, wireless, neurosensor for multiple-location neural interface applications. The device integrates two independent 16-channel intracortical microelectrode arrays and can simultaneously acquire 32 channels of broadband neural data from two separate cortical areas. The system-on-chip implantable sensor is built on a flexible Kapton polymer substrate and incorporates three very low power subunits: two cortical subunits connected to a common subcutaneous subunit. Each cortical subunit has an ultra-low power 16 channel preamplifier and multiplexer integrated onto a cortical microelectrode array. The subcutaneous epicranial unit has an inductively coupled power supply, two analog-to-digital converters, a low power digital controller chip, and microlaser-based infrared telemetry. The entire system is soft encapsulated with biocompatible flexible materials for in vivo applications. Broadband neural data is conditioned, amplified, and analog multiplexed by each of the cortical subunits and passed to the subcutaneous component, where it is digitized and combined with synchronization data and wirelessly transmitted transcutaneously using high speed infrared telemetry. PMID- 22254802 TI - An automated method to determine angular preferentiality using LFPs recorded from rat barrel cortex by brain-chip interface under mechanical whisker stimulation. AB - The sensory information processing in the rodents is mainly done by whisking, through which they explore the environment, perform object localization, texture and shape discrimination very precisely. During whisking, microcircuits in the corresponding barrel columns get activated to segregate and integrate the tactile information through the information processing pathway. To primarily understand the whisking mechanism angular preferentiality determination is very important. In this work we propose an automated method to determine different events present in the local field potentials (LFPs), calculate latencies and amplitudes related to those events and use them along with the stimulation angle information to determine the angular preferentiality. The method is extensively tested on LFPs recorded from S1 barrel cortex of anesthetized rats using EOSFET (Electrolyte Oxide-Semiconductor Field Effect Transistor) based neuronal probes. PMID- 22254803 TI - Point-process analysis of neural spiking activity of muscle spindles recorded from thin-film longitudinal intrafascicular electrodes. AB - Recordings from thin-film Longitudinal Intra-Fascicular Electrodes (tfLIFE) together with a wavelet-based de-noising and a correlation-based spike sorting algorithm, give access to firing patterns of muscle spindle afferents. In this study we use a point process probability structure to assess mechanical stimulus response characteristics of muscle spindle spike trains. We assume that the stimulus intensity is primarily a linear combination of the spontaneous firing rate, the muscle extension, and the stretch velocity. By using the ability of the point process framework to provide an objective goodness of fit analysis, we were able to distinguish two classes of spike clusters with different statistical structure. We found that spike clusters with higher SNR have a temporal structure that can be fitted by an inverse Gaussian distribution while lower SNR clusters follow a Poisson-like distribution. The point process algorithm is further able to provide the instantaneous intensity function associated with the stimulus response model with the best goodness of fit. This important result is a first step towards a point process decoding algorithm to estimate the muscle length and possibly provide closed loop Functional Electrical Stimulation (FES) systems with natural sensory feedback information. PMID- 22254804 TI - Memory efficient on-line streaming for multichannel spike train analysis. AB - Rapid advances in multichannel neural signal recording technologies in recent years have spawned broad applications in neuro-prostheses and neuro rehabilitation. The dramatic increase in data bandwidth and volume associated with multichannel recording requires a significant computational effort which presents major design challenges for brain-machine interface (BMI) system in terms of power dissipation and hardware area. In this paper, we present a streaming method for implementing real-time memory efficient neural signal processing hardware. This method exploits the pseudo-stationary property of neural signals and, thus, eliminates the need of temporal storage in batch-based processing. The proposed technique can significantly reduce memory size and dynamic power while effectively maintaining the accuracy of algorithms. The streaming kernel is robust when compared to the batch processing over a range of BMI benchmark algorithms. The advantages of the streaming kernel when implemented on field-programmable gate array (FPGA) devices are also demonstrated. PMID- 22254805 TI - Simulations of hearing loss and hearing aid: effects on electrophysiological correlates of listening effort. AB - In the last decades, many investigations were done to examine the effects of sensorineural hearing loss on the speech perception ability. Besides testing hearing impaired persons, there is also the possibility to simulate the hearing loss. Therefore, some electrophysiological as well as speech recognition studies were performed in normal hearing subjects using techniques to model the sensorineural hearing loss. Thus, the effects of peripheral hearing loss without central auditory pathologies can be examined. In previous studies, we have shown, that the wavelet phase synchronization stability (WPSS) of auditory late responses could serve as a possible indicator of listening effort. Now, the aims of this present study were to explore the effects on the WPSS by using two different simulations of hearing loss and a simulated hearing aid. The preliminary results showed, that in case of a simultaneous simulation of hearing loss by noise masking and a hearing aid, an objective discrimination between an easy and a difficult listening situation can be achieved. Furthermore, the WPSS reflected also a good discrimination by using the filtered and attenuated paradigms. PMID- 22254806 TI - The effects of age and hearing impairment on the extraction of listening effort correlates. AB - In clinical practice, an objective method to assess listening effort is still not available. The benefit of such a measure would be to reduce the listening effort in hearing impaired persons by an adequate adaption of their personal hearing aids. In foregoing studies, we have shown that the wavelet phase synchronization stability (WPSS) of auditory late responses (ALRs) could serve as a feasible measure of listening effort. Here, tonal and noise embedded syllabic paradigms were employed to achieve ALR sequences in normal hearing subjects. The aims of this ongoing study were 1) to extract the WPSS of ALR sequences in hearing impaired persons, middle-aged normal hearing persons and younger normal hearing subjects, 2) to investigate possible age-related influences on the WPSS and 3) to examine a feasible influence of the hearing loss on the WPSS. It is concluded, that the WPSS of ALR sequences can be extracted in normal hearing as well as in hearing impaired persons. An age related effect regarding the WPSS was not noticeable and the intergroup comparison of the difference of the WPSS showed a tendency to be larger for the hearing impaired compared to the normal hearing middle-aged subjects. The latest can be interpreted that this subject group showed a larger effort to solve the auditory paradigms. PMID- 22254807 TI - EEG-based upper alpha neurofeedback training improves working memory performance. AB - Neurofeedback (NF) training has revealed its therapeutical effects to treat a variety of neurological and psychological disorders, and has demonstrated its feasibility to improve certain cognitive aptitudes in healthy users. Although promising results of NF training exist in recent literature, the reliability of its effects remains questioned due to a lack of deep studies examining its impact on the human electrophysiology. This paper presents a NF training aimed at improving working memory performance in healthy users by the enhancement of upper alpha band. A user-specific training was used (upper alpha was determined for each user using the individual alpha frequency) to reduce the unspecific factors of training the entire classical alpha band as traditional NF usually does. EEG assessments in active and passive open-eyes state were conducted pre/post the NF training. The EEG analyses reveal the UA enhancement during the active tasks which is independent of other frequency bands. UA was also enhanced in the passive state but independence could not be obtained in lower alpha band. Finally, significant improvement in working memory was obtained with regard to a control group. PMID- 22254808 TI - Subject identification through standard EEG signals during resting states. AB - In the present work, we used the brain electroencephalografic activity as an alternative means to identify individuals. 50 healthy subjects participated to the study and 56 EEG signals were recorded through a high-density cap during one minute of resting state either with eyes open and eyes closed. By computing the power spectrum density (PSD) on segments of 10 seconds, we obtained a feature vector of 40 points, notably the PSD values in the standard frequency range (1-40 Hz), for each EEG channel. By using a naive Bayes classifier and K-fold cross validations, we observed high correct recognition rates (CRR) at the parieto occipital electrodes (~78% during eyes open, ~89% during eyes closed). Notably, the eyes closed resting state elicited the highest CRRs at the occipital electrodes (92% O2, 91% O1), suggesting these biometric characteristics as the most suitable, among those investigated here, for identifying individuals. PMID- 22254809 TI - Estimating cortical connectivity in functional near infrared spectroscopy using multivariate autoregressive modeling. AB - Performing cognitive tasks requires close interaction between cortical regions of the brain. Monitoring the functional connectivity during a particular task could contribute to a better understanding of the role and interactions of underlying brain regions. In this paper, we employ time variant Multi-variate Autoregressive (MAR) modeling to establish functional connectivity between regions involved in a cognitive task. Data is collected from neonates whose brain activity was monitored by functional Near Infrared Spectroscopy (fNIRS) while being exposed to 2 different types of auditory stimuli. The method was applied to data from 3 subjects on a predefined set of channels known to be involved in auditory and structural processing. The connectivity analysis reveals a common connectivity pattern among the subjects which is neuroanatomically and functionally relevant. Moreover, investigation of temporal evolution of connectivity between temporal and frontal areas shows an increase in connection strength towards the end of the experiment. PMID- 22254810 TI - Study of the functional hyperconnectivity between couples of pilots during flight simulation: an EEG hyperscanning study. AB - Brain Hyperscanning, i.e. the simultaneous recording of the cerebral activity of different human subjects involved in interaction tasks, is a very recent field of Neuroscience aiming at understanding the cerebral processes generating and generated by social interactions. This approach allows the observation and modeling of the neural signature specifically dependent on the interaction between subjects, and, even more interestingly, of the functional links existing between the activities in the brains of the subjects interacting together. In this EEG hyperscanning study we explored the functional hyperconnectivity between the activity in different scalp sites of couples of Civil Aviation Pilots during different phases of a flight reproduced in a flight simulator. Results shown a dense network of connections between the two brains in the takeoff and landing phases, when the cooperation between them is maximal, in contrast with phases during which the activity of the two pilots was independent, when no or quite few links were shown. These results confirms that the study of the brain connectivity between the activity simultaneously acquired in human brains during interaction tasks can provide important information about the neural basis of the "spirit of the group". PMID- 22254811 TI - BOLD correlations to force in precision grip: an event-related study. AB - The introduction of functional neuroimaging has resulted in a profusion of knowledge on various topics, including how blood oxygenation level dependent (BOLD) signal in the brain is related to force. To date, studies that have explicitly examined this relationship have used block designs. To gain a better understanding of the networks involved in human motor control, analyses sensitive to temporal relationships, such as Granger Causality or Dynamic Causal Modeling, require event-related designs. Therefore the goal of this experiment was to examine whether similar or even better relationships between BOLD and force during precision grip could be determined with an event-related design. Five healthy subjects exerted forces at 10%, 20% and 30% of maximum voluntary force, along with an observation condition. We report that the BOLD signal was linearly correlated with precision grip force in primary sensorimotor cortex and cerebellum, showing slightly better correlations than previous work. The results provide a clearer picture regarding the sensitivity of BOLD signal to force and show that event-related designs can be more appropriate than block designs in motor tasks. PMID- 22254812 TI - ECoG based cortical function mapping using general linear model. AB - Electrocorticography (ECoG) is an emerging tool to map brain functions in the context of neurosurgical intervention. Previous mapping methods based on the event related power spectrum are prone to noise. To improve the robustness of cortical function mapping, general linear model (GLM), which has been widely used in the analysis of functional magnetic resonance imaging (fMRI) data, is applied to bandpass filtered ECoG signals from each electrode. For a specific task, electrodes with best fitting parameters of the signal are identified, and the statistical significance of the fitting is mapped on the standard 3D brain model to provide a personalized map of sensorimotor functions. With the analysis of four patients' data, the proposed approach yields consistent results with those obtained by electrical cortical stimulation (ECS), while showing promising performance against noise. PMID- 22254814 TI - Toward 'optimal' schemes of robot assistance to facilitate motor skill learning. AB - We investigate whether and on what circumstances physical interaction with a robot may facilitate the acquisition of a novel motor skill. We focus on two different motor tasks: (i) intermanual transfer of cursive handwriting and (ii) acquisition of a putting skill. In the case of handwriting, we found that intermanual transfer is facilitated by forms of interaction that account for the temporal aspects of the movements. In the case of putting, we found that guidance is helpful in improving longitudinal error (a matter of speed accuracy), but not directional error (a matter of position accuracy). Based on these results, we draw some tentative conclusions on which tasks can benefit from guidance, and how robots should be programmed to maximize their effect. PMID- 22254813 TI - Task-related MEG source localization via discriminant analysis. AB - To investigate the neural activity corresponding to different cognitive states, it is of great importance to localize the cortical areas that are associated with task-related modulation. In this paper, we propose a novel discriminant pattern source localization (DPSL) method to analyze MEG data. Unlike most traditional source localization methods that aim to find "dominant" sources, DPSL is developed to capture the "differential" sources that distinguish different cognitive states. As will be demonstrated by the experimental results in this paper, the proposed DPSL method offers superior accuracy to identify the spatial locations of task-related sources. PMID- 22254815 TI - MusicGlove: motivating and quantifying hand movement rehabilitation by using functional grips to play music. AB - People with stroke typically must perform much of their hand exercise at home without professional assistance as soon as two weeks after the stroke. Without feedback and encouragement, individuals often lose motivation to practice using the affected hand, and this disuse contributes to further declines in hand function. We developed the MusicGlove as a way to facilitate and motivate at home practice of hand movement. This low-cost device uses music as an interactive and motivating medium to guide hand exercise and to quantitatively assess hand movement recovery. It requires the user to practice functional movements, including pincer grip, key-pinch grip, and finger-thumb opposition, by using those movements to play different musical notes, played along to songs displayed by an interactive computer game. We report here the design of the glove and the results of a single-session experiment with 10 participants with chronic stroke. We found that the glove is well suited for use by people with an impairment level quantified by a Box and Blocks score of at least around 7; that the glove can be used to obtain a measure of hand dexterity (% of notes hit) that correlates strongly with the Box and Blocks score; and that the incorporation of music into training significantly improved both objective measures of hand motor performance and self-ratings of motivation for training in the single session. PMID- 22254816 TI - Classification of strategies for disturbance attenuation in human-human collaborative tasks. AB - Rigorous analyses of the mechanisms human-human physical interaction are only possible if corresponding means of systematically classifying dyad strategies are in place. Previous suggestions for classification of strategies neglect the high level of redundancy that is present when attenuation of external disturbances is required. To address this, we propose a quantitative classification system based on combined interaction force and EMG recordings of the flexion and extension activities of each partner in a given dyad. PMID- 22254817 TI - MEDIFRAME--remote volume rendering visualization framework. AB - Tablet computers, netbooks, and other mobile devices find their way into medical applications. However, advanced visualization such as volume rendering of tomographic data is too demanding for these devices. Hence the concept of remote visualization gains attention again. Using powerful servers views are rendered and transmitted as video-stream to the mobile devices in real-time. In this article we present a new extension to our software framework Mediframe allowing easy setup of remote visualization in the medical imaging domain. We give an overview of the general visualization architecture and explain the remoting component in detail. Tests from different cities in Europe revealed good latency and rendering times as well as a surprisingly smooth user experience. We conclude that our remote visualization framework is a handy, functional extension to medical visualization applications. PMID- 22254818 TI - A semantically-aided approach for online annotation and retrieval of medical images. AB - The need for annotating the continuously increasing volume of medical image data is recognized from medical experts for a variety of purposes, regardless if this is medical practice, research or education. The rich information content latent in medical images can be made explicit and formal with the use of well-defined ontologies. Evolution of the Semantic Web now offers a unique opportunity of a web-based, service-oriented approach. Remote access to FMA and ICD-10 reference ontologies provides the ontological annotation framework. The proposed system utilizes this infrastructure to provide a customizable and robust annotation procedure. It also provides an intelligent search mechanism indicating the advantages of semantic over keyword search. The common representation layer discussed facilitates interoperability between institutions and systems, while semantic content enables inference and knowledge integration. PMID- 22254819 TI - Biomedical devices and systems security. AB - Medical devices have been changing in revolutionary ways in recent years. One is in their form-factor. Increasing miniaturization of medical devices has made them wearable, light-weight, and ubiquitous; they are available for continuous care and not restricted to clinical settings. Further, devices are increasingly becoming connected to external entities through both wired and wireless channels. These two developments have tremendous potential to make healthcare accessible to everyone and reduce costs. However, they also provide increased opportunity for technology savvy criminals to exploit them for fun and profit. Consequently, it is essential to consider medical device security issues. In this paper, we focused on the challenges involved in securing networked medical devices. We provide an overview of a generic networked medical device system model, a comprehensive attack and adversary model, and describe some of the challenges present in building security solutions to manage the attacks. Finally, we provide an overview of two areas of research that we believe will be crucial for making medical device system security solutions more viable in the long run: forensic data logging, and building security assurance cases. PMID- 22254820 TI - Assessing the HIPAA standard in practice: PHR privacy policies. AB - Health service providers are starting to become interested in providing PHRs (Personal Health Records). With PHRs, access to data is controlled by the patient, and not by the health care provider. Companies such as Google and Microsoft are establishing a leadership position in this emerging market. A number of benefits can be achieved with PHRs, but important challenges related to security and privacy must be addressed. This paper presents a review of the privacy policies of 20 free web-based PHRs. Security and privacy characteristics were extracted and assessed according to the HIPAA standard. The results show a number of important differences in the characteristics analyzed. Some improvements can be made to current PHR privacy policies to enhance the audit and management of access to users' PHRs. A questionnaire has been defined to assist PHR designers in this task. PMID- 22254821 TI - Study on self hearing assessment using speech sounds. AB - In this study, we proposed new self assessment of hearing loss in mobile phones and realized a function of compensation for hearing impaired person. The results of experiments on mobile phone showed that the proposed hearing test is sufficient to check hearing loss and the compensation based on the result of the proposed hearing test can improve speech intelligibility of hearing impaired persons. PMID- 22254822 TI - WiiPD--an approach for the objective home assessment of Parkinson's disease. AB - This paper introduces WiiPD, an approach to home-based objective assessment of Parkinson's disease. WiiPD aims to make use of the many capabilities of the Nintendo Wii Remote in combination with a number of bespoke data gathering methods to provide a rich and engaging user experience that can capture a wide range of motor and non-motor metrics. In this paper we discuss the architecture of the approach, and provide details of the implementation and testing of the motor-assessment component of the system. Initial results of testing on 6 users indicate that the system is able to differentiate between normal and abnormal motor performance, suggesting that the system has the potential to monitor the motor fluctuations associated with Parkinson's disease. PMID- 22254823 TI - Rethinking health. AB - Lifestyle is a key determinant in the prevention and management of chronic diseases. If we would exercise regularly, eat healthy, control our weight, sleep enough, manage stress, not smoke and use alcohol only moderately, 90 % of type II diabetes, 80 % of coronary heart disease, and 70 % of stroke could be prevented. Unfortunately, global health statistics show that health promotion campaigns and healthcare have failed to persuade people to change and manage their lifestyles. A disruptive solution to this "tsunami" of chronic conditions is needed to radically improve people's abilities to manage their health. PMID- 22254824 TI - Transient respiratory response to hypercapnia: analysis via a cardiopulmonary simulation model. AB - In recent years, our group has developed a comprehensive cardiopulmonary (CP) model that comprises the heart, systemic and pulmonary circulations, lung mechanics and gas exchange, tissue metabolism, and cardiovascular and respiratory control mechanisms. In this paper, we analyze the response of the model to hypercapnic conditions and hence focus on the chemoreflex control mechanism. Particularly, we have enhanced the peripheral chemoreceptor model in order to better reflect respiratory control physiology. Using the CO(2) fraction in the inspired air as input to the CP model, we were able to analyze the transient response of the system to CO(2) step input at different levels, in terms of alveolar gas partial pressures, tidal volume, minute ventilation and respiratory frequency. Model predictions were tested against experimental data from human subjects [1]. Results show good agreement for all the variables under study during the transient phases and low root mean square errors at steady state. This indicates the potential for the model to be used as a valid tool for clinical practice and medical research, providing a complementary way to experience-based clinical decisions. PMID- 22254825 TI - The impact of gravity during head-up tilt. AB - The impact of gravity during head-up tilt, a test often used in the clinic to diagnose patients who suffer from dizziness or frequent episodes of syncope, is not well described. This study uses mathematical modeling to analyze experimental blood pressure data measured at the level of the aorta and the carotid sinuses in a healthy volunteer. During head-up tilt the head is lifted above the heart stimulating gravitational pooling of blood in the lower extremities. This shift in volume is followed by an increase in blood pressure in the lower body, while the pressure in the head decreases, while the pressure at the level of the heart is either constant or increases. At the same time, the normal response to head-up tilt is an increase in heart rate. The change in posture, and subsequent change in heart rate, is believed to be mediated via baroreflex inhibition. Traditional understanding of the baroreceptor system is that inhibition is a result of a blood pressure drop. However, only the carotid sinus blood pressure is decreased during head-up tilt, suggesting that the receptors at this location are more prominent than the receptors in the aortic arch. To explore this hypothesis further, we developed a model predicting hydrostatic height between the two locations. Results from this model were compared with measurements. Furthermore, we show, using a differential equations model predicting blood pressure, that it is possible to predict blood pressure measured at the level of the carotid sinuses using heart rate as an input. Finally, we discuss our results in relation to measurements obtained at the two locations. PMID- 22254826 TI - Modeling study of the failing heart and its interaction with an implantable rotary blood pump. AB - The effectiveness of clinical diagnosis and treatment of heart failure is a direct function of clinical signs that can be measured in a patient within cost and safety constraints. Large-scale mathematical modeling can be a key tool in revealing important, measurable clinical signs of heart failure, furthering medical understanding and development of treatment. In the first part of this study we have created two models of left heart failure--diastolic and systolic, using our human cardiovascular-respiratory system (H-CRS) model, and we present a comparison of the two types with emphasis on novel and differentiating clinical signs, such as tricuspid flow and septal motion. In the event of compromised left ventricular performance, mechanical left ventricular assist devices (LVAD) are often implanted to augment or completely replace the pumping action of the left ventricle (LV). One such type is the implantable rotary blood pump (iRBP). Several design issues related to the iRBP are difficult to study experimentally due to procedure complexity and limitations in animal models of heart failure [2]. Therefore, modeling has become a key tool in iRBP development. In the second part of this study, we have introduced an iRBP model based on [1]-[2] in the systolic failing heart to study the interactions. We consider optimal motor settings for different levels of LV assistance, the effects of the iRBP on the right heart, septum, and pulmonary circulation. Our model results align with those reported in [1]-[2]. Improvement in cardiac output, pulmonary congestion, and heart work are seen with the iRBP. We observe lowered septal assistance to RV and LV ejection with increasing pump speeds, elevating right ventricular (RV) work, reducing LVET, and causing ventricular mechanical dyssynchrony in ejection. These results suggest right heart compromise via the septum's reduced role with the introduction of an iRBP. This work emphasizes the critical role of modeling in heart failure and treatment studies. PMID- 22254827 TI - Toward online, noninvasive, nonlinear assessment of cerebral autoregulation. AB - Online estimation of cerebral autoregulation (CA) may be advantageous in neurosurgical and neurointensive care units. Data from transcranial Doppler, and continuous arterial blood pressure are readily available at high temporal resolution and may be used to assess CA. There are currently no methods for nonlinear, noninvasive, online assessment of CA. We frame the assessment of CA as a parameter estimation problem, in which we estimate the parameters of a nonlinear mathematical model of CA using the ensemble Kalman filter (EnKF). In this simulation study, we use the EnKF to estimate the parameters of a model of cerebral hemodynamics which predicts intracranial pressure and cerebral blood flow velocity, generated from real patient arterial blood pressure measurements. We examine the flexibility and appropriateness of the EnKF for CA assessment. PMID- 22254828 TI - A multiscale bidirectional coupling framework. AB - The lung is geometrically articulated across multiple scales from the trachea to the alveoli. A major computational challenge is to tightly link ODEs that describe lower scales to 3D finite element or finite volume models of airway mechanics using iterative communication between scales. In this study, we developed a novel multiscale computational framework for bidirectionally coupling 3D CFD models and systems of lower order ODEs. To validate the coupling framework, a four and eight generation Weibel lung model was constructed. For the coupled CFD-ODE simulations, the lung models were truncated at different generations and a RL circuit represented the truncated portion. The flow characteristics from the coupled models were compared to untruncated full 3D CFD models at peak inhalation and peak exhalation. Results showed that at no time or simulation was the difference in mass flux and/or pressure at a given location between uncoupled and coupled models was greater than 2.43%. The flow characteristics at prime locations for the coupled models showed good agreement to uncoupled models. Remarkably, due to reuse of the Krylov subspace, the cost of the ODE coupling is not much greater than uncoupled full 3D-CFD computations with simple prescribed pressure values at the outlets. PMID- 22254829 TI - Modeling cardio-respiratory system response to inhaled CO2 in patients with congestive heart failure. AB - In this paper we examine a cardiovascular-respiratory model of mid-level complexity designed to predict the dynamics of end-tidal carbon dioxide (CO(2)) and cerebral blood flow velocity in response to a CO(2) challenge. Respiratory problems often emerge as heart function diminishes in congestive heart failure patients. To assess system function, various tests can be performed including inhalation of a higher than normal CO(2) level. CO(2) is a key quantity firstly because any perturbation in system CO(2) quickly influences ventilation (oxygen perturbations need to be more severe). Secondly, the CO(2) response gain has been associated with respiratory system control instability. Thirdly, CO(2) in a short time impacts the degree of cerebral vascular constriction, allowing for the assessment of cerebral vasculature function. The presented model can be used to study key system characteristics including cerebral vessel CO(2) reactivity and ventilatory feedback factors influencing ventilatory stability in patients with congestive heart failure. Accurate modeling of the dynamics of system response to CO(2) challenge, in conjunction with robust parameter identification of key system parameters, can help in assessing patient system status. PMID- 22254830 TI - Robustness of inverse perturbation for discrete event control. AB - We study the robustness of the inverse perturbation solution in discrete-time systems modeled by homogeneous Markov chains. We cast the optimal inverse perturbation control as a strictly convex optimization problem, which admits a unique global solution. We show that the optimal inverse perturbation control is robust to estimation errors in the original network. The derived results are applied to the Human melanoma gene regulatory network, where the aim is to force the network to converge to a desired steady-state distribution of gene regulation. PMID- 22254831 TI - An analytical study of relay neuron's reliability: dependence on input and model parameters. AB - Relay neurons are widely found in our nervous system, including the Thalamus, spinal cord and lateral geniculate body. They receive a modulating input (background activity) and a reference input. The modulating input modulates relay of the reference input. This modulation is critical for correct functioning of relay neurons, but is poorly understood. In this paper, we use a biophysical based model and systems theoretic tools to calculate how well a single relay neuron relays a reference input signal as a function of the neuron's electro physiological properties (i.e. model parameters), the modulating signal, and the reference signal parameters. Our analysis is more rigorous than previous related works and is generalizable to all relay cells in the body. Our analytical expression matches relay performance obtained in simulation and suggest that increasing the frequency of a sinusoidal modulating input or decreasing its DC offset increases the relay cell reliability. PMID- 22254832 TI - An application of monotone functions decomposition to the reconstruction of gene regulatory networks. AB - We describe the reconstruction of a gene regulatory network involved with the Toll-like Receptor signaling pathways. By applying our recent identification algorithm to a time series gene expression dataset, we identify regulatory interactions between genes and construct discrete-time piece-wise affine regulatory functions. Our validation shows that our model predicts the expression levels of the genes involved in the network with good accuracy. PMID- 22254833 TI - GIST: a Gibbs sampler to identify intracellular signal transduction pathways. AB - Identification of intracellular signal transduction pathways plays an important role in understanding the mechanisms of how cells respond to external stimuli. The availability of high throughput microarray expression data and accumulating knowledge of protein-protein interactions have provided us with useful information to infer condition-specific signal transduction pathways. We propose a novel method called Gibbs sampler to Infer Signal Transduction pathways (GIST) to search dys-regulated pathways from large-scale protein-protein interaction networks. GIST incorporates different knowledge sources to extract paths that are highly associated with biological phenotypes or clinical information. One of the most attractive features of GIST is that the algorithm will not only provide the single optimal path according to the defined cost function but also reveal multiple suboptimal paths as alternative solutions, which can be utilized to study the pathway crosstalk. As a proof-of-concept, we test our GIST algorithm on yeast PPI networks and the identified MAPK signaling pathways are well supported by existing biological knowledge. We also apply the GIST algorithm onto a breast cancer patient dataset to show its feasibility of identifying potential pathways for further biological validation. PMID- 22254834 TI - Insight into DNA periodicity by a single-channel sequence data approach. AB - It has not been obvious how to map a genomic sequence into the numbers to elucidate its periodicities by digital signal processing (DSP) in accord with the underlying biology [1]. The well known DNA spectra and their extensions appear the A-T-C-G--base-wise by Fourier (FT), wavelet (WT) or related transforms of the indicatory functions (IF-s) of these bases. The IF assumes either 1-in the presence or 0-in the absence of the indicated base in sequence. The IF's spectra can be next combined in a different way including the optimal one to provide the net spectrum [2]. In this contribution, it is attempted, and not limited to; showing that single channel numeric DNA also turns out to be sufficient for biologically meaningful results by DSP with accompanying merits. Plausibility is possible considering any RNA message as a single-channel coded waveform; by the triplets of the codon bases which code for 20 different amino acids. This in turn enables a clear justification for the coding rhythm in terms of the codon usage frequency (CUF) and the gene series autocorrelation. The latter simply assesses a self-similarity of the message. Along with appending well established communication insight to biological perspectives, the answer to how the genetic code is becoming specific, inducing the self-similarity of the coded sequences under the three-base-shift case is addressed. Supporting the focus, there are some findings in vertebrates' genes data elucidated by the EMD of Huang-Hilbert transform (H-HT) [3]; these are long-term spectra relevant to the coding, the content of dicodons and the structural properties of coded proteins [4]. Also a new finding in the coding rhythm--the one which is attributed to the coding DNA, is included. This is the net coding rhythms in Homo sapiens, Homo sapiens house keeping and vertebrates' genes comparison by histograms of adaptively tracked amplitudes case. It is intriguing how spectral features of genomic sequences correspond to related physical phenomena [5-8]. PMID- 22254835 TI - GPU-accelerated protein sequence alignment. AB - Smith-Waterman (S-W) algorithm is an optimal sequence alignment method and is widely used for genetic databases. This paper presents a Graphics Processing Units (CPUs) accelerated S-W implementation for protein sequence alignment. The paper proposes a new sequence database organization and several optimizations to reduce the number of memory accesses. The new implementation achieves a performance of 21.4 GCUPS, which is 1.13 times better than the state-of-the-art implementation on an NVIDIA GTX 275 graphics card. PMID- 22254836 TI - Non-thermal dielectric barrier discharge plasma induces angiogenesis through reactive oxygen species. AB - Vascularization plays a key role in processes such as wound healing and tissue engineering. Non-thermal plasma, which primarily produces reactive oxygen species (ROS), recently emerged as an efficient tool in medical applications. Liquids and endothelial cells were treated with a non-thermal dielectric barrier discharge plasma. Plasma treatment of phosphate buffered saline (PBS) and serum-free medium increased ROS concentration in a dose-dependent manner, with a higher concentration in serum-free medium. ROS concentration in cells peaked 1 hour after treatment. 4.2 J/cm(2) increased cell proliferation, 2D and 3D migration, as well as tube formation. A fibroblast growth factor-2 (FGF-2) neutralizing antibody and ROS scavengers for hydrogen peroxide and hydroxyl radicals abrogated these angiogenic effects. Non-thermal plasma may be a potential tool for applying ROS in precise doses to enhance vascularization. PMID- 22254837 TI - Electrical detachment of cells for engineering capillary-like structures in a photocrosslinkable hydrogel. AB - A major challenge in tissue engineering is the fabrication of vascular networks capable of delivering oxygen and nutrients throughout tissue constructs. Because cells located more than a few hundred micrometers away from the nearest capillaries are susceptible to oxygen shortages, it is crucial to develop microscale technologies for engineering a vascular structure in three dimensionally thick tissues. This study describes an electrochemical approach for fabricating capillary-like structures precisely aligned within micrometer distances, the internal surfaces of which are covered with vascular endothelial cells in a photocrosslinkable hydrogel. PMID- 22254838 TI - A study on the cellular structure during stress solicitation induced by BioMEMS. AB - The investigation of single cells is a topic in continuous evolution. The complexity of the cellular matrix, the huge variety of cells, the interaction of one cell with the other are all factors that must be taken into consideration in the study of the cellular structure and mechanics. In this project, we developed different types of bioMEMS for cell's stretching, both transparent devices based on silicon nitride and non-transparent silicon based. While the use of silicon devices is limited to reflection microscopes, transparent bioMEMS can be used with transmission and reflection microscopes but can also be easily coupled with other tools such as patch clamp analyzers or atomic force microscope. This improvement will open brand new possibilities in the biological investigation field. We used these two BioMEMS to stretch a single cell in a controlled way and, as a first investigation, we focused on its morphology. We noticed that during a controlled stretch, cells react to the applied deformation. A hysteretic behavior on the ratio between area and perimeter has been highlighted. PMID- 22254839 TI - Fabrication of interpenetrate chitosan: bioactive glass, using dense gas CO2. AB - Success of bone tissue engineering relies on using bioactive scaffolds with ideal pore morphology which can mimic the properties of the natural extracellular matrix (ECM). The objective of this study was to interpenetrate bioactive glass components throughout the three dimensional (3D) structure of the chitosan scaffold to increase the average pore size of the scaffold and also the osteoconductivity and osteoinductivity of the fabricated scaffold. Scanning electron microscopy was used to observe the microsturcture of the hydrogel. The results of this study demonstrated that the average pore size in the hydrogel was increased significantly (p<0.05) from 97 +/- 44 MUm to 150 +/- 24 MUm by increasing the BG concentration from 0 wt% to 40 wt%. This effect might be due to the interaction between ceramic and chitosan. The composite hydrogel fabricated swell in water and has high potential to be used for bone tissue engineering applications; bioactive glass can substantially improve bioactivity of the bone tissue engineering scaffolds However, further studies are required to investigate the effect of BG on the biocompatibility of the scaffolds. In addition, in vitro cell studies are also required to confirm the suitability of the fabricated scaffold for bone tissue engineering. PMID- 22254840 TI - Optimal scaffold design and effective progenitor cell identification for the regeneration of vascularized bone. AB - Bone tissue engineering offers perhaps the most attractive treatment option for bone repair/regeneration as it eliminates complications of other bone grafting options (i.e., availability and immunogenicity issues of autografts and allografts, respectively). However, scaffold-based bone tissue engineering is largely limited by inadequate vascaularization, and as a result, bone formation is often restricted to the construct's periphery. In this study, we offer a two pronged approach to overcome periphery-limited bone and vascular formation. We have developed optimally designed, mechanically strong, biodegradable scaffolds with increased porosity and interconnectivity. We have also identified and isolated superior, clinically-relevant cell populations (peripheral blood-derived endothelial progenitor cells (EPCs), and bone marrow-derived mesenchymal stem cells (MSCs)). In combination, we have developed a synthetic graft system suitable for the regeneration of vascularized bone. PMID- 22254841 TI - The use of sonication treatment to completely decellularize blood arteries: a pilot study. AB - We have developed a novel sonication decellularization system to prepare completely decellularized bioscaffolds in a short treatment time. The aim of the study is to investigate the sonication decellularization efficiency and its relation with ultrasonic power output and dissolved oxygen (DO) concentration in different detergent solution. In the study, we used aorta samples to evaluate sonication decellularization efficiency, which assessed treatment duration, sonication power and SDS detergent with/without saline. The treated samples were evaluated histologically by Hematoxylin Eosin (HE) staining and scanning electron microscopic (SEM) photographs. The concentration of DO was monitored to identify the effect of sonication on cavitation-related DO concentration in the solution. From histological results, the sonication decellularization efficiency was better than the other preparation methods. Decellularization efficiency was tended to increase significantly when DO value decreasing after 6 hours of treatment. In conclusion, we conclude that sonication treatment can be used to prepare the complete decellularized scaffolds in short treatment time. PMID- 22254842 TI - Multi-signal electromechanical cardiovascular monitoring on a modified home bathroom scale. AB - A commercially available bathroom scale was modified to enable unobtrusive and robust cardiovascular monitoring in the home. Handlebar electrodes were interfaced to an ultra-low power, two-electrode electrocardiogram (ECG) acquisition circuit providing consistent and clean heartbeat timing information. In addition, the footpad electrodes were used to detect lower-body electromyogram (EMG) and lower-body impedance plethysmogram (IPG) signals using two parallel circuits. The lower-body EMG signal was used as an indication of excessive motion of the subject on the scale. The lower-body IPG signal is related to blood flow through the legs, and will be investigated further in future studies. Finally, the component of bodyweight that varies with time--the ballistocardiogram (BCG) signal--was amplified from the existing strain gauges built into the scale. A preliminary validation was completed on five healthy subjects of varying sizes. The average signal-to-noise ratio (SNR) values computed over all five subjects for the ECG, IPG, and BCG signals were 17.2, 12.0, and 9.0 dB, respectively. PMID- 22254843 TI - Beating-heart mitral valve chordal replacement. AB - Replacing open-heart surgical procedures with beating-heart interventions substantially decreases the trauma and risk of a procedure. One of the most challenging procedures to perform on the beating heart is valve repair. To address this need, this paper proposes a tool for replacing mitral valve chordae to correct regurgitation. The chordae is secured to the papillary muscle and leaflet using NiTi tissue anchors that also incorporate an internal adjustment mechanism to enable initial adjustment as well as subsequent readjustment of chordae length. Efficacy of the proposed tool for chordae replacement and reduction of regurgitation was demonstrated in an ex-vivo heart simulator. PMID- 22254844 TI - Preferred patterns of diastolic timed vibrations for pre-hospitalization treatment of acute coronary ischemia. AB - This paper presents and evaluates preferred patterns of vibrations and active breaking techniques for the Diastolic Timed Vibrator (DTV). DTV uses low frequency mechanical vibrations applied to the chest to help in clot dissolution in pre-hospitalization treatment of acute coronary ischemia. In this work, we argue that random and ramp type vibration patterns increase the performance of the DTV method. Furthermore, we present results for various methods of vibration stopping aiming at reduction of vibration overspill into the systole of heart cycle of the patient. PMID- 22254845 TI - The impact of various backboard configurations on compression stiffness in a manikin study of CPR. AB - When performing cardiopulmonary resuscitation (CPR) it is important that adequate back support is given to the patient in order to allow the medical practitioner to produce an appropriate technique during chest compression (CC). The current study investigates how backboard configuration (i.e., orientation and size) impact compression stiffness during CPR using a torso CPR training manikin. The effect of backboard size on CC performance during CPR was found to be significant with the 94.8% larger backboard producing an increase in compression stiffness of as much as 62.7% relative to the smaller backboard. The impact of backboard orientation was also found to be important with a longitudinal orientation producing an increase in compression stiffness of as much as 60.3% relative to a latitudinal orientation. Backboard configuration should be considered by clinicians when trying to achieve optimal CC performance during CPR in hospital settings. PMID- 22254846 TI - Designing for reliable textile neonatal ECG monitoring using multi-sensor recordings. AB - When designing an ECG monitoring system embedded with textile electrodes for comfort, it is challenging to ensure reliable monitoring, because textile electrodes suffer from motion artifacts and incidental poor signal quality. For the design of a comfortable monitoring system for prematurely born babies in the Neonatal Intensive Care Unit (NICU), we propose the concepts of 'diversity measurement' and 'context awareness' to improve reliability. Clinical multi-modal sensor data was collected in the NICU with the Smart Jacket connected to a state of-the-art amplifier. We found that the ECG signals quality varied among sensors and varied over time, and found correlations between ECG signal, acceleration data, and context, which supports the feasibility of the concepts. Our explorative system level approach has lead to design parameters and meta-insights into the role of clinical validation in the design process. PMID- 22254847 TI - Blood pressure estimation using oscillometric pulse morphology. AB - A novel pulse morphology-based approach for estimation of blood pressure from non invasive oscillometric blood pressure measurement is presented. Quantitative measures that describe the pulse morphology are utilized to obtain the estimates of mean arterial, systolic, and diastolic pressures. Preliminary results obtained from a small set of measurements are used to demonstrate the feasibility of the proposed approach. The estimates obtained through pulse morphology-based approach is compared with those obtained from a commercial blood pressure device. PMID- 22254848 TI - Fabric circuit board-based dry electrode and its characteristics for long-term physiological signal recording. AB - This paper presents a dry fabric electrode and its characteristics. For long-term physiological signal monitoring, conventional wet type electrode such as an Ag/AgCl electrode may not be sufficient, because captured signal strength degrades over time as its electrolyte dehydrates. Moreover, the electrolyte may cause skin irritation over a period of time. As a complement, a dry electrode can be used. In this work, fabric-based dry electrodes are introduced. Planar-Fabric Circuit Board (P-FCB) technology enables low cost and uniform productions of such electrodes; electrical properties of the electrodes with various materials, sizes, and time are shown. Both the strengths and drawbacks of the fabric-based electrodes are also discussed. PMID- 22254849 TI - eEmergency health care information systems. AB - In this paper we provide an overview of the way that information and communication technologies have been used for emergency healthcare support. The paper provides a literature review of case studies exploring information systems for monitoring signals, images, medical videos, as well as information protocols used during emergency health care support, and describes future trends. We anticipate that eEmergency systems can significantly improve the delivery of healthcare during emergency cases. However, the monitoring and evaluation of these systems and especially their use in daily practice still remains a goal to be achieved. PMID- 22254850 TI - A Web services-based exergaming platform for senior citizens: the Long Lasting Memories project approach to e-health care. AB - This piece of research describes an innovative e-health service that supports the cognitive and physical training of senior citizens and promotes their active ageing. The approach is adopted by the Long Lasting Memories (LLM) project, elements of which are discussed herein in the light of the functionalities provided to the users and the therapists. The aim of this work is to describe those technical elements that demonstrate the unique and integrative character of the LLM service, which is based on a modular Web service architecture, rendering the system available in different settings like the homes of seniors. The underlying database as well as the remote user interface empower therapists to set personalized training schemes, to view the progress of training sessions, as well as, adding new games and exercises into the system, thereby increasing the services sustainability and marketability. PMID- 22254851 TI - Recording of electrohysterogram laplacian potential. AB - Preterm birth is the main cause of the neonatal morbidity. Noninvasive recording of uterine myoelectrical activity (electrohysterogram, EHG) could be an alternative to the monitoring of uterine dynamics which are currently based on tocodynamometers (TOCO). The analysis of uterine electromyogram characteristics could help the early diagnosis of preterm birth. Laplacian recordings of other bioelectrical signals have proved to enhance spatial selectivity and to reduce interferences in comparison to monopolar and bipolar surface recordings. The main objective of this paper is to check the feasibility of the noninvasive recording of uterine myoelectrical activity by means of laplacian techniques. Four bipolar EHG signals, discrete laplacian obtained from five monopolar electrodes and the signals picked up by two active concentric-ringed-electrodes were recorded on 5 women with spontaneous or induced labor. Intrauterine pressure (IUP) and TOCO were also simultaneously recorded. To evaluate the uterine contraction detectability of the different noninvasive methods in comparison to IUP the contractions consistency index (CCI) was calculated. Results show that TOCO is less consistent (83%) than most EHG bipolar recording channels (91%, 83%, 87%, and 76%) to detect the uterine contractions identified in IUP. Moreover laplacian EHG signals picked up by ringed-electrodes proved to be as consistent (91%) as the best bipolar recordings in addition to significantly reduce ECG interference. PMID- 22254852 TI - Novel approach to admittance to volume conversion for ventricular volume measurement. AB - The conductance catheter is a widely used tool to determine ventricular volumes in animal models. A tetra-polar catheter is inserted into the ventricle to measure instantaneous conductance, which is a combination of ventricular blood and surrounding myocardium. Various techniques have been used to separate the blood conductance signal from the combined measured signal [1], [2]. The blood conductance is then converted to volume using a linear relationship proposed by Baan [1] or an improved non linear relationship proposed by Wei [3]. We propose a novel approach that uses the combined blood-muscle signal to calculate volume, thereby eliminating the need to subtract out the muscle. In vivo experiments were performed in mice to validate this new approach and the results were compared with volumes obtained using ultrasound imaging. PMID- 22254853 TI - In-cycle myocardium tissue electrical impedance monitoring using broadband impedance spectroscopy. AB - Measurements of myocardium tissue impedance during the cardiac cycle have information about the morphology of myocardium cells as well as cell membranes and intra/extra cellular spaces. Although the variation with time of the impedance cardiac signal has information about the myocardium tissue activity during the cardiac cycle, this information has been usually underestimated in the studies based on frequency-sweep Electrical Impedance Spectroscopy (EIS) technique. In these cases, the dynamic behavior was removed from the impedance by means of averaging. The originality of this research is to show the time evolution of in-vivo healthy myocardium tissue impedance during the cardiac cycle, being measured with a multisine excitation at 26 frequencies (1 kHz-1 MHz). The obtained parameters from fitting data to a Cole model are valid indicators to explain the time relation of the systolic and diastolic function with respect to the myocardium impedance time variation. This paper presents a successful application of broadband Impedance Spectroscopy for time-varying impedance monitoring. Furthermore, it can be extended to understand various unsolved problems in a wide range of biomedical and electrochemical applications, where the system dynamics are intended to be studied. PMID- 22254854 TI - An unpowered, wireless contact lens pressure sensor for point-of-care glaucoma diagnosis. AB - The development of a wireless, microfluidic pressure sensor composed of Polydimethylsiloxane (PDMS) and dyed glycerol is presented for point-of-care glaucoma diagnosis. Design, fabrication and test results are presented. PMID- 22254855 TI - Impedance changes according to the degree of atopi dermatitis in mice. AB - Variations in electrical impedance over frequency might be used to distinguish the degree of atopic dermatitis (AD), even if the mechanisms of the skin barrier impairment due to AD are still unknown. We observed the skin bioimpedance of normal mice and of abnormal mice having atopic with instrument measuring electrical impedance. Electrical impedance was measured from 20 Hz to 1 MHz at many frequencies and normalized with several indices such as IMP, PIX, IMIX, RIX, and et al. to reduce variation in subjects. The results showed the high relationship between subjective score and indices, especially, the capacitance change and impedance ratio, abs(Z(1 kHz))/abs(Z(10 kHz)). These results indicate electrical impedance may be a promising clinical diagnostic tool to monitor prognosis of skin care for atopic dermatitis. Using developed software application we easily acquired complex impedance data from the instrument and got the analysis results for very kinds of frequency. This may be useful in various bioimpedance studies such as skin cancer assessment or body composition analysis, or etc. PMID- 22254856 TI - Fitting the frequency response in acoustic reflectometry for an in vitro model of a human upper airway. AB - Acoustic reflectometry has been used earlier to estimate the bore profile of a human upper airway and endotracheal tubes using thousands of acoustic pulses. The axial resolution of the profile computed depends on generating a broad frequency response, filtering undesired frequencies and compensating for wave propagation losses. The work presented here shows that acoustic reflectometry may be performed by using few Gaussian-sinusoidal acoustic waves, equally spaced along the bandwidth, and the Ware-Aki algorithm. In this way, the frequency content is controlled, the computational cost is reduced, and the axial resolution is improved. This entails fitting the frequency impulse response, compensating for propagation losses in the amplitude response, and analyzing the phase response. The methodology was validated in the laboratory with an in vitro model of a human upper airway, coupled to an acoustic reflectometer. Only one hundred acoustic waves, with a frequency step of 100 Hz, were needed to reconstruct a profile with an axial resolution within an acceptable margin of error. PMID- 22254857 TI - Multivariate synchrony modules identified through multiple subject community detection in functional brain networks. AB - The functional connectivity of the human brain may be described by modeling interactions among its neural assemblies as a graph composed of vertices and edges. It has recently been shown that functional brain networks belong to a class of scale-free complex networks for which graphs have helped define an association between function and topology. These networks have been shown to possess a heterogenous structure composed of clusters, dense regions of strongly associated nodes, which represent multivariate relationships among nodes. Network clustering algorithms classify the nodes based on a similarity measure representing the bivariate relationships and similar to unsupervised learning is performed without a priori information. In this paper, we propose a method for partitioning a set of networks representing different subjects and reveal a community structure common to multiple subjects. We apply this community identifying algorithm to functional brain networks during a cognitive control task, in particular the error-related negativity (ERN), to evaluate how the brain organizes itself during error-monitoring. PMID- 22254858 TI - Assessment of linear regression techniques for modeling multisensor data for non invasive continuous glucose monitoring. AB - New scenarios in diabetes treatment have been opened in the last ten years by continuous glucose monitoring (CGM) sensors. In particular, Non-Invasive CGM sensors are particularly appealing, even though they are still at an early stage of development. Solianis Monitoring AG (Zurich, Switzerland) has proposed an approach based on a multisensor concept, embedding primarily dielectric spectroscopy and optical sensors. This concept requires a mathematical model able to reconstruct the glucose concentration from the 150 channels measured with the device. Assuming a multivariate linear regression model (valid and usable for different individuals), the aim of this paper is the assessment of some techniques usable for determining such a model, namely Ordinary Least Squares (OLS), Partial Least Squares (PLS) and Least Absolute Shrinkage and Selection Operator (LASSO). Once the model is identified on a training set, the accuracy of prospective glucose profiles estimated from "unseen" multisensor data is assessed. Preliminary results obtained from 18 in-clinic study days show that sufficiently accurate reconstruction of glucose levels can be achieved if suitable model identification techniques, such as LASSO, are considered. PMID- 22254859 TI - Parallel independent component analysis using an optimized neurovascular coupling for concurrent EEG-fMRI sources. AB - The complexity of the human brain and the limitation of any one imaging approach motivates the need for multimodal measurements to better understand cerebral processing. A very natural goal is to integrate electrophysiological and hemodynamic activity. Among them, concurrent EEG-fMRI studies have shown great promise for understanding intrinsic brain properties yet analyzing such data presents a significant methodological challenge. Here, we propose a multivariate parallel ICA decomposition incorporating dynamic neurovascular coupling for concurrent EEG-fMRI recordings. The goal of our algorithm is to fuse multimodal EEG-fMRI information and detect/interpret the relationship between electrophysiological and hemodynamic sources via a temporal neurovascular connection enhancement. We analyze the performance of the algorithm on a valid simulation based on real EEG and fMRI components (sources) from our previous works and a neurovascular coupling built from an extended 'balloon model'. The results from our simulations yield an accurate source tracking and linkage for concurrent EEG-fMRI, and provide a novel and efficient way to combine EEG and hemodynamic responses. PMID- 22254860 TI - Statistical characterization of complex-valued EEG spectrum during mental imagery tasks. AB - Electroencephalogram (EEG) recordings of brain activities can be processed in order to augment the brain's cognitive, sensory, or motor functionality. A representative, yet analytically tractable, model is essential to EEG processing. Several studies have examined different statistical models for EEG power spectrum. But recent studies have shown that not only the power, but also the phase of the spectrum, carries relevant information on brain activities. As a result, this paper focuses on the complex-valued spectrum of EEG, and proposes a general non-circularly-symmetric multivariate Gaussian model for this spectrum. This simple model can encapsulate the information in both power and phase of the spectrum, and its validity for EEG data has been verified using standard statistical tests. PMID- 22254861 TI - System identification of baroreflex response to mild lower body negative pressure. AB - The effect of mild lower body negative pressure (LBNP) on baroreflex control of arterial blood pressure (ABP) has long been thought to affect cardiopulmonary baroreflex only, although recent studies have pointed out that arterial baroreceptors may be transiently unloaded too after the rapid onset of mild LBNP. This paper presents a spectral decomposition method for the black box identification of the contribution of arterial and cardiopulmonary baroreflexes to beat-by-beat variability of ABP in response to mild LBNP levels. The significant decrease of mean and diastolic arterial pressure and of the arterial baroreflex mediated contribution to overall variability of ABP which was found, suggested that the unloading of arterial baroreceptors may be reflected by an altered dynamic response of arterial baroreflex, too. In addition, arterial baroreflex mediated modulations were found to be the main player in the modulation of beat-by-beat fluctuations of ABP, while the role of cardiopulmonary baroreflex mediated responses appeared to contribute very little. PMID- 22254862 TI - Factors influencing differences between invasive and spontaneous baroreflex estimates: distinct methods or different data? AB - Currently invasive BRS estimates are obtained with drug-induced data assuming a sigmoidal SBP-RR relationship, while spontaneous BRS estimates are obtained with non-sigmoidal estimators. In particular, the events (sequences) technique provides a spontaneous BRS estimate based on baroreflex events, BEs (baroreflex sequences, BSs). In this work, BRS estimates are compared considering that can be obtained with different estimators and evaluated in different conditions. All BRS estimates were found to be significantly correlated. In comparison with BS estimates, BE estimates from spontaneous data exhibited higher correlation with sigmoidal estimates and their differences were associated with differences in SBP levels from invasive to spontaneous condition. BE estimator evaluated in different conditions decreased the differences between BRS estimates, pointing out differences due to the use of distinct methods, and such differences were correlated with differences in SBP and RR levels from invasive to spontaneous conditions. Finally, sigmoid estimates were more correlated with BE estimates in invasive data in comparison with those evaluated from BS. In conclusion, BRS analysis from BEs provides an estimate that exhibits higher correlation and lower differences between BRS estimates from different conditions, and reflects properly the BRS physiology. PMID- 22254863 TI - A waveform independent cell identification method to study long-term variability of spike recordings. AB - Extracellular potential recordings are important in neuroscience; however the variability of spike waveforms has not been extensively studied to date. This study examines the variability of spike recordings within and between sessions. Place cell recordings were used in order to identify the cells across successive sessions. Place cells allow neuron spike recordings to be identified across different sessions using place fields, which are independent of the cell's spike waveform. The results show that the distribution of the residues within a session does not follow a normal distribution, a t-distribution is more suitable. The results also show that the amplitude of the spikes can vary largely between successive sessions (up to 47%), this is an important factor to be considered in long term spike recording systems. PMID- 22254864 TI - Changes in dynamical characteristics of epileptic EEG in rats using recurrence quantification analysis. AB - In this paper, we used Recurrence Quantification Analysis (RQA) in order to study pre-epileptic characteristics in rat's EEG recordings. Four adult rats were used to collect epileptic EEG data in an experiment of animal model of epilepsy. Three RQA measures, recurrence rate, determinism, and entropy were calculated from EEG recordings from rats. A moving average filter was used to identify the decreasing trend in pre-epileptic dynamics which will be useful early detection of seizures. PMID- 22254865 TI - Seizure prediction in intracranial EEG: a patient-specific rule-based approach. AB - In this study, we report our development of a patient-specific rule-based seizure prediction system. Five univariate and one bivariate nonlinear measures were extracted from non-overlapping 10-second segments of intracranial EEG (iEEG) data recorded using both depth electrodes in the brain and subdural electrodes over the cortical surface. Nonlinear features representing the specific characteristic properties of EEG signal were then integrated spatio-temporally in a way to predict to predict seizure with high sensitivity. The present system was tested on 58 hours of iEEG data containing ten seizures recorded in two patients with medically intractable focal epilepsy. Within a prediction horizon of 30 and 60 minutes, our method showed an average sensitivity of 90% and 96.5% with an average false prediction rate of 0.06/h and 0.055/h, respectively. The present results suggest that such a rule-based system can become potentially a useful approach for predicting seizures prior to onset. PMID- 22254866 TI - EEG analysis for estimation of duration and inter-event intervals of seizure-like events recorded in vivo from mice. AB - Rett syndrome is a neurodevelopmental disorder of the brain that affects females more often than males. Its cause is linked to the mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2). Presently, there is little information regarding how the loss of MeCP2 affects brain activity. It has been documented that during awake but immobile state, the MeCP2 deficient mice exhibit spontaneous, rhythmic electroencephalogram (EEG) seizure-like events (SLEs) in the range of 6-9 Hz. In this study, we analyze the cortical EEG activity in female MeCP2-deficient mice over 24 hour recordings. Characterizing the SLE and inter-SLE durations by fitting to a gamma distribution we show similarity to previous in vivo epilepsy studies. These results suggest that the SLE and inter SLE dynamics differ. More precisely, the SLE terminations appear to be a result of time-dependent mechanisms, whereas the inter-SLEs are a result of a random process. PMID- 22254867 TI - Auto-mutual information function of the EEG as a measure of depth of anesthesia. AB - Monitoring the depth of anesthesia (DOA) is necessary in order to decrease the incident of awareness in anesthesia and to prevent delays in the recovery phase. In the last decades a number of noninvasive methods have been proposed for the analysis of the electroencephalogram (EEG) for monitoring DOA. The objective of this work was to apply auto mutual information function (AMIF) to EEGs of patients under anesthesia in order to find variables able to characterize the following 4 states: awake, sedated, anesthetized and burst suppression episodes. The results show that the single and combined AMIF parameters were able to correctly classify the states in the range 72.2%-94.1% and 61.1%-100%, respectively. PMID- 22254868 TI - Phase-based features for motor imagery brain-computer interfaces. AB - Motor imagery (MI) brain-computer interfaces (BCIs) translate a subject's motor intention to a command signal. Most MI BCIs use power features in the mu or beta rhythms, while several results have been reported using a measure of phase synchrony, the phase-locking value (PLV). In this study, we investigated the performance of various phase-based features, including instantaneous phase difference (IPD) and PLV, for control of a MI BCI. Patterns of phase synchrony differentially appear over the motor cortices and between the primary motor cortex (M1) and supplementary motor area (SMA) during MI. Offline results, along with preliminary online sessions, indicate that IPD serves as a robust control signal for differentiating between MI classes, and that the phase relations between channels are relatively stable over several months. Offline and online trial-level classification accuracies based on IPD ranged from 84% to 99%, whereas the performance for the corresponding amplitude features ranged from 70% to 100%. PMID- 22254869 TI - Time-domain ECG signal analysis based on smart-phone. AB - In this paper, a time domain algorithm architecture is presented and implemented on a smart-phone for ECG signal analysis. Using the QRS detection algorithm suggested by Pan-Tompkins and the beat classification method, the heart beats are detected and classified as normal beats and premature ventricular contractions (PVCs). Subsequently, a computationally efficient method is presented to separate ventricular tachycardia (VT) and ventricular fibrillation (VF). This method utilizes Lempel and Ziv complexity analysis combined with K-means algorithm for the coarse-graining process. In addition, a new classification rule is presented to recognize VT and VF in our study. The proposed system provides fairly good performance when applied to the MIT-BIH Database. This algorithm architecture can be efficiently used on the mobile platform. PMID- 22254870 TI - Topographic imaging of the atrial electrical activity during atrial fibrillation for the analysis of uniform distributions of the surface electrical potentials. AB - Atrial fibrillation (AF) is a progressive arrhythmia which causes time dependent impairing of the cardiac muscle. This makes that proper therapeutic interventions depend on the degree of AF progression, i.e., on the temporal decrease of the organization of the electrical patterns observed during AF. Standard effective treatments are still lacking nowadays, and this calls for suitable noninvasive analysis of AF. In this sense, an appropriate therapy relies on the knowledge of AF characteristics, as its degree of organization. To this purpose, fast and accurate imaging of cardiac electrical activity can be helpful. Relying on the results of previous work on noninvasive assessment of the complexity of AF, we put forward a method to obtain visual maps of the topographic projection of the main atrial activity (AA) component given by principal component analysis, which is shown to provide detailed information about AA potential pattern distributions on the body surface. Different AA potential pattern distributions can then be identified, depending on the underlying degree of AF organization. An automated way to assess AF organization degree is then proposed, based on topographic projections. Similarities with previous studies suggest its usefulness for determining uniform distributions in the activation patterns on the body surface. PMID- 22254871 TI - Preliminary feasibility analysis of remote subject identification during hemodynamic monitoring by Radio Frequency Impedance. AB - Non-contact, non-invasive monitoring of hemodynamic parameters would be ideal for medical monitoring in a variety of environments. Radio Frequency Impedance Interrogation (RFII) measures hemodynamic function via resonance frequency coupling to a hydrophilic protein molecule. While the application of this technology to hemodynamic monitoring has demonstrated initial success, this preliminary study examined the use of RFII for subject identification by waveform signal analysis, which would allow confirmation of the identity of a subject in an operational setting prior to rescue efforts. Preliminary results demonstrate an excellent recognition rate using the RFII signature and pattern classification. Each individual has a consistent pattern during the initial waveform identification period that is visually distinct from the other individuals in the data set. These results suggest that RFII may be of great utility in the pre-hospital triage setting for patient monitoring and for the rapid identification of subjects in the operational setting. PMID- 22254872 TI - Affective assessment of computer users based on processing the pupil diameter signal. AB - Detecting affective changes of computer users is a current challenge in human computer interaction which is being addressed with the help of biomedical engineering concepts. This article presents a new approach to recognize the affective state ("relaxation" vs. "stress") of a computer user from analysis of his/her pupil diameter variations caused by sympathetic activation. Wavelet denoising and Kalman filtering methods are first used to remove abrupt changes in the raw Pupil Diameter (PD) signal. Then three features are extracted from the preprocessed PD signal for the affective state classification. Finally, a random tree classifier is implemented, achieving an accuracy of 86.78%. In these experiments the Eye Blink Frequency (EBF), is also recorded and used for affective state classification, but the results show that the PD is a more promising physiological signal for affective assessment. PMID- 22254873 TI - Entropy measures for discrimination of 'awake' Vs 'anaesthetized' state in recovery from general anesthesia. AB - Approximate Entropy (ApEn) and Permutation Entropy (PE) have been recently introduced for assessment of anesthetic depth. Both measures have previously been shown to track changes in the electrical brain activity related to the administration of anesthetic agents. In this paper ApEn and PE are compared for the automatic classification of 'awake' and 'anesthetized' state using a Support Vector Machine to assess their robustness for potential use in a device for monitoring awareness during general anesthesia. It was found that both measures provide linearly separable features and we are able to discriminate between the two states with accuracy greater than 96% using either of the two entropy measures. PMID- 22254874 TI - Classification of multichannel uterine EMG signals. AB - Classification of multichannel uterine electromyogram (EMG) signals is addressed. Signals were recorded by a matrix of 16 electrodes. First, signals corresponding to each channel were individually classified using an artificial neural network (ANN) based on radial basis functions (RBF). The results have shown that the classification performance varies from one channel to another. Then, a decision fusion method based on these classification performances was tested. After fusion, the network yielded better classification accuracy than any individual channel could provide. The high percentage of correctly classified labor/non labor events proves the efficiency of multichannel recordings in detecting labor. These findings can be very useful for the aim of classifying antepartum versus labor patients. PMID- 22254875 TI - Automatic retinal vessel profiling using multi-step regression method. AB - Caliber of the retinal blood vessel is widely used for risk assessment of cardiovascular diseases. Accurate and automatic caliber measurement requires a precise model to be made for the vessel profile. In this paper, we present a new approach for retinal vessel profiling in which the background noise, uneven illuminations and specular reflections have all been considered. In this method, regression analysis is performed with a series of second-order Gaussians to filter and up-sample the original vessel profile. This is then segmented to identify and represent the vessel edges by two Generalized Gaussian functions. The technique has been applied to retinal images and the results have been verified and compared with the state of the art automatic techniques. PMID- 22254876 TI - Scale-invariant vesselness filtering for simultaneous extraction of optimal medial and boundary paths in retinal images. AB - In this paper we present a new multiscale vesselness filtering technique to simultaneously compute optimal medial axes and boundaries on fundus images of the retina. The scale-invariance of the vessel cross-sectional profile in the frequency domain is examined, and phase congruency implementing the scale invariance is utilised for multiscale vesselness filtering. This allows the vessel ridge and boundary evidence to be preserved under single filtering settings. We have performed width measurement experiments on a dataset of fundus images, using an optimal medial axis skeletonisation scheme as a post-processing step, to compare the proposed technique with a generalised Gaussian profile modelling approach. PMID- 22254877 TI - Improving vessel segmentation in ultra-wide field-of-view retinal fluorescein angiograms. AB - Vessel segmentation on ultra-wide field-of-view fluorescein angiogram sequences of the retina is a challenging problem. Vessel appearance undergoes severe changes, as different portions of the vascular structure become perfused in different frames. This paper presents a method for segmenting vessels in such sequences using steerable filters and automatic thresholding. We introduce a penalization stage on regions with high vessel response in the filtered image, improving the detection of peripheral vessels and reducing false positives around the optic disc and in regions of choroidal vessels and lesions. Quantitative results are provided, in which the penalization stage improves the segmentation precision segmentation by 11.84%, the recall by 12.98% and the accuracy by 0.40%. To facilitate further evaluation, usage, and algorithm comparison, the algorithm, the data set used, the ground truth, and the results are made available on the internet. PMID- 22254878 TI - Joint spatio-temporal registration and microvasculature segmentation of retinal angiogram sequences. AB - We discuss the problem of 2D+t intra- and inter-sequential registration of retinal angiograms. A joint spatio-temporal registration algorithm is presented based on a RANSAC (RANdom SAmple Consensus) approach incorporating a quadratic model to describe "pairwise" image homography. This is incorporated into a local to-global hierarchical joint registration framework. After registration, vessel centrelines are segmented to subpixel accuracy by applying multi-scale steerable complex wavelet filters. Frame-by-frame microvascular centrelines in Regions-of Interest (ROIs) are evaluated against segmented centrelines of the temporal average of the registered sequences. The microvascular centrelines in registered sequences can be compared intra-sequentially and inter-sequentially, allowing non invasive clinical monitoring of micro-circulation. This has the potential to detect the presence of microemboli and pathological structural alterations. PMID- 22254879 TI - Computerized analysis of narrow-field ROP images for the assessment of vessel caliber and tortuosity. AB - Retinopathy of prematurity (ROP) is a disease involving abnormal development of retinal vasculature in premature infants, which might eventually lead to retinal detachment and visual loss. The quantitative assessment of vessel morphological features, such as width and tortuosity, can improve the clinical diagnosis and evaluation of ROP. We propose here a computerized system for the vascular analysis of narrow-field premature infant images. It is based on the manual drafting of the vessel axis, followed by automatic Canny filter edge extraction and automatic caliber and tortuosity estimation. We implemented this method as a web-based tool, ROPnet, which allows the quantitative assessment of vessel width and tortuosity simply using a web browser. To test the accuracy of the estimated parameters, fifteen narrow-field (30 degrees ) retinal images were acquired in infants with a non-contact fundus camera and analyzed with ROPnet. We compared the results with the corresponding ground-truth values derived from manual analysis. Average widths and tortuosities estimated with ROPnet vs. manual ones showed a correlation coefficient of 0.96 and 0.90, respectively. PMID- 22254880 TI - Model-based optic nerve head segmentation on retinal fundus images. AB - The optic nerve head (optic disc) plays an important role in the diagnosis of retinal diseases. Automatic localization and segmentation of the optic disc is critical towards a good computer-aided diagnosis (CAD) system. In this paper, we propose a method that combines edge detection, the Circular Hough Transform and a statistical deformable model to detect the optic disc from retinal fundus images. The algorithm was evaluated against a data set of 325 digital color fundus images, which includes both normal images and images with various pathologies. The result shows that the average error in area overlap is 11.3% and the average absolute area error is 10.8%, which outperforms existing methods. The result indicates a high correlation with ground truth segmentation and thus demonstrates a good potential for this system to be integrated with other retinal CAD systems. PMID- 22254881 TI - Hextuple registration of interim and follow-up PET-CT images for the accurate tracking of patient recovery after therapy. AB - An extended registration framework is presented to accurately register follow-up PET-CT study triples. Since there are six images to register, sophisticated feature extraction and similarity measurement methods are proposed. An irregular sampling method is introduced to decrease the processing speed of the hextuple registration. The similarity measurement is based on a normalized hybrid extended SSD (Sum of Squared Differences) and and extended NMI (Normalized mutual Information). The method has been tested on a huge amount of simulated data to avoid observer specific results. Based on the validation, our method outperforms prior solutions in both speed and accuracy, hence it should be the subject of further investigations. PMID- 22254882 TI - Image geometric corrections for a new EMCCD-based dual modular x-ray imager. AB - An EMCCD-based dual modular x-ray imager was recently designed and developed from the component level, providing a high dynamic range of 53 dB and an effective pixel size of 26 MUm for angiography and fluoroscopy. The unique 2 * 1 array design efficiently increased the clinical field of view, and also can be readily expanded to an MxN array implementation. Due to the alignment mismatches between the EMCCD sensors and the fiber optic tapers in each module, the output images or video sequences result in a misaligned 2048 * 1024 digital display if uncorrected. In this paper, we present a method for correcting display registration using a custom-designed two layer printed circuit board. This board was designed with grid lines to serve as the calibration pattern, and provides an accurate reference and sufficient contrast to enable proper display registration. Results show an accurate and fine stitching of the two outputs from the two modules. PMID- 22254883 TI - A robust registration method for real-time ultrasound image fusion with pre acquired 3D dataset. AB - In recent years real-time ultrasound (US) image fusion with pre-acquired 3D dataset has become widely used in both diagnosis and image-guided interventions. The accuracy of a US image fusion system heavily depends on the image registration method. However, the registration procedure of this application is inevitably interfered by possible outliers in the corresponding point pairs. This is either caused by image feature difference between two modalities or by tissue shifting and deformation of patient body between two imaging studies. While traditional methods often ignore the position error of registration points, we present a random sample consensus-based algorithm to reduce the impact of outliers and improve the robustness. To evaluate our algorithm, a simulation study is carried out, and the new method is compared with state-of-the-art, least square (LS) method. It is shown that our new method is comparable with LS method under non-outlier condition, but it performs significantly better when outliers exist. PMID- 22254884 TI - Learning-based multi-modal rigid image registration by using Bhattacharyya distances. AB - Multi-modal image registration is a momentous technology in medical image processing and analysis. In order to improve the robustness and accuracy of multi modal rigid image registration, a novel learning-based dissimilarity function is proposed in this paper. This novel dissimilarity function is based on measuring the dissimilarity between the joint intensity distribution of the testing image pair and the expected intensity distributions, which is learned from a registered image pair, with Bhattacharyya distances. Then, the aim of the registration process is to minimize the dissimilarity function. Eight hundred randomized CT - T1 registrations were performed and evaluated by the Retrospective Image Registration Evaluation (RIRE) project. The experimental results demonstrate that the proposed method can achieve higher robustness and accuracy, as compared with a closely related approach and a state-of-the-art method. PMID- 22254885 TI - Three-dimensional quantification of regional left-ventricular dyssynchrony by magnetic resonance imaging. AB - Heart failure accounts for over five million patients in the United States alone. Many of them present dyssynchronous left ventricular (LV) contraction, whose treatment by cardiac resynchronization therapy (CRT) is until now guided by electrocardiographic analysis. One third of the selected patients, however, does not respond to the therapy. Aiming at improving the response rate, recent studies showed the importance of left bundle branch block (LBBB) configurations. Therefore, in order to detect motion patterns that relate to LBBB, this paper presents a novel method for three-dimensional quantification of regional LV mechanical dyssynchrony. LV wall-motion analysis is performed on magnetic resonance imaging (MRI) cines segmented by commercial software. Mutual delays between endocardial wall motion in different LV regions are estimated by cross correlation followed by phase difference analysis in frequency domain, achieving unlimited time resolution. Rather than focusing on the systolic phase, the full cardiac cycle is used to estimate the contraction timing. The method was successfully validated against MRI tagging in five dogs before and after LBBB induction. Preliminary validation in humans with 10 LBBB patients and 7 healthy subjects showed the method feasibility and reproducibility, with sensitivity and specificity in LBBB detection equal to 95.1% and 99.4%, respectively. PMID- 22254886 TI - Myocardial strain estimated from standard cine MRI closely represents strain estimated from dedicated strain-encoded MRI. AB - A method of non-rigid image registration was developed and evaluated for the purpose of quantifying myocardial displacement and strain from cine MRI using DENSE MRI as the reference standard. The objective of this paper was to study the potential use of cine MRI with image registration, as a means of measuring strain. The local displacement of the left ventricle was modelled by free-form deformations using b-splines. Cardiac MRI images were obtained from four healthy volunteers at 1.5T and analysed by the implementation of image registration algorithms in cine data and with DENSE view in DENSE data. The results indicated there was less than 3% difference between the strain values obtained from cine and DENSE scans averaging across the regions of the left ventricle in healthy subjects (n=4). There lies great potential in the implementation of cine MRI as a means of strain estimation. As such the measurement of strain from standard cine MRI poses an appealing and potentially clinically useful new option for assessing patients with myocardial dysfunction. PMID- 22254887 TI - Parameterization of real-time 3D speckle tracking framework for cardiac strain assessment. AB - Cross-correlation based 3D speckle tracking algorithm can be used to automatically track myocardial motion on three dimensional real-time (RT3D) echocardiography. The goal of this study was to experimentally investigate the effects of different parameters associated with such algorithm to ensure accurate cardiac strain measurements. The investigation was performed on 10 chronic obstructive pulmonary disease RT3DE cardiac ultrasound images. The following two parameters were investigated: 1) the gradient threshold of the anisotropic diffusion pre-filtering and 2) the window size of the cross correlation template matching in the speckle tracking. Results suggest that the optimal gradient threshold of the anisotropic filter depends on the average gradient of the background speckle noise, and that an optimal pair of template size and search window size can be identified determines the cross-correlation level and computational cost. PMID- 22254888 TI - Manifold learning for shape guided segmentation of cardiac boundaries: application to 3D+t cardiac MRI. AB - In this paper we propose a new method for shape guided segmentation of cardiac boundaries based on manifold learning of the shapes represented by the phase field approximation of the Mumford-Shah functional. A novel distance is defined to measure the similarity of shapes without requiring deformable registration. Cardiac motion is compensated and phases are mapped into one reference phase, that is the end of diastole, to avoid time warping and synchronization at all cardiac phases. Non-linear embedding of these 3D shapes extracts the manifold of the inter-subject variation of the heart shape to be used for guiding the segmentation for a new subject. For validation the method is applied to a comprehensive dataset of 3D+t cardiac Cine MRI from normal subjects and patients. PMID- 22254889 TI - Comparison of different segmentation approaches without using gold standard. Application to the estimation of the left ventricle ejection fraction from cardiac cine MRI sequences. AB - A statistical method is proposed to compare several estimates of a relevant clinical parameter when no gold standard is available. The method is illustrated by considering the left ventricle ejection fraction derived from cardiac magnetic resonance images and computed using seven approaches with different degrees of automation. The proposed method did not use any a priori regarding with the reliability of each method and its degree of automation. The results showed that the most accurate estimates of the ejection fraction were obtained using manual segmentations, followed by the semiautomatic methods, while the methods with the least user input yielded the least accurate ejection fraction estimates. These results were consistent with the expected performance of the estimation methods, suggesting that the proposed statistical approach might be helpful to assess the performance of estimation methods on clinical data for which no gold standard is available. PMID- 22254890 TI - Cubic Hermite Bezier spline based reconstruction of implanted aortic valve stents from CT images. AB - Mechanical forces and strain induced by transcatheter aortic valve implantation are usually named as origins for postoperative left ventricular arrhythmia associated with the technique. No quantitative data has been published so far to substantiate this common belief. As a first step towards quantitative analysis of the biomechanic situation at the aortic root after transapical aortic valve implantation, we present a spline-based method for reconstruction of the implanted stent from CT images and for locally measuring the deformation of the stent. PMID- 22254891 TI - Testing for nonlinearity in non-stationary physiological time series. AB - Testing for nonlinearity is one of the most important preprocessing steps in nonlinear time series analysis. Typically, this is done by means of the linear surrogate data methods. But it is a known fact that the validity of the results heavily depends on the stationarity of the time series. Since most physiological signals are non-stationary, it is easy to falsely detect nonlinearity using the linear surrogate data methods. In this document, we propose a methodology to extend the procedure for generating constrained surrogate time series in order to assess nonlinearity in non-stationary data. The method is based on the band-phase randomized surrogates, which consists (contrary to the linear surrogate data methods) in randomizing only a portion of the Fourier phases in the high frequency domain. Analysis of simulated time series showed that in comparison to the linear surrogate data method, our method is able to discriminate between linear stationarity, linear non-stationary and nonlinear time series. Applying our methodology to heart rate variability (HRV) records of five healthy patients, we encountered that nonlinear correlations are present in this non-stationary physiological signals. PMID- 22254892 TI - EEG seizure identification by using optimized wavelet decomposition. AB - A methodology for wavelet synthesis based on lifting scheme and genetic algorithms is presented. Often, the wavelet synthesis is addressed to solve the problem of choosing properly a wavelet function from an existing library, but which may be not specially designed to the application in hand. The task under consideration is the identification of epileptic seizures over electroencephalogram recordings. Although basic classifiers are employed, results rendered that the proposed methodology is successful in the considered study achieving similar classification rates that had been reported in literature. PMID- 22254893 TI - On automated assessment of Levodopa-induced dyskinesia in Parkinson's disease. AB - A method for the analysis of accelerometer and gyroscope signals in order to automatically assess the Levodopa-induced dyskinesia (LID) in patients with Parkinson's disease is presented in this paper. Several accelerometers and gyroscopes are placed on certain positions on the subject's body and the obtained signals are analyzed in order to extract several features that depict the energy distribution over the frequency spectrum and the non-linear properties of the signal. These features are fed into an artificial neural network which is used for LID detection and severity classification. The method has been evaluated using a group of 29 subjects. Results are presented related to the body locations that the accelerometers and the gyroscopes are placed. The obtained results indicate high classification ability (84.3% average classification accuracy). PMID- 22254894 TI - Discriminative time-frequency kernels for gait analysis for amyotrophic lateral sclerosis. AB - Many stochastic systems show certain trends which in turn govern their underlying non-stationary time varying behavior. In order to facilitate efficient quantification of such signals, their analysis necessitates the use of robust tools for discerning between different classes of data. Research show that, use of time-frequency techniques offer intelligible representations for non stationary signals, along with facilitating computation of instantaneous parameters. Further, in order to obtain efficient discrimination machine learning (ML) modules are often used alongside suitable representation techniques. In this work, we exploit the concepts of ML-kernel functions directly by incorporating them in the ambiguity time-frequency (TF) space, thereby obtaining a one-step discrimination between different non-stationary patterns. The proposed technique is evaluated for quantification applications for gait signal analysis. An overall classification accuracy of 93.1% is reported for the neurological gait database consisting of signals from 16-control and 13-amyotrophic lateral sclerosis (ALS) subjects. Results indicate that this scheme offers great potential in designing robust tools for time-varying signal analysis. PMID- 22254895 TI - Optimal two-stage filtering of elastograms. AB - In ultrasound elastography, tissue axial strains are obtained through the differentiation of measured axial displacements. However, during the measurement process, the displacement signals are often contaminated with de-correlation noise caused by changes in the speckle pattern in the tissue. Thus, the application of the gradient operator on the displacement signals results in the presence of amplified noise in the axial strains, which severely obscures the useful information. The use of an effective denoising scheme is therefore imperative. In this paper, a method based on a two-stage consecutive filtering approach is proposed for the accurate estimation of axial strains. The presented method considers a cascaded system of a frequency filter and a time window, which are both designed such that the overall system operates optimally in a mean square error sense. Experimentation on simulated signals shows that the two-stage scheme employed in this study has good potential as a denoising method for ultrasound elastograms. PMID- 22254896 TI - New insight into arrhythmia onset using HRV and BPV analysis. AB - In this paper Heart Rate Variability (HRV) and Blood Pressure Variability (BPV) were analyzed before the onset of cardiac arrhythmia in order to derive markers for short-term forecasting. The (a) coherence between systolic blood pressure (SBP) and cardiac oscillations in low-frequency (LF) and high-frequency (HF) band; (b) fluctuations of phase; (c) HRV and BPV as a LF power and HF power in frequency and time-frequency domain; (d) transfer function analysis of cardiovascular signals were analyzed. Arrhythmia was preceded by: a) lower coherence; b) increase in fluctuations of phase between signals; c) higher spectral energy associated with respiratory frequency in blood pressure signal; d) raise of sympathetic outflow to the heart; e) decreased HRV. Cardiac arrhythmia was characterized mainly by an increase in LF power of blood pressure, cardiac signal and transfer function. During self-termination of arrhythmia a larger increased in total BPV and HRV was recorded. These results suggest that important information about both neuronal cardiovascular control and risk for spontaneous arrhythmia can be provided by combined analysis of frequency, phase, and time-frequency analysis of blood pressure and cardiac oscillation. PMID- 22254897 TI - Quantification of cardiovascular and cardiorespiratory coupling during hypoxia with Joint Symbolic Dynamics. AB - Newborn mammals suffering from moderate hypoxia during or after birth are able to compensate a transitory lack of oxygen by adaptation of their vital functions. However, limited information is available about bivariate couplings of the underlying complex processes controlled by the autonomic nervous system. In this study an animal model of seven newborn piglets (2-3 days old, 1.71 +/- 0.15 kg) was used. The aim of this study was to analyze the cardiovascular and cardiorespiratory interactions of autonomous nervous system during sustained hypoxia and the interrelationship of these autonomic time series after induced reoxygenation. For this purpose we applied a new high resolution version of the nonlinear method of Joint Symbolic Dynamics (JSD) for analysis of couplings between heart rate and blood pressure and respiration rate time series, respectively. This new method is characterized by using three defined symbols (JSD3) instead of two and the application of thresholds for the symbol transformation. Our results demonstrate that in contrast to the traditional JSD the comparison of cardiovascular interactions reveals only significant differences between normoxic and hypoxic conditions using JSD3 whereas for cardiorespiratory interactions significant differences were revealed by indices from both JSD2 and JSD3 due to reoxygenation. These results suggest that the application of JSD3 reveals more detailed information about cardiovascular and cardiorespiratory interactions of autonomic regulation and might be useful for monitoring of critical human newborns. PMID- 22254898 TI - System identification to characterize human use of ethanol based on generative point-process models of video games with ethanol rewards. AB - The influence of family history and genetics on the risk for the development of abuse or dependence is a major theme in alcoholism research. Recent research have used endophenotypes and behavioral paradigms to help detect further genetic contributions to this disease. Electronic tasks, essentially video games, which provide alcohol as a reward in controlled environments and with specified exposures have been developed to explore some of the behavioral and subjective characteristics of individuals with or at risk for alcohol substance use disorders. A generative model (containing parameters with unknown values) of a simple game involving a progressive work paradigm is described along with the associated point process signal processing that allows system identification of the model. The system is demonstrated on human subject data. The same human subject completing the task under different circumstances, e.g., with larger and smaller alcohol reward values, is assigned different parameter values. Potential meanings of the different parameter values are described. PMID- 22254899 TI - A 1.72MUW, 23.2fj/conversion step successive approach ADC for bio-medical signal acquisition. AB - This paper presents a successive approach register (SAR) analog-to-digital converter (ADC) with a novel hybrid digital-to-analog converter (DAC) architecture: half junction splitting (J.S.) and half binary weighted capacitor DAC. This DAC maintains low power consumption of J.S. DAC and the high signal-to noise plus distortion ratio (SNDR) of binary weighted capacitor DAC. The power dissipation of the circuit is 1.72 MUW, SNDR 59.17 dB, spurious free dynamic range (SFDR) 73.39 dB, and the FOM 23.2 fj/conversion step with 0.9 V supply voltage. The proposed circuit is fabricated in TSMC 0.18 MUm 1P6M CMOS process technology. PMID- 22254900 TI - Theoretical & experimental analysis of the Non Markov Parameter to detect low frequency synchronisation in time series analysis. AB - A theoretical investigation into the behaviour of the Non-Markov Parameter is performed from a signal processing perspective in contrast to previous methodologies based on stochastic processes theory. The results indicate that the NMP can be regarded as an informational metric which is indicative of the degree of low frequency synchronisation in a complex system. These results have deep implications for physiological analysis of biological systems where the presence of sychronisation is often a marker of pathological functioning. The NMP measure is then applied to in vivo micro-electrode recordings from the subthalamic nucleus. PMID- 22254901 TI - ECG baseline wander correction by mean-median filter and discrete wavelet transform. AB - Electrocardiographic (ECG) analysis plays an important role in diagnosis of heart diseases. High quality ECG pushes forward new drug development and improves clinical diagnosis. This paper introduces a novel method to correct baseline wander (BW) components of ECG signals based on Mean-Median (MEM) filter and discrete wavelet transform (DWT). We obtain the BW estimation via MEM, and decompose the estimation into different scales by DWT. Then, an iterative sifting process based on t-test is adopted to select the scales to reconstruct the refined BW components. The proposed method is applied to MIT-BIH Arrhythmia Database. The experimental results verify that the proposed method can effectively remove BW components and preserve useful waveform information. PMID- 22254902 TI - Interpretation of coarse-graining of Lempel-Ziv complexity measure in ECG signal analysis. AB - Lempel-Ziv (LZ) complexity measure has been applied to classify ventricular tachycardia (VT) and ventricular fibrillation (VF). The coarse-graining process plays a crucial role in the LZ complexity measure analysis, which directly affects the separating performance of VT and VF in ECG signal analysis. The question of different coarse-graining approaches interpretability in ECG signal analysis and their influence on the performance of ECG classification have not yet been previously addressed in the literature. In this paper, we present four coarse-graining process approaches, K-Means, Mean, Median and Mid-point. Our test shows that K-Means algorithm is superior to the other three approaches in VT and VF separation rate, Particularly, optimum performance is achieved at a 8-second window length. PMID- 22254903 TI - Analysis of degree of nonlinearity and stochastic nature of HRV signal during meditation using delay vector variance method. AB - Heart rate variability analysis is fast gaining acceptance as a potential non invasive means of autonomic nervous system assessment in research as well as clinical domains. In this study, a new nonlinear analysis method is used to detect the degree of nonlinearity and stochastic nature of heart rate variability signals during two forms of meditation (Chi and Kundalini). The data obtained from an online and widely used public database (i.e., MIT/BIH physionet database), is used in this study. The method used is the delay vector variance (DVV) method, which is a unified method for detecting the presence of determinism and nonlinearity in a time series and is based upon the examination of local predictability of a signal. From the results it is clear that there is a significant change in the nonlinearity and stochastic nature of the signal before and during the meditation (p value > 0.01). During Chi meditation there is a increase in stochastic nature and decrease in nonlinear nature of the signal. There is a significant decrease in the degree of nonlinearity and stochastic nature during Kundalini meditation. PMID- 22254904 TI - Recurrence quantification analysis of heart rate variability and respiratory flow series in patients on weaning trials. AB - Autonomic nervous system regulates the behavior of cardiac and respiratory systems. Its assessment during the ventilator weaning can provide information about physio-pathological imbalances. This work proposes a non linear analysis of the complexity of the heart rate variability (HRV) and breathing duration (T(Tot)) applying recurrence plot (RP) and their interaction joint recurrence plot (JRP). A total of 131 patients on weaning trials from mechanical ventilation were analyzed: 92 patients with successful weaning (group S) and 39 patients that failed to maintain spontaneous breathing (group F). The results show that parameters as determinism (DET), average diagonal line length (L), and entropy (ENTR), are statistically significant with RP for T(Tot) series, but not with HRV. When comparing the groups with JRP, all parameters have been relevant. In all cases, mean values of recurrence quantification analysis are higher in the group S than in the group F. The main differences between groups were found on the diagonal and vertical structures of the joint recurrence plot. PMID- 22254905 TI - Complexity-based analysis for the detection of heart murmurs. AB - While a healthy human heart produce a rhythmic pattern of sounds, some heart disorder induce deviations perceived as abnormal sounds called murmurs. Despite many murmurs can be considered harmless, other constitute the first basis of a heart disorder. In this sense, a correct diagnosis remains essential; however, due to the subjectivity on using human ear to make diagnosis, automatic detection systems appear as useful tools for helping medical specialists on improving diagnosis accuracy. Complexity analysis has become one important tool for the study of physiological signals, because tracking sudden alteration on the inherent complexity on biological processes might be useful for detecting pathologies. The present paper presents a complexity-based analysis methodology, which uses regularity features for the detection of heart murmurs, including Approximate Entropy, Sample Entropy, Gaussian Kernel Approximate Entropy, and Fuzzy Entropy. The results show the high discriminative power, up to 90%, of the Gaussian Kernel Approximate Entropy and Fuzzy Entropy for the proposed labour. PMID- 22254906 TI - Nonlinear dynamics of voices in esophageal phonation. AB - The present study investigated the difference in voice perturbation measures and parameters obtained from nonlinear dynamic analysis between normal laryngeal phonation and standard esophageal (SE) phonation. Jitter, shimmer, correlation dimension and Kolmogorov entropy were measured from 10 SE and 10 normal male speakers of Cantonese. Jitter and shimmer values were significantly higher for SE than laryngeal voice. But jitter values were found to be significantly different when length of sound samples was altered. In addition, both correlation dimension and Kolmogorov entropy values were significantly higher for SE than laryngeal voice and sample length did not appear to affect the result. These results suggest that SE voices are more chaotic than laryngeal voice. It follows that the technique of nonlinear dynamic analysis may be more reliable and stable for evaluating the acoustic characteristics of SE voices. PMID- 22254907 TI - epsilon-Tube regression: a new method for motion artifact reduction. AB - This paper introduces a new regression method, called epsilon-tube regression (epsilon-TR), for motion artifact reduction in physiological signals. It forms a tube arround the data which leads to an approximation that models only the motion artifact and not the target signal. Moreover, epsilon-TR prescribes the shape of the approximation using the available information about the motion artifact. The results show that epsilon-TR can effectively remove the motion artifacts from the impedance signal measured on the arms. PMID- 22254908 TI - An improved algorithm for quantifying real-time impedance biosensor signals. AB - In previously published work [1] we presented a real-time electrochemical impedance biosensor prototype system and a state-space estimation algorithm for signal quantification. Experiments in the interim have revealed some algorithm failure modes which reduced the reliability and repeatability of quantification. The present work describes a related algorithm that introduces constraints based on a priori knowledge of the expected signals predicted by the biosensor signal model. The improvements in reliability and repeatability bring the system close to deployment for real-world trials. PMID- 22254909 TI - ECG biometric using multilayer perceptron and radial basis function neural networks. AB - This paper proposes a new method to identify people using Electrocardiogram (ECG), particularly the QRS complex which has been proven to be stable against heart rate variability and convenient to be used alone as a biometric feature. 324 QRS complexes are extracted from ECGs of 18 subjects in Physionet's MIT-BIH Normal Sinus Rhythm Database (NSRDB). Multilayer Perceptron (MLP) and Radial Basis Function (RBF) neural networks are used to classify those QRS complexes. If the training data are chosen carefully to cover a wide range of input values (i.e. QRS complexes), then the classification accuracy rates can reach above 98% using MLP and 97% using RBF. PMID- 22254910 TI - Individual identification with high frequency ECG : preprocessing and classification by neural network. AB - In this research, we proposed that high frequency component of HFECG was applicable biometric feature for new identification system. We developed identification method by using neural network (NN), and aimed at the improvement of the classification rate. Preprocessing prior to NN is performed by justification on time axis and normalization on amplitude. As a result, an average of 99% classification rate was obtained from 9 subjects. We also made an attempt to identify in shorter time by shifting of the HFECG by a few samples to NN. PMID- 22254911 TI - Using artificial neural networks to classify unknown volatile chemicals from the firings of insect olfactory sensory neurons. AB - The olfactory system detects volatile chemical compounds, known as odour molecules or odorants. Such odorants have a diverse chemical structure which in turn interact with the receptors of the olfactory system. The insect olfactory system provides a unique opportunity to directly measure the firing rates that are generated by the individual olfactory sensory neurons (OSNs) which have been stimulated by odorants in order to use this data to inform their classification. In this work, we demonstrate that it is possible to use the firing rates from an array of OSNs of the vinegar fly, Drosophila melanogaster, to train an Artificial Neural Network (ANN), as a series of a Multi-Layer Perceptrons (MLPs), to differentiate between eight distinct chemical classes. We demonstrate that the MLPs when trained on 108 odorants, for both clean and 10% noise injected data, can reliably identify 87% of an unseen validation set of chemicals using noise injection. In addition, the noise injected MLPs provide a more accurate level of identification. This demonstrates that a 10% noise injected series of MLPs provides a robust method for classifying chemicals from the firing rates of OSNs and paves the way to a future realisation of an artificial olfactory biosensor. PMID- 22254912 TI - Predicting odorant chemical class from odorant descriptor values with an assembly of multi-layer perceptrons. AB - Chemical descriptors are a way to define information concerning the physical, chemical and biological properties of a chemical compound. Machine learning methods such as the Artificial Neural Network (ANN) can be used to learn and predict such compounds by training on the compounds chemical descriptors. The motivation of our work is to predict odorant molecules for the development of an artificial biosensor. In this work, we demonstrate using a set of 32 optimized odorant descriptors how an assembly of MultiLayer Perceptrons (MLPs) can be successfully trained to differentiate among eight different chemical classes of odorant. In this communication, we demonstrate how it is possible to predict all 15/15 vectors from an unseen validation set with a high average prediction accuracy of 88.5% for the validation vectors. Furthermore, an introduction of a 10% noise injection level to the training set, increased the learning rate significantly as well as improve the average prediction accuracy of the MLPs to 92% for the validating vectors. Thus, this work indicates the promise of using odorant descriptor values to accurately predict chemical class and so move us forward to the realisation of an artificial odorant biosensor. PMID- 22254913 TI - Identification of hypoglycemic states for patients with T1DM using various parameters derived from EEG signals. AB - For patients with Type 1 Diabetes Mellitus (T1DM), hypoglycemia is a very common but dangerous complication which can lead to unconsciousness, coma and even death. The variety of hypoglycemia symptoms is originated from the inadequate supply of glucose to the brain. In this study, we explore the connection between hypoglycemic episodes and the electrical activity of neurons within the brain or electroencephalogram (EEG) signals. By analyzing EEG signals from a clinical study of five children with T1DM, associated with hypoglycemia at night, we find that some EEG parameters change significantly under hypoglycemia condition. Based on these parameters, a method of detecting hypoglycemic episodes using EEG signals with a feed-forward multi-layer neural network is proposed. In our application, the classification results are 72% sensitivity and 55% specificity when the EEG signals are acquired from 2 electrodes C3 and O2. Furthermore, signals from different channels are also analyzed to observe the contributions of each channel to the performance of hypoglycemia classification. PMID- 22254914 TI - Detection of arousals in Parkinson's disease patients. AB - Arousal from sleep are short awakenings, which can be identified in the EEG as an abrupt change in frequency. Arousals can occur in all sleep stages and the number and frequency increase with age. Frequent arousals during sleep results in sleep fragmentation and is associated with daytime sleepiness. Manual scoring of arousals is time-consuming and the inter-score agreement is highly varying especially for patients with sleep related disorders. The aim of this study was to design an arousal detection algorithm capable of detecting arousals from sleep, in both non-REM and REM sleep in patients suffering from Parkinson's disease (PD). The proposed algorithm uses features from EEG, EMG and the manual sleep stage scoring as input to a feed-forward artificial neural network (ANN). The performance of the algorithm has been assessed using polysomnographic (PSG) recordings from a total of 8 patients diagnosed with PD. The performance of the algorithm was validated using the leave-one-out method resulting in a sensitivity of 89.8 % and a positive predictive value (PPV) of 88.8 %. This result is high compared to previous presented arousal detection algorithms. PMID- 22254915 TI - Classification of morphological features extracted from intracranial pressure recordings in the diagnosis of Normal Pressure Hydrocephalus (NPH). AB - The intracranial pressure (ICP) monitoring is a common procedure in neuro intensive care for pathologies such traumatic brain injuries or hemorrhages, but also for chronic ones as the Normal Pressure Hydrocephalus (NPH). The only available treatment for NPH is the surgical implantation of a shunt with the aim of routing cerebrospinal fluid (CSF) away from the brain to another part of the body. In this study, using the classification software WEKA, an intensive investigation of ICP signals has been conducted. In particular we studied 14 ICP recordings of different patients who underwent an infusion test, with the aim of investigating the presence of NPH through the ICP recording. More precisely, 20 morphological features are extracted from the ICP pulsed wave, the trend have been computed and, for each one, 9 statistical functions determined. The 180 features have been selected and passed for the classification. The results obtained shows how, among the 14 patients, a number of 12 out of 14 (85.7%) have been correctly classified, looking at just 3 features. In particular 8 out of 9 not-NPH-affected patients were correctly identified (88.89%) while 4 out of 5 NPH affected patients were correctly identified (80%). PMID- 22254916 TI - Binary particle swarm optimization for feature selection in detection of infants with hypothyroidism. AB - Hypothyroidism in infants is caused by the insufficient production of hormones by the thyroid gland. Due to stress in the chest cavity as a result of the enlarged liver, their cry signals are unique and can be distinguished from the healthy infant cries. This study investigates the effect of feature selection with Binary Particle Swarm Optimization on the performance of MultiLayer Perceptron classifier in discriminating between the healthy infants and infants with hypothyroidism from their cry signals. The feature extraction process was performed on the Mel Frequency Cepstral coefficients. Performance of the MLP classifier was examined by varying the number of coefficients. It was found that the BPSO enhances the classification accuracy while reducing the computation load of the MLP classifier. The highest classification accuracy of 99.65% was achieved for the MLP classifier, with 36 filter banks, 5 hidden nodes and 11 BPS optimised MFC coefficients. PMID- 22254917 TI - Optimization of head movement recognition using Augmented Radial Basis Function Neural Network. AB - For people with severe spine injury, head movement recognition control has been proven to be one of the most convenient and intuitive ways to control a power wheelchair. While substantial research has been done in this area, the challenge to improve system reliability and accuracy remains due to the diversity in movement tendencies and the presence of movement artifacts. We propose a Neural Network Configuration which we call Augmented Radial Basis Function Neural Network (ARBF-NN). This network is constructed as a Radial Basis Function Neural Network (RBF-NN) with a Multilayer Perceptron (MLP) augmentation layer to negate optimization limitation posed by linear classifiers in conventional RBF-NN. The RBF centroid is optimized through Regrouping Particle Swarm Optimization (RegPSO) seeded with K-Means. The trial results of ARBF-NN on Head-movement show a significant improvement on recognition accuracy up to 98.1% in sensitivity. PMID- 22254918 TI - Development and validation of a prototypal neural networks-based tumor tracking method. AB - In radiotherapy, intra-fractional organ motion introduces uncertainties in target localization, leading to unacceptable inaccuracy in dose delivery. Especially in highly selective treatments, such as those delivered with particles beams instead of photons, organ motion may results in severe side effects and/or limited tumor control. Tumor tracking is a motion mitigation strategy that allows an almost continuous dose delivery while the beam is dynamically steered to match the position of the moving target in real-time. Currently, tumor tracking is applied clinically only in the CyberKnife system for photon radiotherapy, whereas neither clinical solutions nor dedicated methodologies are available for particle therapy. Consequently, the aim of the proposed study is to develop a neural networks-based prototypal tracking algorithm intended for particle therapy. We developed a method that exploits three independent neural networks to estimate the internal target position as a function of external surrogate signals. This method was tested on data relative to 20 patients treated with CyberKnife, whose performance was used as benchmark. Results show that the developed algorithm allows targeting error reduction with respect to the CyberKnife system, thus proving the potential value of artificial neural networks for the implementation of tumor tracking methodologies. PMID- 22254919 TI - Investigation of acupoint specificity by whole brain functional connectivity analysis from fMRI data. AB - Previous neuroimaging studies on acupuncture have primarily adopted functional connectivity analysis associated with one or a few preselected brain regions. Few have investigated how these brain regions interacted at the whole brain level. In this study, we sought to investigate the acupoint specificity by exploring the whole brain functional connectivity analysis on the post-stimulus resting brain modulated by acupuncture at acupoint PC6, with the same meridian acupoint PC7 and different meridian acupoint GB37. We divided the whole brain into 90 regions and analyzed functional connectivity for each condition. Then we identified statistically significant differences in functional correlations throughout the entire brain following acupuncture at PC6 in comparison with PC7 as well as GB37. For direct comparisons, increased correlations for PC6 compared to PC7 were primarily between the prefrontal regions and the limbic/paralimbic and subcortical regions, whereas decreased correlations were mainly between the parietal regions and the limbic/paralimbic and subcortical regions. On the other hand, increased correlations for PC6 compared to GB37 were primarily between the prefrontal regions and somatosensory regions, whereas decreased correlations were mainly related with the occipital regions. Our findings demonstrated that acupuncture at different acupoints may exert heterogeneous modulatory effects on the post-stimulus resting brain, providing new evidences for the relatively function-oriented specificity of acupuncture effects. PMID- 22254920 TI - High temporal resolution dynamic contrast-enhanced MRI at 7 Tesla: a feasibility study with mouse liver model. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been widely applied to evaluate microcirculatory parameters in clinical settings. However, pre-clinical studies involving DCE-MRI of small animals remain challenging with the requirement for high spatial and temporal resolution for quantitative tracer kinetic analysis. This study illustrates the feasibility of applying a high temporal resolution (2 s) protocol for liver imaging in mice by analyzing the DCE MRI datasets of mice liver with a dual-input two-compartment tracer kinetic model. Phantom studies were performed to validate the T(1) estimates derived by the proposed protocol before applying it in mice studies. The DCE-MRI datasets of mice liver were amendable to tracer kinetic analysis using a dual-input two compartment model. Estimated micro-circulatory parameters were consistent with liver physiology, indicating viability of applying the technique for pre-clinical drug developments. PMID- 22254921 TI - In-vivo MRI and in-vivo electro-anatomical voltage map characteristics of infarct heterogeneity in a swine model. AB - The arrhythmogenic substrate in patients with prior myocardial infarct (MI) is located at the border zone, BZ. In this study we correlated the BZ identified by two methods: electro-anatomical voltage mapping (EAVM) and a novel MRI method, multi-contrast late enhancement (MCLE). A pre-clinical porcine model with chronic MI was used to characterize BZ via MRI and EAVM. Results focus on the comparison between scar percentage and BZ percentage identified by each method. The correlation coefficient for BZ percentage between the two methods was 0.74 with a p-value of less the 0.0001. Bland-Altman plots were also used to compare between the two methods (slope of 0.83 +/- 0.045). For a case of subtle infarct, there was only 1.3% infarct identified on EAVM compared to 22.2% on the corresponding slice on MCLE. The percentage of infarct on MCLE in subtle infarct does not relate to percentage of infarct in EAVM. Future registration between T(1) maps and EAVM will permit a quantitative comparison of MRI and EAVM measures. PMID- 22254922 TI - Diffusion kurtosis imaging discriminates patients with white matter lesions from healthy subjects. AB - This work illustrates that DKI reveals white matter lesions and also discriminates healthy subjects from patients with white matter lesions. To show this capability, we have investigated DKI images of a healthy subject and a patient with white matter lesions. The analysis was performed both between and within subjects. Regions of Interest (ROIs) for lesion and normal white matter in the patient images are selected manually (for within subject study) and also the corresponding ROIs in the healthy subject are defined (for between subject study). The results of comparing the estimated values for apparent diffusion and kurtosis parameters show that both D(app) and K(app) can distinguish normal and abnormal tissues. K(app) (D(app)) of the normal regions is greater (lower) than that of the abnormal regions. Another investigation over all voxels in the brain shows an important feature of kurtosis in determining white matter lesions. PMID- 22254923 TI - Accurate positioning of magnetic microparticles beyond the spatial resolution of clinical MRI scanners using susceptibility artifacts. AB - Susceptibility-based negative contrast in magnetic resonance imaging (MRI) provides a mean to visualize magnetic microparticles. In the presence of a number of microparticles in the field of view (FOV), the shape of the artifact is affected by the dipole-dipole interaction between the particles. Due to the limited spatial resolution of the clinical MR scanners, the exact positioning of the particles in MR images is not possible. However, the shape of the artifact can shed light on how the particles are distributed within the FOV. In this work, a simulation model and in-vitro experiments were used to study the shape and the amount of the susceptibility artifact for various spacing and angulations between the microparticles. The results showed that for a pair of identical particles with a diameter of D, the signal loss starts to change when particles are separated ~15 * D and they become fully distinguishable when their distance reaches ~ 40 * D. PMID- 22254924 TI - Rapid flow quantification in iliac arteries with spiral phase-contrast MRI. AB - Phase contrast MRI is a powerful tool for blood flow quantification. Conventional cartesian phase contrast sequences require lengthy acquisition on the order of several minutes. Spiral acquisition phase-contrast (PC) MRI is capable of reducing the TR and TE in order to minimize flow dependent artifacts and total imaging time. Despite this, in general, spiral phase contrast sequences suffer from off-resonance artifacts and inconsistent data artifacts. In this work, we show that short interleaved spiral readout trajectories have the capability to obtain high spatio-temporal resolution flow images in the common iliac artery distal to the aortoiliac bifurcation with little or no artifacts and with significant savings in image acquisition time over the Cartesian trajectory. To verify the accuracy, we compare our results with a Conventional cartesian trajectory. PMID- 22254925 TI - Correlation between hemodynamic parameters and intra-arterial septum motion in DeBakey Type III aortic dissections using 2D pcMRI and 4D MRA. AB - Outcome prediction in DeBakey Type III aortic dissections (AD) remains challenging. Large variations in AD morphology, physiology and treatment exist. A patient-specific approach towards a detailed understanding of the distinct features of each single case might be needed to account for this variation. In particular, an improved characterization of hemodynamic parameters in addition to geometrical quantities may yield deeper insight into this complex disease. Advances in cardiovascular magnetic resonance imaging (CMR) have resulted in pulse sequences that provide time-resolved information of blood velocities, aortic wall motion and, with the administration of exogenous intravenous contrast bolus, contrast passage timings. Here we provide a combined approach in a group of 10 AD patients using 2D phase contrast magnetic resonance imaging (2D pcMRI) and Time-resolved Angiography With Interleaved Stochastic Trajectories (TWIST) to quantify blood velocities, flow rates, maximum signal enhancement from exogenous contrast and time to maximum signal enhancement in the true lumen (TL) and false lumen (FL). The FL-TL dynamic pressure gradient was derived from 2D pcMRI velocity measurements. These hemodynamic parameters were correlated with dynamic parameters for the intra-arterial septum (IS) wall motion derived from 2D pcMRI. A strong positive correlation was found between the TL-FL dynamic pressure gradient and maximum IS extension (R=0.76) as well as with maximum IS contraction (R=-0.51) Taking the ratio of maximum extension to maximum contraction, the correlation increased to R= 0.81. The ratio of TL to FL volumetric flow rate showed a high correlation with the difference in FL-TL times to maximum enhancement (R=0.87) illustrating that higher flow in the TL will result in delayed contrast arrival in the FL and vice versa. Analogous, the TL to FL ratio of maximum enhancement correlated with the TL to FL ratio of the maximum volumetric flow rate (R=0.85). 2D pcMRI and 4D MRA in combination with exogenous intravenous contrast bolus allows characterization of hemodynamics in DeBakey type III AD. High correlations between IS wall motion, TL and FL pressure differences, flows and times to maximum enhancement were found. An extension of our analysis to follow-up imaging examinations are warranted to establish the potential for hemodynamic parameters determined with CMR as a marker for clinical outcome in longitudinal studies. PMID- 22254926 TI - Exploring the evolution of post-acupuncture resting-state networks combining ICA and multivariate Granger causality. AB - The sustained effects of acupuncture have been widely applied to clinical treatment, thus it can be assumed that the relatively functional specificity of acupoints may evolve as the function of time. In this study, we originally combined ICA and multivariate Granger causality analysis to explore the causal interactions within and among the post-acupuncture resting-state networks (RSNs) at a hearing-related acupoint GB40, with the cognition-related acupoint KI3 as a control. Following acupuncture at GB40, the superior temporal gyrus (STG) and anterior insula (AI) within auditory network appeared persistent bidirectional connection with maximal strength, and the interactions between the auditory network and others became more complex as time passed. For KI3, both the superior parietal lobule (SPL) and dorsolateral prefrontal cortex (DLPFC), as vital nuclei of cognitive function, emerged increased causal outflows and inflows as time went on. We concluded that acupuncture at different acupoints may exert different evolutive effects on causal interactions within and across the RSNs during segmented post-stimulus resting states. PMID- 22254927 TI - Venous vessel boundary delineation at high field using sigmoid-SWI. AB - Susceptibility Weighted Imaging (SWI) is an increasingly utilised MRI technique for enhancing image contrast by attenuating magnitude data with a mask derived from the phase data. It is particularly useful for venography, however at higher field strengths, the effects of localised magnetic susceptibility differences lead to ill-defined edges within SWI images and overestimation of widths in large veins oriented perpendicular to the main field. We propose a variation on SWI, sigmoid-SWI, that removes the vessel boundary artefacts, resulting in clearer visibility of edges and more accurate widths of venous vessels. PMID- 22254928 TI - Model-driven, probabilistic level set based segmentation of magnetic resonance images of the brain. AB - Accurate segmentation of magnetic resonance (MR) images of the brain to differentiate features such as soft tissue, tumor, edema and necrosis is critical for both diagnosis and treatment purposes. Region-based formulations of geometric active contour models are popular choices for segmentation of MR and other medical images. Most of the traditional region-based formulations model local region intensity by assuming a piecewise constant approximation. However, the piecewise constant approximation rarely holds true for medical images such as MR images due to the presence of noise and bias field, which invariably results in a poor segmentation of the image. To overcome this problem, we have developed a probabilistic region-based active contour model for automatic segmentation of MR images of the brain. In our approach, a mixture of Gaussian distributions is used to accurately model the arbitrarily shaped local region intensity distribution. Prior spatial information derived from probabilistic atlases is also integrated into the level set evolution framework for guiding the segmentation process. Our experiments with a series of publicly available brain MR images show that the proposed active contour model gives stable and accurate segmentation results when compared to the traditional region based formulations. PMID- 22254929 TI - A combined HRV-fMRI approach to assess cortical control of cardiovagal modulation by motion sickness. AB - Nausea is a commonly occurring symptom typified by epigastric discomfort with the urge to vomit. To date, the brain circuitry underlying the autonomic nervous system response to nausea has not been fully understood. Functional MRI (fMRI), together with a point process adaptive recursive algorithm for computation of the high-frequency (HF) index of heart rate variability (HRV) was combined to evaluate the brain circuitry underlying autonomic nervous system response to nausea. Alone, the point process analysis revealed increasing sympathetic and decreasing parasympathetic response during nausea with significant increased heart rate (HR) and decreased HF. The combined HRV-fMRI analysis demonstrated that the fMRI signal in the medial prefrontal cortex (MPFC) and pregenual anterior cingulate cortex (pgACC), regions of higher cortical functions and emotion showed a negative correlation at the baseline and a positive correlation during nausea. Overall, our findings confirm a sympathovagal shift (toward sympathetic) during nausea, which was related to brain activity in regions associated with emotion and higher cognitive function. PMID- 22254930 TI - Ambiguity and regularization in parallel MRI. AB - In this paper, we formulate the parallel magnetic resonance imaging(pMRI) as a multichannel blind deconvolution problem with subsampling. First, the model allows formal characterization of image solutions consistent with data obtained by uniform subsampling of k-space. Second, the model allows analysis of the minimum set of required calibration data. Third, the filter bank formulation provides analysis of the sufficient sizes of interpolation kernels in widely used reconstruction techniques. Fourth, the model suggests principled development of regularization terms to fight ambiguity and ill-conditioning; specifically, subspace regularization is adapted from the blind image super-resolution work of Sroubek et al. [11]. Finally, characterization of the consistent set of image solutions leads to a cautionary comment on L1 regularization for the peculiar class of piece-wise constant images. Thus, it is proposed that the analysis of the subsampled blind deconvolution task provides insight into both the multiply determined nature of the pMRI task and possible design strategies for sampling and reconstruction. PMID- 22254931 TI - The optimization of an 8-channel transceive volume array for small animal MRI at 9.4T. AB - A shielded, non-overlapped 9.4T 8-element transceive volume array was designed and constructed for small animal MRI studies. The coil configuration was optimized to obtain an appropriate trade-off between coil sensitivity, field penetration, and mutual decoupling. The simulated and experimental results presented herein demonstrate that the new volume array is capable of offering higher RF penetration, efficiency and minimum mutual coupling; the proposed technique can also be implemented for a wide range of ultra high-field applications, including dense coil arrays for human studies. PMID- 22254932 TI - A MOM/FEM-based coil sensitivity mapping method for high-field parallel MRI. AB - In this study, an electromagnetics-based inverse sensitivity mapping method is introduced for applications in high field MRI. Instead of using simplistic numerical approximations, the sensitivity of the radio-frequency coil was determined through a field approach by using iterative optimization. The current study is an extension to previous studies on the inverse method, which has restricted itself to low-field applications due to the use of the Biot-Savart integration to account for the H field calculations. In the current study, full wave solutions to the Maxwell's equations based MOM/FEM hybrid algorithm were employed to provide H field evaluation. It is demonstrated that the proposed method is able to produce high-fidelity sensitivity estimation which result in images with significantly less artefact power. PMID- 22254933 TI - Visual cortex activation induced by tactile stimulation in late-blind individuals with retinitis pigmentosa. AB - The inter-subject variability of visual cortex reorganization was assessed in late-blind subjects suffering from retinitis pigmentosa (RP), a degenerative retinal disease that results in tunnel vision and eventual loss of sight. fMRI BOLD responses were measured as blindfolded RP and blindfolded sighted control groups completed a tactile discrimination task (in which subjects determined the relative roughness of sandpaper discs) during successive scans in a 3T Siemens scanner. Resulting activation patterns were compared between the two groups in a whole-brain analysis. We found that vision deprivation leads to elevated activation of the visual cortex elicited with tactile stimuli, and the degree of activation correlates with the degree of visual field loss: higher visual cortex activation is associated with greater vision loss. The location of vision loss in the visual field also correlates with the location of tactile responses in the visual cortex, with greater peripheral vision loss leading to stronger activation in the peripheral of V1. Visual cortex responses to tactile stimuli may hence be used as a diagnostic marker in determining the extent of an individual's vision loss and tracking sight recovery following treatments. PMID- 22254934 TI - 3D selective pulse design with variable spoke trajectories for parallel excitation. AB - Three dimensional spatial selective RF pulse of practical length has been demonstrated using parallel transmission technique in Magnetic Resonance Imaging. Currently, spoke trajectory, which is a set of parallel k-space straight lines, is widely used for 3-D slab excitation to achieve sharp slice profile and a uniform or smoothly varying in-plane profile. The better control of in-plane profile mainly comes from an increased number of spokes. In this paper, we proposed three types of modified spoke trajectories for the 3-D tailored RF pulse design which traverse k-space more efficiently. Simulations are used to characterize the proposed trajectories. PMID- 22254935 TI - A novel strategy for long-term implantable artificial pancreas. AB - Technology has recently changed type 1 diabetes treatment by introducing several advancements able to improve patients' quality of life. However, despite of several decades of research efforts, the dream of a fully-automated implanted artificial pancreas is quite far from its realization. The need for periodically restoring the implanted battery charge and refilling the implanted insulin reservoir are the main issues, for which invasive surgery, transcutaneous catheters or external portable devices are presently the only solutions. In this paper we propose a novel approach to these issues, describing a totally implanted closed-loop artificial pancreas with a wireless battery charger and a non invasive strategy for insulin refilling, based on sensorized swallowable "insulin carrier" capsules. Such system has the potential to represent a final solution for diabetes treatment, by fully restoring patients' quality of life. PMID- 22254936 TI - A SU-8-based compact implantable wireless pressure sensor for intraocular pressure sensing application. AB - Telemetric sensing has received a great deal of attention in noncontact human disease detection. To take advantage of this method, this paper presents a SU-8 based compact (1.52 mm * 3.23 mm * 0.2 mm) passive wireless pressure sensor, especially designed to measure the intraocular pressure. The sensor was microfabricated using biocompatible materials such as gold and SU-8 [1] to form the LC parallel circuit and the pressure sensitive diaphragm. The surface of the sensor is fully covered by SU-8, which isolates the working circuit from the biological tissue medium. The pressure signal can be detected by an external readout coil with up to 6 mm distance from the implanted sensor. The pressure sensitivity of the sensor was characterized in both air and saline environment. The microfabricated sensor has high sensitivity (>7,000 ppm/mmHg). PMID- 22254937 TI - Low-power implantable ultrasound imager for online monitoring of tumor growth. AB - Clinicians all over the world agree that the most effective way to deal with a malignant tumor growth within internal organs is to detect it early. In most cases, early detection requires automated localized high resolution scanning of a region of interest--such as lungs, brain, small intestine, and gastro-intestinal tract. External or endoscopic ultrasound technologies are often not effective for imaging deep inside organs due to lack of adequate spatial resolution. In this paper, we propose using a miniature, low power implantable ultrasound imager for online monitoring of tumor growth in internal body parts. We explore the design space for such an implantable ultrasonic imaging system targeted to early detection or post-surgery monitoring of a malignant growth. The system can be placed locally in a susceptible region or for post-operative monitoring of relapse. The proposed system is capable of providing high-resolution image of a volume of interest at periodic intervals, using a relatively safe imaging technology, thus providing a chronic, reliable, and cost-effective monitoring option. PMID- 22254938 TI - A 64-channel neuron recording system. AB - This paper presents a fully integrated low-power neuron recording front-end system in TSMC 65 nm 1p6m CMOS technology. The proposed system is comprised of two recording modules, each containing 32 recording channels with tunable bandwidth and gain, a 32-to-1 multiplexer, one differential successive approximation register (SAR) analog-to-digital converter (ADC) with programmable sampling rate on each channel, and a digital control module to govern the signal digitization as well as to encode and serialize the digitized neuron signal from two ADCs. The recording amplifier presents a low power and low noise merits of 6 MUW and input-referred noise of 3.8 MUV(rms). The ADC digitizes the neural signal at a sampling rate of 40 kS/s with 9-bit resolution. The overall power consumption of the entire system is 2.56 mW and occupies an area of 3 * 4mm(2). PMID- 22254939 TI - In vitro study of titanium nitride electrodes for neural stimulation. AB - For neural stimulation, reliable high density charge transfer into tissue is required. One electrode material for these applications is titanium nitride (TiN). In this paper, a method for lifetime analysis of TiN electrodes is discussed. Our method significantly differs from open literature. The tests were run for much longer durations. Special attention was paid to the optical appearance and electrode voltage response to different input current pulses. According to our investigations, TiN electrodes are able to deliver at most 0.2 mC/cm(2) charge density for square shaped electrodes with 50 MUm * 50 MUm dimensions in safe operation, which is less compared to previous reports. The safe operation window for TiN was confirmed to be +/- 1 V in terms of electrode potential with the counter electrode considered as reference. We found that the shape of the waveform does not affect electrode lifetime. Our measurements show that rectangular voltage waveforms inject the most amount of charge into the electrodes compared to other shapes. This makes rectangular electrode voltage signals optimal for highest charge injection at a given lifetime. In our case with square electrodes, the absolute electrode potential is found to be the more important parameter in electrode lifetime, compared to Helmholtz capacitor voltage drop. PMID- 22254940 TI - Hydrogel optimization towards fibroblast-friendly biomimetic coatings for implantable devices. AB - In this paper we present our investigations related to the optimization of hydrogels for the coating/packaging of biomedical devices. In order for hydrogels to be a viable interface/packaging material, a number of conditions must be met. We outline the tailoring of the mechanical properties of a HEMA based hydrogel by exploiting the influence of individual hydrogel components to achieve these requirements. The water sorption, the elasticity and the porosity of various hydrogel materials were tested and the effects of the different hydrogel components was determined. These components include gelatin (used as a pore generator or porogen), alginate (to influence mechanical properties) and collagen (to improve cell adhesion). We also report the results of in vitro fibroblast testing on various hydrogel types. PMID- 22254941 TI - Delivering optical power to subcutaneous implanted devices. AB - In this paper, a new, easy-to-implement, and MRI-compatible approach for delivering power to implantable devices is presented. The idea is to harvest the energy of light within the therapeutic window wavelengths, where the optical absorption is small, by using subcutaneous photovoltaic (PV) cells. Depending on the application, this energy can then be used to directly drive the embedded electronics of an implanted device or recharge its battery. To show the feasibility of this system, a CMOS chip based on this concept has been implemented and tested. The experimental results demonstrate that MUW's of power in ambient light conditions can be harvested using mm(2)-size PV cells. This amount of power is sufficient to address the needs of many low-power applications. PMID- 22254942 TI - Flexible PET/ITO electrode array for implantable biomedical applications. AB - Flexible PET/ITO (PolyEthylene Terephthalate/ Indium Tin Oxide) implantable electrode array for spinal cord stimulation and retina prosthesis have been developed. The electrode array is fabricated on a thin PET/ITO substrate and encapsulated with insulating material, SU-8. The PET substrate made electrodes flexible so that they could shape to contoured tissues. A layer of gold on the stimulation sites served to reduce the electrode/tissue interface impedance. Prototypes of 1 * 8 and 3 * 8 electrode arrays are fabricated for monophasic and biphasic stimulation of spinal cord respectively. The exposed electrode dimensions are 3 mm2 for monophasic and 6 mm2 for biphasic stimulation with 100 MUm of interconnection paths. The prototype of 4 * 4 electrode arrays were also fabricated with the same process for retinal prosthesis with exposed electrode diameter of 125 MUm. To verify the functionality of the subdural electrodes, the electrochemical impedance spectroscopy was measured. The electrode/tissue impedance was 500 Omega at 1KHz for 3 mm2 area. PMID- 22254943 TI - Design of double layer printed spiral coils for wirelessly-powered biomedical implants. AB - In this paper employing double layer printed spiral coils (PSCs) is proposed for wireless power transmission in implantable biomedical applications. Detailed modeling of this type of PSCs is presented. Both calculations and measurements of fabricated double layer PSCs indicate that this structure can decrease the size of typical single layer PSCs without any change in the most important parameters of the coils, such as quality factor. Also, it is shown that with equal PSC dimensions and design parameters, double layer PSCs achieve significantly higher inductances and quality factors. Ultimately, a pair of double layer PSCs with a distance of 5 mm in air is used in an inductive link. The power transfer efficiency of this link is about 79.8% with a carrier frequency of 5 MHz and coupling coefficient of 0.189. PMID- 22254944 TI - Implantable radio frequency identification sensors: wireless power and communication. AB - There are significant technical challenges in the development of a fully implantable wirelessly powered neural interface. Challenges include wireless transmission of sufficient power to the implanted device to ensure reliable operation for decades without replacement, minimizing tissue heating, and adequate reliable communications bandwidth. Overcoming these challenges is essential for the development of implantable closed loop system for the treatment of disorders ranging from epilepsy, incontinence, stroke and spinal cord injury. We discuss the development of the wireless power, communication and control for a Radio-Frequency Identification Sensor (RFIDS) system with targeted power range for a 700 mV, 30 to 40 uA load attained at -2 dBm. PMID- 22254945 TI - Design and implementation of a volume conduction based RFID system for smart implants. AB - As the population ages, knee and hip replacement surgeries are more and more popular, and embedding an RFID (radio frequency identification) tag on these implants for identification becomes an important issue. Traditional operation of an RFID tag by wireless means will not work on the implantable knees or hips which are made of metal because of the interference caused by metallic objects degrading the field strength near the RFID tag. This paper proposes a method of operating an RFID tag using volume conduction while avoiding the RF interference in a metallic environment. To increase the efficiency of power transmission, electrodes in this paper are designed and optimized for a real knee implant. Experiments using saline have been conducted and the results have shown that volume conduction has a better performance than wireless methods in that signal attenuation is far less in metallic environments. Finally, the experiment on reading an implanted RFID tag through pig skin shows that volume conduction is an effective method to operate an RFID tag embedded on a metallic implant. PMID- 22254946 TI - Ultra-high density packaging technology for injectable medical devices. AB - Future implantable medical devices will be highly miniaturized and almost certainly leverage die-level electronics miniaturization and packaging. Here, an integrated ultra-high density packaging platform is proposed to enable a new class of medical devices. Dense modules are obtained by interconnecting existing ASICs and discrete components using a process which achieves the highest packaging densities available. PMID- 22254947 TI - Biocompatible nanolayered polymerization of MEMS devices. AB - Deposition of polymeric and biocompatible nanolayers on the solid-state substrates is done using a simple vacuum chamber. The chemical characteristics of the deposited nanolayer are analyzed using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The surface morphology of the nanolayers is analyzed using contact angle goniometer and scanning electron microscopy. The coated nanolayers show excellent stability in different chemical surroundings including the physiological pH therefore making it applicable in coating 3D MEMS devices and body implants which need medicated coating. A micropore is coated with this approach and results depict uniform coating of the structure. PMID- 22254948 TI - Optimal secondary coil design for inductive powering of the Artificial Accommodation System. AB - Age-related ailments like presbyopia and cataract are increasing concerns in the aging society. Both go along with a loss of ability to accommodate. A new approach to restore the patients' ability to accommodate is the Artificial Accommodation System. This micro mechatronic system will be implanted into the capsular bag to replace the human crystalline lens. Depending on the patients' actual need for accommodation, the Artificial Accommodation System autonomously adapts the refractive power of its integrated optical element in a way that the projection on the patients' retina results in a sharp image. As the Artificial Accommodation System is an active implant, its subsystems have to be supplied with electrical energy. Evolving technologies, like energy harvesting, which can potentially be used to power an implant like the Artificial Accommodation System are at the current state of art not sufficient to power the Artificial Accommodation System autonomously [1]. In the near future, therefore an inductive power supply system will be developed which includes an energy storage to power the Artificial Accommodation System autonomously over a period of 24 h and can be recharged wirelessly. This Paper describes a new possibility to optimize the secondary coil design in a solely analytical way, based on a new figure of merit. Within this paper the developed figure of merit is applied to optimize the secondary coil design for the Artificial Accommodation System. PMID- 22254949 TI - A MICS telemetry implant powered by a 27MHz ISM inductive link. AB - An implantable telemetry device is presented, inductively powered by a 5.8 mW 27 MHz ISM-band supply and received with a stacked-spiral implantable power coil. A 15th harmonic 405 MHz MICS-band data carrier is generated from the power signal, data-modulated, filtered and sent to a receiver via a wireless data link. The implantable module is tested in a biological environment, successfully proving the concept. PMID- 22254950 TI - Reactive component selection for TET powered medical devices. AB - Transcutaneous energy transfer (TET) is capable of supplying power across the skin to implantable devices and avoids the risk of infection associated with wires passing through the skin. These systems rely on a high frequency magnetic field to overcome the relatively low coupling between a coil located outside the body, and a coil implanted within the body. This paper introduces a new optimisation procedure to choose tuning capacitors that minimises the amount of power dissipated in the power transfer coils of an implantable TET system. The frequency of operation is determined by the selection of the resonant reactive components. By analysing the overall circuit impedance it is possible to observe that a Zero Voltage Switched TET system may dissipate different amounts of power in the power transfer coils while delivering the same amount of power. In this study an objective function was developed to determine the best configuration of resonant capacitors for any particular set of TET coils in order to minimize power loss. The method is used to find the value of the resonant capacitors for a system delivering 15 W over a coupling range of k=0.1 to 0.55 (corresponding to a separation of up to 20mm). PMID- 22254951 TI - Wireless intra-brain communication for image transmission through mouse brain. AB - We demonstrate wireless image data transmission through a mouse brain. The transmission characteristics of mouse brain is measured. By inserting electrodes into the brain, the transmission efficiency is drastically increased. An AM signal modulated with the image data from an implantable image sensor was launched into the brain and the received signal was demodulated. The data was successfully transmitted through the brain and the image was reproduced. PMID- 22254952 TI - Development of a novel six-axis force/moment sensor attached to a prosthetic limb for the unrestrained gait measurement. AB - Since the number of trans-femoral amputees has increased by industrial or traffic accidents in modern society, a prosthetic limb has been required. In this case, those amputees must regain moving pattern by efficient gait training using load conditions on a prosthetic limb as quantitative evaluation indices. However, conventional gait training systems cannot measure long continuous walking motions. In this paper, a novel six-axis force/moment sensor, which is attached to a prosthetic limb for the unrestrained gait measurement, is developed. As a result of applying response surface method and desirability function, optimum design variables to reduce interference components are obtained. Finally, characteristics test by applying optimum design variables is performed and the effectiveness of the developed sensor is validated. PMID- 22254953 TI - MEMS-based bubble pressure sensor for prosthetic socket interface pressure measurement. AB - The ability to chronically monitor pressure at the prosthetic socket/residual limb interface could provide important data to the research and clinical communities. With this application in mind, we describe a novel type of sensor which consists of a MEMS pressure sensor and custom electronics packaged in a fluid-filled bubble. The sensor is characterized and compared to two commercially available technologies. The bubble sensor has excellent drift performance and good sensing resolution. It exhibits hysteresis which may be due to the silicone that the sensor is molded in. To reduce hysteresis, it may be advisable to place the sensor between the liner and the socket rather molding directly into the liner. PMID- 22254954 TI - Slip detection and grip adjustment using optical tracking in prosthetic hands. AB - We have designed a closed loop control system that adjusts the grasping force of a prosthetic hand based on the amount of object slip detected by an optical tracking sensor. The system was designed for the i-Limb (a multi-fingered prosthetic hand from Touch Bionics Inc.) and is comprised of an optical sensor embedded inside a silicone prosthetic glove and a control algorithm. In a proof of concept study to demonstrate the effectiveness of optical tracking in slip sensing, we record slip rate while increasing the weight held in the grasp of the hand and compare two cases: grip adjustment on and grip adjustment off. The average slip rate was found to be 0.314 slips/(s . oz) without grip adjustment and 0.0411 slips/(s . oz) with grip adjustment. This paper discusses the advantages of the optical approach in slip detection and presents the experiment and results utilizing the optical sensor and grip control algorithm. PMID- 22254955 TI - Ultra-high photosensitivity silicon nanophotonics for retinal prosthesis: electrical characteristics. AB - Retinal degenerative diseases such as age related macular degeneration (AMD) and retinitis pigmentosa (RP), lead to the loss of the photoreceptor cells rendering the retina incapable of detecting light. Several engineering approaches have aimed at replacing the function of the photoreceptors by detecting light via an external camera or photodiodes and electrically stimulating the remaining retinal tissue to restore vision. These devices rely heavily on off-device processing to solve the computational challenge of matching the performance of the PRs. In this work, we present a unique ultra-high sensitivity photodetector technology with light sensitivity, signal amplification, light adaptation that shows signal transduction performance approaching those of the rods and cones in the mammalian retina. In addition, the technology offers nanoscale control over photodetectors topography with the potential to reproduce the visual acuity of the natural retina. This technology promises to drastically reduce the foot print, power consumption and computational needs of the current retinal prothesis, while reproducing high resolution vision. PMID- 22254956 TI - A transparent MUECoG array for simultaneous recording and optogenetic stimulation. AB - In this paper we report for the first time the design, fabrication and characterization of an optically transparent electrode array for micro electrocorticography. We present a 49-channel MUECoG array with an electrode pitch of 800 MUm and a 16-channel linear MUECoG array with an electrode pitch of 200 MUm. The backing material was Parylene C. Transparent, sputtered indium tin oxide (ITO) was used in conjunction with e-beam evaporated gold to fabricate the electrodes. We provide electrochemical impedance characterization and light transmission data for the fabricated devices. PMID- 22254957 TI - Dynamically characterizing bioimpedance of fingertip skin through a developed CVD based electrotactile rendering system. AB - In this paper, by combining a newly developed constant-voltage-driver (CVD) based electrotactile rendering system with an on-line identification method, parameters of the resistor-capacitor (R-C) load bioimpedance model of fingertip skin are dynamically characterized and analyzed. The CVD rendering system is capable of producing varying stimulation voltage/current waveforms to fingertip. The proposed on-line identification method is a discrete-time extended least squares (ELS) iterative approach with forgetting factor (FF), which serves as an adaptive law to estimate parameters of the bioimpedance model of fingertip skin during performing the stimulation current tracking control in z-domain. Experimental results demonstrate dynamic characteristics of the identified fingertip skin bioimpedance for the sampled population. PMID- 22254958 TI - A 8.6 MUW 3-bit programmable gain amplifier for multiplexed-input neural recording systems. AB - We report a fully-integrated low-power 3-bit programmable-gain amplifier (PGA) that can be used as the second stage amplifier to adjust the gain for multi channel neural recording systems. The design strategy maximizes energy-efficiency using a technique by optimizing a slew rate, gain and phase margin. The PGA consumes 8.66 MUW from 1-V single supply. This is an order of magnitude lower than the previous designs reported up to date. Analysis, simulation, and measurement results will be described in detail for a part of a multiplexed 16 channels neural recording system. In this implementation, while giving a full flexibility of gain control, the overhead for each channel is quite negligible: only 0.54 MUW in power and less than 0.002 mm(2) in area. PMID- 22254959 TI - A comparison of tripolar concentric ring electrode and spline Laplacians on a four-layer concentric spherical model. AB - We have simulated a four-layer concentric spherical head model. We calculated the spline and tripolar Laplacian estimates and compared them to the analytical Laplacian on the spherical surface. In the simulations we used five different dipole groups and two electrode configurations. The comparison shows that the tripolar Laplacian has higher correlation coefficient to the analytical Laplacian in the electrode configurations tested (19, standard 10/20 locations and 64 electrodes). PMID- 22254960 TI - A blister-test apparatus for studies on the adhesion of materials used for neural electrodes. AB - A blister test apparatus has been developed, which allows a quantitative adhesion analysis of thin-film metallizations on polymers manufactured in cleanroom conditions suitable for micromachining of neural electrode arrays. The device is capable of pressurizing metallic membranes at wafer level, monitoring the pressure and the height of the developing blister while detecting the moment of delamination, allowing the calculation of the adhesion energy between metal film and polymer. The machine is designed for quantitative long-term studies of materials used in neural microelectrode arrays. PMID- 22254961 TI - Single-crystal cubic silicon carbide: an in vivo biocompatible semiconductor for brain machine interface devices. AB - Single crystal silicon carbide (SiC) is a wide band-gap semiconductor which has shown both bio- and hemo-compatibility [1-5]. Although single crystalline SiC has appealing bio-sensing potential, the material has not been extensively characterized. Cubic silicon carbide (3C-SiC) has superior in vitro biocompatibility compared to its hexagonal counterparts [3, 5]. Brain machine interface (BMI) systems using implantable neuronal prosthetics offer the possibility of bi-directional signaling, which allow sensory feedback and closed loop control. Existing implantable neural interfaces have limited long-term reliability, and 3C-SiC may be a material that may improve that reliability. In the present study, we investigated in vivo 3C-SiC biocompatibility in the CNS of C56BL/6 mice. 3C-SiC was compared against the known immunoreactive response of silicon (Si) at 5, 10, and 35 days. The material was examined to detect CD45, a protein tyrosine phosphatase (PTP) expressed by activated microglia and macrophages. The 3C-SiC surface revealed limited immunoresponse and significantly reduced microglia compared to Si substrate. PMID- 22254962 TI - The first neural probe integrated with light source (blue laser diode) for optical stimulation and electrical recording. AB - In this paper, we report a neural probe which can selectively stimulate target neurons optically through Si wet etched mirror surface and record extracellular neural signals in iridium oxide tetrodes. Consequently, the proposed approach provides to improve directional problem and achieve at least 150/m gap distance between stimulation and recording sites by wet etched mirror surface in V-groove. Also, we developed light source, blue laser diode (OSRAM Blue Laser Diode_PL 450), integration through simple jig for one-touch butt-coupling. Furthermore, optical power and impedance of iridium oxide tetrodes were measured as 200 MUW on 5 mW from LD and 206.5 k Omega at 1 kHz and we demonstrated insertion test of probe in 0.5% agarose-gel successfully. We have successfully transmitted a light of 450 nm to optical fiber through the integrated LD using by butt-coupling method. PMID- 22254963 TI - Realization of an active book for multichannel intrathecal root stimulation in spinal cord injury--preliminary results. AB - After spinal cord injury, electrical stimulation of the roots inside the spinal column at the level of the cauda equina is a safe and effective way to regain some degree of control over lower body function, e.g. bladder and bowel management and leg movement. The success of current systems used for so-called intrathecal stimulation is limited by the low number of stimulation channels, which are in consequence of the maximum acceptable number of transdural cables. In order to overcome this limitation, we developed an active electrode with integrated electronics, providing four individual stimulation channels that requires one cable only. This paper outlines the different elements of the so called active book with the emphasis on its preliminary construction and assembly. PMID- 22254964 TI - Polymer-based shaft microelectrodes with optical and fluidic capabilities as a tool for optogenetics. AB - In this work, we describe the fabrication of a polymer-based shaft electrode which can conduct light as well as fluids to a target brain region and record electrical neural signals from the same tissue volume simultaneously. This multifunctional neural probe is intended to facilitate optogenetic in vivo experiments. PMID- 22254965 TI - A novel flex-rigid and soft-release ECoG array. AB - This article addresses a novel fabrication process for an electrocorticogram (ECoG) electrode array. It consists of three regions: a flexible recording area, a flexible cable, and a rigid field for soldering the connectors. The flexible components can adapt to the curved shape of the cerebral cortex. Furthermore, the entire structure is a free-standing membrane, attached by removable polyimide straps to its carrier substrate. This configuration allows for a high level of control during soldering, electrode characterization and sterilization, as well as a soft release of the array off its carrier just before implantation. The array contains 128 gold electrodes, each 300 nm thick, sandwiched between two 5 MUm thick polyimide films. The measuring area of the device is a regular hexagon with a side length of 7.2 mm, designed for implantation on the primary visual cortex of a Rhesus monkey. The flexible cable is 4 cm long. The rigid soldering area was designed for 4 * 32 OMNETICS connectors. The line resistance from an electrode site to the corresponding electrical connector pin is 540 Omega. PMID- 22254966 TI - Process development for dry etching polydimethylsiloxane for neural electrodes. AB - In order to create high density electrode arrays, a reactive ion (dry) etching process was developed using sulphur hexafluoride (SF(6)) and oxygen (O(2)) plasma to pattern micro-structures in medical grade polydimethylsiloxane (PDMS). The surface topography and etch performance were analyzed by employing surface profilometry, scanning electron micrographs (SEM) and atomic force miscroscopy (AFM). The maximum etch rate was approximately 0.22 MUm/min. The chemical modification of the PDMS structure in SF(6) and O(2) plasma was investigated through x-ray photoelectron spectroscopy (XPS). Micro-scale openings in PDMS were achieved using a dry etching method to allow charge injection at the electrode tissue interface. PMID- 22254967 TI - A 1.5V 120nW CMOS programmable monolithic reference generator for wireless implantable system. AB - We implement and characterize a 1.5 V 120 nW CMOS programmable monolithic reference generator for wireless implantable system. The proposed generator is optimized to be tolerable for power supply variation in a small area with programmability to generate various reference voltages and currents. The measured power line sensitivity are 0.02 / 1.1%/V for voltage and current reference, respectively. This reference generator can operate for input voltage ranging from 1.5 V to 3.5 V and implemented in an area of 0.011 mm(2), which is the smallest monolithic reference generator in 0.25 MUm technology to the best of our knowledge. The output can vary from 20 nA to 33 nA for current reference and from 0.71 V to 1.03 V for voltage reference. PMID- 22254968 TI - Achievable peak electrode voltage reduction by neurostimulators using descending staircase currents to deliver charge. AB - This paper considers the achievable reduction in peak voltage across two driving terminals of an RC circuit when delivering charge using a stepped current waveform, comprising a chosen number of steps of equal duration, compared with using a constant current over the total duration. This work has application to the design of neurostimulators giving reduced peak electrode voltage when delivering a given electric charge over a given time duration. Exact solutions for the greatest possible peak voltage reduction using two and three steps are given. Furthermore, it is shown that the achievable peak voltage reduction, for any given number of steps is identical for simple series RC circuits and parallel RC circuits, for appropriate different values of RC. It is conjectured that the maximum peak voltage reduction cannot be improved using a more complicated RC circuit. PMID- 22254969 TI - Fascicle-selective multi-contact cuff electrode. AB - Neural recording is one of the main issues to be addressed in order to allow closed-loop functional electrical stimulation systems. Because each fascicle in nerves carry specific information, new sensors providing high spatial selectivity are required for chronic implantable devices. This work aims at evaluating the feasibility of a new device using a highly spatial-selective multi-contact cuff electrode. The proposed electrode configuration is evaluated based on simulations using a model of a nerve comprising multiple fascicles. Study of the electrode selectivity is done and compared with a state-of-the-art electrode designed for the same purpose and shows that activity of two fascicles separated by as little as 1 mm can be distinguished. Implementation challenges and perspectives for such electrodes are also discussed. PMID- 22254970 TI - Chronic recordings from the rat spinal cord descending tracts with microwires. AB - This study investigated the feasibility of chronically recording descending signals from the rat spinal cord using microwire electrodes. Eight 25 MUm diameter Pt-Ir microwires were implanted in the dorsolateral rubrospinal tract (RST) bilaterally at the c5 level in each of the four adult Long Evans rats trained for food reach-to-grasp task. Signal stability was assessed by calculating the signal-to-noise ratio (SNR) and mean signal amplitude during the four week recording period. The results of ANOVA did not suggest significant difference between sessions for any of the electrodes, indicating stability. Immunohistology suggested minimal tissue response to these microwires during the four week implant period. The results of this study show that microwire electrodes can be used for short-term chronic recordings of signals from the descending motor tracts in experimental animals. PMID- 22254971 TI - Real-time implementation of an intent recognition system for artificial legs. AB - This paper presents a real-time implementation of an intent recognition system on one transfemoral (TF) amputee. Surface Electromyographic (EMG) signals recorded from residual thigh muscles and the ground reaction forces/moments collected from the prosthetic pylon were fused to identify three locomotion modes (level-ground walking, stair ascent, and stair descent) and tasks such as sitting and standing. The designed system based on neuromuscular-mechanical fusion can accurately identify the performing tasks and predict intended task transitions of the patient with a TF amputation in real-time. The overall recognition accuracy in static states (i.e. the states when subjects continuously performed the same task) was 98.36%. All task transitions were correctly recognized 80-323 ms before the defined critical timing for safe switch of prosthesis control mode. These promising results indicate the potential of designed intent recognition system for neural control of computerized, powered prosthetic legs. PMID- 22254972 TI - Surface modification of neural stimulating/recording electrodes with high surface area platinum-iridium alloy coatings. AB - High-surface area platinum-iridium alloys were electrodeposited by on Pt and Au microelectrodes using a potential sweep technique. Detailed investigations of the structure and morphology and the electrochemical properties of the electrodeposited Pt-Ir alloy coatings were performed. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) were used for the determination of the surface morphology and the chemical composition of the Pt-Ir coatings, respectively. The elemental analysis by EDS showed a nearly 60-40% Pt Ir composition of the coatings. The electrochemical properties of the Pt-Ir coatings were evaluated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). CV and EIS measurements revealed that the Pt-Ir coated electrodes exhibit significantly increased charge storage capacity and real surface area compared to uncoated Pt electrodes. Charge injection experiments of the Pt-Ir coated microelectrodes revealed low potential excursions, indicating high charge injection capabilities within safe potential limits. PMID- 22254973 TI - Analytical design equations for self-tuned Class-E power amplifier. AB - For many emerging neural prosthesis designs that are powered by inductive coupling, their small physical size requires large current in the extracorporeal transmitter coil, and the Class-E power amplifier topology is often used for the transmitter design. Tuning of Class-E circuits for efficient operation is difficult and a self-tuned circuit can facilitate the tuning. The coil current is sensed and used to tune the switching of the transistor switch in the Class-E circuit in order to maintain its high-efficiency operation. Although mathematically complex, the analysis and design procedure for the self-tuned Class-E circuit can be simplified due to the current feedback control, which makes the phase angle between the switching pulse and the coil current predetermined. In this paper explicit analytical design equations are derived and a detailed design procedure is presented and compared with the conventional Class E design approaches. PMID- 22254974 TI - Feasibility study for future implantable neural-silicon interface devices. AB - The emerging neural-silicon interface devices bridge nerve systems with artificial systems and play a key role in neuro-prostheses and neuro rehabilitation applications. Integrating neural signal collection, processing and transmission on a single device will make clinical applications more practical and feasible. This paper focuses on the wireless antenna part and real-time neural signal analysis part of implantable brain-machine interface (BMI) devices. We propose to use millimeter-wave for wireless connections between different areas of a brain. Various antenna, including microstrip patch, monopole antenna and substrate integrated waveguide antenna are considered for the intra-cortical proximity communication. A Hebbian eigenfilter based method is proposed for multi channel neuronal spike sorting. Folding and parallel design techniques are employed to explore various structures and make a trade-off between area and power consumption. Field programmable logic arrays (FPGAs) are used to evaluate various structures. PMID- 22254975 TI - Modeling two-photon calcium fluorescence of episodic V1 recordings using multifrequency analysis. AB - The use of two-photon microscopy allows for imaging of deep neural tissue in vivo. This paper examines frequency-based analysis to two-photon calcium fluorescence images with the goal of deriving smooth tuning curves. We present a multifrequency analysis approach for improved extraction of calcium responses in episodic stimulation experiments, that is, when the stimulus is applied for a number of frames, then turned off for the next few frames, and so on. Episodic orientation stimulus was applied while recording from the primary visual cortex of an anesthetized mouse. The multifrequency model demonstrated improved tuning curve descriptions of the neurons. It also offers perspective regarding the characteristics of calcium fluorescence imaging of the brain. PMID- 22254976 TI - Coupling biotic and abiotic metrics to create a testbed for predicting neural electrode performance. AB - In this work, we develop an experimental testbed that couples biotic and abiotic metrics for studying, quantifying and predicting the effects of chronic electrode implantation on neural electrode performance. The rationale is based on the observation that long-term functionality is the outcome of the interactions between the dynamics of the neuronal environment and the properties of the electrode itself. By combining and analyzing the substantially richer information available in the spatiotemporal dynamics of neurons with biotic and abiotic metrics such as biochemical markers, histochemistry, SEM imaging, and electrochemistry, we seek to quantitatively improve our understanding of the functional modifications underlying the long-term responses of electrode implants. The goal is to ultimately enable the design of future reliable interfaces. In our preliminary analysis using this biotic-abiotic approach of an electrode 18 days post-implant, we observed both structural and histochemical responses related to chronic electrode implantation. These were coupled to daily functional changes in electrode performance. Interestingly, these changes were not correlated with markers of brain injury at the time of electrode explantation. Future work using this multidisciplinary approach is directed to providing a detailed perspective into long-term microelectrode performance. PMID- 22254978 TI - Multi-layer coils for efficient Transcutaneous Power Transfer. AB - TETS (Transcutaneous Energy Transfer System) has been successfully used for powering medical implants for different purposes such as for neural recordings and drug delivery. Yet, due to their low power transfer efficiency, these devices can cause unacceptable increase in skin temperature limiting their scalability to high power levels. Although, the efficiency of these systems can be improved by increasing coil diameter, in many cases this is not practical due to strict physical constraints on the coil diameter. In this paper, we investigate using multi-layer coils as secondary coils in the TETS to increase the power transfer efficiency, and thus allowing the delivery of the desired power safely for a longer period. Our experiments show a 5* increase in the duration of safe power delivery (not increasing the skin temperature more than 2 C) using multi-layer coils as the secondary coil compared to using single-layer coils even when there is a 50% misalignment in between primary and secondary coils. This increase in duration of safe power transfer is shown to be over 16* more when the coils are aligned. The improvement in the duration of safe power transfer is achieved without increasing the coil diameter and with a coil thickness of 2 mm. PMID- 22254977 TI - Developing implantable neuroprosthetics: a new model in pig. AB - A new model has been established in the domestic pig for neural prosthetic device development and testing. To this end, we report on a complete neural prosthetic developmental system using a wireless sensor as the implant, a pig as the animal model, and a novel data acquisition paradigm for actuator control. A new type of stereotactic frame with clinically-inspired fixations pins that place the pig brain in standard surgical plane was developed and tested with success during the implantation of the microsystem. The microsystem implanted was an ultra-low power (12.5 mW) 16-channel intracortical/epicranial device transmitting broadband (40 kS/s) data over a wireless infrared telemetric link. Pigs were implanted and neural data was collected over a period of 5 weeks, clearly showing single unit spiking activity. PMID- 22254979 TI - A programmable and implantable microsystem for multimodal processing of ensemble neural recordings. AB - Conditioning raw neural signals recorded through microelectrode arrays implanted in the brain is an important first step before information extraction can take place. This paper reports on the design and implementation of a programmable and fully implantable microsystem that fulfills this purpose. The system design builds on our earlier work that relies on a sparse representation of the neural signals to combat the limited telemetry bandwidth when wireless communication with the external world is sought. The system has a multimodal processing capability to support a wide range of scenarios in real experimental conditions. A transmission link with rate-dependent compression and spike sorting strategy is shown to preserve information fidelity. At 32 channels sampled at 25 kHz, the power consumption of the system is 5.19 mW and has been implemented on a 5 mm * 5 mm nano-FPGA, bringing its performance within the implantable power-size constraints for clinical applications. PMID- 22254980 TI - Optimization of stimulus parameters for selective peripheral nerve stimulation with multi-contact electrodes. AB - This study describes a method for optimizing selective stimulus parameters for multi-contact peripheral electrodes. Overlap between pairs of contacts is quantified by the deviation in their combined response from linear addition of their individual responses. Mathematical models are fit to recruitment and overlap data, and a cost function is defined to maximize recruitment and minimize overlap between all contacts. Results are presented for two four-contact nerve cuff electrodes stimulating bilateral femoral nerves of one human subject with spinal cord injury. Knee extension moments between 11.6 and 17.2 Nm are achieved through two contacts of each nerve-cuff with less than 10% overlap between each pair of contacts. These results suggest that optimization can provide an automated means of determining stimulus parameters to achieve strong, selective muscle contractions through multi-contact peripheral nerve electrodes. PMID- 22254981 TI - Effect of functional electrical stimulation (FES) combined with robotically assisted treadmill training on the EMG profile. AB - Functional electrical stimulation (FES) is used to assist spinal cord injury patients during walking. However, FES has yet to be shown to have lasting effects on the underlying neurophysiology which lead to long-term rehabilitation. A new approach to FES has been developed by which stimulation is timed to robotically controlled movements in an attempt to promote long-term rehabilitation of walking. This approach was tested in a rodent model of spinal cord injury. Rats who received this FES therapy during a 2-week training period exhibited peak EMG activity during the appropriate phase of the gait cycle; whereas, rats who received stimulation which was randomly timed with respect to their motor activity exhibited no clear pattern in their EMG profile. These results from our newly developed FES system serve as a launching point for many future studies to test and understand the long-term effect of FES on spinal cord rehabilitation. PMID- 22254982 TI - A hybrid tool for reaching and grasping rehabilitation: the ArmeoFES. AB - Many research groups are currently working with robotic devices for hand grasp rehabilitation and restoration. A common problem in this area is the fact that existing and commercially available robotic exoskeletons are able to provide gravity compensation of the shoulder and elbow but do not provide any support for the grasping and releasing movements of the hand. The lack of a flexible support technology for the hand reduces the possible ways in which clinicians can deal with the issue of a personalized, effective rehabilitation. This paper presents new software that allows FES assisted grasping to integrate with the ArmeoSpring (Hocoma AG). The system uses a Man-In-The-Loop control approach, whereby surface EMG signals from proximal muscles are used to trigger and modulate multichannel FES applied to distal muscles, thus allowing patient induced and strength adapted movement control of the hand. Combining volitionally controlled FES with arm weight-compensation allows early adoption of FES assisted therapy for patients, augmenting their functionalities and extending training capabilities with the ArmeoSpring. PMID- 22254983 TI - First permanent human implant of the Stimulus Router System, a novel neuroprosthesis: preliminary testing of a polarity reversing stimulation technique. AB - Neuroprostheses (NPs) are electrical stimulators that help to restore sensory or motor functions lost as a result of neural damage. The Stimulus Router System (SRS) is a new type of NP developed in our laboratory. The system uses fully implanted, passive leads to "capture" and "route" some of the current flowing between pairs of surface electrodes to the vicinity of the target nerves, hence eliminating the need for an implanted stimulator. In June 2008, 3 SRS leads were implanted in a tetraplegic man for restoration of grasp and release. To reduce the size of the external wristlet and thereby optimize usability, we recently implemented a polarity reversing stimulation technique that allowed us to eliminate a reference electrode. Selective activation of three target muscles was achieved by switching the polarities of the stimulus current delivered between pairs of surface electrodes located over the pick-up terminals of the implanted leads and reducing the amplitude of the secondary phases of the stimulus pulses. PMID- 22254984 TI - Neuromuscular electrical stimulation to augment reach and hand opening after stroke. AB - Functional Electrical Stimulation (FES) may be able to augment functional arm and hand movement after stroke. However, neuroprostheses that combine voluntary effort and FES must take into account the co-contraction patterns (synergies) that are common across multiple joints. The goal of this study is to determine the principles under which voluntary effort and FES can be combined to achieve useful reach and hand opening. A reach and hand opening task is performed where different levels of voluntary effort and FES are applied to produce reach while measuring the level of hand opening that FES can produce at the hand. Initial results indicate that low levels of voluntary effort allow both greater reach and the largest hand opening response to FES. PMID- 22254985 TI - Activity level classification algorithm using SHIMMERTM wearable sensors for individuals with rheumatoid arthritis. AB - In rheumatoid arthritis (RA) it is believed that symptoms associated with the progression of the disease result in a reduction in the physical activity level of the patient. One of the key flaws of the research surrounding this hypothesis to date is the use of non-validated physical activity outcomes measures. In this study, an algorithm to estimate physical activity levels in patients as they perform a simulated protocol of typical activities of daily living using SHIMMER kinematic sensors, incorporating tri-axial gyroscopes and accelerometers, is proposed. The results are validated against simultaneously recorded energy expenditure data and the defined activity protocol and demonstrate that SHIMMER can be used to accurately estimate physical activity levels in RA populations. PMID- 22254986 TI - An instrumented sit-to-stand test used to examine differences between older fallers and non-fallers. AB - An instrumented version of the five-times-sit-to-stand test was performed in the homes of a group of older adults, categorised as fallers or non-fallers. Tri axial accelerometers were secured to the sternum and anterior thigh of each participant during the assessment. Accelerometer data were then used to examine the timing of the movement, as well as the root mean squared amplitude, jerk and spectral edge frequency of the mediolateral (ML) acceleration during the total assessment, each sit-stand-sit component and each postural transition (sit-stand and stand-sit). Differences between fallers and non-fallers were examined for each parameter. Six parameters significantly discriminated between fallers and non-fallers: sit-stand time, ML acceleration for the total assessment, and the ML spectral edge frequency for the complete assessment, individual sit-stand-sit components, as well as sit-stand and stand-sit transitions. These results suggest that each of these derived parameters would provide improved discrimination of fallers from non-fallers, for the cohort examined, than the standard clinical measure - the total time to complete the assessment. These results indicate that accelerometry may enhance the utility of the five-times-sit-to-stand test when assessing falls risk. PMID- 22254987 TI - Locating the sources for cross-modal interactions and decision making during judging the visual-affected auditory intensity change. AB - Audiovisual interaction has been one of the most important topics in cognitive neurosciences. Visual stimuli could significantly impact the auditory perception, and vice versa. Nevertheless, how much the change in visual stimuli would influence the perception of auditory change remains to be investigated. In this paper, we designed an audiovisual experiment in which subjects were required to judge whether there is a change in the intensities of two sounds with 150 ms interval, while there are two simultaneously presented size-changed visual stimuli. Behavioral results demonstrated that incongruent audiovisual change could result in the illusory perception of the change in sound intensity. For the correctly judged trials, source analysis showed two characteristic windows post the first auditory stimulus, i.e., (i) the 160-200 ms window including the auditory P200 and visual N100 wave, which was related to audiovisual interaction and working memory of the first stimulus with localized sources in insula and agranular retrolimbic area; and (ii) the 300-400 ms window for P300 with sources in premotor cortex and caudate nucleus, which were related to later audiovisual interaction, change discrimination and working memory. These preliminary results implied two stages in the audiovisual change perception task, with the involvement of insula, agranular retrolimbic, premotor cortex and caudate nucleus. PMID- 22254989 TI - A novel method for EOG features extraction from the forehead. AB - We have shown that the slow eye movements extracted from electrooculogram (EOG) signals can be used to estimate human vigilance in our previous work. However, the traditional method for recording EOG signals is to place the electrodes near the eyes of subjects. This placement is inconvenient for users in real-world applications. This paper aims to find a more practical placement for acquiring EOG signals for vigilance estimation. Instead of placing the electrodes near the eyes, we place them on the forehead. We extract EOG features from the forehead EOG signals using both independent component analysis and support vector machines. The performance of our proposed method is evaluated using the correlation coefficients between the forehead EOG signals and the traditional EOG signals. The results show that a correlation of 0.84 can be obtained when the users make 14 different face movements and for merely eye movements it reaches 0.93. PMID- 22254988 TI - Switching rate changes associated with mental fatigue for assistive technologies. AB - This paper presents research that investigated the effects of mental fatigue on brain activity associated with eyes open and eyes closed conditions. The changes associated with electroencephalography (EEG) alpha wave activity (8-13 Hz) during eye closure has previously been shown to be an effective strategy for switching and activating devices as an environmental control system (ECS) designed for people with severe disability like spinal cord injury (SCI). The results showed that switching times did increase due to fatigue, however, these increases were not large (around 1 second longer to switch) and this difference was not significant. When baselines were readjusted taking into account the change in alpha wave activity due to the fatigue, switching reduced to times typically seen when the person was alert. Error rates were similar between the alert and fatigue sates. Implications of these results for a hands-free ECS are discussed. PMID- 22254990 TI - Implicit visual distortion modulates human gait. AB - We are investigating different adaptive strategies for training with the MIT Skywalker, a novel robotic device for gait training. In this paper, we describe our studies on an implicit "visual distortion" paradigm and demonstrate its potential on a set of experiments with healthy subjects. Our results suggest that a gradual distortion of visual feedback of step symmetry, during a treadmill walking exercise, induced changes away from symmetry. This implies a contribution of supraspinal brain circuitry for the control of gait and that a therapeutic program which includes a visual feedback distortion without any explicit knowledge of the manipulation may provide an effective way to help patients correct gait patterns; it is one of the potential manipulations of our adaptive algorithm during gait training. PMID- 22254991 TI - The impact of electrode characteristics on electrocorticography (ECoG). AB - Used clinically since Penfield and Jasper's pioneering work in the 1950's, electrocorticography (ECoG) has recently been investigated as a promising technology for brain-computer interfacing. Many researchers have attempted to analyze the properties of ECoG recordings, including prediction of optimal electrode spacing and the improved resolution expected with smaller electrodes. This work applies an analytic model of the volume conductor to investigate the sensitivity field of electrodes of various sizes. The benefit to spatial resolution was minimal for electrodes smaller than ~1mm, while smaller electrodes caused a dramatic decrease in signal-to-noise ratio. The temporal correlation between electrode pairs is predicted over a range of spacings and compared to correlation values from a series of recordings in subjects undergoing monitoring for intractable epilepsy. The observed correlations are found to be much higher than predicted by the analytic model and suggest a more detailed model of cortical activity is needed to identify appropriate ECoG grid spacing. PMID- 22254992 TI - A method for real-time cortical oscillation detection and phase-locked stimulation. AB - Neural oscillations are important features in a working central nervous system, facilitating efficient communication across large networks of neurons. To better study the role of these oscillations in various cognitive processes, and to be able to build clinical applications around them, accurate and precise estimations of the instantaneous frequency and phase are required. Here, we present methodology based on autoregressive modeling to accomplish this in real time. This allows the targeting of stimulation to a specific phase of a detected oscillation. Using intracranial EEG recorded from two patients performing a Sternberg memory task, we characterize our algorithm's phase-locking performance on physiologic theta oscillations. PMID- 22254993 TI - An unsupervised method for identifying regions that initiate seizures on intracranial EEG. AB - Epilepsy patients who do not respond to pharmacological treatments currently have only brain surgery as a major alternative therapy. Identifying which brain areas to remove is thus of critical importance for physicians and the patient. Currently, this process is almost entirely manual, can vary greatly between clinical experts and centers, and depends only on qualitative EEG features, all of which may help explain the only modest success of extratemperal lobe epilepsy surgery. In this study, we explore an unsupervised, quantitative method for identifying seizure onset regions. A Gaussian mixture model (GMM) was used to cluster 500 ms epochs of intracranial electroencephalogram (EEG) prior to (preictal) and during (ictal) seizures in week-long continuous recordings from three patients during evalulation for epilepsy surgery. The GMM learning paradigm determines the optimal number of clusters for each patient. For the two patients whose epochs sorted into two clusters, we found that one cluster was predominantly composed of seizure epochs, and a subset of the channels made brief "forays" into that cluser in the time leading up to seizure onset. This observation is in keeping with the clinical hypothesis that certain brain areas may be the initiators of seizure activity, and we find that the channels independently labeled by physicians as seizure onset zones (SOZs) are statistically overrepesented in the seizure-defined cluster. Nevertheless, we also find that a subset of channels not labeled as SOZs has similar properties as those labeled SOZs. In this study we have tried to avoid many of the assumptions commonly made about what features and events are indicative of epileptogenic activity and believe that such analysis can help avoid many of the pitfalls of manual, non-objective human SOZ marking. PMID- 22254994 TI - Discrete gamma oscillations identify the seizure onset zone in some pediatric epilepsy patients. AB - Intracranial electroencephalography (IEEG) plays an important role in guiding epilepsy surgery in pediatric epilepsy patients. Recently, there has been increased interest in higher frequency components of clinical IEEG recordings and their potential relationship to epileptogenic brain tissue. We employ a previously validated, automated discrete gamma oscillation (GO) detection algorithm to determine the prevalence of discrete gamma events over prolonged, representative segments of IEEG recorded from ten patients. Approximately 8 h of IEEG, 16 randomly selected 30-min segments of continuous interictal IEEG per patient, were analyzed. The electrodes within the seizure onset zone were found to have significantly higher mean GO activity averaged across these 16 segments in five of the ten patients. There was observed variability between individual 30 min segments in these patients, indicating that longer recordings of interictal activity improved localization. Our data suggest this method of automated GO detection across long periods may be useful in planning epilepsy surgery in certain children with intractable epilepsy. Further research is required to help determine which patients would benefit from this technique. PMID- 22254995 TI - Spectral features of electroencephalogram in characterizing various brain states under anesthesia. AB - The administration of the anesthetic agents is known to alter the electroencephalogram (EEG) signal significantly with the brain being their primary target. In this study, we analyzed the EEG recorded from six ASA I/II patients undergoing a 1-2 hour surgery. The EEG was collected before and during induction, maintenance and recovery of anesthesia using the 10/20 lead-system. A combination of fentanyl and propofol (+/- rocuronium) was used for induction and a Sevoflurane in air/O(2) mixture was administered through an endotracheal tube to achieve the steady minimum alveolar concentration (MAC). This study showed that 0 to 4 Hz signal power was most sensitive to the changes associated with induction of anesthesia whereas the 4 to 12 Hz power was important in classifying states during maintenance of anesthesia. Anesthesia also promoted heightened phase coherence in 8 to 16 Hz and 16 to 30 Hz ranges during maintenance and induction of anesthesia, respectively. Additionally, strong cross-frequency coupling between 7 to 20 Hz and 10 to 40 Hz was observed during anesthesia suggesting alteration of neural coding. PMID- 22254996 TI - Fibre-selective recording from peripheral nerves using a multiple-contact cuff: report on pilot pig experiments. AB - A single cuff electrode with multiple-contacts permits fibre selective recording from peripheral nerves. This has been demonstrated in frog nerve in vitro and earth worm before. In this paper we apply this method successfully to the peripheral median nerve of pig in vivo. Compound action potentials (CAPs) were electrically excited at the median nerve close to the wrist of the forelimb. The CAPs were recorded by a recording nerve cuff located proximal to the stimulation cuff. Applying simple mathematical routines allowed for generating a profile of nerve fibre activation as a function of propagation velocity. PMID- 22254997 TI - Selective control of physiological responses by temporally-patterned electrical stimulation of the canine vagus nerve. AB - Vagus nerve stimulation (VNS) is effective for treating epilepsy and depression, and has emerging indications for anxiety and heart failure. However, stimulation evoked side effects remain a challenge for long-term compliance. We investigated the feasibility of reducing VNS side effects by using a temporally-modified stimulation pattern. In 4 anesthetized canines, we measured changes in both the heart rate and evoked laryngeal muscle activity. Compared to baseline, we found that a 5% duty cycle (measured by the number of pulses per second of stimulation) could still evoke a 21% reduction in heart rate; whereas compared to continuous stimulation (3 mA, 300 MUs pulsewidth, 20 Hz) the same 5% duty cycle reduced the evoked laryngeal muscle activity by 90%. The results of this study indicate that temporally-patterned stimulation may provide an effective tool for optimizing VNS therapy. PMID- 22254998 TI - Haptically facilitated bimanual training combined with augmented visual feedback in moderate to severe hemiplegia. AB - This study describes the design and feasibility testing of a hand rehabilitation system that provides haptic assistance for hand opening in moderate to severe hemiplegia while subjects attempt to perform bilateral hand movements. A cable actuated exoskeleton robot assists the subjects in performing impaired finger movements but is controlled by movement of the unimpaired hand. In an attempt to combine the neurophysiological stimuli of bilateral movement and action observation during training, visual feedback of the impaired hand is replaced by feedback of the unimpaired hand, either by using a sagittaly oriented mirror or a virtual reality setup with a pair of virtual hands presented on a flat screen controlled with movement of the unimpaired hand, providing a visual image of their paretic hand moving normally. Joint angles for both hands are measured using data gloves. The system is programmed to maintain a symmetrical relationship between the two hands as they respond to commands to open and close simultaneously. Three persons with moderate to severe hemiplegia secondary to stroke trained with the system for eight, 30 to 60 minute sessions without adverse events. Each demonstrated positive motor adaptations to training. The system was well tolerated by persons with moderate to severe upper extremity hemiplegia. Further testing of its effects on motor ability with a broader range of clinical presentations is indicated. PMID- 22254999 TI - Expert strategy switching in the control of a bimanual manipulandum with an unstable task. AB - The goal of this study is to better understand how the central nervous system switches between alternative stabilization strategies when presented with an unstable task. A haptic, bimanual manipulandum has been used to emulate an unstable task, which requires subjects to stabilize a virtual mass under the action of a saddle force field with two nonlinear springs, whose stiffness increases with the amount of stretch. Subjects learn to position the mass at various target points by adjusting the rest length, and thus the stiffness of the two springs. From a previous study we know that subjects can stabilize the mass by either 1) applying large forces to stretch the springs and increase the mechanical stiffness of the system beyond a critical level or by 2) applying small force impulses that intermittently adjust the position of the mass. In this study we report the performance of a subject who was trained extensively to use one strategy or the other in order to characterize the mechanism of target switching, from the high-stiffness to the low-stiffness regime and back. PMID- 22255000 TI - Development of a network FES system for stroke rehabilitation. AB - This paper describes a Functional Electrical Stimulation (FES) system based on the distributed network structure for rehabilitation of stroke patients. This FES system performs surface stimulation to activate the nerve of paretic muscles for training stroke patients to relearn motor functions. The main components of the networked FES system include a master unit (MU), a distributed stimulation-sensor unit (DSSU), and a clinical computer. In this system, the MU can drive a set of DSSUs, which is located at the node on the distributed network structure. The MU also stores the stimulation plan of rehabilitation training prescribed by clinicians. The DSSU serves as a single channel stimulator whose current amplitude, duration and frequency can be modulated by the MU. This system has two distinctive characters. First, since a stimulator is designed as a node on the network, the number of stimulation channels could be expanded according to specific needs. Second, a sensor component can be incorporated in the DSSU to allow monitoring physiological variables. The two features of system design make the networked FES system practical and flexible in clinical applications. We have completed a prototype of system including hardware and software. The evaluation test indicates that the system performance meets design specifications. PMID- 22255001 TI - Development of a progressive task regulation algorithm for robot-aided rehabilitation. AB - Patient motivation is an important factor in rehabilitation. The difficulty level of the motor task, the awareness of the performance obtained, and the quantity and quality of feedbacks presented to the patient can influence patient motivation and produce different ways of acting and different performances. This study presents a Progressive Task Regulation algorithm able to evaluate the patient's performance during training and automatically change the features of the reaching movement, so as to adapt automatically the difficulty level of the motor task to the patient's ability. Use of the progressive task regulation algorithm should promote patient motivation throughout the course of treatment. PMID- 22255002 TI - Bilateral transfer in active and passive guidance-reproduction based bimanual tasks: effect of proprioception and handedness. AB - Recently, bilateral movement training based on robot-assisted rehabilitation systems has been attracting a lot of attention as a post-stroke motor rehabilitation protocol. Since humans generate coordinated motions based on their motor and sensory systems, investigation of the innate properties of human motor or sensory systems may provide insight into planning of effective bilateral movement training. In this study, we investigate the effects of proprioception and handedness on the movement of the contra-lateral upper limb, under both active and passive guidance conditions of the robot manipulators. Active and passive guidance-reproduction based bimanual tasks were used in this study; in these the subject is asked to hold both the right and left knobs installed at the end-effectors of two robot manipulators. The results indicate that better reproducing performance was obtained when the proprioceptive input was acquired from the active guidance condition. PMID- 22255003 TI - Low-power sensing for vestibular prostheses. AB - This paper describes a novel sensing approach for reducing power requirements of implantable vestibular prostheses. A passive, microfabricated polymeric inertial sensor for detecting angular head rotations based on the biomechanics of the human semicircular canal is described. Angular head motion is coded by deflection of a highly compliant capacitor plate placed in parallel with a rigid reference electrode. This capacitance change serves to detect instantaneous angular velocity along a given axis of rotation. Designed for integration with a microelectromechanical systems-based fully implantable vestibular prosthesis, this sensing method can provide substantial power savings when compared with contemporary gyroscopes. PMID- 22255004 TI - Development of the boston retinal prosthesis. AB - A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, and it received both power and data wirelessly from external sources. The prosthesis drove a sub-retinal thin-film array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing the 16-channel stimulator chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by a power amplifier. Power was delivered by a 500 KHz carrier, and data were delivered by frequency shift keying. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. Through an 'outbound' telemetry channel, electrode impedances were monitored by an on-board analog to digital converter that sampled the output voltage waveforms. The final assembly was tested in vitro in physiological saline and in vivo in two mini-pigs for up to three months by measuring stimulus artifacts generated by the implant's current drivers. PMID- 22255005 TI - Towards optogenetic sensory replacement. AB - Over the last several years we have developed a rapidly-expanding suite of genetically-encoded reagents (e.g., ChR2, Halo, Arch, Mac, and others) that, when expressed in specific neuron types in the nervous system, enable their activities to be powerfully and precisely activated and silenced in response to light. If the genes that encode for these reagents can be delivered to cells in the body using gene therapy methods, and if the resultant protein payloads operate safely and effectively over therapeutically important periods of time, these molecules could subserve a set of precise prosthetics that use light as the trigger of information entry into the nervous system, e.g. for sensory replacement. Here we discuss the use of ChR2 to make the photoreceptor-deprived retina, as found in diseases such as retinitis pigmentosa, sensitive to light, enabling restoration of functional vision in a mouse model of blindness. We also discuss arrays of light sources that could be useful for delivering patterned sensory information into the nervous system. PMID- 22255006 TI - Restoring the 3D vestibulo-ocular reflex via electrical stimulation: the Johns Hopkins multichannel vestibular prosthesis project. AB - Bilateral loss of vestibular sensation causes difficulty maintaining stable vision, posture and gait. An implantable prosthesis that partly restores normal activity on branches of the vestibular nerve should improve quality of life for individuals disabled by this disorder. We have developed a head-mounted multichannel vestibular prosthesis that restores sufficient semicircular canal function to partially recreate a normal 3-dimensional angular vestibulo-ocular reflex in animals. Here we describe several parallel lines of investigation directed toward refinement of this approach toward eventual clinical application. PMID- 22255007 TI - Designing patient-centric applications for chronic disease management. AB - Chronic diseases such as diabetes and heart disease are the leading causes of disability and death in the developed world. Technological interventions such as mobile applications have the ability to facilitate and motivate patients in chronic disease management, but these types of interventions present considerable design challenges. The primary objective of this paper is to present the challenges arising from the design and implementation of software applications aiming to assist patients in chronic disease management. We also outline preliminary results regarding a self-management application currently under development targeting young adults suffering from type 1 diabetes. PMID- 22255008 TI - Congestive Heart Failure home monitoring pilot study in urban Denver. AB - With a growing number of low-income patients developing Congestive Heart Failure in urban Denver, accessible and affordable solutions are needed to provide home management options. A multidisciplinary team evaluated currently available options for telemonitoring and developed a solution for an initial pilot study. This system is currently used in the Denver Metro area (Colorado) for 44 CHF patients. Preliminary results show this approach is effective and has reduced the patients' average length of stay at the hospital compared to historical data and control patients who do not use a remote monitoring system. PMID- 22255009 TI - Data acquisition in a wireless diabetic and cardiac monitoring system. AB - A telemedicine system is described for monitoring the vital signs and general health indicators of patients with cardiac and diabetic conditions. Telemetry from wireless sensors and readings from other instruments are combined into a comprehensive patient health dataset. The data can be stored, accessed and displayed using mobile Internet communications with a server. The paper concentrates on the data acquisition process, using an alternative sensor network protocol to Bluetooth and manual data entry into a smartphone application and HTML5 web browser. PMID- 22255010 TI - Implementing home telemanagement of congestive heart failure using Xbox gaming platform. AB - Gaming platforms have been recognized for user-friendly interface which does not require previous computer-related experience. Easy to use and wide availability of these platforms at patient households make them an attractive means to facilitate consumer health. The potential of such widely used platforms as Xbox for self-management of chronic health conditions has not yet been fully uncovered. We developed a Home Automated Telemanagement (HAT) system which utilizes Xbox to access personal health record, receive self-care support and exchange information with health care providers. The system questions patients with congestive heart failure (CHF) to monitor symptoms, weight changes, medication adherence and quality of life while educating the patient on their disease. The patients receive an instant feedback on their condition in the form of a 3-zone CHF action plan. The patient self-management information can be reviewed by a provider on a designated web site. The system is programmed to run on the Microsoft Xbox videogame console using an active internet connection and a connection to a computer running Windows Media Center. The system is designed to be as simple as possible making it usable by patients with no prior computer or videogame experience. The feasibility of this approach was tested in ten adults with no previous Xbox experience who completed attitudinal surveys and semi structured qualitative interviews after using the system. All participants claimed that they did not have any problems in using the system and that they would use the system in the future if necessary. An Xbox-based telemanagement system has potential to optimize the care of patients with CHF and other chronic conditions. PMID- 22255011 TI - Concept and modular telemedicine platform for measuring of vital signs, ADL and behavioral patterns of elderly in home settings. AB - In this contribution a new centralized platform for telemedicine is presented. It combines functions for measuring of vital signs, ADL and behavioral patterns and is especially designed for home care scenarios and the use by elderly people who are not familiar with the use of a PC. Unlike many other approaches we did not use a modified standard PC but developed a new dedicated hardware platform. It comes with various interfaces to communicate with different medical home care systems. We implemented a modular software architecture, which allows managing multiple user accounts with different personal settings. Every account can be adapted individually to the user. Every medical device that can be connected to the platform has its own software module, in which data is analyzed, displayed, stored to an internal database or transmitted to a server. Though the user is not bothered with technical issues such as setting up a connection to the internet, he keeps control on his data because he decides if and when data is transferred to a web server. The device was developed in an iterative process and evaluated in focus groups by n = 31 subjects (average age: 67 years) under the supervision of a psychogerontologist. All findings obtained from those sessions were directly incorporated in the presented work. PMID- 22255012 TI - caREMOTE: the design of a cancer reporting and monitoring telemedicine system for domestic care. AB - After receiving cancer treatment, patients often experience a decline of HRQoL (health-related quality of life). Physicians typically evaluate HRQoL during periodic clinical visits. However, out-patient reporting of vital signals between two visits could be used to interpret the decline of HRQoL. Considering that the vast majority of patients recovering from cancer are not in hospitals, it is often impractical for the care providers to collect these data. In this paper, we design and prototype caREMOTE, a cancer reporting and monitoring telemedicine system, which can be used in domestic cancer care. By extending a standard clinical trial informatics model, we build a prototype on cloud computing services that can be accessed by a mobile application. We aim to maximize the potential of caREMOTE to help medical practitioners efficiently monitor discharged patients' HRQoL and vital signals, and facilitate data reusability and system interoperability in future collaborative cancer research. PMID- 22255013 TI - Computerized decision support system for kidney paired donation program. AB - In order to assist physicians and other health professionals for health care improvement, clinical decision support systems, through interactive computerized software, become very popular in clinical practice. The crisis associated with kidney organ shortage has triggered an innovative strategy, termed as Kidney Paired Donation (KPD) program, to address a rapidly expanding demand for donor kidneys. KPD program involves how to making optimal decision for allowing patients with incompatible living donors to receive compatible organs by best matching donors. Although some computerized optimization tools are being used in the current KPD program, there still lacks a general decision support system which enables us to evaluate and compare different kidney allocation strategies and effects of policy. In this paper, we discuss a general computer-based KPD decision model that appropriately reflects the real world clinical application. Also, the whole decision process is to be visualized by our Graphical User Interface (GUI) software, which offers a user friendly platform not only to provide a convenient interface for clinicians but also to assess different kidney exchange strategies of clinical importance. PMID- 22255014 TI - Information fusion for diagnosis coding support. AB - All patient-related medical information during a hospital stay in France, has to be collected and coded in the compilation of medical units discharge documents, according to a standardized approach. The process of describing a patient disease in terms of appropriate diagnostic codes is nevertheless, a non-intuitive operation for the physician. As a consequence, coding errors, inaccuracies and missing data are frequent, leading to potentially severe economical upshots. A coding support system developed to improve medical coding results, integrates three information processing methodologies, using the outputs from various Hospital Information System applications. Each methodology generates partial heterogeneous information, with considerable semantic variety. In order to properly synthesize these outputs, information fusion is required to produce enriched contextualized information, presented to the physician as an ordered list of suggested codes. This paper explores two information fusion approaches: voting system and possibilistic. Both methods are tested on a database of 1,000 discharge summaries, to show the interest of information fusion in this context. Results show that fusion methods perform better in most of the cases than partial information extraction methods. PMID- 22255015 TI - Implementation of the 7-point checklist for melanoma detection on smart handheld devices. AB - In this paper we implement the 7-point checklist, a set of dermoscopic criteria widely used by clinicians for melanoma detection, on smart handheld devices, such as the Apple iPhone and iPad. The application developed is using sophisticated image processing and pattern recognition algorithms, yet it is light enough to run on a handheld device with limited memory and computational speed. When combined with a commercially available handheld dermoscope that provides proper lesion illumination, this application provides a truly self-contained handheld system for melanoma detection. Such a device can be used in a clinical setting for routine skin screening, or as an assistive diagnostic device in underserved areas and in developing countries with limited healthcare infrastructure. PMID- 22255016 TI - Missing data imputation for remote CHF patient monitoring systems. AB - Congestive heart failure (CHF) is a leading cause of death in the United States. WANDA is a wireless health project that leverages sensor technology and wireless communication to monitor the health status of patients with CHF. The first pilot study of WANDA showed the system's effectiveness for patients with CHF. However, WANDA experienced a considerable amount of missing data due to system misuse, nonuse, and failure. Missing data is highly undesirable as automated alarms may fail to notify healthcare professionals of potentially dangerous patient conditions. In this study, we exploit machine learning techniques including projection adjustment by contribution estimation regression (PACE), Bayesian methods, and voting feature interval (VFI) algorithms to predict both non binomial and binomial data. The experimental results show that the aforementioned algorithms are superior to other methods with high accuracy and recall. This approach also shows an improved ability to predict missing data when training on entire populations, as opposed to training unique classifiers for each individual. PMID- 22255017 TI - SVM-based multi-sensor fusion for free-living physical activity assessment. AB - This paper presents a sensor fusion method for assessing physical activity (PA) of human subjects, based on the support vector machines (SVMs). Specifically, acceleration and ventilation measured by a wearable multi-sensor device on 50 test subjects performing 13 types of activities of varying intensities are analyzed, from which the activity types and related energy expenditures are derived. The result shows that the method correctly recognized the 13 activity types 84.7% of the time, which is 26% higher than using a hip accelerometer alone. Also, the method predicted the associated energy expenditure with a root mean square error of 0.43 METs, 43% lower than using a hip accelerometer alone. Furthermore, the fusion method was effective in reducing the subject-to-subject variability (standard deviation of recognition accuracies across subjects) in activity recognition, especially when data from the ventilation sensor was added to the fusion model. These results demonstrate that the multi-sensor fusion technique presented is more effective in assessing activities of varying intensities than the traditional accelerometer-alone based methods. PMID- 22255018 TI - Guideline-driven telemonitoring and follow-up of cardiovascular implantable electronic devices using IEEE 11073, HL7 & IHE profiles. AB - For patients with Cardiovascular Implantable Electronic Devices (CIEDs), telemonitoring promises improved quality of life and safety, since events recorded by the device or observed by the patient can alert a health professional. Taking into account the latest clinical guidelines when responding to such alerts, is a topic of active research addressed by the iCARDEA project. A key technical challenge is correlating telemonitoring CIED report data in a vendor-independent format with Electronic Health Record (EHR) data collected in the hospital and Personal Health Record (PHR) data entered by the patient, in guideline-driven care processes. The iCARDEA CIED exposure service component presented in this paper employs standards specifications from ISO/IEEE 11073 (Health Informatics, Point-of-care Medical Device Communication) and HL7v2.x in the context of Integrating the Healthcare Enterprise (IHE) profiles to deliver telemonitoring CIED report data from two different CIED vendors to the adaptive care planner that implements guideline-driven care plans. Experience gained with implementation and initial component testing is discussed, while challenges and expectations for future health information standards to effectively support EHR integrated guide-line-driven telemonitoring services are highlighted. PMID- 22255019 TI - Normal non-regular snores as a tool for screening SAHS severity. AB - Snoring is one of the earliest and most consistent sign of upper airway obstruction leading to Sleep Apnea-Hypopnea Syndrome (SAHS). Several studies on post-apneic snores, snores that are emitted immediately after an apnea, have already proven that this type of snoring is most distinct from that of normal snoring. However, post-apneic snores are more unlikely and sometimes even inexistent in simple snorers and mild SAHS subjects. In this work we address that issue by proposing the study of normal non-regular snores. They correspond to successive snores that are separated by normal breathing cycles. The results obtained establish the feasibility of acoustic parameters of normal non-regular snores as a promising tool for a prompt screening of SAHS severity. PMID- 22255020 TI - Automated unsupervised respiratory event analysis. AB - We recently presented a comprehensive automated off-line method for supervised respiratory event classification from uncalibrated respiratory inductive plethysmography signals. This method required training with a sample of clinical measurements classified by an expert. This human intervention is labor intensive and involves subjective judgments that may introduce bias to the automated classification. To address this we developed a novel method for unsupervised respiratory event classification, named AUREA (Automated Unsupervised Respiratory Event Analysis). This paper describes the algorithm underlying AUREA and demonstrates its successful application to respiratory signals acquired from infants in the postoperative recovery room. The advantages of AUREA are: first, it provides real-time classification of respiratory events; second, it requires no human intervention; and lastly, it has substantially better performance than the supervised method. PMID- 22255021 TI - Comparison of upper airway respiratory resistance measurements with the esophageal pressure/airflow relationship during sleep. AB - Measurement of upper airway resistance is of interest in sleep disordered breathing to estimate upper airway patency. Resistance is calculated with the airflow and respiratory effort signals. However, there is no consensus on a standard for upper airway resistance measurement. This study proposes a new benchmarking method to objectively compare different upper airway resistance measurement methods by objectively differentiating between breaths with inspiratory flow limitation (high resistance) and non-limited breaths (low resistance). Resistance was measured at peak-Pes, at peak-flow, at the linear portion of a polynomial equation, as an area comparative and as average resistance for an inspiration. A total of 20 patients with systematic, gold standard esophageal pressure and nasal airflow acquisition were analyzed and 109,955 breaths were automatically extracted and evaluated. Relative resistance values in relationship to a reference resistance value obtained during wakefulness were also analyzed. The peak-Pes measurement method obtained the highest separation index with significant (p < 0.001) differences to the other methods, followed by the area comparative and the peak-flow methods. As expected, average resistances were significantly (p < 0.001) lower for the non-IFL than for the IFL group. Hence, we recommend employing the peak-Pes for accurate upper airway resistance estimation. PMID- 22255022 TI - Concurrent variations of cerebral blood flow and arterial blood pressure in simulated sleep apnea. AB - Obstructive Sleep Apnea (OSA) is one of the most common sleep disordered breathing which affects about 15 % of US adult population. OSA is considered to be an important risk factor for the development of cardiac dysfunction and stroke. In this paper, we present the initial results of our investigation of the relationship between arterial blood pressure and cerebral blood flow velocity in simulated apnea. Sixteen healthy subjects (9 male, 7 female) of 29 +/- 4.89 yrs age and body mass index of 24.07 +/- 4.84 kg/m(2) participated in the study. Our findings indicate that cerebral blood flow velocity variations has a relatively high correlation to changes in blood pressure during simulated apnea (r = 0.74 +/ 0.06), suggesting that cerebral autoregulation may not compensate for the pressure changes during apnea. PMID- 22255023 TI - A novel respiratory rate estimation method for sound-based wearable monitoring systems. AB - The respiratory rate is a vital sign that can provide important information about the health of a patient, especially that of the respiratory system. The aim of this study is to develop a simple method that can be applied in wearable systems to monitor the respiratory rate automatically and continuously over extended periods of time. In this paper, a novel respiratory rate estimation method is presented to achieve this target. The proposed method has been evaluated in both the open-source data as well as the local-hospital data, and the results are encouraging. The findings of this study revealed strong linear correlation to the reference respiratory rate. The correlation coefficients for the open-source data and the in-hospital data are 0.99 and 0.96 respectively. The standard deviation of the estimation error is less than 7% for both types of data. PMID- 22255024 TI - Respiratory rate detection using a wearable electromagnetic generator. AB - Wearable health and fitness monitoring systems are a promising new way of collecting physiological data without inconveniencing patients. Human energy harvesting may be used to power wearable sensors. In this paper, we explore this zero-net energy biosensor concept through sensing and harvesting of respiratory effort. An off the shelf servo motor operation in reverse was used to successfully obtain respiratory rate, while also demonstrating significant harvested power. These are the first reported respiratory rate sensing results using electromagnetic generators. PMID- 22255025 TI - Structure-based prediction of protein activity changes: assessing the impact of single residue replacements. AB - A computational mutagenesis methodology founded upon a structure-dependent and knowledge-based four-body statistical potential is utilized in generating feature vectors that characterize over 8500 individual amino acid substitutions occurring in seven proteins, each mutant having been experimentally ascertained for its relative effect on native protein activity. The proteins are diverse with respect to host organism (viral, bacterial, human) and function (enzymatic, nucleic acid binding, signaling), the structures span all four major SCOP classifications, and the mutations occur at positions well distributed throughout the seven structures. Implementation of the random forest algorithm, for classifying mutant activity as either unaffected or affected relative to the native protein, yields 84% accuracy based on tenfold cross-validation. A freely available online server for obtaining predictions with the trained model, which also displays 84% accuracy on an independent test set of mutants, is available at http://proteins.gmu.edu/automute/AUTO-MUTE_Activity.html. PMID- 22255026 TI - A structure-based computational mutagenesis elucidates the spectrum of stability activity relationships in proteins. AB - Protein engineering experiments involving single amino acid substitutions are routinely implemented for the analysis of protein structure, stability, and function. The resulting change in just one of these characteristics relative to the native protein constitutes the focus of any single study, as is the case with predictive computational models developed for the same purpose. Other than investigations into stability-activity trade-offs specifically resulting from active site residue replacements in a few enzymes, a literature survey fails to reveal a comprehensive analysis of stability-activity relationships in proteins upon mutation. Here, we employ a computational mutagenesis for quantifying overall protein structural change upon mutation, which is applied to a dataset of 938 single residue replacements distributed at positions throughout twenty diverse proteins. These mutants are selected based on the availability of both experimental stability and activity change data, and their structural change data are used to characterize the full range of stability-activity relationships. PMID- 22255027 TI - On modeling peptidomimetics in complex with the SH2 domain of Stat3. AB - Signal transducer and activator of transcription 3 (Stat3) plays a role in human cancers. One of the main approaches towards inhibiting its activity is the development of phosphopetides or peptidomimetics that competitively bind to the SH2 domain of Stat3. This work reports, to the best of our knowledge, the first computational molecular docking study to model all of the 142 peptidomimetics that mimic the Stat3 inhibitory pTyr-X-X-Glu motif. We used the docking programs AUTODOCK and VINA to model SH2 domain-peptidomimetic complexes and estimate their binding affinities. We obtained better screening accuracy using AUTODOCK which ranked the most potent inhibitor as second highest. Experimental binding energy values and scores from docking programs correlated poorly, confirming the limitations of many current docking programs when dealing with ligands that have a large number of rotatable bonds. Nevertheless, for close to 65% of peptidomimetics, the structures of complexes computed by AUTODOCK are in agreement with current understanding of the structures. Modeling of the SH2 domain-peptidomimetic complexes is essential to better understand and design drug compounds for curing cancer. Our study is an important first step forward towards that goal. PMID- 22255028 TI - An identification and prediction methods for feature-subsets of CpG islands methylation based on human peripheral blood leukocytes of chromosome 21q. AB - The pace of technology has allowed classification of feature-subset of methylated and unmethylated of CpG islands of DNA sequence properties. As methylation of CpG islands is involved in various biological phenomena and function of the DNA methylation is correlated to various human diseases such as cancer, analysis of the CpG islands has become important and useful in characterizing and modelling biological phenomena and understanding mechanism of such diseases. However, analysis of the data associated with the CpG islands is a quite new and challenging subject in bioinformatics, systems biology and epigenetics. In this paper, the problems associated with prediction of methylated and unmethylated CpG islands on human chromosome 21q are addressed. In order to carry out the prediction, a data set of 132 samples of the CpG islands from human peripheral blood leukocytes of chromosomes 21q and 4 different feature sub-sets totalling 44 attributes that characterise the methylated and unmethylated groups is extracted for each sample. Due to the nature of this unbalanced data set, in order to avoid disadvantages of traditional leave-one-out (LOO) and m-fold cross validation methods, the LOO method is modified by incorporating the m-fold cross validation approach. In addition, K-nearest neighbour classifier is then adapted for the prediction. The results gained through 440 different comprehensive analyses shows that the methylated CpG islands can be distinguished from the unmethylated CpG islands by a predictive accuracy of between 75% and 80%. More importantly, the modified LOO identifies more clearly and reliably when the feature sub-sets are combined. Another interesting observation is that the modified-LOO-based analysis reveals that the CpGI-specific feature-set achieve the highest predictive accuracy when combined with the other feature sets, which is not the case in the traditional LOO. This also further supports the robustness of the modified-LOO cross validation approach as CpGI-specific feature-set is one of the most important and effective attributes shown in other studies. PMID- 22255029 TI - Drug design for cardiovascular disease: the effect of solvation energy on Rac1 ligand interactions. AB - 'OMICS' techniques have deeply changed the drug discovery process. The availability of many different potential druggable genes, generated by these new techniques, have exploited the complexity of new lead compounds screening. 'Virtual screening', based on the integration of different analytical tools on high performance hardware platforms, has speeded up the search for new chemical entities suitable for experimental validation. Docking is a key step in the screening process. The aim of this paper is the evaluation of binding differences due to solvation. We have compared two commonly used software, one of which takes into account solvation, on a set of small molecules (Morpholines, flavonoids and imidazoles) which are able to target the RAC1 protein--a cardiovascular target. We have evaluated the degree of agreement between the two different programs using a machine learning approach combined with statistical test. Our analysis, on a sample of small molecules, has pointed out that 35% of the molecules seem to be sensitive to solvation. This result, even though quite preliminary, stresses the need to combine different algorithms to obtain a more reliable filtered set of ligands. PMID- 22255030 TI - SN-38:beta-cyclodextrin inclusion complex for in situ solidifying injectable polymer implants. AB - One of the most useful techniques to treat cancer is chemotherapy. However, anticancer drugs, such as SN-38, have limited solubility with strong side effects. This work aims to use SN-38:beta-cyclodextrin (beta-CD) inclusion complex for an injectable polymeric in situ forming implant containing poly(ethylene glycol) (PEG), poly(epsilon-caprolactone), and poly(D, L-lactide). It was found that implant formation and SN-38 encapsulation efficiency directly depended on weight ratio of SN-38 and beta-CD. At the ratio of SN-38:beta-CD of 1:7, the implant could not be formed perfectly and had lower encapsulation efficiency. Reduction of the amount of beta-CD to the ratio of 1:3 showed the higher encapsulation efficiency at 89.7 %. SN-38 release rate was also found to depend on beta-CD content and the implant weight. In addition, their active form was protected when encapsulated inside implants. PMID- 22255031 TI - PEG-b-PCL and PEG-b-PLA polymeric micelles as nanocarrieres for lamellarin N delivery. AB - Lamellarin N (Lam N) is a member of an interesting marine natural product class isolated from mollusks and subsequently found in ascidians and sponges. The limited aqueous solubility of Lam N hinders further studies on its cytotoxic activity against cancer cells. In this study, micelles comprising poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) and poly(ethylene glycol) block-poly(D, L-lactide) (PEG-b-PLA) were developed to circumvent Lam N limited aqueous solubility. The results showed that an increase in the molecular weight of both core materials resulted in higher Lam N loading content, whereas the release of Lam N decreased as a function of molecular weight of PCL and PLA. With less hydrophobic property, PLA micelles provided faster Lam N release. Thus, polymeric micelles could be utilized as controlled-release delivery systems for poorly water soluble Lam N. PMID- 22255032 TI - Anticancer effectiveness of polymeric drug nanocarriers on colorectal cancer cells. AB - Doxifluridine, a prodrug of 5-fluorouracil (5-FU), was used as the initiator directly in ring-opening polymerization of epsilon-caprolactone to form hydrophobic doxifluridine-poly(epsilon-caprolactone) (doxifluridine-PCL) that was further grafted with hydrophilic chitosan to synthsize amphiphilic doxifluridine PCL-chitosan copolymer. This amphiphilic copolymer was self-assembled into micellar nanoparticles. After HT-29 colon cancer cells were treated with the polymeric drug nanocarrier, prodrug doxifluridine was converted into 5 fluorouracil by endogenous thymidine phosphorylase (TP) and thereby resulting in cell death. Chemotherapy drug 7-ethyl-10-hydroxy-camptothecin (SN-38), an active water insoluble metabolite of irinoetcan hydrochloride, was further encapsulated in the hydrophobic core of the polymeric drug nanocarriers and treated with HT-29 cells. The anticancer effectiveness of the polymeric drug nanocarriers was extensively enhanced by synergistic anticancer activity of slowly released cytotoxic drugs (i.e., 5-FU and SN-38). HT-29 cells transfected with TP-encoding plasmids were selected by antibiotic G418 to obtain HT-29/TP cells. These cells overexpressed with TP enzyme were challenged with doxifluridine-PCL-chitosan polymeric prodrug micelles. The viability of HT-29/TP cells were dropped significantly after 72-h treatment. PMID- 22255033 TI - Next generation brain implant coatings and nerve regeneration via novel conductive nanocomposite development. AB - Composite materials based on the coupling of conductive organic polymers and carbon nanotubes have shown that they possess properties of the individual components with a synergistic effect. Multi-wall carbon nanotube (MWCNT)/ polymer composites are hybrid materials that combine numerous mechanical, electrical and chemical properties and thus, constitute ideal biomaterials for a wide range of regenerative medicine applications. Although, complete dispersion of CNT in a polymer matrix has rarely been achieved, in this study we have succeeded high dispersibility of CNT in POSS-PCU and POSS-PCL, novel polymers based on polyprolactone and polycarbonate polyurethane (PCU) and poly(caprolactoneurea)urethane both having incorporated polyhedral oligomeric silsesquioxane (POSS). We report the synthesis and characterization of a novel biomaterial that possesses unique properties of being electrically conducting and thus being capable of electronic interfacing with tissue. To this end, POSS PCU/MWCNT composite can be used as a biomaterial for the development of nerve guidance channels to promote nerve regeneration and POSS-PCL/MWCNT as a substrate to increase electronic interfacing between neurons and micro-machined electrodes for potential applications in neural probes, prosthetic devices and brain implants. PMID- 22255034 TI - Microfluidics-mediated isothermal detection of enzyme activity at the single molecule level. AB - Conventional analysis of enzymatic activity, often carried out on pools of cells, is blind to heterogeneity in the population. Here, we combine microfluidics with a previously developed isothermal rolling circle amplification-based assay to investigate multiple enzymatic activities in down to single cells. This microfluidics-meditated assay performs at very high sensitivity in picoliter incubators with small quantities of biological materials. Furthermore, we demonstrate the assay's capability of multiplexed detection of at least three enzyme activities at the single molecule level. PMID- 22255035 TI - Development of an in vitro method for modeling drug release and subsequent tissue drug uptake and deposition in a pulsatile flow network. AB - A novel benchtop model of drug elution and arterial drug deposition following stent implantation has been developed. The model contains a single drug loaded strut and a compartment simulating the vessel wall, housed in a flow chamber under a pulsatile flow regime. Each component has programmable transport properties that can be implemented into a computational model of drug elution. An initial experiment determining the effects of luminal flow on drug deposition patterns was performed. The results show that spatial distribution of drug correlates with areas of low and recirculating flow surrounding the strut. This spatial distribution of drug was shown to be dependent on both transient release behavior and the local flow field surrounding the strut. Furthermore, these results showed that the novel method could be used to study the effects of luminal flow in the presence of single or multiple struts. The method could also be used to explore more complex drug release strategies. PMID- 22255036 TI - Clinical application of neuromuscular electrical stimulation induced cardiovascular exercise. AB - We need to find novel ways of increasing exercise participation, particularly in those populations who find it difficult to participate in voluntary exercise. In recent years researchers have started to investigate the potential for using electrical stimulation to artificially stimulate a pattern of muscle activity that would induce a physiological response consistent with cardiovascular exercise. Work to date has indicated that this is best achieved by using a stimulation protocol that results in rapid rhythmical isometric contractions of the large leg muscle groups at sub tetanic frequencies. Studies completed by our group indicate that this technique can serve as a viable alternative to voluntary cardiovascular exercise. Apart from being able to induce a cardiovascular exercise effect in patient populations (e.g. heart failure, COPD, spinal cord injury, obesity), this approach may also have value in promotion of exercise activity in a microgravity environment. PMID- 22255037 TI - Medical application and clinical validation for reliable and trustworthy physiological monitoring using functional textiles: experience from the HeartCycle and MyHeart project. AB - Functional textiles are seen as promising technology to enable healthcare services and medical care outside hospitals due to their ability to integrate textile-based sensing and monitoring technologies into the daily life. In the past much effort has been spent onto basic functional textile research already showing that reliable monitoring solutions can be realized. The challenge remains to find and develop suited medical application and to fulfil the boundary conditions for medical endorsement and exploitation. The HeartCycle vest described in this abstract will serve as an example for a functional textile carefully developed according to the requirements of a specific medical application, its clinical validation, the related certification aspects and the next improvement steps towards exploitation. PMID- 22255038 TI - Textile electrodes and integrated smart textile for reliable biomonitoring. AB - Since birth the first and the most natural interface for the body is fabric, a soft, warm and reassuring material. Cloth is usually covering more than 80 % of the skin; which leads us to consider textile material as the most appropriate interface where new sensorial and interactive functions can be implemented. The new generation of personalised monitoring systems is based on this paradigm: functions like sensing, transmission and elaboration are implementable in the materials through the textile technology. Functional yarns and fibres are usable to realise garments where electrical and computing properties are combined with the traditional mechanical characteristics, giving rise to textile platforms that are comparable with the cloths that are normally used to produce our garments. The feel of the fabric is the same, but the functionality is augmented. Nowadays, consumers demand user-friendly connectivity and interactivity; sensing clothes are the most natural and ordinary interface able to follow us, everywhere in a non-intrusive way, in natural harmony with our body. PMID- 22255039 TI - Printed organic conductive polymers thermocouples in textile and smart clothing applications. AB - This work reports on an experimental investigation of the potential of using selected commercially available organic conductive polymers as active ingredients in thermocouples printed on textiles. Poly(3, 4-ethylenedioxythiophene): poly(4 styrenesulfonate) (PEDOT:PSS) and polyaniline (PANI) were screen printed onto woven cotton textile. The influence of multiple thermocycles between 235 K (-38 degrees C) and 350 K (+77 degrees C) on resistivity and thermoelectric properties was examined. The Seebeck coefficients of PEDOT:PSS and PANI were found to be about +18 MUV/K and +15 uV/K, respectively, when "metal-polymer" thermocouples were realized by combining the polymer with copper. When "polymer polymer" thermocouples were formed by combining PEDOT:PSS and PANI, a thermoelectric voltage of about +10 MUV/K was observed. A challenge recognized in the experiments is that the generated voltage exhibited drift and fluctuations. PMID- 22255040 TI - AD5933-based electrical bioimpedance spectrometer. Towards textile-enabled applications. AB - Advances on System-On-Chip and Textile technology allows the development of Textile-enabled measurement instrumentation. Textile Electrodes (Textrodes) have been proven reliable for performing Electrical Bioimpedance Spectroscopy (EBIS) measurements, and the availability of a integrated circuit impedance spectrometer, the AD5933, has allowed the implementation of small size EBIS spectrometers. In this work an AD5933-based spectrometer has been implemented, and its performance on 2R1C circuits and for tetrapolar total right side EBIS measurements has been compared against the commercially available spectrometer SFB7. The study has been focused on the working upper frequency range and the estimation of the Cole parameters required for assessment of body fluid distribution: R(0) and R(infinity). The results indicate that AD5933-based spectrometer implemented in this work can perform accurate impedance measurements well above the upper limits recommended in the datasheet. The AD5933-EBIS presents a good performance compared with the SFB7 on the 2R1C circuit and the total right side measurements, showing a smaller error in the resistance spectrum and small deviation error in the reactance when measuring over 270 kHz. The comparison on the Cole parameters estimation obtained with the SFB7 and the AD5933-based spectrometer exhibit a difference below 1% for the estimation of R(0) and R(infinity). Consequently the overall measurement performance shown by the implemented AD5933-based spectrometer suggests its feasible use for EBIS measurements using dry Textrodes. This is of special relevance for the proliferation of EBI-based personalized health monitoring systems for patients that require to monitor the distribution of body fluids, like in dialysis. PMID- 22255041 TI - Polymer substrate temperature sensor array for brain interfaces. AB - We developed an implantable thin film transistor temperature sensor (TFT-TS) to measure temperature changes in the brain. These changes are assumed to be associated with cerebral metabolism and neuronal activity. Two prototype TFT-TSs were designed and tested in-vitro: one with 8 diode-connected single-ended sensors, and the other with 4 pairs of differential-ended sensors in an array configuration. The sensor elements are 25 ~ 100 pm in width and 5 MUm in length. The TFT-TSs were fabricated based on high-speed ZnO TFT process technology on flexible polyimide substrates (50 MUm thick, 500 MUm width, 20 mm length). In order to interface external signal electronics, they were directly bonded to a prototype printed circuit board using anisotropic conductive films The prototypes were characterized between 23 ~ 38 degrees C using a commercial temperature sensor and custom-designed temperature controlled oven. The maximum sensitivity of 40 mV/ degrees C was obtained from the TFT-TS. PMID- 22255042 TI - Human thermoregulatory system state estimation using non-invasive physiological sensors. AB - Small teams of emergency workers/military can often find themselves engaged in critical, high exertion work conducted under challenging environmental conditions. These types of conditions present thermal work strain challenges which unmitigated can lead to collapse (heat exhaustion) or even death from heat stroke. Physiological measurement of these teams provides a mechanism that could be an effective tool in preventing thermal injury. While indices of thermal work strain have been proposed they suffer from ignoring thermoregulatory context and rely on measuring internal temperature (IT). Measurement of IT in free ranging ambulatory environments is problematic. In this paper we propose a physiology based Dynamic Bayesian Network (DBN) model that estimates internal temperature, heat production and heat transfer from observations of heart rate, accelerometry, and skin heat flux. We learn the model's conditional probability distributions from seven volunteers engaged in a 48 hour military field training exercise. We demonstrate that sum of our minute to minute heat production estimates correlate well with total daily energy expenditure (TDEE) measured using the doubly labeled water technique (r(2) = 0.73). We also demonstrate that the DBN is able to infer IT in new datasets to within +/-0.5 degrees C over 85% of the time. Importantly, the additional thermoregulatory context allows critical high IT temperature to be estimated better than previous approaches. We conclude that the DBN approach shows promise in enabling practical real time thermal work strain monitoring applications from physiological monitoring systems that exist today. PMID- 22255043 TI - The development of feedback monitoring device for CPR. AB - CPR (Cardio-Pulmonary Resuscitation) is known as the most basic aid in emergency situations. For successful CPR, the chest compression depth, cycle, and compressing point are important factors. In I.C.U.'s (Intensive Care Unit) and E.R.'s (Emergency Room), monitoring devices are used to monitor the chest compressions correctly. These devices use accelerometers or pressure sensors. Because the mattress under the patient compresses together, these devices overestimate the compression depth. To overcome this problem, two accelerometers are used in this study, one is on the chest, and the other is between the back of the patient and the mattress. The measurement setup and algorithm to estimate the compression depth are explained. According to the experiment with the mannequin, when CPR is done on a mattress, the actual compression depth was 43.7 mm (S.D. 1.93 mm). The estimated compression depth was 61.4mm (S.D. 1.87 mm) when using an acceleration sensor. This includes the depth of compression of the mattress. When we use two acceleration sensors, estimated compression depth is 44.6mm (S.D. 1.59 mm), which is similar to the actual compression depth. In conclusion, the dual accelerometer gives more accurate estimated compression depth than conventional devices. PMID- 22255044 TI - Wireless dry EEG for drowsiness detection. AB - Fatigue is a well recognized safety concern for drivers and other industrial workers who must stay alert and attentive for long periods of time. Currently, drowsiness detectors using EEG technology exist but are cumbersome and unreliable. The large number of standard EEG channels requires extensive wiring, while the conventional wet electrodes cause discomfort in long-term monitoring. We propose a simple and cheap one-channel drowsiness detection technology suitable for detecting drowsiness in a variety of environments. Our design incorporates pronged dry-AgCl electrodes in a headband harness, which eliminates the discomfort of gel electrodes while obtaining strong signals from hair covered areas of the scalp. The electrodes send signals to a wireless base unit which then transfers the signal to a computer where it is analyzed using an unique algorithm. With solely this one-channel system, we obtained strong EEG signals from which alpha, beta and theta waves can be observed. PMID- 22255045 TI - On-line classification of human activity and estimation of walk-run speed from acceleration data using support vector machines. AB - The awareness of the physical activity that human subjects perform, and the quantification of activity strength and duration are important tasks that a wearable sensor system would fulfill to be valuable in several biomedical applications, from health monitoring to physical medicine and rehabilitation. In this work we develop a wearable sensor system that collect data from a single thigh-mounted tri-axial accelerometer; the system performs activity classification (sit, stand, cycle, walk, run), and speed estimation for walk (run) labeled data features. These classification/estimation tasks are achieved by cascading two Support Vector Machines (SVM) classifiers. Activity classification accuracy higher than 99% and root mean square errors E(RMS) = 0.28 km/h for speed estimation are obtained in our preliminary experiments. The developed wearable sensor system provides activity labels and speed point estimates at the pace of two readings per second. PMID- 22255046 TI - Efficient feature selection for sleep staging based on maximal overlap discrete wavelet transform and SVM. AB - In this paper, a novel algorithm is proposed with application in sleep/awake detection and in multiclass sleep stage classification (awake, non rapid eye movement (NREM) sleep and REM sleep). In turn, NREM is further divided into three stages denoted here by S1, S2, and S3. Six electroencephalographic (EEG) and two electro-oculographic (EOG) channels were used in this study. The maximum overlap discrete wavelet transform (MODWT) with the multi-resolution Analysis is applied to extract relevant features from EEG and EOG signals. The extracted feature set is transformed and normalized to reduce the effect of extreme values of features. A set of significant features are selected by mRMR which is a powerful feature selection method. Finally the selected feature set is classified using support vector machines (SVMs). The system achieved 95.0% of average accuracy for sleep/awake detection. As concerns the multiclass case, the average accuracy of sleep stages classification was 93.0%. PMID- 22255047 TI - Combined multivariate matching pursuit and support vector machine: a way forward to classify single-sweep evoked potentials? AB - Evoked brain potentials averaged over multiple sweeps provide a valuable objective measure of abnormal pain processing due to sensitization of the central nervous system. However, the average procedure cancel out important information regarding phase resetting and non-phase locked oscillations. Hence, assessment of the pain processing could be optimized by analyzing single-sweeps. To develop improved methods to assess single-sweeps, we applied a new approach in one healthy volunteer participating in a placebo controlled study of widespread hyperalgesia induced by perfusion of acid and capsaicin in the esophagus. The evoked potentials were recorded during electrical stimulations in the rectosigmoid colon. Features from the single-sweeps were extracted by a multivariate matching pursuit algorithm with Gabor atoms, and features were discriminated by a support vector machine with a linear kernel. The classification performance for the optimal number of atoms was 95% when discriminating the sensitization response from the placebo response, which was above change level compared to the performance when discriminating the two baseline responses (P < 0.001). The discriminative capacity was increased power in the delta, theta, and alpha frequency bands. This result corresponds to previous characteristics seen in chronic pain patients who exhibit central sensitization. The new approach to classify single-sweeps on a single subject basis might in the future prove to be a useful tool in assessing mechanisms in central sensitization, and could be applied to improve enriched enrollment of study subjects in clinical trial units. PMID- 22255048 TI - Feature extraction using time-frequency/scale analysis and ensemble of feature sets for crackle detection. AB - Pulmonary crackles are used as indicators for the diagnosis of different pulmonary disorders. Crackles are very common adventitious sounds which have transient characteristic. From the characteristics of crackles such as timing and number of occurrences, the type and the severity of the pulmonary diseases can be obtained. In this study, a novel method is proposed for crackle detection. In this method, various feature sets are extracted using time-frequency and time scale analysis. The extracted feature sets are fed into support vector machines both individually and as an ensemble of networks. Besides, as a preprocessing stage in order to improve the success of the model, frequency bands containing no information are removed using dual tree complex wavelet transform, which is a shift invariant transform with limited redundancy and an improved version of discrete wavelet transform. The comparative results of individual feature sets and ensemble of sets with pre-processed and non pre-processed data are proposed. PMID- 22255049 TI - Detection of ventricular suction in an implantable rotary blood pump using support vector machines. AB - A new suction detection algorithm for rotary Left Ventricular Assist Devices (LVAD) is presented. The algorithm is based on a Lagrangian Support Vector Machine (LSVM) model. Six suction indices are derived from the LVAD pump flow signal and form the inputs to the LSVM classifier. The LSVM classifier is trained and tested to classify pump flow patterns into three states: No Suction, Approaching Suction, and Suction. The proposed algorithm has been tested using existing in vivo data. When compared to three existing methods, the proposed algorithm produced superior performance in terms of classification accuracy, stability, and learning speed. The ability of the algorithm to detect suction provides a reliable platform in the development of a pump speed controller that has the capability of avoiding suction. PMID- 22255050 TI - Customizing the training dataset to an individual for improved heartbeat recognition performance in long-term ECG signals. AB - This work presents an investigation of the potential benefits of customizing the analysis of long-term ECG signals, collected from individuals using wearable sensors, by incorporating small amount of data from these individuals in the training set of our classifiers. The global training dataset selected was from the MIT-BIH Arrhythmias Database. This proposal is validated on long-term ECG recordings collected via wearable technology in unsupervised environments, as well on the MIT-BIH Normal Sinus Rhythm Database. Results illustrate that heartbeat classification performance could improve significantly if short periods of data (e.g., data from the first 5-minutes of every 2 hours) from the specific individual are regularly selected and incorporated into the global training dataset for training a customized classifier. PMID- 22255051 TI - Tracking the changes of hippocampal population nonlinear dynamics in rats learning a memory-dependent task. AB - Neurobiological processes associated with learning are known to be highly nonlinear, dynamical, and time-varying. Characterizing the time-varying functional input-output properties of neural systems is a critical step to understand the neurobiological basis of learning. In this paper, we present a study on tracking of the changes of neural dynamics in rat hippocampus during learning of a memory-dependent delayed nonmatch-to-sample (DNMS) task. The rats were first trained to perform the DNMS task without a delay between the sample and response events. After reaching a performance level, they were subjected to the DNMS task with variable delays with a 5s mean duration. Spike trains were recorded from hippocampal CA3 (input) and CA1 (output) regions during all training sessions and constitute the input-output data for modeling. We applied the time-varying Generalized Laguerre-Volterra Model to study the changes of the CA3-CA1 nonlinear dynamics using these data. Result showed significant changes in the Volterra kernels after the introduction of delays. This result suggests that the CA3-CA1 nonlinear dynamics established in the initial training sessions underwent a functional reorganization as animals were learning to perform the task that now requires delays. PMID- 22255052 TI - Estimation and statistical validation of event-invariant nonlinear dynamic models of hippocampal CA3-CA1 population activities. AB - To develop hippocampal prosthetic devices that can restore the memory-dependent cognitive functions lost in diseases or injuries, it is essential to build a computational model that sufficiently captures the transformations of multiple memories performed by hippocampal sub-regions. A universal model with a single set of coefficients for all memories is desirable, since it can transform the memories without explicitly knowing what those memories represent and thus avoids switching between multiple models for multiple memories in implementation. In this study, we test the feasibility of such universal models of hippocampal CA3 CA1 by estimating the multi-input, multi-output (MEMO) nonlinear dynamic models using input (CA3) and output (CA1) spike trains recorded during multiple behavioral events representing multiple memories from rats performing a delayed nonmatch-to-sample task. We further statistically evaluated the model performances of the MEMO models on the different events. Results show that the models accurately replicate the output spike patterns during those events, and thus can be used as event-invariant nonlinear dynamic models that continuously predict the ongoing CA1 spatio-temporal patterns as the ongoing CA3 spatio temporal patterns unfold. PMID- 22255053 TI - Dynamic nonlinear modeling of interactions between neuronal ensembles using principal dynamic modes. AB - We present a novel methodology for modeling the interactions between neuronal ensembles that utilizes the concept of Principal Dynamic Modes (PDM) and their associated nonlinear functions (ANF). This new approach seeks to reduce the complexity of the multi-input/multi-output (MIMO) model of the interactions between neuronal ensembles--an issue of critical practical importance in scaling up the MIMO models to incorporate hundreds (or even thousands) of input-output neurons. Global PDMs were extracted from the data using estimated first-order and second-order kernels and singular value decomposition (SVD). These global PDMs represent an efficient "coordinate system" for the representation of the MIMO model. The ANFs of the PDMs are estimated from the histograms of the combinations of PDM output values that lead to output spikes. For initial testing and validation of this approach, we applied it to a set of data collected at the pre frontal cortex of a non-human primate during a behavioral task (Delayed Match-to Sample). Recorded spike trains from Layer-2 neurons were viewed as the "inputs" and from Layer-5 neurons as the outputs. Model prediction performance was evaluated by means of computed Receiver Operating Characteristic (ROC) curves. The results indicate that this methodology may greatly reduce the complexity of the MIMO model without significant degradation of performance. PMID- 22255054 TI - Restorative encoding memory integrative neural device: "REMIND". AB - Construction and application of a neural prosthesis device that enhances existing and replaces lost memory capacity in humans is the focus of research described here in rodents. A unique approach for the analysis and application of neural population firing has been developed to decipher the pattern in which information is successfully encoded by the hippocampus where mnemonic accuracy is critical. A nonlinear dynamic multi-input multi-output (MIMO) model is utilized to extract memory relevant firing patterns in CA3 and CA1 and to predict online what the consequences of the encoded firing patterns reflect for subsequent information retrieval for successful performance of delayed-nonmatch-to-sample (DNMS) memory task in rodents. The MIMO model has been tested successfully in a number of different contexts, each of which produced improved performance by a) utilizing online predicted codes to regulate task difficulty, b) employing electrical stimulation of CA1 output areas in the same pattern as successful cell firing, c) employing electrical stimulation to recover cell firing compromised by pharmacological agents and d) transferring and improving performance in naive animals using the same stimulation patterns that are effective in fully trained animals. The results in rodents formed the basis for extension of the MIMO model to nonhuman primates in the same type of memory task that is now being tested in the last step prior to its application in humans. PMID- 22255055 TI - Functional connectivity during surround suppression in macaque area V4. AB - Surround suppression is a common feature of sensory neurons. For neurons of the visual cortex, it occurs when a visual stimulus extends beyond a neuron's classical receptive field, reducing the neuron's firing rate. While several studies have been attributing the suppression effect on horizontal, long-range lateral or feedback connections, the underlying circuitry for surround modulation remain unidentified. Since most of these models have been relying on single neuron recordings, the contribution of lateral connections can only be suggested from the surround field properties. A more straightforward approach would be to detect these connections and their dynamics using simultaneous recordings from multiple neurons in one or more visual areas. We have developed a method for estimating these connections and we analyzed data obtained from 100-electrode Utah arrays chronically implanted into area V4 of the macaque monkey. Using a method based on the nonlinear Volterra modeling approach, we computed estimates of the strength and statistical reliability of connections among neurons, including nonlinear interactions and excitatory and inhibitory connections. Our results thus far reveal a pattern of connectivity within V4 that conforms to the results of previous anatomical work: Excitatory connections are far more common than inhibitory connections (~65%), stronger connections are found among neurons that are physically near one another, and connections are stronger among neurons with similar receptive field properties. However, this connectivity is capable of reorganizing on short time scales according to the stimulus: Stimuli that evoke strong suppression at the single-unit level introduce stronger inhibition among V4 neurons, identifying recurrent connectivity as the source of the suppression. Overall, these results provide insight into the dynamic nature of neuronal organization within V4 and its contribution to surround suppression. PMID- 22255056 TI - Fractal behavior of spontaneous neurotransmitter release: from single-synapse to whole-cell recordings. AB - Spontaneous release of neurotransmitter vesicles at brain chemical synapses has been deeply investigated in the last decades at several levels. First and second order statistics have been widely adopted as a tool for assessing, inter-alia, dependence of spontaneous release on the concentration of ionic species in the intra- or extra-cellular environment. Furthermore, several studies demonstrated that spontaneous release exhibits fractal, and generally non purely random, behavior. Most experimental work on this topic exploits population whole-cell patch-clamp recordings in order to acquire post-synaptic currents elicited by neurotransmitter release into the synaptic cleft. Since several synapses merge on the dendritic arbor of a single neuronal cell, whole-cell recordings of miniature excitatory post-synaptic currents (mEPSCs) implies the temporal superimposition of releasing events from all active synapses on the arbor. This limitation can be overcome by exploiting the loose-patch clamp technique on single synapses, thus acquiring spontaneous release events from individual synapses. Here, we present results obtained by applying well-established methods for the quantification of fractal behavior in the series of mEPSCs acquired through the use of both whole cell and single-synapse loose-patch recording techniques on hippocampal neurons and synapses. Our long-term aim is to get a better understanding of the release process and of the mechanisms of neuronal integration when the information is coming from several simultaneously active synaptic sites. PMID- 22255057 TI - A comparison of the effects of majority vote and a decision-based velocity ramp on real-time pattern recognition control. AB - Movement misclassifications often occur during real-time pattern recognition control. Majority vote and a decision-based velocity ramp are two different post processing methods that have been suggested to improve real-time control. With majority vote, spurious misclassifications are removed at the expense of an additional controller delay. With a decision-based velocity ramp, the effect of misclassifications is minimized by attenuating movement speed following a change in decision from the classifier. The goal of the study was to determine which, if any, post-processing method improved real-time control above a baseline condition that did not involve post-processing. Five non-amputee subjects controlled a virtual prosthesis in real time using pattern recognition. While performing a challenging target achievement test in a virtual environment, subjects had significantly higher completion rates (p < 0.04) and more direct paths to the target (p < 0.02) while using the velocity ramp than while using majority vote or the control condition. There were no significant differences in completion rate or path efficiency between the majority vote conditions and the control condition (p > 0.6). The benefits of removing misclassifications through majority vote may be offset by the added controller delay. These results highlight the need for real-time performance measures, as methods that have been shown to reduce errors during offline analysis may not improve real-time control. PMID- 22255058 TI - A comparison of proportional control methods for pattern recognition control. AB - Few studies have focused on proportional control with multi-channel electromyographic (EMG) pattern recognition systems. In a simple proportional control algorithm, movement speed is often calculated by averaging the mean absolute values of all EMG channels. The aim of our study was to compare the performance of two types of pattern recognition control (simple proportional and binary on/off) to direct proportional control. Six EMG channels were collected from non-targeted forearm muscles of four healthy subjects. Subjects were prompted to perform eight medium force isometric repetitions of the following contractions: wrist flexion/extension, wrist pronation/supination, hand open/close, and no movement (rest). Control performances were measured during a one-dimensional position-tracking task using a custom-made graphical user interface. The results show that a simple proportional control algorithm for the pattern recognition system outperformed binary on/off control and was comparable to the performance achieved with direct proportional control. PMID- 22255059 TI - Interpreting sign components from accelerometer and sEMG data for automatic sign language recognition. AB - The identification of constituent components of each sign gesture is a practical way of establishing large-vocabulary sign language recognition (SLR) system. Aiming at developing such a system using portable accelerometer (ACC) and surface electromyographic (sEMG) sensors, this work proposes a method for automatic SLR at the component level. The preliminary experimental results demonstrate the effectiveness of the proposed method and the feasibility of interpreting sign components from ACC and sEMG data. Our study improves the performance of SLR based on ACC and sEMG sensors and will promote the realization of a large vocabulary portable SLR system. PMID- 22255060 TI - Sparse representation via l1-minimization for underdetermined systems in classification of tumors with gene expression data. AB - The development of cancer diagnosis models and cancer discovery from DNA microarray data are of great interest in bioinformatics and medicine. In pattern recognition and machine learning, a classification problem refers to finding an algorithm for assigning a given input data into one of several categories. Many natural signals are sparse or compressible in the sense that they have short representations when expressed in a suitable basis. Motivated by the recent successful algorithm developments for sparse signal recovery, we apply the selective nature of sparse representation to perform the above mentioned classification. In order to find such sparse representation we implement an l(1) minimization algorithm. This methodology overcomes the lack of robustness with respect to outliers. In contrast to other classification algorithms, no model selection dependency is involved. The minimization algorithm is a convex relaxation-like that has been proven to efficiently recover sparse signals. To study its performance, the proposed method is applied to six tumor gene expression datasets and numerically compared with various support vector machine methods (SVM). The numerical results show that the l(1)-minimization algorithm proposed performs at least comparably and often better than SVMs. PMID- 22255061 TI - Classification of upper limb motions in stroke using high density surface EMG. AB - Myoelectric pattern recognition techniques have been developed to infer user's intention of performing different functional movements, which can be used to provide volitional control of assisted devices for people with disabilities. The pattern recognition based myoelectric control systems have rarely been designed for stroke survivors. Aiming at developing such a system for stroke rehabilitation, this study assessed the myoelectric control information remained in the affected limb of stroke survivors using high density surface electromyogram (EMG) recording and pattern recognition techniques. The experimental results from 3 stroke subjects indicate that high accuracies (92.42% +/- 5.51%) can be achieved in classification of 20 different intended movements of the affected limb. This study confirms that substantial motor control command can be extracted from paretic muscles of stroke survivors, potentially facilitating their rehabilitation. PMID- 22255062 TI - Classification performance of the frequency-related parameters derived from uterine EMG signals. AB - Frequency-related parameters derived from the uterine electromyogram (EMG) signals are widely used in many pregnancy monitoring and preterm delivery prediction studies. Although they are classical parameters, they are well suited for quantifying uterine EMG signals and have many advantages over amplitude related parameters. The present work aims to compare various frequency-related parameters according to their classification performances (pregnancy vs. labor) using the receiver operating characteristic (ROC) curve analysis. The comparison between the parameters indicates that median frequency is the best frequency related parameter that can be used for distinguishing between pregnancy and labor contractions. We conclude that median frequency can be the representative frequency-related parameter for classification problems of uterine EMG. PMID- 22255063 TI - Automated diagnosis of referable maculopathy in diabetic retinopathy screening. AB - This paper introduces an algorithm for the automated diagnosis of referable maculopathy in retinal images for diabetic retinopathy screening. Referable maculopathy is a potentially sight-threatening condition requiring immediate referral to an ophthalmologist from the screening service, and therefore accurate referral is extremely important. The algorithm uses a pipeline of detection and filtering of "peak points" with strong local contrast, segmentation of candidate lesions, extraction of features and classification by a multilayer perceptron. The optic nerve head and fovea are detected, so that the macula region can be identified and scanned. The algorithm is assessed against a reference standard database drawn from the Birmingham City Hospital (UK) diabetic retinopathy screening programme, against two possible modes of use: independent screening, and pre-filtering to reduce human screener workload. PMID- 22255064 TI - From laboratory to clinic: the development of web-based tools for the estimation of retinal diagnostic parameters. AB - Over the years, tools for the analysis of retinal images have been developed by several research groups but their usage has been mainly confined within the developing institutions. One possibility to foster their adoption is to develop them as web-based tools. We present here three such systems we recently developed. They are specifically focused on the estimation of retinal vascular parameters, such as arteriolar narrowing (AVR parameter), vessel tortuosity, and vessel caliber narrowing and tortuosity in retinopathy of prematurity (ROP) images. These systems have been successfully evaluated as regards their reliability and will soon be publicly available to interested health care providers. PMID- 22255065 TI - Automatic glaucoma diagnosis from fundus image. AB - Glaucoma is currently diagnosed by glaucoma specialists using specialized imaging devices like HRT and OCT. Fundus imaging is a modality widely used in primary healthcare. An automatic glaucoma diagnosis system based on fundus image can be deployed to primary healthcare clinics and has potential for early disease diagnosis. A mass glaucoma screening program can also be facilitated using such a system. We present an automatic fundus image based cup-to-disc ratio measurement system; and demonstrate its potential for automatic objective glaucoma diagnosis and screening. It provides strong support to use fundus image as the modality for automatic glaucoma diagnosis. PMID- 22255066 TI - Automatic measurement of cup to disc ratio based on line profile analysis in retinal images. AB - Retinal image examination is useful for early detection of glaucoma, which is a leading cause of permanent blindness. In order to evaluate the presence of glaucoma, ophthalmologists may determine the cup and disc areas and diagnose glaucoma using a vertical cup-to-disc ratio. However, determination of the cup area based on computation algorithm is very difficult, thus we propose a method to measure the cup-to-disc ratio using a vertical profile on the optic disc. The edge of optic disc was then detected by use of a Canny edge detection filter. The profile was then obtained around the center of the optic disc. Subsequently, the edges of the cup area were determined by classification of the profiles based on zero-crossing method. Lastly, the vertical cup-to-disc ratio was calculated. Using forty five images, including twenty three glaucoma images, the AUC of 0.947 was achieved with this method. PMID- 22255067 TI - VAMPIRE: Vessel assessment and measurement platform for images of the REtina. AB - We present VAMPIRE, a software application for efficient, semi-automatic quantification of retinal vessel properties with large collections of fundus camera images. VAMPIRE is also an international collaborative project of four image processing groups and five clinical centres. The system provides automatic detection of retinal landmarks (optic disc, vasculature), and quantifies key parameters used frequently in investigative studies: vessel width, vessel branching coefficients, and tortuosity. The ultimate vision is to make VAMPIRE available as a public tool, to support quantification and analysis of large collections of fundus camera images. PMID- 22255068 TI - 3D optical coherence tomography super pixel with machine classifier analysis for glaucoma detection. AB - Current standard quantitative 3D spectral-domain optical coherence tomography (SD OCT) analyses of various ocular diseases is limited in detecting structural damage at early pathologic stages. This is mostly because only a small fraction of the 3D data is used in the current method of quantifying the structure of interest. This paper presents a novel SD-OCT data analysis technique, taking full advantage of the 3D dataset. The proposed algorithm uses machine classifier to analyze SD-OCT images after grouping adjacent pixels into super pixel in order to detect glaucomatous damage. A 3D SD-OCT image is first converted into a 2D feature map and partitioned into over a hundred super pixels. Machine classifier analysis using boosting algorithm is performed on super pixel features. One hundred and ninety-two 3D OCT images of the optic nerve head region were tested. Area under the receiver operating characteristic (AUC) was computed to evaluate the glaucoma discrimination performance of the algorithm and compare it to the commercial software output. The AUC of normal vs glaucoma suspect eyes using the proposed method was statistically significantly higher than the current method (0.855 and 0.707, respectively, p=0.031). This new method has the potential to improve early detection of glaucomatous structural damages. PMID- 22255069 TI - A new hierarchical method for multi-level segmentation of bone in pelvic CT scans. AB - Pelvic bone segmentation is a vital step in analyzing pelvic CT images and assisting physicians with diagnostic decisions in traumatic pelvic injuries. A new hierarchical segmentation algorithm is proposed using a template-based best shape matching method and Registered Active Shape Model (RASM) to automatically extract pelvic bone tissues from multi-level pelvic CT images. A novel hierarchical initialization process for RASM is proposed. 449 CT images across seven patients are used to test and validate the reliability and robustness of the proposed method. The segmentation results show that the proposed method performs better with higher accuracy than standard ASM method. PMID- 22255070 TI - Centerline extraction with principal curve tracing to improve 3D level set esophagus segmentation in CT images. AB - For radiotherapy planning, contouring of target volume and healthy structures at risk in CT volumes is essential. To automate this process, one of the available segmentation techniques can be used for many thoracic organs except the esophagus, which is very hard to segment due to low contrast. In this work we propose to initialize our previously introduced model based 3D level set esophagus segmentation method with a principal curve tracing (PCT) algorithm, which we adapted to solve the esophagus centerline detection problem. To address challenges due to low intensity contrast, we enhanced the PCT algorithm by learning spatial and intensity priors from a small set of annotated CT volumes. To locate the esophageal wall, the model based 3D level set algorithm including a shape model that represents the variance of esophagus wall around the estimated centerline is utilized. Our results show improvement in esophagus segmentation when initialized by PCT compared to our previous work, where an ad hoc centerline initialization was performed. Unlike previous approaches, this work does not need a very large set of annotated training images and has similar performance. PMID- 22255071 TI - A chance-constrained programming level set method for longitudinal segmentation of lung tumors in CT. AB - This paper presents a novel stochastic level set method for the longitudinal tracking of lung tumors in computed tomography (CT). The proposed model addresses the limitations of registration based and segmentation based methods for longitudinal tumor tracking. It combines the advantages of each approach using a new probabilistic framework, namely Chance-Constrained Programming (CCP). Lung tumors can shrink or grow over time, which can be reflected in large changes of shape, appearance and volume in CT images. Traditional level set methods with a priori knowledge about shape are not suitable since the tumors are undergoing random and large changes in shape. Our CCP level set model allows to introduce a flexible prior to track structures with a highly variable shape by permitting a constraint violation of the prior up to a specified probability level. The chance constraints are computed from two given points by the user or from segmented tumors from a reference image. The reference image can be one of the images studied or an external template. We present a numerical scheme to approximate the solution of the proposed model and apply it to track lung tumors in CT. Finally, we compare our approach with a Bayesian level set. The CCP level set model gives the best results: it is more coherent with the manual segmentation. PMID- 22255072 TI - Inter-observer variability assessment of a left ventricle segmentation tool applied to 4D MDCT images of the heart. AB - Multiple detector row computed tomography (MDCT) cardiac angiography provides a large amount of data concerning multiple cardiac phases which are not often considered. Segmentation is a first step towards exploring how this additional data can be used to perform left ventricle functional analysis or myocardial perfusion assessment. We present preliminary results regarding the assessment of inter-observer variability for a semi-automatic (multi-phase) segmentation tool for the left-ventricle. PMID- 22255073 TI - Automated CT liver segmentation using improved Chan-Vese model with global shape constrained energy. AB - In this paper, we propose an automated liver segmentation method to overcome the challenging issues of high degree of variations in liver shape / size and similar density distribution shared by the liver and its surrounding structures. To improve the performance of conventional statistical shape model for liver segmentation, in our method, the signed distance function is utilized so that the landmarks correspondence is not required when performing the principle component analysis. We improve the Chan-Vese model to bind the shape energy and local intensity feature to evolve the surface both globally and locally toward the closest shape driven by the PCA. In our experiments, 20 clinical CT studies were used for training and 25 clinical CT studies were used for validation. Our experimental results demonstrate that our method can achieve accurate and robust liver segmentation from both of low-contrast and high-contrast CT images. PMID- 22255074 TI - Optimal multiresolution 3D level-set method for liver segmentation incorporating local curvature constraints. AB - Advanced liver surgery requires a precise pre-operative planning, where liver segmentation and remnant liver volume are key elements to avoid post-operative liver failure. In that context, level-set algorithms have achieved better results than others, especially with altered liver parenchyma or in cases with previous surgery. In order to improve functional liver parenchyma volume measurements, in this work we propose two strategies to enhance previous level-set algorithms: an optimal multi-resolution strategy with fine details correction and adaptive curvature, as well as an additional semiautomatic step imposing local curvature constraints. Results show more accurate segmentations, especially in elongated structures, detecting internal lesions and avoiding leakages to close structures. PMID- 22255075 TI - An algorithm for cancer nest feature extraction from pathological images. AB - Here, we propose an algorithm to automatically obtain extraction filters for the affected regions from cancer images. The proposed algorithm consists of two steps: extraction of affected region candidates and elimination of false positives. Useful features of cancer images, such as the area and degree of circularity of cancer nests, etc., are extracted using the derived filters. These features are useful for supporting pathological diagnosis. Automatic Construction of Tree-structural Image Transformation (ACTIT) was used to construct these filters to extract the affected regions from the image. The proposed algorithm was applied to a mouth cancer pathological image. The results confirmed that the proposed algorithm can obtain good filters capable of extracting cancer nests. The derived filters were also applied to other images from the same specimen. The results also indicated that the generated filters show general versatility in extracting cancer nest candidates. The area and degree of circularity of the cancer nets were also derived automatically. PMID- 22255076 TI - Detection of prostate cancer on histopathology using color fractals and Probabilistic Pairwise Markov models. AB - In this paper we present a system for detecting regions of carcinoma of the prostate (CaP) in H&E stained radical prostatectomy specimens using the color fractal dimension. Color textural information is known to be a valuable characteristic to distinguish CaP from benign tissue. In addition to color information, we know that cancer tends to form contiguous regions. Our system leverages the color staining information of histology as well as spatial dependencies. The color and textural information is first captured using color fractal dimension. To incorporate spatial dependencies, we combine the probability map constructed via color fractal dimension with a novel Markov prior called the Probabilistic Pairwise Markov Model (PPMM). To demonstrate the capability of this CaP detection system, we applied the algorithm to 27 radical prostatectomy specimens from 10 patients. A per pixel evaluation was conducted with ground truth provided by an expert pathologist using only the color fractal feature first, yielding an area under the receiver operator characteristic curve (AUC) curve of 0.790. In conjunction with a Markov prior, the resultant color fractal dimension + Markov random field (MRF) classifier yielded an AUC of 0.831. PMID- 22255077 TI - Automated lymph node detection and classification on breast and prostate cancer SPECT-CT images. AB - We present a novel detection and classification method to process SPECT-CT images representing breast and prostate lymph nodes. Lymph nodes are those nodes that are near the primer tumor and may become cancerous in time, hence their early detection is a key factor for the successful treatment of the patient. Prior methods focus on the visual aid to manually detect the lymph nodes which still makes the process time-consuming. Other solutions segment the lymph nodes only on CT, where the small lymph nodes may not be located accurately. Our solution processed both SPECT and CT data to provide an accurate classification of all SPECT hot spots. The method has been validated on a huge amount of medical data. Results show that our method is a very effective tool to support physicians working with related images in the field of nuclear medicine. PMID- 22255078 TI - Computer aided analysis of epi-illumination and transillumination images of skin lesions for diagnosis of skin cancers. AB - Skin lesion pigmentation area from surface, or, epi-illumination (ELM) images and blood volume area from transillumination (TLM) images are useful features to aid a dermatologist in the diagnosis of melanoma and other skin cancers in early curable stages. However, segmentation of these areas is difficult. In this work, we present an automatic segmentation tool for ELM and TLM images that also provides additional choices for user selection and interaction with adaptive learning. Our tool uses a combination of k-means clustering, wavelet analysis, and morphological operations to segment the lesion and blood volume, and then presents the user with six segmentation suggestions for both ELM and TLM images. The final selection of segmentation boundary may then be iteratively improved through scoring by multiple users. The ratio of TLM to ELM segmented areas is an indicator of dysplasia in skin lesions for detection of skin cancers, and this ratio is found to show a statistically significant trend in association with lesion dysplasia on a set of 81 pathologically validated lesions (p = 0.0058). We then present a support vector machine classifier using the results from the interactive segmentation method along with ratio, color, texture, and shape features to characterize skin lesions into three degrees of dysplasia with promising accuracy. PMID- 22255079 TI - Automated analysis of cervix images to grade the severity of cancer. AB - This paper discusses a method to objectively analyze the severity of cancer in images obtained from cervix. We propose a novel method to identify the transformation zone in post Lugol's iodine images and acetic acid images that are obtained from the cervix to grade the severity of cancer. We segment the Lugol's iodine image to identify the abnormal tissues and map them to acetic acid images to accurately identify the abnormal tissues in post acetic acid images as well. This information is further used to obtain an opacity difference score that could be used for grading the cancer. PMID- 22255080 TI - An integrated texton and bag of words classifier for identifying anaplastic medulloblastomas. AB - In this paper we present a combined Bag of Words and texton based classifier for differentiating anaplastic and non-anaplastic medulloblastoma on digitized histopathology. The hypothesis behind this work is that histological image signatures may reflect different levels of aggressiveness of the disease and that texture based approaches can help discriminate between more aggressive and less aggressive phenotypes of medulloblastoma. The bag of words approach attempts to model the occurrence of differently expressed image features. In this work we choose to model the image features via textons which can quantitatively capture and model texture appearance in the images. The texton-based features, obtained via two methods, the Haar Wavelet responses and MR8 filter bank, provide spatial orientation and rotation invariant attributes. Applying these features to the bag of words framework yields textural representations that can be used in conjunction with a classifier (kappa-nearest neighbor) or a content based image retrieval system. Over multiple runs of randomized cross validation, a kappa-NN classifier in conjunction with Haar wavelets and the texton, bag of words approach yielded a mean classification accuracy of 80, an area under the precision recall curve of 87 and an area under the ROC curve of 83 in distinguishing between anaplastic and non-anaplastic medulloblastomas on a cohort of 36 patient studies. PMID- 22255081 TI - Experimental evaluation of a coaxial needle insertion assistant with enhanced force feedback. AB - During needle insertion in soft tissue, detection of change in tissue properties is important both for diagnosis to detect pathological tissue and for prevention to avoid puncture of important structures. The presence of a membrane located deep inside the tissue results in a relatively small force variation at the needle tip that can be masked by relatively large friction force between the needle shaft and the surrounding tissue. Also, user perception of force can be limited due to the overall small force amplitude in some applications (e.g. brain surgery). A novel robotic coaxial needle insertion assistant was developed to enhance operator force perception. The coaxial needle separates the cutting force at the needle tip from shear friction on the needle shaft. The assistant is force controlled (admittance control), providing the operator with force feedback that is a scaled version of the force applied by the needle tip to the tissue. The effectiveness of the assistant in enhancing the detection of different tissue types was tested experimentally. Users were asked to blindly insert a needle into artificial tissues with membranes at various depths under two force feedback conditions: (1) shaft and tip force together, and (2) only tip force. The ratio of successful to unsuccessful membrane detection was significantly higher when only the needle tip force is displayed to the user. The system proved to be compliant with the clinical applications requirements. PMID- 22255082 TI - Assessing the quality of force feedback in soft tissue simulation. AB - Many types of deformable models have been proposed for simulation of soft tissue in surgical simulators, but their realism in comparison to actual tissue is rarely assessed. In this paper, a nonlinear mass-spring model is used for realtime simulation of deformable soft tissues and providing force feedback to a human operator. Force-deformation curves of real soft tissue samples were obtained experimentally, and the model was tuned accordingly. To test the realism of the model, we conducted two human-user experiments involving palpation with a rigid probe. First, in a discrimination test, users identified the correct category of real and virtual tissue better than chance, and tended to identify the tissues as real more often than virtual. Second, users identified real and virtual tissues by name, after training on only real tissues. The sorting accuracy was the same for both real and virtual tissues. These results indicate that, despite model limitations, the simulation could convey the feel of touching real tissues. This evaluation approach could be used to compare and validate various soft-tissue simulators. PMID- 22255083 TI - Design and evaluation of a multi-modal haptic skin stimulation apparatus. AB - Human grasping and manipulation are facilitated by cutaneous mechanoreceptors that provide information about contact location, pressure, and events such as making and breaking contact. A challenge in designing haptic feedback devices for the wearer of a prosthetic hand is simultaneous display of multiple types of haptic information. We present the preliminary design and evaluation of an apparatus for relaying multi-modal haptic information. The apparatus moves a set of contact points tangentially over the skin at a controlled speed, with controlled normal force. We apply this stimulus to an artificial skin instrumented with an embedded accelerometer, and characterize the resulting signals. Vibration frequency increases with applied normal force and tangential speed, whereas vibration amplitude increases with normal force and depends on skin properties. The results indicate that different forces and speeds can, under some conditions, be discriminated using vibration signals alone. Accurate identification of speeds is provided by series of vibration events that depend on the spatial distribution of contact points. This study motivates future work to perform human perception studies and create a wearable haptic display for prosthetics based on this concept. PMID- 22255084 TI - Towards an augmented ultrasound guided spinal needle insertion system. AB - We propose a haptic-based simulator for ultrasound-guided percutaneous spinal interventions. The system is composed of a haptic device to provide force feedback, a camera system to display video and augmented computed tomography (CT) overlay, a finite element model for tissue deformation and US simulation from a CT volume. The proposed system is able to run a large finite element model at the required haptic rate for smooth force feedback, and uses haptic device position measurements for a steady response. The simulated US images from CT closely resemble the vertebrae images captured in vivo. This is the first report of a system that provides a training environment to couple haptic feedback with a tracked mannequin, and a CT volume overlaid on a visual feed of the mannequin. PMID- 22255085 TI - Development of a spatially transparent electrotactile display and its performance in grip force control. AB - An important function for a tactile navigation system of a handheld tool, such as a surgical scalpel, is the spatial transparency of the device. This paper proposed a new tactile display that can augment touch sensation at the finger pulps without the need for a stimulator between the tool and the finger pulps. We utilized transcutaneous electrical nerve stimulation at the middle phalanx of a finger to separate the stimulated and the perceived areas. In order to verify the effects of the spatial transparency, the performances of grip force control were examined. The results indicated that the proposed display was effective in helping the user to maintain the stable control of the grip force when using a handheld tool. PMID- 22255086 TI - Characterization of an air jet haptic lump display. AB - During manual palpation, clinicians rely on distributed tactile information to identify and localize hard lumps embedded in soft tissue. The development of tactile feedback systems to enhance palpation using robot-assisted minimally invasive surgery (RMIS) systems is challenging due to size and weight constraints, motivating a pneumatic actuation strategy. Recently, an air jet approach has been proposed for generating a lump percept. We use this technique to direct a thin stream of air through an aperture directly on the finger pad, which indents the skin in a hemispherical manner, producing a compelling lump percept. We hypothesize that the perceived parameters of the lump (e.g. size and stiffness) can be controlled by jointly adjusting air pressure and the aperture size through which air escapes. In this work, we investigate how these control variables interact to affect perceived pressure on the finger pad. First, we used a capacitive tactile sensor array to measure the effect of aperture size on output pressure, and found that peak output pressure increases with aperture size. Second, we performed a psychophysical experiment for each aperture size to determine the just noticeable difference (JND) of air pressure on the finger pad. Subject-averaged pressure JND values ranged from 19.4-24.7 kPa, with no statistical differences observed between aperture sizes. The aperture-pressure relationship and the pressure JND values will be fundamental for future display control. PMID- 22255087 TI - Redundancy resolution of a human arm for controlling a seven DOF wearable robotic system. AB - The human arm including the shoulder, elbow, wrist joints and exclusion scapular motion has 7 Degrees of Freedom (DOF) while positioning of the wrist in space and orientating the palm is a task that requires 6 DOF. As such it includes one more DOF than is needed to complete the task. Given the redundant nature of the arm, multiple arm configurations can be used to complete a task, which is expressed mathematically by none unique solution for the inverse kinematics. Despite this mathematical difficulty, the motor control provides a unique solution for the arm redundancy as the arm is moved in space. Resolving this redundancy is becoming critical as the human interacts with a wearable robotic system(exoskeleton) which includes the same redundancy as the human arm. Therefore, the inverse kinematics solution resolving the redundancy of these two coupled systems must be identical in order to guarantee a seamless integration. The redundancy of the arm can be formulated kinematically by defining the swivel angle - the rotation angle of the plane including the upper and lower arm around a virtual axis connecting the shoulder and wrist joints which are fixed in space. Analyzing reaching tasks recorded with a motion capture lab indicates that the swivel angle is selected such that when the elbow joint is flexed, the palm points the head. Based on these experimental results, selecting the point around the center of the head as a stationary target allows to calculate the swivel angle and in that way to resolve the human arm redundancy. Experimental results indicated that by using the proposed redundancy resolution criteria the error between the predicted swivel angle and the actual swivel angle adopted by the motor control system is less then 5 Deg. This criterion or a synthesis of several additional criteria may improve the synergistic relationships between an operator and a wearable robotic system. PMID- 22255088 TI - Detecting changes in human motion using stochastic distance measures. AB - We propose a stochastic framework to analyze and compare differences in human motions for applications in injury prevention, rehabilitation, sports training and performance research. Human motions are modeled as Hidden Markov Models and the differences between the motions are measured using the Kullback-Leibler distance metric. The distance metric is recomputed with degrees of freedom excluded to determine which degree of freedom most influences the difference between a set of motions. The proposed system is tested on a human motion dataset consisting of lifting movements under differing load weights and ankle bracing conditions. Results indicate that the algorithm is capable of successfully determining which joints are impacted and ranking them according to importance. PMID- 22255089 TI - Joint angle estimation in rehabilitation with inertial sensors and its integration with Kinect. AB - In this paper, we explore the combined use of inertial sensors and the Kinect for applications on rehabilitation robotics and assistive devices. In view of the deficiencies of each individual system, a new method based on Kalman filtering was developed in order to perform online calibration of sensor errors automatically whenever measurements from Kinect are available. The method was evaluated on experiments involving healthy subjects performing multiple DOF tasks. PMID- 22255090 TI - A concurrent comparison of inertia sensor-based walking speed estimation methods. AB - This study performed a concurrent comparison of two walking speed estimation methods using shank- and foot-mounted inertial measurement units (IMUs). Based on the cyclic gait pattern of the stance leg during walking, data was segmented into a series of individual stride cycles. The angular velocity and linear accelerations of the shank and foot over each of these cycles were then integrated to determine the walking speed. The evaluation was performed on 10 healthy subjects during treadmill walking where known treadmill speeds were compared with the estimated walking speeds under normal and toe-out walking conditions. Results from the shank-mounted IMU sensor yielded more accurate walking speed estimates, with a maximum root mean square estimation error (RMSE) of 0.09 m/s in normal walking and 0.10 m/s in toe-out conditions; while the foot mounted IMU sensors yielded a maximum RMSE of 0.14 m/s in normal walking and 0.26 m/s in toe-out conditions. Shank-mounted IMU sensors may prove to be of great benefit in accurately estimating walking speeds in patients whose gait is characterized by abnormal foot motions. PMID- 22255091 TI - An optimization algorithm for joint mechanics estimate using inertial measurement unit data during a squat task. AB - The use of dynamic optimization as a tool to estimate joint kinematics and kinetics, and ground reaction forces using data from a single inertial measurement unit (IMU) positioned on the lower trunk was investigated. The feasibility of this approach and its accuracy was explored for the analysis of a squat task, focusing on the ankle, knee and hip joints. An optimal motor control strategy aimed at minimizing the sum of the intersegmental couples and of their time derivatives was imposed to estimate the mechanics of a three-segment sagittal model. Moreover, in the optimization process constraints to the measured vertical acceleration, to the maximal vertical IMU excursion, and with regard to the maintenance of dynamic balance were imposed. Experiments were performed using 10 volunteers. Data were collected from the IMU, from a stereophotogrammetric system (SS) and from a force platform for validation purposes. Results showed a very good consistency of the model output with the lower limb joint trajectories, as obtained using the SS, and with the measured vertical component of the ground reaction (low root mean square differences (<10%) and high correlation coefficients (0.98)). PMID- 22255092 TI - Using a shoe mounted tri-axial accelerometer to detect kinematic changes during stiff ankle walking. AB - Ubiquitous analysis of gait is a rapidly emerging field in which research and commercial development has been focused mainly on determining spatio-temporal parameters. In this preliminary research we have developed an algorithm to determine gait metrics from a shoe mounted accelerometer and compared them with concurrent kinematic data. Subjects were tested at different walking speeds as well as an artificially induced stiff ankle condition, to determine what metrics estimate kinematic changes that are related to speed and those that are related to real kinematic changes. These preliminary findings suggest that accelerometer outputs from the foot combined with contextual knowledge of the general walking speed of the subject can be used to estimate ankle plantar flexion angular velocity in terminal stance. PMID- 22255093 TI - Enhancing the performance of upper limb gesture reconstruction through sensory fusion. AB - A novel method devoted to the reconstruction of the joint angles in a kinematic chain is described. The reconstruction algorithm is based on the fusion of the information deriving from inertial sensors (accelerometers) and conductive elastomer strain sensors. Accelerometers provide a reliable reconstruction when they are employed as inclinometers in quasi-static conditions. They suffer from artifacts when they are used to detect fast movements or when interactions with the environment occur. The knowledge of the frequency components of the movement to be detected permits removal of these artifacts. Conversely, conductive elastomer sensors have a complex dynamic response, but they can easily provide the frequency content of the movement to be detected. A filtering strategy of the inertial sensor signals based on the elastomer sensor response provides a reliable reconstruction of joint variables during the movement. PMID- 22255094 TI - Load identification during object handling. AB - In this paper a new concept to identify environmental loads during the interaction with the human body by sensing interface forces and movement is proposed. Mass and spring loads were moved by hand over a fixed height difference. Kinematic and kinetic quantities were measured between the hand and the load using an instrumented handle. Force was measured using a force transducer module, movement was measured using an accelerometer and rate gyroscope. Under the condition that the human body was actively generating force at the load, while the load was passive, the dynamic characteristics of the load could be estimated. The estimated parameter values were compared to their specified values and appeared to be accurate within 4% for both mass and spring loads. PMID- 22255095 TI - Wearable smart systems: from technologies to integrated systems. AB - Wearable technology and integrated systems, so called Smart Wearable Systems (SWS) have demonstrated during the last 10-15 years significant advances in terms of, miniaturisation, seamless integration, data processing & communication, functionalisation and comfort. This is mainly due to the huge progress in sciences and technologies e.g. biomedical and micro & nano technologies, but also to a strong demand for new applications such as continuous personal health monitoring, healthy lifestyle support, human performance monitoring and support of professionals at risk. Development of wearable systems based of smart textile have, in addition, benefited from the eagerness of textile industry to develop new value-added apparel products like functionalized garments and smart clothing. Research and development in these areas has been strongly promoted worldwide. In Europe the major R&D activities were supported through the Information & Communication Technologies (ICT) priority of the R&D EU programs. The paper presents and discusses the main achievements towards integrated systems as well as future challenges to be met in order to reach a market with reliable and high value-added products. PMID- 22255096 TI - A comparison of treatment effects after sensor- and robot-based task-oriented arm training in highly functional stroke patients. AB - A large number of rehabilitation technologies for stroke patients has been developed in the last decade. To date it is insufficiently clear what the strengths of these different technologies are in relation to certain patient characteristics, such as the level of muscle strength and/or functional ability. One of the reasons is that research protocols differ so much that comparison of treatment results is impossible. This paper compares, while using the same patient inclusion criteria and training protocol, the effectivity of a sensor supported versus robot-supported task-oriented arm training for highly functional chronic stroke patients. It appeared that individual improvements over time and Hedges's g effect sizes were twice as large for the sensor-based training compared to the robot-supported training in stroke patients with high functional levels. New research is planned to compare both therapy approaches for stroke patients with low and average functional levels. PMID- 22255097 TI - Radio frequency identification--an innovative solution to guide dexterous prosthetic hands. AB - Dexterous manipulation of a multi-fingered prosthetic hand requires far more cognitive effort compared to typical 1 degree of freedom hands, which hinders their acceptance clinically. This paper presents a Myoelectrically-Operated Radio Frequency Identification (RFID) Prosthetic Hand (MORPH); an implementation of RFID with a myoelectric prosthetic hand as a means to amplify the controllable degrees of freedom. Contextual information from an object equipped with an RFID tag allows automatic preshaping along with dexterous control in an attempt to reduce the cognitive effort required to operate the terminal device. The myoelectric-RFID hybrid has been demonstrated in a proof-of-concept case study where an amputee was fitted with the device and subjected to activities adapted from the Jebsen Hand Function Test and the Smith Hand Function Evaluation with RFID-tagged and untagged items. Evaluation tests revealed that the MORPH system performed significantly better in 4 of the 8 tasks, and comparable to the control in the remainder. PMID- 22255098 TI - Series elastic actuator control of a powered exoskeleton. AB - A motorized upper extremity orthosis based on the passive WREX system is being developed. The orthosis is a 4 dof arm controlled by user residual force inputs. The arm is intended for people with neuromuscular weakness due to muscular dystrophy or spinal muscular atrophy. Previous work determined that actuation in parallel with gravity balancing springs required less torque than actuation in series. Compliance is achieved by using a series elastic actuator (SEA) by placing torsional springs between the motors and the WREX. A torque control was implemented on the SEA at the joint level. The response of the control law was characterized without disturbances. The SEAs were then attached to the orthosis to test the response with disturbances, and the control provided accurate joint torques. PMID- 22255099 TI - Chronic stimulation of the semicircular canals using a multichannel vestibular prosthesis: effects on locomotion and angular vestibulo-ocular reflex in chinchillas. AB - Bilateral loss of vestibular sensation causes difficulty maintaining stable vision, posture and gait. An implantable prosthesis that partly restores vestibular sensation could significantly improve quality of life for individuals disabled by this disorder. We have developed a head-mounted multichannel vestibular prosthesis (MVP) that restores sufficient semicircular canal function to recreate a 3D angular vestibulo-ocular reflex (aVOR). In this study, we evaluated effects of chronic MVP stimulation on locomotion in chinchillas. Two of three animals examined exhibited significant improvements in both locomotion and aVOR. PMID- 22255100 TI - The design and development of a production prototype balance belt. AB - This paper discusses the development of a balance device from lab to clinic/home use. An emerging practice among physical therapists in balance training and falls prevention addresses a major health problem in the United States: imbalance and its consequences. The annual cost for treating balance disorders exceeds $1 billion, not including the cost to treat falls. We aim to develop a non-invasive device worn around the waist. It detects when a person is tipping too far in any direction and vibrates on that side, signaling the wearer to stay within their limits of stability. Because this new technology gets a patient to a higher level of function in a shorter number of trials, it offers an opportunity to advance rehabilitation by enabling more effective outcomes for the same number of treatment sessions. PMID- 22255101 TI - The effects of rotational platform training on balance and ADLs. AB - Patients with vestibular dysfunction complain of postural instability and disorientation long after the central compensation is thought to be complete. Previously it has been demonstrated that patients with unilateral vestibular loss who orient more to vertical have better perceived functional status. We proposed that performing balance training with surface perturbations at velocities that target the vestibular system would lead to increased reliance on vestibular information, and therefore improve function. The purpose of this study was to determine whether patients who train using repetitive platform perturbations at these vestibular dependent velocities demonstrate improved postural stability and greater functional abilities than patients who perform traditional balance therapy. Twelve subjects with chronic vestibular and balance dysfunction (age 58 +/- 15 years; 3 males, 8 females) and 4 healthy control subjects (age 62 +/- 23 years; 4 females) participated. Patients were randomized into 3 groups: clinical balance training (CBT n=3) and training with ramp platform perturbations (4 deg amplitude) either at vestibular (1, 2, 4 deg/sec; VESTIB n=6) or at non vestibular velocities (0.5, 8, 16 deg/sec; Non-VESTIB n=3). The healthy control subjects completed training at vestibular velocities. Subjects' kinematic and kinetic responses to ramp rotational platform perturbations (0.5, 1, 2, 4, 8, 16 deg/sec at 6 deg amplitude), and scores on the Activities-specific Balance Confidence Scale (ABC), Dizziness Handicap Inventory (DHI), Vestibular Activities of Daily Living Scale (VADL) and Functional Gait Assessment (FGA) were compared before and after the 2 week, 3x/week training sessions. Control subjects demonstrated minimal change in orientation to vertical during platform rotations following training. The VESTIB group demonstrated greater improvements in orientation to vertical during ramp perturbations following training than the Non VESTIB or CBT groups. Both the CBT and VESTIB groups demonstrated improvements on a composite clinical score incorporating the ABC, DHI, VADL, and FGA following training whereas the Non-VESTIB group did not demonstrate improvement. These preliminary results indicate that training using platform rotations may be an effective intervention for improving postural control following vestibular loss. Further research is needed to explore the efficacy of incorporating rotational platform training with clinical balance training. PMID- 22255102 TI - Effects of attractive versus repulsive vibrotactile instructional cues during motion replication tasks. AB - The Mobile Instrument for Motion Instruction and Correction (MIMIC) enables an expert (i.e., physical therapist) to map his/her movements to a trainee (i.e., patient) in a hands-free fashion. MIMIC comprises an Expert Module (EM) and a Trainee Module (TM); both modules include six-degree-of-freedom inertial measurement units, microcontrollers, and batteries. The TM also includes actuators that provide the trainee with vibrotactile instructional cues. The estimated expert body motion information is transmitted wirelessly to the trainee; based on the computed difference between the motions of the expert and trainee, directional instructions are displayed to the trainee's skin via vibrotactile stimulation. This study examined anterior-posterior trunk movements using a simplified version of the MIMIC system in which only two actuators were used to provide feedback and pre-recorded target trajectories were used to represent ideal expert movements. The study was designed to investigate the effects of attractive versus repulsive vibrotactile instructional cues when the motion speed and task complexity were varied. Preliminary results (n = 12) suggest that repulsive vibrotactile instructional cues lead to the greatest correlation between expert and subject motion, the least time delay, and the least tilt error. PMID- 22255103 TI - Real-time communication of head velocity and acceleration for an externally mounted vestibular prosthesis. AB - Loss of vestibular function results in imbalance, disorientation, and oscillopsia. Several groups have designed and constructed implantable devices to restore vestibular function through electrical stimulation of the vestibular nerve. We have designed a two-part device in which the head motion sensing and signal processing elements are externally mounted to the head, and are coupled through an inductive link to a receiver stimulator that is based on a cochlear implant. The implanted electrode arrays are designed to preserve rotational sensitivity in the implanted ear. We have tested the device in rhesus monkeys by rotating the animals in the plane of the implanted canals, and then using head velocity and acceleration signals to drive electrical stimulation of the vestibular system. Combined electrical and rotational stimulation results in a summation of responses, so that one can control the modulation of eye velocity induced by sinusoidal yaw rotation. PMID- 22255104 TI - The effect of robot-assisted lokomotor training on gait recovery: a multivariate analysis. AB - To explore the effect of LOKOMAT and LOKOMAT+Tizanidine on the improvement of walking capacity for people with spinal cord injury (SCI), 20 SCI subjects with hypertonia spasticity at their ankle joints participated in a 12-session Lokomat training; among them, 10 subjects received Tizanidine. 1-hour LOKOMAT training was provided 3 times per week for 4-weeks. Subjects were evaluated 4 times for Timed-Up-and-Go, 10-Meter-Walking, and 6-Minute-Walking testings, at the baseline, 1-, 2- and 4-weeks after training. Latent Class Growth model was used to classify the LOKOMAT training speed, and clinical walking evaluations. Subjects in each treatment group could be classified into two subclasses for training speed and clinical evaluation. It was found that the training speed increased in all treatment group, while the subjects in LOKOMAT+Tizanidine presented a significant improvement of their training speed from the training session. The clinical evaluations classified subjects similarly, and no significant improvement of clinical measurements was observed for either treatment. The MVC dorsiflexion torque at the ankle joint was able to predict the class memberships of subjects for their walking capacity and can be used as a significant predictor for therapeutic functional recovery after spinal cord injury. PMID- 22255105 TI - Accessing to electronic medical history using a mobility intra hospital system. AB - The aim of this paper is to describe the solution that has been developed in Valencia Region (Spain) to provide health professionals (physicians and nurses) access to all the functionalities of a Hospital Information System (HIS) already available at fixed clients workstations. These functionalities are adapted to the care process carried out at patient bedside. In this way, professionals will have access to treatment and administration, recording of vital signs, nursing assessment, scales, care plan, extractions, medical records, progress notes so that they have all necessary information at the bedside, and record swiftly changes that occur in-situ. In addition, clinical safety is reinforced, including RFID patient identification mechanisms and barcode readers for blood samples or unidosis medication. PMID- 22255106 TI - A mobile feedback system for integrated E-health platforms to improve self-care and compliance of diabetes mellitus patients. AB - Exploiting the full potential of telemedical systems means using platform based solutions: data are recovered from biomedical sensors, hospital information systems, care-givers, as well as patients themselves, and are processed and redistributed in an either centralized or, more probably, decentralized way. The integration of all these different devices, and interfaces, as well as the automated analysis and representation of all the pieces of information are current key challenges in telemedicine. Mobile phone technology has just begun to offer great opportunities of using this diverse information for guiding, warning, and educating patients, thus increasing their autonomy and adherence to their prescriptions. However, most of these existing mobile solutions are not based on platform systems and therefore represent limited, isolated applications. This article depicts how telemedical systems, based on integrated health data platforms, can maximize prescription adherence in chronic patients through mobile feedback. The application described here has been developed in an EU-funded R&D project called METABO, dedicated to patients with type 1 or type 2 Diabetes Mellitus. PMID- 22255107 TI - METABO: a new paradigm towards diabetes disease management. An innovative business model. AB - Dealing with a chronic disease and, more specifically, with Diabetes Mellitus and other metabolic disorders, represents a great challenge for care givers, patients and the healthcare systems as their treatment requires continuous medical care and patient self management. The engagement of patients in the adoption of healthy lifestyles with a positive impact in the progression of their diseases is fundamental to avoid the appearance of chronic complications or co-morbidities. This paper presents the externalization of the health management of diabetic patients as an alternative to the current models of care for these patients that can help improve the quality of follow up and care delivery and contribute to the sustainability of the healthcare systems. PMID- 22255108 TI - A fully integrated continuous-time 50-Hz notch filter with center frequency tunability. AB - A novel continuous-time notch filter based on current steering technique was described in this paper. The second-order notch filter consisted of two integrators, one unity-gain inverter and two alpha blocks that were fully integrated onto a silicon chip. The circuit was implemented in SMIC mixed-signal 0.18 nm 1P6M process with the die area of 0.06 mm(2). Post-annotated simulation indicated the continuous-time notch filter was capable of providing 55.4 dB attenuation for the 50 Hz power line interference and its center frequency was tunable against process variations. PMID- 22255109 TI - Improvement of fuzzy vault scheme for securing key distribution in body sensor network. AB - The security of Body Sensor Network (BSN) has become a vital concern, as the massive development of BSN applications in healthcare. A family of biometrics based security methods has been proposed in the last several years, where the bio information derived from physiological signals is used as entity identifiers (EIs) for multiple security purposes, including node recognition and keying material protection. Among them, a method named as Physiological Signal based Key Agreement (PSKA) was proposed to use frequency-domain information of physiological signals together with Fuzzy Vault scheme to secure key distribution in BSN. In this study, the PSKA scheme was firstly analyzed and evaluated for its practical usage in terms of fuzzy performance, the result of which indicates that the scheme is not as good as claimed. An improved scheme with the deployment of Fuzzy Vault and error correcting coding was then proposed, followed by simulation analysis. The results indicate that the improved scheme is able to improve the performance of Fuzzy Vault and thus the success rate of authentication or key distribution between genuine nodes of a BSN. PMID- 22255110 TI - Effect of gravity on learning and memory of prism adaptation. AB - Our body motion is adjusted properly under 1G on the earth. Thus changes in gravitational environment have significant impact on our motor control. Further, it may affect on our ability in motor learning and memory. Although some astronauts informally reported difficulties in their body control under microgravity, no quantitative research on this issue has been conducted. Here we performed the prism adaptation of a hand-reaching task under different gravitational environments. We compared learning and forgetting curves, and memory retention rates of the prism adaptation performed in upright vs. supine position under 1G, and those under 1G vs. 2G in upright position. We demonstrate that quicker learning, less forgetting and greater memory retention rates are obtained in supine position and under 2G in comparison with their counter part. PMID- 22255111 TI - Is the reduction of dimensionality to a small number of features always necessary in constructing predictive models for analysis of complex diseases or behaviours? AB - Gene expression and genome wide association data have provided researchers the opportunity to study many complex traits and diseases. When designing prognostic and predictive models capable of phenotypic classification in this area, significant reduction of dimensionality through stringent filtering and/or feature selection is often deemed imperative. Here, this work challenges this presumption through both theoretical and empirical analysis. This work demonstrates that by a proper compromise between structure of the selected model and the number of features, one is able to achieve better performance even in large dimensionality. The inclusion of many genes/variants in the classification rules can help shed new light on the analysis of complex traitstraits that are typically determined by many causal variants with small effect size. PMID- 22255112 TI - Data-driven prediction of stem cell expansion cultures. AB - Stem cell expansion culture aims to generate sufficient number of clinical-grade cells for cell-based therapies. One challenge for ex vivo expansion is to decide the appropriate time to perform subculture. Traditionally, this decision has been reliant on human estimation of cell confluency and predicting when confluency will approach a desired threshold. However, the use of human operators results in highly subjective decision-making and is prone to inter- and intra-operator variability. Using a real-time cell image analysis system, we propose a data driven approach to model the cell growth process and predict the cell confluency levels, signaling times to subculture. This approach has great potential as a tool for adaptive real-time control of subculturing, and it can be integrated with robotic cell culture systems to achieve complete automation. PMID- 22255113 TI - Modeling neuron-glia interactions: from parametric model to neuromorphic hardware. AB - Recent experimental evidence suggests that glial cells are more than just supporting cells to neurons - they play an active role in signal transmission in the brain. We herein propose to investigate the importance of these mechanisms and model neuron-glia interactions at synapses using three approaches: A parametric model that takes into account the underlying mechanisms of the physiological system, a non-parametric model that extracts its input-output properties, and an ultra-low power, fast processing, neuromorphic hardware model. We use the EONS (Elementary Objects of the Nervous System) platform, a highly elaborate synaptic modeling platform to investigate the influence of astrocytic glutamate transporters on postsynaptic responses in the detailed micro environment of a tri-partite synapse. The simulation results obtained using EONS are then used to build a non-parametric model that captures the essential features of glutamate dynamics. The structure of the non-parametric model we use is specifically designed for efficient hardware implementation using ultra-low power subthreshold CMOS building blocks. The utilization of the approach described allows us to build large-scale models of neuron/glial interaction and consequently provide useful insights on glial modulation during normal and pathological neural function. PMID- 22255114 TI - Quantitative analysis of viral persistence and transient viral load rebound from HIV clinical data. AB - Highly active antiretroviral therapy (HAART) suppresses HIV RNA viral load below the limit of detection for many patients. However, clinical data demonstrates that the HIV virus is not eradicated by HAART, even in patients who have had no detectable virus for 7 years [1]. One possible reason is that a stable resting latent reservoir with a long half-life exists in resting memory CD4(+)T cells [2]. In this paper, we propose a mathematical model with a constant contribution of a stable latent reservoir and identified this constant by using one patient's data from AutoVac HAART interruption study [3]. Many patients also have transient rebounds of plasma viral RNA (viral blips) under otherwise successful control of the virus by HAART. Activation of latently infected cells can explain these transient rebounds of viral load. Little quantitative analysis about the activation of reservoir has been done based on any clinical experiment data. Here, we model the activation dynamics of the reservoir by a time-independent activation rate and estimate this rate by using the clinical data from the AutoVac HAART interruption study [3]. PMID- 22255115 TI - PhenOMIM: an OMIM-based secondary database purported for phenotypic comparison. AB - Phenotypic comparison may provide crucial information for obtaining insights into molecular interactions underlying various diseases. However, few attempts have been made to systematically analyze the phenotypes of hereditary disorders, mainly owing to the poor quality of text descriptions and lack of a unified system of descriptors. Here we present a secondary database, PHENOMIM, for translating the phenotypic data obtained from the Online Mendelian Inheritance in Man (OMIM) database into a structured form. Moreover, a web interface has also been developed for visualizing the data and related information from the OMIM and PhenOMIM databases. The data is freely available online for reviewing and commenting purposes and can be found at http://faculty.neu.edu.cn/bmie/han/PhenOMIM/. PMID- 22255116 TI - Improving the bioactivity of bioglass/ (PMMA-co-MPMA) organic/inorganic hybrid. AB - Binary system of CaO-SiO(2) glasses enables the apatite formation in simulated body fluid (SBF). However, the presence of phosphate content in SiO(2)-CaO P(2)O(5) glasses leads to the formation of orthophosphate nanocrystalline nuclei, which facilitates the generation of carbonate hydroxyapatite; this compound is more compatible with natural bone. The brittle and less flexible properties of bioactive glasses are the major obstacle for their application as bone implant. The hybridization of essential constituents of bioactive glasses and glass ceramics with polymers such as PMMA can improve their poor mechanical properties. The aim of this study was to improve the bioactivity of nanocomposites fabricated from poly(methyl metacrylate) (PMMA) and bioglass for bone implant applications. Bioglass compounds with various phosphate contents were used for the preparation of PMMA/bioglass hybrid matrices. Since the lack of adhesion between the two phases impedes the homogenous composite formation, a silane coupling agent such as 3-(trimethoxysilyl)propyl methacrylates (MPMA) was incorporated into the polymer structure. The effect of addition of MPMA on the molecular structure of composite was investigated. Furthermore, the presence of MPMA in the system improved the homogeneity of sample. Increasing phosphate content in the inorganic segment of hybrid up to 10 mol% resulted in the formation of apatite layer on the surface; hence the hybrid was bioactive and suitable candidate for bone tissue engineering. PMID- 22255117 TI - Nanostructured, highly aligned poly(hydroxy butyrate) electrospun fibers for differentiation of skeletal and cardiac muscle cells. AB - The influence of novel nanostructured anisotropically electrospun poly(hydroxy butyrate) matrices on skeletal and cardiac muscle-like cell proliferation and differentiation was investigated, in comparison with isotropic and no topographically cues-provided substrates. After the matrix characterization, in terms of surface SEM imaging and mechanical properties, cell differentiation on the different substrates was evaluated. Myogenin and F-actin staining at several differentiation time-points suggested that aligned nanofibers promote differentiation of both cell types. Moreover, quantitative parameters for each cell line are provided to clarify which aspects of the differentiation process are influenced by the different matrix topographies. PMID- 22255118 TI - An implantable electrical bioreactor for enhancement of cell viability. AB - Low survival of injected cells which are prepared by ex-vivo culture is main obstacle in cell-based tissue regeneration. To elevate cell adaptation, we designed an implantable electrical bioreactor where human mesenchymal stromal cells (hMSCs) can be cultured and stimulated electrically. Bioreactor was composed of biocompatible cylindrical Teflon body containing a flexible polyimide electrode and implantable stimulator. The Teflon body has about 300 holes with a diameter of 300 um for effective nutrients supply inside the bioreactor and has a length of 17 mm and a diameter of 8mm for implantation. After hMSCs seeded on the collagen sponge that serves as scaffold to form a bone tissue graft, they are cultured in the bioreactor with biphasic electric current (BEC) stimulation. BEC stimulation with amplitude of 20/40 uA, duration of 100 us and a frequency of 100 Hz was applied for one week in the early stage of cultivation. Subsequently, after hMSCS were cultured for another week without electrical stimulation, cell response such as cell proliferation, cell attachment and gene expression are evaluated. In vitro and In vivo culture of hMSCs showed 19% and 22% increase in cell proliferation at stimulated groups, compared to unstimulated control. The expression of type I collagen increased significantly at stimulated group. These results suggest that the usage of implantable electrical bioreactor can be a good strategy to enhance the efficiency of stem cell-based tissue engineering. PMID- 22255119 TI - First human hNT astrocytes patterned to single cell resolution on parylene C/silicon dioxide substrates. AB - In our previous work we developed a successful protocol to pattern the human hNT neuron (derived from the human teratocarcinoma cell line (hNT)) on parylene C/SiO(2) substrates. This communication, reports how we have successfully managed to pattern the supportive cell to the neuron, the hNT astrocyte, on such substrates. Here we disseminate the nanofabrication, cell differentiation and cell culturing protocols necessary to successfully pattern the first human hNT astrocytes to single cell resolution on parylene-C/SiO(2) substrates. This is performed for varying parylene strip widths providing excellent contrast to the SiO(2) substrate and elegant single cell isolation at 10 MUm strip widths. The breakthrough in patterning human cells on a silicon chip has widespread implications and is valuable as a platform technology as it enables a detailed study of the human brain at the cellular and network level. PMID- 22255120 TI - Cell settling effects on a thermal inkjet bioprinter. AB - This paper seeks to quantify cell settling in the print media reservoir of a bioprinter in order to determine its effect on consistent cell delivery per printed drop. The bioprinter studied here is based on the thermal inkjet HP26A cartridge, but any system that dispenses controlled volumes of fluid may be affected similarly. A simple model based on Stokes' law suggests that the cell concentration in the bottom of the reservoir should increase linearly up to some maximum and that the cell concentration in the printed drops should follow this trend. The results show that cell output initially followed the predicted increasing trend, but then peaked and decreased. The timing and rate of the decrease related to the number of use cycles for the cartridges. The results provide guidance for modifications to the printing process to ensure consistent printing of cells. PMID- 22255121 TI - Microfabrication- and microfluidics-based patterning of cultured neuronal network. AB - The cultured neuronal monolayer has been a promising model system for studying the neuronal dynamics, from single cell to network-wide level. Randomness in the reconstituted network structure has, however, hindered regulated signal transmissions from one neuron to another or from one neuronal population to another. Applying microfabrication-based cell patterning techniques is a promising approach to handling these problems. In the present study, we attempt to regulate the direction of axon development and the pathway of signal transmissions in cultured neuronal networks using micro-fabrication and - fluidic techniques. We created a PDMS-based culture device, which consisted of arrays of U-shaped cell trapping microwells, and placed it onto a chemically micropatterned glass substrate. After 6 days in vitro, we confirmed that cortical neurons extended neurites along the medium flow direction and the micropatterned regions. PMID- 22255122 TI - A disease-centered approach to biomaterials education and medical device design. AB - This paper describes the development of a novel elective course in biomaterials which integrates clinical medicine with engineering principles. In this educational approach, students are first introduced to disease pathologies and clinical needs, and then exposed to engineering technologies that can fulfill unmet needs. The course is directed toward the question, "Where are clinical needs most urgent, and how can engineering be applied to meet those needs?" This clinically-oriented, disease-centered approach is valuable for science and engineering education, as it relays to students the centrality of engineering in solving the world's most pressing healthcare problems. PMID- 22255123 TI - Tsinghua-Johns Hopkins Joint Center for Biomedical Engineering Research: scientific and cultural exchange in undergraduate engineering. AB - A model for an international undergraduate biomedical engineering research exchange program is outlined. In 2008, the Johns Hopkins University in collaboration with Tsinghua University in Beijing, China established the Tsinghua Johns Hopkins Joint Center for Biomedical Engineering Research. Undergraduate biomedical engineering students from both universities are offered the opportunity to participate in research at the overseas institution. Programs such as these will not only provide research experiences for undergraduates but valuable cultural exchange and enrichment as well. Currently, strict course scheduling and rigorous curricula in most biomedical engineering programs may present obstacles for students to partake in study abroad opportunities. Universities are encouraged to harbor abroad opportunities for undergraduate engineering students, for which this particular program can serve as a model. PMID- 22255124 TI - Integrative learning through the design of an electrocardiogram acquisition system. AB - This paper presents an electrocardiogram acquisition system course design project for an upper year bioinstrumentation course. The objective of this design project is to provide students an opportunity for an integrative learning, enhancing their educational experience. Unlike similar electrocardiogram instrumentation projects, this project is based on a commercially available instrumentation amplifier enabling better systems-level thinking. The project is described along with observations made from our pilot implementation of the project. The initial offering of the project is considered a success with positive feedback from students. Recommendations for improvements are also discussed. PMID- 22255125 TI - Biomedical engineering education in developing countries: research synthesis. AB - Biomedical engineering (BME) contributes to development through improving human health. This paper examines BME education to address the needs of developing countries. Components of different BME programs described in the literature are synthesized to represent what has been proposed or implemented for the production of graduates able to address health problems in a manner suited to the local environment in which they occur. Published research on BME education is reviewed with reference to problem context, interventions and their mechanisms, and intended outcomes. PMID- 22255126 TI - The dilemma of BME research projects in developing countries: a case study. AB - Researchers are faced with huge challenges when undertaking BME research projects in developing countries. Various administrative, technical, economic and even cultural barriers have to be overcome whereas the quality and quantity of the output has to be comparable with the developed world in order to make results publishable. This paper uses a real project context to highlight the major problems and the necessity of a holistic approach which would take into consideration all stakeholders interests. It is only by tackling problems such as relationship between academia-industry and administration efficiency at their root that significant progress can be achieved. PMID- 22255127 TI - Design of a wearable physical activity monitoring system using mobile phones and accelerometers. AB - This paper describes the motivation for, and overarching design of, an open source hardware and software system to enable population-scale, longitudinal measurement of physical activity and sedentary behavior using common mobile phones. The "Wockets" data collection system permits researchers to collect raw motion data from participants who wear multiple small, comfortable sensors for 24 hours per day, including during sleep, and monitor data collection remotely. PMID- 22255128 TI - Real-time monitoring of occupational stress of nurses. AB - Prolonged exposure to stress has been associated with chronic diseases, depression, and immune disorders. Stress perception is highly subjective. Assessment of occupational stress requires personalized physiological monitoring and timely collection of individual characterization of sources of stress. We implemented a wearable system for monitoring of occupational stress of nurses- UAHealth. Personal monitors are implemented on iPhone smartphones with Ant+ wireless interface. Interbeat intervals are collected from a chest belt, and step count and cadence from foot pod sensor. All data are processed in real-time on the phone to assess stress index. A 30-minute personalized maximum over predefined threshold initiates a questionnaire to collect assessment of sources of stress. In this paper we present system organization and preliminary results. PMID- 22255129 TI - Smartphone-centred wearable sensors network for monitoring patients with bipolar disorder. AB - Bipolar Disorder is a severe form of mental illness. It is characterized by alternated episodes of mania and depression, and it is treated typically with a combination of pharmacotherapy and psychotherapy. Recognizing early warning signs of upcoming phases of mania or depression would be of great help for a personalized medical treatment. Unfortunately, this is a difficult task to be performed for both patient and doctors. In this paper we present the MONARCA wearable system, which is meant for recognizing early warning signs and predict maniac or depressive episodes. The system is a smartphone-centred and minimally invasive wearable sensors network that is being developing in the framework of the MONARCA European project. PMID- 22255130 TI - Wearable sensor systems: the challenges. AB - Given the soaring costs associated with the treatment of ever more prevalent chronic disease, it is widely agreed that a revolution is required in health care provision. It is often thought that the necessary technology already exists for the home-based monitoring of such patients and that it is other factors which are holding back the more widespread clinical uptake of these new tools. The authors suggest that the necessary sensor-related technologies are often not as advanced as may first appear; certainly they are generally not adequate for the robust, long-term monitoring of patients under real-life conditions. An additional problem is the evident efforts to apply a given sensor and related technology platform to any and all monitoring scenarios without sufficient consideration of patient needs and the clinical requirements. The authors review the key sensing platforms and suggest the applications for which they are best suited. PMID- 22255131 TI - Wrist actigraphy for scratch detection in the presence of confounding activities. AB - Scratching is a symptom of many dermatological disorders, especially atopic dermatitis. For the development of anti-itch medications, there is a need for objective measures of scratching. Wrist actigraphy (monitoring wrist and hand movements with micro-accelerometers) is a promising method for assessing scratching; however, currently available technology has a limited capacity to discriminate scratching from other similar movements. In this study, we investigated methods to improve the specificity of actigraphy for scratch detection on movement data collected from subjects using the PAM-RL actigraph. A k-means cluster analysis was used to differentiate scratching from walking and restless sleep, which are potential confounds for nighttime scratching. Features used in the analysis include variance, peak frequency, autocorrelation value at one lag, and number of counts above 0.01 g's. The k-means cluster analysis exhibited a high sensitivity (0.90 +/- 0.10) and specificity for walking (0.98 +/ 0.05) and restless sleep (0.88 +/- 0.06), respectively, demonstrating the separability of these activities. This work indicates that the features described here can be used to develop a classifier that discriminates scratch from other activities. The described method of scratch detection shows promise as an objective method for assessing scratching movements in clinical trials and longitudinal studies of scratch. PMID- 22255132 TI - Effects of BMI and abdominal volume on the accuracy of step count obtained from a tri-axial accelerometer. AB - Accelerometers are widely accepted as practical wearable devices capable of measuring and assessing physical activity. These devices may, however, be subject to errors which could impact on their ability to acquire an accurate step count. A limited number of studies have examined the effects of body mass index (BMI) on the accuracy of accelerometers functioning as step counters. It has been suggested that BMI may not be the best indicator of adiposity. The aim of the present study was to assess the effects of BMI and abdominal volume on the accuracy of a step count obtained from a tri-axial accelerometer. Accelerometers were placed directly onto the skin at the chest, waist and lower back of 12 participants. Participants then walked on a motorized treadmill at 0.89 m/s and 1.34 m/s. Analysis of the results indicated that BMI and abdominal volume did not affect the accuracy of the step count obtained from accelerometers under any conditions. Walking speed, however, had a significant effect with step count accuracy decreasing at the slower speed. PMID- 22255133 TI - Dielectric spectroscopy of molecular interactions based on the avidin-biotin complex. AB - Dielectric spectroscopy is used to probe the electrical properties of biomolecules dissolved in liquids. A 40 MUl cell is constructed out of acrylic with polished, stainless steel electrodes. Experiments are performed on avidin and biotin-labeled BSA, showing characteristics of aggregation. Experiments with avidin and biotin demonstrate shifts in dielectric relaxation of the avidin associated with changes in the dipole moment and size of the molecule due to biotin binding. These shifts are analyzed in the context of biomolecular changes. These experiments demonstrate the utility of impedance spectroscopy to detect changes due to small molecules binding to proteins. PMID- 22255134 TI - Discrimination and characterization of breath from smokers and non-smokers via electronic nose and GC/MS analysis. AB - The objective of this study was to prove the general applicability of an electronic nose for analyzing exhaled breath considering the dependency on smoking. At first, odor compounds from spices (n=6) were detected via the electronic nose and further characterized and classified with gas chromatography/ mass spectrometry to demonstrate the principle ability of the electronic nose. Then, the exhaled breath from smokers and non-smokers were analyzed to prove the influence of smoking on breath analyses with the electronic nose. The exhaled breath was sampled from 11 smokers and 11 non-smokers in a special sampling bag with the mounted sensor chip of the electronic nose. Additionally, solid phase micro-extraction (SPME) technique was established for detection of the specific chemical compounds with gas chromatography and mass spectrometry (GC/MS). For analyses of the sensor signals the principle component analysis (PCA) was applied and the groups were differentiated by linear discriminant function analysis. In accordance to the discrimination between the different spices and between smokers and non-smokers the PCA analysis leads to an optimum accuracy of 100%. The results of this study show that an electronic nose has the ability to detect different changes of odor components and provides separation of smoking side effects in smelling different diseases. PMID- 22255135 TI - A point-of-care instrument for rapid multiplexed pathogen genotyping. AB - We are leveraging recent advances in rapid nucleic acid amplification chemistries, self-powered microfluidics, and low-cost optoelectronics to develop instrumentation for pathogen genotyping in the developing world. A growing number of correlations are emerging between genetic mutations in pathogens and their infectivity, origin, and drug resistance. Particularly for diseases like tuberculosis, where multi-drug resistance is a growing concern, a rapid diagnostic which could inform prescription decisions for newly diagnosed patients would not only save lives and reduce prolonged sickness but would help slow the emergence of more virulent strains. Additionally, for pathogens such as HIV, there is a need for new assay formats which can inexpensively and quantitativly monitor pathogen load. We have developed a portable instrument which uses disposable microfluidic assay cartridges pre-loaded with lyophilized reagents for genetic amplification of multiple markers. The cartridges can be adapted for a variety of sample types (blood, sputum, saliva). The instrument controls assay temperature and quantitatively monitors real-time fluorescence signals from 96 individual reaction chambers. The platform can be tailored for different economic situations--from a quantitative electronic readout to a simple binary readout with the naked eye. PMID- 22255136 TI - Raman based hepatocellular carcinoma biomarker detection. AB - Highly sensitive and selective biomarker detection is required for early detection of hepatocellular carcinoma (HCC). Disease progression has been shown to correlate with specific fucosylation of a validated HCC serum glycoprotein biomarker, alpha-fetoprotein (AFP) Carbohydrate binding proteins, such as lectins, can be used as diagnostic indicators for monitoring glycosylation changes during disease progression in hepatitis B virus (HBV) or hepatitis C virus (HCV) infected patients. We prepared surface-enhanced Raman spectroscopy (SERS) substrates, which provide controllable, well-organized nanoparticles on the surface, for the analysis of a fucose binding lectin AAL. The SERS based assay provides fast (<10 s), and reproducible (<5% variation) detection. PMID- 22255137 TI - Development of a Point-of-Care device to quantify serum zinc to aid the diagnosis and follow-up of pediatric septic shock. AB - In the Unites States Pediatric septic shock is a major health problem with about 42,000 cases per y ear and a mortality rate of about 10% [1]. Studies have indicated that children with pediatric septic shock have demonstrated critically low levels of serum z inc (Zn) and supplementation of Zn is being suggested as a therapeutic strategy. However, to protect patient safety, it is vital that Z n levels be monitored during supplementation to insure the Zn concentration levels remain at or near physiologic normal levels. Currently Atomic Absorption Spectroscopy (AAS) is used to quantify Zn levels in serum samples. Unfortunately, AAS frequently involves sending serum samples to external laboratory facilities which yields measurement turnaround time that range from hours to days. Thus, timely monitoring of Zn levels is critical to preventing over supplementation that could result in critical conditions such as heavy metal (Zn) toxicity. This paper reports on the development of a Point-of-Care device for rap id electrochemical measurement of Zn. The prototype device is able to accurately quantify Zn in serum with a turn-around time of about 30 minutes. The devices is based on a three electrode sensor which uses Anodic stripping voltammetry (ASV) for sensing Zn levels. The ASV electrode sensor is read using a reader that has be en developed using commercially available embedded system components and custom analog circuitry. PMID- 22255138 TI - Out-of-plane, high strength, polymer microneedles for transdermal drug delivery. AB - This paper reports on the high strength of high-aspect ratio (> 50) hollow, polymer microneedles fabricated out-of-plane using a fairly repeatable fabrication process. Further, these microneedle tips were sharpened by a molding principle, with a simple anisotropic etch of silicon wafer. Also, an enhanced elegant process was explored to incorporate the mounting of the microneedle onto a platform without using any additional material, such that the bore of the microneedle is continuous with the bore of the platform in order to facilitate microfluidic delivery through the hollow needles. The high aspect ratio microneedles undergo failure at the critical load of around 4 N, while the insertion force for such a needle into agar gel, which is a fairly good equivalent of the human skin due to its inherent visco-elastic properties, is 7 mN, which translates into a safety factor (ratio of critical loading force to the maximum applied force) of greater than 500 thus, making it adequately strong for skin penetration. PMID- 22255139 TI - A vision-free brain-computer interface (BCI) paradigm based on auditory selective attention. AB - Majority of the recently developed brain computer interface (BCI) systems have been using visual stimuli or visual feedbacks. However, the BCI paradigms based on visual perception might not be applicable to severe locked-in patients who have lost their ability to control their eye movement or even their vision. In the present study, we investigated the feasibility of a vision-free BCI paradigm based on auditory selective attention. We used the power difference of auditory steady-state responses (ASSRs) when the participant modulates his/her attention to the target auditory stimulus. The auditory stimuli were constructed as two pure-tone burst trains with different beat frequencies (37 and 43 Hz) which were generated simultaneously from two speakers located at different positions (left and right). Our experimental results showed high classification accuracies (64.67%, 30 commands/min, information transfer rate (ITR) = 1.89 bits/min; 74.00%, 12 commands/min, ITR = 2.08 bits/min; 82.00%, 6 commands/min, ITR = 1.92 bits/min; 84.33%, 3 commands/min, ITR = 1.12 bits/min; without any artifact rejection, inter-trial interval = 6 sec), enough to be used for a binary decision. Based on the suggested paradigm, we implemented a first online ASSR based BCI system that demonstrated the possibility of materializing a totally vision-free BCI system. PMID- 22255140 TI - Accuracy of a BCI based on movement-related and error potentials. AB - New paradigms for brain computer interfacing (BCI), such as based on imagination of task characteristics, require long training periods, have limited accuracy, and lack adaptation to the changes in the users' conditions. Error potentials generated in response to an error made by the translation algorithm can be used to improve the performance of a BCI, as a feedback extracted from the user and fed into the BCI system. The present study addresses the inclusion of error potentials in a BCI system based on the decoding of movement-related cortical potentials (MRCPs). We theoretically quantify the improvement in accuracy of a BCI system when using error potentials for correcting the output decision, in the general case of multiclass classification. The derived theoretical expressions can be used during the design phase of any BCI system. They were applied to experimentally estimated accuracies in decoding MRCPs and error potentials. The average misclassification rate (n = 6 subjects) of MRCPs associated to the imagination of elbow flexions at two speeds was 26%, with a bit transfer rate of 0.17. The inclusion of error potentials, experimentally recorded and classified with misclassification rate of 20%, led to a theoretical error rate of 14% with a bit transfer rate of 0.30. PMID- 22255141 TI - Revealing the neural response to imperceptible peripheral flicker with machine learning. AB - Lighting in modern-day devices is often discrete. The sharp onsets and offsets of light are known to induce a steady-state visually evoked potential (SSVEP) in the electroencephalogram (EEG) at low frequencies. However, it is not well-known how the brain processes visual flicker at the threshold of conscious perception and beyond. To shed more light on this, we ran an EEG study in which we asked participants (N=6) to discriminate on a behavioral level between visual stimuli in which they perceived flicker and those that they perceived as constant wave light. We found that high frequency flicker which is not perceived consciously anymore still elicits a neural response in the corresponding frequency band of EEG, con-tralateral to the stimulated hemifield. The main contribution of this paper is to show the benefit of machine learning techniques for investigating this effect of subconscious processing: Common Spatial Pattern (CSP) filtering in combination with classification based on Linear Discriminant Analysis (LDA) could be used to reveal the effect for additional participants and stimuli, with high statistical significance. We conclude that machine learning techniques are a valuable extension of conventional neurophysiological analysis that can substantially boost the sensitivity to subconscious effects, such as the processing of imperceptible flicker. PMID- 22255142 TI - Sensor-fault tolerant control of a powered lower limb prosthesis by mixing mode specific adaptive Kalman filters. AB - Machine learning methods for interfacing humans with machines is an emerging area. Here we propose a novel algorithm for interfacing humans with powered lower limb prostheses for restoring control of naturalistic gait following amputation. Unlike most previous neural machine interfaces, our approach fuses control information from the user with sensor information from the prosthesis to approximate the closed loop behavior of the unimpaired sensorimotor system. We present a Bayesian framework to control an artificial knee by probabilistically mixing of process state estimates from different Kalman filters, each addressing separate regimes of locomotion such as level ground walking, walking up a ramp, and walking down a ramp. We show its utility as a mode classifier that is tolerant to temporary sensor faults which are frequently experienced in practical applications. PMID- 22255143 TI - A pilot study on two stage decoding strategies. AB - Brain-machine interfaces (BMIs) use neural activity related to motion parameters to enable brain directly control external devices. Some linear and nonlinear decoding techniques have been used successfully to infer arm trajectory from neural data. Unfortunately, these One stage decoding techniques can hardly get high accuracy and low computational demands at the same time. Here we introduce a Two Stage Model (TSM) which consists of two linear models, on the basis that different motion states have different neural firing patterns when rats were doing the lever pressing task. The accuracies of the neural firing patterns classification were higher than 90% for all the three datasets. The Correlation coefficients (CC) between the trajectory predicted by TSM and the measured one were up to 0.89, 0.85 and 0.95 for the three datasets respectively higher than those of Kalman Filter (KF) and Partial Least Squares Regression (PLSR). The time consumption of TSM was about only 10% of that of Generalized Regression Neural Network (GRNN). These results show that TSM can simultaneously get both high accuracy and low computational cost. PMID- 22255144 TI - Matched subspace detector based feature extraction for sorting of multi-sensor action potentials. AB - This paper proposes a novel matched subspace detector (MSD) based algorithm for extracting discriminant features from multi-sensor measurements of extracellular action potentials (APs) to facilitate their subsequent separation according to the neuron of origin. The method does not require the construction of AP templates, and is therefore suitable for unsupervised AP sorting applications. In addition, detailed simulations show that the proposed algorithm outperforms existing single-sensor based feature extraction approaches. PMID- 22255145 TI - Using semantic web technologies to manage complexity and change in biomedical data. AB - Data in biomedicine are characterised by their complexity, volatility and heterogeneity. It is these characteristics, rather than size of the data, that make managing these data an issue for their analysis. Any significant data analysis task requires gathering data from many places, organising the relationships between the data's entities and overcoming the issues of recognising the nature of each entity such that this organisation can take place. It is the inter-relationship of these data and the semantic confusion inherent in the data that make the data complex. On top of this we have volatility in the domain's data, knowledge and experimental techniques that make the processing of data from the domain a distinct challenge, even before those data are organised. In this article we describe these challenges with respect to a project that is using data mining techniques to analyse data from the kidney and urinary pathway (KUP) domain. We are using Semantic Web technologies to manage the complexity and change in our data and we report on our experiences in this project. PMID- 22255146 TI - Modeling signaling pathways in articular cartilage. AB - Chondrocytes, the only cell type in articular cartilage, are responsible for maintaining the composition of cartilage extracellular matrix (ECM) through a complex interplay of anabolic and catabolic stimuli. Although understanding the way chondrocytes respond to stimuli is of utmost importance for shedding light into the etiology of joint diseases, an integrative approach to studying their signaling transduction mechanisms is yet to be introduced. Herein, we propose an approach that combines high throughput proteomic measurements and state of the art optimization algorithms to construct a predictive model of chondrocyte signaling network, downstream of 78 receptors of interest. PMID- 22255147 TI - Unifying the integration, analysis and interpretation of multi-omic datasets: exploration of the disease networks of Obstructive Nephropathy in children. AB - The wealth of data amassed by the utilization of various high-throughput techniques, in various layers of molecular dissection, stresses the critical role of the unification of the computational methodologies applied in biological data handling, storage, analysis and visualization. In this article, a generic workflow is showcased in a multi-omic dataset that is used to study Obstructive Nephropathy (ON) in children, integrating microarray data from several biological layers (transcriptomic, post-transcriptomic, proteomic). The workflow exploits raw measurements and through several analytical stages (preprocessing, statistical and functional), which entail various parsing steps, reaches the visualization stage of the heterogeneous, broader, molecular interacting network derived. This network, where the interconnected entities are exploiting the knowledge stored in public repositories, represents a systems level interpretation of the pathological state probed. PMID- 22255148 TI - Statistical data mining of streaming motion data for fall detection in assistive environments. AB - The analysis of human motion data is interesting for the purpose of activity recognition or emergency event detection, especially in the case of elderly or disabled people living independently in their homes. Several techniques have been proposed for identifying such distress situations using either motion, audio or video sensors on the monitored subject (wearable sensors) or the surrounding environment. The output of such sensors is data streams that require real time recognition, especially in emergency situations, thus traditional classification approaches may not be applicable for immediate alarm triggering or fall prevention. This paper presents a statistical mining methodology that may be used for the specific problem of real time fall detection. Visual data captured from the user's environment, using overhead cameras along with motion data are collected from accelerometers on the subject's body and are fed to the fall detection system. The paper includes the details of the stream data mining methodology incorporated in the system along with an initial evaluation of the achieved accuracy in detecting falls. PMID- 22255149 TI - EEG complexity drug-induced changes in disorders of consciousness: a preliminary report. AB - The goal of this work is to investigate EEG (ElectroEncephaloGram) dynamics after drug intake in patients being in states of Disorders Of Consciousness (DOC) after brain injury. Four patients were involved in the study. All the patients exhibit cerebral lesions located in the same anatomical region. Two nonlinear indexes, such as Lempel-Ziv Complexity (LZC) and Approximate Entropy (ApEn), along with power spectra, were calculated for EEG signals gathered from electrodes placed on both injured and non-injured regions. Experimental results show that after drug administration the two nonlinear indexes calculated from EEG taken from injured regions increase (p < 0.001) while power spectra decrease or remain unchanged. These results do not pretend to draw conclusions about consciousness level either suggest promising therapeutical treatments, but represent only an experimental evidence about the change in the EEG complexity after drug administration. PMID- 22255150 TI - Recursive least squares estimation of nonlinear multiple-input systems using orthonormal function expansions. AB - We present a computational scheme to obtain adaptive non-linear, multiple-input models of the Volterra-Wiener class, by utilizing function expansions of the Volterra kernels in a recursive least-squares formulation. Function expansions have been proven successful in linear and nonlinear systems identification as they result in a significant reduction of the required free parameters, which is a major limiting factor particularly for nonlinear systems, whereby this number depends exponentially on the nonlinear system order. We illustrate the performance of the proposed scheme by presenting results for a simulated linear two-input system with time-varying characteristics. PMID- 22255151 TI - Four-dimensional MR cardiovascular imaging: method and applications. AB - Magnetic resonance imaging (MRI) has long been recognized as a powerful tool for cardiovascular imaging because of its unique potential to measure blood flow, cardiac wall motion and tissue properties jointly. However, many clinical applications of cardiac MRI have been limited by low imaging speed. Three dimensional cardiovascular MRI in real-time, or 4D cardiovascular MRI without cardiac and respiratory gating or triggering, remains an important technological goal of the MR cardiovascular research community. In this paper, we present a novel technique to achieve 4D cardiovascular MR imaging in unprecedented spatiotemporal resolution. This breakthrough is made possible through a creative use of sparse sampling theory and parallel imaging with phased array coils and a novel implementation of data acquisition and image reconstruction. We have successfully used the technique to perform 4D cardiovascular imaging on rats, achieving 0.65 mm * 0.65 mm * 0.31 mm spatial resolution with a frame rate of 67 fps. This capability enables simultaneous imaging of cardiac motion, respiratory motion, and first-pass myocardial perfusion. This in turn allows multiple cardiac assessments including measurement of ejection fraction, cardiac output, and myocardial blood flow in a single experiment. We believe that the proposed technique can open up many important applications of cardiovascular imaging and have significant impact on the field. PMID- 22255152 TI - Compressive sensing imaging with randomized lattice sampling: applications to fast 3D MRI. AB - Fast MRI makes it possible to visualize dynamic biological phenomena and can potentially reduce the cost of diagnostic imaging. Constrained imaging methods such as compressive sense (CS) and optimal lattice sampling (OLS) have proven to be effective for speeding up MRI. In doing so, CS takes advantage of the image sparsity or compressibility and OLS utilizes the known signal/spectrum support. Interestingly, while CS requires sampling to be "randomized" to obtain incoherent artifacts which is critical for reconstruction, OLS mandates sampling to be on a structured lattice. In this paper, we proposed a method to integrate CS with OLS so that both the sparsity and support constraints can be used simultaneously. The method randomizes the sampling on the lattice and minimizes a convex cost function with sparsity constraint and data fidelity terms. Computer simulations in 3D MRI show that the proposed method allows greater accelerations with minimal degradation of the image quality. PMID- 22255153 TI - Adapting magnetic resonance imaging performance using nonlinear encoding fields. AB - Nonlinear spatial encoding fields for magnetic resonance imaging (MRI) hold great promise to improve on the linear gradient approaches. Unlike the linear techniques, the nonlinear encoding leads to a spatially varying signal-to-noise ratio (SNR). This paper demonstrates the possibility to tailor the encoding fields to focus the high SNR areas to a region of interest. To achieve this, a metric is derived to quantify the spatially dependent performance for arbitrary encoding schemes. PMID- 22255154 TI - A joint acquisition-reconstruction paradigm for correcting inhomogeneity artifacts in MR echo planar imaging. AB - One of the main sources of signal degradation in rapid MR acquisitions, such as Echo Planar Imaging (EPI), is magnetic field variations caused by field inhomogeneities and susceptibility gradients. If unaccounted for during the reconstruction process, this spatially-varying field can cause severe image artifacts. In this paper, we show that correcting for the resulting degradations can be formulated as a blind image deconvolution problem. We propose a novel joint acquisition-processing paradigm to solve this problem. We describe a practical implementation of this paradigm using a multi-image acquisition strategy and a corresponding joint estimation-reconstruction algorithm. The estimation step computes the spatial distribution of the field maps, while the reconstruction step yields a Minimum Mean Squared Error (MMSE) estimate of the imaged slice. Our simulations show that this proposed joint acquisition reconstruction method is robust and efficient, offering factors of improvement in the quality of the reconstructed image as compared to other traditional methods. PMID- 22255155 TI - Adaptive sampling design for compressed sensing MRI. AB - Compressed Sensing (CS) takes advantage of the sparsity of MR images in certain bases or dictionaries to obtain accurate reconstructions from undersampled k space data. The (pseudo) random sampling schemes used most often for CS may have good theoretical asymptotic properties; however, with limited data they may be far from optimal. In this paper, we propose a novel framework for improved adaptive sampling schemes for highly undersampled CS MRI. While the proposed framework is general, we apply it with a recently proposed MRI reconstruction algorithm employing adaptive image-patch based sparsifying dictionaries. Numerical experiments demonstrate up to 7 dB improvements in reconstruction PSNR using the adapted sampling scheme, on top of the large improvements reported in our previous work for the adaptive patch-based reconstruction scheme over analytical sparsifying transforms. PMID- 22255156 TI - The validation of complete Fourier direct MR method for diffusion MRI via biological and numerical phantoms. AB - The equations of the Complete Fourier Direct (CFD) MR model are explicitly derived for diffusion weighted NMR experiments. The CFD-MR theory is validated by comparing a biological phantom constructed from nerve bundles and agar gel with its numerical implementation. The displacement integral distribution function estimated from the experimental data is in high agreement with the numerical phantom. CFD-MR's ability to estimate accurately and fully spin diffusion properties demonstrated here, provides the experimental validation of the theoretical CFD-MR model. PMID- 22255157 TI - Robust adaptive feedback canceller based on modified pseudo affine projection algorithm. AB - This paper presents an adaptive feedback cancellation (AFC) algorithm with robust and stable performance. The proposed algorithm is based on the pseudo affine projection (PAP) algorithm which approximates the affine projection (AP) with a complexity comparable to the NLMS. Direct application of the PAP to AFC, however, often exhibits instability because of the delayed estimate of the linear prediction (LP) coefficients. This problem is solved in the proposed algorithm by utilizing an inverse gain filter (IGF) before the update of adaptive filter and by estimating the LP coefficients from the input signal without delay. Simulation results confirmed robustness and stability of the proposed algorithm. PMID- 22255158 TI - Reconstruction of ECG signals in presence of corruption. AB - We present an approach to identifying and reconstructing corrupted regions in a multi-parameter physiological signal. The method, which uses information in correlated signals, is specifically designed to preserve clinically significant aspects of the signals. We use template matching to jointly segment the multi parameter signal, morphological dissimilarity to estimate the quality of the signal segment, similarity search using features on a database of templates to find the closest match, and time-warping to reconstruct the corrupted segment with the matching template. In experiments carried out on the MIT-BIH Arrhythmia Database, a two-parameter database with many clinically significant arrhythmias, our method improved the classification accuracy of the beat type by more than 7 times on a signal corrupted with white Gaussian noise, and increased the similarity to the original signal, as measured by the normalized residual distance, by more than 2.5 times. PMID- 22255159 TI - Stability analysis of QRS features to evaluate signal quality for multi-lead QRS dectection. AB - In automated ECG monitoring, QRS detection performance is dependent on noise measurements on individual leads. A new signal quality measurement based on stability analysis of QRS complex features has been developed to assess individual ECG lead quality. The new method was evaluated on the records of the MIT-BIH arrhythmia and NST databases. Results showed that the new signal quality measurement can be used to accurately assess ECG signal quality and can be easily incorporated into an existing multi-lead QRS detection algorithm for performance improvement. PMID- 22255160 TI - Person identification in irregular cardiac conditions using electrocardiogram signals. AB - This paper presents a person identification mechanism in irregular cardiac conditions using ECG signals. A total of 30 subjects were used in the study from three different public ECG databases containing various abnormal heart conditions from the Paroxysmal Atrial Fibrillation Predicition Challenge database (AFPDB), MIT-BIH Supraventricular Arrthymia database (SVDB) and T-Wave Alternans Challenge database (TWADB). Cross correlation (CC) was used as the biometric matching algorithm with defined threshold values to evaluate the performance. In order to measure the efficiency of this simple yet effective matching algorithm, two biometric performance metrics were used which are false acceptance rate (FAR) and false reject rate (FRR). Our experimentation results suggest that ECG based biometric identification with irregular cardiac condition gives a higher recognition rate of different ECG signals when tested for three different abnormal cardiac databases yielding false acceptance rate (FAR) of 2%, 3% and 2% and false reject rate (FRR) of 1%, 2% and 0% for AFPDB, SVDB and TWADB respectively. These results also indicate the existence of salient biometric characteristics in the ECG morphology within the QRS complex that tends to differentiate individuals. PMID- 22255162 TI - Detection of circaseptan rhythm and the "Monday effect" from long-term pulse rate dynamics. AB - This study proposes a methodology to detect circaseptan (CS) rhythm in pulse rate (PR) data and to investigate the "Monday effect" in CS rhythm. Daily PR was collected from a middle-aged healthy working woman over one year. PR, SDNN index and sample entropy (SampEn) were chosen as the indexes of PR dynamics. In order to avoid interference from other biorhythms, ensemble empirical mode decomposition (EEMD) method was used to decompose the original PR series into multiple components. And the single cosinor method was applied to fit the detrended component signal. An optimal 7-day period was found in all indexes (P = 0.0103, P = 0.0133, P = 0.0122 for PR, SDNN index and SampEn, separately) that demonstrated an underlying CS rhythm. In the following study, a statistical Monday decrease in PR dynamics was observed especially significant in the detrended signal. The results suggested a direct relationship between the "Monday effect" and the CS variation, and also indicated a cardiac susceptibility to the social activities. The findings in CS periodicity and the "Monday effect" may help understand the human's biorhythm, provide evidence for preventive and optimized timing treatment, and also serve to daily health management. PMID- 22255161 TI - Heart rate variability analysis for arterial hypertension etiological diagnosis during surgical procedures under tourniquet. AB - Pneumatic tourniquets are widely used to provide a bloodless operative field during upper or lower limb surgery. If tourniquet inflation during general anesthesia is initially a mild stimulus, a long duration of inflation can imply heart rate and blood pressure increasing. However, heart rate or blood pressure increasing can also be caused by other external stimuli. Indeed, in the case of an insufficient analgesia, painful surgical stimuli can also cause an increase in heart rate and blood pressure. Therefore, in the case of the use of a tourniquet during surgery, it's very difficult for the anesthesiologist to distinguish hypertension caused by pain from hypertension caused by tourniquet inflation. In such a case, an efficient and reliable hypertension diagnosis could help the anesthesiologist in the medication choice. We have previously developed and evaluated an Analgesia / Nociception Index (ANI) based on the magnitude analysis of the respiratory patterns on the RR series. We hypothesize that the use of such an index could help in the arterial hypertension etiological diagnosis during surgical procedures under tourniquet. PMID- 22255163 TI - Analysis of the vascular sounds of the arteriovenous fistula's anastomosis. AB - In this paper, the vascular sounds of the arteriovenous fistula at the anastomosis and five centimeters downstream the anastomosis were analyzed. The analysis of the sounds was based on features extracted from the power spectral density (PSD) and wavelet decomposition. The database consists of 15 recordings at the anastomosis and 15 reference recordings obtained from 15 patients. The results showed that the vascular sounds at the anastomosis can be characterized as an extra energy in the higher frequencies (200-1000 Hz) i.e. higher mean frequency of the PSD than the reference recordings. Moreover, the wavelet decomposition of the anastomosis recordings showed a similar energy pattern, in the finer scales, to that found in studies of arterial and venous stenosis. PMID- 22255164 TI - Estimation of baroreflex sensitivity during anesthesia induction with propofol. AB - This paper presents the analysis of the autonomic nervous system (ANS) control and cardiac baroreflex sensitivity in patients undergoing general anesthesia for major surgery, with the goal of evaluating the effects of anesthesia bolus induction with propofol on autonomic control of heart rate (HR) and arterial blood pressure (ABP). The increase in baroreflex gain in the LF band observed through two different methods hints at the fact that the baroreflex may increase heart period (HP) following a transient ABP decrease, but its response displays a larger amplitude, to compensate for the blunting of the sympathetic action on heart rate and vascular resistance. PMID- 22255165 TI - Plateau waves and baroreflex sensitivity in patients with head injury: a case study. AB - The study aimed to investigate baroreceptor reflex sensitivity in a patient with head injury for whom plateau waves of intracranial pressure (ICP) were recorded. Baroreflex sensitivity index was separately estimated on top of plateau waves and during intermediate intervals between two consecutive waves. The EuroBaVar data set was utilized to verify and validate the results. A very high baroreflex sensitivity associated with dominant parasympathetic activity was observed spontaneous to the acute elevations of ICP. The high vagal afferent discharge was found to be suggestive for the high firing rate of carotid baroreceptors and probably an active Cushing reflex mechanism during plateau waves. PMID- 22255166 TI - Investigation of parameters highlighting drug induced small changes of the T wave's morphology for drug safety studies. AB - In guideline E14, the American Food and Drug Administration (FDA) requests for clinical studies to investigate the prolongation of the heart rate corrected QT interval (QTc) of the ECG. As drug induced QT-prolongation can be caused by changes in the repolarisation of the ventricles, it is so far a thorough ECG biomarker of risk for ventricular tachyarrhythmias and Torsade de Pointes (TdP). Ventricular repolarisation changes not only change QT but also influence the morphology of the T-wave. In a (400 mg single dose) Moxifloxacin positive control study both, QTc and several descriptors describing the T-wave morphology have been measured. Moxifloxacin is changing two shape dependent descriptors significantly (P<0.05) about 3 to 4 hours after a 400 mg oral single dose of Moxifloxacin. PMID- 22255167 TI - Effects of lead spatial resolution on the spectrum of cardiac signals: a simulation study. AB - Spectral analysis is widely applied to bioelectric cardiac signals for quantifying the spatiotemporal organization of cardiac tissue. Nevertheless, to date it is not well understood how lead characteristics affect the spectrum of recorded cardiac signals and, as a consequence, the interpretation of cardiac spectrum is still controversial. In this paper we use simulation methods to investigate the effects of lead spatial resolution on the spectrum of cardiac signals. We simulate three cardiac rhythms of different degrees of spatiotemporal organization in a square sample of cardiac tissue. Then, by using a lead field approach, we synthesize the signals recorded by four idealized leads of different spatial resolution. Finally, we estimate the spectrum of simulated cardiac signals. Our simulations indicate that lead spatial resolution affects cardiac spectrum, although the effects depend on the organization of the underlying rhythm. Specifically, our simulations show that for highly organized rhythms, the smaller the lead resolution region, the broader the distribution of power in frequency. Since lead resolution can affect significantly cardiac spectrum, we conclude that caution should be used when quantifying cardiac spatiotemporal organization based on the spectrum of cardiac signals. PMID- 22255168 TI - A point process model of respiratory dynamics in early physiological development. AB - Interbreath interval (IBI), the time interval between breaths, and its variations in time around the mean, the IBI variability, are important measures associated with irregularity of breathing. The IBI histogram generally follows a power law distribution with its characterizing parameters changing with maturation. To assess the dynamics of breathing we propose a point process model of IBI with a lognormal parametric structure to appropriately represent the stochastic nature of the IBI distribution. We estimate the time varying evolution of the characterizing parameters to represent the dynamic nature of breathing, and thereby provide a time-varying measure of irregularity in breathing. The reliability of the model to capture the data is assessed using Kolmogorov-Smirnov (KS) and independence tests. Our results validate the novel approach in the assessment of the irregularity of breathing by analyzing respiratory recordings from newborn rats and preterm infants. PMID- 22255169 TI - Noninvasive method for measuring respiratory system compliance during pressure support ventilation. AB - PURPOSE: To date, few methods have been accepted for assessing the respiratory system compliance (C(rs)) in patients under assisted ventilation at the bedside. The aim of this study was to evaluate our adaptive time slice method (ATSM) to continuously calculate the C(rs). METHODS: One breath is divided into several time periods (slices). For each slice, a compliance value C(i) is calculated. The slice width is adapted according to the confidence interval of C(i). After all C(i) values are obtained and the outliers are eliminated, the C(rs) of this breath is calculated as the mean value of the remainder of C(i)'s. Seven patients with Chronic Obstructive Pulmonary Disease were evaluated during pressure support ventilation. The results are compared with the values calculated with the transdiaphragmatic pressure (P(di)). RESULTS: 95 +/- 4% of the recorded data could be analyzed with ATSM. In 6 patients out of 7, the results delivered with ATSM and with P(di) had similar variation (standard deviation) and accuracy (difference<20%). They were strongly correlated (weighted correlation coefficient = 0.86, p<10(-5)) with a mean difference of 3.22 ml/mbar. CONCLUSIONS: The ATSM is a robust method and able to provide accurate C(rs) in spontaneously breathing patients during pressure support ventilation noninvasively without extra instrumentation or complicated maneuvers. PMID- 22255170 TI - Quantifying respiratory variation with force sensor measurements. AB - Measuring the variation of the respiratory rate makes it possible to analyze the structure of sleep. The variation is high when awake or in REM sleep, and decreases in deep sleep. With sleep apnea, the respiratory variation is disturbed. We present a novel method for extracting respiratory rate variation from indirect measurements of respiration. The method is particularly suitable for force sensor signals, because, in addition to the respiratory phenomenon, they typically contain also other disturbing features, which makes the accurate detection of the respiratory rate difficult. Respiratory variation is calculated by low-pass filtering a force sensor signal at different cut-off frequencies and, at every time instant, selecting one of them for the determination of respiration cycles. The method was validated with a single-night reference recording, which showed that the proposed method detects the respiratory variation accurately. Of the 3421 calculated respiration cycle lengths, 95.9% were closer than 0.5 seconds to the reference. PMID- 22255172 TI - Evaluation of the respiratory muscles efficiency during an incremental flow respiratory test. AB - The aim of this study was to evaluate the respiratory muscles efficiency during a progressive incremental flow (IF) respiratory test in healthy and Chronic Obstructive Pulmonary Disease (COPD) subjects. To achieve this, the relationship between mouth Inspiratory Pressure (IP) increment, which is a measure of the force produced by respiratory muscles, and respiratory muscular activity increment, evaluated by means of Mechanomyografic (MMG) signals of the diaphragm muscle, was analyzed. Moreover, the correlation between the respiratory efficiency measure and the obstruction severity of the subjects was also examined. Data from two groups of subjects were analyzed. One group consisted of four female subjects (two healthy subjects and two moderate COPD patients) and the other consisted of ten male subjects (six severe and four very severe COPD patients). All subjects performed an easy IF respiratory test, in which small IP values were reached. We have found that there is an increase of amplitude and a displacement towards low frequencies in the MMG signals when the IP increases. Furthermore, it has also been found that respiratory muscles efficiency is lower when greater the obstructive severity of the patients is, and it is lower in women than in men. These results suggest that the information provided by MMG signals could be used to evaluate the muscular efficiency in healthy and COPD subjects. PMID- 22255171 TI - Unobtrusive in-home assessment by means of everyday computer mouse usage. AB - An important component of future proactive healthcare is the detection of changes in the individual's physical or cognitive performance, especially for aging and for those with neurodegenerative diseases. For a variety of reasons, the current techniques for neuropsychological assessment are not suitable for continuous monitoring and assessment. This paper proposes a technique for continuous monitoring of behaviors that could potentially be used to complement the traditional assessment techniques. In particular we monitor the movements of a computer pointing device (mouse) to assess cognitive and sensory-motor functionality of human users unobtrusively. The focus of this paper is on an approach that can be used to identify moves so that they can later be used as the basis for constructing sensory-motor measures. Due to the nature of the data the distinction between moves and pauses between moves is not immediately apparent. The segmentation of the data into moves is done by constructing an estimated distribution of the mouse cursor velocity for the entire computer session and locating a particular minimum which indicates a likely point of division between active moves and inter-move intervals. We analyzed computer usage data for 113 elderly participants over a period of two years, and the technique applied to that data was able to divide data from a session of computer usage into a series of mouse moves in 98% of observed computer sessions with a physically sensible value for the cutoff dividing moves from stops. PMID- 22255173 TI - Validation of respiratory signal derived from suprasternal notch acceleration for sleep apnea detection. AB - This study evaluates the respiration signal derived from an accelerometer mounted on the suprasternal notch in three body positions and three respiration types simulating normal sleep conditions. The Acceleration Derived Respiratory signal (ADR) is compared with single strain gauge belt and a standard spirometry signal taken as reference. The results demonstrate the potential of ADR as a simple, low cost and unintrusive method of screening breath disorders such as obstructive sleep apnea/hypopnea. PMID- 22255174 TI - EEG spectro-temporal modulation energy: a new feature for automated diagnosis of Alzheimer's disease. AB - There is recent indication that Alzheimer's disease (AD) can be characterized by atypical modulation of electrophysiological brain activity caused by fibrillar amyloid deposition in specific regions of the brain, such as those related to cognition and memory. In this paper, we propose to objectively characterize EEG sub-band modulation in an attempt to develop an automated noninvasive AD diagnostics tool. First, multi-channel full-band EEG signals are decomposed into five well-known frequency sub-bands: delta, theta, alpha, beta, and gamma. The temporal amplitude envelope of each sub-band is then computed via a Hilbert transformation. The proposed 'spectro-temporal modulation energy' feature measures the rate with which each sub-band is modulated. Modulation energy features are computed for 19 referential EEG signals and seven bipolar signals. Salient features are then selected and used to train four different classifiers, namely, support vector machines, logistic regression, classification and regression trees, and neural networks. Experiments with a database of 34 participants, 22 of which have been clinically diagnosed with probable-AD, show a neural network classifier achieving over 91% accuracy, thus significantly outperforming a classifier trained with conventional spectral-based features. PMID- 22255175 TI - EEG-rhythm dynamics during a 2-back working memory task and performance. AB - Working memory is an essential component of human cognition and determines to a large extent an individual's intellectual ability. In this paper, the human brain oscillatory response system associated with working memory performance is evaluated in an experimental and analysis setting involving 10 volunteers performing a visual 2-back task. Event-related dynamics in three bands: theta (3.5-7 Hz), alpha (7.5-12 Hz) and upper beta (17-29 Hz) at 32 locations distributed over the scalp are examined analyzing the event-related desynchronization (ERD)/synchronization (ERS) in these bands. Both global dynamics as well as trial- and subject-specific trends were considered. The overall across participants trend shows that the theta level synchronizes during working memory engagement, whereas beta and alpha desynchronizes. While common features seem to emerge, different subjects exhibit equally significant but opposite in direction correlation between reaction time and power dynamics. PMID- 22255176 TI - EEG recovery enhanced by acute aerobic exercise after performing mental task with listening to unpleasant sound. AB - The present paper investigated response of electroencephalogram (EEG) to aerobic exercise with low intensity after performing mental task with listening to acoustic stimuli in order to measure a recovery effect of the acute exercise on the EEG. The mean amplitude of the alpha wave (8-13 Hz) was significantly reduced during performing mental arithmetic and/or listening to 5 KHz unpleasant tone. In particular, the mean reduction rate of the amplitude was more than 20 % in the low-frequency range of the alpha wave (8-10 Hz) under both stressors. On the other hand, the alpha wave was fixed after an acute exercise of 20 min; the mean amplitude of the alpha wave exceeded 30 % of spontaneous level prior to stressed conditions in the low-frequency range but unchanged in the high-frequency range. Response of the theta wave was similar to the low-alpha wave, while beta and gamma waves showed no significant change in response to the stressors and exercise. The observation indicates that the acute exercise with low intensity may be responsible for the rapid recovery and enhancement of the alpha wave in the low-frequency range and theta wave. PMID- 22255177 TI - Spectral EEG features for evaluating cognitive load. AB - This study was undertaken to investigate spectral features derived from EEG signals for measuring cognitive load. Measurements of this kind have important commercial and clinical applications for optimizing the performance of users working under high mental load conditions, or as cognitive tests. Based on EEG recordings for a reading task in which three different levels of cognitive load were induced, it is shown that a set of spectral features--the spectral entropy, weighted mean frequency and its bandwidth, and spectral edge frequency--are all able to discriminate the three load levels effectively. An interesting result is that spectral entropy, which reflects the distribution of spectral energy rather than its magnitude, provides very good discrimination between cognitive load levels. We also report those EEG channels for which statistical significance between load levels was achieved. The effect of frequency bands on the spectral features is also investigated here. The results indicate that the choice of optimal frequency band can be dependent on the spectral feature extracted. PMID- 22255178 TI - An analysis of brain and muscle activity in arousal maintenance state against sleepiness. AB - Recently, we have developed a new method to analyze brain activity from electroencepharogram (EEG) based on a concept of instantaneous equivalent bandwidths (IEBWs). The essence of the method using the IEBW is to track bandwidths changes of EEG signals. Arousal maintenance state against sleepiness can be considered to be in a different physiological state compared to the normal sleep onset. The method was therefore applied to the EEG signals in the wakefulness maintenance state against sleepiness in order to capture the feature of the EEG signals. As a result, we have revealed that EEG signals while the subjects were trying to maintain wakefulness state against sleepiness had wide bandwidth compared to the EEG signals in normal sleep onset because of the EEG desynchronization. It can be considered that neuron activities from the frontal association area which coordinates behavior to hypothalamus which coordinates wakefulness and sleep were raised in order to maintain wakefulness state against sleepiness. Meanwhile, it is considered that EEG activity in gamma band is influenced by muscle activity. We therefore measured electromyograms (EMG) at mentalis muscle and trapezius muscle in order to evaluate the influence of the EMGs for the EEGs. The results showed that the EMG and the EEG were not correlated each other. PMID- 22255179 TI - The influence of stimulus onset asynchrony on neuronal suppressive phenomenon in face processing: an event-related potential study. AB - It has been reported that if two sensory stimuli are presented consecutively with stimulus onset asynchrony (SOA) of as short as several hundreds of milliseconds, the neural activity, elicited by the second stimulus, in the stimulus-sensitive area will be inhibited, say, suppressive phenomenon. Using a paired-stimulus paradigm, in which two visual stimuli were successively presented, we investigated the influence of SOA (200 ms, 400 ms & 600 ms) on suppressive phenomenon in face processing. Twelve subjects were asked to passively view randomly ordered paired stimuli and single stimuli, while their event-related potentials (ERPs) were recorded simultaneously. To evaluate the suppression, we compared the ERPs elicited by the second face stimulus of the paired stimuli with that elicited by the single face stimulus. It was found that, comparing with the ERPs elicited by single faces, in all three SOA conditions, the ERPs elicited by the second face stimulus of the intra-category trials (face_face trials) were more suppressed than those of the inter-category trials (blank_face and building_face trials) in both occipitotemporal and frontal regions. We surmised that these results might support a "domain specific" theory, which suggested that visual processing of faces and non-face objects involve separate and specialized networks in the ventro-lateral temporal cortex. Interestingly, for the face_face trials, as the SOA increased, the ERP suppression in the frontal region diminished gradually. Such phenomenon might be due to the lasting effect of semantic processing for the first face stimulus. PMID- 22255180 TI - Effect of age and gender on the surface electromyogram during various levels of isometric contraction. AB - This study reports the effects of age and gender on the surface electromyogram while performing isometric contraction. Experiments were conducted with two age groups--Young (Age: 20-29) and Old (Age: 60-69) where they performed sustained isometric contractions at various force levels (50%, 75%, 100% of maximum voluntary contraction). Traditional features such as root mean square (RMS) and median frequency (MDF) were computed from the recorded sEMG. The result indicates that the MDF of sEMG was not significantly affected by age, but was impacted by gender in both age groups. Also there was a significant change in the RMS of sEMG with age and gender at all levels of contraction. The results also indicate a large inter-subject variation. This study will provide an understanding of the underlying physiological effects of muscle contraction and muscle fatigue in different cohorts. PMID- 22255181 TI - Repeatability of surface EMG-based single parameter muscle fatigue assessment strategies in static and cyclic contractions. AB - The repeatability of a spectral surface electromyography-based fatigue assessment strategy was evaluated. Variability of two fatigue-trend tracking parameters was used as an indicator for repeatability. The parameters were the natural logarithm of the slope of linear mean frequency decline lnMF(S) and the percent drop in mean frequency MF(D). The coefficient of variation CoV was used as the metric for repeatability, representing the ratio of the standard deviation to the mean of repeated measures from the same individual. Five weekly fatigue tests on the right biceps brachii were conducted on 11 participants with a fatiguing regime comprising of alternating static and cyclic segments, collecting seven channels of differential EMG. The resulting 95% confidence intervals of the CoV were: 15.38-24.87% (Static lnMF(S)), 12.21-23.36% (Cyclic lnMF(S)), 13.18-21.85% (Static MF(D)), and 12.37-24.39% (Cyclic MF(D)). There was no statistically significant difference in repeatability between any combination of parameter and types of motion. PMID- 22255182 TI - Solving EMG-force relationship using Particle Swarm Optimization. AB - The Particle Swarm Optimization (PSO) algorithm is applied to the problem of "load sharing" among muscles acting on the same joint for the purpose of estimating their individual mechanical contribution based on their EMG and on the total torque. Compared to the previously tested Interior-Reflective Newton Algorithm (IRNA), PSO is more computationally demanding. The mean square error between the experimental and reconstructed torque is similar for the two algorithms. However, IRNA requires multiple initializations and tighter constraints found by trial-and-errors for the input variables to find a suitable optimum which is not the case for PSO whose initialization is random. PMID- 22255183 TI - Influence of neuromuscular electrical stimulation on the conduction velocity measured using EMG signals provided by linear arrays of electrodes. AB - Neuromuscular electrical stimulation (NMES) can alter the functioning of muscles and even assist muscle rehabilitation. In this paper, we evaluate the effect of NMES on the conduction velocity (CV) of the brachial biceps' motor units. We used a linear array of electrodes to acquire electromyographic signals, as different subjects perform isometric voluntary contractions (IVCs), with and without prior NMES. Our results show that, after NMES, the CVs at the beginning of the IVCs tend to increase, with respect to the case without NMES. Also, we observed that, while in the absence of NMES, the CVs tend to decrease over time with continued IVCs, this does not happen after 20 minutes of NMES, and the CVs can, in some cases, increase with the contractions. PMID- 22255184 TI - Evaluation of higher order statistics parameters for multi channel sEMG using different force levels. AB - The electromyograpy (EMG) signal provides information about the performance of muscles and nerves. The shape of the muscle signal and motor unit action potential (MUAP) varies due to the movement of the position of the electrode or due to changes in contraction level. This research deals with evaluating the non Gaussianity in Surface Electromyogram signal (sEMG) using higher order statistics (HOS) parameters. To achieve this, experiments were conducted for four different finger and wrist actions at different levels of Maximum Voluntary Contractions (MVCs). Our experimental analysis shows that at constant force and for non fatiguing contractions, probability density functions (PDF) of sEMG signals were non-Gaussian. For lesser MVCs (below 30% of MVC) PDF measures tends to be Gaussian process. The above measures were verified by computing the Kurtosis values for different MVCs. PMID- 22255185 TI - Effects of interelectrode distance on the robustness of myoelectric pattern recognition systems. AB - Myoelectric pattern recognition control can potentially provide upper limb amputees with intuitive control of multiple prosthetic functions. However, the lack of robustness of myoelectric pattern recognition algorithms is a barrier for clinical implementation. One issue that can contribute to poor system performance is electrode shift, which is a change in the location of the electrodes with respect to the underlying muscles that occurs during donning and doffing and daily use. We investigated the effects of interelectrode distance and feature choice on system performance in the presence of electrode shift. Increasing the interelectrode distance from 2 cm to 4 cm significantly (p<0.01) improved classification accuracy in the presence of electrode shifts of up to 2 cm. In a controllability test, increasing the interelectrode distance from 2 cm to 4 cm improved the user's ability to control a virtual prosthesis in the presence of electrode shift. Use of an autoregressive feature set significantly (p<0.01) reduced sensitivity to electrode shift when compared to use of a traditional time domain feature set. PMID- 22255186 TI - EMG-based detection of muscle fatigue during low-level isometric contraction: effects of electrode configuration and blood flow restriction. AB - This study assessed muscle fatigue during low-level contraction, which is sometimes difficult to observe. Surface EMG signals were recorded with monopolar and bipolar configurations during low-level isometric muscle contraction under a blood flow restriction condition (BFR condition) and a non-blood flow restriction condition (CON condition). As indices of fatigue, center frequency (CF) of the power spectral density (PSD) of the surface EMG and rating of perceived exertion (RPE) with the Borg CR-10 Scale were used. Results suggested that the monopolar configuration, which has a wider detection area relative than the bipolar one, was well suited for obtaining wave slowing accompanied by muscle fatigue. In addition, the monopolar configuration could detect differences in muscle condition in the BFR and CON conditions. PMID- 22255187 TI - Vectorial analysis of the electrohysterogram for prediction of preterm delivery: a preliminary study. AB - Electrophysiological measurement of uterine contractions, referred to as electrohysterogram (EHG), is potentially more informative than methods currently used during pregnancy for timely recognition of complications such as preterm labor. Unfortunately, EHG measurement and interpretation remain challenging. Recently, some attention has been dedicated to the analysis of the EHG propagation, which is hypothetically predictive of the delivery time. This hypothesis, though physiologically reasonable, has not been investigated yet. A dedicated maximum likelihood (ML) method has been proposed and validated for identifying the conduction velocity vector of single EHG spikes. This validated ML method is here employed for comparing the conduction velocity vector in two groups of pregnant women with uterine contractions that were prospectively classified as productive or unproductive contractions. The estimated conduction velocity vector showed significant differences in the two groups. The spikes extracted from those contractions eventually classified as unproductive showed a significantly lower conduction velocity amplitude (CV = 4.89 +/- 1.19 cm.s(-1) vs CV = 8.63 +/- 2.92 cm.s(-1)) and a higher occurrence of upward propagation relative to productive contractions. These results suggest that productive and unproductive uterine contractions are associated to significantly different properties of the conduction velocity vector, which is likely to be proven fundamental in predicting preterm delivery. PMID- 22255188 TI - Motion P3 demonstrates neural nature of motion ERPs. AB - The technical challenges of recording electroencephalographic (EEG) data during motion are considerable, but would enable the possibility of investigating neural function associated with balance, motor function and motion perception. The challenges include finding a reliable method of motion stimulus reproduction, removing artifacts, and ensuring that the recordings retain sufficient EEG signal for proper interpretation. This study details the use of the P3 waveform to validate the concept of motion-based EEG data, and discusses some potential future uses in experimental and clinical settings. PMID- 22255189 TI - Propagation of electrical field in the brain using electrical intra-cerebral stimulations. AB - For drug resistant partial epilepsy, intra-cerebral electrical stimulation (Deep Brain Stimulation--DBS) constitutes one of the means to locate epileptic volume. This paper investigates, in the framework of source localization problem, the propagation of the electrical field and current density distribution induced in the brain during in vivo electrical stimulation. There are three objectives in this work: to validate the propagation model for different large frequencies, to highlight the problem of the close field with the DBS source and to show the influence of the proximity to the skull on the results. We compared the Stereo EEG data, recorded during DBS, with those obtained using: (i) the simplest model, the dipolar model in an infinite homogeneous medium, (ii) a more realistic approach with a numerical method, the Boundary Element Method (BEM). Studies on ten subjects with 234 stimulations showed that the dipole model could be used in the brain far from the skull in direction of dipole moment but that BEM was more appropriate close to the skull. PMID- 22255190 TI - On sparse forward solutions in non-stationary domains for the EIT imaging problem. AB - In the forward EIT-problem numerical solutions of an elliptic partial differential equation are required. Given the arbitrary geometries encountered, the Finite Element Method (FEM) is, naturally, the method of choice. Nowadays, in EIT applications, there is an increasing demand for finer Finite Element mesh models. This in turn results to a soaring number of degrees of freedom and an excessive number of unknowns. As such, only piece-wise linear basis functions can practically be employed to maintain inexpensive computations. In addition, domain reduction and/or compression schemes are often sought to further counteract for the growing number of unknowns. In this paper, we replace the piece-wise linear with wavelet basis functions (coupled with the domain embedding method) to enable sparse approximations of the forward computations. Given that the forward solutions are repeatedly, if not extensively, utilised during the image reconstruction process, considerable computational savings can be recorded whilst maintaining O(N) forward problem complexity. We verify with numerical results that, in practice, less than 5% of the involved coefficients are actually required for computations and, hence, needs to be stored. We finalise this work by addressing the impact to the inverse problem. It is worth underlining that the proposed scheme is independent of the actual family of wavelet basis functions of compact support. PMID- 22255191 TI - Evaluation of EM absorption loss over breast mass for breast cancer diagnosis. AB - This paper presents electromagnetic (EM) absorption loss over breast mass as a new approach in the detection of breast cancer tumors. A linear curve of absorption loss over breast mass is used to establish acceptable normal absorption loss values. Since tumor-infected breast tissues should have higher absorption loss than normal breast tissues, the measured absorption loss of a tumor-infected breast will be higher than the established normal absorption loss value, and the breast will be diagnosed as infected. EM simulations of normal and infected breast tissues are run at 915, 2450, and 4000 MHz. Results show that 915 MHz presents the best linear curve fit and resolution. Also, the absorption loss for an infected breast, at 915 MHz, is higher than the absorption loss for a normal breast and is least affected by tumor location. PMID- 22255192 TI - Automatic detection of the seizure onset zone based on ictal EEG. AB - In this paper we show a proof of concept for novel automatic seizure onset zone detector. The proposed approach utilizes the Austrian Institute of Technology (AIT) seizure detection system EpiScan extended by a frequency domain source localization module. EpiScan was proven to detect rhythmic epileptoform seizure activity often seen during the early phase of epileptic seizures with reasonable high sensitivity and specificity. Additionally, the core module of EpiScan provides complex coefficients and fundamental frequencies representing the rhythmic activity of the ictal EEG signal. These parameters serve as input to a frequency domain version of the Minimum Variance Beamformer to estimate the most dominant source. The position of this source is the detected seizure onset zone. The results are compared to a state of the art wavelet transformation approach based on a manually chosen frequency band. Our first results are encouraging since they coincide with those obtained with the wavelet approach and furthermore show excellent accordance with the medical report for the majority of analyzed seizures. In contrast to the wavelet approach our method has the advantage that it does not rely on a manual selection of the frequency band. PMID- 22255193 TI - Detection of motor planning and suppression with the help of electroencephalography. AB - The aim of this study was to investigate, if it is possible to detect brain activity related to motor planning and suppression with the help of Electroencephalograms (EEG), the ultimate goal being, to simultaneously measure EEG and functional magnetic resonance imaging (fMRI). Towards this end we engaged a delayed response task from an earlier fMRI study, thereby ensuring, as a first step, that the results of both EEG and fMRI would be directly comparable. Motor preparatory signals were recorded in seven subjects using 10-20-system fMRI compatible EEG equipment. The a and p frequency bands of the EEG recordings were analyzed first individually and then on the group level. Using a non-parametric statistical test, significant clusters relating to motor planning were mainly found over the motor and posterior parietal cortex of the right hemisphere. Activity corresponding with motor suppression was exhibited over the parietal and occipital cortex, located mainly medially for the lower p band (13-20 Hz) and extended towards the right hemisphere for the a band. Active regions corresponded well to the ones revealed in our previous fMRI study. Simultaneous EEG and fMRI of this task in the future could thus provide us with combined information on timing (EEG), locality (fMRI) and activity characteristics (both) during motor planning and suppression. PMID- 22255194 TI - Electrocortical source imaging of intracranial EEG data in epilepsy. AB - Here we report first results of numerical methods for modeling the dynamic structure and evolution of epileptic seizure activity in an intracranial subdural electrode recording from a patient with partial refractory epilepsy. A 16-min dataset containing two seizures was decomposed using up to five competing adaptive mixture independent component analysis (AMICA) models. Multiple models modeled early or late ictal, or pre- or post-ictal periods in the data, respectively. To localize sources, a realistic Boundary Element Method (BEM) head model was constructed for the patient with custom open skull and plastic (non conductive) electrode holder features. Source localization was performed using Sparse Bayesian Learning (SBL) on a dictionary of overlapping multi-scale cortical patches constructed from 80,130 dipoles in gray matter perpendicular to the cortical surface. Remaining mutual information among seizure-model AMICA components was dominated by two dependent component subspaces with largely contiguous source domains localized to superior frontal gyrus and precentral gyrus; these accounted for most of the ictal activity. Similar though much weaker dependent subspaces were also revealed in pre-ictal data by the associated AMICA model. Electrocortical source imaging appears promising both for clinical epilepsy research and for basic cognitive neuroscience research using volunteer patients who must undergo invasive monitoring for medical purposes. PMID- 22255195 TI - Analysis of the criteria of activation-based inverse electrocardiography using convex optimization. AB - In inverse electrocardiography (ECG), the problem of finding activation times on the heart noninvasively from body surface potentials is typically formulated as a nonlinear least squares optimization problem. Current solutions rely on iterative algorithms which are sensitive to the presence of local minima. As a result, improved initialization approaches for this problem have been of considerable interest. However, in experiments conducted on a subject with Wolff-Parkinson White syndrome, we have observed that there may be a mismatch between favorable solutions of the optimization problem and solutions with the desired physiological characteristics. In this work, we use a method based on a convex optimization framework to explore the solution space and analyze whether the optimization criteria target their intended objective. PMID- 22255196 TI - Wavelet-based ultrasound image denoising: performance analysis and comparison. AB - Ultrasound images are generally affected by multiplicative speckle noise, which is mainly due to the coherent nature of the scattering phenomenon. Speckle noise filtering is thus a critical pre-processing step in medical ultrasound imaging provided that the diagnostic features of interest are not lost. A comparative study of the performance of alternative wavelet based ultrasound image denoising methods is presented in this article. In particular, the contourlet and curvelet techniques with dual tree complex and real and double density wavelet transform denoising methods were applied to real ultrasound images and results were quantitatively compared. The results show that curvelet-based method performs superior as compared to other methods and can effectively reduce most of the speckle noise content of a given image. PMID- 22255197 TI - ARM-based visual processing system for prosthetic vision. AB - A growing number of prosthetic devices have been shown to provide visual perception to the profoundly blind through electrical neural stimulation. These first-generation devices offer promising outcomes to those affected by degenerative disorders such as retinitis pigmentosa. Although prosthetic approaches vary in their placement of the stimulating array (visual cortex, optic nerve, epi-retinal surface, sub-retinal surface, supra-choroidal space, etc.), most of the solutions incorporate an externally-worn device to acquire and process video to provide the implant with instructions on how to deliver electrical stimulation to the patient, in order to elicit phosphenized vision. With the significant increase in availability and performance of low power consumption smart phone and personal device processors, the authors investigated the use of a commercially available ARM (Advanced RISC Machine) device as an externally-worn processing unit for a prosthetic neural stimulator for the retina. A 400 MHz Samsung S3C2440A ARM920T single-board computer was programmed to extract 98 values from a 1.3 Megapixel OV9650 CMOS camera using impulse, regional averaging and Gaussian sampling algorithms. Power consumption and speed of video processing were compared to results obtained to similar reported devices. The results show that by using code optimization, the system is capable of driving a 98 channel implantable device for the restoration of visual percepts to the blind. PMID- 22255198 TI - A multi-scale non-linear vessel enhancement technique. AB - We present an enhancement method based on nonlinear diffusion filter and statistical intensity approaches for smoothing and extracting 3-D vascular system from Magnetic Resonance Angiography (MRA) data. Our method distinguishes and enhances the vessels from the other embedded tissues. The Expectation Maximization (EM) technique is employed with non-linear diffusion in order to find the optimal contrast for enhancing vessels; therefore, smoothing while dimming the embedded tissues around the vessels and brightening the vessels. The non-linear diffusion filter smooths the homogeneous regions while preserving edges. The EM technique finds the optimal statistical parameters based on the probability distribution of the classes to discriminate the tissues in the image. Our enhancement technique has been applied to 4 3-D MRA-TOF datasets consisting of around 300 images and has been compared to the regularized Perona and Malik filter. Our experimental results show that the proposed method enhances the image, keeping only the vessels while eliminating the signal from other tissues. In comparison, the conventional non-linear diffusion filter keeps unwanted tissues in addition to the vessels. PMID- 22255199 TI - A fast mapping method in the ISAF reconstruction algorithm. AB - ISAF (icosahedral symmetry-adapted functions) algorithm is the new high resolution algorithm of icosahedral molecules. But its running speed is very slow because of the time-consuming operations of mapping sampling points into 3D space. In this paper, a fast mapping method is proposed to increase the running speed of this stage. First of all, the angle corresponding to one pixel arc in the maximum Fourier ring was taken as the sampling angle and the same angle sampling was applied in every rings. After that, the sampling points in ring R=1 were mapped into 3D space. Finally, the 3D spatial positions of radial sampling points in other rings were deduced according to the rotate angle invariability of radial sampling points. The simulated data of PSV-F (Penicillium stoloniferum virus F) and experimental Cryo-EM data of CPV (cytoplasmic polyhedrosis virus) were used for validating this method. The results show that the whole speedup reaches to an order of magnitude at the premise of assuring accuracy. In addition, the speedup is increasing with the increase of the maximum Fourier radius and the number of projections. PMID- 22255200 TI - A critical review of the effects of de-noising algorithms on MRI brain tumor segmentation. AB - One can find in the literature numerous techniques to reduce noise in Magnetic Resonance Images (MRI). This paper critically reviews modern de-noising algorithms (Gaussian filter, anisotropic diffusion, wavelet, and non-local mean) in terms of their efficiency, statistical assumptions, and their ability to improve brain tumor segmentation results. We will show that although different techniques do reduce the noise, many generate artifacts that are incompatible with precise brain tumor segmentation. We also show that the non-local means algorithm is the best de-noising technique for brain tumor segmentation. PMID- 22255201 TI - An attempt of microwave CT system which discriminates the transmission path by means of time domain measurement. AB - A microwave-based computed tomography system was developed based on a method that uses time domain measurement to determine the shortest path of propagation components between two antennas. The method calculates shortest path of propagation components by examining mixer output DC components, delivering similar precision as chirp-pulse microwave computed tomography. Because post mixer signal processing need only concerns DC currents, the effects of overshoot characteristics of baseband filters and the like are removed, simplifying measurement. System circuit composition is also simplified, lowering system costs. This paper provides a theoretical framework for the method, an S-parameter verification of the theory, and an experimental verification using a basic hardware construction. Results showed a restored image from the measurement data, indicating the utility of the method for microwave imaging. PMID- 22255202 TI - Software-based microwave CT system consisting of antennas and vector network analyzer. AB - We have developed a software-based microwave CT (SMCT) that consists of antennas and a vector network analyzer. Regardless of the scanner type, SMCT collects the S-parameters at each measurement position in the frequency range of interest. After collecting all the S-parameters, it calculates the shortest path to obtain the projection data for CPMCT. Because of the redundant data in SMCT, the calculation of the projection is easily optimized. Therefore, the system can improve the accuracy and stability of the measurement. Furthermore, the experimental system is constructed at a reasonable cost. Hence, SMCT is useful for imaging experiments for CP-MCT and particularly for basic studies. This paper describes the software-based microwave imaging system, and experimental results show the usefulness of the system. PMID- 22255203 TI - Total variation regularization for bioluminescence tomography with an adaptive parameter choice approach. AB - In this paper, we explore the application of total variation regularization method for bioluminescence tomography (BLT) with an adaptive regularization parameter choice approach. Since BLT is a seriously ill-posed problem, therefore, l(2) regularized methods are frequently adopted to recover the bi-oluminescent sources. However, l(2) regularized methods typically lead to smooth reconstructions. In this paper, we investigated the use of total variation (TV) regularization to improve the quality of BLT reconstruction. Furthermore, the regularization parameter in TV method was chosen adaptively to make the proposed algorithm more stable. Results on simulation data provide evidence that the reconstructed source can be localized accurately compared with l(2) method. Meanwhile, the effectiveness of utility of the parameter choice were illustrated. Finally, different levels of noisy data were added to validate the performance of the proposed algorithm. PMID- 22255204 TI - Retinal vessel extraction by combining radial symmetry transform and iterated graph cuts. AB - In this paper, we propose a new method for the extraction of blood vessels in retinal images. This approach starts with a Hessian-based multiscale filtering method to enhance blood vessels in gray retinal images. Subsequently, a new radial symmetry transformation, which is based on line kernels, is proposed to improve the detection of vessel structures and restrain the response of nonvessel structures. Finally, an iterated segmentation algorithm is used to extract retinal vessels. The proposed approach has been tested on the two publicly available databases, DRIVE and STARE. The experimental results show the feasibility of the proposed method. PMID- 22255205 TI - Automatic vessel segmentation in wide-field retina images of infants with retinopathy of prematurity. AB - The earliest signs of Retinopathy of Prematurity (ROP) are tortuosity and dilation of retinal vessels. Such vascular changes are considered of primary importance for the diagnosis and the follow-up of the disease. However, a widely accepted computerized system for their quantitative measurement is still missing. Images taken from a preterm baby's eye are often low-contrast, noisy, and blurred. Algorithms that have been successfully applied to analyze adult retinal images do not work well in ROP images. We propose here a novel method for the automatic extraction of vessel centerline in wide-field ROP retinal images, based on a sparse tracking scheme. After a set of seed points is identified all over the image, vessels are traced by connecting those seeds by means of minimum cost paths, whose weights depend on similarity features and alignment evaluated by a custom line operator. The performance of the method was assessed on a dataset of 20 images acquired with the RetCam fundus camera. A sensitivity of 0.78 and a false detection rate of 0.15 were obtained with respect to manual ground truth reference. PMID- 22255206 TI - Geographic atrophy segmentation in infrared and autofluorescent retina images using supervised learning. AB - Geographic Atrophy (GA) of the retinal pigment epithelium (RPE) is an advanced form of atrophic age-related macular degeneration (AMD) and is responsible for about 20% of AMD-related legal blindness in the United States. Two different imaging modalities for retinas, infrared imaging and autofluorescence imaging, serve as interesting complimentary technologies for highlighting GA. In this work we explore the use of neural network classifiers in performing segmentation of GA in registered infrared (IR) and autofluorescence (AF) images. Our segmentation achieved a performance level of 82.5% sensitivity and 92.9% specificity on a per pixel basis using hold-one-out validation testing. The algorithm, feature extraction, data set and experimental results are discussed and shown. PMID- 22255207 TI - Automatic screening of age-related macular degeneration and retinal abnormalities. AB - We describe a novel approach for screening retinal imagery to detect evidence of abnormalities. In this paper, we focus our efforts on age-related macular degeneration (AMD), a pathology that may often go undetected in the early or intermediate stages, and can lead to a neovascular form often resulting in blindness, if untreated. Our strategy for retinal anomaly detection is to employ a single class classifier applied to fundus imagery. We use a multiresolution locally-adaptive scheme that identifies both normal and anomalous regions within the retina. We do this by using a hybrid parametric/non-parametric characterization of the support of the probability distribution of normal retinal tissue in color and intensity feature space. We apply this approach to screen for evidence of AMD on a dataset of 66 healthy and pathological cases and found a detection sensitivity and specificity of 95% and 96%. PMID- 22255208 TI - Augmenting the classification of retinal lesions using spatial distribution. AB - This paper introduces SAGE--an algorithm that uses the spatial clustering of objects to enhance their classification. It assumes that discrete objects can be identified and classified based on their individual appearance, and further that they tend to appear in spatial clusters (for example, circinate exudates). The algorithm builds spatial distribution maps for objects and confounds for a given image, and adjusts individual object confidence levels to reflect their spatial clustering. SAGE may be combined with a wide range of object identification and classification methods; we demonstrate it using a Multi-Layered Perceptron (MLP) Neural Network and a Support Vector Machine (SVM) classifier types for both dark and bright retinal lesions. Using ROC analysis SAGE improves classifier performance as much as 83%. PMID- 22255209 TI - Supervised retinal biometrics in different lighting conditions. AB - Retinal image has been considered for number of health and biometrics applications. However, the reliability of these has not been investigated thoroughly. The variation observed in retina scans taken at different times is attributable to differences in illumination and positioning of the camera. It causes some missing bifurcations and crossovers from the retinal vessels. Exhaustive selection of optimal parameters is needed to construct the best similarity metrics equation to overcome the incomplete landmarks. In this paper, we extracted multiple features from the retina scans and employs supervised classification to overcome the shortcomings of the current techniques. The experimental results of 60 retina scans with different lightning conditions demonstrate the efficacy of this technique. The results were compared with the existing methods. PMID- 22255210 TI - Influence of the multisine excitation amplitude design for biomedical applications using Impedance Spectroscopy. AB - Electrical Impedance Spectroscopy (EIS) is a powerful tool to collect data from many biological materials in a wide variety of applications. Body composition fluid or tissue and organ state monitoring are just some examples of these applications. While the classical EIS is based on frequency sweep, the EIS technique using broadband excitations allows to acquire simultaneous impedance spectrum data. The strength and weakness of broadband EIS relies on the fact that it enables multiple Electrical Bio-Impedance (EBI) data collection in a short measuring time but at the cost of losing impedance spectrum accuracy. In general, there is a relationship between the broadband excitation time/frequency properties and the final EBI's accuracy obtained. This paper studies the influence of the multisine broadband excitation amplitude's design over the EBI accuracy by means of the resultant Noise-to-Signal Ratio (NSR) obtained when measuring with a custom impedance analyzer. Theory has been supported by a set of validation experiments. PMID- 22255211 TI - Real-time, in vivo investigation of mechanical stimulus on cells with remotely activated, vibrational magnetoelastic layers. AB - A system was developed for real-time, in vivo investigation of the relationship between local cell-level nano-mechanical perturbation and cell response to chemical-physical biomaterial surface properties. The system consisted of a magnetoelastic (ME) layer that could be remotely set to vibrate, at submicron levels, at a predetermined amplitude and profile. Experiments result indicated that submicron localized vibrations coupled with tailored biomaterial surface properties could selectively control cellular adhesion and possibly guide phenotypic gene expression. Practical application of this system includes modulation and monitoring of the surface of implantable biomaterials. The ME based vibrational system is the first of its kind for use in vitro for culture based mechanical testing, which could be readily deployed in situ as an in vivo system to apply local mechanical loads. It could be applied to specific implant surface sites and then subsequently sealed prior to long-term implantation. The potential advantage of this system over other similar approaches is that the system is translatable--the functional layer can serve as a "cellular workbench" material but could also be adapted and applied to the surface of implantable biomaterials and devices. PMID- 22255212 TI - Using microelectrode models for real time cell-culture monitoring. AB - This paper proposes a cell-microelectrode model for cell biometry applications, based on the area overlap as main parameter. The model can be applied to cell size identification, cell count, and their extension to cell growth and dosimetry protocols. Experiments performed with comercial electrodes are presented, illustrating a procedure to obtain cell number in both growth and dosimetry processes. Results obtained for the AA8 cell line are promising. PMID- 22255213 TI - Temperature elevation inside neural tissue illuminated by NIR laser. AB - Near infrared (NIR) light energy has been used in medical applications both for diagnostic and treatment purposes. Temperature elevation is the main concern in the neural tissue when illuminated with NIR light. In this report, an NIR light beam was pulsed into a rat brain cortex. The spatial maps of temperature elevation inside the neural tissue were measured directly using a micro probe. The results indicate that the temperature inside the neural tissue saturates with increasing levels of laser power. PMID- 22255214 TI - Measuring movement of denim trousers for garment-integrated sensing applications. AB - The movement of everyday garments over the body surface during wearing often presents a problematic source of noise or error for garment-integrated wearable sensors. This paper describes early results of an assessment of the impact of body location and garment ease on movement of the garment over the body surface. The method implemented uses a running mannequin with a repeatable gait cycle as the source of humanoid motion, and measures the movement of a set of custom graded denim trousers in 5 ease amounts over the mannequin's surface during the gait cycle. Initial results show consistent patterns of displacement over the body surface. PMID- 22255215 TI - A new proposal of tailored bioinstrumentation using rapid prototyping and three dimensional CAD--first trial to develop individually designed cuff-units for continuous blood pressure measurement. AB - The concept of tailored bioinstrumentation using rapid prototyping and three dimensional CAD (3D-CAD) was proposed. This concept is to make individually designed and fabricated sensor unit to attach human body. Within the proposed concept, cuff-units for continuous blood pressure measurement were individually designed using 3D-CAD and fabricated automatically. As the result, blood pressure wave forms can be obtained using the finally developed cuff units. Using rapid prototyping device, the design and fabrication process were accelerated without any artisan-like high skilled persons. PMID- 22255216 TI - High-order sliding-mode control for blood glucose regulation in the presence of uncertain dynamics. AB - The success of blood glucose automatic regulation depends on the robustness of the control algorithm used. It is a difficult task to perform due to the complexity of the glucose-insulin regulation system. The variety of model existing reflects the great amount of phenomena involved in the process, and the inter-patient variability of the parameters represent another challenge. In this research a High-Order Sliding-Mode Control is proposed. It is applied to two well known models, Bergman Minimal Model, and Sorensen Model, to test its robustness with respect to uncertain dynamics, and patients' parameter variability. The controller designed based on the simulations is tested with the specific Bergman Minimal Model of a diabetic patient whose parameters were identified from an in vivo assay. To minimize the insulin infusion rate, and avoid the hypoglycemia risk, the glucose target is a dynamical profile. PMID- 22255217 TI - Enhanced video images for tympanic membrane characterization. AB - The objective of this article is to introduce portable devices capable of providing video images of the tympanic membrane and tympanic cavity of the ear. Specifically, digital video otoscopy is introduced as an effective platform for tympanic membrane characterization. In addition, we show how digital image enhancement and segmentation processing techniques can be applied to the acquired images, which could provide more visual detail and objective clinical interpretation. PMID- 22255218 TI - Development of a reflectance photoplethysmographic sensor used for the assessment of free flap perfusion. AB - Monitoring of free flap perfusion and early identification of flap failure is an indispensable prerequisite for flap salvage. Although many methods of free flap monitoring are available, there is still no single reliable continuous non invasive perfusion monitoring technique which will also assist in the early recognition of flap failure. In order to overcome the current technological limitations, we have developed a multi-wavelength photoplethysmographic (PPG) sensor and processing system to systematically investigate the perfusion mechanism in flaps used in reconstructive plastic microsurgery. The new prototype reflectance photoplethysmographic sensor was evaluated on three anaesthetized patients undergoing elective breast reconstructive (Deep Inferior Epigastric Perforator Flap) surgery. PPG signals were successfully obtained pre-operatively, intra-operatively and post-operatively. These preliminary results suggest that a PPG sensor may be a suitable method for evaluating the perfusion of free flap. PMID- 22255219 TI - Analysis and design of data transmission protocol for 1024-channel retinal prosthesis. AB - Epiretinal prostheses deliver electrical pulses through a great number of stimulation electrodes to generate visual perception. Since a large amount of stimulation parameters have to be sent into the eye wirelessly, the transmission efficiency and data loss are critical design factors. While the error rate of wireless transmission might not be perfect due to the limited power dissipation allowed in the eyeball, data loss can be reduced by altering the size of data packets. In this paper, the correlation between packet length and data loss are analyzed, and we find that more than 10 times of reduction in data loss can be achieved by shortening the data packets. The costs and benefits of using error correcting codes (ECC) are also evaluated. A data packet protocol for 1024 channel retinal prosthesis as well as the corresponding receiver circuitry are then designed based on the results of the analyses. The circuit occupies 330 MUm * 262 MUm using 0.18 MUm CMOS technology. With the flexibility provided by the protocol and receiver circuitry, data packet configuration (size and ECC on/off) can be adaptively adjusted to optimize for real-time wireless channel error conditions. PMID- 22255220 TI - Study of performance and propagation characteristics of wire and planar structures around human body. AB - Continued miniaturization of electronic devices and technological advancements in wireless communications has made wearable body-centric telemedicine systems viable. Antennas play a crucial role in characterizing the efficiency and reliability of these systems. The performance characteristics such as the radiation pattern, gain, efficiency of the antennas get adversely affected due to the presence of lossy human body tissues. In this paper we investigate the above mentioned performance parameters and radio frequency transmission properties of wire and planar structures operating at ISM frequency band of 2.40-2.50 GHz in the proximity of human body. PMID- 22255221 TI - Design and simulation of printed spiral coil used in wireless power transmission systems for implant medical devices. AB - Printed Spiral Coil (PSC) is a coil antenna for near-field wireless power transmission to the next generation implant medical devices. PSC for implant medical device should be power efficient and low electromagnetic radiation to human tissues. We utilized a physical model of printed spiral coil and applied our algorithm to design PSC operating at 13.56 MHz. Numerical and electromagnetic simulation of power transfer efficiency of PSC in air medium is 77.5% and 71.1%, respectively. The simulation results show that the printed spiral coil which is optimized for air will keep 15.2% power transfer efficiency in human subcutaneous tissues. In addition, the Specific Absorption Ratio (SAR) for this coil antenna in subcutaneous at 13.56 MHz is below 1.6 W/Kg, which suggests this coil is implantable safe based on IEEE C95.1 safety guideline. PMID- 22255222 TI - Development of walking analysis system consisting of mobile force plate and motion sensor. AB - In walking analysis, which is one useful method for efficient physical rehabilitation, the ground reaction force, the center of pressure, and the body orientation data are measured during walking. In the past, these data were measured by a 3D motion analysis system consisting of high-speed cameras and force plates, which must be installed in the floor. However, a conventional 3D motion analysis system can measure the ground reaction force and the center of pressure just on force plates during a few steps. In addition, the subjects' stride lengths are limited because they have to walk on the center of the force plate. These problems can be resolved by converting conventional devices into wearable devices. We used a measuring device consisting of portable force plates and motion sensors. We developed a walking analysis system that calculates the ground reaction force, the center of pressure, and the body orientations and measured a walking subject to estimate this system. We simultaneously used a conventional 3D motion analysis system to compare with our development system and showed its validity for measurements of ground reaction force and the center of pressure. PMID- 22255223 TI - Spatio-temporal image analysis of particle streaks in micro-channels for low-cost electro-hydrodynamic flow characterization. AB - Flow characterization is a primary analytical method for performance evaluation of microfluidic devices. With the increasing prevalence of microfluidic devices in recent years, there is a growing need for simple methods of automated flow estimation. In this work, a novel flow diagnostic technique based on image analysis of particle streaks is introduced, to characterize local flow velocities. While 1D velocimetry using particle tracks has occasionally been discussed for macro-scale environments, the use of particle streaks for 2-D flow characterization in micro-channels has not been explored. The proposed technique is qualitatively validated against electrokinetic experiment and numerically validated with simulated flows. PMID- 22255224 TI - Stimulation and artifact-free extracellular electrophysiological recording of cells in suspension. AB - We have developed instrumentation which stimulates and records electrophysiological signals from populations of suspended cells in microfluidic channels. We are employing this instrumentation in a new approach to cell sorting and flow cytometry which distinguishes cells based on their electrophysiology. This label-free approach is ideal for applications where labeling or genetic modification of cells is undesirable, such as in purifying cells for tissue replacement therapies. Electrophysiology is a powerful indicator of phenotype for electrically-excitable cells such as myocytes and neurons. However, extracellular field potential signals are notoriously weak and large stimulus artifacts can easily obscure these signals if care is not taken to suppress them. This is particularly true for suspended cells. Here, we describe a novel microelectrode configuration and the associated instrumentation for suppressing stimulus artifacts and faithfully recovering the extracellular field potential signal. We show that the device is capable of distinguishing cardiomyocytes from non cardiomyocytes derived from the same stem cell population. Finally, we explain the relationship between extracellular field potentials and the more familiar transmembrane action potential signal, noting the physiologically important features of these signals. PMID- 22255225 TI - Shape dependent Laplace vortices in deformed liquid-liquid slug flow. AB - Understanding the hydrodynamics of liquid-liquid slug flow is important in the emerging field of plug-based microfluidics; however, the subtle aspects of the vortex geometry are still not comprehensively understood. This paper discusses the hydrodynamics of deformation dependent vortices that develop inside a water in-oil slug as it flows through a channel. In contrast to prior studies, our simulations and experiments on slug flow reveal multiple vortices inside the moving slug, caused by the deformation of the hemispherical caps by Laplace pressures. These vortices appear in the front and rear of the plug at capillary number between 10(-4) and 10(-2). A theoretical and simulation model shows the cause of asymmetry in slug deformation and the resulting vortices. Understanding the relevant parameters helps in optimizing slug flow for mixing and particle manipulation, which is important for plug-based microreactors and bead based assays. PMID- 22255226 TI - Improvements in design of spectra of multisine and binary excitation signals for multi-frequency bioimpedance measurement. AB - The paper discusses the usability of multi-frequency binary waveforms for broadband excitation in fast measurements of impedance spectrum of biological objects. It is shown that up to 70% of the energy of the amplitude spectrum of such two-level binary signals can be concentrated into the selected separate frequencies. The levels of selected frequency components are controllable in tens and hundreds of times. In this way we can underline the most important frequencies enhancing the corresponding amplitudes in the spectrum of excitation signal. As an implementation example, we consider the impedance spectroscopy in micro-fluidic devices for inline measurement of the conductivity of droplets in segmented flow. We use a thin-walled glass capillary with electrodes contacting the outer surface so that the contactless measurement of conductivity of liquid with biologic cells becomes possible. PMID- 22255227 TI - Broadband RF impedance spectroscopy in micromachined microfluidic channels. AB - Impedance spectroscopy in the radio frequency range from 100 MHz to 20 GHz can reveal the dielectric relaxations of biological and chemical solutions. S parameters for a coplanar waveguide are derived. To perform these measurements, a coplanar waveguide device was fabricated on a conventional FR-4 substrate for fluid interrogation. The microfluidic channel was formed by milling conventional waveguides and laser-cutting channels in the dielectric substrate. Measurements using this device were performed on standards: deionized water, isopropyl alcohol, and air. These measurements were compared to those taken with a conventional dielectric probe. The results demonstrate the ability of the fabricated device to extract varying transmission parameters due to changing sample properties. PMID- 22255228 TI - Motor adaptation during redundant tasks with the wrist. AB - This study analyzes motor adaptation during a redundant tasks with the wrist. The goal is threefold: (i) understanding if motor adaptation also occurs when CNS is involved in the solution of the redundancy problem; (ii) addressing whether motor strategies used to solve redundancy (i.e Donders' law) are disrupted or not during adaptation; (iii) verifying if motor strategies remain the same during adaptation and washout or they themselves adapt. First of all, our data confirm that CNS adapts its movements to the perturbation also when it is committed in the execution of a redundant task. Secondly, we showed that motor strategies used to solve redundancy (i.e Donders' law) are not disrupted during adaptation, since absolute values of thickness during the whole protocol remain in the range of physiological values. Lastly, analysis of the curvature of Donders' surfaces suggests that motor strategies, such as Donders' law, remain invariant during motor adaptation in redundant tasks. PMID- 22255229 TI - Adaptation to dynamic environments displays local generalization for voluntary reaching movements. AB - The shape of the directional generalization function for adaptation to a viscous force-field environment has been controversial. Some studies have suggested wide, essentially global generalization and others have suggested narrow, local generalization. Here, we show definitively that motor adaptation displays narrow generalization with a minimal global component and a peak at the trained movement direction for both single-trial and asymptotic adaptation. Furthermore, we find that reaching movements in opposite directions do not interfere with one another during force-field learning. PMID- 22255230 TI - Smart mug to measure hand's geometrical mechanical impedance. AB - A novel device, which looks like a mug, has been proposed for measuring the impedance of human hand. The device is designed to have convenient size and light weight similar to an ordinary coffee mug. It contains a 2-axis inertia sensor to monitor vibration and a small motor to carry an eccentric mass (m=100 gr, r=2 cm, rpm=600). The centrifugal force due to the rotating mass applies a dynamic force to the hand that holds the mug. Correlation of the acceleration signals with the perturbing force gives the geometrical mechanical impedance. Experimental results on a healthy subject shows that impedance is posture dependant while it changes with the direction of the applied perturbing force. For nine postures the geometrical impedance is obtained all of which have elliptical shapes. The method can be used for assessment of spasticity and monitoring stability in patients with stroke or similar problems. PMID- 22255231 TI - The motor system estimates uncertainty and higher order statistics for the control of grip forces. AB - Successful manipulation of an object requires exerting grip forces (GF) sufficient to prevent slippage. To prevent slip in more uncertain environments, GF would need to increase. Here we investigate the brain's ability to efficiently control grasp by producing GFs that correspond to confidence estimates of uncertain environments that are characterized by probability density functions of different variances and higher order moments. We found that GFs increased dramatically with the level of environmental uncertainty, and even when environmental uncertainty was held constant while higher order moments were varied, GFs changes in a way that was appropriate for kurtosis. PMID- 22255232 TI - Neural mechanisms of limb position estimation in the primate brain. AB - Understanding the neural mechanisms of limb position estimation is important both for comprehending the neural control of goal directed arm movements and for developing neuroprosthetic systems designed to replace lost limb function. Here we examined the role of area 5 of the posterior parietal cortex in estimating limb position based on visual and somatic (proprioceptive, efference copy) signals. Single unit recordings were obtained as monkeys reached to visual targets presented in a semi-immersive virtual reality environment. On half of the trials animals were required to maintain their limb position at these targets while receiving both visual and non-visual feedback of their arm position, while on the other trials visual feedback was withheld. When examined individually, many area 5 neurons were tuned to the position of the limb in the workspace but very few neurons modulated their firing rates based on the presence/absence of visual feedback. At the population level however decoding of limb position was somewhat more accurate when visual feedback was provided. These findings support a role for area 5 in limb position estimation but also suggest that visual signals regarding limb position are only weakly represented in this area, and only at the population level. PMID- 22255233 TI - Contribution of sensory and motor components to motor control asymmetries: an analytical model approach. AB - Proprioceptive and motor information contribute to movement representation; however, the equivalence of homologous contralateral information has received little attention. In a recent study using the matching paradigm we showed that upper limb position sense, based on feedback control, is asymmetric and this asymmetry could be associated with a difference in gain between left (L) and right (R) sensorimotor systems. The current results also show that movement sense is asymmetric in males and this asymmetry is dependent on handedness. It is assumed that a difference in gain between each sensorimotor system may be associated with asymmetric kinesthetic representations in cortical areas. Outcomes of models representing position and velocity control respectively suggest that velocity matching may be primarily controlled in a feed forward mode. Furthermore, compatibility between the models representing position control and velocity control also indicate that i) a difference between the L and R motor gains alone is not possible and ii) there must be a difference between the L and R sensory gains. Hence, the results strongly suggest a difference in movement representation between the two hand/hemisphere systems. PMID- 22255234 TI - Probabilistic modeling of selective stimulation of the human sciatic nerve with a flat Interface Nerve Electrode. AB - Proper ankle control is critical to both standing balance and efficient walking. This study hypothesized that a Flat Interface Nerve Electrode (FINE) placed around the sciatic nerve with a fixed number of contacts at predetermined locations and without a priori knowledge of the nerve's underlying neuroanatomy can selectively control each ankle motion. Models of the human sciatic nerve surrounded by a FINE of varying size were created and used to calculate the probability of selective activation of axons within any arbitrarily designated group of fascicles. Simulations suggest that currently available implantable technology cannot selectively recruit each target plantar flexor individually but can restore plantar flexion or dorsiflexion from a site on the sciatic nerve without spillover to antagonists. Successful activation of individual ankle muscles in 90% of the population can be achieved by utilizing bipolar stimulation and/or by increasing the number of contacts within the cuff. PMID- 22255235 TI - A model of motoneuron behavior and muscle-force generation for sustained isometric contractions. AB - A model for the simulation of motoneuron firing behavior and muscle force during sustained constant-force isometric contractions was developed. It provides a non linear relationship between the excitation to the motoneuron pool of a muscle and the firing behavior of motor units; it implements muscle mechanical changes induced by fatigue and it comprises a feedback loop to maintain the muscle force at a given target level. We simulated a series of repeated force contractions sustained at 20% MVC with the first dorsal interosseous muscle of the hand and the vastus lateralis muscle of the thigh. The model generates force and firing behaviors which are consistent with experimental findings and underscores the influence of muscle mechanical changes on the control behavior of motor units during sustained contractions. The model predicts the increase of force fluctuation with fatigue in both muscles, likely due to recruitment of high threshold high-amplitude twitch motor units. Force variability is greater in the first dorsal interosseous muscle than in the vastus lateralis muscle at any time during the contraction series, due to the different electrical and mechanical properties of the muscles. PMID- 22255236 TI - On force regulation strategies in predictable environments. AB - This paper is focused on investigating force regulation strategies employed by human central nervous system (CNS). The mechanism responsible for force control is extremely important in people's lives, but not yet well understood. We formulate the general model of force regulation and identify several possible control strategies. An experimental approach is used to determine which of the force control strategies could actually be used by the CNS. Obtained results suggest that the force regulation process involves not only the pure force controller, but also a coupled motion controller, relying on the internal model of the environment. PMID- 22255237 TI - Effect of self-gating on action potential firing at neuromuscular junction. AB - The neuromuscular junction (NMJ) is the place where the axon terminal of motoneuron connects the 'endplate' of a muscle fiber. During this transduction a large depolarization (endplate potential) caused by the nerve impulse opens a large number of voltage-sensitive sodium channels at the post-junctional terminal. As a result, action potentials are generated and propagated along the muscle fiber causing contraction. This work shows simulated results of the voltage-dependent sodium channels' firing behavior at the NMJ using a mathematical model. It is found that the firing behavior of the sodium channels change basing on their activation and inactivation kinetics which are highly influenced by the self-gating behavior of the sodium conductances. The simulation results showed that self-gating of sodium channels increase conduction efficiency at the NMJ and decrease threshold for firing. PMID- 22255238 TI - A physiologically and biomechanically approximate model for surface electromyography amplitude estimation. AB - Surface electromygraphy (sEMG) provides information of the neural drive to the muscle, so muscle force estimation by sEMG is of high relevance in biomechanical studies and in bionic applications. Even though mean absolute value (MAV) has been widely used for sEMG amplitude estimation due to the probabilistic nature of sEMG, but it has been used without any comprehensive physiological justification. A physiologically and biomechanically approximate model for the force estimation would enable a clear understanding of the relationships between sEMG and the force, and it can be used as sEMG amplitude estimation method. We proposed a new sEMG amplitude estimation method comprising two procedures: MUAP (motor unit action potential) event detection and muscle force indication using a biomechanical muscle model. The estimation performances were evaluated with nine subjects and compared with MAV. The performance (R(2)) of the proposed method (0.94 +/- 0.03) outperformed it of MAV (0.90 +/- 0.02). The method we proposed should be widely applicable to quantitatively analysis muscle activities by sEMG. PMID- 22255239 TI - Automated way to obtain motor units' signatures and estimate their firing patterns during voluntary contractions using HD-sEMG. AB - A new, automated way to obtain signatures of active motor units (MUs) from high density surface EMG recordings during voluntary contractions is presented. It relies on clustering of repetitive shapes corresponding to different MU action potentials (MUAPs) present. The number of clusters and the mean shapes of the MUAPs as observed on the electrode grid, are estimated in a fast way without user interaction. The algorithm is tested on simulated signals mimicking a small muscle. Our results show that at least 8 MUAPs can be reliably reconstructed and their MU mean firing frequencies can be estimated. PMID- 22255240 TI - Optimal measurement position estimation by discriminant analysis based on Wilks' lambda for myoelectric hand control. AB - This paper describes an optimal measurement position estimation by the discriminant analysis based on Wilks' lambda for the myoelectric hand control. In the past studies, the myoelectric signals were measured from the same positions for the motions discrimination. However, the optimal measurement positions of the myoelectric signals for the motion discrimination are different according to the remaining muscle situation of amputees. Therefore the purpose of this study is to estimate the optimal and fewer measurement positions for the precise motion discrimination of the human forearm. This study proposes the estimation method of the optimal measurement positions by the discriminant analysis based on Wilks' lambda among the myoelectric signal measured from multiple positions. Some experiments on the myoelectric hand simulator show the effectiveness of the proposed optimal measurement position estimation method. PMID- 22255241 TI - Recognition of hand motions via surface EMG signal with rough entropy. AB - The rough entropy (RoughEn) is developed based on the rough set theory. It has the advantage of low computational complexity, because there is no parameter to set in RoughEn. In this paper, we characterized the feature of surface electromyography (SEMG) signal with RoughEn and then used support vector machine to classify six different hand motions. The sample entropy, wavelet entropy and approximate entropy were compared with RoughEn to evaluate the performance of characterizing SEMG signals. The experimental results indicated that the RoughEn based classification outperformed other entropy based methods for recognizing six hand motions from four-channel SEMG signals with the best recognition accuracy of 95.19 +/- 2.99%. The results suggest that RoughEn has the potential to be used in the SEMG-based prosthetic control as a method of feature extraction. PMID- 22255243 TI - Changes in spatial distribution of flexor digitorum superficialis muscle activity is correlated to finger's action. AB - Multitendoned extrinsic muscles of the human hand can be divided into several neuromuscular compartments (NMCs), each of which contributes to the ability of human finger to produce independent finger movements or force. The aim of this study was to investigate the changes in the spatial activation of flexor digitorum superficialis (FDS) during the fingertip force production with non invasive multichannel surface electromyography (sEMG) technique. 7 healthy Subjects were instructed to match the target force level for 5s using individual index finger (I), individual middle finger (M) and the combination of the index and middle finger (IM) respectively. Simultaneously, a 2 * 6 electrode array was employed to record multichannel sEMG from FDS as finger force was produced. The entropy and center of gravity of the sEMG root mean square (RMS) map were computed to assess the spatial inhomogeneity in muscle activation and the change in spatial distribution of EMG amplitude related to the force generation of specific task finger. The results showed that the area and intensity of high amplitude region increased with force production, and the entropy increased with force level under the same task finger. The findings indicate that the change of spatial distribution of multitendoned extrinsic hand muscle activation is correlated to specific biomechanical functions. PMID- 22255242 TI - Quantification of isolated muscle compartment activity in extrinsic finger muscles for potential prosthesis control sites. AB - Prosthetic hands are becoming more advanced and gaining degrees-of-freedom similar to their human counterparts. However, the command interface enabling control of these prostheses needs to be improved for more intuitive functional use. One barrier to using electromyographic (EMG) signals as the command interface is measuring independent muscle control sites in the residual limb. Surface electrodes are commonly used to detect muscle activity in the forearm; however, the measured signals are often comprised of EMG signals from multiple muscles that are close together. This study investigated the suitability of the index and middle finger compartments of the extrinsic muscles as control sites for prostheses using a direct myocontrol interface. Fine-wire intramuscular electrodes were inserted into seven subjects and their ability to achieve isolated activations of each compartment was tested. The results showed five of the six compartments yield signals suitable for independent volitional control. The middle finger compartment of extensor digitorum communis was found to be incapable of isolated contractions and is therefore not recommended as a control site for direct myocontrol prostheses. A cross-correlation threshold was used to verify that simultaneously measured EMG signals were free from crosstalk and were therefore attributed to muscle co-activations. PMID- 22255244 TI - Psychophysical detection thresholds in anterior horizontal translations of seated and standing blindfolded subjects. AB - To help separate out the contributions of the somatosensory and vestibular systems to postural and sway control, short (1, 4 and 16 mm) anterior translations of lengths less than the normal sway path length were made of a platform upon which blindfolded young adult test subjects (n=12) stood or sat. Acceleration detection thresholds from these short moves were compared in standing vs seated conditions using a 2-Alternative [Interval] Forced-Choice psychophysical test protocol. A negative power law trading relationship was found between peak acceleration threshold and move length and duration for standing subjects. For these same subjects while seated, acceleration thresholds for all lengths were nearly constant, and showed a weak positive power law trade between threshold and move length or duration. This latter observation is consistent with that of Benson et al '86, who also observed a positive power law trade relationship between acceleration threshold and move duration for seated subjects. Thresholds were higher at 1mm for standing vs. seated tests; while at 16 mm, standing tests had lower thresholds compared to those obtained for the seated tests. These results suggest that the vestibular system provides the principal input for detecting these short translations while seated, but not while standing. PMID- 22255245 TI - Subtle grip force estimation from EMG and muscle stiffness--relationship between muscle character frequency and grip force. AB - A number of upper limb amputees experience difficulty in picking up a food bowl during a meal, because grip force estimation using EMG currently does not provide sufficient accuracy for this task. In this paper, we propose a grip force estimation system that allows amputees to pick up a bowl with a prosthetic hand by using the properties of muscle stiffness in addition to EMG. We have chosen a tray holding task to evaluate the proposed system. A weight is dropped on the tray and the subjects are expected to control the tray's attitude during the task. Actual grip force, EMG, and muscle stiffness are measured, and the actual measured grip force is compared with the estimated grip force for evaluation. As a result, the proposed algorithm is found to be able to estimate grip force with an error of just 18[N], which is 30% smaller than in the method that uses only EMG. From the result that the response time estimated by proposed system is even less than a human's mechanical reaction time, the effectiveness of the proposed method has been validated. PMID- 22255246 TI - Estimation of joint impedance using short data segments. AB - Joint impedance is an important property of the human muscular system and plays a role in the control of movement and posture. Previous studies showed that joint impedance varies with the position of the joint and activation level of the surrounding muscles; however, it remains unknown how it varies during movement. Non-parametric algorithms that estimate time-varying impedance do exist; however these algorithms require hundreds of realizations of the same time-varying behavior. In this paper we develop a non-parametric algorithm that can estimate slowly time-varying impedance using multiple short data segments. Using simulated data we evaluate the desired data segment length and the number of realizations needed to yield accurate estimates. PMID- 22255247 TI - Efficient estimation of time-varying intrinsic and reflex stiffness. AB - Dynamic joint stiffness defines the dynamic relationship between the position of the joint and the torque acting about it; hence it is important in the control of movement and posture. Joint stiffness consists of two components: intrinsic stiffness and reflex stiffness. Measuring intrinsic and reflex torques directly is not possible, thus estimating intrinsic and reflex stiffness is challenging. A further complication is that both intrinsic and reflex stiffness vary with joint position and torque. Thus, the measurement of dynamic joint stiffness during movement requires a time-varying algorithm. Recently we described an algorithm to estimate time-varying intrinsic and reflex stiffness and demonstrated its application. This paper describes modifications to that algorithm that significantly improves the accuracy of the estimates it generates while increasing its computational efficiency by a factor of seven. PMID- 22255248 TI - Controlling a virtual forehand prosthesis using an adaptive and affective Human Machine Interface. AB - This paper presents the design of an adaptable Human-Machine Interface (HMI) for controlling virtual forearm prosthesis. Direct physical performance measures (obtained score and completion time) for the requested tasks were calculated. Furthermore, bioelectric signals from the forehead were recorded using one pair of electrodes placed on the frontal region of the subject head to extract the mental (affective) measures while performing the tasks. By employing the proposed algorithm and above measures, the proposed HMI can adapt itself to the subject's mental states, thus improving the usability of the interface. The quantitative results from 15 subjects show that the proposed HMI achieved better physical performance measures in comparison to a conventional non-adaptive myoelectric controller (p < 0.001). PMID- 22255249 TI - Robotic-assisted locomotor training impact on neuromuscular properties and muscle strength in spinal cord injury. AB - We studied the effects of Robotic-Assisted Locomotor (LOKOMAT) Training on neuromuscular properties and muscle strength of the spastic ankle in persons with incomplete Spinal Cord Injury (SCI). LOKOMAT training was performed 3 days/week during a 1-hr period including set-up time. The training was provided for 4 weeks and subjects were evaluated before and after 1, 2, and 4 weeks of training. A system identification technique was used to quantify the effects of LOKOMAT training on neuromuscular abnormalities. The effect of LOKOMAT training on muscle strength was determined by measuring isometric maximum voluntary contraction (MVC) of ankle extensor and flexor muscles. Our results indicated that the reflex stiffness, abnormally increases in SCI, was significantly reduced (up to 65%) following 4-weeks of LOKOMAT training. Similarly, intrinsic (muscular) stiffness, which also abnormally increases in SCI, decreased significantly (up to 60%). MVCs were increased substantially (up to 93% in extensors and 180% in flexors) following 4-week training. These findings demonstrate that LOKOMAT training is effective in reducing spasticity and improving muscle strength in SCI. PMID- 22255250 TI - The impact of shoulder abduction loading on EMG-based intention detection of hand opening and closing after stroke. AB - Many stroke patients are subject to limited hand functions in the paretic arm due to a significant loss of Corticospinal Tract (CST) fibers. A possible solution for this problem is to classify surface Electromyography (EMG) signals generated by hand movements and uses that to implement Functional Electrical Stimulation (FES). However, EMG usually presents an abnormal muscle coactivation pattern shown as increased coupling between muscles within and/or across joints after stroke. The resulting Abnormal Muscle Synergies (AMS) could make the classification more difficult in individuals with stroke, especially when attempting to use the hand together with other joints in the paretic arm. Therefore, this study is aimed at identifying the impact of AMS following stroke on EMG pattern recognition between two hand movements. In an effort to achieve this goal, 7 chronic hemiparetic chronic stroke subjects were recruited and asked to perform hand opening and closing movements at their paretic arm while being either fully supported by a virtual table or loaded with 25% of subject's maximum shoulder abduction force. During the execution of motor tasks EMG signals from the wrist flexors and extensors were simultaneously acquired. Our results showed that increased synergy-induced activity at elbow flexors, induced by increasing shoulder abduction loading, deteriorated the performance of EMG pattern recognition for hand opening for those with a weak grasp strength and EMG activity. However, no such impact on hand closing has yet been observed possibly because finger/wrist flexion is facilitated by the shoulder abduction-induced flexion synergy. PMID- 22255251 TI - Changes in input-output relations in the corticospinal pathway to the lower limb muscles during robot-assisted passive stepping. AB - We investigated input (stimulus)-output (response) relations of the corticospinal pathway in the lower limb muscles during passive stepping using a robotic driven gait orthosis. Nine healthy adult subjects passively stepped with 40% body weight unloading (ground stepping) and 100% body weight unloading in the air (air stepping). During passive stepping, the motor evoked potentials (MEPs) of the lower limb muscles elicited by transcranial magnetic stimulation (TMS) were recorded at late-stance, early-, and late-swing phases of 2 stepping conditions. The input-output relation at each phase of the stepping conditions was obtained by increasing stimulus intensity in 5% increments from 40% to 70% of maximal stimulator output. The slopes of input-output relations were steeper at the early swing phase in the rectus femoris muscle and at the late-stance and late-swing phases in the biceps femoris muscle in both stepping conditions. There were no significant differences in the MEP responses of the rectus femoris and biceps femoris muscles at each phase between the 2 conditions. Low muscle activity was seen at the late-stance phase of ground stepping in the soleus muscle and the MEP amplitude at this phase became larger. The slopes in the tibialis anterior muscle were steep at the early- and late-swing phases of ground stepping. There was a significant difference in the MEPs of the tibialis anterior muscle between the late-swing phases in ground and air stepping. The present study indicates that corticospinal excitability to the lower limb muscles is modulated by sensory inputs elicited by passive stepping. PMID- 22255252 TI - Robot applied stance loading increases hindlimb muscle mass and stepping kinetics in a rat model of spinal cord injury. AB - Following spinal cord injury (SCI) reduced limb usage typically results in muscle atrophy. While robotic locomotor training has been shown to improve several aspects of stepping ability following SCI, little is known regarding the effects of automated training on the preservation of muscle function. The purpose of this study was to evaluate the effects of two robotic locomotor training algorithms on hindlimb strength and muscle mass in a rat model of SCI. Eighteen Sprague-Dawley rats received a mid-thoracic spinal cord transection at 5 days of age, and were randomly assigned to one of three groups: control (no training), standard robotic training, and robotic training with a downward force applied to the shank during the stance phase of gait. Training occurred 5 days/week for 5 min/day, and animals received 90% body weight support for all sessions. Following 4 weeks of training, vertical and propulsive ground reaction force during stepping and en vitro mass of two plantarflexor muscles were significantly increased for all of the trained animals when compared to the untrained control group. Post hoc analysis revealed that standard robotic training did not appear to increase ground reaction force and muscle mass to the same extent as the loaded condition. These results indicate that automated robotic training helps to preserve hindlimb muscle function in rats following SCI. Further, the addition of a plantarflexion stance load appears to promote greater increases in muscle mass and stepping kinetics. PMID- 22255253 TI - Simulation and analysis of split gradient coil performance in MRI. AB - Split magnet systems for hybrid imaging, such as positron emission tomography magnetic resonance imaging (PET-MRI) and Radiotherapy-MRI, require gradient coils designed with similar shapes as their corresponding main magnet. This introduces challenges in the gradient coil design of good performance and manufacturing. In this paper the effect of the gap size in shielded transverse split gradient coils and split cryostat "warm" bore over the coil efficiency, shielding efficiency, wire spacing, cryostat ohmic power loss and mechanical vibration have been simulated and studied. A "free-surface" gradient coil design method was used to design the split, actively-shielded transverse gradient coils with an axial gap. A network method was used to calculate the eddy currents induced in the split cryostat "warm" bore. The shielding efficiency and the minimum wire spacing were found to decrease when the size of the central gap is increased. The ohmic power loss and the amplitude of the radial vibrations in the split cryostat "warm" bore increases when the gap size in the gradient coil and "warm" bore is increased. It is hoped that these investigations will be useful for the development of new hybrid imaging modalities involving MRI. PMID- 22255254 TI - Development of a feedback stimulation for drowsy driver using heartbeat rhythms. AB - We investigated the physiological response of a vibratory stimulation, which has the rhythm of heartbeats, and examined whether it is useful for the feedback stimulation for drowsy driving. We evaluated the efficiency of 4 types of vibratory rhythms for stimulation by using the sleepiness level estimated by the multiple linear regression model made from the indices of ECG and respiration. As the result, the vibratory rhythm, which has the real time heartbeats of subjects themselves, had an effect of inducing their physiological condition closer to the condition when they were struggling against the drowsiness. We concluded that the stimulation might be useful to prevent a drowsy driving if we could give it to the driver before he or she gets the severe drowsiness. PMID- 22255255 TI - Development of a patient simulator for teaching and evaluation of the basic cardio-pulmonary reanimation protocol. AB - Providing appropriate cardio-pulmonary reanimation after cardio-pulmonary arrest is paramount for survival. An effective and low-cost approach to learn and practice the cardio-pulmonary reanimation is through a computerized life-size patient simulator. The present work describes the development of a patient simulator for the Centre of Education and Certification of Medical Aptitudes (CECAM) from the UNAM's Faculty of Medicine. This patient simulator has many new and innovative features, such real-time feedback to the medical student, which improves the whole teaching/learning experience. PMID- 22255256 TI - A pulse wave simulator for palpation in the oriental medicine. AB - Pulse diagnosis, which is one of methods of diagnosis, is an important factor in oriental medicine. However, a problem in diagnosis with the pulse is that there is no objective standard. Therefore, the practitioners pass on the skill and students learn about pulse diagnosis as a method that depends on speech. In this study, the electronic pulse wave reproduction apparatus, which is an objective and accurate means for measuring the pulse, was developed. The previous model reproduced the pulse wave in one part of the point, but it was made by using three pairs of voice coil motors (VCM) in order to similarly express the three parts of the pulse: Cun, Guan and Chi. To evaluate this system, the output of the pulse wave was confirmed in order to reproduce the pulse wave with these settings. Consequently, the targets for slow pulse and rapid pulse have a 7 ms standard deviation, which is within the error tolerance. A voltage value of H(1), utilized to verify vacuous pulse and the replete pulse, has a standard deviation range of 4.7-5.4 mV. This system, which is similar to a person's pulse diagnosis, can be used to educate others in pulse diagnosis both quantitatively and scientifically. PMID- 22255257 TI - High-frequency limit of neural stimulation with ChR2. AB - Optogenetic technology based on light activation of genetically targeted single component opsins such as Channelrhodopsin-2 (ChR2) has been changing the way neuroscience research is conducted. This technology is becoming increasingly important for neural engineering as well. The efficiency of neural stimulation with ChR2 drops at high frequencies, often before the natural limit of the neuron is reached. This study aims to investigate the underlying mechanisms that limit the efficiency of the stimulation at high frequencies. The study analyzes the dynamics of the spikes induced by ChR2 in comparison to control stimulations using patch clamp current injection. It shows that the stimulation dynamics is limited by two mechanisms: 1) a frequency independent reduction in the conductance-to-irradiance yield due to the ChR2 light adaptation process and 2) a frequency dependent reduction in the conductance-to-current yield due to a decrease in membrane re-polarization level between spikes that weakens the ionic driving force. The effect of the first mechanism can be minimized by using ChR2 mutants with lower irradiance threshold. In contrast the effect of the second mechanism is fundamentally limited by the rate the native ion channels re polarize the membrane potential. PMID- 22255258 TI - Comparing linear and quadratic models of the human auditory system using EEG. AB - Recent studies have highlighted the importance of system identification as an approach for assessing sensory processing in humans using electroencephalography (EEG). These studies typically use linear impulse response estimates of visual and, more recently, auditory function. These methods, which are known as the VESPA and AESPA (Visual/Auditory Evoked Spread Spectrum Analysis) respectively, have been found to be useful for studying sensory processing in both healthy populations and clinical groups and for studying the effects of cognition on sensory processing. While a nonlinear extension of the VESPA has been previously described, no such extension has yet been examined for the AESPA. This paper investigates such an extension and quantifies the relative contribution of linear and quadratic processes to the EEG in response to novel auditory stimuli. While the ability to accurately predict novel EEG is poor, it is highly significant, with a slightly, but again significantly, greater ability to predict using a quadratic model (r=0.0418) over a linear model (r=0.0361). PMID- 22255259 TI - Assessing neuronal interactions of cell assemblies during general anesthesia. AB - Understanding the way in which groups of cortical neurons change their individual and mutual firing activity during the induction of general anesthesia may improve the safe usage of many anesthetic agents. Assessing neuronal interactions within cell assemblies during anesthesia may be useful for understanding the neural mechanisms of general anesthesia. Here, a point process generalized linear model (PPGLM) was applied to infer the functional connectivity of neuronal ensembles during both baseline and anesthesia, in which neuronal firing rates and network connectivity might change dramatically. A hierarchical Bayesian modeling approach combined with a variational Bayes (VB) algorithm is used for statistical inference. The effectiveness of our approach is evaluated with synthetic spike train data drawn from small and medium-size networks (consisting of up to 200 neurons), which are simulated using biophysical voltage-gated conductance models. We further apply the analysis to experimental spike train data recorded from rats' barrel cortex during both active behavior and isoflurane anesthesia conditions. Our results suggest that that neuronal interactions of both putative excitatory and inhibitory connections are reduced after the induction of isoflurane anesthesia. PMID- 22255260 TI - Modulations in the oscillatory activity of the Globus Pallidus internus neurons during a behavioral task-A point process analysis. AB - The behavioral state of a subject is hypothesized to be reflected in the oscillatory modulations of the spiking activity of certain groups of neurons. In particular, the beta- and gamma-bands have been experimentally shown to be related to movement in the motor cortex and parts of the basal ganglia. Here, we analyze the relationship between directional tuning and oscillations in the beta- and gamma-bands of the neurons in the Globus Pallidus internus (GPi) of two healthy nonhuman primates during a radial center-out motor task. We find that, during the planning stages of the movement, the percentage of directionally tuned neurons displaying gamma oscillations increases when compared to the percentage of directionally tuned neurons displaying beta oscillations. A similar trend is not seen in non-directionally tuned neurons. This suggests that the GPi neurons involved in the planning of movement communicate information using an emergence of oscillations in the gamma-band. PMID- 22255261 TI - Learning of spatial relationships between observed and imitated actions allows invariant inverse computation in the frontal mirror neuron system. AB - It has been suggested that the human mirror neuron system can facilitate learning by imitation through coupling of observation and action execution. During imitation of observed actions, the functional relationship between and within the inferior frontal cortex, the posterior parietal cortex, and the superior temporal sulcus can be modeled within the internal model framework. The proposed biologically plausible mirror neuron system model extends currently available models by explicitly modeling the intraparietal sulcus and the superior parietal lobule in implementing the function of a frame of reference transformation during imitation. Moreover, the model posits the ventral premotor cortex as performing an inverse computation. The simulations reveal that: i) the transformation system can learn and represent the changes in extrinsic to intrinsic coordinates when an imitator observes a demonstrator; ii) the inverse model of the imitator's frontal mirror neuron system can be trained to provide the motor plans for the imitated actions. PMID- 22255262 TI - Synaptic weighting for physiological responses in recurrent spiking neural networks. AB - Recurrently connected neural networks have been used extensively in the literature to describe various neuro-physiological phenomena, such as coordinate transformations during sensorimotor integration. Due to the directed cycles that can exist in recurrent networks, there is no well-known way to a priori specify synaptic weights to elicit neuron spiking responses to stimuli based on available neurophysiology. Using a common mean field assumption in which synaptic inputs are uncorrelated for sufficiently large populations of neurons, we show that the connection topology and a neuron's response characteristics can be decoupled. This allows specification of neuron steady-state responses independent of the connection topology. We provide evidence from two case studies which serve to validate this synaptic weighting approach. PMID- 22255263 TI - An automatic ocular artifacts removal method based on wavelet-enhanced canonical correlation analysis. AB - In this paper, a new method for automatic ocular artifacts (OA) removal in EEG recordings is proposed based on wavelet-enhanced canonical correlation analysis (wCCA). Compared to three popular ocular artifacts removal methods, wCCA owns two advantages. First, there is no need to identify the artifact components by subjective visual inspection, because the first canonical components found by CCA for each dataset, also the most common component between the left and right hemisphere, are definitely related to artifacts. Second, quantitative evaluation of the corrected EEG signals demonstrates that wCCA removed the most ocular artifacts with minimal cerebral information loss. PMID- 22255264 TI - High-density EEG and independent component analysis mixture models distinguish knee contractions from ankle contractions. AB - Decoding human motor tasks from single trial electroencephalography (EEG) signals can help scientists better understand cortical neurophysiology and may lead to brain computer interfaces (BCI) for motor augmentation. Spatial characteristics of EEG have been used to distinguish left from right hand motor imagery and motor action. We used independent component analysis (ICA) of EEG to distinguish right knee action from right ankle action. We recorded 264-channel EEG while 5 subjects performed a variety of knee and ankle exercises. An adaptive mixture independent component analysis (ICA) algorithm generated two distinct mixture models from a merged set of EEG signals (including both knee and ankle actions) without prior knowledge of the underlying exercise. The ICA mixture models parsed EEG signals into maximally independent component (IC) processes representing electrocortical sources, muscle sources, and artifacts. We calculated a spatially fixed equivalent current dipole for each IC using an inverse modeling approach. The fit of the models to the single trial EEG signals distinguished knee exercises from ankle exercise with 90% accuracy. For 3 of 5 subjects, accuracy was 100%. Electrocortical current dipole locations revealed significant differences in the knee and ankle mixture models that were consistent with the somatotopy of the tasks. These data demonstrate that EEG mixture models can distinguish motor tasks that have different somatotopic arrangements, even within the same brain hemisphere. PMID- 22255265 TI - Calibrating EEG-based motor imagery brain-computer interface from passive movement. AB - EEG data from performing motor imagery are usually collected to calibrate a subject-specific model for classifying the EEG data during the evaluation phase of motor imagery Brain-Computer Interface (BCI). However, there is no direct objective measure to determine if a subject is performing motor imagery correctly for proper calibration. Studies have shown that passive movement, which is directly observable, induces Event-Related Synchronization patterns that are similar to those induced from motor imagery. Hence, this paper investigates the feasibility of calibrating EEG-based motor imagery BCI from passive movement. EEG data of 12 healthy subjects were collected during motor imagery and passive movement of the hand by a haptic knob robot. The calibration models using the Filter Bank Common Spatial Pattern algorithm on the EEG data from motor imagery were compared against using the EEG data from passive movement. The performances were compared based on the 10*10-fold cross-validation accuracies of the calibration data, and off-line session-to-session transfer kappa values to other sessions of motor imagery performed on another day. The results showed that the calibration performed using passive movement yielded higher model accuracy and off-line session-to-session transfer (73.6% and 0.354) than the calibration performed using motor imagery (71.3% and 0.311), and no significant differences were observed between the two groups (p=0.20, 0.23). Hence, this study shows that it is feasible to calibrate EEG-based motor imagery BCI from passive movement. PMID- 22255266 TI - Eye fixation related potentials in a target search task. AB - Typically BCI (Brain Computer Interfaces) are found in rehabilitative or restorative applications, often allowing users a medium of communication that is otherwise unavailable through conventional means. Recently, however, there is growing interest in using BCI to assist users in searching for images. A class of neural signals often leveraged in common BCI paradigms are ERPs (Event Related Potentials), which are present in the EEG (Electroencephalograph) signals from users in response to various sensory events. One such ERP is the P300, and is typically elicited in an oddball experiment where a subject's attention is orientated towards a deviant stimulus among a stream of presented images. It has been shown that these types of neural responses can be used to drive an image search or labeling task, where we can rank images by examining the presence of such ERP signals in response to the display of images. To date, systems like these have been demonstrated when presenting sequences of images containing targets at up to 10 Hz, however, the target images in these tasks do not necessitate any kind of eye movement for their detection because the targets in the images are quite salient. In this paper we analyse the presence of discriminating EEG signals when they are offset to the time of eye fixations in a visual search task where detection of target images does require eye fixations. PMID- 22255267 TI - Comparisons between linear and nonlinear methods for decoding motor cortical activities of monkey. AB - Brain Machine Interfaces (BMI) aim at building a direct communication link between the neural system and external devices. The decoding of neuronal signals is one of the important steps in BMI systems. Existing decoding methods commonly fall into two categories, i.e., linear methods and nonlinear methods. This paper compares the performance between the two kinds of methods in the decoding of motor cortical activities of a monkey. Kalman filter (KF) is chosen as an example of linear methods, and General Regression Neural Network (GRNN) and Support Vector Regression (SVR) are two nonlinear approaches evaluated in our work. The experiments are conducted to reconstruct 2D trajectories in a center-out task. The correlation coefficient (CC) and the root mean square error (RMSE) are used to assess the performance. The experimental results show that GRNN and SVR achieve better performance than Kalman filter with average improvements of about 30% in CC and 40% in RMSE. This demonstrates that nonlinear models can better encode the relationship between the neuronal signals and response. In addition, GRNN and SVR are more effective than Kalman filter on noisy data. PMID- 22255269 TI - Improved BCI performance with sequential hypothesis testing. AB - One of the primary challenges in noninvasive brain-computer interface (BCI) control is low information transfer rate (ITR). An approach that employs a power based sequential hypothesis testing (SHT) technique is presented for real-time detection of motor commands. Electroencephalogram (EEG) recordings obtained during a BCI task were first analyzed with a hypothesis testing (HT) method. Using serial analysis we minimized the time to determine a cued motor imagery cursor control decision. Experimental results show that the accuracy of the SHT method was above 80% for all the subjects (n = 3). The average decision time was 3.4 s, as compared with 6.0 s for the HT method. Moreover, the proposed SHT method has three times the information transfer rate (ITR) compared with the HT method. PMID- 22255268 TI - Behavioral rehabilitation of the eye closure reflex in senescent rats using a real-time biosignal acquisition system. AB - In this paper the replacement of a lost learning function of rats through a computer-based real-time recording and feedback system is shown. In an experiment two recording electrodes and one stimulation electrode were implanted in an anesthetized rat. During a classical-conditioning paradigm, which includes tone and airpuff stimulation, biosignals were recorded and the stimulation events detected. A computational model of the cerebellum acquired the association between the stimuli and gave feedback to the brain of the rat using deep brain stimulation in order to close the eyelid of the rat. The study shows that replacement of a lost brain function using a direct bidirectional interface to the brain is realizable and can inspire future research for brain rehabilitation. PMID- 22255270 TI - Brisk movement imagination for the non-invasive control of neuroprostheses: a first attempt. AB - The consequences of a spinal cord injury (SCI) are tremendous for the patients. The loss of motor functions, especially of grasping, leads to a dramatic decrease in quality of life. With the help of neuroprostheses, the grasp function can be substantially improved in cervical SCI patients. Nowadays, systems for grasp restoration can only be used by patients with preserved voluntary shoulder and elbow function. In patients with lesions above the 5th vertebra, not only the voluntary movements of the elbow are restricted, but also the overall number of preserved movements available for control purposes decreases. In this work, a new method for the non-invasive use of a Brain-Computer Interface (BCI) for the control of the hand and elbow function is presented. PMID- 22255271 TI - Design principles for noninvasive brain-machine interfaces. AB - With the advent of sophisticated prosthetic limbs, the challenge is now to develop and demonstrate optimal closed-loop control of the these limbs using neural measurements from single/multiple unit activity (SUA/MUA), electrocorticography (ECoG), local field potentials (LFP), scalp electroencephalography (EEG) or even electromyography (EMG) after targeted muscle reinnervation (TMR) in subjects with upper limb disarticulation. In this paper we propose design principles for developing a noninvasive EEG-based brain-machine interface (BMI) for dexterous control of a high degree-of-freedom, biologically realistic limb. PMID- 22255272 TI - Brain-controlled telepresence robot by motor-disabled people. AB - In this paper we present the first results of users with disabilities in mentally controlling a telepresence robot, a rather complex task as the robot is continuously moving and the user must control it for a long period of time (over 6 minutes) to go along the whole path. These two users drove the telepresence robot from their clinic more than 100 km away. Remarkably, although the patients had never visited the location where the telepresence robot was operating, they achieve similar performances to a group of four healthy users who were familiar with the environment. In particular, the experimental results reported in this paper demonstrate the benefits of shared control for brain-controlled telepresence robots. It allows all subjects (including novel BMI subjects as our users with disabilities) to complete a complex task in similar time and with similar number of commands to those required by manual control. PMID- 22255273 TI - EEG single-trial classification of visual, auditive and vibratory feedback potentials in Brain-Computer Interfaces. AB - Feedback stimuli are fundamental components in Brain-Computer Interfaces. It is known that the presentation of feedback stimuli elicits certain brain potentials that can be measured and classified. As stimuli can be given through different sensory modalities, it is important to understand the effects of different types of feedback on brain responses and their impact on classification. This paper presents a protocol used to obtain brain potentials elicited by visual, auditive or vibrotactile feedback stimuli. Experiments were carried out with five different subjects for each modality. Four different single-trial classification strategies were compared, according to the information used to train the classifier, achieving a classification rate of approximately 80% for each modality. PMID- 22255274 TI - Goal selection vs. process control in non-invasive brain-computer interface. AB - Today's brain-computer interfaces (BCIs) record the electrical signal from the cortex and use that signal to control an external device, such as a computer cursor, wheelchair, or neuroprosthetic. Two control strategies used by BCIs, process control and goal selection, differ in the amount of assistance the BCI system provides the user. This paper looks at non-invasive studies that directly compare goal selection to process control. In these studies, the assistance provided by a BCI using goal selection 1) increased the user's performance with the BCI and 2) resulted in an EEG signal that was more conducive to good performance. PMID- 22255275 TI - Estimating bladder pressure from sacral dorsal root ganglia recordings. AB - Individuals with dysfunctional bladders may benefit from devices that track the bladder state. Recordings from pelvic and sacral nerve cuffs can detect bladder contractions, however they often have low signal quality and are susceptible to interference from non-bladder signals. Microelectrode recordings from sacral dorsal root ganglia (DRG) neurons may provide an alternate source for obtaining high quality sensory signals for bladder pressure monitoring. In this study, penetrating microelectrode arrays were inserted in the S1 and S2 DRG in two cats to record afferent spiking activity at different bladder pressures. Multivariate linear regression models were used to estimate bladder pressure from the spiking activity of DRG neurons. The best estimates were obtained with populations of 5 10 units primarily from the S2 DRG, with root mean square errors of 3.0-3.2 cm H(2)O (correlation coefficients of 0.5-0.9). This work demonstrates the feasibility of monitoring bladder pressure from DRG recordings. PMID- 22255276 TI - Performance of electromyography recorded using textile electrodes in classifying arm movements. AB - Electromyography (EMG) signals are commonly recorded using the Ag/AgCl gel electrodes in myoelectric prosthetic control. While a gelled electrode may provide high-quality EMG recordings, it is inconvenient in clinical application of a myoelectric prosthesis. A novel type of signal sensors-textile electrodes should be ideal in control of myoelectric prostheses. However, it is unknown whether the performance of textile electrodes is comparable to commonly used electrodes in classifying arm movements. In this study, the custom-made bipolar textile electrodes were fabricated using copper-based nickel-plated conductive fabric and were used to record EMG signals. The performance of EMG signals recorded with textile electrodes in identifying nine arm and hand movements were investigated. Our pilot results showed that the average classification accuracy across six able-bodied subjects was 94.05% when using textile electrodes and 94.26% when using conventional electrodes, with no significant difference between the two types of electrodes (p=0.81). The pilot results suggest that the textile electrodes could achieve similar performance in classifying arm movements in control of myoelectric prostheses as the gelled metal electrodes. PMID- 22255277 TI - A multi-modal approach for hand motion classification using surface EMG and accelerometers. AB - For decades, electromyography (EMG) has been used for diagnostics, upper-limb prosthesis control, and recently even for more general human-machine interfaces. Current commercial upper limb prostheses usually have only two electrode sites due to cost and space limitations, while researchers often experiment with multiple sites. Micro-machined inertial sensors are gaining popularity in many commercial and research applications where knowledge of the postures and movements of the body is desired. In the present study, we have investigated whether accelerometers, which are relatively cheap, small, robust to noise, and easily integrated in a prosthetic socket; can reduce the need for adding more electrode sites to the prosthesis control system. This was done by adding accelerometers to a multifunction system and also to a simplified system more similar to current commercially available prosthesis controllers, and assessing the resulting changes in classification accuracy. The accelerometer does not provide information on muscle force like EMG electrodes, but the results show that it provides useful supplementary information. Specifically, if one wants to improve a two-site EMG system, one should add an accelerometer affixed to the forearm rather than a third electrode. PMID- 22255278 TI - An algorithm for source signal extraction from the peripheral nerve. AB - Extracting physiological signals to control external devices such as prosthetics is a field of research that offers great hope for patients suffering from disabilities. In this paper, a novel source signal extraction algorithm, based on the source localization method Champagne, is presented. The algorithm constructs spatial filters that not only maximizes the signal to noise ratio (SNR > 13 dB) of the source activities but also minimizes the cross-talk interference between the sources 10log((P(source of interest)/P(interference sources)) > 14 dB. PMID- 22255279 TI - Improving the performance of a neural-machine interface for artificial legs using prior knowledge of walking environment. AB - A previously developed neural-machine interface (NMI) based on neuromuscular mechanical fusion has showed promise for recognizing user locomotion modes; however, errors of NMI during mode transitions were observed, which may challenge its real application. This study aimed to investigate whether or not the prior knowledge of walking environment could further improve the NMI performance. Linear Discriminant Analysis (LDA)-based classifiers were designed to identify user intent based on electromyographic (EMG) signals from residual muscles of leg amputees and ground reaction force (GRF) measured from the prosthetic leg. The prior knowledge of the terrain in front of the user adjusted the prior possibility in the discriminant function. Therefore, the boundaries of LDA were adaptive to the prior knowledge of the walking environment. This algorithm was evaluated on a dataset collected from one patient with a transfemoral (TF) amputation. The preliminary results showed that the NMI with adaptive prior possibilities outperformed the NMI without using the prior knowledge; it produced 98.7% accuracy for identifying tested locomotion modes, accurately predicted all the task transitions with 261-390 ms prediction time, and generated stable decision during task transitions. These results indicate the potential of using prior knowledge about walking environment to further improve the NMI for prosthetic legs. PMID- 22255280 TI - An EMG-controlled neuroprosthesis for daily upper limb support: a preliminary study. AB - MUNDUS is an assistive platform for recovering direct interaction capability of severely impaired people based on upper limb motor functions. Its main concept is to exploit any residual control of the end-user, thus being suitable for long term utilization in daily activities. MUNDUS integrates multimodal information (EMG, eye tracking, brain computer interface) to control different actuators, such as a passive exoskeleton for weight relief, a neuroprosthesis for arm motion and small motors for grasping. Within this project, the present work integreted a commercial passive exoskeleton with an EMG-controlled neuroprosthesis for supporting hand-to-mouth movements. Being the stimulated muscle the same from which the EMG was measured, first it was necessary to develop an appropriate digital filter to separate the volitional EMG and the stimulation response. Then, a control method aimed at exploiting as much as possible the residual motor control of the end-user was designed. The controller provided a stimulation intensity proportional to the volitional EMG. An experimental protocol was defined to validate the filter and the controller operation on one healthy volunteer. The subject was asked to perform a sequence of hand-to-mouth movements holding different loads. The movements were supported by both the exoskeleton and the neuroprosthesis. The filter was able to detect an increase of the volitional EMG as the weight held by the subject increased. Thus, a higher stimulation intensity was provided in order to support a more intense exercise. The study demonstrated the feasibility of an EMG-controlled neuroprosthesis for daily upper limb support on healthy subjects, providing a first step forward towards the development of the final MUNDUS platform. PMID- 22255281 TI - A wearable system for the seismocardiogram assessment in daily life conditions. AB - Seismocardiogram (SCG) is the recording of the minute body accelerations induced by the heart activity, and reflects mechanical aspects of heart contraction and blood ejection. So far, most of the available systems for the SCG assessment are designed to be used in a laboratory or in controlled behavioral and environmental conditions. In this paper we propose a modified version of a textile-based wearable device for the unobtrusive recording of ECG, respiration and accelerometric data (the MagIC system), to assess the 3d sternal SCG in daily life. SCG is characterized by an extremely low magnitude of the accelerations (in the order of g * 10(-3)), and is masked by major body accelerations induced by locomotion. Thus in daily life recordings, SCG can be measured whenever the subject is still. We observed that about 30 seconds of motionless behavior are sufficient for a stable estimate of the average SCG waveform, independently from the subject's posture. Since it is likely that during spontaneous behavior the subject may stay still for at least 30 seconds several times in a day, it is expected that the SCG could be repeatedly estimated and tracked over time through a prolonged data recording. These observations represent the first testing of the system in the assessment of SCG out of a laboratory environment, and open the possibility to perform SCG studies in a wide range of everyday conditions without interfering with the subject's activity tasks. PMID- 22255282 TI - Three-dimensional ballistocardiography in microgravity: a review of past research. AB - This paper gives a short review of research on ballistocardiography in microgravity and indicates the benefits from this research for the use of BCG as a terrestrial cardiac monitoring system. In the past, 3-D methods required large devices to decouple the subject from the terrestrial environment and hence, BCG on Earth is usually limited to unidirectional recordings of the motion in the head-to-foot direction. However, microgravity provides a suspension-free environment where accelerations can be measured in all directions without the influence of gravity. Microgravity research indicated that along with the acceleration in the head-to-foot direction, the accelerations in the lateral and dorso-ventral direction are important in understanding the physiological forces during a cardiac cycle. Further, lung volume has a large influence on the transmission of cardiac forces to the surface of the body. To date, only the three separate components of the acceleration vector have been analyzed in 3-D BCG studies. Using the true acceleration and displacement vector (orientation and magnitude), rather than the three separate components, may permit more accurate cardiac event detection. PMID- 22255283 TI - Three dimensional ballistocardiography: methodology and results from microgravity and dry immersion. AB - Balistocardiography was recorded in 3-D on a free floating astronaut in space as well as on healthy volunteers participating to a dry immersion study in a terrestrial laboratory. We demonstrate a new technique suitable for the analysis of 3-D BCG. The spatial curve of the displacement vector is analyzed instead of the three components of acceleration. The technique presented is invariant from the axis of representation and provides important novel physiological information. PMID- 22255284 TI - Infrasonic cardiac signals: complementary windows to cardiovascular dynamics. AB - New approaches to fairly old noninvasive cardiology tools, based on studying low frequency vibrations created by the heart on the body, were reviewed. These signals were divided and studied in two categories and compared in their capability for estimation of hemodynamic parameters. In particular one representative signal of each category, seismocardiogram and ultra-low frequency ballistocardiogram, were selected and compared to each other in their correspondence to physiological events behind their waves. PMID- 22255286 TI - Cardiac sounds from a wearable device for sternal seismocardiography. AB - Seismocardiography is the body-surface recording of vibrations produced by the beating heart. A high frequency (HF) accelerometric component of the seismocardiogram (SCG) is related to the heart sounds generated by the closure of atrio-ventricular and semilunar valves. This paper evaluates the feasibility of recording the SCG component associated to cardiac sounds by means of a wearable device originally designed for monitoring ECG, respiratory movements, body accelerations and posture in freely moving subjects. The method is based on the averaging of the HF component of the acceleration vector measured by the wearable system, and on the subsequent extraction of features from its envelope. The method is applied on data recorded in healthy volunteers in different postures and during sleep. Results indicate that it is possible to reliably identify the time of occurrence of the first and second heart sound within the cardiac cycle. They also show significant differences in the HF component of SCG between supine and standing postures. Analyzing the HF SCG in a volunteer sleeping at high altitude (4554 m asl) substantial differences were also found among three body positions (lying supine or on the left or right side). These differences are likely to reflect changes in cardiac mechanics induced by different postures of the body. PMID- 22255285 TI - Ballistocardiography--a method worth revisiting. AB - The field of ballistocardiography seems to be enjoying a recent resurgence, most notably through the development of novel technologies and signal processing methods for measurement and analysis. After the method almost vanished in the late 80's and 90's, it is reasonable to wonder what is different this time, and if the technique has now more chances of becoming what its pioneer always wanted a widespread clinical tool. This paper is an effort to compare and contrast this novel wave of research (notably in the context of the authors' own work). It also suggests that the new approaches have several key differences with past embodiments that place them in a good position to address some specific issues such as cardiac resynchronization therapy device optimization or congestive heart failure monitoring. This optimism is largely fed by the recent technological advances enabling the measurement of the BCG unobtrusively, frequently, at home or in a hospital, and by a re-focus on monitoring and trending applications. PMID- 22255287 TI - A comparative study on extra-corporal circulation control. AB - Hydraulic models of the human circulatory system allow simulation of hemodynamics in a standardized setting. In this work we use such a model to compare concurrent control strategies for extra-corporal circulation control. Patients suffering from cardio-vascular diseases under extra-corporal circulation can benefit from an automated regulation. The control task is to keep either the pump flow or the pressure in the cardio-vascular system at a constant target value, despite any parameter variations or external perturbations. We implement four control strategies that seem favorable for our task: a Proportional-Integral Controller, a H(infinity)-Controller, a PI-Fuzzy Controller and a Model Reference Adaptive Controller. The methods are compared quantitatively and their advantages and drawbacks are discussed. PMID- 22255288 TI - Robust, beat-to-beat estimation of the true pulse transit time from central and peripheral blood pressure or flow waveforms using an arterial tube-load model. AB - We proposed a technique for estimating beat-to-beat pulse transit time (PTT) from central and peripheral blood pressure or flow waveforms based on an arterial tube load model of wave reflection. The technique effectively estimates PTT from the entire waveforms after mathematically eliminating the reflected wave. So, unlike the conventional foot-to-foot detection technique, this technique should be robust to artifact while revealing the true PTT (i.e., the PTT in absence of wave reflection). We compared the two techniques, as applied to blood pressure and flow waveforms, in terms of the ability of their PTT estimates to correlate with blood pressure (a) during baseline (for which the naturally occurring beat-to beat changes were small), (b) during low heart rate (wherein wave reflection was profound), and (c) in the presence of actual measurement artifact. In all three cases, the PTT estimates of the arterial tube-load model technique yielded markedly superior correlation to blood pressure. PMID- 22255289 TI - Impact of baroreflex on venous return surface. AB - BACKGROUND: Although Guyton's concept of venous return (VR) revolutionized circulatory physiology, the pulmonary circulation is invisible in its original framework. Since the pulmonary circulation is critical in left heart failure, we characterized the VR as a surface described by right (P(RA)) and left atrial (P(LA)) pressures and demonstrated that the VR surface was capable of representing mechanics of pulmonary as well as systemic circulation. However how baroreflex impacts the VR surface remains unknown. METHODS/RESULTS: In 8 dogs, we isolated the carotid sinuses and replaced both ventricles with pumps. We varied cardiac output, shifted blood distribution between the systemic and pulmonary circulation at carotid sinus pressures (CSP) of 100 or 140 mmHg. The coefficient of determination of the VR surface ranged 0.96-0.99 indicating how flat the surface is. Increasing CSP decreased maximum VR (233 +/- 27 vs. 216 +/- 33 ml/kg/min, p<0.05), whereas did not change the slopes of VR along P(RA) or P(LA) axes. CONCLUSIONS: Baroreflex parallel shifts the VR surface, thereby stressed volume, without changing its slopes. PMID- 22255290 TI - Reduction of myocardial oxygen demand by controlling heart rate and hemodynamics simultaneously by novel circulatory model. AB - We were already capable of restoring automatically blood pressure, cardiac output, and left atrial pressure by an inotropic, a vasodilator, and volume infusion/a diuretic. Countermeasures for cardioprotection, however, should be integrated to improve the long-term outcomes. We established a full control of heart rate and examined if such a control was useful for decreasing cardiac oxygen consumption. Based on a simulation result, we conducted an animal experiment. In 7 dogs with acute heart failure, we treated hemodynamics, and then lowered heart rate. Compared to the treatment for hemodynamics alone, the addition of bradycardia decreased cardiac oxygen consumption. It was possible to maintain hemodynamics without sacrificing cardiac oxygen consumption. PMID- 22255291 TI - Haemodynamic modeling of the cardiovascular system using mock circulation loops to test cardiovascular devices. AB - Comprehensive testing and evaluation of cardiovascular device function and performance is required prior to clinical implementation. Initial proof of concept investigations are conducted within in-vitro mock circulation loops, before proof of principle is demonstrated via in-vivo animal testing. To facilitate the rapid transition of cardiovascular devices through this development period, a testing apparatus was developed that closely models the natural human cardiovascular system haemodynamics. This mock circulation system accurately replicates cardiac function, coupled to systemic and pulmonary circulations. The physiological response produced by a number of clinical cardiovascular conditions can be actively controlled by variable parameters such as vascular resistance, arterial/venous compliance, ventricle contractility, heart rate, and heart /vascular volumes, while anatomical variations such as valve regurgitation and septal defects can be included. Auto-regulation of these parameters was attempted to reproduce the Frank-Starling mechanism, baroreceptor reflex, skeletal muscle pump, and postural changes. Steady state validation of loop performance was achieved by replicating the progression of a patient's clinical haemodynamics from heart failure, through VAD support, to heart transplantation. The system has been used to evaluate pulsatile and non-pulsatile ventricular assist devices, counter pulsation devices, non-invasive cardiac output monitors and cardiovascular stents. The interaction of these devices with the cardiovascular system was also investigated with regards to physiological control strategies and cannula placement. The system is a valuable tool for the accelerated progression of cardiovascular device development. PMID- 22255292 TI - The response of hepatocyte cell volume to hyperthermia and its role in oedema. AB - A novel mathematical model for hepatocytes and surrounding volume is presented here; in addition to tracking ion transport and diffusion the new model allows for changing cell volume. Using temporally and spatially varying temperature as an input, this paper shows how differences between diffusion coefficients directly influence increases in cell volume. The multiscale nature of the model presents a possible link from established cellular equations to the observed clinical result of oedema present in thermal treatments of cancer. PMID- 22255293 TI - Patient-specific modeling of stress/strain for surgical planning and guidance. AB - We describe a method for performing modeling and simulation to predict the strain and stress experienced by tissues resulting from reconstructive cardiothoracic surgery. Stress computation is an important predictor of the quality and longevity of a repair and can therefore be used as guidance by a surgeon when deciding between various repair options. This paper uses the mitral valve repair as a use case because of its relevance and prevalence among reconstructive cardiac interventions. The modeling method presented here is informed by the patient specific anatomical structure recovered from real time 3D echocardiography. The method exploits hyperelastic models to infer realistic strain-stresses. We show through experiments using actual clinical data that results are in line with physiological expectations. PMID- 22255294 TI - Mechanistic modeling of drug elimination by the liver using local volume averaging method. AB - Local volume averaging method and local mass (drug) equilibrium were used for developing a mathematical model for transient drug transport and elimination in the liver. Taking into account the liver porosity and tortuosity, physio-chemical properties of the drug, the drug effective diffusivity, dispersion, convection, local plasma-hepatocyte equilibrium and hepatocellular drug metabolism, the governing partial differential equation was developed and numerically solved to describe a transient drug transfer and elimination across the liver following intravenous (IV) administration. The predicted values of hepatic clearance and bioavailability had very good agreement with the reported observations for different drugs. Unlike the well-stirred, parallel tube and dispersion models of hepatic clearance, the proposed mechanistic model is able to predict the drug concentration gradient across the liver with time and position in very dynamic conditions associated with drug absorption process in the intestine. PMID- 22255295 TI - Comprehensive mechanism-based antibody pharmacokinetic modeling. AB - Pharmacokinetic models of antibody distribution and dynamics are useful for predicting and optimizing therapeutic behavior. Targeted antigens are produced and distributed in various tissues in specific patterns in disease phenotypes. Existing models leave out significant mechanistic detail which would enable an understanding of how to modify therapeutics in an optimal manner to allow appropriate tissue penetration in either a healthy or diseased state. The model presented here incorporates additional complexity such as diffusion through endothelial barriers, differential transcytosis properties, FcRn-mediated recycling, and incorporates these properties in an organ-specific manner. This creates a platform which can be expanded upon to include understanding of the effect of target on therapeutic distribution and clearance, differences in dynamics during a diseased versus healthy state, differential dose strategies, and mechanistic translation between animal models and human disease state. This model represents a superior alternative to typical and potentially over simplified scaling strategies utilized in most existing physiologically-based pharmacokinetic models. Ultimately, this will enable better therapeutic design and greater pharmacological effects. PMID- 22255296 TI - A framework for personalization of computational models of the human atria. AB - A framework for step-by-step personalization of a computational model of human atria is presented. Beginning with anatomical modeling based on CT or MRI data, next fiber structure is superimposed using a rule-based method. If available, late-enhancement-MRI images can be considered in order to mark fibrotic tissue. A first estimate of individual electrophysiology is gained from BSPM data solving the inverse problem of ECG. A final adjustment of electrophysiology is realized using intracardiac measurements. The framework is applied using several patient data. First clinical application will be computer assisted planning of RF ablation for treatment of atrial flutter and atrial fibrillation. PMID- 22255297 TI - Geometric modeling of pelvic organs. AB - The pelvic floor can be subjected to different disorders, coming from a physiological change in the spatial configuration of the organs of interest: the bladder, the rectum, the uterus and the vagina. However, resort to surgery to replace them is complicated to achieve. In order to support the decision of the surgeon as to the invasive method to use for the patient, the MoDyPe (Pelvis Dynamics Modeling) project was launched, aiming at building a patient specific pelvic organ behavior. Our approach consists in creating thick surfaces of hollow organs, using periodic B-splines and offsets, then in controlling their discretization and in exporting a hexahedral model to provide input data for the study on the dynamics of the soft bodies of interest. From a segmentation step providing a dataset of 3D points, a function is built to measure the bidirectional distance between the surface and the data. It is minimized with an alternate iterative Hoschek-like method, by updating the parametric map and moving the control points. Several offsets of the base surface are then created to build up the thickness of the organ. PMID- 22255298 TI - Single cell-mediated collagen reorganization in 3D matrices. AB - Cells use cytoskeletally-generated force to adhere, migrate and remodel their environment. While cellular forces generated by cells plated on 2D substrates is well-studied, much less is known about the forces generated by cells in 3D matrices, which more closely mimic the in vivo environment. Here, an approach to characterize cellular forces in 3D using confocal reflectance microscopy is presented. Remodeling of collagen fibrils due to the forces exerted by embedded cells was imaged in real-time as cells adhere to and contract the matrix. We implemented this approach in conjunction with 2D Traction Force Microscopy to compare cytoskeletally-mediated forces of cells in 3D collagen matrices to forces exerted by cells on 2D collagen-coated hydrogel substrates. Our results indicate that confocal reflectance microscopy of collagen fibrils can provide semi quantitative information regarding cellular force in 3D matrices, and that the actin cytoskeleton plays a similar role in regulating cell contractility in both 2D and 3D microenvironments. PMID- 22255299 TI - Pulse pressure monitoring through non-contact cardiac motion detection using 2.45 GHz microwave Doppler radar. AB - The use of a Continuous Wave (CW) quadrature Doppler radar is proposed here for continuous non-invasive Pulse Pressure monitoring. A correspondence between the variation in systemic pulse and variation in the displacement of the chest due to heart is demonstrated, establishing feasibility for the approach. Arctangent demodulation technique was used to process baseband data from radar measurements on two test subjects, in order to determine the absolute cardiac motion. An Omron digital Blood pressure cuff was used to measure the systolic and diastolic blood pressures from which the pulse pressure was calculated. Correlation between pulse pressure and cardiac motion was observed through changes induced due to different postures of the body. PMID- 22255300 TI - A novel system for continuous peripheral arterial pressure-volume loop measurement. AB - This study develops a system to obtain continuous blood pressure signal and impedance plethysmography (IPG) signal, simultaneously. Based on the principle of impedance measurement, the peripheral vessel volume change can be computed from the IPG signal. Equipped with simultaneous information of pressure and volume, a pressure-volume (PV) loop can be constructed. It is well known that the left ventricular pressure-volume loop contains a number of feature points indicating the performance of cardiac function. Therefore, in this study, the same principle is used to try to discuss the peripheral vessel pressure-volume loop. Ten volunteers were recruited for this study. Subjects went through the cold pressor test by immersing their left foot into ice water. Blood pressure signal and impedance changed were recorded using a custom-made system. The results illustrated that the pressure-volume loop, as it was expected, demonstrated a contraction phenomenon after stimulation in five out of ten subjects. The areas of those pressure-volume loops reduced as much as 70% in some subject. However, loop responses to stressors varied from subject to subject and the slope of the loop did not alter significantly. In conclusion, the proposed system is a potential way to measure and to investigate the compliance and characteristic of peripheral blood vessel. PMID- 22255301 TI - Adaptive control with self-tuning for non-invasive beat-by-beat blood pressure measurement. AB - Up to now, we have successfully carried out the non-invasive beat-by-beat measurement of blood pressure (BP) in the root of finger, superficial temporal and radial artery based on the volume-compensation technique with reasonable accuracy. The present study concerns with improvement of control method for this beat-by-beat BP measurement. The measurement system mainly consists of a partial pressurization cuff with a pair of LED and photo-diode for the detection of arterial blood volume, and a digital self-tuning control method. Using healthy subjects, the performance and accuracy of this system were evaluated through comparison experiments with the system using a conventional empirically tuned PID controller. The significant differences of BP measured in finger artery were not showed in systolic (SBP), p=0.52, and diastolic BP (DBP), p=0.35. With the advantage of the adaptive control with self-tuning method, which can tune the control parameters without disturbing the control system, the application area of the non-invasive beat-by-beat measurement method will be broadened. PMID- 22255303 TI - Investigation of pulse oximeter failure rates during artificial hypoperfusion utilising a custom made multimode pulse oximetery sensor. AB - Pulse oximetry utilises the technique of photoplethysmography (PPG) to estimate arterial oxygen saturation values (SpO2). In poorly perfused tissues, SpO2 readings may be compromised due to the poor quality of the PPG signals. In order to investigate further the threshold where pulse oximetry fails to produce accurate SpO2 values, we have developed a custom made multimode finger pulse oximetry probe that operates in conventional, reflectance and transmittance mode independently and also in a combined mode called transreflectance. Experiments on twenty healthy volunteers undergoing induced artificial hypoperfusion utilising a brachial blood pressure cuff were performed in order to investigate the possible threshold of failure to accurately estimate SpO2 values from all pulse oximetry modes. The results suggest that the transreflectance pulse oximeter endures more in estimating accurately SpO2 values when compared with the other two custom made pulse oximeters and a commercial finger pulse oximeter. PMID- 22255302 TI - Electro-optical plethysmography for non-invasive estimation of hemoglobin concentration. AB - Novel sensors and instrumentation are currently being investigated with the intended application of determining the concentration of hemoglobin and other optically absorbing compounds in blood using non-invasive methods. In order to measure concentration, the mass or amount of a compound must be known in addition to the volume of liquid. In principle, it may be possible to estimate hemoglobin concentration from a change in optical absorbance occurring over the cardiac cycle divided by a corresponding change in measured blood volume during the cycle measured from peripheral tissue, e.g. the finger or ear. Electrical and optical sensors were evaluated in vitro using a tissue phantom and an absorbing liquid medium. The effect of changes in optical absorption and pulse pressure on the capacitance and optical absorbance were studied. PMID- 22255304 TI - Refinement and evaluation of a hydraulic bed sensor. AB - Research indicates that long-term monitoring of vital signs and activity in elderly adults may provide opportunities for maintaining quality-of-life and extending independence into later years. Such a strategy requires development of a system to collect this data while imposing minimal intrusion into the lives of those being monitored. To further this goal, we have developed a hydraulic bed sensor to non-invasively monitor heartbeat and respiration during sleep. This paper describes the refinement of our developed prototype and signal processing methods, along with an evaluation of the robustness of our algorithms and results from testing. An evaluation of our sensor on a group of five diverse subjects (ranging in age from 24 to 67, two with cardiac history), in three different positions, demonstrates accuracy within 8 beats per minute up to 97.5% of the time. PMID- 22255305 TI - Photoplethysmograph quality estimation through multichannel filtering. AB - Information about the quality of a recorded physiological waveform can be valuable for the detection of critical medical conditions. This work presents a new point-by-point signal quality index (SQI) based on adaptive multichannel prediction which does not rely on ad-hoc morphological feature extraction from the target waveform. An application of the SQI to photoplethysmograph waveforms showed that the SQI is monotonically related to SNR (simulated by adding white noise) and subjective human quality assessment of 1,313 waveform epochs. A receiver-operating-characteristic (ROC) curve analysis, with the human "bad" quality label as negative and the human "good" quality label as positive, yielded an area under the ROC curve of 0.863. For photoplethysmograph waveforms, a SQI greater than 0.8 seems in general to be indicative of good signal quality. PMID- 22255306 TI - Tracking single dynamic MEG dipole sources using the projected Extended Kalman Filter. AB - This paper presents two new algorithms based on the Extended Kalman Filter (EKF) for tracking the parameters of single dynamic magnetoencephalography (MEG) dipole sources. We assume a dynamic MEG dipole source with possibly both time-varying location and dipole orientation. The standard EKF-based tracking algorithm performs well under the assumption that the dipole source components vary in time as a Gauss-Markov process, provided that the background noise is temporally stationary. We propose a Projected-EKF algorithm that is adapted to a more forgiving condition where the background noise is temporally nonstationary, as well as a Projected-GLS-EKF algorithm that works even more universally, when the dipole components vary arbitrarily from one sample to the next. PMID- 22255307 TI - A hidden Markov model-based technique for gait segmentation using a foot-mounted gyroscope. AB - In this paper, we describe an application of hidden Markov models (HMMs) to the problem of time-locating specific events in normal gait movement patterns. The use of HMMs in this paper is mainly related to the opportunity they offer to segment gait data collected at different walking speeds and inclinations of the walking surface. A simple four-state left-right HMM is trained on a dataset of signals collected from a mono-axial gyro during treadmill walking trials performed at different speed and incline values. The gyro is mounted at the foot instep, with its sensitivity axis oriented in the medio-lateral direction. A rule based method applied to gyro signals is used for data annotation. Sensitivity and specificity of phase classification detection higher than 95% are obtained. The estimation accuracy of heel strike, flat foot, heel off and toe off events is about 35 ms on average. PMID- 22255308 TI - On-line apnea-bradycardia detection using hidden semi-Markov models. AB - In this work, we propose a detection method that exploits not only the instantaneous values, but also the intrinsic dynamics of the RR series, for the detection of apnea-bradycardia episodes in preterm infants. A hidden semi-Markov model is proposed to represent and characterize the temporal evolution of observed RR series and different pre-processing methods of these series are investigated. This approach is quantitatively evaluated through synthetic and real signals, the latter being acquired in neonatal intensive care units (NICU). Compared to two conventional detectors used in NICU our best detector shows an improvement of around 13% in sensitivity and 7% in specificity. Furthermore, a reduced detection delay of approximately 3 seconds is obtained with respect to conventional detectors. PMID- 22255309 TI - Objective measure of upper extremity motor impairment in Parkinson's disease with inertial sensors. AB - Functional motor impairment caused by Parkinson's disease and other movement disorders is currently measured with rating scales such as the Unified Parkinson's Disease Rating Scale (UPDRS). These are typically comprised of a series of simple tasks that are visually scored by a trained rater. We developed a method to objectively quantify three upper extremity motor tasks directly with a wearable inertial sensor. Specifically, we used triaxial gyroscopes and adaptive filters to quantify how predictable and regular the signals were. We found that simply using the normalized mean squared error (NMSE) as a test statistic permitted us to distinguish between subjects with and without Parkinson's disease who were matched for age, height, and weight. A forward linear predictor based on the Kalman filter was able to attain areas under the curve (AUC) in receiver operator characteristic (ROC) curves in the range of 0.76 to 0.83. Further studies and development are warranted. This technology has the potential to more accurately measure the motor signs of Parkinson's disease. This may reduce statistical bias and variability of rating scales, which could lead to trials with fewer subjects, less cost, and shorter duration. PMID- 22255310 TI - Ordering samples along environmental gradients using particle swarm optimization. AB - Due to the enormity of the solution space for sequential ordering problems, non exhaustive heuristic techniques have been the focus of many research efforts, particularly in the field of operations research. In this paper, we outline an ecologically motivated problem in which environmental samples have been obtained along a gradient (e.g. pH), with which we desire to recover the sample order. Not only do we model the problem for the benefit of an optimization approach, we also incorporate hybrid particle swarm techniques to address the problem. The described method is implemented on a real dataset from which 22 biological samples were obtained along a pH gradient. We show that we are able to approach the optimal permutation of samples by evaluating only approximately 5000 solutions--infinitesimally smaller than the 22! possible solutions. PMID- 22255311 TI - Monitoring the depth of anesthesia from rat EEG using modified Shannon entropy analysis. AB - In this paper, an entropy based method for quantifying the depth of anesthesia from rat EEG is presented. The proposed index for the depth of anesthesia called modified Shannon entropy (MShEn) is based on Shannon entropy (ShEn) and spectral entropy (SpEn) which are widely used for analyzing non-stationary signals. Discrimination power (DP), as a performance indicator for indexes, is defined and used to derive the final index for the depth of anesthesia. For experiment, EEG from anesthetized rats are measured and analyzed by using MShEn. MShEn shows both high stability and high correlation with other indexes for depth of anesthesia. PMID- 22255313 TI - A method for detecting and editing MUPTs contaminated by false classification errors during EMG signal decomposition. AB - A robust method for detecting motor unit potential trains (MUPTs) contaminated with false classification errors (FCEs) during EMG signal decomposition and then removing the FCEs from a contaminated train is presented. Using motor unit (MU) firing pattern information provided by each MUPT, the developed algorithm first determines whether a given train is contaminated by high number of FCEs and needs to be edited. For contaminated MUPTs, the method uses both MU firing pattern and motor unit potential (MUP) shape information to detect MUPs that were erroneously assigned to the train (i.e., represent FCEs). For the simulated data used in this study contaminated MUPTs could be detected with 88.7% accuracy. For a given contaminated MUPT, the algorithm on average correctly detected 83.4% of the FCEs and left 93.4% of the correctly assigned MUPs. The accuracy of the MUPs classified to a MUPT was estimated to be 92.1% on average. PMID- 22255314 TI - Atrial fibrillation source identification. AB - Atrial Fibrillation, a common arrhythmia accompanied by an increased morbidity and mortality remains difficult to treat either with medications or invasive procedures. Targeted destruction of atrial fibrillation triggers offers the best hope for permanent resolution of the arrhythmia. In this work, identification of atrial triggers is based on the analysis of complex endocardial recordings. Here, we propose a novel algorithm to detect the source of atrial fibrillation by classifying the signals originating from the four pulmonary veins in the left atrium. PMID- 22255315 TI - Quantification of velocity anisotropy during gastric electrical arrhythmia. AB - In this study, an automated algorithm was developed to identify the arrhythmic gastric slow wave activity that was recorded using high-resolution mapping technique. The raw signals were processed with a Savitzky-Golay filter, and the slow wave activation times were identified using a threshold-varying method and grouped using a region-growing method. Slow wave amplitudes and velocities were calculated for all cycles. Arrhythmic events were identified when the orientation of a slow wave at an electrode exceeded the 95% confidence interval of the averaged orientation of several normal cycles. A second selection criterion was further developed to identify the arrhythmic events by an anisotropy ratio. In both pig and human studies, arrhythmias were associated with the emergence of circumferential velocity components and higher amplitudes. PMID- 22255316 TI - Aberrant auditory evoked responses in schizophrenia: evidence from single-trial analysis. AB - The average N100 (a negative response occurring around 100 ms poststimulus) component of the auditory evoked potential (EP) has been recently used in the study of schizophrenia. Averaging, however, eliminates all temporal variability of the recorded signals and, therefore, hampers the exploration of the temporal dynamics underlying the generation of the N100 component. In this study, we analyzed EPs on a single-trial basis using an iterative independent component analysis procedure that is capable of extracting individual components out of an entire EP waveform. This approach allowed estimation of an N100 in each single trial and measurement of its morphological features such as polarity, which could be either negative (most frequently) or positive (less frequently). In the latter case, the N100 component was termed aberrant. We analyzed responses from 23 normal controls (NC) and 15 schizophrenia (SZ) patients in a paired stimulus paradigm, where a first stimulus S(1) was followed by a second one S(2) 0.5 s later. To compare N100 responses within and across the two subject groups, we defined a negative polarity index NPI as the percentage of single trials that had a negative polarity N100. Our results show significantly higher NPI values in NC compared to SZ, for both the S(1) and S(2) responses. Additionally, the difference in NPI values between the S(1) and S(2) responses was significant in NC but not in SZ. We conclude that both normal and schizophrenia subjects exhibit aberrant N100 responses, but these events are more frequent in the SZ patient group. The higher number of aberrant responses can explain the lower amplitude EPs typically observed in schizophrenia, and may be one of the factors contributing to sensory gating deficits consistently reported in these patients. PMID- 22255317 TI - Separation of multiunit signals by independent component analysis in complex valued time-frequency domain. AB - Multiunit recording with a multi-electrode in the brain has been widely used in neuroscience studies. After the data recording, neuronal spikes should be sorted according to spike waveforms. For the spike sorting, independent component analysis (ICA) has recently been used because ICA potentially solves the problem to separate even overlapped multiple neuronal spikes into the single. However, we found that multiunit signals are recorded in each electrode channel with channel specific delay. This situation does not satisfy the instantaneous mixture condition prerequisite for most of ICA algorithms. Actually, this delayed mixture situation was shown to degrade the performance of an ordinary ICA. In this study, in order to overcome this problem, complex-valued processing in the time frequency domain is applied to multiunit signals by the wavelet transform. In the space spanned by the wavelet coefficients, the condition of instantaneous mixture is almost fulfilled. By application to a synthetic multiunit signal, the ICA algorithm extended to complex-valued signals makes much improvement in spike sorting performance so that even overlapped multiple spikes are successfully separated. Taken together, the complex-valued method could be a powerful tool for spike sorting. PMID- 22255318 TI - Reconstructing ECG precordial leads from a reduced lead set using independent component analysis. AB - In this paper, precordial lead reconstruction from a reduced set of leads is considered. We propose the use of independent component analysis to train patient specific transforms from a reduced lead set to the six precordial leads of the standard 12-lead electrocardiogram. The proposed approach is applied to a publicly available database comprising 549 ECG recordings of patients with varying cardiovascular conditions. The fidelity of reconstruction is measured using percent correlation between the actual and reconstructed signals following a 30 seconds time lapse. The mean correlation is over 95% with a standard deviation under 12.7% for all reconstructed leads. The results demonstrate the potential of the suggested approach to provide a reliable solution to precordial leads reconstruction. PMID- 22255319 TI - Functional network connectivity during rest and task: comparison of healthy controls and schizophrenic patients. AB - Functional connectivity examines temporal statistical dependencies among distant brain regions by means of seed-based analysis or independent component analysis (ICA). Spatial ICA also makes it possible to investigate functional connectivity at the network level, termed functional network connectivity (FNC). The dynamics of each network (ICA component) which may consist of several remote regions is described by the ICA time-course of that network; hence FNC studies statistical dependencies among ICA time-courses. In this paper, we compare comprehensively FNC in the resting state and during performance of an auditory oddball task in 28 healthy subject and 28 schizophrenic patients on relevant (non-artifactual) brain networks. The results show abnormalities both in the resting state and during the task but also the difference of the two states. Moreover, our results suggest that using data both in the resting-state and during the task can better separate the two groups. It is demonstrated that for three pairs of networks, the FNC of the healthy controls resides within a confined region of the correlation space whereas patients behave more sparsely. This can be used to discriminate the two groups based on partitioning the correlation space during the resting state and the task data. PMID- 22255320 TI - Assessment of artefact suppression by ICA and spatial filtering on reduced sets of EEG signals. AB - In recorded EEG signals, the signal components under interest are typically embedded in noise and artefacts. Independent Component Analysis has been demonstrated to be very successful at signal-to-noise ratio enhancement and artefact suppression, but mainly on a large set of EEG channels (20 or more) and typically on signals from healthy young subjects. In this paper, we assess the artefact suppression performance of five different ICA methods (AMUSE, FASTICA, RUNICA, SOBI and THINICA) combined with four different spatial filters on reduced sets of EEG channels from elderly tremor patients. Results demonstrate that a suitable combination of ICA and spatial filtering can effectively suppress artefacts in clinical EEG signals, even on very small sets with only three EEG channels. PMID- 22255321 TI - Light-weight single trial EEG signal processing algorithms: computational profiling for low power design. AB - Brain Computer Interface (BCI) systems translate brain rhythms into signals comprehensible by computers. BCI has numerous applications in the clinical domain, the computer gaming, and the military. Real-time analysis of single trial brain signals is a challenging task, due to the low SNR of the incoming signals, added noise due to muscle artifacts, and trial-to-trial variability. In this work we present a computationally lightweight classification method based on several time and frequency domain features. After preprocessing and filtering, wavelet transform and Short Time Fourier Transform (STFT) are used for feature extraction. Feature vectors which are extracted from theta and alpha frequency bands are classified using a Support Vector Machine (SVM) classifier. EEG data were recorded from 64 electrodes during three different Go/NoGo tasks. We achieved 91% classification accuracy for two-class discrimination. The high recognition rate and low computational complexity makes this approach a promising method for a BCI system running on wearable and mobile devices. Computational profiling shows that this method is suitable for real time signal processing implementation. PMID- 22255322 TI - Estimation of the gain and threshold of the stretch reflex with a novel subspace identification algorithm. AB - Reflex stiffness is often modeled as a Hammerstein system comprising a cascade of a static nonlinear element and a linear dynamic element. The nonlinearity is frequently modeled as a half wave rectifier so that changes in the reflex response can only be modeled by changes in the parameters of the linear element. This is an oversimplification since there are physiological mechanisms that could change both the threshold of the nonlinearity and the linear dynamics. This study explores the ability of a new subspace identification algorithm to distinguish changes in parameters of the nonlinear element from those of the linear element. Simulation studies demonstrate that the method does so very effectively even in the presence of substantial output noise. Pilot experiments in which the method was applied to stretch reflex EMG data revealed that both the threshold of the nonlinearity and the gain of the linear element change with muscle activation. PMID- 22255323 TI - Forearm motion discrimination technique using real-time EMG signals. AB - The objective of this study is to develop a method of discriminating real-time motion from electromyogram (EMG) signals. We previously proposed a motion discrimination method. This method could discriminate five motions (hand opening, hand closing, hand chucking, wrist extension, and wrist flexion) at a rate of above 90 percent from four channel EMG signals in the forearm. The method prevents elbow motions from interfering with hand motion discrimination. However, discrimination processing time of this method is more than 300 ms, and the shortest delay time that is perceivable by the user is generally regarded to be roughly 300 ms. Furthermore, a robot hand has a mechanical delay time. Thus, the discrimination time should be less than 300 ms. Here, we propose a real-time motion discrimination method using a hyper-sphere model. In comparison with the old model, the hyper-sphere models can make more complex decision regions which can discriminate at the state of the motion. Furthermore, this model can learn EMG signals in real-time. We experimentally verified that the discrimination accuracies of this method were above 90 percent. Moreover, elbow motions did not interfere with the hand motion discrimination. The discrimination processing time was less than 300 ms, and was about 30 percent shorter than that of the old method. PMID- 22255324 TI - Joint angle-based EMG amplitude calibration. AB - A calibration method is proposed to compensate for the changes in the surface electromyogram (SEMG) amplitude level of the biceps brachii at different joint angles due to the movement of the muscle bulk under the EMG electrodes for a constant force level. To this end, an experiment was designed, and SEMG and force measurements were collected from 5 subjects. The fast orthogonal search (FOS) method was used to find a mapping between SEMG from the biceps and force recorded at the wrist. Comparison between evaluation values from models trained with calibrated and non-calibrated SEMG signals revealed a statistically significant superiority of models trained with the calibrated SEMG. PMID- 22255325 TI - A CPG synergy model for evaluation of human finger tapping movements. AB - This paper proposes the CPG synergy model--a biomimetic rhythm generator model based on central pattern generators (CPGs) and muscle synergy theory to enable evaluation of rhythmic motions with non-stationary characteristics such as human finger tapping movements. The model consists of multiple CPGs to approximate the complex rhythmic movement of humans, and has the potential to allow evaluation of abnormal movements in patients with motor function impairments such as Parkinson's disease (PD). To verify the validity of the proposed model, comparison experiments were conducted using model parameters (i.e., synergies, weight coefficients and time-shift parameters) extracted from finger tapping movements performed by individuals in a healthy subject group and a PD patient group. The results showed that the number of synergies, the second moment of synergy shapes and the coefficient of variation of maximum weight coefficients show significant differences for each subject group, and indicated that the model could be used to evaluate irregular rhythmic movements as well as regular ones. PMID- 22255326 TI - Fall algorithm development using kinematic parameters measured from simulated falls performed in a quasi-realistic environment using accelerometry. AB - This study aims to determine the optimal temporal, angular and acceleration parameters and thresholds for an accelerometer based, chest-worn, fall detection algorithm. In total, 10 healthy male subjects performed 14 different fall types, 3 times by each. The falls were performed onto in a quasi-realistic environment consisting of mats of a minimum thickness. Optimum parameters for; t(falling): time-to-fall, theta(max): max-angle, t(thetamax) : max-angle-time, t(RTStanding) : Return-to-standing-time and t(lying) : lying-time were determined using a data set consisting of a total of 420 falls. PMID- 22255327 TI - Robust identification of multi-joint human arm impedance based on dynamics decomposition: a modeling study. AB - Multi-joint/multi-degree of freedom (DOF) human arm impedance estimation is important in many disciplines. However, as the number of joints/DOFs increases, it may become intractable to identify the system reliably. A robust, unbiased and tractable estimation method based on a systematic dynamics decomposition, which decomposes a multi-input multi-output (MIMO) system into multiple single-input multi-output (SIMO) subsystems, is developed. Accuracy and robustness of the new method were validated through a human arm and a 2-DOF exoskeleton robot simulation with various magnitudes of sensor resolution and nonlinear friction. The approach can be similarly applied to identify more sophisticated systems with more joints/DOFs involved. PMID- 22255328 TI - Ground surface segmentation for navigation with a low resolution visual prosthesis. AB - We propose the use of ground surface segmentation to enhance the perception of obstacles in low to medium resolution prosthetic visual representations. We apply a recently proposed algorithm for segmenting traversable space in stereo disparity data, and show how such a scheme may be utilised to enhance the distinction between the ground surface and obstructions (in particular, small trip hazards). Qualitative comparisons with intensity and straight depth-based representations highlight advantages for the visualisation of obstacles, offering potential gains for visual navigation with low resolution and low dynamic range visual prostheses. PMID- 22255329 TI - Acquisition and interactive 3D exploration of the internal structure of a dissected specimen. AB - We present a system to keep track of a destructive process such as a medical specimen dissection, from data acquisition to interactive and immersive visualization, in order to build ground truth models. Acquisition is a two-step process, first involving a 3D laser scanner to get a 3D surface, and then a high resolution camera for capturing the texture. This acquisition process is repeated at each step of the dissection, depending on the expected accuracy and the specific objects to be studied. Thanks to fiducial markers, surfaces are registered on each others. Experts can then explore data using interaction hardware in an immersive 3D visualization. An interactive labeling tool is provided to the anatomist, in order to identify regions of interest on each acquired surface. 3D objects can then be reconstructed according to the selected surfaces. We aim to produce ground truths which for instance can be used to validate data acquired with MRI. The system is applied to the specific case of white fibers reconstruction in the human brain. PMID- 22255330 TI - Real-time retrieval of similar videos with application to computer-aided retinal surgery. AB - This paper introduces ongoing research on computer-aided ophthalmic surgery. In particular, a novel Content-Based Video Retrieval (CBVR) system is presented. Its purpose is the following: given a video stream captured by a digital camera monitoring the surgery, the system should retrieve, in real-time, similar video subsequences in video archives. In order to retrieve semantically-relevant videos, most existing CBVR systems rely on temporally flexible distance measures such as Dynamic Time Warping. These distance measures are slow and therefore do not allow real-time retrieval. In the proposed system, temporal flexibility is introduced in the way video subsequences are characterized, which allows the use of simple and fast distance measures. As a consequence, realtime retrieval of similar video subsequences, among hundreds of thousands of examples, is now possible. Besides, the proposed system is adaptive: a fast training procedure is presented. The system has been successfully applied to automated recognition of retinal surgery steps on a 69-video dataset: areas under the Receiver Operating Characteristic curves range from A(z)=0.809 to A(z)=0.989. PMID- 22255331 TI - Thoracic image matching with appearance and spatial distribution. AB - Positron emission tomography--computed tomography (PET-CT) produces co-registered anatomical (CT) and functional (PET) patient information (3D image set) from a single scanning session, and is now accepted as the best imaging technique to accurately stage the most common form of primary lung cancer--non-small cell lung cancer (NSCLC). This paper presents a content-based image retrieval (CBIR) method for retrieving similar images as a reference dataset to potentially aid the physicians in PET-CT scan interpretation. We design a spatial distribution to describe the spatial information of each region-of-interest (ROI), and a pairwise ROI mapping scheme between images to compute the image matching level. Similar images are then retrieved based on the local and spatial information of the detected ROIs, and a learned weighted sum of ROI distances. Our evaluation on clinical data shows good image retrieval performance. PMID- 22255332 TI - Blind forensics in medical imaging based on Tchebichef image moments. AB - In this paper, we present a blind forensic approach for the detection of global image modifications like filtering, lossy compression, scaling and so on. It is based on a new set of image features we proposed, called Histogram statistics of Reorganized Block-based Tchebichef moments (HRBT) features, and which are used as input of a set of classifiers we learned to discriminate tampered images from original ones. In this article, we compare the performances of our features with others proposed schemes from the literature in application to different medical image modalities (MRI, X-Ray ...). Experimental results show that our HRBT features perform well and in some cases better than other features. PMID- 22255333 TI - Reversible watermarking based on invariant image classification and dynamical error histogram shifting. AB - In this article, we present a novel reversible watermarking scheme. Its originality stands in identifying parts of the image that can be watermarked additively with the most adapted lossless modulation between: Pixel Histogram Shifting (PHS) or Dynamical Error Histogram Shifting (DEHS). This classification process makes use of a reference image derived from the image itself, a prediction of it, which has the property to be invariant to the watermark addition. In that way, watermark embedded and reader remain synchronized through this image of reference. DEHS is also an original contribution of this work. It shifts predict-errors between the image and its reference image taking care of the local specificities of the image, thus dynamically. Conducted experiments, on different medical image test sets issued from different modalities and some natural images, show that our method can insert more data with lower distortion than the most recent and efficient methods of the literature. PMID- 22255334 TI - Focal edge association to glaucoma diagnosis. AB - Glaucoma is an optic nerve disease resulting in the loss of vision. There are two common types of glaucoma: open angle glaucoma and angle closure glaucoma. Glaucoma type classification is important in glaucoma diagnosis. Clinically, ophthalmologists examine the iridocorneal angle between iris and cornea to determine the glaucoma type as well as the degree of closure. However, manual grading of the iridocorneal angle images is subjective and often time consuming. In this paper, we propose focal edge for automated iridocorneal angle grading. The iris surface is located to determine focal region and focal edges. The association between focal edges and angle grades is built through machine learning. A modified grading system with three grades is adopted. The experimental results show that the proposed method can correctly classify 87.3% open angle and 88.4% closed angle. Moreover, it can correctly classify 75.0% grade 1 and 77.4% grade 0 for angle closure cases. PMID- 22255335 TI - Atherosclerotic plaque characterization in Optical Coherence Tomography images. AB - Optical Coherence Tomography (OCT) is a fiber--optic imaging modality which produces high resolution tomographic images of the coronary lumen and outer vessel wall. While OCT images present morphological information in highly resolved detail, the characterization of the various plaque components relies on trained readers. The aim of this study is to extract a set of features in grayscale OCT images and to use them in order to classify the atherosclerotic plaque. Intensity and texture based features we used in order to classify the plaque in four plaque types: Calcium (C), Lipid Pool (LP), Fibrous Tissue (FT) and Mixed Plaque (MP). 50 OCT annotated images from 3 patients were used to train and test the proposed plaque characterization method. Using a Random Forests classifier overall classification accuracy 80.41% is reported. PMID- 22255336 TI - AtheromaticTM: symptomatic vs. asymptomatic classification of carotid ultrasound plaque using a combination of HOS, DWT & texture. AB - Quantitative characterization of carotid atherosclerosis and classification into either symptomatic or asymptomatic is crucial in terms of diagnosis and treatment planning for a range of cardiovascular diseases. This paper presents a computer aided diagnosis (CAD) system (AtheromaticTM, patented technology from Biomedical Technologies, Inc., CA, USA) which analyzes ultrasound images and classifies them into symptomatic and asymptomatic. The classification result is based on a combination of discrete wavelet transform, higher order spectra and textural features. In this study, we compare support vector machine (SVM) classifiers with different kernels. The classifier with a radial basis function (RBF) kernel achieved an accuracy of 91.7% as well as a sensitivity of 97%, and specificity of 80%. Encouraged by this result, we feel that these features can be used to identify the plaque tissue type. Therefore, we propose an integrated index, a unique number called symptomatic asymptomatic carotid index (SACI) to discriminate symptomatic and asymptomatic carotid ultrasound images. We hope this SACI can be used as an adjunct tool by the vascular surgeons for daily screening. PMID- 22255337 TI - Probabilistic lung nodule classification with belief decision trees. AB - In reading Computed Tomography (CT) scans with potentially malignant lung nodules, radiologists make use of high level information (semantic characteristics) in their analysis. Computer-Aided Diagnostic Characterization (CADc) systems can assist radiologists by offering a "second opinion"--predicting these semantic characteristics for lung nodules. In this work, we propose a way of predicting the distribution of radiologists' opinions using a multiple-label classification algorithm based on belief decision trees using the National Cancer Institute (NCI) Lung Image Database Consortium (LIDC) dataset, which includes semantic annotations by up to four human radiologists for each one of the 914 nodules. Furthermore, we evaluate our multiple-label results using a novel distance-threshold curve technique--and, measuring the area under this curve, obtain 69% performance on the validation subset. We conclude that multiple-label classification algorithms are an appropriate method of representing the diagnoses of multiple radiologists on lung CT scans when ground truth is unavailable. PMID- 22255339 TI - Automated scoring of liver fibrosis through combined features from different collagen groups. AB - Liver biopsy remains the gold standard in monitoring progression of liver fibrosis associated with an abnormal increase in collagen. Descriptive scoring systems are still being widely used to grade biopsy samples. In this study, we propose a new set of features by clustering collagen fibers into three groups first based on their localization and connectivity properties, and then by extracting morphological features of collagen fibers. The new feature set is compared to the earlier features used in classification of liver fibrosis, which were based on the total amount of collagen fibers. Our results show that new features lead to more accurate grading of liver fibrosis. PMID- 22255338 TI - Classification of Alzheimer's Disease from structural MRI using sparse logistic regression with optional spatial regularization. AB - In this paper, we apply Sparse Logistic Regression Classifiers to the classification of 69 Alzheimer's Disease and 60 normal control subjects based on voxel-wise grey matter volumes derived from structural MRI. Methods such as standard logistic regression cannot be used in such problems because of the large number of voxels in comparison to the number of training subjects. Sparse Logistic Regression (SLR) addresses this issue by incorporating a sparsity penalty into the log-likelihood, which effects an automatic feature selection within the classification framework. We apply two different formulations of sparse logistic regression and compare their classification accuracy with that of Penalized Logistic Regression (PLR) and Maximum uncertainty Linear Discriminant Analysis (MLDA). In the first approach, we use the original formulation of SLR in which correlated voxels are forced to have similar weights. In the second approach we use a spatially regularized formulation, SRSLR, to force the discriminating vector to be spatially smooth when viewed as an image. Evaluation of the methods using cross-validation shows similar classification accuracies for SLR and SRSLR, with both performing better than PLR and MLDA. In addition, SRSLR produced classifiers that were spatially smoother than those produced by SLR, which may better reflect the regional effects of Alzheimer's Disease. PMID- 22255340 TI - Gradual anisometric-isometric transition for human-machine interfaces. AB - Human-machine interfaces (HMIs) are widely used in biomedical applications, from teleoperated surgical systems to rehabilitation devices. This paper investigates a method of control that allows an HMI to transition from anisometric to isometric mode, shifting the control input from position to force as the user's movement is gradually reduced. Two different approaches for achieving this transition are discussed: one is based on the natural system dynamics, whereas the other involves selecting and controlling dynamics. The two approaches were implemented on a custom haptic device in a targeting task. Anisometric to isometric transitioning can potentially be used for training purposes, enabling transfer of what was learned in one mode to the other, as well as novel studies of the human sensorimotor system. PMID- 22255341 TI - Lower-limb-driven energy harvesting: preliminary analysis. AB - In this paper, we present a new lower limb driven biomechanical energy harvester and its preliminary performance analysis. An estimate of the mechanical available power, estimated user felt resistance, and preliminary testing were conducted in this study. The estimated total available mechanical power and user felt resistance are based on the kinematic motion data and the mathematical model of the energy harvester prototype. Two key advantages of the new model are: generation of a higher mean power and application to a wider range of subject motion. The device is mounted on a backpack with lower limb attachments. Power generation occurs during the swing phase where negative power occurs. The new energy harvester prototype is capable of harvesting power on the same order of magnitude as previous models. PMID- 22255342 TI - Development and evaluation of a social robot platform for therapy in autism. AB - People with ASD (Autism Spectrum Disorders) have difficulty in managing interpersonal relationships and common life social situations. A modular platform for Human Robot Interaction and Human Machine Interaction studies has been developed to manage and analyze therapeutic sessions in which subjects are driven by a psychologist through simulated social scenarios. This innovative therapeutic approach uses a humanoid robot called FACE capable of expressing and conveying emotions and empathy. Using FACE as a social interlocutor the psychologist can emulate real life scenarios where the emotional state of the interlocutor is adaptively adjusted through a semi closed loop control algorithm which uses the ASD subject's inferred "affective" state as input. Preliminary results demonstrate that the platform is well accepted by ASDs and can be consequently used as novel therapy for social skills training. PMID- 22255343 TI - Development of support system to handle ultrasound probe by coordinated motion with medical robot. AB - We have developed a support system using our ultrasound diagnosis robot, which is able to support manual handling of ultrasound probe in echography to alleviate fatigue of examiner. This system realizes a coordinated motion according to the motion of the probe, which is hold by the robot and is moved by an examiner. We have established four kinds of situations, which are initial fixation, coordinate motions with/without contact on the body surface, and automatic chase motion of an internal organ. The system recognizes when the examiner grasps the ultrasound probe by 6-axis force sensor and touches it on body surface by processing echograms. Not only unskilled examiners but also a professional sonographer have evaluated the performance of the system after elucidating multiple parameters for compliance control and self-weight and moment compensation of the probe. As the results, this system has the potential to be able to support advanced diagnosis for conventional echography. PMID- 22255344 TI - Estimation of mental workload using saccadic eye movements in a free-viewing task. AB - This study proposes a new method to automatically estimate a person's mental workload (MWL) using a specific type of eye movements called saccadic intrusions (SI). Previously, the most accurate existing method to estimate MWL was the pupil diameter measure [1]. However, pupil diameter is not practical in a vehicle driving environment because it is overly sensitive to brightness changes. A new method should be independent from environment brightness changes, robust in most driving environments, and accurately reflect MWL. This study used SI as an indicator of MWL because eye movements, including SI, are independent from brightness changes. SI are a specific type of eye-gaze deviations. SI are known to be closely related to cognitive activities [2], [3]. This means that SI may be also closely related to MWL. Eye movements were recorded using a non-intrusive eye tracking camera, located 550 mm away from a participant. Participants were instructed to move their eye gaze to examine a highway driving scenery picture. In the data set of the recorded eye movements, our new algorithm detected SI and quantified SI behavior into a SI measure. Participants were also engaged in a secondary N-back task. The N-back task is a popular task used in cognitive sciences to systematically control a MWL level of participants. In our results, all 14 participants exhibited more SI eye movements when their MWL level was high compared to when their MWL level was low. Moreover, our results showed that the SI measure was a more accurate measure of MWL than the pupil diameter measure. This finding indicates that MWL of the person can be estimated by observation of SI eye movements. This new method has a wide range of applications. One of them is to predict a person's MWL, thus predicting when a person is capable of driving a vehicle in a safe or dangerous manner. PMID- 22255345 TI - Gesture recognition in upper-limb prosthetics: a viability study using dynamic time warping and gyroscopes. AB - One of the significant challenges in the upper-limb-prosthetics research field is to identify appropriate interfaces that utilize the full potential of current state-of-the-art neuroprostheses. As the new generation of such prostheses paces towards approximating the human physiological performance in terms of movement dexterity and sensory feedback, it is clear that current non-invasive interfaces are still severely limited. Surface electromyography, the interface ubiquitously used in the field, is riddled with several shortcomings. Gesture recognition, an interface pervasively used in wearables and mobile devices, shows a strong potential as a non-invasive upper-limb prosthetic interface. This study aims at showcasing its potential in the field by using gyroscope sensors. To this end, we (1) explore the viability of Dynamic Time Warping as a classification method for upper-limb prosthetics and (2) look for appropriate sensor locations on the body. Results indicate an optimal classification rate of 97.53%, sigma = 8.74 using a sensor located proximal to the endpoint performing a gesture. PMID- 22255346 TI - Designing an active motor skill learning platform with a robot-assisted laparoscopic trainer. AB - Laparoscopic Surgery poses significant complexity in hand-eye coordination to the surgeon. In order to improve their proficiency beyond the limited exposure in the operating theatre, surgeons need to practice on laparoscopic trainers. We have constructed a robotic laparoscopic trainer with identical degrees of freedom and range of motion as a conventional laparoscopic instrument. We hypothesize that active robotic assistance through a laparoscopic trainer improves training efficacy as compared to autonomous practice. In order to test the hypothesis, we have divided the subjects into two groups. The control group practiced on two laparoscopic tasks manually without feedback or supervision. The other group practiced on the same tasks with robotic assistance. Results from the robot assisted group show that tool orientation (pitch and yaw joint motion) in the pointing task improved by more than 15%. PMID- 22255347 TI - Pilot study on effectiveness of simulation for surgical robot design using manipulability. AB - Medical technology has advanced with the introduction of robot technology, which facilitates some traditional medical treatments that previously were very difficult. However, at present, surgical robots are used in limited medical domains because these robots are designed using only data obtained from adult patients and are not suitable for targets having different properties, such as children. Therefore, surgical robots are required to perform specific functions for each clinical case. In addition, the robots must exhibit sufficiently high movability and operability for each case. In the present study, we focused on evaluation of the mechanism and configuration of a surgical robot by a simulation based on movability and operability during an operation. We previously proposed the development of a simulator system that reproduces the conditions of a robot and a target in a virtual patient body to evaluate the operability of the surgeon during an operation. In the present paper, we describe a simple experiment to verify the condition of the surgical assisting robot during an operation. In this experiment, the operation imitating suturing motion was carried out in a virtual workspace, and the surgical robot was evaluated based on manipulability as an indicator of movability. As the result, it was confirmed that the robot was controlled with low manipulability of the left side manipulator during the suturing. This simulation system can verify the less movable condition of a robot before developing an actual robot. Our results show the effectiveness of this proposed simulation system. PMID- 22255348 TI - Pilot study of design method for surgical robot using workspace reproduction system. AB - Recent development methods for surgical robots have an inherent problem. The user friendliness of operating robot cannot be revealed until completion of the robot. To assist the design of a surgical robot that is user-friendly in terms of surgeon's operation, we propose a system that considers the operation manner of surgeon during the design phase of the robot. This system includes the following functionality: 1) a master manipulator that measures the operation manner of the surgeon (operator), and 2) a slave simulator in which the mechanical parameters can be configured freely. The operator can use the master manipulator to operate the slave simulator. Using this system, we investigate the necessity of considering the operator's manner when developing a surgical robot. In the experiment, we used three instruments with mechanisms that differed with respect to the length between bending joints and measured the trajectory of each instrument tip position during the surgical task. The results show that there are differences in the trajectories of each mechanism. Based on the results, changes in the mechanism of the surgical robot influenced the operator's manner. Therefore, when designing the mechanism for a surgical robot, there is a need to consider how this influences the operator's manner. PMID- 22255349 TI - A viscoelastic model of a breast phantom for real-time palpation. AB - Palpation of soft tissues helps to diagnose varying diseases within the tissues. Using a phantom, the current method of training palpation lacks for feedback of the training. Similar to a robot-assisted surgical system, a virtual reality (VR) system could be potential for such training due to its interactive nature. In such a VR system, studies revealed the observation that the human perception of objects is insensitive to subtle discrepancies in a simulation. Based upon this observation, we propose a real-time viscoelastic model of a breast phantom (as soft tissues). The model consists of a surface membrane and an inside gel. We evaluate this model through a comparison with a Finite Element Method (FEM) model, featuring physical parameters and different force contacts. The results show that the model can handle multi vertex force contact on an arbitrary location and yields reasonable accurate deformation compared to the FEM model. PMID- 22255350 TI - Integration of biomechanical parameters in tetrahedral mass-spring models for virtual surgery simulation. AB - Surgical simulation requires to have an operating scenario as similar as possible to the real conditions that the surgeon is going to face. Not only visual and geometric patient properties are needed to be reproduced, but also physical and biomechanical properties are theoretically required. In this paper a physically based patient specific simulator for solid organs is described, recalling the underlying theory and providing simulation results and comparisons. The main biomechanical parameters (Young's modulus and density) have been integrated in a Mass-Spring-Damper model (MSDm) based on a tetrahedral structured network. The proposed algorithms allow the automatic setting of node mass and spring stiffness, while the damping coefficient have been modeled using the Rayleigh approach. Moreover, the method automatically detects the organ external layer, allowing the usage of both the surface and internal Young's moduli: for the capsule (or stroma) and for the internal part (or parenchyma). Finally the model can be manually tuned to represent lesions with specific biomechanical properties. The method has beed tested with various material samples. The results have shown a good visual realism ensuring the performance required by an interactive simulation. PMID- 22255351 TI - Next-generation micromanipulator for computer-assisted laser phonomicrosurgery. AB - This paper describes a new motorized laser micromanipulator created for computer assisted laser laryngeal microsurgeries. This new device is based on a single tip/tilt fast steering mirror driven by a parallel kinematics mechanism, which is shown to improve previous laser micromanipulator designs by offering highly accurate motorized laser aiming control from a small, simple, and robust system created for real operating settings. The integration of this new device to a previously developed assistive surgical system is also described, including the new calibration model implemented to enable precise laser beam control from the live microscope video displayed on a computer screen. High system accuracy is demonstrated by the results of trajectory following experiments, which reveal an average RMSE of only 0.06 mm over an 8.5 mm diameter circular path. These numbers are also shown to favorably compare to those obtained with a traditional laser micromanipulator, evidencing a 70% error reduction when using the new system. In addition, experiments under higher optical magnification (40* instead of 16*) demonstrate even better accuracy results, proving the new system is highly scalable and indicating it has the potential to greatly improve laser microsurgery quality and safety. PMID- 22255352 TI - A gaze independent spelling based on rapid serial visual presentation. AB - An event-related potential (ERP) speller is a brain computer interface (BCI) based on the detection on ERPs that can be used as spelling device for those people deprived of other means of communication. In the present online study we investigated in twelve participants the performance of an ERP speller based on the rapid serial visual presentation paradigm (RSVP). Three variants of the RSVP speller have been investigated regarding chromaticism and speed of stimulus presentation. All the subjects were able to successfully operate the RSVP speller and high mean symbol selection accuracies were reached in all conditions, (93.6% to 94.8%). Offline analysis revealed a possible mean spelling speed of about 2 symb/min for an optimized number of stimulus sequences. The RSVP speller is intuitive to use and it is gaze independent, which makes it suitable for patients with deterioration of oculomotor control. PMID- 22255353 TI - Integrating the spatial profile of the N200 speller for asynchronous brain computer interfaces. AB - The N200 speller is a novel brain-computer interface (BCI) paradigm utilizing the overt attention effects on motion onset visual evoked potentials (mVEP). However, the asynchronous performance of the N200 BCI has not been fully explored. In this paper, a novel algorithm was proposed, integrating the spatial profile of the visual speller to provide a more precise description of the mVEP responses. Most importantly, only control state data were used in the algorithm to train a classifier which can detect the non-control state effectively. Using offline recorded data, the asynchronous performance of the proposed algorithm was shown to be significantly better than that of a similar algorithm without using the spatial information. The proposed algorithm can be used for developing a practical, asynchronous N200 BCI system. PMID- 22255354 TI - An auditory brain-computer interface using virtual sound field. AB - Brain-computer interfaces (BCIs) exploring the auditory communication channel might be preferable for amyotrophic lateral sclerosis (ALS) patients with poor sight or with the visual system being occupied for other uses. Spatial attention was proven to be able to modulate the event-related potentials (ERPs); yet up to now, there is no auditory BCI based on virtual sound field. In this study, auditory spatial attention was introduced by using stimuli in a virtual sound field. Subjects attended selectively to the virtual location of the target sound and discriminated its relevant properties. The concurrently recorded ERP components and the users' performance were compared with those of the paradigm where all sounds were presented in the frontal direction. The early ERP components (100-250 ms) and the simulated online accuracies indicated that spatial attention indeed added effective discriminative information for BCI classification. The proposed auditory paradigm using virtual sound field may lead to a high-performance and portable BCI system. PMID- 22255355 TI - Multimodal human-machine interface based on a brain-computer interface and an electrooculography interface. AB - This paper describes a multimodal interface that combines a Brain-Computer Interface (BCI) with an electrooculography (EOG) interface. The non-invasive spontaneous BCI registers the electrical brain activity through surface electrodes. The EOG interface detects the eye movements through electrodes placed on the face around the eyes. Both kind of signals are registered together and processed to obtain the mental task that the user is thinking and the eye movement performed by the user. Both commands (mental task and eye movement) are combined in order to move a dot in a graphic user interface (GUI). Several experimental tests have been made where the users perform a trajectory to get closer to some targets. To perform the trajectory the user moves the dot in a plane with the EOG interface and using the BCI the dot changes its height. PMID- 22255356 TI - EEG auditory steady state responses classification for the novel BCI. AB - An auditory modality brain computer interface (BCI) is a novel and interesting paradigm in neurotechnology applications. The paper presents a concept of auditory steady state responses (ASSR) utilization for the novel BCI paradigm. Two EEG feature extraction approaches based on a bandpass filtering and an AR spectrum estimation are tested together with two classification schemes in order to validate the proposed auditory BCI paradigm. The resulting good classification scores of users intentional choices, of attending or not to the presented stimuli, support the hypothesis of the ASSR stimuli validity for a solid BCI paradigm. PMID- 22255357 TI - Performance optimization of ERP-based BCIs using dynamic stopping. AB - Brain-computer interfaces based on event-related potentials face a trade-off between the speed and accuracy of the system, as both depend on the number of iterations. Increasing the number of iterations leads to a higher accuracy but reduces the speed of the system. This trade-off is generally dealt with by finding a fixed number of iterations that give a good result on the calibration data. We show here that this method is sub optimal and increases the performance significantly in only one out of five datasets. Several alternative methods have been described in literature, and we test the generalization of four of them. One method, called rank diff, significantly increased the performance over all datasets. These findings are important, as they show that 1) one should be cautious when reporting the potential performance of a BCI based on post-hoc offline performance curves and 2) simple methods are available that do boost performance. PMID- 22255358 TI - Asynchronous decoding of grasp aperture from human ECoG during a reach-to-grasp task. AB - Recent studies in primate neurophysiology have focused on decoding multi-joint kinematics from single unit and local field potential recordings. However, the extent to which these results can be generalized to human subjects is not known. We have recorded simultaneous electrocorticographic (ECoG) and hand kinematics in a human subject performing reach-grasp-hold of objects varying in shape and size. All Spectral features in various gamma bands (30-50 Hz, 70-100 Hz and 100-150 Hz frequency bands) were able to predict the time course of grasp aperture with high correlation (max r = 0.80) using as few as one ECoG feature from a single electrode (max r for single feature = 0.75) in single trials without prior knowledge of task timing. These results suggest that the population activity captured with ECoG contains information about coordinated finger movements that potentially can be exploited to control advanced upper limb neuroprosthetics. PMID- 22255359 TI - Towards a non-invasive brain-machine interface system to restore gait function in humans. AB - Before 2009, the feasibility of applying brain-machine interfaces (BMIs) to control prosthetic devices had been limited to upper limb prosthetics such as the DARPA modular prosthetic limb. Until recently, it was believed that the control of bipedal locomotion involved central pattern generators with little supraspinal control. Analysis of cortical dynamics with electroencephalography (EEG) was also prevented by the lack of analysis tools to deal with excessive signal artifacts associated with walking. Recently, Nicolelis and colleagues paved the way for the decoding of locomotion showing that chronic recordings from ensembles of cortical neurons in primary motor (M1) and primary somatosensory (S1) cortices can be used to decode bipedal kinematics in rhesus monkeys. However, neural decoding of bipedal locomotion in humans has not yet been demonstrated. This study uses non invasive EEG signals to decode human walking in six nondisabled adults. Participants were asked to walk on a treadmill at their self-selected comfortable speed while receiving visual feedback of their lower limbs, to repeatedly avoid stepping on a strip drawn on the treadmill belt. Angular kinematics of the left and right hip, knee and ankle joints and EEG were recorded concurrently. Our results support the possibility of decoding human bipedal locomotion with EEG. The average of the correlation values (r) between predicted and recorded kinematics for the six subjects was 0.7 (+/- 0.12) for the right leg and 0.66 (+/ 0.11) for the left leg. The average signal-to-noise ratio (SNR) values for the predicted parameters were 3.36 (+/- 1.89) dB for the right leg and 2.79 (+/- 1.33) dB for the left leg. These results show the feasibility of developing non invasive neural interfaces for volitional control of devices aimed at restoring human gait function. PMID- 22255360 TI - Dynamic Brain-Machine Interface: a novel paradigm for bidirectional interaction between brains and dynamical systems. AB - Brain-Machine Interfaces (BMIs) are systems which mediate communication between brains and artificial devices. Their long term goal is to restore motor functions, and this ultimately demands the development of a new generation of bidirectional brain-machine interfaces establishing a two-way brain-world communication channel, by both decoding motor commands from neural activity and providing feedback to the brain by electrical stimulation. Taking inspiration from how the spinal cord of vertebrates mediates communication between the brain and the limbs, here we present a model of a bidirectional brain-machine interface that interacts with a dynamical system by generating a control policy in the form of a force field. In our model, bidirectional communication takes place via two elements: (a) a motor interface decoding activities recorded from a motor cortical area, and (b) a sensory interface encoding the state of the controlled device into electrical stimuli delivered to a somatosensory area. We propose a specific mathematical model of the sensory and motor interfaces guiding a point mass moving in a viscous medium, and we demonstrate its performance by testing it on realistically simulated neural responses. PMID- 22255361 TI - Single-trial classification of feedback potentials within neurofeedback training with an EEG brain-computer interface. AB - Neurofeedback therapies are an emerging technique used to treat neuropsychological disorders and to enhance cognitive performance. The feedback stimuli presented during the therapy are a key factor, serving as guidance throughout the entire learning process of the brain rhythms. Online decoding of these stimuli could be of great value to measure the compliance and adherence of the subject to the training. This paper describes the modeling and classification of performance feedback potentials with a Brain-Computer Interface (BCI), under a real neurofeedback training with five subjects. LDA and SVM classification techniques are compared and are both able to provide an average performance of approximately 80%. PMID- 22255362 TI - A subject-independent brain-computer interface based on smoothed, second-order baselining. AB - A brain-computer interface (BCI) enables direct communication from the brain to devices, bypassing the traditional pathway of peripheral nerves and muscles. Traditional approaches to BCIs require the user to train for weeks or even months to learn to control the BCI. In contrast, BCIs based on machine learning only require a calibration session of less than an hour before the system can be used, since the machine adapts to the user's existing brain signals. However, this calibration session has to be repeated before each use of the BCI due to inter session variability, which makes using a BCI still a time-consuming and an error prone enterprise. In this work, we present a second-order baselining procedure that reduces these variations, and enables the creation of a BCI that can be applied to new subjects without such a calibration session. The method was validated with a motor-imagery classification task performed by 109 subjects. Results showed that our subject-independent BCI without calibration performs as well as the popular common spatial patterns (CSP)-based BCI that does use a calibration session. PMID- 22255363 TI - Neuron selection for decoding dexterous finger movements. AB - Many brain machine interfaces (BMI) seek to use the activity from hundreds of simultaneously recorded neurons to reconstruct an individual's kinematics. However, many of these neurons are not task related since there is no way to surgically target those neurons. This causes model based decoding to suffer easily from over-fitting on noisy unrelated neurons. Previous methods, such as correlation analysis and sensitivity analysis, seek to select neurons based on which reduced order model best matches the ensemble model and thus does not worry about over fitting. To address this issue, this paper presents a new method, cross model validation, that ranks neuron importance on the neuron model's ability to generalize well to data from correct movements and poorly to data from incorrect movements. This method attempts to highlight the neurons that are able to distinguish between movements the best and decode accurately. Selecting neurons using cross model validation scores as opposed to randomly selecting them can increase decoding accuracy up to 2.5 times or by 44%. These results showcase the importance of neuron selection in decoding and the ability of cross model validation in discerning each neuron's utility in decoding. PMID- 22255364 TI - Massively parallel neural signal processing: System-on-Chip design with FPGAs. AB - This work discusses the architectural layout and performance results of a SoC design for parallel neural signal processing. Architectural framework for scalability and scalar reconfigurability are presented. Architectural requirements for massive parallelism in neural recordings are presented. Prototype architecture with dual processors and multi-level reconfigurable platform design is presented. Functional modules of the platform include real time spike detector and sorter for several hundreds of neural channels. Performance of the platform for a 300 channel interface is also discussed. PMID- 22255365 TI - FPGA implementation of hardware processing modules as coprocessors in brain machine interfaces. AB - Real-time computation, portability and flexibility are crucial for practical brain-machine interface (BMI) applications. In this work, we proposed Hardware Processing Modules (HPMs) as a method for accelerating BMI computation. Two HPMs have been developed. One is the field-programmable gate array (FPGA) implementation of spike sorting based on probabilistic neural network (PNN), and the other is the FPGA implementation of neural ensemble decoding based on Kalman filter (KF). These two modules were configured under the same framework and tested with real data from motor cortex recording in rats performing a lever pressing task for water rewards. Due to the parallelism feature of FPGA, the computation time was reduced by several dozen times, while the results are almost the same as those from Matlab implementations. Such HPMs provide a high performance coprocessor for neural signal computation. PMID- 22255366 TI - Modular particle filtering FPGA hardware architecture for brain machine interfaces. AB - As the computational complexities of neural decoding algorithms for brain machine interfaces (BMI) increase, their implementation through sequential processors becomes prohibitive for real-time applications. This work presents the field programmable gate array (FPGA) as an alternative to sequential processors for BMIs. The reprogrammable hardware architecture of the FPGA provides a near optimal platform for performing parallel computations in real-time. The scalability and reconfigurability of the FPGA accommodates diverse sets of neural ensembles and a variety of decoding algorithms. Throughput is significantly increased by decomposing computations into independent parallel hardware modules on the FPGA. This increase in throughput is demonstrated through a parallel hardware implementation of the auxiliary particle filtering signal processing algorithm. PMID- 22255367 TI - An information-theoretic approach to motor action decoding with a reconfigurable parallel architecture. AB - Methods for decoding movements from neural spike counts using adaptive filters often rely on minimizing the mean-squared error. However, for non-Gaussian distribution of errors, this approach is not optimal for performance. Therefore, rather than using probabilistic modeling, we propose an alternate non-parametric approach. In order to extract more structure from the input signal (neuronal spike counts) we propose using minimum error entropy (MEE), an information theoretic approach that minimizes the error entropy as part of an iterative cost function. However, the disadvantage of using MEE as the cost function for adaptive filters is the increase in computational complexity. In this paper we present a comparison between the decoding performance of the analytic Wiener filter and a linear filter trained with MEE, which is then mapped to a parallel architecture in reconfigurable hardware tailored to the computational needs of the MEE filter. We observe considerable speedup from the hardware design. The adaptation of filter weights for the multiple-input, multiple-output linear filters, necessary in motor decoding, is a highly parallelizable algorithm. It can be decomposed into many independent computational blocks with a parallel architecture readily mapped to a field-programmable gate array (FPGA) and scales to large numbers of neurons. By pipelining and parallelizing independent computations in the algorithm, the proposed parallel architecture has sublinear increases in execution time with respect to both window size and filter order. PMID- 22255368 TI - Using general-purpose graphic processing units for BCI systems. AB - BioMEMS electrode array fabrication techniques are used to develop high-density arrays with hundreds of channels. However, it was previously impossible to process more than a fraction of these channels real-time for online BCI experiments due to computational resource restraints. It is now possible to use graphics processing units (GPUs), which can have several hundred processing cores each, to processes large amounts of data quickly. This paper summarizes advances in using GPUs for BCI processing for EEG, ECoG, and micro-electrode systems, with speedups of more than 30 times that of current state-of-the-art CPU-based BCI implementations. PMID- 22255369 TI - Development of a BCI master switch based on single-trial detection of contingent negative variation related potentials. AB - To control the startup/shutdown of a conventional brain-computer interface (BCI) that is always running for daily use, we proposed and developed a new BCI system called a BCI master switch. We designed it with on/off switching functions by detecting the contingent negative variation (CNV)--related potentials. We chose CNV to improve the single-trial discrimination of user intentions to switch because CNV had a high signal-to-noise ratio and needed high concentration for its elicitation. We also applied a support vector machine (SVM) to improve the single-trial detection of CNV-related potentials. As the best parameters of SVM were estimated and applied, the offline evaluation's best performance achieved a CNV detection rate of 99.3% for the intention to switch and 2.1% for the intention not to switch. Remarkably, this performance was achieved from single trial detection, imaginary response of user's intention without physical reaction, and the data from only one recording electrode. These results suggest that our proposed BCI system might work as a master switch by single-trial detection. PMID- 22255370 TI - Control of neural interfacing in peripheral nerves through regenerative molecular guidance. AB - Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control of robotic prosthetic devices. However, random axonal pathfinding during peripheral nerve regeneration leads to mixed populations of sensory and motor neurons at the electrode interfaces preventing the precise identification of the modality nature of the recorded action potentials; motor or specific sensory sub-modalities. This study present evidence that supports the notion that type-specific neurotrophins can be used to preferentially entice and segregate the growth of defined axonal populations from transected peripheral nerves. Segregation of mixed sensory fibers from dorsal root ganglion neurons was evaluated in vitro by compartmentalized diffusion delivery of nerve growth factor (NGF) and neurotrophin-3 (NT-3), to preferentially entice the growth of trkA+ nociceptive and trkC+ proprioceptive subsets of sensory neurons, respectively. PMID- 22255371 TI - Activities on PNS neural interfaces for the control of hand prostheses. AB - The development of interfaces linking the human nervous system with artificial devices is an important area of research. Several groups are working on the development of devices able to restore sensory-motor function in subjects affected by neurological disorders, injuries or amputations. Neural electrodes implanted in peripheral nervous system, and in particular intrafascicular electrodes, seem to be a promising approach for the control of hand prosthesis thanks to the possibility to selectively access motor and sensory fibers for decoding motor commands and delivering sensory feedback. In this paper, activities on the use of PNS interfaces for the control of hand prosthesis are presented. In particular, the design and feasibility study of a self-opening neural interface is presented together with the decoding of ENG signals in one amputee to control a dexterous hand prosthesis. PMID- 22255372 TI - Recording sensory and motor information from peripheral nerves with Utah Slanted Electrode Arrays. AB - Recording and stimulation via high-count penetrating microelectrode arrays implanted in peripheral nerves may help restore precise motor and sensory function after nervous system damage or disease. Although previous work has demonstrated safety and relatively successful stimulation for long-term implants of 100-electrode Utah Slanted Electrode Arrays (USEAs) in feline sciatic nerve [1], two major remaining challenges were 1) to maintain viable recordings of nerve action potentials long-term, and 2) to overcome contamination of unit recordings by myoelectric (EMG) activity in awake, moving animals. In conjunction with improvements to USEAs themselves, we have redesigned several aspects of our USEA containment and connector systems. Although further increases in unit yield and long-term stability remain desirable, here we report considerable progress toward meeting both of these goals: We have successfully recorded unit activity from USEAs implanted intrafascicularly in sciatic nerve for periods up to 4 months (the terminal experimental time point), and we have developed a containment system that effectively eliminates or substantially reduces EMG contamination of unit recordings in the moving animal. In addition, we used a 100 channel wireless recording integrated circuit attached to implanted USEAs to transmit broadband or spike-threshold data from nerve. Neural data thusly obtained during imposed limb movements were decoded blindly to drive a virtual prosthetic limb in real time. These results support the possibility of using USEAs in peripheral nerves to provide motor control and cutaneous or proprioceptive sensory feedback in individuals after limb loss or spinal cord injury. PMID- 22255373 TI - A framework for the discrimination of neural pathways using multi-contact nerve cuff electrodes. AB - Monitoring the activity of specific neural pathways in a peripheral nerve is a task with numerous applications in implanted neuroprosthetic systems. Achieving selective recording using multi-contact nerve cuff electrodes is appealing because these devices are well suited for chronic use, but no viable general solution to the task of discriminating combinations of active pathways from extra neural recordings has yet been proposed. Bioelectric source localization approaches have been suggested, but their effectiveness is limited by the accuracy of the nerve model used to solve the forward problem. We propose a model free alternative to the pathway discrimination task, in which experimental data is used to estimate a solution to the forward problem. The method was evaluated using a 56-channel cuff placed on the rat sciatic nerve. 3 pathways were discriminated with a 94.2% success rate when individually active, whereas further improvements are needed in order to recover combinations of simultaneously active pathways. PMID- 22255374 TI - A summary of the theory of velocity selective neural recording. AB - This paper describes improvements to the technique of velocity selective recording (VSR) in which multiple neural signals are matched and summed to identify excited axon populations in terms of velocity. This form of recording has been termed intrinsic velocity selective recording (IVSR). The signals are acquired using a multi-electrode cuff (MEC) which is now available as a component for use in implantable neuroprostheses. The improvements outlined in the paper involve the use of bandpass filters at the output of the system which allows a higher level of selectivity to be obtained than is possible using IVSR. PMID- 22255375 TI - Recovery of neural activity from nerve cuff electrodes. AB - The ability to recover signals from the peripheral nerves would provide natural and physiological signals for controlling artificial limbs and neural prosthetic devices. Current cuff electrode systems can provide multiple channels but the signals have low signal to noise ratio and are difficult to recover. Previous work has shown that beamforming algorithms provide a method to extract such signals from peripheral nerve activiy [1]. This paper describes in-silico and in vivo experiments done to validate that method in a more realistic case. A modified beam forming algorithm capable of significantly decrease cross talk between channels is described and the results of the a 16-channel Flat Interface Nerve Electrode used to recover signals from the sciatic nerve in rabbit while the distal tibial and peroneal branches were stimulated The beamforming spatial filters were able to distinguish which branch was being stimulated, and in many cases how strongly, over a large range of stimulation intensities. PMID- 22255376 TI - Regression methods for parameter sensitivity analysis: applications to cardiac arrhythmia mechanisms. AB - Mathematical models are used extensively in studies of cardiac electrophysiology and arrhythmia mechanisms. Models can generate novel predictions, suggest experiments, and provide a quantitative understanding of underlying mechanisms. Limitations of present modeling approaches, however, include non-uniqueness of both parameters and the models themselves, and difficulties in accounting for experimental variability. We describe new approaches that can begin to address these limitations, and show how these can provide novel insight into mathematical models of cardiac myocytes. PMID- 22255377 TI - Automated image analysis of cardiac myocyte Ca2+ dynamics. AB - Intracellular Ca(2+) dynamics act as a key link between the electrical and mechanical activity of the heart. Here we present a method for high-throughput measurement, automated cell segmentation and signal analysis of Ca(2+) transients in isolated adult ventricular myocytes. In addition to increasing experimental throughput ~10-fold compared to conventional approaches, this approach allows the study of individual cell-cell variability and relationships between Ca(2+) signaling and cell morphology. PMID- 22255378 TI - CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte. AB - Cardiac voltage-gated Na(+) channels underlie membrane depolarization during the upstroke of the action potential (AP). These channels also exhibit a late, slowly inactivating component of current (late I(Na)) that may be enhanced under pathological conditions such as heart failure, and may therefore promote AP prolongation and increase the likelihood of arrhythmia. Ca(2+)/calmodulin dependent protein kinase II (CaMKII) functionally modifies Na(+) channels, however it remains unclear if the CaMKII-dependent changes in late I(Na) are a major contributor to cellular arrhythmias such as early after depolarizations (EADs). In this study we develop a model of I(Na), including CaMKII-dependent effects, based on experimental measurements. The Na(+) channel model is incorporated into a computational model of the whole myocyte which describes excitation-contraction coupling via stochastic simulation of individual Ca(2+) release sites. Simulations suggest that relatively small augmentation of late I(Na) is sufficient to significantly prolong APs and lead to the appearance of EADs. PMID- 22255379 TI - Interactions between cardiac fibrosis spatial pattern and ionic remodeling on electrical wave propagation. AB - Cardiac fibrosis is an important form of pathological tissue remodeling. Fibrosis can electrically-uncouple neighboring excitable cardiomyocytes thus acting as an obstacle to electrical propagation. In this study, we investigated the effects of fibrosis spatial pattern on electrical propagation in control, decreased maximum sodium conductance, and increased intracellular resistivity conditions. Simulations were performed with a monodomain approach and a realistic canine ionic model. We found that the propagation failure is highly dependent on the spatial pattern of fibrosis for all conditions studied with maximum sensitivity for patterns with combination of small and large clusters. However, the effect is particularly sensitive to reduced sodium current condition where conduction block occurred at lower fibrosis density. PMID- 22255380 TI - Metabolic control analysis applied to mitochondrial networks. AB - To understand the control and regulation of mitochondrial energy metabolism a generalized matrix method of Metabolic Control Analysis has been applied to a computational model of mitochondrial energetics. The computational model of Cortassa et al. (2003) encompasses oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and ion dynamics across the inner mitochondrial membrane. Control of respiration and ATP synthesis fluxes were found to be distributed among various mitochondrial processes. Control is shared by processes associated with ATP synthesis and ATP/ADP transport, as well as by Ca(2+) dynamics. The analysis of flux control coefficients and response coefficients has led to the notion of control by diffuse loops, that points to the regulatory interactions exerted by processes that are mechanistically only indirectly related with each other. The approach we have utilized demonstrates how properties of integrated systems may be understood through applications of computational modeling and control analysis. PMID- 22255381 TI - Stochastic simulation of cardiac ventricular myocyte calcium dynamics and waves. AB - A three dimensional model of calcium dynamics in the rat ventricular myocyte was developed to study the mechanism of calcium homeostasis and pathological calcium dynamics during calcium overload. The model contains 20,000 calcium release units (CRUs) each containing 49 ryanodine receptors. The model simulates calcium sparks with a realistic spontaneous calcium spark rate. It suggests that in addition to the calcium spark-based leak, there is an invisible calcium leak caused by the stochastic opening of a small number of ryanodine receptors in each CRU without triggering a calcium spark. The model also explores the mechanism of calcium wave propagation between release sites under the conditions of calcium overload. PMID- 22255382 TI - Statistical model for cardiovascular signals with independent respiratory modulation for tracking pulse pressure variation. AB - Cardiovascular signals including the electrocardiogram, pressure signals, and photoplethysmographs such as those used in pulse oximetry contain a wealth of information. Statistical models of these signals provide a means of representing and quantifying this information, and often lead to natural and optimal estimation algorithms. One powerful statistical model uses a Fourier approach to model cardiovascular signals as a harmonic sum of sinusoids with a fundamental frequency, amplitudes, and phases that vary slowly over time. We have further developed this model to incorporate respiratory effects including an additive component, pulse pressure variation (PPV), and respiratory sinus arrhythmia. PPV may be viewed as a form of amplitude modulation of the cardiovascular signal due to respiration. Current models do not explain the asymmetry between the upper and lower envelopes observed in cardiovascular pressure signals, and consequently are not appropriate for PPV estimation. We propose a model in which each of the cardiac harmonics is independently modulated by the respiratory signal. This improves the estimation accuracy and permits more accurate cardiovascular tracking and estimation. The proposed model is more accurate in PPV estimation applications. PMID- 22255383 TI - Atrial Fibrillation detection using time-varying coherence function and Shannon Entropy. AB - We introduce a novel method for automatic detection of Atrial Fibrillation (AF) using time-varying coherence functions (TVCF) and Shannon Entropy (SE). The TVCF is estimated by the multiplication of two time-varying transfer functions (TVTFs). Two TVTFs are obtained using two adjacent data segments with one data segment as the input signal and the other data segment as the output to produce the first TVTF; the second TVTF is produced by reversing the input and output signals. The detection algorithm was tested on RR interval time series derived from two databases: the MIT-BIH Atrial Fibrillation (AF) and the MIT-BIH normal sinus rhythm (NSR). The MIT-BIH database contains a variety of short and long AF beats from 25 subjects and the MIT-BIH NSR database consists of only normal sinus rhythms from 18 subjects. Using the receiver operating characteristic curves from the combination of TVCF and SE, we obtained the accuracy of 97.49%, sensitivity of 97.41% and specificity of 97.54% for the MIT-BIH AF database. Furthermore, the specificity of the MIT-BIH NSR database was 100%. PMID- 22255384 TI - Time-frequency phase differences and phase locking to characterize dynamic interactions between cardiovascular signals. AB - In this paper cross time-frequency (TF) analysis is used to estimate the phase differences and the phase locking between cardiovascular signals. Phase differences give a measure of the changes in the synchronization between two oscillations, while phase locking measures the degree of similarity of these changes across subjects. The methodology is based on the smoothed pseudo Wigner Ville distribution and includes coherence analysis. In a simulation study involving R-R variability (RRV) signals, this methodology provided accurate estimates of phase differences, with an error characterized by interquartile ranges lower than 2% and 10% for SNR of 20 dB and 0 dB, respectevely. A comparative study showed that the proposed estimator outperformed an estimator based on the integration of the difference between the instantaneous frequencies of the signal spectral component. The presented methodology was used to characterize the interactions between RRV and systolic arterial pressure variability during tilt table test. Head-up tilt caused the phase differences (time delay) to change about 0.48 rad (361 ms) in HF range [0.15, 0.5 Hz]. The phase locking, which decreased immediately after the head-up tilt, was restored in about 2 minutes. PMID- 22255385 TI - Detection and removal of ventricular ectopic beats in atrial fibrillation recordings via principal component analysis. AB - Ectopic beats are early heart beats with remarkable large amplitude that provoke serious disturbances in the analysis of electrocardiograms (ECG). These beats are very common in atrial fibrillation (AF) and are the source of important residua when the QRST is intended to be removed. Given that QRST cancellation is a binding step in the appropriate analysis of atrial activity (AA) in AF, a method for ventricular ectopic beats cancellation is proposed as a previous step to the application of any QRST removal technique. First, the method discriminates between normal and ectopic beats with an accuracy higher than 99% through QRS morphological characterization. Next, the most similar ectopic beats to the one under cancellation are clustered and serve to get their eigenvector matrix by principal component analysis. Finally, the highest variance eigenvector is used as cancellation template. The reduction ectopic rate (RER) has been defined to evaluate the method's performance by using templates generated with 5, 10, 20, 40 or 80 ectopics. Optimal results were reached with the 5 most similar complexes, yielding a RER higher than 5.5. In addition, a decreasing RER trend was noticed as the number of considered ectopics for cancellation increased. As conclusion, given that ectopics presented a remarkable variability in their morphology, the proposed cancellation approach is a robust ectopic remover and can notably facilitate the later application of any QRST cancellation technique to extract the AA in the best conditions. PMID- 22255386 TI - Hypoglycemia detection based on cardiac repolarization features. AB - Hypoglycemia is known to affect repolarization characteristics of the heart. These changes are shown from ECG by prolonged QT-time and T-wave flattening. In this study we constructed a classifier based on these ECG parameters. By using the classifier we tried to detect hypoglycemic events from measurements of 22 test subjects. Hypoglycemic state was achieved using glucose clamp technique. Used test protocol consisted of three stages: normoglycemic period, transition period (blood glucose concentration decreasing) and hypoglycemic period. Subjects were divided into three groups: 9 healthy controls (Healthy), 6 otherwise healthy type 1 diabetics (T1DM) and 7 type 1 diabetics with disease complications (T1DMc). Detection of hypoglycemic event could be made passably from 15/22 measurements. In addition, we found that detection process is easier for healthy and T1DM groups than T1DMc group diabetics because in T1DMc group subjects' have lower autonomic response to hypoglycemic events. Also we noticed that changes in ECG occurs few minutes after blood glucose is decreased below 3.5 mmol/1. PMID- 22255387 TI - T waves segmentation and analysis using inverse normalized integrals. AB - Stress tests are typical protocols that exhibit T waves changes for healthy and ischemic subjects. ST-T elevation is one example among others that characterizes ischemic patient. A more complex description of T wave changes needs extended models with a cost of higher identification pitfalls. We propose here to work in the inverse normalized integrals domain. This domain permits us an estimation of all pertinent parameters for the characterization of T waves shape. These parameters stand for the delay, the width (defined in the paper as the scaling factor) and the offset. In contrast, direct application of PCA on the data (defined in the paper as time-domain approach) assumes perfectly aligned waves with identical widths. Time-varying parameters values corresponding to exercise tests are estimated by using both approaches. It is shown that results are consistent with clinical knowledge. PMID- 22255388 TI - Bayesian analysis of trinomial data in behavioral experiments and its application to human studies of general anesthesia. AB - Accurate quantification of loss of response to external stimuli is essential for understanding the mechanisms of loss of consciousness under general anesthesia. We present a new approach for quantifying three possible outcomes that are encountered in behavioral experiments during general anesthesia: correct responses, incorrect responses and no response. We use a state-space model with two state variables representing a probability of response and a conditional probability of correct response. We show applications of this approach to an example of responses to auditory stimuli at varying levels of propofol anesthesia ranging from light sedation to deep anesthesia in human subjects. The posterior probability densities of model parameters and the response probability are computed within a Bayesian framework using Markov Chain Monte Carlo methods. PMID- 22255389 TI - Understanding the effects of anesthetic agents on the EEG through neural field theory. AB - Anesthetic and analgesic agents act through a diverse range of pharmacological mechanisms. Existing empirical data clearly shows that such "microscopic" pharmacological diversity is reflected in their "macroscopic" effects on the human electroencephalogram (EEG). Based on a detailed mesoscopic neural field model we theoretically posit that anesthetic induced EEG activity is due to selective parametric changes in synaptic efficacy and dynamics. Specifically, on the basis of physiologically constrained modeling, it is speculated that the selective modification of inhibitory or excitatory synaptic activity may differentially effect the EEG spectrum. Such results emphasize the importance of neural field theories of brain electrical activity for elucidating the principles whereby pharmacological agents effect the EEG. Such insights will contribute to improved methods for monitoring depth of anesthesia using the EEG. PMID- 22255390 TI - Modeling the temporal architecture of rat sleep-wake behavior. AB - The fine architecture of sleep-wake behavior shows a distinct dynamic structure with distributions of rat sleep and wake bout durations displaying qualitatively different profiles. Wake bout durations follow a power-law relation whereas sleep bout durations are exponentially distributed. We show that a physiologically based sleep-wake regulatory network model with an underlying deterministic structure governing neuronal interactions can generate realistic rat sleep-wake behavior as assessed by both standard summary statistics and survival analysis of bout distributions. Obtaining appropriate bout duration distributions depended on stochastic elements included in the model, the existence of multiple mechanisms for state transitions, and specific relationships among time constants governing state maintenance. This model provides a novel framework for exploring the disruptions of sleep-wake architecture associated with pharmacological, genetic, and disease states. PMID- 22255391 TI - Estimating integrated information with TMS pulses during wakefulness, sleep, and under anesthesia. AB - This paper relates a recently proposed measure of information integration to experiments investigating the evoked high-density electroencephalography (EEG) response to transcranial magnetic stimulation (TMS) during wakefulness, early non rapid eye movement (NREM) sleep and under anesthesia. We show that bistability, arising at the cellular and population level during NREM sleep and under anesthesia, dramatically reduces the brain's ability to integrate information. PMID- 22255392 TI - Near-real-time connectivity estimation for multivariate neural data. AB - Optical imaging in vivo is an important tool for allowing researchers to understand neural ensemble interactions during awake behavior, sleep, anesthesia and during seizure activity. A major bottleneck in the overall efficiency of neural imaging experiments is the need for post-hoc analysis of imaging data. Computational capabilities are now at the point where real- or near-real-time multivariate analysis of imaging data is possible as data is acquired. In this paper we address the feasibility of performing real-time data analysis with a desktop computer, MATLAB, and a graphics processing unit (GPU). Important components of any real-time functional imaging analysis system are 1) dimensional reduction of the data, 2) visualization of the reduced vector space and 3) rapid calculation of functional connectivities. The ability to assess sources of variability in the data, and connectivity estimates on the fly, are potentially transformative for the way imaging laboratories perform their work. Here, we present benchmarks for analysis of functional imaging data using dimensional reduction methods and estimation of functional connectivities using least-squares and ridge regression methods. PMID- 22255394 TI - A continuous, wearable, and wireless heart monitor using head ballistocardiogram (BCG) and head electrocardiogram (ECG). AB - Continuous and wearable heart monitoring is essential for early detection and diagnosis of cardiovascular diseases. We demonstrate a continuous, wearable, and wireless heart monitor that is worn at the ear. The device has the form factor of a hearing aid and is wirelessly connected to a PC for data recording and analysis. With the ear as an anchoring point, the heart monitor measures the ballistocardiographic (BCG) motion of the head using a MEMS tri-axial accelerometer, which is an electrode-less method to measure heart rate. Additionally, electrocardiogram (ECG) is measured locally near the ear using a single-lead configuration. The peak timing delay between the head ECG and the head BCG, or RJ interval, can be extracted in the presence of noise using cross correlation. The RJ interval is shown to correlate to the heart's pre-ejection period during both Valsalva and whole-body tilt maneuvers. PMID- 22255393 TI - Robust time-varying multivariate coherence estimation: application to electroencephalogram recordings during general anesthesia. AB - Coherence analysis characterizes frequency-dependent covariance between signals, and is useful for multivariate oscillatory data often encountered in neuroscience. The global coherence provides a summary of coherent behavior in high-dimensional multivariate data by quantifying the concentration of variance in the first mode of an eigenvalue decomposition of the cross-spectral matrix. Practical application of this useful method is sensitive to noise, and can confound coherent activity in disparate neural populations or spatial locations that have a similar frequency structure. In this paper we describe two methodological enhancements to the global coherence procedure that increase robustness of the technique to noise, and that allow characterization of how power within specific coherent modes change through time. PMID- 22255395 TI - A portable autonomous multisensory intervention device (PAMID) for early detection of anxiety and agitation in patients with cognitive impairments. AB - The negative behavioral and psychological symptoms (NBPS) seen in patients with cognitive impairment (CI), such as anxiety, agitation and aggression have been reported to be the most problematic for healthcare providers. The consequences of delayed detection of NBPS can be devastating for both patients and caregivers; therefore early detection of symptoms that may lead into NBPS is essential. A proprietary device called portable autonomous multisensory intervention device (PAMID) has been developed to not only wirelessly monitor physiological conditions as a means for early detection of NBPS, but also automatically provide a real-time multisensory intervention to reduce NBPS in patients with CI if thresholds of physiological parameters reflecting the symptoms are detected. This paper outlines the enhancement of PAMID and test results from a pilot study. This device to be developed will have significant applications in the emerging Tele healthcare systems. PMID- 22255396 TI - A portable inertial sensing-based spinal motion measurement system for low back pain assessment. AB - Spinal motion measurement during dynamic conditions may help identify differences between individuals with and without low back pain (LBP). The purpose of this paper is to demonstrate the feasibility of an inertial sensing based, portable spinal motion measurement system for investigating the differences of the spinal motions between an LBP group and a healthy control group. During a fast flexion/extension test, we measured 3D angular motions of the pelvis, lumbar spine and thoracic spine of the two groups using the inertial sensing based system. Range of motions (ROM) and peak angular velocities were investigated to determine which variables have significant differences between the two groups (p < 0.05). Also, a logistic regression analysis was carried out to see the classifying ability of the LBP patients from controls using the proposed system. The result shows that LBP was particularly associated with significant decreases in peak velocities of the lumbar spinal extension motion, having the maximum 90% sensitivity and 80% specificity in the classification according to the regression analysis. The result demonstrates the possibility of the proposed inertial sensing-based system to be served as an efficient tool in providing an accurate and continuous measurement of the spinal kinematics. PMID- 22255397 TI - Wireless monitoring of reconstructed 12-lead ECG in atrial fibrillation patients enables differential diagnosis of recurrent arrhythmias. AB - Differential diagnosis of symptomatic events in post-ablation atrial fibrillation (AF) patients (pts) is important; in particular, accurate, reliable detection of AF or atrial flutter (AFL) is essential. However, existing remote monitoring devices usually require attached leads and are not suitable for prolonged monitoring; moreover, most do not provide sufficient information to assess atrial activity, since they generally monitor only 1-3 ECG leads and rely on RR interval variability for AF diagnosis. A new hand-held, wireless, symptom-activated event monitor (CardioBip; CB) does not require attached leads and hence can be conveniently used for extended periods. Moreover, CB provides data that enables remote reconstruction of full 12-lead ECG data including atrial signal information. We hypothesized that these CB features would enable accurate remote differential diagnosis of symptomatic arrhythmias in post-ablation AF pts. METHODS: 21 pts who underwent catheter ablation for AF were instructed to make a CB transmission (TX) whenever palpitations, lightheadedness, or similar symptoms occurred, and at multiple times daily when asymptomatic, during a 60 day post ablation time period. CB transmissions (TXs) were analyzed blindly by 2 expert readers, with differences adjudicated by consensus. RESULTS: 7 pts had no symptomatic episodes during the monitoring period. 14 of 21 pts had symptomatic events and made a total of 1699 TX, 164 of which were during symptoms. TX quality was acceptable for rhythm diagnosis and atrial activity in 96%. 118 TX from 10 symptomatic pts showed AF (96 TX from 10 pts) or AFL (22 TX from 3 pts), and 46 TX from 9 pts showed frequent PACs or PVCs. No other arrhythmias were detected. Five pts made symptomatic TX during AF/AFL and also during PACs/PVCs. CONCLUSIONS: Use of CB during symptomatic episodes enabled detection and differential diagnosis of symptomatic arrhythmias. The ability of CB to provide accurate reconstruction of 12 L ECGs including atrial activity, combined with its ease of use, makes it suitable for long-term surveillance for recurrent AF in post-ablation patients. PMID- 22255398 TI - Low-cost and disposable pressure sensor mat for non-invasive sleep and movement monitoring applications. AB - Sleep has profound effects on the physical and mental well-being of an individual. The National Institutes of Health (NIH) Sleep Disorder Research Plan gives particular emphasis to non-invasive sleep monitoring methods. Older adults experience sleep fragmentation due to sleep disorders. Unobtrusive non-contact monitoring can be the only realistic solution for long term home-based sleep monitoring. The demand for a low-cost and non-invasive sleep monitoring system for in-home use is more than before due to an increasingly stressful life style. Cost and complexity of current sensor elements hinder the development of low-cost sleep monitoring devices for in-home use. This paper presents the design, development and implementation of a low-cost and disposable pressure sensor mat that could be useful for in-home sleep and movement monitoring applications. The sensor mat design is based on a compressible foam sandwiched between two orthogonal arrays of cPaper capacitance sensors. A low-cost conducting paper has been developed for use as the capacitance sensor electrode. Typical mat design uses a 3 mm thick foam with 5 mm row/column grid array shows that it has a measurement resolution of 0.1 PSI pressure. The resolution can be controlled by both modifying properties of the conducting paper and the foam. Since this pressure mat design is based on low-cost paper, the sensor electrodes are disposable or semi-durable and hence it is ideal for the use in point-of-care physiological monitoring, pervasive healthcare and consumer electronic devices. PMID- 22255399 TI - Privacy versus autonomy: a tradeoff model for smart home monitoring technologies. AB - Smart homes are proposed as a new location for the delivery of healthcare services. They provide healthcare monitoring and communication services, by using integrated sensor network technologies. We validate a hypothesis regarding older adults' adoption of home monitoring technologies by conducting a literature review of articles studying older adults' attitudes and perceptions of sensor technologies. Using current literature to support the hypothesis, this paper applies the tradeoff model to decisions about sensor acceptance. Older adults are willing to trade privacy (by accepting a monitoring technology), for autonomy. As the information captured by the sensor becomes more intrusive and the infringement on privacy increases, sensors are accepted if the loss in privacy is traded for autonomy. Even video cameras, the most intrusive sensor type were accepted in exchange for the height of autonomy which is to remain in the home. PMID- 22255400 TI - Robotic wheelchair commanded by SSVEP, motor imagery and word generation. AB - This work presents a robotic wheelchair that can be commanded by a Brain Computer Interface (BCI) through Steady-State Visual Evoked Potential (SSVEP), Motor Imagery and Word Generation. When using SSVEP, a statistical test is used to extract the evoked response and a decision tree is used to discriminate the stimulus frequency, allowing volunteers to online operate the BCI, with hit rates varying from 60% to 100%, and guide a robotic wheelchair through an indoor environment. When using motor imagery and word generation, three mental task are used: imagination of left or right hand, and imagination of generation of words starting with the same random letter. Linear Discriminant Analysis is used to recognize the mental tasks, and the feature extraction uses Power Spectral Density. The choice of EEG channel and frequency uses the Kullback-Leibler symmetric divergence and a reclassification model is proposed to stabilize the classifier. PMID- 22255401 TI - "AmI for health: chronic disease management". AB - Several students of Bioengineering complain about the excess of theoretical classes and the difficulty to assimilate the subject taught. This work presents a strategy to mix theory and practice when teaching, thus motivating students to engage in their studies. PMID- 22255402 TI - Platinum microwire for subdural electrocorticography over human neocortex: millimeter-scale spatiotemporal dynamics. AB - Platinum microwires, terminated at regular intervals to form a grid of contacts, were used to record electric potentials at the surface of the cerebral cortex in human subjects. The microwire grids were manufactured commercially with 75 MUm platinum wire and 1 mm grid spacing, and are FDA approved. Because of their small size and spacing, these grids could be used to explore the scale of spatiotemporal dynamics in cortical surface potentials. Electrochemical impedance spectroscopy was used to characterize their recording properties and develop a frequency-dependent electrical model of the micro-electrodes. Data recorded from multiple sites in human cortex were analyzed to explore the relationship between linear correlation and separation distance. A model was developed to explore the impact of cerebrospinal fluid on signal spread among electrodes. Spatial variation in the per-electrode performance decoding articulated speech from face motor and Wernicke's areas of cortex was explored to understand the scale of information processing at the cortex. We conclude that there are important dynamics at the millimeter scale in human subdural electrocorticography which may be important in maximizing the performance of neural prosthetic applications. PMID- 22255403 TI - Characterization of functional biointerface on silicon nanowire MOSFET. AB - Biointerface between biological organisms and electronic devices has attracted a lot of attention since a biocompatible and functional interface can revolutionize medical applications of bioelectronics. Here, we used 3-aminopropyl trimethoxysilane (APTMS) self-assembled monolayer (SAM) to modify the surface of nanowire-based metal-oxide-semiconductor field-effect transistors (NW-MOSFETs) for pH sensing and later creation of biointerface. Electrical measurement was utilized to first verify the sensing response of unmodified NW-MOSFETs and then examine pH sensing on APTMS modified NW-MOSFETs. A biointerface was then created by immobilizing polylysine, either poly-D-lysine (PDL) or poly-L-lysine (PLL), on APTMS modified NW-MOSFETs. This biointerface was characterized by electron spectroscopy for chemical analysis (ESCA), cell biocompatibility, and fluorescent images. The results of ESCA verified the amide bonding (CONH) between polylysine and APTMS modified surface. After PC12 cultured on polylysine-APTMS modified area, highly selective areas for cell growth were observed by fluorescent microscope. Analysis and improvement of selectively cell-growth biointerface on the NW-MOSFETs gave us an insight into future development of neuronal biosensors. PMID- 22255404 TI - Direct imaging of DNA motif sequences with encoded nanoparticles. AB - We present a method for encoded tagging and imaging of short nucleic acid motif chains (oligomotifs) using selective hybridization of heterogeneous Au nanoparticles. The resulting encoded nanoparticle string is thus representative of the underlying motif sequence. Since the nanoparticles are much more massive than the motifs; the motif chain order can be directly observed using scanning electron microscopy. Using this technique we demonstrate direct sequencing of oligomotifs in single DNA molecules consisting of four 100-bp motif chains tagged with four different types of nanoparticles. The method outlined is a precursor for a high density direct sequencing technology. PMID- 22255405 TI - A nanoelectromechanical biosensor based on precise quantification and control of DNA orientation. AB - We utilize spectral self-interference fluorescent microscopy (SSFM) to measure fluorophore height with sub-nm precision to precisely quantify DNA orientation. A novel polymeric 3D scaffold is used to functionalize the sensor surface and to control orientation of the surface anchored DNA. PMID- 22255407 TI - Can driven-right-leg circuits increase interference in ECG amplifiers? AB - The Driven-Right-Leg (DRL) circuit has been used for about 50 years to reduce interference due to common-mode voltage in biopotential amplifiers in scenarios that range from fixed equipment supplied from power lines to battery-supplied ambulatory monitors, and for systems that use gelled, dry, textile, and capacitive electrodes. However, power-line interference models predict that for isolation amplifiers, currently mandated by safety standards, power-line interference can often couple mostly in differential mode rather than in common mode. In this work we analyze the effect of the DRL circuit in different ECG leads to elucidate its actual effect on power-line interference reduction. It turns out that that the DRL circuit, which effectively reduces common-mode interference, affects differential-mode interference in an unpredictable way and can increase interference. PMID- 22255406 TI - Calibrating the photo-thermal response of magneto-fluorescent gold nanoshells. AB - We report the photothermal response and Near Infrared (NIR) imaging sensitivities of magneto-fluorescent silica core gold nanocomplexes designed for molecular image guided thermal therapy of cancer. Approximately 160 nm Silica core gold nanoshells were designed to provide NIR fluorescent and Magnetic Resonance (MR) contrast by incorporating FDA approved dye indocyanine green (ICG) and iron-oxide within an outer silica epilayer. The imaging and therapeutic sensitivity, and the stability of fluorescence contrast for 12 microliters of suspension (containing approximately 7.9 * 10(8) or 1.3 femtoMole nanoshells) buried at depths of 2-8 mm in tissue mimicking scattering media is reported. PMID- 22255408 TI - The design of CMOS general-purpose analog front-end circuit with tunable gain and bandwidth for biopotential signal recording systems. AB - In this paper an 8-channel CMOS general-purpose analog front-end (AFE) circuit with tunable gain and bandwidth for biopotential signal recording systems is presented. The proposed AFE consists of eight chopper stabilized pre-amplifiers, an 8-to-1 analog multiplexer, and a programmable gain amplifier. It can be used to sense and amplify different kinds of biopotential signals, such as electrocorticogram (ECoG), electrocardiogram (ECG) and electromyogram (EMG). The AFE chip is designed and fabricated in 0.18-MUm CMOS technology. The measured maximum gain of AFE is 60.8 dB. The low cutoff frequency can achieve as low as 0.8 Hz and high cutoff frequency can be adjusted from 200 Hz to 10 kHz to suit for different kinds of biopotential signals. The measured input-referred noise is 0.9 MUV(rms), with the power consumption of 18MUW per channel at 1.8-V power supply. And the noise efficiency factor (NEF) is only 1.3 for pre-amplifier. PMID- 22255409 TI - Design of a high sensitive double-gate field-effect transistor biosensor for DNA detection. AB - The study of interactions between organic biomolecules and semiconducting surfaces is an important consideration for the design and fabrication of field effect-transistor (FET) biosensor. This paper demonstrates DNA detection by employing a double-gate field effect transistor (DGFET). In addition, an investigation of sensitivity and signal to noise ratio (SNR) is carried out for different values of analyte concentration, buffer ion concentration, pH, reaction constant, etc. Sensitivity, which is indicated by the change of drain current, increases non-linearly after a specific value (~ 1 nM) of analyte concentration and decreases non-linearly with buffer ion concentration. However, sensitivity is linearly related to the fluidic gate voltage. The drain current has a significant effect on the positive surface group (-NH(2)) compared to the negative counterpart (-OH). Furthermore, the sensor has the same response at a particular value of pH (5.76) irrespective of the density of surface group, although it decreases with pH value. The signal to noise ratio is improved with higher analyte concentrations and receptor densities. PMID- 22255410 TI - A bio-impedance probe to assess liver steatosis during transplant surgery. AB - This work addresses the design of a bioimpedance probe to assess steatosis on the exposed liver in the donor during liver transplant surgery. Whereas typically bioimpedance uses needle probes to avoid surface effects, for clinical reasons a non-penetrative probe is required. In addition the need to ensure that the measurement is representative of the bulk tissue suggests a larger probe than is normally used to ensure a sufficiently large measurement volume. Using a simple model, simulations and tests on bovine liver, this paper investigates the relationship between probe dimensions and depth of measurement penetration and investigates the accuracy which might be expected in a configuration suitable for use in the operating theatre on intact but exposed livers. A probe using ECG electrodes is proposed and investigated. PMID- 22255411 TI - Rapid impedance measurement of tethered bilayer lipid membrane biosensors. AB - Tethered bilayer lipid membranes (tBLM) offer a promising means to immobilize membrane proteins for sensor applications and study biological phenomena including membrane-nanoparticle interactions. tBLM biointerfaces are typically characterized using electrochemical impedance spectroscopy (EIS) in the 1 mHz to 1 Hz range due to interface parasitics. To enable rapid characterization of biointerfaces for high throughput applications, this paper introduces a method for high resolution EIS characterization of tBLMs at higher frequencies. The tBLM equivalent electrical model is analyzed, and the benefit of extracting the real portion of interface admittance is described. Mathematical analysis shows that the maximum frequency for measuring membrane resistance is a function of membrane characteristics and that small area membranes could enable measurement well into the kHz range, permitting observation of millisecond membrane protein activity in biosensor arrays. PMID- 22255412 TI - Design of a novel digital phantom for EIT system calibration. AB - This paper presented the design method of a novel digital phantom for electrical impedance tomography system calibration. By current sensing, voltage generating circuitry and digital processing algorithms implemented in FPGA, the digital phantom can simulate different impedances of tissues. The hardware of the digital phantom mainly consists of current sensing section, voltage generating section, electrodes switching section and a FPGA. Concerning software, the CORDIC algorithm is implemented in the FPGA to realize direct digital synthesis (DDS) technique and related algorithms. Simulation results show that the suggested system exhibits sufficient accuracy in the frequency range 10 Hz to 2 MHz. With the advantages offered by digital techniques, our approach has the potential of speed, accuracy and flexibility of the EIT system calibration process. PMID- 22255413 TI - Using DWT for ECG motion artifact reduction with noise-correlating signals. AB - Dealing with motion artifacts in long-term ECG recordings is a big issue. The frequency spectrum of motion artifacts is similar to the frequencies of the QRS complex--the wanted signal in the ECG. The deletion of motion artifacts often leads to a deformation of QRS complexes, too. These risks can be minimized by using a noise-correlating signal as a second channel for artifact reduction. This paper presents an approach using the electrode-skin impedance as a second channel for the reduction of motion artifacts. Using the discrete wavelet transform, motion artifacts can be deleted time and frequency selective. This filter approach leads to an improvement of the automatic QRS detection and decreases the number of false detections by 35 %. PMID- 22255414 TI - HRV analysis in local anesthesia using Continuous Wavelet Transform (CWT). AB - Spectral analysis of Heart Rate Variability (HRV) is used for the assessment of cardiovascular autonomic control. In this study Continuous Wavelet Transform (CWT) has been used to evaluate the effect of local anesthesia on HRV parameters in a group of fourteen patients undergoing axillary brachial plexus block. A new method which takes signal characteristics into account has been presented for the estimation of the variable boundaries associated with the low and the high frequency band of the HRV signal. The variable boundary method might be useful in cases when the power related to respiration component extends beyond the traditionally excepted range of the high frequency band (0.15-0.4 Hz). The statistical analysis (non-parametric Wilcoxon signed rank test) showed that the LF/HF ratio decreased within an hour of the application of the brachial plexus block compared to the values fifteen minutes prior to the application of the block. These changes were observed in thirteen of the fourteen patients included in this study. PMID- 22255415 TI - Wavelet based data analysis for implantable pulse oximetric sensors. AB - Cardiovascular data recording by implantable sensor modules exhibits a number of advantages over extra-corporeal standard approaches. Implantable sensors feature their benefits in particular for high risk patients suffering from chronic heart diseases, because diagnosis can be combined with therapy in a closed loop system. Nevertheless, the measured photoplethysmographic signals reveal different kinds of noise and artifacts. There are several parametric and non-parametric mathematical techniques that try to achieve optimality and generality in estimating the actual signal out of its noisy representation. The determination of blood oxygen saturation and pulse transit time requires one of these mathematical techniques for gaining the exact position and magnitude of maxima and minima in the photoplethysmograph. A robust wavelet algorithm resolves the difficulties arising from physiological data. PMID- 22255416 TI - Symmetrical modified dual tree complex wavelet transform for processing quadrature Doppler ultrasound signals. AB - Dual-tree complex wavelet transform (DTCWT), which is a shift invariant transform with limited redundancy, is an improved version of discrete wavelet transform. Complex quadrature signals are dual channel signals obtained from the systems employing quadrature demodulation. An example of such signals is quadrature Doppler signal obtained from blood flow analysis systems. Prior to processing Doppler signals using the DTCWT, directional flow signals must be obtained and then two separate DTCWT applied, increasing the computational complexity. In this study, in order to decrease computational complexity, a symmetrical modified DTCWT algorithm is proposed (SMDTCWT). A comparison between the new transform and the symmetrical phasing-filter technique is presented. Additionally denoising performance of SMDTCWT is compared with the DWT and the DTCWT using simulated signals. The results show that the proposed method gives the same output as the symmetrical phasing-filter method, the computational complexity for processing quadrature signals using DTCWT is greatly reduced and finally the SMDTCWT based denoising outperforms conventional DWT with same computational complexity. PMID- 22255417 TI - Generic single-channel detection of absence seizures. AB - A long-term EEG-monitoring system, which automatically marks seizure events, is useful for diagnosing and treating epilepsy. A generic method utilizing the low inter-and intra-patient variabilities in EEG-characteristics during absence seizures is proposed. This paper investigates if the spike-and-wave behaviour during absence seizures is so distinct that a single-channel implementation is possible. 18 channels of scalp electroencephalography (EEG), from 19 patients suffering from childhood absence epilepsy, are analysed individually. The characteristics of the seizures are captured using the energy content of wavelet transform subbands and classified using a support vector machine. To ease the evaluation of the method, we present a new graphical visualization of the performance based on the topographical distribution on the scalp. The presented seizure detection method shows that the best result is obtained for the derivation F7-FP1. Using this channel a sensitivity of 99.1 %, positive predictive value of 94.8 %, mean detection latency of 3.7 s, and false detection rate value of 0.5/h was obtained. The topographical visualization of the results clearly shows that the frontal, midline, and parietal channels outperform detection based on the channels in the occipital region. PMID- 22255418 TI - Automated detection of sleep EEG slow waves based on matching pursuit using a restricted dictionary. AB - In this paper, an original method to detect sleep slow waves (SSW) in electroencephalogram (EEG) recordings is proposed. This method takes advantage of a Matching Pursuit algorithm using a dictionary reduced to Gabor functions reproducing the main targeted waveform characteristics. By describing the EEG signals in terms of SSW properties, the corresponding algorithm is able to identify waveforms based on the largest matching coefficients. The implemented algorithm was tested on a database of whole night sleep EEG recordings collected in 9 young healthy subjects where SSW have been visually scored by an expert. Besides being fully automated and much faster than visual scoring analysis, the results obtained to the proposed method were in excellent agreement with the expert with 98% of correct detections and a 77% concordance in event time position and duration. These results were superior from those of the classical method both in terms of sensibility and precision. PMID- 22255419 TI - Improving myoelectric pattern recognition positional robustness using advanced training protocols. AB - The control of powered upper limb prostheses using the surface electromyogram (EMG) is an important clinical option for amputees. There have been considerable recent improvements in prosthetic hands, but these currently lack a control scheme that can decode movement intent from the EMG to exploit their mechanical dexterity. Pattern recognition based control has the potential to decode many classes of movement intent, but is confounded when using the prosthesis in varying positions during activities of daily living. This work describes the degradation that can occur when using pattern recognition in varying positions, during both static positioning tasks and dynamic activities of daily living. It is shown that training with dynamic activities can greatly improve positional robustness for both static and dynamic tasks, without requiring a complex and lengthy training session. PMID- 22255420 TI - Resolving signal complexities for ambulatory monitoring of motor function in Parkinson's disease. AB - Automatic tracking of movement disorders in patients with Parkinson's disease (PD) is dependent on the ability of machine learning algorithms to resolve the complex and unpredictable characteristics of wearable sensor data. The challenge reflects the variety of movement disorders that fluctuate throughout the day which can be confounded by voluntary activities of daily life. Our approach is the development of multiple dynamic neural network (DNN) classifiers whose application are governed by a rule-based controller within the Integrated Processing and Understanding of Signals (IPUS) framework. Solutions are described for time-varying occurrences of tremor and dyskinesia, classified at 1 s resolution from surface electromyographic (sEMG) and tri-axial accelerometer (ACC) data acquired from patients with PD. The networks were trained and tested on separate datasets, respectively, while subjects performed unscripted and unconstrained activities in a home-like setting. Performance of the classifiers achieved an overall global error rate of less than 10%. PMID- 22255421 TI - Resolving signal complexities for ambulatory monitoring of motor function in Parkinson's disease. AB - Automatic tracking of movement disorders in patients with Parkinson's disease (PD) is dependent on the ability of machine learning algorithms to resolve the complex and unpredictable characteristics of wearable sensor data. The challenge reflects the variety of movement disorders that fluctuate throughout the day which can be confounded by voluntary activities of daily life. Our approach is the development of multiple dynamic neural network (DNN) classifiers whose application are governed by a rule-based controller within the Integrated Processing and Understanding of Signals (IPUS) framework. Solutions are described for time-varying occurrences of tremor and dyskinesia, classified at 1 s resolution from surface electromyographic (sEMG) and tri-axial accelerometer (ACC) data acquired from patients with PD. The networks were trained and tested on separate datasets, respectively, while subjects performed unscripted and unconstrained activities in a home-like setting. Performance of the classifiers achieved an overall global error rate of less than 10%. PMID- 22255422 TI - What is IPUS and how does it help resolve biosignal complexity? AB - Integrated Processing and Understanding of Signals (IPUS) combines signal processing and artificial intelligence approaches to develop algorithms for resolving signal complexity. It has also led to development over the last decade and a half of software tools for supporting the algorithm design process. The signals to be analyzed are the superposition of temporally localized and temporally overlapping signal components from broadly defined signal classes pertinent to the given application. Resolving a signal's complexity thus amounts to "decoding" it to reveal details of the specific signal components that are present at each point of a dense temporal grid defined on the signal. IPUS uses artificial intelligence techniques such as rule-based inference in conjunction with parameterized signal processing transformations to combat the combinatorial explosion encountered in any exhaustive search among the possible decoding answers for a given signal. Originally developed in the mid 1990's for auditory scene analysis, the IPUS approach has since been refined and extended in the context of various applications. In this paper, we present an overview of IPUS and discuss why its latest developments significantly impact biosignal analysis in diverse rehabilitation applications. PMID- 22255423 TI - Continuous monitoring of functional activities using wearable, wireless gyroscope and accelerometer technology. AB - The development of functional activity monitors (FAMs) will allow rehabilitation researchers and clinicians to evaluate treatment efficacy, to monitor compliance to exercise instructions, and to provide real time feedback in the treatment of movement disorders during the performance of daily activities. The purpose of the present study was to develop and test a small sized wearable FAM system comprised of three sensors positioned on the sternum and both thighs, wireless Bluetooth transmission capability to a smartphone, and computationally efficient activity detection algorithms for the accurate detection of functional activities. Each sensor was composed of a tri-axial accelerometer and a tri-axial gyroscope. Computationally efficient activity recognition algorithms were developed, using a sliding window of 1 second, the variability of the tilt angle time series and power spectral analysis. In addition, it includes a decision tree that identifies postures such as sitting, standing and lying, walking at comfortable, slow and fast speeds, transitions between these functional activities (e.g, sit-to-stand and stand-to-sit), activity duration and step frequency. In a research lab setting the output of the FAM system, video recordings and a 3D motion analysis system were compared in 10 healthy young adults. The results show that the agreement between the FAM system and the video recordings ranged from 98.10% to 100% for all postures, transfers and walking periods. There were no significant differences in activity durations and step frequency between measurement instruments. PMID- 22255424 TI - Signal acquisition and processing techniques for sEMG based silent speech recognition. AB - sEMG based silent speech recognition systems seek to bypass the limitations of acoustic speech recognition by measuring and interpreting muscle activity of the facial and neck musculature involved in speech production. However, this speech recognition modality introduces unique challenges of its own. This paper describes signal acquisition and processing strategies that we have employed to address these challenges during our development of a silent speech recognition system. PMID- 22255425 TI - Identification and attenuation of physiological noise in fMRI using kernel techniques. AB - Functional magnetic resonance imaging (fMRI) techniques enable noninvasive studies of brain functional activity under task and resting states. However, the analysis of brain activity could be significantly affected by the cardiac- and respiration-induced physiological noise in fMRI data. In most multi-slice fMRI experiments, the temporal sampling rates are not high enough to critically sample the physiological noise, and the noise is aliased into frequency bands where useful brain functional signal exists, compromising the analysis. Most existing approaches cannot distinguish between the aliased noise and signal if they overlap in the frequency domain. In this work, we further developed a kernel principal component analysis based physiological removal method based on our previous work. Specifically, two kernel functions were evaluated based on a newly proposed criterion that can measure the capability of a kernel to separate the aliased physiological noise from fMRI signal. In addition, a mutual information based criterion was designed to select principal components for noise removal. The method was evaluated by human experimental fMRI studies, and the results demonstrate that the proposed method can effectively identify and attenuate the aliased physiological noise in fMRI data. PMID- 22255426 TI - Hexagonal adaptive filtering on compound ultrasound images. AB - This paper describes an approach to improve the contrast and signal to noise ratio on ultrasound images. Images with sub-pixel lateral displacements were re sampled using a hexagonal grid, registered and compounded. The resultant image was filtered using a hexagonal adaptive masking filter. This approach was evaluated with simulated images and real images from a breast phantom. The results show total improvements in signal to noise ratio of up to 313% in simulated images, and 182% in phantom images. Contrast to noise ratio was improved by 286% in simulated images and 56% in phantom images. PMID- 22255427 TI - Digital image processing for visual prosthesis: filtering implications. AB - Investigators around the world are working on retinal neurostimulation as it may restore functional vision to the blind. The image is captured by a camera and after being processed, a series of electrical stimuli are applied to the surviving ganglion cells of the retina. This visual perception is expected to have low resolution. Therefore, there is a need of new algorithms that present the information contained in a visual scene understandable to humans. This study presents a novel multi-resolution algorithm based on wavelet analysis to extract the useful features of an image. Participants in this experiment were able to configure a filter bank to complete a set of everyday tasks. This study shows that wavelet-based algorithms may facilitate improved functional performance in prosthetic vision. PMID- 22255428 TI - A novel method for informative frame selection in wireless capsule endoscopy video. AB - Wireless capsule endoscopy (WCE) has been validated to be an important tool in the evaluation of gastrointestinal (GI) tract. Compared with traditional endoscope technologies, its non-invasiveness property meets with great favor of patients. However, from physician's point of view, WCE video suffers from low resolution, limited illumination, irregular movement, more importantly, imbalanced rate of abnormality which brings a lot of challenges for diagnosis. These challenges motivate us to devise an approach to guide the physicians to focus on the informative frames which could be convenient for review of the content of the GI tract. This paper presents a novel approach for automatic selection of the WCE video frames with lumen and coherent motility. We adopt lumen detection based on mean shift to provide robust and reliable selection of lumen. Together with the evaluation of coherent motility, we can provide a full and fast approach to select the informative frames for diagnosis. The experiments on real date are presented to show the performance of our proposed method. PMID- 22255429 TI - Vision correction for computer users based on image pre-compensation with changing pupil size. AB - Many computer users suffer varying degrees of visual impairment, which hinder their interaction with computers. In contrast with available methods of vision correction (spectacles, contact lenses, LASIK, etc.), this paper proposes a vision correction method for computer users based on image pre-compensation. The blurring caused by visual aberration is counteracted through the pre-compensation performed on images displayed on the computer screen. The pre-compensation model used is based on the visual aberration of the user's eye, which can be measured by a wavefront analyzer. However, the aberration measured is associated with one specific pupil size. If the pupil has a different size during viewing of the pre compensated images, the pre-compensation model should also be modified to sustain appropriate performance. In order to solve this problem, an adjustment of the wavefront function used for pre-compensation is implemented to match the viewing pupil size. The efficiency of these adjustments is evaluated with an "artificial eye" (high resolution camera). Results indicate that the adjustment used is successful and significantly improves the images perceived and recorded by the artificial eye. PMID- 22255430 TI - Alternating direction method of multipliers applied to 3D light sheet fluorescence microscopy image deblurring using GPU hardware. AB - This paper focuses on the deblurring and denoising of Poisson noise contaminated images acquired with a new imaging technique producing large 3D data sets: Light Sheet Fluorescence Microscopy. This paper details the optimization algorithm used, which is based on the Alternating Direction Method of Multipliers, and its efficient implementation using GPU hardware. In practice, a 3D 100 million voxel image is deconvolved in five minutes, which is at least 25 times faster than a state-of-the-art MATLAB implementation. PMID- 22255431 TI - Deformable registration of histological sections to brain MR images using a hybrid boundary-based slice-to-volume approach. AB - Registration of histology to three-dimensional (3D) magnetic resonance (MR) images is often required for the analysis of brain structure and investigation of brain pathologies. A novel algorithm for deformable registration of an individual histological section to a brain MR image is described. The cost function uses a novel hybrid intensity- and boundary surface-based measure that reflects the contrast of histological slice intensities across the boundary of the pial and inner cortical surface. The algorithm relies on implicit representation of cortical surfaces reconstructed from an anatomical MR image, and computes the cost function in a level set framework. The algorithm is evaluated on cross modality registration of myelin-stained histological sections to a high resolution MR image of the human brain. PMID- 22255432 TI - Model-based 3D/2D deformable registration of MR images. AB - A method is proposed for automatic registration of 3D preoperative magnetic resonance images of deformable tissue to a sequence of its 2D intraoperative images. The algorithm employs a dynamic continuum mechanics model of the deformation and similarity (distance) measures such as correlation ratio, mutual information or sum of squared differences for registration. The registration is solely based on information present in the 3D preoperative and 2D intraoperative images and does not require fiducial markers, feature extraction or image segmentation. Results of experiments with a biopsy training breast phantom show that the proposed method can perform well in the presence of large deformations. This is particularly useful for clinical applications such as MR-based breast biopsy where large tissue deformations occur. PMID- 22255433 TI - Ranking of stopping criteria for log domain diffeomorphic demons application in clinical radiation therapy. AB - Deformable Image Registration is a complex optimization algorithm with the goal of modeling a non-rigid transformation between two images. A crucial issue in this field is guaranteeing the user a robust but computationally reasonable algorithm. We rank the performances of four stopping criteria and six stopping value computation strategies for a log domain deformable registration. The stopping criteria we test are: (a) velocity field update magnitude, (b) vector field Jacobian, (c) mean squared error, and (d) harmonic energy. Experiments demonstrate that comparing the metric value over the last three iterations with the metric minimum of between four and six previous iterations is a robust and appropriate strategy. The harmonic energy and vector field update magnitude metrics give the best results in terms of robustness and speed of convergence. PMID- 22255434 TI - Multi-scale optical flow including normalized mutual information for planar deformable lung motion estimation from 4D CT. AB - A novel energy function for computing planar optical flow from X-ray CT images was presented and reported in detail in [1]. The technique combines four terms: brightness constancy, gradient constancy, continuity equation based on mass conservation, and discontinuity-preserving spatio-temporal smoothness. Both qualitative and quantitative evaluation of the proposed method demonstrated that the method results in significantly better angular errors than previous well known techniques for optical flow estimation. A multi-scale approach to motion field computation based on this framework is presented in this paper. The proposed approach significantly speeds up the calculations, realizing computational savings. Additionally, an approach to determination of optimum values of scalar weights in the energy function is herein proposed. Normalized mutual information measured between the first image warped with the estimated motion and the second image is used to determine the optimum value for weighting parameters. PMID- 22255435 TI - Non-rigid registration of longitudinal brain tumor treatment MRI. AB - To evaluate changes in brain structure or function, longitudinal images of brain tumor patients must be non-rigidly registered to account for tissue deformation due to tumor growth or treatment. Most standard non-rigid registration methods will fail to align these images due to the changing feature correspondences between treatment time points and the large deformations near the tumor site. Here we present a registration method which jointly estimates a label map for correspondences to account for the substantial changes that may occur during tumor treatment. Under a Bayesian parameter estimation framework, we employ different probability distributions depending on the correspondence labels. We incorporate models for image similarity, an image intensity prior, label map smoothing, and a transformation prior that encourages deformation near the estimated tumor location. Our proposed algorithm increases registration accuracy compared to a traditional voxel-based registration method as shown using both synthetic and real patient images. PMID- 22255436 TI - GPU implementation of a deformable 3D image registration algorithm. AB - We present a parallel implementation of a new deformable image registration algorithm using the Computer Unified Device Architecture (CUDA). The algorithm co registers preoperative and intraoperative 3-dimensional magnetic resonance (MR) images of a deforming organ. It employs a linear elastic dynamic finite-element model of the deformation and distance measures such as mutual information and sum of squared differences to align volumetric image data sets. Computationally intensive elements of the method such as interpolation, displacement and force calculation are significantly accelerated using a Graphics Processing Unit (GPU). The result of experiments carried out with a realistic breast phantom tissue shows a 37 fold speedup for the GPU-based implementation compared with an optimized CPU-based implementation in high resolution MR image registration. The GPU implementation is capable of registering 512 * 512 * 136 image sets in just over 2 seconds, making it suitable for clinical applications requiring fast and accurate processing of medical images. PMID- 22255437 TI - Assessment of piano-related injuries using infrared imaging. AB - Playing the piano is a repetitive task that involves the use of the hands and the arms. Pain related to piano-playing can result in extending the tissues and ligaments of the hands and arms beyond their mechanical tolerance. Infrared imaging records the skin temperature and produces a thermal map of the imaged body part; small variations in the skin temperature could be a sign of inflammation or stress of the tissues. In this paper, we used statistical analysis to examine the difference in hand and arm temperatures of pianists with pain and pianists without pain related to piano-playing. We found that there is a statistically significant difference in hand temperatures between the two populations, but not in the lower arm and upper arm temperatures. PMID- 22255438 TI - Medical thermal imaging of electrically stimulated woman breast: a simulation study. AB - Tissues have different electrical conductivity and metabolic energy consumption values depending on their state of health and species. Since metabolic heat generation values show differences from tissue to tissue, thermal imaging has started to play an important role in medical diagnoses. Temperature differences of healthy and cancerous tissue may be changed by means of frequency dependent current stimulation within medical safety limits, and thus, depth dependent imaging performance can be increased. In this study, a three-dimensional realistic model of a woman breast and malignant tissue is generated and frequency dependent feasibility work for the proposed method is implemented. Temperature distributions are obtained by solving Pennes Bio Heat Equation (using finite element method). Temporal and spatial temperature distribution images are obtained at desired depths for two cases; with and without current application. Different temperature distributions are imaged by altering the frequency of the applied current and the corresponding conductivity value. Improvement in the imaging performance can be provided by current stimulation, and the temperature difference generated by 40 mm(3) tumor at 1.5 cm depth can be detected on breast surface with the state-of-the-art thermal imagers. PMID- 22255439 TI - Sparse MEG source imaging in Landau-Kleffner syndrome. AB - Epilepsy patients with Landau-Kleffner syndrome (LKS) usually have a normal brain structure, which makes it a challenge to identify the epileptogenic zone only based on magnetic resonance imaging (MRI) data. A sparse source imaging technique called variation based sparse cortical current density (VB-SCCD) imaging was adopted here to reconstruct cortical sources of magnetoencephalography (MEG) interictal spikes from an LKS patient. Realistic boundary element (BE) head and cortex models were built by segmenting structural MRI. 148-channel MEG was recorded for 10 minutes between seizures. Total 29 epileptiform spikes were selected for analysis. The primary cortical sources were observed locating at the left intra- and perisylvian cortex. Multiple extrasylvian sources were identified as the secondary sources. The spatio-temporal patterns of cortical sources provide more insights about the neuronal synchrony and propagation of epileptic discharges. Our observations were consistent with presurgical diagnosis for this patient and observation of aphasia in LKS. The present results suggest that the promising of VB-SCCD technique in assisting with presurgical planning and studying the neural network for LKS in determining the lateralization of epileptic origins. It can further be applied to non-invasively localize and/or lateralize eloquent cortex for language for epilepsy patients in general in the future. PMID- 22255440 TI - In-vitro cell quantification method based on depth dependent analysis of brain tissue microscopic images. AB - In this study we developed a new automatic quantification method to count the number of targeted fluorescently labeled molecules of in-vitro rat brain tissue images. NG2+ glial cells were monitored in order to detect their proliferation to their same kind of cells or to another astrocyte cells using different fluorescently labeled molecules. The method is based on morphological segmentation followed by depth-dependent detection operation applied to a stack of confocal microscopic images. The number of local maxima peak points was used to count the number of the labeled cells. The method shows good promise for the computer-aided assessment in neurological studies for accurate automatic counting systems. PMID- 22255441 TI - MEG-fMRI integration to visualize brain dynamics while perceiving 3-D object shape from motion. AB - Here, we combine magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to detect the dynamic brain responses to 3D-SFM. We manipulated the coherence of randomly moving dots to create different levels of 3D perception and investigated the associated changes in brain activity. Results of the fMRI analysis were used to impose plausible constraints on the MEG inverse calculation to improve spatial resolution of the spatiotemporal activity estimates. Time frequency analysis was also employed to elucidate spatiotemporal dynamic changes in the spontaneous brain activities. MEG-fMRI combined analysis showed that the activities the posterior infero-temporal (pIT), parieto-occipital (PO), and intra parietal (IP) regions were increased at different latencies during highly coherent motion conditions in which subjects perceived a robust 3D object. Results of the time-frequency analysis indicated the suppression of alpha- and beta-band activities in these regions which reflect the commitment of these areas in the perception of 3D-SFM. Current results suggest that the interactions between the dorsal and ventral visual subsystems are crucial for the perception of 3D object from 2D optic flow. PMID- 22255442 TI - Health status detection for patients in physiological monitoring. AB - A primary difficulty in physiological monitoring is detecting changes of health status for patients. In order to address this difficulty, we propose a new framework in patient-specific physiological monitoring by defining a density ratio using the training density and testing density to denote the changes of patient status, such as health, sub-health and abnormalities. We use a Least Square-based algorithm to estimate density ratio parameters without involving density estimation. For verifying the availability and efficacy of the proposed framework, we apply our approach to physiological monitoring data (11901 beats) from the Physionet database to do the pilot experiments. Results demonstrate that the approach is effective in detecting the patient status. PMID- 22255443 TI - Service oriented architecture to support real-time implementation of artifact detection in critical care monitoring. AB - The quality of automated real-time critical care monitoring is impacted by the degree of signal artifact present in clinical data. This is further complicated when different clinical rules applied for disease detection require source data at different frequencies and different signal quality. This paper proposes a novel multidimensional framework based on service oriented architecture to support real-time implementation of clinical artifact detection in critical care settings. The framework is instantiated through a Neonatal Intensive Care case study which assesses signal quality of physiological data streams prior to detection of late-onset neonatal sepsis. In this case study requirements and provisions of artifact and clinical event detection are determined for real-time clinical implementation, which forms the second important contribution of this paper. PMID- 22255444 TI - Algorithms for characterizing brain metabolites in two-dimensional in vivo MR correlation spectroscopy. AB - Traditional analyses of in vivo 1D MR spectroscopy of brain metabolites have been limited to the inspection of one-dimensional free induction decay (FID) signals from which only a limited number of metabolites are clearly observable. In this article we introduce a novel set of algorithms to process and characterize two dimensional in vivo MR correlation spectroscopy (2D COSY) signals. 2D COSY data was collected from phantom solutions of topical metabolites found in the brain, namely glutamine, glutamate, and creatine. A statistical peak-detection and object segmentation algorithm is adapted for 2D COSY signals and applied to phantom solutions containing varied concentrations of glutamine and glutamate. Additionally, quantitative features are derived from peak and object structures, and we show that these measures are correlated with known phantom metabolite concentrations. These results are encouraging for future studies focusing on neurological disorders that induce subtle changes in brain metabolite concentrations and for which accurate quantitation is important. PMID- 22255445 TI - Fall detection algorithm for the elderly using acceleration sensors on the shoes. AB - The rate of increase in the number of aging population in Korea is very rapid among OECD-member countries. And fall accident is one of the most common factors that threaten the health of the elderly. Therefore, it is needed to develop a fall detection system for the elderly. Most fall detection systems use accelerometers attached on the torso. And in various studies, it was verified that these systems have high sensitivity and high specificity. However, the elderly would feel uncomfortable when banding a sensor on the chest every day. Therefore, in this study, we attached an accelerometer on the shoes to detect fall in the elderly. This prototype system would be improved as a smaller, low power system in the next study. Also, applying energy harvesting device to this shoe system is being developed to reduce the weight of battery. PMID- 22255446 TI - Rotary spectra analysis applied to static stabilometry. AB - Static stabilometry is a technique aimed at quantifying postural sway during quiet standing in the upright position. Many different models and many different techniques to analyze the trajectories of the Centre of Pressure (CoP) have been proposed. Most of the parameters calculated according to these different approaches are affected by a relevant intra- and inter-subject variability or do not have a clear physiological interpretation. In this study we hypothesize that CoP trajectories have rotational characteristics, therefore we decompose them in clockwise and counter-clockwise components, using the rotary spectra analysis. Rotary spectra obtained studying a population of healthy subjects are described through the group average of spectral parameters, i.e., 95% spectral bandwidth, mean frequency, median frequency, and skewness. Results are reported for the clockwise and the counter-clockwise components and refer to the upright position maintained with eyes open or closed. This study demonstrates that the approach is feasible and that some of the spectral parameters are statistically different between the open and closed eyes conditions. More research is needed to demonstrate the clinical applicability of this approach, but results so far obtained are promising. PMID- 22255447 TI - A methodology for validating artifact removal techniques for fNIRS. AB - fNIRS recordings are increasingly utilized to monitor brain activity in both clinical and connected health settings. These optical recordings provide a convenient measurement of cerebral hemodynamic changes which can be linked to motor and cognitive performance. Such measurements are of clinical utility in a broad range of conditions ranging from dementia to movement rehabilitation therapy. For such applications fNIRS is increasingly deployed outside the clinic for patient monitoring in the home. However, such a measurement environment is poorly controlled and motion, in particular, is a major source of artifacts in the signal, leading to poor signal quality for subsequent clinical interpretation. Artifact removal techniques are increasingly being employed with an aim of reducing the effect of the noise in the desired signal. Currently no methodology is available to accurately determine the efficacy of a given artifact removal technique due to the lack of a true reference for the uncontaminated signal. In this paper we propose a novel methodology for fNIRS data collection allowing for effective validation of artifact removal techniques. This methodology describes the use of two fNIRS channels in close proximity allowing them to sample the same measurement location; allowing for the introducing of motion artifact to only one channel while having the other free of contamination. Through use of this methodology, for each motion artifact epoch, a true reference for the uncontaminated signal becomes available for use in the development and performance evaluation of signal processing strategies. The advantage of the described methodology is demonstrated using a simple artifact removal technique with an accelerometer based reference. PMID- 22255448 TI - Detecting failures of the glucose sensor-insulin pump system: improved overnight safety monitoring for Type-1 diabetes. AB - New sensors for real-time continuous glucose monitoring (CGM) and pumps for continuous subcutaneous insulin infusion (CSII), possibly mounted on the same device, opened new scenarios for Type-1 diabetes treatment. However, possible failures of either CGM or CSII can expose diabetic patients to risks that can be dangerous especially overnight. In this contribution we present a proof-of concept method, developed in a state-space context and implemented through a Kalman estimator, to detect in real time possible overnight failures of the sensor-pump system by simultaneously using CGM and CSII data. The method is tested on two simulated and one real subject. Results show that the method is able to correctly generate alerts for sensor-pump failures and stimulates further investigation on its development. PMID- 22255449 TI - Mapping small intestine bioelectrical activity using high-resolution printed circuit-board electrodes. AB - In this study, novel methods were developed for the in-vivo high-resolution recording and analysis of small intestine bioelectrical activity, using flexible printed-circuit-board (PCB) electrode arrays. Up to 256 simultaneous recordings were made at multiple locations along the porcine small intestine. Data analysis was automated through the application and tuning of the Falling-Edge Variable Threshold algorithm, achieving 92% sensitivity and a 94% positive-predictive value. Slow wave propagation patterns were visualized through the automated generation of animations and isochronal maps. The methods developed and validated in this study are applicable for use in humans, where future studies will serve to improve the clinical understanding of small intestine motility in health and disease. PMID- 22255450 TI - Effects of windowing and zero-padding on Complex Resonant Recognition Model for protein sequence analysis. AB - Signal processing techniques such as Fourier Transform have widely been studied and successfully applied in many different areas. Techniques such as zero-padding and windowing have been developed and found very useful to improve the outcome of the signal processing methods. Resonant Recognition Model (RRM) and Complex Resonant Recognition Model (CRRM) that are based on the discrete Fourier Transform and widely used for the analysis of protein sequences do not consider such methods, which can however improve or alter the features extracted from the protein sequences. Therefore, in this paper, an extensive analysis was carried out to investigate into the influence of the zero-padding and windowing on the features extracted from the Complex Resonant Recognition Model. In order to present such effects, five different classes of influenza A virus Neuraminidase genes, which include H1N1, H1N2, H2N2, H3N2 and H5N1 genes, were used as a case study. For each of the Influenza A subtypes, two sets of Common Frequency Peaks (CFP) were extracted, one where windowing is applied and the other one where windowing is suppressed, for each signal length set for the analysis. In order to make all the signals (protein sequence) the same length, zero-padding was used. The signal lengths used in this study are set to 470, which is the maximum protein length, and also 512, 1024, 2048, 4096, 8192 and 16384 for further analysis. The results suggest that the windowing and zero-padding have key impact on CFP extracted from the Influenza A subtypes as the best match with CFP extracted from influenza A subtypes using CRRM is when the signal length of 4096 and windowing were both applied. Therefore, the outcome of this study should be taken into consideration for more accurate and reliable analysis of the protein sequences. PMID- 22255451 TI - Development of a device for measuring the sensitivity area of coil arrays for magnetic induction measurements. AB - Combining single coils to form a coil array provide advantages for magnetic induction measurements of breathing or heart activity. The main goal for such combination could be a coil configuration which makes the whole measurement system less sensitive for moving artifacts of the patient due to the capability of using many coils for signal acquisition. Such setup could be designed and tested with FEM software. But in most cases, the technical realization differs from theoretical, for instance due to cable effects or the presence of amplifiers attached very close to the coils. Thus, a measurement system for detecting the sensitive area of real arrays is required. In this article, such a device is presented. Based on a crane construction, it is well suited for testing arrays which are built for an integration under a bed or within an incubator for vital parameter monitoring. We will describe the construction as well as first example measurements of a test array. PMID- 22255452 TI - A computational framework for the standardization of motion analysis exploiting wearable inertial sensors. AB - Movement analysis is a powerful tool for the diagnosis of neurological conditions, as well as patient assessment and follow-up during rehabilitation programs. In spite of the available systems allowing a quantitative analysis of a subject's movement control performances, the clinical assessment and diagnostic approach still relies mostly on non-quantitative exams, such as clinical scales. Further, studying balance control, gait and activities of daily living poses relevant technical challenges, which greatly limit the availability of testing facilities. The goal of our project was therefore to develop a new system based on wearable sensors for movement analysis and scoring of performances. A prototype 3-sensors system was tested on a group of 4 normal subjects while carrying out a set of full body movement exercises drawn by clinical scales for the assessment of movement and balance control. PMID- 22255453 TI - Real-time wearable telecardiology from representative signals. AB - Electrocardiograms and other similar techniques (e.g. Photoplethysmograph) are very effective tools for the detection of cardiac abnormalities. Automated analyses of ECG signals may be used for this purpose, but due to their complexity -often involving a Neural Network or Principal Component Analysis--the signal needs to be transmitted to be analysed on a powerful device. Thus, even if signals are compressed before being sent, a significant amount of non-critical information is transmitted, unnecessarily consuming bandwidth and resulting in delays. This is problematic as lives may depend on how fast and accurately an ECG signal can be analysed. We present here a fast, simple and accurate technique that works in real time to detect some ECG abnormalities. We base our analysis on correlations of the time sequence with a Representative Signal (RS) to detect abnormal behaviour. We have implemented this scheme on a standard, inexpensive portable device, so abnormalities may be automatically detected immediately on the device itself, without the need for transmission. PMID- 22255454 TI - Statistical approach for the detection of motion/noise artifacts in Photoplethysmogram. AB - Motion and noise artifacts (MNA) have been a serious obstacle in realizing the potential of Photoplethysmogram (PPG) signals for real-time monitoring of vital signs. We present a statistical approach based on the computation of kurtosis and Shannon Entropy (SE) for the accurate detection of MNA in PPG data. The MNA detection algorithm was verified on multi-site PPG data collected from both laboratory and clinical settings. The accuracy of the fusion of kurtosis and SE metrics for the artifact detection was 99.0%, 94.8% and 93.3% in simultaneously recorded ear, finger and forehead PPGs obtained in a clinical setting, respectively. For laboratory PPG data recorded from a finger with contrived artifacts, the accuracy was 88.8%. It was identified that the measurements from the forehead PPG sensor contained the most artifacts followed by finger and ear. The proposed MNA algorithm can be implemented in real-time as the computation time was 0.14 seconds using Matlab(r). PMID- 22255455 TI - Characterization of typical and atypical atrial flutter loops from the vectorcardiogram. AB - Current techniques for atrial flutter (AFL) treatment involve radiofrequency ablation. This is a relatively simple and short procedure for typical AFL, whereas becomes more complex and unpredictable in the case of atypical AFL. Therefore, non-invasive characterization of AFL would be helpful for the management of ablation procedures. In this study the behavior of typical and atypical AFL groups is characterized from the vectorcardiographic AFL loops. The initial hypothesis is that typical AFL loops resemble each other, whereas atypical AFL loops differ from typical AFL ones. All patient loops were compared to a reference, by analyzing the global trajectory, pathway complexity and distance to the reference loop. The distance was the most significative parameter, being 0.445 +/- 0.135 and 0.799 +/- 0.144 for typical and atypical AFL (p = 8.00 e-5). In addition, an intrapatient analysis revealed a higher stability of typical AFL loops than in the case of atypical AFL. PMID- 22255456 TI - A time domain based classifier for ECG pattern recognition. AB - Pattern recognition, and in particular dynamic time warping has been applied to the ECG for many different purposes over the last decade. Significant research on creating adaptive, feature based, and more complex forms of the algorithm in order to increase its ability to classify an ECG signal accurately has been performed. Despite this increase in complexity and in the number of variations of the dynamic time warping algorithm there has been less focus on actually using the results of dynamic time warping to relate the reference and test signals to each other as accurately as possible. The majority of dynamic time warping algorithms published in the literature, even the most complex of them, classify the most accurate match to a reference signal based only on resulting Euclidean distance or slope difference between samples of the known reference and unknown query signal. This article demonstrates how a combination of measurements including heart-rate, amplitude and required warping time alignment can be used to reduce the resulting error in the classification of a query signal after the query and reference signals have been warped together. Its benefits are verified with significant testing. PMID- 22255457 TI - Premature Ventricular beat classification using a dynamic Bayesian Network. AB - This paper investigates the viability of using the dynamic Bayesian Network framework as a tool to classify heart beats in long term ECG records. A Decision Support System composed by two layers is considered. The first layer performs the segmentation of each heartbeat available in the ECG record, whereas the second layer classifies the heartbeat as Premature Ventricular Contraction (PVC) or Other. The use of both static and dynamic Bayesian Networks is evaluated through using the records available in the MIT-BIH database, and the results show that the Dynamic one performs better, obtaining 95% of sensitivity and 98% of positive predictivity, showing that to consider the temporal relation among events is a good strategy to increase the certainty about present events. PMID- 22255458 TI - How the choice of samples for building arrhythmia classifiers impact their performances. AB - Arrhythmia (i.e., irregular cardiac beat) classification in electrocardiogram (ECG) signals is an important issue for heart disease diagnosis due to the non invasive nature of the ECG exam. In this paper, we analyze and criticize the results of some arrhythmia classification methods presented in the literature in terms of how the samples are chosen for training/testing the classifier and the impact this choice has on their performance (i.e., accuracy/sensitivity/specificity). From our implementation, we also report new accuracies for these methods, establishing a new state-of-the-art method, in terms of results. PMID- 22255459 TI - Detection of Atrial fibrillation from non-episodic ECG data: a review of methods. AB - Atrial fibrillation (A-fib) is the most common cardiac arrhythmia. To effectively treat or prevent A-fib, automatic A-fib detection based on Electrocardiograph (ECG) monitoring is highly desirable. This paper reviews recently developed techniques for A-fib detection based on non-episodic surface ECG monitoring data. A-fib detection methods in the literature can be mainly classified into three categories: (1) time domain methods; (2) frequency domain methods; and (3) non linear methods. In general the performances of these methods were evaluated in terms of sensitivity, specificity and overall detection accuracy on the datasets from the Physionet repository. Based on our survey, we conclude that no promising A-fib detection method that performs consistently well across various scenarios has been proposed yet. PMID- 22255460 TI - Feature extraction in time-frequency signal analysis by means of matched wavelets as a feature generator. AB - The goal of presented work was to compare the usage of standard basic wave let function like e.g. bio-orthogonal or dbn with the optimized wavelet created to the best match analyzing ECG signals in the context of P-wave and atrial fibrillation detection. A library of clinical expert evaluated typical atrial fibrillation evolutions was created as a database for optimal matched wavelet construction. Whole data set consisting of 40 cases with long term ECG recording s were divided into learning and verifying set for the multilayer perceptron neural network used as a classifier structure. Compared with other wavelet filters, the matched wavelet was able to improve classifier performance for a given ECG signals in terms of the Sensitivity and Specificity measures. PMID- 22255461 TI - Classification of English vowels using speech evoked potentials. AB - The objective of this study is to investigate whether Speech Evoked Potentials (SpEPs), which are auditory brainstem responses to speech stimuli, contain information that can be used to distinguish different speech stimuli. Previous studies on brainstem SpEPs show that they contain valuable information about auditory neural processing. As such, SpEPs may be useful for the diagnosis of central auditory processing disorders and language disability, particularly in children. In this work, we examine the spectral amplitude information of both the Envelope Following Response, which is dominated by spectral components at the fundamental (F0) and its harmonics, and Frequency Following Response, which is dominated by spectral components in the region of the first formant (F1), of SpEPs in response to the five English language vowels (?a?,?e?,?ae?,?i?,?u?). Using spectral amplitude features, a classification accuracy of 78.3% is obtained with a linear discriminant analysis classifier. Classification of SpEPs demonstrates that brainstem neural responses in the region of F0 and F1 contain valuable information for discriminating vowels. This result provides an insight into human auditory processing of speech, and may help develop improved methods for objectively assessing central hearing impairment. PMID- 22255462 TI - Breast density characterization using texton distributions. AB - Breast density has been shown to be one of the most significant risks for developing breast cancer, with women with dense breasts at four to six times higher risk. The Breast Imaging Reporting and Data System (BI-RADS) has a four class classification scheme that describes the different breast densities. However, there is great inter and intra observer variability among clinicians in reporting a mammogram's density class. This work presents a novel texture classification method and its application for the development of a completely automated breast density classification system. The new method represents the mammogram using textons, which can be thought of as the building blocks of texture under the operational definition of Leung and Malik as clustered filter responses. The new proposed method characterizes the mammographic appearance of the different density patterns by evaluating the texton spatial dependence matrix (TDSM) in the breast region's corresponding texton map. The TSDM is a texture model that captures both statistical and structural texture characteristics. The normalized TSDM matrices are evaluated for mammograms from the different density classes and corresponding texture models are established. Classification is achieved using a chi-square distance measure. The fully automated TSDM breast density classification method is quantitatively evaluated on mammograms from all density classes from the Oxford Mammogram Database. The incorporation of texton spatial dependencies allows for classification accuracy reaching over 82%. The breast density classification accuracy is better using texton TSDM compared to simple texton histograms. PMID- 22255463 TI - Retinal vessel extraction using a piecewise Gaussian scaled model. AB - Automated analysis of retinal images usually requires estimating the positions and appearance of blood vessels, which contain important features for abnormality detection. Although there is a wide literature on detecting vessel positions from retinal images by modelling cross-sectional profiles, little attention has been given to extracting vessel appearance in intensity. In this paper, we introduce a piecewise Gaussian scaled model to characterise the intensity distributions of vessel cross-sections. Based on a newly developed vessel detection scheme, we describe the use of the proposed model for extracting vessel appearance. The preliminary experimental results obtained from angiographic pairs and images of an SLO sequence are reported. PMID- 22255464 TI - Compression of surface myoelectric signals using MP3 encoding. AB - The potential of MP3 compression of surface myoelectric signals is explored in this paper. MP3 compression is a perceptual-based encoder scheme, used traditionally to compress audio signals. The ubiquity of MP3 compression (e.g., portable consumer electronics and internet applications) makes it an attractive option for remote monitoring and telemedicine applications. The effects of muscle site and contraction type are examined at different MP3 encoding bitrates. Results demonstrate that MP3 compression is sensitive to the myoelectric signal bandwidth, with larger signal distortion associated with myoelectric signals that have higher bandwidths. Compared to other myoelectric signal compression techniques reported previously (embedded zero-tree wavelet compression and adaptive differential pulse code modulation), MP3 compression demonstrates superior performance (i.e., lower percent residual differences for the same compression ratios). PMID- 22255465 TI - Testing the asymptotic statistic for the assessment of the significance of Partial Directed Coherence connectivity patterns. AB - Partial Directed Coherence (PDC) is a powerful tool to estimate a frequency domain description of Granger causality between multivariate time series. One of the main limitation of this estimator, however, has been so far the criteria used to assess the statistical significance, which have been obtained through surrogate data approach or arbitrarily imposed thresholds. The aim of this work is to test the performances of a validation approach based on the rigorous asymptotic distributions of PDC, recently proposed in literature. The performances of this method, defined in terms of percentages of false positives and false negatives, were evaluated by means of a simulation study taking into account factors like the Signal to Noise Ratio (SNR) and the amount of data available for the estimation and the use of different methods for the statistical corrections for multiple comparisons. Results of the Analysis Of Variance (ANOVA) performed on false positives and false negatives revealed a strong dependency of the performances from all the factors investigated. In particular, results indicate an amount of Type I errors below 7% for all conditions, while Type II errors are below 10% when the SNR is at least 1, the data length of at least 50 seconds and the appropriate correction for multiple comparisons is applied. PMID- 22255466 TI - Localization of ictal onset zones in Lennox-Gastaut syndrome using directed transfer function method. AB - Neuroscientists are becoming interested in the application of computational EEG analysis to the identification of ictal onset zones, however, most studies have focused on the localization of ictal onset zones in focal epilepsy. The present study aimed to estimate the ictal onset zone of Lennox-Gastaut syndrome (LGS) with bilaterally synchronous epileptiform discharges from intracranial electroencephalography (iEEG) recordings using directional connectivity analysis. We analyzed ictal iEEG data acquired from three patients with LGS. To identify the ictal onset zones, we estimated the functional directional connectivity network among the intracerebral electrodes using the directed transfer function (DTF) method. The analysis results demonstrated that areas with high average outflow values corresponded well with the surgical resection areas identified using electrophysiologic data and conventional neuroimaging modalities. Our results suggest that the DTF analysis can be a useful auxiliary tool for determining surgical resection areas prior to epilepsy surgery in LGS patients. PMID- 22255467 TI - Maximum multiple-correlation beamformer for estimating source connectivities in electromagnetic brain activities. AB - Synchrony is a phenomenon of local-scale and long-range integrations within a brain circuit. Synchronous activities manifest themselves in similar temporal structures that can be statistically quantified by temporal correlation. In previous studies, synchronous activities were estimated by calculating the correlation coefficient or coherence between a single reference signal and the activity in a brain region. However, a brain circuit may involve multiple brain regions and these regions may communicate to each other through different temporal patterns. Therefore, temporal correlation to multiple reference signals is effective in quantify the source connectivities in the brain. This paper proposes a novel algorithm to calculate the maximum multiple-correlation for each brain region which has an activity estimated by a beamformer. Furthermore, this algorithm can accommodate various latencies of activities in a circuit. Experimental results demonstrate that the proposed method can accurately detect source activities correlated to the given multiple reference signals, even when unknown latencies exist between the source and references. PMID- 22255468 TI - EEG preprocessing for synchronization estimation and epilepsy lateralization. AB - The global framework of this paper is the synchronization analysis in EEG recordings. Two main objectives are pursued: the evaluation of the synchronization estimation for lateralization purposes in epileptic EEGs and the evaluation of the effect of the preprocessing (artifact and noise cancelling by blind source separation, wavelet denoising and classification) on the synchronization analysis. We propose a new global synchronization index, based on the classical cross power spectrum, estimated for each cerebral hemisphere. After preprocessing, the proposed index is able to correctly lateralize the epileptic zone in over 90% of the cases. PMID- 22255469 TI - Wavelet frequency-temporal relative phase pattern analysis for intermuscular synchronization of dynamic surface EMG signals. AB - Cross-correlation is often used as the primary technique to compare two biological signals. Cross-correlation is an effective means to measure the synchronization of two signals assuming the relative phases of all frequencies are distributed linearly, that is, a group delay. The group delay assumption imposes an unfavorable restriction on signals with varying relative phase correlation at different frequencies. The traditional Fourier technique provides phase information for each frequency component, but it is not suitable for biological signals with non-stationary statistics. The application of a wavelet based phase analysis technique is discussed in this study. The frequency decomposition and temporally localized nature of the wavelet transform provides localized phase-frequency information for two signals. The merits and weaknesses of using the wavelet relative phase pattern for determining the synchronization of surface electromyographic signals from two muscle sites is discussed. PMID- 22255470 TI - Statistical threshold for nonlinear Granger Causality in motor intention analysis. AB - Directed influence between multiple channel signal measurements is important for the understanding of large dynamic systems. This research investigates a method to analyze large, complex multi-variable systems using directional flow measure to extract relevant information related to the functional connectivity between different units in the system. The directional flow measure was completed through nonlinear Granger Causality (GC) which is based on the nonlinear predictive models using radial basis functions (RBF). In order to extract relevant information from the causality map, we propose a threshold method that can be set up through a spatial statistical process where only the top 20% of causality pathways is shown. We applied this approach to a brain computer interface (BCI) application to decode the different intended arm reaching movement (left, right and forward) using 128 surface electroencephalography (EEG) electrodes. We also evaluated the importance of selecting the appropriate radius in the region of interest and found that the directions of causal influence of active brain regions were unique with respect to the intended direction. PMID- 22255471 TI - Automatic skull stripping in MRI based on morphological filters and fuzzy c-means segmentation. AB - In this paper a new automatic skull stripping method for T1-weighted MR image of human brain is presented. Skull stripping is a process that allows to separate the brain from the rest of tissues. The proposed method is based on a 2D brain extraction making use of fuzzy c-means segmentation and morphological operators applied on transversal slices. The approach is extended to the 3D case, taking into account the result obtained from the preceding slice to solve the organ splitting problem. The proposed approach is compared with BET (Brain Extraction Tool) implemented in MRIcro software. PMID- 22255472 TI - Automatic detection of cortical and PSC cataracts using texture and intensity analysis on retro-illumination lens images. AB - Cataract remains a leading cause for blindness worldwide. Cataract diagnosis via human grading is subjective and time-consuming. Several methods of automatic grading are currently available, but each of them suffers from some drawbacks. In this paper, a new approach for automatic detection based on texture and intensity analysis is proposed to address the problems of existing methods and improve the performance from three aspects, namely ROI detection, lens mask generation and opacity detection. In the detection method, image clipping and texture analysis are applied to overcome the over-detection problem for clear lens images and global thresholding is exploited to solve the under-detection problem for severe cataract images. The proposed method is tested on 725 retro-illumination lens images randomly selected from a database of a community study. Experiments show improved performance compared with the state-of-the-art method. PMID- 22255473 TI - Bayesian model evidence for order selection and correlation testing. AB - Model selection is a critical component of data analysis procedures, and is particularly difficult for small numbers of observations such as is typical of functional MRI datasets. In this paper we derive two Bayesian evidence-based model selection procedures that exploit the existence of an analytic form for the linear Gaussian model class. Firstly, an evidence information criterion is proposed as a model order selection procedure for auto-regressive models, outperforming the commonly employed Akaike and Bayesian information criteria in simulated data. Secondly, an evidence-based method for testing change in linear correlation between datasets is proposed, which is demonstrated to outperform both the traditional statistical test of the null hypothesis of no correlation change and the likelihood ratio test. PMID- 22255474 TI - A new spatially constrained NMF with application to fMRI. AB - In this paper the problem of BOLD detection is addressed. The focus here is on non-negative matrix factorization (NMF), which is a data driven method and able to provide part-based representation of data. A new constrained optimization problem is proposed for the purpose of BOLD detection. The proposed constraint imposes some prior spatial information of active area inside the brain, on the decomposition process. The constraint is built up based on the type of stimulus and available physiological knowledge of the brain performance. The simulation results on both synthetic and real fMRI data show that applying the proposed constraint improves the BOLD detection performance. PMID- 22255475 TI - Assessment of functional and structural connectivity between motor cortex and thalamus using fMRI and DWI. AB - Connectivity evaluations have been performed in a noninvasive manner by examining resting state fMRI alongside diffusion-weighted images (DWI). The spatial structures of coherent spontaneous BOLD fluctuations provided the most convincing preliminary evidence that the BOLD signal was predominantly of neuronal origin rather than non-neuronal, artifactual noise. In this study we have shown that in thalamocortical network, the results of functional connectivity analysis and DWI correspond well with each other, thereby providing cross-validation of the two techniques. We have used the resting state fMRI data of 3 subjects with 10 minute resting state functional images via a 3T Siemens scanner. we used cross correlation for functional analysis and reported thalamocortical results with p value=0.01 and cluster size=100, Then showed corresponding tracts connecting premotor cortex and thalamus. In addition, both techniques correspond well to histological delineation and invasive tract tracing, which provides a 'gold standard' validation of the two techniques. The degree of structural connectivity has been shown to correlate with the strength of functional connectivity, thereby providing a potentially straightforward structural explanation for many of the changes in functional connectivity in disease states. PMID- 22255476 TI - An fMRI study of abrupt-awake episodes during behavioral microsleeps. AB - This paper reports the brain activation patterns of five subjects who were abruptly awakened from microsleeps in a simulated automotive driving experiment. By comparing the BOLD signals between behavioral microsleep (BM), abrupt awakening (AA) and post-abrupt awakening (post-AA) stages, we observed that visual area, frontal cortex, limbic lobe manifested more intense activation during the AA stage while frontal cortex, temporal cortex, primary motor area and insula were more activated during the post-AA stage. These results suggested that the subjects were likely in mental states differ from those associated with decision making processes as they went through and emerged from the abrupt awakening episodes. PMID- 22255477 TI - A generalized estimating equations approach for resting-state functional MRI group analysis. AB - An Alzheimer's fMRI study has motivated us to evaluate inter-regional correlations between groups. The overall objective is to assess inter-regional correlations at a resting-state with no stimulus or task. We propose using a generalized estimating equation (GEE) transition model and a GEE marginal model to model the within-subject correlation for each region. Residuals calculated from the GEE models are used to correlate brain regions and assess between group differences. The standard pooling approach of group averages of the Fisher-z transformation assuming temporal independence is a typical approach used to compare group correlations. The GEE approaches and standard Fisher-z pooling approach are demonstrated with an Alzheimer's disease (AD) connectivity study in a population of AD subjects and healthy control subjects. We also compare these methods using simulation studies and show that the transition model may have better statistical properties. PMID- 22255478 TI - Composite features for automatic diagnosis of intervertebral disc herniation from lumbar MRI. AB - Lower back pain is widely prevalent in the world today, and the situation is aggravated due to a shortage of radiologists. Intervertebral disc disorders like desiccation, degeneration and herniation are some of the major causes of lower back pain. In this paper, we propose a robust computer-aided herniation diagnosis system for lumbar MRI by first extracting an approximate Region Of Interest (ROI) for each disc and then using a combination of viable features to produce a highly accurate classifier. We describe the extraction of raw, LBP (Local Binary Patterns), Gabor, GLCM (Gray-Level Co-occurrence Matrix), shape, and intensity features from lumbar SPIR T2-weighted MRI and also present a thorough performance comparison of individual and combined features. We perform 5-fold cross validation experiments on 35 cases and report a very high accuracy of 98.29% using a combination of features. Also, combining the desired features and reducing the dimensionality using LDA, we achieve a high sensitivity (true positive rate) of 98.11%. PMID- 22255479 TI - An improved classification scheme for chromosomes with missing data. AB - Karyotyping, or the automatic classification of human chromosomes, is mostly based on the analysis of the chromosome specific banding pattern. Unfortunately, the most informative phases of the cell division cycle are composed of long chromosomes that easily overlap: the involved banding pattern information is corrupted, resulting in a drastic increase of the classification error. Assuming the availability of a probabilistic classifier, the improvement of the classification of chromosomes with corrupted data would require the additional estimation of the joint probability density of the observed and missing data for each chromosome class. Given the number of classes, the possible position and extension of the corrupted data within a chromosome, and the dimensionality of the feature space, a reliable estimation would need an impossible number of training samples. We chose to circumvent the estimation problem by developing a statistical generative model of the pattern of each class, so that the corrupted part can be substituted with a partial pattern synthetically generated from the model. This allows to obtain a Monte Carlo estimate of the maximum a posteriori probability for the class given the observation and the missing data, which reduces to a simple voting scheme if the a priori probability for each class is equal. Moreover, this Monte Carlo classification is superior to the voting scheme based on the simple imputation of the classes mean to the missing data. PMID- 22255480 TI - Contactless abnormal gait detection. AB - We present a new method to detect abnormal gait based on the symmetry verification of the two-leg movement. Unlike other methods requiring special motion captors, the proposed method uses image processing techniques to correctly track leg movement. Our method first divides each leg into upper and lower parts using anatomical knowledge. Then each part is characterised by two straight lines approximating its two borders. Finally, leg movement is represented by the angle evolution of these lines. In this process, we propose a new line approximation algorithm which is robust to the outliers caused by incorrect separation of leg into upper / lower parts. In our experiment, the proposed method got very encouraging results. With 281 normal / abnormal gait videos of 9 people, this method achieved a classification accuracy of 91%. PMID- 22255481 TI - Interplay between bias field correction, intensity standardization, and noise filtering for T2-weighted MRI. AB - Magnetic Resonance Imaging (MRI) is known to be significantly affected by a number of acquisition artifacts, such as intensity non-standardness, bias field, and Gaussian noise. These artifacts degrade MR image quality significantly, obfuscating anatomical and physiological detail and hence need to be corrected for to facilitate application of computerized analysis techniques such as segmentation, registration, and classification. Specifically, algorithms are required to correct for bias field (intensity inhomogeneity), intensity non standardness (drift in tissue intensities across patient acquisitions), and Gaussian noise, an artifact that significantly affects and blurs tissue boundaries (resulting in poor gradients). While clearly one needs to correct for all these artifacts, the exact sequence in which all three operations need to be applied in order to maximize MR image quality has not been explored. In this paper, we empirically evaluate the interplay between distinct algorithms for bias field correction (BFC), intensity standardization (IS), and noise filtering (NF) to study the effect of these operations on image quality in the context of 3 Tesla T2-weighted (T2w) prostate MRI. 7 different sequences comprising combinations of BFC, IS, and NF were quantitatively evaluated in terms of the percent coefficient of variation (%CV), a statistic which attempts to quantify the intensity inhomogeneity within a region of interest (prostate). The different combinations were also independently evaluated in the context of a classifier scheme for detection of prostate cancer on high resolution in vivo T2w prostate MRI. A secondary contribution of this work is a novel evaluation measure for quantifying the level of intensity non-standardness, called difference of modes (DoM). Experimental evaluation of the different sequences of operations across 22 patient datasets revealed that the sequence of BFC, followed by NF, and IS provided the best image quality in terms of %CV as well as classifier accuracy. The DoM measure was able to accurately capture the level of intensity non standardness present in the images resulting from the different sequences of operations. PMID- 22255482 TI - Automatic classification of fish germ cells through optimum-path forest. AB - The spermatogenesis is crucial to the species reproduction, and its monitoring may shed light over some important information of such process. Thus, the germ cells quantification can provide useful tools to improve the reproduction cycle. In this paper, we present the first work that address this problem in fishes with machine learning techniques. We show here how to obtain high recognition accuracies in order to identify fish germ cells with several state-of-the-art supervised pattern recognition techniques. PMID- 22255483 TI - Creating a virtual slide map of sputum smears by auto-stitching. AB - Under a microscope, only a small field of a slide can be seen through the eye piece. A digital replication of a large section of the smear on a slide is desirable for several applications, including image-based auto-positioning for automated microscopy and telepathology. To achieve this, images of the various fields on the slide can be captured and stitched automatically to form a virtual slide map. We compared two auto-stitching methods, namely the geometric hashing and the scale invariant feature transform (SIFT), applied to images of tuberculosis-infected sputum smears. Experimental results show good agreement between the two methods. PMID- 22255484 TI - A novel shape representation of the dental arch and its applications in some dentistry problems. AB - Standardized digital images of maxillary dental casts of 47 subjects were analyzed using MATLAB software whereby the two hamular notches and the incisive papilla defines the Cartesian vertical and horizontal axes, as well as the origin. The angle and length of the midpoints of the anterior teeth, mesiobuccal and distobuccal cusp of the posterior teeth were measured from the origin and denoted as theta(1), ..., theta(18) and l(1), ..., l(18) respectively. These values were collectively used to represent the shape of each dental cast. Clustering and principal component analyses were employed to find possible groups of dental arches using the above measure of shape. The main result of this study is that the 3 groups of dental arch shape may be represented by the novel feature vector v(k) = (theta(k)(1), l(k)(1), theta(k)(3), l(k)(3), theta(k)(5), l(k)(5), theta(k)(13), l(k)(13)), k = 1, 2, 3. Knowledge of v(k) implies three impression trays should be sufficient in a particular prosthetic dentistry application for Malaysian patients. Further, given that v(k) are accurately measured they may be potential candidates as evidence in specific application of forensic dentistry. PMID- 22255485 TI - Automatic detection of tree-in-bud patterns for computer assisted diagnosis of respiratory tract infections. AB - Abnormal nodular branching opacities at the lung periphery in Chest Computed Tomography (CT) are termed by radiology literature as tree-in-bud (TIB) opacities. These subtle opacity differences represent pulmonary disease in the small airways such as infectious or inflammatory bronchiolitis. Precisely quantifying the detection and measurement of TIB abnormality using computer assisted detection (CAD) would assist clinical and research investigation of this pathology commonly seen in pulmonary infections. This paper presents a novel method for automatically detecting TIB patterns based on fast localization of candidates using local scale information of the images. The proposed method combines shape index, local gradient statistics, and steerable wavelet features to automatically identify TIB patterns. Experimental results using 39 viral bronchiolitis human para-influenza (HPIV) CTs and 21 normal lung CTs achieved an overall accuracy of 89.95%. PMID- 22255486 TI - A Wavelet-packet-based approach for breast cancer classification. AB - In this paper, a new approach for non-invasive diagnosis of breast diseases is tested on the region of the breast without undue influence from the background and medically unnecessary parts of the images. We applied Wavelet packet analysis on the two-dimensional histogram matrices of a large number of breast images to generate the filter banks, namely sub-images. Each of 1250 resulting sub-images are used for computation of 32 two-dimensional histogram matrices. Then informative statistical features (e.g. skewness and kurtosis) are extracted from each matrix. The independent features, using 5-fold cross-validation protocol, are considered as the input sets of supervised classification. We observed that the proposed method improves the detection accuracy of Architectural Distortion disease compared to previous works and also is very effective for diagnosis of Spiculated Mass and MISC diseases. PMID- 22255487 TI - Hybrid cosine and Radon transform-based processing for digital mammogram feature extraction and classification with SVM. AB - A new methodology to automatically extract features from mammograms and classify them is presented. It relies on a hybrid processing system that sequentially uses the discrete cosine transform (DCT) to obtain the high frequency component of the mammogram and then applies the Radon transform to the obtained DCT image in order to extract its directional features. The features are subsequently fed to a support vector machine for classification. The approach was tested on a database of one hundred images and shows improved classification accuracy in comparison to using the discrete cosine transform or the Radon transform alone, as done in others works. PMID- 22255488 TI - An automated method for hemorrhage detection in traumatic pelvic injuries. AB - Hemorrhage is the main cause of deaths that occurs within first 24 hours after a traumatic pelvic injury. Therefore, it is very important to determine hemorrhage quickly. Hemorrhages are detected using a CT scan. However, it is very time consuming for physicians to look for hemorrhage in all CT slices. Therefore, an automated system is needed. This paper proposes an automated hemorrhage detection technique by incorporating anatomical information of pelvic region. The results showed method performs comparably to manual methods. A statistical test is conducted to see if the volume of hemorrhage detected using this technique is significantly different from the volume assessed manually. PMID- 22255489 TI - Quantitative texture analysis of MRI images for detection of cartilage-related bone marrow edema. AB - This paper presents a study that investigated the potential of texture analysis using Fluid Sensitive Fat Suppressed MRI images for the use in detection of bone marrow edema. A total of 168 slices of knee MRI from 10 subjects were involved. Six histogram-based textures (mean intensity, standard deviation, smoothness, third moment, uniformity and entropy) were calculated in both 2D and 3D, and were compared between healthy group and group affected by bone marrow edema. Two sample t-tests were performed to assess the difference between healthy group and group affected by edema. The intensity third moment in 2D showed significant difference between the slices of healthy subjects and the slices affected by edema (p<0.05). Smoothness and standard deviation in 2D showed a modest significance between healthy and affected groups. No significant difference was found in the 3D textures of healthy group and group affected by edema. PMID- 22255490 TI - A salient information processing system for bionic eye with application to obstacle avoidance. AB - In this paper we present a visual processing system for bionic eye with a focus on obstacle avoidance. Bionic eye aims at restoring the sense of vision to people living with blindness and low vision. However, current hardware implant technology limits the image resolution of the electrical stimulation device to be very low (e.g., 100 electrode arrays, which is approx. 12 * 9 pixels). Therefore, we need a visual processing unit that extracts salient information in an unknown environment for assisting patients in daily tasks such as obstacle avoidance. We implemented a fully portable system that includes a camera for capturing videos, a laptop for processing information using a state-of-the-art saliency detection algorithm, and a head-mounted display to visualize results. The experimental environment consists of a number of objects, such as shoes, boxes, and foot stands, on a textured ground plane. Our results show that the system efficiently processes the images, effectively identifies the obstacles, and eventually provides useful information for obstacle avoidance. PMID- 22255491 TI - Detecting the pigment network in dermoscopy images: a directional approach. AB - Several algorithms have been recently proposed for the analysis of dermoscopy images and the detection of melanomas. However, the pigment network is not considered in most of these works, although this cue plays a major role in clinical diagnosis routines. This paper proposes an algorithm for the detection of the pigment network. The algorithm is based on a bank of directional filters (difference of Gaussians) and explores color, directionality and topological properties of the network. PMID- 22255492 TI - Automatic estimation of pelvic organ anatomical references. AB - Pelvic floor diseases cover pathologies of which physiopathology is not well understood. 2D sagittal MRI sequences used in the clinical assessment allow to visualize the dynamic behavior of the main organs involved (bladder, uterus vagina and rectum). Clinicians use anatomical landmarks and measurements related to the pelvic organs in their pathology assessment. Usually, those tasks are performed manually which results in being both tedious and subject to operator dependency. A methodology is proposed to attempt a quantitative and objective characterization of the organ behaviors under abdominal strain condition. This approach automatically assesses the organ movements, through the estimation of characteristic angles (anorectal angle, uterovaginal angle, bladder inclination), and the tracking of anatomically significant points (anorectal angle vertex, uterovaginal angle vertex, bladder neck). From a multi-subject analysis, pathological organs have been distinguished from healthy ones, which shows the relevance of the computed features. In addition, a stability analysis has shown the soundness of the approach. PMID- 22255493 TI - Staging tissues with conditional random fields. AB - We present a framework for identifying disease states by classifying cells in the pathological regions of tissues into different categories. We use conditional random fields (CRF) to incorporate characteristics of cells and their spatial distributions. The efficacy of CRF to model cell-cell feature interactions is demonstrated by using a lung tissue dataset and a synthesized cancer tissue dataset. Comparisons with an independent cell model and a contextual model based on a Markov random field indicate that CRF effectively incorporates features of both cells and their spatial distributions for identification of pathological cells. PMID- 22255494 TI - The usefulness of ultrasound in the classification of chronic liver disease. AB - Chronic Liver Disease is a progressive, most of the time asymptomatic, and potentially fatal disease. In this paper, a semi-automatic procedure to stage this disease is proposed based on ultrasound liver images, clinical and laboratorial data. In the core of the algorithm two classifiers are used: a k nearest neighbor and a Support Vector Machine, with different kernels. The classifiers were trained with the proposed multi-modal feature set and the results obtained were compared with the laboratorial and clinical feature set. The results showed that using ultrasound based features, in association with laboratorial and clinical features, improve the classification accuracy. The support vector machine, polynomial kernel, outperformed the others classifiers in every class studied. For the Normal class we achieved 100% accuracy, for the chronic hepatitis with cirrhosis 73.08%, for compensated cirrhosis 59.26% and for decompensated cirrhosis 91.67%. PMID- 22255495 TI - Depth Energy Image for gait symmetry quantification. AB - This paper introduces a new quantification method for gait symmetry based on depth information acquired from a structured light system. First, the new concept of Depth Energy Image is introduced to better visualize gait asymmetry problems. Then a simple index is computed from this map to quantify motion symmetry. Results are presented for six subjects with and without gait problems. Since the method is markerless and cheap, it could be a very promising solution in the future for gait clinics. PMID- 22255496 TI - Detection of malaria parasites in thick blood films. AB - Malaria, caused by a blood parasite of the genus plasmodium, kills millions of people each year. According to the World Health Organization, the standard for malaria diagnosis is microscopic examination of a stained blood film. We have developed a two-stage algorithm for the automatic detection of plasmodia in thick blood films. The focus of the first stage is on high detection sensitivity while accepting high numbers of false-positive detections per image. The second stage reduces the number of false-positive detections to an acceptable level while maintaining the detection sensitivity of the first stage. The algorithm can detect plasmodia at a sensitivity of 0.97 with a mean number of 0.8 false positive detections per image. Our results indicate that the proposed algorithm is suitable for the development of an automated microscope for computer-aided malaria screening. PMID- 22255498 TI - CARES 3.0: a two stage system combining feature-based recognition and edge-based segmentation for CIMT measurement on a multi-institutional ultrasound database of 300 images. AB - The intima-media thickness of the carotid artery (CIMT) is a validated marker of atherosclerosis. Accurate CIMT measurement can be performed by specifically designed computer algorithms. We improved a previous CIMT measurement technique by introducing a smart heuristic search for the lumen-intima (LI) and media adventitia (MA) interfaces of the carotid distal wall. We called this new release as CARES 3.0 (a class of AtheroEdgeTM system, a patented technology from Global Biomedical Technologies, Inc., CA, USA). CARES 3.0 is completely automated and adopts an integrated approach for carotid location in the image frame, followed by segmentation based on edge snapper and heuristic search. CARES 3.0 was benchmarked against three other techniques on a 300 image multi-institutional database. One of the techniques was user-driven. The CARES 3.0 CIMT measurement bias was -0.021 +/- 0.182 mm, which was better than that of the semi automated method (-0.036 +/- 0.183 mm). CARES 3.0 outperformed the other two fully automated methods. The Figure-of-Merit of CARES 3.0 was 97.4%, better than that of the semi-automated technique (95.4%). PMID- 22255497 TI - VirtualShave: automated hair removal from digital dermatoscopic images. AB - VirtualShave is a novel tool to remove hair from digital dermatoscopic images. First, individual hairs are identified using a top-hat filter followed by morphological postprocessing. Then, they are replaced through PDE-based inpainting with an estimate of the underlying occluded skin. VirtualShave's performance is comparable to that of a human operator removing hair manually, and the resulting images are almost indistinguishable from those of hair-free skin. PMID- 22255499 TI - A landmark-free framework for the detection and description of shape differences in embryos. AB - This paper introduces a new method to quantify and characterize shape changes during early facial development without the use of landmarks. Landmarks are traditionally used in morphometric analysis, but very few can be identified reliably across all stages of embryonic development. This method uses deformable registration to produce a dense vector field describing the point correspondences between two images. Low and mid-level features are extracted from the deformable vector field to find regions of organized differences that are biologically relevant. These methods are shown to detect regions of difference when evaluated on chick embryo images warped with small magnitude deformations in regions critical to midfacial development. PMID- 22255500 TI - Extraction of samples from airway and vessel trees in 3D lung CT based on a multi scale principal curve tracing algorithm. AB - The extraction of airway and vessel trees plays an important role in the diagnosis and treatment planning of lung diseases. However, this is a challenging task due to the small size of the anatomical structures, noise, or artifacts in the image. The similar intensity values between the lung parenchyma and airway lumen, the airway wall and the blood vessels make extraction particularly difficult. Our method detailed herein presents an automatic extraction of samples of both the airways and vessels from the three-dimensional computed tomography (3D-CT) based on the multi-scale principal curve algorithm. The image is first thresholded to find airway or vessel candidates according to their corresponding Hounsfield units (HU). The Frangi filter is then used to extract the tubular structures and remove background noise. Finally, a multi-scale principal curve projection and tracing algorithm is applied on the filtered image to identify the centerlines of the airway and vessel trees. PMID- 22255501 TI - Feature selection applied to ultrasound carotid images segmentation. AB - The automated tracing of the carotid layers on ultrasound images is complicated by noise, different morphology and pathology of the carotid artery. In this study we benchmarked four methods for feature selection on a set of variables extracted from ultrasound carotid images. The main goal was to select those parameters containing the highest amount of information useful to classify the pixels in the carotid regions they belong to. Six different classes of pixels were identified: lumen, lumen-intima interface, intima-media complex, media-adventitia interface, adventitia and adventitia far boundary. The performances of QuickReduct Algorithm (QRA), Entropy-Based Algorithm (EBR), Improved QuickReduct Algorithm (IQRA) and Genetic Algorithm (GA) were compared using Artificial Neural Networks (ANNs). All methods returned subsets with a high dependency degree, even if the average classification accuracy was about 50%. Among all classes, the best results were obtained for the lumen. Overall, the four methods for feature selection assessed in this study return comparable results. Despite the need for accuracy improvement, this study could be useful to build a pre-classifier stage for the optimization of segmentation performance in ultrasound automated carotid segmentation. PMID- 22255502 TI - Automatic extraction of sulcal lines on the cortical surface using shortest path probability maps. AB - This paper describes an automatic procedure for extracting sulcal lines from cortical surface meshes of the human brain, which will serve as a tool for landmark extraction as well as for investigating the morphometry of sulci. The procedure consists in a sequence of steps, including sulcal basin segmentation based on local curvature information, estimating a bundle of depth-constrained geodesic paths and determining a robust probability map of sulcal lines crossing. In this experiment, we present quantitative validations on two main sulci to observe the agreement of our method with manually traced curves. PMID- 22255503 TI - Profiling the features of pre-segmented healthy liver CT scans: towards fast detection of liver lesions in emergency scenario. AB - Automating the detection of lesions in liver CT scans requires a high performance and robust solution. With CT-scan start to become the norm in emergency department, the need for a fast and efficient liver lesions detection method is arising. In this paper, we propose a fast and evolvable method to profile the features of pre-segmented healthy liver and use it to detect the presence of liver lesions in emergency scenario. Our preliminary experiment with the MICCAI 2007 grand challenge datasets shows promising results of a fast training time, ability to evolve the produced healthy liver profiles, and accurate detection of the liver lesions. Lastly, the future work directions are also presented. PMID- 22255504 TI - Contour detection of atherosclerotic plaques in IVUS images using ellipse template matching and particle swarm optimization. AB - It is valuable for diagnosis of atherosclerosis to detect lumen and media adventitia contours in intravascular ultrasound (IVUS) images of atherosclerotic plaques. In this paper, a method for contour detection of plaques is proposed utilizing the prior knowledge of elliptic geometry of plaques. Contours are initialized as ellipses by using ellipse template matching, where a matching function is maximized by particle swarm optimization. Then the contours are refined by boundary vector field snakes. The method was evaluated via 88 in vivo images from 21 patients. It outperformed a state-of-the-art method by 3.8 pixels and 4.8% in terms of the mean distance error and relative mean distance error, respectively. PMID- 22255505 TI - Automated cavity detection of infectious pulmonary tuberculosis in chest radiographs. AB - The presence of cavities in the upper lung zones is an important indicator of highly infectious Tuberculosis (TB). Diagnoses performed by the radiologists are labor intensive and of high inter-reader variation. After analyzing the existing computer-aided detection techniques, we propose an fully automated TB cavity detection system which combines a 2D Gaussian-model-based template matching (GTM) for candidates detection with Hessian-matrix-based image enhancement (HIE) for the following cavity segmentation and feature extraction. Experimental results demonstrate that our approach outperforms the existing TB cavity detection technique with higher accuracy and lower false positive rate. PMID- 22255506 TI - Us'em: the user-centered design of a device for motivating stroke patients to use their impaired arm-hand in daily life activities. AB - Stroke leaves the majority of its survivors with an impairment of the upper extremity that affects their ability to live independently and their quality of life. Rehabilitation research shows that practice of everyday life activities in a natural context may sustain or even improve arm-hand performance, even during chronic stages after stroke. Based on this insight we designed, developed and evaluated Us'em; this consists of two watch-like accelerometry devices that provide feedback to stroke patients regarding the usage of their impaired versus their non-affected upper extremity. System usability and treatment credibility/expectancy were evaluated positively by therapists and patients. PMID- 22255507 TI - Multidimensional control using a mobile-phone based brain-muscle-computer interface. AB - Many well-known brain-computer interfaces measure signals at the brain, and then rely on the brain's ability to learn via operant conditioning in order to control objects in the environment. In our lab, we have been developing brain-muscle computer interfaces, which measure signals at a single muscle and then rely on the brain's ability to learn neuromuscular skills via operant conditioning. Here, we report a new mobile-phone based brain-muscle-computer interface prototype for severely paralyzed persons, based on previous results from our group showing that humans may actively create specified power levels in two separate frequency bands of a single sEMG signal. Electromyographic activity on the surface of a single face muscle (Auricularis superior) is recorded with a standard electrode. This analog electrical signal is imported into an Android-based mobile phone. User modulated power in two separate frequency band serves as two separate and simultaneous control channels for machine control. After signal processing, the Android phone sends commands to external devices via Bluetooth. Users are trained to use the device via biofeedback, with simple cursor-to-target activities on the phone screen. PMID- 22255508 TI - Repeatability of the accelerometric-based method to detect step events for hemiparetic stroke patients. AB - This study is to evaluate the repeatability of the accelerometric-method to detect step events for hemiparetic stroke patients. To evaluate this method, four adults with chronic hemiparetic stroke were participated. The repeatability of this method using a single three-axis accelerometer was evaluated with a six optical camera motion capture system. The correlation statistics and Bland-Altman plot were then used to evaluate the agreement between the step-time differences from the accelerometer data and the reflective markers data. The correlation coefficient of each two data was 0.99 (p < 0.001) and retest result was 0.99 (p < 0.001). The mean +/- standard deviation (SD) between each two data along with the 95% limits of agreement (LOA = +/- 1.96 SD) was 2.58 +/- 2.37 ms (LOA = -2.07 ms and 7.23 ms), and retest result was 3.73 +/- 2.02 ms (LOA = -0.22 ms and 7.68 ms). These results show that the suggested method is useful to detect step events for hemiparetic stroke patients. PMID- 22255509 TI - A real-time auditory feedback system for retraining gait. AB - Stroke is the third leading cause of death in the United States and the principal cause of major long-term disability, incurring substantial distress as well as medical cost. Abnormal and inefficient gait patterns are widespread in survivors of stroke, yet gait is a major determinant of independent living. It is not surprising, therefore, that improvement of walking function is the most commonly stated priority of the survivors. Although many such individuals achieve the goal of walking, the caliber of their walking performance often limits endurance and quality of life. The ultimate goal of the research presented here is to use real time auditory feedback to retrain gait in patients with chronic stroke. The strategy is to convert the motion of the foot into an auditory signal, and then use this auditory signal as feedback to inform the subject of the existence as well as the magnitude of error during walking. The initial stage of the project is described in this paper. The design and implementation of the new feedback method for lower limb training is explained. The question of whether the patient is physically capable of handling such training is explored. PMID- 22255510 TI - Wireless vibrotactile feedback system for postural response improvement. AB - This paper presents an evaluation of a real-time wireless body sensor network for the improvement of postural balance response. The system senses body sway using accelerometers and provides vibrotactile feedback to multiple points on the inner forearm, allowing the subject to obtain a clear indication of imbalanced movements within their center of gravity and respective surroundings. The wireless body sensor network is ergonomic, allowing the subject to feel comfortable and experience unconfined movements during its use. The system transmits realtime data to a local host computer, where the data is recorded and displayed graphically. This recorded data monitors the subject's progress and allows any sudden falling movements to be overseen by care-givers. Pilot data measuring postural responses to perturbations with and without the system are conducted. Results obtained suggest that this system can improve postural responses, where it is demonstrated that such an intelligent and user-friendly system can be applied to rehabilitate the loss of balance in hospital and home care patients. PMID- 22255511 TI - A special purpose embedded system for neural machine interface for artificial legs. AB - This paper presents a design and implementation of a neural-machine interface (NMI) for artificial legs that can decode amputee's intended movement in real time. The newly designed NMI integrates an FPGA chip for fast processing and a microcontroller unit (MCU) with multiple on-chip analog-to-digital converters (ADCs) for real-time data sampling. The resulting embedded system is able to sample in real time 12 EMG signals and 6 mechanical signals and execute a special complex phase-dependent classifier for accurate recognition of the user's intended locomotion modes. The implementation and evaluation are based on Altera's Stratix III 3S150 FPGA device coupled with Freescale's MPC5566 MCU. The experimental results for classifying three locomotion modes (level-ground walking, stairs ascent, and stairs descent) based on data collected from an able bodied human subject have shown acceptable performance for real-time controlling of artificial legs. PMID- 22255512 TI - Characterizing walking activity in people with stroke. AB - Stroke is the leading cause of disability in the U.S. Many people with stroke have limited walking ability and are inactive. In this paper we describe a novel shoe based sensor, SmartShoe, and a signal processing technique to identify walking activity. The technique was validated with 6 people with walking impairment due to stroke. The results suggest that the SmartShoe is able to accurately identify walking activity. This device could be used to monitor walking activity as well as provide behavioral enhancing feedback to increase activity levels and walking ability in people with stroke for extended periods of time in the real world. PMID- 22255513 TI - Elbow functional compensation using a lightweight magnetorheological clutch. AB - There are many applications for which a patient needs functional compensation due to motor disorders in daily activities. Classic research has focused on robotics solutions in terms of actuators or motors, but the point of this paper is to analyze new solutions combining both biological and artificial structures, in order to improve standard developments. Nowadays wearable Robots are taking an important role in rehabilitation purposes, due to this issue lots of new designs are emerging, but most of them are not still prepared to be used in terms of autonomy, weight, etc. Under the Hybrid Neuroprosthetic and Neurorobotic devices for Functional Compensation and Rehabilitation (HYPER) project, new actuator technologies have been developed in order to improve the adaptability and portability of rehabilitation devices. The designed device is based on a lightweight magnetorheological (MR) clutch which is able to transmit torque from a motor to the injured joint. Though it is intended to work in human upper limb (elbow mainly), other future designs will also be studied for other human joints. Simulation results using Simulink(r), MSC Adams(r)and MSMS(r)are reported to illustrate the viability of the proposed device. PMID- 22255514 TI - Sensor-enabled RFID system for monitoring arm activity in daily life. AB - After stroke, capacity to carry out tasks in the treatment setting with the more affected arm is a poor index of actual use of that extremity in daily life. However, objective methods currently available for monitoring real-world upper extremity use only provide information on amount of activity. These methods, which rely on movement sensors worn by patients, do not provide information about type of activity (e.g., functional vs. nonfunctional movement). The benchmark testing reported here evaluated an approach that involves placing sensors on patients and objects. An accelerometer and the transmitter component of a prototype radio frequency proximity sensor were attached to household objects. The receiver component was placed on the experimenter's right arm. This device triggered an on-board radio frequency identification tag to signal proximity when that arm was within 23 cm of the objects. The system detected > 99% of 6 cm or greater movements of objects. When handling of objects by the right or left arm was determined randomly, 100% of right arm trials were detected. No signals were recorded when objects were at rest or moved by the left arm. Testing of this approach, which monitors manipulation of objects (i.e., functional movement), is now warranted in stroke patients. PMID- 22255515 TI - A neck mounted interface for sensing the swallowing activity based on swallowing sound. AB - This study proposes a novel interface for sensing swallowing activities (based on the sound produced when swallowing) that is mounted on the back of the neck. Recently, owing to the aging of the population, the number of dysphagia patients has been increasing. Although various types of diacrisis and dysphagia testing methodologies already exist, several problems remain. For example, the videofluorography methodology requires extensive preparation; it presents risks of aspiration and demands knowledge about diacrisis, and it must be performed in a medical facility. This study introduces a wearable sensing system that can be used in daily life. As it gives direct, real-time information regarding swallowing movements, this device is also aimed at being used for rehabilitation purposes. The proposed system uses a new evaluation technique that is based on the duration of the swallowing action. PMID- 22255516 TI - Development and evaluation of vision rehabilitation devices. AB - We have developed a range of vision rehabilitation devices and techniques for people with impaired vision due to either central vision loss or severely restricted peripheral visual field. We have conducted evaluation studies with patients to test the utilities of these techniques in an effort to document their advantages as well as their limitations. Here we describe our work on a visual field expander based on a head mounted display (HMD) for tunnel vision, a vision enhancement device for central vision loss, and a frequency domain JPEG/MPEG based image enhancement technique. All the evaluation studies included visual search paradigms that are suitable for conducting indoor controllable experiments. PMID- 22255517 TI - A new safety support system for wandering elderly persons. AB - We have developed a new mobile phone-based safety support system for transmitting information of a wandering elderly person's location and the environmental sounds around that person. The system consists of a wearable sensor and a conventional desktop PC with Internet access acting as the server computer. The wearable sensor, which is attached behind the neck of the elderly person's shirt, is composed of a low transmitting power mobile phone (W-SIM), a small microphone and a one chip microcontroller. The wandering elderly person's location is identified within 100 m from the mobile phone company's antenna ID via the W-SIM. The caregiver sets the elderly person's movement area by specialized computer software. When the elderly person goes out of the area, the sensor automatically records the environmental sound around the wandering elderly person for the presumption of the person's situation with the small microphone. The W-SIM sends both the wandering elderly person's location and the environmental sound to the server computer. The server computer informs automatically the caregiver by the e mail. The caregiver can monitor the sound and the map of the wandering person's location via Internet. The sound enables the presumption of an accurate location and the situation of the wandering elderly person. PMID- 22255518 TI - Development of a mobile phone based ophthalmoscope for telemedicine. AB - Regular retinal examinations can contribute to the management of both hypertensive and diabetic retinopathy. One of the most successful means of evaluating these retinopathies is by means of a fundus camera generating a fundus photograph. Patients in rural clinics unfortunately often lack the financial means to undergo regular examinations. This study produced a handheld ophthalmoscope that combines with a digital camera to capture retinal images. The images are transferred to a mobile phone and then sent to a central website for evaluation. The evaluation report is automatically returned to the mobile phone via SMS. The quality of the images was rated as acceptable for clinical use by medical specialists at the Department of Ophthalmology of the Health Sciences Faculty of Stellenbosch University, South Africa. PMID- 22255519 TI - Towards remote evaluation of movement disorders via smartphones. AB - Recent advances in mobile phone technology have placed an impressive array of sensing and communication equipment at the hands of an ever-growing number of people. One of the areas which can potentially be transformed by the availability of what is essentially a cheap, ubiquitous networked sensor, is that of remote diagnosis of movement disorders, such as Parkinson's disease. This work describes a smartphone-based method for detecting and quantifying the hand tremor associated with movement disorders using signals from the accelerometer and gyroscope embedded in the patient's phone. Our approach is web-based and user friendly, requiring minimal user interaction. In clinical experiments with twenty subjects, we found that by combining both accelerometer and gyroscope signals, we were able to correctly identify those with hand tremor, using very simple signal metrics. PMID- 22255520 TI - ContextProvider: Context awareness for medical monitoring applications. AB - Smartphones are sensor-rich and Internet-enabled. With their on-board sensors, web services, social media, and external biosensors, smartphones can provide contextual information about the device, user, and environment, thereby enabling the creation of rich, biologically driven applications. We introduce ContextProvider, a framework that offers a unified, query-able interface to contextual data on the device. Unlike other context-based frameworks, ContextProvider offers interactive user feedback, self-adaptive sensor polling, and minimal reliance on third-party infrastructure. ContextProvider also allows for rapid development of new context and bio-aware applications. Evaluation of ContextProvider shows the incorporation of an additional monitoring sensor into the framework with fewer than 100 lines of Java code. With adaptive sensor monitoring, power consumption per sensor can be reduced down to 1% overhead. Finally, through the use of context, accuracy of data interpretation can be improved by up to 80%. PMID- 22255521 TI - The PLR-DTW method for ECG based biometric identification. AB - There has been a surge of research on electrocardiogram (ECG) signal based biometric for person identification. Though most of the existing studies claimed that ECG signal is unique to an individual and can be a viable biometric, one of the main difficulties for real-world applications of ECG biometric is the accuracy performance. To address this problem, this study proposes a PLR-DTW method for ECG biometric, where the Piecewise Linear Representation (PLR) is used to keep important information of an ECG signal segment while reduce the data dimension at the same time if necessary, and the Dynamic Time Warping (DTW) is used for similarity measures between two signal segments. The performance evaluation was carried out on three ECG databases, and the existing method using wavelet coefficients, which was proved to have good accuracy performance, was selected for comparison. The analysis results show that the PLR-DTW method achieves an accuracy rate of 100% for identification, while the one using wavelet coefficients achieved only around 93%. PMID- 22255522 TI - Change-of-state determination to recognize mobility activities using a BlackBerry smartphone. AB - A Wearable Mobility Monitoring System (WMMS) can be a useful tool for rehabilitation decision-making. This paper presents preliminary design and evaluation of a WMMS proof-of-concept system. Software was developed for the BlackBerry 9550, using the integrated three axes accelerometer, GPS, video camera, and timer to identify mobility changes-of-state (CoS) between static activities, walking-related activities, taking an elevator, bathroom activities, working in the kitchen, and meal preparation (five able-bodied subjects). This pilot project provides insight into new algorithms and features that recognize CoS and activities in real-time. Following features extraction from the sensor data, two decision trees were used to distinguish the CoS and activities. Real time CoS identification triggered BlackBerry video recording for improved mobility context analysis during post-processing. PMID- 22255523 TI - Mobile energy expenditure tracking system based on heart rate and motion providing extra extensions for personalized care. AB - In order to keep a healthy body it is very important to have balanced energy expenditure (EE). The proposed system utilized the phonocardiogram (PCG) and motion from the user to generate the heart rate. The heart rate has been deemed as a very reliable index to estimate the EE of human body. Efforts are put on developing our system to deal the situations when severe interference coupled into the system while the user is exercising. Accelerometer is used to get the motion status and also the posture of the user which is monitored to determine any anomaly. If anomaly is detected, the system actively issues notification to whom that might give back a timely aid. PMID- 22255524 TI - Validation of heart rate extraction through an iPhone accelerometer. AB - Ubiquitous medical technology may provide advanced utility for evaluating the status of the patient beyond the clinical environment. The iPhone provides the capacity to measure the heart rate, as the iPhone consists of a 3-axis accelerometer that is sufficiently sensitive to perceive tiny body movements caused by heart pumping. In this preliminary study, an iPhone was tested and evaluated as the reliable heart rate extractor to use for medical purpose by comparing with reference electrocardiogram. By comparing the extracted heart rate from acquired acceleration data with the extracted one from ECG reference signal, iPhone functioning as the reliable heart rate extractor has demonstrated sufficient accuracy and consistency. PMID- 22255525 TI - The potential of Internet of m-health Things "m-IoT" for non-invasive glucose level sensing. AB - An amalgamated concept of Internet of m-health Things (m-IoT) has been introduced recently and defined as a new concept that matches the functionalities of m health and IoT for a new and innovative future (4G health) applications. It is well know that diabetes is a major chronic disease problem worldwide with major economic and social impact. To-date there have not been any studies that address the potential of m-IoT for non-invasive glucose level sensing with advanced opto physiological assessment technique and diabetes management. In this paper we address the potential benefits of using m-IoT in non-invasive glucose level sensing and the potential m-IoT based architecture for diabetes management. We expect to achieve intelligent identification and management in a heterogeneous connectivity environment from the mobile healthcare perspective. Furthermore this technology will enable new communication connectivity routes between mobile patients and care services through innovative IP based networking architectures. PMID- 22255526 TI - Sleep, mood and sociability in a healthy population. AB - Sleep and mood problems have a considerable public health impact with serious societal and significant financial effects. In this work, we study the relationship between these factors in the everyday life of healthy young adults. More importantly, we look at these factors from a social perspective, studying the impact that couples have on each other and the role that face-to-face interactions play. We find that there is a significant bi-directional relationship between mood and sleep. More interestingly, we find that the spouse's sleep and mood may have an effect on the subject's mood and sleep. Further, we find that subjects whose sleep is significantly correlated with mood tend to be more sociable. Finally, we observe that less sociable subjects show poor mood more often than their more sociable contemporaries. These novel insights, especially those involving sociability, measured from quantified face to-face interaction data gathered through smartphones, open up several avenues to enhance public health research through the use of latest wireless sensing technologies. PMID- 22255527 TI - Education, reregistration, and recommendation effect of iPhone Poomsae education app in Taekwondo academy. AB - This paper analyzed the effect of a smartphone application in Taekwondo Academy. The iPhone app was self-developed to display Taekwondo education contents for Poomsae training. From the viewpoint of education, reregistration and recommendation effect, it showed statistically significant difference in 196 trainee sample survey. Therefore, the research suggest that the use of smartphone technology in Poomsae education would be a great help to the trainee for the acquisition of Taekwondo knowledge and make a great contribution to the growth of Taekwondo. PMID- 22255528 TI - Design of an unobtrusive wireless sensor network for nighttime falls detection. AB - A significant portion of government health care funding is spent treating falls related injuries among older adults. This cost is set to rise due to population aging in developed societies. Wearable sensors systems, often comprised of triaxial accelerometers and/or gyroscopes, have proven useful for real-time falls detection. However, a large percentage of falls occur at home and many of those happen at nighttime, when the person is unlikely to be wearing such an ambulatory monitoring device. It is envisaged that systems utilizing unobtrusive wireless sensors can be employed to survey the living space and identify unusual activity patterns which may indicate that a fall has happened at nighttime. In this study, a nighttime falls detection system designed for a single individual living at home, based on the use of passive infrared and pressure mat sensors, is explored. This paper describes both the sensor and system design, and investigates the feasibility of performing nighttime falls detection through the use of scripted scenarios using a single healthy test volunteer. In addition to normal movement activity, falls with unconsciousness, falls with repeated failed attempts to recover, and falls with successful recovery, are considered. By analyzing the location of sensor activity, periods of sensor inactivity, and unusual sensor activation patterns in uncommon locations, a sensitivity and specificity of 88.89% and 100%, respectively, are obtained (excluding falls followed by complete recovery). This demonstrates a proof-of-principle that nighttime falls detection might be achieved using a low complexity and completely unobtrusive wireless sensor network in the home. PMID- 22255529 TI - A web-based image viewer for multiple PET-CT follow-up studies. AB - There exist many viewers for single-modal medical images that are efficient and are equipped with powerful analysis tools. However, there is a distinct lack of efficient image viewers for multi-modality images, particularly for displaying multiple follow-up studies that depict a patient's response to treatment over time. Such viewers would be required to display large amounts of image data. In this study, we present the TAGIGEN viewer--a web-based image viewer designed specifically for the visualisation of multi-modality follow-up studies. We innovate by defining a series of dynamically generated image grid layouts that display sets of related images together in order to improve the ability to compare and assimilate the myriad images. We adopted a web-based client-server image streaming technology, thus enabling interactive navigation of the images in a computationally efficient manner. Furthermore, our web-based approach is interoperable and requires no software installation. We evaluated the ability of our viewer in displaying and understanding a patient's follow-up images in a case study with combined positron emission tomography and computed tomography (PET-CT) follow-up scans. We conducted a usability survey on 10 participants to measure the usefulness of our viewer, used as an outpatient viewer e.g. viewer designed for use by the patients, in tracking a patient's disease state across four PET-CT studies. Our initial results suggest that our viewer was able to efficiently visualise the patient data over time, and that the web-based implementation was fast (loading on average within 5.6 seconds with real-time navigation) and easy to use (overall survey score higher than 4 / 5). PMID- 22255530 TI - Mental health promotion system. AB - Mental activity promotion system is presented that analyzes, quantifies, trains and prescribes based on analysis of logical, memorizing, concentrative, decisive, in conditions where time and space is involved, possibility of dementia, and on evaluation of lifestyle of subjects. Special consideration has been made to make the system motivational, persuasive, attractive and fun to use. The system has been successfully deployed in Bitgeoul Senior health town, Gwangju, South Korea. PMID- 22255531 TI - Online survey system for image-based clinical guideline studies using the Delphi method. AB - The increasing use of health information technology (HIT) is due to a rising interest in improving the quality of health care. HIT has the potential to reduce cost and transform services. Proper clinical support systems will contribute to the meaningful use of HIT systems by providing a wide array of data to clinicians for the diagnosis and treatments. Clinical guidelines, created by a consensus of experts, can be put in place to assist physicians in making clinical decisions. Delphi methods are commonly used to create consensus from surveys completed by a team of experts. Image based studies could create guidelines that standardize severity, deformity or other clinical classifications. As these studies were traditionally conducted using paper based media, the cost and time requirement often make the process impractical. Ware proposing a web based system to aid medical researchers in conducting image based Delphi studies for improved clinical guidelines and decision support. PMID- 22255532 TI - The sweet-home project: audio technology in smart homes to improve well-being and reliance. AB - The Sweet-Home project aims at providing audio-based interaction technology that lets the user have full control over their home environment, at detecting distress situations and at easing the social inclusion of the elderly and frail population. This paper presents an overview of the project focusing on the multimodal sound corpus acquisition and labelling and on the investigated techniques for speech and sound recognition. The user study and the recognition performances show the interest of this audio technology. PMID- 22255534 TI - Nighttime in-home action monitoring for eldercare. AB - In this work, we develop a system to automatically monitoring actions of elderly people at home for safety enhancement and health monitoring. We use an Infrared camera embedded in a living environment to capture images. We study the characteristics of different clothing in Infrared images and develop an efficient silhouette extraction method for Infrared (IR) images using spatio-temporal filtering. We recognize human action using supervised learning methods. Our experimental results demonstrate that our proposed method is efficient. PMID- 22255533 TI - Assessing task compliance following mobile phone-based video reminders. AB - In the development of technology for people with mild dementia it is essential to achieve a combination of the features which provide both support and monitoring along with the ability to offer a level of personalization. Reminding support by means of personalized video reminders portraying a relative or friend combined with sensors to assess whether the requested task was performed lends itself as an ideal combination to achieve this aim. This study assesses the potential of using low cost, off the shelf sensors combined with a mobile phone-based video reminding system to assess compliance with task completion. A validation study has been conducted in a lab-based environment with 10 healthy young participants. The work presented discusses the implementation of the approach adopted, data analysis of the results attained along with outlining future developments of this approach. PMID- 22255535 TI - A web based tool for storing and visualising data generated within a smart home. AB - There is a growing need to re-assess the current approaches available to researchers for storing and managing heterogeneous data generated within a smart home environment. In our current work we have developed the homeML Application; a web based tool to support researchers engaged in the area of smart home research as they perform experiments. Within this paper the homeML Application is presented which includes the fundamental components of the homeML Repository and the homeML Toolkit. Results from a usability study conducted by 10 computer science researchers are presented; the initial results of which have been positive. PMID- 22255536 TI - Usage monitoring of electrical devices in a smart home. AB - Profiling the usage of electrical devices within a smart home can be used as a method for determining an occupant's activities of daily living. A nonintrusive load monitoring system monitors the electrical consumption at a single electrical source (e.g., main electric utility service entry) and the operating schedules of individual devices are determined by disaggregating the composite electrical consumption waveforms. An electrical device's load signature plays a key role in nonintrusive load monitoring systems. A load signature is the unique electrical behaviour of an individual device when it is in operation. This paper proposes a feature-based model, using the real power and reactive power as features for describing the load signatures of individual devices. Experimental results for single device recognition for 7 devices show that the proposed approach can achieve 100% classification accuracy with discriminant analysis using Mahalanobis distances. PMID- 22255537 TI - DigiSpenser--a GSM-based drug management and compliance monitoring system. AB - Approximately one-third of all independently living elderly people are not compliant with their drug therapy. This lack of medication management results either in undermedication or overmedication, causing unnecessary and often serious health risks. This problem will worsen in the future with the change of demographics and cost constraints in the health sector. Therefore there is a need for (cost-) effective reliable approaches to compliance monitoring. To date numerous care schemes, retrospective assessment procedures and compliance supports tools have been introduced, but none of them has fully solved the problem of medication non-compliance yet. This paper will address some of the factors that need to be considered when designing such systems and will showcase DigiSpenser, a recently developed compliance monitoring and drug management system. PMID- 22255538 TI - Indoor waypoint navigation via magnetic anomalies. AB - A wide assortment of technologies have been proposed to construct indoor navigation services for the blind and vision impaired. Proximity-based systems and multilateration systems have been successfully demonstrated and employed. Despite the technical success of these technologies, broad adoption has been limited due to their significant infrastructure and maintenance costs. An alternative approach utilizing the indoor magnetic signatures inherent to steel frame buildings solves the infrastructure cost problem; in effect the existing building is the location system infrastructure. Although magnetic indoor navigation does not require the installation of dedicated hardware, the dedication of resources to produce precise survey maps of magnetic anomalies represents a further barrier to adoption. In the present work an alternative leader-follower form of waypoint-navigation system has been developed that works without surveyed magnetic maps of a site. Instead the wayfarer's magnetometer readings are compared to a pre-recorded magnetic "leader" trace containing magnetic data collected along a route and annotated with waypoint information. The goal of the navigation system is to correlate the follower's magnetometer data with the leader's to trigger audio cues at precise points along the route, thus providing location-based guidance to the user. The system should also provide early indications of off-route conditions. As part of the research effort a smartphone based application was created to record and annotate leader traces with audio and numeric data at waypoints of interest, and algorithms were developed to determine (1) when the follower reaches a waypoint and (2) when the follower goes off-route. A navigation system utilizing this technology would enable a low-cost indoor navigation system capable of replaying audio annotations at precise locations along pre-recorded routes. PMID- 22255539 TI - An affordable compact humanoid robot for Autism Spectrum Disorder interventions in children. AB - Autism Spectrum Disorder impacts an ever-increasing number of children. The disorder is marked by social functioning that is characterized by impairment in the use of nonverbal behaviors, failure to develop appropriate peer relationships and lack of social and emotional exchanges. Providing early intervention through the modality of play therapy has been effective in improving behavioral and social outcomes for children with autism. Interacting with humanoid robots that provide simple emotional response and interaction has been shown to improve the communication skills of autistic children. In particular, early intervention and continuous care provide significantly better outcomes. Currently, there are no robots capable of meeting these requirements that are both low-cost and available to families of autistic children for in-home use. This paper proposes the piloting the use of robotics as an improved diagnostic and early intervention tool for autistic children that is affordable, non-threatening, durable, and capable of interacting with an autistic child. This robot has the ability to track the child with its 3 degree of freedom (DOF) eyes and 3-DOF head, open and close its 1-DOF beak and 1-DOF each eyelids, raise its 1-DOF each wings, play sound, and record sound. These attributes will give it the ability to be used for the diagnosis and treatment of autism. As part of this project, the robot and the electronic and control software have been developed, and integrating semi autonomous interaction, teleoperation from a remote healthcare provider and initiating trials with children in a local clinic are in progress. PMID- 22255540 TI - A sensor for monitoring pulse rate, respiration rhythm, and body movement in bed. AB - A non-constraint cardiac vibration, respiration, and body movement monitoring system has been developed. The sensor system is designed to be easily installable under an existing bed mattress. The sensor consists of a 40-kHz ultrasound transmitter and receiver pair. The transmitted ultrasound is reflected on the mattress' undersurface, and the amplitude of the received ultrasonic wave is modulated by the shape of the mattress, and parameters such as respiration, cardiac vibration, and movement. The physiological parameters can be extracted from the reflected ultrasound by an envelope detection circuit. To confirm the accuracy of the developed system, measurements were performed on 6 normal male subjects aged 25.0 +/- 6.7 years, using 2 pocket spring coil mattresses and a polyurethane foam mattress. The results revealed that the physiological parameters were monitored with an 84.2% average accuracy for all mattresses when the subjects lay on the beds in the supine, lateral, and prone positions. PMID- 22255541 TI - Multidisciplinary approach for developing a new robotic system for domiciliary assistance to elderly people. AB - This paper aims to show the effectiveness of a (inter / multi)disciplinary team, based on the technology developers, elderly care organizations, and designers, in developing the ASTRO robotic system for domiciliary assistance to elderly people. The main issues presented in this work concern the improvement of robot's behavior by means of a smart sensor network able to share information with the robot for localization and navigation, and the design of the robot's appearance and functionalities by means of a substantial analysis of users' requirements and attitude to robotic technology to improve acceptability and usability. PMID- 22255542 TI - Development of a platform to combine sensor networks and home robots to improve fall detection in the home environment. AB - Over the last decade, significant progress has been made in the development of wearable sensor systems for continuous health monitoring in the home and community settings. One of the main areas of application for these wearable sensor systems is in detecting emergency events such as falls. Wearable sensors like accelerometers are increasingly being used to monitor daily activities of individuals at a risk of falls, detect emergency events and send alerts to caregivers. However, such systems tend to have a high rate of false alarms, which leads to low compliance levels. Home robots can enable caregivers with the ability to quickly make an assessment and intervene if an emergency event is detected. This can provide an additional layer for detecting false positives, which can lead to improve compliance. In this paper, we present preliminary work on the development of a fall detection system based on a combination sensor networks and home robots. The sensor network architecture comprises of body worn sensors and ambient sensors distributed in the environment. We present the software architecture and conceptual design home robotic platform. We also perform preliminary characterization of the sensor network in terms of latencies and battery lifetime. PMID- 22255544 TI - Using Participatory Design in a Health Information System. AB - This article describes the experience of developing an interactive Health Information System (iHIS) currently under test in a hospital, which benefited from the practices of the User-Centred Design (UCD), in a Participatory Design (PD) approach. Techniques from the Human-Computer Interaction (HCI) and/or Usability Engineering (UE), combined with traditional Software Engineering (SE), allowed an effective and usable solution from the user's point of view. The good results usually achieved with this approach were confirmed. Despite these good results, we deem that if there is not some control of the procedure by the project manager, it may be difficult to end the requirement analysis, since requirement reformulation is fostered. PMID- 22255543 TI - A touchscreen-equipped medicine case as a medical interface for assisting an elderly person in medication management. AB - In this paper, we propose a new intelligent medicine case with a home medical interface (iMec G2) to assist an elderly recipient in taking his/her medicine adequately. A touchscreen was equipped in the front surface of the iMec which was tilted backward. The home medical interface for self-medication support was displayed on the touchscreen and handled by the recipient's fingers. The elderly recipient could confirm the information related to his/her prescription by touching a virtual medicine and could contact a recipient's caregiver by clicking an icon if necessary. The new iMec recognized medicine in its storage cartridge by an improved image processing method and evaluated the adequacy of dosage and dosing timing. By an experiment, we verified that the iMec G2 was able to create the home medical interface correctly and indicate a particular medicine which should be taken. PMID- 22255545 TI - HoCoS: Home Companion Software. A service oriented solution for elderly home accompanying and remote healthcare monitoring. AB - The age of the population in all societies around the world is increasing. Elderly people prefer to maintain their independence, their autonomy and live at home as long as possible. We propose as a solution to this issue a Home Companion Software baptized HoCoS. This solution aims to help the elderly with daily life by providing an ergonomic and familiar interface. The second purpose is to integrate transparent remote healthcare monitoring service that ensures elderly security without disturbing the ergonomics of the application. We present service oriented architecture that offers extensibility and interoperability between heterogonous systems in order to combine several technologies and operators. We carried out ergonomic tests on this solution to evaluate its comfort and ease of use. PMID- 22255546 TI - Investigating tactile event recognition in child-robot interaction for use in autism therapy. AB - The work presented in this paper is part of our investigation in the ROBOSKIN project. The project aims to develop and demonstrate a range of new robot capabilities based on robot skin tactile feedback from large areas of the robot body. The main objective of the project is to develop cognitive mechanisms exploiting tactile feedback to improve human-robot interaction capabilities. The project aims also to investigate the possible use of this technology in robot assisted play in the context of autism therapy. This article reports progress made in investigating tactile child-robot interactions where children with autism interacted with the humanoid robot KASPAR equipped with the first prototype of skin patches, introducing a new algorithm for tactile event recognition which will enhance the observational data analysis that has been used in the past. PMID- 22255547 TI - Development of a wireless electromyographically controlled electrolarynx voice prosthesis. AB - The most common artificial voice source for post-laryngectomy speech rehabilitation is the handheld buzzer or electrolarynx (EL). EL speech is often described as mechanical-sounding (robotic), and typically lacks pitch variation, making it monotone and unnatural. Prior studies have shown improved perceptual ratings of speech naturalness when pitch variation is added to EL speech, and a proof-of-concept EL prosthesis has been developed to provide pitch variation and voice on/off control in relation to neck muscle electromyographic (EMG) signals. The goal of the present study was to design a new wireless version of the EMG controlled EL (EMG-EL) that could provide a flexible mixture of manual (push button) and automatic (EMG-based) control options for voice onset/offset and pitch, and that could be manufactured at a reasonable cost for widespread patient use. This paper describes both technical and human factors considered while designing the new EMG-EL voice prosthesis. PMID- 22255548 TI - Measuring gaze of children with Autism Spectrum Disorders in naturalistic interactions. AB - In this paper, we report on a study on gaze behavior by children with Autism Spectrum Disorder (ASD) during a dyadic interaction in a naturalistic environment. Twelve children with ASD were contrasted to twelve typically developing (TD) children, in a semi-structured interaction with a selection of items from the Early Social Communication Scale (ESCS). We used the WearCam, a novel head-mounted eye-tracker designed for children, to obtain gaze information across the broad field of view from the viewpoint of the child. Children with ASD looked downwards more often, and explored their lateral field of view more extensively compared to TD children. We discuss a number of hypotheses in support of these observations. PMID- 22255549 TI - Brain-machine interfaces for real-time speech synthesis. AB - This paper reports on studies involving brain-machine interfaces (BMIs) that provide near-instantaneous audio feedback from a speech synthesizer to the BMI user. In one study, neural signals recorded by an intracranial electrode implanted in a speech-related region of the left precentral gyrus of a human volunteer suffering from locked-in syndrome were transmitted wirelessly across the scalp and used to drive a formant synthesizer, allowing the user to produce vowels. In a second, pilot study, a neurologically normal user was able to drive the formant synthesizer with imagined movements detected using electroencephalography. Our results support the feasibility of neural prostheses that have the potential to provide near-conversational synthetic speech for individuals with severely impaired speech output. PMID- 22255550 TI - Message formulation, organization, and navigation schemes for icon-based communication aids. AB - Individuals with severe speech and motor impairments rely on assistive communication devices to convey their needs and desires in social, educational, and vocational situations. Users with limited motor control or literacy often choose to use icon-based devices that afford increased speed of message formulation at the cost of fully generative language formulation on letter-based devices. A major challenge with large vocabulary icon-based systems is rate of communication. Message formulation, vocabulary organization, and navigation schemes can be used to mitigate the trade-off between vocabulary size and communication rate. This paper summarizes our research efforts to leverage semantic frame theory, situational context, and rapid serial visual presentation to improve message formulation speed and completeness in our iconCHAT and RSVP iconCHAT systems. Usability data and persisting challenges are discussed. PMID- 22255551 TI - Social robots for health applications. AB - Social robots are designed to interact with people in a manner that is consistent with human social psychology. They are a particularly intriguing technology in health domains due to their ability to engage people along social and emotional dimensions. In this paper, we highlight a number of interesting opportunities for social robots in healthcare related applications. PMID- 22255552 TI - Toward a hybrid snake robot for single-port surgery. AB - We propose a new snake-like robot for use in single-port minimally invasive surgery. The snake robot is made of a concentric tube robot and a highly articulated robotic probe. The probe operates as a stiff shield for the concentric tube robot. Consequently, the snake robot provides simultaneously high tip stiffness and dexterity that cannot be obtained by the single use of any of two robots. A critical design challenge is achieving a small radius of curvature for the hybrid snake. A mechanic model is presented for computing the minimum achievable radius of curvature for the hybrid snake. Experiments validate the mechanic model. PMID- 22255553 TI - Inertial navigation system for bladder endoscopy. AB - The usage of video endoscopes in cystoscopic interventions of the urinary bladder impedes an intuitive navigation. Although image-based solutions such as panorama images can provide extended views of the surgical field, a real-time 3-D navigation is not supported. Furthermore, the integration of common tracking systems in ambulant clinics is often hindered due to low usability and high costs. Thus, we discuss in this paper a first low-cost inertial navigation system. Our evaluation results show that in spite of lower sensor accuracies, mean errors between < 1 degrees and 4 degrees are achieved for solid angles. Using endoscopes with different view angles we apply an extended endoscope model for an adaptive displacement correction. Furthermore, we implement a first guided navigation tool for tumor re-identification in real-time. PMID- 22255554 TI - Target motion predictions for pre-operative planning during needle-based interventions. AB - During biopsies, breast tissue is subjected to displacement upon needle indentation, puncture, and penetration. Thus, accurate needle placement requires pre-operative predictions of the target motions. In this paper, we used ultrasound elastography measurements to non-invasively predict elastic properties of breast tissue phantoms. These properties were used in finite element (FE) models of indentation of breast soft tissue phantoms. To validate the model predictions of target motion, experimental measurements were carried out. Breast tissue phantoms with cubic and hemispherical geometries were manufactured and included materials with different elastic properties to represent skin, adipose tissue, and lesions. Ultrasound was used to track the displacement of the target (i.e., the simulated lesion) during indentation. The FE model predictions were compared with ultrasound measurements for cases with different boundary conditions and phantom geometry. Maximum errors between measured and predicted target motions were 12% and 3% for the fully supported and partially supported cubic phantoms at 6.0 mm indentation, respectively. Further, FE-based parameter sensitivity analysis indicated that increasing skin elastic modulus and reducing the target depth location increased the target motion. Our results indicate that with a priori knowledge about the geometry, boundary conditions, and linear elastic properties, indentation of breast tissue phantoms can be accurately predicted with FE models. FE models for pre-operative planning in combination with robotic needle insertions, could play a key role in improving lesion targeting for breast biopsies. PMID- 22255555 TI - Development and evaluation of an identification method for the biomechanical parameters using robotic force measurements, medical images, and FEA. AB - This paper presents a new identification method for the biomechanical parameters of human tissues for the purpose of improving the accuracy of dynamic organ simulation. We describe the formulation of the method, and also design a robotic system to implement the method using a robotic probe, a medical imaging device, and a numerical simulator for the finite element analysis (FEA). We carried out an experiment using an experimental system and a tissue phantom to verify the effectiveness of the method. The results of this experiment show that the Young's modulus of the tissue phantom can be estimated with the experimental system. We also compared the estimated values of the Young's moduli with the measured values from a rheometer. These results confirm that the identification method and the system design, proposed and developed in this work, are effective for accurately simulating organ behavior. PMID- 22255556 TI - A MRI-based platform for catheter navigation. AB - The development of minimally invasive surgical techniques using magnetism is expanding. Our research group is exploring catheter steering using the gradient field of a modified clinical Magnetic Resonance Imaging (MRI) system. This paper focuses on the upgrade of the MRI testing platform towards an integrated system allowing for in vitro and in vivo experiments. The expected steering capabilities of the platform are evaluated through experimental tests, and catheter tracking is adapted accordingly while being tested for potential medical interventions. PMID- 22255557 TI - Gaze-contingent autofocus system for robotic-assisted minimally invasive surgery. AB - A gaze-contingent autofocus system using an eye-tracker and liquid lens has been constructed for use with a surgical robot, making it possible to rapidly (within tens of milliseconds) change focus using only eye-control. This paper reports the results of a user test comparing the eye-tracker to a surgical robot's in-built mechanical focusing system. In the clinical environment, this intuitive interface removes the need for an external mechanical control and improves the speed at which surgeons can make decisions, based on the visible features. Possible applications include microsurgery and gastrointestinal procedures where the object distance changes due to breathing and/or peristalsis. PMID- 22255558 TI - Flexible organic electronics for use in neural sensing. AB - Recent research in brain-machine interfaces and devices to treat neurological disease indicate that important network activity exists at temporal and spatial scales beyond the resolution of existing implantable devices. High density, active electrode arrays hold great promise in enabling high-resolution interface with the brain to access and influence this network activity. Integrating flexible electronic devices directly at the neural interface can enable thousands of multiplexed electrodes to be connected using many fewer wires. Active electrode arrays have been demonstrated using flexible, inorganic silicon transistors. However, these approaches may be limited in their ability to be cost effectively scaled to large array sizes (8 * 8 cm). Here we show amplifiers built using flexible organic transistors with sufficient performance for neural signal recording. We also demonstrate a pathway for a fully integrated, amplified and multiplexed electrode array built from these devices. PMID- 22255559 TI - High-porous platinum electrodes for functional electrical stimulation. AB - This paper reports on the preparation and characterization of highly porous platinum electrodes for functional electrical stimulation. Thin-film platinum electrodes were roughened by electrochemical deposition of platinum-copper alloys and subsequent removal of copper using cyclic voltammetry (CV). Prepared samples were characterized by electrochemical impedance spectroscopies (EIS), CVs and long-term pulse testing. The electrodes exhibited an increased porosity by a factor of ~238 when compared to sputtered platinum electrodes. EIS measurements showed a decreased impedance of about 85% and pulse tests suggested a stable coating over at least 250 million pulses. PMID- 22255560 TI - "Capacitive" pulse shapes for platinum cuff electrodes. AB - Artificial electrical stimulation of the peripheral nervous system is an established therapy for several pathologies and motor impairments. Therapeutic outcomes can be improved with targeted patterns of neural activation, but the required signal amplitudes to achieve this response exceed the limits for safe stimulation. This can lead to electrode corrosion and tissue damage. In this paper, we present a novel approach to pulse shape design based on the properties of the electrode-electrolyte interface. We aim to improve electrode stability at higher voltages by exploiting the potential-independent mechanisms of charge injection. We identified signal parameters associated with capacitive current flow at the platinum interface and incorporated these features into the design of cathodal pulse shapes. A pulse shape comprising 4 high-frequency 'capacitive' harmonics demonstrated a 40 fold performance benefit compared to a conventional square pulse, but irreversible reactions could not be completely avoided during current flow. However, the enhanced electrode stability with the 'capacitive' pulse shapes suggests further optimization of pulse designs according to a surface 'stability function' might allow for safe stimulation with greater electrode voltages. PMID- 22255561 TI - In vivo polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT) in rodent cerebral cortex. AB - Maintaining a reliable neural interface is a well-known challenge with implanted neural prostheses. Here we evaluate a method of forming an integrated neural interface through polymerization of PEDOT in vivo. Polymerization resulted in lower impedance and improved recording quality of local field potentials on implanted electrodes in the rat cerebral cortex. Histological analysis by optical microscopy confirmed successful integration of the PEDOT within tissue surrounding implanted electrodes. This technique offers a unique neural interfacing approach with potential to improve the long-term functionality of neural prostheses. PMID- 22255563 TI - Bioelectrical enhancement in tissue-electrode coupling with metamorphic-stage insertions for insect machine interfaces. AB - Implanting microtechnologies into insects with an aim of domesticating its locomotion poses certain challenges, however, performing surgical implantation during the early stages of metamorphic growth was shown to mitigate some of the related detriments. This study reports the bioelectrical enhancement at the tissue-electrode interface allowed with these metamorphic stage insertions, where the electrodes implanted in the insect during the early pupal stages and right after emergence were compared. An average 1 kHz impedance of 8.9 kOmega was obtained with pupal stage inserted electrodes, ten days after the emergence, as compared to 12.1 kOmega observed when electrodes were implanted in the adult state. Charge storage capacity also increased to 52 mC/cm(2) from 38 mC/cm(2) with the early metamorphic insertions. The performed voltage excursion studies also confirmed the enhancement demonstrating an increase from 3.5 mC/cm(2) to 5.1 mC/cm(2) in the injectable amount of charge in the water window. PMID- 22255562 TI - Electrical performance of penetrating microelectrodes chronically implanted in cat cortex. AB - Penetrating multielectrode arrays with electrode coatings of sputtered iridium oxide (SIROF) have been implanted chronically in cat cortex for periods over 300 days. The ability of these electrodes to inject charge at levels above expected thresholds for neural excitation has been examined in vivo by measurements of voltage transients in response to current-controlled, cathodal stimulation pulsing. The effect of current pulse width from 150 MUs to 500 MUs and voltage biasing of the electrodes in the interpulse period at two levels, 0.0 V and 0.6 V vs. Ag|AgCl, were also investigated. The results of in vivo characterization of the electrodes by open-circuit potential measurements, cyclic voltammetry and impedance spectroscopy are also reported. PMID- 22255564 TI - Classification of multichannel ECoG related to individual finger movements with redundant spatial projections. AB - We tackle the problem of classifying multichannel electrocorticogram (ECoG) related to individual finger movements for a brain machine interface (BMI). For this particular aim we applied a recently developed hierarchical spatial projection framework of neural activity for feature extraction from ECoG. The algorithm extends the binary common spatial patterns algorithm to multiclass problem by constructing a redundant set of spatial projections that are tuned for paired and group-wise discrimination of finger movements. The groupings were constructed by merging the data of adjacent fingers and contrasting them to the rest, such as the first two fingers (thumb and index) vs. the others (middle, ring and little). We applied this framework to the BCI competition IV ECoG data recorded from three subjects. We observed that the maximum classification accuracy was obtained from the gamma frequency band (65200 Hz). For this particular frequency range the average classification accuracy over three subjects was 86.3%. These results indicate that the redundant spatial projection framework can be used successfully in decoding finger movements from ECoG for BMI. PMID- 22255565 TI - Dealing with noisy gaze information for a target-dependent neural decoder. AB - We tend to look at targets prior to moving our hand towards them. This means that our eye movements contain information about the movements we are planning to make. This information has been shown to be useful in the context of decoding of movement intent from neural signals. However, this is complicated by the fact that occasionally, subjects may want to move towards targets that have not been foveated, or may be distracted and temporarily look away from the intended target. We have previously accounted for this uncertainty using a probabilistic mixture over targets, where the gaze information is used to identify target candidates. Here we evaluate how the accuracy of prior target information influences decoding accuracy. We also consider a mixture model where we assume that the target may be foveated or, alternatively, that the target may not be foveated. We found that errors due to inaccurate target information were reduced by including a generic model representing movements to all targets into the mixture. PMID- 22255566 TI - Continuous movement decoding using a target-dependent model with EMG inputs. AB - Trajectory-based models that incorporate target position information have been shown to accurately decode reaching movements from bio-control signals, such as muscle (EMG) and cortical activity (neural spikes). One major hurdle in implementing such models for neuroprosthetic control is that they are inherently designed to decode single reaches from a position of origin to a specific target. Gaze direction can be used to identify appropriate targets, however information regarding movement intent is needed to determine when a reach is meant to begin and when it has been completed. We used linear discriminant analysis to classify limb states into movement classes based on recorded EMG from a sparse set of shoulder muscles. We then used the detected state transitions to update target information in a mixture of Kalman filters that incorporated target position explicitly in the state, and used EMG activity to decode arm movements. Updating the target position initiated movement along new trajectories, allowing a sequence of appropriately timed single reaches to be decoded in series and enabling highly accurate continuous control. PMID- 22255567 TI - Exploring time-scales of closed-loop decoder adaptation in brain-machine interfaces. AB - Performing closed-loop modifications of a brain-machine interface (BMI) decoder is a technique that shows great promise for improving performance. We compare two algorithms for implementing adaptations that update decoder parameters on different time-scales (discrete batches vs. online), and present experimental results of a non-human primate performing a standard center-out BMI task. To ensure that our experimental training models are representative of a broad range of paralyzed patients, our decoders were initially trained using neural activity recorded during subject observation of cursor movement. We find that both closed loop adaptation algorithms can be used to boost BMI performance from 20-30% to 80%, yielding movement kinematics similar to natural arm movements. Based on insights derived from the performance of each algorithm, we propose that a hybrid of batch and online decoder adaptation may be the best approach. PMID- 22255568 TI - The tracking of reaches in three-dimensions. AB - Prosthetic devices to replace upper limb function have made great progress over the last decade. However, current control modalities for these prosthetics still have severe limitations in the degrees of freedom they offer patients. Brain machine interfaces offer the possibility to improve the functionality of prosthetics. Current research on brain machine interfaces is limited by our understanding of the neural representations for various movements. Few electrophysiology studies have examined the encoding of unconstrained multi-joint movements in neural signals. Here we present a system for the high-speed tracking of multiple joints in three dimensions while recording, optimizing and decoding neural signals. PMID- 22255569 TI - Reconstructing hand kinematics during reach to grasp movements from electroencephalographic signals. AB - With continued research on brain machine interfaces (BMIs), it is now possible to control prosthetic arm position in space to a high degree of accuracy. However, a reliable decoder to infer the dexterous movements of fingers from brain activity during a natural grasping motion is still to be demonstrated. Here, we present a methodology to accurately predict and reconstruct natural hand kinematics from non-invasively recorded scalp electroencephalographic (EEG) signals during object grasping movements. The high performance of our decoder is attributed to a combination of the correct input space (time-domain amplitude modulation of delta band smoothed EEG signals) and an optimal subset of EEG electrodes selected using a genetic algorithm. Trajectories of the joint angles were reconstructed for metacarpo-phalangeal (MCP) joints of the fingers as well as the carpo-metacarpal (CMC) and MCP joints of the thumb. High decoding accuracy (Pearson's correlation coefficient, r) between the predicted and observed trajectories (r = 0.76 +/- 0.01; averaged across joints) indicate that this technique may be suitable for use with a closed-loop real-time BMI to control grasping motion in prosthetics with high degrees of freedom. This demonstrates the first successful decoding of hand pre-shaping kinematics from noninvasive neural signals. PMID- 22255570 TI - Development of a self-contained accelerometry based system for control of functional electrical stimulation in hemiplegia. AB - For stroke patients, functional electrical stimulation (FES) has been shown in the past to greatly reduce gait impairments. A critical element of the success of this intervention is accurate and reliable triggering of the stimulation for step initiation. Foot switches are the most commonly used devices for triggering hemiplegic FES gait, but they have been known to produce unreliable results and degrade over time. This paper outlines the development of a self-contained accelerometry-based gait stimulation system that can be worn around the waist and unlike other systems, adds no additional hardware or equipment to don or doff. An acceleration algorithm was developed and shown to have significantly shorter heel strike detection delays than when detecting with a heel sensor which could lead to improved stimulation timing for step initiation. PMID- 22255571 TI - Preliminary design of a terrain recognition system. AB - This paper aims to design a wearable terrain recognition system, which might assist the control of powered artificial prosthetic legs. A laser distance sensor and inertial measurement unit (TMU) sensors were mounted on human body. These sensors were used to identify the movement state of the user, reconstruct the geometry of the terrain in front of the user while walking, and recognize the type of terrain before the user stepped on it. Different sensor configurations were investigated and compared. The designed system was evaluated on one healthy human subject when walking on an obstacle course in the laboratory environment. The results showed that the reconstructed terrain height demonstrated clearer pattern difference among studied terrains when the laser was placed on the waist than that when the laser was mounted on the shank. The designed system with the laser on the waist accurately recognized 157 out of 160 tested terrain transitions, 300 ms-2870 ms before the user switched the negotiated terrains. These promising results demonstrated the potential application of the designed terrain recognition system to further improve the control of powered artificial legs. PMID- 22255572 TI - Towards a movement quantification system capable of automatic evaluation of upper limb motor function after neurological injury. AB - The paper proposes an integrated system to automatically assess motor function after neurological injury. A portable motion capture system was developed in order to obtain all the relevant three dimensional kinematics of the upper limb movement. These kinematics were analyzed by means of a decision tree classifier which features where inferred from the Functional Ability Score (FAS) of the Wolf Motor Function Test (WMFT). In addition, the system is able to correctly quantify the performance time of each selected task of the WMFT. In terms of the FAS the system and the clinician show coherent results for 3 out of 5 patients in the first task tested and 4 out of 5 for the second task tested. Regarding performance time, the mean error between the system and the clinician was of 0.216 s for the 25 trials performed (5 patients, 5 tasks each). These results represent an important proof of concept towards a system capable of precisely evaluate upper limb motor function after neurological injury. PMID- 22255573 TI - A clinical trial of a prototype of wireless surface fes rehabilitation system in foot drop correction. AB - The purpose of this study is to develop a wireless FES rehabilitation system to assist effective improvement of the lower limbs. In this report, a prototype system combined with foot drop correction and gait evaluation using wireless surface electrical stimulator and the wireless inertial sensors was developed and tested with a right hemiplegic subject. For gait evaluation, lower limb joint angles and segment angles were estimated by the Kalman filter from the data measured with wireless inertial sensors. Electrical stimulation was applied to the common peroneal nerve or the tibialis anterior muscle by detecting stimulus timing automatically from the data of wireless inertial sensor attached on the shank of the hemiplegic side. The maximum joint angle of ankle dorsiflexion of the paralyzed side at the swing phase was increased approximately to the value of the healthy side by applying the electrical stimulation. The developed system was performed well in foot drop correction and the measured data of the inertial sensors showed the characteristics and difference of paralyzed side with and without electrical stimulation using the segment angles and joint angles. PMID- 22255574 TI - Command detection and classification in tongue drive assistive technology. AB - Tongue Drive System (TDS) is a new assistive technology that enables individuals with severe disabilities such as those with spinal cord injury (SCI) to regain environmental control using their tongue motion. We have developed a new sensor signal processing (SSP) algorithm which uses four 3-axial magneto-resistive sensor outputs to accurately detect and classify between seven different user control commands in stationary as well as mobile conditions. The new algorithm employs a two-stage classification method with a combination of 9 classifiers to discriminate between 4 commands on the left or right side of the oral cavity (one neutral command shared on both sides). Evaluation of the new SSP algorithm on five able-bodied subjects resulted in true positive rates in the range of 70-99% with corresponding false positive rates in the range of 5-7%, showing a notable improvement in the resulted true-false (TF) differences when compared to the previous algorithm. PMID- 22255575 TI - Tests of wireless wearable sensor system in joint angle measurement of lower limbs. AB - The aim of this study was to test the wireless wearable sensor system consists of inertial sensors considering application to rehabilitation. The sensor system was evaluated in measurement of hip, knee and ankle joint angles with healthy subjects comparing to those measured with a 3D motion measurement system. Then, the lower limb joint angles of elderly subjects including paralyzed subjects were measured during gait on the level floor with the sensor system. Evaluation of measured joint angles in comparison with the motion measurement system showed that mean values of the RMSE were smaller than 4 deg for all the joint angles, and mean values of the correlation coefficient were larger than 0.985 for hip and knee joint angles and about 0.90 for ankle joint angle. In measurement with elderly subjects, the sensor system showed some differences in joint angles between the paralyzed and the non-paralyzed sides. PMID- 22255576 TI - Influence of white matter conductivity anisotropy on electric field strength induced by electroconvulsive therapy. AB - The goal of this study is to investigate the influence of white matter conductivity anisotropy on the electric field strength induced by electroconvulsive therapy (ECT). We created an anatomically-realistic finite element human head model incorporating tissue heterogeneity and white matter conductivity anisotropy using structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. The electric field spatial distributions of three conventional ECT electrode placements (bilateral, bifrontal, and right unilateral) and an experimental electrode configuration, focal electrically administered seizure therapy (FEAST), were computed. A quantitative comparison of the electric field strength was subsequently performed in specific brain regions of interest thought to be associated with side effects of ECT (e.g., hippocampus and in-sula). The results show that neglecting white matter conductivity anisotropy yields a difference up to 19%, 25% and 34% in electric field strength in the whole brain, hippocampus, and insula, respectively. This study suggests that white matter conductivity anisotropy should be taken into account in ECT electric field models. PMID- 22255577 TI - Optical stimulation of visual cortex with pulsed 620-nm red light. AB - To explore the optical neural stimulation with visible light, 620-nm red light pulse emitted by LED was used to stimulate the left primary visual cortex of adult rat. The neural response in right primary visual cortex was recorded with a flexible microelectrode. By synchronized averaging the raw signal, optical evoked potentials (OEPs) were observed a negative wave and positive wave after optical stimuli. Furthermore, the amplitude and occurrence of the negative and positive wave were modulated by the strength and pulse width of the optical stimulus. The preliminary experiment suggested that, beyond the infrared laser, the pulse of visible light (e.g. red light) can modulate the neural activity in central nervous system. PMID- 22255578 TI - A dual-shank neural probe integrated with double waveguides on each shank for optogenetic applications. AB - This paper presents a dual-shank neural probe integrated with double-waveguides on each shank, which enables both optical stimulation and electrical recording. Two 15-MUm-thick polymeric (SU-8) waveguides on each neural probe shank have been precisely defined by photolithography with a width of 24 MUm and a spacing of 10 MUm. The waveguides transmit a light coupled from optical fibers which are placed in the grooves located at the neural probe body. Each shank has 8 iridium recording electrodes which have the area of 11 MUm * 13 MUm. In front of each waveguide, four recording sites are deployed with a pitch of 100 MUm. Blue light (473 nm in wavelength) has been successfully transmitted to the stimulation sites located at the end of the fabricated neural probe tips. PMID- 22255579 TI - Electroconvulsive therapy simulations using an anatomically-realistic head model. AB - Electroconvulsive therapy (ECT) is a highly effective treatment for severe depressive disorder. Efficacy and cognitive outcomes have been shown to depend on variations in treatment technique. A high resolution finite element model of a human head was generated from MRI scans and implemented with tissue heterogeneity and an excitable ionic neural model incorporated in the brain. The model was used to compare the effects of three common ECT electrode configurations, including the spatial profiles of electric field and excitation in the brain. The results showed that electrode placement has a significant effect in determining the spatial extent of activation in different brain regions, which would account for differences seen in clinical outcomes. PMID- 22255580 TI - Electric fields in hippocampus due to transcranial focal electrical stimulation via concentric ring electrodes. AB - As epilepsy affects approximately one percent of the world population, electrical stimulation of brain has recently shown potential as an additive seizure control therapy. In this study we applied focal transcranial electrical stimulation (TFS) on the surface of the skull of rats via concentric ring electrodes. We recorded electric potentials with a bipolar electrode consisting of two stainless steel wires implanted into the left ventral hippocampus. TFS current was gradually increased by 20% starting at 103 MUA allowing us to assess the relationship between TFS current and both potentials recorded from the bipolar electrode and the resulting electric field. Generally, increases in TFS current resulted in increases in the electric field. This allows us to estimate what extra-cranial TFS current would be sufficient to cause the activation of neurons in the hippocampus. PMID- 22255581 TI - Effect of white matter anisotropy in modeling electroconvulsive therapy. AB - White matter in the brain exhibits strong anisotropic conductivity. Modeling studies on electroencephalography have found that such anisotropic conductivity greatly influences the estimated dipole source. In this study, we made a detailed comparison of the effects of conductivity anisotropy using a computational model of electroconvulsive therapy (ECT). The human head model was a high resolution finite element model generated from MRI scans, implemented with tissue heterogeneity and an excitable neural model incorporated in the brain. Results showed that anisotropy in conductivity had minimal effects on the location of the brain region that was maximally activated, but it had relatively large effects on deep brain structures. PMID- 22255582 TI - Cardiac output monitoring by long time interval analysis of a radial arterial blood pressure waveform with correction for arterial compliance changes using pulse transit time. AB - We previously developed a technique for estimating relative cardiac output (CO) change by long time interval analysis of a radial arterial blood pressure waveform. This technique analyzes the slow, beat-to-beat changes in the waveform to circumvent the confounding wave reflections but assumes constant arterial compliance (AC). Here, we sought to correct the CO estimates of the technique for potential AC changes using pulse transit time--a conveniently measured index of AC. For proof-of-concept, we compared the original and corrected techniques using invasive swine hemodynamic data. The corrected technique reduced the overall calibrated CO estimation error by 18% relative to the original technique. PMID- 22255583 TI - Early detection of spontaneous blood loss using amplitude modulation of Photoplethysmogram. AB - The present study was designed to investigate can the amplitude modulation (AM) of Photoplethysmogram (PPG) be used as an indicator of blood loss and if so what is the best PPG probe site. PPG from ear, finger and forehead probe sites, standard ECG, and Finapres blood pressure waveforms were continuously recorded from 8 healthy volunteers during baseline, blood withdrawal of 900 ml followed by the blood reinfusion. The instantaneous amplitude modulations present in heart rate (AM(HR)) and breathing rate (AM(BR)) band frequencies of PPG were extracted from high-resolution time-frequency spectrum. HR and pulse pressure showed no significant changes during the protocol. The AM(HR) significantly (P<0.05) decreased at 100 ml through 900 ml blood loss from ear and finger probe sites. The mean percent decrease in AM(HR) at 900 ml blood loss compared to baseline value was 45.2%, 42.0%, and 42.3% for ear, finger and forehead PPG signals, respectively. In addition, significant increases in AM(BR) were found due to blood loss in ear and finger PPG signals. Even without baseline AM(HR) values, 900 ml blood loss detection was shown possible with specificity and sensitivity both 87.5% from ear PPG signals. The present technique has great potential to serve as a valuable tool in the intraoperative and trauma settings to detect hemorrhage. PMID- 22255584 TI - Continuous Multiorgan Variability monitoring in critically ill patients- complexity science at the bedside. AB - Complex systems science has led to valuable insights regarding the care and understanding of critical illness, but has not led to fundamental improvements to care to date. Realizing the fact that there is inherent uncertainty in patient trajectory, we have developed Continuous Individual Multiorgan Variability Analysis (CIMVA) as a tool theoretically and practically designed to track the systemic emergent properties of the host response to injury or infection. We present an overview of CIMVA software, and discuss four separate potential clinical applications that we are evaluating; including early detection of infection, better prediction of extubation failure, continuous monitoring of severity of illness in the ICU, and the evaluation of cardiopulmonary fitness. Future challenges are discussed in conclusion. PMID- 22255585 TI - Photoplethysmographic variability analysis in critical care--current progress and future challenges. AB - The concept of early goal-directed therapy emphasizes the need for early diagnosis and intervention to achieve better therapeutic outcomes in critical care. There has been rapidly growing interest in the use of the photoplethysmogram (PPG), also known as the "pulse oximetry waveform", as a noninvasive diagnostic tool in this clinical setting. The peripheral PPG exhibits beat-to-beat variability driven by physiological mechanisms such as respiration and sympathetic vascular activity. This paper provides an overview of the current progress towards the application of PPG waveform variability (PPGV) in emergency and intensive care. Studies to date have demonstrated the potential value of PPGV for assessing a range of pathophysiological conditions including blood loss, sepsis and low systemic vascular resistance. Translation of research findings into clinical practice poses several future challenges, including the need for large scale validation studies with appropriate measurement systems, more robust solutions to signal quality issues (such as motion artifacts), and better physiological understanding of the information-rich PPGV. PMID- 22255586 TI - Alteration of autonomic blood pressure control during hemodialysis in peripheral vascular disease patients. AB - Blood pressure (BP) response to volume depletion induced by hemodialysis (HD) treatment may be important to understand the pathophysiology of the increased mortality in HD patients with vascular calcification. In the present study a comparison between end stage renal disease (ESRD) patients affected by peripheral vascular disease (PVD) and ESRD patients without PVD was performed. Continuous blood pressure was recorded at the beginning and at the end of HD. BP and heart rate variability (HRV) were analyzed to quantify the autonomic nervous system regulation of heart beat and peripheral resistance. PVD patients showed an increase of pulse pressure (PP) during HD, an altered autonomic peripheral control, a lower sympathetic activity, with respect to ESRD patients without PVD. PMID- 22255587 TI - Predictive monitoring for early detection of subacute potentially catastrophic illnesses in critical care. AB - We wish to save lives of patients admitted to ICUs. Their mortality is high enough based simply on the severity of the original injury or illness, but is further raised by events during their stay. We target those events that are subacute but potentially catastrophic, such as infection. Sepsis, for example, is a bacterial infection of the bloodstream, that is common in ICU patients and has a >25% risk of death. Logically, early detection and treatment with antibiotics should improve outcomes. Our fundamental precepts are (1) some potentially catastrophic medical and surgical illnesses have subclinical phases during which early diagnosis and treatment might have life-saving effects, (2) these phases are characterized by changes in the normal highly complex but highly adaptive regulation and interaction of the nervous system and other organs such as the heart and lungs, (3) teams of clinicians and quantitative scientists can work together to identify clinically important abnormalities of monitoring data, to develop algorithms that match the clinicians' eye in detecting abnormalities, and to undertake the clinical trials to test their impact on outcomes. PMID- 22255588 TI - Validation of surface atrial fibrillation organization indicators through invasive recordings. AB - Studies related to atrial fibrillation (AF) have shown that surface lead V(1) reflects mainly the dominant atrial frequency (DAF) of the right atrium (RA), which has been widely used to analyze this arrhythmia. AF organization and fibrillatory (f) waves amplitude are two recently proposed non-invasive AF markers, which have not been yet validated with invasive recordings. In this work, these two non-invasive metrics have been compared with similar measures recorded from two unipolar atrial electrograms (AEGs). Results obtained from 38 patients showed statistically significant correlations between the values measured from surface and invasive recordings, thus corroborating the usefulness of the aforesaid markers in the non-invasive study of AF. Precisely, for AF organization, the correlation coefficients between surface and both AEGs were R = 0.926 (p < 0.001) and R = 0.932 (p < 0.001), respectively. For f waves amplitude, slightly lower significant relationships were noticed, the correlation coefficients being R = 0.765 (p < 0.001) and R = 0.842 (p < 0.001), respectively. These outcomes together with interesting linear relationships found among the parameters, suggest that AF organization and f waves amplitude can characterize non-invasively the epicardial activity related to AF. PMID- 22255589 TI - Pathogenesis of AF: impact on intracardiac signals. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is responsible for the highest number of rhythm-related disorders and cardioembolic strokes worldwide. Intracardiac signal analysis during the onset of paroxysmal AF led to the discovery of pulmonary vein as a triggering source of AF, which has led to the development of pulmonary vein ablation--an established curative therapy for drug-resistant AF. Complex, multicomponent and rapid electrical activity widely involving the atrial substrate characterizes persistent/permanent AF. Widespread nature of the problem and complexity of signals in persistent AF reduce the success rate of ablation therapy. Although signal processing applied to extraction of relevant features from these complex electrograms has helped to improve the efficacy of ablation therapy in persistent/permanent AF, improved understanding of complex signals should help to identify sources of AF and further increase the success rate of ablation therapy. PMID- 22255590 TI - A time-domain approach for the identification of atrial fibrillation drivers. AB - The localization of atrial fibrillation (AF) driver sources, characterized by rapid and regular electrical activity, is crucial for an effective ablation treatment. This work proposes a double-criteria approach for the identification of AF drivers based on a time-domain evaluation of atrial rate and AF organization. These two features are quantified by the measurement of atrial cycle length (ACL) and wave-similarity (WS). Based on ACL/WS formalism, AF drivers can be operatively defined as sites displaying electrical activity with high-rate and high-similarity (HR AND HS). The capability of ACL/WS analysis to identify AF driver sites and distinguish them from non-critical areas is shown in representative examples. The double-criteria evaluation for the identification of AF drivers, provided by our time-domain approach, might open new perspectives for the development of electrogram-guided ablation strategies in the single patient. PMID- 22255591 TI - Non-invasive prediction of catheter ablation outcome in persistent atrial fibrillation by exploiting the spatial diversity of surface ECG. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Radiofrequency catheter ablation (CA) is becoming one of the most widely employed therapies. Yet selection of patients who will benefit from this treatment remains a challenging task. Previous works have examined several electrocardiogram (ECG) parameters as potential predictors of CA success, such as fibrillatory wave (f-wave) amplitude. However, they require a manual computation and consider only a subset of electrodes, so inter-lead spatial variability of the 12-lead ECG is not fully exploited. The present study puts forward an automatic procedure for f-wave amplitude computation to non-invasively predict CA outcome. An extension of this quantitative measure to the whole set of leads is also proposed, based on Principal Component Analysis (PCA). We show that exploiting the spatial diversity present in the surface ECG not only improves the robustness to electrode selection but also increases the predictive power of the amplitude parameter. PMID- 22255592 TI - Propagation pattern analysis during atrial fibrillation based on the adaptive group LASSO. AB - The present study introduces sparse modeling for the estimation of propagation patterns in intracardiac atrial fibrillation (AF) signals. The estimation is based on the partial directed coherence (PDC) function, derived from fitting a multivariate autoregressive model to the observed signals. A sparse optimization method is proposed for estimation of the model parameters, namely, the adaptive group least absolute selection and shrinkage operator (aLASSO). In simulations aLASSO was found superior to the commonly used least-squares (LS) estimation with respect to estimation performance. The normalized error between the true and estimated model parameters dropped from 0.20 +/- 0.04 for LS estimation to 0.03 +/- 0.01 for aLASSO when the number of available data samples exceeded the number of model parameters by a factor of 5. The error reduction was more pronounced for short data segments. Propagation patterns were also studied on intracardiac AF data, the results showing that the identification of propagation patterns is substantially simplified by the sparsity assumption. PMID- 22255593 TI - Mapping of complex fractionated atrial electrograms as target sites for AF ablation. AB - The myriad pathologies leading to and resulting from atrial fibrillation (AF) have led to many theories regarding how substrate should be defined and how to reconcile substrate ablation with trigger ablation. The identification of spatiotemporally stable areas of very low amplitude short cycle length CFAE in a sea of otherwise discrete normal amplitude and relatively longer cycle length electrograms led to ablate the complex fractionated atrial electrogram (CFAE) as a marker of abnormal substrate. This pure substrate-based ablation strategy has shown promising result of benefit in stroke and mortality reduction in high-risk patients. In this review which has been modified and abridged from the recent publication on this subject [1], we discuss the prevailing mechanisms underlying CFAE, how to map and ablate CFAE sites, correlation of CFAE areas to those of ganglionic plexi, clinical outcomes of the approach, and the controversy surrounding targeting CFAE as substrate sites for AF ablation. PMID- 22255594 TI - Discovery of lung cancer pathways using reverse phase protein microarray and prior-knowledge based Bayesian networks. AB - The goal of this paper is to infer the signaling pathway related to lung cancer using Reverse Phase Protein Microarray (RPPM), which provides information on post translational phosphorylation events. The computational inferring of pathways is obtained by performing Bayesian network in combination with prior knowledge from Protein-Protein Interaction (PPI). A clustering based Linear Programming Relaxation is developed for the searching of optimal networks. The PPI prior knowledge is incorporated into a new scoring function definition based on minimum description length (MDL). In the experiment, we first evaluate the algorithm performance with synthetic networks and associated data. Then we show our signaling network inference for lung cancer using RPPM data. Through the study, we expect to derive new signalling pathways and insight on protein regulatory relationships, which are yet to be known for lung cancer study. PMID- 22255595 TI - An evolutionary optimization strategy using graphics processing units to efficiently investigate gene-gene interactions in genetic association studies. AB - The analysis of gene-gene interactions related to common complex human diseases is complicated by the increasing scale of genetic association analysis. Concurrent with the advances in genetic technology that led to these large data sets, improvements have been made in parallel computing with graphics processing units (GPUs). The data-intensive nature of genetic association analysis makes this problem particularly suitable for improved computation with the powerful computing resources available in GPUs. In this study, we present a GPU accelerated discrete optimization strategy to improve the computational efficiency of multi-locus association analysis. We implemented an adaptive evolutionary algorithm that takes advantage of linkage disequilibrium to reduce the need for exhaustive search for combinations of genetic markers. The proposed GPU algorithm was shown to have improved efficiency and equivalent power relative to the CPU version. PMID- 22255596 TI - A disease annotation study of gene signatures in a breast cancer microarray dataset. AB - Breast cancer is a complex disease with heterogeneity between patients regarding prognosis and treatment response. Recent progress in advanced molecular biology techniques and the development of efficient methods for database mining lead to the discovery of promising novel biomarkers for prognosis and prediction of breast cancer. In this paper, we applied three computational algorithms (RFE-LNW, Lasso and FSMLP) to one microarray dataset for breast cancer and compared the obtained gene signatures with a recently described disease-agnostic tool, the Genotator. We identified a panel of 152 genes as a potential prognostic signature and the ERRFI1 gene as possible biomarker of breast cancer disease. PMID- 22255597 TI - Detection of copy number variation using scale space filtering. AB - This study proposes a novel CNV detection algorithm based on scale space filtering. It uses Gaussian filter for the convolution with a scale parameter. The range of the scale parameter is adjusted according to the coverage level of read data. The position of a CNV region is determined through a coarse and a fine searches over the scales. The results showed low dependency of the performance of the proposed method on the coverage level compared to the conventional methods. The results also showed that the proposed method outperforms the conventional methods by 63.29 ~ 73.57 %. PMID- 22255598 TI - Nearest hyperplane distance neighbor clustering algorithm applied to gene co expression analysis in Alzheimer's disease. AB - Microarray analysis can contribute considerably to the understanding of biologically significant cellular mechanisms that yield novel information regarding co-regulated sets of gene patterns. Clustering is one of the most popular tools for analyzing DNA microarray data. In this paper, we present an unsupervised clustering algorithm based on the K-local hyperplane distance nearest-neighbor classifier (HKNN). We adapted the well-known nearest neighbor clustering algorithm for use with hyperplane distance. The result is a simple and computationally inexpensive unsupervised clustering algorithm that can be applied to high-dimensional data. It has been reported that the NFkB1 gene is progressively over-expressed in moderate-to-severe Alzheimer's disease (AD) cases, and that the NF-kB complex plays a key role in neuroinflammatory responses in AD pathogenesis. In this study, we apply the proposed clustering algorithm to identify co-expression patterns with the NFkB1 in gene expression data from hippocampal tissue samples. Finally, we validate our experiments with biomedical literature search. PMID- 22255599 TI - Estimation of correlations between copy-number variants in non-coding DNA. AB - Allelic DNA aberrations across our genome have been associated with normal human genetic heterogeneity as well as with a number of diseases and disorders. When copy-number variations (CNVs) occur in gene-coding regions, known relationships between genes may help us understand correlations between CNVs. However, a large number of these aberrations occur in non-coding, extragenic regions and their correlations may be characterized only quantitatively, e.g., probabilistically, but not functionally. Using a signal processing approach to CNV detection, we identified distributed CNVs in short, non-coding regions across chromosomes and investigated their potential correlations. We estimated predominantly local correlations between CNVs within the same chromosome, and a small number of apparently random long-distance correlations. PMID- 22255600 TI - Spatiotemporal control of cell fate and cardiac differentiation. AB - Congestive heart failure is a leading cause of morbidity and mortality in the United States and worldwide [1]. Although not the only cause of congestive heart failure, loss of myocardium due to obstructive coronary artery disease is a major contributor to this condition [2,3]. The loss of myocardium is mainly regional and, therefore, localized therapy holds the most promise. In recent years, many clinical studies have been initiated to deliver localized therapy in the form of various cell types for reconstitution of the myocardium [4-6]. However, there is much debate on the optimal cell type, whether or not stem cells can differentiate into functional myocardium and the long-term effects of these non-myocytes. In addition to exogenous cell delivery, paracrine effects arising from delivery of angiogenic factors and other biochemical agents suggest that the myocardium retains the ability to remodel and heal [7,8]. Understandably, there has been tremendous focus on both growth factor- and gene therapy-based therapeutics. While a source of great promise, direct growth factor delivery to the myocardium will most likely be inefficient as several studies have noted that many of these small proteins are carried away in the highly vascularized cardiac tissue [9,10]. Gene therapy, while providing an excellent analytical tool, has not met with enthusiasm clinically, mostly due to the inability to quantify delivery and nonspecific targeting in vivo. This body of work supports two crucial conclusions: (1) appropriate biological cues that act locally on the myocardium can improve functional outcomes, and (2) spatiotemporal control over the delivery and presentation of these cues remains challenging and inefficient. The current body of work on cardiac drug delivery and stem cell therapy support two crucial conclusions: (1) appropriate biological cues that act locally on the myocardium can improve functional outcomes, and (2) spatiotemporal control over the delivery and presentation of these cues remains challenging and inefficient. Using specialized biomaterials, we are able to address this. Our laboratory has used functional nanoparticles to deliver regenerative cues with both spatial and temporal control. By adding biomimetic signals to the surface of the nanoparticles, we are able to enhance nonphagocytic cell uptake, achieve cell specific targeting, and deliver molecules in a time-controlled manner. Furthermore, by combining our nanoparticles with self-assembling peptide nanofibers, we can achieve some of these in 3D while retaining implanted cells. Following infarction, and during cell differentiation and survival, there are unique sequences of events that contribute to the pathophysiology of the processes. By enhanced understanding of these signals, and the spatiotemporal control needed to deliver them, it will help design better therapeutics for cardiac regeneration. Using high-throughput screening, we have identified several carbohydrates that bind with high affinity to both cardiomyocytes and cardiac progenitor cells. For example, n-acetylglucasmine (GlcNAc) and related sugars bound with high affinity to both of these important cell types. Modification of the sugars with phospholipds allowed incorporation of into hydrophobic nanoparticles with high fidelity. When delivered to cardiomyocytes or cardiac progenitor cells, these biologically-modified nanoparticles enhanced uptake by several fold. In addition to using sugars, we also used metal affinity chromatography chemistry to link Nickel-NTA to the outside of nanoparticles. This not only allowed for conjugation of Histidine-tagged proteins to the outside for temporal delivery, but also allowed for conjugation of cell-specific targeting agents as well. Indeed, when His-VE-Cadherin was used as a model targeting agent, binding and uptake by endothelial cells increased significantly. For cell therapy, incorporation of proper signals to the micoenvironment is critical. One such signal that greatly impacts differentiation is the Notch1 pathway. We were able to immobilize Jagged1, the ligand of Notch1, on to self-assembling peptide nanofibers. Inclusion of this bioactive signal significantly enhanced cardiogenic differentiation. Morever, by including time release nanoparticles, we were able to improve differentiation and survival significantly more, underscoring the need to spatiotemporal control of drug delivery for enhancing cell therapy. PMID- 22255601 TI - Optimization-based dosimetry planning for brachytherapy. AB - Algorithms for improving dosimetry plans for brachytherapy procedures have been developed. In particular, the algorithms focus on creating an optimized dosimetry plan automatically, as well as updating the plan in real time to compensate for errors in seed placements. The overall performance of the algorithms is compared with currently existing dosimetry planning software. The plans are particularly suited for use in robotics-assisted procedures. PMID- 22255602 TI - Ultrasound enhanced delivery of macromolecular agents in brain tumor rat model. AB - The purpose of this study was to evaluate the permeability of the blood-brain barrier (BBB) after focused ultrasound (FUS) exposure and to investigate if such an approach increases the tumor-to-ipsilateral brain permeability ratio. Normal rats and F98 glioma-bearing rats were injected intravenously with Evans blue (EB); these treatments took place with or without BBB disruption induced by transcranial FUS of one hemisphere of the brain. Sonication was applied at an ultrasound frequency of 1 MHz with a 5% duty cycle, and a repetition frequency of 1 Hz. The permeability of the BBB was quantitatively assessed by means of the extravasation of EB. Contrast-enhanced MR images were used to monitor the gadolinium deposition path associated with transcranial FUS and the influence of size and location was also investigated. Furthermore, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t test. The accumulation of EB in brains and the tumor-to-ipsilateral brain permeability ratio of EB were significantly increased after FUS exposure. EB injection followed by sonication showed an increase in the tumor-to-ipsilateral brain ratio of the target tumors of about two-fold compared with the control tumors on day 8 after tumor implantation. MR images showed that FUS locally enhances the permeability of the BBB in the glioma-bearing rats. The BBB can be locally disrupted with FUS in the presence of microbubbles. This technology may offer new opportunities that will allow enhanced synergistic effects with respect to other brain tumor treatment regimens. PMID- 22255603 TI - Heating mechanisms in gold nanoparticles at radio frequencies. AB - Gold nanoparticles are under study as a potentially viable mechanism for hyperthermia tumor treatment in two regimes of the electromagnetic spectrum: laser and radio frequency excitation. Gold nanoparticles, nanorods and nanoshells have been applied with visible laser sources that excite the particles at or near their plasmon resonance frequency, and this mechanism has been well studied. The physical processes that describe the experimentally observed heating at radio frequencies (13.56 MHz) are not as well understood. Differing results have been reported in semi-solid phantom materials and liquid phase suspensions. This numerical modeling study was undertaken to inspect the relative importance of several candidate physical processes. PMID- 22255604 TI - Experimental characterization of intrapulse tissue conductivity changes for electroporation. AB - Cells exposed to short electric pulses experience a change in their transmembrane potential, which can lead to increased membrane permeability of the cell. When the energy of the pulses surpasses a threshold, the cell dies in a non-thermal manner known as irreversible electroporation (IRE). IRE has shown promise in the focal ablation of pathologic tissues. Its non-thermal mechanism spares sensitive structures and facilitates rapid lesion resolution. IRE effects depend on the electric field distribution, which can be predicted with numerical modeling. When the cells become permeabilized, the bulk tissue properties change, affecting this distribution. For IRE to become a reliable and successful treatment of diseased tissues, robust predictive treatment planning methods must be developed. It is vital to understand the changes in tissue properties undergoing the electric pulses to improve numerical models and predict treatment volumes. We report on the experimental characterization of these changes for kidney tissue. Tissue samples were pulsed between plate electrodes while intrapulse voltage and current data were measured to determine the conductivity of the tissue during the pulse. Conductivity was then established as a function of the electric field to which the tissue is exposed. This conductivity curve was used in a numerical model to demonstrate the impact of accounting for these changes when modeling electric field distributions to develop treatment plans. PMID- 22255605 TI - Laser Interstitial Thermotherapy for pancreatic tumor ablation: theoretical model and experimental validation. AB - This study aims to develop and verify a theoretical model to reproduce the thermal response of pancreatic tissue undergone Laser Induced Interstitial Thermotherapy (LITT). The model provides the evaluation of: a) ablated volumes induced by thermal ablation; b) tissue response time to irradiation; and c) heat extinction time. Theoretical volume values were compared with ex vivo healthy tissue and in vivo healthy and neoplastic tissue volume values. The theoretical model takes into account the differences between healthy and neoplastic tissue due to blood perfusion. Mathematical model shows that ablated volume of ex vivo healthy tissue is greater than in vivo one after the same treatment. Moreover, ablated neoplastic in vivo tissue volume is greater than healthy in vivo one, because of tumour angiogenesis. Ablated volume values were compared with experimental data obtained by laser treatment of 30 ex vivo porcine pancreases. Experimental ablated volume values show a good agreement with theoretical values, with an estimated increase of 61% when power increases from 3 W to 6 W, versus 46% of experimental data, and an estimated increase of 14% from 6 W to 10 W, versus 21% of experimental values. LITT could be an alternative or a neo-adjuvant treatment to surgical resection for pancreas cancer removal, and the proposed model could be the basis to supervising the evolution of ablated volumes during tumor treatment. PMID- 22255606 TI - Dependence of aggregate formation of microbubbles upon ultrasound condition and exposure time. AB - We have previously reported our attempts to control microbubbles (microcapsules) behavior in flow by primary Bjerknes force to increase the local concentration of the bubbles at a diseased part. However, there was a limitation in efficiency to propel bubbles of MUm-order size. Thus we consider that forming aggregates of bubbles is effective to be propelled before entering into an ultrasound field by making use of secondary Bjerknes force under continuous ultrasound exposure. In this study, we observed the phenomena of aggregates formation by confirming variation of diameter and density of aggregates under various conditions of ultrasound exposure. Then we elucidated frequency dependence of the size of aggregates of micro-bubbles. PMID- 22255607 TI - The center for integration of medicine and innovative technologies (CIMIT): a proven model to speed the cycle of healthcare innovation. AB - CIMIT is a Boston-wide consortium of premier clinical, research and academic institutions dedicated to improving patient care through application of innovative enabling technology. PMID- 22255608 TI - Magneto-harmonic pressure sensor for biomedical applications. AB - A wireless and passive pressure sensor was developed for biomedical applications such as monitoring pressure in an abdominal aortic aneurysm sac after a stenting procedure to detect potential leakage from the stent graft. The sensor, referred to as the magneto-harmonic pressure sensor, was an airtight chamber consisting of a rigid well structure capped with an elastic membrane. A magnetically soft material was placed at the bottom of the well, while a magnetically hard material was attached to the membrane. Under the excitation of a magnetic AC field, the magnetically soft material produced a magnetic field at frequencies higher than the excitation frequency (the higher-order harmonic fields) that can be remotely detected with an external detection system. The pattern of the higher-order harmonic fields was dependent on the magnitude of the magnetic DC field produced by the magnetically hard material. When the ambient pressure varied, the membrane of the sensor deflected, changing the separation distance between the magnetically hard and soft materials. This in turn changed the magnitude of the magnetic DC field, causing a shift in the higher-order harmonic field pattern. This paper describes the design and fabrication of the sensor, and its implementation to mice to evaluate its performance in a biological environment. PMID- 22255609 TI - In-mouth antenna for tongue controlled wireless devices: characteristics and link loss. AB - We have investigated the possibility of using a curved dipole antenna inside the mouth for the tongue controlled wireless devices in 2.45 GHz ISM band. These devices can be interfaced with the wheelchair or the computer used by the paraplegic patients. Two antenna placement positions have been investigated: in front of the teeth and behind the teeth. The investigations were done through the FDTD simulations on a realistic heterogeneous phantom with the mouth closed and open. The link loss between the in-mouth dipole antenna and an external dipole antenna at 400 mm from the center of the head was calculated. It was found that the radiation pattern changed according to the placement of the antennas inside the mouth and whether the mouth was open or closed. The link loss for the in front of the teeth placement was found to be 9 dB-11 dB lower than the behind the teeth placement depending on the open or the closed mouth. The variation in the link loss was 1 dB-4 dB for the open mouth when compared with the closed mouth depending on the antenna placement position. By using these results, a reliable wireless link for the in-mouth device can be designed. PMID- 22255610 TI - Comparison of TOA and RSS based techniques for RF localization inside human tissue. AB - Localization inside the human body using radio frequency (RF) transmission is gaining importance in a number of applications such as Capsule Endoscopy. The accuracy of RF localization depends on the technology adopted for this purpose. The two most common RF localization technologies use received signal strength (RSS) and time-of-arrival (TOA). This paper presents a comparison of the accuracy of TOA and RSS based localization inside human tissue. Analysis of the propagation of radio waves inside the human body is extremely challenging and computationally intensive. We use our proprietary finite difference time domain (FDTD) technique algorithm reported in [1] to simulate waveform transmissions inside the human body, which is almost 60 times faster than commercially available solvers used for similar purposes. The RSS and TOA of the waveforms are extracted for localization and the accuracies of the two methods are compared. The accuracy of each technique is compared with traditional CRLB commonly used for calculation of bounds for the performance of localization techniques. PMID- 22255611 TI - A daily living activity remote monitoring system for solitary elderly people. AB - A daily living activity remote monitoring system has been developed for supporting solitary elderly people. The monitoring system consists of a tri-axis accelerometer, six low-power active filters, a low-power 8-bit microcontroller (MC), a 1GB SD memory card (SDMC) and a 2.4 GHz low transmitting power mobile phone (PHS). The tri-axis accelerometer attached to the subject's chest can simultaneously measure dynamic and static acceleration forces produced by heart sound, respiration, posture and behavior. The heart rate, respiration rate, activity, posture and behavior are detected from the dynamic and static acceleration forces. These data are stored in the SD. The MC sends the data to the server computer every hour. The server computer stores the data and makes a graphic chart from the data. When the caregiver calls from his/her mobile phone to the server computer, the server computer sends the graphical chart via the PHS. The caregiver's mobile phone displays the chart to the monitor graphically. PMID- 22255612 TI - Wirelessly powered stimulator and recorder for neuronal interfaces. AB - Functional Electrical Stimulation (FES) is widely adopted in neuro-engineering to partially alleviate diseased functions in the brain, retina and cochlea. We present a 32-channel wirelessly powered constant current stimulator and low power recording amplifier for FES based applications. The biphasic stimulator utilizes innovative techniques for matched positive/ negative currents and thus improves charge balance. Electrode discharging scheme is added for stimulation artifact suppression. An improved low power amplifier is incorporated for evoked response measurements. Electrical performance is characterized using simulated electrode electrolyte impedance. Closed-loop stimulation and recording experiments have been performed. Stimulation current magnitudes of 2 MUA-200 MUA and up to 400 Hz rate have been realized. Theory and limitation of discharging scheme is explored while suppressing artifacts down to 3 ms. Alternate anodic-first and cathodic first stimulation pulses are adopted for enhanced charge balancing. The low power amplifier exhibits gain of 1200 and bandwidth 350 Hz-1.02 KHz. A multiplexer/ demultiplexer is used to share the front-end among 32 electrodes. The inductively coupled wireless energy harvester works at 125 KHz-135 KHz that can remotely deliver 1.4 mW at 1cm distance to an equivalent of 10K load. The system can accommodate multielectrodes with impedance up to 100 K Omega. The entire hybrid analog-digital system consumes 360 MUW quiescent power. Miniaturization makes it suitable for in-vivo applications. PMID- 22255613 TI - A generic miniature multi-feature programmable wireless powering headstage ASIC for implantable biomedical systems. AB - Wireless powering holds immense promise to enable a variety of implantable biomedical measurement systems with different power supply and current budget requirements. Effective power management demands more functionality in the headstage design like power level detection for range estimation and power save modes for sleep-wake operation. This paper proposes a single chip ASIC solution that addresses these problems by incorporating digitally programmable features and thus has the potential to enable wireless powering for many implantable systems. The ASIC includes an RF rectifier which has a peak efficiency of 17.9% at 900 MHz and 11.0% at 2.4 GHz, a robust 1 V bandgap reference and LDO voltage regulator whose output can be programmed in the range of 1 V-1.5 V, and can drive upto 4 mA of load current. The input RF power level detector has a threshold of 1.6 V and the power management block can be programmed to give a 6%, 12.5% or 25% duty cycle power line to the transmitter resulting in upto 60% reduction in average power. The ASIC was fabricated using the TSMC 65 nm process, occupies 1mm(2) die area and the headstage consumes ~300 MUA at 1.2V regulated supply. PMID- 22255614 TI - Introducing a modular activity monitoring system. AB - In this paper, the idea of a modular activity monitoring system is introduced. By using different combinations of the system's three modules, different functionality becomes available: 1) a coarse intensity estimation of physical activities 2) different features based on HR-data and 3) the recognition of basic activities and postures. 3D-accelerometers--placed on lower arm, chest and foot- and a heart rate monitor were used as sensors. A dataset with 8 subjects and 14 different activities was recorded to evaluate the performance of the system. The overall performance on the intensity estimation task, relying on the chest-worn accelerometer and the HR-monitor, was 94.37%. The overall performance on the activity recognition task, using all three accelerometer placements and the HR monitor, was 90.65%. This paper also gives an analysis of the importance of different accelerometer placements and the importance of a HR-monitor for both tasks. PMID- 22255615 TI - OLAM: A wearable, non-contact sensor for continuous heart-rate and activity monitoring. AB - A wearable, multi-modal sensor is presented that can non-invasively monitor a patient's activity level and heart function concurrently for more than a week. The 4 in(2) sensor incorporates both a non-contact heartrate sensor and a 5-axis inertial measurement unit (IMU), allowing simultaneous heart, respiration, and movement monitoring without requiring physical contact with the skin [1]. Hence, this Oregon State University Life and Activity Monitor (OLAM) provides the unique opportunity to combine motion data with heart-rate information, enabling assessment of actual physical activity beyond conventional movement sensors. OLAM also provides a unique platform for non-contact sensing, enabling the filtering of movement artifacts generated by the non-contact capacitive interface, using the IMU data as a movement noise channel. Intended to be used in clinical trials for weeks at a time with no physician intervention, the OLAM allows continuous non-invasive monitoring of patients, providing the opportunity for long-term observation into a patient's physical activity and subtle longitudinal changes. PMID- 22255616 TI - Upper limb joint angle tracking with inertial sensors. AB - Wearable inertial systems have recently been used to track human movement in and outside of the laboratory. Continuous monitoring of human movement can provide valuable information relevant to individual's level of physical activity and functional ability. Traditionally, orientation has been calculated by integrating the angular velocity from gyroscopes. However, a small drift in the measured velocity leads to large integration errors that grow with time. To compensate for that drift, complementary data from accelerometers are normally fused into the tracking systems using the Kalman or extended Kalman filter (EKF). In this study, we combine kinematic models designed for control of robotic arms with the unscented Kalman filter (UKF) to continuously estimate the angles of human shoulder and elbow using two wearable sensors. This methodology can easily be generalized to track other human joints. We validate the method with an optical motion tracking system and demonstrate correlation consistently greater than 0.9 between the two systems. PMID- 22255617 TI - Tetherless ergonomics workstation to assess nurses' physical workload in a clinical setting. AB - Nurses are at risk of physical injury when moving immobile patients. This paper describes the development and testing of a tetherless ergonomics workstation that is suitable for studying nurses' physical workload in a clinical setting. The workstation uses wearable sensors to record multiple channels of body orientation and muscle activity and wirelessly transmits them to a base station laptop computer for display, storage, and analysis. In preparation for use in a clinical setting, the workstation was tested in a laboratory equipped for multi-camera video motion analysis. The testing included a pilot study of the effect of bed height on student nurses' physical workload while they repositioned a volunteer posing as a bedridden patient toward the head of the bed. Each nurse subject chose a preferred bed height, and data were recorded, in randomized order, with the bed at this height, at 0.1 m below this height, and at 0.1 m above this height. The testing showed that the body orientation recordings made by the wearable sensors agreed closely with those obtained from the video motion analysis system. The pilot study showed the following trends: As the bed height was raised, the nurses' trunk flexion at both thoracic and lumbar sites and lumbar muscle effort decreased, whereas trapezius and deltoid muscle effort increased. These trends will be evaluated by further studies of practicing nurses in the clinical setting. PMID- 22255618 TI - Development of an in-shoe pressure-sensitive device for gait analysis. AB - In this work, we present the development of an in-shoe device to monitor plantar pressure distribution for gait analysis. The device consists in a matrix of 64 sensitive elements, integrated with in-shoe electronics and battery which provide an high-frequency data acquisition, wireless transmission and an average autonomy of 7 hours in continuous working mode. The device is presented along with its experimental characterization and a preliminary validation on a healthy subject. PMID- 22255619 TI - A computationally efficient QRS detection algorithm for wearable ECG sensors. AB - In this paper we present a novel Dual-Slope QRS detection algorithm with low computational complexity, suitable for wearable ECG devices. The Dual-Slope algorithm calculates the slopes on both sides of a peak in the ECG signal; And based on these slopes, three criterions are developed for simultaneously checking 1)Steepness 2)Shape and 3)Height of the signal, to locate the QRS complex. The algorithm, evaluated against MIT/BIH Arrhythmia Database, achieves a very high detection rate of 99.45%, a sensitivity of 99.82% and a positive prediction of 99.63%. PMID- 22255620 TI - Brain tumour classification using Gaussian decomposition and neural networks. AB - The development, implementation and use of computer-based medical decision support systems (MDSS) based on pattern recognition techniques holds the promise of substantially improving the quality of medical practice in diagnostic and prognostic tasks. In this study, the core of a decision support system for brain tumour classification from magnetic resonance spectroscopy (MRS) data is presented. It combines data pre-processing using Gaussian decomposition, dimensionality reduction using moving window with variance analysis, and classification using artificial neural networks (ANN). This combination of techniques is shown to yield high diagnostic classification accuracy in problems concerning diverse brain tumour pathologies, some of which have received little attention in the literature. PMID- 22255621 TI - Detecting freezing-of-gait during unscripted and unconstrained activity. AB - We present a dynamic neural network (DNN) solution for detecting instances of freezing-of-gait (FoG) in Parkinson's disease (PD) patients while they perform unconstrained and unscripted activities. The input features to the DNN are derived from the outputs of three triaxial accelerometer (ACC) sensors and one surface electromyographic (EMG) sensor worn by the PD patient. The ACC sensors are placed on the shin and thigh of one leg and on one of the forearms while the EMG sensor is placed on the shin. Our FoG solution is architecturally distinct from the DNN solutions we have previously designed for detecting dyskinesia or tremor. However, all our DNN solutions utilize the same set of input features from each EMG or ACC sensor worn by the patient. When tested on experimental data from PD patients performing unconstrained and unscripted activities, our FoG detector exhibited 83% sensitivity and 97% specificity on a per-second basis. PMID- 22255622 TI - A new neural network approach for short-term glucose prediction using continuous glucose monitoring time-series and meal information. AB - In the last decade, improvements in diabetes daily management have become possible thanks to the development of minimally-invasive portable sensors which allow continuous glucose monitoring (CGM) for several days. In particular, hypo and hyperglycemia can be promptly detected when glucose exceeds the normal range thresholds, and even avoided through the use of on-line glucose prediction algorithms. Several algorithms with prediction horizon (PH) of 15-30-45 min have been proposed in the literature, e.g. including AR/ARMA time-series modeling and neural networks. Most of them are fed by CGM signals only. The purpose of this work is to develop a new short-term glucose prediction algorithm based on a neural network that, in addition to past CGM readings, also exploits information on carbohydrates intakes quantitatively described through a physiological model. Results on simulated data quantitatively show that the new method outperforms other published algorithms. Qualitative preliminary results on a real diabetic subject confirm the potentialities of the new approach. PMID- 22255623 TI - Beat-to-beat cardiac output inference using heart sounds. AB - Cardiac output (CO) change is the primary compensatory mechanism that responds to oxygenation demand. Its continuous monitoring has great potential for the diagnosis and management of cardiovascular diseases, both in hospital as well as in ambulatory settings. However, CO measurements are currently limited to hospital settings only. In this paper, we present an extension of the model proposed by Finkelstein for beat-to-beat CO assessment. We use a nonlinear model consisting of a two-layer feed-forward artificial neural network. In addition to demographic (body surface area and age) and physiological parameters (HR), surrogates of contractility, afterload and mean arterial pressure based on systolic time intervals (STIs), estimated from echocardiography and heart sounds are used as inputs to our models. The results showed that the proposed models- with echocardiography as reference--produce better estimations of stroke volume/CO than the Finkelstein model (12.83 +/- 10.66 ml vs 7.23 +/- 6.6 ml), as well as higher correlation (0.46 vs 0.82). PMID- 22255624 TI - Reinforcement learning via kernel temporal difference. AB - This paper introduces a kernel adaptive filter implemented with stochastic gradient on temporal differences, kernel Temporal Difference (TD)(lambda), to estimate the state-action value function in reinforcement learning. The case lambda=0 will be studied in this paper. Experimental results show the method's applicability for learning motor state decoding during a center-out reaching task performed by a monkey. The results are compared to the implementation of a time delay neural network (TDNN) trained with backpropagation of the temporal difference error. From the experiments, it is observed that kernel TD(0) allows faster convergence and a better solution than the neural network. PMID- 22255625 TI - Block based neural network for hypoglycemia detection. AB - In this paper, evolvable block based neural network (BBNN) is presented for detection of hypoglycemia episodes. The structure of BBNN consists of a two dimensional (2D) array of fundamental blocks with four variable input-output nodes and weight connections. Depending on the structure settings, each block can have one of four different internal configurations. To provide early detection of hypoglycemia episodes, the physiological parameters such as heart rate (HR) and corrected QT interval (QTc) of electrocardiogram (ECG) signal are used as the inputs of BBNN. The overall structure and weights of BBNN are optimized by an evolutionary algorithm called hybrid particle swarm optimization with wavelet mutation (HPSOWM). The optimized structures and weights of BBNN are capable to compensate large variations of ECG patterns caused by individual and temporal difference since a fixed structure classifiers are easy to fail to trace ECG signals with large variations. The ECG data of 15 patients are organized into a training set, a testing set and a validation set, each of which has randomly selected 5 patients. The simulation results shows that the proposed algorithm, BBNN with HPSOWM can successfully detect the hypoglycemic episodes in T1DM in term of testing sensitivity (76.74%) and test specificity (50.91%). PMID- 22255626 TI - BioSignalML--a meta-model for biosignals. AB - The multitude of biosignal file formats used in research has hampered the easy exchange of biosignals and their use with physiological modelling software. We describe an abstract data model that accommodates the diversity of formats, along with a software implementation which links biosignal data into the Semantic Web, using existing data formats. Initial application of our work is to sleep study research. PMID- 22255627 TI - A directionally-selective neuromorphic circuit based on reciprocal synapses in Starburst Amacrine Cells. AB - Starburst Amacrine Cells (SACs) play a major role in the detection of directional motion in the biological retina. The starburst amacrine cell has intrinsic electrical mechanisms for producing directional selectivity (DS). GABA transmitter-receptor interactions between two overlapping SACs make DS more robust. We present a compartmentalized CMOS neuromorphic circuit that models a portion of two biological starburst amacrine cells in the retina and includes a simplified model of reciprocal interaction between the dendritic branches of SACs. We demonstrate that a neuromorphic circuit incorporating the reciprocal synapses enhances the responses in the neuromorphic dendritic tip and generates robust directional selectivity. PMID- 22255628 TI - Subspace detection of the impulse response function from intra-partum cardiotocography. AB - Recording of maternal uterine pressure (UP) and fetal heart rate (FHR) during labour and delivery is a procedure referred to as cardiotocography (CTG). We model this as an input-output system to estimate its dynamics in terms of an impulse response function (IRF). CTG data is very noisy and missing data are common. In this paper, we identify the models using subspace methods, which incorporate noise-suppression and permit the use of non-contiguous data. Using contiguous data, the subspace method performed better than linear regression; more of the 57 CTG pathological records in our database were modelled (30 vs. 26). Allowing non-contiguous data, even more pathological records were modelled with this approach (49). Furthermore, the models were discriminating; compared to linear regression, the IRF gain showed statistically significant differences more often between normal and pathological records (in 15/18 vs. 10/18 epochs) over the final three hours of labour. PMID- 22255630 TI - A dynamical model for generating synthetic Phonocardiogram signals. AB - In this paper we introduce a dynamical model for Phonocardiogram (PCG) signal which is capable of generating realistic synthetic PCG signals. This model is based on PCG morphology and consists of three ordinary differential equations and can represent various morphologies of normal PCG signals. Beat-to-beat variation in PCG morphology is significant so model parameters vary from beat to beat. This model is inspired of Electrocardiogram (ECG) dynamical model proposed by McSharry et al. and can be employed to assess biomedical signal processing techniques. PMID- 22255629 TI - A compressive sensing approach for glioma margin delineation using mass spectrometry. AB - Surgery, and specifically, tumor resection, is the primary treatment for most patients suffering from brain tumors. Medical imaging techniques, and in particular, magnetic resonance imaging are currently used in diagnosis as well as image-guided surgery procedures. However, studies show that computed tomography and magnetic resonance imaging fail to accurately identify the full extent of malignant brain tumors and their microscopic infiltration. Mass spectrometry is a well-known analytical technique used to identify molecules in a given sample based on their mass. In a recent study, it is proposed to use mass spectrometry as an intraoperative tool for discriminating tumor and non-tumor tissue. Integration of mass spectrometry with the resection module allows for tumor resection and immediate molecular analysis. In this paper, we propose a framework for tumor margin delineation using compressive sensing. Specifically, we show that the spatial distribution of tumor cell concentration can be efficiently reconstructed and updated using mass spectrometry information from the resected tissue. In addition, our proposed framework is model-free, and hence, requires no prior information of spatial distribution of the tumor cell concentration. PMID- 22255631 TI - Analysis of the respiratory pattern variability of patients in weaning process using autoregressive modeling techniques. AB - One of the most challenging problems in intensive care is the process of discontinuing mechanical ventilation, called weaning process. An unnecessary delay in the discontinuation process and an early weaning trial are undesirable. This paper proposes to analysis the respiratory pattern variability of these patients using autoregressive modeling techniques: autoregressive models (AR), autoregressive moving average models (ARMA), and autoregressive models with exogenous input (ARX). A total of 153 patients on weaning trials from mechanical ventilation were analyzed: 94 patients with successful weaning (group S); 38 patients that failed to maintain spontaneous breathing (group F), and 21 patients who had successful weaning trials, but required reintubation in less than 48 h (group R). The respiratory pattern was characterized by their time series. The results show that significant differences were obtained with parameters as model order and first coefficient of AR model, and final prediction error by ARMA model. An accuracy of 86% (84% sensitivity and 86% specificity) has been obtained when using order model and first coefficient of AR model, and mean of breathing duration. PMID- 22255632 TI - Fuzzy approach toward reducing false positives in the detection of small multiple sclerosis lesions in magnetic resonance images. AB - The large number of false positives that result when automatic algorithms are considered for segmenting small multiple sclerosis lesions in magnetic resonance imaging hampers the posterior evaluation of lesion load. To address this problem we propose a fuzzy system which can improve the differentiation between true and false positive detections in proton density- and T2-weighted images. On the basis of an earlier work, which was focused on the detection of hyperintense regions in MR brain images, the system here presented introduces fuzzy restrictions derived from the regional analysis of the main features in such regions. Results show a reduction to a 3.6% in the number of false detections while preserving most of the true detections obtained using previous algorithm. PMID- 22255633 TI - Segmentation of scarred and non-scarred myocardium in LG enhanced CMR images using intensity-based textural analysis. AB - The Late Gadolinium (LG) enhancement in Cardiac Magnetic Resonance (CMR) imaging is used to increase the intensity of scarred area in myocardium for thorough examination. Automatic segmentation of scar is important because scar size is largely responsible in changing the size, shape and functioning of left ventricle and it is a preliminary step required in exploring the information present in scar. We have proposed a new technique to segment scar (infarct region) from non scarred myocardium using intensity-based texture analysis. Our new technique uses dictionary-based texture features and dc-values to segment scarred and non scarred myocardium using Maximum Likelihood Estimator (MLE) based Bayes classification. Texture analysis aided with intensity values gives better segmentation of scar from myocardium with high sensitivity and specificity values in comparison to manual segmentation by expert cardiologists. PMID- 22255634 TI - Bladder segmentation in MRI images using active region growing model. AB - Prostate segmentation in MRI may be difficult at the interface with the bladder where the contrast is poor. Coupled-models that segment simultaneously both organs with non-overlapping constraints offer a good solution. As a pre segmentation of the structures of interest is required, we propose in this paper a fast deformable model to segment the bladder. The combination of inflation and internal forces, locally adapted according to the gray levels, allow to deform the mesh toward the boundaries while overcoming the leakage issues that can occur at weak edges. The algorithm, evaluated on 33 MRI volumes from 5 different devices, has shown good performance providing a smooth and accurate surface. PMID- 22255635 TI - Atlas-based segmentation for globus pallidus internus targeting on low-resolution MRI. AB - In this paper we report a method to automatically segment the internal part of globus pallidus (GPi) on the pre-operative low-resolution magnetic resonance images (MRIs) of patients affected by Parkinson's disease. Herein we used an ultra-high resolution human brain dataset as electronic atlas of reference on which we segmented the GPi. First, we registered the ultra-high resolution dataset on the low-resolution dataset using a landmarks-based rigid registration. Then an affine and a non-rigid surface-based registration guided by the structures that surround the target was applied in order to propagate the labels of the GPi on the low-resolution un-segmented dataset and to accurately outline the target. The mapping of the atlas on the low-resolution MRI provided a highly accurate anatomical detail that can be useful for localizing the target. PMID- 22255636 TI - Robust local estimation in anisotropic diffusion process. AB - In this work we propose to use an anisotropic diffusion process using robust statistics. We show that smoothing, while preserving edges, helps the segmentation of upper limb bones (shoulder) in MRI data bases. The anisotropic diffusion equation is mainly controlled using an automatic edge stopping function based on Tukey's biweight function, which depends on the values of gradients pixels. These values are divided into two classes: high gradients for pixels belonging to edges or noisy pixels, low ones otherwise. This process also depends on a threshold gradient parameter which splits both former classes. So a robust local estimation method is proposed to better eliminate the noise in the image while preserving edges. Firstly, the efficiency of the model in the noise reduction is quantified using an entropy criterion on synthetic data with different noise levels to evaluate the smoothing of the regions. Secondly, we use the Pratt's Figure of Merit (FOM) method to evaluate edges preservation. Eventually, a qualitative edge evaluation is given on a MRI volume of the shoulder joint. PMID- 22255637 TI - Biomedical image segmentation via constrained graph cuts and pre-segmentation. AB - In this paper we present a high-fidelity method for 2D and 3D image boundary segmentation. The algorithm is a novel combination of graph-cuts and initial image segmentation. The pre-segmentation using anisotropic vector diffusion and the fast marching method is employed so that the size of the graph being considered is significantly reduced. To further improve the segmentation accuracy, some user guidance is taken into account in finding the minimal graph cut. To this end, a user-friendly graphical user interface (GUI) is developed not only for visualization purposes but for user input and editing as well. The approaches and tools developed are validated on a number of 2D/3D biomedical imaging data, showing the high efficiency and effectiveness of our method. PMID- 22255638 TI - Reference-guided sparsifying transform design for compressive sensing MRI. AB - Compressive sensing (CS) MRI aims to accurately reconstruct images from undersampled k-space data. Most CS methods employ analytical sparsifying transforms such as total-variation and wavelets to model the unknown image and constrain the solution space during reconstruction. Recently, nonparametric dictionary-based methods for CS-MRI reconstruction have shown significant improvements over the classical methods. These existing techniques focus on learning the representation basis for the unknown image for a synthesis-based reconstruction. In this paper, we present a new framework for analysis-based reconstruction, where the sparsifying transform is learnt from a reference image to capture the anatomical structure of unknown image, and is used to guide the reconstruction process. We demonstrate with experimental data the high performance of the proposed approach over traditional methods. PMID- 22255640 TI - Interactive 3D reconstruction of the spine from radiographs using a statistical shape model and second-order cone programming. AB - Three-dimensional models of the spine are commonly used to diagnose, to treat, and to study spinal deformities. Creating these models is however time-consuming and, therefore, expensive. We propose in this paper a reconstruction method that finds the most likely 3D reconstruction given a maximal error bound on a limited set of landmark locations supplied by the user. This problem can be solved using second-order cone programming, leading to a globally convergent method that is considerably faster than currently available methods. A user can, with our current implementation, interactively modify the landmark locations and receive instantaneous feedback on the effect of those changes on the 3D reconstruction instead of blindly selecting landmarks. The proposed method was validated on a set of 53 patients who had adolescent idiopathic scoliosis using real and synthetic tests. Test results showed that the proposed method is considerably faster than currents methods (about forty times faster), is extremely flexible, and offers comparable accuracy. PMID- 22255639 TI - Motion-robust MRI through real-time motion tracking and retrospective super resolution volume reconstruction. AB - Magnetic Resonance Imaging (MRI) is highly sensitive to motion; hence current practice is based on the prevention of motion during scan. In newborns, young children, and patients with limited cooperation, this commonly requires full sedation or general anesthesia, which is time consuming, costly, and is associated with significant risks. Despite progress in prospective motion correction in MRI, the use of motion compensation techniques is limited by the type and amount of motion that can be compensated for, the dependency on the scanner platform, the need for pulse sequence modifications, and/or difficult setup. In this paper we introduce a novel platform-independent motion-robust MRI technique based on prospective real-time motion tracking through a miniature magnetic field sensor and retrospective super-resolution volume reconstruction. The technique is based on fast 2D scans that maintain high-quality of slices in the presence of motion but are degraded in 3D due to inter-slice motion artifacts. The sensor, conveniently attached to the subject forehead, provides real-time estimation of the motion, which in turn gives the relative location of the slice acquisitions. These location parameters are used to compensate the inter-slice motion to reconstruct an isotropic high-resolution volumetric image from slices in a super-resolution reconstruction framework. The quantitative results obtained for phantom and volunteer subject experiments in this study show the efficacy of the developed technique, which is particularly useful for motion robust high-resolution T2-weighted imaging of newborns and pediatric subjects. PMID- 22255641 TI - Microwave imaging for breast cancer detection: advances in three--dimensional image reconstruction. AB - Microwave imaging is based on the electrical property (permittivity and conductivity) differences in materials. Microwave imaging for biomedical applications is particularly interesting, mainly due to the fact that available range of dielectric properties for different tissues can provide important functional information about their health. Under the assumption that a 3D scattering problem can be reasonably represented as a simplified 2D model, one can take advantage of the simplicity and lower computational cost of 2D models to characterize such 3D phenomenon. Nonetheless, by eliminating excessive model simplifications, 3D microwave imaging provides potentially more valuable information over 2D techniques, and as a result, more accurate dielectric property maps may be obtained. In this paper, we present some advances we have made in three-dimensional image reconstruction, and show the results from a 3D breast phantom experiment using our clinical microwave imaging system at Dartmouth Hitchcock Medical Center (DHMC), NH. PMID- 22255642 TI - Compressed sensing MRI using Singular Value Decomposition based sparsity basis. AB - Magnetic Resonance Imaging (MRI) is an essential medical imaging tool limited by the data acquisition speed. Compressed Sensing is a newly proposed technique applied in MRI for fast imaging with the prior knowledge that the signals are sparse in a special mathematic basis (called the 'sparsity' basis). During the exploitation of the sparsity in MR images, there are two kinds of 'sparsifying' transforms: predefined transforms and data adaptive transforms. Conventionally, predefined transforms, such as the discrete cosine transform and discrete wavelet transform, have been adopted in compressed sensing MRI. Because of their independence from the object images, the conventional transforms can only provide ideal sparse representations for limited types of MR images. To overcome this limitation, this work proposed Singular Value Decomposition as a data-adaptive sparsity basis for compressed sensing MRI that can potentially sparsify a broader range of MRI images. The proposed method was evaluated by a comparison with other commonly used predefined sparsifying transformations. The comparison shows that the proposed method could give a sparser representation for a broader range of MR images and could improve the image quality, thus providing a simple and effective alternative solution for the application of compressed sensing in MRI. PMID- 22255643 TI - Microwave dielectric contrast imaging in a magnetic resonant environment and the effect of using magnetic resonant spatial information in image reconstruction. AB - Microwave Tomography (MT) can determine the permittivity and conductivity of a volume of interest; it has been shown that a contrast exists between these electrical properties in healthy and malignant tissues, and MT can be used to discern the dielectric contrast image of these tissues by recovering their electrical property values. Simulation and phantom experiments of objects with known spatial locations have shown that using boundary information derived from internal structures in the imaged volume greatly increases the accuracy of the recovered property values. In practice this spatial information, which will be used for reconstructing the tissue's electrical property images, must be determined with high enough resolution to segment boundary regions and internal structures of interest. This experiment investigates the use of Magnetic Resonant Imaging (MRI) in obtaining the desired spatial information used in mesh generation for image reconstruction and provides microwave image results comparing electrical properties recovered with and without this prior spatial information. PMID- 22255644 TI - Depth-resolved mapping of tissue mechanical properties using a novel optical approach. AB - Progression of most diseases, such as atherosclerosis, cancer, neurodegenerative disease and osteoarthritis is accompanied with drastic changes in biomechanics of tissue. Hence, non-contact and non-invasive technologies for 3-dimensional mapping of tissue biomechanics are invaluable for diagnostic purposes. Laser speckle Microrheology (LSM) is developed in our lab to enable high resolution mechanical evaluation of tissue. To this end, the tissue sample is illuminated by a coherent and focused laser beam and the back-scattered laser speckle pattern is spatio-temporally processed to extract a color-map of tau, which is the decay time constant of intensity decorrelation at each pixel in the image plane. Time constant, tau, is proven to be closely correlated with tissue mechanical properties. In this paper we validate the theoretical basis for LSM technology and investigate the potential for acquiring depth-resolved information from a light-scattering point of view. The patch analysis approach is introduced and the inter-relation between tau, number of scattering events, and penetration depth is explored for each patch. Axial variation of tau is characterized for two sample arterial regions and in-depth changes of mechanical properties are characterized. Finally, the required corrective measures are discussed. PMID- 22255645 TI - Measurement of bulk mechanical properties of tissue using laser speckle rheology. AB - In virtually all tissues, disease progression is accompanied by changes in the mechanical properties. Laser speckle rheology (LSR) is a new technique we have developed to measure the mechanical properties of tissue. By illuminating the sample with coherent laser light and calculating the speckle intensity modulations from reflected laser speckle patterns, LSR calculates tau, the decay time constant of intensity decorrelation which is closely associated with tissue mechanical properties. In this paper we validate the use of LSR technology in measuring mechanical properties of tissue. LSR measurements of tau are performed on a variety of phantom and tissue samples and compared with the complex shear modulus G*, measured using a rheometer. In all cases, strong correlation is observed between tau and G* (r=0.95, p < 0.002). These results demonstrate the efficacy of LSR as a non-invasive and non-contact technology for mechanical evaluation of biological samples. PMID- 22255646 TI - Effect of force tightening on cable tension and displacement in greater trochanter reattachment. AB - The purpose of this study was to evaluate cable tension during installation, and during loading similar to walking in a cable grip type greater trochanter (GT), reattachment system. A 4th generation Sawbones composite femur with osteotomised GT was reattached with four Cable-Ready(r) systems (Zimmer, Warsaw, IN). Cables were tightened at 3 different target installation forces (178, 356 and 534 N) and retightened once as recommended by the manufacturer. Cables tension was continuously monitored using in-situ load cells. To simulate walking, a custom frame was used to apply quasi static load on the head of a femoral stem implant (2340 N) and abductor pull (667 N) on the GT. GT displacement (gap and sliding) relative to the femur was measured using a 3D camera system. During installation, a drop in cable tension was observed when tightening subsequent cables: an average 40+12.2% and 11 +/- 5.9% tension loss was measured in the first and second cable. Therefore, retightening the cables, as recommended by the manufacturer, is important. During simulated walking, the second cable additionally lost up to 12.2+3.6% of tension. No difference was observed between the GT-femur gaps measured with cables tightened at different installation forces (p=0.32). The GT sliding however was significantly greater (0.9 +/- 0.3 mm) when target installation force was set to only 178 N compared to 356 N (0.2 +/- 0.1 mm); p<0.001. There were no significant changes when initial tightening force was increased to 534 N (0.3 +/- 0.1 mm); p=0.11. In conclusion, the cable tightening force should be as close as possible to that recommended by the manufacturer, because reducing it compromises the stability of the GT fragment, whereas increasing it does not improve this stability, but could lead to cable breakage. PMID- 22255647 TI - Modeling the internal pressure dependence of thermal conductivity and in vitro temperature measurement for lung RFA. AB - Radio frequency ablation (RFA) for lung cancer has increasingly been used over the past few years because RFA is minimally invasive treatment for patients. As a feature of RFA for the lung cancer, lung has the air having low thermal conductivity. Therefore, RFA for lung has the advantage that only the tumor is coagulated because heating area is confined to the immediate vicinity of the heating point. However, it is difficult for operators to control the precise formation of coagulation zones due to inadequate imaging modalities. We propose a method using numerical simulation to analyze the temperature distribution of the organ in order to overcome the current deficiencies. Creating an accurate thermophysical model was a challenging problem because of the complexities of the thermophysical properties of the organ. In this work, as the processes in the development of ablation simulator, measurement of the pressure dependence of lung thermal conductivity and in vitro estimation of the temperature distribution during RFA is presented. PMID- 22255648 TI - Force relaxation and sprinback of novel elastic orthopedic cables. AB - Cerclage cables have proven to be very useful in the orthopedic field for bones stabilization and plate fixation but the initial enthusiasm for metallic cables has declined with their high complication rates. Metal materials provide limited elastic deformation compromising their ability to maintain compression. This study compares the mechanical properties of new elastic cables with cobalt-chrome and stainless-steel cables. METHODS: Stainless-steel, cobalt-chrome, nylon and nickel-titanium cables were first loaded up to 356 N, then elongation was maintained for 12 hours, next unloaded and finally reloaded to failure. Initial elongation (%), Relative force relaxation (% loss of initial load after a 12h), elastic springback (%) and force to failure (N) were extracted from force elongation curves. FINDINGS: Initial elongation was the highest for nylon cables (9%), followed by the nickel-titanium (4%) and both metallic cables (0.3%). During 12 hours, no relaxation was observed for the nickel-titanium and the cobalt-chrome cables, whereas 28 and 45% of the tension was lost respectively for the stainless-steel and the nylon cables. The elastic springback of the nickel titanium and nylon cables (4.4 and 4.7% respectively) was 20 times higher than that of the stainless-steel and cobalt-chrome cables (0.12 and 0.16% respectively). The force to failure of the stainless steel and cobalt-chrome cables was twice that of the nickel-titanium cables. INTERPRETATION: Multi braided stainless-steel and cobalt-chrome cables have a high-stiffness with limited ability to tolerate displacement, leading to early cable loosening. Novel low-stiffness cables made of nylon or nickel-titanium offer significant elastic springback improving binding stability. PMID- 22255649 TI - Semi-autonomous wheelchair developed using a unique camera system configuration biologically inspired by equine vision. AB - This paper is concerned with the design and development of a semi-autonomous wheelchair system using cameras in a system configuration modeled on the vision system of a horse. This new camera configuration utilizes stereoscopic vision for 3-Dimensional (3D) depth perception and mapping ahead of the wheelchair, combined with a spherical camera system for 360-degrees of monocular vision. This unique combination allows for static components of an unknown environment to be mapped and any surrounding dynamic obstacles to be detected, during real-time autonomous navigation, minimizing blind-spots and preventing accidental collisions with people or obstacles. This novel vision system combined with shared control strategies provides intelligent assistive guidance during wheelchair navigation and can accompany any hands-free wheelchair control technology. Leading up to experimental trials with patients at the Royal Rehabilitation Centre (RRC) in Ryde, results have displayed the effectiveness of this system to assist the user in navigating safely within the RRC whilst avoiding potential collisions. PMID- 22255650 TI - Preliminary assessment of Tongue Drive System in medium term usage for computer access and wheelchair control. AB - Tongue Drive System (TDS) is a wireless, wearable assistive technology that enables individuals with severe motor impairments access computers, drive wheelchairs, and control their environments using tongue motion. In this paper, we have evaluated the TDS performance as a computer input device using ISO9241-9 standard tasks for pointing and selecting, based on the well known Fitts' Law, and as a powered wheelchair controller through an obstacle course navigation task. Nine able-bodied subjects who already had tongue piercing participated in this trial over 5 sessions during 5 weeks, allowing us to study the TDS learning process and its current limiting factors. Subjects worn tongue rings made of titanium in the form of a barbell with a small rare earth magnetic tracer hermetically sealed inside the upper ball. Comparing the results between 1(st) and 5(th) sessions showed that subjects' performance improved in all the measures through 5 sessions, demonstrating the effects of learning. PMID- 22255651 TI - A novel selective stimulus presentation for P300 speller. AB - The P300 speller is one of the brain-computer interfaces, allowing users to spell letters just by thoughts. Due to the low signal-to-noise ratio of the P300, however, stimuli are repeatedly presented so that EEG signals can be averaged, which improves the accuracy but degrades the speed. The authors have proposed to discontinue the stimulus presentation adaptively to the P300 response and have shown its superiority in the performance over the standard way that presents a prefixed number of stimuli. In addition to this adaptive stimulus termination, this paper proposes to select stimuli to be presented to avoid presenting redundant stimuli. Both off-line and on-line experiments show that the proposed method is more effective than our conventional method. PMID- 22255652 TI - Fusion with language models improves spelling accuracy for ERP-based brain computer interface spellers. AB - Event related potentials (ERP) corresponding to a stimulus in electroencephalography (EEG) can be used to detect the intent of a person for brain computer interfaces (BCI). This paradigm is widely utilized to build letter by-letter text input systems using BCI. Nevertheless using a BCI-typewriter depending only on EEG responses will not be sufficiently accurate for single trial operation in general, and existing systems utilize many-trial schemes to achieve accuracy at the cost of speed. Hence incorporation of a language model based prior or additional evidence is vital to improve accuracy and speed. In this paper, we study the effects of Bayesian fusion of an n-gram language model with a regularized discriminant analysis ERP detector for EEG-based BCIs. The letter classification accuracies are rigorously evaluated for varying language model orders as well as number of ERP-inducing trials. The results demonstrate that the language models contribute significantly to letter classification accuracy. Specifically, we find that a BCI-speller supported by a 4-gram language model may achieve the same performance using 3-trial ERP classification for the initial letters of the words and using single trial ERP classification for the subsequent ones. Overall, fusion of evidence from EEG and language models yields a significant opportunity to increase the word rate of a BCI based typing system. PMID- 22255653 TI - Stability of MEG for real-time neurofeedback. AB - Movement-related field potentials can be extracted and processed in real-time with magnetoencephalography (MEG) and used for brain machine interfacing (BMI). However, due to its immense sensitivity to magnetic fields, MEG is prone to a low signal to noise ratio. It is therefore important to collect enough initial data to appropriately characterize motor-related activity and to ensure that decoders can be built to adequately translate brain activity into BMI-device commands. This is of particular importance for therapeutic BMI applications where less time spent collecting initial open-loop data means more time for performing neurofeedback training which could potentially promote cortical plasticity and rehabilitation. This study evaluated the amount of hand-grasp movement and rest data needed to characterize sensorimotor modulation depth and build classifier functions to decode brain states in real-time. It was determined that with only five minutes of initial open-loop MEG data, decoders can be built to classify brain activity as grasp or rest in real-time with an accuracy of 84 +/- 6%. PMID- 22255654 TI - Classification of hand posture from electrocorticographic signals recorded during varying force conditions. AB - In the presented work, standard and high-density electrocorticographic (ECoG) electrodes were used to record cortical field potentials in three human subjects during a hand posture task requiring the application of specific levels of force during grasping. We show two-class classification accuracies of up to 80% are obtained when classifying between two-finger pinch and whole-hand grasp hand postures despite differences in applied force levels across trials. Furthermore, we show that a four-class classification accuracy of 50% is achieved when predicting both hand posture and force level during a two-force, two-hand-posture grasping task, with hand posture most reliably predicted during high-force trials. These results suggest that the application of force plays a significant role in ECoG signal modulation observed during motor tasks, emphasizing the potential for electrocorticography to serve as a source of control signals for dexterous neuroprosthetic devices. PMID- 22255655 TI - Noninvasive brain-computer interface driven hand orthosis. AB - Neurological conditions, such as stroke, can leave the affected individual with hand motor impairment despite intensive treatments. Novel technologies, such as brain-computer interface (BCI), may be able to restore or augment impaired motor behaviors by engaging relevant cortical areas. Here, we developed and tested an electroencephalogram (EEG) based BCI system for control of hand orthosis. An able bodied subject performed contralateral hand grasping to achieve continuous online control of the hand orthosis, suggesting that the integration of a noninvasive BCI with a hand orthosis is feasible. The adoption of this technology to stroke survivors may provide a novel neurorehabilitation therapy for hand motor impairment in this population. PMID- 22255656 TI - Nerve lesioning with direct current. AB - Spastic hypertonus (muscle over-activity due to exaggerated stretch reflexes) often develops in stroke and spinal cord injury (SCI) survivors and individuals who suffer from multiple sclerosis. In previous published experiments we have shown that Direct Current (DC), when used to lesion nerves, can attenuate muscle force in a gradual manner, and this attenuation can last for several months. In this paper we present initial experimental results that profile the current required to cause controlled nerve ablation. PMID- 22255657 TI - Training to improve volitional muscle activity in clinically paralyzed muscles for neuroprosthesis control. AB - Neuroprostheses are devices that use electrical stimulation to activate paralyzed muscles in a coordinated manner to restore functional movements. These systems utilize a voluntarily-generated command signal for control of function. Current command signals include electromyographic (EMG) activity from muscles above the injury level that remain under volitional control. In individuals with cervical level spinal cord injury (SCI), these signal sources are limited in number. Our recent research suggests that volitional muscle activity from below the injury level in individuals with motor complete spinal cord injury may be a viable source of command information. The signals from these muscles are small, and therefore the goal of this study is to determine if training using visual feedback can improve the quality of these muscle signals. Results to date indicate that training with visual feedback can increase both the magnitude and consistency of EMG signals in clinically paralyzed muscles. PMID- 22255659 TI - Continuous decoding of intended movements with a hybrid kinetic and kinematic brain machine interface. AB - Although most brain-machine interface (BMI) studies have focused on decoding kinematic parameters of motion, it is known that motor cortical activity also correlates with kinetic signals, including hand force and joint torque. In this experiment, a monkey used a cortically-controlled BMI to move a visual cursor and hit a sequence of randomly placed targets. By varying the contributions of separate kinetic and kinematic decoders to the movement of a virtual arm, we evaluated the hypothesis that a BMI incorporating both signals (Hybrid BMI) would outperform a BMI decoding kinematic information alone (Position BMI). We show that the trajectories generated by the Hybrid BMI during real-time decoding were straighter and smoother than those of the Position BMI. These results may have important implications for BMI applications that require controlling devices with inherent, physical dynamics or applying forces to the environment. PMID- 22255658 TI - Restoring stepping after spinal cord injury using intraspinal microstimulation and novel control strategies. AB - The overall objective of this project is to develop a feedback-driven intraspinal microstimulation (ISMS) system. We hypothesize that ISMS will enhance the functionality of stepping by reducing muscle fatigue and producing synergistic movements by activating neural networks in the spinal cord. In the present pilot study, the controller was tested with ISMS and external sensors (force plates, gyroscopes, and accelerometers). Cats were partially supported in a sling and bi laterally stepped overground on a 4-m instrumented walkway. The walkway had variable friction. Limb angle was controlled to within 10 degrees even in the presence of variable friction. Peak ground reaction forces in each limb were approximately 12% of body weight (12.5% was full load bearing in this experimental setup); rarely, the total supportive force briefly decreased to as low as 4.1%. Magnetic resonance images were acquired of the excised spinal cord and the implanted array. The majority of electrodes (75%) were implanted successfully into their target regions. This represents the first successful application of ISMS for overground walking. PMID- 22255661 TI - Optimizing nerve cuff stimulation of targeted regions through use of genetic algorithms. AB - A nerve cuff electrode is a viable technology for use in a neuroprostheses system to restore loss of function due to neurological injury. The Flat Interface Nerve Electrode (FINE) is a nerve cuff that gently reshapes the nerve to bring the axons closer to the stimulating contacts. The overall goal of this work is to optimize nerve cuff stimulation in upper extremity nerves. Recently, highly efficient and accurate linear models of neuronal activation have been developed in our lab. Using the fast calculations from the newly developed linear activation method, nerve stimulation parameters such as current pulse width and pulse amplitude at many electrode contacts can be explored by employing optimization algorithms. Finite element nerve models with high density electrodes were constructed based on upper extremity cadaveric nerve cross sections. An objective function was developed to target specific groups of nerve fascicles and minimize overlap amongst these groups. By changing the objective function and using a genetic search algorithm, stimulation parameters can be optimized for many contacts. PMID- 22255660 TI - Robot-driven spinal epidural stimulation compared with conventional stimulation in adult spinalized rats. AB - Epidural stimulation to trigger locomotion is a promising treatment after spinal cord injury (SCI). Continuous stimulation during locomotion is the conventional method. To improve recovery, we tested an innovative robot-driven epidural stimulation method, combined with a trunk-based neurorobotic system. The system was tested in rat, and the results were compared with the results of the neurorobotic therapy combined with the conventional epidural stimulation method. The rats had better recovery after treatment with the robot-driven epidural stimulation than conventional stimulation in our neurorobotic rehabilitation system. PMID- 22255662 TI - Wireless inertial measurement unit with GPS (WIMU-GPS)--wearable monitoring platform for ecological assessment of lifespace and mobility in aging and disease. AB - This paper proposes an innovative ambulatory mobility and activity monitoring approach based on a wearable datalogging platform that combines inertial sensing with GPS tracking to assess the lifespace and mobility profile of individuals in their home and community environments. The components, I/O architecture, sensors and functions of the WIMU-GPS are presented. Outcome variables that can be measured with it are described and illustrated. Data on the power usage, operating autonomy of the WIMU-GPS and the GPS tracking performances and time to first fix of the unit are presented. The study of lifespace and mobility with the WIMU-GPS can potentially provide unique insights into intrapersonal and environmental factors contributing to mobility restriction. On-going studies are underway to establish the validity and reliability of the WIMU-GPS in characterizing the lifespace and mobility profile of older adults. PMID- 22255663 TI - Foot worn inertial sensors for gait assessment and rehabilitation based on motorized shoes. AB - Fall prevention in elderly subjects is often based on training and rehabilitation programs that include mostly traditional balance and strength exercises. By applying such conventional interventions to improve gait performance and decrease fall risk, some important factors are neglected such as the dynamics of the gait and the motor learning processes. The EU project "Self Mobility Improvement in the eLderly by counteractING falls" (SMILING project) aimed to improve age related gait and balance performance by using unpredicted external perturbations during walking through motorized shoes that change insole inclination at each stance. This paper describes the shoe-worn inertial module and the gait analysis method needed to control in real-time the shoe insole inclination during training, as well as gait spatio-temporal parameters obtained during long distance walking before and after the 8-week training program that assessed the efficacy of training with these motorized shoes. PMID- 22255664 TI - Carbon nanotubes (CNTs) based strain sensors for a wearable monitoring and biofeedback system for pressure ulcer prevention and rehabilitation. AB - This paper presents an overview of the functioning principles of CNTs and their electrical and mechanical properties when used as strain sensors and describes a system embodiment for a wearable monitoring and biofeedback platform for use in pressure ulcer prevention and rehabilitation. Two type of CNTs films (multi layered CNTs film vs purified film) were characterized electrically and mechanically for potential use as source material. The loosely woven CNTs film (multi-layered) showed substantial less sensitivity than the purified CNTs film but had an almost linear response to stress and better mechanical properties. CNTs have the potential to achieve a much higher sensitivity to strain than other piezoresistors based on regular of conductive particles such as commercially available resistive inks and could become an innovative source material for wearable strain sensors. We are currently continuing the characterization of CNTs based strain sensors and exploring their use in a design for 3-axis strain sensors. PMID- 22255665 TI - Wearable systems with minimal set-up for monitoring and training of balance and mobility. AB - With the objective to release solutions which can be easily manageable by their final users, including older users, we worked to design methods and devices which rely on a minimal set-up for monitoring and rehabilitation of balance and mobility. A single inertial sensing unit, typically worn on the trunk, was hence engineered to accomplish for activity monitoring and event detection (including fall detection), tremor rejection, instrumented clinical tests (e.g. stabilometry, Timed-Up and Go), and sensory biofeedback (audio, visual or tactile). The sensing unit is wirelessly connected with a processing unit, which can in turn act as a gateway to remote applications or caregivers. Promising results were obtained, which may pave the way to novel intensive and pervasive neurorehabilitation strategies. PMID- 22255666 TI - Capturing whole-body mobility of patients with Parkinson disease using inertial motion sensors: expected challenges and rewards. AB - While many studies have reported on the use of kinematic analysis on well controlled, in-laboratory mobility tasks, few studies have examined the challenges of recording dynamic mobility in home environments. This preliminary study evaluated whole body mobility in eleven patients with Parkinson disease (H&Y 2-4). Patients were recorded in their home environment during scripted and non-scripted mobility tasks while wearing a full-body kinematic recording system using 11 inertial motion sensors (IMU). Data were analyzed with principal component analysis (PCA) in order to identify kinematic variables which best represent mobility tasks. Results indicate that there was a large degree of variability within subjects for each task, across tasks for individual subjects, and between scripted and non-scripted tasks. This study underscores the potential benefit of whole body multi-sensor kinematic recordings in understanding the variability in task performance across patients during daily activity which may have a significant impact on rehabilitation assessment and intervention. PMID- 22255667 TI - Estimating Fugl-Meyer clinical scores in stroke survivors using wearable sensors. AB - Clinical assessment scales to evaluate motor abilities in stroke survivors could be used to individualize rehabilitation interventions thus maximizing motor gains. Unfortunately, these scales are not widely utilized in clinical practice because their administration is excessively time-consuming. Wearable sensors could be relied upon to address this issue. Sensor data could be unobtrusively gathered during the performance of motor tasks. Features extracted from the sensor data could provide the input to models designed to estimate the severity of motor impairments and functional limitations. In previous work, we showed that wearable sensor data collected during the performance of items of the Wolf Motor Function Test (a clinical scale designed to assess functional capability) can be used to estimate scores derived using the Functional Ability Scale, a clinical scale focused on quality of movement. The purpose of the study herein presented was to investigate whether the same dataset could be used to estimate clinical scores derived using the Fugl-Meyer Assessment scale (a clinical scale designed to assess motor impairments). Our results showed that Fugl-Meyer Assessment Test scores can be estimated by feeding a Random Forest with features derived from wearable sensor data recorded during the performance of as few as a single item of the Wolf Motor Function Test. Estimates achieved using the proposed method were marked by a root mean squared error as low as 4.7 points of the Fugl-Meyer Assessment Test scale. PMID- 22255668 TI - Sensitivity of a frequency-selective electrode based on spatial spectral properties of the extracellular AP of myelinated nerve fibers. AB - In the context of functional electrical stimulation, neural recording is one of the main issues. For instance, the control of the limbs in people with motor deficiencies needs information about the muscle lengths and speeds that can be extracted from electroneurograms (ENG) carried on afferent peripheral nerves. The aim of this study is to propose an non-invasive and spatial-selective electrode (because specific informations are carried into different fascicles). To do so, we investigate the spatial properties of an extracellular action potential (AP). This properties are described qualitatively and quantitatively using analytical study on an inhomogeneous an anisotropic nerve model. Then, a spectral analysis on this spatial signal discriminates the different frequency components. Low spatial frequencies represent the global shape of the signal, whereas high frequencies are related to the type of fibers. We show that the latter is rapidly attenuated with the distance and thus, being a local phenomenon, can be used as a selective measurement. Finally, we propose a spatial filtering based on electrode design and an electronic architecture to extract this high frequencies. PMID- 22255669 TI - A low-power high-sensitivity CMOS mixed-signal seizure-onset detector. AB - In this paper, we present a new seizure detection algorithm and the associated CMOS circuitry implementation. The proposed low-power seizure detector is a good candidate for an implantable epilepsy prosthesis. The device is designed for patient-specific seizure detection with a one variable parameter. The parameter value is extracted from a single seizure that is subsequently excluded from the validation phase. A two-path system is also proposed to minimize the detection delay. The algorithm is first validated using MATLAB(r) tools and then implemented and validated using circuits designed in a standard 0.18-MUm CMOS process with a total power dissipation of 7.08 MUW. A total of 13 seizures from two drug-resistant epileptic patients are assessed using the proposed algorithm and resulted in 100% sensitivity and a mean detection delay of 9.7 s after electrical onset. PMID- 22255670 TI - Micro-Watt building blocks for biomedical RF tranceivers. AB - The development of Wireless Body Area Network (WBAN) is a key point enabling the mobility health. Among the most critical constrains in WBAN implementation is the power consumption of wireless featuring nodes. This work focuses on the development of ultra low power radio building blocks dedicated to 2.4 GHz ISM band. A novel design approach based on device optimization is first presented. It is then applied to the implementation of a Low Noise Amplifier (LNA) and a mixer in a 0.13 MUm CMOS technology. The LNA provides a 13.1 dB gain and a 5.3 dB NF for a 60 MUW/0.4 V power consumption. The mixer achieves a conversion gain of 17.5 dB and a NF of 12 dB at 0 dBm LO power. It consumes 350 MUW for a 0.8 V supply. PMID- 22255671 TI - Approaches for the efficient extraction and processing of biopotentials in implantable neural interfacing microsystems. AB - The accelerating pace of research in neurosciences and rehabilitation engineering has created a considerable demand for implantable microsystems capable of interfacing with large groups of neurons. Such microsystems must provide multiple recording channels incorporating low-noise amplifiers, filters, data converters, neural signal processing circuitry, power management units and low-power transmitters to extract and wirelessly transfer the relevant neural data outside the body for computing and storage. This paper is reviewing several electronic recording strategies to address the challenge of operating large numbers of channels to gather the neural information from several neurons within very low power constraints. PMID- 22255672 TI - Low-power SoC design for ligament balance measuring system in total knee arthroplasty. AB - A design of a low-power wireless System-on-Chip (SoC) for the Ligament Balance Measuring System (LBMS) in Total Knee Arthroplasty (TKA) is presented in this paper. It includes a signal conditioning circuit that can support up to 15 force sensors, a 433 MHz RF front-end for data transmission, an 8-bit low-power microprocessor, and a FIFO with a digital filter. Idle and wake-up modes are well designed to reduce the power consumption since the device should be used for the whole surgical procedure. Test results show that the signal conditioning circuit with 16-bit single line output can operate under a wide voltage range, which is from 1.2V to 3.6V. The minimal power consumption is 139MU.W@1.2V with a 200 KHz clock. Experimental results demonstrated in static and body tests are given in the paper also. The chip will be used in an aided monitoring system for Total Knee Arthroplasty in the future work. PMID- 22255673 TI - An overview of the recent wideband transcutaneous wireless communication techniques. AB - Neuroprosthetic devices such as cochlear and retinal implants need to deliver a large volume of data from external sensors into the body, while invasive brain computer interfaces need to deliver sizeable amounts of data from the central nervous system to target devices outside of the body. Nonetheless, the skin should remain intact. This paper reviews some of the latest techniques to establish wideband wireless communication links across the skin. PMID- 22255674 TI - T-wave alternans detection using a Bayesian approach and a Gibbs sampler. AB - The problem of detecting T-wave alternans (TWA) in ECG signals has received considerable attention in the biomedical community. This paper introduces a Bayesian model for the T waves contained in ECG signals. A block Gibbs sampler was recently studied to estimate the parameters of this Bayesian model (including wave locations, amplitudes and shapes). This paper shows that the samples generated by this Gibbs sampler can be used efficiently for TWA detection via different statistical tests constructed from odd and even T-wave amplitude samples. The proposed algorithm is evaluated on real ECG signals subjected to synthetic TWA and compared with two classical algorithms. PMID- 22255675 TI - Amplitude of Dominant T-Wave Alternans assessment on ECGs obtained from a biophysical model. AB - The Amplitude of Dominant T-Wave Alternans (ADTWA) is a recently introduced index which quantifies the presence of microvolt T Wave Alternans (TWA) on surface ECG recordings. In this paper we investigate the reliability of ADTWA and its robustness against broadband noise. At this regard, we generated synthetic 12 leads ECG recordings through a forward electrophysiological model and we added TWA, at different extent, by modulating the variation of the repolarization times of transmembrane action potentials across even and odd beats. Using a stochastic model, we derived an analytical relationship between the repolarization variation injected into the model and TWA at the surface, thus offering a strategy to evaluate lead sensitivity. In terms of robustness, the results of the simulations show that ADTWA correctly measured the amplitude of synthetic TWA with an average error of 3.3% +/- 5.8% in absence of noise. When a 100 MUV peak-to-peak broadband noise is present, its effects on estimation errors were kept limited by singular value decomposition on which ADTWA builds. PMID- 22255676 TI - Patient-specific ventricular beat classification without patient-specific expert knowledge: a transfer learning approach. AB - We present an adaptive binary classification algorithm, based on transductive transfer learning. We illustrate the method in the context of electrocardiogram (ECG) analysis. Knowledge gained from a population of patients is automatically adapted to patients' records to accurately detect ectopic beats. On patients from the MIT-BIH Arrhythmia Database, we achieve a median sensitivity of 94.59% and positive predictive value of 96.24%, for the binary classification task of separating premature ventricular contractions (PVCs), a type of ectopic beat, from non-PVCs. PMID- 22255677 TI - Noise detection in heart sound recordings. AB - Coronary artery disease (CAD) is the leading cause of death in the United States. Although progression of CAD can be controlled using drugs and diet, it is usually detected in advanced stages when invasive treatment is required. Current methods to detect CAD are invasive and/or costly, hence not suitable as a regular screening tool to detect CAD in early stages. Currently, we are developing a noninvasive and cost-effective system to detect CAD using the acoustic approach. This method identifies sounds generated by turbulent flow through partially narrowed coronary arteries to detect CAD. The limiting factor of this method is sensitivity to noises commonly encountered in the clinical setting. Because the CAD sounds are faint, these noises can easily obscure the CAD sounds and make detection impossible. In this paper, we propose a method to detect and eliminate noise encountered in the clinical setting using a reference channel. We show that our method is effective in detecting noise, which is essential to the success of the acoustic approach. PMID- 22255678 TI - Spatiotemporal estimation of activation times of fractionated ECGs on complex heart surfaces. AB - Identification of electrical activation or depolarization times on sparsely sampled complex heart surfaces is of importance to clinicians and researchers in cardiac electrophysiology. We introduce a spatiotemporal approach for activation time estimation which combines prior results using spatial and temporal methods with our own progress on gradient estimation on triangulated surfaces. Results of the method applied to simulated and canine heart data suggest that improvements are possible using this novel combined approach. PMID- 22255679 TI - Computerized intrapartum electronic fetal monitoring: analysis of the decision to deliver for fetal distress. AB - We applied computerized methods to assess the Electronic Fetal Monitoring (EFM) in labor. We analyzed retrospectively the last hour of EFM for 1,370 babies, delivered by emergency Cesarean sections before the onset of pushing (data collected at the John Radcliffe Hospital, Oxford, UK). There were two cohorts according to the reason for intervention: (a) fetal distress, n(1) = 524 and (b) failure to progress and/or malpresentation, n(2) = 846. The cohorts were compared in terms of classical EFM features (baseline, decelerations, variability and accelerations), computed by a dedicated Oxford system for automated analysis- OxSys. In addition, OxSys was employed to simulate current clinical guidelines for the classification of fetal monitoring, i.e. providing in real time a three tier grading system of the EFM (normal, indeterminate, or abnormal). The computerized features and the simulated guidelines corresponded well to the clinical management and to the actual labor outcome (measured by umbilical arterial pH). PMID- 22255680 TI - Multi-input GNL-HybELS: an automated tool for the analysis of oculomotor dynamics during visual-vestibular interactions. AB - The eyes play a major role in our everyday activities. Eye movements are controlled by the oculomotor system, which enables us to stay focused on visual targets, switch visual attention, and compensate for external perturbations. This system's response to isolated visual or vestibular stimuli has been studied for decades, but what seems to be more critical is to know how it would respond to a combination of these stimuli, because in most natural situations, multiple stimuli are present. It is now believed that sensory fusion does not affect the dynamics of oculomotor modalities, despite studies suggesting otherwise. However, these interactions have not been studied in mathematical detail due to the lack of proper analysis tools and poor stimulus conditions. Here we propose an automated tool to analyze oculomotor responses without a-priori classification of nystagmus segments, where visual and vestibular stimuli are uncorrelated. Our method simultaneously classifies and identifies the responses of a multi-input multi-mode system. We validated our method on simulations, estimating sensory delays, semicircular canal time constant, and dynamics in both slow and fast phases of the response. Using this method, we can now investigate the effect of sensory fusion on the dynamics of oculomotor subsystems. With the analysis power of our new method, clinical protocols can now be improved to test these subsystems more efficiently and objectively. PMID- 22255681 TI - Dynamic analysis of EEG signals during spatial working memory used for either perception discrimination or planning of action. AB - We analysed multi-channel electroencephalographic (EEG) recordings during a spatial Working Memory (WM) task in order to test the hypothesis that segmentation of perception and action is present when the visual stimulus has been stored in spatial WM. To detect the interactions between different regions of the brain depending on the task we employed both Short Time Fourier Transformation (STFT) and the concept of Granger Causality (GC). Our computational analysis supports evidence that the Parietal Cortex (PC) is involved in WM processing. PMID- 22255682 TI - Local field potential driven Izhikevich model predicts a subthalamic nucleus neuron activity. AB - An interesting question has been raised recently regarding the relationship between the local field potentials (LFPs) and the single unit spiking activity. In this study, we investigate whether a linear modification of the LFPs, acquired from microelectrode recordings inside the subthalamic nucleus (STN) of Parkinson's disease patients, can provide input to an appropriately parameterized Izhikevich model to predict the spikes of an STN neuron. We show that the model is able to predict both the exact timing and the rhythm of the recorded spikes with high accuracy in 5 out of 7 intranuclear single neuron recordings. For the rest of the models, one model shows a lower accuracy in predicting the rhythm and the second one shows a lower accuracy in predicting the timing of the spikes. Overall, the results dictate that the LFPs can reliably predict the occurrence of spikes. PMID- 22255683 TI - Decoding ensemble activity from neurophysiological recordings in the temporal cortex. AB - We study subjects with pharmacologically intractable epilepsy who undergo semi chronic implantation of electrodes for clinical purposes. We record physiological activity from tens to more than one hundred electrodes implanted in different parts of neocortex. These recordings provide higher spatial and temporal resolution than non-invasive measures of human brain activity. Here we discuss our efforts to develop hardware and algorithms to interact with the human brain by decoding ensemble activity in single trials. We focus our discussion on decoding visual information during a variety of visual object recognition tasks but the same technologies and algorithms can also be directly applied to other cognitive phenomena. PMID- 22255684 TI - Multiscale information for network characterization in epilepsy. AB - We have developed a multiscale approach for the estimation of neuronal network coordination in the epileptic brain, from continuous (long-term) non-invasive electroencephalograms (EEG). The proposed approach specifically assesses the effect of large-scale network behavior on local network coordination, at individual dominant frequencies (modes) of the EEG spectrum. For this purpose a set of conditional information parameters is proposed to explicitly quantify the effect of global network correlation in the brain on pairwise (local) mutual information, via conditioning. These parameters are shown to be modulated in a frequency-specific manner at baseline, as well as during seizure evolution. PMID- 22255685 TI - The Volterra-Wiener approach in neuronal modeling. AB - Systems identification is being used increasingly in quantitative neurophysiology, including the auditory, visual and somatosensory systems. In this context, the Volterra-Wiener approach, which is an important branch of nonlinear systems identification, has met with considerable success in neuronal systems modeling, as these systems often exhibit complex nonlinear behavior. The Volterra-Wiener approach provides a comprehensive data-driven framework that does not place any a priori assumptions on the system structure. Therefore, it can approximate highly complex nonlinear mappings provided that experimental protocols are carefully designed in order to meet the requirements of the corresponding estimation procedure. In the present paper, we present a brief overview of Volterra-Wiener models and methodologies for their estimation as they relate to modeling neuronal systems. We also examine a specific example from a mechanoreceptor system. PMID- 22255686 TI - Analyzing coherent brain networks with Granger causality. AB - Multielectrode neurophysiological recording and functional brain imaging produce massive quantities of data. Multivariate time series analysis provides the basic framework for analyzing the patterns of neural interactions in these data. Neural interactions are directional. Being able to assess the directionality of neuronal interactions is thus a highly desired capability for understanding the cooperative nature of neural computation. Research over the last few years has identified Granger causality as a promising technique to furnish this capability. In this paper, we first introduce the concept of Granger causality and then present results from the application of this technique to multichannel local field potential data from an awake-behaving monkey. PMID- 22255687 TI - Assessing directional interactions among multiple physiological time series: the role of instantaneous causality. AB - This paper deals with the assessment of frequency domain causality in multivariate (MV) time series with significant instantaneous interactions. After providing different causality definitions, we introduce an extended MV autoregressive modeling approach whereby each definition is described in the time domain in terms of the model coefficients, and is quantified in the frequency domain by means of novel measures of directional connectivity. These measures are illustrated in a theoretical example showing how they reduce to known indexes when instantaneous causality is trivial, while they describe peculiar aspects of directional interaction in the presence of instantaneous causality. The application on real MV cardiovascular and EEG time series is then reported to investigate the role played by instantaneous causality in the practical evaluation of frequency domain connectivity. PMID- 22255688 TI - Role of respiration in setting causality among cardiovascular variability series. AB - We checked whether the observed shift of the dominant causality from heart period (HP) to systolic arterial pressure (SAP) in supine position to the reverse causal direction in upright position could be the result of the exogenous action of respiration on both variables. A model-based approach exploiting a multivariate dynamic adjustment class was utilized to decompose HP and SAP dynamics into partial processes and cancel respiratory-related influences from HP and SAP series. Causality was assessed in the information domain through a bivariate approach based on cross-conditional entropy. After canceling respiratory-related influences we observed the same trend on causality from supine to upright position as detected from the original series, thus suggesting that respiratory influences are not responsible per se for HP-SAP causal relations. PMID- 22255689 TI - Semiparametric detection of nonlinear causal coupling using partial directed coherence. AB - Infering causal relationships from observed time series has attracted much recent attention. In cases of nonlinear coupling, adequate inference is often hindered by the need to specify coupling details that call for many parameters and global minimization of nonconvex functions. In this paper we use an example to investigate a new concept, termed here running entropy mapping, whereby time series are mapped onto other entropy related time sequences whose analysis via a linear parametric time series methods, such as partial directed coherence, is able to expose the presence of formerly linearly undetectable causal relationships. PMID- 22255690 TI - Multivariate analysis of dynamical processes with applications to the neurosciences. AB - Nowadays, data are recorded with increasing spatial and temporal resolution. Commonly these data are analyzed using univariate or bivariate approaches. Most of the analysis techniques assume stationarity of the underlying dynamical processes. Here, we present an approach that is capable of analyzing multivariate data, the so-called renormalized partial directed coherence. It utilizes the concept of Granger causality and is applicable to non-stationary data. We discuss its abilities and limitations, and demonstrate its usefulness in an application to murine electroencephalography (EEG) data during sleep transitions. PMID- 22255691 TI - Symbolic coupling traces for causality analysis of cardiovascular control. AB - Directional coupling analysis of time series is an important subject of current research. In this paper, a method based on symbolic dynamics for the detection of time-delayed coupling in biosignals is presented. The symbolic coupling traces, defined as the symmetric and diametric traces of the bivariate word distribution, allow for a more reliable quantification of coupling and are compared with established methods like mutual information and cross recurrence analysis. The symbolic coupling traces method is applied to appropriate model systems and cardiological data which demonstrate its advantages especially for nonstationary and noisy data. Moreover, the method of symbolic coupling traces is used to analyze and quantify time-delayed coupling of cardiovascular measurements during different sleep stages. Significant different regulatory mechanisms are detected not only between the deep sleep and the other sleep stages but also between healthy subjects and patients. The proposed method may help to indicate pathological changes in cardiovascular regulation and also effects of continuous positive airway pressure therapy on the cardiovascular system. PMID- 22255692 TI - Microaneurysm detection with radon transform-based classification on retina images. AB - The creation of an automatic diabetic retinopathy screening system using retina cameras is currently receiving considerable interest in the medical imaging community. The detection of microaneurysms is a key element in this effort. In this work, we propose a new microaneurysms segmentation technique based on a novel application of the radon transform, which is able to identify these lesions without any previous knowledge of the retina morphological features and with minimal image preprocessing. The algorithm has been evaluated on the Retinopathy Online Challenge public dataset, and its performance compares with the best current techniques. The performance is particularly good at low false positive ratios, which makes it an ideal candidate for diabetic retinopathy screening systems. PMID- 22255693 TI - Evaluation of the grading performance of an ensemble-based microaneurysm detector. AB - In this paper, results of a diabetic retinopathy screening experiment are presented which is based solely on the findings of a microaneurysm detector. For this purpose, an ensemble-based algorithm developed by our research group was used; this provided promising results in our earlier experiments. At its best, the 1200 image of the Messidor database is classified by this detector with a sensitivity of 96%, a specificity of 51% and achieved an AUC of 0.87. As anticipated, larger microaneurysm counts are recognized with higher level of certainty. Therefore, this approach might be expected to have good performance in relation to the severity of the disease. PMID- 22255694 TI - Computerized detection of peripapillary chorioretinal atrophy by texture analysis. AB - Presence of peripapillary chorioretinal atrophy (PPA) is considered one of the risk factors for glaucoma. It can be identified as bright regions in retinal fundus images, and therefore, incorrectly included as the part of the optic disc regions in the automated disc detection scheme. For potential risk assessment and use in improving optic disc segmentation, a computerized detection of PPA was investigated. By using texture analysis, the sensitivity for detecting the moderate to severe PPA regions in the test dataset was 73% with the specificity of 95%. The proposed method may be useful for identifying the cases with the PPA in retinal fundus images. PMID- 22255695 TI - Machine learning and pattern classification in identification of indigenous retinal pathology. AB - Diabetic retinopathy (DR) is a complication of diabetes, which if untreated leads to blindness. DR early diagnosis and treatment improve outcomes. Automated assessment of single lesions associated with DR has been investigated for sometime. To improve on classification, especially across different ethnic groups, we present an approach using points-of-interest and visual dictionary that contains important features required to identify retinal pathology. Variation in images of the human retina with respect to differences in pigmentation and presence of diverse lesions can be analyzed without the necessity of preprocessing and utilizing different training sets to account for ethnic differences for instance. PMID- 22255696 TI - An automated retinal image quality grading algorithm. AB - This paper introduces an algorithm for the automated assessment of retinal fundus image quality grade. Retinal image quality grading assesses whether the quality of the image is sufficient to allow diagnostic procedures to be applied. Automated quality analysis is an important preprocessing step in algorithmic diagnosis, as it is necessary to ensure that images are sufficiently clear to allow pathologies to be visible. The algorithm is based on standard recommendations for quality analysis by human screeners, examining the clarity of retinal vessels within the macula region. An evaluation against a reference standard data-set is given; it is shown that the algorithm's performance correlates closely with that of clinicians manually grading image quality. PMID- 22255697 TI - Automatic detection of retina disease: robustness to image quality and localization of anatomy structure. AB - The automated detection of diabetic retinopathy and other eye diseases in images of the retina has great promise as a low-cost method for broad-based screening. Many systems in the literature which perform automated detection include a quality estimation step and physiological feature detection, including the vascular tree and the optic nerve / macula location. In this work, we study the robustness of an automated disease detection method with respect to the accuracy of the optic nerve location and the quality of the images obtained as judged by a quality estimation algorithm. The detection algorithm features microaneurysm and exudate detection followed by feature extraction on the detected population to describe the overall retina image. Labeled images of retinas ground-truthed to disease states are used to train a supervised learning algorithm to identify the disease state of the retina image and exam set. Under the restrictions of high confidence optic nerve detections and good quality imagery, the system achieves a sensitivity and specificity of 94.8% and 78.7% with area-under-curve of 95.3%. Analysis of the effect of constraining quality and the distinction between mild non-proliferative diabetic retinopathy, normal retina images, and more severe disease states is included. PMID- 22255698 TI - Spatiotemporal measurement of tumor oxygenation reveals repeat hypoxic phenomenon in mice. AB - Tumor hypoxia is considered a potential therapeutic problem because it reduces the effects of radiation therapy. Clinical experience has shown that long-term tumor oxygenation cannot be achieved with oxygen inhalation, but the mechanisms behind this phenomenon remain unknown. In this study, we designed an optical system for evaluating spatiotemporal changes in tissue oxygen tension (pO(2)) by phosphorescence quenching. The system can measure continuous changes in pO(2) at a fixed point and can also perform two-dimensional mapping of pO(2) in any part of the tumor tissue. We implanted tumor tissue in a dorsal skinfold chamber of C57BL/6 mice and observed tumor growth. After the tumor attained a diameter of 2 mm, the mice received oxygen inhalation and pO(2) was measured. Tumor pO(2) increased after inhalation but the oxygen level was not maintained despite continuous inhalation of pure oxygen; the tumor returned to a hypoxic state. These results mimic the clinical experience of oxygen inhalation treatment in radiation therapy. Our system reproduces the repeat hypoxic phenomenon in a murine tumor model and can be used to determine the mechanisms of oxygen metabolism in tumors. PMID- 22255699 TI - 3D imaging for quantitative assessment of toxicity on vascular development in zebrafish. AB - In this study, we describe the utility of the zebrafish model of in-vivo blood vessel formation as a tool for chemical risk assessment. Time-lapse confocal imaging of embryonic vasculature in the zebrafish is used in conjunction with digital image analysis to monitor and quantify the effect of toxins on vascular development. Non-rigid registration is used to capture changes in vascular morphology over time. Vascular formation in healthy normal and arsenic treated embryos was evaluated for differences in vascular structure using the algorithms developed. Although, the temporal progression of vascular development was similar, significant differences were observed in vessel structure between the toxin treated and healthy fish. This study revealed, for the first time, that vital vascular structures in fish maybe affected by exposure to arsenic. This technique allowed visualization of vascular abnormalities in embryos showing no external signs of malformations. PMID- 22255700 TI - Subcellular particles tracking in time-lapse confocal microscopy images. AB - Automatically tracking and analyzing the mobility of live subcellular structures will expedite the understanding of signaling pathways, protein-protein interaction, drug delivery, protein synthesis and functionality. Traditional computer vision tracking methods produce yet-to-be-satisfactory results due to the complexity of the particles recorded in spatial-temporal video sequences from confocal images. The difficulties arise from diverse modalities of motion patterns (translational, Brownian, or sessile), changes in behavior during tracking, and cluttered background. In this paper, we present an effective framework to detect and track subcullular particles in different motion modalities. The methodology begins with a Divergence Filter design for motion modality detection. After that, an improved a' trous wavelet is presented for segmenting particles. Represented by Euclidean Distance Map which contains information on object position, size, and intensity, the multiple particle tracking is carried out by solving a linear assignment problem. The proposed framework can also simultaneously evaluate particle population change by automatically counting the number of newly appeared or disappeared particles in time space. PMID- 22255701 TI - Dynamic phase imaging for in vitro process monitoring and cell tracking. AB - This paper describes a new, novel quantitative interference microscope system and presents images, videos and data of live biological samples. The specially designed optical system enables instantaneous 4-dimensional video measurements of dynamic motions within and among live cells without the need for contrast agents. This "label-free", vibration insensitive imaging system enables measurement of biological objects in reflection using harmless light levels with a variety of magnifications and wavelengths with fields of view from several hundred microns up to a millimeter. At the core of the instrument is a phase measurement camera (PMC) enabling simultaneous measurement of multiple interference patterns utilizing a pixelated phase mask taking advantage of the polarization properties of light. Phase values are converted to optical thickness data enabling volumetric, motion and morphological studies. Data from organisms such as flagellates and rotifers will be presented, as will measurements of human breast cancer cells with the addition of various agents that break down the cells. These data highlight examples of monitoring different biological processes and cellular motions. PMID- 22255702 TI - Lensless fluorescent on-chip microscopy using a fiber-optic taper. AB - We demonstrate a lensfree on-chip fluorescent microscopy platform that can image fluorescently labeled cells over ~60 mm(2) field-of-view with <4 urn spatial resolution. In this lensfree imaging system, micro-objects of interest are directly located on a tapered fiber-optic faceplate which has > 5-fold higher density of fiber-optic waveguides in its top facet compared to the bottom facet. For excitation, an incoherent light source (e.g., a simple light emitting diode- LED) is used to pump fluorescent objects through a glass hemi-sphere interface. Upon interacting with the entire sample volume, the excitation light is rejected by total internal reflection process occurring at the bottom of the sample substrate. Fluorescent emission from the objects is then collected by the smaller facet of the tapered faceplate and is delivered to a detector-array with an image magnification of ~2.4X. A compressive sampling based decoding algorithm is used for sparse signal recovery, which further increases the space-bandwidth-product of our lensfree on-chip fluorescent imager. We validated the performance of this lensfree imaging platform using fluorescent micro-particles as well as labeled water-borne parasites (e.g., Giardia Muris cysts). Such a compact and wide-field fluorescent microscopy platform could be valuable for cytometry and rare cell imaging applications as well as for micro array research. PMID- 22255703 TI - Employing temporal information for cell segmentation using max-flow/min-cut in phase-contrast video microscopy. AB - Cell segmentation is a crucial step in many bio-medical image analysis applications and it can be considered as an important part of a tracking system. Segmentation in phase-contrast images is a challenging task since in this imaging technique, the background intensity is approximately similar to the cell pixel intensity. In this paper we propose an interactive automatic pixel level segmentation algorithm, that uses temporal information to improve the segmentation result. This algorithm is based on the max-flow/min-cut algorithm and can be solved in polynomial time. This method is not restricted to any specific cell shape and segments cells of various shapes and sizes. The results of the proposed algorithm show that using the temporal information does improve segmentation considerably. PMID- 22255704 TI - Supervised learning framework for screening nuclei in tissue sections. AB - Accurate segmentation of cell nuclei in microscope images of tissue sections is a key step in a number of biological and clinical applications. Often such applications require analysis of large image datasets for which manual segmentation becomes subjective and time consuming. Hence automation of the segmentation steps using fast, robust and accurate image analysis and pattern classification techniques is necessary for high throughput processing of such datasets. We describe a supervised learning framework, based on artificial neural networks (ANNs), to identify well-segmented nuclei in tissue sections from a multistage watershed segmentation algorithm. The successful automation was demonstrated by screening over 1400 well segmented nuclei from 9 datasets of human breast tissue section images and comparing the results to a previously used stacked classifier based analysis framework. PMID- 22255705 TI - An ICA-based method for the segmentation of pigmented skin lesions in macroscopic images. AB - Segmentation is an important step in computer-aided diagnostic systems for pigmented skin lesions, since that a good definition of the lesion area and its boundary at the image is very important to distinguish benign from malignant cases. In this paper a new skin lesion segmentation method is proposed. This method uses Independent Component Analysis to locate skin lesions in the image, and this location information is further refined by a Level-set segmentation method. Our method was evaluated in 141 images and achieved an average segmentation error of 16.55%, lower than the results for comparable state-of-the art methods proposed in literature. PMID- 22255706 TI - A novel approach to automated cell counting for studying human corneal epithelial cells. AB - A novel automated cell counting technique for cell sample images used to study the side-effects of lens cleaning solutions on human corneal epithelial cells is developed. The proposed multi-step approach integrates non-maximum suppression, seeded region growing, connected component analysis, and adaptive thresholding to produce segmentation and classification results that are robust to background illumination variation and clustering of cells. The proposed algorithm is computationally efficient, and experimental results show that the average detection rate of nucleated cells is greater than 90% with the proposed technique as opposed to the state-of-the-art level set method which gives an accuracy of less than 65%. PMID- 22255707 TI - Estimation of the population of neutrophils induced to differentiate from the MPRO mouse promyelocytic cell line. AB - Neutrophils derived from induced-differentiated mouse promyleocyte (MPRO) cell lines provide an alternative source of mouse neutrophils for in vitro experiments, substituting for primary mouse neutrophils that are normally obtained by sacrificing mice. One issue with using induced-differentiated MPRO cells (or NEUTs) is that they are usually composed of not only mature neutrophils, but also neutrophil precursors. Here, we report on an assessment of an automated image analysis system to estimate mature neutrophil proportion in giemsa-stained NEUTs, and compare the accuracy with manual cell counting and flow cytometry results. PMID- 22255708 TI - Interactive liver tumor segmentation from ct scans using support vector classification with watershed. AB - In this paper, we present an interactive method for liver tumor segmentation from computed tomography (CT) scans. After some pre-processing operations, including liver parenchyma segmentation and liver contrast enhancement, the CT volume is partitioned into a large number of catchment basins under watershed transform. Then a support vector machines (SVM) classifier is trained on the user-selected seed points to extract tumors from liver parenchyma, while the corresponding feature vector for training and prediction is computed based upon each small region produced by watershed transform. Finally, some morphological operations are performed on the whole segmented binary volume to refine the rough segmentation result of SVM classification. The proposed method is tested and evaluated on MICCAI 2008 liver tumor segmentation challenge datasets. The experiment results demonstrate the accuracy and efficiency of the proposed method so that indicate availability in clinical routines. PMID- 22255709 TI - Associating ECG features with firefighter's activities. AB - In this paper we associate features obtained from ECG signals with the expected levels of stress of real firefighters in action when facing specific events such as fires or car accidents. Five firefighters were monitored using wearable technology collecting ECG signals. Heart rate and heart rate variability features were analyzed in consecutive 5-min intervals during several types of events. A questionnaire was used to rank these types of events according to stress and fatigue and a measure of association was applied to compare this ranking to the ECG features. Results indicate associations between this ranking and both heart rate and heart rate variability features extracted in the time domain. Finally, an example of differences in inter personal responses to stressful events is shown and discussed, motivating future challenges within this research field. PMID- 22255710 TI - Modulation filtering for noise detection in heart sound signals. AB - Cardiac auscultation has proven to be an excellent diagnostic tool. Heart sound processing algorithms are not completely robust in the presence of noise, requiring clean segments of heart sounds to extract reliable diagnostic features. This paper presents a new approach to detect transient noises mixed with heart sound. The algorithm explores a single channel source separation algorithm and evaluates the non-stationary separated signals. It has the potential to be applied in real-time. Using a database of heart sounds acquired in real-life scenario, the method showed a sensitivity and a specificity of 93.6% and 92.3%, respectively. PMID- 22255711 TI - Cough detection algorithm for monitoring patient recovery from pulmonary tuberculosis. AB - In regions of the world where tuberculosis (TB) poses the greatest disease burden, the lack of access to skilled laboratories is a significant problem. A lab-free method for assessing patient recovery during treatment would be of great benefit, particularly for identifying patients who may have drug-resistant tuberculosis. We hypothesize that cough analysis may provide such a test. In this paper we describe algorithm development in support of a pilot study of TB patient coughing. We describe several approaches to event detection and classification, and show preliminary data which suggest that cough count decreases after the start of treatment in drug-responsive patients. Our eventual goal is development of a low-cost ambulatory cough analysis system that will help identify patients with drug-resistant tuberculosis. PMID- 22255712 TI - Investigating the statistical properties of the swallowing sounds. AB - In this paper the statistical properties of the swallowing sound is discussed. This knowledge is required for the acoustical modeling of the swallowing mechanism as it is important to select an appropriate type of the system (i.e. linear vs. nonlinear) for modeling. The tests of linearity and gaussianity were performed. The results of the statistical test of gaussianity showed a nonGaussian distribution of the swallowing sound signals. Also, the test of linearity exhibited the nonlinear characteristics of the model that represents the swallowing sound generation. PMID- 22255714 TI - Identification of CpG islands in DNA sequences using matched filters. AB - CpG islands (CGIs), rich in CG dinucleotides, are usually located in the promoter regions of genes in DNA sequences and are used as gene markers. Identification of CGIs plays an important role in the analysis of DNA sequences. In this paper, we propose a new digital signal processing (DSP) based approach using matched filters for the identification of CGIs. We also formulate a new/reliable CGI identification characteristic replacing the several existing probability transition tables for CGIs and non-CGIs. The peaks in matched filter output, obtained by correlating the CGI characteristic with the DNA sequence to be analyzed, accurately and reliably identify CGIs. This approach is tested on a number of DNA sequences and is proved to be capable of identifying CpG islands efficiently and reliably. PMID- 22255713 TI - Conduction velocity of the uterine contraction in serial magnetomyogram (MMG) data: event based simulation and validation. AB - We propose a novel approach to calculate the conduction velocity (CV) of the uterine contraction bursts in magnetomyogram (MMG) signals measured using a multichannel SQUID array. For this purpose, we partition the sensor coordinates into four different quadrants and identify the contractile bursts using a previously proposed Hilbert-wavelet transform approach. If contractile burst is identified in more than one quadrant, we calculate the center of gravity (CoG) in each quadrant for each time point as the sum of the product of the sensor coordinates with the Hilbert amplitude of the MMG signals normalized by the sum of the Hilbert amplitude of the signals over all sensors. Following this we compute the delay between the CoGs of all (six) possible quadrant pairs combinations. As a first step, we validate this approach by simulating a stochastic model based on independent second-order autoregressive processes (AR2) and we divide them into 30 second disjoint windows and insert burst activity at specific time instances in preselected sensors. Also we introduce a lag of 5 +/- 1 seconds between different quadrants. Using our approach we calculate the CoG of the signals in a quadrant. To this end, we compute the delay between CoGs obtained from different quadrants and show that our approach is able to reliably capture the delay incorporated in the model. We apply the proposed approach to 19 serial MMG data obtained from two subjects and show an increase in the CV as the subjects approached labor. PMID- 22255715 TI - Modeling high-level descriptions of real-life physical activities using latent topic modeling of multimodal sensor signals. AB - We propose a new methodology to model high-level descriptions of physical activities using multimodal sensor signals (ambulatory electrocardiogram (ECG) and accelerometer signals) obtained by a wearable wireless sensor network. We introduce a two-step strategy where the first step estimates likelihood scores over the low-level descriptions of physical activities such as walking or sitting directly from sensor signals and the second step infers the high-level description based on the estimated low-level description scores. Assuming that a high-level description of a certain physical activity may consist of multiple low level physical activities and a low-level physical activity can be observed in multiple high-level descriptions of physical activities, we introduce the statistical concept of latent topics in physical activities to model the high level status with low-level descriptions. With an unsupervised approach using a database from unconstrained free-living settings, we show promising results in modeling high-level descriptions of physical activities. PMID- 22255716 TI - A wavelet-based approach for time series pattern detection and events prediction applied to telemonitoring data. AB - This work aims the development of a predictive strategy able to estimate future events with relevant impact in the cardiovascular status. Based on wavelet transform, a new time series similarity metric is introduced, which is capable to detect a pre-defined pattern in time series data. In addition, a methodology combining a wavelet scheme with state space multi-models is proposed to achieve the prediction of future signal values. Blood pressure signals, collected by a telemonitoring platform (TEN-HMS), are used to detect the occurrence of future hypertension events. PMID- 22255717 TI - A method to determine the optimal features for control of a powered lower-limb prostheses. AB - Lower-limb prostheses are rapidly advancing with greater computing power and sensing modalities. This paper is an attempt to begin exploring the trade-off between extrinsic and intrinsic control modalities. In this case, between electromyographic (extrinsic) and several internal sensors that can be used for intrinsic control. We propose a method that will identify the particular features, taken from two trans-femoral amputee and one trans-tibial amputee, during locomotion on varying terrain, that perfectly discriminate between locomotion modes. From this we are able to identify the source of the discriminability from a large-set of features that does not depend on the type of amputation. Also, we comment on the use of this algorithm in selecting the most discriminatory and least encumbering sensor/feature combination for transitions when the ground underneath the foot is unknown for trans-tibial amputees. PMID- 22255718 TI - Analysis of human motions with arm constraint. AB - This paper investigates a quantization and clustering issue on human motion performance constrained by disabilities. In a longitudinal study of medical therapy on motion disorder, stages of patient disability condition change over time. We investigate four different stages of one arm constrained walking motions by restricting 0%, 10%, 16% and 22% of arm swing angles. For analysis we use One way ANOVA and K-mean clustering to indentify the most significant features and to partition four different motion constrained groups. Our experimental result shows that all four arm constraints during walking motion are clustered with an average accuracy of 91.7% on two different feature conditions: a mixture of singular value decomposition (SVD) and power spectral density (PSD); and SVD only on selected gait cycles. The proposed method can be integrated with a ubiquitous system (using wearable sensors) for a remote distance patient monitoring system analysis. PMID- 22255719 TI - Assessment of features for automatic CTG analysis based on expert annotation. AB - Cardiotocography (CTG) is the monitoring of fetal heart rate (FHR) and uterine contractions (TOCO) since 1960's used routinely by obstetricians to detect fetal hypoxia. The evaluation of the FHR in clinical settings is based on an evaluation of macroscopic morphological features and so far has managed to avoid adopting any achievements from the HRV research field. In this work, most of the ever-used features utilized for FHR characterization, including FIGO, HRV, nonlinear, wavelet, and time and frequency domain features, are investigated and the features are assessed based on their statistical significance in the task of distinguishing the FHR into three FIGO classes. Annotation derived from the panel of experts instead of the commonly utilized pH values was used for evaluation of the features on a large data set (552 records). We conclude the paper by presenting the best uncorrelated features and their individual rank of importance according to the meta-analysis of three different ranking methods. Number of acceleration and deceleration, interval index, as well as Lempel-Ziv complexity and Higuchi's fractal dimension are among the top five features. PMID- 22255720 TI - Drowsiness detection by thoracic effort signal analysis in real driving environments. AB - Detection of drowsiness while driving is a leading objective in advanced driver assistance systems. This work presents a new index to assess the alertness state of drivers based on the respiratory dynamics derived from an inductive band. More than 100 hours of driving in real environments from 13 healthy subjects were analyzed. The proposed method has a sensitivity of 93.7% and specificity of 86.3% in detecting full awake drivers while it has a sensitivity of 83.1% and specificity of 95.3% in detecting drowsy drivers. The results show that the proposed index may be promising to assess the alertness state of real drivers. PMID- 22255721 TI - Single channel-based myoelectric control of hand movements with Empirical Mode Decomposition. AB - Myoelectric control has been an important area of research for the past 40 years for prosthetic control, since it targets amputees who lost their body limbs. Advances were achieved concerning the number of movements to be classified with high accuracy. Hence, not much research was done to extract information from single channel Electromyogram (EMG). This paper presents Empirical Mode Decomposition (EMD) for Feature Extraction (FE) from single-channel EMG for ten class wrist movements and handgrips. Two classification schemes were applied based on Time Domain-Auto Regression (TDAR) features (a commonly used approach in the Literature) and EMD, with Principle Component Analysis (PCA) for dimensionality reduction, and Support Vector Machine (SVM) for classification. With the use of only one single-channel EMG, the EMD achieved an improvement in the classification rate for a single flexor and extensor EMG channel of 11.2% (from 83.7% to 94.4%) and 13% (from 80.16% to 93.16%), respectively. The results suggested that EMD remarkably improves the classification performance for a single-channel EMG over the traditional time domain FE technique. This will reduce the computational cost of applying only one channel EMG and facilitates the acquisition of the EMG. The main drawback of using EMD technique is that it is not suitable for real time processing of prosthetic control. PMID- 22255722 TI - Automatic REM sleep detection associated with idiopathic rem sleep Behavior Disorder. AB - Rapid eye movement sleep Behavior Disorder (RBD) is a strong early marker of later development of Parkinsonism. Currently there are no objective methods to identify and discriminate abnormal from normal motor activity during REM sleep. Therefore, a REM sleep detection without the use of chin electromyography (EMG) is useful. This is addressed by analyzing the classification performance when implementing two automatic REM sleep detectors. The first detector uses the electroencephalography (EEG), electrooculography (EOG) and EMG to detect REM sleep, while the second detector only uses the EEG and EOG. METHOD: Ten normal controls and ten age matched patients diagnosed with RBD were enrolled. All subjects underwent one polysomnographic (PSG) recording, which was manual scored according to the new sleep-scoring standard from the American Academy of Sleep Medicine. Based on the manual scoring, an automatic computerized REM detection algorithm has been implemented, using wavelet packet combined with artificial neural network. RESULTS: When using the EEG, EOG and EMG modalities, it was possible to correctly classify REM sleep with an average Area Under Curve (AUC) equal to 0.90 +/- 0.03 for normal subjects and AUC = 0.81 +/- 0.05 for RBD subjects. The performance difference between the two groups was significant (p < 0.01). No significant drop (p > 0.05) in performance was observed when only using the EEG and EOG in neither of the groups. CONCLUSION: The overall result indicates that the EMG does not play an important role when classifying REM sleep. PMID- 22255723 TI - A rule-based automatic sleep staging method. AB - In this paper, a rule-based automatic sleep staging method was proposed. Twelve features, including temporal and spectrum analyses of the EEG, EOG, and EMG signals, were utilized. Normalization was applied to each feature to reduce the effect of individual variability. A hierarchical decision tree, with fourteen rules, was constructed for sleep stage classification. Finally, a smoothing process considering the temporal contextual information was applied for the continuity. The average accuracy and kappa coefficient of the proposed method applied to the all night polysomnography (PSG) of twenty subjects compared with the manual scorings reached 86.5% and 0.78, respectively. This method can assist the clinical staff reduce the time required for sleep scoring in the future. PMID- 22255724 TI - Bayes classification of snoring subjects with and without Sleep Apnea Hypopnea Syndrome, using a Kernel method. AB - The gold standard for diagnosing Sleep Apnea Hypopnea Syndrome (SAHS) is the Polysomnography (PSG), an expensive, labor-intensive and time-consuming procedure. It would be helpful to have a simple screening method that allowed to early determining the severity of a subject prior to his/her enrolment for a PSG. Several differences have been reported in the acoustic snoring characteristics between simple snorers and SAHS patients. Previous studies usually classify snoring subjects into two groups given a threshold of Apnea-Hypoapnea Index (AHI). Recently, Bayes multi-group classification with Gaussian Probability Density Function (PDF) has been proposed, using snore features in combination with apnea-related information. In this work we show that the Bayes classifier with Kernel PDF estimation outperforms the Gaussian approach and allows the classification of SAHS subjects according to their severity, using only the information obtained from snores. This could be the base of a single channel, snore-based, screening procedure for SAHS. PMID- 22255726 TI - On determining available stochastic features by spectral splitting in obstructive sleep apnea detection. AB - Heart rate variability (HRV) is one of the promising directions for a simple and noninvasive way for obstructive sleep apnea syndrome detection. The time frequency representations has been proposed before to investigate the non stationary properties of the HRV during either transient physiological or pathological episodes. Within the framework of the filter-banked feature extraction, estimation of the spectral splitting for stochastic features extraction is an open issue. Usually, this splitting is fixed empirically without taking into account the actual informative distribution of time-frequency representations. In the present work, a relevance-based approach that aims to find a priori a boundaries in the frequency domain for the spectral splitting upon t-f planes is proposed. Results show that the approach is able to find the most informative frequency bands, achieving accuracy rate over 75%. PMID- 22255725 TI - Detection of post apnea sounds and apnea periods from sleep sounds. AB - Obstructive Sleep Apnea Syndrome (OSAS) is defined as a sleep related breathing disorder that causes the body to stop breathing for about 10 seconds and mostly ends with a loud sound due to the opening of the airway. OSAS is traditionally diagnosed using polysomnography, which requires a whole night stay at the sleep laboratory of a hospital, with multiple electrodes attached to the patient's body. Snoring is a symptom which may indicate the presence of OSAS; thus investigation of snoring sounds, which can be recorded in the patient's own sleeping environment, has become popular in recent years to diagnose OSAS. In this study, we aim to develop a new method to detect post-apnea snoring episodes with the goal of diagnosing apnea or creating new criteria similar to apnea / hypopnea index. Emphasis is placed on detecting post apnea episodes, hence the apnea periods. In this method, first segmentation is done to eliminate the silence parts. Then, these episodes are represented by distinctive features; some of these features are available in literature but some of them are novel. Finally, episodes are classified using supervised methods. False alarm rates are reduced by adding additional constraints into the detection algorithm. These methods are applied to snoring sound signals of OSAS patients, recorded in Gulhane Military Medical Academy, to verify the success of our algorithms. PMID- 22255727 TI - Individualising EEG frequency bands for sleep deprivation studies. AB - A method for determining individualised frequency bands from electroencephalographic (EEG) power spectral density (PSD) plots is presented. EEG was collected during the performance of a computerised multitask test from 21 healthy male subjects, of which an experimental group of 14 subjects underwent sleep deprivation and 7 subjects formed the control group. EEG PSD plots were compared between the groups and were used to determine individual theta, alpha and beta bands for the subjects by studying the points of intersection between the individual subjects' normalised spectra and the normalised average spectrum of the control group. The results show that the frontal and occipital locations are best suited for the determination of individualised frequency bands. The proposed method can be used to enhance EEG spectral analysis of task-induced cognitive effort during sleep deprivation. PMID- 22255728 TI - Optimization of EEG frequency bands for improved diagnosis of Alzheimer disease. AB - Many clinical studies have shown that electroencephalograms (EEG) of Alzheimer patients (AD) often have an abnormal power spectrum. In this paper a frequency band analysis of AD EEG signals is presented, with the aim of improving the diagnosis of AD from EEG signals. Relative power in different EEG frequency bands is used as features to distinguish between AD patients and healthy control subjects. Many different frequency bands between 4 and 30 Hz are systematically tested, besides the traditional frequency bands, e.g., theta band (4-8 Hz). The discriminative power of the resulting spectral features is assessed through statistical tests (Mann-Whitney U test). Moreover, linear discriminant analysis is conducted with those spectral features. The optimized frequency ranges (4-7 Hz, 8-15 Hz, 19-24 Hz) yield substantially better classification performance than the traditional frequency bands (4-8 Hz, 8-12 Hz, 12-30 Hz); the frequency band 4 7 Hz is the optimal frequency range for detecting AD, which is similar to the classical theta band. The frequency bands were also optimized as features through leave-one-out crossvalidation, resulting in error-free classification. The optimized frequency bands may improve existing EEG based diagnostic tools for AD. Additional testing on larger AD datasets is required to verify the effectiveness of the proposed approach. PMID- 22255729 TI - Generalizations of the subject-independent feature set for music-induced emotion recognition. AB - Electroencephalogram (EEG)-based emotion recognition has been an intensely growing field. Yet, how to achieve acceptable accuracy on a practical system with as fewer electrodes as possible is less concerned. This study evaluates a set of subject-independent features, based on differential power asymmetry of symmetric electrode pairs [1], with emphasis on its applicability to subject variability in music-induced emotion classification problem. Results of this study have evidently validated the feasibility of using subject-independent EEG features to classify four emotional states with acceptable accuracy in second-scale temporal resolution. These features could be generalized across subjects to detect emotion induced by music excerpts not limited to the music database that was used to derive the emotion-specific features. PMID- 22255730 TI - EpiScan: online seizure detection for epilepsy monitoring units. AB - An online seizure detection algorithm for long-term EEG monitoring is presented, which is based on a periodic waveform analysis detecting rhythmic EEG patterns and an adaptation module automatically adjusting the algorithm to patient specific EEG properties. The algorithm was evaluated using 4.300 hours of unselected EEG recordings from 48 patients with temporal lobe epilepsy. For 66% of the patients the algorithm detected 100% of the seizures. A mean sensitivity of 83% was achieved. An average of 7.2 false alarms within 24 hours for unselected EEG makes the algorithm attractive for epilepsy monitoring units. PMID- 22255731 TI - Optimal design of a bank of spatio-temporal filters for EEG signal classification. AB - The spatial weights for electrodes called common spatial pattern (CSP) are known to be effective in EEG signal classification for motor imagery based brain computer interfaces (MI-BCI). To achieve accurate classification in CSP, the frequency filter should be properly designed. To this end, several methods for designing the filter have been proposed. However, the existing methods cannot consider plural brain activities described with different frequency bands and different spatial patterns such as activities of mu and beta rhythms. In order to efficiently extract these brain activities, we propose a method to design plural filters and spatial weights which extract desired brain activity. The proposed method designs finite impulse response (FIR) filters and the associated spatial weights by optimization of an objective function which is a natural extension of CSP. Moreover, we show by a classification experiment that the bank of FIR filters which are designed by introducing an orthogonality into the objective function can extract good discriminative features. Moreover, the experiment result suggests that the proposed method can automatically detect and extract brain activities related to motor imagery. PMID- 22255732 TI - Brain tumor detection using scalp eeg with modified Wavelet-ICA and multi layer feed forward neural network. AB - Use of scalp EEG for the diagnosis of various cerebral disorders is progressively increasing. Though the advanced neuroimaging techniques such as MRI and CT-SCAN still stay as principal confirmative methods for detecting and localizing brain tumors, the development of automated systems for the detection of brain tumors using the scalp EEG has started attracting the researchers all over the world notably since 2000. This is because of two important facts: (i) cheapness and easiness of methods of recording and analyzing the scalp EEG and (ii) lower risk and possible early detection. This paper presents a method of detecting the brain tumor using the first, second and third order statistics of the scalp EEG with a Modified Wavelet-Independent Component Analysis (MwICA) technique and a multi layer feed-forward neural network. PMID- 22255733 TI - Characterization of entropy measures against data loss: application to EEG records. AB - This study is aimed at characterizing three signal entropy measures, Approximate Entropy (ApEn), Sample Entropy (SampEn) and Multiscale Entropy (MSE) over real EEG signals when a number of samples are randomly lost due to, for example, wireless data transmission. The experimental EEG database comprises two main signal groups: control EEGs and epileptic EEGs. Results show that both SampEn and ApEn enable a clear distinction between control and epileptic signals, but SampEn shows a more robust performance over a wide range of sample loss ratios. MSE exhibits a poor behavior for ratios over a 40% of sample loss. The EEG non stationary and random trends are kept even when a great number of samples are discarded. This behavior is similar for all the records within the same group. PMID- 22255734 TI - Wavelet transform cardiorespiratory coherence detects patient movement during general anesthesia. AB - Heart rate variability (HRV) may provide anesthesiologists with a noninvasive tool for monitoring nociception during general anesthesia. A novel wavelet transform cardiorespiratory coherence (WTCRC) algorithm has been developed to calculate estimates of the linear coupling between heart rate and respiration. WTCRC values range from 1 (high coherence, no nociception) to 0 (low coherence, strong nociception). We have assessed the algorithm's ability to detect movement events (indicative of patient response to nociception) in 39 pediatric patients receiving general anesthesia. Sixty movement events were recorded during the 39 surgical procedures. Minimum and average WTCRC were calculated in a 30 second window surrounding each movement event. We used a 95% significance level as the threshold for detecting nociception during patient movement. The 95% significance level was calculated relative to a red noise background, using Monte Carlo simulations. It was calculated to be 0.7. Values below this threshold were treated as successful detection. The algorithm was found to detect movement with sensitivity ranging from 95% (minimum WTCRC) to 65% (average WTCRC). The WTCRC algorithm thus shows promise for noninvasively monitoring nociception during general anesthesia, using only heart rate and respiration. PMID- 22255735 TI - Development of double density whole brain fNIRS with EEG system for brain machine interface. AB - Brain-machine interfaces (BMI) are expected as new man-machine interfaces. Non invasive BMI have the potential to improve the quality of life of many disabled individuals with safer operation. The non-invasive BMI using the functional functional near-infrared spectroscopy (fNIRS) with the electroencephalogram (EEG) has potential applicability beyond the restoration of lost movement and rehabilitation in paraplegics and would enable normal individuals to have direct brain control of external devices in their daily lives. To shift stage of the non invasive BMI from laboratory to clinical, the key factor is to develop high accuracy signal decoding technology and highly restrictive of the measurement area. In this article, we present the development of a high-accuracy brain activity measurement system by combining fNIRS and EEG. The new fNIRS had high performances with high spatial resolution using double density technique and a large number of measurement channels to cover a whole human brain. PMID- 22255736 TI - Measurements of right / left hemisphere activation using functional near-infrared spectroscopy during incongruent Stroop test. AB - The human brain automatically processes information at multiple sites when recognizing various types of information at the same time, such as color, shape, etc. Cognitive conflict may occur when conflicting information is recognized at the same time. Functional near-infrared spectroscopy (fNIRS) is often used to examine the brain activity associated with this phenomenon. To examine activation of the visual system, we measured brain activity in the right / left hemispheres during cognitive conflict in the Stroop test. Consistent with the results reported previously by Ehlis, the brain activity in the near inferior-frontal gyrus of the left hemisphere was increased during the incongruent task. The brain activity also increased in the near inferior-frontal gyrus of the right hemisphere during the incongruent task. These results indicated that fNIRS can be used to detect brain activity in the inferior-frontal gyrus of the right / left hemispheres during the Stroop test. PMID- 22255737 TI - A statistical model of retinal optical coherence tomography image data. AB - Optical coherence tomography (OCT) is an important mode of biomedical imaging for the diagnosis and management of ocular disease. Here we report on the construction of a synthetic retinal OCT image data set that may be used for quantitative analysis of image processing methods. Synthetic image data were generated from statistical characteristics of real images (n = 14). Features include: multiple stratified layers with representative thickness, boundary gradients, contour, and intensity distributions derived from real data. The synthetic data also include retinal vasculature with typical signal obscuration beneath vessels. This synthetic retinal image can provide a realistic simulated data set to help quantify the performance of image processing algorithms. PMID- 22255738 TI - Optical coherence tomography: Health information embedded on OCT signal statistics. AB - Optical coherence tomography is becoming one of the most important imaging modalities in the area of ophthalmology because of being noninvasive and by allowing to visualize the human retina structure in detail. It was recently proposed that OCT data embeds functional information from the human retina. Specifically, it was proposed that blood-retinal barrier status information is present within OCT data. Following this rationale, in this work we illustrate (based on support vector machines) the possibility to discriminate between eyes from healthy volunteers, eyes from type 2 diabetic patients with no signs of diabetic retinopathy (ETDRS level 10 eyes) and eyes diagnosed with diabetic macular edema, thus confirming the presence within OCT data of information on the BRB status. PMID- 22255739 TI - 23 kHz MEMS based swept source for optical coherence tomography imaging. AB - The transition from benchtop to clinical system often requires the medical technology to be robust, portable and accurate. This poses a challenge to current swept source optical coherence tomography imaging systems, as the bulk of the systems footprint is due to laser components. With the recent advancement of micromachining technology, we demonstrate the characterization of a microelectromechanical system (MEMS) swept source laser for optical coherence tomography imaging (OCT). This laser utilizes a 2 degree of freedom MEMS scanning mirror and a diffraction grating, which are arranged in a Littrow configuration. This resulted in a swept source laser that was capable of scanning at 23.165 kHz (bidirectional) or 11.582 kHz (unidirectional). The free spectral range of the laser was ~ 100 nm with a central wavelength of ~ 1330 nm. The 6 dB roll off depth was measured to be at 2.5 mm. Furthermore, the structural morphology of a human finger and tadpole (Xenopus laevis) were evaluated. The overall volumetric footprint of the laser source was measured to be 70 times less than non-MEMS swept sources. Continued work on the miniaturization of OCT system is on going. It is hypothesized that the overall laser size can be reduced for suitable OCT imaging for a point of care application. PMID- 22255740 TI - Ontology-based malaria parasite stage and species identification from peripheral blood smear images. AB - The diagnosis and treatment of malaria infection requires detecting the presence of the malaria parasite in the patient as well as identification of the parasite species. We present an image processing-based approach to detect parasites in microscope images of a blood smear and an ontology-based classification of the stage of the parasite for identifying the species of infection. This approach is patterned after the diagnosis approach adopted by a pathologist for visual examination, and hence, is expected to deliver similar results. We formulate several rules based on the morphology of the basic components of a parasite, namely, chromatin dot(s) and cytoplasm, to identify the parasite stage and species. Numerical results are presented for data taken from various patients. A sensitivity of 88% and a specificity of 95% is reported by evaluation of the scheme on 55 images. PMID- 22255741 TI - Development of three dimensional blood vessel search system by using on stereo and autofocus hybrid method. AB - In this study, we developed an accurate three dimensional blood vessel search (3D BVS) system and an automatic operated blood sampling system. These systems were implemented into the point-of-care system for the ubiquitous medical care, which was featured as the portable type self-monitoring blood glucose (SMBG) devise. It resolved the human error problem, which causes by the complicated manual operation of blood sampling and blood glucose measurement in conventional SMBG devices. In this study, we mainly discuss the performance examination of accurate position detection of blood vessel. Our 3D BVS system employed the near-infrared (NIR) light imaging process and the stereo and autofocus hybrid method to determine the 3D blood vessel location accurately. We evaluated the accuracy of our 3D BVS system by using the phantom of human skin, blood vessel and blood. As a result, we validated a very good performance ability of our 3D BVS system for a portable type SMBG device. PMID- 22255742 TI - Thermal infrared imaging: toward diagnostic medical capability. AB - Thermal infrared imaging (TIRI) employs a focal plane array (FPA) of infrared detectors, with associated optics and optoelectronics to remotely detect and topographically map thermal emittance. Thermal and optical properties of human physioanatomy are not fully understood yet confounding diagnostic interpretation of human TIRI's. Elucidation of the specific physical mechanism via which thermal emission arises from human anatomy in-vivo requires empirical investigation under objective clinical protocols. This paper characterizes the fundamental architecture of the clinical TIRI system with a view to facilitation of objective protocol development, elucidation of the mechanism/s of human thermal infrared emittance, and eventual validation of TIRI as a diagnostic medical tool. Relevant recent and ongoing empirical studies by the authors are also summarized. PMID- 22255743 TI - Spatiotemporal changes of cerebral blood flow following hemorrhagic stroke by laser speckle imaging. AB - Hemorrhagic stroke accounts for more than 15% of all stroke hospitalization with much higher mortality than ischemic stroke. In this study, we investigated the spatiotemporal changes of the cerebral blood flow (CBF) following intracerebral hemorrhagic (ICH) stroke by laser speckle imaging. Adult male C57BL/6 mice were divided into ICH group (n=7) and saline group (n=4). CBF images were recorded before injury, 30 minutes, 24, 48, and 72 hours after stroke. Results showed that both ipsilateral CBF and contralateral CBF significantly reduced in two groups, which suggested that the mass effect was the dominant factor in the early stage of hemorrhagic brain injury. In ICH group, although the lesion was mainly around the injection location at first, hematoma could last for a long period of time and cause a secondary brain injury. The preliminary results showed that laser speckle imaging demonstrated its reliability with high spatiotemporal resolution in imaging mouse CBF with hemorrhagic stroke. PMID- 22255744 TI - Detection of unstained living neurospheres from phase contrast images with very large illumination variations. AB - Live imaging of neural stem cells and progenitors is important to follow the biology of these cells. Non-invasive imaging techniques, such as phase contrast microscopy, are preferred as neural stem cells are very sensitive to photoxic damage cause by excitation of fluorescent molecules. However, large illumination variations and weak foreground/background contrast make phase contrast images challenging for image processing. In the current work, we propose a new method to segment neurospheres imaged under phase contrast microscopy by employing high dynamic range imaging and advanced level-set method. The use of high dynamic range imaging enhances the fused image by expressing cell signatures from various exposure captures. We apply advanced level-set method in cell segmentation to improve the detection rate over simple methods such as thresholding. Validation experiments in the analysis of 21 images containing over 400 cells have demonstrated accuracy improvements over existing techniques. PMID- 22255745 TI - L1-regularized Cerenkov luminescence tomography with a SP3 method and CT fusion. AB - Imaging modality of radionuclides has been enriched by an optical approach, Cerenkov luminescence tomography (CLT). Referred to the traditional radionuclide imaging, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), any incremental improvement of CLT imaging is consistent with the application to information needs. In this contribution, the paper presents an l(1)-regularized imaging method for CLT problem. After utilizing the Vavilov-Cerenkov effect via third-order simplified spherical harmonics (SP(3)) approximation, we establish the large-scale linear equations in the CLT framework. The derived linear problem is seriously ill-posed, and transformed into an l(1)-regularized least squares program. The inverse solution to these equations is the three-dimensional radioisotope recovery data by an interior-point method. In the physical phantom and the in vivo mouse experiment, results demonstrate that the proposed technique produces better imaging quality and improves the reconstruction efficacy, compared with those from diffusion approximation with the Tikhonov regularization. PMID- 22255746 TI - Mosaicing of optical microscope imagery based on visual information. AB - Tools for high-throughput high-content image analysis can simplify and expedite different stages of biological experiments, by processing and combining different information taken at different time and in different areas of the culture. Among the most important in this field, image mosaicing methods provide the researcher with a global view of the biological sample in a unique image. Current approaches rely on known motorized x-y stage offsets and work in batch mode, thus jeopardizing the interaction between the microscopic system and the researcher during the investigation of the cell culture. In this work we present an approach for mosaicing of optical microscope imagery, based on local image registration and exploiting visual information only. To our knowledge, this is the first approach suitable to work on-line with non-motorized microscopes. To assess our method, the quality of resulting mosaics is quantitatively evaluated through on purpose image metrics. Experimental results show the importance of model selection issues and confirm the soundness of our approach. PMID- 22255747 TI - Vignetting correction by exploiting an optical microscopy image sequence. AB - Vignetting is one of the most common problem that may affect digital imaging. The effect becomes particularly evident when images are stitched together to increase the camera's field of view (e.g., when building a mosaic), where it can lead to errors in automatic analyses. To correct the effect, the most common approach is to acquire an empty field image in advance that is used later to perform a flat field correction on every subsequently acquired image. However, in several cases, such as when dealing with off-line images or with real time acquisitions, this is not a viable option. The method we propose relies on a non parametric model to characterize in real time the vignetting function from the specimen itself, by using our foreground/background segmentation algorithm. The function is computed over a background built incrementally, detecting regions free of objects of interest. The experiments carried out using cell cultures and histological samples prove that our method yields results at least comparable to those achieved by using empty field. PMID- 22255748 TI - Next generation optical surface sensing for real-time measurement in radiotherapy. AB - With the introduction of intensive new treatments such as hypo-fractionation and proton beam therapy, localization of the tumor target volume and tracking of points across the skin entrance surface have become critically important. Optical metrology has been used to monitor the patient's bulk position and motion throughout treatment. However systems have not been capable of high temporal and spatial resolution whole-surface topology measurement. We describe the implementation of such a system based on Fourier profilometry. Its algorithm is split into four separate processing stages, including spatial phase determination: descriptions of each stage are given along with the modifications made to increase performance. The optimized system is capable of processing 23 frames per second (fps), with each frame providing 512 * 512 measured points. The data density, accuracy and performance of the system are an order of magnitude improvement on commercially available clinical systems. We show that this performance permits genuinely real-time measurement of a patient, live during both setup and radiation treatment delivery. It is also fast enough to provide smooth dynamic visualizations of motion at all points on the wrap-around body surface for radiotherapy staff and intuitive, direct feed-back to patients. PMID- 22255749 TI - Automatic cell tracking applied to analysis of cell migration in wound healing assay. AB - The wound healing assay in vitro is widely used for research and discovery in biology and medicine. This assay allows for observing the healing process in vitro in which the cells on the edges of the artificial wound migrate toward the wound area. The influence of different culture conditions can be measured by observing the change in the size of the wound area. For further investigation, more detailed measurements of the cell behaviors are required. In this paper, we present an application of automatic cell tracking in phase-contrast microscopy images to wound healing assay. The cell behaviors under three different culture conditions have been analyzed. Our cell tracking system can track individual cells during the healing process and provide detailed spatio-temporal measurements of cell behaviors. The application demonstrates the effectiveness of automatic cell tracking for quantitative and detailed analysis of the cell behaviors in wound healing assay in vitro. PMID- 22255750 TI - Synthesis of cervical tissue second harmonic generation images using Markov random field modeling. AB - This paper presents a statistical image modeling approach based on Markov random field to synthesize cervical tissue second harmonic generation (SHG) images. Binary images representing fiber and pore areas of the cervix tissue are first obtained from SHG images using an image processing pipeline consisting of noise removal, contrast enhancement and optimal thresholding. These binary images are modeled using a Markov random field whose parameters are estimated via the least squares method. The parameters are then used to synthesize fiber and pore areas of cervical tissue in the form of binary images. The effectiveness of the synthesis is demonstrated by reporting the classification outcome for two classes of cervical SHG images collected from mice at two different stages of normal pregnancy. The developed synthesis allows generation of realistic fiber and pore area binary images for cervical tissue studies. PMID- 22255751 TI - Improving osteoporosis diagnosis in children using image texture analysis. AB - Bone mineral density (BMD) is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk. From a technical point of view Quantitative Computed Tomography (QCT) should be the gold standard in bone densitometry. On the other hand, it is known that a greater percentage increase in skin dose is needed as the patient size is increased: positive results and side effect of long term steroid treatment as obesity have been found for Duchenne muscular dystrophy (DMD), characterized by a progressive muscle degeneration and substitution with fat. The present work is an effort to improve osteoporosis diagnostic efficacy in children by analyzing the trabecular bone texture in CT L3 vertebra by two methods which are independent of image intensity: fractal dimension with power spectrum and wavelet packets. As results, comparing healthy children (44 children both sexes) with osteoporotic subjects (13 adult women, aged 52-87 years) great differences were noticed in all image texture indicators (p<0.0146). For DMD children (7 boys, not overweight) classified by z-score as osteoporotic because of their low BMD, texture image analysis did not exhibited high spatial frequencies as in the osteoporotic group; the probability that these two groups were similar was weak (p<0.0059), suggesting a more similar bone condition to normal or osteopenia. None of the pediatric groups exhibited as high spatial frequencies as did the osteoporotic women group. These analyses could help to determine osteoporosis in children, where it is often a diagnostic challenge. PMID- 22255752 TI - Semi-automated segmentation and classification of digital breast tomosynthesis reconstructed images. AB - Digital breast tomosynthesis (DBT) is a limited-angle tomographic x-ray imaging technique that reduces the effect of tissue superposition observed in planar mammography. An integrated imaging platform that combines DBT with near infrared spectroscopy (NIRS) to provide co-registered anatomical and functional imaging is under development. Incorporation of anatomic priors can benefit NIRS reconstruction. In this work, we provide a segmentation and classification method to extract potential lesions, as well as adipose, fibroglandular, muscle and skin tissue in reconstructed DBT images that serve as anatomic priors during NIRS reconstruction. The method may also be adaptable for estimating tumor volume, breast glandular content, and for extracting lesion features for potential application to computer aided detection and diagnosis. PMID- 22255753 TI - Spatially different, real-time temporal filtering and dose reduction for dynamic image guidance during neurovascular interventions. AB - Fluoroscopic systems have excellent temporal resolution, but are relatively noisy. In this paper we present a recursive temporal filter with different weights (lag) for different user selected regions of interest (ROI) to assist the neurointerventionalist during an image guided catheter procedure. The filter has been implemented on a Graphics Processor (GPU), enabling its usage for fast frame rates such as during fluoroscopy. We first demonstrate the use of this GPU implemented rapid temporal filtering technique during an endovascular image guided intervention with normal fluoroscopy. Next we demonstrate its use in combination with ROI fluoroscopy where the exposure is substantially reduced in the peripheral region outside the ROI, which is then software-matched in brightness and filtered using the differential temporal filter. This enables patient dose savings along with improved image quality. PMID- 22255754 TI - Osteophyte detection for hand osteoarthritis identification in x-ray images using CNNs. AB - In this paper we describe a class of analog algorithms based on the concept of cellular neural networks (CNNs) for detecting osteoarthritis (OA) from x-ray images. The indicator of OA that we examine is the presence of bony spurs or osteophytes in the vicinity of the weight bearing joints of the fingers. Results on a series of hand x-ray images are shown to be promising. PMID- 22255755 TI - Efficient and effective regularised ART for computed tomography. AB - Algebraic Reconstruction Technique (ART) is a widely employed method in computed tomography since it has certain advantages, such as allowing reconstruction of data with missing projections in some angle ranges, over other techniques such as Filtered Back Projection (FBP). Recently, a regularisation technique for ART, RegART, was introduced which provides greatly reduced noise levels. However, a serious drawback of both ART and RegART is the computational complexity of the methods. In this paper, we present a fast version of RegART, which makes use of nVidia's CUDA technology, and show that this approach performs favourably compared to FBP. PMID- 22255756 TI - Automatic Dent-landmark detection in 3-D CBCT dental volumes. AB - Orthodontic craniometric landmarks provide critical information in oral and maxillofacial imaging diagnosis and treatment planning. The Dent-landmark, defined as the odontoid process of the epistropheus, is one of the key landmarks to construct the midsagittal reference plane. In this paper, we propose a learning-based approach to automatically detect the Dent-landmark in the 3D cone beam computed tomography (CBCT) dental data. Specifically, a detector is learned using the random forest with sampled context features. Furthermore, we use spacial prior to build a constrained search space other than use the full three dimensional space. The proposed method has been evaluated on a dataset containing 73 CBCT dental volumes and yields promising results. PMID- 22255757 TI - An automatic detection method for carotid artery calcifications using top-hat filter on dental panoramic radiographs. AB - The purpose of this study is to develop an automated carotid artery calcification (CAC) detection scheme on dental panoramic radiographs (DPRs). The CAC is one of the indices for predicting the risk of arteriosclerosis. First, regions of interest (ROIs) that include CACs were determined on the basis of inflection points of the mandibular contour. Initial CAC candidates were detected by using a grayscale top-hat filter and simple grayscale thresholding technique. Finally, a rule-based approach and support vector machine to reduce the number of false positive (FP) findings were applied using features such as area, location, and circularity. Thirty-four DPRs were used to evaluate the proposed scheme. The sensitivity for the detection of CACs was 93.6% with 4.4 FPs per image. Experimental results showed that our computer-aided detection scheme may be useful to detect CACs. PMID- 22255758 TI - Recognition-based segmentation and registration method for image guided shoulder surgery. AB - For any image guided surgery, independently of the technique which is used (navigation, templates, robotics), it is necessary to get a 3D bone surface model from CT or MR images. Such model is used for planning, registration and visualization. We report that graphical representation of patient bony structure and the surgical tools, interconnectively with the tracking device and patient-to image registration are crucial components in such a system. For Total Shoulder Arthroplasty (TSA), there are many challenges, The most of cases that we are working with are pathological cases such as rheumatoid arthritis, osteoarthritis disease. The CT images of these cases often show a fusion area between the glenoid cavity and the humeral head. They also show severe deformations of the humeral head surface that result in a loss of contours. This fusion area and image quality problems are also amplified by well-known CT-scan artifacts like beam-hardening or partial volume effects. The state of the art shows that several segmentation techniques, applied to CT-Scans of the shoulder, have already been disclosed. Unfortunately, their performances, when used on pathological data, are quite poor [1, 2]. The aim of this paper is to present a new image guided surgery system based on CT scan of the patient and using bony structure recognition, morphological analysis for the operated region and robust image-to-patient registration. PMID- 22255759 TI - Monitoring pulmonary fibrosis by fusing clinical, physiological, and computed tomography features. AB - Advances in medical imaging and screening tests have made possible the detection and diagnosis of many diseases in their early stages. Those advances have enabled more effective planning, execution, and monitoring of a treatment plan. However, early detection has also resulted in an increase of the number of longitudinal radiographs requested for most patients, thus increasing the risk for potential long-term effects of ionizing radiation exposure and increasing the cost associated with a specific treatment plan. The aim of this paper is to study the associations between clinical measurements and quantitative image features in patients with pulmonary fibrosis. The association between these multi-modal features could be used to more accurately determine the state of the disease and could potentially be used to predict many of the longitudinal image features when CT images are not available. Our results show how textural image features are highly correlated with the severity of fibrosis, how clinical variables can be combined to monitor progression, and how simple blood features can be used to predict statistical image attributes of the lungs. PMID- 22255760 TI - Principal curve based semi-automatic segmentation of organs in 3D-CT. AB - Radiation therapy plays an important and effective role in the treatment of cancer. A main goal in radiation therapy is to deliver high radiation doses to the perceived tumors while minimizing radiation to surrounding normal tissues. Manual delineation of tumors and organs-at-risk(OARs) on three-dimensional computed tomography (3D-CT) is both a time-consuming and labor intensive task, and there maybe variability between manual delineations by different radiation oncologists. In this paper, we present a semi-supervised method to segment the contours of organs represented by piecewise linear segments connected with a small number of points given the user's input in one or more slices as an approximate initialization. This method detects ridge samples from the kernel interpolation of the edge map and approximates the shape of organs using piecewise linear segments among those sample points based on the principal curve score. Results are provided in two 3D-CT scans. Evaluation of the efficacy of our semiautomatic segmentation method is based on the overlapping ratio between the manually delineated contours and the semiautomatic segmented contours represented by a small number of points. The preserved points can be as low as 10 percent of the initial manual points, and the Dice Coefficients are approximately 0.93 for lung segmentation. PMID- 22255761 TI - Automatic optic disc segmentation with peripapillary atrophy elimination. AB - Optic disc segmentation from retinal fundus image is a fundamental but important step for automatic glaucoma diagnosis. In this paper, an optic disc segmentation method is proposed based on peripapillary atrophy elimination. The elimination is done through edge filtering, constraint elliptical Hough transform and peripapillary atrophy detection. With the elimination, edges that are likely from non-disc structures especially peripapillary atrophy are excluded to make the segmentation more accurate. The proposed method has been tested in a database of 650 images with disc boundaries marked by trained professionals manually. The experimental results by the proposed method show average m(1), m(2) and m(VD) of 10.0%, 7.4% and 4.9% respectively. It can be used to compute cup to disc ratio as well as other features for application in automatic glaucoma diagnosis systems. PMID- 22255762 TI - MRMR optimized classification for automatic glaucoma diagnosis. AB - Min-Redundancy Max-Relevance (mRMR) is a feature selection methodology based on information theory. We explore the mRMR principle for automatic glaucoma diagnosis. Optimal candidate feature sets are acquired from a composition of clinical screening data and retinal fundus image data. An mRMR optimized classifier is further trained using the candidate feature sets to find the optimized classifier. We tested the proposed methodology on eye records of 650 subjects collected from Singapore Eye Research Institute. The experimental results demonstrate that the new classifier is much compact by using less than 1/4 of the initial feature set. The ranked feature set also enables the clinicians to better access the diagnostic process of the algorithm. The work is a further step towards the advancement of the automatic glaucoma diagnosis. PMID- 22255763 TI - Automated detection of red lesions from digital colour fundus photographs. AB - Earliest signs of diabetic retinopathy, the major cause of vision loss, are damage to the blood vessels and the formation of lesions in the retina. Early detection of diabetic retinopathy is essential for the prevention of blindness. In this paper we present a computer-aided system to automatically identify red lesions from retinal fundus photographs. After pre-processing, a morphological technique was used to segment red lesion candidates from the background and other retinal structures. Then a rule-based classifier was used to discriminate actual red lesions from artifacts. A novel method for blood vessel detection is also proposed to refine the detection of red lesions. For a standarised test set of 219 images, the proposed method can detect red lesions with a sensitivity of 89.7% and a specificity of 98.6% (at lesion level). The performance of the proposed method shows considerable promise for detection of red lesions as well as other types of lesions. PMID- 22255764 TI - Statistical characterization and segmentation of drusen in fundus images. AB - Age related Macular Degeneration (AMD) is a disease of the retina associated with aging. AMD progression in patients is characterized by drusen, pigmentation changes, and geographic atrophy, which can be seen using fundus imagery. The level of AMD is characterized by standard scaling methods, which can be somewhat subjective in practice. In this work we propose a statistical image processing approach to segment drusen with the ultimate goal of characterizing the AMD progression in a data set of longitudinal images. The method characterizes retinal structures with a statistical model of the colors in the retina image. When comparing the segmentation results of the method between longitudinal images with known AMD progression and those without, the method detects progression in our longitudinal data set with an area under the receiver operating characteristics curve of 0.99. PMID- 22255765 TI - Retinal image registration based on multiscale products and optic disc detection. AB - This paper presents a new approach to segmentation-driven retinal image registration. The proposed algorithm aims to help physicians to detect changes that occur in the blood vasculature due to various diseases. The proposed approach uses multiscale products, which augment the difference between blood vessels and the rest of the retina. The result of scale multiplication is then iteratively thresholded in order to obtain a binary map of vessels inside the retina. For the registration part, the centre of the optic disc is detected and used as control point. Having determined both the position of the blood vessels and the centre of the optic disc, translational and rotational differences between the images can be eliminated and registration can be achieved. The centroid of the optic disc is used as the center of rotation. The final registration is then achieved by searching the best match between the two images using a XOR operation. PMID- 22255766 TI - Predicting phosphene elicitation in patients with retinal implants: a mathematical study. AB - Single pulse waveforms were considered in a recent model for phosphene elicitation in patients with a retinal prosthesis. Waveforms are constrained to charge-balanced stimuli consisting of a single cathodic and anodic pulse pair. Mathematical models of such stimuli have been constructed and presented based upon patient testimonials. In this work, we derive analytic expressions that may be employed to determine equibrightness levels for different waveforms. We provide an example calculation to show quantitative improvements in stimulation efficiency that are consistent with qualitative findings on waveform effects. PMID- 22255767 TI - Thermographic investigation of osseous stress pathology. AB - The debilitating pathology of stress fracture accounts for 10% of all athletic injuries[2], with prevalence as high as 20% in modern military basic training cohorts [3]. Increasing concerns surrounding adverse effects of radiology [5], combined with the 12.5% contribution of diagnostic imaging to Australian Medicare benefits paid in 2009-10 [6], have prompted the search for alternative/adjunct electronic decision support systems[7]. Within conducive physioanatomic milieu, thermal infrared imaging (TIRI) may feasibly be used to remotely detect and topographically map diagnostically useful signs of suprathreshold thermodynamic pathophysiology. This paper details a three month clinical pilot study into TIRI based detection of osseous stress pathology in the lower legs of Australian Army basic trainees. A dataset of over 500 TIRI's was amassed. The apparent 'normal' thermal profile of the anterior aspect of the asymptomatic lower leg is topographically defined and validated against current thermophysiological theory [8] via cadaveric dissection. PMID- 22255768 TI - Changes of skin temperature of parts of the body and serum asymmetric dimethylarginine (ADMA) in type-2 diabetes mellitus Indian patients. AB - In India, number of people with type 2 Diabetes Mellitus (DM) would be 87 million by the year 2030. DM disturbs autonomic regulation of skin micro-circulation, and causes decrease in resting blood flows through the skin. The skin blood flow has a major effect on its temperature. The aim of the study was to evaluate changes of skin temperature of all parts of the body and serum asymmetric dimethylarginine, ADMA (MUmol/L) in type-2 DM Indian patients. Group-I: Normal (n = 17; M/F: 10/15, mean +/- SD = 43.2 +/- 9.4 years); Group-II: Type-2 DM without cardiovascular (CV) complications (n = 15; M/F: 10/7, mean +/- SD = 46.3 +/- 14.0 years); Thermograms of all parts of the body were acquired using a non-contact infrared (IR) thermography camera (ThermaCAM T400, FLIR Systems, Sweden). Blood parameters and thyroid hormone were measured biochemically. Indian diabetic risk score (IDRS) was calculated for each subject. In type-2 DM patients without CV group (n = 15), there was a statistically significant (p = 0.01) negative correlations between HbA(1c) and skin temperature of eye and nose (r = -0.57 and r = -0.55 respectively). ADMA was correlated significantly (p = 0.01) with HbA(1c) (r = 0.65) and estimated average glucose, eAG (r = 0.63). In normal subjects, mean minimum and maximum values of skin temperatures were observed at posterior side of sole (26.89 degrees C) and ear (36.85 degrees C) respectively. In type-2 DM without CV, mean values of skin temperature in different parts of the body from head to toe were lesser than those values in control group; but this decreases were statistically significant in nose (32.66 Vs 33.99 degrees C, p = 0.024) as well as in tibia (32.78 Vs 33.13 degrees C, p = 0.036) regions. PMID- 22255769 TI - A method for measuring the accuracy of multi-modal image fusion system for catheter-based cardiac interventions using a novel motion enabled targeting phantom. AB - Targeted stem cell therapy offers great potential for the repair of infarcted cardiac tissue following heart attack. Safe delivery of stem-cells via catheter based interventions remains a challenge. A multi-modal image fusion approach has been considered for safe targeting of myocardial infarct border zones. In this paper we present an apparatus and method for measuring the accuracy of catheter based injections using a multi-modal image fusion system. We also present results of the accuracy of our image fusion system under varying levels of cardio respiratory motion. PMID- 22255770 TI - Gait analysis with multiple depth cameras. AB - The gait movement seems simple at first glance, but in reality it is a very complex neural and biomechanical process. In particular, if a person is affected by a disease or an injury, the gait may be modified. To help detecting such change, we propose a new method based on multiple depth cameras. The aim of this paper is to show the possibility to reconstruct the body 3D volume in real time during gait in order to detect a pathological problem related to this movement and eventually improve diagnosis. Preliminary results showed that the system is sensitive to gait change produced by a heel prosthesis (heel cup) inserted in one shoe of subjects walking on a treadmill. The system detected a difference between maximal forward and backward positions of lower limbs for this pathological walk, a difference that was negligible for normal walk. These promising results were obtained with only 3 low cost depth cameras; we therefore believe that such methodology opens a new and affordable way for 3D volumetric gait analysis. PMID- 22255771 TI - Spatially weighted mutual information (SWMI) for registration of digitally reconstructed ex vivo whole mount histology and in vivo prostate MRI. AB - In this work, we present a scheme for the registration of digitally reconstructed whole mount histology (WMH) to pre-operative in vivo multiprotocol prostate MR imagery (T2w and DCE) using spatially weighted mutual information (SWMI). Spatial alignment of ex vivo histological sections to pre-operative in vivo MRI for prostate cancer (CaP) patients undergoing radical prostatectomy is a necessary first step in the discovery of quantitative multiprotocol MRI signatures for CaP. This may be done by spatially mapping delineated extent of disease on ex vivo histopathology onto pre-operative in vivo MRI via image registration. Apart from the challenges in spatially registering multi-modal data (histology and MRI) on account of (a) modality specific differences, (b) deformation due to the endorectal coil and tissue loss on histology, another complication is that the ex vivo histological sections, in the lab, are usually obtained as quadrants. This means they need to be reconstituted as a pseudo-whole mount histologic section (WMHS) prior to registration with MRI. An additional challenge is that most registration techniques rely on availability of the pre-segmented prostate capsule on T2w MRI. The novel contribution of this paper is that it leverages a spatially weighted mutual information (SWMI) scheme to automatically register and map CaP extent from WMHS onto pre-operative, multiprotocol MRI. The SWMI scheme obviates the need for pre-segmentation of the prostate capsule on MRI. Additionally, we leverage a program developed by our group, Histostitcher(c), for interactive stitching of individual histology quadrants to digitally reconstruct the pseudo WMHS. Our registration methodology comprises the following main steps, (1) affine registration of T2w and DCE MRI, (2) affine registration of stitched WMHS to multiprotocol T2w and DCE MRI, and (3) multimodal image registration of WMHS to multiprotocol T2w and DCE MRI using SWMI. We quantitatively and qualitatively evaluated all aspects of our methodology in the multimodal registration of a total of 7 corresponding histology and MRI sections from 2 different patients. For the 7 studies, we obtained an average Hausdorff distance of 1.85 mm, mean absolute distance of 0.99 mm, RMS of 1.65 mm, and DICE of 0.83, when comparing the capsular alignment on MRI to histology. PMID- 22255772 TI - Real-time quantitative ex vivo direct autoradiography with 10 MUm pixel resolution. AB - We present three new autoradiography methods to map positron emission rate of a bio-specimen slice with high resolution. One is based on LBNL scientific charge coupled device (CCD) and the other two are based on conventional CCDs. High conversion efficiency (100k e-h pairs / 0.5 MeV positron) and low dark current (1.75 * 10(-4) e-/pix/sec) can be achieved using the LBNL CCD. The theoretical calculations and preliminary experiments show that an 86 MUm spatial resolution can be achieved when imaging a 100 MUm thick tissue soaked with (18)F which produce higher energy positron. The main disadvantage of the LBNL CCD we tested is that a very low operating temperature is required to eliminate dark current. This dramatically increases the system cost. In addition, the integration time of the CCD needs to be short enough to avoid overlapping of the positron trajectories. Conventional CCDs have lower conversion efficiency (2k e-h pairs / 0.5 MeV positron) and higher dark current (200 e-/pix/sec), but are more cost efficient and the requirement for the readout frequency is much lower. The conversion efficiency of the conventional CCD imager can be improved by 17 times by inserting a 100 MUm layer of phosphor between the sample and the imager. However, the light emitted from the phosphor screen will be ~100 MUm diameter, which severely degrades the spatial resolution. A high readout frequency is also required to avoid the overlapping. The CCD systems designed in this study will be used to map positron emission rate of bio-specimens such as cancerous tissues acquired in regular biopsy procedure. They can also be used to corroborate tracer kinetic modeling at a cellular level. PMID- 22255773 TI - An EEG-based brain computer interface for rehabilitation and restoration of hand control following stroke using ipsilateral cortical physiology. AB - The loss of motor control severely impedes activities of daily life. Brain computer interfaces (BCIs) offer new possibilities to treat nervous system injuries, but conventional BCIs use signals from primary motor cortex, the same sites most likely damaged in a stroke causing paralysis. Recent studies found distinct cortical physiology associated with contralesional limb movements in regions distinct from primary motor cortex. To capitalize on these findings, we designed and implemented a BCI that localizes and acquires these brain signals to drive a powered, hand orthotic which opens and closes a patient's hand. PMID- 22255774 TI - Classification of intended motor movement using surface EEG ensemble empirical mode decomposition. AB - Noninvasive electroencephalography (EEG) brain computer interface (BCI) systems are used to investigate intended arm reaching tasks. The main goal of the work is to create a device with a control scheme that allows those with limited motor control to have more command over potential prosthetic devices. Four healthy subjects were recruited to perform various reaching tasks directed by visual cues. Independent component analysis (ICA) was used to identify artifacts. Active post parietal cortex (PPC) activation before arm movement was validated using EEGLAB. Single-trial binary classification strategies using support vector machine (SVM) with radial basis functions (RBF) kernels and Fisher linear discrimination (FLD) were evaluated using signal features from surface electrodes near the PPC regions. No significant improvement can be found by using a nonlinear SVM over a linear FLD classifier (63.65% to 63.41% accuracy). A significant improvement in classification accuracy was found when a normalization factor based on visual cue "signature" was introduced to the raw signal (90.43%) and the intrinsic mode functions (IMF) of the data (93.55%) using Ensemble Empirical Mode Decomposition (EEMD). PMID- 22255775 TI - Classification of resting, anticipation and movement states in self-initiated arm movements for EEG brain computer interfaces. AB - In the last years, there has been an increasing interest in using Brain Computer Interfaces (BCI) within motor rehabilitation therapies that use robotic devices or functional electro stimulation to help or guide the efforts of the patient to move her body. A crucial step of these therapies is to provide help to the user just when she is actually trying to accomplish a certain motion or task One of the most promising applications of BCI systems in this context is its ability to measure the user intentions and actions to trigger the rehabilitation devices accordingly. This paper studies the single-trial classification based on EEG measurements of three basic states during the execution of self-initiated motion: rest, motion preparation (or anticipation) and motion. We conducted an experiment where the participants had to reach at their will eight different locations from a fixed starting position. Results for seven healthy subjects show that it is possible to achieve good classification rates given that features are carefully selected for each subject and for each pair of states. PMID- 22255776 TI - Single-trial EEG discrimination between wrist and finger movement imagery and execution in a sensorimotor BCI. AB - Brain-computer interface (BCI) may be used to control a prosthetic or orthotic hand using neural activity from the brain. The core of this sensorimotor BCI lies in the interpretation of the neural information extracted from electroencephalogram (EEG). It is desired to improve on the interpretation of EEG to allow people with neuromuscular disorders to perform daily activities. This paper investigates the possibility of discriminating between the EEG associated with wrist and finger movements. The EEG was recorded from test subjects as they executed and imagined five essential hand movements using both hands. Independent component analysis (ICA) and time-frequency techniques were used to extract spectral features based on event-related (de)synchronisation (ERD/ERS), while the Bhattacharyya distance (BD) was used for feature reduction. Mahalanobis distance (MD) clustering and artificial neural networks (ANN) were used as classifiers and obtained average accuracies of 65 % and 71 % respectively. This shows that EEG discrimination between wrist and finger movements is possible. The research introduces a new combination of motor tasks to BCI research. PMID- 22255777 TI - Decoding semantic information from human electrocorticographic (ECoG) signals. AB - This study examined the feasibility of decoding semantic information from human cortical activity. Four human subjects undergoing presurgical brain mapping and seizure foci localization participated in this study. Electrocorticographic (ECoG) signals were recorded while the subjects performed simple language tasks involving semantic information processing, such as a picture naming task where subjects named pictures of objects belonging to different semantic categories. Robust high-gamma band (60-120 Hz) activation was observed at the left inferior frontal gyrus (LIFG) and the posterior portion of the superior temporal gyrus (pSTG) with a temporal sequence corresponding to speech production and perception. Furthermore, Gaussian Naive Bayes and Support Vector Machine classifiers, two commonly used machine learning algorithms for pattern recognition, were able to predict the semantic category of an object using cortical activity captured by ECoG electrodes covering the frontal, temporal and parietal cortices. These findings have implications for both basic neuroscience research and development of semantic-based brain-computer interface systems (BCI) that can help individuals with severe motor or communication disorders to express their intention and thoughts. PMID- 22255778 TI - Using scalp electrical biosignals to control an object by concentration and relaxation tasks: design and evaluation. AB - In this paper we explore the use of electrical biosignals measured on scalp and corresponding to mental relaxation and concentration tasks in order to control an object in a video game. To evaluate the requirements of such a system in terms of sensors and signal processing we compare two designs. The first one uses only one scalp electroencephalographic (EEG) electrode and the power in the alpha frequency band. The second one uses sixteen scalp EEG electrodes and machine learning methods. The role of muscular activity is also evaluated using five electrodes positioned on the face and the neck. Results show that the first design enabled 70% of the participants to successfully control the game, whereas 100% of the participants managed to do it with the second design based on machine learning. Subjective questionnaires confirm these results: users globally felt to have control in both designs, with an increased feeling of control in the second one. Offline analysis of face and neck muscle activity shows that this activity could also be used to distinguish between relaxation and concentration tasks. Results suggest that the combination of muscular and brain activity could improve performance of this kind of system. They also suggest that muscular activity has probably been recorded by EEG electrodes. PMID- 22255779 TI - Mental tasks classification for BCI using image correlation. AB - This paper describes a classifier based on image correlation of EEG maps to distinguish between three mental tasks in a Brain-Computer Interface (BCI). The data set V of BCI Competition 2003 has been used to test the classifier. To that end, the EEG maps obtained from this data set have been studied to find the ideal parameters of processing time and frequency. The classifier designed is based on a normalized cross-correlation of images which makes possible to obtain a proper similarity index to perform the classification. The success percentage of the classifier has been shown for different combinations of data. The results obtained are very successful, showing that this kind of techniques may be able to classify between three mental tasks with good results in a future online testing. PMID- 22255781 TI - Multimodal target detection using single trial evoked EEG responses in single and dual-tasks. AB - The detection of event-related potentials in the electroencephalogram signal is a common way for creating a brain-computer interface (BCI). Successful detection of evoked responses can be enhanced by the user selectively attending to specific stimuli presented in the BCI task. Because BCI users need a system that performs well in a variety of contexts, even ones that may impair selective attention, it is critical to understand how single trial detection is affected by attention. We tested 16 participants using a rapid serial visual/auditory presentation paradigm under three conditions, one in which they detected the presence of a visual target, one in which they detected the presence of an auditory target, and one in which they detected both visual and auditory targets. The behavioral performance indicates that the visual task was more difficult than the auditory task. Consistent with the higher behavioral difficulty of the visual task, single trial performance showed no difference between single and dual-task for the visual target detection (mean=0.76). However, the area under the curve for the auditory target detection was significantly lower than the dual-task (mean=0.81 for single task, 0.75 for dual-task). The results support the conclusion that single-trial target detection is impaired when attention is divided between multiple tasks. PMID- 22255780 TI - Effect of competing stimuli on SSVEP-based BCI. AB - Steady-state visual evoked potential (SSVEP)-based Brain-Computer Interface (BCI) works on the basis that an attended stimulus shows an enhanced visual evoked response. By examining EEG power at the frequency of the dominant evoked response, we are able to determine which stimulus the subject is attending. However, due to the limited processing capability of human visual system, when presented with multiple stimuli in the same visual field, the stimuli will compete for neural representations in the cortices. This study elucidates the effect of competing stimuli on SSVEP amplitudes by exploring the relationship between the number of stimuli and their inter-distance on the power spectra of attended stimuli. Results show that competing stimuli, when placed less than five degrees from the centre of the fovea, create a significant suppressive effect on the dominant frequency response. This result should guide how visual stimuli of SSVEP-based BCIs are spatially designed. PMID- 22255782 TI - Skilled hindlimb reaching task in rats as a platform for a brain-machine interface to restore motor function after complete spinal cord injury. AB - Behavioral tasks utilized as models for decoding neural activity for use in brain machine interfaces are constrained primarily to forelimb tasks or locomotion. We present here our methodology for training adult rats in a novel skilled hindlimb 'reaching' task in which the animal is trained to make different types of hindlimb movements. 6 adult Long-Evans rats were trained to make variable duration (<1 or >1.5 s) hindlimb presses cued by a spatially-independent visual cue. 5 of 6 animals (83.3%) were able to learn the task to proficiency. The training paradigm introduced here serves as a platform to investigate the ability of the animal to transfer motor cortical activity in response to a cue originally generated during normal movments, to a novel context in the absecense of movement and ultimately after complete mid-thoracic spinal cord transection. We also present preliminary results of offline classification of neural activity during trial performance for two trained animals. PMID- 22255783 TI - A wireless multichannel EEG recording platform. AB - A wireless multichannel data acquisition system is being designed for ElectroEncephaloGraphy (EEG) recording. The system is based on a custom integrated circuit (ASIC) for signal conditioning, amplification and digitization and also on commercial components for RF transmission. It supports the RF transmission of a 32-channel EEG recording sampled at 1 kHz with a 12-bit resolution. The RF communication uses the MICS band (Medical Implant Communication Service) at 402-405 Mhz. This integration is a first step towards a lightweight EEG cap for Brain Computer Interface (BCI) studies. Here, we present the platform architecture and its submodules. In vivo validations are presented with noise characterization and wireless data transfer measurements. PMID- 22255784 TI - Motor imagery based brain-computer interface: a study of the effect of positive and negative feedback. AB - Co-adaptation between the human brain and computers is an important issue in brain-computer interface (BCI) research. However, most of the research has focused on the computer side of BCI, such as developing powerful machine-learning algorithms, while less research has focused on investigating how BCI users may optimally adapt. This paper assesses the influences of positive and negative visual feedback on motor imagery (MI) skills by evaluating the performance. More precisely, a MI based BCI paradigm was employed with fake visual feedback, regardless of subjects' real performance. Subjects were exposed to two experimental conditions--one positive and one negative, in which 80% or 30% of the trials were associated with positive feedback, respectively. The main EEG feature for MI-BCI classification--the asymmetry of mu-rhythm between hemispheres -was more prominent only after the negative feedback session. In addition, the negative feedback condition was accompanied by larger heart rate variability compared to the positive feedback condition. Our results suggest that visual feedback is an important aspect to take into account when designing BCI skill acquisition sessions. PMID- 22255785 TI - An optical brain computer interface for environmental control. AB - A brain computer interface (BCI) is a system that translates neurophysiological signals detected from the brain to supply input to a computer or to control a device. Volitional control of neural activity and its real-time detection through neuroimaging modalities are key constituents of BCI systems. The purpose of this study was to develop and test a new BCI design that utilizes intention-related cognitive activity within the dorsolateral prefrontal cortex using functional near infrared (fNIR) spectroscopy. fNIR is a noninvasive, safe, portable and affordable optical technique with which to monitor hemodynamic changes, in the brain's cerebral cortex. Because of its portability and ease of use, fNIR is amenable to deployment in ecologically valid natural working environments. We integrated a control paradigm in a computerized 3D virtual environment to augment interactivity. Ten healthy participants volunteered for a two day study in which they navigated a virtual environment with keyboard inputs, but were required to use the fNIR-BCI for interaction with virtual objects. Results showed that participants consistently utilized the fNIR-BCI with an overall success rate of 84% and volitionally increased their cerebral oxygenation level to trigger actions within the virtual environment. PMID- 22255786 TI - Estimating human response to taste using EEG. AB - In order to implement affective computing, there have been several studies to elicit human emotion using audio and video stimuli or by recalling previous events. Taste-elicited emotion has also been investigated using food to induce different levels of pleasure. This is monitored using a range of methods, from questionnaire feedback to electrophysiological responses of autonomic nervous system (ANS) and central nervous system (CNS). In this work, we establish that emotions elicited by taste can be monitored using electroencephalogram (EEG), and, for rigour, compare the response to a taste stimulus against the response to the recall of the same taste. The character of emotions were assessed using a subjective measurement, the hedonic score, which describes the pleasant or unpleasant moods of subjects in response to each taste. The classification performance of EEG responses shows excellent separability between the different emotions induced by different tastes. In addition, it is shown that emotion elicited by taste recall is stronger than the stimulus-elicited emotion. PMID- 22255787 TI - Hand movement decoding by phase-locking low frequency EEG signals. AB - Being noninvasive, low-risk and inexpensive, EEG is a promising methodology in the application of human Brain Computer Interface (BCI) to help those with motor dysfunctions. Here we employed a center-out task paradigm to study the decoding of hand velocity in the EEG recording. We tested the hypothesis using a linear regression model and found a significant correlation between velocity and the low pass filtered EEG signal (<2 Hz). The low-pass filtered EEG was not only tuned to the direction but also phase-locked to the amplitude of velocity. This suggests an EEG form of the neuronal population vector theory, which is considered to encode limb kinematic information, and provides a new method of BCI implementation. PMID- 22255788 TI - Towards a BCI for sensorimotor training: initial results from simultaneous fNIRS and biosignal recordings. AB - This paper presents the concept and initial results of a novel approach for robot assisted sensorimotor training in stroke rehabilitation. It is based on a brain body-robot interface (B(2)RI), combining both neural and physiological recordings, that detects the intention to perform a motor task. By directly including the injured brain into the therapy, we ultimately aim at providing a new method for severely impaired patients to engage in active movement therapy. In the present study, seven healthy subjects performed an isometric finger pinching task while functional near-infrared spectroscopy (fNIRS) signals from motor cortical areas and biosignals were recorded simultaneously. Results showed an insignificant increase in the blood pressure during the preparation period prior to motor execution. During the execution period, significant changes in oxy and deoxyhemoglobin were found in the primary motor cortex, accompanied by an increase in blood pressure, respiration rate and galvanic skin response (GSR). Cortical measurements of premotor areas and heart rate revealed significant changes at the subject level with large inter-subject variability. The results presented here will serve as priors for the design of further studies to test the efficacy of the concept with stroke patients, and the found effects will provide a basis for the development of a classifier for a future B(2)RI. PMID- 22255789 TI - Performance of common spatial pattern under a smaller set of EEG electrodes in brain-computer interface on chronic stroke patients: a multi-session dataset study. AB - Brain-computer interface (BCI) uses non-muscular channel of the nervous system for communication. Common Spatial Pattern (CSP) is a popular spatial filtering method used to reduce the effect of volume conduction on EEG signals. It is thought that CSP requires a large number of electrodes to be effective. Using a 20-session dataset of motor imagery BCI usage by 5 stroke patients, we demonstrated that after channel selection, CSP can still maintain a high accuracy with low number of electrodes using a newly proposed channel selection method called CSP-rank (higher than 90% with 8 electrodes). The results showed that using only the first session for channel selection, a high accuracy can be maintained in subsequent sessions. CSP-rank has been compared to the popular support vector machine recursive feature elimination (SVM-RFE). The results showed that the CSP-rank required less electrodes to maintain accuracy higher than 90% (a minimum of 8 compared to 12 of SVM-RFE) and it attained a higher maximum accuracy (91.7% compared with 90.7% of SVM-RFE). This could support clinicians to apply more BCI in routine rehabilitation. PMID- 22255790 TI - Electronic performance of a dual inductive link for a wireless neural recording implant. AB - This paper reports a dual inductive link to provide two-way wireless communication and power for a neural recording system. Particular emphasis is placed on explaining the challenges associated with two inductive links operating in the same space and possible solutions. This system uses a class E converter to sustain a large AC current in an external coil for transcutaneous energy transfer to an implant coil. A telemetry circuit generates a reverse-telemetry carrier frequency using an Integer-N PLL to support multiple outward data channels. Interference from the class E converter fundamental and harmonics is rejected using a differential coil configuration. An approach to filtering harmonic interference from the external power coil is also presented. PMID- 22255791 TI - SSVEP-BCI implementation for 37-40 Hz frequency range. AB - This work presents a Brain-Computer Interface (BCI) based on Steady State Visual Evoked Potentials (SSVEP), using higher stimulus frequencies (>30 Hz). Using a statistical test and a decision tree, the real-time EEG registers of six volunteers are analyzed, with the classification result updated each second. The BCI developed does not need any kind of settings or adjustments, which makes it more general. Offline results are presented, which corresponds to a correct classification rate of up to 99% and a Information Transfer Rate (ITR) of up to 114.2 bits/min. PMID- 22255792 TI - Classifying real and imaginary finger press tasks on a P300-based brain-computer interface. AB - Brain computer interfaces based on P300 and sensory-motor rhythms are widely studied and recent advances show some interest in the combination of the two. In this paper, typical P300 paradigm is modified by adding animation guide of the finger press as a stimulus and by using different response strategies (silent counting and actual/imaginary left or right index finger press following the animation). Both P300 potentials and sensory-motor rhythms are directly exploited and discussed. Classification results showed that even under very demanding conditions, which was, 200 ms inter-stimulus interval of the P300 stimuli and actual/imaginary finger press once per 1.6s, the paradigm can evoke both P300 potentials and sensory-motor rhythms simultaneously. Actual finger press increased single trial P300 selection accuracy of different subjects by 5-29.5% compared with silent counting; imaginary finger press did not increase the P300 selection accuracy apparently for most subjects except the two who were very poor at counting task. This showed by using different interface design and adopting certain mental response strategies, the 'BCI illiteracy' may be cured. Also imaginary task had good performance of left versus right classification (with the best subject reached 81.1% of accuracy), which is an additional information that can be used to improve system performance. PMID- 22255793 TI - GIBS block speller: toward a gaze-independent P300-based BCI. AB - Brain-computer interface (BCI) opens a new communication channel for individuals with severe motor disorders. In P300-based BCIs, gazing the target event plays an important role in the BCI performance. Individuals who have their eye movements affected may lose the ability to gaze targets that are in the visual periphery. This paper presents a novel P300-based paradigm called gaze independent block speller (GIBS), and compares its performance with that of the standard row-column (RC) speller. GIBS paradigm requires extra selections of blocks of letters. The online experiments made with able-bodied participants show that the users can effectively control GIBS without moving the eyes (covert attention), while this task is not possible with RC speller. Furthermore, with overt attention, the results show that the improved classification accuracy of GIBS over RC speller compensates the extra selections, thereby achieving similar practical bit rates. PMID- 22255794 TI - Neural decoding using local field potential based on partial least squares regression. AB - Recent studies have shown that a promising cortical control signal in brain machine interface is local field potential (LFP), of which low and high frequencies bands contains information about planning or executing dexterous movement. In this paper, we analyzed LFP signals recorded from primary motor cortex of rats as they performed a lever-pressing task. The decoding performance of partial least squares regression (PLSR) in LFP was evaluated by comparing with two traditional decoding algorithms, Wiener filtering (WF) and Kalman filtering (KF). The results demonstrated that PLSR not only had good performance as the other two methods, but also had particular predominance in avoiding over-fitting and computation complexity, due to its capability in dealing with the small sample capacity and high variable dimension that exist in LFP decoding. PMID- 22255795 TI - Minimizing calibration time using inter-subject information of single-trial recognition of error potentials in brain-computer interfaces. AB - One of the main problems of both synchronous and asynchronous EEG-based BCIs is the need of an initial calibration phase before the system can be used. This phase is necessary due to the high non-stationarity of the EEG, since it changes between sessions and users. The calibration process limits the BCI systems to scenarios where the outputs are very controlled, and makes these systems non friendly and exhausting for the users. Although it has been studied how to reduce calibration time for asynchronous signals, it is still an open issue for event related potentials. Here, we propose the minimization of the calibration time on single-trial error potentials by using classifiers based on inter-subject information. The results show that it is possible to have a classifier with a high performance from the beginning of the experiment, and which is able to adapt itself making the calibration phase shorter and transparent to the user. PMID- 22255796 TI - Somatosensory evoked potentials elicited by stimulating two fingers from one hand -usable for BCI? AB - Steady-state somatosensory evoked potentials (SSSEPs) have been elicited using vibro-tactile stimulation on two fingers of the right hand. Fourteen healthy subjects participated in this study. A screening session, stimulating each participant's thumb, was conducted to determine individual optimal resonance-like frequencies. After this screening session, two stimulation frequencies per subject were selected. Stimulation was then applied simultaneously on the participant's thumbs and middle finger. It was investigated whether it is possible to classify SSSEP changes based on an attention modulation task to determine possible BCI applications. A cue indicated the participants to shift their attention to either the thumb or the middle finger. Offline classification with a lock-in analyzer system (LAS) and a linear discriminant analysis (LDA) classifier was performed. One bipolar channel and no further optimization methods were used. All participants except one reached classification results above chance level classifying a reference period without focused attention against focused attention either to the thumb or the middle finger. Only two subjects reached accuracies above chance, classifying focused attention to the thumb vs. attention to the middle finger. PMID- 22255797 TI - A concept to standardize raw biosignal transmission for brain-computer interfaces. AB - With this concept we introduced the attempt of a standardized interface called TiA to transmit raw biosignals. TiA is able to deal with multirate and block oriented data transmission. Data is distinguished by different signal types (e.g., EEG, EOG, NIRS, ...), whereby those signals can be acquired at the same time from different acquisition devices. TiA is built as a client-server model. Multiple clients can connect to one server. Information is exchanged via a control- and a separated data connection. Control commands and meta information are transmitted over the control connection. Raw biosignal data is delivered using the data connection in a unidirectional way. For this purpose a standardized handshaking protocol and raw data packet have been developed. Thus, an abstraction layer between hardware devices and data processing was evolved facilitating standardization. PMID- 22255798 TI - Impact of target probability on single-trial EEG target detection in a difficult rapid serial visual presentation task. AB - In non-invasive brain-computer interface (BCI), the analysis of event-related potentials (ERP) has typically focused on averaged trials, a current trend is to analyze single-trial evoked response individually with new approaches in pattern recognition and signal processing. Such single trial detection requires a robust response that can be detected in a variety task conditions. Here, we investigated the influence of target probability, a key factor known to influence the amplitude of the evoked response, on single trial target classification in a difficult rapid serial visual presentation (RSVP) task. Our classification approach for detecting target vs. non target responses, considers spatial filters obtained through the maximization of the signal to signal-plus-noise ratio, and then uses the resulting information as inputs to a Bayesian discriminant analysis. The method is evaluated across eight healthy subjects, on four probability conditions (P=0.05, 0.10, 0.25, 0.50). We show that the target probability has a statistically significant effect on both the behavioral performance and the target detection. The best mean area under the ROC curve is achieved with P=0.10, AUC=0.82. These results suggest that optimal performance of ERP detection in RSVP tasks is critically dependent on target probability. PMID- 22255799 TI - A square root ensemble Kalman filter application to a motor-imagery brain computer interface. AB - We here investigated a non-linear ensemble Kalman filter (SPKF) application to a motor imagery brain computer interface (BCI). A square root central difference Kalman filter (SR-CDKF) was used as an approach for brain state estimation in motor imagery task performance, using scalp electroencephalography (EEG) signals. Healthy human subjects imagined left vs. right hand movements and tongue vs. bilateral toe movements while scalp EEG signals were recorded. Offline data analysis was conducted for training the model as well as for decoding the imagery movements. Preliminary results indicate the feasibility of this approach with a decoding accuracy of 78%-90% for the hand movements and 70%-90% for the tongue toes movements. Ongoing research includes online BCI applications of this approach as well as combined state and parameter estimation using this algorithm with different system dynamic models. PMID- 22255800 TI - Towards neuro-silicon interface using reconfigurable dynamic clamping. AB - Dynamic clamp emerges as an important apparatus to study the intrinsic neuronal properties through close-loop interactions between models and biological neurons. Modelling large-scale neuronal networks in software will result in significant computational delay that becomes a bottleneck to apply dynamic clamp for more complicated systems. In this paper, we present a real-time dynamic clamping system based on field programmable gate arrays (FPGAs) to accelerate the necessary computations. It also provides a flexible platform to reconfigure various model parameters and topologies. Realtime neuronal and synaptic models were implemented in FPGA, and interconnected with the stomatograstric ganglion (STG) nervous system to exemplify the real-time dynamics. Results show that our method can be effectively configured to mimic various biological neural networks and is two orders of magnitude faster than software approach using desktop computer. PMID- 22255801 TI - Using speech recognition to enhance the Tongue Drive System functionality in computer access. AB - Tongue Drive System (TDS) is a wireless tongue operated assistive technology (AT), which can enable people with severe physical disabilities to access computers and drive powered wheelchairs using their volitional tongue movements. TDS offers six discrete commands, simultaneously available to the users, for pointing and typing as a substitute for mouse and keyboard in computer access, respectively. To enhance the TDS performance in typing, we have added a microphone, an audio codec, and a wireless audio link to its readily available 3 axial magnetic sensor array, and combined it with a commercially available speech recognition software, the Dragon Naturally Speaking, which is regarded as one of the most efficient ways for text entry. Our preliminary evaluations indicate that the combined TDS and speech recognition technologies can provide end users with significantly higher performance than using each technology alone, particularly in completing tasks that require both pointing and text entry, such as web surfing. PMID- 22255802 TI - Dual inductive link coil design for a neural recording system. AB - This paper reports an approach to the physical design of the coils used in a dual inductive link to provide two-way wireless communication and power for a neural recording system. The design approach makes use of an analytic model of the link performance in terms of the physical parameters of the link, which allows physical parameters to be iterated on a computer rather than on the bench to find the optimal design within the physical restrictions imposed. In particular, this approach was used to choose the optimal implant data coil sizing to maximize the difference between the contributions of the constructive and destructive paths of the reverse telemetry signal. PMID- 22255804 TI - A P300-based BCI system for controlling computer cursor movement. AB - A P300-based BCI (brain-computer interface) system for controlling the movement of the cursor displayed on the computer screen was proposed and evaluated. On the LCD computer screen, the cursor was displayed with the surrounded eight small circles, each of which was blinked sequentially in a random order. Five healthy subjects were requested to gaze at one of the circles placed in the preferred direction. The P300 activities elicited by the random blink of the target circle were detected by pattern classifier and they were used to move the cursor to the same direction as the target circle. It was shown that all of the subjects could control the movement of the cursor to their preferred direction by moving their gaze point in a short distance. This system can be applied to the voluntary control of the movement of the computer cursor, and the navigation of robot or video camera, without using users' extremities. PMID- 22255803 TI - Identifying neuron communities during a reach and grasp task using an unsupervised clustering analysis. AB - Recent advances in brain-machine interfaces (BMIs) have allowed for high density recordings using microelectrode arrays. However, these large datasets present a challenge in how to practically identify features of interest and discard non task-related neurons. Thus, we apply a previously reported unsupervised clustering analysis to neural data acquired from a non-human primate as it performed a center-out reach-and-grasp task. Although neurons were recorded from multiple arrays across motor and premotor areas, neurons were found to cluster into only two groups which differ by their mean firing rate. No spatial distribution of neurons was evident in different groups, either across arrays or at different depths. Using a Kalman filter to decode arm, hand, and finger kinematics, we find that using neurons from only one of the groups resulted in higher decoding accuracy (r=0.73) than using randomly selected neurons (r=0.68). This suggests that the proposed method can be used to prune the input space and identify an optimal population of neurons for BMI tasks. PMID- 22255805 TI - A 64-channel neural signal processor/ compressor based on Haar wavelet transform. AB - A signal processor/compressor dedicated to implantable neural recording microsystems is presented. Signal compression is performed based on Haar wavelet. It is shown in this paper that, compared to other mathematical transforms already used for this purpose, compression of neural signals using this type of wavelet transform can be of almost the same quality, while demanding less circuit complexity and smaller silicon area. Designed in a 0.13-MUm standard CMOS process, the 64-channel 8-bit signal processor reported in this paper occupies 113 MUm x 110 MUm of silicon area. It operates under a 1.8-V supply voltage at a master clock frequency of 3.2 MHz. PMID- 22255806 TI - Behaviour patterns detection for persuasive design in Nursing Homes to help dementia patients. AB - Nursing homes usually host large accounts of persons with different levels of dementia. Detecting dementia process in early stages may allow the application of mechanisms to reduce or stop the cognitive impairment. Our ultimate objective is to demonstrate that the use of persuasive techniques may serve to motivate these subjects and induct re-learning mechanisms to stop mental impairment. Nevertheless, this requires the study of the behaviour of each patient individually in order to detect conduct disorders in their living ambient. This study presents a behavior pattern detection architecture based on the Ambient Assisted Living paradigm and Workflow Mining technology to enable re-learning mechanisms in dementia processes via providing tools to automate the conduct disorder detection. This architecture fosters the use of Workflows as representation languages to allow health professionals to represent persuasive motivation protocols in the AAL environment to react individually to dementia symptoms detected. PMID- 22255807 TI - Using pre-treatment electroencephalography data to predict response to transcranial magnetic stimulation therapy for major depression. AB - We investigate the use of machine learning methods based on the pre-treatment electroencephalograph (EEG) to predict response to repetitive transcranial magnetic stimulation (rTMS), which is a non-pharmacological form of therapy for treating major depressive disorder (MDD). The learning procedure involves the extraction of a large number of candidate features from EEG data, from which a very small subset of most statistically relevant features is selected for further processing. A statistical prediction model based on mixture of factor analysis (MFA) model is constructed from a training set that classifies the respective subject into responder and non-responder classes. A leave-2-out (L2O) cross validation procedure is used to evaluate the prediction performance. This pilot study involves 27 subjects who received either left high-frequency (HF) active rTMS therapy or simultaneous left HF and right low-frequency active rTMS therapy. Our results indicate that it is possible to predict rTMS treatment efficacy of either treatment modality with a specificity of 83% and a sensitivity of 78%, for a combined accuracy of 80%. PMID- 22255808 TI - Use of radial basis functions in computer-aided diagnosis of prostate cancer. AB - In this paper, we show the results of a study in which we try to test the feasibility of using radial basis functions neural networks (RBFs for short) in clinical decision support systems. We have implemented two instances of RBFs in order to diagnose possible prostate cancer cases from a clinical database. To give an idea about how good the results are, we follow a two-fold approach. On the one hand they are independently evaluated in terms of accuracy, sensitivity and specificity and on the other hand they are compared with the performance over the same database of a classifier widely applied to the medical field problems, as it is multi-layer perceptron (MLP). The experimental results show that RBFs are a useful tool to build up clinical decision support systems. PMID- 22255809 TI - iSyNCC: an intelligent system for patient monitoring & clinical decision support in Neuro-Critical-Care. AB - Close monitoring and timely treatment are extremely crucial in Neuro Intensive/Critical Care Units (NICUs) to prevent patients from secondary brain damages. However, the current clinical practice is labor-intensive, prone to human errors and ineffective. To address this, we developed an integrated and intelligent system, namely iSyNCC, to enhance the effectiveness of patient monitoring and clinical decision makings in NICUs. The requirements of the system were investigated through interviews and discussions with neurosurgeons, neuroclinicians and nurses. Based on the summarized requirements, a modular 2 tier system is developed. iSyNCC integrates and stores crucial patient information ranging from demographic details, clinical & treatment records to continuous physiological monitoring data. iSyNCC enables remote and centralized patient monitoring and provides computational intelligence to facilitate clinical decision makings. PMID- 22255810 TI - Development and usability testing of a parent decision support tool for the neonatal intensive care unit. AB - In this paper we present the development and evaluation of a parent decision support tool for a neonatal intensive care unit (NICU), known as PPADS or Physician and Parent Decision Support. The NICU interprofessional (IP) team uses advanced technology to care for the sickest infants in the hospital, some at the edge of viability. Many difficult care decisions are made daily for this vulnerable population. The PPADS tool, a computerized decision support system, aims to augment current NICU decision-making by helping parents make more informed decisions, improving physician-parent communication, increasing parent decision-making satisfaction, decreasing conflict, and increasing decision efficiency when faced with ethically challenging situations. The development and evaluation of the PPADS tool followed a five step methodology: assessing the clinical environment, establishing the design criteria, developing the system design, implementing the system, and performing usability testing. Usability testing of the PPADS tool with parents of neonates who have graduated (survived) from a tertiary level NICU demonstrates the usefulness and ease of use of the tool. PMID- 22255811 TI - Supervised regularized canonical correlation analysis: integrating histologic and proteomic data for predicting biochemical failures. AB - Multimodal data, especially imaging and non-imaging data, is being routinely acquired in the context of disease diagnostics; however computational challenges have limited the ability to quantitatively integrate imaging and non-imaging data channels with different dimensionalities for making diagnostic and prognostic predictions. The objective of this work is to create a common subspace to simultaneously accommodate both the imaging and non-imaging data, called a metaspace. This metaspace can be used to build a meta-classifier that produces better classification results than a classifier that is based on a single modality alone. In this paper, we present a novel Supervised Regularized Canonical Correlation Analysis (SRCCA) algorithm that (1) enables the quantitative integration of data from multiple modalities using a feature selection scheme, (2) is regularized, and (3) is computationally cheap. We leverage this SRCCA framework towards the fusion of proteomic and histologic image signatures for identifying prostate cancer patients at risk for biochemical recurrence following radical prostatectomy. For a cohort of 19 prostate cancer patients, SRCCA was able to yield a lower fused dimensional metaspace comprising both the histological and proteomic attributes. In conjunction with SRCCA, a random forest classifier was able to identify patients at risk for biochemical failure with a maximum accuracy of 93%. The classifier performance in the SRCCA space was statistically significantly higher compared to the fused data representations obtained either with Canonical Correlation Analysis (CCA) or Regularized CCA. PMID- 22255812 TI - Rough Set Theory based prognostication of life expectancy for terminally ill patients. AB - We present a novel knowledge discovery methodology that relies on Rough Set Theory to predict the life expectancy of terminally ill patients in an effort to improve the hospice referral process. Life expectancy prognostication is particularly valuable for terminally ill patients since it enables them and their families to initiate end-of-life discussions and choose the most desired management strategy for the remainder of their lives. We utilize retrospective data from 9105 patients to demonstrate the design and implementation details of a series of classifiers developed to identify potential hospice candidates. Preliminary results confirm the efficacy of the proposed methodology. We envision our work as a part of a comprehensive decision support system designed to assist terminally ill patients in making end-of-life care decisions. PMID- 22255813 TI - Quantitative determination of arterial pulse wave velocity by non-interfering bioimpedance sensing. AB - Measurement of pulse wave velocity (PWV) in arteries is demonstrated with a novel measurement technique. Localized measurements are facilitated over arterial lengths below 10 cm on both the bicep and the wrist. Measurements do not interfere with the physiological state of the person or patient on which the measurement is performed. The scheme is based on impedance sensing utilizing novel conjugate impedances that eliminate destructive cross coupling between sets of electrodes. Initial measurements show that the test subject has a PWV of 8.0 +/- 0.1 m/s and 7.1 +/-0.2 on the wrist and bicep, respectively. The measurement distances were 8 cm and 5 cm, respectively. PMID- 22255814 TI - Robustness of the P-U and lnD-U loop wave speed estimation methods: effects of the diastolic pressure decay and vessel wall non-linearities. AB - Arterial wave speed estimated invasively from pressure (P) and velocity (U) measurements using the P-U loop method, or non-invasively from diameter (D) and U measurements using the lnD-U loop method, assume that during early systole 1) backward-running waves are absent and 2) wave speed is constant. These assumptions also form the basis of a method for correcting time lags between P (or lnD) and U in which the R(2) of the early-systolic linear regression is maximized. However, neither of the two assumptions are strictly valid in vivo, where the diastolic pressure decay from the previous beat may give rise to some non-zero backward-running P, U and wave intensity (WI) components, and the pressure-dependency of wave speed may lead to curvilinearity in the early systolic P-U and lnD-U relations. Accordingly, this study assessed the robustness of three phase correction algorithms, (including two that are not dependent on the two assumptions stated above, i.e., aligning the times of the peak 2nd derivative or peak signal curvature) and of the P-U and lnD-U loop wave speed estimation methods under a range of diastolic decay rates and degrees of vessel wall non-linearity. Results from a simple computer model of the arterial circulation suggested that although an apparent phase lag may be introduced by assuming linearity, the magnitude of this phase lag is likely to be small considering the sample intervals normally used in experimental studies; however, under highly non-linear flow conditions, the apparent lag may be comparable to hardware-related lags. Predicted errors in estimated wave speed using the P-U loop method were generally less than 10%, while somewhat higher errors were found in the lnD-U loop method (up to 15-20%). In both, higher diastolic pressure decay rates were associated with higher wave speed errors, although this effect was eliminated by subtracting the extrapolated diastolic pressure curve from the measured pressure. Overall, each of the time lag correction algorithms and wave speed estimation methods were generally satisfactory, although further experimental work is required to assess the curvature-based phase correction method and pressure adjustment in vivo. PMID- 22255815 TI - Effects of pressure-dependent segmental arterial compliance and postural changes on pulse wave transmission in an arterial model of the human upper limb. AB - With increasing interest in the effect of postural changes on arterial blood pressure and vascular properties, it is important to understand effects of pressure-dependent arterial compliance. This study investigates effects of pressure-dependent compliance on pulse wave velocity (PWVar), pressure wave shape, and transmission characteristics in an arterial model of the human arm from heart to radial artery from supine to standing. Estimated central pressure waveform was used as the input for the model, calculated using a validated transfer function (SphygmoCor, AtCor Medical) from recorded radial pulses in 10 healthy male subjects (53.8 +/- 7.9 years) during 0, 30, 60 and 90 degree head-up tilt. A 5-segment linear model was optimized using estimated central and recorded radial arterial pulse; each segment represented by an equivalent inductance, resistance and capacitance (compliance (C)) Pressure-dependent compliance (C(P)=a . e(b . P) was added to develop a nonlinear model, and the radial pulse calculated. Comparison of the radial pulse calculated by the linear and nonlinear models showed no statistical difference in systolic, diastolic, mean, and pulse pressure in any position of tilt. However, waveform shape was increasingly divergent at higher angles of tilt (RMS error 2.3 +/- 1.2 mmHg supine, 6.5 +/- 3.0 mmHg standing) as was PWVar (0% increase from supine to standing in the linear model, 16.7% increase in nonlinear model). Fourier analysis demonstrated peak amplitude of transmission being at higher frequencies and phase delay being lower in the nonlinear model relative to the linear model. Pressure-dependent arterial compliance, whilst having no effect on peak values of pressure, has significant effects on waveform shape and transmission speed, especially with a more upright position. PMID- 22255816 TI - Age-related changes in reservoir and excess components of central aortic pressure in asymptomatic adults. AB - Study of humans aging has presented difficulties in separating the aging process from concomitant disease and/or in defining normality and abnormality during its development. In accordance with this, aging associates structural and functional changes evidenced in variations in vascular parameters witch suffer alterations during atherosclerosis and have been proposed as early markers of the disease. The absence of adequate tools to differentiate the expected (normal) vascular changes due to aging from those related with a vascular disease is not a minor issue. For an individual, an early diagnosis of a vascular disease should be as important as the diagnosis of a healthy vascular aging. Recent studies have proposed that the capacitive or reservoir function of the aorta and large elastic arteries plays a major role in determining the pulse wave morphology. The arterial pressure waveform can be explained in terms of a reservoir pressure, related to the arterial system compliance, and an "excess" or wave-related pressure, associated with the traveling waves. The aim of this study was to evaluate, by means of a mathematical approach, age-related changes in measured, reservoir and excess central aortic pressure in order to determine if age-related changes are concentrated in particular decades of life. Central aortic pressure waveform was non-invasively obtained in healthy subjects (age range: 20-69 years old). Age-related profiles in measured, reservoir and excess pressure were calculated. PMID- 22255817 TI - Carotid-radial pulse wave velocity as a discriminator of intrinsic wall alterations during evaluation of endothelial function by flow-mediated dilatation. AB - Flow-mediated dilatation (FMD) is the most accepted technique for the evaluation of endothelial function. However, it has been show a great inter-subject variability limiting its clinical use. Carotid-radial pulse wave velocity (PWVcr) was proposed as an alternative tool for the evaluation of endothelial function. At the present, there is no doubt that PWVcr reduces its values in response to reactive hyperemia test (RHT) in healthy subjects. AIMS: a) to determine simultaneously the temporal profile of FMD, PWVcr and shear rate in response to RHT and b) to describe and analyze how subjects "FMD responders" or "non responders" behave regards to PWVcr changes. METHODS: 34 Healthy young subjects were included. The PWVcr (strain gauge mechanotransducers), brachial diameter (B Mode ultrasound and blood flow velocity (Doppler ultrasound) were measured before (baseline) the cuff was inflated and after its deflation (5 minutes). 10(th) percentiles FMD and PWVcr changes in the population were used for the definition of the subjects ("responders and non-responders"). RESULTS: Changes in PWVcr, brachial arterial diameter and shear rate were evidenced after the cuff release (p<0.05). There were differences in the PWV and FMD temporal profiles. Within "FMD responders" there were "PWV responders and non-responders". CONCLUSION: Assessing RHT-related changes in PWVcr in the context of a FMD evaluation, could be useful as a discriminator of intrinsic wall alterations giving additional information of vascular dynamics. PMID- 22255818 TI - Pulse arrival time is not an adequate surrogate for pulse transit time in terms of tracking diastolic pressure. AB - We compared pulse arrival time (PAT) and pulse transit time (PTT) in terms of their ability to track diastolic pressure (DP). We performed the comparison using high fidelity, invasive arterial waveforms recorded from six dogs during multiple interventions. On average, DP ranged from 40 to 106 mmHg and therefore varied widely. PAT and PTT were able to predict DP with average root-mean-squared-errors of 9.8 +/- 5.8 mmHg and 5.7 +/- 2.0 mmHg (p = 0.02). Thus, even though PAT is simpler to measure, we can only recommend using PTT for tracking DP. PMID- 22255819 TI - A multidimensional signal processing approach for classification of microwave measurements with application to stroke type diagnosis. AB - A multidimensional signal processing method is described for detection of bleeding stroke based on microwave measurements from an antenna array placed around the head of the patient. The method is data driven and the algorithm uses samples from a healthy control group to calculate the feature used for classification. The feature is derived using a tensor approach and the higher order singular value decomposition is a key component. A leave-one-out validation method is used to evaluate the properties of the method using clinical data. PMID- 22255820 TI - Early detection and characterization of Alzheimer's disease in clinical scenarios using Bioprofile concepts and K-means. AB - Alzheimer's Disease (AD) is the most common neurodegenerative disease in elderly people. There is a need for objective means to detect AD early to allow targeted interventions and to monitor response to treatment. To help clinicians in these tasks, we propose the creation of the Bioprofile of AD. A Bioprofile should reveal key patterns of a disease in the subject's biodata. We applied k-means clustering to data features taken from the ADNI database to divide the subjects into pathologic and non-pathologic groups in five clinical scenarios. The preliminary results confirm previous findings and show that there is an important AD pattern in the biodata of controls, AD, and Mild Cognitive Impairment (MCI) patients. Furthermore, the Bioprofile could help in the early detection of AD at the MCI stage since it divided the MCI subjects into groups with different rates of conversion to AD. PMID- 22255821 TI - SVS: data and knowledge integration in computational biology. AB - In this paper we present a framework for structured variable selection (SVS). The main concept of the proposed schema is to take a step towards the integration of two different aspects of data mining: database and machine learning perspective. The framework is flexible enough to use not only microarray data, but other high throughput data of choice (e.g. from mass spectrometry, microarray, next generation sequencing). Moreover, the feature selection phase incorporates prior biological knowledge in a modular way from various repositories and is ready to host different statistical learning techniques. We present a proof of concept of SVS, illustrating some implementation details and describing current results on high-throughput microarray data. PMID- 22255822 TI - A hybrid framework for genome wide epistasis discovery. AB - A hybrid framework integrating Random Forest and Logistic Regression is proposed and implemented for genome-wide epistasis study. The two-stage approach first uses random forest model to capture a pool of epistasis-prone single nucleotide polymorphisms (SNPs), followed by using logistic regression to identify the significant pair-wise epistasis SNPs. We tested the proposed framework on data obtained from Singapore Malay Eye Study (SiMES), in which, 3280 subjects were genotyped on Illumina 610 quad arrays and optic nerve parameters were measured in ocular examination. Case-control data set is labeled by choosing the high/low end of vertical Cup-to-Disc ratio (vCDR) values which is a measure of optic nerve degeneration. Our method identified 230 pairs of interacting SNPs with P-values below 5 * 10(-8). A preliminary search identified a protein interaction network at a high confidence score of 0.9. The proteins are known to participate in the WNT pathway with involvement in the survival and differentiation of the retina ganglion cells, inferring a strong association with vCDR. The experimental results demonstrate that the proposed framework is valid and efficient for large scale epistatsis study. PMID- 22255823 TI - MEET: motif elements estimation toolkit. AB - MEET is an R package that integrates a set of algorithms for the detection of transcription factor binding sites (TFBS). The MEET R package includes five motif searching algorithms: MEME/MAST(Multiple Expectation-Maximization for Motif Elicitation), Q-residuals, MDscan (Motif Discovery scan), ITEME (Information Theory Elements for Motif Estimation) and MATCH. In addition MEET allows the user to work with different alignment algorithms: MUSCLE (Multiple Sequence Comparison by Log-Expectation), ClustalW and MEME. The package can work in two modes, training and detection. The training mode allows the user to choose the best parameters of a detector. Once the parameters are chosen, the detection mode allows to analyze a genome looking for binding sites. Both modes can combine the different alignment and detection methods, offering multiple possibilities. Combining the alignments and the detection algorithms makes possible the comparison between detection models at the same level, without having to care about the differences produced during the alignment process. The MEET R package can be downloaded from http://sisbio.recerca.upc.edu/R/MEET_1.0. tar.gz. PMID- 22255824 TI - Using multimodal information for the segmentation of fluorescent micrographs with application to virology and microbiology. AB - In order to improve reproducibility and objectivity of fluorescence microscopy based experiments and to enable the evaluation of large datasets, flexible segmentation methods are required which are able to adapt to different stainings and cell types. This adaption is usually achieved by the manual adjustment of the segmentation methods parameters, which is time consuming and challenging for biologists with no knowledge on image processing. To avoid this, parameters of the presented methods automatically adapt to user generated ground truth to determine the best method and the optimal parameter setup. These settings can then be used for segmentation of the remaining images. As robust segmentation methods form the core of such a system, the currently used watershed transform based segmentation routine is replaced by a fast marching level set based segmentation routine which incorporates knowledge on the cell nuclei. Our evaluations reveal that incorporation of multimodal information improves segmentation quality for the presented fluorescent datasets. PMID- 22255825 TI - Passive in-home measurement of stride-to-stride gait variability comparing vision and Kinect sensing. AB - We present an analysis of measuring stride-to-stride gait variability passively, in a home setting using two vision based monitoring techniques: anonymized video data from a system of two web-cameras, and depth imagery from a single Microsoft Kinect. Millions of older adults fall every year. The ability to assess the fall risk of elderly individuals is essential to allowing them to continue living safely in independent settings as they age. Studies have shown that measures of stride-to-stride gait variability are predictive of falls in older adults. For this analysis, a set of participants were asked to perform a number of short walks while being monitored by the two vision based systems, along with a marker based Vicon motion capture system for ground truth. Measures of stride-to-stride gait variability were computed using each of the systems and compared against those obtained from the Vicon. PMID- 22255826 TI - Unobtrusive monitoring of the longitudinal evolution of in-home gait velocity data with applications to elder care. AB - Gait velocity has repeatedly been shown to be an important indicator and predictor of both cognitive and physical function, especially in elderly. However, clinical gait assessments are conducted infrequently and cannot distinguish between abrupt changes in function and changes that occur more slowly over time. Collecting gait measurements continuously in-home has recently been proposed and validated to overcome these clinical limitations. In this paper, we describe the longitudinal analysis of in-home gait velocity collected unobtrusively from passive infrared motion sensors. We first describe a model for the probability density function of the in-home gait velocities. We then describe estimation of the evolution of the density function over time and report empirically determined algorithm parameters that have performed well over a wide variety of different gait velocity data. Finally, we demonstrate how this approach allows detection of significant events (abrupt changes in function) and slower changes over time in gait velocity data collected from a sample of two elderly subjects in the Intelligent Systems for Assessing Aging Changes (ISAAC) study. PMID- 22255827 TI - Body-worn sensor based surrogates of minimum ground clearance in elderly fallers and controls. AB - Falls in the elderly are a major problem worldwide with enormous associated economic and societal costs. Minimum ground clearance (MGC) is an important gait variable when considering trip-related falls risk. This study aimed to investigate the clinical relevance of inertial sensor derived parameters, previously shown to be related to MGC. Previous research by the authors reported a surrogate method for assessing minimum ground clearance (MGC) using shank mounted inertial sensors in young controls. The present study tests this method on a cohort of 114 community dwelling elderly adults, with and without a history of falls, completing a 30 m continuous walk. Parameters based on the shank angular velocity signals that were shown to be associated with MGC showed significant differences (p<0.05) between fallers and non-fallers yet did not correlate strongly (r<0.7) with two standard measures of falls risk (TUG & BBS). Weak correlations were observed between the angular velocity derived parameters and gait velocity. We conclude that these parameters are clinically meaningful and therefore may constitute a new measure of falls risk. PMID- 22255828 TI - Estimation of end point foot clearance points from inertial sensor data. AB - Foot clearance parameters provide useful insight into tripping risks during walking. This paper proposes a technique for the estimate of key foot clearance parameters using inertial sensor (accelerometers and gyroscopes) data. Fifteen features were extracted from raw inertial sensor measurements, and a regression model was used to estimate two key foot clearance parameters: First maximum vertical clearance (m x 1) after toe-off and the Minimum Toe Clearance (MTC) of the swing foot. Comparisons are made against measurements obtained using an optoelectronic motion capture system (Optotrak), at 4 different walking speeds. General Regression Neural Networks (GRNN) were used to estimate the desired parameters from the sensor features. Eight subjects foot clearance data were examined and a Leave-one-subject-out (LOSO) method was used to select the best model. The best average Root Mean Square Errors (RMSE) across all subjects obtained using all sensor features at the maximum speed for m x 1 was 5.32 mm and for MTC was 4.04 mm. Further application of a hill-climbing feature selection technique resulted in 0.54-21.93% improvement in RMSE and required fewer input features. The results demonstrated that using raw inertial sensor data with regression models and feature selection could accurately estimate key foot clearance parameters. PMID- 22255829 TI - Laboratory in a box: wearable sensors and its advantages for gait analysis. AB - Until recently, many gait studies explored potential gait alteration due to various disorders in the gait lab and using camera based systems and force platforms. However, these strategies may not replicate normal outdoor walking. Using this equipment, it is more difficult to measure the variability of walking which is important for maintaining balance and responding to different walking challenges. Additionally, subjects may mask their problem or exaggerate it when they are walking in a short walking distance offered by laboratory based technology. This study overviews some of the key advantages of wearable technology compared to laboratory-based instrument. Additionally, it explored gait patterns over ample distance of walking compared to walking distance restricted to a gait laboratory environment. Walking patterns of ten healthy young subjects were examined using a wearable sensor technology in a random order over a distance of 7 m, 14 m, and 20 m. Results suggest that participants walk significantly faster by increasing walking distance on average by 15% and 3% when walking distance was increased respectively from 7 m to 14 and from 14 m to 20 m (p<0.05). Interestingly despite a high test-retest reliability for averaged gait parameters (ICC>0.89), the test-retest reliability for gait variability was only acceptable during 20 m walking distance (ICC<0.3 for 7 m and 14 m v. ICC=0.65 for 20 m). Taken together, our findings indicate that for valid and reliable assessment of gait parameters, gait should be performed over ample walking distances. Body worn sensor technology facilitates assessing gait outside of a gait laboratory, over ample walking distance, different footwear condition, different walking surface, and in environment where mimics better true environment where the subject is active in. PMID- 22255830 TI - Using a tri-axial accelerometer to detect technique breakdown due to fatigue in distance runners: a preliminary perspective. AB - Accelerometer technology is becoming increasingly smaller and cheaper to develop. As a direct result, such devices can potentially be easily integrated into footwear to capture data that provides information about the quality of a person's running technique in the later stages of a fatiguing run. The purpose of this study is to determine if it is possible to detect technique breakdown due to fatigue in a distance runner using shoe mounted accelerometers. We present an algorithm that uses computationally light data from tri-axial foot mounted accelerometers and compares outputs from them to kinematic changes in the runner as the runner fatigues. These preliminary findings show that kinematic changes due to fatigue can be reasonably estimated using outputs from a shoe mounted tri axial accelerometer. PMID- 22255831 TI - Branding the bio/biomedical engineering degree. AB - The future challenges to medical and biological engineering, sometimes referred to as biomedical engineering or simply bioengineering, are many. Some of these are identifiable now and others will emerge from time to time as new technologies are introduced and harnessed. There is a fundamental issue regarding "Branding the bio/biomedical engineering degree" that requires a common understanding of what is meant by a B.S. degree in Biomedical Engineering, Bioengineering, or Biological Engineering. In this paper we address some of the issues involved in branding the Bio/Biomedical Engineering degree, with the aim of clarifying the Bio/Biomedical Engineering brand. PMID- 22255832 TI - Project-based learning with international collaboration for training biomedical engineers. AB - Training biomedical engineers while effectively keeping up with the fast paced scientific breakthroughs and the growth in technical innovations poses arduous challenges for educators. Traditional pedagogical methods are employed for coping with the increasing demands in biomedical engineering (BME) training and continuous improvements have been attempted with some success. Project-based learning (PBL) is an academic effort that challenges students by making them carry out interdisciplinary projects aimed at accomplishing a wide range of student learning outcomes. PBL has been shown to be effective in the medical field and has been adopted by other fields including engineering. The impact of globalization in healthcare appears to be steadily increasing which necessitates the inclusion of awareness of relevant international activities in the curriculum. Numerous difficulties are encountered when the formation of a collaborative team is tried, and additional difficulties occur as the collaboration team is extended to international partners. Understanding and agreement of responsibilities becomes somewhat complex and hence the collaborative project has to be planned and executed with clear understanding by all partners and participants. A model for training BME students by adopting PBL with international collaboration is proposed. The results of previous BME project work with international collaboration fit partially into the model. There were many logistic issues and constraints; however, the collaborative projects themselves greatly enhanced the student learning outcomes. This PBL type of learning experience tends to promote long term retention of multidisciplinary material and foster high-order cognitive activities such as analysis, synthesis and evaluation. In addition to introducing the students to experiences encountered in the real-life workforce, the proposed approach enhances developing professional contracts and global networking. In conclusion, despite initial challenges, adopting project-based learning with international collaboration has strong potentials to be valuable in the training of biomedical engineering students. PMID- 22255835 TI - Bioengineering education @ NUS: a design-centered curriculum. AB - In resonance with the NUS Mission, the aim of the Bioengineering undergraduate degree program is to produce engineers with a strong foundation in the relevant engineering, sciences and technology, who are able to contribute to the biomedical sciences through innovation, enterprise and leadership. Our educational program in Bioengineering is characterised by a strong emphasis on scientific and engineering fundamentals and a high degree of flexibility which can provide a wide diversity of educational experiences. By providing graduates with a combination of broad-based fundamentals and specialized knowledge, the Bioengineering program strives to graduate versatile engineers who would be best positioned to lead and be an integral part of the Bioengineering industries in the future. This paper describes the bioengineering program, both at undergraduate and postgraduate levels in the Division of Bioengineering at Faculty of Engineering in National University of Singapore. PMID- 22255833 TI - Promoting harmonization of BME education in Europe: the CRH-BME Tempus project. AB - Biomedical Engineers should be prepared to adapt to existing or forecasted needs. There is a strong pressure on education, training and life long learning programs to continuously adapt their objectives in order to face new requirements and challenges. The main objective of the TEMPUS IV, CRH-BME project is to update existing curricula in the field of Biomedical Engineering (BME) in order to meet recent and future developments in the area, address new emerging inter disciplinary domains that appear as a result of the R&D progress and respond to the BME job market demands. The first step is to extensively review the curricula in the BME education field. In this paper, a proposal for a generic curriculum in the BME education is presented, in order to meet recent and future developments and respond to the demands of the BME job market. Adoption of the core program structure will facilitate harmonization of studies as well as student and staff exchange across Europe, thus promoting the European Higher Education Area. PMID- 22255836 TI - An EEG workload classifier for multiple subjects. AB - EEG data has been used to discriminate levels of mental workload when classifiers are created for each subject, but the reliability of classifiers trained on multiple subjects has yet to be investigated. Artificial neural network and naive Bayesian classifiers were trained with data from single and multiple subjects and their ability to discriminate among three difficulty conditions was tested. When trained on data from multiple subjects, both types of classifiers poorly discriminated between the three levels. However, a novel model, the naive Bayesian classifier with a hidden node, performed nearly as well as the models trained and tested on individuals. In addition, a hierarchical Bayes model with a higher level constraint on the hidden node can further improve its performance. PMID- 22255837 TI - Physiological cognitive state assessment: applications for designing effective human-machine systems. AB - Significant growth in the field of neuroscience has occurred over the last decade such that new application areas for basic research techniques are opening up to practitioners in many other areas. Of particular interest to many is the principle of neuroergonomics, by which the traditional work in neuroscience and its related topics can be applied to non-traditional areas such as human-machine system design. While work in neuroergonomics certainly predates the use of the term in the literature (previously identified by others as applied neuroscience, operational neuroscience, etc.), there is great promise in the larger framework that is represented by the general context of the terminology. Here, we focus on the very specific concept that principles in brain-computer interfaces, neural prosthetics and the larger realm of machine learning using physiological inputs can be applied directly to the design and implementation of augmented human machine systems. Indeed, work in this area has been ongoing for more than 25 years with very little cross-talk and collaboration between clinical and applied researchers. We propose that, given increased interest in augmented human-machine systems based on cognitive state, further progress will require research in the same vein as that being done in the aforementioned communities, and that all researchers with a vested interest in physiologically-based machine learning techniques can benefit from increased collaboration. We thereby seek to describe the current state of cognitive state assessment in human-machine systems, the problems and challenges faced, and the tightly-coupled relationship with other research areas. This supports the larger work of the Cognitive State Assessment 2011 Competition by setting the stage for the purpose of the session by showing the need to increase research in the machine learning techniques used by practitioners of augmented human-machine system design. PMID- 22255838 TI - QUASAR's QStates cognitive gauge performance in the cognitive state assessment competition 2011. AB - The Cognitive State Assessment Competition 2011 was organized by the U.S. Air Force Research Laboratory (AFRL) to compare the performance of real-time cognitive state classification software. This paper presents results for QUASAR's data classification module, QStates, which is a software package for real-time (and off-line) analysis of physiologic data collected during cognitive-specific tasks. The classifier's methodology can be generalized to any particular cognitive state; QStates identifies the most salient features extracted from EEG signals recorded during different cognitive states or loads. PMID- 22255839 TI - Estimation of task workload from EEG data: new and current tools and perspectives. AB - We report, as part of the EMBC meeting Cognitive State Assessment (CSA) competition 2011, an empirical comparison using robust cross-validation of the performance of eleven computational approaches to real-time electroencephalography (EEG) based mental workload monitoring on Multi-Attribute Task Battery data from eight subjects. We propose a new approach, Overcomplete Spectral Regression, that combines several potentially advantageous attributes and empirically demonstrate its superior performance on these data compared to the ten other CSA methods tested. We discuss results from computational, neuroscience and experimentation points of view. PMID- 22255840 TI - An assessment of non-stationarity in physiological cognitive state assessment using artificial neural networks. AB - With increased attention toward physiological cognitive state assessment as a component in the larger field of applied neuroscience, the need to develop methods for robust, stable assessment of cognitive state has been expressed as critical to designing effective augmented human-machine systems. The technique of cognitive state assessment, as well as its benefits, has been demonstrated by many research groups. In an effort to move closer toward a realized system, efforts must now be focused on critical issues that remain unsolved, namely instability of pattern classifiers over the course of hours and days. This work, as part of the Cognitive State Assessment Competition 2011, seeks to explore methods for 'learning' non-stationarity as a mitigation for more generalized patterns that are stable over time courses that are not widely discussed in the literature. PMID- 22255841 TI - Particle swarm optimization-based feature selection for cognitive state detection. AB - This manuscript proposes a particle swarm-based feature extraction to monitors brain activity with the goal of identifying correlate cognitive states and intensity of a task. This in turn would allow us to develop a pattern recognition system that will classify such cognitive states and thus to redistribute the workload to other subjects. In this abstract, we present a recognition system that employ multiple features from different domains, a feature selection method using a Particle Swarm Optimization (PSO) search algorithm while the classification is provided using a k-nearest neighbor. Through this approach, we are able to achieve an averaged classification accuracy of 90.25% on held-out, cross-validated data among the eight subjects. PMID- 22255842 TI - Assessment of diabetic cardiac autonomic neuropathy in type I diabetic mice. AB - Diabetic cardiac autonomic neuropathy (DCAN) is one of the most common complications of diabetes. One reason why the pathogenesis of DCAN is unclear is that non-invasive assessment of DCAN in humans and animals has been problematic. To overcome this limitation, we utilized a sensitive and non-invasive method to assess cardiac autonomic dysregulation from ECG records. The method, which could be easily applied to humans, is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV). The method is unique, in that is able to separately identify the activities of the parasympathetic and sympathetic systems without pharmacological intervention. In our study, ECG was measured via telemetry in ten sex- and age-matched (4 month old male) C57 (n=5) and Akita (n=5) mice, a model of insulin-dependent type 1 diabetes. The results indicate significant reduced cardiac autonomic function in the diabetic mice in comparison to the controls. Further, both immunohistochemical and Western blot analyses show a reduction in nerve density in Akita mice as compared to the control mice, thus, corroborating our PDM data analysis of HRV records. PMID- 22255843 TI - Monitoring in cardiovascular disease patients by nonlinear biomedical signal processing. AB - Due to recent advances in technology extensive cardiovascular monitoring is widely introduced today. An essential component of cardiovascular monitoring is the analysis of several biosignals as electrocardiogram, blood pressure and other vital signs. This manuscript provides an overview about several application fields of cardiovascular monitoring with the main focus on nonlinear dynamics analysis. PMID- 22255844 TI - Advances in monitoring cardiovascular signals. Contribution of nonlinear signal processing. AB - Monitoring procedures are the basis to evaluate the clinical state of patients and to assess changes in their status, thus providing necessary interventions in time. To obtain this important objective it is necessary to integrate technological development with systems performing biomedical knowledge extraction and classification. Methods extracting non linear characteristics from HRV signal are presented and discussed to stress that integrated and multiparametric signal processing approaches can contribute to new diagnostic and classification indices. Examples report heart rate variability analysis in long periods in patients with cardiovascular disease. Fetal ECG monitoring is another example. In this case, coupling nonlinear parameters and linear time and frequency techniques increases diagnostic power and reliability of the monitoring. The paper shows that integrated signal analysis is very helpful to describe pathophysiological mechanisms involved in the cardiovascular and neural system control. It is a reliable basis to set up knowledge-based monitoring systems. PMID- 22255845 TI - EEG/MEG source localization using source deflated matching pursuit. AB - A matching pursuit (MP) based algorithm, called source deflated matching pursuit (SDMP), is proposed for locating sources of brain activity. By iteratively deflating the contribution of identified sources to multiple measurement vectors (MMVs), the SDMP algorithm transforms the original multi-basis-vector/matrix selection problem into a single-basis-vector/matrix selection problem, which not only mitigates the residual-source interference but also remedies the intrinsic bias when locating deep sources. The robustness of the proposed algorithm to two bias factors is verified through simulations. PMID- 22255846 TI - Investigaton of the neuronal efficacy and EEG source power under steady-state visual stimulation. AB - Understanding the nature of the link between neuronal activity and BOLD signal plays a crucial role i) for improving the interpretability of BOLD images and ii) on the design of more realistic models for the integration of EEG and fMRI. The aim of this study is to investigate the neural mechanism underlying hemodynamic behavior in a series of visual stimulation frequencies and explore possible implications for the neurovascular coupling. We studied the relationship between electrophysiological and hemodynamic measures by performing simultaneous steady state electroencephalography (EEG) and fMRI recordings in a healthy human subject during a series of visual stimulation frequencies (6 Hz, 8 Hz, 10 Hz, 12 Hz). BOLD amplitudes were computed for voxels within an anatomical mask which was obtained by mapping the significantly active voxels using general linear modelling (GLM) on fMRI data. On the same anatomical map, EEG power time series belonging to the fundamental frequency and its harmonics due to the stimulation are estimated using a distributed source imaging technique. The neuronal efficacies which represent the vascular inputs driving the BOLD response are estimated by use of an extended version of Balloon model. A nonlinear relationship is demonstrated between the mean EEG source powers and the neuronal efficacies driving the BOLD response. The result suggests that BOLD signal which is an indicator of the metabolic demand of both synchronized and non-synchronized neuronal activities; changes independent of EEG activity which is a measure sensitive to the synchronicity of neuronal activity. PMID- 22255847 TI - Neonatal seizure detection using blind distributed detection with correlated decisions. AB - Seizure is the result of excessive electrical discharges of neurons, which usually develops synchronously and happens suddenly in the central nervous system. Clinically, it is difficult for physician to identify neonatal seizures visually, while EEG seizures can be recognized by the trained experts. By extending our previous results on multichannel information fusion, we propose an automated distributed detection system consisting of the existing detectors and a fusion centre to detect the seizure activities in the newborn EEG assuming that the decisions of local detectors are correlated. The advantage of this proposed technique is that it accounts for correlated decisions of the local detectors. It has been shown that correlation between local detectors can lead to severe performance degradation if not modelled properly. Therefore our proposed technique can potentially improve the performance of existing single and multichannel neonatal seizure detection algorithms. PMID- 22255848 TI - EEG signal classification using time-varying autoregressive models and common spatial patterns. AB - The performance of EEG signal classification methods based on Common Spatial Patterns (CSP) depends on the operational frequency bands of the events to be discriminated. This problem has been recently addressed by using a sub-band decomposition of the EEG signals through filter banks. Even though this approach has proven effective, the performance still depends on the number of filters that are stacked and the criteria used to determine their cutoff frequencies. Therefore, we propose an alternative approach based on an eigenstructure decomposition of the signals' time-varying autoregressive (TVAR) models. The eigen-based decomposition of the TVAR representation allows for subject-specific estimation of the principal time-varying frequencies, then such principal eigencomponents can be used in the traditional CSP-based classification. A series of simulations show that the proposed classification scheme can achieve high classification rates under realistic conditions, such as low signal-to-noise ratio (SNR), a reduced number of training experiments, and a reduced number of sensors used in the measurements. PMID- 22255849 TI - Functional Near Infrared Spectroscopy (fNIRS) synthetic data generation. AB - Accurately modelled computer-generated data can be used in place of real-world signals for the design, test and validation of signal processing techniques in situations where real data is difficult to obtain. Bio-signal processing researchers interested in working with fNIRS data are restricted due to the lack of freely available fNIRS data and by the prohibitively expensive cost of fNIRS systems. We present a simplified mathematical description and associated MATLAB implementation of model-based synthetic fNIRS data which could be used by researchers to develop fNIRS signal processing techniques. The software, which is freely available, allows users to generate fNIRS data with control over a wide range of parameters and allows for fine-tuning of the synthetic data. We demonstrate how the model can be used to generate raw fNIRS data similar to recorded fNIRS signals. Signal processing steps were then applied to both the real and synthetic data. Visual comparisons between the temporal and spectral properties of the real and synthetic data show similarity. This paper demonstrates that our model for generating synthetic fNIRS data can replicate real fNIRS recordings. PMID- 22255850 TI - EMG contributes to improve Cerebral State Index modeling in dogs anesthesia. AB - Cerebral State Index (CSI) is a measure of depth of anesthesia (DoA) developed for humans, which is traditionally modeled with the Hill equation and the propofol effect-site concentration (Ce). The CSI has been studied in dogs and showed several limitations related to the interpretation of EEG data. Nevertheless, the CSI has a lot of potential for DoA monitoring in dogs, it just needs to be adjusted for this species. In this work, an adapted CSI model is presented for dogs considering a) both Ce and EMG as inputs and b) a fuzzy logic structure with parameters optimized using the ANFIS method. The new model is compared with traditional Hill model using data from dogs in routine surgery. The results showed no significant impact in the model performance with the change of model structure (Fuzzy instead of Hill). The residuals of the Hill model were significantly correlated with the EMG, indicating that the latter should be considered in the model. In fact, the EMG introduction in CSI model significantly decreased the modeling error: 11.8 [8.6; 15.2] (fuzzy logic) versus 20.9 [16.4; 29.0] (Hill). This work shows that CSI modeling in dogs can be improved using the current human anesthesia set-up, once the EMG signal is acquired simultaneously with the CSI index. However, it does not invalidate the search of new DoA indices more adjusted to use in dog's anesthesia. PMID- 22255851 TI - Evaluating descriptors for the lateral translocation of membrane proteins. AB - Microscopic images of tissue sections are used for diagnosis and monitoring of therapy, by analysis of protein patterns correlating to disease states. Spatial protein distribution is influenced by protein translocation between different membrane compartments and quantified by comparison of microscopic images of biological samples. Cholestatic liver diseases are characterized by translocation of transport proteins, and quantification of their dislocation offers new diagnostic options. However, reliable and unbiased tools are lacking. The nowadays used manual method is slow, subjective and error-prone. We have developed a new workflow based on automated image analysis and improved it by the introduction of scale-free descriptors for the translocation quantification. This fast and unbiased method can substitute the manual analysis, and the suggested descriptors perform better than the earlier used statistical variance. PMID- 22255852 TI - Features for cells and nuclei classification. AB - The performance of automated analysis of cellular images is heavily influenced by the features that characterize cells or cell nuclei. In this paper, an exhaustive set of features including morphological, topological, and texture features are explored to determine the optimal features for classification of cells and cell nuclei. The optimal subset of features are obtained using popular feature selection methods. The results of feature selection indicate that Zernike moment, Daubechies wavelets, and Gabor wavelets give the most important features for the classification of cells or cell nuclei in fluorescent microscopy images. PMID- 22255853 TI - Towards building computerized image analysis framework for nucleus discrimination in microscopy images of diffuse glioma. AB - As an effort to build an automated and objective system for pathologic image analysis, we present, in this paper, a computerized image processing method for identifying nuclei, a basic biological unit of diagnostic utility, in microscopy images of glioma tissue samples. The complete analysis includes multiple processing steps, involving mode detection with color and spatial information for pixel clustering, background normalization leveraging morphological operations, boundary refinement with deformable models, and clumped nuclei separation using watershed. In aggregate, our validation dataset includes 220 nuclei from 11 distinct tissue regions selected at random by an experienced neuropathologist. Computerized nuclei detection results are in good concordance with human markups by both visual appraisement and quantitative measures. We compare the performance of the proposed analysis algorithm with that of CellProfiler, a classical analysis software for cell image process, and present the superiority of our method to CellProfiler. PMID- 22255854 TI - New robust algorithm for tracking cells in videos of Drosophila morphogenesis based on finding an ideal path in segmented spatio-temporal cellular structures. AB - In this paper, we present a novel algorithm for tracking cells in time lapse confocal microscopy movie of a Drosophila epithelial tissue during pupal morphogenesis. We consider a 2D + time video as a 3D static image, where frames are stacked atop each other, and using a spatio-temporal segmentation algorithm we obtain information about spatio-temporal 3D tubes representing evolutions of cells. The main idea for tracking is the usage of two distance functions--first one from the cells in the initial frame and second one from segmented boundaries. We track the cells backwards in time. The first distance function attracts the subsequently constructed cell trajectories to the cells in the initial frame and the second one forces them to be close to centerlines of the segmented tubular structures. This makes our tracking algorithm robust against noise and missing spatio-temporal boundaries. This approach can be generalized to a 3D + time video analysis, where spatio-temporal tubes are 4D objects. PMID- 22255855 TI - An active particle-based tracking framework for 2D and 3D time-lapse microscopy images. AB - The process required to track cellular structures is a key task in the study of cell migration. This allows the accurate estimation of motility indicators that help in the understanding of mechanisms behind various biological processes. This paper reports a particle-based fully automatic tracking framework that is able to quantify the motility of living cells in time-lapse images. Contrary to the standard tracking methods based on predefined motion models, in this paper we reformulate the tracking mechanism as a data driven optimization process to remove its reliance on a priory motion models. The proposed method has been evaluated using 2D and 3D deconvolved epifluorescent in-vivo image sequences that describe the development of the quail embryo. PMID- 22255856 TI - Spherical Harmonics based extraction and annotation of cell shape in 3D time lapse microscopy sequences. AB - Understanding the mechanisms involved in cell deformation and motility is of major interest in numerous areas of life sciences. Precise quantification of cell shape requires robust shape description tools to be amenable to subsequent analysis and classification. The main difficulty lies in the great variability of cell shapes within a given homogeneous population. In this work, we propose a framework for cell shape extraction and classification for 3D time-lapse sequences of living cells, based on the SPherical HARMonics transform (SPHARM). Starting from an initial segmentation of the cell surface over time, this mathematical representation enables us to represent each extracted surface by a unique set of coefficients, while taking into account invariance properties such as translation or orientation. Then, unsupervised classification is conducted using a multi-class K-Means approach, so as to extract the most pertinent number of classes representing the different phases of the cell deformation. Experimental results on several sequences give encouraging results, and show that the proposed approach can be used to perform automated sequence annotation, and can be further applied to compare shape characteristics across different cell populations. PMID- 22255857 TI - Real-time laryngoscopic measurements of vocal-fold vibrations. AB - We have developed a high-frame-rate laryngoscope that can measure the vibration distribution of a human vocal fold in real time at hundreds of hertz. Our laryngoscope can extract a vocal-fold contour at 4000 fps as 20 pairs of its left and right border points from 256 * 512-pixel images to quantify left-right asymmetry of vocal-fold vibrations. Experiments on artificial vocal-fold-like vibrations of a silicon rubber membrane were performed to confirm the laryngoscope's effectiveness, and the vocal folds of human subjects, including patients with laryngeal diseases, were examined under clinical conditions. PMID- 22255858 TI - Towards integrating temporal information in capsule endoscopy image analysis. AB - Analysis of Wireless Capsule Endoscopy (CE) images has become a very active area of research since this novel technology enabled access to previously inaccessible areas of the gastrointestinal tract, especially the small intestine. Art has investigated automatic segmentation of organ boundaries, detection of lesions and bleeding as well as other supervised and unsupervised analysis. However, all of this art has focused on treating the images as individual and independent observations that contribute towards a unique and separate decision. Given the overlap between the images, this is clearly not the case. A human, by contrast, performs assessment by combining the information seen in all neighboring views of the anatomy in a study. This article makes two significant contributions. Towards combining information from multiple images, we propose a supervised classification approach using an HMM framework. Secondly, we use a weak (k-NN) classifier to prototype and evaluate such a framework for regions of the GI tract containing polyps. The combined framework significantly improves the performance of the individual classifier and experiments show promising performance with accuracy > 0.9. PMID- 22255859 TI - Compressed domain topographic classification for capsule endoscopy. AB - In this paper we compare the classification accuracy of using compressed domain color (CDC) descriptors versus traditional full decoded images, for the purposes of topographic classification of wireless capsule endoscopy images. Results using a dataset of 26469 images, divided into stomach, small intestine and large intestine show a difference in classification accuracy below 1%. We also show that errors are mostly located near zone transitions (the pylorus and the ileocecal valve) and motivate the need for other visual descriptors (e.g. shape, motion) for addressing these specific areas. We conclude we can use the advantages of CDC in this type of classification with minor accuracy sacrifice. PMID- 22255860 TI - Gap detection in endoscopic video sequences using graphs. AB - In minimal invasive surgery (MIS) a complete and seamless inspection of organs, e.g. the urinary bladder, using video endoscopes is often required for diagnostics. Since the endoscope is usually guided by free-hand, it is difficult to ensure a sequence of seamless frame transitions. Also 2-D panoramic images showing an extended field of view (FOV) do not provide always reliable results, since their interpretations are limited by potentially strong geometric distortions. To overcome these limitations and provide a direct verification method, we develop a gap detection algorithm using graphs. Exploiting the motion information of the applied zig-zag scan, we construct a graph representation of the video sequence. Without any explicit global image visualization our graph search algorithm identifies reliably frame discontinuities, which would lead to holes and slit artifacts in a panoramic view. The algorithm shows high detection rates and provides a fast method to verify frame discontinuities in the whole video sequence. Missed regions are highlighted by local image compositions which can be displayed during the intervention for assistance and inspection control. PMID- 22255861 TI - Feature-based tracking of urethral motion in low-resolution trans-perineal ultrasound. AB - This paper describes a novel algorithm for tracking the motion of the urethra from trans-perineal ultrasound. Our work is based on the structure-from-motion paradigm and therefore handles well structures with ill-defined and partially missing boundaries. The proposed approach is particularly well-suited for video sequences of low resolution and variable levels of blurriness introduced by anatomical motion of variable speed. Our tracking method identifies feature points on a frame by frame basis using the SURF detector/descriptor. Inter-frame correspondence is achieved using nearest-neighbor matching in the feature space. The motion is estimated using a non-linear bi-quadratic model, which adequately describes the deformable motion of the urethra. Experimental results are promising and show that our algorithm performs well when compared to manual tracking. PMID- 22255862 TI - Bleeding detection in wireless capsule endoscopy images based on color invariants and spatial pyramids using support vector machines. AB - Wireless capsule endoscopy (WCE) is a revolutionary imaging technique that enables detailed inspection of the interior of the whole gastrointestinal tract in a non-invasive way. However, viewing WCE videos is a very time-consuming, and labor intensive task for physicians. In this paper, we propose an automatic method for bleeding detection in WCE images. A novel series of descriptors which combine color and spatial information is designed in a way that local and global features are also incorporated together. And a kernel based classification method using histogram intersection or chi-square is deployed to verify the performance of the proposed descriptors. Experiments demonstrate that the proposed kernel based scheme is very effective in detecting bleeding patterns of WCE images. PMID- 22255863 TI - IVUS-based assessment of 3D morphology and virtual histology: prediction of atherosclerotic plaque status and changes. AB - Comprehensive analysis of coronary morphology, plaque composition, hemodynamics, and systemic cardiovascular biomarkers is hypothesized to allow prediction of plaque development. We report the status of a comprehensive project, in which baseline and follow-up intravascular ultrasound imaging of coronary arteries during routine coronary interventions serve as a source of quantitative data for development of a predictive classifier for determining plaque progression over the course of a year from baseline data. PMID- 22255864 TI - Automated high-performance cIMT measurement techniques using patented AtheroEdgeTM: a screening and home monitoring system. AB - The evaluation of the carotid artery wall is fundamental for the assessment of cardiovascular risk. This paper presents the general architecture of an automatic strategy, which segments the lumen-intima and media-adventitia borders, classified under a class of Patented AtheroEdgeTM systems (Global Biomedical Technologies, Inc, CA, USA). Guidelines to produce accurate and repeatable measurements of the intima-media thickness are provided and the problem of the different distance metrics one can adopt is confronted. We compared the results of a completely automatic algorithm that we developed with those of a semi automatic algorithm, and showed final segmentation results for both techniques. The overall rationale is to provide user-independent high-performance techniques suitable for screening and remote monitoring. PMID- 22255865 TI - First and second order statistical texture features in carotid plaque image analysis: preliminary results from ongoing research. AB - Carotid plaques have been associated with ipsilateral neurological symptoms. High resolution ultrasound can provide information not only on the degree of carotid artery stenosis but also on the characteristics of the arterial wall including the size and consistency of atherosclerotic plaques. The aim of this study was to determine cerebrovascular risk stratification based on ultrasonic plaque texture features and clinical features in patients with asymptomatic internal carotid artery (ICA) stenosis. It is shown that cerebrovascular risk stratification is possible using a combination of clinical and ultrasonic plaque features with very satisfactory results. However, these findings need to be validated in additional prospective studies in patients having current medical intervention. PMID- 22255866 TI - Autonomous locomotion of capsule endoscope in gastrointestinal tract. AB - Autonomous locomotion in gastrointestinal (GI) tracts is achieved with a paddling based capsule endoscope. For this, a miniaturized encoder module was developed utilizing a MEMS fabrication technology to monitor the position of paddles. The integrated encoder module yielded the high resolution of 0.0025 mm in the linear motion of the paddles. In addition, a PID control method was implemented on a DSP to control the stroke of the paddles accurately. As a result, the average accuracy and the standard deviation were measured to be 0.037 mm and 0.025 mm by a laser position sensor for the repetitive measurements. The locomotive performance was evaluated via ex-vivo tests according to various strokes in paddling. In an in-vivo experiment with a living pig, the locomotion speed was improved by 58% compared with the previous control method relying on a given timer value for reciprocation of the paddles. Finally, the integrated encoder module and the control system allow consistent paddling during locomotion even under loads in GI tract. It provides the autonomous locomotion without intervention in monitoring and controlling the capsule endoscope. PMID- 22255867 TI - Electromagnetic drive of microrobot geometrically constrained in blood vessel. AB - We propose new electromagnetic actuation of a microrobot by utilizing geometric constraints in a blood vessel. In our concept, a microrobot travels in a vascular network while keeping the contact to the vascular wall. In the paper, forces working on the microrobot are modeled in two dimensions, and conditions to propel the microrobot while pushing it against the vascular wall are described. The design of the microrobot composed of three permanent magnets is also presented. The feasibility of the 2D actuation of the microrobot was confirmed using an experimental setup composed of four pairs of coils generating both uniform magnetic fields and uniform magnetic field gradients. Finally, the model was extended to 3D in order to investigate 3D actuation of the microrobot. PMID- 22255868 TI - Encapsulation of magnetotactic bacteria for targeted and controlled delivery of anticancer agents for tumor therapy. AB - We showed that magnetotactic bacteria (MTB) have great potentials to be used as microcarriers for targeted delivery of therapeutic agents. Indeed, magnetotaxis inherent in MTB can be exploited to direct them towards a tumor while being propelled by their own flagellated molecular motors. Nonetheless, although the thrust propelling force above 4 pN of the MC-1 MTB showed to be superior compared to other technologies for displacement in the microvasculature, MTB becomes much less efficient when travelling in larger blood vessels due to higher blood flow. In the latter case, a new technique developed by our group and referred to as Magnetic Resonance Navigation (MRN), has been successfully applied in larger vessels using synthetic microcarriers nut proved to be less efficient in the microvasculature due mainly to technological constraints. These findings called for the need to integrate both approaches by encapsulating MTB in special MRN compatible microcarriers to be release in the vicinity of microvascular networks where they becomes more effective for targeting purposes in tumoral lesions. In this study Magnetococcus strain MC-1 were encapsulated in giant vesicles. The survival of the encapsulated bacteria was monitored. The release of bacteria from giant vesicles was also studied in different time intervals and conditions. PMID- 22255869 TI - Human neuroblastoma cultures for biorobotics. AB - This paper introduces a new biorobotic system using human neuroblastoma cultures and centre of area learning for basic robotic guidance. Multielectrode Arrays Setups have been designed for direct culturing neural cells over silicon or glass substrates, providing the capability to stimulate and record simultaneously populations of neural cells. The main objective of this work will be to control a robot using this biological neuroprocessor and a new simple centre of area learning scheme. The final system could be applied for testing how chemicals affect the behaviour of the robot or to establish the basis for new hybrid optogenetic neuroprostheses based on stimulating optically genetic-modified neurons. PMID- 22255871 TI - An image-based guidewire navigation method for robot-assisted intravascular interventions. AB - This paper aims at using a newly developed robotic system to automatically deliver guidewires or catheters to the target site on percutaneous coronary interventions (PCIs) or electrophysiology interventions. An autonomous delivery strategy using electromagnetic tracking technology is introduced and phantom experiments are performed to validate this strategy. In order to advance the guidewire into the planned branch, the strategy classifies this branch selection problem into three cases according to the width of the vessels and employs an image-based algorithm for the first and second cases. Another image-based algorithm specifically designed for the third case is also presented. PMID- 22255872 TI - Robust 3D tracking for robotic-assisted beating heart surgery. AB - The past decades have witnessed the notable development of minimally invasive surgery (MIS). The benefits of this modality of surgery for patients are numerous, shortening convalescence, reducing trauma and surgery costs. In this context, robotic assistance aims to make the surgical act more intuitive and safer. In the domain of cardiac MIS, heartbeat and respiration represent two important sources of disturbances. Even though miniaturized versions of heart stabilizers have been conceived for the MIS scenario, residual motion is still considerable and has to be manually canceled by the surgeon. Our work focuses on computer vision techniques for estimating the 3D motion of the heart relying solely on natural structures on the heart surface for active compensation of physiological motions. We have developed in [2] a visual tracking method for estimating the 3D deformation of a region of interest on the heart surface based on the visual feedback of a stereo endoscope. The method is robust to illumination variations and large tissue deformations (Fig. 1). PMID- 22255873 TI - Approaches to creating and controlling motion in MRI. AB - Magnetic Resonance Imaging (MRI) can provide three dimensional (3D) imaging with excellent resolution and sensitivity making it ideal for guiding and monitoring interventions. The development of MRI-compatible interventional devices is complicated by factors including: the high magnetic field strength, the requirement that such devices should not degrade image quality, and the confined physical space of the scanner bore. Numerous MRI guided actuated devices have been developed or are currently being developed utilizing piezoelectric actuators as their primary means of mechanical energy generation to enable better interventional procedure performance. While piezoelectric actuators are highly desirable for MRI guided actuation for their precision, high holding force, and non-magnetic operation they are often found to cause image degradation on a large enough to scale to render live imaging unusable. This paper describes a newly developed piezoelectric actuator driver and control system designed to drive a variety of both harmonic and non-harmonic motors that has been demonstrated to be capable of operating both harmonic and non-harmonic piezoelectric actuators with less than 5% SNR loss under closed loop control. The proposed system device allows for a single controller to control any supported actuator and feedback sensor without any physical hardware changes. PMID- 22255874 TI - Towards a soft-tissue cutting simulator using the cohesive zone approach. AB - Advancements in computational techniques have provided the ability to utilize detailed models in surgical training systems. The development of more complicated procedures coupled with reduced training time for medical residents has driven the need for accurate reality-based medical simulators. Extensive research has been conducted in the area of modeling general deformation of biological tissue; however few studies have focused on the physical properties of specific tool tissue interactions such as cutting. This paper presents a fracture mechanics based method to model the scalpel cutting of porcine liver by implementing a cohesive zone approach. Using in vivo cutting data, the parameters of the cohesive zone model are defined for the scalpel cutting process of soft biological tissues. PMID- 22255875 TI - Force detecting gripper and flexible micro manipulator for neurosurgery. AB - In order to realize a less invasive robotic neurosurgery for the deeply seated tumor, a force detecting gripper with a flexible micro manipulator has been developed. Gripping force applied on the gripper is detected by strain gages fit on the gripper clip. Signal is conducted to the amplifier by the cables through the inner pipe of the manipulator. In order to approach to the deeply seated tumor through a narrow hole, a micro manipulator which can flex at the end part to face the gripper for the target and can rotate the closing direction of the gripper at the end of the manipulator has been developed. Some operation test showed that the developed manipulator can approach flexibly to the target, and the taking out force of a target on the soft material was detected clearly. PMID- 22255876 TI - Microsurgical skill assessment: toward skill-based surgical robotic control. AB - A surgical skill assessment system was developed to quantify microsurgical skills. Infrared optical makers, an inertial measurement unit, and strain gauges were mounted on tweezers to record surgical tasks. In preliminary experiments, the tool tip trajectory, acceleration, and applied force were measured and microsurgery videos were evaluated by three expert surgeons. The preliminary results indicated the feasibility of the system by showing the significant difference between unskilled and skilled surgeons. PMID- 22255877 TI - Haptic feedback control in medical robots through fractional viscoelastic tissue model. AB - In this paper, we discuss the design of an adaptive control system for robot assisted surgery with haptic feedback. Through a haptic device, the surgeon teleoperates the medical instrument in free space, fixed on a remote robot or in contact. In free space, the surgeon feels the motion of the robot. In the present paper, we evaluated the performance of the controller on viscoelastic tissue, modeled by a fractional derivative equation. In addition, we propose a novel controller using an integer formalization process that is suitable for these tissue properties. The simulation results suggested that performance, in terms of force control and telepresence, became poorer when the conventional controller, which was designed for elastic target object, was applied to the viscoelastic tissues. In contrast, the results suggested that our proposed controller maintained its performance on the viscoelastic tissues. PMID- 22255878 TI - Rehabilitation robotics: an academic engineer perspective. AB - In this paper, we present a retrospective review of our efforts to revolutionize the way physical medicine is practiced by developing and deploying rehabilitation robots. We present a sample of our clinical results with well over 600 stroke patients, both inpatients and outpatients. We discuss the different robots developed at our laboratory over the past 20 years and their unique characteristics. All are configured both to deliver reproducible interactive therapy and also to measure outcomes with minimal encumbrance, thus providing critical measurement tools to help unravel the key remaining question: what constitutes "best practice"? While success to date indicates that this therapeutic application of robots has opened an emerging new frontier in physical medicine and rehabilitation, the barrier to further progress lies not in developing new hardware but rather in finding the most effective way to enhance neuro-recovery. We close this manuscript discussing some of the tools required for advancing the effort beyond the present state to what we believe will be the central feature of research during the next 10 years. PMID- 22255879 TI - Single- and multi-unit activity recorded from the surface of the dorsal root ganglia with non-penetrating electrode arrays. AB - Non-penetrating surface electrode recording techniques are typically associated with field potential recordings, while extracellular recordings from single neurons are made using penetrating metal wire or microfabricated microelectrode arrays. Here, we report on single- and multi-unit neuronal recordings made using non-penetrating electrodes placed on the epineural surface of the dorsal root ganglia (DRG). Across four experiments in anesthetized cats, approximately 40% of the electrodes recorded single- and multi-unit spiking activity with spike-rates that covaried significantly with hindlimb movement. In two intraoperative experiments in humans, compound activity was recorded from the DRG surface in response to peripheral stimulation of the common peroneal nerve. This approach may have advantages over penetrating electrode arrays in terms of clinical acceptability and recording longevity. PMID- 22255880 TI - Chip-scale hermetic feedthroughs for implantable bionics. AB - Most implantable medical devices such as cochlear implants and visual prostheses require protection of the stimulating electronics. This is achieved by way of a hermetic feedthrough system which typically features three important attributes: biocompatibility with the human body, device hermeticity and density of feedthrough conductors. On the quest for building a visual neuroprosthesis, a high number of stimulating channels is required. This has encouraged new technologies with higher rates of production yield and further miniaturization. An Al(2)O(3) based feedthrough system has been developed comprising up to 20 platinum feedthroughs per square millimeter. Ceramics substrates are shown to have leak rates below 1 * 10(-12) atm * cc/s, thus exceeding the resolution limits of most commercially available leak detectors. A sheet resistance of 0.05 Omega can be achieved. This paper describes the design, fabrication process and hermeticity testing of high density feedthroughs for use in neuroprosthetic implants. PMID- 22255881 TI - Theoretical framework for estimating the conductivity map of the retina through finite element analysis. AB - A mathematical framework for estimation of the conductivity map of the retina is presented. The problem is formulated and solved in two-dimensional space considering hypothetical inhomogeneity in the conductivity profile at each layer of the retina in x and y directions. Finite element analysis is used to solve the equation of continuity in steady state to simulate voltage measurements as well as estimate the conductivity map. The results of simulated noisy data for an inhomogeneous retina layer and the fovea, which has a more complicated geometry, are presented. The error study of the estimated conductivity map shows that the error for an inhomogeneous conductivity profile is approximately 2% and the error for calculating the fovea conductivity map is just above 8%. This method can be extended to three-dimensions and can also be used to measure the impedance of different layers of the retina for alternating currents. PMID- 22255882 TI - Interphase gap decreases electrical stimulation threshold of retinal ganglion cells. AB - The most common electrical stimulation pulse used in retinal implants is a symmetric biphasic current pulse. Prior electrophysiological studies in peripheral nerve have shown that adding an interphase gap (IPG) between the two phases makes stimulation more efficient. We investigated the effect of IPG duration on retinal ganglion cell (RGC) electrical threshold. We used calcium imaging to measure the activity of RGCs in isolated retina in response to electrical stimulation. By varying IPG duration, we were able to examine the effect of duration on threshold. We further studied this effect by simulating RGC behavior with a Hodgkin-Huxley-type model. Our results indicate that the threshold for electrical activation of RGCs can be reduced by increasing the length of the IPG. PMID- 22255883 TI - A prototype 64-electrode stimulator in 65 nm CMOS process towards a high density epi-retinal prosthesis. AB - This paper presents a highly flexible 64-electrode stimulator using 65 nm CMOS process fabricated as a stage towards a 1024-electrode epi-retinal prosthesis, which aims to restore partial vision in patients suffering from eye diseases such as retinitis pigmentosa (RP) and age-related macular degradation (AMD). The stimulator drives 64 electrodes with many flexible features, which are necessary before making a complete 1024-electrode implant chip. Each electrode driver can provide a bi-phasic stimulus current with fully programmable parameters such as amplitude, pulse duration, inter-phase gap, and stimulation rate. The electrode driver operates in an alternately pull-push manner with only one current source working at a time, which helps reduce headroom voltage while controlling charge balance at the active electrode. The stimulator varies both stimulus current amplitude and stimulation rate to represent phosphene brightness. The stimulus current amplitude starts from the tissue depolarization threshold with 64 different levels. The selection of active and return electrodes is arbitrary, any electrodes and any number of them can be selected at any time. The power consumption of the stimulator is 400 MUW excluding the stimulus power. Measurement results verify correct operation. The stimulator is easily scaled up to drive 1024 electrodes. PMID- 22255884 TI - CMOS-based smart-electrode-type retinal stimulator with bullet-shaped bulk Pt electrodes. AB - A CMOS-based flexible retinal stimulator equipped with bullet-shaped bulk Pt electrodes was fabricated and demonstrated. We designed a new CMOS unit chip with an on-chip stimulator, single- and multi-site stimulation modes, and monitoring functions. We have developed a new structure and packaging process of flexible retinal stimulator with bullet-type bulk Pt electrode. We have confirmed the retinal stimulation functionality in an in vivo stimulation trial on rabbit's retina. PMID- 22255885 TI - Towards a chip scale neurostimulator: system architecture of a current-driven 98 channel neurostimulator via a two-wire interface. AB - With more clinical trials proving viability of visual prosthesis follows the demand for higher resolution devices. As the number of electrodes increases, due to surgical difficulties, it is preferred to keep their length short by placing the implant close to the stimulation site, where there are considerable constraints on device size. On the contrary, the physical volume of the implant generally increases with increasing number of electrodes. Splitting the implant into two modules and placing only the essential circuits near the site of stimulation solves the aforementioned problem. However now the problem is redirected to the robustness and the safety of the interface joining these modules. A novel two-wire interface driving a 98 channel neurostimulator incorporating the split-architecture is presented. The stimulator is provided with both power and data by sending square current waveforms via the two-wire interface. The stimulator itself is fabricated using 0.35 MUm HVCMOS technology and occupies 4.9 * 4.9 mm(2) and requires no external decoupling capacitor. PMID- 22255887 TI - Preliminary investigation into the effects of visual feedback distortion on range of motion. AB - In this study, a robotic orthotic device with one degree of freedom was used for assessment of individuals with chronic stroke and resultant hemiparesis. The specific aim was to investigate the effect of visual feedback distortion on range of motion (ROM) at the elbow and wrist joints as measured by the Arm IntelliStretch platform from Rehabtek LLC. It was hypothesized that introducing visual feedback distortion in increments under the just noticeable difference of two degrees would directly correspond to an increase in ROM at both the wrist and elbow joints when compared to ROM measured by the IntelliStretch system without visual feedback distortion. Ten individuals an average of 11 years post stroke (SD: 9.7) participated in this study. At the elbow joint, repeated measures ANOVA showed a significant effect of distortion (F(4, 36) = 2.69, p < 0.047). Similar trends were seen at the wrist joint, though these results were not statistically significant. PMID- 22255886 TI - Smart calibration for video game play by people with a movement impairment. AB - People with movement impairment often cannot move with the range, speed, or acceleration required to play an off-the-shelf video game. This paper describes a smart calibration algorithm designed to facilitate video game play by people with movement impairment. The algorithm continuously adapts the calibration of the gaming input device by comparing the maximum range of motion measured in previous time periods, then adjusting the current required range of motion based on their difference. In several experiments with simple acceleration-based video games using a Nintendo Wiimote, we show that the algorithm adapts the calibration to allow healthy users to play the game with their full available range of acceleration without need for a special calibration protocol. Importantly, the algorithm described here can be used without altering the game software by inserting a hardware or software module between the gaming input device and the game console. Thus, the algorithm can be used with off-the-shelf video games without altering their source code. PMID- 22255888 TI - Adaptive rehabilitation gaming system: on-line individualization of stroke rehabilitation. AB - The effects of stroke differ considerably in degree and symptoms for different patients. It has been shown that specific, individualized and varied therapy favors recovery. The Rehabilitation Gaming System (RGS) is a Virtual Reality (VR) based rehabilitation system designed following these principles. We have developed two algorithms to control the level of task difficulty that a user of the RGS is exposed to, as well as providing controlled variation in the therapy. In this paper, we compare the two algorithms by running numerical simulations and a study with healthy subjects. We show that both algorithms allow for individualization of the challenge level of the task. Further, the results reveal that the algorithm that iteratively learns a user model for each subject also allows a high variation of the task. PMID- 22255889 TI - Sensorimotor enhancement with a mixed reality system for balance and mobility rehabilitation. AB - We have developed a mixed reality system incorporating virtual reality (VR), surface perturbations and light touch for gait rehabilitation. Haptic touch has emerged as a novel and efficient technique to improve postural control and dynamic stability. Our system combines visual display with the manipulation of physical environments and addition of haptic feedback to enhance balance and mobility post stroke. A research study involving 9 participants with stroke and 9 age-matched healthy individuals show that the haptic cue provided while walking is an effective means of improving gait stability in people post stroke, especially during challenging environmental conditions such as downslope walking. PMID- 22255890 TI - Human Augmentics: augmenting human evolution. AB - Human Augmentics (HA) refers to technologies for expanding the capabilities, and characteristics of humans. One can think of Human Augmentics as the driving force in the non-biological evolution of humans. HA devices will provide technology to compensate for human biological limitations either natural or acquired. The strengths of HA lie in its applicability to all humans. Its interoperability enables the formation of ecosystems whereby augmented humans can draw from other realms such as "the Cloud" and other augmented humans for strength. The exponential growth in new technologies portends such a system but must be designed for interaction through the use of open-standards and open-APIs for system development. We discuss the conditions needed for HA to flourish with an emphasis on devices that provide non-biological rehabilitation. PMID- 22255891 TI - Simultaneous coordinate representations are influenced by visual feedback in a motor learning task. AB - It has been widely accepted that the CNS develops a representation (model) of the environment, but what is not entirely clear is the coordinate reference frame used. We explored how visual feedback influenced the coordinate frame in which the CNS stores and recalls these memories of learned skills in a reaching generalization task. Four groups of subjects trained to perform reaching movements in a perturbing force field, two with aligned (first person) visual feedback and two with non-aligned (vertical screen). After 170 trials of practice, we asked subjects to extrapolate (generalize) what they learned to a new part of the workspace in novel force environments (endpoint-based versus joint-based extrapolated force fields). Regardless of the test condition, all subjects improved their ability to generalize skills to the new workspace. There was evidence that the extrapolation of their learned skills was based on both object-centered and joint-based coordinates. Consistent with previous studies, subjects performed significantly better in joint-extrapolated force field, but only if the visual feedback was vertical. Subjects performed equivalently in both force fields with aligned (first person) feedback. These findings suggest that the type of visual feedback biases the way subjects perform, and that learning results can be significantly influenced by feedback. PMID- 22255892 TI - Cortical mapping of the optically evoked responses in channelrhodopsin-2 mouse model. AB - Little is known about the information transfer properties of large-scale neural circuit in brain system. We applied optical deep brain stimulation to define the properties of information flow within a living brain assisted by channel rhodopsin-2 (ChR2) transgenic mice, of which neurons express the light-activated ion channel. We first characterized the responses of neuronal ensemble to the impinged light with respect to stimulation parameters by co-registering local field potentials with optical stimulation. Secondly, we applied recently developed polyimide based microarray for mouse electroencephalogram (EEG) to obtain the cortical responses with respect to deep brain stimulation. Particularly, the spatiotemporal cortical mapping with respect to deep brain stimulation of primary somatosensory cortex and hippocampus CA1 were presented in this article. PMID- 22255893 TI - Study on DBS device for small animals. AB - Although deep brain stimulation (DBS) therapy has been achieved, fine tuning on the operational parameters and the equipment are needed in order to make the stimulation treatment more applicable. Thus, the purpose of this study is to design and produce a deep brain stimulation device for DBS experiments for small animals (e.g. rats). Physical size, durability, cost of device and convenience of operation are the major focuses in this study. The designed pulse generator can produce pulses with adjustable frequencies, pulse widths and amplitudes. Telemetry and remote control of the system reduced the physical size of the implant component. Battery voltage measurement and electrode impedance measurement justified the values of parameters applied for stimulation. Power consumption is low enough and test results show it is expected to work for more than three months when using typical pulse parameters. Finally, we use the device on the DBS experiment of rats. The results prove that the design of the device can fulfill the requirements for deep brain stimulation in animal experiments. PMID- 22255894 TI - Instrumentation to record evoked potentials for closed-loop control of deep brain stimulation. AB - Closed-loop deep brain stimulation (DBS) systems offer promise in relieving the clinical burden of stimulus parameter selection and improving treatment outcomes. In such a system, a feedback signal is used to adjust automatically stimulation parameters and optimize the efficacy of stimulation. We explored the feasibility of recording electrically evoked compound action potentials (ECAPs) during DBS for use as a feedback control signal. A novel instrumentation system was developed to suppress the stimulus artifact and amplify the small magnitude, short latency ECAP response during DBS with clinically relevant parameters. In vitro testing demonstrated the capabilities to increase the gain by a factor of 1,000* over a conventional amplifier without saturation, reduce distortion of mock ECAP signals, and make high fidelity recordings of mock ECAPs at latencies of only 0.5 ms following DBS pulses of 50 to 100 MUs duration. Subsequently, the instrumentation was used to make in vivo recordings of ECAPs during thalamic DBS in cats, without contamination by the stimulus artifact. The signal characteristics were similar across three experiments, suggesting common neural activation patterns. The ECAP recordings enabled with this novel instrumentation may provide insight into the type and spatial extent of neural elements activated during DBS, and could serve as feedback control signals for closed-loop systems. PMID- 22255895 TI - Epileptic seizure detection with the local field potential of anterior thalamic of rats aiming at real time application. AB - Treating epilepsy with deep brain stimulation (DBS) is attracting more and more attention these years, especially the close loop method that gives stimuli when needed so that the implanted device will work longer. People have tried to detect seizure with electrocorticogram (ECoG), but the extra implants put more risks to it. We plan to detect seizure with local field potential (LFP) that recorded with depth electrodes of traditional DBS. To prove the validation of this method, we recorded local field potential (LFP) of anterior thalamic (ANT) of rats who have been induced to acute temporal lobe epilepsy (TLE) by kainic acid injected in hippocampus, and succeeded in detecting electrographic onset (EO) in these data. A variation of generic Osorio-Frei algorithm (GOFA) was used as the detection method with some adjustments which mainly focus on increasing calculation speed and decreasing number of total calculations to meet the future need of transplanting to battery powered embedded medical device. PMID- 22255896 TI - Application of non-linear control theory to a model of deep brain stimulation. AB - Deep brain stimulation (DBS) effectively alleviates the pathological neural activity associated with Parkinson's disease. Its exact mode of action is not entirely understood. This paper explores theoretically the optimum stimulation parameters necessary to quench oscillations in a neural-mass type model with second order dynamics. This model applies well established nonlinear control system theory to DBS. The analysis here determines the minimum criteria in terms of amplitude and pulse duration of stimulation, necessary to quench the unwanted oscillations in a closed loop system, and outlines the relationship between this model and the actual physiological system. PMID- 22255897 TI - Quantitative measurement of motor symptoms in Parkinson's disease: a study with full-body motion capture data. AB - Recent advancements in the portability and affordability of optical motion capture systems have opened the doors to various clinical applications. In this paper, we look into the potential use of motion capture data for the quantitative analysis of motor symptoms in Parkinson's Disease (PD). The standard of care, human observer-based assessments of the motor symptoms, can be very subjective and are often inadequate for tracking mild symptoms. Motion capture systems, on the other hand, can potentially provide more objective and quantitative assessments. In this pilot study, we perform full-body motion capture of Parkinson's patients with deep brain stimulator off-drugs and with stimulators on and off. Our experimental results indicate that the quantitative measure on spatio-temporal statistics learnt from the motion capture data reveal distinctive differences between mild and severe symptoms. We used a Support Vector Machine (SVM) classifier for discriminating mild vs. severe symptoms with an average accuracy of approximately 90%. Finally, we conclude that motion capture technology could potentially be an accurate, reliable and effective tool for statistical data mining on motor symptoms related to PD. This would enable us to devise more effective ways to track the progression of neurodegenerative movement disorders. PMID- 22255898 TI - Measuring changes in activity patterns during a norovirus epidemic at a retirement community. AB - Ubiquitous and unobtrusive in-home monitoring has the potential to detect physical and mental decline earlier and with higher precision than current clinical methods. However, given that this field is in its infancy, the specific metrics through which these changes are detected are not well defined. The work presented here offers room-transitions, the act of physically moving from one area of a home to another, as a quantifiable measure for total daily activity that can be inferred from a network of passive infrared sensors. We describe a method to calculate this value from raw sensor data and validate this method on an acute health event: an 18-day quarantine at a retirement community that was initiated in the midst of a norovirus outbreak. The results from this case study show that room-transition values increased significantly as subjects remained in their homes during the quarantine, demonstrating a mean increase of 12 transitions per day. Furthermore, a time-adjusted measure of room-transitions is examined that did not significantly change across the group. Finally, the healthy subjects and those that fell ill were analyzed separately, and significant differences were found between them for both the raw and time-adjusted metrics. As detection algorithms improve, these types of measures may be useful in the early detection of a change in health status. PMID- 22255899 TI - Detailed analysis of the relationship between tracheal breath sounds and airflow in relation to OSA during wake and sleep. AB - Tracheal respiratory sound analysis is a simple, inexpensive and non-invasive way to study the pathology of the upper airways. Recently, it has attracted considerable attention for acoustical flow estimation and investigation of obstruction in the upper airways. Obstructive sleep apena (OSA) is characterized by periods of reduction or complete cessation of airflow during sleep. However, the flow-sound relationship is highly variable among OSA and non-OSA individuals; it also changes for the same person at different body postures and during wake and sleep. In this study we recorded respiratory sound and flow from 93 non-OSA individuals as well as 13 OSA patients during sleep and wake. We investigated the statistical correlation between the flow-sound model parameters and anthropometric features in the non-OSA group. The results have shown that gender, height and smoking are the most significant factors that affect the model parameters. We compared the flow-sound relationship in OSA and non-OSA groups in the sitting position while awake. We also examined the variations in the model parameters in OSA patients during sleep and wake in the recumbent position. The results show that the model parameters are different in the two groups even when accounted for height, gender and position. In OSA group, the model parameters change from wake to sleep, even at the same position. The variations in the model parameters can be used to investigate the characteristics of upper airways and examine the factors that can lead to the upper airways obstruction during sleep. PMID- 22255901 TI - Instrumented insole vs. force plate: a comparison of center of plantar pressure. AB - Instrumented insoles allow analysis of gait outside of the confines of a motion analysis lab and capture motion data on every step. This study assesses the concurrent validity of center of plantar pressure (COPP) measurements during walking, and shows that our custom instrumented insoles compare favorably to an Advanced Mechanical Technology Inc. (AMTI) force plate in a clinical motion laboratory, particularly when the large difference in price is considered (an insole is nearly two orders of magnitude less expensive than a force plate). Deploying inexpensive insoles such as ours for ubiquitous health monitoring allows measurement of gait in more typical environments. This affords the opportunity to evaluate the gait of older adults in the home environment, and a future opportunity of providing real-time feedback corresponding to changes in gait. PMID- 22255900 TI - Wide-field fluorescent microscopy on a cell-phone. AB - We demonstrate wide-field fluorescent imaging on a cell-phone, using compact and cost-effective optical components that are mechanically attached to the existing camera unit of the cell-phone. Battery powered light-emitting diodes (LEDs) are used to side-pump the sample of interest using butt-coupling. The pump light is guided within the sample cuvette to excite the specimen uniformly. The fluorescent emission from the sample is then imaged with an additional lens that is put in front of the existing lens of the cell-phone camera. Because the excitation occurs through guided waves that propagate perpendicular to the detection path, an inexpensive plastic color filter is sufficient to create the dark-field background needed for fluorescent imaging. The imaging performance of this light-weight platform (~28 grams) is characterized with red and green fluorescent microbeads, achieving an imaging field-of-view of ~81 mm(2) and a spatial resolution of ~10 MUm, which is enhanced through digital processing of the captured cell-phone images using compressive sampling based sparse signal recovery. We demonstrate the performance of this cell-phone fluorescent microscope by imaging labeled white-blood cells separated from whole blood samples as well as water-borne pathogenic protozoan parasites such as Giardia Lamblia cysts. PMID- 22255902 TI - Aedes aegypti egg counting system. AB - New monitoring methods of dengue vector and evaluation of public policies on dengue control are major concerns for several tropical countries. Drawback on monitoring methods base on oviposition surveys are the counting process of mosquito eggs, information store and analysis. Here we present a new automated egg counting system for remote Aedes aegypti population survey. The system is base on an optical scanning platform, a man-machine interface, and a software for mosquitoes eggs counting. Acquired information are sent over the internet and remotely analyzed. Prototypes of the device were installed and implement in two different cities. PMID- 22255903 TI - Liquid cooling system for the vibro-tactile threshold device. AB - Vibrotactile threshold testing has been used to investigate activation of human somatosensory pathways. A portable vibrotactile threshold testing device called the Vibrotactile Threshold Evaluator for the Workplace (VTEW) was designed for screening of carpal tunnel syndrome in the workplace, and initially contained a small fan for cooling. During subject testing, the device is operated intermittently, which causes the linear actuator to warm the tactile probe. The probe causes discomfort for some subjects. During testing, the probe heated to 42 degrees C within 90 seconds of continuous operation. A liquid cooling system was implemented to dissipate heat from the probe. The liquid cooling system maintains a steady state temperature of 36 degrees C for continuous actuation of the probe. The liquid cooling system is capable of maintaining a safe operating temperature, without adding erroneous vibrations to the device. However, the cooling system deters the portability of the device. Further research will investigate how to make the liquid cooling system portable and implements vibrotactile threshold testing in the workplace to quickly evaluate whether or not a person has early symptoms of carpal tunnel syndrome. PMID- 22255904 TI - Left ventricular model parameters and cardiac rate variability. AB - A recent functional model of the left ventricle characterizes the ventricle's contractile state with parameters, rather than variables. The ventricle is treated as a pressure generator that is time and volume dependent. The heart's complex dynamics develop from a single equation based on the formation and relaxation of crossbridge bonds within underlying heart muscle. This equation permits the calculation of ventricular elastance via E(v) = ?p(v)/?V(v). This heart model is defined independently from load properties, and ventricular elastance is dynamic and reflects changing numbers of crossbridge bonds. The model parameters were extracted from measured pressure and volume data from isolated canine hearts. The purpose of this paper is to present in some detail how to describe a particular canine left ventricle from measured data. The model is also extended to include heart rate variability, which arises naturally from the model structure. Computed results compare favorably with measurements both in this study and from the literature. PMID- 22255905 TI - CMRI based 3D left ventricle motion analysis on patients with acute myocardial infarction. AB - 3D Quantitative measurement of left ventricle (LV) motion on patients with acute myocardial infarction has been recognized as essential for effective LV function diagnosis. This paper presents a method to quantify 3D LV motion obtained from conventional CINE MRI using image analysis based on mathematical modeling. Level set method is employed for segmentation, and a 3D LV geometry was reconstructed by co-registering different views of MRI images. A mathematical model of LV geometry was then constructed to quantitatively describe the LV wall inward motion. The results using real data show that the method is able to quantify the LV inward motion, and can clearly represent the changed motion pattern with the follow-up data. Furthermore, the LV motion analysis for 8 patients with acute myocardial infarction (MI) show that high inward motion occurs mainly in the basal region of LV while a negative relation is found between LV ejection fraction (EF) improvement after acute MI and solely basal region inward motion, which could be helpful for diagnosis and LV EF recovery prediction. PMID- 22255906 TI - Replication of the Frank-Starling response in a mock circulation loop. AB - Mock circulation loops (MCLs) are used to evaluate cardiovascular devices prior to in-vivo trials; however they lack the vital autoregulatory responses that occur in humans. This study aimed to develop and implement a left and right ventricular Frank-Starling response in a MCL. A proportional controller based on ventricular end diastolic volume was used to control the driving pressure of the MCL's pneumatically operated ventricles. Ventricular pressure-volume loops and end systolic pressure-volume relationships were produced for a variety of healthy and pathological conditions and compared with human data to validate the simulated Frank-Starling response. The non-linear Frank-Starling response produced in this study successfully altered left and right ventricular contractility with changing preload and was validated with previously reported data. This improvement to an already detailed MCL has resulted in a test rig capable of further refining cardiovascular devices and reducing the number of in vivo trials. PMID- 22255907 TI - Polynomial regularization for robust MRI-based estimation of blood flow velocities and pressure gradients. AB - In cardiovascular diagnostics, phase-contrast MRI is a valuable technique for measuring blood flow velocities and computing blood pressure values. Unfortunately, both velocity and pressure data typically suffer from the strong image noise of velocity-encoded MRI. In the past, separate approaches of regularization with physical a-priori knowledge and data representation with continuous functions have been proposed to overcome these drawbacks. In this article, we investigate polynomial regularization as an exemplary specification of combining these two techniques. We perform time-resolved three-dimensional velocity measurements and pressure gradient computations on MRI acquisitions of steady flow in a physical phantom. Results based on the higher quality temporal mean data are used as a reference. Thereby, we investigate the performance of our approach of polynomial regularization, which reduces the root mean squared errors to the reference data by 45% for velocities and 60% for pressure gradients. PMID- 22255908 TI - Identification of nonlinear cardiac cell dynamics using radial basis function regression. AB - We present a novel method for the identification of the dynamics of physiological cardiac cell models. The main aim of the technique is to improve the computational efficiency of large-scale simulations of the electrical activity of the heart. The method identifies the dynamical attractor of a detailed physiological model using statistical learning techniques. In particular, a radial basis function regression method is used to capture the intrinsic dynamical features of the model, thus reducing the computational cost to quantitatively generate cardiac action potentials in a wide range of pacing conditions. The approach permits to recover key properties such as the action potential morphology and duration in a wide range of pacing frequencies. PMID- 22255909 TI - A Phenotype-Driven Dimension Reduction (PhDDR) approach to integrated genomic association analyses. AB - An immediate challenge in integrated genomic analysis involving several types of genomic factors all measured genome-wide is the ultra-high dimensionality. Screening all possible relationships among the genomic factors is an NP-hard problem; therefore in practice proper dimension reduction is necessary. In this paper we develop the Phenotype-Driven Dimension Reduction (PhDDR) approach to the analysis of gene co-expressions, and discuss its extensions to integration of other genetic factors. This approach is then illustrated by an application to gene co-expression analysis of treatment response of childhood leukemia. PMID- 22255910 TI - Image processing challenges in the creation of spatiotemporal gene expression atlases of developing embryos. AB - To properly understand and model animal embryogenesis it is crucial to obtain detailed measurements, both in time and space, about their gene expression domains and cell dynamics. Such challenge has been confronted in recent years by a surge of atlases which integrate a statistically relevant number of different individuals to get robust, complete information about their spatiotemporal locations of gene patterns. This paper will discuss the fundamental image analysis strategies required to build such models and the most common problems found along the way. We also discuss the main challenges and future goals in the field. PMID- 22255911 TI - Analysis of incomplete gene expression dataset through protein-protein interaction information. AB - This paper shows a graph based method to analyze proteomic expression data. The method allows the prediction of the expression of genes not measured by the gene expression technology based on the local connectivity properties of the measured differentially expressed gene set. The prediction of the expression jointly with the stability of this prediction as a function of the variation of the initial expressed set is computed. The method is able to correctly predict one third of the proteins with independence of variations on the selection of the initial set. The algorithm is validated through a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometer (MALDI-TOF) protein expression experiment aiming the study of the protein expression patterns and post-translational modifications in human endothelial vascular cells exposed to atherosclerotic levels of Low Density Lipoproteins (LDL). PMID- 22255912 TI - Phenotype prediction by integrative network analysis of SNP and gene expression microarrays. AB - A long-term goal of biomedical research is to decipher how genetic processes influence disease formation. Ubiquitous and advancing microarray technology can measure millions of DNA structural variants (single-nucleotide polymorphisms, or SNPs) and thousands of gene transcripts (RNA expression microarrays) in cells. Both of these information modalities can be brought to bear on disease etiology. This paper develops a Bayesian network-based approach to integrate SNP and expression microarray data. The network models SNP-gene interactions using a phenotype-centric network. Inferring the network consists of two steps: variable selection and network learning. The learned network illustrates how functionally dependent SNPs and genes influence each other, and also serves as a predictor of the phenotype. The application of the proposed method to a pediatric acute lymphoblastic leukemia dataset demonstrates the feasibility of our approach and its impact on biological investigation and clinical practice. PMID- 22255913 TI - Prioritizing predicted cis-regulatory elements for co-expressed gene sets based on Lasso regression models. AB - Computational prediction of cis-regulatory elements for a set of co-expressed genes based on sequence analysis provides an overwhelming volume of potential transcription factor binding sites. It presents a challenge to prioritize transcription factors for regulatory functional studies. A novel approach based on the use of Lasso regression models is proposed to address this problem. We examine the ability of the Lasso model using time-course microarray data obtained from a comprehensive study of gene expression profiles in skin and mucosal wounds in mouse over all stages of wound healing. PMID- 22255914 TI - Topology aware functional similarity of protein interaction networks based on gene ontology. AB - Functional comparison and alignment of Protein Interaction Networks (PINs) will enable a better understanding of cellular organization and processes. Gene Ontology (GO) provides a structured standard vocabulary of functional terms of gene products, and has been used to measure the functional similarity between proteins. In this study, we propose an algorithm to measure the functional similarity between PINs based on GO. The algorithm simultaneously takes the PIN's network topology and semantic similarity of the component proteins into account. We employ the algorithm to measure the similarity between pathways present in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and cluster the pathways according to similarity. The results show great consistency with the function of these pathways. PMID- 22255915 TI - Nanosecond pulsed electric field ablation of hepatocellular carcinoma. AB - Hepatocellular carcinoma often evades effective therapy and recurrences are frequent. Recently, nanosecond pulsed electric field (nsPEF) ablation using pulse power technology has emerged as a local-regional, non-thermal, and non-drug therapy for skin cancers. In the studies reported here we use nsPEFs to ablate murine, rat and human HCCs in vitro and an ectopic murine Hepa 1-6 HCC in vivo. Using pulses with 60 or 300 ns and electric fields as high as 60 kV/cm, murine Hepa 1-6, rat N1S1 and human HepG2 HCC are readily eliminated with changes in caspase-3 activity. Interestingly caspase activities increase in the mouse and human model and decrease in the rat model as electric field strengths are increased. In vivo, while sham treated control mice survived an average of 15 days after injection and before humane euthanasia, Hepa 1-6 tumors were eliminated for longer than 50 days with 3 treatments using one hundred pulses with 100 ns at 55 kV/cm. Survival was 40% in mice treated with 30 ns pulses at 55 kV/cm. This study demonstrates that nsPEF ablation is not limited to effectively treating skin cancers and provides a rationale for treating orthotopic hepatocellular carcinoma in pre-clinical applications and ultimately in clinical trials. PMID- 22255916 TI - Mathematical study of the effects of different intrahepatic cooling on thermal ablation zones. AB - Thermal ablation of a tumour in the liver with Radio Frequency energy can be accomplished by using a probe inserted into the tissue under the guidance of medical imaging. The extent of ablation can be significantly affected by heat loss due to the high blood perfusion in the liver, especially when the tumour is located close to large vessels. A mathematical model is thus presented here to investigate the heat sinking effects of large vessels, combining a 3D two equation coupled bio-heat model and a 1D model of convective heat transport across the blood vessel surface. The model simulation is able to recover the experimentally observed different intrahepatic cooling on thermal ablation zones: hepatic veins showed a focal indentation whereas portal veins showed broad flattening of the ablation zones. Moreover, this study also illustrates that this shape derivation can largely be attributed to the temperature variations between the microvascular branches of portal vein as compared with hepatic vein. In contrast, different amount of surface heat convection on the vessel wall between these two types of veins, however, has a minor effect. PMID- 22255917 TI - A new system architecture improves output power regulation in electrosurgical generators. AB - A new system architecture for electrosurgical generators inherently produces the ideal electrosurgical output characteristic with near-deadbeat control. Compared to existing technology, this converter significantly improves power regulation, leading to improved surgical outcomes by minimizing thermal spread and tissue charring. PMID- 22255918 TI - Design of a new probe for tumor treatment in the alternate thermal system based on numerical simulation. AB - A new probe for tumor treatment is designed and simulated in this study. This probe combines the cryosurgery and hyperthermia which is suitable for the treatment of subcutaneous tumors. Simulations of the cooling and heating processes demonstrate that the probes are capable of treating the tumor effectively. And the numerical results indicate that the lengths of the probe, the diameters of the inner tube and the pressures of liquid nitrogen influence the probes' cooling ability. The temperature responses at the tumor base induced by different probes are similar, though the great differences appear on the treatment interface of the probes, thus the temperature gradient within the tumor. Based on the simulation results, the heating effect of the probe is shown to be effective in damaging the tumor while protecting normal tissue in the surrounding. Animal experiments will be carried out using this type of probe to treat tumor in the near future. PMID- 22255919 TI - Experimental and theoretical study of an internally cooled bipolar electrode for RF coagulation of biological tissues. AB - Although some types of bipolar electrodes have been broadly employed in clinical practice to coagulate biological tissue by means of radiofrequency (RF) currents, there is still scanty available information about their electrical-thermal behaviour. We are focused on internally cooled bipolar electrodes. The goal of our study was to know more about the behavior of this kind of electrodes. For that, we planned an experimental and theoretical model. The experimental study was based on bovine hepatic ex vivo tissue and the theoretical model was based on the Finite Element Method (FEM). In order to check the feasibility of the theoretical model, we assessed both theoretically and experimentally the effect of the internal cooling characteristics of the bipolar electrode (flow rate and coolant temperature) on the impedance progress during RF heating and coagulation zone dimensions. The experimental and theoretical results were in good agreement, which suggests that the theoretical model could be useful to improve the design of cooled bipolar electrodes. PMID- 22255920 TI - An in-the-ear platform for recording electroencephalogram. AB - We introduce a novel approach to brain monitoring based on electroencephalogram (EEG) recordings from within the ear canal. While existing clinical and wearable systems are limited in terms of portability and ease of use, the proposed in-the ear (ITE) recording platform promises a number of advantages including ease of implementation, minimally intrusive electrodes and enhanced accuracy (fixed electrode positions). It thus facilitates a crucial step towards the design of brain computer interfaces that integrate naturally with daily life. The feasibility of the ITE concept is demonstrated with recordings made from electrodes embedded on an earplug which are benchmarked against conventional scalp electrodes for a classic EEG paradigm. PMID- 22255921 TI - Ultra-Thin Chip Package (UTCP) and stretchable circuit technologies for wearable ECG system. AB - A comfortable, wearable wireless ECG monitoring system is proposed. The device is realized using the combination of two proprietary advanced technologies for electronic packaging and interconnection : the UTCP (Ultra-Thin Chip Package) technology and the SMI (Stretchable Mould Interconnect) technology for elastic and stretchable circuits. Introduction of these technologies results in small fully functional devices, exhibiting a significant increase in user comfort compared to devices fabricated with more conventional packaging and interconnection technologies. PMID- 22255922 TI - Swallowing detection by sonic and subsonic frequencies: a comparison. AB - The detection of swallowing events by acoustic means represents an important tool to assess and diagnose swallowing disorders as well as to objectively monitor ingestive behavior of individuals. Acoustic sensors used to register swallowing sounds may also capture sound artifacts arising from intrinsic speech and external noise affecting the detection. In this paper we tested if subsonic frequencies are less prone to artifacts from speech, chewing and other intrinsic sounds than sonic frequencies. A simple method using a throat and an ambient microphone was employed to compare the swallowing detection accuracy by acoustic signals acquired in the sonic (20-2500 Hz) and subsonic (<= 5 Hz) ranges. Averaged recall values were higher than 85% for both ranges. However, averaged precision values of 50% for subsonic frequencies and of 42% for sonic frequencies were caused by a high number of false positives. These results indicated no significant difference between averaged precision values which may suggest that subsonic frequencies were not less prone to intrinsic sound artifacts than frequencies in the sonic range. Further examination with the addition of a signal classification layer is proposed as a future step to confirm this statement. PMID- 22255923 TI - A real time, wearable ECG and continous blood pressure monitoring system for first responders. AB - The study of stress and fatigue among First Responders is a major step in mitigating this public health problem. Blood pressure, heart rate variability and fatigue related arrhythmia are three of the main "windows" to study stress and fatigue. In this paper we present a wearable medical device, capable of acquiring an electrocardiogram and estimating blood pressure in real time, through a pulse wave transit time approach. The system is based on an existent certified wearable medical device called "Vital Jacket" and is aimed to become a tool to allow cardiologists in studying stress and fatigue among first response professionals. PMID- 22255924 TI - Telefetalcare: a first prototype of a wearable fetal electrocardiograph. AB - Fetal heart rate monitoring is fundamental to infer information about fetal health state during pregnancy. The cardiotocography (CTG) is the most common antepartum monitoring technique. Abdominal ECG recording represents the most valuable alternative to cardiotocography, as it allows passive, non invasive and long term fetal monitoring. Unluckily fetal ECG has low SNR and needs to be extracted from abdominal recordings using ad hoc algorithms. This work describes a prototype of a wearable fetal ECG electrocardiograph. The system has flat band frequency response between 1-60 Hz and guarantees good signal quality. It was tested on pregnant women between the 30(th) and 34(th) gestational week. Several electrodes configurations were tested, in order to identify the best solution. Implementation of a simple algorithm for FECG extraction permitted the reliable detection of maternal and fetal QRS complexes. The system will allow continuative and deep screening of fetal heart rate, introducing the possibility of home fetal monitoring. PMID- 22255926 TI - Initial study on pulse wave velocity acquired from one hand using two synchronized wireless reflectance pulse oximeters. AB - Pulse wave velocity (PWV) has garnered attention as a means to estimate vessel elasticity. This paper presents an approach to measure PWV using two synchronized, wireless pulse oximeters placed on the wrist and fingertip of the same hand. A MATLAB interface acquires and time-aligns these incoming photoplethysmograms (PPGs), and then it calculates PWVs using time differences at three waveform features: the foot, inflection point, and peak of the rising slope in each PPG. Consistent with expectations, PWV values for inflection points are larger than those calculated at waveform feet, since PWV is known to increase with increased intra-arterial pressure. However, the presence of pulse wave reflections complicates the interpretation of PWVs calculated from the PPG peaks since the reflected components impose a varying time delay on the related peaks. PMID- 22255925 TI - A wearable ECG-HR detector and its application to automatic assist-mode selection of an electrically assisted bicycle. AB - Recently, an electrically assisted bicycle has been widely used in daily life and becomes very popular. The user selects the stepwise assist-mode to determine the assistive torque for pleasurable running. From the viewpoint of improvement of health by exercise, the electrically assisted bicycle can be an exercise machine like a treadmill. The heart rate (HR) is regarded as an indication of exercise load. This paper presents an automatic assist-mode selection system based on the HR of the bicycle user. The HR is obtained from the R-waves measured by the proposed wearable electrocardiograph on the user. The mode-selection system is simply implemented by a personal computer, USB-connected interface, and some electronic switching circuits. The running experiments confirm that the proposed assist-mode selection method has practicability. PMID- 22255927 TI - A trimodal system for the acquisition of synchronous echocardiography, electrocardiography, and seismocardiography data. AB - A novel system was developed to acquire synchronous echocardiography, electrocardiography (EKG), and seismocardiography (SCG) data. The system was developed to facilitate the study of the relationship between the mechanical and electrical characteristics of the heart. The system has both a hardware and software component. The hardware component consists of an application-specific device designed and built to acquire both SCG and EKG signals simultaneously. The software component consists of a package developed to record and synchronize data from both the device and a clinical ultrasound machine. A feasibility test was performed by simultaneous acquisition of a synchronous dataset from a human subject. PMID- 22255928 TI - The Smart Patches and Wearable Band (W-Band) for comfortable sleep monitoring system. AB - The Smart Patches and Wearable Band (W-Band) are proposed for comfortable sleep monitoring system which recognizes and diagnoses sleep disorders. By using Planar Fashionable Circuit Board (P-FCB) techniques, the Smart Patches are implemented with the plain fabric patch so that it can have light weight and small size. And the stretchability of the W-Band can achieve user convenience, low manufacturing cost, and low power consumption all at once. The data display program is developed on the external PC so that the user can check the monitoring result after wake-up. The proposed sleep monitoring system is fully implemented and tested on the human during normal sleep. PMID- 22255929 TI - A wireless modular multi-modal multi-node patch platform for robust biosignal monitoring. AB - In this paper a wireless modular, multi-modal, multi-node patch platform is described. The platform comprises low-cost semi-disposable patch design aiming at unobtrusive ambulatory monitoring of multiple physiological parameters. Owing to its modular design it can be interfaced with various low-power RF communication and data storage technologies, while the data fusion of multi-modal and multi node features facilitates measurement of several biosignals from multiple on-body locations for robust feature extraction. Preliminary results of the patch platform are presented which illustrate the capability to extract respiration rate from three different independent metrics, which combined together can give a more robust estimate of the actual respiratory rate. PMID- 22255930 TI - Development of a body joint angle measurement system using IMU sensors. AB - This paper presents an approach for measuring and monitoring human body joint angles using inertial measurement unit (IMU) sensors. This type of monitoring is beneficial for therapists and physicians because it facilitates remote assessment of patient activities. In our approach, two IMUs are mounted on the upper leg and the lower leg to measure the Euler angles of each segment. The Euler angles are sent via Bluetooth protocols to a pc for calculating the knee joint angle. In our experiments, we utilized a motion capture system to accurately measure the knee joint angle and used this as the ground truth to assess the accuracy of the IMU system. The range of average error of the system across a variety of motion trials was 0.08 to 3.06 degrees. In summary, the accuracy of the IMU measurement system currently outperforms existing wearable systems such as conductive fiber optic sensors and flex-sensors. PMID- 22255931 TI - Development of the wireless ultra-miniaturized inertial measurement unit WB-4: preliminary performance evaluation. AB - This paper presents the preliminary performance evaluation of our new wireless ultra-miniaturized inertial measurement unit (IMU) WB-4 by compared with the Vicon motion capture system. The WB-4 IMU primarily contains a mother board for motion sensing, a Bluetooth module for wireless data transmission with PC, and a Li-Polymer battery for power supply. The mother board is provided with a microcontroller and 9-axis inertial sensors (miniaturized MEMS accelerometer, gyroscope and magnetometer) to measure orientation. A quaternion-based extended Kalman filter (EKF) integrated with an R-Adaptive algorithm for automatic estimation of the measurement covariance matrix is implemented for the sensor fusion to retrieve the attitude. The experimental results showed that the wireless ultra-miniaturized WB-4 IMU could provide high accuracy performance at the angles of roll and pitch. The yaw angle which has reasonable performance needs to be further evaluated. PMID- 22255932 TI - ECG-based detection of body position changes using a Laplacian noise model. AB - Body position changes (BPC), which are often manifested in the ECG as shifts in the electrical axis of the heart, result in ST changes, and thus, may be misclassified as ischemic events during ambulatory monitoring. We have developed a BPC detector by modeling shifts as changes in the Karhunen-Loeve transform coefficients of the QRS complex and the ST-T waveform. The noise is assumed to have a Laplacian distribution. A generalized likelihood ratio test has been chosen as the strategy to detect BPCs. Two different databases have been used to assess detection performance. The obtained results were 93%/99% in terms of sensitivity/positive predictivity value (S/+PV) and a false alarm rate of 2 events/hour. The results clearly outperform current techniques (S/+PV: 85%/99%) based on the Gaussian noise assumption. PMID- 22255933 TI - Latency variable source separation for heart rate detection in low-quality ECG signals. AB - Monitoring of the heart rate can provide vital clinical information, but can, in specific situations, be complicated due to the low signal to noise ratio (SNR) of the available physiological signals. Several methods to enhance the SNR are known from literature, e.g. wavelet-based enhancement methods, but most of these methods require a priori information on the recorded signals and are only applicable in specific situations. In this paper a generic method is presented that uses latency variable source separation (LVSS) to derive a matched filter for enhancement of electrocardiogram (ECG) signals. Besides its use on ECG signals, the LVSS method has the potential capability to enhance any kind of (quasi-) periodical signal. The LVSS method is evaluated by comparing its performance in SNR enhancement to the performance of a wavelet-based enhancement method. This performance demonstrates that for low-SNR ECG signals, the LVSS method outperforms the wavelet-based method. PMID- 22255934 TI - Using confidence intervals to assess the reliability of instantaneous heart rate and respiratory rate. AB - Physiological waveform signals collected from unstructured environments are noisy, requiring automated algorithms to assess the reliability of the derived vital signs, such as heart rate (HR) and respiratory rate (RR), before they can be used for automated decision support. We recently proposed a weighted regularized least squares method to estimate instantaneous HR (HR(R)), which readily provides analytically based confidence intervals (CIs). Accordingly, this method can be extended to the estimation of instantaneous RR (RR(R)). In this study, we aim to investigate whether we can use CIs to select reliable HR(R) and RR(R). We calculated HR(R) and RR(R) for 532 and 370 trauma patients, respectively, grouped the rates according to their CIs, and investigated their reliability by determining their ability to diagnose major hemorrhage. The areas under a receiver operating characteristic curve of HR(R) and RR(R) with CI <= 5 bpm (beats per minute for HR and breaths per minute for RR) were 0.70 and 0.66, respectively. RR(R) was superior to the average output of the clinical monitor (p < 0.05 by DeLong's test), while HR(R) was equivalent. HR(R) and RR(R) provide a new approach to systematically and automatically assess the reliability of noisy, field-collected vital signs. PMID- 22255935 TI - A new density-ratio based approach for patient-specific biomedical monitoring. AB - In order to denote the abnormalities of the patients, we propose a novel approach to detect anomaly in biomedical monitoring using density ratio values as the Patient Status Index (PSI). The key idea of the proposed method is to define the ratio of training and testing data densities, where training dataset only consist of normal data and testing dataset consist of both normal and abnormal data, and identify irregular samples for testing patients' dataset. Furthermore, we define four inequalities to denote the interval values of density ratio and give the corresponding status for patients. In addition, the applied Kullback-Leibler based algorithm for calculating density ratio values without involving density estimation is equipped with a cross validation (CV) model selection procedure, allowing us to objectively optimize values of tuning parameters. We select training and testing data from Physionet database to do our pilot experiment. The experimental results for 11901 beats show that the density-ratio based approach work very well in terms of specificity and sensitivity. PMID- 22255936 TI - An efficient method for ectopic beats cancellation based on radial basis function. AB - The analysis of the surface Electrocardiogram (ECG) is the most extended noninvasive technique in cardiological diagnosis. In order to properly use the ECG, we need to cancel out ectopic beats. These beats may occur in both normal subjects and patients with heart disease, and their presence represents an important source of error which must be handled before any other analysis. This paper presents a method for electrocardiogram ectopic beat cancellation based on Radial Basis Function Neural Network (RBFNN). A train-able neural network ensemble approach to develop customized electrocardiogram beat classifier in an effort to further improve the performance of ECG processing and to offer individualized health care is presented. Six types of beats including: Normal Beats (NB); Premature Ventricular Contractions (PVC); Left Bundle Branch Blocks (LBBB); Right Bundle Branch Blocks (RBBB); Paced Beats (PB) and Ectopic Beats (EB) are obtained from the MIT-BIH arrhythmia database. Four morphological features are extracted from each beat after the preprocessing of the selected records. Average Results for the RBFNN based method provided an ectopic beat reduction (EBR) of (mean +/- std) EBR = 7, 23 +/- 2.18 in contrast to traditional compared methods that, for the best case, yielded EBR = 4.05 +/- 2.13. The results prove that RBFNN based methods are able to obtain a very accurate reduction of ectopic beats together with low distortion of the QRST complex. PMID- 22255937 TI - Sympathetic neural recruitment patterns during the Valsalva maneuver. AB - Sympathetic nerve activity is an important regulator of blood pressure and blood flow in humans. Our understanding about how sympathetic neurons are recruited during baroreflex stress is limited. This paper investigates the sympathetic neural recruitment patterns during the Valsalva maneuver. Using microneurography, muscle sympathetic nerve activity was recorded in seven healthy subjects during baseline and the Valsalva maneuver. A new algorithm for detection and classification of action potentials was employed to study the differences between the recruitment of sympathetic neurons during baseline and the Valsalva maneuver. The data suggests that the Valsalva maneuver increases the number of spikes per sympathetic bursts and also recruits at least one additional new cluster of larger, faster conducting neurons. Also, action potential's latencies (i.e., inverse of conduction velocity) were shifted downward for all action potential clusters during this maneuver. PMID- 22255938 TI - Blind separation and localization of correlated P300 subcomponents from single trial recordings using extended PARAFAC2 tensor model. AB - A novel mathematical model based on multi-way data construction and analysis with the goal of simultaneously separating and localizing the brain sources specially the subcomponents of event related potentials (ERPs) is introduced. We represent multi-channel EEG data using a third-order tensor with modes: space (channels), time samples, and number of segments. Then, a multi-way technique, in particular, generalized version of PARAFAC2 method, is developed to blindly separate and localize mutually/temporally correlated P3a and P3b sources as subcomponents of P300 signal. In this paper the non-orthogonality of the ERP subcomponents is defined within the tensor model. In order to obtain essentially unique estimation of the signal components one parametric and one structural constraint are defined and imposed. The method is applied to both simulated and real data and has been shown to perform very well even in low signal to noise ratio situations. In addition, the method is compared with spatial principal component analysis (sPCA) and its superiority is demonstrated by using simulated signals. PMID- 22255939 TI - Learning event-related potentials (ERPs) from multichannel EEG recordings: a spatio-temporal modeling framework with a fast estimation algorithm. AB - Extracting event-related potentials (ERPs) from multichannel EEG recordings remains a challenge due to the poor signal-to-noise ratio (SNR). This paper presents a multivariate statistical model of ERPs by exploiting the existing knowledge about their spatio-temporal properties. In particular, a computationally efficient algorithm is derived for fast model estimation. The algorithm, termed SIM, can be intuitively interpreted as maximizing the signal-to noise ratio in the source space. Using both simulated and real EEG data, we show that the algorithm achieves excellent estimation performance and substantially outperforms a state-of-the-arts algorithm in classification accuracies in a P300 target detection task. The results demonstrate that the proposed modeling framework offers a powerful tool for exploring the spatio-temporal patterns of ERPs as well as learning spatial filters for decoding brain states. PMID- 22255940 TI - A non-orthogonal SVD-based decomposition for phase invariant error-related potential estimation. AB - The estimation of the Error Related Potential from a set of trials is a challenging problem. Indeed, the Error Related Potential is of low amplitude compared to the ongoing electroencephalographic activity. In addition, simple summing over the different trials is prone to errors, since the waveform does not appear at an exact latency with respect to the trigger. In this work, we propose a method to cope with the discrepancy of these latencies of the Error Related Potential waveform and offer a framework in which the estimation of the Error Related Potential waveform reduces to a simple Singular Value Decomposition of an analytic waveform representation of the observed signal. The followed approach is promising, since we are able to explain a higher portion of the variance of the observed signal with fewer components in the expansion. PMID- 22255941 TI - Morphology quantification of atrial fibrillation under propofol using principal components analysis. AB - The effect of the most useful anaesthetic in cardiovascular therapy, called propofol, was evaluated in patients with atrial fibrillation (AF). In order to represent the electrogram recordings in a more efficient manner Principal component analysis (PCA) has been applied. Moreover, to reduce the data set to a few representative activations PCA was applied again to measure the average dissimilarity between consecutive activations of an intracardiac signal. In addition PCA was applied directly to the activations extracted from each dipole to analysis temporal varibility, and spatial variability with the comparation of the signals from different dipoles. The proposed indexes show different behaviour patterns along the atrial area during the anaesthetic effects. PMID- 22255942 TI - A hybrid least squares and principal component analysis algorithm for Raman spectroscopy. AB - The least squares fitting algorithm is the most commonly used algorithm in Raman spectroscopy. In this paper, however, we show that it is sensitive to variations in the background signal when the signal of interest is weak. To address this problem, we propose a novel algorithm to analyze measured spectra in Raman spectroscopy. The method is a hybrid least squares and principal component analysis algorithm. It explicitly accounts for any variations expected in the reference spectra used in the signal decomposition. We compare the novel algorithm to the least squares method with a low-order polynomial residual model, and demonstrate the novel algorithm's superior performance by comparing quantitative error metrics. Our experiments use both simulated data and data acquired from an in vitro solution of Raman-enhanced gold nanoparticles. PMID- 22255943 TI - A pipeline for copy number variation detection based on principal component analysis. AB - DNA copy number variation (CNV), an important structural variation, is known to be pervasive in the human genome and the determination of CNVs is essential to understanding their potential effects on the susceptibility to diseases. However, CNV detection using SNP array data is challenging due to the low signal-to-noise ratio. In this study, we propose a principal component analysis (PCA) based approach for data correction, and present a novel processing pipeline for reliable CNV detection. Tested data include both simulated and real SNP array datasets. Simulations demonstrate a substantial reduction in the false positive rate of CNV detection after PCA-correction. And we also observe a significant improvement in data quality in real SNP array data after correction. PMID- 22255944 TI - Multi-parametric analysis and registration of brain tumors: constructing statistical atlases and diagnostic tools of predictive value. AB - We discuss computer-based image analysis algorithms of multi-parametric MRI of brain tumors, aiming to assist in early diagnosis of infiltrating brain tumors, and to construct statistical atlases summarizing population-based characteristics of brain tumors. These methods combine machine learning, deformable registration, multi-parametric segmentation, and biophysical modeling of brain tumors. PMID- 22255945 TI - 3D Slicer as a tool for interactive brain tumor segmentation. AB - User interaction is required for reliable segmentation of brain tumors in clinical practice and in clinical research. By incorporating current research tools, 3D Slicer provides a set of interactive, easy to use tools that can be efficiently used for this purpose. One of the modules of 3D Slicer is an interactive editor tool, which contains a variety of interactive segmentation effects. Use of these effects for fast and reproducible segmentation of a single glioblastoma from magnetic resonance imaging data is demonstrated. The innovation in this work lies not in the algorithm, but in the accessibility of the algorithm because of its integration into a software platform that is practical for research in a clinical setting. PMID- 22255946 TI - Multiresolution texture models for brain tumor segmentation in MRI. AB - In this study we discuss different types of texture features such as Fractal Dimension (FD) and Multifractional Brownian Motion (mBm) for estimating random structures and varying appearance of brain tissues and tumors in magnetic resonance images (MRI). We use different selection techniques including KullBack Leibler Divergence (KLD) for ranking different texture and intensity features. We then exploit graph cut, self organizing maps (SOM) and expectation maximization (EM) techniques to fuse selected features for brain tumors segmentation in multimodality T1, T2, and FLAIR MRI. We use different similarity metrics to evaluate quality and robustness of these selected features for tumor segmentation in MRI for real pediatric patients. We also demonstrate a non patient-specific automated tumor prediction scheme by using improved AdaBoost classification based on these image features. PMID- 22255947 TI - Combination of nonlinear registration methods with high resolution fMRI for a fine exploration of human primary motor hand area. AB - Functional investigation of human hand representation in the motor area M1 requires high resolution functional imaging, to finely separate activation in M1, and a perfect alignment of individual central sulci to improve functional areas overlap and significance of statistical parametric maps obtained from different hand movements. Based on anatomical measures, we show how recent global diffeomorphic registration techniques impact positively on the alignment of sulcal folds in M1 area. With functional measures, we evaluate their effect on the robust detection and localization of group brain activation for flexion/extension of right and left thumbs/fingers and wrists. The methodology we propose opens the way to a non invasive functional exploration of the human hand motor cortex at the group level under different normal, pathological or after rehabilitative conditions. PMID- 22255948 TI - Continuous arterial spin labeling of mouse cerebral blood flow using an actively detuned two-coil system at 9.4T. AB - Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into the passage of blood through the brain's vascular network non-invasively. Studying disease models and transgenic mice would intrinsically help understanding the underlying brain functions, cerebrovascular disease and brain disorders. This study evaluates the feasibility of performing continuous arterial spin labeling (CASL) on all cranial arteries for mapping murine cerebral blood flow at 9.4 T. We showed that with an active-detuned two-coil system, a labeling efficiency of 0.82 +/- 0.03 was achieved with minimal magnetization transfer residuals in brain. The resulting cerebral blood flow of healthy mouse was 99 +/- 26 mL/100g/min, in excellent agreement with other techniques. In conclusion, high magnetic fields deliver high sensitivity and allowing not only CASL but also other MR techniques, i.e. (1)H MRS and diffusion MRI etc, in studying murine brains. PMID- 22255949 TI - On the accuracy of unwarping techniques for the correction of susceptibility induced geometric distortion in magnetic resonance Echo-planar images. AB - Rapid and efficient imaging of the brain to monitor brain activity and neural connectivity is performed through functional MRI and diffusion tensor imaging (DTI) using the Echo-planar imaging (EPI) sequence. An entire volume of the brain is imaged by EPI in a few seconds through the measurement of all k-space lines within one repetition time. However, this makes the sequence extremely sensitive to imperfections of magnetic field. In particular, the error caused by susceptibility induced magnetic field inhomogeneity accumulates over the duration of phase encoding, which in turn results in severe geometric distortion (warping) in EPI scans. EPI distortion correction through unwarping can be performed by field map based or image based techniques. However, due to the lack of ground truth it has been difficult to compare and validate different approaches. In this paper we propose a hybrid field map guided constrained deformable registration approach and compare it to field map based and image based unwarping approaches through a novel in-vivo validation framework which is based on the acquisition and alignment of EPI scans with different phase encoding directions. The quantitative evaluation results show that our hybrid approach of field map guided deformable registration to an undistorted T2-weighted image outperforms the other approaches. PMID- 22255950 TI - Cluster sizes in interleaved silent steady state (ISSS) imaging. AB - The effect of increasing the number of scans in the "cluster" of an interleaved silent steady state (ISSS) fMRI imaging scheme from 1 to 2, and then to 3 was examined by a fixed-effects analysis of an auditory short-term memory task with four subjects. Compared to a cluster size of 1, a cluster of 2 scans improved sensitivity at detecting brain activity and statistical power, while a cluster of 3 scans further improved statistical power but seemed not to improve sensitivity beyond that achieved with a cluster of 2 scans. The findings reveal that cluster size is a vital parameter for an ISSS imaging scheme. PMID- 22255951 TI - In vivo manganese-enhanced MRI and diffusion tensor imaging of developing and impaired visual brains. AB - This study explored the feasibility of high-resolution Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) for in vivo assessments of the development and reorganization of retinal and visual callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Using MEMRI, intravitreal Mn(2+) injection into one eye resulted in maximal T1-weighted hyperintensity in neonatal contralateral superior colliculus (SC) 8 hours after administration, whereas in adult contralateral SC signal increase continued at 1 day post injection. Notably, mild but significant Mn(2+) enhancement was observed in the ipsilateral SC in normal neonatal rats, and in adult rats after neonatal monocular enucleation (ME) but not in normal adult rats. Upon intracortical Mn(2+) injection to the visual cortex, neonatal binocularly-enucleated (BE) rats showed an enhancement of a larger projection area, via the splenium of corpus callosum to the V1/V2 transition zone of the contralateral hemisphere in comparison to normal rats. For DTI, the retinal pathways projected from the enucleated eyes possessed lower fractional anisotropy (FA) 6 weeks after BE and ME. Interestingly, in the optic nerve projected from the remaining eye in ME rats a significantly higher FA was observed compared to normal rats. The results of this study are potentially important for understanding the axonal transport, microstructural reorganization and functional activities in the living visual brain during early postnatal development and plasticity in a global and longitudinal setting. PMID- 22255952 TI - Generalized regional disorder-sensitive-weighting scheme for 3D neuroimaging retrieval. AB - 3D functional neuroimaging is used in the diagnosis and management of neurological disorders. The efficient management and analysis of these large imaging datasets has prompted research in the field of content-based image retrieval. In this context, our generalized regional disorder-sensitive-weighting (DSW) scheme gives greater weight to brain regions affected by the diseases than regions that are relatively spared. We used two DSW matrices; one matrix is based on the occurrence maps that highlight abnormal functional regions; the other is based on the regional Fisher discriminant ratio. Our results suggest that our DSW matrices enhance neuroimaging data retrieval and provide a flexible weighting solution for the clinical analysis of different types of neurological disorders. PMID- 22255953 TI - Investigation of EEG and MEG source imaging accuracy in reconstructing extended cortical sources. AB - Electroencephalography (EEG) and magneto-encephalography (MEG) are both currently used to reconstruct brain activity. The performance of inverse source reconstructions is dependent on the modality of signals in use as well as inverse techniques. Here we used a recently proposed sparse source imaging technique, i.e., the variation-based sparse cortical current density (VB-SCCD) algorithm to compare the use of EEG or MEG data in reconstructing extended cortical sources. We conducted Monte Carlo simulations as comparison to two other widely used source imaging techniques. The VB-SCCD technique was further evaluated in experimental EEG and MEG data. Our present results indicate that EEG and MEG have similar reconstruction performance as indicated by a metric, the area under the receiver operating characteristic curve (AUC). Furthermore, EEG and MEG have different advantages and limitations in revealing different aspects of features of extended cortical sources, which are complimentary to each other. A simultaneous EEG and MEG analysis framework is thus promising to produce much improved source reconstructions. PMID- 22255954 TI - A new method for localizing the sources of correlated cross-frequency oscillations in human brains. AB - Anatomically distributed areas are dynamically linked to form functional networks for processing and integrating the different modalities of information in the human brain. A part of such networks is considered to be realized with synchronization of neuronal activities, which can generate correlated neural oscillation at the same and/or different frequency bands. To investigate the networks with the synchronization, analysis of connectivity between not only same frequency oscillation but also different frequency (i.e. cross-frequency) is needed. For source estimation with electroencephalogram (EEG) or magneto encephalogram (MEG) signals, a spatial filtering technique is recently applied as an alternative method for equivalent current dipole (ECD) estimation technique. Non-adaptive type of spatial filtering technique, such as the Standardized low resolution brain electromagnetic tomography (sLORETA), is reported to discriminate correlated sources. However, it may lead to inaccurate results due to its low spatial resolution. In the present study, we proposed a new systematic approach for localizing the sources of correlated cross-frequency oscillations. The method we propose can overcome the limitation of the non-adaptive spatial filtering technique by proactively using identified information in sensor level analysis (e.g. cross-correlation map and correlation topography), which allow us to focus on target sources. The performance of our proposed method is evaluated with simulated EEG signals, and is compared with traditional method. PMID- 22255955 TI - Objective evaluation of somatic sensation for mechanical stimuli by means of cortical dipole layer imaging. AB - In clinical situations, the objective evaluation of somatic sensations is expected without a patient's subjective opinions to reduce social problems such as those related to lawsuits for nerve injuries and malingering. In this study, the somatosensory evoked potential (SEP) using the mechanical stimulations of the tactile sensation was measured and analyzed in spatiotemporal domains. The spatial resolution of SEP maps was improved by application of cortical dipole layer imaging. The experimentally obtained results suggest that the spatiotemporal distributions of the SEPs reflect the differences for positions, strengths, and patterns of somatosensory stimulations. PMID- 22255956 TI - High-resolution MREIT using low imaging currents. AB - Magnetic Resonance Electrical Impedance Tomography (MREIT) produces cross sectional images of a conductivity distribution inside the human body. We use an MRI scanner as a tool to measure induced internal magnetic flux density distributions subject to externally injected currents. Recent experimental MREIT studies demonstrated conductivity image reconstructions of in vivo animal and human subjects with a few millimeter pixel size using 3 mA current injections. To enhance the clinical applicability of MREIT especially in neuroimaging applications, it is necessary to develop high-resolution MREIT techniques using low imaging currents. In this study, we demonstrate the capability of MREIT to perform conductivity imaging with less than 1 mA injection currents. The experimental results using a 3 T MRI scanner with a multi-echo ICNE pulse sequence and high-performance RF coils demonstrate that we can distinguish two different anomalies in reconstructed conductivity images with less than 1 mm pixel sizes. We plan to apply the developed experimental method to in vivo head imaging of small animals to investigate the feasibility of functional MREIT as a new neuro-imaging method. PMID- 22255957 TI - A portable instrument for high-speed brain function imaging: FEITER. AB - Electrical Impedance Tomography (EIT) can resolve dynamic physiological information deep within human subjects [1], but its sensitivity is challenged in the case of imaging the head [2]. Here, we report a new system called fEITER that has been designed and built to enable functional imaging of the human brain using EIT via scalp-mounted electrodes, integrated with stimulation of evoked responses. Using Field-Programmable Gate Array (FPGA) technology, it provides excellent flexibility in terms of current-pattern excitation and signal processing. The instrument operates at 100 frames/second (fps) with noise of 1 MUV on the rms voltage measurements. Clinical trials have been authorized by the UK MHRA and example data from human subjects are presented. PMID- 22255958 TI - Electrical impedance tomography reconstruction through Simulated Annealing with incomplete evaluation of the objective function. AB - The EIT reconstruction problem is approached as an optimization problem where the difference between a simulated impedance domain and the observed one is minimized. This optimization problem is often solved by Simulated Annealing (SA), but at a large computational cost due to the expensive evaluation process of the objective function. We propose here, a variation of SA applied to EIT where the objective function is evaluated only partially, while ensuring upper boundaries on the deviation on the behavior of the modified SA. The reconstruction method is evaluated with simulated and experimental data. PMID- 22255959 TI - Design of a force-reflective master robot for haptic telesurgery applications: RoboMaster1. AB - With the increasing trend toward Minimally Invasive Surgery (MIS) procedures, the need to develop new robotic systems to facilitate such surgeries is more and more recognized. This paper describes the design and development of a 4 DOF force reflective master robot (RoboMaster1) for haptic telesurgery applications. A two double parallelogram robot is introduced including a novel mechanism at the base for producing and control of the end effector's linear motion. This eliminates the deficiencies caused due to suspending massive actuators at the end effector or cabling from the base. The kinematics and work space of the system were analyzed and a prototype was developed for primary practical evaluations. The results showed that the system can effectively simulate the surgeon's hand maneuvers inside the abdominal cavity with a Remote Center of Motion (RCM) located at the backside. With this important feature, the system is expected to facilitate the key hole surgeries by eliminating the need for inverse and/or scaled maneuvers during minimally invasive surgeries. PMID- 22255961 TI - In vivo experiments of a surgical robot with vision field control for Single Port Endoscopic Surgery. AB - Recently, robotics systems are focused to assist in Single Port Endoscopic Surgery (SPS). However, the existing system required a manual operation of vision and viewpoint, hindering the surgical task. We proposed a surgical endoscopic robot for SPS with dynamic vision control, the endoscopic view being manipulated by a master controller. The prototype robot consists of a manipulator for vision control, and dual tool tissue manipulators (gripping: 5DOFs, cautery: 3DOFs) can be attached at the tip of sheath manipulator. In particular, this paper focuses on an in vivo experiment. We showed that vision control in the stomach and a cautery task by a cautery tool could be effectively achieved. PMID- 22255960 TI - Fourier modeling of porcine heartbeat and respiration in vivo for synchronization of HeartLander robot locomotion. AB - HeartLander is a small mobile robot which adheres to and navigates over the surface of the heart to provide therapies in a minimally invasive manner. HeartLander's ability to efficiently operate in this dynamic environment is greatly affected by physiological motion, namely the cardiac and respiration cycles. Synchronization of robot motion with minimal intrapericardial pressure results in safer and more efficient travel. The work presented models the physiological components of motion using Fourier series and estimates their parameters using an Extended Kalman Filter. Using the Fourier series parameters, estimates of physiological phase values are calculated to be used for step synchronization. The proposed methods are demonstrated on data from a HeartLander animal study for four locations on the heart. Mean respiration phase estimates are shown to be within 5% of the true respiration phases, while mean cardiac phase estimates are shown to have a minimum error of 11%. PMID- 22255962 TI - Real-time control and evaluation of a teleoperated miniature arm for Single Port Laparoscopy. AB - This paper presents the control architecture and the first performance evaluation results of a novel and highly-dexterous 18 degrees of freedom (DOF) miniature master/slave teleoperated robotic system called SPRINT (Single-Port la-paRoscopy bimaNual roboT). The system was evaluated in terms of positioning accuracy, repeatability, tracking error during local teleoperation and end-effector payload. Moreover, it was experimentally verified that the control architecture is real-time compliant at an operating frequency of 1 kHz and it is also reliable in terms of safety. The architecture accounts for cases when the robot is lead through singularities, and includes other safety mechanisms, such as supervision tasks and watchdog timers. Peliminary tests that were performed by surgeons in vitro suggest that the SPRINT robot, along with its real-time control architecture, could become in the near future a reliable system in the field of Single Port Laparoscopy. PMID- 22255963 TI - 3D force control for robotic-assisted beating heart surgery based on viscoelastic tissue model. AB - Current cardiac surgery faces the challenging problem of heart beating motion even with the help of mechanical stabilizer which makes delicate operation on the heart surface difficult. Motion compensation methods for robotic-assisted beating heart surgery have been proposed recently in literature, but research on force control for such kind of surgery has hardly been reported. Moreover, the viscoelasticity property of the interaction between organ tissue and robotic instrument further complicates the force control design which is much easier in other applications by assuming the interaction model to be elastic (industry, stiff object manipulation, etc.). In this work, we present a three-dimensional force control method for robotic-assisted beating heart surgery taking into consideration of the viscoelastic interaction property. Performance studies based on our D2M2 robot and 3D heart beating motion information obtained through Da VinciTM system are provided. PMID- 22255965 TI - Spike detection in the preterm fetal sheep EEG using Haar wavelet analysis. AB - Perinatal hypoxia is a significant cause of brain injury in preterm infants. Neuroprotective treatments have proven beneficial when commenced within 6-8 hours post hypoxic-ischemic insult. However, as the exact time of injury is unknown, there are no current means to determine which infants are in the treatment phase of the evolving injury. Recent studies suggest epileptiform transients in the first 6-8 hours are predictive of outcome. To quantify this further an automated means of transient identification is required. In this paper we describe a method using Haar wavelets to detect spikes in the preterm fetal sheep EEG after asphyxia in utero. The method exhibits good sensitivity and selectivity over 3 specific time periods and demonstrates the feasibility of using wavelets for spike detection in fetal sheep. PMID- 22255964 TI - Wepilet, optimal orthogonal wavelets for epileptic seizure prediction with one single surface channel. AB - Wepilet is a series of novel orthogonal wavelets optimized for Electroencephalogram (EEG) signals, specialized for epileptic seizure prediction. The main idea is to design a mother wavelet that when applied to EEG signal to create the feature space, should enable a better classification of the brain state. Wepilet is developed by an iterative optimization process, employing Genetic Algorithm (GA). Frequency sub-band features are first extracted using wepilet under design for the EEG signal captured by one single surface channel. These features are then fed to Support Vector Machines (SVMs) that classify the cerebral state in preictal and inter-ictal classes. The results of the classification are then used to compute the Probability of Error Rate (PER), which in turn is the GA objective function to be minimized. Results in a group of four patients, indicate the efficiency of optimized mother wavelet compared to the well-known Daubechies wavelet in EEG processing. PMID- 22255966 TI - Electroencephalographic compression based on modulated filter banks and wavelet transform. AB - Due to the large volume of information generated in an electroencephalographic (EEG) study, compression is needed for storage, processing or transmission for analysis. In this paper we evaluate and compare two lossy compression techniques applied to EEG signals. It compares the performance of compression schemes with decomposition by filter banks or wavelet Packets transformation, seeking the best value for compression, best quality and more efficient real time implementation. Due to specific properties of EEG signals, we propose a quantization stage adapted to the dynamic range of each band, looking for higher quality. The results show that the compressor with filter bank performs better than transform methods. Quantization adapted to the dynamic range significantly enhances the quality. PMID- 22255967 TI - Multiscale autoregressive identification of neuro-electrophysiological systems. AB - Electrical signals between connected neural nuclei are difficult to model because of the complexity and high number of paths within the brain. Simple parametric models are therefore often used. A multiscale version of the autoregressive with exogenous input (MS-ARX) model has recently been developed which allows selection of the optimal amount of filtering and decimation depending on the signal-to noise ratio and degree of predictability. In this paper we apply the MS-ARX model to cortical electroencephalograms and subthalamic local field potentials simultaneously recorded from anesthetized rodent brains. We demonstrate that the MS-ARX model produces better predictions than traditional ARX modeling. We also adapt the MS-ARX results to show differences in inter-nuclei predictability between normal rats and rats with 6OHDA-induced parkinsonism, indicating that this method may have broad applicability to other neuro-electrophysiological studies. PMID- 22255968 TI - Towards automated ingestion detection: swallow sounds. AB - Obesity is a worldwide epidemic and is a cause of many major chronic diseases. In most cases, obesity is a result of an imbalance between food intake and calories burned. Steps toward automated ingestion detection are being made. In order to automate the process of capturing ingestion, a method for detecting, analyzing, and recording sounds related to ingestion is being developed. In this paper, preliminary swallow sound analysis is presented and compared with various other noises captured from a throat mounted microphone. Initial frequency analysis indicates a stronger presence at high frequency intervals for swallow sounds in relation to other captured sounds such as voice. Comparisons show that a single high-pass filter can offer similar results as wavelet decomposition. Two simple methods for event detection are given. PMID- 22255969 TI - Efficient thresholding-based ECG compressors for high quality applications using cosine modulated filter banks. AB - The aim of electrocardiogram (ECG) compression is to achieve as much compression as possible while the significant information is preserved in the reconstructed signal. Lossy thresholding-based compressors have shown good performance needing low computational resources. In this work, two compression schemes that include nearly perfect reconstruction cosine modulated filter banks for the signal decomposition are proposed. They are evaluated for highly reliable applications, where the reconstructed signal must be very similar to the original. The whole MIT-BIH Arrhythmia Database and suitable metrics are used in the assessment, to obtain representative results. Results show that the proposed compressors yield better performance than discrete wavelet transform-based techniques, when high quality requirements are imposed. PMID- 22255970 TI - Effect of acute myocardial ischemia on different high-frequency bandwidths and temporal regions of the QRS. AB - The purpose of this study was to describe the changes in high-frequency QRS (HF QRS) components due to myocardial ischemia provoked by prolonged artery occlusion during percutaneous coronary interventions (PCI). Signal-averaged ECGs from 69 patients were obtained during PCI procedures and comparison of high-frequency components of the QRS at different temporal regions and frequency bandwidth were performed. Continuous wavelet transform was applied to estimate the energy contents over the studied time-frequency regions. Seven frequency bands from 50 to 300 Hz, with bandwidth = 100 Hz were considered. The sum of all 12 leads energy decreased significantly (p < 0.001) from pre-PCI to PCI during both second half and total QRS complex in all frequency bands, but the main effect was found in the 200-300 Hz band. The energy changes were more marked toward higher frequency bands. The second half of QRS complex was more sensitive to changes due to myocardial ischemia. PMID- 22255971 TI - A wavelet based technique for suppression of EMG noise and motion artifact in ambulatory ECG. AB - A wavelet-based denoising technique is investigated for suppressing EMG noise and motion artifact in ambulatory ECG. EMG noise is reduced by thresholding the wavelet coefficients using an improved thresholding function combining the features of hard and soft thresholding. Motion artifact is reduced by limiting the wavelet coefficients. Thresholds for both the denoising steps are estimated using the statistics of the noisy signal. Denoising of simulated noisy ECG signals resulted in an average SNR improvement of 11.4 dB, and its application on ambulatory ECG recordings resulted in L(2) norm and max-min based improvement indices close to one. It significantly improved R-peak detection in both the cases. PMID- 22255972 TI - Cubic spline interpolation with overlapped window and data reuse for on-line Hilbert Huang transform biomedical microprocessor. AB - On-chip implementation of Hilbert-Huang transform (HHT) has great impact to analyze the non-linear and non-stationary biomedical signals on wearable or implantable sensors for the real-time applications. Cubic spline interpolation (CSI) consumes the most computation in HHT, and is the key component for the HHT processor. In tradition, CSI in HHT is usually performed after the collection of a large window of signals, and the long latency violates the realtime requirement of the applications. In this work, we propose to keep processing the incoming signals on-line with small and overlapped data windows without sacrificing the interpolation accuracy. 58% multiplication and 73% division of CSI are saved after the data reuse between the data windows. PMID- 22255973 TI - Telephone-quality pathological speech classification using empirical mode decomposition. AB - This paper presents a computationally simple and effective methodology based on empirical mode decomposition (EMD) for classification of telephone quality normal and pathological speech signals. EMD is used to decompose continuous normal and pathological speech signals into intrinsic mode functions, which are analyzed to extract physically meaningful and unique temporal and spectral features. Using continuous speech samples from a database of 51 normal and 161 pathological speakers, which has been modified to simulate telephone quality speech under different levels of noise, a linear classifier is used with the feature vector thus obtained to obtain a high classification accuracy, thereby demonstrating the effectiveness of the methodology. The classification accuracy reported in this paper (89.7% for signal-to-noise ratio 30 dB) is a significant improvement over previously reported results for the same task, and demonstrates the utility of our methodology for cost-effective remote voice pathology assessment over telephone channels. PMID- 22255974 TI - Differential neural responses to acupuncture revealed by MEG using wavelet-based time-frequency analysis: a pilot study. AB - Acupoint specificity, lying at the core of the Traditional Chinese Medicine, still faces many controversies. As previous neuroimaging studies on acupuncture mainly adopted relatively low time-resolution functional magnetic resonance imaging (fMRI) technology and inappropriate block-designed experimental paradigm due to sustained effect, in the current study, we employed a single block designed paradigm together with high temporal-resolution magnetoencephalography (MEG) technology. We applied time-frequency analysis based upon Morlet wavelet transforming approach to detect differential oscillatory brain dynamics induced by acupuncture at Stomach Meridian 36 (ST36) using a nearby nonacupoint (NAP) as control condition. We observed that frequency power changes were mainly restricted to delta band for both ST36 group and NAP group. Consistently increased delta band power in contralateral temporal regions and decreased power in the counterparts of ipsilateral hemisphere were detected following stimulation at ST36 on the right leg. Compared with ST36, no significant delta ranges were found in temporal regions in NAP group, illustrating different oscillatory brain patterns. Our results may provide additional evidence to support the specificity of acupuncture modulation effects. PMID- 22255975 TI - Simulating electrical stimulation of degenerative retinal ganglion cells with bi phasic pulse trains. AB - The aim of this work was to investigate how retinal ganglion cells (RGCs) respond to repetitive electrical stimulation in degenerative retina. The response of modeled ON and OFF cells was examined to bi-phasic pulse train stimulation of varying frequencies. Previously developed models of RGCs were extended to include an experimentally observable balance of excitatory and inhibitory currents in degenerative retina. The phenomena of fading and dark phosphenes with retinal implants were investigated. A hypothesis for a mechanism contributing to these phenomena was formulated. PMID- 22255976 TI - Effect of subthalamic nucleus interconnectivity at deep brain stimulation onset and offset: a simulation study. AB - Deep brain stimulation (DBS) has been demonstrated to effectively improve the motor symptoms of Parkinson's disease. However, the underlying mechanisms are not known. It has been reported that a period of time is required before the full effect on motor symptoms is realized after DBS is initiated and that suppression of symptoms persists after DBS ends under parkinsonian conditions. A computational model is presented to investigate the hypothesis that interconnectivity and transmission delays within the subthalamic nucleus (STN) neurons may induce a gradual decay and recovery of pathological oscillations at DBS onset and offset under simulated parkinsonian conditions. Interconnectivity strength between the STN neurons and the number of STN neurons directly stimulated by DBS are both varied to examine the gradual decay and recovery of oscillatory STN activity. Weaker interconnectivity and lower numbers of STN neurons directly receiving DBS input were found to result in longer decay and recovery times at the onset and offset of DBS, respectively. PMID- 22255977 TI - Artificial neural network based intracranial pressure mean forecast algorithm for medical decision support. AB - Although the future mean of intracranial pressure (ICP) is of critical concern of many clinicians for timely medical treatment, the problem of forecasting the future ICP mean has not been addressed yet. In this paper, we present a nonlinear autoregressive with exogenous input artificial neural network based mean forecast algorithm (ANN(NARX)-MFA) to predict the ICP mean of the future windows based on features extracted from past windows and segmented sub-windows. We compare its performance with nonlinear autoregressive artificial neural network algorithm (ANN(NAR)) without features extracted from window segmentation. Experimental results showed that, ANN(NARX)-MFA algorithm outperforms ANN(NAR) algorithm in prediction accuracy, because additional features extracted from finer segmented sub-windows help to catch the subtle changes of ICP trends. This verifies the effectiveness of decomposing the whole window into sub-windows to obtain features in making predictions on future windows. Based on the forecast of ICP mean, medical treatments can be planned in advance to control ICP elevation, in order to maximize recovery and optimize outcome. PMID- 22255978 TI - Cramer-Rao bounds on the performance of simulated annealing and genetic algorithms in EEG source localization. AB - In this paper, we evaluate the performance of simulated annealing (SA) and the genetic algorithm (GA) when used for electroencephalographic (EEG) source localization. The performance is evaluated on the variance of the estimated localizations as a function of the optimization's initialization parameters and the signal-to-noise ratio (SNR). We use the concentrated likelihood function (CLF) as objective function and the Cramer-Rao bound (CRB) as a reference on the performance. The CRB sets the lower limit on the variance of our estimated values. Then, our simulations on realistic EEG data show that both SA and GA are highly sensitive to noise, but adjustments on their parameters for a fixed SNR value do not improve performance significantly. Our results also confirm that SA is more sensitive to noise and its performance may be affected by correlated sources. PMID- 22255979 TI - Diagnostic biomarkers for Alzheimer's disease using dynamic nonlinear models based on Principal Dynamic Modes. AB - Sensitive and robust diagnostic biomarkers for Alzheimer's disease (AD) were sought using dynamic nonlinear models of the causal interrelationships among time series (beat-to-beat) data of arterial blood pressure, end-tidal CO(2) and cerebral blood flow velocity collected in human subjects (4 AD patients and 4 control subjects). These models were based on Principal Dynamic Modes (PDM) and yielded a reliable biomarker for AD diagnosis in the form of the "Effective CO(2) Reactivity Index" (ECRI). The results from this initial set of subjects corroborated the efficacy of the ECRI biomarker for accurate AD diagnosis. PMID- 22255980 TI - Video assessment of finger tapping for Parkinson's disease and other movement disorders. AB - Functional motor impairment due to Parkinson's disease and other movement disorders are currently assessed with visual rating scales such as the Unified Parkinson's Disease Rating Scale (UPDRS). These methods rely on the subjective judgment of a rater to assign scores representing the extent of impairment while subjects perform prescribed activities. We describe a new model-based framework that uses statistical video processing to automatically track movement during prescribed activities. This approach has many advantages over traditional clinical rating scales. It can completely characterize movement during prescribed tasks over time objectively and precisely using hardware that is inexpensive and readily available. We demonstrate the potential of this framework with a simple statistical model applied to a paced finger tapping test. This technology could be deployed in a natural home environment for frequent assessments. This technology could ultimately improve both clinical practice and clinical trials. PMID- 22255981 TI - Surface EMG model of the bicep during aging: a preliminary study. AB - Reduction in the median frequency and the amplitude of surface electromyogram (sEMG) has been observed among older subjects compared with the younger cohort. These changes in sEMG have been associated with a reduction in the number of muscle fibers and a drop in the ratio of type II muscle fibers. However, the details of this association are not known. This paper has experimentally determined the difference between the magnitude and spectrum of sEMG of the younger and older cohorts, and estimated the changes to the muscle by populating a lifelike model with the experimental data. Experiments were conducted on subjects belonging to younger (20-28 years) and older (61-69) age groups. From the simulated results, it is shown that experimental sEMG signals are matched by the model representing the older cohort with a substantially reduced number of motor units compared to the younger people. In the model, the best match with experimental results was observed when the ratio of the bicep motor units between the older and the younger subjects was 0.5. The results also indicate a substantial reduction in the ratio of fast fibers, from 0.45 in the younger cohort to 0.11 in the older cohort. PMID- 22255982 TI - System identification of mechanomyograms detected with an acceleration sensor and a laser displacement meter. AB - The purpose of this study is to investigate the transfer functions of mechanomyograms (MMGs) detected with an acceleration sensor and a laser displacement meter. The MMGs evoked by electrical stimulation to the peroneal nerve were recorded on the skin of the tibial anterior muscle. The displacement MMG (DMMG) and the acceleration MMG (AMMG) systems were identified using a singular value decomposition method. The appropriate order of the AMMG system was six and that of the DMMG system was four. The undamped natural frequencies of the systems were compared to resonance frequencies of human soft tissue. Some of the undamped natural frequencies estimated from the AMMG systems agreed with the resonance frequencies in the literature but others were lower than the resonance frequencies. The undamped natural frequencies estimated from the DMMG systems were lower than the resonance frequencies. PMID- 22255983 TI - Modeling MR induced artifacts contaminating electrophysiological signals recorded during MRI. AB - The purpose of this paper is to present a novel parametric model for Magnetic Resonance (MR) induced artifacts contaminating electrophysiological signals (ECG, EEG, EMG, etc.) recorded simultaneously during MRI. The aim to construct an analytical representation of these artifacts is of great importance as it helps to understand and make appropriate hypotheses about the artifacts' generation process. The model presented in this paper assumes a periodic and stationary nature of these artifacts. Statistical KPSS tests were applied to confirm that observed artifacts are weak-sense stationary. The model based on a sum of sinusoids of different amplitudes, frequencies and phase delays {A, f, Phi} was most suited to represent these artifacts. The sinusoidal model parameters {A, f, Phi} were estimated by BFGS optimization. The lowest mean square error (MSE) is used to determine the model with the optimum parameters. Pearson's correlation coefficients were used as indices to evaluate the accuracy of the calculated model. PMID- 22255984 TI - Simulated performance intensity functions. AB - Measuring speech intelligibility for different hearing aid fitting methods in a simulated environment would allow rapid prototyping and early design assessment. A simulated performance intensity function (SPIF) test methodology has been developed to allow experimentation using an auditory nerve model to predict listeners' phoneme recognition. The test discriminates between normal hearing and progressively degrading levels of sensorineural hearing loss. Auditory nerve discharge patterns, presented as neurograms, can be subjectively ranked by visual inspection. Here, subjective inspection is substituted with an automated ranking using a new image similarity metric that can quantify neurogram degradation in a consistent manner. This work reproduces the test results of a real human listener with moderate hearing loss, in unaided and aided scenarios, using a simulation. The simulated results correlate within comparable error margins to the real listener test performance intensity functions. PMID- 22255985 TI - A whole body statistical shape model for radio frequency simulation. AB - The development of ultra low power wireless sensors for customized wearable and implantable medical devices requires patient specific models for radio frequency simulation to understand wave propagation in the body. In practice, the creation of a patient specific whole-body model is difficult and time consuming to create. It is therefore necessary to establish a method for studying a population in a statistical manner. In this paper, we present a statistical shape model for the whole body for RF simulation. It is built from 10 male and 10 female subjects of varying size and height. This model has the ability to instantiate a new surface mesh with the parameters allowed by the training set. This model would provide shapes of varying sizes for studies, without the requirement of obtaining subject specific whole body models. Results from finite-differences time-domain simulation are presented on the extreme shapes from the model and demonstrate the need for a full understanding of the range in body shapes. PMID- 22255986 TI - Classification of multi-modal data in a self-paced binary BCI in freely moving animals. AB - The goal of the present article is to compare different classifiers using multi modal data analysis in a binary self-paced BCI. Individual classifiers were applied to multi-modal neuronal data which was projected to a low dimensional space of latent variables using the Iterative N-way Partial Least Squares algorithm. To create a multi-way feature array, electrocorticograms (ECoG) recorded from animal brains were mapped to the spatial-temporal-frequency space using continuous wavelet transformation. To compare the classifiers BCI experiments were simulated. For this purpose we used 9 recordings from behavioral experiments previously recorded in rats free to move in a nature like environment. PMID- 22255987 TI - EEG source localization based on multivariate autoregressive models using Kalman filtering. AB - The estimation of current distributions from electroencephalographic recordings poses an inverse problem, which can approximately be solved by including dynamical models as spatio-temporal constraints onto the solution. In this paper, we consider the electrocardiography source localization task, where a specific structure for the dynamical model of current distribution is directly obtained from the data by fitting multivariate autoregressive models to electroencephalographic time series. Whereas previous approaches consider an approximation of the internal connectivity of the sources, the proposed methodology takes into account a realistic structure of the model estimated from the data, such that it becomes possible to obtain improved inverse solutions. The performance of the new method is demonstrated by application to simulated electroencephalographic data over several signal to noise ratios, where the source localization task is evaluated by using the localization error and the data fit error. Finally, it is shown that estimating MVAR models makes possible to obtain inverse solutions of considerably improved quality, as compared to the usual instantaneous inverse solutions, even if the regularized inverse of Tikhonov is used. PMID- 22255988 TI - Community detection for directional neural networks inferred from EEG data. AB - One major challenge in neuroscience is to identify the functional modules from multichannel, multiple subjects recordings. Most research on community detection has focused on finding the association matrix based on functional connectivity, instead of effective connectivity, thus not capturing the causality in the network. In this paper, we propose a community detection algorithm suitable for weighted and asymmetric (directed) networks representing effective connectivity, and apply the algorithm to multichannel electroencephalogram (EEG) data. In addition, we extend the algorithm to find one common community structure from multiple subjects. PMID- 22255989 TI - Detection and removal of stimulation artifacts in electroencephalogram recordings. AB - Stimulation artifacts are short-duration, high-amplitude spikes which can be observed in electroencephalogram (EEG) recordings whenever surface functional electrical stimulation (FES) is applied during recordings. Stimulation artifacts are of non-physiologic origin and hence have to be removed before analysis of the EEG can take place. In this paper, algorithms for the detection and removal of stimulation artifacts are presented. The algorithms require only little computational resources and can be applied online, while signals are recorded. Therefore, the algorithms are suitable for applications such as online control of FES based neuroprostheses by a brain-computer interface. Tests are performed with datasets recorded from two subjects for artifact durations ranging from 0.5 ms to 10 ms. After application of the artifact removal algorithms the signal-to-noise ratio of the reconstructed signals ranges from 15 dB to 45 dB, depending on the duration of artifacts and the type of algorithm. PMID- 22255990 TI - Comparative muscle study fatigue with sEMG signals during the isotonic and isometric tasks for diagnostics purposes. AB - The study of fatigue is an important tool for diagnostics of disease, sports, ergonomics and robotics areas. This work deals with the analysis of sEMG most important fatigue muscle indicators with use of signal processing in isometric and isotonic tasks with the propose of standardizing fatigue protocol to select the data acquisition and processing with diagnostic proposes. As a result, the slope of the RMS, ARV and MNF indicators were successful to describe the fatigue behavior expected. Whereas that, MDF and AIF indicators failed in the description of fatigue. Similarly, the use of a constant load for sEMG data acquisition was the best strategy in both tasks. PMID- 22255991 TI - Sparse approximation of long-term biomedical signals for classification via dynamic PCA. AB - Sparse approximation is a novel technique in applications of event detection problems to long-term complex biomedical signals. It involves simplifying the extent of resources required to describe a large set of data sufficiently for classification. In this paper, we propose a multivariate statistical approach using dynamic principal component analysis along with the non-overlapping moving window technique to extract feature information from univariate long-term observational signals. Within the dynamic PCA framework, a few principal components plus the energy measure of signals in principal component subspace are highly promising for applying event detection problems to both stationary and non stationary signals. The proposed method has been first tested using synthetic databases which contain various representative signals. The effectiveness of the method is then verified with real EEG signals for the purpose of epilepsy diagnosis and epileptic seizure detection. This sparse method produces a 100% classification accuracy for both synthetic data and real single channel EEG data. PMID- 22255992 TI - Principle component analysis on photoplethysmograms: blood oxygen saturation estimation and signal segmentation. AB - Most pulse oximeters determine blood oxygen saturation (SpO(2)) after calculating a coefficient, R, that represents the normalized ratiometric contributions of the pulsatile red and near-infrared photoplethysmograms (PPGs) acquired by the sensor. This paper presents a new approach that uses principle component analysis (PCA) to separate the signal and noise components of unfiltered PPGs and provide the determination of R. Also, rather than use peak-to-valley time intervals to obtain R, this technique uses eigenvalue and eigenvector data obtained during PCA to optimize these time intervals and improve the R calculation. Early analyses on unfiltered PPGs from 16 subjects indicate that these R values compare to those obtained from FFT-based methods and yield SpO(2) values consistent with those reported by a commercial unit. All signal data are considered during the PCA process, so this technique shows promise to precisely segment clean versus noise corrupted PPGs. PMID- 22255993 TI - Bed posture classification for pressure ulcer prevention. AB - Pressure ulcer is an age-old problem imposing a huge cost to our health care system. Detecting and keeping record of the patient's posture on bed, help care givers reposition patient more efficiently and reduce the risk of developing pressure ulcer. In this paper, a commercial pressure mapping system is used to create a time-stamped, whole-body pressure map of the patient. An image-based processing algorithm is developed to keep an unobtrusive and informative record of patient's bed posture over time. The experimental results show that proposed algorithm can predict patient's bed posture with up to 97.7% average accuracy. This algorithm could ultimately be used with current support surface technologies to reduce the risk of ulcer development. PMID- 22255994 TI - Dimensionality reduction for the quantitative evaluation of a smartphone-based Timed Up and Go test. AB - The Timed Up and Go is a clinical test to assess mobility in the elderly and in Parkinson's disease. Lately instrumented versions of the test are being considered, where inertial sensors assess motion. To improve the pervasiveness, ease of use, and cost, we consider a smartphone's accelerometer as the measurement system. Several parameters (usually highly correlated) can be computed from the signals recorded during the test. To avoid redundancy and obtain the features that are most sensitive to the locomotor performance, a dimensionality reduction was performed through principal component analysis (PCA). Forty-nine healthy subjects of different ages were tested. PCA was performed to extract new features (principal components) which are not redundant combinations of the original parameters and account for most of the data variability. They can be useful for exploratory analysis and outlier detection. Then, a reduced set of the original parameters was selected through correlation analysis with the principal components. This set could be recommended for studies based on healthy adults. The proposed procedure could be used as a first-level feature selection in classification studies (i.e. healthy-Parkinson's disease, fallers-non fallers) and could allow, in the future, a complete system for movement analysis to be incorporated in a smartphone. PMID- 22255995 TI - Comparison of EEG blind source separation techniques to improve the classification of P300 trials. AB - This paper provides a comparison of several blind source separation (BSS) techniques as they are applied to EEG signals. Specifically, this work focuses on the P300 speller paradigm and assesses the classification accuracies for the identification of P300 trials. Previous work has shown that BSS methods such as independent component analysis (ICA) are useful in extracting the P300 source information from the background noise, increasing the classification rates. ICA will be compared with two other BSS methods, maximum noise fraction (MNF) and principal component analysis (PCA). In addition to this, we will analyze the effect of adding temporal information to the original data, which allows these BSS algorithms to find more complex spatio-temporal patterns. PMID- 22255997 TI - A momentum-based constraint on optical flow tracking of the endocardial surface. AB - Echocardiography is the standard of care for the evaluation of cardiac function in a variety of clinical scenarios. Despite the increasing availability of RT3D imaging, its utility remains limited due to a lack of tools available to analyze 3D+t datasets. In previous work, we have proposed and validated optical flow as an effective correlation-based technique to track myocardial motion and deformation in RT3D datasets. However, OF's ability to track small regions of tissue (e.g. the endocardial surface) is diminished in less optimal acquisitions. Our goal, therefore, is to develop additional constraints on OF-estimated motion in order to increase the robustness of endocardial surface tracking. We present several modifications to OF-based tracking including motion field smoothing and momentum correction that results in improved OF tracking. PMID- 22255996 TI - Ultrasound standoff optimization for maximum image quality of a robot-assisted flat-panel ultrasound device. AB - Ultrasonography is a widespread intraoperative imaging modality. However, it suffers from several shortcomings e.g. its dependance on the skills of the operator for the image quality. To overcome this shortcoming, Gumprecht et al. [1] recently proposed a new robot-assisted flat-panel ultrasound device for continuous intraoperative imaging during laparoscopic tumor resection in urology. This device is integrated in the OR-table and performs its imaging through the back of a supine patient. The ultrasound probe resides in a tank, filled with a fluid that is traversable by the ultrasound waves. A flexible membrane is stretched over the tank and is in contact with the fluid and the patient. Through is flexibility, the membrane can adapt to the shape of the patient. Therefore, the membrane assures for sufficient coupling of ultrasound waves into the patient. We based the selection of the membrane and the fluid upon the quality of the ultrasound images that can be recorded with this combination. In this paper, we present the results of the experiment that lead to the standoff used in the robotic device of Gumprecht et al. [1]. PMID- 22255998 TI - Development of an interactive Coronary Doppler Vibrometry system for detection of coronary artery disease. AB - Coronary artery disease is a deadly and costly condition and represents an important public health issue globally. Coronary Doppler vibrometry (CDV), a new noninvasive coronary artery stenosis detection technique, showed encouraging results in our recent clinical study. However, the CDV system required lengthy offline data analysis, thus it did not provide any feedback during examination on the quality of data, not to mention analysis results. To overcome these limitations, we have developed a new CDV system that interactively performs acquisition, analysis and display of a complete data set while a subject is still on the examination table. Our system is based on a commercial ultrasound machine, and it will be a useful tool for CDV research and clinical studies in the future. PMID- 22255999 TI - Imaging of sebaceous glands of human skin by three-dimensional ultrasound microscopy and its relation to elasticity. AB - High frequency ultrasound imaging has realized high resolution in vivo imaging of the biological tissues at a microscopic level. Human skin structure, especially sebaceous glands at the deep part of the dermis, was observed by three dimensional ultrasound microscopy with the central frequency of 120 MHz. The visco-elasticity and surface sebum level of the observed region were measured by established testing devices. Both sebaceous glands density and surface sebum level were higher in cheek than those in forearm. The viscosity of forearm was lower than that of cheek. These results suggest that sebaceous glands may act as cushions of the skin besides their classical role of secreting sebum and some hormones. High frequency ultrasound imaging contributes to the evaluation of human skin aging. PMID- 22256000 TI - Tubular structure enhancement for surgical instrument detection in 3D ultrasound. AB - Three-dimensional ultrasound has been an effective imaging modality for diagnostics and is now an emerging modality for image-guided minimally-invasive interventions since it enables visualization of both instruments and tissue. Challenges to ultrasound-guided interventions arise, however, due to the low signal-to-noise ratio and the imaging artifacts created by the interventional instruments. Metallic instruments, in particular, are strong scatters and so produce a variety of artifacts. For many interventions, the manual or robotic instrument is comprised of a long curved tubular structure with specialized tooling at its tip. Toward the goal of developing a surgical navigation system, this paper proposes an image processing algorithm for enhancing the tubular structure of imaged instruments while also reducing imaging artifacts. Experiments are presented to evaluate the effectiveness of the approach in the context of robotic instruments whose shape comprises a smooth curve along their length. PMID- 22256001 TI - Effect of therapeutic ultrasound on acoustically sensitive microcapsules. AB - In the area of therapeutic ultrasound activated drug delivery, difficulties exist in designing a carrier that responds to ultrasound for triggering and imaging but also provides adequate treatment potential. In this paper, we report on a novel acoustically sensitive microcapsule reservoir that can be activated with therapeutic ultrasound for payload release and can be potentially tracked using imaging. It is being designed for increased longevity and is not planned for the circulation. Here, we describe its unique formulation and demonstrate effects of therapeutic ultrasound on it at 1 MHz using a combined optical-acoustic setup on a microscope. We see membrane bulging and damage for small and large capsules with both continuous and pulsed ultrasound. We also show some preliminary work on understanding the mechanism behind these effects. The reservoirs show potential for future ultrasound activated release and imaging while being patent in form and function over several weeks. PMID- 22256002 TI - A quantitative study to design an experimental setup for photoacoustic imaging. AB - During the last decade, a new modality called photoacoustic imaging has emerged. The increasing interest for this new modality is due to the fact that it combines advantages of ultrasound and optical imaging, i.e. the high contrast due to optical absorption and the low acoustic attenuation in biological tissues. It is thus possible to study vascularization because blood has high optical absorption coefficient. Papers in the literature often focus on applications and rarely discuss quantitative parameters. The goal of this paper is to provide quantitative elements to design an acquisition setup. By defining the targeted resolution and penetration depth, it is then possible to evaluate which kind of excitation and reception systems have to be used. First, we recall theoretical background related to photoacoustic effect before to describe the experiments based on a nanosecond laser at 1064 nm and 2.25-5 MHz transducers. Second, we present results about the relation linking fluence laser to signal amplitude and axial and lateral resolutions of our acquisition setup. We verify the linear relation between fluence and amplitude before to estimate axial resolution at 550 MUm for a 2.25 MHz ultrasonic transducer. Concerning lateral resolution, we show that a reconstruction technique based on curvilinear acquisition of 30 lines improves it by a factor of 3 compared to a lateral displacement. Future works will include improvement of lateral resolution using probes, like in ultrasound imaging, instead of single-element transducers. PMID- 22256003 TI - Automatic left ventricle detection in echocardiographic images for deformable contour initialization. AB - The accurate left ventricular boundary detection in echocardiographic images allow cardiologists to study and assess cardiomyopathy in patients. Due to the tedious and time consuming manner of manually tracing the borders, deformable models are generally used for left ventricle segmentations. However, most deformable models require a good initialization, which is usually outlined manually by the user. In this paper, we propose an automated left ventricle detection method for two-dimensional echocardiographic images that could serve as an initialization for deformable models. The proposed approach consists of pre processing and post-processing stages, coupled with the watershed segmentation. The pre-processing stage enhances the overall contrast and reduces speckle noise, whereas the post-processing enhances the segmented region and avoids the papillary muscles. The performance of the proposed method is evaluated on real data. Experimental results show that it is suitable for automatic contour initialization since no prior assumptions nor human interventions are required. Besides, the computational time taken is also lower compared to an existing method. PMID- 22256004 TI - Segmentation of 2D fetal ultrasound images by exploiting context information using conditional random fields. AB - This paper proposes a novel approach for segmenting fetal ultrasound images. This problem presents a variety of challenges including high noise, low contrast, and other US imaging properties such as similarity between texture and gray levels of two organs/ tissues. In this paper, we have proposed a Conditional Random Field (CRF) based framework to handle challenges in segmenting fetal ultrasound images. Clinically, it is known that fetus is surrounded by specific maternal tissues, amniotic fluid and placenta. We exploit this context information using CRFs for segmenting the fetal images accurately. The proposed CRF framework uses wavelet based texture features for representing the ultrasound image and Support Vector Machines (SVM) for initial label prediction. Initial results on a limited dataset of real world ultrasound images of fetus are promising. Results show that proposed method could handle the noise and similarity between fetus and its surroundings in ultrasound images. PMID- 22256005 TI - Non-invasive assessment for endothelial CD81 expression via targeted microbubbles. AB - The aim of our study was to investigate the use of targeted ultrasound microbubbles (MBs) for molecular imaging of murine endothelial CD81 expression. In the study, the anti-CD81-coated MBs was successfully prepared and characterizated. Murine bEnd.3 cells were stimulated with phenazine methosulfate (PMS) to induce the up-regulation of CD81 expression. Changes in CD81 expression after stimulation were tracked with anti-CD81-coated MBs and imaged by using SONIX RP ultrasound imaging system. Our results showed that endothelial CD81 expression was gradually up-regulated with the increase of PMS concentration. Correspondingly, the accumulation of targeted MBs was also gradually improved and could be inhibited competitively. The mean video intensity of stimulated cells from backscatter of the CD81-targeted MBs was significantly higher than that of the non-stimulated control (mean +/- SD: 17.5 +/- 3.6 versus 12.1 +/- 2.9 pixel intensity; P < 0.01). In conclusion, CD81-targeted MBs allows non-invasive assessment of the expression levels of CD81 on the bEnd.3 cells and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring using molecular ultrasound imaging. PMID- 22256006 TI - Computational study of subdural and epidural cortical stimulation of the motor cortex. AB - Cortical stimulation (CS) has gained wide attention for its use in augmenting neurological recovery in various conditions. Noninvasive cortical stimulations using transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are less invasive when delivering the electrical current to the patient's brain, but have several limitations. Direct cortical stimulation (DCS) using an implantable stimulation system consisting of epidurally or subdurally placed electrodes and pulse generators, provides cortical stimulation and concurrent rehabilitative training in a stable fashion without limiting a patient's activities. The effectiveness of these two types of DCS--epidural cortical stimulation (ECS) and subdural cortical stimulation (SCS)--has not been compared. In this work, a computer simulation study was conducted to predict the current density distributions (CDD) through cortical stimulations using subdurally or epidurally placed electrodes. The simulation study is based on the human motor cortex model with a three-dimensional finite element model (FEM). The change in CDD depending on the shape of the electrode (disc or ring) is discussed. The output current induced by SCS was about four times larger than that of ECS when voltage stimulations with the same magnitude were regulated. Thus, SCS showed substantially better penetration of the current into gray or white matter. Further, the ring electrode performed comparably or slightly inferior to the disc electrode in both cortical stimulations. PMID- 22256007 TI - A fully implantable stimulator with wireless power and data transmission for experimental use in epidural spinal cord stimulation. AB - Epidural spinal cord stimulation (ESCS) combined with partial weight bearing therapy (PWBT) has been reported to facilitate recovery of functional walking for individuals after chronic incomplete spinal cord injury. This paper describes a low cost, fully implantable, advanced ESCS stimulator that can be manufactured in a research laboratory for use in small animals. The system is composed of four main parts: an external personal digital assistant (PDA), an external controller, an implantable pulse generator (IPG), lead extension and electrode. The PDA allows the experimenter to program the stimulation parameters through a user friendly graphical interface. The external controller placed on the rat back communicates with PDA via RF telemetry. The IPG generates the biphasic charge balanced voltage-regulated pulses, which are delivered to the bipolar electrode by the lead extension to achieve chronic ESCS in freely moving rats. A RF carrier from the Class-E amplifier in the external controller provides both data and power for the implanted circuitry through a closely coupled inductive link. The IPG is hermetically packaged using a silicon elastomer and measures 22 mm * 23 mm * 7 mm with a mass of ~3.78 g. PMID- 22256008 TI - Mechanical power of ankle plantar flexion and subjective pain by monophasic electrical stimulation. AB - The aim of this study was to investigate the mechanical power of the ankle plantar flexion. The investigated power of the ankle plantar flexion would help to improve effectively the FES walking system using the ankle plantar flexion for patients and aged people in slow walking. The subjective pain by electrical stimulation sometimes becomes the burden to use the FES system. We also investigated the relationship between the mechanical power in ankle plantar flexion by electrical stimulation and the subjective pain. We developed the device to measure the ankle movement by electrical stimulation against load resistance torque. The device consisted of pads to support a single lower leg, a rotational footplate with a large pulley and a vertical weight to generate the load resistance torque, and a monophasic electrical stimulator via surface electrodes. Our results showed the proportional relationship between the mechanical power of the ankle plantar flexion and the subjective pain by electrical stimulation. To generate the same level in the ankle plantar flexor power 2.75 W under the maximum voluntary exertion, the subjective pain by electrical stimulation exceeded 70, which means the feeling of crying at the Face Pain Scale. This result would help the better design of the FES walking system using the ankle plantar flexion for patients and aged people. PMID- 22256009 TI - Efficient search and fit methods to find nerve stimulation parameters for multi contact electrodes. AB - This paper describes a method to efficiently sample EMG recruitment space over a wide range of pulse amplitude (PA) and pulse width (PW). A gradient based search method is developed to find high information areas of a recruitment surface. This search method is first examined in the context of simulated EMG recruitment data and its ability to sample and subsequently fit Gompertz-Function-inspired surfaces to it. The search method is then used to determine parameters when stimulating through an 8 contact flat interface nerve electrode (FINE). The recorded EMG recruitment data are then used to validate the Gompertz surface fitting method as well as the search method. PMID- 22256010 TI - Correlation between mechanomyography features and passive movements in healthy and paraplegic subjects. AB - Mechanomyography (MMG) measures both muscular contraction and stretching activities and can be used as feedback in the control of neuroprostheses with Functional Electrical Stimulation (FES). In this study we evaluated the correlation between MMG features and passive knee angular movement of rectus femoris and vastus lateralis muscles acquired from healthy volunteers (HV) and spinal cord injured volunteers (SCIV). Twelve HV and thirteen SCIV were submitted to passive and FES elicited knee extensions and in each extension, eleven windows of analysis with 0.5s length were inspected. Temporal (RMS and INT) and frequency (MF and MU3) features were extracted. Spearman correlation coefficients (p) were computed in order to check correlations between the features obtained from both MMG sensors. The correlation between MMG(MF) and MMG temporal analysis (RMS and INT) to HV was classified as positive, moderate (p from 0.635 to 0.681) and high (p from 0.859 to 0.870), and weak (positive e negative) to SCIV. These results differ from those obtained in voluntary contraction or artificially evoked by functional electrical stimulation and may be relevant in applications with closed loop control systems. PMID- 22256011 TI - Online feedback control of functional electrical stimulation using dorsal root ganglia recordings. AB - In neuroprostheses that use functional electrical stimulation (FES) to restore motor function, closed-loop feedback control may compensate for muscle fatigue, perturbations and nonlinearities in the behavior of the effected muscles. Kinematic state information is naturally represented in the firing rates of primary afferent neurons, which may be recorded with multi-electrode arrays at the level of the dorsal root ganglia (DRG). Previous work in cats has shown that it is feasible to estimate the kinematic state of the hind limb with a multivariate linear regression model of the neural activity in the DRG. In this study we extend these results to estimate the limb state in real-time during intramuscular stimulation in an anesthetized cat. Furthermore, we used the limb state estimates as feedback to a finite state FES controller to generate rudimentary walking behavior. This work demonstrates the feasibility of using DRG activity in a closed-loop FES system. PMID- 22256012 TI - Development of a Bayesian recursive algorithm to find free-spaces for an intelligent wheelchair. AB - This paper introduces a new shared control strategy for an intelligent wheelchair using a Bayesian recursive algorithm. Using the local environment information gathered by a laser range finder sensor and commands acquired through a user interface, a Bayesian recursive algorithm has been developed to find the most appropriate free-space, which corresponds to the highest posterior probability value. Then, an autonomous navigation algorithm will assist to manoeuvre the wheelchair in the chosen free-space. Experiment results demonstrate that the new method provides excellent performance with great flexibility and fast response. PMID- 22256013 TI - Classification of EMG signals using artificial neural networks for virtual hand prosthesis control. AB - Computer-based training systems have been widely studied in the field of human rehabilitation. In health applications, Virtual Reality presents itself as an appropriate tool to simulate training environments without exposing the patients to risks. In particular, virtual prosthetic devices have been used to reduce the great mental effort needed by patients fitted with myoelectric prosthesis, during the training stage. In this paper, the application of Virtual Reality in a hand prosthesis training system is presented. To achieve this, the possibility of exploring Neural Networks in a real-time classification system is discussed. The classification technique used in this work resulted in a 95% success rate when discriminating 4 different hand movements. PMID- 22256014 TI - Pneumatic robotic device for early delivering of rehabilitation therapy. AB - This paper describes a new pneumatic rehabilitation robot for upper limbs to deliver Proprioceptive Neuro-muscular Facilitation (PNF) therapies to the acute post-stroke patients, even if they are still in supine position. The robotic device assists the therapist in repetitive PNF therapies, learning the defined movement by therapist at the same time that the patient, and then repeating it with different level of assistance. Moreover, the rehabilitation device was designed to be used for relearning daily living skills like: take a glass, drinking, etc. The proposed solution is composed by two robotic arms actuated by pneumatic swivel modules and a virtual environment for the motivation of the patient. PMID- 22256015 TI - Visuomotor discordance in virtual reality: effects on online motor control. AB - Virtual reality (VR) applications are rapidly permeating fields such as medicine, rehabilitation, research, and military training. However, VR-induced effects on human performance remain poorly understood, particularly in relation to fine grained motor control of the hand and fingers. We designed a novel virtual reality environment suitable for hand-finger interactions and examined the ability to use visual feedback manipulations in VR to affect online motor performance. Ten healthy subjects performed a simple finger flexion movement toward a kinesthetically-defined 45 degrees target angle while receiving one of three types of VR-based visual feedback in real-time: veridical (in which the virtual hand motion corresponded to subjects' actual motion), or scaled-down / scaled-up feedback (in which virtual finger motion was scaled by 25% / 175% relative to actual motion). Scaled down-and scaled-up feedback led to significant online modifications (increases and decreases, respectively) in angular excursion, despite explicit instructions for subjects to maintain constant movements across conditions. The latency of these modifications was similar across conditions. These findings demonstrate that a VR-based platform may be a robust medium for presenting visuomotor discordances to engender a sense of ownership and drive sensorimotor adaptation for (retraining motor skills. This may prove to be particularly important for retraining motor skills in patients with neurologically-based movement disorders. PMID- 22256016 TI - Planar saline bath phantom of the Rush head model. AB - The Rush head model is an approximation of the volume conducting properties of the human head. A planar saline bath phantom was developed to simulate the key properties of the Rush head model while creating a testing platform for implantable neural devices. The phantom closely mimics electrical properties of human tissue such as increased resistivity through the skull region and current flow that wraps around the head. Preliminary testing shows good agreement of the saline bath phantom to predictions from a computer model. PMID- 22256017 TI - A mathematical model to explore the interdependence between the serotonin and orexin/hypocretin systems. AB - Among their multitude of physiological and behavioral effects, the neurochemicals serotonin (5-HT) and orexin (Ox) have been closely linked to major depressive disorders (MDD) and sleep alterations. The dorsal raphe nucleus (DRN) and the lateral hypothalamus area (LHA) are brain regions that are sources of 5-HT and Ox, and there is evidence that suggests a reciprocal interaction between them. This lends support to the hypothesis of a close relationship between MDD and sleep disorders. Based on various experimental data, and appropriate assumptions, we construct a mathematical model of the coupled DRN-LHA neural circuit. Our model relates the dynamics of four important variables that can be experimentally measured: (i) the firing rate of 5-HT-containing neurons in DRN, (ii) the firing rate of Ox-containing neurons in the LHA, (iii) 5-HT concentration level in LHA, and (iv) Ox concentration level in DRN. Simulations show that our model supports the co-existence of baseline activities and concentration levels as observed in various separate experiments. It also allows circuit-level exploration of various parameters not yet identified experimentally, e.g. the rise and decay of Ox concentration levels due to Ox neural activity, and the exact dependence of Ox neural activity on 5-HT level. Finally we have made some model predictions regarding the effects of the 5-HT antagonist on the circuit. Our model, which can be subjected to verification and refinement as new experimental data accumulates, provides unified quantitative relationships and predictions between two important connected brain regions strongly tied to MDD and sleep disorders. PMID- 22256018 TI - Iono-neuromorphic implementation of spike-timing-dependent synaptic plasticity. AB - Spike-timing-dependent plasticity (STDP) is the ability of a synapse to increase or decrease its efficacy in response to specific temporal pairing of pre- and post-synaptic activities. It is widely believed that such activity-dependent long term changes in synaptic connection strength underlie the brain's capacity of learning and memory. However, current phenomenological models of STDP fail to reproduce classical forms of synaptic plasticity that are based on stimulus frequency (BCM rule) instead of timing (STDP rule). In this paper, we implemented a novel biophysical synaptic plasticity model by using analog VLSI (aVLSI) circuits biased in the subthreshold regime. We show that the aVLSI synapse model successfully emulates both the STDP and BCM forms of synaptic plasticity as predicted by the biophysical model. PMID- 22256019 TI - Information transfer between neurons in the motor cortex triggered by visual cues. AB - It was previously shown that beta oscillations of local field potentials in the arm area of the primary motor cortex (MI) of nonhuman primates propagate as travelling waves across MI of monkeys during movement preparation and execution and are believed to subserve cortical information transfer. To investigate the information transfer and its change over time at the single-cell level, we analyzed simultaneously recorded multiple MI neural spike trains of a monkey using a Granger causality measure for point process models before and after visual cues instructing the onset of reaching movements. In this analysis, we found that more pairs of neurons showed information transfer between them after appearances of upcoming movement targets than before, and the directions of the information transfer across neurons in MI were coincident with the directions of the propagating waves. These results suggest that the neuron pairs identified in the current study are the candidates of neurons that travel with spatiotemporal dynamics of beta oscillations in the MI. PMID- 22256020 TI - A hardware-based computational platform for Generalized Laguerre-Volterra MIMO model for neural activities. AB - A parallelized and pipelined architecture based on FPGA and a higher-level Self Reconfiguration Platform are proposed in this paper to model Generalized Laguerre Volterra MIMO system essential in identifying the time-varying neural dynamics underlying spike activities. Our proposed design is based on the Xilinx Virtex-6 FPGA platform and the processing core can produce data samples at a speed of 1.33 * 10(6)/s, which is 3.1 * 10(3) times faster than the corresponding C model running on an Intel i7-860 Quad Core Processor. The ongoing work of the construction of the advanced Self Reconfiguration Platform is presented and initial test results are provided. PMID- 22256021 TI - A mechanism to explain zero-delay bilateral seizure synchronization. AB - Synchronization in bilateral CA3 regions via fimbria-fornix-hippocampal commissures system (FFHC) in rodent hippocampus has revealed that bilateral seizures can sometimes be synchronized with very small delays (< 1 ms). This observed small time delay at the start of afterdischarges between the left and right CA3 regions is unexpected given the propagation time across the hemispheres (> 6 ms). The possibility of a common source was first eliminated by in-vitro brain slices experiments. We then tested the hypothesis that, in the presence of noise, synchronization can take place before the seizure activity is sufficient large to be detected generating an apparent zero-delay between the two sides. This hypothesis was tested with computer simulation with a network of interconnected hippocampal neurons. These results provide an explanation for this aberrant simultaneous seizure detection and indicate the importance of noise in the interpretation of the timing of neuronal events. PMID- 22256022 TI - Addition of deep brain stimulation signal to a local field potential driven Izhikevich model masks the pathological firing pattern of an STN neuron. AB - The crucial engagement of the subthalamic nucleus (STN) with the neurosurgical procedure of deep brain stimulation (DBS) that alleviates medically intractable Parkinsonian tremor augments the need to refine our current understanding of STN. To enhance the efficacy of DBS as a result of precise targeting, STN boundaries are accurately mapped using extracellular microelectrode recordings (MERs). We utilized the intranuclear MER to acquire the local field potential (LFP) and drive an Izhikevich model of an STN neuron. Using the model as the test bed for clinically acquired data, we demonstrated that stimulation of the STN neuron produces excitatory responses that tonically increase its average firing rate and alter the pattern of its neuronal activity. We also found that the spiking rhythm increases linearly with the increase of amplitude, frequency, and duration of the DBS pulse, inside the clinical range. Our results are in agreement with the current hypothesis that DBS increases the firing rate of STN and masks its pathological bursting firing pattern. PMID- 22256023 TI - Implantable neural spike detection using lifting-based stationary wavelet transform. AB - Spike detection from high data rate neural recordings is desired to ease the bandwidth bottleneck of bio-telemetry. An appropriate spike detection method should be able to detect spikes under low signal-to-noise ratio (SNR) while meeting the power and area constraints of implantation. This paper introduces a spike detection system utilizing lifting-based stationary wavelet transform (SWT) that decomposes neural signals into 2 levels using 'symmlet2' wavelet basis. This approach enables accurate spike detection down to an SNR of only 2. The lifting based SWT architecture permits a hardware implementation consuming only 6.6 MUW power and 0.07 mm(2) area for 32 channels with 3.2 MHz master clock. PMID- 22256024 TI - Real-time neuronal networks reconstruction using hierarchical systolic arrays. AB - The correlation network of neurons emerges as an important mathematical framework for a spectrum of applications including neural modeling, brain disease prediction and brain-machine interface. However, construction of correlation network is computationally expensive, especially when the number of neurons is large and this prohibits realtime applications. This paper proposes a hardware architecture using hierarchical systolic arrays to reconstruct the correlation network. Through mapping an efficient algorithm for cross-correlation onto a massively parallel structure, the hardware can accomplish the network construction with extremely small delay. The proposed structure is evaluated using Field Programmable Gate Array (FPGA). Results show that our method is three orders of magnitudes faster than the software approach using desktop computer. This new method enables real-time network construction and leads to future novel devices of realtime neuronal network monitoring and rehabilitation. PMID- 22256025 TI - LivBioSig: development of a toolbox for online bio-signals processing and experimentation. AB - Various research fields, such as brain computer interface, requires online acquisition and analysis of biological data to validate assumptions or to help obtaining insights into the physiological processes of the human body. In this paper we introduce the LivBioSig toolbox for online bio-signals processing and experimentation. This open source and modularized MATLAB toolbox allows performing various experiment paradigms involving online signal processing. These currently include synchronous and asynchronous BCI experiments, and event related stimulation experiments. The use of Graphic User Interfaces (GUI) makes the system suitable even for beginner Matlab users, and the experiments easily configurable. The modularized structure allows advanced users to develop the toolbox further to adapt it to the needs of the research fields. PMID- 22256026 TI - A data-driven process for the development of an eyes-closed EEG normative database. AB - A normative database constitutes a representative sample of a neurologically and clinically healthy population. The practical utility of a normative EEG database is to evaluate the clinical status of a subject whose EEG patterns statistically diverge from average population patterns. These normative data are daily used in clinical practice and in the evaluation of therapeutical interventions. The main obstacle of all normative databases developed to date is inter-individual variability. Such difficulty has been addressed by stratifying the population by age and then using regression in the EEG groups to bound variability, which is always an approximation. This paper describes the first data-driven EEG normative database that explicitly deals with EEG variability by stratifying the population based on their EEG patterns. The database has been constructed for 84 subjects in eyes-closed condition and has been validated by cross validation, leading to a global specificity of 100%. PMID- 22256027 TI - Afferent and efferent activity control in the design of brain computer interfaces for motor rehabilitation. AB - Stroke is a cardiovascular accident within the brain resulting in motor and sensory impairment in most of the survivors. A stroke can produce complete paralysis of the limb although sensory abilities are normally preserved. Functional electrical stimulation (FES), robotics and brain computer interfaces (BCIs) have been used to induce motor rehabilitation. In this work we measured the brain activity of healthy volunteers using electroencephalography (EEG) during FES, passive movements, active movements, motor imagery of the hand and resting to compare afferent and efferent brain signals produced during these motor related activities and to define possible features for an online FES-BCI. In the conditions in which the hand was moved we limited the movement range in order to control the afferent flow. Although we observed that there is a subject dependent frequency and spatial distribution of efferent and afferent signals, common patterns between conditions and subjects were present mainly in the low beta frequency range. When averaging all the subjects together the most significant frequency bin comparing each condition versus rest was exactly the same for all conditions but motor imagery. These results suggest that to implement an on-line FES-BCI, afferent brain signals resulting from FES have to be filtered and time-frequency-spatial features need to be used. PMID- 22256028 TI - Independent component analysis as a preprocessing step for data compression of neonatal EEG. AB - We propose a novel approach for compressive sampling of the neonatal electro encefalogram (EEG) data. The method assumes that the set of EEG data is generated by linearly mixing a fewer number of source signals. Another assumption is that the sources are nearly-sparse in Gabor dictionary. The presented method, instead of compressing original EEG channels, first performs a data-reduction, and then compresses the obtained sources. With this approach we showed that the gain in reconstruction speed is 33%-50%, whereas the compression rate is enhanced by 33%. PMID- 22256029 TI - Detection and classification of multiple finger movements using a chronically implanted Utah Electrode Array. AB - The ability to detect and classify individual and combined finger movements from neural data is rapidly advancing. The work that has been done has demonstrated the feasibility of decoding finger movements from acutely recorded neurons. There is a need for a recording model that meets the chronic requirements of a neuroprosthetic application and to address this need we have developed an algorithm that can detect and classify individual and combined finger movements using neuronal data acquired from a chronically implanted Utah Electrode Array (UEA). The algorithm utilized the firing rates of individual neurons and performed with an average sensitivity and an average specificity that were both greater than 92% across all movement types. These results lend further support that a chronically implanted UEA is suitable for acquiring and decoding neuronal data and also demonstrate a decoding method that can detect and classify finger movements without any a priori knowledge of the data, task, or behavior. PMID- 22256030 TI - Assessing directed information as a method for inferring functional connectivity in neural ensembles. AB - Neurons in the brain form complicated networks through synaptic connections. Traditionally, functional connectivity between neurons has been analyzed using simple metrics such as correlation, which do not provide direction of influence. Recently, an information theoretic measure known as directed information has been proposed as a way to capture directionality in the relationship, thereby moving towards a model of effective connectivity. This measure is grounded upon the concept of Granger causality and can be estimated by modeling neural spike trains as point process generalized linear models. However, the added benefit of using directed information to infer connectivity over conventional methods such as correlation is still unclear. Here, we propose a novel estimation procedure for the directed information. Using physiologically realistic simulations, we demonstrate that directed information can outperform correlation in determining connections between neural spike trains while also providing directionality of the relationship, which cannot be assessed using correlation. PMID- 22256031 TI - Stochastic resonance with a mixture of sub-and supra-threshold stimuli in a population of neuron models. AB - This paper presents a novel type of stochastic resonance (SR) with a mixture of sub- and supra-threshold stimuli in a population of neuron models beyond regular SR and Supra-threshold SR (SSR) phenomena. We investigate through computer simulations if the novel type of SR can be observed or not, using the mutual information (MI) estimated from a population of neural spike trains as an index of information transmission. Computer simulations showed that the MI had a typical type of SR curves, even when the balance between sub-and supra-threshold stimuli was varied, suggesting the novel type of SR. Moreover, the peak of MI increased as the balance of supra-threshold stimuli got stronger, i.e., as the situation was getting close to the SSR from the regular SR. This finding could accelerate our understanding about how fluctuations play a role in processing information carried by a mixture of sub-and supra-threshold stimuli. PMID- 22256032 TI - Fully-automated test of upper-extremity function. AB - With the advent of new approaches to upper extremity recovery after stroke and spinal cord injury, the quantitative evaluation of hand function has become a crucial component of outcome evaluation. Recently we developed a workstation, the ReJoyce (Rehabilitation Joystick for Computer Exercise) on which subjects perform a variety of movement tasks while playing computer games. An important feature of the system is the ReJoyce Automated Hand Function Test (RAHFT). In this study we compared and validated the RAHFT against two widely-used clinical tests, the Action Research Arm Test (ARAT) [1][2] and the Fugl-Meyer Assessment (FMA) [3]. All three tests were performed in 34 separate sessions in 13 tetraplegic individuals. Principal component and regression analyses revealed that both the ARAT and the RAHFT correlated well with the first principle component fitted to the scores of the three tests. The FMA was less well correlated. These data help validate the RAHFT as a quantitative, automated alternative to the ARAT and FMA. The RAHFT is the first comprehensive test of hand function that does not depend on human judgment. PMID- 22256033 TI - Mobility profile and wheelchair driving skills of powered wheelchair users: sensor-based event recognition using a support vector machine classifier. AB - This paper presents a method to automatically recognize events and driving activities during the use of a powered wheelchair (PW). The method uses a support vector machine classifier, trained from sensor-based data from a datalogging platform installed on the PW. Data from a 3D accelerometer positioned on the back of the PW were collected in a laboratory space during PW driving tasks. 16 segmented events and driving activities (i.e. impacts from different side on different objects, rolling down or up on incline surface, going across threshold of different height) were performed repeatedly (n=25 trials) by one operator at three different speeds (slow, normal, high). We present results from an experiment aiming to classify five different events and driving activities from the sensor data acquired using the datalogging platform. Classification results show the ability of the proposed method to reliably segment 100% of events, and to identify the correct event type in 80% of events. PMID- 22256034 TI - Investigation of sit-to-stand and stand-to-sit in an above knee amputee. AB - The objective of this pilot study is twofold: 1) to extract key factors/features in sit-to-stand and stand-to-sit (STS) performed by an above knee (AK) amputee; 2) to propose a convenient way to quantify symmetry. One male unilateral transfemoral amputee participated in the pilot study. The subject was instructed to rise in a comfortable and natural manner and conduct a series of sit-to-stand, stand-to-sit. We simultaneously measured kinematics, kinetics and muscle activities. Principal component analysis (PCA) was used to reduce the dimension and identify modes and a convenient index of STS symmetry (slope of the major axis of the error ellipse) is proposed using the insole pressure sensors. Based on the preliminary results it is recommended that kinematics and kinetics in both the sagittal and frontal planes be considered for an AK amputee performing STS. The information might be useful for further research on amputee STS. PMID- 22256035 TI - New ergonomic headset for Tongue-Drive System with wireless smartphone interface. AB - Tongue Drive System (TDS) is a wireless tongue-operated assistive technology (AT), developed for people with severe physical disabilities to control their environment using their tongue motion. We have developed a new ergonomic headset for the TDS with a user-friendly smartphone interface, through which users will be able to wirelessly control various devices, access computers, and drive wheelchairs. This headset design is expected to act as a flexible and multifunctional communication interface for the TDS and improve its usability, accessibility, aesthetics, and convenience for the end users. PMID- 22256036 TI - Regression equations for RT3 activity monitors to estimate energy expenditure in manual wheelchair users. AB - Activity monitors (AMs) can assist persons with Spinal Cord Injury (SCI) who use manual wheelchairs to self-assess regular physical activity to move towards healthier lifestyles. In this study we evaluated the validity of an accelerometer based RT3 AM in predicting energy expenditure (EE) of manual wheelchair users with SCI. Twenty-four subjects performed four types of physical activities including wheelchair propulsion, arm-ergometry exercise, deskwork, and resting in a laboratory setting. Subjects wore two RT3 AMs: an RT3 around the waist (RT3W) per the manufacturer's instruction and an RT3 on the upper arm (RT3A). Criterion EE was collected by a portable metabolic system. The absolute EE estimation error for the RT3W varied from 21.3%-55.2% for different activities. Two EE prediction equations (general and activity-specific) were developed from 19 randomly selected subjects and validated on the remaining 4 subjects for the RT3A, RT3W, and RT3 AMs combined. The results showed that the general and activity-specific regression equations for the RT3A performed better than the RT3W and similar to the RT3 AMs combined. The general EE equation for RT3A consisted of both the demographic variable weight and accelerometer variables showing it is sensitive to subject parameters and upper extremity movement. The activity-specific EE equations for RT3A showed demographic variable weight to be a significant predictor during resting and deskwork and accelerometer variables along with weight to be significant predictors during propulsion and arm-ergometry. The validation results from the activity-specific equations for the RT3A showed that the absolute EE estimation error varied from 12.2%-38.1%. Future work will recruit more subjects and refine the prediction equations for the RT3 AM to quantify physical activity in MWUs with SCI. PMID- 22256037 TI - Control of reaching finger movement accompanied with inhibitory intention. AB - In the present study, we investigated the motor control of reaching finger movement interfered by the inhibitory intention triggered by the stop-signal. In the experiment, the subject started the reaching movement of the index finger with the go-signal of a green LED and stopped the ongoing movement with the stop signal of a red LED. The stop-signal delay (SSD) was set at 0, 100, 200, 300 and 400 ms. The movement trajectory was measured during the task. The index finger was able to stop prior to the target point when SSD was less than 400 ms, whereas not when SSD was 400 ms. We also measured electroencephalogram (EEG) during the task. A negative peak around the stop-signal response time (SSRT) and a positive peak around 400-600 ms of the event-related potentials (ERPs) were observed at Fz and Cz. These results indicate that these components of the ERPs were associated with the stop-signal task in the human reaching movement. PMID- 22256038 TI - Visual and proprioceptive contributions to compensatory and pursuit tracking movements in humans. AB - An ongoing debate in the field of motor control considers how the brain uses sensory information to guide the formation of motor commands to regulate movement accuracy. Recent research has shown that the brain may use visual and proprioceptive information differently for stabilization of limb posture (compensatory movements) and for controlling goal-directed limb trajectory (pursuit movements). Using a series of five experiments and linear systems identification techniques, we modeled and estimated the sensorimotor control parameters that characterize the human motor response to kinematic performance errors during continuous compensatory and pursuit tracking tasks. Our findings further support the idea that pursuit and compensatory movements of the limbs are differentially controlled. PMID- 22256039 TI - Evidence of rapid gender processing revealed by ERSP. AB - In this research, we used EEG signals to analyze gender processing with the ERSP method. Not only facial images, but also images of clothing and shoes, were used. We applied the ICA method to obtain a gender-related component which appeared quite significant in the majority of electrode sites for the occipital lobe. This showed differences of energy between the two genders, even for the clothing and shoe images. Our results indicate that not only facial gender processing, but also a gender discrimination task for objects influences the energy of EEGs from 50 ms after the onset of stimuli at all frequencies, especially lower band. This provides convincing evidence for rapidity of gender processing. PMID- 22256040 TI - Evaluation system for minor nervous dysfunction by pronation and supination of forearm using wireless acceleration and angular velocity sensors. AB - We developed a simple, portable and easy system to the motion of pronation and supination of the forearm. This motion was measured by wireless acceleration and angular velocity sensor. The aim of this system is evaluation of minor nervous dysfunction. It is for the screening of the developmental disorder child. In this study, in order to confirm the effectiveness of this system, the reference curve of the neuromotor development was experimentally obtained. We studied 212 participants (108 males, 104 females) aged 7 to 12 years attending the kindergarten school. We could obtain the reference curve of the neuromotor development using this system. We also investigated the difference of neuromotor function between normally developed children and a ADHD child. There is a possibility that abnormality of the minor nervous dysfunction can be detected by using this system. PMID- 22256041 TI - Evaluation of a synergistic handheld instrument for resternotomy controlled by an integrated optical sensor. AB - Re-Sternotomy is an important part of many interventions in cardiac or thoracic surgery. It is performed close to critical structures such as the ascending aorta or the heart with an inherent high risk of serious damage. In this paper, a system for improving the safety of this surgical procedure is presented. A soft tissue preserving saw is combined with automatic depth regulation. The depth is controlled on the basis of the optical characteristics (visible light) of the tissue aligned to the saw blade, which is analyzed using a color sensor. Detection of the blades' position in the bone during the cutting process is possible through the integration of an optical fiber into the tip of the saw blade. The automatic depth control is realized using a hysteresis controller running on a real time system. To show the feasibility of this approach, the sensor technology was integrated into a prototypal sternal saw and evaluated on artificial bone. As part of the experiments the influence of water for cooling and dust particles from the process on the systems control stability were analyzed. The system performed stable and accurate. Future research will focus on the control algorithm and cadaver trials. PMID- 22256042 TI - Towards a micropositioning system for targeted drug delivery in wireless capsule endoscopy. AB - This paper describes a novel micropositioning mechanism for achieving 1 ml of targeted drug delivery within wireless capsule endoscopes. The mechanism allows a needle to be positioned within a 22.5 degrees segment of a cylindrical capsule and be extendible by up to 4mm. The mechanism achieves both these functions using only a single micromotor and occupying a volume of just 200 mm(3) (including micromotor), this represents only 6.6% of the total available space. Through a detailed stress analysis it has been shown that the proposed mechanism can be fabricated using FDA approved materials and requires a power budget of under 3.3% of the available capacity. It is envisaged this mechanism would empower a new breed of capsule microrobots for therapy in addition to diagnostics for pathologies such as ulcerative colitis and small intestinal Crohn's disease. PMID- 22256043 TI - Comparative evaluation of user interfaces for robot-assisted laser phonomicrosurgery. AB - This research investigates the impact of three different control devices and two visualization methods on the precision, safety and ergonomics of a new medical robotic system prototype for assistive laser phonomicrosurgery. This system allows the user to remotely control the surgical laser beam using either a flight simulator type joystick, a joypad, or a pen display system in order to improve the traditional surgical setup composed by a mechanical micromanipulator coupled with a surgical microscope. The experimental setup and protocol followed to obtain quantitative performance data from the control devices tested are fully described here. This includes sets of path following evaluation experiments conducted with ten subjects with different skills, for a total of 700 trials. The data analysis method and experimental results are also presented, demonstrating an average 45% error reduction when using the joypad and up to 60% error reduction when using the pen display system versus the standard phonomicrosurgery setup. These results demonstrate the new system can provide important improvements in terms of surgical precision, ergonomics and safety. In addition, the evaluation method presented here is shown to support an objective selection of control devices for this application. PMID- 22256044 TI - Robotic endoscope motor module and gearing design. AB - Actuation of a robotic endoscope with increased torque output is presented. This paper will specifically focus on the motor module section of a robotic endoscope, which comprises of a pair of motors and gear reduction assemblies. The results for the endoscope and biopsy tool stiffness, as well as the stall force and force versus speed characteristics of the motor module assembly are shown. The scope stiffness was found to be 0.006 N/degree and additional stiffness of the biopsy tools were found to be in the range of 0.09 to 0.13 N/degree. Calculations for worm gearing and efficiency are discussed. PMID- 22256045 TI - A fuzzy-based shared controller for brain-actuated simulated robotic system. AB - The primary problems of brain-computer interface (BCI) are the low channel capacity and high error rate. Therefore, an assistive motion control method is important for the brain-actuated robot to realize real-time and reliable control. To make the brain-actuated robot respond to the external environments with more flexibility, a shared control method based on fuzzy logic is proposed. Experimental results obtained with ten healthy voluntary subjects show that the proposed fuzzy-based shared controller has improved performance compared with direct control approach. PMID- 22256046 TI - Analysis of foot pressure distribution data for the evaluation of foot arch type. AB - In order to develop an evaluation system for foot arch type in the elderly using foot pressure distribution data, foot pressure distribution parameters were selected and the data thereby derived were discussed. Results from the study show that the midfoot area and pressure ratios were correlated to foot arch type determined by visual analysis and were not correlated to arch height parameters. It is assumed that foot pressure distribution parameters reflect a different phenomenon from that of arch height parameters. The inconsistency between them is considered to be a result of the effect of the forefoot arch on the arch height parameters. PMID- 22256047 TI - Palpation nonlinear reaction force analysis for characterization of breast tissues. AB - This paper addresses a diagnostic palpation system based on the measurement of nonlinear elasticity. An indentation probe is used to press against breast tissue. Then, the measured reaction force is used to estimate the parameters of nonlinear elasticity, which enables the identification of tissue type, such as fat, muscle, mammary gland or tumor. Here, we present the basic concept of our study and preliminary experimental and simulation results from pilot studies. More specifically, we measured the nonlinear response of reaction force using the breast of a goat. In addition, we also simulated the reaction force using nonlinear biomechanical simulation with several tissue types. Large differences in reaction force occur only in the nonlinear range in both experimental and simulation situations. Our results confirmed the feasibility of our concept. PMID- 22256048 TI - Validation of a software program for measuring fatigue-related changes in keystroke durations. AB - Intensive computer use has been associated with musculoskeletal disorders (MSDs). Although the underlying mechanisms are still not fully understood, muscle fatigue is thought to be a contributing factor. Previous studies have shown that keystroke durations are related to muscle twitch durations and may be used as a surrogate measure of muscle fatigue. Software tools have been developed to measure keystroke durations; however, the accuracy of these programs may be influenced by the computer and/or the operating system (OS). Keystrokes were collected from six subjects and analyzed to determine whether there were any differences in keystroke durations measured by an OS-dependant software program and keystrokes collected directly from the keyboard using a USB analyzer (gold standard). The results demonstrated that the OS-dependant software program underestimated keystroke durations by 3.8 ms (103.5 vs. 107.3 ms; p < 0.0001) but keystroke durations at the individual level were highly correlated between the two systems (R(2) = 0.997). Despite the small differences, the high correlation between systems indicated that the software program could be used to collect keystroke durations. PMID- 22256049 TI - Physical human interaction for an inflatable manipulator. AB - There is a growing need for robots that can function in close proximity to human beings and also physically interact with them safely. We believe inherent safety is extremely important for robots in human environments. Towards this end, we are exploring the use of inflatable structures for manipulators instead of traditional rigid structures, to improve safety in physical human robot interaction (pHRI). This paper develops a contact detection and reaction scheme for an inflatable manipulator prototype. The resulting scheme is used for physical interaction tasks with humans. Experiments verifying the efficacy of the contact detection scheme are shown using two interaction scenarios. PMID- 22256050 TI - Evaluation and comparison of the nonlinear elastic properties of the soft tissues of the breast. AB - As the number of breast cancer patients increases, there is an increasing need for accurate non-invasive methods for the diagnosis of breast cancer. It is possible that the nonlinear elastic properties of soft tissues of the breast can be used as a basis for diagnostic methods. Therefore, we have proposed a robotic palpation system for diagnosis based on the nonlinear elastic properties of tissue. Here, we measured the nonlinear elastic properties of soft tissues of the breast using creep tests and three parameters of the nonlinear elastic model were acquired. Two of these parameters are significantly different among soft tissues of the breast and that the magnitude of these parameters was determined by the tissue structure. These parameters could be used to differentiate between tissue types and aid in the diagnosis of breast cancer. PMID- 22256051 TI - Cortical response to psycho-physiological changes in auto-adaptive robot assisted gait training. AB - Robot-assisted treadmill training improves motor function and walking ability in neurologically impaired patients. However, despite attention having been shown to play a role in training success, psychological responsiveness to task difficulty and motivational levels at task onset have not been measured. Seven healthy subjects participated in a robot-assist treadmill training task. Subjects engaged in a virtual task with varying difficulty levels that was shown to induce a feeling of being bored, excited and over-stressed. The participants' mental engagement was measured using the ECG-based heart rate variability in real time, during gait training as a proxy for EEG and psychological test batteries. Heart rate variability (HRV), which has been shown to reflect cortical engagement for both cognitive and physical tasks, was measured using nonlinear measures obtained from the Poincare plot. We show that the cortical response to the task measured with HRV varies in relation to the level of mental engagement in response to the difficulty level of the virtual task. From these results we propose that nonlinear measures quantify cortical response / motivational level to robot assist motor learning tasks and that the adaptation to the task is dependent on the level of motivation. PMID- 22256052 TI - An automatic control model for rat-robot. AB - In this paper, a control model is developed to automate the process of navigation in rat-robot-a new type of bio-robot based on BCI(Brain-Computer Interface) technique. Because of the particular difficulties in rat-robot control, we design a novel control model to 'learn' and 'imitate' the control behavior of human guidance. General Regression Neural Network (GRNN) model is used to analyze the control commands made by human operators, with the locomotion information of rat robot recorded and analyzed in a video-based experimental system. The results of the control model shows that the human control process could be well understood and predicted, and expected to generate control commands automatically in future real-time rat-robot navigation experiments. PMID- 22256053 TI - Estimation of direction of attention using EEG and out-of-head sound localization. AB - Brain-Machine Interfaces (BMIs) are being researched controlling external devices such as robots and computers by measuring the cranial nerve activity of the operator. The brain activities evoked by visual stimuli have been studied intensively. However, few studies have considered a BMI that uses the brain activities evoked by auditory stimuli. This study investigated whether a person's direction of attention can be estimated using an event-related potential (ERP) generated by selective attention to an auditory stimulus. An auditory stimulus and an out-of-head sound localization system that can create an audio image outside the head that is presented through an earphone were used instead of a loudspeaker system. This system was experimentally evaluated by presenting the subject auditory cues from one of six directions while the subject directed his attention in one direction. An EEG response similar to an ERP was observed. The direction of attention was estimated using support vector machine with an accuracy of 89.2[%] on average for the three subjects. This suggests that a BMI system based on the estimated direction of attention can be developed by using out-of-head sound localization. PMID- 22256054 TI - A hybrid brain interface for a humanoid robot assistant. AB - We present an advanced approach towards a semi-autonomous, robotic personal assistant for handicapped people. We developed a multi-functional hybrid brain robot interface that provides a communication channel between humans and a state of-the-art humanoid robot, Honda's Humanoid Research Robot. Using cortical signals, recorded, processed and translated by an EEG-based brain-machine interface (BMI), human-robot interaction functions independently of users' motor control deficits. By exploiting two distinct cortical activity patterns, P300 and event-related desynchronization (ERD), the interface provides different dimensions for robot control. An empirical study demonstrated the functionality of the BMI guided humanoid robot. All participants could successfully control the robot that accomplished a shopping task. PMID- 22256055 TI - Temporal representation of arm force direction using fNIRS signals. AB - We investigated the possibility of creating a temporal representation of brain activity from fNIRS signals. In an experiment, subjects performed isometric arm movements in four directions, and fNIRS signals were measured over the primary motor area in the left hemisphere of their brain. We estimated the direction of the arm force from the fNIRS signals by using two classifiers: sparse linear regression (SLR) and support vector machine(SVM). Classification accuracy was approximately 70% with SLR. The temporal distribution of the features selected with SLR was the same as those selected with SVM. The results indicated that the fNIRS signals possibly included information about arm force direction in 4-6 [s] after stimulus onset and offset. PMID- 22256056 TI - EEG correlates of submovements. AB - Numerous studies on motor control in humans and primates have suggested that the Central Nervous System (CNS) generates and controls continuous movement via discrete, elementary units of movement or submovements. While most studies are based on analysis of kinematic data, investigations of neural correlates have been lacking. To fill this gap we recorded and analyzed kinematic and high density electroencephalographic (64-channel EEG) data from three right-handed normal adults during a reaching task that required online movement corrections. Each kinematic submovement was accompanied by stereotyped scalp maps. Furthermore, the peaks of event-related potentials (ERP) recorded at electrode C1 (over contralateral motor cortex) were time-locked to kinematic submovement peaks. These results provide further evidence for the hypothesis that the CNS generates and controls continuous movement via discrete submovements. Applications include design of quantitative outcome metrics for motor disorders of neurological origin such as stroke and Parkinson's disease. PMID- 22256057 TI - Strength evaluation of a variable diameter acetabular trial implant under realistic loading conditions. AB - A variable diameter acetabular trial implant (VDATI) was designed to reduce the costs related to cleaning, sterilisation and storage of surgical instruments used for total hip arthroplasty. The purpose of this study was to evaluate the mechanical strength of a functional prototype of the VDATI. Experimental testing was performed to identify if the VDATI can resist loading conditions similar to the ones occurring during the surgical procedure and to validate a finite element model (FEM) of the VDATI. The results highlighted the potential of the current concept of the VDATI and demonstrated the relevance to continue its development. PMID- 22256058 TI - Blood flow measurement algorithms to detect bleeding source noninvasively. AB - The purpose of this paper is to propose ultrasound visual servoing algorithms for controlling a robotic system equipped with an ultrasound probe for large pulsation and a displacement towards the out-of-plane of a US image. In this study, we aim to develop a robotic system for detecting bleeding source based on the blood flow measured by using a non-invasive modality like an ultrasound (US) imaging device. Some problems related to the measurement error still need to be addressed. As the first step in solving these problems, we focused on the large pulse amplitude and displacement of the artery towards the out-of-plane of a US image, and developed US visual servoing algorithms to control the probe. We conducted preliminary blood flow measurement experiments using an phantom containing artery model and a manipulator equipped with a US probe (BASIS-1). The results present the first experimental validation of the proposed algorithms. PMID- 22256059 TI - Estimation of intraoperative blood flow during liver RF ablation using a finite element method-based biomechanical simulation. AB - Radiofrequency ablation is increasingly being used for liver cancer because it is a minimally invasive treatment method. However, it is difficult for the operators to precisely control the formation of coagulation zones because of the cooling effect of capillary vessels. To overcome this limitation, we have proposed a model-based robotic ablation system using a real-time numerical simulation to analyze temperature distributions in the target organ. This robot can determine the adequate amount of electric power supplied to the organ based on real-time temperature information reflecting the cooling effect provided by the simulator. The objective of this study was to develop a method to estimate the intraoperative rate of blood flow in the target organ to determine temperature distribution. In this paper, we propose a simulation-based method to estimate the rate of blood flow. We also performed an in vitro study to validate the proposed method by estimating the rate of blood flow in a hog liver. The experimental results revealed that the proposed method can be used to estimate the rate of blood flow in an organ. PMID- 22256060 TI - Simulations and experimental demonstration of coupling molecular and macroscopic level modalities with a robotic manipulator. AB - Established and emerging molecular and cellular modalities, such as optical imaging and spectroscopy, offer new opportunities for assessing tissue pathophysiology in situ. A challenge with such applications is their limited tissue penetration and low sensitivity that can be addressed with trans-needle or trans-catheter access. In this work, we describe the use of an actuated manipulator to physically manipulate such sensors to scan an area of interest generating 1-D scans while registering them to a guiding modality. Simulations were performed for a miniature RF coil to determine the voxel size, and experimental studies were conducted using a miniature RF coil manipulated by the MR-compatible device. The experimental results on phantom studies show that potential diagnostic information can be collected by using this methodology. This system was pursued to address a critical limitation of emerging molecular and near-cellular modalities; the limited tissue penetration. PMID- 22256061 TI - Stability of a double inverted pendulum model during human quiet stance with continuous delay feedback control. AB - Recent debate about neural mechanisms for stabilizing human upright quiet stance focuses on whether the active and time delay neural feedback control generating muscle torque is continuous or intermittent. A single inverted pendulum controlled by the active torque actuating the ankle joint has often been used for the debate on the presumption of well-known ankle strategy hypothesis claiming that the upright quiet stance can be stabilized mostly by the ankle torque. However, detailed measurements are showing that the hip joint angle exhibits amount of fluctuations comparable with the ankle joint angle during natural postural sway. Here we analyze a double inverted pendulum model during human quiet stance to demonstrate that the conventional proportional and derivative delay feedback control, i.e., the continuous delay PD control with gains in the physiologically plausible range is far from adequate as the neural mechanism for stabilizing human upright quiet stance. PMID- 22256062 TI - Local analysis of trabecular bone fracture. AB - Assessment of bone fracture risk is the first step in the prevention of traumatic events. In several previous study the use of bone mineral density and bone volume fraction was suggested for the identification of the failure zone, nonetheless the limits of this approach were also investigated, underling the need of other information to fully describe the failure event. In the present study, a comparison between fracture and non-fracture zones of trabecular bone is proposed with the aim of analyze the local structural differences attempting to identify the morphometrical parameters who best can describe the trabecular fracture zone. Eighteen trabecular specimens were extracted from the lower limb of two donors without skeletal disorders. All the specimens were scanned by means of a micro-CT and mechanically tested. After the mechanical compression every specimen was scanned again obtaining for every specimen two datasets: pre- and post-failure. An automatic registration scheme, comprising of a three-dimensional automatic registration method to define the differences between the two datasets, and the application of a criterion for defining "broken" or "unbroken" trabeculae, was applied for the identification of the full 3D fracture zone. The morphometrical analysis of fracture and non-fracture zone was performed by the study of several morphometrical parameters, such as bone volume fraction, off-axis angle, structural model index, connectivity density, etc. The results of the two different structures were compared by means of a Wilcoxon non-parametric test. Ten out of 12 morphometrical parameters were found statistically significantly different between fracture and non-fracture zones, underlining the strong structural difference between the two areas. Nonetheless, only three of them have shown differences superior to 30%, with a reduce overlapping of their distributions: off-axis angle, structural model index and connectivity density. On the other hand, bone volume fraction showed a smaller, even if significant, difference with great overlap of the distributions, in agreement with the limits already pointed out in the literature. PMID- 22256063 TI - Quantifying anti-gravity torques in the design of a powered exoskeleton. AB - Designing an upper extremity exoskeleton for people with arm weakness requires knowledge of the passive and active residual force capabilities of users. This paper experimentally measures the passive gravitational torques of 3 groups of subjects: able-bodied adults, able bodied children, and children with neurological disabilities. The experiment involves moving the arm to various positions in the sagittal plane and measuring the gravitational force at the wrist. This force is then converted to static gravitational torques at the elbow and shoulder. Data are compared between look-up table data based on anthropometry and empirical data. Results show that the look-up torques deviate from experimentally measured torques as the arm reaches up and down. This experiment informs designers of Upper Limb orthoses on the contribution of passive human joint torques. PMID- 22256065 TI - Control of an omnidirectional walking support walker by forearm pressures. AB - We have been developing an omnidirectional walker (ODW) for walking support. In walking support, it is necessary control the ODW following the user's direction and velocity intentions. In this paper, a novel interface is proposed to recognize the user's intentions according to the forearm pressures. The forearm pressures exerted to the ODW by the user with wrists and elbows are measured by 4 force sensors embedded in the ODW's armrest. The relationship between forearm pressure and user intentions was extracted as fuzzy rules and an algorithm was proposed for directional intention identification based on the distance-type fuzzy reasoning method. We conduct a path tracking experiment with the proposed method. The results show that the algorithm is applicable to control the ODW. PMID- 22256064 TI - Design and evaluation of a prosthetic shoulder controller. AB - The first goal of this study was to develop a 2 degree of freedom (DOF) upper limb controller utilizing shoulder elevation/depression and protraction/retraction. Its primary purpose is to control powered prosthetic shoulder joints being incorporated into a new generation of prosthetic arms for shoulder disarticulation and very high transhumeral amputees. More generally, however, such a controller can be applied to simultaneously control any 2 DOF's under a direct, proportional control scheme. There is no generally accepted method to objectively and quantitatively evaluate prosthesis and prosthesis control performance, and the second goal of this study was to develop one based on Fitts Law. The evaluation protocol has quite general applicability as well, and can be used to compare different reaching/ pointing devices, or to compare variations in the design or operation of a particular device. PMID- 22256066 TI - Predicting efficacy of robot-aided rehabilitation in chronic stroke patients using an MRI-compatible robotic device. AB - We are investigating the neural correlates of motor recovery promoted by robot mediated therapy in chronic stroke. This pilot study asked whether efficacy of robot-aided motor rehabilitation in chronic stroke could be predicted by a change in functional connectivity within the sensorimotor network in response to a bout of motor rehabilitation. To address this question, two stroke patients participated in a functional connectivity MRI study pre and post a 12-week robot aided motor rehabilitation program. Functional connectivity was evaluated during three consecutive scans before the rehabilitation program: resting-state; point to-point reaching movements executed by the paretic upper extremity (UE) using a newly developed MRI-compatible sensorized passive manipulandum; resting-state. A single resting-state scan was conducted after the rehabilitation program. Before the program, UE movement reduced functional connectivity between the ipsilesional and contralesional primary motor cortex. Reduced interhemispheric functional connectivity persisted during the second resting-state scan relative to the first and during the resting-state scan after the rehabilitation program. Greater reduction in interhemispheric functional connectivity during the resting-state was associated with greater gains in UE motor function induced by the 12-week robotic therapy program. These findings suggest that greater reduction in interhemispheric functional connectivity in response to a bout of motor rehabilitation may predict greater efficacy of the full rehabilitation program. PMID- 22256067 TI - Feasibility of entrainment with ankle mechanical perturbation to treat locomotor deficit of neurologically impaired patients. AB - Entraining human gait with periodic torque from a robot may provide a novel approach to robot-aided walking therapy that is competent to exploit the natural oscillating dynamics of human walking. To test the feasibility of this strategy we applied a periodic ankle torque to neurologically impaired patients (one with stroke and one with multiple sclerosis). As observed in normal human walking, both patients adapted their gait periods to synchronize with the perturbation by phase-locking the robotic torque at terminal stance phase. In addition, their gait cadence became significantly faster due to the training with clear after effects when the perturbation ceased. These results support a new strategy for walking therapy that exploits an embedded neural oscillator interacting with peripheral mechanics and the resulting natural dynamics of walking, which are essential but hitherto neglected elements of walking therapy. PMID- 22256068 TI - Development of a dynamic model for bevel-tip flexible needle insertion into soft tissues. AB - In this paper, we develop a mechanics-based dynamic model for bevel-tip flexible needle insertion into soft tissues. We use Newton-Euler formulation to account for the effect of actuation, friction, tissue interactions, and bevel-tip forces on the needle. The soft tissue deformation is modeled by finite element analysis, whereas the mechanics-based model is used to predict needle deflections due to bevel-tip asymmetry. The proposed needle-tissue model is then experimentally evaluated by comparing the needle deflections for various insertion depths in a tissue phantom with those achieved from simulations. PMID- 22256069 TI - Develop a wearable ankle robot for in-bed acute stroke rehabilitation. AB - Movement training is important in motor recovery post stroke and early intervention is critical to stroke rehabilitation. However, acute stroke survivors are actively trained with activities helpful for recovery of mobility in only 13% of the time in the acute phase. Considering the first few months post stroke is critical in stroke recovery (neuroplasticity), there is a strong need for movement therapy and manipulate/mobilize the joints. There is a lack of in bed robotic rehabilitation in acute stroke. This study seeks to meet the clinic need and deliver intensive passive and active movement therapy using a wearable robot to enhance motor function in acute stroke. Passively, the wearable robot stretches the joint to its extreme positions safely and forcefully. Actively, movement training is conducted and game playing is used to guide and motivate the patient in movement training. PMID- 22256070 TI - Filtering essential tremor noise on surface EMG based on squared sine wave approximation. AB - Essential Tremor (ET) refers to involuntary movements of a part of the body. ET patients have serious difficulties in performing daily living activities. Our ultimate goal is to develop a system that can enable ET patients to perform daily living activities. We have been developing an exoskeleton robot for ET patients. We make use of the electromyogram (EMG) signal to control this robot. However, the EMG signal of ET patients contains not only signals from voluntary movements but also noise from involuntary tremors. In this paper, we focus on developing a signal processing method to suppress tremor noise present in the surface EMG signal. The proposed filter detected attenuation ratio by the correlation between the last EMG data and one period squared sine wave. The filtered EMG signals indicated that essential tremor noise of the elbow flexed posture while holding a water-filled bottle was suppressed. In addition, voluntary information was less affected by the filter. Welch's t-value test confirmed that ease of extraction of voluntary movement was increased by the proposed filter. PMID- 22256071 TI - Overview of the boston retinal prosthesis: challenges and opportunities to restore useful vision to the blind. AB - A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, and it received both power and data wirelessly from external sources. The prosthesis drove a sub-retinal thin-film array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing the 16-channel stimulator chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by a power amplifier. Power was delivered by a 500 KHz carrier, and data were delivered by frequency shift keying. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. Through an 'outbound' telemetry channel, electrode impedances were monitored by an on-board analog to digital converter that sampled the output voltage waveforms. The final assembly was tested in vitro in physiological saline and in vivo in two mini-pigs for up to three months by measuring stimulus artifacts generated by the implant's current drivers. PMID- 22256072 TI - EMG and acceleration signal analysis for quantifying the effects of medication in Parkinson's disease. AB - Parkinson's disease (PD) is characterized by motor disabilities that can be alleviated reasonably with appropriate medication. However, there is a lack of objective methods for quantifying the efficacy of treatment in PD. We applied here an objective method for quantifying the effects of medication in PD using EMG and acceleration measurements and analysis. In the method, four signal features were calculated from the EMG and acceleration recordings of both sides of the body: the kurtosis and recurrence rate of EMG, and the amplitude and sample entropy of acceleration. Principal component approach was used for reducing the number of variables. EMG and acceleration data measured from nine PD patients were used for analysis. The patients were measured in four different medication conditions: with medication off, and two and three and four hours after taking the medication. The results showed that in eight patients the EMG recordings changed into less spiky and the acceleration recordings into more complex after taking the medication. A reverse phenomenon in the signal characteristics was observed in seven patients 3-4 hours after taking the medication. The results indicate that the presented method is potentially useful for quantifying objectively the effects of medication on the neuromuscular function in PD. PMID- 22256073 TI - A SNR-independent formulation of a double threshold algorithm for the estimation of muscle activation intervals. AB - The aim of this work is to propose an improvement to the double threshold algorithm for muscular activation intervals estimation developed by Bonato and his co-workers. The proposed method has been designed in order to be adaptive also when the Signal to Noise ratio (SNR) of the sEMG signal changes during the trial, by re-evaluating the parameters of the algorithm according to the estimated local SNR and the desired detection and false alarm probabilities. This novel implementation is also suitable for working in pseudo real-time since it can give information on burst estimation shortly after the end of the current muscular activity. The proposed method was tested on simulated signals taking into account changes in the SNR during the trial, and results were compared with those obtained with the classical implementation of the algorithm. PMID- 22256074 TI - Alterations in spike amplitude distribution of the surface electromyogram post stroke. AB - We examined surface electromyogram (EMG) characteristics during voluntary isometric activation of the first dorsal interosseous (FDI) muscle in stroke survivors. Five stroke subjects participated in the study. They were instructed to generate isometric contraction at different force levels. The recording was performed in both paretic and contralateral muscles using a matched force protocol. Comparisons of the spike amplitude distribution of the surface EMG signals were made between paretic and contralateral muscles. For a given contraction level, a widened or narrowed spike amplitude distribution was observed in paretic muscles of stroke subjects. Such differences may be induced by degeneration of some spinal motoneurons and/or disorganization of motor unit control properties after stroke. PMID- 22256075 TI - Detection of tremor bursts from the sEMG signal: an optimization procedure for different detection methods. AB - Two different detection techniques for EMG burst detection are here used to reveal tremor in both a set of synthetic data and in a small sample of experimental trials. An optimization procedure that employs the minimization of a cost function to provide the parameter set characterizing the two techniques is here presented and its performance assessed. The results obtained with the optimization procedure are satisfactory and suitable for practical use: the values for both bias and standard deviation in the estimation of both onset and offset time instants are lower than 10 ms, and the sensitivity and positive predictive value in the detection of tremor bursts are > 96% for SNR levels higher than 6 dB. PMID- 22256076 TI - Noninvasive analysis of motor unit behavior in pathological tremor. AB - A robust surface EMG decomposition tool, referred to as tremor-optimized Convolution Kernel Compensation (CKC) technique, is described. This technique modifies and extends the previously published CKC method in order to circumvent the typical assumption on regularity and asynchrony of motor unit firings in normal condition and adapt to the discharge patterns in pathological tremor. The results on synthetic and experimental surface EMG signals demonstrate high performance of decomposition. In the case of simulated surface EMG with 20 dB SNR, excitation level of 20% maximum voluntary contraction (MVC) and simulated tremor frequency of 8 Hz, the newly proposed method identified 8 +/- 2 motor units with sensitivity of motor unit discharge identification >= 95 % and false alarm and miss rates <= 5%. The performance worsened with increasing noise power, with 5 +/- 2 motor units identified at 10 dB SNR and 3 +/- 1 at 0 dB SNR. In 24 recordings of high-density surface EMG signals from four tremor-affected patients, the modified CKC technique identified 134 motor units (6 +/- 4 motor units per contraction). PMID- 22256077 TI - Trust sensor interface for improving reliability of EMG-based user intent recognition. AB - To achieve natural and smooth control of prostheses, Electromyographic (EMG) signals have been investigated for decoding user intent. However, EMG signals can be easily contaminated by diverse disturbances, leading to errors in user intent recognition and threatening the safety of prostheses users. To address this problem, we propose a trust sensor interface (TSI) that contains 2 modules: (1) abnormality detector that detects diverse disturbances with high accuracy and low latency and (2) trust evaluation that dynamically evaluates the reliability of EMG sensors. Based on the output of the TSI, the user intention recognition (UIR) algorithm is able to dynamically adjust their operations or decisions. Our experiments on an able-bodied subject have demonstrated that the proposed TSI can effectively detect two types of disturbances (i.e. motion artifacts and baseline shifts) and improve the reliability of the UIR. PMID- 22256078 TI - Designing stimulation patterns for an afferent BMI: representation of kinetics in somatosensory cortex. AB - In recent years, much attention has been focused on developing stimulating strategies for somatosensory prostheses. One application of such a somatosensory prosthesis is to supply proprioceptive feedback in a brain machine interface application. One strategy for the development of such a stimulation regime is to mimic the natural representation of limb state variables. In this paper, we demonstrate that end point force is represented in primary somatosensory cortex of the macaque and force, in addition to velocity, can be decoded from S1 neural recordings. Force is represented in S1 in both a movement and isometric tasks; however, models that predict force in one condition do not generalize to the other. Possible interpretations of these apparently contradictory results are discussed. PMID- 22256079 TI - Approaches to optical neuromodulation from rodents to non-human primates by integrated optoelectronic devices. AB - Methods on rendering neurons in the central nervous system to be light responsive has led to a boom in using optical neuromodulation as a new approach for controlling brain states and understanding neural circuits. In addition to the developing versatility to "optogenetically" labeling of neural cells and their subtypes by microbiological methods, parallel efforts are under way to design and implement optoelectronic devices to achieve simultaneous optical neuromodulation and electrophysiological recording with high spatial and temporal resolution. Such new device-based technologies need to be developed for full exploitation of the promise of optogenetics. In this paper we present single- and multi-element optoelectronic devices developed in our laboratories. The single-unit element, namely the coaxial optrode, was utilized to characterize the neural responses in optogenetically modified rodent and primate models. Furthermore, the multi element device, integrating the optrode with a 6*6 microelectrode array, was used to characterize the spatiotemporal spread of neural activity in response to single-site optical stimulation in freely moving rats. We suggest that the particular approaches we employed can lead to the emergence of methods where spatio-temporal optical modulation is integrated with real-time read out from neural populations. PMID- 22256080 TI - Chronically implanted hyperdrive for cortical recording and optogenetic control in behaving mice. AB - Neural stimulation technology has undergone a revolutionary advance with the introduction of light sensitive ion channels and pumps into genetically identified subsets of cells. To exploit this technology, it is necessary to incorporate optical elements into traditional electrophysiology devices. Here we describe the design, construction and use of a "hyperdrive" capable of simultaneous electrical recordings and optical stimulation. The device consists of multiple microdrives for moving electrodes independently and a stationary fiber for delivering light to the tissue surrounding the electrodes. We present data demonstrating the effectiveness of inhibitory recruitment via optical stimulation and its interaction with physiological and behavioral states, determined by electrophysiological recording and videographic monitoring. PMID- 22256081 TI - Effects of spatial and temporal parameters of primary afferent microstimulation on neural responses evoked in primary somatosensory cortex of an anesthetized cat. AB - Patterned microstimulation of muscle and cutaneous afferent neurons may provide tactile and proprioceptive feedback to users of advanced prosthetic limbs. However, it is unclear what types of stimulation patterns will be effective, and the parameter space for creating these patterns is prohibitively large to explore systematically using only psychophysics paradigms. In this study, we used an array of microelectrodes in primary somatosensory cortex (S1) of an isoflurane anesthetized cat to measure responses in a population of neurons evoked by various patterns of primary afferent microstimulation delivered to the L6 and L7 dorsal root ganglia (DRG). Each pattern consisted of a 300 ms train of microstimulation pulses having a fixed amplitude, pulse rate, and location in the array of DRG electrodes. Evoked responses were detectable on many S1 channels at the lowest amplitude tested (5 MUA) and pulse rate (10 pulses per second). Increasing the pulse rate lowered the threshold amplitude for evoking a response on some S1 channels. Location effects were also observed. Adjacent stimulation sites evoked discriminable responses at low but not high (20 MUA) amplitudes. In summary, we observed interactions between stimulation pulse rate, pulse amplitude, and location. Such interactions must be considered when designing stimulation patterns for transmitting sensory feedback by primary afferent microstimulation. PMID- 22256082 TI - Robustness of implantable algorithms to detect epileptiform activity in the presence of broad-spectrum background noise. AB - Detection of epileptiform activity is of interest for responsive stimulation and diagnostic or monitoring devices in epilepsy; some implantable systems use low computational-complexity algorithms such as line length trending and half-wave detection. Broadband noise was added to recorded electrocorticographic signals in order to model the potential impact of factors such as electrode-tissue interface properties and distance from the epileptic focus on these detection tools. Simulation demonstrated that half-wave and line length tools can yield consistent results in the presence of moderate amounts of noise. PMID- 22256083 TI - Rat behavioral model for high-throughput parametric studies of intracortical microstimulation. AB - In the development of sensory prosthetic devices based on intracortical microstimulation (ICMS) an important objective is to optimize the stimulus waveform. However, because of the large design space such optimization is an imposing challenge. This study highlights the ability of individual rats, trained using a conditioned avoidance paradigm and performing an adaptive task, to generate highly consistent and significant data. Three experiments on the effects of phase delay, stimulus pulse rate, and waveform asymmetry were completed and revealed detailed and significant results. These results, consisting of 244 individual thresholds, were generated by one rat in 19 days. PMID- 22256084 TI - A novel unsupervised spike sorting algorithm for intracranial EEG. AB - This paper presents a novel, unsupervised spike classification algorithm for intracranial EEG. The method combines template matching and principal component analysis (PCA) for building a dynamic patient-specific codebook without a priori knowledge of the spike waveforms. The problem of misclassification due to overlapping classes is resolved by identifying similar classes in the codebook using hierarchical clustering. Cluster quality is visually assessed by projecting inter- and intra-clusters onto a 3D plot. Intracranial EEG from 5 patients was utilized to optimize the algorithm. The resulting codebook retains 82.1% of the detected spikes in non-overlapping and disjoint clusters. Initial results suggest a definite role of this method for both rapid review and quantitation of interictal spikes that could enhance both clinical treatment and research studies on epileptic patients. PMID- 22256085 TI - Epileptic seizure prediction using variational mixture of Gaussians. AB - We propose a novel patient-specific method for predicting epileptic seizures by analysis of positive zero-crossing intervals in scalp electroencephalogram (EEG). In real-time analysis, the histogram of these intervals for the current EEG epoch is computed, and the values which correspond to the bins discriminating between interictal and preictal references are selected as an observation. Then, the set of observations from the last 5 min is compared with two reference sets of data points (interictal and preictal) using a variational Gaussian mixture model (GMM) of the data, and a combined index is computed. Comparing this index with a patient-specific threshold, an alarm sequence is produced for each channel. Finally, a seizure prediction alarm is generated according to channel-based information. The proposed method was evaluated using ~40.3 h of scalp EEG recordings from 6 patients with total of 28 partial seizures. A high sensitivity of 95% was achieved with a false prediction rate of 0.134/h and an average prediction time of 22.8 min for the test dataset. PMID- 22256086 TI - Rapid identification of epileptogenic sites in the intracranial EEG. AB - The paper presents a novel computationally simple, easy-to-interpret compressed EEG display for multichannel intracranial EEG recordings. The compressed display is based on the level of sharp activity (relative sharpness index (RSI)) in the EEG, which profoundly increases during paroxysmal activities. RSI is graphically presented as a color-intensity plot that allows compressing several hours of EEG into a single display page. RSI display is a bird's-eye-view of the EEG that may reveal seizure evolution ('build-up'), seizure precursors, or sites associated with the seizures. We present examples from two patients to illustrate the method's ability to identify epileptogenic sites that may be difficult to observe in the conventional review process. RSI is compared with the color density spectral array (CDSA) and amplitude integrated EEG (aEEG) display. Examples demonstrate the RSI display to be simple, easy to interpret, computationally light and fast enough for online application. PMID- 22256087 TI - A study of multi-site brain dynamics during limbic seizures. AB - Neuronal populations in the brain achieve levels of synchronous electrophysiological activity as a consequence of both normal brain functions as well as during pathological states such as in epileptic seizures. Understanding the nature of this synchrony and the dynamics of neuronal oscillators in the brain is a critical component towards decoding such complex behaviors. We have sought to achieve a more in-depth understanding of the dynamics underlying the evolution of seizures in limbic epilepsy by analyzing recordings of local field potentials from three subcortical nuclei that are part of the circuit of Papez in a kainic acid rat model of temporal lobe epilepsy using the empirical mode decomposition technique. The empirical mode decomposition allows for an adaptive and nonlinear decomposition of the local field potentials into a series of finite oscillatory components. We calculated the frequencies, power, and measures of phase synchrony of these oscillatory components as seizures evolve in the brain and discovered patterns of phase synchrony that varies between the different stages of the seizures. PMID- 22256089 TI - Seizure prediction based on classification of EEG synchronization patterns with on-line retraining and post-processing scheme. AB - Epilepsy is one of the most common brain disorders in the world. The spontaneous seizure onset influences the daily life of epilepsy patients. The studies on feature extraction and feature classification from Electroencephalography(EEG) signal in seizure prediction methods have shown great improvement these years. However, the variation issue of EEG signal (being awake, being asleep, severity of epilepsy, etc.) poses a fundamental difficulty in seizure prediction problem. The traditional off-line training method trains the model using a fixed training set, and expects the performance of the model to remain stable even after a long period of time, and thus suffers from variation issue. In this paper, we propose an on-line retraining method to leverage the recent input data by gradually enlarging the training set and retraining the model. Also, a simple post processing scheme is incorporated to reduce false alarms. We develop our method based on the state of the art machine learning based classification of bivariate patterns method. The performance of the method is evaluated on Electrocorticogram(ECoG) recording from Freiburg database as well as long-term scalp EEG recording from CHB-MIT EEG Database and National Taiwan University Hospital. The proposed method achieves 74.2% sensitivity on ECoG database and 52.2% sensitivity on scalp EEG database, while improving the sensitivity of off line training method by 29.0% and 17.4% in ECoG database and EEG database respectively. The experimental result suggests that on-line retraining can greatly improve the reliability and is promising for future seizure prediction method development. PMID- 22256088 TI - Transcranial focal stimulation via concentric ring electrodes reduced power of pentylenetetrazole-induced seizure activity in rat electroencephalogram. AB - As epilepsy affects approximately one percent of the world population, electrical stimulation of the brain has recently shown potential for additive seizure control therapy. In this study we applied noninvasive transcranial focal stimulation (TFS) via concentric ring electrodes on the scalp of rats after inducing seizures with pentylenetetrazole (PTZ) to assess the effect of TFS on the electrographic activity. Grand average power spectral densities were calculated to compare different stages of seizure development. They showed a significant difference between the TFS treated group and the control group. In case of the TFS treated group, after TFS, the power spectral density was reduced further towards a pre-seizure "baseline" than it was for the control group. The difference is the most drastic in delta, theta and alpha frequency bands. Application of general likelihood ratio test showed that TFS significantly (p<0.001) reduced the power of electrographic seizure activity in the TFS treated group compared to controls in more than 86% of the cases. These results suggest that TFS may have an anticonvulsant effect. PMID- 22256090 TI - Legal changes necessitate proactive management of Musculoskeletal Disorders: the role of electrodiagnostic functional assessment Soft Tissue Management program. AB - Musculoskeletal Disorders (MSD) often classified as sprains and strains to the low back, neck, shoulder or knee are the leading cost drivers in the workers compensation system. In 2009, soft tissue muscle injuries accounted for 40% of total injury cases requiring days away from work. The demand on U.S. employers to comply with all applicable mandates has exponentially increased as the regulatory landscape grows more complex evidenced by recent legislation from Equal Employment Opportunity Commission (EEOC), American With Disability Act 2.0 and Center for Medicare and Medicaid Services (CMS) Mandatory Reporting Act. Employers should revisit their return to work policies and engage in the interactive process to stay in compliance and avoid legal quagmire. EFA Soft Tissue Management (STM) is a comprehensive and compliant risk management program for objective diagnosis of work-related injuries that directs timely and proper allocation of resources to optimize injured worker (IW) outcomes. This bookend solution comparing pre- and post-loss data is a best practice to accurately determine between compensable acute workplace injury and exacerbation of a preexisting injury from chronic unrelated conditions. The EFA is an evidenced based objective tool to assist in measuring functional status of the IW and make return to work determinations. PMID- 22256091 TI - Assessing disease and wellness in the occupational setting: Electrodiagnostic Functional Assessment from wired to wireless. AB - Technology Assessment is the study and evaluation of new technologies. It is based on the premise that developments and discoveries within the scientific and medical communities are relevant to the population at large. Proper technology assessment is an approach that is vital to address the current limitations of the worker's compensation system. The aim of this presentation is to discuss the need for objective diagnostic tools, such as Electrodiagnostic Functional Assessment (EFA), in the workers' compensation system with a focus on musculoskeletal disorders (MSD). Workers' compensation musculoskeletal claims may benefit from a wireless assessment to diagnose and monitor soft tissue injuries and this technology may be applicable to wellness and healthcare programs. PMID- 22256092 TI - Impact of wireless health on proactive loss control and wellness strategies. AB - The Bureau of Labor Statistics reports that despite an overall decrease in the number of workers compensation claims, indemnity, medical costs and days away from work have continued to rise. Musculoskeletal Disorders (MSD) account for 33 percent of these costs. OSHA Defines an MSD as: "Disorders of the muscles, nerves, tendons, ligaments, joints, cartilage and spinal discs. Wireless technology will play an important role in prevention and diagnosing these injuries. In fact, today's escalating medical costs and ever changing legal and regulatory environment necessitate proactive loss control and wellness strategies. This paper will discuss existing evaluation and diagnostic methods as well as the new wireless EFA technology which will enable employers to proactively prevent and manage MSD cases under a broader range of conditions. PMID- 22256093 TI - Event detection in an assisted living environment. AB - This paper presents the design of a wireless event detection and in building location awareness system. The systems architecture is based on using a body worn sensor to detect events such as falls where they occur in an assisted living environment. This process involves developing event detection algorithms and transmitting such events wirelessly to an in house network based on the 802.15.4 protocol. The network would then generate alerts both in the assisted living facility and remotely to an offsite monitoring facility. The focus of this paper is on the design of the system architecture and the compliance challenges in applying this technology. PMID- 22256094 TI - Public transportation assistant for the cognitively impaired. AB - This project developed and evaluated the utility of a mobility assistant cognitive prosthetic that leverages the computing power and GPS location determination capabilities of smart phones to provide location-sensitive mobility assistance. New relatively inexpensive smart phones offer powerful computing and location sensing capabilities. A prototype cognitive prosthetic was developed to assist users in their use of transportation systems. User Interface design included remote caregiver programming features, and automated SMS status generation. Location specific memory cues are triggered by comparing current GPS coordinate location with expected route coordinates obtained from stored route databases based on the GTFS feeds from transit systems. Additional development focused on developing algorithms to identify potential user errors, such as wrong bus. These reminders and instructions will allow cognitively disabled persons to utilize public transportation systems with greater confidence leading to greater mobility and independence. PMID- 22256095 TI - Improving acoustic fall recognition by adaptive signal windowing. AB - Each year more than a third of elderly fall in the United States. To address this problem we are developing an acoustic fall detection system based on a microphone array. The main task of the acoustic system is to detect all the falls that occur in an indoor environment while producing as few as possible false alarms. One of the challenges of this task is to accurately locate where the fall signal comes from so that beamforming can be applied to improve the recognition of fall signals. In this paper we describe a simple fall signal location procedure that proved effective in preliminary testing. PMID- 22256096 TI - Activity recognition using correlated pattern mining for people with dementia. AB - Due to the rapidly aging population around the world, senile dementia is growing into a prominent problem in many societies. To monitor the elderly dementia patients so as to assist them in carrying out their basic Activities of Daily Living (ADLs) independently, sensors are deployed in their homes. The sensors generate a stream of context information, i.e., snippets of the patient's current happenings, and pattern mining techniques can be applied to recognize the patient's activities based on these micro contexts. Most mining techniques aim to discover frequent patterns that correspond to certain activities. However, frequent patterns can be poor representations of activities. In this paper, instead of using frequent patterns, we propose using correlated patterns to represent activities. Using simulation data collected in a smart home testbed, our experimental results show that using correlated patterns rather than frequent ones improves the recognition performance by 35.5% on average. PMID- 22256097 TI - Indoor localization using pedestrian dead reckoning updated with RFID-based fiducials. AB - We describe a low-cost wearable system that tracks the location of individuals indoors using commonly available inertial navigation sensors fused with radio frequency identification (RFID) tags placed around the smart environment. While conventional pedestrian dead reckoning (PDR) calculated with an inertial measurement unit (IMU) is susceptible to sensor drift inaccuracies, the proposed wearable prototype fuses the drift-sensitive IMU with a RFID tag reader. Passive RFID tags placed throughout the smart-building then act as fiducial markers that update the physical locations of each user, thereby correcting positional errors and sensor inaccuracy. Experimental measurements taken for a 55 m * 20 m 2D floor space indicate an over 1200% improvement in average error rate of the proposed RFID-fused system over dead reckoning alone. PMID- 22256098 TI - Design of a home-based adaptive mixed reality rehabilitation system for stroke survivors. AB - This paper presents the design of a home-based adaptive mixed reality system (HAMRR) for upper extremity stroke rehabilitation. The goal of HAMRR is to help restore motor function to chronic stroke survivors by providing an engaging long term reaching task therapy at home. The system uses an intelligent adaptation scheme to create a continuously challenging and unique multi-year therapy experience. The therapy is overseen by a physical therapist, but day-to-day use of the system can be independently set up and completed by a stroke survivor. The HAMMR system tracks movement of the wrist and torso and provides real-time, post trial, and post-set feedback to encourage the stroke survivor to self-assess his or her movement and engage in active learning of new movement strategies. The HAMRR system consists of a custom table, chair, and media center, and is designed to easily integrate into any home. PMID- 22256099 TI - Quantitative analysis of 180 degree turns for fall risk assessment using video sensors. AB - In this paper, we present a method for quantitatively and objectively assessing 180 degree turns using low cost video sensors. A three-dimensional voxel reconstruction, which is built using silhouettes captured from two calibrated web camera views, is used to represent the human body. Experiments were conducted in which participants performed the standard Timed Up and Go tests where 180 degree turns are evaluated. Our two calibrated cameras captured the images during the test. Two key parameters including turn time and turn steps are extracted using the voxel data. Good agreement for the turn time was found for our system compared to the expert rating. The extracted numbers of turn steps are one step less than the expert rating in many test runs. The difference comes mainly from the nature of the pivot turns, and the turn time difference between the expert rating and the algorithm, namely the determination of the time duration from the beginning to the end of the turn. The development of this technology provides potential for assessing 180 degree turns in the home setting as part of a balance, stability and fall risk assessment tool. PMID- 22256100 TI - Generation of intervention strategy for a genetic regulatory network represented by a family of Markov Chains. AB - Genetic Regulatory Networks (GRNs) are frequently modeled as Markov Chains providing the transition probabilities of moving from one state of the network to another. The inverse problem of inference of the Markov Chain from noisy and limited experimental data is an ill posed problem and often generates multiple model possibilities instead of a unique one. In this article, we address the issue of intervention in a genetic regulatory network represented by a family of Markov Chains. The purpose of intervention is to alter the steady state probability distribution of the GRN as the steady states are considered to be representative of the phenotypes. We consider robust stationary control policies with best expected behavior. The extreme computational complexity involved in search of robust stationary control policies is mitigated by using a sequential approach to control policy generation and utilizing computationally efficient techniques for updating the stationary probability distribution of a Markov chain following a rank one perturbation. PMID- 22256101 TI - A dual Kalman filter for parameter-state estimation in real-time DNA microarrays. AB - Affinity-based biosensors rely on chemical attraction between analytes (targets) and their molecular complements (probes) to detect presence and quantify amounts of the analytes of interest. Real-time DNA microarrays acquire multiple temporal samples of the target-probe binding process. In this paper, estimation of the amount of targets based on early kinetics of the binding reaction is studied. A dual Kalman filter for the parameter-state estimation is proposed. Computational studies demonstrate efficacy of the proposed method. PMID- 22256102 TI - Exploring the feasibility of next-generation sequencing and microarray data meta analysis. AB - Emerging next-generation sequencing (NGS) technology potentially resolves many issues that prevent widespread clinical use of gene expression microarrays. However, the number of publicly available NGS datasets is still smaller than that of microarrays. This paper explores the possibilities for combining information from both microarray and NGS gene expression datasets for the discovery of differentially expressed genes (DEGs). We evaluate several existing methods in detecting DEGs using individual datasets as well as combined NGS and microarray datasets. Results indicate that analysis of combined NGS and microarray data is feasible, but successful detection of DEGs may depend on careful selection of algorithms as well as on data normalization and pre-processing. PMID- 22256103 TI - Neuromuscular electrical stimulation training results in enhanced activation of spinal stabilizing muscles during spinal loading and improvements in pain ratings. AB - Low back pain is associated with dysfunction in recruitment of muscles in the lumbopelvic region. Effective rehabilitation requires preferential activation of deep stabilizing muscle groups yet training these muscles poses challenges in a clinical setting. This study was carried out in order to quantify the response of deep stabilizing muscles (transverses abdominis and deep fibres of multifidus) to a period of training using a novel neuromuscular electrical stimulation (NMES) application in a group of patients with chronic low back pain. Analysis of results revealed clinically and statistically significant improvements in indicators of both muscle groups' performance, as evidenced by ultrasound evaluation of activation during voluntary activity. These improvements were associated with significant improvements in self reported pain levels, suggesting that NMES has an important role to play in CLBP rehabilitation. PMID- 22256104 TI - Central sleep apnea detection and stimulation. AB - This paper proposes a system to detect and intervene in instances of central sleep apnea. The system is composed of a detection module and a stimulation module, which provides sensory stimulation to the patient when an apnea event has occurred. The system is currently in prototype and has not yet undergone patient trials. PMID- 22256105 TI - Hemodynamic performance of NMES in the early post operative period following orthopaedic surgery. AB - Patients post total hip arthroplasty (THA) remain at high risk of developing Deep Vein Thrombosis (DVT) during the recovery period following surgery. The use of calf muscle neuromuscular electrical stimulation (NMES) during the hospitalized recovery period on this patient group may be effective at preventing DVT. However, the haemodynamic effectiveness and comfort characteristics of NMES in post-THA patients immediately following surgery has yet to be demonstrated. The popliteal veins of 5 patients, who had undergone unilateral total hip replacement surgery on the day previous to the study, were measured using Doppler ultrasound during a 4 hour calf-muscle NMES session. The effect of calf muscle NMES on peak venous velocity and volume flow were compared to resting values. Comfort was assessed using a 100 mm non-hatched visual analogue scale taken before application of NMES, once NMES was initiated and before NMES was withdrawn. Results of the study showed that NMES produces a beneficial hemodynamic response in patients in the early postoperative period following orthopaedic surgery. This patient group found extended periods of calf-muscle NMES tolerable. PMID- 22256106 TI - Preliminary results on the design of a tool for inserting of transverse intrafascicular multichannel electrodes (TIME) into the peripheral nervous system. AB - Transverse intrafascicular multichannel electrodes (TIMEs) are polyimide-based microelectrodes, which are potentially very interesting to restore sensorimotor functions in disabled people. By means of microstimulation of the nerve stump of an amputee, it can be possible to manipulate the phantom limb sensation, to provide sensory feedback to upper limb amputees, and to investigate methods of treatment of phantom limb pain. The current insertion procedure of TIMEs is completely done by hand. This makes the task difficult. This paper presents the preliminary results related to the development of a robotic tool to increase the accuracy in electrode placement and reduced size of the working area. The possibility to manage insertion parameters such as force, velocity, and positioning, could decrease the risk of damaging the nervous tissue, improving the coordination, and making placements repeatable. With the aim of solving the issues avbove, we developed a first prototype of a 4DoF multi-axis device. Additional strategies concerning system components and control are discussed. We performed characterization of implantation mechanics to derive mechanical design specifications for the robotic device. Force caracterization of the pig peripheral nerve during penetration of the needle at three velocities (1, 30, 40mm/sec) was executed. Results shown inverse relationship between maximal force and velocities values. The force values extracted varied between 0.081-0.174 N. PMID- 22256109 TI - Laboratory skinpatches and smart cards based on foils. AB - This paper presents: (i) a hand held system consisting of a portable platform and disposable polymeric Lab-on-a-card capable of performing a nucleic acid concentration, amplification and detection with reagents inside; and a (ii) wearable diagnostic Lab-on-a-Paper skinpatch system, capable of performing in situ sweat sampling, analyte pre-concentration, and immunoassay analysis. The skinpatch works in conjunction with a hand-held optoelectronic reader / micro PC fluorescence analysis interface. PMID- 22256110 TI - Micro-sized syringes for single-cell fluidic access integrated on a micro electrode array CMOS chip. AB - Very-large scale integration and micro-machining have enabled the development of novel platforms for advanced and automated examination of cells and tissues in vitro. In this paper, we present a CMOS chip designed in a commercial 0.18 MUm technology with integrated micro-syringes combined with micro-nail shaped electrodes and readout electronics. The micro-syringes could be individually addressed by a through-wafer micro-fluidic channel with an inner diameter of 1 MUm. We demonstrated the functionality of the micro-fluidic access by diffusion of fluorescent species through the channels. Further, hippocampal neurons were cultured on top of an array of micro-syringes, and focused ion beam-scanning electron microscopy cross-sections revealed protrusion of the cells inside the channels, creating a strong interface between the membrane and the chip surface. This principle demonstrates a first step towards a novel type of automated in vitro platforms, allowing local delivery of substances to cells or advanced planar patch clamping. PMID- 22256111 TI - Monolithically integrated Mach-Zehnder biosensors for real-time label-free monitoring of biomolecular reactions. AB - Arrays of monolithically integrated Mach-Zehnder interferometers were fabricated by standard silicon technology and applied to the label-free real-time monitoring of biomolecular interactions. Chips accommodating 10 MZIs were functionalized with recognition biomolecules and encapsulated in wafer scale. Detection is based on Frequency-Resolved Mach-Zehnder Interferometry, a new concept that takes advantage of the broad-band input spectrum by monitoring the changes for every input frequency. The sensitivity of the device in terms of refractive index changes (Deltan) was calculated using isopropanol/water solutions. A detection limit of Deltan = 4 * 10(-6) was calculated. The bioanalytical capabilities of the device there demonstrated through model binding assays (biotin/streptavidin) as well as the detection of total prostate specific antigen in serum samples using devices coated with antigen-specific monoclonal antibody. Detection limits at the pM range were determined. PMID- 22256112 TI - Evaluation of a closed loop inductive power transmission system on an awake behaving animal subject. AB - This paper presents in vivo experimental results for a closed loop wireless power transmission system to implantable devices on an awake behaving animal subject. In this system, wireless power transmission takes place across an inductive link, controlled by a commercial off-the-shelf (COTS) radio frequency identification (RFID) transceiver (TRF7960) operating at 13.56 MHz. Induced voltage on the implantable secondary coil is rectified, digitized by a 10-bit analog to digital converter, and transmitted back to the primary via back telemetry. Transmitter (Tx) and receiver (Rx) circuitry were mounted on the back of an adult rat with a nominal distance of ~7 mm between their coils. Our experiments showed that the closed loop system was able to maintain the Rx supply voltage at the designated 3.8 V despite changes in the coils' relative distance and alignment due to animal movements. The Tx power consumption changed between 410 ~ 560 mW in order to deliver 27 mW to the receiver. The open loop system, on the other hand, showed undesired changes in the Rx supply voltage while the Tx power consumption was constant at 660 mW. PMID- 22256113 TI - In-vivo signal transmission using an intra-corporal RF transmitter. AB - In clinical routine, measurements of human physiological parameters are very important. In this paper, a study of RF transmission from the inside to the outside of a biological body is described. In the course of this work, an overview of the state of the art of wireless biotelemetry and the basics of biological tissue attenuation are given. In addition, several prototype transmitters were designed and developed with frequencies ranging from 50 to 700 MHz. With these transmitters a study of an in-vivo transmission was run to measure realistic attenuation values of a living biological subject. In the evaluation phase, a prototype transmitter was placed in the esophagus, near the heart, of a narcotized living pig. This allows demonstrating the transmission out of an animal with human-like tissue properties. The results show a possible transmission at 58, 119, 240, 418 and 672 MHz with acceptable loss. PMID- 22256114 TI - A high bandwidth fully implantable mouse telemetry system for chronic ECG measurement. AB - We report on the development of a novel system that enables the wireless transmission of high-bandwidth physiological data from a freely moving mouse. The system employs inductive power transfer (IPT) to continuously power a battery less transmitter using an array of overlapping planar coils placed under the animal. This arrangement provides a minimum of 20 mW at all locations and orientations across the mouse cage by selecting a coil which will sufficiently power the transmitter. Coil selection is performed by feedback control across the 2.4 GHz wireless link. A device was constructed utilizing this novel IPT system and was used to capture high-fidelity electrocardiogram (ECG) signal sampled at 2 kHz in mice. Various attributes of the ECG signal such as QT, QRS, and PR intervals could be obtained with a high degree of accuracy. This system potentially provides lifetime continuous high bandwidth measurement of physiological signals from a fully implanted telemeter in a freely moving mouse. PMID- 22256115 TI - Fundamental sensing limit of electrochemical glucose sensors. AB - This paper investigates the inherent sensitivity limit, deactivation of glucose oxidase, of a glucose oxidase based electrochemical glucose sensor for in vivo monitoring of blood glucose concentration. Results in this paper show that the current density sensitivity to glucose decreases from 1200 nA/mm(2)/mM at initial implantation to 100 nA/mm(2)/mM after an implantation time of 2 years, when degradation due to glucose oxidase deactivation only is considered. Even as the sensor signal strength decreases, if the sensing electronics are sufficiently discriminating then a useful measure of blood glucose concentration can be extracted. This work aims to determine both how the glucose oxidase based sensor's signal-to-noise ratio degrades over long time scales and the electronic circuit requirements to achieve multi-year device lifetimes. Two sensing amplifier techniques are presented which can be used to detect the signal generated by the sensor. The noise performance of each technique is compared with the noise performance of the sensor and mutli-year lifetimes are shown to be feasible. PMID- 22256116 TI - Development of cost-effective biocompatible packaging for microelectronic devices. AB - A cost-effective, miniaturized and biocompatible packaging method for medical devices is proposed, resulting in a small, soft and comfortable implantable package. Towards this end, the barrier materials and fabrication process for the individual die encapsulation are largely explored. We demonstrate that various common clean room materials are good candidates for preventing metal leaching into body. In accelerated tests at higher temperature, several conductive barrier materials are damaged by the test bio-fluid, suggesting insufficient resistance to body fluids in long term. Covering electrodes by noble metals will solve this problem. For metallization, noble metals as Pt are best candidates. CoO calculations showed that selective plating of Pt is more cost-effective than sputtering. To reduce the cost of a sputter process, Pt recycling is very important. PMID- 22256117 TI - Optimization of kinetic energy harvesters design for fully implantable Cochlear Implants. AB - Fully implantable Cochlear Implants (CIs) would represent a tremendous advancement in terms of quality of life, comfort and cosmetics, for patients with profound sensorineural deafness. One of the main challenges involved in the development of such implants consists of finding a power supply means which does not require recharging. To this aim an inertial Energy Harvester (EH), exploiting the kinetic energy produced by vertical movements of the head during walking, has been investigated. Compared to existing devices, the EH needs to exploit very low frequency vibrations (<2.5 Hz) with small amplitude (<9 m/s(2)). In order to maximize the power transduced, an optimization method has been developed, which is the objective of this paper. The method consists in calculating the dynamical behavior of the EH using discrete transforms of experimentally measured acceleration profiles. It is shown that the quick integration of the second order dynamical equation allows the use of computationally intensive optimization techniques, such as Genetic Algorithms (GAs). The robustness of the solution is also evaluated. PMID- 22256118 TI - Eavesdropping on echolocation: recording the bat's auditory experience. AB - Insectivorous bats are able to locate and capture insects in complete darkness while flying at high speeds. They may consume hundreds of insects each night while avoiding obstacles in a complex environment. To investigate the processes associated with bat echolocation, we have developed instrumentation that allows us to record and visualize what a bat hears while flying through its natural environment. Recordings were made using a miniaturized radio telemetry system mounted directly on the back of the bat. This paper describes the design and testing of the components of this system, presents echolocation data collected from bats and discusses issues associated with the visualization and analysis of echoes recorded in a natural setting from the bat's point-of-view. It presents a new tool for visualizing a bat's experience by generating call sequence sonograms (CSSs) based on various signal parameters. CSSs based on time series amplitude, band-limited spectral magnitude and Q-factor are presented. This work demonstrates that CSSs based on Q-factor (computed by dividing a peak frequency estimate by a bandwidth estimate) provides a relatively clear representation of the objects producing echoes encountered by a bat during a continuous flight. PMID- 22256119 TI - In vivo characterization of ultrasonic transducers for the detection of airway occlusion in Sleep Disordered Breathing. AB - Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS) is the most common form of Sleep Disordered Breathing (SDB) and it is estimated to affect approximately 15% of US adult population. Various methods have been proposed for the development of inexpensive screening methods to detect SDB to reduce the need for costly nocturnal polysomnography (NPSG). In this paper, a description of the ultrasonic transducer design and characterization is presented, followed by the results of a full night sleep study. The findings show a significant difference in the temporal features extracted from the received ultrasonic waveform during apneic breathing, compared to the hyperventilation that follows. Therefore, the findings indicate the feasibility of developing an ultrasonic detection device for low cost diagnosis of SDB. PMID- 22256120 TI - A label-free cell separation using surface acoustic waves. AB - We present two-stage microfluidic platform for a continuous label-free cell separation using surface acoustic waves. In the proposed platform, cells are first lined up at the center of the channel by using standing surface acoustic waves without introducing any external sheath flow. After focused at the center of the channel, the cells are then entered to the actual cell separation stage where the larger cell are exposed to more lateral displacement in the channel towards the pressure node due to the acoustic force differences. Consequently, different size cells are separated into multiple collection outlets. The focusing and separation of the cells can be accomplished simultaneously in the present two stage microfluidic device. The device doesn't require the use of the sheath flow for positioning or aligning of cells. In this study, we demonstrated the separation of two different size particle streams (3 MUm and 10 MUm) with this microfluidic platform without introducing any external sheath flow. PMID- 22256121 TI - Bioacoustics response of small benign or malignant nodules. AB - One of the most important features of separation between benign or malignant tissues is their smooth or rough shape. This article presents a new method for early diagnosis of thyroid cancer by knowing the resonance frequencies of a certain tissue. Two types of nodules were investigated: spherical and elliptical. Their external surfaces were smooth or rough with different values of spicules. Propagation of sound through the human body was modeled by a classical partial differential equation associated with Neumann or Dirichlet boundary conditions. The assessments of about ten acoustic eigenfrequencies are enough to decide the type of external surfaces: smooth or rough, or whether nodule is benign or malignant. Data obtained by this method refers to the result of investigating 3D bodies smaller than 5 mm, when other medical devices such as ultrasound or CT cannot evaluate their surface shape because of their limited spatial resolution. PMID- 22256122 TI - Design of a clinically viable pneumatic system for the acquisition of pressure compensated otoacoustic emissions. AB - Otoacoustic emission (OAE) screening is perhaps one of the most common diagnostic tools used on both adults and children alike to clinically asses hearing health. However small to moderate middle ear pressures (both positive and negative), which are quite prevalent among the general population, are known to significantly reduce the OAE response specifically among frequencies below 2 kHz. This study focuses on the design and development of a software controlled syringe pump which will be used for the automatic compensation of middle ear pressure. This study reports validating test results which confirm the feasibility of using this system for future clinical trials. PMID- 22256123 TI - Feature selection using a genetic algorithm in a motor imagery-based Brain Computer Interface. AB - This study performed an analysis of several feature extraction methods and a genetic algorithm applied to a motor imagery-based Brain Computer Interface (BCI) system. Several features can be extracted from EEG signals to be used for classification in BCIs. However, it is necessary to select a small group of relevant features because the use of irrelevant features deteriorates the performance of the classifier. This study proposes a genetic algorithm (GA) as feature selection method. It was applied to the dataset IIb of the BCI Competition IV achieving a kappa coefficient of 0.613. The use of a GA improves the classification results using extracted features separately (kappa coefficient of 0.336) and the winner competition results (kappa coefficient of 0.600). These preliminary results demonstrated that the proposed methodology could be useful to control motor imagery-based BCI applications. PMID- 22256124 TI - A quality parameter for the detection of the intentionality of movement in patients with neurological tremor performing a finger-to-nose test. AB - The identification of the intentionality of movement is a key-aspect for the development of brain-computer interfaces (BCIs) applicable to daily life in neurological patients. We present a novel method of processing of electroencephalography (EEG) signals for the extraction of movement intention in neurological patients with upper limb tremor. This method is based on event related EEG desynchronization, considering alpha (8-12 Hz), beta (13-30 Hz), and gamma (30-40 Hz) bands. We have analyzed the EEG signals from the sensorimotor areas of 4 neurological patients presenting an upper limb tremor (grade 1 to 3/4) and executing successive finger-to-nose movements. A Quality Parameter (QP) for the detection of intentionality of movement has been extracted, by considering: (a) the changes in the beta2/alpha and beta/alpha ratio (representing bursts of beta-gamma frequencies) during the pre-movement period; (b) an appropriate threshold predicting the movement; (c) the number of movements executed. This QP allows the prediction of the voluntary movement with a probability between 70% and 90%. This method could be implemented in a wearable BCI to detect the intentionality of movement and could be used, for instance, to trigger the electrical stimulation in selected muscles of upper limbs with the aim of blocking the emergence of tremor. PMID- 22256125 TI - Adaptive control of deep brain stimulator for essential tremor: entropy-based tremor prediction using surface-EMG. AB - Entropy, as a measure of randomness in time-varying signals, is widely used in areas such as thermodynamics, statistical mechanics and information theory. This paper investigates the use of two commonly employed entropy measures, namely Wavelet Entropy and Approximate Entropy, as a predictor of tremor reappearance in Essential Tremor patients; the predictor input is a raw surface-electromyographic (sEMG) signal measured from tremor affected muscles of patients implanted with a Deep Brain Stimulator (DBS). A combination of both types of entropy measure is shown to successfully predict the occurrence of tremor few seconds before its visual manifestation. This result can potentially lead to a novel sEMG-based adaptive on-off DBS controller that can be added on to existing open-loop DBS systems with minimal changes; an adaptive DBS system provides stimulation only when needed thereby reducing the risk of brain over stimulation, delaying DBS intolerance and prolonging DBS battery life. PMID- 22256126 TI - Seizure onset detection based on one sEMG channel. AB - We present a new method to detect seizure onsets of tonic-clonic epileptic seizures based on surface electromyography (sEMG) data. The proposed method is generic and based on a single channel making it ideal for a small detection or monitoring device. The sEMG signal is high-pass filtered with a Butterworth filter with a cut-off frequency of 150 Hz. The number of zero-crossings with a hysteresis of +/- 50 MUV is the only feature extracted. The number of counts in a window of 1 second and the number of windows to make a detection is tested with a leave-one-out method. On 6 patients the method performs with a sensitivity of 100%, a median latency of 7.6 seconds and a median false detection rate of 0.04/h. PMID- 22256127 TI - Time-frequency characterization of mismatch negativity in nociceptive responses. AB - An efficient way to investigate the neural basis of nociceptive responses is the event-related brain potentials (ERPs). One component belonging to this family of ERPs is the mismatch negativity (MMN). It reflects pre-attentive detection of changes in the incoming stimulus by comparing the new stimulus with sensory memory traces. In this work, single trials of ERP taken from EEG signal recorded under thermal and electric stimulation were analyzed with time-frequency representation (TFR). The main objective of this work was to characterize responses to frequent and infrequent stimuli with TFR functions. Variables defined on instantaneous frequency and instantaneous power presented a statistical significance (p-value<0.0001) differentiating these two kind of responses. Furthermore, differences between the averaged instantaneous power and instantaneous frequency were also analyzed. It was found that instantaneous power and instantaneous frequency were able to better isolate the MMN components from EEG noise in certain frequency bands. PMID- 22256128 TI - Combined frequency and time domain sleep feature calculation. AB - In automated sleep analysis usually both frequency and time domain features are calculated from measured physiological (EEG, EOG, EMG) signals. Usually Discrete Fourier Transform (DFT) is used for different frequency domain measures and Digital Filtering (FIR or IIR) for time domain measurement. Here we demonstrate potential usefulness of using modified inverse DFT as a step for time domain feature calculation. Analytical formulas are shown for calculating interpolation, velocity and acceleration of filtered signals. Preliminary examples of electro oculography (EOG) signal analysis during sleep are presented. Although same results could be obtained with conventional filtering followed by numerical differentiation the presented could be useful in some cases. PMID- 22256129 TI - Framework for adaptive multiscale analysis of nonhomogeneous point processes. AB - We develop the methodology for hypothesis testing and model selection in nonhomogeneous Poisson processes, with an eye toward the application of modeling and variability detection in heart beat data. Modeling the process' non-constant rate function using templates of simple basis functions, we develop the generalized likelihood ratio statistic for a given template and a multiple testing scheme to model-select from a family of templates. A dynamic programming algorithm inspired by network flows is used to compute the maximum likelihood template in a multiscale manner. In a numerical example, the proposed procedure is nearly as powerful as the super-optimal procedures that know the true template size and true partition, respectively. Extensions to general history-dependent point processes is discussed. PMID- 22256130 TI - Diagnosis of sleep apnea by the analysis of heart rate variation: a mini review. AB - Cyclic variation of heart rate (CVHR) associated with sleep apnea/hypopnea episodes has been suggested as a marker of sleep disordered breathing (SDB). This study examined the utility of ECG-based CVHR detection for diagnosing SDB using simultaneous polysomnography as the reference standard. We used a previously developed automated CVHR detection algorithm (autocorrelated wave detection with adaptive threshold, ACAT) that provides the number of CVHR per hour (CVHR index). The ACAT was refined using a polysomnographic database of 194 subjects with various severities of SDB and then, applied to a single channel ECG obtained during standard overnight polysomnography in 862 consecutive subjects referred for SDB diagnosis. Using multiple thresholds of CVHR index >= 38 and <27, positive and negative predictive values of 95.6% and 95.1%, respectively, were achieved for detecting and excluding subjects with apnea-hypopnea index (AHI) >= 30, leaving 58 (6.7%) unclassified subjects. Positive and negative likelihood ratios (LRs) were 97.3 and 0.23, respectively. Also, thresholds of CVHR index >= 29 and <7 provided 96.1% and 95.1% of positive and negative predictive values, respectively, for subjects with AHI >= 15 (LRs, 50.6 and 0.11), leaving 426 (49.4%) unclassified subjects. The CVHR correlated with the AHI (r = 0.86) and showed the limits of agreement with the AHI of 19.6 and -18.6. Automated detection of CVHR by the ACAT algorithm provides useful screening tool for both increasing and decreasing probability of moderate and sever SDB with adequate thresholds. PMID- 22256131 TI - Instantaneous monitoring of sleep fragmentation by point process heart rate variability and respiratory dynamics. AB - We present a novel, automatic point-process approach that is able to provide continuous, instantaneous estimates of heart rate variability (HRV) and respiratory sinus arrhythmia (RSA) in long duration data recordings such as those during an entire night of sleep. We analyze subjects with and without sleep apnea who underwent diagnostic polysomnography. The proposed algorithm is able to quantify multi-scale high time resolution autonomic signatures of sleep fragmentation, such as arousals and stage transitions, throughout an entire night. Results demonstrate the ability of our methods to track fast dynamic transitions from sleep to wake and between REM sleep and other sleep stages, providing resolution details not available in sleep scoring summaries. An automatic threshold-based procedure is further able to detect brief arousals, with the instantaneous indices characterizing specific arousal dynamic signatures. PMID- 22256132 TI - HRV strongly depends on breathing. Are we questioning the right suspect? AB - The fact that the heart rate variability (HRV) depends on breathing is well known. The HRV is an important phenomenon which reflects the functional state of the autonomous nervous system (ANS), although there are some doubts concerning the actual interpretation of spectral components of HRV and their postulated balance. The assessment of the functional state of the ANS is the task of paramount importance in risk stratification of cardiological patients. HRV is considered to depend mainly on the properties of the sinus node (SN), which achieves neurohumoral input from the ANS. Interestingly, there is growing evidence that the relation between the heart rate (HR) and breathing rate (BR) is really strong. The variety of breathing-related effects that are present in HRV is very rich, including respiratory sinus arrhythmia (RSA), cardiorespiratory synchronization and vivid heart rate response to breathing disorders. If the mean frequency of any of rhythms is changed, the other rhythm adjusts itself. This provokes the question on the actual source of the dynamics observed in the HRV. Is it possible that we observe mainly the dynamics of the respiratory rhythm which is just transduced by the heart effector? What might be the role of the intrinsic dynamics of this effector? Is the RSA a product of neural regulation or rather a by-product: what is its teleological role? In consequence: if we concentrate on the sinus node and its properties in order to understand the nature of the HRV - are we questioning the right suspect? The reasoning is supplied by suitable choice of literature and by the analysis of the computational model. Various consequences are discussed. PMID- 22256133 TI - Asymmetric intermittency observed in human heart rate dynamics. AB - To gain a deeper understanding of intermittent fluctuations observed in complex, real-world systems, we propose positive- or negative-directional non-Gaussian statistics. As a numerical example of asymmetric intermittent fluctuations, we heuristically introduce a random cascade-type model. Using our method, it is demonstrated that the asymmetric properties of heart rate variability depend on aging. This provides new insight into the physiological mechanism controlling heart rate dynamics in health and in autonomic disorder. PMID- 22256134 TI - Heart rate variability analysis for newborn infants prolonged pain assessment. AB - Pain management is a general concern for healthcare quality. In the particular context of neonatal care, it's well known that an efficient pain management will decrease mortality and morbidity of newborn infants. Furthermore, the plasticity of developing brain is vulnerable to pain and/or stress, that in turn may cause long term neurodevelopmental changes, including altered pain sensitivity and neuroanatomic and behavioural abnormalities. During neonatal intensive care stay, large number of painful procedures are performed, the majority of which are not accompanied by adequate analgesia. Optimal management requires competent pain assessment which can be especially difficult to perform in this non verbal population. We have developed an instantaneous heart rate variability (HRV) analysis method, non intrusive and user-friendly, based on the ECG signal acquisition. This analysis method enabled us to design parameters related to the influence of pain on the Autonomic Nervous System (ANS) activity. This paper presents the application of this method, previously validated for adults under general anesthesia, to the domain of newborn infants prolonged pain assessment. PMID- 22256135 TI - 3D segmentation of keratin intermediate filaments in confocal laser scanning microscopy. AB - In this paper, we propose and compare different methods for the 3D segmentation of keratin intermediate filaments (KFs) in images acquired using confocal laser scanning microscopy (CLSM). KFs are elastic cables forming a complex scaffolding within epithelial cells. They are involved in many basic cell functions. To understand the mechanisms of filament formation and network organisation under physiological and pathological conditions, quantitative measurements of dynamic network alterations are essential. Segmenting KFs is a key component for analyzing their dynamic and biomechanical properties. KFs were labeled with fluorescent keratins to allow high resolution imaging of network dynamics in native cells. Our segmentation methods follow the principle of ridge enhancement filtering and subsequent centerline extraction. The evaluation of the methods is two-fold: (i) We develop synthetic data that exhibit the characteristics of real CLSM data to evaluate the precision of the different methods in terms of centerline localisation and (ii) we perform a connected component analysis on the segmentation results of real KF data to assess whether the connectivity of highly complex networks is being preserved by the segmentation. Our evaluation shows that in the presence of strong noise and despite the highly anisotropic spatial resolution of CLSM images the proposed method is able to accurately localize the centerlines of the KFs and to preserve the KF networks' connectivity. Taken together this is a strong indicator that also the network topology is being preserved. PMID- 22256136 TI - Motor neuron morphology estimation for its classification in the Drosophila brain. AB - Type-specific dendritic arborization patterns dictate synaptic connectivity and are fundamental determinants of neuronal function. We exploit the morphological stereotypy and relative simplicity of the Drosophila nervous system to model the diverse dendritic morphologies of individual motor neurons (MNs) to understand underlying principles of synaptic connectivity in a motor circuit. The genetic tractability of Drosophila allows us to label single MNs with green fluorescent protein (GFP) and serially reconstruct identifiable MNs in 3D with confocal microscopy. Our computational approach aims at the robust segmentation of the MN volumes and the simultaneous partitioning into their compartments, namely the soma, axon and dendrites. We use the idea of co-segmentation, where every image along the z-axis (depth) is clustered using information from 'neighboring' depths. As appearance we use a 3D extension of Haar features and for the shape we define an implicit representation of the segmentation domain. PMID- 22256137 TI - Fully automated detection of the counting area in blood smears for computer aided hematology. AB - For medical diagnosis, blood is an indispensable indicator for a wide variety of diseases, i.e. hemic, parasitic and sexually transmitted diseases. A robust detection and exact segmentation of white blood cells (leukocytes) in stained blood smears of the peripheral blood provides the base for a fully automated, image based preparation of the so called differential blood cell count in the context of medical laboratory diagnostics. Especially for the localization of the blood cells and in particular for the segmentation of the cells it is necessary to detect the working area of the blood smear. In this contribution we present an approach for locating the so called counting area on stained blood smears that is the region where cells are predominantly separated and do not interfere with each other. For this multiple images of a blood smear are taken and analyzed in order to select the image corresponding to this area. The analysis involves the computation of an unimodal function from image content that serves as indicator for the corresponding image. This requires a prior segmentation of the cells that is carried out by a binarization in the HSV color space. Finally, the indicator function is derived from the number of cells and the cells' surface area. Its unimodality guarantees to find a maximum value that corresponds to the counting areas image index. By this, a fast lookup of the counting area is performed enabling a fully automated analysis of blood smears for medical diagnosis. For an evaluation the algorithm's performance on a number of blood smears was compared with the ground truth information that has been defined by an adept hematologist. PMID- 22256139 TI - Motion flow analysis in cell videos using a multi-level clustering method. AB - Analyzing motion flow of cells is an important task for many biomedical applications. It is a challenging problem due to noise in images and uncontrolled motion of cells. In this study, a method to find regions of organized motion and direction of flow is proposed. Since dense optical flow methods might fail due to homogeneous regions and irregular motion patterns, the technique involves analyzing trajectories of strong corner features. Trajectories are clustered to find dominant flow patterns for different regions of the frame, where a multilevel clustering scheme is followed. Experiments show that the technique gives accurate results for detecting region and direction of flow. PMID- 22256140 TI - Refractive effects on optical measurement of alveolar volume: a 2-D ray-tracing approach. AB - Lung imaging and assessment of alveoli geometry in the lung tissue is of great importance. Optical coherence tomography (OCT) is a real-time imaging technique used for this purpose, based on near-infrared interferometry, that can image several layers of distal alveoli in the lung tissue. The OCT measurements use low coherence interferometry, where light reflections from surfaces in the tissue are used to construct 2D images of the tissue. OCT images provide better depth compared to other optical microscopy techniques such as confocal reflectance and two-photon microscopy. Therefore, it is important to detect and verify optical distortions that happens with OCT, including refractive effect at the tissue-air alveoli wall interface which is not taken into account in the OCT imaging model. In this paper, the refractive effect at the tissue-air interface of the alveoli wall is modeled using exact ray tracing and direct implementation of Snell's law, and differences between alveoli area computed from OCT imaging and those measured by exact ray tracing of the OCT signal are analyzed. PMID- 22256141 TI - Breast skin-line detection using dynamic programming. AB - In this paper, we present a novel method to extract the breast skin-line based on dynamic programming. Skin-line extraction is an important preprocessing step in CAD systems; however, it is a challenging problem due to the presence of noise, underexposed regions, which results in a low contrast area near the skin-air interface, and artifacts such as labels. Our proposal utilizes the stroma edge to constrain searching for the border. In order to cope with noise, we consider several candidate points for the border interface which are obtained by the Laplace operator applied in pre-defined directions in the mammogram. The breast contour is obtained from the candidate points using a dynamic programming algorithm. This utilizes a criterion of optimality to obtain the optimum contour by minimization of a cost function. The method was evaluated using 82 mammograms whose contour were manually extracted by a radiologist from the mini-MIAS database. The Polyline Distance Measure was evaluated for each contour selected with the proposed method, obtaining a mean error of 2.05 pixels and a standard deviation of 0.80. PMID- 22256142 TI - Segmenting anatomy in chest x-rays for tuberculosis screening. AB - In this paper we describe the development of a screening system for pulmonary pathologies (i.e. pneumonia, tuberculosis) application in global healthcare settings. As a first step toward this goal, the paper presents a novel approach for detecting lungs and ribs in chest radiographs. The approach is a unified method combining two detection schemes resulting in reduced cost. The novelty of our approach lies on the fact that instead of using pixel-wise techniques exclusively we used region-based features computed as wavelet features that take into consideration the orientation of anatomic structures. Initial results are described. Next steps include classification of non-rib lung regions for radiographic patterns suggesting tuberculosis infection. PMID- 22256143 TI - Automated patient couch removal algorithm on CT images. AB - The current paper proposes a novel automated patient couch removal method on Computed Tomography (CT) images. Patient couch is often considered to be an unnecessary artifact especially when 3D rendered techniques are used. The method is based on measuring similarity between selected axial slices and the assumption that the bed object is constant on different slices. Due to the weight of the patient the couch could bend which is identifiable as sagittal movement on consecutive axial slices. Therefore the method focuses on finding this movement after an initial segmentation. According to initial validation performed on real medical data, our method is an effective tool to remove patient couch without user interaction. PMID- 22256144 TI - EMCCD-based high resolution dynamic x-ray detector for neurovascular interventions. AB - We have designed and developed from the discrete component level a high resolution dynamic detector for neurovascular interventions. The heart of the detector is a 1024 * 1024 pixel electron multiplying charge coupled device (EMCCD) with a pixel size of 13 * 13 MUm(2), bonded to a fiber optic plate (FOP), and optically coupled to a 350 MUm micro-columnar CsI(TI) scintillator via a 3.3:1 fiber optic taper (FOT). The detector provides x-ray images of 9 cycles/mm resolution at 15 frames/sec and real time live video at 30 frames/sec with binning at a lower resolution, both independent of gain applied to EMCCD, as needed for region-of-interest (ROI) image guidance during neurovascular interventions. PMID- 22256145 TI - Development of synchrotron radiation x-ray intravital microscopy for in vivo imaging of rat heart vascular function. AB - This study elucidates the vascular internal diameter response of coronary arterial circulation in closed-chest rats to evaluate endothelium-dependent and endothelium-independent vasodilatory ability and to investigate disease mechanisms. For this study, we developed an X-ray intravital microscopy system using a microangiography technique and a synchrotron radiation source at SPring 8. An X-ray direct-conversion type detector with 7-MUm spatial resolution was used for real-time imaging. Microangiographic images were stored in a digital frame memory system at a maximum rate of 30 frame/s with a 1024 * 1024-pixel, 10 bit format. In imaging experiments, the small coronary arteries were visualized after iodine contrast agent injection into the coronary artery. PMID- 22256146 TI - Two new stable anatomical landmarks on the Central Sulcus: definition, automatic detection, and their relationship with primary motor functions of the hand. AB - We present a method to automatically detect two new stable anatomical landmarks L(1) and L(2) on the Central Sulcus (CS). Those landmarks are shown to be representative of the Central Sulcus morphology and linked to the functional primary motor area of the hand. Detection is performed after introducing a new morphological characteristic, the sulcal profile. We show that when matching explicitly L(1) and L(2) across individuals the inter-subject matching of the central sulcus anatomy is improved, as well as the inter-subject matching of the primary motor area of the hand. This opens possibilities for morphological studies of the CS, more precise functional studies of primary motor function, and a better understanding of motor representations along the CS. PMID- 22256147 TI - Blob-like feature extraction and matching for brain MR images. AB - The cerebral cortex of the human brain is highly folded. It is useful for neuroscientists and clinical researchers to identify and/or quantify cortical folding patterns across individuals. The top (gyri) and bottom (sulci) of these folds resemble the "blob-like" features used in computer vision. In this article, we evaluate different blob detectors and descriptors on brain MR images, and introduce our own, the "brain blob detector and descriptor (BBDD)." For the first time blob detectors are considered as spatial filters under the scale-space framework and their impulse responses are manipulated for detecting the structures in our interest. The BBDD detector is tailored to the scale and structure of blob-like features that coincide with cortical folds, and its descriptors performed well at discriminating these features in our evaluation. PMID- 22256148 TI - Change detection and classification in brain MR images using change vector analysis. AB - The automatic detection of longitudinal changes in brain images is valuable in the assessment of disease evolution and treatment efficacy. Most existing change detection methods that are currently used in clinical research to monitor patients suffering from neurodegenerative diseases--such as Alzheimer's--focus on large-scale brain deformations. However, such patients often have other brain impairments, such as infarcts, white matter lesions and hemorrhages, which are typically overlooked by the deformation-based methods. Other unsupervised change detection algorithms have been proposed to detect tissue intensity changes. The outcome of these methods is typically a binary change map, which identifies changed brain regions. However, understanding what types of changes these regions underwent is likely to provide equally important information about lesion evolution. In this paper, we present an unsupervised 3D change detection method based on Change Vector Analysis. We compute and automatically threshold the Generalized Likelihood Ratio map to obtain a binary change map. Subsequently, we perform histogram-based clustering to classify the change vectors. We obtain a Kappa Index of 0.82 using various types of simulated lesions. The classification error is 2%. Finally, we are able to detect and discriminate both small changes and ventricle expansions in datasets from Mild Cognitive Impairment patients. PMID- 22256149 TI - Comparison between skeleton-based and atlas-based approach in the assessment of corpus callosum damages in Mild Cognitive Impairment and Alzheimer Disease. AB - The damage of specific bundles in the brain white matter (WM) is currently assessed in Alzheimer Disease (AD) and amnestic Mild Cognitive Impairment (aMCI) by tractography based on diffusion tensor imaging (DTI) and the consequent evaluation of diffusion parameters in reconstructed tracts. Controversial results may be due to the use of different techniques. This work aims at comparing an atlas-based technique to compute fractional anisotropy (FA) in specific tracts with the voxelwise approach of Tract-Based Spatial Statistics (TBSS). FA was evaluated in 7 portions of the corpus callosum (CC) of 10 elderly healthy controls (HC), 10 aMCI and 10 mild AD patients with both approaches. Atlas-based tractography revealed concordant results with TBSS, displaying the same significant differences between AD and HC and no significant difference between aMCI and HC. However, as regards the AD to aMCI contrast only the atlas-based method was able to find significantly lowered FA in AD in frontal and parietal CC portions. This finding shows that a proper analysis which considers a higher number of voxels, not restricting the observation to the skeleton in the assessment of CC damages, could be useful for AD to aMCI differential diagnosis and prognosis. PMID- 22256150 TI - Impact of Markov Random Field optimizer on MRI-based tissue segmentation in the aging brain. AB - Automatically segmenting brain magnetic resonance images into grey matter, white matter, and cerebrospinal fluid compartments is a fundamentally important neuroimaging problem whose difficulty is heightened in the presence of aging and neurodegenerative disease. Current methods overlap greatly in terms of identifiable algorithmic components, and the impact of specific components on performance is generally unclear in important real-world scenarios involving serial scanning, multiple scanners, and neurodegenerative disease. Therefore we evaluated the impact that one such component, the Markov Random Field (MRF) optimizer that encourages spatially-smooth tissue labelings, has on brain tissue segmentation performance. Two challenging elderly data sets were used to test segmentation consistency across scanners and biological plausibility of tissue change estimates; and a simulated young brain data set was used to test accuracy against ground truth. Belief propagation (BP) and graph cuts (GC), used as the MRF optimizer component of a standardized segmentation system, provide high segmentation performance on aggregate that is competitive with end-to-end systems provided by SPM and FSL (FAST) as well as the more traditional MRF optimizer iterated conditional modes (ICM). However, the relative performance of each method varied strongly by performance criterion and differed between young and old brains. The findings emphasize the unique difficulties involved in segmenting the aging brain, and suggest that optimal algorithm components may depend in part on performance criteria. PMID- 22256151 TI - A sparse based approach for detecting activations in fMRI. AB - In this paper, we propose a simple approach for detecting activated voxels in fMRI data by exploiting the inherent sparsity property of the BOLD signal. The proposed approach addresses the solution of the inverse problem induced by the General Linear Model through an l(0)-regularized Least Absolute Deviation (l(0) LAD) regression method. Under this framework, the activated voxels are detected by a two-stages process: estimation and basis selection. First, an estimate of the coefficients that minimizes the absolute deviation error is found by means of the weighted median operator. Then, a thresholding operator is applied on the estimated value in order to decide whether or not a stimulus is present in the observed BOLD signal. The threshold parameter turns out to be the regularization parameter that controls the model sparseness. The method was proven on real fMRI data leading to similar activated regions than those activated by the Statistical Parametric Mapping (SPM) software. PMID- 22256152 TI - Functional asymmetry in a five-link 3D bipedal walker. AB - This paper uses a symmetrical five-link 3D biped model to computationally investigate the cause, function, and benefit of gait asymmetry. We show that for a range of mass distributions, this model has asymmetric walking patterns between the left and right legs, which is due to a phenomenon known as period-doubling bifurcation. The ground reaction forces of each leg reflect different roles, roughly corresponding to support, propulsion, and motion control as proposed by the hypothesis of functional asymmetry in human walking. These results suggest that natural mechanics could be responsible for asymmetry in able-bodied walking, rather than neurophysiological mechanisms such as leg dominance. PMID- 22256153 TI - Wireless gyroscope suit for gait stability estimation. AB - Gait stability is primary in assessing individuals with high risk of falling, particularly the elderly. Custom made self-adjustable wireless gyroscope suit is used as a sensing device to quantify gait stability. A nonlinear time series analysis i.e. maximum Lyapunov exponent (lambda*) was employed to estimate the short term and long term stability and it is closely related to the ability of human neuro-muscular control system in maintaining gait stability. Experimental analysis and tests validated the efficacy of this novel approach. The results achieved are comparable with the findings of multiple kinematic and dynamic parameters derived from optical motion capture system and force platform which are widely used as gold standard. PMID- 22256154 TI - A method to simulate motor control strategies to recover from perturbations: application to a stumble recovery during gait. AB - Perturbations during human gait such as a trip or a slip can result in a fall, especially among frail populations such as the elderly. In order to recover from a trip or a stumble during gait, humans perform different types of recovery strategies. It is very useful to uncover the mechanisms of the recovery to improve training methods for populations at risk of falling. Moreover, human recovery strategies could be applied to implement controllers for bipedal robot walker, as an application of biomimetic design. A biomechanical model of the response to a trip during gait might uncover the control mechanisms underlying the different recovery strategies and the adaptation of the responses found during the execution of successive perturbation trials. This paper introduces a model of stumble in the multibody system framework. This model is used to assess different feedforward strategies to recover from a trip. First of all, normal gait patterns for the musculoskeletal system model are obtained by solving an optimal control problem. Secondly, the reference gait is perturbed by the application of forces on the swinging foot in different ways: as an instantaneous inelastic collision of the foot with an obstacle, as an impulsive horizontal force or using a force curve measured experimentally during gait perturbation experiments. The influence of the type of perturbation, the timing of the collision with respect to the gait cycle, as well as of the coefficient of restitution was investigated previously. Finally, in order to test the effects of different muscle excitation levels on the initial phases of the recovery response, several muscle excitations were added to selected muscles of the legs, thus providing a simulation of the recovery reactions. These results pave the way for future analysis and modeling of the control mechanisms of gait. PMID- 22256155 TI - The effect of perturbation onset timing and length on tripping recovery strategies. AB - In control subjects, trips during the early and late swing phase of walking elicit elevating and lowering strategies, respectively. However, the transition between these recovery strategies during mid-swing is unclear. A better understanding of this transition would provide insight into what factors cause individuals to choose one strategy over another. Three control subjects walked on a treadmill while attached to a custom-made tripping device. Perturbations of various lengths (ranging from 50 ms to 350 ms) were applied throughout the swing phase of gait. The results suggest that as perturbation length increased, the transition from elevating to lowering strategies occurred at earlier perturbation onsets. The transition period varied linearly with perturbation length. Perturbation lengths of 150 ms to 250 ms more closely replicated strategy selection in trips induced by real obstacles. Perturbations that are longer in duration force the transition from an elevating to a lowering strategy to occur at an earlier percentage of swing. These results show that perturbation length affects recovery strategy selection in response to trips. PMID- 22256156 TI - Mechanisms and models of postural stability and control. AB - Though simple in appearance, postural stabilization is a complex neuromuscular task requiring coordination among multiple joints. Mechanisms of postural stability and control in the body include supraspinal processes responsible for anticipatory postural adjustments (APA) and internal model control, lower level motor servo, and passive viscoelasticity of the musculo-tendon complex (MTC). Nevertheless, active control mechanisms may have limited effectiveness due to intrinsic delays in the reflex pathways and muscle low-pass characteristics. The use of control-oriented mathematical models, aided by analytical methods, help provide insight into neuro-physiology. Control of balance in human upright standing is particularly well suited for modeling, and is also a popular experimental paradigm. This paper examines neuro-physiological basis of postural stability and control in the background of popular biomechanic and neuroscientific models. PMID- 22256157 TI - Modeling the walking patterns of Reciprocating Gait Orthosis users with a novel Lower Limb Paralysis Simulator. AB - A mechanical Lower Limb Paralysis Simulator (LLPS) was developed for able-bodied persons to model the gait of Reciprocating Gait Orthosis (RGO) users. The purpose of this study was to determine if able-bodied subjects ambulating with the LLPS exhibited gait characteristics typical of RGO users. Five able-bodied persons were trained to ambulate with the LLPS and underwent a motion gait analysis. LLPS users were found to exhibit gait patterns that were characteristic of RGO assisted gait. PMID- 22256158 TI - A novel method of detection and classification of motor nerve late-wave activity. AB - In motor nerve conduction studies, important diagnostic information is provided by the late-wave responses, comprised of F-waves, A-waves, and repeaters. Late waves in addition to contamination from power line interference and baseline disturbance, are of low amplitude and random in nature. This makes computer-based analysis of late-wave activity very challenging, especially the computer-based F wave onset latency assignment. Currently available algorithms assign latency independently on a trace-by-trace basis without considering the information present in an entire ensemble of traces. A novel algorithm that takes into account the ensemble information for segmenting and classifying regions of late wave data is described in this paper, which in turn can be used to improve the performance of computer-based F-wave onset latency assignment. PMID- 22256159 TI - Classifying features of the Intrinsic Mode Functions generated by Empirical Mode Decomposition of isometric force response using a fuzzy classifier. AB - The analysis of isometric force may provide early detection of certain types of neuropathology such as Parkinson's disease. Our long term goal is to determine if there are detectable differences between model parameters of healthy verses unhealthy individuals. As a first step toward our long-term goal, we studied 24 healthy young adults ages 18 through 24 years, both male and female. The experiments involved the participants exerting isometric force over a range from 5% to 65% of maximal voluntary contraction. The analysis involved the steady state portion of the recorded time series. Each times-series was decomposed into a set of Intrinsic Mode Functions using Empirical Mode Decomposition. Next, eight features were extracted and used to train a Fuzzy Set Classifier. The participants in this study were assigned to two categories: (1) high strength; and (2) low strength based upon the values of the eight extracted features. Even though the participants were all healthy and young, the features exhibited enough differences to successfully classify 99% of the participants. This finding suggests that, when clinical data become available, the features extracted from the Intrinsic Mode Functions and input into the Fuzzy Set Classifier may be capable of discriminating between healthy individuals and those who are in an early stage of neurodegenerative disease. PMID- 22256160 TI - Hierarchical domain adaptation for SEMG signal classification across multiple subjects. AB - Large variations in Surface Electromyogram (SEMG) signal across different subjects make the process of automated signal classification as a generalized tool, challenging. In this paper, we propose a domain adaptation methodology that addresses this challenge. In particular we propose a hierarchical sample selection methodology, that selects samples from multiple training subjects, based on their similarity with the target subject at different levels of granularity. We have validated our framework on SEMG data collected from 8 people during a fatiguing exercise. Comprehensive experiments conducted in the paper demonstrate that the proposed method improves the subject independent classification accuracy by 21% to 23% over the cases without domain adaptation methods and by 14% to 20% over the existing state-of-the-art domain adaptation methods. PMID- 22256161 TI - Improving Parkinson's disease identification through evolutionary-based feature selection. AB - Parkinson's disease (PD) automatic identification has been actively pursued over several works in the literature. In this paper, we deal with this problem by applying evolutionary-based techniques in order to find the subset of features that maximize the accuracy of the Optimum-Path Forest (OPF) classifier. The reason for the choice of this classifier relies on its fast training phase, given that each possible solution to be optimized is guided by the OPF accuracy. We also show results that improved other ones recently obtained in the context of PD automatic identification. PMID- 22256162 TI - Programming an offline-analyzer of motor imagery signals via python language. AB - Brain Computer Interface (BCI) systems control the user's environment via his/her brain signals. Brain signals related to motor imagery (MI) have become a widespread method employed by the BCI community. Despite the large number of references describing the MI signal treatment, there is not enough information related to the available programming languages that could be suitable to develop a specific-purpose MI-based BCI. The present paper describes the development of an offline-analysis system based on MI-EEG signals via open-source programming languages, and the assessment of the system using electrical activity recorded from three subjects. The analyzer recognized at least 63% of the MI signals corresponding to three classes. The results of the offline analysis showed a promising performance considering that the subjects have never undergone MI trainings. PMID- 22256163 TI - Basic study on combined motion estimation using multichannel surface EMG signals. AB - To improve degree of freedom (DOF) of system control using surface electromyogram (SEMG), we made a basic study of the estimation of user's intended motion including combined motion which is performed by more than one basic motion simultaneously. Our developed system requested to obtain three SEMG characteristics of basic motion and one SEMG characteristics of rest state. This study defines the motion of grasp, supination and pronation as basic motion, and two combined motion which is "grasp +supination" and "grasp + pronation" are set. Our system investigates the possibility of combined motion estimation based on SEMG characteristics of basic motions. Estimation method which is utilizing optimal SEMG that are derived from multichannel SEMG signals is performed by canonical discriminant space and tendency of degree of similarity between combined motion and basic motion. In experimental results, we succeeded in estimation of combined motion although it was included an estimation of basic motions which were constructed elements of combined motion. PMID- 22256164 TI - A system for activity recognition using multi-sensor fusion. AB - This paper proposes a system for activity recognition using multi-sensor fusion. In this system, four sensors are attached to the waist, chest, thigh, and side of the body. In the study we present two solutions for factors that affect the activity recognition accuracy: the calibration drift and the sensor orientation changing. The datasets used to evaluate this system were collected from 8 subjects who were asked to perform 8 scripted normal activities of daily living (ADL), three times each. The Naive Bayes classifier using multi-sensor fusion is adopted and achieves 70.88%-97.66% recognition accuracies for 1-4 sensors. PMID- 22256165 TI - Gabor filter for enhanced recognition of assisted turning events. AB - Nursing facility residents at high risk for pressure ulcers are turned in bed by staff at regular intervals. In an ongoing large, multi-site randomized clinical trial (RCT) the impacts of 2, 3, and 4 hour turning intervals are being studied on pressure ulcer outcomes. In the RCT, it is necessary to objectively confirm the reported times of assisted turning by certified nurse assistants using activity data. Activity peaks in Gaussian-smoothed activity data were unable to confirm all turning events in a supporting pilot study with observer notes of assisted turns. A new technique is presented using one-dimensional Gabor filters that enhances activity peaks due to turning events and diminishes the signal during extended activity. As a result, all assisted turns in the pilot study were detected and confirmed. Moreover, the dependence of detection sensitivity on decision threshold is lowered in this method. PMID- 22256166 TI - Accelerometer-based fetal movement detection. AB - Monitoring fetal wellbeing is a compelling problem in modern obstetrics. Clinicians have become increasingly aware of the link between fetal activity (movement), well-being, and later developmental outcome. We have recently developed an ambulatory accelerometer-based fetal activity monitor (AFAM) to record 24-hour fetal movement. Using this system, we aim at developing signal processing methods to automatically detect and quantitatively characterize fetal movements. The first step in this direction is to test the performance of the accelerometer in detecting fetal movement against real-time ultrasound imaging (taken as the gold standard). This paper reports first results of this performance analysis. PMID- 22256167 TI - A method for classification of movements in bed. AB - Sleep is characterized by episodes of immobility interrupted by periods of voluntary and involuntary movement. Increased mobility in bed can be a sign of disrupted sleep that may reduce sleep quality. This paper describes a method for classification of the type of movement in bed using load cells installed at the corners of a bed. The approach is based on Gaussian Mixture Models using a time domain feature representation. The movement classification system is evaluated on data collected in the laboratory, and it classified correctly 84.6% of movements. The unobtrusive aspect of this approach is particularly valuable for longer-term home monitoring against a standard clinical setting. PMID- 22256168 TI - 3D accelerometer features' differences between young and older people, and between lower back and neck band sensor placements. AB - In the earlier studies we have developed activity recognition algorithms which are based on features calculated from data of 3D accelerometer sensor placed on the hip, close to the centre of mass. In the development subjects have been young adults. Now we study if the input features of the algorithm are generalized for different set-ups; for older adults and when the sensor is worn as a necklace. From the 3D accelerometer resultant magnitude the following features were calculated for each second: spectral entropy, peak frequency, power and range. The frequency domain features behaved in a relatively stable manner in the set ups but the time domain features differed significantly from statistical and algorithm perspective between the set-ups. By developing time domain features to be more inter-individual independent would be beneficial for activity recognition algorithms. PMID- 22256169 TI - Adaptive neuro-fuzzy logic analysis based on myoelectric signals for multifunction prosthesis control. AB - The myoelectric signal is a sign of control of the human body that contains the information of the user's intent to contract a muscle and, therefore, make a move. Studies shows that the Amputees are able to generate standardized myoelectric signals repeatedly before of the intention to perform a certain movement. This paper presents a study that investigates the use of forearm surface electromyography (sEMG) signals for classification of five distinguish movements of the arm using just three pairs of surface electrodes located in strategic places. The classification is done by an adaptive neuro-fuzzy inference system (ANFIS) to process signal features to recognize performed movements. The average accuracy reached for the classification of five motion classes was 86-98% for three subjects. PMID- 22256170 TI - Application of fractal dimension on vestibular response signals for diagnosis of Parkinson's disease. AB - In this paper, a novel method based on analysis of dynamic response of vestibular system for diagnosis of Parkinson's Disease (PD) is introduced. Electrovestibulography (EVestG) signals are recorded from the ear canal in response to a vestibular stimulus. EVestG signals are in fact the vestibular response modulated by more cortical brain signals. We used EVestG data of 20 patients with PD and 26 age-matched healthy controls recorded in a previous study. We calculated the Katz Fractal Dimension (FD) of the extracted timing signal of firings during contralateral and ipsilateral stimuli of both left and right ear. We used multivariate analysis of variance (MANOVA) to select pairs of features showing the most significant differences between the groups. Then, Linear and Quadratic Discriminant (LDA, QDA) classification algorithms were applied on the selected features. The results have shown above 77.27% accuracy. Given the small population of the subjects and the patients were at different stage of disease, the results encourage continuing exploration of the application of EVestG for PD diagnosis and perhaps as a quick and non-invasive screening tool. PMID- 22256171 TI - Optimum gravity vector and vertical acceleration estimation using a tri-axial accelerometer for falls and normal activities. AB - This study aims to determine an optimum estimate for the gravitational vector and vertical acceleration profiles using a body-worn tri-axial accelerometer during falls and normal activities of daily living (ADL), validated using a camera based motion analysis system. Five young healthy subjects performed a number of simulated falls and normal ADL while trunk kinematics were measured by both an optical motion analysis system and a tri-axial accelerometer. Through low-pass filtering of the trunk tri-axial accelerometer signal between 1 Hz and 2.7 Hz using a 1(st) order or higher, Butterworth IIR filter, accurate gravity vector profile can be obtained using the method described here. RESULTS: A high mean correlation (>= 0.83: Coefficient of Multiple Correlations) and low mean percentage error (<= 2.06 m/s(2)) were found between the vertical acceleration profile generated from the tri-axial accelerometer based sensor to those from the optical motion capture system. This proposed system enables optimum gravity vector and vertical acceleration profiles to be measured from the trunk during falls and normal ADL. PMID- 22256172 TI - Gait feature extraction in Parkinson's disease using low-cost accelerometers. AB - The clinical hallmarks of Parkinson's disease (PD) are movement poverty and slowness (i.e. bradykinesia), muscle rigidity, limb tremor or gait disturbances. Parkinson's gait includes slowness, shuffling, short steps, freezing of gait (FoG) and/or asymmetries in gait. There are currently no validated clinical instruments or device that allow a full characterization of gait disturbances in PD. As a step towards this goal, a four accelerometer-based system is proposed to increase the number of parameters that can be extracted to characterize parkinsonian gait disturbances such as FoG or gait asymmetries. After developing the hardware, an algorithm has been developed, that automatically epoched the signals on a stride-by-stride basis and quantified, among others, the gait velocity, the stride time, the stance and swing phases, the single and double support phases or the maximum acceleration at toe-off, as validated by visual inspection of video recordings during the task. The results obtained in a PD patient and a healthy volunteer are presented. The FoG detection will be improved using time-frequency analysis and the system is about to be validated with a state-of-the-art 3D movement analysis system. PMID- 22256173 TI - Wireless accelerometer iPod application for quantifying gait characteristics. AB - The capability to quantify gait characteristics through a wireless accelerometer iPod application in an effectively autonomous environment may alleviate the progressive strain on highly specific medical resources. The iPod consists of the inherent attributes imperative for robust gait quantification, such as a three dimensional accelerometer, data storage, flexible software, and the capacity for wireless transmission of the gait data through email. Based on the synthesis of the integral components of the iPod, a wireless accelerometer iPod application for quantifying gait characteristics has been tested and evaluated in an essentially autonomous environment. The quantified gait acceleration waveforms were wirelessly transmitted using email for postprocessing. The site for the gait experiment occurred in a remote location relative to the location where the postprocessing was conducted. The wireless accelerometer iPod application for quantifying gait characteristics demonstrated sufficient accuracy and consistency. PMID- 22256174 TI - Frequency tracking and variable bandwidth for line noise filtering without a reference. AB - This paper presents a method for filtering line noise using an adaptive noise canceling (ANC) technique. This method effectively eliminates the sinusoidal contamination while achieving a narrower bandwidth than typical notch filters and without relying on the availability of a noise reference signal as ANC methods normally do. A sinusoidal reference is instead digitally generated and the filter efficiently tracks the power line frequency, which drifts around a known value. The filter's learning rate is also automatically adjusted to achieve faster and more accurate convergence and to control the filter's bandwidth. In this paper the focus of the discussion and the data will be electrocorticographic (ECoG) neural signals, but the presented technique is applicable to other recordings. PMID- 22256175 TI - Adaptive cancellation of variable feedback path for hearing aid using misalignment-dependent step size values. AB - Various methods have been proposed to overcome the problem of compensating the acoustic feedback path that negatively impacts the performance of hearing aid devices. However, in most of them feedback path model is assumed to be fixed which is not quite realistic. In this paper, we consider fixed and variable feedback paths and analyze for each case the performance of one of the robust Adaptive Feedback Cancellation (AFC) schemes, i.e. the Prediction Error Method AFC which uses Partitioned Block Frequency-Domain Normalized Least Mean Square (PBFD-NLMS) algorithm. Based on the analysis results we propose varying the step size values for the same adaptive algorithm on the fly by monitoring the misalignment criteria. The experimental results using the proposed method show improvement made on the system performance. PMID- 22256176 TI - Noise reduction for binaural hearing aids using unsupervised diffuse noise estimator. AB - In this paper a new noise reduction algorithm for binaural hearing aids is proposed. This algorithm is capable of suppressing both nonstationary diffuse noise and unknown directional interferences without distorting the directional cues. For the estimation of the diffuse noise power spectral density (PSD), we utilize the eigenstructure of the 2 * 2 input covariance matrix, together with a compensation process for preventing the underestimation at low frequencies. The interference PSD is estimated from the target cancelled input signals through the signal prediction. Effectiveness of the proposed algorithm was confirmed according to the computer simulations in terms of noise reduction and binaural cue preservation. PMID- 22256177 TI - A new delayless sub-band filtering method for cancelling the effect of feedback path in hearing aid systems. AB - Performance of commonly used Hearing aid systems is degraded by the presence of acoustic feedback between loudspeaker and microphone. Prediction Error Method Adaptive Feedback Canceller (PEM-AFC) has been proposed recently that could attenuate the feedback effect. In this paper, we present a new delayless frequency-based sub-band filtering method for alleviating the effect of feedback path for the Hearing aid systems. The proposed method avoids sub-band distortions and has low computational complexity making it suitable for low-power cost effective hearing aid system designs. Performances of the two methods are compared and simulation results are presented. PMID- 22256178 TI - Eye position prediction in the case of nystagmus and refixations. AB - Nystagmus is a condition in which the eyes move in an uncontrolled fashion. These eye movements confound attempts to identify patient fixation, as desired eye positions cannot be maintained. We aim to estimate the eye positions in the case of refixations and superimposed uncontrolled motion. By incorporating saccade detection and resetting our estimation algorithms, we are able to track the nystagmus motion independently of fixation direction. We employ our algorithm on data collected from patients with latent/manifest-latent and pendular nystagmus conditions. PMID- 22256179 TI - Automatic continuous ECG monitoring system for over-drug detection in Brugada Syndrome. AB - This paper is concerned with the automatic control of drug administration in patients suffering from Brugada Syndrome (BS). Drugs such as flecainide, procainamide, ajmaline and pilsicainide should be administrated under carefully controlled electrocardiogram (ECG) monitoring given that the treatment must be stopped if some ECG disturbing conditions appear. These conditions are, among others the development of premature ventricular contraction (PVC), atrial fibrillation (AF) and the widening of the QRS wave. The proposed system can detect these abnormalities by using a pattern recognition approach based on Hidden Markov Models (HMM) with features extracted from three scales of the Wavelet Transform (WT). Performances higher than 98% were reached regarding the classification of normal and abnormal pulses. The system was trained and tested mainly in data from the standard MIT-BIH arrhythmia database. PMID- 22256180 TI - Adaptive filtering for suppression of respiratory artifact in impedance cardiography. AB - Impedance cardiography is a noninvasive technique, based on sensing the variation in the electrical impedance of the thorax caused by variation in the blood volume during the cardiac cycle, for monitoring the stroke volume and some other cardiovascular indices. Respiratory and motion artifacts cause baseline drift in the sensed impedance waveform, particularly during or after exercise. This paper presents an LMS-based adaptive filtering technique for suppression of respiratory artifact for improving the estimation of the indices without smearing the beat-to beat variations. It uses a reference signal, closely related to the respiratory artifact, obtained by a least-squares approximation based B-spline fitting on the contaminated impedance cardiogram in synchronism with the respiratory phases. The technique is evaluated on signals with simulated artifacts and on signals from nine healthy subjects and five patients with cardiovascular disorders. The values of the stroke volume, estimated on beat-to-beat basis, after suppression of respiratory artifact showed a good agreement with those from Doppler echocardiography. PMID- 22256181 TI - Adaptive comb filtering for motion artifact reduction from PPG with a structure of adaptive lattice IIR notch filter. AB - Photoplethysmographic (PPG) signal can provide important information about cardiovascular and respiratory conditions of individuals in a hospital or daily life. However, PPG can be distorted by motion artifacts significantly. Therefore, the reduction of the effects of motion artifacts is very important procedure for monitoring cardio-respiratory system by PPG. There have been many adaptive techniques to reduce motion artifacts from PPG signal including normalized least mean squares (NLMS) method, recursive least squares (RLS) filter, and Kalman filter. In the present study, we propose the adaptive comb filter (ACF) for reducing the effects of motion artifacts from PPG signal. ACF with adaptive lattice infinite impulse response (IIR) notch filter (ALNF) successfully reduced the motion artifacts from the quasi-periodic PPG signal. PMID- 22256182 TI - CleanEMG--power line interference estimation in sEMG using an adaptive least squares algorithm. AB - This paper presents an adaptive least squares algorithm for estimating the power line interference in surface electromyography (sEMG) signals. The algorithm estimates the power line interference, without the need for a reference input. Power line interference can be removed by subtracting the estimate from the original sEMG signal. The algorithm is evaluated with simulated sEMG based on its ability to accurately estimate power line interference at different frequencies and at various signal-to-noise ratios. Power line estimates produced by the algorithm are accurate for signal-to-noise ratios below 15 dB (SNR estimation error at 15 dB is 14.7995 dB + 1.6547 dB). PMID- 22256183 TI - Predicting human subcutaneous glucose concentration in real time: a universal data-driven approach. AB - Continuous glucose monitoring (CGM) devices measure and record a patient's subcutaneous glucose concentration as frequently as every minute for up to several days. When coupled with data-driven mathematical models, CGM data can be used for short-term prediction of glucose concentrations in diabetic patients. In this study, we present a real-time implementation of a previously developed offline data-driven algorithm. The implementation consists of a Kalman filter for real-time filtering of CGM data and a data-driven autoregressive model for prediction. Results based on CGM data from 3 different studies involving 34 type 1 and 2 diabetic patients suggest that the proposed real-time approach can yield ~10-min-ahead predictions with clinically acceptable accuracy and, hence, could be useful as a tool for warning against impending glucose deregulation episodes. The results further support the feasibility of "universal" glucose prediction models, where an offline-developed model based on one individual's data can be used to predict the glucose levels of any other individual in real time. PMID- 22256184 TI - Characterization of subcortical structures during deep brain stimulation utilizing support vector machines. AB - In this paper we discuss an efficient methodology for the characterization of Microelectrode Recordings (MER) obtained during deep brain stimulation surgery for Parkinson's disease using Support Vector Machines and present the results of a preliminary study. The methodology is based in two algorithms: (1) an algorithm extracts multiple computational features from the microelectrode neurophysiology, and (2) integrates them in the support vector machines algorithm for classification. It has been applied to the problem of the recognition of subcortical structures: thalamus nucleus, zona incerta, subthalamic nucleus and substantia nigra. The SVM (support vector machines) algorithm performed quite well achieving 99.4% correct classification. In conclusion, the use of a computer based system, like the one described in this paper, is intended to avoid human subjectivity in the localization of the subcortical structures and mainly the subthalamic nucleus (STN) for neurostimulation. PMID- 22256185 TI - Parallel artefact rejection for epileptiform activity detection in routine EEG. AB - The EEG signal is very often contaminated by electrical activity external to the brain. These artefacts make the accurate detection of epileptiform activity more difficult. A scheme developed to improve the detection of these artefacts (and hence epileptiform event detection) is introduced. A structure of parallel Support Vector Machine classifiers is assembled, one classifier tuned to perform the identification of epileptiform activity, the remainder trained for the detection of ocular and movement-related artefacts. This strategy enables an absolute reduction in false detection rate of 21.6% with the constraint of ensuring all epileptic events are recognized. Such a scheme is desirable given that sections of data which are heavily contaminated with artefact need not be excluded from analysis. PMID- 22256186 TI - Machine Learning classification of MRI features of Alzheimer's disease and mild cognitive impairment subjects to reduce the sample size in clinical trials. AB - There is a need for objective tools to help clinicians to diagnose Alzheimer's Disease (AD) early and accurately and to conduct Clinical Trials (CTs) with fewer patients. Magnetic Resonance Imaging (MRI) is a promising AD biomarker but no single MRI feature is optimal for all disease stages. Machine Learning classification can address these challenges. In this study, we have investigated the classification of MRI features from AD, Mild Cognitive Impairment (MCI), and control subjects from ADNI with four techniques. The highest accuracy rates for the classification of controls against ADs and MCIs were 89.2% and 72.7%, respectively. Moreover, we used the classifiers to select AD and MCI subjects who are most likely to decline for inclusion in hypothetical CTs. Using the hippocampal volume as an outcome measure, we found that the required group sizes for the CTs were reduced from 197 to 117 AD patients and from 366 to 215 MCI subjects. PMID- 22256187 TI - Ventricular repolarization variability for hypoglycemia detection. AB - Hypoglycemia is the most acute and common complication of Type 1 diabetes and is a limiting factor in a glycemic management of diabetes. In this paper, two main contributions are presented; firstly, ventricular repolarization variabilities are introduced for hypoglycemia detection, and secondly, a swarm-based support vector machine (SVM) algorithm with the inputs of the repolarization variabilities is developed to detect hypoglycemia. By using the algorithm and including several repolarization variabilities as inputs, the best hypoglycemia detection performance is found with sensitivity and specificity of 82.14% and 60.19%, respectively. PMID- 22256188 TI - Classification of astrocytomas and oligodendrogliomas from mass spectrometry data using sparse kernel machines. AB - Glioma histologies are the primary factor in prognostic estimates and are used in determining the proper course of treatment. Furthermore, due to the sensitivity of cranial environments, real-time tumor-cell classification and boundary detection can aid in the precision and completeness of tumor resection. A recent improvement to mass spectrometry known as desorption electrospray ionization operates in an ambient environment without the application of a preparation compound. This allows for a real-time acquisition of mass spectra during surgeries and other live operations. In this paper, we present a framework using sparse kernel machines to determine a glioma sample's histopathological subtype by analyzing its chemical composition acquired by desorption electrospray ionization mass spectrometry. PMID- 22256189 TI - Brain tissue segmentation in PET-CT images using probabilistic atlas and variational Bayes inference. AB - PET-CT provides aligned anatomical (CT) and functional (PET) images in a single scan, and has the potential to improve brain PET image segmentation, which can in turn improve quantitative clinical analyses. We propose a statistical segmentation algorithm that incorporates the prior anatomical knowledge represented by probabilistic brain atlas into the variational Bayes inference to delineate gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) in brain PET-CT images. Our approach adds an additional novel aspect by allowing voxels to have variable and adaptive prior probabilities of belonging to each class. We compared our algorithm to the segmentation approaches implemented in the expectation maximization segmentation (EMS) and statistical parametric mapping (SPM8) packages in 26 clinical cases. The results show that our algorithm improves the accuracy of brain PET-CT image segmentation. PMID- 22256190 TI - Segmentation of brain tumors in MRI images using multi-scale gradient vector flow. AB - The gradient vector flow (GVF) algorithm has been used extensively as an efficient method for medical image segmentation. This algorithm suffers from poor robustness against noise as well as lack of convergence in small scale details and concavities. As a cure to this problem, in this paper the idea of multi scale is applied to the traditional GVF algorithm for segmentation of brain tumors in MRI images. Using this idea, the active contour is evolved with respect to scaled edge maps in a multi scale manner. The edge detection performance of the modified GVF algorithm is further enhanced by applying a threshold-based edge detector to improve the edge map. The Bspline snake is selected for representation of the active contour, due to its ability to capture corners and its local control. The results showed an improvement of 30% in the accuracy of tumor segmentation against traditional GVF and 10 % as compared to Bspline GVF in the presence of noise, besides the repeatability of the algorithm in contrast to traditional GVF. The clinical evaluation also proved the accuracy and sensitivity of the proposed method as 92.8% and 95.4%, respectively. PMID- 22256191 TI - A feature-based approach for refinement of model-based segmentation of low contrast structures. AB - Accuracy and robustness are fundamental requirements of any automated method used for segmentation of medical images. Model-based segmentation (MBS) is a well established technique, where uncertainties in image content can be to a certain extent compensated by the use of prior shape information. This approach is, however, often problematic in cases where image information does not allow for generating a strong feature response, one example being soft tissue organs in CT data, which typically appear in low contrast. In this paper, we enhance our recently proposed framework for voxel classification-based refinement of MBS using a level-set segmentation technique with shape priors. We also introduce a novel feature weighting methodology that improves the performance of the classifier, demonstrating results superior to the previous feature selection method. Results of fully automated segmentation of low contrast organs in head and neck CT are presented. Compared to our previous approach, we have achieved an increase of up to 22% in segmentation accuracy. PMID- 22256192 TI - Automatic 3D graph cuts for brain cortex segmentation in patients with focal cortical dysplasia. AB - In patients with intractable epilepsy, focal cortical dysplasia (FCD) is the most frequent malformation of cortical development. Identification of subtle FCD lesions using brain MRI scans is very often based on the cortical thickness measurement, where brain cortex segmentation is required as a preprocessing step. However, the accuracy of the selected segmentation method can highly affect the final FCD lesion detection. In this work, we propose an improved graph cuts algorithm integrating Markov random field-based energy function for more accurate brain cortex MRI segmentation. Our method uses three-label graph cuts and preforms automatic 3D MRI brain cortex segmentation integrating intensity and boundary information. The performance of the method is tested on both simulated MR brain images with different noise levels and real patients with FCD lesions. Experimental quantitative segmentation results showed that the proposed method is effective, robust to noise and achieves higher accuracy than other popular brain MRI segmentation methods. The qualitative validation, visually verified by a medical expert, showed that the FCD lesions were segmented well as a part of the cortex, indicating increased thickness and cortical deformation. The proposed technique can be successfully used in this, as well as in many other clinical applications. PMID- 22256193 TI - Temporal segmentation of lung region from MRI sequences using multiple active contours. AB - Segmentation of the lung is particularly difficult because of the large variation in image quality. A modified Hough transform in combination with a mask creation algorithm can robustly determine synchronous respiratory patterns. The synchronicity restriction is relaxed by applying a greedy active contour algorithm. The respiratory patterns define a point cloud near the lung region boundary representing a subjective contour. The gravitation vector field (GVF) active contour algorithm is used to create an initial segmentation exclusively based on the point cloud. A final active contours algorithm is executed to adjust the boundary to the images. The algorithm was tested with healthy subjects and COPD patients, and the result was checked through temporal registration of coronal and sagittal images. PMID- 22256194 TI - Boundary delineation for hepatic hemangioma in ultrasound images. AB - Hemangioma is one of the most common benign congenital complications of the human body which can arise in interior organs and external limbs. The main aim of this work is to present a new method for automatic detection of liver hemangioma and its boundaries in ultrasound images, using image processing techniques. Overall there are two phases, the preprocessing procedure and the boundary delineation phase. The preprocessing phase includes three main stages: 1. Image contrast enhancement using Difference of Offset Gaussian (DoOG) method, 2. Applying Canny edge filtering, 3. Applying an adaptive threshold in order to detect the ROI (hemangioma). Following, the snake algorithm is used to segment the hemangioma region in the second phase. For the quantitative assessment of the proposed method for the segmentation stage, the results derived via the proposed algorithms have been compared with the corresponding segmented regions determined by an expert using three similarity criteria. The results showed 73 percent similarity without pre-processing and 90 percent similarity with pre-processing. PMID- 22256195 TI - Automated segmentation of recuts abdominis muscle using shape model in X-ray CT images. AB - Our purpose in this study is to segment the rectus abdominis muscle region in X ray CT images, and we propose a novel recognition method based on the shape model. In this method, three steps are included in the segmentation process. The first is to generate a shape model for the rectus abdominis muscle. The second is to recognize anatomical feature points corresponding to the origin and insertion of the muscle, and the third is to segment the rectus abdominis muscles based on the shape model. We generated the shape model from 20 CT cases and tested the model to recognize the muscle in 20 other CT cases. The average values for the Jaccard similarity coefficient (JSC) and true segmentation coefficient (TSC) were 0.841 and 0.863, respectively. The results suggest the validity of the model based segmentation for the rectus abdominis muscle. PMID- 22256196 TI - Unsupervised malaria parasite detection based on phase spectrum. AB - In this paper, we propose a novel method for malaria parasite detection based on phase spectrum. The method first obtains the amplitude spectrum and phase spectrum for blood smear images through Quaternion Fourier Transform (QFT). Then it gets the reconstructed image based on Inverse Quaternion Fourier transform (IQFT) on a constant amplitude spectrum and the original phase spectrum. The malaria parasite areas can be detected easily from the reconstructed blood smear images. Extensive experiments have demonstrated the effectiveness of this novel method. PMID- 22256197 TI - Maximal curvature-based segmentation of 3D vessel contours. AB - The segmentation of three-dimensional vascular trees is an important topic in medical image processing. Although it may seem to be an easy task, many different techniques have been proposed in the literature during the last decade and many difficulties remain. One can wonder why the human eye is usually able to understand the connectivity and the topology of the different structures while most algorithms fail to do so. In this paper, we propose an original approach that classifies the different contours by applying a geodesic distance transform on the contours of the vessels, where the evolution speed depends directly on the maximal curvature of the contours. This proposition comes from the observation that the maximal curvature on a standard vessel is usually positive and almost constant while it approaches zero or becomes negative on the contour at the contact with other structures. We describe our method in details and present promising results on synthetic and real images, where the method has been able to detect complex vascular structures without leaking into bones or mixing different vascular networks. PMID- 22256198 TI - A computer-aided method for automatic localization and thickness measurement of peritoneum in ultrasound images. AB - This paper presents a method of automatically measuring peritoneum thickness in ultrasound images. In our previous work, a method of manually selecting the region of interest (ROI) area has been developed. To achieve an automatic ROI area selection, two phases: Gaussian high-pass filtering and bilateral filtering, are used in the proposed method. In the bilateral filtering phase, the ultrasound image is enhanced for obtaining more details of the peritoneum so that probable areas can be extracted. In the other phase, the ultrasound image is processed with a Gaussian high pass filter, and the result is used to locate the precise area of peritoneum in the first phase result. The experimental results show that the proposed method has high accuracy and fast processing speed in determining the peritoneum area and its thickness distribution. PMID- 22256199 TI - Model-based segmentation of flexor tendons from magnetic resonance images of finger joints. AB - Trigger finger is a common hand disease, causing swelling, painful popping and clicking in moving the affected finger joint. To better evaluate patients with trigger finger, segmentation of flexor tendons from magnetic resonance (MR) images of finger joints, which can offer detailed structural information of tendons to clinicians, is essential. This paper presents a novel model-based method with three stages for automatically segmenting the flexor tendons. In the first stage, a set of tendon contour models (TCMs) is initialized from the most proximal cross-sectional image via two-step ellipse estimation. Each of the TCMs is then propagated to its distally adjacent image by affine registration. The propagation is sequentially performed along the proximal-distal direction until the most distal image is reached, as the second stage of segmentation. The TCMs on each cross-sectional image are refined in the last stage with the snake deformation. MR volumes of three subjects were used to validate the segmentation accuracy. Compared with the manual results, our method showed good accuracy with small average margins of errors (within 0.5 mm) and large overlapping ratio (dice similarity coefficient above 0.8). Overall, the proposed method has great potential for morphological change assessment of flexor tendons and pulley-tendon system modeling for image guided surgery. PMID- 22256200 TI - Digital staining for histopathology multispectral images by the combined application of spectral enhancement and spectral transformation. AB - In this paper we introduced a digital staining method for histopathology images captured with an n-band multispectral camera. The method consisted of two major processes: enhancement of the original spectral transmittance and the transformation of the enhanced transmittance to its target spectral configuration. Enhancement is accomplished by shifting the original transmittance with the scaled difference between the original transmittance and the transmittance estimated with m dominant principal component (PC) vectors;the m-PC vectors were determined from the transmittance samples of the background image. Transformation of the enhanced transmittance to the target spectral configuration was done using an nxn transformation matrix, which was derived by applying a least square method to the enhanced and target spectral training data samples of the different tissue components. Experimental results on the digital conversion of a hematoxylin and eosin (H&E) stained multispectral image to its Masson's trichrome stained (MT) equivalent shows the viability of the method. PMID- 22256201 TI - Substituting depth for intensity and real-time phosphene rendering: visual navigation under low vision conditions. AB - Navigation and way finding including obstacle avoidance is difficult when visual perception is limited to low resolution, such as is currently available on a bionic eye. Depth visualisation may be a suitable alternative. Such an approach can be evaluated using simulated phosphenes with a wearable mobile virtual reality kit. In this paper, we present two novel approaches: (i) an implementation of depth visualisation; and, (ii) novel methods for rapid rendering of simulated phosphenes with an empirical comparison between them. Our new software-based method for simulated phosphene rendering shows large speed improvements, facilitating the display in real-time of a large number of phosphenes with size and brightness dependent on pixel intensity, and with customised output dynamic range. Further, we describe the protocol, navigation environment and system used for visual navigation experiments to evaluate the use of depth on low resolution simulations of a bionic eye perceptual experience. Results for these experiments show that a depth-based representation is effective for navigation, and shows significant advantages over intensity-based approaches when overhanging obstacles are present. The results of the experiments were reported in [1], [2]. PMID- 22256202 TI - Automatic quantification and 3D visualisation of edema in cardiac MRI. AB - Viability assessment of heart muscle after a myocardial infarction is an important step for diagnosis and therapy planning. It is important to quantify the area of edema because it can differentiate between viable and death myocardial tissues. In this paper an automatic method to quantify cardiac edema is presented. The method is based on a combination of morphological operations and statistical thresholding. Using real MRI data it is demonstrated that the proposed method can delineate edema region comparable to manual segmentation with a linear correlation coefficient r=0.76 and the mean difference is around 9.95%. The quantification result is also used to generate 3D visualisation model showing normal myocardial wall and edema region, which will enhance clinician diagnosis capability with real pattern of edema distribution and quantitative description. PMID- 22256203 TI - An extended registration framework for the triple registration of IBZM SPECT, DATSCAN SPECT and MRI brain images to support the evaluation of brain dopamine receptor scintigraphies. AB - An extended registration model is presented to register medical image triples acquired for brain dopamine receptor scintigraphies. The model operates with rigid and nonlinear transformations in parallel, where all transformation parameters are optimized by one optimization method. The concept of the transformation-sampling-similarity measurement minimizes the memory usage of a real implementation. A partial-fine sampling method is proposed to decrease the processing time of the registration. Real medical data was collected to compare our method with well-known prior ones. The first tests show that the model outperforms the classic registration methods in both speed and accuracy. PMID- 22256204 TI - A fully automatic method to register the prostate gland on T2-weighted and EPI DWI images. AB - Prostate adenocarcinoma (PCa) is the most frequent noncutaneous cancer among men in developed countries. Magnetic Resonance (MR) has been used to detect PCa and several clinical trials report on the accuracy of the test. Multiparametric MR imaging (mpMRI) is defined as the integration of information from different morphological and functional datasets. mpMRI could be used to increase the performances of prostate MR, therefore allowing a more accurate assessment of the tumor gland extent, while reducing reporting time and interobserver variability. The first step to perform such a multiparametric analysis is to correct for voluntary and involuntary movements during the acquisitions, as well as for image distortion in the Diffusion Weighted (DWI) images. The aim of this work is to present a fully automatic registration algorithm between T2w and DWI images, able to realign the images and to correct the distortions in the DWI. Results showed a good overlap after registration and a strong decrease of mean surface distance in both the central gland and peripheral zone. These promising results suggest that the algorithm could be integrated in a CAD system which will combine the pharmacokinetic parameters derived from DCE-MRI, T2w MRI and DWI MR to generate one comprehensive value assessing the risk of malignancy. However to perform such a multiparametric analysis, it is necessary to correct for voluntary and involuntary (breathing, heart beating) movements during the DCE-MRI acquisition, and to realign also the DCE-MRI sequence to the T2w sequence. PMID- 22256205 TI - Segmentation of lumbar vertebrae from clinical CT using active shape models and GVF-snake. AB - Lumbar area of the vertebral column bears the most load of the human body and thus it is responsible for the major portion of lower back pain from which 80% to 90% of people suffer from during their lifetime. Vertebra related diseases are mainly fracture and are usually diagnosed from X-ray radiographs or CT scans depending on the severity of the problem. In this paper, we propose a fully automated lumbar vertebra segmentation that accurately and robustly produces a smooth contour around each of the vertebrae. This segmentation is very useful in any subsequent CAD system for diagnosis and quantification of vertebrae fractures. It also serves the radiologist during the clinical routine. Our method shows an excellent level of vertebra boundary smootheness that was visually approved by our collaborating radiologist for each vertebra and each case from our fifty cases dataset that includes both normal and abnormal cases. PMID- 22256206 TI - Investigation on the use of deformable registrations in lymph node tracking over time. AB - Evolutionary features of lymph nodes such as change in size over time are decisive descriptors to assess disease progression in cancer patient. Other than study at one point in time, it is more useful to derive temporal analysis on structures of interest. The paper presents the use of deformable registration in lymph node tracking, particularly in the context of disease progression. We found that the extent of disease progression plays an important role in determining the performance of deformable registration in aligning up small anatomic structures, such as lymph node. Both Demons and B-spline registrations have their own advantages in different medical context. PMID- 22256207 TI - Estimation of affine motion from projection data using a mass conservation model. AB - An approximate model for the effect of respiration is that the cross section of the thoracic area under interrogation experience time-varying magnification and displacement along two perpendicular axes - we propose to model this motion as parametric affine motion. A theoretical framework for determination of parameters of affine motion modeling the global respiratory motion based on the sinogram data in the projection domain is described. It is assumed that the spatial image considered is a density image where conservation of mass holds. PMID- 22256208 TI - Simultaneous segmentation and inhomogeneity correction in magnetic resonance images. AB - In Magnetic Resonance Imaging (MRI), intensity inhomogeneity has been an issue affecting the quality of post processing. In this paper, we present a simultaneous segmentation and inhomogeneity correction (IC) method based on active contour algorithm. It uses a generative model which is a modified Mumford Shah functional proposed by Chan and Vese. The piecewise constant image model in the functional is multiplied by an underlying intensity inhomogeneity field. The inhomogeneity field and piecewise constant function are jointly estimated in an iterative way including solving the associated contour evolution equation and updating corresponding parameters. The algorithm is implemented using the level set framework. Test on MRI leg data shows our method achieves more accurate segmentation and IC results than other related methods in MR images with strong intensity inhomogeneity. PMID- 22256209 TI - Elastic registration based on particle filter in radiotherapy images with brain deformations. AB - This paper presents the evaluation of the accuracy of an elastic registration algorithm, based on the particle filter and an optical flow process. The algorithm is applied in brain CT and MRI simulated image datasets, and MRI images from a real clinical radiotherapy case. To validate registration accuracy, standard indices for registration accuracy assessment were calculated: the dice similarity coefficient (DICE), the average symmetric distance (ASD) and the maximal distance between pixels (Dmax). The results showed that this registration process has good accuracy, both qualitatively and quantitatively, suggesting that this method may be considered as a good new option for radiotherapy applications like patient's follow up treatment. PMID- 22256210 TI - A fully automated method using active contours for the evaluation of the intima media thickness in carotid US images. AB - The thickness of the intima-media complex (IMC) of the common carotid artery (CCA) wall is important in the evaluation of the risk for the development of atherosclerosis. This paper presents a fully automated algorithm for the segmentation of the IMC. The segmentation of the IMC of the CCA wall is important for the evaluation of the intima media thickness (IMT) on B-mode ultrasound images. The presented algorithm is based on active contours and active contours without edges. It begins with image normalization, followed by speckle removal. The level set formulation of Chan and Vese using random initialization provides a segmentation of the CCA ultrasound (US) images into different distinct regions, one of which corresponds to the carotid wall region above the lumen whilst another corresponds to the carotid wall region below the lumen and includes the IMC. The results of the corresponding segmentation combined with anatomical information provide a very accurate outline of the lumen-intima boundary. This outline serves as an excellent initialization for segmentation of the IMC using parametric active contours. The method lends itself to the development of a fully automated method for the delineation of the IMC. The mean and standard deviation of the thickness of the automatically segmented regions are 0.65 mm +/-0.17 mm and the corresponding values for the ground truth IMT are 0.66 mm +/-0.18 mm. The Wilcoxon rank sum test shows no significant difference. PMID- 22256211 TI - Motion estimation in ultrasound imaging applied to the diagnostic of pelvic floor disorders. AB - The main purpose of this paper is to show the potential of tissue motion estimation in ultrasound imaging for the diagnostic of pelvic floor disorders. We propose to evaluate the tissue motion using a method based on a local deformable model and on image features (local phase and orientation) extracted from the monogenic signal. The proposed method is well adapted to the pelvic organ deformations and estimates motion with subpixel precision without the need for interpolation. The estimated motion is used to visualize the bladder local deformation and to extract quantitative figures such as the deformation parameters and the bladder angle variation. These results could potentially be interesting to characterize the degree of the pelvic organ prolapse. PMID- 22256212 TI - Medical image integrity control and forensics based on watermarking- approximating local modifications and identifying global image alterations. AB - In this paper we present a medical image integrity verification system that not only allows detecting and approximating malevolent local image alterations (e.g. removal or addition of findings) but is also capable to identify the nature of global image processing applied to the image (e.g. lossy compression, filtering ...). For that purpose, we propose an image signature derived from the geometric moments of pixel blocks. Such a signature is computed over regions of interest of the image and then watermarked in regions of non interest. Image integrity analysis is conducted by comparing embedded and recomputed signatures. If any, local modifications are approximated through the determination of the parameters of the nearest generalized 2D Gaussian. Image moments are taken as image features and serve as inputs to one classifier we learned to discriminate the type of global image processing. Experimental results with both local and global modifications illustrate the overall performances of our approach. PMID- 22256213 TI - A joint watermarking/encryption algorithm for verifying medical image integrity and authenticity in both encrypted and spatial domains. AB - In this paper, we propose a new joint watermarking/encryption algorithm for the purpose of verifying the reliability of medical images in both encrypted and spatial domains. It combines a substitutive watermarking algorithm, the quantization index modulation (QIM), with a block cipher algorithm, the Advanced Encryption Standard (AES), in CBC mode of operation. The proposed solution gives access to the outcomes of the image integrity and of its origins even though the image is stored encrypted. Experimental results achieved on 8 bits encoded Ultrasound images illustrate the overall performances of the proposed scheme. By making use of the AES block cipher in CBC mode, the proposed solution is compliant with or transparent to the DICOM standard. PMID- 22256214 TI - A 2D 3D registration with low dose radiographic system for in vivo kinematic studies. AB - The knowledge of the poses and the positions of the knee bones and prostheses is of a great interest in the orthopedic and biomechanical applications. In this context, we use an ultra low dose bi-planar radiographic system called EOS to acquire two radiographs of the studied bones in each position. In this paper, we develop a new method for 2D 3D registration based on the frequency domain to determine the poses and the positions during quasi static motion analysis for healthy and prosthetic knees. Data of two healthy knees and four knees with unicompartimental prosthesis performing three different poses (full extension, 30 degrees and 60 degrees of flexion) were used in this work. The results we obtained are in concordance with the clinical accuracy and with the accuracy reported in other previous studies. PMID- 22256215 TI - An efficient point based registration of intra-operative ultrasound images with MR images for computation of brain shift; a phantom study. AB - Intra-operative brain deformation (brain shift) limits the accuracy of image guided neuro-surgery systems. Ultrasound imaging as a simple, fast and being real time has become an alternative to MR imaging which is an expensive system for brain shift calculation. The main challenges due to speckle noise and artifacts in US images, is to perform an accurate and fast registration of Us images with pre-operative MR images. In this paper an efficient point based registration method based on the alignment of probability density functions called Coherent Point Drift (CPD) is implemented and compared to the conventional ICP method. To perform this, a brain phantom that allows simulating the brain deformation is made. As the results of our phantom study confirm the CPD method clearly outperforms the ICP algorithm for brain shift calculation. Also the result proves that using intra-operative US has led to recover almost 80% of displacement in the region of interest. PMID- 22256216 TI - Towards segmentation of the thymus in fat and water parametric MR images. AB - The thymus, an organ responsible for the development, selection, and maintenance of the peripheral T-cell population, is an important regulator of the immune system. Despite its physiological significance, it has received little attention in the medical image analysis literature. In practice, the anatomical location and variable shape of this gland pose challenges both in the image acquisition and analysis processes. We present an automated method for segmenting the thymus from water and fat parametric MR images that permits further analysis of volumetrics and tissue characterization. We compute fat ratio and water ratio parametric images and introduce the use of a stochastic edge detector that is embedded in a geometric variational segmentation model. Validation experiments of the proposed algorithm against manual delineations of the thymus indicate the applicability of our approach. PMID- 22256217 TI - Automatic segmentation of time-lapse microscopy images depicting a live Dharma embryo. AB - Biological inferences about the toxicity of chemicals reached during experiments on the zebrafish Dharma embryo can be greatly affected by the analysis of the time-lapse microscopy images depicting the embryo. Among the stages of image analysis, automatic and accurate segmentation of the Dharma embryo is the most crucial and challenging. In this paper, an accurate and automatic segmentation approach for the segmentation of the Dharma embryo data obtained by fluorescent time-lapse microscopy is proposed. Experiments performed in four stacks of 3D images over time have shown promising results. PMID- 22256218 TI - Lossless 3-D reconstruction and registration of semi-quantitative gene expression data in the mouse brain. AB - As imaging, computing, and data storage technologies improve, there is an increasing opportunity for multiscale analysis of three-dimensional datasets (3 D). Such analysis enables, for example, microscale elements of multiple macroscale specimens to be compared throughout the entire macroscale specimen. Spatial comparisons require bringing datasets into co-alignment. One approach for co-alignment involves elastic deformations of data in addition to rigid alignments. The elastic deformations distort space, and if not accounted for, can distort the information at the microscale. The algorithms developed in this work address this issue by allowing multiple data points to be encoded into a single image pixel, appropriately tracking each data point to ensure lossless data mapping during elastic spatial deformation. This approach was developed and implemented for both 2-D and 3D registration of images. Lossless reconstruction and registration was applied to semi-quantitative cellular gene expression data in the mouse brain, enabling comparison of multiple spatially registered 3-D datasets without any augmentation of the cellular data. Standard reconstruction and registration without the lossless approach resulted in errors in cellular quantities of ~ 8%. PMID- 22256219 TI - Simple and effective ultrasound needle guidance system. AB - In this paper, we describe our prototype of an ultrasound guidance system to address the need for an easy-to-use, cost-effective, and portable technology to improve ultrasound-guided procedures. The system consists of a lockable, articulating needle guide that attaches to an ultrasound probe and a user interface that provides real-time visualization of the predicted needle trajectory overlaid on the ultrasound image. Our needle guide ensures proper needle alignment with the ultrasound imaging plane. Moreover, the calculated needle trajectory is superimposed on the real-time ultrasound image, eliminating the need for the practitioner to estimate the target trajectory, and thereby reducing injuries from needle readjustment. Finally, the guide is lockable to prevent needle deviation from the desired trajectory during insertion. This feature will also allow the practitioner to free one hand to complete simple tasks that usually require a second practitioner to perform. Overall, our system eliminates the experience required to develop the fine hand movement and dexterity needed for traditional ultrasound-guided procedures. The system has the potential to increase efficiency, safety, quality, and reduce costs for a wide range of ultrasound-guided procedures. Furthermore, in combination with portable ultrasound machines, this system will enable these procedures to be more easily performed by unskilled practitioners in non-ideal situations such as the battlefield and other disaster relief areas. PMID- 22256220 TI - Similarity enhancement for automatic segmentation of cardiac structures in computed tomography volumes. AB - The aim of this research is proposing a 3-D similarity enhancement technique useful for improving the segmentation of cardiac structures in Multi-Slice Computerized Tomography (MSCT) volumes. The similarity enhancement is obtained by subtracting the intensity of the current voxel and the gray levels of their adjacent voxels in two volumes resulting after preprocessing. Such volumes are: a. - a volume obtained after applying a Gaussian distribution and a morphological top-hat filter to the input and b. - a smoothed volume generated by processing the input with an average filter. Then, the similarity volume is used as input to a region growing algorithm. This algorithm is applied to extract the shape of cardiac structures, such as left and right ventricles, in MSCT volumes. Qualitative and quantitative results show the good performance of the proposed approach for discrimination of cardiac cavities. PMID- 22256221 TI - Speckle detection in ultrasonic images using unsupervised clustering techniques. AB - In ultrasonic images, identification of speckled regions helps to estimate probe movement as well as improve performance of algorithms for adaptive speckle suppression and the elevational separation of B-scans by speckle decorrelation. By tracking FDS patch displacements over time we can calculate strain and detect tumor location. Previous studies for speckle detection were based on classification techniques which estimated parameters of the statistical distribution which were based on observation data and ultrasound echo envelope signal. However, in this study, we proposed a new combination of statistical features which were extracted from the ultrasound images and explored their properties for the speckle detection. These features were used as inputs to the unsupervised clustering algorithms for the speckle classification. We used five different types of unsupervised techniques and compared their performance by feeding different combinations of the statistical features. In order to quantitatively compare statistical features and classification methods, as ground truth, we used simulations of cyst and fetus ultrasound images which were generated using Field II ultrasound simulation program[1]. Initial results showed that by combining two statistical models (K and Rayleigh distributions) we can get best speck detection signatures to feed unsupervised classifiers and maximize speckle detection performance. PMID- 22256222 TI - Independent component analysis of resting brain activity reveals transient modulation of local cortical processing by transcranial direct current stimulation. AB - Neuroplasticity induced by transcranial direct current stimulation (tDCS) contributes to motor learning although the underlying mechanisms are incompletely understood. Here, we investigated the effects of tDCS on resting brain dynamics recorded by whole-head magnetoencephalography (MEG) pre- and up to 35 minutes post-tDCS or sham over the left primary motor cortex (M1) in healthy adults. Owing to superior temporal and spatial resolution of MEG, we sought to apply a robust, blind and data-driven analytic approach such as independent component analysis (ICA) and statistical clustering to these data to investigate potential neuroplastic effects of tDCS during resting state conditions. We found decreased alpha and increased gamma band power that outlasted the real tDCS stimulation period in a fronto-parietal motor network relative to sham. However, this method could not find differences between anodal and cathodal polarities of tDCS. These results suggest that tDCS over M1 modulates resting brain dynamics in a fronto parietal motor network (that includes the stimulated location), indicative of within-network enhanced localized cortical processing. PMID- 22256223 TI - Relationship between pulse number of rTMS and inter reversal time of perceptual reversal. AB - The aim of this study is to investigate the stimulus parameter which affects the repetitive Transcranial Magnetic Stimulation (rTMS) effect. It is said that the condition under 1Hz rTMS induces the inhibition effect. On the other hand, the condition over 1 Hz rTMS induces the facilitation effect. However the number of pulses of rTMS is also important factor. In this study, we focused on the number of pulses. We used the cognitive task of perceptual reversal and compared the rTMS effects of different condition under 1 Hz which is the inhibition condition. It has been known that the right superior parietal lobule (SPL) has a role in perceptual reversal. We applied rTMS over the SPL and measured the inter-reversal time (IRT) of perceptual reversal. The results showed that when 0.25 Hz 60 pulses, 0.5 Hz 60 pulses and 1 Hz 60 pulses of rTMS was applied over the right SPL, the IRT was significantly smaller. On the other hand, when 1 Hz 240 pulses of rTMS was applied over the right SPL, the IRT was significantly longer. When 0.25 Hz 12 0 pulses, 0.5 Hz 120 pulses and 1Hz 120 pulses of rTMS was applied over the right SPL, there were no significant differences. Furthermore, to investigate the rTMS effects, when rTMS are applied over the motor area, we measured the motor evoked potential (MEP). The more pulses of rTMS was applied, the smaller the amplitude of MEP became. From these results, it was found that the IRT of perceptual reversal and the amplitude of MEP primarily affected by the number of pulses of rTMS. PMID- 22256224 TI - Investigation on the pleasantness of music perception in monolateral and bilateral cochlear implant users by using neuroelectrical source imaging: a pilot study. AB - There is a debate in the specialized literature about the quality of fruition of music for patients that received a cochlear implant. Interestingly, very few studies have investigated the hypothesis that patients that use a bilateral cochlear implant could perceive the music in a more pleasant way as compared to unilaterally implanted patients. Previous observations in healthy subjects have indicated that variations of particular EEG rhythms correlated with the pleasantness of the perceived music. The aim of the present pilot study is then to apply the state of the art neuroelectrical imaging and the analysis of cortical representation of EEG rhythms to monitor the perceived pleasantness during the observation of a simple videoclip in one patient with a unilateral cochlear implant and in one receiving a bilateral cochlear implant. Results of this pilot study showed that on the base of such previously validated EEG rhythms, the fruition of music and video, in terms of pleasantness, is statistically higher in the bilaterally implanted patient when compared to the monolateral implanted patient. PMID- 22256225 TI - Functional connectivity in vergence and saccade eye movement tasks assessed using Granger Causality analysis. AB - Throughout the day, the human visual system acquires information using saccade and vergence eye movements. Previously, functional MRI (fMRI) experiments have shown both shared neural resources and spatial differentiation between these two systems. FMRI experiments can reveal which regions are activated within an experimental task but do not yield insight into how regions of interest (ROIs) interact with each other. This study investigated the number and direction of influences among ROIs using a Granger Causality Analysis (GCA)--a statistical technique used to identify if an ROI is significantly influencing or 'connected' to another ROI. Two stimulus protocols were used: first, a simple block design of fixation versus random eye movements; and second, a more cognitively demanding task using random versus predictable movements. Each protocol used saccadic movements and was then repeated using vergence movements. Eight subjects participated in each of the four experiments. Results show that when prediction was evoked, more connections between ROIs were observed compared to the simple tracking experiment. More connections were also observed during the vergence prediction task compared to the saccade prediction task. Differences within the number of connections may be due to the type of oculomotor eye movements, as well as to the amount of higher-level executive cognitive demand. PMID- 22256226 TI - Mechanisms of neural reorganization in chronic stroke subjects after virtual reality training. AB - This study investigates patterns of brain reorganization in chronic stroke subjects after two weeks of robot-assisted arm and hand training in virtual reality (VR). Four subjects were studied with event-related fMRI while doing simple paretic hand finger movements before (double baseline) and after training. Bilateral hand movements were recorded and used to provide real-time feedback to subjects during scanning to eliminate performance confounds on fMRI results. The kinematic parameters of each movement were also used in the general linear model with the BOLD signal to investigate training-induced changes in neuromotor coupling. Univariate analysis showed an increase in BOLD signal in the ipsilesional hemisphere in two subjects and a decrease in activity in the other two subjects. Seed voxel based functional connectivity analysis revealed an increase in connectivity between ipsilesional motor cortex and bilateral sensorimotor cortex during finger movements in all four subjects. Hemispheric laterality index values showed a tendency to decrease reflecting a reduction in the over-dominance of the contralesional hemisphere. The study is novel in terms of 1) tracking finger movement during a motor task in the scanner, 2) monitoring motor performance during the experiment and 3) giving online visual feedback of subjects' movement. This pilot study introduces a novel approach to study neural plasticity by combining measures of regional intensity, interregional interactions (using functional connectivity analysis and hemispheric laterality index), and modulation in the strength of neuromotor coupling. PMID- 22256227 TI - Estimation of neuronal responses from fMRI data. AB - In this paper we describe a deconvolution technique for estimation of the neuronal signal from an observed hemodynamic responses in fMRI data. Our approach, based on the Rauch-Tung-Striebel smoother for square-root cubature Kalman filter, enables us to accurately infer the hidden states, parameters, and the input of the dynamic system. Additionally, we enhance the cubature Kalman filter with a variational Bayesian approach for adaptive estimation of the measurement noise covariance. PMID- 22256228 TI - A pneumatically-actuated lower-limb orthosis. AB - Powered lower-limb orthosis is a type of wearable mechanical devices that can serve a wide variety of important biomedical purposes. Due to the constraints associated with the actuation technology, the majority of current lower-limb orthoses are either passive or tethered to external power sources, limiting the functionality of such devices. In this paper, the authors present their preliminary research results towards a fully mobile (i.e. untethered) powered lower-limb orthosis, leveraging the high power density of pneumatic actuators for the joint power generation. The design of the orthosis is presented, with the objectives of providing full assistance in the locomotion of various common locomotive modes, and generating minimum level of restriction to the wearer's daily activities. To regulate the power delivery on the joints for a natural gait assistance, a finite-state impedance controller is developed, which simulates an artificial impedance to enable an effective interaction with the wearer. Preliminary testing demonstrated that the orthosis was able to provide a natural gait and comfortable user experience in the treadmill walking experiments. PMID- 22256229 TI - Design considerations for an active soft orthotic system for shoulder rehabilitation. AB - Strokes affect over 750,000 people annually in the United States. This significant and disabling condition can result in paralysis that must be treated by regular sessions with a dedicated physical therapist in order to regain motor function. However, the use of therapists is expensive, in high demand, and requires patient travel to a rehabilitation clinic. We propose an inexpensive and wearable upper body orthotics system that can be used at home to provide the same level of rehabilitation as the current physical therapy standard of care. The system is composed of a soft orthotic device with an integrated cable actuation system that is worn over the upper body, a limb position sensing system, and an actuator package. This paper presents initial design considerations and the evaluation of a proof of concept system for shoulder joint rehabilitation. Through simulations and experimental evaluation, the system is shown to be adjustable, easily wearable, and adaptable to misalignment and anatomical variations. Insights provided by these initial studies will inform the development of a complete upper body orthotic system. PMID- 22256230 TI - On the mechanics of the ankle in the stance phase of the gait. AB - In this paper we explore the mechanical behavior of the ankle in the progression stage of stance during normal walking. We show that the torque/angle behavior of the ankle during this stage can be approximated by an augmented linear torsional spring. The mechanical parameters completely specifying this spring are identified, including stiffness, amount of rotation, and angle of zero moment. The effect of load weight, gait speed and ground slope on those parameters and the propulsive work of the ankle are also discussed. The findings of this paper can be applied to the design of leg orthoses, prostheses and exoskeletons, and bipedal robots in general, allowing the implementation of human-like leg compliance during stance with a relatively simple latched-spring mechanism. PMID- 22256231 TI - A detailed 3D ankle-foot model for simulate dynamics of lower limb orthosis. AB - The objective of this study is to develop a 3D ankle-foot model containing toe expression for designing an AFO (ankle-foot orthosis) with a training function. Two experiments were conducted to (1) show the influence of toes by comparing walking with and without an AFO, and (2) clarify the functions of toes during walking by correlating the activity of the major muscles controlling the ankle and the toes to the sole pressure data during walking. By analyzing the results of these two experiments, the necessary components and conditions of a detailed 3D foot-ankle model for developing an AFO with a training effect were clarified. A model was built and examined with empirical facts, and data were collected from the AFO simulation. PMID- 22256232 TI - Control of human spine in repetitive sagittal plane flexion and extension motion using a CPG based ANN approach. AB - The complexity associated with musculoskeletal modeling, simulation, and neural control of the human spine is a challenging problem in the field of biomechanics. This paper presents a novel method for simulation of a 3D trunk model under control of 48 muscle actuators. Central pattern generators (CPG) and artificial neural network (ANN) are used simultaneously to generate muscles activation patterns. The parameters of the ANN are updated based on a novel learning method used to address the kinetic redundancy due to presence of 48 muscles driving the trunk. We demonstrated the feasibility of the proposed method with numerical simulation of experiments involving rhythmic motion between upright standing and 55 degrees of flexion. The tracking performance of the model is accurate to within 2 degrees while reciprocal muscle activation patterns were similar to the observed experimental coordination patterns in normal subjects. The suggested method can be used to map high-level control strategies to low-level control signals in complex biomechanical and biorobotic systems. This will also provide insight about underlying neural control mechanisms. PMID- 22256233 TI - Experimental validation of a reach-and grasp optimization algorithm inspired to human arm-hand control. AB - Taking inspiration from neurophysiological studies on synergies in the human grasping action, this paper tries to demonstrate that it is possible to find a general rule for performing a stable, human-like cylindrical grasp with a robotic hand. To this purpose, the theoretical formulation and the experimental validation of a reach-and-grasp algorithm for determining the optimal hand position and the optimal finger configuration for grasping a cylindrical object with known features are presented. The proposed algorithm is based on the minimization of an objective function expressed by the sum of the distances of the hand joints from the object surface. Algorithm effectiveness has preliminarily been tested by means of simulation trials. Experimental trials on a real arm-hand robotic system have then been carried out in order to validate the approach and evaluate algorithm performance. PMID- 22256234 TI - Redundancy and joint limits of a seven degree of freedom upper limb exoskeleton. AB - The seven degree of freedom arm model is widely used in robotics, computer graphics, and much more. For wearable robotic systems, which are subject to joint limits, it is desirable to relate the joint limits to the redundantly of the system. A brief review of the arm model, redundant space and kinematics is presented. Following this review a closed form method is developed calculate the interval of the swivel angle (which characterizes the redundancy) that produces arm configurations that stay within joint limits. PMID- 22256235 TI - Upper extremity wheelchair kinematics in children with spinal cord injury. AB - Current methods for the evaluation of upper extremity dynamics during wheelchair mobility in children are limited. The goal of this study was to characterize upper extremity joint kinematics during wheelchair mobility. A 3-D biomechanical model of the upper extremities is presented for kinematic assessment of manual wheelchair propulsion in children with Spinal Cord Injury (SCI). The bilateral upper extremity model consists of the thorax, upper arms, forearms, and hands. The model was applied to thirteen (13) children with SCI. Joint angles and joint ranges of motion of the shoulders, elbows, and wrists were quantified. Peak joint motions during the stroke cycle were compared between right and left sides for further insight to mobility patterns. This work will provide insight to be used in future kinetic studies of wheelchair mobility. PMID- 22256236 TI - Towards using musculoskeletal models for intelligent control of physically assistive robots. AB - With the increasing number of robots being developed to physically assist humans in tasks such as rehabilitation and assistive living, more intelligent and personalized control systems are desired. In this paper we propose the use of a musculoskeletal model to estimate the strength of the user, from which information can be utilized to improve control schemes in which robots physically assist humans. An optimization model is developed utilizing a musculoskeletal model to estimate human strength in a specified dynamic state. Results of this optimization as well as methods of using it to observe muscle-based weaknesses in task space are presented. Lastly potential methods and problems in incorporating this model into a robot control system are discussed. PMID- 22256237 TI - Contributions of non-spherical hip joint cartilage surface to hip joint contact stress. AB - The natural non-spherical incongruent hip joint cartilage surface is normally assumed as spherical in shape, which has been extensively applied in orthopedic clinic, hip joint simulation studies and hip joint prosthesis design. The aim of the study was to investigate the contributions of non-spherical incongruent hip joint cartilage surface to the hip joint contact stress, and to assess the effect of simplified spherical assumption on the predicted contact stress. Based on our previous anatomic studies that the acetabular cartilage surface was demonstrated as rotational ellipsoid in shape, three finite element (FE) models involving the natural hip joint cartilage shape, the hip joint cartilage shape replaced by the rotational ellipsoid and the sphere, respectively, were developed using the computed tomography (CT) image data of healthy volunteers. The FE predictions of contact stress on the replaced hip joint cartilage surface were compared with that on the natural hip joint cartilage surface. The result showed that the non spherical hip joint cartilage surface contributed to the optimal contact stress magnitude and distribution. The replaced fitting spherical surface led to the increased contact stress of hip joint and the uneven distributed patterns of contact stress, whereas the replaced fitting rotational ellipsoid surface was comparatively more consistent with the natural results than the sphere one. The surface fitting error of the replaced rotational ellipsoid was fewer than that of the replaced sphere. These results indicate that the simplified spherical assumption will lead to misestimating the contact mechanics of hip joint, and the rotational ellipsoid model rather than the sphere model may represent the hip joint contact surface applied in the hip joint simulation study and the hip joint prosthesis design. PMID- 22256238 TI - Preliminary design of a novel system for estimating end-point stiffness. AB - Quantification of arm stiffness is of great interest for a wide group of different research branches, because modulation of muscular stiffness represents the principal mechanism of motor control of movements. Past literature concentrated efforts in defining different methods to identify multijont hand stiffness, but the required computational burden make them hard to implelement. In the present work we aim to propose a novel design of a single degree of freedom mechanism conceived to estimate arm stiffness in a reduced amount of time; a rotary mechanism coupled to a commercial six axes force sensor allows to apply known cyclic radial perturbation to the human arm and acquiring the restoring forces. The outcomes have reported that the device is reliable and stiffness measurements on a test bench can be performed in a reduced amount of time (about 1 second). A modular system has been also developed to conduct experiment on humans while performing motor adaptation. PMID- 22256239 TI - A novel energy-efficient rotational variable stiffness actuator. AB - This paper presents the working principle, the design and realization of a novel rotational variable stiffness actuator, whose stiffness can be varied independently of its output angular position. This actuator is energy-efficient, meaning that the stiffness of the actuator can be varied by keeping constant the internal stored energy of the actuator. The principle of the actuator is an extension of the principle of translational energy-efficient actuator vsaUT. A prototype based on the principle has been designed, in which ball-bearings and linear slide guides have been used in order to reduce losses due to friction. PMID- 22256240 TI - Design and validation of a platform robot for determination of ankle impedance during ambulation. AB - In order to provide natural, biomimetic control to recently developed powered ankle prostheses, we must characterize the impedance of the ankle during ambulation tasks. To this end, a platform robot was developed that can apply an angular perturbation to the ankle during ambulation and simultaneously acquire ground reaction force data. In this study, we detail the design of the platform robot and characterize the impedance of the ankle during quiet standing. Subjects were perturbed by a 3 degrees dorsiflexive ramp perturbation with a length of 150 ms. The impedance was defined parametrically, using a second order model to map joint angle to the torque response. The torque was determined using the inverted pendulum assumption, and impedance was identified by the least squares best estimate, yielding an average damping coefficient of 0.03 +/- 0.01 Nms/ degrees and an average stiffness coefficient of 3.1 +/- 1.2 Nm/ degrees . The estimates obtained by the proposed platform robot compare favorably to those published in the literature. Future work will investigate the impedance of the ankle during ambulation for powered prosthesis controller development. PMID- 22256241 TI - An analysis of leg joint synergy during bipedal walking in Japanese macaques. AB - We analyzed bipedal locomotion of Japanese macaques from the view point of leg joint synergy by the UCM (Uncontrolled manifold) analysis in order to examine how and when hip, knee and ankle joints cooperate so as to suppress the variances of the toe position relative to the hip position. Our results showed that joint synergy is exploited at some moments during walking. For instance, the variance of the vertical toe position was suppressed by joint synergy when the tip of the finger passes its lowest position from the ground. Some characteristics of the synergy pattern of macaques have been also reported in human walking, on the other hand, some differences between humans and macaques were found. For instance, high degree of joint synergy that suppresses the variance of hip height was observed around the end of stance phase in human walking, but such synergy was weak in macaques. The results suggest that different control strategies are used in bipedal walking of macaques and humans. PMID- 22256242 TI - Influence of muscular fatigue on skiing performance during parallel turns. AB - Muscular fatigue and muscle-activation patterns during a skiing demonstration (down a coarse around 4000 m long) was evaluated. Nine subjects participated in skiing trials and pre-training with a squat exercise. Surface electromyogram (SEMG) signals from the agonist and antagonist muscles around the knee at certain knee-joint angles were recorded. The SEMG signals showed that experienced skiers maintained their posture regardless of muscle fatigue by means of sustained muscle contractions in accordance with the change in inclination of the slope. In contrast, intermediate skiers did not maintain their posture (because of muscle fatigue) and distributed their strength over muscles to co-contract with each other. It is concluded from this result that the influence of muscle fatigue on skiing performance is related to skill level.(1). PMID- 22256243 TI - SERVANDO: an extensible platform for home-care services providing. AB - This paper presents an extensible distributed platform that aims to speed up the development of personalized telemedicine systems, dealing with a series of recurrent problems in this kind of system, particularly: (1) functionality encapsulation and reuse in a set of services; (2) communications between the patient's home and the hospital, through a flexible scheme for bidirectional message exchange; and (3) the interaction between patients and the system. Home supervision is carried out through last generation smartphones. To date, the platform has been used for the follow-up of patients with COPD and cardiovascular diseases. PMID- 22256244 TI - Lossless watermarking of categorical attributes for verifying medical data base integrity. AB - In this article, we propose a new lossless or reversible watermarking approach that allows the embedding of a message within categorical data of relational database. The reversibility property of our scheme is achieved by adapting the well known histogram shifting modulation. Based on this algorithm we derive a system for verifying the integrity of the database content, it means detecting addition, removal or modification of any t-uples or attributes. Such a content integrity check is independent of the manner the database is stored or structured. We illustrate the overall capability of our method and its constraints of deployment considering one medical database of inpatient hospital stay records. Especially, we reversibly watermark ICD-10 diagnostic codes. PMID- 22256245 TI - MiRTE: Mixed Reality Triage and Evacuation game for Mass Casualty information systems design, testing and training. AB - In this paper we introduce a Mixed Reality Triage and Evacuation game, MiRTE, that is used in the development, testing and training of Mass Casualty Incident (MCI) information systems for first responders. Using the Source game engine from Valve software, MiRTE creates immersive virtual environments to simulate various incident scenarios, and enables interactions between multiple players/first responders. What distinguishes it from a pure computer simulation game is that it can interface with external mass casualty incident management systems, such as DIORAMA. The game will enable system developers to specify technical requirements of underlying technology, and test different alternatives of design. After the information system hardware and software are completed, the game can simulate various algorithms such as localization technologies, and interface with an actual user interface on PCs and Smartphones. We implemented and tested the game with the DIORAMA system. PMID- 22256246 TI - Design of an x-ray / ventilator synchronization system in an integrated clinical environment. AB - Patients in an ICU may receive daily chest x-rays. These x-rays are taken manually and may be at different phases of respiration, which limits their clinical usefulness. We examine design issues around automatically synchronizing an x-ray and ventilator in an interoperable manner, including requirements on the individual devices and new safety hazards introduced by connecting them into a system. PMID- 22256247 TI - Portable and cost-effective pixel super-resolution on-chip microscope for telemedicine applications. AB - We report a field-portable lensless on-chip microscope with a lateral resolution of <1 MUm and a large field-of-view of ~24 mm(2). This microscope is based on digital in-line holography and a pixel super-resolution algorithm to process multiple lensfree holograms and obtain a single high-resolution hologram. In its compact and cost-effective design, we utilize 23 light emitting diodes butt coupled to 23 multi-mode optical fibers, and a simple optical filter, with no moving parts. Weighing only ~95 grams, we demonstrate the performance of this field-portable microscope by imaging various objects including human malaria parasites in thin blood smears. PMID- 22256248 TI - Development of a ubiquitous healthcare monitoring system combined with non conscious and ambulatory physiological measurements and its application to medical care. AB - The demand for ubiquitous healthcare monitoring has been increasingly raised for prevention of lifestyle-related diseases, acute life support or chronic therapies for inpatients and/or outpatients having chronic disorder and home medical care. From these view points, we developed a non-conscious healthcare monitoring system without any attachment of biological sensors and operations of devices, and an ambulatory postural changes and activities monitoring system. Furthermore in this study, in order to investigate those applicability to the ubiquitous healthcare monitoring, we have developed a new healthcare monitoring system combined with the non-conscious and the ambulatory measurements developed by us. In patients with chronic cardiovascular disease or stroke, the daily health conditions such as pulse, respiration, activities and so on, could be continuously measured in the hospital, the rehabilitation room and subject's own home, using the present system. The results demonstrated that the system appears useful for the ubiquitous healthcare monitoring not only at medical facility, but also during daily living at home. PMID- 22256249 TI - Investigating the efficiency of IEEE 802.15.4 for medical monitoring applications. AB - Recent advancements in wireless communications technologies bring us one step closer to provide reliable Telecare services as an alternative to patients staying in a hospital mainly for monitoring purposes. In this research we investigate the efficiency of IEEE 802.15.4 in a simple scenario where a patient is being monitored using an ECG and a blood analysis module. This approach binds well with assisted living solutions, by sharing the network infrastructure for both monitoring and control while taking advantage of the low power features of the protocol. Such applications are becoming more and more realistic to implement as IEEE 802.15.4 compatible hardware becomes increasingly available. Our aim is to examine the impact of Beacon and Superframe Order in the medium access delay, dropped packets, end to end delay, average retransmission attempts and consumed power focusing on this bandwidth demanding situation where the network load does not allow low duty cycles, in order to draw some conclusions on the effect that this will have to telemonitoring applications. PMID- 22256250 TI - Secure communications for PACS in a cloud environment. AB - Picture Archiving and Communication Systems (PACS) have been traditionally constrained to the premises of the healthcare provider. This has limited the availability of these systems in many parts of the world and mandated major costs in infrastructure for those who employ them. Public cloud services could be a solution that eases the cost of ownership and provide greater flexibility for PACS implementations. Moving these systems to the public cloud requires that an authentication and encryption policy for communications is established within the PACS environment. This paper investigated an implementation which uses Transport Layer Security for communications between a cloud-based PACS server and client. PMID- 22256251 TI - The effects of voluntary, involuntary, and forced exercises on motor recovery in a stroke rat model. AB - Stroke rehabilitation with different exercise paradigms has been investigated, but a comparison study on motor recovery after voluntary, involuntary, and forced exercises is limited. The current study used a rat brain ischemia model to investigate the effects of voluntary wheel running, involuntary muscle movement caused by functional electrical stimulation (FES), and forced treadmill exercise on motor recovery and brain BDNF changes. The results showed that voluntary exercise is the most effective intervention in upregulating the hippocampal BDNF level, and facilitating motor recovery after brain ischemia. PMID- 22256252 TI - A quantitative and standardized robotic method for the evaluation of arm proprioception after stroke. AB - Stroke often results in both motor and sensory deficits, which may interact in the manifested functional impairment. Proprioception is known to play important roles in the planning and control of limb posture and movement; however, the impact of proprioceptive deficits on motor function has been difficult to elucidate due in part to the qualitative nature of available clinical tests. We present a quantitative and standardized method for evaluating proprioception in tasks directly relevant to those used to assess motor function. Using a robotic manipulandum that exerted controlled displacements of the hand, stroke participants were evaluated, and compared with a control group, in their ability to detect such displacements in a 2-alternative, forced-choice paradigm. A psychometric function parameterized the decision process underlying the detection of the hand displacements. The shape of this function was determined by a signal detection threshold and by the variability of the response about this threshold. Our automatic procedure differentiates between participants with and without proprioceptive deficits and quantifies functional proprioceptive sensation on a magnitude scale that is meaningful for ongoing studies of degraded motor function in comparable horizontal movements. PMID- 22256254 TI - Dynamic Time Warping as a spatial assessment of sensorimotor impairment resulting from stroke. AB - Robotic assessment of sensorimotor impairment began in the mid 1990s as a means to address some of the issues regarding inter-rater reliability and the lack of precision associated with traditional measures of sensorimotor impairment. Robotic measures of postural control, reaction time, movement smoothness, and movement error associated with robotic assessment of the upper-limb fail to recognize the inherent spatial and geometric differences between stroke and control hand path trajectories. In this study we propose the application of a class of algorithms, Dynamic Time Warping, designed to quantify the spatial difference and skew between hand written characters and vocal waveforms as a means for identifying individuals exhibiting sensorimotor impairment. In order to achieve this 85 stroke subjects, and 54 age, gender, and handedness matched control subjects, underwent robotic assessment of the upper-limb. Subjects were identified as either stroke or control using a K Nearest Neighbour classifier with a Dynamic Time Warping distance metric. Classification accuracy, sensitivity, and specificity in excess of %80 percent was achieved. PMID- 22256253 TI - Quantifying loss of independent joint control in acute stroke with a robotic evaluation of reaching workspace. AB - Early recovery after stroke is significant for slow emergence of volitional movement. Initial movements are constrained by stereotypical co-activation of muscle groups such as shoulder abductors and distal limb flexors resulting in the loss of independent joint control. The objective of this study was to utilize new quantitative methods to evaluate the emergence and progression of the loss of independent joint control in the acute phase of recovery from stroke. Fifteen participants have been followed a maximum range of 2 to 32 weeks post-stroke. Participants underwent weekly and monthly robotic evaluations of horizontal plane reaching workspace as a function of abduction loading (0%-200% of limb weight). The magnitude of loss of independent joint control, indicated by the rate of work area reduction as a function of abduction loading, was evident even as early as 2 weeks post-stroke. Group analysis indicated that individuals with mild stroke show immediate presence of the impairment with an exponential rate of recovery over time while individuals with severe stroke show persistent impairment. Early detection and quantification of reaching impairments, such as the loss of independent joint control, will allow clinicians to more efficiently identify patients who would benefit from impairment-based targeted interventions. For example, patients with severe loss of independent joint control will likely benefit from early administration of an intervention attempting to reduce abnormal shoulder abductor/distal limb flexor co-activations during reaching. The field of rehabilitation robotics has demonstrated such interventions to be promising in the chronic severe stroke population. PMID- 22256255 TI - Influence of visual feedback in the regulation of arm stiffness following stroke. AB - Stroke survivors strongly rely on visual feedback to control their movements, since segmental reflexes are characterized by an inherent hyper-excitability. To test the effect of visual feedback on the modulation of arm stability we estimated the stiffness of the paretic arm in nine stroke survivors during robot mediated therapy, where subjects trained with and without vision. While several studies found a negligible effect in unimpaired individuals, our results highlighted a marked reduction of stroke survivors' arm stiffness in absence of visual feedback. PMID- 22256256 TI - Examination of motor unit control properties in stroke survivors using surface EMG decomposition: a preliminary report. AB - The objective of this pilot study was to examine alterations in motor unit (MU) control properties, (i.e. MU recruitment and firing rate) after stroke utilizing a recently developed high-yield surface electromyogram (EMG) decomposition technique. Two stroke subjects participated in this study. A sensor array was used to record surface EMG signals from the first dorsal interosseous (FDI) muscle during voluntary isometric contraction at varying force levels. The recording was performed in both paretic and contralateral muscles using a matched force protocol. Single motor unit activity was extracted using the surface EMG decomposition software from Delsys Inc. The results from the two stroke subjects indicate a reduction in the mean motor unit firing rate and a compression of motor unit recruitment range in paretic muscle as compared with the contralateral muscles. These findings provide further evidence of spinal motoneuron involvement after a hemispheric brain lesion, and help us to understand the complex origins of stroke induced muscle weakness. PMID- 22256257 TI - Towards a complete description of grasping kinematics: a framework for quantifying human grasping and manipulation. AB - This paper proposes a framework for tracking both human hand kinematics and object contour during grasping task. The framework is based on modeling the object as point cloud and the use of marker-based tracking. We introduce how to estimate contact sites on both the hand and object, hand enclosing space, and graspable features from recorded data. Two experiments were performed to 1) verify the accuracy of contact site estimation (less than 5 mm), and 2) validate the feature extraction. Our approach can provide significant insight into how humans plan grasping and manipulation based on object recognition. PMID- 22256258 TI - Cortical network modeling for inverse kinematic computation of an anthropomorphic finger. AB - The performance of reaching movements to visual targets requires complex kinematic mechanisms such as redundant, multijointed, anthropomorphic actuators and thus is a difficult problem since the relationship between sensory and motor coordinates is highly nonlinear. In this article, we present a neural model able to learn the inverse kinematics of a simulated anthropomorphic robot finger (ShadowHandTM finger) having four degrees of freedom while performing 3D reaching movements. The results revealed that this neural model was able to control accurately and robustly the finger when performing single 3D reaching movements as well as more complex patterns of motion while generating kinematics comparable to those observed in human. The long term goal of this research is to design a bio-mimetic controller providing adaptive, robust and flexible control of dexterous robotic/prosthetics hands. PMID- 22256259 TI - Comparing a passive-elastic and a powered prosthesis in transtibial amputees. AB - Passive-elastic foot prostheses cannot produce net work. Consequently, passive elastic foot prostheses are limited in their ability to enable a biologically realistic gait pattern in transtibial amputees. This shortcoming results in difficulties in balance and walking and leads to high levels of oxygen consumption during locomotion. A powered prosthesis has the potential for overcoming these problems and allowing transtibial amputees to achieve a biologically-realistic gait pattern. In this study, we compared the effects of the Ceterus by Ossur, a traditional passive-elastic prosthesis, with those of the PowerFoot Biom (iWalk, Cambridge, MA), a recently-developed powered prosthesis. Gait biomechanics and metabolic cost were compared in a group of 5 transtibial amputees during level-ground walking. The results provided preliminary evidence that the use of a powered prosthesis leads to a decrease in the level of oxygen consumption during ambulation due to improvements in ankle kinematics and kinetics primarily during late stance. An average decrease in oxygen consumption of 8.4% was observed during the study when subjects used the PowerFoot compared to the Ceterus. An average increase of 54% was observed in the peak ankle power generation during late stance. Our results suggest that powered prostheses have the potential for significantly improving ambulation in transtibial amputees. PMID- 22256260 TI - Knee-extension-assist for knee-ankle-foot orthoses. AB - Individuals with quadriceps muscle weakness often have difficulty generating the knee-extension moments required for common mobility tasks. A new device that provides a knee-extension moment was designed to help individuals perform sit-to stand and stand-to-sit. The knee-extension-assist (KEA) was designed as a modular component to be incorporated into existing knee-ankle-foot-orthoses (KAFO). The KEA loads a set of springs as the knee flexes under bodyweight and returns the stored energy as an extension moment during knee extension. The springs can be locked in place at the end of flexion to prevent unwanted knee extension while seated. When the affected leg is unloaded, the device disengages, allowing free joint motion. A prototype KEA underwent mechanical testing and biomechanical evaluation on an able-bodied individual during sit-to-stand and stand-to-sit. PMID- 22256261 TI - Cost function tuning improves muscle force estimation computed by static optimization during walking. AB - Muscle force estimation while a dynamic motor task is carried out still presents open questions. In particular, concerning locomotion, although the inverse dynamic based static optimization has been widely accepted as a suitable method to obtain reliable results, appropriate modifications of the object function may improve results. This paper was aimed at analyzing the sensitivity of estimated muscle forces when modifications of the objective function are adopted to better fit EMG signals of healthy subjects. A 7 links and 9 degrees of freedom biomechanical model accounting for 14 lower limb muscles, grouped in 9 equivalent actuators, was developed. Muscle forces were estimated by using the inverse dynamic based static optimization in which the performance criteria was the sum of muscle stresses raised to a certain n power. This exponent was gradually changed (from 2 to 100) and the agreement between force patterns and EMG signals was estimated by both the correlation coefficient and the Coactivation Index. Results suggested that force estimation can be improved by slightly modifying the cost function. In particular, with respect to adopted data, when the exponent belong to the interval between 2.75 and 4, estimated forces better captured general features of EMG signals. Concluding, a more reliable solution can be obtained by suitably tuning the cost function in order to fit EMG signals. PMID- 22256262 TI - A neuromuscular elbow model for analysis of force and movement variability in slow movements. AB - In this paper, we present a neuromuscular elbow model with both motor unit pool recruitment and Hill-based contraction dynamics. The model builds upon various models reported in the literature and provides a way to quantify force and movement variability in both isometric and non-isometric contractions. The model's accuracy in estimating muscle force variability at low force levels (at less than 20% maximum voluntary contraction) is evaluated in isometric contraction case and compared with experimental results from the literature. This comparison suggests that the model is accurate in estimating force variability within the low force range and can be used to explore effects of muscle force variability in increased kinematic variability during slow movements. PMID- 22256263 TI - Dynamic imaging of ictal rhythmic activity using dense-array EEG. AB - Electroencephalogram (EEG) is an important component of the pre-surgical evaluation in the treatment of medically intractable epilepsy. However, clinical EEG uses 19 to 32 electrodes that significantly limits its localization ability. Recent development of dense-array recording techniques has suggested that increased spatial sampling rate improves the accuracy of source localization. In the current study, we proposed a 76-channel EEG system for the long-term monitoring of epilepsy patients, and proposed a dynamic seizure imaging (DSI) technique to image the ictal rhythmic activity that may evolve through time, space and frequency. We tested the system in a cohort of 8 patients and our results show that the DSI estimated the seizure activity in good correlation with intracranial recordings, successful surgery outcomes and other clinical evidence. The proposed dense-array recording and DSI imaging approach enable a non-invasive but quantitative imaging of continuous seizure activity. The results suggest that DSI may potentially be useful to assist the pre-surgical evaluation in patients with intractable epilepsy. PMID- 22256264 TI - Markerless video analysis for movement quantification in pediatric epilepsy monitoring. AB - This paper proposes a markerless video analytic system for quantifying body part movements in pediatric epilepsy monitoring. The system utilizes colored pajamas worn by a patient in bed to extract body part movement trajectories, from which various features can be obtained for seizure detection and analysis. Hence, it is non-intrusive and it requires no sensor/marker to be attached to the patient's body. It takes raw video sequences as input and a simple user-initialization indicates the body parts to be examined. In background/foreground modeling, Gaussian mixture models are employed in conjunction with HSV-based modeling. Body part detection follows a coarse-to-fine paradigm with graph-cut-based segmentation. Finally, body part parameters are estimated with domain knowledge guidance. Experimental studies are reported on sequences captured in an Epilepsy Monitoring Unit at a local hospital. The results demonstrate the feasibility of the proposed system in pediatric epilepsy monitoring and seizure detection. PMID- 22256265 TI - Multivariate analysis of SEEG signals during seizure. AB - Epilepsy is a neurological disorder that affects tens of millions of people every year and is characterized by sudden-onset seizures which are often associated with physical convulsions. Effective treatment and management of epilepsy would be greatly improved if convulsions could be caught quickly through early seizure detection. However, this is still a largely open problem due to the challenge of finding a robust statistic from the neural measurements. This paper suggests a new multivariate statistic by combining spectral techniques with matrix theory. Specifically, stereoelectroencephalography (SEEG) data was used to generate a series of coherence connectivity matrices which were then examined using singular value decomposition. Tracking the relative angles of the first singular vectors generated from this data provides an effective way of defining the most dominant characteristics of the SEEG during the normal, the pre-ictal, and the ictal states. This paper indicates that the first singular vector has a characteristic direction indicative of the seizure state and illustrates a data analysis method that incorporates all neural data as opposed to a small selection of channels. PMID- 22256266 TI - Algorithm for automatic detection of pentylenetetrazole-induced seizures in rats. AB - Epilepsy affects approximately one percent of the world population. Antiepileptic drugs are ineffective in approximately 30% of patients and have side effects. We are developing a noninvasive, or minimally invasive, transcranial focal electrical stimulation (TFS) system through our novel concentric ring electrodes to control seizures. Here we report on the development of a seizure detecting algorithm to be used for automatic application of TFS. A cumulative sum (CUSUM) algorithm was evaluated that detected the electrographic seizure activity in all experiments well in advance of the behavioral seizure activity. PMID- 22256267 TI - Noise-assisted intrinsic mode function coherence in seizure anticipation. AB - Epilepsy is a common neurological disorder characterized by recurrent electrophysiological activities, known as seizures. We explore the applicability of noise-assisted Ensemble Empirical Mode Decomposition (EEMD) for patient specific seizure anticipation. Intracranial EEG data were obtained from invasive pre-surgical epilepsy monitoring at the Epilepsy Center of the University Hospital of Freiburg. Data from six patients (19 seizure recordings) with hippocampal foci were analyzed. For each recorded channel, twelve levels of intrinsic mode functions (IMFs) were produced. The coherence between the IMFs (denoted as IMF-Coh) between different channel pairs was computed. Statistical distributions of IMF coherence were determined from three hours of interictal data. Patient-, IMF level-, and channel pair-specific IMF-Coh were used to determine the earliest anticipation times for detected ictal events. Our study shows that while not all channel pairs are able to detect every ictal event, in general, low IMFs (containing frequency components greater than 1 Hz) can discriminate between interictal and periictal activities. Our results suggest patient-specific increases in coherence for one or more IMF levels during seizure progression. The anticipation window ranges from 30 to 53 minutes prior to clinical manifestation. We propose an anticipation optimality index as a joint indicator of sensitivity and earliest anticipation times to help select relevant channel pairs and IMF levels. In future work, we will incorporate cross validation techniques with more interictal data as well as investigate patient specific, automated selection of high-sensitivity channel pairs. PMID- 22256268 TI - Using support vector machines to detect medical fraud and abuse. AB - This paper examines the architecture and efficacy of Quash, an automated medical bill processing system capable of bill routing and abuse detection. Quash is designed to be used in conjunction with human auditors and a standard bill review software platform to provide a complete cost containment solution for medical claims. The primary contribution of Quash is to provide a real world speed up for medical fraud detection experts in their work. There will be a discussion of implementation details and preliminary experimental results. In this paper we are entirely focused on medical data and billing patterns that occur within the United States, though these results should be applicable to any financial transaction environment in which structured coding data can be mined. PMID- 22256269 TI - An intelligent Decision Support System for the treatment of patients receiving ventricular assist device (VAD) support. AB - The scope of this paper is to present the Specialist's Decision Support System (SDSS), part of the overall Decision Support Framework that is developed under the SensorART platform. The SensorART platform focuses on the management and remote treatment of patients suffering from end-stage heart failure. The SDSS assists specialists on designing the best treatment plan for their patients before and after VAD implantation, analyzing patients' data, extracting new knowledge, and making informative decisions. It creates a hallmark in the field, supporting medical and VAD experts through the different phases of VAD therapy. PMID- 22256270 TI - A personalized approach for predicting the effect of aerobic exercise on blood pressure using a Fuzzy Inference System. AB - Regular aerobic exercise is a recommended treatment for elevated blood pressure (BP). However, making permanent lifestyle changes is not easy. Having personally relevant information about the treatment, about its effects and importance, is a precondition for motivation. Thus, the first step towards a successful lifestyle change is appropriate education. This paper describes a Sugeno-type Fuzzy Inference System (FIS) that predicts the effect of regular aerobic exercise on blood pressure based on the exercise dose variables, exercise frequency and intensity, as well as demographics (age, gender, ethnicity), and the baseline BP of a person. Since BP response to exercise varies largely between individuals, the system takes an initial step towards personalized prediction. Hence, the system can be used to educate a person about the benefits of exercise on BP in a personally relevant way, providing more accurate information than traditional education materials. Furthermore, preliminary validation results of the performance of the FIS are promising. The predictions comply with the findings of medical research for populations, though the individual-level validation remains still to be done. PMID- 22256271 TI - Heterogeneous data fusion and intelligent techniques embedded in a mobile application for real-time chronic disease management. AB - CHRONIOUS system is an integrated platform aiming at the management of chronic disease patients. One of the most important components of the system is a Decision Support System (DSS) that has been developed in a Smart Device (SD). This component decides on patient's current health status by combining several data, which are acquired either by wearable sensors or manually inputted by the patient or retrieved from the specific database. In case no abnormal situation has been tracked, the DSS takes no action and remains deactivated until next abnormal situation pack of data are being acquired or next scheduled data being transmitted. The DSS that has been implemented is an integrated classification system with two parallel classifiers, combining an expert system (rule-based system) and a supervised classifier, such as Support Vector Machines (SVM), Random Forests, artificial Neural Networks (aNN like the Multi-Layer Perceptron), Decision Trees and Naive Bayes. The above categorized system is useful for providing critical information about the health status of the patient. PMID- 22256272 TI - Gene expression profiling towards the prediction of oral cancer reoccurrence. AB - In this work we perform gene expression profiling on tissue specimen obtained from patients with oral squamous cell carcinoma with a twofold aim: i) to identify a limited number of genes that capture perturbations at molecular level dictating the development of a potential disease relapse after remission, and ii) to employ these genes in order to build a classifier that is able to calculate the probability of disease reoccurrence for new patients, subsequently discriminating patients into high and low risk groups based on reoccurrence probability. The proposed analysis yielded 94% overall accuracy, 100% sensitivity and 89% specificity, for discriminating patients with and without a disease relapse. PMID- 22256273 TI - Mining data from CFD simulation for aneurysm and carotid bifurcation models. AB - Arterial geometry variability is present both within and across individuals. To analyze the influence of geometric parameters, blood density, dynamic viscosity and blood velocity on wall shear stress (WSS) distribution in the human carotid artery bifurcation and aneurysm, the computer simulations were run to generate the data pertaining to this phenomenon. In our work we evaluate two prediction models for modeling these relationships: neural network model and k-nearest neighbor model. The results revealed that both models have high prediction ability for this prediction task. The achieved results represent progress in assessment of stroke risk for a given patient data in real time. PMID- 22256274 TI - Open-access MIMIC-II database for intensive care research. AB - The critical state of intensive care unit (ICU) patients demands close monitoring, and as a result a large volume of multi-parameter data is collected continuously. This represents a unique opportunity for researchers interested in clinical data mining. We sought to foster a more transparent and efficient intensive care research community by building a publicly available ICU database, namely Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II). The data harnessed in MIMIC-II were collected from the ICUs of Beth Israel Deaconess Medical Center from 2001 to 2008 and represent 26,870 adult hospital admissions (version 2.6). MIMIC-II consists of two major components: clinical data and physiological waveforms. The clinical data, which include patient demographics, intravenous medication drip rates, and laboratory test results, were organized into a relational database. The physiological waveforms, including 125 Hz signals recorded at bedside and corresponding vital signs, were stored in an open-source format. MIMIC-II data were also deidentified in order to remove protected health information. Any interested researcher can gain access to MIMIC-II free of charge after signing a data use agreement and completing human subjects training. MIMIC II can support a wide variety of research studies, ranging from the development of clinical decision support algorithms to retrospective clinical studies. We anticipate that MIMIC-II will be an invaluable resource for intensive care research by stimulating fair comparisons among different studies. PMID- 22256275 TI - Developing quantitative physiological phenotypes of sleep apnea for epidemiological studies. AB - Existing physiological databases have not been sufficiently detailed to provide relevant and important information for characterizing the pathophysiology of obstructive sleep apnea. Critical collapsing pressure (P(CRIT)) is a standard method for determining upper airway patency during sleep, however is labor intensive and prohibits large-scale studies. Based on previously published data indicating R(US) does not significantly vary between groups, our aim was to develop an approach to estimate the P(CRIT) from airflow at atmospheric pressure (V(atm)). In a dataset of 126 subjects, where P(CRIT) and R(US) were measured using standard techniques. We then determined the minimum sample size required to estimate the R(US) mean and variance by utilizing a bootstrap procedure (30 times for n=3 to 126). We first estimated the minimum number of subjects needed for obtaining a group for a two-tailed (z=1.96) standard error for R(US) in the population. Then in 75 individuals, quantitative estimates of airflow were obtained at atmospheric pressure. Using the estimated R(US) and atmospheric, we determined an estimated P(CRIT) (?P(CRIT)). Bland-Altman plots were generated to determine the agreement between the measured P(CRIT) and ?P(CRIT). For the entire population the mean +/- SEM R(US) was 23 +/- 1 cmH(2)O/L/s (+/- 95% CI: 21, 25). ~40 subjects represent the minimum sample required to estimate the population variance within +/- 2 SEM. In the subsample with atmospheric flow measurements, a linear regression model (?P(CRIT) [cmH(2)O] = V(@PN) [L/s]x-23[cmH(2)O/L/s]), ?P(CRIT) ranged from 0 to -9.6 cmH(2)O. In the Bland-Altman analysis there was no mean difference between the measured P(CRIT) and ?P(CRIT) (-0.01 cmH(2)O; p=0.8) with upper and lower limits of agreement at +/- 2.3 cmH(2)O. The variance of upstream resistance approaches a constant value in groups with approximately 40 subjects. Utilizing a fixed up-stream resistance to estimate P(CRIT) from the airflow at atmospheric pressure agrees with the measured values. These data suggest that measurements of quantitative airflow during standard polysomnography can be used to determine upper airway properties in large cohorts. PMID- 22256276 TI - The SIESTA database and the SIESTA sleep analyzer. AB - Sleep research and sleep medicine require the recording of biosignals during sleep and their subsequent analysis. The sleep recording is called cardiorespiratory polysomnography. Currently the analysis of the recorded signals is performed by experienced and certified sleep technicians. In addition to visual sleep scoring many attempts had been made to develop computer assisted sleep analysis. In order to develop a computer assisted sleep analysis a systematic database with sleep recording from 200 healthy subjects and of 100 subjects with selected sleep disorders of high prevalence had been compiled as part of a European Commission funded research project. This database was the start for a normative polysomnography database and for the development of a computer based sleep analysis. The computer based sleep analysis is available as an internet service and is now used by many sleep centers for sleep research questions and clinical sleep evaluation in patients with sleep disorders. PMID- 22256277 TI - PhysioNet: physiologic signals, time series and related open source software for basic, clinical, and applied research. AB - PhysioNet provides free web access to over 50 collections of recorded physiologic signals and time series, and related open-source software, in support of basic, clinical, and applied research in medicine, physiology, public health, biomedical engineering and computing, and medical instrument design and evaluation. Its three components (PhysioBank, the archive of signals; PhysioToolkit, the software library; and PhysioNetWorks, the virtual laboratory for collaborative development of future PhysioBank data collections and PhysioToolkit software components) connect researchers and students who need physiologic signals and relevant software with researchers who have data and software to share. PhysioNet's annual open engineering challenges stimulate rapid progress on unsolved or poorly solved questions of basic or clinical interest, by focusing attention on achievable solutions that can be evaluated and compared objectively using freely available reference data. PMID- 22256278 TI - Snoring analysis for the screening of Sleep Apnea Hypopnea Syndrome with a single channel device developed using polysomnographic and snoring databases. AB - Several studies have shown differences in acoustic snoring characteristics between patients with Sleep Apnea-Hypopnea Syndrome (SAHS) and simple snorers. Usually a few manually isolated snores are analyzed, with an emphasis on postapneic snores in SAHS patients. Automatic analysis of snores can provide objective information over a longer period of sleep. Although some snore detection methods have recently been proposed, they have not yet been applied to full-night analysis devices for screening purposes. We used a new automatic snoring detection and analysis system to monitor snoring during full-night studies to assess whether the acoustic characteristics of snores differ in relation to the Apnea-Hypopnea Index (AHI) and to classify snoring subjects according to their AHI. A complete procedure for device development was designed, using databases with polysomnography (PSG) and snoring signals. This included annotation of many types of episodes by an expert physician: snores, inspiration and exhalation breath sounds, speech and noise artifacts, The AHI of each subject was estimated with classical PSG analysis, as a gold standard. The system was able to correctly classify 77% of subjects in 4 severity levels, based on snoring analysis and sound-based apnea detection. The sensitivity and specificity of the system, to identify healthy subjects from pathologic patients (mild to severe SAHS), were 83% and 100%, respectively. Besides, the Apnea Index (AI) obtained with the system correlated with the obtained by PSG or Respiratory Polygraphy (RP) (r=0.87, p<0.05). PMID- 22256279 TI - Facilitated self-assembly of novel dendron-based copolymers. AB - Self-assembly of newly synthesized dendron-based amphiphilic copolymers with controlled hydrophilic-lipophilic balances has been investigated to evaluate their potential as a novel nanocarrier. The hydroxyl-terminated polyester dendron (G3) bearing a focal alkyne moiety was used to mediate the combination of poly(s caprolactone) (PCL) with multiple polyethylene glycol (PEG) moieties. Four types of PCL-G3-mPEG with different block lengths were prepared and their structures were confirmed by (1)H NMR, FT-IR, and GPC. Critical micelle concentration (CMC) values varied from 6.50 * 10(-8) to 3.52 * 10(-7) M, which were lower than those reported for linear PCL-mPEG. TEM revealed that all PCL-G3-mPEG micelles were spherical with an average diameter of 20 nm. The drug release profile for each PCL-G3-mPEG was investigated by loading indomethacin (IMC), as a model drug, within the micelles. IMC was released in a controlled manner over 72 hours. Synthesized copolymers used in this study were also found to be non-cytotoxic at concentrations up to 100 MUM. The low CMC, along with the controlled morphology, release profile and biocompatibility, all demonstrate the potential of the dendron-based micelles as a novel nanocarrier. PMID- 22256281 TI - Sensor architecture for a two-actuator robotic endoscope tip. AB - An angular positioning methodology for a two-actuator robotic endoscope tip is presented. The actuators used to position the tip of the endoscope and tools in the tool channel are miniature rotary motors configured to pull mono-filament cables. The sensors used in this system are a camera at the tip and two three axis gyroscopes. This paper discusses the electrical hardware and communications architecture of the system. A model to account for the dynamic nonlinearities in the system is introduced, experimental results are presented, and control schemes necessary to position the tip is outlined. It was found that the maximum rotational speed of the tip is 400 degrees per second and that the windup delay is around 50 ms which allows for fast angular positioning. PMID- 22256280 TI - Drug-polyester conjugated nanoparticles for cancer drug delivery. AB - We report here the synthesis of camptothecin-polylactide conjugate via camptothecin-initiated lactide polymerization and the formation of nanoconjugates for drug delivery applications. PMID- 22256282 TI - Distributed parameter statics of magnetic catheters. AB - We discuss how to use special Cosserat rod theory for deriving distributed parameter static equilibrium equations of magnetic catheters. These medical devices are used for minimally-invasive diagnostic and therapeutic procedures and can be operated remotely or controlled by automated algorithms. The magnetic material can be lumped in rigid segments or distributed in flexible segments. The position vector of the cross-section centroid and quaternion representation of an orthonormal triad are selected as DOF. The strain energy for transversely isotropic, hyperelastic rods is augmented with the mechanical potential energy of the magnetic field and a penalty term to enforce the quaternion unity constraint. Numerical solution is found by 1D finite elements. Material properties of polymer tubes in extension, bending and twist are determined by mechanical and magnetic experiments. Software experiments with commercial FEM software indicate that the computational effort with the proposed method is at least one order of magnitude less than standard 3D FEM. PMID- 22256283 TI - Neuroscience robotics to investigate multisensory integration and bodily awareness. AB - Humans experience the self as localized within their body. This aspect of bodily self-consciousness can be experimentally manipulated by exposing individuals to conflicting multisensory input, or can be abnormal following focal brain injury. Recent technological developments helped to unravel some of the mechanisms underlying multisensory integration and self-location, but the neural underpinnings are still under investigation, and the manual application of stimuli resulted in large variability difficult to control. This paper presents the development and evaluation of an MR-compatible stroking device capable of presenting moving tactile stimuli to both legs and the back of participants lying on a scanner bed while acquiring functional neuroimaging data. The platform consists of four independent stroking devices with a travel of 16-20 cm and a maximum stroking velocity of 15 cm/s, actuated over non-magnetic ultrasonic motors. Complemented with virtual reality, this setup provides a unique research platform allowing to investigate multisensory integration and its effects on self location under well-controlled experimental conditions. The MR-compatibility of the system was evaluated in both a 3 and a 7 Tesla scanner and showed negligible interference with brain imaging. In a preliminary study using a prototype device with only one tactile stimulator, fMRI data acquired on 12 healthy participants showed visuo-tactile synchrony-related and body-specific modulations of the brain activity in bilateral temporoparietal cortex. PMID- 22256284 TI - Structural design of a newly developed pediatric circulatory assist device for Fontan circulation by using shape memory alloy fiber. AB - Total cavopulmonary connection (TCPC) is commonly applied for the surgical treatment of congenital heart disease such as single ventricle in pediatric patients. Patients with no ventricle in pulmonary circulation are treated along with Fontan algorithm, in which the systemic venous return is diverted directly to the pulmonary artery without passing through subpulmonary ventricle. In order to promote the pulmonary circulation after Fontan procedure, we developed a newly designed pulmonary circulatory assist device by using shape memory alloy fibers. We developed a pulmonary circulatory assist device as a non-blood contacting mechanical support system in pediatric patients with TCPC. The device has been designed to be installed like a cuff around the ePTFE TCPC conduit, which can contract from outside. We employed a covalent type functional anisotropic shape memory alloy fiber (Biometal, Toki Corporation, Tokyo Japan) as a servo actuator of the pulmonary circulatory assist device. The diameter of this fiber was 100 microns, and its contractile frequency was 2-3 Hz. Heat generation with electric current contracts these fibers and the conduit. The maximum contraction ratio of this fiber is about 7% in length. In order to extend its contractile ratio, we fabricated and installed mechanical structural units to control the length of fibers. In this study, we examined basic contractile functions of the device in the mock system. As a result, the internal pressure of the conduit increased to 63 mmHg by the mechanical contraction under the condition of 400 msec-current supply in the mock examination with the overflow tank of 10 mmHg loading. PMID- 22256285 TI - Wireless power delivery for retinal prostheses. AB - Delivering power to an implanted device located deep inside the body is not trivial. This problem is made more challenging if the implanted device is in constant motion. This paper describes two methods of transferring power wirelessly by means of magnetic induction coupling. In the first method, a pair of transmit and receive coils is used for power transfer over a large distance (compared to their diameter). In the second method, an intermediate pair of coils is inserted in between transmit and receive coils. Comparison between the power transfer efficiency with and without the intermediate coils shows power transfer efficiency to be 11.5 % and 8.8 %, respectively. The latter method is especially suitable for powering implanted devices in the eye due to immunity to movements of the eye and ease of surgery. Using this method, we have demonstrated wireless power delivery into an animal eye. PMID- 22256286 TI - A programmable and configurable multi-port System-on-Chip for stimulating electrokinetically-driven microfluidic devices. AB - Recent research has demonstrated the use of microfluidic devices and electro kinetics in areas such as medicine, genetics, embryology, epidemiology and pollution analysis, where manipulation of particles suspended in liquid media is required. Micro-fabrication technology has made it possible to increase system complexity and functionality by allowing integration of different processing and analysis stages in a single chip. However, fully integrated and autonomous microfluidic systems supporting ad-hoc stimulation have yet to be developed. This paper presents a flexible, configurable and programmable stimulator for electro kinetically driven microfluidic devices. The stimulator is a dedicated System-on Chip (SoC) architecture that generates sine, triangle, and sawtooth signals within a frequency range of 1 Hz to 20 MHz, capable of delivering single, dual, and superimposed waveforms, in a user defined test sequence for a selected time period. The system is designed to be integrated into complete, autonomous Lab-on Chip, portable or implantable devices. As such, it is expected to help significantly advance current and future research on particle manipulation. PMID- 22256287 TI - Biosensing and environmental sensing for emergency and protection e-Textiles. AB - The ProeTEX project introduced for the first time a complete set of smart garments integrating sensors for the physiological and environmental monitoring of emergency operators. These "smart" garments have been deeply tested in emergency-like contexts by professional rescuers, in order to assess real-time acquisition, processing and transmission of data from moving subjects while operating in harsh conditions. Here we report an overview of the main results obtained during field trials performed in 2010 by Italian and French professional firefighters, in specialized training centers, while dressing the ProeTEX prototypes. Results clearly demonstrate the benefit and step forward of such a system in order to monitor and coordinate rescuers even during intervention far away from the emergency headquarter. PMID- 22256288 TI - Electroactive polymer patches for wearable haptic interfaces. AB - Fully wearable and unobtrusive sensing will enable the possibility of monitoring people anywhere and anytime, for healthcare, well-being, protection and safety. Many research groups have exploited textiles as the ideal platform for pervasive monitoring. This paper reports advances in electroactive polymer technology oriented to mechanical sensing and actuation within textile interfaces. The preliminary development of a textile-based glove in which electroactive polymers act as force/position sensors and haptic feedback actuators is presented. PMID- 22256289 TI - Elastic components for prosthetic skin. AB - We have developed two fundamental components to manufacture a prosthetic skin: a stretchable pressure sensor formed of piezoelectric elastomer/ferroelectret multilayer sandwiched between stretchable electrodes and stretchable thin-film transistors. The components are prepared and embedded in silicone rubber, a polymer, which mimics the mechanical compliance of human skin. We demonstrate the stretchability of the sensory unit. In both relaxed and stretched states, the soft sensor skin transduces kPa pressures into electrical currents in the MUA range. PMID- 22256290 TI - Fabric opto-electronics enabling healthcare applications; a case study. AB - Textiles are a ubiquitous part of human life. By combining them with electronics to create electronic textile systems, new application fields emerge. In this paper, technology and applications of light-emitting textile systems are presented, with emphasis on the healthcare domain: A fabric substrate is described for electronic textile with robust interwoven connections between the conductive yarns in it. This fabric enables the creation of different forms of comfortable light therapy systems. Specific challenges to enable this use in medical applications are discussed. PMID- 22256291 TI - Miniaturized osmotic pump for oromucosal drug delivery with external readout station. AB - We report on a miniaturized, exchangeable drug delivery cartridge for Parkinson's Disease which is integrated in a partial removable prosthesis. An osmotic pumping principle uses saliva to release constantly a separately stored drug to the buccal mucosa, thus avoiding first pass metabolism and drug plasma level fluctuations. Therapeutic relevant information and fill level of the cartridge can be determined before and after usage with an external readout station. The selected material combinations of the cartridge fulfill both, functional and regulatory aspects as well as requirements for assembly and packaging, e.g. thermal fusion bonding, solvent bonding and capillary stop bonding. By using the cartridge, highly precise release rates over 97% of its storage capacity with a rate deviation of only 1.1% can be achieved. PMID- 22256292 TI - A low cost solution for the fabrication of dielectrophoretic microfluidic devices and embedded electrodes. AB - The versatility of a simple method for producing microfluidic devices with embedded electrodes is demonstrated through the fabrication and operation of two dielectrophoretic devices; one employing interdigitated electrode structures on glass and the other employing contactless electrode reservoirs. Device manufacture is based on the precipitation of silver and subsequent photolithography of thin film resists conducted outside of a cleanroom environment. In current experiments, minimum channel widths of 50 microns and electrode widths of 25 microns are achieved when the distance between features is 40 microns or greater. These results illustrate this technique's potential to produce microfluidic devices with embedded electrodes for lab on chip applications while significantly reducing fabrication expense. PMID- 22256293 TI - An integrated open-cavity system for magnetic bead separation and manipulation. AB - Superparamagnetic beads are generally used in biomedical assays to manipulate, maneuver, separate, and transport bio-materials. We present a low-cost integrated system designed in bulk 0.5 MUm process to automate the manipulation and separation process of magnetic beads. The system consists of an 8 * 8 coil-array suitable for a single bead manipulation, or collaborative manipulation using pseudoparallel executions. The size of a single coil is 30 MUm * 30 MUm and the driver DC current source supports 8 different levels up to 1.5 mA. The total power consumption of the entire system is 9 mW when running at full power and it occupies an area of 248 MUm * 248 MUm. PMID- 22256294 TI - PCR-free, microfluidic single molecule analysis of circulating nucleic acids in lung cancer patient serum. AB - Circulating nucleic acid (CNA) has been the focus of much recent research, studied both as a diagnostic marker and as a marker for enrichment of diseased DNA. Among these markers, circulating DNA fragment size has shown promise for discerning the source of CNA molecules in cancer and prenatal diagnostics due to differences in average size between cancer vs. healthy or fetal vs. maternal DNA. We describe a 1-step assay for analyzing circulating DNA size and quantity directly in human serum that replaces complicated nested qPCR analysis. Microfluidic cylindrical illumination confocal spectroscopy and fluorescence burst size analysis were used to individually count and size fluorescently labeled CNA molecules as they were driven through a microfluidic constriction. First, single molecule sizing was performed on lambda Hind III digest DNA to obtain a size calibration curve. A linear relation between DNA length and fluorescent burst size was seen from 564 bp-23.1 kbp. Then, the single molecule assay was used to analyze an in vitro model of DNA fragmentation. Finally, DNA sizing analysis was successfully performed on serum samples from both early and late stage lung cancer patients. This assay was performed directly in patient serum using only a single reagent, a simple DNA intercalating dye. Furthermore, it eliminated the need for DNA isolation or enzymatic amplification. This demonstrates that microfluidic single molecule spectroscopy can be a rapid, facile, and inexpensive alternative to the established PCR-based methods. PMID- 22256296 TI - Green microfluidics made of corn proteins. AB - Petroleum-based polymer such as Poly(dimethylsiloxane) has been widely used to make mesoscale and microscale fluidic devices. The main drawback of such devices in disposable applications is the potential environmental pollution since they are not biodegradable. Biodegradable microfluidic devices have been fabricated out of zein, a prolamin protein found in corn, that can be utilized as disposable health and environmental-friendly micro-chips. Using stereo lithography and soft lithography, micro-chambers and micro-channels features have been replicated on zein films and enclosed zein microfluidic devices are created by bonding to glass substrate using a simple vapor-deposition method. The bonding strength of the zein microfluidic devices has been found to exceed the tensile strength of the zein film and hydraulic pressure, and fluid flow through large-area complex microfluidic designs shows no leakage or distortion. High optical clarity and fluorescent imaging in the zein microfluidic devices are demonstrated by visualizing micro-particles and Rhodamine B. Zein microfluidic devices enable truly disposable microfluidics with intrinsic biocompatibility and biodegradability that can be fabricated using existing techniques. PMID- 22256295 TI - Capillary fractionation of HPLC substrates by a microfluidic droplet generator for high throughput analysis. AB - Biochemical samples are complex mixtures containing 1000's of components which often must be fractionated prior to analysis. Conventional fraction collectors, which can only accommodate 10's of fractions, are not well suited for high throughput analysis. This paper describes microfractionation in droplets (MUFD), a scalable microfluidic technique for generating thousands of fractions. A drop generator, placed downstream from a high performance liquid chromatography (HPLC) column, encapsulates the separated components into a serial array of monodisperse droplets. The droplets can be stored in a capillary or immediately used in subsequent assays. Using MUFD, a mixture of 3 dyes separated in a C18 column was fractionated into 2,160 droplets in <6 min. The volume and frequency of the droplet fractions are governed by the capillary number (Ca), which depends on the viscosity of the carrier fluid, flow rate, and interfacial tension. With HPLC compatible flow rates of 0.38-0.7 mL/min, in a 1.5 mm Teflon capillary, fractions contain volumes of 1-6 MUL and are generated at 2-10 drops/s. Droplet fractions can be mixed with a subsequent reagent using a downstream tee junction. In theory, MUFD can be coupled to a wide variety of separation processes, enabling high throughput fractionation and screening of complex mixtures in MUL to sub-nL volumes. PMID- 22256297 TI - On-chip incubation system for long-term microfluidic cell culture. AB - We demonstrate the use of a microfluidic cell culture chip with Braille pin driven pumping, capable of on-chip CO2 incubation that does not require an external chamber or gas supply. The proposed chip consists of a poly(dimethylsiloxane)(PDMS)-made microfluidic chip, flip-mounted on a glass slide, that contains a nested pair of cell culture media reservoirs and water jacket, insulated by a permeable PDMS wall. By using 0.8 M sodium bicarbonate with 65 mM sodium carbonate as the water-jacket and placing on a 37 degrees C surface, the chip maintained osmolality shift and the pCO2 in the media reservoir stabilized within < 3 mmol/kg and 5.0% +/- 0.2% over at least 24 hours. The incubation capabilities were demonstrated through microfluidic culture of CV-1 epithelial cells under an inverted microscope for at least 12 days. PMID- 22256298 TI - Towards a cellular multi-parameter analysis platform: fluorescence in situ hybridization (FISH) on microhole-array chips. AB - Highly-sensitive analysis systems based on cellular multi-parameter are needed in the diagnostics. Therefore we improved our previously developed chip platform for another additional analysis method, the fluorescence in situ hybridization. Fluorescence in situ hybridization (FISH) is a technique used in the diagnostics to determine the localization and the presence or absence of specific DNA sequence. To improve this labor- and cost-intensive method, we reduced the assay consumption by a factor of 5 compared to the standard protocol. Microhole chips were used for making the cells well addressable. The chips were fabricated by semiconductor technology on the basis of a Silicon wafer with a thin deposited silicon nitride layer (Si(3)N(4)). Human retina pigment epithelia (ARPE-19) cells were arrayed on 5-MUm holes of a 35 * 35 microhole-array by a gently negative differential pressure of around 5 mbar. After 3 hours of incubation the cells were attached to the chip and the FISH protocol was applied to the positioned cells. A LabView software was developed to simplify the analysis. The software automatically counts the number of dots (positive labeled chromosome regions) as well as the distance between adjacent dots. Our developed platform reduces the assay consumption and the labor time. Furthermore, during the 3 hours of incubation non-invasive or minimal-invasive methods like Raman- and impedance spectroscopy can be applied. PMID- 22256299 TI - A robust microfluidic in vitro cell perifusion system. AB - We present here a robust microfluidic cell perifusion device for in vitro primary tissue cell secretion studies. This system increases the sample concentration to perifusion volume ratio by an order of magnitude compared with standard multi well plate static incubation assays. Further, this device achieves physiologically relevant flow rates, pressures, and temperature. It has been manufactured with typical machining facilities, principally drilling and milling. No specialist clean room equipment is required to replicate it. We show its capability here with hormone perifusion experiments on primary pancreatic tissue from mice. This device can increase cell secretion concentrations by up to a factor of 20, allowing for the first time the direct measurement of islet glucagon using mass spectrometry. PMID- 22256300 TI - Optimization for enhancement of signal effectiveness in three-dimensional (3D) cell based electrochemical biosensor. AB - This study addresses the optimization for enhancement of signal effectiveness in 3D cell based electrochemical biosensor. While 2D culture has a structural limitation to mimic an in vivo, 3D culture can provide more similar cell responses. In addition, although 3D cultured cells have been applied to measure electrically, the intensity of electrical signal from cells on the electrode was extremely low. Thus, we have optimized and evaluated the condition of gelation between several types of sol-gel and cancer cells using the electrical measurement to make fine 3D cell structure on the electrode. These results show that our work can be an useful method for monitoring cell activity by compensating a limitation of 2D culture in real time. PMID- 22256301 TI - A planar structure sensitive to out-of-plane forces for the force-controlled injection of suspended and adherent cells. AB - We present a novel force sensor for the injection of both suspended and adherent cells. Unlike most configurations, this force sensor is independent of the tool interacting with the cells. It is a planar structure that provides a surface sensitive to out-of-plane forces where living cells can be placed for manipulation. It also integrates two beam resonators. Forces perpendicular to the sensor's plane are estimated via frequency shifts of the resonators. In this paper, we develop a theoretical study for predicting and optimizing the structure's sensitivity. As a proof of concept, we report the fabrication and characterization of a first prototype designed for the injection of spherical cells with a diameter of ~100-600 MUm. In air, our prototype presently offers a quality factor of 700, and a linear force sensitivity of ~2.6 Hz/mN. The measurement of forces applied upon lobster eggs is also experimentally demonstrated. PMID- 22256302 TI - An inexpensive alternative bath system for electrophysiological characterization of isolated cardiac tissue. AB - A tissue bath system, to be used as an alternative to complex perfusion chambers, was constructed for use in cardiac electrophysiological studies. This system consists of an acrylic chamber to hold circulating physiological medium such as DMEM, suspended in a water bath warmed by a hot plate. Temperature and pH were controlled to mimic physiological conditions. Rat and porcine cardiac tissues, were used to test viability of the conditions presented in the bath system. Using a cardiac mapping system, the tissues were stimulated and responses recorded. From the recordings we were able to calculate conduction velocities and spatial dispersion of activation indices. The results are comparable to previous in-vivo work, which suggests that the tissue bath system design can maintain tissue viability. This tissue bath system is a relatively simple alternative for ex-vivo testing of cardiac tissues. PMID- 22256303 TI - Arterial blood pressure regulation following aorta clamping and declamping during surgery. AB - In this paper, we propose the use of black box models for the system identification of the cardiopulmonary baroreflex control of arterial resistance and of ventricular contractility and of arterial baroreflex control of heart rate (HR) from invasive, continuous measurements of arterial blood pressure (ABP) and central venous pressure (CVP), and non invasive, continuous recordings of ECG and respiration. Two crucial phases of the abdominal aortic aneurism (AAA) repair were investigated: the clamping and declamping of aorta. The objective of the present work is to evaluate and to test the ability to monitor baroreflex responses to clamping and declamping maneuvers preceding and following aneurism removal. PMID- 22256304 TI - Cold intermittent cardioplegia reduces the acidosis during prolonged cardiac surgery with cardiopulmonary bypass. AB - The effect on acid-base balance efficacy of intermittent warm and cold blood cardioplegia (IWBC, ICBC) was assessed in 44 patients who underwent cardiac surgery with prolonged aortic cross clamping. With this purpose a customized multi sensor probe was inserted in the coronary sinus, and pH, PO(2), PCO(2) and temperature were continuously measured at 1 Hz sampling rate. The mean cross clamping time was of 76 +/- 26 min on 19 IWBC cases and of 80 +/- 24 min on 14 ICBC cases. With IWBC perfusion, at the end of every ischemic period, the lowest pH and PO(2) progressively decreased and the maximal PCO(2) increased. During ICBC the minimum of pH and PO(2) and maximum of PCO2 at the end of different ischemic period during time were constant, also during long cross-clamping time. With IWBC, myocardial ischemia seemed not completely reversed by standardized reperfusions, as reflected by steady deterioration of PCO(2) and pH after each reperfusion. PMID- 22256305 TI - Challenges in intraoperative monitoring. AB - Predicting major adverse events following surgery remains a significant problem. Currently, the perioperative period is too often considered a black box, with risk assessment and prediction largely based on static pre-surgical parameters. Here, we review the problem of intraoperative hypotension and outline some of the opportunities for improved monitoring during surgery. PMID- 22256306 TI - Intra- and inter-beat modeling of cardiovascular dynamics and control: assessing haemodynamic stability and responsiveness. AB - In critical care patient management, extensive and invasive patient monitoring is routinely performed in order to quantify patient status in view of therapeutic interventions. Little quantitative integration is performed when collecting information from multiple monitors, and processing algorithms are often based on little physiological understanding. Mechanistic modeling can offer insight into the mechanisms underlying patient stability and sensitivity to alterations in physiological variables. Starting from existing models, we construct an integrated model which combines detailed neural cardiovascular regulation with realistic circulation modeling, using Monte-Carlo techniques for reparameterisation when merging the two models. The combined model is analyzed in terms of its dynamical stability and sensitivity to parameter perturbations under simulated conditions of fluid deficit, anaesthesia, and dilatative cardiomyopathy. The results exemplify how a structural model can serve as a quantitative guide in assessing how different underlying patient states can alter the haemodynamics impact of external therapeutic intervention. PMID- 22256307 TI - Instantaneous assessment of autonomic cardiovascular control during general anesthesia. AB - We present a comprehensive probabilistic point process framework to estimate and monitor the instantaneous heartbeat dynamics as related to specific cardiovascular control mechanisms and hemodynamics. Assessment of the model's statistics is established through the Wiener-Volterra theory and a multivariate autoregressive (AR) structure. A variety of instantaneous cardiovascular metrics, such as heart rate (HR), heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and baroreceptor-cardiac reflex (BRS), can be rigorously derived within a parametric framework and instantaneously updated with an adaptive algorithm. Instantaneous metrics of nonlinearity, such as the bispectrum of heartbeat intervals, can also be derived. We have applied the proposed point process framework to experimental recordings from healthy subjects in order to monitor cardiovascular regulation under propofol anesthesia. Results reveal interesting dynamic trends across different pharmacological interventions, confirming the ability of the algorithm to track important changes in cardiorespiratory elicited interactions, and pointing at our mathematical approach as a promising monitoring tool for an accurate, noninvasive assessment of general anesthesia. PMID- 22256308 TI - Voxel-based, parallel simulation of light in skin tissue for the reconstruction of subsurface skin lesion volumes. AB - Early detection and diagnosis of skin cancer is essential to treating the malignancy and preventing death. Subsurface features and depth information are critical in evaluating a skin lesion for this early malignancy screening. We present a novel voxel-based Monte Carlo simulation of light propagation in skin tissue which runs in a highly parallel environment on desktop graphics processors, resulting in an extremely fast simulation of millions of photons in less than one second. We then use this model in a genetic algorithm for the inverse 3D volume reconstruction of a skin lesion, given a set of multispectral images obtained using non-invasive transillumination imaging. Our method demonstrates improved accuracy at a superior resolution to existing methods. PMID- 22256309 TI - 3-D Image-guided diffuse optical tomography using boundary element method and MPI implementation. AB - Boundary elements provide an attractive method for image-guided multi-modality near infrared spectroscopy in three dimensions using only surface discretization. This method operates under the assumption that the underlying tissue contains piece-wise constant domains whose boundaries are known a priori from an alternative imaging modality such as MRI or microCT. This significantly simplifies the meshing process providing both speed-up and accuracy in the forward solution. Challenges with this method are in solving dense matrices, and working with complex heterogeneous domains. Solutions to these problems are presented here, with applications in breast cancer imaging and small - animal molecular imaging. PMID- 22256310 TI - Automated spatial alignment of 3D torso images. AB - This paper describes an algorithm for automated spatial alignment of three dimensional (3D) surface images in order to achieve a pre-defined orientation. Surface images of the torso are acquired from breast cancer patients undergoing reconstructive surgery to facilitate objective evaluation of breast morphology pre-operatively (for treatment planning) and/or post-operatively (for outcome assessment). Based on the viewing angle of the multiple cameras used for stereophotography, the orientation of the acquired torso in the images may vary from the normal upright position. Consequently, when translating this data into a standard 3D framework for visualization and analysis, the co-ordinate geometry differs from the upright position making robust and standardized comparison of images impractical. Moreover, manual manipulation and navigation of images to the desired upright position is subject to user bias. Automating the process of alignment and orientation removes operator bias and permits robust and repeatable adjustment of surface images to a pre-defined or desired spatial geometry. PMID- 22256311 TI - A photogrammetry-based system for 3D surface reconstruction of prosthetics and orthotics. AB - The objective of this study is to develop an innovative close range digital photogrammetry (CRDP) system using the commercial digital SLR cameras to measure and reconstruct the 3D surface of prosthetics and orthotics. This paper describes the instrumentation, techniques and preliminary results of the proposed system. The technique works by taking pictures of the object from multiple view angles. The series of pictures were post-processed via feature point extraction, point match and 3D surface reconstruction. In comparison with the traditional method such as laser scanning, the major advantages of our instrument include the lower cost, compact and easy-to-use hardware, satisfactory measurement accuracy, and significantly less measurement time. Besides its potential applications in prosthetics and orthotics surface measurement, the simple setup and its ease of use will make it suitable for various 3D surface reconstructions. PMID- 22256312 TI - Optofluidic on-chip tomography. AB - The first demonstration of optofluidic tomography is presented. Using partially coherent illumination, holograms of objects are recorded at multiple viewing angles, as they flow through a microfluidic channel placed directly on the top of an opto-electronic sensor array. These lensfree holograms are then digitally processed to compute pixel super-resolved tomograms of micro-objects to achieve sectional opto-fluidic imaging on a chip. PMID- 22256313 TI - Tractographic reconstruction protocol optimization in the rat brain in-vivo: towards a normal atlas. AB - The tractographic reconstruction of anatomical and microstructural features provided by Magnetic Resonance (MR) Diffusion Tensor Imaging (DTI) gives essential information of brain damage in several pathological animal models. The optimization of a tractographic protocol is undertaken in normal rats for the future construction of a reference atlas, as prerequisite for preclinical pathological in-vivo studies. High field, preclinical in-vivo DTI faces important difficulties relevant to Signal-to-Noise Ratio (SNR), distortion, high required resolution, movement sensitivity. Given a pixel-size of 0.17 mm and TE/TR = 29/6500 ms, b value and slice thickness were fixed at 700 s/mm(2) and 0.58 mm, respectively, on preventive ex-vivo studies. In-vivo studies led to the choice of 30 diffusion directions, averaged on 16 runs. The final protocol required 51 min scanning and permitted a reliable reconstruction of main rat brain bundles. Tract reconstruction stopping rules required proper setting. In conclusion, the viability of DTI tractography on in-vivo rat studies was shown, towards the construction of a normal reference atlas. PMID- 22256314 TI - A correlation and LS-SVM based approach to mitigate motion artifacts in FDK based 3D cone-beam tomography. AB - Head motion during brain CT studies can degrade the reconstructed image by introducing distortion and loss of resolution, thereby contributing to misdiagnosis of diseases. In this paper, we have proposed a correlation coefficient and Least Squares Support Vector Machines (LS-SVM) based approach to detect and mitigate motion artifacts in FDK based three-dimensional cone-beam tomography. Motion is detected using correlation between adjacent x-ray projections. Artifacts, caused by motion, are mitigated either by replacing motion corrupted projections with their counterpart 180 degrees apart projections under certain conditions, or by estimating motion corrupted projections using LS-SVM based time series prediction. The method has been evaluated on 3D Shepp-Logan phantom. Simulation results validate our claims. PMID- 22256315 TI - Segmentation of brain blood vessels using projections in 3-D CT angiography images. AB - Segmenting cerebral blood vessels is of great importance in diagnostic and clinical applications, especially in quantitative diagnostics and surgery on aneurysms and arteriovenous malformations (AVM). Segmentation of CT angiography images requires algorithms robust to high intensity noise, while being able to segment low-contrast vessels. Because of this, most of the existing methods require user intervention. In this work we propose an automatic algorithm for efficient segmentation of 3-D CT angiography images of cerebral blood vessels. Our method is robust to high intensity noise and is able to accurately segment blood vessels with high range of luminance values, as well as low-contrast vessels. PMID- 22256316 TI - A graph-theoretic approach for segmentation of PET images. AB - Segmentation of positron emission tomography (PET) images is an important objective because accurate measurement of signal from radio-tracer activity in a region of interest is critical for disease treatment and diagnosis. In this study, we present the use of a graph based method for providing robust, accurate, and reliable segmentation of functional volumes on PET images from standardized uptake values (SUVs). We validated the success of the segmentation method on different PET phantoms including ground truth CT simulation, and compared it to two well-known threshold based segmentation methods. Furthermore, we assessed intra-and inter-observer variation in delineation accuracy as well as reproducibility of delineations using real clinical data. Experimental results indicate that the presented segmentation method is superior to the commonly used threshold based methods in terms of accuracy, robustness, repeatability, and computational efficiency. PMID- 22256317 TI - The impact of reconstruction algorithms on semi-automatic small lesion segmentation for PET: a phantom study. AB - A robust lesion segmentation method is critical for quantification of lesion activity in positron emission tomography (PET), especially for the cases where lesion boundary is not discernible in the corresponding computed tomography (CT). However, lesion delineation in PET is a challenging task, especially for small lesions, due to the low intrinsic resolution, image noise and partial volume effect. The combinations of different reconstruction methods and post reconstruction smoothing on PET images also affect the segmentation result significantly which has always been overlooked. Therefore, the aim of this study was to investigate the impact of different reconstruction methods on semi automated small lesion segmentation for PET images. Four conventional segmentation methods were evaluated including region growing technique based on maximum intensity (RGmax) and mean intensity (RGmean) thresholds, Fuzzy c-mean (FCM) and watershed (WS) technique. All these methods were evaluated on a physical phantom scan which was reconstructed with Ordered Subset Expectation Maximization (OSEM) with Gaussian post-smoothing and Maximum a Posteriori (MAP) with quadratic prior respectively. The results demonstrate that: 1) the performance of all the segmentation methods subject to the smoothness constraint applied on the reconstructed images; 2) FCM method applied on MAP reconstructed images yielded overall superior performance than other evaluated combinations. PMID- 22256318 TI - Constrained Bayesian streak artifact reduction approach for contrast enhanced computed tomography imaging of the intervertebral disc. AB - A promising approach for the study of progressive herniation damage of the intervertebral discs under flexion/extension motions as well as compressive loads is the use of contrast-enhanced computed tomography (CECT). One of the biggest limitations of using CECT is the presence of significant streak artifacts in the acquired tomograms, due primarily to the contrast agent injected into the intervertebral disc. To address this issue, a novel constrained Bayesian approach to streak artifact reduction in CECT imagery is introduced in this paper. The problem of artifact reduction is formulated as a constrained Bayesian estimation problem in projection space, and a non-parametric Parzen window estimation approach is employed to estimate the underlying posterior distributions. Experimental results show that the proposed approach provides significant artifact reduction while preserving the intervertebral disc regions to allow for clear visualization of progressive intervertebral disc damage. PMID- 22256319 TI - Image enhancement by spectral-error correction for dual-energy computed tomography. AB - Dual-energy CT (DECT) was reintroduced recently to use the additional spectral information of X-ray attenuation and aims for accurate density measurement and material differentiation. However, the spectral information lies in the difference between low and high energy images or measurements, so that it is difficult to acquire accurate spectral information due to amplification of high pixel noise in the resulting difference image. In this work, an image enhancement technique for DECT is proposed, based on the fact that the attenuation of a higher density material decreases more rapidly as X-ray energy increases. We define as spectral error the case when a pixel pair of low and high energy images deviates far from the expected attenuation trend. After analyzing the spectral error sources of DECT images, we propose a DECT image enhancement method, which consists of three steps: water-reference offset correction, spectral-error correction, and anti-correlated noise reduction. It is the main idea of this work that makes spectral errors distributed like random noise over the true attenuation and suppressed by the well-known anti-correlated noise reduction. The proposed method suppressed noise of liver lesions and improved contrast between liver lesions and liver parenchyma in DECT contrast-enhanced abdominal images and their two-material decomposition. PMID- 22256320 TI - Using ultrasound imaging to identify landmarks in vertebra models to assess spinal deformity. AB - Scoliosis is a type of spinal deformity that commonly develops in adolescents. Cobb angle, using the most tilted vertebrae, is the gold standard to assess scoliosis on radiographs. However, regularly taking radiographs introduces harmful ionizing radiation to patients, thus non-ionizing radiation methods have been explored for many years. Ultrasound has been proposed as one of the non ionizing radiation methods to measure the deformity. This research was divided into two studies: 1) to investigate the reliability and repeatability of a new proposed method to measure Cobb angle; 2) to determine if landmarks can be identified from ultrasound images to measure curvature of spine. Based on the two studies, the feasibility of using ultrasound images to assess spinal deformity will be determined. Thirty-nine radiographs were used in the first study. The new method agreed well with the traditional Cobb method with intraclass correlation coefficient (ICC) value greater than 0.7 in different severity groups, and the average angle difference was 1.6 degrees +/- 3.1 degrees . The second study showed laminae and transverse processes could be recognized from ultrasound images. The difference of the width of the laminae between the phantom and the ultrasound image was 0.3 mm. Therefore, it is feasible to use the proposed method and the laminae from the ultrasound images to assess the severity of scoliosis. PMID- 22256321 TI - Ultrasonic tissue characterization of prostate biopsy tissues by ultrasound speed microscope. AB - Ultrasound speed microscope was developed for quantitative measurement of ultrasonic parameters of soft tissues. The system can measure the ultrasonic attenuation and sound speed in the tissue using fast Fourier transform of a single pulsed wave instead of burst waves used in conventional acoustic microscopy. Prostate biopsy tissues were formalin-fixed and sectioned approximately 5-6 MUm in thickness. They were mounted on glass slides without cover slips. The ultrasonic transducer was mechanically scanned over the specimen. Attenuation was 1.42 +/- 0.08 dB/mm and the sound speed was 1584 +/- 12 m/s in prostatic cancer while both values were 1.86 +/- 0.14 dB/mm and 1614 +/- 30 m/s in normal prostate. The basic measurements of ultrasonic properties would help understanding the interpretation of clinical echography in diagnosis of prostate cancer. PMID- 22256322 TI - Three-dimensional mapping of strain in ex vivo porcine cornea with an ultrasound elasticity microscope. AB - High frequency strain mapping of a porcine cornea was produced by three dimensional speckle tracking of a three-dimensional confocally merged ultrasonic data set. Previous two-dimensional elasticity imaging was limited by speckle moving in the non-imaged dimension. This study used an ultrasonic transducer (53 MHz center frequency, 31 MHz bandwidth, 1.67 f#) scanned in three dimensions. A fresh porcine eye globe was embedded in gelatin up to the cornea/sclera junction and pressurized to physiological pressure. A portion of the cornea was imaged with a single element transducer scanned in three directions. Three-dimensional volume sets were created from the data by confocally merging volume sets at several depths. In the vertical dimension, parallel to ultrasonic propagation, the transducer was moved by nearly half its depth of field. Overlaps between adjacent depths were correlated using phase-sensitive speckle tracking to determine precise shifts. Two-dimensional images over multiple depths of field were combined to form a single 2-D image over an entire vertical scan range. Multiple planes were then stacked in the remaining direction to form a 3-D volume set. Next, the cornea was deformed and then imaged again. Three-dimensional speckle tracking was used to create strain maps from the two volume sets. Vertical strain, horizontal strain, and transverse strain behave as expected and provide insight into mechanical properties of corneal tissue. PMID- 22256323 TI - Simulating ultrasound fields for 2D phased-array probes design optimization. AB - Nowadays, ultrasound diagnostic imaging is one of the non-invasive techniques mostly used in the clinical practice. Recent advances in this field have brought to the development of small and portable systems. New bidimensional probes consisting of 2D phased arrays, allow to obtain real-time 3D representations of moving organs and blood vessels anatomy. Being the complexity of such 4D ultrasound imaging systems significantly increased, new challenges concerning electronics integration arise for designers. In this paper a software simulator is described, which has been developed in order to model ultrasound wave generation, pressure field distribution and echoes reception, with the aim to become a useful tool for optimizing the probe design. The paper mainly focuses on linear ultrasound field modeling; preliminary results on non-linear interactions with contrast agents are also here introduced. PMID- 22256324 TI - Integrating active shape models into ultrasound elastography to diagnose musculoskeletal injuries: a 2D simulation study. AB - We build on ultrasound elastography (UE) by offering a new method for diagnosing musculoskeletal injuries from estimated tissue displacements. Our strategy is to isolate the portion of tissue displacements that arise due to injury. Active shape models are constructed capturing displacement variation among normal tissue. New tissue is then evaluated by estimating displacements with (1) the active shape models and (2) a traditional UE tracking algorithm. The difference between the two estimates defined virtual axial displacement and used to identify injured tissue. Our method was tested by simulating planar tissue examined with ultrasound elastography. Images are presented of axial displacement and virtual axial displacement as well as axial strain and virtual axial strain, i.e. partial derivative of the respective displacements with respect to the axial coordinate. Injured tissue and uninjured tissue were not statistically different when comparing mean absolute value of axial strain covarying with the loading conditions. In contrast, uninjured tissue and injured tissue were statistically different when comparing absolute value of virtual axial strain covarying with loading conditions (p < 0.0001). Statistical significance was considered p < 0.05. PMID- 22256325 TI - Stiffness mapping prostate biopsy samples using a tactile sensor. AB - Previous studies have demonstrated that the stiffness of cancerous cells reflects their pathological stage and progression rates, with increased cancerous cell stiffness associated with increased aggressiveness. Therefore, the elasticity of the cancerous cells has the potential to be used as an indicator of the cancer's aggressiveness. However, the sensitivity and resolution of current palpation and imaging techniques are not sufficient to detect small cancerous tissues. In previous studies, we developed a tactile-based device to map with high resolution the stiffness of a tissue section. The purpose of this study is to evaluate this device using different tissues (BPH, Cancer and PZ) collected from human prostates. The preliminary results show that the tactile device is sensitive enough to tell the differences of the stiffness of different tissues. The results also disclosed the factors (humidity, temperature and tissue degradation) which could dramatically affect the results of stiffness mapping. The tactile technology described in this paper has the potential to help disclose the underlying mechanical mechanisms that lead to increased stiffness in prostate tumors. PMID- 22256326 TI - Antagonistic active knee prosthesis. A metabolic cost of walking comparison with a variable-damping prosthetic knee. AB - This paper examines the impact of a biomimetic active knee prosthesis on the metabolic costs associated with a unilateral transfemoral amputee walking at self selected speed. In this study we compare the antagonistic active knee prosthesis developed at MIT to an electronically controlled, variable-damping commercial knee prosthesis, the Otto Bock C-leg. Use of the active knee prosthesis resulted in both, a 17% increase in an amputee's average self selected walking speed from 1.12 m/s to 1.31 m/s, and a 6.8% reduction in metabolic cost. The results of this study suggest that an agonist-antagonist active knee prosthesis design with variable impedance control can offer walking energetic advantages over commercially available systems. PMID- 22256327 TI - Static ankle impedance in stroke and multiple sclerosis: a feasibility study. AB - Quantitative characterization of ankle mechanical impedance is critical for understanding lower extremity function in persons with neurological disorders. In this paper, we examine the feasibility of employing an ankle robot and multivariable analysis to determine static ankle impedance in 4 patients: 1 with multiple sclerosis and 3 with stroke. We employed a scalar based vector field approximation method which was successful in identifying young healthy subjects' ankle impedance. It enabled clear interpretation of spatial ankle impedance structure and intermuscular feedback at the ankle for both affected and unaffected legs. Measured impedance of two patients was comparable to healthy young subjects, while the other two patients had significantly different static ankle impedance properties. PMID- 22256328 TI - Accuracy and reliability of haptic spasticity assessment using HESS (Haptic Elbow Spasticity Simulator). AB - Clinical assessment of spasticity tends to be subjective because of the nature of the in-person assessment; severity of spasticity is judged based on the muscle tone felt by a clinician during manual manipulation of a patient's limb. As an attempt to standardize the clinical assessment of spasticity, we developed HESS (Haptic Elbow Spasticity Simulator), a programmable robotic system that can provide accurate and consistent haptic responses of spasticity and thus can be used as a training tool for clinicians. The aim of this study is to evaluate the accuracy and reliability of the recreated haptic responses. Based on clinical data collected from children with cerebral palsy, four levels of elbow spasticity (1, 1+, 2, and 3 in the Modified Ashworth Scale [MAS]) were recreated by HESS. Seven experienced clinicians manipulated HESS to score the recreated haptic responses. The accuracy of the recreation was assessed by the percent agreement between intended and determined MAS scores. The inter-rater reliability among the clinicians was analyzed by using Fleiss's kappa. In addition, the level of realism with the recreation was evaluated by a questionnaire on "how realistic" this felt in a qualitative way. The percent agreement was high (85.7+/-11.7%), and for inter-rater reliability, there was substantial agreement (kappa=0.646) among the seven clinicians. The level of realism was 7.71+/-0.95 out of 10. These results show that the haptic recreation of spasticity by HESS has the potential to be used as a training tool for standardizing and enhancing reliability of clinical assessment. PMID- 22256329 TI - Assessment of the effect of time in the repeatability of the stabilometric parameters in diabetic and non-diabetic subjects during bipedal standing using the LorAn pressure distribution measurement system. AB - This study was designed to assess the effect of time on the repeatability of the LorAn pressure distribution measurement system, and evaluate the variability of plantar pressure and postural balance, during barefoot standing in diabetic and non-diabetic subjects, for future diabetic foot clinical evaluation. Fourteen subjects were evaluated (8 females, 6 males, 8 non-diabetics and 6 diabetics, age range 30-70 years) and had no musculoskeletal symptoms. Four variables were measured with the platform in the barefoot standing position. Ten measurements were taken using two different techniques for feet and posture positioning, during three sessions, once a week. The MANOVA test confirmed that the platform measurements are reproducible for variables body baricenter (x) and foot baricenter (x) through time, being the coefficients of variation, with a 99% confidence interval, lower than 1.6% for body baricenter (x), and lower than 2.06% for foot baricenter (x), for all studied conditions. For the remaining variables, the results were not stabilized through time, which makes necessary to standardize the measurement protocol that guarantees the repeatability in all variables. PMID- 22256330 TI - Comparison of Tone compensation and Spring assistance for hand rehabilitation in HEXORR. AB - Robotic rehabilitation techniques have the capacity to provide high dosage therapy without the labor burden of conventional methods. The most effective means of using robots to retrain function is not yet known, though many studies now support providing assistance to movement while the user actively participates in that movement. In this study, we compare, in three chronic stroke subjects, a novel Tone assistance mode to a Spring assistance method commonly used in other robots. The Tone mode provides assistance comparable to the subject's own resistance to extension while Spring mode provides a spring-like force to pull the subject to the target. All three subjects produced larger finger movements with robotic assistance, but they also produced much more positive work with the Tone assistance compared to the Spring assistance. This demonstrates that subjects were actively driving the movements in Tone mode to a greater extent than in Spring mode. Two out of three subjects showed similar results in the thumb. In the third subject, work was comparable across all modes. With Tone assistance, subjects produced movement and torque profiles more similar to that of Unassisted movement than Spring-assisted movement for both fingers and thumb. These results suggest that providing assistance tailored to the user's own tone profile may be an effective means of enhancing range of motion to ultimately enable gains in hand function. PMID- 22256331 TI - A novel cable-driven robotic training improves locomotor function in individuals post-stroke. AB - A novel cable-driven robotic gait training system has been tested to improve the locomotor function in individuals post stroke. Seven subjects with chronic stroke were recruited to participate in this 6 weeks robot-assisted treadmill training paradigm. A controlled assistance force was applied to the paretic leg at the ankle through a cable-driven robotic system. The force was applied from late stance to mid-swing during treadmill training. Body weight support was provided as necessary to prevent knee buckling or toe drag. Subjects were trained 3 times a week for 6 weeks. Overground gait speed, 6 minute walking distance, and balance were evaluated at pre, post 6 weeks robotic training, and at 8 weeks follow up. Significant improvements in gait speed and 6 minute walking distance were obtained following robotic treadmill training through a cable-driven robotic system. Results from this study indicate that it is feasible to improve the locomotor function in individuals post stroke through a flexible cable-driven robot. PMID- 22256333 TI - Bibliography. Oculoplastic and orbital surgery. Current world literature. PMID- 22256332 TI - Prenatal exposure to polycyclic aromatic hydrocarbons, benzo[a]pyrene-DNA adducts, and genomic DNA methylation in cord blood. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic environmental pollutants generated during incomplete combustion. After exposure and during metabolism, PAHs can form reactive epoxides that can covalently bind to DNA. These PAH-DNA adducts are established markers of cancer risk. PAH exposure has been associated with epigenetic alterations, including genomic cytosine methylation. Both global hypomethylation and hypermethylation of specific genes have been associated with cancer and other diseases in humans. Experimental evidence suggests that PAH-DNA adduct formation may preferentially target methylated genomic regions. Early embryonic development may be a particularly susceptible period for PAH exposure, resulting in both increased PAH DNA adducts and altered DNA methylation. OBJECTIVE: We explored whether prenatal exposure to PAHs is associated with genomic DNA methylation in cord blood and whether methylation levels are associated with the presence of detectable PAH-DNA adducts. METHODS: In a longitudinal cohort study of nonsmoking women in New York City, we measured PAH exposure during pregnancy using personal air monitors, assessed PAH internal dose using prenatal urinary metabolites (in a subset), and quantified benzo[a]pyrene-DNA adducts and genomic DNA methylation in cord blood DNA among 164 participants. RESULTS: Prenatal PAH exposure was associated with lower global methylation in umbilical cord white blood cells (p = 0.05), but global methylation levels were positively associated with the presence of detectable adducts in cord blood (p = 0.01). CONCLUSIONS: These observations suggest that PAH exposure was adequate to alter global methylation in our study population. Additional epidemiologic studies that can measure site-specific cytosine methylation and adduct formation will improve our ability to understand this complex molecular pathway in vivo. PMID- 22256334 TI - Topical penile microbicide use by men to prevent recurrent bacterial vaginosis in sex partners: a randomized clinical trial. AB - BACKGROUND: Bacterial vaginosis (BV) recurs frequently after metronidazole treatment. This randomized, single-masked clinical trial evaluated the efficacy of topical application of 62% ethyl alcohol in emollient gel (gel) to the penis by male partners of women diagnosed with BV for preventing post-treatment BV recurrence. METHODS: Among 587 Kenyan women presenting with vulvovaginal symptoms, 236 had BV (vaginal Gram stain Nugent score >=7), of whom 223 (94.3%) agreed, along with their partners, to be randomized: 115 to the intervention and 108 to the control arm. In the intervention arm, male partners agreed to apply gel each morning, and before and after sexual intercourse. All couples received counseling, condoms, and syndromic treatment of sexually transmitted infection symptoms. Follow-up visits were scheduled 1 week, 1 month, and 2 months postenrollment, with vaginal Gram stains at every visit and culture for H2O2 producing lactobacilli at the 2-month visit. The primary outcome was time to diagnosis of BV during follow-up. RESULTS: In the primary intent-to-treat analysis, diagnosis of BV was significantly more frequent in the intervention arm (hazard ratio: 1.44, 95% confidence interval: 1.01-2.04). After adjustment for baseline covariates, the hazard ratio was 1.39 (95% confidence interval: 0.98 1.99). At the 2-month visit, prevalences of any vaginal lactobacilli or of H2O2 producing lactobacilli did not differ appreciably in the 2 study arms (P = 0.81 and 0.32, respectively). CONCLUSION: Daily use of the 62% ethyl alcohol gel by men before and after sex significantly increased persistence or early recurrence of BV in their partners through 2 months after metronidazole treatment. However, no difference was observed in prevalences of vaginal lactobacilli within this same period. PMID- 22256335 TI - Chlamydia trachomatis in the age of the genome: application of molecular genotyping to improve our understanding of the immunopathogenesis of Chlamydia genital tract disease. PMID- 22256337 TI - Emergence of herpes simplex virus-1 syncytial variants with altered virulence for mice after selection with a natural carrageenan. AB - BACKGROUND: Antiviral therapy against herpes simplex virus based on sulfated polysaccharides, like carrageenans, represents a new alternative for genital herpes infections treatment and arises the concern about the appearance of resistant viral populations. METHODS: We characterized the F strain of herpes simplex virus-1 passaged in the presence of a natural carrageenan isolated from the red seaweed Gigartina skottbergii in view of the virulence for mice of isolated viral clones. RESULTS: Viral clones (syn14-1 and syn17-2) showed a syncytial phenotype and a mild resistance to carrageenan, heparin, acyclovir, and brivudine. Both clones were avirulent for BALB/c mice when inoculated intravaginally, whereas F strain produced high mortality. Attenuation correlated with low levels of TNF-[alpha], interleukin-6, and IFN-[gamma] in vaginal lavages although virus titers were similar to those obtained for F strain. On the contrary, they showed a marked virulence when inoculated intranasally leading to a generalized spreading of virus. CONCLUSIONS: Results confirm the hypothesis that selection of herpes simplex virus-1 with a carrageenan in vitro leads to the emergence of variants with a differential virulence when compared to the original virus. This finding should be addressed when an antiviral therapy against genital herpes infection employing a natural carrageenan is under consideration. PMID- 22256336 TI - The incidence and correlates of symptomatic and asymptomatic Chlamydia trachomatis and Neisseria gonorrhoeae infections in selected populations in five countries. AB - BACKGROUND: Asymptomatic Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) infections pose diagnostic and control problems in developing countries. METHODS: Participants in China, India, Peru, Russia, and Zimbabwe were screened for C. trachomatis and N. gonorrhoeae infections and symptoms. RESULTS: A total of 18,014 participants were evaluated at baseline, 15,054 at 12 months, and 14,243 at 24 months. The incidence of chlamydia in men was 2.0 per 100 person years both from baseline to 12 months and from 12 to 24 months, and in women, 4.6 from baseline to 12 months and 3.6 from 12 to 24 months; a range of 31.2% to 100% reported no symptoms across the 5 countries. The incidence of gonorrhea in men was 0.3 per 100 person years both from baseline to 12 months and from 12 to 24 months, and in women, 1.4 from baseline to 12 months and 1.1 from 12 to 24 months; a range of 66.7% to 100% reported no symptoms. Being female, aged 18 to 24 years, and having more than 1 partner were associated with both the infections. In addition, being divorced, separated, or widowed was associated with gonorrhea. Being male, having 6+ years of education, and reporting only 1 partner were associated with having no symptoms among those infected with chlamydia. No variables correlated with asymptomatic gonorrhea among those infected. CONCLUSION: A high prevalence and incidence of asymptomatic sexually transmitted infections was identified among men and women in a wide variety of settings. More effective programs are needed to identify and treat chlamydia and gonorrhea infections, especially among women, young adults, those with multiple partners, those repeatedly infected, and particularly those at risk without symptoms. The risk of transmission from persons with no symptoms requires further study. PMID- 22256338 TI - "Are you iffy?": A social marketing campaign to address uncertainty in HIV status communication among men who have sex with men. PMID- 22256339 TI - Acquired skills in sexually transmitted disease prevention: partner services and tailoring interventions to populations. PMID- 22256340 TI - High human immunodeficiency virus incidence in a cohort of Rwandan female sex workers. AB - BACKGROUND: Measurement of human immunodeficiency virus(HIV) incidence among female sex workers in Rwanda is a key part of preparing for HIV prevention trials. METHODS: HIV-negative, nonpregnant female sex workers (N =397) were tested for HIV-1, sexually transmitted infections, and pregnancy quarterly for 12 months, and again at a 1-time year 2 visit. Additional women (N=156) were tested for HIV at baseline and 6 to 12 months thereafter in a parallel study. RESULTS: A total of 19 participants seroconverted during follow-up,with 13 in the first 12 months. The 12-month HIV incidence rate (IR)was 3.5 (95% confidence interval: 1.6, 5.4) per 100 person-years (PY).There was a nonsignificant downward trend from 4.6/100 PY (1.6, 7.7)in the first 6 months to 2.2 (0.1, 4.4) in the second 6 months (IR ratio:2.1 [95% confidence interval: 0.7, 7.8]). The year 2 IR was 2.1 (0.4,3.7), and the HIV IR in the parallel study (in the absence of frequent study visits) was 3.3/100 PY (0, 7.0). HIV testing history, lifetime pregnancies, recent initiation of sex work, gonorrhea, syphilis, and change in reproductive intentions were associated with incident HIV infection. Incidence of pregnancy, herpes simplex virus-type 2,trichomoniasis, gonorrhea, chlamydia, and syphilis per 100 PY were as follows: 26.3 (21.9, 30.7), 8.7 (4.0, 13.4), 16.9 (12.7, 21.1), 12.1 (8.2,15.9), 8.1 (5.1, 11.2), and 6.2 (3.7, 8.7). CONCLUSIONS: The HIV/sexually transmitted infections burden int his group was high. HIV IR was highest in the first 6 months of the cohort, and in the parallel study in which there were no risk-reduction procedures. HIV prevention and family planning interventions are needed. PMID- 22256341 TI - Aciclovir treatment for human immunodeficiency virus-1: is the "juice worth the squeeze?". PMID- 22256342 TI - How does your kindergarten classroom affect your earnings? Evidence from Project Star. AB - In Project STAR, 11,571 students in Tennessee and their teachers were randomly assigned to classrooms within their schools from kindergarten to third grade. This article evaluates the long-term impacts of STAR by linking the experimental data to administrative records. We first demonstrate that kindergarten test scores are highly correlated with outcomes such as earnings at age 27, college attendance, home ownership, and retirement savings. We then document four sets of experimental impacts. First, students in small classes are significantly more likely to attend college and exhibit improvements on other outcomes. Class size does not have a significant effect on earnings at age 27, but this effect is imprecisely estimated. Second, students who had a more experienced teacher in kindergarten have higher earnings. Third, an analysis of variance reveals significant classroom effects on earnings. Students who were randomly assigned to higher quality classrooms in grades K-3-as measured by classmates' end-of-class test scores-have higher earnings, college attendance rates, and other outcomes. Finally, the effects of class quality fade out on test scores in later grades, but gains in noncognitive measures persist. PMID- 22256343 TI - Saving babies? Revisiting the effect of very low birth weight classification. AB - We reconsider the effect of very low birth weight classification on infant mortality. We demonstrate that the estimates are highly sensitive to the exclusion of observations in the immediate vicinity of the 1,500-g threshold, weakening the confidence in the results originally reported in Almond, Doyle, Kowalski, and Williams (2010). PMID- 22256344 TI - Integrating care for posttraumatic stress and physical comorbidities: the road is clear. PMID- 22256346 TI - [Not Available]. PMID- 22256345 TI - [Not Available]. PMID- 22256347 TI - [Not Available]. PMID- 22256348 TI - [Being a doctor...and do the Camino de Santiago]. PMID- 22256349 TI - Republican presidential candidates united on health care. PMID- 22256350 TI - Grassroots project shines hope on Nairobi slum life. PMID- 22256351 TI - Pro-anorexia websites pose public health challenge. PMID- 22256352 TI - The short life of a race drug. PMID- 22256353 TI - Analysis and function of oxysterols and other regulatory and lipotoxic molecular lipid species. Proceedings of the LipidomicNet-ENOR Joint Workshop. November 19 20, 2010. Munich, Germany. PMID- 22256354 TI - Window of opportunity: menopause, estrogens and the brain. Proceedings of a multidisciplinary Window of Opportunity workshop. January 15-17, 2010. Stanford, California, USA. PMID- 22256355 TI - [Abstracts of the 28th Congress of the French Endocrinology Society. Clermont Ferrand, France. October 10-13, 2011]. PMID- 22256356 TI - Photoreductive synthesis of water-soluble fluorescent metal nanoclusters. AB - Water-soluble fluorescent copper, silver and gold nanoclusters with quantum yields of 2.2, 6.8 and 5.3%, respectively, are prepared by a robust photoreduction of their inorganic precursors in the presence of poly (methacrylic acid) functionalized with pentaerythritol tetrakis 3-mercaptopropionate. PMID- 22256357 TI - Cannabinoids in biology and medicine. Festschrift to celebrate the 80th birthday of Professor Mechoulam. October 2012. Jerusalem, Israel. PMID- 22256358 TI - Proceedings of the 28th World Congress of Endourology and SWL. Chicago, Illinois, USA. PMID- 22256360 TI - Proceedings of the IV International Conference: Modeling and Design of Molecular Materials (MDMM 2010). July 4-8, 2010. Wroclaw, Poland. PMID- 22256359 TI - Proceedings of the Satellite Workshop on Comparative Genomics, Research in Computational Molecular Biology (RECOMB-CG). Ottawa, Canada. October 2010. PMID- 22256361 TI - Proceedings of the SOO Annual Meeting. June 2010. La Rochelle, France. PMID- 22256362 TI - Festschrift in Memory of Erminio Costa. PMID- 22256364 TI - Vaccine Technology III. Advances in vaccine technology. Proceedings of the ECI Conference. June 6-11. 2011. Puerto Vallarta, Mexico. PMID- 22256363 TI - Bone fracture healing and strengthening. Proceedings of the Fifth Meeting on Bone Quality. June 2010. France. PMID- 22256365 TI - Proceedings of the XVIII Congress of the International Society of Electrophysiology and Kinesiology (ISEK 2010). Aalborg, Denmark. June 16-19, 2010. PMID- 22256366 TI - The emerging neuroscience of autism spectrum disorders. Proceedings of a satellite symposium to the Annual Meeting of the Society for Neuroscience. November 11-12, 2010. San Diego, California, USA. PMID- 22256367 TI - [Abstracts of the 10th Congress of the French Society of Vascular Medicine. September 21-24, 2011]. PMID- 22256368 TI - [Proceedings of the Sixteenth Congress of the French Federation for the Study of Reproduction. September 21-23, 2011. Marsielle, France]. PMID- 22256369 TI - Proceedings of the 2010 Conference of the European Association of Communication in Health Care (EACH). Verona, Italy. 2010. PMID- 22256370 TI - Journal introduction. PMID- 22256371 TI - Largest healthcare unions. Ranked by national membership within the healthcare industry, 2011. PMID- 22256372 TI - Cost management for ORs moves from minor to the major leagues. PMID- 22256373 TI - Hospitals prepare for SSI reporting as part of trend toward transparency. PMID- 22256374 TI - OR business managers to participate in workshop. PMID- 22256375 TI - Proposed CoP reg to expand use of nonphysicians. PMID- 22256376 TI - Surgery, supply chain teams forge stronger link. PMID- 22256377 TI - Changing behavior to boost OR's productivity. PMID- 22256378 TI - Largest patient-satisfaction measurement firms. Ranked by total number of engagements in 2010. PMID- 22256379 TI - When we can't fix what is broken. PMID- 22256380 TI - Multiple sclerosis. AB - From April 2001 to March 2011 in BEACH, multiple sclerosis(MS) was managed at a rate of 0.9 per 1000 general practice encounters, suggesting an average 98 000 multiple sclerosis general practice patient encounters per year nationally. PMID- 22256381 TI - The dead donor rule and means-end reasoning--a reply to Gardiner and Sparrow. PMID- 22256382 TI - The dead donor rule and means-end reasoning. A reply to Napier. PMID- 22256383 TI - [Neuronarigalion in surgery of atlanto-avial instability: "the spinal shift"]. PMID- 22256384 TI - When snouted wild-boars routing tender corn / Anger our huntsman. PMID- 22256385 TI - Alcohol as a gender symbol. PMID- 22256387 TI - Eugenics and the sterilization debate in Sweden and Britain before World War II. PMID- 22256386 TI - Economic and ecologic determinants of household organisation in the northeastern Baltic region. PMID- 22256388 TI - Eugenics in Scandinavia after 1945: change of values and growth in knowledge. PMID- 22256389 TI - International eugenics: Swedish sterilization in context. PMID- 22256390 TI - Music and violence in working class Cork: the "band nuisance," 1879-82. PMID- 22256391 TI - Office workers, business elites and the disappearance of the "ladder of success" in Edwardian Glasgow. PMID- 22256392 TI - Peasant mutual aid committees in Riazan province during the new economic policy (1921-27): based on materials from Riazan province. PMID- 22256394 TI - Power, status, and wealth. PMID- 22256393 TI - Penetrating and monitoring the market: the development of the continental market for Scottish herring in the nineteenth and early twentieth centuries. PMID- 22256395 TI - [The historical roots of the concept of center of origin in dispersalist biogeography: from the biblical Eden to the Darwin-Wallace model]. PMID- 22256396 TI - Sanitary inspectors and the reform of housing conditions for Irish migratory potato workers in Scotland from 1945 to the 1970s. PMID- 22256397 TI - Science and political culture: eugenics in comparative perspective. PMID- 22256398 TI - Sickness benefits prior to the welfare state - the case of Sweden, 1850-1955. PMID- 22256399 TI - The "People's Pensioner"in Sweden 1914-1954 - on the changing moral content of a social category. PMID- 22256400 TI - The Danish welfare state under bourgeois reign. PMID- 22256401 TI - The Russian peasant family in the second half of the nineteenth century: based on materials from Riazan province. PMID- 22256402 TI - All dressed up: l'Abbe de Choisy and the theatricality of subversion. PMID- 22256403 TI - Hospitals are an essential element of health services. PMID- 22256404 TI - Drug dispensing systems in Gaza hospitals: a comparative study. AB - Implementing an appropriate drug dispensing system in hospitals is essential to ensure the safe and rational use of drugs. This study aimed to assess the unit dose drug dispensing system (DDS) and the ward-stock DDS utilized in Gaza hospitals to ascertain which system is more beneficial. The quantitative, comparative cross-sectional design utilized structured interviews with pharmacists and head nurses, missing drug registration sheets and drug administration observation checklists. The number of missing units per drug item dispensed (mean 3.4 and 1.8 respectively) and medication administration errors per patient (mean 1.8 and 0.9 respectively) were statistically significantly lower in the hospital using the unit-dose DDS than the ward-stock DDS. The unit dose DDS appeared to be safer, with fewer missing drugs, was more positively perceived by staff and was more supportive of good clinical pharmacy practice. Its use in other hospitals in the Gaza Strip is recommended. PMID- 22256405 TI - Assessment of medical waste management in the main hospitals in Yemen. AB - No previous studies about the management of medical waste have been published in Yemen. This research in 5 government and 12 private hospitals in Sana'a aimed to evaluate waste-workers' and hospital administrators' knowledge and practices regarding medical waste handling. Interviews and observations showedadministrators' knowledge and practices regarding medical waste handling. Interviews and observations showed that the waste-workers were collecting medical and nonmedical wastes together manually in all hospitals without receiving adequate training and without using proper protection equipment. There was poor awareness about medical waste risks and safe handling procedures among hospital administrators, and most hospitals did not differentiate between domestic and medical waste disposal. Budgets were not allocated for waste management purposes, which led to shortages in waste handling equipment and an absence of training programmes for staff. Poor knowledge and practices and a high rate of injuries among waste-workers were noted, together with a risk of exposure of staff and visitors to hazardous waste. PMID- 22256406 TI - Transition towards health promoting hospitals: adapting a global framework to Pakistan. AB - The World Health Organization encourages hospitals to become Health Promoting Hospitals (HPH) but adapting this concept to Pakistan has not been investigated. We explore perceptions of healthcare stakeholders about strategies and a priority action-plan to encourage HPHs in Pakistan. We conducted a qualitative study in 2007 where key-informant interviews and focus group discussions were held with healthcare stakeholders in Karachi. Thematic analysis was done and emerging themes were categorized. The HPH core components were perceived as the "standard framework"; however more emphasis was placed on priority actions as to satisfy "basic needs" of patients, staff and the community. This included basic facilities of comfort, health, hygiene, safety, security and emotional support. A change in the traditional mindset from cure to care and identification of key personnel, awareness-raising and cooperation would strengthen advocacy efforts for HPH in Pakistan. PMID- 22256407 TI - Predictive value of plasma haematocrit level in early diagnosis of pre-eclampsia. AB - While pre-eclampsia is the most common complication of pregnancy, a definitive screening test for early diagnosis is still elusive. In this study, haematocrit value was assessed as a screening test for pre-eclampsia in 660 women at 24-28 weeks of pregnancy attending a hospital in Tehran, Islamic Republic of Iran. Mean haematocrit values were significantly higher in pre-eclamptic than non-pre eclamptic women: 37.7% (SD 2.0%) and 35.9% (SD 1.7%) respectively. The receiver operating characteristics curve showed that the most appropriate cut-off point for the haematocrit test in this sample of women was 38%; at this value the sensitivity was 58.6% and specificity was 88.9%; positive and negative predictive values were 33.7% and 95.7% respectively. The haematocrit, done as a routine screening test for anaemia at 24-28 weeks of pregnancy, may also be useful as a screening test for early diagnosis of pre-eclampsia. PMID- 22256408 TI - Interferon-gamma release assay for detection of latent tuberculosis infection in casual and close contacts of tuberculosis cases. AB - The tuberculin skin test (TST) has many limitations for the diagnosis of latent tuberculosis (TB infection. The aim of this study in Egypt was to estimate the usefulness of an interferon-gamma release assay (IFN-gamma) assay for the detection of latent TB infection in contacts of active TB cases. A total of 116 participants were enrolled and divided into 3 groups: community controls, casual (laboratory and clinic) contacts and close (household) contacts. Subjects diagnosed with latent TB infection by TST were 11.5% of controls, 71.1% of casual contacts and 29.6% of close contacts. Subjects diagnosed as latent TB infection by IFN-gamma assay (QuantiFERON-TB Gold In-Tube) were 5.9% of controls, 31.0% of casual contacts and 33.3% of close contacts. The overall agreement between TST and IFN-gamma was 66.7% (kappa = 0.28). The IFN-gamma method could be more helpful than TST for detection of latent TB infection in contacts. PMID- 22256409 TI - Age-specific seroprevalence of hepatitis A in Sari, northern Islamic Republic of Iran. AB - The declining incidence of hepatitis A virus (HAV) infection in the Islamic Republic of Iran may be reducing the population's natural immunity. This was the first systemized, population-based survey of the seroprevalence of HAV antibodies in urban and rural inhabitants of Sari, Mazandaran province. Serum from 1034 individuals aged 1-25 years in 2007 were tested for anti-HAV lgG antibody using a commercial enzyme immunoassay kit. The overall seroprevalence was 38.9%. The lowest prevalence (5.2%) was among the younger age group (1-5 years) from urban areas and the highest prevalence (82.0%) in the older age group (15-25 years) from rural areas. Seropositivity was significantly higher at higher age, among females and in rural areas. Sari is no longer classified as an area of high endemicity, and immunization against HAV may be needed in our population in the future. PMID- 22256410 TI - Prevalence of hepatitis B and C among students of health colleges in Saudi Arabia. AB - This study determined the prevalence of hepatitis B surface antigen (HB(s)Ag) and antibody to hepatitis C virus (anti-HCV) among students at health colleges in Saudi Arabia from 2000 to 2007. Data were obtained from student records. A total of 16 570 (9852 male and 6718 female) students were included. Their mean age was 21 years and they were divided in 2 age groups of 18-21 and 22-30 years. Residence (rural or urban) was recorded. The prevalence of HB(s)Ag for males and females was 0.17% and 0.78% respectively in the 18-21-year-olds and 0.39% and 0.90% in the 22-30-year-olds. The prevalence of anti-HCV for males and females was 0.03% and 0.07% respectively in the 18-21-year-olds and 0.31% and 0.40% in the 22-30-year-olds. There was a statistically significant relationship between age and rural/urban background and HB(s)Ag and anti-HCV positivity (P < 0.005). PMID- 22256412 TI - Road safety in the Eastern Mediterranean Region--findings from the Global Road Safety Status Report. AB - A secondary data analysis using the Global Status Report on Road Safety (GSRRS) was carried out to assess the epidemiology of road traffic injuries (RTIs) and preventive strategies in the Eastern Mediterranean egion (EMR). EMR countries ranked equal first in the world for the highest number of fatalities due to RTIs (32.2 per 100 000 population). The region had about 4% of the world's vehicles with 0.097 registered vehicles per person. The number of injured cases in EMR was 210.1 per 100 000 population. Only 15% of EMR countries had a funded, independent, multisectoral body for road safety. Only 25% had mandatory seat-belt laws for both front-seat and rear-seat passengers, 60% had mandatory helmet laws for both drivers and passengers of motorized two-wheelers and 10% had child restraint laws. Road safety in EMR countries needs more attention and consideration. PMID- 22256411 TI - Study of antibiotic prescribing among dental practitioners in Shiraz, Islamic Republic of Iran. AB - Inappropriate prescribing of antibiotics by health care professionals is a worldwide concern. This study evaluated the knowledge and practices of dental practitioners in the city of Shiraz, Islamic Republic of Iran regarding their therapeutic use of antibiotics for patients with dentoalveolar infections. Of 219 (48.6%) dentists responding to the questionnaire more than 40% would prescribe antibiotics for localized fluctuant swelling and for problems for which antibiotics are not required according to good practice guidelines (acute pulpitis, chronic apical infection, periodontal abscess, chronic gingivitis, chronic periodontitis, pericoronitis and dry socket). A majority correctly prescribed antibiotics for acute periapical infection (77.2%), cellulitis (75.3%) and acute ulcerated gingivitis (63.0%). Amoxicillin was the most frequently prescribed antibiotic for all clinical conditions but there was a wide variation in dosage, frequency and duration for all antibiotics used. Guidelines on rational antibiotic use are needed for dental practitioners in the Islamic Republic of Iran. PMID- 22256413 TI - Psychiatric co-morbidity with type 1 and type 2 diabetes mellitus. AB - We evaluated the prevalence of diabetes comorbidity in Greek psychiatric patients, differences between type 1 and type 2 diabetics and the outcome of psychiatric disorder. Of 800 psychiatric patients meeting our inclusion criteria, 82 (10.2%) had diabetes mellitus; 28% type 1 and 72% type 2. The mean age at onset of mental illness was earlierfortype 1 diabetics (mean 26.95, SD 9.09 years) than type 2 (mean 33.22, SD 10.71 years) (P < 0.015) and the duration of untreated mental illness was shorter (mean 2.86, SD 3.06 years compared with mean 4.13, SD 6.24 years for type 2 diabetics). Schizophrenia was the commonest psychiatric diagnosis in both types of diabetes. There was no significant difference in outcome of psychiatric disorder between the 2 types of diabetics. Existence of diabetes mellitus (regardless of type), duration of untreated mental illness and lack of patient therapeutic education were negative predictors of (unfavourable) outcome. These findings provide evidence of a high prevalence of diabetes in psychiatric patients and that having diabetes has an adverse effect on outcome of psychiatric illness. PMID- 22256414 TI - Health care system in Saudi Arabia: an overview. AB - The government of Saudi Arabia has given high priority to the development of health care services at all levels: primary, secondary and tertiary. As a consequence, the health of the Saudi population has greatly improved in recent decades. However, a number of issues pose challenges to the health care system, such a shortage of Saudi health professionals, the health ministry's multiple roles, limited financial resources, changing patterns of disease, high demand resulting from free services, an absence of a national crisis management policy, poor accessibility to some health care facilities, lack of a national health information system, and the underutilization of the potential of electronic health strategies. This paper reviews the historical development and current structure of the health care system in Saudi Arabia with particular emphasis on the public health sector and the opportunities and challenges confronting the Saudi health care system. PMID- 22256415 TI - Beliefs about euthanasia among university students: perspectives from Pakistan. AB - Opinions of university students about euthanasia were studied in 4 cities in Pakistan using convenience sampling. A total of 836 students (316 males and 520 females) completed a questionnaire in which euthanasia was defined as deliberate administration of an overdose of a drug by a doctor to relieve pain and suffering of a dying patient at his/her explicit request to end his/her life. Only 25.6% of students agreed that euthanasia should be legalized in Pakistan. The most common reason cited for legalization of euthanasia was to relieve patient's suffering but only when a committee of physicians agreed to recommend it. Students who opposed legalization (74.4%) cited impediments to future medical research as the most common reason, followed by the risk of misuse by physicians or family members. Only 8.9% of students cited religious beliefs as a reason against legalization. There is a need in Pakistan for more debate about euthanasia. PMID- 22256416 TI - Churg-Strauss syndrome with broad spectrum clinical presentations: a report of 3 cases. PMID- 22256417 TI - The Argument. Facing that end in the road? PMID- 22256418 TI - When you wish upon a star. Nothing of practical value comes from it. PMID- 22256419 TI - House arrest. When the fallen is one of our own, emotions run high. PMID- 22256420 TI - On-the-Job training: Part 2. What the student experiences during training will forge their future. PMID- 22256421 TI - Processing the patient refusal. PMID- 22256422 TI - Five steps to becoming a learning organization. In times of great change, certain qualities can help an agency thrive. PMID- 22256423 TI - Reader meter. Lessons, insights and experiences from the field. PMID- 22256424 TI - Cell surface expression and internalization of the murine erythroid AE1 anion exchanger tagged with an extracellular FLAG epitope. AB - Anion exchanger 1 (AE1) is the most abundant integral membrane protein in red cells and is essential for maintaining red cell mechanical stability. However, the mechanism for the assembly of AE1 into the membrane skeletal network remains unknown. Several mutants of murine AE1 tagged with an N-terminal enhanced green fluorescent protein (EGFP) and/or an extracellular FLAG epitope inserted adjacent to the N-glycosylation site were prepared, and their expression was analyzed in HEK293 or COS-1 cells by immunofluorescence microscopy, biotinylation, and deglycosylation. The EGFP- and FLAG-tagged AE1 mutant, as well as the wild-type AE1, exhibited cell surface expression in transfected cells and showed a rapid internalization that appeared to occur through the early endosome into the Golgi apparatus. Interestingly, the form of the protein with an endoglycosidase H (endo H)-sensitive N-glycan was the major component of EGFP-tagged and wild-type AE1. By contrast, the polypeptide with an endo H-resistant oligosaccharide was the predominant form of FLAG-tagged AE1. These data demonstrate that the processing of N-glycan is not a prerequisite to cell surface expression of AE1 and suggest that the FLAG tag insertion altered the accessibility of the N-glycan to enzymes in the Golgi which facilitate processing of oligosaccharides. Although whether this structural alteration would affect the structural and functional properties of AE1 remains unknown, cell surface expression and endocytic internalization of FLAG-tagged AE1 mutants indicate that these mutants are suitable for studying the mechanisms of the assembly and plasma membrane insertion of AE1. PMID- 22256425 TI - Human amniotic membrane and vitamin E/selenium for control of postoperative adhesion in dogs. AB - This study was undertaken to compare between the human amniotic membrane (HAM) and intraperitoneal vitamin E (Vit E) and selenium in prevention of postoperative adhesions in dogs. A total of 18 apparently healthy adult Mongrel dogs were divided into three equal groups and the group (I) was treated with a sterile solution of 0.9% sodium chloride intraperitoneally as a control. Group II was treated with the HAM at jejunal enterotomy while group III was treated with Vit E and selenium administered intraperitonally. Dogs were euthanized 30 days postoperatively for histopathological examination. The results showed that both HAM and Vit E and selenium were effective in reduction of the postoperative adhesion in comparison with the group I. In terms of extent of adhesions, there was no significant difference between the HAM group and the Vit E and selenium group. PMID- 22256426 TI - Basosquamous carcinoma with systemic metastasis in a miniature Pinscher. AB - Basosquamous carcinoma (BSCC) is a rare malignancy, primarily composed of basal cells with foci of squamous differentiation. It is considered to be histologically an intermediate type between basal cell carcinoma and squamous cell carcinoma, and is known to have aggressive behaviors. BSCC occurred in a 17 year-old female minipin with a history of surgical excision for a mammary tumor. The right upper hindlimb was severely enlarged to 8 x 5 cm. Cross-section showed a homogenous white to yellow-white mass compressing the surrounding muscular tissues. The tumor metastasized also to the lungs, heart, abdominal cavity, liver and salivary gland. Microscopically, basaloid cells were crowded into solid nests or lobules separated by well-developed fibrous tissues with occasional keratinizations. Since there was no skin lesions, the tumor is assumed to be originated from the formerly present tumor in mammary gland. To our literature review, this case is the first BSCC with systemic metastasis in a dog. PMID- 22256427 TI - Who will lead? PMID- 22256428 TI - Leo Finley Jr. CDS President, 1989-90. Remembering a champion for organized dentistry. PMID- 22256429 TI - The benefits of mentorship. PMID- 22256431 TI - Coming together for CURE. PMID- 22256430 TI - Smartphone apps for your practice. PMID- 22256432 TI - Test your dento-legal knowledge. PMID- 22256433 TI - Laughter as medicine. PMID- 22256434 TI - Earl Renfroe: pioneer, Renaissance man. PMID- 22256435 TI - A swan song for CODA? PMID- 22256436 TI - Doolin lecture 2011: Emily O'Reilly, Ombudsman. 'Health care in Ireland--an Ombudsman perspective'. PMID- 22256437 TI - The diminishing role of biochemistry in subarachnoid haemorrhage diagnosis. PMID- 22256438 TI - Vaccination, not vacillation. PMID- 22256439 TI - A prospective study of injury and activity profile in elite soccer referees and assistant referees. AB - Injuries to soccer players have been extensively examined, but not the injury experience of referees and assistant referees. This study aimed to determine the injury incidence and activity profile of soccer match officials. A 12 month prospective cohort study was used to collect activity and injury data of 31 participants who reported their training and match exposure and their injury incidence by means of weekly online questionnaire. Study participants spent a mean of 2632 hrs training and 1704 hrs officiating over the 12 month study period. Thirty eight injuries were recorded, (8.8 injuries/1000 hr of training (CI 6.2 to 12.0) and 16.4 injuries/1000 hr for match officiating (CI 10.9 to 23.8)), (Risk Ratio 4.3, 2.1 to 8.9). Fifty five percent (CI 40 to 70%) of the injuries were to muscles, and 76% (CI 61 to 87%) were to the lower leg. Overuse injuries represented 61% (CI 45 to 74%) of all cases. Findings showed that the injury frequency rate associated with soccer referees is higher than that in a number of other non contact sports. The injury incidence associated with training for soccer referees is higher than that associated with training for soccer players. Further prospective studies are merited to examine effectiveness and availability of injury management programmes to establish the welfare of this population. PMID- 22256440 TI - H1N1 influenza in an Irish population: patterns of chest radiograph abnormality in patients testing positive. AB - The winter of 2010/2011 saw a second peak in the number of H1N1 cases detected in Ireland. The purpose of this study was to investigate the radiological characteristics of patients diagnosed during this period. A retrospective analysis of these cases was performed. Chest radiographs were classified as normal or abnormal. A total of 37 patients were included. Of these, 22 (59%) of chest radiographs were abnormal and 15 (41%) were normal. In the 7 paediatric patients, 4 (57%) had a perihilar distribution of disease, 2 (28%) had peripherally based disease with 1 (14%) having a mixed distribution. A series of radiographs was available for 9 patients, 6 of these showed a radiographic deterioration from the initial study. The majority of chest radiographs of patients with confirmed H1N1 infection will be abnormal. In children, disease is more likely to be perihilar in distribution. Chest radiography is an important initial investigation in patients with H1N1 infection and is useful to track progression of disease in the subset of patients requiring hospitalization for severe disease. PMID- 22256441 TI - Epidural analgesia for labour: maternal knowledge, preferences and informed consent. AB - Epidural analgesia has become increasingly popular as a form of labour analgesia in Ireland. However obtaining true inform consent has always been difficult. Our study recruited 100 parturients who had undergone epidural analgesia for labour, aimed to determine the information they received prior to regional analgesia, and to ascertain their preferences regarding informed consent. Only 65 (65%) of patients planned to have an epidural. Knowledge of potential complications was variable and inaccurate, with less than 30 (30%) of women aware of the most common complications. Most women 79 (79%) believed that discomfort during labour affected their ability to provide informed consent, and believe consent should be taken prior to onset of labour (96, 96%). The results of this study helps define the standards of consent Irish patients expect for epidural analgesia during labour. PMID- 22256442 TI - Development of an adhesive surgical ward round checklist: a technique to improve patient safety. AB - Checklists have been shown to improve patient outcomes. Checklist use is seen in the pre-operative to post-operative phases of the patient pathway. An adhesive checklist was developed for ward rounds due to the positive impact it could have on improving patient safety. Over an eight day period data were collected from five consultant-led teams that were randomly selected from the surgical department and divided into sticker groups and control groups. Across the board percentage adherence to the Good Surgical Practice Guidelines (GSPG) was markedly higher in the sticker study group, 1186 (91%) in comparison with the control group 718 (55%). There was significant improvement of documentation across all areas measured. An adhesive checklist for ward round note taking is a simple and cost-effective way to improve documentation, communication, hand-over, and patient safety. Successfully implemented in a tertiary level centre in Dublin, Ireland it is easily transferable to other surgical departments globally. PMID- 22256443 TI - The impact of MRSA infection in the airways of children with cystic fibrosis; a case-control study. AB - The prevalence of Methicillin Resistant Staphylococcus Aureus (MRSA) in patients with Cystic Fibrosis (CF) has risen dramatically over the past 10 years. The clinical significance of MRSA in CF patients remains undetermined. We conducted a review of patients with CF infected with MRSA over a 10 year period at Our Lady's Children's Hospital, Crumlin between 1999 and 2009. We collected data from 24 patients infected with MRSA and 24 control patients without MRSA There was a significant difference between the two groups in the rate of decline in percentage FEV1 two years after MRSA infection (Difference: -17.4, 95% CI: 30.48, -4.31, p = 0.01). A similar trend was seen for FVC% and FEF25-75% predicted. This study suggests that persistent MRSA infection in the airways of children with CF is associated with diminished lung function two years post acquisition, when compared to a matched control cohort without MRSA. PMID- 22256444 TI - Atypical fractures on long term bisphosphonates therapy. AB - Bisphosphonates reduce fractures risk in patients with osteoporosis. A new pattern of fractures is now being noted in patients on prolonged bisphosphonate therapy. We report a case of an atypical femoral fracture with preceding pain and highlight the characteristics of these fractures. PMID- 22256445 TI - Successful catheter directed thrombolysis of IVC and renal vein occlusive thrombus. AB - Thrombus formation is a recognised complication of IVC filter placement, however IVC and bilateral renal vein occlusion secondary to thrombus is much less common. We present a case of infrahepatic caval and bilateral renal vein occlusion secondary to thrombosis of a suprarenal IVC filter. With progressive clinical deterioration and failure of conservative medical management the patient underwent successful mechanical disruption and catheter directed thrombolysis. PMID- 22256446 TI - Pyroglutamic aciduria: a cause of high anion-gap metabolic acidosis associated with common drugs. AB - Pyroglutamic aciduria is a rare and probably under-recognised cause of metabolic acidosis which may be precipitated by certain common drugs. PMID- 22256447 TI - Are fathers underused advocates for breastfeeding? AB - Fathers' knowledge base and attitudes influence breastfeeding practice. We aimed to evaluate if Irish fathers felt included in the breastfeeding education and decision process. 67 fathers completed questionnaires, which assessed their role in the decision to breastfeed, knowledge regarding the benefits of breastfeeding and attitude towards breastfeeding.Forty-two (62.7%) of their partners were breastfeeding. Antenatal classes were attended by 38 (56.7%); 59 (88.1%) discussed breastfeeding with their partners and 26 (38.8%) felt that the decision was made together. Twelve (48%) fathers of formula fed infants were unaware that breastfeeding was healthier for the baby. Most fathers (80.6%) felt that breastfeeding was the mother's decision and most (82.1%) felt that antenatal information was aimed at mothers only. Irish fathers remain relatively uninformed regarding the benefits of breastfeeding. This may contribute to their exclusion from the decision to breastfeed. Antenatal education should incorporate fathers more, and this may result in an improvement in our breastfeeding rates. PMID- 22256448 TI - A life in medicine. PMID- 22256449 TI - A case of occupational gout. AB - Gout can occur in any joint but most commonly afflicts the first metatarsophalangeal joint. Many theories have been suggested as explanations for this preferential joint involvement. We describe a case of gout occurring in the fingers of a man with occupational cold exposure, a case of "occupational" gout, and support for the involvement of temperature in acute attacks of gout. PMID- 22256450 TI - Child safety restraints: advice to parents. PMID- 22256452 TI - Take up the care challenge. PMID- 22256451 TI - Medical staff closure antitrust considerations. PMID- 22256453 TI - Nurses urged to be part of campaign for better care. PMID- 22256454 TI - Mystery shoppers check out quality of patient experience. PMID- 22256455 TI - 'Dragons' den' initiative offers nurses chance to share clinical innovations. PMID- 22256456 TI - Invest your skills in improving global health. PMID- 22256457 TI - Debriefing tool can relieve stress. PMID- 22256458 TI - Familiar territory. PMID- 22256459 TI - Excellence in action. PMID- 22256460 TI - Australian health care: closing the service gap. AB - Nurses have an unmatched presence in a range of healthcare settings, and can extend their services well beyond the boundaries of the acute system. By doing so, they can help healthcare providers meet the Millennium Development Goals set by the United Nations, for example by improving care for Indigenous Australians and those living in remote areas. PMID- 22256461 TI - Care adjustments for people with learning disabilities in hospitals. AB - Health inequalities start early in life for people with learning disabilities. In the UK, they can arise from various barriers that people experience when trying to access care that should be appropriate, timely and effective. Inequalities in health care are likely to result in many NHS organisations breaching their legal responsibilities, as outlined in the Disability Discrimination Acts 1995 and 2005, the Equality Act 2010 and the Mental Capacity Act 2005 (Emerson and Baines 2010). This article seeks to help nurses, healthcare professionals and hospital managers ensure that better services are delivered by encouraging them to explore how reasonable adjustments can improve outcomes for people with learning disabilities. PMID- 22256462 TI - Support for practitioners switching work environments mid-career. AB - Patterns of healthcare demand are changing, so services are increasingly being located in communities. Nurses and nurse managers must. therefore, prepare themselves for mid-career transitions into new roles or working environments. This article explains how these transitions can best be made and offers some tips for nurses and nurse managers who are about to make them, or who want to help colleagues make them, successfully. PMID- 22256463 TI - Understanding the relationship between followers and leaders. AB - Contemporary healthcare policies tend to imply that successful leadership can be attributed to a single leader. Such an understanding of leadership ignores the significant contribution followers make to successful leadership and their influence on leaders. In reality, followers rarely simply follow leaders. Following is a complex process that depends on the context and involves followers making judgements about prospective leaders while deciding whether or not to follow them. This interdependence is ignored all too often or misunderstood by those who see leadership as something that can resolve the problems of the NHS. Using data from a study of leadership in community nursing in which the authors were involved, they argue that senior staff who ignore followers and their contribution to leadership do so at the peril of their organisations. PMID- 22256464 TI - Focused on safety. PMID- 22256465 TI - Doppler study of umbilical artery in Thai fetus. AB - OBJECTIVE: Create reference centile charts for Doppler study of Pulsatile index (PI), Resistance index (RI) and Systolic to Diastolic (S/D) ratio ofumbilical artery in Thai fetus throughout gestation. MATERIAL AND METHOD: Six hundred fifty eight pregnant women between 13-40 weeks gestation who attended the antenatal clinic at Siriraj Hospital, Mahidol University, Bangkok, were recruited. Each fetus was measured only once for the purpose of the present study. The mean and fitted centiles were estimated at each week of gestation using linear regression modeling. RESULTS: Doppler study of Pulsatile index (PI), Resistance index (RI), and Systolic to Diastolic (S/D) ratio of umbilical artery were measured in 658 fetuses. The mean 95% confidence intervals for Doppler study of Pulsatile index (PI), Resistance index (RI), and Systolic to Diastolic (S/D) ratio of umbilical artery at each gestational age were fitted to estimate by linear regression models. The centile chart of this parameter was also presented. CONCLUSION: Reference centile chart for Doppler study of Pulsatile index (PI), Resistance index (RI) and Systolic to Diastolic (S/D) ratio of umbilical artery of Thai fetuses was presented. PMID- 22256466 TI - Outcome of second trimester amniocentesis in singleton pregnancy at Songklanagarind Hospital. AB - OBJECTIVE: To evaluate the outcome of genetic amniocentesis in singleton gestation at Songklanagarind Hospital. MATERIAL AND METHOD: This was a descriptive study that included all singleton pregnant women who had a second trimester amniocentesis for chromosome studies at the Maternal Fetal Medicine Unit, Department of Obstetrics and Gynecology, Songklanagarind Hospital between January 1998 and 2006 to assess the outcome including risk of fetal loss in such cases. RESULTS: Advanced maternal age was the most common indication for amniocentesis. Amniocentesis after positive screening aneuploidy test increased. The fetal loss within 14 days after the procedure was 0.12% (10/8,073). Leakage of amniotic fluid occurred 0.1% (5/8,073) but only one case aborted. Fever occurred in two cases and a case of chorioamnionitis was diagnosed. CONCLUSION: The rate of fetal loss within 14 days after amniocentesis in singleton pregnant women was lower than the authors' previous 10 years. The anxiety of the family and difficulty of counseling to the family will be reduced because of a lower complication rate. Moreover the pregnant women who have a high degree of anxiety for genetic abnormalities are a likely choice for genetic amniocentesis if the risk rate regarding the patient's age, ultrasonographic finding, or maternal serum screening is around 0.1%. PMID- 22256467 TI - Seasonal variation in the prevalence of preeclampsia. AB - OBJECTIVE: To determine whether there is a seasonal impact on the prevalence of preeclampsia in the tropical climate of Bangkok. MATERIAL AND METHOD: Medical records of all singleton pregnant women who delivered in the authors' institution between 2008 and 2009 were reviewed. The meteorological variables during the study period were obtained from database of the Thai Meteorological Department. The period of study was then divided into two main seasons: monsoon and dry seasons. The rates of preeclampsia occurring in the two seasons, based on the date of conception and date of delivery, were compared. RESULTS: Data of 7,013 gravidas were included for analysis. Of these, 327 (4.7%) developed preeclampsia. The monsoon season had lower mean maximum temperature (37.0 degrees C vs. 38.1 degrees C, p = 0.114), was more humid (77.0% vs. 68.7%, p < 0.001) and had higher daily rainfall (196.5 mm vs. 37.0 mm, p < 0.001) than dry season. Women who conceived in the dry season were at greater risk to develop preeclampsia than those who conceived in the monsoon season (5.3% vs. 3.7%, adjusted OR 1.51; 95% CI 1.18-1.93). The preeclampsia rates of women who delivered in both seasons were not significantly different: 5.0% in the dry season vs. 4.3% in the monsoon, p = 0.178. CONCLUSION: There is a seasonal impact on the prevalence of preeclampsia based on the time of conception, but not the time of delivery. The rate of preeclampsia is significantly higher when conception occurs in the dry season. PMID- 22256468 TI - Alcohol septal ablation without myocardial contrast echocardiography for hypertrophic obstructive cardiomyopathy. AB - OBJECTIVE: Review the efficacy and safety of using the anatomical characteristics of the first septal branch to select the target vessel for alcohol septal ablation (ASA) in treating patients with medically refractory symptoms hypertrophic obstructive cardiomyopathy (HOCM), ASA without guided myocardial contrast echocardiography (MCE). MATERIAL AND METHOD: Fifteen patients with HOCM and refractory to medical therapy were screened by echocardiography and coronary angiography between November 2007 and January 2010 in Songklanagarind university hospital. The procedure was abandoned in three patients due to vessel unsuitability. The clinical and hemodynamic data of 12 patients with HOCM before and after ASA were reviewed. The authors used the anatomical characteristics of vessel to identify the suitable septal perforator artery. RESULTS: ASA was done successfully in 12 patients. The averages of left ventricular outflow tract (LVOT) peak/mean pressure gradients (PPG/MPG) were 92.4 +/- 22.5/48.8 +/- 12.8 before and 21.6 +/- 11/12.8 +/- 5 mmHg immediately after ASA. The mean absolute alcohol volume was 2.5 +/- 0.64 ml. One patient had to have alcohol injection into two septal branches. Transient complete atrioventricular block occurred in two patients. All patients reported substantial symptomatic improvement. CONCLUSION: Most patients with medically refractory symptom HCOM have suitable first septal branches for ASA. ASA without MCE in those with suitable first septal branches is effective and safe. PMID- 22256469 TI - Development of needs and resources for self-management assessment instrument in Thais with type 2 diabetes: cross-cultural adaptation. AB - OBJECTIVE: (1) To develop the Chronic Illness Resources Survey (CIRS) questionnaire for Thais with type 2 diabetes and (2) to examine validity and reliability of the instrument. MATERIAL AND METHOD: The present study consisted of two phases, phrase I was development of the comprehensive assessment form, for which the qualitative study was utilized and Glasgow's original CIRS was used as the initial input, and phrases II was tested for validity and reliability of the assessment form, for which quantitative study design was utilized. RESULTS: Final version of Thai comprehensive CIRS composed of 60 items in seven subscales, physician and health care team, family and friends, personal, community, neighborhood, media and policy, and community organization. Worksites subscale was deleted if it differed from original version. Its internal consistency was 0.93 (Cronbach's alpha coefficient = 0.93, p < 0.05). CONCLUSION: The present study demonstrates that the Thai CIRS is appropriate for Thai patients with type 2 diabetes. The instrument has acceptable validity and reliability. However, further research is required to evaluate these properties in other areas. Furthermore, the Thais CIRS should examine psychometric properties before it will be used in other chronic illness patients. PMID- 22256470 TI - HIV prevention with positives and disclosure of HIV status: practice and views of Thai healthcare providers. AB - OBJECTIVE: The present study provides information from health care providers about sexual practices of and preventive and disclosure counseling for People Living with HIVand AIDS (PLWHA). MATERIAL AND METHOD: A survey of health care providers attending HIV prevention workshops was undertaken using self administered and anonymous questionnaires. RESULTS: Of 678 respondents, 72% were nurses. Ninety-six percent agreed that they had duty to provide prevention services and measures. However, less than half (46%) had enough time for counseling. Asking health providers to estimate different aspects of sexual practice in their patients, the highest chosen band estimation was 'unsafe sex' (21-40%), 'partner disclosure' (41-60%) and 'abstinence' (0-10%). When patients did not disclose their HIV status to partner most health care providers kept HIV serostatus of patient confidential from their sexual partners. The main reasons for not notifying were patients 'rights and fear of adverse effects on patients. Some (9%) did notify the patient's partner directly or indirectly. The main notification reasons were for preventing HIV transmission and recognizing the partner's right to be informed. Seventy percent agreed that a law should require disclosure of HIV status to husband, wife, or intimate partner. CONCLUSION: Health care providers supported the 'Prevention with Positives' strategy. HIVstatus disclosure is a continuing ethical dilemma since there are conflicts of principle between confidentiality of patients and right to healthy life of their partner Improved or new interventions are needed to prevent HIV transmission with consideration of both rights of PLWHA and of HIV risk reduction for sexual partner. PMID- 22256471 TI - Prospective evaluation of gastrointestinal lesions by bidirectional endoscopy in patients with iron deficiency anemia. AB - BACKGROUND: Occult bleeding from the gastrointestinal (GI) lesions is a common cause of iron deficiency anemia (IDA). The information concerning the prevalence and the appropriate strategy for evaluation of IDA in Thai patients is scanty. OBJECTIVE: Prospectively evaluate Thai patients with IDA for GI lesions using bidirectional endoscopy MATERIAL AND METHOD: Consecutive patients with IDA were investigated by esophagogastroduodenoscopy (EGD) and colonoscopy. Significant GI lesions were identified. Clinical data and results of the fecal occult blood testing (FOBT) were collected to determine factors associated with the presence of GI lesions. RESULTS: One hundred three patients were included in this study and the mean age was 63.6 +/- 15.2 years old. Significant GI lesions were detected in 58 patients (56%), 43% by EGD, 25% by colonoscopy. Twelve patients (12%) had dual lesions identified from both EGD and colonoscopy The most common lesions were peptic ulcers (22%) and colonic carcinoma (13%). Anti-platelets use and positive FOBT were associated with the significant GI lesions with odds ratios of 2.37 (95% CI 1.05-5.36, p = 0.036) and 2.83 (95% CI 1.05-7.68, p = 0.038), respectively FOBT had sensitivity, specificity, positive predictive value, and negative predictive value for significant GI lesions at 81%, 40%, 68%, and 66%, respectively. Site-specific symptoms correctly guided the route of endoscopy in 60-80% of the patients. CONCLUSION: EGD resulted in a better yield than colonoscopy and was the preferred route of initial endoscopy unless there was suggestive site-specific symptom. Bidirectional endoscopy was finally required in most patients unless a cancerous lesion was detected by the initial endoscopy. PMID- 22256472 TI - Reduction of LDL-cholesterol in mildly hypercholesterolemic Thais with plant stanol ester-fortified soy milk. AB - OBJECTIVE: To investigate the effects of soy milk fortified with plant stanol ester on changes in LDL-cholesterol, fat-soluble vitamins and sex hormones in Thai volunteers. MATERIAL AND METHOD: In a double-blind, placebo-controlled study, 120 mildly hypercholesterolemic Thais were randomly assigned to stanol and control groups that were comparable in lipid profile and body mass index. Subjects consumed regular or 2g stanol-containing soymilk once a day and postprandially for six weeks. The serum lipid profile was measured at weeks 0, 2 and 6; serum fat-soluble vitamins and sex hormones were measured at weeks 0 and 6. RESULTS: The mean reduction in total cholesterol was 8.2 % in the stanol group (p < 0.0001) and 0.6% in the control group. LDL-cholesterol declined in both groups at week two, but the reduction was maintained to week six only in the stanol group. The mean reduction in LDL-cholesterol was 13.5% in the stanol group (p < 0.0001) at week 6, compared to a 4.6% decrease in the control group. Adjusted serum beta-cryptoxantene and beta-carotene levels decreased at week six for the stanol group. Serum sex hormone levels in both groups remained unchanged. CONCLUSION: Consumption of stanol-ester-containing soymilk for six weeks significantly reduced LDL-cholesterol in mildly hypercholesterolemic Thais. No adverse effect on sex hormones was observed However, stanol-ester consumers are at risk of fat-soluble-vitamin deficiencies if the vitamin intake from foods is inadequate. PMID- 22256473 TI - Urine potassium per hour as a marker for renal potassium losses. AB - BACKGROUND: Hypokalemia, serum potassium (K) < 3.5 mEq/L, is a serious and common clinical problem. The traditional diagnosis of renal potassium losses is 24-hr urine potassium (24U(K)) > or = 20 mEq/day during hypokalemia. Immediate replacement of potassium is often required to prevent complication but may normalize serum K during 24-hr urine collection and render the test inconclusive. MATERIAL AND METHOD: The authors examined the ability of urinary indices including 24U(K), transtubular potassium gradient (TTKG), fractional excretion of potassium (FE(K)), urine potassium-creatinine ratio (U(K/Cr)) and spot U(K) and introduced urine potassium per hour during the first 8 hours (U(K)/hr) as a novel index for evaluation of hypokalemia during treatment. Any serum K level > or = 4 mEq/L during urine collection was defined as normalized serum K. In the present study, the final classification of renal K losses in non-normalized 24-hr serum K group was made when 24U(K) > or = 20 mEq/day. In normalized group, the final classification of renal or non-renal K losses was based on the majority of the results of four urine indices including TTKG, FE(K) U(K/Cr) and spot U(K). RESULTS: Of 61 patients (renal:non-renal = 50:11), 51% and 18% met the criteria of normalized 24-hr and 8-hr serum K. Over all, the U(K)/hr > or = 0.9 mEq/hr can indicate renal K losses with a sensitivity of 96% and specificity of 72.7% compared with the 24U(K) > or = 20 mEq/day of 100% and 54.5%, respectively. In a subgroup of normalized 24-hr serum K, the sensitivity and specificity of U(K)/hr = 95.5% and 77.8% whereas 24U(K) = 100% and 44.4%, respectively CONCLUSION: U(K)/hr is a new practical, simple, and reliable marker that can be applied to evaluate hypokalemic patients during treatment with comparable sensitivity and specificity with 24U(K). PMID- 22256474 TI - Severe obesity is a risk factor for severe obstructive sleep apnea in obese children. AB - OBJECTIVE: To determine the association between degree of obesity and severity of OSA in Thai children MATERIAL AND METHOD: The present retrospective study recruited obese children aged 3 to 15 years who had habitual snoring and underwent polysomnography (PSG) between January 2009 and June 2010. Obesity was defined as percentage of ideal weight for height (%W/H) > or = 120 and was classified as mild (%W/H of 120-139), moderate (140-159), severe (160-199) and morbid (> or = 200). OSA was classified as severe (AHI > or = 10) and non-severe (AHI < 10). RESULTS: Of 73 obese children, the mean age was 9.92 +/- 3.42 years of which 60.3% were boys. The mean +/- SD of BMI was 28.38 +/- 5.99 kg/m2 and %W/H +/- SD was 162.63 +/- 26 26. Gender age, height, weight and BMI were not significantly different between severe and non-severe OSA groups. However, the %W/H of the severe OSA group (171.38% +/- 29.54%) was significantly greater than the non-severe group (157.19% +/- 22.68%) (p = 0.02). Severe to morbid obesity (OR 2.80, 95% CI 1.06-7.42; p = 0.038) and enlarged tonsils at least 3+ (OR 3.28, 95% CI 1.22-8.81; p = 0.018) were the risk factors for severe OSA. CONCLUSION: Severe to morbid obesity was a predicting factor for severe OSA. These results suggested that severely obese children with snoring should have early recognition for severe OSA, which is highly contributing to multiple sequalae. PMID- 22256475 TI - Chronic subdural hematoma: drainage vs. no drainage. AB - OBJECTIVE: To compare the result of chronic subdural hematoma (CSDH) treatment by burr hole with and without closed system drainage in 143 Thai patients at Ramathibodi Hospital. MATERIAL AND METHOD: A retrospective study of 143 patients with CSDH treatment at Ramathibodi Hospital between 2002 and 2008 was performed They underwent burr hole with or without drainage according to the preference of the attending neurosurgeons. The authors compared the result of the two CSDH methods by using CT or MRI of brain post-operatively, complications, recovery condition, mortality rate, and recurrence. RESULTS: Ninety-seven patients were treated with closed system drainage and 46 were treated without drainage. There was no statistical significant distribution in the clinical profiles of both groups. The coagulopathy in both groups might contribute for the recurrence of CSDH while there was no correlation of the recurrence to the other clinical profiles. Fifteen patients (16%) in the drainage group had CSDH recurrence while there were 12 patients (26%) in the no drainage group. CONCLUSION: Concerning the complete neurological recovery and the recurrence rate of CSDH treatment, there were more complete neurological recovery cases and a lower recurrence rate of CSDH cases in the drainage group but there was no statistical significant difference. PMID- 22256476 TI - Comparison of the efficacy and safety between generic intravenous omeprazole (Zefxon) and original omeprazole (Losec) in the adjunct treatment of non-variceal upper gastrointestinal bleeding in Siriraj Hospital. AB - BACKGROUND: Clinical efficacy and safety of generic omeprazole have not been well studied in Thailand. OBJECTIVE: Determine whether generic omeprazole (Zefxon) is inferior to original omeprazole (Losec) in the treatment of non-variceal upper gastrointestinal bleeding (UGIB) in Siriraj Hospital. MATERIAL AND METHOD: Medical records of adult patients with the diagnosis of non-variceal UGIB receiving intravenous omeprazole (either Zefxon or Losec) in Siriraj Hospital between January 2006 and September 2010 were reviewed Noninferiority study was used to investigate whether the generic omeprazole was no more than 10% less effective than the original omeprazole. The primary endpoints were recurrent bleeding and mortality within seven and 30 days. Surgery, endoscopic retreatment, blood transfusions, length of hospital stay and safety were also analyzed RESULTS: Of 200 randomly selected patients in each group, there was no difference in age, gender co-morbidities, severity of UGIB, endoscopic findings and endoscopic intervention between patients receiving generic omeprazole and original omeprazole. Overall rate of recurrent bleeding, mortality, and surgical intervention within 30 days were 12.3%, 5.5% and 2.0%, respectively. The rates of recurrent bleeding, overall mortality, and non-variceal UGIB related mortality within seven and 30 days were not significantly different between the two groups. Neither were the rates of endoscopic retreatment and surgery. The incidence of adverse side effects was 3.5% in each group. Cox regression analysis showed no significant association between type of omeprazole and recurrent bleeding or mortality. Compared to the original omeprazole, the hazard ratio of recurrent bleeding, overall mortality, and non-variceal UGIB related mortality in patients receiving generic omeprazole was 1.44 (95% CI 0.82-2.53; p = 0.21), 2.12 (95% CI 0.90-5.43; p = 0.08) and 1.82 (95% CI 0.53-6.21; p = 0.34), respectively. CONCLUSION: Although the original omeprazole Losec tended to have more favorable outcomes in the treatment of non-variceal UGIB in the present study, non inferiority test showed that the efficacy and safety of the generic omeprazole Zefxon was not inferior to those of the original omeprazole. PMID- 22256477 TI - Risk factors for mortality in head-injured patients with probability of survival greater than 0.5. AB - BACKGROUND: Traumatic brain injury is one of the major problems and leading cause of death worldwide. The present study was aimed to identify factors responsible for mortality by comparing survivors and nonsurvivors in patients that had a low probability of mortality. MATERIAL AND METHOD: A nested case-control study was conducted at Sawanpracharak Hospital from January 1, 2007 to December 31, 2007. All head injury deaths that had TRISS-PS greater than 0.5 were enrolled as the "case" patients. Head injured patients with TRISS-PS greater than 0.5 and that survived were chosen as the "control" patients. The number of controls per case was 2:1. Patients with ages < 15 were excluded from the present study. RESULTS: Six factors associated with increased mortality are age > or = 45 years (OR = 1.61, 95% CI = 1.1-2.3), alcohol intoxication (OR = 3.11, 95% CI = 1.4-6.9), admission GCS 3-8 (OR = 4.16, 95% CI = 2.4-7.2), arrival GCS-M < or = 4 (OR = 1.46, 95% CI = 1.0-2.0), Head-AIS > or = 4 (OR = 3.31, 95% CI = 1.3-8.3), and admission SBP < 90 mmHg (OR = 13.36, 95% CI = 3.2-56.3). CONCLUSION: Head injury continues to be a substantial public health problem. Deaths that met criteria for low probability of mortality, especially in those without associated risk factors should be analyzed for errors that may be preventable. PMID- 22256478 TI - The usage of two umbrella made-mesh plugs in herniorrhaphy: comparative study with Bassini and Lichtenstein method. AB - BACKGROUND: Operation to cure groin hernia remains a clinical problem. The most effective technique for hernia repairs is unknown and the presented recurrence rate varies between 1% and 10% at five years. Although surgeries with improved techniques with implanted materials are performed worldwide, they are limited because of the cost associated with hernia repair. OBJECTIVE: To determine the results of the presented two umbrella made-mesh plugs for inguinal hernia repair compared to other methods of herniorrhaphy. MATERIAL AND METHOD: The 194 patients, aged 16-86 years who had primary diagnosis of indirect inguinal hernia were prospectively selected into two periods of elective surgery. The first period included, 58 cases operated with Bassini repair and 11 cases needed relaxing incision, 42 in Bassini repair with umbrella made-mesh plug from polypropylene mesh and six cases that needed relaxing incision. The second period included 40 cases of Lichtenstein repair, 54 cases using umbrella made-mesh plug with patching tail. The outcomes for study were postoperative complications, hospital staying time, and recurrence rate of hernia within two years. RESULTS: All these patients had no mortality. Mean operative time was 31.8 minutes (25-50) of Bassini repair 47.7 minutes (30-60) of Bassini repair with umbrella made-mesh plug, 53.2 minutes (38-60) of Lichtenstein repair and 54.8 minutes (40-65) for usage of umbrella made-mesh plug with patching tail. Overall duration of hospital stay was one to seven days (mean 3.5 days). Some complications were ecchymosis or seroma three in Bassini repair, three in Bassini repair with umbrella made-mesh plug, and one in Lichtenstein repair Wound infections were found with one case of Bassini repair and two of Bassini repair with umbrella made-mesh plug. Within two years of follow-up time, eight of 58 (13.8%) had recurrence by Bassini repair while three of 42 (7.1%) in Bassini repair with umbrella made-mesh plug, but no recurrence in Lichtenstein repair or umbrella made-mesh plug with patching tail. CONCLUSION: The usage of both umbrella made-mesh plugs were safe for 94/96 cases of groin herniorrhaphy with only two infected meshes. The used mesh material (polypropylene) was easily made with an umbrella like shape during operation and lowered the cost. The mesh plug with patching tail had a suitable use for patching at wide hernia floor, so relaxing incisions were unnecessarily done. For cases with small or no space of floor defect, repaired by mesh plug without patching may be adequate. Their two-year recurrence rates were lower than Bassini repair alone whereas the repair by using umbrella made-mesh plug with patching tail and Lichtenstein repair had no recurrence. There was no difference in postoperative complications among all operations. PMID- 22256479 TI - Audiological outcomes of cochlear implantation in Ramathibodi Hospital. AB - OBJECTIVE: To evaluate the outcomes of the patients at 1-year post cochlear implantation emphasized on audiological outcomes. MATERIALS AND METHOD: Retrospective study of hearing response follow in three, six, and 12 months of 143 ears undergoing cochlear implantation between 1995 and 2009. Only 77 ears were found to have the completed data for analysis. Deaf patients were categorized into five groups in which they were operated by four different cochlear implant devices. The two parameters used to evaluate the outcomes included the aided response (AR), assessing the hearing threshold of cochlear implant user; and the Categories of Auditory Performance (CAP) which assess their auditory receptive abilities. RESULTS: Demographic data showed male:female ratio was 4:3. Age ranged from 2 to 68 years. Although the aided hearing threshold among five groups of deafness showed improvement without statistical difference, the auditory ability showed significance higher score in post-lingual than pre lingual deaf patients (p < 0.05). Patients with aural communication prior to surgery also showed higher auditory ability than those without aural communication (p < 0.05). The outcomes of CAP were analyzed among patients operated with different cochlear implant devices. Users with Pulsar CI 100 Opus 2, HiRes 90K Auria, and HiRes 90 K Harmony showed better auditory ability than with Combi 40+ Tempo+. Both mean scores of AR and CAP were higher at six and 12 months than at three months. At 12 months the scores were higher than at six months (p < 0.05). CONCLUSIONS: Cochlear implant surgery resulted in good hearing, however the improvement of speech understanding need more time to practice. Patients using cochlear implant at 12 months showed more improvement of hearing and performance than those using for less than 12 months. PMID- 22256480 TI - Computed tomographic features of adenocarcinoma compared to malignant lymphoma of the stomach. AB - OBJECTIVE: To compare the CT findings of adenocarcinoma and malignant lymphoma of the stomach. MATERIAL AND METHOD: The authors retrospectively reviewed the computed tomographic images of 21 patients who received a definite pathologic diagnosis of adenocarcinoma or malignant lymphoma of the stomach. The images were taken at Srinagarind Hospital between January 2006 and February 2009. Seventeen patients with gastric adenocarcinoma and four with malignant gastric lymphoma were included in the present study. The pattern of involvement, the location of lesion, the perigastric fat plane, the perigastric lymphadenopathy and the extension of disease on CT images were evaluated and analyzed by Chi-square and Fisher exact tests. RESULTS: There was a statistically significant difference between gastric adenocarcinoma and malignant gastric lymphoma in the pattern of involvement of disease (p = 0.010), the perigastric fat plane (p = 0.002) and the location of disease (p = 0.008). By contrast, there was no respective statistically significant difference in the perigastric lymphadenopathy (p = 0.950) and the extension of disease (p = 0.175) in between gastric adenocarcinoma and malignant gastric lymphoma. CONCLUSION: The CT findings helpful for differentiating gastric adenocarcinoma from malignant gastric lymphoma are the pattern of involvement, the perigastric fat plane, and the location of lesion. Localized involvement of the lesion, abnormal perigastric fat plane and location involving one region of the stomach tend to indicate gastric adenocarcinoma; while diffused involvement of the lesion, preserved perigastric fat plane and location involving more than one region of the stomach tend to indicate malignant gastric lymphoma. PMID- 22256481 TI - Detection of alveolar rhabdomyosarcoma in pleural fluid with immunocytochemistry on cell block and determination of PAX/FKHR fusion mRNA by reverse transcription polymerase chain reaction. AB - BACKGROUND: Alveolar rhabdomyosarcoma is a primitive malignant round cell neoplasm, which shows skeletal muscle differentiation. Although their histopathologic and immunohistochemical findings are well known, the cytology, immunocytochemistry and molecular study on pleural effusion have not been well documented. OBJECTIVE: To apply molecular method in the diagnosis and monitoring of alveolar rhabdomyosarcoma. CASE REPORT: The case of a 14-year-old Thai male, who presented with dyspnea and left pleural effusion. Computed tomography of the chest and abdomen showed a huge heterogeneous enhancing mass at the left retroperitoneum. Pleural fluid cytology showed malignant small round blue cells. Immunocytochemical stains on cell block material showed positive reactivity to vimentin, sarcomeric actin, desmin, MyoD1, myogenin, and CD56 in round cell tumor Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated PAX/FKHR fusion transcript. The patient received chemotherapeutic regimen for advanced stage rhabdomyosarcoma. Finally, he succumbed to the disease, thirteen months after the diagnosis. CONCLUSION: Immunocytochemistry on cell block in conjunction with determination of PAX/FKHR fusion mRNA by RT-PCR is a molecular method in the diagnosis and monitoring of alveolar rhabdomyosarcoma inpleural fluid. PMID- 22256482 TI - Gastric schwannoma presenting with perforation and abscess formation: a case report and literature review. AB - Gastric schwannoma represent only 0.2% of all gastric tumors and 4% of all benign gastric neoplasms. They are usually asymptomatic but can present with variable symptoms. The authors report a case of a 29-year-old male patient who presented with fever and abdominal pain with epigastric mass. Pre-operative diagnosis was gastric lymphoma with perforation and an abscess formation. Hemigastrectomy with Billroth II anastomosis was performed The pathologic examination and immunohistochemical studies confirmed gastric schawannoma as the diagnosis. The post-operative course was uneventful. Gastric schwannoma are difficult if not impossible to diagnose preoperatively as endoscopic and radiologic findings are nonspecific. The treatment of choice is complete surgical resection because of diagnostic uncertainty and the long-term outcome is excellent. This is the first report of gastric schwannoma presenting with concealed perforation and an abscess formation. The literature was reviewed. PMID- 22256483 TI - Cadaveric study of median nerve entrapment in the arm: report of two anatomical cases. AB - The authors report two anatomic cases of median nerve entrapment, which can be one of the causes of carpal tunnel syndrome. Both cases were soft tissue thickening on the distal arm. The first case was the thickening of brachial fascia that resembles the Struther's ligament. The second case was the thickening of the bicipital aponeurosis combined with the supernumerary biceps brachii. Both cases demonstrated the possible cause of median nerve entrapment at the arm, which mimicked the carpal tunnel syndrome that normally occurs at the wrist. The study reports other possibly sites of causes of median nerve entrapment that clinicians should be aware of the median nerve in the arm proximal to the wrist where the carpal tunnel syndrome normally occurs. These are other points of medina nerve entrapment that clinicians should aware. PMID- 22256484 TI - Immune response to Burkholderia pseudomallei. AB - Burkholderia pseudomallei are the causative agents of melioidosis, a disease found mostly in people with underlying risk factors. Fifty percent of cases are community-acquired septicemias and manifestation can vary from acute septicemia (with or without shock), to chronic, to subclinical infections. There is no vaccine to prevent the condition. It is difficult to eradicate the bacteria. Prolonged antibiotic therapy is required. Finally, there is a high rate of relapse when therapy is not completed The bacteria can activate both innate and adaptive immune responses but B. pseudomallei employ numerous tactics to evade these immune responses. The pathogenesis of melioidosis is poorly understood, especially the interaction between the host and the pathogen that results in acute and chronic infections. The objective of this review was to summarize the current understanding of the immunology of melioidosis. This review presents an overview of host immune response to B. pseudomallei and benefits the development of research into immunology and promotes an understanding of the mechanism and pathology of B. pseudomallei infection. PMID- 22256485 TI - [Good and bad secrets]. PMID- 22256486 TI - [Professional secret and confidentiality responsibility. "But please don't tell anyone!"]. PMID- 22256487 TI - [Electronic nursing assessment. Rehabilitation specific and customized]. PMID- 22256488 TI - [Advanced nursing practice. A shared responsibility]. PMID- 22256489 TI - ["Nurse practitioners" in the USA. Guarantee of high quality primary care]. PMID- 22256490 TI - [A change in leadership in geriatric and nursing homes. Systematic preparation is a key factor]. PMID- 22256491 TI - [Health promotion. Physically ill in psychiatry]. PMID- 22256492 TI - [General practice implementation project for discharge planning. Educating parents of newborn infants with heart disease]. PMID- 22256493 TI - [Uganda. Hoping for the network]. PMID- 22256494 TI - [Successful use of herbal remedies]. PMID- 22256495 TI - ["The Joder initiative would give nursing a new kick" (interview by Urs Luthi)]. PMID- 22256496 TI - [Thematic weeks. Providing practical knowledge]. PMID- 22256497 TI - [Too many dark secrets]. PMID- 22256498 TI - [Leenards awards and grants. Quality of life for the elderly]. PMID- 22256499 TI - [Restraint measures and psychological sequelae. Greatest caution required]. PMID- 22256500 TI - [Painful nursing care of newborn infants. Maternal breast feeding, an effective analgesic]. PMID- 22256501 TI - [Home nursing of a parent . A little respite for family caregivers]. PMID- 22256502 TI - [Thierry Ott at the Geneva University Hospital. The image beyond lost words]. PMID- 22256503 TI - [Policy decision. Dismissal due to pregnancy]. PMID- 22256504 TI - ["Money versus ethics"]. PMID- 22256505 TI - Social media in health care. PMID- 22256506 TI - Social media: ubiquitous community and patient engagement. AB - The business model of healthcare is changing. Value-based purchasing and accountable care initiatives, along with reimbursement incentives and penalties, are creating pressures that are reshaping healthcare delivery approaches and care processes. And today's patients are more engaged and familiar with multimedia information technologies. This article highlights how healthcare organizations are applying social media technologies to address the challenges they face. I explore how these tools are useful for monitoring conversations, proactively resolving complaints, and facilitating transparency. I also review how these tools contribute to enhanced patient experiences and help organizations comply with meaningful use criteria, such as engaging patients and families in their care, improving quality and care coordination, and reducing disparities. The story of Louise, a virtual patient-discharge advocate, demonstrates how social media is helping providers improve health outcomes, reduce costs, and decrease rehospitalizations. Other examples highlight how one secure social networking community is helping case managers better support patients who are on the road to recovery from addiction and describe one hospital's use of a virtual world to help train staff for emergency evacuation. Social media can be used to deliver more patient-centered care and fluid care processes between patients and physicians. Combined with today's mobile technologies, it is a ubiquitous tool that can easily be applied in healthcare environments to solve today's challenges. PMID- 22256507 TI - Conversations with the community: the Methodist Hospital System's experience with social media. AB - The Methodist Hospital System has maintained a social media presence on Facebook, Twitter, and YouTube since 2009. After initial unofficial excursions into the world of social media, we discovered that social media can be a useful tool to extend a conversation with our patients and the community at large and share our hospital's culture with a larger base of like-minded people. But with this new power comes a heightened responsibility--platforms that can potentially reach millions of viewers and readers also provide a potential for misuse that can jeopardize patient privacy and place hospitals at risk. Because of their unique restrictions, even hospitals that use the tools regularly have much left to learn about social media. With constant monitoring and stewardship and a commitment to educating staff, hospitals can effectively use social media tools for marketing and education. PMID- 22256508 TI - The foray into social media: a clinician, and skeptic, sold. PMID- 22256509 TI - Brand awareness and engagement: a case study in healthcare social media. PMID- 22256510 TI - Social media for healthcare makes sense. PMID- 22256511 TI - Historically, health service delivery has centred on a rigid set of practices, standard operating procedures. PMID- 22256512 TI - Evaluating acceptance of an electronic data management system at a tertiary care institution. AB - This research reports on satisfaction with the introduction of an electronic document management system in a tertiary hospital environment. A buffet of training and familiarization options were offered: one-on-one training, open house, drop-in, e-learning, classroom training, and self-study. It was found that professions differ in their pattern of satisfaction with training and they also differ in their satisfaction with both the usefulness and the ease of use of the system. Satisfaction among administrators was highest and that among nurses lowest. There was an association between attendance at the open house event and satisfaction with the system. PMID- 22256513 TI - Canada's health human resource challenges: what is the fate of our healthcare heroes? AB - Each year, the Canadian health education system graduates thousands of health professionals who have the best intentions of practising to their full scope of knowledge and skills to help improve the patient care experience in this country. However, a recent research study points to the fact that members of the healthcare team may be practising in a challenging environment in which only a limited number of their skills are actually being used. The Michener Institute for Applied Health Sciences believes that these issues, which include increased role specialization, limited scopes of practice, rapidly advancing technology, and challenges transitioning from hospital to community settings, have broader health education and health system implications that need to be addressed by policy makers, educators, and healthcare system leaders in order to enhance health professional education as well as patient care. PMID- 22256514 TI - Collaborative practice: matching staff skills to patient needs and checking baseline staffing levels. AB - Vancouver Coastal Health uses a collaborative practice process to enable nursing units to be proactive and adapt quickly to changing patient population needs using a standardized and integrated approach. The process involves clinical directors, frontline managers, staff, and union representatives from the outset and is based on a registered nurse/licensed practical nurse/patient care aide collaborative model of practice. Results show a total return on investment in 2.4 years. PMID- 22256515 TI - Bridging the gap between family doctors and regional health authorities. AB - The communication between family doctors and regional health authorities has become more complex and fragmented over the last 2 decades. By using a novel approach, we developed a medical advisory committee structure for community physicians enshrined in the regional health authority bylaws. This has improved bilateral communication, policy making that affects patients in the community, linkages between programs and family doctors, and input into the institutional care of our patients. We believe this model could be implemented or adapted by regional health authorities elsewhere in Canada having as its ultimate goal better patient care. PMID- 22256516 TI - Optimizing community and stakeholder engagement in a merger of community health centres. AB - Community Health Centres (CHCs) are grounded in a model of care that includes engagement with the community and have a history of working with communities to respond to emerging needs. Although most CHCs consider themselves to be integrated, mergers in this sector are uncommon. In Ontario, the first voluntary merger of CHCs showed the importance of community engagement to realize the intended benefits of the integration and to effectively manage change. PMID- 22256517 TI - [Promoting nursing education]. PMID- 22256518 TI - [Advanced nursing practicums contribute to the interdisciplinary strategy of nursing care. Interview by Sylvie Warnet]. PMID- 22256519 TI - [Sexuality in an institution, between denial and recommendation]. AB - Sexuality is a difficult subject to tackle, even in the 21st century in the West. It remains as complex, if not more so, to talk about it in care, medical-social or social institutions. Taking into account the sexuality of people in institutions requires collective consideration as well as individual introspection. An overview of the situation as it stands today. PMID- 22256520 TI - [When patients' sexuality finds its way into daily care activities]. AB - The sexual life and desire of patients manifest themselves in the care environment in various ways. These different situations open up debates and undermine convictions. This article presents some nurses' testimonies. PMID- 22256521 TI - [Young people with motor disabilities facing their sexuality]. AB - In a care and rehabilitation centre in Vaucresson, the nursing team in charge of the medical and paramedical care of young boarders with motor disabilities is regularly confronted with adolescents' questions relating to their relationships and sex life. An adapted global and individual support structure has been set up. The keystone is the creation of a relationship of trust. PMID- 22256522 TI - [Disabled people must be able to determine their sex life. Interview by Isabelle Clavagnier]. AB - A qualified sexologist and public health worker, Sheila Warembourg works as a trainer of student nurses and educators and provides continuous training for nursing teams. She also leads support groups for disabled people and their families to discuss issues relating to intimacy and sexuality. Interview. PMID- 22256523 TI - [Prevention of risky sexual behavior in psychiatry]. AB - Sexual activity in psychiatric hospitals is a reality. Preventing risky behaviour is becoming a responsability for institutions, one which has long been "neglected". Establishing a dialogue between nurses and patients around the latter's sexual and emotional life must focus on enlightened, consensual and safe practices. This article shares the practices of a hospital team of the prevention and sexuality AIDS committee (CSSP). PMID- 22256525 TI - [The expertise of the nursing in occupational health]. PMID- 22256524 TI - [The sexuality of the elderly in care institutions]. AB - While evolutions in society influence hospitals, the place of sexuality in such institutions remains marginal. The subject is taboo even within families and especially if the patient is elderly. However, the expression of this natural need often occurs in day-to-day care activities meaning the inclusion of sexuality in the elderly person's care and life project should be discussed within the team. A sharing of experience. PMID- 22256526 TI - [The reform of psychiatric care]. AB - Psychiatric care has until now often been synonymous with hospitalisation. A reform of the law last summer requires a strict protocol to be implemented which results in the patient either being admitted as an inpatient or being treated via a modular care programme, at home for example. The bringing together of medical expertise and opinions, as well as the involvement of the liberty and custody judge, ensure that patients' rights are respected. PMID- 22256527 TI - [Hygiene rules for community nurses]. AB - Community nurses must respect hygiene measures in order to maintain the health of the home patient. The patient, however, does not always consider him/herself to be ill which requires the nurse to tactfully explain basic hygiene rules. The patient's environment must also be kept scrupulously clean. On this point the nurse has an important role to play in educating the patient and his/her family. PMID- 22256528 TI - [Challenges and limits of hospital support groups]. AB - Every day nurses come across others who are suffering, and are consequently confronted with their own emotions, which can have implications on the provision of care. A support group can help them take a step back and think about their professional practice. Thanks to the exchanges made in the presence of a psychologist, everyone can reflect, within a group, on his or her relationship with care. The aim of these discussion groups is to modify everyone's subjective reality. PMID- 22256529 TI - [A pain assessment logbook]. AB - Fighting pain is one of nurses' duties. At Dreux general hospital, the medical and nursing staff of the physical medicine and rehabilitation department has gradually put in place since 2004 an information and treatment logbook. It constitutes a way of recording and assessing each patient's pain and consequently facilitates its treatment. PMID- 22256530 TI - [Preventing cancer of the upper respiratory and digestive tracts]. AB - In 2003, the Prevart association, in collaboration with community practitioners and the hospital, set up in Bethune, then in Lens, a plan for the detection and prevention of cancers of the upper air and digestive passages particularly widespread in the Nord-Pas-de-Calais department. Thanks to a central appointment desk and to the detection work of nurses, patients have been able to benefit from fast and adapted treatment. PMID- 22256531 TI - Sophie administers a blood transfusion. PMID- 22256532 TI - [Caring for the diabetic ketoacidosis patient]. PMID- 22256533 TI - [Transference and counter transference]. PMID- 22256534 TI - [Administering medications]. PMID- 22256535 TI - [Isolating patients]. PMID- 22256536 TI - The perils and benefits of assessment. PMID- 22256537 TI - Family supports and resources for parents of children who are deaf or hard of hearing. AB - The study examined family supports after identification of children's hearing loss. On a questionnaire, 456 respondents rated the importance of different aspects of family support, the quality of supports they experienced, and their preferences about informational resources. They verified the importance of informational resources, social-emotional support, and educational advocacy. Families expressed a preference for discussion with other parents of children with hearing loss over discussion with parents of children without hearing loss. The quality of support was rated higher by parents of children with cochlear implants than by parents of children with hearing aids. Top-ranked sources of support included individual professionals and service providers, other parents of children with hearing loss, family support organizations, and grandparents and extended-family members. Open-ended written responses indicated that parents desired additional opportunities to connect with mentors, role models, and other parents. PMID- 22256538 TI - Verbatim, standard, or edited? Reading patterns of different captioning styles among deaf, hard of hearing, and hearing viewers. AB - One of the most frequently recurring themes in captioning is whether captions should be edited or verbatim. The authors report on the results of an eye tracking study of captioning for deaf and hard of hearing viewers reading different types of captions. By examining eye movement patterns when these viewers were watching clips with verbatim, standard, and edited captions, the authors tested whether the three different caption styles were read differently by the study participants (N = 40): 9 deaf, 21 hard of hearing, and 10 hearing individuals. Interesting interaction effects for the proportion of dwell time and fixation count were observed. In terms of group differences, deaf participants differed from the other two groups only in the case of verbatim captions. The results are discussed with reference to classical reading studies, audiovisual translation, and a new concept of viewing speed. PMID- 22256539 TI - Serving and supporting young children with a dual diagnosis of hearing loss and autism: the stories of four families. AB - The research on young children with a dual diagnosis of hearing loss and autism spectrum disorder (ASD) is meager and scattered. Pockets of research on this population of children suggest that it is difficult to make the diagnosis of ASD in children with hearing loss. A case study design was used to examine the diagnostic process for young children and their families. The study found that the diagnosis of hearing loss was made first and that obtaining an ASD diagnosis and the appropriate services was complicated. The findings provide insight into how to support and provide intervention to families with children who have a dual diagnosis. PMID- 22256540 TI - Enhancing sequential time perception and storytelling ability of deaf and hard of hearing children. AB - A 3-month intervention was conducted to enhance the sequential time perception and storytelling ability of young children with hearing loss. The children were trained to arrange pictorial episodes of temporal scripts and tell the stories they created. Participants (N = 34, aged 4-7 years) were divided into 2 groups based on whether their spoken-language gap was more or less than 1 year compared to age norms. They completed A. Kaufman and N. Kaufman's (1983) picture series subtest and Guralnik's (1982) storytelling test at pretest and posttest. Measures demonstrated significant improvement in sequential time and storytelling achievement postintervention. Three of the examined demographic variables revealed correlations: Participants with genetic etiology showed greater improvement in time sequencing and storytelling than participants with unknown etiology; early onset of treatment correlated with better achievement in time sequencing; cochlear implant users showed greater storytelling improvement than hearing aid users. PMID- 22256541 TI - Memory skills of deaf learners: implications and applications. AB - The author reviews research on working memory and short-term memory abilities of deaf individuals, delineating strengths and weaknesses. Among the areas of weakness that are reviewed are sequential recall, processing speed, attention, and memory load. Areas of strengths include free recall, visuospatial recall, imagery, and dual encoding. Phonological encoding and rehearsal appear to be strengths when these strategies are employed. The implications of the strengths and weaknesses for language learning and educational achievement are discussed. Research questions are posed, and remedial and compensatory classroom applications are suggested. PMID- 22256543 TI - Study proves link between accreditation and performance improvement. PMID- 22256542 TI - Education of deaf and hard of hearing students and accountability reform: issues for the future. AB - The No Child Left Behind Act of 2001 (NCLB) has had a monumental impact over the past decade on how educational reform is viewed in the United States. As a result of how the law is structured, schools for students who are deaf or hard of hearing have been the focus of attention for educational reform under NCLB. While there have been some shifts in policy, reauthorization of NCLB will need to respond to some of the larger calls for changes to the law. The author discusses some key issues related to assessment and accountability that are central to how the reauthorization of NCLB affects the education of deaf and hard of hearing students. PMID- 22256544 TI - New Joint Commission partner offers ISO certification option. PMID- 22256545 TI - Joint Commission revises influenza vaccination standard. Applicability extending to all accreditation programs in 2012. PMID- 22256546 TI - CORRECTION: Existing requirements missing from home care Update 2. PMID- 22256547 TI - Missing text in home care Update 2. PMID- 22256548 TI - New Joint Commission R3 Report examines CAUTIs. PMID- 22256549 TI - JCR flu vaccination challenge enters fourth season. Participants achieved 80% flu vaccination average for health care workers in 2010-2011. PMID- 22256550 TI - Clarification: volume criteria and eligibility for continued advanced VAD certification. PMID- 22256551 TI - Reminder: Home health deemed status organizations must show track record of compliance at resurvey. PMID- 22256552 TI - The next generation of stroke and heart failure care. Joint Commission and American Heart Association/American Stroke Association enhance alliance. PMID- 22256553 TI - An open mind, discussion, debate and the testing of new ideas: the way of the future. PMID- 22256554 TI - Factors influencing the supervision of nursing students administering medication: the registered nurse perspective. AB - Administering medication is an important function of registered nurses. It is therefore necessary that nursing students develop knowledge and skill in this field. Given the propensity for, and negative consequences of, medication errors, it is essential that nursing students are property supervised in this role. There is currently a paucity of research examining the practices of supervising medication administration by nursing students, particularly from the perspectives of registered nurses. The aim of this study was to explore the opinions and insights of registered nurses regarding the supervision of nursing students administering medication. Focus groups were conducted with registered nurses with experience of working with students in the clinical environment. Focus groups were transcribed verbatim and data analysis was conducted using the five stage framework approach. Four main themes were identified that reflected the participants' views of the factors most strongly influencing the provision of supervision: communication, busyness, attitudes, and pressure to conform. The participants identified the importance of providing student supervision and suggested strategies for improvement, such as a closer working relationship between the clinical facilitator and the registered nurses providing supervision. PMID- 22256555 TI - Do inquiries into health system failures lead to change in clinical governance systems? AB - AIM: This paper reports the first part of a case study investigation to examine the changes at King Edward Memorial Hospital (KEMH) following an inquiry established to review the quality of obstetric and gynaecological services. BACKGROUND: Common findings from a range of health inquiries in recent times include that there have been inadequate adverse event reporting systems, the absence of transparent systems for staff and patients to report concerns about quality of patient care, and an ineffective medical credentialing and performance review system. The similarity of findings from many health inquiries raises the question of whether an inquiry does lead to changes to improve patient care and safety. There has been very little reported in the literature about this. METHOD: Using a case study strategy the areas of medical credentialing, performance review and involvement of consumers in care were chosen as the KEMH clinical governance processes to be examined for changes post inquiry. Documents, archives and interviews were used as data sources for this case study. Documents were examined using a normative analytic approach and the Miles and Huberman framework was used for data analysis of the interviews. FINDINGS: There were significant changes in the area of credentialing and performance review evident in analysis of all sources of data. There were some improvements in the processes of involving consumers in care, but deficits were identified in regard to the provision of training and upskilling for clinicians to improve their communication skills and interactions with patients and families. PMID- 22256556 TI - Extending the prescribing framework to nurses: lessons from the past. AB - This paper highlights the parallels between the journey to prescribing for nurse practitioners when the role was initially introduced in New Zealand and the journey now towards extending the prescribing framework to registered nurses. Nurse practitioners are the only nurses who can prescribe medicines, and their numbers are few. There are several thousand experienced registered nurses who meet the education requirements to be a nurse practitioner but who have not applied to the regulatory body for registration. Attention has begun to turn from this model, in which nurse practitioners are the only category of nurse who can prescribe, towards independent and supplementary nurse prescribing models. The New Zealand government is yet to fully commit to a specific plan for extending prescribing responsibilities to registered nurses, but feedback has been sought on two different proposals. Dependent prescribing arrangements used elsewhere appear to disregard the implications for professional autonomy. The proposed models of nurse prescribing for New Zealand impose oppressive restrictions, which nurse leaders over the last decade have fought hard to resist. Regulations are needed to allow nurses who have the appropriate education to be designated prescribers in their named area of specialisation. The difference between advanced practice nurses with prescribing rights and nurse practitioners must be clarified to minimise the impact of other prescribers on the nurse practitioner role. Lessons from the past and from the United Kingdom's experience could be drawn upon in order to better utilise the existing well-educated nursing workforce. PMID- 22256557 TI - Towards improved organisational support for nurses working in research roles in the clinical setting: a mixed method investigation. AB - BACKGROUND: The clinical research workforce within nursing is growing including those employed to lead studies, coordinate research and many hybrid roles. Several studies have reported high job satisfaction among research nurses. However, there have also been reports of limited options for career development and professional integration, likely reflecting typical informal, departmentally based management models. Institution-wide studies of issues related to research nurses are lacking, thus hampering the design and implementation of effective organisational frameworks to support and develop these positions. AIMS: To explore experiences of nurses employed in research positions regarding organisational structures and support for research career pathways, and determine what reforms would strengthen an effective research specialisation pathway. METHODS: A mixed-methods, cross-sectional approach, using a 104-item survey and semistructured interviews of 11 staff in research roles at an acute care hospital in Queensland, Australia. RESULTS: Research nurses lack organisational support in many job aspects that they deem important. A management model for the coordination of research nurses within a health district could maximise development of this field. Academic liaison and mentoring for nurses in research, and recognition for effort, are key areas for a management model to target. CONCLUSION: Nurses in research roles need individual mentorship, collective support, and the professional recognition and status that researchers in other settings are afforded. A comprehensive research management model would provide structured organisational support for nurses in research, improve professional development opportunities, ensure efficient use of human resources, synergistic working partnerships, and further contribute to a culture of evidence-based healthcare. PMID- 22256558 TI - Developing advanced rural nursing practice: a whole new scope of responsibility. AB - Rural registered nurses' experiences of advanced clinical nursing practice were explored whilst they were enrolled in an advanced primary care course of study. Thirty-two nurses employed in rural health services in Victoria, Australia, studied advanced practice nursing by distance education with a clinical component. At course conclusion, focus groups and a quantitative on-line survey were conducted to explore outcomes. Nurses reported positive self-perceptions of their educational preparation with scores of >7/10 for competence, confidence, preparedness for advanced practice and job satisfaction. Focus group discussions concurred with positive survey results. The course was valuable in developing skills and knowledge, enabling more holistic patient care. The main themes that emerged related to the advancement of the nurse as a professional, and enhancement of patient care. Within their scope of practice, nurses assessed, diagnosed and treated minor patient illness presentations either independently or collaboratively with medical advice. The context of rural health services dictated practice and levels of autonomy. Nurses perceived the new role reduced an overload of medical work, whilst increasing patients' access to care. As a result of the course 24% of participants reported a change in their work role. Nurses employed in rural health services reported positive potential for advanced collaborative practice in rural health care, in association with medical professionals. Defined role boundaries, role responsibilities and dedicated advanced practice positions will be required to achieve implementation of the role. PMID- 22256559 TI - Investigation into the vasospastic mechanisms in the pathogenesis of glaucomatous neuropathy. AB - Spasm of blood vessels supplying the optic nerve head is considered one of possible ischaemic mechanisms of glaucomatous optic neuropathy. PURPOSE: The aim of the study was to evaluate the role of two potent and long-acting vasoconstrictors: endothelin-1 (ET-1) and neuropetide Y (NPY) in the pathogenesis of glaucoma by: 1) measurement of plasma ET-1 and NPY concentrations in primary open-angle glaucoma (POAG) patients with high intraocular pressure (HTG patients) and with normal intraocular pressure (NTG patients) at baseline and following peripheral exposure to cold (cold-pressor test), 2) assessment whether changes, if any, in the plasma concentrations of both peptides following the cold-pressor test correlate with visual field defects. MATERIAL AND METHODS: The study was conducted in three groups of subjects: 1) HTG patients, 2) NTG patients and 3) controls. All subjects were young and free from any cardiovascular disorders. ET 1 and NPY concentrations in the plasma were measured by radioimmunoassay (ET-1: Amersham International UK, NPY: Peninsula Laboratories INC). The cold-pressor test was performed by immersing the whole hand in ice-cold water (4 degrees C) for 2 minutes. Visual fields were examined using standard automated perimetry (Octopus 101, G-2 programme, normal strategy). RESULTS: In the NTG patients the mean baseline plasma ET-1 concentration was significantly lower and the mean baseline plasma NPY concentration significantly higher compared to controls. On the other hand, there were no statistically significant differences in the mean baseline peptide levels between the HTG patients and the control subjects. After the cold-pressor test the mean ET-1 concentrations considerably increased in the three groups. The highest increase was seen in the NTG group and it was statistically significant compared to the HTG group and controls. Following the cold-pressor test the mean NPY concentration was significantly decreased in the NTG group, but remained virtually unchanged in the HTG group and controls. In the NTG patients, significant increase in the mean ET-1 concentration and decrease in the mean NPY concentration seen after the cold-pressor test were accompanied by a significant decrease in the mean MS (mean retinal sensitivity) value in the second eye examined after the cold-pressor test, but no correlation was found between changes in the MS values and changes in the ET-1 and NPY concentrations. There were no significant changes in the mean MS values after cold-pressor test in the HTG patients and controls. CONCLUSIONS: Our findings suggest abnormal neuro-endothelial mechanisms of vascular tone control in NTG patients, related to the effects of ET-1 and NPY, secondary to endothelial dysfunction and to dysregulation of the autonomic nervous system. These abnormalities may involve potentiation of the vasoconstrictive effects of both ET-1 and NPY leading to the optic nerve head ischaemia and subsequent development of visual field defects in the course of normal-tension glaucoma. PMID- 22256560 TI - Visual outcomes three and six months after implantation of diffractive and refractive multifocal IOL combinations. AB - PURPOSE: To evaluate 3 and 6 months binocular visual outcomes after cataract surgery using a multifocal IOL "mix and match" approach, with a refractive (ReZoom) IOL in the dominant eye and a diffractive (Tecnis) IOL in the fellow eye. MATERIAL AND METHODS: Three and 6 months after bilateral cataract surgery, 40 eyes of 20 patients were evaluated for binocular UDVA, UNVA and UIVA (logMAR), spectacle independence, contrast sensitivities (CS), stereoscopic vision, subjective symptoms, patient satisfaction and complications. RESULTS: Three months after surgery mean binocular UDVA did not differ from the six-month follow up (-0.13 +/- 0.08 vs. -0.18 +/- 0.08; p = NS ). All patients achieved binocular UNVA of 0.0 at both follow-ups. Mean binocular UIVA improved significantly from 0.06 to 0.01 (p<0.027), 6 months after surgery. All patients had very function at good visual all distances and were totally spectacle independent. CS under various conditions was within normal age-matched limits at both follow-ups. For some spatial frequencies six months postoperative results were significantly better than for the 3 months follow-up (p<0.05). Stereoscopic vision was normal. A low degree of glare/halo was detected in 75% of subjects. Overall patient satisfaction was very high (9.6/10). There were no postoperative complications. CONCLUSIONS: Mixing and matching multifocal IOLs in selected cataract patients provides an excellent visual outcome, a high level of patient satisfaction and spectacle-free visual function. A period of neuroadaptation lasting at least six months is necessary to obtain better visual function results. PMID- 22256561 TI - Results of implantation a new type of foldable anterior chamber intraocular lens. AB - In aphakic patients, lack of capsular support or insufficient capsular support require an implantation of an anterior chamber intraocular lens or a sclerally fixated lens. Rigid PMMA (polymethylmetacrylate) anterior chamber intraocular lenses or transscleral intraocular lenses require an incision 6.0-7.0 mm wide. PURPOSE: Of this study was to evaluate anatomic and functional results of a new foldable acrylic anterior chamber intraocular lens (Acri.Lyc 15A, Acritec) through a small incision (2.8 mm). MATERIAL AND METHODS: The examined group consisted of 30 eyes in 30 patients, at the age from 48 to 87 years (mean 70.90 years, SD +/- 10.57 years), who received a new type foldable acrylic anterior chamber intraocular lens (AC IOL). Examinations were performed before operation and 1-3 days, 1-2 weeks, 3-4 months, 6-8 months after the surgery. During all control examinations visual acuity, intraocular pressure, refraction, corneal endothelium density, pachymetry, keratometry, anterior and posterior segment of the eye were evaluated. RESULTS: Preoperative mean best corrected visual acuity (BCVA) was 0.32 +/- 0.36 and increased to 0.63 +/- 0.33, 6-8 months after the surgery. We observed that mean corneal endothelial cell density (ECD) gradually decreased in the postoperative period. We observed some minor complications after implantation of the AC IOL (e.g. corneal edema, Descemet folds, raised IOP, hyphaema, distorted pupil shape, "iris bombe", blood in the vitreous, displaced IOL and cystic macular edema), most of them were minor and did not influence the final results. CONCLUSIONS: The application of foldable anterior chamber intraocular lenses through a small incision is a safe alternative for rigid PMMA anterior chamber intraocular lenses and transscleral intraocular lenses. PMID- 22256562 TI - [The role of circulating endothelial progenitor cells in the progression of retinopathy of prematurity--a prospective study]. AB - PURPOSE: Retinopathy of prematurity (ROP) is the primary cause of visual impairment in preterm infants. There are available data confirming that circulating endothelial progenitor cells (EPCs) are involved in forming the growing network of blood vessels in the developing retina. In this study we sought to explore potential relationship between concentration of circulating bone marrow-derived EPCs and development of ROP in prospective study. MATERIAL AND METHODS: The study groups consisted of 90 preterm (23-36 weeks of gestational age), and 52 full-term control infants. EPCs were analyzed in cord blood (CB) and subsequently in peripheral blood (PB) in second and sixth week since delivery. The incidence and stage of ROP was prospectively documented in the preterm infants. RESULTS: EPC concentration in CB was considerably higher in the preterm infants developing ROP. In the preterm infants a noticeable decrease in PB EPC concentration within six weeks of the follow up was found, whereas in full-term infants EPC concentration was maintained at invariable level. Of note, in the sixth week since delivery, EPC concentration in preterm infants with ROP was lower compared to preterm infants without ROP. CONCLUSIONS: Increase in CB EPC concentration in preterm infants, including those developing ROP, indicates that the circulating EPC cells contribute to the process of blood vessel formation, and their number in CB reflects the degree of prematurity. Impaired blood vessel formation within retina in the course of ROP may result from decrease in circulating EPC number observed at the sixth week since delivery. PMID- 22256563 TI - [Elevated level of circulating endothelial cells as an exponent of chronic vascular dysfunction in the course of AMD]. AB - PURPOSE: In recent years, emerging data support the concept of endothelial dysfunction in the course of age-related macular degeneration (AMD). Circulating endothelial cells (CECs) are desquamated mature cells that have detached from the intimal monolayer in response to endothelial injury. In this study we sought to explore the potential role of endothelial dysfunction in pathogenesis of AMD by measuring the concentration of CECs in peripheral blood of AMD patients. MATERIAL AND METHODS: Peripheral blood samples from 31 patients with diagnosed dry AMD and 46 patients with neovascular AMD were collected. Forty six, age- and sex-matched volunteers without AMD were enrolled as a control group. CECs were counted and analyzed by flow cytometry. RESULTS: Multivariate analyses of patients and controls adjusted for age, gender, presence of ischemic heart disease, hypertension and smoking (current or past) revealed that both wet (beta = +0.45, p = 0.0003) and dry (beta = +0.28, p = 0.027) forms of AMD are independent factors associated with higher number of CECs. CONCLUSIONS: Our results suggest that there is an endothelial alteration accompanying AMD. Increased numbers of CECs AMD patients reflect a severe vascular disturbance and may contribute to the disease process. These findings can help expand our knowledge of the pathogenic mechanisms of AMD and may be relevant to the potential treatment of this disease. PMID- 22256564 TI - [Combined photodynamic therapy and intravitreal injection of triamcinolone acetonide in patients with wet form of AMD. Introductory report]. AB - PURPOSE: To evaluate the efficacy of combined PDT and 4 mg intravitreal triamcinolone acetonide injection, performed 48-72 hours after PDT, in patients with wet form of AMD. MATERIAL AND METHODS: Nonrandomised, interventional case series, 13 eyes of 13 patients with subfoveal CNV due to AMD that did not respond to PDT monotherapy - 7 females, 6 males - at the age of 65-85 (average age 76.6 +/- 6.7 years); standard PDT was performed in all patients followed by a 4 mg intravitreal injection of triamcinolone acetonide given 48-72 hours after PDT. Follow up visits were scheduled 1 and 7 days after the injection and then every 3 months afterwards and included: BVCA (Snellen chart), IOP measurements, FA, OCT, slit lamp and eye fundus examination. Lesions with active CNV leakage in FA were retreated every 3 months. RESULTS: Average observation time was 10.8 +/- 3.5 months. Baseline visual acuity before PDT monotherapy was applied (Vo) was 0.17 +/- 0.12 (0.06-0.5), and after the therapy decreased to (V1) 0.14 +/- 0.13 (0.05 0.2). After combined PDT and Tc treatment BVCA increased to (V2) 0.21 +/- 0.13 (0.06-0.5), p<0,03. 76,9% of patients gained or maintained visual acuity after combined therapy in the observation time. In 70% of eyes no signs of active CNV was observed in AF and OCT after 1 session of combined PDT and Tc treatment. Only 4 patients required 1 repeated treatment session. CONCLUSIONS: 1. Combination of PDT and IVTA may be effective in patients with wet AMD with no response to PDT alone and significantly reduces the repeated treatment rate. 2. Intravitreal Tc injection performed 48-72 hours after PDT may improve the final functional effects in treated eyes as compared with PDT monotherapy. Our results need further investigation. PMID- 22256565 TI - [Malherbe's calcifying epithelioma (pilomatrixoma)--own experience]. AB - PURPOSE: Malherbe's calcifying epithelioma is a rare hair matrix tumor. The objective is to present clinical cases and to analyze the variability of its image. MATERIAL AND METHODS: Among nearly 3500 patients with ocular tumors operated during the last 10 years in the Department of Ophthalmology and Ocular Oncology in Krakow we identified a group of 7 patients with histologically confirmed pilomatrixoma. A retrospective evaluation of their medical history was performed, paying particular attention to the co-existence of other diseases, form of growth and location of tumors, as well as treatment methods and their effectiveness. The results were compared with other clinical studies. RESULTS: Malherbe's calcifying epithelioma is characterized by clinical polymorphism and similarity to other much more frequent eyelid tumors. It usually has the form of a single, small, movable, slowly growing nodule covered by intact skin. In addition to the classic form described there are pediculated tumors, huge, fast growing, perforating, as well as tumors in unusual locations and multiple lesions. CONCLUSIONS: The consequences of variation pilomatrixoma are clinical diagnostic errors. The one, sure and reliable criterion is a histopathology evaluation. PMID- 22256566 TI - [Condition of the visual system and school achievements in 6 to 10 years old children from Wielkopolska region as detected by visual screening and questionnaire studies]. AB - PURPOSE: The study aimed at comparing results of the visual screening with school achievements and results of questionnaire studies. MATERIAL AND METHODS: Basic optometric tests, including visual acuity, phoria, stereo near vision, colour vision, near point of convergence and plus lens test were examined in 1138 children, 6 to 10 years of age, 88 pupils were examined in their glasses. Also questionnaire studies were conducted among parents and teachers, related to visual condition of studied children. For every of the children data were obtained on his/her school achievements. RESULTS: A relationship was demonstrated between visual complaints and results of the visual screening and also between school achievements and vision screening results. CONCLUSIONS: The results corroborate the assumption that school achievements require efficient visual system in near and distant vision. Proper condition of the visual system exerts significant effects on educational and perceptive functions of a child. PMID- 22256567 TI - Culture morphology of the autologous cultivated corneal epithelium. AB - PURPOSE: Ocular surgery based on cultivated corneal epithelium has become a very promising procedure eligible to restore the ocular surface. Analysis of morphologic features and the phenotype of cultivated epithelial cells determines their quality and eligibility of transplantation. MATERIAL AND METHODS: Corneal epithelial cultures were carried out in 25 patients suffering from limbal deficiency after chemical or thermal burns. Fellow healthy eyes were the source of limbal epithelium for the culture. Limbal cells from a 2 mm2 biopsy were seeded on an amniotic membrane after enzymatic pretreatment. Cultures were carried in standard conditions in a supplemented DMEM HAM/F12 medium in the presence of 3T3 fibroblasts. Light microscopy was used to analyze the regularity of the cultivated epithelial layer, histologic examination was used to establish number of epithelial layers, and immunohistochemistry for epithelial and proliferation markers was applied to confirm cell origin and proliferative potential. Staining for cytokeratin 3, 12, 19, connexin 43, and protein p63 was performed. RESULTS: In 25 donors, 27 cultures of the epithelium were performed. In 2 cases, plates were contaminated. Both cultures were repeated. In 84% of the cultures, regular stratified growth of the epithelium with complete covering of amniotic membrane was observed. In 16% of cultures, growth was not regular, showing differences in the number of cell layers. Staining for cytokeratin 3/12 confirmed the corneal origin of cultivated epithelia. The number of epithelial layers ranged from 3 to 9; the average was 5.3 +/- 1.9 layers. CONCLUSION: Cultures of limbal epithelial cells are a valuable source of tissue for restoration of the corneal epithelium. PMID- 22256568 TI - Malignant glaucoma and central retinal vein occlusion after Nd: YAG laser posterior capsulotomy. AB - PURPOSE: The purpose of this paper is to present the case of malignant glaucoma complicated by CRVO occurring after Nd: YAG laser posterior capsulotomy. MATERIAL AND METHODS: A 75 years old woman with pseudophakia and cardiovascular disease had undergone Nd: YAG laser posterior capsulotomy, the day after capsulotomy IOP increased in that eye up to 50 mmHg. Medical treatment alone appeared to be unsuccessful. IOP remained elevated (50 mmHg) and lack of anterior chamber occurred. In the examination, the eye showed circumcorneal congestion, diffuse corneal edema, uniformly flat anterior chamber with dilated, nonreacting pupil, optic disc edema, retinal hemorrhages, dilated tortuous retinal veins and macular edema. Surgical therapy (pars plana vitrectomy and the anterior chamber reformation with air bubble) was performed in urgent course. RESULTS: Twenty four hours after surgical intervention anterior chamber remained deep, IOP reduced to 12,2 mmHg, B-scan ultrasonography did not show any aqueous pockets in the vitreous. In the following 10 days, the IOP remained within normal limits with a well-formed anterior chamber. The final best-corrected visual acuity of the eye was 0.3. CONCLUSIONS: Early recognition of malignant glaucoma and proper treatment is the most important step to save the eye from severe consequences and prevent irreversible vision loss. PMID- 22256569 TI - [Optical coherence tomography in diagnosis of intracranial hypertension in children]. AB - Intracranial hypertension (IH) is important cause of optic disc edema. It is essential to distinguish the primary and secondary causes of IH. Persistent increasement of intracranial pressure over 200-250 mmH2O is caused by impairment of the balance between production and absorption of cerebrospinal fluid. Though the exact mechanism of IH is still unknown. PURPOSE: Assessment of usefulness of spectral optical coherence tomography with dual beam eye tracking (SLO/OCT) in diagnosis of intracranial hypertension in children. MATERIALS AND METHODS: 4 children (at the age of 3-12 years) with IH underwent an comprehensive ophthalmological examination, including visual acuity testing (Snellen charts), color vision (Ishihara charts), evaluation of anterior and posterior segment of the eye in slit lamp. On SLO/OCT (Spectralis, Heidelberg) scans RNFL profile of the optic disc was assessed at admission day and after 8 weeks of treatment with oral diuretics. In all patients MRI of the central nervous system was performed. RESULTS: In all children best corrected visual acuity and MRI scans were normal. 3 of 4 patients had secondary IH. Median global RNFL was 273 microm at admission day. In 3 of 4 children remission of optic disc edema was observed after 8 weeks of treatment with diuretics - median global RNFL was 138 microm. CONCLUSIONS: Diagnosis of intracranial hypertension requires interdisciplinary cooperation. SLO/OCT is useful in monitoring remission of the optic disc edema. PMID- 22256570 TI - [Clinical ocular manifestation of Patau's syndrom (trisomy 13)--own observations]. AB - PURPOSE: The purpose of the article is to present the clinical abnormalities of Patau's syndrome (trisomy13). MATERIAL AND METHODS: Examination was performed on 18 months old girl with trisomy13 in which we noted characteristic malformations in ocular system. The patient underwent cataract surgery and intraocular lens implantation in right eye. In this case the diagnosis of trisomy 13 was confirmed by karyotype. RESULTS: Inferonasal iris colobomas, anterior-posterior form of persistent hyperplastic primary vitreus (PHPV), persistent tunica vasculosa lentis (PTVL), coloboma of the lens and cataract in right eye were found. Cataract surgery was performed with good results. Systemic abnormalities included heart defect, brain defect, cleft palate, small head, dysplastic ears, mental retardation, epilepsy and increased muscle tone. CONCLUSIONS: The child with the presence of inferonosal iris colobomas and cataract and with other systemic and dysmorfic findings, should have kariotype examination to look for trisomy 13. PMID- 22256571 TI - [The role of ophthalmological examination in the diagnosis of gangliosidosis GM1]. AB - Gangliosidosis GM1 belongs to a group of lysosomal storage diseases and results from the deficiency of acidic beta-galactosidase activity. The enzyme is essential for the degradation of ganglioside GM1 and its derivatives. The disease causes multi-organ injury, however accumulation of ganglioside GM1 mainly in the brain white and gray matter results in predomination of neurological symptoms. Based on the actual knowledge--the condition is untreatable and especially in the very severe infantile form, the duration of the survival is very short. One of the characteristic symptoms of some lysosomal storage diseases, including gangliosidosis GM1, is "cherry-red" spot found in the fundus of the eye. In the publication the clinical course of gangliosidosis GM1 in two infants is presented. The value of an ophthalmological examination in the diagnosis of this rare condition has been emphasized. PMID- 22256572 TI - [Adjustable suture as a method of guarded filtration in trabeculectomy--review of current techniques]. AB - Filtration surgery has evolved during the last decades. Guarded filtration surgery especially adjustable and releasable suture techniques are significant advancement in conventional trabeculectomy. The aim of this article is to provide a survey of currently used methods of adjustable suture with respect to main trabeculectomy techniques. PMID- 22256573 TI - [Malherbe's calcifying epithelioma (pilomatrixoma)]. AB - Malherbe's calcifying epithelioma (pilomatrixoma)--is a rare, benign tumor of hair matrix. PURPOSE: Of this study is to present the clinical variability of epithelioma, pathomorfological appearance of the tumor and the views on its pathogenesis. RESULTS: Malherbe's calcifying epithelioma has a very different, sometimes unusual appearance, similar to other, more frequent laesions. Due to this fact and the rarity of the tumor it is sometimes overlooked in diagnostic considerations, or confused with more common tumors. Genetic analysis at this stage, allows to establish a probable causal relationship between mutations in the beta-catenins coding gene and development of pilomatrixoma. Extremely rare epithelioma may undergo transformation into pilomatrix carcinoma. CONCLUSIONS: The only reliable criterion of diagnosis remains pathological evaluation which despite the deceptive macroscopic appearance of the tumor provides correct diagnosis. PMID- 22256574 TI - [Professor Stanislaw Mondelski--the prominent ophthalmologist in Poznan. In the twentieth anniversary of the death]. AB - Stanislaw Mondelski was born the 21.01.1914 in Tarnow. He graduated the University of Medical Siences in 1948. He became the professor of the Ophtalmology Departament of the University of Medical Siences in Poznan in 1983. He was the author of above 100 scientific works. The subject matter of works concerned of the diagnosis and the treatment of the illnesses of retina, the oculistic oncology, improving the diagnostic methods and the operating techniques, the relationship between the eyes iseases and the general condition of the human organism, the treatment of glaucoma. Beyond the scientific and didactic activity, he dedicated many attentions to improving and constructing the investigative and healing apparatus. Professor Stanislaw Mondelski died in 1992 in Poznan. PMID- 22256575 TI - [Interesting life father's of Polish ophthalmology--Wiktor Feliks Szokalski (1811 1891)--in 200 years anniversary of his birth]. AB - Victor Szokalski is considered to be the father of Polish ophthalmology. He was born in Warsaw in 1811, where he also began his medical studies. He fought in the November's Uprising. He was awarded the Military Cross Virtuti. After its fall he went to Germany, where he continued his studies. In 1834 he defended his doctoral thesis. Then he moved to France, where worked at the Eye Clinic of Jules Sichel. He wrote many articles for medical journals and taught students. Already in Paris he acted in a number of social societies, collaborated with Prince Adam Czartoryski, was a friend of Adam Mickiewicz. Fifteen years later he returned to Warsaw, where became a consultant, then the chief at the Ophthalmic Institute. For 33 years he has served as secretary of the Warsaw Medical Society. He wrote the first Polish original textbook of ophthalmology. He died in Warsaw in 1891. PMID- 22256576 TI - [Effect of continuous intravenous infusion of flurbiprofen axetil and tramadol hydrochloride for postoperative pain management of laparoscopic colectomy]. AB - BACKGROUND: In this study, we evaluated the efficacy of continuous intravenous infusion of flurbiprofen axetil (FA) combined with tramadol hydrochloride (TH) for postoperative pain control after laparoscopic colectomy. METHODS: Fifty patients scheduled for laparoscopic colectomy were randomly assigned to one of the following three groups : the saline group which received saline, the FA alone group which received FA 4 mg kg-1 . 24hr-1, and the FA plus TH group which received FA 4 mg kg-1 . 24 hr-1 and TH 2 mg kg-1 . 24 hr-1 intravenously after bolus injection of FA 50 mg immediately before the end of the operation. We examined the pain scores at 4 and 24 hr, and postoperative analgesic medication use during 0-4, 4-24, and 24-48 hours. RESULTS: Although no significant difference was observed among pain scores for these three groups, the FA plus TH group required the lowest dose of analgesic medication. For lower abdominal incision, the FA plus TH group required the least analgesic medication in 4-48 hr. No significant difference concerning analgesic medication was observed among the three groups for upper abdominal incision. CONCLUSIONS: Continuous intravenous injection of FA plus TH is more effective than FA alone for postoperative pain management after laparoscopic colectomy. PMID- 22256577 TI - [Usefulness of epidural anesthesia for percutaneous endoscopic lumbar discectomy (PELD)]. AB - BACKGROUND AND METHODS: To study feasibility of epidural anesthesia for percutaneous endoscopic lumbar discectomy (PELD), we made a retrospective comparison of three anesthetic groups (28 cases with epidural anesthesia, 19 cases with local anesthesia, and 28 cases with general anesthesia) undergoing PELD. RESULTS: Three groups matched each other in age, the surgical site, and the duration of surgery; however, the frequency of male patients was significantly greater in the local anesthesia (LA) group. In the epidural anesthesia (EA) group, there was no patient who required a change of the anesthetic technique or analgesics administration during surgery. In EA group, patients received smaller amount of local anesthetic but spent longer time in the operating room compared with those in LA group. EA and GA groups included several cases staying long time in the hospital and presented wide statistical dispersion of the duration of hospitalization. There was no difference in the dose of local anesthetics, the duration of total procedure, or time to discharge between EA and GA groups. CONCLUSIONS: Epidural anesthesia is suggested to be a useful option for anesthetic techniques in patients undergoing PELD. PMID- 22256578 TI - [On the characteristics of axillary veins and internal jugular veins in pediatric patients]. AB - BACKGROUND: Axillary veins (AxV) are increasingly selected instead of the subclavian veins (SCV) for safe and successful catheterization in adults using ultrasound echo although quite rarely in children. The diameters and depths of the pediatric internal jugular veins (IJV) are well known but those of pediatric AxV are unfamiliar even to anesthesiologists. We evaluated the diameters and the depths of the AxV and IJV in children undergoing cardiac surgery. METHODS: The diameters and the depths of the AxV and IJV were measured using an ultrasound echo apparatus (TiTAN, SonoSite) in fifty pediatric patients. RESULTS: The patients' ages, heights, and weights averaged about 27.5 months, 77.3cm, and 9.8kg, respectively. The maximal widths, lengths and depths of the AxV and IJV were about 4.2, 3.3 and 10 mm and 7.5, 4.9 and 6.6 mm, respectively. The widths of the AxV and IJV correlated well with the patients' heights (r=0.831 and 0.700, respectively). CONCLUSIONS: The diameters of the AxV are about 0.6 times and the depths are about 1.5 times those of the IJV and it seems difficult to use AxV for pediatric CVC from the standpoint of venous diameters and depths. PMID- 22256579 TI - [Anesthetic management for electroconvulsive therapy using rocuronium bromide and sugammadex sodium in a patient with suspected malignant syndrome]. AB - A 62-year-old woman was treated for schizophrenia for 40 years. When the symptoms had deteriorated and new medications had to be added, CPK rose and she malignant syndrome was suspected. The electroconvulsive therapy (ECT) was proposed because of no improvement of the symptoms. We employed rocuronium bromide instead of suxamethonium considering malignant syndrome. The maintenance of anesthesia was necessary, because the duration of rocuronium bromide is longer than that of suxamethonium chloride. Anesthesia was induced and maintained using target controlled infusion (TCI) of propofol. After ECT was performed, sugammadex sodium 4 mg . kg-1 was administered at 2 post-tetanic counts (PTC) and the patient could come out the operating room safely and speedy. ECT using rocuronium bromide and sugammadex sodium can be performed safely and speedily, when suxamethonium chloride cannot be used. PMID- 22256580 TI - [Successful anesthetic management of tracheal reconstruction and omentopexy with thoracic epidural anesthesia and transversus abdominis plane block]. AB - A 64-year-old man was diagnosed to have a tracheal tumor 2 cm proximal to the carina. He was scheduled for tracheal resection and reconstruction with omentopexy. An epidual tube was placed at the level of T5-6. After induction of anesthesia by propofol and remifentanil, a tracheal tube was inserted with the aid of bronchofiberscopy. Bilateral transversus abdominis plane block (TAPB) was performed with 0.5% ropivacaine 40 ml under ultrasound guidance. Anesthesia was maintained by sevoflurane and remifentanil, together with epidural infusion of ropivacaine and fentanyl. During tracheal resection and reconstruction, his left main bronchus was intubated directly from the cutting edge. After the operation, he was extubated under anesthesia without coughing. No pain was complained during postoperative course. Epidural anesthesia combined with TAPB provided sufficient postoperative analgesia, especially in tracheal resection and reconstruction with omentopexy. PMID- 22256581 TI - [Skin lesions on the back along the epidural Catheter]. AB - We report a patient with anemia and hypoalbuminemia who developed decubitus ulcer along the epidural catheter. A 35-year-old woman underwent cesarean section under combined spinal-epidural anesthesia. Erosive and erythematous skin lesions along the epidural catheter were noted 48 hours after insertion of the epidural catheter. The skin lesions were thought to be decubitus ulcer along the epidural catheter due to mechanical pressure caused by fixation of the catheter with an adhesive tape after prolonged supine position. PMID- 22256582 TI - [Case of emergent caesarean delivery in a patient with aplastic anemia complicated with pregnant induced hypertension]. AB - A 32-year-old pregnant woman diagnosed with aplastic anemia was admitted for emergent caesarean delivery of 26th week of the gestation due to PIH (pregnancy induced hypertension) and NRFS (non-reassuring fetal status). After compensating platelets counts to 5.3x10(4) microl-1, general anesthesia was induced with propofol and rocuronium. Anesthesia was maintained with O2 and sevoflurane until delivery and with modified-NLA after delivery. She was additionally monitored with Vigileo/FloTrac system (Edwards Lifesciences, USA) and TOF-WATCH SX (Nihon Kohden, Tokyo). After 8 minutes of operation her baby was born with the 5-minute Apgar score of 5 and the UA-pH of 7.387. It was only 2 hours and 12 minutes that the baby was born after she was admitted. The baby was tracheally intubated and transferred to NICU. Blood loss during operation was 835 g and two units of RCC was transfused. Circulatory values were kept acceptable and neuromuscular blocking was completely reversed by sugammadex and extubated in the operating room. Bleeding tendency and atonic bleeding were not observed. She survived perioperative period and was to be treated for aplastic anemia. Her baby was discharged neurologically free. We should be ready to respond to anesthetic requirement for urgent cases of aplastic anemia. PMID- 22256583 TI - [Case of facial nerve palsy accompanied with swelling of the parotid gland following the surgery with left lateral decubitus position]. AB - A 70-year-old woman (142 cm in height, 75 kg in weight, BMI 37) received right total hip arthroplasty in the left lateral decubitus position. The operation time was 9 and a half hours. The morning after the operation, erythema accompanied with bullae was observed on the skin of the left parotid gland and left shoulder, and left facial nerve palsy developed. The palsy was almost paralysis with marked facial asymmetry and severe blepharoptosis. Ultrasonography showed diffuse swelling of the left parotid gland. The serum amylase level was 642 IU . l-1 (normal range : 40-113). Prolonged parotid gland compression during the operation would have caused acute swelling of the parotid gland and facial nerve palsy. The palsy resolved completely after 5 months. PMID- 22256584 TI - [Anesthetic management of caesarean section using common iliac artery balloon occlusion in patients with placenta previa]. AB - We report anesthetic management of caesarean section using common iliac artery balloon occlusion in 6 patients with placenta previa. Placenta previa might induce critical hemorrhage during caesarean section. We performed caesarean section safely, with preoperative placement of occlusive balloon catheters in the bilateral common iliac arteries. This technique provided satisfactory condition for control of bleeding during the operation. There was no perioperative complication in these patients. Common iliac artery balloon occlusion could reduce blood loss during caesarean section in patients with placenta previa. PMID- 22256585 TI - [Acute subdural hematoma secondary to cerebrospinal fluid drainage during thoracic endovascular aortic repair (TEVAR): A case report]. AB - We report a case of acute subdural hematoma which occurred following cerebrospinal fluid (CSF) drainage during thoracic endovascular aortic repair (TEVAR) surgery. A 63-year-old woman was scheduled to receive TEVAR for thoracic abdominal aneurysm extending from the descending aorta (T10) to 15 mm above the celiac trunk. Before the TEVAR operation, a lumbar cerebrospinal drain was inserted at L4-5. CSF pressure was maintained at 10cmH2O throughout the operation. The surgical procedure was completed uneventfully. At the end of the surgery, the attending anesthesiologist recognized an inequality in the patient's pupil size. Emergency CT scan reviewed left acute subdural hematoma. The patient underwent emergency external decompression surgery. The benefits of CSF drainage for spinal cord protection is well established, and ischemia of Adamkiewicz artery is prevented by careful control of CSF pressure. However, the use of CSF drainage has been associated with the risk of acute subdural hematoma. Careful observation for amount of CSF drainage is necessary during thoracoabdominal aortic aneurysm repair. PMID- 22256586 TI - [Use of sugammadex in a patient with amyotrophic lateral sclerosis]. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving motor neurons. The anesthetic problem is increased susceptibility to non-depolarizing muscle relaxants and the feasibility of spinal and epidural anesthesia. An 86 year-old man with ALS underwent colostomy to the ileus. We chose general anesthesia with propofol, remifentanil, rocuronium and sugammadex. We administered 30 mg (0.52 mg . kg-1) of rocuronium only for induction. TOF-count was 2 at the end of operation. At spontaneous neuromuscular recovery to TOF-count 3, we administered sugammadex 2.1 mg . kg-1. The patient emerged from general anesthesia smoothly, and was extubated. Post-operative course was uneventful. Our anesthetic management of ALS patient using sugammadex was successful. Further evidence is required to establish appropriate use of sugammadex for ALS patients. PMID- 22256587 TI - [Change of surgeons' opinion against anesthesiologists after introduction of enhanced recovery after surgery (ERAS) protocols: questionnaire survey among surgeons who participated ERAS care]. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols aim to improve patient care, reducing complication rates, and shortening hospital stay following colorectal surgery in Europe. In cooperation of colorectal surgeons and anesthesiologists, ERAS protocols were initially introduced in our hospital to the patients who underwent open colorectal resection in July 2010. METHODS: Using a questionnaire, we surveyed the change of surgeons' opinion against anesthesiologists after introduction of ERAS among 15 surgeons at Metropolitan Bokutoh hospital. RESULTS: Surgeons realized that introduction of ERAS made strong communication between surgeons and anesthesiologists. And they also thought it is not surgeons themselves nor anesthesiologists themselves but 'team care' which could produce positive outcome of ERAS. CONCLUSIONS: Introduction of ERAS as collaboration of surgeons and anesthesiologists resulted in facilitating communication of surgeons and anesthesiologists. PMID- 22256588 TI - [Management of drugs used by anesthesiologists in the operating room]. AB - We report the results of reviews by pharmacists of clerical errors in drugs used in the operating room by anesthesiologists from August 2005 to March 2007 at Fukuoka University Hospital. During the period, 9907 surgical patients were managed by anesthesiologists. There were 4868 clerical errors by anesthesiologists. Failed description of used drugs was the most frequent error (n=3,777). One medication error was detected by the review. The review of used drugs in the operating room by pharmacists can prevent financial loss and improve patients' safety. PMID- 22256589 TI - [Report of International Medical Relief Activity for Haiti earthquake as a delegate of Japanese Red Cross Society]. AB - The author joined the emergency health operation of the International Red Cross for Haiti earthquake as one of Japanese Red Cross delegates for about one month in May, 2010. Althought I was not expected to offer the skills and experiences as an anesthesiologist, but those of a general practicing, I learned many valuable things from seeing local people, especially about the characteristic diseases and symptoms after disasters caused by living in the camp which was not an ideal environment to be in so long. It is difficult to know much about such typical problems through our usual work as an anesthesiologist. If we want to join these kinds of mission, we have to have some extra knowledge for helping people after such disasters. PMID- 22256590 TI - [Mechanism of withdrawal syndrome in alcohol dependence]. AB - Pathophysiological process of ethanol physical dependence and its withdrawal syndrome is supposed to result from adaptive changes in a number of neurotransmission systems, and several reports have demonstrated functional relationship between behavioral responses and neurotransmission systems in ethanol-dependent and -withdrawn animals. However, the molecular mechanisms underlying behavioral responses observed in these animals are still controversial at present. Alterations of beta-adrenergic receptor (beta-AR) function in the brains of mice physically dependent on ethanol were examined because of few available data on functional changes of beta-ARs and its significance in ethanol withdrawal signs. The protein level of beta-ARs also significantly increased in the frontal cortex of mouse with ethanol physical dependence and conditions withdrawn from ethanol after chronic treatment with ethanol vapor for 9 days. Intracerebroventricular administration of nadolol, a non-selective antagonist for beta-ARs, immediately after discontinuation of ethanol inhalation clearly attenuated the expression of withdrawal signs. These findings suggests that ethanol physical dependence induces beta-AR up-regulation, that is their increased number and facilitation of beta-AR signaling, which may at least in part participates in expression of tonic-clonic convulsion as one of ethanol withdrawal signs. We further investigated relationship between actin of cytoskeleton and relapse of alcohol dependence after withdrawal from alcohol vapor inhalation for 9 days. After 3 days of withdrawal from alcohol vapor alcohol-induced place preference was enhanced, which was blocked by the treatment with an actin polymerization inhibitor, cytochalasin D, and anactin depolymerization inhibitor, phalloidin, during 3 days after ethanol withdrawal. These findings suggest that changes in actin turnover on withdrawal from alcohol vapor involve in sensitization of alcohol-induced place preference. PMID- 22256591 TI - [Effects of alcohol consumption on traumatic brain injury]. AB - It has been well known that alcohol consumption affects traumatic brain injury. The mechanism of detrimental effect of ethanol on traumatic brain injury has not been clarified. This review focused on the relationship among traumatic brain injury, ethanol and aquaporin-4. We have reported that ethanol increased brain edema after brain contusion and decreased survival rates in rats. It was suggested that increasing brain edema by ethanol after brain contusion may be caused by oxidative stress. Brain edema consists of cytotoxic brain edema, vasogenic brain edema, interstitial brain edema and osmotic edema. Ethanol mainly increases cytotoxic brain edema. Both alcohol consumption and brain contusion cause oxidative stress. Antioxidant treatment decreases cytotoxic brain edema. Aquaporin-4, an water channel, was increased by ethanol 24 hr after traumatic brain injury in rat. The aquaporin-4 inhibitor decreased brain edema after brain contusion and increased survival rates under ethanol consumption. Aquaporin-4 may have strict relation between ethanol and brain edema increasing after brain contusion. PMID- 22256592 TI - [Investigation of patients suspected of drinking, who visited emergency department, and their negative influence on emergency medical system]. AB - We investigated the drunken patients visiting the emergency department (ED) to determine their negative influence on emergency medical system in our community. One hundred seven (1.2%) of 8,812 referred patients, including children, was suspected of drinking by the medical stuffs in the ED on the basis of the interview, smell of alcohol on breath, pre-hospital information, and so on. Objective analysis of drinking, such as blood alcohol concentration measurement, was not performed. Both the mean age and the median of the patients were 45 years old. The number of male was 4 times higher than female. Three fourths visited ED during the period from the evening to early morning, when it tends to be confused in ED. Eighty percents were delivered by ambulance service. Over 90% visited ED within 12 hours after drinking. Half of them were classified as moderate or more severe alcohol intoxication level on visiting ED. The medical practice was significantly disturbed by some patients, who were restless, violent, or uncooperative with the medical stuffs. Seven patients attempted suicides during drinking before visiting ED. Two thirds of the patients were diagnosed as mild, and left ED after simple medical treatment. Only 6.5% were indicated to admission and the urgent operations were performed on three patients. The CAGE was obtained from 55 patients, and half of them were positive to two or more questions, indicating suffering from alcohol disorder. Half of the patients drank over 60g of alcohol in one day, and 61% drank in four or more days in one week. Result of the investigation of the drunken patients visiting ED reveals negative influence on emergency medical system. PMID- 22256593 TI - [Implications of nicotine detected in autopsy cases of newborn babies and infants from the perspective of social medicine]. AB - Smoking by pregnant and parturient women is generally suspected to increase nicotine levels in fetal and infant blood. Supportive data of nicotine levels in infants is, however, inadequate. We investigated blood and muscle nicotine and cotinine levels in 14 autopsy cases of newborn babies and infants using gas chromatography. Among the 14 cases investigated, nicotine or cotinine was detected in six cases (42.9%). In each of these six cases, the mother was a smoker. Route of exposure to nicotine originating from smoking was transplacental in three cases, via breast milk in one case and secondhand smoke in two cases. Nicotine and cotinine levels in blood from the two cases with placental exposure were 10.6-84.4 ng/ml and 20.3-183 ng/ml, and levels in muscle from one case were 43.9 ng/g and 308 ng/g, respectively. Nicotine and cotinine levels in blood from exposure via breast milk were 19.1 ng/ml and 87.1 ng/ml, and from secondhand smoke were 0 ng/ml and 14.6-20.1 ng/ml. Mean concentrations of blood nicotine and cotinine in 68 autopsy cases of adult habitual smokers were 30.0 ng/ml and 247 ng/ml. Our data for nicotine and cotinine levels in infant blood seem to indicate that some infants who are born and develop under exposure to smoking by family members, particularly the mother, may show high nicotine levels in blood and experience possible health risks. PMID- 22256594 TI - [Effects of autism features on alcoholism--especially from the aspect of recovery promoting factors]. AB - OBJECTIVE: It is important to evaluate and classify individual features of patients to select an appropriate treatment for alcoholism. In this study, we classified alcoholism types according to strength/weakness of autism features and investigated how these features were associated with onset, course, and especially continuation of abstinence. SUBJECTS AND METHODS: The subjects were 102 man outpatients diagnosed with alcoholism. The investigations were made on 3 areas: 1. Basic background including age, family and occupational information, 2. Medical variables including the number of years since the first visit, with/without juvenile onset, psychiatric complications, hospital admission history, self-help group participation, and the longest abstinence period, and 3. Autism-spectrum Quotient (AQ) scores. The AQ test is a self-administered test of autism features on a maximum scale of 50 points, based on the concept of "autism spectrum". RESULTS: The mean (standard deviation) of AQ scores of 102 subjects was 22.6 (7.18) with normal distribution. 78 subjects who had been followed-up for more than 2 years were classified into the low score (0-15) group of 11 subjects, the average score (16-29) group of 51 subjects, and the high score (30 50) group of 16 subjects, according to their AQ scores. No significant difference was observed in terms of patients' background and medical variables, but the number of subjects with stable abstinence (more than 2 years) was higher in the high score group compared to the average and low score groups (p = 0.0208). CONCLUSION: At least for men, it was presumed that continuation of alcohol abstinence was more difficult in the average score group (general type) and the low score group (over-empathy type) compared to the high score group (autism type) (odds ratio: 5.76); treatment approaches should be managed appropriately for these 3 types. It was also shown that the AQ test was a useful indicator for abstinence prognosis. PMID- 22256595 TI - [Results of 10-year cohort study on Japanese adolescent drinking]. AB - This article reports the first longitudinal cohort study on Japanese adolescent alcohol use and abuse from 1997 to 2007. The purpose of the cohort study is to show that factors which promote adolescent problem drinking, will develop into the early alcohol dependence syndrome. A total of 802 subjects with a mean age 13.5 years old was recruited from four junior high schools in Kanagawa prefecture. The survey was conducted annually by mail using self-reported questionnaires concerning drinking status and alcohol-related problems. In the 2007 survey at 10 years after the first survey, the respondents numbered 493 with a mean age of 23.8 years old, and the follow-up rate was 61.5%. In the 2007 survey, 25.2% of male and 14.3% of female subjects were found to be problem drinkers from the scores of the Alcohol Use Disorder Identification Test (AUDIT). We divided the subjects into two groups according to the AUDIT scores, problem drinkers and non-problem drinkers. The two groups were compared concerning family relationships, first drinking age and drinking status of parents with the respons es of the 1997 survey. A multiple regression analysis was performed to determine problem drink promoting factors. The factors determined were fathers with moderate to heavy drinking in male subjects and having drinking experiences at 13.5 years old at the start of the survey in female subjects. Furthermore, we confirmed a continuity of problem drinking from adolescents to young adults. Problem drinkers in the 2002 survey had significantly increased in the 2007 survey when compared with non-problem drinkers in the 2002 survey. We concluded that first drinking in junior high school and having moderate to heavy drinking fathers promote adult problem drinking, and problem drinking continued from adolescents to young adults. PMID- 22256596 TI - [Discovery and molecular function analysis of sulfur- and selenium-eliminating enzymes crucial for biosynthesis of iron-sulfur clusters and selenoproteins]. PMID- 22256597 TI - [Molecular mechanisms of synaptic plasticity underlying learning and memory]. PMID- 22256598 TI - [Regulation of Wnt-3a signaling and diffusion by sulfated glycosaminoglycans]. PMID- 22256599 TI - [Mechanism of pigment granule migration in Drosophila photoreceptors]. PMID- 22256600 TI - [Sortilin, sorting disorders, and life-style diseases]. PMID- 22256601 TI - [Metabolomics approach for enzyme discovery]. PMID- 22256602 TI - [Epigenetic regulation of transcription in heart development]. PMID- 22256603 TI - [Structural basis of the glutaminyl-tRNA synthesis in bacteria]. PMID- 22256604 TI - [Phospholipid scrambling by TMEM16F]. PMID- 22256605 TI - [Regulation of the adult brain function by Src family tyrosine kinases]. PMID- 22256606 TI - [Generation of high quality induced pluripotent stem cells]. PMID- 22256607 TI - [Neuronal development of the hyperdopaminergic animal model]. AB - Dopamine transporter knockout (DAT KO) mice exhibited hyperdopaminergic tone in the nucleus accumbens and striatum, whereas they showed normal levels of extracellular dopamine in the prefrontal cortex. DAT KO mice showed numerous behavioral alterations that can be linked to abnormal dopaminergic function, including hyperlocomotion, deficits of prepulse inhibition (1PI) and impairment of working memory. PPI deficits were also shown in schizophrenic patients and hyperlocomotion was observed in AD/HD patients; therefore DAT KO mice had face validity for these psychiatric disorders. Impairment of neuronal development such as brain volume loss and decrease in spine density was reported especially in the prefrontal cortex of schizophrenia and AD/HD patients. We therefore investigated the neuronal development of DAT KO mice. Our results indicated that DAT KO mice had deficits of neuronal development in the prefrontal cortex similar to schizophrenia and AD/HD patients at least in part. These findings suggest that DAT KO mice are one of the useful models to investigate the impairment of neuronal development observed in psychiatric disorders including schizophrenia and AD/HD. PMID- 22256608 TI - [PolyI:C-induced neurodevelopmental animal model for schizophrenia]. AB - Schizophrenia affects nearly 1% of the population and is clinically characterized by positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. affective flattening, apathy and social withdrawal) and cognitive dysfunction. Genetic susceptibility factors for schizophrenia, such as neuregulinl, dysbindin and disrupted-in-schizophrenia 1 (DISC1), have recently been reported, some of which play a role in neurodevelopment. Furthermore, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidylic acid (polyI:C), a toll-like receptor 3 ligand, induces a strong innate immune response. Maternal immune activation by polyI:C exposure in rodents induces a wide spectrum of behavioral and neurochemical abnormalities in adult offspring. We have reported that neonatal injection of polyI:C in mice results in schizophrenia-like behavioral abnormalities in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood, by injecting polyI:C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI:C-treated DN-DISC1 mice are a validated animal model for schizophrenia with gene-environment interactions. PMID- 22256609 TI - [Vulnerability of dopamine circuit development to cytokines from the periphery: implication in schizophrenia]. AB - Epidermal growth factor (EGF) and neuregulin-1 (NRG) belong to the ErbB ligand family and both exert neurotrophic actions on midbrain dopamine neurons. According to the immune inflammatory hypothesis for schizophrenia, we have established rodent models for this illness by exposing their neonates to these cytokines. At post-pubertal stage, these animals develop various neurobehavioral abnormalities such as prepulse inhibition (PPI) and social interaction deficits. In this review, we introduce neurochemical features of the EGF-treated rats and NRG-treated mice, which exhibit persistent increases in tyrosine hydroxylase levels and dopamine release in the globus pallidus and prelimbic cortex (medial prefrontal cortex), respectively. Local blockade of the hyperdopaminergic state in EGF-treated rats ameliorates their behavioral deficits. These findings suggest that development of the midbrain dopamine system is vulnerable to circulating cytokines at perinatal and/or prenatal stages and potentially influences schizophrenia risk or neuropathology. The dopamine hypothesis for schizophrenia is re-evaluated with the obtained results as well as with published literatures in this review. PMID- 22256610 TI - [Mouse model for human chromosome abnormality]. AB - Autism is a complex psychiatric illness which has received considerable attention as a developmental brain disorder. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice using chromosome engineering to generate a 6.3-Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display autistic behavioral features such as poor social interaction and stereotypical behavior, and exhibit abnormal ultrasonic vocalizations. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will be a founder mouse for forward genetics of autistic disease and an invaluable tool for its therapeutic development. I will present our analyses on these mice towards understanding the molecular pathophysiology of autism spectrum disorders. PMID- 22256611 TI - [Connectomics of orexin-producing neurons: analysis using mouse models]. AB - Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are hypothalamic neuropeptides that we discovered thirteen years ago. Initially, these peptides were recognized as regulators of feeding behavior. Subsequently, several studies suggested that orexin deficiency causes narcolepsy in humans and other mammalian species, highlighting roles of this hypothalamic neuropeptide in the regulation of sleep and wakefulness. Studies of efferent and afferent systems of orexin-producing neurons have shown that the orexin neuronal system has close interactions with systems that regulate emotion, energy homeostasis, reward, and arousal. These observations suggest that orexin neurons are involved in sensing the body's external and internal environments, and regulate vigilance states accordingly. PMID- 22256612 TI - [Application of pre-clinical PET imaging for drug development]. AB - Positron emission tomography (PET) is a sophisticated method for the quantitative and noninvasive imaging of biological functions by monitoring the delivery of tracers labeled with positron emitters (1C, 'aN, '"O, and 8F). The distribution and kinetic patterns of a labeled compound in relation to the specific biomolecule in the target tissue are assumed to reflect specific biological functions in the living body. A wide variety of labeled compounds as molecular probes have been developed to measure biochemical and physiological parameters, such as blood flow, glucose and oxygen metabolism, protein synthesis, and neurotransmitter receptor functions. Recently, PET has gradually been introduced into the research field of drug development both in pre-clinical and clinical stages. In the present chapter, the applications of animal PET with small animals (rats and mice) and non-human primates in drug development in the pre-clinical stage will be discussed based on our own experiences. In the course of drug development, the pre-clinical studies with experimental animals are indispensable, and these studies are expected to provide useful information to facilitate the development of drug candidates with more efficacy and fewer adverse effects in the clinical stage with PMID- 22256613 TI - [Approaches to the development of the Japanese academic version of the MATRICS Consensus Cognitive Battery]. AB - Cognitive impairment is related to functional outcome (e.g., work skills and community activities) in patients with schizophrenia; therefore, many researchers view these impairments as important treatment targets for psychopharmacological treatment. To stimulate the development of new treatments for cognitive impairments, the US National Institute of Mental Health's (NIMH's) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative developed a standard cognitive battery, i.e., the MATRICS Consensus Cognitive Battery (MCCB). In Japan, the MCCB has been initially translated as an academic version. This paper describes the process of developing the Japanese academic version and focuses on pilot studies on subtests of this battery. PMID- 22256614 TI - [Outcome studies of cognitive remediation for schizophrenia]. AB - Cognitive remediation purports to improve the cognitive dysfunction of schizophrenia, and has many forms. Eighty percent of people with schizophrenia suffer from cognitive dysfunction. The impact of cognitive dysfunction on everyday activity is widespread. Cognitive remediation as a non-pharmaceutical, psychosocial treatment modality for cognitive dysfunction has received attention as medical treatment has been able to make only limited gains. The ultimate goal of cognitive remediation is to improve the functional outcome. The increased interest in cognitive remediation resulted in numerous reports of outcome studies and meta-analysis. This paper reports different methods of cognitive remediation, evaluations of outcome studies, and various outcome indices. Cognitive remediation differs according to whether specific cognitions are targeted, and whether a method takes a compensatory or restorative approach. This paper briefly reviews methods of cognitive remediation which demonstrated their effect through RCT: IPT, NEAR, CET, and NET. Cognitive remediation often includes sessions that aim for transfer of the gained learning, such as verbal sessions or vocational skills training. Cognitive remediation is considered most effective when included as part of a comprehensive rehabilitation program. It is important to note that various studies report different outcome indices, control groups, and effect sizes in evaluating the effect of cognitive remediation. PMID- 22256615 TI - [Functional outcome in schizophrenia: relation to the MATRICS consensus cognitive battery]. AB - Functional outcome includes a wide range of abilities from successful performance on neurocognitive tests to managing independent living in the community. Assessment of functional outcome has been one of the main concerns in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), as it is supposed to mirror the cognitive improvement on the primary measure (i.e. MATRICS Consensus Cognitive Battery; MCCB) . The first step was to identify an optimal level of functional outcome; functional capacity was specified as co-primary measures for MCCB. Subsequently, appropriate co-primary measures were explored both in performance-based and interview-based approaches. To study a higher level of functional outcome, functional performance has also been considered, which predicts the ability of patients to adjust themselves to the community. Among the community functioning measures developed recently, the Modified SFS/SAS for MATRICS-PASS (Social Functioning Scale/Social Adjustment Scale for MATRICS-Psychonomic and Standardization Study) was introduced, based on its ability to predict social functioning in patients with schizophrenia. Finally, the author discussed several issues concerning the translation of functional outcome measures into non-English languages. PMID- 22256616 TI - [Schizophrenia Cognition Rating Scale Japanese version (SCoRS-J) as a co-primary measure assessing cognitive function in schizophrenia]. AB - The assessment of cognitive function is important for patients with schizophrenia because cognitive impairment is a core feature of the disease, and is a major determinant of functional outcome. To implement a practical assessment tool, we previously developed the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia that objectively measures cognitive domains relevant to outcome. Meanwhile, the U.S. Food and Drug Administration took the position that a drug to improve coghition should show changes on an additional measure (a co-primary), in addition to an accepted consensus cognitive performance measure that is considered functionally meaningful. Thus, four potential co-primary measures, two measures of functional capacity and two interview-based measures of cognition, were evaluated for psychometric properties and validity. The Schizophrenia Cognition Rating Scale (SCoRS) is one of the interview-based measures of cognition. It consists of 20 questions to measure attention, memory, reasoning and problem solving, working memory, language production, and motor skills, which are related to day-to-day functioning. University of California at San Diego Performance-Based Skills Assessment (UPSA) is one of the measures of functional capacity. For its clinical application, we developed the Japanese language version of the SCoRS (SCoRS-J) and UPSA (UPSA-J) through back translation into English. PMID- 22256617 TI - [Molecular mechanisms of the brain reward system]. AB - The brain possesses a reward system which produces positive emotion. To reveal the mechanisms of the brain reward system, investigation of mechanisms underlying actions of substances of abuse can be one of the promising research approaches. Various behavioral tests using animals and methods in genomic science are also useful for these studies. I introduce our findings obtained by these ideas and techniques as follows: (i) Inhibition of methamphetamine preference by G-protein activated inwardly rectifying potassium (GIRK) channel inhibitors. (ii) Essential role of NMDA receptor channel GluN2D subunit in phencyclidine effects on animal behavior. (iii) Association of polymorphisms in the mu-opioid receptor and GIRK genes with opioid sensitivity. PMID- 22256618 TI - [What does Reelin actually do in the developing brain?]. AB - In mammalian brains, most neuronal cells form a layer structure. This structure is established thorough correct migration of neuronal cells, and underlies proper functions of the brain. It is thus important to understand the molecular mechanism that regulates neuronal migration and layer formation. Reelin is a large secreted protein essential for neuronal migration and layer formation in mammals. Since its identification in 1995, a number of models and hypotheses have been proposed regarding Reelin function. However, tbe primary role of Reelin in the developing brain and its underlying molecular mechanism still remain unresolved. In this review, I try to summarize what is known and what we can infer about Reelin. I also mention why studying Reelin is difficult. PMID- 22256619 TI - Germophobia: the dilemma of hand washing and protection from germs. PMID- 22256620 TI - Mesotherapy. PMID- 22256621 TI - The problem with "depressed plaque". PMID- 22256622 TI - Skin needling in the treatment of the aging neck. AB - The aim of this study was to estimate the efficacy of skin needling in the treatment of the aging neck. Eight patients with aging necks were included in the study. Each patient was treated with 2 sessions of needling. The evaluation of treatment effectiveness was based on changes from baseline on the Global Aesthetic Improvement Scale, the Wrinkle Severity Rating Scale, photographic and ultrasonographic images, and silicone rubber microrelief impressions of a selected neck region before and after therapy. Analysis of the photographs, the degree of irregularity of the surface microrelief, and the ultrasound images showed that, after 2 sessions, the lesions' severity grade was reduced in almost 90% of the patients. The present study presents evidence for the efficacy of skin needling for the aging neck. PMID- 22256623 TI - General features and treatment of notalgia paresthetica. AB - Notalgia paresthetica is a neurocutaneous disorder that most commonly manifests as pruritus and a brownish macula in the patient's upper back. Pain, burning, and paresthesias to a variable degree have also been reported. Although the physiopathology of notalgia paresthetica is still obscure, it is currently considered a sensory neuropathy caused by damage to the spinal nerves. To date, no definitive treatment has been described for this disorder. Alternatives, including physical therapies and topical, systemic, and intralesional drugs, have been tested with diverse results. A review of the current knowledge on notalgia paresthetica and its treatment is provided. PMID- 22256624 TI - Nicotinamide in dermatology and photoprotection. AB - Nicotinamide (the amide form of vitamin B3) has been used in dermatology for more than 40 years for a diverse range of conditions including acne, rosacea, autoimmune bullous dermatoses, and now the treatment and prevention of photoaging and photoimmunosuppression. The broad clinical effects of nicotinamide may be explained by its role as a cellular energy precursor, a modulator of inflammatory cytokines, and an inhibitor of the nuclear enzyme poly(adenosine diphosphate ribose) polymerase-1, which plays a significant role in DNA repair, maintenance ofgenomic stability, and cellular response to injury including inflammation and apoptosis. This review outlines the use of nicotinamide for inflammatory dermatoses and photoaging and focuses on its emerging role in photoprotection. PMID- 22256625 TI - Historical diagnosis & treatment: scleroderma. PMID- 22256626 TI - Noninsulin-dependent, type II diabetes mellitus-related dermatoses: part III. PMID- 22256627 TI - Alcohol-based disinfectants irritate and damage skin more than ordinary soap- true or false? PMID- 22256628 TI - Segmental lesions in pityriasis rosea: a rare presentation. AB - A 34-year-old nonpregnant woman noted a mildly pruritic skin lesion on her right breast for 1 week following an episode of coryza, malaise, and low-grade fever of 3 days' duration. The latter symptoms subsided without any treatment. Ketoconazole cream prescribed by her family physician did not resolve the breast eruption after 1 week, so was stopped. A week later, multiple skin lesions erupted suddenly on her right chest wall starting near the herald patch in midaxillary line and spread distally until the midback. She then consulted the authors. She denied a history of abrasion or trauma to the affected areas. Travel, contact, sexual, and drug histories were unremarkable. She categorically denied past or family history of eczema, psoriasis, contact dermatitis, and drug eruptions. On examination, the initial lesion was an annular and well-demarcated erythematous plaque on her right breast in the upper outer quadrant. Multiple small oval scaly plaques were noted, extending distally along the ribs to the midline on her back, not crossing the midline, predominantly over the distribution of right T4 dermatome (Figure 1). Peripheral collarette scaling was noted (Figure 2). A few scattered small lesions were also noted in the vicinity of this dermatome. Three isolated small plaques were also present on the trunk, one in the supramammary area and the other two on the abdomen and back, respectively. Palmoplantar and mucosal surfaces were uninvolved. The rest of the skin and systemic examination revealed no abnormalities. Complete blood cell counts, fasting glucose, and urinalysis were normal. Venereal Disease Research Laboratory (VDRL) results were nonreactive and human immunodeficiency virus (HIV) antibodies were negative. Repeat testing ofVDRL in serial dilutions and HIV antibodies after 3 months were also nonreactive and negative, respectively. Scrapings from the initial large lesion and subsequent smaller eruptions did not show any evidence of fungal infection on potassium hydroxide smear examination. The patient declined skin biopsy; however, we thought that the most diagnostic label for this condition was pityriasis rosea. Hence, we treated her with triamcinolone acetonide ointment 0.025% to be applied twice daily and desloratadine tablet 5 mg daily for 10 days. The patient demonstrated complete resolution, leaving postinflammatory hypopigmentation. There was no recurrence until 1 year after complete remission. PMID- 22256629 TI - Neutrophilic dermatosis caused by azathioprine. PMID- 22256630 TI - Wells on natural selection: right for the wrong reason--described a giant congenital nevus. PMID- 22256631 TI - Propranolol as a novel addition to anti-Kaposi sarcoma armamentarium: a hypothesis. PMID- 22256632 TI - Rosette sign in dermatoscopy: a polarized finding. PMID- 22256633 TI - [Knee osteoarthritis treated with moxibustion: a randomized controlled trial]. AB - OBJECTIVE: To observe the efficacy of moxibustion on the improvement in pain, stiffness and motor disturbance for the patients with knee osteoarthritis (OA) and evaluate the effectiveness and safety of moxibustion therapy. METHODS: Fifty nine cases of knee OA were randomly divided into a moxibustion group (31 cases) and a placebo moxibustion group (28 cases), in which moxa cone and placebo moxa sticker were applied to Neixiyan (EX-LE 4), Dubi (ST 35) and Ashi points separately, 3 cones on each point in each treatment. The treatment was given once every two days, 3 times per week, continuously for 6 weeks. The follow-up visit was performed in 6 weeks after the end of treatment. The Western Ontario and Mcmaster Universities Osteoarthritis Index (WOMAC) and the time of 46-meter walking at the fastest speed were adopted to evaluate the recovery of joint function. UT-325 digital thermal detector was used to record the temperature change at the most apparent pain points of knee joint before and after moxibustion treatment. RESULTS: In moxibustion group, the scores in WOMAC were reduced apparently in 3 and 6 weeks treatment and during follow-up visit, separately (P < 0.05, P < 0.01, P < 0.001). In placebo moxibustion group, during follow-up visit, the score of stiffness was lower as compared with that before treatment (P < 0.05). In 6 weeks of treatment and during follow-up visit, the scores of pain, stiffness and motor disturbance in moxibustion group were reduced much more remarkably as compared with placebo moxibustion group (P < 0.01, P < 0.05). In moxibustion group, after treatment for 6 weeks,the time of 46-meter walking at the fastest speed was shorter apparently as compared with that before treatment (P < 0.01), but there was no apparent improvement after treatment in placebo moxibustion group (P > 0.05). The difference was not significant statistically in group comparison (P > 0.05). After moxibustion, the temperature at treatment point was (49.81 +/- 3.10) degrees C in moxibustion group and was (40.98 +/- 1.67) degrees C in placebo moxibustion group. The local skin temperature increased apparently as compared with that before treatment in either group (P < 0.001, P < 0.01), but the temperature increasing in moxibustion group was much more remarkable (P < 0.001). CONCLUSION: Moxibustion can obviously improve in the clinical symptoms for the patients with knee osteoarthritis, such as pain, stiffness and motor disturbance. It is a safe and effective therapy. PMID- 22256634 TI - [Knee osteoarthritis treated with acupuncture at the points selected according to syndrome differentiation: a randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy difference between acupuncture and western medication in the treatment of knee osteoarthritis. METHODS: One hundred and twenty cases were randomly divided into an acupunc ture group and a western medication group, 60 cases in each group. In acupuncture group, acupuncture was applied mainly to Neixiyan (EX-LE 4), Dubi (ST 35), Yinlingquan (SP 9) and Yanglingquan (GB 34) and to the other acupoints selected according to syndrome differentiation. In western medication group, Glucosamine Hydrochloride capsules were applied for oral administration, 2 capsules each time, 3 times per day. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36, Chinese version) were used to assess the therapeutic effect before treatment, after 4 weeks treatment and in follow-up visit of 9 weeks after treatment separately. RESULTS: After 4 weeks treatment, the total effective rate was 86.7% (52/60) in acupuncture group and was 88.3% (53/60) in western medication group, indicating no statistical significant difference in the comparison between two groups (P > 0.05). In 9 weeks after treatment, the total effective rate was 83.3% (50/60) in acupuncture group, which was better than 61.7% (37/60, P < 0.05) in western medication group. The scores of WOMAC and SF-36 were all improved after treatment as compared with those before treatment in two groups (P < 0.05, P < 0.01). There were no significant differences in comparison between two groups after 4 weeks treatment (all P > 0.05). But, in follow-up visit of 9 weeks after treatment, the scores of WOMAC and SF-36 in acupuncture group were superior to those in western medication group (P < 0.05, P < 0.01). CONCLUSION: The short-term efficacies on osteoarthritis of knee in acupuncture group according to syndrome differentiation are similar to that of oral adiministration of Glucosamine Hydrochloride, but the long-term efficacy in acupuncture group is better than that in western medication group. PMID- 22256635 TI - [Efficacy observation of Thoroughfare Vessel theory in acupuncture for post stroke dysphasia]. AB - OBJECTIVE: To compare the difference in the efficacy on post-stoke dysphagia between the point selection according to Thoroughfare Vessel theory and conventional point selection in treatment. METHODS: Seventy-eight patients were randomly divided into an observation group (n = 42) and a control group (n = 36). In observation group, acupuncture was applied to the acupoints selected according to Thoroughfare Vessel theory such as Dazhu (BL 11), Shangjuxu (ST 37), Xiajuxu (ST 39), Neiguan (PC 6) and Gongsun (SP 4) Mainly. In control group, acupuncture was applied to the conventional acupoints such as Fengchi (GB 20), Lianquan (CV 23), Tiantu (CV 22), Neiguan (PC 6) and Zusanli (ST 36), etc. Acupuncture was given once per day in either group, 12 treatments made one session and 4 sessions of treatment were required. The water swallow test was adopted to assess the swallowing function in two groups. RESULTS: The effective rate was 100.0% (42/42) in observation group and was 77.8% (28/36) in control group. The efficacy in observation group was superior to control group (P < 0.05). The curative time was (28.65 +/- 10.42) days in observation group and was (38.74 +/- 21.30) days in control group. The time was shorter apparently in observation group as compared with control group (P < 0.05). CONCLUSION: The Thoroughfare Vessel theory in acupuncture treatment for post-stroke dysphasia achieves a superior efficacy as compared with the conventional acupoint selection, and this theory may quickly determine the point prescription in treatment. PMID- 22256636 TI - [Senilis pruritus treated with pricking method combined with cupping]. PMID- 22256637 TI - [Long-term efficacy and safety research on functional dyspepsia treated with electroacupuncture and Zhizhu Kuanzhong capsule]. AB - OBJECTIVE: To observe the long-term efficacy and safety on functional dyspepsia treated with electroacupuncture and Zhizhu Kuanzhong capsule and explore the therapeutic mechanism. METHODS: Three hundreds and twenty patients with confirmed diagnosis as functional dyspepsia were randomly divided into 4 groups: an electroacupuncture group, a Zhizhu Kuanzhong capsule group, a combined therapy group and a western medication group, 80 cases in each group. In electroacupuncture group, acupuncture was applied to Zusanli (ST 36), Zhongwan (CV 12), Neiguan (PC 6), Taichong (LR 3) and Gongsun (SP 4), twice per day, continuously for 5 days each week. In Zhizhu Kuanzhong capsule group, Zhizhu Kuanzhong capsule, 1.29 g was administered for oral application, three times each day. In combined therapy group, the therapeutic programs in the above-mentioned groups were applied in combination. In western medication group, Mosapride 5 mg, three times per day; Omeprazole 20 mg, twice per day and Amitriptyline 25 mg, twice per day were administered for oral application. Six weeks treatment was required in each group. The symptoms score, the Nepean Dyspepsia Symptom Index (NDSI), the Nepean Dyspepsia Life Quality Index (NDLQI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), electrogastrography, plasma motilin, gastric emptying by B-sonography and adverse reactions were observed before and after treatment, as well as 4 weeks after treatment separately. RESULTS: Compared with those before treatment, the symptom score and NDSI decreased apparently after treatment (all P < 0.01), NDLQI, SF-36, electrogastrographic frequency, plasma motilin and gastric emptying were up-regulated apparently (all P < 0.01) after treatment in each group. The results of the above-mentioned indices in combined therapy group were superior to the other groups (all P < 0.05). As compared with the condition at the end of treatment, in 4 weeks after treatment, the above indices were not rebound apparently in electroacupuncture group and combined therapy group (all P > 0.05). But they were rebound obviously in Zhizhu Kuanzhong capsule group and western medication group (all P < 0.05). The short term and long-term efficacies in combined therapy group were significantly higher than the total effective rates in the other groups (P < 0.05, P < 0.01). No serious adverse reaction was reported in each group. CONCLUSION: Electroacupuncture and Zhizhu Kuanzhong capsule all up-regulate plasma motilin and electrogastrographic frequency, promote gastric emptying, alleviate the symptom of functional dyspepsia and improve NDLQI. But the combined medication achieves much better efficacy and presents better safety and long-term therapeutic effect. PMID- 22256638 TI - [Comparative study on therapeutic effect of Ashi-points and anti-ashi-points on external humeral epicondylitis]. AB - OBJECTIVE: To compare the clinical efficacy between Ashi-points and anti-Ashi points for external humeral epicondylitis. METHODS: Sixty-eight cases were randomly devided into an anti-Ashi-points group (group A) and an Ashi-points group (group B), 34 cases in each group. In the group A, anti-Ashi-points (points of pain relief or disappearance after local press) were selected for acupuncture; in the group B, Ashi-points (pain spots) were selected for acupuncture and surrounded needling therapy was added . Once other day, 10 treatments made one session, altogether 2 courses. The clinical effects were observed at the ending day, the 7th day, the 30th day, the 6th months and one year after treatment. RESULTS: The effective rates at the ending day, the 7th day, the 30th day after treatment in the group A were 100.0% (34/34), 94.1% (32/34) and 91.2% (31/34), which were superior to those of 73.5% (25/34), 70.6% (24/34), 67.6% (23/34) respectively in group B (all P < 0.01). In the group A, the effective rates at the 6 th months and one year after treatment were 73.5% (25/34) and 52.9% (18/34); in group B, they were 64.7% (22/34) and 61.8% (21/34) respectively, there were no significant differences between the two groups (both P > 0.05). CONCLUSION: The acupoint selection of anti-Ashi-points has a better transient effect on external humeral epicondylitis, but it's long-term curative effects is similar to Ashi-points. PMID- 22256639 TI - [Observation on therapeutic effect of child amblyopia treated with auricular point sticking therapy]. AB - OBJECTIVE: To compare the differences in the therapeutic effect on child amblyopia between auricular point sticking therapy and routine complex treatment. METHODS: Two hundreds and thirty cases of amblyopia were randomly divided into an observation group and a control group, 120 cases (212 eyes) were in the observation group and 110 cases (194 eyes) were in the control group. The observation group was treated with auricular point sticking therapy. The main points were Yan (eye), Shenmen, Gan (liver), Pi (spleen) and Shen (kidney), etc. The control group was treated with routine complex treatment, such as wearing glasses, shade therapy and family refined performance therapy. The changes of vision were observed after treatment in the two groups. The follow-up was 3 years. RESULTS: The effective rate was 81.0% (64/79) in the observation group of ametropic amblyopia and 52.2% (36/69) in the control group. The effective rate was 73.1% (49/67) in the observation group of anisometropic amblyopia and 47.7% (31/65) in the control group. The effective rate was 71.2% (47/66) in the observation group of strabismic amblyopia and 45.0% (27/60) in the control group. The therapeutic effect of the observation group was superior to that of the control group (all P < 0.05). CONCLUSION: Auricular point sticking therapy can obviously improve child visual acuity with simple manipulation. PMID- 22256640 TI - ["Confusion of thinking" in Miraculous Pivot and its clinical significance]. PMID- 22256641 TI - [Sixty-three cases of cervical headache treated with electroacupuncture at Ashi points combined with independent movements]. PMID- 22256642 TI - [Analysis on resistance testing and technological research of acupoints]. AB - In order to summarize and analyze the progresses and problems of resistance testing and technology research on acupoints, investigate the related solutions, articles on resistance testing from 1990 to 2011 were collected, and advantages and shortcomings of different types of testing instruments were discussed in this article as well. Detection technology of acupoint impedance has under updating changes, which are often applied on locating acupoints and clinical diagnosis. The progresses of those technologies are mainly embodied in improvement of circuit model, which enable a longer testing duration, less media interference and so on. The previous studies often focus on resistance testing of the skin. Since dermal resistance does not equal to acupoint resistance, the designation of equivalent circuit does not embody the condition of cells, tissues and nerves at acupoints, and testing technology is often affected by factors such as polarization of electrodes, contact medium and anatomical characteristics of acupoints, the resistance of acupoints can not be taken as the effective framework of the diagnostic standard and judgement of therapeutic effect in clinic. Based on the key problems in resistance testing of acupoints, it is proposed by the article that the techniques and designation of circuit model should be reformed, and mathematical model should be established in the study to meet the requirement of the life system. Inductance of human body should be considered in resistance research of acupoints, and interference factors should be eliminate as far as possible in designation of equipments. Thus, the change law of acupoint resistance in the inner part of the body can be fully embodied by the designation of experiments. PMID- 22256643 TI - [Case of sequela of intramedullary spinal cord cavernous angioma after operation]. PMID- 22256644 TI - [Present study on antagonistic effect of acupoints compatibility]. AB - Compatibility of acupoints is an important component of acupuncture prescription, and it is the key point to achieve the therapeutic effect of acupuncture. Antagonism and synergism are held as two possible results of acupoints compatibility. Recent literatures are summarized and analyzed in this article. And clinical trials and laboratorial studies indicate that antagonism is a result of acupoints compatibility. However, since the relative studies are not enough, extensive attentions are not aroused among researchers. Therefore, in the future studies, based on specificity of acupoints, interdisciplinary research methods should be adopted to explore the effect of antagonism of acupoint compatibility on enhancing the clinical therapeutic effect and expound the mechanism of acupuncture and moxibustion. It is considered to be a significant topic which is worth to be deeply studied. PMID- 22256645 TI - [Chilblain treated by ginger-separated moxibustion in summer]. PMID- 22256646 TI - [Digital visualization construction and research on Jiuwei (CV 15)]. AB - OBJECTIVE: To establish the digitized visible human with Jiuwei (CV 15) involved. METHODS: With the virtual Chinese human (VCH) datasets and three-dimensional modeling software adopted, the knowledge on acupuncture and moxibustion as well as acupoint anatomy combined and the computer image processing software applied, the visualized browser software of Jiuwei (CV 15) was established. RESULTS: By establishing the interactive three-dimensional visualization browser software of acupoints, the location of Jiuwei (CV 15) was enabled to be expressed directly from all the levels, as well as the main adjacent tissue structure. It was suggested that Jiuwei (CV 15) should be punctured obliquely downward to avoid injuring the vital organs such as the heart and liver, and the safe depth of insertion should be 1.0-1.5 cm. CONCLUSION: The technology of digital visible human enables the three-dimensional expression of acupoint, which can be the platform of the digital teaching pattern. The research on the angle and depth of needling insertion at acupoint can be conducted in combination with teaching materials. PMID- 22256647 TI - [Bilateral bleeding at achilles tendon for infantile aphthae]. PMID- 22256648 TI - [Effect of pre-electroacupuncture at "Zusanli" (ST 36) on DA and 5-HT contents and their ratio in hypothalamus and striatum in exercise rats]. AB - OBJECTIVE: To observe anti-fatigue effect and mechanisms of pre electroacupuncture (EA) at "Zusanli" (ST 36) in rats undergoing acute treadmill running. METHODS: Fifty male SD rats were randomly divided into three groups: a quiet group (group Q, n = 10), a model group (group M, n = 20) and an EA preconditioning group (group EAP, n = 20). After adaptation for undergoing treadmill running, all the rats in group M and group EAP were trained on acute treadmill running. Besides, EA with continuous waves, 2 Hz in frequency and 2 mA in intensity was applied at bilateral "Zusanli" (ST 36) for 30 min, which was applied once daily for continuous 6 days before treadmill running for the rats in Group EAP. Plasma lactate contents were measured immediately and 3 hours after treadmill running, respectively. Changes of dopamine (DA) and serotonin (5-HT) contents obtained immediately and 3 hours after treadmill running, respectively, in hypothalamus and striatum, were detected and compared, and DA/5-HT ratios were calculated. RESULTS: Compared with group Q, the levels of blood lactate and hypothalamic 5-HT tented to increase in rats of group M, and the contents of hypothalamic DA increased significantly (P < 0.01), while the contents of striatal DA and 5-HT in group M decreased significantly (both P < 0.01) at 3 h after treadmill running. Immediately after treadmill running, the contents of DA and 5-HT increased significantly in hypothalamus (both P < 0.01), but decreased significantly in striatum (both P < 0.01) in group EAP, compared with those in group M. Moreover, EA pretreatment markedly decreased the levels of blood lactate (P < 0.05) and hypothalamic 5-HT (P < 0.01), and obviously elevated the ratio of DA/5-HT in the hypothalamus (P < 0.01) at 3 h after treadmill running. CONCLUSION: Preventive EA at "Zusanli" (ST 36) can accelerate recovery from fatigue, which may be related to its reducing accumulation of blood lactate, elevating DA/ 5-HT ratio in the hypothalamus of the rats undergoing treadmill running. PMID- 22256649 TI - [Analgesic and anti-inflammatory effects of balance acupuncture on experimental scapulohumeral periarthritis in rabbits]. AB - OBJECTIVE: To investigate therapeutic effects of balance acupuncture on scapulohumeral periarthritis (SP)and the mechanisms. METHODS: Thirty male New Zealand rabbits were randomly divided into a blank group (group B), a model group (group M) and a balance acupuncture group (group BA) with 10 rabbits in each group. SP model was established by using persistent mechanical strain and ice compress. Balance acupuncture at "Jiantong" point was applied in the animals in group BA, but not in the rabbits of the other two groups. Joint movement and pathological changes in tissues around the affected shoulder joint were observed, and interleukin-1beta (IL-1beta), 5-hydroxytryptamine (5-HT) in plasma and the affected surrounding tissues, and DNA contents in tendon of supraspinatus muscle were measured. RESULTS: The content of plasma 5-HT in group BA [(18.16 +/- 4.44) ng/mL] was significantly lower than that in group M [(23.28 +/- 5.89) ng/mL] (P < 0.05), but without obvious difference in IL-1beta content between the two groups (P > 0.05). Compared with group M, the contents of IL-1beta, 5-HT in affected surrounding tissues, and DNA expression in tendon of supraspinatus muscle were significantly lowered to va rious extent in group BA (P < 0.01, P < 0.05). CONCLUSION: Balance acupuncture can effectively improve local and systemic pathological situation induced by SP by way of reducing pain-producing factors, inflammatory factors and DNA expression to alleviate local organization and adhesions in rabbits with experimental SP. PMID- 22256650 TI - [Acupotomology: returning to the ancients and innovation of acupuncture]. AB - Acupotomology is a technique of percutaneous minimally invasive soft tissue releasing. It can be found in traditional acupuncture, but is deemphasized in modern times. Therefore, the development of acupotomology is held as restoring of ancient ways of acupuncture. Compared with traditional acupuncture, acupotomology makes modern interpretations on the theory of muscle regions, absorbs theories of anatomy and pathology as well as techniques of asepsis and anaesthesia. It improves traditional needling tool. Therefore, it is also held as an innovation of acupuncture. The development of acupotomology makes up for the deficiency of acupuncture study. It. will promote the differentiation and crossing of acupuncture discipline, and become a new trend of acupuncture. PMID- 22256651 TI - [Study on acupoints selection of anorectal diseases]. PMID- 22256652 TI - [Acute infantile diarrhea treated with infantile Tuina: a multicentre randomized controlled trial]. AB - OBJECTIVE: To generalize the application of Tuina in treating infantile diseases and evaluate the validity and safety of Tuina. METHODS: By a multicentre randomized controlled study, 240 patients were randomly divided into an observation group (n = 180) and a control group (n = 60). The observation group was treated by tonifying Pijing and clarifying Dachangjing, and Tuina on Lanmen, Qi, Fu Shangqijiegu, Guiwei and Zusanli (ST 36), etc. Banmen and Sanguan were used as the supplementary point according to the syndrome differentiation. The control group was treated by oral administration of Smecta. After 5 day treatments, Chinese syndrome score and the clinical effect were evaluated. RESULTS: After the third and fifth treatment, the Chinese syndrome score of both groups descended obviously. The decline of the observation group was superior to that of the control group (all P < 0.01). The cured rate of 75.6% (136/180) in the observation group was better than 21.7% (13/60) in the control group (P < 0.001). The clinical cured rate of 95.0% (171/180) according to Chinese syndrome score in the observation group was better than 58.3% (35/60) in the control group (P < 0.001). There was no adverse reaction in both groups. CONCLUSION: Infantile Tuina has a better therapeutic effect in the treatment of acute infantile diarrhea than oral administration of Smecta. PMID- 22256653 TI - [Chronic headache treated with acupuncture, Chinese massage and herbal medicine in Switzerland]. AB - OBJECTIVE: To observe the therapeutic effect of Chinese medicine on chronic disease in foreign country. METHODS: Forty-two cases of chronic headache were treated with acupuncture, Chinese massage and herbal medicine in Switzerland. The efficacy assessment was performed for the symptom score and the physical and mental improvements by the patients themselves before and after treatment. RESULTS: The total effective rate of symptom scores was 85.7% (36/42) and the total effective rate of the self-assessment was 88.1% (37/42). CONCLUSION: Chinese medicine achieves a significant and sustainable efficacy on chronic headache, which is similar to the effect of western medication. The Swiss patients with chronic headache much prefer to Chinese medical therapy. PMID- 22256654 TI - [U. S. acupuncturists qualification tests of clean needle technique (CNT) examination]. AB - Clean needle technique (CNT) examination is required for all applicants seeking National Certification Commission for Acupuncture and Oriental Medicines' (NCCAOM) certification. CNT examination is one of compulsory subjects of certification of professional competence to practice acupuncture safely and effectively for the sake of the health and safety of the public, which is developed by the Council of Colleges of Acupuncture and Oriental Medicine (CCAOM). The uniform standard of practice for acupuncture, the content of CNT course, application procedure and the requirements of CNT examination are introduced in this paper. PMID- 22256655 TI - [Acute tonsillitis treated by blood-letting at Shaoshang (LU 1)]. PMID- 22256656 TI - [Early morphological concepts of acupoint]. AB - The idea of acupoint in Internal Classic was investigated in this article. And it is held that obvious morphological features, including sunk surfaces, joint caves, gaps between muscles, collate-rals, pulses, blocked tendons and tenderness at the surface of the body can be found at where acupoints locate. The morphological characters of acupoint conform to its original meanings. To locate acupoints by their morphological features provides evidence basis for point locating in clinic, which is considered to be favourable for clinical practice. Since locations of acupoints gradually fixed in later ages, which take proportional measurement as the main method, acupoint locating is also gradually divorced from their early concepts and practice. PMID- 22256657 TI - [Constitution identification and treatment with acupuncture-moxibustion for menopausal women]. AB - According to the theory of constitution and disease prevention of Chinese medicine, kidney deficiency, lack of nourishment of the Thoroughfare Vessel and the Conception Vessel as well as qi sufficiency and blood deficiency are taken as the main features of body constitutions of women during menopausal period. Acupuncture-moxibustion treatment before or in the early stage of menopausal period are discussed initially. Methods of tonifying the kidney and regulate qi and blood are held as the main treating principles. Acupuncture points such as Sanyinjiao (SP 6), Shenshu (BL 23), Guanyuan (CV 4) and Baihui (GV 20) are adopted as the main points. And proper stimulation of needling and moxibustion are applied. Thus, a new way of thinking is provided for disease prevention and health keeping of women during menopausal period in China. PMID- 22256658 TI - [Summery and recommendations for acupuncture for peripheral facial paralysis]. AB - Articles on acupuncture for peripheral facial paralysis were picked up from CNKI database. The retrieved original studies were evaluated and summarized. The problems of acupuncture for peripheral facial paralysis were analyzed, and concrete solutions were proposed. Problems that differential diagnosis, prognosis, treatment of severe facial paralysis, and identification of sequelae and compliation were not embasized in clinical treatment of facial paralysis. Consequently, the effectiveness of acupuncture for peripheral facial paralysis will be improved by sloving above problems. PMID- 22256659 TI - [Meridians and acupoints with opposite locations]. AB - A new combination of acupoints with opposite locations in clinic was proposed according to the running course of meridians and the relation between meridians and acupoints in order to enrich the theory of acupuncture-moxibustion and enhance the therapeutic effect. Points with opposite location refers to bigeminal acupoints locates at the medial and lateral aspects of the limbs or at the anterior or posterior aspects of the trunk, such as Neiguan (PC 6) and Waiguan (TE 5), Quchi (LI 11) and Shaohai (HT 3) as well as Yinlingquan (SP 9) and Yanglingquan (GB 34). Those pairs of points locate respectively at yin meridians and yang meridians with opposite locations or at meridians interiorly and exteriorly related with each other. The application of the combination and the therapeutic effects can be found both in ancient and modern time. Its theoretical foundation rests with the theory of yin-yang and meridians, which takes yin-yang as the core. The characteristics of the combination are as the follows: firstly, it can regulate yin and yang, qi and blood at the same time. Secondly, yin and yang can influence each other; it is easy to locate the other point when one of the pair is located, and it is easy to manipulate by needling two points oppositely at the same time or doing through-and-through needling. The technique is also known with its selection of less point but better effect. PMID- 22256660 TI - [Systematic review of randomized controlled trials of acupuncture for glaucoma]. AB - OBJECTIVE: To assess the efficacy of acupuncture for glaucoma. METHODS: The search was conducted through database to identify randomized controlled trials of acupuncture for glaucoma until September 2010. The quality assessment, data extraction and Meta-analysis were performed by Cochrane Handbook for Systematic Re views of Interventions. RESULTS: Eight articles were included. Meta-analysis showed that acupuncture did not decrease intraocular pressure compared with eye drops [SMD = -0.1 66, 95% CI (-1.45, 0.13)]. However, acupuncture increased the effectiveness rate of treatment for glaucoma [OR = 4.45, 95% CI (1.96,10.09)]. Compared with placebo, acupuncture did not decrease intraocular pressure 20 min after acupuncture (P = 0.13) and 24 hours after acupuncture (P = 0.21). Nonetheless, acupuncture increased the effectiveness rate of treatment for glaucoma [OR = 45.00, 95% CI (9.73, 208.08)]. Compared with acupuncture, quantitative acupuncture manipulation increased the effectiveness rates of treatment for glaucoma [OR = 2.23, 95% CI (1.14, 4.36)]. CONCLUSION: Acupuncture therapy has potential to increase effectiveness rates of treatment for glaucoma. It lacks reliable evidence to prove that acupuncture decreases intraocular pressure. More trials with high quality are needed to estimate adverse effects and cost effectiveness of acupuncture therapy. PMID- 22256661 TI - Meeting the four-hour deadline in an A&E department. AB - PURPOSE: Accident and emergency (A&E) departments experience a secondary peak in patient length of stay (LoS) at around four hours, caused by the coping strategies used to meet the operational standards imposed by government. The aim of this paper is to build a discrete-event simulation model that captures the coping strategies and more accurately reflects the processes that occur within an A&E department. DESIGN/METHODOLOGY/APPROACH: A discrete-event simulation (DES) model was used to capture the A&E process at a UK hospital and record the LoS for each patient. Input data on 4,150 arrivals over three one-week periods and staffing levels was obtained from hospital records, while output data were compared with the corresponding records. Expert opinion was used to generate the pathways and model the decision-making processes. FINDINGS: The authors were able to replicate accurately the LoS distribution for the hospital. The model was then applied to a second configuration that had been trialled there; again, the results also reflected the experiences of the hospital. PRACTICAL IMPLICATIONS: This demonstrates that the coping strategies, such as re-prioritising patients based on current length of time in the department, employed in A&E departments have an impact on LoS of patients and therefore need to be considered when building predictive models if confidence in the results is to be justified. ORIGINALITY/VALUE: As far as the authors are aware this is the first time that these coping strategies have been included within a simulation model, and therefore the first time that the peak around the four hours has been analysed so accurately using a model. PMID- 22256662 TI - Steering whilst rowing: governing and managing health services from the centre. AB - PURPOSE: The article seeks to explore the practical and theoretical implications of the ways in which senior figures in the National Health Service (NHS) interpret the role of the centre in relation to the delivery units of the health service. This is important in the light of recent plans for reorganisation of the NHS advanced by the new Conservative-Liberal coalition government. DESIGN/METHODOLOGY/APPROACH: The article is based on interviews with civil servants and NHS staff at senior levels in the centre and in the strategic health authorities (SHAs). FINDINGS: It is found that, in practice, despite numerous attempts to separate out policy making from implementation/management, the two continue to be closely coupled and intertwined. Central staff and regional officials are found to be both steering and rowing. RESEARCH LIMITATIONS/IMPLICATIONS: Only a small selection of senior officials at the centre and only a small proportion of SHA senior managers and directors were interviewed. PRACTICAL IMPLICATIONS: The implications are far-reaching. Unless special steps are taken, it seems likely that these senior officials, despite the creation of some new institutions and the curtailment of others, will continue to behave in broadly similar ways to those described here. ORIGINALITY/VALUE: Empirical studies of the thinking, assumptions and behaviour of very senior officials in the health service are rare. The analysis in this paper explores the organisational conditions that shape the actions of these senior players. PMID- 22256663 TI - Managing cultural diversity in healthcare partnerships: the case of LIFT. AB - PURPOSE: The National Health Service (NHS) Local Improvement Finance Trust (LIFT) programme was launched in 2001 as an innovative public-private partnership to address the historical under-investment in local primary care facilities in England. The organisations from the public and private sector that comprise a local LIFT partnership each have their own distinctive norms of behaviour and acceptable working practices - ultimately different organisational cultures. The purpose of this article is to assess the role of organisational culture in facilitating (or impeding) LIFT partnerships and to contribute to an understanding of how cultural diversity in public-private partnerships is managed at the local level. DESIGN/METHODOLOGY/APPROACH: The approach taken was qualitative case studies, with data gathering comprising interviews and a review of background documentation in three LIFT companies purposefully sampled to represent a range of background factors. Elite interviews were also conducted with senior policy makers responsible for implementing LIFT policy at the national level. FINDINGS: Interpreting the data against a conceptual framework designed to assess approaches to managing strategic alliances, the authors identified a number of key differences in the values, working practices and cultures in public and private organisations that influenced the quality of joint working. On the whole, however, partners in the three LIFT companies appeared to be working well together, with neither side dominating the development of strategy. Differences in culture were being managed and accommodated as partnerships matured. RESEARCH LIMITATIONS/IMPLICATIONS: As LIFT develops and becomes the primary source of investment for managing, developing and channelling funding into regenerating the primary care infrastructure, further longitudinal work might examine how ongoing partnerships are working, and how changes in the cultures of public and private partners impact upon wider relationships within local health economies and shape the delivery of patient care. ORIGINALITY/VALUE: To the authors' knowledge this is the first study of the role of culture in mediating LIFT partnerships and the findings add to the evidence on public private partnerships in the NHS. PMID- 22256664 TI - Integrating or disintegrating effects of customised care: the role of professions beyond NPM. AB - PURPOSE: This paper aims to describe the integrating and disintegrating effects of professional actions in customised care. DESIGN/METHODOLOGY/APPROACH: Using a qualitative case study, the authors examine the work practices and cultures of three Swedish child and adolescent psychiatric care units (CAP) charged with providing customised care in collaboration with other organisations. The authors conducted 62 interviews, made 11 half-day observations, and shadowed employees for two days. FINDINGS: The social embeddedness of action is crucial to understanding the professions' integrating/disintegrating activities. In the internal social context of CAP, the professions adapt to productivity-enhancing new public management (NPM) principles, resulting in integrating effects between the different professions and administrative management in the CAP units. However, CAP exercises professional dominance over the cooperating organisations. Thus, in the external social context, CAP's resistance to customised care principles exacerbates the disintegration problems among the different organisations. PRACTICAL IMPLICATIONS: The study concludes that, contrary to findings in many other studies, neither the professional logic nor NPM/customised care reforms determine the actions of professionals. In this case, the institutionalisation of some NPM methods blocks the adoption of customised care practices. ORIGINALITY/VALUE: Contrary to the widely accepted idea that resource restriction is a main source of conflict between management and the professions, the professions accept and adapt to resource restrictions, even at the expense of de-emphasising the practices of customised care. Thus, since professionals choose different operational strategies depending on the social context, the success of a normative reform measure may depend in part on its social context. PMID- 22256665 TI - Managing professionals: exploring the role of the hospital HR function. AB - PURPOSE: The purpose of this paper is to consider the role of the HR function in the management of professional and non-professional staff in the acute hospital sector. DESIGN/METHODOLOGY/APPROACH: A qualitative approach was adopted. Empirical data from three hospital case studies is utilised to explore the role of the hospital HR function. Cases were compiled from 45 interviews, observation and secondary data analysis. FINDINGS: The paper finds that in two of the three cases the human resource (HR) function predominantly provides services to non professional workforce groups. However, the effective and strategic management of professionals is undertaken in the third case, without a professional HR function. RESEARCH LIMITATIONS/IMPLICATIONS: The findings of this paper require some caution in extrapolation, being based on research in one national context. The authors suggest the delivery of service as a useful lens to explore the enacted practice of HRM in hospitals. PRACTICAL IMPLICATIONS: The paper draws attention to a significant deficit in the role of the HR function in managing core professional staff. ORIGINALITY/VALUE: The paper applies an existing conceptual framework to explore the role of the HR function in hospitals. It identifies a significant deficit in the management of core professional staff. On this basis the paper suggests alternative research methodologies to investigate the management of all hospital staff. PMID- 22256666 TI - Job and career influences on the career commitment of health care executives: the mediating effect of job satisfaction. AB - PURPOSE: While there is considerable evidence supporting the relationship between job satisfaction and organizational commitment, the relationship between the antecedents of job satisfaction, organizational commitment and career commitment are not clearly understood. This study seeks to clarify whether these antecedents have an effect independent of job satisfaction on career commitment or whether these antecedents are mediated by job satisfaction. DESIGN/METHODOLOGY/APPROACH: In total, 2,799 questionnaires were mailed out to members of the American College of Healthcare Executives (ACHE). The responses received were 643 (22.9 percent) and after eliminating retirees or students, a sample of 456 respondents currently employed in the health care industry was obtained. Path analysis was conducted to test the hypothetical relationships between work situation, career experiences and career commitment. FINDINGS: It was found that job satisfaction mediated the influences of job tenure and career pattern on career commitment. Job satisfaction partially mediated the influences of perceived job security and one's satisfaction with career on career commitment. Both of these measures had a direct influence on career commitment. Career experience such as sector change was also positively associated with career commitment. RESEARCH LIMITATIONS/IMPLICATIONS: While the research offers some insights into the factors affecting the career commitment of health care executives, the sample was limited to respondents who were members of the American College of Healthcare Executives, and thus may not represent the views of all managers in the health care sector. PRACTICAL IMPLICATIONS: To retain high-valued health care workers it is important that an organization has a work environment that enhances their commitment to their occupation as well as their careers. ORIGINALITY/VALUE: This study clarifies the influence of job satisfaction on the career commitment of health care managers during a very dynamic period. PMID- 22256667 TI - Design and evaluation of a public installation of an eye-gaze system. AB - This article evaluates an eye-tracking device ("I Can Speak With My Eyes") designed for a museum exhibition. An eye-tracking system is designed not only for able individuals, but also for bedridden patients or physically handicapped people who intend to use computers. With one video CCD camera and frame grabber analyzing a series of images taken of the human pupil gazing at a screen, an auto range-finding algorithm can be used to obtain the location of the pupil in real time. The computers will produce speech according to the location of where the eyes are gazing. In essence, the participants can speak with their eyes to achieve the advantages of learning and communicating. After the system was implemented, an experimental evaluation with innovation diffusion theory was conducted to survey users' feelings regarding the system. The implications of the evaluation findings are discussed to aid further research and education. PMID- 22256668 TI - Evaluation of the benefits of assistive reading software: perceptions of high school students with learning disabilities. AB - Using assistive reading software may be a cost-effective way to increase the opportunity for independent learning in students with learning disabilities. However, the effectiveness and perception of assistive reading software has seldom been explored in English-as-a-second language students with learning disabilities. This research was designed to explore the perception and effect of using assistive reading software in high school students with dyslexia (one subtype of learning disability) to improve their English reading and other school performance. The Kurzweil 3000 software was used as the intervention tool in this study. Fifteen students with learning disabilities were recruited, and instruction in the usage of the Kurzweil 3000 was given. Then after 2 weeks, when they were familiarized with the use of Kurzweil 3000, interviews were used to determine the perception and potential benefit of using the software. The results suggested that the Kurzweil 3000 had an immediate impact on students' English word recognition. The students reported that the software made reading, writing, spelling, and pronouncing easier. They also comprehended more during their English class. Further study is needed to determine under which conditions certain hardware/software might be helpful for individuals with special learning needs. PMID- 22256669 TI - Use of different bath grab bar configurations following a balance perturbation. AB - Although commonly prescribed, little research exists on bath grab bars. This study examined the use of bath grab bars following an experimentally induced balance perturbation, the influence of the task on grab bar use, and the influence of balance loss on acceptance of grab bars. A mixed design documented the use of four different grab bar configurations: (a) no bars, (b) vertical/horizontal combination, (c) L-shaped bar, and (d) vertical/angled combination following balance loss. Eighty adults were randomly assigned to three groups. Each group tried the "no bar" configuration and one of the other grab bar configurations. In 25% of the trials for each configuration, balance perturbation was induced. Older adults used grab bars 59.4% of time to regain balance, compared to 13.6% for younger adults. The vertical bar on the side wall was favored by both groups of participants during both bathtub entry and exit. To promote safety in the home, existing building codes must be revised to recommend minimally a vertical grab bar on the side wall. Additional bars may be needed to ensure safety during stand-to-sit and sit-to-stand phases of bath transfers. Initiatives must be taken to decrease the prejudice associated with grab bars. PMID- 22256670 TI - Urinary incontinence: a vibration alert system for detecting pad overflow. AB - A sensor and electronics system is described that monitors the leakage of urine from continence pads into surrounding underwear. Urinary incontinence is involuntary loss of urine and occurs when the bladder muscles contract without warning or the sphincter muscles surrounding the urethra are too weak to prevent leakage. The system comprises a wetness sensor and electronics unit. The sensor is stitched into the underwear and detects overspills of urine from the pad. The electronics unit is attached to the underwear and responds by vibrating, signaling to the wearer that pad has failed. This system has application for individuals who use continence pads in the community, but it could also be used in care homes. PMID- 22256671 TI - Biomechanical evaluation of an innovative spring-loaded axillary crutch design. AB - We evaluated an innovative spring-loaded crutch design by comparing its performance with standard crutches through a biomechanical approach. Gait analysis was conducted for 7 male subjects under two conditions: walking with standard crutches and with spring-loaded crutches. Three-dimensional kinematic data and ground reaction force were recorded. Spatiotemporal variables, external mechanical work, and elastic energy (for spring crutches) were calculated based on recorded data. The trajectories of vertical ground reaction forces with standard crutches had two main peaks before and after mid-stance, and those with optimized spring-loaded crutches had only one main peak. The magnitude of external mechanical work was significantly higher with spring-loaded crutches than with standard crutches for all subjects, and the transferred elastic energy made an important contribution to the total external work for spring-loaded crutches. No significant differences in the spatiotemporal parameters were observed. Optimized spring-loaded crutches can efficiently propel crutch walkers and could reduce the total energy expenditure in crutch walking. Further research using optimized spring-loaded crutches with respect to energy efficiency is recommended. PMID- 22256672 TI - International mobility technology research: a Delphi study to identify challenges and compensatory strategies. AB - We sought to identify logistical and ethical challenges to performing wheelchair related research in low- and middle-income countries and to generate a list of compensatory strategies to address these challenges. Thirteen individuals with experience in the field participated in an online Delphi study. The surveys asked participants to identify research challenges, suggest strategies to address the selected challenges, and critique each other's strategies. Participants identified challenges in the use of research techniques, compensation for participation that does not result coercion, oral and written translation materials, funding for research, collaboration with local professionals, and "respect for persons." Effective international mobility research requires time, cultural sensitivity, collaboration, and careful planning. An understanding of these requirements can allow researchers to anticipate and compensate for common pitfalls of their work, thus making the research more productive and beneficial to subjects. Future research is required to verify the general effectiveness of compensatory strategies. PMID- 22256673 TI - Studies on the effect of an Enterococcus faecium probiotic on T cell populations in peripheral blood and intestinal epithelium and on the susceptibility to Salmonella during a challenge infection with Salmonella Typhimurium in piglets. AB - Although Enterococcus faecium is used as a probiotic feed supplement in animal production, feeding of the bacterium to piglets resulted in a more severe infection with Salmonella Typhimurium DT104 during a challenge experiment. To enlighten the mode of action by which E. faecium affected the piglets' health, we investigated the influence of the probiotic bacterium on the development of intestinal and circulating immune cells during a challenge experiment with S. Typhimurium DT104. To minimise varying impacts of the maternal immunity on the course of infection, only piglets were implemented that descended from Salmonella free sows. In addition, the potency of purified blood and intraepithelial immune cells to control the growth of Salmonella was tested in vitro. In animals treated with E. faecium, a reduction of intraepithelial CD8alphabeta T cells, reduced circulating CD8alphabeta T cells and a less efficient control of intracellular Salmonella growth, mediated by peripheral blood mononuclear cells, were observed. PMID- 22256674 TI - Effect of a microencapsulated feed additive of lactic and formic acid on the prevalence of Salmonella in pigs arriving at the abattoir. AB - The main objective of this work was to investigate the potential of a microencapsulated mixture of organic acids (formic and lactic acid) added to the feed of fattening pigs to reduce the prevalence and shedding of Salmonella when arriving to the abattoir. Two trials were performed. In Trial 1, 24 fattening pigs received one of three diets: a control diet, the same diet including lactic and formic acid (0.4% each) (non-protected blend; NPB), or a lipid microencapsulated blend (0.14% each acid) (protected blend; PB). After 10 days, digesta samples from various parts of gastrointestinal tract were taken. No changes were detected either in pH, total short chain fatty acids (SCFA), lactic/formic acid concentrations in any of the sections studied or in caecal lactic acid bacteria or enterobacteria. In Trial 2, 261 pigs from a commercial farm were distributed between the three previous diets in the five weeks before slaughtering. At the abattoir, no change was detected in caecal pH, but increased concentrations (p < 0.05) of formic and lactic acid were found with the NPB and PB treatments. The total SCFA concentration was higher with the PB compared to the control diet (p = 0.002) with a lower percentage of branched chain fatty acids. Both acidified diets decreased enterobacteria in the caecum but did not modify lactobacilli. NPB treatment decreased Salmonella seroprevalence (p < 0.001). A significant (p < 0.05) increase in Salmonella faecal shedding was found related to the stress previous to slaughter with the control group and PB, but not in the NPB group. More studies will be needed to confirm the usefulness of protected acids to prevent Salmonella prevalence and shedding at the abattoir. PMID- 22256675 TI - Effect of different carbohydrates on in vitro fermentation activity and bacterial numbers of porcine inocula under osmotic stress conditions. AB - The bacteria of the intestine have to cope with varying osmotic conditions in their ecosystem. In this in vitro study, the modified Hohenheim gas test (HGT) was used to determine fermentation activity and bacterial composition of pig's faecal microbial inoculum, when fermenting different carbohydrates (inulin, corn starch, potato starch, cellulose, pectin), under normal buffered and osmotic stress conditions (elevated medium salinity). After 24 h of fermentation, gas, ammonia and short-chain fatty acid (SCFA) production was measured, and the cell numbers of total eubacteria, Lactobacillus spp., Bifidobacterium spp. and enterobacteria were analysed, using real-time polymerase chain reaction. There was a significant reduction in gas production after 24 h when comparing osmotic stress conditions with normal buffered conditions, and there were also differences among carbohydrates under both conditions. The content of SCFA was significantly lower when comparing osmotic stress with normal buffered conditions. Under osmotic stress, inulin and corn starch increased (p < 0.05) cell numbers of total eubacteria, while Bifidobacterium spp. and enterobacteria were higher (p < 0.05) when corn starch and pectin were fermented, respectively, in comparison to the other carbohydrates. The in vitro system of the modified HGT appears to be suitable to scrutinise effects of carbohydrates on the metabolic activity and composition of the microbial community under osmotic stress conditions, as they might occur during situations of osmotic diarrhoea. PMID- 22256676 TI - Effects of high dietary fibre diets formulated from by-products from vegetable and agricultural industries on plasma metabolites in gestating sows. AB - The aim of the present study was to examine the biochemical influence of feeding high dietary fibre (DF) diets formulated from by-products from the vegetable and agricultural industries to sows during early to mid-gestation. The effect of feeding frequency (once vs. twice daily) on diurnal plasma metabolites patterns was also examined. The study included a total of 48 gestating sows from four blocks (12 gestating sows in each block). The sows were fed four different diets containing varying levels of starch (304-519 g/kg dry matter (DM)) and DF (171 404 g/kg DM) but with equal amounts of net energy. The low-DF diet (control) was based on barley and wheat, and the three high-DF diets formulated by replacing barley and wheat by pectin residue, sugar beet pulp and potato pulp, respectively. The experimental design comprised two periods of 4 weeks each. Half the sows were fed once daily at 08:00 h in the first period and twice daily at 08:00 and 15:00 h during the second period, and vice versa for the other half of the sows. Plasma samples from vena jugularis were collected by venipuncture at 07:00, 09:00, 12:00 and 19:00 h. Feeding high-DF increased plasma short-chain fatty acids (p = 0.02) and non-esterified fatty acids (p < 0.001). However, there was no clear effect of DF on glucose and insulin responses. A negative correlation between amount of DF in the diets and plasma creatine (R2 = 1.00; diet effect: p = 0.02) suggested that plasma creatine concentrations was an indicator for the level of glucose-glycogen interchange. Furthermore, an explorative approach using nuclear magnetic resonance spectroscopy-based metabonomics identified betaine (p < 0.001), dimethyl sulfone (DMSO2; p < 0.001) and scyllo-inositol (p < 0.001) as biomarkers for the different by-products; pectin residue was related to high plasma levels of DMSO2, sugar beet pulp to plasma betaine, DMSO2 and scyllo-inositol, and potato pulp to plasma DMSO2 and scyllo-inositol. In conclusion, replacing starch by DF affected surprisingly few metabolites in peripheral plasma. No negative effects were found in feeding pectin residue, sugar beet pulp or potato pulp for gestating sows as judged from the minor metabolic changes. PMID- 22256677 TI - Effect of different iron loads on serum and tissue biochemical parameters and liver hepcidin mRNA abundance of neonatal piglets. AB - Iron (Fe) is an essential and important trace element for animals. In order to study its metabolism and relationship with hepcidin, piglet models of Fe deficiency and Fe-overload were established by intramuscular injection with different doses of Fe-dextran (150 mg Fe/ml) within 1 week of age. Twelve piglets were divided into three groups of four animals: deficiency, regular and overload group, receiving 0 ml, 1 ml and 6 ml Fe-dextran, respectively. The piglets were euthanised at the age of 7 days for analysis. The results showed that the Fe concentrations in liver, spleen and serum of piglets in the overload group were higher than in the regular and deficiency groups (p < 0.05). In the overload group, several serum biochemical parameters, e.g. globulin, total bilirubin, total cholesterol, high density lipoprotein (HDL), malondialdehyde, glutathione peroxidase (GPx), peroxidase and xanthine oxidase were higher, while alkaline phosphatase (AKP) and triglycerides were lower, compared with the regular group (p < 0.05). The serum concentrations of AKP, total bilirubin and peroxidase in the deficiency group were lower, while HDL and GPx were higher, compared with the regular group (p < 0.05). Hepcidin mRNA abundance was 131 times lower in the liver of piglets with Fe-deficiency, and 7 times higher in the overloaded group than that in the regular group (p < 0.05). In conclusion, Fe-overload and deficiency would influence Fe-metabolism, serum biochemical indexes, oxidation state and hepcidin mRNA abundance in piglet liver. PMID- 22256678 TI - The influence of dietary sodium on bone development in growing rats. AB - The present study investigated the effects of dietary sodium on bone growth in young rats. Five-week-old rats were fed one of three different diets for 60 days: low sodium (NaCl, 0.32 g/kg diet), normal sodium (NaCl, 2.6 g/kg) and high sodium (NaCl, 20 g/kg). The proximal tibial metaphysis (PTM), the fifth lumbar vertebra (LV5) and the middle part of the tibia shaft (TX) were analysed by bone histomorphometry. The expression of three osteogenesis genes, Runx2, osteopontin and osteocalcin, was determined by RT-PCR in bone samples from the skull. In both the PTM and LV5, trabecular area and thickness were increased by the low-sodium diet, while the high-sodium diet decreased trabecular area in LV5. Dynamic data revealed that sodium restriction increased bone formation parameters in the PTM and LV5, but decreased bone resorption in LV5. In TX, endosteal bone formation was enhanced by the low-sodium diet and depressed by the high-sodium diet compared to the normal sodium group. But there were no statistically changes in the cortical bone area of TX. Low-sodium intake significantly enhanced the expression of all three osteogenesis genes compared to the normal sodium group, while high-sodium intake suppressed osteogenic gene expression. Our results suggest that sodium restriction in growing rats promotes bone development by influencing both bone formation and resorption. PMID- 22256679 TI - Differences in portal flow rates of amino acids and liver composition between rats fed casein or lactalbumin. AB - The portal appearance rates and net rates of amino acids' absorption were studied in rats fed semi-synthetic diets containing either casein or lactalbumin (CAS and LA, respectively) as the only protein sources. Rats were pre-adapted to the experimental diets for 5 days prior to the absorption studies. Rats fed the LA diet had higher (p < 0.05) portal vein concentrations of free essential amino acids than those fed the CAS diet at 0, 60, 105 and 150 min after feeding. Portal and arterial concentrations of arginine, leucine, tryptophan, lysine and methionine were higher (p < 0.05) in rats fed LA at most time points tested, while concentrations of tyrosine were higher (p < 0.05) in CAS fed rats. When portal flow rates were compared, values for arginine, threonine, alanine, leucine, tryptophan and lysine were higher (p < 0.05) in LA at most time points tested, while proline, tyrosine and valine were higher (p < 0.05) for CAS fed rats after 60 and 105 min feeding. Portal blood flow varied (p < 0.05) with time in rats fed protein-free or LA diets, and was higher (p < 0.05) than that of CAS at 105 min. Intestinal net rates of absorption of tyrosine, valine, leucine and lysine were higher (p < 0.05) for LA fed rats as compared to those fed CAS at most time points tested, while alanine and proline net rates were higher (p < 0.05) for CAS fed rats at 60, 105 and 150 min. Amounts of protein in stomach contents of rats fed the CAS diet were significantly higher (p < 0.05) than those in LA fed rats at 60, 105 and 150 min after feeding. The relative liver weight of the rats fed the CAS diet was lower (p < 0.05) than that of animals fed the LA diet. Lower (p < 0.05) liver glycogen and lipid contents were determined in rats fed CAS diet respect to LA or protein-free fed rats. Results indicate that dietary and plasma amino acids profile are only partially related, and that under normal feeding conditions amino acids from CAS and LA are absorbed at different rates, which is likely to affect liver composition and metabolism. PMID- 22256680 TI - The dual moral self: moral centrality and internal moral motivation. AB - In this study, the relationship between two aspects of the moral self, moral centrality and internal moral motivation, was analyzed. It is argued that these 2 aspects are conceptually distinct but nonetheless empirically related. Based on a cross-sectional study of 205 adolescents (M age = 14.83 years, SD = 2.21 years) it was found that moral centrality and internal moral motivation, even though substantially correlated, interacted in predicting moral emotion expectancies. Even though moral centrality was unrelated to adolescents' age it predicted a longitudinal increase in internal moral motivation over a 1-year interval. Overall, the findings call for a differentiation of moral centrality and internal moral motivation as 2 distinct but interrelated aspects of moral self-development that follow different developmental trajectories and are differentially related to age. At the same time, the study points out that adolescence may be less important for the development of the moral self than commonly assumed. PMID- 22256681 TI - The Attachment and Clinical Issues Questionnaire (ACIQ): scale development. AB - In line with dynamic systems and dialectical theories of development, it was theorized that a psychopathology such as an addiction could have several causes (equifinality) and that more specific diagnoses and treatments of the most salient clinical issues for individuals coming from different developmental paths could increase the success rates of most therapies. Further, the issues from a developmental dynamic systems perspective should include not only individual clinical issues, but also relational, familial, peer, and organizational functioning. The Attachment and Clinical Issues Questionnaire (ACIQ) was developed as a research and clinical instrument relevant to these concerns. The 29 scales were based on naturalistic observations of patients in treatment and 12 step groups, attachment theory, and the clinical literature dealing with the addictions. The attachment scales were taken from classic attachment theory but, in line with more recent formulations, included relations to mother, father, and partner. Study 1 found the ACIQ to have good coefficient alphas (.79), and factor analyses revealed that the eight factors loaded on different attachment figures and sets of clinical issues rather than attachment styles per se. Study 2 found test-retest reliability to be, on average, .79. The results were in line with the developmental hypothesis that partner and father attachments are different than attachments to mother, and that family and peer relations as well as clinical issues need to be considered separately. PMID- 22256682 TI - Parental attitudes, attachment styles, social networks, and psychological processes in autism spectrum disorders: a cross-cultural perspective. AB - In this study the authors used a cross-cultural approach to examine parental attitudes, attachment styles, social networks, and some of the psychological processes involved in Autism Spectrum Disorders (ASD). Fifty-two children (aged 4 11 years) took part in the study: 30 Italians (15 with ASD and 15 controls) and 22 Cubans (11 with ASD and 11 controls). Findings indicated significant differences between the two cultural groups in terms of the structure of the children's social network and parental attitudes toward their children. However, the mother-child attachment relationship and cognitive and emotional functioning of the study participants were independent of culture. PMID- 22256683 TI - Children's responses to entry failure: attention deployment patterns and self regulation skills. AB - In this study the authors investigated associations among children's observed responses to failure in an analogue entry situation, their attention deployment patterns, and skills and processes associated with self-regulation. Participants were 54 kindergarten and first-grade students who were either aggressive-rejected or low aggressive-popular based on peer nominations. Inhibitory control predicted the tendency to respond to entry failure by stopping and watching the group's activity. Baseline vagal tone and other-directed attention predicted children's tendency to change entry strategies after failure. Parent-rated attention skills moderated the relation between children's attention deployment patterns during the entry task and their responses to entry failure. Children who engaged in more other-directed attention were less likely to turn to solitary play after entry failure but only if they had high or moderate levels of attentional control. Other-directed attention was related to repeating previous entry bids without modification after entry failure but only when children had high levels of attention problems. PMID- 22256684 TI - Why do we eat? Children's and adults' understanding of why we eat different meals. AB - In this study the author examined why children and adults think they need to eat. Preschoolers through adults were provided with physiological, social, psychological, and routine causes for eating breakfast, lunch, snack, and dinner, and were asked to either agree or disagree with the causal responses provided. A 4 Reason x 4 Meal repeated measures analysis of variance revealed significant main effects for meals and reasons, as well as significant Meal x Reason and Meal x Reason x Grade interactions. The effect sizes ranged from 0.1 to 0.7. Across all age groups, participants acknowledged physiological needs and desires (fulfilling hunger and needs to stay healthy) and routine (e.g., it is dinner time) as the primary causes for eating breakfast, lunch, and dinner. However, for snack physiological needs were the primary reason. Second-grade students onward spontaneously produced biological justifications such as the need for energy and nutrition as important reasons for food consumption. These results lend support to the developmental model that children's and adults' understanding of eating changes in middle childhood. PMID- 22256685 TI - Development of inhibition as a function of the presence of a supernatural agent. AB - In this study the author examined the developmental differences in inhibition and cognition of 4-8-year-old children as a function of the suggested presence of a supernatural agent. Previous evolutionarily-relevant research has suggested that humans are naturally primed to think in terms of supernatural agents and that, given the correct context, individuals readily accept novel supernatural entities and alter their behavior accordingly. All children in this study played 4 games designed to assess their present level of inhibitory and cognitive development. Children in the experimental condition were also introduced to an invisible Princess Alice and were told that she was watching during the games. Following these measures, all children engaged in a resistance-to-temptation task. Results revealed that cognitively advanced children were more likely to express belief in Princess Alice than were less cognitively advanced children. This research provides support that cognitive maturity, rather than immaturity, may be necessary for children to express belief in novel supernatural agents. PMID- 22256686 TI - Mesomorphy correlates with experiential cognitive style. AB - The purpose of this study was to test for a relationship between mesomorphy and experiential cognitive style (S. Epstein, 1994) in a sample of university students (30 women and 24 men). Anthropometric somatotypes were obtained using the Heath-Carter procedure (J. E. L. Carter, 2002). Experiential cognitive style was operationalized as scores on the experiential scale of the Rational Experiential Inventory for Adolescents (A. D. Marks, D. W. Hine, R. L. Blore, & W. J. Phillips, 2008). Nonparametric bootstrap correlations were calculated using 80% confidence intervals. There were significant correlations between mesomorphy and experiential cognitive style for men (r(s) = .33) and women (r(s) = .25). For men, experiential cognitive style was also correlated with endomorphy (r(s) = .39) and ectomorphy (rs = -.48). PMID- 22256687 TI - Reputation management of adolescents in relation to antisocial behavior. AB - Recent studies have emphasized the need to consider psychosocial and motivational variables in the study of antisocial behavior in adolescents. Thus, several studies have highlighted the importance of reputation management as a possible explanatory factor. This process of reputation management enables young people to form an image of themselves that they may use in their social interactions. In this study the authors carried out an investigation with data from a sample of 493 adolescents and analyzed (a) the relationships between adolescent reputation management and antisocial behavior and (b) the role of gender in this relationship. The results revealed that a perceived social identity as nonconforming was the best predictor of adolescent antisocial behavior, especially for girls, The data support previous findings on the importance of considering the establishment and management of reputation in the analysis of adolescent antisocial behavior. PMID- 22256688 TI - Teenagers in the United States: sexual activity, contraceptive use, and childbearing, 2006-2010 national survey of family growth. AB - OBJECTIVE: This report presents national estimates of sexual activity, contraceptive use, and births among males and females aged 15-19 in the United States in 2006-2010 from the National Survey of Family Growth (NSFG). For selected indicators, data are also presented from the 1988, 1995, and 2002 NSFG, and from the 1988 and 1995 National Survey of Adolescent Males, conducted by the Urban Institute. METHODS: Descriptive tables of numbers and percentages are presented and discussed. Data were collected through in-person interviews of the household population of males and females aged 15-44 in the United States, between July 2006 and June 2010. Interviews were conducted with 22,682 men and women, including 4,662 teenagers (2,284 females and 2,378 males). For both the teen subsample and the total sample, the response rate was 77%. RESULTS: In 2006 2010, about 43% of never-married female teenagers (4.4 million), and about 42% of never-married male teenagers (4.5 million) had had sexual intercourse at least once. These levels of sexual experience have not changed significantly from 2002. Seventy-eight percent of females and 85% of males used a method of contraception at first sex according to 2006-2010 data, with the condom remaining the most popular method. Teenagers' contraceptive use has changed little since 2002, with a few exceptions: there was an increase among males in the use of condoms alone and in the use of a condom combined with a partner's hormonal contraceptive; and there was a significant increase in the percentage of female teenagers who used hormonal methods other than a birth-control pill, such as injectables and the contraceptive patch, at first sex. Six percent of female teenagers used a nonpill hormonal method at first sex. PMID- 22256689 TI - Protecting children from HPV: challenges and opportunities. PMID- 22256690 TI - Efficacy and safety considerations in topical treatments for atopic dermatitis. AB - As no cure exists for atopic dermatitis, the goals of treatment include reducing symptoms and prolonging periods between flares. Proper skin care can improve skin barrier function, reducing susceptibility to triggers of flares. Topical corticosteroids and topical calcineurin inhibitors may improve symptoms. PMID- 22256691 TI - Parents' experiences supporting self-management of middle adolescents with type 1 diabetes mellitus. AB - The purpose of this article is to describe the experiences of parents regarding the fostering of self-management of diabetes mellitus with their middle adolescents with type 1 diabetes mellitus (T1DM). A purposive sample of parents of 16- to 18-year-old adolescents with T1DM from 23 families who attended the endocrinology clinic of a children's hospital were interviewed about their experience with their adolescent's diabetes management and how they supported or inhibited their adolescent's diabetes self-management. Qualitative description was used to analyze the transcripts of audio-recorded interviews. Parents often described having negative experiences involving struggle, frustration, and worry about adolescent self-management. Parents supported their adolescent's self management primarily by reminding, recognizing positive aspects of the adolescent's diabetes management, and granting more freedom. Conversely, parents inhibited their adolescents' diabetes management by scolding and judging, checking and nagging, and becoming emotional. Clinicians can help parents share their experiences, cope with their emotions, and practice effective strategies to motivate adolescent diabetes self-management in the transition to later adolescence. PMID- 22256692 TI - Cultural differences in parent-adolescent agreement on the adolescent's asthma related quality of life. AB - The primary purpose of this exploratory, cross-sectional study was to determine the degree of agreement between parents' and adolescents' rating of adolescents' asthma-related quality of life (QOL). A secondary aim was to compare the degree of agreement between parent-adolescent dyads in two countries; 15 dyads each were recruited from Kentucky and Iceland. Both adolescent and adult participants completed separate paper surveys at the time of the adolescent's clinic appointment. The QOL instrument used (PedsQL 3.0 Asthma Module) contains the subscales of asthma symptoms, asthma treatment, worry, and communication. Parent adolescent differences were determined using paired t-tests; associations were assessed with intraclass correlation coefficients (ICCs). Two-sample t-tests investigated between-country differences in parent-child consistency in the assessment of the adolescent's asthma-related QOL. Adolescents rated their QOL higher than their parents did, but not significantly. The ICC of the QOL score for the 30 dyads was 0.39. The degree of agreement was high for asthma symptoms, but low for asthma treatment, worry, and communication. U.S. parents tended to underrate their child's QOL, while parents from Iceland overrated it (p = 0.007). Family-centered interventions may improve parents' understanding of how asthma affects QOL in adolescents, and such interventions may have to be tailored for cultural differences. PMID- 22256693 TI - The paired t-test. PMID- 22256694 TI - Improve staffing, improve care: A new model for the NICU. PMID- 22256695 TI - Congenital hypothyroidism. PMID- 22256696 TI - Heads up! Head pain in an 11-year-old male. PMID- 22256698 TI - Virtual dental education. PMID- 22256697 TI - Anorexia nervosa: patient and family-centered care. PMID- 22256699 TI - More than 1,417,000 seniors (including 568,700 with disabilities) will reside in Tennessee in 2030. AB - In the coming years, Tennessee and the rest of the country will experience a burgeoning number of senior residents, including those with disabilities. A review of these developments in one state and its counties, and the anticipated demand for dental services, is presented. PMID- 22256700 TI - Computer assisted learning: a new paradigm in dental education. AB - Computer assisted simulation is an important teaching modality in the preclinical training of students. In order to maximize the potential of this learning tool, the University of Tennessee's College of Dentistry has successfully incorporated DentSim technology into the restorative curriculum and has recently acquired the technology to make image guided implantology available to students, residents and faculty. This article describes the university's history and experience with simulation as a learning tool. The purpose of this article is to provide information to other educational institutions on the use of virtual reality simulation in the classroom. PMID- 22256701 TI - Tennessee smiles: the UT grassroots oral health outreach initiative. AB - Access to and awareness of oral healthcare in the United States have been highlighted in the mass media and discussed among diverse populations. The current surge to provide access to oral healthcare for citizens springs from this quagmire of oral healthcare issues which affects global to local (grassroots) communities. Publications by the World Health Organization's (WHO) Health for All and the United States' Healthy People have set into motion an agenda by which institutions, healthcare professionals and governments can develop action plans to foster and nurture grassroots organizations to address these issues. An initiative has been undertaken by members of the faculty, student doctors and staff of the University of Tennessee Health Science Center, College of Dentistry (UTHSC CoD) and its partners. This cadre of volunteers has implemented grassroots efforts for the citizens of western Tennessee to date as the flagship of Tennessee Smiles: UT Grassroots Oral Health Outreach Initiative (Tennessee Smiles). By participation in health fairs, school programs and other cultural events, these volunteers have made a difference in the lives of thousands of Tennessee citizens who need exposure to information regarding their oral health care needs. The authors discuss the basis for the Tennessee Smiles organization, their successes and challenges. Future plans and the need for support of the organization are emphasized. PMID- 22256702 TI - We are the future of nursing. PMID- 22256703 TI - From suits to scrubs. PMID- 22256704 TI - Global initiatives in nursing. PMID- 22256705 TI - The consequences of hazing. PMID- 22256706 TI - NSNA alumni. PMID- 22256707 TI - Show your professionalism by getting to know healthcare. PMID- 22256708 TI - Nursing: the future is yours! PMID- 22256709 TI - Prepare yourself for a future in research: understanding evidence-based practice for the evolving nurse. PMID- 22256710 TI - What the future of nursing--leading change, advancing health report means to you. PMID- 22256711 TI - Career pathways under threat. PMID- 22256712 TI - Nurse-led initiative focuses on parents to lessen health-related school absences. PMID- 22256714 TI - Holistic interventions in complex care. PMID- 22256713 TI - Fears over allergy test skills. PMID- 22256715 TI - Treating buckle fractures in children with removable splints. AB - Buckle fractures of the distal radius are unique to children. Immobilising the limb in a plaster cast is the traditional treatment. An alternative is to use a removable wrist splint and this has been adopted at the author's clinic. In this article, literature on the change of practice is reviewed, the change is described and the outcomes evaluated. It was found that treatment with the wrist splint was cost-effective and was preferred by children, families and carers. PMID- 22256716 TI - Promoting independence for children on long-term ventilation. AB - It is the responsibility of children's nurses to enable children and young people who are on long-term ventilation (LTV) to live independent and varied lives. This article considers the common challenges faced by such children and reflects on personal experience in planning and undertaking a respite week for a young person on LTV with Duchenne's muscular dystrophy without his parents. PMID- 22256717 TI - How to encourage children to use mobile phones safely. AB - The safe use of mobile phones is part of the health promotion duty of children's nurses and those nurses working in schools. In this article the author advocates that children and young people should be encouraged to keep and use their mobiles in a safe place, avoid lengthy and incessant calls, provide their number only to those they feel they can trust and switch off the phone as soon as possible. They need to take care with the type of messages they send and to tell someone they can trust about any cyberbullying. The nurse can also help with school policies and can attend groups in schools and youth organisations to discuss the positive and negative aspects of mobile phone technology. PMID- 22256718 TI - Care and nursing management of a child with a chest drain. AB - Caring for and managing an infant or a child with a chest drain may cause the children's nurse some anxiety because, although the management is relatively simple, there is potential for disconnection of the equipment, re-accumulation of the pneumothorax and complications--such as pain and infection--that adversely affect the health and wellbeing of the child. Understanding the underlying anatomy and physiology, the pathology behind air leaks, the principles of asepsis, and the assessment and management of a child with a chest drain will enhance the children's nurse's confidence and reduce the likelihood of adverse incidents. PMID- 22256719 TI - Turn a negative into a positive. PMID- 22256720 TI - Patients' concerns inspire campaign for better care. PMID- 22256721 TI - Nurses given unequivocal advice on assisted suicide. PMID- 22256722 TI - Taking the stigma out of dementia. PMID- 22256723 TI - Seasonal offering. PMID- 22256724 TI - Spirituality: how should we assess the spiritual needs of our patients? PMID- 22256725 TI - Guide to providing mouth care for older people. AB - The authors provide an overview of oral health, why it is important for older people and how poor oral health can affect nutritional status and quality of life. Practical advice is given on assessment of oral health; cleaning of natural teeth and dentures; and care of oral problems that commonly affect older people. An oral healthcare education session is recommended to provide hands-on advice to caregivers. The article is not intended as an exhaustive reference and the reader should always ask for professional dental advice and assistance if in doubt about any aspect of oral care. PMID- 22256726 TI - Older people's experiences of relocation to long-term care. AB - AIM: The aim of this study was to explore older people's experience of the decision to relocate to long-term care and their early experiences post relocation. METHOD: Interviews were held with eight older people who had recently relocated to long-term care settings in southern Ireland. Data were analysed using Collaizzi's (1978) phenomenological method. FINDINGS: There was evidence of poor communication with, and minimal participation of, older people in the decision to relocate. Their experiences differed according to respective contexts and events that led up to the move. CONCLUSION: Nurses have an important part to play in reducing the negative consequences associated with individuals transferring to long-term care. PMID- 22256727 TI - The challenges of caring for patients with influenza. AB - Influenza is an acute, highly infectious viral infection. Seasonal outbreaks occur annually across the world, presenting a major public health challenge. Older people and those with chronic conditions are most at risk and for these groups secondary infection and complications can be severe. Implementing infection prevention and control measures is not straightforward because of the types of settings where many older people receive care, the special needs of frail older people likely to be most seriously affected, and because little is known about the mode of transmission of the virus. PMID- 22256728 TI - Leading by example. PMID- 22256729 TI - Physiology: evolving, not declining. PMID- 22256730 TI - Institute for integrative physiology: resurrection of physiology at the University of Chicago. PMID- 22256731 TI - Two APS members awarded the 2011 ASBMB STEM SEED grant for PhUn week activities. PMID- 22256732 TI - APS comments on the future of the biomedical workforce. PMID- 22256733 TI - Summer research programs. AB - A summer research experience is an excellent opportunity for undergraduate students to gain valuable research experience. With a little bit of planning, students can become familiar with the research area in which they are interested and begin to make connections with experts in the field. Time spent discussing goals for the project can yield peer-reviewed abstracts and publications. As a result, an application to graduate school can be greatly improved by a summer research experience, and students can have more options to consider as they embark on graduate training. PMID- 22256734 TI - [Study in safety of total thyroidectomy]. AB - OBJECTIVE: To study the complications in total thyroidectomies and the safety of total thyroidectomy. METHOD: Retrospective analyses 351 cases underwent total thyroidectomy in our department. Preoperative and postoperative electronic laryngoscopy were used to assess the vocal cord function. All patients have serum calcium analysis on the operative day and 3rd and 7th day after operation. RESULT: Temporary hypocalcaemia occurred in 47.01% after total thyroidectomy, but only 15.67% with severe symptom temporarily,and 21.37% with temporary mild numbness. Permanent hypoparathyroidism occurred in 0.85% patients. None with bilateral recurrent laryngeal nerve palsy, and temporary unilateral vocal cord palsy occurred in 1.42% patients and permanent unilateral recurrent laryngeal nerve palsy occurred in 0.56% patients. CONCLUSION: Total thyroidectomy is safe with low complications. PMID- 22256735 TI - [Evaluation the curative effect of supracricoid partial laryngectomy for laryngeal cancer]. AB - OBJECTIVE: To analyze the oncological outcomes, functional outcomes in patients undergoing supracricoid partial laryngectomy (SCPL). Provide clinical experience for application of SCPL. METHOD: A retrospective analysis of the 115 cases with laryngeal carcinoma accepted SCPL in our department from Jan 1996 to Dec 2004. Use the Kaplan-Meier method to analyze the patients'survival rate. Evaluate the value of reserve larynx function. RESULT: The 5-years survival rates and the decannulation rate was 80.8%, 99.1% respectively; and the average decannulation time was 22.25 days. The mean time of removal of gastric tube was 9.57 days. The function of CHEP was superior to CHP. The vocal function of 115 cases were all achieved in general communication. CONCLUSION: SCPL get better oncological and functional outcomes and allows the preservation of the basic function of the larynx. It's a safe, effective technique and deserved to generalization. PMID- 22256736 TI - [Cancer stem cells promotes resistance of laryngeal squamous cancer to irradiation mediated by hypoxia]. AB - OBJECTIVE: To study whether cancer stem cells promotes resistance of laryngeal squamous cancer to irradiation mediated by hypoxia. METHOD: Hep-2 cells were respectively cultured in hypoxia and normoxia environment, and the express of HIF la was detected by western blot. Then they were radiated with different doses of gamma-rays. After that we detected growth inhibition ratio with MTT assay, cell circle and ratio of CD133+ cells with Flow cytometry at different times. RESULT: MTT assay showed that inhibition ratio of the hypoxia group was lower than that of the normoxia group after different doses of gamma-rays at each time point, and the difference was significant 24 h after 10 Gy irradiation (P < 0.05). The results of Flow cytometry demonstrated that cells of the two groups were arrested at G1 phase, and cells ratio in G1 phase of the hypoxia group was higher than that of he normoxia group after 10 Gy irradiation. The ratio of CD133-positive cells was higher in the hypoxia group than in the normoxia group after radiation, and difference was significant 24 h after 10 Gy irradiation (P < 0.05). In each group, the ratio of CD133-positive cells became higher after radiation than that before radiation (P < 0. 05). CONCLUSION: We can conclude that cancer stem cells play an important role in radioresistance mediated by hypoxia. PMID- 22256738 TI - [Nasopharyngeal and oropharyngeal airway in obstructive sleep apnea syndrome, multi-plane operation application of perioperative]. AB - OBJECTIVE: To compare the mitigation role of nasopharyngeal and oropharyngeal airway in obstructive sleep apnea hypopnea syndrome (OSAHS) patients with upper airway obstruction after multiple plane operation. Observed parameters included life quality, the clinical value and reliability of nasopharyngeal and oropharyngeal airway. METHOD: The nasopharyngeal airway group, 56 patients with PSG in patients diagnosed with severe OSAHS, after setting nasopharyngeal airway. Oropharyngeal airway group, 45 cases of OSAHS by PSG confirmed severe patients home after oropharyngeal airway, the same as the other treatment groups. Line postoperative ECG, oxygen saturation and hemodynamic monitoring. Two groups were compared in 24 h breathing difficulties, low oxygen saturation, hemodynamics, pharyngeal pain and discomfort of the situation. RESULT: The multiplane after 24 h, the nasopharyngeal airway in patients hemodynamics HR (82.3 +/- 2.65) times/min, SBP(124.5 +/- 13.95) mmHg, DBP (76.2 +/- 8.1) mmHg, RPP(10282.0 +/- 1481.7), port pharyngeal airway in patients hemodynamics HR (93.4 +/- 2.89)times/min, SBP (135.1 +/- 16.5) mmHg, DBP (92.25 +/- 11.25) mmHg. There was significant difference between the two group (P < 0.05); pharyngeal pain nasopharyngeal airway group (1.71 +/- 0.45) points, oropharyngeal airway group (310) points, there was significant difference between the two (P < 0.05); nasopharyngeal airway breathing difficulties Group 0, 0 oropharyngeal airway group, no significant difference between the two (P > 0.05); the lowest oxygen saturation nasopharyngeal airway group (95.2 +/- 1.6)%, oropharyngeal airway group (95.41 +/- 1.34)%, no significant difference between the two (P > 0.05). 24 h before and after surgery between patients with the same group in the hemodynamic parameters (HR,SBP,DBP,RPP), pharyngeal pain, lowest oxygen saturation difference was statistically significant areas (P < 0.05). CONCLUSION: Ventilation tube in the nasopharynx and oropharynx in patients with severe OSAHS the same period of postoperative respiratory management plane could well lift the upper airway obstruction. However, nasopharyngeal ventilation tube has a better hemodynamic stability and tolerance, it can reduce patient suffering and increased health and safety from, it is a more safe, minimally invasive and effective method. PMID- 22256737 TI - [The expression and its potentially clinical significance of EphA2 in nasopharyngeal carcinoma]. AB - OBJECTIVE: To observe the expression of EphA2, and investigate its correlation with the development, progression, invasion, metastasis, angiogenesis and prognosis in nasopharyngeal carcinoma(NPC). METHOD: Immunohistochemical staining was used to determine the expression level of EphA2 protein in 61 cases NPC and 20 cases chronic nasopharyngitis samples. The clinically pathological data and results of follow-up were collected. Microvessel density (MVD) was also measured by immunohistochemical staining method with CD34 in NPC. RESULT: The positive rate of EphA2 protein staining in NPC was 60.66% (37/61), while that in nasopharyngitis samples was 10.0% (2/20). The positive rates of EphA2 protein in NPC were 27.27% (3/11) in stage I, 56.25% (9/16) in stage II, 68.19% (15/22) in stage III, and 83.33% (10/12) in stage IV. The positive expressions of EphA2 in T1 + T2 and T3 + T4 with neck lymph node and distant metastasis were 58.33% (7/12) and 88.89% (16/18) respectively, while those in T1 +T2 and T3 + T4 without metastasis were 31.25% (5/16) and 50.00% (6/12) respectively. The cumulative survival of patients in the EphA2 positive group at 5 years was only 0.324 (12/37), while 0.500 (12/24) in the EphA2 negative group. The positive expression of EphA2 protein was correlated with the clinical stage, the neck lymph node metastasis and distant metastasis, and prognosis of NPC, respectively (P < 0.05). MVD in EphA2 protein positive group (45.32 +/- 4.91) was significantly higher than that in EphA2 protein negative group (28.69 +/- 3.99, P < 0.01). CONCLUSION: EphA2 may play an important role in the development and progression of NPC. It is closely associated with the invasion, metastasis, angiogenesis and prognosis of NPC. PMID- 22256739 TI - [Clinical significance of MRP8 and cypA expression in laryngeal squamous cell carcinoma tissues]. AB - OBJECTIVE: To study differential expression of MRP8, CypA protein in the patients of laryngeal squamous cell carcinoma (LSCC) and the relationship in the development of LSCC. METHOD: Immunohistochemistry was used to detect the expression of MRP8,CypA protein in LSCC tissues of 41 cases and matched paraneoplastic normal tissues of 41 cases,with results compared to the clinical data to determine significance. RESULT: The expression of MRP8, CypA protein in carcinoma and normal tissues and composition of different positive grades were in statistical significance (P < 0.01). The expression levels of MRP8 were no significant correlations were identified against any parameter (age,sex and cervical lymphatic metastasis) examined (P > 0.05), but related to pathological stage (P < 0.05). CONCLUSION: MRP8 protein is on intimate terms with different pathological differentiation stage of LSCC. MRP8, CypA protein may play an important role in the development and progression of LSCC. PMID- 22256740 TI - [Analysis of influencing factors for curative effect of maxillofacial fractures]. AB - OBJECTIVE: To explore the influencing factors for curative effect of maxillofacial fractures. METHOD: Retrospective analysis of the 86 patients for maxillofacial fractures from Jan. 2008 to Dec. 2010 in our hospital, to observe data, sex, type, reason, associated injury, methods of treatment, and so on. RESULT: The success rate of curing was 95.35%. The length of stay for the 86 patients was from 7 days to 28 days, average 16. 8 days. The type, reason, associated injury, methods of treatment were the influencing factors for curative effect of for maxillofacial fracture. The success rate of curing for different ways of operation were different. Recovery rate of operation was 6.097%, it of expectant treatment was 75%, they were statistical different significantly (P < 0.05). CONCLUSION: The type, reason, associated injury, methods of treatment were the influencing factors for curative effect of for maxillofacial fracture. PMID- 22256741 TI - [Expression of MEF2D on nasopharyngeal carcinoma tissues and its influence of prognostic]. AB - OBJECTIVE: To explore the expression of MEF2D in NPC tissues, study the relationship between the expression and prognostic. METHOD: Specimens from 101 NPC patients who were follow-up visited 1 to 7 years were analyzed for MEF2D by using immunohistochemistry. RESULT: (1) The expression of MEF2D was higher in the higher clinical stage. (2) Density and Grey of MEF2D was negative correlated (|r| = 0.865, P < 0.01). (3) NPC patients' survival rate after therapies was 52.5%, the survival curve of 1th clinical stage was higher than 4th. (4) The survival curves of MEF2D stages were no statistical significance. CONCLUSION: There's statistical significance of the MEF2D expression in clinical stages, but not in survival curve, which indicated that MEF2D concerned with invasion and metastatic of NPC. PMID- 22256742 TI - [Effects and mechanism of genistein on the proliferation and apoptosis in human nasopharyngeal carcinoma cell lines CNE]. AB - OBJECTIVE: To investigate the effects and mechanism of genistein on proliferation inhibition and onset of apoptosis in nasopharyngeal carcinoma cell line CNE. METHOD: Antiproliferative effect of genistein against CNE was tested by MTT method. Apoptotic phenotype of CNE was observed by electron microscope. Cell apoptosis percentage and cell cycle phase distribution of CNE were measured by flow cytometric assay. RESULT: A time dependent and dose dependent proliferation inhibition was demonstrated in CNE, the high potency has the obvious suppression on tumor growth function; Genistein induces nasopharyngeal cancer cell early apoptosis rate but to strengthen along with the density increase, 200 micromol/L group is highest, is 49.9%; and genistein induced a G2/ M cell cycle arrest. The characteristic morphological changes of apoptosis in CNE cells was observed after treated by genistein. CONCLUSION: The time dependent and dose dependent proliferation inhibitory effect of genistein on nasopharyngeal cancer cells. Genistein's mechanism on suppressing effect is probably associated with inducing the cell apoptosis and intervening the cell circle of carcinoma cell. The results provide evidence for the potential usefulness of genistein in the prevention and treatment of human nasopharyngeal carcinoma. PMID- 22256743 TI - [Study of expression and significance of DSCR1 gene in laryngopharynx cancer and peri-cancerous tissues]. AB - OBJECTIVE: To study the expressions of DSCR1 gene in laryngopharynx cancer and peri-cancerous tissues, to understand the relationship between its expression and tumor clinical features, to discussed the influence of DSCR1 gene on the biological behaviours of laryngopharynx squamous cell carcinoma. METHOD: Immunohistochemical p-V9000 method,used rabbit DSCR1 antibody DCT3, detected the expressions of DSCR1 gene protein in laryngopharynx cancer and peri-cancerous tissues, between them and clinical data were statistically analyzed. RESULT: Positive rates of DSCR1 gene expression in the tumor tissues was 94.9%, normal tissues was 35.9%, there was a statistically significant (t = 23.69, P < 0.01); There was significant difference of DSCR1 gene expressions in different pathological degree and TNM staging (P < 0.05). There was no significant difference in different age, gender, site, growth mode, lymph node metastasis and smoking history. CONCLUSION: DSCR1 gene has an important role in the occurrence and development process of laryngopharynx squamous cell carcinoma, and can influence the biological behavior of tumors. PMID- 22256744 TI - [Genetic variability and interrelationships of mainly quantitative traits in Glycyrrhiza uralensis cultivated population]. AB - OBJECTIVE: The main aim of the research was to evaluate genetic variability and interrelationships of mainly quantitative traits in 2-year population, and provide a basis for high-yield breeding of Glycyrrhiza uralensis. METHOD: Four genotype G. uralensis population were transplanting in four different environment using complete randomized block design with three replication, and the 10 quantitative traits, including plant height (PH), stem diameter (SD), tiller number (TN), taproot length (TRL), root length (RL), root diameter (RD), diameter of 20 cm below the root head (D20), taperingness (TR), lateral root number (LRN) and root fresh weight (RFW) were measured in field. RESULT: The difference among population for all evaluated traits were significant (P<0.05) through Duncan's multiple range tests, and the coefficient of variation of RFW and LRN were above 25%. The analysis of variance was used to evaluate the traits of four populations across to four different environment Genotype, environment and their interaction effect were significant (P<0.05) or highly significant (P<0.01) for mainly evaluated traits. Simple correlation between traits showed that PH, SD, LRN, RL, RD and D20 had highly significant (P<0.01) and positive correlation with RFW. Results of the path coefficient analyses showed that D20 had the greatest positive direct effect on RFW, followed by the traits of PH and RL. CONCLUSION: Selection for increased D20, RL and PH would be the best indirect selection traits for increasing root yield. Meanwhile, ample genetic variability exists in the G. uralensis 2-year population, it could be used for breeding improvement of root yield. PMID- 22256745 TI - [Study on preservation of Fritillaria anhuiensis by vitrification in vitro]. AB - OBJECTIVE: To establish cryopreservation system of shoot-tips from Fritillaria anhuiensis. METHOD: Taking vitrification as system of cryopreservation, the shoot tips with length 2-3 mm were precultured in MS medium enriched with 0.4 mol x L( 1) sucrose for 3 d. They were treated for 20 min with 60% PVS2 at 25 degrees C, and then subjected to ice-cooled vitrification solution for 60 min and transferred to 2 mL cryotubes with fresh vitrification solution (PVS2) and plunged into liquid nitrogen. After rapid thawing in 40 degrees C water bath for 1 min, shoot-tips were expelled into MS medium containing 1.2 mol x L(-1) sucrose for 20 min. Further recovery and growth took place on regeneration medium in the dark at 25 degrees C for 2 weeks, and then with light/dark cycle of 12/12 h. The genetic integrity of cryopreserved shoot-tips was identified through products of PCR with arbitrary primers. RESULT AND CONCLUSION: The highest survival rates of shoot-tips reached 79.9% by vitrification, and the regeneration rates were 52.3%. No changes were found between treated materials and untreated materials in genomic DNA. PMID- 22256746 TI - [Variation of monosacchride composition of polysacchrides in Dendrobium officinale by pre-column derivatization HPLC method]. AB - The monosacchride composition of polysacchrides in Dendrobium officinal of different germplasms, physiological ages and closely related species were determined by pre-column derivatization HPLC. The results showed that the absolute and relative volumes of all monosacchrides were significantly different between D. officinale and its closely related species, different germplasms and physiological ages of D. officinale. Absolute peak areas of mannose ranged from 0.854 x 10(7) to 10.340 x 10(7) in closely related species of D. officinale, ranged from 1.467 x 10(7) to 8.475 x 10(7) in different germplasms of D. officinale and were 4.411 x 10(7) (2.577 x 10(7)-6.516 x 10(7)), 5.528 x 10(7) (3.179 x 10(7)-8.475 x 10(7)) and 3.601 x 10(7) (1.467 x 10(7)-5.888 x 10(7)), respectively, in one to three physiological ages of D. officinale. The ratio of mannose to glucose peak areas (relative peak area) ranged from 0.976 to 16.599 in closely related species of D. officinale and from 2.679 to 7.831 in different germplasms of D. officinale. Only the relative peak areas of D. pendulum and D. primulinum were in the range of different germplasms of D. officinale in all tested samples. The results revealed the variation of monosacchride composition of polysacchrides in D. officinale. Monosacchride composition of D. officinale could be altered by breeding new varieties and controlling harvesting season. Most adulterants of D. officinale could be ruled out according to the relative peak areas of D. officinale, providing a basis for quality control and resources training of D. officinale. PMID- 22256747 TI - [Effect of different light of LED light quality on growth and antioxidant enzyme activities of Ganoderma lucidum]. AB - OBJECTIVE: To study the effect of light quality on growth, antioxidant enzyme activities of Ganoderma lucidum mycelium. METHOD: G. lucidum mycelium was cultured under different light qualities by light emitting diodes (LED). The growth G. lucidum mycelium was observed and antioxidant enzyme activities was determined in different growth periods. RESULT: Under the red LED, the blue LED and dark condition (CK), the mycelium grew faster than that under other light qualities. The white LED resulted in a largest increase in the amount of the mycelium and always kept the activities of CAT high level. Major fluctuations of POD activities emerged under the green LED, while enhanced severely in the late phase. Under the yellow LED, the activities of SOD appeared high level. However, SOD activities on dark (CK) raised obviously in late period. At the late stage, the content of mycelium polysaccharides was significant higher than that under the blue LED. CONCLUSION: The light quality could influence the growth and metabolism of G. lucidum mycelium. PMID- 22256748 TI - [Distribution and influencing factors of magnoflorine in Epimedium]. AB - Eighty samples of Epimedium from 29 species and were determined in this study. The content of magnoflorine in leaves range between 0. 003% and 2. 603%. The results showed that the content of magnoflorine was quite stable within species except E. wushanense, E. acuminatum, E. hunanense. Genetic factors might be the main influencing ones. The contents of different parts and different collecting time of the medicinal materials were variable. PMID- 22256749 TI - [Fast analytical method on content and transfer rate of marker component in ethanol precipitation of cinobufacini by near infrared spectroscopy]. AB - The method of near infrared spectroscopy was established to analyze the content and transfer rate of the marker component, indole alkaloids, of cinobufacini in the process of ethanol precipitation. The samples of cinobufacini were collected, and the concentration of indole alkaloids was determined by the reference method, UV-vis spectroscopy. After the rejection of abnormal samples, the pretreatment of spectra and the choice of the corresponding wave band, the multivariate calibration models were established using PLS algorithm between spectra and the UV values. The samples in ethanol precipitation, which did not participate in modeling, were used to examine the performance of the models. The correlation coefficient of the calibration model was 0.9613. Root mean square error of calibration (RMSEC) and root mean square error of prediction (RMSEP) were 0.172 and 0.169, respectively. Furthermore, residual predictive deviation (RPD) of the model was 4.13, which meant quantity analysis was feasible. It is concluded that near infrared spectroscopy can be considered as a fast, effective and non destructive analysis method applied in the process of ethanol precipitation for traditional Chinese medicine. PMID- 22256750 TI - [Study on method of Corydalis yanhusuo producing and concocting integration processing]. AB - OBJECTIVE: To establish integration processing method for pretreating and vinegar producing Corydalis yanhusuo. METHOD: Different processing methods were contrasted with the traditional processing technology, and contents of corydalis B, water extract and ethanol extract in samples of different processing products were determined. RESULT: The content of corydalis B were best in the samples of vacuumizing C. yanhusuo chips scaked in rice vinegar for twice or soaked in rice vinegar after chip drying. The water extract was highest in the samples of chip soaked in rice vinegar after drying, followed with chip vacuumizing twice, and there were no remarkable difference between the other samples and the traditional process. The difference of ethanol extract was not remarkable in all the samples. CONCLUSION: The study provide the feasibility of C. yanhusuo producing and concocting integration processing. PMID- 22256751 TI - [Study on rat nasal absorption in situ of borneol based on single pass perfusion method]. AB - OBJECTIVE: To investigate the absorption characteristic of borneol. METHOD: Using single pass perfusion model, the active ingredient of borneol were detected by GC. The drug concentration, perfusion rate and pH value on the absorption of borneol were studied. RESULT: Perfusion rate on the absorption rate constants (Ka) had significant effects. Drug concentration and pH value on the absorption rate constants had no significant impact. CONCLUSION: the absorption of borneol is good by nasal. The absorption rate constants of borneol have no effected by drug concentration. The absorption of borneol is via a simple diffusion. PMID- 22256752 TI - [Preparation and pharmacodynamics studies on anti-inflammatory effect of catechu gel]. AB - OBJECTIVE: To prepare the gel of Chinese medicine catechu,study its release mechanism in vitro and observe the anti-inflammatory activity in rats. METHOD: Using the amount of catechin and epicatechin in dry extract as major evaluation factors, orthogonal experiment was carried out to investigate four influential factors of the ethanol concentration, ratio of raw material to solvent, ultrasonic time and extraction temperature. The catechu gel was prepared by using carbomer-940 as the gel base, and triethanomine as neutralizer. The experiments on drug-releasing profiles in vitro and the phamacodynamics studies on the anti inflammatory in rats were carried out, respectively. RESULT: The optimum condition of extraction from catechu was as follows, the concentration of ethanol, ratio of raw material to solvent, ultrasonic time, and extraction temperature were 50% , 1: 12, 35 min and 60 degrees C, respectively. The formulation of catechu gel was carbomer-9 400.5 g, glycerol 5.0 g, the extracts of catechu 50.0 mL, and triethanomine 0.5 mL The gel was semitransparent and stable. The drugs released quickly. The catechu gel reduced the paw edema considerably in dose-dependent manner compared to carrageenan-induced rat. CONCLUSION: The formulation of the catechu gel is reasonable, and it shows remarkable anti-inflammatory activity. It is worth doing further research. PMID- 22256753 TI - [X-ray diffraction Fourier fingerprint of mineral Chinese medicine Chloriti Lapis]. AB - The technology of powder X-ray diffraction (XRD) was used for analysis Chloriti Lapis and the XRD Fourier fingerprints were established. The dates were analyzed by fuzzy cluster and fingerprint similarity evaluation software to compare the similarity of samples. XRD fingerprint with 10 common peaks of 14 batches of Chloriti Lapis were established. The average, median coefficients of crystal lattice spacing d (A), peak position 2 theta, relative intensity value I/I0 (%) were all more than 0.95. And similarity( angle cosine value) were all more than 0. 97. There were small number samples differed from others. And obvious differences between the pre-and post-processing samples. This paper shows the powder XRD Fourier fingerprint can be used for appraisal and study of the Chloriti Lapis. PMID- 22256754 TI - [Chemical constituents from root bark of Tripterygium hypoglaucum]. AB - OBJECTIVE: To investigate chemical constituents of the root bark of Tripterygium hypoglaucum. METHOD: Compounds were isolated by column chromatography on silica gel and Sephadex LH-20, and their structures were identified on the basis of spectral data (MS, 1H-NMR and 13C-NMR). RESULT: Twelve compounds were isolated and identified as friedelin (1), 3-oxo-olean-9(11),12-diene (2), canophyllal (3), 3-acetoxy oleanolic acid (4), triptophenolide (5), triptonoterpene methyl ether (6), tricosanoic acid (7), beta-sitosterol (8), stearic acid (9), glut-5-en 3beta,28-diol (10), palmitic acid (11) and daucostorol (12). CONCLUSION: Compounds 1, 2, 3, 7 and 10 were isolated from T. hypoglaucum and 7 from the genus Tripterygium for the first time. PMID- 22256755 TI - [Phenolic and amide constituents from Lycianthes marlipoensis]. AB - Ten known phenolic compounds including [4]-gingerol (1), [6]-gingerol (2), [10] gingerol (3), (3S,5S)-3,5-dihydroxy-1-(4-hydroxy-3-methoxyphenyl) decane (4), (3R,5S) -3, 5-dihydroxy-1-(4-hydroxy-3-methoxyphenyl) decane (5), [6]-shogaol (6), [10]-shogaol (7), gingerenone A (8), hexahydrocurcumin (9), and (3R,5R)-3,5 dihydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl) heptane (10), and seven amides including piperine (11), isochavicine (12), isopiperine (13), N-trans-p-coumaroyl tyramine (14), N-trans-feruloyl tyramine (15), N-trans-p-coumaroyl octopamine (16), N-trans-feruloyl octopamine (17), were isolated and identified from the roots of Lycianthes marlipoensis. Compounds 1-13 and 17 were isolated from the genus Lycianthes for the first time. PMID- 22256756 TI - [Triterpenes and sterols from Nauclea latifolia]. AB - OBJECTIVE: To investigate the chemical constituents of Nauclea latifolia, which is an African folk medicine and collected from Guinea. METHOD: The chemical constituents were isolated by silica gel and Sephadex LH-20 column chromatographies, and structurally elucidated by spectral evidence together with physiochemical properties. RESULT: Twelve compounds including 8 triterpenes and 4 sterols were isolated from the roots of N. latifolia, and their structures were defined as 24-en-cycloartenone (1), ursolic aldehyde (2), quinovic acid (3), rotundic acid (4), 3beta,19alpha,23,24-tetrahydroxyurs-12-en-28-oic acid (5), pyrocincholic acid 3beta-O-beta-D-fucopyranoside (6), quinovic acid 3beta-O-beta D-glucopyranoside (7), quinovic acid-3b-O-D-glucopyranosyl-(28-->1)-beta-D glucopyranosyl ester (8), beta-sitosterol (9), stigmastan-3,6-dione (10), stigmast-4-en-6beta-ol-3-one (11) and daucosterol (12) . CONCLUSION: All compounds except for 4,9, andl2 are isolated from this plant for the fist time, while compounds 2, 6, 10, and 11 are isolated from the genus Nauclea for the first time. PMID- 22256757 TI - [Studies on metabolites from marine microorganism Aspergillus terreus collected from nature reserve region of mangrove]. AB - OBJECTIVE: To search for new antitumor active lead compounds from marine microorganism. METHOD: A marine strain, Aspergillus terreus, was cultured and up scaled in artificial seawater media, from which the metabolites were isolated and elucidated by using modern spectroscopy techniques. RESULT: Twelve compounds were isolated from mycelia and fermentation broth of A. terreus. CONCLUSION: Compounds 1-4 were steroids, compounds 5-8 were organic acids and esters, compound 9 was an alkaloid, compound 10 was an isocoumarin, compound 11 was ceramide, compound 12 was propenyl cyclic pentanediol. PMID- 22256758 TI - [Simultaneous determination of three sesquiterpene lactones in Inula hupehensis by RP-HPLC]. AB - OBJECTIVE: A RP-HPLC method was developed for simultaneous determination of bigelovin, ergolide and tomentosin in Inula hupehensis. METHOD: An Agilent C18 column (4.6 mm x 250 mm, 5 microm) was used for separation at 40 degrees C. The mobile phase was acetonitrile-water, and the flow rate was 1.2 mL x min(-1). The detection wavelength was set at 210 nm. RESULT: The method has good linearity in the ranges of 0.01792-0.1792 g x L(-1) (r =0.9999) for bigelovin, 0.0424-0.4240 g x L(-1) (r =0.9996) for ergolide, and 0.044 8-0.4480 g x L(-1) (r = 0.9996) for tomentosin. The average recoveries of bigelovin, ergolide, and tomentosin were 98.5%, 98.2%, 98.4%, with the RSD of 1. 3%, 1.3%, 1.7%, respectively. The results demonstrated that there was a significant difference in the contents of three sequterpene lactones among the tested Inulae Flos. CONCLUSION: The results indicated that the present RP-HPLC method is simple, quick and accurate, and can be used for the quality control of I. hupehensis, especially for the authentication of Inulae Flos. PMID- 22256759 TI - [Study on HPLC chromatographic fingerprint of anti-tumor active site SSCE of Caulis spatholobi]. AB - OBJECTIVE: To establish the chromatographic fingerprints for the anti-tumor flavonoids of Caulis spatholobi (SSCE). It could used to reflect the chemical information in this part comprehensively, and identify the chemical consitituents preliminarily. METHOD: The HPLC-DAD analysis method was performed on the column Kromasil 100-5PHENYL (4.6 mm x 250 mm, 5 microm). The mobile phase was water (0.5% acetic acid)- methanol in gradient elution and the detection wavelength was 254 nm. RESULT: The chromatographic fingerprint of SSCE was established, which showed 16 characteristic peaks from 10 batches of medicinal materials. Among them, the peaks 1, 3, 4, 5, 8, 9, 10, 12, 13, and 16 were identified 3,4 dihodroxybenzoic acid, 4-Hydroxybenzoic Acid, epicatechin, puerarin, daidzein, liquiritigenin, calycosin, genistein, formononetin, and prunetin, respectively. CONCLUSION: The method is convenient, reproducibility and stability. It can used for quality control of the anti-tumor flavonoids of C. spatholobi (SSCE). PMID- 22256760 TI - [Establishment and application of co-transfection screening method for phytoestrogen active constituents]. AB - OBJECTIVE: To establish a highly sensitive screening method for phytoestrogen active constituents and to primarily screen the phytoestrogenic active constituents from the chickpea extractions by the method. METHOD: Human ERalpha cDNA was cloned using MCF-7 total RNA as the template by RT-PCR and then was constructed into a pcDNA3 and named as pERalpha. The cell line MCF-7 was co transfected with pERalpha and the reporter plasmid pERE-Luc which carrying the estrogen response element (ERE) plus the luciferase reporter gene. The luciferase activity was then assayed. The model was optimized by changing the ratio of two plasmids. The feasibility of the optimized model was further proved by the several known phytoestrogen compounds including fermononetin, biochanin A and genistein, et al. As an application of the model, the phytoestrogen activity of the extracts of the chickpea was assayed. RESULT: The recombinant plasmid (pERalpha) can enhance luciferase activities of pERE-Luc transfected MCF-7 cells. The highest transfection efficiency and luciferase activity were found at the ratio of 10:1 (pERE-Luc: pERalpha), the luciferase activity was improved five times as high as the unique pERE-Luc transfection. The co-transfection screening model also indicated that fermononetin, biochanin A and genistein could induce ERE-driven luciferase activity and ICI 182,780 suppressed the induced transcription. As the application of the model, the results showed that the ethanol (70%) total extraction, the ethyl acetate extraction and the ligarine extraction of the chickpea can induce ERE-driven luciferase activity. Concurrent treatment with ICI 182,780 abolished the induced luciferase activity. CONCLUSION: A phytoestrogen active constituent screening mode have been established based on co-transfection method. It is sensitive to assay the phytoestrogen active constituents and can be applied to screen the active component of phytoestrogens. PMID- 22256761 TI - [Effects of aconite root on energy metabolism and expression of related genes in rats]. AB - OBJECTIVE: To study the influence of aconite root, a Chinese medicinal herb with hot property, on energy metabolism and gene expression spectrum, and to analyze the possible mechanism of it effect. METHOD: Thirty two SPF Wistar rats were randomly divided into aconite root group and control group. Decoction of aconite root and NS were intragastrically administrated with the concentration of 10 mL x kg(-1) respectively once a day for 20 days. Temperature, energy intake (EI), digestive energy (DE) and metabolic energy (ME) were measured. The activity of ATPase and succinate dehydrogenase (SDH) in liver was detected by colorimetry. The gene expression of liver was detected with Illumina's rat ref-12 gene array. The differential expression genes were selected, annotated and classified based on gene ontology (GO). Real-time quantitative reverse-transcriptase PCR (Q-RT PCR) was used to test the accuracy of the array results. RESULT: Compared with the control group, the toe temperature (TT) on the 10th and 20th day after the administration,the EI/BM( body mass), DE/BM, ME/BM and the activity of Na+ - K+ - ATPase, Ca2+ - Mg2+ - ATPase and SDH of liver in the aconite root group increased significantly (P<0.05). There were 592 differential expression genes in aconite root group compared with the control group. Based on Go analysis, the most significant genes was related to metabolic process (lgP = - 15.5897). CONCLUSION: Aconite root could improve the energy metabolism in rats, by influencing the metabolic process of sugar, lipid and amino acid, which may be the main molecular mechanism of warming yang and dispelling cold for the treatment of the cold syndrome according to Chinese medicine theory. PMID- 22256762 TI - [Effect of recombinant trichosanthin on proliferation of human cevical cancer Caski cells]. AB - OBJECTIVE: To observe the effects of high expression of recombinant trichosanthin (rTCS) on the cell proliferation and cell cycle of human cervical cancer Caski cells. METHOD: Eukaryotic expression plasmid pcDNA3.1(-)/6His-TCS was constracted and stably transfected into Caski cells. RT-PCR,Western-blot were used to select the clones with rTCS high-expressing. Using pcDNA3.1(-)-transfected cells as the control, MTT assay and flowcytometry were used to elucidate the effects of rTCS high expression on cell growth and cycle regulation in Caski cells. RESULT: The Caski cells with stable high expression of rTCS was successfully established, which could inhibit the cell growth (P<0.01) and arrest Caski cells in G1 and G2 phases (P<0.05) obviously. CONCLUSION: High expression of rTCS can inhibit the growth of Caski cervical cancer cells, which might provide a new pathway for the therapy of cervical cancer. PMID- 22256763 TI - [Studies on influence of Siwu decoction and its composite drugs on chemical induced blood-deficiency model mice]. AB - OBJECTIVE: To investigate Siwu decoction and its composite drugs on the blood deficiency model mice induced by acetylphenyhydrazine and cyclophosphamide. METHOD: Acetylphenyhydrazine and cyclophosphamide were used to copy the blood deficiency model mice. Automatic hematology analyzer was used to test the peripheral hemogram. Weighting method was used to test the liver index and spleen index; Kits for ATPase test was used to test the activities of Na+ - K+ - ATPase/Ca2+ - Mg2+ - ATPase in erythrocyte membrane. Flow cytometry was used to test the bone marrow cells' cell cycle. RESULT: Angelicar Sinensis Radix and Paeoniae Radix Alba had the most effective activity on the peripheral hemogram. Paeoniae Radix Alba, the drug pair including Angelicar Sinensis Radix and the drug- group including Paeoniae Radix Alba had the most effective activity on the liver index. All the drugs, drug-pairs, drug-groups and the formula had effect on the spleen index. To the activity of Na+ - K+ - ATPase in erythrocyte membrane, Rehmanniae Radix Praeparata, the drug-pairs and drug-groups including Angelicar Sinensis Radix exhibited the most effective activity. All the drugs, drug-pairs, drug-groups and the formula had the protective effect on the damaged bone marrow cells. CONCLUSION: Siwu decoction and its composite drugs all had effect on the blood-deficiency model mice, but the action intensity was different. Angelicar Sinensis Radix and Paeoniae Radix Alba exhibited the most effective activity to the protection of the blood-deficiency model mice. PMID- 22256764 TI - [Anti-HIV activity and mechanism of Cynanchum otophyllum glucan sulfate in vitro]. AB - OBJECTIVE: To study anti-HIV activity and mechanism of Cynanchum otophyllum glucan sulfate in vitro. METHOD: Anti-HIV-1 activity was detected with syncytial formation assay and quantitative P24 enzyme-linked immunosorbent assay (ELISA); cytotoxicity was tested with MTT colorimetric assay. Antiviral mechanism was investigated by fusion inhibition, time of addition and pre-treatment experiments. RESULT: The 50% inhibition concentrations (IC50) of PS20 for HIV 1(IIIB), HIV-1(Ada-M), and HIV-1(Bal), were 0.26, 0.46, 0.90 micromol x L(-1), respectively. Studies on antiviral mechanism of PS20 showed that target molecule may be viral envelope protein. CONCLUSION: The results suggested that PS20 had high anti-HIV activity and was worth to be studied further. PMID- 22256765 TI - [Curcumin down-regulates CX3CR1 expression in spinal cord dorsal horn and DRG in neuropathic pain rats]. AB - OBJECTIVE: To investigate the effects of curcumin on the behavior of chronic constrictive injury (CCI) rats and the CX3CR1 expression in spinal cord dorsal horn and dorsal root ganglia (DRG). METHOD: Seventy-two male SD rats were randomly divided into 4 groups: 1) Sham operation group (Sham); 2) Chronic constrictive injury group (CCI); 3) Curcumin treated group (Cur), administrated with curcumin 100 mg x kg(-1) x d(-1) ip for 14 days after CCI; 4) Solvent contrast group (SC), administrated with an equal volume of solvent for 14 days after CCI. Paw thermal withdrawal (PTWL) and paw mechanical withdrawal threshold (PMWT) were measured on 2 pre-operative and 1, 3, 5, 7, 10, 14 post-operative days respectively. The lumbar segments L4-5 of the spinal cord and the L4, L5 DRG were removed at 3, 7, 14 days after surgery. The expression of CX3CR1 was determined by immunohistochemical staining. RESULT: Compared with Sham group, PTWL and PMWT in CCI group were significantly lower on each post-operative day (P<0.01), which reached a nadir on the 3rd day after CCI (PTWL was 6.5 +/- 1.1, PMWT was 22.6 +/- 5.1), and the expression of CX3CR1 were markedly increased in spinal cord dorsal horn and DRG. In Cur group, PTWL were higher than in CCI group on 7, 10, 14 post-operative day (P<0.05), and PMWT were higher than those in CCI group on 10 and 14 post-operative day (P<0.05). The administration of curcumin could significantly attenuate the activation of CX3CR1 induced by CCI. CONCLUSION: The study suggests that curcumin ameliorates the CCI-induced neuropathic pain, probably by attenuating the expression of CX3CR1 in spinal cord dorsal horn and dorsal root ganglia. PMID- 22256766 TI - [Research on mechanism of energy metabolism disorders of rat's hepatoxicity induced by saikosaponins]. AB - OBJECTIVE: To study the influence of saikosaponins on function of rats' liver mitochondria, its liver damage mechanism was discussed. METHOD: Administrating alcohol eluent of saikosaponins of different dose for 15 days to rats, and the high, middle and low lose-group are separately 300, 150, 50 mg x kg(-1) caculated by total saikosaponins. The liver index in serum, the respiratory function of liver mitochondria,the content of ATP and the activity of ATP enzyme were detected. The weight of heart, liver, spleen, lung, renal of rats were precisionly weighed, and the ratio of organ to body were calculated. The histopathologic examination of hepatic tissue were examined. RESULT: Alcohol eluent of saikosaponins of different dose can induce apparent decrease of PCR, P/O value, respiratory oxygen consumption and the activity of ATP enzyme; the level of ALT, AST and ALB in serum increased; the liver weight and the ratio of liver to body increaseed, and the hepatic tissue damage is obvious in the histopathologic examination of hepatic tissue. The above-mentioned changes gradually aggravates with dose increasing, and it is obviously discrepancy compared with control group. CONCLUSION: Alcohol eluent of saikosaponins can induce liver damage by restraining the respiratory function of mitochondria and effecting liver's energy metabolism. Other hepatoxicity mechanism still need to be discussed. PMID- 22256767 TI - [Effects of aromatic resuscitation drugs on blood brain barrier in cerebral ischemia-reperfusion injury model rats]. AB - OBJECTIVE: To research the effects of moschus, borneol, styrax and benzoinum on the structure and function of blood brain barrier in cerebral ischemia reperfusion injury model rats. METHOD: Focal middle cerebral artery occlusion (MCAO) was introduced as an in vivo ischemic model in rats. After 2 h MCAO, nylon suture was pulled up 1 cm to give blood reperfusion. After 22 h reperfusion, all animals were decapitated. The ultramicrostructure of blood brain barrier of ischemia hemisphere side in fronto-parietal cortex region by transmission electron microscope, and the content of VEGF and MMP-9 in ischemia side brain tissue were measured by ELISA. RESULT: In model and solvent group rats, the capillary endothelium cells, astro-glial cells and nerve cells in ischemia hemisphere side in fronto-parietal region were emerged in different degree compared with sham-operated groups, which exhibited tight junction between endothelial cells being opened, basal lamina being dissolved, and permeability increasing, and cellularedema. In borneol (0.2 g x kg(-1)) group rats, the structure of three kinds of cells were nearly normal, which tight junction structure was clear, rough endoplasmic reticulum and polyribosome could be found in cytoplasm. In moschus (66.6 mg x kg(-1)) group rats, the structure of capillary endothelium cells and astrocytes were nearly normal as well as the basal lamina, but the electrons in neurons was maldistribution. In styrax (1.332 g x kg(-1)) group rats, astrocytes were nearly normal, while capillary endothelial cells and neurons exhibited oedema in different degrees. And the basal lamina was discontinuous, augmentation of cell spaces in endothelial cells increased the permeability, some endoplasmic reticulum broadened and ribosome ablated. In benzoinum (1.0 g x kg(-1)) group rats, oedema of capillary endothelial cells and astrocytes was significant, basal lamina broke. Meanwhile endoplasmic reticulum broadened as vacuole, the number of ribosome in rough endoplasmic reticulum decreased, crista mitochondriales in some neurons disappeared as vacuole which hint oedema happened. Results also showed that borneol decrease the level of VEGF in ischemia side brain tissue significantly, while has little influence on the level of MMP-9. Moschus showed the tendency to decrease the level of VEGF and MMP-9 in ischemia side brain tissue. CONCLUSION: Aromatic resuscitation drugs showed the protection effect on blood brain barrier in cerebral ischemia-reperfusion injury rats, which the protection effect of moschus and borneol were better than that of styrax and benzoinum. The mechanism of protection effect maybe related to decrease the level of VEGF and MMP-9. PMID- 22256768 TI - [Effect of zibuganshenfang on the expression and activity of tyrosinase on B16 cells]. AB - OBJECTIVE: ZiBuGanShenFang (ZBGSF) is a traditional herbal formula, which has showed an outstanding therapeutic effect on vitiligo clinically. Our aim is to investigate the influence of ZBGSF drug serum on the expression and activity of Tyrosinase in B16 cells, explore the mechanism of ZBGSF on Vitiligo treatment further. METHOD: tyrosinase activity was measured by zymological methods, western blotting and RT-PCR were used to measure the protein content and mRNA level of tyrosinase and related proteins, respectively. RESULT: ZBGSF drug serum had no effect on the proliferation of B16 cells. But it could promote Tyrosinase activity significantly and increase protein content and mRNA level of tyrosinase and related proteins in B16 cells. CONCLUSION: Promoting the expression of tyrosinase protein and mRNA may be the elementary basis of ZBGSF on Vitiligo treatment. PMID- 22256769 TI - [Study on effect of fushenkeli on expression of TAK1 in human renal tubular epithelial cells and its possible mechanism]. AB - OBJECTIVE: To investigate the effects of fushenkeli on the expression of TAK1 in the proliferation of the renal tubular epithelial cells induced by TGF-beta1 and its possible mechanism. METHOD: Human renal tubular epithelial (HK-2) cells were divided into five groups:blank control group, TGF-beta1 group (5 microg x L(-1)), intervention group 1 (5 microg x L(-1) of TGF-beta1 + 100 mg x L(-1) of fushenkeli), intervention group 2 (5 microg x L(-1) of TGF-beta1 + 500 mg x L(-1) of fushenkeli) and intervention group 3 (5 microg x L(-1) of TGF-beta1 + 1 g x L( 1) of fushenkeli). HK-2 proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay. Type IV collagen in the supernatants of the cultured HK 2 was detected by ELISA at 12, 24, 48 hours respectively. The protein and mRNA expressions of TAK1 was measured by Western blot and real-time quantitative PCR. RESULT: 1) The cell proliferation and the expression of type IV collagen were increased compared with the control group (P<0.05, P<0.01), but they were decreased in intervention group. 2) The expressions of protein and mRNA of TAK1 in TGF-beta1 group were upregulating significantly compared with control group (P<0.01), but they were downregulating in intervention group, especially in intervention group 3. CONCLUSION: Fushenkeli could inhibits TAK1 expression induced by TGF-beta1 in the proliferation of HK-2 cell. PMID- 22256770 TI - [Correlation between change of immunotoxicology indexes of cerum and the occurrence of anaphylaxis in patients induced by qingkailing injection: a clinical study]. AB - OBJECTIVE: To determine the relation between the change of immunotoxicology indexes of serum and the occurrence of anaphylaxis in patients induced by Qingkailing injection, which is composed by cholic acid, mother-of-pearl, gardenia, cornu bubali, isatis root, baicalin, honeysuckle, and to establish the method of detection of the type of anaphylaxis in patients induced by traditional Chinese medicine (TCM) injection. METHOD: In a prospective nested case-control study, we compared the concentration of IgE, IgG, IL-4, histamine of 18 cases in anaphylaxis induced by Qingkailing injection with those from 72 matched controls who remained normal after the using Qingkailing injection. The correlation between the change of IgE, IgG, IL-4, histamine of serum and the occurrence of anaphylaxis in patients induced by Qingkailing injection was determined, and we also evaluate the clinical values of IgE, IgG, IL-4, histamine of serum in diagnosis of anaphylaxis in patients induced by Qingkailing injection by receiver operating characteristic (ROC) curves. RESULT: The concentrations of IgE, IgG, IL 4, histamine of serum of 18 cases were significantly higher than those in controls (P<0.05), the area under the curve (AUC) of IL-4, IgG, IgE, histamine were 0.362 (95.0% CI. for EXP was 0.978-2.405), 0.349 (95.0% CI. for EXP was 1.448-316.232), 0.350 (95.0% CI. for EXP was 1.262-601.306), 0.374 (95.0% CI. for EXP was 1.003-45.413), respectively. CONCLUSION: The allergic reaction caused by Qingkailing injection may be due to type I allergic reactions; The presence of IgE, IgG, IL-4, Histamine can serve as clinical evaluation indicators in evaluation the damage degree of immune system caused by anaphylaxis in patients induced by Qingkailing injection. Cytokines are more likely to become the effective evaluation index in diagnosis of anaphylaxis in patients induced by TCM injection. PMID- 22256771 TI - [Effect of Shuxuetong injection on neuron-specific enolase of serum and recovery of function in patients with acute cerebral infarction]. AB - OBJECTIVE: To observe the clinical effect and the influences of Shuxuetong injection on serum neuron-specific enolase (NSE) level, the neurological deficit and activities of daily living in patients with acute cerebral infarction. METHOD: The 80 patients with acute cerebral infarction were randomly divided into Shuxuetong treatment group (40 cases) and routine control group (40 cases), both received routine treatment, while Shuxuetong injection was given additionally to treatment group. The serum NSE level, the National Insitute of Health Stroke Scale (NIHSS) scores and the clinical effect were observed pre-and post treatment. The Barthel Index (BI) was evaluated after one month. RESULT: The serum NSE level and NIHSS scores in two groups of post-treatment decreased obviously than those of pre-treatment, and after treatment in Shuxuetong treatment group the serum NSE level and NIHSS scores were significantly lower than those in control group, the differences were significant (P<0.05). Effective rate of Shuxuetong treatment group was 87.5%, and control group was 65%, the difference of the clinical effect between the two groups was significance (P<0.05). After one month BI of post-treatment in two groups improved than those of pre-treatment, and Shuxuetong treatment group was significantly better compared with control group (P<0.05). CONCLUSION: Shuxuetong injection has the remarkable neuronal protective effect, can decrease the serum level of NSE after acute cerebral infarction, promote recovery of nerve function, reduce disability rate, and improve quality of life and prognosis of patients with acute cerebral infarction. PMID- 22256772 TI - [Mechanism of traditional Chinese medicine on animal model of Parkinson's disease]. AB - Parkinson's disease (PD) is a common degenerative disease of the central nervous system, but no drug has been found to be surely able to protect neurons so far, delay onset or slow progression of the disease. Currently there are a variety of Chinese formulas, single herb medicines, active fractions and monomers showed prophylactic and therapeutic effect on PD animal models. The mechanisms include protection of substantia nigra cells, improvement of neurotransmitter content, anti-oxidation, immune regulation, enhancement of Western medicine efficacy, reduction of side effects, etc. All these mechanisms may play integrated effect and slow disease progression. In particular, Chinese medicine compound may have some advantages in neuroprotective treatment of PD, because a variety of active ingredients can exert multi-links, multi-levels and multi-targets integrated regulation effect on human body. However, the level and standard of Chinese medicine studies on PD animal still need to be improved. PMID- 22256773 TI - [Review of traditional Chinese medicine external applications to treat chemistry phlebitis]. AB - This article reviewed the literatures in this area over the past 5 years according to three parts: simple traditional Chinese medicine external application, combination of traditional Chinese medicine and Western medicine, combination of traditional Chinese medicine and physical therapy, and came to several effective prescriptions. PMID- 22256774 TI - [Ideas and methods of fresh herb basic research based on constituent structure theory]. AB - Application of fresh herbs is a kind of special forms of traditional Chinese medicine. In China, there is a long and rich experience in clinical application of fresh herbs. Many studies showed that the efficacy of fresh herbs was better than that of dried herbs, but the further study about the difference of their chemical composition, effective components and the overall material basis were few. In this paper, the ideas and methods to study on material basis of the fresh herbs by comparing the difference of the fresh and dry herbs in medicine chemical composition and pharmacological activity of effective components with modern advanced separation, analysis and screening technology under the "Constituent structure theory" were proposed. It was an effectual method for studying on the reasonable development of Chinese medicine and fresh herbs resources. PMID- 22256775 TI - [Investigation and collection development pattern for genuineness of Aconitum carmichali]. AB - OBJECTIVE: To study the collection the development pattern for genuineness of Aconitum carmichalii, which lays a good basis for the sustainable utilization of A. carmichalii resources. METHOD: We adopted the combined methods of investigation of herbal literatures, researching of origins in A. carmichalii and consultation with the experts, identified the development pattern of A. carmichalii. From genuine producing areas and its genuineness. RESULT: The genuine producing area of A. carmichali is Jiangyou district of Sichuan province, genuine medicinal materials of A. carmichalii is mainly oriented by production techniques. It has cultivation techniques, unique and exquisite processing, which have trim root delicately and remove top complexly. CONCLUSION: A. carmichalii from Jiangyou is famous genuine medicinal materials in Sichuan Province. It should strengthen the inheritance and creative research for cultivation techniques, unique and exquisite processing, ensure the safety and effect in medication. PMID- 22256777 TI - Absorption and plasma disposition of genistin differ from those of genistein in healthy women. AB - The chemical forms in which isoflavones appear in food or supplements seem to play an important role in their absorption efficiency. However, the influence of the chemical form of isoflavones on their plasma disposition has never been reported, although the metabolites of isoflavones circulating in the blood may have biological activity themselves. The purpose of the study was to investigate the pharmacokinetic profiles of genistein (GEN) and its phase II metabolites in the plasma and urine of healthy young women after multiple doses of pure aglycone and glucoside forms of GEN. Genistein-7-glucuronide (G-7-G), 4'-glucuronide (G-4' G), 7-sulfate (G-7-S), 4'-sulfate (G-4'-S), 4',7-diglucuronide (G-4',7-diG), and 7-glucuronide-4'-sulfate (G-7-G-4'-S) besides unconjugated GEN were observed in human plasma after ingestion of GEN and its glucoside. Among these metabolites, G 4',7-diG and G-7-G-4'-S were the major ones, comprising both about 30% of the total amount of GEN in plasma. Compared with the aglycone, the amount of total GEN in vivo and those of G-4',7-diG and G-7-G-4'-S were increased after the glucoside intake. No difference was observed in urinary excretion between the aglycone and the glucoside. Overall, the absorption and plasma disposition of GEN were affected by the glucoside form. PMID- 22256778 TI - Contrasting introduction scenarios among continents in the worldwide invasion of the banana fungal pathogen Mycosphaerella fijiensis. AB - Reconstructing and characterizing introduction routes is a key step towards understanding the ecological and evolutionary factors underlying successful invasions and disease emergence. Here, we aimed to decipher scenarios of introduction and stochastic demographic events associated with the global spread of an emerging disease of bananas caused by the destructive fungal pathogen Mycosphaerella fijiensis. We analysed the worldwide population structure of this fungus using 21 microsatellites and 8 sequence-based markers on 735 individuals from 37 countries. Our analyses designated South-East Asia as the source of the global invasion and supported the location of the centre of origin of M. fijiensis within this area. We confirmed the occurrence of bottlenecks upon introduction into other continents followed by widespread founder events within continents. Furthermore, this study suggested contrasting introduction scenarios of the pathogen between the African and American continents. While potential signatures of admixture resulting from multiple introductions were detected in America, all the African samples examined seem to descend from a single successful founder event. In combination with historical information, our study reveals an original and unprecedented global scenario of invasion for this recently emerging disease caused by a wind-dispersed pathogen. PMID- 22256779 TI - Meningitis: is a major cause of disability amongst Papua New Guinea children? AB - PURPOSE: This article is intended to focus on the need for the use of rehabilitation services, for children with meningitis in Papua New Guinea, which is one of largest developing country in The Pacific with diverse culture and landscape. Meningitis is the fifth leading disease that results in disability in the country. The first line of treatment is usually antibiotics, administration of vaccination is also recommended. Currently community based rehabilitation workers and Physiotherapist offer the rehabilitation services. There is a need for the other rehabilitation professionals and appropriate education to the CBR workers, caregivers for providing effective Rehabilitation. METHOD: Articles related to meningitis were recruited through various electronic database such as Ovid SP, MEDLINE, CINHAL, Google Scholar and HINARI and EBSCOhost for full text. The search includes journal articles, editorials, research reports, systematic reviews and books. RESULTS: The neurological sequelae resulting from meningitis are increasing. There is a need for Hib vaccination to reduce the rate of mortality. Physiotherapists are new professionals that emerged since 2006 and are assisting in reducing the motor and neurological disability. CONCLUSIONS: A multidisciplinary approach is required to manage the child with meningitis. Adequate knowledge, resources and assistance about the condition among the health professionals, carers and teachers would enable the children to achieve the quality of life. PMID- 22256780 TI - Preparing for precision medicine. PMID- 22256781 TI - Association of medication with the human plasma N-glycome. AB - Glycosylation is highly variable depending on many environmental factors. Using our fully quantitative high-throughput normal phase hydrophilic interaction liquid chromatography platform we have identified glycosylation changes associated with medication in the plasma N-glycome from three different population cohorts: ORCADES from the Orkney Islands in Scotland and CROATIA-Vis and CROATIA-Korcula from the Croatian islands of Vis and Korcula. Associations between glycosylation and the use of hormones (oral contraceptives, hormone replacement therapy), nonsteroidal anti-inflammatory drugs (aspirin and other NSAIDs), oral steroids (prednisolone) and steroid inhalers (beclomethasone) were investigated. Significant differences associated with usage of oral contraceptives were found with increased core-fucosylated biantennary glycans. Decreases in core-fucosylated biantennary glycans, core-fucosylated triantennary glycans with outer-arm fucose, and high mannosylated glycans were associated with the use of anti-inflammatory drugs. All of the changes in glycosylation were independent of blood group status. In conclusion, hormones and anti-inflammatory medication were associated with changes in glycosylation, possibly as a result of the modulatory effect of these drugs on the inflammatory response. In general, cancer is associated with inflammation, and many glycoproteins in the plasma are acute phase related to the host response. These preliminary data indicate the importance of correcting the levels of glycans used as biomarkers for the effects of medication. PMID- 22256782 TI - Synthesis of conjugated allenes through copper-catalyzed gamma-selective and stereospecific coupling between propargylic phosphates and aryl- or alkenylboronates. AB - A Cu-catalyzed gamma-selective coupling reaction between propargylic phosphates and aryl- or alkenylboronates afforded aryl- or alkenyl-conjugated allenes. The reaction showed excellent functional group compatibility in both the propargylic substrates and the boronates. The reaction of an enantioenriched propargylic phosphate proceeded with excellent chirality transfer with 1,3-anti stereochemistry to give axially chiral aryl- and alkenylallenes. PMID- 22256783 TI - Enhanced catalytic activity of zeolite encapsulated Fe(III)-Schiff-base complexes for oxidative coupling of 2-napthol. AB - Iron(III) Schiff-base complexes of general formula [Fe(L)(2)Cl].2H(2)O, where L = N,N-bis(salicylidene)ethylenediamine and N,N-disalicylidene-1,2-phenylenediamine have been encapsulated within various alkali exchanged zeolites viz. LiY, NaY, and KY by flexible ligand method. The encapsulated complexes are characterized by EDX, scanning electron microscopy (SEM), powder X-ray diffraction (XRD), FT-IR, UV-vis, diffuse reflectance spectroscopy (DRS), electron spin resonance spectroscopy (ESR) and cyclic voltammetry studies. The diffuse reflectance UV-vis spectra of encapsulated complexes show a dramatic red shift of the charge transfer band with increasing electropositivity of the exchangeable cations. The electrochemical analysis predicts the shifting of the reduction potential toward negative values with increasing size of the alkali exchanged cations. The zeolite encapsulated Schiff-base complexes of iron are found to be catalytically active toward the oxidative coupling of 2-napthol. Metal complexes incorporated in potassium exchanged zeolite-Y are found to be more effective for catalytic conversion of 2-naphthol to binaphthol and induces higher selectivity toward the R-conformation. The catalytic conversion of 2-napthol to BINOL is found to depend on the reduction potential of the catalyst, with a more negative reduction potential being better for the catalytic conversion. Density functional calculation is being carried out on both the neat Fe-Salen and Fe-Salophen complexes and those encapsulated in NaY zeolite to investigate change in structural parameters, energies of the HOMO and LUMO, and global hardness and softness. Fukui functions, as local descriptors, are used to analyze the hard hard interaction at a particular site of the complexes. PMID- 22256786 TI - The six-minute walk test using forehead oximetry is reliable in the assessment of scleroderma lung disease. AB - BACKGROUND AND OBJECTIVE: The six-minute walk test (6MWT) is a validated field test in the assessment of interstitial lung disease but may not be so useful in scleroderma (SSc) lung disease. The aim of this study was to determine the reliability of the 6MWT in patients with SSc and correlate results with morphological and functional measures of disease severity. METHODS: Thirty patients (24 female, mean age 47, mean diffusing capacity of carbon monoxide 65%, vital capacity 77% predicted) with American College of Rheumatology classification of SSc performed two 6MWT using various oximetry sites, 1 week apart, and underwent SSc-specific disease severity and quality-of-life measurements, lung function, high-resolution computed tomography and echocardiography. RESULTS: There was good reliability between the two 6MWT (distance; intraclass correlation coefficient 0.95, r = 0.89, Borg; intraclass correlation coefficient 0.85, r = 0.91, both P < 0.00 for r), and Bland Altman plots demonstrate good agreement between measures 1 week apart. Forehead and finger oximetry were more reliable than earlobe (intraclass correlation coefficient 0.64, 0.60, 0.24; r = 0.46, 0.47, 0.14; n = 22, 17, 7, respectively). Forehead desaturation correlated with forced expiratory volume in 1 s (r = 0.55, P = 0.01) and forced vital capacity (r = 0.59, P = 0.01). Distance correlated with all physiological measures: forced expiratory volume in 1 s (r = 0.55, P = 0.01), forced vital capacity (r = 0.61, P = 0.01) and diffusing capacity of carbon monoxide (r = 0.42, P = 0.05). Computed tomography extent and patterns of disease correlated poorly with 6MWT measures, and global measures of SSc correlated only with post-test Borg score. CONCLUSIONS: The 6MWT is feasible and reliable in SSc lung disease, but forehead oximetry should be used. The test measurements correlate reasonably but variably with functional and morphological measures of disease severity. PMID- 22256787 TI - Adaptive trials in paediatric development: dealing with heterogeneity and uncertainty in pharmacokinetic differences in children. AB - AIMS: To assess whether an adaptive design in early clinical trials based on the paradigm of variable dosing and controlled exposure can provide better dosing recommendations compared with the standard fixed dose approach. METHODS: In a clinical trial simulation setting, a paediatric study was simulated using a pharmacokinetic model previously developed for abacavir. Plasma concentrations following the current recommended dose (8 mg kg-1) were taken at standard sampling times, exposures (AUC) were calculated and doses individually adapted to reach the target exposure (i.e. effective exposure in adults). A second round of simulations followed with the adapted doses, and the resulting concentrations were fitted again with the same model. Exposure distributions in both conditions (i.e. fixed dose and controlled exposure) were compared with the target exposure. RESULTS: The AUC distribution after the current dose resulted in a median exposure of 6.43 mg h l-1 (90th percentile 3.13-10.67 mg h l-1). A total of 61 of 128 subjects showed AUC values either too low or to high compared with the target exposure. After dose adjustment, the median exposure was 6.94 mg h l-1 (5.57-8.25 mg h l-1), and only 14 subjects deviated from the target range. CONCLUSIONS: Adaptive randomization can be used to optimize dosing regimens in early paediatric clinical trials. The randomization of patients to target exposure rather than dose increases the probability of demonstrating efficacy (i.e. study power) compared with dose-controlled trials. Furthermore, it contributes to further understanding of the role of dose on the total heterogeneity in clinical response. PMID- 22256788 TI - Clear cell sarcoma of kidney: morphoproteomic analysis reveals genomic correlates and therapeutic options. AB - We used the morphoproteomic approach to analyze clear cell sarcoma of kidney (CCSK), a rare pediatric renal tumor, for which the exact pathogenesis and reliable diagnostic markers remain inexplicable. The tumor, currently being treated with chemotherapy and radiation therapy before or after radical nephrectomy, has demonstrated improved survival rates after introduction of doxorubicin. Three cases of CCSK were studied. We attempted to decipher the possible pathological mechanisms involved in CCSK and to explore the therapeutic targets and plausible less-toxic chemotherapeutic agents. We propose that cyclin D1 may be a central molecule in the pathogenesis of CCSK, driven mainly by the sonic hedgehog and the nuclear factor-kappa B pathways and secondarily by the mammalian target of rapamycin complex mTORC2/PI3K/Akt pathway, heat shock protein 90, and possibly phospholipase D1. Inclusion of relatively less toxic but effective therapies in the form of statins, 13-cis retinoic acid, curcumin, and 17-AAG in the combinatorial treatment strategies, which can target the involved subcellular pathways, may be considered. PMID- 22256789 TI - Width and elevation of the palatal shelves in unoperated unilateral and bilateral cleft lip and palate patients in the permanent dentition. AB - Patients with cleft left lip and palate (CLP) normally require extensive surgery from an early age up to the end of adolescence. These surgeries affect the growth of the maxillofacial complex. The degree to which the cleft itself affects growth of the maxillofacial complex remains poorly understood. By analysing the width and elevation of the palatal shelves in unoperated adolescents and adults with unilateral and bilateral cleft lip and palate (UCLP and BCLP, respectively) and a non-cleft control group, it is possible to gain more insight into the real intrinsic growth potential of the maxillary structures. In this study, dental casts of the full permanent dentition of individuals with unrepaired UCLP (n = 68) and BCLP (n = 13) and non-cleft controls (n = 24) from the same area of Indonesia were digitized three-dimensionally. Maxillary arch width in the canine, premolar and molar regions, and the width and elevation of the palatal shelves were measured. Results showed that in patients with UCLP, the width of the palatal shelves on the cleft side in all regions, and on the non-cleft side in the canine/first premolar region, was significantly smaller compared with the control group. BCLP subjects showed similar deviations. In the UCLP group, the palatal shelves were rotated cranially and positioned more vertically. In the BCLP group, the palatal shelves were inclined by almost 10 degrees more than the control group. The width of the palatal shelf and width of the maxillary arch positively correlated in the canine and first premolar regions for both the cleft and non-cleft side in patients with UCLP, and in the canine region for patients with BCLP. This means that the wider the palatal shelf, the wider the maxillary arch. The elevation of palatal shelves correlated with the maxillary arch width in all regions in patients with UCLP, and only in the premolar region in the control group. Thus, the wider the arch width, the smaller the elevation angle (the maxillary shelves are less vertical). No correlations between palatal shelf elevation and maxillary arch width were found in the BCLP group. This shows that the intrinsic growth potential in patients with UCLP and BCLP is affected by a smaller palatal shelf width and larger elevation of the shelves. These deviations may result in a wider cleft. PMID- 22256790 TI - Coronin-1a inhibits autophagosome formation around Mycobacterium tuberculosis containing phagosomes and assists mycobacterial survival in macrophages. AB - Mycobacterium tuberculosis is an intracellular bacterium that can survive within macrophages. Such survival is potentially associated with Coronin-1a (Coro1a). We investigated the mechanism by which Coro1a promotes the survival of M. tuberculosis in macrophages and found that autophagy was involved in the inhibition of mycobacterial survival in Coro1a knock-down (KD) macrophages. Fluorescence microscopy and immunoblot analyses revealed that LC3, a representative autophagic protein, was recruited to M. tuberculosis-containing phagosomes in Coro1a KD macrophages. Thin-section electron microscopy demonstrated that bacilli were surrounded by the multiple membrane structures in Coro1a KD macrophages. The proportion of LC3-positive mycobacterial phagosomes colocalized with p62/SQSTM1, ubiquitin or LAMP1 increased in Coro1a KD macrophages during infection. These results demonstrate the formation of autophagosomes around M. tuberculosis in Coro1a KD macrophages. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) was induced in response to M. tuberculosis infection in Coro1a KD macrophages, suggesting that Coro1a blocks the activation of the p38 MAPK pathway involved in autophagosome formation. LC3 recruitment to M. tuberculosis-containing phagosomes was also observed in Coro1a KD alveolar or bone marrow-derived macrophages. These results suggest that Coro1a inhibits autophagosome formation in alveolar macrophages, thereby facilitating M. tuberculosis survival within the lung. PMID- 22256791 TI - HLA-E polymorphisms in hematopoietic stem cell transplantation. AB - Human leukocyte antigen (HLA)-E is an inhibitory ligand of natural killer cells and gamma/delta T-cells. Differential expression of HLA-E alleles on the cell surface has been reported to influence outcome of hematopoietic stem cell transplantation (HSCT). We performed HLA-E genotyping in 116 HSCT patients and their HLA-matched unrelated donors. The impact of HLA-E genotypes on patient's overall survival (OS), disease free survival (DFS), cumulative incidences for relapse, transplant-related mortality (TRM) and acute graft vs host disease (aGvHD) was assessed. Neither univariate nor multivariate analysis showed any influence of HLA-E polymorphisms on the investigated endpoints of HSCT in our cohort. We could not confirm any of the previous observations in our cohort and consider it unlikely that HLA-E polymorphisms affect outcome of HSCT. PMID- 22256792 TI - Filaria monitoring visualization system: a geographical information system-based application to manage lymphatic filariasis in Andhra Pradesh, India. AB - Among various public health diseases, filariasis constitutes a major public health problem in India, wherein an estimated 553.7 million people are at risk of infection. The aim of this article is to present a spatial mapping and analysis of filariasis data over a 3-year period (2004-2007) from Karimnagar, Chittoor, East and West Godavari districts of Andhra Pradesh, India. The data include epidemiological and entomological studies (i.e., infection rate, infectivity rate, mosquito per man hour, and microfilaria rate). These parameters were customized on Geographical Information System (GIS) platform and developed filaria monitoring visualization system (FMVS) for identifying the endemic/risk areas of filariasis among these four districts. GIS map for filariasis transmission from the study areas was created and stratified into different spatial entities like low, medium, and high risk zones. On the basis of the data and FMVS maps, it was demonstrated that filariasis remained unevenly distributed within the districts. Balancing the intervention coverage in different villages with overall mass drug administration and continued promotion of the proper use of control measures are necessary for further reduction of filarial cases in these districts. PMID- 22256793 TI - What factors influence help-seeking for hearing impairment and hearing aid adoption in older adults? AB - OBJECTIVE: The purpose of this review paper was to identify factors that influence older adults' decisions to seek help for hearing impairment and to adopt hearing aids. DESIGN: A literature search of abstracts within peer-reviewed journal articles published in English between 1990 and 2010 was conducted in online bibliographic databases using the keywords: hearing; impair* or loss; seek* or candidate* or applicant* or acquir*; and hearing aid* or help or advice. RESULTS: Twenty-two articles that were directly relevant to this topic were included in this review. CONCLUSIONS: The evidence suggests that individuals are more likely to seek help for hearing impairment and/or adopt hearing aids if they: (1) have a moderate to severe hearing impairment and self-reported hearing related activity limitations or participation restrictions; (2) are older; (3) perceive their hearing as poor; (4) consider there to be more benefits than barriers to amplification; and (5) perceive their significant other/s as supportive of hearing rehabilitation. A barrier to help-seeking for hearing impairment and hearing aid adoption appears to be general practitioners' management of age-related hearing impairment. PMID- 22256796 TI - Plate tectonics and planetary habitability: current status and future challenges. AB - Plate tectonics is one of the major factors affecting the potential habitability of a terrestrial planet. The physics of plate tectonics is, however, still far from being complete, leading to considerable uncertainty when discussing planetary habitability. Here, I summarize recent developments on the evolution of plate tectonics on Earth, which suggest a radically new view on Earth dynamics: convection in the mantle has been speeding up despite its secular cooling, and the operation of plate tectonics has been facilitated throughout Earth's history by the gradual subduction of water into an initially dry mantle. The role of plate tectonics in planetary habitability through its influence on atmospheric evolution is still difficult to quantify, and, to this end, it will be vital to better understand a coupled core-mantle-atmosphere system in the context of solar system evolution. PMID- 22256795 TI - Demonstration of alpha-helical structure of peptides tethered to gold surfaces using surface infrared and circular dichroic spectroscopies. AB - Gold and quartz surfaces terminated in an alkane thiol self-assembled monolayer (SAM) that were partially terminated with azide were reacted with a helical peptide containing two alkyne groups in a Cu(I)-catalyzed Huisgen cycloaddition. Surface grazing incidence angle reflection-absorption infrared spectroscopy (GRAS IR) was used to determine that when the Au surface was terminated with 25% of the monolayer containing azide groups, 92% of available azide groups reacted with the peptide. The majority of peptides reacted with both alkynes, resulting in peptides tethered to the surface through two covalent bonds. This was confirmed by comparison to a control peptide containing only one reactive alkyne group. Surface circular dichroic (CD) spectroscopy showed that while the helical structure of the peptide was distorted in the reaction solution, alpha-helical structure was induced when tethered on the SAM functionalized Au surface. Demonstration of the preservation of desired secondary structure of helical elements at a chemically functionalized surface is an important advance in preparing robust biologically mimetic surfaces to integrate functioning proteins into inorganic materials. PMID- 22256797 TI - General stress sigma factor RpoS influences time required to enter the viable but non-culturable state in Salmonella enterica. AB - In stressful conditions, bacteria enter into the viable but non-culturable (VBNC) state; in this state, they are alive but fail to grow on conventional media on which they normally grow and develop into colonies. The molecular basis underlying this state is unknown. We investigated the role of the alternative sigma factor RpoS (sigma(38)) in the VBNC induction using Salmonella Dublin, Salmonella Oranienburg and Salmonella Typhimurium LT2. VBNC was induced by osmotic stress in LT2 and Oranienburg. Dublin also entered the VBNC state, but more slowly than LT2 and Oranienburg did. The LT2 rpoS gene was initiated from an alternative initiation codon, TTG; therefore, LT2 had smaller amounts of RpoS than Dublin and Oranienburg. Oranienburg had a single amino acid substitution (D118N) in RpoS (RpoS(SO)). Disruption of rpoS caused rapid VBNC induction. VBNC induction was significantly delayed by Dublin-type RpoS (RpoS(SD)), but only slightly by RpoS(SO). These results indicate that RpoS delays VBNC induction and that the rapid induction of VBNC in LT2 and Oranienburg may be due to lower levels of RpoS and to the D118N amino acid substitution, respectively. Reduced RpoS intracellular level was observed during VBNC induction. During the VBNC induction, Salmonella might regulate RpoS which is important for maintenance of culturablity under stresses. PMID- 22256799 TI - Exploring the experience of post-stroke fatigue in community dwelling stroke survivors: a prospective qualitative study. AB - PURPOSE: To explore the experience of post-stroke fatigue in community-dwelling stroke survivors with and without post-stroke mood disturbance within one year of stroke. METHODS: This was a prospective qualitative cohort study including semistructured interviews undertaken at baseline (stroke onset), 3, 6, 9 and 12 months in 23 stroke survivors; eight single interviews were held with "supplementary" participants. Qualitative data analysis involved an inductive thematic approach using a process of constant comparison. RESULTS: Thirty-one participants (17 men, 14 women; age range 37-94 years) took part in 122 interviews. The majority of participants was independent and experienced few major depressive symptoms. Three trajectories emerged regarding the participants' experiences of fatigue including experience of fatigue, coping strategies and knowledge. CONCLUSIONS: The results of this study suggest that in spite of reasonable objective physical recovery post-stroke, fatigue in community-dwelling stroke survivors may be disabling. The use of qualitative methodology was sensitive in identifying the factors that play a role in the experience of fatigue. The essential role of health professionals in this context is to provide support and education regarding fatigue and to promote participation after stroke in therapy programs. Routine practice for stroke services should include fatigue advice prior to discharge. PMID- 22256800 TI - Development of a family functioning scale for major depressive disorder. AB - OBJECTIVE: To better understand depression's impact on family functioning from the perspectives of patients with major depressive disorder (MDD) and their partners; to develop and test patient and partner versions of a new self-reported measure, the Depression and Family Functioning Scale (DFFS), for use in clinical trials. METHODS: Concept elicitation interviews were conducted with 32 adults with clinician-diagnosed moderate-to-severe MDD and their respective partners. Twenty-six items were drafted to address relevant aspects of family functioning and were then tested and refined through two iterative sets of cognitive debriefing interviews, each conducted by the same pair of highly experienced researchers, including a licensed clinical psychologist. RESULTS: Depression negatively affects family functioning through poorer communication, increased conflicts, decreased family interaction, and decreased intimacy. No existing instrument measured all domains of interest, or had been rigorously developed and psychometrically validated in the target populations. The draft DFFS items generally tested well and only minor modifications were made to the items after the second set of interviews. Both patients and partners indicated that the final set of 15 DFFS items addresses all concepts of importance. CONCLUSIONS: The DFFS evaluates the impact of depression on family functioning and has the potential to provide important information that can facilitate a more comprehensive evaluation of new treatments in clinical trial settings. Although MDD severity was not confirmed with a standardized interview, in clinical practice in the US, MDD is generally not diagnosed with the use of a structured clinical interview or clinician-administered tool. In the current study, depression severity had little (if any) impact on the specific concepts elicited as being important to family functioning. In fact, patients with milder depression had more insight and were able to better articulate changes in family functioning with treatment. PMID- 22256802 TI - Alleviating suffering 101--pain relief in the United States. PMID- 22256801 TI - Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study. AB - OBJECTIVE: To examine the efficacy and tolerability of rosuvastatin 5 mg at daily and non-daily dosing regimens. RESEARCH DESIGN AND METHODS: A retrospective survey was conducted at nine primary, secondary and tertiary healthcare centres in the United Kingdom. MAIN OUTCOME MEASURES: Changes in lipid fractions from baseline values after more than 3 months' treatment. RESULTS: A total of 325 patients were identified. These patients were aged 63 +/- 10 years, 50% male and prescription was mostly for primary prevention of cardiovascular disease (CVD) (59%). Co-morbidities included: established CVD present in 41%, type 2 diabetes mellitus (15%), hypertension (74%) and smoking (9%). Adverse effects had been documented to simvastatin (75%) or atorvastatin (63%). A total of 289 patients (89%) tolerated rosuvastatin well and were still adherent after a median follow up of 14.9 (3-79) months. The remainder (n = 36; 11%) discontinued the medication after median 5 months' treatment due to adverse effects. Efficacy was assessed in 224 patients who had adequate data. Baseline lipids were total cholesterol (TC) 7.41 +/- 1.50 mmol/L, triglycerides (TG) 2.26 (range 0.36-18.4) mmol/L; high density lipoprotein cholesterol (HDL-C) 1.43 +/- 0.47 mmol/L and low density lipoprotein cholesterol (LDL-C) 4.76 +/- 1.38 mmol/L. Daily rosuvastatin (n = 134) reduced mean TC by 31%, TG 15% and LDL-C 43% (p < 0.001). Rosuvastatin 5 mg 2-3 times weekly (n = 79) reduced TC 26%, TG 16% and LDL-C 32% (p < 0.001). Weekly rosuvastatin (n = 11) reduced TC 17%, LDL-C by 23% (p < 0.001) but had no effect on TGs. Targets were attained in 17% of CHD-risk equivalent patients and 41% of primary prevention patients by National Cholesterol Education Program criteria and 27% and 68% using UK targets. No myositis or rhabdomyolysis was observed and alanine aminotransferase (ALT) and creatine kinase (CK) were similar to baseline. CONCLUSIONS: In this retrospective observational multicentre study, rosuvastatin 5 mg was found to be safe and biochemically effective either as daily or intermittent therapy in patients intolerant to other conventional statin regimens. PMID- 22256803 TI - Painful inequities--palliative care in developing countries. PMID- 22256804 TI - RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. AB - BACKGROUND: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS: Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS: Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.). PMID- 22256805 TI - Preliminary study of two antiviral agents for hepatitis C genotype 1. AB - BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen. METHODS: This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had >=2 log(10) decline in HCV RNA after >=12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period. RESULTS: A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range. CONCLUSIONS: This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.). PMID- 22256807 TI - Cognitive and neurologic outcomes after coronary-artery bypass surgery. PMID- 22256806 TI - Bone-density testing interval and transition to osteoporosis in older women. AB - BACKGROUND: Although bone mineral density (BMD) testing to screen for osteoporosis (BMD T score, -2.50 or lower) is recommended for women 65 years of age or older, there are few data to guide decisions about the interval between BMD tests. METHODS: We studied 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, -1.00 or higher) or osteopenia (T score, -1.01 to -2.49) and with no history of hip or clinical vertebral fracture or of treatment for osteoporosis, followed prospectively for up to 15 years. The BMD testing interval was defined as the estimated time for 10% of women to make the transition to osteoporosis before having a hip or clinical vertebral fracture, with adjustment for estrogen use and clinical risk factors. Transitions from normal BMD and from three subgroups of osteopenia (mild, moderate, and advanced) were analyzed with the use of parametric cumulative incidence models. Incident hip and clinical vertebral fractures and initiation of treatment with bisphosphonates, calcitonin, or raloxifene were treated as competing risks. RESULTS: The estimated BMD testing interval was 16.8 years (95% confidence interval [CI], 11.5 to 24.6) for women with normal BMD, 17.3 years (95% CI, 13.9 to 21.5) for women with mild osteopenia, 4.7 years (95% CI, 4.2 to 5.2) for women with moderate osteopenia, and 1.1 years (95% CI, 1.0 to 1.3) for women with advanced osteopenia. CONCLUSIONS: Our data indicate that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia. (Funded by the National Institutes of Health.). PMID- 22256808 TI - Images in clinical medicine. Pulmonary cement embolism after vertebroplasty. PMID- 22256809 TI - Case records of the Massachusetts General Hospital. Case 2-2012. A 63-year-old woman with dyspnea and rapidly progressive respiratory failure. PMID- 22256810 TI - RAF around the edges--the paradox of BRAF inhibitors. PMID- 22256811 TI - A watershed moment in the treatment of hepatitis C. PMID- 22256813 TI - Clostridium difficile infection and colonization. PMID- 22256815 TI - Panretinal photocoagulation for diabetic retinopathy. PMID- 22256816 TI - Panretinal photocoagulation for diabetic retinopathy. PMID- 22256817 TI - Panretinal photocoagulation for diabetic retinopathy. PMID- 22256818 TI - Restrictions on use of prescribing data for drug promotion. PMID- 22256820 TI - More on hemophilia A induced by ipilimumab. PMID- 22256822 TI - Medical devices--balancing regulation and innovation. PMID- 22256823 TI - Factor XIII in the treatment of hemophilia A. PMID- 22256825 TI - Images in clinical medicine. Tophaceous gout. PMID- 22256827 TI - Aripiprazole augmentation in 13 patients with refractory obsessive-compulsive disorder: a case series. AB - OBJECTIVES: The primary treatment for obsessive-compulsive disorder (OCD) is selective serotonin reuptake inhibitors (SSRI). However, approximately a third of patients do not respond to SSRIs and remain chronically affected. METHODS: Therefore, we added aripiprazole to SSRI therapy for 13 patients with treatment refractory OCD (subjects who failed to respond to SSRI therapy for at least 2 months, and for an average of 508 days). Participants underwent at least 7 weeks of treatment with aripiprazole augmentation. RESULTS: Patients were evaluated using the Y-BOCS and GAF scales. Aripiprazole (3-12 mg)/SSRI co-therapy significantly improved Y-BOCS and GAF scores. However, many patients needed to take antiparkinsonian drugs to control extrapyramidal symptoms. CONCLUSIONS: These results suggest that aripiprazole augmentation of SSRI therapy may be effective for treatment-refractory OCD. PMID- 22256828 TI - Small amygdala-high aggression? The role of the amygdala in modulating aggression in healthy subjects. AB - OBJECTIVE: Several lines of evidence suggest an association between the amygdala and the modulation of aggressive behaviour. Previous morphometric brain imaging studies have focused on the role of the amygdala in the context of pathologic neuropsychiatric conditions like depression, personality disorders, and dysphoric and aggressive behaviour in epilepsy. In order to better understand the physiological role of the amygdala in modulating aggressive behaviour we investigated the relationship between amygdala volumes and lifetime aggression in healthy subjects. METHODS: Morphometric brain scans were obtained in 20 healthy volunteers. Amygdala volumes were measured by manually outlining the boundaries of the structure following a well established and validated protocol. Careful psychiatric and psychometric assessment was done to exclude any psychiatric disorder and to assess lifetime aggressiveness with an established and validated psychometric instrument (i.e., Life History of Aggression Assessment (LHA)). RESULTS: All volunteers scored in the normal range of lifetime aggression. Volunteers with higher aggression scores displayed a 16-18% reduction of amygdala volumes. There was a highly significant negative correlation between amygdala volumes and trait aggression. CONCLUSION: The extent of volumetric differences in this study is remarkable and suggests that amygdala volumes might be a surrogate marker for the personality property of aggressiveness in healthy human beings. PMID- 22256829 TI - Participation of children with ABI and the relationship with discharge functional status. AB - AIMS: To investigate the relationship between children's functional status at discharge from inpatient rehabilitation and participation in home, school and community life following paediatric acquired brain injury (ABI). METHODS: The Child and Adolescent Scale of Participation (CASP) was mailed to 60 families of school-aged children who had sustained an ABI. Functional status data was obtained from the hospital database. Twenty-eight families participated in the study. RESULTS: No statistically significant correlations between functional status at discharge and participation levels were found. CONCLUSIONS: The lack of correlation raised questions regarding the sensitivity of the PEDI and the CASP. Therapists should consider the implication that children who perform well in functional tasks on the PEDI at discharge may not necessarily participate at age expected levels upon return home. Environmental and child factors that hinder or support participation, such as physical infrastructure and impairments resulting from paediatric ABI, need to be considered when planning services. PMID- 22256830 TI - The conductive environment enhances gross motor function of girls with Rett syndrome. A pilot study. AB - INTRODUCTION: Rett syndrome (RTT) is a neurological disorder usually associated with a mutation in the MECP2 gene. Conductive Education (CE) is an educational approach that has not yet been explored with regard to children with RTT. OBJECTIVE: Assessing functional abilities of individuals with RTT due to CE intervention. DESIGN: A single subject, AB design. method: This study assessed the functional skills of three girls with RTT aged 3-5 years before and during participation in a CE programme. RESULTS: Gross motor function improvements were observed at the end of the intervention period. Gross motor skills declined slightly in all participants over the summer holidays but improved again a few months after recommencement of the educational year. CONCLUSION: Replication of this study with more subjects is justified as is comparison with other educational methods. A home intervention programme should be constructed to prevent decline of skills over the summer vacation. PMID- 22256831 TI - Mild traumatic brain injuries in children between 0-16 years of age: a survey of activities and places when an accident occurs. AB - OBJECTIVE: The aim of this study was to identify what activities cause most mild traumatic brain injury (MTBI) among boys and girls between 0-16 years of age. METHODS: Based on a randomized controlled study, a retrospective analysis was conducted among 765 children. RESULT: The most common causes of injury were falls from a height and falls from the same level. The most common place where the accident occurred was at 'home' followed by 'pre-school/school'. The highest incidence was 'play' followed by 'hit by another person', thereafter 'baby nursing'. Boys are more often injured than girls, but with no difference between boys and girls in terms of which activities that cause MTBI. CONCLUSION: Supervision during play at home as well as better designed schoolyards and playgrounds are required to prevent accidents. Furthermore, well-documented medical records are necessary to identify activities causing MTBI among children. PMID- 22256832 TI - Special text messaging communication systems for persons with multiple disabilities. AB - OBJECTIVE: To expand recently-developed text messaging systems with new technology-based solutions so as to allow persons with multiple disabilities to write messages. METHOD: Two case studies were conducted. In Study I, the new technology-based solution involved vocal scanning of the alphabet letters to allow letter selection/writing and was assessed with a woman with blindness and extensive motor disability. In Study II, the new technology-based solution involved a touch-screen superimposed on letter symbols arranged alphabetically and was assessed with a man with acquired brain injury, motor disability and lack of speech. Each study involved an ABAB design. RESULTS: Participants learned to write their messages, to send them out and to listen to incoming messages during intervention sessions of nearly 30 and 20 minutes, respectively. CONCLUSION: Text messaging systems can be developed that allow participants with multiple disabilities to write messages. PMID- 22256833 TI - Partial motor restoration upon administration of sildenafil: a case study. AB - OBJECTIVE: Extensive research in the past decade has confirmed that the adult brain maintains some plasticity, including neural cell birth, migration and integration. Pre-clinical data strongly suggest that phosphodiesterase type 5 (PDE5) inhibitors promote cerebral neovascularization and neurogenesis. Animal studies of cerebral stroke suggest potential regenerative benefits following treatment with sildenafil citrate, a PDE5 inhibitor. This study reports a case in which compassionate use of sildenafil was investigated as a treatment to improve physical functioning, more than 4 decades after development of spastic quadriplegia during the 1st-2nd year of life. METHODS: Sildenafil 100 mg was administered every 24 hours for 7 months. RESULTS: Sildenafil treatment was associated with clinical (functional) improvement. CONCLUSIONS: The activity of sildenafil on cerebral neovascularization and neurogenesis may be the mechanism for the observed functional benefits. PMID- 22256834 TI - Intensive treatment of dysarthria in two adults with Down syndrome. AB - OBJECTIVE: This study investigated the impact of an established behavioural dysarthria treatment on acoustic and perceptual measures of speech in two adults with Down syndrome (DS) and dysarthria to obtain preliminary measures of treatment effect, effect size and treatment feasibility. METHODS: A single subject A-B-A experimental design was used to measure the effects of the Lee Silverman Voice treatment (LSVT(r)) on speech in two adults with DS and dysarthria. Dependent measures included vocal sound pressure level (dB SPL), phonatory stability and listener intelligibility scores. RESULTS: Statistically significant improvements (p < 0.05) in vocal dB SPL and phonatory stability were present following treatment in both participants. Speech intelligibility scores improved in one of the two participants. CONCLUSIONS: These data suggest that people with DS and dysarthria can respond positively to intensive speech treatment such as LSVT. Further investigations are needed to develop speech treatments specific to DS. PMID- 22256835 TI - Fatigue in cerebral palsy: a critical review. AB - OBJECTIVE: Fatigue contributes to the deterioration or cessation of walking ability in adults with cerebral palsy (CP). However, conflict exists as to its role. Studies involving functional tasks reported increased, and earlier onset of, fatigue in CP, whereas laboratory studies have reported individuals with CP to be more fatigue-resistant than their peers. METHODS: A critical review of the literature related to fatigue in CP was conducted. RESULTS: This review describes factors that contribute to the observed fatigue resistance in laboratory tasks and how a decreased force-production in CP can result in higher energy expenditure to perform the same amount of work as their peers. CONCLUSION: More research regarding the process of fatigue and recovery for individuals with CP is needed; specifically studies that focus on functional movements requiring the integration of the whole body, thereby stressing the neuromuscular system in a different way than previously explored. PMID- 22256838 TI - JAVMA news. PMID- 22256836 TI - Participation and environmental aspects in education and the ICF and the ICF-CY: findings from a systematic literature review. AB - BACKGROUND: This paper presents findings from a systematic review of the literature related to participation and the ICF/ICF-CY in educational research. OBJECTIVES: To analyse how and investigate the application of participation in educational research. Specifically, how participation is related to the environmental dimensions availability, accessibility, affordability, accommodability and acceptability. METHODS: A systematic literature review using database keyword searches and refinement protocols using inclusion and exclusion criteria at abstract, full-text and extraction. RESULTS: Four hundred and twenty one initial works were found. Twenty-three met the inclusion criteria. Availability and accommodations are the most investigated dimensions. Operationalization of participation is not always consistent with definitions used. CONCLUSION: Research is developing a holistic approach to investigating participation as, although all papers reference at least one environmental dimension, only four of the 11 empirical works reviewed present a fully balanced approach when theorizing and operationalizing participation; hopefully this balanced approach will continue and influence educational policy and school practice. PMID- 22256839 TI - Corrections regarding hyperkalemia pathophysiology. PMID- 22256840 TI - What is your diagnosis? Extraskeletal osteosarcoma. PMID- 22256841 TI - Pathology in practice. Listeria monocytogenes. PMID- 22256842 TI - A review of canine parainfluenza virus infection in dogs. PMID- 22256843 TI - Effects of intravenous, low-dose ketamine-diazepam sedation on the results of hematologic, plasma biochemical, and coagulation analyses in cats. AB - OBJECTIVE: To evaluate the effects of an IV, low-dose ketamine-diazepam combination used for short-duration chemical restraint on the results of clinicopathologic testing in cats and to assess its practicality and tolerance. DESIGN: Prospective case series. ANIMALS: 42 client-owned cats of various breeds, ages, and health status. PROCEDURES: Blood samples were obtained just prior to and just after IV injection of ketamine chlorhydrate (10 mg) and diazepam (0.5 mg). A CBC, plasma biochemistry panel, and coagulation profile were performed on each sample (ie, before and after chemical restraint). Practicality of the procedure was assessed, and cats were monitored for immediate and delayed effects. RESULTS: Significant changes were observed for most of the analytes tested. However, the magnitude of the observed changes was notably low and likely not of clinical relevance. The chemical-restraint procedure appeared effective, safe, and well tolerated. CONCLUSIONS AND CLINICAL RELEVANCE: The IV, low-dose ketamine-diazepam combination used for short-duration chemical restraint in the present study may be suitable to assist physical restraint for blood sampling for assessment of hematologic, serum biochemical, and coagulation parameters in cats. PMID- 22256844 TI - Erythroleukemia in a retrovirus-negative cat. AB - CASE DESCRIPTION: A 5-year-old spayed female cat was evaluated because of lethargy of 3 days' duration, acute respiratory distress, and anemia. CLINICAL FINDINGS: Physical examination revealed the cat was in good body condition but had pale mucous membranes and elevated heart and respiratory rates. Results of hematologic analysis indicated the cat had severe anemia (Hct, 0.07 L/L; reference range, 0.28 to 0.49 L/L) and marked rubricytosis (19.0 * 10(9) cells/L; reference value, 0 cells/L). Results of serologic and PCR assays for detection of FeLV and FIV and PCR assays for detection of Mycoplasma spp were negative. Cytologic evaluation of a bone marrow aspirate and histologic evaluation of a biopsy specimen revealed a predominance of rubriblasts and rubricytes with granulocytopenia. Cytologic evaluation of fine-needle aspirates of the spleen and liver also revealed numerous rubriblasts. TREATMENT AND OUTCOME: The cat received transfusions of packed RBCs, and supportive treatment was administered. Analysis of test results yielded a diagnosis of acute myeloid leukemia (erythroid subtype). Because of continued hemolysis and anemia in combination with the diagnosis of erythroleukemia (which has a poor prognosis), the cat was euthanized. CLINICAL RELEVANCE: To the authors' knowledge, erythroleukemia has only been reported in cats infected with FeLV. However, results of all diagnostic assays for FeLV were negative in the cat reported here, which suggested that erythroleukemia can develop in cats in the absence of FeLV infection. PMID- 22256845 TI - Use of end-to-side arterial and venous anastomosis techniques for renal transplantation in two dogs. AB - CASE DESCRIPTION: A sexually intact male Old English Sheepdog and a sexually intact female Bull Terrier were evaluated for renal dysplasia and chronic renal failure, respectively. CLINICAL FINDINGS: Both dogs were anemic and had high serum concentrations of urea nitrogen and creatinine. Electrolyte abnormalities (calcium and phosphorus) were also evident. The decision was made to pursue renal transplantation, and donor dogs were identified. TREATMENT AND OUTCOME: End-to side anastomosis of the renal artery and vein of each donor's left kidney to the recipient's ipsilateral external iliac artery and vein, respectively, was performed. The left caudal abdominal musculature was scarified by making an incision, and nephropexy to that musculature was performed with a simple interrupted pattern of polypropylene sutures. No intraoperative or postoperative complications associated with the vascular anastomoses were encountered. Azotemia, anemia, and electrolyte imbalances resolved after transplantation. CLINICAL RELEVANCE: The end-to-side anastomosis technique described here, which is a preferred method in human medicine, was successful, providing an alternative to other renal transplantation techniques in dogs. Additional studies are needed to determine whether any vascular anastomosis technique is preferable for use in dogs requiring renal transplantation. PMID- 22256846 TI - Dexrazoxane treatment of doxorubicin extravasation injury in four dogs. AB - CASE DESCRIPTION: 4 dogs were treated with dexrazoxane for known or suspected doxorubicin extravasation. Records were retrospectively reviewed. Doses and number of doses of dexrazoxane were variable. Dexrazoxane was administered within 2 hours after known extravasation in 3 dogs and 48 hours after suspected extravasation in 1 dog. Additional medical treatments included tissue cooling in all dogs, topically administered dimethyl sulfoxide ointment in 3, and orally administered piroxicam in 1. CLINICAL FINDINGS: Mild erythema and edema at the extravasation site developed within 1 to 6 days after extravasation in the 3 dogs that received dexrazoxane within 2 hours after extravasation. Extensive tissue necrosis occurred in the dog treated 48 hours after suspected extravasation. TREATMENT AND OUTCOME: Only the dog with severe tissue necrosis required surgical intervention. Lesions in the other 3 dogs resolved with medical management alone. All dogs survived the event. CLINICAL RELEVANCE: To date, use of dexrazoxane in the management of doxorubicin extravasation has not been reported in dogs. Treatment was successful in 3 of 4 patients. The most effective dosage and timing of administration are unknown; however, there is evidence to suggest that administration within 6 hours after the event is warranted. Further studies are needed to confirm efficacy and to optimize use of this drug in the prevention and treatment of anthracycline extravasation injury in veterinary patients. PMID- 22256847 TI - Effect of sedation with detomidine on intraocular pressure with and without topical anesthesia in clinically normal horses. AB - OBJECTIVE: To determine the effect of sedation with detomidine on intraocular pressure (IOP) in standing horses and whether topical ocular application of anesthetic alters this effect. DESIGN: Clinical trial. ANIMALS: 15 clinically normal horses. PROCEDURES: Horses were assigned to group 1 (n = 7) or 2 (8). Intraocular pressure measurements were obtained at baseline (before sedation) and 10 minutes after IV administration of detomidine (0.02 mg/kg [0.009 mg/lb]). Group 1 horses had an additional IOP measurement at 20 minutes after sedation. For group 2 horses, topical ocular anesthetic was administered 10 minutes prior to baseline IOP measurements. RESULTS: Mean +/- SD baseline IOP for horses without topical anesthesia (group 1 horses; IOP, 24.30 +/- 3.09 mm Hg) was significantly lower, compared with that of horses with topical anesthesia (group 2 horses; IOP, 30.40 +/- 3.25 mm Hg). Compared with baseline values, IOP at 10 minutes after sedation decreased significantly in all horses (by 3.61 +/- 1.48 mm Hg and 5.78 +/- 4.32 mm Hg in groups 1 and 2, respectively). In group 1 horses, IOP at 10 (20.69 +/- 3.45 mm Hg) and 20 (19.96 +/- 2.13 mm Hg) minutes after sedation was significantly decreased, compared with baseline values; however, the difference between IOP at 10 versus 20 minutes was not significant. The difference in IOP between group 1 and 2 horses at 10 minutes after sedation was not significant. CONCLUSIONS AND CLINICAL RELEVANCE: IV administration of detomidine caused a decrease in IOP in clinically normal horses and may be a safe sedative when performing ocular procedures. PMID- 22256848 TI - Development of a diagnostic diagram for rapid field assessment of acidosis severity in diarrheic calves. AB - OBJECTIVE: To develop a diagnostic diagram for rapid field assessment of acidosis severity in diarrheic calves. DESIGN: Prospective cross-sectional study. ANIMALS: 148 Piedmontese calves (38 calves in preliminary experiments; 83 diarrheic calves and 27 healthy control calves in the primary experiment). PROCEDURES: Physical examination was performed and a standard data collection form was completed for each calf. Blood samples were obtained and submitted for evaluation of acid-base balance, performance of a CBC, and measurement of electrolyte and total protein concentrations. RESULTS: Severe metabolic acidosis (extracellular base excess more negative than -10 mmol/L) was associated with abnormal mental status, delayed or absent suckle reflex, abnormal posture or gait, enophthalmos, and cold oral mucosal membranes. Clinical signs associated with severe metabolic acidosis were arranged into a grid to create a diagnostic diagram. Sensitivity and specificity of the diagnostic diagram for the prediction of severe metabolic acidosis were 88% and 79%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Use of the diagnostic diagram may aid differentiation between severe and nonsevere acidosis patterns as determined on the basis of clinical signs. PMID- 22256849 TI - Metabolic and respiratory derangements associated with death in cold-stunned Kemp's ridley turtles (Lepidochelys kempii): 32 cases (2005-2009). AB - OBJECTIVE: To assess selected clinicopathologic variables at hospital admission (day 1) for cold-stunned Kemp's ridley turtles (Lepidochelys kempii) that died during the first 3 days after admission (nonsurvivors) and turtles that survived (survivors) and to determine the percentage change of each variable from day 1 to day of death (nonsurvivors) or to day 2 or 3 of hospitalization (survivors). DESIGN: Retrospective case-control study. Animals-64 stranded, cold-stunned Kemp's ridley turtles hospitalized from October 2005 through December 2009. PROCEDURES: Blood gas, pH, Hct, and selected biochemical values in blood samples determined on day 1 and day of death (nonsurvivors; n = 32) or day 2 or 3 of hospitalization (survivors; 32) were obtained from medical records. For each variable, initial values and percentage changes (from initial values to values at the day of death or day 2 or 3 of hospitalization) were compared between survivors and nonsurvivors. RESULTS: Compared with blood analysis findings for survivors, nonsurvivors initially had significantly higher potassium concentration and Pco(2) and significantly lower Po(2), pH, and bicarbonate concentration than did survivors. For the first 2 or 3 days of hospitalization, percentage changes in potassium, lactate, and ionized calcium concentrations were significantly higher and percentage changes in pH and plasma glucose and bicarbonate concentrations were significantly lower in nonsurvivors. CONCLUSIONS AND CLINICAL RELEVANCE: At hospital admission, cold-stunned Kemp's ridley turtles were affected by metabolic and respiratory derangements; severe derangements were associated with death. Evaluation of blood gas, pH, Hct, and selected clinicopathologic variables provided useful clinical and prognostic information during rehabilitation of cold-stunned Kemp's ridley turtles. PMID- 22256850 TI - Diagnosis and treatment of Sarcocystis neurona-induced myositis in a free-ranging California sea lion. AB - CASE DESCRIPTION: An underweight, lethargic adult female California sea lion (Zalophus californianus) became stranded along the California shore and was captured and transported to a rehabilitation hospital for assessment and care. CLINICAL FINDINGS: Initial physical assessment revealed the sea lion was lethargic and in poor body condition. Active myositis was diagnosed on the basis of concurrent elevations in activities of alanine aminotransferase and creatine kinase detected during serum biochemical analysis. Infection with Sarcocystis neurona was diagnosed after serologic titers increased 4-fold over a 3-week period. Diagnosis was confirmed on the basis of histopathologic findings, positive results on immunohistochemical staining, and results of quantitative PCR assay on biopsy specimens obtained from the diaphragm and muscles of the dorsal cervical region. TREATMENT AND OUTCOME: Anticoccidial treatment was instituted with ponazuril (10 mg/kg [4.5 mg/lb], PO, q 24 h) and continued for 28 days. Prednisone (0.2 mg/kg [0.09 mg/lb], PO, q 12 h) was administered for 2 days and then every 24 hours for 5 days to treat associated inflammation. At the end of treatment, the sea lion was clinically normal, alanine aminotransferase and creatine kinase values were within reference limits, and antibody titers against S neurona had decreased 6-fold. The sea lion was released approximately 3 months after becoming stranded. CLINICAL RELEVANCE: S neurona-induced myositis was diagnosed in a free-ranging California sea lion. On the basis of the successful treatment and release of this sea lion, anticoccidial treatment should be considered for marine mammals in which protozoal disease is diagnosed. PMID- 22256853 TI - Direct catalytic azidation of allylic alcohols. AB - A direct catalytic azidation of primary, secondary, and tertiary allylic alcohols has been developed. This new azidation reaction affords the corresponding allylic azides in high to excellent yields and regioselectivities. The reaction provides straightforward access to allylic azides that are valuable intermediates in organic synthesis, including the preparation of primary amines or 1,2,3-triazole derivatives. PMID- 22256854 TI - Degradation versus self-assembly of block co-polymer micelles. AB - The stability of micelles self-assembled from block co-polymers can be altered by the degradation of the blocks. Slow degradation shifts the equilibrium size distribution of block co-polymer micelles and changes their properties. The quasi equilibrium scaling theory shows that the degradation of hydrophobic blocks in the core of micelles destabilizes the micelles, reducing their size, while the degradation of hydrophilic blocks forming coronas of micelles favors larger micelles and may, at certain conditions, induce the formation of micelles from individual chains. PMID- 22256855 TI - The effect of galectins on leukocyte trafficking in inflammation: sweet or sour? AB - The trafficking of leukocytes from the blood stream to the surrounding tissue is a fundamental feature of an inflammatory response. Although many of the adhesion molecules and chemokines that direct leukocyte trafficking have been identified, there is still much to be discovered, particularly with regard to the persistence of leukocyte infiltrates in chronic inflammation. Elucidating the molecular mechanisms involved in this process is critical to understanding and treating inflammatory pathologies. Recent studies have identified members of the galectin family as immunoregulatory proteins. Included among the actions of galectins are modulatory effects, both positive and negative, on leukocyte recruitment. The focus of this review is to summarize current knowledge on the role of galectins in leukocyte trafficking during inflammation. A better understanding of the function of this family of endogenous lectins will open new avenues for innovative drug discovery. PMID- 22256856 TI - Disclosure and nondisclosure among people newly diagnosed with HIV: an analysis from a stress and coping perspective. AB - Disclosing HIV status to friends, family, and sex partners is often stressful. However, HIV disclosure has been associated with improved physical health, psychological well-being, and improved health behaviors. The aim of this study was to address some of the gaps in the literature regarding the disclosure process by conducting a mixed-methods study of disclosure in people newly diagnosed with HIV and the relationship of disclosure to stigma and social support. The CHAI (Coping, HIV, and Affect Interview) Study was a longitudinal cohort study that followed individuals who were newly diagnosed with HIV. The study took place from October 2004 to June 2008 in the San Francisco Bay Area. This sample includes data from 50 participants who were interviewed 1, 3, and 9 months following diagnosis with HIV. We identified four main approaches to HIV disclosure that revealed distinct differences in how participants appraised disclosure, whether disclosure was experienced as stressful, and whether disclosure or nondisclosure functioned as a way of coping with an HIV diagnosis. Implications of these findings for disclosure counseling are discussed. PMID- 22256857 TI - ESX-5-deficient Mycobacterium marinum is hypervirulent in adult zebrafish. AB - ESX-5 is a mycobacterial type VII protein secretion system responsible for transport of numerous PE and PPE proteins. It is involved in the induction of host cell death and modulation of the cytokine response in vitro. In this work, we studied the effects of ESX-5 in embryonic and adult zebrafish using Mycobacterium marinum. We found that ESX-5-deficient M. marinum was slightly attenuated in zebrafish embryos. Surprisingly, the same mutant showed highly increased virulence in adult zebrafish, characterized by increased bacterial loads and early onset of granuloma formation with rapid development of necrotic centres. This early onset of granuloma formation was accompanied by an increased expression of pro-inflammatory cytokines and tissue remodelling genes in zebrafish infected with the ESX-5 mutant. Experiments using RAG-1-deficient zebrafish showed that the increased virulence of the ESX-5 mutant was not dependent on the adaptive immune system. Mixed infection experiments with wild type and ESX-5 mutant bacteria showed that the latter had a specific advantage in adult zebrafish and outcompeted wild-type bacteria. Together our experiments indicate that ESX-5-mediated protein secretion is used by M. marinum to establish a moderate and persistent infection. PMID- 22256858 TI - Molecular characteristics and alterations during early development of the human vagina. AB - Unresolved questions remain concerning the derivation of the vagina with respect to the relative contributions from the Mullerian ducts, the urogenital sinus, and the Wolffian ducts. Recent molecular and cellular studies in rodents have opened up a large gap between the level of understanding of vaginal development in mice and understanding of human vaginal development, which is based on histology. To compare the findings in mice with human vaginal development and to address this gap, we analysed molecular characteristics of the urogenital sinus, Wolffian ducts, and Mullerian ducts in 8-14-week-old human specimens using immunohistochemical methods. The monoclonal antibodies used were directed against cytokeratin (CK) 14, CK19, vimentin, laminin, p63, E-cadherin, caspase-3, Ki67, HOX A13, and BMP-4. The immunohistochemical analysis revealed that, during weeks 8-9, the epithelium of the Mullerian ducts became positive for p63 as p63 positive cells that originated from the sinus epithelium reached the caudal tip of the fused Mullerian ducts via the Wolffian ducts. The lumen of the fused Mullerian ducts was closed by an epithelial plug that contained both vimentin positive and vimentin-negative cells. Subsequently, the resulting epithelial tube enlarged by proliferation of basal p63-positive cells. The first signs of squamous differentiation were detected during week 14, with the appearance of CK14-positive cells. According to our results, all three components, namely, the urogenital sinus, Wolffian ducts, and Mullerian ducts, interacted during the formation of the human vagina. The sinus epithelium provided p63-positive cells, the Wollfian ducts acted as a 'transporter', and the Mullerian ducts contributed the guiding structure for the vaginal anlagen. Epithelial differentiation began at the end of the period studied and extended in a caudo-cranial direction. The present study is one of the first to provide up-to-date molecular correlates for human vaginal development that can be compared with the results of cell biological studies in rodents. PMID- 22256859 TI - Engineering of benzylglucosinolate in tobacco provides proof-of-concept for dead end trap crops genetically modified to attract Plutella xylostella (diamondback moth). AB - Glucosinolates are biologically active natural products characteristic of crucifers, including oilseed rape, cabbage vegetables and the model plant Arabidopsis thaliana. Crucifer-specialist insect herbivores, like the economically important pest Plutella xylostella (diamondback moth), frequently use glucosinolates as oviposition stimuli. This suggests that the transfer of a glucosinolate biosynthetic pathway to a non-crucifer would stimulate oviposition on an otherwise non-attractive plant. Here, we demonstrate that stable genetic transfer of the six-step benzylglucosinolate pathway from A. thaliana to Nicotiana tabacum (tobacco) results in the production of benzylglucosinolate without causing morphological alterations. Benzylglucosinolate-producing tobacco plants were more attractive for oviposition by female P. xylostella moths than wild-type tobacco plants. As newly hatched P. xylostella larvae were unable to survive on tobacco, these results represent a proof-of-concept strategy for rendering non-host plants attractive for oviposition by specialist herbivores with the long-term goal of generating efficient dead-end trap crops for agriculturally important pests. PMID- 22256860 TI - Homology model-guided 3D-QSAR studies of HIV-1 integrase inhibitors. AB - In the present study, we report the exploration of binding modes of potent HIV-1 integrase (IN) inhibitors MK-0518 (raltegravir) and GS-9137 (elvitegravir) as well as chalcone and related amide IN inhibitors we recently synthesized and the development of 3D-QSAR models for integrase inhibition. Homology models of DNA bound HIV-1 IN were constructed on the basis of the X-ray crystal structure of the foamy virus IN-DNA complex (PDB ID: 3L2T ) and used for docking. The binding modes of raltegravir and elvitegravir in our homology models are in accordance with those in the foamy virus structure revealing interactions important for inhibitor-IN binding. To gain further insights into the structural requirements for IN inhibition, three-dimensional quantitative structure activity relationship (3D-QSAR) studies were conducted using raltegravir, elvitegravir, and their analogs; our synthesized 3-keto salicylic acid IN inhibitor series; as well as other structurally related HIV-1 IN inhibitors. In the first part of the study with 103 compounds, atom-fit alignments, I and II, and docking-based alignment, III, were used to develop 3D-QSAR models 1, 2, and 3, respectively, each comprising comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSARs. This initial analysis indicated that the docking-based (structure-based) model 3 performed better than the atom fit (ligand-based) models 1 and 2, in terms of statistical significance and robustness. Thus, the docking-based alignment was then subsequently used with an expanded data set of 296 compounds for building a more comprehensive 3D-QSAR, model 4. Model 4 afforded good q2 values of 0.70 and 0.75 for CoMFA and CoMSIA 3D QSARs, respectively, and showed good predictive performance on an external validation test set of 59 compounds with predictive r2 values up to 0.71. The HIV IN-DNA homology model of biological relevance and the comprehensive 3D-QSAR models developed in the present study provide insights and new predictive tools for structure-based design and optimization of IN inhibitors. PMID- 22256862 TI - Combinatorial therapies to overcome B-RAF inhibitor resistance in melanomas. PMID- 22256861 TI - The immune evasion protein Sbi of Staphylococcus aureus occurs both extracellularly and anchored to the cell envelope by binding lipoteichoic acid. AB - The Sbi protein of Staphylococcus aureus comprises two IgG-binding domains similar to those of protein A and a region that triggers the activation of complement C3. Sbi is expressed on the cell surface but its C-terminal domain lacks motifs associated with wall or membrane anchoring of proteins in Gram positive bacteria. Cell-associated Sbi fractionates with the cytoplasmic membrane and is not solubilized during protoplast formation. S. aureus expressing Sbi truncates of the C-terminal Y domain allowed identification of residues that are required for association of Sbi with the membrane. Recombinant Sbi bound to purified cytoplasmic membrane material in vitro and to purified lipoteichoic acid. This explains how Sbi partitions with the membrane in fractionation experiments yet is partially exposed on the cell surface. An LTA-defective mutant of S. aureus had reduced levels of Sbi in the cytoplasmic membrane. PMID- 22256865 TI - A predictive model for efavirenz dosing. PMID- 22256863 TI - Pharmacogenetics of alcoholism: a clinical neuroscience perspective. PMID- 22256866 TI - Report on the pharmacogenomics and personalized medicine 2011 conference: part 1. AB - The joint Wellcome Trust/Cold Spring Harbor Conference on pharmacogenomics and personalized medicine, held in the UK and USA in alternate years, focuses on the opportunities presented by the growing contribution of genomic information and technologies to interdisciplinary approaches in the study of variable human responses to therapeutic agents. This year's meeting provided in depth discussions on diverse fields that are driving forward the new era of personalized medicine including the use of next-generation sequencing technologies to identify common and rare variants determining response to drugs; the interface of pharmacogenomics and complex disease, including cancer; understanding and managing serious adverse drug reactions and public health pharmacogenetics. This year's meeting followed the UK Pharmacogenetics and Stratified Medicine Network 2011 meeting (Cambridge, UK), and marked the Conference's tenth anniversary. In the first of this two-part conference report, sessions on personalized medicines, public health pharmacogenetics and next generation sequencing will be discussed. PMID- 22256867 TI - Lack of association between ABCC2 gene variants and treatment response in epilepsy. AB - AIM: The aim of this study was to replicate a previously reported association between drug resistance in epilepsy patients and the 24C>T variant of the ABCC2 gene that codes for the drug efflux transporter MRP2. PATIENTS & METHODS: We genotyped 381 Caucasian epileptic patients (337 drug resistant and 44 drug responsive) and 247 healthy controls for the ABCC2 gene -24C>T polymorphism (rs717620) and two other nearby SNPs in linkage disequilibrium (1249G>A and 3972C>T). Genotype, allele and three-SNP-haplotype frequencies were compared between groups. Patients were further stratified into four groups according to their degree of drug resistance (as measured by seizure frequency under medication) to perform regression analysis against genotypes and haplotpyes. RESULTS: We detected no significant differences in the distribution of any of the tested alleles, genotypes or haplotypes between the investigated groups. Neither was there an association between genotypes or haplotypes and degree of drug resistance. This study was adequately powered to detect genotype relative risks of above two. CONCLUSION: Although adequately powered to detect the previously reported effect size and although our definition of drug resistance, following the International League Against Epilepsy guidelines, was slightly stricter than in the original study, we failed to confirm an association between the 24C>T variant in the ABCC2 gene and drug resistance in epilepsy. PMID- 22256868 TI - Genomic approach towards personalized anticancer drug therapy. AB - Stratification of patients for multidrug response is a promising strategy for cancer treatment. Genome-based prediction models have great potential for this purpose because the extent of drug sensitivity may be attributed to the heterogeneity of the underlying genetic characteristics of cancer. However, microarray data is difficult to analyze and is not reproducible. Several machine learning algorithms have therefore been developed in a repeatable manner. Random forests algorithm, which uses an ensemble approach based on classification and regression trees, appears to be superior for predicting multidrug sensitivity. This is because ensemble methods are more effective when there are much more predictors than samples. Here, we review recent advances in the development of classification algorithms using microarray technology for prediction of anticancer sensitivity, discuss the availability of ensemble methods for prediction models, and present data regarding the identification of potential responders to FOLFOX therapy using random forests algorithm. PMID- 22256869 TI - Semantically enabling pharmacogenomic data for the realization of personalized medicine. AB - Understanding how each individual's genetics and physiology influences pharmaceutical response is crucial to the realization of personalized medicine and the discovery and validation of pharmacogenomic biomarkers is key to its success. However, integration of genotype and phenotype knowledge in medical information systems remains a critical challenge. The inability to easily and accurately integrate the results of biomolecular studies with patients' medical records and clinical reports prevents us from realizing the full potential of pharmacogenomic knowledge for both drug development and clinical practice. Herein, we describe approaches using Semantic Web technologies, in which pharmacogenomic knowledge relevant to drug development and medical decision support is represented in such a way that it can be efficiently accessed both by software and human experts. We suggest that this approach increases the utility of data, and that such computational technologies will become an essential part of personalized medicine, alongside diagnostics and pharmaceutical products. PMID- 22256870 TI - Integrating heterogeneous high-throughput data for meta-dimensional pharmacogenomics and disease-related studies. AB - The current paradigm of human genetics research is to analyze variation of a single data type (i.e., DNA sequence or RNA levels) to detect genes and pathways that underlie complex traits such as disease state or drug response. While these studies have detected thousands of variations that associate with hundreds of complex phenotypes, much of the estimated heritability, or trait variability due to genetic factors, remain unexplained. We may be able to account for a portion of the missing heritability if we incorporate a systems biology approach into these analyses. Rapid technological advances will make it possible for scientists to explore this hypothesis via the generation of high-throughput omics data - transcriptomic, proteomic and methylomic to name a few. Analyzing this 'meta dimensional' data will require clever statistical techniques that allow for the integration of qualitative and quantitative predictor variables. For this article, we examine two major categories of approaches for integrated data analysis, give examples of their use in experimental and in silico datasets, and assess the limitations of each method. PMID- 22256871 TI - Pharmacogenetics of drugs withdrawn from the market. AB - The safety and efficacy of candidate compounds are critical factors during the development of drugs, and most drugs have been withdrawn from the market owing to severe adverse reactions. Individuals/populations with different genetic backgrounds may show significant differences in drug metabolism and efficacy, which can sometimes manifest as severe adverse drug reactions. With an emphasis on the mechanisms underlying abnormal drug effects caused by genetic mutations, pharmacogenetic studies may enhance the safety and effectiveness of drug use, provide more comprehensive delineations of the scope of usage, and change the fates of drugs withdrawn from the market. PMID- 22256872 TI - Biomarkers predicting treatment outcome in depression: what is clinically significant? AB - AIM: To extend to biomarker studies the consensus clinical significance criterion of a three-point difference in Hamilton Rating Scale for Depression. MATERIALS & METHODS: We simulated datasets modeled on large clinical trials. RESULTS: In a typical clinical trial comparing active treatment and placebo, a difference of three Hamilton Rating Scale for Depression (HRSD) points at the end of treatment corresponds to 6.3% of variance in outcome explained. To achieve a similar explanatory power, genotypes with minor allele frequencies of 5, 10, 20, 30 and 50% need to attain a per allele difference of 4.7, 3.6, 2.8, 2.4 and 2.2 HRSD points, respectively. A normally distributed continuous biomarker will need an effect size of 1.5 HRSD points per standard deviation. A number needed to assess of three suggests that with this effect size, a biomarker will significantly improve the prediction of outcome in one out of every three patients assessed. CONCLUSION: This report provides guidance on assessing clinical significance of biomarkers predictive of outcome in depression treatment. PMID- 22256874 TI - Journal of Women & Aging. From the editor. PMID- 22256875 TI - Factors associated with tobacco smoking practices among middle-aged and older women in Texas. AB - This study examines middle-aged and older women's smoking practices and identifies factors associated with tobacco use and cessation in this population. Data of 593 women were analyzed from a seven-county random household sample in Texas. Sequential multinomial logistic regression compared associations with having never smoked, having quit smoking, and currently smoking. Compared to smokers, never smokers and past smokers were significantly more likely to be older, more educated, of better general health, and report past-year physician visits and fewer depressive symptoms. Mental health and smoking are interrelated, indicating the need for addressing depression in smoking-cessation efforts for aging women. PMID- 22256876 TI - Use of complementary and alternative medicine for physical performance, energy, immune function, and general health among older women and men in the United States. AB - We examined use of complementary and alternative medicine (CAM) for health and well-being by older women and men. Data were from the 2007 National Health Interview Survey, representing 89.5 million Americans ages 50+. Multivariate logistic regression accounted for the survey design. For general health, 52 million people used CAM. The numbers for immune function, physical performance, and energy were 21.6, 15.9, and 10.1 million respectively. In adjusted results, women were much more likely than men to use CAM for all four reasons, especially energy. Older adults, particularly women, could benefit from research on CAM benefits and risks. PMID- 22256877 TI - Critical feminist gerontology: in the back room of research. AB - The article takes a feminist approach to gerontology. It examines the stereotypes of ageism that derive from the relationship between culture and old age. It establishes the requirements for a type of research that reflects women's own experience of growing older, as well as the social construction of values related to women's old age. It focuses on the sociocultural features of this population, which faces old age with certain limitations, but also with unparalleled assets. PMID- 22256878 TI - Improvements in quality of life in women after resistance training are not associated with age. AB - Twenty-three women completed a resistance training program three or four days per week. At baseline and after eight weeks they completed the Vitality Plus Scale measuring exercise-related changes in quality of life. Greater scores indicated better quality of life. Significant improvements in quality of life (p < .001), upper body strength (p < .001), and lower body strength (p < .001) were observed despite training frequency. Age was not associated with quality of life or strength either pre- or posttraining. Resistance exercise three days a week improved quality of life in women, and these improvements were not influenced by age. PMID- 22256879 TI - "Yes, I worry about my weight... but for the most part I'm content with my body": older women's body dissatisfaction alongside contentment. AB - The majority of body image research has studied younger women and girls, ignoring older age groups. Therefore, the purpose of this study was to explore body image among retirement-age women. The sample included 13 women aged 60 to 69. Data collection occurred in two phases. Participants completed individual in-depth interviews and attended follow-up focus groups. Transcripts from both phases of data collection were analyzed thematically using the constant comparison method. Themes emerged regarding the participants' definitions of body image, their attitudes about appearance, and their current perceptions of their bodies. Findings highlighted the complexity of older women's body image as characterized by the dual existence of contentment and desire for physical change. Participants offered explanations for this seeming contradiction, including consideration of age, prioritization of preferred aspects of the body or the self, and focus on aspects of appearance that are perceived to be within the individual's control. PMID- 22256884 TI - Nursing theory and concept development: a theoretical model of clinical nurses' intentions to stay in their current positions. AB - AIM: We describe a theoretical model of staff nurses' intentions to stay in their current positions. BACKGROUND: The global nursing shortage and high nursing turnover rate demand evidence-based retention strategies. Inconsistent study outcomes indicate a need for testable theoretical models of intent to stay that build on previously published models, are reflective of current empirical research and identify causal relationships between model concepts. DATA SOURCES: Two systematic reviews of electronic databases of English language published articles between 1985-2011. DISCUSSION: This complex, testable model expands on previous models and includes nurses' affective and cognitive responses to work and their effects on nurses' intent to stay. The concepts of desire to stay, job satisfaction, joy at work, and moral distress are included in the model to capture the emotional response of nurses to their work environments. The influence of leadership is integrated within the model. IMPLICATIONS FOR NURSING: A causal understanding of clinical nurses' intent to stay and the effects of leadership on the development of that intention will facilitate the development of effective retention strategies internationally. Testing theoretical models is necessary to confirm previous research outcomes and to identify plausible sequences of the development of behavioral intentions. CONCLUSION: Increased understanding of the causal influences on nurses' intent to stay should lead to strategies that may result in higher retention rates and numbers of nurses willing to work in the health sector. PMID- 22256885 TI - Magnetic resonance imaging-detected adaptation and pathology in the distal condyles of the third metacarpus, associated with lateral condylar fracture in Thoroughbred racehorses. AB - REASONS FOR PERFORMING THE STUDY: Lateral condylar (LC) fractures of the third metacarpus (McIII) are a common reason for euthanasia in racehorses, and may be the result of repetitive overloading or cumulative pathological change. Magnetic resonance imaging (MRI) allows monitoring of bone and cartilage to detect pathological and adaptive changes that may be precursors of fracture. OBJECTIVES: To describe bone and cartilage MRI features in the distal condyles of McIII of Thoroughbred racehorses, with and without condylar fracture. HYPOTHESES: 1) A greater degree of bone and cartilage adaptation or pathology will be seen in fractured McIIIs compared with their respective contralateral McIIIs. 2) Contralateral McIIIs will have a greater degree of bone and cartilage adaptation or pathology than McIIIs from control horses that did not sustain a LC fracture. METHODS: The McIIIs from 96 horses subjected to euthanasia at racecourses were divided into 3 groups: Group 1: nonfractured bones from horses without LC fracture; Group 2: nonfractured bones from horses with unilateral LC fracture; and Group 3: fractured bones from horses with unilateral LC fracture. The MR images were examined and graded for bone and cartilage changes. RESULTS: Nine percent of Group 1 (n = 9) and 11% of Group 2 bones (n = 5) had incomplete LC fractures. Focal palmar necrosis was most frequently detected in bones from Group 1 (12%) compared with Groups 2 (9%) and 3 (4%). The prevalence of bone and/or cartilage abnormalities tended to increase from Group 1 to Group 2 to Group 3. CONCLUSIONS: Magnetic resonance imaging is able to detect cartilage and bone changes that may be associated with LC fracture. There was no significant difference in bone/cartilage changes between bones from Groups 1 and 2, despite increased pathology in Group 2 bones. POTENTIAL RELEVANCE: Periodic monitoring of bone and/or cartilage changes in distal McIII of Thoroughbred racehorses may help to prevent catastrophic LC fractures. PMID- 22256886 TI - Modulation of luminescence by subtle anion-cation and anion-pi interactions in a trigonal Au(I)...Cu(I) complex. AB - The trigonally coordinated [AuCu(PPh(2)py)(3)](BF(4))(2) (1) crystallizes in two polymorphs and a pseudopolymorph, each of which contains a trigonally coordinated cation with short Au(I)-Cu(I) separations of ~2.7 A. Under UV illumination, these crystals luminesce different colors ranging from blue to yellow. The structures of these cations are nearly superimposable, and the primary difference resides in the relative placement of the anions and solvate molecules. As confirmed by time dependent density functional theory calculations, it is these interactions that are responsible for the differential emission properties. PMID- 22256888 TI - Test-retest reliability and practice effects of executive function tasks in preschool children. AB - This study examined the test-retest reliability of executive function tasks in preschool children. Measures of working memory, response inhibition, attentional flexibility, and planning were administered to thirty three preschool children between the ages of 36 and 72 months (M = 54.75 months) on two testing occasions approximately three weeks apart (M interval = 21.64 days). Working memory tasks showed higher test-retest reliability than measures of response inhibition. There were significant practice effects on three measures of complex working memory. Implications of these findings for the assessment of executive function in preschool children are discussed. PMID- 22256889 TI - Random blood glucose measurement for epidemiological studies: its significance and limitations. PMID- 22256890 TI - Proteomic analysis of eccrine sweat: implications for the discovery of schizophrenia biomarker proteins. AB - Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and multiple reaction monitoring mass spectrometry (MRM-MS) proteomics analyses were performed on eccrine sweat of healthy controls, and the results were compared with those from individuals diagnosed with schizophrenia (SZ). This is the first large scale study of the sweat proteome. First, we performed LC-MS/MS on pooled SZ samples and pooled control samples for global proteomics analysis. Results revealed a high abundance of diverse proteins and peptides in eccrine sweat. Most of the proteins identified from sweat samples were found to be different than the most abundant proteins from serum, which indicates that eccrine sweat is not simply a plasma transudate and may thereby be a source of unique disease-associated biomolecules. A second independent set of patient and control sweat samples were analyzed by LC-MS/MS and spectral counting to determine qualitative protein differential abundances between the control and disease groups. Differential abundances of selected proteins, initially determined by spectral counting, were verified by MRM-MS analyses. Seventeen proteins showed a differential abundance of approximately 2-fold or greater between the SZ pooled sample and the control pooled sample. This study demonstrates the utility of LC-MS/MS and MRM-MS as a viable strategy for the discovery and verification of potential sweat protein disease biomarkers. PMID- 22256891 TI - Islands and streams: clusters and gene flow in wild barley populations from the Levant. AB - The domestication of plants frequently results in a high level of genetic differentiation between domesticated plants and their wild progenitors. This process is counteracted by gene flow between wild and domesticated plants because they are usually able to inter-mate and to exchange genes. We investigated the extent of gene flow between wild barley Hordeum spontaneum and cultivated barley Hordeum vulgare, and its effect on population structure in wild barley by analysing a collection of 896 wild barley accessions (Barley1K) from Israel and all available Israeli H. vulgare accessions from the Israeli gene bank. We compared the performance of simple sequence repeats (SSR) and single nucleotide polymorphisms (SNP) marker data genotyped over a core collection in estimating population parameters. Estimates of gene flow rates with SSR markers indicated a high level of introgression from cultivated barley into wild barley. After removing accessions from the wild barley sample that were recently admixed with cultivated barley, the inference of population structure improved significantly. Both SSR and SNP markers showed that the genetic population structure of wild barley in Israel corresponds to the three major ecogeographic regions: the coast, the Mediterranean north and the deserts in the Jordan valley and the South. Gene flow rates were estimated to be higher from north to south than in the opposite direction. As has been observed in other crop species, there is a significant exchange of alleles between the wild species and domesticated varieties that needs to be accounted for in the population genetic analysis of domestication. PMID- 22256892 TI - Coping with multiple sclerosis as a couple: 'peaks and troughs' - an interpretative phenomenological exploration. AB - PURPOSE: Multiple Sclerosis (MS) is a chronic degenerative condition where illness uncertainty is a key difficulty that people with MS and their significant others have to cope with. Clinicians acknowledge that people with MS need to be seen in the context of their families, however there is little knowledge on what to expect about how people cope as a couple, which this study set out to explore. METHOD: Interpretative Phenomenological Analysis (IPA) exploring, through semi structured interviews, how seven couples, where one had MS, experienced coping with their situation. RESULTS: Two overarching themes pertaining to coping as a couple emerged from the data: Coping Together: "Peaks and Troughs" and Coping Over the Long Haul, with each overarching theme relating to sub-themes. Two integrative themes emerged also, which were called Faith in Self and Faith in Each Other. CONCLUSIONS: These results will assist clinicians better comprehend how those with MS and their spouses cope in an interconnected way and this in turn affects their experience of rehabilitation. Results from this research indicated that clinicians need to be sensitive to the individual coping strategies of both members of a couple where one has MS, and address the changing needs of their relationship. PMID- 22256893 TI - Heart rate variability in the irritable bowel syndrome: a review of the literature. AB - BACKGROUND: Patients with irritable bowel syndrome (IBS) often present with disturbances of bowel habits (diarrhea, constipation) and abdominal pain/discomfort that are modulated by the autonomic nerve system (ANS). In this narrative review, we analyzed studies that measured ANS functioning in IBS by means of heart rate variability (HRV). METHODS: The PUBMED was searched with the keywords 'irritable bowel syndrome' AND ('heart rate variability' OR 'autonomic function'). We included only papers that used 'traditional' HRV indices and diagnosed IBS based on Manning or Rome criteria. Studies were sub-grouped according to methodological features of HRV analysis (24-h monitoring, short-term laboratory records, records during sleep). KEY RESULTS: Most studies reported no difference in HRV when the IBS population was compared to healthy controls. Dividing the IBS sample into subgroups--according to their predominant bowel symptoms, the severity of clinical course, the presence of depressive symptoms, or a history of abuse in the past--revealed changes in autonomic functioning. CONCLUSIONS & INFERENCES: Patients with IBS appear to experience symptoms that may be the result of changes in ANS functioning. HRV measures in clinical routine may allow assessing these changes, but further studies performed in a standardized fashion should improve the validity of HRV measures for clinical research first. PMID- 22256894 TI - Protein function and allostery: a dynamic relationship. AB - Allostery is a fundamental process by which distant sites within a protein system sense each other. Allosteric regulation is such an efficient mechanism that it is used to control protein activity in most biological processes, including signal transduction, metabolism, catalysis, and gene regulation. Over recent years, our view and understanding of the fundamental principles underlying allostery have been enriched and often utterly reshaped. This has been especially so for powerful techniques such as nuclear magnetic resonance spectroscopy, which offers an atomic view of the intrinsic motions of proteins. Here, I discuss recent results on the catabolite activator protein (CAP) that have drastically revised our view about how allosteric interactions are modulated. CAP has provided the first experimentally identified system showing that (i) allostery can be mediated through changes in protein motions, in the absence of changes in the mean structure of the protein, and (ii) favorable changes in protein motions may activate allosteric proteins that are otherwise structurally inactive. PMID- 22256895 TI - Nanoporous Pt@Au(x)Cu(100-x) by hydrogen evolution assisted electrodeposition of Au(x)Cu(100-x) and galvanic replacement of Cu with Pt: electrocatalytic properties. AB - Electrodeposition of high-surface-area nanoporous Au-Cu foams under conditions of hydrogen codeposition is studied. The honeycomb-like Au(x)Cu(100-x) foams with 0 <= x <= 100 are electrodeposited by controlling the amount of corresponding ions in the solution. The amount of metal ions in deposited films follows that in used electrolytes. Compared to monometallic foams, the Au(x)Cu(100-x) structures are characterized by smaller ligament or particle sizes (less than 10 nm) and improved stability. The addition of even a small amount of Cu to the Au matrix is found to dramatically improve the stability of the structure in air environment or an acidic medium. Pt@Au(x)Cu(100-x) structures are formed by the galvanic displacement of Cu from Au(x)Cu(100-x) templates. During the displacement of Cu by Pt, Au serves as a buffer, decreasing mechanical stresses and preventing the detachment of the foam from the substrate. The surface ratio of Pt to Au atoms is controlled by adjusting the amount of Cu in the template. Pt@Au(x)Cu(100-x) electrodes are investigated as novel electrocatalysts for methanol oxidation in alkaline media. The Au-enriched surfaces show higher catalytic activity toward methanol oxidation, while the electrodes with a higher amount of Pt are more stable. PMID- 22256899 TI - Ir(I)-catalyzed intermolecular regio- and enantioselective hydroamination of alkenes with heteroaromatic amines. AB - A cationic Ir(I)-C(3)-TUNEPHOS complex catalyzed an intermolecular hydroamination of styrene derivatives with various heteroaromatic amines. The reaction gave Markovnikov products with perfect regioselectivity and good enantioselectivity under solvent-free conditions. PMID- 22256898 TI - Photoinitiated nitric oxide-releasing tertiary S-nitrosothiol-modified xerogels. AB - The synthesis of a tertiary thiol-bearing silane precursor (i.e., N-acetyl penicillamine propyltrimethoxysilane or NAPTMS) to enable enhanced NO storage stability at physiological temperature is described. The novel silane was co condensed with alkoxy- or alkylalkoxysilanes under varied synthetic parameters (e.g., water to silane ratio, catalyst and solvent concentrations, and reaction time) to evaluate systematically the formation of stable xerogel films. The resulting xerogels were subsequently nitrosated to yield tertiary RSNO-modified coatings. Total NO storage ranged from 0.87 to 1.78 MUmol cm(-2) depending on the NAPTMS concentration and xerogel coating thickness. Steric hindrance near the nitroso functionality necessitated the use of photolysis to liberate NO. The average NO flux for irradiated xerogels (20% NAPTMS balance TEOS xerogel film cast using 30 MUL) in physiological buffer at 37 degrees C was ~23 pmol cm(-2) s(-1). The biomedical utility of the photoinitiated NO-releasing films was illustrated by their ability to both reduce Pseudomonas aeruginosa adhesion by ~90% relative to control interfaces and eradicate the adhered bacteria. PMID- 22256896 TI - Trafficking and release of Leishmania metacyclic HASPB on macrophage invasion. AB - Proteins of the Leishmania hydrophilic acylated surface protein B (HASPB) family are only expressed in infective parasites (both extra- and intracellular stages) and, together with the peripheral membrane protein SHERP (small hydrophilic endoplasmic reticulum-associated protein), are essential for parasite differentiation (metacyclogenesis) in the sand fly vector. HASPB is a 'non classically' secreted protein, requiring N-terminal acylation for trafficking to and exposure on the plasma membrane. Here, we use live cell imaging methods to further explore this pathway to the membrane and flagellum. Unlike HASPB trafficking in transfected mammalian cells, we find no evidence for a phosphorylation-regulated recycling pathway in metacyclic parasites. Once at the plasma membrane, HASPB18-GFP (green fluorescent protein) can undergo bidirectional movement within the inner leaflet of the membrane and on the flagellum. Transfer of fluorescent protein between the flagellum and the plasma membrane is compromised, however, suggesting the presence of a diffusion barrier at the base of the Leishmania flagellum. Full-length HASPB is released from the metacyclic parasite surface on to macrophages during phagocytosis but while expression is maintained in intracellular amastigotes, HASPB cannot be detected on the external surface in these cells. Thus HASPB may be a dual function protein that is shed by the infective metacyclic but retained internally once Leishmania are taken up by macrophages. PMID- 22256900 TI - Viscosity measurements of antibody solutions by photon correlation spectroscopy: an indirect approach - limitations and applicability for high-concentration liquid protein solutions. AB - Photon correlation spectroscopy (PCS) is compared with classic rheological measurements using the cone-and-plate technique for the determination of the viscosity of protein solutions. The potential advantages using PCS are small sample volume and fast determination of zero-shear viscosity. The present study assesses potentials and limitations of the applicability of this method for the determination of viscosity of antibody solutions in protein science development. The principle of the assay is based on the determination of the apparent hydrodynamic radius of commercial available latex beads of known size added to protein solutions. Using the Stokes-Einstein equation, the hydrodynamic radius can be converted to viscosity. Several latex particle sizes and concentrations were evaluated and the assay optimized. The PCS assay for viscosity determination was tested using water/glycerol-mixtures, where the viscosity was measured with rheometer using the cone-and-plate method and also compared with published data. Different protein solutions of bovine serum albumin, lysozyme and monoclonal antibodies were then used and the PCS results were compared with viscosity data obtained by the cone-and-plate method. It could be shown that the PCS assay has limitations for the determination of the viscosity of protein solutions, especially monoclonal antibodies. The main reason is due to protein-latex bead interactions leading to the formation of larger aggregates. The use of surface modification of the latex beads can in principle prevent this interaction. PMID- 22256901 TI - Strength of women. PMID- 22256904 TI - Solvothermal synthesis of NiCo alloy icosahedral nanocrystals. AB - New dimensional NiCo alloy icosahedral nanocrystals with controllable size have been first reported and synthesized through an Ostwald ripening process in a template-absent solvothermal reaction system. The proposed synthesis is corroborated by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), energy-dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS). The as-obtained NiCo icosahedral nanocrystals exhibit the size- and component-dependent magnetic behaviors. The coercivity (H(c)) depends on both the magnetocrystalline and structure anisotropy, and the saturation magnetizations (M(s)) decided by the content of Co. H(c) decreases from 189.02 to 147.95 Oe with the increase of the icosahedral NCs size from 200 to 850 nm. Especially, the H(c) of the icosahedral NCs at 157.38 Oe is higher than that of nanospheres at 104.02 Oe. In addition, M(s) and H(c) increased with the increasing Co content. It can be an ideal building block for applications in magnetic media, sensors, and other devices. PMID- 22256903 TI - Synovial fluid chondroitin sulphate indicates abnormal joint metabolism in asymptomatic osteochondritic horses. AB - REASONS FOR PERFORMING STUDY: Alternative methods to evaluate the joint condition in asymptomatic osteochondrosis dissecans (OCD) and other joint diseases may be useful. OBJECTIVES: To investigate possible changes in synovial fluid composition that may lead to joint conditions in asymptomatic OCD, in mature horses. METHODS: Animals aged >2 years, of different breeds, with OCD in the intermediate ridge of distal tibia, symptomatic or not, were studied. Synovial fluid samples (10 healthy; 11 asymptomatic OCD; 25 symptomatic OCD) were collected by arthroscopy from 29 horses. Glycosaminoglycans (GAGs) were analysed by a combination of agarose gel electrophoresis and enzymatic degradation with specific GAG lyases. The viscosity, white blood cell (WBC) count, protein concentration and hyaluronic acid (HA) molecular weight were also determined. RESULTS: The method used here to analyse synovial fluid GAGs is reliable, reproducible and specific. The main synovial fluid GAGs are HA and chondroitin sulphate (CS), 93% and 7% respectively in normal horses. In symptomatic OCD, the concentrations of both increased (expressed as GAG/urea ratios), but CS increased more. The CS increased also in asymptomatic OCD. An inflammatory reaction was suggested by the increased WBC counts in OCD. The molecular weight of the synovial fluid HA was reduced in OCD, explaining the lower viscosity observed. CONCLUSIONS: The increased CS in synovial fluid of OCD joints in mature horses suggests that the synovial fluid CS and the WBC count are good markers of the joint conditions, allowing the identification of pathological phase in joint diseases. POTENTIAL RELEVANCE: The analysis of synovial fluid GAGs shows that cartilage damage occurs even in asymptomatic OCD, implying that arthroscopic removal of osteochondral fragments should be performed even in asymptomatic OCD. PMID- 22256906 TI - The Dutch Activity Card Sort institutional version was reproducible, but biased against women. AB - PURPOSE: To examine the reproducibility of the institutional version of the Dutch Activity Card Sort (ACS-NL) and the possible presence of gender bias. METHODS: Older rehabilitation inpatients (N = 52) were included. Intra- and inter-rater agreement for the ACS-NL total and subscale scores was examined by intraclass correlations (ICC), and agreement of individual items by the kappa coefficient (k). Gender bias was examined by the proportion of men and women selecting an ACS item. RESULTS: ICC for inter-rater agreement of the ACS total score ranged between 0.78 and 0.87, ICC for intra-rater agreement ranged between 0.79 and 0.89. Median inter-rater kappa for ACS-NL items was 0.72 (interquartile scores; 0.62-0.80). The inter-rater agreement (k = 0.43) and intra-rater agreement (k = 0.39) for the five most important activities was lower. Twenty ACS activities favoured men and seven activities favoured women. As a result, men scored systematically higher on the ACS-NL than women. Logistic regression analysis correcting for activity engagement level confirmed our findings. CONCLUSIONS: The reproducibility of the ACS-NL was high. The ACS-NL institutional version score may be biased in favour of men. PMID- 22256907 TI - Recovery from visual neglect after right hemisphere stroke: does starting point in cancellation tasks change after 6 months? AB - In the acute phase of stroke, patients with left visual neglect (VN) automatically orient to the right hemispace. This study examined the presence of rightward bias after right hemisphere stroke within 10 days of stroke onset and after 6 months. Our sample comprised 43 patients and 49 healthy controls. Presence of VN was evaluated with the six conventional subtests of the Behavioral Inattention Test (BITC). Starting points were determined in three BITC cancellation tasks by measuring the distance between the starting point and the median line of the stimulus sheet in centimeters. Activities of daily living (ADL) were assessed with the Barthel Index. At baseline VN patients showed more robust rightward bias than patients without VN. The magnitude of rightward bias decreased clearly in the VN patients at follow-up. A favorable ADL outcome was observed in 90% of the patients with VN and in all of the patients without VN. The magnitude of rightward bias differed clearly between the patient groups and controls. Our result implies that VN was likely to have improved as measured by BITC sum scores, but symptoms of rightward attention bias were still detected. We therefore suggest that, for clinical purposes, it is important that attention bias is measured accurately after right hemisphere stroke. PMID- 22256908 TI - Mixed-treatment comparison of anabolic (teriparatide and PTH 1-84) therapies in women with severe osteoporosis. AB - PURPOSE: The recent development of compounds with anabolic action on bone have increased the range of therapeutic options for the treatment of osteoporosis and the prevention of fractures. Two major PTH analogs, the synthetic full-length 1 84 PTH molecule and the recombinant 1-34 N-terminal fragment (teriparatide), are available for the treatment of osteoporosis in many countries. There have bee no comparative trials on the bone anabolic effects of these compounds. MATERIALS AND METHODS: In this study we applied a mixed treatment comparison (MTC) to compare the efficacy of teriparatide versus PTH 1-84 for the prevention of vertebral and non-vertebral fractures in women with severe osteoporosis. With this approach the relative treatment effect of one intervention over another can be obtained in the absence of head-to-head comparison. Among the candidate papers selected for analysis, two randomized controlled trials investigating the effects of teriparatide and PTH 1-84 met the selection criteria and underwent MTC analysis. RESULTS: Based on a fixed-effect MTC model analysis of data from two RCTs, teriparatide (20 ug/day) showed a 70% and 94% probability of being the best treatment for the prevention of vertebral and non-vertebral fractures, respectively. Together with a lack of statistical significance, this study has additional limitations. Some differences in trial procedures and populations exist; another limitation concerns the impossibility of carrying out a randomized effect model MTC, due to sample exiguity. Furthermore, in order to consider unknown or unmeasured differences of covariates across trials, a random-effects approach would be preferred in order to assess the presence of heterogeneity across comparisons. In contrast, in our analysis a fixed-effect MTC model only was used. CONCLUSIONS: Teriparatide is expected to provide a greater efficacy over PTH 1-84 with both vertebral and non-vertebral fracture prevention in postmenopausal women with severe osteoporosis. PMID- 22256909 TI - A multicenter, randomized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis. AB - OBJECTIVE: To compare the efficacy and safety of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T) and dexamethasone 0.1%/tobramycin 0.3% (DM/T) ophthalmic suspensions in a Chinese population with ocular inflammation associated with blepharokeratoconjunctivitis (BKC). RESEARCH DESIGN AND METHODS: This study was a multicenter, randomized, investigator-masked, parallel-group clinical trial. Patients aged >=18 years with a clinical diagnosis of BKC in at least one eye received LE/T or DM/T administered 4 times daily for 2 weeks. At baseline and on days 3, 8, and 15 (visits 2, 3, and 4), clinical assessments of ocular signs and symptoms, visual acuity (VA), biomicroscopy, and intraocular pressure (IOP) were performed in both eyes. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline (CFB) to visit 4 in the signs and symptoms composite score in designated study eyes using a non-inferiority metric to compare LE/T to DM/T. Safety evaluation included adverse events, biomicroscopy findings, and changes in VA and IOP. CLINICAL TRIAL REGISTRATION: NCT number, NCT01028027. RESULTS: A total of 308 patients were included in the per protocol population (n = 156 LE/T, n = 152 DM/T). A significant CFB in composite signs and symptoms was seen with both treatments at each follow-up visit (p < 0.0001). The mean (SD) CFB at visit 4 was -11.63 (4.56) and -12.41 (4.71) in the LE/T and DM/T groups, respectively, and the upper bound of the 90% confidence interval for the difference was less than the prespecified non-inferiority margin. Comparable results were found for secondary efficacy outcomes. Patients treated with DM/T experienced a significantly greater increase in mean CFB in IOP compared to those treated with LE/T at all follow-up visits (p <= 0.0186) and nearly twice as many IOP elevations >=5 mmHg (p = 0.0020). CONCLUSION: Treatment with LE/T was at least as effective as DM/T in Chinese patients with BKC and had a better safety profile with respect to change in IOP. PMID- 22256912 TI - Professional Services Review: the audit process we have to have. PMID- 22256911 TI - Quantotypic properties of QconCAT peptides targeting bovine host response to Streptococcus uberis. AB - Mammalian host response to pathogens is associated with fluctuations in high abundant proteins in body fluids as well as in regulation of proteins expressed in relatively low copy numbers like cytokines secreted from immune cells and endothelium. Hence, efficient monitoring of proteins associated with host response to pathogens remains a challenging task. In this paper, we present a targeted proteome analysis of a panel of 20 proteins that are widely believed to be key players and indicators of bovine host response to mastitis pathogens. Stable isotope-labeled variants of two concordant proteotypic peptides from each of these 20 proteins were obtained through the QconCAT method. We present the quantotypic properties of these 40 proteotypic peptides and discuss their application to research in host-pathogen interactions. Our results clearly demonstrate a robust monitoring of 17 targeted host-response proteins. Twelve of these were readily quantified in a simple extraction of mammary gland tissues, while the expression levels of the remaining proteins were too low for direct and stable quantification; hence, their accurate quantification requires further fractionation of mammary gland tissues. PMID- 22256914 TI - Late mortality after severe traumatic brain injury. AB - The first Australian report is welcome and should help inform policy. PMID- 22256915 TI - Should infants and adults sleep in the same bed together? AB - Health professionals should educate families about risk factors for accidental asphyxiation in shared-sleeping arrangements. PMID- 22256916 TI - A watchdog to bite the giants? AB - Ray Moynihan explores the push for new powers and strong opposition to it. PMID- 22256917 TI - Do the benefits of screening mammography outweigh the harms of overdiagnosis and unnecessary treatment?--yes. AB - Yes. Public health adviser David Roder and Cancer Council Australia CEO Ian Olver believe the reduction in breast cancer mortality in Australia reflects both treatment and screening effects. PMID- 22256918 TI - Do the benefits of screening mammography outweigh the harms of overdiagnosis and unnecessary treatment?--no. AB - No. Breast cancer researchers Robin Bell and Robert Burton believe that screening can result in overdiagnosis. PMID- 22256919 TI - What is wrong with Medicare? AB - Lack of audit control and inability to adapt to change leads to massive waste. PMID- 22256920 TI - Professional Services Review: unnatural justice. AB - Lack of transparency and reliance on statistics alone make doctors vulnerable. PMID- 22256921 TI - Comparative effectiveness research--a proposal for a new NHMRC funding stream. AB - Opportunities to examine the relevance of health interventions in actual clinical scenarios need to be created. PMID- 22256922 TI - Designing payments for GPs to improve the quality of diabetes care. AB - Three features are essential in designing the flexible funding payments and pay for-performance elements. PMID- 22256923 TI - Can Alberta's primary care networks provide any lessons for Medicare Locals? AB - Australia's Medicare Locals are in a formative period, and any comparison so far has focused on the United Kingdom. PMID- 22256924 TI - Falling through the cracks: the hidden economic burden of chronic illness and disability on Australian households. AB - Major reform plus targeted strategies have the potential to provide relief. PMID- 22256925 TI - Workforce shortages in medical oncology: a looming threat to quality cancer care. AB - Supply must meet demand to maintain our high standards of cancer care. PMID- 22256926 TI - Adhesive tape in the health care setting: another high-risk fomite? PMID- 22256927 TI - Early experience with antimicrobial stewardship ward rounds at a tertiary referral hospital. PMID- 22256928 TI - Decision making in older patients with advanced cancer: does doctor know best? PMID- 22256929 TI - Uptake of oncology multidisciplinary meeting recommendations. PMID- 22256930 TI - Tools to inform general practitioners' decision making on driving following a stroke. PMID- 22256931 TI - Prevalence and characteristics of complaint-prone doctors in private practice in Victoria. PMID- 22256932 TI - Should doctors feel able to practise according to their personal values and beliefs? PMID- 22256933 TI - Late mortality after severe traumatic brain injury in New South Wales: a multicentre study. AB - OBJECTIVES: To determine the long-term mortality pattern of adults with severe traumatic brain injury (TBI), and to identify the risk factors associated with death in this group. DESIGN, PATIENTS AND SETTING: Inception cohort study of 2545 adults consecutively discharged from one of three metropolitan tertiary, post acute inpatient rehabilitation services of the New South Wales Brain Injury Rehabilitation Program from 1 January 1990 to 1 October 2007 after inpatient rehabilitation for primary TBI. MAIN OUTCOME MEASURE: Survival status at 1 October 2009. RESULTS: 258 deaths were recorded in this sample, yielding a standardised mortality ratio of 3.19 (95% CI, 2.80-3.60). Risk of death remained elevated above societal norms for at least 8 years after discharge from rehabilitation. Mortality risk was increased by: functional dependence at discharge; age at injury; pre-injury drug and alcohol misuse; pre-injury epilepsy; and discharge to an aged care facility. The risk of death from external causes, and respiratory system and nervous system disorders was six to seven times higher, and the risk of death from disorders of the digestive system, and mental and behavioural disorders was five times higher in adults with severe TBI than in the general population. CONCLUSIONS: People who survive to discharge from inpatient rehabilitation following a severe TBI were found to have a sustained increase in risk of death for eight years post discharge. Various demographic and injury-related variables selectively increase mortality risk and may be modifiable in order to reduce the observed increase in mortality. PMID- 22256934 TI - Energy drinks: health risks and toxicity. AB - OBJECTIVES: To describe the epidemiology and toxicity of caffeinated energy drink exposures in Australia. DESIGN, SETTING AND SUBJECTS: Retrospective observational study analysing data from calls regarding energy drink exposures recorded in the database of an Australian poisons information centre over 7 years to 2010. MAIN OUTCOME MEASURES: Type of exposure; co-ingestants; symptoms reported; and reported hospitalisations. RESULTS: Callers reported 297 exposures to energy drinks, which showed an increasing annual trend from 12 in 2004 to 65 in 2010. Median age for the 217 subjects with recreational exposure was 17 years (interquartile ratio [IQR], 15-21; range, 11-60) and 57% were male. One hundred recreational users co-ingested other substances, predominantly alcohol (50) or other caffeinated products (44). The number of energy drinks consumed in one session varied greatly (median, 5 units; IQR, 3-8; range, 1-80). Most subjects who reported recreational use reported experiencing symptoms (87%). The most common symptoms were palpitations, agitation, tremor and gastrointestinal upset. Twenty-one subjects had signs of serious cardiac or neurological toxicity, including hallucinations, seizures, arrhythmias or cardiac ischaemia. At least 128 subjects (57 with no co-ingestants) required hospitalisation. CONCLUSIONS: Reports of caffeine toxicity from energy drink consumption are increasing, particularly among adolescents, warranting review and regulation of the labelling and sale of these drinks. Educating adolescents and increasing the community's awareness of the hazards from energy drinks is of paramount importance. PMID- 22256935 TI - A national census of medicines use: a 24-hour snapshot of Australians aged 50 years and older. AB - OBJECTIVE: To explore the current use of conventional and complementary medicines in Australians aged >= 50 years. DESIGN, SETTING AND PARTICIPANTS: Cross sectional postal survey sent to a random sample of 4500 Australians aged >= 50 years between June 2009 and February 2010. MAIN OUTCOME MEASURES: Prevalence of medicines use, reasons for medicines use and sources of medicines. RESULTS: Response rate was 37.3%. Medicines use was very common; 87.1% of participants took one or more medicines and 43.3% took five or more in the previous 24 hours. Complementary medicines were used by 46.3% of participants, 87.4% of whom used both conventional and complementary medicines. The most commonly used medicines were antihypertensive agents (43.2% of participants), natural marine and animal products including fish oil and glucosamine (32.4%) and lipid-lowering agents (30.4%). Doctors recommended 79.3% of all medicines and 93.0% of conventional medicines. Pharmacists commonly recommended occasional medicines (ie, as needed), while friends, family and media most often influenced use of complementary medicines. CONCLUSIONS: The use of multiple medicines is common and higher than reported in the 1995 National Health Survey. Today, much medicines use is to prevent future disease by influencing risk factors. High levels of polypharmacy highlight the need to support the safe and effective use of medicines in the community. Although doctors recommend or prescribe most medicines, self-directed medication use is common. This highlights the need for consumer access to accurate information and strategies to improve health literacy about medicines. PMID- 22256936 TI - Outcomes of lymphoma in South Australia, 1977-2007. AB - OBJECTIVE: To determine survival rates of patients with lymphoma in South Australia. DESIGN AND SETTING: De-identified data from the SA Cancer Registry on all patients with lymphoma were analysed, as well as the subgroup treated at the Royal Adelaide Hospital (RAH). For non-Hodgkin lymphoma (NHL), we used the International Working Formulation (IWF) grading. SA and RAH data on survival rates were compared with those for the whole of Australia and the United States. PATIENTS: All patients diagnosed with lymphoma and treated in SA in 1977-2007. OUTCOME MEASURES: 5-year survival rates for patients with lymphoma, by type of lymphoma and age. RESULTS: Of the total of 8651 patients with lymphoma, 939 were classified as having Hodgkin lymphoma (HL) and 7712 as having NHL. Of those with NHL, 1805 had low-grade, 3576 intermediate-grade, and 510 high-grade NHL. In another 1821 patients, the data were insufficient to make an IWF grading. There was a substantial increase in 5-year survival rates for patients with lymphoma between 1977 and 2007 in SA. While the increase in 5-year survival rates for HL was 7.6 percentage points, survival rates peaked at 88%. For NHL, there was an 18.7 percentage points increase in 5-year survival rates. The first significant increase of 7 percentage points was associated with the introduction of bone marrow transplantation; this was maintained with the increase in 5-year survival rates reaching 14 percentage points by 1995-1999. Since 1999, there has been a further increase of 5 percentage points in 5-year survival rates with the introduction of rituximab. CONCLUSION: Outcomes in patients with NHL have improved significantly, most likely because of the use of bone marrow transplantation and rituximab. Hospital- and state-based cancer registry data reflect the reality of population outcomes and the impact of new technologies. PMID- 22256937 TI - The shortage of medical oncologists: the Australian Medical Oncologist Workforce Study. AB - OBJECTIVE: To determine current and projected supply, demand and shortfall of medical oncologists (MOs) and the Australian chemotherapy utilisation rate. DESIGN, SETTING AND PARTICIPANTS: A 2009 cross-sectional observational study of Australian adult medical oncology practice work patterns. INSTRUMENT: Electronic or paper self-administered questionnaire. MAIN OUTCOME MEASURES: The 2009 and projected (2014) supply, demand and shortfall of full-time equivalent (FTE) MOs, and the chemotherapy utilisation rate. RESULTS: 476 medical oncology positions comprising 234 FTE MOs were identified. Of the 150 medical oncology practices, 117 (78%) were in metropolitan locations and 33 (22%) were in rural locations. The average number of new patients seen per FTE MO was 270 patients (ranging by state from 191 to 343). The demand for FTE MOs was estimated at 326 to 391 in 2009 and 361 to 432 in 2014. The shortfall of FTE MOs was estimated at 92 to 157 in 2009 and 84 to 156 in 2014. The chemotherapy utilisation rate was 19%. CONCLUSIONS: The current shortage of MOs is expected to persist in the future. National strategies are needed to increase the capacity of the medical oncology workforce and the chemotherapy utilisation rate. PMID- 22256938 TI - Prevalence of polycystic ovary syndrome in a sample of Indigenous women in Darwin, Australia. AB - OBJECTIVE: To document the prevalence of polycystic ovary syndrome (PCOS) and its associated characteristics in a sample of urban Indigenous women. DESIGN: A cross sectional survey of Indigenous women, including biochemical and anthropometric assessments. PCOS was assessed using the National Institutes of Health 1990 criteria. SETTING AND PARTICIPANTS: Indigenous women, aged 15-44 years, living in a defined area in and around Darwin, Northern Territory, Australia, September 2003-March 2005. MAIN OUTCOME MEASURES: Proportion of participants with PCOS overall and measures of obesity. RESULTS: Among 248 women eligible for assessment, the proportion who had PCOS was 15.3% (95% CI, 10.8%-19.8%). The proportion with PCOS was similar across age groups, but was significantly higher (P = 0.001) in women with a body mass index (BMI) of >= 30.0 kg/m(2) (30.5%) compared with women with a BMI of 25.0-29.9 kg/m(2) (8.2%) or a BMI of < 25.0 kg/m(2) (7.0%). CONCLUSIONS: A high proportion of these Indigenous women had PCOS. The significant relationship with obesity gives a strong rationale for screening for PCOS during routine care of Indigenous women who are obese and of reproductive age. PMID- 22256939 TI - Lessons learned from 20 years of newborn screening for cystic fibrosis. AB - OBJECTIVE: To compare three cystic fibrosis (CF) newborn screening strategies used in Victoria since 1989. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of newborn screening and clinical records for people with CF born in Victoria between 1989 and 2008 to compare screening strategies: repeat immunoreactive trypsinogen (IRT) testing (IRT/IRT, 1989-1990), IRT and p.F508del mutation analysis (IRT/p.F508del, 1991-2006) and IRT with analysis of 12 CFTR mutations (IRT/12 mutations, 2007-2008). MAIN OUTCOME MEASURES: Total number of infants screened, people identified with CF (by screening or clinical diagnosis), number of CF-affected terminations of pregnancy, and number of carriers detected. RESULTS: There were 420 people born with CF (live-birth prevalence, 1/3139; 95% CI, 1/2853-1/3462) and 78 CF-affected pregnancy terminations (overall prevalence, 1/2647; 95% CI, 1/2425-1/2896). Of the babies born with CF, 283 (67.4%) were detected by newborn screening alone, 61 (14.5%) had meconium ileus, 33 (7.9%) had a family history of CF, nine (2.1%) were diagnosed antenatally, and 34 (8.1%) were missed by screening (17 missed because IRT level was < 99th percentile, two with repeat IRT level not elevated, 14 without a screened CFTR mutation, and one with missing data). The sensitivities of the protocols were 86.6% for IRT/IRT, 89.9% for IRT/p.F508del, and 95.8% for IRT/12 mutations. Including 12 mutations in the analysis detected one patient who would otherwise have been missed and, had this protocol been implemented from 1989, it would have detected four others. CONCLUSION: Most babies with CF without meconium ileus, a family history or antenatal diagnosis are detected by newborn screening. Despite improved sensitivity with the 12-mutation analysis, most infants detected would have been diagnosed using the IRT/p.F508del protocol. PMID- 22256940 TI - Synovial sarcoma of the pharynx causing airway obstruction. AB - This is the first reported Australian case of synovial sarcoma of the pharynx. A 29-year-old man had a large hypopharyngeal mass excised and received radiotherapy and chemotherapy. No recurrence was seen 12 months later. PMID- 22256941 TI - A seminal monograph: Mackay and Burnet's Autoimmune diseases. AB - Mackay and Burnet's Autoimmune diseases, published in 1962, marked the beginning of autoimmunity as a clinical science and led to the future acceptance of the existence of autoimmunity. While there is still controversy regarding the mechanisms of autoimmunity, the authors' insightful hypothesis based on clonal selection theory and the emergence of "forbidden clones", due to somatic mutations, is still current, with recent evidence giving further credence to this hypothesis. We salute Mackay and Burnet on the 50th anniversary of this seminal publication. It is particularly pleasing that it has an iconic Australian origin. PMID- 22256942 TI - We'll drink to that: the 200th anniversary of Australia's oldest hospital. AB - An elderly lady with an interesting clinical history. PMID- 22256945 TI - Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago-vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study. AB - BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), gamma-aminobutyric acid type B (GABA(B)), gamma aminobutyric acid type A (GABA(A)), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. METHODS: Using immunohistochemistry, we investigated the distribution of mGluR5, GABA(A), GABA(B), CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. KEY RESULTS: MGluR5, GABA(B), CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABA(A) receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. CONCLUSIONS & INFERENCES: Human mGluR5, GABA(A,B), and CB(1,2) receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective. PMID- 22256946 TI - Nurse practitioners in Ontario primary healthcare: referral patterns and collaboration with other healthcare professionals. AB - The purpose of this study is to examine referrals of nurse practitioners providing primary healthcare (PHC NPs) to better understand how PHC NPs collaborate with other healthcare professionals and contribute to interprofessional care. The analysis is based on the data from a survey of 378 PHC NPs registered in Ontario, Canada in 2008. Overall, 69% of PHC NPs made referrals to family physicians (FPs) and 67% of PHC NPs received referrals from FPs. Almost 50% of PHC NPs had bidirectional referrals between them and FPs. Eighty-nine percent of PHC NPs made referrals to specialist physicians. Bidirectional referrals between PHC NPs and social workers and mental health workers were common in family health teams and community health centers. Patterns of referrals (bidirectional, unidirectional and no referrals) between PHC NPs and FPs, social workers, mental and allied health workers in various practice settings indicate development of collaborative relationships between PHC NPs and other healthcare professionals and reflect the influence of practice models on delivery of interprofessional care. These findings are discussed in light of the development of NPs' role and integration of PHC NPs in the Ontario healthcare system. Implications for policy changes and future research are also suggested. PMID- 22256947 TI - Wet season range fidelity in a tropical migratory ungulate. AB - 1. In migratory populations, the degree of fidelity and dispersal among seasonal ranges is an important population process with consequences for demography, management, sensitivity to habitat change and adaptation to local environmental conditions. 2. Characterizing patterns of range fidelity in ungulates, however, has remained challenging because of the difficulties of following large numbers of marked individuals across multiple migratory cycles and of identifying the appropriate scale of analysis. 3. We examined fidelity to wet season (i.e. breeding) ranges in a recently declining population of wildebeest Connochaetes taurinus Burchell in northern Tanzania across 3 years. We used computer-assisted photographic identification and capture-recapture to characterize return patterns to three wet season ranges that were ecologically discrete and topographically isolated from one another. 4. Among 2557 uniquely identified adult wildebeest, we observed 150 recaptures across consecutive wet seasons. Between the two migratory subpopulations, the probability of remaining faithful to wet season areas ranged between 0.82 and 1.00. Animals from a non-migratory segment of the population (near Lake Manyara National Park) were rarely observed in other wet season ranges, despite proximity to one of the migratory pathways. 5. We found no effect of sex on an individuals' probability of switching wet season ranges. However, the breeding status of females in year i had a strong influence on patterns of range selection in year i + 1, with surviving breeders over three times as likely to switch ranges as non-breeders. 6. Social-group associations between pairs of recaptured animals were random with respect to an individual's wet season range during the previous or forthcoming wet seasons, suggesting that an individual's herd identity during the dry season does not predict wet season range selection. 7. Examining fidelity and dispersal in terrestrial migrations improves our understanding of the constraints that migrants experience when they face rapid habitat changes or fluctuations in environmental conditions. PMID- 22256948 TI - Why should we need a European Federation of Addiction Societies? PMID- 22256949 TI - The history of the development of buprenorphine as an addiction therapeutic. AB - This paper traces the early 21st century success of the agonist-antagonist buprenorphine and the combination drug buprenorphine with naloxone within the broader quest to develop addiction therapeutics that began in the 1920s as the search for a nonaddictive analgesic. Drawing on archival research, document analysis, and interviews with contemporary actors, this paper situates the social organization of laboratory-based and clinical research within the domestic and international confluence of several issues, including research ethics, drug regulation, public attitudes, tensions around definitions of drug addiction, and the evolving roles of the pharmaceutical industry. The fervor that drove the champions of buprenorphine must be understood in relation to (1) the material work of research and pharmaceutical manufacturing; (2) the symbolic role of buprenorphine as a solution to numerous problems with addiction treatment evident by the mid-1970s; the destigmatization and individualization of addicts as patients; and (3) the complex configurations of public and private partnerships. PMID- 22256950 TI - Initial hydrogenations of pyridine on MoP(001): a density functional study. AB - The initial hydrogenations of pyridine on MoP(001) with various hydrogen species are studied using self-consistent periodic density functional theory (DFT). The possible surface hydrogen species are examined by studying interaction of H(2) and H(2)S with the surface, and the results suggest that the rational hydrogen source for pyridine hydrogenations should be surface hydrogen atoms, followed by adsorbed H(2)S and SH. On MoP(001), pyridine has two types of adsorption modes, i.e., side-on and end-on; and the most stable eta(5)(N,C(alpha),C(beta),C(beta),C(alpha)) configuration of the side-on mode facilitates the hydrogenation of pyridine. The optimal hydrogenation path of pyridine with surface hydrogen atoms in the Langmuir-Hinshelwood mechanism is the formation of 3-monohydropyridine, followed by producing 3,5-dihydropyridine, in which the two-step hydrogenations take place on the C(beta) atoms. When adsorbed H(2)S is considered as the source of hydrogen, slightly higher hydrogenation barriers are always involved, while the energy barriers for hydrogenations involving adsorbed SH are much lower. However, the hydrogenation of pyridine should be suppressed by the adsorption of H(2)S, and the promotion effect of adsorbed SH is limited. PMID- 22256951 TI - Blindly using Wald's test can miss rare disease-causal variants in case-control association studies. AB - There are four tests--the likelihood ratio (LR) test, Wald's test, the score test and the exact test--commonly employed in genetic association studies. On comparison of the four tests, we found that Wald's test, popular in genome-wide screens due to its low computational demands, exhibited a paradoxical behaviour in that the test statistic decreased as the effect size of the variant increased, resulting in a loss of power. The LR test always achieved the most significant P values, followed by the exact test. We further examined the results in a real data set composed of high- and low-cholesterol subjects from the Dallas Heart Study (DHS). We also compared the single-variant LR test with two multi-variant analysis approaches--the burden test and the C-alpha test--in analysing the sequencing data by simulation. Our results call for caution in using Wald's test in genome-wide case-control association studies and suggest that the LR test is a better alternative in spite of its computational demands. PMID- 22256952 TI - Ligand-free Ni-catalyzed reductive cleavage of inert carbon-sulfur bonds. AB - A catalytic reductive cleavage of C(sp(2))- and C(sp(3))-SMe bonds under ligandless conditions is presented. The method is characterized by its wide scope and high chemoselectivity profile including challenging substrate combinations, allowing the design of orthogonal and site-selectivity approaches. PMID- 22256953 TI - Experimental and modeling approaches in characterizing coating uniformity in a pan coater: a literature review. AB - This review provides a comprehensive record of experimental and modeling approaches that can be used to study the effect of critical process parameters affecting the coating uniformity in pharmaceutical coating operation. Explicit reference is given to the development of the approach and its previous usage with particular emphasis on the advantages, limitations and model assumptions. PMID- 22256954 TI - Polymorphs and aurophilic interactions in colorless crystals of Au2(MU-1,2 bis (diphenylarsino)ethane)X2, (X = Cl, Br, I). AB - Solutions containing the components Au(+), dpae (dpae is 1,2 bis (diphenylarsino)ethane), and X(-) (X is Cl, Br, or I) can produce two different types of crystals with the composition Au(2)(MU-dpae)X(2): colorless blocks and colorless needles. Crystallographic studies of these crystals show that they are polymorphs with different structural motifs. In the alpha-polymorphs, which are isostructural, individual molecules of Au(2)(MU-dpae)X(2) form discrete dimers through two identical Au...Au contacts. In the beta-polymorphs, which each have unique crystallographic parameters, the Au(2)(MU-dpae)X(2) molecules assemble into polymeric chains through aurophilic interactions. The Au...Au contacts in the alpha-polymorph (3.1163(2), 3.1064(3), and 3.0842(2) A for Cl, Br, I, respectively) are somewhat shorter than those in the beta-polymorph (3.1668(3), 3.1042(8), and 3.1046(2) for Cl, Br, I respectively). The systematic study we now report shows an increase in the strength of this aurophilic interaction for the alpha-form in the series X = Cl < Br < I, which is in good agreement with theoretical studies by Pyykko and his co-workers. PMID- 22256956 TI - Processing relative clauses in supportive contexts. AB - Results from two self-paced reading experiments in English are reported in which subject- and object-extracted relative clauses (SRCs and ORCs, respectively) were presented in contexts that support both types of relative clauses (RCs). Object extracted versions were read more slowly than subject-extracted versions across both experiments. These results are not consistent with a decay-based working memory account of dependency formation where the amount of decay is a function of the number of new discourse referents that intervene between the dependents (Gibson, 1998; Warren & Gibson, 2002). Rather, these results support interference based accounts and decay-based accounts where the amount of decay depends on the number of words or on the type of noun phrases that intervene between the dependents. In Experiment 2, presentation in supportive contexts was directly contrasted with presentation in null contexts. Whereas in the null context the extraction effect was only observed during the RC region, in a supportive context the extraction effect was numerically larger and persisted into the following region, thus showing that extraction effects are enhanced in supportive contexts. A sentence completion study demonstrated that the rate of SRCs versus ORCs was similar across null and supportive contexts (with most completions being subject extractions), ruling out the possibility that an enhanced extraction effect in supportive contexts is due to ORCs being less expected in such contexts. However, the content of the RCs differed between contexts in the completions, such that the RCs produced in supportive contexts were more constrained, reflecting the lexical and semantic content of the preceding context. This effect, which we discuss in terms of expectations/lexico-syntactic priming, suggests that the enhancement of the extraction effect in supportive contexts is due to the facilitation of the subject-extracted condition. PMID- 22256957 TI - The "Miserable Minority" following mild traumatic brain injury: who are they and do meta-analyses hide them? AB - Ruff et al. (1994; Ruff, Camenzuli, & Mueller, 1996) hypothesized that some mild traumatic brain injury (MTBI) patients will suffer chronic symptomatic complaints and impairments, identifying this subgroup as the "miserable minority." However, several meta-analyses of the effects of MTBI have been published (e.g., Rohling et al., 2011) showing no significant cognitive impairments following recovery. Recently Pertab, James, and Bigler (2009) suggested that meta-analysis might be obscuring impairments in some MTBI patients, presenting a hypothetical score distribution to illustrate their claim. Our statistical analyses of their hypothetical figure and of several other potential distributions containing an impaired subgroup that varied as a function of effect size and base rate of occurrence did not support the existence of a miserable minority that is obscured in meta-analyses by the larger group of MTBI patients experiencing full recovery. Indeed, given our recent published MTBI effect size of -0.07 (Rohling et al., 2011), for an impaired subgroup to exist, the level of impairment would have to be just under a tenth of a standard deviation, equivalent to a WMS-IV Index score value of 1 point. At effect sizes this small, any cut score chosen on a test to diagnose patients would result in more false positives than true positives. This greatly increases the risk of misdiagnosis in persons who are susceptible to misattribution, expectancy effects, and "diagnosis threat," thereby increasing the risk of iatrogenic illness. PMID- 22256958 TI - Physical activity and disability among adolescents and young adults with non specific musculoskeletal pain. AB - PURPOSE: To compare physical activity levels of adolescents and young adults with chronic pain with that of healthy participants. To investigate the impact of pain intensity, pain catastrophizing and depressive symptoms on the level of physical activity and disability of adolescents and young adults with chronic pain. METHODS: Case-control study. Levels of physical activity and disability of adolescents and young adults with chronic non-specific musculoskeletal pain (n = 42) were compared with that of healthy participants (n = 42). For participants with chronic pain, measures of pain catastrophizing, pain intensity and depression were examined for their ability to explain levels of physical activity and disability. STATISTICS: multivariate regression analysis, Mann-Whitney testing, Pearson correlation analysis. RESULTS: Participants with chronic pain were as active as healthy participants (p = 0.22) (confidence interval [CI] 95%), although they seemed to be less active in sports and heavy-loaded activities. Pain intensity (beta = 0.32) and depressive symptoms (beta = 0.36) contributed significantly to disability (CI 95%). There was no significant association between physical activity and disability (CI 95%). CONCLUSIONS: Chronic non specific musculoskeletal pain is a disabling condition for adolescents and young adults. The level of physical activity in the daily life of adolescents and young adults with chronic pain is comparable to that of healthy counterparts, although the performance of sports and heavy-loaded activities seems diminished. Both pain intensity and depressive symptoms are disabling. [ IMPLICATIONS FOR REHABILITATION: * Chronic non-specific musculoskeletal pain is a disabling condition for adolescents and young adults.* Pain intensity and depressive symptoms predict disability.* The effect of pain on the physical-activity level of adolescents and young adults with chronic non-specific musculoskeletal pain seems to be small.* Assessment and improvement of emotional well-being may improve treatment programs for adolescents and young adults with chronic non specific musculoskeletal pain.] PMID- 22256960 TI - Mutualistic cleaner fish initiate trait-mediated indirect interactions by influencing the behaviour of coral predators. AB - 1. Indirect interactions resulting from changes in organismal traits such as behaviour [i.e. trait-mediated indirect interactions (TMIIs)] are widespread in biological communities, yet few studies have explored the potential for mutualisms to initiate TMIIs. 2. This study used a combination of behavioural observations and manipulative field experiments to investigate potential TMIIs resulting from a mutualism between specialized cleaner fish and the 'clients' that visit cleaners for the removal of ectoparasites. 3. Behavioural observations indicate that the bluestreak cleaner wrasse, Labroides dimidiatus, increases local predation pressure on corals at cleaner stations by attracting corallivorous butterflyfish to their territories. 4. Observations of the ornate butterflyfish, Chaetodon ornatissimus, suggest a trade-off between seeking cleaning and foraging; individuals decreased their foraging rate at cleaner stations and shifted their diet to include a greater proportion of less preferred prey items. Nonetheless, predation pressure on corals was higher at cleaner stations because the spatial response of butterflyfish to cleaners more than compensated for their lower foraging rates. 5. The results of a field experiment suggest that the greater predation pressure observed at cleaner stations may be sufficient to reduce the growth rate of the unpreferred coral Porites rus. 6. Together, these results emphasize the need to consider mutualists as potential initiators of TMIIs and highlight the importance of integrating individual movement into conceptual analyses of TMIIs. PMID- 22256961 TI - Detection and quantification of Campylobacter jejuni and Campylobacter coli using real-time multiplex PCR. AB - AIMS: We describe a real-time quantitative multiplex polymerase chain reaction (qmPCR) assay to identify and discriminate between isolates of Campylobacter jejuni and Campylobacter coli. METHODS AND RESULTS: Two novel sets of primers and hydrolysis probes were designed to amplify the unique DNA sequences within the hipO, ccoN and cadF genes that are specific to Camp. jejuni and Camp. coli. Using the designed optimized qmPCR assay conditions, the amplification efficiency is in range from 108 to 116%. These qmPCR assays are highly specific for Camp. jejuni and Camp. coli, as seen through testing of 40 Campylobacter strains and 17 non Campylobacter strains. In chicken juice and tap water models spiked with known quantities of Camp. jejuni, qmPCR detected 10(2) -10(3) CFU ml(-1) within 4 h. CONCLUSIONS: The qmPCR assays developed in this study provide reliable and simultaneous detection and quantification of Camp. jejuni and Camp. coli, with good amplification reaction parameters. SIGNIFICANCE AND IMPACT OF THE STUDY: Following further validation, the qmPCR assay reported here has the potential to be applied to various sample types as an alternative and rapid methodology. PMID- 22256962 TI - Impact of sodium polyacrylate on the amorphous calcium carbonate formation from supersaturated solution. AB - A detailed in situ scattering study has been carried out on the formation of amorphous calcium carbonate (ACC) particles modulated by the presence of small amounts of sodium polyacrylate chains. The work is aiming at an insight into the modulation of ACC formation by means of two polyacrylate samples differing in their molecular weight by a factor of 50. The ACC formation process was initiated by an in situ generation of CO(3)(2-) ions via hydrolysis of 10 mM dimethylcarbonate in the presence of 10 mM CaCl(2). Analysis of the formation process by means of time-resolved small-angle X-ray and light scattering in the absence of any additives provided evidence for a monomer addition mechanism for the growth of ACC particles. ACC formation under these conditions sets in after a lag-period of some 350 s. In the presence of sodium polyacrylate chains, calcium polyacrylate aggregates are formed during the lag-period, succeeded by a modulated ACC growth in a second step. The presence of anionic polyacrylate chains changed the shape of the growing particles toward loose and less homogeneous entities. In the case of low amounts (1.5-7.5 mg/L) of the long chain additive with 97 kDa, the size of the aggregates is comparable to the size of the successively formed hybrid particles. No variation of the lag-period has been observed in this case. Use of the short chain additive with 2 kDa enabled increase of the additive concentration up to 100 mg/L and resulted in a significant increase of the lag-period. This fact, together with the finding that the resulting hybrid particles remained stable in the latter case, identified short chain sodium polyacrylates as more efficient modulators than long chain polyacrylates. PMID- 22256963 TI - Chemical deamidation: a common pitfall in large-scale N-linked glycoproteomic mass spectrometry-based analyses. AB - N-Linked glycoproteins are involved in several diseases and are important as potential diagnostic molecules for biomarker discovery. Therefore, it is important to provide sensitive and reliable analytical methods to identify not only the glycoproteins but also the sites of glycosylation. Recently, numerous strategies to identify N-linked glycosylation sites have been described. These strategies have been applied to cell lines and several tissues with the aim of identifying many hundreds (or thousands) of glycosylation events. With high throughput strategies however, there is always the potential for false positives. The confusion arises since the protein N-glycosidase F (PNGase F) reaction used to separate N-glycans from formerly glycosylated peptides catalyzes the cleavage and deamidates the asparagine residue. This is typically viewed as beneficial since it acts to highlight the modification site. We have evaluated this common large-scale N-linked glycoproteomic strategy and proved potential pitfalls using Escherichia coli as a model organism, since it lacks the N-glycosylation machinery found in mammalian systems and some pathogenic microbes. After isolation and proteolytic digestion of E. coli membrane proteins, we investigated the presence of deamidated asparagines. The results show the presence of deamidated asparagines especially with close proximity to a glycine residue or other small amino acid, as previously described for spontaneous in vivo deamidation. Moreover, we have identified deamidated peptides with incorporation of (18)O, showing the pitfalls of glycosylation site assignment based on deamidation of asparagine induced by PNGase F in (18)O-water in large-scale analyses. These data experimentally prove the need for more caution in assigning glycosylation sites and "new" N-linked consensus sites based on common N-linked glycoproteomics strategies without proper control experiments. Besides showing the spontaneous deamidation, we provide alternative methods for validation that should be used in such experiments. PMID- 22256964 TI - Understanding disgust. AB - Disgust is characterized by a remarkably diverse set of stimulus triggers, ranging from extremely concrete (bad tastes and disease vectors) to extremely abstract (moral transgressions and those who commit them). This diversity may reflect an expansion of the role of disgust over evolutionary time, from an origin in defending the body against toxicity and disease, through defense against other threats to biological fitness (e.g., incest), to involvement in the selection of suitable interaction partners, by motivating the rejection of individuals who violate social and moral norms. The anterior insula, and to a lesser extent the basal ganglia, are implicated in toxicity- and disease-related forms of disgust, although we argue that insular activation is not exclusive to disgust. It remains unclear whether moral disgust is associated with insular activity. Disgust offers cognitive neuroscientists a unique opportunity to study how an evolutionarily ancient response rooted in the chemical senses has expanded into a uniquely human social cognitive domain; many interesting research avenues remain to be explored. PMID- 22256965 TI - Zinc alpha-2 glycoprotein is implicated in dyslipidaemia in HIV-1-infected patients treated with antiretroviral drugs. AB - OBJECTIVES: Treated HIV-1-infected patients with lipodystrophy often develop insulin resistance and proatherogenic dyslipidaemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized adipokine which has been shown to be involved in the development of obesity and metabolic syndrome in uninfected subjects. We assessed the relationship between circulating ZAG levels and metabolic derangements in HIV-1-infected patients receiving antiretroviral drugs. METHODS: Plasma ZAG levels were assessed in 222 individuals: 166 HIV-1-infected patients treated with antiretroviral drugs (77 with lipodystrophy and 89 without lipodystrophy) and 56 uninfected controls. Plasma ZAG levels were assessed by enzyme-linked immunosorbent assay (ELISA) and were correlated with fat distribution abnormalities and metabolic parameters. RESULTS: HIV-1-infected patients had lower plasma ZAG levels compared with uninfected controls (P < 0.001). No differences were found in ZAG plasma levels according to the presence of lipodystrophy, components of the metabolic syndrome or type of antiretroviral treatment regimen. Circulating ZAG levels were strongly determined by high density lipoprotein cholesterol (HDLc) in men (B = 0.644; P < 0.001) and showed a positive correlation with total cholesterol (r = 0.312; P < 0.001) and HDLc (r = 0.216; P = 0.005). CONCLUSIONS: HIV-1-infected patients have lower plasma ZAG levels than uninfected controls. In infected patients, plasma ZAG levels are in close relationship with total cholesterol and HDLc. PMID- 22256966 TI - Preparation and optimization of acetaminophen nanosuspension through nanoprecipitation using microfluidic devices: an artificial neural networks study. AB - The purpose of this study was to find an artificial neural networks model for determining major factors impacting the stability of an acetaminophen nanosuspansion that was prepared using nanoprecipitation in microfluidic reactors. Four variables, namely concentration of surfactant, solvent and antisolvent flow rate and solvent temperature were used as input variables and time of sedimentation of nanoparticles was considered as output variable. The particle size of optimized formulation was measured by transmission electron microscope and dynamic light scattering. Comparing the 3D graphs from the model showed that antisolvent flow rate and temperature have direct relation with time of sedimentation, whereas solvent flow rate generally has reverse relation with the time of sedimentation. Concentration of surfactant was found to be the most important factor in determining the stability of nanosuspension. PMID- 22256967 TI - Improving interprofessional collaboration in a community setting: relationships with burnout, engagement and service quality. AB - The main purpose of this study was, firstly, to evaluate the effect of an intervention aimed at improving interprofessional collaboration and service quality, and secondly, to examine if collaboration could predict burnout, engagement and service quality among human service professionals working with children and adolescents. The intervention included the establishment of local interprofessional teams and offering courses. The sample was recruited from six different small municipalities in Northern Norway (N = 93) and a comparison group from four similar municipalities (N = 58). Participation in the project increased the level of collaboration in the intervention group significantly (Hedges' g = 0.36), but not the perceived level of service quality. Hierarchical regression analyses were used to test a model for predicting burnout, engagement and perceived service quality using work-related factors, including collaboration as predictors. Both burnout and engagement were predicted by job demands and resources after controlling for demographic variables and participation in the project. Service quality was mostly predicted by collaboration. Increasing collaboration seems possible by introducing practice-based changes; however, this intervention did not have the desired effect on perceived service quality. PMID- 22256968 TI - Detection of human Enterovirus 71 reverse transcription loop-mediated isothermal amplification (RT-LAMP). AB - AIMS: In this study, a one-step, single-tube reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed and validated for the detection of human Enterovirus 71 (EV71), the major aetiological agent of hand, foot and mouth disease (HFMD). METHODS AND RESULTS: Reverse transcription loop mediated isothermal amplification assay was optimized to amplify VP1 gene in the presence of a specific primer set and Bst DNA polymerase at an isothermal temperature of 63 degrees C for 1 h. Amplified products were evaluated by visual inspection and agarose gel electrophoresis. The detection limit of RT-LAMP assay was 10(-5) 100 TCID50 or 160 copies in samples after RNA extraction, which was 10 fold higher in sensitivity than traditional reverse transcription polymerase chain reaction (RT-PCR). The specific positive amplification was only observed in EV71 strains, while no amplification was detected in other tested viruses. Digestion with a specific Escherichia coli restriction enzymes V (EcoR V) demonstrated that the amplified product was unique. A good correlation between RT LAMP and real-time RT-PCR was observed on the basis of the analysis of 33 clinical samples. CONCLUSIONS: Reverse transcription loop-mediated isothermal amplification is a novel, alternative microbiological approach for rapid, sensitive and specific detection of EV71 in HFMD. SIGNIFICANCE AND IMPACT OF THE STUDY: Reverse transcription loop-mediated isothermal amplification assay is suitable for the diagnosis of EV71 infection as a routine diagnostic tool for HFMD because of fewer requirements of experimental conditions such as private clinics, field applications as well as an epidemiological survey in epidemic areas. RT-LAMP can also be used as an alternative method for EV71 detection. PMID- 22256969 TI - Stereocontrolled total synthesis of fucoxanthin and its polyene chain-modified derivative. AB - Fucoxanthin exhibits high energy transfer efficiencies to Chlorophyll a (Chl a) in photosynthesis in the sea. In order to reveal how each characteristic functional group, such as the length of the polyene chain, allene, and conjugated carbonyl groups, of this marine natural product are responsible for its remarkably efficient ability, the total synthesis of fucoxanthin by controlling the stereochemistry was achieved. The method established for fucoxanthin synthesis was successfully applied to the synthesis of the C42 longer chain analogue. PMID- 22256970 TI - A high throughput scintillation proximity imaging assay for protein methyltransferases. AB - Protein methyltransferases (PMTs) orchestrate epigenetic modifications through post-translational methylation of various protein substrates including histones. Since dysregulation of this process is widely implicated in many cancers, it is of pertinent interest to screen inhibitors of PMTs, as they offer novel target based opportunities to discover small molecules with potential chemotherapeutic use. We have thus developed an enzymatic screening strategy, which can be adapted to scintillation proximity imaging assay (SPIA) format, to identify these inhibitors. We took advantage of S-adenosyl-L-[3H-methyl]-methionine availability and monitored the enzymatically catalyzed [3H]-methyl addition on lysine residues of biotinylated peptide substrates. The radiolabeled peptides were subsequently captured by streptavidin coated SPA imaging PS beads. We applied this strategy to four PMTs: SET7/9, SET8, SETD2, and EuHMTase1, and optimized assay conditions to achieve Z' values ranging from 0.48 to 0.91. The robust performance of this SPIA for the four PMTs was validated in a pilot screen of approximately 7,000 compounds. We identified 80 cumulative hits across the four targets. NF279, a suramin analogue, was found to specifically inhibit SET7/9 and SETD2 with IC50 values of 1.9 and 1.1 MUM, respectively. Another identified compound, Merbromin, a topical antiseptic, was classified as a pan-active inhibitor of the four PMTs. These findings demonstrate that our proposed SPIA strategy is generic for multiple PMTs and can be successfully implemented to identify novel and specific inhibitors of PMTs. The specific PMT inhibitors may constitute a new class of anti-proliferative agents for potential therapeutic use. PMID- 22256971 TI - Ligand-bridged dinuclear cyclometalated Ir(III) complexes: from metallamacrocycles to discrete dimers. AB - Metallamacrocycles 1, 2, and 3 of the general formula [{Ir(ppy)(2)}(2)(MU BL)(2)](OTf)(2) (ppyH = 2-phenyl pyridine; BL = 1,2-bis(4-pyridyl)ethane (bpa) (1), 1,3-bis(4-pyridyl)propane (bpp) (2), and trans-1,2-bis(4-pyridyl)ethylene (bpe) (3)) have been synthesized by the reaction of [{(ppy)(2)Ir}(2)(MU-Cl)(2)], first with AgOTf to effect dechlorination and later with various bridging ligands. Open-frame dimers [{Ir(ppy)(2)}(2)(MU-BL)](OTf)(2) were obtained in a similar manner by utilizing N,N'-bis(2-pyridyl)methylene-hydrazine (abp) and N,N' (bis(2-pyridyl)formylidene)ethane-1,2-diamine (bpfd) (for compounds 4 and 5, respectively) as bridging ligands. Molecular structures of 1, 3, 4, and 5 were established by X-ray crystallography. Cyclic voltammetry experiments reveal weakly interacting "Ir(ppy)(2)" units bridged by ethylene-linked bpe ligand in 3; on the contrary the metal centers are electronically isolated in 1 and 2 where the bridging ligands are based on ethane and propane linkers. The dimer 4 exhibits two accessible reversible reduction couples separated by 570 mV indicating the stability of the one-electron reduced species located on the diimine-based bridge abp. The "Ir(ppy)(2)" units in compound 5 are noninteracting as the electronic conduit is truncated by the ethane spacer in the bpfd bridge. The dinuclear compounds 1-5 show ligand centered (LC) transitions involving ppy ligands and mixed metal to ligand/ligand to ligand charge transfer (MLCT/LLCT) transitions involving both the cyclometalating ppy and bridging ligands (BL) in the UV-vis spectra. For the conjugated bridge bpe in compound 3 and abp in compound 4, the lowest-energy charge-transfer absorptions are red-shifted with enhanced intensity. In accordance with their similar electronic structures, compounds 1 and 2 exhibit identical emissions. The presence of vibronic structures in these compounds indicates a predominantly (3)LC excited states. On the contrary, broad and unstructured phosphorescence bands in compounds 3-5 strongly suggest emissive states of mixed (3)MLCT/(3)LLCT character. Density functional theory (DFT) calculations have been carried out to gain insight on the frontier orbitals, and to rationalize the electrochemical and photophysical properties of the compounds based on their electronic structures. PMID- 22256972 TI - Revealing plasmonic gap modes in particle-on-film systems using dark-field spectroscopy. AB - Polarization-controlled excitation of plasmonic modes in nanometric Au particle on-film gaps is investigated experimentally using single-particle dark-field spectroscopy. Two distinct geometries are explored: nanospheres on top of and inserted in a thin gold film. Numerical simulations reveal that the three resonances arising in the scattering spectra measured for particles on top of a film originate from highly confined gap modes at the interface. These modes feature different azimuthal characteristics, which are consistent with recent theoretical transformation optics studies. On the other hand, the scattering maxima of embedded particles are linked to dipolar modes having different orientations and damping rates. Finally, the radiation properties of the particle film gap modes are studied through the mapping of the scattered power within different solid angle ranges. PMID- 22256973 TI - Simulations of tryptophan fluorescence dynamics during folding of the villin headpiece. AB - Protein folding kinetics is commonly monitored by changes in tryptophan (Trp) fluorescence intensity. Considerable recent discussion has centered on whether the fluorescence of the single Trp in the much-studied, fast-folding villin headpiece C-terminal domain (HP35) accurately reflects folding kinetics, given the general view that quenching is by a histidine cation (His(+)) one turn away in an alpha-helix (helix III) that forms early in the folding process, according to published MD simulations. To help answer this question, we ran 1.0 MUs MD simulations on HP35 (N27H) and a faster-folding variant in its folded form at 300 K and used the coordinates and force field charges with quantum calculations to simulate fluorescence quenching caused by electron transfer to the local amide and to the His(+). The simulations demonstrate that quenching by His(+) in the fully formed helix III is possible only during certain Trp and His(+) rotamer and solvent conformations, the propensity of which is a variable that can allow Trp fluorescence to report the global folding rate, as recent experiments imply. PMID- 22256975 TI - Equine influenza supplement. PMID- 22256976 TI - Accuracy of diagnostic test interpretations. PMID- 22256978 TI - Epidemiology of bovine Johne's disease (BJD) in beef cattle herds in Australia. AB - OBJECTIVE: To describe the epidemiology of bovine Johne's disease (BJD) in beef herds in Australia. DESIGN: Retrospective survey of beef herds detected with BJD between 1991 and 2006. METHODS: Information about the management and physical characteristics of affected herds, index and clinical cases, testing and control programs, and attitudes to BJD were collated from existing data and personal interviews of herd owners or managers. Herds were excluded if they contained fewer than 30 breeding cows or operated as a dairy farm. RESULTS: Records from 109 herds demonstrated the first detected ('index') case was 3.4-fold more likely to be a beef rather than dairy breed. However, further analysis revealed association with dairy cattle was an important risk factor for introducing BJD. Index cases were most likely detected by veterinarians investigating clinical cases of scouring or ill-thrifty animals during winter, particularly bulls or aged cows. Most herds with clinical BJD had only a single case, with only one high prevalence herd detected in the survey group. Over the period of observation, test and cull programs did not eradicate BJD unless combined with culling of known high-risk animals, but removal of high-risk cattle by partial or total destocking generally restored the trading status of affected herds. CONCLUSION: Excluding cattle with dairy contact from beef herds, ensuring more effective farm biosecurity, promptly seeking veterinary advice regarding scouring cattle and sourcing replacement cattle from demonstrably low-risk herds, such as CattleMAP and 'Beef Only' herds, are simple strategies that should reduce the risk of introducing BJD infection into beef herds. PMID- 22256979 TI - Effect on time in quarantine of the choice of program for eradication of footrot from 196 sheep flocks in southern New South Wales. AB - OBJECTIVE: To identify and compare programs for eradicating virulent footrot (VFR) chosen by owners of quarantined sheep flocks in southern New South Wales. METHOD: Data from 196 sheep flocks in the Wagga Wagga and Young Rural Lands Protection Boards were used to determine the program chosen, the influence of flock size on the program chosen and the effects of the program chosen and the use of contractors on the time in quarantine. RESULTS: The most popular programs in flocks using a single program were: total destocking (61/173; 35.3%) and inspection and culling of affected animals (71/173; 41.0%). Treatment of known infected animals was chosen in 41 flocks and of those, 10 (5.8%) used antibiotics for treatment and 31 (17.9%) used foot-bathing. Combined programs were used in 23 flocks and in 10 flocks a change of program occurred before eradication was achieved. The choice of program was, to some extent, affected by flock size, with owners of small flocks (<500 sheep) more likely to destock. The chosen program strongly influenced the time in quarantine, the shortest time being for destocking (mean 284 days), followed by culling of infected sheep (395 days), treatment with antibiotics (433 days) and finally foot-bathing (502 days). Time in quarantine was significantly shorter when contractors were used. CONCLUSION: All the options chosen led to the eradication of VFR. However, in this sample both the choice of program and the use of contractors influenced the time taken to achieve eradication and therefore the time in quarantine. Based on time in quarantine, foot-bathing was the least desirable option for the eradication of VFR because of the significantly greater time involved, perpetuation of risk to neighbours and increased cost of inspections. These findings were derived from flocks that were quarantined, but they are relevant to all flock owners considering eradication of VFR. PMID- 22256980 TI - Transection of the lateral and long digital extensor tendons in racehorses. AB - OBJECTIVE: To report on the outcome of wounds to the hindlimb of racehorses, and horses with the intended use of racing, where both the long digital extensor (LoDE) and lateral digital extensor (LaDE) tendons had been completely transected. DESIGN: Retrospective case series. METHODS: Records of all horses admitted with hindlimb lacerations between 2002 and 2009 were examined for cases where both the LoDE and LaDE tendons in the hindlimb had been severed, and specifically in horses intended to be used for racing. Outcome was assessed via retrieval of race records and via telephone questioning of the owners. RESULTS: In total, 589 records were retrieved and 34 horses met the inclusion criteria: 26 horses (76%) had proximal wounds that severed both the LoDE and LaDE tendons and 8 (24%) had more distal wounds, where the tendons were severed below the point at which they join; 14 horses (41%) were euthanased prior to discharge. Of the 20 horses discharged, 6 (30%) raced and 12 (60%) did not; 2 (10%) of the treated horses, both Thoroughbred colts, were in race training and showing no signs of lameness at the time of the study. Of the 34 horses presented for treatment, 18% went on to race. CONCLUSIONS: The prognosis for racing after transection of both hindlimb extensor tendons is poor. Clinicians may wish to consider these findings when formulating advice for clients regarding this injury in racehorses. PMID- 22256981 TI - Leucopenia associated with abalone viral ganglioneuritis. AB - OBJECTIVE: To compare microscopic lesion severity with circulating total haemocyte counts (THC) in abalone affected by abalone viral ganglioneuritis (AVG). RESULTS: A herpes-like virus led to severe mortality in a number of Australian abalone farms in 2006. The infection was associated with severe necrotising ganglioneuritis. The microscopic lesions were well demarcated, affecting the neural tissue almost exclusively and were characterised by necrosis and increased cellularity in affected ganglia and nerves. On two farms, the presence or absence of typical AVG pathology was compared with THC. Those abalone with microscopic lesions of AVG had significantly lower haemocyte counts. The mean THC in abalone with no evidence of AVG from both farms was 4.6 * 10(6)/mL (+/-0.3 SE). The THC in AVG-affected abalone in farm 1 was 2.8 * 10(6)/mL (+/-0.5 SE) and farm 2 was 0.98 * 10(6)/mL (+/-0.4 SE). CONCLUSIONS: Severe AVG is associated with leucopenia in affected abalone. PMID- 22256982 TI - Haemochromatosis in a Brazilian tapir (Tapirus terrestris) in an Australian zoo. AB - A 23-year-old Brazilian, or lowland, tapir with a 6-month history of loss of body condition developed clinical signs and laboratory findings consistent with liver failure. The animal was euthanased and a diagnosis of hepatic haemochromatosis was made based on histopathology. Two other healthy tapirs in the same collection had chronically elevated serum and tissue iron concentrations. The excessive accumulation of iron in tissues with resultant tissue damage (i.e. haemochromatosis) has been reported in a range of captive species. This and other reported cases of haemochromatosis in the Brazilian tapir would suggest that this condition is an important consideration in the management of this species in zoos. Further research into the endogenous regulation of iron metabolism, especially the role of hepcidin, in tapirs and other species at risk of iron storage disorders may be helpful in the prevention of this condition. PMID- 22256983 TI - Disseminated Scedosporium prolificans infection in a German Shepherd dog. AB - Disseminated Scedosporium prolificans infection in a 1-year-old female spayed German Shepherd dog is described. Clinical signs were predominantly associated with fungal pyelonephritis and the organism was cultured from the urine. The dog was treated with itraconazole and later, terbinafine was added. Subsequent antifungal susceptibility testing of the isolate showed it to be resistant to all available antifungal drugs. The dog was euthanased because of acute abdominal haemorrhage and associated clinical deterioration. Postmortem examination revealed extensive pyogranulomas containing fungal organisms in the renal parenchyma, myocardium, bone marrow, skeletal muscle, liver, lung, spleen, multiple lymph nodes and pancreas. PMID- 22256984 TI - Osteosarcoma at the site of titanium orthopaedic implants in a dog. AB - An Alaskan Malamute underwent unilateral tibial tuberosity advancement (TTA) surgery to stabilise a stifle joint with a deficient cranial cruciate ligament. The dog made an excellent recovery with no postoperative complications, until 20 months post-surgery when he presented with acute onset ipsilateral pelvic limb lameness. Osteosarcoma (OSA) was diagnosed adjacent to the titanium implants. Currently, there is a paucity of information on the epidemiology of OSA adjacent to orthopaedic implants in canine patients. The clinical, radiological and pathological findings of this case of periprosthetic OSA, and a potential causal relationship between titanium implants and bone neoplasia, are discussed. PMID- 22256985 TI - Torsion of quadrate and right middle liver lobes and gallbladder in a German Shepherd dog. AB - BACKGROUND: An 11-year-old female German Shepherd was referred for assessment and management of a suspected liver tumour. Abdominal ultrasonography revealed abundant abdominal effusion and a right liver mass in continuity with a cystic structure. The dog had undergone splenectomy for a low-grade lymphoma 1 year prior. METHODS: Serum biochemical analysis revealed only a mild increase in alanine aminotransferase. The analysis of the free abdominal fluid showed a modified transudate. Ultrasound confirmed the presence of a hypoechoic lesion involving the right liver lobes, in addition to an over-distended gallbladder. Computed tomography examination demonstrated a massively dilated gallbladder and lower attenuation of the adjacent liver lobes, with no enhancement on quadrate and right middle liver lobes. The fine needle aspirate was compatible with a mixed subacute to chronic inflammation. Based on the investigational findings, an exploratory coeliotomy was performed. TREATMENT AND OUTCOME: The middle right and quadrate liver lobes and the gallbladder were rotated on their axes. The torsed lobes and the cystic duct were removed using a TA stapler without derotating the organs. Histopathological results were suggestive of infarction secondary to torsion of the lobes and gallbladder. The dog recovered from surgery without complications, and 20 months later was in good overall condition. CONCLUSION: Liver lobe torsion is an uncommon condition that rarely affects the right lobes. Gallbladder torsion is even more uncommon. To our knowledge, this is the first recorded case of quadrate and right middle liver lobe and gallbladder torsion. PMID- 22256986 TI - Intimate partner violence and companion animal welfare. AB - OBJECTIVE: To investigate the effect of intimate partner violence (IPV) on companion animal welfare. DESIGN: Self-selected telephone survey of people meeting the criteria. METHODS: Members of the Australian public with experience of IPV and concurrent companion animal ownership were invited to telephone a researcher for a semi-structured interview. RESULTS: In total, 26 Australian women reported one or more companion animals in the household being verbally and/or physically abused by their male partner, usually with prolonged effects on animal behaviour; 92% indicated that they had been unwilling to discuss the animal abuse with a veterinarian. Many were unaware of animal accommodation services for people fleeing violence and those who did know about these were unwilling to use them, citing their bond with the animals as the main reason. Animals targeted for abuse were most likely to be dogs and owned by women rather than men, children or both partners. CONCLUSION: Animals can be severely affected by domestic violence situations and many people experiencing violence are unwilling to confide in veterinarians or seek help from animal shelters. PMID- 22256987 TI - Interactions of the antimalarial drug methylene blue with methemoglobin and heme targets in Plasmodium falciparum: a physico-biochemical study. AB - AIMS: Resistance of Plasmodium falciparum to drugs has led to renewed interest of redox-active methylene blue (MB) for which no resistance has been reported so far. Moreover, MB displays unique interactions with glutathione reductase (GR). However, the mechanisms of action/interaction with potential targets of MB are yet to be elucidated. Our physico-biochemical study on MB and relevant hematin containing targets was performed under quasi-physiological conditions. RESULTS: The water deprotonation of the Fe(III)protoporphyrin dimer, the major building block of beta-hematin, was studied. At pH 6, the predominant dimer possesses water coordinated to both metals. Below pH 6, spontaneous precipitation of beta hematin occurred reminiscent of hemozoin biomineralization at pH 5.0-5.5 in the food vacuole of the malarial parasite. MB also forms dimers (K(Dim)=6800 M(-1)) and firmly binds to hematin in a 2:1 hematin:MB sandwich complex (K(D)=3.16 MUM). MB bioactivation catalyzed by GR induces efficient methemoglobin(Fe(III)) [metHb(Fe(III))] reduction to hemoglobin(Fe(II)). The reduction rate, mediated by leucomethylene blue (LMB), was determined (k(metHb)(red)=991 M(-1).s(-1)) in an assay coupled to the GR/reduced form of nicotinamide adenine dinucleotide phosphate system. INNOVATION AND CONCLUSION: Our work provides new insights into the understanding of (i) how MB interacts with hematin-containing targets, (ii) other relevant MB properties in corroboration with the distribution of the three major LMB species as a function of pH, and (iii) how this redox-active cycler induces efficient catalytic reduction of metHb(Fe(III)) to hemoglobin(Fe(II)) mediated by oxidoreductases. These physico-biochemical parameters of MB open promising perspectives for the interpretation of the pharmacology and pathophysiology of malaria and possibly new routes for antimalarial drug development. PMID- 22256988 TI - Coexistence and genetic variability of Contracaecum rudolphii A and Contracaecum rudolphii B (Nematoda: Anisakidae) in cormorants, Phalacrocorax carbo sinensis, in the Baltic region. AB - Although numerous genetically isolated entities within Contracaecum rudolphii sensu lato are presently defined, information on the distribution and ecology of these groups is nonetheless in demand. In the present study, information based upon DNA sequence data (restriction analysis and sequencing of rDNA) on the distribution of the species C. rudolphii A and C. rudolphii B in the cormorant Phalacrocorax carbo sinensis from the Baltic region (Poland and Finland) is provided. These data corroborate previous work that identified C. rudolphii A in brackish water regions and C. rudolphii B in fresh water sites, although mixed infections also occur. The 2 species may inhabit the same host specimen. One rare heterozygote of the species was recorded. PMID- 22256990 TI - Wet-wrap treatment in children with atopic dermatitis: a practical guideline. AB - Treatment of children with severe atopic dermatitis (AD) can be especially challenging because several possible intervention treatments have (relative) contraindications in childhood. In recent years, wet-wrap treatment (WWT) has been advocated as a relatively safe and efficacious intervention in children with severe or refractory AD. The goal of this article is to provide a practical guideline as a starting point for clinicians who are interested in using WWT in their own clinical practice. We will address several practical issues surrounding the use of WWT by describing our own experiences, supplemented with data from the literature. PMID- 22256989 TI - Hydrophilic prodrug approach for reduced pigment binding and enhanced transscleral retinal delivery of celecoxib. AB - Transscleral retinal delivery of celecoxib, an anti-inflammatory and anti-VEGF agent, is restricted by its poor solubility and binding to the melanin pigment in choroid-RPE. The purpose of this study was to develop soluble prodrugs of celecoxib with reduced pigment binding and enhanced retinal delivery. Three hydrophilic amide prodrugs of celecoxib, celecoxib succinamidic acid (CSA), celecoxib maleamidic acid (CMA), and celecoxib acetamide (CAA) were synthesized and characterized for solubility and lipophilicity. In vitro melanin binding to natural melanin (Sepia officinalis) was estimated for all three prodrugs. In vitro transport studies across isolated bovine sclera and sclera-choroid-RPE (SCRPE) were performed. Prodrug with the highest permeability across SCRPE was characterized for metabolism and cytotoxicity and its in vivo transscleral delivery in pigmented rats. Aqueous solubilities of CSA, CMA, and CAA were 300-, 182-, and 76-fold higher, respectively, than celecoxib. Melanin binding affinity and capacity were significantly lower than for celecoxib for all three prodrugs. Rank order for the % in vitro transport across bovine sclera and SCRPE was CSA > CMA ~ CAA ~ celecoxib, with the transport being 8-fold higher for CSA than celecoxib. CSA was further assessed for its metabolic stability and in vivo delivery. CSA showed optimum metabolic stability in all eye tissues with only 10 20% conversion to parent celecoxib in 30 min. Metabolic enzymes responsible for bioconversion included amidases, esterase, and cytochrome P-450. In vivo delivery in pigmented BN rats showed that CSA had 4.7-, 1.4-, 3.3-, 6.0-, and 4.5-fold higher delivery to sclera, choroid-RPE, retina, vitreous, and lens than celecoxib. CSA has no cytotoxicity in ARPE-19 cells in the concentration range of 0.1 to 1000 MUM. Celecoxib succinamidic acid, a soluble prodrug of celecoxib with reduced melanin binding, enhances transscleral retinal delivery of celecoxib. PMID- 22256991 TI - Indurated hyperpigmented plaques with overlying fibrotic nodules in an adolescent boy. PMID- 22256992 TI - A solitary lesion on the palmar aspect of the right middle finger of an 11 year old boy. PMID- 22256993 TI - Sudden onset of disseminated pruritic blisters in a child. PMID- 22256994 TI - Localized xanthomas associated with primary lymphedema. AB - Cutaneous xanthomas arising in chronic lymphedema are rare. We present a case of verruciform xanthoma involving the left foot and toes of a 10-year-old boy who had developed a primary lymphedema (lymphedema praecox) in the left lower extremity. Laboratory studies demonstrated a normal lipid profile. PMID- 22256995 TI - Pain management for ulcerated infantile hemangiomas. AB - Perioral ulcerated hemangiomas in infants can present a therapeutic challenge to clinicians, especially when associated with severe pain and difficulty feeding. Topical and oral pain medications can be beneficial, but feeding difficulties may still occur while awaiting healing of the ulceration with the use of systemic or topical agents. We present a case of an infant with an ulcerated lip hemangioma treated with an over-the-counter topical sealant in combination with systemic corticosteroid therapy who showed dramatic improvement in pain and tolerance to feeding, resulting in healing of the ulceration. PMID- 22256996 TI - Topical timolol for infantile hemangiomas: putting a note of caution in "cautiously optimistic". PMID- 22256997 TI - Facial port-wine stain: when to worry? PMID- 22256998 TI - Arabidopsis histidine kinase 5 regulates salt sensitivity and resistance against bacterial and fungal infection. AB - * The ability of plants to adapt to multiple stresses imposed by the natural environment requires cross-talk and fine-tuning of stress signalling pathways. The hybrid histidine kinase Arabidopsis histidine kinase 5 (AHK5) is known to mediate stomatal responses to exogenous and endogenous signals in Arabidopsis thaliana. The purpose of this study was to determine whether the function of AHK5 in stress signalling extends beyond stomatal responses. * Plant growth responses to abiotic stresses, tissue susceptibility to bacterial and fungal pathogens, and hormone production and metabolism of reactive oxygen species were monitored in a T-DNA insertion mutant of AHK5. * The findings of this study indicate that AHK5 positively regulates salt sensitivity and contributes to resistance to the bacterium Pseudomonas syringae pv. tomato DC3000 and the fungal pathogen Botrytis cinerea. * This is the first report of a role for AHK5 in the regulation of survival following challenge by a hemi-biotrophic bacterium and a necrotrophic fungus, as well as in the growth response to salt stress. The function of AHK5 in regulating the production of hormones and redox homeostasis is discussed. PMID- 22257000 TI - Association of HIV viral load and CD4 cell count with human papillomavirus detection and clearance in HIV-infected women initiating highly active antiretroviral therapy. AB - OBJECTIVES: The extent to which highly active antiretroviral therapy (HAART) affects human papillomavirus (HPV) acquisition and clearance in HIV-infected women is not well understood. We sought to describe high-risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4 T-cell count, using novel statistical methods. METHODS: We conducted a retrospective analysis of data from the completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high risk HPV types from 2003 and 2009 publications were considered. RESULTS: There was some evidence that VL>400 HIV-1 RNA copies/mL was marginally associated with a higher rate of HPV detection [P=0.068; hazard ratio (HR) =4.67], using the older set of high-risk HPV types. Such an association was not identified using the latest set of HPV types (P=0.343; HR=2.64). CD4 count >350 cells/MUL was significantly associated with more rapid HPV clearance with both sets of HPV types (P=0.001, HR=3.93; P=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 cell count in any of the analyses. CONCLUSIONS: High-risk HPV types vary among studies and can affect the results of analyses. Use of HAART to improve CD4 cell count may have an impact on the control of HPV infection. The decrease in VL may also have an effect, although to a lesser degree. PMID- 22257001 TI - The flavoprotein Cyc2p, a mitochondrial cytochrome c assembly factor, is a NAD(P)H-dependent haem reductase. AB - Cytochrome c assembly requires sulphydryls at the CXXCH haem binding site on the apoprotein and also chemical reduction of the haem co-factor. In yeast mitochondria, the cytochrome haem lyases (CCHL, CC(1) HL) and Cyc2p catalyse covalent haem attachment to apocytochromes c and c(1) . An in vivo indication that Cyc2p controls a reductive step in the haem attachment reaction is the finding that the requirement for its function can be bypassed by exogenous reductants. Although redox titrations of Cyc2p flavin (E(m) = -290 mV) indicate that reduction of a disulphide at the CXXCH site of apocytochrome c (E(m) = -265 mV) is a thermodynamically favourable reaction, Cyc2p does not act as an apocytochrome c or c(1) CXXCH disulphide reductase in vitro. In contrast, Cyc2p is able to catalyse the NAD(P)H-dependent reduction of hemin, an indication that the protein's role may be to control the redox state of the iron in the haem attachment reaction to apocytochromes c. Using two-hybrid analysis, we show that Cyc2p interacts with CCHL and also with apocytochromes c and c(1) . We postulate that Cyc2p, possibly in a complex with CCHL, reduces the haem iron prior to haem attachment to the apoforms of cytochrome c and c(1) . PMID- 22257003 TI - Novel formulation and drug delivery strategies for the treatment of pediatric poverty-related diseases. AB - INTRODUCTION: Due to a lack of approved drugs and formulations, children represent the most vulnerable patients. Magistral, unlicensed formulations obtained by the manipulation of solid forms should undergo clinical evaluation to ensure bioequivalence. The development of new pediatric medicines is complex and faces technological, economic and ethical challenges. This phenomenon has contributed to the emergence of an adult-children gap. To improve the situation, the World Health Organization launched the global campaign 'Make medicines child size' and a number of international initiatives have been established. The situation is more critical in the case of poverty-related diseases (PRDs) that mainly affect poor countries. AREAS COVERED: This review critically discusses different strategies to develop pediatric formulations and drug delivery systems (DDS) in PRDs and their potential implementation in the current market. Readers will gain an updated perspective on the development of pediatric medicines for the treatment of PRDs and the proximate challenges and opportunities faced to ensure an effective pharmacotherapy. EXPERT OPINION: There is an urgent need for the development of innovative, scalable and cost-viable formulations to ensure pediatric patients have access to appropriate medications for PRDs. The guidelines of the International Conference on Harmonisation constitute a very good orientation tool, as they emphasize physiological and developmental aspects that need to be considered in pediatric research. It is important to consider cultural, economic and ethical aspects that make developing nations facing PRDs different from the developed world. Thus, the best strategy would probably be to conceive and engage similar initiatives in the developing world, to address unattended therapeutic niches. PMID- 22257002 TI - Development and evolution of character displacement. AB - Character displacement occurs when competition for either resources or successful reproduction imposes divergent selection on interacting species, causing divergence in traits associated with resource use or reproduction. Here, we describe how character displacement can be mediated either by genetically canalized changes (i.e., changes that reflect allelic or genotype frequency changes) or by phenotypic plasticity. We also discuss how these two mechanisms influence the tempo of character displacement. Specifically, we suggest that, under some conditions, character displacement mediated by phenotypic plasticity might occur more rapidly than that mediated by genetically canalized changes. Finally, we describe how these two mechanisms may act together and determine character displacement's mode, such that it proceeds through an initial phase in which trait divergence is environmentally induced to a later phase in which divergence becomes genetically canalized. This plasticity-first hypothesis predicts that character displacement should be generally mediated by ancestral plasticity and that it will arise similarly in multiple, independently evolving populations. We conclude by highlighting future directions for research that would test these predictions. PMID- 22257004 TI - Detailed behavioral analysis as a window into cross-situational word learning. AB - Recent research has demonstrated that word learners can determine word-referent mappings by tracking co-occurrences across multiple ambiguous naming events. The current study addresses the mechanisms underlying this capacity to learn words cross-situationally. This replication and extension of Yu and Smith (2007) investigates the factors influencing both successful cross-situational word learning and mis-mappings. Item analysis and error patterns revealed that the co occurrence structure of the learning environment as well as the context of the testing environment jointly affected learning across observations. Learners also adopted an exclusion strategy, which contributed conjointly with statistical tracking to performance. Implications for our understanding of the processes underlying cross-situational word learning are discussed. PMID- 22257005 TI - Directly measured activation parameters for the ring expansions of cyclopropylhalocarbenes. AB - Activation parameters have been redetermined for the ring expansions of cyclopropylchlorocarbene and cyclopropylfluorocarbene; agreement between the experimental and computed activation parameters has been significantly improved. PMID- 22257006 TI - Improvement in organic solvent tolerance by double disruptions of proV and marR genes in Escherichia coli. AB - AIMS: To investigate the involvement of osmoprotectant transporters in organic solvent tolerance in Escherichia coli and to construct an E. coli strain with high organic solvent tolerance. METHODS AND RESULTS: The organic solvent tolerance of DeltabetT, DeltaproV, DeltaproP or DeltaputP single-gene knockout mutants of E. coli K-12 strain was examined. Among these mutants, the organic solvent tolerance of the DeltaproV mutant remarkably increased compared with that of the parent strain. It has been known that a marR mutation confers tolerance on E. coli to organic solvents. A DeltaproV and DeltamarR double-gene mutant was more tolerant to organic solvents than the DeltaproV or DeltamarR single-gene mutant. The n-hexane amount accumulated in E. coli cells was examined after incubation in an n-hexane-aqueous medium two-phase system. The intracellular n hexane level in the DeltaproV and DeltamarR double-gene mutant was kept lower than those of the parent strain, DeltaproV mutant and DeltamarR mutant. CONCLUSIONS: The organic solvent tolerance level in E. coli highly increased by dual disruption of proV and marR. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests a new strategy for increasing the organic solvent tolerance level in E. coli to improve the usability of the whole-cell biocatalysts in two-phase systems employing organic solvents. PMID- 22257007 TI - Genome and gene duplications and gene expression divergence: a view from plants. AB - With many plant genomes sequenced, it is now clear that one distinguishing feature of angiosperm (flowering plant) genomes is their high frequency of whole genome duplication. Single-gene duplication is also widespread in angiosperm genomes. Following various mechanisms of gene duplication, genes are often retained or lost in a biased manner, which has suggested recent models for gene family evolution, such as functional buffering and the gene balance hypothesis in addition to now-classical models, including neofunctionalization and subfunctionalization. Evolutionary consequences of gene duplication, often studied through analyzing gene expression divergence, have enhanced understanding of the biological significance of different mechanisms of gene duplication. PMID- 22257008 TI - The photophysics of the orange carotenoid protein, a light-powered molecular switch. AB - To cope with the deleterious effects of excess illumination, photosynthetic organisms have developed photoprotective mechanisms that dissipate the absorbed excess energy as heat from the antenna system. In cyanobacteria, a crucial step in the process is the activation, by blue-green light, of a soluble protein, known as orange carotenoid protein (OCP), which binds the carotenoid 3' hydroxyechinenone as its only pigment. While the spectroscopic properties of the inactive form of OCP have been described, the nature of the excited states in the active form still awaits elucidation. We applied transient absorption spectroscopy to the dark and the light activated forms of OCP to study and compare the excited state dynamics of both forms. We show that excitation of the photoactivated OCP leads to the population of new carotenoid excited states. One of these states populated shortly after excitation is characterized by a very pronounced charge transfer character and a lifetime of about 0.6 ps. When the illuminated sample is exposed to a dark relaxation period, it responds to excitation as the original dark sample, showing that photoactivation and decay of the photoactivated state are fully reversible. Thus OCP functions as a light powered molecular switch that modulates its spectroscopic properties as a response to specific changes in light environment. We discuss the importance of this switch in cyanobacteria photoprotection and propose a mechanism wherein the red state of OCP echinenone acts as an energy dissipator via its charge transfer state. PMID- 22257010 TI - Synthesis, characterization, and reactivity of a novel MU-eta2:eta2 diselenidodicopper(II) complex. AB - The first MU-eta(2):eta(2)-diselenidodicopper(II) complex has been obtained in the reaction of a copper(I) complex with N,N',N"-tribenzyl-cis,cis-1,3,5 triaminocyclohexane and elemental selenium. The structure and reactivity of the complex is described. PMID- 22257011 TI - Cognitive and subjective effects of mephedrone and factors influencing use of a 'new legal high'. AB - AIMS: Use of the stimulant drug mephedrone increased dramatically in 2009, and it is still available in the United Kingdom after being controlled in April 2010. This study aimed to assess mephedrone's acute cognitive and subjective effects. DESIGN: A mixed within- and between-subjects design compared 20 mephedrone users, first while intoxicated (T1) and secondly drug free (T2); and 20 controls twice when drug free (T1 and T2). SETTINGS: Participants' own homes. PARTICIPANTS: Healthy adults recruited from the community. MEASUREMENTS: Subjective effects, episodic and working memory, phonological and semantic fluency, psychomotor speed and executive control at were assessed at T1 and T2. Trait schizotypy, depression, changes in mephedrone use since the ban and attitudes influencing use of a hypothetical new legal high were indexed at T2 only. FINDINGS: Compared with controls, mephedrone users had generally impaired prose recall (P = 0.037) and higher scores in schizotypy (P < 0.001) and depression (P = 0.01). Mephedrone acutely primed a marked 'wanting' for the drug (P < 0.001), induced stimulant like effects, impaired working memory (P < 0.001) and enhanced psychomotor speed (P = 0.024). Impulsivity in mephedrone users correlated with the number of hours in an average (nearly 8 hour) mephedrone session (r = 0.6). Users would be drawn to use a new legal high if it were pure, had no long/short term harms, and was positively rated by friends or on the internet. CONCLUSIONS: Mephedrone impairs working memory acutely, induces stimulant-like effects in users and is associated with binge use. Factors that influence users' attitudes to new drugs might help to predict future trends in use of the many new psychoactive substances emerging on the internet. PMID- 22257013 TI - Clinically meaningful efficacy of a non-estrogen agent: re-analysis of phase-2 data evaluating MF101. AB - OBJECTIVE: To evaluate the level of reduction in hot flushes among a cohort of postmenopausal women randomized to a phase-2 clinical trial evaluating MF101, a selective estrogen receptor beta modulator, for treatment of vasomotor symptoms to determine clinically meaningful efficacy. METHODS: We performed a re-analysis of data from a double-blinded, placebo-controlled trial of 217 postmenopausal women randomized to treatment with MF101 or placebo for 12 weeks. At study termination, participants were asked if they were satisfied enough with medication to continue therapy. RESULTS: Of the women treated, 73% with >=50% reduction in hot flush frequency and 77% with >=60% reduction in hot flush frequency were willing to continue treatment. CONCLUSION: A 50-60% reduction in hot flushes is clinically meaningful among postmenopausal women who are being treated with a non-estrogen agent such as MF101. PMID- 22257012 TI - Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1. AB - Relaxin-3 is a neuropeptide that is implicated in the regulation of stress responses and memory. The elucidation of its precise physiological role(s) has, however, been hampered by cross-activation of the relaxin-2 receptor, RXFP1, in the brain. The current study undertook to develop analogues of human relaxin-3 (H3 relaxin) that can selectively bind and activate its receptor, RXFP3. We developed a high-affinity selective agonist (analogue 2) by removal of the intra A chain disulfide bond and deletion of 10 residues from the N terminus of the A chain. Further truncation of this analogue from the C terminus of the B chain to Cys(B22) and addition of an Arg(B23) led to a high-affinity, RXFP3-selective, competitive antagonist (analogue 3). Central administration of analogue 2 in rats increased food intake, which was blocked by prior coadministration of analogue 3. These novel RXFP3-selective peptides represent valuable pharmacological tools to study the physiological roles of H3 relaxin/RXFP3 systems in the brain and important leads for the development of novel compounds for the treatment of affective and cognitive disorders. PMID- 22257014 TI - Interferon-gamma up-regulates major-histocompatibility-complex class I-related chain A expression and enhances major-histocompatibility-complex class I-related chain A-mediated cytolysis of human corneal epithelium by natural killer cells in vitro. AB - Natural killer (NK) cells are important in the ocular surface innate response against viral and bacterial infection. Major-histocompatibility-complex class I related chain A (MICA) antigens are ligands of natural killer group 2D, an activating or coactivating receptor expressed on NK cells. Recent studies demonstrated that interferon-gamma (IFN-gamma) could modulate MICA expression in tumor cells. However, little is known about MICA expression and regulation in human corneal epithelium. Our study assessed whether the proinflammatory cytokine, IFN-gamma, affects MICA expression in human corneal epithelium. We identified low levels of surface MICA expression in corneal epithelium using flow cytometry. IFN-gamma promoted surface MICA expression in corneal epithelium and increased soluble MICA levels in a dose-dependent manner. IFN-gamma also enhanced NK cell-mediated cytotoxicity against the corneal epithelium. Anti-MICA antibodies could further block this process. In summary, we describe a novel IFN gamma function in the regulation of the innate response in ocular surfaces. PMID- 22257016 TI - A new genus and species of cestode (Rhinebothriidea) from Mobula kuhlii (Rajiformes: Mobulidae) from Malaysian Borneo. AB - The cestode fauna of the shortfin devilray, Mobula kuhlii (Muller & Henle, 1841) was examined for the first time. The work resulted in the discovery of a new genus and species of rhinebothriidean tapeworm. Crassuseptum pietrafacei, n. gen. n. sp. is erected here on the basis of its unique scolex and proglottid morphology. Histological sections and examination by light and scanning electron microscopy demonstrated that this new genus differs from all other rhinebothriidean genera in its possession of bothridia in which the proximal and distal sides are confluent, i.e., not separated by a rim of tissue, and in its possession of testes that extend to the posterior margin of the ovary. This new species is characterized in part by its possession of stalked, elongate bothridia lacking lateral constrictions, with 13-15 prominent transverse bothridial septa and 4 reduced transverse septa, craspedote proglottids, each with 2-3 layers of testes in cross section, and a vas deferens that joins the cirrus sac at its anterior margin. Histological and optical sections through bothridial septa revealed that the transverse septa are formed by septal muscles separate from bothridial radial musculature, extending from the anterior side to the posterior side of each septum. This is only the second species rhinebothriidean cestode reported from mobulids. This study adds to the number of new species and genera of elasmobranch cestodes discovered off of the island of Borneo. PMID- 22257018 TI - Midday dew--an overlooked factor enhancing photosynthetic activity of corticolous epiphytes in a wet tropical rain forest. AB - * Additional water supplied by dew formation is an important resource for microbes, plants and animals in precipitation-limited habitats, but has received little attention in tropical forests until now. * We evaluated the micro environmental conditions of tree stem surfaces and their epiphytic organisms in a neotropical forest, and present evidence for a novel mechanism of diurnal dew formation on these surfaces until midday that has physiological implications for corticolous epiphytes such as lichens. * In the understorey of a lowland forest in French Guiana, heat storage of stems during the day and delayed radiative loss during the night decreased stem surface temperatures by 6 degrees C in comparison to the dew-point temperature of ambient air. This measured phenomenon induced modelled totals of diurnal dew formation between 0.29 and 0.69 mm d-1 on the surface of the bark and the lichens until early afternoon. * Crustose lichens substantially benefit from this dew formation, because it prolongs photosynthetic activity. This previously unrecognized mechanism of midday dew formation contributes to the water supply of most corticolous organisms, and may be a general feature in forest habitats world-wide. PMID- 22257019 TI - Generic method for modular surface modification of cellulosic materials in aqueous medium by sequential "click" reaction and adsorption. AB - A generic approach for heterogeneous surface modification of cellulosic materials in aqueous medium, applicable for a wide range of functionalizations, is presented. In the first step, carboxymethyl cellulose (CMC) modified with azide or alkyne functionality, was adsorbed on a cellulosic substrate, thus, providing reactive sites for azide-alkyne cycloaddition click reactions. In the second step, functional units with complementary click units were reacted on the cellulose surface, coated by the click-modified CMC. Selected model functionalizations on diverse cellulosic substrates are shown to demonstrate the generality of the approach. The concept by sequentially combining the robust physical adsorption ("physical click") and robust chemical reaction ("chemical click") allows versatile, simple, and environmentally friendly modification of a cellulosic substrate with virtually any azide- or alkyne-modified molecule and even functionalization with several types of units. PMID- 22257020 TI - Resistive switching in single epitaxial ZnO nanoislands. AB - Resistive memory is one of the most promising candidates for next-generation nonvolatile memory technology due to its variety of advantages, such as simple structure and low-power consumption. Bipolar resistive switching behavior was observed in epitaxial ZnO nanoislands with base diameters and heights ranging around 30 and 40 nm, respectively. All four different states (initial, electroformed, ON, and OFF) of the nanoscale resistive memories were measured by conductive atomic force microscopy immediately after the voltage sweeping was performed. Auger electron spectroscopy and other experiments were also carried out to investigate the switching mechanism. The formation and rupture of conducting filaments induced by oxygen vacancy migration are responsible for the resistive switching behaviors of ZnO resistive memories at the nanoscale. PMID- 22257021 TI - A new strategy to stabilize oxytocin in aqueous solutions: II. Suppression of cysteine-mediated intermolecular reactions by a combination of divalent metal ions and citrate. AB - A series of studies have been conducted to develop a heat-stable liquid oxytocin formulation. Oxytocin degradation products have been identified including citrate adducts formed in a formulation with citrate buffer. In a more recent study we have found that divalent metal salts in combination with citrate buffer strongly stabilize oxytocin in aqueous solutions (Avanti, C.; et al. AAPS J.2011, 13, 284 290). The aim of the present investigation was to identify various degradation products of oxytocin in citrate-buffered solution after thermal stress at a temperature of 70 degrees C for 5 days and the changes in degradation pattern in the presence of divalent metal ions. Degradation products of oxytocin in the citrate buffer formulation with and without divalent metal ions were analyzed using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In the presence of divalent metal ions, almost all degradation products, in particular citrate adduct, tri- and tetrasulfides, and dimers, were greatly reduced in intensity. No significant difference in the stabilizing effect was found among the divalent metal ions Ca(2+), Mg(2+), and Zn(2+). The suppressed degradation products all involve the cysteine residues. We therefore postulate that cysteine-mediated intermolecular reactions are suppressed by complex formation of the divalent metal ion and citrate with oxytocin, thereby inhibiting the formation of citrate adducts and reactions of the cysteine thiol group in oxytocin. PMID- 22257023 TI - Nutritional counselling and oral nutritional supplements in head and neck cancer patients undergoing chemoradiotherapy. AB - BACKGROUND: The role of nutritional counselling (NC) with or without oral nutritional supplements (ONS) in patients receiving chemoradiotherapy (CRT) for head and neck cancer (HNC) still remains to be clearly defined, particularly with regard to CRT-related toxicity. METHODS: Patients undergoing CRT for HNC received NC by the dietitian within the first 4 days of radiotherapy and weekly for the course of radiotherapy (approximately 6 weeks). A weekly supply of oral nutrition supplements [1560 kJ (373 kcal) per 100 g] for up to 3 months was provided to all patients. RESULTS: Twenty-one patients completed CRT. Mucositis G3 developed in seven (33.3%) patients, whereas mucositis G4 was absent. Dysphagia was present before the start of treatment in four patients. In the remaining 17 patients, dysphagia G3 developed during/at the end of treatment in five cases. The percentage of patients interrupting anti-neoplastic treatment for was 28% for >=6 days, 28% for 3-5 days and 44% for 0-2 days. Mucositis G3 frequency was lower in patients with a baseline body mass index (BMI, kg m(-2) ) >=25 (two out of 12; 16.6%) than in patients with BMI <25 (five out of nine; 55.5%) (P = 0.161) and in patients with a baseline mid arm circumference >30 cm than in those with a mid arm circumference in the range 28.1-30 cm and <28 cm, and higher in patients with a greater weight loss and a greater reduction of serum albumin and mid arm circumference. CONCLUSIONS: Nutritional counselling and ONS are associated with relatively low CRT-related toxicity and with mild deterioration of nutritional parameters. PMID- 22257024 TI - Melatonin increases dendritogenesis in the hilus of hippocampal organotypic cultures. AB - Neuropsychiatric disorders are characterized by hippocampus decreased volume and loss of dendrite arborizations in the subiculum and prefrontal cortex. These structural changes are associated with diminished memory performance. Hilar neurons of the hippocampus integrate spatial memory and are lost in dementia. They receive information from dentate gyrus neurons through dendrites, while they send axonal tracts to the CA3 region. Dendrites are complex structures of neurons that receive chemical information from presynaptic and postsynaptic terminals. Melatonin, the main product of the pineal gland, has neuroprotective actions through its free radical-scavenging properties and decreases neuronal apoptosis. Recently, we found that melatonin increases dendrite maturation and complexity in new neurons formed in the dentate gyrus of mice. In addition, in N1E-115 cultured cells, the indole stimulates early stages of neurite formation, a process that is known to antecede dendrite formation and maturation. Thus, in this study, we explored whether melatonin stimulates dendrite formation and complexity in the adult rat hippocampus in organotypic slice cultures, which is a model that preserves the hippocampal circuitry and their tridimensional organizations of connectivity. The effects of melatonin were studied in nonpathological conditions and in the absence of harmful agents. The results showed that the indole at nocturnal concentrations reached in the cerebrospinal fluid stimulates dendritogenesis at formation, growth, and maturation stages. Also, data showed that dendrites formed became competent to form presynaptic specializations. Evidence strongly suggests that melatonin may be useful in the treatment of neuropsychiatric diseases to repair the loss of dendrites and re-establish lost synaptic connections. PMID- 22257022 TI - Redox active thiol sensors of oxidative and nitrosative stress. AB - SIGNIFICANCE: The reactivity of the thiol in the side chain of cysteines is exploited by bacterial regulatory proteins that sense and respond to reactive oxygen and nitrogen species. RECENT ADVANCES: Charged residues and helix dipoles diminish the pKa of redox active cysteines, resulting in a thiolate that is stabilized by neighboring polar amino acids. The reaction of peroxides with thiolates generates a sulfenic acid (-SOH) intermediate that often gives rise to a reversible disulfide bond. Peroxide-induced intramolecular and intermolecular disulfides and intermolecular mixed disulfides modulate the signaling activity of members of the LysR/OxyR, MarR/OhrR, and RsrA family of transcriptional regulators. Thiol-dependent regulators also help bacteria resist the nitrosative and nitroxidative stress. -SOHs, mixed disulfides, and S-nitrosothiols are some of the post-translational modifications induced by nitrogen oxides in the thiol groups of OxyR and SsrB bacterial regulatory proteins. Sulfenylation, disulfide bond formation, S-thiolation, and S-nitrosylation are reversible modifications amenable to feedback regulation by antioxidant and antinitrosative repair systems. The structural and functional changes engaged in the thiol-dependent sensing of reactive species have been adopted by several regulators to foster bacterial virulence during exposure to products of NADPH phagocyte oxidase and inducible nitric oxide synthase. CRITICAL ISSUES: Investigations with LysR/OxyR, MarR/OhrR, and RsrA family members have helped in an understanding of the mechanisms by which thiols in regulatory proteins react with reactive species, thereby activating antioxidant and antinitrosative gene expression. FUTURE DIRECTIONS: To define the determinants that provide selectivity of redox active thiolates for some reactive species but not others is an important challenge for future investigations. PMID- 22257025 TI - Outcome of smoking cessation counselling of HIV-positive persons by HIV care physicians. AB - OBJECTIVES: Smoking is the most prevalent modifiable risk factor for cardiovascular diseases among HIV-positive persons. We assessed the effect on smoking cessation of training HIV care physicians in counselling. METHODS: The Swiss HIV Cohort Study (SHCS) is a multicentre prospective observational database. Our single-centre intervention at the Zurich centre included a half day of standardized training for physicians in counselling and in the pharmacotherapy of smokers, and a physicians' checklist for semi-annual documentation of their counselling. Smoking status was then compared between participants at the Zurich centre and other institutions. We used marginal logistic regression models with exchangeable correlation structure and robust standard errors to estimate the odds of smoking cessation and relapse. RESULTS: Between April 2000 and December 2010, 11 056 SHCS participants had 121 238 semi-annual visits and 64 118 person years of follow-up. The prevalence of smoking decreased from 60 to 43%. During the intervention at the Zurich centre from November 2007 to December 2009, 1689 participants in this centre had 6068 cohort visits. These participants were more likely to stop smoking [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.07 1.42; P=0.004] and had fewer relapses (OR 0.75; 95% CI 0.61-0.92; P=0.007) than participants at other SHCS institutions. The effect of the intervention was stronger than the calendar time effect (OR 1.19 vs. 1.04 per year, respectively). Middle-aged participants, injecting drug users, and participants with psychiatric problems or with higher alcohol consumption were less likely to stop smoking, whereas persons with a prior cardiovascular event were more likely to stop smoking. CONCLUSIONS: An institution-wide training programme for HIV care physicians in smoking cessation counselling led to increased smoking cessation and fewer relapses. PMID- 22257027 TI - Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study. AB - BACKGROUND: High von Willebrand factor (VWF) plasma levels are associated with an increased risk of stroke. VWF levels are strongly heritable. A previous meta analysis of five large genome-wide association studies identified single nucleotide polymorphisms (SNPs) within eight genetic loci as determinants of VWF levels. Whether these SNPs are associated with stroke risk is not known. The aim of our study was to investigate the association between genetic determinants of VWF levels and stroke risk. METHODS: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged >= 55 years. A total of 5763 participants for whom DNA was available, and who were free of stroke at baseline, were eligible for analysis. VWF antigen (VWF:Ag) levels were measured in 3379 eligible participants. Within each of the eight loci, one top SNP was defined. The association between the eight SNPs and the risk of stroke was analyzed. Then, a genetic score, based on these eight SNPs, was constructed, and its total contribution to VWF plasma levels and stroke risk was investigated. RESULTS: None of the eight SNPs was individually associated with stroke risk. A higher genetic score was significantly associated with a higher VWF:Ag level, but was not associated with an increased risk of stroke. CONCLUSION: Eight SNPs that strongly determine VWF levels are not associated with stroke risk, either individually, or combined in a genetic score. PMID- 22257026 TI - 5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3. AB - Cumulative evidence strongly supports that glycogen synthase kinase-3 (GSK-3) is a pathogenic molecule when it is up-dysregulated, emerging as an important therapeutic target in severe unmet human diseases. GSK-3 specific inhibitors might be promising effective drugs for the treatment of devastating pathologies such as neurodegenerative diseases, stroke, and mood disorders. As GSK-3 has the ability to phosphorylate primed substrates, small molecules able to bind to this site should be perfect drug candidates, able to partially block the activity of the enzyme over some specific substrates. Here, we report substituted 5-imino 1,2,4-thiadiazoles as the first small molecules able to inhibit GSK-3 in a substrate competitive manner. These compounds are cell permeable, able to decrease inflammatory activation and to selectively differentiate neural stem cells. Overall, 5-imino-1,2,4-thiadiazoles are presented here as new molecules able to decrease neuronal cell death and to increase endogenous neurogenesis blocking the GSK-3 substrate site. PMID- 22257029 TI - Reactions of hydridoirida-beta-diketones with amines or with 2-aminopyridines: formation of hydridoirida-beta-ketoimines, PCN terdentate ligands, and acyl decarbonylation. AB - The hydridoirida-beta-diketone [IrHCl{(PPh(2)(o-C(6)H(4)CO))(2)H}] (1) reacts with benzylamine (C(6)H(5)CH(2)NH(2)) to give the hydridoirida-beta-ketoimine [IrHCl{(PPh(2)(o-C(6)H(4)CO))(PPh(2)(o-C(6)H(4)CNCH(2)C(6)H(5)))H}] (2), stabilized by an intramolecular hydrogen bond. 2 reacts with water to undergo hydrolysis and amine coordination giving hydridodiacylamino [IrH(PPh(2)(o C(6)H(4)CO))(2)(C(6)H(5)CH(2)NH(2))] (3). Cyclohexylamine or dimethylamine lead to hydridodiacylamino [IrH(PPh(2)(o-C(6)H(4)CO))(2)L] (4-5). In chlorinated solvents hydridodiacylamino complexes undergo exchange of hydride by chloride to afford [IrCl(PPh(2)(o-C(6)H(4)CO))(2)L] (6-9). The reaction of 1 with hydrazine (H(2)NNH(2)) gives hydridoirida-beta-ketoimine [IrHCl{(PPh(2)(o C(6)H(4)CO))(PPh(2)(o-C(6)H(4)CNNH(2)))H}] (10), fluxional in solution with values for DeltaH(?) of 2.5 +/- 0.3 kcal mol(-1) and for DeltaS(?) of -32.9 +/- 3 eu. A hydrolysis/imination sequence can be responsible for fluxionality. 2 Aminopyridines (RHNC(5)H(3)R'N) react with 1 to afford cis-[IrCl(PPh(2)(o C(6)H(4)CO))(PPh(2)(o-C(6)H(4)CHNRC(5)H(3)R'N))] (R = R' = H (11), R = CH(3), R' = H (12), R = H, R' = CH(3) (13)) containing new terdentate PCN ligands in a facial disposition and cis phosphorus atoms as kinetic products. The formation of 11-13 requires imination of the hydroxycarbene moiety of 1, coordination of the nitrogen atom of pyridine to iridium, and iridium to carbon hydrogen transfer. In refluxing methanol, complexes 11-13 isomerize to afford the thermodynamic products 14-16 with trans phosphorus atoms. Chloride abstraction from complexes [IrCl(PPh(2)(o-C(6)H(4)CO))(PPh(2)(o-C(6)H(4)CHNRC(5)H(4)N))] (R = H or CH(3)) leads to decarbonylation of the acylphosphine chelating group to afford cationic complexes [Ir(CO)(PPh(2)(o-C(6)H(4)))(PPh(2)(o-C(6)H(4)CHNRC(5)H(4)N))]A, 17 (R = H, A = ClO(4)) and 18 (R = CH(3), A = BF(4)) as a cis/trans = 4:1 mixture of isomers. Single crystal X-ray diffraction analysis was performed on 6, 9, 13, and 14. PMID- 22257030 TI - Rh(I)-catalyzed [5+1] cycloaddition of vinylcyclopropanes and CO for the synthesis of alpha,beta- and beta,gamma-cyclohexenones. AB - A cationic Rh(I)-catalyzed [5 + 1] cycloaddition of vinylcyclopropanes and CO has been developed, affording either beta,gamma-cyclohexenones as major products or alpha,beta-cyclohexenones exclusively, under different reaction conditions. PMID- 22257031 TI - Mechanism of the rhodium(III)-catalyzed arylation of imines via C-H bond functionalization: inhibition by substrate. AB - Rh(III)-catalyzed arylation of imines provides a new method for C-C bond formation while simultaneously introducing an alpha-branched amine as a functional group. This detailed mechanistic study provides insights for the rational future development of this new reaction. Relevant intermediate Rh(III) complexes have been isolated and characterized, and their reactivities in stoichiometric reactions with relevant substrates have been monitored. The reaction was found to be first order in the catalyst resting state and inverse first order in the C-H activation substrate. PMID- 22257032 TI - Probing the donor and acceptor substrate specificity of the gamma-glutamyl transpeptidase. AB - gamma-Glutamyl transpeptidase (GGT) is a two-substrate enzyme that plays a central role in glutathione metabolism and is a potential target for drug design. GGT catalyzes the cleavage of gamma-glutamyl donor substrates and the transfer of the gamma-glutamyl moiety to an amine of an acceptor substrate or water. Although structures of bacterial GGT have revealed details of the protein-ligand interactions at the donor site, the acceptor substrate site is relatively undefined. The recent identification of a species-specific acceptor site inhibitor, OU749, suggests that these inhibitors may be less toxic than glutamine analogues. Here we investigated the donor and acceptor substrate preferences of Bacillus anthracis GGT (CapD) and applied computational approaches in combination with kinetics to probe the structural basis of the enzyme's substrate and inhibitor binding specificities and compare them with human GGT. Site-directed mutagenesis studies showed that the R432A and R520S variants exhibited 6- and 95 fold decreases in hydrolase activity, respectively, and that their activity was not stimulated by the addition of the l-Cys acceptor substrate, suggesting an additional role in acceptor binding and/or catalysis of transpeptidation. Rat GGT (and presumably HuGGT) has strict stereospecificity for L-amino acid acceptor substrates, while CapD can utilize both L- and D-acceptor substrates comparably. Modeling and kinetic analysis suggest that R520 and R432 allow two alternate acceptor substrate binding modes for L- and D-acceptors. R432 is conserved in Francisella tularensis, Yersinia pestis, Burkholderia mallei, Helicobacter pylori and Escherichia coli, but not in human GGT. Docking and MD simulations point toward key residues that contribute to inhibitor and acceptor substrate binding, providing a guide to designing novel and specific GGT inhibitors. PMID- 22257033 TI - Plasma membrane H(+) -ATPase gene expression, protein level and activity in growing and non-growing regions of barley (Hordeum vulgare) leaves. AB - Plasma membrane proton ATPase (PM-H+-ATPase) is the key means through which plant cells energize nutrient uptake and acidify the apoplast. Both of these processes aid cell elongation; yet, it is not known how such a suspected role of the PM-H+ ATPase in growth is reflected through changes in its transcript level and activity in grass leaves. In the present study on leaf three of barley, the elongation zone and the emerged blade, which contained fully expanded cells were analyzed. Plasma membranes were isolated and used to assay the activity (ATPase assay) and abundance (western blotting) of PM-H+-ATPase protein. Expression of mRNA was quantified using real-time polymerase chain reaction (qPCR). PM-H+ ATPase transcript and protein level and activity differed little between growing and non-growing leaf regions when values were related to unit extracted total RNA and cell number, respectively. However, when values were related to unit surface area of plasma membrane, they were more than twice as high in growing compared with non-growing leaf tissue. It is concluded that this higher surface density of PM-H+-ATPase activity in growing barley leaf tissue aids apoplast acidification and cell expansion. PMID- 22257034 TI - Late onset hypogonadism in males - think of it - act on it. PMID- 22257035 TI - What IJCP authors think about open access: exploring one possible future for publishing clinical research in a general and internal medicine journal. PMID- 22257036 TI - The development of medical-manager roles in European hospital systems: a framework for comparison. AB - A central motif of health reforms around the world has been the drive to persuade doctors and other clinical professionals to become more actively engaged in the management of services. Examples include moves to extend the commissioning role of primary care doctors (such as general practitioners in the UK) and the introduction of 'clinical directorates' in secondary care. This strategy has been seen as a means of controlling professionals, turning 'poachers into game keepers', especially with regard to resource allocation. However, there is also a mounting body of evidence pointing to how clinical leadership may play a role in stimulating quality improvement and new innovations inservice design, with positive consequences for patient safety and satisfaction (1). Focusing on the top 100 hospitals in the US Goodall (2) finds a strong positive association between the ranked quality of hospitals and whether the chief executive officer was a clinician. A survey of 1200 hospitals across seven countries (UK, US, Germany, France, Italy,Canada and Sweden) conducted by McKinsey and LSE also finds that clinically qualified managers improve both the effectiveness of management decisions and clinical performance of hospitals overall (3). PMID- 22257037 TI - Time for considering other blood pressure target values in elderly patients with type 2 diabetes? AB - Although blood pressure control has undoubtedly proven its benefits in reducing the high cardiovascular risk in patients with type 2 diabetes mellitus (T2DM), it still remains unclear whether intensive antihypertensive treatment in old age (> 75 years) is beneficial. Many of the current guidelines recommend a systolic blood pressure (SBP) < 140 mmHg or lower, unless patients are at high risk for possible adverse events such as postural hypotension (1,2). This perspective aims to get a discussion started on the appropriate target SBP value for patients with T2DM aged older than 75 years.We would like to propose the less stringent value of< 160 mmHg in this specific population. PMID- 22257038 TI - Joint tenderness and swelling in biologic-treated inflammatory arthritis patients - a tricky trade off? AB - OBJECTIVE: To compare the pattern of joint responses in patients with rheumatoid arthritis and psoriatic arthritis treated with TNF inhibitor (TNFi) therapy. METHODS: A total of 182 PsA/Rheumatoid arthritis (RA) patients attending the rheumatology unit of a tertiary referral centre in Ireland were recruited and prospectively followed up by the attendant rheumatologists. Clinical progress of the patients was noted at baseline and 6 months after starting TNFi therapy. RESULTS: A total of 114 RA and 68 PsA patients were assessed; 20% of the patients had one of either tender joints or swollen joints after 6 months of therapy. Rheumatoid arthritis patients had a significantly higher proportion of non-tender swollen joints compared with PsA patients, whereas PsA patients had a higher proportion of tender non-swollen joints (p < 0.05). CONCLUSION: Residual joint swelling was found more commonly in RA patients than in PsA patients following TNFi therapy, whereas residual tender joints occurred more frequently in PsA; this may reflect enthesiopathy or periostitis. PMID- 22257039 TI - Therapeutic effect of alpha-blockers and antimuscarinics in male lower urinary tract symptoms based on the International Prostate Symptom Score subscore ratio. AB - AIMS: To investigate if the International Prostate Symptom Score (IPSS) voiding to-storage subscore ratio (IPSS-V/S) can help to guide the treatment for male lower urinary tract symptoms (LUTS). METHODS: Men aged 40 years or older with a total IPSS (IPSS-T) 8 or more were constitutively enrolled from January 2010 to December 2010. The IPSS voiding (IPSS-V) and storage subscore (IPSS-S) were recorded separately, and the IPSS-V/S was calculated. Patients were divided into two groups according to the baseline IPSS-V/S value. First-line doxazosin (4 mg per day) and tolterodine (4 mg per day) monotherapy were given to patients with IPSS-V/S > 1 and IPSS-V/S <= 1, respectively. The IPSS-T, IPSS-V, IPSS-S, quality of life (QoL), maximum flow rate (Qmax), voided volume and postvoid residual (PVR) were measured at 1 month (visit 1) and 3 months (visit 2) after treatment. RESULTS: After medical treatment for 1 month, 89/116 (76.7%) patients receiving tolterodine and 218/279 (78.1%) patients receiving doxazosin reported an improved outcome (global response assessment, GRA >= 1 point). The mean IPSS-T, IPSS-S decreased, and QoL improved significantly in both groups. Significant increased Qmax, voided volume, decreased IPSS-V and PVR were noted only in patients receiving doxazosin. There was no significant increase of PVR (from 50.1 to 60.4 ml, p = 0.106), and no patient developed urinary retention after tolterodinie monotherapy for 1 month. However, patients aged more than 70 years had significant association with increased PVR (>= 50 ml). CONCLUSION: Initial treatment with doxazosin for patients with IPSS-V/S > 1 and tolterodine for patients with IPSS-V/S <= 1 is safe and feasible. Elderly people (>= 70 years) and patients with Qmax < 10 ml/s are more likely to have increased PVR (>= 50 ml). PMID- 22257040 TI - Is FENO50 useful diagnostic tool in suspected asthma? AB - BACKGROUND: Asthma diagnosis is based on the presence of symptoms and the demonstration of airflow variability. Airway inflammation measured by fractional exhaled nitric oxide, measured at a flow rate of 50 ml/s (FE(NO50)) remains a controversial diagnostic tool. AIM: To assess the ability of FE(NO50) to identify bronchial hyperresponsiveness (BHR) to methacholine (provocative concentration of methacholine causing a 20% fall in FEV(1); PC20M <= 16 mg/ml) and to establish whether or not symptoms relate to FE(NO50) and PC20M in patients with no demonstrated reversibility to beta(2) -agonist. METHODS: We conducted a prospective study on 174 steroid naive patients with respiratory symptoms, forced expiratory volume in 1 s (FEV(1) ) >= 70% predicted and no demonstrated reversibility to beta(2) -agonist. Patients answered to a standardised symptom questionnaire and underwent FE(NO50) and methacholine challenge. Receiver operating characteristic (ROC) curve and logistic regression analysis assessed the relationship between PC20M and FE(NO50) , taking into account covariates (smoking, atopy, age, gender and FEV(1)). RESULTS: A total of 82 patients had a PC20M <= 16 mg/ml and had significantly higher FE(NO50) (19 ppb vs. 15 ppb; p < 0.05). By constructing ROC curve, we found that FE(NO50) cut-off value of 34 ppb was able to identify not only BHR with high specificity (95%) and positive predictive value (88%) but low sensitivity (35%) and negative predictive value (62%). When combining all variables into the logistic model, FE(NO50) (p = 0.0011) and FEV(1) (p < 0.0001) were independent predictors of BHR whereas age, gender, smoking and atopy had no influence. The presence of diurnal and nocturnal wheezing was associated with raised FE(NO50) (p < 0.001 and p < 0.05, respectively). CONCLUSION: The value of FE(NO50) > 34 ppb has high predictive value of PC20M < 16 in patients with suspected asthma in whom bronchodilating test failed to demonstrate reversibility or was not indicated. However, FE(NO50) <= 34 ppb does not rule out BHR and should prompt the clinician to ask for a methacholine challenge. PMID- 22257041 TI - Meniere's disease: an evidence based approach to assessment and management. AB - Meniere's disease (MD) is frequently over-diagnosed in both primary and secondary care. This is unfortunate given the significant medical and social implications of such a diagnosis. Difficulties may arise in differentiating the patient with true MD from those individuals with less clearly defined disorders of cochleo vestibular function. In this review, we suggest a practical evidence based approach to assessment and management of the patient with MD. PMID- 22257042 TI - Systematic review of the cost-effectiveness of varenicline vs. bupropion for smoking cessation. AB - The purpose of this systematic review was to review the cost-effectiveness of first-line non-nicotine therapies (varenicline and bupropion SR) for smoking cessation, identify differences in the models used and their conclusions of cost effectiveness, and to determine which variables, if any, impact conclusions of cost-effectiveness. A systematic literature search was conducted in MEDLINE, PsychINFO, the National Health Service Economic Evaluation Database, the Health Technology Database and the Tufts Cost-effectiveness Analysis Registry from the earliest possible date through May 2011. To be included, studies had to compare cost-effectiveness of varenicline to bupropion using either a Markov model or discrete event simulation and be published as a full text manuscript in English or Spanish. Study selection and data extraction were done in duplicate with disagreement resolved through discussion. Data regarding the model characteristics, results and conclusions were extracted as were details to assess the quality of the study. Model characteristics and cost-effectiveness results were compared across studies and summarised qualitatively. Ten unique studies were included, all of which were Markov models. Eight studies used the Benefits of Smoking Cessation on Outcomes (BENESCO) model and all found varenicline to dominate bupropion. The two non-BENESCO models found varenicline to be cost effective. Conclusions regarding the cost-effectives were changed upon sensitivity analysis with the following variables: time horizon, cost of bupropion, efficacy of either drug, age and the incidence of smoking related disease. Varenicline dominated bupropion in most cost-effectiveness models. However, applicability of models to clinical practice and variables which changed conclusion of cost-effectiveness should be considered in the interpretation of results. PMID- 22257043 TI - Presentation of laryngeal papilloma in childhood: the Leeds experience. AB - INTRODUCTION: The human papilloma virus (HPV) can cause laryngeal papillomatosis in childhood. The aetiology is thought to be vertical transmission. Clinically these children are usually asymptomatic for the first 6 months of life. As the papillomas develop locally, symptoms begin to develop. The symptoms range from voice change to frank hoarseness, and 'noisy' breathing, most commonly inspiratory stridor. METHOD: Clinical images from microlaryngoscopy and bronchoscopy over a 12-year period were assessed for laryngeal papilloma. RESULTS: In Leeds seven cases presented to the specialist centre over the past 12 years, the average age at presentation was 6.8 years and duration of onset of symptoms to specialist review was 21 months. Five of the children had been treated for asthma and two presented in extremis. CONCLUSION: The take home message for clinicians is hoarse voice associated with shortness of breath needs specialist referral. PMID- 22257044 TI - Diagnostic accuracy of 18 F-FDG and 11 C-PIB-PET for prediction of short-term conversion to Alzheimer's disease in subjects with mild cognitive impairment. AB - In recent years, the role of PET imaging in the prediction of mild cognitive impairment (MCI) to Alzheimer's disease (AD) conversion has been the subject of many longitudinal studies. The purpose of this study was to perform a meta analysis to estimate the diagnostic accuracy of (18) F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and (11) C-Pittsburgh Compound B-positron emission tomography (PIB-PET) for prediction of short-term conversion to AD in patients with MCI. The MEDLINE and EMBASE databases were systematically searched for relevant studies. Methodological quality of the included studies was assessed. Sensitivities and specificities of PET in individual studies were calculated and meta-analysis was undertaken with a random-effects model. A summary receiver operating characteristic (SROC) curve was constructed with the Moses-Shapiro-Littenberg method. Heterogeneity was tested, and the presence of publication bias was assessed. Potential sources for heterogeneity were explored by assessing whether or not certain covariates significantly influenced the relative diagnostic odds ratio (DOR). Pooled estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), DOR and the SROC curve of each PET imaging were determined. A total of 13 research studies (seven FDG-PET and six PIB-PET) met inclusion criteria and had sufficient data for statistical analysis. FDG-PET pooled estimates had 78.7% sensitivity (95% CI, 68.7-86.6%),74.0% specificity (95% CI, 67.0-80.3%), 18.1 LR+(95% CI, 7.3-45.0) and 0.32 LR-(95% CI, 0.16-0.61); and PIB-PET pooled estimates had 93.5% sensitivity (95%CI, 71.3-99.9%), 56.2% specificity (95% CI, 47.2-64.8%), 2.01 LR+ (95% CI, 1.57-2.58) and 0.17 LR-(95% CI, 0.08-0.36). Overall DOR was 17.3 (95% CI, 5.08-59.2) for FDG-PET and 12.8 (95% CI, 5.35 30.54) for PIB-PET. Area under the SROC curve was 0.88 +/- 0.05 for FDG-PET and 0.85 +/- 0.04 for PIB-PET. The data from FDG-PET research studies had high heterogeneity and funnel plot suggested a publication bias. The diagnostic accuracy determined for both FDG-PET and PIB-PET in this meta-analysis suggests that they are potentially valuable techniques for prediction of progression in patients with MCI. Both have their advantages and their combined use is a promising option for prediction purposes depending on availability and experience. PMID- 22257045 TI - Effect of teriparatide on bone mineral density and fracture in postmenopausal osteoporosis: meta-analysis of randomised controlled trials. AB - To determine the efficacy of teriparatide supplementation for improving bone mineral density (BMD) and fracture risk in postmenopausal osteoporosis and if effects vary with factors. We identified eight randomised controlled trials (n = 2388) using electronic databases, supplemented by a hand-search of the reference lists. All trials aimed to evaluate the efficacy of daily subcutaneous teriparatide injection in postmenopausal osteoporosis. The main outcomes were fracture risk and percentage change of BMD from baseline. Data were pooled by employing a random-effect model. In trials that reported BMD as an outcome, treatment was associated with an increase of bone mass of 8.14% [95% confidence interval (CI): 6.72-9.55%; eight trials, n = 2206] in spine and 2.48% (95% CI: 1.67-3.29%; seven trials, n = 1303) at the hip. In trials that reported fracture as an outcome, treatment was associated with a 70% risk reduction in vertebral fractures (risk ratio 0.30, 95% CI: 0.21-0.44; three trials, n = 1452) and 38% risk reduction in non-vertebral fractures (risk ratio 0.62, 95% CI: 0.44-0.87; three trials, n = 1842). The PTH treatment with total calcium intake more than 1500 mg was related to a significant increase in BMD gains at total hip (1.40% vs. 3.72%; p = 0.004). However, long-term duration did not appear to contribute to differences in responsiveness to teriparatide. Evidence supports the use of teriparatide in treatment of women with postmenopausal osteoporosis who are at risk for fracture. Further studies directly comparing concurrent therapy and calcium supplement with long-term duration are warranted. PMID- 22257046 TI - Moxifloxacin monotherapy for treatment of complicated intra-abdominal infections: a meta-analysis of randomised controlled trials. AB - To evaluate the efficacy and safety of moxifloxacin monotherapy for treatment of complicated intra-abdominal infections. PubMed, EMBASE, Science Direct, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials were searched to retrieve randomised controlled trials (RCTs) compared moxifloxacin monotherapy with other antibiotics in the treatment of complicated intra abdominal infections from January 1999 to July 2011. A meta-analysis of all included randomised controlled trials was performed. Four randomised controlled trials including a total of 2444 patients with complicated intra-abdominal infections were included for meta-analysis. The results of the meta-analysis indicated that the moxifloxacin was associated with similar clinical cure rate (four RCTs, 1934 patients, OR = 0.80, 95% CI: 0.61, 1.04, p = 0.09), bacteriological success rates (four RCTs, 1484 patients, OR = 0.79, 95% CI: 0.59, 1.05, p = 0.11) and mortality (four RCTs, 2227 patients, OR = 0.91, 95% CI: 0.45, 1.83, p = 0.79) compared with the control group. The overall incidence of adverse events of moxifloxacin was significantly higher than that in the control group (three RCTs, 1367 patients, OR = 1.33, 95% CI: 1.07, 1.63, p = 0.008), although the incidence of drug-related adverse events (three RCTs, 1601 patients, OR = 1.13, 95% CI: 0.69, 1.85, p = 0.63) and serious adverse events (three RCTs, 1815 patients, OR = 1.23, 95% CI: 0.59, 2.60, p = 0.58) were similar between the compared treatment groups. Moxifloxacin is an effective and relatively safe option for the treatment of patients with intra-abdominal infections. Moxifloxacin monotherapy has similar efficacy to combination therapy. PMID- 22257047 TI - Trends, indications and outcomes of cardiac implantable device system extraction: a single UK centre experience over the last decade. AB - BACKGROUND: The rising number of device implantation has seen a parallel in the rising numbers of lead extraction. Herein we have analysed our experience in cardiac device and lead extraction in a single tertiary centre over the last decade. METHOD: Retrospective analysis of all consecutive patients undergoing lead extractions performed between 2001 and 2010. Procedural success and complications as defined by the Heart Rhythm Society policy. RESULTS: A total of 745 leads were extracted with a procedural success of 98.9% [382 cases; partial success in 6.9% (26) cases] and failure in 1.1% (4). Major complication rate was 1% (four cases) and minor complication rate was 3.6%. By both univariate and multivariate analysis only duration of lead implantation was an indicator for success (p < 0.0001). The mean implantation time for failed lead extraction was 203 +/- 64 months compared with 71.8 +/- 16.5 months in the successful cohort (p < 0.0001). Laser-assisted extraction was required in 176 cases. With regard to extraction indication, lead malfunction/recall showed a significant increase during the study period (p = 0.03). On time trend analysis the rise in coronary sinus (CS) lead extraction over time was significant. (p = 0.02) Despite a trend for increased laser use over time this did not achieve statistical significance, p = 0.06. CONCLUSIONS: A decade's experience of percutaneous lead extraction suggests that a high procedural success rate with a low complication rate is achieved in a high-volume centre. During this time, an increase in both defibrillator and CS lead explantation and a rising trend in laser assistance with almost 50% of cases needing laser usage were observed. PMID- 22257048 TI - Healthcare expenditure in the United States of America in the last year of life: where ethics, medicine and economics collide? PMID- 22257049 TI - Cannabis smoking and myocardial infarction. PMID- 22257051 TI - MMP-2 selectivity in hydroxamate-type inhibitors. AB - Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents. PMID- 22257050 TI - Paraventricular nucleus neuropeptide expression in Huntington's disease patients. AB - Neuroendocrine, metabolic and autonomic nervous system dysfunctions are prevalent among patients with Huntington's disease (HD) and may underlie symptoms such as depression, weight loss and autonomic failure. Using post-mortem paraffin embedded tissue, we assessed the integrity of the major neuropeptide populations in the paraventricular nucleus (PVN)-the hypothalamic neuroendocrine and autonomic integration center-in HD patients. The number corticotropin-releasing hormone, cocaine- and amphetamine-regulated transcript, arginine vasopressin and oxytocin immunoreactive (ir) neurons did not differ between HD patients and control subjects. However, the significant positive correlation between arginine vasopressin and oxytocin ir neurons in control subjects (P = 0.036) was absent in patients. Corticotropin-releasing hormone mRNA levels were 68% higher in HD patients (P = 0.046). Thyrotropin-releasing hormone mRNA levels did not differ between HD patients and control subjects, although a negative correlation with disease duration was present in the former (P = 0.036). These findings indicate that the PVN is largely unaffected in HD patients. However, our findings suggest that hypothalamic-pituitary-thyroid axis activity may alter during the course of the disease and that autonomic nervous system dysfunction might partly arise from an imbalance between arginine vasopressin and oxytocin neurons in the PVN. PMID- 22257052 TI - Approaches to target profiling of natural products. AB - Natural products have long been regarded as excellent sources for drug discovery given their structural diversity and wide variety of biological activities. Accordingly, the identification of the molecular targets of natural products is an important aspect of current drug discovery, as knowledge regarding a compound's molecular targets will greatly aid drug development and design. In this review, we will explore genomic, proteomic, and computational approaches to the elucidation of these mechanisms and the implications of these approaches for the target profiling of natural products. The recent applications of target profiling of natural products will also be reviewed. PMID- 22257053 TI - Azole antimycotics--a highway to new drugs or a dead end? AB - Azole antimycotics are a well-known and important class of agents that are used in hospital practice, everyday health care, veterinary medicine and for crop protection. The era of azole fungicides began with the breakthrough of chlormidazole roughly 50 years ago. Since then, more than 20 drugs of this group, including triazoles, have been brought to the market. The specific chemical structure and mechanism of the action of azoles along with the eukaryotic character of fungal pathogens raise several serious issues. Resistance to drugs and disturbance to metabolic pathways are among the most important. On the other hand, these same features are responsible for unique and novel applications of these drugs. As a result, old and ineffective antifungal drugs can be successfully used in the treatment of parasitic diseases, bacterial infections or cancers. Are azoles getting their second wind? PMID- 22257054 TI - Advances in the research of beta-ketoacyl-ACP synthase III (FabH) inhibitors. AB - Fatty acid biosynthesis is essential for bacterial survival. In recent years, components of this biosynthetic pathway have aroused wide concern. beta-ketoacyl acyl carrier protein synthase III (FabH) is a particularly attractive target which catalyzes the initial step of fatty acid biosynthesis. In this review, fatty acid biosynthesis, recent advances in the research of FabH as well as related inhibitors are reviewed. Finally, we also discuss the prospect and developmental trend of FabH inhibitors as anti-bacterial agents. PMID- 22257055 TI - Adiponectin and cardiovascular disease: mechanisms and new therapeutic approaches. AB - Adiponectin is an abundant plasma protein secreted from adipocytes. Its role in energy homeostasis is well-known, including the regulation of hydrocarbons and lipids metabolism as well as the improvement of insulin resistance. It has been thought to be a key molecule in the development of type 2 diabetes mellitus and metabolic syndrome, which are epidemiological targets for preventing cardiovascular disease. In addition to beneficial metabolic effects, adiponectin seems to have anti-inflammatory, anti-atherosclerotic and vasoprotective actions. Furthermore, adiponectin affects signalling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia-reperfusion injury. The ability of adiponectin to reduce insulin resistance in conjunction with its antiinflammatory and cardioprotective properties makes this adipocytokine a promising therapeutic target. On clinical interest, agents that enhance endogenous adiponectin production or action have potential for the treatment of cardiovascular disease. Management strategies that increase adiponectin levels include weight reduction, Mediterranean diet, thiazolidinediones, antihypertensive and lipid lowering drugs. Current knowledge on the main actions of adiponectin and therapeutic approaches for cardiovascular disease is summarized in this review. PMID- 22257056 TI - New developments in the diagnosis and management of resistant hypertension. AB - Arterial hypertension is a well-known disease with a worldwide high prevalence and impaired prognosis with respect to normotensive subjects, due to increased cardiovascular mortality and morbidity. Blood pressure levels over range can be successfully controlled with adequate treatment, but more than 10% of hypertensive people have their blood pressure uncontrolled despite a therapeutic regimen of 3 or more antihypertensive drugs. These patients, named to have resistant hypertension, have a worse cardiovascular prognosis than controlled hypertensive subjects. Twenty-four hour-ambulatory blood pressure monitoring (ABPM) reveals that at least one third of these patients have indeed white-coat resistant hypertension, a rather more benign entity. In view of this evidence, performance of 24 h-ABPM is mandatory and to document the occurrence of subclinical target organ damage in this population before the development of cardiovascular disease is needed. This would help the physician to more rigorously implement adequate measures to control hypertension. On the other hand, the definition itself of the disease implies that conventional pharmacological treatment is not effective enough for these patients to reach normal blood pressure values. To treat resistant hypertensives, recent reports pay attention to the need to recover traditional treatments--either non pharmacologic such as strict sodium diet restriction or pharmacologic such as the use of aldosterone receptor blockers--or to implement those treatments that are novelties, such as renal sympathetic nervous system ablation or carotid barorreceptors stimulation. This review focuses on outlining the current evidence about the diagnostic confirmation of resistant hypertension, the need to characterize these patients through 24 h-ABPM, to identify the presence of subclinical target organ damage, and to deal with not only classical but also novel treatment approaches for blood pressure control. PMID- 22257057 TI - Three decades of P-gp inhibitors: skimming through several generations and scaffolds. AB - Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters, namely P-glycoprotein (P-gp). The discovery of the reversal of multidrug resistance (MDR) by verapamil occured in 1981, and in 1968 MDR Chinese hamster cell lines were isolated for the first time. Since then, P-gp inhibitors have been intensively studied as potential MDR reversers. Initially, drugs to reverse MDR were not specifically developed for inhibiting P-gp; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. An example of this first generation P-gp inhibitors is verapamil. The second generation included more specific with less side-effect inhibitors, such as dexverapamil or dexniguldipine. A third generation of P-gp inhibitors comprised compounds such as tariquidar, with high affinity to P-gp at nanomolar concentrations. These generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate an improvement in therapeutic efficacy. Therefore, new and innovative strategies, such as the fallback to natural products, the design of peptidomimetics and dual activity ligands emerged as a fourth generation of P-gp inhibitors. The chemistry of P-gp inhibitors, as well as their in vitro, in vivo and clinical trials are discussed, and the most recent advances concerning Pgp modulators are reviewed. PMID- 22257058 TI - RAS/RAF/MEK inhibitors in oncology. AB - The RAS/RAF/MEK signaling pathway plays a central role in mediating both proliferation and survival of cancer cells. These proteins are a group of serine/threonine kinases activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface towards both nuclear and cytosolic targets. In combination with several other signaling pathways, they can differentially alter phosphorylation status of the transcription factors. A controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas an unregulated activation of these kinases can result in oncogenesis. Dysregulation of the RAS/RAF/MEK pathway has been detected in more than 30% of human tumors, however mutations in the MEK1 and MEK2 genes are seldom, so that hyperactivation of MEK1/2 usually results from gain-of-function mutations in RAS and/or B-RAF. In addition, alteration of the pathways is often associated with drug resistance in the clinic, such as the case of K-RAS mutant expressing tumors. Since RAS protein is a difficult target, alternative ways altering post-translational modifications using farnesyl transferase inhibitors have been adopted. Drug discovery programs have therefore largely focused on B-RAF and MEK. In this review we will discuss the most promising strategies developed to target these kinases and the most recent inhibitors facing the preclinical and clinical setting, also considering their structure-activity relationship (SAR). PMID- 22257059 TI - Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions. AB - Resveratrol is a polyphenol that among other sources occurs in grapes and for this reason, red wines also contain considerable amounts of this compound. Resveratrol is thought to be responsible for the "French Paradox" which associates red wine consumption to the low incidence of cardiovascular diseases. The interest in resveratrol has increased due to its pharmacological effects that include cardio and neuroprotection and several other benefic actions (e.g. antioxidant, anti-inflammatory, anti-carcinogenic and anti-aging). Despite the therapeutic effects of resveratrol, its pharmacokinetic properties are not favorable since this compound has poor bioavailability being rapidly and extensively metabolized and excreted. To overcome this problem, drug delivery systems have been developed to protect and stabilize resveratrol and to enhance its bioavailability. Herein is presented an up-to-date revision covering the literature reported for nano and microformulations for resveratrol encapsulation that include liposomes, polymeric nanoparticles, solid lipid nanoparticles, lipospheres, cyclodextrins, polymeric microspheres, yeast cells carriers and calcium or zinc pectinate beads. Regarding the interaction of resveratrol with cell membranes, only few studies have been published so far. However, it is believed that this interaction can be implied in the biological activities of resveratrol since transmembranar proteins are one of its cellular targets. Indeed, resveratrol presents the capacity to modulate the membrane organization which may consequently affect the protein functionality. Therefore, the intracellular effects of resveratrol and the effects of this compound at the membrane level were also revised since their knowledge is essential for understanding the pharmacological and therapeutic activities of this bioactive compound. PMID- 22257060 TI - Disease-modifying therapies in frontotemporal lobar degeneration. AB - Frontotemporal Lobar Degeneration (FTLD) is characterized by behavioral changes, executive dysfunctions, and language impairment, sustained by different neuropathological patterns. The collective efforts of clinical, pathological and genetic studies have recently opened new insights into the underpinnings of pathological mechanisms of this complex disorder. Different types of inclusions define the new conceptual framework for FTLD classification. Up to now, Tau (FTLDTau-positive), TAR DNA-binding protein (TDP43, FTLD Tau-negative TDP43 positive) have been recognized as the most frequent neuropathological hallmarks of FTLD. In some clinical cases, monogenic forms are identified, mainly due to Microtubule Associated Protein (MAPT) or Granulin (GRN) mutations. No treatments for FTLD are available yet, and off-label medications studies testing potential modifying treatments on the basis of neuropathological positive, inhibitors of Tau kinases or manipulation of Tau-processing haploinsuffciency associated with GRN mutations, has been counteracted into pathological processing of TDP-43 and other key-molecules involved and their consequent translocation from nucleus to cytoplasm, and growing number of potential therapeutic targets. In this continuously new findings on molecular targets and modifying therapies in FTLD. PMID- 22257061 TI - Nonmuscle myosin heavy chain and histone H3 are intracellular binding partners of lithospermic acid B and mediate its antiproliferative effect on VSMCs. AB - Lithospermic acid B (LAB), an active component of danshen, is known to inhibit the proliferation of vascular smooth muscle cells (VSMCs) and has pharmacological activity scavenging free radicals in VSMCs. However, the precise mechanism through which LAB exerts its antiproliferative effect is unclear. Therefore, we investigated how LAB regulates cellular proliferation in primary cultured rat VSMCs. Using fluorescein isothiocyanate (FITC)-conjugated LAB to track its cellular localization, we show that LAB localizes to the nucleus, specifically to the nucleolus, where it binds to histone H3, leading to the inhibition of the platelet-derived growth factor (PDGF)- induced phosphorylation of histone H3. LAB also only moves into the nucleus during the normal expression of nonmuscle myosin heavy chain (NMHC-IIA), which is associated with LAB in VSMCs. Notably, LAB suppressed the PDGF-induced phosphorylation of Akt and the expression of cyclin D2 in the presence of NMHC-IIA expression. Knockdown of NMHC-IIA expression impeded the function of LAB, which was then unable to inhibit the PDGF-induced proliferation of VSMCs. We conclude that LAB modulates the PDGF-induced proliferation of VSMCs by interacting with NMHC-IIA, which allows LAB to localize in the nucleus and to suppress the PDGF-induced proliferation of VSMCs. PMID- 22257062 TI - DC-SIGN antagonists, a potential new class of anti-infectives. AB - DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non integrin) is a type II C-type lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DCSIGN binds mannose- and fucose based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives. PMID- 22257063 TI - Gemcitabine: a critical nucleoside for cancer therapy. AB - Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is a deoxycytidine nucleoside analogue of deoxycytidine in which two fluorine atoms have been inserted into the deoxyribose ring. Like other nucleoside analogues, gemcitabine is a prodrug. It is inactive in its original form, and depends on the intracellular machinery to gain pharmacological activity. What makes gemcitabine different from other nucleoside analogues is that it is actively transported across the cell membrane, it is phosphorylated more efficiently and it is eliminated at a slower rate. These differences, together with self-potentiation mechanisms, masked DNA chain termination and extensive inhibitory efficiency against several enzymes, are the source of gemcitabine's cytotoxic activity against a wide variety of tumors. This unique combination of metabolic properties and mechanistic characteristics is only found in very few other anticancer drugs, and both the FDA and the EMEA have already approved its use for clinical purposes, for the treatment of several types of tumors. In spite of the promising results associated with gemcitabine, the knowledge of its mode of action and of the enzymes it interacts with is still not fully documented. In this article we propose to review all these aspects and summarize the path of gemcitabine inside the cell. PMID- 22257064 TI - Symmetry breaking analysis of prism adaptation's latent aftereffect. AB - The effect of prism adaptation on movement is typically reduced when the movement at test (prisms off) differs on some dimension from the movement at training (prisms on). Some adaptation is latent, however, and only revealed through further testing in which the movement at training is fully reinstated. Applying a nonlinear attractor dynamic model (Frank, Blau, & Turvey, 2009) to available data (Blau, Stephen, Carello, & Turvey, 2009), we provide evidence for a causal link between the latent (or secondary) aftereffect and an additive force term that is known to account for symmetry breaking. The evidence is discussed in respect to the hypothesis that recalibration aftereffects reflect memory principles (encoding specificity, transfer-appropriate processing) oriented to time translation invariance-when later testing conserves the conditions of earlier training. Forgetting or reduced adaptation effects follow from the loss of this invariance and are reversed by its reinstatement. PMID- 22257065 TI - Behavioral training and predisposed coping strategies interact to influence resilience in male Long-Evans rats: implications for depression. AB - Effective coping strategies and adaptive behavioral training build resilience against stress-induced pathology. Both predisposed and acquired coping strategies were investigated in rats to determine their impact on stress responsiveness and emotional resilience. Male Long-Evans rats were assigned to one of the three coping groups: passive, active, or variable copers. Rats were then randomly assigned to either an effort-based reward (EBR) contingent training group or a non-contingent training group. Following EBR training, rats were tested in appetitive and stressful challenge tasks. Physiological responses included changes in fecal corticosterone and dehydroepiandrosterone (DHEA) metabolites as well as neuropeptide Y (NPY)-immunoreactivity in the hippocampus and amygdala. Regardless of a rat's predisposed coping strategy, EBR rats persisted longer than non-contingent rats in the appetitive problem-solving task. Furthermore, training and coping styles interacted to yield the seemingly most adaptive DHEA/corticosterone ratios in the EBR-trained variable copers. Regardless of training group, variable copers exhibited increased NPY-immunoreactivity in the CA1 region. PMID- 22257066 TI - Chronic foot swelling with purulent discharge. PMID- 22257067 TI - Sodium intake and excretion in individuals with type 2 diabetes mellitus: a cross sectional analysis of overweight and obese males and females in Australia. AB - BACKGROUND: Hypertension is common in individuals with type 2 diabetes mellitus (T2DM). Dietary sodium plays an important regulatory role in blood pressure management. However, dietary sodium intakes and the major food sources of dietary sodium have yet to be thoroughly investigated in individuals with T2DM. METHODS: In a cross-sectional study sample of 88 overweight and obese men (n = 52) and women (n = 36) with T2DM in Adelaide, Australia, sodium intake and excretion was investigated using two different methodologies, including a 4-day weighed food record and 24-h urinary sodium excretion. The major dietary contributors to sodium intake in this population were also explored. RESULTS: Mean (SD) 24-h urinary sodium excretion was greater (P < 0.001) in males [195.1 (74.6) mmol] compared to females [144.3 (41.8) mmol]. Breads and cereals (B&Cs) were the largest contributors to dietary sodium intake (23% of intake). There was an association between sodium intake from B&Cs and 24-h urinary sodium excretion (r = 0.235; P = 0.02); however, when controlled for gender, B&Cs were not associated with urinary sodium excretion (males, r = 0.134; P = 0.343; females, r = 0.102; P = 0.554). CONCLUSIONS: The findings of the present study show that sodium intake and excretion in individuals with T2DM is more than two-fold greater than the current recommendations for chronic disease prevention. B&Cs were the major dietary contributors of sodium intake, suggesting that they are primary targets for a reduction in their sodium content. PMID- 22257068 TI - Effects of temperature and relative humidity on the stability of paper immobilized antibodies. AB - The stability of a paper-immobilized antibody was investigated over a range of temperatures (40-140 degrees C) and relative humidities (RH, 30-90%) using both unmodified filter paper and the same paper impregnated with polyamide epichlorohydrin (PAE) as supports. Antibody stability decreased with increasing temperature, as expected, but also decreased with increasing RH. At 40 degrees C, the half-life was more than 10 days, with little dependence on RH. However, at 80 degrees C, the half-life varied from ~3 days at low RH to less than half an hour at 90% RH, demonstrating that hydration of the antibody promotes unfolding. Antibody stability was not influenced by the PAE paper surface treatment. This work shows that antibodies are good candidates for development of bioactive paper as they have sufficient stability at high temperature to withstand printing and other roll-to-roll processing steps, and sufficient low temperature stability to allow long-term storage of bioactive paper materials. PMID- 22257069 TI - Recovery of speech following total glossectomy: an acoustic and perceptual appraisal. AB - This study involved an acoustic and perceptual analysis of the speech produced by a 31-year-old female following total glossectomy. Speech samples were collected on three occasions within the first 3 months following glossectomy. Vowel articulation was examined acoustically as a function of vowel space and the Euclidean distance separating corner vowels. Perceptual analyses involved presentation of the participant's CV productions to 30 healthy adult listeners who made forced-choice identifications of consonant type. Acoustic analysis revealed improvements in vowel space area and an increase in the Euclidean distances. The perceptual results revealed a statistically significant deterioration in consonants over the 3-month period with anterior sounds being perceived more correctly than medial and posterior sounds. The current study highlights the variable nature of speech following glossectomy, with greater improvements in vowel articulation compared to consonant articulation during the earliest stages of surgical recovery. PMID- 22257070 TI - Prelinguistic communication development in children with childhood apraxia of speech: a retrospective analysis. AB - In a retrospective study of prelinguistic communication development, clinically referred preschool children (n = 9) aged 3-4 years, who as infants had failed a community-based screening program, were evaluated for features of childhood apraxia of speech (CAS). Four children showed no features and either delayed or normal language, five had from three-to-seven CAS features and all exhibited delayed language. These children were matched by age with 21 children with typically-developing (TD) speech and language skills. Case-control comparisons of retrospective data from 9 months of age for two participants with more severe features of CAS at preschool age showed a dissociated pattern with low expressive quotients on the Receptive-Expressive Emergent Language Assessment-Second Edition (REEL-2) and records of infrequent babbling, but normal receptive quotients. However, other profiles were observed. Two children with milder CAS features showed poor receptive and expressive development similar to other clinically referred children with no CAS features, and one child with severe CAS features showed poor receptive but normal expressive developmental milestones at 9 months and records of frequent babbling. Results suggest some but not all children with features of suspected CAS have a selective deficit originating within speech motor development. PMID- 22257071 TI - Phonological awareness of Cantonese-speaking pre-school children with cochlear implants. AB - The study investigated the phonological awareness abilities of Cantonese-speaking pre-schoolers with cochlear implants. Participants were 15 Cantonese-speaking children with cochlear implants (CIs) aged 3.08-6.10, chronological-age-matched with 15 children with normal hearing. Each participant performed 10 tasks evaluating different levels of phonological awareness abilities and phonological knowledge. The results showed that pre-schoolers with cochlear implants and their normal hearing peers had similar levels of syllable awareness, phoneme awareness and rhyme awareness. However, cochlear implant users showed significantly poorer performance on tone awareness and phonological knowledge tasks than their normal hearing peers. Cantonese-speaking pre-schoolers with cochlear implants were able to develop phonological awareness. However, the cochlear implants might not provide enough tonal information for children with hearing impairment for tonal lexical comprehension. Incomplete speech and language stimulation may affect phonological knowledge development in Cantonese-speaking pre-schoolers with cochlear implants. PMID- 22257074 TI - Occurrence of Schistocephalus solidus in anadromous threespine stickleback. AB - Plerocercoids of the cestode Schistocephalus solidus are reported for the first time from the body cavity of anadromous threespine stickleback inhabiting Mud Lake, Alaska. Most infected stickleback harbored a single large plerocerciod (mean weight = 0.447 g, range = 0.228-0.716 g). The overall prevalence of plerocercoids across genders and 2 yr of samples was 1.4%, but prevalence was significantly greater in males than in females. Because of the large size of the plerocercoids, anadromous stickleback were probably infected as juveniles before leaving the lake, suggesting that plerocercoids can live in the body cavity of oceanic stickleback for several years. PMID- 22257075 TI - HIV, HEV and cirrhosis: evidence of a possible link from eastern Spain. AB - OBJECTIVES: The aim of the study was to assess the seroprevalence of hepatitis E virus (HEV) infection in an HIV-infected population, as determined by HEV immunoglobulin G (IgG) antibodies (anti-HEV). METHODS: The design of the study was cross-sectional. Serum anti-HEV IgG was determined by enzyme immunoassay in 238 HIV-infected patients consecutively attending our out-patient clinic between April and May 2011. In HEV-seropositive patients, HEV RNA was analysed by nested reverse transcriptase-polymerase chain reaction (RT-PCR). Associations between anti-HEV and liver cirrhosis, route of HIV infection, hepatitis B virus (HBV) and hepatitis C virus (HCV) serological markers, age, sex and alanine aminotransferase (ALT) levels were examined by univariate and multivariate analysis. RESULTS: One hundred and forty patients (59%) had chronic liver disease (99% were HBV- and/or HCV-coinfected). Liver cirrhosis was detected in 44 individuals (19%). Two hundred and twelve patients (89%) were on antiretroviral treatment; the median CD4 T-cell count was 483 cells/MUL [interquartile range (IQR) 313-662 cells/MUL] and the HIV viral load was <25 HIV-1 RNA copies/mL. Overall, 22 patients (9%) were anti-HEV positive. Liver cirrhosis was the only factor independently associated with the presence of anti-HEV, which was documented in 23% of patients with cirrhosis and 6% of patients without cirrhosis (P=0.002; odds ratio 5.77). HEV RNA was detected in three seropositive patients (14%), two of whom had liver cirrhosis. CONCLUSIONS: Our findings show a high prevalence of anti-HEV in HIV-infected patients, strongly associated with liver cirrhosis. Chronic HEV infection was detected in a significant number of HEV seropositive patients. Further research is needed to ascertain whether cirrhosis is a predisposing factor for HEV infection and to assess the role of chronic HEV infection in the pathogeneses of cirrhosis in this population. PMID- 22257076 TI - Wave-induced mass transport affects daily Escherichia coli fluctuations in nearshore water. AB - Characterization of diel variability of fecal indicator bacteria concentration in nearshore waters is of particular importance for development of water sampling standards and protection of public health. Significant nighttime increase in Escherichia coli (E. coli) concentration in beach water, previously observed at marine sites, has also been identified in summer 2000 from fixed locations in waist- and knee-deep waters at Chicago 63rd Street Beach, an embayed, tideless, freshwater beach with low currents at night (approximately 0.015 m s(-1)). A theoretical model using wave-induced mass transport velocity for advection was developed to assess the contribution of surface waves to the observed nighttime E. coli replenishment in the nearshore water. Using average wave conditions for the summer season of year 2000, the model predicted an amount of E. coli transported from water of intermediate depth, where sediment resuspension occurred intermittently, that would be sufficient to have elevated E. coli concentration in the surf and swash zones as observed. The nighttime replenishment of E. coli in the surf and swash zones revealed here is an important phase in the cycle of diel variations of E. coli concentration in nearshore water. According to previous findings in Ge et al. (Environ. Sci. Technol. 2010, 44, 6731-6737), enhanced current circulation in the embayment during the day tends to displace and deposit material offshore, which partially sets up the system by the early evening for a new period of nighttime onshore movement. This wave-induced mass transport effect, although facilitating a significant base supply of material shoreward, can be perturbed or significantly influenced by high currents (orders of magnitude larger than a typical wave induced mass transport velocity), current-induced turbulence, and tidal forcing. PMID- 22257077 TI - Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting. AB - Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments. PMID- 22257078 TI - Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis. AB - BACKGROUND: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease. OBJECTIVES: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence-based guidelines. PATIENTS/METHODS: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0-3.5, and ASA, 50-650 mg daily, with at least 3 months of follow-up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model. RESULTS: Four thousand four hundred and forty-two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83-1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71-3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61-1.75). Minor bleeding, from a 1748-patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13 2.00). CONCLUSIONS: This meta-analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0-3.5, and ASA, 50 650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients. PMID- 22257079 TI - Funding source and conflict of interest disclosures by authors and editors in gastroenterology specialty journals revisited. AB - BACKGROUND: A survey of journals published in the field of Gastroenterology conducted 5 years ago showed marked variability in reporting of conflicts of interest or funding sources in these journals. AIM: To re-examine reporting of conflicts of interest and funding sources for original articles and editorials in Gastroenterology and Hepatology journals. METHODS: We evaluated all original articles and editorials in 15 leading journals (determined by impact factor Thomson Reuter Science Citation Index) devoted to Gastroenterology and Hepatology for disclosures of conflicts and for editor's self disclosures. We examined each journal's editorial policy by contacting the journal directly if the information was not revealed on the Web site or print versions of the journal. RESULTS: Of the 1574 articles evaluated, a total of 1207 (77%) reported the presence or absence of a potential conflict of interest and 1047 (67%) reported the presence or absence of funding sources. A total of 3 of the 15 (20%) journals (American Journal of Gastroenterology, Gastroenterology, and Alimentary Pharmacology and Therapeutics reported the presence or absence of funding sources in all their published original articles. Only 5 of 15 (33%) journals (Gut, Gastrointestinal Endoscopy, American Journal of Gastroenterology, Neurogastroenterology & Motility and Alimentary Pharmacology and Therapeutics) publicly disclosed the conflicts of interest of the editors. CONCLUSIONS: (i) Funding sources and conflicts of interest are still reported variably in the GI literature. (ii) Editorials and review articles are influential, but have poor reporting of conflicts of interest. (iii) Editors of many journals still do not report their conflicts of interest. PMID- 22257080 TI - Characterization of glioma stem cells through multiple stem cell markers and their specific sensitization to double-strand break-inducing agents by pharmacological inhibition of ataxia telangiectasia mutated protein. AB - Previous studies have shown that tumor-driving glioma stem cells (GSC) may promote radio-resistance by constitutive activation of the DNA damage response started by the ataxia telangiectasia mutated (ATM) protein. We have investigated whether GSC may be specifically sensitized to ionizing radiation by inhibiting the DNA damage response. Two grade IV glioma cell lines (BORRU and DR177) were characterized for a number of immunocytochemical, karyotypic, proliferative and differentiative parameters. In particular, the expression of a panel of nine stem cell markers was quantified by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. Overall, BORRU and DR177 displayed pronounced and poor stem phenotypes, respectively. In order to improve the therapeutic efficacy of radiation on GSC, the cells were preincubated with a nontoxic concentration of the ATM inhibitors KU-55933 and KU-60019 and then irradiated. BORRU cells were sensitized to radiation and radio-mimetic chemicals by ATM inhibitors whereas DR177 were protected under the same conditions. No sensitization was observed after cell differentiation or to drugs unable to induce double-strand breaks (DSB), indicating that ATM inhibitors specifically sensitize glioma cells possessing stem phenotype to DSB-inducing agents. In conclusion, pharmacological inhibition of ATM may specifically sensitize GSC to DSB-inducing agents while sparing nonstem cells. PMID- 22257081 TI - Facile fabrication and enhanced sensing properties of hierarchically porous CuO architectures. AB - Hierarchically porous CuO architectures were successfully fabricated via copper basic carbonate precursor obtained with a facile hydrothermal route. The shape of the precursor is preserved after its conversion to porous CuO architectures by calcination. The obtained CuO are systemically characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, and Brunauer-Emmett-Teller N(2) adsorption-desorption analysis. The results reveal that hierarchical CuO microspheres are monoclinic structure and are assembled by porous single-crystal sub-microplatelets. The Brunauer-Emmett-Teller N(2) adsorption-desorption analysis indicates that the obtained CuO has a surface area of 12.0 m(2)/g with pore size of around 30 nm. The gas sensing performance of the as-prepared hierarchical CuO microspheres were investigated towards a series of typical organic solvents and fuels. They exhibit higher sensing response than that of commercial CuO powder. Their sensing properties can be further improved by loading of Ag nanoparticles on them, suggesting their potential applications in gas sensors. PMID- 22257082 TI - Exanthematous drug eruption due to valsartan. AB - OBJECTIVE: Valsartan is an angiotensin II receptor blocker (ARB) used for treatment of hypertension. The well-known adverse effects of valsartan are dizziness, headache and cough. Valsartan-related cutaneous side effects have been reported previously in a limited number of case reports. MATERIALS AND METHODS: A 47-year-old man admitted with diffuse, itchy erythematous maculopapular eruption all over the body. He has been taking 160 mg valsartan daily for 10 days before onset of the eruption. On the third day of valsartan therapy, erythema had appeared over the face and spread throughout the whole body within a week. Histopathologic examination of the lesions showed lymphocyte exocytosis, spongiosis, necrotic keratinocytes in the epidermis, and mixed inflammatory cell infiltrates including perivascular eosinophils in the dermis. The patient was diagnosed as drug reaction due to valsartan with historical, clinical and histopathologic features. DISCUSSION AND CONCLUSION: Most common antihypertensive agents including diuretics, beta blockers, calcium-channel blockers, angiotensin converting enzyme inhibitors have many cutaneous side effects. However, there are a few reports about the cutaneous side effects of ARBs. Physicians should be aware of the cutaneous side effects of this commonly used agent and valsartan should be considered as a triggering factor of an exanthematous drug reactions. PMID- 22257083 TI - Synthesis and structural characterization of high spin M/Cu (M = Mn, Fe) heterobimetallic and Fe/Cu2 trimetallic phosphinoamides. AB - The heterobimetallic complexes [Mn((i)PrNPPh(2))(3)Cu((i)PrNHPPh(2))] (1) and [Fe((i)PrNPPh(2))(3)Cu((i)PrNHPPh(2))] (2) have been synthesized by the one pot reaction of LiN(i)PrPPh(2), MCl(2) (M = Mn, Fe), and CuI in high yield. Addition of excess CuI into 2 or directly to the reaction mixture led to the formation of a heterotrimetallic [Fe((i)PrNPPh(2))(3)Cu(2)((i)PrNPPh(2))] (3) in good yield. Complexes 1-3 have been characterized by means of elemental analysis, paramagnetic (1)H NMR, UV-vis spectroscopy, cyclic voltammetry, and single crystal X-ray analysis. In all three complexes, Mn or Fe are in the +2 oxidation state and have a high spin electron configuration, as evidenced by solution Evans' method. In addition, the oxidation state of Fe in complex 3 is confirmed by zero-field (57)Fe Mossbauer spectroscopy. X-ray crystallography reveals that the three coordinate Mn/Fe centers in the zwitterionic complexes 1-3 adopt an unusual trigonal planar geometry. PMID- 22257084 TI - Effect of light on the gene expression and hormonal status of winter and spring wheat plants during cold hardening. AB - The effect of light on gene expression and hormonal status during the development of freezing tolerance was studied in winter wheat (Triticum aestivum var. Mv Emese) and in the spring wheat variety Nadro. Ten-day-old plants (3-leaf stage) were cold hardened at 5 degrees C for 12 days under either normal (250 umol m(-2) s(-1) ) or low (20 umol m(-2) s(-1) ) light conditions. Comprehensive analysis was carried out to explore the background of frost tolerance and the differences between these wheat varieties. Global genome analysis was performed, enquiring about the details of the cold signaling pathways. The expression level of a large number of genes is affected by light, and this effect may differ in different wheat genotypes. Photosynthesis-related processes probably play a key role in the enhancement of freezing tolerance; however, there are several other genes whose induction is light-dependent, so either there is cross-talk between signaling of chloroplast originating and other protective mechanisms or there are other light sensors that transduce signals to the components responsible for stress tolerance. Changes in the level of both plant hormones (indole-3-acetic acid, cytokinins, nitric oxide and ethylene precursor 1-aminocyclopropane-1-carboxylic acid) and other stress-related protective substances (proline, phenolics) were investigated during the phases of the hardening period. Hormonal levels were also affected by light and their dynamics indicate that wheat plants try to keep growing during the cold-hardening period. The data from this experiment may provide a new insight into the cross talk between cold and light signaling in wheat. PMID- 22257085 TI - Onset of mucosal, dermal, and general symptoms in relation to biomarkers and exposures in the dwelling: a cohort study from 1992 to 2002. AB - We examined the associations between biomarkers of allergy and inflammation, indoor environment in dwellings, and incidence and remission of symptoms included in the sick building syndrome (SBS) and changes in the home environment of 452 adults who were followed from 1992 to 2002 within the Uppsala part of the European Community Respiratory Health Survey (ECRHS). The 10-year incidence (onset) of general, mucosal, and dermal symptoms was 8.5%, 12.7%, and 6.8%, respectively. Dampness or indoor molds at baseline was a predictor of incidence of general (relative risk [RR] = 1.98), mucosal (RR = 2.28), and dermal symptoms (RR = 1.91). Women had higher incidence of general (RR = 1.74) and mucosal symptoms (RR = 1.71). Indoor painting increased the incidence of general symptoms (RR = 1.62). Bronchial responsiveness (BR), eosinophil counts in blood, total IgE and eosinophilic cationic protein (ECP) in serum at baseline were predictors of incidence of SBS. At follow-up, BR, total IgE, and C-reactive protein (CRP ) were associated with increased incidence of SBS. Moreover, subjects with doctor diagnosed asthma at baseline had a higher incidence of general (RR = 1.65) and mucosal symptoms (RR = 1.97). In conclusion, female gender, dampness or indoor molds, indoor painting, and biomarkers of allergy and inflammation were associated with a higher incidence of SBS symptoms, in particular mucosal symptoms. PRACTICAL IMPLICATIONS: The focus in Sweden on indoor environment issues over the last few decades has resulted in improvements in dwellings, and reduced tobacco smoking, which could be beneficial for public health. Reducing dampness and molds in the dwelling place is another important way of reducing occurrence of SBS symptoms in the general adult population. The association between the incidence of SBS symptoms and clinical biomarkers of allergy and inflammation suggests a common etiology between inflammatory diseases, including asthma, rhinitis, and SBS. Lastly, good agreement between self-reported and clinically diagnosed atopy indicates that questionnaire data on atopy can be used in epidemiological studies. PMID- 22257086 TI - The membrane modulates internal proton transfer in cytochrome c oxidase. AB - The functionality of membrane proteins is often modulated by the surrounding membrane. Here, we investigated the effect of membrane reconstitution of purified cytochrome c oxidase (CytcO) on the kinetics and thermodynamics of internal electron and proton-transfer reactions during O(2) reduction. Reconstitution of the detergent-solubilized enzyme in small unilamellar soybean phosphatidylcholine vesicles resulted in a lowering of the pK(a) in the pH dependence profile of the proton-uptake rate. This pK(a) change resulted in decreased proton-uptake rates in the pH range of ~6.5-9.5, which is explained in terms of lowering of the pK(a) of an internal proton donor within CytcO. At pH 7.5, the rate decreased to the same extent when vesicles were prepared from the pure zwitterionic lipid 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC) or the anionic lipid 1,2-dioleoyl-sn glycero-3-phospho(1-rac-glycerol) (DOPG). In addition, a small change in the internal Cu(A)-heme a electron equilibrium constant was observed. This effect was lipid-dependent and explained in terms of a lower electrostatic potential within the membrane-spanning part of the protein with the anionic DOPG lipids than with the zwitterionic DOPC lipids. In conclusion, the data show that the membrane significantly modulates internal charge-transfer reactions and thereby the function of the membrane-bound enzyme. PMID- 22257087 TI - Language and memory for motion events: origins of the asymmetry between source and goal paths. AB - When people describe motion events, their path expressions are biased toward inclusion of goal paths (e.g., into the house) and omission of source paths (e.g., out of the house). In this paper, we explored whether this asymmetry has its origins in people's non-linguistic representations of events. In three experiments, 4-year-old children and adults described or remembered manner of motion events that represented animate/intentional and physical events. The results suggest that the linguistic asymmetry between goals and sources is not fully rooted in non-linguistic event representations: linguistic descriptions showed the goal bias for both kinds of events, whereas non-linguistic memory for events showed the goal bias only for events involving animate, goal-directed motion. The findings are discussed in terms of the mapping between non-linguistic representations of goals and sources in language, focusing on the role that linguistic principles play in producing a more absolute goal bias from more gradient non-linguistic representations of paths. PMID- 22257088 TI - Self-rated health status as a risk factor for future vascular events and mortality in patients with symptomatic and asymptomatic atherosclerotic disease: the SMART study. AB - OBJECTIVES: Lower self-rated health status has been associated with worse prognosis in patients with coronary artery disease (CAD). We investigated the influence of self-rated physical and mental health status on the risk of future vascular events and mortality for various locations of symptomatic atherosclerotic disease and asymptomatic disease. DESIGN: Patients with CAD (n = 2547), cerebrovascular disease (n = 1061), peripheral arterial disease (PAD; n = 648), abdominal aortic aneurysm (AAA; n = 272) and asymptomatic atherosclerotic disease (n = 1933) were followed for a median of 4 years for the occurrence of a new vascular event or death. Self-rated health status was assessed with the Short Form-36 physical and mental component summary scales. Cox regression models were used to estimate associations between health status and vascular events and death, adjusted for age, sex, vascular risk factors and intima-media thickness. RESULTS: In the total population, lower self-rated physical health status (per 10 point decrease) increased the risk of vascular events [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.24-1.52], and all-cause (HR = 1.45, 95% CI 1.29 1.63) and vascular mortality (HR = 1.40, 95% CI 1.20-1.64). A 10-point decrease in mental health status was associated with a modest increase in the risk of vascular events (HR = 1.19, 95% CI 1.08-1.32), and all-cause (HR = 1.19, 95% CI 1.05-1.34) and vascular mortality (HR = 1.28, 95% CI 1.09-1.49). Risk estimates of physical and mental health status were highest in patients with asymptomatic atherosclerotic disease and lowest in those with PAD. CONCLUSIONS: Poorer self rated physical and mental health status increases the risk of vascular events and mortality in a broad population of patients with symptomatic and asymptomatic atherosclerotic disease. PMID- 22257089 TI - Aspirin: from a historical perspective. AB - Aspirin is one of the oldest medicines. Due to its wide range usage in different fields of medicine, we aimed to present the history, effects and different uses of aspirin in this review. Furthermore, recent patents of novel pharmaceutical interventions in the field of acetylsalicylic acid, expanding treatment options are presented. Literature search was performed in order to reach data and present information about aspirin from a historical perspective. Since its first use as a pain killer, aspirin has found a broad range of use in general medicine, cardiovascular medicine, neurology, obstetrics and gynecology, dentistry, gastroenterology, oncology with its different effects. Aspirin, a painkilling gift of history to mankind, with a history dating back to BC and various healing effects, promises to be of greater use in different fields of medicine with the light of recent studies, inspiring more research and gaining more popularity. PMID- 22257090 TI - Commensurate adsorption of hydrocarbons and alcohols in microporous metal organic frameworks. PMID- 22257091 TI - Radionuclide interaction with clays in dilute and heavily compacted systems: a critical review. AB - Given the unique properties of clays (i.e., low permeability and high ion sorption/exchange capacity), clays or clay formations have been proposed either as an engineered material or as a geologic medium for nuclear waste isolation and disposal. A credible evaluation of such disposal systems relies on the ability to predict the behavior of these materials under a wide range of thermal hydrological-mechanical-chemical (THMc) conditions. Current model couplings between THM and chemical processes are simplistic and limited in scope. This review focuses on the uptake of radionuclides onto clay materials as controlled by mineral composition, structure, and texture (e.g., pore size distribution), and emphasizes the connections between sorption chemistry and mechanical compaction. Variable uptake behavior of an array of elements has been observed on various clays as a function of increasing compaction due to changes in pore size and structure, hydration energy, and overlapping electric double layers. The causes for this variability are divided between "internal" (based on the fundamental structure and composition of the clay minerals) and "external" (caused by a force external to the clay). New techniques need to be developed to exploit known variations in clay mineralogy to separate internal from external effects. PMID- 22257092 TI - Association between transforming growth factor-beta1 polymorphisms and hepatocellular cancer risk: A meta-analysis. AB - AIM: The association between transforming growth factor-beta1 (TGF-beta1) gene polymorphisms and hepatocellular cancer (HCC) risk has been widely reported, but results were somewhat controversial. To derive a more precise estimation of the relationship between TGF-beta1 polymorphisms and HCC risk, we conducted a meta analysis of all available studies relating the C-509T and/or T869C polymorphisms of the TGF-beta1 gene to the risk of developing HCC. METHODS: Two investigators independently searched the MEDLINE, PubMed, Web of Science, Embase, CNKI (China National Knowledge Infrastructure) and CBM (Chinese Biomedical Literature database) for the period up to August 2011. RESULT: A total of nine case control articles were identified. Five studies with 1825 cases and 2869 controls for C-509T polymorphism, and six studies with 536 cases and 1496 controls for T869C polymorphism were included. In the overall analysis, no significant association between the polymorphisms and risk of HCC was observed. Stratified analysis showed that significant association between C-509T polymorphism and HCC was present only in controls with liver disease (T vs. C: odds ratio [OR] = 0.769, 95% confidence interval [CI] = 0.661-0.895; TT vs. CC: OR = 0.570, 95% CI = 0.412-0.788; TT/TC vs. CC: OR = 0.668, 95% CI = 0.523-0.854; TT vs. TC/CC: OR = 0.717, 95% CI = 0.550-0.934), but not in healthy controls. With respect to T869C polymorphism, only a decreased risk was found in recessive models in controls with liver disease. CONCLUSIONS: This meta-analysis supports that the TGF-beta1 C-509T polymorphism may act in a protecting role in HCC susceptibility in populations with related liver disease. PMID- 22257093 TI - The effect of salinity on experimental infections of a Hematodinium sp. in blue crabs, Callinectes sapidus. AB - The parasitic dinoflagellate Hematodinium sp. parasitizes blue crabs along the Atlantic seaboard of the United States. Infections in blue crabs have only been reported from waters where salinity is >11 practical salinity units (psu). Blue crabs maintain a hyperosmotic internal concentration at low salinities (0-5 psu), roughly comparable to 24 psu, and should be capable of maintaining an infection in low-salinity waters even if Hematodinium spp. cells are intolerant of low salinities. We tested this notion by observing the effect of low salinity on the progression of disease in crabs experimentally infected with the parasite. Blue crabs were acclimated to 5 psu or 30 psu salinity treatments. They were inoculated with Hematodinium sp. and necropsied 3, 7, 10, and 15 days post inoculation. The low-salinity treatment did not have an effect on the proliferation of Hematodinium sp. infections in blue crabs; moreover, a greater proportion of infections in crabs in the low-salinity treatment developed dinospore stages than did those in the high-salinity treatment, indicating that salinity may affect the development of the parasite. However, dinospores from in vitro cultures rapidly became inactive when held in salinities <15 psu. Our experiments indicate that Hematodinium spp. can develop in blue crabs at low salinities, but that the parasite is incapable of transmission in this environment, which explains the lack of natural infections in crabs at low salinities. PMID- 22257095 TI - 3-aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A2B adenosine receptor antagonists. AB - In an effort to identify novel ligands possessing high affinity and selectivity for the A(2B) AR subtype, we further investigated the class of 3 aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A(1) AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A(2B) AR, no affinity at A(3) AR, and various degrees of selectivity toward A(1) and A(2A) ARs. Investigation of a new series featuring modified substituents at the 10-position (4'-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A(2B) AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A(2A) AR, conferring high A(2B)/A(2A) AR selectivity. Derivative 13 (X = Cl, R = C(6)H(5)) is the most potent and selective compound, with an IC(50) of 3.10 nM at A(2B) AR and no affinity at A(1), A(2A), and A(3) ARs. PMID- 22257096 TI - A case of invisible leukemic cutaneous T cell lymphoma with a regulatory T cell clone. PMID- 22257097 TI - Optically active thiophenes via an organocatalytic one-pot methodology. AB - A general methodology for the synthesis of trisubstituted, optically active thiophenes by an organocatalytic one-pot reaction cascade is presented. The target products are synthesized in good yields (up to 92%) and with excellent enantioselectivities (up to 98% ee). Importantly, based on practical and easily available starting materials, the presented methodology can be conducted under mild reaction conditions. To further elucidate the generality, the synthesis of optically active thienoindoles, as well as selenophenes, is also demonstrated. PMID- 22257098 TI - Novel approaches to improve prostate cancer diagnosis and management in early stage disease. AB - The reported incidence of prostate cancer has risen since the implementation of screening. It is felt that the introduction of widespread prostate-specific antigen testing is responsible for most patients with prostate cancer now being diagnosed with asymptomatic, clinically localised disease. Diagnosis at this stage is associated with significantly improved treatment outcomes and longer life expectancy. Although there is evidence that screening has reduced prostate cancer mortality, there is a risk of over-diagnosis and over-treatment of early state prostate cancers, including clinically insignificant and indolent cancers. Active surveillance and focal therapy have been advocated as potential management options for some patients. However, these approaches face several challenges. Biopsy sampling errors together with less than optimal imaging of tumours can lead to difficulties in selecting suitable low-risk patients for these options. To overcome these challenges, novel approaches to the staging and monitoring of patients with early prostate cancer are being developed. These include new imaging techniques, such as multi-parametric magnetic resonance imaging, and the development of new biomarkers and biopsy-based methods. These techniques aim to assess the potential of a specific tumour to be aggressive, and to improve patient outcomes. The aim of the present paper is to summarise presentations and debates at the third annual Interactive Genitourinary Cancer Conference concerning the use of population-based screening methods and the roles of active surveillance and focal therapy as prostate cancer treatments. The application of novel imaging biopsy-based methods and biomarkers in early-stage prostate cancer will also be explored. PMID- 22257099 TI - Advances in the management of high-risk localised and metastatic prostate cancer. AB - At the third annual Interactive Genitourinary Cancer Conference, held in Budapest from 30 April to 1 May 2011, the latest developments in the management of patients with high-risk localised and metastatic prostate cancer were discussed. Prostate cancer is the most common cancer in Western men and, for advanced disease, no curative agents are available. For men with high-risk localised disease there is debate about the best treatment approaches, with both radical prostatectomy and radiation therapy shown to improve outcomes. These approaches have started to be augmented as new techniques and therapies are developed. For instance, radiation therapy combined with androgen deprivation therapy has been shown to be more efficacious than radiation therapy alone, and there may also be a role for adjuvant/neoadjuvant chemotherapy. Ultimately a multidisciplinary approach will most probably result in the best outcomes for patients. The use of androgen deprivation therapy in men with prostate cancer needs to be monitored carefully, given that it results in adverse alterations in several metabolic parameters and an increased risk of further coronary events in men with cardiovascular disease in some studies. Until recently there were limited options for the management of men with advanced prostate cancer, but new agents for use in the post-docetaxel setting have recently been approved. These are cabazitaxel and abiraterone acetate, which have both shown a significant survival benefit in patients who have progressed on docetaxel. Additional agents, for these patients and for patients at other stages of disease, are in the later stages of development. The development of new agents has been aided by a greater understanding of the molecular mechanisms of resistance to current therapies and the recognition of new pathophysiological pathways. As the number of available therapeutic options increases, it will become increasingly important to tailor treatments to the individual patient. This may require the development of novel biomarkers or the use of existing or new predictive tools based on prognostic factors. To ensure optimal patient care, early and continuous involvement of the multidisciplinary team will be required. PMID- 22257100 TI - Practical aspects of metastatic castration-resistant prostate cancer management: patient case studies. AB - Interactive case studies formed a key feature of the third annual Interactive Genitourinary Cancer Conference held in April/May 2011 in Budapest, Hungary. These cases were used to discuss the practical aspects of the management of metastatic castration-resistant prostate cancer (mCRPC). Particular emphasis was placed on audience participation with potential management options posed as interactive questions to the delegates. This paper summarises these case studies and the related discussion. Docetaxel is the standard first-line chemotherapeutic agent for patients with mCRPC and, until recently, second-line therapeutic options were limited. Results from the recently completed TROPIC trial showed a statistically and clinically significant improvement in overall survival with the microtubule inhibitor cabazitaxel compared with mitoxantrone. Cabazitaxel has been shown to be well tolerated and has been approved in Europe and the USA as second-line chemotherapy for mCRPC. Prognostic factors have a potential benefit in individualised patient management in mCRPC. Pretreatment prognostic factors, including PSA doubling time, pain, visceral metastases, anaemia and progression of osseous metastases, have been shown to predict survival outcomes and can be used to guide treatment strategies, including appropriate timing of chemotherapy. Multiple treatment options and significant heterogeneity among patients with advanced prostate cancer necessitate multidisciplinary team management in addition to patient education, as part of a patient-centred approach. The development of second-line chemotherapeutic agents together with the use of prognostic factors and a patient-centred multidisciplinary team approach provide encouraging new management prospects for patients with mCRPC. PMID- 22257102 TI - Chairman's foreword. Recent advances in prostate cancer management. AB - Recent advances in prostate cancer management were discussed at the third annual Interactive Genitourinary Cancer Conference (IGUCC3) held from 30 April to 1 May 2011. The objectives of IGUCC3 included exploring available therapeutic options and current controversies in prostate cancer care, promoting closer multidisciplinary collaboration and a patient-centred approach, and considering challenges in the management of metastatic castration-resistant prostate cancer and the opportunities presented by new treatment options. PMID- 22257103 TI - Changes in the levels of thioredoxin and indoleamine-2,3-dioxygenase activity in plasma of patients with colorectal cancer treated with chemotherapy. AB - Increased oxidative stress and indoleamine-2,3-dioxygenase (IDO) activity have been reported in cancer, but their relationship with chemotherapy remains unknown. The aim of the present study was to examine wether the chemotherapy treatments used in colorectal cancer had an additional effect on oxidative stress and on IDO activity. Plasma samples were collected from 27 colorectal cancer patients on cytostatic treatment, 27 with cytostatic drugs plus monoclonal antibodies (cytostatic-Mabs) and 15 non-treated patients. All patients with colorectal cancer had high plasma malondialdehyde (MDA), thioredoxin (Trx) levels, and elevated IDO activity in plasma (IDOp) and in dendritic cells (IDOc). This study shows that treatment with cytostatics have an effect on oxidative stress by increasing MDA levels and by decreasing Trx levels and IDO activity. However, treatment with cytostatic-Mabs showed no effect on MDA levels but decreased Trx levels, and the IDO activity showed values similar to the healthy group. Significant correlations between plasma IDO activity and the levels of Trx (r = 0.2062, p < 0.05) and MDA (r = 0.2873, p < 0.005) were observed. Furthermore, our study suggests that IDO activity measured as kynurenine levels could be used as a marker of the response to the chemotherapy treatments, although further studies are necessary. PMID- 22257104 TI - Lifting gate polydimethylsiloxane microvalves and pumps for microfluidic control. AB - We describe the development and characterization of pneumatically actuated "lifting gate" microvalves and pumps. A fluidic layer containing the gate structure and a pneumatic layer are fabricated by soft-lithography in PDMS and bonded permanently with an oxygen plasma treatment. The microvalve structures are then reversibly bonded to a featureless glass or plastic substrate to form hybrid glass-PDMS and plastic-PDMS microchannel structures. The break-through pressures of the microvalve increase linearly up to 65 kPa as the closing pressure increases. The pumping capability of these structures ranges from the nanoliter to microliter scale depending on the number of cycles and closing pressure employed. The micropump structures exhibit up to 86.2% pumping efficiency from flow rate measurements. The utility of these structures for integrated sample processing is demonstrated by performing an automated immunoassay. These lifting gate valve and pump structures enable facile integration of complex microfluidic control systems with a wide range of lab-on-a-chip substrates. PMID- 22257105 TI - Solution-phase monitoring of the structural evolution of a Molybdenum Blue nanoring. AB - The inorganic host-guest complex Na(22){[Mo(VI)(36)O(112)(H(2)O)(16)]?[Mo(VI)(130)Mo(V)(20)O(442)(OH)(10)(H(2)O)(6 )]}.180H(2)O = {Mo(36)}?{Mo(150)}, compound 1, has been isolated in its solid crystalline state via unconventional synthesis in a custom flow reactor. Carrying out the reaction under controlled flow conditions selected for the generation of {Mo(36)}?{Mo(150)} as the major product, allowing it to be reproducibly isolated in a moderate yield, as opposed to traditional "one-pot" batch syntheses that typically lead to crystallization of the {Mo(36)} and {Mo(150)} species separately. Structural and spectroscopic studies of compound 1 and the archetypal Molybdenum Blue (MB) wheel, {Mo(150)}, identified compound 1 as a likely intermediate in the {Mo(36)} templated synthesis of MB wheels. Further evidence illustrating the template effect of {Mo(36)} to MB wheel synthesis was indicated by an increase in the yield and rate of production of {Mo(150)} as a direct result of the addition of preformed {Mo(36)} to the reaction mixture. Dynamic light scattering (DLS) techniques were also used to corroborate the mechanism of formation of the MB wheels through observation of the individual cluster species in solution. DLS measurement of the reaction solutions from which {Mo(36)} and {Mo(150)} crystallized gave particle size distribution curves averaging 1.9 and 3.9 nm, consistent with the dimensions of the discrete clusters, which allowed the use of size as a possible distinguishing feature of these key species in the reduced acidified molybdate solutions and to observe the templation of the MB wheel by {Mo(36)} directly. PMID- 22257106 TI - Material-selective surface chemistry for nanoplasmonic sensors: optimizing sensitivity and controlling binding to local hot spots. AB - Optical sensors utilizing the principle of localized surface plasmon resonance (LSPR) offer the advantage of a simple label-free mode of operation, but the sensitivity is typically limited to a very thin region close to the surface. In bioanalytical sensing applications, this can be a significant drawback, in particular since the surface needs to be coated with a recognition layer in order to ensure specific detection of target molecules. We show that the signal upon protein binding decreases dramatically with increasing thickness of the recognition layer, highlighting the need for thin high quality recognition layers compatible with LSPR sensors. The effect is particularly strong for structures that provide local hot spots with highly confined fields, such as in the gap between pairs of gold disks. While our results show a significant improvement in sensor response for pairs over single gold disks upon binding directly to the gold surface, disk pairs did not provide larger signal upon binding of proteins to a recognition layer (already for around 3 nm thin layers) located on the gold. Local plasmonic hot spots are however shown advantageous in combination with directed binding to the hot spots. This was demonstrated using a structure consisting of three surface materials (gold, titanium dioxide, and silicon dioxide) and a new protocol for material-selective surface chemistry of these three materials, which allows for controlled binding only in the gap between pairs of disks. Such a design increased the signal obtained per bound molecule by a factor of around four compared to binding to single disks. PMID- 22257107 TI - Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records. AB - BACKGROUND: Delayed correction of blood clotting times as measured by the International Normalized Ratio (INR) is associated with adverse outcomes among certain patients with warfarin-related major bleeding. However, there are limited data on the association between INR correction and mortality. OBJECTIVE: To assess factors associated with 30-day mortality and time to death in patients receiving fresh frozen plasma (FFP) for warfarin-associated major bleeding. METHODS: A retrospective database analysis was undertaken with electronic health record data from a large integrated health system. Patients met the following criteria: major hemorrhage diagnosis; INR >= 2 on the day before or day of receipt of FFP; and prescription fill for warfarin within 90 days. INR correction (defined as INR <= 1.3) was evaluated at the last available test 1 day following the start of FFP administration. Kaplan-Meier curves and Cox proportional hazards models were constructed to assess mortality. RESULTS: Four hundred and five patients met the selection criteria (mean age of 75 years, 54% male), and 67% remained uncorrected at 1 day following the start of FFP administration. Among all patients, 11% died within 30 days of hospital admission. An uncorrected INR was not associated with a higher risk of 30-day mortality for patients overall, but was statistically significant for the subgroup with intracranial hemorrhage (ICH) (adjusted odds ratio 2.55; 95% confidence interval 1.04-6.28). CONCLUSIONS: Among the subgroup of major bleeding patients with warfarin-associated ICH, those not correcting to either INR <= 1.3 or INR <= 1.5 with the use of FFP have an increased rate of mortality at 30 days. PMID- 22257108 TI - Meta-analysis: oral anti-viral agents in adults with decompensated hepatitis B virus cirrhosis. AB - BACKGROUND: The optimal oral anti-viral agent to use in patients with decompensated HBV cirrhosis remains unclear. AIM: We performed a meta-analysis of the oral nucleos(t)ide analogues in patients with decompensated HBV cirrhosis. METHODS: One year efficacy and safety outcomes in 22 studies published in English between '95 and 2010 were analysed. RESULTS: Substantial heterogeneity was noted in the inclusion/exclusion criteria, controls, and sensitivity of the HBV DNA assay used. Pooled 1-year data showed benefit favouring lamivudine (LAM) vs. untreated controls for Child-Turcotte-Pugh (CTP) score improvement by >=2 (OR: 117 (15 921), P <= 0.0001) and transplant-free survival (OR: 3.2 (1.2, 9), P = 0.022). Adefovir (ADV) led to undetectable HBV DNA at 1-year in 41% compared to 83% with LAM and 80% with entecavir (ETV). Overall, 1-year transplant-free survival rates varied from 78% with LAM to 95% and 94% with Tenofovir (TDF) and Telbivudine (TBV), respectively. The 1-year incidence of drug resistant HBV was 0% with ADV, ETV and TDF and 11% with LAM although TBV was associated with a 29% incidence at 2 years. Drug-related adverse events were infrequently reported. CONCLUSIONS: All the oral anti-viral agents were associated with improved virological, biochemical and clinical parameters at 1-year. However, the efficacy of lamivudine and telbivudine is limited by drug resistance, and adefovir is limited by its potency and slower onset of action. Additional studies of tenofovir and entecavir are needed to determine the optimal agent(s) for treatment naive patients and in those with drug-resistant decompensated HBV cirrhosis. PMID- 22257109 TI - Surface functionalization of alumina ceramic foams with organic ligands. AB - Different anchoring groups have been studied with the aim of covalently binding organic linkers to the surface of alumina ceramic foams. The results suggested that a higher degree of functionalization was achieved with a pyrogallol derivative--as compared to its catechol analogue--based on the XPS analysis of the ceramic surface. The conjugation of organic ligands to the surface of these alumina materials was corroborated by DNP-MAS NMR measurements. PMID- 22257110 TI - Implications of nasopharynx-associated lymphoid tissue (NALT) in the development of allergic responses in an allergic rhinitis mouse model. AB - BACKGROUND: Nasopharynx-associated lymphoid tissue (NALT) serves as an important inductive site for mucosal immunity in the upper respiratory tract. Despite its importance in the mucosal immune system, little is known regarding the role of NALT in airway allergic immune responses. We aimed to elucidate the role of NALT in the induction of upper airway allergic responses in a mouse model. METHODS: Inhibitor of DNA binding/differentiation 2 (Id2)(-/-) and Id2(+/-) mice was exposed to the ovalbumin (OVA)-induced allergic rhinitis model, because the former resulted in the NALT deficiency. The allergic parameters, such as allergic symptoms, serum OVA-specific immunoglobulin E (IgE) levels, eosinophil infiltration, and cytokine profiles in the nasal mucosa, were compared between Id2(-/-) and Id2(+/-) groups. RESULTS: NALT-null, Id2(-/-) mice displayed significantly lower allergic responses compared with Id2(+/-) mice, as demonstrated by lower levels of allergic symptoms, serum OVA-specific IgE, eosinophilic infiltration, and local Th2 cytokine transcriptions. To determine which of two factors, that is, the absence of NALT or the alteration of immunocompetent cell populations caused by the Id2 deficiency, has a larger effect on the attenuated allergic immune responses in Id2(-/-) mice, lethally irradiated Id2(-/-) mice were engrafted with C57BL/6 wild-type bone marrow cells and showed still significantly lower allergic immune responses compared with equally treated Id2(+/-) mice. In addition, IgE class switch recombination associated molecules, such as epsilon immunoglobulin heavy-chain germline gene transcript, epsilon mRNA, and activation-induced cytidine deaminase mRNA, were detected in NALT from OVA-sensitized wild-type mice. CONCLUSION: These results show the critical role of NALT for the induction of allergic responses in the upper airway at least in part by means of class switching to IgE in situ. PMID- 22257111 TI - Gold(I)-coordination triggered multistep and multiple photochromic reactions in multi-dithienylethene (DTE) systems. AB - The preparation, characterization, and photochromic properties of a mononuclear gold(I) complex (1oo) with two identical DTE-acetylides and a dinuclear gold(I) complex (2ooo) with both DTE-acetylide and DTE-diphosphine are described. Both gold(I) complexes exhibit multistep and multiple photocyclization/cycloreversion reactions. Particularly, four-state and four-color photochromic switch is successfully achieved for the dinuclear gold(I) complex upon irradiation with appropriate wavelengths of light. In contrast, fully ring-closed form is unattained through multiple photocyclization for the two corresponding model organic compounds coupling with the same DTE units as gold(I) complexes but without gold(I)-participation. It is demonstrated that coordination of gold(I) ion to DTE-acetylides exerts indeed a crucial role in achieving stepwise and selective photocyclization and cycloreversion reactions for both gold(I) complexes, in which the coordinated gold(I) atom acts as an effective "barrier" to prohibit intramolecular energy transfer between multi-DTE moieties. PMID- 22257112 TI - Context effects in multi-alternative decision making: empirical data and a Bayesian model. AB - For decisions between many alternatives, the benchmark result is Hick's Law: that response time increases log-linearly with the number of choice alternatives. Even when Hick's Law is observed for response times, divergent results have been observed for error rates-sometimes error rates increase with the number of choice alternatives, and sometimes they are constant. We provide evidence from two experiments that error rates are mostly independent of the number of choice alternatives, unless context effects induce participants to trade speed for accuracy across conditions. Error rate data have previously been used to discriminate between competing theoretical accounts of Hick's Law, and our results question the validity of those conclusions. We show that a previously dismissed optimal observer model might provide a parsimonious account of both response time and error rate data. The model suggests that people approximate Bayesian inference in multi-alternative choice, except for some perceptual limitations. PMID- 22257113 TI - Theoretical investigation of the effect of sugar substitution on the antioxidant properties of flavonoids. AB - Natural flavonoids are secondary phenolic plant metabolites known for their bioactivity as antioxidants. The evaluation of this property is generally done by the estimation of their direct free radical-scavenging activity as hydrogen or electron donating compounds. This paper reviews experimental results available in the literature for a selection of flavonoids and compares them with calculated quantities characteristic of the hydrogen or electron donation. For that purpose, bond dissociation energies, ionization potentials and electron transfer enthalpies are computed by using DFT methods and the ONIOM procedure implemented in the ab initio program Gaussian. This process has been chosen because it can be extended to the study of large molecules. When acid dissociation and interaction with the solvent are taken into account, the results present very good concordance with experimental results, enlightening the complexity of the processes involved in the classical assays which measure the ability of compounds to scavenge the (2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) radical cation (ABTS (+)) or the 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH(.)). This study demonstrates the good accuracy of theoretical calculations in obtaining the relative energies involved in free radical scavenging abilities and its capacity for predictive behaviour. It also highlights the necessity to take into account the pK(a) of the compounds and the solvent interaction. The ability of the method to calculate the antioxidant properties of larger molecules are tested on glycosylated flavonoids and the effects of sugar substitution on the antioxidant properties of flavonoids are investigated, pointing out the importance of the charges on the oxygen atoms. PMID- 22257114 TI - Investigation of methanol-peptide nuclear Overhauser effects through molecular dynamics simulations. AB - Intermolecular nuclear Overhauser effects (NOEs) produced by interactions of methanol with [val(5)]angiotensin in 25% methanol-water at 0 degrees C were examined through molecular dynamics (MD) simulations and compared to experimental results. Calculated average (3)J(NHCalphaH) spin coupling constants, conformation sensitive chemical shift changes, and intramolecular (1)H-(1)H NOEs indicated that peptide conformations present over the course of simulation trajectories of 100-300 ns are likely similar to those present in the experimental system. Calculated cross-relaxation terms for the methanol-peptide interactions showed the same trends as corresponding experimental data but were about a factor of 3 too large. The lack of agreement between observed and calculated cross-relaxation terms probably has origins in characteristics of the simulations that lead to overestimation of translational diffusion coefficients of the system components. Simulations confirmed the heterogeneity of the methanol-water solvent at the molecular level, with clusters of methanol and water molecules changing their size and composition on a subpicosecond time scale. Most peptide hydrogens are preferentially solvated by interactions with methanol molecules. Simulations suggest that diffusion of water and methanol molecules near the peptide is slowed as these species approach the peptide backbone. PMID- 22257115 TI - Acute generalized exanthematous pustulosis to amoxicillin associated with parvovirus B19 reactivation. AB - We report the case of a 22-year-old male patient with 2 episodes, 4 months apart, of acute generalized exanthematous pustulosis (AGEP) associated with oral intake of amoxicillin and simultaneous reactivation of parvovirus B19 infection proven by positive polymerase chain reaction test in the skin fragment and blood sample and elevation of the IgG antibodies titer. To our knowledge, this is the first report of AGEP resulting from the interaction between drug hypersensitivity and the reactivation of parvovirus B19. A combination of an immunological reaction to the drug and virus infection could be responsible for the clinical picture. PMID- 22257116 TI - Fluorescent microscopy of viable Batrachochytrium dendrobatidis. AB - Batrachochytrium dendrobatidis ( Bd ), a chytrid fungus, is a causative agent of chytridiomycosis and amphibian population declines worldwide. The sequenced genome of Bd provides information necessary for studying the fungus and its molecular biology. Fluorescent microscopy is a technique used to image targeted molecules in live or fixed organisms to understand cellular trafficking and localization, but the use of fluorescent microscopy with Bd has not yet been demonstrated. Two fluorescent stains were tested for their use in live-cell imaging of Bd , i.e., the cell wall-specific fluorophore Solophenyl Flavine 7GFE and the DNA-specific fluorophore DRAQ5. These specific staining patterns were observed in live cultures of Bd when visualized with laser-scanning confocal microscopy. PMID- 22257117 TI - Successful treatment of testicular pain with peripheral nerve stimulation of the cutaneous branch of the ilioinguinal and genital branch of the genitofemoral nerves. AB - OBJECTIVES: To assess the effect of peripheral nerve stimulation on neuropathic testicular pain. MATERIAL AND METHODS: A 30-year-old man with a four-year history of chronic testicular pain following scrotal hydrocele surgery had two percutaneous leads implanted in his groin and low-frequency stimulation of the cutaneous branch of the ilioinguinal and genital branch of the genitofemoral nerves. RESULT: At seven-month follow-up, the pain intensity had declined from 9/10 to 2/10 on the numeric rating scale. CONCLUSION: We report the successful implantation of an ilioinguinal and genitofemoral nerve stimulator for sustained suppression of intractable neuropathic testicular pain. PMID- 22257118 TI - Synthesis of indolo [1,2-a]quinoxalines via a Pd-catalyzed regioselective C-H olefination/cyclization sequence. AB - A highly efficient approach to indolo [1,2-a]quinoxaline derivatives through a Pd catalyzed regioselective C-H olefination/cyclization sequence has been developed. This transformation has a wide range of substrates with various functional groups, and the corresponding heterocyclic products were obtained in good yields. PMID- 22257119 TI - Effect of interferon therapy on first and second recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. AB - AIM: Several investigators have shown that interferon (IFN) therapy can suppress the recurrence of hepatocellular carcinoma (HCC) after curative treatment. We investigated the effect of IFN therapy on the first and second HCC recurrence following hepatic resection of hepatitis C virus (HCV)-related HCC. METHODS: Subjects included 166 patients who had undergone curative resection for a single HCV-related HCC. We analyzed the outcome after initial hepatic resection and risk factors of a second HCC recurrence following treatment for the first HCC recurrence. RESULTS: Using multivariate analysis, a non-sustained virological response (non-SVR) was significantly associated with a high incidence of first HCC recurrence. The rate of second HCC recurrence tended to be higher in the non-SVR group than in the SVR group. In the patients with recurrence of multiple tumors or who received non-curative treatment for recurrent HCC, the second HCC recurrence rates were significantly higher. Multivariate analysis demonstrated that non-curative treatment for first HCC recurrence was an independent risk factor for a second HCC recurrence. Among the patients who received curative treatment for their first HCC recurrence, the rates of second recurrence were significantly higher in the non-SVR group than in the SVR group. Multivariate analysis also revealed that SVR was independently associated with prevention of a second HCC recurrence. CONCLUSIONS: These results suggest that on first HCC recurrence, a curative treatment should be considered in order to prevent a second recurrence if possible. In addition, IFN therapy contributes to improved prognosis after curative treatment, even in patients with recurrent HCC. PMID- 22257120 TI - Identification of catalytic residues in the As(III) S-adenosylmethionine methyltransferase. AB - The enzyme As(III) S-adenosylmethionine methyltransferase (EC 2.1.1.137) (ArsM or AS3MT) is found in members of every kingdom, from bacteria to humans. In these enzymes, there are three conserved cysteine residues at positions 72, 174, and 224 in the CmArsM orthologue from the thermophilic eukaryotic alga Cyanidioschyzon sp. 5508. Substitution of any of the three led to loss of As(III) methylation. In contrast, a C72A mutant still methylated trivalent methylarsenite [MAs(III)]. Protein fluorescence of a single-tryptophan mutant reported binding of As(III) or MAs(III). As(GS)(3) and MAs(GS)(2) bound significantly faster than As(III), suggesting that the glutathionylated arsenicals are preferred substrates for the enzyme. Protein fluorescence also reported binding of Sb(III), and the purified enzyme methylated and volatilized Sb(III). The results suggest that all three cysteine residues are necessary for the first step in the reaction, As(III) methylation, but that only Cys174 and Cys224 are required for the second step, methylation of MAs(III) to dimethylarsenite [DMAs(III)]. The rate-limiting step was identified as the conversion of DMAs(III) to trimethylarsine, and DMAs(III) accumulates as the principal product. PMID- 22257121 TI - Ventilation, temperature, and HVAC characteristics in small and medium commercial buildings in California. AB - This field study of 37 small and medium commercial buildings throughout California obtained information on ventilation rate, temperature, and heating, ventilating, and air-conditioning (HVAC) system characteristics. The study included seven retail establishments; five restaurants; eight offices; two each of gas stations, hair salons, healthcare facilities, grocery stores, dental offices, and fitness centers; and five other buildings. Fourteen (38%) of the buildings either could not or did not provide outdoor air through the HVAC system. The air exchange rate averaged 1.6 (s.d. = 1.7) exchanges per hour and was similar between buildings with and without outdoor air supplied through the HVAC system, indicating that some buildings have significant leakage or ventilation through open windows and doors. Not all buildings had sufficient air exchange to meet ASHRAE 62.1 Standards, including buildings used for fitness centers, hair salons, offices, and retail establishments. The majority of the time, buildings were within the ASHRAE temperature comfort range. Offices were frequently overcooled in the summer. All of the buildings had filters, but over half the buildings had a filter with a minimum efficiency reporting value rating of 4 or lower, which are not very effective for removing fine particles. PRACTICAL IMPLICATIONS: Most U.S. commercial buildings (96%) are small- to medium sized, using nearly 18% of the country's energy, and sheltering a large population daily. Little is known about the ventilation systems in these buildings. This study found a wide variety of ventilation conditions, with many buildings failing to meet relevant ventilation standards. Regulators may want to consider implementing more complete building inspections at commissioning and point of sale. PMID- 22257122 TI - Predictors of change in participation rates following acquired brain injury: results of a longitudinal study. AB - AIM: The purpose of this study was (1) to examine the changes in participation rates over 1 year among children and adolescents after acquired brain injury and (2) to explore the effect of child and family factors on these changes. METHOD: The participation levels of 136 children and young people (88 males; 48 females; age range 4y 11mo-17y 6mo; mean age 11y 6mo) after acquired brain injury (3<= Glasgow Coma Scale score <=15; mean 12.8) were assessed three times: at their return to school, and at 8 and 12 months after returning to school. The Children's Assessment of Participation and Enjoyment measured the participants' diversity and intensity of participation in out-of-school activities. At baseline, information on general family functioning and medical and demographic information was collected as possible predictors. Mixed-effect model analyses of participation scores were performed while controlling for child's age at injury. RESULTS: The severity of the injury explained rates of change across time for participation intensity in recreational, physical, and social activities. Household income influenced changes in the intensity of recreational activities, whereas family functioning predicted changes in the diversity of skill-based activities. INTERPRETATION: Participation is a relevant outcome of recovery that needs to be assessed and monitored post brain injury. Special attention can be directed to severity of injury and family functioning when developing intervention plans. PMID- 22257123 TI - gamma-Enolase C-terminal peptide promotes cell survival and neurite outgrowth by activation of the PI3K/Akt and MAPK/ERK signalling pathways. AB - gamma-Enolase, a glycolytic enzyme, is expressed specifically in neurons. It exerts neurotrophic activity and has been suggested to regulate growth, differentiation, survival and regeneration of neurons. In the present study, we investigated the involvement of gamma-enolase in PI3K (phosphoinositide 3 kinase)/Akt and MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal regulated kinase) signalling, the two pathways triggered predominantly by neurotrophic factors. Whereas the PI3K/Akt pathway, rather than the MAPK/ERK pathway, is involved in gamma-enolase-enhanced cell survival, gamma-enolase stimulated neurite outgrowth requires both pathways, i.e. the activation of both PI3K and ERK1/2, leading to subsequent expression of the growth-cone-specific protein GAP-43 (growth-associated protein of 43 kDa). MEK (MAPK/ERK kinase) and PI3K inhibition blocked or attenuated the neurite outgrowth associated with dynamic remodelling of the actin-based cytoskeleton. We show that gamma-enolase mediated PI3K activation regulates RhoA kinase, a key regulator of actin cytoskeleton organization. Moreover, the inhibition of RhoA downstream effector ROCK (Rho-associated kinase) results in enhanced gamma-enolase-induced neurite outgrowth, accompanied by actin polymerization and its redistribution to growth cones. Our results show that gamma-enolase controls neuronal survival, differentiation and neurite regeneration by activating the PI3K/Akt and MAPK/ERK signalling pathways, resulting in downstream regulation of the molecular and cellular processes of cytoskeleton reorganization and cell remodelling, activation of transcriptional factors and regulation of the cell cycle. PMID- 22257124 TI - D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. AB - BACKGROUND: Quantitative measurement of circulating D-dimer, a product of fibrin degradation, has been shown to be a very useful diagnostic tool in the management of patients with suspected deep vein thrombosis and/or pulmonary embolism. Whether D-dimer can play a similar role in the diagnostic approach to patients with suspected cerebral vein thrombosis (CVT) remains controversial. METHODS: Studies evaluating the diagnostic accuracy of the D-dimer test in the diagnosis of CVT were systematically searched for in the MEDLINE and EMBASE databases (up to July 2011). Weighted mean sensitivity and specificity with 95% confidence intervals (CIs) were calculated with a bivariate random-effects regression approach. RESULTS: Fourteen studies, for a total of 1134 patients, were included. D-dimer accuracy was good, with a resulting weighted mean sensitivity of 93.9% (95% CI 87.5-97.1) and weighted mean specificity of 89.7% (95% CI 86.5-92.2), calculated with a bivariate approach. Potential risk factors for false-negative D dimer results included isolated headache, longer duration of symptoms, and limited sinus involvement. CONCLUSIONS: Our findings suggest that D-dimer may be a useful diagnostic tool in the management of patients with suspected CVT. Future prospective studies are warranted to confirm our preliminary findings. PMID- 22257125 TI - Increased cortical excitability with prefrontal high-frequency repetitive transcranial magnetic stimulation in adolescents with treatment-resistant major depressive disorder. AB - OBJECTIVE: To examine changes in motor cortical excitability in adolescent subjects receiving 30 sessions of high-frequency prefrontal repetitive transcranial magnetic stimulation (rTMS). METHODS: Eight adolescents with treatment-resistant major depressive disorder (MDD) enrolled in an open augmentation trial of 10 Hz rTMS. Resting motor thresholds were obtained by the visualization of movement method with a maximum likelihood threshold hunting computer algorithm at baseline and after every five sessions of rTMS. Motor threshold was recorded as the percentage of total machine output at each measurement. RESULTS: Motor threshold data from baseline, weeks 2, 4, and 5 were included in a mixed model repeated measure analysis to examine a change in least square mean effect over time. The omnibus effect did not reach statistical significance (F=1.25, p=0.32). However, multiple comparisons from the overall model demonstrated a decrease in the least square mean motor threshold. The mean contrast from baseline to week 5 approached significance (p=0.07). Moreover, a post-hoc analysis with a Wilcoxon signed ranks test demonstrated a significant decrease at week 5 (p=0.03). CONCLUSIONS: This suggests that high-frequency rTMS may increase cortical excitability in adolescents with treatment-resistant MDD. PMID- 22257128 TI - A voice for all in mental health research. PMID- 22257126 TI - Insomnia moderates outcome of serotonin-selective reuptake inhibitor treatment in depressed youth. AB - OBJECTIVE: Insomnia is evident in the majority of youth with depression, and is associated with poorer outcomes. There are limited data on the impact of insomnia in response to acute treatment, which is particularly relevant with serotonin selective reuptake inhibitors, given their tendency to worsen sleep architecture. METHODS: Three hundred nine children and adolescents (ages 7-18 years) were randomized to fluoxetine (n=157) or placebo (n=152) for 8-9 weeks (Emslie et al.1997, 2002). Substantial insomnia at baseline was defined as a child's depression rating scale-revised [CDRS-R] sleep item >= 4. Outcome measures were CDRS-R, response, and remission. RESULTS: Insomnia was reported in 172/309 (55.7%) youth, and was associated with higher depression severity and greater fatigue, suicidal ideation, physical complaints, and decreased concentration. While response rates were similar in those with or without insomnia overall (51.7% vs. 55.7%), there is a significant difference by age group. Among adolescents, those with insomnia were less likely to respond to fluoxetine (39.2%; 20/51) than those without (65.9%; 27/41; p=0.013), while in children on fluoxetine, those with insomnia were more likely to respond to fluoxetine (69.4%; 25/36) than those without insomnia (41.4%; 12/29; p=0.027). Insomnia did not impact the response to placebo in either age group. Within adolescents, the overall least squares means for CDRS-R total score (across the 8 weeks of treatment) were significantly different between those who had insomnia versus those who did not within the fluoxetine group (43.65 [SE=1.31] vs. 36.58[SE=1.45], F=12.69, df=1, 169, p=0.0005; d=0.82), but not within the placebo group (44.91[SE=1.34] vs. 43.75[SE=1.68], F=0.29, df=1, 179, p=0.591; d=0.15). CONCLUSIONS: While adolescents reporting substantial insomnia were less likely to respond to antidepressant treatment than those without insomnia, children were more responsive to fluoxetine when they had insomnia. Additional intervention targeting sleep disturbance may be warranted in adolescents. PMID- 22257127 TI - Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen. AB - Using a newly developed competitive binding assay dependent upon the reassembly of a split reporter protein, we have tested the promiscuity of a panel of reported kinase inhibitors against the AGC group. Many non-AGC targeted kinase inhibitors target multiple members of the AGC group. In general, structurally similar inhibitors consistently exhibited activity toward the same target as well as toward closely related kinases. The inhibition data was analyzed to test the predictive value of either using identity scores derived from residues within 6 A of the active site or identity scores derived from the entire kinase domain. The results suggest that the active site identity in certain cases may be a stronger predictor of inhibitor promiscuity. The overall results provide general guidelines for establishing inhibitor selectivity as well as for the future design of inhibitors that either target or avoid AGC kinases. PMID- 22257129 TI - A rationale for service responses to self-injury. AB - BACKGROUND: In this paper, reasons reported by people who self-injure to explain this behaviour are presented. AIMS: Traditional service responses are examined and it is suggested that these may exacerbate the reasons why people self-injure and are likely to create vulnerability to further harm. METHOD: A rationale is presented which suggests that service-providers should aim to respond to the specific feelings underlying self-injury (SI) in a therapeutic way. RESULTS: Guidance is provided for implementing constructive responses to SI within clinical practice. CONCLUSIONS: If service-providers are trained to understand and accept SI as a comprehensible act of coping, then attitudes of respect and empathy are more likely to be exhibited. In turn, these approaches are therapeutic to service-users, potentially mitigating the feelings that initially prompt SI. PMID- 22257130 TI - Assessing fidelity to integrated motivational interviewing and CBT therapy for psychosis and substance use: the MI-CBT fidelity scale (MI-CTS). AB - BACKGROUND: Guidelines for the psychological treatment of psychosis and substance use suggest integrated treatments to address both problems are necessary. One such treatment combines cognitive-behaviour therapy (CBT) and motivational interviewing (MI). While there are a number of scales to assess treatment fidelity to CBT and MI separately, none, to date, assess fidelity to integrated MI and CBT (MI-CBT) for psychosis and substance use. AIMS: This study aimed to develop a reliable and valid scale to assess fidelity to MI-CBT for people with psychosis and problematic substance use. METHOD: Items for a new scale (the MI CTS fidelity scale) were selected from multiple relevant sources. Inter-rater reliability and validity (against the CTS-Psy and Motivational Interviewing Treatment Integrity (MITI)) scales were investigated. RESULTS: The scale had good inter-rater reliability when used to rate adherence versus non-adherence. In relation to validity, the scale related well to CBT and MI scales (the CTS-Psy and MITI). CONCLUSIONS: The MI-CTS is useful for assessing adherence to integrated MI-CBT for psychosis and substance misuse and could aid training and implementation of the approach. PMID- 22257131 TI - VOICE: developing a new measure of service users' perceptions of inpatient care, using a participatory methodology. AB - BACKGROUND: Service users express dissatisfaction with inpatient care and their concerns revolve around staff interactions, involvement in treatment decisions, the availability of activities and safety. Traditionally, satisfaction with acute care has been assessed using measures designed by clinicians or academics. AIMS: To develop a patient-reported outcome measure of perceptions of acute care. An innovative participatory methodology was used to involve services users throughout the research process. METHOD: A total of 397 participants were recruited for the study. Focus groups of service users were convened to discuss their experiences and views of acute care. Service user researchers constructed a measure from the qualitative data, which was validated by expert panels of service users and tested for its psychometric properties. RESULTS: Views on Inpatient Care (VOICE) is easy to understand and complete and therefore is suitable for use by service users while in hospital. The 19-item measure has good validity and internal and test-retest reliability. Service users who have been compulsorily admitted have significantly worse perceptions of the inpatient environment. CONCLUSIONS: A participatory methodology has been used to generate a self-report questionnaire measuring service users' perceptions of acute care. VOICE encompasses the issues that service users consider most important and has strong psychometric properties. PMID- 22257132 TI - Arabic translation and cultural adaptation of the stigma-devaluation scale in Jordan. AB - BACKGROUND: A review of the literature on measuring the concept of stigma related to caring for a relative with mental illness yielded no instrument appropriate for use in Jordan. AIMS: To translate and culturally modify the stigma devaluation scale (SDS) into Arabic, and to test the reliability, content and construct validity of the Arabic version of the SDS. METHOD: The SDS was translated into the Arabic language, modified and culturally adapted by a translation model. Estimation of internal consistency was used to assess the reliability of the SDS. Construct validity was determined by confirmatory factor analysis (CFA). Measurements of content validity and reading level of the Arabic SDS were included. The Arabic SDS was evaluated in a sample of 164 family caregivers in Jordan. RESULTS: Content validity index was determined to be 1.0. Reading level of the Arabic SDS was deemed to be at a sixth grade level or higher. Cronbach's alpha coefficient of the Arabic SDS total scale was 0.87. The results of the CFA revealed that the factor structure of the SDS had a satisfactory fit. CONCLUSION: This study provided psychometric evidence that the modified Arabic SDS is valid and conceptually consistent with the content of the original English SDS. PMID- 22257133 TI - Perceived health risks, attitude and readiness to quit tobacco among euthymic bipolar disorder patients in regular contact with mental health services: an exploratory study from India. AB - BACKGROUND: Patients with bipolar disorder (BD) are at higher risk of tobacco related harm compared with general population. However, they may not fully appreciate health risks even when asymptomatic. AIM: The study aims to explore the perceived health risks, attitude and readiness to quit tobacco among euthymic BD patients. METHOD: The adult male outpatients with Diagnostic and Statistical Manual, 4th edition diagnosis of BD type I and nicotine dependence were selected if they were euthymic and in regular psychiatric follow-up (n = 50). They were assessed using Fagerstrom scale for nicotine dependence, transtheoretical model and a semi-structured questionnaire. RESULTS: The sample was unaware of the full spectrum of tobacco health risks and most of patients could report only one or two tobacco-related diseases. Though the majority correctly recalled the pack health warning, but felt that it should not be taken seriously. The sample perceived its own cancer risk to be lower than that of an average user of similar age. The non-readiness to change tobacco use was predicted by difficulty in quitting due to mood disorder (odds ratio (OR) 0.229) and a higher perceived ability to quit (OR 0.328). CONCLUSION: The knowledge and risk perception for tobacco remains inadequate even among the stable BD type I patients in regular contact with mental health services. PMID- 22257135 TI - Predicting the retention of first-time donors using an extended Theory of Planned Behavior. AB - BACKGROUND: Donor retention is vital to blood collection agencies. Past research has highlighted the importance of early career behavior for long-term donor retention, yet research investigating the determinants of early donor behavior is scarce. Using an extended Theory of Planned Behavior (TPB), this study sought to identify the predictors of first-time blood donors' early career retention. STUDY DESIGN AND METHODS: First-time donors (n=256) completed three surveys on blood donation. The standard TPB predictors and self-identity as a donor were assessed 3 weeks (Time 1) and at 4 months (Time 2) after an initial donation. Path analyses examined the utility of the extended TPB to predict redonation at 4 and 8 months after initial donation. RESULTS: The extended TPB provided a good fit to the data. Post-Time 1 and 2 behavior was consistently predicted by intention to redonate. Further, intention was predicted by attitudes, perceived control, and self-identity (Times 1 and 2). Donors' intentions to redonate at Time 1 were the strongest predictor of intention to donate at Time 2, while donors' behavior at Time 1 strengthened self-identity as a blood donor at Time 2. CONCLUSION: An extended TPB framework proved efficacious in revealing the determinants of first time donor retention in an initial 8-month period. The results suggest that collection agencies should intervene to bolster donors' attitudes, perceived control, and identity as a donor during this crucial post-first donation period. PMID- 22257136 TI - Autotrophic denitrification in microbial fuel cells treating low ionic strength waters. AB - The presence of elevated concentrations of nitrates in drinking water has become a serious concern worldwide. The use of autotrophic denitrification in microbial fuel cells (MFCs) for waters with low ionic strengths (i.e., 1000 MUS.cm(-1)) has not been considered previously. This study evaluated the feasibility of MFC technology for water denitification and also identified and quantified potential energy losses that result from their usage. The low conductivity (<1600 MUS.cm( 1)) of water limited the nitrogen removal efficiency and power production of MFCs and led to the incomplete reduction of nitrate and the nitrous oxide (N(2)O) production (between 4 and 20% of nitrogen removed). Cathodic overpotential was identified as the main energy loss factors (83-90% of total losses). That high overpotential was influenced by denitrification intermediates (NO(2)(-) and N(2)O) and the potential used by microorganisms for growth, activation, and maintenance. PMID- 22257137 TI - Electronic fingerprints of DNA bases on graphene. AB - We calculate the electronic local density of states (LDOS) of DNA nucleotide bases (A,C,G,T), deposited on graphene. We observe significant base-dependent features in the LDOS in an energy range within a few electronvolts of the Fermi level. These features can serve as electronic fingerprints for the identification of individual bases in scanning tunneling spectroscopy (STS) experiments that perform image and site dependent spectroscopy on biomolecules. Thus the fingerprints of DNA-graphene hybrid structures may provide an alternative route to DNA sequencing using STS. PMID- 22257138 TI - Near-thermal reactions of Au(+)(1S,3D) with CH3X (X = F,Cl). AB - Reactions of Au(+)((1)S) and Au(+)((3)D) with CH(3)F and CH(3)Cl have been carried out in a drift cell in He at a pressure of 3.5 Torr at both room temperature and reduced temperatures in order to explore the influence of the electronic state of the metal on reaction outcomes. State-specific product channels and overall two-body rate constants were identified using electronic state chromatography. These results indicate that Au(+)((1)S) reacts to yield an association product in addition to AuCH(2)(+) in parallel steps with both neutrals. Product distributions for association vs HX elimination were determined to be 79% association/21% HX elimination for X = F and 50% association/50% HX elimination when X = Cl. Reaction of Au(+)((3)D) with CH(3)F also results in HF elimination, which in this case is thought to produce (3)AuCH(2)(+). With CH(3)Cl, Au(+)((3)D) reacts to form AuCH(3)(+) and CH(3)Cl(+) in parallel steps. An additional product channel initiated by Au(+)((3)D) is also observed with both methyl halides, which yields CH(2)X(+) as a higher-order product. Kinetic measurements indicate that the reaction efficiency for both Au(+) states is significantly greater with CH(3)Cl than with CH(3)F. The observed two-body rate constant for depletion of Au(+)((1)S) by CH(3)F represents less than 5% of the limiting rate constant predicted by the average dipole orientation model (ADO) at room temperature and 226 K, whereas CH(3)Cl reacts with Au(+)((1)S) at the ADO limit at both room temperature and 218 K. Rate constants for depletion of Au(+)((3)D) by CH(3)F and CH(3)Cl were measured at 226 and 218 K respectively, and indicate that Au(+)((3)D) is consumed at approximately 2% of the ADO limit by CH(3)F and 69% of the ADO limit by CH(3)Cl. Product formation and overall efficiency for all four reactions are consistent with previous experimental results and available theoretical models. PMID- 22257139 TI - Heme flattening is sufficient for signal transduction in the H-NOX family. AB - The H-NOX family of nitric oxide (NO) sensing proteins has received considerable attention because its members include the mammalian NO sensor, soluble guanylate cyclase. Despite this attention, the mechanism of signal transduction has not been elucidated. Structural studies of bacterial members of the family have revealed that the H-NOX heme cofactor is extremely distorted from planarity. Furthermore, it has been determined that heme distortion is maintained primarily by a conserved proline residue located in the proximal heme pocket. It has been suggested that changes in heme planarity may contribute to signal transduction. Here we demonstrate that heme flattening is, indeed, sufficient for signal transduction in the H-NOX family. Using our previously described H NOX/diguanylate cyclase functional partners from Shewanella woodyi, we demonstrate that mutation of the conserved proline (P117 in SwH-NOX) to alanine, which results in heme flattening, has the same affect on phosphodiesterase activity as NO binding to wildtype SwH-NOX. This study demonstrates, for the first time, that heme flattening mimics the activated, NO-bound state of H-NOX and suggests that NO binding induces heme flattening as part of the signal transduction mechanism in the H-NOX family. PMID- 22257140 TI - Positive surgical margins are a risk factor for significant biochemical recurrence only in intermediate-risk disease. AB - What's known on the subject? and What does the study add? Positive surgical margins (PSMs) after radical prostatectomy are common, although their impact on the risk of disease recurrence is unknown. We examined the impact of PSMs on the risk of 'significant' biochemical recurrence stratified by their risk of occult metastatic disease. We find that only in intermediate-risk disease does the presence of a PSM have a significant impact on the risk of recurrence, and this represents a failure of technique. By contrast, for high- and low-risk disease, the risk of recurrence is driven by intrinsic tumour biology, and the presence of a PSM has little impact on outcome. OBJECTIVE: To determine the impact of surgical margin status on the risk of significant biochemical recurrence (prostate-specific antigen [PSA] doubling time <3, <6 or <9 months) after prostatectomy. MATERIALS AND METHODS: Patients undergoing radical prostatectomy with complete clinical and pathological data and detailed PSA follow-up were identified from two prospectively recorded databases. Patients were stratified according to their risk of occult systemic disease (low risk: PSA < 10 ng/dL, pT2 stage and Gleason score <=6; intermediate risk: PSA 10-20 ng/dL, pT2 stage and/or Gleason score 7; high: PSA > 20 ng/dL or pT3-4 stage or Gleason score 8-10) and the impact of a positive surgical margin (PSM) within each stratum determined by univariable and multivariable analysis. RESULTS: Of 1514 patients identified, 276 (18.2%), 761 (50.3%) and 477 (31.5%) were classified as having low-, intermediate and high-risk disease respectively. A total of 370 (24.4%) patients had a PSM and with a median follow-up of 22.2 months, and 165 (7%) patients had a biochemical recurrence. Sufficient PSA data was available to calculate PSA doubling times in 151/165 patients (91.5%). The PSM rate rose significantly, from 11% in low-risk to 43% in high-risk disease (P < 0.001), with similar positive associations noted with tumour grade, stage and serum PSA (P < 0.001). Patients with low-risk disease had essentially identical risks of significant biochemical recurrence over the study period, regardless of surgical margin status. By contrast, in patients with both intermediate- and high-risk disease, a PSM was a strong predictor of significant biochemical recurrence on univariable analysis. On multivariable analysis, howver, PSM predicted significant disease recurrence in intermediate-risk disease only. CONCLUSIONS: PSM is a risk factor for significant biochemical recurrence only in intermediate risk disease. PMID- 22257141 TI - Rapid sample preparation procedure for As speciation in food samples by LC-ICP MS. AB - This paper describes a rapid method for arsenic (As) speciation by LC-ICP-MS in several types of food samples. Prior to analysis, samples were milled and the As species extracted from biological tissues by sonication in only 2 min with a solution containing MeOH (10%, v/v) plus HNO3 (2%, v/v). As species were separated by LC using an anion exchange column. Method detection limits for AsB, As3+, DMA, MMA and As5+ were 1.3, 0.9, 0.6, 0.7 and 0.8 ng g-1, respectively. Method accuracy and precision were traceable to Certified Reference Materials SRM1577 bovine liver from the National Institute of Standards and Technology, CE278 mussel tissue from the Institute of Reference Materials and Measurements and DOLT-3 dogfish liver tissue and DORM-3 fish protein from the National Research Council of Canada. Finally, the method was applied to speciate As in food samples (egg, fish muscle, beef and chicken) purchased in Brazilian markets. PMID- 22257142 TI - Reporting on end-of-life matters - academic meets activists. PMID- 22257143 TI - Diode laser thermal vaporization inductively coupled plasma mass spectrometry. AB - An approach of sample introduction for inductively coupled mass spectrometry (ICPMS), diode laser thermal vaporization (DLTV) is described. The method allows quantitative determination of metals in submicroliter volumes of liquid samples. Laser power is sufficient to induce pyrolysis of a suitable substrate with the deposited sample leading to aerosol generation. Unlike existing sample introduction systems based on laser ablation, it uses a NIR diode laser rather than an expensive high-energy pulsed laser. For certain elements, this sample introduction technique may serve as an alternative to solution analysis with conventional nebulizers. Using a prearranged calibration set, DLTV ICPMS provides rapid and reproducible sample analysis (RSD ~ 10%). Sample preparation is fast and simple, and the prepared samples can easily be archived and transported. The limits of detection for Co, Ni, Zn, Mo, Cd, Sn, and Pb deposited on the preprinted paper were found to be in the range of 0.4-30 pg. The method was characterized, optimized, and applied to the determination of Co in a drug preparation, Pb in whole blood, and Sn in food samples without any sample pretreatment. PMID- 22257144 TI - Cellulose nanofiber orientation in nanopaper and nanocomposites by cold drawing. AB - To exploit the mechanical potential of native cellulose fibrils, we report on the preparation of nanopaper with preferred orientation of nanofibrillated cellulose (TEMPO-NFC) by cold drawing. The preparation route is papermaking-like and includes vacuum filtering of a TEMPO-oxidated NFC water dispersion, drawing in wet state and drying. The orientation of the fibrils in the nanopaper was assessed by AFM and wide-angle X-ray diffraction analysis, and the effect on mechanical properties of the resulting nanopaper structure was investigated by tensile tests. At high draw ratio, the degree of orientation is as high as 82 and 89% in-the-plane and cross-sectional planes of the nanopaper, respectively, and the Young's modulus is 33 GPa. This is much higher than mechanical properties of isotropic nanopaper. The cold drawing method can be also applied to NFC nanocomposites as demonstrated by preparation of TEMPO-NFC/hydroxyethyl cellulose (HEC) nanocomposites. The introduction of the soft HEC matrix allows further tailoring of the mechanical properties. PMID- 22257145 TI - Microbiota and dietary interactions: an update to the hygiene hypothesis? AB - The dramatic increase in the incidence and severity of allergy and asthma has been proposed to be linked with an altered exposure to, and colonization by, micro-organisms, particularly early in life. However, other lifestyle factors such as diet and physical activity are also thought to be important, and it is likely that multiple environmental factors with currently unrecognized interactions contribute to the atopic state. This review will focus on the potential role of microbial metabolites in immunoregulatory functions and highlights the known molecular mechanisms, which may mediate the interactions between diet, microbiota, and protection from allergy and asthma. PMID- 22257146 TI - Synthesis and photophysical properties of a supramolecular host-guest assembly constructed by fullerenes and tryptamine modified hypocrellin. AB - The metal coordination polymer of hypocrellin A bearing tryptamine motif (M DTrpHA) can include fullerene via a two-point interaction, involving pi-pi stacking and electron donor-acceptor interaction. The 1:1 host-guest system M DTrpHA/fullerene exhibits a moderate association constant K(a) (6.62 * 10(4) to 6.46 * 10(5) M(-1)). Both of the metal ions in M-DTrpHA and the substituents connected to the fullerene core play important roles in stabilizing the M DTrpHA/fullerene complex. Transient absorption spectral and NIR absorption spectral results demonstrate that, in the M-DTrpHA/fullerene system, efficient photoinduced electron transfer from the tryptamine group in M-DTrpHA to fullerene may occur, resulting in a long-lived fullerene anion radical. The observed order of quantum yield (Phi(ET)(T)) and rate constants (K(ET)(T)) for electron transfer via (3)C(60)(*) is Y(3+)-DTrpHA > La(3+)-DTrpHA > DTrpHA, consistent with their binding ability to C(60). The nanostructure of M-DTrpHA is rearranged to form an interpenetrating network after interaction with fullerene. PMID- 22257147 TI - Inherited variations in the SOD and GPX gene families and cancer risk. AB - Antioxidant defence enzymes are essential protectors of living organisms against oxidative stress. These enzymes are involved in the detoxification and decomposition of harmful chemical compounds called reactive oxygen species (ROS), which are, first and foremost, a source of intracellular oxidative stress. ROS directly promote the oxidative damage of genes resulting in aberrant regulation of many vital cell processes. As a consequence, the presence of ROS can lead to genomic instability, deregulation of transcription, induction of mitogenic signal transduction pathways and replication errors, all of which may increase the risk of cancer development. Single nucleotide polymorphisms of antioxidant defence genes may significantly modify the functional activity of the encoded proteins; therefore, certain alleles can be established as risk factors for particular cancer types. In the future, these risk alleles may be utilized as genomic markers of cancer predisposition to allow for early prevention measures among carriers of these alleles. The review is devoted to common single nucleotide polymorphisms of the superoxide dismutase (SOD) and glutathione peroxidase (GPX) gene families and their impact on carcinogenesis. The predictive significance of several polymorphisms was determined, and these polymorphisms were recommended for further in-depth research. PMID- 22257148 TI - Role of modelling and simulation: a European regulatory perspective. AB - Modelling and simulation (M&S) of clinical data, e.g. pharmacokinetic, pharmacodynamic and clinical endpoints, is a useful approach for more efficient interpretation of collected data and for extrapolation of knowledge to the entire target population. This type of documentation is included in the majority of marketing authorization applications for new medicinal products. This article summarizes the current status of regulatory review with respect to the role of M&S in Europe from the perspective of the Swedish Medical Products Agency. At present, regulatory bodies in Europe encourage the application of the M&S approach during drug development. However, there is a lack of consensus and transparent guidance documents. The main regulatory usage is in the evaluation of dose choices in sub-populations and as support for the dosing regimen in general. The regulatory review of conestat alfa illustrates how the dose recommendation was revised during the approval procedure based on M&S information. A survey of marketing authorization applications for new medicinal products approved in 2010 revealed that the use of the information gained from M&S documentation varies with respect to both regulatory review and the applicants' presentation of the data in the submitted dossier. Increased utilization and broadened application of M&S is anticipated in pharmaceutical development, where one area of focus is medicines for paediatric patients. Accordingly, the regulatory agencies will need to increase their capability to assess and utilize this type of information, and an interactive process among regulatory agencies is warranted to provide more unified regulatory assessment and guidance. Moreover, applicants are encouraged to expand on the usage of exposure-response models to map the systemic exposure range that yields safe and efficacious treatment and to improve the presentation of the gained knowledge in summary documents of the marketing authorization applications. PMID- 22257150 TI - A guide to rational dosing of monoclonal antibodies. AB - BACKGROUND AND OBJECTIVE: Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach. METHODS: In this analysis, the body weight based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (theta(BW_CL)) and on the central volume of distribution (theta(BW_V1)). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [C(min)] and peak serum concentration [C(max)]) was compared between body weight based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study. RESULTS: Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of theta(BW_CL) and theta(BW_V1) in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight based dosing; when both theta(BW_CL) and theta(BW_V1) are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either theta(BW_CL) or theta(BW_V1) is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (theta(BW_CL) and theta(BW_V1) <0.5 or ~0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%. CONCLUSIONS: The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials. PMID- 22257152 TI - Nail discoloration due to tinzaparin sodium. AB - Tinzaparin sodium is a low molecular weight heparin formed by the enzymatic degradation of porcine unfractionated heparin, and is effective in the prevention and treatment of thromboembolic disease. We report a 31-year-old female patient with a history of recurrent pregnancy loss due to thrombophilia, who developed nail discoloration after 8 weeks of tinzaparin sodium therapy. No other pigmentation was found elsewhere on the skin, mucous membranes, teeth, or sclerae. To our knowledge, nail pigmentation following tinzaparin sodium therapy is an unknown side effect and has not been reported previously in the English literature. PMID- 22257153 TI - Participation following pediatric acquired brain injury and some inherent problems with outcome studies. PMID- 22257154 TI - Urethral stricture caused by schistosomiasis in a renal transplant recipient. PMID- 22257155 TI - Carcinoid tumour management in haemodialysis: a case report. PMID- 22257149 TI - Drug interactions with herbal medicines. AB - In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John's wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms. PMID- 22257156 TI - Size-resolved emission rates of airborne bacteria and fungi in an occupied classroom. AB - The role of human occupancy as a source of indoor biological aerosols is poorly understood. Size-resolved concentrations of total and biological particles in indoor air were quantified in a classroom under occupied and vacant conditions. Per-occupant emission rates were estimated through a mass-balance modeling approach, and the microbial diversity of indoor and outdoor air during occupancy was determined via rDNA gene sequence analysis. Significant increases of total particle mass and bacterial genome concentrations were observed during the occupied period compared to the vacant case. These increases varied in magnitude with the particle size and ranged from 3 to 68 times for total mass, 12-2700 times for bacterial genomes, and 1.5-5.2 times for fungal genomes. Emission rates per person-hour because of occupancy were 31 mg, 37 * 10(6) genome copies, and 7.3 * 10(6) genome copies for total particle mass, bacteria, and fungi, respectively. Of the bacterial emissions, ~18% are from taxa that are closely associated with the human skin microbiome. This analysis provides size-resolved, per person-hour emission rates for these biological particles and illustrates the extent to which being in an occupied room results in exposure to bacteria that are associated with previous or current human occupants. PRACTICAL IMPLICATIONS: Presented here are the first size-resolved, per person emission rate estimates of bacterial and fungal genomes for a common occupied indoor space. The marked differences observed between total particle and bacterial size distributions suggest that size-dependent aerosol models that use total particles as a surrogate for microbial particles incorrectly assess the fate of and human exposure to airborne bacteria. The strong signal of human microbiota in airborne particulate matter in an occupied setting demonstrates that the aerosol route can be a source of exposure to microorganisms emitted from the skin, hair, nostrils, and mouths of other occupants. PMID- 22257157 TI - Cellular immunity to CMV: advancing to the next level. PMID- 22257158 TI - Multiple paternity in the American dog tick, Dermacentor variabilis (Acari: Ixodidae). AB - The reproductive strategies and variation in reproductive success of ticks are poorly understood. We determined variation in multiple paternity in the American dog tick Dermancentor variabilis . In total, 48 blood-engorged female ticks and 22 male companion ticks were collected from 13 raccoon ( Procyon lotor ) hosts. In the laboratory, 56.3% of blood-engorged females laid eggs, of which 37.0% hatched or showed signs of development. We examined the presence of multiple paternity in the ensuing clutches by genotyping groups of eggs and larvae at 5 microsatellite loci and subtracting the known maternal alleles, thereby identifying male-contributed alleles. Seventy-five percent of the clutches presented multiple paternity, with a mode of 2 fathers siring the clutch. Males associated with the females on the host always sired some offspring. In 1 case, a male was the sire of clutches derived from 2 females, indicating both polygyny and polyandry may occur for this species. These results, combined with those of several other recent studies, suggest that multiple paternity might be frequent for ixodid ticks. PMID- 22257159 TI - Green tea polyphenol EGCG induces lipid-raft clustering and apoptotic cell death by activating protein kinase Cdelta and acid sphingomyelinase through a 67 kDa laminin receptor in multiple myeloma cells. AB - EGCG [(-)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCdelta (protein kinase Cdelta) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCdelta and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells. PMID- 22257160 TI - Physical and functional interactions of Caenorhabditis elegans WRN-1 helicase with RPA-1. AB - The Caenorhabditis elegans Werner syndrome protein, WRN-1, a member of the RecQ helicase family, has a 3'-5' DNA helicase activity. Worms with defective wrn-1 exhibit premature aging phenotypes and an increased level of genome instability. In response to DNA damage, WRN-1 participates in the initial stages of checkpoint activation in concert with C. elegans replication protein A (RPA-1). WRN-1 helicase is stimulated by RPA-1 on long DNA duplex substrates. However, the mechanism by which RPA-1 stimulates DNA unwinding and the function of the WRN-1 RPA-1 interaction are not clearly understood. We have found that WRN-1 physically interacts with two RPA-1 subunits, CeRPA73 and CeRPA32; however, full-length WRN 1 helicase activity is stimulated by only the CeRPA73 subunit, while the WRN 1(162-1056) fragment that harbors the helicase activity requires both the CeRPA73 and CeRPA32 subunits for the stimulation. We also found that the CeRPA73(1-464) fragment can stimulate WRN-1 helicase activity and that residues 335-464 of CeRPA73 are important for physical interaction with WRN-1. Because CeRPA73 and the CeRPA73(1-464) fragment are able to bind single-stranded DNA (ssDNA), the stimulation of WRN-1 helicase by RPA-1 is most likely due to the ssDNA binding activity of CeRPA73 and the direct interaction of WRN-1 and CeRPA73. PMID- 22257162 TI - Established preblastocyst- and blastocyst-derived ES cell lines have highly similar gene expression profiles, despite their differing requirements for derivation culture conditions. AB - The efficiency of embryonic stem (ES) cell derivation relies on an optimized culture medium and techniques for treating preimplantation stage embryos. Recently, ES cell derivation from the preblastocyst developmental stage was reported by removing the zona pellucida from embryos of the most efficient strain for ES cell derivation (129Sv) during early preimplantation. Here, we showed that ES cells can be efficiently derived and maintained in a modified medium (MEMalpha), from preblastocysts of a low-efficiency mouse strain (a hybrid consisting of 50% B6, 25% CBA, and 25% DBA). Preblastocyst-derived ES cell lines were normal in terms of pluripotency-related protein expression, and chromosome number. Also, preblastocyst-derived ES cell lines from various culture conditions showed pluripotency in vivo through teratoma analysis. Interestingly, ES cell lines produced from preblastocysts and blastocysts, regardless of the derivation culture conditions, are nearly indistinguishable by their global gene expression profiles. PMID- 22257163 TI - Gene expression profile normalization in cloned mice by trichostatin A treatment. AB - Cloning mammals by somatic cell nuclear transfer (SCNT) has become an established procedure, but the success rate remains low and gene expression abnormalities are also observed. In addition, SCNT pups exhibited an abnormal gene expression profile with a high degree of heterogeneity among individuals. Recently, we reported that somatic clones treated with trichostatin A (TSA) exhibited a significantly improved success rate, probably due to its effects on chromatin remodeling and histone modification in early embryos. Here we show that the TSA treatment also improves the long-term consistency of genome-wide gene expression regulation: the total number of genes commonly exhibiting up- or downregulation in the TSA clone pups decreased to half of the conventional SCNT pups, and the variation among individuals observed in the SCNT pups was also reduced to the level of the pups produced by the intracytoplasmic sperm injection (ICSI) method. Interestingly, the total gene expression profile of the TSA clones came to resemble that of the ICSI pups. PMID- 22257164 TI - Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. AB - BACKGROUND: The clinical use of frozen plasma (FP) continues to increase, both in prophylactic and in therapeutic settings. In 2004, a systematic review of all published randomized controlled trials (RCTs) revealed a lack of evidence that supported the efficacy of FP use. This is an update that includes all new RCTs published since the original review. STUDY DESIGN AND METHODS: Trials involving transfusion of FP up to July 2011 were identified from searches of MEDLINE, EMBASE, CINAHL, The Cochrane Library, and the UKBTS/SRI Transfusion Evidence Library. Methodologic quality was assessed. The primary outcome measure was the effect of FP on survival. RESULTS: Twenty-one new trials were eligible for inclusion. These covered prophylactic and therapeutic FP use in liver disease, in cardiac surgery, for warfarin anticoagulation reversal, for thrombotic thrombocytopenic purpura treatment, for plasmapheresis, and in other settings, including burns, shock, and head injury. The largest number of recent RCTs were conducted in cardiac surgery; meta-analysis showed no significant difference for FP use for the outcome of 24-hours postoperative blood loss (weighted mean difference, -35.24 mL; 95% confidence interval, -84.16 to 13.68 mL). Overall, there was no significant benefit for FP use across all the clinical conditions. Only two of the 21 trials fulfilled all the criteria for quality assessment. CONCLUSION: Combined with the 2004 review, 80 RCTs have investigated FP with no consistent evidence of significant benefit for prophylactic and therapeutic use across a range of indications evaluated. There has been little improvement in the overall methodologic quality of RCTs conducted in the past few years. PMID- 22257165 TI - Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections. AB - The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents. PMID- 22257166 TI - Improvement of the modeling of the low-temperature oxidation of n-butane: study of the primary reactions. AB - This paper revisits the primary reactions involved in the oxidation of n-butane from low to intermediate temperatures (550-800 K) including the negative temperature coefficient (NTC) zone. A model that was automatically generated is used as a starting point and a large number of thermochemical and kinetic data are then re-estimated. The kinetic data of the isomerization of alkylperoxy radicals giving (*)QOOH radicals and the subsequent decomposition to give cyclic ethers has been calculated at the CBS-QB3 level of theory. The newly obtained model allows a satisfactory prediction of experimental data recently obtained in a jet-stirred reactor and in rapid compression machines. A considerable improvement of the prediction of the selectivity of cyclic ethers is especially obtained compared to previous models. Linear and global sensitivity analyses have been performed to better understand which reactions are of influence in the NTC zone. PMID- 22257167 TI - Release property and antioxidant effectiveness of tocopherol-incorporated LDPE/PP blend films. AB - Low-density polyethylene (LDPE)/polypropylene (PP) blend films in various blending ratios containing 3000 mg kg-1 of tocopherol were manufactured by an extrusion process. Tocopherol release properties were characterised and correlated with antioxidant effectiveness in retarding the oxidation of linoleic acid contacting the films at 40 degrees C. The conditions without tocopherol (control) and with instant tocopherol addition corresponding to the amount included in the films were also prepared and compared with the film-contacting solutions. The effect of tocopherol inclusion and the blending ratio on their physical properties was also examined. A wide range of tocopherol diffusivity in 6.6 * 10-16-4.6 * 10-14m2 s-1 were obtained by blend films. As PP content increases, the diffusivity decreased sharply at the beginning and levelled off later. The slower release of tocopherol in LDPE/PP blend films corresponding to lower tocopherol diffusivity retained the higher tocopherol concentration in the linoleic acid system providing better antioxidant effectiveness of the extended induction period in oxidation. The tocopherol inclusion reduced tensile strength and transparency significantly in an affordable range with higher tensile strength given by a higher PP ratio. LDPE/PP blending can be a useful tool to modulate the release profile of tocopherol and thus the antioxidant effectiveness of the tocopherol-incorporated antioxidant packaging film. PMID- 22257168 TI - Singlet exciton fission-sensitized infrared quantum dot solar cells. AB - We demonstrate an organic/inorganic hybrid photovoltaic device architecture that uses singlet exciton fission to permit the collection of two electrons per absorbed high-energy photon while simultaneously harvesting low-energy photons. In this solar cell, infrared photons are absorbed using lead sulfide (PbS) nanocrystals. Visible photons are absorbed in pentacene to create singlet excitons, which undergo rapid exciton fission to produce pairs of triplets. Crucially, we identify that these triplet excitons can be ionized at an organic/inorganic heterointerface. We report internal quantum efficiencies exceeding 50% and power conversion efficiencies approaching 1%. These findings suggest an alternative route to circumvent the Shockley-Queisser limit on the power conversion efficiency of single-junction solar cells. PMID- 22257170 TI - Ameliorative effects of curcumin against acute cadmium toxicity on male reproductive system in rats. AB - The aim of the present study was to investigate the ameliorative effect of curcumin (CMN) against acute cadmium chloride (CdCl(2)) toxicity on male reproductive system in rats. CdCl(2) is known to be a heavy metal and potential environmental pollutant. For this purpose, 28 rats were equally divided into four groups; the first group was kept as control and given distilled water and corn oil as carrier. In second and third groups, CdCl(2) and CMN were administered at the dose with 1 mg kg(-1) day(-1) and 100 mg kg(-1) for 3 days respectively. CdCl(2) and CMN were given together at the same doses in the fourth group. It was determined that acute CdCl(2) exposure caused a significant reproductive damage via increased oxidative stress (increased TBARS levels and decreased SOD, CAT, GPx and GSH levels), histological alterations (necrosis, oedema etc.) and spermatological damage (decreased sperm motility and sperm concentration and increased abnormal sperm rate) in male rats. However, CMN treatment partially reversed these toxic effects of CdCl(2) on the reproductive system. In conclusion, our results show that acute exposure of CdCl(2) may lead to infertility, and CMN could prevent and reverse hazardous effects of CdCl(2) to some degree. Thus, CMN may be useful for the prevention of CdCl(2)-induced reproductive damage. PMID- 22257169 TI - Copper-catalyzed enantioselective intramolecular alkene amination/intermolecular Heck-type coupling cascade. AB - Enantioselective copper-catalyzed cyclization of gamma-alkenylsulfonamides and a delta-alkenylsulfonamide in the presence of a range of vinyl arenes results in variously functionalized 2-substituted chiral nitrogen heterocycles via a formal alkene C-H functionalization process. Application of this reaction to the concise synthesis of a 5-HT(7) receptor antagonist is demonstrated. PMID- 22257171 TI - Novel polypropylene/inorganic fullerene-like WS2 nanocomposites containing a beta nucleating agent: isothermal crystallization and melting behavior. AB - The isothermal crystallization and subsequent melting behavior of isotactic polypropylene (iPP) nucleated with different nucleating agents (NAs) are investigated. Tungsten disulfide (IF-WS(2)) and N,N'-dicyclohexyl-2,6-naphthalene (NJ) and dual-additive mixtures are introduced into an iPP matrix to generate new materials that exhibit variable alpha- and beta-polymorphism. As shown in previous work, small amounts of IF-WS(2) or NJ have a nucleating effect during the crystallization of iPP. However, the isothermal crystallization and melting behavior of iPP nucleated by dual alpha(IF-WS(2))/beta(NJ) additive systems are dependent on both the NA composition balance and the crystallization temperature. In particular, our results demonstrate that it is possible to obtain any alpha phase to beta-phase content ratio by controlling the composition of NAs under appropriate isothermal crystallization conditions. The nucleating behavior of the additives can be illustrated by competitive nucleation, and the correlation between crystallization and melting temperatures and relative alpha- and beta crystals content in iPP in the nanocomposites is discussed. PMID- 22257173 TI - New poly(N,N-dimethylaminoethyl methacrylate)/polyvinyl alcohol copolymer coated QCM sensor for interaction with CWA simulants. AB - A series of copolymers, namely, poly (N, N-dimethylaminoethyl methacrylate)/polyvinyl alcohol (PDMAEMA/PVA), have been obtained through emulsion polymerization. Then, a synthetic copolymer (PDMAEMA/PVA)-coated quartz crystal microbalance sensor (PC-QCM) has been developed to apply in evaluating the interactions between the copolymers and three chemical warfare agent (CWA) simulants, such as diethyl chlorophosphate (DCP), 2,2'-dichlorodiethyl ether (DCE), and dimethyl methylphosphonate (DMMP). The results from the QCM measurements indicate that the PDMAEMA/PVA copolymers not only directly degradate sarin simulants (DCP and DMMP), but also show obvious absorption in mustard gas simulant (DCE). In addition, the mass of degraded DCP by the copolymer is calculated on the basis of resonance frequency shifts (Deltaf) of quartz crystal in the QCM sensor, which may be applied to quantitatively evaluate the reactivity of PDMAEMA/PVA copolymers. Furthermore, the fluorescence of PDMAEMA/PVA copolymers in DMSO solution gradually quenched with the addition of DCP solution, which can be explained that the reactions take place between DCP and reactive groups of PDMAEMA/PVA copolymers. Thus, this PDMAEMA/PVA membrane may be a good candidate for the application in chemical warfare protective materials, and this new PC-QCM technique shows potential application in the rapid, real-time, and sensitive detection of the chemical warfare agents and hazardous chemicals. PMID- 22257172 TI - Prior antiplatelet use and cardiovascular outcomes in patients presenting with acute coronary syndromes. AB - BACKGROUND: Although antiplatelet therapy effectively reduces ischemic events, the cardiovascular (CV) outcome in some cases is still unpredictable. OBJECTIVE: The objective of this study was to evaluate the impact of prior single or dual antiplatelet (PAP) use in patients presenting with acute coronary syndromes (ACS). METHODS: Data were collected from the 2nd Gulf Registry of Acute Coronary Events between October 2008 and June 2009. Patients were grouped according to whether they were PAP users or not (NAP). Patients' characteristics and outcomes were analyzed and compared. Mortality was assessed at 1 and 12 months. RESULTS: Among 7827 consecutive ACS patients, 41% were PAP users (70% aspirin, 1% clopidogrel, and 29% dual antiplatelet agents). In comparison with NAP use, PAP use was associated with a higher rate of co-morbidities, atypical presentation, severe left ventricular dysfunction, three-vessel disease, and a high GRACE risk score. After adjustment for relevant covariates, PAP use was an independent predictor for recurrent ischemia in unstable angina (odds ratio [OR] 1.7; 95% CI 1.17, 2.57) and non-ST-elevation myocardial infarction (NSTEMI) [OR 1.9; 95% CI 1.38, 2.65] and for heart failure in NSTEMI (OR 1.5; 95% CI 1.11, 2.15) and STEMI (OR 1.4; 95% CI 1.08, 1.93). Although PAP use was associated with high mortality in STEMI and NSTEMI, it was not an independent predictor for mortality. Among PAP patients, percutaneous coronary intervention independently reduced the risk of hospital (adjusted OR 0.25; 95% CI 0.20, 0.32), 1-month (OR 0.31; 95% CI 0.26, 0.37), and 12-month mortality (OR 0.28; 95% CI 0.24, 0.33). CONCLUSION: PAP use identified a high-risk population across the ACS spectrum. Early coronary revascularization may improve CV outcomes in these patients. PMID- 22257174 TI - When, what, and how much to reward in reinforcement learning-based models of cognition. AB - Reinforcement learning approaches to cognitive modeling represent task acquisition as learning to choose the sequence of steps that accomplishes the task while maximizing a reward. However, an apparently unrecognized problem for modelers is choosing when, what, and how much to reward; that is, when (the moment: end of trial, subtask, or some other interval of task performance), what (the objective function: e.g., performance time or performance accuracy), and how much (the magnitude: with binary, categorical, or continuous values). In this article, we explore the problem space of these three parameters in the context of a task whose completion entails some combination of 36 state-action pairs, where all intermediate states (i.e., after the initial state and prior to the end state) represent progressive but partial completion of the task. Different choices produce profoundly different learning paths and outcomes, with the strongest effect for moment. Unfortunately, there is little discussion in the literature of the effect of such choices. This absence is disappointing, as the choice of when, what, and how much needs to be made by a modeler for every learning model. PMID- 22257175 TI - EAACI consensus statement for investigation of work-related asthma in non specialized centres. AB - Work-related asthma (WRA) is a relevant problem in several countries, is cause of disability and socioeconomic consequences for both the patient and the society and is probably still underdiagnosed. A correct diagnosis is extremely important to reduce or limit the consequences of the disease. This consensus document was prepared by a EAACI Task Force consisting of an expert panel of allergologists, pneumologists and occupational physicians from different European countries. This document is not intended to address in detail the full diagnostic work-up of WRA, nor to be a formal evidence-based guideline. It is written to provide an operative protocol to allergologists and physicians dealing with asthma useful for identifying the subjects suspected of having WRA to address them to in-depth investigations in a specialized centre. No evidence-based system could be used because of the low grade of evidence of published studies in this area, and instead, 'key messages' or 'suggestions' are provided based on consensus of the expert panel members. PMID- 22257176 TI - Low testosterone level predicts prostate cancer in re-biopsy in patients with high grade prostatic intraepithelial neoplasia. AB - What's known on the subject? and What does the study add? High grade prostatic intraepithelial neoplasia (HGPIN) is a risk factor for prostate cancer (PCa), but only multifocality is an indication for early rebiopsy. Other risk factors for PCa development from HGPIN remain unknown. PCa is related to testosterone. Testosterone has been proven to be linked to PCa detection and poor prognosis PCa. This study shows that low free and bioavailable testosterone levels are associated with an increased risk of PCa in a rebiopsy after HGPIN diagnosis. Men with low testosterone levels and HGPIN could therefore be considered a high-risk cohort for developing PCa. OBJECTIVE: To determine the relevance of the hormonal profile of patients with high grade prostatic intraepithelial neoplasia (HGPIN) and its relationship to prostate cancer (PCa) in rebiopsy. PATIENTS AND METHODS: We prospectively analysed 82 consecutive patients with a diagnosis of HGPIN without PCa in a prostate biopsy between September 2007 and December 2009. Of these 82 patients, 45 underwent rebiopsy and their hormonal profile was determined (testosterone and sex hormone-binding globulin [SHBG]) as part of our clinical protocol. Patient age, PSA level, prostate volume, PSA density, testosterone, free testosterone, bioavailable testosterone and SHBG were recorded prospectively. A comparative study between those patients with a positive rebiopsy and those with a negative rebiopsy was performed. RESULTS: We found that free testosterone (P = 0.04), bioavailable testosterone (P = 0.04) and SHBG (P = 0.02) were significantly associated with a positive rebiopsy. Other variables such as age (P = 0.745), PSA level (P = 0.630), prostate volume (P = 0.690), PSA density (P = 0.950), testosterone (P = 0.981) and prostatic intraepithelial neoplasia multifocality (P = 0.777) were not associated with the presence of adenocarcinoma in the rebiopsy. CONCLUSIONS: Patients with adenocarcinoma of the prostate after a diagnosis of HGPIN have higher SHBG levels and lower calculated free testosterone levels than patients with a negative rebiopsy. Testosterone levels might be a useful indication for rebiopsy after HGPIN diagnosis. PMID- 22257178 TI - Spatially structured populations with a low level of cryptic diversity in European marine Gastrotricha. AB - Species of the marine meiofauna such as Gastrotricha are known to lack dispersal stages and are thus assumed to have low dispersal ability and low levels of gene flow between populations. Yet, most species are widely distributed, and this creates a paradox. To shed light on this apparent paradox, we test (i) whether such wide distribution may be due to misidentification and lumping of cryptic species with restricted distributions and (ii) whether spatial structures exist for the phylogeography of gastrotrichs. As a model, we used the genus Turbanella in NW Europe. DNA taxonomy using a mitochondrial and a nuclear marker supports distinctness of four traditional species (Turbanella ambronensis, T. bocqueti, T. mustela and T. cornuta) and provides evidence for two cryptic species within T. hyalina. An effect of geography on the within-species genetic structure is indeed present, with the potential for understanding colonization processes and for performing phylogeographic inference from microscopic animals. On the other hand, the occurrence of widely distributed haplotypes indicates long-distance dispersal as well, despite the assumed low dispersal ability of gastrotrichs. PMID- 22257179 TI - Richness and diversity of helminth communities in the Japanese grenadier anchovy, Coilia nasus, during its anadromous migration in the Yangtze River, China. AB - To determine the relationship between the species richness, diversity of helminth communities, and migration distance during upward migration from coast to freshwater, helminth communities in the anadromous fish Coilia nasus were investigated along the coast of the East China Sea, the Yangtze Estuary, and 3 localities on the Yangtze River. Six helminth species were found in 224 C. nasus . Changes in salinity usually reduced the survival time of parasites, and thus the number of helminth species and their abundance. Except for the 2 dominant helminths, the acanthocephalan Acanthosentis cheni and the nematode Contracaecum sp., mean abundance of other 4 species of helminths was rather low (<1.0) during the upward migration in the Yangtze River. Mean abundance of the 2 dominant helminths peaked in the Yangtze Estuary and showed no obvious decrease among the 3 localities on the Yangtze River. Mean species richness, Brillouin's index, and Shannon index were also highest in the estuary (1.93 +/- 0.88, 0.28 +/- 0.25, and 0.37 +/- 0.34, respectively) and did not exhibit marked decline at the 3 localities on the Yangtze River. A significant negative correlation was not seen between the similarity and the geographical distance (R = -0.5104, P = 0.1317). The strong salinity tolerance of intestinal helminths, relatively brief stay in the Yangtze River, and large amount of feeding on small fish and shrimp when commencing spawning migration perhaps were responsible for the results. PMID- 22257180 TI - Proteoglycans of uterine fibroids and keloid scars: similarity in their proteoglycan composition. AB - Fibrosis is the formation of excess and abnormal fibrous connective tissue as a result of either a reparative or reactive process. A defining feature of connective tissue is its extracellular matrix, which provides structural support and also influences cellular activity. Two common human conditions that result from fibrosis are uterine fibroids (leiomyomas) and keloid scars. Because these conditions share a number of similarities and because their growth is due primarily to excessive extracellular matrix deposition, we compared the proteoglycans of uterine fibroids and keloid scars with corresponding normal tissues. Our analysis indicates that uterine fibroids and keloid scars contain higher amounts of glycosaminoglycans relative to normal myometrium and normal adult skin respectively. Proteoglycan composition is also different in the fibrotic tissues. Compared with unaffected tissues, uterine fibroids and keloid scars contain higher relative amounts of versican and lower relative amounts of decorin. There is also evidence for a higher level of versican catabolism in the fibrotic tissues compared with unaffected tissues. These qualitative and quantitative proteoglycan differences may play a role in the expansion of these fibroses and in their excessive matrix deposition and matrix disorganization, due to effects on cell proliferation, TGF (transforming growth factor)-beta signalling and/or collagen fibril formation. PMID- 22257181 TI - Cardiac autonomic dysfunction in anabolic steroid users. AB - This study aimed to evaluate if androgenic-anabolic steroids (AAS) abuse may induce cardiac autonomic dysfunction in recreational trained subjects. Twenty-two men were volunteered for the study. The AAS group (n = 11) utilized AAS at mean dosage of 410 +/- 78.6 mg/week. All of them were submitted to submaximal exercise testing using an Astrand-Rhyming protocol. Electrocardiogram (ECG) and respired gas analysis were monitored at rest, during, and post-effort. Mean values of VO2 , VCO2 , and VE were higher in AAS group only at rest. The heart rate variability variables were calculated from ECG using MATLAB-based algorithms. At rest, AAS group showed lower values of the standard deviation of R-R intervals, the proportion of adjacent R-R intervals differing by more than 50 ms (pNN50), the root mean square of successive differences (RMSSD), and the total, the low frequency (LF) and the high-frequency (HF) spectral power, as compared to Control group. After submaximal exercise testing, pNN50, RMSSD, and HF were lower, and the LF/HF ratio was higher in AAS group when compared to control group. Thus, the use of supraphysiological doses of AAS seems to induce dysfunction in tonic cardiac autonomic regulation in recreational trained subjects. PMID- 22257182 TI - Iodine emission in the presence of humic substances at the water's surface. AB - Humic substances that preferentially adsorb at the air/water interfaces of water or aerosols consist of both fulvic and humic acid. To investigate the chemical reactivity for the heterogeneous reaction of gaseous ozone, O(3)(g), with aqueous iodide, I(-)(aq), in the presence of standard fulvic acid, humic acid, or alcohol, cavity ring-down spectroscopy was used to detect gaseous products, iodine, I(2)(g) and an iodine monoxide radical, IO(g). Fulvic acid enhanced the I(2)(g) production yield, but not the IO(g) yield. Humic acid, n-hexanol, n heptanol, and n-octanol did not affect the yields of I(2)(g) or IO(g). We can infer that the carboxylic group contained in fulvic acid promotes the I(2)(g) emission by supplying the requisite interfacial protons more efficiently than water on its surface. PMID- 22257184 TI - Editorial. reagan and the environment. PMID- 22257185 TI - Letters. Environmental theology. PMID- 22257186 TI - Currents. PMID- 22257187 TI - Outlook. PMID- 22257189 TI - Environmental conflict resolution. PMID- 22257188 TI - Regulatory Alert: Clean Air Act: non-compliance penalties. PMID- 22257190 TI - Organic Pollutants in Water: Identification and analysis. PMID- 22257194 TI - Multifilter technique for examination of the size distribution of the natural aerosol in the submicrometer size range. PMID- 22257192 TI - New literature. PMID- 22257195 TI - Ferrate(VI) oxidation of nitrilotriacetic acid. PMID- 22257196 TI - Organic compounds produced by the aqueous free-chlorine-activated carbon reaction. PMID- 22257197 TI - Reaction of free chlorine with humic substances before and after adsorption on activated carbon. PMID- 22257199 TI - Investigations of solvent-regenerable carbon-sulfur surface compounds for phenol removal in a packed column. PMID- 22257198 TI - Scanning electron microscope study of iron-containing particles on foxtail. PMID- 22257200 TI - Determination of mercury emissions from a municipal incinerator. PMID- 22257201 TI - Polychlorinated biphenyls in sediments of the tidal Hudson River, New York. PMID- 22257203 TI - Comparison of three methods for measuring suspended-particulate concentrations. PMID- 22257202 TI - New screening methods for acidic toxic substances using negative chemical ionization mass spectrometry. Tetrachloroterephthalate in human urines. PMID- 22257204 TI - Free, proteinaceous, and humic-bound amino acids in river water containing high concentrations of aquatic humus. PMID- 22257205 TI - Colloidal quantum dot photovoltaics: the effect of polydispersity. AB - The size-effect tunability of colloidal quantum dots enables facile engineering of the bandgap at the time of nanoparticle synthesis. The dependence of effective bandgap on nanoparticle size also presents a challenge if the size dispersion, hence bandgap variability, is not well-controlled within a given quantum dot solid. The impact of this polydispersity is well-studied in luminescent devices as well as in unipolar electronic transport; however, the requirements on monodispersity have yet to be quantified in photovoltaics. Here we carry out a series of combined experimental and model-based studies aimed at clarifying, and quantifying, the importance of quantum dot monodispersity in photovoltaics. We successfully predict, using a simple model, the dependence of both open-circuit voltage and photoluminescence behavior on the density of small-bandgap (large diameter) quantum dot inclusions. The model requires inclusion of trap states to explain the experimental data quantitatively. We then explore using this same experimentally tested model the implications of a broadened quantum dot population on device performance. We report that present-day colloidal quantum dot photovoltaic devices with typical inhomogeneous linewidths of 100-150 meV are dominated by surface traps, and it is for this reason that they see marginal benefit from reduction in polydispersity. Upon eliminating surface traps, achieving inhomogeneous broadening of 50 meV or less will lead to device performance that sees very little deleterious impact from polydispersity. PMID- 22257206 TI - Cu(II) and Mn(II) complexes containing macroacyclic ligand: synthesis, DNA binding, and cleavage studies. AB - The two new metal complexes of Cu(II) and Mn(II) containing macroacyclic ligand of the type [Cu(hpn)](PF(6))(2) (1) and [Mn(hpn)](PF(6))(2) (2) [where hpn = [1 {[2-{[2-hydroxynaphthalen-1-yl)methylidine]amino}phenyl)imino]methyl}naphthalene 2-ol]] have been synthesized and characterized by employing analytical and spectral methods. The DNA binding properties of the complexes with calf thymus DNA were studied by using absorption spectra and viscosity measurements, as well as thermal denaturation experiments. The absorption spectra indicated that the complexes intercalate tightly between the base pairs of the DNA with intrinsic DNA binding constants of 1.8 * 10(4) M(-1) for (1) and 3.7 * 10(4) M(-1) for (2) in 5 mM Tris-HCl/50 mM NaCl buffer at pH 7.2, respectively. The enhancement in the relative viscosity of DNA on binding to the ligand supports the proposed DNA binding modes. The oxidative cleavage activity of complexes (1) and (2) were carried out on double-stranded pUC19 circular plasmid DNA using gel electrophoresis. The complexes show significant nuclease activity. PMID- 22257207 TI - Isolation and characterization of a murine P388 leukemia line resistant to thiarabine. AB - A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias. PMID- 22257208 TI - Effects of locked nucleic acid substitutions on the stability of oligonucleotide hairpins. AB - An understanding of the stability of nucleic acid folding is critical for applications involving RNA viruses, small molecule-RNA binding, and therapeutics, for example. To explore factors that affect this stability, hairpins made from oligonucleotides containing both a GAAA tetraloop and three to five complements in the stem have been used as models where locked nucleic acids (LNAs) have been substituted into the sequence. UV spectroscopy was used to obtain melting curves in 20% by volume formamide, and the enthalpies and entropies of melting were determined. Although LNA substitutions typically increase the stability of a hybrid, we have found a decrease in stability for DNA and RNA GAAA hairpins when LNA is substituted into the loop. Tetraloops synthesized from natural bases show higher enthalpies and entropies of melting compared to the LNA substituted sequences indicating that LNA substitutions can destabilize a hairpin but stabilize the corresponding double stranded structure. PMID- 22257209 TI - 5-substituted pyrimidine L-2'-deoxyribonucleosides: synthetic, quantum chemical, and NMR studies. AB - As a part of an ongoing medicinal chemistry, we report here the synthesis and structure evaluation of 1-(2-deoxy-3,5-di-O-acetylpentofuranosyl)-5-[(3-methyl-5 oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-ylidene) pyrimidine-2,4(1H,3H)-dione 5 and 5-[bis(3-methyl-5-oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-yl)methyl-1-(2-deoxy-3,5 di-O-acetylpentofuranosyl)pyrimidine-2,4(1H,3H)-dione 6 derived from 3',5'-di-O acetyl-5-formyl-2'-deoxy-beta-L-uridine 1. Base hydrolysis of compounds 1 and 6 furnished their deacetylated analogues in good yields, whereas hydrolysis of 5 was troublesome. Structural features of these molecules are discussed by NMR spectra analyses and density functional theory quantum chemical calculations. The newly synthesized L-analogues show no significant activity against vaccinia and cowpox viruses. PMID- 22257210 TI - A tetra-primer amplification refractory mutation system-polymerase chain reaction for the detection of rs8099917 IL28B genotype. AB - Two single nucleotide polymorphisms (SNP, rs8099917, rs12979860) near the IL28B gene have been illustrated as outcome predictors of hepatitis C virus (HCV) treatment with pegylated interferon/ribavirin. The aim of the present study was to design a simple tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) for the evaluation of the rs8099917 IL28B gene polymorphism. We efficiently designed a T-ARMS-PCR for detection of rs8099917 IL28B. Using this method, we genotyped 83 subjects with NAFLD (nonalcoholic fatty liver disease) and 93 healthy subjects. No significant differences were found in allelic and genotypic frequencies of rs8099917 IL28B gene polymorphism between NAFLD subjects and controls. The frequency of minor allele (G allele) was 0.13 in healthy and 0.19 in NAFLD subjects. In conclusion, we designed a simple, inexpensive, and reproducible T-ARMS-PCR for detection of rs8099917 IL28B polymorphism which can be used for routine assay. In addition, we found that rs8099917 polymorphism is not a risk factor for predisposition to NAFLD in a sample of Iranian population. Larger studies with different ethnics are required to validate our findings. PMID- 22257211 TI - The hydrolysis of 5'-CAP dinucleotide analogs: catalysis by bi- and terpyridine complexes of Cu2+ and Zn2+ ions. AB - The kinetics of the hydrolysis of P(1)-(7-methylguanosinyl-5') P(3)-(guanosinyl 5') triphosphate (m(7)GpppG), P(1)-(7-methylguanosinyl-5') P(4)-(guanosinyl-5') tetraphosphate (m(7)GppppG), and diadenosine 5', 5'( ')-P(1),P(3) -triphosphate (ApppA) in the presence of several Cu(2+) or Zn(2+) ions complexed with bi- or terpyridine has been studied at pH 8.0 and 60 degrees C. Time-dependent product distributions at various metal complex concentrations have been determined by capillary zone electrophoresis and reversed-phase high performance liquid chromatography. The results show that the predominant hydrolytic reaction is the cleavage of 5',5'-oligophosphate bridge, with Cu(2+) complexes being approximately 15-fold more efficient catalysts than Zn(2+) chelates. In addition, the effect of metal ions complexes at pH 7.0 and 8.0 on the imidazole ring opening in m(7)Gua mononucleotides has been studied. The influence of Cu(2+) complexes on imidazole ring cleavage of mononucleotides is modest, whereas Zn(2+) complexes are almost inactive. PMID- 22257212 TI - Synthesis of novel aza-analogues of tiazofurin with 2-[5,5 bis(hydroxymethyl)pyrrolidin-2-yl] framework as sugar mimic. AB - The novel aza-analogues of tiazofurin (TZF) with 2-[5,5 bis(hydroxymethyl)pyrrolidin-2-yl] moiety, as sugar mimic, were synthesized from O,O-cyclohexylidene derivative of 4,4-bis(hydroxymethyl)-4-nitrobutanal in multi gram scale. The synthetic route consisted of three stages: (i) the synthesis of corresponding derivative of 5,5-bis(hydroxymethyl)pyrrolidine-2-carbonitrile, (ii) the construction of ethyl thiazole-2-carboxylate part by the conversion of the pyrrolidine-2-carbonitrile into the N-trifluoroacetyl derivative followed by cyclocondensation with L-cysteine ethyl ester and then by dehydrogenation, and (iii) the final transformation of the ethyl thiazole-4-carboxylate into the aza analogues of TZF. The TZF aza-analogues were evaluated for their antiviral activities in cell-culture-based assays. PMID- 22257213 TI - Discovery and development of spleen tyrosine kinase (SYK) inhibitors. PMID- 22257214 TI - Effect-directed assessment of the bioaccumulation potential and chemical nature of Ah receptor agonists in crude and refined oils. AB - Recent studies have indicated that in addition to narcosis certain chemicals in crude oils and refined petroleum products may induce specific modes of action, such as aryl hydrocarbon receptor (AhR) agonism. The risks these toxic compounds pose to organisms depend on internal exposure levels, as driven by the chemicals' bioaccumulation potential. Information on this potential however is lacking, as the chemicals' identity mostly is unknown. This study showed that AhR agonists bioaccumulate from oil-spiked sediments into aquatic worms and persist in the worms for at least several weeks. Chemical fractionations of eight pure oils into saturates, aromatics, resins, and asphaltenes (SARA), followed by effect-directed analyses using in vitro reporter gene assays revealed that the agonists predominantly are aromatic and resin-like chemicals. Some of the compounds were easily metabolized in vitro, while others were resistant to biotransformation. HPLC-assisted hydrophobicity profiling subsequently indicated that the AhR-active chemicals had a high to extremely high bioaccumulation potential, considering their estimated logK(ow) values of 4 to >10. Most of the AhR agonism, however, was assigned to compounds with logK(ow) of 5-8. These compounds were present mainly in the mid to high boiling point fractions of the oils (C(14)-C(32) alkane range), which are usually not being considered (the most) toxic in current risk assessment. The fractionations further revealed considerable oil and fraction dependent antagonism in pure oils and SARA fractions. The results of this study clearly demonstrate that crude oils and refined petroleum products contain numerous compounds that can activate the AhR and which because of their likely persistence and extremely high bioaccumulation potential could be potential PBT (persistent, bioaccumulative and toxic) or vPvB (very persistent and very bioaccumulative) substance candidates. Many chemicals were identified by GC-MS, but the responsible individual compounds could not be exactly identified in the complex mixtures of thousands of compounds. Because this obstructs a classical PBT risk assessment, our results advocate an adapted risk assessment approach for complex mixtures in which low concentrations of very potent compounds are responsible for mixture effects. PMID- 22257215 TI - Anti-apoptotic and anti-oxidant effects of grape seed proanthocyanidin extract in preventing cyclosporine A-induced nephropathy. AB - AIM: Although the pathogenesis of cyclosporine (CsA) nephropathy is not completely understood, it is attributed to oxidative damage and apoptosis. Grape seed proanthocyanidin extract (GSPE) is a molecule with anti-oxidant and anti apoptotic properties. Our aim was to demonstrate the effects of GSPE in preventing CsA nephropathy. METHODS: Twenty-four Sprague-Dawley rats were divided into four groups. The control, GSPE, CsA and CsA+GSPE groups were given 1 mL olive oil, 100 mg/kg GSPE, 25 mg/kg CsA and 100 mg/kg GSPE+25 mg/kg CsA, respectively. On day 21, blood samples were taken for blood urea nitrogen (BUN), creatinine and CsA levels, and renal tissue was used for total oxidant system (TOS), total anti-oxidant system (TAS), oxidative stress index (OSI) and malondialdehyde (MDA) measurements. In addition to renal histopathology, apoptosis staining was performed on renal tissue. RESULTS: The BUN, creatinine, TOS, OSI, MDA, histopathological score, and apoptotic index exhibited increases in the CsA group. In the CsA+GSPE group, however, BUN, creatinine, OSI, MDA, renal histopathological score and apoptotic index (AI) decreased and TAS levels increased. In addition, there was no difference between the CsA and CsA+GSPE groups with regard to CsA levels. CONCLUSION: We demonstrated that GSPE prevents CsA nephropathy and that this effect is achieved by anti-apoptotic and anti oxidant activity. We also achieved a significant recovery in kidney functions without affecting CsA plasma levels. PMID- 22257216 TI - Classification and structural analysis of live and dead Salmonella cells using Fourier transform infrared spectroscopy and principal component analysis. AB - Fourier transform infrared spectroscopy (FT-IR) was used to detect Salmonella Typhimurium and Salmonella Enteritidis food-borne bacteria and to distinguish between live and dead cells of both serotypes. Bacteria cells were prepared in 10(8) cfu/mL concentration, and 1 mL of each bacterium was loaded individually on the ZnSe attenuated total reflection (ATR) crystal surface (45 degrees ZnSe, 10 bounces, and 48 mm * 5 mm effective area of analysis on the crystal) and scanned for spectral data collection from 4000 to 650 cm(-1) wavenumber. Analysis of spectral signatures of Salmonella isolates was conducted using principal component analysis (PCA). Spectral data were divided into three regions such as 900-1300, 1300-1800, and 3000-2200 cm(-1) based on their spectral signatures. PCA models were developed to differentiate the serotypes and live and dead cells of each serotype. Maximum classification accuracy of 100% was obtained for serotype differentiation as well as for live and dead cells differentiation. Soft independent modeling of class analogy (SIMCA) analysis was carried out on the PCA model and applied to validation sample sets. It gave a predicted classification accuracy of 100% for both the serotypes and its live and dead cells differentiation. The Mahalanobis distance calculated in three different spectral regions showed maximum distance for the 1800-1300 cm(-1) region, followed by the 3000-2200 cm(-1) region, and then by the 1300-900 cm(-1) region. It showed that both of the serotypes have maximum differences in their nucleic acids, DNA/RNA backbone structures, protein, and amide I and amide II bands. PMID- 22257217 TI - Anchoring molecular chromophores to colloidal gold nanocrystals: surface-enhanced Raman evidence for strong electronic coupling and irreversible structural locking. AB - High-affinity anchoring groups such as isothiocyanate (ITC, -N?C?S) are often used to attach organic chromophores (reporter molecules) to colloidal gold nanocrystals for surface-enhanced Raman scattering (SERS), to atomically smooth gold surfaces for tip-enhanced Raman scattering, and to scanning tunneling microscopy probes (nanosized electrodes) for single-molecule conductance measurements. However, it is still unclear how the attached molecules interact electronically with the underlying surface, and how the anchoring group might affect the electronic and optical properties of such nanoscale systems. Here we report systematic surface-enhanced Raman studies of two organic chromophores, malachite green (MG) and its ITC derivative (MGITC), that have very different functional groups for surface binding but nearly identical spectroscopic properties. A surprise finding is that, under the same experimental conditions, the SERS signal intensities for MGITC are nearly 500-fold higher than those of MG. Correcting for the intrinsic difference in scattering cross sections of these two dyes, we estimate that the MGITC enhancement factors are ~200-fold higher than for MG. Furthermore, pH-dependent studies reveal that the surface structure of MGITC is irreversibly stabilized or "locked" in its pi-conjugated form and is no longer responsive to pH changes. In contrast, the electronic structure of adsorbed MG is still sensitive to pH and can be switched between its localized and delocalized electronic forms. These results indicate that ITC is indeed an unusual anchoring group that enables strong electronic coupling between gold and the adsorbed dye, leading to more efficient chemical enhancement and higher overall enhancement factors. PMID- 22257218 TI - Altered UV absorbance and cytotoxicity of chlorinated sunscreen agents. AB - Sunscreens are widely utilized due to the adverse effects of ultraviolet (UV) radiation on human health. The safety of their active ingredients as well as that of any modified versions generated during use is thus of concern. Chlorine is used as a chemical disinfectant in swimming pools. Its reactivity suggests sunscreen components might be chlorinated, altering their absorptive and/or cytotoxic properties. To test this hypothesis, the UV-filters oxybenzone, dioxybenzone, and sulisobenzone were reacted with chlorinating agents and their UV spectra analyzed. In all cases, a decrease in UV absorbance was observed. Given that chlorinated compounds can be cytotoxic, the effect of modified UV filters on cell viability was examined. Chlorinated oxybenzone and dioxybenzone caused significantly more cell death than unchlorinated controls. In contrast, chlorination of sulisobenzone actually reduced cytotoxicity of the parent compound. Exposing a commercially available sunscreen product to chlorine also resulted in decreased UV absorbance, loss of UV protection, and enhanced cytotoxicity. These observations show chlorination of sunscreen active ingredients can dramatically decrease UV absorption and generate derivatives with altered biological properties. PMID- 22257219 TI - miR-124, miR-125b, let-7 and vesicle transport proteins in squid lenses in L. pealei. AB - PURPOSE: Studies over the past several decades identified parallels between neuron and lens fiber cell morphology, development, and physiology. Consistent with this, mammalian lens fiber cells were shown to express a substantial complement of genes that cluster with respect to synaptic vesicle transport and exocytosis. Expression of these genes in these two cell types also appears consistent with similarities described between lens fiber cell lateral protrusions and neuronal dendrites. Recently, we showed vertebrate neurons and lens fiber cells share expression of a core set of factors that form an interlocking regulatory network which has a fundamental role in determining neural cell identity. These included the REST/NRSF transcription factor, neural RNA binding proteins and miR-124. In addition, we identified miR-125 and let-7 in mammalian lenses that have been shown to regulate dendrite formation in neurons. The present study examined expression of miR-124, miR-125, and let-7 as well as genes involved in vesicle transport in lens in the squid Loligo (also referred to as Doryteuthis) pealei. METHODS: Northern blot, RT-PCR, immunoblots, and in situ detection were used to analyze expression in squid and vertebrate tissues. RESULTS: The present study provided evidence that miR-124, miR-125, let-7 and vesicle transport-related proteins are produced in squid lenses. Consistent with these mRNAs and miRNAs in squid lenses, and polyribosomes shown by others, we detected substantial levels of tRNA and rRNA in anuclear squid lenses which do not produce an epithelial cell layer that would be analogous to vertebrate lenses. CONCLUSIONS: Our study provided evidence that miR-124, miR-125, and let 7, as well as proteins involved in vesicle transport linked with synaptic and cargo vesicle transport in vertebrates are also expressed in squid lenses. PMID- 22257220 TI - Molecular dynamics simulations of interactions between polyanilines in their inclusion complexes with beta-cyclodextrins. AB - Conductive polymers have several applications such as in flexible displays, solar cells, and biomedical sensors. An inclusion complex of a conductive polymer and cyclodextrin is desired for some applications such as for molecular wires. In this study, different orientations of beta-cyclodextrin rings on a single polyaniline (PANI) chain in an alternating emeraldine form were simulated using molecular dynamics. The simulations were performed in an implicit solvent environment that corresponds to experimental conditions. When the larger opening of the beta-cyclodextrin toroids face the same direction, the cyclodextrins tend to repel each other. Alternating the orientation of the beta-cyclodextrins on the chain causes the beta-cyclodextrin rings to be more attractive to one another and form pairs or stacks of rings. These simulations explain how the beta cyclodextrins can be used to shield the polyaniline from outside chemical action by analyzing the PANI/cyclodextrin interactions from a molecular perspective. PMID- 22257221 TI - Damage of DNA and proteins by major lipid peroxidation products in genome stability. AB - Oxidative stress and lipid peroxidation (LPO) accompanying infections and chronic inflammation may induce several human cancers. LPO products are characterized by carbohydrate chains of different length, reactive aldehyde groups and double bonds, which make these molecules reactive to nucleic acids, proteins and cellular thiols. LPO-derived adducts to DNA bases form etheno-type and propano type exocyclic rings, which have profound mutagenic potential, and are elevated in several cancer-prone diseases. Adducts of long chain LPO products to DNA bases inhibit transcription. Elimination from DNA of LPO-induced lesions is executed by several repair systems: base excision repair (BER), direct reversal by AlkB family proteins, nucleotide excision repair (NER) and recombination. Modifications of proteins with LPO products may regulate cellular processes like apoptosis, cell signalling and senescence. This review summarizes consequences of LPO products' presence in cell, particularly 4-hydroxy-2-nonenal, in terms of genomic stability. PMID- 22257222 TI - A DNA-based nanomechanical device used to characterize the distortion of DNA by Apo-SoxR protein. AB - DNA-based nanomechanical devices can be used to characterize the action of DNA distorting proteins. Here, we have constructed a device wherein two DNA triple crossover (TX) molecules are connected by a shaft, similar to a previous device that measured the binding free energy of integration host factor. In our case, the binding site on the shaft contains the sequence recognized by SoxR protein, the apo form of which is a transcriptional activator. Another active form is oxidized [2Fe-2S] SoxR formed during redox sensing, and previous data suggest that activated Fe-SoxR distorts its binding site by localized DNA untwisting by an amount that corresponds to ~2 bp. A pair of dyes report the fluorescence resonance energy transfer (FRET) signal between the two TX domains, reflecting changes in the shape of the device upon binding of the protein. The TX domains are used to amplify the signal expected from a relatively small distortion of the DNA binding site. From FRET analysis of apo-SoxR binding, the effect of apo-SoxR on the original TX device is similar to the effect of shortening the TX device by 2 bp. We estimate that the binding free energy of apo-SoxR on the DNA target site is 3.2-6.1 kcal/mol. PMID- 22257223 TI - Impacts of climate change on the future of biodiversity. AB - Many studies in recent years have investigated the effects of climate change on the future of biodiversity. In this review, we first examine the different possible effects of climate change that can operate at individual, population, species, community, ecosystem and biome scales, notably showing that species can respond to climate change challenges by shifting their climatic niche along three non-exclusive axes: time (e.g. phenology), space (e.g. range) and self (e.g. physiology). Then, we present the principal specificities and caveats of the most common approaches used to estimate future biodiversity at global and sub continental scales and we synthesise their results. Finally, we highlight several challenges for future research both in theoretical and applied realms. Overall, our review shows that current estimates are very variable, depending on the method, taxonomic group, biodiversity loss metrics, spatial scales and time periods considered. Yet, the majority of models indicate alarming consequences for biodiversity, with the worst-case scenarios leading to extinction rates that would qualify as the sixth mass extinction in the history of the earth. PMID- 22257224 TI - In vitro platelet quality in storage containers used for pediatric transfusions. AB - BACKGROUND: The in vitro quality of small-volume platelet (PLT) aliquots for pediatric transfusions was assessed to determine the best practice approach. STUDY DESIGN AND METHODS: Small volumes (50 mL) of single apheresis PLT components (APCs), collected on either CaridianBCT Trima or Haemonetics MCS+ instruments, were aliquoted on Days 2, 3, 4, and 5 postcollection into Fenwal PL1240 or 4R2014 bags or 60-mL polypropylene syringes. Samples were tested for in vitro quality at their recommended expiry times (4 hr for 4R2014 bags and syringes or Day 5 for PL1240 bags). Assays included pH, CD62P expression, and metabolic measures. RESULTS: CD62P expression increased throughout storage in all containers. Among the small-volume containers, pH, pCO(2) , lactate, and bicarbonate varied considerably. Regardless of the day of aliquoting, pCO(2) was significantly higher and pO(2) was significantly lower in gas-impermeable syringes than other containers. No bacterial growth was detected in any sample. CONCLUSION: The quality of APCs aliquoted into small-volume containers meets regulatory requirements and is generally equivalent to that of full-volume APCs at expiry. PMID- 22257226 TI - Identification and quantification of the migration of chemicals from plastic baby bottles used as substitutes for polycarbonate. AB - The results of a study on the analytical identification and quantification of migration of chemicals from plastics baby bottles found in the European Union market made of materials that are now present as substitutes for polycarbonate (PC) are reported. A total of 449 baby bottles with a focus on first age or sets of bottles were purchased from 26 European Union countries, Canada, Switzerland and the USA. From this collection, which contained several duplicates, a total of 277 baby bottles were analysed. The materials included different types of plastic such as PC, polyamide (PA), polyethersulphone (PES), polypropylene (PP), but also silicone, and from the United States a co-polyester marketed under the trade name TritanTM. The bottles were subjected to the conventional migration test for hot fill conditions, i.e. 2 h at 70 degrees C. The simulant used was that specified in European Union legislation (2007/19/EC) for milk, i.e. 50% ethanol. In a first phase 1, migration was conducted since the scope of this investigation was a screening rather than a true compliance testing check. Second and third migrations were performed on selected articles when migrated substances exceeded limits specified in the legislation. In order to verify some materials, a portion of the bottle was cut to run an FT-IR fingerprint to confirm the nature of the polymer. The migration solutions in general showed a low release of substances. Results showed that bottles made of PP and silicones showed a greater number of substances in the migration solutions and in greater quantity. Chemicals from PP included alkanes, which could be found in >65% of the bottles at levels up to 3500 ug kg-1; and benzene derivatives in 17% of the baby bottles and found at levels up to 113 ug kg-1. Some substances were found on a regular basis such as plasticisers, esters and antioxidants (e.g. tris(2,4-di-tert butylphenyl)phosphate, known as Irgafos 168. Some substances found were not included in the Community positive list, which means that those should not be found even in the first migration. Such substances included 2,6-di isopropylnaphthalene (DIPN), found in 4% of the bottles at levels up to 25 ug kg 1, 2,4-di-tert-butyl phenol (in 90% of the bottles at levels up 400 ug kg-1). Moreover, bisphenol A (BPA) was detected and quantified in baby bottles made of PA, but limited to one brand and model specific (but labelled BPA free). Results for baby bottles made of silicone also indicated the presence of components, e.g. potentially coming from inks (benzophenone, diisopropyl naphtahalene - DIPN, which could come for example from the presence of instruction leaflets in the bottles). In the case of silicone, phthalates were also found in relevant concentrations, with levels for DiBP and DBP from the first migration test of 50 150 ug kg-1 and DEHP at levels 25-50 ug kg-1. PMID- 22257227 TI - Ultrathin, flexible, and transparent polymer multilayer composites for the protection of silver surfaces. AB - Silver coatings at the nanoscale became of high interest for the integration of electronic functionalities on all kinds of objects for daily use. In these thin coatings, corrosion is a big problem as it destroys these thin layers and leads to a loss of conductivity due to missing bulk material. For protection of thin silver coatings against H(2)S induced corrosion, we developed nanocoatings based on the covalent layer-by-layer technique. We prepared composites by subsequent deposition of polyamines like polyethylenimine (PEI) or polyallylamine (PAAm) and polyanhydrides like poly(maleic anhydride-alt-methyl vinyl ether) (Gantrez) or poly(styrene-co-maleic anhydride) (PSMA). For the tuning of the hydrophobicity, the layers were terminated by reaction with palmitoylic acid derivatives. Reflectivity measurements, contact angle measurements, and AFM measurements were made to investigate how the coatings affect the surface properties. All coatings show a lower reflectivity below 450 nm compared to pure silver, depending on the number of layers deposited. The addition of a palmitoylic derivative to the surface increases the hydrophobicity, but only in case of the Gantrez-PVAm composite, this approach leads to real hydrophobicity, reaching contact angles above 90 degrees . AFM measurements show a decrease of the roughness of the polymer coated surfaces compared to the pure metal surfaces. Corrosion tests in a H(2)S atmosphere show a good protective effect of the palmitoyl-terminated composites. Martindale abrasion tests on coated textiles reveal a good stability of the prepared polymer composites. PMID- 22257228 TI - Ordered mesoporous platinum@graphitic carbon embedded nanophase as a highly active, stable, and methanol-tolerant oxygen reduction electrocatalyst. AB - Highly ordered mesoporous platinum@graphitic carbon (Pt@GC) composites with well graphitized carbon frameworks and uniformly dispersed Pt nanoparticles embedded within the carbon pore walls have been rationally designed and synthesized. In this facile method, ordered mesoporous silica impregnated with a variable amount of Pt precursor is adopted as the hard template, followed by carbon deposition through a chemical vapor deposition (CVD) process with methane as a carbon precursor. During the CVD process, in situ reduction of Pt precursor, deposition of carbon, and graphitization can be integrated into a single step. The mesostructure, porosity and Pt content in the final mesoporous Pt@GC composites can be conveniently adjusted over a wide range by controlling the initial loading amount of Pt precursor and the CVD temperature and duration. The integration of high surface area, regular mesopores, graphitic nature of the carbon walls as well as highly dispersed and spatially embedded Pt nanoparticles in the mesoporous Pt@GC composites make them excellent as highly active, extremely stable, and methanol-tolerant electrocatalysts toward the oxygen reduction reaction (ORR). A systematic study by comparing the ORR performance among several carbon supported Pt electrocatalysts suggests the overwhelmingly better performance of the mesoporous Pt@GC composites. The structural, textural, and framework properties of the mesoporous Pt@GC composites are extensively studied and strongly related to their excellent ORR performance. These materials are highly promising for fuel cell applications and the synthesis method is quite applicable for constructing mesoporous graphitized carbon materials with various embedded nanophases. PMID- 22257229 TI - [Positron emission tomography in the diagnosis and monitoring of patients with nonseminomatous germ cell tumours]. AB - The role of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the diagnosis and monitoring of nonseminomatous germ cell tumours is currently unclear. Clinical studies have suggested that FDG-PET has relatively low sensitivity and specificity in the setting of initial staging and viability assessment of post-chemotherapy residual lesions. On the other hand, FDG-PET provides potentially useful information in patients with elevated tumour markers and/or multiple residual lesions with limited resectability. Other possible indications of FDG-PET are the early assessment of tumour chemosensitivity and the diagnosis of inflammatory treatment complications. PMID- 22257230 TI - [Plasminogen activator system and its clinical significance in patients with a malignant disease]. AB - Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, a serine protease participating in the activation of matrixmetaloproteinases, latent elastases, growth factors and cytokines involved in the degradation of extracellular matrix elements. Together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI-1, PAI-2, PAI-3 and protease nexin), it forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. Plasminogen activator inhibitor 1 inhibits uPA dependent invasiveness of some cancer cell lines. The vitronectin-PAI-1 complex inhibits migration of smooth muscle cells by binding alpha(v)beta3 integrin to vitronectin. PAI-1 or its deficiency interferes with signalling pathways such as PI3K/Akt and JAK/STAT and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death. PAI-1 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways. The individual components of PAS undoubtedly play an important role in angiogenesis and metastasising of malignant tumours. In the near future, results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and, at the same time, could serve as the goal for targeted therapies. PMID- 22257231 TI - [Castleman disease]. AB - BACKGROUNDS: Castleman disease is a rare non-clonal lymphoproliferative disorder with the etiopathogenesis not yet thoroughly clarified. Clinically, either unicentric (localized) or multicentric (generalized) forms are recognized while, histopathologically, hyaline-vascular, plasma-cell and mixed variants of the disease exist. These types vary one from another in their clinical courses and, importantly, in methods of therapeutic management. While the unicentric hyaline vascular form usually manifests as benign growth of a single lymph node and treatment response to complete surgical excision reaches up to 100%, the multicentric plasmocellular variant is an aggressive disease with generalized symptoms, laboratory abnormalities and the need for systemic therapy. AIM: The paper provides an overview of information on Castleman disease from its clinical and histopathological signs to diagnostic and therapeutic options. It deals with the role of cytokines and HHV-8 virus infection in the disease pathophysiology and is supplied with ample pictorial documentation of radiographic findings including ultrasonography, computed tomography and hybrid imaging by positron emission tomography (PET) in combination with simultaneously taken full-body computed tomography (CT) scans, the so called PET/CT. We also present photographs of histological specimens taken from an HIV and HHV-8 negative patient with the plasmocellular multicentric form. CONCLUSIONS: Consequent to its low incidence, Castleman disease is often misdiagnosed or diagnosed with a delay. Therefore, it is always necessary to include this rare condition in differential diagnostics of lymphadenopathy, microcytic anemia as well as B-symptoms (night sweats, fevers and weight loss). In conclusion, we also stress the significance of full-body PET/CT scanning during staging and treatment response evaluation. PMID- 22257232 TI - Predictive values of the ultrasound parameters, CA-125 and risk of malignancy index in patients with ovarian cancer. AB - BACKGROUNDS: Assessment of predictive values for CA-125, ultrasound features (US) and risk of malignancy index (RMI) in ovarian malignancy. MATERIAL AND METHODS: 115 patients, divided into: 1) group-A (n = 41)--ovarian malignancy; group-B (n = 74)--benign ovarian tumor; 2) subgroup-CA(a) with low CA-125 (< 35 U/mL) (n = 64); subgroup-CA(b) with slightly elevated CA-125 (35-130 U/ml) (n = 26); subgroup-CA(c) with high CA-125 (> 130 U/ml) (n = 25). RESULTS: 1) patients of group-A were older (p < 0.05); CA-125 < 35 U/ml predominated in group-B (p < 0.001); 2) CA-125 < 35 U/ml showed relatively high NPV, sensitivity and specificity (82.8%; 0732; 0.716, respectively). Our proposed graduation of CA-125 into three grades: a) < 35 U/mL; b) 35-130 U/mL; c) > 130 U/mL increased the specificity for both parameters: CA125 = 35-130 U/mL up to 0.811, and for CA-125 > 130 U/mL up to 0.905, and PPV for the latter parameter up to 72.0%; 3) US: a) highest sensitivity, as indicator for best distinguishing of diseased patients, showed: rugged margins and presence of septum/vegetations (0.878; 0.897, respectively); b) highest specificity, as indicator for best distinguishing of healthy patients: clear distinguish ability of tumor from surrounding tissue and absence of ascites (0.811; 0.932, respectively); c) presence of ascites had highest PPP (100%) i.e. it was the best malignancy predictor; 4) RMI showed only relatively high NPV for RMI < or = 200 (76.8%); 4) additional analysis of RMI in correlation with proposed CA-125 gradation increased the predictive values of RMI: a) subgroup-CA(a): NPV and sensitivity for RMI < or = 200 (81.6%; 0.818, respectively) and NPV for RMI > 200 (86.7%); b) subgroup-CA(b): specificity for RMI < or = 200, as good indicator for distinguishing healthy patients (0.929); c) subgroup-CA(c): sensitivity for RMI > 200, as good indicator for distinguishing diseased patients (0.944). CONCLUSION: CA-125 and US, as single criteria were not accurate. RMI is good indicator only in correlation with CA-125. PMID- 22257233 TI - [Five year-results of chemoresistance testing in cancer patients]. AB - BACKGROUNDS: Translational medicine is a medical field encompassing basic research and development of new diagnostic and therapeutic strategies for clinical practice. The present scientific paper focuses on our previous experience in the field of chemoresistance testing in patients with oncological diseases. MATERIAL AND METHODS: Since 2005, we sampled 71 patients with a leukaemia (AML, ALL and CML) and 92 patients with a solid tumour (lung and gastrointestinal tract cancer). Malignant cell in vitro drug resistance testing was carried out using cytotoxic methyl-thiazol tetrazolium (MTT) assay. RESULTS: Based on the LC50 (lethal concentration of a drug killing 50% of cell population), we found that patients with acute myeloblastic leukaemia exhibit a greater degree of resistance than patients with acute lymphoblastic leukaemia. In patients with bronchogenic carcinomas, primary resistance to cisplatin was identified in 28% of tested samples, paclitaxel 36%, vincristine 50%, etoposide 56%, vinorelbine 57%, topotecan 62%, gemcitabine 77% and dacarbazine 86%. CONCLUSION: In vitro tests with gastrointestinal tract cancers also suggested high effectiveness of cisplatin (with the exception of gastric carcinoma) that was comparable with 5-fluorouracil. Even though the MTT assay has some limitations (insufficient number of vital cells, possible contamination by non malignant cells, etc.), this in vitro method proved very effective in testing malignant cell resistance to clinically used cytostatics. PMID- 22257234 TI - Recent patterns in stomach cancer descriptive epidemiology in the Slovak Republic with reference to international comparisons. AB - BACKGROUNDS: Even though the incidence and mortality from stomach cancer declined dramatically, it remains the third most frequent cancer worldwide. This study analysed the incidence and resulting mortality, and possible reasons for any differences identified between the Slovak Republic and other countries. MATERIAL AND METHODS: Analysis of national data covering the period from 1968 to 2006. Trends have been estimated using linear regression model and are presented with corresponding 95% Confidence Intervals (CI) and p-values with null hypothesis being constant in time. RESULTS: In 2006, standardized incidence index for stomach cancer in Slovak males (related to 1968) declined by 0.28, annual percentage change was -3.2% and the average decrease of standardized incidence represented -0.956/100,000 (95% CI -1.059 to -0.853, p <0.0001). The incidence in men had statistically significantly more rapidly declining tendency in the first half of the analyzed period (1968-1986). Decrease in the mortality index was 0.32 with annual percentage change of -2.9% and the mean decrease in standardized mortality of -0.691/100,000 (95% CI -0.750 to -0.632, p < 0.0001). In 2006, the standardized incidence index for stomach cancer in Slovak females (related to 1968) declined by 0.23, annual percentage change was -3.7% and the mean decrease in standardized incidence was -0.491/100,000 (95% CI -0.554 to -0.428, p < 0.0001), the decline in incidence was more pronounced in the first half of the analyzed period. The mortality index (1968-2006) declined by 0.26, annual percentage change was -3.4% and annual decrement of standardized mortality represented -0.367/100,000 (95% CI -0.407 to -0.326, p < 0.0001). Only a non significant change was identified for the proportions of the individual stomach cancer clinical stages with high proportion of clinical stages III and IV in both sexes. CONCLUSION: Decline in the incidence and mortality appears to be decelerating, intervention in primary prevention is essential. PMID- 22257235 TI - [The late effects in patients treated with allogeneic hematopoietic stem cell transplantation]. AB - BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (HSCT) has become a curative treatment option for a variety of malignant and non-malignant hematological disorders. The number of long-term survivors after HSCT is continuously increasing and quality of their life represents a multidisciplinary concern. The aim of this study was to evaluate the prevalence of the late effects in long-term allogeneic HSCT survivors. PATIENTS AND METHODS: The study included 45 patients aged 12-63 years who survived at least two years after allogeneic HSCT for a hematological disorder. Twelve (26.7%) patients received an irradiation-based conditioning regimen. Median follow-up was 6 years (range 2-18 years). RESULTS: Toxicity varied from subclinical to life-threatening. The prevalence of at least one late toxic effect was 88.9%. Endocrine and metabolic complications included thyroid abnormalities in 12 (26.7%) patients, bone and joints complications in 13 (28.8%) and metabolic syndrome in 13 (28.8%). Ocular complications were diagnosed in 20 (44.4%), cardiovascular abnormalities in 15 (33.3%), pulmonary dysfunction in 6 (13.3%) and secondary malignancies in 3 (6.67%) survivors. The number of complications per patient increased with time from HSCT. Chronic graft-versus-host disease was the most significant risk factor associated with ocular, pulmonary and osteoarticular complications. CONCLUSION: Late toxicity of allogeneic HSCT in patients surviving for more than 2 years after this procedure may facilitate conduct of longer follow-up studies and an implementation of interventions to prevent late effects among survivors of serious hematological diseases PMID- 22257236 TI - Long term follow up of eosinophilic granuloma of the rib. AB - BACKROUNDS: Eosinophilic granuloma is one of the rarest causes of bone tumors, especially in adults. Eosinophilic granuloma is the commonest form of Langerhans cell histiocytosis and represents the unifocal osseous form of the disease which usually affects the skull and long bones. Eosinophilic granuloma, is a benign disease in which diagnosis and differential diagnosis presents more difficulties than treatment. OBSERVATION: We present a case of eosinophilic granuloma of the rib with long term follow-up of 14 years which was treated with a combination of surgery and chemotherapy. CONCLUSION: Prognosis of adult eosinophilic granuloma is excellent and the recurrence rate is limited. All available treatment options, including surgery, chemotherapy, corticosteroids, radiation, and even palliative treatment have very good results and in many cases the disease seems to heal spontaneously. However the disease, due to its rarity and unknown pathogenesis still remains an enigma for the clinical doctor. PMID- 22257237 TI - [The role of chemotherapy and targeted antiVEGF- and antiEGFR-therapy in metastatic colorectal cancer: a case report of long-term and intensive response]. AB - BACKGROUNDS: Colorectal cancer (CRC) is the second most frequent malignancy in the Czech Republic. Treatment of a metastatic disease is based on application of palliative chemotherapy (fluorouracil, leucovorin, irinotecan, oxaliplatin). When combined with targeted agents against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), it can result in significant and long-term response. CASE: We present a case of a 34-years old man with adenocarcinoma of sigmoid colon (Dukes C) with 5 years disease-free survival (DFS) after primary surgery (in 2002) and adjuvant chemotherapy with FOLFIRI (12 cycles). A solitary relapse in retroperitoneal lymph nodes in November 2007 was treated with retroperiotoneal dissection followed by adjuvant chemotherapy with FOLFOX 4 (12 cycles) and targeted radiotherapy of retroperitoneal area (completed in May 2008). An early relapse occurred one month later (June 2008- infraclavicular area, thoracic wall and retroperitoneal lymph nodes), patient underwent first line palliative chemotherapy with XELIRI + bevacizumab leading to partial remission (PR) after 3 months and complete remission (CR) after 6 months of treatment. Bevacizumab monotherapy was continued for the next 8 months up to March 2010, when a progression in the lung occurred. After wild-type status was confirmed, KRAS treatment was changed to the second line combination of irinotecan and cetuximab that resulted in nearly complete remission after 6 months and preservation of this remission after the next 6 months of cetuximab monotherapy. All treatments were well tolerated with good quality of life. CONCLUSION: Our case demonstrates the current options in the treatment of metastatic CRC. There is a trend to gradually use all the above listed cytostatics in combination with anti-VEGF and anti-EGFR monoclonal antibodies. When administered early, it may provide a significant and long-term treatment response. PMID- 22257238 TI - [Trabectedin registry]. AB - BACKGROUNDS: The Yondelis (trabectedin) project was initiated in January 2011 with the aim to obtain basic epidemiological information on patients with soft tissue sarcomas, standard treatment procedures, and results of trabectedin therapy in routine clinical practice. Expert patronage is provided by the Czech Society for Oncology, CzMA JEP. The project covers a representative sample of Comprehensive Cancer Care centres established to provide systematic treatment to patients with soft tissue sarcoma. PATIENTS AND METHODS: 45 patients diagnosed with soft tissue sarcoma were retrospectively included in the database. Median age at the initiation of trabectedin therapy was 51 years (23-72 years). Leiomyosarcoma was the most frequent tumour (35.6%), synovial sarcoma occurred in 13.3% of patients; liposarcoma, peripheral nerve sheath tumours and unspecified sarcomas contributed 6.7% each. 62.2% of sarcomas were larger than 5 cm. Trabectedin was administered in a dose of 1.5 mg/m2 once in 3 weeks. 40% of patients received trabectedin as the 2nd line treatment, 35.6% as the 3rd line, and 34.4% as the 4th line. RESULTS: Median number of administered cycles was 4 (1 10 cycles). Neutropenia (28.9% of patients) and elevated liver enzymes (26.7% of patients) were the most frequent adverse affects. 73.8% of patients terminated the therapy due to disease progression. Treatment response was recorded in 6.6% of patients (complete and partial remission), stable disease in 26.7%, and progression in 53.3%. Median overall survival (95% CI) was 11.7 months (9.6; 13.8), median progression-free survival (95% CI) was 3 months (2.4; 3.6). CONCLUSION: Expert cancer societies have recently recommended trabectedin as the 2nd line palliative treatment for soft tissue sarcomas with documented effectiveness, particularly in liposarcomas and leiomyosarcomas, and good safety profile. PMID- 22257239 TI - The formation of P particle increased immunogenicity of norovirus P protein. AB - As a commentary on a recently published paper in Immunology, this article summaries the principle of norovirus P particle as a promising vaccine against noroviruses. It emphasizes the importance of P particle formation in the immune enhancement of the vaccine and methods for production/verification of high quality P particles which may be easily neglected by researchers. PMID- 22257240 TI - GreenLight HPSTM 120-W laser vaporization vs transurethral resection of the prostate (<60 mL): a 2-year randomized double-blind prospective urodynamic investigation. AB - What's known on the subject? and What does the study add? Photovaporization of the prostate (PVP) is now challenging TURP as the standard treatment for lower LUTS caused by BPH. The learning curve for PVP is short and the main advantages of this method over TURP are a shorter period of hospitalization, a shorter period of postoperative vesical catheterization, lower levels of retrograde ejaculation, rare development of dilutional hyponatraemia syndrome, the lack of a need for postoperative vesical irrigation as a result of extremely low indices of postoperative haematuria, and the lack of a need to suspend anticoagulant medication for the surgery. Traditionally, comparisons of the effectiveness of TURP vs PVP have involved parameters such as peak flow urinary rate and post-void residual urine volume measurements, and have employed questionnaires such as the IPSS and the International Index of Erectile Function instruments. However, studies evaluating detailed urodynamic parameters remain scarce and non comparative The present study compared postoperative, medium-term urodynamic parameters among patients receiving TURP and high-power PVP. We consider the present study to be distinctive because it involved a double-blind, detailed functional analysis of the vesical emptying stage over the course of 2 years, and did not simply comprise an evaluation of clinical parameters and uroflowmetrics. We saw a reduction of infravesical obstruction, as shown by the significant reduction of >=20 cm H(2)O in the mean micturition pressure for the groups studied, as well as a significant reduction in bladder outlet obstruction index. Thus, the present data show that high-power PVP can achieve and maintain the same results as TURP over a period of 24 months regarding an aspect that is particularly important for maintaining vesical health (i.e. detrusor pressure during the evacuation of the bladder). Such urodynamic data describing the functional outcome of PVP are currently missing from the literature. OBJECTIVE: To assess the impact of GreenLight HPSTM 120-W (American Medical System Incorporation, Minnetonka, MN, USA) laser photovaporization of the prostate (PVP) compared to transurethral resection of the prostate (TURP) on urodynamic results, voiding function and sexual function. PATIENTS AND METHODS: In total, 20 men with intermediate/severe lower urinary tract symptoms as a result of benign prostatic hyperplasia (BPH) were randomly selected and equally divided into two groups: TURP and PVP. Urodynamic evaluation was performed and International Prostate Symptom Score (IPSS), International Index of Erectile Function-5 and International Consultation on Incontinence Questionnaire - Short Form questionnaires were completed. The results were assessed at 2 years. RESULTS: Mean IPSS scores were reduced in both groups, although they did not differ between the TURP and PVP groups. There was no significant change in International Index of Erectile Function-5 scores. Half of the patients in the PVP group developed urge urinary incontinence with spontaneous resolution. The urodynamic parameters analyzed showed an improvement for both groups, although the values in the TURP group values were not significantly different from those in the PVP group. CONCLUSIONS: Bladder storage symptoms may represent a major concern, although they are of limited duration in patients undergoing PVP. High-power PVP can achieve and maintain the same results as TURP over a period of 24 months. PMID- 22257241 TI - Translation and measurement properties of the Swedish version of ACL-Return to Sports after Injury questionnaire. AB - Psychological factors may be a hindrance for returning to sport after an anterior cruciate ligament (ACL) reconstruction. The ACL-Return to Sport after Injury scale (ACL-RSI) measures athletes' emotions, confidence in performance, and risk appraisal in relation to return to sport. The aim of this study was to translate the ACL-RSI scale from English to Swedish and to examine some of the measurement properties of the Swedish version. The ACL-RSI was translated and culturally adapted. A professional expert group and five patients evaluated face validity. One hundred and eighty-two patients completed the translated ACL-RSI, a project specific questionnaire, the Tampa Scale of Kinesiophobia (TSK), the Knee-Self Efficacy Scale (K-SES), the Multidimensional Health Locus of Control (MHLC-C), the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Anterior Cruciate Ligament-Quality of Life (ACL-QoL) questionnaires. Fifty-three patients answered the ACL-RSI twice to examine reproducibility. The ACL-RSI showed good face validity, internal consistency (Cronbach's alpha = 0.948), low floor and ceiling effects and high construct validity when evaluated against the TSK, K SES, MHLC-C, KOOS, and ACL-QoL scales. The reproducibility was also high (intra class correlation = 0.893). Therefore, the ACL-RSI can be used to evaluate psychological factors relevant to returning to sport after ACL reconstruction surgery. PMID- 22257242 TI - A new genus and species of proteocephalidean tapeworm (Cestoda) from Pangasius larnaudii (Siluriformes: Pangasiidae) in Southeast Asia. AB - A new proteocephalidean cestode is described from spot pangasius, Pangasius larnaudii (Siluriformes: Pangasiidae), from Tonle Sap Lake in Cambodia and a new genus, Pangasiocestus , is proposed to accommodate it. The genus is placed in the Gangesiinae because its scolex possesses a large rostellum-like apical organ and its genital organs (testes, ovary, vitellarium, and uterus) are situated in the medulla, with some vitelline follicles paramuscular. Pangasiocestus romani n. gen. and n. sp., the type and only species of the new genus, is characterized mainly by its rosette-like scolex composed of 4 lobes bearing a small sucker in their center, and the apical part with a large, discoidal, rostellum-like apical organ devoid of hooks, by weakly developed inner longitudinal musculature formed by very few isolated muscle fibers, uneven size of testes in immature and mature proglottids, with lateral testes smaller and more dense than median ones, by very narrow lateral bands of vitelline follicles, formed usually by single follicles, and by the vagina anterior to the cirrus sac. This is the first proteocephalidean cestode from a pangasiid catfish identified to the species level (proteocephalidean cestodes from 3 Pangasius spp. reported in an unpublished account from Vietnam, misidentified as Proteocephalus osculatus (Goeze, 1782) [ = Glanitaenia osculata ], are not considered). PMID- 22257243 TI - Representing and intervening: 'doing' good care in first trimester prenatal knowledge production and decision-making. AB - This article investigates processes of knowledge production and decision-making in the practice of the first trimester prenatal risk assessment (FTPRA) at an ultrasound clinic in Denmark. On the basis of ethnographic material and interviews with professionals facilitating FTPRAs in Denmark, we draw attention to the active engagement of health professionals in this process. Current professional and policy debate over the use of prenatal testing emphasises the need for informed choice making and for services that provide prospective parents with what is referred to as 'non-directive counselling'. Studies focusing on professional practice of prenatal counselling tend to deal mainly with how professionals fail to live up to such ideals in practice. In this article we extend such studies by drawing attention to practices of care in prenatal testing and counselling. In doing so, we identify three modes of 'doing' good care: attuning expectations and knowledge, allowing resistance and providing situated influence in the relationship between the pregnant woman and the professional. Such practices may not be seen as immediately compatible with the non-directive ethos, but they express ways of reducing emotional suffering and supporting a pregnant woman's ability to make meaningful choices on the basis of uncertain knowledge. As such, these practices can be seen as representing another (caring) solution to the problem of paternalism and authoritarian power. In opposition to an ethics aiming at non-interference (non-directiveness) such modes of doing good care express an ethics of being locally accountable for the ways in which programmes of prenatal testing intervene in pregnant women's lives and of taking responsibility for the entities and phenomena that emerge through such knowledge production. PMID- 22257244 TI - Bronsted acid mediated cyclization of enaminones. Rapid and efficient access to the tetracyclic framework of the Strychnos alkaloids. AB - The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is described. Enaminone 16, synthesized in high yield, has been cyclized under the influence of a Bronsted acid to provide the core tetracyclic framework 17 of the Strychnos alkaloids in optically active form or alternatively to the beta ketoester tetrahydro-beta-carboline (THBC) unit 18, by varying the equivalents of acid and the molar concentration. Attempts to utilize 18 to form the C7-C16 bond of the akuammiline related alkaloids represented by strictamine (22), using metal carbenoid chemistry, are also described. PMID- 22257246 TI - Development of an air quality standard for lead from community studies. PMID- 22257247 TI - A novel integrative technique for locating and monitoring polynuclear aromatic hydrocarbon discharges to the aquatic environment. PMID- 22257248 TI - Trace enrichment of fluorinated organic acids used as ground-water tracers by liquid chromatography. PMID- 22257249 TI - Formaldehyde and other carbonyls in Los Angeles ambient air. PMID- 22257250 TI - Liquid chromatography with precolumn sample preconcentration and electrochemical detection: determination of aromatic amines in environmental samples. PMID- 22257251 TI - Reactions of chlorine dioxide with hydrocarbons: effects of activated carbon. PMID- 22257252 TI - Correlation of bioconcentration factors. PMID- 22257253 TI - Gaseous hydrocarbons around an active offshore gas and oil field. PMID- 22257254 TI - Air-sea exchange of high-molecular weight organic pollutants: laboratory studies. PMID- 22257255 TI - Hydrocarbon gases emitted from vehicles on the road. 1. A qualitative gas chromatography/mass spectrometry survey. PMID- 22257256 TI - Notes. Floc breakage during HIAC light-blocking analysis. PMID- 22257257 TI - Notes. Microorganisms responsible for the oxidation of carbon monoxide in soil. PMID- 22257259 TI - Density functional theory study of semiquinone radical anions of polychlorinated biphenyls in the syn- and anti-like conformation. AB - Polychlorinated biphenyls (PCBs) can be metabolized to reactive metabolites, such as PCB semiquinone radical anions (SQ(*-)), whose structure and role in PCB induced toxicity are difficult to investigate due to their relative instability. The unrestricted UB3LYP/6-311G** method was used to investigate several molecular descriptors of the syn- and anti-like conformation of SQs(*-). The bond lengths and angles of the quinone moiety of the SQs(*-) were in between the values reported for PCB quinones and hydroquinones, which is consistent with the distribution of the alpha highest occupied molecular orbital (alpha-HOMO). The dihedral angles between the two ring systems increased in the presence of ortho chlorine substituents and were smaller compared to the corresponding PCB quinones. The ground-state energies indicate that the anti-like conformation of the SQs(*-) is more favorable than the syn-like conformation. Molecular descriptor used for modeling of quantitative structure-activity relationships displayed some dependence on the conformation. These findings suggest that SQs(* ) in both the syn- and antilike conformation may interact differently with target molecules, which may have implications for the toxicity of PCBs. PMID- 22257260 TI - Emerging phytopathogen Macrophomina phaseolina: biology, economic importance and current diagnostic trends. AB - Macrophomina phaseolina (Tassi) Goid. is an important phytopathogenic fungus, infecting a large number of plant species and surviving for up to 15 years in the soil as a saprophyte. Although considerable research related to the biology and ecology of Macrophomina has been conducted, it continues to cause huge economic losses in many crops. Research is needed to improve the identification and characterization of genetic variability within their epidemiological and pathological niches. Better understanding of the variability within the pathogen population for traits that influence fitness and soil survival will certainly lead to improved management strategies for Macrophomina. In this context, the present review discusses various biological aspects and distribution of M. phaseolina throughout the world and their importance to different plant species. Accurate identification of the fungus has been aided with the use of nucleic acid based molecular techniques. The development of PCR-based methods for identification and detection of M. phaseolina are highly sensitive and specific. Early diagnosis and accurate detection of pathogens is an essential step in plant disease management as well as quarantine. The progress in the development of various molecular tools used for the detection, identification and characterization of Macrophomina isolates were also discussed. PMID- 22257261 TI - Introduction and evaluation of computer-assisted education in an undergraduate dental hygiene course. AB - OBJECTIVE: This paper introduced newly developed computer-assisted learning materials and reports of a survey of junior college dental hygiene students who have used them. METHODS: We authored new educational material to promote students' basic dental hygiene practice skills using a simulation software generator. A set of five developed materials were tested by 43 female second-year dental hygiene students during the second semester at a college in Chiba, Japan. The evaluation was conducted in the form of a questionnaire including open-ended questions. Students' opinions were analysed using characteristic diagrams, a troubleshooting tool that can be used to visually illustrate the causes and effects of a problem. RESULT: The overall results of the evaluation were positive. The students were given five sets of simulation learning materials (SLMs). Eighty-three percent of the students felt that they could carry out independent study of clinical practice better after the virtual practice. Ninety three percent of them felt that the exercises should be continued in the future, and eighty-eight percent of them felt that this virtual practice deepened their interest in other classes and training sessions. All of the students found the virtual practice beneficial for their learning. DISCUSSION: The present results suggest that the students became conscious of their lack of knowledge through SLMs. These findings indicate that SLMs for practicing basic clinical procedures is beneficial. PMID- 22257262 TI - Iowa caucuses and the environment. PMID- 22257263 TI - Does the applicability of Bacillus strains in probiotics rely upon their taxonomy? AB - The taxonomic position and biological activities of two Bacillus strains used in veterinary probiotics were studied in this work. These microorganisms inhibit growth of a broad spectrum of pathogenic cultures. They synthesize proteolytic enzymes and other biologically active metabolites, and to some extent, supplement each other with probiotic activities. It is not clear whether these versatile activities are properties of individual strains or bacterial taxa as whole. 16S rRNA comparisons were conducted and illustrated the relatedness of these strains to Bacillus amyloliquefaciens . Their cell wall fatty acid contents were consequently analysed and specified a relation to the " Bacillus velezensis " ecomorph. On account of the previous observations, a simple method of 16S rRNA profiling by polymorphic nucleotides was proposed to determine a group of organisms closely related to "B. velezensis" and B. amyloliquefaciens subsp. plantarum, for they are biologically active strains suitable for use in biotechnology. The extreme genetic plasticity of these bacteria endowed each strain with a unique spectrum of antagonistic activity. PMID- 22257264 TI - Rigid body Brownian dynamics as a tool for studying ion channel blockers. AB - Using a novel rigid body Brownian dynamics algorithm, we investigate how a spherically asymmetrical polyamine molecule, a branched analogue of spermine, interacts with the external vestibule of the voltage-gated potassium channel, Kv1.2. Simulations reveal that the blocker, with a charge of +4e, inserts one of its charged amine groups into the selectivity filter, while another forms a salt bridge with an aspartate residue located just outside the entrance of the pore. This binding mode mimics features of the binding of polypeptides such as the scorpion venom charybdotoxin to the channel. The potential of mean force constructed with Brownian dynamics is a reasonable match to that obtained from molecular dynamics simulations, with dissociation constants of 4.7 and 22 MUM, respectively. The current-voltage relationships obtained with and without a blocker in the external reservoir show that the inward current is severely attenuated by the presence of the blocker, whereas the outward current is only moderately reduced. The computational molecular modeling technique we introduce here can provide detailed insights into ligand-channel interactions and can be used for rapidly screening potential blocker molecules. PMID- 22257266 TI - Synthesis of Cu2O nanocrystals from cubic to rhombic dodecahedral structures and their comparative photocatalytic activity. AB - In this study, a new series of Cu(2)O nanocrystals with systematic shape evolution from cubic to face-raised cubic, edge- and corner-truncated octahedral, all-corner-truncated rhombic dodecahedral, {100}-truncated rhombic dodecahedral, and rhombic dodecahedral structures have been synthesized. The average sizes for the cubes, edge- and corner-truncated octahedra, {100}-truncated rhombic dodecahedra, and rhombic dodecahedra are approximately 200, 140, 270, and 290 nm, respectively. An aqueous mixture of CuCl(2), sodium dodecyl sulfate, NaOH, and NH(2)OH.HCl was prepared to produce these nanocrystals at room temperature. Simple adjustment of the amounts of NH(2)OH.HCl introduced enables this particle shape evolution. These novel particle morphologies have been carefully analyzed by transmission electron microscopy (TEM). The solution color changes quickly from blue to green, yellow, and then orange within 1 min of reaction in the formation of nanocubes, while such color change takes 10-20 min in the growth of rhombic dodecahedra. TEM examination confirmed the rapid production of nanocubes and a substantially slower growth rate for the rhombic dodecahedra. The rhombic dodecahedra exposing only the {110} facets exhibit an exceptionally good photocatalytic activity toward the fast and complete photodegradation of methyl orange due to a high number density of surface copper atoms, demonstrating the importance of their successful preparation. They may serve as effective and cheap catalysts for other photocatalytic reactions and organic coupling reactions. PMID- 22257265 TI - Degradability of poly(lactic acid)-containing nanoparticles: enzymatic access through a cross-linked shell barrier. AB - Comparative studies of bulk samples of hydrolytically degradable poly(lactic acid) (PLA) vs core-shell block copolymer micelles having PLA cores revealed remarkable acceleration in the proteinase K enzymatic hydrolysis of the nanoparticulate forms and demonstrated that even with amidation-based shell cross linking the core domain remained accessible. Kinetic analyses by (1)H NMR spectroscopy showed less than 20% lactic acid released from enzymatically catalyzed hydrolysis of poly(l-lactic acid) in bulk, whereas ca. 70% of the core degraded within 48 h for block copolymer micelles of poly(N (acryloyloxy)succinimide-copolymer-N-acryloylmorpholine)-block-poly(L-lactic acid) (P(NAS-co-NAM)-b-PLLA), with only a slight reduction to ca. 50% for the shell cross-linked derivatives. Rigorous characterization measurements by NMR spectroscopy, fluorescence spectroscopy, dynamic light scattering, atomic force microscopy, and transmission electron microscopy were employed to confirm core excavation. These studies provide important fundamental understanding of the effects of nanoscopic dimensions on protein-polymer interactions and polymer degradability, which will guide the development of these degradable nanoconstructs to reach their potential for controlled release of therapeutics and biological clearance. PMID- 22257267 TI - Case of mucosal lentiginous melanoma in situ on the upper lip with a long radial growth phase. PMID- 22257268 TI - Inbreeding alters volatile signalling phenotypes and influences tri-trophic interactions in horsenettle (Solanum carolinense L.). AB - The ecological consequences of inter-individual variation in plant volatile emissions remain largely unexplored. We examined the effects of inbreeding on constitutive and herbivore-induced volatile emissions in horsenettle (Solanum carolinense L.) and on the composition of the insect community attracted to herbivore-damaged and undamaged plants in the field. Inbred plants exhibited higher constitutive emissions, but weaker induction of volatiles following herbivory. Moreover, many individual compounds previously implicated in the recruitment of predators and parasitoids (e.g. terpenes) were induced relatively weakly (or not at all) in inbred plants. In trapping experiments, undamaged inbred plants attracted greater numbers of generalist insect herbivores than undamaged outcrossed plants. But inbred plants recruited fewer herbivore natural enemies (predators and parasitoids) when damaged. Taken together, these findings suggest that inbreeding depression negatively impacts the overall pattern of volatile emissions - increasing the apparency of undamaged plants to herbivores, while reducing the recruitment of predatory insects to herbivore-damaged plants. PMID- 22257269 TI - Highly enantioselective nitro-Mannich reaction catalyzed by cinchona alkaloids and N-benzotriazole derived ammonium salts. AB - The catalytic enantio- and diastereoselective nitro-Mannich reaction of alpha amido sulfones in the mixed solvent of toluene/H(2)O has been realized using a phase-transfer catalyst (PTC) derived from cinchona alkaloids and N benzotriazole. It performed well over a wide range of substrates to give the desired products in good yields (up to 94%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1). PMID- 22257270 TI - Adsorption of HSA, IgG and laminin-1 on model hydroxyapatite surfaces--effects of surface characteristics. AB - Ellipsometry and mechanically assisted sodium dodecyl sulphate elution was utilized to study the adsorption of human serum albumin (HSA), human immunoglobulin G (IgG), and laminin-1, as well as competitive adsorption from a mixture of these proteins on spin-coated and sintered hydroxyapatite (HA) surfaces, respectively. The HA surfaces were characterized with respect to wettability and roughness by means of water contact angles and atomic force microscopy, respectively. Both surface types were hydrophilic, and the average roughness (Sa) and surface enlargement (Sdr) were lower for the sintered compared to the spin-coated HA surfaces. The adsorbed amounts on the sintered HA increased as follows: HSA < laminin-1 < IgG < the protein mixture. For the competitive adsorption experiments, the adsorbed fractions increased accordingly: HSA < laminin-1 < IgG on both types of HA substratum. However, a higher relative amount of HSA and laminin-1 and a lower relative amount of IgG was found on the spin coated surfaces compared to the sintered surfaces. The effects observed could be ascribed to differences in surface roughness and chemical composition between the two types of HA substratum, and could have an influence on selection of future implant surface coatings. PMID- 22257272 TI - Suprapubic catheter insertion using an ultrasound-guided technique and literature review. AB - What's known on the subject? and What does the study add? The conventional 'blind' technique for suprapubic catheter (SPC) insertion relies on adequate filling of the bladder to displace bowel away from the site of needle puncture. However, in a small percentage of patients this fails to happen, which can occasionally lead to life-threatening bowel injury. Recently published British Association of Urological Surgeons (BAUS) guidelines have recommended that ultrasonography (US) may be helpful to identify bowel loops and recommends its usage whenever possible. This paper describes the technique of US-guided needle puncture and SPC insertion to reduce the likelihood of bowel injury. The paper addresses training, equipment and logistical issues associated with this advice. We have reviewed the available publications on the outcomes from this technique and also present our experience. Suprapubic catheter (SPC) insertion is a common method of bladder drainage in contemporary urological practice. The procedure involves insertion of a sharp trocar into the bladder percutaneously, usually by palpation, percussion or cystoscopy for guidance. Although generally considered a safe procedure, the risk of bowel injury is estimated at up to 2.4% with a mortality rate of 1.8%. Recently published British Association of Urological Surgeons (BAUS) guidelines have recommended that ultrasonography (US) may be helpful to identify bowel loops and recommends its usage whenever possible. The present paper describes the use of US for SPC insertion and discusses the implications of this advice. This paper is designed to support and supplement practical techniques learnt on a course and in clinical practice. PMID- 22257274 TI - Implementing a statin switching programme in primary care: patients' views and experiences. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Switching of patients' prescribed medicines within a therapeutic class is a common strategy to reduce prescribing costs, and in England a standard methodology has been promoted for switching processes. * Previous work to date suggests many patients are sceptical of generic products and switching may reduce compliance. * Patients' views on switching in general and the processes used have not been widely sought. WHAT THIS STUDY ADDS: * Patients may be less accepting of therapeutic switching programmes than is currently assumed. * Patients lacked understanding of the reason for the switch, despite standard letters and information leaflets being used, and few sought consultations. * Greater explanation of switching, possibly with involvement of community pharmacists, could lead to improved patient understanding and acceptance. INTRODUCTION Estimates suggest L200 million could be saved on prescribing costs in England by implementing medication switches. Few studies have evaluated patients' views or understanding of therapeutic switches. AIM: To obtain patient and pharmacist perspectives on switching from atorvastatin to simvastatin within an English Primary Care Trust (PCT). METHOD: All patients undergoing this switch, in seven self-selected East Lancashire practices, were sent postal questionnaires covering demographics, experiences and views regarding switching, with no reminder. Practice pharmacists implementing switches in these practices were interviewed about processes and their views on these. RESULTS: Pharmacists' switching process involved a standard letter offering a telephone consultation or appointment, plus an information leaflet. They considered most patients accepted switches, with few requesting consultations. Four hundred and ninety-four patients were identified and a response rate of 48.6% (240) obtained. The majority of respondents were happy with the switch (53.7%) and how they were informed (60.1%), with these findings being positively correlated. However over half (52.9%) did not understand the reason for the switch, particularly those with lower educational qualifications. Patients unhappy about switching perceived they had experienced side effects, or only learned of the switch on collecting a prescription or did not recall the consultation offer. Respondents indicated a preference for future switches to involve a face-to-face consultation (59.8%), with two-thirds (65.2%) agreeing that community pharmacists should explain medication switches. CONCLUSION: The standard process used, in line with nationally-designed templates, resulted in many patients being unhappy with or lacking understanding of switching statins, suggesting that improvements may be needed. PMID- 22257273 TI - The effect of humeral torsion on rotational range of motion in the shoulder and throwing performance. AB - Several recent studies have found that throwing athletes typically have lower humeral torsion (retroversion) and a greater range of external rotation at the shoulder than non-athletes. How these two parameters are related is debated. This study uses data from a sample of both throwers and non-throwers to test a new model that predicts torsion values from a range of motion data. The model proposes a series of predicted regressions which can help provide new insight into the factors affecting rotational range of motion at the shoulder. Humeral torsion angles were measured from computed tomography scans collected from 25 male subjects. These values are compared to predicted torsion values for the same subjects calculated from both kinematic and goniometric range-of-motion data. Results show that humeral torsion is negatively correlated (goniometric: r = 0.409, P = 0.047; kinematic: r = -0.442, P = 0.035) with external rotational range of motion and positively correlated (goniometric: r = 0.741, P < 0.001; kinematic: r = 0.559, P = 0.006) with internal rotational range of motion. The predicted torsion values are highly correlated (goniometric: r = 0.815, P < 0.001; kinematic: r = 0.617, P = 0.006) with actual torsion values. Deviations in the data away from predicted equations highlight significant differences between high torsion and low torsion individuals that may have significant functional consequences. The method described here may be useful for non-invasively assessing the degree of torsion in studies of the evolution and biomechanics of the shoulder and arm, and for testing hypotheses about the etiology of repetitive stress injuries among athletes and others who throw frequently. PMID- 22257277 TI - Macrophage infiltration and renal damage are independent of matrix metalloproteinase 12 in the obstructed kidney. AB - AIM: To determine whether matrix metalloproteinase-12 (MMP-12) plays a functional role in renal interstitial macrophage accumulation, interstitial fibrosis or tubular apoptosis in the unilateral ureteric obstruction (UUO) model. BACKGROUND: MMP-12 is an enzyme that can cleave a number of extracellular matrix proteins and plays a role in macrophage-mediated injury in experimental models of emphysema and antibody-dependent glomerular disease. Macrophages are thought to promote renal fibrosis and tubular damage in the obstructed kidney. Furthermore, upregulation of MMP-12 expression by infiltrating macrophages in the obstructed kidney has been described, but the potential role of MMP-12 in renal injury induced by this non-immune insult is unknown. METHODS: Groups of eight MMP-12 gene deficient (MMP-12(-/-)) and wild type (WT) C57BL/6J mice were killed 3, 7 or 14 days after UUO. RESULTS: Analysis of three different lineage markers found no difference in the degree of interstitial macrophage accumulation between MMP-12( /-) and WT UUO groups at any time point. Examination of renal fibrosis by total collagen staining, alpha-SMA + myofibroblast accumulation, and TGF-beta1, PAI-1 and collagen IV mRNA levels showed no difference between MMP-12(-/-) and WT UUO groups. Finally, tubular damage (KIM-1 levels) and tubular apoptosis (cleaved caspase-3) in the obstructed kidney was not affected by MMP-12 gene deletion. CONCLUSION: In contrast to lung injury and antibody-dependent glomerular injury, MMP-12 is not required for renal interstitial macrophage accumulation, interstitial fibrosis or tubular damage in the obstructed kidney. PMID- 22257275 TI - In vitro antifungal activity of terpinen-4-ol, eugenol, carvone, 1,8-cineole (eucalyptol) and thymol against mycotoxigenic plant pathogens. AB - The aim of this study was to examine the effect of five naturally occurring compounds from essential oils on 10 different species of mycotoxigenic fungi involved in several plant diseases. The antifungal activities of terpinen-4-ol, eugenol, carvone, 1,8-cineole (eucalyptol) and thymol were observed in vitro on Fusarium subglutinans, Fusarium cerealis, Fusarium verticillioides, Fusarium proliferatum, Fusarium oxysporum, Fusarium sporotrichioides, Aspergillus tubingensis, Aspergillus carbonarius, Alternaria alternata and Penicillium sp. The naturally occurring compounds tested showed toxic effects on in vitro mycelium growth of all fungal species but with different level of potency. The results are encouraging for further investigations of in planta antifungal activities of these essential oils components. PMID- 22257278 TI - Laboratory evolution of new lactate transporter genes in a jen1Delta mutant of Saccharomyces cerevisiae and their identification as ADY2 alleles by whole-genome resequencing and transcriptome analysis. AB - Laboratory evolution is a powerful approach in applied and fundamental yeast research, but complete elucidation of the molecular basis of evolved phenotypes remains a challenge. In this study, DNA microarray-based transcriptome analysis and whole-genome resequencing were used to investigate evolution of novel lactate transporters in Saccharomyces cerevisiae that can replace Jen1p, the only documented S. cerevisiae lactate transporter. To this end, a jen1Delta mutant was evolved for growth on lactate in serial batch cultures. Two independent evolution experiments yielded growth on lactate as sole carbon source (0.14 and 0.18 h(-1) , respectively). Transcriptome analysis did not provide leads, but whole-genome resequencing showed different single-nucleotide changes (C755G/Leu219Val and C655G/Ala252Gly) in the acetate transporter gene ADY2. Introduction of these ADY2 alleles in a jen1Delta ady2Delta strain enabled growth on lactate (0.14 h(-1) for Ady2p(Leu219Val) and 0.12 h(-1) for Ady2p(Ala252Gly) ), demonstrating that these alleles of ADY2 encode efficient lactate transporters. Depth of coverage of DNA sequencing, combined with karyotyping, gene deletions and diagnostic PCR, showed that an isochromosome III (c. 475 kb) with two additional copies of ADY2(C755G) had been formed via crossover between retrotransposons YCLWDelta15 and YCRCDelta6. The isochromosome formation shows how even short periods of selective pressure can cause substantial karyotype changes. PMID- 22257279 TI - Who's to blame? Accounts of genetic responsibility and blame among Ashkenazi Jewish women at risk of BRCA breast cancer. AB - Genetic knowledge of disease risk may induce a sense of genetic responsibility whereby those who are at risk feel an obligation to take certain actions not only in relation to their own personal health but also to their family, their children and many other aspects of their life. This article examines genetic responsibility among Ashkenazi Jewish women at increased risk of BRCA genetic breast cancer. It demonstrates the ways in which accounts of blame help to mitigate or allocate genetic responsibility and in particular focuses on the temporal nature of women's accounts. Women locate responsibility or blame for genetic disease in the collective reproductive history of Ashkenazi Jews, currently among specific groups of Ashkenazi Jews, and this knowledge can have potential future reproductive consequences. A contradiction may arise between a pre-existing sense of responsibility to produce future generations of Jews with that of producing future breast cancer free children. The research is based on in depth qualitative interviews with 14 high-risk Ashkenazi Jewish women in London, England. PMID- 22257281 TI - Prediction of buffer catalysis in field and laboratory studies of pollutant hydrolysis reactions. PMID- 22257280 TI - ATR-FTIR studies on the adsorption/desorption kinetics of dimethylarsinic acid on iron-(oxyhydr)oxides. AB - Dimethylarsinic acid (DMA) is an organoarsenical compound that, along with monomethylarsonic acid, poses a health and an environmental risk, and a challenge to the energy industry. Little is known about the surface chemistry of DMA at the molecular level with materials relevant to geochemical environments and industrial sectors. We report herein the first in situ and surface-sensitive rapid kinetic studies on the adsorption and desorption of DMA to/from hematite and goethite at pH 7 and I = 0.01 M KCl using ATR-FTIR. Values for the apparent rates of adsorption and desorption were extracted from experimental data as a function of spectral components, flow rate of the aqueous phase, film thickness of hematite, and using chloride and hydrogen phosphate as desorbing agents. The adsorption kinetic data show fast and slow rates, consistent with the formation of more than one type of adsorbed DMA. Apparent adsorption and desorption rate constants were extracted from the dependency of the initial adsorption rates on [DMA(aq)]. Desorption rate constants were also extracted from desorption experiments using hydrogen phosphate and chloride solutions, and were found to be higher by 1-2 orders of magnitude than those using chloride. In light of the complex ligand exchange reaction mechanism of DMA desorption by phosphate species at pH 7, apparent desorption rate constants were found to depend on [hydrogen phosphate] with an order of 0.3. The impact of our studies on the environmental fate of DMA in geochemical environments, and the design of technologies to reduce arsenic content in fuels is discussed. PMID- 22257282 TI - Membrane-filter, direct-transfer technique for the analysis of asbestos fibers or other inorganic particles by transmission electron microscopy. PMID- 22257283 TI - Effects of metal chelates on wet flue gas scrubbing chemistry. PMID- 22257285 TI - Interspecies correlations of acute aquatic median lethal concentration for four standard testing species. PMID- 22257284 TI - A distribution model for binding of protons and metal ions by humic substances. PMID- 22257286 TI - Polycyclic aromatic ketones in environmental samples. PMID- 22257287 TI - The acute toxicity of butyl benzyl phthalate to the saltwater fish English sole, Parophrys vetulus. PMID- 22257289 TI - Organic free radicals associated with idiopathic liver lesions of English sole (Parophrys vetulus) from polluted marine environments. PMID- 22257288 TI - Interactions of polycyclic aromatic hydrocarbons with atmospheric pollutants. PMID- 22257290 TI - Adsorption and surface precipitation of metals on amorphous iron oxyhydroxide. PMID- 22257291 TI - Kinetics of the short-term consumption of chlorine by fulvic acid. PMID- 22257293 TI - Genomic consequences of genetic rescue in an insular population of bighorn sheep (Ovis canadensis). AB - Genetic rescue is a management intervention whereby a small population is supplemented with individuals from other populations in an attempt to reverse the effects of inbreeding and increased genetic load. One such rescue was recently documented in the population of bighorn sheep (Ovis canadensis) within the National Bison Range wildlife refuge (Montana, USA). Here, we examine the locus specific effects of rescue in this population using a newly developed genome-wide set of 195 microsatellite loci and first-generation linkage map. We found that the rate of introgression varied among loci and that 111 loci, 57% of those examined, deviated from patterns of neutral inheritance. The most common deviation was an excess of homozygous genotypes relative to neutral expectations, indicative of directional selection. As in previous study of this rescue, individuals with more introduced alleles had higher reproductive success and longevity. In addition, we found 30 loci, distributed throughout the genome, which seem to have individual effects on these life history traits. Although the potential for outbreeding depression is a major concern when translocating individuals between populations, we found no evidence of such effects in this population. PMID- 22257294 TI - Congenital diaphragmatic defects: proposal for a new classification based on observations in 234 patients. AB - Congenital diaphragmatic defects (CDDs) are a common group of birth defects, yet we presently know little about their pathogenesis. No systematic study documenting the detailed morphology of CDD has been performed, and current classification schemata of diaphragm phenotypes incompletely capture the location and extent of diaphragmatic involvement. To define the range of CDD anatomy, diaphragmatic pathology was reviewed from an examination of 181 autopsy records of children with CDDs at Children's Hospital Boston between 1927 and 2006. Defects were classified according to several parameters, including type (communicating versus noncommunicating) and location (anterior, posterior, etc.). The information permitted development of a phenotyping worksheet for prospective use on patients undergoing diaphragmatic repair at Children's Hospital Boston or MassGeneral Hospital for Children. Fifty-three patients who died between 1990 and 2006 had a total of 63 defects. Thirty-nine had a "classic" CDD phenotype (64% posterolateral, 18% hemidiaphragmatic aplasia, and 18% anterior). The remaining 19 defects, not fitting classical descriptions, were located in the posteromedial, anterolateral, or lateral regions of the diaphragm. Prospective data collected during surgical repair revealed posterolateral defects in 34 of 41 cases that demonstrated wide phenotypic variability in size, location, shape, type, and extent of organ displacement. Congenital diaphragmatic defects display significant phenotypic variation. Because rigorous anatomic evaluation and documentation are important steps towards elucidating the developmental biology of these disorders, we suggest establishment of a new and more precise classification using the model presented herein. PMID- 22257297 TI - Novel vancomycin-resistance transposon, plasmid replicon types, and virulence factors of vancomycin-resistant Enterococci in Zhejiang, China. AB - Forty-seven vancomycin-resistant Enterococcus (VRE) strains were isolated from clinical samples in 13 Zhejiang hospitals and fecal samples from ICU patients in a large teaching hospital in China. No VRE isolates were detected in healthy human subjects. CC17 was the main clonal complex in clinical Enterococcus faecium isolates but not in isolates from healthy human subjects. Novel vancomycin resistance transposons were detected among VRE strains. This is the first report demonstrating insertion of tnpA and fosB genes in the vanRS-vanH intergenic region of Tn1546 leading to coresistance to vancomycin and fosfomycin. The four plasmid replicon types (pRUM, pRE25, pEF418, and pB82) were more common in VRE isolates, suggesting their association with vancomycin resistance and nosocomial transmission. The prevalence rate of vancomycin-resistant Staphylococcus aureus related Inc18-like plasmid, pIP501, in VRE was 21.3%. The prevalence of the esp gene among VRE isolates was high (76.6%). In several VRE strains, the esp and hyl genes were cotransferred with the vanA gene by conjugation. Although the frequency of VRE is low in Chinese hospitals, its association with virulence determinants, the vancomycin-resistance transposon with other resistance gene insertions or plasmids may lead to multidrug resistance and the evolution of pathogenic VRE. PMID- 22257295 TI - Sialylation-independent mechanism involved in the amelioration of murine immune thrombocytopenia using intravenous gammaglobulin. AB - BACKGROUND: Sialylation of the N-linked glycan on asparagine-297 within the Fc region of intravenous gammaglobulins (IVIgs) was shown to be necessary for efficacy of IVIg in the amelioration of experimental inflammatory arthritis. To test the role for Fc sialylation of IVIg in immune modulating therapies beyond the K/BxN arthritis model, we examined the efficacy of sialylated compared to nonsialylated IVIg for the ability to attenuate immune thrombocytopenia (ITP) in a mouse model that approximates the clinical setting of human ITP. STUDY DESIGN AND METHODS: We used a published, passive anti-platelet (PLT) dose-escalation mouse model of ITP that approximates clinical ITP. PLT counts were followed over time before and after IVIg treatment. IVIg from two different manufacturers was used to prepare untreated and neuraminidase-treated IVIg. Sambucus nigra agglutinin (SNA) affinity chromatography was used to obtain sialic acid-enriched and -depleted IVIg. Sialic acid content was determined using Western blot, enzyme linked immunosorbent assay, and high-performance liquid chromatography. RESULTS: Results were the same using sialylated and desialylated (neuraminidase-treated) IVIg from two different manufacturers. No differences were observed between sialic acid-enriched and -depleted IVIg compared to normal IVIg in their efficacy to alleviate ITP. Using quantitative reverse transcription-polymerase chain reaction, no increase in the spleen FcgammaRIIB mRNA was detectable, but a pronounced increase of FcgammaRIIB mRNA in the marrow was seen after IVIg administration. CONCLUSIONS: We conclude that IVIg ameliorates experimental ITP by a mechanism that is independent of sialylation either in the Fc or the Fab region of IVIg. PMID- 22257298 TI - Soft vesicles in the synthesis of hard materials. AB - Vesicles of surfactants in aqueous solution have received considerable attention because of their use as simple model systems for biological membranes and their applications in various fields including colloids, pharmaceuticals, and materials. Because of their architecture, vesicles could prove useful as "soft" templates for the synthesis of "hard materials". The vesicle phase, however, has been challenging and difficult to work with in the construction of hard materials. In the solution-phase synthesis of various inorganic or macromolecular materials, templating methods provide a powerful strategy to control the size, morphology, and composition of the resulting micro- and nanostructures. In comparison with hard templates, soft templates are generally constructed using amphiphilic molecules, especially surfactants and amphiphilic polymers. These types of compounds offer advantages including the wide variety of available templates, simple fabrication processes under mild conditions, and easy removal of the templates with less damage to the final structures. Researchers have used many ordered molecular aggregates such as vesicles, micelles, liquid crystals, emulsion droplets, and lipid nanotubes as templates or structure directing agents to control the synthesis or assembly hard micro- and nanomaterials composed from inorganic compounds or polymers. In addition to their range of sizes and morphologies, vesicles present unique structures that can simultaneously supply different microenvironments for the growth and assembly of hard materials: the inner chamber of vesicles, the outer surface of the vesicles, and the space between bilayers. Two main approaches for applying vesicles in the field of hard materials have been explored: (i) in situ synthesis of micro- or nanomaterials within a specific microenvironment by vesicle templating and (ii) the assembly or incorporation of guest materials during the formation of vesicles. This Account provides an in-depth look at the research concerning the association of soft vesicles with hard materials by our laboratory and others. We summarize three main principles of soft vesicle usage in the synthesis of hard materials and detailed procedures for vesicle templating and the characterization of the synthetic mechanisms. By use of these guiding principles, a variety of inorganic materials have been prepared, such as quantum dots, noble metal nanoparticles, mesoporous structures, and hollow capsules. Polymerization within the vesicle bilayers enhances vesicle stability, and this strategy has been developed to synthesize hollow polymer materials. Since 2004, our group has pursued a completely different strategy in the synthesis of micro- and nanomaterials using vesicles as reactive templates. In this method, the vesicles act not only as templates but also as reactive precursors. Because of the location of metal ions on the bilayer membranes, such reactions are restricted to the interface of the vesicle membrane and solution. Finally, using the perspective of soft matter chemistry, we stress some basic criteria for vesicle templating. PMID- 22257299 TI - Gila monster bite. AB - A 29-year-old man was bitten on the forearm by a wild Gila monster. Radiographs demonstrated subcutaneous air. During a period of observation, erythema and edema progressed from the forearm to the axilla and he developed a significant leukocytosis. No purulence was found upon surgical evaluation. We hypothesize that air was introduced into the wound by the "pulsing," chewing-like action that the Gila monster made while it was attached to the man's forearm. PMID- 22257300 TI - QM/MM molecular dynamics study of purine-specific nucleoside hydrolase. AB - Although various T. vivax purine-specific inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH) crystal structures were determined in recent years, the mechanistic details for the cleavage of N-glycosidic bond and the release of base are still unclear. Herein, the irreversible hydrolysis reaction has been studied by ab initio QM/MM MD simulations, and the results indicate a highly dissociative and concerted mechanism. The protonation of substrate at N7 of inosine is found to strongly facilitate the hydrolysis process, while the hydrolysis reaction is less sensitive to the protonation state of Asp 40 residue. The proton-transfer channel and the dependence of activity on the anti/syn-conformation of substrate are also explored. PMID- 22257302 TI - Enhancing meaningful learning and self-efficacy through collaboration between dental hygienist and physiotherapist students - a scholarship project. AB - INTRODUCTION: Within the field of Dental Hygiene (DH) and Physiotherapy (PT), students are taught to use an evidence-based approach. Educators need to consider the nature of evidence-based practice from the perspective of content knowledge and learning strategies. Such effort to seek best available evidence and to apply a systematic and scholarly approach to teaching and learning is called scholarship of teaching and learning. OBJECTIVES: To evaluate the application of the scholarship model including an evidence-based approach to enhance meaningful learning and self-efficacy among DH and PT students. METHODS: Based on the research on student learning, three central theories were identified (constructivism, meaningful learning and self-efficacy). These were applied in our context to support learner engagement and the application of prior knowledge in a new situation. The DH students performed an oral health examination on the PT students, and the PT students performed an individual health test on the DH students; both groups used motivational interviewing. Documentation of student's learning experience was carried out through seminars and questionnaires. RESULTS: The students were overall satisfied with the learning experience. Most appreciated are that it reflected a 'real' professional situation and that it also reinforced important learning from their seminars. CONCLUSION: The scholarship model made the teachers aware of the importance of evidence-based teaching. Furthermore, the indicators for meaningful learning and increased self efficacy were high, and the students became more engaged by practising in a real situation, more aware of other health professions and reflected about tacit knowledge. PMID- 22257303 TI - Sunitinib-induced hand-foot syndrome in a renal cell carcinoma: a sclerodermatous and rheumatoid arthritis-like case. PMID- 22257304 TI - Internal morphology of human facet joints: comparing cervical and lumbar spine with regard to age, gender and the vertebral core. AB - Back pain constitutes a major problem in modern societies. Facet joints are increasingly recognised as a source of such pain. Knowledge about the internal morphology and its changes with age may make it possible to include the facets more in therapeutic strategies, for instance joint replacements or immobilisation. In total, 168 facets from C6/7 and L4/5 segments were scanned in a micro-computed tomography. Image analysis was used to investigate the internal morphology with regard to donor age and gender. Additional data from trabecular bone of the vertebral core allowed a semi-quantitative comparison of the morphology of the vertebral core and the facets. Porosity and pore spacing of the cortical sub-chondral bone does not appear to change with age for either males or females. In contrast, bone volume fraction decreases in females from approximately 0.4 to 0.2 , whereas it is constant in males. Trabecular thickness decreases during the ageing process in females and stays constant in males , whereas trabecular separation increases during the ageing process in both genders. The results of this study may help to improve the understanding of pathophysiological changes in the facet joints. Such results could be of value for understanding back pain and its treatment. PMID- 22257305 TI - Is the Chronic Kidney Disease Epidemiology Collaboration four-level race equation better than the cystatin C equation? AB - AIM: To evaluate the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) four-level race equation in the assessment of glomerular filtration rate (GFR) in Chinese people with chronic kidney disease (CKD), which was published in 2011, compared with the cystatin C-based GFR estimation equation (CysC GFR) and the combination of CysC and serum creatinine equation (CysC-Scr GFR). METHODS: The CKD-EPI four-level race equation estimated GFR (CKD-EPI GFR) was compared with the CysC GFR and CysC-Scr GFR. Three equations were compared with body surface area (BSA) standardized GFR (sGFR), which was measured by (99m) Tc-DTPA renal dynamic imaging method in 111 CKD cases. RESULTS: A statistically significant correlation was found between sGFR and CKD-EPI GFR, CysC GFR and CysC-Scr GFR. Three estimated GFR (eGFR) equations of 30% accuracy were 58.6%, 56.8% and 63.5%, respectively. Average deviations of eGFR from sGFR were 2.34, 1.19, and 1.32 (mL/min per 1.73 m(2)) (P > 0.05), respectively. There was no significant deviation in the CKD from stages 1 to 5 in CKD-EPI GFR and CysC-Scr GFR. However, when estimated by CysC GFR, the deviation was increased, with the value of 12.41 mL/min per 1.73 m(2) (P= 0.002) in CKD stage 5. CONCLUSION: Our results showed that in a Chinese population with CKD, CKD-EPI GFR, CysC GFR and CysC-Scr GFR of bias and overall accuracy of 30% were very similar. There was little advantage in adding Asian coefficient to modifying the CKD-EPI equation. CysC GFR overestimated GFR in patients with CKD stages 4 and 5. PMID- 22257306 TI - Impaired cognitive performance in subjects with methamphetamine dependence during exposure to neutral versus methamphetamine-related cues. AB - BACKGROUND: Chronic methamphetamine abuse is associated with cognitive deficits that may impede treatment in methamphetamine-dependent patients. Exposure to methamphetamine-related cues can elicit intense craving in chronic users of the drug, but the effects of exposure to drug cues on cognitive performance in these individuals are unknown. OBJECTIVES: This study assessed whether exposure to methamphetamine-related visual cues can elicit craving and/or alter dual task cognitive performance in 30 methamphetamine-dependent subjects and 30 control subjects in the laboratory. METHODS: Reaction time, response errors, and inhibition errors were assessed on an auditory Go-No Go task performed by adult participants (total N = 60) while watching neutral versus methamphetamine-related video cues. Craving was assessed with the Within-Session Rating Scale modified for methamphetamine-dependent subjects. RESULTS: Exposure to methamphetamine related cues elicited craving only in methamphetamine-dependent subjects. Even in the absence of methamphetamine cues, methamphetamine-dependent subjects exhibited slower reaction times and higher rates of both inhibition and response errors than control subjects did. Upon exposure to methamphetamine cues, rates of both response errors and inhibition errors increased significantly in methamphetamine dependent subjects. Control subjects exhibited no increase in inhibition errors and only slightly increased rates of response errors upon exposure to methamphetamine cues. Response error rates, but not inhibition error rates or reaction times, during methamphetamine cue exposure were significantly associated with craving scores in methamphetamine-dependent subjects. CONCLUSIONS AND SIGNIFICANCE: Methamphetamine-dependent individuals exhibit cognitive performance deficits that are more pronounced during exposure to methamphetamine-related cues. Interventions that reduce cue reactivity may have utility in the treatment of methamphetamine dependence. PMID- 22257307 TI - Ruthenium-catalyzed oxidative C-H bond olefination of N-methoxybenzamides using an oxidizing directing group. AB - Ruthenium-catalyzed oxidative C-H bond olefination of N-methoxybenzamides using an oxidizing directing group with a broad substrate scope is reported. The reactions of N-methoxybenzamides with acrylates in MeOH and styrene (or norbornadiene) in CF(3)CH(2)OH afforded two types of products. PMID- 22257308 TI - The ColRS system of Xanthomonas oryzae pv. oryzae is required for virulence and growth in iron-limiting conditions. AB - Xanthomonas oryzae pv. oryzae, the causal agent of bacterial blight of rice, produces siderophores only under iron-limiting conditions. We screened 15 400 mTn5-induced mutants of X. oryzae pv. oryzae and isolated 27 mutants that produced siderophores even under iron-replete conditions. We found that the mTn5 insertions in 25 of these mutants were in or close to six genes. Mutants with insertions in five of these genes [colS, XOO1806 (a conserved hypothetical protein), acnB, prpR and prpB] exhibited a deficiency for growth on iron-limiting medium and a decrease in virulence. Insertions in a sixth gene, XOO0007 (a conserved hypothetical protein), were found to affect the ability to grow on iron limiting medium, but did not affect the virulence. Targeted gene disruptants for colR (encoding the predicted cognate regulatory protein for ColS) also exhibited a deficiency for growth on iron-limiting medium and a decrease in virulence. colR and colS mutants were defective in the elicitation of hypersensitive response symptoms on the nonhost tomato. In addition, colR and colS mutants induced a rice basal defence response, suggesting that they are compromised in the suppression of host innate immunity. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that a functional ColRS system is required for the optimal expression of several genes encoding components of the type 3 secretion system (T3SS) of X. oryzae pv. oryzae. Our results demonstrate the role of several novel genes, including colR/colS, in the promotion of growth on iron-limiting medium and the virulence of X. oryzae pv. oryzae. PMID- 22257311 TI - Adrenal cytomegaly is a frequent pathologic finding in hemoglobin bart hydrops fetalis. AB - Adrenocortical cytomegaly (AC) is a relatively uncommon phenomenon but tends to occur in certain situations, including specific congenital anomalies and hydrops due to maternal-fetal Rhesus incompatibility. Because the pathology in the latter condition does not differ greatly from hemoglobin (Hb) Bart hydrops fetalis, we performed a retrospective review of fetal and perinatal autopsy cases with Hb Bart to determine the prevalence of AC in that condition. Over a 10-year period (2001-2010) at King Chulalongkorn Memorial Hospital, there were 16 hydropic cases confirmed to have Hb Bart. Adrenocortical cytomegaly was found in 13 cases (81%). For comparison, we determined the occurrence of AC in cases of hydrops fetalis not due to Hb Bart (n = 33) and a heterogeneous group of congenital anomalies (n = 34). Adrenocortical cytomegaly was identified in only 1 case of Beckwith Wiedemann syndrome and 2 cases of anencephaly. Thus, AC is a common finding in cases of Hb Bart, a finding not previously documented. Moreover, our study suggests that Hb Bart is one of the conditions most commonly associated with AC. The reasons for this are not known. The mean Hb levels for the hydrops cases with Hb Bart and those with other forms of anemia showed no significant difference (P = 0.63), nor was there any significant difference in Hb levels between cases of Hb Bart with and without AC. Nonetheless, the consistency of AC in cases of Hb Bart suggests that further study of this particular group of patients might shed light on the pathogenesis of this poorly understood pathologic finding. PMID- 22257309 TI - Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Metabolic disturbances represent a well-known side effect of second generation antipsychotics. However, studies comparing second generation antipsychotic drugs (SGAPs) and first generation antipsychotic drugs (FGAPs) through administrative databases have shown contrasting findings, which may be attributable to methodological differences. WHAT THIS PAPER ADDS: * The definition of antipsychotic exposure impacts on the association between antipsychotics and metabolic risk in studies carried out through administrative databases. * Considering cumulative exposure to antipsychotics or including patients exposed to an antipsychotic drug for months or years is likely to over-represent patients who tolerate the drug well with a depletion of susceptible effects. * Antipsychotic drug exposure is a time-varying determinant and episodes of no use, past use and current use should be distinguished over the study period to avoid any misclassification bias that might lead to misleading findings. AIMS: To assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and 'conventional' mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration). METHODS: A historical fixed cohort was identified from the 2004-2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti diabetic or lipid-lowering drug. RESULTS: A metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P= 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P= 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P= 0.20). CONCLUSIONS: The definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results. PMID- 22257312 TI - Evaluation and remediation of bulk soap dispensers for biofilm. AB - Recent studies evaluating bulk soap in public restroom soap dispensers have demonstrated up to 25% of open refillable bulk-soap dispensers were contaminated with ~ 6 log(10)(CFU ml(-1)) heterotrophic bacteria. In this study, plastic counter-mounted, plastic wall-mounted and stainless steel wall-mounted dispensers were analyzed for suspended and biofilm bacteria using total cell and viable plate counts. Independent of dispenser type or construction material, the bulk soap was contaminated with 4-7 log(10)(CFU ml(-1)) bacteria, while 4-6 log(10)(CFU cm(-2)) biofilm bacteria were isolated from the inside surfaces of the dispensers (n = 6). Dispenser remediation studies, including a 10 min soak with 5000 mg l(-1) sodium hypochlorite, were then conducted to determine the efficacy of cleaning and disinfectant procedures against established biofilms. The testing showed that contamination of the bulk soap returned to pre-test levels within 7-14 days. These results demonstrate biofilm is present in contaminated bulk-soap dispensers and remediation studies to clean and sanitize the dispensers are temporary. PMID- 22257313 TI - Genomic signature of natural and anthropogenic stress in wild populations of the waterflea Daphnia magna: validation in space, time and experimental evolution. AB - Natural populations are confronted with multiple selection pressures resulting in a mosaic of environmental stressors at the landscape level. Identifying the genetic underpinning of adaptation to these complex selection environments and assigning causes of natural selection within multidimensional selection regimes in the wild is challenging. The water flea Daphnia is a renowned ecological model system with its well-documented ecology, the possibility to analyse subfossil dormant egg banks and the short generation time allowing an experimental evolution approach. Capitalizing on the strengths of this model system, we here link candidate genome regions to three selection pressures, known to induce micro evolutionary responses in Daphnia magna: fish predation, parasitism and land use. Using a genome scan approach in space, time and experimental evolution trials, we provide solid evidence of selection at the genome level under well-characterized environmental gradients in the wild and identify candidate genes linked to the three environmental stressors. Our study reveals differential selection at the genome level in Daphnia populations and provides evidence for repeatable patterns of local adaptation in a geographic mosaic of environmental stressors fuelled by standing genetic variation. Our results imply high evolutionary potential of local populations, which is relevant to understand the dynamics of trait changes in natural populations and their impact on community and ecosystem responses through eco-evolutionary feedbacks. PMID- 22257314 TI - The effect of blood storage duration on in-hospital mortality: a randomized controlled pilot feasibility trial. AB - BACKGROUND: Whether the duration of storage of blood has an impact on patient outcomes remains controversial. The objective was to determine feasibility of a comparative effectiveness trial to evaluate duration of storage of blood before transfusion on in-hospital mortality. STUDY DESIGN AND METHODS: A single-center randomized controlled trial was performed at an acute care hospital in Canada between June and December 2010, involving consecutive hospitalized patients needing blood transfusion. Patients (n=910) were randomly assigned in a 1:2 ratio to receive freshest available versus standard-issue (oldest available) blood. Four feasibility criteria were measured: proportion of eligible patients randomized, contrast in age of blood between treatment groups, real-time data acquisition, and trial impact on blood outdating. In-hospital mortality was also reported. RESULTS: A total of 1075 of 1129 patients (95.2%) were eligible and 910 of 1075 (84.7%) were randomized: 309 received freshest available blood (1157 units), and 601 received standard-age blood (2369 units). Contrast in mean age of the oldest blood transfused between groups was 14.6 days: 12.0 (standard deviation [SD], 6.8) days in the fresh arm and 26.6 (SD, 7.8) days in the standard arm. Weekly recruitment and event reporting were achieved for all patients. The blood outdate rate was 0.10%. In-hospital mortality was 10.5%: 35 deaths (11.3%) in the fresh arm and 61 deaths (10.1%) in the standard arm (odds ratio, 1.13; 95% confidence interval [CI], 0.73, 1.76). CONCLUSION: It is feasible to conduct a large comparative effectiveness trial comparing the effect of freshest available versus standard-issue blood on in-hospital mortality. The wide CI around the estimate for in-hospital mortality supports the need for a large trial. PMID- 22257317 TI - Multimodal characterization of a linear DNA-based nanostructure. AB - Designer DNA structures have garnered much interest as a way of assembling novel nanoscale architectures with exquisite control over the positioning of discrete molecules or nanoparticles. Exploiting this potential for a variety of applications such as light-harvesting, molecular electronics, or biosensing is contingent on the degree to which various nanoarchitectures with desired molecular functionalizations can be realized, and this depends critically on characterization. Many techniques exist for analyzing DNA-organized nanostructures; however, these are almost never used in concert because of overlapping concerns about their differing character, measurement environments, and the disparity in DNA modification chemistries and probe structure or size. To assess these concerns and to see what might be gleaned from a multimodal characterization, we intensively study a single DNA nanostructure using a multiplicity of methods. Our test bed is a linear 100 base-pair double-stranded DNA that has been modified by a variety of chemical handles, dyes, semiconductor quantum dots, gold nanoparticles, and electroactive labels. To this we apply a combination of physical/optical characterization methods including electrophoresis, atomic force microscopy, transmission electron microscopy, dynamic light scattering, Forster resonance energy transfer, voltammetry, and structural modeling. In general, the results indicate that the differences among the techniques are not so large as to prevent their effective use in combination, that the data tend to be corroborative, and that differences observed among them can actually be quite informative. PMID- 22257319 TI - Rare case of basal cell carcinoma arising in a nevus sebaceous on the upper arm. PMID- 22257321 TI - EPHX1 gene polymorphisms in alcohol dependence and their distribution among the Indian populations. AB - BACKGROUND: The microsomal epoxide hydrolase is a phase II enzyme of the biotransformation. The human epoxide hydrolase 1 (EPHX1) gene lies in the chromosomal region 1q42.1 and exhibits polymorphism. Two single nucleotide polymorphisms (SNPs) have been described in the coding region of the EPHX1 gene that produces two protein variants. SUBJECTS AND METHODS: A total of 604 samples belonging to 13 Indian populations were included in this study. Based on the DSM IV criteria, 184 individuals from Kota population were classified into alcoholism cases (100) and controls (84). Genotypes of Tyr113His and His139Arg polymorphisms in the EPHX1 gene were determined using PCR and sequencing. Associations were tested using Pearson's chi(2) test and haplotype analyses. RESULTS: We found significant association between EPHX1 gene Tyr113His polymorphism and alcoholism in the Kota population (T vs. C: OR = .615, 95% CI = .399-.949, p = .027; TT vs. CC + CT: OR = .536, 95% CI = .297-.969, p = .038). The very slow activity haplotype CA (113His-139His) was also found to be associated with alcohol dependence (p = .048). Analysis of additional populations demonstrated that the Tyr113His polymorphism significantly deviated from Hardy-Weinberg equilibrium in four populations but only one population deviated for the His139Arg locus. All populations shared the four possible two-site haplotypes. Linkage disequilibrium between these two loci was not significant in any of the population studied. CONCLUSION: EPHX1 gene polymorphisms and haplotypes are associated with an increased risk for alcoholism in the Kota population. This is the first report from India that will serve as a template for future investigations of the prevalence of EPHX1 alleles in association with various clinical entities. PMID- 22257323 TI - Oversimplifying the complexities of nursing. PMID- 22257322 TI - The serine-proline turn: a novel hydrogen-bonded template for designing peptidomimetics. AB - Serine-Proline (SP) dipeptide motifs have been shown to form unique hydrogen bonding patterns in protein crystal structures. Peptides were designed to mimic these patterns by forming the 6 + 10 and the 9 + 10 hydrogen-bonded rings. Factors that contribute to the formation of SP turns include controlling backbone flexibility and amino acid chirality along with creating a hydrophobic environment around the intramolecular hydrogen bonds. PMID- 22257324 TI - Status of costing hospital nursing work within Australian casemix activity-based funding policy. AB - Australia has a long history of patient level costing initiated when casemix funding was implemented in several states in the early 1990s. Australia includes, to some extent, hospital payment based on nursing intensity adopted within casemix funding policy and the Diagnostic Related Group system. Costing of hospital nursing services in Australia has not changed significantly in the last few decades despite widespread introduction of casemix funding policy at the state level. Recent Commonwealth of Australia National Health Reform presents change to the management of the delivery of health care including health-care costing. There is agreement for all Australian jurisdictions to progress to casemix-based activity funding. Within this context, nurse costing infrastructure presents contemporary issues and challenges. An assessment is made of the progress of costing nursing services within casemix funding models in Australian hospitals. Valid and reliable Australian-refined nursing service weights might overcome present cost deficiencies and limitations. PMID- 22257325 TI - The health-care environment through the eyes of a child--does it soothe or provoke anxiety? AB - Health-care environments can be intimidating and scary places especially in the eyes of a child. When attempting to create spaces that are engaging to children, how do we know what works and are the needs the same across the age groups? In a 2011 comprehensive systematic review, a total of 20 studies were reviewed to answer the question: Can the health-care environment have an impact on children's anxiety? The results of the review showed that the built environment can support and enhance the coping strategies utilized by children, however further research is needed. The aim of this article is to summarize the findings of the review highlighting simple design strategies of minimal cost to large construction projects warranting extensive resources. Careful evaluation of space incorporating end-user input can result in age appropriate environments that support safe, quality care and enhance a positive health-care experience for all. PMID- 22257326 TI - Nursing students' perceptions about nursing care plans: a Turkish perspective. AB - This descriptive study was planned in order to assess self-perceived sufficiency levels of nursing students at preparing nursing care plans and also determine the effect of these plans on students' occupational development. Sample of the study was consisted of 55 nursing students who were taking oncological training. Data were collected by using Personal Information Form and Student Care Plan Evaluation Form. Non-parametric tests were used in data analysis. Students perceived themselves 'insufficient' although assessing reproductive neurological and cardiovascular systems, respectively, and also interpreting results of hemogram and urine tests. No significant difference was found between the initial and last nursing care plans prepared by the students during clinical training. Sixty % of students reported that preparing and implementing nursing care plans had favourable effects on their occupational development. Results suggest that students should be well prepared before clinical training programmes and also nursing care plans should be revised and used in more proper and practical ways in order to enhance students' occupational development. PMID- 22257327 TI - The assessment of quality of life in female Turkish patients with overactive bladder. AB - The objective of this study was to examine the quality of life in female Turkish patients with overactive bladder (OAB). The investigation was conducted as a cross-sectional study between January and April 2010. Two hundred eighty female patients responded to the Overactive Bladder Validated Eight-Question Screener, the OAB disease-specific health-related quality-of-life scale (OAB questionnaire (OAB-q)) and the general quality-of-life scale EuroQol Five-Dimensional Questionnaire (EQ-5D) for the study. Of the 280 patients, 38.9% was classified as having OAB. The mean age was 47.0 +/- 8.7. All of the quality-of-life domains (coping, concern, sleep and social) and OAB-q total scores in women with OAB were significantly worse than in women without OAB (P < 0.001 for all). Similarly, the EQ-5D(index) and EQ-5D(VAS) scores for women with OAB were significantly worse than for women without OAB (P < 0.001 and P = 0.006, respectively). OAB-q and EQ 5D(index) scores in menopausal women were significantly lower than non-menopausal women (P < 0.05) in patients with OAB. In conclusion, OAB negatively affects quality of life in Turkish women. However, many women's quality of life can be improved if the patients seek medical treatment. Thus, nurses should encourage the patients to seek medical support in order to cope with health-related quality of-life problems. PMID- 22257328 TI - Participants' perspectives of a multi-component, group-based weight loss programme supplement for cardiac rehabilitation: a qualitative study. AB - Addressing overweight and obesity in people with cardiovascular risk factors is an important aspect of cardiac rehabilitation, but minimal implementation of targeted strategies has occurred. The aim of this study was to describe participants' perspectives of a multi-component, group-based weight loss supplement to cardiac rehabilitation programmes. Four focus groups of participants completing the intervention (n = 16) and maintenance phases (n = 19) of the Healthy Eating and Exercise Lifestyle Program (HEELP) were conducted. Interviews were transcribed and thematically analyzed using an inductive process. The overall theme of participants' responses was that HEELP helped them reprogramme their lifestyle behaviours to achieve weight loss. The programme was unique compared with other weight loss programmes because it was delivered and developed by familiar and expert health professionals who tailored the programme to participants' health status. Themes included the process of recognizing and deciding to make a commitment to managing their weight problem and feeling supported by the group and the staff to do this. Participants valued the group based structure and the specific tools used in the programme. The programme content and structure provides a framework for the development of supplemental programmes for overweight and obese people at high cardiovascular risk. PMID- 22257329 TI - Critical discourse analysis: understanding change in maternity services. AB - This paper provides an example of the use of critical discourse analysis (CDA) in the area of maternity care policy and describes the process of CDA as an effective research method for understanding the influences of change in the context of Australian maternity services. CDA is a methodological approach that examines how discourse is formed and given power, as a result of how power is used, who uses it and the context within which this usage takes place. The application of CDA is described in this study for the purpose of examining key stakeholder use of knowledge and power for the purpose of influencing the direction of the maternity services reform. The CDA theoretical framework guided discourse identification and analysis of the purpose behind the discourse through examination of power relationships between key stakeholders. The use of a theoretical lens in the form of neoliberalism to supplement the theoretical framework facilitated the exposure of forces intrinsic to the maternity care context driving change. PMID- 22257330 TI - Self-care strategies to facilitate sleep in patients with heart disease--a qualitative study. AB - This study aimed at exploring and describing the self-care management strategies used by patients with coronary artery disease to facilitate sleep. Qualitative interviews in a dialogue manner, in a phenomenographic reference frame analyzed according to manifest and latent principles of qualitative content analysis, were performed. A purposeful sampling technique was used including 11 patients with coronary heart disease in a Heart Medical Unit in a general hospital setting. Two main themes were identified: 'sleep-rhythm' and 'sleep-hygiene' including four descriptive categories. The categories reveal five basic responses including emotions, cognition, physical symptoms (reactions), behaviours and/or the sleep environment, which were related to perceived or actual presence of sleep-wake problems and health that were the underlying reason for the self-care management strategies. Basically, intervention studies that address these five responses for choice of non-pharmacological methods based on cognitive behavioural therapy provided by nurses are needed. PMID- 22257331 TI - Efficacy of frequent blood pressure and heart rate monitoring for early identification of bleeding following percutaneous coronary intervention. AB - Monitoring of patients' vital signs is an important component of postpercutaneous coronary intervention (post-PCI) for bleeding early detection. This study was performed in order to identify the efficacy of frequent blood pressure (BP) and heart rate (HR) monitoring for early identification of bleeding following PCI. The descriptive study was conducted at the cardiology unit of a university hospital with a study sample of 1292 patients. Data collection instruments were designed by the authors. In a comparison of the presence of abnormal BP-HR between the groups with and without bleeding, the difference was not significant on arrival and not at 15, 45 and 60 min posttransfer. There is no association between the frequent vital sign measurement in the first hour and early diagnosis of bleeding. The frequency of follow up after PCI should be based on the patient's condition, the nurse's clinical expertise and the institutional protocols. PMID- 22257332 TI - Rapid intervention and treatment zone: redesigning nursing services to meet increasing emergency department demand. AB - The impact of emergency nursing roles in demand management systems is poorly understood. The aim of this study was to evaluate emergency nurses' role in a specific emergency department (ED) demand management system: rapid intervention and treatment zone (RITZ). A descriptive exploratory approach was used. Data were collected from audit of 193 randomly selected patient records and 12 h of clinical practice observation. The median age of participants was 31 years, 51.8% were males and 99.5% were discharged home. Nurse qualifications or seniority had no significant effect on waiting time or length of stay (LOS). There were disparities between documented and observed nursing practice. The designation and qualifications of RITZ nurses made little difference to waiting times and ED LOS. Specific documentation and communication systems for areas of the ED that manage large numbers of low complexity patients warrant further research. PMID- 22257333 TI - Nurses' burnout and unmet nursing care needs of patients' relatives in a Turkish State Hospital. AB - One of the biggest problems of work life today is burnout. With burnout, satisfaction of clients and service givers reduces. In this study, burnout levels of nurses working in the internal, surgical and intensive care units of a university hospital and the unmet needs of the patients' relatives related to nursing care were investigated. In the study, 225 nurses and 222 relatives of patients constituted the sample group of this study. Three separate forms were used in the study, namely, Nurse and Patient Relative Identification Form, the Maslach Burnout Inventory and the Nursing Services Satisfaction Inventory. In the study, burnout levels of the nurses were found to be high. Conditions like younger ages, scarcity of experience in the profession, lower levels of education, having chosen the profession and the unit they work in not willingly and working in environments like intensive care increase the burnout and as a result, expectations of the relatives of patients from nursing care are not fully met. Some suggestions have been made to make some regulations to prevent the burnout of nurses and to increase the satisfaction of relatives. PMID- 22257334 TI - The use of multidose vials and fingerstick blood sampling devices in Korean emergency departments and intensive care units. AB - This study was performed to compare compliance with standard precautions for the use of multidose vials (MDVs) and fingerstick devices in emergency departments (EDs) and intensive care units (ICUs). Between December 2007 and February 2008, 389 nurses from the EDs or ICUs of six university-affiliated hospitals in Korea were asked to complete the questionnaire. A total of 338 (86.9%) nurses completed the survey, corresponding to 159 of 184 ED and 179 of 205 ICU nurses. A comparison of MDV use in EDs and ICUs indicated a significant difference only in disinfection of the rubber septum of heparin vials; 88.1% of ED nurses and 96.6% of ICU nurses stated that they always disinfected the rubber septum of heparin vials whenever drawing medication (P = 0.003). The use of separate fingerstick devices for each patient (71.7% vs. 54.5%) and disinfection of these devices after each use (36.5% vs. 26.0%) were more common in ED nurses. The rate of good hand hygiene was lower in ED nurses, both before (43.7% vs. 74.3%) and after (64.6% vs. 91.6%) the use of fingerstick devices (P < 0.001 for both). There is a need to improve compliance with standard precautions, especially hand hygiene, in EDs. PMID- 22257335 TI - Nature and intensity of the pain following thoracotomy. AB - The aim of this study is to clearly define and describe the pain characteristics that disturb the patients having thoracotomy in postoperative period. It can be possible to manage to get pains under control according to pain characteristics. The study included 70 patients who underwent thoracotomy (lobectomy or segmentectomy and mean duration of surgery was 90 min) and were hospitalized in the intensive care unit of the Thoracic Surgery Department of Akdeniz University Hospital between November 2007 and November 2008. In this study, 68.6% of the patients were male and mean age was 49.90. The study was achieved. Consider that the patients have pain in the first 24 h postoperatively and the effect of sedation, the Behavioural Pain Scale, which is filled out by a researcher, and the Verbal Category Scale, which allows the patient to define his/her pain with short responses, were used for pain assessment. Pain was assessed at the postoperative 4th, 8th, 16th, 24th and 48th hours, following extubation. The patients mostly reported throbbing (65.7%), stabbing (65.7%) and stinging (62.9%) pain in the incision site, while 40% of them (n = 28) reported a 'sharp', 'exhausting' and 'splitting' pain. The investigation of the factors increasing pain during the postoperative period revealed that most of the patients (85.7%) reported that their pain increased due to movement in bed and/or walking, while 74.3%, 68.6%, 54.3% and 37.1% of them stated that their pain increased due to breathing, coughing, chest tube movement and noisy environment, respectively. Each pain characteristics, throbbing, stabbing and stinging, can be specifically relief using one or more methods such as touching on the incision site, little press on the thoracotomy region, talking to the patient about pain, etc. We determined that the patients experienced a sharp, stabbing and unbearable pain in the first 48 postoperative hours. Therefore, our study suggests that some interventions such as pressure exertion and touching to the painful area were stated to provide pain relief to the patients. PMID- 22257336 TI - Nurses' protective measures during chemotherapy preparation and administration in Turkey*. AB - Chemotherapeutic agents are known to be carcinogenic, teratogenic and mutagenic to humans. Occupational exposure to chemotherapeutic agents is a potential risk. The aim of this study was to determine the safety measures on personal and environmental protection taken by nurses during chemotherapy preparation and administration. Current study was conducted between 1 April and 30 June 2007 in the chemotherapy administration units of all hospitals in Samsun, North of the Turkey. Seventy-three nurses were included in the study group. Data were obtained via questionnaire form. Findings for nurses' safety behaviour and usage of recommended health safety measures showed that, notwithstanding the rules and regulations pertaining to chemotherapeutics, nurses did not comply with them fully. The study expanded that health providers and clinical environment are under threat for contamination of chemotherapeutics. The results clearly point the importance of need for regular education programme. This study also revealed the necessity for improvement of the working environment. PMID- 22257337 TI - Psychometric evaluation of the Norwegian version of the Person-centred Care Assessment Tool. AB - The Person-centred Care Assessment Tool (P-CAT) was developed as a self-reporting assessment scale for staff ratings of the person-centredness of their nursing practice. This study investigates the psychometric properties of P-CAT in a sample of staff working in residential units for older people. Descriptive characteristics were calculated for each item and an independent-sample t-test was used to compare ratings from different groups. Internal consistency and reliability were examined using the Cronbach's alpha coefficient. Exploratory factor analysis was used to evaluate construct validity. Test-retest reliability was examined by means of intra-class correlation and the Pearson correlation coefficient. The mean score of P-CAT was 45.3 (standard deviation 7.8). Cronbach's alpha was 0.83. The factor analysis resulted in a two-component solution organizing the items into two subscales. There were significant differences between ordinary care units and special-care units and between various occupational groups, indicating a discriminating ability of the tool. PMID- 22257338 TI - Increased accumulation and stability of rotavirus VP6 protein in tobacco chloroplasts following changes to the 5' untranslated region and the 5' end of the coding region. AB - Rotavirus is the main cause of gastroenteritis in children worldwide, and the World Health Organisation has recommended that a rotavirus vaccine should be included in all infant immunization programmes. VP6 is the most immunogenic rotavirus subunit and is a potential target for an oral subunit vaccine. VP6 accumulated at up to 3% of total soluble protein in the young leaves of transplastomic tobacco plants, but the protein was unstable and was lost as the leaves aged. The aim of this study was to alter the 5'-untranslated region (5' UTR) and the 5' end of the coding region of VP6 cDNA in an attempt to increase the expression and stability of VP6 protein in tobacco chloroplasts. The inclusion of the 5'-UTR from gene 10 of bacteriophage T7 (T7g10) and the addition of 15 nucleotides, encoding five additional amino acid residues, at the 5' end of the coding region increased the expression to >15% of total leaf protein and stabilized the protein in ageing leaves. Plants containing VP6 expression constructs with the rbcL 5'-UTR and with the native VP6 5' end of the coding region produced VP6 protein at only 1.9% of total leaf protein. Both the T7g10 5' UTR and the additional 15 nucleotides increased transcript accumulation and translational efficiency compared with VP6 constructs containing the rbcL 5'-UTR. The VP6 protein produced from all gene constructs appeared to be susceptible to proteolytic processing at its N-terminal region. However, in all transplastomic lines, VP6 proteins assembled into the trimeric form found in the rotavirus capsid. PMID- 22257339 TI - Eudragit((r)) RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets. AB - The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit((r)) RL PO, Eudragit((r)) RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7 kN. The tablets were thermally treated at different temperatures (50 and 75 degrees C) for 5 h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit((r)) RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit((r)) RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled. PMID- 22257340 TI - A method for the determination of acrylamide in a broad variety of processed foods by GC-MS using xanthydrol derivatization. AB - A novel GC-MS method was developed for the determination of acrylamide, which is applicable to a variety of processed foods, including potato snacks, corn snacks, biscuits, instant noodles, coffee, soy sauces and miso (fermented soy bean paste). The method involves the derivatization of acrylamide with xanthydrol instead of a bromine compound. Isotopically labelled acrylamide (d3-acrylamide) was used as the internal standard. The aqueous extract from samples was purified using Sep-PakTM C18 and Sep-PakTM AC-2 columns. For amino acid-rich samples, such as miso or soy sauce, an ExtrelutTM column was used for purification or extraction. After reaction with xanthydrol, the resultant N-xanthyl acrylamide was determined by GC-MS. The method was validated for various food matrices and showed good linearity, precision and trueness. The limit of detection and limit of quantification ranged 0.5-5 and 5-20 ug kg-1), respectively. The developed method was applied as an exploratory survey of acrylamide in Japanese foods and the method was shown to be applicable for all samples tested. PMID- 22257341 TI - In vivo accuracy of three electronic root canal length measurement devices: Dentaport ZX, Raypex 5 and ProPex II. AB - AIM: To compare in vivo three different electronic root canal length measurement devices: Dentaport ZX, Raypex 5 and ProPex II. METHODOLOGY: Thirty single-rooted permanent teeth scheduled for extraction because of periodontal disease were selected from 10 adult patients (ranging from 45 to 67 years) and divided into three groups of 10 teeth. Before the extraction, an access cavity was prepared and the crown was adjusted to establish a stable reference point for all measurements. The working length in Group 1 was determined using the Dentaport ZX apex locator. A K-file with the largest diameter that could reach the last green bar on the screen was stabilized in the canal using a dual-curable flow resin composite. The same procedure was used for the Raypex 5 (the file reached the last yellow bar) and Propex II (0.0 orange bar) apex locators. The teeth were then extracted and cleared. The distance between the tip of the file and the major foramen was then calculated for each tooth using digital photography according to Axiovision AC software (Carl Zeiss). Positive values were assigned when the file tip passed beyond the major foramen, negative values when the tip was short of the foramen and zero value when the file tip and the foramen coincided. Statistical analysis was performed using the chi-squared test or Fisher's exact test (P <= 0.05). RESULTS: Dentaport ZX, Raypex 5 and ProPex IotaIota produced, respectively, 6, 2 and 4 out of 10 correct measurements, 0, 6 and 5 long measurements and 4, 2, and 1 short measurements. The differences between the three electronic root canal length measurement devices were not significant (P = 0.507). CONCLUSIONS: Under the in vivo conditions of this study, the three electronic root canal length measurement devices were not significantly different in terms of locating the major foramen. PMID- 22257343 TI - Editorial: Phosphate here, phosphate there.... PMID- 22257344 TI - Currents. PMID- 22257345 TI - Regulating cancer risks. PMID- 22257346 TI - Contaminant degradation in water. PMID- 22257347 TI - Regulatory Focus: Groundwater monitoring. PMID- 22257349 TI - Miami meeting report. PMID- 22257348 TI - ES Views: Ocean incineration of hazardous wastes: An update. PMID- 22257350 TI - New conceptual formulation for predicting filter performance. PMID- 22257351 TI - Estimation of vapor pressures for polychlorinated biphenyls: a comparison of eleven predictive methods. PMID- 22257352 TI - Phase-transfer-catalyzed methylation of hydroxyaromatic acids, hydroxyaromatic aldehydes, and aromatic polycarboxylic acids. PMID- 22257353 TI - Identification of intermediates leading to chloroform and C-4 diacids in the chlorination of humic acid. PMID- 22257354 TI - Relationships between octanol-water partition coefficient and aqueous solubility. PMID- 22257355 TI - Composition of fine particle regional sulfate component in Shenandoah Valley. PMID- 22257357 TI - Using electrophoresis in modeling sulfate, selenite, and phosphate adsorption onto goethite. PMID- 22257356 TI - Removal of arsenic from geothermal fluids by adsorptive bubble flotation with colloidal ferric hydroxide. PMID- 22257358 TI - Acidification of southern Appalachian lakes. PMID- 22257359 TI - Improved aqueous scrubber for collection of soluble atmospheric trace gases. PMID- 22257360 TI - Comparative neuropsychology of adult obsessive-compulsive disorder and attention deficit/hyperactivity disorder: implications for a novel executive overload model of OCD. AB - Research implicates frontostriatal pathophysiology in both attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Nevertheless, ADHD is characterized with frontostriatal hypoactivity and OCD with hyperactivity. Furthermore, both disorders seem to lie on opposite ends of a clinical impulsive-compulsive continuum. While never having directly been compared, and despite these differences, OCD and ADHD appear to share similar neuropsychological impairments especially in executive functions. This study aimed at comparing adults with OCD and adults with ADHD on neuropsychological measures and behavioural impulsivity and OC measures. Thirty OCD, 30 ADHD, and 30 matched healthy control (HC) participants were administered a comprehensive neuropsychological battery and completed several questionnaires. The groups were compared on all neuropsychological and clinical measures and correlations between neuropsychological and clinical symptoms were computed. The ADHD and OCD groups performed more poorly than HC on all neuropsychological domains and most domain subtests. The ADHD group reported significantly higher impulsivity than the OCD group. OCD patients did not differ from HC on behavioural impulsivity. A unique dissociation was found between impulsivity and response inhibition where both clinical groups showed similar response inhibition deficit, but differed significantly on impulsivity. Moreover, a negative association between OC symptoms and response inhibition and a bias in self-perception of impulsivity was found only in the OCD group. We propose an executive overload model of OCD that views neuropsychological impairments in OCD as an epiphenomenon, according to which continuous attempts to control automatic processes are associated with obsessive thoughts overflow that causes an overload on the executive system. PMID- 22257361 TI - Vocal anatomy, tongue protrusion behaviour and the acoustics of rutting roars in free-ranging Iberian red deer stags (Cervus elaphus hispanicus). AB - Roaring in rutting Iberian red deer stags Cervus elaphus hispanicus is unusual compared to other subspecies of red deer, which radiated from the Iberian refugium after the last glacial maximum. In all red deer stags, the larynx occupies a permanent low mid-neck resting position and is momentarily retracted almost down to the rostral end of the sternum during the production of rutting calls. Simultaneous with the retraction of the larynx, male Iberian red deer pronouncedly protrude the tongue during most of their rutting roars. This poses a mechanical challenge for the vocal tract (vt) and for the hyoid apparatus, as tongue and larynx are strongly pulled in opposite directions. This study (i) examines the vocal anatomy and the acoustics of the rutting roars in free-ranging male C. e. hispanicus; (ii) establishes a potential mechanism of simultaneous tongue protrusion and larynx retraction by applying a two-dimensional model based on graphic reconstructions in single video frames of unrestrained animals; and (iii) advances a hypothesis of evaporative cooling by tongue protrusion in the males of a subspecies of red deer constrained to perform all of the exhausting rutting activities, including acoustic display, in a hot and arid season. PMID- 22257362 TI - Calabi-Yau manifolds and their degenerations. AB - Calabi-Yau manifolds are geometric objects of central importance in several branches of mathematics, including differential geometry, algebraic geometry, and mathematical physics. In this paper, we give a brief introduction to the subject aimed at a general mathematical audience and present some of our results that shed some light on the possible ways in which families of Calabi-Yau manifolds can degenerate. PMID- 22257363 TI - Biomechanical evaluation of predictive parameters of progression in adolescent isthmic spondylolisthesis: a computer modeling and simulation study. AB - BACKGROUND: Pelvic incidence, sacral slope and slip percentage have been shown to be important predicting factors for assessing the risk of progression of low- and high-grade spondylolisthesis. Biomechanical factors, which affect the stress distribution and the mechanisms involved in the vertebral slippage, may also influence the risk of progression, but they are still not well known. The objective was to biomechanically evaluate how geometric sacral parameters influence shear and normal stress at the lumbosacral junction in spondylolisthesis. METHODS: A finite element model of a low-grade L5-S1 spondylolisthesis was constructed, including the morphology of the spine, pelvis and rib cage based on measurements from biplanar radiographs of a patient. Variations provided on this model aimed to study the effects on low grade spondylolisthesis as well as reproduce high grade spondylolisthesis. Normal and shear stresses at the lumbosacral junction were analyzed under various pelvic incidences, sacral slopes and slip percentages. Their influence on progression risk was statistically analyzed using a one-way analysis of variance. RESULTS: Stresses were mainly concentrated on the growth plate of S1, on the intervertebral disc of L5-S1, and ahead the sacral dome for low grade spondylolisthesis. For high grade spondylolisthesis, more important compression and shear stresses were seen in the anterior part of the growth plate and disc as compared to the lateral and posterior areas. Stress magnitudes over this area increased with slip percentage, sacral slope and pelvic incidence. Strong correlations were found between pelvic incidence and the resulting compression and shear stresses in the growth plate and intervertebral disc at the L5-S1 junction. CONCLUSIONS: Progression of the slippage is mostly affected by a movement and an increase of stresses at the lumbosacral junction in accordance with spino-pelvic parameters. The statistical results provide evidence that pelvic incidence is a predictive parameter to determine progression in isthmic spondylolisthesis. PMID- 22257364 TI - Factors linked to severe thrombocytopenia during antiviral therapy in patients with chronic hepatitis c and pretreatment low platelet counts. AB - BACKGROUND: Baseline low platelet count (< 150,000/MUL) increases the risk of on treatment severe thrombocytopenia (platelet count < 50,000/MUL) in patients with chronic hepatitis C (CHC) undergoing antiviral therapy, which may interrupt treatment. The purpose of this study was to identify risk factors for severe thrombocytopenia during treatment for CHC in patients with baseline thrombocytopenia. METHODS: Medical records were reviewed for 125 patients with CHC treated with antiviral therapy according to the standard of care, with regular follow-up examinations. Early platelet decline was defined as platelet decrease during the first 2 weeks of therapy. RESULTS: Severe thrombocytopenia developed in 12.8% of patients with baseline thrombocytopenia, and predicted a higher therapeutic dropout rate. Multivariate analysis revealed baseline platelet count < 100,000/MUL and rapid early platelet decline (> 30% decline in the first 2 weeks) were significantly associated with severe thrombocytopenia (P < 0.001 and 0.003, odds ratios, 179.22 and 45.74, respectively). In these patients, baseline PLT >= 100,000/MUL and lack of rapid early platelet decline predicted absence of severe thrombocytopenia (negative predictive values were 95.1% and 96.6%, respectively). In contrast, baseline platelet count < 100,000/MUL combined with rapid early platelet decline predicted severe thrombocytopenia (positive predictive value was 100%). CONCLUSIONS: For patients with CHC on antiviral therapy, baseline platelet counts < 100,000/MUL and rapid early platelet decline can identify patients at high risk of developing on-treatment severe thrombocytopenia. PMID- 22257365 TI - Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design. AB - BACKGROUND: Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. METHODS/DESIGN: Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), or the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. DISCUSSION: The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00849563. PMID- 22257367 TI - Trends of reporting of 'serious'vs. 'non-serious' adverse drug reactions over time: a study in the French PharmacoVigilance Database. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Several factors are known to influence spontaneous reporting of adverse drug reactions (ADRs). Among them, 'seriousness' of the reaction is one of the most important. * However, evolution in the reporting of 'serious'vs.'non-serious' ADRs over time for the same drug remains unknown. WHAT THIS STUDY ADDS: * Spontaneous reports mainly involve 'non serious' ADRs during the first years of marketing and 'serious' ADRs later, particularly for drugs with non-hospital use. AIM: To investigate trends in spontaneous reporting to the French Pharmacovigilance system of 'serious' (SADRs) and 'non-serious' (NSADRs) adverse drug reactions over time. METHODS: Annual SADR : NSADR ratios were calculated for each drug and their evolution tested with linear trend tests. RESULTS: Among the 39 new active substances commercialized in France in 2000, 16 had sufficient data to perform linear trend tests. An increasing linear relation was found for five widely prescribed drugs, a non significant increasing trend for eight others, i.e. drugs mostly used in hospitals. CONCLUSION: ADR reports mainly concern NSADRs during first years of marketing. Reports of SADRs are proportionally more frequent later. PMID- 22257368 TI - Case of drug-induced hypersensitivity syndrome involving multiple-drug hypersensitivity. PMID- 22257369 TI - The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice. AB - Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Patients with FXS do not only suffer from cognitive problems, but also from abnormalities/deficits in procedural memory formation. It has been proposed that a lack of fragile X mental retardation protein (FMRP) leads to altered long-term plasticity by deregulation of various translational processes at the synapses, and that part of these impairments might be rescued by the inhibition of type I metabotropic glutamate receptors (mGluRs). We recently developed the Erasmus Ladder, which allows us to test, without any invasive approaches, simultaneously, both procedural memory formation and avoidance behavior during unperturbed and perturbed locomotion in mice. Here, we investigated the impact of a potent and selective mGluR5 inhibitor (Fenobam) on the behavior of Fmr1 KO mice during the Erasmus Ladder task. Fmr1 KO mice showed deficits in associative motor learning as well as avoidance behavior, both of which were rescued by intraperitoneal administration of Fenobam. While the Fmr1 KO mice did benefit from the treatment, control littermates suffered from a significant negative side effect in that their motor learning skills, but not their avoidance behavior, were significantly affected. On the basis of these studies in the FXS animal model, it may be worthwhile to investigate the effects of mGluR inhibitors on both the cognitive functions and procedural skills in FXS patients. However, the use of mGluR inhibitors appears to be strongly contraindicated in healthy controls or non-FXS patients with intellectual disability. PMID- 22257371 TI - Is (18)F-fluorodeoxyglucose-PET/CT useful for the presurgical characterization of thyroid nodules with indeterminate fine needle aspiration cytology? AB - BACKGROUND: Thyroid nodules found incidentally on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) have been shown to be malignant in 30%-50% of cases. The American Thyroid Association recommends performing fine needle aspiration cytology (FNAC) for thyroid nodules showing FDG uptake. On the other hand, the role of FDG-PET in characterizing thyroid nodules with indeterminate cytology before surgery is not clear. The goal of this study was to evaluate the role of FDG-PET/computed tomography (CT) in predicting malignancy of thyroid nodules with indeterminate FNAC and to correlate FDG uptake with pathological and ultrasonographic (US) features. METHODS: Between November 2006 and October 2009, 55 patients (42 women, mean age: 50 years) planned for surgery for 56 thyroid nodules with indeterminate FNAC were prospectively included and considered for analysis. All patients underwent presurgical FDG-PET/CT (Siemens Biograph, mean FDG injected activity: 165 MBq) and neck US. Pathology of the corresponding surgical specimen was the gold standard for statistical analysis. RESULTS: At pathology 34 nodules were benign, 10 were malignant (7 papillary and 3 follicular carcinomas), and 12 were tumors of uncertain malignant potential (TUMP). The median size of the thyroid nodules was 21 mm (range: 10-57). Sensitivity, specificity, positive (PPV), and negative predictive (NPV) values of FDG-PET in detecting cancer/TUMP were 77%, 62%, 57%, and 81%, respectively. In multivariate analysis, cellular atypia was the only factor predictive of FDG uptake (p<0.001). Hurthle cells and poorly differentiated components were independent predictive factors of high (>=5) SUV Max (p=0.02 and p=0.02). Sensitivity, specificity, PPV, and NPV of US in detecting cancer/TUMP were 82%, 47%, 50%, and 80%, respectively. In multivariate analysis, hypervascularization was correlated with malignancy/TUMP (p=0.007) and cystic features were correlated with benignity (p=0.03). CONCLUSION: Adding FDG-PET findings to neck US provided no diagnostic benefit. The sensitivity and specificity of FDG-PET in the presurgical evaluation of indeterminate thyroid nodules are too low to recommend FDG-PET routinely. PMID- 22257370 TI - A longitudinal study of the association between dietary factors, serum lipids, and bone marrow lesions of the knee. AB - INTRODUCTION: Bone marrow lesions (BMLs) play an important role in knee osteoarthritis, but their etiology is not well understood. The aim of this longitudinal study was to describe the association between dietary factors, serum lipids, and BMLs. METHODS: In total, 394 older men and women (mean age, 63 years; range, 52 to 79) were measured at baseline and approximately 2.7 years later. BMLs were determined by using T2-weighted fat-saturation magnetic resonance imaging (MRI) by measuring the maximal area of the lesion. Nutrient intake (total energy, fat, carbohydrate, protein, and sugar) and serum lipids were assessed at baseline. RESULTS: Cross-sectionally, dietary factors and lipids were not significantly associated with BMLs. Energy, carbohydrate, and sugar intake (but not fat) were positively associated with a change in BML size (beta = 15.44 to 19.27 mm2 per 1 SD increase; all P < 0.05). High-density lipoprotein (HDL) cholesterol tended to be negatively associated with BML change (beta = -11.66 mm2 per 1 SD increase; P = 0.088). CONCLUSIONS: Energy, carbohydrate, and sugar intake may be risk factors for BML development and progression. HDL cholesterol seems protective against BMLs. These results suggest that macronutrients and lipids may be important in BML etiology and that dietary modification may alter BML natural history. PMID- 22257374 TI - Tract recurrence of a follicular thyroid neoplasm following transaxillary endoscopic thyroidectomy. AB - BACKGROUND: Endoscopic thyroidectomy is gaining popularity, particularly in Asian countries, as an alternative to conventional cervical thyroidectomy. Multiple large case series have been published that confirm the feasibility and safety of this procedure compared to conventional methods. However, no data are available that demonstrate long-term oncologic outcomes or complications. PATIENT FINDINGS: A patient who underwent transaxillary gas insufflation thyroidectomy for a follicular neoplasm presented to the authors with a mass along the operative tract 31 months after her first surgery. The mass was found to be a recurrence of the thyroid neoplasm. SUMMARY: Since this is a relatively new procedure, the potential complications differ from those of conventional cervical thyroidectomy. Further studies are needed to determine size limitations on nodules considered for endoscopic resection. CONCLUSION: When performing these procedures, care should be taken to ensure that the specimen is removed entirely and in one piece. Long-term outcomes data for endoscopic thyroidectomy are warranted prior to this becoming an acceptable standard of care for thyroid surgery. PMID- 22257372 TI - History of the clinical endocrinology branch of the National Institute of Diabetes and Digestive and Kidney Diseases: impact on understanding and treatment of diseases of the thyroid gland. PMID- 22257375 TI - The GM-CSF receptor family: mechanism of activation and implications for disease. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pluripotent cytokine produced by many cells in the body, which regulates normal and malignant hemopoiesis as well as innate and adaptive immunity. GM-CSF assembles and activates its heterodimeric receptor complex on the surface of myeloid cells, initiating multiple signaling pathways that control key functions such as cell survival, cell proliferation, and functional activation. Understanding the molecular composition of these pathways, the interaction of the various components as well as the kinetics and dose-dependent mechanics of receptor activation provides valuable insights into the function of GM-CSF as well as the related cytokines, interleukin-3 and interleukin-5. This knowledge provides opportunities for the development of new therapies to block the action of these cytokines in hematological malignancy and chronic inflammation. PMID- 22257377 TI - Some supplementary methods for the analysis of WAIS-IV index scores in neuropsychological assessment. AB - OBJECTIVES: To develop supplementary methods for the analysis of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) in neuropsychological assessment. DESIGN AND METHODS: Psychometric. RESULTS: The following methods are made available: (a) provision of traditional confidence intervals (CIs) on index scores, (b) expression of the endpoints of CIs as percentile ranks; (c) quantification of the number of abnormally low index scores exhibited by a case and accompanying estimate of the percentage of the normative population expected to exhibit at least this number of low scores; (d) quantification of the reliability and abnormality of index score deviations from an individual's index score mean (thereby offering an alternative to the pairwise approach to index score comparisons available in the WAIS-IV manual); (e) provision of CIs on an individual's deviation scores or pairwise difference scores, (f) estimation of the percentage of the normative population expected to exhibit at least as many abnormal deviations or abnormal pairwise differences as a case; and (g) calculation of a case's Mahalanobis distance index (MDI), thereby providing a multivariate estimate of the overall abnormality of an index score profile. With the exception of the MDI, all the methods can be applied using tables provided in this paper. However, for ease and speed of application, and to reduce the possibility of clerical error, all the methods have also been implemented in a computer program. CONCLUSIONS: The methods are useful for neuropsychological interpretation of the WAIS-IV. PMID- 22257379 TI - The expanding role of alpha2-3 sialylation for leukocyte trafficking in vivo. AB - The ability of leukocytes to navigate through the different body compartments is an essential component for functioning immune defense and surveillance systems. In order to exit the blood circulation, leukocytes follow distinct recruitment steps, including capture of free-flowing leukocytes to, and rolling along, the vessel wall; firm leukocyte arrest on the endothelial lining; and postarrest modifications (spreading and crawling), which prepare the leukocyte for transmigration through the vascular wall. Post-translational glycosylation (including sialylation) has been known for many years to be functionally relevant for selectin ligands and, hence, selectin-mediated capture and rolling. Recently, sialylation by the alpha2-3 sialyltransferase ST3Gal-IV was identified to significantly influence chemokine-triggered firm leukocyte arrest, expanding the role of alpha2-3 sialylation from leukocyte rolling to subsequent chemokine triggered leukocyte arrest. These findings make ST3Gal-IV an interesting drug target for modulating leukocyte trafficking in human disorders, including autoimmune diseases and cancer. PMID- 22257380 TI - Nano-hydroxyapatite/beta-tricalcium phosphate ceramics scaffolds loaded with cationic liposomal ceftazidime: preparation, release characteristics in vitro and inhibition to Staphylococcus aureus biofilms. AB - In the current study, nano-hydroxyapatite/beta-tricalcium phosphate (HA/beta-TCP) ceramics scaffolds loaded with cationic liposomal ceftazidime (CLCs) prepared by modified reverse phase evaporation method, the investigations of their release characteristics were performed by the dissolution tests, in vitro anti-biofilm activity of the scaffolds was studied by the determination of bacterial susceptibility with ELISA. The mean particle size, zeta potential, pH and entrapment efficiency of the CLCs studied were 161.5 +/- 5.37 nm, 60.60 +/- 5.24 mV, 6.90 +/- 0.07 and 16.57 +/- 0.13%, respectively. Electron microscopic images of the samples indicated that the liposomes were well preserved in the scaffolds and that it was the CLCs rather than free ceftazidime releasing from the scaffolds. The minimal inhibitory concentrations (MICs) to Staphylococcus aureus of free ceftazidime and its liposomal formulation were 6.00 MUg/mL and the release behaviors of both CLCs and free ceftazidime from scaffolds were based on the dissolution/diffusion processes, Fick's law. These results demonstrated that CLCs could inhibit remarkably the formation of S. aureus biofilm more effectively than free ceftazidime (P < 0.05). The study demonstrated that the HA/beta-TCP ceramic scaffolds was such a material that could sustain release CLCs and maintain the adequate amounts of CLCs to absorb to biofilm. It provided an ideal way to inhibit bacterial biofilms for clinical practices. PMID- 22257381 TI - Evaluation of the chronic obstructive pulmonary disease assessment test for measurement of health-related quality of life in patients with interstitial lung disease. AB - BACKGROUND AND OBJECTIVE: A well-validated instrument that is simple to use is needed to assess health-related quality of life in patients with interstitial lung disease (ILD). The COPD assessment test (CAT) is a recently introduced, short and simple questionnaire for COPD patients, which shows good and valid measurement properties. This study was conducted to evaluate the validity of the CAT in patients with ILD. METHODS: Patients with ILD (n = 55) completed the CAT and the St. George's Respiratory Questionnaire (SGRQ). These patients also completed the Medical Research Council (MRC) dyspnoea scale, the Leicester Cough Questionnaire (LCQ), and the hospital anxiety and depression scale; performed 6 min walk tests and pulmonary function tests; and provided samples for arterial blood gas analysis. RESULTS: There was a very strong correlation between the CAT score and the SGRQ total score (r = 0.93, P < 0.0001). The CAT score was also significantly correlated with the SGRQ symptoms score (r = 0.74, P < 0.0001), the SGRQ activity score (r = 0.87, P < 0.0001) and the SGRQ impact score (r = 0.89, P < 0.0001). Stepwise multiple regression analysis demonstrated that the MRC and LCQ scores contributed most to both the CAT score and the SGRQ total score. CONCLUSIONS: The CAT is a short and simple questionnaire that shows good and valid measurement properties for assessing the health status of patients with ILD. PMID- 22257382 TI - Targeting proliferation and survival pathways in head and neck cancer for therapeutic benefit. AB - Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. Recent studies have elucidated a key signaling axis, the EGFR-STAT3-Bcl-XL signaling axis, that is aberrantly activated in a majority of HNSCC and contributes to the proliferation and survival of malignant cells. Considerable effort is being placed on developing highly specific inhibitors of different components of this pathway. This review highlights the progress that is being made towards achieving potent inhibition of the EGFR-STAT3-Bcl-XL signaling axis in HNSCC and the promising therapeutic strategies that are currently under development for this disease. PMID- 22257383 TI - Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy. AB - Establishing Epstein-Barr virus(EBV)-specific cytolytic T lymphocytes(EBV-CTLs) from peripheral blood mononuclear cells(PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma(NPC). In the current study, we performed ex vivo expansion of tumor-infiltrating lymphocytes(TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody(OKT3), recombinant human interleukin(IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+ T cells, a variable percentage of CD3+CD8+ and CD3+CD4+ T cells, and less than 10% of CD3-CD16+ natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNgamma) and tumor necrosis factor-alpha (TNF-alpha), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC. PMID- 22257386 TI - Autostratification in drying colloidal dispersions: experimental investigations. AB - In films cast from a colloidal dispersion comprising two particle sizes, we experimentally examine the distribution of particles normal to the substrate. The particle concentrations at various positions in the film are determined through atomic force microscopy and NMR profiling. The results are compared to a previously derived diffusional model. Evidence for diffusional driven stratification is found, but the importance of other flows is also highlighted. The conditions that enhance particle stratification are found to be a colloidally stable dispersion, low initial volume fractions, a low concentration of the stratifying particle, and for the Peclet numbers of the two components to straddle unity. PMID- 22257384 TI - Role of ABC transporters in cancer chemotherapy. AB - Multidrug resistance (MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette (ABC) transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs. This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR. PMID- 22257385 TI - Use of Lean response to improve pandemic influenza surge in public health laboratories. AB - A novel influenza A (H1N1) virus detected in April 2009 rapidly spread around the world. North American provincial and state laboratories have well-defined roles and responsibilities, including providing accurate, timely test results for patients and information for regional public health and other decision makers. We used the multidisciplinary response and rapid implementation of process changes based on Lean methods at the provincial public health laboratory in British Columbia, Canada, to improve laboratory surge capacity in the 2009 influenza pandemic. Observed and computer simulating evaluation results from rapid processes changes showed that use of Lean tools successfully expanded surge capacity, which enabled response to the 10-fold increase in testing demands. PMID- 22257387 TI - Prevalence, correlates, and comorbidity of DSM-IV obsessive-compulsive personality disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - Although recognized for over 100 years, there is a relative dearth of empirical research on obsessive compulsive personality disorder (OCPD). The goal of the current study is to present nationally representative findings on prevalence, sociodemographic correlates, and comorbidity of OCPD among men and women. The current study uses nationally representative data to examine sociodemographic correlates and comorbidity of OCPD. Face-to-face interviews were conducted with 43,093 adults in the United States. The prevalence of lifetime OCPD was 7.8%, with rates the same for men and women. OCPD was significantly less common in younger adults and in Asians and Hispanics but was significantly more common in individuals with a high school education or less. When sociodemographic variables and other comorbidities were controlled for, current associations remained significant for all mood and anxiety disorders as well as lifetime personality disorders among both men and women. OCPD is a prevalent personality disorder in the US population and is equally represented in men and women. The results highlight the need for further research to identify common pathophysiological elements common to OCPD and associated disorders. PMID- 22257388 TI - Evaluation of total oxidative status in adult attention deficit hyperactivity disorder and its diagnostic implications. AB - Adult Attention Deficit Hyperactivity Disorder (A-ADHD) is one of the psychiatric disorders which awareness is growing. The exact causes of A-ADHD are still unknown. In addition to neurochemical and neuroanatomic disorders, genetic and environmental factors are discussed in its etiology. In our study, we aimed to evaluate the oxidative status of A-ADHD patients and investigate whether oxidative metabolites can be used as diagnostic tools or not in A-ADHD. Blood samples were taken from enrolled 50 A-ADHD patients and 31 controls in appropriate way and Total Antioxidative Status (TAS), Total Oxidative Status (TOS), and Oxidative Stress Index (OSI) were studied in Harran University Biochemistry Labs. Results were compared between groups and ROC curve was drawn in order to evaluate diagnostic performances. Patients' TAS, TOS and OSI were significantly higher than controls. There was not a significant difference between comorbid cases and only A-ADHD patients in terms of measured values. A ADHD can be predicted for TOS over 9.8575 MUmol H(2)O(2) Eqv./L level with 86% positive predictive value and %100 negative predictive value. In A-ADHD, oxidative balance is impaired. High antioxidant levels may be compensatory against the oxidant increase. Oxidative parameters may be used in A-ADHD diagnosis. PMID- 22257391 TI - Currents. PMID- 22257390 TI - Editorial: What price a clean environment? PMID- 22257392 TI - Controlling acid deposition: the role of FGD. PMID- 22257394 TI - Regulatory Focus: New guidelines for risk assessment. PMID- 22257393 TI - Removing dissolved organic contaminants from water. PMID- 22257395 TI - Tellurium and selenium in aerosols. PMID- 22257396 TI - Reaction products and rates of disappearance of simple bromoalkanes, 1,2 dibromopropane, and 1,2-dibromoethane in water. PMID- 22257397 TI - Biotransformations of selected alkylbenzenes and halogenated aliphatic hydrocarbons in methanogenic aquifer material: a microcosm study. PMID- 22257398 TI - Degradation of phenol and chlorophenols by sunlight and microbes in estuarine water. PMID- 22257399 TI - Acetaldehyde: the mutagenic activity of its photooxidation products. PMID- 22257400 TI - Dissolution of iron sulfates from pyritic coal waste. PMID- 22257401 TI - Kinetics of oxidation of dimethyl sulfide by hydrogen peroxide in acidic and alkaline medium. PMID- 22257402 TI - Structural characteristics of polycyclic aromatic hydrocarbon isomers in coal tars and combustion products. PMID- 22257403 TI - Molecular weight distribution, carboxylic acidity, and humic substances content of aquatic organic matter: implications for removal during water treatment. PMID- 22257404 TI - Ionic alkylleads in herring gulls from the Great Lakes region. PMID- 22257405 TI - Vapor-particle partitioning of semivolatile organic compounds: estimates from field collections. PMID- 22257406 TI - Atmospheric loss processes of 1,2-dibromo-3-chloropropane and trimethyl phosphate. PMID- 22257407 TI - A new model describing the adsorption of copper on manganese dioxide. PMID- 22257409 TI - Radical formation and polymerization of chlorophenols and chloroanisole on copper(II)-smectite. PMID- 22257408 TI - Enhancement of N-nitrosamine formation on granular-activated carbon from N methylaniline and nitrite. PMID- 22257410 TI - Platinum and palladium in roadside dust. PMID- 22257411 TI - Using UNIFAC to calculate aqueous solubilities. PMID- 22257412 TI - [Pancreatic rupture and Roux-en-Y reconstruction after abdominal trauma]. PMID- 22257413 TI - [Unusual cutaneous metastasis of transitional carcinoma]. PMID- 22257414 TI - [Ectopic pancreas in the gallbladder]. PMID- 22257415 TI - [Preoperative weight loss in bariatric surgery candidate patients. evidence-based recommendations]. AB - INTRODUCTION: Bariatric surgery is becoming increasingly more common in the treatment of morbid obesity in our hospitals. One of the measures being used to optimise the results of this surgery seems to be the standardising the preoperative weight loss. As there are no universal recommendations for carrying out this weight loss, a review of this topic is presented. OBJECTIVES: To analyse whether sufficient scientific evidence exists to recommend preoperative weight loss in candidate patients for bariatric surgery. What would be the best options to carry out this weight loss is also analysed, as well as making some recommendations based on the scientific evidence. RESULTS: There is great heterogeneity in the designs of the different studies, with different guidelines for weight loss and various surgical techniques. However, preoperative weight loss leads to a decrease in the size of the liver and intra-abdominal fat, which improves the surgical field and intra-operative view, which in turn helps during the surgical act, both in open as well as laparoscopic surgery. There is no consensus on the effect of preoperative weight loss has in predicting the medium or long term results after bariatric surgery. CONCLUSION: The current scientific evidence makes preoperative weight loss recommendable in candidate patients for bariatric surgery. However, there is no consensus on what is the best procedure to achieve this preoperative weight loss. PMID- 22257416 TI - Subepidermal calcified nodule of the knee with transepidermal elimination of calcium. PMID- 22257417 TI - The effect of hyperglycemia and hypoglycemia on glucose transport and expression of glucose transporters in human lymphocytes B and T: an in vitro study. AB - Glucose transport in lymphocytes is regulated by many agents. It is interesting if only changing glucose concentrations in environment involves the impact on glucose uptake. The aims of this study were to investigate the impact of changing glucose concentrations in medium on deoxy-d-glucose uptake and what these conditions impact on the percent of cells with expression of chosen glucose transporters in human lymphocytes B and T. Isolated lymphocytes B and T obtained from healthy subject were cultivated in different concentrations of glucose. The experiments were carried out using tritium labeled deoxy-d-glucose and flow cytometry. In comparison to normoglycemia, hyperglycemia impairs the uptake of deoxy-d-glucose more than hypoglycemia. Lymphocytes B manifest significantly lower uptake of deoxy-d-glucose than lymphocytes T. Lymphocytes incubated in hyperglycemic and hypoglycemic medium show lower percent cells with expression of GLUT 1 and GLUT 3, and higher percent cells with expression of GLUT 4. The incubation of lymphocytes in hyperglycemic and hypoglycemic medium does not stimulate translocation of glucose transporters 3 and 4 to plasma membrane. Study shows that a change in concentration of glucose in incubation environment influence intracellular expression of glucose transporters in a significant part of lymphocytes B and T. PMID- 22257418 TI - Combination therapy with liraglutide and sulfonylurea for a type 2 diabetic patient with high titer of anti-insulin antibodies produced by insulin therapy. PMID- 22257419 TI - Use of haemoglobin A1c to detect impaired fasting glucose or Type 2 diabetes in a United Kingdom community based population. AB - AIMS: To evaluate the diagnostic accuracy of haemoglobin A1c (HbA1c) in screening for impaired fasting glucose and Type 2 diabetes (T2DM). METHODS: We screened 3904 adults aged 45-70 (mean age 58.6 [standard deviation (SD) 6.9] years, mean body mass index (BMI) 29.9 [SD 4.7]kg/m(2)), with fasting plasma glucose (FPG) and HbA1c as part of a large diabetes prevention programme. We assessed the diagnostic accuracy of HbA1c for predicting impaired fasting glucose (IFG), (defined either as FPG 5.6-6.9 mmol/l, or 6.1-6.9 mmol/l), and T2DM (FPG >= 7.0 mmol/l). RESULTS: The prevalences of IFG were 13.8% (FPG 5.6-6.9 mmol/l) and 4.5% (FPG 6.1-6.9 mmol/l) and of T2DM was 2.1%. Using FPG 5.6-6.9 mmol/l as the IFG reference standard, HbA1c of 39-47 mmol/mol (5.7-6.4%) was 63% sensitive and 81% specific, and HbA1c 43-47 mmol/mol (6.1-6.4%) was 21% sensitive and 98% specific, in diagnosing IFG. HbA1c >= 48 mmol/mol (6.5%) was 61% sensitive and 99% specific in diagnosing T2DM. Having HbA1c 39-47 mmol/mol (5.7-6.4%), male sex, and body mass index >29.5 together increased the odds of IFG 6.5-fold (95% confidence interval (CI) 5.5-7.8) compared to the pre-test odds. CONCLUSION: Defining 'pre diabetes' at a lower HbA1c threshold of 39 mmol/mol (5.7%) instead of 47 mmol/mol (6.1%) increases its sensitivity in diagnosing IFG, but current American Diabetes Association definitions of 'pre-diabetes' based on HbA1c would fail to detect almost 40% of people currently classified as IFG. This has implications for current and future diabetes prevention programmes, for vascular risk management, and for clinical advice given to people with 'pre-diabetes' based on fasting glucose data. PMID- 22257421 TI - Test-retest reliability and practice effects of the Wechsler Memory Scale-III. AB - Although serial administration of cognitive tests is increasingly common, there is a paucity of research on test-retest reliabilities and practice effects, both of which are important for evaluating changes in functioning. Reliability is generally conceptualized as involving short-lasting changes in performance. However, when repeated testing occurs over a period of years, there will be some longer lasting effects. The implications of these longer lasting effects and practice effects on reliability were examined in the context of repeated administrations of the Wechsler Memory Scale-III in 339 community-dwelling women aged 40-79 years over 2 to 7 years. The results showed that Logical Memory and Verbal Paired Associates subtests were consistently the most reliable subtests across the age cohorts. The magnitude of practice effects varied as a function of subtests and age. The largest practice effects were found in the youngest age cohort, especially on the Faces, Logical Memory, and Verbal Paired Associates subtests. PMID- 22257420 TI - Health beliefs among individuals at increased familial risk for type 2 diabetes: implications for prevention. AB - AIM: To evaluate perceived risk, control, worry, and severity about diabetes, coronary heart disease (CHD) and stroke among individuals at increased familial risk of diabetes. METHODS: Data analyses were based on the Family HealthwareTM Impact Trial. Baseline health beliefs were compared across three groups: (1) no family history of diabetes, CHD or stroke (n=836), (2) family history of diabetes alone (n=267), and (3) family history of diabetes and CHD and/or stroke (n=978). RESULTS: After adjusting for age, gender, race, education and BMI, scores for perceived risk for diabetes (p<0.0001), CHD (p<0.0001) and stroke (p<0.0001) were lowest in Group 1 and highest in Group 3. Similar results were observed about worry for diabetes (p<0.0001), CHD (p<0.0001) and stroke (p<0.0001). Perceptions of control or severity for diabetes, CHD or stroke did not vary across the three groups. CONCLUSIONS: Among individuals at increased familial risk for diabetes, having family members affected with CHD and/or stroke significantly influenced perceived risk and worry. Tailored lifestyle interventions for this group that assess health beliefs and emphasize approaches for preventing diabetes, as well as its vascular complications, may be an effective strategy for reducing the global burden of these serious but related chronic disorders. PMID- 22257423 TI - Radical prostatectomy for long-term functional and oncologic outcomes. PMID- 22257422 TI - Efficacy of inhaled N-acetylcysteine monotherapy in patients with early stage idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder for which there are currently no specific or effective medical treatments. A multicentre, prospective, randomized, controlled clinical trial was conducted to assess the efficacy of inhaled N-acetylcysteine (NAC) monotherapy in Japanese patients with early stage IPF. METHODS: Eligible patients had well-defined IPF of mild-to-moderate severity, with no desaturation on exercise. Of 100 patients screened, 76 were randomly assigned to an NAC treatment group (group A; n = 38) that received 352.4 mg of NAC by inhalation twice daily or to a control group (group B; n = 38) that received no therapy. The primary endpoint was the change from baseline in forced vital capacity (FVC) at 48 weeks. RESULTS: There were no significant overall differences in the change in FVC between groups A and B. Post hoc exploratory analyses showed that NAC therapy was associated with stability of FVC in (i) a subset of patients with initial FVC <95% of predicted (n = 49; difference in FVC decline 0.12 L; P = 0.02) and (ii) in patients with initial diffusing capacity of carbon monoxide <55% of predicted (n = 21; difference in FVC decline 0.17 L; P = 0.009). CONCLUSIONS: These findings indicate that NAC monotherapy may have some beneficial effect in patients with early stage IPF. Further trials in more select IPF populations with progressive disease are required to prove the efficacy of inhaled NAC. PMID- 22257424 TI - Radiofrequency ablation versus partial nephrectomy in patients with solitary clinical T1a renal cell carcinoma: comparable oncologic outcomes at a minimum of 5 years of follow-up. AB - BACKGROUND: Long-term comparative outcomes for radiofrequency ablation (RFA) versus partial nephrectomy (PN) for the primary treatment of clinical T1a renal cell carcinoma (RCC) have not previously been reported. OBJECTIVE: Report comparative 5-yr oncologic outcomes for RFA versus PN in patients with clinical T1a RCC. DESIGN, SETTING, AND PARTICIPANTS: Observational single-institution cohort study, involving consecutive patients with a solitary histologically confirmed T1a RCC treated by RFA or PN and followed for a minimum of 5 yr. Those presenting with synchronous multiple, metachronous, bilateral, and/or metastatic disease, a history of hereditary RCC syndromes, a family history of RCC, and with post-treatment follow-up <5 yr were excluded from analysis. MEASUREMENTS: The Kaplan-Meier method was used to determine 5-yr overall survival (OS), cancer specific survival (CSS), local recurrence-free survival (local RFS), overall disease-free survival (DFS), and metastasis-free survival (MFS) for RFA versus PN. Survival curves were compared using the log-rank test. A p value <= 0.05 was considered statistically significant. RESULTS AND LIMITATIONS: A total of 37 patients in each group met the selection criteria. The RFA cohort was significantly older and had more advanced comorbidities, but other patient characteristics were similar. For RFA versus PN, median follow-up was 6.5 yr (interquartile range [IQR]: 5.8-7.1) versus 6.1 yr (IQR: 5.4-7.3) (p = 0.68), respectively. The 5-yr OS was 97.2% versus 100% (p = 0.31), CSS was 97.2% versus 100% (p = 0.31), DFS was 89.2% versus 89.2% (p = 0.78), local RFS was 91.7% versus 94.6% (p = 0.96), and MFS was 97.2% versus 91.8% (p = 0.35), respectively. Study limitations are retrospective data analysis, loss to follow-up, limited statistical power, and limited generalizability of our data. CONCLUSIONS: In appropriately selected patients, RFA is an effective minimally invasive therapy for the treatment of cT1a RCC, yielding comparable long-term oncologic outcomes to nephron-sparing surgery. PMID- 22257426 TI - Diffusion abnormality maps in demyelinating disease: correlations with clinical scores. AB - BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) has been explored as a noninvasive tool to assess pathology in multiple sclerosis (MS) patients. However, the correlation between classical MRI measures and physical disability is modest in MS. The diffusion tensor imaging (DTI) MRI technique holds particular promise in this regard. The present study shows brain regions where FA and individual diffusivities abnormalities are present and check their correlations with physical disability clinical scores. METHODS: Eight patients and 12 matched healthy controls were recruited. The Multiple Sclerosis Functional Composite was administered. For MR-DTI acquisitions, a Genesis Signa 1.5 T MR system, an EP/SE scanning sequence, 25 gradient directions were used. RESULTS: Tract Based Spatial Statistics (TBSS) group comparisons showed reduced FA and increased individual diffusivities in several brain regions in patients. Significant correlations were found between FA and: EDSS, 9-HPT(NON)DOM and 25 FW score; between lambda2 and: P100 (r&l), 9-HPT(NON)DOM and 25 FW; between lambda3 and: 9-HPT(NON)DOM and 25 FW score. CONCLUSIONS: Fractional anisotropy and individual radial diffusivities proved to be important markers of motor disabilities in MS patients when the disease duration mean and the disability scores values range are relatively high. PMID- 22257425 TI - Increase of ATP-sensitive potassium (K(ATP)) channels in the heart of type-1 diabetic rats. AB - BACKGROUND: An impairment of cardiovascular function in streptozotocin (STZ) diabetic rats has been mentioned within 5 days-to-3 months of induction. ATP sensitive potassium (K(ATP)) channels are expressed on cardiac sarcolemmal membranes. It is highly responsive to metabolic fluctuations and can have effects on cardiac contractility. The present study attempted to clarify the changes of cardiac K(ATP) channels in diabetic disorders. METHODS: Streptozotocin-induced diabetic rats and neonatal rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr) were used to examine the effect of hyperglycemia on cardiac function and the expression of K(ATP) channels. K(ATP) channels expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of K(ATP) channels by Western blot and Northern blot analysis. RESULTS: The result shows diazoxide produced a marked reduction of heart rate in control group. Furthermore, the methods of Northern blotting and Western blotting were employed to identify the gene expression of K(ATP) channel. Two subunits of cardiac K(ATP) channel (SUR2A and kir 6.2) were purchased as indicators and showed significantly decreased in both diabetic rats and high glucose treated rat cardiac myocytes. Correction of hyperglycemia by insulin or phlorizin restored the gene expression of cardiac K(ATP) in these diabetic rats. CONCLUSIONS: Both mRNA and protein expression of cardiac K(ATP) channels are decreased in diabetic rats induced by STZ for 8 weeks. This phenomenon leads to result in desensitization of some K(ATP) channel drugs. PMID- 22257427 TI - Relationship between thyroid function and ICU mortality: a prospective observation study. AB - INTRODUCTION: Although nonthyroidal illness syndrome is considered to be associated with adverse outcome in ICU patients, the performance of thyroid hormone levels in predicting clinical outcome in ICU patients is unimpressive. This study was conducted to assess the prognostic value of the complete thyroid indicators (free triiodothyronine (FT3), total triiodothyronine; free thyroxine, total thyroxine, thyroid-stimulating hormone and reverse triiodothyronine) in unselected ICU patients. METHODS: A total of 480 consecutive patients without known thyroid diseases were screened for eligibility and followed up during their ICU stay. We collected each patient's baseline characteristics, including the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and thyroid hormone, N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels. The primary outcome was ICU mortality. Potential predictors were analyzed for possible association with outcomes. We also evaluated the ability of thyroid hormones together with APACHE II score to predict ICU mortality by calculation of net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. RESULTS: Among the thyroid hormone indicators, FT3 had the greatest power to predict ICU mortality, as suggested by the largest area under the curve (AUC) of 0.762+/-0.028. The AUC for FT3 level was less than that for APACHE II score (0.829+/-0.022) but greater than that for NT-proBNP level (0.724+/-0.030) or CRP level (0.689+/-0.030). Multiple regression analysis revealed that FT3 level (standardized beta=-0.600, P=0.001), APACHE II score (standardized beta=0.912, P<0.001), NT-proBNP level (standardized beta=0.459, P=0.017) and CRP level (standardized beta=0.367, P=0.030) could independently predict primary outcome. The addition of FT3 level to APACHE II score gave an NRI of 54.29% (P<0.001) and an IDI of 36.54% (P<0.001). The level of FT3 was significantly correlated with NT-proBNP levels (r=-0.344, P<0.001) and CRP levels (r=-0.408, P<0.001). CONCLUSION: In unselected ICU patients, FT3 was the most powerful and only independent predictor of ICU mortality among the complete indicators. The addition of FT3 level to the APACHE II score could significantly improve the ability to predict ICU mortality. PMID- 22257429 TI - Health-related quality of life among breast cancer patients in Lebanon. AB - BACKGROUND: High incidence rates of breast cancer (BC) emphasize the need to address health-related quality of life (QoL) in this population. The aim of this study was to evaluate the QoL, symptom prevalence and management, functional ability, and quality of care in Lebanese women with BC at a tertiary health care facility. METHODS: Cross-sectional descriptive survey targeting Lebanese adults with cancer and using a combination of four instruments: European Organization for Research and treatment of Cancer-Quality of Life Questionnaire, Memorial Symptom Assessment Scale; Barthel Index; Needs at End of life Screening Tool, and a demographic/clinical characteristics section. 89 breast cancer patients participated in the study; data was collected from 2009 to 2010. Descriptive analysis in addition to independent sample t-test, ANOVA, and Pearson r correlation were used for data analysis. RESULTS: The most prevalent symptoms were feeling nervous, feeling sad, lack of energy, and pain; symptom management was inadequate; high scores were reported on functional ability, medical care, spirituality, and relationships. Younger, single, and better educated participants who were diagnosed for less than 30 months, had no metastasis, and paid less than $450 dollars per month on medical expenses showed better global health status/QoL. Payments per month for medical expenses, presence of metastasis, time since diagnosis, and type of treatment received were significantly associated with QoL, the different functioning dimensions, and symptoms. CONCLUSION: Strategies addressing symptom management in particular psychological symptoms need to be developed and implemented in addition to a holistic multidisciplinary palliative care approach. PMID- 22257430 TI - Isolated reversible hypoglossal nerve palsy as the initial manifestation of pre eclampsia. AB - Isolated hypoglossal nerve lesions often reflect sinister neoplastic or vascular pathology. Rarely, reversible lesions occur, perhaps via mechanisms similar to Bell's palsy. We report a patient with reversible isolated hypoglossal nerve palsy as the first and predominant early manifestation of pre-eclampsia and speculate on the pathogenesis behind this abnormality. PMID- 22257431 TI - A review on gastric diverticulum. AB - The gastric fundal diverticulae are rare. They can present with variable symptoms. We are enclosing a literature review on gastric fundal diverticulum. Lessons have emerged which may help in the management of this rare condition in future. PMID- 22257432 TI - A quick and cost effective method for the diagnosis of Mycobacterium ulcerans infection. AB - BACKGROUND: Buruli ulcer (BU), a neglected tropical skin disease caused by Mycobacterium ulcerans, has been reported in over 30 countries worldwide and is highly endemic in rural West and Central Africa. The mode of transmission remains unknown and treatment is the only alternative to disease control. Early and effective treatment to prevent the morbid effects of the disease depends on early diagnosis; however, current diagnosis based on clinical presentation and microscopy has to be confirmed by PCR and other tests in reference laboratories. As such confirmed BU diagnosis is either late, inefficient, time consuming or very expensive, and there is the need for an early diagnosis tool at point of care facilities. In this paper we report on a simple, quick and inexpensive diagnostic test that could be used at point of care facilities, in resource-poor settings. METHODS: The methodology employed is based on the loop mediated isothermal amplification (LAMP) technique. Four sets of Primers, targeting the mycolactone encoding plasmid genome sequence of M. ulcerans were designed. The BU LAMP assay was developed and tested on five M. ulcerans strains from patients in Ghana and two American Type Culture Control (ATCC) reference isolates; Ghana #970321 (D19F9) and Benin #990826 (D27D14). We also tested the assay on other closely related, mycolactone-producing mycobacterial strains; M. marinum 1218, M. marinum DL240490, M. liflandii and M. pseudoshotsii, as well as experimentally infected laboratory animal and clinical samples. RESULTS: The results revealed a high specificity of the BU-LAMP assay for selectively detecting M. ulcerans. Compared to the conventional IS-2404 PCR, the new assay is cheaper and simpler and ten times more sensitive. Test results can be obtained within 1 hour. CONCLUSIONS: This study indicates that the BU-LAMP assay could be suitable for early disease diagnosis and application in low-resource health facilities. PMID- 22257434 TI - Differential mortality rates by ethnicity in 3 influenza pandemics over a century, New Zealand. AB - Evidence suggests that indigenous populations have suffered disproportionately from past influenza pandemics. To examine any such patterns for Maori in New Zealand, we searched the literature and performed new analyses by using additional datasets. The Maori death rate in the 1918 pandemic (4,230/100,000 population) was 7.3* the European rate. In the 1957 pandemic, the Maori death rate (40/100,000) was 6.2* the European rate. In the 2009 pandemic, the Maori rate was higher than the European rate (rate ratio 2.6, 95% confidence interval 1.3-5.3). These findings suggest some decline in pandemic-related ethnic inequalities in death rates over the past century. Nevertheless, the persistent excess in adverse outcomes for Maori, and for Pacific persons residing in New Zealand, highlights the need for improved public health responses. PMID- 22257435 TI - [Is the critical patient competent for decision taking? Psychological and psychopathological reasons of cognitive impairment]. AB - BACKGROUND: Emotional factors may lead to cognitive impairment that can adversely affect the capacity of patients to reason, and thereby, limit their participation in decision taking. PURPOSES: To analyze critical patient aptitude for decision taking, and to identify variables that may influence competence. DESIGN: An observational descriptive study was carried out. SETTING: Intensive care unit. PATIENTS: Participants were 29 critically ill patients. MAIN VARIABLES: Social, demographic and psychological variables were analyzed. Functional capacities and psychological reactions during stay in the ICU were assessed. RESULTS: The patients are of the firm opinion that they should have the last word in the taking of decisions; they prefer bad news to be given by the physician; and feel that the presence of a psychologist would make the process easier. Failure on the part of the professional to answer their questions is perceived as the greatest stress factor. Increased depression results in lesser cognitive capacity, and for patients with impaired cognitive capacity, participation in the decision taking process constitutes a burden. The variables anxiety and depression are significantly related to decision taking capacity. PMID- 22257436 TI - Usefulness of procalcitonin clearance as a prognostic biomarker in septic shock. A prospective pilot study. AB - OBJECTIVE: To evaluate procalcitonin clearance as a prognostic biomarker in septic shock. DESIGN: Prospective, observational pilot study. SETTING: Intensive care unit. PATIENTS: Patients admitted to the ICU due to septic shock and multiorgan dysfunction. INTERVENTIONS: Serum concentrations of procalcitonin were determined within 12h of onset of septic shock and multiorgan dysfunction (coinciding with admission to the ICU), and the following extractions were obtained after 24, 48 and 72h in patients who survived. DATA COLLECTED: Demographic data, Acute Physiology and Chronic Health Evaluation II score, and Sequential Organ Failure Assessment score, data on the primary focus of infection, and patient outcome (ICU mortality). RESULTS: Procalcitonin clearance was higher in survivors than in non-survivors, with significant differences at 24h (73.9 [56.4-83.8]% vs 22.7 [-331-58.4], p<0.05) and 48h (81.6 [71.6-91.3]% vs -7.29 [-108.2-82.3], p<0.05). The area under the ROC curve was 0.74 (95%CI, 0.54 0.95, p<0.05) for procalcitonin clearance at 24h, and 0.86 (95%CI, 0.69-1.0, p<0.05) at 48h. CONCLUSIONS: ICU mortality was associated to sustained high procalcitonin levels, suggesting that procalcitonin clearance at 48h may be a valuable prognostic biomarker. PMID- 22257437 TI - Detailed analysis of the S-RESPDOR solid-state NMR method for inter-nuclear distance measurement between spin-1/2 and quadrupolar nuclei. AB - We present a detailed analysis of the Symmetry-based Resonance-Echo Saturation Pulse DOuble-Resonance (S-RESPDOR) method in order to measure the inter-nuclear distances between spin-1/2 and quadrupolar nuclei. This recently introduced sequence employs a symmetry-based recoupling scheme on the observed spin-1/2 channel and a saturation pulse on the quadrupolar channel. This method requires a low radio-frequency (rf) field, is compatible with high MAS frequency and allows a rapid determination of inter-nuclear distances by fitting the experimental signal fraction to an analytical expression. Here, we analyze in detail the influence of the various experimental and spin-interaction parameters on the S RESPDOR signal fraction and the measured distance. We show that the S-RESPDOR signal fraction only depends on the quadrupole interaction and the inter-nuclear distance. We demonstrate that the required rf-field on the quadrupolar channel is smaller than that required for an adiabatic-passage pulse in REAPDOR-type experiments. The only limitation of the method is the requirement of accurate rotor synchronization between the two parts of the dipolar recoupling sequences. Using S-RESPDOR, we have quantitatively measured a (31)P-(51)V distance of 357 pm in a mono-vanadium-substituted polyoxo-tungstate, K(4)PVW(11)O(40), from the Keggin family and a (13)C-(67)Zn distance of 286 pm in [80%-(67)Zn]zinc [1 (13)C]acetate. These results show that S-RESPDOR can be employed in the challenging cases of quadrupolar nuclei exhibiting a high spin number and either large chemical-shift anisotropy ((51)V) or low gyromagnetic ratio ((67)Zn). PMID- 22257438 TI - Bartonella quintana transmission from mite to family with high socioeconomic status. PMID- 22257439 TI - Perinatal effects on in vivo measures of human brain serotonin synthesis in adulthood: a 27-year longitudinal study. AB - There is an increasing evidence that prenatal and early postnatal stressors have life long impacts on physical and mental health problems. Animal studies have shown that this could include enduring changes to brain serotonin neurotransmission. In the present study, we tested whether perinatal adversity in humans has a long-term impact on brain serotonin neurotransmission in adulthood. Twenty-six healthy males, recruited from a 27-year longitudinal study, underwent a positron emission tomography scan with the tracer alpha-[11C]methyl-L tryptophan (11C-AMT), as an index of serotonin synthesis capacity. The trapping constant is taken as a proxy for the regional 5-HT synthesis. Birth complications, especially a delivery where the fetus showed signs of physiological distress, predicted lower 11C-AMT trapping in the hippocampus and medial orbitofrontal cortex. Lower 11C-AMT trapping in the medial orbitofrontal cortex was also predicted by maternal smoking and lower birth weight. There were no effects of childhood or recent adversity. This is the first human study reporting associations between perinatal adversity and adult 11C-AMT trapping in the hippocampus and medial orbitofrontal cortex. The associations suggest that limbic serotonin pathways may be particularly vulnerable to environmental challenges during the period when they undergo the most prominent neurodevelopmental changes. In combination with other risk factors, perinatal stressors may contribute to increased vulnerability for psychiatric disorders in which serotonin plays a major role. PMID- 22257441 TI - Identification of the putative specific pathogenic genes of Porphyromonas gingivalis with type II fimbriae. AB - Porphyromonas gingivalis, the key etiologic agent of periodontitis, can be classified into six types (I to V and Ib) based on the fimA genes that encode FimA (a subunit of fimbriae). Accumulated evidence indicates that P. gingivalis expressing Type II fimbriae (Pg-II) is the most frequent isolate from severe periodontitis cases and is more virulent than other types of P. gingivalis. However, during the Pg-II infection process, which specific virulence factors play the key role is still unclear. In this study, we examined the capabilities of three Pg-II strains to invade and modulate the inflammatory cytokine expression of human gingival epithelial cells (GECs) compared to two Pg-I strains. P. gingivalis oligo microarrays were used to compare gene expression profiles of Pg-II strains that invade GECs with Pg-I strains. The differential gene expression of Pg-II was confirmed by quantitative reverse transcription polymerase chain reaction. Our results showed that all of the Pg-II strains could induce interleukin (IL)-1beta and IL-6 secretion significantly when compared to Pg-I strains. Thirty-seven genes that were specifically expressed during the pathogenic process of Pg-II were identified by a microarray assay. These findings provide a new insight at the molecular level to explain the specific pathogenic mechanism of Pg-II strains. PMID- 22257442 TI - Clarification of data for a recent meta-analysis--epidermal growth factor polymorphisms and cancer risk: involving 9,779 cases and 15,932 controls. PMID- 22257443 TI - Amount of airflow required for olfactory perception in laryngectomees: a prospective interventional study. AB - OBJECTIVES: To determine minimum airflow rate required for olfactory stimulation in successfully rehabilitated laryngectomised patients after learning the polite yawning technique (PYT) and to confirm the hypothesis that sense of smell is rehabilitated once the nasal airflow is re-established. DESIGN: Prospective open interventional trial. SETTING: Tertiary academic hospital. PARTICIPANTS: The study population comprised 100 laryngectomised patients. The control group consisted of 100 non-laryngectomised patients of similar age and sex. Rhinomanometry was used to measure air flow in the right and left nostrils, respectively, while the Smell Diskettes Olfaction test (SDOT) was used to test each individual's sense of smell. MAIN OUTCOME MEASURES: The primary endpoint was increasing the airflow, while the secondary endpoint was improvement in the Smell Diskettes Olfaction test score after learning the polite yawning technique. RESULTS: The difference in the Smell Diskettes Olfaction test results before and after introducing the polite yawning technique was statistically significant (F = 53.077; P < 0.001). The number of accurately identified odours increased with each measurement. There was a significant difference among rhinomanometric measurements of airflow through the right (F = 65.002; P < 0.001) and left nostrils (F = 75.465; P < 0.001). Nasal airflow improved with each measurement. The minimum airflow required for olfactory stimulation in successfully rehabilitated patients was approximately 60 cm(3) /s. The control group had considerably better airflow in both nostrils than the laryngectomised group. The difference between the total number of rehabilitated (normosmic) patients (48%) in the laringectomised group and normosmic participants (56%) in the control group (z = 1.132; P = 0.129) was not statistically significant. CONCLUSION: The number of odours identified by laryngectomised patients increased with the volume of nasal airflow. The number of patients with rehabilitated olfactory function approximated the percentage of normosmic individuals in the non-laryngectomised population. These findings confirm the hypothesis that sense of smell is rehabilitated once the nasal airflow is re-established. PMID- 22257444 TI - Effect of cadmium on glutathione S-transferase and metallothionein gene expression in coho salmon liver, gill and olfactory tissues. AB - The glutathione S-transferases (GSTs) are a multifunctional family of phase II enzymes that detoxify a variety of environmental chemicals, reactive intermediates, and secondary products of oxidative damage. GST mRNA expression and catalytic activity have been used as biomarkers of exposure to environmental chemicals. However, factors such as species differences in induction, partial analyses of multiple GST isoforms, and lack of understanding of fish GST gene regulation, have confounded the use of GSTs as markers of pollutant exposure. In the present study, we examined the effect of exposure to cadmium (Cd), a prototypical environmental contaminant and inducer of mammalian GST, on GST mRNA expression in coho salmon (Oncorhynchus kisutch) liver, gill, and olfactory tissues. GST expression data were compared to those for metallothionein (MT), a prototypical biomarker of metal exposure. Data mining of genomic databases led to the development of quantitative real-time PCR (qPCR) assays for salmon GST isoforms encompassing 9 subfamilies, including alpha, mu, pi, theta, omega, kappa, rho, zeta and microsomal GST. In vivo acute (8-48 h) exposures to low (3.7 ppb) and high (347 ppb) levels of Cd relevant to environmental scenarios elicited a variety of transient, albeit minor changes (<2.5-fold) in tissue GST profiles, including some reductions in GST mRNA expression. In general, olfactory GSTs were the earliest to respond to cadmium, whereas, more pronounced effects in olfactory and gill GST expression were observed at 48 h relative to earlier time points. Although evaluation of GSTs reflected a cadmium-associated oxidative stress response, there was no clear GST isoform in any tissue that could serve as a reliable biomarker of acute cadmium exposure. By contrast, metallothionein (MT) mRNA was consistently and markedly induced in all three tissues by cadmium, and among the tissues examined, olfactory MT was the most sensitive marker of cadmium exposures. In summary, coho salmon exhibit a complex GST tissue profile consisting of at least 9 isoforms, all of which are present in the peripheral olfactory system. Short-term exposure to environmental levels of Cd causes transient changes in salmon GST consistent with oxidative stress, and in some cases, includes a loss of GST. In a biomarker context, however, monitoring of tissue MT mRNA expression, especially in the peripheral olfactory system, may be of greater utility for assessing short-term environmental exposures to cadmium. PMID- 22257445 TI - Quantification of the increase in Pb bioavailability to marine organisms caused by different types of DOM from terrestrial and river origin. AB - Dissolved organic matter (DOM) has metal binding properties and decreases the concentration of free metal ions in the aquatic environments. However, humic acids (HA) have been shown to increase Pb bioavailability for marine invertebrates, including Pb toxicity to sea urchin embryos. The low solubility and other properties of commercially available HA, which may not be the most representative fraction of DOM in natural waters, limit the environmental relevance of these findings. The present study tested the effect of more soluble DOM, fulvic acids (FA) and DOM extracted from the Suwannee River (SRDOM), on the acute toxicity of Pb to Paracentrotus lividus embryos. It was confirmed that FA and SRDOM, despite their Pb binding properties, also increased Pb toxicity for sea urchin embryos, even though this increase was not as high as that previously observed for HA. The enhancing effect of DOM on Pb bioavailavility was quantified using multiple regression equations for the present data, as well as for previously published data on Pb uptake by the gills of the marine mussel Mytilus sp. and Pb internalization by the marine microalgae Isochrysis galbana and Thalassiosira weissflogii. These results confirm that dissolved Pb bioavailability in seawater in the presence of DOM is higher than predicted using current bioavailability models based on chemical equilibrium chemistry. The experimental evidence suggests that the mechanisms by which DOM enhances Pb uptake and toxicity implies direct contact of the organic compounds with the plasma membrane. PMID- 22257446 TI - Evidence regarding the hypothesis that the histidine-histidine contact pairs may affect protein stability. AB - It has been lately proposed that the interaction between like-charged residues stabilizes the native state of proteins. To explore this, we created a histidine histidine pair in the Ca-III binding site of the Bacillus amyloliquefaciens alpha amylase (BAA) and then examined the impact of this pairing on the BAA. For this purpose, we used site-directed mutagenesis (SDM) to substitute Pro407 with His, Ala, Gln, Arg, and Glu in the BAA. Subsequently, thermostability, kinetic parameters and structural properties of these variants were measured. Moreover, His-His pairing effect on the BAA thermostability was examined by simultaneous mutation of two residues (P407H/H406A and P407H/H406N). The data exhibited a significant improve in thermostability and structural features of enzyme by His replacement instead of Pro407. Other substitutions in this site did not have a significant effect on the enzyme properties, except for P407R, which yielded a partial improvement. The results also showed that the thermostabilities of double mutants significantly decreased compared with that of the P407H mutant. Moreover, the thermostability of P407H remarkably increased compared with that of other variants even in the absence of Ca(2+). Our data clearly demonstrated that His406 His407 pairing was the major cause for improved thermal stability. PMID- 22257447 TI - Phospholipids and insulin resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia. AB - BACKGROUND: Several theories have been proposed to conceptualize the pathological processes inherent to schizophrenia. The 'prostaglandin deficiency' hypothesis postulates that defective enzyme systems converting essential fatty acids to prostaglandins lead to diminished levels of prostaglandins, which in turn affect synaptic transmission. METHODS: Here we sought to determine the lipidomic profiles associated with schizophrenia in twin pairs discordant for schizophrenia as well as unaffected twin pairs. The study included serum samples from 19 twin pairs discordant for schizophrenia (mean age 51 +/- 10 years; 7 monozygotic pairs; 13 female pairs) and 34 age and gender matched healthy twins as controls. Neurocognitive assessment data and gray matter density measurements taken from high-resolution magnetic resonance images were also obtained. A lipidomics platform using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry was applied for the analysis of serum samples. RESULTS: In comparison to their healthy co-twins, the patients had elevated triglycerides and were more insulin resistant. They had diminished lysophosphatidylcholine levels, which associated with decreased cognitive speed. CONCLUSIONS: Our findings may be of pathophysiological relevance since lysophosphatidylcholines, byproducts of phospholipase A2-catalyzed phospholipid hydrolysis, are preferred carriers of polyunsaturated fatty acids across the blood-brain barrier. Furthermore, diminishment of lysophosphatidylcholines suggests that subjects at risk of schizophrenia may be more susceptible to infections. Their association with cognitive speed supports the view that altered neurotransmission in schizophrenia may be in part mediated by reactive lipids such as prostaglandins. PMID- 22257448 TI - [Immunosuppression in kidney donors with rapamycin and tacrolimus. Proinflammatory cytokine expression]. AB - The ischemia-reperfusion injury (IRI) remains a major problem in transplantation. The objective of this study was to evaluate the effects of preconditioning a donor group with rapamycin and another donor group with tacrolimus to prevent IRI. Twelve hours before nephrectomy, donor Wistar rats received immunosuppressive drugs. The sample was divided into four experimental groups: a sham group, an untreated control group, a group treated with rapamycin (2 mg/kg) and a group treated with tacrolimus (0.3 mg/kg). Left kidneys were removed and, after three hours of cold ischemia, grafts were transplanted. Twenty-four hours later, the transplanted organs were recovered for histological analysis and evaluation of cytokine expression. The pre-conditioning treatment with rapamycin or tacrolimus significantly reduced donor blood urea nitrogen and creatinine levels compared with control group (BUN: p < 0.001 vs. control and creatinine: p < 0.001 vs. control). Acute tubular necrosis was significantly lower in donors treated with immunosuppressant drugs compared with the control group (p < 0.001). Finally, inflammatory cytokines such as TNF-a, IL-6 and rIL-21 showed lower levels in the graft of pre-treated animals. This exploratory experimental study shows that preconditioning donors with rapamycin and tacrolimus in different groups improves clinical outcome and pathology in recipients and reduces in situ pro-inflammatory cytokines associated with Th17 differentiation, creating a favorable environment for the differentiation of regulatory T cells (Tregs). PMID- 22257449 TI - [Usefulness of transient elastography (Fibroscan(r)) in the assessment of fibrosis in patients with chronic liver disease]. AB - The prognosis and management of chronic liver disease largely depends on the extent and progression of liver fibrosis. Unfortunately, liver biopsy, an invasive and painful technique with several limitations, continues to be the gold standard for the staging and grading of fibrosis. Therefore, accurate noninvasive tests for liver injury are urgently needed. During the last years, transient elastography (Fibroscan(r)) has been proposed for the assessment of hepatic fibrosis in patients with chronic liver disease, by measuring liver stiffness. The aim of this study was to evaluate the effectiveness, objectivity and safety of this technique. We included 68 patients who underwent a liver biopsy in the last 18 months with a wide spectrum of chronic liver diseases. All procedures as well as the liver biopsies according to the METAVIR scoring system were analyzed by the same sonographer and the same specialist in pathology, respectively. Median value of stiffness with none or mild fibrosis (F0 and FI), and severe fibrosis or cirrhosis (F3 and F4) was 6.8 +/- 3.0 kPa and 21.0 +/- 15.1 kPa, respectively, with a significant difference between them (p < 0.01). The areas under the receiver operating characteristic curves showed the optimal liver stiffness cut-off values for each group. We found also a positive correlation between liver stiffness found by transient elastography and fibrosis stage on biopsy in all patients, independently of the liver disease etiology. Fibroscan(r) is an easy, quick to perform and safe non-invasive method, reliable for assessing liver fibrosis. PMID- 22257450 TI - [Aerobic training improves antioxidant defense system in women with metabolic syndrome]. AB - A 12-week training protocol increased antioxidant defense system in young adult women with metabolic syndrome. It is generally accepted that oxidative stress is implicated in the pathogenesis of metabolic syndrome. Furthermore, recent studies have reported that stress may be acting as a therapeutic target in metabolic syndrome. Consequently, this study was designed to explore whether aerobic training may increase plasmatic total antioxidant status in women with metabolic syndrome. A total of 100 young adult women with metabolic syndrome according to the criteria reported by the National Cholesterol Education Program (Adult Treatment-Panel-III) volunteered for this study. Of them, 60 were randomly included in the experimental group to enter a 12-week aerobic training program, 5 days/week, at low/moderate intensity. The control group included 40 age, sex and body mass index (BMI)-matched women with metabolic syndrome who did not enter any training program. Total antioxidant status (TAS) was assayed in plasma using colorimetric Randox kits. This protocol was approved by an Institutional Ethics Committee. When compared to baseline, plasmatic TAS was significantly increased (0.79 +/- 0.05 Vs 1.01 +/- 0.03 mmol/l; p = 0.027). No changes were found in controls. A 12-week aerobic training program increased plasmatic TAS in adult women with metabolic syndrome. Further long-term well-conducted studies are required in order to highlight the potential clinical benefits of TAS improvement. PMID- 22257451 TI - [Levels of antiplatelet factor 4-heparin antibodies and 4T score for heparin induced thrombocytopenia]. AB - Heparin induced thrombocytopenia (HIT) is an immune-mediated disorder due to antibodies anti platelet factor 4-heparin (HPIA). Thrombocytopenia is often moderate but certain patients can develop morbid thrombotic complications. HPIA detection by ELISA has high sensitivity but low specificity, and low titers (without clinical significance) are frequent. A pretest clinical score (4T's) was developed in order to recognize patients that are at high risk of HIT. The aim of this study was to correlate HPIA levels and the 4T's score of consecutive patients derived to our center. We evaluated 84 patients (35 of them developed thrombosis); the clinical questionnaire was sent along with the sample and was analyzed by an investigator who did not know the patients' characteristics, and 4T's scores were calculated before performing the laboratory tests. HPIA were measured by ELISA (Asserachrom HPIA) that detects IgG, IgM and IgA isotypes, (the only reagent available in our country). 4T's score correlated with HPIA levels (rho spearman 0.472, p < 0.001). Patients with 4T's = 6 had higher absorbance percentages than those with = 5 (67 vs. 39%, p < 0.001), and patients with thrombosis also presented higher titers (59 vs. 39%, p = 0.017) than those who did not develop this complication. In conclusion, high titers of HPIA measured by EIA which detects the 3 isotypes, clearly correlate with 4T's score = 6 and are more frequent in patients who develop thrombosis, just as reported when an IgG specific ELISA is used. PMID- 22257452 TI - [Mucormycosis. An emergent mycosis]. AB - Mucormycosis is an opportunistic infection caused by fungi of the order Mucorales. It is characterized by rapid progression and high morbidity and mortality in the absence of early diagnosis and prompt treatment. It was an infrequent disease, but in recent years, its incidence appears to have increased. The aim of this paper is to report the cases of mucormycosis diagnosed from 1982 to 2010 at the Hospital de Clinicas Jose de San Martin, University of Buenos Aires. We diagnosed 10 cases of mucormycosis; the first three between 1982 and 2004 and the last 7 between 2005 and 2010. The incidence from 1980 to 2004 was 0.13 patient-years and the frequency 0.1/10 000 discharges (95% CI 0.00- 0.3). In the period 2005 to 2010, the incidence was 0.86 patients per year with 1.1/10 000 discharges (95% CI 0.5-2.4). There was a pulmonary mucormycosis case (in a patient treated with corticosteroids) and nine rhinocerebral cases, two in neutropenic and seven in diabetic patients. The diagnosis was made by observation of cenocytic hyphae in 10/10 patients. Mucorales were recovered in 8/9 cultures (5 Rhizopus spp and 3 Mucor spp.). In one case diagnosis of pulmonary mucormycosis was made post-mortem. Nine patients were treated with amphotericin B deoxycholate (in 3 patients supplemented with liposomal amphotericin B) and surgery. Three patients underwent hyperbaric chamber. Seven patients had favorable outcome. In conclusion, mucormycosis is a rare disease, but its incidence has increased over the past five years. A good evolution of the patients is linked to early diagnosis and treatment. PMID- 22257453 TI - [Rhinoviruses. Frequency in nonhospitalized children with acute respiratory infection]. AB - Molecular methods for human rhinoviruses (HRV) have increased the sensitivity in their diagnosis. HRV may cause acute respiratory infections (ARI) of the upper and lower respiratory tract. HRV infection during childhood is a predictor of asthma development. In this study, the HRV frequency in outpatient children with ARI was determined, and their clinical features and previous conditions were evaluated. A total of 186 respiratory samples of children under 6 year old attending the CEMIC pediatric emergency room from June 1, 2008 to May 31, 2010, were studied. Classical respiratory viruses were detected by immunofluorescence. A real time RT-PCR that amplifies part of the 5' non coding genomic region was used for HRV detection. Viral detection was obtained in 61% of children. The frequency was: 27% for HRV, 16% for respiratory syncytial virus (RSV), 9% for influenza, 8% for parainfluenza, 7% for metapneumovirus and 0.5% for adenovirus. Dual coinfection was detected in 8 children and HRV were the most frequent, detected in 4 of them. HRV circulated during the two year period of the study, with peaks during winter and spring. No clinical difference was observed between patients with or without HRV, except an increase percent of children with HRV without fever. HRV were the most frequent viruses detected in this population, mainly in children under 2 year old, the second cause of bronchiolitis after RSV and more frequently detected in children exposed to passive smoking (OR = 2.91; p = 0.012), and were detected as the sole etiologic agent in 28% of bronchiolitis. PMID- 22257454 TI - [Kikuchi-Fujimoto disease]. AB - Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare, benign, self-limited condition of unknown etiology. A 16-year-old woman with no relevant clinical history seeks medical attention for fever and cervical adenopathies. In a physical examination the patient is found to be febrile (38.5 C) with multiple bilateral, hard-elastic cervical adenopathies, congestive oropharynx and mild splenomegaly with no other relevant pathological findings. The laboratory examination shows signs of pancytopenia and an increase in the erythrocyte sedimentation rate, Beta2-microglobulin, transaminases and lactate dehydrogenase. Several serological tests are carried out with negative results except for immunoglobulin G for parvovirus, which is positive. A computerized axial tomography scan of head, neck, thorax, abdomen and pelvis shows bilateral lateral cervical adenomegalies (the largest with a size of 15 mm) and bilateral axillary adenomega- lies of less than 10 mm in diameter; small basal lung condensations with mild pleural effusion, mild homogeneous splenomegaly, and a small amount of free fluid in the abdominal cavity at the bottom of the Douglas cul-de-sac. Possible respiratory and gynecological infections are treated with ampicillin/sulbactam together with doxycycline. The patient progresses with persistence of the symptoms. A lymph node biopsy is then performed, revealing a morphology compatible with Kikuchi-Fujimoto disease. Treatment with prednisone is initiated with a clinical and laboratory improvement in the patient's condition. Kikuchi-Fujimoto disease is probably under-reported and under-diagnosed due to the low index of suspicion. Greater awareness of this illness would result in clinicians arriving at this diagnosis more often. PMID- 22257455 TI - [Chronic peripheral arterial disease induced by cocaine]. AB - Cocaine induced acute peripheral thrombosis, though a rare complication, has been described in the literature. Although there are reports describing the chronic effects of cocaine on the peripheral arterial system, there are no published cases of this complication when other risk factors are lacking. We report on a 22 year old female patient, with intranasal consumption of 3 grams of cocaine per week for a year, who consulted for intermittent claudication at 200 meters, associated to left lower limb pain and paresthesiae for the last two months. Arterial Doppler ultrasonography showed a stenosis greater than 70% in the superficial left femoral artery. Other probable etiologies were excluded. Treatment was initiated with acetylsalicylic acid, cilostazol and graded physical exercise, associated to support therapy in order to maintain cocaine consumption avoidance, with good response. This case emphasizes the relevance of patients information, as most people ignore the cardiovascular complication of this addiction. It is also essential to inquire about cocaine consumption in young patients with peripheral arteriopathy and no apparent risk factors. PMID- 22257456 TI - [Human diphyllobothriosis. A case in non-endemic area of Argentina]. AB - Diphyllobothriosis is an intestinal parasitosis caused by cestodes infection of the genus Diphyllobothrium. In Argentina, the Andean Patagonia is considered an endemic area for this parasitosis. Diphyllobothrium latum infection has not been previously reported in the province of Mendoza, Argentina. We are now reporting then the first case. Diphyllobothriosis was confirmed by examination of morphologic characteristics of the eggs eliminated in the patients' feces. These results suggest the requirement of a more specific training of health workers in the diagnosis and treatment of non endemic parasitosis. We want to emphasize the need of health workers' education on diagnosis and treatment of endemic and non endemic parasitosis. PMID- 22257457 TI - [Spontaneous spinal epidural hematoma]. PMID- 22257458 TI - [Baboon syndrome]. PMID- 22257459 TI - [Immunomodulation and antiangiogenesis in cancer therapy. From basic to clinical research]. AB - Basic and pre-clinic research in cellular and molecular oncology are the main supports accounting for the advancement in cancer therapeutics. The findings achieved, and their implementation in clinical practice are responsible for the permanent improvement in the treatment of the neoplastic disease. Our present objective is to summarize and discuss the pre-clinical findings in immunomodulation and anti-angiogenesis for the treatment of several types of tumors obtained in our Institute during the last 15 years, and the subsequent translation and application of the acquired experimental knowledge in a Phase I/II Clinical Trial. We present the results and mechanisms of action of antimetastatic immunomodulation with cyclophosphamide, the metronomic chemotherapy with different single drugs and their combinations, and finally the design and preliminary results of a clinical trial with metronomic chemotherapy for patients with advanced breast cancer. PMID- 22257460 TI - [Blood glucose control during cardiac surgery. Report of the Emergency Council of the Argentine Society of Cardiology]. AB - Hyperglycemia after cardiac surgery is a common finding associated with the worse outcomes affecting both diabetic and non diabetic patients. Despite the large number of publications available, there is no universally accepted approach to this problem. In an initiative of the Emergency Council of the Argentine Society of Cardiology, local experts gathered to discuss the management of hyperglycemia after adult cardiac surgery. The main objective of the present paper is to summarize the current state of knowledge regarding glycemic control in postoperative cardiac surgery. PMID- 22257461 TI - [Amiodarone and thyroid dysfunction]. AB - Amiodarone is a structural analogue of thyroid hormone, and some of its anti arrhythmic actions and toxicity are attributable to its interaction with nuclear receptors of thyroid hormones. Being highly lipophilic, amiodarone is concentrated in many tissues and is eliminated, consequently, very slowly. It is preferably employed to manage life-threatening arrhythmias, including ventricular fibrillation and unstable ventricular tachycardia. Other indications include atrial fibrillation and flutter, severe congestive heart failure, prevention of atrial fibrillation recurrence, and even in emergency medical situations to prevent sudden cardiac death. The aim of this review is to provide an updated approach on amiodarone and its influence on thyroid physiology and to discuss and analyze in depth its potential and not infrequent thyroidal adverse effects such as hypothyroidism and thyrotoxicosis. PMID- 22257462 TI - [Septic shock, multiple mieloma and septic vasculitis]. PMID- 22257463 TI - [History of our journal, Medicina (Buenos Aires)]. PMID- 22257464 TI - [Her-2/neu oncogen amplification in breast cancer]. PMID- 22257466 TI - Precision of heavy-light peptide ratios measured by maldi-tof mass spectrometry. AB - We have investigated the precision of peptide quantitation by MALDI-TOF mass spectrometry (MS) using six pairs of proteotypic peptides (light) and same sequence stable isotope labeled synthetic internal standards (heavy). These were combined in two types of dilution curves spanning 100-fold and 2000-fold ratios. Coefficients of variation (CV; standard deviation divided by mean value) were examined across replicate MALDI spots using a reflector acquisition method requiring 100 000 counts for the most intense peak in each summed spectrum. The CV of light/heavy peptide centroid peak area ratios determined on four replicate spots per sample, averaged across 11 points of a 100-fold dilution curve and over all six peptides, was 2.2% (ranging from 1.5 to 3.7% among peptides) at 55 fmol total (light + heavy) of each peptide applied per spot, and 2.5% at 11 fmol applied. The average CV of measurements at near-equivalence (light = heavy, the center of the dilution curve) for the six peptides was 1.0%, about 17-fold lower CV than that observed when five peptides were ratioed to a sixth peptide (i.e., a different-sequence internal standard). Response curves across the 100-fold range were not completely linear but could be closely modeled by a power law fit giving R(2) values >0.998 for all peptides. The MALDI-TOF MS method was used to determine the endogenous level of a proteotypic peptide (EDQYHYLLDR) of human protein C inhibitor (PCI) in a plasma digest after enrichment by capture on a high affinity antipeptide antibody, a technique called stable isotope standards and capture by anti-peptide antibodies (SISCAPA). The level of PCI was determined to be 770 ng/mL with a replicate measurement CV of 1.5% and a >14 000-fold target enrichment via SISCAPA-MALDI-TOF. These results indicate that MALDI-TOF technology can provide precise quantitation of high-to-medium abundance peptide biomarkers over a 100-fold dynamic range when ratioed to same-sequence labeled internal standards and enriched to near purity by specific antibody capture. The robustness and throughput of MALDI-TOF in comparison to conventional nano-LC-MS technology could enable currently impractical large-scale verification studies of protein biomarkers. PMID- 22257465 TI - Acute and chronic animal models for the evaluation of anti-diabetic agents. AB - Diabetes mellitus is a potentially morbid condition with high prevalence worldwide thus being a major medical concern. Experimental induction of diabetes mellitus in animal models is essential for the advancement of our knowledge and understanding of the various aspects of its pathogenesis and ultimately finding new therapies and cure. Experimental diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic (immunological) manipulations. Most of the experiments in diabetes are carried out in rodents, although some studies are still performed in larger animals. The present review highlights the various methods of inducing diabetes in experimental animals in order to test the newer drugs for their anti-diabetic potential. PMID- 22257467 TI - Obesity, body composition, and prostate cancer. AB - BACKGROUND: Established risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer. METHODS: The study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression. RESULTS: Body size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (OR(BMI) = 1.039 (1.000, 1.081), OR(WC) = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (OR(BMI) = 0.998 (0.946, 1.052), OR(WC) = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (OR(FFM) = 1.030 (1.008, 1.052)) and Gleason 8-10 (OR(FFM) = 1.044 (1.014, 1.074)) after controlling for FM. CONCLUSIONS: Our results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age. PMID- 22257468 TI - Predicting restoration of kidney function during CRRT-free intervals. AB - BACKGROUND: Renal failure is common in critically ill patients and frequently requires continuous renal replacement therapy (CRRT). CRRT is discontinued at regular intervals for routine changes of the disposable equipment or for replacing clogged filter membrane assemblies. The present study was conducted to determine if the necessity to continue CRRT could be predicted during the CRRT free period. MATERIALS AND METHODS: In the period from 2003 to 2006, 605 patients were treated with CRRT in our ICU. A total of 222 patients with 448 CRRT-free intervals had complete data sets and were used for analysis. Of the total CRRT free periods, 225 served as an evaluation group. Twenty-nine parameters with an assumed influence on kidney function were analyzed with regard to their potential to predict the restoration of kidney function during the CRRT-free interval. Using univariate analysis and logistic regression, a prospective index was developed and validated in the remaining 223 CRRT-free periods to establish its prognostic strength. RESULTS: Only three parameters showed an independent influence on the restoration of kidney function during CRRT-free intervals: the number of previous CRRT cycles (medians in the two outcome groups: 1 vs. 2), the "Sequential Organ Failure Assessment"-score (means in the two outcome groups: 8.3 vs. 9.2) and urinary output after the cessation of CRRT (medians in two outcome groups: 66 ml/h vs. 10 ml/h). The prognostic index, which was calculated from these three variables, showed a satisfactory potential to predict the kidney function during the CRRT-free intervals; Receiver operating characteristic (ROC) analysis revealed an area under the curve of 0.798. CONCLUSION: Restoration of kidney function during CRRT-free periods can be predicted with an index calculated from three variables. Prospective trials in other hospitals must clarify whether our results are generally transferable to other patient populations. PMID- 22257469 TI - Daily newspaper view of dengue fever epidemic, Athens, Greece, 1927-1931. AB - During the late summers of 1927 and 1928, a biphasic dengue epidemic affected the Athens, Greece, metropolitan area; >90% of the population became sick, and >1,000 persons (1,553 in the entire country) died. This epidemic was the most recent and most serious dengue fever epidemic in Europe. Review of all articles published by one of the most influential Greek daily newspapers (I Kathimerini) during the epidemic and the years that followed it did not shed light on the controversy about whether the high number of deaths resulted from dengue hemorrhagic fever after sequential infections with dengue virus types 1 and 2 or to a particularly virulent type 1 virus. Nevertheless, study of the old reports is crucial considering the relatively recent introduction of Aedes albopictus mosquitoes and the frequent warnings of a possible reemergence of dengue fever in Europe. PMID- 22257471 TI - Dengue outbreak in Key West, Florida, USA, 2009. AB - After 3 dengue cases were acquired in Key West, Florida, we conducted a serosurvey to determine the scope of the outbreak. Thirteen residents showed recent infection (infection rate 5%; 90% CI 2%-8%), demonstrating the reemergence of dengue in Florida. Increased awareness of dengue among health care providers is needed. PMID- 22257473 TI - Management of acute, severe ulcerative colitis. AB - When a patient is hospitalized with acute, severe ulcerative colitis, the primary decision is whether or not to proceed directly to surgery. Absolute indications for an immediate colectomy include exsanguinating hemorrhage, perforation and cancer. If medical therapy is undertaken, however, the decision for urgent surgery or non-operative salvage therapy will still be required in 15-50% of the patients in which there is a failure to respond within 3-5 days to a standard regimen of i.v. steroids, antibiotics, decompressive maneuvers, fluid and electrolyte replacement and other supportive measures. The options for medical salvage therapy are usually cyclosporine or infliximab. There are theoretical and practical arguments on each side; the current GETAID and CONSTRUCT trials will probably provide support for either. The choice between colectomy or medical salvage therapy, however, must not be delayed under any circumstances. Before choosing salvage therapy, one must first be certain that there is the luxury of time, that there is a post-hospital strategy for the maintenance of remission and that the colon is worth saving. The priority is not so much saving colons as it is saving lives. PMID- 22257474 TI - Liver X receptors bridge hepatic lipid metabolism and inflammation. AB - Liver X receptors (LXRs) are members of the superfamily of metabolic nuclear receptors, which play central roles in the regulation of cholesterol absorption, efflux, transportation and excretion and many other processes correlating with lipid metabolism. LXRs can also regulate inflammation in vitro and in vivo. Accumulating evidence demonstrates that LXR are involved in the metabolism and inflammation in human diseases. Nonalcoholic fatty liver disease (NAFLD) is classically associated with lipid metabolic disorders and inflammatory responses, especially in the nonalcoholic steatohepatitis (NASH) phase. The effects of LXRs on cholesterol metabolism and inflammation make them attractive as a potential target for the treatment of NAFLD. Since the ability to synthesize triglycerides may be protective in obesity and fatty liver, the hepatic lipogenesis by LXRs should not rule out the possibility of the use of LXRs in NAFLD. PMID- 22257475 TI - The characteristics of respiratory function and pulmonary hemodynamics in patients with portal hypertension. AB - OBJECTIVE: To investigate the respiratory function and pulmonary hemodynamics in patients with portal hypertension (PHT). METHODS: A total of 148 patients with PHT were divided into three groups according to Child-Pugh classification. Results of blood biochemistry test, lung function test, arterial blood gas analysis, free portal pressure (FPP) and pulmonary hemodynamics measurements of the three Child-Pugh grade groups were compared with those of the control group. RESULTS: The overall incidence of arterial hypoxemia was 27.0% in PHT patients. Arterial oxygen tension (PaO(2) ) had a significant negative correlation with FPP (r=-0.76, P<0.01) and Child-Pugh grade (r=-0.42, P<0.01), as well as a positive correlation with systemic vascular resistance (SVR, r=0.24, P=0.01). Alveolar arterial oxygen difference (A-aDO(2) ) increased in Child-Pugh grade C group when compared with Child-Pugh grade A and B groups (P<0.05). Restrictive impairment of lung function was seen in Child-Pugh grade C group. Direct measurement of the hemodynamics in PHT patients revealed a hyperdynamic disturbance in both systemic and portal venous systems, and was illustrated in pulmonary circulation as an increase of mean pulmonary arterial pressure (MPAP) and pulmonary arterial wedged pressure (PAWP) as well as a decrease of pulmonary vascular resistance (PVR). CONCLUSIONS: High output and low resistance are the key characteristics of pulmonary circulation in PHT patients and the decrease of PVR can be detected even when liver function is still compensated. PMID- 22257472 TI - NGS technologies for analyzing germplasm diversity in genebanks. AB - More than 70 years after the first ex situ genebanks have been established, major efforts in this field are still concerned with issues related to further completion of individual collections and securing of their storage. Attempts regarding valorization of ex situ collections for plant breeders have been hampered by the limited availability of phenotypic and genotypic information. With the advent of molecular marker technologies first efforts were made to fingerprint genebank accessions, albeit on a very small scale and mostly based on inadequate DNA marker systems. Advances in DNA sequencing technology and the development of high-throughput systems for multiparallel interrogation of thousands of single nucleotide polymorphisms (SNPs) now provide a suite of technological platforms facilitating the analysis of several hundred of Gigabases per day using state-of-the-art sequencing technology or, at the same time, of thousands of SNPs. The present review summarizes recent developments regarding the deployment of these technologies for the analysis of plant genetic resources, in order to identify patterns of genetic diversity, map quantitative traits and mine novel alleles from the vast amount of genetic resources maintained in genebanks around the world. It also refers to the various shortcomings and bottlenecks that need to be overcome to leverage the full potential of high throughput DNA analysis for the targeted utilization of plant genetic resources. PMID- 22257477 TI - Video capsule endoscopy in celiac disease: current clinical practice. AB - OBJECTIVE: A complete examination of the small intestine is possible by video capsule endoscopy (VCE). The aim of this study was to evaluate current indications for performing VCE in celiac disease. METHODS: In all 84 celiac disease patients on a gluten-free diet who had undergone VCE were enrolled at five centers in Europe. The indications, findings and clinical impact of VCE were recorded by a structured questionnaire. VCE was also carried out in 34 consecutive patients with untreated celiac disease (controls) in another center. RESULTS: Out of the 84 patients, 34 had overt symptoms and small intestinal histology compatible with refractory celiac disease. VCE was normal in 9 patients, and 7 had only proximal and one distal atrophy, 14 had intestinal ulcer and 2 an intestinal stricture. VCE was used in the adjustment of immunosuppressive treatment in 9 patients. In the remaining 50 patients, a VCE was performed because of less severe symptoms, 31 of which had an earlier histological recovery. The VCE showed proximal small bowel atrophy in 21 and distal atrophy in 3 patients, and 3 ulcers were seen. In this group the patients received mainly advice with a view to achieving better dietary compliance. Of the 34 newly detected celiac patients, 4 were normal, 27 proximal and 3 had distal small intestinal atrophy in the VCE. CONCLUSIONS: VCE has a definite impact on the management of refractory sprue. In the remaining patients with established celiac disease, the procedure plays a more limited role. PMID- 22257476 TI - 6-Mercaptopurine transport in human lymphocytes: correlation with drug-induced cytotoxicity. AB - OBJECTIVE: 6-mercaptopurine (6-MP) is efficacious in the treatment of inflammatory bowel disease (IBD). However, about one-third of patients respond poorly to therapy. This study aimed to characterize the inherent differences in 6 MP transport that may cotribute to the differences in treatment responses. METHODS: Intracellular 6-MP accumulation was assayed in Epstein-Barr virus (EBV)-transformed lymphocytes from IBD patients, using (14) C-radiolabeled 6-MP. Cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. Apoptosis was assayed based on the activation of caspase 3. The expressions of 15 potential 6-MP transporters were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Intracellular 6-MP accumulation, varying significantly among patients, was carrier-dependent and partially sodium dependent. 6-MP cytotoxicity was, at least in part, due to apoptosis and correlated with intracellular drug accumulation. The efflux transporters did not appear to contribute to the variability of intracellular drug accumulation between patients, since none correlated with drug accumulation or cytotoxicity. Rather, differential expression of five influx/uptake transporters might be a key contributor to the difference in the accumulation of and susceptibility to the drug. CONCLUSIONS: The heterogeneity of the drug transporters may be the reason for the therapeutic sensitivity of 6-MP in IBD patients. As the 6-MP uptake is a carrier-mediated and partially sodium-dependent process, future studies are necessary to evaluate the role of the putative transporters and their correlation with drug sensitivity in patients. PMID- 22257478 TI - Rapid high-performance liquid chromatography method for determination of tryptophan in gastric juice. AB - OBJECTIVE: To develop a rapid, high-performance liquid chromatography (HPLC) method for the determination of tryptophan in gastric juice to help the differentiation between gastric cancer and benign gastric disease. METHODS: HPLC was performed on a restricted access material Shiseido Capcell Pak MF SCX SG80 column. Phosphate buffered solution (90mmol/L, pH 3.5)-acetonitrile (ACN; 80/20, V/V) was chosen as the mobile phase. Separation was done at room temperature using a constant flow rate of 1.0mL/min. Fluorescence emission signal intensity at 330nm excited by 288nm ultra violet light was detected and measured. RESULTS: Thirty-eight gastric juice samples from patients with gastric cancer and 48 gastric juice samples of patients with benign gastric disease were tested. A linear relationship in the range of 0.20-100mg/L was obtained between the concentration of tryptophan and its fluorescence emission signal intensity at 330nm. The limit of detection was 0.05mg/L. The recovery rate was 77.4-90.6%. CONCLUSIONS: An HPLC method based on strong cation-exchange restricted access columns for determination of concentration of tryptophan in gastric juice was developed. The method has excellent precision and stability. It is compatible with the analysis of gastric juice and has the potential to be used for gastric cancer screening. PMID- 22257479 TI - International survey of enteral nutrition protocols used in children with Crohn's disease. AB - OBJECTIVE: Differing protocols have been utilized in published studies evaluating exclusive enteral nutrition (EEN) in the management of active pediatric Crohn's disease. This study aimed to ascertain the protocols currently utilized in different pediatric centers around the world and to highlight their similarities and differences. METHODS: A questionnaire was circulated to individuals at pediatric centers in countries in Europe, North America and Asia Pacific. Respondents were asked to indicate the number of children treated with EEN at their centers in the previous years and to provide details of their protocol used for administering EEN to these children. RESULTS: Responses were received from 35 separate centers (42% of those asked). The duration of EEN varied from <6 weeks to >12 weeks, but was most commonly 6 to 8 weeks. Although 23 different formulas were utilized across the centers, most (90%) used polymeric formulas. Flavourings were commonly added to formulas but wide variations existed between centers with the prescription of food and fluids permitted during the EEN period. The reintroduction of food after EEN also varied greatly: the most common recommendations were for an initial low-fiber diet (26%) or the gradual introduction of food quantity as the formula volume decreased (52%). CONCLUSIONS: This questionnaire-based study has shown the wide variations in EEN protocols used in different areas of the world. The development of consistent protocols may enhance the acceptance, efficacy and wider utilization of this therapy. PMID- 22257480 TI - Acid inhibition effect of ilaprazole on Helicobacter pylori-negative healthy volunteers: an open randomized cross-over study. AB - OBJECTIVE: The aim of this study was to evaluate the effects and safety of different doses of ilaprazole on healthy volunteers without a Helicobacter pylori infection. METHODS: A total of 12 healthy Chinese volunteers were enrolled and divided into four groups randomly, with a 5-day treatment of oral ilaprazole 5mg, 10mg and 20mg or omeprazole 20mg, respectively. After an interval of a 14-day washout phase, each was switched to another dose group and eventually completed all four regimens. The percentage time of intragastric pH>4 was the major index. The polymorphisms of the metabolic enzyme CYP2C19 in these volunteers were also detected. RESULTS: The percentage time of intragastric pH>4 in the ilaprazole 5, 10 and 20mg groups were 80.4%, 88.1% and 91.0%, respectively, during the first 24h, compared to that of the 20mg omeprazole group (76.6%, P>0.05). Ilaprazole 20mg provided a significant higher mean 24-h pH than that of the same dose of omeprazole both on Day 1 (7.78 vs 6.67, P<0.01) and Day 5 (7.95 vs 7.44, P<0.05). No CYP2C19-dependent difference or obvious adverse effect were found in any ilaprazole groups. CONCLUSION: Low dose ilaprazole offers a gastric acid inhibition comparable to a routine dose of omeprazole, and further investigations in patients with acid-associated diseases are needed. PMID- 22257481 TI - A huge retroperitoneal liposarcoma presenting as a hepatic space-occupying lesion: a case report. PMID- 22257482 TI - ApoA-IV modulates the secretory trafficking of apoB and the size of triglyceride rich lipoproteins. AB - Although the evidence linking apoA-IV expression and triglyceride (TG)-rich lipoprotein assembly and secretion is compelling, the intracellular mechanisms by which apoA-IV could modulate these processes remain poorly understood. We therefore examined the functional impact of apoA-IV expression on endogenous apoB, TG, and VLDL secretion in stably transfected McA-RH7777 rat hepatoma cells. Expression of apoA-IV modified with the endoplasmic reticulum (ER) retention signal KDEL (apoA-IV-KDEL) dramatically decreased both the rate and efficiency of endogenous apoB secretion, suggesting a presecretory interaction between apoA-IV KDEL and apoB or apoB-containing lipoproteins. Expression of native apoA-IV using either a constitutive or tetracycline-inducible promoter delayed the initial rate of apoB secretion and reduced the final secretion efficiency by ~40%. However, whereas apoA-IV-KDEL reduced TG secretion by 75%, expression of native apoA-IV caused a 20-35% increase in TG secretion, accompanied by a ~55% increase in VLDL associated apoB, an increase in the TG:phospholipid ratio of secreted d < 1.006 lipoproteins, and a 10.1 nm increase in peak VLDL(1) particle diameter. Native apoA-IV expression had a negligible impact on expression of the MTP gene. These data suggest that by interacting with apoB in the secretory pathway, apoA-IV alters the trafficking kinetics of apoB-containing TG-rich lipoproteins through cellular lipidation compartments, which in turn, enhances particle expansion and increases TG secretion. PMID- 22257483 TI - 5-alpha-reductase type I (SRD5A1) is up-regulated in non-small cell lung cancer but does not impact proliferation, cell cycle distribution or apoptosis. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most frequent malignancies and has a high mortality rate due to late detection and lack of efficient treatments. Identifying novel drug targets for this indication may open the way for new treatment strategies. Comparison of gene expression profiles of NSCLC and normal adjacent tissue (NAT) allowed to determine that 5-alpha reductase type I (SRD5A1) was up-regulated in NSCLC compared to NAT. This raised the question whether SRD5A1 was involved in sustained proliferation and survival of NSCLC. METHODS: siRNA-mediated silencing of SRD5A1 was performed in A549 and NCI-H460 lung cancer cell lines in order to determine the impact on proliferation, on distribution during the different phases of the cell cycle, and on apoptosis/necrosis. In addition, lung cancer cell lines were treated with 4 azasteroids, which specifically inhibit SRD5A1 activity, and the effects on proliferation were measured. Statistical analyses using ANOVA and post-hoc Tamhane-T2-test were performed. In the case of non-parametric data, the Kruskal Wallis test and the post-hoc Mann-Whitney-U-test were used. RESULTS: The knock down of SRDA51 expression was very efficient with the SRD5A1 transcripts being reduced to 10% of control levels. Knock-down efficiency was furthermore confirmed at the protein level. However, no effect of SRD5A1 silencing was observed in the proliferation assay, the cell cycle analysis, and the apoptosis/necrosis assay. Treatment of lung cancer cell lines with 4-azasteroids did not significantly inhibit proliferation. CONCLUSIONS: In summary, the results suggest that SRD5A1 is not a crucial enzyme for the sustained proliferation of NSCLC cell lines. PMID- 22257484 TI - Candida spp. with acquired echinocandin resistance, France, 2004-2010. AB - We report 20 episodes of infection caused by acquired echinocandin-resistant Candida spp. harboring diverse and new Fksp mutations. For 12 patients, initial isolates (low MIC, wild-type Fksp sequence) and subsequent isolates (after caspofungin treatment, high MIC, mutated Fksp) were genetically related. PMID- 22257485 TI - Programmed cell death in type II neuroblast lineages is required for central complex development in the Drosophila brain. AB - BACKGROUND: The number of neurons generated by neural stem cells is dependent upon the regulation of cell proliferation and by programmed cell death. Recently, novel neural stem cells that amplify neural proliferation through intermediate neural progenitors, called type II neuroblasts, have been discovered, which are active during brain development in Drosophila. We investigated programmed cell death in the dorsomedial (DM) amplifying type II lineages that contribute neurons to the development of the central complex in Drosophila, using clonal mosaic analysis with a repressible cell marker (MARCM) and lineage-tracing techniques. RESULTS: A significant number of the adult-specific neurons generated in these DM lineages were eliminated by programmed cell death. Programmed cell death occurred during both larval and pupal stages. During larval development, approximately one quarter of the neuronal (but not glial) cells in the lineages were eliminated by apoptosis before the formation of synaptic connectivity during pupal stages. Lineage-tracing experiments documented the extensive contribution of intermediate neural progenitor-containing DM lineages to all of the major modular substructures of the adult central complex. Moreover, blockage of apoptotic cell death specifically in these lineages led to prominent innervation defects of DM derived neural progeny in the major neuropile substructures of the adult central complex. CONCLUSIONS: Our findings indicate that significant neural overproliferation occurs normally in type II DM lineage development, and that elimination of excess neurons in these lineages through programmed cell death is required for the formation of correct neuropile innervation in the developing central complex. Thus, amplification of neuronal proliferation through intermediate progenitors and reduction of neuronal number through programmed cell death operate in concert in type II neural stem-cell lineages during brain development. PMID- 22257486 TI - NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: an observational study. AB - BACKGROUND: Cell surface NKG2D ligands (NKG2DL) bind to the activating NKG2D receptor present on NK cells and subsets of T cells, thus playing a role in initiating an immune response. We examined tumor expression and prognostic effect of NKG2DL in breast cancer patients. METHODS: Our study population (n = 677) consisted of all breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed paraffin-embedded tumor tissue was immunohistochemically stained with antibodies directed against MIC-A/MIC-B (MIC AB), ULBP-1, ULBP-2, ULBP-3, ULBP-4, and ULBP-5. RESULTS: NKG2DL were frequently expressed by tumors (MIC-AB, 50% of the cases; ULBP-1, 90%; ULBP-2, 99%; ULBP-3, 100%; ULBP-4, 26%; ULBP-5, 90%) and often showed co-expression: MIC-AB and ULBP-4 (p = 0.043), ULBP-1 and ULBP-5 (p = 0.006), ULBP-4 and ULBP-5 (p < 0.001). MIC-AB (p = 0.001) and ULBP-2 (p = 0.006) expression resulted in a statistically significant longer relapse free period (RFP). Combined expression of these ligands showed to be an independent prognostic parameter for RFP (p < 0.001, HR 0.41). Combined expression of all ligands showed no associations with clinical outcome. CONCLUSIONS: We demonstrated for the first time that NKG2DL are frequently expressed and often co-expressed in breast cancer. Expression of MIC AB and ULBP-2 resulted in a statistically significant beneficial outcome concerning RFP with high discriminative power. Combination of all NKG2DL showed no additive or interactive effect of ligands on each other, suggesting that similar and co-operative functioning of all NKG2DL can not be assumed. Our observations suggest that among driving forces in breast cancer outcome are immune activation on one site and tumor immune escape on the other site. PMID- 22257487 TI - Vascular endothelial growth factor gene +813CC polymorphism of foetus is associated with preterm labour but not with pre-eclampsia in Turkish pregnant women. AB - We investigated the effect of polymorphism at +813 locus of vascular endothelial growth factor (VEGF) gene on predisposition to preterm labour and pre-eclampsia (PE). We examined polymorphism of the VEGF +813 gene of foetuses from umbilical cord blood in 31 cases of preterm labour, 34 pre-eclamptic and 58 healthy term labour. VEGF +813 gene polymorphisms were studied using a polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. In preterm group, foetal CC genotype was found at 80.6%, and CT genotype was seen at 19.4%. No any TT genotype was detected in preterm group. CC genotype of VEGF 813 gene was significantly more frequent than CT genotype (P = 0.04). Foetuses with CC genotype VEGF+813 gene have an increased risk for preterm labour. C allele frequency was 90.3 and 76.7% in preterm and control groups, respectively. T allele frequency was 9.7 and 23.3% in preterm and control groups, respectively. C allele was significantly associated with preterm labour (P = 0.02). OR of C and T alleles for preterm labour was 2.8 (CI: 1.1-7.2). In PE group, foetal CC genotype of +813 locus was found in 67.6%, and CT genotype was seen in 29.4%. Only one TT genotype was detected in 2.9% of PE group. There was no association between PE and VEGF gene genotypes and alleles at +813 locus. These results suggest that foetal VEGF gene polymorphism of +813 CC seems to be highly associated with preterm labour, whereas in PE, foetal VEGF gene polymorphism at +813 locus is not related. Especially, C allele was significantly associated with preterm labour. Carriage of the +813C allele of the VEGF gene has been found 2.8 times increased susceptibility to the development of preterm labour in Turkish women and may be an independent risk factor for prematurity. There was no association between PE and VEGF gene genotypes and alleles at +813 locus. We suggest to search for foetal aetiologies or genetic susceptibility in preterm labour, whereas in PE, not foetal, but maternal susceptibility is to be investigated. PMID- 22257488 TI - Asymmetric type F botulism with cranial nerve demyelination. AB - We report a case of type F botulism in a patient with bilateral but asymmetric neurologic deficits. Cranial nerve demyelination was found during autopsy. Bilateral, asymmetric clinical signs, although rare, do not rule out botulism. Demyelination of cranial nerves might be underrecognized during autopsy of botulism patients. PMID- 22257489 TI - Drought-induced root aerenchyma formation restricts water uptake in rice seedlings supplied with nitrate. AB - Previous studies demonstrated that ammonium nutrition results in higher water uptake rate than does nitrate nutrition under water stress, and thus enhances the tolerance of rice plants to water stress. However, the process by which water uptake is related to nitrogen form under water stress remains unknown. A hydroponic experiment with simulated water stress induced by polyethylene glycol (PEG6000) was conducted in a greenhouse to study the relationship between root aerenchyma formation and water uptake rate, such as xylem sap flow rate and hydraulic conductance, in two different rice cultivars (cv. 'Shanyou 63' hybrid indica and cv. 'Yangdao 6' indica, China). The results showed that root aerenchyma tissue increased in water-stressed plants of both cultivars fed by nitrate. No significant difference was found in root hydraulic conductivity and/or xylem sap flow rate between the two rice cultivars fed by ammonium regardless of water status, whereas these parameters decreased significantly in water-stressed plants fed by nitrate. It was concluded that aerenchyma that formed in the root cortex impeded the radial transport of water in the root cylinder and decreased water uptake in water-stressed rice plants fed by nitrate. Water transport occurred mainly through Hg-sensitive water channels in rice roots supplied with ammonium. PMID- 22257490 TI - Plate-based transfection and culturing technique for genetic manipulation of Plasmodium falciparum. AB - Genetic manipulation of malaria parasites remains an inefficient, time-consuming and resource-intensive process. Presented here is a set of methods for 96-well plate-based transfection and culture that improve the efficiency of genetic manipulation of Plasmodium falciparum. Compared to standard protocols plate-based transfection requires 20-fold less DNA, transient transfection efficiency achieved is approximately seven-fold higher, whilst stable transfection success rate is above 90%. Furthermore the utility of this set of protocols to generate a knockout of the PfRH3 pseudogene, screened by whole-cell PCR, is demonstrated. The methods and tools presented here will facilitate genome-scale genetic manipulation of P. falciparum. PMID- 22257492 TI - Outbreak of leptospirosis after flood, the Philippines, 2009. AB - After a typhoon in September 2009, an outbreak of leptospirosis occurred in Metro Manila, the Philippines; 471 patients were hospitalized and 51 (10.8%) died. A hospital-based investigation found risk factors associated with fatal infection to be older age, hemoptysis, anuria, jaundice, and delayed treatment with antimicrobial drugs. PMID- 22257494 TI - Spoligotyping of Mycobacterium africanum, Burkina Faso. AB - Using Ziehl-Neelsen-positive slides collected from tuberculosis diagnostic centers in Burkina Faso, we showed that 20% of 80 spoligotyping-positive DNA samples had a characteristic Mycobacterium africanum-specific genomic signature. This result suggests that M. africanum is still present in Burkina Faso at almost the same prevalence as 15-20 years ago. PMID- 22257495 TI - Patterns of visual dyslexia. AB - This study reports two Hebrew-speaking individuals with acquired visual dyslexia. They made predominantly visual errors in reading, in all positions of the target words. Although both of them produced visual errors, their reading patterns crucially differed in three respects. KD had almost exclusively letter substitutions, and SF also made letter omissions, additions, letter position errors, and between-word migrations. KD had difficulties accessing abstract letter identity in single-letter tasks, and in letter naming, unlike SF, who named letters well. KD did not show lexical effects such as frequency and orthographic neighbourhood effects and produced nonword responses, whereas SF showed lexical effects, with a strong tendency to produce word responses. We suggest that these two patterns stem from two different deficits - KD has letter identity visual dyslexia, which results from a deficit in abstract letter identification in the orthographic-visual analysis system, yielding erroneous letter identities, whereas SF has visual-output dyslexia, which results from a deficit at a later stage, a stage that combines the outputs of the various functions of the orthographic-visual analyzer. PMID- 22257493 TI - Identifying co-targets to fight drug resistance based on a random walk model. AB - BACKGROUND: Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. RESULTS: We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH) related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. CONCLUSIONS: With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance. PMID- 22257496 TI - The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort. AB - BACKGROUND: The purpose of this study was to investigate current patterns of management and outcomes of intermittent distance exotropia [X(T)] in the UK. METHODS: This was an observational cohort study which recruited 460 children aged < 12 years with previously untreated X(T). Eligible subjects were enrolled from 26 UK hospital ophthalmology clinics between May 2005 and December 2006. Over a 2 year period of follow-up, clinical data were prospectively recorded at standard intervals from enrolment. Data collected included angle, near stereoacuity, visual acuity, control of X(T) measured with the Newcastle Control Score (NCS), and treatment. The main outcome measures were change in clinical outcomes (angle, stereoacuity, visual acuity and NCS) in treated and untreated X(T), 2 years from enrolment (or, where applicable, 6 months after surgery). Change over time was tested using the chi-square test for categorical, Wilcoxon test for non parametric and paired-samples t-test for parametric data. RESULTS: At follow-up, data were available for 371 children (81% of the original cohort). Of these: 53% (195) had no treatment; 17% (63) had treatment for reduced visual acuity only (pure refractive error and amblyopia); 13% (50) had non surgical treatment for control (spectacle lenses, occlusion, prisms, exercises) and 17% (63) had surgery. Only 0.5% (2/371) children developed constant exotropia. The surgically treated group was the only group with clinically significant improvements in angle or NCS. However, 8% (5) of those treated surgically required second procedures for overcorrection within 6 months of the initial procedure and at 6 month follow-up 21% (13) were overcorrected. CONCLUSIONS: Many children in the UK with X(T) receive active monitoring only. Deterioration to constant exotropia, with or without treatment, is rare. Surgery appears effective in improving angle of X(T) and NCS, but rates of overcorrection are high. PMID- 22257497 TI - A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children. AB - INTRODUCTION: Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. OBJECTIVE: To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. DESIGN: Multicentre, open-label, follow-on from randomised, head-to-head trial. SETTING: Five UK sites (Southampton, Oxford, Bristol, London and Exeter). PARTICIPANTS: Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. INTERVENTIONS: In the previous study, children were randomised (in a 1 : 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. MAIN OUTCOME MEASURES: Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre >= 1 : 40 and a haemagglutination titre >= 1 : 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. RESULTS: A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was >= 1 : 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when >= 3 years old; the HI titre was >= 1 : 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was >= 1 : 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when >= 3 years old; the HI titre was >= 1 : 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre >= 1 : 40 and HI titre >= 1 : 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever >= 38 degrees C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. CONCLUSIONS: Nearly all children who received two doses of AS03B-adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre >= 1 : 32, MN titre >= 1 : 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. TRIAL REGISTRATION: ClinicalTrials.gov NCT01239537. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22257499 TI - Psychoactive substances and the political ecology of mental distress. AB - The goal of this paper is to both understand and depathologize clinically significant mental distress related to criminalized contact with psychoactive biotic substances by employing a framework known as critical political ecology of health and disease from the subdiscipline of medical geography. The political ecology of disease framework joins disease ecology with the power-calculus of political economy and calls for situating health-related phenomena in their broad social and economic context, demonstrating how large-scale global processes are at work at the local level, and giving due attention to historical analysis in understanding the relevant human-environment relations. Critical approaches to the political ecology of health and disease have the potential to incorporate ever-broadening social, political, economic, and cultural factors to challenge traditional causes, definitions, and sociomedical understandings of disease. Inspired by the patient-centered medical diagnosis critiques in medical geography, this paper will use a critical political ecology of disease approach to challenge certain prevailing sociomedical interpretations of disease, or more specifically, mental disorder, found in the field of substance abuse diagnostics and the related American punitive public policy regimes of substance abuse prevention and control, with regards to the use of biotic substances. It will do this by first critically interrogating the concept of "substances" and grounding them in an ecological context, reviewing the history of both the development of modern substance control laws and modern substance abuse diagnostics, and understanding the biogeographic dimensions of such approaches. It closes with proposing a non-criminalizing public health approach for regulating human close contact with psychoactive substances using the example of cannabis use. PMID- 22257498 TI - Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury. AB - BACKGROUND: Proline-rich tyrosine kinase 2 (Pyk2) is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI) remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. METHODS: C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. RESULTS: Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1) myeloperoxidase content in lung tissues, 2) vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3) the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. CONCLUSIONS: These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and that pharmacological inhibition of Pyk2 might provide a potential therapeutic strategy in the pretreatment for patients at imminent risk of developing acute lung injury. PMID- 22257500 TI - Babesiosis among elderly Medicare beneficiaries, United States, 2006-2008. AB - We used administrative databases to assess babesiosis among elderly persons in the United States by year, sex, age, race, state of residence, and diagnosis months during 2006-2008. The highest babesiosis rates were in Connecticut, Rhode Island, New York, and Massachusetts, and findings suggested babesiosis expansion to other states. PMID- 22257501 TI - A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes. AB - Mutations in the pore-forming subunit of the skeletal muscle sodium channel (SCN4A) are responsible for hyperkalemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are classified based on their cardinal symptoms, myotonia and/or paralysis. We report the case of a Japanese boy with a novel mutation of SCN4A, p.I693L, who exhibited severe episodic myotonia from infancy and later onset mild paralytic attack. He started to have apneic episodes with generalized hypertonia at age of 11 months, then developed severe episodic myotonia since 2 years of age. He presented characteristic generalized features which resembled Schwarz-Jampel syndrome. After 7 years old, paralytic episodes occurred several times a year. The compound muscle action potential did not change during short and long exercise tests. Functional analysis of the mutant channel expressed in cultured cell revealed enhancement of the activation and disruption of the slow inactivation, which were consistent with myotonia and paralytic attack. The severe clinical features in his infancy may correspond to myotonia permanence, however, he subsequently experienced paralytic attacks. This case provides an example of the complexity and overlap of the clinical features of sodium channel myotonic disorders. PMID- 22257502 TI - Comparison of phosphorylated TDP-43-positive inclusions in oculomotor neurons in patients with non-ALS and ALS disorders. AB - TDP-43 has been identified as a major component of the pathological inclusions in most forms of frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). In the present study, paraffin sections of the midbrain in 112 patients with various non-ALS disorders and 27 patients with sporadic ALS were immunostained with antibody against phosphorylated TDP-43 (pTDP-43). pTDP-43-positive inclusions in oculomotor neurons were detected in 18 of 112 patients with non-ALS disorders (16.1%). The appearance of the inclusions showed fine filamentous structures rather than the skein-like inclusions seen in the anterior horn cells of ALS spinal cords. The incidence was increased in the age range of 80-89 years old (10/37 cases; 27.0%), in which 6 of 10 cases demonstrated AD pathology in the temporal lobes. Twenty seven ALS patients were examined and the findings were compared with those of non ALS patients. There were 13 cases demonstrating pTDP-43-positive inclusions (48.1%) which showed stronger immunoreactivities in ALS cases. This is the first report demonstrating fine filamentous pTDP-43-positive inclusions in oculomotor neurons in non-ALS disorders. Although the mechanisms underlying pTDP-43 in oculomotor neurons are currently unknown, its detection is of interest, and the expression may occur not only in ALS but also during the aging process. PMID- 22257503 TI - Bobath Concept versus constraint-induced movement therapy to improve arm functional recovery in stroke patients: a randomized controlled trial. AB - OBJECTIVE: To compare the effects of the Bobath Concept and constraint-induced movement therapy on arm functional recovery among stroke patients with a high level of function on the affected side. DESIGN: A single-blinded, randomized controlled trial. SETTING: Outpatient physiotherapy department of a stroke unit. SUBJECTS: A total of 24 patients were randomized to constraint-induced movement therapy or Bobath Concept group. INTERVENTION: The Bobath Concept group was treated for 1 hour whereas the constraint-induced movement therapy group received training for 3 hours per day during 10 consecutive weekdays. MAIN MEASURES: Main measures were the Motor Activity Log-28, the Wolf Motor Function Test, the Motor Evaluation Scale for Arm in Stroke Patients and the Functional Independence Measure. RESULTS: The two groups were found to be homogeneous based on demographic variables and baseline measurements. Significant improvements were seen after treatment only in the 'Amount of use' and 'Quality of movement' subscales of the Motor Activity Log-28 in the constraint-induced movement therapy group over the the Bobath Concept group (P = 0.003; P = 0.01 respectively). There were no significant differences in Wolf Motor Function Test 'Functional ability' (P = 0.137) and 'Performance time' (P = 0.922), Motor Evaluation Scale for Arm in Stroke Patients (P = 0.947) and Functional Independence Measure scores (P = 0.259) between the two intervention groups. CONCLUSIONS: Constraint-induced movement therapy and the Bobath Concept have similar efficiencies in improving functional ability, speed and quality of movement in the paretic arm among stroke patients with a high level of function. Constraint-induced movement therapy seems to be slightly more efficient than the Bobath Concept in improving the amount and quality of affected arm use. PMID- 22257504 TI - A systematic review of case-mix adjustment models for stroke. AB - OBJECTIVE: To identify any externally validated prognostic model for predicting outcome in unselected populations following acute stroke comprising variables feasible for collection in routine care. DATA SOURCES: Searches were run in MEDLINE, EMBASE, CINAHL, PsycInfo, AMED and ISI Web of Science with no limits on publication date or language. REVIEW METHODS: Any study describing the development or external validation of a discernible prognostic model to predict any valid outcome following acute stroke was included. Papers were retained if they met pre-specified inclusion criteria identified from previous reviews and pertinent discussion papers. Data extraction focused on methodological quality of model development, generalizability and feasibility of variable collection. Model performance was examined through consideration of external validation studies. RESULTS: Seventeen externally validated models were identified from 43 papers fulfilling inclusion criteria. Quality of studies describing model development was variable and model performance in external validation studies was generally poor. Models were generally constructed through secondary use of randomized trial or stroke database data. Prognostic variables broadly encompassed markers of stroke severity, pre-stroke function and comorbidities. One model that fulfilled the review criteria and had extensive external validation in a range of post stroke populations was identified (the Six Simple Variables model). CONCLUSION: The Six Simple Variables model performed well in six external validation studies, although prediction of outcome in patients with milder strokes was less reliable. Other models identified in this review have been developed using robust methodology but comprise more complex clinical variables which may limit their utility in routine stroke care. PMID- 22257505 TI - Respiratory biofeedback accuracy in chronic renal failure patients: a method comparison. AB - OBJECTIVE: To analyse respiratory biofeedback effects on respiratory muscle strengthening in chronic renal failure patients. DESIGN: Randomized controlled study. SETTING: Nephrology and dialysis centre. SUBJECTS AND INTERVENTION: Forty one end-stage renal patients on haemodialysis treatment were allocated into three groups: control (n = 10), G-1 (inspiratory muscle training using Threshold IMT device; n = 16) and G-2 (biofeedback; n = 15) and given respiratory muscle training (three sessions/week for six weeks). MAIN MEASURES: Forced vital capacity (FVC), expiratory volume in the first second (FEV(1)), FEV(1)/FVC ratio, maximal voluntary ventilation (MVV) and maximal inspiratory (MIP) and expiratory (MEP) pressures were measured before and after the respiratory muscle training programme. RESULTS: Both training methods were efficient since we found an increase after training in the FVC in the G-1 group (from 2.45 +/- 0.17 to 2.85 +/- 0.16; P = 0.001) and in the G-2 group (from 2.35 +/- 0.19 to 2.55 +/- 0.19; P = 0.007), in the FEV(1) in G-1 (from 2.18 +/- 0.16 to 2.46 +/- 0.14; P = 0.01) and in G-2 (from 1.97 +/- 0.17 to 2.20 +/- 0.15; P < 0.0001), MIP in G-1 (from 70.63 +/- 4.03 to 108.75 +/- 7.41; P < 0.0001) and in G-2 (from 67.67 +/- 5.02 to 96.33 +/- 8.30; P < 0.001) and MEP in G-1 (from 73.13 +/- 5.10 to 82.50 +/- 6.74; P = 0.007) and in G-2 (from 67.67 +/- 5.41 to 76.00 +/- 4.29; P = 0.002). CONCLUSIONS: Respiratory biofeedback is efficient as a respiratory muscle training modality for patients with chronic renal failure. PMID- 22257506 TI - Home-based treadmill training for individuals with Parkinson's disease: a randomized controlled pilot trial. AB - OBJECTIVE: To investigate the feasibility and effectiveness of six weeks of home based treadmill training in people with mild Parkinson's disease. DESIGN: Pilot randomized controlled trial of a six-week intervention followed by a further six weeks follow-up. SETTING: Home-based treadmill training with outcome measures taken at a hospital clinic. PARTICIPANTS: Twenty cognitively intact participants with mild Parkinson's disease and gait disturbance. Two participants from the treadmill training group and one from the control group dropped out. INTERVENTIONS: The treadmill training group undertook a semi-supervised home based programme of treadmill walking for 20-40 minutes, four times a week for six weeks. The control group received usual care. MAIN OUTCOME MEASURES: The feasibility of the intervention was assessed by recording exercise adherence and acceptability, exercise intensity, fatigue, muscle soreness and adverse events. The primary outcome measure of efficacy was walking capacity (6-minute walk test distance). RESULTS: Home-based treadmill training was feasible, acceptable and safe with participants completing 78% (SD 36) of the prescribed training sessions. The treadmill training group did not improve their walking capacity compared to the control group. The treadmill training group showed a greater improvement than the control group in fatigue at post test (P = 0.04) and in quality of life at six weeks follow-up testing (P = 0.02). CONCLUSIONS: Semi supervised home-based treadmill training is a feasible and safe form of exercise for cognitively intact people with mild Parkinson's disease. Further investigation regarding the effectiveness of home-based treadmill training is warranted. PMID- 22257507 TI - Human health risk from soil heavy metal contamination under different land uses near Dabaoshan Mine, Southern China. AB - Soil heavy metal contamination is a major environmental concern, and the ecological risk associated with heavy metals is increasing. In this paper, we investigated heavy metal contamination near Dabaoshan Mine by: using sequential indicator simulation to delineate the spatial patterns of soil data; fitting multiple linear regression models for heavy metal uptake by crops; interpreting land uses from remote sensing images and integrating the spatial patterns, uptake models and land uses into a dose-response model for human health risks from heavy metals. The areas with elevated soil heavy metal concentrations are mainly located at the Dabaoshan Mine site and in the watershed basins of the Hengshi, Tielong and Chuandu rivers. The average concentrations of Cu, Zn, Cd and Pb in soil in the study area are all above the natural soil background levels, but Cd is the major contributor to human health risk in the area. Areas of low soil pH are also found throughout the watershed basins of the Hengshi, Tielong and Chuandu rivers. Of the different land use types in the study area, agricultural and residential land uses have the highest human health risk because ingestion is the dominant exposure pathway for heavy metals. The spatial patterns of the heavy metal concentrations and soil pH indicate that the areas with the highest human health risk regions do not directly coincide with the areas of highest heavy metal concentrations, but do coincide with the areas of lower soil pH. The contamination with high concentrations of heavy metals provides the risk source, but the combination of high heavy metal concentrations, low pH and agricultural or residential land use is required for human health risks to be present. The spatial pattern of the hazard quotients indicates that Cd is the most important pollutant contributing to the human health risk. PMID- 22257508 TI - Mercury biomagnification in the food web of a neotropical stream. AB - Anthropogenic and natural mercury (Hg) contamination have been a major concern in South America since the early 1900s, but it remains unclear whether Hg levels pose a hazard to human health in regions that lack point sources. We studied Hg biomagnification patterns in the food web of Rio Las Marias, an Andean piedmont stream in northern Venezuela, which supports a major subsistence fishery. Mercury concentrations and trophic positions in the food web (based on stable isotopes of nitrogen and carbon) were characterized for 24 fish species representing seven trophic guilds (piscivore, generalized carnivore, omnivore, invertivore, algivore, terrestrial herbivore, detritivore). Mercury showed significant biomagnification through the food web, but vertical trophic position explained little of the variation. Muscle Hg concentrations also increased with body mass across the food web. Trophic guild assignments offered a useful alternative to explicit analysis of vertical trophic position; piscivores showed the highest Hg concentrations and terrestrial herbivores had the lowest. There were no consistent seasonal differences in Hg concentrations within the 5 species sampled during both the wet and dry seasons, suggesting that bioavailability is unaffected by strong seasonal variation in rainfall. From a human health perspective, many medium- to large-bodied species that are commonly eaten had Hg concentrations that exceeded International Marketing Limit (IML) (0.5 MUg/g) and World Health Organization (WHO) guidelines (0.2 MUg/g) for consumption. We conclude that Hg concentrations may pose a health concern for local subsistence fishermen and their families. Our results suggest a need to perform risk assessment and better understand contaminant levels in subsistence and commercial fisheries even in areas that lack known Hg point sources. PMID- 22257509 TI - [Interactions of insulin and estrogen in the regulation of cell proliferation and carcinogenesis]. AB - Equilibrium of sexual steroids and metabolic processes has close correlations. Insulin is a potent regulator of human sexual steroid hormone production and modulates their signals at receptor level. Insulin resistance and excessive insulin production provoke hyperandrogenism and estrogen deficiency in women resulting not only in anovulatory dysfunction but also a high risk for cardiovascular diseases and cancer. Physiologic functions of all female organs have higher estrogen demand as compared with men. In healthy women estrogen predominance against androgens is a favor in their reproductive period, which means a strong defense against insulin resistance and its complications. However, in postmenopausal cases the increasing prevalence of insulin resistance and type 2 diabetes associated with estrogen deficiency and androgen excess, result in a gender specific higher risk for precancerous lesions and cancer as compared with men. Estrogen has beneficial effect on the energy metabolism, glucose homeostasis and on the lipid metabolism of liver and of peripheral tissues as well. A moderate or severe decrease in serum estrogen level enhances the prevalence of insulin resistant states. In premenopausal women long or irregular menstrual cycles are predictors for the risk of insulin resistance and type-2 diabetes. Moreover, in postmenopausal estrogen deficient cases elevated fasting glucose, increased body weight and abdominal fat deposition are often observed progressively with age in correlation with an impaired glucose tolerance. In the rare cases of estrogen deficient men severe type-2 diabetes seems to be a characteristic complication. Upon becoming familiar with the cancer risk of insulin resistance and estrogen deficiency, there would be plenty of possibilities for primary cancer prevention. In patients with cancer the treatment of hormonal and metabolic disturbances may become effective adjuvant therapy. PMID- 22257510 TI - [Quality assurance and quality improvement in medical practice - Part 2. Evidence based medicine]. AB - For assuring and improving quality of healthcare, everyday medical practice should be based on appropriate scientific evidence and results of health technology assessment. Evidence-based medicine is the integration of clinical expertise, patient values, and the best evidence into the decision making process for patient care, when health technologies are used. On one hand health technologies which proved to be effective should be available for all patients, on the other hand, because of the limited financial resources of the health care system, they should be cost-effective, not to spend on interventions proved to be ineffective or even harmful. For effective implementation of evidence-based practice, development of more clinical guidelines, that contain explicit recommendations, and improvement of quality approach are necessary in Hungary. PMID- 22257511 TI - [The possible options for the prevention of preeclampsia]. AB - This review summarizes the possible options for the prevention of preeclampsia based on important factors of patomechanism. The effects of antioxidants have been described in numerous clinical researches based on the oxidative hypothesis. Another important factor is the change of nitric oxide activity. Nitric oxide donors are able to compensate the symptoms of preeclampsia. The inverse relationship between the calcium intake and gestational hypertension has been known for a long time. The calcium supplementation seems to be a good opportunity to prevent preeclampsia. With low molecular weight heparins we can intervene in the patomechanisms of preeclampsia by antithrombocyte effects, vasoactive properties and impact on throphoblast cell morphology and differentiation. Thrombocyte aggregation inhibitors were examined in number of studies because they reduced thromboxane mediated vasoconstriction and inhibited placental thrombosis. Several studies verify whether prophylaxis with low molecular weight heparins and low dose aspirin could improve pregnancy outcome in preeclampsia. PMID- 22257512 TI - [The medical faculty of Debrecen in Halle -- 1944-1945]. PMID- 22257513 TI - [Ferenc Gerlei (1901-1970). Correction to a Kossuth-award winner doctor's biography]. PMID- 22257515 TI - Prediction of coma and anisocoria based on computerized tomography findings in patients with supratentorial intracerebral hemorrhage. AB - OBJECTIVES: Coma and anisocoria are the two common signs of a crucial state of neurological dysfunction. The ability to forecast the occurrence of these conditions would help clinicians make clinical risk assessments and decisions. PATIENTS AND METHODS: From October 2006 to September 2008, 118 patients with supratentorial intracerebral hemorrhage (SICH) were enrolled in this retrospective investigation. Patients were distributed into 3 groups according to occurrence of the signs of coma and/or anisocoria in the observation unit during a 30-day period. Group 1 included 52 patients who had normal or impaired consciousness, group 2 included 27 patients who had coma with no anisocoria and group 3 consisted of 39 patients who had coma with anisocoria. The clinical characteristics and parameters on computerized tomography (CT) findings were compared using univariate analysis to determine the factors that were related to the level of consciousness. Logistic regression models established the predictive equations for coma and anisocoria. RESULTS: Univariate analysis revealed that hematoma volume, the score of intraventricular hemorrhage (IVH score) and the amplitude of midline shift were the factors related to coma and anisocoria. Mean hematoma volume was 24.0 +/- 13.0 ml, 53.6 +/- 12.6 ml and 80.5 +/- 24.6 ml, the mean amplitudes of midline shift were 1.3 +/- 2.0 mm, 5.9 +/- 4.9 mm and 10.1 +/- 5.5 mm, and the mean IVH score was 0.8 +/- 1.3, 3.3 +/- 3.3 and 5.9 +/- 3.4 in groups 1, 2 and 3, respectively. Multivariate analysis showed that hematoma volume and IVH score were independent prognostic factors for coma and anisocoria. The predictive equations for coma and anisocoria were LogitP = 0.279X(HV) + 0.521X(IVH)-18.164 and LogitP = 0.125X(HV)+0.326X(IVH)-6.864, respectively. CONCLUSIONS: Hematoma volume and IVH score were the independent prognostic factors for coma and anisocoria. Logistic regression models established the fitted predictive equations, which could help clinicians make clinical risk assessments and decisions. PMID- 22257516 TI - Aneurysm of the lateral spinal artery: a case report. PMID- 22257517 TI - Primary intracranial adenoid cystic carcinoma. PMID- 22257518 TI - Profound gastroparesis after bilateral posterior inferior cerebellar artery territory infarcts. PMID- 22257519 TI - A US-based survey on ventriculostomy practices. AB - BACKGROUND: The incidence of ICP monitoring has increased over the years and the indications for placement have expanded. Although ventriculostomy and ICP monitor placement are among the most commonly performed neurosurgical procedures, the current practice patterns have rarely been studied. METHODS: A 10-question survey was sent to 2006 neurosurgeons and 1060 neurosurgery residents in the US. Demographic information and data regarding estimated success rates of ventriculostomies, the steps taken in failure and use of technological aids used was sought. RESULTS: 479 neurosurgeons and 108 residents responded to our survey (response rates 23.9% and 10.2%, respectively). No catheter misplacements were reported by 19.8% respondents in the previous year whereas 2.2% reported misplacing more than 30%. With regards to ventriculostomy for patients with slit ventricles, image guidance was used by 51.7%; freehand technique was preferred by 41.6% and the Ghajar guide was used by 6.7% of respondents. We found that 56.9% of respondents abandoned free-hand placement after 3 failed passes. After abandoning free-hand cannulation, respondents used an ICP bolt or similar intra parenchymal pressure monitoring device in trauma patients. Other approaches included leaving the catheter in place and readjusting it after repeating a CT scan. CONCLUSIONS: This survey sheds light on the current practice of ventriculostomy placement. Both residents and neurosurgeons admit to multiple attempts and frequent catheter misplacement. In order to consider a change in practice, respondents cited an increase in available data about guidance systems and ability to accommodate abnormal ventricular anatomy as primary requirements. A prospective study could help establish true evidence based practice for this common neurosurgical procedure. PMID- 22257520 TI - Feasibility and limitations of C1 lateral mass screw placement in patients of atlas assimilation. AB - BACKGROUND: C1 lateral mass is a common place for screw fixation in normal anatomy; whereas there is no research about whether screw placement is suitable in patients of C1 assimilation (C1A). OBJECTIVE: To study the feasibility and limitations of C1 lateral mass screw placement in patients with C1A. PATIENTS AND METHODS: From April 2008 to March 2009, C1 lateral mass of 17 C1A patients with atlantoaxial instability (AAI) or dislocation (AAD) was observed and measured using CT reconstruction; and factors determining C1 lateral mass screw placement were studied before and during the operation. RESULTS: A screw of 3.5mm in diameter could be virtually inserted in 31 C1 lateral masses of total 17 C1A patients with maximal length of the screw 18.1+/-2.7mm; but the entry point of screw had to be modified in the posterior part of inferior facet of C1 instead of posterior middle wall of C1 lateral mass. Clinically, abnormal course of vertebral artery in 6 of 30 (20%) and abundance of venous plexi prevented the proper exposure of C1 lateral mass and screw placement. Hypoglossal canal also had potential risk of injury during screw placement. CONCLUSION: In patients of C1A, when C1 lateral mass screw placement is programmed, factors limit its use should be well studied, and CT angiography is essential. PMID- 22257521 TI - An in vitro injury model for SH-SY5Y neuroblastoma cells: effect of strain and strain rate. AB - There is a great need to have in vitro cell injury model wherein a wide range of strain (E) and strain rate (epsilon) can be precisely and independently applied. Such a model will enable exploration of various biomechanical loading conditions cells normally encounter during either blunt or blast impact-induced traumatic brain injuries (TBIs). In combination with a highly automated data acquisition and analysis system, this method can quickly generate a large data set of experimental results to yield identification of bio-mechanical and chemical sequelae following injury. A proper understanding of these sequelae will enable the discovery of the time window of opportunity available for pharmacological interventions. In this study we present such an injury model, a modified version of the Cultured Axonal Injury (CAI) device, and demonstrate its efficacy through viability of SH-SY5Y cells at different ranges of strain (0-140%) and strain rate (15-68 s-1). We identified three different regimes in the stretch-induced dose response of curves of SH-SY5Y cells, with a very sharp decline from live to dead in a narrow range of strain (30-55%). The effect of strain rate is minimal when the final strain in the cells was fixed at 50%. The model further shows that time after-injury plays a vital role in the determination of recovery-deterioration pathways and the biological selection depends on the severity of initial injury. These data point out the initial strain level is vital to the cell fate and emphasize the need to study the various mechanisms triggered by different magnitudes of initial injuries. PMID- 22257522 TI - Don't pick the loser: lessons from the GeparQuinto trial. PMID- 22257525 TI - Early detection of ovarian cancer in symptomatic women. PMID- 22257526 TI - [Health, hospitality sector and tobacco industry]. AB - To present the strategies used by the tobacco industry to meet government regulatory measures of its products. To demonstrate the relationship between tobacco industry and the hospitality sector. Note that the arguments and strategies used routinely by the hospitality industry have been previously provided by the tobacco industry. Location of key documents by meta-search, links to declassified documents, specific websites of the tobacco and hospitality industry, news sources and published articles in health journals. This review reveals the close relationship between tobacco industry and hospitality sector. It highlights the strategies carried out by the tobacco industry, including strategic hoarding of information, public relations, lobbying, consultation program, smoker defence groups, building partnerships, intimidation and patronage. The arguments and strategies used by the hospitality industry to match point by point that used by the tobacco industry. These arguments are refutable from the point of view of public health as it is scientifically proven that totally smoke-free environments are the only way to protect non-smokers from tobacco smoke exposure and its harmful effects on health. PMID- 22257523 TI - Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. AB - BACKGROUND: We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy. METHODS: In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554. FINDINGS: Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30.3%) of 307 patients in the ECH-TH group and 70 (22.7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0.68 [95%CI 0.47-0.97]; p=0.04). Chemotherapy with trastuzumab was associated with more oedema (119 [39.1%] vs 88 [28.7%]) and dyspnoea (90 [29.6%] vs 66 [21.4%]), and ECL-TL with more diarrhoea (231 [75.0%] vs 144 [47.4%]) and skin rash (169 [54.9%] vs 97 [31.9%]). 43 (14.0%) patients discontinued in the ECH-TH group and 102 (33.1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group. INTERPRETATION: This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy. FUNDING: GlaxoSmithKline, Roche, and Sanofi-Aventis. PMID- 22257524 TI - Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project. AB - BACKGROUND: Around 90% of deaths from ovarian cancer are due to high-grade serous cancer (HGSC), which is frequently diagnosed at an advanced stage. Several cancer organisations made a joint recommendation that all women with specified symptoms of ovarian cancer should be tested with the aim of making an early diagnosis. In the Diagnosing Ovarian Cancer Early (DOvE) study we investigated whether open access assessment would increase the rate of early-stage diagnosis. METHODS: Between May 1, 2008, and April 30, 2011, we enrolled women who were aged 50 years or older and who had symptoms of ovarian cancer. They were offered diagnostic testing with cancer antigen (CA-125) blood test and transvaginal ultrasonography (TVUS) at a central and a satellite open-access centre in Montreal, QC, Canada. We compared demographic characteristics of DOvE patients with those of women in the same age-group in the general population of the area, and compared indicators of disease burden with those in patients with ovarian cancer referred through the usual route to our gynaecological oncology clinic (clinic patients). FINDINGS: Among 1455 women assessed, 402 (27.6%) were in the highest-risk age group (>= 65 years). 239 (16.4%) of 1455 required additional investigations. 22 gynaecological cancers were diagnosed, 11 (50%) of which were invasive ovarian cancers, including nine HGSC. The prevalence of invasive ovarian cancer, therefore, was one per 132 women (0.76%), which is ten times higher than that reported in screening studies. DOvE patients were significantly younger, more educated, and more frequently English speakers than were women in the general population. They also presented with less tumour burden than did the 75 clinic patients (median CA 125 concentration 72 U/mL, 95% CI 12-1190 vs 888 U/mL, 440-1936; p=0.010); Eight (73%) tumours were completely resectable in DOvE patients, compared with 33 (44%) in clinic patients (p=0.075). Seven (78%) of the HGSC in the DOvE group originated outside the ovaries and five were associated with only slightly raised CA-125 concentrations and minimal or no ovarian abnormalities on TVUS. INTERPRETATION: The proportion of HGSC that originated outside the ovaries in this study suggests that early diagnosis programmes should aim to identify low volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. Although testing symptomatic women may result in earlier diagnosis of invasive ovarian cancer, large-scale implementation of this approach is premature. FUNDING: Canadian Institutes of Health Research, Montreal General Hospital Foundation, Royal Victoria Hospital Foundation, Cedar's Cancer Institute, and La Fondation du Cancer Monique Malenfant-Pinizzotto. PMID- 22257527 TI - A low-grade chondrosarcoma presenting as an unusual cervical mass in the hyoid bone: a case report. AB - INTRODUCTION: A chondrosarcoma originating from the hyoid bone is very rare. Here, we describe a case of low-grade chondrosarcoma of hyoid origin and discuss its preoperative imaging features, including those on positron emission tomography-computed tomography, and its recurrence rate. CASE PRESENTATION: A 42 year-old Japanese man noticed a mass in the right submandibular region of his neck. A hard 3.0 * 2.8 cm tumor was noted on the right side of his hyoid bone. The mass was immobile and moved with deglutition. CONCLUSION: Even though radiographic studies, including positron emission tomography-computed tomography, were inconclusive, the cartilaginous tumor was surgically removed en bloc, and the tumor was diagnosed based on the results of pathological investigations. Close follow-up is recommended in such cases due to the potential for recurrences, because local recurrence occurred in 50% of the reported cases of grade one chondrosarcomas. PMID- 22257528 TI - A review on coumarins as acetylcholinesterase inhibitors for Alzheimer's disease. AB - Acetylcholinesterase (AChE) enzyme inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the main stay drugs for its management. Coumarins are the phytochemicals with wide range of biological activities including AChE inhibition. The scientists have attempted to explore the coumarin template for synthesizing novel AChE inhibitors with additional pharmacological activities including decrease in beta-amyloid (Abeta) deposition and beta-secretase inhibition that are also important for AD management. Most of the designed schemes have involved incorporation of a catalytic site interacting moiety at 3- and 4-positions of the coumarin ring. The present review describes these differently synthesized coumarin derivatives as AChE inhibitors for management of AD. PMID- 22257529 TI - Influence of the skeleton on the cytotoxicity of flavonoids. AB - Analogs of 3'-amino-5-hydroxy-3,6,7,8,4'-pentamethoxy-flavone, a strongly cytotoxic and antimitotic semisynthetic flavone, were synthesized in the aurone, isoflavone and isoflavanone series. Comparison of the biological activity of these new compounds with the reference showed a potent cytotoxicity only in the flavone series. Influence of the hydroxy group (at C-5 in flavones, at C-4 in aurones) on the cytotoxicity, known to be favorable in flavones, was found to be detrimental in aurones. This observation was related to the hydrogen bonding formed with the carbonyl group, strong in the flavones, but of weak intensity in the aurones. PMID- 22257530 TI - Cell surface biotinylation by azaelectrocyclization: easy-handling and versatile approach for living cell labeling. AB - Versatile method for living cell labeling has been established. Cell surfaces are initially biotinylated by azaelectrocyclization, and then treated with the fluorescence-labeled avidin or the anti-biotin antibody. PMID- 22257531 TI - Complications as indicators of quality assurance after 401 consecutive colorectal cancer resections: the importance of surgeon volume in developing colorectal cancer units in India. AB - BACKGROUND: The low incidence of colorectal cancer in India, coupled with absence of specialized units, contribute to lack of relevant data arising from the subcontinent. We evaluated the data of the senior author to better define the requirements that would enable development of specialized units in a country where colorectal cancer burden is increasing. METHODS: We retrospectively analyzed data of 401 consecutive colorectal resections from a prospective database of the senior author. In addition to patient demographics and types of resections, perioperative data like intraoperative blood loss, duration of surgery, complications, re-operation rates and hospital stay were recorded and analyzed. RESULTS: The median age was 52 years (10-86 years). 279 were males and 122 were females. The average duration of surgery was 220.32 minutes (range 50 480 min). The overall complication rate was 12.2% (49/401) with a 1.2% (5/401) mortality rate. The patients having complications had an increase in their median hospital stay (from 10.5 days to 23.4 days) and the re-operation rate in them was 51%. The major complications were anastomotic leaks (2.5%) and stoma related complications (2.7%). CONCLUSIONS: This largest ever series from India compares favorably with global standards. In a nation where colorectal cancer is on the rise, it is imperative that high volume centers develop specialized units to train future specialist colorectal surgeons. This would ensure improved quality assurance and delivery of health care even to outreach, low volume centers. PMID- 22257532 TI - Predictors of and reasons for pacifier use in first-time mothers: an observational study. AB - BACKGROUND: The use of pacifiers is commonplace in Australia and has been shown to be negatively associated with breastfeeding duration. In order to influence behaviour related to the use of pacifiers it is important to understand the reasons for their use. The primary aim of this observational study was to investigate who (if anyone) advises first-time mothers to give a pacifier and the reasons for which they first give (or try to give) a pacifier to their infant. Additionally, this study investigated the predictors of pacifier use and the relationship between pacifier use and breastfeeding duration. METHODS: In total, 670 Australian first-time mothers recruited as part of the NOURISH trial completed a questionnaire regarding infant feeding and pacifier use. RESULTS: Pacifiers were introduced by 79% of mothers, of whom 28.7% were advised to use a pacifier by their mother/mother-in-law with a further 22.7% being advised by a midwife. The majority of mothers used a pacifier in order to soothe their infant (78.3%), to help put them to sleep (57.4%) and to keep them comforted and quiet (40.4%). Pacifiers given to infants before four weeks (adjHR 3.67; 95%CI 2.14 6.28) and used most days (adjHR 3.28; 95%CI 1.92-5.61) were significantly associated with shorter duration of breastfeeding. CONCLUSIONS: This study identifies an opportunity for educating new mothers and their support network, particularly their infant's grandmothers, with regards to potential risks associated with the early and frequent use of a pacifier, and alternative methods for soothing their infant, in order to reduce the use of pacifiers and their potentially negative effect on breastfeeding duration. PMID- 22257533 TI - Core module biomarker identification with network exploration for breast cancer metastasis. AB - BACKGROUND: In a complex disease, the expression of many genes can be significantly altered, leading to the appearance of a differentially expressed "disease module". Some of these genes directly correspond to the disease phenotype, (i.e. "driver" genes), while others represent closely-related first degree neighbours in gene interaction space. The remaining genes consist of further removed "passenger" genes, which are often not directly related to the original cause of the disease. For prognostic and diagnostic purposes, it is crucial to be able to separate the group of "driver" genes and their first-degree neighbours, (i.e. "core module") from the general "disease module". RESULTS: We have developed COMBINER: COre Module Biomarker Identification with Network ExploRation. COMBINER is a novel pathway-based approach for selecting highly reproducible discriminative biomarkers. We applied COMBINER to three benchmark breast cancer datasets for identifying prognostic biomarkers. COMBINER-derived biomarkers exhibited 10-fold higher reproducibility than other methods, with up to 30-fold greater enrichment for known cancer-related genes, and 4-fold enrichment for known breast cancer susceptible genes. More than 50% and 40% of the resulting biomarkers were cancer and breast cancer specific, respectively. The identified modules were overlaid onto a map of intracellular pathways that comprehensively highlighted the hallmarks of cancer. Furthermore, we constructed a global regulatory network intertwining several functional clusters and uncovered 13 confident "driver" genes of breast cancer metastasis. CONCLUSIONS: COMBINER can efficiently and robustly identify disease core module genes and construct their associated regulatory network. In the same way, it is potentially applicable in the characterization of any disease that can be probed with microarrays. PMID- 22257534 TI - Cognitive procedural learning in early Alzheimer's disease: impaired processes and compensatory mechanisms. AB - INTRODUCTION: The aim of this study was to study cognitive procedural learning in early Alzheimer's disease (AD). METHODS: Cognitive procedural learning was assessed using the Tower of Hanoi (TH) task. In order to take account of possible interactions between different systems during cognitive procedural learning, we also measured non-verbal intellectual functions, working memory, and declarative memory. RESULTS: Our results showed an apparent preservation of cognitive procedural learning in AD and a deleterious effect of the disease on verbal intelligence and declarative memory. Correlational analyses revealed a difference between AD patients and control participants in the type of processing they applied to the task. CONCLUSION: The non-involvement of declarative memory would appear to be partly responsible for a slowdown in the cognitive procedural dynamics of AD patients. As the AD patients were unable to use their declarative memory, they were still in a problem-solving mode at the end of the learning protocol and had to implement higher order cognitive processes (i.e., compensatory mechanisms) to perform the procedural task. PMID- 22257535 TI - Infections and infestations of the gastrointestinal tract. Part 1: bacterial, viral and fungal infections. AB - The purpose of this article is to review the imaging findings of various infections affecting the gastrointestinal tract. Barium examinations, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography all play an important role in the diagnostic workup of gastrointestinal tract infections. Knowledge of differential diagnosis, sites of involvement, and typical imaging features of different infections can help in accurate diagnosis and guide treatment. PMID- 22257536 TI - Identification of five gelatins by ultra performance liquid chromatography/time of-flight mass spectrometry (UPLC/Q-TOF-MS) using principal component analysis. AB - An ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC/Q-TOF-MS) method coupled with a principal component analysis (PCA) was developed and applied toward identifying donkey-hide gelatin, bovine hide gelatin, pig-hide gelatin, tortoise shell glue, and deerhorn glue. The UPLC MS data of the trypsin digested samples were subjected to principal component analysis (PCA) in order to classify these five gelatins. Additionally, marker peptides given by the loadings plot of PCA were identified based on a comparison of recorded LC-MS data with a previously reported database of the corresponding gelatin variants. The results from this study indicate that the proposed method is reliable, and it has been successfully applied to the identification of variants of gelatins commonly used in Traditional Chinese Medicine (TCM). PMID- 22257537 TI - The response of rice grain quality to ozone exposure during growth depends on ozone level and genotype. AB - The effects of ozone exposure during the cropping season on rice grain quality were investigated in chamber experiments employing four ozone treatments (charcoal filtered air, ambient, 2* ambient, and 2.5* ambient concentration) and six genotypes. The concentrations of protein and lipids in brown rice increased significantly in response to ozone, while starch concentration and thousand kernel mass decreased. Other parameters, including the concentrations of iron, zinc, phenolics, stickiness and geometrical traits did not exhibit significant treatment effects. Total brown rice yield, protein yield, and iron yield were negatively affected by ozone. Numerous genotypic differences occurred in the response to ozone, indicating the possibility of optimizing the grain quality in high ozone environments by breeding. It is concluded that although the concentrations of two important macronutrients, proteins and lipids, increased in ozone treated grains, the implications for human nutrition are negative due to losses in total grain, protein and iron yield. PMID- 22257538 TI - Serum fetuin-A levels increased following parathyroidectomy in uremic hyperparathyroidism. AB - BACKGROUND: Both fetuin-A and hyperparathyroidism play crucial roles in vascular calcification (VC) and bone metabolism. However, the correlation between secondary hyperparathyroidism (SHPT), parathyroidectomy (PTX) and fetuin-A levels in dialysis patients has not yet been studied. METHODS: For this study, we included 27 consecutive dialysis patients with severe SHPT who underwent total PTX with autotransplantation over a period of 2 years (from Oct 2006 to Sep 2008). Serum ionized calcium (iCa), phosphorus (Pi), bone-specific alkaline phosphatase (bAP), intact parathyroid hormone (iPTH), and fetuin-A were checked basally and 2, 7, 14, 30, and 60 days after PTX. RESULTS: Two days after PTX, the iPTH, serum iCa, and Pi concentrations significantly decreased. Serum bAP levels gradually increased after PTX, peaked after 14 days (p < 0.05), and then gradually decreased. Serum fetuin-A levels significantly increased during the first 7 days after PTX, peaked 14 days after PTX (0.21 +/- 0.05 vs. 0.35 +/- 0.07 mg/ml, p < 0.05), and then remained at a stable level 60 days after PTX. There were significant correlations between percentage increase in serum fetuin-A levels and percentage decrease in serum iPTH levels 2 days and 7 days after PTX (r = 0.526, p < 0.01; r = 0.403, p < 0.05, respectively) and correlations between percentage increase in serum fetuin-A levels and percentage decrease in serum iCa levels 30 and 60 days after PTX (r = 0.449, p < 0.05; r = 0.474, p < 0.05, respectively). CONCLUSIONS: Serum fetuin-A significantly increased after PTX in uremic patients with SHPT. The percentage increase in serum fetuin-A after PTX was closely correlated with the percentage decrease in serum iPTH levels immediately after PTX, and with the percentage decrease in serum iCa levels in the later stage after PTX. Further investigations are necessary to further understand the regulation of fetuin-A in dialysis patients with sSHPT. PMID- 22257539 TI - Is transiliac bone biopsy a painful procedure? AB - Despite an increased availability of non-invasive procedures to assess bone mass, histological examination of undecalcified transiliac bone biopsies remains a very valuable tool in the diagnosis of metabolic or malignant bone disorders. Nonetheless, clinicians are sometimes reluctant to perform this "invasive" examination, arguing that it might be a painful procedure. The aim of our study was to evaluate pain and anxiety described by patients in the months following the biopsy and to characterize potential early or late side effects. A single interviewer conducted a phone survey (19 items questionnaire) in 117 patients in whom a bone biopsy had been performed by two experienced physicians, with the same material and similar anesthetic and technical procedure. The topics covered pain during or after the biopsy, anxiety, comparison of other potentially painful procedures, early or late side effects as well as global evaluation by the patients. Bone biopsy was judged as non-painful by almost 70% of patients; some discomfort was present in 25% in the following days. The procedure was described as similar as or less painful than bone marrow aspiration, venipuncture or tooth extraction. About 90% of the patients estimated that it was a quite bearable diagnostic procedure. Side effects were not serious. About 7% remembered a vasovagal episode, 47% of local bruising in the following days. There was no report of hematoma or infection. In experienced hands and adapted trephine, transiliac bone biopsy is a safe procedure that brings invaluable information in bone disorders. PMID- 22257540 TI - Impact of mean arterial pressure on progression of arterial stiffness in peritoneal dialysis patients under strict volume control strategy. AB - INTRODUCTION: Arterial stiffness is an important contributor to the increased cardiovascular burden of uremia. The aim of the study was to identify determinants of arterial stiffness progression in peritoneal dialysis (PD) patients with strict volume control. PATIENTS AND METHODS: 89 prevalent PD patients were enrolled. Assessment of arterial stiffness was performed at baseline and after nine months on average (range 8 - 12 months) by carotid femoral pulse wave velocity (cf-PWV). RESULTS: Mean age was 51 +/- 13 y; preceeding time on PD was 40 +/- 34 months. 57% of the patients were men and 9% were diabetic. At baseline, mean cf- PWV was 8.7 +/- 2.7 m/s and was significantly higher in patients with diabetes and on automated PD therapy. Cf PWV was positively correlated with age, history of cardiovascular disease, mean arterial pressure (MAP), blood glucose, left atrium diameter and left ventricular mass index. Sixty patients underwent a second cf-PWV measurement. 36% had progression of arterial stiffness. Delta cf- PWV value was 2.08 +/- 1.89 m/s for progressors and -1.25 +/- 1.43 m/s; p < 0.01 for nonprogressors (p < 0.01). In logistic regression analysis, the change in MAP was the only predictor for progression of arterial stiffness. CONCLUSIONS: MAP is the main determinant of arterial stiffness progression. Our results suggest that efficient blood pressure control may contribute to preserved or reduced arterial stiffness in PD patients. PMID- 22257541 TI - Duodenal biopsy for diagnosis of renal involvement in amyloidosis. AB - Amyloidosis results from extracellular deposition of a fibrillary protein in various organs, and renal biopsy is the best, but a complicated tool for diagnosis. Therefore, alternative biopsy sites have been proposed with varying degrees of sensitivity. We aimed to find the most appropriate biopsy site in patients with chronic kidney disease (CKD) in whom renal biopsy is contraindicated or unavailable. 42 patients (29 male; mean age 46 +/- 16 y) with CKD in whom amyloidosis was suspected as the underlying etiology on clinical grounds, but renal biopsy was not available (Group I), and 36 patients (25 male; mean age 40 +/- 16 y) with CKD in whom renal biopsy revealed AA-amyloidosis (Group II) were investigated. Upper and lower gastrointestinal tract (GIT) endoscopies were performed and multiple biopsies from gingiva, esophagus, antrum, duodenum and rectum were obtained. In Group I, no amyloidosis was detected in gingival and GIT biopsies among 13 patients. In the remaining 29 patients AA amyloidosis was detected in various sites with the following frequencies: duodenum 100%, rectum 83%, antrum 79%, esophagus 44% and gingiva 29%. In Group II, frequency of amyloid deposition was 97% in duodenum, 76% each in antrum and rectum, 59% in esophagus and 32% in gingival mucosa. In conclusion, duodenal biopsy is sensitive for diagnosing amyloidosis in CKD patients, and highly correlates with renal amyloidosis. PMID- 22257542 TI - omega-3 fatty acids therapy for IgA nephropathy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The efficacy of omega-3 fatty acids (O3FA) in IgA nephropathy remains a controversial issue. The aim of the current updated meta-analysis is to assess the efficacy of O3FA treatment for adult IgA nephropathy. METHODS: We searched PubMed/MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials that compared O3FA treatments with placebo or no treatment in adult IgA nephropathy. Outcomes of interest were effects on urine protein excretion (UPE) and renal function. RESULTS: Five RCTs (239 patients) were included for analysis. Compared with control groups, O3FA treatments did not show significant benefits for reducing UPE (standardized mean difference (SMD), 0.111; 95% confidence interval (CI), -0.369 - 0.147) or improving glomerular filtration rate (GFR) or estimated GFR (SMD, 0.177; 95% CI, -0.082 - 0.435), although the pooled results slightly favored O3FA. On the other hand, a lower risk of an increase of 50% or more in serum creatinine and ESRD were found in O3FA-treated IgA nephropathy patients (RR 0.189; 95% CI 0.068 - 0.524, p = 0.001; RR 0.236; 95% CI 0.094 - 0.594, p = 0.002), but the two outcomes were reported in only two trials. CONCLUSION: The current metaanalysis suggests that there are insufficient data to confirm the efficacy of O3FA treatments for proteinuria and renal function in IgA nephropathy. Further large scale trials are needed to shed more light on this issue. PMID- 22257543 TI - A multicenter, randomized trial of increased mycophenolic acid dose using enteric coated mycophenolate sodium with reduced tacrolimus exposure in maintenance kidney transplant recipients. AB - Mycophenolic acid (MPA) dose is frequently reduced in tacrolimus-treated kidney transplant patients, but alternatively the recommended MPA dose can be maintained with reduced tacrolimus exposure. In a 6-month, multicenter, randomized, openlabel study, maintenance kidney transplant patients receiving MPA (mycophenolate mofetil 1g/d or enteric-coated mycophenolate sodium (EC-MPS) 720 mg/d) and tacrolimus were randomized to convert to EC-MPS 1,440 mg/d with reduced tacrolimus (n = 46), or receive EC-MPS 720 mg/d with unchanged tacrolimus (n = 48). Mean estimated GFR (eGFR, aMDRD) at Month 6 was 49.1 +/- 11.1 and 44.7 +/- 11.5 ml/min/1.73 m2 in the EC-MPS 1,440 mg and 720 mg groups, respectively (p = 0.07). The primary endpoint, change in eGFR from Day 0 to Month 6, was 2.48 +/- 0.95 ml/min/1.73 m2 with EC-MPS 1,440 mg and -0.48 +/- 0.93 ml/min/1.73 m2 with EC-MPS 720 mg (difference 2.96 ml/min/1.73 m2; 95% CI 0.32 - 5.60; p = 0.028). There were no deaths, graft losses or acute rejections. Adverse events were more frequent with EC-MPS 1,440 mg than 720 mg (66.7% vs. 44.7%, p = 0.034). Adverse events with suspected relation to EC-MPS occurred in 26.7% and 21.3% of patients, respectively (p = 0.59). Conversion of kidney transplant patients to increased MPA dosing using EC-MPS 1,440 mg/d, with reduced tacrolimus exposure, appears an effective immunosuppression strategy and may improve renal function. Adverse events overall, but not those with a suspected relation to EC-MPS, were higher with ECMPS 1,440 mg/d. PMID- 22257544 TI - Impact of periodontal treatment in combination with tonsillectomy plus methylprednisolone pulse therapy and angiotensin blockade for pediatric IgA nephropathy. AB - BACKGROUND: We previously reported the efficacy of extensive eradication of infectious foci in oral and ENT lesions, combined with tonsillectomy plus methylprednisolone (MP) pulse therapy, for curing pediatric Henoch-Schonlein purpura (HSP) and HSP nephritis. In the present study, we used this therapy in patients with pediatric IgA nephropathy (IgAN) to assess whether similar results could be obtained. PATIENTS AND METHODS: In 11 pediatric patients newly diagnosed with IgAN, exploration for infectious foci showed severe oral infection, including dental caries and apical periodontitis, in many. The overall decayed, missing and filled teeth score was elevated to 5.91. Two patients had rhinosinusitis. After extensive treatment of infectious foci, patients underwent tonsillectomy plus MP pulse therapy with angiotensin II receptor blockade. RESULTS: Clinical remission was achieved in all patients with pediatric IgAN (various histologic grades). Remission was achieved by 7.2 +/- 5.7 months after initiation of steroid therapy, and disappearance of proteinuria by 3.3 +/- 3.0 months. The mean duration of oral steroid administration was 9.5 +/- 3.6 months. No relapse has occurred during follow-up of 4.3 +/- 2.4 y. CONCLUSIONS: Careful examination and thorough elimination of infectious foci in oral and ENT lesions can optimize the effect of tonsillectomy plus MP pulse therapy, promoting recovery from IgAN. PMID- 22257545 TI - IgA nephropathy in a patient with ulcerative colitis, Graves' disease and positive myeloperoxidase ANCA. AB - We report a case of a 38-year old woman with a history of ulcerative colitis and Graves' disease who presented with pyoderma gangrenosum, microscopic hematuria, proteinuria, and positive myeloperoxidase ANCA. A renal biopsy revealed a focal proliferative glomerulonephritis with IgA deposits. All these manifestations are likely secondary to ulcerative colitis or to a common pathogenetic mechanism. PMID- 22257546 TI - Peculiar renal endarteritis in a patient with acute endocapillary proliferative glomerulonephritis. AB - Acute glomerulonephritis (AGN) is one of the most common renal diseases. They are often associated with infections and can result in diffuse proliferative glomerulonephritis (GN). This case report reviews an interesting case in which renal endarteritis coexisted in AGN with diffuse endocapillary proliferation. The discussion highlights important pathological findings and clinical aspects in acute endocapillary proliferative GN with renal endarteritis. Coexisting endarteritis should be in the differential diagnosis of AGN in patients with persistent clinical courses. PMID- 22257547 TI - Renal actinomycosis with concomitant renal vein thrombosis. AB - Renal actinomycosis is a rare infection caused by fungi of the genus Actinomyces. A 74-year-old male was admitted to our hospital because of gross hematuria with urinary symptoms and intermittent chills. Computed tomography of the abdomen showed thrombosis in the left renal vein and diffuse, heterogeneous enlargement of the left kidney. After nephrectomy, sulfur granules with chronic suppurative inflammation were seen microscopically, and the histopathological diagnosis was renal actinomycosis. Our case is the first report of renal actinomycosis with renal vein thrombosis. PMID- 22257548 TI - Hereditary renal hypouricemia: a cause of calcium oxalate urolithiasis in a young female. AB - Although renal hypouricemia is mostly asymptomatic, it is known to present a high risk of exercise-induced acute renal failure, especially in young males. However, there is little information regarding the clinical features of urolithiasis as a complication in childhood renal hypouricemia. Here we report a 4-year old female with idiopathic renal hypouricemia who presented with macroscopic hematuria due to obstructive calcium oxalate urolithiasis. She was treated successfully with percutaneous nephrolithotripsy and thereafter hematuria disappeared. Sequence analysis of the patient and her family's URAT1 gene confirmed a nonsense mutation in exon 4 (W258X). To the best of our knowledge, this is the youngest case of hereditary renal hypouricemia caused by URAT1 gene mutation, which was found by hematuria due to calcium oxalate urolithiasis. PMID- 22257549 TI - Thrombotic microangiopathic nephropathy, pulmonary hypertension and nephromegaly: case report of a patient treated with endothelin receptor antagonist. AB - The coexistence of thrombotic microangiopathic nephropathy and pulmonary hypertension has only been described in association with malignancy and its treatment. Here we describe a 14-year-old boy with no prior medical history who presented with hypertension, proteinuria and nephromegaly, and then developed progressive pulmonary hypertension. Renal histology showed lesions consistent with glomerulopathy due to thrombotic microangiopathy (TMA). Pulmonary hypertension was controlled by the use of an oral endothelin receptor antagonist (bosentan). Although renal function deteriorated at the onset of pulmonary hypertension, an improvement was observed after the bosentan treatment. Nephromegaly persisted, but current creatinine clearance values are within the normal range. While this case exemplifies how thrombotic microangiopathic nephropathy may be associated with pulmonary hypertension, a therapeutic role of endothelin antagonists is suggested, not only for pulmonary hypertension but also for microangiopathic nephropathy. PMID- 22257550 TI - Foodborne outbreak and nonmotile Salmonella enterica variant, France. AB - We report a food-related outbreak of salmonellosis in humans caused by a nonmotile variant of Salmonella enterica serotype Typhimurium in France in 2009. This nonmotile variant had been circulating in laying hens but was not considered as Typhimurium and consequently escaped European poultry flock regulations. PMID- 22257551 TI - Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion. AB - It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7-36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion. PMID- 22257552 TI - Evolution of phytoplankton cultures after ultraviolet light treatment. AB - Introducing invasive species in new environments through ballast water is a specific problem of contamination and has recently become one of the main concerns of Maritime Organizations. Ultraviolet-C radiation (UV-C) is a technological alternative to prevent this maritime pollution. This study addresses the effect of UV-C on different phytoplankton cultures and also the ability to recover following exposure to damage. A UV-C low-pressure lamp irradiates the cultures. The distance from the source and the thickness of the layer prevent part of the energy from reaching the culture and the disinfective process is diminished. Some cultures such as Chlorella autotrophica and Chaetoceros calcitrans can easily recover from UV-C damage. However, Phaeocystis globosa does not have this ability. C. calcitrans forms cysts and exhibits two different behaviours depending on the dose applied. PMID- 22257553 TI - Terrestrial pollutant runoff to the Great Barrier Reef: An update of issues, priorities and management responses. AB - The Great Barrier Reef (GBR) is a World Heritage Area and contains extensive areas of coral reef, seagrass meadows and fisheries resources. From adjacent catchments, numerous rivers discharge pollutants from agricultural, urban, mining and industrial activity. Pollutant sources have been identified and include suspended sediment from erosion in cattle grazing areas; nitrate from fertiliser application on crop lands; and herbicides from various land uses. The fate and effects of these pollutants in the receiving marine environment are relatively well understood. The Australian and Queensland Governments responded to the concerns of pollution of the GBR from catchment runoff with a plan to address this issue in 2003 (Reef Plan; updated 2009), incentive-based voluntary management initiatives in 2007 (Reef Rescue) and a State regulatory approach in 2009, the Reef Protection Package. This paper reviews new research relevant to the catchment to GBR continuum and evaluates the appropriateness of current management responses. PMID- 22257554 TI - The effect of polyethylene glycol recombinant human growth hormone on growth and glucose metabolism in hypophysectomized rats. AB - OBJECTIVE: To study the effect of polyethylene glycol recombinant human growth hormone on growth and glucose metabolism in hypophysectomized rats, and compare the effect of treatment between recombinant human growth hormone (rhGH) and polyethylene glycol rhGH (PEG-rhGH). METHODS: Hypophysectomy was performed in juvenile rats to build the animal model of GH deficiency. The hypophysectomized animals were randomly assigned into three groups and treated with saline (negative control, n=20), rhGH (n=20) and PEG-rhGH (n=20). A sham operation was performed to set up the normal control (n=20). Body weight, body length and tail length were recorded every 2days for a 14-day treatment and bone growth was measured at the end of therapy. Glucose infusion rate (GIR) determined by euglycemic hyperinsulinemic clamp was used to evaluate insulin sensitivity after GH treatment. We also examined plasma glucose and serum insulin levels RESULTS: Compared with the negative control, the body weight, body length, tail length and bone growth increased significantly in hypophesectomized rats treated by GH (P<0.01). Although the weight gain in the first 10days was higher in the PEG-rhGH group than in the rhGH group (P<0.05), the growth promoting effect was similar between rhGH and PEG-rhGH (P>0.05). Neither rhGH nor PEG-rhGH impaired glucose tolerance of rats after hypophesectomy. Compared with negative controls, according to decreased serum insulin, reduced insulin expression in pancreatic cells and increased GIR in the clamp, both rhGH and PEG-rhGH groups had improved insulin sensitivity within 14 days (P<0.01). However, with prolonged treatment, the GIR in the rhGH-treated rats decreased significantly (P<0.05); while PEG-rhGH did not interfere with GIR, even after a doubled dose (P>0.05). CONCLUSIONS: PEG rhGH had the same linear growth promoting efficacy as unmodified rhGH. The short term GH replacement could improve insulin sensitivity in hypophysectomized rats, especially after PEGylation. PMID- 22257555 TI - Virulence without catalysis: how can a pseudokinase affect host cell signaling? AB - A hallmark of the pathogenic lifestyle is the secretion of enzymes and other effectors that dysregulate host signaling. Intriguingly, the most potent virulence locus identified in the intracellular parasite Toxoplasma gondii encodes a family of related catalytically inactive protein kinases, or pseudokinases. Toxoplasma has in its kinome among the highest percentage of pseudokinases among all sequenced organisms, and the majority of these appear to be secreted into the host cell. We posit that the pseudokinase fold represents a particularly well-suited domain for functional diversification, discuss the relevance of gene expansion at these loci, and outline potential mechanisms by which a pseudokinase might affect host signaling. PMID- 22257556 TI - Life on the edge: the balance between macrofauna, microflora and host immunity. AB - Mammals, microflora and gut-dwelling macrofauna have co-evolved over many millions of years until relatively recently when the geographical prevalence of macrofauna in humans has become restricted to the developing world. Immune homeostasis relies on a balance in the composition of intestinal microflora; long lived macrofauna have also been shown to regulate immune function, and their absence in Western lifestyles is suggested to be a factor for the increasing frequency of allergy and autoimmunity. The intestinal nematode Trichuris muris was recently demonstrated to utilise microflora to initiate its life cycle. The interdependence on one another of all three factors is such that when the balance is perturbed it must be realigned or the consequences may be detrimental to the mammalian host. PMID- 22257557 TI - Design of a trial-based economic evaluation on the cost-effectiveness of employability interventions among work disabled employees or employees at risk of work disability: the CASE-study. AB - BACKGROUND: In the Netherlands, absenteeism and reduced productivity due to work disability lead to high yearly costs reaching almost 5% of the gross national product. To reduce the economic burden of sick leave and reduced productivity, different employability interventions for work-disabled employees or employees at risk of work disability have been developed. Within this study, called 'CASE study' (Cost-effectiveness Analysis of Sustainable Employability), five different employability interventions directed at work disabled employees with divergent health complaints will be analysed on their effectiveness and cost-effectiveness. This paper describes a consistent and transparent methodological design to do so. METHODS/DESIGN: Per employability intervention 142 participants are needed whereof approximately 66 participants receiving the intervention will be compared with 66 participants receiving usual care. Based on the intervention-specific characteristics, a randomized control trial or a quasi-experiment with match criteria will be conducted. Notwithstanding the study design, eligible participants will be employees aged 18 to 63, working at least 12 h per week, and at risk of work disability, or already work-disabled due to medical restrictions. The primary outcome will be the duration of sick leave. Secondary outcomes are health status and quality of life. Outcomes will be assessed at baseline and then 6, 12 and 18 months later. Economic costs will consist of healthcare costs and cost of lost production due to work disability, and will be evaluated from a societal perspective. DISCUSSION: The CASE-study is the first to conduct economic evaluations of multiple different employability interventions based on a similar methodological framework. The cost-effectiveness results for every employability intervention will be published in 2014, but the methods, strengths and weaknesses of the study protocol are discussed in this paper. To contribute to treatment options in occupational health practice and enable the development of guidelines on how to conduct economic evaluation better suited to this field; this paper provides an important first step. TRIAL REGISTRATION: Four trials involved in the CASE-study are registered with the Netherlands Trial Registry: Care for Work (NTR2886), Health and Motion (NTR3111), Guidance to Excel in Return to Work (NTR3151), Care for Companies/Second Care (NTR3136). PMID- 22257558 TI - Global trend of survival and damage of systemic lupus erythematosus: meta analysis and meta-regression of observational studies from the 1950s to 2000s. AB - OBJECTIVE: To assess systemically with meta-analysis the trend of survival and its determinants, which are hindering further improvement of survival of patients with systemic lupus erythematosus (SLE) over the past 5 decades. METHODS: Retrospective, cross-sectional, and prospective observational studies addressing survival and damage in SLE patients published between 1 January 1950 and 31 July 2010 were identified in electronic databases. Using the random-effects model, effect size was calculated based on the logit of the overall 5- and 10-year survival rates. The pooled logit and its robust 95% confidence interval were transformed back into the 5- and 10-year survival rates, after adjusting for potential dependence on the data. Potential factors predicting the pooled survival rates were explored by meta-regression. RESULTS: Seventy-seven studies involving 18,998 SLE patients were analyzed. Between the 1950s and the 2000s, their overall survival significantly increased, from 74.8% to 94.8% and 63.2% to 91.4% for the overall 5-year and 10-year survival, respectively (P < 0.001). The survival improvement, however, appeared to slow down between 1980 and 1990. Meta regression revealed that neuropsychiatric and renal damage negatively affected the overall 5-year survival, whereas neuropsychiatric damage remained so for the 10-year survival for the past 50 years. Furthermore, the prevalence of neuropsychiatric damage has been significantly increasing over the past 5 decades. CONCLUSIONS: For the past 50 years, damage involving the renal and neuropsychiatric systems has been negatively affecting survival of SLE patients. Early detection and aggressive management of renal and neuropsychiatric involvement may potentially improve further the survival of lupus patients. PMID- 22257559 TI - [Combination of bla(VIM-1) and qnrS2 on the same plasmid in Klebsiella oxytoca and Klebsiella pneumoniae isolates in Seville]. AB - BACKGROUND: Combined resistance to quinolones and beta-lactams is common in Enterobacteriaceae. The appearance in enterobacteria coding for metallo-beta lactamases and determinants of plasmid-mediated quinolone resistance are an emerging problem in our country. METHODS: The susceptibility was determined by E test. The resistance genes were detected by PCR and the corresponding plasmids were characterised. RESULTS: This study describes 2 strains (1 Klebsiella oxytoca, 1 Klebsiella pneumoniae) carrying the genes qnrS2 and blaVIM-1 in a transferable plasmid of 70-Kb isolated in surveillance cultures at the University Hospital Virgen Macarena in Seville. CONCLUSION: This is the first combination of qnrS2 and bla(VIM-1) on the same non-typeable plasmid isolated in our centre. PMID- 22257560 TI - Prostaglandin receptors EP and FP are regulated by estradiol and progesterone in the uterus of ovariectomized rats. AB - BACKGROUND: Prostaglandins are important for female reproduction. Prostaglandin E2 acts via four different receptor subtypes, EP1, EP2, EP3 and EP4 whereas prostaglandin-F2alpha acts through FP. The functions of prostaglandins depend on the expression of their receptors in different uterine cell types. Our aim was to investigate the expression of EPs and FP in rat uterus and to identify the regulation by estradiol, progesterone and estrogen receptor (ER) selective agonists. METHODS: We performed four different rat experiments involving treatments with estradiol, progesterone and ER agonists. Real-time PCR and immunohistochemistry were employed to evaluate receptor expression. RESULTS: Our results showed that all mRNAs and proteins of EPs and FP are expressed in the rat uterus. The expression pattern and intensity of immunostaining vary between different cell types and treatments. The mRNA expression of all EPs and FP are downregulated by estradiol and the ERalpha specific agonist PPT, whereas the ERbeta specific agonist DPN downregulates only EP2 and EP4. The protein expression however, showed an increase in EP2 and EP3 after estradiol treatment. When treated with estradiol and progesterone in combination, the expressions of EP1 and EP3 are upregulated. CONCLUSIONS: Regulation of EPs and FP expression by estradiol appears to be mainly modulated via ERalpha for EP1, EP3 and FP, while EP2 and EP4 also are affected by the ERbeta selective ligand. Our immunohistochemical data shows a cell specific regulation of prostaglandin receptors under the influence of ovarian steroids, where EP2 is estrogen regulated in all uterine tissues examined. EP1 and EP3 are upregulated by the combination of estradiol and progesterone. Thus, our observations indicate that estradiol and progesterone regulate the mRNA and protein expression of EPs and FP in a receptor and tissue specific way. PMID- 22257561 TI - Depletion of the actin bundling protein SM22/transgelin increases actin dynamics and enhances the tumourigenic phenotypes of cells. AB - BACKGROUND: SM22 has long been studied as an actin-associated protein. Interestingly, levels of SM22 are often reduced in tumour cell lines, while they are increased during senescence possibly indicating a role for SM22 in cell fate decisions via its interaction with actin. In this study we aimed to determine whether reducing levels of SM22 could actively contribute to a tumourigenic phenotype. RESULTS: We demonstrate that in REF52 fibroblasts, decreased levels of SM22 disrupt normal actin organization leading to changes in the motile behaviour of cells. Interestingly, SM22 depletion also led to an increase in the capacity of cells to spontaneously form podosomes with a concomitant increase in the ability to invade Matrigel. In PC3 prostate epithelial cancer cells by contrast, where SM22 is undetectable, re-expression of SM22 reduced the ability to invade Matrigel. Furthermore SM22 depleted cells also had reduced levels of reactive oxygen species when under serum starvation stress. CONCLUSIONS: These findings suggest that depletion of SM22 could contribute to tumourigenic properties of cells. Reduction in SM22 levels would tend to promote cell survival when cells are under stress, such as in a hypoxic tumour environment, and may also contribute to increases in actin dynamics that favour metastatic potential. PMID- 22257562 TI - Vacuolation and mineralisation as dominant age-related findings in hamster brains. AB - Syrian golden hamsters (Mesocricetus auratus) are laboratory animals increasingly used for research and toxicological studies. Despite the need for an adequate knowledge of spontaneously occurring lesions, studies investigating the background pathology of different organ systems in hamsters are lacking. The aim of this study was to investigate the occurrence of spontaneous, age-dependent lesions in the central nervous system of this species. Multiple brain and spinal cord transverse sections of 520 hamsters of 1, 3, 6, 12, and 24 months of age were investigated using histology and immunohistochemistry. Vacuolation of grey matter neuropil and mineralisation especially in the brain stem were the most prominent findings. They gradually increased in severity and frequency with age. Vacuolation and mineralisation affected approximately 100% and 50% of 24-month old hamsters, respectively. In addition, pigment deposition and mast cell infiltration were commonly detected. Whether vacuolation and mineralisation represent an incidental finding or are related to a cognitive dysfunction syndrome remains to be determined. PMID- 22257563 TI - Towards real-time metabolic profiling of a biopsy specimen during a surgical operation by 1H high resolution magic angle spinning nuclear magnetic resonance: a case report. AB - INTRODUCTION: Providing information on cancerous tissue samples during a surgical operation can help surgeons delineate the limits of a tumoral invasion more reliably. Here, we describe the use of metabolic profiling of a colon biopsy specimen by high resolution magic angle spinning nuclear magnetic resonance spectroscopy to evaluate tumoral invasion during a simulated surgical operation. CASE PRESENTATION: Biopsy specimens (n = 9) originating from the excised right colon of a 66-year-old Caucasian women with an adenocarcinoma were automatically analyzed using a previously built statistical model. CONCLUSIONS: Metabolic profiling results were in full agreement with those of a histopathological analysis. The time-response of the technique is sufficiently fast for it to be used effectively during a real operation (17 min/sample). Metabolic profiling has the potential to become a method to rapidly characterize cancerous biopsies in the operation theater. PMID- 22257564 TI - Olfactory classical conditioning in neonatal mouse pups using thermal stimuli. AB - Mouse models are increasingly used to investigate genetic contributions to developmental disorders in children, especially newborns. In particular, early cognitive assessment in newborn mice is critical to evaluate pediatric drug efficacy and toxicity. Unfortunately, methods for behavioral tests in newborn mice are scarce. Therefore, developing such tests for newborn mice is a priority challenge for neurogenetics and pharmacological research. The aim of the present study was to develop a conditioning method well suited to high-throughput cognitive screening in newborn mice. To this end, we developed an odor-preference conditioning test using ambient temperature as an unconditioned stimulus (US) and artificial odors as conditioned stimuli (CS). First, we showed that mouse pups move toward the thermoneutral temperature when offered a choice between a thermoneutral and cold environment, thus showing thermotaxis. Second, we conducted a classical conditioning paradigm in pups aged six to ten days. In terms of central nervous system development, this period corresponds to extreme prematurity to early post-term period in humans. During acquisition, the pups were alternatively exposed to odor CS paired with either cold or warm temperatures. Immediately after acquisition, the pups underwent a two-odor choice test, which showed preference for the odor previously paired with the warm temperature, thus showing conditioning. The proposed paradigm is easy to conduct, and requires modest experimenter interference. The method is well suited for high throughput screening of early associative disorders in newborn mice. PMID- 22257565 TI - Social interaction experiences of adults with Moebius Syndrome: a focus group. AB - This focus group study explored the social interaction experiences and strategies of 12 adults with Moebius Syndrome, a rare congenital condition characterized by facial paralysis. Content analysis revealed five themes of social functioning: social engagement/disengagement; resilience/sensitivity; social support/stigma; being understood/misunderstood; and public awareness/lack of awareness of Moebius Syndrome. Participants used compensatory expressive strategies such as vocal tone, gestures, and humor. The combination of being unable to express oneself with the face, having a facial difference, and having a rare disease is particularly stigmatizing. Increasing public awareness and developing social skills programs for people with facial paralysis could facilitate social functioning. PMID- 22257566 TI - Implementation of the Tallinn Charter in the WHO European region: where is the evidence? A systematic comparison of online information before and after the end of the year of signature. AB - BACKGROUND: The "Tallinn Charter: Health Systems, Health and Wealth" signed by 53 member states of the WHO European Region provides guidance for strengthening health systems. OBJECTIVES: A systematic search was conducted to compare studies and actions related to the commitments of the Tallinn Charter. MATERIALS AND METHODS: Target keywords were identified directly from the Charter. Structured web search was conducted on Pubmed/Google. Results for 2007-2010 were analyzed as frequencies before/after the end of the year of signature and classified by relevance and category of content. RESULTS: Searches for 2007-2010 extracted N=717 papers in Medline and N=634 links in Google using combined keywords. Additional N=165 direct links to the Charter were found by Google for 2008-2010. An increase by 18% (scientific literature) and 10% (grey literature) was observed after 2008. DISCUSSION: The number of conceptual, methodological, analytical or system evaluation reports related to the themes of the Charter increased after 2008, while benchmarking and cross-country comparisons were less frequent. Opposite trends were observed for the grey literature. CONCLUSIONS: The implementation of the Tallinn Charter is supported by more information available on the topic. The methodology used to perform a rapid search may be usefully repeated to monitor the process. PMID- 22257567 TI - The evaluation of neutron and gamma ray dose equivalent distributions in patients and the effectiveness of shield materials for high energy photons radiotherapy facilities. AB - In this study, the MCNP5 code was used to model radiotherapy room of a medical linear accelerator operating at 18 MV and to evaluate the neutron and the secondary gamma ray fluences, the energy spectra and the dose equivalent distributions inside a liquid tissue-equivalent (TE) phantom. The obtained results were compared with measured data published in the literature. Moreover, the shielding effects of various neutron material shields on the radiotherapy room wall were also investigated. Our simulation results showed that paraffin wax containing boron carbide presents enough effectiveness to reduce both neutron and secondary gamma ray doses. PMID- 22257568 TI - Physiological responses and tolerance mechanisms to Pb in two xerophils: Salsola passerina Bunge and Chenopodium album L. AB - Lead (Pb) has great toxicity to human beings and other livings. Although there are varied ways to rehabilitate the Pb contaminated area, phytoremediation of Pb pollution in arid lands is still a difficult task, it is therefore urgent to find and identify Pb tolerant plants in arid areas. The physiological responses and tolerance mechanisms to Pb stress (expressed as the Pb concentration, e.g., 0, 50, 150, 300, 600, 800, 1000 mg/L) were investigated for the xerophils Salsola passerina Bunge and Chenopodium album L. Results indicated that S. passerina exhibited higher Pb tolerance than Ch. album in terms of the seed germination rate, bio-activities of SOD and POD, and lower MDA production. There were two ways for S. passerina to reduce Pb toxicity in organism level, e.g., cell wall precipitation and state transfer of free Pb into anchorage. These findings demonstrate that S. passerina is a Pb tolerant species and may have potential application in phytoremediation of Pb contaminated arid lands. PMID- 22257569 TI - In vitro biodurability of the product of thermal transformation of cement asbestos. AB - To safely recycle the product of the thermal transformation of cement-asbestos as secondary raw material, its toxicity potential should be assessed by in vitro biodurability tests. In this work, the acellular in vitro biodurability of the products of transformation of cement-asbestos at 1200 degrees C (named KRY.AS) was tested using both inorganic and organic simulated lung fluids at pH 4.5. The dissolution kinetics were followed using chemical, mineralogical and microstructural analyses. The total dissolution time estimated from the experiments with inorganic HCl diluted solution is one order of magnitude higher than that determined from the experiments with buffered Gamble solution (253 days vs. 20 days). The key parameter determining the difference in dissolution rate turns out to be the solidus/liquidus ratio which prompts a fast saturation of the solution with monosilicic acid. The calculated dissolution rate constants showed that the biodurability in vitro of KRY.AS is much lower with respect to that of standard chrysotile asbestos (total estimated dissolution time of 20 days vs. 298 days, respectively). This proves a low potential toxicity of this secondary raw material. PMID- 22257570 TI - Serotonin transporter clustering in blood lymphocytes as a putative biomarker of therapeutic efficacy in major depressive disorder. AB - BACKGROUND: Serotonin transporter (SERT) binding is decreased in lymphocytes of depression patients and this decrease is partially reversed by antidepressant medication. However, recent evidence has shown that clustering of SERT on cell membranes is very important for receptor functionality. Alteration in SERT clustering on peripheral lymphocytes does not affect symptoms severity. At the most it is associated or predicts responsivity to treatment. METHODS: We collected blood samples from 38 untreated and newly diagnosed depression patients at the time of diagnosis and after 8weeks of pharmacological treatment and of 38 control subjects. We used the Hamilton Scale to quantify the level of depression in patients both before and after pharmacological treatment. We then used immunocytochemistry to assess SERT protein clusters in lymphocyte blood samples. RESULTS: We found an increase in SERT cluster size, but not the number of SERT clusters, in naive depression patients compared to control subjects. Based on the distribution of SERT cluster size we differentiated the naive depression patients into two groups (D-I and D-II). Naive D-I and D-II patients initially showed similar Hamilton scores. However, after pharmacological treatment the D-II patients showed a greater decrease in Hamilton scores than did the D-I patients, and they had an increase in the number of SERT clusters. LIMITATIONS: The data should be replicated in a larger cohort of patients and with a proper clinical trial. CONCLUSIONS: We propose that SERT clustering in blood lymphocytes may be a putative biomarker for antidepressant efficacy in major depressive disorder. PMID- 22257571 TI - Identification of CTX-M beta-lactamases among Escherichia coli from the community in New York City. AB - We have identified CTX-M group 1 beta-lactamases in 87% of community-acquired Escherichia coli isolates that produce extended-spectrum beta-lactamases, with the majority harboring CTX-M-15 and representing the ST131 clonal group. Seventy percent of CTX-M-bearing isolates were from urine specimens; a large proportion was nonsusceptible to levofloxacin, trimethoprim/sulfamethoxazole, and beta lactam antimicrobials. Many patients were relatively youthful (41% <=65 years old; youngest, age 32). Patients with symptomatic bacteriuria received drugs to which the organisms were susceptible, and most had favorable outcomes. Timely recognition of such isolates could help physicians choose more appropriate antibacterial therapy. PMID- 22257572 TI - Degradation of Direct Black 38 dye under visible light and sunlight irradiation by N-doped anatase TIO2 as photocatalyst. AB - The N-doped TiO(2) photocatalyst was prepared by calcination of a hydrolysis product composed of titanium (IV) isopropoxide with ammonia as the precipitator. X-ray diffraction, surface area, XPS and UV-vis spectra analyses showed a nanosized anatase structure and the appearance of a new absorption band in the visible region caused by nitrogen doping. The degradation of Direct Black 38 dye on the nitrogen-doped TiO(2) photocatalyst was investigated under visible light and sunlight irradiation. The N-doped anatase TiO(2) demonstrated excellent photocatalytic activity under visible light. Under sunlight irradiation, the N doped sample showed slightly higher activity than that of the non-doped sample. PMID- 22257573 TI - Navigation as a source of geometric knowledge: young children's use of length, angle, distance, and direction in a reorientation task. AB - Geometry is one of the highest achievements of our species, but its foundations are obscure. Consistent with longstanding suggestions that geometrical knowledge is rooted in processes guiding navigation, the present study examines potential sources of geometrical knowledge in the navigation processes by which young children establish their sense of orientation. Past research reveals that children reorient both by the shape of the surface layout and the shapes of distinctive landmarks, but it fails to clarify what shape properties children use. The present study explores 2-year-old children's sensitivity to angle, length, distance and direction by testing disoriented children's search in a variety of fragmented rhombic and rectangular environments. Children reoriented themselves in accord with surface distances and directions, but they failed to use surface lengths or corner angles either for directional reorientation or as local landmarks. Thus, navigating children navigate by some but not all of the abstract properties captured by formal Euclidean geometry. While navigation systems may contribute to children's developing geometric understanding, they likely are not the sole source of abstract geometric intuitions. PMID- 22257574 TI - Representational neglect for words as revealed by bisection tasks. AB - In the present study, we showed that a representational disorder for words can dissociate from both representational neglect for objects and neglect dyslexia. This study involved 14 brain-damaged patients with left unilateral spatial neglect and a group of normal subjects. Patients were divided into four groups based on presence of left neglect dyslexia and representational neglect for non verbal material, as evaluated by the Clock Drawing test. The patients were presented with bisection tasks for words and lines. The word bisection tasks (with words of five and seven letters) comprised the following: (1) representational bisection: the experimenter pronounced a word and then asked the patient to name the letter in the middle position; (2) visual bisection: same as (1) with stimuli presented visually; and (3) motor bisection: the patient was asked to cross out the letter in the middle position. The standard line bisection task was presented using lines of different length. Consistent with the literature, long lines were bisected to the right and short lines, rendered comparable in length to the words of the word bisection test, deviated to the left (crossover effect). Both patients and controls showed the same leftward bias on words in the visual and motor bisection conditions. A significant difference emerged between the groups only in the case of the representational bisection task, whereas the group exhibiting neglect dyslexia associated with representational neglect for objects showed a significant rightward bias, while the other three patient groups and the controls showed a leftward bisection bias. Neither the presence of neglect alone nor the presence of visual neglect dyslexia was sufficient to produce a specific disorder in mental imagery. These results demonstrate a specific representational neglect for words independent of both representational neglect and neglect dyslexia. PMID- 22257575 TI - Self-medication of upper gastrointestinal symptoms with hydrotalcite: a noninterventional community pharmacy study on drug usage and patient satisfaction. AB - OBJECTIVE: Acid-related gastrointestinal symptoms are widely prevalent. These complaints are often self-medicated with antacids. For the community pharmacy setting little is known about how patients' perceptions of self-treating symptoms are met, e.g., via patient satisfaction. Such outcomes are difficult to determine in clinical trials, therefore, non-interventional studies (NIS) are one applicable method for gaining data under real-world conditions. This study was conducted to investigate: (1) characteristics of gastrointestinal symptoms and patients' global health status, (2) drug usage and symptom relief, and (3) patient satisfaction with the medication. METHODS: This prospective, cross sectional NIS was performed in cooperation with 137 community pharmacies in Germany. Participants were recruited from customers, after they had purchased the antacid, and were asked to complete a self-administered questionnaire. Patient satisfaction with hydrotalcite was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) on the scales effectiveness, side effects, convenience, and global satisfaction. RESULTS: 548 patients answered the questionnaire. The following symptoms were reported most frequently: heartburn (65%) and acid regurgitation (37%). In comparison to the general population, more participants rated their global health in lower categories, e.g., satisfying (35% vs. 23%) or poor (12% vs. 5%). Drug usage patterns were found to be in accordance with the principles of self-medication. The majority of patients reported a noticeable symptom relief within 15 min after drug intake. TSQM mean scores were high in all four scales; an excellent score was achieved in the scale side effects. Study results also revealed that the self-perceived global health status of the patients had an impact on their global satisfaction with the medication. CONCLUSIONS: This NIS shows that patients (1) are often affected in their global health when suffering from acid-related symptoms, (2) observed a fast symptom relief after drug intake, and (3) are highly satisfied with the antacid hydrotalcite. PMID- 22257576 TI - Bioavailability and pharmacodynamics of two 10-mg estradiol valerate depot formulations following IM single dose administration in healthy postmenopausal volunteers. AB - OBJECTIVE: To establish the bioequivalence (BE) between two i.m. estradiol valerate (E2V) depot formulations, i.e., Estradiol-Depot 10 mg(r) (test) and Progynon Depot-10(r) (reference). To compare the effect of both treatments on the vaginal maturation index and on the increase of the endometrial thickness after administration of both formulations. METHODS: A total of 24 postmenopausal females aged 54.7 +/- 5.35 year (BMI 25.84 +/- 1.98 kg/m2) completed this BE assessment. The investigation was planned and designed as a single center, openlabel, single dose, cross-over study including 2 periods with 2 treatments and 2 sequences. Baseline levels were obtained for all subjects. Single doses of 10-mg E2V of each product were administered and pharmacokinetics and pharmacodynamics were assessed over 2 weeks with a washout period of 4 weeks. A gas chromatographic-mass spectrometric method with negative chemical ionization and selected ion monitoring was applied, after validation, for the determination of estradiol (E2), estrone (E1) and internal standard estradiol-D4 derivatives. The cytology of the vaginal smear (parabasal, intermediate and superficial cells from lateral wall opposite tip of cervix) was assessed by investigation of ~ 200 cells. The vaginal maturation index (VMI) was calculated by the equation: VMI (%) = (superficial cells * 1) (%) + (intermediate cells * 0.5) (%). Endometrial thickness was measured by transvaginal ultrasonic scans and recorded in mm. RESULTS: The geometric means (Gmeans) of the measured values of Cmax and AUC0-t for E2 were 543.5 pg/ ml and 84,734 pg * h/ml for test and 505.7 pg/ml and 82,660 pg * h/ml for reference, whereas those for E1 were 219.0 pg/ml and 38,950 pg * h/ml for test and 204.9 pg/ml and 37,159 pg * h/ml for reference, respectively. The point estimates (PEs) of the Test/ Reference (T/R) mean ratios of the variables Cmax and AUC0-t for E2 (measured values) were 107.3% and 102.5%, respectively. The PEs of the T/R mean ratios of the variables Cmax and AUC0-t for E1 (measured values) were 106.9% and 105.0%, respectively. Median endometrial thickness increased in Period I from baseline levels of ~ 3 mm (Day -2) to ~ 7 mm (Day 21) after administration of both products without returning completely to baseline prior to the next administration. In Period II, median values of 7 mm were also reached (Day 21) after administration of both products. Median vaginal maturation indices increased in Period I from baseline levels of ranging from 45 60% (Day -2) to 86 - 94.5% (Day 21). In Period II maturation indices of >= 90% were calculated as baselines (Day -2) and these levels remained constant until the end of the assessment (Day 21) independently from the products. After 21 days of treatment, test and reference presented practically no differences in terms of their effects on endometrial thickness and vaginal maturation index. CONCLUSIONS: The 95% CIs for the T/R mean ratios of AUC0-t and Cmax for E2 and E1 fell within the acceptance limits of 80 - 125% and therefore bioequivalence could be demonstrated for both formulations. The changes in endometrial thickness and the vaginal maturation index indicated that the pharmacodynamic effect is pronounced already after the first administration and that the effect continued notably for longer time compared to the presence of E2 and E1 in plasma. A 4-week washout phase was insufficient to avoid residual pharmacological effects after the administration of both preparations. PMID- 22257577 TI - Pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD). AB - OBJECTIVE: NVA237 (glycopyrronium bromide) is a once-daily longacting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild-tomoderate COPD patients. METHODS: In this double-blind, parallel-group study, COPD patients were randomized to a 14-day treatment with NVA237 (25, 50, 100 or 200 MUg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14. RESULTS: The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min postinhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0-24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0-24) was approximately dose proportional over the 50 - 200 MUg dose range. The average exposure was 1.4- to 1.7- fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t1/2) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within 1 week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 l/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate. CONCLUSIONS: The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalation. PMID- 22257578 TI - Clinical research: benefits of Bhattacharya modeling. AB - BACKGROUND: Bhattacharya modeling is a Gaussian method recommended by the Food and Agricultural Organization of the United Nations Guidelines for analyzing the eco-system. It is rarely used in clinical research. OBJECTIVE: To investigate the performance of Bhattacharya modeling for clinical data analysis. METHODS: Using as examples simulated vascular lab scores we assessed the performance of the Bhattacharya method. SPSS statistical software is used. RESULTS: 1. The Bhattacharya method better fitted the data from a single sample than did the usual Gaussian curve derived from the mean and standard deviation with 15 vs. 9 cuts. 2. Bhattacharya models demonstrated a significant difference at p < 0.0001 between the data from two parallel-groups, while the usual t-test and Mann Whitney test were insignificant at p = 0.051 and 0.085. 3. Bhattacharya modeling of a histogram suggestive of certain subsets identified three Gaussian curves. CONCLUSIONS: We recommend that Bhattacharya modeling be more often considered in clinical research for the purpose of (1) unmasking normal values of diagnostic tests, (2) improving the p-values of data testing and (3) objectively searching subsets in the data. PMID- 22257579 TI - Clinical and economic impact of a pharmacist-managed i.v.-to-p.o. conversion service for levofloxacin in Taiwan. AB - OBJECTIVE: A pharmacist-managed antibiotic intravenous to oral (i.v.-top. o.) conversion program has been incorporated to minimize unnecessary i.v. antibiotic usage. This study evaluated the clinical and economical impacts of a pharmacist directed i.v.-to-p.o. conversion program for levofloxacin in Taiwan. METHODS: Data was retrospectively collected by chart review during the pre-intervention period (PIP). During the intervention proactive conversion period (PCP), pharmacists reviewed and intervened on all levofloxacin orders. The detailed reimbursements for medications and inpatient expenses from the Bureau of National Health Insurance (NHI), Taiwan were calculated. The clinical impacts during the PIP and PCP were compared with the duration of the i.v. levofloxacin therapy, total used i.v./p.o. ratio levofloxacin, and total length of hospital stay. The financial impact was compared with medication costs and total inpatient expenditures. RESULTS: The mean length of hospital stay was significantly decreased from 27.2 days to 16.1 days (p = 0.001) after the conversion program was implemented. The i.v. over p.o. ratio for DDD was 3.0 +/- 0.6 vs. 2.1 +/- 0.6 for PIP vs. PCP group (p = 0.032). The cost of the levofloxacin was significantly decreased ($ 568.9 +/- 262.9 vs. $ 449.0 +/- 266.4, PIP vs. PCP, p = 0.044). The total inpatient expenditures were also significantly reduced ($ 6,096 +/- 5,164.0 vs. $ 3,649.6 +/- 3, 740.4, PIP vs. PCP, p = 0.017). CONCLUSIONS: The pharmacist managed i.v.-to-p.o. conversion service not only decreased the length of hospital stays, but also produced significant cost savings, both on medication costs and the total inpatient expenditures. This represents strong evidence for implementing the i.v.-to-p.o. conversion service in Taiwan. PMID- 22257580 TI - Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination. AB - OBJECTIVE: Pharmacokinetic (PK) profiles of glimepiride and metformin have been established for the combination drug as well as each agent individually. However, the PK profiles of a combination drug containing glimepiride and sustained release (SR) metformin have not been reported. To compare the pharmacokinetic profiles of glimepiride/SR metformin (2 mg/500 mg) with the PK of immediate release (IR) formulations, an open-label, randomized, 3-period, 3-sequence, 3 treatment, crossover study was conducted in 12 healthy subjects. METHODS: After a single administration of glimepiride/SR metformin 2 mg/500 mg (Treatment) or glimepiride/metformin IR 2 mg/500 mg (Reference 1), or administration of 2 doses of glimepiride/metformin IR 1 mg/250 mg 12 h apart (Reference 2), serial blood samples were collected and drug concentrations determined by liquid chromatography/ tandem mass spectrometry. PK parameters (Cmax and AUC24) for glimepiride and metformin were log-transformed and compared using a mixed-effects model analysis of variance (ANOVA). The mean differences and 95% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios along with the CIs for the ratios. RESULTS: Treatment demonstrated similar systemic exposures for glimepiride; the geometric mean ratio (95% CIs) for glimepiride AUC24 was 1.05 (0.97 - 1.13) for Treatment relative to Reference 1 and 1.08 (1.00 - 1.17) for Treatment relative to Reference 2. The SR formulation showed a delay in the time to reach maximum concentration for metformin from 1.0 - 4.0 h to 4.0 8.0 h and a decreased AUC24 value; the geometric mean ratio for metformin AUC24 was 0.87 (0.74 - 1.03) for Treatment relative to Reference 1 and 0.75 (0.63 - 0.88) for Treatment relative to Reference 2. CONCLUSIONS: This study demonstrates for the first time that fixed-dose glimepiride and SR metformin 2 mg/500 mg shows a PK profile similar to that of glimepiride, but with a delayed time to maximum concentration and slightly decreased bioavailability for metformin compared with the IR fixed-dose combination, in healthy volunteers. PK profiles from this exploratory study will be helpful in designing and conducting further studies in diabetic patients. PMID- 22257581 TI - Absolute bioavailability of tolvaptan and determination of minimally effective concentrations in healthy subjects. AB - Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US) or cardiac edema (Japan). Tolvaptan absolute bioavailability was determined in a single-center, open-label, sequential administration trial in which intravenous (i.v.) placebo (Day -2), i.v. 1 mg tolvaptan (Day 1) and an oral 30 mg tablet (Day 8) were administered to 14 healthy subjects. Urine volume and osmolality were determined on Days -2, 1 and 8 at multiple intervals postdose; 24-h fluid balance was also assessed. On Days 1 and 8, blood samples for tolvaptan were collected for 48 h postdose. Mean absolute bioavailability was determined to be 56% (range 42 - 80). Mean peak tolvaptan concentration at 1 h (end-of-infusion) was 32.7 (range 18 - 45) ng/ml compared to 231 (range 87 - 410) ng/ml for the oral dose. In the 4-h period from start of the 1 mg tolvaptan i.v. infusion, 12 of 14 subjects experienced increased urine volume and decreased urine osmolality; both parameters were affected for 24 h postdose following the 30 mg oral dose. Minimally effective concentrations are rapidly achieved after oral dosing as all subjects had tolvaptan concentrations > 20 ng/ml at 1 h postdose. PMID- 22257582 TI - Modeling insights into Haemophilus influenzae type b disease, transmission, and vaccine programs. AB - In response to the 2007-2009 Haemophilus influenzae type b (Hib) vaccine shortage in the United States, we developed a flexible model of Hib transmission and disease for optimizing Hib vaccine programs in diverse populations and situations. The model classifies population members by age, colonization/disease status, and antibody levels, with movement across categories defined by differential equations. We implemented the model for the United States as a whole, England and Wales, and the Alaska Native population. This model accurately simulated Hib incidence in all 3 populations, including the increased incidence in England/Wales beginning in 1999 and the change in Hib incidence in Alaska Natives after switching Hib vaccines in 1996. The model suggests that a vaccine shortage requiring deferral of the booster dose could last 3 years in the United States before loss of herd immunity would result in increasing rates of invasive Hib disease in children <5 years of age. PMID- 22257583 TI - A concept analysis of competence and its transition in nursing. AB - Competence is one of the most commonly used words in nursing internationally, yet is a nebulous concept defined in diverse ways by different healthcare practitioners. The slippery nature of the concept often exists purely in the eye of the beholder however, the universal principles are deeply rooted in the measurement of the Registered Nurse's (RN) ability to perform effectively. Competence is a simpler thing to define when recognising where it does not exist in the form of incompetence. The aim of this paper is to present finding from a concept analysis that explored various facets of competence, particularly how it has been interpreted, applied and transformed over the years within nurse education in the United Kingdom. The analysis utilised a systematic review of contemporary evidence base based on theory construction by Walker and Avant (2005), a primary concern being to understand the underpinning conceptual principles that define the concept of competence and competency development and how these may be used to inform our understandings. The analysis identified how influential academics and professional bodies have attempted to provide definitions and concluded that it may be the existence of so many of these definitions, which has compounded the conundrum of what competence really is. PMID- 22257584 TI - Developing information literacy skills in pre-registration nurses: an experimental study of teaching methods. AB - AIM: To compare the effectiveness of an online information literacy tutorial with a face-to-face session for teaching information literacy skills to nurses. DESIGN: Randomised control trial. PARTICIPANTS: Seventy-seven first year undergraduate pre-registration diploma nursing students. INTERVENTION: Online in house information literacy tutorial COMPARISON: One hour face-to-face session, covering the same material as the intervention, delivered by the nursing subject librarian. METHODS: Search histories were scored using a validated checklist covering keyword selection, boolean operators, truncation and synonyms. Skills retention was measured at 1 month using the same checklist. Inferential statistics were used to compare search skills within and between groups pre and post-session. RESULTS: The searching skills of first year pre-registration nursing students improve following information literacy sessions (p<0.001), and remain unchanged 1 month later, regardless of teaching method. The two methods produce a comparable improvement (p=0.263). There is no improvement or degradation of skills 1 month post-session for either method (p=0.216). CONCLUSION: Nurses Information literacy skills improve after both face-to-face and online instruction. There is no skills degradation at 1 month post intervention for either method. PMID- 22257585 TI - Delayed onset ureteral obstruction following Deflux(r) injection for vesicoureteral reflux. AB - Endoscopic injection treatment of vesicoureteral reflux is an increasingly common and successful option. Obstruction is an infrequent postoperative complication, occurring in 1% of patients; delayed onset of obstruction is even rarer. There is a paucity of literature describing possible treatments. We present a novel approach by excision of the implanted material. PMID- 22257586 TI - Cardiovascular magnetic resonance in pulmonary hypertension. AB - Pulmonary hypertension represents a group of conditions characterized by higher than normal pulmonary artery pressures. Despite improved treatments, outcomes in many instances remain poor. In recent years, there has been growing interest in the use of cardiovascular magnetic resonance (CMR) in patients with pulmonary hypertension. This technique offers certain advantages over other imaging modalities since it is well suited to the assessment of the right ventricle and the proximal pulmonary arteries. Reflecting the relatively sparse evidence supporting its use, CMR is not routinely recommended for patients with pulmonary hypertension. However, it is particularly useful in patient with pulmonary arterial hypertension associated with congenital heart disease. Furthermore, it has proven informative in a number of ways; illustrating how right ventricular remodeling is favorably reversed by drug therapies and providing explicit confirmation of the importance of the right ventricle to clinical outcome. This review will discuss these aspects and practical considerations before speculating on future applications. PMID- 22257587 TI - Distribution pattern of CART-containing neurons and cells in the human pancreas. AB - Cocaine- and amphetamine-regulated transcript (CART) has been shown to play a critical role in appetite suppression, cell survival, thermoregulation, glucose sensing, stimulation of hormone secretion, as well as for the regulatory function of the islets of Langerhans. Although the principal site of CART synthesis has already been reported, our knowledge of the subject is mainly based on and limited to research conducted on animals owing to difficulties in obtaining human samples. Therefore, the primary goal of the reported study was an attempt to identify and localize CART in healthy human pancreas. Nineteen deceased subjects (donors of organs) with normal pancreas and alimentary tract were used in the study. After determination of brain death and confirmation of death by the relevant doctors committee, pancreas samples, about 1cm long, were collected from each corpse (the same part of the pancreas) after the organs were harvested for transplantation. Paraffin sections were made and stained with hematoxylin and eosin and then subjected to CART immunohistochemistry. In the normal pancreas of human adults, CART is mainly present in both nerve fibers and in nerve cell bodies in pancreatic ganglia. In addition to pancreatic neurons, immunoreactivity to CART was also seen in islet endocrine cells. This is the first report on the presence of CART-IR structures in the normal human pancreas. CART should be now added to the numerous regulatory peptides that are involved in the complex regulation of pancreatic endocrine and exocrine processes. PMID- 22257589 TI - Diabetes, HIV and other health determinants associated with absenteeism among formal sector workers in Namibia. AB - BACKGROUND: As countries in sub-Saharan Africa develop their economies, it is important to understand the health of employees and its impact on productivity and absenteeism. While previous studies have assessed the impact of single conditions on absenteeism, the current study evaluates multiple health factors associated with absenteeism in a large worker population across several sectors in Namibia. METHODS: From March 2009 to June 2010, PharmAccess Namibia conducted a series of cross-sectional surveys of 7,666 employees in 7 sectors of industry in Namibia. These included a self-reported health questionnaire and biomedical screenings for certain infectious diseases and non-communicable disease (NCD) risk factors. Data were collected on demographics, absenteeism over a 90-day period, smoking behavior, alcohol use, hemoglobin, blood pressure, blood glucose, cholesterol, waist circumference, body mass index (BMI), HIV status, and presence of hepatitis B antigens and syphilis antibodies. The associations of these factors to absenteeism were ascertained using negative binomial regression. RESULTS: Controlling for demographic and job-related factors, high blood glucose and diabetes had the largest effect on absenteeism (IRR: 3.67, 95%CI: 2.06-6.55). This was followed by anemia (IRR: 1.59, 95%CI: 1.17-2.18) and being HIV positive (IRR: 1.47; 95%CI: 1.12-1.95). In addition, working in the fishing or services sectors was associated with an increased incidence of sick days (IRR: 1.53, 95%CI: 1.23-1.90; and IRR: 1.70, 95%CI: 1.32-2.20 respectively). The highest prevalence of diabetes was in the services sector (3.6%, 95%CI:-2.5-4.7). The highest prevalence of HIV was found in the fishing sector (14.3%, 95%CI: 10.1 18.5). CONCLUSION: Both NCD risk factors and infectious diseases are associated with increased rates of short-term absenteeism of formal sector employees in Namibia. Programs to manage these conditions could help employers avoid costs associated with absenteeism. These programs could include basic health care insurance including regular wellness screenings. PMID- 22257588 TI - Rates of evolution in stress-related genes are associated with habitat preference in two Cardamine lineages. AB - BACKGROUND: Elucidating the selective and neutral forces underlying molecular evolution is fundamental to understanding the genetic basis of adaptation. Plants have evolved a suite of adaptive responses to cope with variable environmental conditions, but relatively little is known about which genes are involved in such responses. Here we studied molecular evolution on a genome-wide scale in two species of Cardamine with distinct habitat preferences: C. resedifolia, found at high altitudes, and C. impatiens, found at low altitudes. Our analyses focussed on genes that are involved in stress responses to two factors that differentiate the high- and low-altitude habitats, namely temperature and irradiation. RESULTS: High-throughput sequencing was used to obtain gene sequences from C. resedifolia and C. impatiens. Using the available A. thaliana gene sequences and annotation, we identified nearly 3,000 triplets of putative orthologues, including genes involved in cold response, photosynthesis or in general stress responses. By comparing estimated rates of molecular substitution, codon usage, and gene expression in these species with those of Arabidopsis, we were able to evaluate the role of positive and relaxed selection in driving the evolution of Cardamine genes. Our analyses revealed a statistically significant higher rate of molecular substitution in C. resedifolia than in C. impatiens, compatible with more efficient positive selection in the former. Conversely, the genome-wide level of selective pressure is compatible with more relaxed selection in C. impatiens. Moreover, levels of selective pressure were heterogeneous between functional classes and between species, with cold responsive genes evolving particularly fast in C. resedifolia, but not in C. impatiens. CONCLUSIONS: Overall, our comparative genomic analyses revealed that differences in effective population size might contribute to the differences in the rate of protein evolution and in the levels of selective pressure between the C. impatiens and C. resedifolia lineages. The within-species analyses also revealed evolutionary patterns associated with habitat preference of two Cardamine species. We conclude that the selective pressures associated with the habitats typical of C. resedifolia may have caused the rapid evolution of genes involved in cold response. PMID- 22257590 TI - A useful method for observing intracellular structures of free and cultured cells by scanning electron microscopy. AB - Scanning electron microscopy (SEM) using osmium-maceration methods has been used for analyzing the three-dimensional structure of cell organelles in tissue samples, but it has been quite difficult to observe free and cultured cells with this technique. The present study was performed to develop a method that can be applied to free and cultured cells for SEM studies of intracellular structures after osmium maceration. The method was also applied to light microscopy (LM) and to transmission electron microscopy (TEM). HeLa cells and human leukocytes were fixed with a mixture of 0.5% paraformaldehyde and 0.5% glutaraldehyde followed by an additional fixation with 1% osmium tetroxide. These cells were embedded in low melting-point agarose. A temperature-responsive dish was also used for collection of cultured cells before embedding. For LM and TEM, the cell-embedded agarose was further embedded in epoxy resin, and semi- and ultrathin sections were examined conventionally. For SEM, the agarose was freeze-fractured in 50% dimethyl sulfoxide, processed for osmium maceration and observed in a high-resolution SEM. Low-melting-point agarose was useful as an embedding medium for SEM, because it was well preserved during prolonged osmication for SEM. Thus, the fine structure of cell organelles was clearly analyzed by SEM after osmium-maceration treatment. These SEM images could also be compared with those of LM and TEM of the agarose embedded tissues. PMID- 22257599 TI - Antibacterial activity of Thymus maroccanus and Thymus broussonetii essential oils against nosocomial infection - bacteria and their synergistic potential with antibiotics. AB - The aim of this study was to evaluate the antibacterial effect of the association between conventional antibiotics and essential oils (EOs) of endemic Moroccan thyme species, Thymus maroccanus and T. broussonetii, on antibiotic-resistant bacteria involved in nosocomial infections. Synergistic interactions between antibiotics (ciprofloxacin, gentamicin, pristinamycin, and cefixime) and EOs, and between T. maroccanus and T. Broussonetii EOs were determined by the checkerboard test. Serial dilutions of two antimicrobial agents were mixed together so that each row (and column) contained a fixed amount of the first agent and increasing amounts of the second one. The results indicate that the oils had a high inhibitory activity against tested bacteria, except for Pseudomonas aeruginosa. In parallel with the increase of cellular killing, the release of 260nm-absorbing materials from bacterial cells, treated with EOs, increased in response to oil concentration. Out of 80 combinations tested between EOs and antibiotics, 71% showed total synergism, 20% had partial synergistic interaction and 9% showed no effect. Combination with carvacrol, the major constituent of T. maroccanus and T. broussonetii, showed also an interesting synergistic effect in combination with ciprofloxacin. The effect on Gram-positive bacteria was more important than on Gram-negative bacteria. These findings are very promising since the use of these combinations for nosocomial infections treatment is likely to reduce the minimum effective dose of the antibiotics, thus minimizing their possible toxic side effects and treatment cost. However, further investigations are needed to assess the potential for therapeutic application. PMID- 22257600 TI - Mobile phone-assisted basic life support augmented with a metronome. AB - BACKGROUND: Basic life support (BLS) performed by lay rescuers is poor. We developed software for mobile phones augmented with a metronome to improve BLS. STUDY OBJECTIVES: To assess BLS in lay rescuers with or without software assistance. METHODS: Medically untrained volunteers were randomized to run through a cardiac arrest scenario with ("assisted BLS") or without ("non-assisted BLS") the aid of a BLS software program installed on a mobile phone. RESULTS: Sixty-four lay rescuers were enrolled in the "assisted BLS" and 77 in the "non assisted BLS" group. The "assisted BLS" when compared to the "non-assisted BLS" group, achieved a higher overall score (19.2 +/- 7.5 vs. 12.9 +/- 5.7 credits; p < 0.001). Moreover, the "assisted BLS" when compared to the "non-assisted" group checked (64% vs. 27%) and protected themselves more often from environmental risks (70% vs. 39%); this group also called more often for help (56% vs. 27%), opened the upper airway (78% vs. 16%), and had more correct chest compressions rates (44% +/- 38% vs. 14% +/- 28%; all p < 0.001). However, the "assisted BLS" when compared to the "non-assisted BLS" group, was slower in calling the dispatch center (113.6 +/- 86.4 vs. 54.1 +/- 45.1 s; p < 0.001) and starting chest compressions (165.3 +/- 93.3 vs. 87.1 +/- 53.2 s; p < 0.001). CONCLUSIONS: "Assisted BLS" augmented by a metronome resulted in a higher overall score and a better chest compression rate when compared to "non-assisted BLS." However, in the "assisted BLS" group, time to call the dispatch center and to start chest compressions was longer. In both groups, lay persons did not ventilate satisfactorily during this cardiac arrest scenario. PMID- 22257601 TI - An incidental finding? Pneumatosis intestinalis after minor trauma. AB - BACKGROUND: Pneumatosis intestinalis (PI) refers to the identification of air within the wall of the gastrointestinal tract. This finding often marks serious underlying pathology, which can be potentially surgical in nature. However, this process may also occur within a benign context, for example, in patients who are chronically immunosuppressed. The prevalence of benign PI may be greater than previously anticipated, because its discovery is facilitated by the increasingly widespread use of computed tomography (CT) scanning. OBJECTIVES: We will illustrate how widespread use of CT scanning after trauma leads to incidental findings, some of which are difficult to distinguish from acute pathologic findings. We will also discuss the differential diagnosis for PI and the associated clinical significance. CASE REPORT: A female patient with two autoimmune disorders requiring immunosuppression presented after minor trauma. Her clinical stability and benign examination led us to refrain from ordering a full radiographic evaluation, including an abdominal CT scan. She was safely discharged; however, per CT several days later, the incidental finding was made of PI with free intraperitoneal air. These findings after trauma commonly prompt an exploratory laparotomy. However, given her persistent stability, we attributed this to immunosuppression rather than to recent trauma. CONCLUSION: The indications for ordering CT scans after minor trauma must be carefully considered, and incidental findings must be interpreted in the context of the overall clinical scenario. PMID- 22257602 TI - [Appetite regulation: neuroendocrine basis and clinical approaches]. AB - The control of food intake and energy metabolism depends on the complex interaction between energy homeostasis, hedonic control of feeding, and environmental cues. Experimental research in animal models and also the clinical observation of patients with feeding disorders have led to an increased knowledge of the mechanisms that regulate appetite. The hypothalamus is the key component of this network. Hypothalamic nuclei send to and receive signals from the insula, orbitofrontal cortex, nucleus accumbens, dopaminergic reward system, and multiple chemical signals, including peptides and gastrointestinal hormones, to regulate feeding behavior. Recent studies have provided insight into the complex interactions between the homeostatic and hedonic control of feeding behavior, sharing some neurobiological mechanisms with addictions. Identification of potential therapeutic targets will allow the development of useful drugs to treat feeding behavior disorders, such as obesity. PMID- 22257603 TI - [Fever and neutropenia in a 20-year-old woman]. PMID- 22257604 TI - [Spanish cultural adaptation and psychometrical validation of the Treatment Benefit Scale (TBS) in the symptomatic treatment of overactive bladder]. AB - BACKGROUND AND OBJECTIVE: Psychometric validation of the Spanish version of the Treatment Benefit Scale (TBS) scale for assessing the patient's treatment benefit on symptoms associated to overactive bladder. PATIENTS AND METHODS: The Spanish version of the TBS was administered in the final visit of a prospective observational clinic study, after 3 months of a clinical intervention. Overactive bladder patients, above 18 years old, of both genders, with an OAB-V8 score >=8, and able to understand health questionnaires in Spanish were recruited. RESULTS: A total of 246 patients (57.7 years, 76% women) were included. The scale was not completed by 1.7% of patients. Extreme improvement was experienced by 30% of patients, 58% improved, 11% did not change, and 2% worsened after medical intervention. The TBS significantly correlated with the clinical criterion of change; (r=0.743; P<.001). A linear association was observed with changes in both OABq-SF scale domains; severity: F(linear)=33.89, P<.001 and health related quality of life: F(linear)=41.69, P<.001. The TBS was able to distinguish between groups of patients by severity and quality of life, F=11.17, P<.001 and F=13.95, P<.001. CONCLUSION: The Spanish version of the TBS scale has shown good validity psychometric properties in Spanish overactive bladder patients, supporting its use in routinely clinical practice for assessing subjective outputs related to overactive bladder treatment. PMID- 22257605 TI - [Liver damage in heatstroke]. PMID- 22257606 TI - [Relationship between procalcitonin serum levels and complications and outcome of patients with hematological malignancy admitted to Intensive Care Unit]. AB - BACKGROUND AND OBJECTIVE: Patients with hematological neoplasms transferred to an Intensive Care Unit (ICU) for a life-threatening complication have a poor outcome. In these patients, it is crucial to identify clinical and biologic parameters with potential prognostic significance. This study prospectively evaluated the usefulness of serum procalcitonin (PCT) levels as a predictor of complications (infectious or not) and outcome in these patients. PATIENTS AND METHOD: One hundred patients with hematological malignancy were admitted to the ICU from October 2004 until August 2009. In 59 of them serum PCT levels were daily measured from the ICU admission until a maximum period of 10 consecutive days. RESULTS: Hematological diseases were acute leukemia (n=30), lymphoma and other lymphoproliferative disorders (n=18), multiple myeloma (n=7) and other (n=4). Twenty-five patients (42%) had received hematopoietic stem cell transplantation. Thirty-seven patients (63%) presented neutropenia. Those patients who could not be discharged alive from the ICU presented higher PCT levels on days 1, 2 and 3. PCT levels were significantly higher in those patients with neutropenia or septic shock or other causes of hemodynamic instability. The presence of a microbiologically documented infection, respiratory failure or the need of mechanical ventilation support did not significantly affect PCT levels in this study. CONCLUSIONS: Early serum PCT levels measurement might be useful for predicting mortality in patients with hematological malignancy requiring advanced life support. PMID- 22257607 TI - [Percutaneous coronary revascularization in patients with renal insufficiency]. AB - BACKGROUND AND OBJECTIVE: An ideal strategy of percutaneous coronary revascularization in patients with renal insufficiency has not been established yet. Our aim was to compare in this group the clinical results of bare metal stents and drug-eluting stents, and identify predictors. PATIENTS AND METHOD: In a group of 200 patients with renal disease, 93 received bare metal stents and 107 drug-eluting stents; for over 2 years we studied rates of a combined event: death, non fatal myocardial infarction, or target lesion revascularization. RESULTS: We did not identify differences in the combined event. With multivariate analysis, peripheral arterial disease, left ventricular ejection fraction <45% and treatment with statins were predictor factors. CONCLUSIONS: We had no evidence of the superiority of any type of stent in the revascularization in patients with chronic renal insufficiency. PMID- 22257608 TI - [New alternatives to liver transplantation: transplantation of hepatocytes]. PMID- 22257610 TI - [Streptococcus bovis bacteremia. What explorations should be performed?]. PMID- 22257609 TI - [Guidelines for diagnosis, treatment and monitoring of primary immune thrombocytopenia]. AB - The consensus document on the diagnosis, treatment and monitoring of primary immune thrombocytopenia was developed in 2010 by specialists with recognized expertise in this disease under the auspices of the Spanish Society of Hematology and Hemotherapy and the Spanish Society of Pediatric Hematology and Oncology, with the aim to adapt to Spain the recommendations of the recently published international consensus documents. The decision to start treatment is based on bleeding manifestations and platelet count (<20*10(9)/L). The first-line treatment is corticosteroids, albeit for a limited period of 4-6 weeks. The addition of intravenous immunoglobulin is reserved to patients with severe bleeding. Splenectomy is the most effective second-line treatment. For patients refractory to splenectomy and those with contraindications or patient refusal, the new thrombopoietic agents are the drugs of choice due to their efficacy and excellent safety profile. The other treatment options have highly variable response rates, and the absence of controlled studies does not allow to establish clear recommendations. Monitoring should be individualized. In patients without active treatment, blood counts are recommended every 3-6 months, and the patient should be instructed to consult in case of bleeding, surgery or invasive procedure and pregnancy. In most of the pediatric population, the disease tends to spontaneous remission. High-dose corticosteroids in short course and intravenous immunoglobulin are the treatment of choice. Second- and further-line treatments should be monitored in specialized centers. PMID- 22257611 TI - [Profile of lay members of ethics committees in Catalonia (Spain)]. PMID- 22257612 TI - Prefrontal cortex dysfunction and 'Jumping to Conclusions': bias or deficit? AB - The 'beads task' is used to measure the cognitive basis of delusions, namely the 'Jumping to Conclusions' (JTC) reasoning bias. However, it is not clear whether the task merely taps executive dysfunction - known to be impaired in patients with schizophrenia - such as planning and resistance to impulse. To study this, 19 individuals with neurosurgical excisions to the prefrontal cortex, 21 unmedicated adults with Attention Deficit Hyperactivity Disorder (ADHD), and 25 healthy controls completed two conditions of the beads task, in addition to tests of memory and executive function as well as control tests of probabilistic reasoning ability. The results indicated that the prefrontal lobe group (in particular, those with left-sided lesions) demonstrated a JTC bias relative to the ADHD and control groups. Further exploratory analyses indicated that JTC on the beads task was associated with poorer performance in certain executive domains. The results are discussed in terms of the executive demands of the beads task and possible implications for the model of psychotic delusions based on the JTC bias. PMID- 22257613 TI - Improving safe and appropriate use of antibiotics. PMID- 22257614 TI - SF-6D utility index as measure of minimally important difference in health status change. AB - OBJECTIVES: To combine anchor- and distribution-based approaches to identify minimally important differences (MIDs) for the short-form six-dimension utility index (SF-6D) and to identify variables associated with self-reported health status change. DESIGN: Descriptive, exploratory, nonexperimental study. SETTING: United States between April 1, 1999, and October 31, 1999. PATIENTS: 2,317 participants of SADD-Sx (Study of Antihypertensive Drugs and Depressive Symptoms), aged 50 years or older and with hypertension and coronary artery disease. INTERVENTION: Patients were randomized into a verapamil SR- or atenolol led hypertensive treatment strategy and mailed baseline and 1-year surveys. MAIN OUTCOME MEASURE: SF-6D utility scores for patients completing both surveys. RESULTS: The pooled mean (+/-SD) MID change on the SF-6D of patients whose health status minimally changed was 0.035 +/- 0.095. The anchor-based change scores had a median value of 0.036 (interquartile range -0.03 to 0.10). One-third and one half of the SD of SF-6D change scores were 0.035 and 0.053, respectively. Whites were less likely to report minimally improved health status compared with nonwhites (odds ratio 0.59 [95% CI 0.40-0.88]). Change in SF-6D scores improved prediction of health status change. CONCLUSION: We recommend using the MID range based on all patients combined (-0.03 to 0.10) to interpret SF-6D scores. These estimates can be used in conjunction with other measures of efficacy to determine meaningful changes. SF-6D demonstrates potential utility in predicting minimally important improvement or worsening among patients receiving different pharmacologic medications. PMID- 22257615 TI - Pharmacists' knowledge, attitudes, and practices regarding influenza vaccination and treatment of pregnant women. AB - OBJECTIVES: To understand pharmacists' knowledge, attitudes, and practices regarding vaccination and treatment of pregnant women for seasonal influenza and pandemic 2009 influenza A (H1N1). DESIGN: Descriptive, exploratory, nonexperimental study. SETTING: United States between January 21, 2010, and February 9, 2010. PARTICIPANTS: 606 pharmacists who participated in the American Pharmacists Association (APhA) Immunization Certificate Training Program and practice in chain, supermarket, mass merchandise, and independent pharmacies. INTERVENTION: Electronic survey sent by APhA to 7,356 pharmacists who had participated in its Immunization Certificate Training Program. MAIN OUTCOME MEASURES: Pharmacists' knowledge, attitudes, and practices regarding vaccination and antiviral treatment of pregnant women for seasonal and H1N1 influenza. RESULTS: Respondents were more likely to recognize that pregnant women are at an increased risk associated with H1N1 influenza (85%) than to recognize the increased risk associated with seasonal influenza (78%). However, respondents were less likely to believe that they have an important role in vaccinating pregnant women compared with the general public (82% vs. 97%) and less likely to agree that 2009 H1N1 vaccine was safe during pregnancy compared with the seasonal influenza vaccine (78% vs. 87%). Pharmacists who had been vaccinated themselves were more likely to recommend vaccination for pregnant patients. Only 38% believed that antiviral medications such as oseltamivir can be given during pregnancy because the benefits outweigh the risks. However, in response to case studies of pregnant women who were candidates for antiviral medications, respondents indicated that they would take extraordinary steps to ensure that pregnant women were either referred for medical assessment or for assistance in obtaining prescribed antiviral medications. CONCLUSION: Education efforts that focus on the effectiveness and safety of influenza vaccination during pregnancy and the benefits of treating pregnant women with confirmed or suspected influenza with antiviral medications may be useful in improving pharmacists' support of pharmaceutical interventions to reduce the impact of influenza in pregnant women. Pharmacists' personal decisions regarding vaccination may be a marker for their overall assessment of risks and benefits and may influence their recommendations for pregnant patients. PMID- 22257616 TI - Prevalence and predictors of human papillomavirus vaccination in adolescent girls. AB - OBJECTIVES: To determine the prevalence and predictors of human papillomavirus (HPV) vaccination in adolescent girls who were recommended to receive the vaccine by their health care providers. DESIGN: Cross-sectional study. SETTING: United States in 2007-08. PARTICIPANTS: Parents or guardians most knowledgeable about health and health care of adolescent girls aged 12 to 17 years participating in the 2007 National Survey of Children's Health (NSCH). INTERVENTION: NCSH was a population-based telephone survey using a complex probability sampling design. MAIN OUTCOME MEASURES: Prevalence of HPV vaccination in adolescent girls who were recommended to receive the HPV vaccine and predisposing, enabling, and need factors associated with HPV vaccination. RESULTS: Of 12.38 million adolescent girls aged 12 to 17 years, 3.69 million (29.76%) were recommended to receive the HPV vaccine by their health care provider. The majority who received the HPV vaccine recommendation were 13 to 17 years of age (83%), were white (71%), and had one or more preventive visits (94%). Among those for whom the HPV vaccine was recommended, 48.75% (95% CI 45.37-52.13) received the vaccine. Multivariate logistic regression analysis of those who were recommended revealed that enabling and predisposing factors were significantly associated with the HPV vaccination. Children living at 101% to 200% of the Federal Poverty Level (odds ratio 0.54 [95% CI 0.30-0.98]) and children in households with two or more adults (0.51 [0.33-0.80]) were negatively associated with HPV vaccination, whereas children with any preventive medical care visit(s) (2.28 [1.36-3.84]) in the previous year were positively associated with HPV vaccination. CONCLUSION: Nearly one-half of adolescent girls received the HPV vaccine among those who were recommended by their health care provider. The study finding emphasizes the importance of predisposing and enabling factors for HPV vaccination. Policy and education efforts can focus on these factors to improve HPV vaccination rates. PMID- 22257617 TI - Identifying discrepancies in electronic medical records through pharmacist medication reconciliation. AB - OBJECTIVES: To describe the types and causes of medication discrepancies in the electronic medical record identified by pharmacist medication reconciliation during outpatient medical visits and to identify patient characteristics associated with the presence of discrepancies. DESIGN: Observational case series study. SETTING: Indigent primary care clinic in Pittsburgh, PA, from April 2009 to May 2010. PATIENTS: 219 adults presenting for follow-up medical visits and self-reporting medication use. INTERVENTION: Medication reconciliation as part of patient interview and concurrent chart review. MAIN OUTCOME MEASURES: Frequency, types, and reasons for medication discrepancies and demographic variables, patient knowledge, and adherence. RESULTS: Of 219 patients interviewed, 162 (74%) had at least one discrepancy. The most common type of discrepancy was an incorrect medication documented on the chart. The most common reasons included over-the-counter (OTC) use of medications and patients not reporting use of medications. The presence of one or more medication discrepancies was associated with the use of three or more medications. Patient factors such as gender, age, and race were not associated with discrepancies. Patients able to recall the strength for more than 75% of their medications had fewer discrepancies, while knowledge of the medication name, indication, or regimen had no association with discrepancies. CONCLUSION: Pharmacists play a critical role in identifying discrepancies between charted medication lists and self-reported medication use, independent of adherence. Inaccuracies in charted medications are frequent and often are related to use of OTC therapies and lack of communication and documentation during physician office visits. Knowledge of patient-related variables and other reasons for discrepancies may be useful in identifying patients at greatest risk for discrepancies and interventions to prevent and resolve them. PMID- 22257618 TI - Pharmacy provision of influenza vaccinations in medically underserved communities. AB - OBJECTIVE: To demonstrate the extent to which a community pharmacy can provide influenza immunizations in communities designated as medically underserved. METHODS: This retrospective study examined the number of influenza immunizations administered and populations served in areas with limited access to health care by Walgreens pharmacies during the 2009-10 influenza season. RESULTS: More than 43% of the U.S. population resides in medically underserved areas (MUAs), and our results show that Walgreens pharmacies served nearly one-half of this population. Nationwide, more than one-third of influenza immunizations were administered by pharmacies located in MUAs. In states with the highest proportion of their population in MUAs, the percentage of influenza vaccines provided in MUAs was much greater (up to 77.1%). CONCLUSION: Community pharmacies are convenient and accessible venues at which patients can obtain seasonal influenza vaccines and other immunizations. They are well-positioned throughout the country, including in areas that are otherwise medically underserved. These factors help community pharmacists eliminate one of the most important barriers to vaccination: accessibility. PMID- 22257619 TI - Preventing and resolving drug therapy problems by understanding patients' medication experiences. AB - OBJECTIVES: To provide tools for pharmacists to uncover patients' medication experiences and to discuss strategies that medication therapy management (MTM) pharmacists use to prevent and resolve drug therapy problems rooted in patients' medication experiences. DESIGN: Qualitative study. SETTING: Health care delivery system in the Minneapolis/Saint Paul, MN, area from January to October 2010. PARTICIPANTS: 10 MTM pharmacists. INTERVENTION: Thematic analysis of data from a focus group of MTM pharmacists and an MTM pharmacist's practice diary. RESULTS: Patients' medication experiences were revealed as a foundational aspect of MTM pharmacists' daily practices because they had to take these experiences into consideration to be effective practitioners. According to MTM pharmacists, patients express attitudes toward drug therapy in many different ways, thereby affecting how each patient takes his/her medications. Patients' medication experiences often were at the root of drug therapy problems (DTPs). From MTM pharmacists' examples, we identified DTPs at the root of patients' medication experiences and several strategies used by pharmacists to address patients' needs and concerns regarding medications. MTM pharmacists approached patients in a nonjudgmental way so that patients would feel comfortable sharing their perspectives and goals. After understanding patients' motivations and the basis of their attitudes and decision making, pharmacists could negotiate the process of behavioral change, if needed. CONCLUSION: If pharmacists understand patients' medication experiences, they may be able to address and resolve DTPs to ultimately improve therapeutic outcomes and reduce adverse events. PMID- 22257620 TI - Hospital emergency preparedness: Push-POD operation and pharmacists as immunizers. AB - OBJECTIVE: To describe Montefiore Medical Center's participation in a point-of distribution (POD) exercise in which pharmacists were drilled on the ability to provide immunizations in the face of an emergency. SETTING: New York City on October 9, 2007. SUMMARY: Rapid and appropriate response to a terrorism event can limit morbidity and mortality. After the events of September 11, 2001, the New York City Department of Health and Mental Hygiene (DOHMH) recognized the need to develop a uniform procedure in the case of a potential health disaster. During the fiscal year occurring between September 1, 2006, and August 31, 2007, DOHMH requested that all citywide hospitals participate in a POD drill. All participating hospitals were required to have a team of five health professionals, including one pharmacist, one physician, two nurses, and another member of the institution. The drill was to be conducted within a 4-hour interval to simulate a situation of mass prophylaxis using influenza as a surrogate vaccine or pharmaceutical agent needed in the event of a public health emergency. MAIN OUTCOME MEASURE: Number of health care workers immunized in 4-hour period. RESULTS: During the 4-hour period, the team was able to immunize 942 heath care workers. Predicting a 24/7 operation in the event of a biological terrorism event, the Push-POD operation would have the capacity to immunize 12,000 health care workers-the approximate population of the hospital-in 48 hours. This exercise was replicated for the 2008 influenza program, and the results were identical. CONCLUSION: By allowing pharmacists to expand their scope of practice, New York State will inevitably see a drastic improvement in its adult immunization rates for influenza and pneumococcal vaccinations through greater public awareness and expanded vaccine access. PMID- 22257621 TI - Medications and breast-feeding: Current concepts. AB - OBJECTIVES: To describe the various factors that come into play when a breast feeding mother is taking medications, including use of prescription drugs, over the-counter medications, recreational drugs, galactogogues, and herbal remedies and to provide a framework used for counseling breast-feeding women. SETTING: Community and hospital pharmacy and health care settings. PRACTICE DESCRIPTION: Consultative services provided to breast-feeding mothers who had been prescribed or were using medications. MAIN OUTCOME MEASURES: Use of pharmacokinetic factors, maternal and child factors, a list of questions to ask breast-feeding mothers, and a stepwise approach to counsel breast-feeding mothers on the compatibility of using medications while breast-feeding. RESULTS: By positive intervention of pharmacists and health care providers, up to 1 million breast-feeding mothers, who must use medications, can continue to breast-feed while taking medications. CONCLUSION: Objectively weighing the benefits of drugs and breast-feeding versus the risks of drugs and not breast-feeding, in most cases, allows for pharmacists to give current and practical advice to mothers and other health professionals who counsel mothers. PMID- 22257625 TI - Nicotine conjugate vaccines: A novel approach in smoking cessation. PMID- 22257626 TI - Boceprevir, telaprevir, and rilpivirine hydrochloride. PMID- 22257627 TI - Telephonic education of inhaler technique, antiretroviral prescribing for black and white patients, and progression to insulin. PMID- 22257629 TI - [Indirect comparisons]. PMID- 22257630 TI - Photodegradation of wood at elevated temperature: colour change. AB - The purpose of this investigation was to evaluate the effect of elevated temperature on the photodegradation of solid wood. The work presented here, dealt with the changes of colour during the degradation process. Wood samples were irradiated by mercury vapour lamp at 80 degrees C and at 30 degrees C to screen out the effect of thermal decomposition during photodegradation. Results demonstrated that the same light irradiation resulted in considerably greater redness increase at 80 degrees C than at 30 degrees C. Pine samples showed 57% higher redness change at 80 degrees C than at 30 degrees C during the 200h light exposure. Corresponding data for spruce, ash and poplar were 33%, 40% and 15%, respectively. Results indicated that the extractive content has an important role in thermal decomposition during photodegradation. The elevated environmental temperature did not affect yellowness. PMID- 22257631 TI - Genotoxicity of citrus wastewater in prokaryotic and eukaryotic cells and efficiency of heterogeneous photocatalysis by TiO(2). AB - The presence of (+/-)alpha-pinene, (+)beta-pinene, (+)3-carene, and R-(+)limonene terpenes in wastewater of a citrus transformation factory was detected and analyzed, in a previous study, by using Solid Phase Micro-extraction (SPME) followed by GC analyses. Purpose of that research was to compare the genotoxic responses of mixtures of terpenes with the genotoxicity of the individual compounds, and the biological effects of actual wastewater. Genotoxicity was evaluated in the Salmonella reversion assay (Ames test) and in V79 cells by Comet assay. Ames tests indicated that the four single terpenes did not induce an increase of revertants frequency. On the contrary, the mixtures of terpenes caused, in the presence of metabolic activation, a highly significant increase of the revertants in TA100 strain in comparison to the control. The Comet assay showed a significant increase in DNA damage in V79 cells treated for 1h with single or mixed terpenes. Moreover, the actual wastewater was found highly genotoxic in bacterial and mammalian cells. Photocatalytic tests completely photodegraded the pollutants present in aqueous wastewater and the initial high genotoxicity of samples of wastewater collected during the photocatalytic run, was completely lose in 3h of irradiation. PMID- 22257632 TI - Aberrant expression of the apoptosis-related proteins BAK and MCL1 in T cells in multiple sclerosis. AB - Pathogenic T cells of multiple sclerosis (MS) patients have been suggested to be endowed with an increased resistance to apoptosis, contributing to their increased survival. We report herein increased levels of the anti-apoptotic MCL1 protein and its half-life in activated lymphocytes of MS patients, which were not associated with differences in MCL1 RNA levels or with alterations in the expression levels of the known E3 ligases of MCL1-beta-TrCP and HUWE1. Concomitantly, the expression levels of the pro-apoptotic protein BAK were decreased in MS patients at relapse. These findings suggest the dysregulation of the apoptosis-related proteins MCL1 and BAK in MS. PMID- 22257633 TI - A complex 'mRNA degradation code' controls gene expression during animal development. AB - Current understanding of the molecular mechanisms underlying mRNA degradation indicates that specific mRNA degradation rates are primarily encoded within the mRNA message itself in the form of cis-regulatory elements bearing particular primary sequences and/or secondary-structures. Such control elements are operated by RNA-binding proteins (RBPs) and/or miRNA-containing complexes. Based on the large number of RBPs and miRNAs encoded in metazoan genomes, their complex developmental expression and that specific RBP and miRNA interactions with mRNAs can lead to distinct degradation rates, I propose that developmental gene expression is shaped by a complex 'mRNA degradation code' with high information capacity. Localised cellular events involving the modification of RBP and/or miRNA target sequences in mRNAs by alternative polyadenylation added to the activation of specific RBP and miRNA activities via cell signalling are predicted to further expand the capacity of the mRNA degradation code by coupling it to dynamic events experienced by cells at specific spatiotemporal coordinates within the developing embryo. PMID- 22257634 TI - Proteomic analysis of rat retina after methanol intoxication. AB - OBJECTIVE: In order to investigate markers of toxic injury and elucidate the mechanisms underlying methanol intoxication at the protein level, proteomics technology was applied to study variations in retinal protein expression between normal rats and rat models of methanol intoxication. METHODS: Seven rats were administered saline and methanol respectively by gavage. After seven days, retinal function was assessed by electroretinography and retinal proteins were extracted and separated by two-dimensional gel electrophoresis. The gels were then stained with AgNO3 and analyzed with Pdquest software. The differential expression of proteins was analyzed by MALDI-TOF-TOF MS, and related proteins were searched in a protein database. RESULTS: Twenty-eight spots with significant differences were found, 24 of which were successfully identified. Specifically, there were 14 increased expression proteins, such as aldehyde dehydrogenase, tropomyosin alpha-1 chain, myosin light chain, and crystallin family proteins. There were 10 decreased expression ones, such as glyceraldehyde-3-phosphate dehydrogenase, recoverin, ATP synthase alpha subunit in rats with methanol toxicity. CONCLUSIONS: Retinal function was greatly destroyed upon methanol intoxication. Several key proteins were up- or down-regulated upon induced retinal toxicity, indicating that there are other mechanisms underlying methanol poisoning besides oxidative injury. Together, this data provides insight and knowledge for future studies in this field. PMID- 22257635 TI - Advanced squamous cell carcinoma involving both upper and lower lips and oral commissure with simultaneous reconstruction by local flap: a case report. AB - INTRODUCTION: Squamous cell carcinoma is one of the most common malignant tumors of the skin and oral mucosa. However, squamous cell carcinoma involving near total upper and lower lip and oral commissure is rarely seen in the English literature. Simultaneous reconstruction of the upper and lower lips has been inconclusive and presents a challenge to the surgeon. We report such a case and outline our simultaneous reconstruction with local flaps. To the best of our knowledge this has never been reported. CASE PRESENTATION: A 73-year-old Thai woman presented with a large rapidly growing squamous cell carcinoma involving the upper lip, lower lip, left oral commissure and left cheek. En bloc resection of upper lip, lower lip, left oral commissure and buccal region was performed. Left radical neck dissection and right modified neck dissection were performed. Reconstruction of the upper lip with a left nasolabial-cheek cervicofacial rotational-advancement flap and right cheek advancement with perialar crescent flap was performed. The lower lip was reconstructed with bilateral labiomental advancement flaps. CONCLUSIONS: Squamous cell carcinoma can grow rapidly and spread along the orbicularis oris muscle and across the oral commissure to the opposite lip. In advanced cancer, multimodal treatment is necessary. No gold standard in the reconstruction of both upper and lower lips has been established. We report the case of an advanced squamous cell carcinoma involving both the upper lip, lower lip, left oral commissure and buccal area and simultaneous reconstruction with local flap coverage that, to the best of our knowledge, has never been reported. PMID- 22257636 TI - A systematic review of compliance to oral nutritional supplements. AB - BACKGROUND & AIMS: Oral nutritional supplements (ONS) play a key role in the management of malnutrition. This systematic review examined patients' compliance with ONS across healthcare settings and the influence of patient and ONS-related factors. METHODS: A systematic review identified 46 studies (n = 4328) of ONS in which data on compliance (% of prescribed quantity of ONS consumed) was available. Pooled mean %compliance was assessed overall and according to study design and healthcare setting. Inter-relationships between compliance and ONS related and patient-related factors, and total energy intake were assessed. RESULTS: Overall mean compliance with ONS was 78% (37%-100%; 67% hospital, 81% community; overall mean ONS intake 433 kcal/d). Percentage compliance was similar in randomised (79%) and non-randomised (77%) trials, with little variation between diagnostic groups. Compliance across a heterogeneous group of unmatched studies was positively associated with higher energy-density ONS and greater ONS and total energy intakes, negatively associated with age, and unrelated to amount or duration of ONS prescription. CONCLUSIONS: This systematic review suggests that compliance to ONS is good, especially with higher energy-density ONS, resulting in improvements in patients' total energy intakes that have been linked with clinical benefits. Further research is required to address the compliance and effectiveness of other common methods of oral nutritional support. PMID- 22257637 TI - Early detection of pandemic (H1N1) 2009, Bangladesh. AB - To explore Bangladesh's ability to detect novel influenza, we examined a series of laboratory-confirmed pandemic (H1N1) 2009 cases. During June-July 2009, event based surveillance identified 30 case-patients (57% travelers); starting July 29, sentinel sites identified 252 case-patients (1% travelers). Surveillance facilitated response weeks before the spread of pandemic (H1N1) 2009 infection to the general population. PMID- 22257638 TI - New Editor-in-Chief: Manuel Espinosa-Urgel. PMID- 22257639 TI - Integration of morphogen signalling within the growth regulatory network. AB - The need to coordinate patterning and growth has been appreciated for many years. The logic that enables seamless integration of the relevant inputs is beginning to be elucidated, particularly in wing imaginal discs of Drosophila. In this tissue, multiple regulatory layers involving the two morphogens Wingless and Dpp, the wing-specific determinant, Vestigial, and the Hippo pathway, converge to regulate growth. Intricate cross-regulation between these components may explain why, at the local level, there is no direct correlation between growth and the graded signalling activity of Wingless and Dpp, despite the requirement of these two pathways for growth. PMID- 22257640 TI - Comparison of coconut water and a carbohydrate-electrolyte sport drink on measures of hydration and physical performance in exercise-trained men. AB - BACKGROUND: Sport drinks are ubiquitous within the recreational and competitive fitness and sporting world. Most are manufactured and artificially flavored carbohydrate-electrolyte beverages. Recently, attention has been given to coconut water, a natural alternative to manufactured sport drinks, with initial evidence indicating efficacy with regard to maintaining hydration. We compared coconut water and a carbohydrate-electrolyte sport drink on measures of hydration and physical performance in exercise-trained men. METHODS: Following a 60-minute bout of dehydrating treadmill exercise, 12 exercise-trained men (26.6 +/- 5.7 yrs) received bottled water (BW), pure coconut water (VitaCoco(r): CW), coconut water from concentrate (CWC), or a carbohydrate-electrolyte sport drink (SD) [a fluid amount based on body mass loss during the dehydrating exercise] on four occasions (separated by at least 5 days) in a random order, single blind (subject and not investigators), cross-over design. Hydration status (body mass, fluid retention, plasma osmolality, urine specific gravity) and performance (treadmill time to exhaustion; assessed after rehydration) were determined during the recovery period. Subjective measures of thirst, bloatedness, refreshed, stomach upset, and tiredness were also determined using a 5-point visual analog scale. RESULTS: Subjects lost approximately 1.7 kg (~2% of body mass) during the dehydrating exercise and regained this amount in a relatively similar manner following consumption of all conditions. No differences were noted between coconut water (CW or CWC) and SD for any measures of fluid retention (p > 0.05). Regarding exercise performance, no significant difference (p > 0.05) was noted between BW (11.9 +/- 5.9 min), CW (12.3 +/- 5.8 min), CWC (11.9 +/- 6.0 min), and SD (12.8 +/- 4.9 min). In general, subjects reported feeling more bloated and experienced greater stomach upset with the CW and CWC conditions. CONCLUSION: All tested beverages are capable of promoting rehydration and supporting subsequent exercise. Little difference is noted between the four tested conditions with regard to markers of hydration or exercise performance in a sample of young, healthy men. Additional study inclusive of a more demanding dehydration protocol, as well as a time trial test as the measure of exercise performance, may more specifically determine the efficacy of these beverages on enhancing hydration and performance following dehydrating exercise. PMID- 22257641 TI - Increased sensitivity of next generation sequencing-based expression profiling after globin reduction in human blood RNA. AB - BACKGROUND: Transcriptome analysis is of great interest in clinical research, where significant differences between individuals can be translated into biomarkers of disease. Although next generation sequencing provides robust, comparable and highly informative expression profiling data, with several million of tags per blood sample, reticulocyte globin transcripts can constitute up to 76% of total mRNA compromising the detection of low abundant transcripts. We have removed globin transcripts from 6 human whole blood RNA samples with a human globin reduction kit and compared them with the same non-reduced samples using deep Serial Analysis of Gene Expression. RESULTS: Globin tags comprised 52-76% of total tags in our samples. Out of 21,633 genes only 87 genes were detected at significantly lower levels in the globin reduced samples. In contrast, 11,338 genes were detected at significantly higher levels in the globin reduced samples. Removing globin transcripts allowed us to also identify 2112 genes that could not be detected in the non-globin reduced samples, with roles in cell surface receptor signal transduction, G-protein coupled receptor protein signalling pathways and neurological processes. CONCLUSIONS: The reduction of globin transcripts in whole blood samples constitutes a reproducible and reliable method that can enrich data obtained from next generation sequencing-based expression profiling. PMID- 22257642 TI - The effect of facial blood flow on ratings of blushing and negative affect during an embarrassing task: preliminary findings. AB - Expecting to blush is a common source of social anxiety, and is associated with heightened perceptions of blushing and embarrassment. To assess whether sensory cues associated with heightened facial blood flow are an additional source of anxiety, the vasodilator niacin (100mg) or placebo was administered double-blind to 33 participants, and facial blood flow was investigated when they sang a children's song. Vasodilatation during singing was greater in the niacin than placebo condition, and niacin-evoked flushing and increases in pulse rate were greater in participants with high than low fear of negative evaluation. Nevertheless, ratings of embarrassment, anxiety, blushing and facial heat were similar in both drug conditions. This dissociation implies that cognitive appraisals or negative affect overrode more subtle physiological cues of blushing during embarrassment. Clarifying how judgments about blushing are made could be crucial for correcting faulty assumptions about blushing in people who are frightened of this response. PMID- 22257643 TI - Ethnic discrimination prevalence and associations with health outcomes: data from a nationally representative cross-sectional survey of secondary school students in New Zealand. AB - BACKGROUND: Reported ethnic discrimination is higher among indigenous and minority adult populations. There is a paucity of nationally representative prevalence studies of ethnic discrimination among adolescents. Experiencing ethnic discrimination has been associated with a range of adverse health outcomes. NZ has a diverse ethnic population. There are health inequalities among young people from Maori and Pacific ethnic groups. METHODS: 9107 randomly selected secondary school students participated in a nationally representative cross-sectional health and wellbeing survey conducted in 2007. The prevalence of ethnic discrimination by health professionals, by police, and ethnicity-related bullying were analysed. Logistic regression was used to examine the associations between ethnic discrimination and six health/wellbeing outcomes: self-rated health status, depressive symptoms in the last 12 months, cigarette smoking, binge alcohol use, feeling safe in ones neighbourhood, and self-rated school achievement. RESULTS: There were significant ethnic differences in the prevalences of ethnic discrimination. Students who experienced ethnic discrimination were less likely to report excellent/very good/good self-rated general health (OR 0.51; 95% CI 0.39, 0.65), feel safe in their neighbourhood (OR 0.48; 95% CI 0.40, 0.58), and more likely to report an episode of binge drinking in the previous 4 weeks (OR 1.77; 95% CI 1.45, 2.17). For all these outcomes the odds ratios for the group who were 'unsure' if they had experienced ethnic discrimination were similar to those of the 'yes' group.Ethnicity stratified associations between ethnic discrimination and the depression, cigarette smoking, and self-rated school achievement are reported. Within each ethnic group participants reporting ethnic discrimination were more likely to have adverse outcomes for these three variables. For all three outcomes the direction and size of the association between experience of ethnic discrimination and the outcome were similar across all ethnic groups. CONCLUSIONS: Ethnic discrimination is more commonly reported by Indigenous and minority group students. Both experiencing and being 'unsure' about experiencing ethnic discrimination are associated with a range of adverse health/wellbeing outcomes. Our findings highlight the progress yet to be made to ensure that rights to be free from ethnic discrimination are met for young people living in New Zealand. PMID- 22257644 TI - Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcgammaRIIb with Fc-engineered antibody. AB - BACKGROUND: Sequestration of IgE to prevent its binding to high-affinity IgE receptor FcepsilonRI on basophils and mast cells is an effective therapy for allergic asthma. IgE production requires differentiation of activated IgE(+) B cells into plasma cells upon allergen sensitization. B-cell receptor signaling is suppressed by the inhibitory IgG Fc receptor FcgammaRIIb; therefore, we reasoned that a therapeutic antibody that coengages FcgammaRIIb and IgE B-cell receptor would not only sequester IgE but also suppress its production by blocking IgE(+) B-cell activation and differentiation to IgE-secreting plasma cells. OBJECTIVE: To explore the effects of IgE sequestration versus IgE suppression by comparing omalizumab to FcgammaRIIb-optimized anti-IgE antibodies in humanized mouse models of immunoglobulin production. METHODS: By using a murine anti-IgE antibody as a template, we humanized, increased IgE binding, and modified its Fc domain to increase affinity for FcgammaRIIb. We next compared effects of this antibody (XmAb7195) versus omalizumab on the secretion of IgE and other isotypes in human PBMC cultures and in PBMC-engrafted severe combined immunodeficiency mice. RESULTS: Relative to omalizumab, XmAb7195 has a 5-fold higher affinity for human IgE and more than 400-fold higher affinity for FcgammaRIIb. In addition to sequestering soluble IgE, XmAb7195 inhibited plasma cell differentiation and consequent human IgE production through coengagement of IgE B-cell receptor with FcgammaRIIb. In PBMC-engrafted mice, XmAb7195 reduced total human IgE (but not IgG or IgM) levels by up to 40-fold relative to omalizumab. CONCLUSION: XmAb7195 acts by IgE sequestration coupled with an FcgammaRIIb-mediated inhibitory mechanism to suppress the formation of IgE-secreting plasma cells and reduce both free and total IgE levels. PMID- 22257645 TI - The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa. AB - Anorexia nervosa (AN) is characterized by subnormal estrogen and dehydroepiandrosterone (DHEA) levels. We sought to determine whether the combination of DHEA + estrogen/progestin is superior to placebo in preserving skeletal health over 18 months in AN. Females with AN, aged 13 to 27 years, were recruited for participation in this double-blind, placebo-controlled, randomized trial. Ninety-four subjects were randomized, of whom 80 completed baseline assessments and received either study drug (oral micronized DHEA 50 mg + 20 ug ethinyl estradiol/0.1 mg levonorgestrel combined oral contraceptive pill [COC] daily; n = 43) or placebo (n = 37). Serial measurements of areal bone mineral density (aBMD), bone turnover markers, and serum hormone concentrations were obtained. Sixty subjects completed the 18-month trial. Spinal and whole-body aBMD z scores were preserved in the DHEA + COC group, but decreased in the placebo group (comparing trends, P = .008 and P = .001, respectively). Bone turnover markers initially declined in subjects receiving DHEA + COC and then returned to baseline. No differences in body composition, adverse effects of therapy, or alterations in biochemical safety parameters were observed. Combined therapy with DHEA + COC appears to be safe and effective for preventing bone loss in young women with AN, whereas placebo led to decreases in aBMD. Dehydroepiandrosterone + COC may be safely used to preserve bone mass as efforts to reverse the nutritional, psychological, and other hormonal components of AN are implemented. PMID- 22257646 TI - Energy content of weight loss: kinetic features during voluntary caloric restriction. AB - The classic rule stating that restricting intake by 3500 kcal/wk will lead to a 1 lb/wk rate of weight loss has come under intense scrutiny. Generally not a component of most weight loss prediction models, the "early" rapid weight loss phase may represent a period during which the energy content of weight change (DeltaEC/DeltaW) is low and thus does not follow the classic "rule." The current study tested this hypothesis. Dynamic DeltaEC/DeltaW changes were examined in 23 Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Study overweight men and women evaluated by dual-energy x-ray absorptiometry during weight loss at treatment weeks 4 to 24. Changes from baseline in body energy content were estimated from fat and fat-free mass. Repeated-measures analysis of variance was used to determine if DeltaEC/DeltaW changed significantly over time. The evaluation was expanded with addition of the Kiel 13-week weight loss study of 75 obese men and women to test with adequate power if there are sex differences in DeltaEC/DeltaW. The analysis of variance CALERIE time effect was significant (P < .001), with post hoc tests indicating that DeltaEC/DeltaW (kilocalories per kilogram) increased significantly from week 4 (X +/- SEM; 4, 858 +/- 388) to 6 (6, 041 +/- 376, P < .01) and changed insignificantly thereafter; DeltaEC/DeltaW was significantly larger for Kiel women (6, 804 +/- 226) vs men (6, 119 +/- 240, P < .05). Sex-specific dynamic relative changes in body composition and related DeltaEC/DeltaW occur with weight loss initiation that extend for 1 month or more. These observations provide new information for developing energy balance models and further define limitations of the 3500-kcal energy deficit -> 1-lb weight loss rule. PMID- 22257648 TI - A morphologic study of chronic type B aortic dissections and aneurysms after thoracic endovascular stent grafting. AB - BACKGROUND: The long-term results of treating chronic aortic dissections and aneurysms in association with dissections with thoracic endovascular aortic repair (TEVAR) are unknown, and the timing for intervention is uncertain. We evaluated the morphology of stent graft and aorta remodeling and the volumetric changes in these patients after successful TEVAR. METHODS: Serial computed tomography scans of 32 patients who underwent TEVAR for uncomplicated chronic dissections (group A, n = 17) and chronic dissections with aneurysms (group B, n = 15) were analyzed at 1, 6, 12, and 36 months. Stent graft diameter changes and positional migration were assessed three-dimensionally using Mimics 14.0 (Materialize, Leuven, Belgium). Volumetric data for true lumen, false lumen, thrombus load, and aortic size were measured by Aquarius iNtuition 4.4 software (TeraRecon, San Mateo, Calif). Results were compared between the two groups and with stent graft diameter, length, and oversizing. RESULTS: Aortic stent grafts remodeled progressively, with inlet area increasing 4.4%, 10.1%, and 14.2% and outlet area increasing 42.6%, 67.2%, and 72.3%, respectively, at 6, 12, and 36 months. True lumen volume increased progressively in group A (114 to 174 mL) and group B (124 to 190 mL) from baseline to 36 months. False lumen volume decreased in group A (150 to 88 mL) and group B (351 to 250 mL), whereas thrombus load in the false lumen increased from 73% to 80% in group A and 84% to 87% in group B in 3 years. Eight patients (4 in each group) showed an increase in total aortic volume of >10%, 12 showed a static volume, and 12 showed shrinkage. Aortic volume change had no relationship to pathology, stent graft sizing, and thrombus load but was positively associated with the placement of a longer graft. A small but progressive distal migration of stent grafts was noted in all patients (3.1, 4.5, and 5.1 mm at 6, 12, and 36 months) but was more prominent in shorter stent grafts (<= 162 mm). No deaths, rupture, or secondary interventions occurred during follow-up. CONCLUSIONS: Aortic remodeling after TEVAR in chronic dissection is a continuous process. There were no significant differences between chronic dissections and aneurysms in all volumetric parameters. Treating chronic dissections early, before aneurysm formation, did not appear to have a morphologic advantage. PMID- 22257649 TI - Creating a virtual slide map from sputum smear images for region-of-interest localisation in automated microscopy. AB - We address the location of regions-of-interest in previously scanned sputum smear slides requiring re-examination in automated microscopy for tuberculosis (TB) detection. We focus on the core component of microscope auto-positioning, which is to find a point of reference, position and orientation, on the slide so that it can be used to automatically bring desired fields to the field-of-view of the microscope. We use virtual slide maps together with geometric hashing to localise a query image, which then acts as the point of reference. The true positive rate achieved by the algorithm was above 88% even for noisy query images captured at slide orientations up to 26 degrees . The image registration error, computed as the average mean square error, was less than 14 pixel2 (corresponding to 1.02 MUm2). The algorithm is inherently robust to changes in slide orientation and placement and showed high tolerance to illumination changes and robustness to noise. PMID- 22257650 TI - Results of an online community needs assessment for psychoeducational interventions among partners of hereditary breast cancer previvors and survivors. AB - BACKGROUND: Spouses and partners ("partners") of women at-risk for ("previvors") and surviving with hereditary breast/ovarian cancer are a primary source of support within their families. Yet, little is known about partners' needs for psychoeducational intervention to enhance their cancer risk knowledge, coping, and support role functioning. OBJECTIVE: To determine the type and range of need for psychoeducational intervention among partners of hereditary breast cancer previving and surviving women, and to understand the potential role of the Internet and other communication channels in meeting that need. METHODS: We conducted a secondary data analysis on partners' needs that were originally assessed via an online community-based organization devoted to hereditary breast cancer. Partners' demographic characteristics, need for psychoeducation, and likelihood of using various communication channels were assessed along with other constructs. Analyses examined commonly-occurring clusters of likely intervention use and by communication channel. RESULTS: Partners (n =143) endorsed a moderately high level of need for psychoeducation and did so across multiple content areas (e.g., role functioning, decision making, communication, intimacy). Factor analysis identified three commonly-preferred communication channels: 1) self-help materials, 2) online interactions, and 3) interpersonal interactions. A cluster analysis among these factors identified three groups of partners based on their likelihood of psychoeducational intervention use (low [18%], moderate [55%], and high [27%] users). In a covariate-adjusted MANOVA, moderate and high intervention users reported significantly greater need for psychoeducation compared to low users (F(2,132) = 9.15, P < .001). CONCLUSIONS: A majority of assessed partners perceived a need for psychoeducational interventions surrounding hereditary breast cancer risk. Internet-based, interactive resources may be an efficient mechanism to reach large numbers of partners with tailored content. Research is warranted to inform the design and deployment of these resources to ensure quality and high impact, and ultimately to examine ways to integrate these resources into clinical care. PMID- 22257651 TI - Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. AB - The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use. Two second-generation irreversible EGFR TKIs, afatinib (BIBW 2992) and dacomitinib (PF-00299804), that can potentially overcome the majority of these resistances are in late stage clinical development. Here I will review the clinical data of EGFR TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC: whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches. PMID- 22257652 TI - Target therapy in elderly breast cancer patients. AB - Substantial progress has been made in the management of breast cancer by targeting HER2 and VEGF pathways. Although the efficacy and safety of target therapy in breast cancer have been established, no specific phase III trial has addressed these issues in the elderly population and the only data available derive from subanalyses or retrospective series. The aim of this review is to summarize the available evidence in this special population and to encourage further well designed studies in elderly breast cancer patients. PMID- 22257653 TI - Will SBRT replace conventional radiotherapy in patients with low-intermediate risk prostate cancer? A review. AB - Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. Emerging data show the safety and efficacy of this treatment modality in prostate cancer. Preclinical data, clinical experience, and challenges are reviewed and discussed. PMID- 22257654 TI - Unequal impairment in the recognition of positive and negative emotions after right hemisphere lesions: a left hemisphere bias for happy faces. AB - The processing of several important aspects of a human face was investigated in a single patient (LZ), who had a large infarct of the right hemisphere involving the parietal, and temporal lobes with extensions into the frontal region. LZ showed selective problems with recognizing emotional expressions, whereas she was flawless in recognizing gender, familiarity, and identity. She was very poor in recognizing negative facial expressions (fear, disgust, anger, sadness), but scored as well as the controls on the positive facial expression of happiness. However, in two experiments using both static and dynamic face stimuli, we showed that LZ also did not have a proper notion of what a facial expression of happiness looks like, and could not adequately apply this label. We conclude that the proper recognition of both negative and positive facial expressions relies on the right hemisphere, and that the left hemisphere produces a default state resulting in a bias towards evaluating expressions as happy. We discuss the implications of the current findings for the main models that aim to explain hemispheric specializations for processing of positive and negative emotions. PMID- 22257655 TI - A case of rickettsialpox in Northern Europe. AB - We report the first case of rickettsialpox caused by Rickettsia akari in the Netherlands. The diagnosis was suspected based on clinical grounds and was confirmed by Western blot analysis with cross-adsorption. Because the arthropod vector (Liponyssoides sanguineus) is ubiquitous, we suspect that the disease is under-diagnosed in non-endemic areas. PMID- 22257656 TI - Beyond my hamster wheel. PMID- 22257657 TI - Olaryngologic manifestations in children with chronic neutropenia. AB - OBJECTIVE: Chronic neutropenia of childhood (CNC) is a rare disorder in which the absolute neutrophil count is below 1500/MUL over an extended period of time. The objective of this study is to describe the otolaryngolgic manifestations associated with CNC to facilitate diagnosis and treatment of this condition. METHODS AND MATERIALS: We performed a retrospective chart review of patients with the diagnosis of CNC between 1970 and 2005 at a tertiary pediatric hematology center. After Institutional Review Board approval, 43 patients were evaluated. The average age at hematologic diagnosis was 49 months (range: 1 month - 15 years with 35% <1 year, 44% 1-10 years, 21% >10 years). A total of 2049 encounters were analyzed from the hospital charts. RESULTS: Twenty four subjects (56%) presented with recurrent otitis media (ROM), sinusitis or pharyngo-tonsillitis, while 11% presented with oral mucosal lesions. After diagnosis, otolaryngologic problems persisted, including ROM (81%), viral upper respiratory tract infection (67%), oral ulcers or gingivitis (53%), tonsillitis (39%) and sinusitis (37%) and were more common than other systemic infections. Myringotomy tube placement, endoscopic sinus debridement, adeno-tonsillectomy or tracheostomy were required in 42% of patients. After G-CSF (granulocyte colony-stimulating factor) became available in the early 1990s, the infection rate markedly decreased. Five deaths occurred (12% mortality) including one due to sepsis from otolaryngologic infection. CONCLUSION: The majority of children with CNC had otolaryngologic problems at presentation and these continued after diagnosis. While managing common otolaryngologic infections in children, a high index of suspicion for chronic neutropenia is necessary. An otolaryngologist is frequently one of the first physicians to encounter children with this condition. Awareness of CNC and its management will enhance earlier diagnosis and more effective treatment for these children. PMID- 22257658 TI - [A 20-year old woman with fever and cervical abnormal lymph nodes]. PMID- 22257659 TI - [Churg-Strauss syndrome associated with Wells syndrome]. PMID- 22257660 TI - [Septic arthritis in multiple myeloma patient]. PMID- 22257661 TI - [Reflections on the clinical reports "minimum data set"]. AB - Royal Decree 1093/2010 (3 September 2010) establishes the minimum data set that the clinical reports of discharges and outpatient visits elaborated in the facilities of the National Health System should contain, among others. Until then, the Ministerial Order 221/1984, that only required the drawing up of a discharge report for patients seen in a hospital-regime health care establishment, was in force. In spite of the importance of these documents, their quality is far from that desired, especially that of the reports on visits, which, among other things, are not performed in a high percentage of the cases. Recently the Sociedad Espanola de Medicina Interna (SEMI) (Spanish Society of Internal Medicine), in collaboration with other scientific societies, issued some recommendations for the drawing up of the discharge reports. In this present work, a series of thoughts are made on the implications of the new decree, especially in the case of the reports of the outpatient clinics. PMID- 22257662 TI - Human herpesvirus 8 seroprevalence, China. AB - To summarize the seroprevalence of human herpesvirus 8 (HHV-8) in mainland China, we conducted a systematic review and meta-analysis based on available literature. Data show that differences in HHV-8 prevalence vary considerably among different ethnic groups and geographic regions. Blood-borne transmission could be a potential route for HHV-8 infection in China. PMID- 22257663 TI - Primary follicular lymphoma of the epididymis positive for t(14;18)(q32;q21)/IGH BCL2 and negative for BCL2 protein expression: a case report. AB - INTRODUCTION: Non-Hodgkin lymphoma (NHL) can involve the paratesticular organs as the primary disease, as primary testicular lymphoma that secondarily involves the paratesticular structures, as the initial site of presentation of occult nodal disease or as the result of disease dissemination. Primary follicular lymphoma of the epididymis in an adult is extremely rare. Little is known about primary adult paratesticular/epididimal lymphomas. CASE PRESENTATION: We report a rare case of primary follicular non-Hodgkin lymphoma of the epididymis in a 90-year-old Caucasian man who presented with a left scrotal mass. Bone marrow biopsy was negative and computed tomography of the total body revealed no evidence of extratesticular involvement. Macroscopically, the epididymis was replaced completely by a uniform mass. Histologic studies revealed a dense lymphoid infiltrate predominantly composed of centrocytes with admixed centroblasts. Immunohistochemical analyses demonstrated that neoplastic cells strongly expressed CD45RB, CD20, CD79a, bcl-6 and CD10; bcl-2 immunostaining was negative. Molecular studies showed the presence of the monoclonal IgH gene rearrangement and the IgH/BCL2 rearrangement. The lymphoma was classified as follicular lymphoma, low grade, grade 1-2. The patient subsequently underwent radical orchiectomy, did not receive chemotherapy and post-operative follow-up showed absence of disease recurrence. CONCLUSIONS: The case of primary follicular lymphoma of epididymis, reported here, is considered a very rare event. It is characterized by clinically indolent localized disease, a good clinical outcome, lack of expression of BCL2 protein and the presence of the t(14;18)(q32;q21)/IGH BCL2. Even if it is a single case, the primary follicular lymphoma epididymis with t(14;18) could represent either a variant of the previously reported t(14;18)-negative primary paratesticular follicular lymphoma or a distinct biological entity. To report additional cases in the future would be helpful in resolving this question. PMID- 22257664 TI - Infiltrating/sealing proximal caries lesions: a 3-year randomized clinical trial. AB - This randomized split-mouth controlled clinical trial aimed at assessing the therapeutic effects of infiltration vs. sealing for controlling caries progression on proximal surfaces. Out of 90 adult students/patients assessed at university clinics and agreeing to participate, 39, each with 3 proximal lesions identified radiographically around the enamel-dentin junction to the outer third of the dentin, were included. Lesions were randomly allocated for treatment to test-A (Infiltration: ICON-pre-product; DMG), test-B (Sealing: Prime-Bond-NT; Dentsply), or control-C (Placebo). Primary outcome after 1, 2, and 3 yrs of radiographically observed lesion progression was assessed by an independent examiner blinded to groups, using pair-wise and digital-subtraction readings. No adverse events occurred. In 37 participants assessed after 3 yrs, 10 lesions (A 4; B-2; C-4) progressed deep into dentin and needed operative treatment. The 3 year therapeutic effect, based on pair-wise radiographic readings between infiltration and placebo, was 37.8% (95% CI: 20.5-55.2%) and that between sealing and placebo was 29.7% (95% CI: 20.2-35.0%). One-year follow-up digital subtraction readings showed significant differences in lesion progression between infiltration and placebo (P = 0.0012) and between sealing and placebo (P = 0.0269). The study showed that infiltration and sealing are significantly better than placebo treatment for controlling caries progression on proximal lesions. No significant difference was seen between infiltration and sealing (ClinicalTrials.gov number NCT01417832). PMID- 22257665 TI - Functional properties of tooth pulp neurons responding to thermal stimulation. AB - The response properties of tooth pulp neurons that respond to noxious thermal stimulation of the dental pulp have been not well-studied. The present study was designed to characterize the response properties of tooth pulp neurons to noxious thermal stimulation of the dental pulp. Experiments were conducted on 25 male ferrets, and heat stimulation was applied by a computer-controlled thermode. Only 15% of tooth pulp neurons (n = 39) responded to noxious thermal stimulation of the teeth. Tooth pulp neurons were found in both the superficial and deep nuclear regions of the subnucleus caudalis (Vc) and in the interface between the nucleus caudalis and interpolaris (Vc/Vi). Thirty-seven neurons had cutaneous receptive fields and were classified as either NS (16) or WDR (21) neurons. Repeated heat stimulation of the dental pulp sensitized and increased the number of electrically evoked potentials of tooth pulp neurons. These results provide evidence that both the Vc and Vc/Vi regions contain neurons that respond to noxious thermal stimulation of the dental pulp, and that these cells may contribute to the sensitization process associated with symptomatic pulpitis. PMID- 22257666 TI - Exact coalescent simulation of new haplotype data from existing reference haplotypes. AB - MOTIVATION: We introduce a coalescent-based method (RECOAL) for the simulation of new haplotype data from a reference population of haplotypes. A coalescent genealogy for the reference haplotype data is sampled from the appropriate posterior probability distribution, then a coalescent genealogy is simulated which extends the sampled genealogy to include new haplotype data. The new haplotype data will, therefore, contain both some of the existing polymorphic sites and new polymorphisms added based on the structure of the simulated coalescent genealogy. This allows exact coalescent simulation of new haplotype data, compared with other methods which are more approximate in nature. RESULTS: We demonstrate the performance of our method using a variety of data simulated under a coalescent model, before applying it to data from the 1000 Genomes project. PMID- 22257667 TI - FX: an RNA-Seq analysis tool on the cloud. AB - FX is an RNA-Seq analysis tool, which runs in parallel on cloud computing infrastructure, for the estimation of gene expression levels and genomic variant calling. In the mapping of short RNA-Seq reads, FX uses a transcriptome-based reference primarily, generated from ~160 000 mRNA sequences from RefSeq, UCSC and Ensembl databases. This approach reduces the misalignment of reads originating from splicing junctions. Unmapped reads not aligned on known transcripts are then mapped on the human genome reference. FX allows analysis of RNA-Seq data on cloud computing infrastructures, supporting access through a user-friendly web interface. AVAILABILITY: FX is freely available on the web at (http://fx.gmi.ac.kr), and can be installed on local Hadoop clusters. Guidance for the installation and operation of FX can be found under the 'Documentation' menu on the website. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22257668 TI - COPICAT: a software system for predicting interactions between proteins and chemical compounds. AB - Since tens of millions of chemical compounds have been accumulated in public chemical databases, fast comprehensive computational methods to predict interactions between chemical compounds and proteins are needed for virtual screening of lead compounds. Previously, we proposed a novel method for predicting protein-chemical interactions using two-layer Support Vector Machine classifiers that require only readily available biochemical data, i.e. amino acid sequences of proteins and structure formulas of chemical compounds. In this article, the method has been implemented as the COPICAT web service, with an easy to-use front-end interface. Users can simply submit a protein-chemical interaction prediction job using a pre-trained classifier, or can even train their own classification model by uploading training data. COPICAT's fast and accurate computational prediction has enhanced lead compound discovery against a database of tens of millions of chemical compounds, implying that the search space for drug discovery is extended by >1000 times compared with currently well used high-throughput screening methodologies. AVAILABILITY: The COPICAT server is available at http://copicat.dna.bio.keio.ac.jp. All functions, including the prediction function are freely available via anonymous login without registration. Registered users, however, can use the system more intensively. PMID- 22257669 TI - The sva package for removing batch effects and other unwanted variation in high throughput experiments. AB - Heterogeneity and latent variables are now widely recognized as major sources of bias and variability in high-throughput experiments. The most well-known source of latent variation in genomic experiments are batch effects-when samples are processed on different days, in different groups or by different people. However, there are also a large number of other variables that may have a major impact on high-throughput measurements. Here we describe the sva package for identifying, estimating and removing unwanted sources of variation in high-throughput experiments. The sva package supports surrogate variable estimation with the sva function, direct adjustment for known batch effects with the ComBat function and adjustment for batch and latent variables in prediction problems with the fsva function. PMID- 22257670 TI - AnnTools: a comprehensive and versatile annotation toolkit for genomic variants. AB - AnnTools is a versatile bioinformatics application designed for comprehensive annotation of a full spectrum of human genome variation: novel and known single nucleotide substitutions (SNP/SNV), short insertions/deletions (INDEL) and structural variants/copy number variation (SV/CNV). The variants are interpreted by interrogating data compiled from 15 constantly updated sources. In addition to detailed functional characterization of the coding variants, AnnTools searches for overlaps with regulatory elements, disease/trait associated loci, known segmental duplications and artifact prone regions, thereby offering an integrated and comprehensive analysis of genomic data. The tool conveniently accepts user provided tracks for custom annotation and offers flexibility in input data formats. The output is generated in the universal Variant Call Format. High annotation speed makes AnnTools suitable for high-throughput sequencing facilities, while a low-memory footprint and modest CPU requirements allow it to operate on a personal computer. The application is freely available for public use; the package includes installation scripts and a set of helper tools. AVAILABILITY: http://anntools.sourceforge.net/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22257671 TI - Interface modification effect between p-type a-SiC:H and ZnO:Al in p-i-n amorphous silicon solar cells. AB - Aluminum-doped zinc oxide (ZnO:Al) [AZO] is a good candidate to be used as a transparent conducting oxide [TCO]. For solar cells having a hydrogenated amorphous silicon carbide [a-SiC:H] or hydrogenated amorphous silicon [a-Si:H] window layer, the use of the AZO as TCO results in a deterioration of fill factor [FF], so fluorine-doped tin oxide (Sn02:F) [FTO] is usually preferred as a TCO. In this study, interface engineering is carried out at the AZO and p-type a-SiC:H interface to obtain a better solar cell performance without loss in the FF. The abrupt potential barrier at the interface of AZO and p-type a-SiC:H is made gradual by inserting a buffer layer. A few-nanometer-thick nanocrystalline silicon buffer layer between the AZO and a-SiC:H enhances the FF from 67% to 73% and the efficiency from 7.30% to 8.18%. Further improvements in the solar cell performance are expected through optimization of cell structures and doping levels. PMID- 22257672 TI - Dual inhibition of HER2 in breast cancer treatment. PMID- 22257674 TI - Parent-infant interaction in infant siblings at risk of autism. AB - Recent models of the early emergence of autism spectrum disorder (ASD) propose an interaction between risk susceptibility and the infant's social environment, resulting in a progressively atypical developmental trajectory. The infant's early social environmental experience consists mostly of interaction with caregivers, yet there has been little systematic study of early parent-infant interaction in infants at risk of ASD. This study examined the global characteristics of parent-infant interaction in 6- to 10-month-old infants with an older sibling diagnosed with ASD (at-risk sibs), in comparison with a group of infants with no family history of ASD (low-risk sibs). As part of the British Autism Study of Infant Siblings (BASIS), 6-min videotaped unstructured play interactions of mother-infant dyads (45 at-risk sibs and 47 low-risk sibs) were rated on global aspects of parent-infant interaction, blind to participant information. Differences in global characteristics of interaction were observed in both infant and parent contributions in the at-risk group compared to low-risk controls. In analyses adjusted for age and developmental level, at-risk sib infants were less lively, and their parents showed higher directiveness, and lower sensitive responding (as a trend after adjustment). Level of infant liveliness was independent of other interactive behaviour. Consistent with reports in previous literature in older children with autism and in other neurodevelopmental disorders, our findings may suggest that infants at genetic risk are exposed to a more directive interactive style relatively early in infancy. We discuss possible explanations for these findings and implications for further developmental study and intervention. PMID- 22257675 TI - Health inequalities in the Netherlands: a cross-sectional study of the role of Type D (distressed) personality. AB - BACKGROUND: In the Netherlands, as in many European countries, inequalities in health exist between people with a high and a low socioeconomic status (SES). From the perspective of the 'indirect selection hypothesis', this study was designed to expand our understanding of the role of Type D personality as an explanation of health inequalities. METHODS: Data came from two cross-sectional Dutch surveys among the general population (aged between 19 and 64 years, response 53.7%, n = 12,090). We analyzed the relative risks of low SES, assessed using education and income, and Type D personality, assessed using the Type D Scale-14 (DS14), for different outcomes regarding lifestyle-related risk factors and health, using multivariate Generalized Linear Models. RESULTS: Results showed that Type D personality was significantly associated with low SES (OR = 1.7 for both low education and low income). Moreover, the relative risks of Type D personality and low SES were significantly elevated for most adverse health outcomes, unconditionally as well as conditionally. CONCLUSION: The cross sectional design hinders the making of definite etiological inferences. Nevertheless, our findings suggest that Type D personality does not explain the socioeconomic health inequalities, but is a risk factor in addition to low SES. Prevention of adverse health outcomes in low SES populations may have more effect when it takes into account that persons with a low SES in combination with a Type D personality are at highest risk. PMID- 22257676 TI - [The arthroscopic distal pole resection of the scaphoid: clinical results in STT osteoarthritis]. AB - We present the results of surgical treatment of eight patients operated in the service of osteoarthritis scapho-trapezo-trapezoidienne (STT) by resection of the distal pole of the scaphoid under arthroscopic. Studies have already shown the good results of this technique in open surgery. This is a retrospective study of eight patients of mean age 70 years. They had an isolated STT osteoarthritis, which is not relieved by medical treatment. They were operated between 2004 and 2007 by the same surgeon and were reviewed at a mean of 13 months by an independent examiner. The evaluation was focused on pain, range of motion and grip strength. A radiological assessment was conducted to examine a possible carpal mal-alignment. Two patients were excluded because they had received a trapeziectomy for rhizarthrosis associated. The pain had decreased in seven cases with complete disappearance in six cases. The force had been increased or stabilized in seven cases and the mobility is the same in six cases. We got six very good results, one good result and one bad result without aggravation. Furthermore, no patient had been taken, nor any complications noted. The good results obtained with this minimally invasive outpatient surgery, encourages us to offer first-line therapy in patients with isolated STT osteoarthritis is not relieved by medical treatment. The resection of the distal pole of the scaphoide under arthoscopy gives less burdensome and less complication that the arthrodesis, while providing very good results. PMID- 22257673 TI - Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. AB - BACKGROUND: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. METHODS: In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg [DOSAGE ERROR CORRECTED], subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. FINDINGS: 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51.3%; 95% CI 43.1-59.5]) than in the group given trastuzumab alone (44 of 149 patients [29.5%; 22.4-37.5]; difference 21.1%, 9.1-34.2, p=0.0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24.7%, 18.1-32.3]) and the trastuzumab (difference -4.8%, -17.6 to 8.2, p=0.34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23.4%]) and lapatinib plus trastuzumab (32 [21.1%]) than with trastuzumab (three [2.0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17.5%]) and lapatinib plus trastuzumab (15 [9.9%]) than with trastuzumab (11 [7.4%]). INTERPRETATION: Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. FUNDING: GlaxoSmithKline. PMID- 22257677 TI - ERalpha, microRNAs, and the epithelial-mesenchymal transition in breast cancer. AB - The most common form of breast cancer, luminal A, is estrogen receptor alpha (ERalpha)-positive and epithelial, but nevertheless can metastasize. The process of epithelial-mesenchymal transition (EMT) is probably the first step in the metastasis of epithelial cancers. We discuss the characteristics of EMT, including factors that induce EMT, and the relationship of EMT to cancer stem cells (CSCs). Estrogen/ERalpha signaling maintains an epithelial phenotype and suppresses EMT. An overview of microRNAs in breast cancer is presented, including how microRNA biogenesis is altered in cancer and regulated by ERalpha. We also discuss the role of the miR-200 family in opposing EMT. Finally, we discuss specific microRNAs that target ERalpha and regulate EMT in breast cancer, and the role of these microRNAs in breast cancer progression. PMID- 22257678 TI - Preserved and impaired task-switching abilities in non-demented patients with Parkinson's disease. AB - Existing studies on task switching in Parkinson's disease (PD) patients have led to somewhat different results. In particular, it is unclear whether PD patients have a deficit in attentional control. In this study, we assessed task-switching abilities in samples of non-demented PD patients and elderly controls. We used a paradigm in which there was a random task sequence and the task was cued in every trial. This allowed the investigation of both task-set reconfiguration and task set dissipation. In terms of the proportion of errors made, the patients showed increased switch cost and congruency effects. For reaction times, PD patients showed enlarged congruency effects on switch trials, specifically in the condition in which we used a short constant response-cue interval (RCI). Nevertheless, in a similar fashion to older controls, the patients showed reductions in reaction time switch cost from a short to a long cue-target interval (CTI) and from a short to a long RCI. While these latter findings, respectively, suggest unimpaired task preparation and task dissipation on correct trials in the PD patients, the overall results show that they have a deficit in biasing and selecting currently relevant task sets and more generally argue in favour of a failure of attentional control in PD. PMID- 22257679 TI - [Prognostic factors in psoriatic arthritis]. AB - Peripheral psoriatic arthritis is an inflammatory and progressive disease; its burden, either at the structural level or the function and quality of life, is similar to other chronic poliarthritidies. In spite of treatment with synthetic or biologic DMARDs, remission is only achieved in about 30% of the patients. From a clinical point of view, persistent joint activity (tender and swollen joints) is a factor leading to joint damage progression. These data indicate the need for a tight follow up and treatment of the patients. PMID- 22257680 TI - Patient reported outcome measures: what is their importance? PMID- 22257682 TI - The Cassie equation: how it is meant to be used. AB - A review of literature shows that the majority of papers cite a potentially incorrect form of the Cassie and Cassie-Baxter equations to interpret or predict contact angle data. We show that for surfaces wet with a composite interface, the commonly used form of the Cassie-Baxter equation, costheta(c)=f(1)costheta-(1-f), is only correct for the case of flat topped pillar geometry without any penetration of the liquid. In general, the original form of the Cassie-Baxter equation, costheta(c)=f(1)costheta(1)-f(2), with f(1)+f(2)>=1, should be used. The differences between the two equations are discussed and the errors involved in using the incorrect equation are estimated to be between ~3 degrees and 13 degrees for superhydrophobic surfaces. The discrepancies between the two equations are also discussed for the case of a liquid undergoing partial, but increasing, levels of penetration. Finally, a general equation is presented for the transition/stability criterion between the Cassie-Baxter and Wenzel modes of wetting. PMID- 22257683 TI - Early (pre-DLVO) studies of particle aggregation. AB - The history of colloid science, from its modern foundations in the mid-nineteenth century, has been strongly concerned with studies of the aggregation of colloidal particles. It was Thomas Graham (1861) who defined the word "colloid" (from the Greek word for glue) for those materials which could not pass through membranes, unlike smaller, truly-dissolved materials. Subsequently, Graham (1864), following earlier studies, principally by Selmi and Faraday, described "the power possessed by salts for destroying colloidal solutions". Although numerous, quantitative studies of particle aggregation were made in the years that followed, in particular, the determination of minimum electrolyte concentrations for the onset of particle aggregation and aggregation rates, no general theoretical framework emerged to account for these quantitative findings until the middle of the twentieth century. It was during and immediately following the Second World War that two sets of authors, Derjaguin and Landau, in Russia, and Verwey and Overbeek, in the Netherlands, independently came up with the theory that is now universally referred to as the DLVO theory of particle interactions and aggregation. All modern developments of the theory of particle aggregation use the DLVO theory as the keystone. However, the DLVO theory itself was based on a large body of experimental data in regard to particle aggregation obtained over the previous hundred years or so. This article is an attempt to review that body of experimental data and to show how this guided the DLVO authors in their thinking. PMID- 22257681 TI - Neoplastic "Black Ops": cancer's subversive tactics in overcoming host defenses. AB - Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack. PMID- 22257684 TI - Prevalence and spectrum of GATA6 mutations associated with familial atrial fibrillation. PMID- 22257686 TI - Role of vitamin D in the cardiac remodeling induced by tobacco smoke exposure. PMID- 22257685 TI - Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: insights from the SOLVD Treatment trial. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). METHODS: In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction <= 35% and serum creatinine level <= 2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m(2)). RESULTS: Overall, during 35 months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74-0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73 1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69-0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66-0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70-0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04 mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7 mm Hg, both) and serum potassium (mean increase, 0. /L, both). CONCLUSIONS: Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD. PMID- 22257687 TI - The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence. AB - BACKGROUND: Matrix metalloproteinase-8 (MMP-8) is involved in the breakdown of the extracellular matrix increasing the vulnerability of atherosclerotic lesions. We analysed the diagnostic value of serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations in acute coronary syndrome (ACS) and their prognostic value in ACS recurrence. METHODS: The population comprised 343 patients with ACS [including 108 unstable angina pectoris and 235 acute myocardial infarctions (AMI)] and 326 healthy controls. Additionally, 157 (45.8%) patients were resampled during the recovery. The ACS patients were followed up for 6 years. RESULTS: MMP-8, TIMP-1, and their molar ratio distinguished the cases from the controls; C-statistic of the multivariate model (95% CI, p-value) including the MMP-8/TIMP-1 ratio regarding its discriminating ability for AMI was 0.922 (0.893-0.950, p<0.001). After the acute phase of ACS, median MMP-8 and TIMP 1 concentrations decreased (p<0.001) by 34.5 and 28.7%, respectively, but ended up on a different level than those found in the controls. In the follow-up, acute phase and recovery period TIMP-1 concentrations associated with cardiovascular death with hazard ratios 4.31 (2.00-9.26, p<0.001) and 4.69 (1.10-20.01, p=0.037), respectively. CONCLUSIONS: The increase of serum MMP-8 and TIMP-1 concentrations may reflect plaque instability and tissue damage. TIMP-1 concentrations are associated with poor outcome in patients with ACS. The findings may have practical implications in both diagnostics and therapeutics. PMID- 22257688 TI - TRPC6, a potential novel target for enhancing cardiac repair of bone marrow mesenchymal stem cells. PMID- 22257689 TI - Coronary aneurysm formation following biodegradable polymer drug-eluting stent implantation. PMID- 22257690 TI - Survival benefit of new anticoagulants compared with warfarin in patients with atrial fibrillation: a meta-analysis. PMID- 22257691 TI - Preischemic efferent vagal stimulation increases the size of myocardial infarction in rabbits. Role of the sympathetic nervous system. PMID- 22257692 TI - Pulmonary infection caused by Mycobacterium conceptionense. PMID- 22257693 TI - Centromere-associated repeat arrays on Trypanosoma brucei chromosomes are much more extensive than predicted. AB - BACKGROUND: African trypanosomes belong to a eukaryotic lineage which displays many unusual genetic features. The mechanisms of chromosome segregation in these diploid protozoan parasites are poorly understood. Centromeres in Trypanosoma brucei have been localised to chromosomal regions that contain an array of ~147 bp AT-rich tandem repeats. Initial estimates from the genome sequencing project suggested that these arrays ranged from 2 - 8 kb. In this paper, we show that the centromeric repeat regions are much more extensive. RESULTS: We used a long-range restriction endonuclease mapping approach to more accurately define the sizes of the centromeric repeat arrays on the 8 T. brucei chromosomes where unambiguous assembly data were available. The results indicate that the sizes of the arrays on different chromosomes vary from 20 to 120 kb. In addition, we found instances of length heterogeneity between chromosome homologues. For example, values of 20 and 65 kb were obtained for the arrays on chromosome 1, and 50 and 75 kb for chromosome 5. CONCLUSIONS: Our results show that centromeric repeat arrays on T. brucei chromosomes are more similar in size to those of higher eukaryotes than previously suspected. This information provides a firmer framework for investigating aspects of chromosome segregation and will allow epigenetic features associated with the process to be more accurately mapped. PMID- 22257695 TI - Trichostatin A reduced phospholipase C gamma-1 transcript and protein contents in MCF-7 breast cancer cells. AB - It has recently been demonstrated that phospholipase C gamma-1 (PLCgamma1) activation may contribute to breast carcinoma cell motility and their metastasis. Employing MCF-7 breast cancer cells, we showed the effect of trichostatin A (TSA) on the cellular contents of the PLCgamma1 molecule. Using reverse transcription, real-time quantitative PCR and western blot analysis, we demonstrated that TSA reduced the PLCgamma1 transcript and protein levels in MCF-7 cells. We also found that TSA decreased the half-life of the PLCgamma1 transcript from approximately 7hours to 5hours. Moreover, we observed that protein synthesis appears to be essential in the TSA reduction of PLCgamma1 mRNA stability. Since PLCgamma1 activation is considered a key factor in the initiation of events that increase malignant cell motility, our observations may support the validity of TSA in anticancer studies. PMID- 22257694 TI - Evidence of 131I and (134,137)Cs activities in Bordeaux, France due to the Fukushima nuclear accident. AB - Following the Fukushima nuclear accident, low-background gamma spectrometry measurements were performed with HPGe detectors at the PRISNA platform located at the CENBG laboratory in Bordeaux, France. Different kinds of samples were collected and measured between March 26 and May 14, 2011. The first fission product observed was (131)I with maximum activity values of 2.4 mBq/m(3) in atmospheric dusts in air, 3.5 Bq/L in rain water, 15 Bq/kg in grass and 0.9 Bq/L in cow milk. The (134,137)Cs isotopes were also detected in air and in grass at a maximum level of 0.2 mBq/m(3) and 0.7 Bq/kg respectively, around one order of magnitude less than (131)I activity, but they were below detection limits in the other samples. All these activity values were consistent with others measured in France by IRSN and were well below those reported in May 1986 after the Chernobyl accident. PMID- 22257696 TI - Role of the purinergic system in patients with cervical intraepithelial neoplasia and uterine cancer. AB - INTRODUCTION: Cervical cancer remains the second leading cause of death among women. Intraepithelial neoplasias and uterine invasive cancer are frequently associated with disturbances in coagulation and changes in the concentrations of adenine nucleotides. This work intended to analyze changes in extracellular adenine nucleotide hydrolysis and blood platelet aggregation in patients diagnosed for cervical intraepithelial neoplasia in different stages as well as uterine invasive cancer. PATIENTS AND METHODS: NTPDase, E-NPP, 5'-nucleotidase, total ADA and its isoforms (ADA1 and ADA2), as well as the platelet aggregation from patients with different stages of cervical intraepithelial neoplasia (NICs I, NIC II, NIC III) and uterine invasive cancer were verified. RESULTS: Neither ATP hydrolysis nor E-NPP activity was changed by the neoplasia stage. On the other hand, ADP and AMP hydrolysis as well as ADA activity were enhanced in NIC I group. AMP hydrolysis was also increased in the cancer group. ADA 1 was the ADA isoform found in platelets from both control and patient groups. CONCLUSION: Our results showed for the first time that NTPDase, 5'-nucleotidase, E-NPP and ADA are not sensible regarding the grade of neoplasia development, since no significant difference was found between the groups studied. Only ADP hydrolysis and ADA activity showed a significant enhancement in NIC I group related to the other stages possibly as a result of the beginning of the neoplasic transformation. This increase could be reflecting a body's reaction against the probable high adenosine levels. We propose for the first time that the ADA isoform present in platelets is ADA 1. PMID- 22257697 TI - CCR6 is not necessary for functional effects of human CCL18 in a mouse model. AB - CCL18, a chemokine with no known receptor, has been implicated in several fibrotic pulmonary diseases associated with T-lymphocyte infiltration. It has been hypothesized that CCL18 may act through CCR6. Gene delivery of human CCL18 to the lungs of wild-type mice induced pulmonary infiltration of T-lymphocytes, less than 5% of which expressed CCR6. In the lungs of CCR6-deficient mice, CCL18 driven infiltration of T-lymphocytes was attenuated but not fully abrogated. It was concluded that CCR6 is not necessary for CCL18-induced changes in mice in vivo and that CCR6 is not the main functional receptor for CCL18 in this model. PMID- 22257698 TI - Projecting the environmental profile of Singapore's landfill activities: Comparisons of present and future scenarios based on LCA. AB - This article aims to generate the environmental profile of Singapore's Semakau landfill by comparing three different operational options associated with the life cycle stages of landfilling activities, against a 'business as usual' scenario. Before life cycle assessment or LCA is used to quantify the potential impacts from landfilling activities, an attempt to incorporate localized and empirical information into the amounts of ash and MSW sent to the landfill was made. A linear regression representation of the relationship between the mass of waste disposed and the mass of incineration ash generated was modeled from waste statistics between years 2004 and 2009. Next, the mass of individual MSW components was projected from 2010 to 2030. The LCA results highlighted that in a 'business as usual' scenario the normalized total impacts of global warming, acidification and human toxicity increased by about 2% annually from 2011 to 2030. By replacing the 8000-tonne barge with a 10000-tonne coastal bulk carrier or freighter (in scenario 2) a grand total reduction of 48% of both global warming potential and acidification can be realized by year 2030. Scenario 3 explored the importance of having a Waste Water Treatment Plant in place to reduce human toxicity levels - however, the overall long-term benefits were not as significant as scenario 2. It is shown in scenario 4 that the option of increased recycling championed over all other three scenarios in the long run, resulting in a total 58% reduction in year 2030 for the total normalized results. A separate comparison of scenarios 1-4 is also carried out for energy utilization and land use in terms of volume of waste occupied. Along with the predicted reductions in environmental burdens, an additional bonus is found in the expanded lifespan of Semakau landfill from year 2032 (base case) to year 2039. Model limitations and suggestions for improvements were also discussed. PMID- 22257699 TI - Experimental and numerical analysis of metal leaching from fly ash-amended highway bases. AB - A study was conducted to evaluate the leaching potential of unpaved road materials (URM) mixed with lime activated high carbon fly ashes and to evaluate groundwater impacts of barium, boron, copper, and zinc leaching. This objective was met by a combination of batch water leach tests, column leach tests, and computer modeling. The laboratory tests were conducted on soil alone, fly ash alone, and URM-fly ash-lime kiln dust mixtures. The results indicated that an increase in fly ash and lime content has significant effects on leaching behavior of heavy metals from URM-fly ash mixture. An increase in fly ash content and a decrease in lime content promoted leaching of Ba, B and Cu whereas Zn leaching was primarily affected by the fly ash content. Numerically predicted field metal concentrations were significantly lower than the peak metal concentrations obtained in laboratory column leach tests, and field concentrations decreased with time and distance due to dispersion in soil vadose zone. PMID- 22257700 TI - Co-morbid depression is associated with poor work outcomes in persons with cardiovascular disease (CVD): a large, nationally representative survey in the Australian population. AB - BACKGROUND: Co-morbid major depressive disorder (MDD) and cardiovascular disease (CVD) is associated with poor clinical and psychological outcomes. However, the full extent of the burden of, and interaction between, this co-morbidity on important vocational outcomes remains less clear, particularly at the population level. We examine the association of co-morbid MDD with work outcomes in persons with and without CVD. METHODS: This study utilised cross-sectional, population based data from the 2007 Australian National Survey of Mental Health and Wellbeing (n = 8841) to compare work outcomes of individuals with diagnostically defined MDD and CVD, MDD but not CVD, CVD but not MDD, with a reference group of "healthy" Australians. Workforce participation was defined as being in full- or part-time employment. Work functioning was measured using a WHO Disability Assessment Schedule item. Absenteeism was assessed using the 'days out of role' item. RESULTS: Of the four groups, those with co-morbid MDD and CVD were least likely to report workforce participation (adj OR:0.4, 95% CI: 0.3-0.6). Those with MDD only (adj OR:0.8, 95% CI:0.7-0.9) and CVD only (adj OR:0.8, 95% CI: 0.6 0.9) also reported significantly reduced odds of participation. Employed individuals with co-morbid MDD and CVD were 8 times as likely to experience impairments in work functioning (adj OR:8.1, 95% CI: 3.8- 17.3) compared with the reference group. MDD was associated with a four-fold increase in impaired functioning. Further, individuals with co-morbid MDD and CVD reported greatest likelihood of workplace absenteeism (adj. OR:3.0, 95% CI: 1.4-6.6). Simultaneous exposure to MDD and CVD conferred an even greater likelihood of poorer work functioning. CONCLUSIONS: Co-morbid MDD and CVD is associated with significantly poorer work outcomes. Specifically, the effects of these conditions on work functioning are synergistic. The development of specialised treatment programs for those with co-morbid MDD and CVD is required. PMID- 22257701 TI - An optimized method for tremor detection and temporal tracking through repeated second order moment calculations on the surface EMG signal. AB - In this study, the problem of detecting and tracking tremor from the surface myoelectric signal is addressed. A method based on the calculation of a Second Order Moment Function (SOMF) inside a window W sliding over the sEMG signal is here presented. An analytical formulation of the detector allows the extraction of the optimal parameters characterizing the algorithm. Performance of the optimized method is assessed on a set of synthetic tremor sEMG signals in terms of sensitivity, precision and accuracy through the use of a properly defined cost function able to explain the overall detector performance. The obtained results are compared to those emerging from the application of optimized versions of traditional detection techniques. Once tested on a database of synthetic tremor sEMG data, a quantitative assessment of the SOMF algorithm performance is carried out on experimental tremor sEMG signals recorded from two patients affected by Essential Tremor and from two patients affected by Parkinson's Disease. The SOMF algorithm outperforms the traditional techniques both in detecting (sensitivity and positive predictive value >99% for SNR higher than 3dB) and in estimating timings of muscular tremor bursts (bias and standard deviation on the estimation of the onset and offset time instants lower than 8ms). Its independence from the SNR level and its low computational cost make it suitable for real-time implementation and clinical use. PMID- 22257702 TI - Gingival recession and adult orthodontics: a clinical evidence-based treatment proposal. AB - The presence of a gingival recession prior to orthodontic treatment is a real problem. Patients are concerned about losing their teeth but may also complain of their unpleasant appearance or root sensitivity in the exposed area. The orthodontist is not sure whether orthodontic treatment can be performed or whether the tooth movement will not aggravate the recession and whether periodontal surgery needs to be done before or after orthodontic treatment. The aim of this paper is to present recent data from the literature and several clinical situations in adults in order to submit a treatment sequence and clarify the role of different periodontal plastic surgery root coverage procedures. PMID- 22257704 TI - Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer. AB - BACKGROUND: Febrile neutropenia is a frequently occurring and occasionally life threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people. METHODS: This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485. RESULTS: We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules. CONCLUSIONS: The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study. PMID- 22257705 TI - Impairment in material-specific long-term memory following unilateral mediodorsal thalamic damage and presumed partial disconnection of the mammillo-thalamic tract. AB - Neuropsychological findings suggest material-specific lateralization of the medial temporal lobe's role in long-term memory, with greater left-sided involvement in verbal memory, and greater right-sided involvement in visual memory. Whether material-specific lateralization of long-term memory also extends to the anteromedial thalamus remains uncertain. We report two patients with unilateral right (OG) and left (SM) mediodorsal thalamic pathology plus probable correspondingly lateralized damage of the mammillo-thalamic tract. The lesions were mapped using high-resolution structural magnetic resonance imaging and schematically reconstructed. Mean absolute volume estimates for the mammillary bodies, hippocampus, perirhinal cortex, and ventricles are also presented. Estimates of visual and verbal recall and item recognition memory were obtained using the Doors and People, the Rey Complex Figure Test, and the Logical Memory subtests of the Wechsler Memory Scales. Each patient's performance was compared to a group of healthy volunteers matched for demographic characteristics, premorbid IQ, and current levels of functioning. A striking double dissociation was evident in material-specific long-term memory, with OG showing significant impairments in visual memory but not verbal memory, and SM showing the opposite profile of preserved visual memory and significantly impaired verbal memory. These impairments affected both recall and item recognition. The reported double dissociation provides the strongest evidence yet that material-specific lateralization of long-term memory also extends to the anteromedial thalamus. The findings are also discussed in relation to proposals that distinct anatomical regions within the medial temporal lobe, anteromedial thalamus, and associated tracts make qualitatively different contributions to recall and item recognition. PMID- 22257706 TI - Effects of hydrofluoric acid and anodised micro and micro/nano surface implants on early osseointegration in rats. AB - Our aim was to evaluate the effects of hydrofluoric acid and anodised micro and micro/nano surface implants on bony ingrowth in the earliest stage of implantation in rats. Sixty cylindrical screwed titanium alloy implants with machined, micro, and hierarchical hybrid micro/nano surfaces (n=20 in each group) were inserted into the distal femurs of 30 female Sprague-Dawley rats. In vivo microcomputed tomography (micro CT) was used to assess microarchitectural changes in the bone around the implants 2 weeks after implantation. All the animals were then killed and the femurs with implants harvested for histological analysis and pull-out testing. Micro CT analysis showed that the trabecular thickness and the bone:volume ratio (bone volume:total volume) (BV:TV) increased significantly in the micro/nano group compared with the other two groups, while the trabecular separation decreased significantly in the micro/nano group compared with the machined group. The mean (SD) bone-implant contacts (%) were 38.94 (9.48), 41.67 (8.71), and 51.49 (12.49) in the machined, micro, and micro/nano groups, respectively. The maximum pull-out forces (N) were 64.95 (6.11), 71.45 (7.15), and 81.90 (13.1), respectively. Both bone-implant contacts and maximum pull-out forces were significantly higher in the micro/nano group, but there was no significant difference between the micro group and the machined group. These data indicate that the hierarchical hybrid micro/nano surface of the implant can promote osseointegration in the earliest stage of implantation, and may be a promising option for further clinical use. PMID- 22257707 TI - The polysaccharide fraction of Propionibacterium acnes modulates the development of experimental focal segmental glomerulosclerosis. AB - The pathogenesis of focal segmental glomerulosclerosis (FSGS) appears to be associated with type-2 cytokines and podocyte dysfunction. In this study, we tested the hypothesis that immunization with the polysaccharide fraction of Propionibacterium acnes (PS), a pro-Th1 agonist, may subvert the type-2 profile and protect podocytes from adriamycin-induced glomerulosclerosis. Adriamycin injection resulted in albuminuria and increased serum creatinine in association with loss of glomerular podocin and podoplanin expression, which is consistent with podocyte dysfunction. Renal tissue analysis revealed the expression of transcripts for GATA3 and fibrogenic-related proteins, such as TGF-beta, tissue inhibitor of metalloproteinase-1 (TIMP-1) and metalloproteinase 9 (MMP9). In association with the expression of fibrogenic transcripts, we observed peri glomerular expression of alpha-smooth muscle actin (alpha-SMA), indicating epithelial-to-mesenchymal transition, and increased expression of proliferating cell nuclear antigen (PCNA) in tubular cells, suggesting intense proliferative activity. Previous immunization with PS inhibited albuminuria and serum creatinine in association with the preservation of podocyte proteins and inhibition of fibrogenic transcripts and the expression of alpha-SMA and PCNA proteins. Tissue analysis also revealed that PS treatment induced expression of mRNA for GD3 synthase, which is a glycosiltransferase related to the synthesis of GD3, a ganglioside associated with podocyte physiology. In addition, PS treatment inhibited the influx of inflammatory CD8(pos) and CD11b(pos) cells to kidney tissue. Finally, PS treatment on day 4 post-ADM, a period when proteinuria was already established, was able to improve renal function. Thus, we demonstrate that the PS fraction of P. acnes can inhibit FSGS pathogenesis, suggesting that immunomodulation can represent an alternative approach for disease management. PMID- 22257708 TI - Midregional pro-A-type natriuretic peptide for diagnosis and prognosis in patients with suspected acute myocardial infarction. AB - We hypothesized that midregional pro-A-type natriuretic peptide (MR-proANP), the stable midregional epitope of proANP, might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). In this multicenter study we measured MR-proANP, cardiac troponin T (cTnT), and high-sensitive cTnT (hs-cTnT) at presentation in 675 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed 360 days for mortality and AMI. AMI was the final diagnosis in 119 patients (18%). Median MR-proANP levels at presentation were significantly higher in patients with AMI (189 pmol/L, interquartile range 97 to 341) versus patients with another final diagnosis (83 pmol/L, 49 to 144, p <0.001). However, neither the combination of MR-proANP with cTnT nor its combination with hs-cTnT significantly improved diagnostic accuracy as quantified by area under the receiver operating characteristic curve (0.91 vs 0.89 for cTnT alone, p = 0.086; 0.95 vs 0.96 for hs cTnT, respectively, p = 0.02). Cumulative 360-day mortality/AMI rates were 2.4% in the first, 3.6% in the second, 9.5% in the third, and 18.8% in the fourth quartiles of MR-proANP (p <0.001). MR-proANP (area under the curve 0.76) predicted mortality/AMI independently of and more accurately than cTnT (area under the curve 0.62), hs-cTnT (area under the curve 0.71), and Thrombolysis In Myocardial Infarction risk score (area under the curve 0.72). Net reclassification improvements offered by the additional use of MR-proANP were 0.388 (p <0.001), 0.425 (p <0.001), and 0.217 (p = 0.007), respectively. In conclusion, MR-proANP improves risk prediction for 360-day mortality/AMI but does not seem to help in the early diagnosis of AMI. PMID- 22257709 TI - Contribution of central adiposity to left ventricular diastolic function (from the Baltimore Longitudinal Study of Aging). AB - We examined the relations of central adiposity with left ventricular (LV) diastolic dysfunction in men and women who participated in the Baltimore Longitudinal Study of Aging, a prospective community-based study of older persons. The sample for this cross-sectional analysis included 399 women and 370 men. Central adiposity was estimated using the waist circumference (WC) and global adiposity using the body mass index (BMI). Using data from a comprehensive echocardiographic study that included tissue Doppler imaging, diastolic function was graded according to 3 parameters (E/A ratio, E/Em ratio, and left atrial volume index). In the logistic regression models adjusted for age, gender, cardiovascular risk factors, and hemodynamic parameters, WC and BMI were both independently associated with LV diastolic dysfunction. However, when both WC and BMI were in the same model, only WC remained significantly associated with LV diastolic dysfunction (odds ratio 1.04, 95% confidence interval 1.01 to 1.08, p = 0.02). In the gender-stratified analyses, WC was significantly associated with LV diastolic dysfunction-independently of BMI-in women (odds ratio 1.08, 95% confidence interval 1.04 to 1.14, p <0.001) but not in men (odds ratio 1.00, 95% confidence interval 0.95 to 1.05, p = 0.91). Additional adjustment for LV mass index failed to modify these relations. In conclusion, the adverse effect of central adiposity on LV diastolic function was independent of general adiposity and more pronounced among women. The effect of visceral adiposity on LV diastolic dysfunction would benefit from confirmation in longitudinal studies. PMID- 22257710 TI - Comparison of outcome of higher versus lower transvalvular gradients in patients with severe aortic stenosis and low (<40%) left ventricular ejection fraction. AB - Left ventricular systolic dysfunction in patients with severe aortic stenosis (AS) is associated with poor outcome. This analysis was designed primarily to describe the clinical course of a large series of consecutive patients with severe AS and low ejection fraction (EF) (<40%) who, because of high surgical risk, were referred for transcatheter aortic valve implantation consideration. A cohort of 270 patients with severe AS and low EF (<40%) who were referred to participate in a clinical trial of transcatheter aortic valve implantation was studied. Clinical, hemodynamic, and periprocedural complications and follow-up mortality data were collected and compared between patients with low mean transvalvular gradients (<=40 mm Hg, n = 170 [63%]) and high transvalvular gradients (>40 mm Hg, n = 100 [37%]). Patients with low gradients were younger (mean age 79.8 +/- 9.1 vs 83.8 +/- 7.7 years, p <0.001) and had higher incidences of coronary artery disease and renal failure. Mean aortic valve area was larger (0.73 +/- 0.23 vs 0.53 +/- 0.18 cm(2), p <0.001), while mean EF (26.4 +/- 6.9% vs 30.5% +/- 6.6%, p <0.001), cardiac output (3.7 +/- 1.1 vs 4.1 +/- 1.3 L/min, p = 0.04), and cardiac index (1.9 +/- 0.5 vs 2.1 +/- 0.6 L/min/m(2), p = 0.04) were lower in patients with lower gradients compared to those with higher gradients, respectively. Mortality was higher in patients with low gradients (53.8%) at a mean follow-up of 151 days compared to those with high gradients (41%) at a mean follow-up of 256 days (p = 0.01). In conclusion, patients with severe AS and low EF with low transvalvular gradients are at higher risk for worse outcomes compared to patients with high transvalvular gradients. Surgery or transcatheter aortic valve implantation treatment and high baseline transvalvular gradient are associated with EF improvement. PMID- 22257711 TI - Repetition, not number of sources, increases both susceptibility to misinformation and confidence in the accuracy of eyewitnesses. AB - Are claims more credible when made by multiple sources, or is it the repetition of claims that matters? Some research suggests that claims have more credibility when independent sources make them. Yet, other research suggests that simply repeating information makes it more accessible and encourages reliance on automatic processes-factors known to change people's judgments. In Experiment 1, people took part in a "misinformation" study: people first watched a video of a crime and later read eyewitness reports attributed to one or three different eyewitnesses who made misleading claims in either one report or repeated the same misleading claims across all three reports. In Experiment 2, people who had not seen any videos read those same reports and indicated how confident they were that each claim happened in the original event. People were more misled by-and more confident about-claims that were repeated, regardless of how many eyewitnesses made them. We hypothesize that people interpreted the familiarity of repeated claims as markers of accuracy. These findings fit with research showing that repeating information makes it seem more true, and highlight the power of a single repeated voice. PMID- 22257712 TI - Total sulfur determination in residues of crude oil distillation using FT-IR/ATR and variable selection methods. AB - Total sulfur concentration was determined in atmospheric residue (AR) and vacuum residue (VR) samples obtained from petroleum distillation process by Fourier transform infrared spectroscopy with attenuated total reflectance (FT-IR/ATR) in association with chemometric methods. Calibration and prediction set consisted of 40 and 20 samples, respectively. Calibration models were developed using two variable selection models: interval partial least squares (iPLS) and synergy interval partial least squares (siPLS). Different treatments and pre-processing steps were also evaluated for the development of models. The pre-treatment based on multiplicative scatter correction (MSC) and the mean centered data were selected for models construction. The use of siPLS as variable selection method provided a model with root mean square error of prediction (RMSEP) values significantly better than those obtained by PLS model using all variables. The best model was obtained using siPLS algorithm with spectra divided in 20 intervals and combinations of 3 intervals (911-824, 823-736 and 737-650 cm(-1)). This model produced a RMSECV of 400 mg kg(-1) S and RMSEP of 420 mg kg(-1) S, showing a correlation coefficient of 0.990. PMID- 22257713 TI - Vibrational spectroscopic study of the copper silicate mineral kinoite Ca2Cu2Si3O10(OH)4. AB - Kinoite Ca2Cu2Si3O10(OH)4 is a mineral named after a Jesuit missionary. Raman and infrared spectroscopy have been used to characterise the structure of the mineral. The Raman spectrum is characterised by an intense sharp band at 847 cm( 1) assigned to the nu1 (A1g) symmetric stretching vibration. Intense sharp bands at 951, 994 and 1000 cm(-1) are assigned to the nu3 (Eu, A2u, B1g) SiO4 antisymmetric stretching vibrations. Multiple nu2 SiO4 vibrational modes indicate strong distortion of the SiO4 tetrahedra. Multiple CaO and CuO stretching bands are observed. Raman spectroscopy confirmed by infrared spectroscopy clearly shows that hydroxyl units are involved in the kinoite structure. Based upon the infrared spectra, it is proposed that water is also involved in the kinoite structure. Based upon vibrational spectroscopy, the formula of kinoite is defined as Ca2Cu2Si3O10(OH)4.xH2O. PMID- 22257714 TI - Raman spectroscopy of the multianion mineral gartrellite PbCu(Fe3+,Cu)(AsO4)2(OH,H2O)2. AB - The multianion mineral gartrellite PbCu(Fe3+,Cu)(AsO4)2(OH,H2O)2 has been studied by a combination of Raman and infrared spectroscopy. The vibrational spectra of two gartrellite samples from Durango and Ashburton Downs were compared. Gartrellite is one of the tsumcorite mineral group based upon arsenate and sulphate anions. Crystal symmetry is either triclinic in the case of an ordered occupation of two cationic sites, triclinic due to ordering of the H bonds in the case of species with 2 water molecules per formula unit, or monoclinic in the other cases. Characteristic Raman spectra of the minerals enable the assignment of the bands to specific vibrational modes. These spectra are related to the structure of gartrellite. The position of the hydroxyl and water stretching vibrations are related to the strength of the hydrogen bond formed between the OH unit and the AsO4 anion. PMID- 22257715 TI - Chemical, spectroscopic characterization, DFT studies and antibacterial activities in vitro of a new gold(I) complex with rimantadine. AB - A novel gold(I) complex with rimantadine (RTD) was obtained and structurally characterized by a set of chemical and spectroscopic analysis. 1H, 13C and 15N nuclear magnetic resonance (NMR) and infrared (IR) spectroscopic measurements suggest coordination of the ligand to Au(I) through the N atom of the ethanamine group. Theoretical (DFT) calculations confirmed the IR assignments and permit proposing an optimized geometry for the complex. The gold(I)-rimantadine complex (Au-RTD) is soluble in methanol, ethanol, dimethylsulfoxide, acetone and acetonitrile. The preliminary kinetic studies based on UV-vis spectroscopic measurements indicate the stability of the compound in solution. Antibacterial activities of the complex were evaluated by an antibiogram assay. The Au-RTD complex showed an effective in vitro antibacterial activity against the Pseudomonas aeruginosa, Escherichia coli (Gram-negative), and Staphylococcus aureus (Gram-positive) bacterial strains. PMID- 22257716 TI - Spectral, thermal and optical properties of adenosinium picrate: a nonlinear optical single crystal. AB - A new organic nonlinear optical material adenosinium picrate (C10H14N5O4+, C6 H2 N3 O7-) was synthesized. The single crystal X-ray diffraction revealed the non centrosymmetric crystal structure, which is an essential criterion for second harmonic generation. The crystalline nature of the grown crystals was confirmed using powder XRD techniques. Molecular structure was confirmed by NMR spectral analysis and functional groups were identified by FT-IR spectral analysis. The optical transmittance window and the lower cutoff wavelength of the AP have been identified by UV-vis-NIR studies. Thermo gravimetric analysis (TGA) and differential thermal analysis (DTA) were used to study its thermal properties. Powder test with Nd:YAG laser radiation shows second harmonic generation. PMID- 22257717 TI - IR and Raman spectra of nitroanthracene isomers: substitional effects based on density functional theory study. AB - Structure, IR and Raman spectra of 1-, 2- and 9-nitroanthracene isomers (1-NA, 2 NA and 9-NA) were calculated and analyzed through density functional theory computations using the B3LYP functional with the 6-311+G** basis set. Steric and pi-conjugative effects determine the characteristic ONCC dihedral angles, which vary from 0 degrees (2-NA) to 28-29 degrees (1-NA) and 59 degrees (9-NA), influencing the relative order of stability along the series 9-NA<1-NA<2-NA. The spectral regions at wavenumber values>3000 cm(-1) and <1000 cm(-1) little depend on the substituent position. The Raman and IR intensity values of the characteristic symmetric nitro group stretching transition, appearing between 1310 and 1345 cm(-1), are rather sensitive to the position of the substituent, decreasing regularly on passing from the planar to the NO2-rotated isomers (9 NA<1-NA<2-NA). In the medium-energy spectral region (1000-1700 cm(-1)), the number and the relative position of the strongest Raman bands are of potential utility to discriminate the NA isomers. Structural and spectroscopic results suggest that the unknown mutagenic activity of 1-NA is expected to be between that of 9-NA and 2-NA. PMID- 22257718 TI - Physicochemical studies of chemosensor imidazole derivatives: DFT based ESIPT process. AB - A series of substituted imidazoles have been synthesized in very good yield under a solvent free condition using molecular iodine as the catalyst. An excited state intramolecular proton transfer (ESIPT) process in hydroxy imidazole has been studied using emission spectroscopy. DFT calculations on energy, dipole moment, charge distribution of the rotamers in the ground and excited states of the imidazole derivatives have been performed and discussed. DFT analysis about HOMO, HOMO-1, LUMO and LUMO+1 has been carried out and discussed. The energy barrier for the interconversion of two rotamers is too high in the excited state than the ground state that is shown by PES calculation. The molecular electrostatic potential surface (MEP) has also been employed to show the higher electron density at N(3) nitrogen. Fluorescence enhancement has been found in the presence of transition metal ions and this may result from the suppression of radiationless transitions from the n-pi* state in the chemosensors. PMID- 22257719 TI - The effect of the Fermi resonance on the Raman scattering cross sections of the Fermi doublet nu1 and 2nu2 of liquid carbon disulfide in benzene. AB - The effect of the Fermi resonance (FR) on the Raman scattering cross sections (RSCSs) of the Fermi doublet nu1, 2nu2 of liquid CS2 in C6H6 using the method of changing the volume concentration of the solution is investigated. We have calculated the RSCSs of the Fermi doublet nu1, 2nu2 using Onsager's theory with the 992 cm(-1) Raman line of C6H6 as the internal standard. The result shows that the RSCS of the nu1 line decreases with decreasing the volume concentration of CS2, while that of the 2nu2 line unexpectedly increases. With decreasing the volume concentration of CS2, two main effects of the solvent effect (SE) and the FR in binary solution that can make the nu1, 2nu2 RSCSs change: the SE, as calculated, reduces both the nu1 and 2nu2 RSCSs; the FR plays a significant role in reducing the nu1 RSCS and enhancing the 2nu2 RSCS. In comparison with our previous investigation [J. Raman Spectrosc. 41 (2010) 776-779], it was found that the stronger the FR is, the more the RSCS of the nu1 decreases and the 2nu2 increases. Thus, we proposed that the result can be best explained by taking into account the effect of the FR on the RSCSs of the Fermi doublet. In addition, this paper also gives an explanation to the experimental results deviating from the theoretical results of the scattering coefficients of CS2 in solvent C6H6 as mentioned in Fini's paper. PMID- 22257720 TI - Cutaneous leishmaniasis acquired in Jura, France. PMID- 22257721 TI - Microarray analysis on germfree mice elucidates the primary target of a traditional Japanese medicine juzentaihoto: acceleration of IFN-alpha response via affecting the ISGF3-IRF7 signaling cascade. AB - BACKGROUND: The traditional Japanese medicine juzentaihoto (JTX) is a pharmaceutical grade multi-herbal medicine widely used for the prevention of cancer metastasis and infection in immuno-compromized patients in Japan. The effect of JTX has been supposed to be intimately affected by the immunological properties of host and enteric microflora. The influence of JTX on the gene expression profile in the large and small intestines was investigated by microarray analyses using mice of different strains with or without enteric microflora. RESULTS: In all types of mice, including germfree (GF) animals, the genes most affected by two-week oral JTX treatment were the type 1 interferon (IFN)-related genes including Stat1, Isgf3g and Irf7, which play a critical role in the feedback loop of IFN-alpha production cascade. In IQI specific pathogen free (SPF) mice JTX increased the steady state level of the expression of IFN related genes, but had the opposite effect in IQI GF and BALB/c SPF mice. Promoter analysis suggests that tandem repeated $IRFF (the promoter sequences for interferon regulatory factors) may be a primary target for JTX action. Pre treatment of JTX accelerated the effects of an oral IFN "inducer" 2-amino-5-bromo 6-methyl-4-pyrimidinol (ABMP) (up-regulation of IFN-alpha production in IQI strain and down-regulation in BALB/c mice), which is in good accordance with the effect of JTX on gene expression of type 1 IFN-related genes. CONCLUSIONS: Microarray analysis revealed that the target of JTX might be the transcription machinery regulating the steady-state level of genes involved in the ISGF3-IRF7 cascade, whose effect is bi-directional in a strain- and microbiota-dependent manner. PMID- 22257722 TI - The impact of PLGA scaffold orientation on in vitro cartilage regeneration. AB - The success of in vitro cartilage regeneration provides a promising approach for cartilage repair. However, the currently engineered cartilage in vitro is unsatisfactory for clinical application due to non-homogeneous structure, inadequate thickness, and poor mechanical property. It has been widely reported that orientation of scaffolds can promote cell migration and thus probably contributes to improving tissue regeneration. This study explored the impact of microtubular oriented scaffold on in vitro cartilage regeneration. Porcine articular chondrocytes were seeded into microtubule-oriented PLGA scaffolds and non-oriented scaffolds respectively. A long-term in vitro culture followed by a long-term in vivo implantation was performed to evaluate the influence of scaffold orientation on cartilage regeneration. The current results showed that the oriented scaffolds could efficiently promote cell migration towards the inner region of the constructs. After 12 weeks of in vitro culture, the chondrocyte scaffold constructs in the oriented group formed thicker cartilage with more homogeneous structure, stronger mechanical property, and higher cartilage matrix content compared to the non-oriented group. Furthermore, the in vitro engineered cartilage based on oriented scaffolds showed better cartilage formation in terms of size, wet weight, and homogeneity after 12-week in vivo implantation in nude mice. These results indicated that the longitudinal microtubular orientation of scaffolds can efficiently improve the structure and function of in vitro engineered cartilage. PMID- 22257723 TI - Responsive fluorescent Bi(2)O(3)@PVA hybrid nanogels for temperature-sensing, dual-modal imaging, and drug delivery. AB - The polymer-inorganic hybrid nanogels with temperature-responsive characteristic are of considerable current interest to many fields ranging from fundamental biomaterials science to bionanomedicine. This paper reports the preparation of temperature-responsive hybrid nanogels by immobilization of Bi(2)O(3) quantum dots (QDs) in the interior of a nanogel of poly(vinyl alcohol) (PVA). Unlike conventional temperature-responsive hybrid nanogels with the responsive features deriving from the temperature-responsive polymers (e.g. PNIPAMs or non-linear PEGs), we demonstrate that QDs can work cooperatively with the gel networks of PVA, an unconventional responsive polymer, to enable the temperature-induced volume phase transition of the designed Bi(2)O(3)@PVA hybrid nanogels. Building on the rationales, Bi(2)O(3)@PVA hybrid nanogels can adapt to a surrounding fluids of different temperatures over the physiologically important range of 37 40 degrees C, convert the disruptions in homeostasis of environmental temperature into high-sensitive fluorescent signals, enter into the mouse melanoma B16F10 cells for dark-field and fluorescence dual-modal imaging, and regulate the release of a model anticancer drug temozolomide. The unconventional strategy that can broaden the design scheme of temperature-responsive hybrid nanogels for theranostic action should enhance our ability to address the complexity of biological systems. PMID- 22257724 TI - The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. AB - Gastric ulcer is a multifaceted process that involves reactive oxygen species (ROS) generation, extracellular matrix degradation and mitochondrial damage. Mitochondria play a crucial role for homeostasis of ROS and cell survival. In our study, we investigated the efficacy and mechanism of polymeric nanocapsuled quercetin (NQC) over the free quercetin (QC) molecule in prevention of ethanol induced gastric ulcer in rat. NQC possessed significantly higher efficacy (~20 fold) than free QC while preventing gastric ulcers. Our data show that prior administration of NQC and/or QC significantly blocked synthesis and secretion of matrix metalloproteinase (MMP)-9 as well as infiltration of inflammatory cells and oxidative damage in rat gastric tissues. As compared to free QC, NQC protected much better the mitochondrial integrity and size along with mitochondrial functions by controlling succinate dehydrogenase and NADH oxidase in rat gastric tissues. In addition, both free QC and NQC down regulated PARP-1 as well as apoptosis during protection against ethanol-induced gastric ulcer. Herein, the effect of NQC was greater than QC on expression of enzymes like cyclooxygenase and nitric oxidase synthase (NOS)-2. We conclude that NQC with greater bioavailability offers significantly higher potency in downregulating MMP 9 and NOS-2 as well as oxidative stress in blocking ethanol-induced gastric ulcer. PMID- 22257725 TI - Balancing osteoblast functions and bacterial adhesion on functionalized titanium surfaces. AB - The demand for orthopedic and dental implants will continue to grow, and for these applications, titanium and its alloys have been used extensively. While these implants have achieved high success rates, two major complications may be encountered: the lack of bone tissue integration and implant-centered infection. The surface of the implant, through its interactions with proteins, bacteria and tissue cells, plays a determining role in the success or failure of the implant. Ideally, to enhance the success of implants, their surfaces should inhibit bacterial colonization and concomitantly promote osteoblast functions. In this article, we discuss strategies for tailoring implant surfaces by exploiting the differences in the response of bacteria and osteoblasts to proteins and surface structures. Nevertheless, limitations still exist in the quest for an ideal implant surface. Further advances in this field will require concurrent development in surface modification techniques and a better understanding of the complex and highly inter-related events occurring at the implant surface after implantation. PMID- 22257726 TI - First report on the occurrence of Rickettsia slovaca and Rickettsia raoultii in Dermacentor silvarum in China. AB - BACKGROUND: Rickettsioses are among both the longest known and most recently recognized infectious diseases. Although new spotted fever group rickettsiae have been isolated in many parts of the world including China, Little is known about the epidemiology of Rickettsia pathogens in ticks from Xinjiang Autonomous Region of China. METHODS: In an attempt to assess the potential risk of rickettsial infection after exposure to ticks in Xinjiang Uygur Autonomous Region of China, a total of 200 Dermacentor silvarum ticks collected in Xinyuan district were screened by polymerase chain reaction based on the outer membrane protein A gene. RESULTS: 22 of the 200 specimens (11%) were found to be positive by PCR. Phylogenetic analysis of OmpA sequences identified two rickettsial species, Rickettsia raoultii (4.5%) and Rickettsia slovaca (6.5%). CONCLUSIONS: This study has reported the occurrence of Rickettsia raoultii and Rickettsia slovaca in Xinjiang Autonomous Region of China and suggests that Dermacentor silvarum could be involved in the transmission of rickettsial agents in China. Further studies on the characterization and culture of rickettsial species found in Dermacentor silvarum should be performed to further clarify this. Additionally, the screening of human specimens for rickettsial disease in this region will define the incidence of infection. PMID- 22257727 TI - Pyrazinamide susceptibility testing in all isolates of the Mycobacterium tuberculosis complex - a critical analysis. PMID- 22257728 TI - Emerging narrative discourse skills 18 months after traumatic brain injury in early childhood. AB - This study examined the longer term effect of traumatic brain injury (TBI), approximately 18 months post-injury, on emerging narrative discourse skills of 85 children with orthopaedic injury (OI), 43 children with moderate TBI, and 19 children with severe TBI who were between 3 years and 6 years 11 months at injury. Children with TBI performed worse than children with OI on most discourse indices. Children with severe TBI were less proficient than children with moderate TBI at identifying unimportant story information. Age and pragmatic skills were predictors of discourse performance. PMID- 22257729 TI - Exploring the relationships between housing, neighbourhoods and mental wellbeing for residents of deprived areas. AB - BACKGROUND: Housing-led regeneration has been shown to have limited effects on mental health. Considering housing and neighbourhoods as a psychosocial environment, regeneration may have greater impact on positive mental wellbeing than mental ill-health. This study examined the relationship between the positive mental wellbeing of residents living in deprived areas and their perceptions of their housing and neighbourhoods. METHODS: A cross-sectional study of 3,911 residents in 15 deprived areas in Glasgow, Scotland. Positive mental wellbeing was measured using the Warwick-Edinburgh Mental Wellbeing Scale. RESULTS: Using multivariate mulit-nomial logistic regressions and controlling for socio demographic characteristics and physical health status, we found that several aspects of people's residential psychosocial environments were strongly associated with higher mental wellbeing. Mental wellbeing was higher when respondents considered the following: their neighbourhood had very good aesthetic qualities (RRR 3.3, 95% CI 1.9, 5.8); their home and neighbourhood represented personal progress (RRR 3.2 95% CI 2.2, 4.8; RRR 2.6, 95% CI 1.8, 3.7, respectively); their home had a very good external appearance (RRR 2.6, 95% CI 1.3, 5.1) and a very good front door (both an aesthetic and a security/control item) (RRR 2.1, 95% CI 1.2, 3.8); and when satisfaction with their landlord was very high (RRR 2.3, 95% CI 2.2,4.8). Perception of poor neighbourhood aesthetic quality was associated with lower wellbeing (RRR 0.4, 95% CI 0.3, 0.5). CONCLUSIONS: This study has shown that for people living in deprived areas, the quality and aesthetics of housing and neighbourhoods are associated with mental wellbeing, but so too are feelings of respect, status and progress that may be derived from how places are created, serviced and talked about by those who live there. The implication for regeneration activities undertaken to improve housing and neighbourhoods is that it is not just the delivery of improved housing that is important for mental wellbeing, but also the quality and manner of delivery. PMID- 22257731 TI - Structural and functional topography of the human ribosome. AB - This review covers data on the structural organization of functional sites in the human ribosome, namely, the messenger RNA binding center, the binding site of the hepatitis C virus RNA internal ribosome entry site, and the peptidyl transferase center. The data summarized here have been obtained primarily by means of a site directed cross-linking approach with application of the analogs of the respective ribosomal ligands bearing cross-linkers at the designed positions. These data are discussed taking into consideration available structural data on ribosomes from various kingdoms obtained with the use of cryo-electron microscopy, X-ray crystallography, and other approaches. PMID- 22257730 TI - Designing and evaluating risk-based surveillance systems: potential unwarranted effects of applying adjusted risk estimates. AB - Risk-based surveillance systems reveal occurrence of disease or infection in a sample of population units, which are selected on the basis of risk factors for the condition under study. The purpose of such systems for supporting practical animal disease policy formulations and management decisions are: A: to detect an emerging disease or infection, if it becomes introduced into a population; or B: to substantiate freedom from a condition in a population; or C: to detect cases and estimate the prevalence of an endemic condition in a population. In risk based surveillance these aims should be met with prudent use of resources while maintaining acceptable system performance. High-risk category units are selected for testing by identification of the presence of specific high-risk factor(s), while disregarding other factors that might also influence the risk. On this basis we argue that the most applicable risk estimate for use in designing and evaluating a risk-based surveillance system would be a crude (unadjusted) relative risk, odds ratio or apparent prevalence. Risk estimates found in the published literature, however, are often the results of multivariable analyses implicitly adjusting the estimates for confounding from other risk factors. We describe some potential unintentional effects when using adjusted risk estimates in evaluating the efficacy and sensitivity of risk-based surveillance systems (SSe). In two examples, we quantify and compare the efficacy and SSe using adjusted and crude risk estimates. The examples use Danish surveillance data from previously published studies to evaluate systems aimed at risk-based detection of new cases of an endemic infection, i.e. Salmonella in dairy cattle herds (Example 1), and for substantiating the absence of a specific infection, i.e. Trichinella in the national slaughter pig population (Example 2), respectively. PMID- 22257732 TI - Comparative evaluation of T11 target structure and its deglycosylated derivative nullifies the importance of glycan moieties in immunotherapeutic efficacy. AB - Sheep red blood cell (SRBC), a non-specific biological response modifier that has long been used as a classical antigen, has been shown to exert an immunomodulatory and anti-tumor activities in experimental animals. The active component of SRBC, which is responsible for such effects, was found to be a cell surface acidic glycoprotein molecule, known as T11 target structure (T11TS). In the present study, T11TS was isolated and purified to homogeneity using a five step protocol involving isolation of sheep erythrocyte membrane from packed cell volume, 20% ammonium sulfate cut of the crude membrane proteins mixture, immunoaffinity purification using mouse anti-sheep CD58 mAb (L180/1) tagged matrix, preparative gel electrophoresis, and gel electroelution process. Finally, the purity and identity of the proteins were confirmed by the matrix-assisted laser desorption/ionization (MALDI) mass spectrometric analysis. The in silico glycosylation site analysis showed that the extracellular domain contained three N-glycosylation sites (N-12, N-62, and N-111) and one O-glycosylation site (T 107). However, the experimental analysis negated the presence of O-linked glycan moieties on T11TS. To investigate the role of glycan moieties in the current immunotherapeutic regime, T11TS and its deglycosylated form (dT11TS) were administered intraperitoneally (i.p.) in N-ethyl-N-nitrosourea-induced immune compromised mice at 0.4 mg/kg body weight. It was observed that both the forms of T11TS could activate the compromised immune status of mice by augmenting immune receptor expression (CD2, CD25, CD8, and CD11b), T-helper 1 shift of cytokine network, enhanced cytotoxicity, and phagocytosis activity. Therefore, the results nullify the active involvement of the N-linked glycan moieties in immunotherapeutic efficacy of T11TS. PMID- 22257733 TI - [Morphometric analysis of the human endometrium during the implantation window. Light and transmission electron microscopy study]. AB - OBJECTIVES: To perform a morphometric and ultrastructural analysis of the various cellular components that constitutes the endometrial epithelium during the implantation window. METHODS: Endometrial biopsies of six patients in ageing to procreate were realized during the implantation window and analyzed using light and transmission electron microscopy (TEM). RESULTS: During the implantation window, four endometrial cell types are identified in distinct proportions: microvilli-rich cells, pinopode cells, ciliated cells and others without apical differentiation. We highlighted important differences between surface and glandular epitheliums. Pinopode cells are present in all biopsies; they are more frequent in glands than surface. Their maximum expression in the glandular epithelium is at the day 20 and in the surface epithelium at the day 22. The pinopodes are present since day 19, they appeared fully developed with a maximum at day 22. Using TEM for ultrastructural analysis, we showed images of endocytosis and numerous secretory vesicles in epithelial cells of the endometrium. Their plasmic membrane present apical differentiations in the form of microvilli covered with a very developed cell coat indicating a high activity of exchange with the extracellular compartment. The endometrial cells exhibit extensive signs of communication between neighboring cells appeared to be preserved. CONCLUSION: Our data suggest each cell type and each cell structure as a very precise function in order to prepare the endometrium to be receptive. PMID- 22257734 TI - Resonance acoustic microbalance with naked-embedded quartz (RAMNE-Q) biosensor fabricated by microelectromechanical-system process. AB - A resonance acoustic microbalance with a naked-embedded quartz (RAMNE-Q) is realized by a microfabrication method, aiming at broader applications of quartz crystal microbalance (QCM) biosensors. The RAMNE-Q biosensor consists of three layers; a silicon layer with an engraved microchannel and sandwiching glass layers. The naked AT-cut quartz resonator of 9.3 or 28.5 MUm thick is located in the microchannel and supported by the silicon micropillars and semicircular walls without fixing, and it is encapsulated by the rigid body. Cupper antennas are used for generating and receiving electromagnetic fields to excite and detect the shear vibration of the quartz oscillator during the solution flow, thereby achieving the noncontact measurement of the resonance frequency. Because of the isolated resonator, the Q factor is high enough (about 1500 at 170-180 MHz) even in the flowing solution. We succeeded in detecting 1 ng/ml human immunoglobulin G in phosphate-buffered-saline solution via Staphylococcus aureus protein A immobilized nonspecifically on the quartz surfaces, demonstrating the high sensitivity and high signal-to-noise ratio of the RAMNE-Q biosensor. It does not require electrodes and is a replacement-free biosensor, and its reusability is confirmed. PMID- 22257735 TI - A printed superoxide dismutase coated electrode for the study of macrophage oxidative burst. AB - The miniaturization of electrochemical sensors allows for the minimally invasive and cost effective examination of cellular responses at a high efficacy rate. In this work, an ink-jet printed superoxide dismutase electrode was designed, characterized, and utilized as a novel microfluidic device to examine the metabolic response of a 2D layer of macrophage cells. Since superoxide production is one of the first indicators of oxidative burst, macrophage cells were exposed within the microfluidic device to phorbol myristate acetate (PMA), a known promoter of oxidative burst, and the production of superoxide was measured. A 46 +/- 19% increase in current was measured over a 30 min time period demonstrating successful detection of sustained macrophage oxidative burst, which corresponds to an increase in the superoxide production rate by 9 +/- 3 attomoles/cell/s. Linear sweep voltammetry was utilized to show the selectivity of this sensor for superoxide over hydrogen peroxide. This novel controllable microfluidic system can be used to study the impact of multiple effectors from a large number of bacteria or other invaders along a 2D layer of macrophages, providing an in vitro platform for improved electrochemical studies of metabolic responses. PMID- 22257736 TI - Detection of single-nucleotide polymorphisms with novel leaky surface acoustic wave biosensors, DNA ligation and enzymatic signal amplification. AB - This manuscript describes a new technique for detecting single-nucleotide polymorphisms (SNPs) by integrating a leaky surface acoustic wave (LSAW) biosensor, enzymatic DNA ligation and enzymatic signal amplification. In this technique, the DNA target is hybridized with a capture probe immobilized on the surface of a LSAW biosensor. Then, the hybridized sequence is ligated to biotinylated allele-specific detection probe using Taq DNA ligase. The ligation does not take place if there is a single-nucleotide mismatch between the target and the capture probe. The ligated detection probe is transformed into a streptavidin-horseradish peroxidase (SA-HRP) terminal group via a biotin streptavidin complex. Then, the SA-HRP group catalyzes the polymerization of 3,3 diaminobenzidine (DAB) to form a surface precipitate, thus effectively increasing the sensitivity of detecting surface mass changes and allowing detection of SNPs. Optimal detection conditions were found to be: 0.3 mol/L sodium ion concentration in PBS, pH 7.6, capture probe concentration 0.5 MUmol/L and target sequence concentration 1.0 MUmol/L. The detection limit was found to be 1 * 10(-12)mol/L. Using this technique, we were able to detect a single-point mutation at nucleotide A2293G in Japanese encephalitis virus. PMID- 22257737 TI - Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats. AB - BACKGROUND: Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route. METHODS: ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 MUg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-alpha, IL-1beta, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry. RESULTS: Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 MUg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 MUg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-alpha, IL 1beta, and IL-6 production 1, 3 and 7 days post-ICH. CONCLUSION: Systemic post ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen. PMID- 22257738 TI - Navigator channel adaptation to reconstruct three dimensional heart volumes from two dimensional radiotherapy planning data. AB - BACKGROUND: Biologically-based models that utilize 3D radiation dosimetry data to estimate the risk of late cardiac effects could have significant utility for planning radiotherapy in young patients. A major challenge arises from having only 2D treatment planning data for patients with long-term follow-up. In this study, we evaluate the accuracy of an advanced deformable image registration (DIR) and navigator channels (NC) adaptation technique to reconstruct 3D heart volumes from 2D radiotherapy planning images for Hodgkin's Lymphoma (HL) patients. METHODS: Planning CT images were obtained for 50 HL patients who underwent mediastinal radiotherapy. Twelve image sets (6 male, 6 female) were used to construct a male and a female population heart model, which was registered to 23 HL "Reference" patients' CT images using a DIR algorithm, MORFEUS. This generated a series of population-to-Reference patient specific 3D deformation maps. The technique was independently tested on 15 additional "Test" patients by reconstructing their 3D heart volumes using 2D digitally reconstructed radiographs (DRR). The technique involved: 1) identifying a matching Reference patient for each Test patient using thorax measurements, 2) placement of six NCs on matching Reference and Test patients' DRRs to capture differences in significant heart curvatures, 3) adapting the population-to Reference patient-specific deformation maps to generate population-to-Test patient-specific deformation maps using linear and bilinear interpolation methods, 4) applying population-to-Test patient specific deformation to the population model to reconstruct Test-patient specific 3D heart models. The percentage volume overlap between the NC-adapted reconstruction and actual Test patient's true heart volume was calculated using the Dice coefficient. RESULTS: The average Dice coefficient expressed as a percentage between the NC-adapted and actual Test model was 89.4 +/- 2.8%. The modified NC adaptation technique made significant improvements to the population deformation heart models (p = 0.01). As standard evaluation, the residual Dice error after adaptation was comparable to the volumetric differences observed in free-breathing heart volumes (p = 0.62). CONCLUSIONS: The reconstruction technique described generates accurate 3D heart models from limited 2D planning data. This development could potentially be used to retrospectively calculate delivered dose to the heart for historically treated patients and thereby provide a better understanding of late radiation related cardiac effects. PMID- 22257739 TI - Visceral Leishmaniasis during Italian Renaissance, 1522-1562. PMID- 22257740 TI - Housing, medical, and food deprivation in poor urban contexts: implications for multiple sexual partnerships and transactional sex in Nairobi's slums. AB - Identifying the factors that lead to sexual risk behavior is crucial in addressing the HIV epidemic in sub-Saharan Africa. Scholars have primarily relied on traditional measures of SES (income, wealth, and education) to predict risk, overlooking measures of deprivation in important social arenas such as housing, medical care, and food expenses. Findings demonstrated that all three deprivation measures, particularly housing and health care, were robust influences of sexual risk even while controlling for traditional SES measures. A multifaceted deprivation framework appears crucial to the development of effective policy interventions to diminish HIV infection. PMID- 22257741 TI - Health care and socioeconomic impact of falls in the elderly. AB - BACKGROUND: Elderly falls are associated with long hospital stays, major morbidity, and mortality. We sought to examine the fate of patients >=75 years of age admitted after falls. METHODS: We reviewed all fall admissions in 2008. Causes, comorbidities, injuries, procedures, mortality, readmission, and costs were analyzed. RESULTS: Seven hundred eight patients >=75 years old were admitted after a fall, with 89% being simple falls. Short-term mortality was 6%. Male sex, atrial fibrillation, acute myocardial infarction, congestive heart failure (CHF), intracranial hemorrhage, hospital-acquired pneumonia, trigger events, Clostridium difficile, and intubation were predictors of death (P < .05). Thirty-day readmission occurred in 14%; CHF, craniotomy, and acute renal failure were predictive. The median cost of hospitalization was $11,000 with cardiac disease, anemia, major orthopedic and neurosurgical procedures, pneumonia, and intubation as predictive. CONCLUSIONS: Simple falls in the elderly have high morbidity, mortality, and costs. Methodologies for prevention are warranted and should be studied intensively. PMID- 22257742 TI - Sequencing and comparative genomic analysis of 1227 Felis catus cDNA sequences enriched for developmental, clinical and nutritional phenotypes. AB - BACKGROUND: The feline genome is valuable to the veterinary and model organism genomics communities because the cat is an obligate carnivore and a model for endangered felids. The initial public release of the Felis catus genome assembly provided a framework for investigating the genomic basis of feline biology. However, the entire set of protein coding genes has not been elucidated. RESULTS: We identified and characterized 1227 protein coding feline sequences, of which 913 map to public sequences and 314 are novel. These sequences have been deposited into NCBI's genbank database and complement public genomic resources by providing additional protein coding sequences that fill in some of the gaps in the feline genome assembly. Through functional and comparative genomic analyses, we gained an understanding of the role of these sequences in feline development, nutrition and health. Specifically, we identified 104 orthologs of human genes associated with Mendelian disorders. We detected negative selection within sequences with gene ontology annotations associated with intracellular trafficking, cytoskeleton and muscle functions. We detected relatively less negative selection on protein sequences encoding extracellular networks, apoptotic pathways and mitochondrial gene ontology annotations. Additionally, we characterized feline cDNA sequences that have mouse orthologs associated with clinical, nutritional and developmental phenotypes. Together, this analysis provides an overview of the value of our cDNA sequences and enhances our understanding of how the feline genome is similar to, and different from other mammalian genomes. CONCLUSIONS: The cDNA sequences reported here expand existing feline genomic resources by providing high-quality sequences annotated with comparative genomic information providing functional, clinical, nutritional and orthologous gene information. PMID- 22257743 TI - Comprehensive assessment of metabolic syndrome among rural Bangladeshi women. AB - BACKGROUND: Metabolic syndrome (MS), defined as a constellation of cardiovascular disease (CVD) risk factors, is one of the fastest growing public health burdens in the Asia-Pacific region. This trend is despite the fact that people in this region are no more overweight than Europeans and Americans. Unfortunately, in South Asia, MS screening has only been performed in a few countries other than Bangladesh. Therefore the present study is designed to conduct a comprehensive screening of MS in Bangladeshi rural women, which includes estimation of prevalence and assessment of risk factor. METHODS: A total of 1535 rural Bangladesh women aged >= 15 years were studied using a population based cross sectional survey. The prevalence of MS was estimated using NCEP ATP III, modified NCEP ATP III and IDF criteria. RESULTS: The prevalence rates of MS were 25.60% (NCEP ATP III), 36.68% (modified NCEP ATP III), and 19.80% (IDF), as revealed by the present study. Furthermore, based on the NCEP ATP III criteria, 11.60% of the subjects were found to have excess waist circumference; 29.12% had elevated blood pressure, 30.42% had elevated fasting plasma glucose level, 85.47% had low HDL values and 26.91% had increased triglyceride values. Low plasma HDL level was found to be the most common abnormality in the target population and elevated waist circumference was the least frequent component. CONCLUSIONS: The present study reveals a high prevalence of MS and its associated risk factors in rural Bangladeshi women. These findings are important in that they provide insights that will be helpful in formulating effective public health policy, notably the development of future health prevention strategies in Bangladesh. PMID- 22257744 TI - [Retrospective analysis of 24 recurrent glioblastoma after chemoradiation and treated with nitrosoureas or irinotecan and bevacizumab]. AB - Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB. PMID- 22257745 TI - Rebelling against the brain: public engagement with the 'neurological adolescent'. AB - The adolescent brain has become a flourishing project for cognitive neuroscience. In the mid 1990s, MRI studies mapped out extended neuro-development in several cortical regions beyond childhood, and during adolescence. In the last ten years, numerous functional MRI studies have suggested that functions associated with these brain regions, such as cognitive control and social cognition undergo a period of development. These changes have been anecdotally and clinically used to account for behavioural changes during adolescence. The interpretation of these data that the "teen brain" is different has gained increasing visibility outside the neuroscience community, among policy makers and in the media, resonating strongly with current cultural conceptions of teenagers in Western societies. In the last two years, a new impetus has been placed on public engagement activities in science and in the popular science genre of the media that specifically attempts to educate children and teenagers about emerging models of the developing brain. In this article, we draw on data from an adolescent focus group and a questionnaire completed by 85 teenage students at a UK school, to show how teens may hold ambivalent and sometimes resistant views of cognitive neuroscience's teen brain model in terms of their own self-understandings. Our findings indicate that new "neuro"-identity formations are more fractured, resisted and incomplete than some of the current social science literature on neuro-subjectivities seem to suggest and that the effects of public policy and popular education initiatives in this domain will be more uneven and complex than currently imagined. PMID- 22257746 TI - Migration, "illegality," and health: mapping embodied vulnerability and debating health-related deservingness. PMID- 22257747 TI - Arterio-arterial vascular anastomoses in monochorionic twin placentas with and without twin anemia-polycythemia sequence. AB - We performed a matched case-control study to analyze the placental angioarchitecture, in particular the diameter of arterio-arterial (AA) anastomoses in monochorionic placentas from pregnancies with spontaneous twin anemia-polycythemia sequence (TAPS) compared to a control group of uncomplicated monochorionic placentas. Placental angioarchitecture was analyzed using colored dye injection. AA anastomoses were detected in 20% (3/15) of spontaneous TAPS placentas. The median diameter of AA anastomoses in the group with and without TAPS was 0.4 mm and 2.2 mm, respectively (p = 0.01). In conclusion, AA anastomoses are rarely detected in TAPS placentas. When present, the AA anastomosis is very small, preventing equilibration of hemoglobin levels between both twins. PMID- 22257748 TI - cDNA-AFLP analysis of salt-inducible genes expression in Chrysanthemum lavandulifolium under salt treatment. AB - Chrysanthemum lavandulifolium (Fisch. ex Trautv.) Makino is a halophyte species that belongs to the Asteraceae family, and the genus Chrysanthemum. It is one of the ancestors of C.*morifolium Ramatella. Understanding the tolerance mechanism associated with salt stress in C. lavandulifolium could provide important information for explaining the salt tolerance of higher plants and could also help enhancing breeding programs of cultivated Chrysanthemum. In this study, cDNA amplified fragment length polymorphism (cDNA-AFLP) was used to detect differential gene expression in leaves of C. lavandulifolium in response to NaCl treatment. The determination of membrane permeablility, peroxidase activity (POD), malon-dialdehyde (MDA), as well as proline and leaf chlorophyll contents under different NaCl concentrations showed that a 200 mM NaCl treatment was an optimal condition for the cDNA-AFLP experiment. Using this concentration during different times (0, 3 h, 12 h, 24 h and 48 h), we obtained 1930 cDNA fragments using 64 primers. After sequencing 234 randomly chosen cDNA clones and BLASTx analyzing, we got 129 expressed sequence tags (ESTs) which had no significant homology with other sequences, 85 ESTs were homologous to genes with known functions, whereas the rest of ESTs showed homology to unclassified or putative proteins. 25 ESTs that were similar to known functional genes involved in several abiotic and biotic stresses were confirmed by semi-quantitative RT-PCR and qRT PCR. The expression patterns of these salt-responsive genes not only responded to salt stress but also to plant hormones, such as abscisic acid (ABA), and to other abiotic stresses such as drought and cold. These results indicate an extensive cross-talk among several stresses. Our results provide interesting information for further understanding the molecular mechanisms of salt tolerance in C. lavandulifolium. PMID- 22257749 TI - Development and qualification of an antibody rapid deglycosylation method. AB - N-linked glycosylation can influence the biological activity and safety of an antibody as well as be a measure of the consistency of the production process. The released N-glycans is an important part of the development of a therapeutic antibody. The traditional method for N-glycan analysis requires complex and laborious sample preparation and lengthy analysis time. Two preparation steps with limited control are removal of the antibody backbone by ice-cold ethanol precipitation and water removal before 2-AB fluorescent dye labeling. Simplification of the sample preparation and better control of key steps that allows for the characterization/quantitation of glycans during all stages of development of a therapeutic antibody is desired. Recently Prozyme introduced a rapid deglycosylation kit and a rapid tagging kit that address some of these issues. The deglycosylation kit immobilizes the antibody on a membrane, thereby eliminating the precipitation step. An instant fluorescent tag kit eliminates the water removal before the 2-AB labeling step. In addition use of a new chromatography column can improve the glycan resolution and shorten the analysis time. The evaluation and qualification of the Rapid Deglycosylation Kit (RDK) and instant 2-AB tagging with the improved chromatography are highlighted. PMID- 22257750 TI - Actinidin, a protease from kiwifruit, induces changes in morphology and adhesion of T84 intestinal epithelial cells. AB - Actinidin belongs to the papain-like family of cysteine proteases and is a major kiwifruit allergen. In this study, the effect of actinidin on cellular morphology and adhesion of T84 intestinal cells was investigated. Both rounding and detachment of T84 cells were observed upon actinidin treatment. The morphological changes and cell desquamation was protease-dependent, as well as time- and concentration-dependent. Changes of intercellular adhesion and adhesion of epithelial cells to collagen upon actinidin treatment could be responsible for the cell rounding and give rise to discontinuous breaches in the epithelial monolayer observed in this study. Actinidin's action on cell morphology, adhesion and monolayer integrity were not due to compromised viability of T84 epithelial cells, as confirmed by MTT assay and flow cytometric analysis of the cell cycle. Damage to the epithelial monolayer of the intestine induced by actinidin should be further evaluated as an important factor in the development of kiwifruit allergy and other intestinal disorders. PMID- 22257751 TI - Characterizing the effects of cell settling on bioprinter output. AB - The time variation in bioprinter output, i.e. the number of cells per printed drop, was studied over the length of a typical printing experiment. This variation impacts the cell population size of bioprinted samples, which should ideally be consistent. The variation in output was specifically studied in the context of cell settling. The bioprinter studied is based on the thermal inkjet HP26A cartridge; however, the results are relevant to other cell delivery systems that draw fluid from a reservoir. A simple mathematical model suggests that the cell concentration in the bottom of the reservoir should increase linearly over time, up to some maximum, and that the cell output should be proportional to this concentration. Two studies were performed in which D1 murine stem cells and similarly sized polystyrene latex beads were printed. The bead output profiles were consistent with the model. The cell output profiles initially followed the increasing trend predicted by the settling model, but after several minutes the cell output peaked and then decreased. The decrease in cell output was found to be associated with the number of use cycles the cartridge had experienced. The differing results for beads and cells suggest that a biological process, such as adhesion, causes the decrease in cell output. Further work will be required to identify the exact process. PMID- 22257752 TI - Imaging plants dynamics in heterogenic environments. AB - Noninvasive imaging sensors and computer vision approaches are key technologies to quantify plant structure, physiological status, and performance. Today, imaging sensors exploit a wide range of the electromagnetic spectrum, and they can be deployed to measure a growing number of traits, also in heterogenic environments. Recent advances include the possibility to acquire high-resolution spectra by imaging spectroscopy and classify signatures that might be informative of plant development, nutrition, health, and disease. Three-dimensional (3D) reconstruction of surfaces and volume is of particular interest, enabling functional and mechanistic analyses. While taking pictures is relatively easy, quantitative interpretation often remains challenging and requires integrating knowledge of sensor physics, image analysis, and complex traits characterizing plant phenotypes. PMID- 22257753 TI - Are females who inject drugs at higher risk for HIV infection than males who inject drugs: an international systematic review of high seroprevalence areas. AB - OBJECTIVE: There are multiple reasons why females who inject drugs may be more likely to become infected with HIV than males who inject drugs. Where this is the case, special HIV prevention programs for females would be needed. DESIGN: International systematic review and meta-analysis of studies across 14 countries. METHODS: Countries with high seroprevalence (>20%) HIV epidemics among persons who inject drugs (PWID) were identified from the Reference Group to the UN on HIV and Injecting Drug Use. Systematic literature reviews collected data on HIV prevalence by gender for these countries. Non-parametric and parametric tests along with meta-analytic techniques examined heterogeneity and differences in odds ratios (OR) across studies. RESULTS: Data were abstracted from 117 studies in 14 countries; total sample size N = 128,745. The mean weighted OR for HIV prevalence among females to males was 1.18 [95% CI 1.10-1.26], with high heterogeneity among studies (I(2)= 70.7%). There was a Gaussian distribution of the log ORs across studies in the sample. CONCLUSION: There was a significantly higher HIV prevalence among females compared to males who inject drugs in high seroprevalence settings, but the effect size is extremely modest. The high level of heterogeneity and the Gaussian distribution suggest multiple causes of differences in HIV prevalence between females and males, with a specific difference determined by local factors. Greater understanding of factors that may protect females from HIV infection may provide insights into more effective HIV prevention for both females and males who inject drugs. PMID- 22257754 TI - Developmental momentum toward substance dependence: natural histories and pliability of risk factors in youth experiencing chronic stress. AB - BACKGROUND: Mitigation of substance use (SU) disorder (SUD) risk factors is a common goal of prevention. Research has clarified much about risk factors including their prediction of SU/SUD, associations with other etiological variables and mediation of SU outcomes. Greater understanding of the emergence of risk factors themselves may improve prevention. For example, in lieu of experimental data, the level of resistance to change of a risk factor (its pliability) could inform "dosage" of intervention needed to reduce the risk. METHODS: Two attributes of 22 previously-documented predictors of SU/SUD were quantified: natural history (average age-related trend) and pliability (quantified using correlations between intercepts and growth parameters of hierarchical linear modeling trajectories). The longitudinal sample of 1147 8- through 16-year-olds were recruited from a northeastern summer camp for youth experiencing chronic stress due to one or more stressors (X-=2.2stressors, SD=1.41) which typically last at least one year. Half were male, 69.3% were European-American, 8.5% were African-American, and the remaining were small proportions each of other or mixed races/ethnicities. RESULTS: Average trajectories of 21 predictors correspond to increasing SUD risk with age. Predictor pliability varied greatly, ranging from extremely high for School Commitment to extremely low for Peer Pressure Susceptibility. CONCLUSIONS: Results suggest different intervention strategies may be needed to manage risk factors over the long-term. To illustrate, maintaining a high school commitment appears to require boosters whereas reducing peer pressure susceptibility appears to require high initial "dosage" with less need for boosters. PMID- 22257755 TI - Study of the expression levels of Hepatocyte nuclear factor 4 alpha and 3 beta in patients with different outcome of HBV infection. AB - Hepatocyte nuclear factors 4 alpha (HNF4alpha) and 3 beta (HNF3beta) are members of a group of liver-enriched transcription factors (LETFs) that play important roles in regulating the replication of hepatitis B virus (HBV) and liver inflammation. However, the relationship of the level of HNF4alpha and HNF3beta with the severity of HBV-infected liver diseases is unclear. In this study, liver tissue samples from different types of HBV patients were collected, and HNF4alpha and HNF3beta expression were detected by immunohistochemistry. The expression of HNF4alpha was significant higher in patients with severe hepatitis B(SHB) than those with chronic hepatitis B(CHB) and liver cirrhosis(LC) (both P < 0.05), but similar between patients with CHB and LC (P > 0.05). And the expression of HNF3beta was similar among patients with CHB, LC and SHB (P > 0.05 for all pairwise comparison). This suggests that the expression level of HNF4alpha was different in patients with different outcome of HBV infection, high expression level of HNF4alpha may correlate with occurrence of SHB. PMID- 22257756 TI - Randomized clinical trial of LigaSure versus conventional suture ligation in thyroid surgery. AB - BACKGROUND: In thyroid surgery vessel division and haemostasis make up an important and time consuming part of the operation. While the presence of the recurrent laryngeal nerve limits the liberal use of diathermia, the many arterial and venous branches to and from the thyroid gland necessitates the use of numerous conventional suture ligatures.This study evaluates the effect of using a vessel sealing system on operation time during thyroid surgery. METHODS: A randomized clinical trial was performed between September 2005 and October 2008 in a teaching hospital. Forty patients undergoing total hemithyroidectomy participated in the trial. Twenty were randomized to the intraoperative use of the LigaSure PreciseTM vessel sealing system, and twenty to the use of conventional suture ligatures. RESULTS: The total median operation time was 10 minutes shorter in the LigaSure group (56 versus 66 minutes, P = 0.001). No significant differences in complications were noticed. CONCLUSION: Using an electrothermal vessel sealing system during thyroid surgery is time saving. TRIAL REGISTRATION: This trial was registered in the international standard randomized controlled trials number register (ISRCTNR) under number ISRCTNR82389535. PMID- 22257757 TI - Intestinal toxemia botulism in 3 adults, Ontario, Canada, 2006-2008. AB - Five cases of intestinal toxemia botulism in adults were identified within an 18 month period in or near Toronto, Ontario, Canada. We describe findings for 3 of the 5 case-patients. Clinical samples contained Clostridium botulinum spores and botulinum neurotoxins (types A and B) for extended periods (range 41-61 days), indicative of intestinal toxemia botulism. Patients' clinical signs improved with supportive care and administration of botulinum antitoxin. Peanut butter from the residence of 1 case-patient yielded C. botulinum type A, which corresponded with type A spores found in the patient's feces. The food and clinical isolates from this case-patient could not be distinguished by pulsed-field gel electrophoresis. Two of the case-patients had Crohn disease and had undergone previous bowel surgery, which may have contributed to infection with C. botulinum. These cases reinforce the view that an underlying gastrointestinal condition is a risk factor for adult intestinal toxemia botulism. PMID- 22257758 TI - Serotonin-mediated modulation of Na+/K+ pump current in rat hippocampal CA1 pyramidal neurons. AB - BACKGROUND: The aim of this study was to investigate whether serotonin (5 hydroxytryptamine, 5-HT) can modulate Na+/K+ pump in rat hippocampal CA1 pyramidal neurons. RESULTS: 5-HT (0.1, 1 mM) showed Na+/K+ pump current (Ip) densities of 0.40 +/- 0.04, 0.34 +/- 0.03 pA/pF contrast to 0.63 +/- 0.04 pA/pF of the control of 0.5 mM strophanthidin (Str), demonstrating 5-HT-induced inhibition of Ip in a dose-dependent manner in hippocampal CA1 pyramidal neurons. The effect was partly attenuated by ondasetron, a 5-HT3 receptor (5-HT3R) antagonist, not by WAY100635, a 5-HT1AR antagonist, while 1-(3-Chlorophenyl) biguanide hydrochloride (m-CPBG), a 5-HT3R specific agonist, mimicked the effect of 5-HT on Ip. CONCLUSION: 5-HT inhibits neuronal Na+/K+ pump activity via 5-HT3R in rat hippocampal CA1 pyramidal neurons. This discloses novel mechanisms for the function of 5-HT in learning and memory, which may be a useful target to benefit these patients with cognitive disorder. PMID- 22257759 TI - Arsenic biomethylation by photosynthetic organisms. AB - Arsenic (As) is a ubiquitous element that is widespread in the environment and causes numerous health problems. Biomethylation of As has implications for its mobility and toxicity. Photosynthetic organisms may play a significant role in As geochemical cycling by methylating it to different As species, but little is known about the mechanisms of methylation. Methylated As species have been found in many photosynthetic organisms, and several arsenite S-adenosylmethionine (SAM) methyltransferases have been characterized in cyanobacteria and algae. However, higher plants may not have the ability to methylate As. Instead, methylated arsenicals in plants probably originate from microorganisms in soils and the rhizosphere. Here, we propose possible approaches for developing 'smart' photosynthetic organisms with an enhanced and sensitive biomethylation capacity for bioremediation and safer food. PMID- 22257760 TI - Comparison and transfer testing of multiplex ligation detection methods for GM plants. AB - BACKGROUND: With the increasing number of GMOs on the global market the maintenance of European GMO regulations is becoming more complex. For the analysis of a single food or feed sample it is necessary to assess the sample for the presence of many GMO-targets simultaneously at a sensitive level. Several methods have been published regarding DNA-based multidetection. Multiplex ligation detection methods have been described that use the same basic approach: i) hybridisation and ligation of specific probes, ii) amplification of the ligated probes and iii) detection and identification of the amplified products. Despite they all have this same basis, the published ligation methods differ radically. The present study investigated with real-time PCR whether these different ligation methods have any influence on the performance of the probes. Sensitivity and the specificity of the padlock probes (PLPs) with the ligation protocol with the best performance were also tested and the selected method was initially validated in a laboratory exchange study. RESULTS: Of the ligation protocols tested in this study, the best results were obtained with the PPLMD I and PPLMD II protocols and no consistent differences between these two protocols were observed. Both protocols are based on padlock probe ligation combined with microarray detection. Twenty PLPs were tested for specificity and the best probes were subjected to further evaluation. Up to 13 targets were detected specifically and simultaneously. During the interlaboratory exchange study similar results were achieved by the two participating institutes (NIB, Slovenia, and RIKILT, the Netherlands). CONCLUSIONS: From the comparison of ligation protocols it can be concluded that two protocols perform equally well on the basis of the selected set of PLPs. Using the most ideal parameters the multiplicity of one of the methods was tested and 13 targets were successfully and specifically detected. In the interlaboratory exchange study it was shown that the selected method meets the 0.1% sensitivity criterion. The present study thus shows that specific and sensitive multidetection of GMO targets is now feasible. PMID- 22257761 TI - Damage recognition in nucleotide excision DNA repair. AB - Nucleotide excision repair (NER) is a highly versatile DNA repair process. Its ability to repair a large number of different damages with the same subset of recognition factors requires structural tools for damage recognition that are both broad and very accurate. Over the past few years detailed structural information on damage recognition factors from eukaryotic and prokaryotic NER has emerged. These structures shed light on the toolkit utilized in the damage recognition process and help explain the broad substrate specificity of NER. PMID- 22257762 TI - Atomistic molecular simulations of protein folding. AB - Theory and experiment have provided answers to many of the fundamental questions of protein folding; a remaining challenge is an accurate, high-resolution picture of folding mechanism. Atomistic molecular simulations with explicit solvent are the most promising method for providing this information, by accounting more directly for the physical interactions that stabilize proteins. Although simulations of folding with such force fields are extremely challenging, they have become feasible as a result of recent advances in computational power, accuracy of the energy functions or 'force fields', and methods for improving sampling of folding events. I review the recent progress in these areas, and highlight future challenges and questions that we may hope to address with these methods. I also attempt to place atomistic models into the context of the energy landscape view of protein folding, and coarse-grained simulations. PMID- 22257763 TI - Bone transport techniques in posttraumatic bone defects. AB - INTRODUCTION: The treatment of posttraumatic diaphyseal bone defects (BD) calls on a number of techniques including bone transport techniques: isolated shortening, compression-distraction at the fracture site, shortening followed by lengthening in a corticotomy distant from the site and segmental bone transport. PATIENTS AND METHODS: The multicenter retrospective study combined 38 cases: 22 cases of initial diaphyseal bone defect and 16 cases of secondary diaphyseal BD, sometimes associated with metaphyseal or metaphyseal-epiphyseal BD, involving the humerus, the forearm, the femur and the tibia. These techniques were mainly used on the lower extremity (33 cases), for the most part on the tibia (22 cases) in young men. RESULTS: Bone healing was acquired in 37 cases out of 38 after a mean 14.9 months (range, 6-62 months). A mean 4.3 secondary interventions were required to obtain final union; most notably, a bone graft was necessary at the docking site for the segmental bone transport procedures. DISCUSSION: Many reconstruction techniques can be proposed to treat posttraumatic BD. None responds to all situations. Bone transport techniques have their place and their indications. Isolated shortening is intended for bone loss not exceeding 3cm, notably in the humerus and to a lesser degree in the lower extremity. Shortening associated with lengthening is valuable in the femur and the tibia for bone loss up to 6cm. Segmental bone transport is the only technique that can treat bone defects associated with shortening in the lower limb. For substantial bone loss beyond 10cm, segmental bone transport is particularly indicated. However, these cases of substantial bone loss tend to be resolved by a hybridization of the procedures. The distraction gap of a bone segment can, for example, be prepared using an induced-membrane technique. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 22257764 TI - Surgery for femoroacetabular impingement using a minimally invasive anterolateral approach: analysis of 118 cases at 2.2-year follow-up. AB - INTRODUCTION: Treatment of femoroacetabular impingement (FAI) has progressed over time from using long incisions and dislocation to using arthroscopic surgery. Minimally invasive treatment has rarely been evaluated and a minimally invasive, anterolateral approach has not been used up to now for this indication. A prospective, on-going study was performed to evaluate surgical treatment of FAI with a minimally invasive, anterolateral approach. HYPOTHESIS: Femoral neck, acetabulum and labrum abnormalities can be corrected without significant morbidity using a minimally invasive, anterolateral approach without dislocation. PATIENTS AND METHODS: Treatment of 120 FAI cases (108 patients, 16 women, 92 men, 12 bilateral cases during one surgical session), average age: 34 years (18.9-63.5 years), was done prospectively and in an uninterrupted series. Two cases were lost to follow-up; 106 patients (118 FAI cases) were evaluated with a follow-up of at least 1 year. Assessments consisted of the Non-Arthritic Hip Score (NAHS), WOMAC, measurement of internal rotation with 90 degrees flexion and the Notzli alpha angle on an A/P radiograph in 45 degrees of flexion, 45 degrees abduction and 30 degrees external rotation. RESULTS: Blood loss averaged 1.2g/dl (range 0.5 to 2.7g/dl) and the average operative time was 44.9 minutes (range 30 to 65). With an average follow-up of 2.2 years (range 12 to 54 months), the NAHS changed by 32.5 points (P<0.0001), internal rotation by 19.0 degrees (P<0.0001) and the alpha angle by -24.9 degrees (P<0.0001). Eight surgical revisions were required (6.8%) (four haematomas, two capsular debridement, two additional procedures on the acetabulum) and these had a good outcome; there were no nerve-related or infection-related complications. Four failures (3.5%) were revised by arthroplasty (two patients experienced residual pain and two patients rapidly progressed to osteoarthritis). Eighteen cases progressed by only one Tonnis stage. Brooker stage II and III ossification were observed in 12 cases (10.2%) but these did not affect the functional score and range of motion improvement. DISCUSSION: This approach, which can be learned and performed quickly, does not require any specific materials and yields a reliable surgical procedure without major complications. This short-term study, where the central cartilaginous compartment was not explored and the labrum was not sutured, comprised a consecutive, non-selected series of patients (independent of age, weight, osteoarthritis stage) and had encouraging results. LEVEL OF EVIDENCE: Level III, prospective study, no control group. PMID- 22257766 TI - Applications and perspectives of multi-parameter flow cytometry to microbial biofuels production processes. AB - Conventional microbiology methods used to monitor microbial biofuels production are based on off-line analyses. The analyses are, unfortunately, insufficient for bioprocess optimization. Real time process control strategies, such as flow cytometry (FC), can be used to monitor bioprocess development (at-line) by providing single cell information that improves process model formulation and validation. This paper reviews the current uses and potential applications of FC in biodiesel, bioethanol, biomethane, biohydrogen and fuel cell processes. By highlighting the inherent accuracy and robustness of the technique for a range of biofuel processing parameters, more robust monitoring and control may be implemented to enhance process efficiency. PMID- 22257765 TI - Functional performance after hip resurfacing or total hip replacement: a comparative assessment with non-operated subjects. AB - INTRODUCTION: Several studies reported better clinical results with total hip resurfacing than with conventional total hip replacement, including in young patients, but without comparative stabilometry assessment. HYPOTHESIS: Resurfacing arthroplasty provides better functional performance than conventional total hip replacement. OBJECTIVES: To test the above hypothesis in a stabilometry study comparing balance and functional performance in patients with total hip resurfacing or conventional total hip replacement and healthy controls. MATERIALS AND METHODS: Results were analyzed on three cohorts of 20 patients: healthy control subjects, with unilateral total hip replacement or unilateral total hip resurfacing. The 40 operated patients were comparable in gender, age, weight (body-mass index), date of operation and clinical results. The 20 control subjects were younger and served as reference. Balance analysis employed a force platform commonly used in stabilometry, standardizing both leg or single leg stance balance analysis. The software interpreted individual balance by measuring plantar pressure center variation during the analysis so as to contour an individual both leg or single leg area of balance (statokinesigram, in mm(2)). RESULTS: Balance analysis on both leg found comparable results in the control and resurfacing groups. The weight-bearing statokinesigraphic both leg balance area was greater in the hip replacement than in either of the other two groups (p<0.05), and five times greater than in the resurfacing group (p<0.05). The single leg weight-bearing balance results were significantly better in the resurfacing group, with a statokinesigraphic balance area half that of the hip replacement group, whether on the operated or the non-operated side (p<0.001). DISCUSSION AND CONCLUSION: The present functional performance results confirm the advantage of resurfacing over conventional hip replacement, and help explain the excellent radioclinical results reported for total hip resurfacing. LEVEL OF EVIDENCE: III, comparative case-control study. PMID- 22257767 TI - Cytological detection of trophoblasts for rapid diagnosis of pregnancy of unknown location. PMID- 22257768 TI - Intimate partner violence and its association with women's reproductive health in Pakistan. AB - OBJECTIVE: To determine the prevalence of intimate partner violence in Pakistan and its association with reproductive health outcomes. METHODS: A cross-sectional survey was conducted in 8 hospitals in Lahore and Sialkot between October 2008 and January 2009. Information from randomly selected ever-married women of reproductive age was collected via a structured interview. Psychologic, physical, and sexual violence was categorized as "no" or "severe" violence. Associations between reproductive health outcomes and violence were assessed by multivariate logistic regression. RESULTS: Among 373 women interviewed, 75.9% reported severe psychologic, 34.6% reported severe sexual, and 31.9% reported severe physical violence at least once in marital life. Women who experienced severe physical violence were more likely to have their husband's noncooperation in using contraceptives (adjusted odds ratio [AOR], 3.31; 95% confidence interval [CI], 1.93-5.68), poor prenatal care (AOR, 2.11; 95% CI, 1.23-3.69), unplanned pregnancies (AOR, 2.29; 95% CI, 1.39-3.76), and poor self-reported reproductive health (AOR, 2.95; 95% CI, 1.71-4.91) as compared with non-abused women. Similar associations existed for other types of violence. CONCLUSION: The results highlight the magnitude of violence and its association with reproductive health of women. Urgent action is needed to mitigate the violence and its consequential damage to health. PMID- 22257769 TI - Risk factors for eclampsia in Japan between 2005 and 2009. AB - OBJECTIVE: To determine risk factors for eclampsia among Japanese women with singleton pregnancies. METHODS: A retrospective observational study was carried out among patients with and those without eclampsia who were registered on the Japan Society of Obstetrics and Gynecology registry system and who gave birth to singleton infants at 22 weeks or more between 2005 and 2009. Multivariate logistic regression analyses were performed to determine independent risk factors for eclampsia. RESULTS: One-third (75/225) of eclampsia patients developed the condition in the absence of hypertension. Maternal age, nulliparity, and pregnancy-induced hypertension (PIH) were all independent risk factors for eclampsia. The risk of eclampsia decreased by 3.0% per 1-year increase in maternal age, and increased 2.6-fold and 35.4-fold in nulliparous women and women with PIH, respectively. Among teenaged girls with hypertension, the prevalence of eclampsia was 1 case per 28 teenagers. CONCLUSION: Hypertension alone was not a reliable predictor of eclampsia. More intensified monitoring of nulliparous women and teenaged girls with hypertension is needed in order to prevent eclampsia. PMID- 22257770 TI - Acute fatty liver of pregnancy over a 10-year period at a Tunisian tertiary care center. PMID- 22257772 TI - [Foreword]. PMID- 22257771 TI - TNF-alpha- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism. AB - BACKGROUND: Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention. RESULTS: We addressed this question both in vitro using differentiated myotubes treated with TNF-alpha, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-alpha was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-alpha, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin 1, and partially protected muscle tissue from atrophy. CONCLUSIONS: Ceramide accumulation induced by TNF-alpha or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations. PMID- 22257773 TI - [Long-term results of posterior chamber phakic intraocular lens implantation for correction of high ametropia]. AB - PURPOSE: To assess efficacy, stability and safety of posterior chamber phakic intraocular lens implantation with STAAR Visian ICL for correction of high ametropia, with a mean follow-up of 5 years (3.5-10 years). PATIENTS AND METHODS: Ninety eyes of 53 highly ametropic patients (45 myopia, ten hyperopia and 35 with mixed astigmatism) were included in a retrospective single-surgeon study, using primarily the V4 ICL model (87 eyes). We studied pre- and postoperative refractive efficacy, endothelial cell density, crystalline lens opacification and intraocular clearances within the various compartments of the eye. RESULTS: Mean uncorrected visual acuity was 0.77 at the 12th postoperative month; 17 of 90 eyes required adjunctive photoablation for residual astigmatism. Forty-eight percent of eyes gained at least one line of best corrected visual acuity. After implantation, the decrease in endothelial cell density remained stable at 0.69%/year, and 91% of eyes showed no opacification of the crystalline lens. Mean endothelium-ICL and ICL-crystalline lens distances were 2.41 mm and 0.52 mm respectively. Overall patient satisfaction achieved was 96% at 36 months postoperatively. DISCUSSION AND CONCLUSION: These results demonstrate efficacy, stability and safety of the ICL V4 phakic IOL for the correction of high ametropia. Long-term follow-up did not show a significant increase in cataract formation in implanted eyes. PMID- 22257774 TI - [Toric IOL's]. AB - Toric intraocular lenses have been increasingly utilized in cataract surgery and are considered "premium lenses" They provide a reliable and effective option for patients with astigmatism undergoing cataract surgery. We present various methods for the correction of astigmatism during cataract surgery. We present the available models of pseudophakic toric IOL's, including monofocal and multifocal lenses. We present indications for toric IOL's in cases of regular and irregular astigmatism. PMID- 22257775 TI - Canine parvovirus in asymptomatic feline carriers. AB - Canine parvovirus (CPV) and feline panleukopaenia virus (FPLV) are two closely related viruses, which are known to cause severe disease in younger unvaccinated animals. As well as causing disease in their respective hosts, CPV has recently acquired the feline host range, allowing it to infect both cats and dogs. As well as causing disease in dogs, there is evidence that under some circumstances CPV may also cause disease in cats. This study has investigated the prevalence of parvoviruses in the faeces of clinically healthy cats and dogs in two rescue shelters. Canine parvovirus was demonstrated in 32.5% (13/50) of faecal samples in a cross sectional study of 50 cats from a feline only shelter, and 33.9% (61/180) of faecal samples in a longitudinal study of 74 cats at a mixed canine and feline shelter. Virus was isolated in cell cultures of both canine and feline origin from all PCR-positive samples suggesting they contained viable, infectious virus. In contrast to the high CPV prevalence in cats, no FPLV was found, and none of 122 faecal samples from dogs, or 160 samples collected from the kennel environment, tested positive for parvovirus by PCR. Sequence analysis of major capsid VP2 gene from all positive samples, as well as the non-structural gene from 18 randomly selected positive samples, showed that all positive cats were shedding CPV2a or 2b, rather than FPLV. Longitudinally sampling in one shelter showed that all cats appeared to shed the same virus sequence type at each date they were positive (up to six weeks), despite a lack of clinical signs. Fifty percent of the sequences obtained here were shown to be similar to those recently obtained in a study of sick dogs in the UK (Clegg et al., 2011). These results suggest that in some circumstances, clinically normal cats may be able to shed CPV for prolonged periods of time, and raises the possibility that such cats may be important reservoirs for the maintenance of infection in both the cat and the dog population. PMID- 22257776 TI - Updating our understanding of pulmonary disease associated with HIV infection. AB - The introduction of highly active antiretroviral therapy (HAART) has resulted in a reduction of opportunistic infections associated with cellular and humoral immunosuppression. However, what is still unclear is the impact of HAART on the development of other diseases not associated with AIDS, such as lung cancer and COPD. The aim of this paper is to review the most innovative and relevant aspects of lung pathology in patients infected with HIV. PMID- 22257777 TI - [Radiation-induced sarcoma of the head and neck]. AB - INTRODUCTION: Radiation-induced sarcoma (RIS) of the head and neck is a late and rare complication of cancer treatment by radiation therapy. It occurs mostly within the limits of the irradiated area. Its incidence is increasing and related to an improved survival rate of treated patients. But it does not rule out the use of radiotherapy in the treatment of this cancer. OBSERVATION: We report two cases of sarcoma having appeared in the irradiated area, in patients treated by adjuvant radiotherapy for head and neck neoplasm. DISCUSSION: The prognosis for this sarcoma depends mainly on how early the diagnosis is made and the quality of surgical resection. Adjuvant chemotherapy or radiotherapy can be considered. Ongoing research on the expression of RIS genes could soon lead to new treatments. PMID- 22257778 TI - Viewing metastatic colorectal cancer as a curable chronic disease. AB - Improved survival of colorectal cancer has been made over the last 3 decades; reasons may be attributed to early detection through screening, and better treatment options. Advancements in modern systemic chemotherapy for colorectal cancer include oxaliplatin-based and irinotecan-based combination and the introduction of biological agents such as bevacizumab and cetuximab. Systemic therapies need to be used in patients with high risk stage II and stage III colorectal cancer and in patients with metastatic disease. Evidence for liver resection and ablation, pulmonary metastasectomy and/or radiofrequency ablation, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy for metastasis to sites of the liver, lung, and peritoneum respectively are well established. The biggest challenge is to select the right patients for metastasectomy and to pursue metastatic disease as a chronic disease to ensure appropriate personalized therapy, pursue second-line therapies or repeat surgeries, and minimize toxicities of therapies. PMID- 22257779 TI - SSRIs may (or may not) be a safe treatment for depression in GBM. PMID- 22257780 TI - The 1918-19 influenza pandemic in Boyaca, Colombia. AB - To quantify age-specific excess-mortality rates and transmissibility patterns for the 1918-20 influenza pandemic in Boyaca, Colombia, we reviewed archival mortality records. We identified a severe pandemic wave during October 1918 January1919 associated with 40 excess deaths per 10,000 population. The age profile for excess deaths was W shaped; highest mortality rates were among infants (<5 y of age), followed by elderly persons (>60 y) and young adults (25 29 y). Mean reproduction number was estimated at 1.4-1.7, assuming 3- or 4-day generation intervals. Boyaca, unlike cities in Europe, the United States, or Mexico, experienced neither a herald pandemic wave of deaths early in 1918 nor a recrudescent wave in 1920. In agreement with reports from Mexico, our study found no death-sparing effect for elderly persons in Colombia. We found regional disparities in prior immunity and timing of introduction of the 1918 pandemic virus across populations. PMID- 22257781 TI - First-line endocrine therapy alone could be a reasonable treatment option for hormone-positive, HER2-positive metastatic breast cancer. AB - PURPOSE: The treatment strategy for hormone receptor-positive (ER+) HER2-positive (HER2+) metastatic breast cancer has been modified since several randomized trials have proven the effectiveness of anti-HER2 targeted therapy. Previously validated clinical practice guidelines recommending the use of endocrine therapy alone in first line might be changed. METHODS: This study focused on the outcomes of women with ER+ HER2+ metastatic breast cancer receiving first-line endocrine therapy alone at the Leon-Berard Centre, Lyon, France. RESULTS: Of 290 patients with ER+ HER2+ tumors, 32 (11%) met the criteria for inclusion. The median age was 54 years (29-79 years). Eighteen patients (56%) had only bone and/or soft tissue metastases. Most patients (n = 21; 65%) had only one metastatic site. Fifteen (47%) had histological grade III disease. The median progression free survival (PFS) was 8.2 months (95% CI: 0.1-16.3) and the median overall survival (OS) was 48 months (95% CI: 22.9-72.9). The overall response rate was 25% (95% CI: 11-49%), including one patient with complete response and seven with partial responses. Ten patients (31%) had stable disease. After failure of endocrine therapy, all patients received trastuzumab. The median PFS after first-line chemotherapy was 8.4 months (95% CI: 5.1-11.8). We identified a group of 10 patients with good prognostic factor (tumor grade < 3 tumors and no visceral metastases), for whom median PFS was 15.5 months (95% CI: 7-23). CONCLUSIONS: Our result suggests that first-line endocrine therapy is a viable therapeutic option for a selected population of metastatic breast cancer patients with HER2-positive tumors. Genomic and transcriptomic signature could help to identify tumors that remain dependant of estrogen-signaling pathway. PMID- 22257782 TI - Data for improvement and clinical excellence: protocol for an audit with feedback intervention in home care and supportive living. AB - BACKGROUND: Although considerable evidence exists about the effectiveness of audit coupled with feedback, very few audit-with-feedback interventions have been done in either home care or supportive living settings to date. With little history of audit and feedback in home care or supportive living there is potential for greater effects, at least initially. This study extends the work of an earlier study designed to assess the effects of an audit-with-feedback intervention. It will be delivered quarterly over a one-year period in seven home care offices and 11 supportive living sites. The research questions are the same as in the first study but in a different environment. They are as follows: 1. What effects do feedback reports have on processes and outcomes over time? 2. How do different provider groups in home care and supportive living sites respond to feedback reports based on quality indicator data? METHODS: The research team conducting this study includes researchers and decision makers in continuing care in the province of Alberta, Canada. The intervention consists of quarterly feedback reports in 19 home care offices and supportive living sites across Alberta. Data for the feedback reports are based on the Resident Assessment Instrument Home Care tool, a standardized instrument mandated for use in home care and supportive living environments throughout Alberta. The feedback reports consist of one page, printed front and back, presenting both graphic and textual information. Reports are delivered to all employees working in each site. The primary evaluation uses a controlled interrupted time-series design, both adjusted and unadjusted for covariates. The concurrent process evaluation includes observation, focus groups, and self-reports to assess uptake of the feedback reports. The project described in this protocol follows a similar intervention conducted in our previous study, Data for Improvement and Clinical Excellence--Long-Term Care. We will offer dissemination strategies and spread of the feedback report approach in several ways suited to various audiences and stakeholders throughout Alberta. SIGNIFICANCE: This study will generate knowledge about the effects of an audit with feedback intervention in home care and supportive living settings. Our dissemination activities will focus on supporting sites to continue to use the Resident Assessment Instrument data in their quality improvement activities. PMID- 22257783 TI - When the heart stops: a review of cardiac arrest in pregnancy. AB - Cardiac arrest is a rare occurrence in pregnancy and may be related to obstetric or medical causes. Pregnancy is associated with profound physiologic changes that prepare the gravida for the challenges of labor and delivery, and resuscitation of the pregnant patient needs to take these changes into consideration. Cardiac output and plasma volume increase in pregnancy and distribute differently with the uterine circulation receiving approximately 17% of the total cardiac output. On the other hand, cardiac output is sensitive to positional changes in the second half of pregnancy but may improve with a lateral tilt of the gravida. Both oxygen reserve and upper airway size decrease in pregnancy, leading to difficulties surrounding airway management. Changes in the volume of distribution, renal and hepatic clearance may impact drug effects and need to be recognized. This review will discuss an overview of pregnancy physiology that is relevant to cardiac resuscitation, detail the challenges in the various resuscitative steps including a synopsis on perimortem delivery, and describe obstetric and nonobstetric causes of mortality and cardiac arrest in pregnancy. PMID- 22257784 TI - The effect of statutory limitations on the authority of substitute decision makers on the care of patients in the intensive care unit: case examples and review of state laws affecting withdrawing or withholding life-sustaining treatment. AB - While the ethics and critical care literature is replete with discussion of medical futility and the ethics of end-of-life care decisions in the intensive care unit, little attention is paid to the effect of statutory limitations on the authority of substitute decision makers during the course of treatment of patients in the critical care setting. In many jurisdictions, a clear distinction is made between the authority of a health care power of attorney, who is legally designated by a competent adult to make decisions regarding withholding or withdrawing life-sustaining treatment, and of next-of-kin, who are limited in this regard. However, next-of-kin are often relied upon to consent to necessary procedures to advance a patient's medical care. When conflicts arise between critical care physicians and family members regarding projected patient outcome and functional status, these statutory limitations on decision-making authority by next of kin can cause paralysis in the medical care of severely ill patients, leading to practical and ethical impasses. In this article, we will provide case examples of how statutory limitations on substitute decision making authority for next of kin can impede the care of patients. We will also review the varying jurisdictional limitations on the authority of substitute decision makers and explore their implications for patient care in the critical care setting. Finally, we will review possible ethical and legal solutions to resolve these impasses. PMID- 22257785 TI - Brimonidine (Alphagan) associated anterior uveitis. PMID- 22257786 TI - Can virtual reality simulation help to determine the importance of stereopsis in intraocular surgery? AB - AIM: To establish the effect of acute loss of stereopsis on simulated intraocular surgical performance. METHODS: This study was performed using the EYESi ophthalmic surgical simulator. Thirty junior doctors with no previous ophthalmic surgical experience were enrolled and distance visual acuity (Snellen), near visual acuity and stereoacuity (Frisby) were recorded. All participants completed a standard introductory programme on the forceps module to eliminate the learning curve. They then undertook four attempts of level 4 forceps module binocularly and another four monocularly to simulate an acute loss of stereopsis. Total score, odometer movement, corneal area injured, lens area injured and total time taken were recorded. RESULTS: Mean age was 31 years (SD+/-9). None had amblyopia, with all demonstrating distance visual acuity of 6/6 or better and N6 for near. Mean stereopsis was 35 s of arc (SD+/-18). Average total score decreased from 60 while operating binocularly to 47 monocularly (p<0.05). Average corneal area injured increased from 0.95 mm(2) to 2.30 mm(2) (p<0.05), average lens area injured increased from 1.76 mm(2) to 3.53 mm(2) (p<0.05) and average time taken increased from 69.6 s to 77.4 s (p<0.05). CONCLUSION: The importance of stereopsis for intraocular surgery is difficult to establish in a live theatre setting without compromising patient safety. Virtual reality simulators provide a safe alternative. This study demonstrates a statistically significant decrease in simulated intraocular surgical performance with acute loss of stereopsis in potential ophthalmic training applicants. Caution is recommend in using these results to advocate stereopsis testing as a screening tool in interviews because some participants performed well despite an absence of stereopsis. PMID- 22257787 TI - The nitric oxide donating triamcinolone acetonide NCX 434 does not increase intraocular pressure and reduces endothelin-1 induced biochemical and functional changes in the rabbit eye. AB - BACKGROUND: NCX 434 is a nitric oxide (NO)-donating triamcinolone acetonide (TA), shown to enhance optic nerve head (ONH) oxygen saturation in non-human primate eyes. Here, the effects of a single intravitreal (IVT) injection of TA were compared with those of NCX 434 on intraocular pressure (IOP), retinal function and retrobulbar haemodymamics in endothelin-1 (ET-1) induced ONH ischaemia/reperfusion in rabbits. Biochemical changes were also assessed in the aqueous humour and in retinal biopsies. METHODS: IOP and resistivity index of ophthalmic artery (RI-OA) were recorded using TonoPen and ecocolor Doppler, respectively. Retinal function was assessed using photopic electroretinography. Cytokine expression and oxidative stress markers were evaluated with immunoassay techniques. RESULTS: At 4 weeks post IVT treatment, TA increased IOP and RI-OA while NCX 434 did not (IOP(Vehicle)=13.6+/-1.3, IOP(NCX 434)=16.9+/-2.2, IOP(TA)=20.9+/-1.9 mm Hg; p<0.05 vs vehicle; RI-OA(Vehicle)=0.44+/-0.03; RI OA(NCX 434)=0.47+/-0.02; RI-OA(TA)=0.60+/-0.04). Both NCX 434 and TA reversed ET 1 induced decrease in electroretinography amplitude to similar extents. NCX 434 attenuated ET-1 induced oxidative stress markers and nitrotyrosine in retinal tissue, and interleukin-6 and tumour necrosis factor-alpha in aqueous humour more effectively than TA. CONCLUSION: NCX 434 attenuates ET-1 induced ischaemia/reperfusion damage without increasing IOP, probably due to NO release. If data are confirmed in other species and models, this compound could represent an interesting new therapeutic option for retinal and ONH diseases, including diabetic retinopathy. PMID- 22257788 TI - Anti-tubercular treatment is not required in latent tuberculosis. PMID- 22257789 TI - Surgical outcome and risk stratification for primary retinal detachment repair: results from the Scottish Retinal Detachment study. AB - OBJECTIVES: To report the early surgical outcome, risk of failure and predictive value of rhegmatogenous retinal detachment (RRD) classification based on all participants in the Scottish Retinal Detachment study. METHODS: Over 2 years, all incident cases of RRD in Scotland were approached for recruitment. Early postoperative success was defined as an attached retina following one procedure with a minimum follow-up of 6-8 weeks. Using a regression model, the influence of clinical factors on the failure risk was estimated and the sensitivity and specificity of the Royal College of Ophthalmologists (RCOphth) grading for RRD and the vitrectomy in retinal detachment stratification risk formula (VR-SRF) in predicting operative failure were assessed. RESULTS: Primary outcome data were available for 86.2% (975/1130) of patients. The overall primary success rate was 80.8% (95% CI 78.1 to 83.3%). The presence of preoperative proliferative vitreoretinopathy of any degree and each additional clock hour of detachment increased the risk of failure by an OR of 2.4 and 1.13 respectively (p<0.05). A specificity of >95% in predicting early surgical failure was noted for highly complex RRDs according to the VR-SRF formula and the RCOphth classification. CONCLUSIONS: Consistent with previous series, the overall early success rate of RRD repair was 80% after one operation. The type of surgical repair did not influence overall success rates. Significant predictors of failure are the presence of preoperative proliferative vitreoretinopathy of any grade and the extent of detachment. The analytical value of current classification systems in predicting failure is most useful in complex RRDs. PMID- 22257790 TI - Timing of surgery for hip fracture and in-hospital mortality: a retrospective population-based cohort study in the Spanish National Health System. AB - BACKGROUND: While the benefits or otherwise of early hip fracture repair is a long-running controversy with studies showing contradictory results, this practice is being adopted as a quality indicator in several health care organizations. The aim of this study is to analyze the association between early hip fracture repair and in-hospital mortality in elderly people attending public hospitals in the Spanish National Health System and, additionally, to explore factors associated with the decision to perform early hip fracture repair. METHODS: A cohort of 56,500 patients of 60-years-old and over, hospitalized for hip fracture during the period 2002 to 2005 in all the public hospitals in 8 Spanish regions, were followed up using administrative databases to identify the time to surgical repair and in-hospital mortality. We used a multivariate logistic regression model to analyze the relationship between the timing of surgery (< 2 days from admission) and in-hospital mortality, controlling for several confounding factors. RESULTS: Early surgery was performed on 25% of the patients. In the unadjusted analysis early surgery showed an absolute difference in risk of mortality of 0.57 (from 4.42% to 3.85%). However, patients undergoing delayed surgery were older and had higher comorbidity and severity of illness. Timeliness for surgery was not found to be related to in-hospital mortality once confounding factors such as age, sex, chronic comorbidities as well as the severity of illness were controlled for in the multivariate analysis. CONCLUSIONS: Older age, male gender, higher chronic comorbidity and higher severity measured by the Risk Mortality Index were associated with higher mortality, but the time to surgery was not. PMID- 22257791 TI - Combining capecitabine and bevacizumab in metastatic breast cancer: a comprehensive review. AB - Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine bevacizumab combination therapy. PMID- 22257792 TI - Radiomics: extracting more information from medical images using advanced feature analysis. AB - Solid cancers are spatially and temporally heterogeneous. This limits the use of invasive biopsy based molecular assays but gives huge potential for medical imaging, which has the ability to capture intra-tumoural heterogeneity in a non invasive way. During the past decades, medical imaging innovations with new hardware, new imaging agents and standardised protocols, allows the field to move towards quantitative imaging. Therefore, also the development of automated and reproducible analysis methodologies to extract more information from image-based features is a requirement. Radiomics--the high-throughput extraction of large amounts of image features from radiographic images--addresses this problem and is one of the approaches that hold great promises but need further validation in multi-centric settings and in the laboratory. PMID- 22257793 TI - The antitumour activities induced by pegylated liposomal cytochalasin D in murine models. AB - Cytochalasin D targets actin and is ubiquitous in eukaryotic cells. When cytochalasin D is used as a cytotoxic agent in cancer therapy, it causes significant side effects. To prevent this, cytochalasin D can be encapsulated in polyethylene liposomes. In this study, high-performance liquid chromatography observation of the biodistribution of pegylated liposomal cytochalasin D in tumour-bearing mice showed that liposomal cytochalasin D could be conveniently dissolved in water for i.v. injection and that it specifically accumulated in tumour tissues, more than natural cytochalasin D did. The half-time of liposomal cytochalasin D in the plasma was also significantly longer than that of natural cytochalasin D (4h versus 10 min). MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay showed that liposomal cytochalasin D treatment could cause significant inhibition of cell proliferation in vitro in a manner similar to that of natural cytochalasin D. The antitumour activities of liposomal cytochalasin D were investigated in B16 melanoma, CT26 colorectal carcinoma and H22 hepatoma models, and the results indicated that liposomal cytochalasin D could significantly inhibit tumour growth and prolong survival in a manner similar to that of cisplatin. TUNEL-based apoptosis assays showed that liposomal cytochalasin D induced significant tumour cell apoptosis. Significant inhibition of tumour angiogenesis was observed in mice treated with liposomal cytochalasin D. In addition, no significant side effects were observed in mice treated with liposomal cytochalasin D. Our results show that liposomal cytochalasin D increases solubility and bioavailability, a lower incidence of side effects and improves antitumour effects, indicating its potential as a chemical agent for cancer therapy. PMID- 22257794 TI - Source identification of eight hazardous heavy metals in agricultural soils of Huizhou, Guangdong Province, China. AB - One hundred and four surface samples and 40 profiles samples in agricultural soils collected from Huizhou in south-east China were monitored for total contents of 8 heavy metals, and analyzed by multivariate statistical techniques and enrichment factor (EF), in order to investigate their origins. The results indicate that the concentrations of Cu, Zn, Ni, Cr, Pb, Cd, As and Hg in soils are 16.74, 57.21, 14.89, 27.61, 44.66, 0.10, 10.19 and 0.22 mg/kg, respectively. Compared to the soil background contents in Guangdong Province, the mean concentrations of Hg, Cd, Zn, Pb and As in soil of Huizhou are higher, especially Hg and Cd, which are 2.82 and 1.79 times the background values, respectively. Cr, Ni, Cu, partially, Zn and Pb mainly originate from a natural source. Cd, As, partially, Zn mainly come from agricultural practices. However, Hg, partially, Pb originate mainly from industry and traffic sources. PMID- 22257795 TI - Endothelin in hypertension: an update. AB - PURPOSE OF REVIEW: The purpose of this review of the vascular biology of endothelin-1 (ET-1) is the presentation of recent data including the use of endothelin-receptor antagonists for the treatment of hypertension. RECENT FINDINGS: Recent discoveries regarding the pharmacology of ET-1 in the vascular wall and its effect on signalling transduction and gene expression in vascular smooth muscle cells are reviewed, as well as mechanisms controlling blood pressure in normal conditions and in hypertension, discovered using genetically modified models. Finally, studies of endothelin antagonists for treatment of hypertension will be summarized. SUMMARY: Pharmacological studies demonstrate that calcitonin gene-related peptide is a physiological antagonist of ET-1 that terminates the long-lasting contraction induced by ET-1. ET-1-induced rise in [Ca]i involves the newly described stromal-interaction molecule-1/orai1 pathway to increase store-operated calcium entry. Sensitization of contractile proteins to calcium during ET-1-induced contraction of vascular smooth muscle cells includes activation of p63Rho guanine nucleotide exchange factor and increase in O-GlcNAcylation, a form of posttranslational modification. Genetically modified mice have demonstrated that endothelial ET-1 is involved in the regulation of normal blood pressure and development of vascular disease. Gene expression induced by endothelial overexpression of ET-1 in mice demonstrated upregulation of lipid metabolism, inflammatory and signal transduction genes. Crossing these mice with apoE mice was associated with acceleration of atherosclerosis on a high fat diet and blood pressure elevation. Finally, the DORADO clinical trial has demonstrated that the ETA-receptor antagonist darusentan is able to decrease the blood pressure of patients with refractory hypertension. PMID- 22257797 TI - Challenges in the diagnostic and therapeutic approach to nephrolithiasis. AB - PURPOSE OF REVIEW: The incidence of renal stones is rising along with the costs and morbidity associated with this condition. With careful evaluation and management, the great majority of recurrent stones are preventable. The cornerstone of this evaluation remains the 24-h urine collection. This review details the physiological rationale for commonly requested urine studies and details how these results should guide therapy with special emphasis on recent advances in the understanding of risk factors for stone disease. Challenges associated with the complicated patient will be addressed. RECENT FINDINGS: Long term follow-up and repeated evaluations are effective at preventing recurrent stones and increasing patient satisfaction. There is growing appreciation of the complexity of dietary risks for stone disease, and traditional risk-factors such as dietary oxalate must be reevaluated. SUMMARY: The key to stone prevention is the individualization of therapy to specific patient risk factors with a recognition that these factors can change over time leading to a need for alterations in preventive therapies. PMID- 22257796 TI - Endothelin as a final common pathway in the pathophysiology of preeclampsia: therapeutic implications. AB - PURPOSE OF REVIEW: Preeclampsia remains a major health concern in the United States and worldwide. Recent research has begun to shed light on the underlying mechanisms responsible for the symptoms of preeclampsia, and may provide new avenues for therapy for the preeclamptic patient. RECENT FINDINGS: The central role of placental ischemia in the manifestation of preeclampsia has provided new understanding for the origin of pathogenic factors in the preeclamptic patient. The release of soluble factors into the maternal bloodstream from the ischemic placenta is now recognized as a central mechanism in disease manifestation. Specifically, the importance of the vascular endothelial growth factor antagonist soluble fms-like tyrosine kinase and immune factors as factors regulating maternal endothelial dysfunction has become widely acknowledged. Furthermore, mounting evidence implicates the signaling protein endothelin-1 as the final converging factor in the multifaceted cascades that are responsible for the symptomatic manifestation of preeclampsia. Endothelin-1, as a final common pathway in the pathogenic cascade of preeclampsia, presents an intriguing new therapeutic approach for preeclamptic patients. SUMMARY: Identification of antiangiogenic, autoimmune, and inflammatory factors produced in response to placental ischemia have provided potential new avenues for future research into novel therapies for the preeclamptic patient, and suggest new therapeutic avenues for the treatment of preeclampsia. PMID- 22257798 TI - APOL1 and kidney disease. AB - PURPOSE OF REVIEW: We review recent work on the genetic basis of kidney disease in African Americans and its relationship to variation in the APOL1 gene. RECENT FINDINGS: People of recent African ancestry develop kidney disease at rates 4-5 times higher than most other groups. This observation holds for kidney disease attributed to hypertension, as well as focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Recent work suggests that the high risk for all of these forms of kidney disease in African Americans is conferred by the same genetic risk factors, specifically two coding sequence variants in the APOL1 gene. SUMMARY: Future studies aimed at understanding the clinical implications of APOL1 genotype in the setting of HIV infection, proteinuria, and hypertension associated kidney disease will help clarify how these recent findings should influence a nephrologist's decisions about patient care. Studies exploring the cellular and molecular mechanisms of APOL1-associated disease may lead to new methods of treatment. PMID- 22257799 TI - AT2 receptor agonists: hypertension and beyond. AB - PURPOSE OF REVIEW: Research about the angiotensin AT2 receptor (AT2R) has been hampered in the past by the lack of a specific and selective agonist with in-vivo stability. Such an eagerly awaited agonist, compound 21, has recently become available, giving momentum to AT2R research which so far has resulted in 14 original publications. This article is intending to review those publications which address AT2R function by direct in-vivo stimulation instead of indirect approaches such as receptor blockade or genetic alteration of AT2R expression. RECENT FINDINGS: Studies reviewed in this article looked at the effect of AT2R stimulation in disease models of hypertension, renal disease, stroke, Alzheimer's disease and myocardial infarction. AT2R stimulation does not have an antihypertensive effect, but promoted tissue protection in all models in which it was tested. Antiinflammation and antiapoptosis seem important features of the AT2R underlying improved outcome in experimental disease models. SUMMARY: Availability of nonpeptidic, orally active AT2R agonists will facilitate future AT2R research and hopefully contribute to the clarification of many still open questions regarding AT2R signalling and function. Furthermore, AT2R agonists represent a potential novel class of drugs and are expected to enter a phase I clinical study in 2012. PMID- 22257800 TI - New insights into mechanisms of hypertension. PMID- 22257802 TI - Can comprehensive echocardiographic evaluation provide an advantage to predict anthracycline-induced cardiomyopathy? AB - OBJECTIVES: No definite markers have been established to identify patients in whom anthracycline-containing chemotherapy may represent a high risk for the development of cardiotoxicity. We aimed to evaluate the predictive value of comprehensive echocardiography in anthracycline-induced cardiomyopathy. STUDY DESIGN: In a prospective design, the study included 39 patients (9 males, 30 females; mean age 53.7+/-11.5 years) who received antineoplastic therapy including anthracycline. Comprehensive echocardiographic examination including tissue Doppler imaging and coronary flow reserve was performed before treatment with anthracycline and at the end of a six-month follow-up. RESULTS: Eight patients (20.5%) developed cardiomyopathy during the follow-up period. Compared to patients with unaffected left ventricular ejection fraction at 6 months, patients with cardiomyopathy exhibited significant differences in baseline left ventricular systolic diameter, mitral E/A, E-wave deceleration time, Sm, Em, Em/Am ratio, Sm-Em duration, and the Tei index. In univariate logistic regression analysis, only Sm (OR 0.40, p=0.002) and the Tei index (OR 3.24, p=0.02) were significant variables for the development of cardiotoxicity. These two were also the only independent predictors of anthracycline cardiotoxicity in multivariate linear regression analysis. Receiver operating characteristic curve analysis yielded a cut-off value of 8 cm/sec for Sm and 0.38 for the Tei index to predict cardiomyopathy. CONCLUSION: Our findings suggest that Sm and myocardial performance index (the Tei index) are significant independent markers to identify patients at high risk for the development of anthracycline-induced cardiomyopathy. PMID- 22257803 TI - Thymosin beta4 levels after successful primary percutaneous coronary intervention for acute myocardial infarction. AB - OBJECTIVES: Thymosin beta4 (Tbeta4) has been shown to have an important role in healing of damaged tissues and promoting cardiomyocyte survival in acute coronary syndromes. We evaluated endogenous Tbeta4 levels in patients presenting with ST elevation acute myocardial infarction (STEMI) before and after successful primary percutaneous coronary intervention (PCI). STUDY DESIGN: The study included 24 consecutive patients (7 females, 17 males; mean age 55.0+/-10.9 years) who underwent successful primary PCI for STEMI and 24 age- and sex-matched healthy controls (13 females, 11 males; mean age 57.5+/-11.7 years) with angiographically normal coronary arteries. To determine Tbeta4 levels, blood samples were obtained from STEMI patients on admission and 48 hours after successful PCI, and from controls immediately after coronary angiography. RESULTS: Compared to controls, baseline levels of high-density lipoprotein cholesterol (46.2+/-8.9 vs. 34.2+/ 7.2 mg/dl, p<0.001) and Tbeta4 (2.9+/-1.5 vs. 1.5+/-1.0 ug/ml, p<0.001) were significantly lower, and white blood cell counts (7.6+/-2.2 vs. 11.4+/-3.0 103/ul, p<0.001) were significantly higher in the STEMI group. After 48 hours of PCI, the mean Tbeta4 level increased significantly to 2.3+/-0.8 ug/ml (p<0.001) and became similar to that of the control group (p=0.068). There was a significant negative correlation between serum Tbeta4 and white blood cell count (r=-0.347, p=0.016). CONCLUSION: Considering the significant increase in serum Tbeta4 levels following successful primary PCI in patients with STEMI, Tbeta4 may prove to be a new marker in the assessment of reperfusion success in addition to those used currently. PMID- 22257804 TI - Percutaneous revascularization of total or subtotal left main occlusion in the setting of acute myocardial infarction. AB - OBJECTIVES: We evaluated the effect of percutaneous coronary intervention (PCI) for total or subtotal left main coronary occlusion (LMCO) in the setting of acute myocardial infarction (AMI), together with clinical features, outcome, and prognostic determinants. STUDY DESIGN: Between March 2008 and June 2010, PCI was performed for total or subtotal thrombotic LMCO in eight patients with AMI. All the patients were males with a mean age of 55.5 years (range 25 to 75 years). The primary endpoints were the occurrence of major adverse cardiac events including death from any cause, nonfatal myocardial infarction, and target lesion revascularization. RESULTS: Five patients were admitted with anterior AMI and three patients with non-ST elevation AMI. Seven patients were in cardiogenic shock. The mean symptom duration was 195 min (range 15 min to 10 hr). Predilatation was performed in six patients, and postdilatation was performed in two patients. Six patients received a single stent with the cross-over technique and the simultaneous kissing stent technique was used in one patient. Mortality occurred in three patients (37.5%). Two deaths developed in the catheterization laboratory, one before stent implantation. One patient died six days after the procedure due to subacute stent thrombosis. After a mean follow-up of 79 weeks (range 27 to 152 weeks), two patients underwent elective bypass surgery because of restenosis, while the rest of the patients remained free of any cardiac event. CONCLUSION: Percutaneous coronary intervention in patients with LMCO complicated by AMI is feasible and effective, and offers a good mid-term outcome for hospital survivors. PMID- 22257805 TI - [Percutaneous closure of the left atrial appendage: a new option for the prevention of thromboembolic stroke]. AB - OBJECTIVES: Percutaneous left atrial appendage (LAA) closure is an important therapeutic option for prevention of thromboembolic stroke in patients with atrial fibrillation (AF), especially when contraindications exist for oral anticoagulation. We aimed to evaluate our short-term results of LAA closure (initial experience) using the WATCHMAN LAA system. STUDY DESIGN: Eleven patients (8 men, 3 women; mean age 68.4+/-7.0 years) with nonvalvular AF, a high risk for cardioembolic stroke (mean CHADS2 score 2.6+/-1.2, mean CHA2DS2-VASc score 4.0+/ 1.5), and contraindications to oral anticoagulation underwent percutaneous LAA closure using the WATCHMAN LAA system. All the procedures were performed under general anesthesia and fluoroscopy and transesophageal echocardiography (TEE) guidance. The patients were evaluated clinically (at 45 days and 6 months) and by TEE (at 45 days). RESULTS: The LAA was successfully occluded in all the patients (100%). The mean procedural and fluoroscopy times were 58.6+/-8.1 and 19.1+/-5.2 minutes, respectively. The mean diameter of the LAA ostium was measured as 20.4+/ 3.8 mm by TEE. The mean device size was 24.6+/-3.8 mm. The mean hospital stay was 1.7+/-0.9 days. Follow-up TEE showed closure of all LAA orifices without device related thrombus formation. Two patients (18.2%) had minimal peri-device leaks (<3 mm). None of the patients experienced major adverse events during a median follow-up of 90 days (interquartile range 60-185 days). CONCLUSION: Our initial experience suggests that percutaneous LAA closure with the WATCHMAN LAA system is safe and feasible, with favorable short-term clinical outcomes. PMID- 22257806 TI - [A retrospective analysis of our paclitaxel-eluting stent (Genius TAXCOR I) implantations and follow-up results]. AB - OBJECTIVES: We evaluated our paclitaxel-eluting stent (Genius TAXCOR I) implantations and follow-up results in patients with coronary artery disease. STUDY DESIGN: The study included 101 patients (75 men, 26 women; mean age 60+/-10 years) who underwent elective paclitaxel-eluting stent deployment for de novo native coronary artery lesions. Sixteen patients received two stents. Lesion types were as follows: type A (23.9%), type B1 (29.1%), type B2 (32.5%), and type C (14.5%). Twelve lesions (10.3%) exhibited mild tortuosity, 32 (27.4%) had mild calcification, 12 had (10.3%) an angulation of more than 45 degrees, while eight (7.7%) had thrombus. Following stent implantation, the patients were examined at 1, 6, and 12 months, and annually thereafter. The mean follow-up period was 48.9+/-5.7 months (range 35 to 60 months). RESULTS: Stent implantation was successful in all the patients. The mean diameter stenosis was 82.8+/-9.9%, the mean stent diameter was 3.1+/-0.6 mm, and the mean stent length was 16.0+/-5.2 mm. During the follow-up period, 46 patients (45.5%) required coronary angiography, of which eight (17.4%) received target vessel revascularization, and four (8.7%) received target lesion revascularization. One patient (1.0%) died from sudden cardiac death. CONCLUSION: The clinical and angiographic follow-up results of this study involving relatively low- and intermediate-risk patients indicate that the use of the Genius TAXCOR I stents is effective and beneficial for the prevention of stent thrombosis and restenosis. PMID- 22257801 TI - The prevalence of microalbuminuria and relevant cardiovascular risk factors in Turkish hypertensive patients. AB - OBJECTIVES: A growing body of data illustrates the importance of microalbuminuria (MAU) as a strong predictor of cardiovascular risk in the hypertensive population. The present study was designed to define the prevalence of MAU and associated cardiovascular risk factors among Turkish hypertensive outpatients. STUDY DESIGN: Representing the Turkish arm of the multinational i-SEARCH study involving 1,750 sites in 26 countries around the world, a total of 1,926 hypertensive patients from different centers were included in this observational and cross-sectional survey study. Patients with reasons for a false-positive MAU test were excluded. The prevalence of MAU was assessed using a dipstick test, and patients were inquired about comorbidities, comedication, and known cardiovascular risk factors. RESULTS: The overall prevalence of MAU was 64.7% and there was no difference between genders. Most of the patients (82.5%) had uncontrolled hypertension, 35.6% had dyslipidemia, and 35.5% had diabetes, predominantly type 2. Almost one-third of the patients (26.4%) had at least one cardiovascular-related comorbidity, with 20.3% having documented coronary artery disease (CAD). Almost all patients (96.8%) had one or more risk factors for cardiovascular disease in addition to hypertension, including family history of myocardial infarction or CAD, diabetes, dyslipidemia, lack of physical exercise, and smoking. A trend towards higher MAU values in the presence of CAD was determined. CONCLUSION: Microalbuminuria tests should be routinely used as a screening and monitoring tool for the assessment of subsequent cardiovascular morbidity and mortality among hypertensive patients. PMID- 22257807 TI - Pacemakers do not always tell the truth: diagnosis of ventricular tachycardia for supraventricular tachycardia on pacemaker telemetry. AB - Pacemaker telemetry reflects algorithm-dependent interpretations about the cardiac rhythm. For these data to be useful, it is necessary to recognize the limitations of each algorithm and its interactions with pacing and sensing parameters. We report on a case in which pacemaker Holter recording showed several episodes of nonsustained supraventricular tachycardia which were erroneously classified as ventricular tachycardia. PMID- 22257808 TI - A hidden cause of hemoptysis: coronary artery-to-pulmonary parenchyma fistula. AB - A 60-year-old man presented with complaints of chronic hemoptysis present for many years and a six-month history of chest pain. Physical examination showed a grade II/VI continuous murmur at the left sternal border. Electrocardiography showed normal sinus rhythm and nonspecific ST-T changes in lateral leads. Echocardiography showed mild left ventricular hypertrophy. Exercise test was discontinued because of anginal symptoms and occurrence of lateral ST depression. Hemoptysis was observed a few times during hospitalization. Computed tomography of the thorax showed no abnormality to explain hemoptysis. Coronary angiography revealed a critical lesion in the left anterior descending artery and a large, tortuous right coronary artery with a fistulization tract originating from its proximal region and draining into the left lung parenchyma. The lesion in the left anterior descending artery was stented and percutaneous coil embolization of the fistula was performed in another session. Coronary angiography showed complete occlusion of the fistula and no residual shunting. In the six-month period after the procedure, the patient was free of symptoms of angina and hemoptysis. PMID- 22257809 TI - A rare cause of severe mitral regurgitation: mitral valve aneurysm. AB - Perforation of a mitral valve aneurysm is a rare cause of acute mitral regurgitation, and valvular aneurysm formation and its rupture without infectious involvement are unusual. An 80-year-old man was admitted with acute onset and progressive dyspnea. He had no history of chest pain, palpitation, or fever. Laboratory findings did not suggest any signs of infection. Transthoracic echocardiography revealed an aneurysm of the mitral septal leaflet protruding into the left atrium during systole and color-flow Doppler ultrasonography showed severe mitral regurgitation. There was no aortic regurgitation nor evidence for rheumatic involvement of the valvular structures. Pulmonary artery systolic pressure estimated from the tricuspid regurgitation jet was 50 mmHg. Transesophageal echocardiography showed a saccular, thin-walled, mitral valve aneurysm on the atrial surface, expanding during systole and a small tissue defect on the aneurysmatic segment of the mitral leaflet. There were no signs of connective tissue disease. The patient was submitted to surgery. The aneurysmatic and perforated parts on the septal leaflet were resected and an annuloplasty ring was placed. The histopathological examination of the mitral valve tissue showed nonspecific degenerative changes. The postoperative period was uneventful and the patient was discharged on the fifth postoperative day. PMID- 22257810 TI - [Supra-His complete atrioventricular block in a patient with subclinical hyperthyroidism]. AB - Subclinical hyperthyroidism is a difficult entity to diagnose because of silent clinical features and it may be easily underdiagnosed unless it is suspected and thyroid hormone levels are examined. Although atrioventricular (AV) conduction abnormalities such as complete heart block may occasionally be seen in hyperthyroidism, its association with subclinical hyperthyroidism has not been reported previously. We report on a 50-year-old female patient who did not have any systemic or cardiovascular disease or history of drug use that could affect AV conduction and presented with presyncope and complete heart block with narrow QRS complexes. Thyroid function tests showed subclinical hyperthyroidism and an electrophysiological study showed the supra-His level as the site of complete AV block. After initiation of antithyroid treatment (propylthiouracil), the patient's rhythm improved to second-degree AV block on the third day and returned to normal sinus rhythm on the fourth day. PMID- 22257811 TI - [Pneumopericardium after pericardiocentesis: a case report]. AB - Pneumopericardium is defined by the presence of air in the pericardial sac. We present a 61-year-old cachectic woman who developed pneumopericardium after pericardiocentesis. She presented with complaints of fatigue and shortness of breath. The chest X-ray showed an increased cardiothoracic ratio, and echocardiographic examination showed a marked pericardial effusion. Pericardiocentesis was performed and a total of 860 ml hemorrhagic pericardial fluid was aspirated. At the end of the first week after removal of the catheter, control chest radiography showed air-fluid levels in the pericardial cavity, and echocardiography revealed dense air bubbles in the decreased pericardial effusion. As the patient was hemodynamically stable, she was monitored on medical treatment. However, five days later, pericardiocentesis was repeated due to a significant increase in the pericardial effusion despite decreased amount of air. As no etiologic factor could be elicited, a connective tissue disease was considered and a corticosteroid was added to her treatment, which resulted in a rapid decline in the pericardial effusion on follow-up chest radiography and echocardiography. She was discharged on steroid therapy. PMID- 22257812 TI - [Giant coronary artery aneurysm in a patient with rheumatoid arthritis]. AB - A 52-year-old men with rheumatoid arthritis of 12-year history presented with severe chest pain. The electrocardiogram was consistent with acute inferior myocardial infarction. Transthoracic echocardiography showed increased left ventricular dimensions and hypokinesia in the inferolateral wall. Coronary angiography performed for percutaneous coronary intervention showed aneurysmatic dilatation (15-16 mm) and total occlusion of the right coronary artery by a large thrombus. As there was no stent available for dilated right coronary artery and due to the large thrombus burden, medical therapy was decided and tissue plasminogen activator infusion was started. The patient's chest pain progressively decreased. Coronary angiography performed on the fifth day of admission showed TIMI 3 flow in the right coronary artery. Warfarin was added to standard anti-ischemic treatment with a target INR of 2.5-3.0. Our literature search yielded no reported case of such aneurysmatic dilatation associated with rheumatoid arthritis. PMID- 22257813 TI - Almanac 2011: acute coronary syndromes. The national society journals present selected research that has driven recent advances in clinical cardiology. AB - This overview highlights some recent advances in the epidemiology, diagnosis, risk stratification and treatment of acute coronary syndromes. The sheer volume of new studies reflects the robust state of global cardiovascular research but the focus here is on findings that are of most interest to the practising cardiologist. Incidence and mortality rates for myocardial infarction are in decline, probably owing to a combination of lifestyle changes, particularly smoking cessation, and improved pharmacological and interventional treatment. Troponins remain central for diagnosis and new high-sensitivity assays are further lowering detection thresholds and improving outcomes. The incremental diagnostic value of other circulating biomarkers remains unclear and for risk stratification simple clinical algorithms such as the GRACE score have proved more useful. Primary PCI with minimal treatment delay is the most effective reperfusion strategy in ST elevation myocardial infarction (STEMI). Radial access is associated with less bleeding than with the femoral approach, but outcomes appear similar. Manual thrombectomy limits distal embolisation and infarct size while drug-eluting stents reduce the need for further revascularisation procedures. Non-culprit disease is best dealt with electively as a staged procedure after primary PCI has been completed. The development of antithrombotic and antiplatelet regimens for primary PCI continues to evolve, with new indications for fondaparinux and bivalirudin as well as small-molecule glycoprotein (GP)IIb/IIIa inhibitors. If timely primary PCI is unavailable, fibrinolytic treatment remains an option but a strategy of early angiographic assessment is recommended for all patients. Non-ST segment elevation myocardial infarction(NSTEMI) is now the dominant phenotype and out-comes after the acute phase are significantly worse than for STEMI. Many patients with NSTEMI remain undertreated and there is a large body of recent work seeking to define the most effective antithrombotic and antiplatelet regimens for this group of patients.The benefits of early invasive treatment for most patients are not in dispute but optimal timing remains unresolved. Cardiac rehabilitation is recommended for all patients with acute myocardial infarction but take-up rates are disappointing. Home-based programmes are effective and may be more acceptable for many patients. Evidence for the benefits of lifestyle modification and pharmacotherapy for secondary prevention continues to accumulate but the argument for omega-3 fatty acid supplements is now hard to sustain following recent negative trials. Implantable cardioverter defibrillators for patients with severe myocardial infarction protect against sudden death but for pri-mary prevention should be based on left ventricular ejection fraction measurements late (around 40 days)after presentation, earlier deployment showing no mortality benefit. PMID- 22257814 TI - Almanac 2011: cardiac arrhythmias and pacing. The national society journals present selected research that has driven recent advances in clinical cardiology. PMID- 22257815 TI - [How to evaluate the function of the prosthetic valve in the aortic position?]. PMID- 22257816 TI - Acute myocardial infarction due to a large coronary aneurysm in Behcet's disease. PMID- 22257817 TI - Angina resulting from coronary-subclavian steal syndrome. PMID- 22257818 TI - Three-dimensional imaging of a huge right atrial leiomyosarcoma. PMID- 22257819 TI - Symptomatic isolated giant hydatid cyst in the posterolateral region of the left ventricle. PMID- 22257820 TI - [Giant interatrial septal aneurysm in a case with paroxysmal atrial fibrillation]. PMID- 22257821 TI - Spontaneous right coronary artery dissection possibly associated with clonidine transdermal patch. PMID- 22257822 TI - [Dislodgement of a sirolimus-eluting stent in the circumflex artery and its successful deployment with a small-balloon technique]. PMID- 22257823 TI - [Frequency of sublingual nitroglycerin prescription in patients with coronary artery disease and angina and awareness of patients about the shelf life of the drug]. PMID- 22257824 TI - The removal from plasma of chylomicrons and remnants is reduced in heterozygous familial hypercholesterolemia subjects with identified LDL receptor mutations: study with artificial emulsions. AB - Chylomicron remnants bind to both their specific receptors (LRP) and to the LDL receptor (LDLR) in the liver. There is controversy whether disturbances of chylomicron metabolism occur in subjects with familial hypercholesterolemia (FH). The aim of this study was to evaluate whether there are defects on the removal from plasma of chylomicrons and their remnants in heterozygous FH patients with determined LDLR mutations. We studied 20 heterozygous FH patients (43.2+/-12 years old, 60% males) and 50 normolipidemic subjects matched for age and gender. FH subjects were not in use of LDL-lowering drugs for at least 6 weeks. The removal from plasma of chylomicrons and their remnants was measured by isotopic decay after venous injection of a chylomicron-like emulsion radiolabeled with (14)C-cholesteryl ester ((14)C-CE) and (3)H-triolein ((3)H-TO). These track respectively removal from plasma of chylomicrons and remnants and lipolysis. There was a significant reduction in the fractional catabolic rates (FCR in h( 1)) of (14)C-CE in FH in comparison with normolipidemics: 0.048 (1.46.10(-7); 0.57) vs. 0.71(0.049; 1.62), [median (25th-75th percentile)], p=0.003. No differences were found in FCR of (3)H-TO between FH and controls, respectively 1.62 (1.02; 2.331) and 1.914 (1.34; 2.878), p=0.405. In conclusion heterozygous FH subjects had a significant decrease on the removal from plasma of chylomicrons and their remnants compared with normolipidemics. PMID- 22257825 TI - Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a randomised phase II trial. AB - BACKGROUND AND PURPOSE: This randomised phase II study evaluated the use of Temozolomide (TMZ) concomitant with 30 Gray (Gy) of Whole-brain irradiation (WBI) for 2 weeks without adjuvant TMZ vs. WBI alone in patients with Brain metastases (BM) from solid tumours. MATERIALS AND METHODS: Fifty-five patients were randomised into the following groups: 28 patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with once-daily 200 mg TMZ on Mondays, Wednesdays, and Fridays, and 300 mg TMZ on Tuesdays and Thursdays (TMZ plus WBI arm). Twenty-seven patients received the same schedule of WBI alone (control arm). RESULTS: The objective response (OR) was 78.6% for the TMZ plus WBI arm, (95% confidence interval [CI], 63.4-93.8%) and 48.1% (29.3-66.9%) for the control arm (p=0.019). Median Progression-free survival (PFS) of BM was 11.8 months (CI, 4.7-8.9 months) and 5.6 months (4.9-6.2 months) for the TMZ plus WBI and control arms, respectively, (Hazard ratio [HR], 0.24; CI, 0.09-0.65; p=0.005). Overall survival (OS) of 8.0 Months for the TMZ plus WBI arm and 8.1 months for the control arm, were not significantly different. CONCLUSION: A daily fixed dose of TMZ during WBI without adjuvant TMZ was well tolerated and significantly improved local control of BM compared with WBI alone. These findings require confirmation in a phase III trial (ClinicalTrials.gov number, NCT01015534). PMID- 22257826 TI - The distribution pattern of critically short telomeres in human osteoarthritic knees. AB - INTRODUCTION: Telomere shortening is associated with a number of common age related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence. METHODS: Samples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF). RESULTS: The load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length. CONCLUSIONS: These in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA. PMID- 22257827 TI - Withdrawal of life-sustaining treatment for newborn infants from a Christian perspective. AB - The more vulnerable a person, of whatever age, therefore, the more there must be a presumption in favour of life; and care must be offered with particular respect and dignity, and in the best interests of the infant her/himself, not in those of others. The principles, that guide Christians in making ethical healthcare decisions, were derived from two core Christian beliefs: that all human beings, of whatever age, are "made in the image of God"--so human beings have a distinctive dignity and value, and may not be treated as possessions or commodities; and that we are therefore made to live relationally--so communal, as well as individual, perspectives ought to be considered in ethical decision making. The article then notes and explores three areas in which it may not be in the infant's best interests for life-sustaining treatment to continue or to be initiated, noting the complexity of "quality of life" questions, and the danger of considering others' quality of life over that of the infant. So, to safeguard the vulnerable, the threshold for acceptable "quality of life" needs to be set at a "low" level; and a distinction should be drawn, in considering withdrawing life sustaining treatment, between medical intervention and "assisted-care" - so that there are very limited circumstances in which life-sustaining treatments ought to be withheld or withdrawn from newborn infants. PMID- 22257828 TI - Isolation and characterization of RNA-containing exosomes. AB - The field of exosome research is rapidly expanding, with a dramatic increase in publications in recent years. These small vesicles (30-100 nm) of endocytic origin were first proposed to function as a way for reticulocytes to eradicate the transferrin receptor while maturing into erythrocytes, and were later named exosomes. Exosomes are formed by inward budding of late endosomes, producing multivesicular bodies (MVBs), and are released into the environment by fusion of the MVBs with the plasma membrane. Since the first discovery of exosomes, a wide range of cells have been shown to release these vesicles. Exosomes have also been detected in several biological fluids, including plasma, nasal lavage fluid, saliva and breast milk. Furthermore, it has been demonstrated that the content and function of exosomes depends on the originating cell and the conditions under which they are produced. A variety of functions have been demonstrated for exosomes, such as induction of tolerance against allergen, eradication of established tumors in mice, inhibition and activation of natural killer cells, promotion of differentiation into T regulatory cells, stimulation of T cell proliferation and induction of T cell apoptosis. Year 2007 we demonstrated that exosomes released from mast cells contain messenger RNA (mRNA) and microRNA (miRNA), and that the RNA can be shuttled from one cell to another via exosomes. In the recipient cells, the mRNA shuttled by exosomes was shown to be translated into protein, suggesting a regulatory function of the transferred RNA. Further, we have also shown that exosomes derived from cells grown under oxidative stress can induce tolerance against further stress in recipient cells and thus suggest a biological function of the exosomal shuttle RNA. Cell culture media and biological fluids contain a mixture of vesicles and shed fragments. A high quality isolation method for exosomes, followed by characterization and identification of the exosomes and their content, is therefore crucial to distinguish exosomes from other vesicles and particles. Here, we present a method for the isolation of exosomes from both cell culture medium and body fluids. This isolation method is based on repeated centrifugation and filtration steps, followed by a final ultracentrifugation step in which the exosomes are pelleted. Important methods to identify the exosomes and characterize the exosomal morphology and protein content are highlighted, including electron microscopy, flow cytometry and Western blot. The purification of the total exosomal RNA is based on spin column chromatography and the exosomal RNA yield and size distribution is analyzed using a Bioanalyzer. PMID- 22257830 TI - Mea culpa: scientific misconduct. PMID- 22257829 TI - Postoperative respiratory failure after cardiac surgery: use of noninvasive ventilation. AB - OBJECTIVES: To analyze the use of noninvasive ventilation (NIV) in respiratory failure after extubation in patients after cardiac surgery, the factors associated with respiratory failure, and the need for reintubation. DESIGN: Retrospective observational study. SETTING: Intensive care unit in a university hospital. PARTICIPANTS: Patients (n = 63) with respiratory failure after extubation after cardiac surgery over a 3-year period. INTERVENTIONS: Mechanical NIV. MEASUREMENTS AND MAIN RESULTS: Demographic and surgical data, respiratory history, causes of postoperative respiratory failure, durations of mechanical ventilation and spontaneous breathing, gas exchange values, and the mortality rate were recorded. Of 1,225 postsurgical patients, 63 (5.1%) underwent NIV for respiratory failure after extubation. The median time from extubation to the NIV application was 40 hours (18-96 hours). The most frequent cause of respiratory failure was lobar atelectasis (25.4%). The NIV failed in 52.4% of patients (33/63) who had a lower pH at 24 hours of treatment (7.35 v 7.42, p = 0.001) and a higher hospital mortality (51.5% v 6.7%, p = 0.001) than those in whom NIV was successful. An interval <24 hours from extubation to NIV was a predictive factor for NIV failure (odds ratio, 4.6; 95% confidence interval, 1.2-17.9), whereas obesity was associated with NIV success (odds ratio, 0.22; 95% confidence interval, 0.05-0.91). CONCLUSIONS: Reintubation was required in half of the NIV treated patients and was associated with an increased hospital mortality rate. Early respiratory failure after extubation (<=24 hours) is a predictive factor for NIV failure. PMID- 22257831 TI - Bile leakage after hepatobiliary and pancreatic surgery: is the ISGLS definition too simple? PMID- 22257832 TI - Fungal melanonychia. AB - Fungal melanonychia is a relatively rare nail disorder caused by nail infection that produces brown-to-black pigmentation of the nail unit. The number of organisms implicated as etiologic agents of fungal melanonychia is increasing, and the list currently tops 21 species of dematiaceous fungi and at least 8 species of nondematiaceous fungi. These superficial infections may clinically mimic subungual melanoma and are often not responsive to traditional antifungal therapy. This article reviews the literature on fungal melanonychia and the role of fungal melanin in infection. PMID- 22257833 TI - High TNF-alpha and IL-8 levels predict low blood dendritic cell counts in primary cytomegalovirus infection. AB - BACKGROUND: In vitro studies suggest that human cytomegalovirus (CMV) modulates the functions of dendritic cells (DCs). However, there are limited data on DC homeostasis in CMV-infected patients. OBJECTIVES: The aim of this study was to characterize circulating DCs and plasma cytokine levels in immunocompetent patients with primary, symptomatic CMV infections. STUDY DESIGN: The study population consisted of 14 patients suffering of CMV mononucleosis and 14 healthy volunteers (11 CMV-seropositive and 3 CMV-seronegative subjects) included as controls. Peripheral blood mononuclear cells were isolated and used to characterize DCs and to quantify CMV in the blood. Plasma levels of pro inflammatory and anti-inflammatory cytokines were also measured. RESULTS: We observed that patients who were developing CMV mononucleosis presented lower myeloid and plasmacytoid DC counts in peripheral blood compared with healthy controls. We also noted elevated levels of inflammatory mediators, of which tumor necrosis factor-alpha (TNF-alpha)-which activates DCs and endothelial cells-was the highest. Notably, the decrease in blood DCs correlated with high TNF-alpha and IL-8 levels by a hyperbolic function. CONCLUSIONS: Our results suggest that increased levels of inflammatory factors facilitate alterations in DC homeostasis during primary CMV infection, which may contribute to viral-induced modulation of host immunity. PMID- 22257834 TI - Secondary extramammary Paget's disease with underlying recurrent bladder carcinoma. PMID- 22257835 TI - Cutaneous amyloidosis: a concept review. AB - Concepts and semantics are crucial for good communication between clinicians and pathologists. Amyloidosis was described more than 150 years ago. Therefore, the terminology related to it is abundant, varied, and sometimes complex. In this report, we intend to discuss several terms related to the disease, with special emphasis on cutaneous amyloidosis. We present a review, from Virchow to present, of the concepts related to amyloidosis: its nature, the classification of cutaneous forms of the disease, and the techniques used in its diagnosis. PMID- 22257836 TI - A comparative analysis of cutaneous marginal zone lymphoma and cutaneous chronic lymphocytic leukemia. AB - The morphologic distinction between cutaneous marginal zone lymphoma (CMZL) and secondary cutaneous involvement by B-cell chronic lymphocytic leukemia (B-CLL) can be difficult. Both entities can show very similar architectural patterns of involvement in the skin and not uncommonly, the skin can be the first site of presentation of B-CLL in the elderly. We reviewed biopsies of 13 patients with cutaneous B-CLL and 14 patients with CMZL to compare their histologic and immunohistochemical features. CMZL and cutaneous B-CLL both predominantly exhibited a nodular pattern of skin involvement (9 of 13 B-CLL, 9 of 14 CMZL) with a minority of cases demonstrating a diffuse pattern (4 of 13 B-CLL, 4 of 14 CMZL). Although reactive germinal centers (12 of 14 cases) and plasma cells (10 of 14 cases) were seen more often in CMZL, plasma cells were also observed in cases of B-CLL (4 of 13). The lesional cells of B-CLL expressed CD79, CD5, CD23, and CD43, although CMZL did not express CD5 or CD43. Although we noted light chain restriction in 13 of 14 cases of CMZL cases, we also observed light chain restriction in 4 of 13 cases of B-CLL. Our results indicate that CMZL and B-CLL can be morphologically similar and both may show light chain restriction. Complete immunophenotyping is necessary to ensure that all cases are correctly classified. PMID- 22257837 TI - Itchy scaly bumps on trunk and extremities: challenge. PMID- 22257839 TI - A two-marker haplotype in the IRF5 gene is associated with inflammatory bowel disease in a North American cohort. AB - Interferon regulatory factor 5 (IRF5) located on human chromosome 7q32 is associated with many chronic inflammatory disorders. IRF5 is the key regulator of proinflammatory cytokines and type I interferons. We surveyed two cohorts of inflammatory bowel disease (IBD) patients from a North American Consortium. Six single-nucleotide polymorphisms and a 5-base-pair (bp) insertion-deletion (CGGGG indel)polymorphism were investigated. Cytokine secretion was measured in primary lymphocytes after toll-like receptor 9 stimulation. Two-marker haplotypes containing the pairs (rs4728142-CGGGG indel) and (CGGGG indel-rs7808907) were associated with IBD protection (P=2.89 * 10(-6), P=9.32 * 10(-4) (non-Jewish ancestry) and P=4.68 * 10(-8), P=2.50 * 10(-8) (Jewish ancestry)) and IBD risk (P=0.004, P=0.003 (Jewish ancestry), respectively. IRF5 polymorphisms were risk factors for IBD in a single cohort. Interleukin-12-p70 cytokine production was higher (P=0.04) in lymphocytes from controls with two alleles of the 5-bp insertion. IRF5 polymorphisms contribute to the risk profile for Crohn's disease and ulcerative colitis along with ancestry and NOD2 genotypes. PMID- 22257840 TI - Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. AB - We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 * 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 * 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 * 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC. PMID- 22257841 TI - Good interobserver agreement was attainable on outcome adjudication in patients with stable coronary heart disease. AB - OBJECTIVE: In clinical trials, agreement on outcomes is of utmost importance for valid estimation of intervention effects. As there is limited knowledge about adjudicator agreement in cardiology, we examined the level of agreement among three cardiology specialists adjudicating all possible events in a randomized controlled clinical trial of patients with stable coronary heart disease. STUDY DESIGN AND SETTING: All information (hospital records, death certificates, etc.) was forwarded to two randomly selected blinded adjudicators. If they disagreed, the third arbiter had to choose the more likely of the two alternatives. Files of 5,475 nonfatal and 362 fatal events were evaluated. RESULTS: For nonfatal outcomes, pairwise kappa values ranged from 0.75 to 0.80. The three adjudicators had 4.3%, 9.5%, and 6.1% of their nonfatal outcome classifications overruled by their arbiter. If stable angina pectoris, unstable angina pectoris, and acute myocardial infarction were treated as one, agreement increased minimally. For fatal outcomes, the pairwise kappa values ranged from 0.65 to 0.90. The three adjudicators had 12%, 9%, and 10% of their death classifications overruled. CONCLUSION: Specialists in cardiology can attain a reasonably high agreement on outcomes in patients with stable coronary heart disease. PMID- 22257850 TI - Ion channels: Cooperativity in twin gatings. PMID- 22257851 TI - Glycobiology: Enzyme deficiencies deciphered. PMID- 22257852 TI - Signaling: An oxysterol ligand for Smoothened. PMID- 22257853 TI - Sparing the anterior cruciate ligament remnant: is it worth the hassle? AB - INTRODUCTION: Anterior cruciate ligament (ACL) rupture is the most common surgically treated ligament injury. Many efforts have been taken to reconstruct it as anatomically as possible to restore knee stability and, possibly, prevent knee osteoarthritis. SOURCES OF DATA: A literature search was performed using the isolated or combined keywords 'ACL augmentation remnant', 'ACL reconstruction and remnant and stump', 'ACL reconstruction and remnant and stump preserving and stability' and 'ACL remnant complete tear' with no limit regarding the year of publication. We identified seven published studies. AREAS OF AGREEMENT: The ACL remnant might accelerate the vascularization and the ligamentization of the graft and contribute to faster graft innervation leading to a better proprioception. AREAS OF CONTROVERSY: The role of the ACL remnant is debated, because, although it may increase the risk of impingement and the formation of cyclops lesion, its preservation can improve proprioception, biomechanical functions and vascularity. However, the current assessment methods to assess proprioception, vascularization and the ligamentization do not lead to hard evidence that preservation of the remnant confers clinically relevant advantages over its excision. GROWING POINTS: The ACL remnant has been demonstrated in experimental studies to have a role in improving revascularization, ligamentization and reinnervation of the graft, but these findings are still not supported by clinical findings. A more direct way to assess proprioceptive function after ACL reconstruction and appropriately conducted powered and rigorously prospective randomized double-blind studies comparing the clinical outcomes of excising the remnant to leaving it in situ are necessary. PMID- 22257855 TI - Mechanisms of removing pollutants from aqueous solutions by microorganisms and their aggregates: a review. AB - With the public's enhanced awareness of eco-safety, environmentally benign measures based on microorganisms and microbial aggregates have become more accepted as methods of removing pollutants from aquatic systems. In this review, the application of microorganisms and microbial aggregates for removing pollutants from aqueous solutions is introduced and described based on mechanisms such as assimilation, adsorption, and biodegradation. The advantages of and future studies regarding the use of microorganisms and microbial aggregates to remove pollutants are discussed. Due to the limitation of a single microorganism species in adapting to heterogeneous conditions, this review demonstrates that the application of microbial aggregates consisting of multiple photoautotrophic and heterotrophic microorganisms, is a promising method of removing multiple pollutants from complex wastewaters and warrants further research. PMID- 22257854 TI - Exotic plant invasion in the context of plant defense against herbivores. PMID- 22257856 TI - Shifts in microbial community structure of granular and liquid biomass in response to changes to infeed and digester design in anaerobic digesters receiving food-processing wastes. AB - There have been few studies, to date, examining the effect of seed sludge on the microbial community established in a new anaerobic digestion (AD) system and whether or not the population present in the seed sludge establishes it self as the predominant population. Further, no reported studies have yet examined the differences in microbial populations that result from the formation of granular biomass in upflow anaerobic sludge blanket (UASB) systems. This study focused on examining the changes in microbial diversity between the initial seed sludge and the community that becomes established in a new digester. Using 16S rRNA clone libraries the diversity of microbes in both the granular and liquid biomass fractions from 3 AD sludge samples was examined and compared. Results showed that each sample had unique microbial community, with the distribution of sequences at the phylum level highly variable. This suggests that the feedstock had an effect of enriching microbial populations that are uniquely suited to a particular feedstock. Differences between the granular and liquid biomass fractions of each sample were less pronounced than differences attributable to the change in feedstock, however the results suggest that there are different functional groups in each fraction. PMID- 22257858 TI - Biological catalyzed denitrification by a functional electropolymerization biocarrier modified by redox mediator. AB - Electropolymerization biocarriers were prepared by the electropolymerization of polypyrrole (PPy) on an active carbon felt (ACF) electrode using doping anions anthraquinone-2-sulfonate (AQS) or Na(2)SO(4). The functional electropolymerization biocarrier (ACF/PPy/AQS) with AQS was used as an immobilized redox mediator for the denitrification process. The characteristics of the electropolymerization biocarriers were analyzed by scanning electron microscope, elemental analyses, Fourier transform infrared (FTIR) spectroscopy and Raman spectroscopy. The results suggested that the denitrification efficiency increased nearly 1.5-fold with ACF/PPy/AQS (0.04 mmol L(-1) AQS) compared to the control. A linear correlation was found for the k value and the AQS concentration (C(AQS)), which was k=624.71C(AQS)+83.87 (R(2)=0.9893). The ORP value stabilized around -200 mV for the denitrification process with ACF/PPy/AQS, which was -25 mV lower than that with ACF/PPy/Na(2)SO(4). Repeated-batch operations indicated that the denitrification efficiency with ACF/PPy/AQS maintained over 90% of the original value and exhibited better catalytic activity and durability. PMID- 22257857 TI - Modes of hydrocarbon oil biosynthesis revealed by comparative gene expression analysis for race A and race B strains of Botryococcus braunii. AB - To clarify the oil biosynthetic routes of the oil-producing green alga Botryococcus braunii, here the race-specific gene expression patterns were examined using representative strains of race A and race B producing fatty acid- and triterpene-derived hydrocarbon oils, respectively. The strain-specific gene expression patterns in the BOT-88-2 strain (race A) and the BOT-22 strain (race B) were revealed by transcriptome comparison and real-time PCR quantification. For race A, it was inferred from the gene expression patterns that the fatty acid elongation in the acyl-carrier-protein (acp)-bound form followed by further elongation in the coenzyme A (CoA)-bound form is the major route of oil biosynthesis. The fatty acids may be desaturated in both acp- and CoA-bound forms and once metabolized into glycerolipids prior to further elongation. For race B, relatively direct entry of photosynthetic products from the reductive pentose phosphate cycle into the mevalonate-independent triterpene biosynthesis was implicated. PMID- 22257859 TI - The implication of mediators for enhancement of laccase oxidation of sulfonamide antibiotics. AB - In this study, the transformation of sulfonamide antibiotics (SAs, 50 mg L(-1)) was investigated in systems consisting of a fungal laccase (6 IU) and six mediators (1mM). The results illustrate that the laccase had limited effect on the removal of sulfadimethoxine and sulfamonomethoxine. However, laccase oxidation with the mediators (LMS) led to significant declines of the SAs. Two mediators, 2-2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) and violuric acid, provided the fastest transformations of SAs in LMS, with t(1/2)s of 1.8-4.1 min; slower transformations in syringaldehyde and 4-hydroxybenzyl alcohol, with t(1/2)s of 19.0-131 min; and the slowest or no significant decline in 4 hydroxyacetophenone and 4-cyanophenol, with t(1/2)s > 330 min. The decline of the re-added SAs in LMS was slower than that of the first addition. De-aniline and oxidative coupling are the two detectable pathways for the transformation of SAs. The results indicated that some mediators enhanced laccase oxidation of the SAs. PMID- 22257860 TI - Sporulation and spore stability of Bacillus megaterium enhance Ketogulonigenium vulgare propagation and 2-keto-L-gulonic acid biosynthesis. AB - Bacillus spp. is widely used as the companion bacterium in the two-step biosynthesis of 2-keto-L-gulonic acid (2-KLG), which is the direct precursor in the production of vitamin C by Ketogulonigenium vulgare. To understand the effects of sporulation and spore stability on 2-KLG production, the spo0A and spoVFA deletion mutants of Bacillus megaterium were constructed. The sorbose conversion rates of spo0A and spoVFA mutant co-culture systems were 33% and 70% lower, respectively, than that of the wild-type co-culture system. In addition, K. vulgare cell numbers in the two mutant systems declined by 15% and 49%, respectively, compared to the value in the wild-type system. Correlation analysis indicated that the 2-KLG concentration is positively related to sorbose dehydrogenase activity and the K. vulgare cell number. This study demonstrated that sporulation and spore stability of the wild-type companion play key roles in the enhancement of K. vulgare propagation and 2-KLG biosynthesis. PMID- 22257861 TI - Efficient saccharification of ammonia soaked rice straw by combination of Clostridium thermocellum cellulosome and Thermoanaerobacter brockii beta glucosidase. AB - Clostridium thermocellum is known to produce the cellulosomes with efficient plant cell wall degradation ability. To bring out the maximum cellulolytic ability of the cellulosomes, it is necessary to eliminate the end product inhibition by cellobiose. Combinations of beta-glucosidases from thermophilic anaerobic bacteria and Aspergillusniger and C.thermocellum S14 cellulosomes were evaluated for optimization of cellulose degradation. beta-Glucosidase (CglT) from Thermoanaerobacterbrockii, in combination with cellulosomes, exhibited remarkable saccharification ability for microcrystalline cellulose. When rice straw, soaked in 28% aqueous ammonia for 7 days at 60 degrees C, was hydrolyzed by an enzyme loading combination of 2mg cellulosome and 10 units CglT per g glucan, 91% of glucan was hydrolyzed to glucose, indicating roughly1/10 the enzyme load of a Trichodermareesei cellulase (Celluclast 1.5L) and Novozyme-188 combination is enough for the combination of C.thermocellum S14 cellulosomes and CglT to achieve the same level of saccharification of rice straw. PMID- 22257862 TI - Interocular comparison by in vivo confocal microscopy of the 2-dimensional architecture of the normal human corneal subbasal nerve plexus. AB - PURPOSE: To investigate the configuration of the living human corneal subbasal nerve plexus in paired eyes of normal subjects using in vivo confocal microscopy. METHODS: Laser scanning in vivo confocal microscopy was performed on both corneas of healthy human subjects, and a grid fixation pattern facilitated examination of consistent areas of central to midperipheral cornea. Macromedia/Adobe Freehand 10 was used to manually arrange images into contiguous montages. The subbasal nerve density and overall patterns were analyzed. RESULTS: Both eyes of 6 subjects (3 women and 3 men, aged between 25 and 36 years) were examined. In all subjects, the subbasal nerve plexus exhibited a clockwise whorl configuration inferior to the central cornea. The mean subbasal nerve density at the whorl was 39.17+/-4.95 mm/mm and 41.36+/-4.19 mm/mm in the right and left eyes, respectively. There was no significant difference in the nerve density between the eyes (P=0.61). Bland and Altman analysis confirmed high intraobserver repeatability and moderate interobserver repeatability. CONCLUSIONS: This study reveals the marked similarities between the corneal subbasal nerve plexus configuration in the right and left eyes of the living human cornea, highlighting that the typical mirror image symmetry in corneal topographic patterns is not obeyed in respect to corneal innervation and that a clockwise orientation of the subbasal plexus is typically encountered. There was no statistical difference in the subbasal nerve density between the eyes. PMID- 22257863 TI - Posterior dislocation and immediate retrieval of a descemet stripping automated endothelial keratoplasty graft. AB - PURPOSE: To report a case of intraoperative graft dislocation into the vitreous cavity during Descemet stripping automated endothelial keratoplasty (DSAEK) in an aniridic eye despite the presence of an iris prosthetic lens, and the surgical technique for immediate rescue of the donor lenticule. METHODS: A 30-year-old man, who had undergone previous pars plana vitrectomy, penetrating keratoplasty, and iris prosthetic lens implantation (Morcher Aniridia Implants 67G) for traumatic aniridia, underwent DSAEK for failed penetrating keratoplasty. Intraoperatively, the graft dislocated into the posterior segment through the gap between the lens implant and the scleral wall. The dislocated graft was grasped with a 23-gauge vitrectomy forceps inserted through the temporal scleral incision and the implant-scleral wall gap. The straight endoglide insertion forceps was then introduced through a nasal paracentesis and used to pull the donor from the posterior segment into the anterior chamber through the implant-scleral wall gap. RESULTS: Postoperatively, the patient did well with no evidence of graft dislocation or retinal detachment, and rapid clearing of the donor and recipient cornea. Donor endothelial cell loss was only 11% at 6 months after DSAEK. CONCLUSIONS: Graft dislocation into the vitreous cavity can occur during DSAEK, even in the presence of a large iris prosthetic lens implant. In a previously vitrectomized eye, immediate retrieval of the donor from the retina can be performed using a vitrectomy forceps inserted through the existing temporal scleral DSAEK incision into the posterior segment, thus obviating the need for further pars plana incisions. PMID- 22257864 TI - Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye. AB - PURPOSE: Resolvin E1 (RvE1; RX-10001) belongs to a new class of endogenous immunoregulating mediators, originally identified as a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid. Based on its proven efficacy in models of chronic inflammation, this study investigated the efficacy of resolvin E1 in a murine model of dry eye. METHODS: C57/B6 mice, aged 6 to 8 weeks, were treated with systemic scopolamine and exposed to air draft and low humidity for 16 hours/day for 5 days and allocated to the following groups: unexposed controls, disease controls, treatment with vehicle or RvE1 delivered topically as its methyl ester prodrug, RX-10005, to enhance corneal surface penetration. Treatment was initiated at the time of desiccating stress induction. Treatment efficacy was assessed by corneal permeability using Oregon Green Dextran and by conjunctival goblet cell density using periodic acid-Schiff reagent. RESULTS: RvE1 reduced the increase in corneal staining by 80% compared with untreated disease controls. Goblet cell density was reduced by 20% in disease controls but fully maintained in the group receiving RvE1. CONCLUSIONS: RvE1, delivered as its methyl ester prodrug, improved the outcome measures of corneal staining and goblet cell density in this murine model of dry eye, indicating the potential utility of endogenous resolvins and resolvin analogues in the treatment of dry eye. PMID- 22257865 TI - Isolation of primary mouse trophoblast cells and trophoblast invasion assay. AB - The placenta is responsible for the transport of nutrients, gasses and growth factors to the fetus, as well as the elimination of wastes. Thus, defects in placental development have important consequences for the fetus and mother, and are a major cause of embryonic lethality. The major cell type of the fetal portion of the placenta is the trophoblast. Primary mouse placental trophoblast cells are a useful tool for studying normal and abnormal placental development, and unlike cell lines, may be isolated and used to study trophoblast at specific stages of pregnancy. In addition, primary cultures of trophoblast from transgenic mice may be used to study the role of particular genes in placental cells. The protocol presented here is based on the description by Thordarson et al., in which a percoll gradient is used to obtain a relatively pure trophoblast cell population from isolated mouse placentas. It is similar to the more widely used methods for human trophoblast cell isolation. Purity may be assessed by immunocytochemical staining of the isolated cells for cytokeratin 7. Here, the isolated cells are then analyzed using a matrigel invasion assay to assess trophoblast invasiveness in vitro. The invaded cells are analyzed by immunocytochemistry and stained for counting. PMID- 22257866 TI - Estimating Lyme disease risk using pet dogs as sentinels. AB - The reported number of cases of Lyme disease, Borrelia burgdorferi sensu lato, is thought to have increased in the UK over the past decade, but consistent surveillance data are lacking. Here the prevalence of B. burgdorferi in ticks attached to pet dogs was examined - using them as sentinels for human disease risk. Dogs give a good indication of the exposure of their human owners to infected ticks, since they largely share the same environment and visit the same outdoor areas. PCR was used to test 739 tick samples collected from 3534 dogs selected at random as they visited veterinary practices over a period of six months. Overall, the prevalence of infected ticks on all dogs was 0.5% giving an estimated 481 infected ticks per 100,000 dogs. The data suggest that the prevalence of Borrelia in the UK tick population is considerably higher than most recent estimates indicate. PMID- 22257867 TI - Time to include the gut microbiota in the hygienic standardisation of laboratory rodents. AB - The gut microbiota (GM) composition and its impact on animal experiments has become currently dramatically relevant in our days: (1) recent progress in metagenomic technologies, (2) the availability of large scale quantitative analyses to characterize even subtle phenotypes, (3) the limited diversity of laboratory rodent GM due to strict barriers at laboratory animal vendors, and (4) the availability of up to 300.000 different transgenic mouse strains from different sources displaying a huge variety in their GM composition. In this review the GM is described as a variable in animal experiments which need to be reduced for scientific as well as ethical reasons, and strategies how to implement this in routine diagnostic procedures are proposed. We conclude that we have both enough information available to state that the GM has an essential impact on animal models, as well as the methods available to start dealing with these impacts. PMID- 22257868 TI - The importance of collecting patients' medical histories. PMID- 22257869 TI - A novel approach for filling tunnel-prepared teeth with composites of two different consistencies: a case presentation. AB - A new approach to fill tunnel preparations with composites of two different consistencies is presented. Removal of caries through a narrow access space and reliably filling this cavity are the two main problems with tunnel-prepared teeth. Caries removal can be supplemented by the use of hand instruments, especially curettes, but filling the lesion with composite of a single consistency is problematic. Flowable composite alone does not create enough pressure to place the filling material into shallow extensions of the lesion; packable composite does not flow well enough. A solution for this problem may be a dual-consistency technique: flowable composite is placed, followed by packable composite, with no light curing in between. The flowable composite is pressed into small details of the cavity by the pressure created by the packable composite. PMID- 22257870 TI - Painful trigeminal neuropathy induced by oral bisphosphonate-related osteonecrosis of the jaw: a new etiology for the numb-chin syndrome. AB - We describe the management of BRONJ triggered by dental implants in a patient on oral bisphosphonates. The sequestrum in the body of the mandible was large and involved the inferior alveolar nerve, causing a painful neuropathy. A successful outcome was obtained by combining conservative and surgical interventions. PMID- 22257871 TI - Analysis of soft tissue display in Chinese subjects during an enjoyment smile. AB - OBJECTIVE: Due to global migration, clinicians often see patients with different ethnic backgrounds. Planning esthetic prosthodontic treatment for patients with different ethnicities can be a challenge. The aim of this study is to analyze the smile features of Chinese individuals. METHOD AND MATERIALS: Sixty-two Han Chinese subjects with a mean age of 28.5 years were enrolled and photographed. Standardized digital photographs were made to measure the height of displayed maxillary gingivae, papillae, and teeth during an enjoyment smile. The data were then compared with the data acquired from Caucasians in a previous study. Statistical analysis was performed using the Mann-Whitney test and two-factorial nonparametric analysis. RESULTS: The mean display of the central incisors was 10 mm, with no significant difference between sexes (P = .74). The mean amount of display of the molars and premolars was significantly lower in Chinese (P < .001) than in Caucasians. The mean displayed gingiva in all subjects (n = 62) was 1.3 mm (0 to 8 mm). There was no significant difference between sexes (P > .05), but there was a significantly lower display of gingiva at the molars in Chinese (P < .001). Of all the subjects, 16.1% (n = 10) displayed gingivae from the central incisor to the first molar with a mean gingival height of 2.8 mm. The subjects showed a mean papilla height of 3.4 mm (0 to 11.6 mm) with no significant difference between sexes (P > .05). Again, a significantly lower display of papilla at the molar (P < .001) was found in Chinese. Of all subjects, 43.5% (n = 27) of all subjects showed papilla from the central incisor to the first molar. The mean papilla height of these subjects was 3.9 mm. All subjects displayed at least one papilla. CONCLUSION: The results indicate that pink esthetics is a prime factor for both Chinese men and women in the esthetic restoration from the central incisors to the premolars. PMID- 22257872 TI - Correlation between probing pocket depth and neutrophil counts in dental plaque, saliva, and gingival crevicular fluid. AB - OBJECTIVE: Neutrophils play a critical role in the innate immune response. There are no studies that have correlated the neutrophils in plaque, saliva, and gingival crevicular fluid (GCF) to probing pocket depth (PPD) and to each other in periodontally healthy and diseased subjects. The aim of the present investigation was to assess and correlate the neutrophil levels in dental plaque, saliva, and GCF in periodontally healthy and diseased subjects. METHOD AND MATERIALS: Forty-five subjects were recruited. They were divided into three groups based on the Gingival Index (GI) and the Russell Periodontal Index (PI) as clinically healthy (group 1), gingivitis (group 2), and chronic generalized periodontitis (group 3). Saliva and GCF samples were collected using a Durapore filter, and plaque samples were collected using an area-specific subgingival curette. Neutrophils were counted using an improved Neubauer chamber. RESULTS: Neutrophils were present in the plaque, saliva, and GCF of all three samples. There was a statistically significant difference between the neutrophil numbers in all the samples with respect to the severity of periodontal disease. The strength of association was the strongest between PPD and plaque neutrophils. CONCLUSION: The neutrophils in dental plaque samples correlated positively with PPD in periodontally healthy and diseased subjects. PMID- 22257873 TI - Passive fit and accuracy of three dental implant impression techniques. AB - OBJECTIVE: To reassess the accuracy of three impression techniques relative to the passive fit of the prosthesis. METHOD AND MATERIALS: An edentulous maxillary cast was fabricated in epoxy resin with four dental implants embedded and secured with heat-cured acrylic resin. Three techniques were tested: closed tray, open tray nonsplinted, and open tray splinted. One light-cured custom acrylic tray was fabricated for each impression technique, and transfer copings were attached to the implants. Fifteen impressions for each technique were prepared with medium bodied consistency polyether. Subsequently, the impressions were poured in type IV die stone. The distances between the implants were measured using a digital micrometer. The statistical analysis of the data was performed with ANOVA and a one-sample t test at a 95% confidence interval. RESULTS: The lowest mean difference in dimensional accuracy was found within the direct (open tray) splinted technique. Also, the one-sample t test showed that the direct splinted technique has the least statistical significant difference from direct nonsplinted and indirect (closed tray) techniques. All discrepancies were less than 100 MUm. CONCLUSION: Within the limitations of this study, the best accuracy of the definitive prosthesis was achieved when the impression copings were splinted with autopolymerized acrylic resin, sectioned, and rejoined. However, the errors associated with all of these techniques were less than 100 MUm, and based on the current definitions of passive fit, they all would be clinically acceptable. PMID- 22257874 TI - Clinical and esthetic outcomes of single-tooth implants in the anterior maxilla. AB - The aim of this study was to evaluate the clinical and esthetic outcomes of 10 consecutive single-tooth implant restorations in the anterior maxilla. A specific treatment protocol consisting of (1) atraumatic extraction of the failing tooth, (2) placement of an SLActive bone-level implant with simultaneous guided bone regeneration at 6 to 8 weeks postextraction, (3) loading of a provisional restoration at 2 to 3 months following implant placement, (4) production of a customized impression coping, and (5) loading of the definitive all-ceramic abutment and crown 6 months after delivery of the provisional restoration was utilized in all cases. The outcomes were assessed 1 year after loading of the definitive restoration using standard clinical parameters: pink (PES) and white esthetic scores (WES). All implants were successfully integrated, accounting for a 100% survival and success rate. Besides clinical success, the application of the specific treatment protocol may be able to provide esthetically pleasing single-tooth implant restorations in the anterior maxilla, as was demonstrated by the results for PES (7.9 +/- 1.7) and WES (7.0 +/- 1.5). PMID- 22257875 TI - Intraoral granular cell tumors: clinicopathologic and immunohistochemical study. AB - OBJECTIVE: To describe a case series of intraoral granular cell tumors in terms of clinical, histologic, and immunohistochemical features. METHOD AND MATERIALS: Nine cases of intraoral granular cell tumors were described in terms of clinical features (patient sex and age, anatomical location, size, type, time to clinical progression, and lesion treatment), histologic features (necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity, high nuclear to cytoplasmic ratio, and pleomorphism) and immunohistochemical features using S 100, CD68, neurofilament protein, desmin, and galectin-1. RESULTS: Studied patients were mostly women with a mean age of 32 years. Lesions arose as solitary nodules on the tongue, with size ranging from 0.1 to 3.0 cm. Mean time to evolution was 21.83 months. All cases were treated by surgical excision. Two cases were classified as atypical and seven as benign. All cases presented immunoreactivity for S-100, CD68, and galectin-1, and there was no reactivity for desmin and neurofilament protein. CONCLUSION: General practitioners should consider granular cell tumors during the differential diagnosis of nodular lesions on the tongue. Results suggest that histologic criteria may be used to distinguish between benign and atypical intraoral granular cell tumors. Finally, analysis of the clinical profile and the use of immunohistochemical markers may facilitate diagnosis and clarify the histogenesis of these lesions. PMID- 22257876 TI - Noninvasive aspergillosis as a maxillary antrolith: report of a rare case. AB - Maxillary antrolithiasis is characterized by masses of tissue of endogenous or exogenous origin that calcify within the maxillary sinuses. Aspergillosis is a fungal disease in which the maxillary sinus is a primary site of infection. Aspergillosis mycetoma, its noninvasive form, is the most prevalent modality of the disease in the maxillary sinuses. In approximately half of the cases reported in the literature, calcification of the fungal mycelia, which later became antroliths, was verified. This article reports a rare case of the accidental discovery of a maxillary antrolith associated with noninvasive aspergillosis in an immunocompetent and asymptomatic 56-year-old woman. The diagnosis and therapeutic procedures used in treating the patient are discussed as well as the probable iatrogenic origin of the fungal pathology. PMID- 22257877 TI - Periodontal conditions in patients with oral lichen planus: a pilot study. AB - OBJECTIVE: To evaluate the periodontal status of patients with oral lichen planus and compare it with that of healthy controls. The association between periodontal condition and the extent of disease in oral lichen planus patients was also examined. METHOD AND MATERIALS: A descriptive clinical study was made of the periodontal condition of 80 consecutive patients with clinically and histologically diagnosed oral lichen planus and 40 healthy controls. Measurements were made of the Gingival Index, Plaque Index, and Community Periodontal Index of Treatment Needs (CPITN). RESULTS: Mean CPITN scores were significantly higher in oral lichen planus patients (2.8 +/- 0.7) than in the healthy controls (1.1 +/- 0.8) (P < .001).The patients with oral lichen planus showed no statistically significant difference in CPITN scores according to the extent of the lesions or their clinical form of presentation. CONCLUSION: The periodontal condition of the oral lichen planus patients was significantly worse than in the control group. PMID- 22257878 TI - Improving the efficiency of an Er:YAG laser on enamel and dentin. AB - OBJECTIVE: To evaluate the influence of air pressure, water flow rate, and pulse frequency on the removal speed of enamel and dentin as well as on their surface morphology. METHOD AND MATERIALS: Twenty-four bovine incisors were horizontally cut in slices. Each sample was mounted on an experimental assembly, allowing precise orientation. Eighteen cavities were prepared, nine in enamel and nine in dentin. Specific parameters for frequency, water flow rate, and air pressure were applied for each experimental group. Three groups were randomly formed according to the air pressure settings. Cavity depth was measured using a digital micrometer gauge, and surface morphology was checked by means of scanning electron microscopy. Data was analyzed with ANOVA and Duncan post hoc test. RESULTS: Irradiation at 25 Hz for enamel and 30 Hz for dentin provided the best ablation rates within this study, but efficiency decreased if the frequency was raised further. Greater tissue ablation was found with water flow rate set to low and dropped with higher values. Air pressure was found to have an interaction with the other settings, since ablation rates varied with different air pressure values. CONCLUSION: Fine-tuning of all parameters to get a good ablation rate with minimum surface damage seems to be key in achieving optimal efficiency for cavity preparation with an Er:YAG laser. PMID- 22257879 TI - Effect of filler content on the microtensile bond strength of composite resin and dentin in Class I cavities. AB - OBJECTIVE: To investigate the effect of filler content on microtensile bond strength (MU-TBS) in Class I cavities. METHOD AND MATERIALS: Experimental composites with filler contents of 80%, 76%, 70%, 60%, and 50% by weight were used. Polymerization shrinkage was measured with Acuvol, and a three-point flexural test was performed to determine flexural properties. For evaluation of MU-TBS, 25 extracted human molars were randomly divided into five groups and Class I cavities were prepared. After filling with one of the experimental composites and curing for 40 seconds, teeth were serially sectioned perpendicular to the cavity floor. Stick-shaped samples were tested with a microtensile tester. Statistical analysis was conducted using ANOVA and Pearson correlation tests. RESULTS: Significant correlations were found between filler content and polymerization shrinkage (r = -0.973, P < .05) and the filler content and Young modulus (r = 0.891, P < .05). Different filler contents in the experimental composites had no significant effect on MU-TBS or flexural strength. CONCLUSION: In a Class I cavity model, this in vitro study showed that the filler content did not influence the flexural strength of experimental composite resins and had no effect on the microtensile bond strength between composite resin and dentin. PMID- 22257880 TI - Microbial profile of patients with periodontitis compared with healthy subjects. AB - OBJECTIVE: To define and compare the microbiologic profile of subgingival plaque in German patients with periodontitis (including aggressive and advanced chronic periodontitis) and healthy subjects and to determine significant association between isolates and clinical status. Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Tannerella forsythia are major periodontal pathogens, though it is recognized that other species may also contribute to the pathogenesis of periodontal disease. METHOD AND MATERIALS: Thirty-three patients with clinical and radiologic proof of aggressive and advanced chronic periodontitis and 20 healthy subjects were enrolled in this study. Clinical indices were recorded as six-point measurements on each tooth. Samples of the subgingival plaque were taken with paper points from four teeth of each individual. The samples were divided into two parts. One part was immediately cultivated, while the other one was stored at -20 degrees C until analyzed by real-time polymerase chain reaction. RESULTS: A total of 284 anaerobic isolates (224 isolates from patients and 60 isolates from healthy controls) were identified. Forty different anaerobic species were isolated, with a mean of 6.78 species per patient and 3 species per healthy control subject. Significant differences in prevalence (after adjusting for multiple comparisons, P < .001) were found for Prevotella intermedia and nigrescens, Fusobacterium nucleatum, T forsythia, Treponema denticola, and Veillonella parvula. The first four species were associated with the aggressive periodontitis group and V parvula with healthy subjects. CONCLUSION: When compared with healthy controls, the microbial profile of subgingival plaque from periodontitis was found to contain known periodontal pathogens with a different prevalence to that described in earlier studies. P intermedia/nigrescens, F nucleatum, T forsythia, and T denticola have been found in lower proportions and small quantities in healthy subjects. PMID- 22257881 TI - Why is autophagy important in human diseases? AB - The process of macroautophagy (referred to hereafter as autophagy), is generally characterized by the prominent formation of autophagic vesicles in the cytoplasm. In the past decades, studies of autophagy have been vastly expanded. As an essential process to maintain cellular homeostasis and functions, autophagy is responsible for the lysosome-mediated degradation of damaged proteins and organelles, and thus misregulation of autophagy can result in a variety of pathological conditions in human beings. Although our understanding of regulatory pathways that control autophagy is still limited, an increasing number of studies have shed light on the importance of autophagy in a wide range of physiological processes and human diseases. The goal of the reviews in the current issue is to provide a general overview of current knowledge on autophagy. The machinery and regulation of autophagy were outlined with special attention to its role in diabetes, neurodegenerative disorders, infectious diseases and cancer. PMID- 22257882 TI - Molecules and their functions in autophagy. AB - Autophagy is a self-degradation system of cellular components through an autophagosomal-lysosomal pathway. Over the last 15 yr, yeast genetic screens led to the identification of a number of genes involved in the autophagic pathway. Most of these autophagy genes are present in higher eukaryotes and regulate autophagy process for cell survival and homeostasis. Significant progress has recently been made to better understand the molecular mechanisms of the autophagy machinery. Especially, autophagy process, including the regulation of autophagy induction through mTOR and the nucleation and elongation in autophagosome formation through class III phosphatidylinositol 3-kinase complex and ubiquitin like conjugation systems, became evident. While many unanswered questions remain to be answered, here, we summarize the recent process of autophagy with emphasis on molecules and their protein complexes along with advanced molecular mechanisms that regulate the autophagy machinery. PMID- 22257883 TI - Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic beta cells. AB - Type 2 diabetes mellitus is characterized by insulin resistance and failure of pancreatic beta-cells producing insulin. Autophagy plays a crucial role in cellular homeostasis through degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER). Here we discussed the role of beta cell autophagy in development of diabetes, based on our own studies using mice with beta-cell-specific deletion of Atg7 (autophagy-related 7 ), an important autophagy gene, and studies by others. beta-cell-specific Atg7-null mice showed reduction in beta-cell mass and pancreatic insulin content. Insulin secretory function ex vivo was also impaired, which might be related to organelle dysfunction associated with autophagy deficiency. As a result, beta-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, diabetes never developed in those mice. Obesity and/or lipid are physiological ER stresses that can precipitate beta-cell dysfunction. Our recent studies showed that beta cellspecific Atg7-null mice, when bred with ob/ob mice, indeed become diabetic. Thus, autophagy deficiency in beta-cells could be a precipitating factor in the progression from obesity to diabetes due to inappropriate response to obesity induced ER stress. PMID- 22257884 TI - Neuronal autophagy and neurodegenerative diseases. AB - Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma. Defects in autophagy affect the intercellular communication and subsequently, contributing to neurodegeneration. The presence of abnormal autophagic activity is frequently observed in selective neuronal populations afflicted in common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These observations have provoked controversy regarding whether the increase in autophagosomes observed in the degenerating neurons play a protective role or instead contribute to pathogenic neuronal cell death. It is still unknown what factors may determine whether active autophagy is beneficial or pathogenic during neurodegeneration. In this review, we consider both the normal and pathophysiological roles of neuronal autophagy and its potential therapeutic implications for common neurodegenerative diseases. PMID- 22257885 TI - Autophagy and bacterial infectious diseases. AB - Autophagy is a housekeeping process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic constituents. Over the past several years, accumulating evidence has suggested that autophagy can function as an intracellular innate defense pathway in response to infection with a variety of bacteria and viruses. Autophagy plays a role as a specialized immunologic effector and regulates innate immunity to exert antimicrobial defense mechanisms. Numerous bacterial pathogens have developed the ability to invade host cells or to subvert host autophagy to establish a persistent infection. In this review, we have summarized the recent advances in our understanding of the interaction between antibacterial autophagy (xenophagy) and different bacterial pathogens. PMID- 22257887 TI - Vascular differentiation of multipotent spermatogonial stem cells derived from neonatal mouse testis. AB - We previously reported the successful establishment of embryonic stem cell (ESC) like multipotent spermatogonial stem cells (mSSCs) from neonatal mouse testis. Here, we examined the ability of mSSCs to differentiate into vascular endothelial cells and smooth muscle cells, and compared to that of mouse ESCs. We used real time reverse transcriptase polymerase chain reaction and immunohistochemistry to examine gene expression profiles of mSSCs and ESCs during in vitro vascular differentiation. Both mSSCs and ESCs exhibited substantial increase in the expression of mesodermal markers, such as Brachyury, Flk1, Mesp1, Nkx2.5, and Islet1, and a decrease in the expression of pluripotency markers, such as Oct3/4 and Nanog during the early stage of differentiation. The mRNA levels of vascular endothelial (VE)-cadherin and CD31 gradually increased in both differentiated mSSCs and ESCs. VE-cadherin- or CD31-positive cells formed sprouting branch-like structures, as observed during embryonic vascular development. At the same time, vascular smooth muscle cell-specific markers, such as myocardin and alpha-smooth muscle actin (SMA), were also highly expressed in differentiated mSSCs and ESCs. Immunocytochemical analysis revealed that the differentiated cells expressed both alpha-SMA and SM22-alpha proteins, and exhibited the intracellular fibril structure typical of smooth muscle cells. Overall, our findings showed that mSSCs have similar vascular differentiation abilities to those of ESCs, suggesting that mSSCs may be an alternative source of autologous pluripotent stem cells for vascular regeneration. PMID- 22257886 TI - Autophagy and cancer. AB - Basal autophagy plays a critical role in maintaining cellular homeostasis and genomic integrity by degrading aged or malfunctioning organelles and damaged or misfolded proteins. However, autophagy also plays a complicated role in tumorigenesis and treatment responsiveness. It can be tumor-suppressing during the early stages of tumorigenesis (i.e., it is an anti-tumor mechanism), as reduced autophagy is found in tumor cells and may be associated with malignant transformation. In this case, induction of autophagy would seem to be beneficial for cancer prevention. In established tumors, however, autophagy can be tumor- promoting (i.e., it is a pro-tumor mechanism), and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress. The pharmacological and/or genetic inhibition of autophagy was recently shown to sensitize cancer cells to the lethal effects of various cancer therapies, including chemotherapy, radiotherapy and targeted therapies, suggesting that suppression of the autophagic pathway may represent a valuable sensitizing strategy for cancer treatments. In contrast, excessive stimulation of autophagy may also provide a therapeutic strategy for treating resistant cancer cells having high apoptotic thresholds. In order for us to develop successful autophagy- modulating strategies against cancer, we need to better understand how the roles of autophagy differ depending on the tumor stage, cell type and/or genetic factors, and we need to determine how specific pathways of autophagy are activated or inhibited by the various anti-cancer therapies. PMID- 22257888 TI - A neural network model to predict knee adduction moment during walking based on ground reaction force and anthropometric measurements. AB - The external knee adduction moment (KAM) is a major variable for the evaluation of knee loading during walking, specifically in patients with knee osteoarthritis. However, assessment of the KAM is limited to locations where full motion laboratories are available. The purpose of this study was to develop and test a simple method to predict the KAM using only force plate and anthropometric measurements. Three groups of 28 knees (asymptomatic, mild osteoarthritis, and severe osteoarthritis) were studied. Walking trials were collected at different speeds using a motion capture system and a force plate. The reference KAM was calculated by inverse dynamics. For the prediction, inter-subject artificial neural networks were designed using 11 inputs coming from the ground reaction force and the mechanical axis alignment. The predicted KAM curves were similar to the reference curves with median mean absolute deviation (MAD) of 0.36%BW*Ht and median correlation coefficient of 0.966 over 756 individual trials. When comparing mean group curves, the median MAD was 0.09%BW*Ht and the median correlation coefficient 0.998. The peak values and the angular impulses extracted from the predicted and reference curves were significantly correlated, and the same significant differences were obtained among the three groups when the predicted or when the reference curves were used for 95% of the comparisons. In conclusion, this study demonstrated that a simple method using a generic artificial neural network can predict the KAM curve during walking with a high level of significance and provides a practical option for a broader evaluation of the KAM. PMID- 22257889 TI - Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups. AB - Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1 phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats. PMID- 22257890 TI - Pre-microRNA binding aminoglycosides and antitumor drugs as inhibitors of Dicer catalyzed microRNA processing. AB - Over-expressions of miRNAs are being increasingly linked with many diseases including different types of cancer. In this study, the role of some known small molecular therapeutics has been investigated for their ability to bind with the pre-miRNA target (hsa-mir-155) and thereby to interfere with the Dicer catalyzed miRNA processing. Potential binding and inhibition effects have been demonstrated by some of these analogs. They can be used as leads for further development of potent small molecular miRNA-antagonists. PMID- 22257891 TI - Efficient double-strand scission of plasmid DNA by quaternized-chitosan zinc complex. AB - N-[(2-Hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTACC) was prepared to construct a chitosan-based zinc complex (HTACC-Zn(II)) as a catalyst with good water solubility for rapid DNA cleavage. Results indicated that the observed rate constant (k(obs)) of plasmid DNA cleaved by HTACC-Zn(II) could be enhanced by 10(7)-fold compared with that of uncatalyzed DNA cleavage. The kinetic behavior of HTACC-Zn(II) for DNA cleavage is well fitted by Michaelis-Menten model. The results of gel electrophoresis suggested that HTACC-Zn(II) preferentially perform double-strand break of plasmid DNA. PMID- 22257892 TI - Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators. AB - In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, a series of nineteen analogues (1b-5) of racemic [6] gingerol (1a) was synthesized and tested on TRPV1 and TRPA1 channels. The exploration of the structure-activity relationships, by modulating the three pharmacophoric regions of [6]-gingerol, led to the identification of some selective TRPV1 agonists/desensitizers of TRPV1 channels (3a, 3f, and 4) and of some full TRPA1 antagonists (2c, 2d, 3b, and 3d). PMID- 22257893 TI - Design and synthesis of 8-substituted benzamido-phenylxanthine derivatives as MAO B inhibitors. AB - Monoamine oxidase-B (MAO-B) inhibitor has been used as neuroprotectants to treat the motor deficits of Parkinson's disease (PD). We designed and synthesized a class of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors. The compounds have various inhibitory effects, with compound 6a having a K(i) value of 0.26 MUM. Their promising activity in vitro suggests potential use in the treatment of PD. PMID- 22257894 TI - Synthesis of a spin-labeled anti-estrogen as a dynamic motion probe for the estrogen receptor ligand binding domain. AB - The preparation and characterization of a novel nitroxide spin probe based on a steroidal anti-estrogen is described. The probe 5 demonstrated very high binding affinity for both the alpha and beta isoforms of the estrogen receptor-ligand binding domain. EPR spectrometric studies demonstrate conformational constraints for the ligand, consistent with the nitroxyl moiety occupying a position just beyond the receptor-solvent interface. PMID- 22257895 TI - Pramipexole-induced increased probabilistic discounting: comparison between a rodent model of Parkinson's disease and controls. AB - The dopamine agonist pramipexole (PPX) can increase impulsiveness, and PPX therapy for neurological diseases (Parkinson's disease (PD) and restless leg syndrome) is associated with impulse control disorders (ICDs) in subpopulations of treated patients. A commonly reported ICD is pathological gambling of which risk taking is a prominent feature. Probability discounting is a measurable aspect of risk taking. We recently developed a probability discounting paradigm wherein intracranial self-stimulation (ICSS) serves as the positive reinforcer. Here we used this paradigm to determine the effects of PPX on discounting. We included assessments of a rodent model of PD, wherein 6-OHDA was injected into the dorsolateral striatum of both hemispheres, which produced persistent PD-like deficits in posture adjustment. Rats were trained to perform ICSS-mediated probability discounting, in which PD-like and control groups exhibited similar profiles. Rats were treated twice daily for 2 weeks with 2 mg/kg (+/-)PPX (ie, 1 mg/kg of the active form), a dose that improved lesion-induced motor deficits. In both groups, (+/-)PPX increased discounting; preference for the large reinforcer was enhanced 30-45% at the most uncertain probabilities. Tolerance did not develop with repeated treatments. Increased discounting subsided within 2 weeks of (+/-)PPX cessation, and re-exposure to (+/-)PPX reinstated heightened discounting. Such findings emulate the clinical scenario; therefore, ICSS for discounting assessments in rats exhibited high face validity. This model should prove useful in medication development where assessment of the propensity of a putative therapy to induce risk-taking behaviors is of interest. PMID- 22257896 TI - Prenatal NMDA receptor antagonism impaired proliferation of neuronal progenitor, leading to fewer glutamatergic neurons in the prefrontal cortex. AB - N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID- 22257898 TI - Leukemia cutis amidst a psoriatic flare: a case report. AB - Leukemia Cutis (LC) has many clinical morphologies that present a diagnostic challenge. This case report of a 58-year-old man experiencing a flare of psoriasis elucidates the need for clinical suspicion when a history of leukemia is present. A skin biopsy revealed histopathologic findings of psoriasis and an infiltrate of mononuclear cells consistent with LC. Upon review of the literature, 2 additional cases were reported of concurrent psoriasis and LC. PMID- 22257897 TI - Postpartum and depression status are associated with lower [[11C]raclopride BP(ND) in reproductive-age women. AB - The early postpartum period is associated with increased risk for affective and psychotic disorders. Because maternal dopaminergic reward system function is altered with perinatal status, dopaminergic system dysregulation may be an important mechanism of postpartum psychiatric disorders. Subjects included were non-postpartum healthy (n=13), postpartum healthy (n=13), non-postpartum unipolar depressed (n=10), non-postpartum bipolar depressed (n=7), postpartum unipolar (n=13), and postpartum bipolar depressed (n=7) women. Subjects underwent 60 min of [11C]raclopride-positron emission tomography imaging to determine the nondisplaceable striatal D2/3 receptor binding potential (BP(ND)). Postpartum status and unipolar depression were associated with lower striatal D2/3 receptor BP(ND) in the whole striatum (p=0.05 and p=0.02, respectively) that reached a maximum of 7-8% in anteroventral striatum for postpartum status (p=0.02). Unipolar depression showed a nonsignificant trend toward being associated with 5% lower BP(ND) in dorsal striatum (p=0.06). D2/3 receptor BP(ND) did not differ significantly between unipolar depressed and healthy postpartum women or between bipolar and healthy subjects; however, D2/3 receptor BP(ND) was higher in dorsal striatal regions in bipolar relative to unipolar depressives (p=0.02). In conclusion, lower striatal D2/3 receptor BP(ND) in postpartum and unipolar depressed women, primarily in ventral striatum, and higher dorsal striatal D2/3 receptor BP(ND) in bipolar relative to unipolar depressives reveal a potential role for the dopamine (DA) system in the physiology of these states. Further studies delineating the mechanisms underlying these differences in D2/3 receptor BP(ND), including study of DA system responsivity to rewarding stimuli, and increasing power to assess unipolar vs bipolar-related differences, are needed to better understand the affective role of the DA system in postpartum and depressed women. PMID- 22257899 TI - Vascular congenital dermatofibrosarcoma protuberans: a new histological variant of dermatofibrosarcoma protuberans. AB - We describe a case of congenital dermatofibrosarcoma protuberans (DFSP) that masqueraded as a vascular tumor both clinically and histologically. Based on the infiltrative growth pattern, presence of capillary-sized vessels, and spindle cell areas with slit-like vascular spaces and numerous thin-walled vessels at the periphery of the tumor, a kaposiform hemangioendothelioma was initially diagnosed. Strong diffuse CD34 positivity and the extension into the subcutaneous fat with a sieve-like effect prompted the fluorescence in situ hybridization analysis, which demonstrated a reciprocal t(17;22) translocation. According to our knowledge, this is the first report of a vascular histological variant of DFSP. This unique variant represents a potential pitfall for dermatopathologists and underlines the importance of cytogenetic diagnostics in unusual cases of DFSP. PMID- 22257900 TI - Characteristics of spitzoid melanoma and clues for differential diagnosis with spitz nevus. AB - The different features of spitzoid melanoma are not well characterized in the literature, and the lesion often has to be described in comparison with Spitz nevus. We evaluated the histopathological appearance of spitzoid melanoma by reviewing all spitzoid melanomas treated at our hospital and all referrals from 1998 to 2010. The final study sample comprised 18 cases, 11 from our institution and 7 referrals from other centers. We recorded clinical parameters (eg, age, sex, site, time between onset and excision, recurrence, and death) and a series of histopathological parameters (eg, size, ulceration, symmetry, Clark level, Breslow thickness, cell density, atypia, mitosis). Clinical and histopathological criteria were not available for the 7 referrals. Mean age was 35.2 years (15-56), and 8 patients were women. Mean size of the lesions was 7.27 mm (Clark III/IV and Breslow 2.51 mm), and these were found on the limbs and trunk. Cell density was high in 10 cases and atypia present in 9 (marked in 1). Mitoses were observed in 8 cases (atypical in 4, clusters in 4). Maturation was absent in 9 cases and zonation in 8. Our analysis revealed 5 previously undefined subtypes of spitzoid melanoma (genuine (7 cases), uniform (5 cases), packed (5 cases), polypoid (3 cases) and pigmented (2 cases)]. Four cases showed 2 patterns at the same time. The most useful parameters for the differential diagnosis were cell density, mitosis, zonation, infiltration pattern, and consumption of the epidermis. Assignation of a spitzoid melanoma to 1 of more of our 5 subtypes can enable a more confident diagnosis to be made. PMID- 22257901 TI - Role of CD10, wide-spectrum keratin, p63, and podoplanin in the distinction of epithelioid and spindle cell tumors of the skin: an immunohistochemical study of 81 cases. AB - Cutaneous epithelioid and spindle cell neoplasms occasionally pose a significant diagnostic challenge on purely histologic grounds. Given the substantial clinicopathologic overlap between these lesions, especially in small biopsies, the use of immunohistochemical studies are essential. We evaluated the utility of a battery of immunohistochemical markers, including podoplanin (D2-40), CD10, p63, and wide-spectrum cytokeratin, for distinguishing cutaneous epithelioid and spindle cell tumors. A total of 81 cases, including 42 atypical fibroxanthoma (AFX), 13 spindle cell melanoma, 10 sarcomatoid carcinoma, 9 leiomyosarcoma (LMS), and 7 leiomyoma, formed the basis of our study. Immunohistochemical results were as follows-AFX: CD10 (35 of 42), p63 (1 of 42), CK (1 of 42), and podoplanin (19 of 42); spindle cell melanoma: CD10 (7 of 13), p63 (0 of 13), CK (0 of 13), and podoplanin (2 of 13); sarcomatoid carcinoma: CD10 (5 of 10), p63 (7 of 10), CK (4 of 10), and podoplanin (7 of 10); LMS: CD10 (4 of 9), p63 (0 of 9), CK (2 of 9), and podoplanin (1 of 9); and leiomyoma: CD10 (0 of 7), p63 (0 of 7), CK (0 of 7), and podoplanin (1 of 7). Our findings showed that the combination of certain immunohistochemical markers may be a useful adjunct in the evaluation of epithelioid and spindle cell tumors of the skin. In this study, we found that a combination of wide-spectrum cytokeratin and p63 are most helpful in the distinction of sarcomatoid carcinomas from other tumors; however, there remains a substantial minority of cases of sarcomatoid carcinoma that will consistently demonstrate negative staining for these markers. We also found that CD10 and podoplanin (D2-40) have limited diagnostic utility in epithelioid and spindle cell tumors of the skin; however, a strong and diffuse pattern of staining will favor the diagnosis of AFX. Caution should also be observed in the diagnosis of spindle cell malignant melanoma because some cases may express CD10, p63, and podoplanin while being nonreactive to S100 protein. Awareness of the limitations of the use of these stains and familiarity with their staining patterns in spindle and epithelioid cell tumors of the skin are extremely important because the prognostic and therapeutic implications for such neoplasms may be quite different. PMID- 22257902 TI - Olanzapine-induced eccrine squamous syringometaplasia. AB - Eccrine squamous syringometaplasia is a histopathologic pattern that has mainly been described in patients receiving chemotherapy. Its association to nonchemotherapeutic agents is rare, with very few cases reported in the literature. We present the case of a 55-year-old patient with schizophrenia, who developed a skin eruption 5 weeks after initiating treatment with olanzapine. The histopathologic study revealed squamous syringometaplasia of the dermal eccrine ducts. PMID- 22257903 TI - Acceleration of astrocytic differentiation in neural stem cells surviving X irradiation. AB - Neural stem cells (NSCs) are highly susceptible to DNA double-strand breaks; however, little is known about the effects of radiation in cells surviving radiation. Although the nestin-positive NSCs predominantly became glial fibrillary acidic protein (GFAP)-positive in differentiation-permissive medium, little or no cells were GFAP positive in proliferation-permissive medium. We found that more than half of the cells surviving X-rays became GFAP positive in proliferation-permissive medium. Moreover, localized irradiation stimulated differentiation of cells outside the irradiated area. These results indicate for the first time that ionizing radiation is able to stimulate astrocyte-specific differentiation of surviving NSCs, whose process is mediated both by the direct activation of nuclear factor-kappaB and by the indirect bystander effect induced by X-irradiation. PMID- 22257904 TI - Extraversion and striatal dopaminergic receptor availability in young adults: an [18F]fallypride PET study. AB - Extraversion is a core personality trait associated with individual differences in reward sensitivity and has been linked to the dopaminergic brain system. We investigated whether dopaminergic receptor availability in the striatum was directly associated with individual differences in extraversion using the high affinity radiotracer [18F]fallypride and PET. Seventeen healthy male and female participants completed an [18F]fallypride PET scan at rest. Extraversion was assessed using the revised Eysenck Personality Questionnaire. Dopamine receptor availability in predefined striatal regions of interest was assessed as [18F]fallypride binding potential using a reference tissue model for [18F]fallypride. Both region of interest and voxel-based whole-brain analyses showed that extraversion was significantly correlated with dopaminergic receptor availability in the striatum bilaterally. This finding contributes to our understanding of the dopaminergic neural mechanisms underlying individual differences in extraversion. PMID- 22257905 TI - Does treatment of metabolic syndrome components improve psoriasis? Report of three cases. PMID- 22257906 TI - Human bone marrow adiposity is linked with serum lipid levels not T1-diabetes. AB - Increased marrow adiposity is often associated with bone loss. Little is known about the regulation of marrow adiposity in humans. Marrow adiposity is increased in several mouse models including type I (T1)-diabetic mice, which also display bone loss. However, the impact of metabolic disease on marrow adiposity in humans has yet to be examined. This study measured bone marrow adiposity levels with iterative decomposition of water and fat with echo asymmetry and least-squares estimation magnetic resonance imaging and determined their relationship with T1 diabetes, bone mineral density (BMD), and serum lipid levels. Participants were adult T1-diabetic patients (glycosylated hemoglobin averaging 7.70%+/-0.4%) and age- and body-mass-index-matched nondiabetic subjects. Consistent with previous reports, serum osteocalcin levels were lower in subjects with T1-diabetes compared to controls (reaching statistical significance in females) and negatively correlated with disease duration (r=-0.50, P<.01). Furthermore, femur neck BMD inversely correlated with diabetes severity (r=-0.417, P<.05). While marrow adiposity was not altered by T1-diabetes, there was a striking positive correlation between vertebral, femur, and tibia marrow adiposity and serum lipid levels (low-density lipoprotein, total cholesterol, cholesterol:high-density lipoprotein ratio, and triglyceride; r>=0.383), reaching a significance of P<.001 in some comparisons. Marrow adiposity also displayed strong intrasubject correlations at multiple bone sites (r>=0.411, P<.05), increased with age (r=0.410, P<.05 at vertebral sites), and was reciprocally related to bone density (r>=-0.378, P<.05). Taken together, our data suggest that marrow adiposity may be an indicator of elevated serum lipid levels and decreased bone density. PMID- 22257907 TI - Tef polymorphism is associated with sleep disturbances in patients with Parkinson's disease. AB - OBJECTIVE: Circadian mechanisms play an important role in the regulation of sleep. A circadian clock-controlled gene, Tef, has been suggested to be associated with depressive symptoms, restless legs syndrome, and slow wave sleep in patients with sleep disorders. The present study sought to explore the association between Tef and sleep disturbances in patients with Parkinson's disease (PD). METHODS: Three hundred and ninety-two unrelated patients with PD were recruited for this study. All of them completed the PD Sleep Scale (PDSS) and other clinical and demographic assessments. rs738499, a single nucleotide polymorphism of the Tef gene, was genotyped by polymerase chain reaction restriction fragment length polymorphism. RESULTS: Mean total PDSS scores were 111.5 (standard deviation [SD] 23.0) in the TT genotype and 122.2 (SD 18.2) in the TG+GG genotypes (P<0.01). Significant differences were found between genotypes (TT vs TG+GG) for 14 item scores (all P<0.05). Total and item scores displayed negative associations with the TT genotype (all P<0.05) except Item 2 (P=0.178). Linear regression adjusted for gender, duration, depression and disease severity showed that the polymorphism could explain 0.9% of the variance in PDSS scores. CONCLUSIONS: These preliminary results suggest that the TT genotype in Tef rs738499 is associated with sleep disturbances in PD. Depression and disease severity are the main contributors to these findings, but rs738499 itself is an independent risk factor. PMID- 22257908 TI - Reply to: 'Hand hygiene: are we trying to make the patient the fail safe system?'. PMID- 22257909 TI - 3D segmentation of abdominal aorta from CT-scan and MR images. AB - We designed a generic method for segmenting the aneurismal sac of an abdominal aortic aneurysm (AAA) both from multi-slice MR and CT-scan examinations. It is a semi-automatic method requiring little human intervention and based on graph cut theory to segment the lumen interface and the aortic wall of AAAs. Our segmentation method works independently on MRI and CT-scan volumes and has been tested on a 44 patient dataset and 10 synthetic images. Segmentation and maximum diameter estimation were compared to manual tracing from 4 experts. An inter observer study was performed in order to measure the variability range of a human observer. Based on three metrics (the maximum aortic diameter, the volume overlap and the Hausdorff distance) the variability of the results obtained by our method is shown to be similar to that of a human operator, both for the lumen interface and the aortic wall. As will be shown, the average distance obtained with our method is less than one standard deviation away from each expert, both for healthy subjects and for patients with AAA. Our semi-automatic method provides reliable contours of the abdominal aorta from CT-scan or MRI, allowing rapid and reproducible evaluations of AAA. PMID- 22257910 TI - Blood cadmium, mercury, and lead in children: an international comparison of cities in six European countries, and China, Ecuador, and Morocco. AB - Children's blood-lead concentration (B-Pb) is well studied, but little is known about cadmium (B-Cd) and mercury (B-Hg), in particular for central Europe. Such information is necessary for risk assessment and management. Therefore, we here describe and compare B-Pb, B-Cd and B-Hg in children in six European, and three non-European cities, and identify determinants of these exposures. About 50 school children (7-14 years) from each city were recruited (totally 433) in 2007 2008. Interview and questionnaire data were obtained. A blood sample was analyzed: only two laboratories with strict quality control were used. The European cities showed only minor differences for B-Cd (geometric means 0.11-0.17 MUg/L) and B-Pb (14-20 MUg/L), but larger for B-Hg (0.12-0.94 MUg/L). Corresponding means for the non-European countries were 0.21-0.26, 32-71, and 0.3 3.2 MUg/L, respectively. For B-Cd in European samples, traffic intensity close to home was a statistically significant determinant, for B-Hg fish consumption and amalgam fillings, and for B-Pb sex (boys higher). This study shows that European city children's B-Cd and B-Pb vary only little between countries; B-Hg differs considerably, due to varying tooth restoration practices and fish intake. Traffic intensity seemed to be a determinant for B-Cd. The metal concentrations were low from a risk perspective but the chosen non-European cities showed higher concentrations than the cities in Europe. PMID- 22257911 TI - Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. AB - Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-alpha, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals. PMID- 22257912 TI - Visualizing carrier status: fragile X syndrome and genetic diagnosis since the 1940s. AB - What does it look like to be the carrier of a genetic disease? Carrier status may be determined through the visual analysis of both genotypic and phenotypic evidence. Over the past 70 years, clinical geneticists have depended upon multiple strategies for identifying disease carriers within a family. This has included pedigree analysis, which was based upon clinical observations of individual family members and, in recent decades, cytogenetic and molecular methods. Newer techniques have offered novel opportunities to actually see the suspected etiological markers of certain genetic diseases, such as Fragile X syndrome. The visualization of these markers has both clarified and confused previously observed inheritance patterns, in some cases leading to the development of newly distinct diagnostic categories. As a result, what it means to be affected by, or the carrier of, a genetic disease has continuously evolved. PMID- 22257913 TI - [Biotechnological innovation to the benefit of the rheumatic patient]. PMID- 22257914 TI - [Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)]. AB - The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has elaborated the following guidelines about the definition, prevention and treatment of inadequate vitamin D status. The highlights are presented here. Daily vitamin D allowance ranges from 1,500 IU (healthy adults) to 2,300 IU (elderly with low calcium intake). Since the average Italian diet includes around 300 IU/day, subjects with no effective sun exposure should be supplemented with 1,200-2,000 IU vitamin D per day. The serum 25-hydroxy-vitamin D [25(OH)D] levels represents the most accurate way to assess vitamin D repletion, even though there are still no standardized assay methods. Conditions of "deficiency" and "insufficiency" are defined by the following ranges of 25(OH)D levels: less than 20 ng/ml and 20-30 ng/ml, respectively. In Italy, approximately 50% of young healthy subjects have vitamin D insufficiency during the winter months. The prevalence of deficiency increases with ageing, affecting almost all elderly subjects not on vitamin D supplements. When a condition of deficiency has been identified, a cumulative dose of 300,000-1,000,000 IU, over 1 4 weeks is recommended. In subjects recently treated for deficiency insufficiency, a maintenance dose of 800-2,000 IU/day (or weekly equivalent) is recommended. In patients on daily doses over 1,000 IU, 25(OH)D levels should be checked regularly (e.g. once every two years). The highest tolerated daily dose has been identified as 4,000 IU/day. Vitamin D supplementation should be carefully monitored in patients at higher risk of vitamin D intoxication (granulomatosis) or with primary hyperparathyroidism. In pregnant women, vitamin D supplements should be given as in non-pregnant women, but bolus administration (i.e.: single dose >25,000 IU) should be avoided. PMID- 22257915 TI - Cardiovascular involvement in psoriatic arthritis. AB - Psoriasis is a chronic, genetically determined and immunomediated inflammatory skin disease that affects 2-3% of the Caucasian population. A considerable proportion of these patients develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), although the prevalence of this has not been well defined. Patients with PsA have a higher mortality rate than the general population and the risk of mortality is related to disease severity at the time of presentation. Endothelial dysfunction and early atherosclerosis have been found in patients with PsA without any cardiovascular disease (CVD) risk factors, and experts believe that CVD is one of the leading causes of death, as it is in patients with rheumatoid arthritis (RA). Various disease-related mechanisms may be involved in the development of premature vascular damage in both cases, including an increased synthesis of proinflammatory mediators (such as cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors. In a recent study of 22 patients with PsA without any signs of CVD, we found that the plasma concentration of asymmetric dimethylarginine (ADMA) levels were significantly high and coronary flow reserve (CFR) was significantly reduced. Moreover, there was a significant correlation between CFR and plasma ADMA levels in the PsA group. The significant correlation between the reduced CRF and increased ADMA levels suggests that, like patients with early RA, PsA patients suffer from endothelial dysfunction and impaired coronary microcirculation. Active PsA is a risk factor for CVD, and so PsA patients should be screened for subclinical forms of the disease and its risk factors, and an early treatment approach should be adopted. PMID- 22257916 TI - GISEA: an Italian biological agents registry in rheumatology. AB - The GISEA registry is an independent database that was established by the Italian Group for the Study of Early Arthritis (GISEA) in 2008, funded by the Italian Association of Rheumatic Patients (ANMAR - ONLUS). In line with the network's epidemiological strategy, the initial protocol was designed to collect long-term follow-up data concerning patients with rheumatic diseases treated with biological agents in order to investigate the realworld characteristics in terms of disease activity, comorbidities and survival on treatment. We here describe the design and methodology used to collect patient data. Information concerning demographics, disease activity, treatment changes (including the reasons for changing and the duration of each therapy), concomitant therapies and adverse events is available to all the members of the study groups by means of a web based interface that allows queries and the presentation of numerical data, as well as graphics to illustrate trends. Fourteen Italian rheumatology centres have contributed patients to the database which, at the time writing, includes 5145 patients (72% women) with a mean age of 53 years (range 16-88). The initial diagnoses were rheumatoid arthritis (3494 patients, 67.9%), psoriatic arthritis (833, 16.2%), ankylosing spondylitis (493, 9.6%), undifferentiated spondylo arthritides (307, 5.9%), enteropathic arthritis (14, 0.3%) and spondylitis following reactive arthritis (4, 0.1%). These patients have been followed for up to 10 years, and 1927 (35.8%) have been treated for at least three years. The biological treatments received include etanercept, infliximab, anakinra, adalimumab, abatacept, rituximab and tocilizumab. A total of 2926 adverse events have been observed, with 1171 patients (22%) reporting at least one. Analysis of the accumulated data will provide insights into the critical early phase of the studied arthritides, and enable us to identify the clinical and laboratory profiles that may predict responsiveness to a specific therapy. PMID- 22257917 TI - [MALDI-TOF and SELDI-TOF analysis: "tandem" techniques to identify potential biomarker in fibromyalgia]. AB - OBJECTIVE: Fibromyalgia (FM) is characterized by the presence of chronic widespread pain throughout the musculoskeletal system and diffuse tenderness. Unfortunately, no laboratory tests have been appropriately validated for FM and correlated with the subsets and activity. The aim of this study was to apply a proteomic technique in saliva of FM patients: the Surface Enhance Laser Desorption/Ionization Time-of-Flight (SELDI-TOF). METHODS: For this study, 57 FM patients and 35 HC patients were enrolled. The proteomic analysis of saliva was carried out using SELDI-TOF. The analysis was performed using different chip arrays with different characteristics of binding. The statistical analysis was performed using cluster analysis and the difference between two groups was underlined using Student's t-test. RESULTS: Spectra analysis highlighted the presence of several peaks differently expressed in FM patients compared with controls. The preliminary results obtained by SELDI-TOF analysis were compared with those obtained in our previous study performed on whole saliva of FM patients by using electrophoresis. The m/z of two peaks, increased in FM patients, seem to overlap well with the molecular weight of calgranulin A and C and Rho GDP-dissociation inhibitor 2, which we had found up-regulated in our previous study. CONCLUSION: These preliminary results showed the possibility of identifying potential salivary biomarker through salivary proteomic analysis with MALDI-TOF and SELDI-TOF in FM patients. The peaks observed allow us to focus on some of the particular pathogenic aspects of FM, the oxidative stress which contradistinguishes this condition, the involvement of proteins related to the cytoskeletal arrangements, and central sensibilization. PMID- 22257918 TI - Splenic tuberculosis in a patient with ankylosing spondylitis treated with adalimumab. AB - We present a rare case of splenic tuberculosis in a 42-year old man with long standing ankylosing spondylitis treated with adalimumab. We review the association between antitumor necrosis factor therapy and splenic tuberculosis. Our case, like many other reported cases, illustrates that the index of suspicion of tuberculosis in patients treated with anti TNF therapies must be high and emphasizes that this rare infection may occur even with negative tuberculosis screening before the initiation of therapy. PMID- 22257919 TI - [Multimodal imaging in the differential diagnosis of soft tissue calcinosis]. AB - Soft tissue calcinosis is a common radiographic finding, which may be related to different types of pathological processes. Multimodality imaging, combined with analysis of clinical and laboratory data, plays an important role for the differential diagnosis of these conditions. Conventional radiography is considered the first line approach to soft tissue calcinosis; CT and MRI may provide further information to better characterize calcified deposits. Imaging may help to distinguish metabolic calcification, such as primary tumoral calcinosis and the secondary one (associated with acquired disorders of calcium or phosphate regulation), from dystrophic calcification, which is associated to normal blood values of phosphate. The sedimentation sign typical of tumoral calcinosis has been demonstrated by plain film radiography, CT, MRI, and, more recently, by ultrasonography. Other types of soft tissue calcinosis may have a degenerative, metaplastic or neoplastic origin, and their characterization strongly relies on multimodality imaging. PMID- 22257920 TI - [A short history of anti-rheumatic therapy--VII. Biological agents]. AB - The introduction of biological agents has been a major turning-point in the treatment of rheumatic diseases, particularly in rheumatoid arthritis. This review describes the principle milestones that have led, through the knowledge of the structure and functions of nucleic acids, to the development of production techniques of the three major families of biological agents: proteins, monoclonal antibodies and fusion proteins. A brief history has also been traced of the cytokines most involved in the pathogenesis of inflammatory rheumatic diseases (IL-1 and TNF) and the steps which have led to the use of the main biological drugs in rheumatology: anakinra, infliximab, adalimumab, etanercept and rituximab. PMID- 22257921 TI - [Remembering Claudio Cervini]. PMID- 22257922 TI - [Remembering Stefano Di Vittorio]. PMID- 22257923 TI - High-throughput crystallization of membrane proteins using the lipidic bicelle method. AB - Membrane proteins (MPs) play a critical role in many physiological processes such as pumping specific molecules across the otherwise impermeable membrane bilayer that surrounds all cells and organelles. Alterations in the function of MPs result in many human diseases and disorders; thus, an intricate understanding of their structures remains a critical objective for biological research. However, structure determination of MPs remains a significant challenge often stemming from their hydrophobicity. MPs have substantial hydrophobic regions embedded within the bilayer. Detergents are frequently used to solubilize these proteins from the bilayer generating a protein-detergent micelle that can then be manipulated in a similar manner as soluble proteins. Traditionally, crystallization trials proceed using a protein-detergent mixture, but they often resist crystallization or produce crystals of poor quality. These problems arise due to the detergent's inability to adequately mimic the bilayer resulting in poor stability and heterogeneity. In addition, the detergent shields the hydrophobic surface of the MP reducing the surface area available for crystal contacts. To circumvent these drawbacks MPs can be crystallized in lipidic media, which more closely simulates their endogenous environment, and has recently become a de novo technique for MP crystallization. Lipidic cubic phase (LCP) is a three-dimensional lipid bilayer penetrated by an interconnected system of aqueous channels. Although monoolein is the lipid of choice, related lipids such as monopalmitolein and monovaccenin have also been used to make LCP. MPs are incorporated into the LCP where they diffuse in three dimensions and feed crystal nuclei. A great advantage of the LCP is that the protein remains in a more native environment, but the method has a number of technical disadvantages including high viscosity (requiring specialized apparatuses) and difficulties in crystal visualization and manipulation. Because of these technical difficulties, we utilized another lipidic medium for crystallization-bicelles (Figure 1). Bicelles are lipid/amphiphile mixtures formed by blending a phosphatidylcholine lipid (DMPC) with an amphiphile (CHAPSO) or a short-chain lipid (DHPC). Within each bicelle disc, the lipid molecules generate a bilayer while the amphiphile molecules line the apolar edges providing beneficial properties of both bilayers and detergents. Importantly, below their transition temperature, protein-bicelle mixtures have a reduced viscosity and are manipulated in a similar manner as detergent-solubilized MPs, making bicelles compatible with crystallization robots. Bicelles have been successfully used to crystallize several membrane proteins (Table 1). This growing collection of proteins demonstrates the versatility of bicelles for crystallizing both alpha helical and beta sheet MPs from prokaryotic and eukaryotic sources. Because of these successes and the simplicity of high-throughput implementation, bicelles should be part of every membrane protein crystallographer's arsenal. In this video, we describe the bicelle methodology and provide a step-by-step protocol for setting up high throughput crystallization trials of purified MPs using standard robotics. PMID- 22257924 TI - Reply to Comments on the separation efficiency of asymmetrical Flow Field-Flow fractionation in channels of constant channel and crossflow velocities leading to constant separation efficiency. AB - The membrane or cross-flow velocity in asymmetric Flow Field-Flow fractionation is not constant in usual geometries. Previously theoretical models however were developed with the hypothesis of a constant membrane velocity. The argument about peak broadening in the comments of K.-G. Wahlund (J. Chromatogr. A 1218 (2011) 6848) is based on this kind of model. Such an assumption was not included in the recently proposed model used to determine the conditions of constant velocities. The model goes beyond this approximation and anyway can provide the two velocity fields in various geometries. PMID- 22257925 TI - Multi-residue method for fast determination of pesticide residues in plants used in traditional chinese medicine by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. AB - An ultra-high-performance liquid chromatographic-tandem mass spectrometry (UHPLC MS/MS) method for the simultaneous quantification and identification of 116 pesticide residues which were most widely used in plants used in Traditional Chinese Medicine (TCM) in 15 min has been developed and validated. Samples were extracted and cleaned up with modified QuEChERS method and detected by UHPLC MS/MS under multiple reactions monitoring mode, and quantified by matrix-match calibration. The validation study was carried out on five different matrixes following DG SANCO/2007/3131 of the European Quality Control Guidelines. The linearity of the calibration was good between 5 and 100 ng ml-1 concentration ranges, and the limits of quantification (LOQs) less than 0.01 mg/kg for most pesticides. The mean recoveries of almost all pesticides were in the range from 70% to 120% at three concentration levels ranging from 0.01 mg/kg to 0.1mg/kg with relative standard deviations (RSD) better than 15%. The method was applied on 138 real samples from 102 different kinds of Chinese herbal medicine. 95 positive samples were detected. This method is fast, robust, accurate, selective, sensitive and easy to operate. PMID- 22257926 TI - Determination of vegetable oils and fats adulterants in diesel oil by high performance liquid chromatography and multivariate methods. AB - The current legislation requires the mandatory addition of biodiesel to all Brazilian road diesel oil A (pure diesel) marketed in the country and bans the addition of vegetable oils for this type of diesel. However, cases of irregular addition of vegetable oils directly to the diesel oil may occur, mainly due to the lower cost of these raw materials compared to the final product, biodiesel. In Brazil, the situation is even more critical once the country is one of the largest producers of oleaginous products in the world, especially soybean, and also it has an extensive road network dependent on diesel. Therefore, alternatives to control the quality of diesel have become increasingly necessary. This study proposes an analytical methodology for quality control of diesel with intention to identify and determine adulterations of oils and even fats of vegetable origin. This methodology is based on detection, identification and quantification of triacylglycerols on diesel (main constituents of vegetable oils and fats) by high performance liquid chromatography in reversed phase with UV detection at 205nm associated with multivariate methods. Six different types of oils and fats were studied (soybean, frying oil, corn, cotton, palm oil and babassu) and two methods were developed for data analysis. The first one, based on principal component analysis (PCA), nearest neighbor classification (KNN) and univariate regression, was used for samples adulterated with a single type of oil or fat. In the second method, partial least square regression (PLS) was used for the cases where the adulterants were mixtures of up to three types of oils or fats. In the first method, the techniques of PCA and KNN were correctly classified as 17 out of 18 validation samples on the type of oil or fat present. The concentrations estimated for adulterants showed good agreement with the reference values, with mean errors of prediction (RMSEP) ranging between 0.10 and 0.22% (v/v). The PLS method was efficient in the quantification of mixtures of up to three types of oils and fats, with RMSEP being obtained between 0.08 and 0.27% (v/v), mean precision between 0.07 and 0.32% (v/v) and minimum detectable concentration between 0.23 and 0.81% (v/v) depending on the type of oil or fat in the mixture determined. PMID- 22257927 TI - Planar covariation of elevation angles in prosthetic gait. AB - In order to achieve efficacious walking, transfemoral amputees must adapt coordination within both the artificial and the sound lower limb. We analyzed kinematic strategies in amputees using the planar covariation of lower limb segments approach. When the elevation angles of the thigh, shank and foot are plotted one versus the others, they describe a regular loop which lies close to a plane in normal adults' gait. Orientation of this plane changes with increased speed, in relation to mechanical energetic saving. We used an opto-electronic device to record the elevation angles of both limbs' segments of novice and expert transfemoral amputees and compared them to those of control subjects. The statistical structure underlying the distribution of these angles was described by principal component analysis and Fourier transform. The typical elliptic loop was preserved in prosthetic walking, in both limbs in both novice and expert transfemoral amputees. This reflects a specific control over the thigh elevation angle taking into account knowledge of the other elevation angles throughout the gait cycle. The best-fitting plane of faster trials rotates around the long axis of the gait loop with respect to the plane of slower trials for control subjects, and even more for the sound limb of expert amputees. In contrast, plane rotation is very weak or absent for the prosthetic limb. We suggest that these results reveal a centrally commanded compensation strategy. PMID- 22257928 TI - Effects of low intensity noise from aircraft or from neighbourhood on cognitive learning and electrophysiological stress responses. AB - The effects of low intensity noise on cognitive learning and autonomous physiological processes are of high practical relevance but are rarely addressed in empirical investigations. This study investigated the impact of neighbourhood noise (of 45 dB[A], n=20) and of noise coming from passing aircraft (of 48 dB[A] peak amplitude presented once per minute; n=19) during computer based learning of different texts (with three types of text structure, i.e. linear text, hierarchic hypertext, and network hypertext) in relation to a control group (35 dB[A], n=20). Using a between subjects design, reproduction scores, heart rate, and spontaneous skin conductance fluctuations were compared. Results showed impairments of reproduction in both noise conditions. Additionally, whereas in the control group and the neighbourhood noise group scores were better for network hypertext structure than for hierarchic hypertext, no effect of text structure on reproduction appeared in the aircraft noise group. Compared to the control group, for most of the learning period the number of spontaneous skin conductance fluctuations was higher for the aircraft noise group. For the neighbourhood noise group, fluctuations were higher during pre- and post task periods when noise stimulation was still present. Additionally, during the last 5 min of the 15 min learning period, an increased heart rate was found in the aircraft noise group. Data indicate remarkable cognitive and physiological effects of low intensity background noise. Some aspects of reproduction were impaired in the two noise groups. Cognitive learning, as indicated by reproduction scores, was changed structurally in the aircraft noise group and was accompanied by higher sympathetic activity. An additional cardiovascular load appeared for aircraft noise when combined with time pressure as indicated by heart rate for the announced last 5 min of the learning period during aircraft noise with a peak SPL of even 48 dB(A). Attentional mechanisms (attentional control) like being threatened by passing aircraft approaching the airport, higher demands of selective filtering, and difficulties in changing cognitive strategies during noise are discussed as underlying mechanisms. PMID- 22257929 TI - Targeting Cryptosporidium parvum capture. AB - Polymer microarrays offer a high-throughput approach to the screening and assessment of a large number of polymeric materials. Here, we report the first study of protozoan-polymer interactions using a microarray approach. Specifically, from screening hundreds of synthetic polymers, we identified materials that either trap the waterborne protozoan parasite, Cryptosporidium parvum, or prevent its adhesion, both of which have major practical applications. Comparison of array results revealed differences in the adhesion characteristics of viable and non-viable C. parvum oocysts. Material properties, including polymer composition, wettability and surface chemistry, allowed correlation of binding and identification of structure function relationships. Understanding C. parvum binding interactions could assist in improved water treatment processes and the identified polymers could find applications in sensor and filter materials. PMID- 22257930 TI - Solar water disinfection (SODIS) of Escherichia coli, Enterococcus spp., and MS2 coliphage: effects of additives and alternative container materials. AB - The use of alternative container materials and added oxidants accelerated the inactivation of MS2 coliphage and Escherichia coli and Enterococcus spp. bacteria during solar water disinfection (SODIS) trials. Specifically, bottles made from polypropylene copolymer (PPCO), a partially UVB-transparent plastic, resulted in three-log inactivation of these organisms in approximately half the time required for disinfection in bottles made from PET, polycarbonate, or Tritan((r)), which absorb most UVB light. Furthermore, the addition of 125 mg/L sodium percarbonate in combination with either citric acid or copper plus ascorbate tended to accelerate inactivation by factors of 1.4-19. Finally, it was observed that the inactivation of E. coli and enterococci derived from local wastewater was far slower than the inactivation of laboratory-cultured E. coli and Enterococcus spp., while the inactivation of MS2 was slowest of all. These results highlight the importance of UVB in SODIS under certain conditions, and also the greater sunlight resistance of some viruses and of bacteria of fecal origin, as compared to the laboratory-cultured bacteria commonly used to model their inactivation. Furthermore, this study illustrates promising new avenues for accelerating the inactivation of bacteria and viruses by solar disinfection. PMID- 22257931 TI - Fouling of proton exchange membrane (PEM) deteriorates the performance of microbial fuel cell. AB - The fouling characteristics of proton exchange membrane (PEM) in microbial fuel cell (MFC) and the resulting deterioration of MFC performance were explored in this study. It was observed that the ion exchange capacity, conductivity and diffusion coefficients of cations of PEM were reduced significantly after fouling. Imaging analysis coupled with FTIR analysis indicated that the fouling layer attached on PEM consisted of microorganisms encased in extracellular polymers and inorganic salt precipitations. The results clearly demonstrate that PEM fouling deteriorated the performance of MFCs and led to a decrease in electricity generation. Cation transfer limitation might play an important role in the deterioration of MFC performance because of the membrane fouling. This was attributed to the physical blockage of charge transfer in the MFC resulted from the membrane fouling. With the experimental results, the effect of membrane fouling on the electrical generation of MFCs was evaluated. It was found that the decreased diffusion coefficients of cations and cathodic potential loss after membrane fouling contributed mainly to the deterioration of the MFC performance. PMID- 22257932 TI - Food fermentations: microorganisms with technological beneficial use. AB - Microbial food cultures have directly or indirectly come under various regulatory frameworks in the course of the last decades. Several of those regulatory frameworks put emphasis on "the history of use", "traditional food", or "general recognition of safety". Authoritative lists of microorganisms with a documented use in food have therefore come into high demand. One such list was published in 2002 as a result of a joint project between the International Dairy Federation (IDF) and the European Food and Feed Cultures Association (EFFCA). The "2002 IDF inventory" has become a de facto reference for food cultures in practical use. However, as the focus mainly was on commercially available dairy cultures, there was an unmet need for a list with a wider scope. We present an updated inventory of microorganisms used in food fermentations covering a wide range of food matrices (dairy, meat, fish, vegetables, legumes, cereals, beverages, and vinegar). We have also reviewed and updated the taxonomy of the microorganisms used in food fermentations in order to bring the taxonomy in agreement with the current standing in nomenclature. PMID- 22257933 TI - Rapid titration of retroviral vectors using a beta-lactamase protein fragment complementation assay. AB - The availability of rapid and quantitative titration assays for retroviral vectors is important, especially in the context of clinical applications. In this report, we describe a novel assay to titrate lentiviral and gamma retroviral vectors. This rapid assay is based on protein fragment complementation involving the N-terminal (Bla1) and the C-terminal (Bla2) fragments of TEM-1 beta-lactamase (BLAK). The Bla1 protein fragment is incorporated in the vector's envelope during vector production. Bla1-bearing vectors are titrated on Bla2-expressing cells. Upon transduction, Bla1 and Bla2 heterodimerize and restore BLAK's enzymatic function. The enzymatic activity of BLAK is quantified by flow cytometry using the green fluorescent CCF2/AM substrate, which is converted into a blue fluorescent product. The enzymatic conversion of the CCF2/AM substrate was found to be directly related to vector entry, as a neutralizing antibody completely blocked the conversion. The titers obtained using this rapid assay correlated well with the titers measured by functional transduction assays. The whole assay can be finished within 8 h. Thus, it is considerably less time consuming compared with other transduction-based titration assays for lentiviral and gamma retroviral vectors. PMID- 22257935 TI - BRCA1 gene therapy reduces systemic inflammatory response and multiple organ failure and improves survival in experimental sepsis. AB - Sepsis-related complications and mortality remain a major clinical problem. Increased cell death and unresolved cellular repair have been implicated as key upstream mediators of sepsis-induced organ dysfunction and death. We hypothesised that gene therapy with BRCA1, a critical regulator of DNA damage repair and cell survival, would attenuate the sequelae of sepsis and peritonitis in mice subjected to caecal ligation and perforation (CLP) and thioglycollate stimulation. C57Bl/6J mice underwent sham or CLP surgery 3 days following treatment with either human BRCA1 adenovirus (AdBRCA1) or the adeno-CMV-null vector (Adnull). The 24-h post-CLP mortality was 2.8% vs 17.9% (P<0.001) and the median post-CLP survival was 50.5 vs 33 h (P<0.05) for AdBRCA1- vs Adnull-treated mice, respectively. AdBRCA1 therapy blunted CLP-associated cardiac, pulmonary, hepatic and renal dysfunction and also reduced CLP-elicited double strand breaks and apoptosis in the liver. BRCA1 gene therapy was associated with lower CLP evoked cardiac and hepatic superoxide generation that in the liver was in part due to improved reactive oxygen species removal. CLP also elevated mesenteric arteriolar and serum intercellular adhesion molecule-1, both of which were partially abrogated with AdBRCA1 administration. Thioglycollate-challenged AdBRCA1-treated mice displayed reduced peritoneal neutrophil recruitment and dampened cytokine elaboration relative to their Adnull-treated counterparts. Taken together, we report a novel role of BRCA1 gene therapy in limiting systemic inflammation, multiple-organ failure and mortality in experimental sepsis. PMID- 22257934 TI - Zinc-finger nuclease-mediated gene correction using single AAV vector transduction and enhancement by Food and Drug Administration-approved drugs. AB - An emerging strategy for the treatment of monogenic diseases uses genetic engineering to precisely correct the mutation(s) at the genome level. Recent advancements in this technology have demonstrated therapeutic levels of gene correction using a zinc-finger nuclease (ZFN)-induced DNA double-strand break in conjunction with an exogenous DNA donor substrate. This strategy requires efficient nucleic acid delivery and among viral vectors, recombinant adeno associated virus (rAAV) has demonstrated clinical success without pathology. However, a major limitation of rAAV is the small DNA packaging capacity and to date, the use of rAAV for ZFN gene delivery has yet to be reported. Theoretically, an ideal situation is to deliver both ZFNs and the repair substrate in a single vector to avoid inefficient gene targeting and unwanted mutagenesis, both complications of a rAAV co-transduction strategy. Therefore, a rAAV format was generated in which a single polypeptide encodes the ZFN monomers connected by a ribosome skipping 2A peptide and furin cleavage sequence. On the basis of this arrangement, a DNA repair substrate of 750 nucleotides was also included in this vector. Efficient polypeptide processing to discrete ZFNs is demonstrated, as well as the ability of this single vector format to stimulate efficient gene targeting in a human cell line and mouse model derived fibroblasts. Additionally, we increased rAAV-mediated gene correction up to sixfold using a combination of Food and Drug Administration-approved drugs, which act at the level of AAV vector transduction. Collectively, these experiments demonstrate the ability to deliver ZFNs and a repair substrate by a single AAV vector and offer insights for the optimization of rAAV-mediated gene correction using drug therapy. PMID- 22257936 TI - Minicircle DNA electrotransfer for efficient tissue-targeted gene delivery. AB - A major issue for successful human gene therapy or genetic vaccination is a safe high-transgene expression level. Plasmid-based (non-viral) physical methods of gene transfer offered attracting approaches but their low efficiencies have limited their use in human pre-clinical trials. One of the limits appears to be the size of the plasmid that must be transferred across the cell membrane to the nucleus for its processing. In the present work to enhance gene transfer and expression, we evaluated a new generation of DNA vector; the minicircle, combined with the electropulsation technique. Minicircle is a doubled-stranded circular DNA with reduced size as it is devoid of bacterial sequences. We showed that electrotransferred minicircle encoding green fluorescent protein had higher in vitro transfection level compared with full-length plasmid. We demonstrated that minicircle great efficiency was not because of cellular toxicity decrease but was correlated to more efficient vector uptake by cells. Vector electrotransfection was operated in vivo and, using fluorescence imaging, minicircle electrotransfer was shown to enhance the efficiency and duration of tissue-targeted gene delivery and expression. By combining powerful expression and delivery systems, we have provided a valuable method for new approaches in gene therapy and genetic vaccination. PMID- 22257937 TI - What we can learn about running from barefoot running: an evolutionary medical perspective. AB - Barefoot running, which was how people ran for millions of years, provides an opportunity to study how natural selection adapted the human body to run. Because humans evolved to run barefoot, a barefoot running style that minimizes impact peaks and provides increased proprioception and foot strength, is hypothesized to help avoid injury, regardless of whether one is wearing shoes. PMID- 22257939 TI - Defective cell death signalling along the Bcl-2 regulated apoptosis pathway compromises Treg cell development and limits their functionality in mice. AB - The Bcl-2 regulated apoptosis pathway is critical for the elimination of autoreactive lymphocytes, thereby precluding autoimmunity. T cells escaping this process can be kept in check by regulatory T (Treg) cells expressing the transcription and lineage commitment factor Foxp3. Despite the well-established role of Bcl-2 family proteins in shaping the immune system and their frequent deregulation in autoimmune pathologies, it is poorly understood how these proteins affect Treg cell development and function. Here we compared the relative expression of a panel of 40 apoptosis-associated genes in Treg vs. conventional CD4(+) T cells. Physiological significance of key-changes was validated using gene-modified mice lacking or overexpressing pro- or anti-apoptotic Bcl-2 family members. We define a key role for the Bim/Bcl-2 axis in Treg cell development, homeostasis and function but exclude a role for apoptosis induction in responder T cells as relevant suppression mechanism. Notably, only lack of the pro apoptotic BH3-only protein Bim or Bcl-2 overexpression led to accumulation of Treg cells while loss of pro-apoptotic Bad, Bmf, Puma or Noxa had no effect. Remarkably, apoptosis resistant Treg cells showed reduced suppressive capacity in a model of T cell-driven colitis, posing a caveat for the use of such long-lived cells in possible therapeutic settings. PMID- 22257940 TI - Accelerated loss of hearing and vision in the DNA-repair deficient Ercc1(delta/-) mouse. AB - Age-related loss of hearing and vision are two very common disabling conditions, but the underlying mechanisms are still poorly understood. Damage by reactive oxygen species and other reactive cellular metabolites, which in turn may damage macromolecules such as DNA, has been implicated in both processes. To investigate whether DNA damage can contribute to age-related hearing and vision loss, we investigated hearing and vision in Ercc1(delta/-) mutant mice, which are deficient in DNA repair of helix-distorting DNA lesions and interstrand DNA crosslinks. Ercc1(delta/-) mice showed a progressive, accelerated increase of hearing level thresholds over time, most likely arising from deteriorating cochlear function. Ercc1(delta/-) mutants also displayed a progressive decrease in contrast sensitivity followed by thinning of the outer nuclear layer of the eyeball. The strong parallels with normal ageing suggest that unrepaired DNA damage can induce age-related decline of the auditory and visual system. PMID- 22257941 TI - Geriatric psychiatry in the Department of Veterans Affairs: serving the needs of aged and aging veterans. PMID- 22257942 TI - Prevalence of and quality of life related to anal incontinence in women with urinary incontinence and pelvic organ prolapse. AB - OBJECTIVE: To investigate the prevalence of anal incontinence (AI) in woman with urinary incontinence (UI) and pelvic organ prolapse (POP). We also evaluated the impact on quality of life (QoL). STUDY DESIGN: One hundred and ninety patients with UI or POP and 73 controls were recruited. AI was investigated by the Wexner index and the prevalence rates were obtained in all groups. Patients with AI completed the Fecal Incontinence Quality of Life questionnaire (FIQL). QoL was assessed using the Medical Outcome Study 36-item Short Form Health Survey (SF 36). RESULTS: AI prevalence was 40.54% in the UI group and 27.91% in the POP group (p<0.0001). In the UI and POP groups correlations were found between the Wexner score and the domains of the FIQL and SF36. CONCLUSION: The UI group had higher prevalence of AI than the other groups. The AI adversely affected the QoL of patients. PMID- 22257943 TI - Effect of thumb joint mobilization on pressure pain threshold in elderly patients with thumb carpometacarpal osteoarthritis. AB - OBJECTIVE: This study evaluated the effects of Maitland's passive accessory mobilization on local hypoalgesia and strength in thumb carpometacarpal osteoarthritis (TCOA). METHODS: Twenty-eight patients between 70 and 90 years old with secondary TCOA were randomized into glide mobilization and sham groups. This study was designed as a double-blind, randomized controlled trial. Therapy consisted of Maitland's passive accessory mobilization of the dominant hand during 4 sessions over 2 weeks. We measured pressure pain threshold (PPT) at the trapeziometacarpal joint (TMJ), the tubercle of the scaphoid bone, and the unciform apophysis of the hamate bone by algometry. The tip and tripod pinch strength was also measured. Grip strength was measured by a grip dynamometer. Measurements were taken before treatment and after 1 week (first follow-up [FU]) and 2 weeks (second FU). RESULTS: All values in sham group remained unchanged along the treatment period. In the treated group, the PPT in the TMJ was 3.85 +/- 0.35 kg/cm(2), which increased after treatment to 3.99 +/- 0.37 and was maintained at the same level during the first FU 3.94 +/- 0.39 and second FU 4.74 +/- 0.40. In contrast, we found no differences in PPT in the other studied structures after treatment. Similarly, tip, tripod pinch, and grip strength remained without change after treatment. CONCLUSIONS: Passive accessory mobilization increased PPT in the TMJ; however, it did not increase motor function in patients with TCOA. PMID- 22257944 TI - Comparison of third-year medical and physical therapy students' knowledge of anatomy using the carpal bone test. AB - OBJECTIVE: The curricula of all health professionals have an important foundation of human anatomy. A comparison of the anatomy retention between students from different curricula has not been studied. Our aim was to examine the knowledge competency of third-year physical therapy and medical students in carpal bone anatomy. METHODS: The testing was conducted on the third-year medical and physical therapy students at Universidad de Granada. Students were given 5 minutes to answer the carpal bone test, a test which requires the identification of the carpal bones in an illustration of the bony skeleton of carpal region. Differences in the distribution of the responses between groups were analyzed using the chi(2) test. RESULTS: One hundred thirty-four (n = 134) tests were analyzed (n = 54 [41%] physical therapy students, n = 80 [59%] medical students). Only 39 students correctly identified all of the carpal bones (42.6% physical therapy, 20% medical, P < .001). Physical therapy students correctly identified a greater number (P < .001) of carpal bones (mean +/- SD, 5.8 +/- 2.2) than medical students (mean +/- SD, 3.1 +/- 2.9). The capitate was the most frequently identified bone in both physical therapy (96%) and medical (46%) students (P < .001). The hamate bone was the least frequently identified bone by medical students (n = 29, or 36.3%), whereas the trapezoid bone was the least frequently identified bone by physical therapy students (n = 35, or 64.8%). CONCLUSION: There are few studies investigating anatomical knowledge levels between disciplines. This study found that physical therapy students exhibited better retention of anatomy of the carpal bones than medical students. PMID- 22257946 TI - Cerebral perfusion in patients with chronic neck and upper back pain: preliminary observations. AB - OBJECTIVE: The purpose of this study was to determine the correlation between cerebral perfusion levels, Neck Disability Index (NDI) scores, and spinal joint fixations in patients with neck pain. METHODS: Forty-five adult patients (29 were female) with chronic neck/upper thoracic pain during exacerbation were studied. The subjects were grouped according to NDI scores: mild, moderate, and severe. The number of painful/blocked segments in the cervical and upper thoracic spine and costovertebral joints, pain intensity using the visual analog scale, and regional cerebral blood flow of the brain using single-photon emission computed tomography (SPECT) were obtained. The SPECT was analyzed semiquantitatively. Analysis of variance tests were conducted on total SPECT scores in each of the NDI groups (P < .05). Univariate correlations were obtained between blockage, pain, and SPECT scores, as well as age and duration. A multivariate analysis was then conducted. RESULTS: Group 1 (mild) consisted of 14 patients. Cerebral perfusion measured by SPECT was normal in all 8 brain regions. Group 2 (moderate) consisted of 16 patients. In this group, a decrease in cerebral perfusion was observed (range, 20%-35%), predominantly in the parietal and frontal zones. Group 3 (severe) consisted of 15 patients. In this group, the decrease in cerebral perfusion observed was from 30% to 45%, again predominantly in the parietal and frontal zones. A significant difference was found between NDI groups ("moderate" and "severe" showed significantly greater hypoperfusion than "mild"). Total blockage score correlated with SPECT scores at r = 0.47, P = .001. In a multivariate analysis, NDI scores contributed 39% of the variance of SPECT scores. CONCLUSION: In this group of patients with neck and/or upper back pain, NDI scores strongly predicted cerebral hypoperfusion. Spinal joint dysfunction may be involved via hyperactivity in the regional sympathetic nervous system. PMID- 22257945 TI - Geographic variations in availability and use of chiropractic under medicare. AB - OBJECTIVE: The purpose of this study was to measure geographic variations in the availability and use of chiropractic under Medicare. METHODS: A cross-sectional design was used to analyze a large nationally representative sample of Medicare data. Data from a 20% representative sample of all paid Medicare Part B fee-for service claims for 2007 were merged with files containing beneficiary and provider data. The sample was restricted to adults aged 65 to 99 years. Measures of chiropractic availability and use were described and selectively mapped by state. Geographic variations were quantified. Spearman test was used to evaluate for correlation between chiropractic availability and use. RESULTS: The average number of doctors of chiropractic (DC) by state was 1135; average DC per 1000 beneficiaries was 2.5 (SD, 1.1). The average number of chiropractic users by state was 34,502 (SD, 30,844); average chiropractic users per 1000 beneficiaries was 76 (SD, 41). Chiropractic availability by state varied 6-fold, and chiropractic use varied nearly 30-fold. Availability was strongly correlated with use (Spearman rho, 0.86; P < .001). Expenditures per DC were highest in the upper Midwest and lowest in the far West; expenditures per user were highest in New England and New York, and lowest in the West. CONCLUSION: Chiropractic availability and use by older adults under Medicare predominated in rural states in the North Central United States. Expenditures were higher in the East and Midwest and lower in the far West. Chiropractic availability and use by state were highly correlated. Future analyses should use small-area analysis and statistical modeling to identify factors predictive of chiropractic use. PMID- 22257947 TI - Non-bullous congentital ichthyosiform erythroderma associated with homozygosity for a novel missense mutation in an ATP binding domain of ABCA12. AB - A Mutations in the gene encoding the ABCA12 protein are associated with different subtypes of autosomal recessive congenital ichthyosis (ARCI), including Harlequin ichthyosis (HI), lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). Disruption of ABCA12 lead to perturbed lipid transport in lamellar granules and a defective intercellular lipid layer of the stratum corneum. We have identified a large consanguineous Pakistani family affected by NCIE. Autozygosity mapping showed that affected individuals are homozygous for the ABCA12 gene region. Subsequent mutation screening revealed a homozygous c.4676G>T transition in all five affected family members. The mutation results in a novel p.G1559V substitution within the first nucleotide binding domain of ABCA12. The combined results support that an ABCA12 missense mutation, despite its location in a functional domain, may be associated with a mild ichthyosis phenotype. Furthermore, our findings increase the mutational spectrum in ABCA12 associated with ARCI of diagnostic and prognostic importance. PMID- 22257948 TI - Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue. AB - Endometriosis is a chronic, painful disease whose etiology remains unknown. Furthermore, treatment of endometriosis can require laparoscopic removal of lesions, and/or chronic pharmaceutical management of pain and infertility symptoms. The cost associated with endometriosis has been estimated at 22 billion dollars per year in the United States. To further our understanding of mechanisms underlying this enigmatic disease, animal models have been employed. Primates spontaneously develop endometriosis and therefore primate models most closely resemble the disease in women. Rodent models, however, are more cost effective and readily available. The model that we describe here involves an autologous transfer of uterine tissue to the intestinal mesentery (Figure 1) and was first developed in the rat and later transferred to the mouse. The goal of the autologous rodent model of surgically-induced endometriosis is to mimic the disease in women. We and others have previously shown that the altered gene expression pattern observed in endometriotic lesions from mice or rats mirrors that observed in women with the disease. One advantage of performing the surgery in the mouse is that the abundance of transgenic mouse strains available can aid researchers in determining the role of specific components important in the establishment and growth of endometriosis. An alternative model in which excised human endometrial fragments are introduced to the peritoneum of immunocompromised mice is also widely used but is limited by the lack of a normal immune system which is thought to be important in endometriosis. Importantly, the mouse model of surgically induced endometriosis is a versatile model that has been used to study how the immune system, hormones and environmental factors affect endometriosis as well as the effects of endometriosis on fertility and pain. PMID- 22257949 TI - Are snoRNAs and snoRNA host genes new players in cancer? AB - Small nucleolar RNAs (snoRNAs) have long been considered important but unglamorous elements in the production of the protein synthesis machinery of the cell. Recently, however, several independent lines of evidence have indicated that these non-coding RNAs might have crucial roles in controlling cell behaviour, and snoRNA dysfunction could consequently contribute to oncogenesis in previously unsuspected ways. PMID- 22257951 TI - Mouse models of cancer: does the strain matter? AB - Mouse models are indispensible tools for understanding the molecular basis of cancer. However, despite the invaluable data provided regarding tumour biology, owing to inbreeding, current mouse models fail to accurately model human populations. Polymorphism is the essential characteristic that makes each of us unique humans, with different disease susceptibility, presentation and progression. Therefore, as we move closer towards designing clinical treatment that is based on an individual's unique biological makeup, it is imperative that we understand how inherited variability influences cancer phenotypes, how it can confound experiments and how it can be exploited to reveal new truths about cancer biology. PMID- 22257952 TI - Cancer stem cells: TAZ takes centre stage. PMID- 22257950 TI - The diverse and complex roles of NF-kappaB subunits in cancer. AB - It is only recently that the full importance of nuclear factor-kappaB (NF-kappaB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-kappaB activation, it is now becoming clear that the inhibitor of NF-kappaB kinases (IKKs), which regulate NF kappaB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-kappaB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-kappaB subunits. PMID- 22257953 TI - Covered carotid stents as an adjunct in the surgical treatment of carotid body tumors: a report of 2 cases and a review of the literature. AB - BACKGROUND AND IMPORTANCE: Carotid body tumors are a technically challenging surgical problem. One of the primary goals of surgery and often one of the most difficult aspects of management involves preservation of the ipsilateral internal carotid artery (ICA). We report a small case series with challenging aspects to ICA preservation that were successfully treated with covered stenting and review the literature to date on this topic. CLINICAL PRESENTATION: Two patients with carotid body tumors were selected for covered ICA stenting, the first because of bilateral disease and the second because of failure of test occlusion. The patients were initially loaded with antiplatelet agents, and the stents were deployed transfemorally. The patients were kept on dual therapy (acetylsalicylic acid and Plavix) for 6 weeks, followed by acetylsalicylic acid alone, which was discontinued 1 week before surgery. The patients were admitted 3 days before surgery, and intravenous heparin was started and then stopped 6 hours preoperatively. Both tumors were completely resected with minimal blood loss, and the ipsilateral ICA was successfully preserved in both cases. CONCLUSION: The covered ICA stent offers a significant adjunct for preserving the ICA in carotid body tumor resection. PMID- 22257958 TI - Fabrication of fibrin scaffolds with controlled microscale architecture by a two photon polymerization-micromolding technique. AB - Fabrication of three-dimensional (3D) fibrin scaffolds with tightly controllable pore sizes and interconnections has been investigated. The scaffolds were produced using a combination of two-photon polymerization (2PP) and micromolding techniques. Master structures were fabricated by 2PP and regenerated in fibrin by a two-step microreplication procedure. Scanning electron and optical microscopy observations showed that the fibrin scaffolds exhibited a highly porous and interconnected structure. Seeding of endothelial cells in fibrin scaffolds resulted in their directed lining and spreading within network of microreplicated pores, whereas encapsulation of endothelial cells in fibrin gel blocks led to their chaotic and irregular distribution within constructs. These results demonstrate that the 2PP-micromolding technique is suitable for fabrication of complex 3D structures from natural proteins for tissue engineering applications. PMID- 22257959 TI - Novel LaBO3 hollow nanospheres of size 34+/-2 nm templated by polymeric micelles. AB - Novel lanthanum borate (LaBO(3)) hollow nanospheres of size 34+/-2 nm have been reported for the first time by soft-template self-assembly process. Poly(styrene b-acrylic acid-b-ethylene oxide) (PS-PAA-PEO) micelle with core-shell-corona architecture serves as an efficient soft template for fabrication of LaBO(3) hollow particles using sodium borohydride (NaBH(4)) and LaCl(3)?7H(2)O as the precursors. In this template, the PS block (core) acts as a template of the void space of hollow particle, the anionic PAA block (shell) serves as reaction field for metal ion interactions, and the PEO block (corona) stabilizes the polymer/lanthana composite particles. The PS-PAA-PEO micelles and the resulting LaBO(3) hollow nanospheres were thoroughly characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), X-ray diffraction, magic angle spinning-nuclear magnetic resonance ((11)B MAS NMR), energy dispersive X-ray analysis, thermal analyses, Fourier transform infra red spectroscopy, and nitrogen adsorption/desorption analyses. The nitrogen adsorption/desorption analyses and TEM observation of the hollow particles confirmed the presence of disordered mesopores in the LaBO(3) shell domain. The solid state (11)B MAS NMR spectra of LaBO(3) hollow nanospheres revealed that the shell part contains both trigonal and tetrahedral boron species. The LaBO(3) hollow particles were applied to anode materials in lithium-ion rechargeable batteries (LIBs). The hollow particles exhibited high coulombic efficiency and charge-discharge cycling capacities of up to 100 cycles in the LIBs. PMID- 22257960 TI - The production and verification of pristine semi-fluorinated thiol monolayers on gold. AB - The presence of adventitious contamination of self-assembled monolayers (SAMs) is a well-known phenomenon that is often overlooked or underestimated in the literature. Herein, we demonstrate that it is possible to produce pristine self assembled monolayers (SAMs) on gold surfaces that are devoid of adventitious species. The chemical purity or the pristine quality of the SAM was verified by the experimental relative atomic ratios measured by X-ray photoelectron spectroscopy (XPS) of all elements including carbon and corresponded to within 5% of the stoichiometric ratios. Perfluoro-octyl-thiolate (F8) was used as a model compound in this study, where monolayers were assembled from solutions of an acetylated F8 precursor. Quantitative elemental characterization of the acetylated F8 precursor by cold-stage XPS provided valuable reference data for the analysis of the subsequent SAMs. Comprehensive analysis of high-resolution XPS C 1s spectra proved to be essential for establishing the purity of the SAMs, since the peaks of the adventitious species were easily distinguished from those of the F8. Analyses of deliberately contaminated F8 SAMs showed that the adventitious species persisted during the process of self-assembly and therefore co-existed with the SAM in the interfacial region. The work also established that even a lengthy deposition time of 18 h was incapable of displacing the adventitious species present at the interface. PMID- 22257961 TI - Properties of aqueous solutions of hydrophobically modified polyethylene imines in the absence and presence of sodium dodecylsulfate. AB - Four modified hyperbranched polyethylene imines (PEIs) were synthesized by means of the alkylation of PEI. SAXS, viscosity, surface tension, and pyrene fluorescence emission were then used as techniques to examine the conformation and aggregation of the modified PEIs in aqueous solution, in the absence and presence of sodium dodecylsulfate (SDS). Analysis of the SAXS data showed that the radius of gyration decreases with an increase in the alkyl chain length of the polymer, while the viscosity data indicated a decrease in the intrinsic viscosity under the same conditions. The nonmodified PEI was not surface active, while the hydrophobically modified samples showed pronounced surface activity and the presence of hydrophobic domains. On addition of SDS, the onset of the formation of polymer-surfactant complexes was determined, indicating a decrease in the critical aggregate concentration with an increase in the alkyl chain length of the polymer backbone. PMID- 22257962 TI - A cell-based backup to speed up pandemic influenza vaccine production. AB - Influenza vaccines are currently produced through egg-based methods, with one drawback being that this system is slow to respond to the surging global demand during an influenza pandemic. Alternative influenza vaccine production strategies, such as using a cell-based strategy, should be considered in pandemic situations. PMID- 22257963 TI - Raising the index of suspicion for elder abuse: cognitive impairment, falls, and injury patterns in the emergency department. AB - Cognitive impairment limits older adults' abilities to advocate for themselves, thus heightening their risk for abuse. Some older adults with cognitive impairments who seek emergency department (ED) services may present with injuries suspicious of abuse. A portion of these injuries may be erroneously attributed to accidents such as falls. A retrospective analysis of 2 years of ED data using International Classification of Diseases, Ninth Revision (ICD-9) codes was conducted focusing on characteristics of injuries sustained by persons with co occurring cognitive impairment and fall status. Cognitive impairment was not significantly related to falls (P = .533). Findings suggest that persons with cognitive impairment have unique injury patterns based on fall status, which has implications for elder abuse screening. Injuries for persons with no fall history included injury to the upper limb (P = .004), contusions (P = .012), and open wounds (P = .000). An increased recognition of common injuries in older adults can aid in elder abuse assessment by providing a reference point for uncommon injuries. PMID- 22257964 TI - Associations between chewing and swallowing problems and physical and psychosocial health status of long-term care residents in taiwan: a pilot study. AB - Oral health is often overlooked in institutional elder care but may have an impact on general health and ability to communicate. We aimed to determine the factor associated with chewing and swallowing problems among long-term care residents in Taiwan. Staff nurses trained to evaluate oral health assessed 781 residents using relevant sections of the Minimum Data Set 2.1 for nursing homes (Chinese version), including the Cognitive Performance Scale, Index of Social Engagement, and Activities of Daily Living Scale. Individuals with chewing and swallowing problems (n = 345) tended to be women (odds ratio [OR] = 1.51, P = .019) in smaller facilities (OR = 4.18, P < .001) with fewer natural teeth (OR = 0.54, P = .011); more broken, loose, or carious teeth (OR = 1.74, P = .042); and with more frequently inflamed gums (OR = 2.72, P = .025) than residents without chewing and swallowing problems (n = 436). Residents' chewing and swallowing problems were significantly associated with parenteral/enteral intake, oral health status, nutritional status, concomitant disease and infection, cognitive function, and social engagement. PMID- 22257965 TI - Ground hardness and injury in community level Australian football. AB - OBJECTIVES: To describe the risk and details of injuries associated with ground hardness in community level Australian football (AF). DESIGN: Prospective injury surveillance with periodic objective ground hardness measurement. METHODS: 112 ground hardness assessments were undertaken using a Clegg hammer at nine locations across 20 grounds, over the 2007 and 2008 AF seasons. Details of 352 injuries sustained by community level players on those grounds were prospectively collected as part of a large randomised controlled trial. The ground location of the injury was matched to the nearest corresponding ground hardness Clegg hammer readings, in gravities (g), which were classified from unacceptably low (<30 g) to unacceptably high hardness (>120 g). RESULTS: Clegg hammer readings ranged from 25 to 301 g. Clegg hammer hardness categories from low/normal to high/normal were associated with the majority of injuries, with only 3.7% (13 injuries) on unacceptably high hardness and 0.3% (1 injury) on the unacceptably low hardness locations. Relative to the preferred range of hardness, the risk of sustaining an injury on low/normal hardness locations was 1.31 (95%CI: 1.06-1.62) times higher and 1.82 (95%CI: 1.17-2.85) times higher on locations with unacceptably high hardness. The more severe injuries occurred with low/normal ground hardness. CONCLUSIONS: Despite the low number of injuries, the risk of sustaining an injury on low/normal and unacceptably hard grounds was significantly greater than on the preferred range of hardness. Notably, the severity of the injuries sustained on unacceptably hard grounds was lower than for other categories of hardness. PMID- 22257966 TI - Mineralization of mandibular third molars can estimate chronological age- Brazilian indices. AB - Forensic age estimation is an important element of anthropological research, as it produces one of the primary sources of data that researchers use to establish the identity of a person living or the identity of unknown bodily remains. The aim of this study was to determine if the chronology of third molar mineralization could be an accurate indicator of estimated age in a sample Brazilian population. If so, mineralization could determine the probability of an individual being 18 years or older. The study evaluated 407 panoramic radiographs of males and females from the past 5 years in order to assess the mineralization status of the mandibular third molars. The evaluation was carried out using an adaptation of Demirjian's system. The results indicated a strong correlation between chronological age and the mineralization of the mandibular third molars. The results indicated that modern Brazilian generation tends to demonstrate an earlier mandibular third molar mineralization than older Brazilian generation and people of other nationalities. Males reached developmental stages slightly earlier than females, but statistically significant differences between the sex were not found. The probability that an individual with third molar mineralization stage H had reached an age of 18 years or older was 96.8-98.6% for males and females, respectively. PMID- 22257967 TI - Real-time PCR detection and quantification of elephantid DNA: species identification for highly processed samples associated with the ivory trade. AB - The ivory industry is the single most serious threat to global elephant populations. A highly sensitive, species-specific real-time PCR assay has been developed to detect and quantify African elephant (Loxodonta africana), Asian elephant (Elephas maximus) and Woolly Mammoth (Mammuthus primigenius) mitochondrial DNA from highly processed samples involved in the international ivory trade. This assay is especially useful for highly processed samples where there are no distinguishing morphological features to identify the species of origin. Using species-specific Taqman((r)) probes targeting a region of the mitochondrial cytochrome b gene, we developed an assay that can be used to positively identify samples containing elephant or Woolly mammoth DNA faster and more cost-effectively than traditional sequencing methods. Furthermore, this assay provides a diagnostic result based on probe hybridization that eliminates ambiguities associated with traditional DNA sequence protocols involving low template DNA. The real-time method is highly sensitive, producing accurate and reproducible results in samples with as few as 100 copies of template DNA. This protocol can be applied to the enforcement of the Convention on the International Trade of Endangered Species (CITES), when positive identification of species from illegally traded products is required by conservation officers in wildlife forensic cases. PMID- 22257968 TI - The PMMA epidemic in Norway: comparison of fatal and non-fatal intoxications. AB - During a 6 month period (July 2010-January 2011) we observed 12 fatal intoxications and 22 non-fatal cases related to the drug paramethoxymethamphetamine (PMMA) in Norway (4.8 mill inhabitants). This toxic designer drug, also known as "Death", is occasionally found in street drugs offered as "ecstasy" or "amphetamine". The present study aimed to evaluate the cause of death, and to compare the PMMA blood concentrations in fatal and non fatal cases. Methods for identification and quantification of PMMA are presented. The median age of fatalities was 30 years (range 15-50) with 67% males; in non fatal cases 27 years (20-47) with 86% males. In the 12 fatalities, the median PMMA blood concentration was 1.92 mg/L (range 0.17-3.30), which is in the reported lethal range of 0.6-3.1 mg/L in peripheral blood and 1.2-15.8 mg/L in heart blood. In the 22 non-fatal cases, the median PMMA concentration was 0.07 mg/L (range 0.01-0.65). Poly-drug use was frequent both in fatal and non-fatal cases. The PMA concentrations ranging from 0.00 to 0.26 mg/L in both groups likely represented a PMMA metabolite. Three fatalities were attributed to PMMA only, six to PMMA and other psychostimulant drugs, and three to PMMA and CNS depressant drugs, with median PMMA concentrations of 3.05 mg/L (range 1.58-3.30), 2.56 (1.52-3.23) and 0.52 mg/L (0.17-1.24), respectively. Eight victims were found dead, while death was witnessed in four cases, with symptoms of acute respiratory distress, hyperthermia, cardiac arrest, convulsions, sudden collapse and/or multiple organ failure. In summary, all fatalities attributed to PMMA had high PMMA blood concentrations compared to non-fatal cases. Our sample size was too small to evaluate a possible impact of poly-drug use. A public warning is warranted against use and overdose with illegal "ecstasy" or "speed" drugs. PMID- 22257969 TI - Chemical and biological evaluation of some new antipyrine derivatives with particular properties. AB - Starting from 4-amino-antipyrine, six new compounds were synthesized and characterized. The new compounds contain moieties with particular properties, such are ionophore (benzo-15-crown-5), fluorescent (nitrobenzofurazan), stable free radical (nitroxide), or other types of biological active residues, like nitroderivatives, antipyrine or isoniazid residues. They were fully characterized by appropriate means ((1)H and (13)C NMR, IR, UV-Vis, fluorescence, EPR, elemental analysis) and some of their biological properties were evaluated. Hydrophobicity (R(M0), log P), total antioxidant capacity (TAC), and antimicrobial properties are also presented and discussed. PMID- 22257970 TI - Calf tissue oxygenation during exercise in men with and without risk factors for developing peripheral arterial disease. AB - OBJECTIVE: This study aimed to compare calf tissue oxygenation responses to calf exercise in men without diagnosed peripheral arterial disease but with selected risk factors for peripheral arterial disease with those without risk factors. DESIGN: A cross-sectional quasi-experimental design was used. The no-risk group (n = 20) had none of the risk factors (diabetes, hypertension, hyperlipidemia, obesity, current or 10 pack-yr smoking history, or age >=65 yrs). The at-risk group (n = 45) had one to six risk factors. Medial calf tissue oxygenation (percentage saturation) was determined using near-infrared spectroscopy during seven consecutive 5-min test stages: rest, 0-W active plantar/dorsiflexion, rest, 4-W resistive plantar flexion, rest, 8-W resistive plantar flexion, and rest. Resistive exercise was performed on the Stresst'er calf ergometer. RESULTS: Compared with the no-risk group, decrements in calf tissue oxygenation induced by light-to-moderate resistive calf exercise in the at-risk group was significantly greater (by 9% saturation) (4-W: P < 0.001; 8-W: P = 0.002). CONCLUSIONS: Men with risk factors for developing peripheral arterial disease but without such diagnosis demonstrated greater decrements in calf tissue oxygenation during calf exercise compared with men without risk factors. Further development of this test may lead to early diagnosis and intervention to modify risk factors and prevent co-morbidities. PMID- 22257971 TI - Muscle strength loss in the lower limb after total knee arthroplasty. AB - OBJECTIVE: This study aimed to examine functional mobility and strength loss in the ankle plantarflexors and dorsiflexors and knee extensors and flexors after total knee arthroplasty. DESIGN: This was a prospective, longitudinal cohort study. Maximal voluntary isometric contractions and gait speed assessments were performed before and after total knee arthroplasty. RESULTS: Twenty patients undergoing primary total knee arthroplasty were followed. Repeated-measures analysis of variance results indicated an effect of time on muscle strength, with all muscle groups being significantly weaker (knee extensors, P < 0.001; knee flexors, P < 0.001, ankle plantarflexors, P = 0.004; ankle dorsiflexors, P < 0.001) 1 mo postoperatively. Knee extensors were 42% weaker than preoperative levels, and knee flexors were 34% weaker, whereas the ankle plantarflexors were 17% weaker, and the dorsiflexors were 18% weaker. Three and 6 mos after surgery, strength in all muscle groups was similar to preoperative levels (P > 0.05 for all muscle groups). Patient function followed a similar trend, with patients walking slower 1 mo postoperatively (P < 0.001) and recovering to preoperative levels by 3 and 6 mos after surgery (P > 0.05). CONCLUSIONS: Patients may benefit from early postoperative rehabilitation, including strengthening of the plantarflexors and dorsiflexors, although strengthening of the quadriceps and hamstrings muscles should continue to be a priority. PMID- 22257972 TI - Presumed intramedullary spinal cord sarcoidosis in a healthy young adult woman. AB - Sarcoidosis is an inflammatory disease of unknown etiology associated with the development of granulomatous nodules in various organs, most commonly the lungs, eyes, and skin. It rarely affects the central nervous system, with the spinal cord being least common area of involvement. However, when sarcoidosis does affect the central nervous system, it is often the first presentation of the disease, making diagnosis more difficult. Physical examination findings are consistent with spinal cord pathology, and imaging often suggests spinal cord tumor. We present a case of an otherwise healthy young woman with a granulomatous mass in her cervico-thoracic spinal cord presumed to be sarcoid and review the clinical findings, diagnosis, treatment, and prognosis associated with this rare disease. PMID- 22257973 TI - Ultrasonographic findings in chronic inflammatory demyelinating polyneuropathy. PMID- 22257974 TI - Complete paraplegia resulting from surfer's myelopathy. AB - Three patients with diagnoses of surfer's myelopathy (24-31 yrs old; two men, one woman) were admitted to our rehabilitation hospital. All three patients were novice surfers and had a typical clinical course of onset: rapid progression of paraplegia after back pain while taking surfing lessons. Despite months of rehabilitation at our hospital, in all three patients, complete paraplegia (T9 T12) and bladder-bowel dysfunction remained. Our case profiles suggest that the neurologic outcome of surfer's myelopathy is potentially catastrophic, as has been suggested in previous reports. Surfer's myelopathy has been estimated to be an ischemic thoracic myelopathy. From our case profiles and review of the literature, not only the prolonged prone hyperextended posture of paddling but also the repetitive mechanical stress caused by flexion-extension of the spinal column may be related to its pathogenesis. To prevent surfer's myelopathy and to avoid progressive deterioration of neurologic function, increased education and awareness are essential. PMID- 22257975 TI - Sleep propensity at daytime as assessed by Multiple Sleep Latency Tests (MSLT) in patients with schizophrenia increases with clozapine and olanzapine. AB - Sleep propensity at daytime has not been investigated in untreated patients with schizophrenia. Furthermore, while the antipsychotics clozapine and olanzapine are considered to frequently cause 'sleepiness' or 'sedation', this has not been objectified yet. Therefore, 30 patients with schizophrenia were included in this randomized, double-blind study. Sleep propensity was assessed before and after 2, 4 and 6 weeks of treatment with either clozapine or olanzapine using a Multiple Sleep Latency Test (MSLT); in the MSLT, sleep latencies of 5 nap opportunities of 20 min during daytime are averaged. In addition, the number of sleep onsets was recorded. Mean sleep latency in untreated schizophrenic patients was 16.2 +/- 0.8 min at baseline. Both antipsychotics induced an increase of sleep propensity as indicated by a shortened sleep latency and more sleep onsets during the treatment period as compared to baseline. These effects were strongest in the morning. Four patients receiving clozapine and 3 patients receiving olanzapine reported subjective sleepiness, in all but one commencing in the first treatment week and persisting until study end. While the mean sleep latency during treatment was significantly shorter in these patients (12.3 +/- 0.8 min) than in those without subjective sleepiness (14.9 +/- 0.7 min), a short sleep latency was not necessarily associated with subjective sleepiness. In conclusion, mean sleep latency was >36% longer (i.e. sleep propensity was lower) in untreated patients with schizophrenia than in healthy subjects previously consistently reported. Furthermore, clozapine and olanzapine increased sleep propensity in schizophrenic patients. A minority of patients reported subjective sleepiness. PMID- 22257976 TI - Indium Tin Oxide devices for amperometric detection of vesicular release by single cells. AB - The microfabrication and successful testing of a series of three ITO (Indium Tin Oxide) microsystems for amperometric detection of cells exocytosis are reported. These microdevices have been optimized in order to simultaneously (i) enhance signal-to-noise ratios, as required electrochemical monitoring, by defining appropriate electrodes geometry and size, and (ii) provide surface conditions which allow cells to be cultured over during one or two days, through apposite deposition of a collagen film. The intrinsic electrochemical quality of the microdevices as well as the effect of different collagen treatments were assessed by investigating the voltammetric responses of two classical redox systems, Ru(NH(3))(6)(3+/2+) and Fe(CN)(6)(3-/4-). This established that a moderate collagen treatment does not incur any significant alteration of voltammetric responses or degradation of the excellent signal-to-noise ratio. Among these three microdevices, the most versatile one involved a configuration in which the ITO microelectrodes were delimited by a microchannel coiled into a spiral. Though providing extremely good electrochemical responses this specific design allowed proper seeding and culture of cells permitting either single cell or cell cluster stimulation and analysis. PMID- 22257977 TI - Traditional birth attendants are an effective resource. PMID- 22257978 TI - Whose health and safety? PMID- 22257979 TI - Does nicotine replacement really help smokers quit? PMID- 22257980 TI - Bad medicine: medical nutrition. PMID- 22257981 TI - Show us the evidence for telehealth. PMID- 22257982 TI - Changes in baroreflex control of renal sympathetic nerve activity in high-fat-fed rats as a predictor of hypertension. AB - There is evidence that obesity is associated with increased sympathetic activity and hypertension. However, the mechanisms responsible for these changes are not fully understood. Therefore, the aim of the present study was to evaluate the cardiovascular function and the baroreceptor reflex control of renal sympathetic nerve activity (rSNA) in rats exposed to a high-fat diet over different periods (10 and 20 weeks) compared to control rats. Serum leptin levels were assessed for all time points. Male Wistar rats weighing 150-180 g were used. Four groups of rats were studied: control 10 weeks (Ct10), obese 10 weeks (Ob10), control 20 weeks (Ct20), and obese 20 weeks (Ob20). Blood pressure (BP) and rSNA were recorded in urethane-anesthetized rats (1.4 g/kg, intravenous).The sensitivity of rSNA responses to baroreceptor reflex was assessed by changes in BP induced by increasing doses of phenylephrine or sodium nitroprusside. Significant and progressive increases in serum leptin levels were found in the obese rats, but not in the control rats. No changes in basal BP or rSNA were found in the Ob10 and Ob20 groups; however, a significant impairment in the baroreceptor sensitivity was observed in the Ob20 group for phenylephrine (slope Ob20: -0.78 +/- 0.12 vs. Ct20: -1.00 +/- 0.08 potential per second (pps)/mm Hg, P < 0.05) and sodium nitroprusside (slope Ob20: -0.82 +/- 0.09 vs. 1.13 +/- 0.13 pps/mm Hg, P < 0.05). The results suggest that the baroreceptor dysfunction that controls the rSNA is an initial change in the obesity induced in high-fat-fed rats, which might be a predictor of sympathoexcitation and hypertension associated to obesity. PMID- 22257983 TI - Air plasma treated chitosan fibers-stacked scaffolds. AB - Chitosan is a nontoxic, biodegradable and biocompatible polymer. Rapid prototyped chitosan scaffolds were manufactured by liquid-frozen deposition of chitosan fibers in this study. To investigate if the air plasma (AP) treatment could be used to improve the surface properties of these scaffolds for cell attachment, chitosan films were first prepared and treated with AP under different conditions. Under the optimized condition, the water contact angle of chitosan films was significantly reduced from 90 +/- 1 degrees to 19 +/- 1 degrees after AP treatment. On the other hand, the surface charge and nanometric roughness of chitosan films increased after AP treatment. X-ray photoelectron spectroscopy measurement on AP-treated three-dimensional chitosan scaffolds showed that nitrogen and oxygen increased at each location inside the scaffolds as compared to the untreated ones, which indicated that AP could permeate through the fibrous stacks of the scaffolds and effectively modify the interior (visible) surface of the scaffolds. Moreover, AP treatment enabled the migration of MC3T3-E1 cells into the scaffolds, facilitated their proliferation and promoted the bone mineral deposition. These results suggested that fibers-stacked chitosan scaffolds may be produced by liquid-frozen deposition and treated with AP for bone tissue engineering applications. PMID- 22257984 TI - Age-related differences in corticospinal excitability and inhibition during coordination of upper and lower limbs. AB - The ability to coordinate upper and lower limbs--a prerequisite for many everyday activities--is known to decline with age. Here we report 2 experiments in which transcranial magnetic stimulation (TMS) was used to assess corticospinal excitatory and inhibitory processes in younger and older adults during cyclical hand-foot movements. In experiment 1, motor evoked potentials (MEP) and silent period (SP) durations were measured from the active right extensor carpi radialis (ECR) muscle while it executed rhythmic oscillations in conjunction with the right or left foot. Younger adults exhibited increased SP with ipsilateral limb combinations and decreased SP with contralateral limb combinations, relative to a baseline hand only condition. Strikingly, older adults exhibited a reduced SP when ipsilateral limbs moved in opposite directions. This effect was found to be most pronounced in those older adults who exhibited poor coordination performance, suggesting that the inability to regulate inhibitory processes may underlie age-related degradation of task performance. Experiment 2 examined motor evoked potentials and SP duration in the left extensor carpi radialis which maintained a tonic contraction while the coordination task was undertaken by the right arm and right or left foot. For younger adults, coordination of ipsilateral limbs was accompanied by increased inhibition in the ipsilateral motor cortex than during the coordination of contralateral limbs. No differences in SP between conditions were noted for the older adults. In summary, older adults' reduced ability to coordinate upper and lower limbs may be related to the capacity to regulate inhibitory function in both hemispheres. This study suggests for the first time a direct link between age-related differences in interlimb coordination and the control of corticospinal inhibitory processes. PMID- 22257990 TI - High content screening in neurodegenerative diseases. AB - The functional annotation of genomes, construction of molecular networks and novel drug target identification, are important challenges that need to be addressed as a matter of great urgency. Multiple complementary 'omics' approaches have provided clues as to the genetic risk factors and pathogenic mechanisms underlying numerous neurodegenerative diseases, but most findings still require functional validation. For example, a recent genome wide association study for Parkinson's Disease (PD), identified many new loci as risk factors for the disease, but the underlying causative variant(s) or pathogenic mechanism is not known. As each associated region can contain several genes, the functional evaluation of each of the genes on phenotypes associated with the disease, using traditional cell biology techniques would take too long. There is also a need to understand the molecular networks that link genetic mutations to the phenotypes they cause. It is expected that disease phenotypes are the result of multiple interactions that have been disrupted. Reconstruction of these networks using traditional molecular methods would be time consuming. Moreover, network predictions from independent studies of individual components, the reductionism approach, will probably underestimate the network complexity. This underestimation could, in part, explain the low success rate of drug approval due to undesirable or toxic side effects. Gaining a network perspective of disease related pathways using HT/HC cellular screening approaches, and identifying key nodes within these pathways, could lead to the identification of targets that are more suited for therapeutic intervention. High-throughput screening (HTS) is an ideal methodology to address these issues. but traditional methods were one dimensional whole-well cell assays, that used simplistic readouts for complex biological processes. They were unable to simultaneously quantify the many phenotypes observed in neurodegenerative diseases such as axonal transport deficits or alterations in morphology properties. This approach could not be used to investigate the dynamic nature of cellular processes or pathogenic events that occur in a subset of cells. To quantify such features one has to move to multi dimensional phenotypes termed high-content screening (HCS). HCS is the cell-based quantification of several processes simultaneously, which provides a more detailed representation of the cellular response to various perturbations compared to HTS. HCS has many advantages over HTS, but conducting a high throughput (HT)-high-content (HC) screen in neuronal models is problematic due to high cost, environmental variation and human error. In order to detect cellular responses on a 'phenomics' scale using HC imaging one has to reduce variation and error, while increasing sensitivity and reproducibility. Herein we describe a method to accurately and reliably conduct shRNA screens using automated cell culturing and HC imaging in neuronal cellular models. We describe how we have used this methodology to identify modulators for one particular protein, DJ1, which when mutated causes autosomal recessive parkinsonism. Combining the versatility of HC imaging with HT methods, it is possible to accurately quantify a plethora of phenotypes. This could subsequently be utilized to advance our understanding of the genome, the pathways involved in disease pathogenesis as well as identify potential therapeutic targets. PMID- 22257991 TI - Non-symmetrically substituted phenoxazinones from laccase-mediated oxidative cross-coupling of aminophenols: an experimental and theoretical insight. AB - Oxidative cross-coupling reactions of substituted o-aminophenols were catalyzed by a commercial laccase to produce non-symmetrically substituted phenoxazinones for the first time. Identification by (1)H-, (13)C- and (31)P-NMR, and by HPLC PDA and HPLC-MS/MS of exclusively two kinds of substituted phenoxazinones out of four potential heterocyclic frameworks was confirmed by a DFT study. The redox properties of the substrates, their relative rates of conversion and the rigid docking of selected substrates led to a revisited mechanistic pathway for phenoxazinones biosynthesis. Our suggestions concern both the first formal two electron oxidation by laccase and the first intermolecular 1,4-conjugated addition which secures the observed regioselectivity. PMID- 22257992 TI - The distribution of 4-nonylphenol in marine organisms of North American Pacific Coast estuaries. AB - One of the chemical breakdown products of nonylphenol ethoxylates, 4-nonylphenol (4-NP), accumulates in organisms and is of concern as an environmental pollutant due to its endocrine disrupting effects. We measured 4-NP levels in the seawater, sediment, and twelve organisms within the California estuary, Morro Bay, and examined biomagnification of 4-NP using stable isotope abundances (delta(15)N and delta(13)C) to quantify trophic position. 4-NP concentrations in organisms from Morro Bay included 25000+/-8600 ng g(-1) lw in liver of California sea lion, 14000+/-5600 ng g(-1) lw in liver of harbor porpoise, 138000+/-55000 ng g(-1) lw in liver of sea otters, 15700+/-3600 ng g(-1) lw in liver of seabirds, 36100+/ 6100 ng g(-1) lw in arrow goby fish, 62800+/-28400 ng g(-1) lw in oysters, and 12700+/-1300 ng g(-1) lw in mussels. 4-NP levels generally showed a pattern of trophic dilution among organisms in Morro Bay, with exceptions of biomagnification observed between three trophic links: mussel to sea otter (BMF 10.9), oyster to sea otter (BMF 2.2), and arrow goby to staghorn sculpin (BMF 2.7). Our examination of other west coast estuaries of USA and Canada revealed that mean 4-NP concentrations in gobies and mussels from Morro Bay were significantly higher than those from a more urbanized estuary, San Francisco Bay (goby: 11100+/-3800 ng g(-1) lw) and from a remote estuary, Bamfield Inlet, Canada (goby: 9000+/-900 ng g(-1) lw, mussel: 6100+/-700 ng g(-1) lw). Relative to other estuaries worldwide, 4-NP levels in seawater (0.42+/-0.16 MUg L(-1)) and sediment (53+/-14 ng g(-1) dw) of Morro Bay are low, but gobies and oysters have higher 4-NP levels than comparable fauna. PMID- 22257993 TI - Performance of bioelectrical impedance analysis in the diagnosis of metabolic syndrome. AB - OBJECTIVE: Central obesity is a prerequisite for the diagnosis of metabolic syndrome (MetS). Precise measurement of visceral fat by bioelectrical impedance analysis (BIA) has been validated. The aim of this study was to investigate the diagnostic performance of BIA in MetS and validate the best cutoff in a large adult cohort. MATERIALS AND METHODS: The study was performed on the MELEN Study cohort-a prospectively designed survey on the prevalence of cardiometabolic risk factors in Turkish adults. The final cohort consisted of 2219 participants. Weight and visceral body composition were measured without shoes in light indoor clothes using a bioimpedance analyzer (Omron BF 510; Omron Corp, Kyoto, Japan). Plasma concentrations of cholesterol, insulin, fasting triglycerides, high density lipoprotein cholesterol, glucose, and other biochemical variables were measured. The diagnostic performance of visceral fat measurement by BIA in patients with MetS was assessed. RESULTS: Metabolic syndrome was detected in 751 participants (520 women and 231 men with a mean age of 55 [12] years; 34% of the whole study population). Total body fat and visceral fat levels were higher in subjects with MetS. Correlation analyses showed that there were significant correlations between anthropometric and BIA measurements. Receiver operating curve characteristics of visceral adiposity revealed the best cutoff values as greater than 12% for men and greater than 9% for women. The diagnostic performance was good in both sexes (the sensitivity/specificity and area-under the-curve values were 76%/75% and 0.83 for men and 83%/67% and 0.81 for women, respectively). CONCLUSIONS: Visceral fat measured with BIA is an easily applicable and useful method for identifying people with MetS. The best cutoff values were higher than 12% for men and higher than 9% for women. PMID- 22257994 TI - Visibility of surgical site marking: a prospective randomized trial of two skin preparation solutions. AB - BACKGROUND: An important component of the surgical time-out is to confirm surgical site skin markings to prevent wrong-site surgery. Different skin preparation solutions may have variable effects on the visibility of site markings after application. We performed a prospective randomized clinical trial to quantitatively and qualitatively evaluate the visibility of surgical site markings after the use of two commonly available skin preparation solutions. METHODS: We enrolled twenty patients undergoing primary total hip arthroplasty at our institution. Preoperatively, a black permanent marker was used to mark the skin of each patient with a random combination of three letters, underlined by a single black line, and with the surgeon's initials. Patients were randomly selected to receive a chlorhexidine-based or an iodine-based skin preparation according to manufacturer guidelines. The skin markings were photographed digitally, before and after the application of solution. The photographs made after the application of solution were assessed quantitatively, by calculating the contrast (marker to skin) before and after the application of the solutions, and qualitatively by ten orthopaedic surgeons to identify the random initials and to recognize skin markings. RESULTS: The mean change in contrast level after application of the chlorhexidine-based solution was significantly greater than that after application of the iodine-based solution (mean and standard deviation, 59.8 +/- 15.7 U versus 14.9 +/- 11.4 U, respectively; p < 0.0001). Surgeons were an average of twenty-two times less likely (95% confidence interval, eight to sixty-eight) to judge markings as acceptable for site identification after preparation with the chlorhexidine-based solution than after preparation with the iodine-based solution. When examining individual letters, the surgeons correctly identified 296 of 300 letters in the group prepared with the iodine-based solution and 209 of 300 letters in the group prepared with the chlorhexidine based solution; the difference was significant (p < 0.0001). CONCLUSIONS: The use of the chlorhexidine-based solution for skin preparation resulted in significantly greater erasure of the surgical site marking than did the use of the iodine-based solution. PMID- 22257995 TI - Vacuum-assisted minimally invasive biopsy of soft-tissue tumors. AB - BACKGROUND: Although exact histological characterization of soft-tissue tumors is essential for determining the appropriate therapy, the quality of the histological assessment is often limited by the size of the tissue samples. Incisional biopsy and core needle biopsy have been the most effective techniques for obtaining tissue samples from soft-tissue tumors. This study was performed to investigate whether vacuum-assisted biopsy can serve as a new diagnostic tool for soft-tissue neoplasms. METHODS: This retrospective study compared the characterization made with use of vacuum-assisted biopsy of soft-tissue tumors in seventy-five patients between 2004 and 2006 and the characterization made with use of incisional biopsy of tumors in a comparison group of seventy-four patients between 2000 and 2005 with the final characterization made after radical tumor excision. All vacuum-assisted and incisional biopsies were performed by the same experienced surgeons and evaluated by the same experienced pathologists at a single tumor center. The sensitivity, specificity, positive and negative predictive values, and accuracy of the preliminary characterization made with use of each method were calculated on the basis of the final characterization made after excision. RESULTS: The vacuum-assisted biopsy procedure was performed successfully in seventy-four (99%) of the seventy-five patients. The accuracy of vacuum-assisted biopsy (96%) was comparable with that of incisional biopsy (99%). Vacuum-assisted biopsy correctly characterized the tumor as benign or malignant in 96% (95% confidence interval [CI], 92% to 100%) of the seventy-five patients compared with 99% (95% CI, 96% to 100%) of the seventy-four patients who underwent incisional biopsy. Vacuum-assisted biopsy correctly characterized the tumor diagnosis in 95% (95% CI, 90% to 100%) of the patients compared with 95% (95% CI, 89% to 100%) for incisional biopsy. Vacuum-assisted biopsy correctly characterized the tumor grade in 89% (95% CI, 82% to 96%) of the patients compared with 88% (95% CI, 80% to 95%) for incisional biopsy. The sensitivity of vacuum-assisted biopsy was 93% (95% CI, 71% to 100%), the specificity and the positive predictive value were both 100%, and the negative predictive value was 91% (95% CI, 85% to 98%). The overall accuracy of vacuum-assisted biopsy was 96% (95% CI, 92% to 100%). CONCLUSIONS: Vacuum-assisted biopsy appears to be safe and provides a new tool for the diagnosis of soft-tissue tumors. One advantage of vacuum-assisted biopsy is that it can be performed with use of local anesthesia in an outpatient setting. PMID- 22257996 TI - Indications and reoperation rates for total elbow arthroplasty: an analysis of trends in New York State. AB - BACKGROUND: Total elbow arthroplasty was originally used to treat patients with arthritis. As familiarity with total elbow arthroplasty evolved, the indications were expanded to include other disorders. There continues to be a low number of total elbow arthroplasties performed each year in comparison with hip, knee, and shoulder arthroplasties, and few large studies have examined the indications and associated complications of total elbow arthroplasty. The purposes of this study were to evaluate the changes with time in the indications for total elbow arthroplasty and to examine the complications of this procedure in a large database. METHODS: The Statewide Planning and Research Cooperative System database from the New York State Department of Health, a census of all ambulatory and inpatient surgical procedures in the state of New York, was used to identify individuals who underwent primary total elbow arthroplasty during the time period of 1997 to 2006. These total elbow arthroplasties were evaluated for admitting diagnoses, sex and age of patient, readmission and complication data, and time to subsequent elbow surgery. RESULTS: From 1997 to 2006, there were 1155 total elbow arthroplasties performed in New York State. In 1997, 43% of the total elbow arthroplasties were associated with trauma and 48%, with inflammatory conditions. In 2006, this changed to 69% and 19%, respectively. Within ninety days after the primary total elbow arthroplasty, 12% of the patients were readmitted to the hospital with approximately one-half (5.6%) admitted for problems related to the total elbow arthroplasty. The overall revision rate was 6.4%. The revision rates for the traumatic, inflammatory arthritis, and osteoarthritis groups were 4.8%, 8.3%, and 14.7%, respectively. Of particular interest, 90.5% of the total elbow arthroplasties were performed by surgeons with no recorded experience in the database, which began collecting these data in 1986. CONCLUSIONS: This study provides useful information regarding patients undergoing total elbow arthroplasty in New York State. During the study period, the most common indication for total elbow arthroplasty changed from inflammatory arthritis to trauma. Although the number of total elbow arthroplasties being performed each year has increased, there continues to be a high complication and revision rate. PMID- 22257997 TI - Skin sterility after application of ethyl chloride spray. AB - BACKGROUND: Ethyl chloride topical anesthetic spray is labeled as nonsterile, yet it is widely used during injection procedures performed in an outpatient setting. The purpose of this study was to investigate the sterility of ethyl chloride topical anesthetic spray applied before an injection. Our a priori hypothesis was that application of the spray after the skin has been prepared would not alter the sterility of the injection site. METHODS: We conducted a prospective, blinded, controlled study to assess the effect of ethyl chloride spray on skin sterility. Fifteen healthy adult subjects (age, twenty-three to sixty-one years) were prepared for mock injections into both shoulders and both knees, although no injection was actually performed. Three culture samples were obtained from each site on the skin: one before skin preparation with isopropyl alcohol, one after skin preparation and before application of ethyl chloride, and one after ethyl chloride had been sprayed on the site. In addition, the sterility of the ethyl chloride was tested directly by inoculating cultures with spray from the bottles. RESULTS: Growth occurred in 70% of the samples obtained before skin preparation, 3% of the samples obtained after skin preparation but before application of ethyl chloride, and 5% of the samples obtained after the injection site had been sprayed with ethyl chloride. The percentage of positive cultures did not increase significantly after application of ethyl chloride (p = 0.65). Spraying of ethyl chloride directly on agar plates resulted in growth on 13% of these plates compared with 11% of the control plates; this difference was also not significant (p = 0.80). CONCLUSIONS: Although ethyl chloride spray is not sterile, its application did not alter the sterility of the injection sites in the shoulder and knee. PMID- 22257998 TI - Development of knee function after hamstring lengthening as a part of multilevel surgery in children with spastic diplegia: a long-term outcome study. AB - BACKGROUND: Hamstring lengthening commonly is performed for the treatment of flexed knee gait in patients with spastic diplegic cerebral palsy. Satisfactory short-term results after hamstring lengthening have been demonstrated in various studies. However, evidence for the effectiveness of hamstring lengthening to correct flexed knee gait is scant because of small and inhomogeneous case series, different surgical techniques, and short follow-up. METHODS: The long-term results for thirty-nine patients with spastic diplegia and flexed knee gait who were managed with intramuscular hamstring lengthening as a part of multilevel surgery are presented. Standardized three-dimensional gait analyses and clinical examinations were performed for all patients preoperatively and at one, three, and six to twelve years postoperatively. RESULTS: Significant improvements in kinematic parameters and the popliteal angle were noted at short-term follow-up (p < 0.01), supporting the results of previous studies. Long-term results showed significant deterioration of minimum knee flexion in stance and the popliteal angle (p < 0.01), whereas the improvements in the Gross Motor Function Classification System and Gillette Gait Index were maintained. This recurrence of flexed knee gait is partial and measurable. Increased pelvic tilt was found in 49% of the limbs postoperatively, which may represent one factor leading to recurrence of flexed knee gait. Genu recurvatum was seen in eighteen patients (twenty-seven limbs; 35%) one year postoperatively, especially in the patients with a jump knee gait pattern preoperatively. At long-term follow-up, genu recurvatum resolved in many limbs, but 12% of the limbs showed residual genu recurvatum, indicating that overcorrection represents a problem following hamstring lengthening. CONCLUSIONS: The results of the present study are crucial for the prognosis of knee function after hamstring lengthening as a part of multilevel surgery. Recurrence and possible overcorrection should be considered in treatment planning. PMID- 22257999 TI - Hemi-contralateral C7 transfer in traumatic brachial plexus injuries: outcomes and complications. AB - BACKGROUND: In brachial plexus injuries with nerve root avulsions, the options for nerve reconstruction are limited. In select situations, half or all of the contralateral C7 (CC7) nerve root can be transferred to the injured side for brachial plexus reconstruction. Although encouraging results have been reported, CC7 transfer has not gained universal popularity. The purpose of this study was to critically evaluate hemi-CC7 transfer for restoration of shoulder function or median nerve function in patients with severe brachial plexus injury. METHODS: A retrospective review of all patients with traumatic brachial plexus injury who had undergone hemi-CC7 transfer at a single institution during an eight-year period was performed. Complications were evaluated in all patients regardless of the duration of follow-up. The results of electrodiagnostic studies and modified British Medical Research Council (BMRC) motor grading were reviewed in all patients with more than twenty-seven months of follow-up. RESULTS: Fifty-five patients with traumatic brachial plexus injury underwent hemi-CC7 transfer performed between 2001 and 2008 for restoration of shoulder function or median nerve function. Thirteen patients who underwent hemi-CC7 transfer to the shoulder and fifteen patients who underwent hemi-CC7 transfer to the median nerve had more than twenty-seven months of follow-up. Twelve of the thirteen patients in the shoulder group demonstrated electromyographic evidence of reinnervation, but only three patients achieved M3 or greater shoulder abduction motor function. Three of the fifteen patients in the median nerve group demonstrated electromyographic evidence of reinnervation, but none developed M3 or greater composite grip. All patients experienced donor-side sensory or motor changes; these were typically mild and transient, but one patient sustained severe, permanent donor-side motor and sensory losses. CONCLUSIONS: The outcomes of hemi-CC7 transfer for restoration of shoulder motor function or median nerve function following posttraumatic brachial plexus injury do not justify the risk of donor-site morbidity, which includes possible permanent motor and sensory losses. PMID- 22258000 TI - Mid-term results of third-generation alumina-on-alumina ceramic bearings in cementless total hip arthroplasty: a ten-year minimum follow-up. AB - BACKGROUND: Alumina ceramic-on-ceramic bearings have gained popularity in hip arthroplasty because of their properties of low wear and chemical inertness. In a previous study, we reported the excellent clinical results in a series of cementless ceramic-on-ceramic primary total hip arthroplasties at a minimum of five years of follow-up. The purpose of the present study was to determine the results in the same patient cohort at a minimum of ten years of follow-up. METHODS: A series of 301 consecutive primary cementless total hip arthroplasties was assessed clinically and radiographically. Clinical information was available for 244 hips in 227 surviving patients at a minimum of ten years of follow-up, and radiographic information was available for 184 hips in 172 patients. RESULTS: Twenty-six (9.2%) of the patients had died of an unrelated cause and eight (2.7%) had undergone revision arthroplasty by the time of the latest follow-up. The average Harris hip score was 94 points, with 95% (232) of the patients having an excellent or good result and <4% (nine) having moderate residual pain. All radiographic assessments showed evidence of stable osseous ingrowth. Nine revisions had been performed, including four femoral component revisions due to periprosthetic fracture, one femoral revision due to aseptic loosening, one femoral revision secondary to a femoral shortening osteotomy for nerve palsy, two acetabular cup revisions due to psoas tendinitis, and a repeat revision in one of the patients with psoas tendinitis due to acetabular osteolysis. The overall survival rate of the implants was 98% (95% confidence interval, 94.2% to 99.6%) at ten years with revision for any reason as the end point. CONCLUSIONS: The patients in our series had a good implant survival rate, good function, a low implant wear rate as reported in the previous study, and no further radiographic evidence of failure at ten years after cementless primary total hip arthroplasty with alumina ceramic-on-ceramic bearings. PMID- 22258001 TI - Patterns of loosening of polyethylene keeled glenoid components after shoulder arthroplasty for primary osteoarthritis: results of a multicenter study with more than five years of follow-up. AB - BACKGROUND: The aim of this study was to radiographically analyze the long-term glenoid migration patterns following total shoulder arthroplasty to better understand the factors responsible for loosening. METHODS: Complete radiographic follow-up of more than five years was available for 518 total shoulder arthroplasties performed for primary glenohumeral osteoarthritis with use of an anatomically designed prosthesis with a cemented, all-polyethylene, keeled glenoid component. Radiographs were assessed for humeral head subluxation, periprosthetic radiolucent lines, and shifting of the position of the glenoid component. The type of migration of the glenoid was defined according to the direction of tilt, or as subsidence in the case of medial migration. RESULTS: Definite radiographic evidence of glenoid loosening was observed in 166 shoulders (32%) and was characterized by radiolucency of >=2 mm over the entire bone-cement interface in thirty shoulders and by a migration of the glenoid component (shift or subsidence) in 136 shoulders. Three predominant patterns of migration of the glenoid component were observed: superior tilting in fifty-two shoulders (10%), subsidence in forty-one shoulders (7.9%), and posterior tilting in thirty-three shoulders (6.4%). Superior tilting of the glenoid was associated with three risk factors: low positioning of the glenoid component, superior tilt of the glenoid component on the immediate postoperative coronal plane radiographs, and superior subluxation of the humeral head (p < 0.05 for all). Subsidence of the glenoid component was associated with the use of reaming to optimize the seating and positioning of the glenoid component (p < 0.001). Posterior tilting of the glenoid component was associated with preoperative posterior subluxation (i.e., a Walch type-B glenoid) and with excessive reaming (p < 0.01 for both). CONCLUSIONS: The three patterns of migration observed in this study underscore the potential importance of the supporting bone beneath the glenoid component. In some shoulders, use of a keel or pegs to provide fixation of a polyethylene component in the absence of good support from subchondral bone may not be sufficient to resist compressive and eccentric forces, resulting in loosening. Preserving subchondral bone may be important for long-term longevity of the glenoid component. PMID- 22258002 TI - Twenty-three-year outcome of the porous coated anatomic total hip replacement: a concise follow-up of a previous report. AB - We previously reported the ten to fourteen-year results for 311 Porous Coated Anatomic total hip replacements that had been inserted by two surgeons in 279 patients. The purpose of the present report is to update that study and to report the outcome beyond twenty years. The patients were followed prospectively with clinical assessment with use of the Harris hip score and radiographic analysis, and the results were collected in a database. Two hundred and sixty-eight hips were functioning at the time of death or at the time of the latest follow-up. A total of forty-three hips (14%) underwent major revision for all causes, and an additional four hips underwent minor revision. At a mean of twenty-three years of follow-up, Kaplan-Meier analysis revealed a survival rate of 83% with revision for any reason as the end point. The survival rate was 95% for the femoral component and 88% for the acetabular component with revision for any reason as the end point. The rate of survival of the acetabular component was significantly higher in hips with a 26-mm femoral head than in those with a 32-mm femoral head (91% compared with 80%; p = 0.026). PMID- 22258003 TI - The natural progression of symptomatic humeral head osteonecrosis in adults with sickle cell disease. AB - BACKGROUND: Osteonecrosis of the humeral head is a frequent complication in adults with sickle cell disease. However, little is known about the rate of, and the factors influencing, progression of symptomatic shoulder osteonecrosis in patients with this disease. METHODS: Eighty-two adult patients with sickle cell disease and symptomatic osteonecrosis of the humeral head (104 shoulders) were identified with magnetic resonance imaging (MRI) between 1985 and 1993. Nineteen of the eighty-two patients were homozygous for hemoglobin S (S/S genotype), thirty-seven had hemoglobin S/hemoglobin C (S/C), and twenty-six had hemoglobin S/beta-thalassemia (S/T). Shoulder osteonecrosis was graded with the method of Cruess with an adaptation for MRI as proposed by Steinberg et al. for hip osteonecrosis. Annual radiographs were obtained. At the initial evaluation, thirty-eight symptomatic shoulders were designated as stage I (with osteonecrosis seen only on MRI), forty-two symptomatic shoulders were designated as stage II (radiographic evidence without collapse), and twenty-four symptomatic shoulders were designated as stage III or IV (a crescent line or collapse). RESULTS: Partial or total repair with a decrease in the size of the osteonecrotic lesion or in the stage was never observed on MRI. At the time of the most recent follow up (average, twenty years; range, fifteen to twenty-four years), collapse had occurred in eighty-nine shoulders (86%). The mean interval between the onset of pain and collapse was six years (range, six months to seventeen years; median, eight years). Of the 104 symptomatic shoulders, sixty-three (61%) with collapse worsened clinically until surgical treatment was needed. The principal risk factors for development of shoulder osteonecrosis in adults with sickle cell disease were the presence of hip osteonecrosis and the S/T or S/C genotype. The rate and risk of progression of the lesion until collapse occurred were significantly related to the S/S genotype, to a stage of II, to a large size of the osteonecrotic lesion, and to a medial or posterior location of the lesion. CONCLUSION: Untreated symptomatic shoulder osteonecrosis related to sickle cell disease has a high likelihood of progressing to humeral head collapse, and the natural evolution in the long term requires surgical treatment for many of these patients. PMID- 22258004 TI - American Academy of Orthopaedic Surgeons Clinical Practice Guideline on: optimizing the management of rotator cuff problems. PMID- 22258005 TI - Scaphoid fractures: what's hot, what's not. PMID- 22258006 TI - What's new in adult reconstructive knee surgery. PMID- 22258007 TI - Reaching optimal clarity on surgical site marking: commentary on an article by Savyasachi C. Thakkar, MD, and Simon C. Mears, MD, PhD: "Visibility of surgical site marking: a prospective randomized trial of two skin preparation solutions". PMID- 22258008 TI - Vacuum-assisted biopsy is useful for breast tissue, but how useful is it for soft tissue tumors in orthopaedics? Commentary on an article by Zarah Mohr, MD, et al.: "Vacuum-assisted minimally invasive biopsy of soft-tissue tumors". PMID- 22258009 TI - Observations on the epidemiology of total elbow arthroplasties in a statewide database: is it time for a national U.S. joint registry? Commentary on an article by David M. Gay, MD, et al.: "Indications and reoperation rates for total elbow arthroplasty: an analysis of trends in New York State". PMID- 22258010 TI - Does every question need a level-I answer? Pragmatic and ethical considerations of clinical practice guidelines: commentary on an article by Robert A. Pedowitz, MD, PhD, et al.: "American Academy of Orthopaedic Surgeons Clinical Practice Guideline on optimizing the management of rotator cuff problems". PMID- 22258011 TI - Quality guidelines need evidence, not opinion: commentary on an article by Robert A. Pedowitz, MD, PhD, et al.: "American Academy of Orthopaedic Surgeons Clinical Practice Guideline on optimizing the management of rotator cuff problems". PMID- 22258013 TI - Digital artery pseudoaneurysm following percutaneous trigger thumb release: a case report. PMID- 22258014 TI - Delayed radial nerve palsy caused by pin migration in a surgically treated proximal humeral fracture: a case of axonamonosis: a case report. PMID- 22258015 TI - Introducing arthroscopy to a developing nation: when and how to make it sustainable. PMID- 22258016 TI - The uneven distribution of women in orthopaedic surgery resident training programs in the United States. AB - BACKGROUND: Although women represented 58% of undergraduate students and 48% of medical students in the U.S. in the 2008-2009 academic year, only 13% of orthopaedic residents and only 4% of American Academy of Orthopaedic Surgeons (AAOS) Fellows in 2009 were women. Are all orthopaedic surgery programs in the U.S. equal in their ability to attract female medical students and train female orthopaedic surgeons? This study was undertaken to test the hypothesis that all Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic surgery residency programs in the U.S. train a similar number of female residents. METHODS: Data for all ACGME-accredited orthopaedic surgery residency training programs in the U.S. for five academic years (2004-2005 through 2008-2009) were collected with use of the Graduate Medical Education (GME) Track database. RESULTS: Orthopaedic residency programs in the U.S. do not train women at an equal frequency. In the academic years from 2004-2005 through 2008-2009, forty-five programs had no female residents during at least one of the five academic years reviewed, and nine programs had no female residents during any of the years. More than fifty orthopaedic residency programs in the U.S. had an average of <10% female trainees over the five-year period, and more than ten programs had an average of >20%. There was no significant change in the distribution among these categories over the five years examined (p = 0.234). CONCLUSIONS: Significant differences in the representation of women exist among orthopaedic residency training programs in the U.S. Further examination of the characteristics of orthopaedic residency programs that are successful in attracting female residents, particularly the composition of their faculty as role models, will be important in furthering our understanding of how orthopaedic surgery can continue to attract the best and the brightest individuals. Changes in the cultural experiences in programs that have not trained female orthopaedic surgeons, such as an increased number of female faculty, and policies that emphasize diversity may provide a greater opportunity for our orthopaedic profession to attract female medical students. PMID- 22258017 TI - Decomposition of CO2 to carbon and oxygen under mild conditions over a zinc modified zeolite. AB - An electron-rich zinc-modified zeolite Y material shows substantial activity for the decomposition of CO(2) to carbon with the release of O(2) at about 300 degrees C. It is elucidated that electrons delocalized in the vicinity of zinc cations in the zeolite material play an essential role in the decomposition reaction. PMID- 22258018 TI - Reconstructing deconstructed blood for trauma. PMID- 22258019 TI - Optic nerve sheath diameter used as ultrasonographic assessment of the incidence of raised intracranial pressure in preeclampsia: a pilot study. AB - BACKGROUND: In some cases of severe preeclampsia/eclampsia, brain imaging displays signs compatible with raised intracranial pressure. We aimed to estimate the incidence of raised intracranial pressure in preeclampsia using ocular ultrasonography. METHODS: Optic nerve sheath diameter (ONSD) measurements were compared in 26 preeclamptic and 25 healthy pregnant women. For each optic nerve, two measurements were made (transverse plane and sagittal plane) using a 7.5 MHz ultrasound linear probe. Preeclamptic patients were followed-up until postpartum day 7. RESULTS: Median ONSD values were significantly greater in preeclamptic patients compared with healthy pregnant women at delivery (5.4 mm (95% CI: 5.2, 5.7) vs. 4.5 mm (95% CI: 4.3, 4.8), P < 0.0001). At delivery, 5/26 (19%) of preeclamptic patients had ONSD values above 5.8 mm (value associated in the literature with 95% risk of raised intracranial pressure) whereas none of the healthy pregnant group had such high ONSD values. In the preeclamptic group, ONSD decreased after the third postpartum day. ONSD values at day 7 were not significantly different from those obtained in the normal pregnancy group (P = 0.10). CONCLUSION: In about 20% of preeclamptic patients, ONSD reaches values compatible with intracranial pressure above 20 mmHg. Further work is needed to confirm this incidence and to better understand the diagnostic and therapeutic usefulness of this easy-to-do monitoring technique. PMID- 22258020 TI - Surgery and the plastic brain. PMID- 22258021 TI - Neurotoxicity and the need for anesthesia in the newborn: does the emperor have no clothes? PMID- 22258022 TI - Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice. AB - In male coupling factor 6 (CF6)-overexpressing transgenic (TG) mice, a high-salt diet induces hypertension and cardiac systolic dysfunction with excessive reactive oxygen species generation. However, the role of gender in CF6-mediated pathophysiology is unknown. We investigated the effects of ovariectomy and estrogen replacement on hypertension, cardiac dysfunction and Rac1 activity, which activates radical generation and the mineralocorticoid receptor, in female TG mice. Fifteen-week-old male and female TG and wild-type (WT) mice were fed a normal- or high-salt diet for 60 weeks. Systolic and diastolic blood pressures were higher in the TG mice fed a high-salt diet than in those fed a normal-salt diet at 20-60 weeks in males but only at 60 weeks in females. The blood pressure elevation under high-salt diet conditions was concomitant with a decrease in left ventricular fractional shortening. In the WT mice, neither blood pressure nor cardiac systolic function was influenced by a high-salt diet. In the female TG mice, bilateral ovariectomy induced hypertension with cardiac systolic dysfunction 8 weeks after the initiation of a high-salt diet. The ratios of Rac1 bound to guanosine triphosphate (Rac1-GTP) to total Rac1 in the heart and kidneys were increased in the ovariectomized TG mice, and estrogen replacement abolished the CF6-mediated pathophysiology induced under the high-salt diet conditions. The overexpression of CF6 induced salt-sensitive hypertension, complicated by systolic cardiac dysfunction, but its onset was delayed in females. Estrogen has an important role in the regulation of CF6-mediated pathophysiology, presumably via the downregulation of Rac1. PMID- 22258023 TI - 'Memory' and 'legacy' in hypertension and lifestyle-related diseases. PMID- 22258024 TI - Mechanistic insights into the antifibrotic activity of aliskiren in the kidney. PMID- 22258026 TI - Eosinophils: a new player in coronary atherosclerotic disease. PMID- 22258025 TI - Decreased glomerular filtration rate is a significant and independent risk for in hospital mortality in Japanese patients with acute myocardial infarction: report from the Hokkaido acute myocardial infarction registry. AB - Renal dysfunction is a significant risk factor in the prognosis of patients with cardiovascular diseases. We sought to determine the relationship between estimated glomerular filtration rate (eGFR) values and in-hospital mortality in Japanese acute myocardial infarction (AMI) patients. A total of 2266 consecutive AMI patients admitted to 22 hospitals in Hokkaido were registered. The eGFR values were determined using the following equation: eGFR=194 * (serum creatinine)(-1.094) * (age)(-0.287) ( * 0.739 if female). Patients were classified into four groups according to their eGFR values: >=60 (n=1304), 30-59 (n=810), 15-29 (n=87) and <15 ml min(-1) per 1.73 m(2) (n=65). A total of 110 patients (4.9%) died during hospitalization. The in-hospital mortality rate was significantly higher in patients with reduced eGFR values at 2.3, 5.4, 24.1 and 23.1% for eGFR values of >=60, 30-59, 15-29, and <15 ml min(-1) per 1.73 m(2), respectively. The odds ratios for in-hospital all cause death were 8.26 (95% confidence interval (CI): 2.22-30.77) for eGFR<15 ml min(-1) per 1.73 m(2) and 3.42 (95% CI: 1.01-11.61) for eGFR 15-29 ml min(-1) per 1.73 m(2) compared with eGFR >=60 ml min(-1) per 1.73 m(2). Similarly, the odds ratios for in-hospital cardiac death were 8.43 (95% CI: 1.82-39.05) for eGFR<15 ml min(-1) per 1.73 m(2) and 5.47 (95% CI: 1.51-19.80) for eGFR 15-29 ml min(-1) per 1.73 m(2). In conclusion, the eGFR of <30 ml min(-1) per 1.73 m(2) was a significant and independent risk for in-hospital mortality in abroad cohort of Japanese patients with AMI. PMID- 22258027 TI - A common variant of the ABO gene protects against hypertension in a Spanish population. AB - The objective of this study was to establish whether genetic polymorphisms that could be related to angiotensin-converting enzyme (ACE) levels are associated with hypertension. A total of 10 haplotype-tagging single-nucleotide polymorphisms in ACE, the ACE I/D polymorphism, and 2 polymorphisms in the ABO (rs495828 and rs8176746) were investigated for association with hypertension in 269 hypertensive patients and 254 healthy controls. All analyses were adjusted for age and body mass index, and corrected for multiple testing. Only one polymorphism of the ABO gene (rs495828) presented nominal pointwise P<0.05 values (odds ratio = 0.33, 95% CI 0.19-0.58, P = 6 * 10(-5)) and achieved P<3.8 * 10( 3), the nominal P-value considered significant after Bonferroni correction. Analysis of the genotype frequencies showed that the model that correctly explained the observed association was the recessive model (odds ratio = 0.03, 95% CI 0.01-0.15, P = 1 * 10(-6)). These results indicate that genetic variants that could be related to ACE activity are good predictors of hypertension, and identify ABO as a good candidate gene for genetic studies of hypertension risk. Further studies are required to confirm this association. PMID- 22258028 TI - E-selectin gene and essential hypertension. PMID- 22258029 TI - Pre(peri)-natal omega-3 PUFA deficiency-induced hypertension and its broader implications. PMID- 22258030 TI - Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis. AB - Activation of the renin-angiotensin system (RAS) is thought to promote myocardial fibrosis. However, it is unclear whether this physiological fibrotic response results from chronic hemodynamic stress or from direct cellular signaling. Male C57B/6 mice were randomly assigned to receive angiotensin II (AngII) (2.0 MUg kg( 1) min(-1)), AngII+hydralazine (6.9 MUg kg(-1) min(-1)) or saline (control) via osmotic pumps for 7 days. Blood pressure was measured via noninvasive plethysmography. Hearts were harvested and processed for analysis. Cellular infiltration and collagen deposition were analyzed using histological staining. Molecular mediators were assessed using quantitative RT-PCR. As previously described, animals that received AngII developed hypertension and multifocal cellular infiltration by SMA(+)/CD133(+) fibroblast progenitors followed by collagen deposition. The coadministration of hydralazine with AngII completely inhibited the hypertensive effects of AngII (P?0.01) and resulted in minimal cellular infiltration and minimal collagen deposition. These findings were in the context of persistent RAS activation, which was evidenced by elevation in serum aldosterone levels in animals that received AngII or AngII+hydralazine compared with animals that received saline. At the molecular level, infusion of AngII resulted in the significant upregulation of profibrotic factors (connective tissue growth factor-7.8+/-0.7 fold), proinflammatory mediators (TNFalpha-4.6+/ 0.8 fold; IL-1beta-6.4+/-2.6 fold) and chemokines (CCL2-3.8+/-1.0 fold; CXCL12 3.2+/-0.4 fold), which were inhibited when hydralazine was also infused. We provide evidence that myocardial infiltration by fibroblast progenitor cells secondary to AngII and the resultant fibrosis can be prevented by the addition of hydralazine. Furthermore, the beneficial effects of hydralazine were observed while maintaining RAS activation, suggesting that the mechanism of fibrosis is blood pressure dependent. PMID- 22258032 TI - Towards sustainable integrated watershed ecosystem management: a case study in Dingxi on the loess plateau, China. AB - The Chinese government initiated a massive conservation program called "Grain-for Green" in 1999 to reduce soil erosion and improve ecosystem function. Implementing practical sustainable development in the loess plateau still remains problematic, particularly in its eco-fragile areas. Here we discussed an approach for sustainable development at the watershed scale by integrating land use suitability, ecosystem services and public participation in the loess hilly area. We linked land use scenario analysis and economic modeling to compare the outcomes of three scenarios, CLU (Current Land Use), GOLU (Grain-production Oriented Land Use) and PSLU (Potential Sustainable Land Use). The results indicated that compared to PSLU, GOLU may provide a higher economic productivity in the short-term, but not in the long-term. CLU ranked lowest in terms of economic benefits and did not meet the daily needs of the local farmers. To reconcile the land use adjustments with farmers' basic needs, a labor-saving land use strategy is necessary. Since the PSLU scenario assumes that slope cropland should be converted to pastures or orchards, more time may be available for off farm work and for more public participation in integrated ecosystem management. Financial support to the local farmers for environmental conservation should be modulated in function of their positive contribution to ecosystem management. PMID- 22258033 TI - Restless legs syndrome--theoretical roles of inflammatory and immune mechanisms. AB - Theories for restless legs syndrome (RLS) pathogenesis include iron deficiency, dopamine dysregulation and peripheral neuropathy. Increased prevalence of small intestinal bacterial overgrowth (SIBO) in controlled studies in RLS and case reports of post-infectious RLS suggest potential roles for inflammation and immunological alterations. A literature search for all conditions associated with RLS was performed. These included secondary RLS disorders and factors that may exacerbate RLS. All of these conditions were reviewed with respect to potential pathogenesis including reports of iron deficiency, neuropathy, SIBO, inflammation and immune changes. A condition was defined as highly-associated if there was a prevalence study that utilized an appropriate control group. Small case reports were recorded but not included as definite RLS-associated conditions. Fifty four diseases, syndromes and conditions have been reported to cause and/or exacerbate RLS. Of these, 38 have been reported to have a higher prevalence than age-matched controls, 9 have adequate sized reports and have general acceptance as RLS associated conditions and 7 have been reported in case report form. Overall, 42 of the 47 RLS-associated conditions (89%) have also been associated with inflammatory and/or immune changes. In addition, 43% have been associated with peripheral iron deficiency, 40% with peripheral neuropathy and 32% with SIBO. Most of the remaining conditions have yet to be studied for these factors. The fact that 95% of the 38 highly-associated RLS conditions are also associated with inflammatory/immune changes suggests the possibility that RLS may be mediated or affected through these mechanisms. Inflammation can be responsible for iron deficiency and hypothetically could cause central nervous system iron deficiency induced RLS. Alternatively, an immune reaction to gastrointestinal bacteria or other antigens may hypothetically cause RLS by a direct immunological attack on the central or peripheral nervous system. PMID- 22258034 TI - Vasculogenic mimicry and its clinical significance in medulloblastoma. AB - Vasculogenic mimicry (VM), a process involving the formation of a tubular structure by highly invasive and genetically dysregulated tumor cells, can supplement the function of blood vessels to transport nutrients and oxygen to maintain the growth of tumor cells in many malignant tumors. We aimed to explore the existence of VM and its clinical significance in medulloblastoma in this study. VM was identified in 9 out of 41 (22%) medulloblastoma tissues. Immunohistochemical studies revealed that the presence of VM was associated with the expression of MMP-2, MMP-14, EphA2 and laminin 5gamma2. Tumor tissues with VM were associated with lower microvessel density (MVD), which was indirect evidence of the blood supply function of VM. Survival analysis and log-rank tests showed that patients with VM had shorter overall survival time than those without VM. Multivariate analysis and the Cox proportional hazards model identified VM as independent prognostic factor for overall survival. Our results confirmed the existence of VM for the first time and revealed that VM is a strong independent prognostic factor for survival in patients with medulloblastoma. PMID- 22258035 TI - Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype. AB - There has been considerable interest in targeting cell cycle checkpoints particularly in emerging and alternative anticancer strategies. Here, we show that checkpoint abrogation by AZD7762, a potent and selective CHK1/2 kinase inhibitor enhances genotoxic treatment efficacy in immature KG1a leukemic cell line and in AML patient samples, particularly those with a complex karyotype, which display major genomic instability and chemoresistance. Furthermore, these data suggest that constitutive DNA-damage level might be useful markers to select AML patients susceptible to receive checkpoint inhibitor in combination with conventional chemotherapy. Moreover, this study demonstrates for the first time that AZD7762 inhibitor targets the CD34(+)CD38(-)CD123(+) primitive leukemic progenitors, which are responsible for the majority of AML patients relapse. Finally, CHK1 inhibition does not seem to affect clonogenic potential of normal hematopoietic progenitors. PMID- 22258036 TI - Effects of bisphenol A exposure on the proliferation and senescence of normal human mammary epithelial cells. AB - The carcinogenic activity of bisphenol A (BPA) is responsible for stimulating growth in estrogen-dependent breast cancer tissues, cell lines and rodent studies. However, it is not fully understood how this compound promotes mammary carcinogenesis. In our study, we examined the effect of BPA on cellular proliferation and senescence in human mammary epithelial cells (HMEC). Exposure to BPA for 1 week at the early stage at passage 8 increased the proliferation and sphere size of HMEC at the later stage up to passage 16, suggesting that BPA has the capability to modulate cell growth in breast epithelial cells. Interestingly, the number of human heterochromatin protein-1gamma positive cells, which is a marker of senescence, was also increased among BPA-treated cells. Consistent with these findings, the protein levels of both p16 and cyclin E, which are known to induce cellular senescence and promote proliferation, respectively, were increased in BPA-exposed HMEC. Furthermore, DNA methylation levels of genes related to development of most or all tumor types, such as BRCA1, CCNA1, CDKN2A (p16), THBS1, TNFRSF10C and TNFRSF10D, were increased in BPA-exposed HMEC. Our findings in the HMEC model suggested that the genetic and epigenetic alterations by BPA might damage HMEC function and result in complex activities related to cell proliferation and senescence, playing a role in mammary carcinogenesis. PMID- 22258037 TI - A patient with aortic stenosis and angina pectoris. PMID- 22258038 TI - [Does antibiotherapy prevent unnecessary prostate biopsies in patients with high PSA values?]. AB - INTRODUCTION: We investigated if antibiotherapy has any role on total PSA (tPSA), free PSA (fPSA) and fPSA/tPSA ratio in patients with tPSA higher than 2.5ng/ml. We also analyzed if it has any relation with prostate cancer diagnosis rate. MATERIAL AND METHODS: A total 108 patients older than 50 years of age with lower urinary system sypmtoms and tPSA >2.5ng/ml were included in this study. Antibiotherapy was given to all the cases for three weeks. After that, transrectal ultrasound-guided prostate biopsies were taken from all the patients. Before and after antibiotherapy, "The International Prostate Symptom Score" (IPSS) and "National Institutes of Health Chronic Prostatitis Symptom Index" (NIH CPSI) questinories are performed and serum tPSA, fPSA and fPSA/tPSA values were obtained. RESULTS: TPSA, fPSA and fPSA/tPSA ratio alterations prior to and after antibiotherapy did not show any statistically significant difference (p>0.05). When prostate adenocarcinoma was excluded, an statistically significant decrease was found in IPSS and NIH-CPSI scores for all cases. CONCLUSIONS: Antibiotherapy given to patients with PSA levels higher than threshold value has not led to significant change in prostate needle biopsy decision. Prostate biopsy should be considered without trying antibiotherapy in patients with high PSA values if a suspicion of prostatitis does not exist. PMID- 22258039 TI - Safety profile of phenobarbital: can meta-analyses tell us the truth? PMID- 22258040 TI - Lessons learned from a comparison of language localisation using fMRI and electrocortical mapping: case studies of neocortical epilepsy patients. AB - Electrocortical mapping (ECM) is recognised as an established method for localisation of eloquent cortex in patients undergoing resective surgery for epilepsy management. Functional MRI (fMRI) has been utilised for language and other cortical function localisation. We describe language localisation in two patients using both ECM and fMRI. Co-registration of fMRI and ECM revealed that although two fMRI tasks localised multiple language areas, the verb generation task had an advantage over the semantic decision/tone decision task in that there was a clear overlap between the language areas identified by the verb generation task and ECM. In addition to the language areas detected by ECM, fMRI showed other language-related areas that may be important for post-operative language outcome. Therefore, fMRI may provide additional and complementary information to ECM in presurgical evaluation of patients with epilepsy. The correlation between fMRI and ECM may depend on the language testing methods utilised during the procedures. PMID- 22258041 TI - Montreal Cognitive Assessment in cryptogenic epilepsy patients with normal Mini Mental State Examination scores. AB - This cross-sectional study examined the Montreal Cognitive Assessment (MoCA) performance in cryptogenic epileptic patients aged more than 15 years with normal global cognition according to the Mini-Mental State Examination (MMSE) score. We tested our hypothesis that the prevalence of mild cognitive impairment and associated patient correlation factors might be increased (score < 26) according to the MoCA, in spite of a normal MMSE score, and that cognitive impairment might occur in a range of domains of the MoCA. Eighty-five patients participated in this study. The mean MoCA score was 22.44 (+/- 4.32). In spite of a normal MMSE score, which was an inclusion criterion, cognitive impairment was detected in 60% patients based on the MoCA score. The variable that correlated with a higher risk of cognitive impairment was the number of antiepileptic drugs (polytherapy: OR 2.71; CI 1.03-7.15). The mean scores of visuospatial and executive function, naming ability, attention, language, abstraction, delayed recall and orientation among patients with mild cognitive impairment were significantly lower than those of patients with normal cognitive function. These findings suggest that mild cognitive impairment in cryptogenic epileptic patients is common. We suggest using MoCA as a screening test for patients with epilepsy. PMID- 22258042 TI - Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients with refractory epilepsies. AB - AIM: We discuss the effectiveness, tolerability, and safety of vagus nerve stimulation (VNS) as adjunctive therapy in 64 paediatric patients with refractory epilepsies. MATERIALS AND METHODS: Sixty-four patients (34 male and 30 female) implanted with VNS for refractory epilepsy were analysed. Electroclinical features were compatible with Lennox-Gastaut syndrome in 46 patients, focal epilepsies in 10 patients, Dravet syndrome in three patients, epilepsy with myoclonic-astatic seizures in three patients, and West syndrome in two. The NeuroCybernetic Prosthesis (NCP) system (Cyberonics, Webster, TX, USA) was employed and the following stimulation parameters were used: output current of 1 to 2.5mA, signal frequency of 30Hz, signal pulse width of 500MUs, and signal "on" and "off" times of 30 seconds and 5 minutes, respectively. RESULTS: Of 46 patients with LGS, 30 cases showed a significant improvement in seizure control, with a reduction in seizure frequency of at least 50%. Ten patients with focal epilepsy, three patients with myoclonic-astatic seizures, two patients with Dravet, and two patients with West showed a significant improvement in seizure control, with a reduction in seizure frequency of at least 50%. A good clinical response was evident early and efficacy progressively improved with the duration of treatment up to 36 months. In a significant number of patients, reduced seizure severity and shorter recovery time and hospital stay were also observed. VNS was well tolerated in all patients. CONCLUSION: VNS is an effective and well tolerated treatment for paediatric patients with refractory epilepsies, improving quality of life and neuropsychological performance. PMID- 22258043 TI - Reflex seizures in Rett syndrome. AB - Reflex seizures are a rare phenomenon among epileptic patients, in which an epileptic discharge is triggered by various kinds of stimuli (visual, auditory, tactile or gustatory). Epilepsy is common in Rett syndrome patients (up to 70%), but to the authors' knowledge, no pressure or eating-triggered seizures have yet been reported in Rett children. We describe three epileptic Rett patients with reflex seizures, triggered by food intake or proprioception. One patient with congenital Rett Sd. developed infantile epileptic spasms at around seven months and two patients with classic Rett Sd. presented with generalised tonic-clonic seizures at around five years. Reflex seizures appeared when the patients were teenagers. The congenital-Rett patient presented eating-triggered seizures at the beginning of almost every meal, demonstrated by EEG recording. Both classic Rett patients showed self-provoked pressure -triggered attacks, influenced by stress or excitement. Non-triggered seizures were controlled with carbamazepine or valproate, but reflex seizures did not respond to antiepileptic drugs. Risperidone partially improved self-provoked seizures. When reflex seizures are suspected, reproducing the trigger during EEG recording is fundamental; however, self-provoked seizures depend largely on the patient's will. Optimal therapy (though not always possible) consists of avoiding the trigger. Stress modifiers such as risperidone may help control self-provoked seizures. PMID- 22258044 TI - Analysis of acylcarnitine levels by tandem mass spectrometry in epileptic children receiving valproate and oxcarbazepine. AB - This prospective study was designed to investigate whether or not monotherapy with sodium valproate (VPA) or oxcarbazepine (OXC) affects plasma levels of fatty acylcarnitine esters in children with epilepsy. A total of 56 children with idiopathic partial or generalised epilepsy were included in the study. Patients were assigned to receive either VPA or OXC monotherapy. Free carnitine (C0) and acylcarnitine profiles of the patients were investigated using tandem mass spectrometry at baseline and at six and 18 months after commencement of therapy. For patients receiving VPA or OXC monotherapy, there were no significant differences in plasma levels of C0, compared with baseline, at six and 18 months (p>0.05). Treatment with VPA for six and 18 months correlated with a significant increase in 3-hydroxy-isovalerylcarnitine (C5-OH) (six months: +23%; 18 months: +73%), and significant decreases in the following acylcarnitines: C6 acylcarnitine (six months: -60%; 18 months: -66%), C14-acylcarnitine (six months: -25%; 18 months: -38%), C16-acylcarnitine (six months: -73%; 18 months: -73%), and C18:1-OH-acylcarnitine (six months: -60%; 18 months: -70%), compared with baseline (p<0.05). In patients receiving OXC monotherapy, on the other hand, plasma concentrations (MUmol/L) of acylcarnitines (from C2 to C18:1-OH) fell within the normal reference range. The results of this study indicate that there are significant biochemical changes in acylcarnitines in ambulatory children on VPA monotherapy but these are not clinically significant. OXC monotherapy had no effect on acylcarnitine metabolism in ambulatory children. PMID- 22258045 TI - Seizures as a manifestation of multiple sclerosis. AB - The incidence of seizures is generally accepted to be greater in patients with multiple sclerosis (MS) than in the general population, and rarely, MS can initially present as seizure. To present a case report of seizure as the initial symptom of MS, to quantify the occurrence of seizures among MS patients, and to classify patients according to when seizures occur relative to onset of MS. The medical history of patients presenting with MS and seizure in our clinic was examined. In addition, 25 scientific papers were reviewed and the number and characteristics of patients with MS and seizure recorded. Data from the literature review and from our own clinical series were combined and examined. Of the MS patients, 1.95% experienced seizures at any time during life. Patients experiencing seizures before MS diagnosis were classified into three categories: (a) 25 (7.3% of patients with MS and seizures) with seizure as the initial presentation of MS; (b) 27 (7.9%) with seizures appearing with other signs and symptoms of MS; and (c) 68 (20%) with seizures occurring years or an unknown period of time before MS onset. Seizure occurring as a symptom of MS relapse was found in 29 patients. The prevalence of seizures among MS patients was higher than that in the general population, indicating a relationship between seizures and MS. Seizures occurred before MS diagnosis in a small percentage of patients. PMID- 22258046 TI - Early-onset childhood absence epilepsy: is it a distinct entity? AB - Childhood absence epilepsy (CAE) typically starts between four and seven years of age. Onset before three years is rare and has not been previously reported from North America. We retrospectively reviewed the electroencephalography laboratory database and paediatric neurology clinic records (from January 2000 to June 2009) at our institution in order to identify patients with absence seizures beginning before age three. Information was collected for age, gender, neurodevelopment, antiepileptic drugs (AEDs) used, seizure control, follow-up, and side effects. Of 12 patients identified, mean age at onset was 20.5 months (range: 11 months to two years; follow-up: six months to 11 years). Seven of 12 patients had normal neurodevelopment and five had speech delay. Four patients were seizure-free without AEDs, three were seizure-free with a single AED, and five still had seizures with multiple AEDs. Three patients had recurrences after medication withdrawal. Other previously published series have identified better seizure control than that reported here, however, 16% of the 130 patients so far documented are reported to have poorly controlled epilepsy, indicating that early onset CAE is not a homogeneous condition. The debate as to whether early-onset CAE is a distinct epilepsy syndrome therefore continues. We believe that early onset CAE may be a distinct epilepsy syndrome, with some features that overlap with those of typical CAE, as well as unique distinguishing features. Large prospective multicentric studies would be necessary to definitely resolve this matter. PMID- 22258047 TI - Early-onset absence epilepsy at eight months of age. AB - Early-onset absence epilepsy refers to patients with absence seizures beginning before age four and comprises a heterogeneous group of epilepsies. Onset of absence seizures in the first year of life is very rare. We report a girl with intractable absence seizures with onset at age eight months. Her seizures were characterised by loss of responsiveness, with eyes drifting upwards and some myoclonic jerks of the upper and lower limbs. These symptoms were accompanied by bilaterally symmetric high-amplitude 2-2.5 Hz generalised spike-and-wave discharges on the electroencephalogram. Her seizures were refractory to conventional antiepileptic drugs; treatment with adrenocorticotropic hormone was transiently effective. Comprehensive metabolic screening, cytogenetic, and genetic analysis did not determine an underlying cause of her condition. Patients with intractable, very early-onset absence epilepsy with a myoclonic component have an unfavourable outcome and may be classified under a new epileptic syndrome, such as "early infantile absence epilepsy". PMID- 22258048 TI - Limited resection of focal cortical dysplasia and associated epileptogenic cortex may lead to positive surgical outcome. AB - A drug-resistant epilepsy patient with premotor type IIb focal cortical dysplasia is described with a positive postoperative outcome following partial resection of the lesion and epileptogenic zone. Presurgical fMRI of the sensorimotor areas showed haemodynamic responses over the posterior border of the lesion and ictal EEG-fMRI revealed activation of both the primary sensorimotor strip and premotor lesion area. Almost continuous 1-2 Hz interictal spiking was recorded during a chronic ECoG study over the primary sensorimotor cortex. Following partial resection of the lesion, an acute ECoG revealed marked reduction of epileptic activity over the sensorimotor area. Post-operatively, seizure control was significantly improved (class IV ILAE outcome). Although partial FCD resections predict a worse postoperative outcome, individual patients may still respond favourably. The type of lesion, resected portion, and histopathology may be included among factors related to successful outcome. PMID- 22258049 TI - Intracranial localisation of ictal urinary urge epileptogenic zone to the non dominant temporal lobe. AB - Ictal urinary urge is a rare symptom of focal epilepsy usually localising to the non-dominant hemisphere, specifically, the temporal lobe. Lateralisation in previously described cases has been established using scalp video-EEG monitoring or functional imaging. We report the case of a 19-year-old girl with refractory epilepsy and ictal urinary urge arising from the non-dominant temporal lobe, confirmed by invasive, subdural EEG monitoring. Since undergoing a temporal lobectomy two and a half years ago, the patient has not experienced ictal urinary urge. To our knowledge, this is the first report demonstrating localisation of ictal urinary urge epileptogenic zone to the non-dominant temporal lobe by invasive intracranial monitoring. PMID- 22258050 TI - Mirth and laughter elicited during brain stimulation. AB - There are few reports of laughter and/or mirth evoked by electrical stimulation of the brain. In this study, we present a patient with intractable epilepsy in whom mirth and laughter was consistently produced during stimulation of the left inferior frontal gyrus (opercular part) using stereotactically placed depth electrodes. A review of the literature shows that cortical sites that produce mirth when stimulated are located in the dominant hemisphere close to language areas or cortical negative motor areas. PMID- 22258051 TI - Coexistence of two distinct benign EEG variants in the same subject. AB - Rhythmic temporal theta bursts of drowsiness (RTTD), also known as "psychomotor variant", and subclinical rhythmic EEG discharge of adults (SREDA) are two EEG patterns of uncertain significance that occur without any correlation with epilepsy. Each of these patterns has been described to occur alone and in the literature there are no previous reports of co-occurrence of the two distinct benign EEG variants in the same patient. We describe the coexistence of RTTD and SREDA in EEG recordings from the same subject. Although the coexistence of two distinct EEG variants in the same patient is a rarity, these patterns are not so infrequently encountered when present alone and should thus be promptly recognised in order to avoid misdiagnosis of epilepsy due to an over interpretation of normal sharp patterns. PMID- 22258052 TI - Serial EEG and MRI changes in status epilepticus-induced excitotoxic neuronal necrosis. AB - Prolonged status epilepticus may directly cause selective neuronal necrosis due to excitotoxic mechanisms, as observed in experimental models and described in case reports. A 36-year-old woman presented with right hemiplegia and aphasia following a generalised tonic-clonic status epilepticus of two hours duration. Accompanying serial MRI with advanced imaging techniques, EEG and histopathology of the cortical tissue of the patient were all compatible with excitotoxic neuronal necrosis. In this histopathologically-proven rare case of status epilepticus-induced excitotoxic neuronal injury, the observation of delayed cortical laminar necrosis on MRI, together with paroxysmal lateralised epileptiform discharges on the EEG, suggests that these changes may be an early sign of impending and ongoing excitotoxic neuronal injury and delayed cell death caused by glutamate release due to excessive neuronal firing in status epilepticus. PMID- 22258053 TI - aPTT prolongation and skin eruption possibly associated with lamotrigine monotherapy in a paediatric patient. AB - We report the case of a six-year-old female with childhood absence epilepsy who developed combined aPTT prolongation, not corrected by normal plasma, and atypical skin eruption six months after initiating lamotrigine treatment with dose increment. Two weeks after lamotrigine withdrawal, the skin eruption disappeared and aPTT normalised. To our knowledge, this is the first report of aPTT prolongation possibly due to factor inhibitors associated with lamotrigine monotherapy. PMID- 22258054 TI - Seizure or migraine? The eternal dilemma. Comment on: "recurrent occipital seizures misdiagnosed as status migrainosus". PMID- 22258055 TI - Knocking-in the R142C mutation in transglutaminase 1 disrupts the stratum corneum barrier and postnatal survival of mice. AB - BACKGROUND: Mutations in the gene encoding transglutaminase 1 (TG1) are responsible for various types of autosomal recessive congenital ichthyosis (ARCI), such as lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) and some minor variants of ARCI. A point mutation of R143C in the beta sandwich domain of TG1 has been often identified in patients with LI or CIE. OBJECTIVE: To elucidate the effect of that point mutation on skin barrier structures and functions, we generated mice with a point mutation of R142C, which corresponds to the R143C mutation in human TG1. METHODS: A mouse line with the R142C point mutation in TG1 was established using a gene targeting technique and the Cre-loxP system. The skin phenotypes were analyzed in homozygous mutant Tgm1(R142C/R142C) mice. RESULTS: In the skin of Tgm1(R142C/R142C) mice, expression of the mutant transcripts was comparable with wild-type or Tgm1(+/R142C) mice. However, the amount of mutated protein in the skin was markedly decreased in Tgm1(R142C/R142C) mice, and the TG1 activity of Tgm1(R142C/R142C) keratinocytes was almost lost. Tgm1(R142C/R142C) mice exhibited morphological and functional skin barrier defects and neonatal lethality. The stratum corneum of those mice lacked cornified envelopes, and loricrin, the major structural component, failed to assemble at the corneocyte cell periphery. Tgm1(R142C/R142C) mice showed a marked increase in transepidermal water loss and their skin was easily permeable to toluidine blue dye. The intercellular lipid lamellar structures of the stratum corneum were irregular and the 13-nm periodic X-ray diffractions from the stratum corneum lipid molecules were lost in vivo. CONCLUSION: From these results, we suggest that the R142C mutation of TG1 reduces the enzyme stability which is indispensable for development of the stratum corneum and skin barrier function and for postnatal survival of mice. PMID- 22258056 TI - Unrecognized risks of nickel-related respiratory cancer among Canadian electrolysis workers. AB - OBJECTIVES: Nickel compounds, inclusive of water-soluble salts, have been classified as human carcinogens by the International Agency for Research on Cancer (IARC). Nickel producers have disputed the classification of soluble nickel compounds for three decades with reference to an alleged absence of excess respiratory cancer among Canadian nickel-exposed electrolysis workers. We evaluated historical data from two electrolytic refineries in Ontario, both included in prominent Canadian reports on occupational nickel-related cancer. METHODS: For Port Colborne nickel refinery (PCNR) and Copper Cliff copper refinery (CCCR), we identified process descriptions, exposure estimates, and original reports on cancer mortality using reference lists, libraries, and state archives. The documents were written or published between 1930 and 1992. RESULTS: For PCNR, a 1977 US National Institute of Occupational Safety and Health criteria document demonstrated an excess nasal cancer risk among electrolysis workers independent of furnace exposure. PCNR studies published after 1980 excluded 26% of long-term refiners who died from respiratory cancer according to earlier reports, and 42% of the workers had unknown vital status at the end of follow-up, biasing the standardized observed-to-expected mortality ratios downwards, most pronounced in recent reports and for workers without pension or company benefits. CCCR reports did not adequately address soluble nickel exposure in the evaluation of an observed occupational lung cancer excess. CONCLUSIONS: While acknowledging important contributions to the recognition of nickel carcinogenicity from highly exposed Canadian refiners, we conclude that the claimed absence of nickel-related respiratory cancer among electrolysis workers has resulted from an arbitrary overemphasis of biased and inconclusive findings. PMID- 22258057 TI - PHBV/PLLA-based composite scaffolds fabricated using an emulsion freezing/freeze drying technique for bone tissue engineering: surface modification and in vitro biological evaluation. AB - Tissue engineering combines living cells with biodegradable materials and/or bioactive components. Composite scaffolds containing biodegradable polymers and nanosized osteoconductive bioceramic with suitable properties are promising for bone tissue regeneration. In this paper, based on blending two biodegradable and biocompatible polymers, namely poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) and poly(L-lactic acid) (PLLA) with incorporated nano hydroxyapatite (HA), three dimensional composite scaffolds with controlled microstructures and an interconnected porous structure, together with high porosity, were fabricated using an emulsion freezing/freeze-drying technique. The influence of various parameters involved in the emulsion freezing/freeze-drying technique was studied for the fabrication of good-quality polymer scaffolds based on PHBV polymers. The morphology, mechanical properties and crystallinity of PHBV/PLLA and HA in PHBV/PLLA composite scaffolds and PHBV polymer scaffolds were studied. The scaffolds were coated with collagen in order to improve wettability. During in vitro biological evaluation study, it was observed that SaOS-2 cells had high attachment on collagen-coated scaffolds. Significant improvement in cell proliferation and alkaline phosphatase activity for HA-incorporated composite scaffolds was observed due to the incorporation of HA. After 3 and 7 days of culture on all scaffolds, SaOS-2 cells also had normal morphology and growth. These results indicated that PHBV/PLLA-based scaffolds fabricated via an emulsion freezing/freeze-drying technique were favorable sites for osteoblastic cells and are promising for the applications of bone tissue engineering. PMID- 22258058 TI - Orientation effects in Cl + H2 inelastic collisions: characterization of the mechanisms. AB - Based on quantum mechanical scattering (QM) calculations, we have analyzed the polarization of the product hydrogen molecule in Cl + H(2) (v = 0, j = 0) inelastic collisions. The spatial arrangements adopted by the rotational angular momentum and internuclear axis of the departing molecule have been characterized and used to prove that two distinct mechanisms, corresponding to different dynamical regimes, are responsible for the inelastic collisions. Such mechanisms, named as low-b and high-b, correlate with well defined ranges of impact parameter values, add in an essentially incoherent way, and can be clearly differentiated through the quantum mechanical polarization moment that measures the orientation of the products rotational angular momentum with respect to the scattering plane. Other directional effects turn out to fail when it comes to distinguishing the mechanisms. Quasiclassical trajectories (QCT) calculations have been used as a supplement to the purely quantum mechanical analysis. By combining QM and QCT results, which are in very good agreement, we have succeeded in obtaining a clear and meaningful picture of how the two types of collisions take place. PMID- 22258060 TI - Synthesis and self-assembly of dynamic covalent block copolymers: towards a general route to pore-functionalized membranes. AB - A diblock copolymer is designed to have incompatible blocks, unsymmetrical block lengths, and a reversible linkage. This copolymer self-assembles into nanostructured cylindrical morphology in thin films. Removal of the nanosized cylinders by breaking the reversible linkage then affords nanoporous membranes featuring a chemically reactive functionality in the pores. PMID- 22258059 TI - Intravital imaging of the mouse thymus using 2-photon Microscopy. AB - Two-photon Microscopy (TPM) provides image acquisition in deep areas inside tissues and organs. In combination with the development of new stereotactic tools and surgical procedures, TPM becomes a powerful technique to identify "niches" inside organs and to document cellular "behaviors" in live animals. While intravital imaging provides information that best resembles the real cellular behavior inside the organ, it is both more laborious and technically demanding in terms of required equipment/procedures than alternative ex vivo imaging acquisition. Thus, we describe a surgical procedure and novel "stereotactic" organ holder that allows us to follow the movements of Foxp3+ cells within the thymus. Foxp3 is the master regulator for the generation of regulatory T cells (Tregs). Moreover, these cells can be classified according to their origin: ie. thymus-differentiated Tregs are called "naturally-occurring Tregs" (nTregs), as opposed to peripherally-converted Tregs (pTregs). Although significant amount of research has been reported in the literature concerning the phenotype and physiology of these T cells, very little is known about their in vivo interactions with other cells. This deficiency may be due to the absence of techniques that would permit such observations. The protocol described in this paper provides a remedy for this situation. Our protocol consists of using nude mice that lack an endogenous thymus since they have a punctual mutation in the DNA sequence that compromises the differentiation of some epithelial cells, including thymic epithelial cells. Nude mice were gamma-irradiated and reconstituted with bone marrows (BM) from Foxp3-KI(gfp/gfp) mice. After BM recovery (6 weeks), each animal received embryonic thymus transplantation inside the kidney capsule. After thymus acceptance (6 weeks), the animals were anesthetized; the kidney containing the transplanted thymus was exposed, fixed in our organ holder, and kept under physiological conditions for in vivo imaging by TPM. We have been using this approach to study the influence of drugs in the generation of regulatory T cells. PMID- 22258061 TI - Lichen sclerosus: a 5-year follow-up after topical, subdermal, or combined therapy. AB - OBJECTIVE: The purpose of our study was to compare clinical data regarding patients with pruritic lichen sclerosus (LS) at moderate or severe stages using 2 different therapies with a 5-year follow-up. MATERIALS AND METHODS: The study was approved by the institutional review board and was presented as a retrospective clinical data review of patients with pruritic biopsy diagnosis LS who underwent therapy at our university private practice from 2002 to 2005. We compared the results of a weekly topical application of high-potency steroid (HPS) with a combined HPS and monthly anesthetic/steroid subdermal injection (ASI). Outcomes were timed to achieve pruritus-free status, the number of symptomatic recurrences, and patient satisfaction with therapy. RESULTS: Fifty-four patients were diagnosed with LS between 2002 and 2005. There were 13 patients who had mild stage, 25 who had moderate-stage, and 16 who had severe-stage LS. Five-year follow-up data on 17 patients with moderate-stage LS and 14 patients with severe stage LS were obtained. Time to pruritus free was 6 weeks with ASI and 19 weeks with HPS for moderate-stage LS (p = .04) and 9 weeks with ASI and 24 weeks with HPS for severe-stage LS (p = .03). Recurrences were more frequent on HPS for moderate-stage LS (p = .04) but not significant with HPS for severe-stage LS (p = .15). Only ASI was successful at treating patients with recalcitrant pruritus. CONCLUSIONS: In our population, patients with symptomatic moderate-stage LS seem to have a more rapid and prolonged response to ASI than to HPS but are less satisfied with the injections. PMID- 22258062 TI - Colorimetric quantification of galactose using a nanostructured multi-catalyst system entrapping galactose oxidase and magnetic nanoparticles as peroxidase mimetics. AB - A colorimetric method for quantification of galactose, which utilizes a nanostructured multi-catalyst system consisting of Fe(3)O(4) magnetic nanoparticles (MNPs) and galactose oxidase (Gal Ox) simultaneously entrapped in large pore sized mesocellular silica, is described. Gal Ox, immobilized in a silica matrix, promotes reaction of galactose to generate H(2)O(2) that subsequently activates MNPs in silica mesopores to convert a colorimetric substrate into a colored product. By using this colorimetric method, galactose can be specifically detected. Along with excellent reusability via application of simple magnetic capturing, enhanced operational stability was achieved by employing a cross-linked enzyme aggregate (CLEA) method for Gal Ox immobilization. This protocol leads to effective prevention of enzyme leaching from the pores of mesocellular silica. The analytical utility of the new colorimetric biosensor was demonstrated by its use in diagnosing galactosemia, a genetic metabolic disorder characterized by the inability to utilize galactose, through analysis of clinical dried blood spot specimens. A microscale well-plate format was employed that possesses a multiplexing capability. The multi-catalyst system entrapping Gal Ox and MNPs represents a new approach for rapid, convenient, and cost-effective quantification of galactose in human blood and it holds promise as an alternative method for galactosemia diagnosis, replacing the laborious procedures that are currently in use. PMID- 22258063 TI - Hypertension, dyslipidemia and overweight are related to lower testosterone levels in a cohort of men undergoing prostate biopsy. AB - Testosterone deficiency syndrome (TDS) is a clinical and biochemical entity related to sexual and cardiovascular health. Hypertension, diabetes mellitus (DM), dyslipidemia and overweight are four clinical factors strongly related to cardiovascular illnesses. The aim of our study was to determine if the presence and number of cardiovascular risk factors was related to total testosterone levels and the presence of biochemical TDS. We retrospectively analyzed 384 patients referred to our center for prostate biopsy between September 2007 and December 2009. Variables age, height, weight, body mass index (BMI), tobacco use, alcohol intake, hypertension, DM, dyslipidemia (hypercholesterolemia/hypertriglyceridemia) and overweight (BMI>25) were recorded prospectively. Hormonal profile was determined as part of our clinical protocol. We used 231 and 346 ng dl(-1) as total testosterone cut-points (8-12 nmol l(-1)) for diagnosis of biochemical TDS, following ISA-ISSAM-EAU Guidelines. We analyzed the relationship between testosterone levels and the presence of hypertension, DM, dyslipidemia and overweight, and with the number of these cardiovascular risk factors. Mean age was 66 +/- 8 years. Prevalence of TDS was 6.5% within the 231 ng ml(-1) cutoff point and 28.4% for the 346 ng dl(-1) cutoff point. Levels of testosterone were related to hypertension (P=0.007), dyslipidemia (P=0.013), overweight (P=0.036) and the number of cardiovascular risk factors (P=0.018). The prevalence of TDS in our population is comparable to data from international studies. Testosterone levels decrease as the number of cardiovascular risk factors rise. PMID- 22258064 TI - Resection of hepatocellular carcinoma without cirrhosis. AB - OBJECTIVE: The aim of this study was to examine the features and outcomes of noncirrhotic patients undergoing resection for hepatocellular carcinoma. BACKGROUND: Ten percent to 40% of hepatocellular carcinoma cases arise within a noncirrhotic liver parenchyma. Resection is the standard therapy, yet the published resection series from the West are small. METHODS: From January 1987 to December 2009, our center performed 206 partial liver resections for nonfibrotic or minimally fibrotic (Scheuer stage 0-2) hepatocellular carcinoma. We retrospectively reviewed these cases and performed univariate and multivariate analyses for predictors of long-term outcomes. RESULTS: Eighty-one patients (39.3%) had chronic hepatitis B infection and 23 patients (11.2%) had chronic hepatitis C. The remaining 83 (39.8%) had no underlying liver disease. Average age was 60.2 years, and 68.4% of the patients were male. Average tumor size was 8.2 cm. Overall survival at 5 years was 46.3%. Recurrence at 5 years was 50.0%. Independent predictors for decreased survival were tumor size larger than 7.0 cm, creatinine more than 1.0 mg/dL, satellite nodules, albumin less than 3.5 gm/dL, alpha-fetoprotein more than 100 ng/mL, and any vascular invasion. Chronic hepatitis B virus infection predicted longer survival. Independent predictors for decreased time to recurrence were albumin less than 3.5 gm/dL, any vascular invasion, age more than 60 years, tumor size larger than 7.0 cm, and alpha fetoprotein more than 100 ng/mL. Treatment of recurrence with either repeat resection or ablation was associated with a median survival of 50.4 months from time of recurrence. CONCLUSIONS: Hepatocellular carcinoma can develop in a minimally fibrotic hepatitis C patient. Tumor-related factors such as vascular invasion primarily determine long-term outcomes. Hepatitis B virus-associated tumors seem to have a better prognosis in the nonfibrotic or minimally fibrotic population. Aggressive treatment of recurrence is warranted. PMID- 22258065 TI - Feasibility and safety of single-incision laparoscopic colectomy: a systematic review. AB - OBJECTIVE: The aim of this review was to evaluate the feasibility, safety, and potential benefits of single-incision laparoscopic colectomy (SILC). METHODS: We conducted a comprehensive review for the years 1983 to March 2011 to retrieve all relevant articles. RESULTS: A total of 23 studies with 378 patients undergoing SILC were reviewed. All studies except 2 used a commercially available single port device. Range of body mass index was 20.9 to 30.0 kg/m2. Ranges of operative times and estimated blood losses were 83 to 225 minutes and 0 to 115 mL, respectively. Of 378 cases, a total of 6 cases (1.6%) were converted to open, 6 (1.6%) to hand-assisted laparoscopic (HALC), and 14 (4.0%) to conventional (multiport) laparoscopic colectomy (MLC) (overall conversion rate, 6.9%). An additional laparoscopic port was used in 4.9% (12/247) cases. Range of harvested lymph nodes number for malignant cases was 13.5 to 27 and surgical margins were negative in all cases. Overall mortality and morbidity rates were 0.5% (2/378) and 12.9% (45/349), respectively. The length of hospital stay (LOS) varied across reports (1.9-9.8 days). Among 4 case-matched studies, 2 showed shorter LOS after SILC than after HALC (2.7 vs 3.3 days) or after MLC/HALC (3.4 vs 4.6/4.9 days). Furthermore, one of these studies reported that maximum pain score on postoperative days 1 and 2 was significantly lower in SILS than in MLC and HALC. CONCLUSIONS: In early series of highly selected patients, SILC appears to be feasible and safe when performed by surgeons who are highly skilled in laparoscopy. Despite technical difficulties, there may be potential benefits associated with SILC over MLC/HALC but it is yet to be proven objectively. PMID- 22258066 TI - The beneficial impact of revision of Kasai portoenterostomy for biliary atresia: an institutional study. AB - OBJECTIVE: To determine whether portoenterostomy (PE) revision in patients afflicted with biliary atresia (BA) is a viable treatment option and, if so, identify which patients may benefit. BACKGROUND: BA, the most common cause of neonatal liver disease, results in biliary tract obstruction and hepatic fibrosis. Kasai PE is the initial surgical intervention performed and, if successful, restores drainage and preserves the native liver. Portoenterostomy failure warrants liver transplantation, but because of complications related to transplantation, treatment strategies to salvage the native liver may be beneficial. Using uniformly applied criteria, we have revised PEs to delay or avoid transplantation. METHODS: A retrospective review of medical records of patients diagnosed with BA since 1983 was performed. Patient demographics, symptoms, indications for revision, laboratory values, and outcomes were recorded. A cohort of patients who underwent revision after initial PE was identified. Survival rates were assessed using the Kaplan-Meier method. For patients who required transplantation, operative data from the revised PE cohort were compared with those from the unrevised PE cohort. A Cox proportional hazards model was used to determine covariates predictive of a favorable outcome. RESULTS: Of 181 children who underwent PE, 24 underwent revision. Adequate biliary drainage, as evidenced by normalized conjugated bilirubin levels, was achieved in 75% of revised patients. Overall survival in patients who underwent revision, regardless of transplantation, was 87%. Among patients who underwent PE revision, 46% have survived with their native liver. CONCLUSION: Experience at our center suggests that with appropriate patient selection, PE revision may delay the need for liver transplanation yielding encouraging patient outcomes. PMID- 22258067 TI - Increased cardiovascular risk in rats with primary renal dysfunction; mediating role for vascular endothelial function. AB - Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5-10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 +/- 10 vs. CRD 79 +/- 8 ml/min), diastolic dysfunction (E/e') (CD 26 +/- 2 vs. CRD 50 +/- 5) and left ventricular overload (LVEDP CD 10.8 +/- 2.8 vs. CRD 21.6 +/- 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction. PMID- 22258068 TI - A deimmunized bispecific ligand-directed toxin that shows an impressive anti pancreatic cancer effect in a systemic nude mouse orthotopic model. AB - OBJECTIVE: The objective was to test a bispecific ligand-directed toxin (BLT), with reduced immunogenicity for enhanced efficacy in targeting orthotopic pancreatic cancer in vivo. METHOD: A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single chain molecule with deimmunized pseudomonas exotoxin (dEGF4KDEL). Key amino acids dictating B-cell generation of neutralizing antitoxin antibodies were mutated. Bioassays were used to determine whether mutation reduced potency, and enzyme-linked immunosorbent assay studies were performed to determine whether antitoxin antibodies were reduced. A genetically altered luciferase MIA PaCa-2 xenograft model was used to image in real time and determine effects on systemic malignant human cancer. Bispecific ligand-directed toxins targeting B cells were used as specificity controls. RESULTS: Deimmunized EGF4KDEL was significantly effective after systemic injection against established orthotopic MIA PaCa-2 pancreatic cancer and selectively prevented metastasis. Mutagenesis significantly reduced antitoxin levels in vivo with no apparent activity loss in vitro. The drug was effective against 3 human pancreatic cancer lines in vitro, MIA PaCa-2, SW1990, and S2VP10. CONCLUSIONS: Despite the metastatic nature of the MIA PaCa-2 orthotopic tumor xenografted in nude mice, high percentages of tumors responded to extended dEGFKDEL treatment resulting in significant anticancer effects and disease-free survivors. PMID- 22258069 TI - Plasma 25-hydroxyvitamin D levels are favorably associated with beta-cell function. AB - OBJECTIVE: The association of hypovitaminosis D with type 2 diabetes is well recognized. Although hypovitaminosis D is associated with insulin resistance, there is much less information about its impact on beta-cell function in humans. METHODS: We enrolled 150 healthy, glucose-tolerant subjects for the assessment of beta-cell function (acute insulin response) and insulin sensitivity index (ISI) using a hyperglycemic clamp. Adjusted beta-cell function (ABCF) was defined as the product of acute insulin response and ISI. The relations of plasma 25 hydroxyvitamin D [25(OH)D] level with insulin sensitivity and ABCF were examined. RESULTS: Plasma 25(OH)D levels were positively associated with ABCF (P = 0.00004) and ISI (P < 0.00001). The associations remained significant after adjustment for age, sex, body mass index, physical activity, ethnicity, and season of study. CONCLUSIONS: Plasma 25(OH)D levels are positively association with both beta-cell function and insulin sensitivity. Our observations suggest the roles of vitamin D deficiency in the dual defect of type 2 diabetes. PMID- 22258070 TI - Can we distinguish juvenile violent sex offenders, violent non-sex offenders, and versatile violent sex offenders based on childhood risk factors? AB - Understanding the developmental precursors of juvenile violent sex offending can contribute to the promotion of effective early intervention and prevention programs for high-risk children and youth. However, there is currently a lack of research on the early characteristics of adolescents who commit violent sex offenses. Drawing on the literature regarding the generalist and specialist positions of criminal behavior, the aim of the present study was to compare childhood risk factors for three groups of juvenile offenders: (a) pure sex offenders (PSO; n = 28); (b) violent non-sex offenders (VNSO; n = 172); and (c) versatile violent sex offenders (VVSO; n = 24). Nineteen risk factors comprising four life domains (individual, family, peer, and school) were identified from a file review. Three hierarchical logistic regression analyses examined associations between risk factors and offender groups. The results reflected the underlying heterogeneity of the sample, offering support for both the specialist and generalist positions of criminal behavior. PSOs differed from VNSOs on the basis of higher odds for precocious sexual behavior. Second, VVSOs differed from VNSOs on the basis of higher odds for precocious sexual behavior, criminal family members, and an adolescent mother, as well as lower odds for poor school behavior. Third, PSOs were marginally more likely to have engaged in early overt antisocial behavior compared with VVSOs. Fourth, many of the childhood risk factors examined were not associated with any offender group. In conclusion, VVSOs appeared to differ on the greatest number of risk factors from VNSOs, suggesting that VVSOs share a more similar developmental pathway with PSOs. The prevention and future research implications of these findings are discussed. PMID- 22258071 TI - Correlates of handgun carrying among adolescents in the United States. AB - Weapon-related violence, especially the use of handguns, among adolescents is a serious public health concern. Using public-use data file from the adolescent sample (N = 17,842) in the 2008 National Survey on Drug Use and Health (NSDUH), this study examines the behavioral, parental involvement, and prevention correlates of handgun carrying. Overall, 3.1% of adolescents between the ages of 12 and 17 reported carrying a handgun in the past year. Results from a series of logistic regression models indicated that males, selling and using illicit drugs, were robustly associated with an increased probability of handgun carrying among adolescents. Furthermore, youth who carry handguns were significantly less likely to report a parent being involved in their lives and were significantly more likely to have encountered violence and drug prevention programming compared with youth who did not carry handguns. Implications of these results for prevention and policy are discussed. PMID- 22258072 TI - The problem of untested sexual assault kits: why are some kits never submitted to a crime laboratory? AB - Victims of sexual assault are often advised to seek postassault medical care to have a forensic exam, which includes evidence collection (termed a sexual assault kit [SAK]). After the exam, law enforcement personnel are supposed to submit the SAK to a crime laboratory for analysis. However, recent media reports suggest that in many communities throughout the United States, thousands of SAKs are left untested. Few studies have examined the rate at which law enforcement submits SAKs to crime labs or the factors that may predict them to do so. Thus, the purpose of this exploratory study is twofold: (a) to examine the percentage of SAKs law enforcement submits to crime labs in cases in which a sexual assault nurse examiner (SANE) performed the exam with adult victims and (b) to explore whether assault and law enforcement characteristics predict whether SAKs are submitted to a crime lab. This study found that only 58.6% of the SAKs were submitted to the crime lab within a large Midwestern county. Using binary logistic regression, this study found that kits were significantly as likely to be submitted when there were documented physical (nonanogenital) injuries compared with kits that did not have documented physical injuries. In addition, kits that were handled by a law enforcement agency that had a high level of engagement with the SANE program were significantly as likely to be submitted as law enforcement agencies with a low or medium level of engagement. Kits were significantly less likely to be submitted when victims cleaned themselves after the sexual assault (e.g., bathing). No association was found between kit submission and the victim-offender relationship, suspected drug-facilitated sexual assault, anogenital injury, and when the victim consumed alcohol or drugs before the assault. This article concludes with a discussion of the implications for research and practice. PMID- 22258073 TI - Bystander reaction to women fighting: developing a theory of intervention. AB - This article explores accounts of bystanders to female-on-female public violence. Group interviews with participants in the night-time economy are carried out. Whereas men tend to respond to the discussion topic of female-on-female violence with laughter, this laughter reveals ambivalence and discomfort as much as amusement. Men seem to negotiate the tension between the expectation that they should intervene in emergencies and a catalogue of costs that attend intervention. Female bystanders appear to have a different set of concerns. They talk about feelings of shame at the interpersonal and the group level. Women cite the public spectacle, and the opportunity for men to demean or sexualize women, as reasons for intervention. The article concludes with some recommendations about the importance of exploring female violence in its own terms, beginning with a series of identified moral and social dilemmas incurred within possible third-party intervention. PMID- 22258074 TI - Judging risk: key determinants in British domestic violence cases. AB - Data from the largest study to date of the working practices of British victim support workers (known as Independent Domestic Violence Advisors or IDVAs) are used to provide insight into how "risk judgments" are made in cases of domestic violence. Using data from more than 2,000 victims, this study found a convergence between actuarial data and IDVAs' risk judgments when the risk score was high, but in cases with a lower risk score, IDVAs often used their professional judgment to upgrade risk. Next, we identified the specific factors underpinning IDVAs' risk judgments. Consistent with existing research, we found that IDVAs relied on a subset of available information when forming risk judgments, and characteristics of the abusive situation, such as the escalation of violence, use of weapons, stalking, and significant injuries, were particularly salient to them. Furthermore, IDVAs paid attention to victims' perceptions and when they felt very frightened or afraid of further injury then IDVAs were more likely to label them as high risk. Although we identified some encouraging overlap between the subset of factors informing risk judgments and those associated with victims' reabuse at a later date, some notable differences indicate a need for messages from research about the significance of particular risk factors to be reinforced to frontline practitioners on a regular basis. PMID- 22258075 TI - Justification, perception of severity and harm, and criminalization of wife abuse in the Palestinian society. AB - The purpose of this study was to examine the perceptions of Palestinian adults toward different dimensions of wife abuse. A cross-sectional survey, using a combination of self-administered questionnaires and interviews, was conducted among a systematic random sample of 624 adult Palestinian men and women from the West Bank and Gaza Strip (18 years or older). Study results indicated a strong tendency to justify wife beating in different situations, such as when the wife is perceived as having an affair with another man or as physically attacking her husband. Participants considered the following acts of husband's violence against wife as most severe: using a weapon (86%), having sex with the wife against her will (67%), and hitting her with his fist (57%). The majority of participants thought that wife beating should be considered a crime (82.3%). Traditional marital role expectations was the main significant predictor for all of the study criterion variables. Gender, place of residence, age, and marital status were significant predictors of some of the criterion variables. PMID- 22258076 TI - Racial and ethnic disparities in police-reported intimate partner violence perpetration: a mixed methods approach. AB - The objectives of this study were to examine racial and ethnic disparities in perpetrator and incident characteristics and discrepancies between police charges and reported perpetrator behaviors in police-reported intimate partner violence (IPV). This cross-sectional study used standardized police data and victim narratives of IPV incidents reported to the police in Dallas, Texas in 2004. The sample included non-Hispanic White, non-Hispanic Black, and Hispanic male perpetrators who were residents of Dallas (N = 4470). Offense charges were prioritized in descending order: sexual assault, aggravated assault, simple assault, kidnapping, robbery, and intimidation. Textual data from the victim narratives were coded, based on the revised Conflict Tactics Scales (CTS), and categorized in descending order of priority: sexual (severe, minor), physical (severe, minor), and psychological (severe, minor) assault. Perpetrators were more likely to be Black and Hispanic. Perpetrator and incident characteristics varied significantly by race/ethnicity, particularly age, age difference between partners, marital status, injury, and interracial relationships. Qualitative data revealed that greater proportions of Black and Hispanic men perpetrated severe physical, but not sexual violence, compared with White men. The greatest disparity between CTS categories and police charges occurred among those cases identified by the CTS as severe physical IPV; 84% were charged with simple assault. Significant differences by race/ethnicity were found only for simple assault charges, which were coded as severe physical as opposed to minor physical IPV more often among Black (69% and 31%) compared with White (62% and 38%) men. The disparities revealed in this study highlight the need to enhance primary and secondary prevention efforts within Black and Hispanic communities and to increase linkages between police, community, and public health organizations. PMID- 22258077 TI - Opinions about child corporal punishment and influencing factors. AB - The use of corporal punishment has been linked to negative developmental outcomes for children. Despite this finding, Section 43 of the Canadian Criminal Code permits the use of corporal punishment by parents for children 2 to 12 years of age. Therefore, this study's first objective is to investigate opinions toward Section 43 and spanking more generally. The second objective is to investigate predictors of opinions toward Section 43 and spanking more generally. The sample consists of 818 nonparents (70.7% female, 29.0% male) who completed an online study. Results indicate that 38.6% were favorable toward upholding Section 43. However, this decreases to 25.8% when a condition is included, stating that parents would not be prosecuted for mild slaps or spankings. For attitudes toward spanking more generally, results reveal that 16.7% of the participants held favorable attitudes. Hierarchical regression analyses reveal that planning to use corporal punishment upon becoming a parent predicted having a more favorable attitude toward Section 43 as well as toward spanking more generally (after controlling for sociodemographics). In contrast, having experienced violence during one's childhood predicts having less favorable attitudes toward Section 43 and spanking more generally. Significant interactions are found between childhood experiences of corporal punishment and perceptions of parental warmth/support and impulsiveness during discipline in predicting attitudes toward spanking. Those who report experiencing more corporal punishment during childhood but also more parental warmth/support hold more favorable attitudes toward spanking and those who report experiencing more corporal punishment during childhood and also more parental impulsiveness hold less favorable attitudes toward spanking. Findings indicate that examining opinions toward Section 43 and spanking separately is important because these concepts are not synonymous. In addition, both more immediate factors and those related to one's developmental history play a role in predicting opinions toward Section 43 and spanking more generally. PMID- 22258079 TI - Adolescent sexual risk and multiple contexts: interpersonal violence, parenting, and poverty. AB - In this study we estimated the combined effects of violence experiences, parenting processes, and community poverty on sexual onset, alcohol or other drug (AOD) use at last sex, multiple sex partners, and prior pregnancy in a sample of 7th-, 9th-, and 11th-grade adolescents (n = 7,891), and the subsample of sexually experienced adolescents (n = 2,108). Multilevel multivariate logistic regression analyses revealed that having experienced any interpersonal violence, and low levels of perceived parental warmth and parental knowledge predicted sexual onset. Adult sexual abuse or peer sexual coercion increased the odds for AOD use at last sex and having multiple sexual partners. When demographic, violence experiences and parenting behaviors were accounted for, poverty was not associated with sexual onset, AOD use at last sex, or multiple sex partners. Results suggest prevention efforts to reduce teen dating violence may be especially important to diminish sexually risky behaviors among adolescents. PMID- 22258078 TI - Associations between expectancies of alcohol and drug use, severity of partner violence, and posttraumatic stress among women. AB - Women who experience recurrent intimate partner violence (IPV) may use alcohol or drugs because they expect that these substances will help them cope with the negative physical and psychological sequelae of IPV. However, expectancies for alcohol and drug use have not been explored among this population of women. We used the Relaxation and Tension-Reduction Scale, Arousal and Aggression Scale, and Social Assertion Scale of the Alcohol Expectancy Questionnaire and modified its items to assess both alcohol and drug expectancies of 212 community-based, IPV-exposed women. Results of bivariate correlations showed that greater alcohol and drug expectancies were significantly correlated with greater alcohol problems and greater posttraumatic stress total and symptom severity scores. Results of a multivariate regression model showed that after controlling for demographic characteristics and history of childhood trauma, Relaxation and Tension- Reduction expectancies were associated with number of days of alcohol use, alcohol problems, physical and sexual IPV severity scores, and posttraumatic stress total and reexperiencing symptom severity scores. Expectancies do not significantly moderate the relationships between IPV, posttraumatic stress, and problematic alcohol and drug use. Given the strong relationships of expectancies with IPV severity, posttraumatic stress, and alcohol problems, expectancies may serve as targets for interventions to reduce alcohol use and problems and improve health-related outcomes in IPV-exposed women. PMID- 22258081 TI - Photophysical properties of 4,4'-di-tert-butyl-2,2'-bipyridine supported 6 membered 2,2'-diphenyl-X platinacycles (X = CH2, NMe, O). AB - The six-membered platinacycle complex, Pt((t)Bu(2)bpy)(C(6)H(4)OC(6)H(4)) (6) ((t)Bu(2)bpy = 4,4'-di-tert-butyl-2,2'-bipyridine) has been prepared from Pt((t)Bu(2)bpy)Cl(2) and 2,2'-dilithio-diphenyl ether. Platinacycle 6 and its analogs with X = CH(2) (4) and NMe (5) exhibit intense solid-state photoluminescence and nearly identical crystal structures. The photophysical properties of 4-6 in the visible range are dominated by mixed metal-ligand-to ligand charge transfer (MLL'CT) transitions involving high-lying filled mixed metal-ligand orbitals (ML), composed primarily of platinacyclic ring-based d- and pi-orbitals, and a low lying vacant pi* orbital (L') of the (t)Bu(2)bpy ligand. Lone pair donation from the bridging oxygen atom and especially the NMe group increases the energy of the mixed metal-ligand orbital (ML) without altering the energy of the (t)Bu(2)bpy pi* orbital. As a result, the MLL'CT state energy decreases and the absorption and emission wavelengths are red-shifted. DFT and TD DFT calculations support the experimental results. Additional calculations on the unknown platinacycles with X = CO (7) and SO(2) (8) predict a blue-shift for the MLL'CT absorption and emission. Two nearly equal energy triplet minima were located on the DFT triplet surface for 4-6. One of these (4T-6T) has a geometry very similar to the ground-state singlet (as represented by 4-6) and is associated with the emissive (3)MLL'CT excited state. The other triplet-state (4T'-6T') has a distorted structure where the platinacycle ring is twisted out of the Pt((t)Bu(2)bpy) plane. Thermal access to this distorted triplet may be responsible for the loss of photoluminescence in room temperature solutions of 4 6. PMID- 22258080 TI - Molecular identification of Echinococcus species from eastern and southern Qinghai, China, based on the mitochondrial cox1 gene. AB - The Qinghai-Tibetan Plateau (QTP, in western China), which is the largest and highest plateau on Earth, is a highly epidemic region for Echinococcus spp. We collected 70 Echinococcus samples from humans, dogs, sheep, yaks, plateau pikas, and voles in eastern and southern Qinghai and genotyped them using the mitochondrial DNA marker cytochrome oxidase subunit I gene and maximum parsimony and Bayesian reconstruction methods. Based on the 792-bp sequence matrix, we recorded 124 variable sites, of which, 115 were parsimony-informative. Thirty four haplotypes (H1-H34) were detected, of which H1-H15, H16-H17, and H18-H34 belonged to Echinococcus shiquicus, Echinococcus multilocularis, and Echinococcus granulosus, respectively. Within 26 human isolates, three were identified as E. multilocularis and 23 were E. granulosus. We also detected a dual infection case in a dog with E. multilocularis and E. granulosus. The intraspecific haplotype (Hd +/- SD) and nucleotide (Nd +/- SD) diversity of E. shiquicus (0.947 +/- 0.021; 0.00441 +/- 0.00062) was higher than that for E. granulosus (0.896 +/- 0.038; 0.00221 +/- 0.00031) and E. multilocularis (0.286 +/- 0.196; 0.00036 +/- 0.00025). Moreover, the haplotype network of E. shiquicus showed a radial feature rather than a divergent feature in a previous study, indicating this species in the QTP has also evolved with bottleneck effects. PMID- 22258082 TI - A complete volume profile for the reversible binding of camphor to cytochrome P450(cam). AB - The effect of pressure on the kinetics and thermodynamics of the reversible binding of camphor to cytochrome P450(cam) was studied as a function of the K(+) concentration. The determination of the reaction and activation volumes enabled the construction of the first complete volume profile for the reversible binding of camphor to P450(cam). Although the volume profiles constructed for the reactions conducted at low and high K(+) concentrations are rather similar, and both show a drastic volume increase on going from the reactant to the transition state and a relatively small volume change on going from the transition to the product state, the position of the transition state is largely affected by the K(+) concentration in solution. Similarly, the activation volume determined for the dissociation of camphor is influenced by the presence of K(+), which reflects changes in the ease of water entering the active site of camphor-bound P450(cam) that depends on the K(+) concentration. Careful analysis of the components that contribute to the observed volume changes allowed the estimation of the total number of water molecules expelled to the bulk solvent during the binding of camphor to P450(cam) and the subsequent spin transition. The results are discussed in reference to other studies reported in the literature that deal with the kinetics and thermodynamics of the binding of camphor to P450(cam) under various reaction conditions. PMID- 22258083 TI - Cobalt substitution supports an inner-sphere electron transfer mechanism for oxygen reduction in pea seedling amine oxidase. AB - Copper amine oxidases (CAOs) are a large family of proteins that use molecular oxygen to oxidize amines to aldehydes with the concomitant production of hydrogen peroxide and ammonia. CAOs utilize two cofactors for this reaction: topaquinone (TPQ) and a Cu(II) ion. Two mechanisms for oxygen reduction have been proposed for these enzymes. In one mechanism (involving inner-sphere electron transfer to O(2)), Cu(II) is reduced by TPQ, forming Cu(I), to which O(2) binds, forming a copper-superoxide complex. In an alternative mechanism (involving outer-sphere electron transfer to O(2)), O(2) is directly reduced by TPQ, without reduction of Cu(II). Substitution of Cu(II) with Co(II) has been used to distinguish between the two mechanisms in several CAOs. Because it is unlikely that Co(II) could be reduced to Co(I) in this environment, an inner-sphere mechanism, as described above, is prevented. We adapted metal replacement methods used for other CAOs to the amine oxidase from pea seedlings (PSAO). Cobalt-substituted PSAO (CoPSAO) displayed nominal catalytic activity: k(cat) is 4.7% of the native k(cat), and K(M) (O(2)) for CoPSAO is substantially (22-fold) higher. The greatly reduced turnover number for CoPSAO suggests that PSAO uses the inner-sphere mechanism, as has been predicted from (18)O isotope effect studies (Mukherjee et al. in J Am Chem Soc 130:9459-9473, 2008), and is catalytically compromised when constrained to operate via outer-sphere electron transfer to O(2). This study, together with previous work, provides strong evidence that CAOs use both proposed mechanisms, but each homolog may prefer one mechanism over the other. PMID- 22258084 TI - Lung hypoplasia in rats with esophageal atresia and tracheo-esophageal fistula. AB - INTRODUCTION: Survivors of esophageal atresia and tracheo-esophageal fistula (EA TEF) often suffer chronic respiratory tract disease. EA-TEF results from abnormal emergence of the trachea from the foregut. This study in a rat model tests the hypothesis that primary lung maldevelopment might be a downstream consequence of this defect. RESULTS: The lung was hypoplastic in rats with EA-TEF although the histological pattern was normal. Maturation and arteriolar wall thickness were unchanged, but mesenchymal control of airway branching was weakened. This branching was deficient from embryonal day (E13) on in adriamycin-treated explants. DISCUSSION: In conclusion, the lungs were hypoplastic in rats with experimental EA-TEF due to defective embryonal airway branching. However, arteriolar wall and respiratory epithelial patterns remained normal. These findings suggest that similarly defective lung development might contribute to chronic respiratory disease in EA-TEF patients. METHODS: Pregnant rats received either 1.75 mg/kg i.p. adriamycin or vehicle on E7, E8, and E9. Lungs were recovered at E15, E18, and E2. Lung weight/body weight ratio, total DNA and protein, radial alveolar count, arteriolar wall thickness, lung maturity, and mesenchymal control of airway branching were assessed. E13 lungs were cultured for 72 h and explant airway branching was measured daily. For comparisons, nonparametric tests (*P < 0.05) were used. PMID- 22258085 TI - Antenatal exposure to Ureaplasma species exacerbates bronchopulmonary dysplasia synergistically with subsequent prolonged mechanical ventilation in preterm infants. AB - INTRODUCTION: The presence of microorganisms in gastric fluid in neonates at birth is postulated to reflect antenatal infection and also to be associated with the development of bronchopulmonary dysplasia (BPD). RESULTS: A logistic regression analysis, after controlling for other risk factors, indicated that Ureaplasma-positive infants were not at increased risk for moderate/severe BPD (adjusted odds ratio (OR): 2.58, 95% confidence interval (CI): 0.57-6.89, P = 0.12). However, the association between the presence of Ureaplasma species and the risk for moderate/severe BPD increased significantly in infants on mechanical ventilation (MV) >=2 wk (adjusted OR: 4.17, 95% CI: 1.62-44.1, P = 0.009). An analysis using a lung injury marker indicated that Ureaplasma-positive infants with MV >=2 wk, but not other infants, showed higher serum KL-6 levels in samples taken from cord blood, and that KL-6 levels increased time-dependently up to 4 wk of age. DISCUSSION: Antenatal exposure to Ureaplasma species induces lung injury prior to birth and synergistically contributes to the development of BPD in infants requiring prolonged MV (>=2 wk). METHODS: We recovered gastric fluid specimens from 122 infants with gestational age (GA) <29 wk or birth weight <1,000 g to investigate whether these microorganisms influence respiratory outcome of BPD. A PCR analysis was used to detect urease and 16S ribosomal RNA (rRNA) genes to classify neonates into Ureaplasma-positive or Ureaplasma-negative infants. PMID- 22258086 TI - Air-displacement plethysmography for the measurement of body composition in children aged 6-48 months. AB - INTRODUCTION: Air-displacement plethysmography (ADP) is an age-appropriate method for measuring relative fat mass (%FM) in children; however, the accuracy of this method has not been evaluated in children aged 5 y or younger. RESULTS: Mean %FM values measured by ADP (17.9 +/- 8.0%) and by total body water (TBW) (23.7 +/- 6.3%) were significantly different (P < 0.001). Regression analysis of %FM by ADP vs. TBW provided a line of best fit with a slope of 0.089, r(2) = 0.013, and standard error of the estimate (SEE) = 6.3% FM (P = 0.40). DISCUSSION: The error was related to child weight and %FM, but not to behaviors (movement or vocalizations) occurring during the test sequence. A large portion of the error was attributable to imprecision in measuring small volumes. As currently designed, ADP is not an accurate method for measuring %FM in young children. Further investigation of the sources of variability will provide insight into ways of improving the accuracy of this technology for this population. METHODS: This study examined the accuracy of an ADP system modified for young children (BOD POD; Life Measurement, Concord, CA) by comparing %FM results from ADP with those obtained from TBW by deuterium (D(2)O) dilution (reference method) in 72 children aged 6-48 mo. PMID- 22258087 TI - Neonatal and infant outcome in boys and girls born very prematurely. AB - INTRODUCTION: Although important new strategies have improved outcomes for very preterm infants, males have greater mortality/morbidity than females. We investigated whether the excess of adverse later effects in males operated through poorer neonatal profile or if there was an intrinsic male effect. RESULTS: Male sex was significantly associated with higher birth weight, death or oxygen dependency (72% vs. 61%, boys vs. girls), hospital stay (97 vs. 86 days), pulmonary hemorrhage (15% vs. 10%), postnatal steroids (37% vs. 21%), and major cranial ultrasound abnormality (20% vs. 12%). Differences remained significant after adjusting for birth weight and gestation. At follow-up, disability, cognitive delay, and use of inhalers remained significant after further adjustment. DISCUSSION: We conclude that in very preterm infants, male sex is an important risk factor for poor neonatal outcome and poor neurological and respiratory outcome at follow-up. The increased risks at follow-up are not explained by neonatal factors and lend support to the concept of male vulnerability following preterm birth. METHODS: Data came from the United Kingdom Oscillation Study, with 797 infants (428 boys) born at 23-28 wk gestational age. Thirteen maternal factors, 8 infant factors, 11 acute outcomes, and neurological and respiratory outcomes at follow-up were analyzed. Follow-up outcomes were adjusted for birth and neonatal factors sequentially to explore mechanisms for differences by sex. PMID- 22258088 TI - Beyond the Burke-Fahn-Marsden Dystonia Rating Scale: deep brain stimulation in childhood secondary dystonia. AB - PURPOSE: Deep brain stimulation is now widely accepted as an effective treatment for children with primary generalized dystonia. More variable results are reported in secondary dystonias and its efficacy in this heterogeneous group has not been fully elucidated. Deep brain stimulation outcomes are typically reported using impairment-focused measures, such as the Burke-Fahn-Marsden Dystonia Rating Scale, which provide little information about function and participation outcomes or changes in non-motor areas. The aim is to demonstrate that in some cases of secondary dystonia, the sole use of impairment level measures, such as the Burke Fahn-Marsden Dystonia Rating Scale, may be insufficient to fully evaluate outcome following deep brain stimulation. METHODS: Six paediatric cases who underwent deep brain stimulation surgery with a minimum of one year follow up were selected on the basis of apparent non-response to deep brain stimulation, defined as a clinically insignificant change in the Burke-Fahn-Marsden Dystonia Movement Scale (<20%), but where other evaluation measures demonstrated clinical efficacy across several domains. RESULTS: Despite no significant change in Burke-Fahn-Marsden Dystonia Rating Scale scores following deep brain stimulation, parallel outcome measures demonstrated significant benefit in a range of child and family-centred goal areas including: pain and comfort, school attendance, seating tolerance, access to assistive technology and in some cases carer burden. CONCLUSIONS: Sole use of impairment-focused measures, are limited in scope to evaluate outcome following deep brain stimulation, particularly in secondary dystonias. Systematic study of effects across multiple dimensions of disability is needed to determine what deep brain stimulation offers patients in terms of function, participation, care, comfort and quality of life. Deep brain stimulation may offer meaningful change across multiple domains of functioning, disability and health even in the absence of significant change in dystonia rating scales. PMID- 22258089 TI - Contribution of gender and body fat distribution to inflammatory marker concentrations in apparently healthy young adults. AB - OBJECTIVE: This cross-sectional study assessed the potential contribution of gender, body fat distribution, and their interactions to some inflammatory marker concentrations [C-reactive protein (CRP), complement factor 3 (C3), and ceruloplasmin (Cp)] in young adults. METHODS: Measurements included body composition, lifestyle features, blood biochemical and selected inflammatory markers on 317 healthy subjects [122 males/195 females; 22 +/- 3 years; 22.1 +/- 2.8 kg/m(2) (mean +/- SD)]. RESULTS: Women had significantly higher CRP and Cp concentrations than men. No gender difference was noted in C3 concentrations. In a multivariate model of the whole sample, body fat (BF), waist circumference (WC) and the sex * WC interaction term presented the highest R (2) for variance of CRP (11%), C3 (2%), and Cp (12%), respectively. In regression models separated by sex, BF was the adiposity indicator that explained the variability of CRP in men (13%) and women (7%). WC was the only variable significantly associated with C3 concentrations in women (3%). BF presented the highest partial R (2) for Cp in men (8%) and WC in women (16%). CONCLUSION: Our findings indicate a relevant interaction between gender and body fat distribution on the variance of CRP, C3, and Cp concentrations in apparently healthy young adults. PMID- 22258090 TI - The fabrication and cell culture of three-dimensional rolled scaffolds with complex micro-architectures. AB - Cell cultures for tissue engineering are traditionally prepared on two dimensional or three-dimensional scaffolds with simple pores; however, this limits mass transportation, which is necessary for cell viability and function. In this paper, an innovative method is proposed for fabricating porous scaffolds with designed complex micro-architectures. Channels devised by computer-aided design were used to simulate features of blood vessels in native rat liver. Rapid prototyping and microreplication were used to produce a negative polydimethylsiloxane mold, and then a planar porous scaffold with predefined microchannel parameters was obtained by freeze-drying a silk fibroin/gelatin solution of an optimized concentration. After seeding with rat primary hepatocytes, the planar scaffold was rolled up to build spatial channels. By reconstructing the three-dimensional channel model in the scaffold in the form of micro-computed topography data and observing the cross-sections of the scroll, we confirmed that the bent channels were still interconnected, with restricted deviations. A comparison of the primary hepatocyte culture in the scaffolds with and without the devised channels proved that our design influenced cell organization and improved cell survival and proliferation. This method can be used for the construction of complex tissues for implantation and for culturing cells in vitro for biological tests and observations. PMID- 22258091 TI - Oxidative stress and autophagy: mediators of synapse growth? AB - Many neurodegenerative conditions have oxidative stress burdens where levels of reactive oxygen species (ROS) exceed the antioxidant capacity of the neuron. ROS can induce wide-ranging damage in a cell and this is prevented by the activation of antioxidant responses including autophagy. Jun-kinase (JNK) is stimulated by ROS and mediates antioxidant responses via the activation of the transcriptional activators Fos and Jun (AP-1). In recently published work we examined Drosophila mutants with overgrown larval neuromuscular synapses, mutants that also show all the hallmarks of lysosomal storage disease (LSD). We find that we can reverse this synaptic overgrowth by reducing the oxidative stress burden, and that synaptic overgrowth is mediated by autophagy and JNK-AP-1 activity. We also examined animals defective for protection from oxidative stress and found that they too have synapse overgrowth generated by JNK-AP-1 activity. Treatment of larvae with a known ROS-generating toxin, paraquat, yielded similar synaptic responses. The observations that oxidative stress responses, potentially acting through autophagy, can generate synaptic growth suggest that ROS may be a potent regulator of synapse size and function. These findings have intriguing implications for aging neurons, neurodegenerative conditions and the interpretation of metabolic demand during learning and memory. PMID- 22258092 TI - The role of autophagy in endoplasmic reticulum stress-induced pancreatic beta cell death. AB - In pancreatic beta-cells, the endoplasmic reticulum (ER) is the crucial site for insulin biosynthesis, as this is where the protein-folding machinery for secretory proteins is localized. Perturbations to ER function of the beta-cell, such as those caused by high levels of free fatty acid and insulin resistance, can lead to an imbalance in protein homeostasis and ER stress, which has been recognized as an important mechanism for type 2 diabetes. Macroautophagy (hereafter referred to as autophagy) is activated as a novel signaling pathway in response to ER stress. In this review, we outline the mechanism of ER stress mediated beta-cell death and focus on the role of autophagy in ameliorating ER stress. The development of drugs to take advantage of the potential protective effect of autophagy in ER stress, such as glucagon like peptide-1, will be a promising avenue of investigation. PMID- 22258093 TI - Reconstitution of leucine-mediated autophagy via the mTORC1-Barkor pathway in vitro. AB - Supplementation of branched chain amino acids, especially leucine, is critical to improve malnutrition by regulating protein synthesis and degradation. Emerging evidence has linked leucine deprivation induced protein breakdown to autophagy. In this study, we aimed to establish a cell-free assay recapitulating leucine mediated autophagy in vitro and dissect its biochemical requirement. We found that in a cell-free assay, membrane association of Barkor/Atg14(L), a specific autophagosome-binding protein, is suppressed by cytosol from nutrient-rich medium and such suppression is released by nutrient deprivation. We also showed that rapamycin could efficiently reverse the suppression of nutrient rich cytosol, suggesting an essential role of mTORC1 in autophagy inhibition in this cell-free system. Furthermore, we demonstrated that leucine supplementation in the cultured cells blocks Barkor puncta formation and autophagy activity. Hence, we establish a novel cell-free assay recapitulating leucine-mediated autophagy inhibition in an mTORC1-dependent manner; this assay will help us to dissect the regulation of amino acids in autophagy and related human metabolic diseases. PMID- 22258094 TI - Family affluence, school and neighborhood contexts and adolescents' civic engagement: a cross-national study. AB - Research on youth civic engagement focuses on individual-level predictors. We examined individual- and school-level characteristics, including family affluence, democratic school social climate and perceived neighborhood social capital, in their relation to civic engagement of 15-year-old students. Data were taken from the 2006 World Health Organization Health Behaviour in School-aged Children survey. A sample of 8,077 adolescents in 10th grade from five countries (Belgium, Canada, Italy, Romania, England) were assessed. Multilevel models were analyzed for each country and across the entire sample. Results showed that family affluence, democratic school climate and perceived neighborhood social capital positively related to participation in community organizations. These links were stronger at the aggregate contextual than individual level and varied by country. Canadian youth participated most and Romanian youth least of the five countries. Gender predicted engagement in two countries (girls participate more in Canada, boys in Italy). Findings showed significant contributions of the social environment to adolescents' engagement in their communities. PMID- 22258095 TI - EndothelinA-endothelinB receptor cross-talk in rat basilar artery in situ. AB - The rationale for the therapeutic use of dual as opposed to selective endothelin (ET) receptor antagonists stems in part from cross-talk between the ET(A) and ET(B) receptors. However, whether ET(A)-ET(B) receptor cross-talk is present in the cerebral vasculature is difficult to discern since findings of cross-talk contrast even among the few reports available. Thus, this study tested whether ET(A)-ET(B) receptor cross-talk is present in the rat basilar artery. In an in situ cranial window, 0.1 MUM sarafotoxin S6c, an ET(B) receptor agonist, relaxed basilar artery basal tone by 54%. ET-1 (3 nM) in the absence and presence of 10 MUM BQ123, an ET(A) receptor agonist, induced 13% contraction and 15% relaxation, respectively. In contrast, the 3-nM ET-1 plateau contraction was relaxed by only ~50% by 3-10 MUM BQ123 and 10 MUM BQ610, ET(A) receptor antagonists. N(omega) nitro-L: -arginine, an NO synthase inhibitor, did not enhance contraction to 3 nM ET-1, suggesting that the partial relaxation of the ET-1 plateau contraction did not involve unmasked endothelial ET(B) receptor-mediated relaxation. The ~50% ET 1 contraction that remained following ET(A) receptor antagonist was relaxed by 3 10 MUM BQ788, consistent with an ET(B) receptor-mediated component of contraction. However, 10 MUM BQ788 in the absence of prior ET(A) receptor antagonist did not cause relaxation. Subsequent BQ123 addition in the presence of BQ788 completely relaxed the ET-1 contraction. PD145065 (1 MUM), an ET(A/B) receptor antagonist, completely relaxed 3-nM ET-1 contracted vessels in both the absence and presence of BQ123. These findings suggest that the inability of ET(A) receptor antagonist to completely relax the ET-1 plateau contraction in rat basilar artery is due to ET(A)-ET(B) receptor cross-talk. PMID- 22258096 TI - HOTf mediated cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes. AB - The cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes proceed smoothly in freshly distilled HOTf to give the corresponding tetrahydro 5H-benzo[c]fluorene derivatives in good yields along with high stereoselectivities under mild conditions. PMID- 22258097 TI - Temperature responses of carbon monoxide and hydrogen uptake by vegetated and unvegetated volcanic cinders. AB - Ecosystem succession on a large deposit of volcanic cinders emplaced on Kilauea Volcano in 1959 has resulted in a mosaic of closed-canopy forested patches and contiguous unvegetated patches. Unvegetated and unshaded surface cinders (Bare) experience substantial diurnal temperature oscillations ranging from moderate (16 degrees C) to extreme (55 degrees C) conditions. The surface material of adjacent vegetated patches (Canopy) experiences much smaller fluctuations (14-25 degrees C) due to shading. To determine whether surface material from these sites showed adaptations by carbon monoxide (CO) and hydrogen (H(2)) consumption to changes in ambient temperature regimes accompanying succession, we measured responses of CO and H(2) uptake to short-term variations in temperature and long term incubations at elevated temperature. Based on its broader temperature optimum and lower activation energy, Canopy H(2) uptake was less sensitive than Bare H(2) uptake to temperature changes. In contrast, Bare and Canopy CO uptake responded similarly to temperature during short-term incubations, indicating no differences in temperature sensitivity. However, during extended incubations at 55 degrees C, CO uptake increased for Canopy but not Bare material, which indicated that the former was capable of thermal adaptation. H(2) uptake for material from both sites was completely inhibited at 55 degrees C throughout extended incubations. These results indicated that plant development during succession did not elicit differences in short-term temperature responses for Bare and Canopy CO uptake, in spite of previously reported differences in CO oxidizer community composition, and differences in average daily and extreme temperatures. Differences associated with vegetation due to succession did, however, lead to a notable capacity for thermophilic CO uptake by Canopy but not Bare material. PMID- 22258098 TI - The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates. AB - The human gastrointestinal tract (GI tract) harbors a complex community of microbes. The microbiota composition varies between different locations in the GI tract, but most studies focus on the fecal microbiota, and that inhabiting the colonic mucosa. Consequently, little is known about the microbiota at other parts of the GI tract, which is especially true for the small intestine because of its limited accessibility. Here we deduce an ecological model of the microbiota composition and function in the small intestine, using complementing culture independent approaches. Phylogenetic microarray analyses demonstrated that microbiota compositions that are typically found in effluent samples from ileostomists (subjects without a colon) can also be encountered in the small intestine of healthy individuals. Phylogenetic mapping of small intestinal metagenome of three different ileostomy effluent samples from a single individual indicated that Streptococcus sp., Escherichia coli, Clostridium sp. and high G+C organisms are most abundant in the small intestine. The compositions of these populations fluctuated in time and correlated to the short-chain fatty acids profiles that were determined in parallel. Comparative functional analysis with fecal metagenomes identified functions that are overrepresented in the small intestine, including simple carbohydrate transport phosphotransferase systems (PTS), central metabolism and biotin production. Moreover, metatranscriptome analysis supported high level in-situ expression of PTS and carbohydrate metabolic genes, especially those belonging to Streptococcus sp. Overall, our findings suggest that rapid uptake and fermentation of available carbohydrates contribute to maintaining the microbiota in the human small intestine. PMID- 22258099 TI - Variation in local carrying capacity and the individual fate of bacterial colonizers in the phyllosphere. AB - Using a phyllosphere model system, we demonstrated that the term 'carrying capacity', as it is commonly used in microbial ecology, needs to be understood as the sum of many 'local carrying capacities' in order to better explain and predict the course and outcome of bacterial colonization of an environment. Using a green fluorescent protein-based bioreporter system for the quantification of reproductive success (RS) in individual Erwinia herbicola cells, we were able to reconstruct the contribution of individual immigrants to bacterial population sizes on leaves. Our analysis revealed that plant foliage represents to bacteria an environment where individual fate is determined by the local carrying capacity of the site where an immigrant cell lands. With increasing inoculation densities, the RS of most immigrants declined, suggesting that local carrying capacity under the tested conditions was linked to local nutrient availability. Fitting the observed experimental data to an adapted model of phyllosphere colonization indicated that there might exist three types of sites on leaves, which differ in their frequency of occurrence and local carrying capacity. Specifically, our data were consistent with a leaf environment that is characterized by few sites where individual immigrants can produce high numbers of offspring, whereas the remainder of the leaf offered an equal number of sites with low and medium RS. Our findings contribute to a bottom-up understanding of bacterial colonization of leaf surfaces, which includes a quantifiable role of chance in the experience at the individual level and in the outcome at the population level. PMID- 22258100 TI - Links between viruses and prokaryotes throughout the water column along a North Atlantic latitudinal transect. AB - Viruses are an abundant, diverse and dynamic component of marine ecosystems and have a key role in the biogeochemical processes of the ocean by controlling prokaryotic and phytoplankton abundance and diversity. However, most of the studies on virus-prokaryote interactions in marine environments have been performed in nearshore waters. To assess potential variations in the relation between viruses and prokaryotes in different oceanographic provinces, we determined viral and prokaryotic abundance and production throughout the water column along a latitudinal transect in the North Atlantic. Depth-related trends in prokaryotic and viral abundance (both decreasing by one order of magnitude from epi- to abyssopelagic waters), and prokaryotic production (decreasing by three orders of magnitude) were observed along the latitudinal transect. The virus-to-prokaryote ratio (VPR) increased from ~19 in epipelagic to ~53 in the bathy- and abyssopelagic waters. Although the lytic viral production decreased significantly with depth, the lysogenic viral production did not vary with depth. In bathypelagic waters, pronounced differences in prokaryotic and viral abundance were found among different oceanic provinces with lower leucine incorporation rates and higher VPRs in the North Atlantic Gyre province than in the provinces further north and south. The percentage of lysogeny increased from subpolar regions toward the more oligotrophic lower latitudes. Based on the observed trends over this latitudinal transect, we conclude that the viral-host interactions significantly change among different oceanic provinces in response to changes in the biotic and abiotic variables. PMID- 22258101 TI - Non-coding RNAs in marine Synechococcus and their regulation under environmentally relevant stress conditions. AB - Regulatory small RNAs (sRNAs) have crucial roles in the adaptive responses of bacteria to changes in the environment. Thus far, potential regulatory RNAs have been studied mainly in marine picocyanobacteria in genetically intractable Prochlorococcus, rendering their molecular analysis difficult. Synechococcus sp. WH7803 is a model cyanobacterium, representative of the picocyanobacteria from the mesotrophic areas of the ocean. Similar to the closely related Prochlorococcus it possesses a relatively streamlined genome and a small number of genes, but is genetically tractable. Here, a comparative genome analysis was performed for this and four additional marine Synechococcus to identify the suite of possible sRNAs and other RNA elements. Based on the prediction and on complementary microarray profiling, we have identified several known as well as 32 novel sRNAs. Some sRNAs overlap adjacent coding regions, for instance for the central photosynthetic gene psbA. Several of these novel sRNAs responded specifically to environmentally relevant stress conditions. Among them are six sRNAs changing their accumulation level under cold stress, six responding to high light and two to iron limitation. Target predictions suggested genes encoding components of the light-harvesting apparatus as targets of sRNAs originating from genomic islands and that one of the iron-regulated sRNAs might be a functional homolog of RyhB. These data suggest that marine Synechococcus mount adaptive responses to these different stresses involving regulatory sRNAs. PMID- 22258104 TI - Incidence and cause of hypertension during adrenal radiofrequency ablation. AB - PURPOSE: To evaluate the incidence and cause of hypertension prospectively during adrenal radiofrequency ablation (RFA). METHODS: For this study, approved by our institutional review board, written informed consent was obtained from all patients. Patients who received RFA for adrenal tumors (adrenal ablation) and other abdominal tumors (nonadrenal ablation) were included in this prospective study. Blood pressure was monitored during RFA. Serum adrenal hormone levels including epinephrine, norepinephrine, dopamine, and cortisol levels were measured before and during RFA. The respective incidences of procedural hypertension (systolic blood pressure >200 mmHg) of the two patient groups were compared. Factors correlating with procedural systolic blood pressure were evaluated by regression analysis. RESULTS: Nine patients underwent adrenal RFA and another 9 patients liver (n = 5) and renal (n = 4) RFA. Asymptomatic procedural hypertension that returned to the baseline by injecting calcium blocker was found in 7 (38.9%) of 18 patients. The incidence of procedural hypertension was significantly higher in the adrenal ablation group (66.7%, 6/9) than in the nonadrenal ablation group (11.1%, 1/9, P < 0.0498). Procedural systolic blood pressure was significantly correlated with serum epinephrine (R (2) = 0.68, P < 0.0001) and norepinephrine (R (2) = 0.72, P < 0.0001) levels during RFA. The other adrenal hormones did not show correlation with procedural systolic blood pressure. CONCLUSION: Hypertension occurs frequently during adrenal RFA because of the release of catecholamine. PMID- 22258105 TI - Overseas trained doctors in Australia call for inquiry into registration system. PMID- 22258106 TI - Reducing greenhouse gas emissions: on target? PMID- 22258108 TI - Highly sensitive and selective detection of beryllium ions using a microcantilever modified with benzo-9-crown-3 doped hydrogel. AB - A microcantilever sensor modified by chitosan/gelatin hydrogels that are doped with benzo-9-crown-3 has been developed for the sensitive and selective detection of beryllium ions in an aqueous solution. The microcantilever undergoes bending deflection upon exposure to Be(2+) due to selective absorption of Be(2+) in the hydrogel. The detection limit is 10(-11) M. Other metal ions, such as Li(+), Na(+), K(+), Mg(2+), and Ca(2+), have a marginal effect on the deflection of the microcantilever. The mechanism of the bending is discussed and the results showed that the microcantilever may be used for in situ detection of beryllium. PMID- 22258109 TI - Immunostaining of dissected zebrafish embryonic heart. AB - Zebrafish embryo becomes a popular in vivo vertebrate model for studying cardiac development and human heart diseases due to its advantageous embryology and genetics. About 100-200 embryos are readily available every week from a single pair of adult fish. The transparent embryos that develop ex utero make them ideal for assessing cardiac defects. The expression of any gene can be manipulated via morpholino technology or RNA injection. Moreover, forward genetic screens have already generated a list of mutants that affect different perspectives of cardiogenesis. Whole mount immunostaining is an important technique in this animal model to reveal the expression pattern of the targeted protein to a particular tissue. However, high resolution images that can reveal cellular or subcellular structures have been difficult, mainly due to the physical location of the heart and the poor penetration of the antibodies. Here, we present a method to address these bottlenecks by dissecting heart first and then conducting the staining process on the surface of a microscope slide. To prevent the loss of small heart samples and to facilitate solution handling, we restricted the heart samples within a circle on the surface of the microscope slides drawn by an immEdge pen. After the staining, the fluorescence signals can be directly observed by a compound microscope. Our new method significantly improves the penetration for antibodies, since a heart from an embryonic fish only consists of few cell layers. High quality images from intact hearts can be obtained within a much reduced procession time for zebrafish embryos aged from day 2 to day 6. Our method can be potentially extended to stain other organs dissected from either zebrafish or other small animals. PMID- 22258110 TI - Catecholamine pathway gene variation is associated with norepinephrine and epinephrine concentrations at rest and after exercise. AB - OBJECTIVE: To examine the hypothesis that genetic variation in enzymes and transporters associated with synthesis, storage, release, and metabolism of catecholamines contributes to the interindividual variability in plasma catecholamine concentrations at rest and after exercise. METHODS: We measured plasma norepinephrine (NE) and epinephrine concentrations at rest and after a standardized exercise protocol in 165 healthy individuals (60% White, 40% African American) and examined 29 functional or common variants in 14 genes involved in synthesis, transport, or metabolism of catecholamines. We examined the relationship between genotypes and NE concentrations at rest and the increase after exercise (DeltaNE) by multiple linear regression with adjustment for covariates [age, race, sex, BMI, fitness, and resting NE (for DeltaNE)]. As a secondary outcome, we carried out similar analyses for epinephrine concentrations. RESULTS: There was large interindividual variability in resting NE (mean, 204+/-102 pg/ml; range, 39-616 pg/ml) and DeltaNE (mean, 256+/-206 pg/ml; range, -97 to 953 pg/ml). Resting NE was significantly associated with variants of four genes: CYB561 (P<0.001), VMAT2 (P=0.016), CHGA (P=0.039), and PNMT (P=0.038). DeltaNE after exercise was associated with three variants of PNMT (P=0.041) and COMT (P=0.033 and 0.035), and resting and exercise epinephrine concentrations were associated with two variants each. CONCLUSION: The findings of this exploratory study suggest that variation in catecholamine pathway genes contributes to the interindividual variability in plasma NE and epinephrine concentrations at rest and after exercise. PMID- 22258111 TI - Comorbidity and cardiovascular risk factors in adult GH deficiency following treatment for Cushing's disease or non-functioning pituitary adenomas during childhood. AB - OBJECTIVE: Cushing's disease (CD) and non-functioning pituitary adenoma (NFPA) are rare in paediatric patients. The aim of this study was to describe long-term consequences in adults with GH deficiency (GHD) treated for CD or NFPA during childhood. DESIGN, PATIENTS AND METHODS: This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Background characteristics, anthropometry and comorbidity were studied in 47 patients diagnosed with childhood-onset (CO)-CD and 62 patients with CO-NFPA. Data from 100 ACTH-sufficient patients with CO-idiopathic hypopituitarism (CO-Idio) were used for comparison. Cardiovascular risk profile was analysed at baseline and at 1 year on GH treatment in a subgroup of patients (17 CO-CD, 24 CO-NFPA and 55 CO Idio) not receiving GH treatment at study entry. RESULTS: The median age at diagnosis of pituitary tumour was 14.0 years (range 10-17) in patients with CO-CD and 13.7 years (range 8-17) in CO-NFPA. In addition to GHD, 41% of patients with CO-CD had three or four other pituitary hormone deficiencies compared with 78% of patients with CO-NFPA (P<0.001). Eighty-nine per cent of patients with CO-CD had height SDS lower than 0 compared with 61% of patients with CO-NFPA (P=0.002). Hypertension was more common in CO-CD compared with CO-Idio (23 vs 9%, P=0.018). At 1 year on GH treatment, total- and low-density lipoprotein-cholesterol decreased significantly in CO-CD but not in CO-NFPA. CONCLUSION: Adult patients with GHD following treatment for paediatric CD and NFPA have long-term adverse consequences. Despite more severe hypopituitarism in CO-NFPA, patients with CO-CD have more frequently compromised final stature. PMID- 22258112 TI - Persistence at 1 year of oral antiosteoporotic drugs: a prospective study in a comprehensive health insurance database. AB - OBJECTIVE: Treatments against osteoporosis have demonstrated fracture risk reduction but persistence to therapy remains a major issue. Intermittent regimens have been developed to improve persistence. The aim of this 1-year prospective study was to compare, in the general population, the persistence of various oral regimens of antiosteoporotic treatment. METHODS: We conducted this prospective study in the French comprehensive public health insurance database of the Rhone Alpes region. Women aged 45 years or older who had a first reimbursement of an oral antiosteoporotic treatment during February 2007 composed the study cohort. Persistence was defined by the proportion of patients refilling a prescription in the pharmacist delivery register (ERASME). Using statistical analyses like Kaplan Meier survival curves and log-rank tests, we compared the treatment persistence of strontium ranelate, raloxifene, and daily-, weekly-, and monthly bisphosphonates. RESULTS: Two thousand four hundred and nineteen patients were included over a period of 1 month and followed up for 12 months. Two hundred and eighty-nine (11.9%) patients were treated with monthly bisphosphonates, 1298 (53.7%) with weekly bisphosphonates, and 832 (34.4%) with daily treatments (526 strontium ranelate (21.7%), 296 raloxifene (12.2%), and 10 bisphosphonates (0.4%)). At 1 year, overall persistence was 34%. Fifty percent of patients on monthly bisphosphonates were still persistent while only 37% of patients on weekly bisphosphonates, 34% on raloxifene, and 16% on strontium ranelate were persistent. Therapy monitoring with biochemical markers or bone mineral density was associated with improved persistence. CONCLUSION: Overall persistence at 1 year was low, but intermittent regimens were associated with higher persistence rates, along with women who had therapy monitoring. PMID- 22258113 TI - Candidate genes within a 143 kb region of the flower sex locus in Vitis. AB - Wild Vitis species are dioecious plants, while the cultivated counterpart, Vitis vinifera subspec. vinifera, generally shows hermaphroditic flowers. In Vitis the genetic determinants of flower sex have previously been mapped to a region on chromosome 2. In a combined strategy of map-based cloning and the use of the publicly available grapevine reference genome sequence, the structure of the grapevine flower sex locus has been elucidated with the subsequent identification of candidate genes which might be involved in the development of the different flower sex types. In a fine mapping approach, the sex locus in grapevine was narrowed down using a population derived from a cross of a genotype with a Vitis vinifera background ('Schiava Grossa' * 'Riesling') with the male rootstock cv. 'Borner' (V. riparia * V. cinerea). A physical map of 143 kb was established from BAC clones spanning the 0.5 cM region defined by the closest flanking recombination break points. Sequencing and gene annotation of the entire region revealed several candidate genes with a potential impact on flower sex formation. One of the presumed candidate genes, an adenine phosphoribosyltransferase, was analysed in more detail. The results led to the development of a marker for the presence or absence of the female alleles, while the male and hermaphroditic alleles are still to be differentiated. The impact of other candidate genes is discussed, especially with regard to plant hormone actions. The markers developed will permit the selection of female breeding lines which do not require laborious emasculation thus considerably simplifying grapevine breeding. The genetic finger prints displayed that our cultivated grapevines frequently carry a female allele while homozygous hermaphrodites are rare. PMID- 22258114 TI - Applicability of current diagnostic algorithms in geriatric patients suspected of new, slow onset heart failure. AB - BACKGROUND: referral for echocardiography for all geriatric outpatients suspected of heart failure (HF) is not feasible. Diagnostic algorithms could be helpful. OBJECTIVE: to investigate whether available diagnostic algorithms accurately identify (older) patients (aged 70 years or over) eligible for echocardiography, with acceptable numbers of false-negatives. METHODS: algorithms (European Society of Cardiology (ESC)) guideline, National Institute for Health and Clinical Excellence (NICE) guideline, multidisciplinary guideline the Netherlands (NL) and algorithm by Mant et al. were validated in 203 geriatric patients (mean age 82 +/ 6 years, 30% men) suspected of new, slow onset HF. HF was adjudicated by an outcome panel. Applicability of algorithms was evaluated by calculating proportion of patients (i) referred for echocardiography, (ii) with HF among referred patients and (iii) without HF in the non-referred. RESULTS: ninety-two (45%) patients had HF. Applying algorithms resulted in referral for echocardiography in 52% (normal NT-proBNP; ESC), 72% (normal ECG; ESC), 56% (NICE), 93% (NL) and 70% (Mant) of all patients, diagnosing HF in 78, 56, 76, 49 and 62% of those referred, respectively. In patients not referred for echocardiography HF was absent in 90, 82, 93, 100 and 95%, respectively. CONCLUSION: the ESC NT-proBNP (<400 pg/ml)-based algorithm combines the lowest number of referrals for echocardiography (of whom 78% has HF) with a limited number (10%) of false negatives in the non-referred. PMID- 22258115 TI - Questionnaire study of the association between patient numbers and regular visiting by general practitioners in care homes. AB - BACKGROUND: regular visiting in care homes enables proactive care. Surveys of managers found variation in medical care yet little is known about factors influencing general practitioners (GPs) visiting patterns. We examined whether practice factors including numbers of registered patients are associated with regular visiting. DESIGN AND SETTING: postal questionnaires sent to 73 care homes of European Care Group and separate questionnaires to visiting practices. METHODS: information on regularity of visiting was requested from homes and practices. Practices were asked for numbers of doctors and training status. As data were not normally distributed, non-parametric tests were used to compare practices regularly visiting with those visiting only on request in terms of numbers of registered care home patients. RESULTS: forty-seven (64%) of homes responded, with care provided for 1,867 patients by 162 practices. Practices visiting regularly had significantly more patients than practices that did not [median (IQR) 32 (28) versus 3 (5), P < 0.001]. Ninety-five (31%) of practices responded showing a similar association of registrations with regular visiting [median (IQR) 20 (37) versus 4 (4), P < 0.001]. There was no association between numbers of doctors or training status on regular visiting. CONCLUSION: the number of registered patients is strongly associated with regular care home visiting. Aligning practices with care homes thereby increasing registered patients per practice could encourage proactive care. PMID- 22258117 TI - Li-Na ternary amidoborane for hydrogen storage: experimental and first-principles study. AB - Li-Na ternary amidoborane, Na[Li(NH(2)BH(3))(2)], was recently synthesized by reacting LiH and NaH with NH(3)BH(3). This mixed-cation amidoborane shows improved dehydrogenation performance compared to that of single-cation amidoboranes, i.e., LiNH(2)BH(3) and NaNH(2)BH(3). In this paper, we synthesized the Li-Na ternary amidoborane by blending and re-crystallizing equivalent LiNH(2)BH(3) and NaNH(2)BH(3) in tetrahydrofuran (THF), and employed first principles calculations and the special quasirandom structure (SQS) method to theoretically explore the likelihood for the existence of Li(1 x)Na(x)(NH(2)BH(3)) for various Li/Na ratios. The thermodynamic, electronic and phononic properties were investigated to understand the possible dehydrogenation mechanisms of Na[Li(NH(2)BH(3))(2)]. PMID- 22258116 TI - Platelet immunoglobulin and amyloid precursor protein as potential peripheral biomarkers for Alzheimer's disease: findings from a pilot study. AB - BACKGROUND: the diagnosis of dementia, in particular Alzheimer's disease (AD), is enhanced with the use of molecular biomarkers. Since cerebrospinal fluid analysis and molecular neuroimaging are not routinely used in many countries, blood biomarker molecules may be more readily applicable in a routine clinical setting. METHODS: twenty-five subjects with a clinical diagnosis of AD and 26 control participants were assessed for cognitive and behavioural functioning. Platelet measures of amyloid protein precursor (APP), tau protein, clusterin, alpha synuclein and immunoglobulin (Ig) were measured. Linear regression analysis for platelet proteins and cognitive and behavioural status were determined, and receiver operating characteristic (ROC) curves created to assess the discriminating power of each biochemical parameter between AD and control groups. RESULTS: both AD and control subjects had similar platelet levels of measures platelet proteins, with the exception of slightly elevated Ig levels in AD subjects (P = 0.052). The latter were not related to increasing age, or extent of cognitive impairment. APP-N measures were negatively correlated with cognitive scores. CONCLUSION: these preliminary findings suggest that platelet measures of the traditional biomarkers for AD are feasible in the periphery. The measures of platelet APP-N and Ig, in particular, merit further study in a larger cohort of AD and control subjects. PMID- 22258118 TI - The end of evidence-based medicine? AB - It is customary for physicians and surgeons to recommend treatments that have the highest probability of getting the patient a good outcome. Deciding treatment based on results (outcomes actually achieved) has been advocated for hundreds of years. We are now in an era when practice recommendations are supposed to be based on evidence from randomized controlled trials. There are many defects in relying on RCTs which are reviewed in this article. Advantages of observational studies are outlined, and the importance of assessing one's actual results when applying a treatment based on controlled trial evidence is set out. PMID- 22258119 TI - Consecutive multilevel vertebral Paget's disease of the lumbar spine: a rare Asian case and the differential diagnosis. PMID- 22258122 TI - Baby and breast: a dynamic interaction. PMID- 22258120 TI - The use of the Lima reverse shoulder arthroplasty for the treatment of fracture sequelae of the proximal humerus. AB - BACKGROUND: Experience treating proximal humerus fracture sequelae with reverse total shoulder arthroplasty is limited. We report our results. PATIENTS: Forty four patients with sequelae of a proximal humeral fracture were treated with a reverse total shoulder prosthesis. There were 26 women and 18 men, with a mean age of 77 years (range, 74-84 years). The mean follow-up after reverse arthroplasty was 48 months (range, 40-84 months). RESULTS: The mean Constant score increased from 28 preoperatively to 58 postoperatively (p < 0.0001). The average anterior elevation increased from 40 degrees to 100 degrees (p < 0.0001), abduction from 41 degrees to 95 degrees (p < 0.0001), external rotation from 15 degrees to 35 degrees (p < 0.0001) and internal rotation from 25 degrees to 60 degrees (p < 0.0001). The average subjective shoulder score increased from 13% preoperatively to 56% postoperatively (p < 0.0001). All but six patients would undergo the same procedure again if faced with the same problem. Twenty-four patients were very satisfied, 14 satisfied and 6 unhappy with the operation. Six prosthetic dislocations occurred (13.6%). Two of them were successfully treated by adding an extension to the humeral neck component to increase the offset and tension. In the other four dislocations this procedure failed, and the prosthesis was revised and converted to a hemiarthroplasty. There was one case of glenoid component loosening that was converted to a hemiarthroplasty. CONCLUSIONS: The reverse total shoulder arthroplasty improves function and motion in patients with proximal humeral fracture sequelae. However, the dislocation rate is high. PMID- 22258123 TI - Neonatal T-cell maturation and homing receptor responses to Toll-like receptor ligands differ from those of adult naive T cells: relationship to prematurity. AB - INTRODUCTION: Inflammation and infection are associated with premature birth and with activation of the fetal immune system. We hypothesized that exposure to microbial Toll-like receptor (TLR) ligands plays an important role in neonatal T cell maturation and that early exposure to microbial products may result in early T-cell maturation and a tendency for these matured effector cells to change their homing receptor patterns. RESULTS: Expression of the CD45RO marker was induced in term neonatal T cells after in vitro exposure to TLR ligands for 7 days. Interestingly, naive T cells from adult blood were unaffected by TLR ligand exposure. In addition, neonatal T cells had more cells with decreased expression of the alpha4beta7 integrins and increased expression of CCR4 after in vitro exposure of TLR ligands-similar to the expression of these molecules in adult naive T cells. DISCUSSION: These findings are relevant for the understanding of neonatal T-cell maturation and may contribute to our understanding of multiorgan inflammatory complications of prematurity. METHODS: Cord blood was obtained from term and preterm infants. Using flow cytometry, we identified a mature (CD45RO(+)) phenotype in preterm infant cord blood (CB) T cells that had decreased expression of the alpha4beta7 integrins and increased expression of the C-C chemokine receptor 4 (CCR4) as compared with term infant CB. PMID- 22258124 TI - Neuronal nitric oxide synthase, nNOS, regulates renal hemodynamics in the postnatal developing piglet. AB - INTRODUCTION: Nitric oxide (NO) vasodilation critically modulates renal hemodynamics in the neonate compared with the adult. Based on the postnatal expression pattern of renal neuronal nitric oxide synthase (nNOS), the hypothesis was that nNOS is the major NOS isoform regulating renal hemodynamics in the immature, but not mature, kidney. RESULTS: NOS inhibitors did not alter mean arterial pressure (MAP) in either group. Intrarenal S-methyl-L-thiocitrulline (L SMTC) in newborns significantly reduced renal blood flow (RBF) 38 +/- 4%, glomerular filtration rate (GFR) 42 +/- 6%, and increased renal vascular resistance (RVR) 37 +/- 7%, whereas intrarenal L-nitro-arginine methyl ester (L NAME) affected RBF, GFR, and RVR equivalent to L-SMTC treatment. When L-NAME was administered after L-SMTC treatment, newborn renal hemodynamic changes were not further altered from what was observed when L-SMTC was administered alone. In contrast, in the adult, only intrarenal L-NAME, and not L-SMTC, affected renal hemodynamic responses. DISCUSSION: In conclusion, these studies demonstrate that nNOS is an important regulator of renal hemodynamics in the newborn kidney, but not in the adult. METHODS: Experiments compared renal hemodynamic responses with intrarenal infusion of L-NAME, an inhibitor of all NOS isoforms, with the selective nNOS inhibitor L-SMTC in the newborn piglet and the adult pig. PMID- 22258125 TI - Preterm birth with antenatal corticosteroid administration has injurious and persistent effects on the structure and composition of the aorta and pulmonary artery. AB - INTRODUCTION: Preterm birth affects 8-12% of live births and is associated with the development of elevated arterial blood pressure and aortic narrowing in later life; this suggests that preterm birth may alter the development of arteries. Our objective was to determine the effects of preterm birth, accompanied by antenatal corticosteroid administration, on the structure of the aorta and pulmonary artery, which experience different alterations in pressure flow at birth. RESULTS: At 11 wk, preterm lambs had significantly thicker aortic walls and a smaller lumen, whereas the morphometry of the pulmonary artery was unaffected. Elastin deposition was markedly increased in the aorta and pulmonary artery and smooth muscle content was reduced in the aorta only. In preterm lambs we found injury in the aorta only; controls were unaffected. DISCUSSION: We conclude that moderate preterm birth after antenatal betamethasone can cause injury and persistent alterations in the structure and composition of the aorta, with lesser effects in the pulmonary artery. Our findings suggest that preterm birth may increase the risk of atherosclerosis and aortic aneurysms in later life. METHODS: Using an established ovine model of preterm birth, lambs were born at 0.9 of gestation and underwent necropsy at 11 wk after birth; controls were born at term. PMID- 22258126 TI - Changes in the frequency and in vivo vessel-forming ability of rhesus monkey circulating endothelial colony-forming cells across the lifespan (birth to aged). AB - INTRODUCTION: We have identified a novel hierarchy of human endothelial colony forming cells (ECFCs) that are functionally defined by their proliferative and clonogenic potential and in vivo vessel-forming ability. The rhesus monkey provides an excellent model in which to examine the changes in circulating concentrations and functions of ECFCs since this nonhuman primate possesses a long lifespan and has been used extensively to model age-related processes that occur in humans. RESULTS: Endothelial cells (ECs) derived from rhesus monkey ECFCs share a cell-surface phenotype similar to human cord blood ECFCs, rapidly form capillary-like structures in vitro, and form endothelial-lined vessels in vivo upon implantation in immunodeficient mice in an age-dependent manner. Of interest, although ECFCs from the oldest monkeys formed capillary-like structures in vitro, the cells failed to form inosculating vessels when implanted in vivo and displayed a deficiency in cytoplasmic vacuolation in vitro; a critical first step in vasculogenesis. DISCUSSION: Utilizing previously established clonogenic assays for defining different subpopulations of human ECFCs, we have shown that a hierarchy of ECFCs, identical to human cells, can be isolated from the peripheral blood of rhesus monkeys, and that the frequency of the circulating cells varies with age. These studies establish the rhesus monkey as an important preclinical model for evaluating the role and function of circulating ECFCs in vascular homeostasis and aging. METHODS: Peripheral blood samples were collected from 40 healthy rhesus monkeys from birth to 24 years of age for ECFC analysis including immunophenotyping, clonogenic assays, and in vivo vessel formation. PMID- 22258128 TI - Inhibition of neuroblastoma cell proliferation with omega-3 fatty acids and treatment of a murine model of human neuroblastoma using a diet enriched with omega-3 fatty acids in combination with sunitinib. AB - INTRODUCTION: We investigated the use of dietary omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) in the treatment of neuroblastoma both as a sole agent and in combination with sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor. RESULTS: Substitution of all dietary fat with menhaden oil (omega-3 PUFA rich) resulted in a 40-70% inhibition of tumor growth and a statistically significant difference in the levels of several PUFAs (18:2 omega 6, 20:4 omega-6, 22:4 omega-6, 20:5 omega-3) as compared with a control diet. Furthermore, tumors from animals on the omega-3 fatty acid (FA)-enriched diet had an elevated triene/tetraene ratio suggestive of a change in local eicosanoid metabolism in these tissues similar to that seen with essential fatty acid deficiency. The omega-3 FA-enriched diet also decreased tumor-associated inflammatory cells and induced mitochondrial changes suggestive of mitochondrial damage. Combination treatment with sunitinib resulted in further reduction in tumor proliferation and microvessel density. DISCUSSION: These findings suggest a potential role for omega-3 PUFAs in the combination treatment of neuroblastoma. METHODS: We used a murine model of orthotopic and subcutaneous human neuroblastoma and diets that differ in the FA content to define the optimal dietary omega-3/omega-6 (omega-6) FA ratio required for the inhibition of these tumors. PMID- 22258127 TI - Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. AB - INTRODUCTION: Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension. RESULTS: PPHN was significantly (P < 0.05) associated with genetic variants in corticotropin-releasing hormone (CRH) receptor 1, CRHR1 and CRH-binding protein, CRHBP. Association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutations were found in the bone morphogenetic protein receptor type II (BMPR2) gene. DISCUSSION: We describe previously unreported genetic associations between PPHN and CRHR1 and CRHBP. These findings may have implications for further understanding the pathophysiology of PPHN and treatment. METHODS: We performed a family-based candidate gene study to examine a genetic association with PPHN and sequenced the BMPR2 gene in 72 individuals. We enrolled 110 families with infants diagnosed with PPHN based on inclusion criteria. After medical chart review, 22 subjects were excluded based on predefined criteria, and DNA samples from 88 affected infants and at least one parent per infant were collected and genotyped. Thirty-two single-nucleotide polymorphisms in 12 genes involved in vasoconstriction/vasodilation, lung development, surfactant regulation, or vascular endothelial cell function were investigated using family based association tests. PMID- 22258129 TI - Magnetic resonance imaging of the neonatal piglet brain. AB - INTRODUCTION: Appeal for the domestic pig as a preclinical model for neurodevelopmental research is increasing. One limitation, however, is lack of magnetic resonance imaging (MRI) methods for brain volume quantification in the neonatal piglet. The purpose of this study was to develop and validate MRI methods for estimating brain volume in piglets. RESULTS: The results showed that MRI and manual segmentation reliably estimated the changes in volume of different brain regions in 2- and 5-wk-old piglets. Substantial increases in the volumes of all brain regions examined were evident during the 3-wk period. DISCUSSION: MRI can provide accurate estimates of brain region volume during the neonatal period in piglets. A piglet model that can be used in longitudinal studies may be useful for investigating how experimental (e.g., nutrition, infection) factors affect brain growth and development. METHODS: Anatomic MRI data (non-longitudinal) were acquired 2- and 5-wk-old piglets using a three--dimensional T1-weighted magnetization-prepared gradient echo (MPRAGE) sequence on a MAGNETOM Trio 3T imager. Manual segmentation was performed for volume estimates of total brain, cortical, diencephalon, brainstem, cerebellar, and -hippocampal regions. The MRI based hippocampal volume estimates in 2- and 5-wk-old piglets were validated using histological techniques and the Cavalieri method. PMID- 22258130 TI - MR imaging correlates of white-matter pathology in a preterm baboon model. AB - INTRODUCTION: Cerebral white-matter (WM) abnormalities on magnetic resonance imaging (MRI) correlate with neurodevelopmental disability in infants born prematurely. RESULTS: Quantitative histological measures of WM and ventricular volumes correlated with qualitative MRI scores of WM volume loss and ventriculomegaly. Diffuse astrocytosis was associated with signal abnormality on T(2)-weighted imaging and higher apparent diffusion coefficient in WM. Loss of oligodendrocytes was associated with lower relative anisotropy characterized by higher radial diffusivity values. The relationship between histopathology and MRI abnormalities was more pronounced in animals in the 28 d model, equivalent to the term human infant. DISCUSSION: MRI reflects microstructural and anatomical abnormalities that are characteristic of WM injury in the preterm brain, and these changes are more evident on MRI at term-equivalent postmenstrual age. METHODS: We assessed the histopathological correlates of MRI abnormalities in a baboon model of premature birth. Baboons were delivered at 125 d of gestation (dg, term ~185 dg) and maintained in an animal intensive care unit for 14 (n = 26) or 28 d (n = 17). Gestational control animals were delivered at 140 dg (n = 9) or 153 dg (n = 4). Cerebral WM in fixed brains was evaluated using MRI, diffusion tensor imaging (DTI), and histopathology. PMID- 22258131 TI - Histopathologic correlation with diffusion tensor imaging after chronic hypoxia in the immature ferret. AB - INTRODUCTION: Chronic hypoxia in rodents induces white matter (WM) injury similar to that in human preterm infants. We used diffusion tensor imaging (DTI) and immunohistochemistry to study the impact of hypoxia in the immature ferret at two developmental time points relevant to the preterm and term brain. RESULTS: On ex vivo imaging, the apparent diffusion coefficient (ADC) was decreased throughout the WM after 10 days of hypoxia (hypoxia from postnatal day 10 (P10) to P20 and killed at P20 (early hypoxia P20)), corresponding to increased astrocytosis and decreased myelination. Diffusion values normalized after 10 days of normoxia (hypoxia from P10 to P20 and killed at P30 (early hypoxia P30)), but immunohistochemistry revealed significant astrocytosis and hypomyelination. In contrast, ADC and anisotropy were increased after 10 days of hypoxia at a later developmental time point (hypoxia from P20 to P30 and killed at P30 (late hypoxia P30)), with less astrocytosis and more prominent myelination. DISCUSSION: The patterns of alteration in imaging and histology varied in relation to the developmental time at which hypoxia occurred. Normalization of diffusion measures did not correspond to the normalization of underlying histopathology. METHODS: Ferrets were subjected to 10% hypoxia and divided into three groups: early hypoxia P20, early hypoxia P30, and late hypoxia P30. PMID- 22258132 TI - Depression of whole-brain oxygen extraction fraction is associated with poor outcome in pediatric traumatic brain injury. AB - INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Metabolic failure is an integral component of the pathological aftermath of TBI. The oxygen extraction fraction (OEF) is a valuable parameter for characterization and description of metabolic abnormalities; however, OEF measurement has required either invasive procedures or the use of ionizing radiation, which significantly limits its use in pediatric research. RESULTS: Patients with TBI had depressed OEF levels that correlated with the severity of injury. In addition, the OEF measured within 2 weeks of injury was predictive of patient outcome at 3 mo after injury. In pediatric TBI patients, low OEF-a marker of metabolic dysfunction-correlates with the severity of injury and outcome. DISCUSSION: Our findings support previous literature on the role of metabolic dysfunction after TBI. METHODS: Using a recently developed magnetic resonance (MR) technique for the measurement of oxygen saturation, we determined the whole-brain OEF in both pediatric TBI patients and in healthy controls. Injury and outcome were classified using pediatric versions of the Glasgow Coma Scale (GCS) and Glasgow Outcome Scale-Extended (GOS-E), respectively. PMID- 22258133 TI - Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. AB - INTRODUCTION: We sought to determine whether 18- to 22-mo neurodevelopmental outcomes predicted functional outcomes at 7-8 y for survivors of the CoolCap study of therapeutic hypothermia for neonates with hypoxic-ischemic encephalopathy. RESULTS: WeeFIM ratings were completed at 7-8 y of age on 62 (32 cooled; 30 standard care) of 135 surviving children who had had neurodevelopmental assessment at 18 mo. There was 1 refusal, 58 lost to follow up, and 14 children whose centers declined to participate. Disability status at 18 mo was strongly associated with WeeFIM ratings (P < 0.001); there was no significant effect of treatment (P = 0.83). DISCUSSION: Functional outcome at 7-8 y of survivors of neonatal encephalopathy is associated with 18-mo neurodevelopmental assessment, supporting the long-term predictive value of a favorable outcome at 18 mo assessed by published trials of therapeutic hypothermia. METHODS: All surviving children who participated in the CoolCap study and were assessed at 18 mo were eligible for reassessment using the WeeFIM instrument that qualitatively measures self-care, mobility, and cognitive function. Center investigators obtained consent from the families for a certified researcher to administer the WeeFIM instrument by phone. PMID- 22258134 TI - Maternal preeclampsia and risk of bronchopulmonary dysplasia in preterm infants. AB - INTRODUCTION: To better understand whether preeclampsia (PE) increases the risk of bronchopulmonary dysplasia (BPD). RESULTS: Of 753 infants alive at 36 wks, 138 (18.3%) were exposed to PE. BPD was not significantly related to exposure to PE either before (odds ratio (OR) 0.73; 95% confidence interval (CI) 0.50, 1.06) or after adjustment for confounding variables (adjusted OR 1.14; 95% CI 0.71, 1.81). If infants were selected by gestational age alone, there was no association (OR 1.05; 95% CI 0.63, 1.75). In contrast, selecting by birth weight alone, PE was associated with a significant reduction in BPD (OR 0.61, 95% CI 0.41, 0.91). However, this effect disappeared after adjustment for confounding variables. DISCUSSION: Conclusions were unchanged when data from other studies were included in a pooled analysis. PE does not significantly affect the risk of BPD in extremely preterm (EP) or extremely-low-birth-weight (ELBW) subjects. METHODS: We examined data on EP (<28 wks gestation) or ELBW (<1,000 g) infants live born in Victoria, Australia, in three eras: 1991-1992, 1997, and 2005. We compared the incidence of BPD (oxygen requirement at 36 wks' postmenstrual age) in the PE group (infants exposed to PE) with that in the remainder (nonexposed infants). We also contrasted results with comparable reported studies. PMID- 22258135 TI - Birth outcomes associated with cannabis use before and during pregnancy. AB - INTRODUCTION: This study aimed to examine the association between cannabis use before and during pregnancy and birth outcomes. RESULTS: Overall, 26.3% of women reported previous use of cannabis and 2.6% reported current use. Multivariate analysis, controlling for potential confounders, including tobacco smoking, alcohol consumption, and use of other illicit drugs, showed that cannabis use in pregnancy was associated with low birth weight (odds ratio (OR) = 1.7; 95% confidence interval (CI): 1.3-2.2), preterm labor (OR = 1.5; 95% CI: 1.1-1.9), small for gestational age (OR = 2.2; 95% CI: 1.8-2.7), and admission to the neonatal intensive care unit (OR = 2.0; 95% CI: 1.7-2.4). DISCUSSION: The results of this study show that the use of cannabis in pregnancy is associated with increased risk of adverse birth outcomes. Prevention programs that address cannabis use during pregnancy are needed. METHODS: Data were from women birthing at the Mater Mothers' Hospital in Brisbane, Australia, over a 7-y period (2000 2006). Women were interviewed in the initial antenatal visit about their use of cannabis and other substances. Records for 24,874 women who provided information about cannabis use, and for whom birth outcomes data were available, were included in the analysis. PMID- 22258136 TI - Changes in immunomodulatory constituents of human milk in response to active infection in the nursing infant. AB - INTRODUCTION: To investigate whether immunologic factors in breast milk change in response to nursing infants' infection. RESULTS: Total CD45 leukocyte count dropped from 5,655 (median and interquartile range: 1,911; 16,871) in the acute phase to 2,122 (672; 6,819) cells/ml milk after recovery with macrophage count decreasing from 1,220 (236; 3,973) to 300 (122; 945) cells/ml. Tumor necrosis factor-alpha (TNFalpha) levels decreased from 3.66 +/- 1.68 to 2.91 +/- 1.51 pg/ml. The decrease in lactoferrin levels was of borderline statistical significance. Such differences were not recorded in samples of the controls. Interleukin-10 levels decreased in the sick infants' breast milk after recovery, but also in the healthy controls, requiring further investigation. Secretory immunoglobulin A levels did not change significantly in the study or control group. DISCUSSION: During active infection in nursing infants, the total number of white blood cells, specifically the number of macrophages, and TNFalpha levels increase in their mothers' breast milk. These results may support the dynamic nature of the immune defense provided by breastfeeding sick infants. METHODS: Breast milk from mothers of 31 infants, up to 3 months of age, who were hospitalized with fever, was sampled during active illness and recovery. Milk from mothers of 20 healthy infants served as controls. PMID- 22258137 TI - [HDL level or HDL function as the primary target in preventive cardiology]. AB - The risk for myocardial infarction can be reduced by almost 50% solely by lowering LDL cholesterol. Despite success reducing LDL and cholesterol, atherosclerosis and myocardial infarction remain significant challenges. However, mechanisms of the reverse cholesterol transport system might be used more effectively in the foreseeable future. Although the benefit of high HDL cholesterol appears to be obvious, most clinical trials aimed at increasing HDL cholesterol failed to generate convincing results. Therefore, the question arises as to whether indeed only HDL level or perhaps rather more HDL function is of considerable therapeutic relevance. If function is the crucial issue drugs such as CETP (cholesteryl ester transfer protein) activators or SR-B1 (scavenger receptor type B-1) upregulators could be beneficial. These types of drugs could improve HDL metabolism and might have beneficial effects despite the fact that they lower HDL levels. Ongoing studies on next generation CETP inhibitors and nicotinic acid will clarify this question and might help in our struggle against atherosclerosis. PMID- 22258138 TI - A regenerative microchannel neural interface for recording from and stimulating peripheral axons in vivo. AB - Neural interfaces are implanted devices that couple the nervous system to electronic circuitry. They are intended for long term use to control assistive technologies such as muscle stimulators or prosthetics that compensate for loss of function due to injury. Here we present a novel design of interface for peripheral nerves. Recording from axons is complicated by the small size of extracellular potentials and the concentration of current flow at nodes of Ranvier. Confining axons to microchannels of ~100 um diameter produces amplified potentials that are independent of node position. After implantation of microchannel arrays into rat sciatic nerve, axons regenerated through the channels forming 'mini-fascicles', each typically containing ~100 myelinated fibres and one or more blood vessels. Regenerated motor axons reconnected to distal muscles, as demonstrated by the recovery of an electromyogram and partial prevention of muscle atrophy. Efferent motor potentials and afferent signals evoked by muscle stretch or cutaneous stimulation were easily recorded from the mini-fascicles and were in the range of 35-170 uV. Individual motor units in distal musculature were activated from channels using stimulus currents in the microampere range. Microchannel interfaces are a potential solution for applications such as prosthetic limb control or enhancing recovery after nerve injury. PMID- 22258142 TI - Characterization of a carcinogenesis-associated long non-coding RNA. AB - A negative selection strategy was used in the present study to isolate long polyA minus RNAs from the total transcriptome and a long non-coding RNA named Yiya was identified. Yiya is a 1.9 kb long intergenic ncRNA gene mapped to chromosome 1q41, a well-established cancer susceptibility locus. Expression profiling revealed a general and regulated expression pattern of Yiya in major tissues, and more interestingly, identified elevated mRNA levels in different cancers. Quantitative analysis further demonstrated a dynamic regulation of Yiya expression in cell cycle progression, suggesting that it was involved in cell cycle regulation. Supporting this, overexpression of Yiya promotes cell cycle progression at the G1/S transition, therefore identifying Yiya as a cell-cycle associated long non-coding RNA. PMID- 22258141 TI - Evolutionarily conserved A-to-I editing increases protein stability of the alternative splicing factor Nova1. AB - The structural complexity of the vertebrate brain is mirrored by its unparalleled transcriptome complexity. In particular, two post-transcriptional processes, alternative splicing and RNA editing, greatly diversify brain transcriptomes. Here we report a close connection between these two processes: we show A-to-I RNA editing in Nova1, a key brain-specific regulator of alternative splicing. Nova1 editing levels increase during embryonic development in mouse and chicken brains and show significant variation across postnatal brain regions. Evolutionary conservation of both editing and editing-associated RNA secondary structure of the Nova1 mRNA for 300 million years attests to the functional importance of Nova1 editing. Using a combination of different assays in human HEK293T cell lines, we report a novel post-translational role for this RNA editing. Whereas functional assays showed no effect of RNA editing on the regulatory splicing activity of the encoded proteins, we found evidence that edited forms exhibit reduced proteasome targeting and increased protein half-life. In addition, we found evidence for similar regulation of protein half-life by an evolutionarily conserved alternative splicing event in Nova1. These results open new venues of research on the multi-level integration of gene expression by: (1) revealing the novel role of RNA editing in regulating protein stability, and (2) establishing protein stability as a new target of multifaceted regulation. PMID- 22258143 TI - Pseudogenes are not pseudo any more. AB - Recent significant progress toward understanding the function of pseudogenes in protozoa (Trypanosoma brucei), metazoa (mouse) and plants, make it pertinent to provide a brief overview on what has been learned about this fascinating subject. We discuss the regulatory mechanisms of pseudogenes at the post-transcriptional level and advance new ideas toward understanding the evolution of these, sometimes called "garbage genes" or "junk DNA," seeking to stimulate the interest of scientists and additional research on the subject. We hope this point-of-view can be helpful to scientists working or seeking to work on these and related issues. PMID- 22258144 TI - RNase III initiates rapid degradation of proU mRNA upon hypo-osmotic stress in Escherichia coli. AB - Hyper-osmotic stress strongly induces expression of the Escherichia coli proU operon encoding a high affinity uptake system for the osmoprotectants glycine betaine and proline betaine. Osmoregulation of proU takes place at the transcriptional level by upregulation of the promoter at high osmolarity and repression of transcription by the nucleoid-associated protein H-NS at low osmolarity. In the present study, we describe an additional level of proU osmoregulation that is independent of transcriptional regulation. We show that osmoregulation occurs at a post-transcriptional level involving RNase III. RNase III specifically processes the proU mRNA within a conserved secondary structure extending from position +203 to +293 of the transcript. Processing is efficient at low osmolarity, but inhibited at high osmolarity. Blocking of RNase III processing by mutation of the processing site eliminates post-transcriptional osmoregulation of proU. Further, the proU mRNA is relatively stable at high osmolarity with a half-life of approximately 65 sec. However, upon osmotic downshift, RNase III immediately processes the proU mRNA which reduces its half life to less than 4 sec. The data suggest that the primary role of RNase III mediated processing of proU mRNA is to ensure rapid shutdown of proU upon hypo osmotic stress. PMID- 22258145 TI - The HIV-1 Rev response element: an RNA scaffold that directs the cooperative assembly of a homo-oligomeric ribonucleoprotein complex. AB - The HIV-1 Rev response element (RRE) is a ~350 nucleotide, highly structured, cis acting RNA element essential for viral replication. It is located in the env coding region of the viral genome and is extremely well conserved across different HIV-1 isolates. It is present on all partially spliced and unspliced viral mRNA transcripts, and serves as an RNA framework onto which multiple molecules of the viral protein Rev assemble. The Rev-RRE oligomeric complex mediates the export of these messages from the nucleus to the cytoplasm, where they are translated to produce essential viral proteins and/or packaged as genomes for new virions. PMID- 22258146 TI - Single base mismatches in the mRNA target site allow specific seed region mediated off-target binding of siRNA targeting human coagulation factor 7. AB - We have analyzed the off-target activity of two siRNAs (F7-1, F7-2) that knock down human blood coagulation factor 7 mRNA. F7-1 modulates a significant number of non-target transcripts while F7-2 shows high selectivity for the target transcript under various experimental conditions. The 3'-UTRs of all F7-1 off target genes show statistically significant enrichment of the reverse complement of the F7-1 siRNA seed region located in the guide strand. Seed region enrichment was confirmed in off-target transcripts modulated by siRNA targeting the glucocorticoid receptor. To investigate how these sites contribute to off-target recognition of F7-1, we employed CXCL5 transcript as model system because it contains five F7-1 seed sequence motifs with single base mismatches. We show by transient transfection of reporter gene constructs into HEK293 cells that three out of five sites located in the 3'-UTR region are required for F7-1 off-target activity. For further mechanistic dissection, the sequences of these sites were synthesized and inserted either individually or joined in dimeric or trimeric constructs. Only the fusion constructs were silenced by F7-1 while the individual sites had no off-target activity. Based on F7-1 as a model, a single mismatch between the siRNA seed region and mRNA target sites is tolerated for target recognition and the CXCL5 data suggest a requirement for binding to multiple target sites in off-target transcripts. PMID- 22258147 TI - Interleukin-6 receptor specific RNA aptamers for cargo delivery into target cells. AB - Aptamers represent an emerging strategy to deliver cargo molecules, including dyes, drugs, proteins or even genes, into specific target cells. Upon binding to specific cell surface receptors aptamers can be internalized, for example by macropinocytosis or receptor mediated endocytosis. Here we report the in vitro selection and characterization of RNA aptamers with high affinity (Kd = 20 nM) and specificity for the human IL-6 receptor (IL-6R). Importantly, these aptamers trigger uptake without compromising the interaction of IL-6R with its natural ligands the cytokine IL-6 and glycoprotein 130 (gp130). We further optimized the aptamers to obtain a shortened, only 19-nt RNA oligonucleotide retaining all necessary characteristics for high affinity and selective recognition of IL-6R on cell surfaces. Upon incubation with IL-6R presenting cells this aptamer was rapidly internalized. Importantly, we could use our aptamer, to deliver bulky cargos, exemplified by fluorescently labeled streptavidin, into IL-6R presenting cells, thereby setting the stage for an aptamer-mediated escort of drug molecules to diseased cell populations or tissues. PMID- 22258148 TI - Potential G-quadruplexes in the human long non-coding transcriptome. AB - DNA G-quadruplexes are known as modulators of transcription. More recently G quadruplexes, located in the untranslated regions of the mRNA of protein coding genes, have been described to negatively regulate gene expression at the post transcriptional/ translational levels. Here we describe the possibility of the existence of G-quadruplexes in non-coding RNA (ncRNA) and discuss their potential biological roles. Using an in house prediction tool (Quadfinder) we observe a significant occurrence and distribution of G-quadruplexes in ncRNA of various sizes. We also observe that most of non-coding RNAs harboring these potential quadruplex motifs peak at the sizes ranging from 200-300 bases. More importantly we report enrichment for single and dinucleotide loops indicating a degree of high stability of these G-quadruplexes and their potential functions in vivo. Subsequent in vitro analyses of a subset of these sequences were performed which support our predictions. PMID- 22258149 TI - Small aminoacyl transfer centers at GU within a larger RNA. AB - Separate aminoacyl transfer centers related to the small ...GUNNN..: NNNU ribozyme seem possible at the frequent GU sequences dispersed throughout an RNA tertiary structure. In fact, such activity is easily detected and varies more than 2 orders in rate, probabably being faster at sites with less structural constraint. Analysis of a particular constrained active site in an rRNA transcript suggests that its difficulty lies not in substrate strand association, but in binding and/or group transfer from the aminoacyl precursor. Efficient aminoacyl transfer requires accurate complementarity between large or small ribozymes and oligoribonucleotide substrates, even when only three or four base pairs link the two. Thus, multi-site active ribozymal superstructures might have coordinated an RNA metabolism, including aiding an early translation apparatus. PMID- 22258150 TI - A conserved microRNA/NMD regulatory circuit controls gene expression. AB - Nonsense-mediated decay (NMD) is a RNA surveillance pathway that degrades subsets of normal and aberrant mRNAs. Mutations that perturb NMD cause neurological disorders in humans, suggesting that NMD has roles in the brain. Recently, it was shown that NMD is repressed during neural development to allow for the stabilization of NMD mRNA targets. The repression of NMD during development is mediated by a neuron-expressed microRNA, miR-128, which participates in a highly conserved regulatory circuit. miR-128 is induced in differentiating neuronal cells and during brain development, leading to repressed NMD and the consequent upregulation of batteries of mRNAs encoding proteins important for neuron differentiation and function. Together with other results, this suggests the existence of a complex network linking the microRNA and NMD pathways that induce cell-specific transcripts. In this point-of-view article, we will discuss the repercussions of this discovery for neuronal development, brain function and disease. PMID- 22258151 TI - Human mitochondrial tRNA quality control in health and disease: a channelling mechanism? AB - Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. These single nucleotide substitutions in various domains of tRNA molecules may affect different steps of tRNA biogenesis. Often, the prominent decrease of aminoacylation and/or steady-state levels of affected mitochondrial tRNA have been demonstrated in patients' tissues and in cultured cells. Similar effect has been observed for pathogenic mutations in nuclear genes encoding mitochondrial aminoacyl-tRNA-synthetases, while over-expression of mitochondrial aminoacyl-tRNA synthetases or elongation factor EF-Tu rescued mutated tRNAs from degradation. In this review we summarize experimental data concerning the possible regulatory mechanisms governing mitochondrial tRNA steady state levels, and propose a hypothesis based on the tRNA channelling principle. According to this hypothesis, interaction of mitochondrial tRNA with proteins ensures not only tRNA synthesis, maturation and function, but also protection from degradation. Mutations perturbing this interaction lead to decreased tRNA stability. PMID- 22258152 TI - Small RNAs of the Bradyrhizobium/Rhodopseudomonas lineage and their analysis. AB - Small RNAs (sRNAs) play a pivotal role in bacterial gene regulation. However, the sRNAs of the vast majority of bacteria with sequenced genomes still remain unknown since sRNA genes are usually difficult to recognize and thus not annotated. Here, expression of seven sRNAs (BjrC2a, BjrC2b, BjrC2c, BjrC68, BjrC80, BjrC174 and BjrC1505) predicted by genome comparison of Bradyrhizobium and Rhodopseudomonas members, was verified by RNA gel blot hybridization, microarray and deep sequencing analyses of RNA from the soybean symbiont Bradyrhizobium japonicum USDA 110. BjrC2a, BjrC2b and BjrC2c belong to the RNA family RF00519, while the other sRNAs are novel. For some of the sRNAs we observed expression differences between free-living bacteria and bacteroids in root nodules. The amount of BjrC1505 was decreased in nodules. By contrast, the amount of BjrC2a, BjrC68, BjrC80, BjrC174 and the previously described 6S RNA was increased in nodules, and accumulation of truncated forms of these sRNAs was observed. Comparative genomics and deep sequencing suggest that BjrC2a is an antisense RNA regulating the expression of inositol-monophosphatase. The analyzed sRNAs show a different degree of conservation in Rhizobiales, and expression of homologs of BjrC2, BjrC68, BjrC1505, and 6S RNA was confirmed in the free-living purple bacterium Rhodopseudomonas palustris 5D. PMID- 22258155 TI - Robot-assisted gait training in patients with Parkinson disease: a randomized controlled trial. AB - BACKGROUND: . Gait impairment is a common cause of disability in Parkinson disease (PD). Electromechanical devices to assist stepping have been suggested as a potential intervention. OBJECTIVE: . To evaluate whether a rehabilitation program of robot-assisted gait training (RAGT) is more effective than conventional physiotherapy to improve walking. METHODS: . A total of 41 patients with PD were randomly assigned to 45-minute treatment sessions (12 in all), 3 days a week, for 4 consecutive weeks of either robotic stepper training (RST; n = 21) using the Gait Trainer or physiotherapy (PT; n = 20) with active joint mobilization and a modest amount of conventional gait training. Participants were evaluated before, immediately after, and 1 month after treatment. Primary outcomes were 10-m walking speed and distance walked in 6 minutes. RESULTS: . Baseline measures revealed no statistical differences between groups, but the PT group walked 0.12 m/s slower; 5 patients withdrew. A statistically significant improvement was found in favor of the RST group (walking speed 1.22 +/- 0.19 m/s [P = .035]; distance 366.06 +/- 78.54 m [P < .001]) compared with the PT group (0.98 +/- 0.32 m/s; 280.11 +/- 106.61 m). The RAGT mean speed increased by 0.13 m/s, which is probably not clinically important. Improvements were maintained 1 month later. CONCLUSIONS: . RAGT may improve aspects of walking ability in patients with PD. Future trials should compare robotic assistive training with treadmill or equal amounts of overground walking practice. PMID- 22258154 TI - The effects of acute and chronic steady state methadone on memory retrieval in rats. AB - RATIONALE: Although widely prescribed to treat opioid addiction, little is known about the possible side effects of methadone on memory functions. OBJECTIVES: The aim of this study is to compare the effects of acute and chronic methadone on memory retrieval in rats and to explore the selectivity of possible deficits. METHODS: Administration of acute (0, 1.25, 2.5, and 5 mg/kg SC) and chronic steady state methadone (0, 10, 30, and 55 mg/kg/day SC by osmotic mini-pump) was tested on recall of three different types of information: stimulus-reward (10-arm parallel maze), stimulus-response (8-arm radial maze), and stimulus-stimulus (Barnes maze). Acute and steady state methadone doses were also compared on tests of locomotor activity and reactivity to aversive stimuli (i.e., swimming and acoustic startle). RESULTS: In the stimulus-reward task, acute methadone impaired performance as a result of severe depression of locomotion. This motor deficit, however, was modulated by the motivational valence of environmental stimulation. In fact, acute methadone did not eliminate forced swimming behavior. In the stimulus-response and stimulus-stimulus tasks, accuracy was impaired independently of direct motor deficits, but rats were hyper-reactive to aversive stimulation and, in fact, 5 mg/kg enhanced acoustic startle. Importantly, chronic steady state methadone did not affect accuracy of memory retrieval, did not depress motor or swimming activity, and did not change startle reactivity. CONCLUSION: Only acute methadone impaired accuracy and/or performance on three tests of memory retrieval. These findings in rats suggest that memory deficits reported in methadone-maintained individuals may not be directly attributable to methadone. PMID- 22258156 TI - Combined central and peripheral stimulation to facilitate motor recovery after stroke: the effect of number of sessions on outcome. AB - BACKGROUND: Proof-of-principle studies have demonstrated transient beneficial effects of transcranial direct current stimulation (tDCS) on motor function in stroke patients, mostly after single treatment sessions. OBJECTIVE: To assess the efficacy of multiple treatment sessions on motor outcome. METHODS: The authors examined the effects of two 5-day intervention periods of bihemispheric tDCS and simultaneous occupational/physical therapy on motor function in a group of 10 chronic stroke patients. RESULTS: The first 5-day period yielded an increase in Upper-Extremity Fugl-Meyer (UE-FM) scores by 5.9 +/- 2.4 points (16.6% +/- 10.6%). The second 5-day period resulted in further meaningful, although significantly lower, gains with an additional improvement of 2.3 +/- 1.4 points in UE-FM compared with the end of the first 5-day period (5.5% +/- 4.2%). The overall mean change after the 2 periods was 8.2 +/- 2.2 points (22.9% +/- 11.4%). CONCLUSION: The results confirm the efficacy of bihemispheric tDCS in combination with peripheral sensorimotor stimulation. Furthermore, they demonstrate that the effects of multiple treatment sessions in chronic stroke patients may not necessarily lead to a linear response function, which is of relevance for the design of experimental neurorehabilitation trials. PMID- 22258157 TI - Former hand territory activity increases after amputation during intact hand movements, but is unaffected by illusory visual feedback. AB - BACKGROUND: In healthy adults, hand movements are controlled largely by the contralateral primary motor cortex. Following amputation, however, movements of the intact hand are accompanied by increased activity in the sensorimotor cortices of both cerebral hemispheres. OBJECTIVE: The authors tested whether use of the intact hand reactivates the cortical territory formerly devoted to the now missing hand and whether these effects can be augmented by motor imagery (MI) and/or exposure to illusory visual "feedback" (VF) of the absent hand created with a mirror. METHODS: Functional magnetic resonance imaging (fMRI) was used to delineate the boundaries of normative sensorimotor hand representations in healthy controls. Brain activity from 11 unilateral hand amputees was recorded while they performed aurally paced thumb-finger sequencing movements with their intact hands under 4 conditions: (1) motor execution of the intact hand alone (ME), (2) ME with corresponding MI of the amputated hand, (3) ME with VF of the amputated hand, and (4) ME with MI and VF. RESULTS: Intact hand movements increased activity specifically within the former sensorimotor hand territory during all conditions, an effect that may be attributable to decreased levels of interhemispheric inhibition and/or use-dependent functional reorganization following amputation. This effect was not significantly increased by the addition of VF and/or MI of the amputated hand. However, in amputees, MI was associated with an expansion of this ipsilateral response into parietal, premotor, and presupplementary motor areas. CONCLUSION: Active engagement of the intact hand may be critical for therapies seeking to stimulate the former hand territory. PMID- 22258158 TI - Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion. AB - Approximately 3% of the live-born infants have major dysmorphic features, and about two-thirds of which are observed in the maxillofacial region; however, in many cases, the etiology of the dysmorphic features remains uncertain. Recently, the genome-wide screening of large patient cohorts with congenital disorders has made it possible to discover genomic aberrations corresponding to the pathogenesis. In our analyses of more than 536 cases of clinically undiagnosed multiple congenital anomalies and mental retardation (MR) by microarray-based comparative genomic hybridization, we detected two non-consanguineous unrelated patients with microdeletions at 10p11.23-p12.1, which overlapped for 957 kb, including four protein-coding genes: ARMC4, MPP7, WAC and BAMBI. As the two patients had similar phenotypes; for example, MR and multiple maxillofacial abnormalities including midface retrusion, wide mouth and large tongue, we assessed the phenotypes in detail to define the common features, using quantitative evaluations of the maxillofacial dysmorphism. The concordance of the genetic and phenotypic alterations is a good evidence of a new syndrome. Although an interstitial deletion of 10p is rare, the current study is the first trial to examine precisely the craniofacial characteristics of patients with a heterozygous deletion at 10p11.23-p12.1, and presents good evidence to diagnose potential patients with the same genetic cause. PMID- 22258159 TI - Myotonic dystrophy type 2 is rare in the Japanese population. PMID- 22258160 TI - The effective peroxidase-like activity of chitosan-functionalized CoFe2O4 nanoparticles for chemiluminescence sensing of hydrogen peroxide and glucose. AB - Here, we report a highly simple and general protocol for functionalization of the CoFe(2)O(4) NPs with chitosan polymers in order to make CoFe(2)O(4) NPs disperse and stable in solution. The functionalized CoFe(2)O(4) NPs (denoted as CF CoFe(2)O(4) NPs) were characterized by scanning electron microscope (SEM), thermogravimetric (TG), X-ray diffraction (XRD) and FT-IR spectra. It was found that the CoFe(2)O(4) NPs were successfully decorated and uniformly dispersed on the surface of chitosan without agglomeration. The CF-CoFe(2)O(4) NPs were found to increase greatly the radiation emitted during the CL oxidation of luminol by hydrogen peroxide. Results of ESR spin-trapping experiments demonstrated that the CF-CoFe(2)O(4) NPs showed catalytic ability to H(2)O(2) decomposition into OH radicals. On this basis, a highly sensitive and rapid chemiluminescent method was developed for hydrogen peroxide in water samples and glucose in blood samples. Under optimum conditions, the proposed method allowed the detection of H(2)O(2) in the range of 1.0 * 10(-9) to 4.0 * 10(-6) M and glucose in the range of 5.0 * 10(-8) to 1.0 * 10(-5) M with detectable H(2)O(2) as low as 500 pM and glucose as low as 10 nM, respectively. This proposed method has been successfully applied to detect H(2)O(2) in environmental water samples and glucose in serum samples with good accuracy and precision. PMID- 22258161 TI - The prevalence of carpal tunnel syndrome in Latino poultry-processing workers and other Latino manual workers. AB - OBJECTIVE: To determine the prevalence of carpal tunnel syndrome (CTS) in Latino poultry-processing workers. METHODS: Symptoms and nerve conduction studies were used to prospectively assess 287 Latino poultry-processing workers and 226 Latinos in other manual-labor occupations. RESULTS: The prevalence of CTS was higher in poultry-processing (8.7%) compared with nonpoultry manual workers (4.0%; P < 0.0001). The adjusted odds ratio for the prevalence of CTS in poultry workers was 2.51 (95% confidence interval, 1.80-3.50) compared with nonpoultry workers. Within the poultry workers, those who performed packing, sanitation, and chilling had a trend toward less CTS than those who performed tasks requiring more repetitive and strenuous hand movements. DISCUSSION: Latino poultry processing workers have a high prevalence of CTS, which likely results from the repetitive and strenuous nature of the work. PMID- 22258162 TI - Mortality disparities in Appalachia: reassessment of major risk factors. AB - OBJECTIVE: To determine the predictive value of coal mining and other risk factors for explaining disproportionately high mortality rates across Appalachia. METHOD: Mortality and covariate data were obtained from publicly available databases for 2000 to 2004. Analysis employed ordinary least square multiple linear regression with age-adjusted mortality as the dependent variable. RESULTS: Age-adjusted all-cause mortality was independently related to Poverty Rate, Median Household Income, Percent High School Graduates, Rural-Urban Location, Obesity, Sex, and Race/Ethnicity, but not Unemployment Rate, Percent Uninsured, Percent College Graduates, Physician Supply, Smoking, Diabetes, or Coal Mining. CONCLUSIONS: Coal mining is not per se an independent risk factor for increased mortality in Appalachia. Nevertheless, our results underscore the substantial economic and cultural disadvantages that adversely impact health in Appalachia, especially in the coal-mining areas of Central Appalachia. PMID- 22258163 TI - In vitro assembly of semi-artificial molecular machine and its use for detection of DNA damage. AB - Naturally occurring bio-molecular machines work in every living cell and display a variety of designs. Yet the development of artificial molecular machines centers on devices capable of directional motion, i.e. molecular motors, and on their scaled-down mechanical parts (wheels, axels, pendants etc). This imitates the macro-machines, even though the physical properties essential for these devices, such as inertia and momentum conservation, are not usable in the nanoworld environments. Alternative designs, which do not follow the mechanical macromachines schemes and use mechanisms developed in the evolution of biological molecules, can take advantage of the specific conditions of the nanoworld. Besides, adapting actual biological molecules for the purposes of nano-design reduces potential dangers the nanotechnology products may pose. Here we demonstrate the assembly and application of one such bio-enabled construct, a semi-artificial molecular device which combines a naturally-occurring molecular machine with artificial components. From the enzymology point of view, our construct is a designer fluorescent enzyme-substrate complex put together to perform a specific useful function. This assembly is by definition a molecular machine, as it contains one. Yet, its integration with the engineered part - fluorescent dual hairpin - re-directs it to a new task of labeling DNA damage. Our construct assembles out of a 32-mer DNA and an enzyme vaccinia topoisomerase I (VACC TOPO). The machine then uses its own material to fabricate two fluorescently labeled detector units (Figure 1). One of the units (green fluorescence) carries VACC TOPO covalently attached to its 3'end and another unit (red fluorescence) is a free hairpin with a terminal 3'OH. The units are short lived and quickly reassemble back into the original construct, which subsequently recleaves. In the absence of DNA breaks these two units continuously separate and religate in a cyclic manner. In tissue sections with DNA damage, the topoisomerase-carrying detector unit selectively attaches to blunt-ended DNA breaks with 5'OH (DNase II-type breaks), fluorescently labeling them. The second, enzyme-free hairpin formed after oligonucleotide cleavage, will ligate to a 5'PO(4) blunt-ended break (DNase I-type breaks), if T4 DNA ligase is present in the solution. When T4 DNA ligase is added to a tissue section or a solution containing DNA with 5'PO(4) blunt-ended breaks, the ligase reacts with 5'PO(4) DNA ends, forming semi-stable enzyme-DNA complexes. The blunt ended hairpins will interact with these complexes releasing ligase and covalently linking hairpins to DNA, thus labeling 5'PO(4) blunt-ended DNA breaks. This development exemplifies a new practical approach to the design of molecular machines and provides a useful sensor for detection of apoptosis and DNA damage in fixed cells and tissues. PMID- 22258164 TI - Causes of unsuccessful ranibizumab treatment in exudative age-related macular degeneration in clinical settings. AB - PURPOSE: To identify the causes of loss of vision after ranibizumab therapy in patients with exudative age-related macular degeneration treated in three clinical settings. METHODS: A retrospective multicentric analysis of 290 consecutive eyes comprising cohorts from 3 clinical settings showed that 21 eyes lost >= 15 letters on the Early Treatment Diabetic Retinopathy Study chart 1 year after the start of ranibizumab treatment. Fundus images of these eyes were analyzed by two independent readers to investigate the causes of visual loss. The three cohorts were compared. A search was made for factors predisposing to visual loss. A second analysis was performed to compare the baseline characteristics of patients who gained (visual acuity gainers) or lost (visual acuity losers) >= 15 letters. RESULTS: Among the 290 eyes included, the proportions from each center experiencing visual loss were not significantly different (mean, 7.24%, P = 0.2631). Mean visual loss of affected eyes was 27 letters. There was no significant difference between these eyes and others as regards age and gender of patients, laterality, type of choroidal neovascularization, number of visits, or initial visual acuity. Visual loss was secondary to the progression of atrophy in eight eyes, fibrosis in five eyes, a combination of fibrosis and atrophy in three eyes, severe subretinal hemorrhage in three eyes, and retinal pigment epithelial tear in two eyes. A significant difference between visual acuity gainers and losers was observed for 2 parameters: age of patients, 80.9 +/- 5.3 years in visual acuity losers versus 77.5 +/- 7.3 years in visual acuity gainers (P = 0.0473) and visual acuity at diagnosis, respectively, 56.2 +/- 11.2 versus 49.0 +/- 12.0 (P = 0.0288). CONCLUSION: Although uncommon, visual loss may occur during ranibizumab treatment and is because of the natural course of age-related macular degeneration in most cases. PMID- 22258166 TI - Do you need a coach? PMID- 22258167 TI - Autoantibody testing in encephalopathies. PMID- 22258168 TI - A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order. AB - The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic, late-onset, slowly progressive ataxia. Clinical information such as age of onset, rate of progression, family history and certain non-cerebellar features can narrow the differential diagnosis. Brain MRI is almost obligatory and may reveal valuable diagnostic clues. Having ruled out structural lesions, the two other most common diagnoses are inflammatory and degenerative (including genetic) disorders. Although only a minority of underlying diseases are treatable, there are still many options for supportive care. PMID- 22258169 TI - Natalizumab-associated progressive multifocal leucoencephalopathy: a practical approach to risk profiling and monitoring. AB - Natalizumab reduces relapse frequency, delays onset of disease progression and improves disease outcomes in relapsing-remitting multiple sclerosis (MS) and is a cost-effective treatment for rapidly evolving severe relapsing-remitting MS. However, it is associated with the development of progressive multifocal leucoencephalopathy (PML), a serious opportunistic brain infection caused by a neurotropic strain of the JC virus (JCV). Until May 2011, 83 300 patients had received natalizumab for MS. One hundred and twenty-four patients had developed PML, of whom 23 (19%) died. In order to maximise the benefit-risk ratio of natalizumab for MS patients it is important to develop a strategy for risk profiling and monitoring for PML. Central to this is an understanding of the biology of the JCV and the emerging clinical picture of natalizumab-associated PML. This paper reviews the evidence for managing the risk of PML in natalizumab treated patients and the authors propose an algorithm for risk profiling and risk management. Key features of this algorithm include risk stratification based on emerging risk factors, heightened clinical vigilance for the clinical features of natalizumab-associated PML and considerations for temporary and permanent cessation of natalizumab dosing. PMID- 22258170 TI - When stopping the antiplatelet drugs stopped the 'TIAs'. PMID- 22258171 TI - Chorea-acanthocytosis. PMID- 22258172 TI - How to get the most from a consultation with a person who has a learning disability. PMID- 22258173 TI - How it feels to experience three different causes of respiratory failure. PMID- 22258174 TI - The unfolding tale of an unusual brain stem syndrome. PMID- 22258175 TI - Letter from Luxembourg. PMID- 22258176 TI - The horse that wouldn't run. PMID- 22258177 TI - Cranial nerve, spinal root and plexus hypertrophy in chronic inflammatory demyelinating polyneuropathy. PMID- 22258178 TI - Arthroscopic stabilization for Neer type 2 fracture of the distal clavicle fracture. AB - The distal clavicle fractures are divided into three types according to Neer's classification. Types 1 and 3 fractures are treated with a sling to immobilize the upper extremity. However, the treatment of type 2 fractures is controversial. We paid attention to the anatomic basis of type 2 fractures that the disruptions of the conoid ligament lead to the distraction between the two bony fragments. In this study, we describe the arthroscopic procedure to reconstruct the disrupted ligament and stabilize the fracture as a minimally invasive method. The subjects were seven patients with the distal clavicle fractures. According to Neer's or Rockwood's classification on plain radiographs, all seven patients were evaluated as type 2 or 2B, respectively. Our surgical procedure was performed with the patient in the beach chair position. We have used the artificial ligament with an EndoButton (Smith & Nephew Endoscopy, Andover, MA) as the substitute ligament to reconstruct the disrupted conoid ligament. The mean duration of postoperative follow-up was 2 years and 5 months. The bony union was achieved in all patients at a final follow-up. When concerning the range of motion at final examinations, mean forward flexion was 171 degrees , mean abduction was 165 degrees , mean internal rotation was Th11, and mean horizontal adduction was 132 degrees . It is possible to treat the distal clavicle fractures by a minimally invasive arthroscopic procedure without opening the fracture site of clavicle. PMID- 22258179 TI - Temporary cement tectoplasty: a technique to improve prefabricated hip spacer stability in two-stage surgery for infected hip arthroplasty. AB - This technical note describes an intraoperatively custom-made, antibiotic-loaded bone cement roof, used in conjunction with a prefabricated hip spacer to improve component stability, as part of the first stage of a two-stage procedure for an infected hip implant. This technique was successfully used in seven cases who presented with extensive superior and/or posterio-superior acetabular defect, which created a risk of spacer dislocation. With this technique we were able to avoid any further dislocation in these seven cases. We believe that the technique may reduce postoperative spacer dislocation in cases with extensive acetabular defects, while improving clinical outcomes. PMID- 22258180 TI - The human lactase persistence-associated SNP -13910*T enables in vivo functional persistence of lactase promoter-reporter transgene expression. AB - Lactase is the intestinal enzyme responsible for digestion of the milk sugar lactose. Lactase gene expression declines dramatically upon weaning in mammals and during early childhood in humans (lactase nonpersistence). In various ethnic groups, however, lactase persists in high levels throughout adulthood (lactase persistence). Genetic association studies have identified that lactase persistence in northern Europeans is strongly associated with a single nucleotide polymorphism (SNP) located 14 kb upstream of the lactase gene: -13910*C/T. To determine whether the -13910*T SNP can function in vivo to mediate lactase persistence, we generated transgenic mice harboring human DNA fragments with the 13910*T SNP or the ancestral -13910*C SNP cloned upstream of a 2-kb rat lactase gene promoter in a luciferase reporter construct. We previously reported that the 2-kb rat lactase promoter directs a post-weaning decline of luciferase transgene expression similar to that of the endogenous lactase gene. In the present study, the post-weaning decline directed by the rat lactase promoter is impeded by addition of the -13910*T SNP human DNA fragment, but not by addition of the 13910*C ancestral SNP fragment. Persistence of transgene expression associated with the -13910*T SNP represents the first in vivo data in support of a functional role for the -13910*T SNP in mediating the human lactase persistence phenotype. PMID- 22258181 TI - A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. AB - The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69 3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12-3.37, p = 0.018; OR 3.51, 95% CI 1.69-7.26, p = 0.001 and OR 2.05, 95% CI 1.25-3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85-3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05 3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17-3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurrence of fibrosis in patients with NAFLD. PMID- 22258182 TI - Multi-configurational quantum chemical studies of the Tc2X8(n-) (X = Cl, Br; n = 2, 3) anions. Crystallographic structure of octabromoditechnetate(3-). AB - The [Cs((2 + x))][H(3)O((1 - x))]Tc(2)Br(8).4.6H(2)O (x = 0.221) salt has been synthesized and characterized by single crystal XRD. Multi-configurational quantum chemical calculations on Tc(2)X(8)(n-) (X = Cl, Br; n = 2, 3) have been performed and indicate the pi component in the Tc-Tc bond to be stronger for n = 3. PMID- 22258183 TI - Unilateral lacrimal fistula in a patient with uterus didelphys and renal agenesis. AB - A 30-year-old female patient presented to our clinic because of lacrimation from an orifice close to the left lower eyelid. Ocular examinations and analyses revealed uterus didelphys and unilateral renal agenesis associated with a left lacrimal fistula. The patient underwent fistulectomy and external dacryocystorhinostomy. We decided to report on this patient owing to the unusual concurrent systemic abnormalities. PMID- 22258184 TI - Deep sulcus sign. PMID- 22258185 TI - Shoulder lipohaemarthrosis. PMID- 22258186 TI - Evaluation of the quality of different endodontic obturation techniques by digital radiography. AB - OBJECTIVES: This study was aimed to evaluate different endodontic obturation techniques (Thermafil, lateral condensation, and Tagger's hybrid technique) regarding the homogeneity of the obturation radiopacity. MATERIALS AND METHODS: Seventy roots of human upper central incisors were filled using the Thermafil system, lateral condensation. and Tagger's hybrid technique. Radiopacity of the filling was evaluated based on mean of grey levels, and its homogeneity was assessed by the coefficient of variation (CV), analyzing the histograms obtained of digitized and digital radiographs. RESULTS: The increase in mean grey levels (p < 0.001) and reduction in the CV (p < 0.05) were higher for Tagger's hybrid technique compared with other methods. CONCLUSIONS: Tagger's hybrid technique provided better homogeneity of the obturation radiopacity and better apical sealing compared with lateral condensation technique. CLINICAL RELEVANCE: The results suggest that Tagger's hybrid technique provided the best compaction of the root canal filling material, an important factor for the sealing of obturations and, consequently, for the effectiveness of treatment. PMID- 22258187 TI - Towards a synthetic view of potato cold and salt stress response by transcriptomic and proteomic analyses. AB - Potato can suffer from several abiotic stresses such as cold temperature, high soil salinity, lack of water or heavy metal exposure, to name a few. They are known to affect plant growth as well as productivity, with differential regulations at several levels. Potato response to cold and salt exposure was investigated at both transcriptomic and proteomic levels in a growth chamber experiment. Cold exposure in potato resulted in a higher number of significantly differentially regulated genes compared to salt exposure, whereas there were nearly three times more differentially regulated proteins after salt exposure when compared to cold exposure. The allocation of up and down-regulated genes at the functional category level also differed between salt and cold exposure although common trends, previously described in various abiotic stresses, were observed. In both stresses, the majority of photosynthesis-related genes were down-regulated whereas cell rescue and transcription factor-related genes were mostly up-regulated. In the other functional categories no common trend was observed; salt exposure results displayed a strong down-regulation of genes implicated in primary metabolism, detoxication apparatus and signal transduction, whereas upon cold exposure, up and down-regulated genes were similar in number. At the proteomic level, the abundance of the majority of identified proteins was increased except for the photosynthesis-related proteins, which were mostly less abundant after both salt and cold exposure. Common responses between salt and cold stress and specific responses inherent to these abiotic stresses are described. PMID- 22258188 TI - Involvement of globus pallidus and midbrain nuclei in pantothenate kinase associated neurodegeneration: measurement of T2 and T2* time. AB - PURPOSE: To quantify involvement of globus pallidus and two midbrain nuclei (substantia nigra and red nucleus) in Pantothenate Kinase-Associated Neurodegeneration (PKAN). MATERIAL AND METHODS: We performed T2 and T2* weighted imaging with calculation of the corresponding relaxation times on a subset of 5 patients from a larger group of 20 patients with PKAN from the southwest part of the Dominican Republic. Examinations were carried out on a 3T scanner and included a multi-echo spin-echo as well as a multi-echo gradient echo sequence. Results were compared to a control group of 19 volunteers. RESULTS: T2 and T2* weighted sequences showed abnormal signal reduction in the globus pallidus of all patients. On T2* weighted imaging, abnormal signal in the substantia nigra could reliably be detected in 75% of cases, but differentiation from normal was less reliable in T2 weighted scans. Correspondingly, relaxation times differed from normal with very high significance (p < 0.0001) in the globus pallidus, but with with less significance in the substantia nigra (p <= 0.03). The red nucleus was not affected. CONCLUSIONS: Signal reduction in the globus pallidus, which probably is due to abnormal accumulation of iron, is severe in PKAN and can be differentiated from normal with high reliability. The substantia nigra is affected to a lesser degree, and the red nucleus is not involved. The reason for this selective susceptibility of normally iron-rich brain structures for pathological accumulation of iron remains speculative. Our quantitative results might be helpful to assess the value of an iron chelation approach to therapy. PMID- 22258189 TI - [The progression from hypertension to congestive heart failure]. AB - Arterial hypertension still represents one of the major modifiable risk factors for cardiovascular and renal disease. Solid evidences are available demonstrating the large and significant benefits deriving from blood pressure lowering therapies in terms of reduced incidence of major cardiovascular events, including myocardial infarction, ischemic stroke and cardiovascular death. It should be also noted, however, that hypertensive patients are at increased risk of developing congestive heart failure, being this risk substantially independent by the concomitant presence of left ventricular hypertrophy or dysfunction. Indeed, it has been demonstrated that blood pressure reduction and control significantly reduce the risk of developing congestive heart failure. In particular, several recent meta-analyses have demonstrated that the use of diuretics and renin angiotensin system blockers is superior to calcium-antagonists and beta-blockers in terms of prevention of new-onset heart failure. The present paper overviews the main pathophysiological aspects of the progression from arterial hypertension to congestive heart failure and the potential therapeutic interventions able to reduce or prevent this progression. PMID- 22258190 TI - [Perspectives on the contribution of genetics to the pathogenesis of type 2 diabetes mellitus]. AB - Type 2 diabetes mellitus (DM) is a common metabolic-endocrine disorder often associated with overweight or obesity. It is a complex disease determined by both predisposing genetic factors and non-genetic environmental factors and interactions between them, leading to impaired beta-cell insulin secretion and peripheral insulin resistance. Insulin resistance is a prominent feature of most patients with type 2 DM and obesity, resulting in a reduced response of target tissues (muscle, liver and fat) to both endogenous and exogenous insulin. There is considerable evidence that heredity is a major contributor to the insulin resistance of type 2 DM. Initially, among those destined to develop diabetes, the beta cells of the pancreas compensate with increased insulin secretion to maintain normal glucose tolerance. Type 2 DM develops when beta cells fail to compensate. Despite of the numerous studies in the recent years, the actual genetic causes of insulin resistance and type 2 DM have not yet been clearly elucidated. Through linkage and "genome-wide" studies, genes were identified most frequently associated with type 2 DM, such as TCF7L2, considered, until recently, the most important gene among those predisposing to type 2 DM. On the other hand, numerous candidate genes have been analyzed for genetic variants that increase susceptibility to type 2 DM. Several variants have been identified in many of these genes, including the insulin receptor gene, INSR, and other genes involved in adipogenesis and beta-cell insulin secretion. In this context, recently our group has identified a new gene involved in the pathogenesis of insulin resistance and type 2 DM: the HMGA1 gene. Functional genetic variants of the HMGA1 gene, capable of reducing the intracellular levels of INSR in insulin target tissues, were found in 10% of patients with type 2 DM in three distinct populations: Italian, North American and French. PMID- 22258191 TI - [Metabolic syndrome and the risk of breast cancer]. AB - Metabolic syndrome has been associated with an increased risk of various cancers. A multicenter study conducted in Italy and Switzerland on 3,869 cases of breast cancer in post-menopause reported a relative risk of 1.75 in women with the metabolic syndrome, confirming the results of other smaller epidemiological studies. PMID- 22258192 TI - [Prevalence of congenital heart disease in a suburban hospital]. AB - We describe the prevalence of congenital heart disease in a suburban hospital. In fifteen months we visited 270 infants and we diagnosed 59 congenital heart disease (21.9% of examined population). Diagnosis of congenital heart disease in 63.8% occurred after the first month of life; 36.2% during the first month. In this group we found ethnic difference in rates of congenital heart disease. PMID- 22258193 TI - [Late dislocation of the left ventricular lead as a cause of clinical and functional worsening during cardiac resynchronization therapy]. AB - Efficacy of cardiac resynchronization therapy (CRT) in heart failure is also related to correct positioning of the left ventricular lead. We report the case of a patient treated by CRT who presented, after 6 years of implantation, rapid clinical and functional worsening due to dislodgment of the left ventricular lead. PMID- 22258194 TI - [Clinical relevance of genetic testing in hypertrophic cardiomyopathy]. AB - More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care. PMID- 22258195 TI - [Blaise Pascal and his visual experiences]. AB - Blaise Pascal (1623-1662) the mathematician, physicist, and theologian, is often considered as an example of classical French prose. Pascal's primary scientific contribution was the principle of hydrostatics, known as Pascal's Law. Furthermore, he is also regarded as one of the most important French philosophers, principally due to his publication: "Pensees". There is documentation affirming that Pascal suffered from visual migraines with recurring headaches, episodes of blindness in half of his visual field, zigzag, fortification spectra, and other visual hallucinations. It has been hypothesised that these migraine aura experiences acted as a source of inspiration for Pascal's philosophical reflections. Pascal's sudden religious conversion, probably the most decisive moment in Pascal's personal life, during the night of the 23rd to 24th of November 1654, was accompanied by a lighted vision which he interpreted as fire convincing him of God's "reality and presence". This experience may have been triggered by the effects of a migraine aura attack. This spiritual epiphany led him to dedicate the rest of his life to religious and philosophical interests. PMID- 22258196 TI - Female pelvic floor symptoms before and after bariatric surgery. AB - BACKGROUND: Obesity is a risk factor for female pelvic floor disorders. The study objective was to determine whether there was a difference in the subjective reporting of pelvic symptoms before and after bariatric surgery. METHODS: This was a prospective cohort study of female patients that underwent bariatric surgery. Patients completed a demographic questionnaire, the Pelvic Floor Distress Inventory-20 (PFDI-20), and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7) before surgery and at 6 and 12 months following surgery. Body mass index (BMI) was compared between time points using Student's t tests (P < 0.05 significant). Symptom and impact on quality of life prevalence were compared using McNemar's test and questionnaire scores were compared using the Wilcoxon matched pairs test (P < 0.025 significant). RESULTS: At 12 months after surgery, 63 patients had completed the study. Even with significant weight loss (BMI, 43.7 kg/m(2) to BMI, 29 kg/m(2); P < 0.001), there was no significant difference in the prevalence of pelvic floor symptoms before and after surgery (94% to 81%, P = 0.2). Prevalence of pelvic floor symptom impact on quality of life did significantly decrease after surgery (56% to 30%; P = 0.004). Baseline PFDI-20 and PFIQ-7 scores were low; however, there was still a significant reduction in PFDI-20 and PFIQ-7 scores after surgery (P < 0.001). CONCLUSIONS: Prevalence of pelvic floor symptoms did not vary greatly after surgery; however, significant weight reduction did improve the degree of bother and quality of life related to these symptoms. PMID- 22258197 TI - Laparoscopic sleeve gastrectomy with staple line buttress reinforcement in 116 consecutive morbidly obese patients. AB - BACKGROUND: Obesity rates have reached epidemic levels with over 300 million obese individuals worldwide. Laparoscopic sleeve gastrectomy (LSG) as a primarily restrictive bariatric surgical procedure has been shown to be effective in producing marked weight loss. However, LSG-associated gastric leakage and hemorrhages remain the most important challenges postoperatively. Staple line buttress reinforcement has been suggested to reduce these postoperative complications. Our objective was to assess staple line buttress reinforcement via the DuetTM tissue reinforcement stapler system in morbidly obese patients undergoing LSG as part of a comprehensive weight management strategy, focusing on postoperative complications. METHODS: Between January 2008 and April 2011, we retrospectively reviewed the medical records of 116 consecutive patients that underwent LSG with staple line buttress reinforcement at an academic teaching hospital with advanced bariatric fellowship. RESULTS: The mean age of patients was 44.3 +/- 9.5 years, with mean preoperative BMI of 44 +/- 7 kg/m2. The mean operative time to perform LSG was 96 +/- 25 min. Postoperative weight was significantly lower following LSG at 1-year follow-up compared to baseline (104 +/- 25 vs. 125 +/- 27 kg, P < 0.05). There were no postoperative gastric leaks observed. Postoperative bleeding from the gastric staple line occurred in one patient (0.9%) and was treated with conservative management. CONCLUSIONS: In LSG, staple line buttress reinforcement limits postoperative gastric leakage and bleeding in morbidly obese patients. PMID- 22258198 TI - The effect of clinical pathways for bariatric surgery on perioperative quality of care. AB - BACKGROUND: Bariatric surgery demands a multidisciplinary approach and enhanced recovery schemes. Such schemes are complex and cumbersome to introduce into practice. This study evaluates if a clinical pathway (CP) facilitates implementation of an enhanced recovery scheme in bariatric surgery with the goal of improving perioperative quality of care. METHODS: We compared 65 consecutive patients who underwent bariatric surgery in 2009 and were treated with a CP (CP group) with 64 consecutive patients treated without CP in 2007/2008 (pre-CP group). Process quality indicators were catheter management, postoperative mobilization, spirometer training, vitamin B supplementation, diet resumption, intake of supplement drinks, and length of stay. Outcome quality was measured through morbidity, mortality, re-operations, and re-admissions. RESULTS: In the CP group, foley catheters were removed earlier (p < 0.0001), patients were mobilized more often on the surgery day (CP group 92.3% vs. pre-CP group 78.1%, p = 0.03), used spirometers more often (56.9% vs. 28.1%, p = 0.002), were more often supplemented with vitamin B (100% vs. 31.3%, p < 0.0001), and received oral supplement nutrition more often (100% vs. 59.4%, p < 0.0001). Median length of stay was shorter in the CP group (6 vs. 7 days, p = 0.007). There was no significant difference in mortality, morbidity, re-operations, and re-admissions. CONCLUSIONS: Following implementation of an enhanced recovery CP for bariatric surgery, several indicators of process quality improved while outcome quality remained unchanged. A CP seems useful for optimizing treatment of bariatric surgery patients according to enhanced recovery principles. However, future studies are required to better determine which elements of care can be improved most. PMID- 22258199 TI - Spatial and temporal analysis of estuarine bacterioneuston and bacterioplankton using culture-dependent and culture-independent methodologies. AB - Bacterioneuston may play a key role in water-air exchange of gases and in processing organic matter and pollutants that accumulate at the sea-surface microlayer (SML). However, the phylogenetic diversity of bacterioneuston has been poorly characterized. We analyzed 24 samples each from the SML and underlying water (UW) at three sites in the Ria de Aveiro estuary, Portugal. Cultivation and culture-independent techniques were used to compare bacterioneuston and bacterioplankton. Culturable heterotrophic bacteria were enriched in the SML. The culturable community was dominated by Psychrobacter and Acinetobacter. The presence of high numbers of Psychrobacter was a notable result. Differences were confined to a few genera overrepresented in UW samples (Kocuria, Agrococcus and Vibrio). 16S rDNA DGGE profiles were highly stable in terms of number and position of bands between sampling sites and dates but cluster analysis revealed a slight tendency for grouping according to sampled layer. SML-specific DGGE bands affiliated with Actinobacteria, Cyanobacteria, Gammaproteobacteria and Bacteroidetes. Low similarity between nucleotide sequences of DGGE-bands and previously reported sequences suggest the occurrence of SML-specific populations. Enrichment of SML for Pseudomonas and Aeromonas was questioned and the diversity of both communities was analyzed. Consistent differences between SML and UW aeromonads communities were not identified. In terms of Pseudomonas, a culturable operational taxonomic unit was consistently overrepresented within SML samples. Taken together, our results indicate that the similarity between SML and UW communities depends on spatial and temporal factors. PMID- 22258200 TI - Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory. AB - BACKGROUND: Anaesthetics suppress the formation of lasting memories at concentrations that do not suppress perception, but it is unclear which elements of the complex cascade leading from a conscious experience to a lasting memory trace are disrupted. Experiments in conscious humans suggest that subhypnotic concentrations of anaesthetics impair consolidation or maintenance rather than acquisition of a representation (long-term more than short-term memory). We sought to test whether these agents similarly impair learning in rats. METHODS: We used operant conditioning in rats to examine the effect of isoflurane on acquisition compared with long-term (24 h) memory of non-aversive olfactory memories using two different odour discrimination tasks. Rats learned the 'valences' of odour pairs presented either separately (task A) or simultaneously (task B), under control conditions and under isoflurane inhalation. In a separate set of experiments, we tested the ability of the animals to recall a learning set that had been acquired 24 h previously. RESULTS: Under 0.4% isoflurane inhalation, the average number of trials required to reach criterion performance (18 correct responses in 20 successive trials) increased from 21.9 to 43.5 (P<0.05) and 24.2 to 54.4 (P<0.05) for tasks A and B, respectively. Under 0.3% isoflurane inhalation, only task B was impaired (from 24.2 to 31.5 trials, P<0.05). Recall at 24 h was dose-dependently impaired or prevented by isoflurane for both tasks. CONCLUSIONS: Isoflurane interfered with long-term memory of odour valence without preventing its acquisition. This paradigm may serve as a non aversive animal model of conscious amnesia. PMID- 22258201 TI - Factors associated with survival after resection of colorectal adenocarcinoma in 314 patients. AB - BACKGROUND: An analysis of perioperative factors that were independently associated with survival up to 1000 days after scheduled colorectal adenocarcinoma resections in 314 patients. METHODS: The association of 16 perioperative variables with postoperative survival and critical care unit (CCU) admission after scheduled resections for colorectal adenocarcinoma between September 2005 and March 2009 was analysed using multivariable Cox regression analyses and Fisher's exact tests. RESULTS: We followed survivors for a mean of 983 days (range 696-1000 days). Average annual postoperative mortality was 8.5%, 14% after surgery performed in 2005, and 3% after surgery in 2009. Risk of mortality was independently associated with five variables after stratifying for date of surgery: attending a preoperative high-risk clinic [hazard ratio (HR) 0.42, P=0.006], worse World Health Organization performance status (HR 2.1, P=0.001), BMI (HR 0.92, P=0.009), higher nodal stage (HR 2.6, P<0.0001), and unplanned critical care admission (HR 7.2, P<0.0001). Patients who attended the preoperative clinic (207) were older, with worse renal function and ASA grade, than those who did not (107). Planned postoperative critical care admission was more common in patients who attended the high-risk clinic (24% vs 12%, P=0.01) and may have partly accounted for the observed mortality difference. CONCLUSIONS: Immediate perioperative care may have prolonged effects on postoperative survival. Specialized preoperative assessment clinics may reduce mortality after colorectal surgery. PMID- 22258202 TI - Cerebral haemodynamic physiology during steep Trendelenburg position and CO(2) pneumoperitoneum. AB - BACKGROUND: The steep (40 degrees ) Trendelenburg position optimizes surgical exposure during robotic prostatectomy. The goal of the current study was to elucidate the influence of this patient positioning on cerebral blood flow and zero flow pressure (ZFP), and to assess the validity of different methods of evaluating ZFP. METHODS: In 21 consecutive patients who underwent robotic endoscopic radical prostatectomy under general anaesthesia, transcranial Doppler flow velocity waveforms and invasive arterial and central venous pressure (CVP) waveforms suitable for analysis were recorded throughout the whole operative procedure in 14. The ZFP was determined by regression analysis of the pressure flow plot and by different simplified formulas. The effective cerebral perfusion pressure (eCPP), pulsatility index (PI), and resistance index (RI) were determined. RESULTS: While patients were in the Trendelenburg position, the ZFP increased in parallel with the CVP. The PI, RI, gradient between the ZFP and CVP, and the gradient between the CPP and the eCPP did not increase significantly (P<0.05) after 3 h of the steep Trendelenburg position. Using the formula described by Czosnyka and colleagues, the ZFP correlated closely with that calculated by linear regression throughout the course of the operation. CONCLUSIONS: Prolonged steep Trendelenburg positioning and CO(2) pneumoperitoneum does not compromise cerebral perfusion. ZFP and eCPP are reliable variables for assessing brain perfusion during prolonged steep Trendelenburg positioning. PMID- 22258203 TI - Effect of age on the comparability of bispectral and state entropy indices during the maintenance of propofol-sufentanil anaesthesia. AB - BACKGROUND: Manufacturers recommend maintaining anaesthesia at a bispectral index (BIS) or state entropy (SE) index value between 40 and 60. METHODS: We prospectively studied 102 patients receiving propofol-sufentanil anaesthesia administered by anaesthetists blinded to these indices. The main endpoint was crude agreement (P(0)), defined as the proportion of agreement between BIS and SE index among three categories: <40, between 40 and 60, and >60. Discrepancies in recommendation (DR) were also considered. A DR is type 1 if BIS or SE is <40, while the other is simultaneously >60. A DR is type 2 when BIS and SE index values are on different sides of a threshold (40 or 60) with three subtypes according to the magnitude of their difference. A linear multiple regression was performed to identify covariates that are independently associated with P(0). RESULTS: In total, 12 147 pairs of values were studied. P(0) was 59.9 (24.5%) [mean (sd)]. Thirty-three patients presented more than 50% discordant pairs and only seven patients presented more than 95% concordant pairs. Type 1 DR occurred in only 1.1% of all the pairs. The median (inter-quartile range) number of type 2 DR varied from 5 (3-8) to 2 (1-3) according to the degree of difference. Multivariate analysis showed that age (P=0.0004) and electrode position (P=0.0084) were independently associated with P(0). An increase in the age of 10 yr decreases P(0) by 5%. CONCLUSIONS: The agreement between BIS and SE indices is moderate and deteriorates as patients' age increases. This study cannot determine which index is best adapted for elderly patients. Additional work comparing both indices with raw EEG traces is warranted. PMID- 22258205 TI - Comparison of superimposed high-frequency jet ventilation with conventional jet ventilation for laryngeal surgery. AB - BACKGROUND: New ventilators have simplified the use of supraglottic superimposed high-frequency jet ventilation (SHFJV(SG)), but it has not been systematically compared with other modes of jet ventilation (JV) in humans. We sought to investigate whether SHFJV(SG) would provide more effective ventilation compared with single-frequency JV techniques. METHODS: A total of 16 patients undergoing minor laryngeal surgery under general anaesthesia were included. In each patient, four different JV techniques were applied in random order for 10-min periods: SHFJV(SG), supraglottic normal frequency (NFJV(SG)), supraglottic high frequency (HFJV(SG)), and infraglottic high-frequency jet ventilation (HFJV(IG)). Chest wall volume variations were continuously measured with opto-electronic plethysmography (OEP), intratracheal pressure was recorded and blood gases were measured. RESULTS: Chest wall volumes were normalized to NFJV(SG) end-expiratory level. The increase in end-expiratory chest wall volume (EEV(CW)) was 239 (196) ml during SHFJV(SG) (P<0.05 compared with NFJV(SG)). EEV(CW) was 148 (145) and 44 (106) ml during HFJV(SG) and HFJV(IG), respectively (P<0.05 compared with SHFJV(SG)). Tidal volume (V(T)) during SHFJV(SG) was 269 (149) ml. V(T) was 229 (169) ml (P=1.00 compared with SHFJV(SG)), 145 (50) ml (P<0.05), and 110 (33) ml (P<0.01) during NFJV(SG), HFJV(SG), and HFJV(IG), respectively. Intratracheal pressures corresponded well to changes in both EEV(CW) and V(T). All JV modes resulted in adequate oxygenation. However, was lowest during HFJV(SG) [4.3 (1.3) kPa; P<0.01 compared with SHFJV(SG)]. CONCLUSION: SHFJV(SG) was associated with increased EEV(CW) and V(T) compared with the three other investigated JV modes. All four modes provided adequate ventilation and oxygenation, and thus can be used for uncomplicated laryngeal surgery in healthy patients with limited airway obstruction. PMID- 22258204 TI - Recombinant activated factor VII and prothrombin complex concentrates have different effects on bleeding and arterial thrombosis in the haemodiluted rabbit. AB - BACKGROUND: Recombinant activated factor VII (rFVIIa) is indicated in bleeding patients when a life-threatening haemorrhage occurs. Prothrombin complex concentrates (PCCs) are also used for this indication in several countries, without any evidence-based rationale. Our objective was to compare the efficacy and safety of PCC and rFVIIa in a model of bleeding and thrombosis in haemodiluted rabbits. METHODS: Forty-eight rabbits were randomly allocated into four groups: a control group and three treatment groups, in which animals were haemodiluted with hydroxyethyl starch 130/0.4 then administered either placebo, 160 ug kg(-1) rFVIIa, or 25 IU FIX kg(-1) PCC. The primary endpoint was hepatosplenic (HS) blood loss. Secondary endpoints were: (i) ear immersion bleeding time (IBT); (ii) thrombosis risk assessed by cyclic flow reductions (CFRs) of the carotid artery; and (iii) activated partial thromboplastin time (aPTT), and progress of thrombin activity. RESULTS: Haemodilution increased HS blood loss by 80% from 8 g (5-16) (control group) to 14 g (8-45) (placebo group) (P<0.01). HS blood loss was not different in animals receiving either rFVIIa [10 g (7-22)] or PCC [15 g (4-33)] (P<0.05) compared with the placebo group. Ear IBT was reduced with both rFVIIa and PCC. CFRs disappeared after haemodilution and were not restored with any treatment. Although PCC nearly doubled the total amount of thrombin generated, no significant change in the total amount of thrombin was seen in animals treated with rFVIIa. CONCLUSIONS: Neither rVIIa nor PCC reduced HS blood loss, whereas they both controlled the bleeding time, without increasing the thrombosis risk. PMID- 22258206 TI - An ELIME assay for the rapid diagnosis of coeliac disease. AB - Coeliac disease (CD) is a gluten-induced autoimmune enteropathy found in genetically susceptible subjects. Because of the high number of undetected cases, rapid and cheaper screening methods are needed. Currently, the CD diagnosis involves the detection of anti-transglutaminase IgA antibodies (anti-tTG IgA) in blood serum through the use of ELISA systems with confirmation by histology of the intestinal mucosa. A new, rapid magneto-electrochemical immunosensor for CD diagnosis has been developed and applied to serum sample analysis. The system uses magnetic beads coated with tTG antigen to detect anti-tTG antibodies in positive serum samples and an alkaline phosphatase-conjugated anti-human IgA as label. An electrochemical readout, using magnetized screen-printed electrodes coupled with a portable instrument, is made after the addition of alpha-naphtyl phosphate, which is enzymatically converted into the electrochemically active alpha-naphthol product. The work involved the following considerations: (1) optimization of analytical parameters; (2) recovery evaluation, adding known concentrations of anti-tTG IgA to "blank" sera; (3) analysis of 107 blood serum samples; (4) calculation of the ROC curve, resulting in a cut-off of 1.0 U/ml, 100% of clinical sensitivity and 98.36% of clinical specificity; evaluation of the agreement between electrochemical and ELISA kit values (r (2) of 0.943). The system developed could be an useful tool for a correct and rapid CD diagnosis. This method is simple, cheap, rapid, and suitable for screening analyses performed outside of the classical diagnostic laboratory. PMID- 22258207 TI - Fractionation and identification of metalloproteins from a marine cyanobacterium. AB - Trace metals are essential for the growth of marine cyanobacteria, being required for key cellular processes such as photosynthesis and respiration. Despite this, the metalloproteomes of marine cyanobacteria are at present only poorly defined. In this study, we have probed the major cobalt, iron, manganese, and nickel binding proteins in the marine cyanobacterium Synechococcus sp. WH8102 by using two different fractionation approaches combined with peptide mass fingerprinting. For the identification of intact metalloproteins, multidimensional native chromatography was used to fractionate the proteome, followed by inorganic mass spectrometry to identify metal-enriched fractions. This approach led to the detection of nickel superoxide dismutase together with its predicted cofactor. We also explored the utility of immobilized metal affinity chromatography (IMAC) to isolate subpopulations of proteins that display affinity for a particular metal ion. We conclude that low-resolution 2D liquid chromatography is a viable fractionation technique to correlate relatively low-abundance metal ions with their few cellular destinations (e.g. Ni), but challenges remain for more abundant metals with multiple destinations such as iron. IMAC has been shown as a useful pre-fractionation technique to screen for proteins with metal-binding capacity, and may become a particularly valuable tool for the identification of metal-trafficking proteins. PMID- 22258208 TI - Treatment of hypertension in the elderly: data from an international cohort of hypertensives treated by cardiologists. AB - Hypertension in the elderly is a major risk factor for cardiovascular disease. We aimed to analyze determinants of blood pressure (BP) control across different age groups. Population of a large global survey on hypertension treatment and control including 18927 patients was analyzed. A logistic regression analysis was conducted to estimate BP control rates and the prevalence of antihypertensive drug usage according to age. Systolic BP control decreased from 29.6% (95% confidence intervals (CI) 26.0;33.5) at 18-40 years to 22.4% (20.8;24.2) at >75 years (P<0.0001), and diastolic BP control increased from 31.6% (27.9;35.6) to 57.3% (55.2;59.3), respectively (P<0.0001). BP control was worse in diabetic patients, but did not differ substantially with co-morbid conditions, except for a better control in patients with myocardial infarction (MI) (P<0.05). The use of >= 3 antihypertensive drugs increased with age from 16.1 to 37.8% (P<0.0001) due to a more frequent use of loop diuretics (P<0.0001), thiazides (P<0.0001), angiotensin-converting enzyme (ACE) inhibitors (P<0.0001) and calcium channel blockers (P<0.0001). About one third of patients received non-guideline recommended drug-drug combinations. BP control is largely unsuccessful with increasing age. Owing to frequent inadequacies in the combination of antihypertensive drugs, future guidelines and educational programs should devote increased attention to the choice of optimal drug-drug combinations in the elderly. PMID- 22258209 TI - Kiwifruit decreases blood pressure and whole-blood platelet aggregation in male smokers. AB - Lifestyle modifications to reduce risk factors for cardiovascular diseases such as blood pressure (BP) and smoking have been emphasized. Fruits and vegetables may modify such risk factors. The major aim of this randomized, controlled trial was to investigate the effects of (1) kiwifruits and (2) an antioxidant-rich diet compared with (3) a control group on BP and platelet aggregation (that is, whole blood platelet aggregation) after 8 weeks in male smokers (age 44-74 years, n=102). The kiwifruit group received 3 kiwifruits per day, whereas the antioxidant-rich diet group received a comprehensive combination of antioxidant rich foods. In the kiwifruit group, reductions of 10 mm Hg in systolic BP and 9 mm Hg in diastolic BP were observed (P=0.019 and P=0.016 (change from baseline in the kiwifruit group compared with change from baseline in the control group)). In the antioxidant-rich diet group, a reduction of 10 mm Hg in systolic BP was observed among hypertensives (P=0.045). Additionally, a 15% reduction in platelet aggregation and an 11% reduction in angiotensin-converting enzyme activity was observed in the kiwifruit group (P=0.009 and P=0.034). No effects on these parameters were observed in the antioxidant-rich diet group. This study suggest that intake of kiwifruit may have beneficial effects on BP and platelet aggregation in male smokers. PMID- 22258210 TI - Honoring the past and forging the future. PMID- 22258211 TI - 25 years of pressure ulcers and Advances in Skin & Wound Care. PMID- 22258212 TI - Deep tissue injury: 25 years of learning. PMID- 22258213 TI - The Braden Scale for Predicting Pressure Sore Risk: reflections after 25 years. PMID- 22258214 TI - The role of nutrition in wound care. PMID- 22258215 TI - Growing into greatness: reflections on the NPUAP. PMID- 22258216 TI - A 25-year wound care journey within the evolution of wound care. AB - The journey began for George Winter nearly 50 years ago, using pigs in a laboratory setting, as he observed the healing characteristics of acute wounds. The journey began for industry with the launch of "modern" dressings, particularly with films and hydrocolloids. And so the journey began for authors with a clinical or scientific interest in the art of wound care. For all those who have persevered in the wound care field, their endeavor is not only a vocation, but also a lifelong passion. Although some individuals do not understand such passion, others do, and they are the wound care champions and pioneers who have made this 25-year journey possible and the next 25 years exciting. Much progress has been achieved in wound care in the past 25 years, but much work still remains if the profession is to be truly recognized as a clinical specialty. PMID- 22258217 TI - Pressure ulcer care and public policy: exploring the past to inform the future. AB - Over the last 25 years, the quality of pressure ulcer (PrU) care has significantly changed because of sweeping public policy changes from the federal government. In fact, how clinicians think about PrU prevention and treatment can be traced back to several landmark changes made by the federal government that affect the continuum of healthcare. Moreover, the types of reimbursements for providers and institutions have dramatically changed in the last 25 years. The purpose of this article is to briefly review some of the major changes in long term care, acute care, and home healthcare that have been impacted by public policy over the last 25 years. PMID- 22258218 TI - A global perspective of Wound Care(c). AB - Chronic wounds, particularly foot ulcers in persons with diabetes, have become a global pandemic in the developing and developed world. The authors propose a longitudinal interactive education program (knowledge, skills, and attitudes) linked to interprofessional centers of excellence to reduce the incidence of foot ulcers and unnecessary lower-limb amputations. This model is generalizable to other skin and wound conditions. PMID- 22258219 TI - Wound dressings: an evolving art and science. AB - Keeping abreast of the numerous wound dressings available for patient care is an ambitious task. Being able to differentiate among the various treatment options, when and how to apply them, in what combinations, and when to change them has become a challenge for all healthcare practitioners. PMID- 22258221 TI - 25 years of Medicare reimbursement changes for wound care. PMID- 22258222 TI - Liver-specific microRNA-122: Biogenesis and function. AB - microRNA-122 (miR-122) was one of the first examples of a tissue-specific miRNA. It is highly expressed in liver, where it constitutes 70% of the total miRNA pool. miR-122 expression is specific to the vertebrate lineage, where the sequence of the mature miRNA is completely conserved. miR-122 is a target for extensive study due to its association with cholesterol metabolism and hepatocellular carcinoma, and its important role in promoting hepatitis C virus (HCV) replication. This review will discuss the biogenesis and function of miR 122. PMID- 22258223 TI - Transcription beyond borders has downstream consequences. AB - The realization that non-coding RNAs and antisense transcription are pervasive in many genomes has emphasized our relatively poor understanding of what limits transcription and how initiation and termination are linked to processing and turnover of the RNA. In genomes where the density of genes is high it is clearly important to efficiently terminate transcription to prevent read-through into adjacent genes. In a recent paper published in PNAS, we showed that two RNA binding proteins in Arabidopsis thaliana, FCA and FPA, play important roles in limiting intergenic transcription in the A. thaliana genome. Their absence leads to transcriptional read-through over many kilobases (kb), which influences expression, and in some cases chromatin modifications, of associated genes. PMID- 22258224 TI - The DYW-class PPR protein MEF7 is required for RNA editing at four sites in mitochondria of Arabidopsis thaliana. AB - In plant mitochondria and plastids, RNA editing alters about 400 and about 35 C nucleotides into Us, respectively. Four of these RNA editing events in plant mitochondria specifically require the PPR protein MEF7, characterized by E and DYW extension domains. The gene for MEF7 was identified by genomic mapping of the locus mutated in plants from EMS treated seeds. The SNaPshot screen of the mutant plant population identified two independent EMS mutants with the same editing defects as a corresponding T-DNA insertion line of the MEF7 gene. Although the amino acid codons introduced by the editing events are conserved throughout flowering plants, even the combined failure of four editing events does not impair the growth efficiency of the mutant plants. Five nucleotides are conserved between the four affected editing sites, but are not sufficient for specific recognition by MEF7 since they are also present at three other sites which are unaffected in the mutants. PMID- 22258225 TI - An examination of opportunities for the active patient in improving patient safety. AB - BACKGROUND: Patients can make valuable contributions to their health care safety. Little is known, however, about the factors that could affect patient participation in safety-related aspects of their health care management. Examining and understanding how patient involvement in safety-related behaviors can be conceptualized will allow greater insight into why patients may be more willing to participate in some behaviors more than others may. OBJECTIVE: This study aimed to develop a new approach for understanding and conceptualizing patient involvement in safety with specific reference to a surgical patient cohort. METHODS: The authors conducted a review of the key opportunities for patient involvement along the surgical care trajectory and examination and identification of the properties and characteristics of different safety-related behaviors and the barriers to patient involvement they entail. RESULTS: Safety related behaviors comprise 3 main properties including the type of error the behavior is trying to prevent (e.g., medication error), the action required by the patient (e.g., asking questions), and the characteristics of the action (e.g., whether the behavior involves interacting with a health care professional). Barriers to patient involvement that relate to patients and health care professionals can be broadly categorized as interpersonal, intrapersonal, and cultural. CONCLUSIONS: We believe that thinking of patient involvement in safety relating to properties and characteristics of the behavior together with the barriers to involvement could aid the design, implementation, and evaluation of interventions aimed at encouraging patient participation. It will also enable a greater understanding and assessment of not only what interventions may be effective (at encouraging patient involvement) but when they might be effective (i.e., what stage of the care pathway) and why. PMID- 22258226 TI - The "cross-cover" mindset. PMID- 22258227 TI - Interplay between an elusive 4-(isopropylamino)imidazol-2-ylidene and its isolable mesoionic tautomer, and associated reactivities. AB - An elusive free 4-(isopropylamino)imidazol-2-ylidene is engaged in a tautomeric equilibrium with its mesoionic tautomer, 4-(isopropylamido)imidazolium, which displays the typical reactivity of a cyclic diaminocarbene; once coordinated to a Rh(I) centre, it undergoes a smooth 4e(-) oxidation of its backbone to yield an amido-amidino-carbene, a weak electron donor viable only in its complexed form. PMID- 22258228 TI - Locked nucleic acid flow cytometry-fluorescence in situ hybridization (LNA flow FISH): a method for bacterial small RNA detection. AB - Fluorescence in situ hybridization (FISH) is a powerful technique that is used to detect and localize specific nucleic acid sequences in the cellular environment. In order to increase throughput, FISH can be combined with flow cytometry (flow FISH) to enable the detection of targeted nucleic acid sequences in thousands of individual cells. As a result, flow-FISH offers a distinct advantage over lysate/ensemble-based nucleic acid detection methods because each cell is treated as an independent observation, thereby permitting stronger statistical and variance analyses. These attributes have prompted the use of FISH and flow-FISH methods in a number of different applications and the utility of these methods has been successfully demonstrated in telomere length determination, cellular identification and gene expression, monitoring viral multiplication in infected cells, and bacterial community analysis and enumeration. Traditionally, the specificity of FISH and flow-FISH methods has been imparted by DNA oligonucleotide probes. Recently however, the replacement of DNA oligonucleotide probes with nucleic acid analogs as FISH and flow-FISH probes has increased both the sensitivity and specificity of each technique due to the higher melting temperatures (T(m)) of these analogs for natural nucleic acids. Locked nucleic acid (LNA) probes are a type of nucleic acid analog that contain LNA nucleotides spiked throughout a DNA or RNA sequence. When coupled with flow-FISH, LNA probes have previously been shown to outperform conventional DNA probes and have been successfully used to detect eukaryotic mRNA and viral RNA in mammalian cells. Here we expand this capability and describe a LNA flow-FISH method which permits the specific detection of RNA in bacterial cells (Figure 1). Specifically, we are interested in the detection of small non-coding regulatory RNA (sRNA) which have garnered considerable interest in the past few years as they have been found to serve as key regulatory elements in many critical cellular processes. However, there are limited tools to study sRNAs and the challenges of detecting sRNA in bacterial cells is due in part to the relatively small size (typically 50-300 nucleotides in length) and low abundance of sRNA molecules as well as the general difficulty in working with smaller biological cells with varying cellular membranes. In this method, we describe fixation and permeabilzation conditions that preserve the structure of bacterial cells and permit the penetration of LNA probes as well as signal amplification steps which enable the specific detection of low abundance sRNA (Figure 2). PMID- 22258230 TI - Delta neutrophil index: a promising diagnostic and prognostic marker for sepsis. AB - Delta neutrophil index (DN) is the immature granulocyte fraction provided by a blood cell analyzer (ADVIA 2120; Siemens Healthcare Diagnostics, Deerfield, Ill), which is determined by subtracting the fraction of mature polymorphonuclear leukocytes from the sum of myeloperoxidase-reactive cells. The purpose of this study was to define the role of DN in differential diagnosis and prognosis prediction of patients with sepsis. Hospital records of 273 patients were retrospectively collected: 47 with systemic inflammatory response syndrome, 78 with sepsis, 51 with severe sepsis, and 97 control subjects. Delta neutrophil index and C-reactive protein data on the day of the first blood culture were compared among the groups, and 28-day mortality associated with sepsis was assessed. Median values of DN were 0.0% (interquartile range, 0.0%-0.0%) in the control group, 0.8% (0.0%-1.7%) in the systemic inflammatory response syndrome group, 3.4% (1.5%-5.3%) in the sepsis group, and 18.6% (9.3%-24.7%) in the severe sepsis group. Furthermore, there were significant differences among the groups. The receiver operating characteristic curves showed that DN was a better predictor of sepsis than C-reactive protein. The best cutoff value for DN for predicting sepsis was 2.7%. Delta neutrophil index was significantly higher in those who died than in the survivors (median [interquartile range], 11.5% [3.5% 25.0%] vs. 4.7% [2.2%-10.6%], P = 0.008) and was identified to be an independent predictor for 28-day mortality in patients with sepsis by Cox proportional hazards model. Delta neutrophil index may serve as a facile and useful marker for early diagnosis and prognostic assessment of patients with sepsis, as it is included in a routine complete blood count. PMID- 22258229 TI - Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure. AB - Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However, the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (beats/min per mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals: control, 1-week CHF, 2-week CHF, and 3-week CHF. Chronic heart failure was induced by ventricular pacing at 360 beats/min and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening, and an increase in left ventricular end-systolic diameter and left ventricular end-diastolic diameter were observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA (% of maximum) after 1 week of pacing; a small but insignificant rise in RSNA was seen at 2 weeks, and a significant rise in RSNA was observed at 3 weeks. Angiotensin II type 1 (AT-1) receptor protein (Western Blot) and mRNA (reverse transcriptase polymerase chain reaction) expression in the rostral ventrolateral medulla exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT-1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympathoexcitation and overexpression of AT-1 receptors with the progression of CHF, causing further impairment of cardiovascular control. PMID- 22258231 TI - Chemically modified tetracycline 3 prevents acute respiratory distress syndrome in a porcine model of sepsis + ischemia/reperfusion-induced lung injury. AB - Experimental pharmacotherapies for the acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified tetracycline 3 (CMT-3), an anti-inflammatory agent that blocks multiple proteases and cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of inflammation-induced lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A "2-hit" injury was induced: (a) peritoneal sepsis-by placement of a fecal clot in the peritoneum, and (b) ischemia/reperfusion-by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups: CMT-3 group (n = 7) received CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a CMT-3 vehicle (carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial bacteremia. Chemically modified tetracycline 3 treatment prevented ARDS as indicated by PaO(2)/FIO(2) ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of interleukin 1beta (IL-1beta), tumor necrosis factor alpha, IL-6, IL-8, and IL-10. This study presents a clinically relevant model of lung injury in which CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma cytokines. Treatment of sepsis patients with CMT-3 could significantly reduce progression from sepsis into ARDS. PMID- 22258232 TI - Honokiol attenuates the severity of acute pancreatitis and associated lung injury via acceleration of acinar cell apoptosis. AB - Severe acute pancreatitis remains a life-threatening disease with a high mortality rate among a defined proportion of those affected. Apoptosis has been hypothesized to be a beneficial form of cell death in acute pancreatitis. Honokiol, a low-molecular-weight natural product, possesses the ability of anti inflammation and apoptosis induction. Here, we investigate whether honokiol can ameliorate severe acute pancreatitis and the associated acute lung injury in a mouse model. Mice received six injections of cerulein at 1-h intervals, then given one intraperitoneal injection of bacterial lipopolysaccharide for the induction of severe acute pancreatitis. Moreover, mice were intraperitoneally given vehicle or honokiol 10 min after the first cerulein injection. Honokiol protected against the severity of acute pancreatitis in terms of increased serum amylase and lipase levels, pancreas pathological injury, and associated acute lung injury. Honokiol significantly reduced the increases in serum tumor necrosis factor-alpha, interleukin 1, and nitric oxide levels 3 h and serum high-mobility group box 1 24 h after acute pancreatitis induction. Honokiol also significantly decreased myeloperoxidase activities in the pancreas and the lungs. Endoplasmic reticulum stress-related molecules eIF2alpha (phosphorylated) and CHOP protein expressions, apoptosis, and caspase-3 activity were increased in the pancreas of mice with severe acute pancreatitis, which was unexpectedly enhanced by honokiol treatment. These results suggest that honokiol protects against acute pancreatitis and limits the spread of inflammatory damage to the lung in a severe acute pancreatitis mouse model. The acceleration of pancreatic cell apoptosis by honokiol may play a pivotal role. PMID- 22258233 TI - Renal Doppler ultrasound: a new tool to assess renal perfusion in critical illness. AB - Despite our increasing ability to support vital organs and resuscitate patients, the morbidity and mortality of acute kidney injury (AKI) remain high in the intensive care unit (ICU). The ability to predict the occurrence of AKI is crucial for the development of preventive strategies. Early diagnosis of AKI requires markers that are sensitive and easily applicable in clinical practice. The use of Doppler ultrasonography to assess renal perfusion is increasing in many kidney diseases and in the ICU. The Doppler-based renal resistive index, which is a simple, rapid, noninvasive, and repeatable marker, could be a promising tool to prematurely detect the patients most at risk of developing AKI in the ICU and to distinguish transient from persistent AKI. Moreover, the resistive index could also be useful to adjust preventive or therapeutic modalities for the kidney perfusion at the bedside. The recent progress in ultrasound with contrast-enhanced ultrasound gives the opportunity to assess not only the kidney macrocirculation but also the kidney microcirculation in the ICU. PMID- 22258234 TI - Early complementopathy after multiple injuries in humans. AB - After severe tissue injury, innate immunity mounts a robust systemic inflammatory response. However, little is known about the immediate impact of multiple trauma on early complement function in humans. In the present study, we hypothesized that multiple trauma results in immediate activation, consumption, and dysfunction of the complement cascade and that the resulting severe "complementopathy" may be associated with morbidity and mortality. Therefore, a prospective multicenter study with 25 healthy volunteers and 40 polytrauma patients (mean injury severity score = 30.3 +/- 2.9) was performed. After polytrauma, serum was collected as early as possible at the scene, on admission to the emergency room (ER), and 4, 12, 24, 120, and 240 h post-trauma and analyzed for the complement profile. Complement hemolytic activity (CH-50) was massively reduced within the first 24 h after injury, recovered only 5 days after trauma, and discriminated between lethal and nonlethal 28-day outcome. Serum levels of the complement activation products C3a and C5a were significantly elevated throughout the entire observation period and correlated with the severity of traumatic brain injury and survival. The soluble terminal complement complex SC5b-9 and mannose-binding lectin showed a biphasic response after trauma. Key fluid-phase inhibitors of complement, such as C4b-binding protein and factor I, were significantly diminished early after trauma. The present data indicate an almost synchronical rapid activation and dysfunction of complement, suggesting a trauma-induced complementopathy early after injury. These events may participate in the impairment of the innate immune response observed after severe trauma. PMID- 22258235 TI - Adiponectin diminishes organ-specific microvascular endothelial cell activation associated with sepsis. AB - Experimental sepsis was induced in male C57BL/6j, adiponectin-deficient mice (ADPNKO), and wild-type littermates by i.p. injection of 16 mg/kg lipopolysaccharide or cecal ligation and puncture. Blood and tissue samples were harvested 24 h after model induction. Circulating adiponectin is reduced in mice with endotoxemic challenge and after cecal ligation and puncture compared with healthy control mice. Quantitative reverse transcriptase-polymerase chain reaction for adiponectin reveals a pattern of response that is both model- and organ-specific. When challenged with sepsis, adiponectin deficiency results in increased expression of endothelial adhesion and coagulation molecules in the lung, liver, and kidney as quantified by reverse transcriptase-polymerase chain reaction, increased macrophage and neutrophil infiltration by immunohistochemistry, and vascular leakage in the liver and kidney. Adiponectin deficient mice have reduced survival following cecal ligation and puncture and increased blood levels of interleukin 6, soluble vascular endothelial growth factor receptor 1, and soluble endothelial adhesion molecules E-selectin and intercellular adhesion molecule 1. Finally, ADPNKO promoted end-organ injury in the liver and kidney, whereas the lungs were not affected. These data suggest a protective role of adiponectin in diminishing microvascular organ-specific endothelial cell activation during sepsis. PMID- 22258236 TI - A novel approach for the rapid mutagenesis and directed evolution of the structural genes of west nile virus. AB - Molecular clone technology has proven to be a powerful tool for investigating the life cycle of flaviviruses, their interactions with the host, and vaccine development. Despite the demonstrated utility of existing molecular clone strategies, the feasibility of employing these existing approaches in large-scale mutagenesis studies is limited by the technical challenges of manipulating relatively large molecular clone plasmids that can be quite unstable when propagated in bacteria. We have developed a novel strategy that provides an extremely rapid approach for the introduction of mutations into the structural genes of West Nile virus (WNV). The backbone of this technology is a truncated form of the genome into which DNA fragments harboring the structural genes are ligated and transfected directly into mammalian cells, bypassing entirely the requirement for cloning in bacteria. The transfection of cells with this system results in the rapid release of WNV that achieves a high titer (~10(7) infectious units/ml in 48 h). The suitability of this approach for large-scale mutagenesis efforts was established in two ways. First, we constructed and characterized a library of variants encoding single defined amino acid substitutions at the 92 residues of the "pr" portion of the precursor-to-membrane (prM) protein. Analysis of a subset of these variants identified a mutation that conferred resistance to neutralization by an envelope protein-specific antibody. Second, we employed this approach to accelerate the identification of mutations that allow escape from neutralizing antibodies. Populations of WNV encoding random changes in the E protein were produced in the presence of a potent monoclonal antibody, E16. Viruses resistant to neutralization were identified in a single passage. Together, we have developed a simple and rapid approach to produce infectious WNV that accelerates the process of manipulating the genome to study the structure and function of the structural genes of this important human pathogen. PMID- 22258237 TI - HIV cell-to-cell transmission requires the production of infectious virus particles and does not proceed through env-mediated fusion pores. AB - Direct cell-to-cell transmission of human immunodeficiency virus (HIV) is a more potent and efficient means of virus propagation than infection by cell-free virus particles. The aim of this study was to determine whether cell-to-cell transmission requires the assembly of enveloped virus particles or whether nucleic acids with replication potential could translocate directly from donor to target cells through envelope glycoprotein (Env)-induced fusion pores. To this end, we characterized the transmission properties of viruses carrying mutations in the matrix protein (MA) that affect the incorporation of Env into virus particles but do not interfere with Env-mediated cell-cell fusion. By use of cell free virus, the infectivity of MA mutant viruses was below the detection threshold both in single-cycle and in multiple-cycle assays. Truncation of the cytoplasmic tail (CT) of Env restored the incorporation of Env into MA mutant viruses and rescued their cell-free infectivity to different extents. In cell-to cell transmission assays, MA mutations prevented HIV transmission from donor to target cells, despite efficient Env-dependent membrane fusion. HIV transmission was blocked at the level of virus core translocation into the cytosol of target cells. As in cell-free assays, rescue of Env incorporation by truncation of the Env CT restored the virus core translocation and cell-to-cell infectivity of MA mutant viruses. These data show that HIV cell-to-cell transmission requires the assembly of enveloped virus particles. The increased efficiency of this infection route may thus be attributed to the high local concentrations of virus particles at sites of cellular contacts rather than to a qualitatively different transmission process. PMID- 22258238 TI - Role for the phosphatidylinositol 3-kinase-Akt-TOR pathway during sindbis virus replication in arthropods. AB - The efficient transmission of alphaviruses requires the establishment of a persistent infection in the arthropod vector; however, the nature of the virus arthropod host interaction is not well understood. The phosphatidylinositol 3 kinase (PI3K)-Akt-TOR pathway is a signaling pathway with which viruses interact to manipulate cellular functions. The viral activation of this pathway can enhance translation and inhibit apoptosis, potentially promoting viral replication; conversely, repression can enhance cell death. Using a system to study Sindbis virus RNA replication in Drosophila melanogaster, we found that the overexpression of Akt enhanced Sindbis virus replication. In contrast, a decrease in viral replication was observed for flies hypomorphic for the Akt gene. Infection of cultured Drosophila cells led to the phosphorylation and activation of Akt. The chemical inhibition of PI3K, Akt, and TOR in mosquito cells reduced virus replication, suggesting that this pathway is proviral. Early after infection, there was an increase in the TOR-dependent phosphorylation of 4E-BP1 in mosquito cells and a consequent increase in the translation of a capped reporter mRNA. In contrast, no change in 4E-BP1 phosphorylation was seen in mammalian cells, and the level of translation of the reporter decreased following infection. Finally, we found that the increase in the phosphorylation of 4E-BP1 was stimulated by replicon RNA but not by UV-inactivated virus. Our data indicate that Sindbis virus replication complex formation in mosquito cells activates the PI3K-Akt-TOR pathway, causing the phosphorylation of 4E-BP1 and increasing the formation of eukaryotic initiation factor 4F (eIF4F), which promote cap-dependent translation. This virus-induced increase in cap-dependent translation allows the efficient translation of viral mRNA while minimizing the burden on the cell. PMID- 22258239 TI - Human cytomegalovirus infection induces adipocyte-like lipogenesis through activation of sterol regulatory element binding protein 1. AB - Sterol regulatory element binding proteins (SREBPs) are essential transcriptional factors that control expression of lipogenic genes and adipocyte differentiation. Human cytomegalovirus (HCMV) infection has been shown to require the induction of lipogenesis. Here we show that the induction of lipogenesis and expression of key lipogenic enzymes in human fibroblasts occurs by 24 h post-HCMV infection. This activation correlates with increased cleavage of the SREBP1 precursors to form the mature active transcription factors that enter the nucleus to transcriptionally activate lipogenic genes. SREBP1 cleavage is normally inhibited by increased sterol levels; however, our data show that this level of control is overridden in infected cells to allow constitutive activation of lipogenesis. This process requires viral protein synthesis, since UV-irradiated HCMV cannot activate SREBP cleavage. The cleavage of SREBP1 requires it to be in complex with SREBP cleavage activation protein (SCAP). Depleting SCAP using short hairpin RNA (shRNA) showed that SREBP1 cleavage and the induction of lipogenic genes and lipid synthesis are all inhibited in HCMV-infected cells. As a result, production of infectious virions is reduced in SCAP-depleted cells. Thus, the SCAP-mediated mechanism for SREBP cleavage is utilized by HCMV during infection. Our studies suggest that HCMV induces adipocyte-like lipogenesis and overrides normal sterol feedback controls in order to maintain high levels of constitutive lipid synthesis during infection. PMID- 22258240 TI - Mapping of Chikungunya virus interactions with host proteins identified nsP2 as a highly connected viral component. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has been responsible for an epidemic outbreak of unprecedented magnitude in recent years. Since then, significant efforts have been made to better understand the biology of this virus, but we still have poor knowledge of CHIKV interactions with host cell components at the molecular level. Here we describe the extensive use of high-throughput yeast two-hybrid (HT-Y2H) assays to characterize interactions between CHIKV and human proteins. A total of 22 high-confidence interactions, which essentially involved the viral nonstructural protein nsP2, were identified and further validated in protein complementation assay (PCA). These results were integrated to a larger network obtained by extensive mining of the literature for reports on alphavirus-host interactions. To investigate the role of cellular proteins interacting with nsP2, gene silencing experiments were performed in cells infected by a recombinant CHIKV expressing Renilla luciferase as a reporter. Collected data showed that heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and ubiquilin 4 (UBQLN4) participate in CHIKV replication in vitro. In addition, we showed that CHIKV nsP2 induces a cellular shutoff, as previously reported for other Old World alphaviruses, and determined that among binding partners identified by yeast two-hybrid methods, the tetratricopeptide repeat protein 7B (TTC7B) plays a significant role in this activity. Altogether, this report provides the first interaction map between CHIKV and human proteins and describes new host cell proteins involved in the replication cycle of this virus. PMID- 22258241 TI - Induction of immunological tolerance to adenoviral vectors by using a novel dendritic cell-based strategy. AB - The success of helper-dependent adenoviral (HD-Ad) vector-mediated lung gene therapy is hampered by the host immune response, which limits pulmonary transgene expression following multiple rounds of vector readminstration. Here, we show that HD-Ad-mediated pulmonary gene expression is sustained even upon three rounds of readministration to immunodeficient mice, highlighting the need to suppress the adaptive immune response for sustained gene expression following vector readministration. Therefore, we devised a dendritic cell (DC)-based strategy for induction of immunological tolerance toward HD-Ad vectors. DCs derived in the presence of interleukin-10 (IL-10) are refractory to HD-Ad-induced maturation and instead facilitate generation of IL-10-producing Tr1 regulatory T cells which suppress HD-Ad-induced T cell proliferation. Delivery of HD-Ad-pulsed, IL-10 modified DCs to mice induces long-lasting immunological tolerance to HD-Ad vectors, whereby pulmonary DC maturation, the T cell response, and antibody response to HD-Ad vectors are suppressed even after three rounds of pulmonary HD Ad readministration. Moreover, sustained transgene expression is also observed in the lungs of mice immunized with HD-Ad-pulsed, IL-10-modified DCs even after three rounds of pulmonary HD-Ad delivery. Taken together, these studies identify the use of DCs generated in the presence of IL-10 as a novel strategy to induce long-lasting immune tolerance to HD-Ad vectors. PMID- 22258242 TI - Protruding domain of capsid protein is necessary and sufficient to determine murine norovirus replication and pathogenesis in vivo. AB - Human noroviruses (HuNoVs) are the major cause of epidemic, nonbacterial gastroenteritis worldwide. Due to the lack of a tractable model system and the inability to grow HuNoVs in cell culture, factors required for the norovirus (NoV) life cycle and pathogenesis in the host remain largely unknown. The discovery of murine norovirus (MNV) and the development of reverse-genetics systems for this virus provide an opportunity to study these aspects of NoV infection in vitro and in vivo. Previous studies identified a single amino acid at residue 296 in the protruding (P) domain of the capsid protein that is responsible for determining the virulence of the MNV clone MNV1.CW1 in 12956/SvEv background STAT1-deficient (STAT1(-/-)) mice. In this report, we identified and characterized another determinant of lethality in the P domain that is necessary and sufficient to determine the replication and pathogenesis of the MNV clones MNV1.CW3 and CR6.STL1 in C57BL/6 background STAT1(-/-) mice. Furthermore, we describe how the role of residue 296 in MNV virulence differs between STAT1(-/-) mouse strains. We also describe potential interactions between subdomains of the P domain, as well as between other virus elements, which facilitate recovery of MNV using a reverse-genetics system. PMID- 22258243 TI - Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. AB - Our knowledge regarding the contribution of the innate immune system in recognizing and subsequently initiating a host response to an invasion of RNA virus has been rapidly growing over the last decade. Descriptions of the receptors involved and the molecular mechanisms they employ to sense viral pathogen-associated molecular patterns have emerged in great detail. This review presents an overview of our current knowledge regarding the receptors used to detect RNA virus invasion, the molecular structures these receptors sense, and the involved downstream signaling pathways. PMID- 22258244 TI - Self-association of lymphocytic choriomeningitis virus nucleoprotein is mediated by its N-terminal region and is not required for its anti-interferon function. AB - Arenaviruses have a bisegmented, negative-strand RNA genome. Both the large (L) and small (S) genome segments use an ambisense coding strategy to direct the synthesis of two viral proteins. The L segment encodes the virus polymerase (L protein) and the matrix Z protein, whereas the S segment encodes the nucleoprotein (NP) and the glycoprotein precursor (GPC). NPs are the most abundant viral protein in infected cells and virions and encapsidate genomic RNA species to form an NP-RNA complex that, together with the virus L polymerase, forms the virus ribonucleoprotein (RNP) core capable of directing both replication and transcription of the viral genome. RNP formation predicts a self association property of NPs. Here we document self-association (homotypic interaction) of the NP of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), as well as those of the hemorrhagic fever (HF) arenaviruses Lassa virus (LASV) and Machupo virus (MACV). We also show heterotypic interaction between NPs from both closely (LCMV and LASV) and distantly (LCMV and MACV) genetically related arenaviruses. LCMV NP self-association was dependent on the presence of single-stranded RNA and mediated by an N-terminal region of the NP that did not overlap with the previously described C-terminal NP domain involved in either counteracting the host type I interferon response or interacting with LCMV Z. PMID- 22258245 TI - Structural changes in Influenza virus at low pH characterized by cryo-electron tomography. AB - Influenza virus enters host cells by endocytosis. The low pH of endosomes triggers conformational changes in hemagglutinin (HA) that mediate fusion of the viral and endosomal membranes. We have used cryo-electron tomography to visualize influenza A virus at pH 4.9, a condition known to induce fusogenicity. After 30 min, when all virions are in the postfusion state, dramatic changes in morphology are apparent: elongated particles are no longer observed, larger particles representing fused virions appear, the HA spikes become conspicuously disorganized, a layer of M1 matrix protein is no longer resolved on most virions, and the ribonucleoprotein complexes (RNPs) coagulate on the interior surface of the virion. To probe for intermediate states, preparations were imaged after 5 min at pH 4.9. These virions could be classified according to their glycoprotein arrays (organized or disorganized) and whether or not they have a resolved M1 layer. Employing subtomogram averaging, we found, in addition to the neutral-pH state of HA, two intermediate conformations that appear to reflect an outwards movement of the fusion peptide and rearrangement of the HA1 subunits, respectively. These changes are reversible. The tomograms also document pH induced changes affecting the M1 layer that appear to render the envelope more pliable and hence conducive to fusion. However, it appears desirable for productive infection that fusion should proceed before the RNPs become coagulated with matrix protein, as eventually happens at low pH. PMID- 22258246 TI - Antiretroviral therapy reduces the magnitude and T cell receptor repertoire diversity of HIV-specific T cell responses without changing T cell clonotype dominance. AB - After initiation of antiretroviral therapy (ART), HIV loads and frequencies of HIV epitope-specific immune responses decrease. A diverse virus-specific T cell receptor (TCR) repertoire allows the host to respond to viral epitope diversity, but the effect of antigen reduction as a result of ART on the TCR repertoire of epitope-specific CD8(+) T cell populations has not been well defined. We determined the TCR repertoires of 14 HIV-specific CD8(+) T cell responses from 8 HIV-positive individuals before and after initiation of ART. We used multiparameter flow cytometry to measure the distribution of memory T cell subsets and the surface expression of PD-1 on T cell populations and T cell clonotypes within epitope-specific responses from these individuals. Post-ART, we noted decreases in the frequency of circulating epitope-specific T cells (P = 0.02), decreases in the number of T-cell clonotypes found within epitope-specific T cell receptor repertoires (P = 0.024), and an overall reduction in the amino acid diversity within these responses (P < 0.0001). Despite this narrowing of the T cell response to HIV, the overall hierarchy of dominant T cell receptor clonotypes remained stable compared to that pre-ART. CD8(+) T cells underwent redistributions in memory phenotypes and a reduction in CD38 and PD-1 expression post-ART. Despite extensive remodeling at the structural and phenotypic levels, PD-1 was expressed at higher levels on dominant clonotypes within epitope specific responses before and after initiation of ART. These data suggest that the antigen burden may maintain TCR diversity and that dominant clonotypes are sensitive to antigen even after dramatic reductions after initiation of ART. PMID- 22258247 TI - An RNA interference screen identifies the Deubiquitinase STAMBPL1 as a critical regulator of human T-cell leukemia virus type 1 tax nuclear export and NF-kappaB activation. AB - The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein actively shuttles between the nucleus, where it interacts with transcriptional and splicing regulatory proteins, and the cytoplasm, where it activates NF-kappaB. Posttranslational modifications of Tax such as ubiquitination regulate its subcellular localization and hence its function; however, the regulation of Tax trafficking and NF-kappaB activation by host factors is poorly understood. By screening a deubiquitinating (DUB) enzyme small interfering RNA (siRNA) library, we identified the metalloprotease STAM-binding protein-like 1 (STAMBPL1) as a positive regulator of Tax-mediated NF-kappaB activation. Overexpression of wild type STAMBPL1, but not a catalytically inactive mutant, enhanced Tax-mediated NF kappaB activation, whereas silencing of STAMBPL1 with siRNA impaired Tax activation of both the canonical and noncanonical NF-kappaB signaling pathways. STAMBPL1 regulated Tax-induced NF-kappaB signaling indirectly by controlling Tax nuclear/cytoplasmic transport and was required for DNA damage-induced Tax nuclear export. Together, these results reveal that the deubiquitinase STAMBPL1 is a key regulator of Tax trafficking and function. PMID- 22258248 TI - Mutation of the f-protein cleavage site of avian paramyxovirus type 7 results in furin cleavage, fusion promotion, and increased replication in vitro but not increased replication, tissue tropism, or virulence in chickens. AB - We constructed a reverse genetics system for avian paramyxovirus serotype 7 (APMV 7) to investigate the role of the fusion F glycoprotein in tissue tropism and virulence. The AMPV-7 F protein has a single basic residue arginine (R) at position -1 in the F cleavage site sequence and also is unusual in having alanine at position +2 (LPSSR?FA) (underlining indicates the basic amino acids at the F protein cleavage site, and the arrow indicates the site of cleavage.). APMV-7 does not form syncytia or plaques in cell culture, but its replication in vitro does not depend on, and is not increased by, added protease. Two mutants were successfully recovered in which the cleavage site was modified to mimic sites that are found in virulent Newcastle disease virus isolates and to contain 4 or 5 basic residues as well as isoleucine in the +2 position: (RRQKR?FI) or (RRKKR?FI), named Fcs-4B or Fcs-5B, respectively. In cell culture, one of the mutants, Fcs-5B, formed protease-independent syncytia and grew to 10-fold-higher titers compared to the parent and Fcs-4B viruses. This indicated the importance of the single additional basic residue (K) at position -3. Syncytium formation and virus yield of the Fcs-5B virus was impaired by the furin inhibitor decanoyl RVKR-CMK, whereas parental APMV-7 was not affected. APMV-7 is avirulent in chickens and is limited in tropism to the upper respiratory tract of 1-day-old and 2-week-old chickens, and these characteristics were unchanged for the two mutant viruses. Thus, the acquisition of furin cleavability by APMV-7 resulted in syncytium formation and increased virus yield in vitro but did not alter virus yield, tropism, or virulence in chickens. PMID- 22258249 TI - Role of ubiquitin in parainfluenza virus 5 particle formation. AB - Ubiquitin is important for the budding of many retroviruses and other enveloped viruses, but the precise role of ubiquitin in virus budding remains unclear. Here, we characterized the ubiquitination of the matrix (M) protein of a paramyxovirus, parainfluenza virus 5 (PIV5). The PIV5 M protein (but not the PIV5 nucleocapsid protein) was found to be targeted for monoubiquitination in transfected mammalian cells. Major sites of ubiquitin attachment identified by mass spectrometry analysis were lysine residues at amino acid positions 79/80, 130, and 247. The cumulative mutation of lysine residues 79, 80, and 130 to arginines led to an altered pattern of M protein ubiquitination and impaired viruslike particle (VLP) production. However, the cumulative mutation of lysine residues 79, 80, 130, and 247 to arginines restored M protein ubiquitination and VLP production, suggesting that ubiquitin is attached to alternative sites on the M protein when the primary ones have been removed. Additional lysine residues were targeted for mutagenesis based on the UbiPred algorithm. An M protein with seven lysine residues changed to arginines exhibited altered ubiquitination and poor VLP production. A recombinant virus encoding an M protein with seven lysines mutated was generated, and this virus exhibited a 6-fold-reduced maximum titer, with the defect being attributed mainly to the budding of noninfectious particles. The recombinant virus was assembly deficient, as judged by the redistribution of viral M and hemagglutinin-neuraminidase proteins in infected cells. Similar assembly defects were observed for the wild-type (wt) virus after treatment with a proteasome inhibitor. Collectively, these findings suggest that the monoubiquitination of the PIV5 M protein is important for proper virus assembly and for the budding of infectious particles. PMID- 22258250 TI - Cytoplasmic utilization of human immunodeficiency virus type 1 genomic RNA is not dependent on a nuclear interaction with gag. AB - In some retroviruses, such as Rous sarcoma virus and prototype foamy virus, Gag proteins are known to shuttle between the nucleus and the cytoplasm and are implicated in nuclear export of the viral genomic unspliced RNA (gRNA) for subsequent encapsidation. A similar function has been proposed for human immunodeficiency virus type 1 (HIV-1) Gag based on the identification of nuclear localization and export signals. However, the ability of HIV-1 Gag to transit through the nucleus has never been confirmed. In addition, the lentiviral Rev protein promotes efficient nuclear gRNA export, and previous reports indicate a cytoplasmic interaction between Gag and gRNA. Therefore, functional effects of HIV-1 Gag on gRNA and its usage were explored. Expression of gag in the absence of Rev was not able to increase cytoplasmic gRNA levels of subgenomic, proviral, or lentiviral vector constructs, and gene expression from genomic reporter plasmids could not be induced by Gag provided in trans. Furthermore, Gag lacking the reported nuclear localization and export signals was still able to mediate an efficient packaging process. Although small amounts of Gag were detectable in the nuclei of transfected cells, a Crm1-dependent nuclear export signal in Gag could not be confirmed. Thus, our study does not provide any evidence for a nuclear function of HIV-1 Gag. The encapsidation process of HIV-1 therefore clearly differs from that of Rous sarcoma virus and prototype foamy virus. PMID- 22258251 TI - Combination of biological screening in a cellular model of viral latency and virtual screening identifies novel compounds that reactivate HIV-1. AB - Although highly active antiretroviral therapy (HAART) has converted HIV into a chronic disease, a reservoir of HIV latently infected resting T cells prevents the eradication of the virus from patients. To achieve eradication, HAART must be combined with drugs that reactivate the dormant viruses. We examined this problem in an established model of HIV postintegration latency by screening a library of small molecules. Initially, we identified eight molecules that reactivated latent HIV. Using them as templates, additional hits were identified by means of similarity-based virtual screening. One of those hits, 8-methoxy-6-methylquinolin 4-ol (MMQO), proved to be useful to reactivate HIV-1 in different cellular models, especially in combination with other known reactivating agents, without causing T-cell activation and with lower toxicity than that of the initial hits. Interestingly, we have established that MMQO produces Jun N-terminal protein kinase (JNK) activation and enhances the T-cell receptor (TCR)/CD3 stimulation of HIV-1 reactivation from latency but inhibits CD3-induced interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) gene transcription. Moreover, MMQO prevents TCR-induced cell cycle progression and proliferation in primary T cells. The present study documents that the combination of biological screening in a cellular model of viral latency with virtual screening is useful for the identification of novel agents able to reactivate HIV-1. Moreover, we set the bases for a hypothetical therapy to reactivate latent HIV by combining MMQO with physiological or pharmacological TCR/CD3 stimulation. PMID- 22258252 TI - HIV-1 neutralization coverage is improved by combining monoclonal antibodies that target independent epitopes. AB - HIV-1 neutralizing monoclonal antibodies (MAbs) define key targets for vaccine development and are being considered for passive prevention of infection. We analyzed the interaction of MAbs to two independent epitopes on the viral envelope glycoprotein. Potently neutralizing MAbs to the CD4 binding site and V1V2 region displayed no in vitro cross-competition and displayed additive, though not synergistic, neutralization activity. Predicted neutralization coverage of a combination of two MAbs reached 97% on a 208-isolate panel. PMID- 22258253 TI - Nonstructural protein 2 of porcine reproductive and respiratory syndrome virus inhibits the antiviral function of interferon-stimulated gene 15. AB - Type I interferon (alpha/beta interferon [IFN-alpha/beta]) stimulates the expression of interferon-stimulated gene 15 (ISG15), which encodes a ubiquitin like protein, ISG15. Free ISG15 and ISG15 conjugates function in diverse cellular pathways, particularly regulation of antiviral innate immune responses. In this study, we demonstrate that ISG15 overexpression inhibits porcine reproductive and respiratory syndrome virus (PRRSV) replication in cell culture and that the antiviral activity of interferon is reduced by inhibition of ISG15 conjugation. PRRSV nonstructural protein 2 (nsp2) was previously identified as a potential antagonist of ISG15 production and conjugation. The protein contains a papain like protease domain (PLP2) that plays a crucial role in the proteolytic cleavage of the PRRSV replicase polyproteins. PLP2 was also proposed to belong to the ovarian tumor domain-containing superfamily of deubiquitinating enzymes (DUBs), which is capable of inhibiting ISG15 production and counteracting ISG15 conjugation to cellular proteins. To determine whether this immune antagonist function could be selectively inactivated, we engineered a panel of mutants with deletions and/or mutations at the N-terminal border of the nsp2 PLP2-DUB domain. A 23-amino-acid deletion (amino acids 402 to 424 of the ORF1a-encoded protein) largely abolished the inhibitory effect of nsp2 on ISG15 production and conjugation, but no viable recombinant virus was recovered. A 19-amino-acid deletion (amino acids 402 to 420), in combination with a downstream point mutation (S465A), partially relieved the ISG15 antagonist function and yielded a viable recombinant virus. Taken together, our data demonstrate that ISG15 and ISGylation play an important role in the response to PRRSV infection and that nsp2 is a key factor in counteracting the antiviral function of ISG15. PMID- 22258254 TI - Regulation of CHMP4/ESCRT-III function in human immunodeficiency virus type 1 budding by CC2D1A. AB - The detachment of human immunodeficiency type 1 (HIV-1) virions depends on CHPM4 family members, which are late-acting components of the ESCRT pathway that mediate the cleavage of bud necks from the cytosolic side. We now show that in human cells, CHMP4 proteins are to a considerable extent bound to two high molecular-weight proteins that we have identified as CC2D1A and CC2D1B. Both proteins bind to the core domain of CHMP4B, which has a strong propensity to polymerize and to inhibit HIV-1 budding. Further mapping showed that CC2D1A binds to an N-terminal hairpin within the CHMP4 core that has been implicated in polymerization. Consistent with a model in which CC2D1A and CC2D1B regulate CHMP4 polymerization, the overexpression of CC2D1A inhibited both the release of wild type HIV-1 and the CHMP4-dependent rescue of an HIV-1 L domain mutant by exogenous ALIX. Furthermore, small interfering RNA against CC2D1A or CC2D1B increased HIV-1 budding under certain conditions. CC2D1A and CC2D1B possess four Drosophila melanogaster 14 (DM14) domains, and we demonstrate that these constitute novel CHMP4 binding modules. The DM14 domain that bound most avidly to CHMP4B was by itself sufficient to inhibit the function of ALIX in HIV-1 budding, indicating that the inhibition occurred through CHMP4 sequestration. However, N terminal fragments of CC2D1A that did not interact with CHMP4B nevertheless retained a significant level of inhibitory activity. Thus, CC2D1A may also affect HIV-1 budding in a CHMP4-independent manner. PMID- 22258255 TI - Evidence for N-glycan shielding of antigenic sites during evolution of human influenza A virus hemagglutinin. AB - After the emergence of influenza A viruses in the human population, the number of N-glycosylation sites (NGS) in the globular head region of hemagglutinin (HA) has increased continuously for several decades. It has been speculated that the addition of NGS to the globular head region of HA has conferred selective advantages to the virus by preventing the binding of antibodies (Ab) to antigenic sites (AS). Here, the effect of N-glycosylation on the binding of Ab to AS in human influenza A virus subtype H3N2 (A/H3N2) was examined by inferring natural selection at AS and other sites (NAS) that are located close to and distantly from the NGS in the three-dimensional structure of HA through a comparison of the rates of synonymous (d(S)) and nonsynonymous (d(N)) substitutions. When positions 63, 122, 126, 133, 144, and 246 in the globular head region of HA were non-NGS, the d(N)/d(S) was >1 and positive selection was detected at the AS located near these positions. However, the d(N)/d(S) value decreased and the evidence of positive selection disappeared when these positions became NGS. In contrast, d(N)/d(S) at the AS distantly located from the positions mentioned above and at the NAS of any location were generally <1 and did not decrease when these positions changed from non-NGS to NGS. These results suggest that the attachment of N-glycans to the NGS in the globular head region of HA prevented the binding of Ab to AS in the evolutionary history of human A/H3N2 virus. PMID- 22258256 TI - Retargeting of rat parvovirus H-1PV to cancer cells through genetic engineering of the viral capsid. AB - The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds alpha(v)beta(3) and alpha(v)beta(5) integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing alpha(v)beta(5) integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H 1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy. PMID- 22258257 TI - Experimental infection of Cynomolgus Macaques (Macaca fascicularis) with human varicella-zoster virus. AB - Varicella-zoster virus (VZV) is a member of the alphaherpesvirus family and the causative agent of chickenpox and shingles. To determine the utility of cynomolgus macaques (Macaca fascicularis) as a nonhuman primate model to evaluate VZV-based simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) vaccines, we experimentally inoculated 10 animals with the parental Oka (Oka-P) strain of VZV derived from MeWo or Telo-RF cells. VZV DNA could be detected in the lungs as late as 4 days postinfection, with replicating virus detected by shell vial culture assay in one case. Infection did not result in any overt clinical symptoms but was characterized by humoral and cell-mediated immunity in a time frame and at a magnitude similar to those observed following VZV vaccination in humans. The cell line source of VZV inoculum influenced both the magnitude and polyfunctionality of cell-mediated immunity. Animals mounted a vigorous anamnestic antibody response following a second inoculation 12 weeks later. Inoculations resulted in transient increases in CD4(+) T-cell activation and proliferation, as well as a sustained increase in CD4(+) T cells coexpressing CCR5 and alpha4beta7 integrin. In contrast to previous failed attempts to successfully utilize attenuated VZV-Oka as an SIV vaccine vector in rhesus macaques due to suboptimal infectivity and cellular immunogenicity, the ability to infect cynomolgus macaques with Oka-P VZV should provide a valuable tool for evaluating VZV-vectored SIV/HIV vaccines. PMID- 22258258 TI - The C terminus of the large tegument protein pUL36 contains multiple capsid binding sites that function differently during assembly and cell entry of herpes simplex virus. AB - The largest tegument protein of herpes simplex virus type 1 (HSV1), pUL36, is a multivalent cross-linker between the viral capsids and the tegument and associated membrane proteins during assembly that upon subsequent cell entry releases the incoming capsids from the outer tegument and viral envelope. Here we show that pUL36 was recruited to cytosolic progeny capsids that later colocalized with membrane proteins of herpes simplex virus type 1 (HSV1) and the trans-Golgi network. During cell entry, pUL36 dissociated from viral membrane proteins but remained associated with cytosolic capsids until arrival at the nucleus. HSV1 UL36 mutants lacking C-terminal portions of increasing size expressed truncated pUL36 but could not form plaques. Cytosolic capsids of mutants lacking the C terminal 735 of the 3,164 amino acid residues accumulated in the cytosol but did not recruit pUL36 or associate with membranes. In contrast, pUL36 lacking only the 167 C-terminal residues bound to cytosolic capsids and subsequently colocalized with viral and host membrane proteins. Progeny virions fused with neighboring cells, but incoming capsids did not retain pUL36, nor could they target the nucleus or initiate HSV1 gene expression. Our data suggest that residues 2430 to 2893 of HSV1 pUL36, containing one binding site for the capsid protein pUL25, are sufficient to recruit pUL36 onto cytosolic capsids during assembly for secondary envelopment, whereas the 167 residues of the very C terminus with the second pUL25 binding site are crucial to maintain pUL36 on incoming capsids during cell entry. Capsids lacking pUL36 are targeted neither to membranes for virus assembly nor to nuclear pores for genome uncoating. PMID- 22258259 TI - Enterovirus 71 disrupts interferon signaling by reducing the level of interferon receptor 1. AB - The recent outbreak of enterovirus 71 (EV71) infected millions of children and caused over 1,000 deaths. To date, neither an effective vaccine nor antiviral treatment is available for EV71 infection. Interferons (IFNs) have been successfully applied to treat patients with hepatitis B and C viral infections for decades but have failed to treat EV71 infections. Here, we provide the evidence that EV71 antagonizes type I IFN signaling by reducing the level of interferon receptor 1 (IFNAR1). We show that the host cells could sense EV71 infection and stimulate IFN-beta production. However, the induction of downstream IFN-stimulated genes is inhibited by EV71. Also, only a slight interferon response and antiviral effects could be detected in cells treated with recombinant type I IFNs after EV71 infection. Further studies reveal that EV71 blocks the IFN-mediated phosphorylation of STAT1, STAT2, Jak1, and Tyk2 by reducing IFNAR1. Finally, we identified the 2A protease encoded by EV71 as an antagonist of IFNs and show that the protease activity is required for reducing IFNAR1 levels. Taken together, our study for the first time uncovers a mechanism used by EV71 to antagonize type I IFN signaling and provides new targets for future antiviral strategies. PMID- 22258260 TI - The 3A protein from multiple picornaviruses utilizes the golgi adaptor protein ACBD3 to recruit PI4KIIIbeta. AB - The activity of phosphatidylinositol 4-kinase class III beta (PI4KIIIbeta) has been shown to be required for the replication of multiple picornaviruses; however, it is unclear whether a physical association between PI4KIIIbeta and the viral replication machinery exists and, if it does, whether association is necessary. We examined the ability of the 3A protein from 18 different picornaviruses to form a complex with PI4KIIIbeta by affinity purification of Strep-Tagged transiently transfected constructs followed by mass spectrometry and Western blotting for putative interacting targets. We found that the 3A proteins of Aichi virus, bovine kobuvirus, poliovirus, coxsackievirus B3, and human rhinovirus 14 all copurify with PI4KIIIbeta. Furthermore, we found that multiple picornavirus 3A proteins copurify with the Golgi adaptor protein acyl coenzyme A (acyl-CoA) binding domain protein 3 (ACBD3/GPC60), including those from Aichi virus, bovine kobuvirus, human rhinovirus 14, poliovirus, and coxsackievirus B2, B3, and B5. Affinity purification of ACBD3 confirmed interaction with multiple picornaviral 3A proteins and revealed the ability to bind PI4KIIIbeta in the absence of 3A. Mass-spectrometric analysis of transiently expressed Aichi virus, bovine kobuvirus, and human klassevirus 3A proteins demonstrated that the N terminal glycines of these 3A proteins are myristoylated. Alanine-scanning mutagenesis along the entire length of Aichi virus 3A followed by transient expression and affinity purification revealed that copurification of PI4KIIIbeta could be eliminated by mutation of specific residues, with little or no effect on recruitment of ACBD3. One mutation at the N terminus, I5A, significantly reduced copurification of both ACBD3 and PI4KIIIbeta. The dependence of Aichi virus replication on the activity of PI4KIIIbeta was confirmed by both chemical and genetic inhibition. Knockdown of ACBD3 by small interfering RNA (siRNA) also prevented replication of both Aichi virus and poliovirus. Point mutations in 3A that eliminate PI4KIIIbeta association sensitized Aichi virus to PIK93, suggesting that disruption of the 3A/ACBD3/PI4KIIIbeta complex may represent a novel target for therapeutic intervention that would be complementary to the inhibition of the kinase activity itself. PMID- 22258261 TI - Identification of a specific region in the e1 fusion protein involved in zinc inhibition of semliki forest virus fusion. AB - The enveloped alphaviruses infect cells via a low-pH-triggered membrane fusion reaction mediated by the viral transmembrane protein E1. During fusion, E1 inserts into the target membrane and refolds to a hairpin-like postfusion conformation in which domain III (DIII) and the juxtamembrane stem pack against a central core trimer. Although zinc has previously been shown to cause a striking block in alphavirus fusion with liposome target membranes, the mechanism of zinc's effect on the E1 fusion protein is not understood. Here we developed a cell culture system to study zinc inhibition of fusion and infection of the alphavirus Semliki Forest virus (SFV). Inclusion of 2 mM ZnCl(2) in the pH 5.75 fusion buffer caused a decrease of ~5 logs in SFV fusion at the plasma membrane. Fusion was also inhibited by nickel, a chemically related transition metal. Selection for SFV zinc resistance identified a key histidine residue, H333 on E1 DIII, while other conserved E1 histidine residues were not involved. An H333N mutation conferred resistance to both zinc and nickel, with properties in keeping with the known pH-dependent chelation of these metals by histidine. Biochemical studies demonstrated that zinc strongly inhibits formation of the postfusion E1 trimer in wild-type SFV but not in an H333 mutant. Together our results suggest that zinc acts by blocking the fold-back of DIII via its interaction with H333. PMID- 22258262 TI - Arterivirus minor envelope proteins are a major determinant of viral tropism in cell culture. AB - Arteriviruses are enveloped positive-strand RNA viruses for which the attachment proteins and cellular receptors have remained largely controversial. Arterivirus particles contain at least eight envelope proteins, an unusually large number among RNA viruses. These appear to segregate into three groups: major structural components (major glycoprotein GP5 and membrane protein [M]), minor glycoproteins (GP2a, GP3, and GP4), and small hydrophobic proteins (E and the recently discovered ORF5a protein). Biochemical studies previously suggested that the GP5 M heterodimer of porcine reproductive and respiratory syndrome virus (PRRSV) interacts with porcine sialoadhesin (pSn) in porcine alveolar macrophages (PAM). However, another study proposed that minor protein GP4, along with GP2a, interacts with CD163, another reported cellular receptor for PRRSV. In this study, we provide genetic evidence that the minor envelope proteins are the major determinant of arterivirus entry into cultured cells. A PRRSV infectious cDNA clone was equipped with open reading frames (ORFs) encoding minor envelope and E proteins of equine arteritis virus (EAV), the only known arterivirus displaying a broad tropism in cultured cells. Although PRRSV and EAV are only distantly related and utilize diversified transcription-regulating sequences (TRSs), a viable chimeric progeny virus was rescued. Strikingly, this chimeric virus (vAPRRS-EAV2ab34) acquired the broad in vitro cell tropism of EAV, demonstrating that the minor envelope proteins play a critical role as viral attachment proteins. We believe that chimeric arteriviruses of this kind will be a powerful tool for further dissection of the arterivirus replicative cycle, including virus entry, subgenomic RNA synthesis, and virion assembly. PMID- 22258263 TI - West nile virus infections suppress early viral RNA synthesis and avoid inducing the cell stress granule response. AB - West Nile virus (WNV) recently became endemic in the United States and is a significant cause of human morbidity and mortality. Natural WNV strain infections do not induce stress granules (SGs), while W956IC (a lineage 2/1 chimeric WNV infectious clone) virus infections produce high levels of early viral RNA and efficiently induce SGs through protein kinase R (PKR) activation. Additional WNV chimeric viruses made by replacing one or more W956IC genes with the lineage 1 Eg101 equivalent in the W956IC backbone were analyzed. The Eg-NS4b+5, Eg NS1+3+4a, and Eg-NS1+4b+5 chimeras produced low levels of viral RNA at early times of infection and inefficiently induced SGs, suggesting the possibility that interactions between viral nonstructural proteins and/or between viral nonstructural proteins and cell proteins are involved in suppressing early viral RNA synthesis and membrane remodeling during natural WNV strain infections. Detection of exposed viral double-stranded RNA (dsRNA) in W956IC-infected cells suggested that the enhanced early viral RNA synthesis surpassed the available virus-induced membrane protection and allowed viral dsRNA to activate PKR. PMID- 22258264 TI - Inhibition of latent membrane protein 1 impairs the growth and tumorigenesis of latency II Epstein-Barr virus-transformed T cells. AB - Epstein-Barr virus (EBV) is a common human herpesvirus. Infection with EBV is associated with several human malignancies in which the virus expresses a set of latent proteins, among which is latent membrane protein 1 (LMP1). LMP1 is able to transform numerous cell types and is considered the main oncogenic protein of EBV. The mechanism of action is based on mimicry of activated members of the tumor necrosis factor (TNF) receptor superfamily, through the ability of LMP1 to bind similar adapters and to activate signaling pathways. We previously generated two unique models: a monocytic cell line and a lymphocytic (NC5) cell line immortalized by EBV that expresses the type II latency program. Here we generated LMP1 dominant negative forms (DNs), based on fusion between green fluorescent protein (GFP) and transformation effector site 1 (TES1) or TES2 of LMP1. Then we generated cell lines conditionally expressing these DNs. These DNs inhibit NF kappaB and Akt pathways, resulting in the impairment of survival processes and increased apoptosis in these cell lines. This proapoptotic effect is due to reduced interaction of LMP1 with specific adapters and the recruitment of these adapters to DNs, which enable the generation of an apoptotic complex involving TRADD, FADD, and caspase 8. Similar results were obtained with cell lines displaying a latency III program in which LMP1-DNs decrease cell viability. Finally, we prove that synthetic peptides display similar inhibitory effects in EBV-infected cells. DNs derived from LMP1 could be used to develop therapeutic approaches for malignant diseases associated with EBV. PMID- 22258265 TI - Effect of supplementation with cholecalciferol and calcium on 2-y bone mass accrual in HIV-infected children and adolescents: a randomized clinical trial. AB - BACKGROUND: Skeletal abnormalities have been reported in HIV-infected children and adolescents. Although the etiology is not well understood, vitamin D deficiency may be involved. OBJECTIVE: The study objective was to evaluate the effect of vitamin D and calcium supplementation on bone mass accrual in HIV infected youth. DESIGN: Perinatally HIV-infected children were randomly assigned to receive vitamin D (100,000 IU cholecalciferol given every 2 mo) and calcium (1 g/d) (supplemented group) or double placebo (placebo group) for 2 y. The total body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), spine bone mineral content (SBMC), and spine bone mineral density (SBMD) were assessed by using dual-energy X-ray absorptiometry at baseline and at 2 annual follow-up visits. RESULTS: Fifty-nine participants, aged 6-16 y, were randomly assigned to either the supplemented (n = 30) or the placebo (n = 29) group. At enrollment, supplemented and placebo groups did not differ with respect to age, sex, dietary intakes of vitamin D and calcium, mean baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, TBBMC, TBBMD, SBMC, or SBMD. Significant increases in serum 25(OH)D were observed in the supplemented group but not in the placebo group. TBBMC, TBBMD, SBMC, and SBMD increased significantly at 1 and 2 y in both groups. No between-group differences were observed at any time before or after adjustment for stage of sexual maturation by mixed linear model analysis. CONCLUSION: One gram of calcium per day and oral cholecalciferol at a dosage of 100,000 IU every 2 mo administered to HIV-infected children and adolescents did not affect bone mass accrual despite significant increases in serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00724178. PMID- 22258266 TI - Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial. AB - BACKGROUND: Weight loss reduces body fat and lean mass, but whether these changes are influenced by macronutrient composition of the diet is unclear. OBJECTIVE: We determined whether energy-reduced diets that emphasize fat, protein, or carbohydrate differentially reduce total, visceral, or hepatic fat or preserve lean mass. DESIGN: In a subset of participants in a randomized trial of 4 weight loss diets, body fat and lean mass (n = 424; by using dual-energy X-ray absorptiometry) and abdominal and hepatic fat (n = 165; by using computed tomography) were measured after 6 mo and 2 y. Changes from baseline were compared between assigned amounts of protein (25% compared with 15%) and fat (40% compared with 20%) and across 4 carbohydrate amounts (35% through 65%). RESULTS: At 6 mo, participants lost a mean (+/-SEM) of 4.2 +/- 0.3 kg (12.4%) fat and 2.1 +/- 0.3 kg (3.5%) lean mass (both P < 0.0001 compared with baseline values), with no differences between 25% and 15% protein (P >= 0.10), 40% and 20% fat (P >= 0.34), or 65% and 35% carbohydrate (P >= 0.27). Participants lost 2.3 +/- 0.2 kg (13.8%) abdominal fat: 1.5 +/- 0.2 kg (13.6%) subcutaneous fat and 0.9 +/- 0.1 kg (16.1%) visceral fat (all P < 0.0001 compared with baseline values), with no differences between the diets (P >= 0.29). Women lost more visceral fat than did men relative to total-body fat loss. Participants regained ~40% of these losses by 2 y, with no differences between diets (P >= 0.23). Weight loss reduced hepatic fat, but there were no differences between groups (P >= 0.28). Dietary goals were not fully met; self-reported contrasts were closer to 2% protein, 8% fat, and 14% carbohydrate at 6 mo and 1%, 7%, and 10%, respectively, at 2 y. CONCLUSION: Participants lost more fat than lean mass after consumption of all diets, with no differences in changes in body composition, abdominal fat, or hepatic fat between assigned macronutrient amounts. This trial was registered at clinicaltrials.gov as NCT00072995. PMID- 22258267 TI - Beverage consumption, appetite, and energy intake: what did you expect? AB - BACKGROUND: Beverage consumption is implicated in the overweight/obesity epidemic through the weaker energy compensation response it elicits compared with solid food forms. However, plausible mechanisms are not documented. OBJECTIVE: This study assessed the cognitive and sensory contributions of differential postingestive responses to energy- and macronutrient-matched liquid (in beverage form) and solid food forms and identifies physiologic processes that may account for them. DESIGN: Fifty-two healthy adults [mean +/- SD age: 24.7 +/- 5.5 y; BMI (in kg/m(2)): 26.3 +/- 6.3] completed this randomized, 4-arm crossover study. Participants consumed oral liquid and solid preloads that they perceived, through cognitive manipulation, to be liquid or solid in their stomach (ie, oral liquid/perceived gastric liquid, oral liquid/perceived gastric solid, oral solid/perceived gastric liquid, or oral solid/perceived gastric solid). However, all preloads were designed to present a liquid gastric challenge. Appetite, gastric-emptying and orocecal transit times, and selected endocrine responses were monitored for the following 4 h; total energy intake was also recorded. RESULTS: Oral-liquid and perceived gastric-liquid preloads elicited greater postprandial hunger and lower fullness sensations, more rapid gastric-emptying and orocecal transit times, attenuated insulin and glucagon-like peptide 1 release, and lower ghrelin suppression than did responses after oral-solid and perceived gastric-solid treatments (all P < 0.05). Faster gastric-emptying times were significantly associated with greater energy intake after consumption of perceived gastric-liquid preloads (P < 0.05). Energy intake was greater on days when perceived gastric-liquid preloads were consumed than when perceived gastric solids were consumed (2311 +/- 95 compared with 1897 +/- 72 kcal, P = 0.007). CONCLUSIONS: These data document sensory and cognitive effects of food form on ingestive behavior and identify physical and endocrine variables that may account for the low satiety value of beverages. They are consistent with findings that clear, energy-yielding beverages pose a particular risk for positive energy balance. This study was registered at clinicaltrials.gov as NCT01070199. PMID- 22258269 TI - A lipid-based nutrient supplement mitigates weight loss among HIV-infected women in a factorial randomized trial to prevent mother-to-child transmission during exclusive breastfeeding. AB - BACKGROUND: Breastfeeding increases metabolic demands on the mother, and excessive postnatal weight loss increases maternal mortality. OBJECTIVE: We evaluated the efficacy of a lipid-based nutrient supplement (LNS) for prevention of excess weight loss in breastfeeding, HIV-infected women. DESIGN: The BAN (Breastfeeding, Antiretrovirals, and Nutrition) Study was a randomized controlled trial in Lilongwe, Malawi. At delivery, HIV-infected mothers and their infants were randomly assigned according to a 2-arm (with and without LNS) by 3-arm (maternal triple-antiretroviral prophylaxis, infant-nevirapine prophylaxis, or neither) factorial design. The 28-wk LNS intervention provided daily energy (700 kcal), protein (20 g), and micronutrients (except for vitamin A) to meet lactation needs. Women were counseled to breastfeed exclusively for 24 wk and to wean by 28 wk. Weight change (0-28 wk) was tested in an intent-to-treat analysis by using 2-factor ANOVA and with longitudinal mixed-effects models. RESULTS: At delivery, the LNS (n = 1184) and control (n = 1185) groups had similar mean weights and BMIs. Women receiving the LNS had less 0-28-wk weight loss (-1.97 compared with -2.56 kg, P = 0.003). This difference remained significant after adjustment for maternal antiretroviral drug therapy and baseline BMI. Women receiving antiretroviral drugs had more weight loss than did those not receiving antiretroviral drugs (-2.93 compared with -1.90 kg, P < 0.001). The benefit of the LNS for reducing weight loss was observed both in those receiving antiretroviral drugs (-2.56 compared with -3.32 kg, P = 0.019) and in those not receiving antiretroviral drugs (-1.63 compared with -2.16 kg, P = 0.034). CONCLUSIONS: The LNS reduced weight loss among HIV-infected, breastfeeding women, both in those taking maternal antiretroviral prophylaxis to prevent postnatal HIV transmission and in those not receiving antiretroviral prophylaxis. Provision of an LNS may benefit HIV-infected, breastfeeding women in resource-limited settings. This trial was registered at clinicaltrials.gov as NCT00164762. PMID- 22258268 TI - Habitual dietary sodium intake is inversely associated with coronary flow reserve in middle-aged male twins. AB - BACKGROUND: Evidence links dietary sodium to hypertension and cardiovascular disease (CVD), but investigation of its influence on cardiovascular function is limited. OBJECTIVE: We examined the relation between habitual dietary sodium and coronary flow reserve (CFR), which is a measure of overall coronary vasodilator capacity and microvascular function. We hypothesized that increased sodium consumption is associated with lower CFR. DESIGN: Habitual daily sodium intake for the previous 12 mo was measured in 286 male middle-aged twins (133 monozygotic and dizygotic pairs and 20 unpaired twins) by using the Willett food frequency questionnaire. CFR was measured by positron emission tomography [N(13)] ammonia, with quantitation of myocardial blood flow at rest and after adenosine stress. Mixed-effects regression analysis was used to assess the association between dietary sodium and CFR. RESULTS: An increase in dietary sodium of 1000 mg/d was associated with a 10.0% lower CFR (95% CI: -17.0%, -2.5%) after adjustment for demographic, lifestyle, nutritional, and CVD risk factors (P = 0.01). Across quintiles of sodium consumption, dietary sodium was inversely associated with CFR (P-trend = 0.03), with the top quintile (>1456 mg/d) having a 20% lower CFR than the bottom quintile (<732 mg /d). This association also persisted within pairs: a 1000-mg/d difference in dietary sodium between brothers was associated with a 10.3% difference in CFR after adjustment for potential confounders (P = 0.02). CONCLUSIONS: Habitual dietary sodium is inversely associated with CFR independent of CVD risk factors and shared familial and genetic factors. Our study suggests a potential novel mechanism for the adverse effects of dietary sodium on the cardiovascular system. This trial was registered at clinicaltrials.gov as NCT00017836. PMID- 22258270 TI - The link between dietary glycemic index and nutrient adequacy. AB - BACKGROUND: Low-glycemic index (low-GI) diets may be less nutritious because of limited food choices. Alternately, high-GI diets could be less healthful because of a higher intake of refined carbohydrate. OBJECTIVE: The objective was to investigate the association between dietary GI, intakes of carbohydrates from high-GI (CHO(high GI)) and low-GI (CHO(low GI)) sources, and the risk of nutrient inadequacy in children and adolescents. DESIGN: Children, aged 2-16 y, who provided 2 plausible 24-h recalls in a national survey were included (n = 4140). The ORs of not meeting the Australian Nutrient Reference Values (NRVs) were calculated by logistic regression. RESULTS: Subjects with higher intakes of CHO(high GI) were found to be at risk of not meeting the NRVs for a wide range of nutrients, including calcium and iodine (both P-trend < 0.001). In comparison with subjects in the lowest quartile of CHO(high GI), those in the highest quartile had 3 times (adjusted OR: 3.13; 95% CI: 2.47, 3.97; P-trend < 0.001) the risk of not meeting the Estimated Average Requirement for calcium. For iodine, the risk increased >5-fold (adjusted OR: 5.45; 95% CI: 3.97, 7.48; P-trend < 0.001). On the other hand, subjects with higher intakes of CHO(low GI) were less likely to meet Adequate Intakes of unsaturated fatty acids (all P-trend < 0.001), despite having lower risks of not meeting the NRVs for most nutrients. CONCLUSION: Children and adolescents who consume more CHO(low GI) are more likely to meet most nutrient recommendations than those consuming higher GI diets. PMID- 22258271 TI - Monitoring of gluten-free diet compliance in celiac patients by assessment of gliadin 33-mer equivalent epitopes in feces. AB - BACKGROUND: Certain immunotoxic peptides from gluten are resistant to gastrointestinal digestion and can interact with celiac-patient factors to trigger an immunologic response. A gluten-free diet (GFD) is the only effective treatment for celiac disease (CD), and its compliance should be monitored to avoid cumulative damage. However, practical methods to monitor diet compliance and to detect the origin of an outbreak of celiac clinical symptoms are not available. OBJECTIVE: We assessed the capacity to determine the gluten ingestion and monitor GFD compliance in celiac patients by the detection of gluten and gliadin 33-mer equivalent peptidic epitopes (33EPs) in human feces. DESIGN: Fecal samples were obtained from healthy subjects, celiac patients, and subjects with other intestinal pathologies with different diet conditions. Gluten and 33EPs were analyzed by using immunochromatography and competitive ELISA with a highly sensitive antigliadin 33-mer monoclonal antibody. RESULTS: The resistance of a significant part of 33EPs to gastrointestinal digestion was shown in vitro and in vivo. We were able to detect gluten peptides in feces of healthy individuals after consumption of a normal gluten-containing diet, after consumption of a GFD combined with controlled ingestion of a fixed amount of gluten, and after ingestion of <100 mg gluten/d. These methods also allowed us to detect GFD infringement in CD patients. CONCLUSIONS: Gluten-derived peptides could be sensitively detected in human feces in positive correlation with the amount of gluten intake. These techniques may serve to show GFD compliance or infringement and be used in clinical research in strategies to eliminate gluten immunotoxic peptides during digestion. This trial was registered at clinicaltrials.gov as NCT01478867. PMID- 22258273 TI - Three-dimensional networks based on trinuclear motifs with tricomponent azide carboxylate-tetrazolate cobridges: synthesis, structure and magnetic properties. AB - Two 3D coordination polymers of Mn(II) with azide and bifunctional zwitterionic ligands bearing both carboxylate and tetrazolate groups, 1-(carboxylatomethyl)-3 (5-tetrazolato)pyridinium (L(1)) and 1-(carboxylatoethyl)-4-(5 tetrazolato)pyridinium (L(2)), were synthesized, and structurally and magnetically characterized. They are formulated as [Mn(3)(L(1))(2)(N(3))(4)(H(2)O)(2)](n).4nH(2)O (1) and [Mn(3)(L(2))(2)(N(3))(4)(H(2)O)(3)](n).3.5nH(2)O (2). In both compounds, octahedral Mn(II) ions are linked by the mixed (MU(2)-EO-N(3))(MU(2)-syn,syn COO)(MU(2)-N(2),N(3)-CN(4)) (CN(4) = tetrazolate and EO = end-on) triple bridges to give anionic linear trinuclear motifs. The motifs are connected through EE N(3) (EE = end-to-end) bridges to give layers and chains in 1 and 2, respectively, and the cationic pyridinium spacers serve to interlink the layers or chains into three-dimensional frameworks with the alpha-Po and CdSO(4)-type topology, respectively. Magnetic studies demonstrated that the magnetic interactions within and between the trinuclear motifs, through the tricomponent and EE-N(3) bridges, respectively, are both antiferromagnetic in both compounds. PMID- 22258272 TI - Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism. AB - Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI. PMID- 22258274 TI - An allosteric anti-hepsin antibody derived from a constrained phage display library. AB - The serine protease hepsin is highly upregulated in prostate cancer and is implicated in tumor progression. Therefore, specific inhibition of hepsin enzymatic activity by an antibody constitutes an attractive therapeutic approach. Here, we report the identification of the anti-hepsin antibody Fab25 by screening of a Fab phage display library with a restricted chemical diversity at the complementary determining regions. Hepsin with its S1 pocket occupied by 3,4 dichloro-isocoumarin was used as the 'bait' for library screening. Fab25 was highly specific and it potently inhibited hepsin activity toward a panel of synthetic and macromolecular substrates. Biochemical and enzymatic studies with synthetic substrates of variable length suggested that Fab25 acts as an allosteric inhibitor based on non-competitive inhibition kinetics. Isothermal titration calorimetric experiments showed that the high-affinity (K(D) 6.1 nM) binding of Fab25 with hepsin is enthalpically driven. Despite an unusually long CDR-H3 loop with several potential hepsin cleavage sites (Lys, Arg residues), Fab25 was not processed by hepsin. Antibody-25 should be valuable for investigating hepsin's role in cancer progression and for potential therapeutic applications. Furthermore, the herein presented phage display strategy using an active site-modified protease should be widely applicable for identifying potential allosteric anti-protease antibodies. PMID- 22258275 TI - Prediction of hot spots in protein interfaces using a random forest model with hybrid features. AB - Prediction of hot spots in protein interfaces provides crucial information for the research on protein-protein interaction and drug design. Existing machine learning methods generally judge whether a given residue is likely to be a hot spot by extracting features only from the target residue. However, hot spots usually form a small cluster of residues which are tightly packed together at the center of protein interface. With this in mind, we present a novel method to extract hybrid features which incorporate a wide range of information of the target residue and its spatially neighboring residues, i.e. the nearest contact residue in the other face (mirror-contact residue) and the nearest contact residue in the same face (intra-contact residue). We provide a novel random forest (RF) model to effectively integrate these hybrid features for predicting hot spots in protein interfaces. Our method can achieve accuracy (ACC) of 82.4% and Matthew's correlation coefficient (MCC) of 0.482 in Alanine Scanning Energetics Database, and ACC of 77.6% and MCC of 0.429 in Binding Interface Database. In a comparison study, performance of our RF model exceeds other existing methods, such as Robetta, FOLDEF, KFC, KFC2, MINERVA and HotPoint. Of our hybrid features, three physicochemical features of target residues (mass, polarizability and isoelectric point), the relative side-chain accessible surface area and the average depth index of mirror-contact residues are found to be the main discriminative features in hot spots prediction. We also confirm that hot spots tend to form large contact surface areas between two interacting proteins. Source data and code are available at: http://www.aporc.org/doc/wiki/HotSpot. PMID- 22258276 TI - Bacterial diversity in Cr(VI) and Cr(III)-contaminated industrial wastewaters. AB - The bacterial community structure of a chromium water bath, a chromium drainage waste system, a chromium pretreatment tank, and a trivalent chromium precipitation tank from the Hellenic Aerospace Industry S.A. was assessed using 16S rRNA libraries and a high-density DNA microarray (PhyloChip). 16S rRNA libraries revealed a bacterial diversity consisting of 14 distinct operational taxonomic units belonging to five bacterial phyla: Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Actinobacteria, and Bacteroidetes. However, employing a novel microarray-based approach (PhyloChip), a high bacterial diversity consisting of 30 different phyla was revealed, with representatives of 181 different families. This made it possible to identify a core set of genera present in all wastewater treatment stages examined, consisting of members of Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Deltaproteobacteria, Epsilonproteobacteria, and Bacteroidetes. In the chromium pretreatment tank, where the concentration of Cr(VI) is high (2.3 mg/l), we identified the presence of Pseudomonadales, Actinomycetales, and Enterobacteriales in abundance. In the chromium precipitation tank, where the concentration of Cr(III) is high, the dominant bacteria consortia were replaced by members of Rhodocyclales and Chloroflexi. The bacterial community structure changed significantly with changes in the chromium concentration. This in-depth analysis should prove useful for the design and development of improved bioremediation strategies. PMID- 22258278 TI - Effects of sex and sexual orientation on self-reported attraction and viewing times to images of men and women: testing for category specificity. AB - In a paradigm that asked participants to rate the sexual attractiveness of male and female swimsuit models, Lippa, Patterson, and Marelich (2010) showed that heterosexual men's category specificity exceeded heterosexual women's in two ways: (1) Heterosexual men showed much larger differences in their attraction and viewing times to male versus female photo models than heterosexual women, and (2) heterosexual men's attractions to female but not male models increased with model attractiveness whereas heterosexual women's attractions to both sexes increased with model attractiveness. The current study used the same paradigm to study category specificity in homosexual and heterosexual participants. In addition to replicating previous findings for heterosexual men and women, the results showed that homosexual men were high on category specificity, like heterosexual men, whereas lesbians showed lower levels of category specificity than men, but sometimes higher levels than heterosexual women. PMID- 22258279 TI - Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. AB - PURPOSE: To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers. METHODS: Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro-in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2. RESULTS: Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94 pmol/mg microsomal protein for subjects smoking 0, 1-5, 6 10, 11-20, and >20 cigarettes/day respectively. Predicted -fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90 L/h (40%) and 141 L/h (34%) respectively, and 100 L/h (58%) and 131 L/h (33%) respectively. CONCLUSIONS: This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach. PMID- 22258280 TI - Effects of electrode size and spacing on the resolution of intracardiac electrograms. AB - BACKGROUND: Electrogram fractionation can result when multiple groups of cardiac cells are excited asynchronously within the recording region of a mapping electrode. The spatial resolution of an electrode thus plays an important role in mapping complex rhythms. METHODS: We used a computational model, validated against experimental measurements in vitro, to determine how spatial resolution is affected by electrode diameter, electrode length, interelectrode distance (in the case of bipolar recordings), and height of the electrode above a dipole current source. RESULTS: We found that increases in all these quantities caused progressive degradation in two independent measures of spatial resolution, with the strongest effect being due to changes in height above the tissue. CONCLUSION: Our calculations suggest that if electrodes could be constructed to have negligible dimensions compared with those in use today, we would increase resolution by about one order of magnitude at most. PMID- 22258281 TI - Exploring policy compliance of the South African informal milk-producing segment. AB - Our study assessed whether municipal health services were informed about and exerted adequate control over the informal milk-producing sector in South Africa. The results indicated that municipal health services had limited control. Only one municipality was authorised to allow the sale of raw milk in its area. In most metropolitan and district municipalities, the distribution of raw milk continues, even where no statutory investigations assessed the ability to control the practice. The national and provincial government should recognise and support capacity building to enable municipalities to exercise power and perform their functions regarding informal milk distribution, part of the informal sector that has provided opportunities for employment and additional income. This constitutes a challenge particularly in monitoring and control of high-risk foods. PMID- 22258282 TI - The manufacture of lifestyle: the role of corporations in unhealthy living. AB - Recently, researchers have debated two views on the connection between lifestyle and health. In the first, health-related lifestyles including tobacco and alcohol use, diet, and physical activity are seen as primary influences on health. In the second, social stratification is the dominant influence with lifestyles simply markers of social status. Neither approach leads to interventions that can reverse the world's most serious health problems. This article proposes that corporate practices are a dominant influence on the lifestyles that shape patterns of health and disease. Modifying business practices that promote unhealthy lifestyles is a promising strategy for improving population health. Corporations shape lifestyles by producing and promoting healthy or unhealthy products, creating psychological desires and fears, providing health information, influencing social and physical environments, and advancing policies that favor their business goals. Public officials and health professionals can promote health by advocating policies to modify these corporate practices. PMID- 22258283 TI - Protein crystal structures with ferrocene and ruthenocene-based enzyme inhibitors. AB - We have determined the protein X-ray crystal structures of four organometallic inhibitors in complex with their target enzyme carbonic anhydrase II. The barrel shaped hydrophobic ferrocene and ruthenocene moieties have provided a structure based avenue to better occupy the hydrophobic binding patch within the enzyme active site. PMID- 22258284 TI - Perceptions of pandemic influenza vaccines. PMID- 22258285 TI - Unilateral hyperplasia of lamina and spinous process of C6 vertebra: case report. AB - We report a 20-year-old male patient who was admitted to our emergency clinic after a traffic accident and who suffered from neck pain. Radiographic examination of the cervical spine showed hypertrophy of the left lamina and hypertrophy and elongation of the left spinous process of the sixth cervical vertebra (C6). A computed tomography scan revealed the associated schisis of the spinous process at the same level. Magnetic resonance imaging scan demonstrated no abnormality of the neural elements. The patient underwent a surgical operation due to persistent neck pain and the local aesthetic abnormality. PMID- 22258286 TI - Cultivation of human neural progenitor cells in a 3-dimensional self-assembling peptide hydrogel. AB - The influence of 3-dimensional (3D) scaffolds on growth, proliferation and finally neuronal differentiation is of great interest in order to find new methods for cell-based and standardised therapies in neurological disorders or neurodegenerative diseases. 3D structures are expected to provide an environment much closer to the in vivo situation than 2D cultures. In the context of regenerative medicine, the combination of biomaterial scaffolds with neural stem and progenitor cells holds great promise as a therapeutic tool. Culture systems emulating a three dimensional environment have been shown to influence proliferation and differentiation in different types of stem and progenitor cells. Herein, the formation and functionalisation of the 3D-microenviroment is important to determine the survival and fate of the embedded cells. Here we used PuraMatrix (RADA16, PM), a peptide based hydrogel scaffold, which is well described and used to study the influence of a 3D-environment on different cell types. PuraMatrix can be customised easily and the synthetic fabrication of the nano-fibers provides a 3D-culture system of high reliability, which is in addition xeno-free. Recently we have studied the influence of the PM concentration on the formation of the scaffold. In this study the used concentrations of PM had a direct impact on the formation of the 3D-structure, which was demonstrated by atomic force microscopy. A subsequent analysis of the survival and differentiation of the hNPCs revealed an influence of the used concentrations of PM on the fate of the embedded cells. However, the analysis of survival or neuronal differentiation by means of immunofluorescence techniques posses some hurdles. To gain reliable data, one has to determine the total number of cells within a matrix to obtain the relative number of e.g. neuronal cells marked by betaIII-tubulin. This prerequisites a technique to analyse the scaffolds in all 3-dimensions by a confocal microscope or a comparable technique like fluorescence microscopes able to take z-stacks of the specimen. Furthermore this kind of analysis is extremely time consuming. Here we demonstrate a method to release cells from the 3D-scaffolds for the later analysis e.g. by flow cytometry. In this protocol human neural progenitor cells (hNPCs) of the ReNcell VM cell line (Millipore USA) were cultured and differentiated in 3D-scaffolds consisting of PuraMatrix (PM) or PuraMatrix supplemented with laminin (PML). In our hands a PM-concentration of 0.25% was optimal for the cultivation of the cells, however the concentration might be adapted to other cell types. The released cells can be used for e.g. immunocytochemical studies and subsequently analysed by flow cytometry. This speeds up the analysis and more over, the obtained data rest upon a wider base, improving the reliability of the data. PMID- 22258287 TI - Transplanted functional islet mass: donor, islet preparation, and recipient factors influence early graft function in islet-after-kidney patients. AB - BACKGROUND: The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. METHODS: Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C peptide to glucose and creatinine ratio (DeltaCP/GCr). RESULTS: Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to DeltaCP/GCr. A negative association to DeltaCP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after kidney data set. CONCLUSION: The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation. PMID- 22258288 TI - Advising potential recipients on the use of organs from donors with primary central nervous system tumors. AB - Deciding to use an organ from a donor with a primary central nervous system (CNS) tumor necessitates offsetting the risk of tumor transmission with the chances of survival if the patient waits for another offer of a transplant. Published data vary in the quoted risk of tumor transmission. We used data obtained by reviewing 246 UK recipients of organs taken from donors with CNS tumors and found no evidence of a difference in overall patient mortality for recipients of a kidney, liver, or cardiothoracic organ, compared with recipients of organs from donors without a CNS tumor. Recent publication of the UK experience of transplanting organs from CNS tumor donors found no transmission in 448 recipients of organs from 177 donors with a primary CNS tumor (Watson et al., Am J Transplant 2010; 10: 1437). This 0% transmission rate is associated with an upper 95% confidence interval limit of 1.5%. Using a series of assumptions of risk, we compared the risks of dying as a result of the transmission of a primary brain tumor with the risks of dying if not transplanted. On this basis, the use of kidneys from a donor with a primary CNS tumor provides a further 8 years of life over someone who waited for a donor who did not have a primary CNS tumor, in addition to the life years gained by the transplant itself. The benefits for the recipients of livers and cardiothoracic organs were less, but there was no disadvantage in the impact on life expectancy. PMID- 22258289 TI - Budesonide use in pediatric Crohn disease. AB - BACKGROUND AND AIM: Budesonide (BUD) is being used in pediatric Crohn disease (CD) because it is believed to have the potential to reduce corticosteroid related toxicity; however, few data are available describing its use. The aim of the present study was to describe BUD use in an inception cohort of pediatric patients with CD. METHODS: Data were derived from the prospective Pediatric IBD Collaborative Research Group Registry established in 2002 in North America. Use of BUD in children with CD was examined. RESULTS: BUD was used in 119 of 932 (13%) of children with newly diagnosed CD, with 56 of 119 (47%) starting BUD <= 30 days of diagnosis (26/56 with ileum and/or ascending colon [IAC] disease). BUD was used as monotherapy (9%), in combination with 5-aminosalicylates (77%), or in combination with immunomodulators (43%). Forty-three percent (24/56) went on to receive conventional corticosteroid at some point following their first BUD course. For the 63 of 119 (53%) who started BUD beyond the diagnosis period, 51 of 63 (81%) also received prednisone, with BUD used as a means of weaning from prednisone in 17 of 63 (27%). Patients with IAC disease who received BUD <= 30 days of diagnosis were just as likely to have received conventional corticosteroids by 1 year as were those who did not receive BUD <= 30 days of diagnosis. Two-thirds (77/119) of patients received BUD for <= 6 months. CONCLUSIONS: BUD is being used among pediatric patients newly diagnosed as having CD, although the majority does not have disease limited to the IAC. BUD monotherapy was rare, and further data are required to better define the role of BUD in the treatment of pediatric CD. PMID- 22258290 TI - An unusual cause of abdominal pain. PMID- 22258291 TI - Can colonic manometry studies be done on the day of colonic motility catheter placement? AB - BACKGROUND AND AIMS: Colonic manometry has been used to assess colonic neuromuscular integrity in pediatric patients with severe constipation unresponsive to standard medical therapy and to tailor their treatment plans. There are presently no available standard protocols for conducting colonic manometry studies. The aim of the present study was to determine whether colonic manometry studies can be conducted on the same day the colonic motility catheters are placed and to compare the effects of inhaled sevoflurane versus intravenous propofol, used during catheter placement, on colonic motility. METHODS: Twenty patients, randomized to receive sevoflurane or propofol during catheter placement, underwent colonic manometry on the day of catheter placement as well as the day after. The total motility index (MI), change in MI in response to a meal and bisacodyl, and presence of high-amplitude propagating contractions were compared between the 2 studies for each patient. RESULTS: Ten patients were allocated to sevoflurane and 10 patients to propofol. A total of 8 (80%) patients in the sevoflurane group and 9 (90%) patients in the propofol group had no differences in their studies between days 1 and 2 when the tracings were interpreted manually for gross evidence of high-amplitude propagating contractions and gastrocolonic reflex. Similarly, there was no change in the total MI between studies done on days 1 and 2 in either sevoflurane (978 +/- 232 vs 978 +/- 184; P = 0.99) or propofol (968 +/- 200 vs 1078 +/- 227; P = 0.29) group. When comparing change in MI in response to a meal or bisacodyl between the 2 days, there was no statistical difference noted in either group. CONCLUSIONS: Colonic manometry studies can be conducted as early as 4 hours following catheter placement with either propofol or sevoflurane used for anesthesia. PMID- 22258292 TI - National Centers for Biomedical Computing: from the BISTI report to the future. PMID- 22258293 TI - Dual facet of gold(III) in the reactions of gold(III) and porphyrins. AB - We have firstly demonstrated the dual facet of gold(III) in the reaction between gold(III) and porphyrins, which could be tuned through changing the counter ions, ligands and the electronic effect of the substituents of the porphyrins. PMID- 22258294 TI - The effect of perioperative psychological intervention on fatigue after laparoscopic cholecystectomy: a randomized controlled trial. AB - BACKGROUND: Fatigue is one of the main complaints after surgery and may last longer than physical symptoms. It prevents return to normal function and activity. Relaxation interventions, performed prior to abdominal surgery, have been shown to reduce pain, wound erythema, and systemic cortisol levels. However, there is a lack of data on the impact of this intervention on patient well-being, functional recovery, activities of daily living, and fatigue after discharge from hospital. METHODS: The study was a randomised single-blinded trial. Patients who were to undergo elective laparoscopic cholecystectomy for any indication between April 2008 and May 2010 were screened for inclusion. Those in the intervention group attended a standardised 45 min relaxation session with a health psychologist and were given relaxation exercise CDs to take home. The control group did not have the intervention. Patients were followed for 30 days. Fatigue was measured using the identity-consequence fatigue scale. RESULTS: Seventy-five patients were randomised. Fifteen patients were excluded after randomization for various reasons; hence, 60 patients were followed up and analysed. Both groups had similar fatigue at baseline. There was improved fatigue and consequence of fatigue on postoperative day 30 in the intervention group. There was no difference in fatigue at any other time point postoperatively. CONCLUSION: This was the first interventional study targeting fatigue after laparoscopic cholecystectomy by using a brief psychological relaxation intervention. It has shown a reduction of fatigue and impact of fatigue at 30 days postoperatively in the intervention group. PMID- 22258295 TI - A comparative study of endoscopic full-thickness and partial-thickness myotomy using submucosal endoscopy with mucosal safety flap (SEMF) technique. AB - BACKGROUND: Esophageal myotomy using submucosal endoscopy with mucosal safety flap (SEMF) has been proposed as a new treatment of achalasia. In this technique, a partial-thickness myotomy (PTM) preserving the longitudinal outer esophageal muscular layer is advocated, which is different from the usual full-thickness myotomy (FTM) performed surgically. The aim of this study was to compare endoscopic FTM and PTM and analyze the outcomes of each method after a 4 week survival period. METHODS: Twenty-four pigs were randomly assigned into group A (FTM, 12 animals) and group B (PTM) to undergo endoscopic myotomy. Lower esophageal sphincter (LES) pressure was assessed using pull-through manometry. For statistical analysis we compared the average esophageal sphincter pressure values at baseline, after 2 weeks, and after 4 weeks between groups A and B. The P value was set as <0.05 for significance. RESULTS: Eighteen animals were included for statistical analysis. Mean (SD) LES pressures were similar between groups A and B (nine animals each) at baseline [group A = 23 (10.4) mmHg; group B = 20.7 (8.7) mmHg; P = 0.79], after 2 weeks [group A = 19 (7.7) mmHg; group B = 21.8 (8.4) mmHg; P = 0.79], and after 4 weeks [group A = 22.6 (10.2) mmHg; group B = 20.7 (9) mmHg; P = 0.82]. LES pressures were significantly reduced in three animals after 4 weeks: one animal (1%) in group A and two animals (2.5%) in group B. An extended myotomy (3 cm below the cardia) was achieved in three animals and was responsible for the significant drop in LES pressure seen in the two animals from group B. CONCLUSION: Esophageal myotomy using SEMF is a feasible yet challenging procedure in pigs. Full-thickness myotomy does not seem to be superior to partial-thickness myotomy as demonstrated by pull-through manometry. Endoscopic esophageal myotomy results are greatly influenced by obtaining adequate myotomy extension into the gastric cardia. PMID- 22258296 TI - Perioperative polyphenon E- and siliphos-inhibited colorectal tumor growth and metastases without impairment of gastric or abdominal wound healing in mouse models. AB - INTRODUCTION: Perioperative anticancer therapy that does not impair wound healing is needed to counter the persistent proangiogenic plasma compositional changes that occur after colorectal resection. Polyphenon E (PolyE), a green tea derivative (main component EGCG), and Siliphos (main component silibinin), from the milk thistle plant, both have antitumor effects. This study assessed the impact of PolyE/Siliphos (PES) on wound healing and the growth of CT-26 colon cancer in several murine models. METHODS: One wound healing and three tumor studies were performed. Tumor Study (TS)1 assessed the impact of PES on subcutaneous tumor growth, whereas TS2 assessed PES's impact on subcutaneous growth when given pre- and post-CO(2) pneumoperitoneum (pneumo), sham laparotomy, or anesthesia alone. TS3 determined the ability of PES to limit hepatic metastases (mets) after portal venous injection of tumor cells. In the final study, laparotomy and gastrotomy wound healing were assessed several ways. BALB/c mice were used for all studies. The drugs were given via drinking water (PolyE) and gavage (Siliphos), daily, for 7-9 days preprocedure and for 7-21 days postoperatively. Tumor mass, number/size of hepatic mets, and proliferation and apoptosis rates were assessed. The abdominal breaking strength and energy to failure were measured postmortem as was gastric bursting pressures. RESULTS: PES significantly inhibited subcutaneous growth in the nonoperative setting. PES also significantly decreased the number/size of liver mets when given perioperatively. Abdominal wound breaking strength, energy to wound failure, and collagen content were not altered by PES; gastrotomy bursting strength also was not affected by PES. Neither drug alone had a significant impact on tumor growth. CONCLUSIONS: The PES combination inhibited subcutaneous and hepatic tumor growth yet did not impair wound healing. PES holds promise as a perioperative anticancer therapy. PMID- 22258297 TI - Minilaparoscopy-assisted natural orifice total colectomy: technical report of a minilaparoscopy-assisted transrectal resection. AB - BACKGROUND: Experimental experience and the technological evolution of minimally invasive surgical devices have allowed initial reports describing the clinical applicability of natural orifice translumenal endoscopic surgery (NOTES). Colorectal resections are an interesting target for the NOTES platform. Theoretically, the transrectal approach could overcome the proposed limitations of transvaginal access, increasing NOTES clinical applicability. Hybrid procedures such as minilaparoscopy-assisted natural orifice surgery (MA-NOS) are the safe progression to pure NOTES. This report describes the first clinical case of a transrectal MA-NOS total colectomy. METHODS: The patient was a 36-year-old man with severe ulcerative colitis (UC) who experienced failure of immunosuppressive therapy. The standard steps of laparoscopic total colectomy were respected, with basic triangulation maintained throughout the case. A transrectal endoscopic device was used for optic assistance, colon dissection, ileum section, and specimen retrieval. Transrectal MA-NOS total colectomy was assisted by three laparoscopic ports: a 12-mm port used as the terminal ileostomy site, a 2-mm needle epigastric port, and a 5-mm umbilical port used as a drain site at the final intervention. No intraoperative complications occurred. RESULTS: The total operative time was 240 min. Oral intake was initiated on postoperative day 2. Because of UC rectal activity, a course with azathioprine was completed, and the patient was discharged receiving 1 g of rectal mesalazine for maintenance. The final pathology demonstrated pancolonic inflammatory bowel disease in the form of UC with severe activity. CONCLUSIONS: Transrectal MA-NOS total colectomy was feasible and safe in the reported case. Improvement in NOTES instrumentation and selective clinical applications are mandatory before clinical trials. PMID- 22258298 TI - Laparoscopic ultrasound-assisted liposuction for lymph node dissection: a pilot study. AB - BACKGROUND: Lymphadenectomy is a surgical technique for staging and treating cancer. Laparoscopic lymphadenectomy for obese patients is challenging. Laparoscopic ultrasound-assisted liposuction (UAL) has been successful in porcine models. The current study aimed to evaluate whether UAL facilitates pelvic laparoscopic lymphadenectomy in obese subjects. METHODS: The UAL technique was evaluated in two human cadavers and in six obese Ossabaw pigs. Both a standard and a prototype ultrasonic probe with a wider contact surface were tested. Pelvic lymphadenectomy comparing UAL with standard monopolar cautery was performed using obese Ossabaw pigs. The animals were survived for 2 weeks. Descriptive data regarding intra- and postoperative outcomes were recorded, including histologic analysis of dissected tissue after 2 weeks. Cytologic analysis of aspirated fluid coming from UAL also was recorded. RESULTS: The UAL procedure was safely performed for all the cadavers and animals. Lymph node exposure and clean exposure of surrounding structures were dramatic compared with monopolar assisted dissection. One animal was excluded from further analysis due to ultrasonic device malfunction (a broken footswitch cord). In general, UAL notably debulks adipose tissue with dramatic field exposure. Postoperative adhesions were present in all animals undergoing either monopolar or UAL dissection. Histology showed areas of foreign body reaction from mild to severe, with no predominance of either extreme seen with monopolar or UAL dissection. Cytologic analysis of collected pooled oil emulsion did not contain lymph node tissue. CONCLUSION: The UAL approach permits pelvic lymphadenectomy in the obese animal and cadaver model, with excellent exposure of lymph nodes and surrounding pelvic anatomy. The use of a new ultrasonic prototype probe with a wider contact surface allowed dissection with less mechanical and thermal penetration of tissue. Further studies are needed to assess oncologic safety (cancer cell dissemination), postoperative healing, and adhesion formation. PMID- 22258299 TI - Indications, safety, and feasibility of conversion of failed bariatric surgery to Roux-en-Y gastric bypass: a retrospective comparative study with primary laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is considered the "gold standard" revision procedure. The purpose of this study was to compare the surgical outcome of primary laparoscopic RYGB (pLRYGB) to revisional open or laparoscopic Roux-en Y gastric bypass surgery (rRYGB). METHODS: A retrospective analysis of all patients who underwent pLRYGB or rRYGB from January 2003 to December 2009 has been performed. Demographics, indications for revision, and complications have been reviewed. The rRYGB and pLRYGB patients have been compared. RESULTS: Seventy two patients underwent rRYGB, and 652 patients underwent pLRYGB. Mean follow-up was 35 and 45 months, respectively. Fifty-six rRYGB procedures were performed laparoscopically. The primary operations had consisted of laparoscopic gastric banding (n = 28), laparoscopic vertical banded gastroplasty (n = 19), laparoscopic sleeve gastrectomy (n = 6), laparoscopic RYGB (n = 3), and biliopancreatic diversion with duodenal switch (n = 16). Indications included weight regain (n = 29), malabsorption (n = 16), gastrogastric fistula (n = 5), band-associated problems (n = 3), and refractory stomal ulceration (n = 1). There was no significant difference in early or late postoperative complications when comparing rRYGB to pLRYGBP patients (11.1% vs. 5.52%, P = 0.069 and 19.4% vs. 24.2%, P = 0.465 respectively). Five rRYGB patients (7.04%) required reintervention (3 internal hernias, 1 ventral hernia, 1 laparoscopic exploration) compared with 101 pLRYGB patients (15.71%; P = 0.051). None of the patients died. Mean hospital stay was not significantly longer in the rRYGB group (5.38 vs. 4.95 days, P = 0.058). CONCLUSIONS: In our series, hospital stay, morbidity, and mortality of rRYGB were not significantly higher compared with pLRYGB. Furthermore, we believe that this type of revisional bariatric surgery should be performed in high-volume bariatric centers. PMID- 22258300 TI - Laparoscopic and open surgical treatment of left-sided pancreatic lesions: clinical outcomes and cost-effectiveness analysis. AB - BACKGROUND: Previous studies comparing open distal pancreatectomy (ODP) and laparoscopic distal pancreatectomy (LDP) have found advantages related to minimal access surgery. Few studies have compared direct and associated costs after LDP versus ODP. The purpose of the current study was to compare perioperative outcomes of patients undergoing LDP and ODP and to assess whether LDP was a cost effective procedure compared with the traditional ODP. METHODS: A retrospective analysis of a prospectively maintained database of 52 distal pancreatic resections that were performed during a 10-year period was performed. RESULTS: Patients included in the analysis were 16 in the LDP group and 29 in the ODP. Tumors operated laparoscopically were smaller than those removed at open operation, but the length of pancreatic resection was similar. The mean operating time for LDP was longer than ODP (204 +/- 31 vs. 160 +/- 35; P < 0.0001), whereas blood loss was higher in the open group (365 +/- 215 vs. 160 +/- 185, P < 0.0001). Morbidity (25 vs. 41; P = 0.373) and pancreatic fistula (18 vs. 20%; P = 0.6) rates were similar after LDP and ODP, as was 30-day mortality (0 vs. 2%; P = 0.565). LDP had a shorter mean length of hospital stay than ODP (6.4 (2.3) vs. 8.8 (1.7) days; P < 0.0001). Operative cost for LDP was higher than ODP (2889 vs. 1989; P < 0.0001). The entire cost of the associated hospital stay was higher in the ODP group (8955 vs. 6714; P < 0.043). The total cost was comparable in LDP and ODP groups (9603 vs. 10944; P = 0.204). CONCLUSIONS: Laparoscopic distal pancreatectomy for left-sided lesions can be performed safely and effectively in selected patients, with reduced hospital stay and operative blood loss. Major complications, including pancreatic leak, were not reduced, whereas total cost was comparable between LDP and ODP. A selective use of LDP seems to be an effective and cost-efficient alternative to ODP. PMID- 22258301 TI - Elective laparoscopic versus open colectomy for diverticulosis: an analysis of ACS-NSQIP database. AB - BACKGROUND: The benefits of laparoscopic (LC) versus open (OC) colectomy for symptomatic colonic diverticulosis as an elective operation remain unclear. METHODS: Using the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) participant-user file, patients were identified who underwent elective colon resection for symptomatic colonic diverticulosis, between 2005 and 2008. Demographic, clinical, intraoperative variables, and 30 day morbidity and mortality were collected. Logistic regression analysis was performed to determine the association between the surgical approach (LC vs. OC) and risk-adjusted overall mortality, overall morbidity, serious morbidity, and wound complications. RESULTS: A total of 7,629 patients were identified who underwent colon resection for symptomatic diverticulosis. They were subdivided into two groups: OC (3,870 (50.7%)) and LC (3,759 (49.3%)). Patients who underwent OC were significantly older (59.0 vs. 55.7 years, P < 0.0001) with more comorbidities compared with those who underwent LC. After risk-adjusted analysis, it was noted that the patients treated with LC were significantly less likely to experience overall morbidity (11.9% vs. 23.2%), serious morbidity (4.6% vs. 10.9%), and wound complications (9.1% vs. 17.5%), but not mortality (0.3% vs. 0.8%). Operative duration was significantly longer with LC (176.64 vs. 166.70 min, P < 0.0001), but the length of stay was significantly shorter (4.77 vs. 7.68 days, P < 0.0001). Using logistic regression analysis, patients with history of peripheral vascular disease, percutaneous coronary interventions, current steroid use, and hypertension requiring medication were at an increased risk of morbidity and mortality at 30 days. Patients with history of chronic obstructive pulmonary disease and smoking experienced more wound complications at 30 days. CONCLUSIONS: In the elective setting for symptomatic diverticulosis, LC seems to be associated with lower 30-day morbidity and complication rates compared with OC. PMID- 22258302 TI - Collaborative eye tracking: a potential training tool in laparoscopic surgery. AB - BACKGROUND: Eye-tracking technology has been shown to improve trainee performance in the aircraft industry, radiology, and surgery. The ability to track the point of-regard of a supervisor and reflect this onto a subjects' laparoscopic screen to aid instruction of a simulated task is attractive, in particular when considering the multilingual make up of modern surgical teams and the development of collaborative surgical techniques. We tried to develop a bespoke interface to project a supervisors' point-of-regard onto a subjects' laparoscopic screen and to investigate whether using the supervisor's eye-gaze could be used as a tool to aid the identification of a target during a surgical-simulated task. METHODS: We developed software to project a supervisors' point-of-regard onto a subjects' screen whilst undertaking surgically related laparoscopic tasks. Twenty-eight subjects with varying levels of operative experience and proficiency in English undertook a series of surgically minded laparoscopic tasks. Subjects were instructed with verbal queues (V), a cursor reflecting supervisor's eye-gaze (E), or both (VE). Performance metrics included time to complete tasks, eye-gaze latency, and number of errors. RESULTS: Completion times and number of errors were significantly reduced when eye-gaze instruction was employed (VE, E). In addition, the time taken for the subject to correctly focus on the target (latency) was significantly reduced. CONCLUSIONS: We have successfully demonstrated the effectiveness of a novel framework to enable a supervisor eye gaze to be projected onto a trainee's laparoscopic screen. Furthermore, we have shown that utilizing eye-tracking technology to provide visual instruction improves completion times and reduces errors in a simulated environment. Although this technology requires significant development, the potential applications are wide-ranging. PMID- 22258303 TI - Noninvasive continuous beat-to-beat radial artery pressure via TL-200 applanation tonometry. AB - The Tensys TL-200((r)) noninvasive beat-to-beat blood pressure (BP) monitor displays continuous radial artery waveform as well as systolic, mean and diastolic BP from a pressure sensor directly over the radial artery at the wrist. It locates the site of maximal radial pulse signal, determines mean BP from maximal pulse waveform amplitude at optimal artery compression and then derives systolic and diastolic BP. We performed a cross-sectional study of TL-200 BP comparisons with contralateral invasive radial artery (A-Line) BP values in 19 subjects during an average 2.5 h of general anesthesia for a wide range of surgical procedures. Two hundred and fifty random sample pairs/patient resulted in 4,747 systolic, mean and diastolic BP pairs for analysis. A-Line BP ranged from 29 mm Hg diastolic to 211 mm Hg systolic, and heart rate varied between 38 and 210 beats/min. Bland-Altman analysis showed an average 2.3 mm Hg TL-200 versus A-Line systolic BP bias and limits of agreement (1.96 SD) were +/- 15.3 mm Hg. Mean BP showed a 2.3 mm Hg TL-200 bias and +/- 11.7 mm Hg limits of agreement, while diastolic BP showed a 1.7 mm Hg bias and +/- 12.3 mm Hg limits of agreement. Coefficients of determination for TL-200 and A-Line BP regression were r2 = 0.86 for systolic, r2 = 0.86 for mean, and r2 = 80 for diastolic BP, respectively, with no apparent change in correlation at low or high BP. Bland Altman analysis suggested satisfactory agreement between TL-200 noninvasive beat to-beat BP and invasive A-Line BP. Paired TL-200/A-Line BP comparisons showed a high coefficient of determination. PMID- 22258304 TI - Effect of intravenous hydralazine infusion on maternal plasma nitric oxide levels in gestations complicated with severe preeclampsia: a pilot study. AB - AIM: To investigate the effect of intravenous hydralazine infusion on maternal nitric oxide (NO) levels. METHODS: This pilot study comprised 40 (n = 40) gestations complicated with severe preeclampsia to whom maternal plasma NO levels were determined by chemiluminescence before and after hydralazine administration. Blood pressure values were concomitantly assessed. RESULTS: After 20 min of intravenous hydralazine infusion blood pressure values decrease significantly in term and preterm gestations. This was accompanied by an overall significant decrease in mean plasma NO values (38.7 +/- 12.9 to 35.4 +/- 13.9 MUmol/L, p < 0.05). Despite this, NO values decreased in 67.5% of cases (a 17.6% from baseline) and increased in 32.5% (a 14.8% from baseline) (p < 0.05 for both). Blood pressure decrease (%) was lower (systolic and diastolic) among those displaying a NO decrement than in the increment group. Interestingly, gestational age was higher in the group displaying decreased NO; however, this did not reach statistical significance (37.5 +/- 2.7 vs. 35.9 +/- 2.8 weeks, p = 0.08). CONCLUSION: The results of this study fail to demonstrate a similar NO secretion after hydralazine infusion in women with severe preeclampsia. PMID- 22258305 TI - Effects of oral estradiol and levonorgestrel on cardiovascular risk markers in postmenopausal women. AB - PURPOSE: This study aimed at investigating changes in postmenopausal women's cardiovascular risk markers induced by hormone therapy regimens of low (1.0 mg) or ultra-low (0.5 mg) doses of micronized estradiol (mE(2)) and levonorgestrel (LNG). METHODS: Three randomized placebo-controlled trials were reanalyzed with regard to changes in cardiovascular risk markers, such as serum lipids, lipoproteins, and coagulation parameters. Trial 1 (n = 210) was an 8-week study comparing the effects of 1.0 or 0.5 mg of unopposed mE(2) on menopausal symptoms. Trial 2 (n = 194) was a 24-week study comparing the effects of 1.0 mg of mE(2) combined with 10, 20, or 40 MUg of LNG on endometrial safety. Trial 3 (n = 195) was a 52-week study comparing the effects of 1.0 or 0.5 mg mE(2) + 40 MUg LNG on bone metabolism. RESULTS: 1.0 mg of unopposed mE(2) reduced low-density lipoprotein cholesterol (LDL-C) after as little as 8 weeks. 1.0 mg mE(2) for 24 weeks lowered the serum levels of total cholesterol (TC) and LDL-C, whereas the addition of LNG caused decreases in the levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in a dose-dependent fashion. 1.0 or 0.5 mg mE(2) + 40 MUg LNG for 52 weeks also lowered the levels of TC, HDL-C, LDL C, and TG. Both regimens slightly lowered antithrombin and Protein C activities within normal limits. CONCLUSIONS: Hormone therapy using 1.0 or 0.5 mg of mE(2) and LNG lowers the serum levels of TC, HDL-C, LDL-C, and TG without significantly affecting coagulation/fibrinolysis parameters. PMID- 22258306 TI - Body weight changes after the diagnosis of endometrial cancer and their influences on disease-related prognosis. AB - OBJECTIVES: Obesity is associated with the incidence of endometrial cancer. At present it is unclear whether it is also associated with cancer recurrence. This analysis evaluated the consequences of weight changes after diagnosis of endometrial cancer during the follow-up. METHODS: Records of patients with endometrial cancer (n = 705) were reviewed for body weight after the diagnosis of cancer during the follow-up and related to recurrence-free survival. RESULTS: About two-thirds of all endometrial patients gained more or less weight after the diagnosis of endometrial cancer. Patients with moderate weight gain (<= 1 kg/m(2)) 6 months after the diagnosis had the best prognosis, followed by patients with greater weight gain (>1 kg/m(2)) and those with moderate weight loss (<= 1 kg/m(2)). The fact that weight loss was associated with poor prognosis also persisted when the analysis was restricted to recurrences which occurred more than 18 months later. CONCLUSIONS: Weight loss after the diagnosis and treatment of cancer may be an adverse prognostic factor. Although it was impossible to distinguish between intentional and non-intentional weight loss, these results argue against weight loss for risk reduction in patients with confirmed endometrial cancer. However, it may be reasonable regarding the risk reduction of non-cancer related morbidity and mortality. Detailed, prospective randomised trials are warranted. PMID- 22258307 TI - p53 codon 72 polymorphism and endometriosis: a meta-analysis. AB - BACKGROUND: p53 tumour suppressor gene Arg72Pro polymorphism has been associated with endometriosis. However, the current available data were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and endometriosis. METHODS: Electronic screening of PubMed library was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. RESULTS: Six published studies, including 749 endometriosis and 857 controls were identified. The overall results suggested that the variant genotypes were not associated with the endometriosis risk (Pro/Pro + Arg/Pro vs. Arg/Arg: OR = 1.552, 95% CI 0.916 2.632, p = 0.103). In the stratified analysis, individuals carried the Pro allele in a dominant model had increased risk of endometriosis (OR = 2.595, 95% CI 1.005 6.702, p = 0.049) in Asian subjects. The symmetric funnel plot, the Egger's test (p = 0.602), and the Begg's test (p = 0.167) were all suggestive of the lack of publication bias. However, the association was not significant between this polymorphism and endometriosis in Caucasian (OR = 1.005, 95% CI 0.755-1.337, p = 0.972). CONCLUSION: This meta-analysis suggests that p53 codon 72 Pro/Pro + Arg/Pro genotypes are associated with increased risk of endometriosis in Asian. To validate the association between p53 codon 72 polymorphism and endometriosis, further studies with larger participants worldwide are needed. PMID- 22258308 TI - Large gallanes and the PSEPT theory: a theoretical study of Ga(n)H(n+2) clusters (n = 7-9). AB - Do alanes Al(n)H(n+2) and gallanes Ga(n)H(n+2) satisfy the polyhedral skeletal electron pair theory (PSEPT)? Taking into account previous work on this question, this paper provides a convincing answer and proposes the reformulation of the (n + 1) electron pairs rule of Wade and Mingos (W-M) for such systems. Following recent studies of tetra-, penta-, hexa-, hepta-, octa-, and nonaalanes as well as valence-isoelectronic/related gallanes, in this paper we present an analysis of the hydrides of aluminum and gallium A(n)H(n+2) (A = Al, Ga and n = 7-9). The aim is still to examine the applicability of PSEPT, especially the W-M rule, to these clusters. Exploration of the total potential energy surfaces (PESs) of hepta-, octa-, and nonagallanes shows that the absolute minima have a nido-like polyhedron arrangement. Unlike the smaller Ga(n)H(n+2) (n = 4, 5, 6), it seems that the size of the cluster largely dictates its preferred geometry. Although none of them have closed (totally triangular) cages, these clusters exhibit significant compactness, comparable to borane double anions, B(n)H(n) (2-), which are the archetypes for the PSEPT theory. PMID- 22258310 TI - Integrating banana and ruminant production in the French West Indies. AB - Using a mechanistic model, we compared five alternative farming systems with the purpose of transforming monoculture (MON) banana farms into mixed farming systems (MFS) with ruminants feeding banana by-products (leaves, pseudostems and nonmarketable fruits) and forage from the fallow land. The paper presents the main structure of the model (land surface changes, available biomass for animals, stocking rates, productive or reproductive indicators), and impact assessment (change in farm productivity) is discussed. Five MFS with typical local ruminant production systems were used to compare MON to the strategies using forage from fallow and/or integrating Creole cattle (CC), Creole goats (CG) or Martinik sheep (MS) into banana farming. One hectare MON shifted into an MFS allows a stocking rate of 1,184, 285, and 418 kg of live weight per hectare for CC, CG and MS, respectively. Banana by-products seem to be better valorized by the CC scenario. However, parameters such as length of the cycle, local prices for cattle, goat and sheep meat, work time and farmer's skills in ruminant management may have been taken into account by the farmer when choosing the ruminant species to rear. PMID- 22258311 TI - [Arthroscopically assisted reduction of acute acromioclavicular joint separations: comparison of clinical and radiological results of single versus double TightRopeTM technique]. AB - BACKGROUND: The aim of this study was to compare the results of the single (STR) versus double TightRopeTM (DTR) technique for stabilisation of acute separations of the AC joint with the hypothesis that DTR achieves lower CC distance. PATIENTS AND METHODS: A total of 29 consecutive patients treated operatively with the TR technique (mean age 38.1 years, n=26 male) were analysed in a cohort study with a mean follow-up of 13.3 months (12.0-21.7). Acute AC joint separations types III and V according to Rockwood (R) were included; R types I, II, IV and VI were excluded. The prospective scores determined pre-op and 3, 6 and 12 months post-op and X-rays were evaluated. RESULTS: Of the patients 12 suffered an R type III and 17 an R V separation; 14 were treated with STR and 15 with DTR. With STR, 8 R III and 6 R V injuries and with DTR 4 R III and 11 R V injuries were treated arthroscopically. STR achieved an increased CC distance >125% compared to the contralateral AC joint in five cases (36%). Two of them occurred as R V and three as R III injury. DTR achieved a CC distance >125% in two cases of an R V injury (13%). CONCLUSION: The DTR technique provides lower CC distance compared to the STR technique, without a significant difference of CC distance and scores. PMID- 22258312 TI - Abnormal segregation of alleles and haplotypes at the polymorphic site of the PRNP gene within promoter and intron 1 regions in Polish Holstein-Friesian cattle. AB - Allele and haplotype segregation at the polymorphic sites within the promoter (23indel) and intron 1 (12indel) regions of the PRNP gene was analyzed in Polish Holstein-Friesian cattle. More 23del/del homozygotes and fewer 23ins/ins homozygotes than expected were observed in the offspring of ? 23ins/del * ? 23ins/del parents. In the offspring of ? 23ins/del * ? 23del/del parents and ? 23del/del * ? 23ins/del parents, a trend toward more 23del/del animals and fewer 23ins/del animals than expected was noted. At the 12indel polymorphic site, the only trend found was one toward fewer 12ins/ins genotypes and more 12ins/del and 12del/del genotypes than expected in the offspring of ? 12ins/del * ? 12ins/del parents. An analysis of haplotype segregation revealed more 23del-12del/23del 12del diplotypes and fewer 23ins-12ins/23ins-12ins diplotypes at the significance threshold than expected in the offspring of ? 23ins-12ins/23del-12del * ? 23ins 12ins/23del-12del parents. PMID- 22258313 TI - Screening for pheochromocytomas and paragangliomas. AB - Pheochromocytomas and paragangliomas are highly heterogeneous neuroendocrine tumors that must be considered not only in patients with hypertension and other manifestations of catecholamine excess but also in patients with incidentalomas or mutations in one of the ten tumor susceptibility genes identified to date. To first think of the tumor remains the critical step for screening in patients with signs and symptoms. In these patients, biochemical testing is straightforward and should include measurements of plasma or urinary metanephrines, comprising separately measured normetanephrine and metanephrine. Tumors due to an underlying germline mutation are often found in the absence of hypertension or other signs or symptoms of the tumor. Screening for disease in these patients can benefit from an individualized approach according to the particular mutation. Additional measurements of methoxytyramine, the metabolite of dopamine, can be useful in patients with mutations of succinate dehydrogenase genes or patients who are at risk for malignancy. PMID- 22258314 TI - The effect of weight loss in obesity and chronic kidney disease. AB - Several epidemiologic investigations have confirmed that obesity is a significant risk factor for the appearance of proteinuria and end-stage kidney disease in a normal population. Weight loss induced by low-calorie diets, physical exercise, or bariatric surgery is accompanied by an important antiproteinuric effect. Reduction in proteinuria is already observed after a few weeks from the onset of weight loss and it is evident even in patients with modest weight losses. Reduction in proteinuria by weight loss has been described in chronic proteinuric nephropathies of different etiologies. The mechanisms through which weight loss may reverse proteinuria are likely to be plural: better control of blood pressure, improvement of serum lipid profile, improvement of insulin sensitivity, better glycemic control in diabetes patients, decrease of circulating leptin levels, reversal of glomerular hyperfiltration, and decreased activation of the renin-angiotensin-aldosterone system. PMID- 22258315 TI - Efficiency of primary saliva secretion: an analysis of parameter dependence in dynamic single-cell and acinus models, with application to aquaporin knockout studies. AB - Secretion from the salivary glands is driven by osmosis following the establishment of osmotic gradients between the lumen, the cell and the interstitium by active ion transport. We consider a dynamic model of osmotically driven primary saliva secretion and use singular perturbation approaches and scaling assumptions to reduce the model. Our analysis shows that isosmotic secretion is the most efficient secretion regime and that this holds for single isolated cells and for multiple cells assembled into an acinus. For typical parameter variations, we rule out any significant synergistic effect on total water secretion of an acinar arrangement of cells about a single shared lumen. Conditions for the attainment of isosmotic secretion are considered, and we derive an expression for how the concentration gradient between the interstitium and the lumen scales with water- and chloride-transport parameters. Aquaporin knockout studies are interpreted in the context of our analysis and further investigated using simulations of transport efficiency with different membrane water permeabilities. We conclude that recent claims that aquaporin knockout studies can be interpreted as evidence against a simple osmotic mechanism are not supported by our work. Many of the results that we obtain are independent of specific transporter details, and our analysis can be easily extended to apply to models that use other proposed ionic mechanisms of saliva secretion. PMID- 22258316 TI - Ancient origin of four-domain voltage-gated Na+ channels predates the divergence of animals and fungi. AB - The four-domain voltage-gated Na(+) channels are believed to have arisen in multicellular animals, possibly during the evolution of the nervous system. Recent genomic studies reveal that many ion channels, including Na(+) channels and Ca(2+) channels previously thought to be restricted to animals, can be traced back to one of the unicellular ancestors of animals, Monosiga brevicollis. The eukaryotic supergroup Opisthokonta contains animals, fungi, and a diverse group of their unicellular relatives including M. brevicollis. Here, we demonstrate the presence of a putative voltage-gated Na(+) channel homolog (TtrNa(V)) in the apusozoan protist Thecamonas trahens, which belongs to the unicellular sister group to Opisthokonta. TtrNa(V) displays a unique selectivity motif distinct from most animal voltage-gated Na(+) channels. The identification of TtrNa(V) suggests that voltage-gated Na(+) channels might have evolved before the divergence of animals and fungi. Furthermore, our analyses reveal that Na(V) channels have been lost independently in the amoeboid holozoan Capsaspora owczarzaki of the animal lineage and in several basal fungi. These findings provide novel insights into the evolution of four-domain voltage-gated ion channels, ion selectivity, and membrane excitability in the Opisthokonta lineage. PMID- 22258317 TI - Assessing cancer survivors' needs using web-based technology: a pilot study. AB - Development of cancer survivor resources has been hampered by lack of knowledge regarding survivors' needs. The main study aim was to pilot test a Web-based cancer survivor needs assessment survey. The second aim was to pilot three sampling approaches. This cross-sectional study was conducted at the Norris Cotton Cancer Center and nine community-based clinics serving urban and rural populations. Population-based and convenience sampling approaches were used to recruit 547 participants over 4 months. Participants completed a Web-based cancer survivor needs assessment survey. Respondents were mainly white (98%), married (71%) women (80%) with a college education (96%). Although most (66%) (n = 362) had been diagnosed with breast cancer, other cancer diagnoses were represented. Participants reported fatigue (47%), forgetfulness (39%), joint pain (34%), anxiety (31%), trouble sleeping (28%), peripheral neuropathy (27%), inflexibility (23%), and weight gain (23%). Survivors with nonbreast solid tumor malignancies reported more problems than those with breast or hematologic malignancies (P range = .037 to <.0001). Most survivors requested assistance for losing weight (74.2%), decreasing fatigue (50%), and improving flexibility (69.3%), sleep (68.5%), and memory (60.2%). Results supported that cancer survivors struggle with many enduring problems. Web-based technology will facilitate future exploration of unmet needs. PMID- 22258318 TI - Molecular insight into the high selectivity of double-walled carbon nanotubes. AB - Combining experimental knowledge with molecular simulations, we investigated the adsorption and separation properties of double-walled carbon nanotubes (DWNTs) against flue/synthetic gas mixture components (e.g. CO(2), CO, N(2), H(2), O(2), and CH(4)) at 300 K. Except molecular H(2), all studied nonpolar adsorbates assemble into single-file chain structures inside DWNTs at operating pressures below 1 MPa. Molecular wires of adsorbed molecules are stabilized by the strong solid-fluid potential generated from the cylindrical carbon walls. CO(2) assembly is formed at very low operating pressures in comparison to all other studied nonpolar adsorbates. The adsorption lock-and-key mechanism results from perfect fitting of rod-shaped CO(2) molecules into the cylindrical carbon pores. The enthalpy of CO(2) adsorption in DWNTs is very high and reaches 50 kJ mol(-1) at 300 K and low pore concentrations. In contrast, adsorption enthalpy at zero coverage is significantly lower for all other studied nonpolar adsorbates, for instance: 35 kJ mol(-1) for CH(4), and 14 kJ mol(-1) for H(2). Applying the ideal adsorption solution theory, we predicted that the internal pores of DWNTs have unusual ability to differentiate CO(2) molecules from other flue/synthetic gas mixture components (e.g. CO, N(2), H(2), O(2), and CH(4)) at ambient operating conditions. Computed equilibrium selectivity for equimolar CO(2)-X binary mixtures (where X: CO, N(2), H(2), O(2), and CH(4)) is very high at low mixture pressures. With an increase in binary mixture pressure, we predicted a decrease in equilibrium separation factor because of the competitive adsorption of the X binary mixture component. We showed that at 300 K and equimolar mixture pressures up to 1 MPa, the CO(2)-X equilibrium separation factor is higher than 10 for all studied binary mixtures, indicating strong preference for CO(2) adsorption. The overall selective properties of DWNTs seem to be superior, which may be beneficial for potential industrial applications of these novel carbon nanostructures. PMID- 22258319 TI - Inhibition of glycogen synthase kinase-3beta prevents NSAID-induced acute kidney injury. AB - Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3beta inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3beta targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3beta inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3beta, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3beta activity and prevented GSK3beta-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3beta abolished the effects of TDZD-8. Hence, inhibition of GSK3beta ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition. PMID- 22258320 TI - Comparative effectiveness of incident oral antidiabetic drugs on kidney function. AB - Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who filled an incident oral antidiabetic drug prescription for metformin, sulfonylurea, or rosiglitazone, and had an estimated glomerular filtration rate (eGFR) of 60 ml/min or better. The primary composite outcome was a persistent decline in eGFR from baseline of 25% or more (eGFR event) or a diagnosis of end-stage renal disease (ESRD). The secondary outcome was an eGFR event, ESRD, or death. Sensitivity analyses included using a more stringent definition of the eGFR event requiring an eGFR <60 ml/min per 1.73 m(2) in addition to the 25% or more decline; controlling for baseline proteinuria thereby restricting data to 15,065 patients; and not requiring persistent treatment with the initial oral antidiabetic drug. Compared to patients using metformin, sulfonylurea users had an increased risk for both the primary and the secondary outcome, each with an adjusted hazard ratio of 1.20. Results of sensitivity analyses were consistent with the main findings. The risk associated with rosiglitazone was similar to metformin for both outcomes. Thus, compared to metformin, oral antidiabetic drug treatment with sulfonylureas increased the risk of a decline in eGFR, ESRD, or death. PMID- 22258321 TI - Evaluation of urine biomarkers of kidney injury in polycystic kidney disease. AB - Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of autosomal dominant polycystic kidney disease (ADPKD). Here we evaluated the effect of these processes on the expression of Lcn2 (NGAL) and interleukin (IL)-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated, which resulted in early- or adult-onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples collected from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4/year and the mean decline in eGFR 2.4 ml/min/year. The trend of increased mean urine NGAL and IL-18 over 3 years was statistically significant; however, there was no association between tertiles of IL-18 or quartiles of NGAL and change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL 18 excretion is mildly and stably elevated in ADPKD, but does not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder. PMID- 22258322 TI - Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure. AB - Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-alpha (RARalpha)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARalpha agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARalpha agonists to provide additional renal protection. PMID- 22258324 TI - A systematic review of RIFLE criteria in children, and its application and association with measures of mortality and morbidity. AB - The RIFLE criteria were developed to improve consistency in the assessment of acute kidney injury. The high face validity, collaborative development method, and validation against mortality have supported the widespread adoption of the RIFLE to evaluate adult patients; however, its inconsistent application in adult studies is associated with significant effects on the estimated incidence of acute kidney injury. As the RIFLE criteria are now being used to determine acute kidney injury in children, we conducted a systematic review to describe its application and assess associations between the RIFLE and measures of mortality and morbidity in pediatric patients. In 12 studies we found wide variation in the application of the RIFLE, including the range of assessed RIFLE categories, omission of urine output criteria, varying definitions of baseline renal function, and methods for handling missing baseline measurements. Limited and conflicting associations between the RIFLE and mortality, length of stay, illness severity, and measures of kidney function were found. Thus, although the RIFLE was developed to improve the consistency of defining acute kidney injury, there are still major discrepancies in its use in pediatric patients that may undermine its potential utility as a standardized measure of acute kidney injury in children. PMID- 22258325 TI - Transforming growth factor-beta induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction. AB - Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-beta1 (TGF-beta1). The expression of both TGF-beta1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-beta1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-beta1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-beta type I receptor inhibitor LY364947. Thus, TGF-beta1 induces VEGF-C expression, which leads to lymphangiogenesis. PMID- 22258326 TI - Reflectance spectrometry of normal and bruised human skins: experiments and modeling. AB - A stochastic photon transport model in multilayer skin tissue combined with reflectance spectroscopy measurements is used to study normal and bruised skins. The model is shown to provide a very good approximation to both normal and bruised real skin tissues by comparing experimental and simulated reflectance spectra. The sensitivity analysis of the skin reflectance spectrum to variations of skin layer thicknesses, blood oxygenation parameter and concentrations of main chromophores is performed to optimize model parameters. The reflectance spectrum of a developed bruise in a healthy adult is simulated, and the concentrations of bilirubin, blood volume fraction and blood oxygenation parameter are determined for different times as the bruise progresses. It is shown that bilirubin and blood volume fraction reach their peak values at 80 and 55 h after contusion, respectively, and the oxygenation parameter is lower than its normal value during 80 h after contusion occurred. The obtained time correlations of chromophore concentrations in developing contusions are shown to be consistent with previous studies. The developed model uses a detailed seven-layer skin approximation for contusion and allows one to obtain more biologically relevant results than those obtained with previous models using one- to three-layer skin approximations. A combination of modeling with spectroscopy measurements provides a new tool for detailed biomedical studies of human skin tissue and for age determination of contusions. PMID- 22258323 TI - Synthesis and secretion of renin in mice with induced genetic mutations. AB - The juxtaglomerular (JG) cell product renin is rate limiting in the generation of the bioactive octapeptide angiotensin II. Rates of synthesis and secretion of the aspartyl protease renin by JG cells are controlled by multiple afferent and efferent pathways originating in the CNS, cardiovascular system, and kidneys, and making critical contributions to the maintenance of extracellular fluid volume and arterial blood pressure. Since both excesses and deficits of angiotensin II have deleterious effects, it is not surprising that control of renin is secured by a complex system of feedforward and feedback relationships. Mice with genetic alterations have contributed to a better understanding of the networks controlling renin synthesis and secretion. Essential input for the setting of basal renin generation rates is provided by beta-adrenergic receptors acting through cyclic adenosine monophosphate, the primary intracellular activation mechanism for renin mRNA generation. Other major control mechanisms include COX-2 and nNOS affecting renin through PGE2, PGI2, and nitric oxide. Angiotensin II provides strong negative feedback inhibition of renin synthesis, largely an indirect effect mediated by baroreceptor and macula densa inputs. Adenosine appears to be a dominant factor in the inhibitory arms of the baroreceptor and macula densa mechanisms. Targeted gene mutations have also shed light on a number of novel aspects related to renin processing and the regulation of renin synthesis and secretion. PMID- 22258327 TI - Prothrombin complex concentrate (Octaplex(r)) for postsurgical bleeding control in a Stauffer's syndrome. PMID- 22258328 TI - Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells. AB - Ex vivo expansion of hematopoietic stem cells (HSCs) depends on HSC self-renewing proliferation and functional maintenance, which can be negatively affected by HSC differentiation, apoptosis, and senescence. Therefore, inhibition of HSC senescence may promote HSC expansion. To test this hypothesis, we examined the effect of inhibition of p38 mitogen-activated protein kinase (p38) on the expansion of human umbilical cord blood (hUCB) CD133(+) cells because activation of p38 has been implicated in the induction of HSC senescence under various physiological and pathological conditions. Our results showed that ex vivo expansion of hUCB CD133(+) cells activated p38, which was abrogated by the p38 specific inhibitor SB203580 (SB). Inhibition of p38 activity with SB promoted the expansion of CD133(+) cells and CD133(+)CD38(-) cells. In addition, hUCB CD133(+) cells expanded in the presence of SB for 7 days showed about threefold increase in the clonogenic function of HSCs and engraftment in non-obese diabetic/severe combined immunodeficient mice after transplantation compared to the input cells. In contrast, the cells expanded without SB exhibited a significant reduction in these HSC functions. The enhancement of ex vivo expansion of hUCB HSCs is primarily attributable to SB-mediated inhibition of HSC senescence. In addition, inhibition of HSC apoptosis and upregulation of CXCR4 may also contribute to the enhancement. However, p38 inhibition had no significant effect on HSC differentiation and proliferation. These findings suggest that inhibition of p38 activation may represent a novel strategy to promote ex vivo expansion of hUCB HSCs. PMID- 22258330 TI - The C825T GNB3 polymorphism, independent of blood pressure, predicts cerebrovascular risk at a population level. AB - BACKGROUND: The role of C825T polymorphism of the candidate GNB3 gene in predicting cerebrovascular outcome has been poorly explored in longitudinal setting at a population level. METHODS: In an epidemiological setting, 1,678 men and women from general population were genotyped for C825T polymorphism of GNB3 gene and follow-up for 10 years to detect nonfatal and fatal cerebrovascular events (CE). Established cerebrovascular risk factors were used to adjust the multivariate Cox analysis for confounders. RESULTS: Seventy-three nonfatal and 30 fatal CE were recorded. Incidence of CE was higher in TT than in C-carriers (fatal: 2.6 vs. 1.7%, P < 0.03; nonfatal: 7.8 vs. 3.9%, P < 0.03; fatal recurrences: 1.6 vs. 0.6%, P < 0.03). In Cox analysis, the TT genotype predicted nonfatal (hazard ratio 1.99, 95% confidence interval 1.05-3.79, P = 0.03), fatal (2.91, 1.05-8.12, P = 0.04), and fatal recurrent CE (6.82, 1.50-31.1, P = 0.02) also after adjustment for age, gender, systolic and diastolic blood pressure, body adiposity, atherogenetic blood lipids, serum uric acid, diabetes, calories, caffeine and ethanol intake, and coronary events at baseline. Further adjustment for historical CE made the association between TT genotype and incident fatal CE nonsignificant (hazard ratio 2.72, 95% confidence interval 0.96-7.22, P = 0.06). CONCLUSIONS: The TT genotype of GNB3 gene predicts incident CE independent of blood pressure and other established risk factors at a population level. Further studies are needed to clarify the nature and pathways of this association. PMID- 22258329 TI - Spermine synthase overexpression in vivo does not increase susceptibility to DMBA/TPA skin carcinogenesis or Min-Apc intestinal tumorigenesis. AB - Numerous studies have demonstrated a link between elevated polyamine biosynthesis and neoplastic growth, but the specific contribution of spermine synthase to epithelial tumor development has never been explored in vivo. Mice with widespread overexpression of spermine synthase (CAG-SpmS) exhibit decreased spermidine levels, increased spermine and a significant rise in tissue spermine:spermidine ratio. We characterized the response of CAG-SpmS mice to two stage skin chemical carcinogenesis as well as spontaneous intestinal carcinogenesis induced by loss of the Apc tumor suppressor in Apc (Min) (/+) (Min) mice. CAG-SpmS mice maintained the canonical increases in ornithine decarboxylase (ODC) activity, polyamine content and epidermal thickness in response to tumor promoter treatment of the skin. The induction of S adenosylmethionine decarboxylase (AdoMetDC) activity and its product decarboxylated AdoMet were impaired in CAG-SpmS mice, and the spermine:spermidine ratio was increased 3-fold in both untreated and 12-O-tetradecanoylphorbol-13 acetate (TPA)-treated skin. The susceptibility to 7,12-dimethylbenz[a]anthracene (DMBA)/TPA skin carcinogenesis was not altered in CAG-SpmS mice, and SpmS overexpression did not modify the previously described tumor resistance of mice with targeted antizyme expression or the enhanced tumor response in mice with targeted spermidine/spermine-N ( 1) -acetyltransferase expression. CAG-SpmS/Min mice also exhibited elevated spermine:spermidine ratios in the small intestine and colon, yet their tumor multiplicity and size was similar to Min mice. Therefore, studies in two of the most widely used tumorigenesis models demonstrate that increased spermine synthase activity and the resulting elevation of the spermine:spermidine ratio does not alter susceptibility to tumor development initiated by c-Ha-Ras mutation or Apc loss. PMID- 22258331 TI - Role of renin-angiotensin system and oxidative status on the maternal cardiovascular regulation in spontaneously hypertensive rats. AB - BACKGROUND: The purpose of this study was to investigate the contribution of renin-angiotensin system (RAS) and oxidative status on the maternal cardiovascular regulation at the end of pregnancy in normotensive and spontaneously hypertensive rats (SHR). METHODS: Blood pressure (BP), mesenteric arterial bed (MAB) reactivity, mesenteric oxidative damage, protein expression, and antioxidant activities were compared between four groups: SHR (SHR-P) and normotensive Wistar controls (W-P) in the 20th day of pregnancy or age-matched nonpregnant rats (SHR-NP and W-NP). RESULTS: BP in W-P and SHR-P was reduced at the end of pregnancy. The vasodilator effects of angiotensin II (Ang II) and angiotensin 1-7 (Ang-(1-7)) were higher in SHR-P than in other groups. Endothelial nitric oxide synthase (eNOS) expression was increased in W-P and SHR P compared to nonpregnant groups. Angiotensin-converting enzyme (ACE) and AT(1) receptor expressions were increased in SHR-NP compared to normotensive groups and pregnancy reduced their expressions in SHR. No difference was observed in AT(2) receptor expression among the groups. ACE2 expression was higher in hypertensive than normotensive groups. The levels of thiobarbituric acid-reactive substances (TBARS) were reduced in pregnant compared to nonpregnant groups. Superoxide dismutase (SOD) activity was reduced in SHR-P compared to SHR-NP. However, pregnancy increased catalase (CAT) and glutathione peroxidase (GPx) activities in normotensive rats and SHR, respectively. CONCLUSIONS: The results suggest that the reduction of BP to normal values at the end of pregnancy in SHR may be related to an increased NO production and vasorelaxation to Ang II and Ang-(1-7) associated with decreased expression of vascular ACE and AT(1) receptors and oxidative status. PMID- 22258332 TI - Blunted blood pressure response and elevated plasma adiponectin levels in female Sprague Dawley rats. AB - BACKGROUND: Premenopausal women have lower blood pressure (BP) levels than men of similar age. Adiponectin has been shown to play a role in the pathogenesis of hypertension. The aim of the present study was to compare the effect of various stress stimuli on BP and plasma adiponectin levels in male and female Sprague Dawley (SD) rats. METHODS: In three experimental models of hypertension, fructose enriched diet, high salt diet, or L-NAME, were administered for up to 4 weeks. BP, metabolic parameters, and plasma adiponectin were measured at baseline and during the studies. The fructose diet protocol was repeated in female rats for 2 weeks with the addition of testosterone injections or vehicle. RESULTS: Females, in contrast to males, did not develop fructose-induced hypertension. Total plasma triglycerides (TGs) were half in females at baseline (P < 0.001) and a third at 4 weeks (P < 0.05). Plasma insulin levels were 23% lower in females than in males at baseline (P < 0.05) and 42% lower after 4 weeks of fructose-enriched diet (P = 0.001). Plasma adiponectin levels were 65% higher in females than in males at baseline (P = 0.001) and 45% higher after 4 weeks of fructose-enriched diet (P < 0.05). Furthermore, female rats showed blunted BP response and elevated plasma adiponectin in the salt-induced and L-NAME-induced hypertension models. Testosterone injection to female rats reduced plasma adiponectin and reversed the blunted BP response. CONCLUSIONS: Elevated plasma adiponectin levels, perhaps due to lack of suppression by testosterone, are associated with a blunting of BP response in female compared to male SD rats. PMID- 22258334 TI - Symptoms of depression and anxiety and adherence to antihypertensive medication. AB - BACKGROUND: Nonadherence to drug treatment is a major contributor to antihypertensive treatment failure. Mood disorders could impair the patient's desire and ability to follow physician's recommendations. We evaluated the role of symptoms of depression and anxiety on adherence to antihypertensive drug treatment. METHODS: We conducted a longitudinal cohort study in 20-70 years old patients starting antihypertensive drug treatment, without other chronic conditions, and not taking mood-modifying drugs. Severity of symptoms of depression and anxiety were evaluated at enrollment and 3, 6, 9, and 12 months of follow-up, using the Beck depression inventory-II (BDI-II) and the psychological general well-being index (PGWB), respectively. Treatment adherence was measured by pill count. Nonadherence was defined as taking <80% of the prescribed number of pills. Poisson regression was used to model the association of the exposures with adherence. RESULTS: We enrolled 178 patients (58% male; mean age: 50 years; 508 follow-up visits). The risk of nonadherence was 52.6% in 12 months (95% confidence interval (CI): 46.1, 59.1). After adjusting for other risk factors, individuals with at least mild depression (BDI-II >=14) and those with at least mild anxiety (PGWB anxiety score <22) were 2.48 (95% CI: 1.47, 4.18) and 1.59 (95% CI: 0.99, 2.56) times more likely to become nonadherent in the following 3 months, respectively. CONCLUSIONS: Patients with at least mild anxiety and depression symptoms are at increased risk of becoming nonadherent to antihypertensive medication. Screening for depression and anxiety symptoms could be used to identify high-risk patients. Further evidence is needed to elucidate whether interventions targeting these conditions improve adherence. PMID- 22258333 TI - DOCA-salt hypertension does not require the ouabain-sensitive binding site of the alpha2 Na,K-ATPase. AB - BACKGROUND: We have shown that the ouabain-sensitive alpha2 Na,K-ATPase is required for adrenocorticotropic hormone (ACTH)-induced hypertension and gestational blood pressure regulation. It is therefore of interest to explore whether this binding site participates in the development of other forms of hypertension, such as deoxycorticosterone acetate (DOCA)-salt using mutant mice with altered sensitivity to ouabain. METHODS: Wild-type (alpha1 ouabain resistant, alpha2 ouabain-sensitive: alpha(R/R)alpha2(S/S)), alpha1-resistant, alpha2-resistant (alpha1(R/R)alpha2(R/R)) and alpha1-sensitive, alpha2-resistant (alpha1(S/S)alpha2(R/R)) mice were uninephrectomized and implanted with DOCA pellets. The animals were given either tap water or 1% NaCl, and blood pressure was measured before and after DOCA. RESULTS: DOCA-salt-treated alpha1(R/R)alpha2(R/R) mice developed hypertension to the same extent as alpha1(R/R)alpha2(S/S) mice (wild type), and the alpha1(S/S)alpha2(R/R) mice given DOCA-salt also showed no difference from the other two genotypes. The expression of the alpha1 isoform was not changed by DOCA-salt treatment in either alpha1(R/R)alpha2(S/S) or alpha1(R/R)alpha2(R/R) mice. However, the alpha2 subunit was expressed at substantially higher levels in the hearts of alpha1(R/R)alpha2(R/R) than alpha1(R/R)alpha2(S/S) mice, regardless of treatment. Plasma levels of ouabain did not change consistently, but those of marinobufagenin were modestly higher in DOCA-salt treated mice relatively to those without salt. CONCLUSIONS: The ouabain-binding site of either the alpha1 or alpha2 Na,K-ATPase subunit does not play an essential role in the development of DOCA-salt hypertension in this mouse model. These findings indicate that the underlying mechanisms of hypertension induced by DOCA-salt treatment are different from those of ACTH-induced hypertension. PMID- 22258336 TI - Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension. AB - The role of aldosterone in the pathogenesis of hypertension and cardiovascular diseases has been clearly shown in congestive heart failure and endocrine hypertension due to primary aldosteronism. In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP), add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which we designate as "MR-associated hypertension". The MR-associated hypertension is classified into two subtypes, that with elevated plasma aldosterone levels and that with normal plasma aldosterone levels. The former subtype includes primary aldosteronism (PA), aldosterone-associated hypertension which exhibited elevated aldosterone-to-renin ratio and plasma aldosterone levels, but no PA, aldosterone breakthrough phenomenon elicited when angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) is continued to be given, and obstructive sleep apnea. In contrast, the latter subtype includes obesity, diabetes mellitus, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS). The pathogenesis of MR-associated hypertension with normal plasma aldosterone levels is considered to be mediated by MR activation by pathways other than high aldosterone levels, such as increased MR levels, increased MR sensitivity, and MR overstimulation by other factors such as Rac1. For resistant hypertension with high plasma aldosterone levels, MR antagonist should be given as a first-line therapy, whereas for resistant hypertension with normal aldosterone levels, ARB or ACE-I should be given as a first-line therapy and MR antagonist would be given as an add-on agent. PMID- 22258335 TI - Race differences in the physical and psychological impact of hypertension labeling. AB - BACKGROUND: Blood pressure screening is an important component of cardiovascular disease prevention, but a hypertension diagnosis (i.e., label) can have unintended negative effects on patients' well-being. Despite persistent disparities in hypertension prevalence and outcomes, whether the impact of labeling differs by race is unknown. The purpose of this study was to evaluate possible race differences in the relationship between hypertension labeling and health-related quality of life and depression. METHODS: The sample included 308 normotensive and unmedicated hypertensive subjects from the Neighborhood Study of Blood Pressure and Sleep, a cross-sectional study conducted between 1999 and 2003. Labeled hypertension was defined (by self-report) as having been diagnosed with high blood pressure or prescribed antihypertensive medications. Effects of labeling and race on self-reported physical and mental health and depressive symptoms were tested using multivariate analysis of covariance, controlling for age, sex, body mass index (BMI), previous medication use, and "true" hypertension status, defined by average daytime ambulatory blood pressure (ABP). RESULTS: Both black and white subjects who had been labeled as hypertensive reported similarly poorer physical health than unlabeled subjects (P = 0.001). However, labeling was associated with poorer mental health and greater depressive symptoms only among blacks (Ps < 0.05 for the interactions). These findings were not explained by differences in socioeconomic status. CONCLUSIONS: These results are consistent with previous studies showing negative effects of hypertension labeling, and demonstrate important race differences in these effects. Clinical approaches to communicating diagnostic information that avoid negative effects on well-being are needed, and may require tailoring to patient characteristics such as race. PMID- 22258337 TI - CCR5 deficiency does not reduce hypertensive end-organ damage in mice. AB - BACKGROUND: CCR5 is expressed on infiltrating T cells in hypertensive mice and CCR5 antagonists reduce hypertension making CCR5 an interesting target in treatment of hypertension. METHODS: To evaluate the role of CCR5 in hypertensive renal and cardiac end-organ damage, we induced hypertension with desoxycorticosterone acetate (DOCA) and angiotensin II (Ang II) in wild-type (WT) and CCR5-deficient mice. RESULTS: CCR5 expression was increased in renal cortex and cardiac tissue as measured by quantitative PCR. Systolic blood pressure and renal function did not differ between hypertensive CCR5(-/-) and WT mice. DOCA + Ang II induced massive albuminuria and glomerular injury but no difference was found between CCR5(-/-) and WT mice. In addition, no difference was found for renal inflammation as measured by infiltrating T cells, macrophages, and CCL2 expression. The renal expression of the CCR5 ligands, CCL3, and CCL5 was increased in the kidney of hypertensive mice. For CCL3 the increase was significantly higher in CCR5(-/-) than in WT mice. DOCA + Ang II induced cardiac damage as assessed by heart weight, cardiac fibrosis as well as expression of fetal and matrix components but no significant difference was found between CCR5( /-) and WT mice. CONCLUSIONS: CCR5 deficiency does not influence hypertensive renal and cardiac end-organ damage. Cells that infiltrate by expression of CCR5 are either not pathogenic or CCR5-positive leukocytes can migrate via alternative chemokine receptors. Beneficial effects of CCR5 antagonists in hypertension are most likely due to unspecific effects of the antagonists. Possibly, other chemokine receptors in concert with CCR5 are important for hypertensive injury. PMID- 22258338 TI - Studies on 3-oxoalkanenitriles: novel rearrangement reactions observed in studies of the chemistry of 3-heteroaroyl-3-oxoalkanenitriles as novel routes to 2 dialkylaminopyridines. AB - 3-Aroyl and 3-heteroaroyl substituted 3-oxoalkanenitriles were synthesized by the reactions of activated aromatic and hetero-aromatic substances with cyanoacetic acid in the presence of acetic anhydride. As part of studies focusing on the preparation of cyanoacetyl-1-N-methylbenzimidazole, we observed that reaction of N-methyl-benzimidazole with the cyanoanhydride formed by condensation of cyanoacetic acid with acetic anhydride, leads to the formation of 2-(1,3-diacetyl 2,3-dihydro-1H-benzo[d]-imidazol-2-yl)acetonitrile (5), whose structure was confirmed by X-ray crystallographic analysis. 3-Oxoalkanenitriles 3a,b were observed to undergo condensation reactions with dimethylformamide dimethyl acetal (DMFDMA) to afford the corresponding enamino-nitriles, which react with malononitrile to give 2-dialkylaminopyridines through a pathway involving a new, unexpected rearrangement process. Reactions of 3-oxoalkanenitriles with ethyl acetoacetate were found to afford 2-oxopyran-3-carbonitriles, also occurring via this unexpected rearrangement process. Mechanisms to account for both rearrangement reactions are suggested. In addition, reactions of 3 oxoalkanenitriles with acetylacetone in acetic acid in the presence of ammonium acetate result in the formation of pyridine-3-carbonitriles. Finally, upon heating in the presence of zeolite 3-oxoalkanenitriles 3b,c self-trimerized to produce the corresponding aniline derivatives 23b,c. PMID- 22258339 TI - Oligothiophenes as fluorescent markers for biological applications. AB - This paper summarizes some of our results on the application of oligothiophenes as fluorescent markers for biological studies. The oligomers of thiophene, widely known for their semiconductor properties in organic electronics, are also fluorescent compounds characterized by chemical and optical stability, high absorbance and quantum yield. Their fluorescent emission can be easily modulated via organic synthesis by changing the number of thiophene rings and the nature of side-chains. This review shows how oligothiophenes can be derivatized with active groups such as phosphoramidite, N-hydroxysuccinimidyl and 4 sulfotetrafluorophenyl esters, isothiocyanate and azide by which the (bio)molecules of interest can be covalently bound. This paper also describes how molecules such as oligonucleotides, proteins and even nanoparticles, tagged with oligothiophenes, can be used in experiments ranging from hybridization studies to imaging of fixed and living cells. Finally, a few multilabeling experiments are described. PMID- 22258340 TI - Antioxidant effect of Stryphnodendron rotundifolium Martius extracts from Cariri Ceara State (Brazil): potential involvement in its therapeutic use. AB - Stryphnodendron rotundifolium is a phytotherapic used in the northeast of Brazil for the treatment of inflammatory processes which normally are associated with oxidative stress. Consequently, we have tested the antioxidant properties of hydroalcoholic (HAB) and aqueous extracts (AB) from the bark and aqueous extract (AL) from the leaves of Stryphnodendron rotundifolium to determine a possible association between antioxidant activity and the popular use of this plant. Free radical scavenger properties were assessed by the quenching of 1',1'-diphenil-2 picrylhydrazyl (DPPH) and the calculated IC(50) were: HAB = 5.4 +/- 0.7, AB = 12.0 +/- 2.6, and AL = 46.3 +/- 12.3 ug/mL. Total phenolic contents were: HAB = 102.7 +/- 2.8, AB = 114.4 +/- 14.6, and AL = 93.8 +/- 9.1 ug/mg plant). HPLC/DAD analyses indicated that gallic acid, catechin, rutin and caffeic acid were the major components of the crude extracts of S. rotundifolium. Plant extracts inhibited Fe(II)-induced lipid peroxidation in brain homogenates. Iron chelation was also investigated and only HBA exhibited a weak activity. Taken together, the results suggest that S. rotundifolium could be considered an effective agent in the prevention of diseases associated with oxidative stress. PMID- 22258341 TI - Effect of wine and vinegar processing of Rhizoma Corydalis on the tissue distribution of tetrahydropalmatine, protopine and dehydrocorydaline in rats. AB - Vinegar and wine processing of medicinal plants are two traditional pharmaceutical techniques which have been used for thousands of years in China. Tetrahydropalmatine (THP), dehydrocorydaline (DHC) and protopine are three major bioactive molecules in Rhizoma Corydalis. In this study, a simple and reliable HPLC method was developed for simultaneous analysis of THP, DHC and protopine in rat tissues after gastric gavage administration of Rhizoma Corydalis. The validated HPLC method was successfully applied to investigate the effect of wine and vinegar processing on the compounds' distribution in rat tissues. Our results showed that processing mainly affect the T(max) and mean residence time (MRT) of the molecules without changing their C(max) and AUC(0-24)( )(h) Vinegar processing significantly increased the T(max) of DHC in heart, kidney, cerebrum, cerebrellum, brain stem and striatum and prolonged the T(max) of protopine in brain. No significant changes were observed on the T(max) of THP in rat tissues after vinegar processing. Wine processing reduced the T(max) of protopine and DHC in liver and spleen and T(max) of protopine in lung, but increased the T(max) of THP in all the rat tissues examined. To our knowledge, this is the first report on the effects of processing on the tissue distribution of the bioactive molecules from Rhizoma Corydalis. PMID- 22258342 TI - Synthesis, reactions and antimicrobial activities of 8-ethoxycoumarin derivatives. AB - Condensation of 3-acetyl-8-ethoxycoumarin (3) with thiosemicarbazide gave ethylidenehydrazinecarbothioamide 5, which was transformed into the thiazolidin-4 one derivatives 6,7. Interaction of 3 with DMF/POCl(3) gave b-chloroacroline derivative 8. Treatment of 3 with malononitrile gave benzo[c]chromone and 2 aminobenzonitrile derivatives 9 and 10, respectively with respect to the reaction conditions. Condensation of 3-(2-bromoacetyl)-8-ethoxycoumarin (4) with o phenylenediamine gave 3-(quioxaline-2-yl)-8-ethoxycoumarin hydrobromide (11), while 4 reacted with 2-aminopyridine to give chromenopyridopyrimidine derivative 12. Condensation of 4 with potassium thio-cyanate/methanol gave an unexpected derivative, 2H-chromeno-3-carboxy(methyl-carbonimidic)thioanhydride 16, which upon treatment with (NH(2))(2).H(2)O gave 3-ethoxy-2-hydroxybenzaldehyde azine 19. Interaction of 4 with thiourea derivatives gave thiazole derivatives 20a-c. The structures of the newly synthesized compounds were confirmed by their spectra data. The newly synthesized compounds were also screened for their antimicrobial activity. PMID- 22258343 TI - Synthesis, structure and antifungal activity of new 3-[(5-aryl-1,3,4-oxadiazol-2 yl)methyl]benzo[d]thiazol-2(3H)-ones. AB - A series of new 3-[(5-aryl-1,3,4-oxadiazol-2-yl)methy])benzo[d]thiazol-2(3H)-ones were synthesized by reaction of (5-substituted-2-oxobenzothiazolin-3-yl) acetohydrazide with various aromatic acids in POCl(3) under reflux conditions. The structures of the title compounds were confirmed by 1H-NMR, 13C-NMR, IR, MS and elemental analysis. Furthermore, the structure of compound 4i was determined by single-crystal X-ray diffraction. The preliminary bioassy results indicated that some of them showed moderate inhibition activity against Colletotrichum orbiculare, Botrytis cinerea and Rhizoctonia solani. PMID- 22258344 TI - Unicentric Castleman disease relapsed after rituximab-CHOP chemotherapy or radiation therapy in an adolescent. AB - Castleman disease (CD), an atypical lymphoproliferative disorder of unknown etiology, is rare. Unicentric CD can be cured after resection of the involved lymph nodes. However, rarely, patients with the unicentric-plasma cell variant may require additional therapy after resection for persistent systemic symptoms. The clinical course of such patients has not been well characterized. We report the case with relapsed unicentric-plasma cell variant CD who was eventually treated with complete surgical resection. This patient had no response to combination chemotherapy with rituximab after incomplete resection and no response to radiation after relapse. PMID- 22258345 TI - Successful treatment of ICE-rituximab chemotherapy and subsequent bone marrow transplantation in a patient with early-relapse Burkitt leukemia and inverted duplication of 1q. AB - Although childhood acute lymphoblastic leukemias are of good prognosis than leukemias of adulthood, some chromosomal abnormalities may have negative effects on their prognosis. Inverted duplication (1q) is a chromosomal abnormality with negative effect on outcome of Burkitt leukemia and lymphomas. We report a case of CD20 Burkitt leukemia with inverted duplication (1q) mutation, who had an early relapse during NHL-BFM 95 treatment. Two courses of ICE-rituximab treatment were administered after relapse and a successful HLA-full match bone marrow transplantation was carried out. He is in follow-up for 18 months without any problem after the bone marrow transplantation. We suggest the usage of ICE protocol combined with rituximab in childhood CD20 Burkitt leukemia with poor prognostic criteria such as inverted duplication (1q) mutation. PMID- 22258346 TI - Rhabdomyolysis: rare complications with a difficult prognosis in the course of anticancer treatment. AB - Rhabdomyolysis refers to a number of clinical and biochemical symptoms, which result from the destruction of skeletal muscles. The following triad of symptoms is considered typical: myalgia, muscle weakness, and dark urine. The most common reasons for rhabdomyolysis in children are infections. It has also been reported that rhabdomyolysis may be caused by chemotherapy drugs. The most difficult complication of rhabdomyolysis is renal failure. The authors present a 17-year old boy diagnosed with Ewing sarcoma and a 16-year-old boy suffering from acute leukemia, both with rhabdomyolysis developed in the course of infection caused by Clostridium difficile, and drug-induced neutropenia. PMID- 22258347 TI - Abnormal orbital growth in children submitted to enucleation for retinoblastoma treatment. AB - Enucleation is typically performed for the treatment of advanced retinoblastoma in children. After enucleation, the orbit undergoes abnormal development. In this study, orbital asymmetry was calculated using computed tomography measurements obtained from patients who experienced enucleation for unilateral retinoblastoma. Influence factors analyzed included: type of treatment, use of orbital implants, and patient's age at diagnosis. A total of 42 children underwent enucleation with a mean follow-up period of 4.8 years. For 28 patients, treatment included enucleation alone, 14 patients received enucleation plus radiation therapy. Thirty patients kept orbital implants long term. The mean orbital volume asymmetry for treated versus contralateral orbits was 16.8%. Mean asymmetry in orbital volume was greater for patients who underwent enucleation combined to radiation therapy (23.7% vs. 13.3%, P=0.05) and for patients without long-term maintenance of the prosthetic implants (29.3% vs. 11.8%, P<0.01). In conclusion, orbital volume is abnormally affected in children after enucleation of 1 eye for the treatment of retinoblastoma, and computed tomography can precisely quantify the asymmetry that develops. Orbital implants improve volumetric growth after enucleation, with 2-fold greater orbital asymmetry achieved without an implant. PMID- 22258348 TI - Autoimmune hemolytic anemia and immune thrombocytopenia as unusual presentations of childhood Hodgkin lymphoma: a case report and review of the literature. AB - We discuss an unusual clinical presentation of childhood Hodgkin lymphoma; a 16 year-old girl was referred for Coombs-positive severe anemia, thrombocytopenia, and asymptomatic anterior mediastinal mass. Bone marrow examination showed no evidence of neoplastic disease. Biopsy of the mass was possible only after administration of both intravenous immunoglobulins and steroids resulting in a prompt rise of the platelet count and partial hemoglobin level stabilization. The identification of this clinical picture as a possible complication of an underlying Hodgkin lymphoma presents difficulties in diagnosis and management of the primary condition. PMID- 22258349 TI - Successful treatment of disseminated cryptococcal infection in a pediatric acute lymphoblastic leukemia patient during induction. AB - Disseminated cryptococcal infection is rarely reported in the setting of pediatric acute leukemia, despite the immunocompromised state of these patients. However, when present, disseminated cryptococcal infection poses treatment challenges and is associated with significant morbidity and mortality. Treatment of invasive fungal disease in a child with acute leukemia requires a delicate balance between antifungal and antineoplastic therapy. This balance is particularly important early in the course of leukemia, as both the underlying disease and overwhelming infection can be life threatening. We describe the successful management of life-threatening disseminated cryptococcosis in a child with acute lymphoblastic leukemia during induction therapy. PMID- 22258350 TI - Scurvy in a child with autism: magnetic resonance imaging and pathological findings. AB - We present a case of scurvy in a 6-year-old boy with autism and an unbalanced diet. The patient was admitted with difficulties in walking. Magnetic resonance imaging findings of the thigh showed diffuse signal abnormality in the bone marrow, periosteum, and the femoral muscle. A biopsy specimen of the femur showed hematoma, proliferative fibroblasts, and few collagen fibers, which suggested a deficiency of vitamin C. Although recurrent periosteal hematoma may be suggestive of scurvy, this finding was subtle in the current case. It is important to be aware of this rare disease because it is easily cured with vitamin C supplementation. PMID- 22258351 TI - Analysis of rs4671393 polymorphism in hemoglobin E/beta-thalassemia major in Guangxi Province of China. PMID- 22258352 TI - Complete remission and long-term survival in a child with relapsed medulloblastoma with extensive osteosclerotic bony metastasis with a novel metronomic chemobiological approach. AB - Extraneural metastases in medulloblastoma are rare. We report a boy with medulloblastoma who was initially treated with gross total excision of primary tumor followed by radiotherapy. Six years later, he developed disseminated osteosclerotic bony relapse associated with bone marrow involvement. He was successfully salvaged with metronomic low-dose cyclophosphamide, etoposide, and zoledronic acid. In patients with medulloblastoma and bone pain, metastases to bone should be excluded, and medulloblastoma should be considered while investigating osteosclerotic bone lesions. Furthermore, metronomic chemotherapy should be considered in this setting until better therapeutic modalities emerge. PMID- 22258353 TI - beta-Thalassemia in Pakistan: a pilot program on prenatal diagnosis in Multan. AB - Prenatal diagnosis (PND) of beta-thalassemia has been underutilized in Pakistan because of a number of social and economic factors. National Institute for Biotechnology and Genetic Engineering Faisalabad in collaboration with Multan Institute of Nuclear Medicine and Radiotherapy Multan introduced free PND service for carrier couples of Multan district. Multan has a population of about 4 million. More than 170 couples registered for retrospective PND and in 2 years 105 PND were carried out through first trimester chorionic villus sampling. Almost 90% of these couples were unable to afford the cost of PND and would not have undergone the test as free service was not available. Monoplex and Multiplex Amplification Refractory Mutation System-polymerase chain reaction and genomic DNA sequencing were used for detection of IVS (intervening sequence)-I-5 (G-C), FSC (frameshift codon)-8/9 (+G), FSC-41/42 (-TTCT), IVS-I-1 (G-T), 619 bp deletion, and CD-15 (G-A) beta-globin mutations. Eighty-one percent (85/105) couples analyzed were in a consanguineous marriage. Twenty-three fetuses were found homozygous mutant and all couples opted for discontinuation of affected pregnancies. More families are registering for PND after establishment of this free and accessible PND service. PMID- 22258354 TI - HHV-8-related hemophagocytic lymphohistiocytosis in a boy with XLP phenotype. AB - We report a 2.5-year-old boy with an X-linked lymphoproliferative disease (XLP) phenotype who presented with human herpes virus-8 (HHV-8)-related hemophagocytic lymphohistiocytosis (HLH). XLP is a rare primary immunodeficiency characterized by extreme susceptibility to herpes viruses, mainly Epstein-Barr virus (EBV). Approximately 60% of patients with XLP present with fulminant mononucleosis associated with HLH, whereas remaining patients present with hypogammaglobulinemia or lymphoproliferative disease. Most commonly, one of the XLP phenotypes appears after exposure to EBV, but at least 12% of affected individuals developed symptoms without an evidence of EBV infection. Rarely, patients with XLP may present with central nervous system vasculitis or aplastic anemia. HHV-8 is lymphotrophic and it is associated with lymphoproliferative disorders and Kaposi sarcoma in immunodeficient hosts. Kaposi sarcoma rarely occurs in children with well-defined primary immunodeficiency. Also, HHV-8 related HLH was previously reported in 2 siblings with a perforin gene deficiency. Recently, it became evident that besides EBV, other viruses may trigger the symptoms in XLP. We report for the first time HHV-8-related HLH in EBV-negative pediatric patient with an XLP phenotype. PMID- 22258355 TI - Trisomy 7 and deletion of the 9p21 locus as novel acquired abnormalities in a case of pediatric biphenotypic acute leukemia. PMID- 22258356 TI - Dietary exposure estimates of 16 polycyclic aromatic hydrocarbons (PAHs) in Xuanwei and Fuyuan, counties in a high lung cancer incidence area in China. AB - Xuanwei and Fuyuan are located in the southwest of China and have the highest lung cancer incidence in China, possibly even highest in the world. Dietary samples were collected from these two counties and the contamination status of sixteen polycyclic aromatic hydrocarbons (PAHs) were determined. PAH components, food constituents, dietary exposure level, as well as spatial difference, were studied in the different groups. The percentage of dietary intake to total intake of PAHs was calculated and the relationship between the dietary intake of PAHs and the abnormal lung cancer incidence was primarily discussed. The results showed that rice and potatoes were the main foods of the local residents in Xuanwei and Fuyuan. The daily exposure doses of Bap (benzo[a]pyrene), total PAHs, and TEQs (toxic equivalents) based on Bap toxicity in two counties were estimated to be 458 ng d(-1), 14,532 ng d(-1), and 896 ng d(-1), respectively, which were much less than those in other cities reported previously. The lower ingestion amount of food with a relatively higher content of PAHs, such as meat and fish, could account for the lower exposure doses. PAHs with less than 4 rings occupied a high percentage of the total PAHs in food samples. The exposure doses varied significantly among different sites and even different families at the same site. Dietary exposure was not the main exposure route of PAHs at most sites. It appears that there was not a direct relationship between dietary exposure and the lung cancer incidence. However, high ratios of dietary intake to total PAHs intake (1.33%-70.61%) were found in several areas and rational diet suggestions should be given in these areas in the future. PMID- 22258357 TI - Herbivore-mediated effects of glucosinolates on different natural enemies of a specialist aphid. AB - The cabbage aphid Brevicoryne brassicae is a specialist herbivore that sequesters glucosinolates from its host plant as a defense against its predators. It is unknown to what extent parasitoids are affected by this sequestration. We investigated herbivore-mediated effects of glucosinolates on the parasitoid wasp Diaeretiella rapae and the predator Episyrphus balteatus. We reared B. brassicae on three ecotypes of Arabidopsis thaliana that differ in glucosinolate content and on one genetically transformed line with modified concentrations of aliphatic glucosinolates. We tested aphid performance and the performance and behavior of both natural enemies. We correlated this with phloem and aphid glucosinolate concentrations and emission of volatiles. Brevicoryne brassicae performance correlated positively with concentrations of both aliphatic and indole glucosinolates in the phloem. Aphids selectively sequestered glucosinolates. Glucosinolate concentration in B. brassicae correlated negatively with performance of the predator, but positively with performance of the parasitoid, possibly because the aphids with the highest glucosinolate concentrations had a higher body weight. Both natural enemies showed a positive performance-preference correlation. The predator preferred the ecotype with the lowest emission of volatile glucosinolate breakdown products in each test combination, whereas the parasitoid wasp preferred the A. thaliana ecotype with the highest emission of these volatiles. The study shows that there are differential herbivore-mediated effects of glucosinolates on a predator and a parasitoid of a specialist aphid that selectively sequesters glucosinolates from its host plant. PMID- 22258358 TI - Spectrum of fungal infection in a neurology tertiary care center in India. AB - There is a paucity of studies on spectrum of fungal infections in neurology care. This study reports clinical, MRI and outcome of patients with central nervous system (CNS) fungal infections. 39 patients with CNS fungal infections treated in neurology service during the last 3 years were included and a detailed medical history and clinical examination were undertaken. Cranial MRI including paranasal sinuses were carried out and the location and nature of abnormalities were noted. Fungal infection was confirmed by CSF examination or histopathology. Death during hospital stay was noted. The median age was 37 (8-72) years and 8 were females. The clinical features included altered sensorium in 31, focal motor deficits in 13, visual loss in 12, seizures in 10, diplopia in 7, and papilledema in 9 patients. 28 patients had the following predisposing conditions: HIV in 15, diabetes in 8, corticosteroid in 2 and alcohol, immunosuppression, neutropenia and analgesic abuse in 1 patient each. On CT or MRI scan, 5 patients had meningeal enhancement, 7 sinusitis, 10 each granuloma and infarction, 4 hydrocephalous and 1 cerebral venous sinus thrombosis. 28 patients had cryptococcal meningitis, 7 zygomycosis, 2 aspergillosis and 1 each candida and phaeohyphomycosis. Death was related to the type of fungal infection; all patients with zygomycosis and candida infection died. Rhinocerebral form of fungal infection due to zygomycetes has poorer survival compared to meningitis group which was mainly due to cryptococcal infection. PMID- 22258359 TI - 5alpha-reductase 1 regulates spinal cord testosterone after morphine administration. AB - The enzyme 5alpha-reductase 1 (5alpha-R(1)) that converts testosterone (T) to dihydrotestosterone (DHT) is present in many mammalian tissues including the spinal cord. It is established that morphine administration decreases spinal cord T levels, but the mechanism is still undetermined. Here, we investigated the link between T and the enzyme 5alpha-R(1) in the spinal cord after morphine administration. For spinal cord steroid extraction, all the animals were killed 30 min, 2 h (acute) and 14 days (chronic) after first drug injection by decapitation. The whole spinal cord was removed and kept frozen at -20 degrees C until T and DHT extraction. The effects of acute and chronic morphine administration on 5alpha-R(1) expression in the adult male rat spinal cord were evaluated using RT-PCR. Spinal cord T and DHT levels were measured using radioimmunoassay before and after the morphine exposure. Morphine significantly reduced the T concentration after acute and chronic exposure in the spinal cord. In contrast, the 5alpha-R(1) expression and of course DHT levels increased the following chronic morphine administration. One important reason for the decreasing effect of morphine exposure on the spinal cord T level is due to an increase in the 5alpha-R(1) levels. We suggest that morphine plays a regulatory role in metabolism of neurosteroids, especially T in the spinal cord via 5alpha R(1). PMID- 22258360 TI - Acquired encephalopathy associated with carnitine deficiency after cefditoren pivoxil administration. AB - We describe a 47-year-old woman who presented with palinopsia and subacute altered mental change after cefditoren pivoxil administration. The patient showed characteristic clinical manifestations of hypocarnitinemia, which affected her state of consciousness and she had radiologic findings that revealed metabolic encephalopathy with cytotoxic edema in the right occipital area and intracranial hemorrhages in right occipital and left frontal areas. Follow-up imaging after oral carnitine supplementation demonstrated complete resolution of the bilateral frontal subcortical T2 high-intensity lesions. Carnitine deficiency due to cefditoren pivoxil treatment may present as metabolic encephalopathy in adults. This possibility should be considered with the differential diagnosis of encephalopathies, and carnitine levels should be checked in patients treated with cefditoren pivoxil. PMID- 22258361 TI - The VAS-COG clinic: an out-patient service for patients with cognitive and behavioral consequences of cerebrovascular diseases. AB - Services dedicated to patients with cognitive and behavioral consequences of cerebrovascular diseases (CVD) are not established. We started an out-patient clinic (the "VAS-COG clinic") to assess patients with psycho-cognitive disturbances related to CVD. The work-up includes a clinical-neuroimaging diagnostic process and the individuation of the best therapeutic strategies as done in patients with neurodegenerative cognitive impairment. We report the results of the first 5 years of activity. Reasons for patient referral were not only cognitive, language, gait, and psychiatric disturbances related to stroke or chronic CVD, but also neuroimaging evidence of vascular encephalopathy and screening for familial microangiopathies. The patients were evaluated with uniformed protocols. From January 2006 to November 2010, we evaluated 403 patients. Of these, 374 (93%; mean age 69.7 years +/- 15.0) were considered appropriate for the VAS-COG clinic. The following diagnoses were made: vascular dementia (8.6%), Alzheimer disease (2.1%), mixed dementia (vascular plus degenerative) (4.8%), vascular mild cognitive impairment (MCI) (9.1%), amnesic MCI (8.0%), mixed-MCI (4.8%), post-stroke depression (2.7%), post-stroke language disturbances (4.5%), subjective memory complaint (1.3%), familiar microangiopathy (31.3%), vascular encephalopathy evidenced by neuroimaging not associated with specific clinical disturbances (15.3%), and other conditions (7.5%). Psycho cognitive disturbances associated with CVD are heterogeneous. In addition to acute stroke care strategies, long-term assessment of patients with CVD is required. The VAS-COG clinic may represent a model in this regard and might be important for improving the care of patients and offering counseling to their families. The efficacy of this service needs, however, to be proved by successive work. PMID- 22258362 TI - Is there a role for neurologist in an oncological home care team? PMID- 22258363 TI - Spontaneous resolution of syringomyelia in an adult patient with tight cisterna magna. AB - Spontaneous resolution of syringomyelia in adult patients with Chiari malformation is exceptionally rare, with only 10 cases having been reported. A 21 year-old man working as a carpenter presented with a 1-year history of paresthesias in his right arm. A magnetic resonance imaging scan disclosed a cervicothoracic syrinx associated with tight tonsillar impaction of the cisterna magna without herniation. The patient left the carpentry job and underwent close monitoring with serial clinical and neuroradiological controls. The patient's symptoms gradually disappeared and magnetic resonance imaging studies revealed progressive shrinkage of the syrinx despite persistence of crowding of posterior fossa structures at the level of the foramen magnum. This case suggests that spontaneous resolution of syringomyelia can occasionally be triggered by the cessation of daily physical strain in patients with tight cisterna magna. Health care professionals should be aware that strenuous physical activities could affect the natural history of syringomyelia. PMID- 22258364 TI - Lamotrigine-induced hypersensitivity syndrome in a Han Chinese patient with the HLA-B 5801 genotype. PMID- 22258365 TI - Neurophysiological analysis of the cauda equina in POEMS syndrome. PMID- 22258366 TI - Impact of a cancer clinical trials web site on discussions about trial participation: a cluster randomized trial. AB - BACKGROUND: Cancer patients want access to reliable information about currently recruiting clinical trials. PATIENTS AND METHODS: Oncologists and their patients were randomly assigned to access a consumer-friendly cancer clinical trials web site [Australian Cancer Trials (ACT), www.australiancancertrials.gov.au] or to usual care in a cluster randomized controlled trial. The primary outcome, measured from audio recordings of oncologist-patient consultations, was the proportion of patients with whom participation in any clinical trial was discussed. Analysis was by intention-to-treat accounting for clustering and stratification. RESULTS: Thirty medical oncologists and 493 patients were recruited. Overall, 46% of consultations in the intervention group compared with 34% in the control group contained a discussion about clinical trials (P=0.08). The mean consultation length in both groups was 29 min (P=0.69). The proportion consenting to a trial was 10% in both groups (P=0.65). Patients' knowledge about randomized trials was lower in the intervention than the control group (mean score 3.0 versus 3.3, P=0.03) but decisional conflict scores were similar (mean score 42 versus 43, P=0.83). CONCLUSIONS: Good communication between patients and physicians is essential. Within this context, a web site such as Australian Cancer Trials may be an important tool to encourage discussion about clinical trial participation. PMID- 22258367 TI - Reversal of the British trends in place of death: time series analysis 2004-2010. AB - BACKGROUND: Increased attention is being paid to the place where people die with a view to providing choice and adequately planning care for terminally ill patients. Secular trends towards an institutionalised dying have been reported in Britain and other developed world regions. AIM: This study aimed to examine British national trends in place of death from 2004 to 2010. DESIGN AND SETTING: Descriptive analysis of death registration data from the Office for National Statistics, representing all 3,525,564 decedents in England and Wales from 2004 to 2010. RESULTS: There was a slow but steady increase in the proportion of deaths at home, from 18.3% in 2004 to 20.8% in 2010. Absolute numbers of home deaths increased by 9.1%, whilst overall numbers of deaths decreased by 3.8%. The rise in home deaths was more pronounced in cancer, happened for both genders and across all age groups, except for those younger than 14 years and for those aged 65-84, but only up to 2006. The rise was more evident when ageing was accounted for (age-gender standardised proportions of home deaths increased from 20.6% to 23.5%). CONCLUSIONS: Following trends in the USA and Canada, dying is also shifting to people's homes in Britain. Home deaths increased for the first time since 1974 amongst people aged 85 years and over. There is an urgent need across nations for comparative evidence on the outcomes and the costs of dying at home. PMID- 22258369 TI - [Advanced prostate cancer: where are we going?]. PMID- 22258368 TI - Genetic characterization of bluetongue virus serotype 9 isolates from India. AB - Recent incursions of bluetongue virus (BTV) into previously naive geographical areas have emphasised the need to better understand virus movement and epidemiology. Several bluetongue virus (BTV) serotypes are known to exist in India, and some serotype viruses have been isolated. However, the complete genome of not a single isolate is available to date. We report the complete genome sequence of one, and partial sequences of three other Indian isolates of BTV-9. Evolutionary relationships with segment-2 and -6 sequences of BTV isolates around the world, deduced using four different phylogenetic analyses and a similarity programme, show that BTV-9 (Eastern), BTV-9 (Western), and BTV-5 form a triad of equidistant, genetically distinct groups of viruses. The Indian BTV-9 isolates were closely related to Mediterranean and European BTV-9 isolates (Eastern topotype) based on segment-2 and -6 sequences. By contrast, segment-5 analyses clustered the Indian BTV-9 isolates with South African BTV-3 reference strain (98% identity), which belongs to one of the Western types. These results have implications on BTV origin and movement, genotyping, serotyping, and vaccine design. PMID- 22258370 TI - [Inhibitors of androgen and estrogen biosynthesis in castration-resistant prostate cancer]. AB - Advanced prostate cancer remains dependent on androgens and signaling through the androgen receptor despite castrate levels of testosterone defined as testosterone levels <1.7 nmol/l. Ketoconazole, a nonspecific inhibitor of androgen synthesis, has been tested in clinical trials and showed clinical activity; however, high doses are needed which are associated with significant sides effects, mainly neurotoxicity, gastrointestinal intolerance, and liver toxicity. Abiraterone acetate is an irreversible inhibitor of two key enzymes of androgen synthesis, 17a-hydroxylase and 17,20-lyase, and has been tested in a randomized phase III study in patients with castration-resistant prostate cancer who progressed after chemotherapy. Abiraterone plus prednisone resulted in a significant overall survival benefit of 4.6 months compared to prednisone alone. Abiraterone was well tolerated, with mostly mild or moderate side effects consistent with secondary mineralocorticoid excess, namely fluid retention, hypokalemia, and hypertension. Abiraterone plus prednisone is considered a new standard therapy option for patients with castration-resistant prostate cancer who progressed after chemotherapy. PMID- 22258371 TI - [How should hormone therapy for castration-resistant prostate cancer be continued?]. AB - After an average of 18-36 months under androgen suppression therapy by surgical castration, LHRH, and steroidal or non-steroidal antiandrogens, almost all patients with metastatic prostate cancer show PSA progression as a sign of androgen-independent but still androgen-sensitive tumor growth. Our understanding and the treatment of such castration-resistant prostate cancer has changed markedly. The introduction of new drugs like abiraterone and MDV3100 has shown that prostate cancer progression even in the"hormone-refractory" stage is driven by androgen receptor signaling. Based on this information the question of whether androgen deprivation therapy in castration-resistant prostate cancer should be continued or not is still of relevance. This review gives a critical overview of the literature and current guideline recommendations. PMID- 22258372 TI - [Bone metastasis in prostate cancer]. AB - Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients. In addition to established bone-targeted therapies, new drugs such as endothelin A receptor antagonists, MET and VEGFR-2 antagonists or radiopharmaceuticals are in the focus of development. The standard care in prostate cancer patients with bone metastases to prevent skeletal-related events (SRE) are bisphosphonates. Denosumab, a human monoclonal antibody against RANKL, appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases-free survival. In contrast to zoledronic acid, denosumab clearance is not dependent on kidney function and can be administered subcutaneously. Similar rates of toxicity were observed for both substances; however, long-term data for denosumab are limited. PMID- 22258373 TI - [Castration-resistant prostate cancer: surgical and radio-oncological therapeutic options]. AB - Treatment of patients suffering from castration-resistant prostate cancer is a challenge for the attending physician. Due to the polysymptomatic nature of this disease, multidisciplinary cooperation (urology, radiation oncology, medical oncology, palliative care, orthopaedics, neurosurgery) is the centre of attention. Different surgical and radio-oncological therapeutic options are available based on different stages of this disease. Optimizing quality of life should always be the focus of attention in these patients. PMID- 22258374 TI - [Immunotherapy for metastatic prostate cancer: do we really need this?]. AB - Following the approval of Sipuleucel-T, the development of new immunomodulatory approaches such as ipilimumab and tasquinimod, and the development of new antihormonal drugs (abiraterone acetate, MDV3100, TAK-700), treatment of castration-resistant prostate cancer is finally reaching a new era of management. Docetaxel based chemotherapy remains the standard treatment of choice for patients with a high tumour burden, rapidly progressiong castration resistant prostate cancer, and poorly differentiated prostate cancer. Sipuleucel-T might be an option in the pre-docetaxel management of castration-resistant prostate cancer resulting in a 4-months improvement of overall survival. However, as with all other modalities of immunotherapy patients with good prognostic factors such as minimal tumour burden, slow PSA doubling time, Gleason score <= 7, and a long survival probability of > 1 year might be the best candidates taking into account that immunomodulatory approaches demonstrate positive responses after 4-6 months of therapy. Ipilimumab and tasqunimod as inhibitors of the immune checkpoints are additional, promising therapeutic agents with high clinical potential. It is the aim of the current article to critically review the current options of immune therapy in men with castration resistant prostate cancer. PMID- 22258375 TI - [Role of chemotherapy in castration-resistant prostate cancer: are there new approaches?]. AB - Chemotherapy options for the treatment of metastatic castration-resistant prostate cancer (CRPC) have been very limited for many decades. Until 2004, only mitoxantrone was approved, providing palliation, but no survival benefit. With the introduction of docetaxel, the landscape of chemotherapy for CRPC changed substantially. Prednisone and three-weekly docetaxel showed an overall survival (OS) benefit compared to mitoxantrone plus prednisone, in addition to a significant improvement of quality of life and pain reduction. Further strategies to treat CRPC with chemotherapy include reinduction with docetaxel in responding patients and the use of cabazitaxel, a novel semi-synthetic microtubule inhibitor, in the docetaxel-refractory population. This review article is meant to guide physicians through the optimal use of chemotherapy in CRPC patients in daily clinical practice. PMID- 22258377 TI - [U.S. Preventive Services Task Force recommendation or "throwing out the baby with the bath water"]. PMID- 22258378 TI - [Annual program plan 2012 of the German Society of Residents in Urology]. PMID- 22258380 TI - [The impact of ultrasound in urology]. AB - Ultrasound is of great importance in the diagnosis of acute and chronic diseases in urology, such as kidney colic, testicular torsion, low-grade kidney trauma or for follow-up of vesicoureteral reflux, evaluation of infertility, measurement of residual urinary volume and the detection of cancer. An ultrasound examination is time and cost-effective without exposure to ionizing radiation and is routinely performed by practitioners as well as in the clinical daily routine. With technical innovations, such as contrast-enhanced ultrasound or real time elastography, it would for instance be possible to extend the application field of ultrasound. However, in some fields of investigation ultrasound still lacks accuracy and despite its many advantages the validity of ultrasound findings sometimes has to be verified with computed tomography (CT) or magnetic resonance imaging (MRI). PMID- 22258386 TI - The contrasting epidemiology of granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis. AB - OBJECTIVES: Granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) are uncommon and have unknown aetiology. The aim of the study was to investigate the epidemiology of GPA and MPA in a stable, well-defined population looking for differences in the pattern of occurrence, which might suggest a different aetiology. METHODS: Since 1988, we have maintained a prospective register of all patients with systemic vasculitis attending the Norfolk and Norwich University Hospital. Patients presenting with new-onset GPA and MPA as defined by the European Medicines Agency algorithm and registered with general practitioners in the former Norwich Health Authority area between 1988 and 2010 were identified. The population in 2008 was estimated to be 459 000 (221 000 males). RESULTS: One hundred and eleven GPA and 58 MPA incident cases were identified during 1988-2010. The overall annual incidence of GPA and MPA was 11.3/million and 5.9/million, respectively. There was evidence of a cyclical pattern of occurrence with a periodicity of 7.6 years for GPA with a peak incidence of 28.3/million in 2005 and the lowest in 2002 (2.2/million). Other lesser peaks occurred in 1990 and 1996. While the peak incidence of MPA was in 2008 (15.2/million), there was no convincing evidence of periodicity. The incidence of cANCA/PR3- or pANCA/MPO-positive vasculitis showed a similar pattern to GPA and MPA, respectively. CONCLUSION: This study lends support to the notion that the aetiology of GPA and MPA may be distinct conditions with different aetiologies. The cyclical incidence of GPA is possibly an indication for the influence of infection. PMID- 22258387 TI - Metastasin S100A4 is increased in proportion to radiographic damage in patients with RA. AB - OBJECTIVE: To assess the potential of metastasin S100A4 as a biological marker in patients with RA. METHODS: A total of 87 unselected patients with established RA (disease duration 2-44 years) and treated with MTX and infliximab at a single rheumatology centre were included in a cross-sectional study. Radiographs of hands and feet were taken prior to infliximab treatment and at inclusion (time interval 48 +/- 27 months) and scored for the radiographic damage. S100A4 levels were analysed in relation to radiographic damage, clinical disease activity (DAS 28), inflammation (IL-6, CRP, ESR), bone and cartilage markers [MMP-3, COMP, C telopeptide of type I collagen (CTX-I)] and proto-oncogenes [survivin, insulin like growth factor 1 (IGF-1), Flt3 ligand]. RESULTS: High levels of S100A4 were associated with severe radiographic damage (OR = 3.40, P = 0.025), non-response to infliximab (OR = 4.63, P = 0.003), presence of antibodies to infliximab (OR = 6.24, P = 0.003) and high levels of Flt3 ligand (OR = 2.73, P = 0.04). Regression analysis showed that high S100A4 was predictive for radiographic progression during infliximab treatment [positive predictive value (PPV) 0.68, P = 0.05]. Low levels of S100A4 were associated with response to infliximab (OR = 2.67, P = 0.049), clinical remission (OR = 4.01, P = 0.0047) and negative RF (OR = 9.22, P = 0.0047). S100A4 correlated with survivin (r = 0.71, P > 0.0001). CONCLUSION: S100A4 levels are increased in proportion to radiographic damage and its further progression in RA patients. High S100A4 levels were associated with a poor clinical response to infliximab and high rate of anti-infliximab antibodies. The finding of a correlation between S100A4 and survivin and Flt3 ligand suggests that these proteins may represent a new cluster of biomarkers predicting radiographic progression and poor treatment response in RA patients. PMID- 22258388 TI - Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA--a simultaneous study of 130 potentially functional SNPs in 14 candidate genes. AB - OBJECTIVE: Frequent genetic variants may be associated with GCA. Existing studies have analysed a limited number of candidate genes and genetic variants. To expand this information, we performed a case-control study genotyping 130 single nucleotide polymorphisms (SNPs) in 82 biopsy-proven GCA patients and 166 healthy controls from the Spanish population. METHODS: SNPs in coding and regulatory gene regions of 14 candidate genes (CCL2, CCR7, IL10, IL12A, IL1A, IL1B, IL1RN, IL6, IL8, INFG, LTA, NOS2, TNF and VEGF) were explored using the Illumina Bead Array System. Multivariate methods based on logistic regression were used for statistical analysis. RESULTS: Nine SNPs located in five genes had significant association with GCA risk (P < 0.05). These SNPs were located in the NOS2 (rs2779251), VEGF (rs1885657, rs2010963, rs699946 and rs699947), IL1RN (rs17207494), IL6 (rs7805828 and rs1546766) and CCL2 (rs1860190) genes. The strongest associations were seen for rs2779251, rs1885657 and rs2010963 (P = 2.3 * 10(-5), P = 0.0078 and P = 0.0097, respectively). The presence of the minor allele of NOS2 variant rs2779251 had a protective effect on the risk for GCA [odds ratio (OR) = 0.27, 95% CI 0.14, 0.52]. Risk alleles for three of the four SNPs in the VEGF gene (rs2010963, rs699946 and rs699947) were associated in homozygosis with increased risk (OR = 4.22, 95% CI 1.38, 12.87; OR = 9.04, 95% CI 1.58, 51.81; and OR = 2.38, 95% CI 1.05, 5.38, respectively), whereas a minor allele for the other SNP (rs1885657) had a protective effect (OR = 0.46, 95% CI 0.26, 0.84). CONCLUSION: Common genetic variants in NOS2, VEGF, IL6, ILRN1 and CCL2 genes are associated with GCA, indicating a polygenic influence on disease susceptibility. PMID- 22258389 TI - Frequent development of chronic obstructive pulmonary disease in primary SS- results of a longitudinal follow-up. AB - OBJECTIVES: To study the longitudinal development of pulmonary function in patients with primary SS (pSS) and its association with respiratory symptoms, pulmonary radiographic findings and clinical features of pSS. METHODS: Forty-one pSS patients, previously evaluated by pulmonary function tests (PFTs), were included in the study. The patients were studied at baseline and follow-up by PFT and at follow-up also by high-resolution CT scan of the lungs, the St George's Respiratory Questionnaire and by inflammatory and serological tests. The PFT results were compared with previously studied population-based controls, standardizing results with regard to gender, age, height, weight and tobacco consumption. RESULTS: The mean follow-up time was 11 years. The pSS patients displayed signs of both obstructive and restrictive lung disease at baseline and at follow-up, and deteriorated in forced expiratory volume in 1 s (FEV(1)), ratio of FEV(1) to vital capacity and in diffusing capacity for carbon monoxide during follow-up. Chronic obstructive pulmonary disease (COPD) was diagnosed in 37% of the pSS patients at follow-up. In pSS patients, respiratory symptoms and radiographic abnormalities were common, although with a poor association with PFT variables. CONCLUSION: The pSS patients showed signs of both obstructive and restrictive pulmonary disease and COPD commonly developed during follow-up. Respiratory symptoms and radiographic abnormalities were common but poorly associated with PFT in pSS patients. PMID- 22258390 TI - Development of resistance to biologic therapies with reference to IFN-beta. AB - All biotherapeutics have the potential to generate anti-drug antibodies (ADAs) in patients. The main factors leading to an immune response are thought to be product, treatment and patient related. In this review, reasons for the formation of ADAs, and particularly neutralizing antibodies (NAbs), are considered, with a focus on IFN-beta as a well-studied example. The time course for the production of NAbs, the measurement of NAbs, the defining of IFN-beta responders and non responders, the implications for disease progression in patients, and future methods for avoiding the production of ADAs and of tolerizing patients are considered. PMID- 22258391 TI - Loss of metacarpal bone density predicts RA development in recent-onset arthritis. AB - OBJECTIVE: Serum samples taken before the onset of RA suggest that one of the first features of RA is BMD loss. We determined the ability of radiographic BMD loss to predict RA development and arthritis persistency in patients with early undifferentiated arthritis (UA). METHODS: Five hundred and seventeen patients with early UA, included in the Leiden Early Arthritis Clinic, were assessed. Of these, 101 had hand radiographs made at first visit as well as after 6 months. BMD loss was measured using digital X-ray radiogrammetry (DXR) online. The outcome measures fulfilled the 1987 ACR criteria for RA after 1 year and arthritis persistency during a mean follow-up of 7 years. Additionally, it was assessed whether BMD measurements improved predictions compared with a validated prediction rule. RESULTS: A total of 53.8% of UA patients developed RA and 67.5% had persistent disease after 7 years follow-up. Highly elevated BMD loss (>=2.5 mg/cm2/month) was present in 16.3% of patients and associated with RA development [odds ratio (OR) 6.1, 95% CI 1.2, 29.2, positive predictive value (PPV) 85%, negative predictive value (NPV) 52%, sensitivity 26%, specificity 95%]. BMD loss may have an independent effect of anti-CCP when tested in a logistic regression analysis (OR 4.1, 95% CI 0.8, 21.2), although the CI is large. All UA patients that were unclassified with the prediction rule and had highly elevated BMD loss progressed to RA. BMD loss was not significantly associated with arthritis persistency (HR = 0.56, 95% CI 0.14, 2.29). CONCLUSION: Present data suggest that BMD loss predicts RA development. These findings need to be verified in larger studies. PMID- 22258392 TI - Replication of a microsatellite genome-wide association study of Behcet's disease in a Korean population. AB - OBJECTIVE: Behcet's disease is one of the major aetiologies of uveitis causing blindness in Asian countries. A genome-wide association study identified six microsatellite markers as disease susceptibility loci for Japanese patients with Behcet's disease. To confirm our recent results, these microsatellite markers were examined in a Korean population as a replication study. METHODS: Study participants included 119 Behcet's disease patients and 141 controls. All were enrolled in Korea. Association between the six reported microsatellite markers (D3S0186i, D6S0014i, D6S0032i, 536G12A, D12S0645i and D22S0104i) and Behcet's disease was analysed. HLA-B was genotyped by sequence-based typing methods. RESULTS: A microsatellite marker located near the HLA-B region demonstrated significant association with Behcet's disease (P = 0.028). The genotype and phenotype frequencies of the HLA-B*51 gene were significantly increased in patients (23.1 and 39.5%, respectively) compared with healthy controls (11.2 and 20.1%, respectively; P < 0.001). CONCLUSION: Microsatellite analysis revealed that the HLA-B*51 gene was strongly associated with Behcet's disease in a Korean population. PMID- 22258394 TI - Effect of 1 Hz repetitive transcranial magnetic stimulation over the auditory cortex on audiometry and otoacustic emissions. AB - Repetitive transcranial magnetic stimulation (rTMS) at low frequencies (<=1 Hz) delivered to the primary motor cortex for 15 min or longer has been shown to reduce motor cortex excitability. Over the visual cortex, 1 Hz rTMS led to increased phosphene thresholds and over the auditory cortex rTMS reduced auditory evoked potentials. rTMS above the auditory or temporo-parietal cortex has also been reported to reduce the severity of auditory hallucinations and the perception of tinnitus. However, possible unwanted effects on hearing function have not yet been investigated systematically. 12 right-handed normal hearing subjects (5 male, mean age 28.2 +/- 4.3) received a single session of 18 min 1 Hz rTMS at 90% resting motor threshold intensity using an established coil positioning method targeting the Heschl's area of the left superior temporal gyrus. Standard pure tone audiometry and distortion-products otoacustic emissions (DPOAE) were performed before and immediately after stimulation. The main finding was that one session of 1 Hz rTMS over the temporal cortex modified neither the auditory threshold meaningfully nor the presence of DPOAE in healthy subjects. In conclusion, we found in this pilot approach no obvious indication for auditory dysfunctions due to direct electromagnetic stimulation of the superior temporal gyrus after one session of rTMS in healthy controls that may be interpreted as unwanted side effects. Nevertheless monitoring of auditory functions is strongly recommended in future clinical trials stimulating the auditory cortex, as this has not been done systematically in the past. PMID- 22258395 TI - The role of exercise and types of exercise in the rehabilitation of chronic pain: specific or nonspecific benefits. AB - Chronic pain is one of the most common complaints seen in general practitioners' offices, and it contributes to social, emotional, physical, and economical losses. The management of this problem poses challenges for health care providers when the current treatment of choice for chronic pain is pharmacological management, which may not be a sufficient and/or holistic approach to the management of chronic pain. Our goal is to increase awareness of the significance of physical activity, as well as examine additional cost-effective, integrated approaches to help manage the complex and debilitating effects of this condition. This article summarizes the types of exercise in the rehabilitation of chronic pain patients and provides practical recommendations for the clinician based on empirical and clinical experience. This safe, cost-free, nonpharmacologic way of managing pain has been found to reduce anxiety and depression, improve physical capacity, increase functioning and independence, and reduce morbidity and mortality. PMID- 22258396 TI - Interaction between Adiponectin and Aldosterone. AB - More than two thirds of the US population are considered overweight or obese. Adipocytes are now appreciated as important endocrine organs, secreting various factors with hormonal effects. Several different adipokines have been identified, including adiponectin, which is associated with improved insulin sensitivity, a better lipoprotein profile, and lower rates of vascular inflammation and cardiovascular disease. Several studies have identified the renin-angiotensin aldosterone system as important in the regulation of adiponectin. These studies lay the fundamental groundwork for developing targeted therapies with potential to reduce the burden of obesity-associated diseases, such as the cardiorenal metabolic syndrome. PMID- 22258397 TI - The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney. AB - Overnutrition characterized by overconsumption of food rich in fat and carbohydrates is a significant contributor to hypertension, type 2 diabetes, and the cardiorenal syndrome. Overnutrition activates the renin-angiotensin aldosterone system (RAAS) and causes chronic exposure of cardiovascular and renal tissue to increased circulating nutrients, insulin (INS), and angiotensin II (ANG II). Emerging evidence suggests that overnutrition, aldosterone, and ANG II promote INS resistance, a chronic condition that underlies these co-morbidities, through activation of the mammalian target of the rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling pathway in cardiovascular tissue and the kidney. However, a novel ANG II type 2 receptor (AT2R)-mediated cross talk between the RAAS and mTOR pathways ameliorates overnutrition-induced activation of mTOR/S6K1 signaling in cardiovascular tissue of rats, mice, and humans and confers cardioprotection. PMID- 22258398 TI - An Emerging Role for Understanding Orthostatic Hyp'er'tension in the Cardiorenal Syndrome. AB - Orthostatic hypertension (OHT) is a clinically important problem increasingly recognized in persons with borderline hypertension, diabetes mellitus, and autonomic neuropathies, and in the elderly. Moreover, the association of OHT with progression of target end-organ damage, especially coronary heart disease and chronic kidney disease (CKD), and the attendant increased cardiovascular disease (CVD) and CKD risk, is gaining attention but is still underappreciated. There are various mechanisms that contribute to the development of OHT: excessive vascular adrenergic sensitivity, baroreceptor reflex abnormalities, and inappropriate activation of the renin-angiotensin-aldosterone system, which are also mechanisms that lead to cardiorenal metabolic disease (CRS). While the evidence is compelling for the clinical importance of OHT, more investigation is needed to evaluate the effects of OHT on CKD and CVD. The notion that the development of OHT is a risk factor for the development of CRS raises the need for further clinical and investigational attention to this clinical dilemma. PMID- 22258399 TI - The Association between Parathyroid Hormone Levels and the Cardiorenal Metabolic Syndrome in Non-Diabetic Chronic Kidney Disease. AB - AIMS: The relationship between parathyroid hormone (PTH) and the cardiorenal metabolic syndrome was examined among non-diabetic persons with chronic kidney disease (CKD). METHODS: In a cross-sectional analysis, the relationship between PTH levels and the cardiorenal metabolic syndrome was investigated in 3,215 non diabetic participants in the National Kidney Foundation-Kidney Early Evaluation Program (KEEP 2.0) found to have CKD (eGFR <60 ml/min/1.73 m2). RESULTS: In unadjusted analyses, the prevalence of the cardiorenal metabolic syndrome increased along increasing PTH quartiles (31.7, 33.8, 37.3, and 48.7%, respectively, p for trend <0.0001). After multivariate adjustment, as compared to the first PTH quartile, odds of the cardiorenal metabolic syndrome were 16% (p = 0.18), 35% (p = 0.006), and 80% (p < 0.0001) higher for the second, third, and fourth quartiles, respectively. When taken as a continuous predictor, each standard deviation increase of natural log transformed PTH was associated with 26% (p < 0.0001) higher odds of the cardiorenal metabolic syndrome. The association of PTH with the cardiorenal metabolic syndrome was not modified by age or gender (p for interaction was not significant for both modifiers). CONCLUSIONS: Among an outpatient non-diabetic population with CKD, higher PTH levels were associated with a higher prevalence of the cardiorenal metabolic syndrome. PMID- 22258400 TI - Estimated Glomerular Filtration Rate in Short-Risk Stratification in Acute Myocardial Infarction. AB - BACKGROUND/AIMS: Renal dysfunction is associated with a higher risk of cardiovascular disease in patients with acute myocardial infarction (AMI). The aim of this study was to investigate the independent prognostic value of renal dysfunction and its incremental predictability risk after adjusting for well known clinical factors in patients with AMI. METHODS: 751 consecutive patients with AMI admitted to the Coronary Care Unit (CCU) were included. Patients were grouped into 2 categories according to the baseline estimated glomerular filtration rate (eGFR) on admission (eGFR <60 vs. eGFR ?60 ml/min/1.73 m2). C reactive protein and white blood cell count (WBC) as well as clinical prognostic variables were assessed. The endpoint was mortality during CCU stay. The discriminatory power was estimated by the C-index. RESULTS: The patient group with an eGFR <60 ml/min/1.73 m2 was older, had more cardiovascular risk factors, a lower left ventricular ejection fraction and higher cardiovascular mortality during CCU stay (13 vs. 3%). Logistic regression analysis revealed the following predictors of mortality: degree of renal impairment (eGFR <60 ml/min/1.73 m2), hazard ratio (HR) = 2.2 (95% CI 1.1-4.3; p = 0.028); WBC >11,000 * 106/l, HR = 2.3 (95% CI 1.2-4.5; p = 0.017); Killip class on admission, HR = 3.8 (95% CI 1.7 8.5; p = 0.001), and New York Heart Association Functional Classification, HR = 3.6 (95% CI 1.7-7.4; p = 0.001). The adjusted C-index was 0.78 for baseline clinical variables and 0.84 for eGFR. CONCLUSIONS: In patients with AMI, decreased eGFR is an important prognostic factor for impaired cardiac function and mortality in the short-term follow-up. The eGFR may be reliably used in the risk stratification of patients with AMI. PMID- 22258401 TI - Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia. AB - Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome wide array based study of pre-treatment and relapse samples from patients with B cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies. PMID- 22258402 TI - Beat-to-beat systolic time-interval measurement from heart sounds and ECG. AB - Systolic time intervals are highly correlated to fundamental cardiac functions. Several studies have shown that these measurements have significant diagnostic and prognostic value in heart failure condition and are adequate for long-term patient follow-up and disease management. In this paper, we investigate the feasibility of using heart sound (HS) to accurately measure the opening and closing moments of the aortic heart valve. These moments are crucial to define the main systolic timings of the heart cycle, i.e. pre-ejection period (PEP) and left ventricular ejection time (LVET). We introduce an algorithm for automatic extraction of PEP and LVET using HS and electrocardiogram. PEP is estimated with a Bayesian approach using the signal's instantaneous amplitude and patient specific time intervals between atrio-ventricular valve closure and aortic valve opening. As for LVET, since the aortic valve closure corresponds to the start of the S2 HS component, we base LVET estimation on the detection of the S2 onset. A comparative assessment of the main systolic time intervals is performed using synchronous signal acquisitions of the current gold standard in cardiac time interval measurement, i.e. echocardiography, and HS. The algorithms were evaluated on a healthy population, as well as on a group of subjects with different cardiovascular diseases (CVD). In the healthy group, from a set of 942 heartbeats, the proposed algorithm achieved 7.66 +/- 5.92 ms absolute PEP estimation error. For LVET, the absolute estimation error was 11.39 +/- 8.98 ms. For the CVD population, 404 beats were used, leading to 11.86 +/- 8.30 and 17.51 +/- 17.21 ms absolute PEP and LVET errors, respectively. The results achieved in this study suggest that HS can be used to accurately estimate LVET and PEP. PMID- 22258403 TI - Correlation between low-level expression of the tumor suppressor gene TAp73 and the chemoresistance of human glioma stem cells. AB - OBJECTIVE: Glioma stem cells (GSCs) are regarded as the root of glioma growth and recurrence. Chemoresistance is one of the characteristics of GSCs that increases the difficulties in eradicating the cells by anticancer drugs. PURPOSE: The objective of this study is to investigate the correlation between expression of the tumor suppressor gene TAp73 and the chemoresistance of human GSCs. METHODS: MTT and tumor sphere formation assays were used to analyze the chemoresistance phenotype of GSCs derived from primary human glioma specimens under cisplatin exposure. Reverse transcription real-time PCR was applied for assaying mRNA levels of TAp73. Protein levels of TAp73, p21, Bax, and cleared caspase 3 were assayed by western blot. Cell apoptosis was analyzed by flow cytometry after the annexin V fluorescence staining. RESULTS: GSCs exhibited increased chemoresistance compared to differentiated glioma cells (DGCs) derived from the same tumor specimen. The expression of TAp73 was lower in GSCs and was not sensitive to cisplatin treatment as compared to DGCs. Overexpression of TAp73 by transfection increased the apoptosis of GSCs in the presence of cisplatin and reduced the chemoresistance of GSC. TAp73 knockdown by siRNA in DGCs reduced cisplatin-induced apoptosis and increased the resistance to cisplatin. CONCLUSION: These findings indicate that TAp73 silencing is hallmark of GSC to maintain their chemoresistance phenotype. Thus, targeting TAp73 may provide a novel strategy to eradicating GSCs. PMID- 22258404 TI - ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. AB - B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ~8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells harboring mutant B-RAF. In this study, we show that Bmf is regulated at the post translational level by mutant B-RAF-MEK-ERK2 signaling. Extracellular signal regulated kinase (ERK2) directly phosphorylates Bmf on serine 74 and serine 77 residues with serine 77 being the predominant site. In addition, serine 77 phosphorylation reduces Bmf pro-apoptotic activity likely through a mechanism independent of altering Bmf localization to the mitochondria and/or interactions with dynein light chain 2 and the pro-survival proteins, B-cell lymphoma extra large, Bcl-2 and Mcl-1. These data identify a novel mode of regulation in Bmf that modulates its pro-apoptotic activity in mutant B-RAF tumor cells. PMID- 22258405 TI - Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity. AB - Inflammatory responses mediated by activated microglia play a pivotal role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders. Studies on identification of specific targets to control microglia activation and resultant neurotoxic activity are imperative. Increasing evidence indicate that voltage-gated K(+) (K(v)) channels are involved in the regulation of microglia functionality. In this study, we investigated K(v)1.3 channels in the regulation of neurotoxic activity mediated by HIV-1 glycoprotein 120 (gp120)-stimulated rat microglia. Our results showed treatment of microglia with gp120 increased the expression levels of K(v)1.3 mRNA and protein. In parallel, whole-cell patch-clamp studies revealed that gp120 enhanced microglia K(v)1.3 current, which was blocked by margatoxin, a K(v)1.3 blocker. The association of gp120 enhancement of K(v)1.3 current with microglia neurotoxicity was demonstrated by experimental results that blocking microglia K(v)1.3 attenuated gp120-associated microglia production of neurotoxins and neurotoxicity. Knockdown of K(v)1.3 gene by transfection of microglia with K(v)1.3-siRNA abrogated gp120-associated microglia neurotoxic activity. Further investigation unraveled an involvement of p38 MAPK in gp120 enhancement of microglia K(v)1.3 expression and resultant neurotoxic activity. These results suggest not only a role K(v)1.3 may have in gp120-associated microglia neurotoxic activity, but also a potential target for the development of therapeutic strategies. PMID- 22258406 TI - Altered dynamics of ubiquitin hybrid proteins during tumor cell apoptosis. AB - The ubiquitin hybrid genes Uba80 and Uba52 encode ubiquitin (Ub), which is fused to the ribosomal proteins S27a (RPS27a) and L40 (RPL40), respectively. Here, we show that these genes are preferentially over-expressed during hepatoma cell apoptosis. Experiments using the tet-inducible transgenic system revealed that over-expression of the ubiquitin hybrid genes sensitized the cells to apoptosis. Further analysis suggested that Ub, and not RPS27a or RPL40, was associated with apoptotic cell death. Cleavage-resistant mutation analysis revealed that the N terminal portion and the last two amino acids (GG) of Ub are critical for cleavage at the junction between the two protein moieties. An apoptogenic stimulus enhances the nuclear targeting and aggregation of Ub in the nucleus, resulting in histone H2A deubiquitylation followed by abnormal ubiquitylation of the nuclear envelope and the lamina. These events accompany the apoptotic nuclear morphology in the late stage of apoptosis. Each fused RP is localized in the nucleoli. These results suggest a role for Ub hybrid proteins in the altered nuclear dynamics of Ub during tumor cell apoptosis induced by apoptogenic stimuli. PMID- 22258407 TI - Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity. AB - A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity, and reveal novel targets for the design of stroke therapies. PMID- 22258408 TI - Consumption of oxygen: a mitochondrial-generated progression signal of advanced cancer. AB - Changes in mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced phenotype of cancer; however, detailed mechanisms have not been elucidated. We observed that loss of mitochondrial genome reversibly induced overexpression and activation of proto oncogenic Ras, especially K-Ras 4A, responsible for the activation of AKT and ERK leading to advanced phenotype of prostate and breast cancer. Ras activation was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to induce proteasomal degradation of HMGR. Well differentiated prostate and breast cancer cells with high mitochondrial DNA content consumed a large amount of oxygen and induced hypoxia. Loss of mitochondrial genome reduced oxygen consumption and increased in oxygen concentration in the cells. The hypoxic-to normoxic shift led to the overexpression of HMGR through inhibiting proteasomal degradation. Therefore, reduction of mitochondrial genome content induced overexpression of HMGR through hypoxic to normoxic shift and subsequently the endogenous induction of the mevalonate pathway activated Ras that mediates advanced phenotype. Reduction of mitochondrial genome content was associated with the aggressive phenotype of prostate cancer in vitro cell line model and tissue specimens in vivo. Our results elucidate a coherent mechanism that directly links the mitochondrial genome with the advanced progression of the disease. PMID- 22258409 TI - BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy. AB - Poor data have been previously reported about the mutation rates in K-RAS, BRAF, and PIK3CA genes among patients with hepatocellular carcinoma (HCC). Here we further elucidated the role of these genes in pathogenesis of primary hepatic malignancies. Archival tumour tissue from 65 HCC patients originating from South Italy were screened for mutations in these candidate genes by direct sequencing. Overall, oncogenic mutations were detected in 15 (23%) patients for BRAF gene, 18 (28%) for PIK3CA gene, and 1 (2%) for K-RAS gene. Using statistical analysis, BRAF mutations were significantly correlated with the presence of either multiple HCC nodules (P=0.021) or higher proliferation rates (P=0.034). Although further extensive screenings are awaited in HCC patients among different populations, our findings clearly indicated that mutational activation of both BRAF and PIK3CA genes does contribute to hepatocellular tumorigenesis at somatic level in Southern Italian population. PMID- 22258410 TI - Stem cell gene expression in MRPS18-2-immortalized rat embryonic fibroblasts. AB - We have recently found that primary rat embryonic fibroblasts (REFs) could be immortalized by overexpression of the human mitochondrial ribosomal protein MRPS18-2 (S18-2). A derived cell line, designated 18IM, expressed the embryonic stem cell markers SSEA-1 and Sox2. Upon inoculation into severe combined immunodeficiency mice, 18IM cells differentiated to express pan-keratin. They were not tumorigenic. Here we report the gene profiling of 18IM, compared with REF cells. Pathways involved in oxidative phosphorylation, ubiquinone (Coenzyme Q 10) biosynthesis, fatty acid elongation in mitochondria, PI3K/AKT signaling, a characteristic of rapidly proliferating cells, were upregulated in 18IM. Genes involved in the transcription/translation machinery and redox reactions, like elongation factors, ATP synthases, NADH dehydrogenases, mitogen activated kinases were upregulated as well. 18IM cells produced more pyruvate, indicating enhanced ATP synthesis. The expression of Oct4, Sox2, and Nanog that can contribute to the experimental induction of pluripotency in primary fibroblasts was also elevated, in contrast to Klf4 and C-myc that were downregulated. Subsequently, three new immortalized cell lines were produced by S18-2 overexpression in order to check the representativeness of 18IM. All of them showed anchorage-independent growth pattern. Two of three clones lost vimentin and smooth muscle actin, and expressed Sox2 and Oct4. We suggest that S18-2 is involved in the developmental regulation. PMID- 22258412 TI - Protein conducting channels-mechanisms, structures and applications. AB - In the past decade among the main developments in the field of bionanotechnology is the application of proteins in devices. Research focuses on the modification of enzyme systems by means of chemical and physical tools in order to achieve full control of their function and to employ them for specific tasks. Membrane protein channels are intriguing biological devices as they allow the recognition and passage of a variety of macromolecules through an otherwise impermeable lipid bilayer. Hence, membrane proteins can be used as sensory devices for detection or as molecular nanovalves to allow for the controlled release of molecules. Here, we discuss the structure and function of three different channel proteins that mediate the membrane passage of macromolecules using different mechanisms. These systems are described in a comparative manner and an overview is provided of the technological advances in employing these proteins in external (or human) controllable devices. PMID- 22258411 TI - Selective tumor killing based on specific DNA-damage response deficiencies. AB - Organisms constantly undergo various stresses within their life span, which can damage their DNA. In order to maintain genomic stability and counteract the development of unwanted genomic mutations, organisms have evolved a DNA-damage response (DDR) to protect their genome. Due to the critical roles played by DDR in genomic stability, its defects can lead to cellular transformation and potentially tumorigenesis. Consequently, this also provides the opportunity to specifically target tumor cells due to a weakened ability to tolerate genotoxic stresses. In this lies a treatment strategy in which the inhibition of remaining DDR pathways can hyper-sensitize tumors to chemotherapeutic agents while minimizing deleterious effects to healthy cells. Therefore it is important to understand the genotypic background of specific tumors to determine which DDR pathways remain and can be targeted for inhibition. Tumor therapies based on the DDR are ideal not only as a means of increasing the effectiveness of current chemotherapies but also as a means to selectively target tumor cells while leaving healthy cells unharmed. Thus, targeting DDR components as a means of increasing effectiveness and discrimination of current chemotherapeutic tumor treatments is currently the focus of many studies and clinical trials. PMID- 22258413 TI - Creation of a questionnaire to measure stress among nurses engaged in palliative care on general wards. AB - PURPOSE: This study was conducted to create a questionnaire that measures stress among nurses engaged in palliative care on general wards. METHODS: Nurses with at least 3 years of experience involved in palliative care on a general ward in six facilities in Japan were the subjects from September 7 to October 4, 2004. A draft questionnaire on stress factors and conditions of stress in nurses engaged in end-of-life care was created, and question items and content meaning were revised to produce 32 question items, with a four-point Likert scale for the responses. Two pretests were conducted. Internal validity was investigated and resulted in 31 question items. Factor analysis using the principal factor method (Varimax rotation) was performed, and Cronbach's coefficient alpha was used to evaluate internal consistency and check reliability. RESULTS: The survey response rate was 94%, with a valid response rate of 98%. Analysis was conducted using responses from 269 participants, of whom 98.9% were female, with a mean age of 35.4 years. The mean length of experience as a nurse was 13.6 years, and the mean length of experience in cancer nursing was 8 years. Results of factor analysis produced eigenvalues of 5.260-1.558 and a cumulative proportion of 58.032%. After two items were deleted, six stress-related factors were identified; their alpha coefficients were 0.753 to 0.912, ensuring high reliability. CONCLUSIONS: The questionnaire developed had high internal validity and high reliability, and it can thus serve as a first stage in elucidating stress among nurses engaged in palliative care on general wards. PMID- 22258414 TI - A systematic review of the effectiveness of qigong exercise in supportive cancer care. AB - PURPOSE: Qigong as a complementary and alternative modality of traditional Chinese medicine is often used by cancer patients to manage their symptoms. The aim of this systematic review is to critically evaluate the effectiveness of qigong exercise in cancer care. METHODS: Thirteen databases were searched from their inceptions through November 2010. All controlled clinical trials of qigong exercise among cancer patients were included. The strength of the evidence was evaluated for all included studies using the Oxford Centre for Evidence-based Medicine Levels of Evidence. The validity of randomized controlled trials (RCTs) was also evaluated using the Jadad Scale. RESULTS: Twenty-three studies including eight RCTs and fifteen non-randomized controlled clinical trials (CCTs) were identified. The effects of qigong on physical and psychosocial outcomes were examined in 14 studies and the effects on biomedical outcomes were examined in 15 studies. For physical and psychosocial outcomes, it is difficult to draw a conclusion due to heterogeneity of outcome measures and variability of the results in the included studies. Among reviewed studies on biomedical outcomes, a consistent tendency appears to emerge which suggests that the patients treated with qigong exercise in combination with conventional methods had significant improvement in immune function than the patients treated with conventional methods alone. CONCLUSIONS: Due to high risk of bias and methodological problems in the majority of included studies, it is still too early to draw conclusive statements. Further vigorously designed large-scale RCTs with validated outcome measures are needed. PMID- 22258415 TI - Prepregnancy contraceptive use among teens with unintended pregnancies resulting in live births - Pregnancy Risk Assessment Monitoring System (PRAMS), 2004-2008. AB - Approximately 400,000 teens aged 15-19 years give birth every year in the United States (1), and the teen birth rate remains the highest in the developed world. Teen childbearing is a public health concern because teen mothers are more likely to experience negative social outcomes, including school dropout. In addition, infants of teen mothers are more likely to be low birth weight and have lower academic achievement, and daughters of teen mothers are more likely to become teen mothers themselves. To learn why teens wishing to avoid pregnancy become pregnant, CDC analyzed data from the 2004-2008 Pregnancy Risk Assessment Monitoring System (PRAMS). This report describes estimated rates of self-reported prepregnancy contraceptive use among white, black, and Hispanic teen females aged 15-19 years with unintended pregnancies resulting in live births. Approximately one half (50.1%) of these teens were not using any method of birth control when they got pregnant, and of these, nearly one third (31.4%) believed they could not get pregnant at the time; 21.0% used a highly effective contraceptive method (although less than 1% used one of the most effective methods, such as an intrauterine device [IUD]); 24.2% used the moderately effective method of condoms; and 5.1% used the least effective methods, such as rhythm and withdrawal. To decrease teen birth rates, efforts are needed to reduce or delay the onset of sexual activity, provide factual information about the conditions under which pregnancy can occur, increase teens' motivation and negotiation skills for pregnancy prevention, improve access to contraceptives, and encourage use of more effective contraceptive methods. PMID- 22258416 TI - Hospital-associated measles outbreak - Pennsylvania, March-April 2009. AB - Although endemic measles transmission has been interrupted in the United States, importations of this highly infectious virus continue. On March 28, 2009, a physician notified the Pennsylvania Department of Health (PADOH) of a measles case involving an unvaccinated child. Within 5 days, four additional cases were reported to PADOH and the Allegheny County Health Department. All five infected persons had been in the same hospital emergency department (ED) on March 10; one of them was a physician who worked in the ED. To find the source patient, PADOH reviewed electronic records of patients evaluated in the ED on March 10 for fever and rash. This identified a child who arrived recently from India, was treated for viral exanthema, and discharged. On April 3, PADOH obtained serum from this child and confirmed a diagnosis of measles. After an extensive regional search and investigation of the six patients' 4,000 contacts, no additional cases were identified. The hospital reviewed employee health records to identify any exposed personnel who did not have serologic evidence of measles immunity. Among 168 potentially exposed employees, 72 (43%) had no documented measles immunity, thus requiring serologic testing and subsequent vaccination if they lacked serologic evidence of immunity. This outbreak highlights the potential for measles transmission in health-care settings. To decrease transmission, clinicians should know the signs and symptoms of measles, request travel histories of patients suspected of any infectious disease, and isolate potentially infectious patients. Hospital employees should have documented immunity to measles, and employees without evidence of measles immunity should be offered vaccination in accordance with Advisory Committee on Immunization Practices (ACIP) and Hospital Infection Control Practices Advisory Committee (HICPAC) recommendations. PMID- 22258417 TI - Mercury exposure among household users and nonusers of skin-lightening creams produced in Mexico - California and Virginia, 2010. AB - Mercury exposure has been reported among users of skin-lightening creams produced outside the United States but not among nonusers in their households. Mercury exposure can result in irreversible renal and central nervous system damage or death. In March 2010, coordinators of a health study notified members of a Mexican-American family in California with four study participants that they had elevated blood mercury levels and also notified the local health department, which in turn asked the California Department of Public Health (CDPH) to investigate. CDPH interviewed the four study participants and a fifth household member and identified unlabeled skin-lightening creams with mercury content measured at 2.0%-5.7% by weight as the likely source of mercury exposure. CDPH also interviewed friends of the study participants in California who had used similar skin-lightening products, and the Virginia Department of Health (VDH) interviewed relatives in that state who had used skin-lightening products. In all, investigators in the two states collected information and urine specimens for 22 persons in five households. The results indicated that 15 persons had elevated urinary mercury concentrations, including nine users of the cream (six with nonspecific symptoms) and six nonusers. Mercury vapor concentrations as high as 50 ug/m3 were measured in spot household locations; however, the overall concentration for each room in all five households was <1.0 ug/m3, considered a safe level. Both health departments advised users and the public to stop using these creams and issued clinical health alerts notifying physicians about this potential cause of mercury toxicity. PMID- 22258418 TI - Notes from the field: acute muscular sarcocystosis among returning travelers - Tioman Island, Malaysia, 2011. AB - GeoSentinel (the surveillance program of the International Society of Travel Medicine and CDC) has identified 32 cases of suspected acute muscular sarcocystosis in travelers returning from Tioman Island off the east coast of peninsular Malaysia. All the patients traveled to Tioman Island during the summer of 2011. Within days or weeks of returning home, all experienced fever and muscle pain, often severe and prolonged. All had peripheral eosinophilia, and most had elevated serum creatinine phosphokinase levels. Most were tested for acute trichinosis and toxoplasmosis by serology, and all of these tests were negative. Approximately half of the patients were identified in Germany; others were reported elsewhere in Europe, and in North America and Asia. Muscle biopsy from two patients demonstrated organisms consistent with sarcocystosis, one from a group of five ill travelers and one from a group of three. PMID- 22258419 TI - Pulmonary hypertension in chronic hypersensitivity pneumonitis. AB - BACKGROUND: The purpose of this study was to evaluate the prevalence and outcomes of pulmonary hypertension in chronic hypersensitivity pneumonitis and to examine the relationship between pulmonary function tests and pulmonary hypertension. METHODS: We conducted a retrospective review of 120 patients with hypersensitivity pneumonitis seen at two centers for pulmonary diseases over a 5 year interval and identified patients with chronic hypersensitivity pneumonitis for whom both pulmonary function tests and Doppler echocardiography data were available. RESULTS: Chronic hypersensitivity pneumonitis was identified in 83 patients and Doppler echocardiography data were available for 73 of them. Pulmonary hypertension (sPAP >= 50 mmHg) was detected in 14 patients (19%), and was associated with a greater risk of death (median survival = 23 months vs. 98 months; P=0.003). Patients with pulmonary hypertension were older and had a significantly decreased PaO(2). There was a weak correlation between pulmonary function parameters and the underlying sPAP, with significance for FVC, FEV(1), and PaO(2) and inversely with PaCO(2). CONCLUSIONS: Using Doppler echocardiography for evaluation, pulmonary hypertension seems to be common in patients with chronic hypersensitivity pneumonitis, significantly impacts survival, and correlates with FVC, FEV(1), and PaO(2) and inversely with PaCO(2). PMID- 22258420 TI - Association of gastroesophageal reflux disease symptoms with stable chronic obstructive pulmonary disease. AB - BACKGROUND: Patients with various chronic respiratory diseases have a higher incidence of gastroesophageal reflux disease (GERD)-related symptoms, but the mechanisms of the relationship between GERD symptoms and chronic obstructive pulmonary disease (COPD) remain unclear. The aim of the present study was to explore the association of GERD symptoms with impaired pulmonary function and other factors in patients with COPD. METHODS: Patients with clinically stable COPD were consecutively recruited, and a pulmonary function test, visual analogue scale (VAS), and Reflux Diagnostic Questionnaire (RDQ) were administered. The patients were categorized into GERD-positive and GERD-negative groups according to the RDQ. Univariate and multivariate analyses were performed to evaluate the factors associated with the incidence of GERD symptoms in COPD. RESULTS: A total of 1,486 patients with COPD were enrolled. There was no difference in age, gender proportion, body mass index, tobacco exposure, and the use of respiratory medications between the GERD-positive and GERD-negative groups. The respiratory pattern, the values of forced expiratory volume in 1 s, inspiratory capacity (IC), and residual volume, and VAS scores were significantly different between the groups (all P<0.05). Multivariate logistic regression analysis revealed that the decreased IC (odds ratio (OR) =1.56; 95% CI=1.32-2.27; P<0.001) and increased VAS scores (OR=1.38; 95% CI=1.19-1.68; P=0.011) were independent risk factors of GERD symptoms in patients with COPD. CONCLUSION: The severity of hyperinflation and dyspnea may be important associated risk factors for the incidence of GERD symptoms in patients with clinically stable COPD. PMID- 22258421 TI - Novel grading system for quantifying upper-airway obstruction on sleep endoscopy. AB - BACKGROUND: The aim of this study was to present a novel anatomically comprehensive and clinically applicable system for the quantification of sleep endoscopy findings in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: Fifty-five adult patients with a polysomnographic diagnosis of OSAHS were referred for midazolam-induced sleep endoscopy following failure of continuous positive airway pressure. Five anatomical sites of possible obstruction along the upper airway were documented: nose/nasopharynx (N), uvulopalatine plane (P), tongue base (T), larynx (L), and hypopharynx (H). Each involved site was assigned a severity grade of 1 (partial obstruction) or 2 (complete obstruction). The digits representing the obstruction pattern at each level were then added to yield a severity index (SI). The SI for each patient was determined by two independent observers. Findings were correlated with the respiratory disturbance index (RDI) and body mass index (BMI). RESULTS: The SI was significantly correlated with the RDI (R=0.746, Pearson; P<0.0001) and predicted disease severity with 65% accuracy. There was no association with BMI. By site, the tongue base and hypopharynx were significantly correlated with obstruction severity; obstruction in the tongue base predicted disease severity with a sensitivity of 68.8 and sensitivity of 81.1. CONCLUSION: Our easy-to-use endoscopic grading system provides physicians with an accurate picture of the pattern of the upper-airway system obstruction in patients with obstructive sleep apnea/hypopnea syndrome. It is a promising tool for estimating the location and severity of upper airway disease and may have implications for treatment planning. PMID- 22258422 TI - Editorial: Furthering our understanding of cough. PMID- 22258423 TI - Whole-object fluorescence lifetime setup for efficient non-imaging quantitative intracellular fluorophore measurements. AB - In the present study we introduce a Whole-Object Fluorescence Life Time (wo-FLT) measurement approach for ease and a relatively inexpensive method of tracing alterations in intracellular fluorophore distribution and in the physical chemical features of the microenvironments hosting the fluorophore. Two common fluorophores, Rhodamine 123 and Acridine Orange, were used to stain U937 cells which were incubated, with and without either Carbonyl cyanide 3 chlorphenylhydrazon or the apoptosis inducer H(2)O(2). The wo-FLT, which is a non imaging quantitative measurement, was able to detect several fluorescence decay components and corresponding weights in a single cell resolution. Following cell treatment, both decay time and weight were altered. Results suggest that the prominent factor responsible for these alterations and in some cases to a shift in emission spectrum as well, is the intracellular fluorophore local concentration. In this study it was demonstrated that the proposed wo-FLT method is superior to color fluorescence based imaging in cases where the emission spectrum of a fluorophore remains unchanged during the investigated process. The proposed wo-FLT approach may be of particular importance when direct imaging is impossible. PMID- 22258424 TI - Chagas disease screening among HIV-positive Latin American immigrants: an emerging problem. AB - Chagas disease (CD) is an emergent disease in Europe that can behave as an opportunistic infection in HIV positive patients. The objective of this study was to evaluate the implementation of a CD screening programme in an HIV unit. An immunochromatography (ICT) of Trypanosoma cruzi was performed as a screening tool in HIV-positive patients born in CD endemic countries. ELISA and IFAT were used to confirm the diagnosis. A total of 155 patients, 116 males and 38 females, were included. Mean age was 36.9 years (+/- 8.4) and mean length of stay in Spain at the screening was 7.1 years (+/- 4.7). T. cruzi ICT was positive in four cases (2.6%), being confirmed (by ELISA and IFAT) in three of those (1.9%). Factors associated with confirmed positive T.cruzi serology were: Bolivia origin (p=0.016), Bolivia or Argentina origin (p=0.002), Southern Cone origin (p=0.015), rural origin (p=0.023), previously living in an adobe-made (p=0.001) or thatch roofed house (p<0.0001), having a previous CD test (p=0.015), previous knowledge about CD (p=0.019), about vector (p=0.009) or recorded seeing vectors at home (p=0.012). Units dealing with HIV patients from endemic areas of American trypanosomiasis should implement CD screening protocols. Interviews of patients coming from endemic areas should include CD epidemiological questions. PMID- 22258425 TI - Molecular characterisation of methicillin-sensitive Staphylococcus aureus from deep surgical site infections in orthopaedic patients. AB - Staphylococcus aureus is a leading cause of surgical site infections (SSIs). The association between S. aureus genotypes and the severity of illness is, however, incompletely understood. The aim of the study was to genotype S. aureus isolates from deep SSI in orthopaedic patients to identify molecular markers associated with invasive S. aureus infections. DNA microarray analysis was performed on S. aureus isolates collected from 60 patients with deep SSI following major orthopaedic surgery, while 57 isolates from nasal carriers served as controls. Genes associated with antibiotic resistance, adhesion, immune evasion, tissue invasion and toxin production were detected. The bone sialoprotein-binding protein gene (bbp) was more frequent in isolates from SSI patients compared to nasal carriers (95.0% vs. 82.5%), suggesting a role in invasive disease. No major differences in other molecular virulence markers could be distinguished among isolates from the two clinical groups, suggesting that any S. aureus strain may cause invasive infection. Our study reveals important genotypic information on isolates obtained from deep SSI following orthopaedic procedures. PMID- 22258427 TI - Fully relativistic coupled cluster and DFT study of electric field gradients at Hg in 199Hg compounds. AB - We investigate the magnitude and interplay of relativistic and electron correlation effects on the electric field gradient (EFG) at the position of Hg in linear and bent HgL(2) (L = CH(3), Cl, Br, I) and trigonal planar [HgCl(3)](-) compounds using four-component relativistic Dirac-Coulomb (DC) and non relativistic (NR) calculations at the Hartree-Fock (HF), DFT, MP2 and coupled cluster (CC) levels. The relativistic and electron correlation contributions to EFG have opposite signs and are not additive, demonstrating the importance of taking into account relativistic and electron correlation contributions on an equal footing. DC-MP2 overestimates the electron correlation correction by 0.48 0.56 a.u. for Hg-halides and by 0.8 a.u. for Hg(CH(3))(2), respectively, while DC CCSD underestimates the correlation correction by 0.57-0.66 a.u. compared to the reference DC-CCSD-T data. EFGs obtained at the DC-DFT level vary considerably with the functional; DC-CAMB3LYP and DC-BH&H reproduce DC-CCSD-T results within 0.08-0.24 a.u. (1%-3%) for Hg(CH(3))(2) and Hg-halides, respectively. An updated value of the nuclear quadrupole moment of the I = 5/2 excited state of (199)Hg, Q((199)Hg) = 0.675(12) b is derived from the literature. This value compares well with that derived from our calculated EFG at the DC-CCSD-T level and the experimental data for Hg(CH(3))(2); Q((199)Hg) = 0.650 b. PMID- 22258426 TI - Lack of short-term increase in serum mediators of fibrogenesis and in non invasive markers of liver fibrosis in HIV/hepatitis C virus-coinfected patients starting maraviroc-based antiretroviral therapy. AB - The aim of this study was to analyze serum changes in mediators of fibrogenesis and in non-invasive markers of liver fibrosis among HIV/HCV-coinfected patients starting maraviroc (MVC)-based antiretroviral therapy. Patients included in this prospective pilot study met the following criteria: (1) HIV-infection, (2) detectable serum HCV-RNA, and ((3) started MVC. Transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured in serum samples at baseline and 6 months after starting MVC. AST-to-platelet ratio index (APRI) was assessed at the same time points. Twenty-four patients were analyzed. Median (IQR) serum levels at baseline and after 6 months on MVC of TGF-beta1 were 27,295 (20,562-36,844) and 33,753 (18,973-46,130) pg/mL (p=0.116), of MMP-2 were 216 (186-274) and 241 (194-306) ng/mL (p=0.247), and of TIMP-1 were 237 (170-284) and 216 (171-271) ng/mL (p=0.415). APRI levels were 0.99 (0.53-3.46) at baseline and 0.83 (0.48 2.34) at 6 months (p=0.16). Serum mediators of liver fibrogenesis and fibrosis do not change significantly in HIV/HCV-coinfected patients in the short-term after starting MVC. As TGF-beta1 levels have been shown to increase over time in HCV infection and liver fibrosis worsens rapidly in HIV/HCV coinfection, these parameters seem to evolve in a different way in MVC-treated patients. PMID- 22258428 TI - Seed bank persistence of genetically modified canola in California. AB - INTRODUCTION: Canola, which is genetically modified (GM) for tolerance to glyphosate, has the potential to become established as a new glyphosate resistant weed, thus reducing the effectiveness of glyphosate. METHODS: Volunteer from dormant canola seeds produced thousands of plants per hectare in the fourth year (2011) following a 2007 crop harvest. This occurred with no additional canola seed production since the 2007 harvest. RESULTS: Volunteer plants following harvests of annual crops are typically only a problem for the first year after harvest. In California, glyphosate is the core herbicide on over a million hectares of high value row, tree, and vine crops and new glyphosate resistant weeds reduce the effectiveness of glyphosate. CONCLUSIONS: The combination of dormant seed and herbicide resistance makes GM glyphosate-resistant canola a new and difficult California weed which was first observed in the winter of 2009. PMID- 22258429 TI - Groundwater flow and contaminant transport modeling applications in urban area: scopes and limitations. AB - BACKGROUND: A three-dimensional groundwater flow model was used to evaluate the groundwater potential and assess the effects of groundwater withdrawal on the regional water level and flow direction in the central Beijing area. A program of groundwater modeling aimed at estimating current contaminant fluxes to the central area and site streams via groundwater was developed. RESULTS AND DISCUSSION: The conceptual model developed for the site attempted to incorporate a complex stratigraphic profile in which groundwater flow and contaminant transport is strongly controlled by a shallow aquifer. Here, a conceptual model for groundwater flow and contaminant transport in central Beijing is presented. CONCLUSION: Model simulations indicated that a sharp drop in the hydraulic head occurs at the center of the model area, which generates a cone of depression and a continuous decline of head with respect to time as a result of heavy groundwater abstraction. PMID- 22258430 TI - Visual sensitivity loss in the central 30 degrees of visual field is associated with diabetic peripheral neuropathy. AB - AIMS/HYPOTHESIS: Impaired central vision has been shown to predict diabetic peripheral neuropathy (DPN). Several studies have demonstrated diffuse retinal neurodegenerative changes in diabetic patients prior to retinopathy development, raising the prospect that non-central vision may also be compromised by primary neural damage. We hypothesise that type 2 diabetic patients with DPN exhibit visual sensitivity loss in a distinctive pattern across the visual field, compared with a control group of type 2 diabetic patients without DPN. METHODS: Increment light sensitivity was measured by standard perimetry in the central 30 degrees of visual field for two age-matched groups of type 2 diabetic patients, with and without neuropathy (n = 40/30). Neuropathy status was assigned using the neuropathy disability score. Mean visual sensitivity values were calculated globally, for each quadrant and for three eccentricities (0-10 degrees , 11-20 degrees and 21-30 degrees ). Data were analysed using a generalised additive mixed model (GAMM). RESULTS: Global and quadrant between-group visual sensitivity mean differences were marginally but consistently lower (by about 1 dB) in the neuropathy cohort compared with controls. Between-group mean differences increased from 0.36 to 1.81 dB with increasing eccentricity. GAMM analysis, after adjustment for age, showed these differences to be significant beyond 15 degrees eccentricity and monotonically increasing. Retinopathy levels and disease duration were not significant factors within the model (p = 0.90). CONCLUSIONS/INTERPRETATION: Visual sensitivity reduces disproportionately with increasing eccentricity in type 2 diabetic patients with peripheral neuropathy. This sensitivity reduction within the central 30 degrees of visual field may be indicative of more consequential loss in the far periphery. PMID- 22258431 TI - Do infants have a sense of fairness? AB - Two experiments examined infants' expectations about how an experimenter should distribute resources and rewards to other individuals. In Experiment 1, 19-month olds expected an experimenter to divide two items equally, as opposed to unequally, between two individuals. The infants held no particular expectation when the individuals were replaced with inanimate objects, or when the experimenter simply removed covers in front of the individuals to reveal the items (instead of distributing them). In Experiment 2, 21-month-olds expected an experimenter to give a reward to each of two individuals when both had worked to complete an assigned chore, but not when one of the individuals had done all the work while the other played. The infants held this expectation only when the experimenter could determine through visual inspection who had worked and who had not. Together, these results provide converging evidence that infants in the 2nd year of life already possess context-sensitive expectations relevant to fairness. PMID- 22258432 TI - Overcoming the negative consequences of interference from recognition memory testing. AB - Theories of why humans forget have been challenged by the newly discovered list length/output-interference paradox, in which--under certain testing conditions- learning is not harmed by the amount of verbal material studied, whereas retrieval of that material becomes more difficult with increases in the number of items tested. The latter finding is known as output interference, and the results of the experiment reported here indicate that a release from output interference is obtained when the nature of the items is changed during testing. Specifically, when participants are asked to recognize items from two categories, output interference is minimized when items from each category are tested separately in large blocks. This finding supports models of forgetting that assume interference arises from information about the to-be-learned material that is stored in memory; in contrast, this finding is difficult to explain using models that assume forgetting is the result only of changing context. PMID- 22258433 TI - Heterogeneous rates of molecular evolution among cryptic species of the ciliate morphospecies Chilodonella uncinata. AB - While molecular analyses have provided insight into the phylogeny of ciliates, the few studies assessing intraspecific variation have largely relied on just a single locus [e.g., nuclear small subunit rDNA (nSSU-rDNA) or mitochondrial cytochrome oxidase I]. In this study, we characterize the diversity of several nuclear protein-coding genes plus both nSSU-rDNA and mitochondrial small subunit rDNA (mtSSU-rDNA) of five isolates of the ciliate morphospecies Chilodonella uncinata. Although these isolates have nearly identical nSSU-rDNA sequences, they differ by up to 8.0% in mtSSU-rDNA. Comparative analyses of all loci, including beta-tubulin paralogs, indicate a lack of recombination between strains, demonstrating that the morphospecies C. uncinata consists of multiple cryptic species. Further, there is considerable variation in substitution rates among loci as some protein-coding domains are nearly identical between isolates, while others differ by up to 13.2% at the amino acid level. Combining insights on macronuclear variation among isolates, the focus of this study, with published data from the micronucleus of two of these isolates, indicates that C. uncinata lineages are able to maintain both highly divergent and highly conserved genes within a rapidly evolving germline genome. PMID- 22258434 TI - Risk factors for hepatocellular carcinoma in patients with chronic liver disease: a case-control study. AB - The majority of data on risk factors (RFs) for hepatocellular carcinoma (HCC) comes from studies involving populations without underlying liver disease. It is important to evaluate RFs for HCC in patients with chronic liver disease since HCC rarely occurs in those without underlying liver disease. We conducted a hospital-based case-control study of 259 incident HCC cases and 781 controls by convenience sampling between 02/2001 and 12/2009 from the liver clinic at Stanford University Medical Center. The study population was 41% White, 14% Hispanic, 3% African American, 40% Asian American, and 2% other race/ethnicity. RFs were examined through medical records and an in-person questionnaire. Alcohol and tobacco use was calculated by cumulative grams of alcohol or cumulative pack(s) of cigarette consumed over one's lifetime. Diabetes mellitus (DM) was defined by random glucose level of >=200 mg/dL. RFs were evaluated using multivariate logistic regression. Independent predictors of HCC risk, after mutual adjustment and additional control for alcohol use, etiology of liver diseases, and DM, included age >40 (OR = 8.5 [2.6-28.3]), male gender (OR = 3.5 [2.2-5.8]), presence of cirrhosis (OR = 2.8 [1.6-4.9]), Asian ethnicity (OR = 2.8 [1.8-4.6]), AFP > 50 (OR = 4.2 [2.6-6.8]), and cumulative lifetime tobacco use of >11,000 packs (OR = 1.7 [1.0-2.9]). Heavy prolonged cigarette smoking, but not alcohol use, was a significant independent predictor for HCC in patients with underlying liver disease. Besides older age, male gender, presence of cirrhosis, and elevated AFP, Asian ethnicity and heavy cumulative tobacco use are strong independent predictors of HCC. PMID- 22258435 TI - Evidence-based psychotherapies for preschool children with psychiatric disorders. AB - The field of child and adolescent psychiatry is increasingly aware of the existence of psychiatric disorders in preschool-aged children. Concomitantly, there has been a greater understanding of both the effects of parenting on development as well as how a child's brain is shaped by the environment. There has also been a strong trend toward the use of time-limited, evidence-based therapies in adults and school-aged children, but evidence has been limited regarding the use of interventions to treat psychiatric disorders in preschoolers. In recent years, multiple research groups have worked to create effective psychotherapies for use with preschool populations, and there are also novel applications of existing psychotherapies. This review examines the latest evidence-based psychotherapies that treat preschool children with psychiatric disorders. PMID- 22258436 TI - Macrocephaly-capillary malformation: a report of four Chinese patients and literature review. AB - We report a series of four patients with macrocephaly-capillary malformation (M CM) who are the first ever reported M-CM patients among Chinese individuals. The salient clinical features and recent diagnostic criteria are discussed. M-CM is a multisystem disease characterized by macrocephaly and cutaneous vascular malformation. Neurodevelopmental abnormalities such as developmental delay, structural brain malformation, and hydrocephalus are common, and thus vigilant clinical and neuroradiological assessment is essential during the first few years of life. Cardiac and tumour surveillance would also be beneficial in selected cases. PMID- 22258437 TI - Full structural and electrochemical characterization of Li2Ti6O13 as anode for Li ion batteries. AB - A detailed structural and electrochemical study of the ion exchanged Li(2)Ti(6)O(13) titanate as a new anode for Li-ion batteries is presented. Subtle structural differences between the parent Na(2)Ti(6)O(13), where Na is in an eightfold coordinated site, and the Li-derivative, where Li is fourfold coordinated, determine important differences in the electrochemical behaviour. While the Li insertion in Na(2)Ti(6)O(13) proceeds reversibly the reaction of lithium with Li(2)Ti(6)O(13) is accompanied by an irreversible phase transformation after the first discharge. Interestingly, this new phase undergoes reversible Li insertion reaction developing a capacity of 170 mAh g(-1) at an average voltage of 1.7 V vs. Li(+)/Li. Compared with other titanates this result is promising to develop a new anode material for lithium ion rechargeable batteries. Neutron powder diffraction revealed that Na in Na(2)Ti(6)O(13) and Li in Li(2)Ti(6)O(13) obtained by Na/Li ion exchange at 325 degrees C occupy different tunnel sites within the basically same (Ti(6)O(13))(2-) framework. On the other hand, electrochemical performance of Li(2)Ti(6)O(13) itself and the phase released after the first full discharge is strongly affected by the synthesis temperature. For example, heating Li(2)Ti(6)O(13) at 350 degrees C produces a drastic decrease of the reversible capacity of the phase obtained after full discharge, from 170 mAh g(-1) to ca. 90 mAh g(-1). This latter value has been reported for Li(2)Ti(6)O(13) prepared by ion exchange at higher temperature. PMID- 22258438 TI - [A neonate without claviculae]. AB - A 1-week-old girl, term born after a non-complicated parturition, presented with abnormal clavicles. At physical examination small and short clavicles were seen, as well as a widened anterior and posterior fontanelle. An X-ray of the thorax showed hypoplastic clavicles and an X-ray of the skull showed delayed ossification of the bones, hypoplasia of the maxilla and extra teeth. This led to the diagnosis 'cleidocranial dysplasia'. PMID- 22258439 TI - [Home mechanical ventilation in the Netherlands]. AB - Over the last 20 years the number of Dutch patients on home mechanical ventilation has increased from 200 to 2000. Home mechanical ventilation is a cost effective treatment which significantly improves the quality of life of patients. In 2011 83% of patients on home mechanical ventilation in the Netherlands is living at home. In the future further growth can be expected in the number of patients with obesity hypoventilation syndrome and a potential new group of patients with COPD. Strict conditions are necessary to ensure safety in the complex care that home mechanical ventilation entails. PMID- 22258440 TI - [Micro-incision transconjunctival vitrectomy--a safe alternative for conventional vitrectomy]. AB - A vitrectomy is an operation in which the vitreous gel is removed for the treatment of various eye disorders. In the last years new methods have been introduced with the incisions becoming smaller, resulting in a shorter operation time and less trauma to the eye. The newer transconjunctival 23-gauge (G) and 25G vitrectomies are especially suitable for treating less complex vitreo-retinal defects such as epiretinal macular membranes and vitreous haemorrhage. The conventional 20G vitrectomy is, however, the treatment of choice for complex ophthalmic defects such as extensive traction membranes and removal of lens fragments after complicated cataract surgery. PMID- 22258441 TI - [Indications for palliative sedation]. AB - Two male patients, aged 75 and 47 years, suffered from dyspnoea in the terminal phase of their disease, COPD and lung cancer, respectively. Both were given palliative sedation. The palliative consultation team was consulted when problems occurred. Although the Royal Dutch Medical Association issued a guideline on palliative sedation, the practice of administering palliative sedation is still complicated. Determining whether a symptom is 'refractory' and estimating the life expectancy is especially complex. A symptom is refractory when it causes unbearable suffering and conventional modes of treatment are not effective or timely. Knowledge of this guideline, early anticipation of possible scenarios and communication with the patient and his family contribute to good care. The palliative consultation team can help physicians with these decisions, preferably by starting at an early stage. PMID- 22258442 TI - [Cardiorespiratory events after first immunization in premature infants: a prospective cohort study]. AB - OBJECTIVE: To investigate whether all preterm infants born before 33 weeks of gestation need cardiorespiratory monitoring due to the risk of cardiorespiratory disturbances following their first vaccination at 2 months of age. DESIGN: A prospective observational cohort study. METHOD: During a period lasting a little over a year, all preterm infants who were being cared for at the neonatal ward of Medical Centre Alkmaar because they had been born before 33 weeks of gestation received their first immunization at the age of 2 months and were subsequently monitored. Infants who had already been discharged by that time were readmitted for this purpose. RESULTS: In this cohort of 41 premature infants whose mean gestational age was 30.8 weeks (SD: 1.9), 10 of these had a mild decrease in oxygen saturation or bradycardia; three developed a moderate cardiorespiratory event requiring tactile stimulation. The incidence of disturbances was higher in younger and lower-weight infants and those who had experienced more severe morbidity during the neonatal phase. Moderate disturbances only occurred in the infants who had not yet been discharged from hospital after birth. CONCLUSION: It is recommended that still-hospitalized premature infants receive their first immunizations under cardiorespiratory monitoring, as events were observed during a period of 0-24 hours thereafter. In premature infants who had already been discharged - mainly because they were less premature or dysmature - immunization without cardiorespiratory monitoring appeared to be safe. Further research is needed for substantiating this strategy. PMID- 22258443 TI - [Involuntary admission of addict during early pregnancy]. AB - A 30-year-old cocaine-dependent woman was 16 weeks pregnant. Because of possible endangerment of the fetus, an involuntary provisional admission was authorized. Of particular interest is the application of the Dutch Act on Formal Admissions to Psychiatric Hospitals for the primary diagnosis 'addiction' and the fact that the fetus was regarded as a legal 'other'. In severe cases of addiction combined with pregnancy an earlier intervention is needed and arrangement of accelerated legal custody of the newborn before birth should be considered. For the protection of the unborn, we advocate a stricter application of the United Nations Convention on the Rights of the Child. Information for addicted women with preconception counselling can help prevent a compulsory admission. PMID- 22258444 TI - [Health Council of the Netherlands underestimates interactions in undernutrition in the elderly]. AB - The Health Council of the Netherlands has recently published a report on undernutrition in the elderly. Undernutrition is a huge problem associated with negative health outcomes, especially in the frail elderly. Although its review of the recent literature is useful, the report does not contribute anything to clinical practice. The point is that evidence for firm conclusions is still lacking, and that most of all more research is needed to really define undernutrition and that RCTs in homogeneous groups of elderly should yield evidence on the most effective treatment strategies in the different populations in old age. This reductionist viewpoint neglects the fact that undernutrition in the elderly is a geriatric syndrome, which is mainly explained by multifactorial aetiology. Therefore, the only way forward is to study and treat undernutrition in older adults by using a broad geriatric perspective, without aiming for the holy grail of the single best evidenced definition or treatment. PMID- 22258445 TI - Cooperative bird differentiates between the calls of different individuals, even when vocalizations were from completely unfamiliar individuals. AB - Hypotheses proposed to explain the evolution of cooperative behaviour typically require differentiation between either groups of conspecifics (e.g. kin/non-kin) or, more typically, individuals (e.g. reciprocal altruism). Despite this, the mechanisms that facilitate individual or class recognition have rarely been explored in cooperative species. This study examines the individual differentiation abilities of noisy miners (Manorina melanocephala), a species with one of the most complex avian societies known. Miners permanently occupy colonies numbering into hundreds of individuals. Within these colonies, cooperative coalitions form on a fission-fusion basis across numerous contexts, from social foraging through to mobbing predators. Birds often use individually distinctive 'chur' calls to recruit others to a caller's location, facilitating coalition formation. I used the habituation-discrimination paradigm to test the ability of miners to differentiate between the chur calls of two individuals that were both either: (i) familiar, or (ii) unfamiliar to the focal subject. This technique had not, to my knowledge, been used to assess vocalization differentiation in cooperative birds previously, but here demonstrated that miners could correctly use the spectral features of signals to differentiate between the vocalizations of different individuals, regardless of their familiarity. By attending to individual differences in recruitment calls, miners have a communication system that is capable of accommodating even the most complex cooperative hypotheses based upon acoustic information. PMID- 22258446 TI - Environment drives high phylogenetic turnover among oceanic bacterial communities. AB - Although environmental filtering has been observed to influence the biodiversity patterns of marine bacterial communities, it was restricted to the regional scale and to the species level, leaving the main drivers unknown at large biogeographic scales and higher taxonomic levels. Bacterial communities with different species compositions may nevertheless share phylogenetic lineages, and phylogenetic turnover (PT) among those communities may be surprisingly low along any biogeographic or environmental gradient. Here, we investigated the relative influence of environmental filtering and geographical distance on the PT between marine bacterial communities living more than 8000 km apart in contrasted abiotic conditions. PT was high between communities and was more structured by local environmental factors than by geographical distance, suggesting the predominance of a lineage filtering process. Strong phenotype-environment mismatches observed in the ocean may surpass high connectivity between marine microbial communities. PMID- 22258447 TI - Snake modulates constriction in response to prey's heartbeat. AB - Many species of snakes use constriction-the act of applying pressure via loops of their trunk-to subdue and kill their prey. Constriction is costly and snakes must therefore constrict their prey just long enough to ensure death. However, it remains unknown how snakes determine when their prey is dead. Here, we demonstrate that boas (Boa constrictor) have the remarkable ability to detect a heartbeat in their prey and, based on this signal, modify the pressure and duration of constriction accordingly. We monitored pressure generated by snakes as they struck and constricted warm cadaveric rats instrumented with a simulated heart. Snakes responded to the beating heart by constricting longer and with greater total pressure than when constricting rats with no heartbeat. When the heart was stopped midway through the constriction, snakes abandoned constriction shortly after the heartbeat ceased. Furthermore, snakes naive to live prey also responded to the simulated heart, suggesting that this behaviour is at least partly innate. These results are an example of how snakes integrate physiological cues from their prey to modulate a complex and ancient behavioural pattern. PMID- 22258448 TI - Is more better? Polyploidy and parasite resistance. AB - Ploidy-level variation is common and can drastically affect organismal fitness. We focus on the potential consequences of this variation for parasite resistance. First, we elucidate connections between ploidy variation and key factors determining resistance, including allelic diversity, gene expression and physiological condition. We then argue that systems featuring both natural and artificially manipulated ploidy variation should be used to evaluate whether ploidy level influences host-parasite interactions. PMID- 22258449 TI - Cooperation among germinating spores facilitates the growth of the fungus, Neurospora crassa. AB - Fusions between individuals are a common feature of organisms with modular, indeterminate life forms, including plants, marine invertebrates and fungi. The consequences of fusion for an individual fungus are poorly understood. We used wild-type and fusion mutant strains of the genetic model Neurospora crassa to chronicle the fitness in two different laboratory habitats, and in each experiment started colonies from multiple different densities of asexual spores. On round Petri dishes, fusion enabled wild-type colonies to grow larger than mutant (soft) colonies; but in linear 'race tubes', the soft mutant always grew more quickly than the wild-type. Starting a colony with more spores always provided an advantage to a wild-type colony, but was more often neutral or a cost to the soft mutant. The ability to fuse does not provide a consistent advantage to wild-type colonies; net benefits are shaped by both habitat and initial spore densities. PMID- 22258451 TI - ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. AB - ATR kinase activates the S-phase checkpoint when replication forks stall at sites of DNA damage. This event also causes phosphorylation of the Fanconi anemia (FA) protein FANCI, triggering its monoubiquitination of the key DNA repair factor FANCD2 by the FA core E3 ligase complex, thereby promoting this central pathway of DNA repair which permits replication to be restarted. However, the interplay between ATR and the FA pathway has been unclear. In this study, we present evidence that their action is directly linked, gaining insights into this relationship in a DT40 mutant cell line that is conditionally deficient in the critical ATR-binding partner protein ATRIP. Using this system, we showed that ATRIP was crucial for DNA damage-induced FANCD2 monoubiquitination and FANCI phosphorylation. ATR kinase phosphorylated recombinant FANCI protein in vitro, which was facilitated by the presence of FANCD2. Mechanistic investigations revealed that the RPA region but not the TopBP1 region of ATRIP was required for FANCD2 monoubiquitination, whereas Chk1 phosphorylation relied upon both domains. Together, our findings identify ATR as the kinase responsible for activating the FA pathway of DNA repair. PMID- 22258450 TI - Colonic epithelial response to injury requires Myd88 signaling in myeloid cells. AB - Proper colonic injury response requires myeloid-derived cells and Toll-like receptor/Myd88 signaling. However, the precise role of Myd88 signaling specifically in myeloid-derived cells that occurs during tissue damage is unclear. Therefore, we created a mouse line with Myd88 expression restricted to myeloid lineages (Myd88(-/-); LysM(Cre/+); ROSA26(Myd88/+); herein Mlcr). In these mice, Myd88 was appropriately expressed and mediated responses to bacterial ligand exposure in targeted cells. Importantly, the severe colonic epithelial phenotype observed in dextran sodium sulfate-injured Myd88(-/-) mice was rescued by the genetic modification of Mlcr mice. During injury, myeloid cell activation and enrichment of Ptsg2-expressing stromal cells occurred within the mesenchyme that surrounded the crypt bases of Mlcr and Myd88(+/-) mice but not Myd88(-/-) mice. Interestingly, these cellular changes to the crypt base mesenchyme also occurred, but to a lesser extent in uninjured Mlcr mice. These results show that Myd88 expression in myeloid cells was sufficient to rescue intestinal injury responses, and surprisingly, these cells appear to require an additional Myd88 dependent signal from a non-myeloid cell type during homeostasis. PMID- 22258452 TI - Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression. AB - Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Curcumin cooperated in vivo with androgen deprivation as indicated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and histone modification in prostate cancer, thus setting the stage for further development of curcumin as a novel agent to target AR signaling. PMID- 22258453 TI - Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. AB - Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs. PMID- 22258454 TI - Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. AB - Natural killer (NK) cells play a key role in tumor immune surveillance. However, adoptive immunotherapy protocols using NK cells have shown limited clinical efficacy to date, possibly due to tumor escape mechanisms that inhibit NK cell function. In this study, we analyzed the effect of coculturing melanoma cells and NK cells on their phenotype and function. We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cell-mediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2). Together, our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression. PMID- 22258455 TI - Erythrocyte deformability in naive HIV-infected patients. AB - HIV-infected patients are at increased cardiovascular risk. Although several studies have analyzed the hemorheological profile in these patients, studies dealing with erythrocyte deformability are scarce. Moreover, studies have been performed in HIV patients on antiretroviral treatment which may influence this rheological parameter. We analyzed erythrocyte deformability (Elongation Index) at 12, 30 and 60 Pa by means of the Rheodyn SSD in 34 naive HIV-infected patients (22 males and 12 females) and 34 HIV negative control subjects (24 males and 10 females). Erythrocyte indices (MCV, MCH, MCHC), reticulocytes, plasma lipids, iron, folic acid, vitamin B12 and hepatic enzymes were also determined. When compared with controls, naive HIV-infected patients showed lower total cholesterol, iron, bilirubin and folic acid (p = 0.009, p = 0.003, p = 0.004, p = 0.004, respectively) and higher triglycerides (TG), aspartate aminotransferase (AST) and gamma glutamyl transferase (gammaGt) levels (p = 0.017, p = 0.042, p = 0.004, respectively). In the multivariate regression analysis, MCV, gammaGt and triglycerides were independent predictors of EI60. Neither erythrocyte indices nor reticulocyte count showed differences (p > 0.05). No differences in the Elongation Index at any of the shear stresses tested (12, 30, 60 Pa) were found (p > 0.05). The results of the present study indicate that naive HIV-infected patients not on antiretroviral treatment do not present decreased erythrocyte deformability when compared with HIV negative control subjects. PMID- 22258456 TI - Interferon-gamma induced nitric oxide-mediated apoptosis of anemia of chronic disease in rheumatoid arthritis. AB - Proinflammatory cytokines play a role in the pathogenesis of anemia of chronic disease (ACD), which is a common cause of anemia in rheumatoid arthritis (RA). Anemia in RA is associated with increased apoptosis of erythroid cells. However, there is unclear information on the mechanism of ACD in the disease. The purpose of this study is to investigate the role of cytokines on nitric oxide-mediated apoptosis in erythroid progenitor cells of ACD in RA patients. Erythroid progenitor cells from healthy subjects and RA patients with ACD were treated with cytokines like interleukin-1beta, tumor necrosis factor-alpha, and interferon gamma at concentrations of 2, 20, and 40 ng/ml for 14 days. Cell viability and cell apoptosis were analyzed by trypan blue staining and flow cytometry, respectively. The results showed that the highest effect of cytokines on reduction cell viability and induction cell apoptosis was found in 20 ng/ml IFN gamma-treated cells of RA patients. In addition, IFN-gamma showed significantly increased nitric oxide production and iNOS mRNA expression, which was measured by Griess assay and real-time PCR, respectively. The percentage of cell apoptosis and NO production was reduced after an inducible nitric oxide synthase inhibitor, SMT, treatment. In conclusion, IFN-gamma could induce nitric oxide production mediated apoptosis process, which might be involved in the pathogenesis of ACD in RA patients. PMID- 22258457 TI - Clinico-pathological correlation of non specific inflammation in bowel histology with joint manifestation in a tertiary center in South India. AB - The aim of our study was to determine whether the pattern of arthropathy in patients with suspected enteropathic arthritis bore any relation to their gut histology and specifically to chronic nonspecific gut inflammation. Records of 39 patients with suspected enteropathic arthritis from rheumatology clinic between January 2006 and December 2008 who had undergone ileocolonoscopic biopsy were analyzed retrospectively. Patients were grouped into 3 categories, namely those with normal bowel histology, those with mild nonspecific chronic changes, and those with histology suggestive of inflammatory bowel disease. Patients with nonspecific chronic gut inflammation had higher occurrence of axial involvement with or without peripheral articular involvement as compared to those with normal gut histology (8/9 vs. 10/21, P = 0.049), and this pattern was similar to that in patients with IBD. Wrist joint involvement was more common in patients with normal bowel histology (12/21) than the other two groups (P = 0.003). All groups had fared well on follow up while taking treatment with sulphasalazine and methotrexate. PMID- 22258459 TI - The Heart and the Kidneys: Partners in Disease. PMID- 22258458 TI - Histopathology of chondronecrosis development in knee articular cartilage in a rat model of Kashin-Beck disease using T-2 toxin and selenium deficiency conditions. AB - The objective of this study is to observe pathogenic lesions of joint cartilages in rats fed with T-2 toxin under a selenium deficiency nutrition status in order to determine possible etiological factors causing Kashin-Beck disease (KBD). Sprague-Dawley rats were fed selenium-deficient or control diets for 4 weeks prior to their being exposed to T-2 toxin. Six dietary groups were formed and studied 4 weeks later, i.e., controls, selenium-deficient, low T-2 toxin, high T 2 toxin, selenium-deficient diet plus low T-2 toxin, and selenium-deficient diet plus high T-2 toxin. Selenium deficiencies were confirmed by the determination of glutathione peroxidase activity and selenium levels in serum. The morphology and pathology (chondronecrosis) of knee joint cartilage of experimental rats were observed using light microscopy and the expression of proteoglycans was determined by histochemical staining. Chondronecrosis in deep zone of articular cartilage of knee joints was seen in both the low and high T-2 toxin plus selenium-deficient diet groups, these chondronecrotic lesions being very similar to chondronecrosis observed in human KBD. However, the chondronecrosis observed in the rat epiphyseal growth plates of animals treated with T-2 toxin alone or T 2 toxin plus selenium-deficient diets were not similar to that found in human KBD. Our results indicate that the rat can be used as a suitable animal model for studying etiological factors contributing to the pathogenesis (chondronecrosis) observed in human KBD. However, those changes seen in epiphyseal growth plate differ from those seen in human KBD probably because of the absence of growth plate closure in the rat. PMID- 22258460 TI - The Cardiorenal Syndrome: Basis and Common Ground for a Multidisciplinary Patient Oriented Therapy. PMID- 22258461 TI - The Role of Overweight and Obesity in the Cardiorenal Syndrome. AB - The presence of a group of interactive maladaptive factors including hypertension, insulin resistance, metabolic dyslipidemia, obesity, microalbuminuria, and/or reduced renal function constitute the cardiorenal metabolic syndrome (CRS). Overweight, obesity, and chronic kidney disease (CKD) have grown to pandemic proportions in industrialized countries during the past decade. The fact that these interactive factors promote heart and renal disease has been documented in large population-based studies. Obesity seems to be the driving force behind the development of heart disease and CKD and therefore the CRS. The relationship between overweight/obesity and kidney disease begins in early childhood and appears to be related to overconsumption of high-fructose corn syrup and insufficient physical activity. Today, 13 million children are obese, and over 70% of these children are likely to become obese adults. Indeed, approximately 30% of male and 34% of female adults in the United States are obese. This lifestyle-related epidemic will be a major societal medical and economic problem that will accentuate the current epidemic of CKD in the United States and other industrialized and emerging industrialized countries. In this article, we will review the potential mechanisms by which obesity and other metabolic abnormalities interact to promote heart and progressive kidney disease. PMID- 22258462 TI - Cardiorenal Syndrome: The Clinical Cardiologists' Perspective. AB - The term cardiorenal syndrome has evolved over the years. The understanding of the interactions between these two organ systems has led to better recognition and treatment strategies. As cardiovascular mortality is high in individuals with renal dysfunction, it is imperative to understand the pathophysiology behind the disease process. This knowledge may better serve these patients with this syndrome and improve their outcomes. In this review, we examine the key issues of the cardiorenal syndrome from a cardiologist's perspective. PMID- 22258463 TI - Overnutrition and the Cardiorenal Syndrome: Use of a Rodent Model to Examine Mechanisms. AB - Obesity has reached epidemic proportions with far-reaching health care and economic implications. Overnutrition, characterized by excess intake of carbohydrates and fats, has been associated with end-organ damage in several tissues, including the heart and the kidney. Furthermore, overnutrition is one of the most important modifiable and preventable causes of morbidity and mortality associated with cardiovascular and kidney diseases. Insulin resistance and compensatory hyperinsulinemia as well as associated mechanisms, including enhanced renin-angiotensin-aldosterone system activity, inflammation, and oxidative stress, have been implicated in obesity-related cardiorenal injury. In this review, the effect of overnutrition on heart and kidney disease is assessed in a rodent model of overnutrition and obesity, the Zucker obese rat. PMID- 22258464 TI - Effects of Chronic Antagonism of Endocannabinoid-1 Receptors on Glucose Tolerance and Insulin Action in Skeletal Muscles of Lean and Obese Zucker Rats. AB - BACKGROUND/AIMS: Antagonism of the endocannabinoid receptor-1 (CB1R) directly improves whole-body metabolic parameters of insulin resistance. The present investigation determined the effects of chronic CB1R antagonism on whole-body and skeletal-muscle insulin action in insulin-sensitive lean and insulin-resistant obese Zucker rats. METHODS: Animals were either fed ad libitum or in pairs, or treated with SR141716 (10 mg/kg i.p. for 14 days). RESULTS: Food intake was significantly reduced (p < 0.05) after initial SR141716 treatment and remained decreased in both lean and obese animals until day 13. Fasting plasma glucose decreased (24%) and insulin increased (43%) in lean SR141716-treated (24%) rats compared to lean ad libitum-fed controls, but not in the corresponding obese groups. Fasting plasma free fatty acids were reduced by CB1R antagonism in lean (21%) and obese (42%) animals. Whole-body insulin sensitivity was increased (36%) in obese SR141716-treated rats compared to obese ad libitum-fed controls, which was associated with reduced insulin secretion during an oral glucose tolerance test. Insulin-stimulated glucose transport activity in the soleus was greatest in the respective SR141716-treated lean and obese groups compared to the corresponding ad libitum- and pair-fed controls. Chronic SR141716 treatment did not induce alterations in signaling factors associated with the regulation of glucose transport [protein kinase B (Akt), glycogen synthase kinase-3beta, 5'-AMP dependent protein kinase, or p38 mitogen-activated protein kinase] in the soleus. CONCLUSIONS: These results indicate that, while the chronic treatment with CB1R antagonism markedly diminished food intake in lean and obese Zucker rats, there are also significant metabolic improvements in whole-body and skeletal-muscle insulin action mediated by CB1R antagonism through mechanisms independent of reduced caloric intake. PMID- 22258465 TI - Diabetic Cardiovascular Disease Predicts Chronic Kidney Disease Awareness in the Kidney Early Evaluation Program. AB - AIMS: Lack of chronic kidney disease (CKD) awareness is common. Recent data suggest that the presence of concurrent diabetes may heighten CKD awareness, but current data have not supported the hypothesis that healthcare delivery or insurance status improves awareness in the diabetic population. Diabetes is associated with high cardiovascular disease (CVD) morbidity, especially in patients with CKD. We hypothesized that a highly prevalent co-morbid condition such as CVD in patients with diabetes would predict CKD awareness. METHODS: We utilized data from theNational Kidney Foundation-Kidney Early Evaluation Program (KEEPTM), a large screening program designed to identify high-risk individuals for CKD and promote awareness. RESULTS: Among 77,077 participants, CKD was identified in 20,200 and diabetes in 23,082. Prevalence of CVD was higher in participants with than without diabetes (39.5 vs. 22.0%) and in stage 3-5 compared to stage 1-2 CKD (43.3 vs. 34.4%). Patients with diabetes and CVD had a higher level of awareness than those without diabetes (8.2 vs. 2.2%). Among patients with diabetes and CVD, the presence of congestive heart failure was a better predictor of awareness [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.40-2.43] than endpoints such as myocardial infarction or stroke [OR 1.35 (95% CI 1.04-1.73) and OR 1.34 (95% CI 1.04-1.72), respectively]. CONCLUSIONS: While prevalence of CKD awareness remained low, our data suggest that in patients with diabetes the presence of CVD was associated with increased awareness in a targeted screening program for CKD awareness. PMID- 22258466 TI - Central Pressure and Biomarker Responses to Renin Inhibition with Hydrochlorothiazide and Ramipril in Obese Hypertensives: The ATTAIN Study. AB - BACKGROUND/AIMS: In obese, hypertensive subjects, the renin-angiotensin system (RAS) is enhanced and natriuresis impaired, suggesting a role for combination RAS blockade with diuretics. Data suggest that renin inhibition may attenuate diuretic-induced RAS activation and oxidative stress. METHODS: In this 8-week, double-blind study of 386 obese individuals (mean body mass index: 35.3) with stage 2 hypertension (mean age: 54.9 years; mean sitting systolic blood pressure, SBP: ?160 but <200 mm Hg), we compared the efficacy of aliskiren + hydrochlorothiazide (HCTZ) in reducing blood pressure (BP), plasma renin activity (PRA), and a urinary marker of oxidative stress to ramipril. Subjects were randomized to aliskiren/HCTZ 150/12.5 mg or ramipril 5 mg for 1 week, and after the 1st week force titrated to aliskiren/HCTZ 300/25 mg or ramipril 10 mg for 7 weeks. RESULTS: After 8 weeks, aliskiren/HCTZ provided greater reductions in office BP than ramipril (-28.1/-10.1 vs. -16.6/-3.6 mm Hg, p < 0.0001) as well as 24-hour ambulatory and central pressure measures. Aliskiren/HCTZ also lowered PRA (-45 vs. +83%) and the urinary F2-isoprostane/creatinine ratio (-18 vs. +7%) to a greater extent than ramipril. Adverse events (AEs) were similar in the two groups (35.8% with aliskiren/HCTZ vs. 37.3% on ramipril reporting at least one AE). CONCLUSIONS: Our findings suggest that the aliskiren/HCTZ combination reduced BP, PRA, and isoprostanes to a greater extent than did ramipril in obese patients with stage 2 hypertension. PMID- 22258467 TI - Hypoglycemia: A Possible Link between Insulin Resistance, Metabolic Dyslipidemia, and Heart and Kidney Disease (the Cardiorenal Syndrome). AB - Resistance to insulin metabolic signaling in adipose tissue contributes to the lipid abnormalities in obese, hyperinsulinemic, insulin-resistant patients who develop the cardiorenal syndrome. These same metabolic dyslipidemic abnormalities can be found in conditions of caloric energy restriction with decreased adiposity or normal insulin levels, such as anorexia, starvation or non-diabetic kidney disease. In this review, we assess hypoglycemia as an alternative physiological explanation for the biochemical and lipid findings in conditions of insulin resistance (IR). Therefore, PubMed databases (1961-2010) were searched for articles on the effect of hypoglycemia and starvation on non-esterified fatty acid (NEFA) elevation and abnormalities in insulin signaling in muscles as well as abnormal kidney metabolism. The search included articles on NEFA and their role in triglyceride (TG) and high-density lipoprotein (HDL) metabolism, as well as kidney and heart disease. Available studies support that hypoglycemia increases NEFA generation from adipose tissue. Elevated levels of NEFA induce increased plasma levels of TG and decreased levels of HDL cholesterol, and may cause direct kidney and myocardial damage. IR of adipose and skeletal muscle tissue, and the elevation in insulin levels in obese, insulin-resistant patients could be explained by an adaptation to their carbohydrate intake. These molecular abnormalities in insulin metabolic signaling can also be found in hypoglycemia or starvation. In conclusion, IR of adipose tissue cannot fully explain the lipid abnormalities observed in the cardiorenal syndrome. Decreased blood glucose levels (e.g. hypoglycemia) occur frequently in patients at risk for this syndrome. Hypoglycemia-induced increases in NEFA levels can promote lipid abnormalities that contribute to IR and the cardiorenal syndrome. PMID- 22258468 TI - (Q)SAR modeling and safety assessment in regulatory review. AB - The ability to predict clinical safety based on chemical structures is becoming an increasingly important part of regulatory decision making. (Quantitative) structure-activity relationship ((Q)SAR) models are currently used to evaluate late-arising safety concerns and possible nonclinical effects of a drug and its related compounds when adequate safety data are absent or equivocal. Regulatory use will likely increase with the standardization of analytical approaches, more complete and reliable data collection methods, and a better understanding of toxicity mechanisms. PMID- 22258470 TI - Health care utilization and health outcomes: a population study of Taiwan. AB - Facing escalating health care expenditures, the governments of countries with national health insurance programs are trying to control or even to reduce health care utilization. Little research has examined the effects of decreased health care utilization on health outcomes. Applying a natural experiment design to the Taiwan population between 2000 and 2004, which includes the 2003 SARS epidemic when an average 20% decline in health care utilization occurred, this study examines the association between a decline in health care utilization and health outcomes measured by cause-specific mortality rates. We analyse the monthly mortality rates caused by infectious diseases, cancer, diabetes mellitus, nervous system diseases, cerebrovascular diseases, heart and other vascular diseases, respiratory system diseases, digestive system diseases, genitourinary system diseases and accidents. Models control for age, sex, month and year effects. Results show the heterogeneous effect of reduced health care utilization on health outcomes. Patients with diabetes mellitus or cerebrovascular diseases are vulnerable to short-term reductions in health care; compared with the non-SARS period, mortality caused by diabetes mellitus and cerebrovascular diseases significantly increased during the SARS epidemic by 8.4% and 6.2%, respectively. No significant change in mortality rates caused by the other diseases or accidents is found. This study suggests that governments of countries where health care utilization and spending are similar to or inferior to those in Taiwan should carefully evaluate the impact of policies that attempt to reduce health care utilization. Furthermore, when an area encounters an epidemic, governments should be aware of the negative consequences of voluntary restraints on access to health care that accompany decreases in utilization. PMID- 22258471 TI - Hygiene and sanitation promotion strategies among ethnic minority communities in northern Vietnam: a stakeholder analysis. AB - Effective rural hygiene and sanitation promotion (RHSP) is a major challenge for many low-income countries. This paper investigates strategies and stakeholders' roles and responsibilities in RHSP implementation in a multi-ethnic area of northern Vietnam, in order to identify lessons learned for future RHSP. A stakeholder analysis was performed, based on 49 semi-structured individual interviews and one group interview with stakeholders in RHSP in a northern province of Vietnam. Participants came from three sectors (agriculture, health and education), unions supported by the Vietnamese government and from four administrative levels (village, commune, district and province). The study villages represented four ethnic minority groups including lowland and highland communities. Stakeholders' roles, responsibilities and promotion methods were outlined, and implementation constraints and opportunities were identified and analysed using thematic content analysis. Effective RHSP in Vietnam is severely constrained despite supporting policies and a multi-sectorial and multi-level framework. Four main barriers for effective implementation of RHSP were identified: (1) weak inter-sectorial collaborations; (2) constraints faced by frontline promoters; (3) almost exclusive information-based and passive promotion methods applied; and (4) context unadjusted promotion strategies across ethnic groups, including a limited focus on socio-economic differences, language barriers and gender roles in the target groups. Highland communities were identified as least targeted and clearly in need of more intensive and effective RHSP. It is recommended that the Vietnamese government gives priority to increasing capacities of and collaboration among stakeholders implementing RHSP activities. This should focus on frontline promoters to perform effective behaviour change communication. It is also recommended to support more participatory and community-based initiatives, which can address the complex socio-economic and cultural determinants of health in multi-ethnic population groups. These lessons learned can improve future RHSP in Vietnam and are also of relevance for health promotion in other minority population groups in the region and globally. PMID- 22258469 TI - Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. AB - Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated. PMID- 22258472 TI - Human urinary excretion and metabolism of (82)Se-enriched selenite and selenate determined by LC-ICP-MS. AB - Urinary excretion of selenium after ingestion of isotope labeled selenite and selenate was studied in seven healthy volunteers, 4 men and 3 women (age 28-50 years). An aqueous solution containing 330 MUL (82)Se-selenate (corresponding to 74.3 MUg (82)Se) was given orally and urine samples were subsequently collected during the following 24 hours. The scheme was repeated four weeks later with a 280 MUL (82)Se-selenite solution (corresponding to 74.4 MUg (82)Se). The amount of total Se in the urine samples was determined by inductively coupled mass spectrometry. The mean total urinary excretion of (82)Se following (82)Se selenate administration was 33.7% (range 15.6-42.5%) while the mean total excretion of (82)Se after (82)Se-selenite administration was 3.2% (range 2.8 3.9%) of the ingested amount. LC-ICPMS analysis of the urine samples showed that the majority of the selenium excreted after selenate ingestion was unchanged selenate for 6 of the individuals while one individual had metabolized a fraction (approx. 20%) of the selenate to selenosugar. Ingestion of 10 times larger doses of selenite in two individuals resulted in 13-23% excretion primarily excreted as selenosugar. These results show that the human metabolic pathways of selenite and selenate are different and indicate that not all selenate, although well absorbed, may be available for the beneficial health effects. PMID- 22258473 TI - Prognostic impact of circulating tumor cells in patients with small cell lung cancer. AB - BACKGROUND: Enumeration of circulating tumor cells (CTCs) may be valuable for prognostic assessment in lung cancer patients. In this study, we report the clinical significance of CTCs in small cell lung cancer (SCLC). METHODS: In total, 51 consecutive patients newly diagnosed as having SCLC and starting chemotherapy or chemoradiotherapy were prospectively enrolled. Blood samples were drawn at the baseline, after chemotherapy, and at relapse. CTCs were isolated using the CellSearch System (Veridex LLC). Thresholds of 1 to 100 cells at the baseline were systematically correlated with the overall survival. The optimal cutoff was determined by comparing the Cox proportional hazard ratios (HRs). RESULTS: Two or more CTCs were detected at baseline in 35 patients (68.6%; 95% confidence interval, 55.0-79.7). The HR signifying the difference between the unfavorable (more than or equal to threshold) and favorable (less than threshold) groups was maximal at the threshold of 8 CTCs (HR, 3.50; 95% confidence interval, 1.45-8.60). Patients with >=8 CTCs had worse survival than those with <8 CTCs at baseline (p = 0.0014). Patients with >=8 CTCs posttreatment or at relapse also showed worse survival than those with <8 CTCs (p = 0.0096 and <0.0001). Patients whose baseline and posttreatment CTC levels remained <8 tended to show better survival than those whose CTC level converted from >=8 to <8 cells (p = 0.0288) or whose posttreatment CTC level was >=8 cells (p = 0.0047). CONCLUSIONS: CTCs were highly detectable in SCLC, and higher CTC levels were strongly associated with worse survival. Consistently favorable CTC levels were associated with favorable outcomes. PMID- 22258474 TI - Hypoxia-inducible factor-1alpha and excision repair cross-complementing 1 in patients with small cell lung cancer who received front-line platinum-based chemotherapy: a retrospective study. AB - INTRODUCTION: Hypoxia-inducible factor-1alpha (HIF-1alpha), which plays an essential role in the adaptive response of cells to hypoxia, is associated with aggressive tumor behavior. Furthermore, a relationship between excision repair cross-complementing 1 (ERCC1) expression and platinum resistance has been reported in patients with various malignancies. The aim of this study was to investigate the expression of HIF-1alpha and ERCC1 and to elucidate the clinical significance of their expression in patients with small cell lung cancer (SCLC) treated with front-line platinum-based chemotherapy. METHODS: SCLC biopsy samples were obtained before front-line platinum-based chemotherapy from 111 patients with SCLC (limited disease, 29; extensive disease [ED], 82) between January 2002 and December 2009 at Gyeongsang National University Hospital. The expression levels of HIF-1alpha and ERCC1 were assessed by immunohistochemistry. RESULTS: High expression levels of ERCC1 and HIF-1alpha were observed in 49 (44.1%) and 71 (64.0%) of 111 patients, respectively. Expression of ERCC1 and HIF-1alpha was not significantly associated with age, sex, Eastern Cooperative Oncology Group performance status, weight loss, or response to treatment, regardless of stage. In ED-SCLC, low expression in the HIF-1alpha group showed statistically better survival compared with high expression in the HIF-1alpha group (p = 0.018). Multivariate analysis revealed that response to front-line platinum-based chemotherapy (p < 0.001), good Eastern Cooperative Oncology Group performance status (0-1) (p = 0.002), and low expression of HIF-1alpha (p = 0.004) were independent predictors of better overall survival in ED-SCLC. CONCLUSIONS: Low expression of HIF-1alpha may be a useful predictor of better overall survival in ED-SCLC patients treated with front-line platinum-based chemotherapy. PMID- 22258475 TI - Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? AB - INTRODUCTION: To evaluate the influence of pretreatment pulmonary function (PF) on survival, early and late pulmonary toxicity after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. METHODS: Four hundred eighty-three patients with 505 tumors of early-stage non-small cell lung cancer cT1-3 cN0 were treated with image-guided SBRT at five international institutions (1998-2010). Sixty-four percent of the tumors were biopsy-proven and 18F-fluorodeoxyglucose-positron emission tomography was performed for staging in 84%. Image-guided SBRT was performed with a median of three fractions to a median total dose of 54 Gy. Pretreatment PF was available for 423 patients, and 617 posttreatment PF tests from 270 patients were available. RESULTS: A large variability of pretreatment PF was observed: the 90% range of forced expiratory volume in 1 second and diffusing capacity for carbon monoxide was 29 to 109% and 5.5 to 19.1 ml/min/mmHg, respectively. PF was significantly correlated with overall survival but not cause-specific survival: diffusing capacity for carbon monoxide of 11.2 ml/min/mmHg differentiated between 3-year overall survival of 66% and 42%. Radiation-induced pneumonitis grade >=II occurred in 7% of patients and was not increased in patients with lower PF. A significant and progressive change of PF was observed after SBRT: PF decreased by 3.6% and 6.8% on average within 6 and 6 to 24 months after SBRT, respectively. Changes of PF after SBRT were significantly correlated with pretreatment PF: PF improved for worst pretreatment PF and the largest loss was observed for best pretreatment PF. CONCLUSIONS: Image-guided SBRT is safe in terms of acute and chronic pulmonary toxicity even for patients with severe pulmonary comorbidities. SBRT should be considered as a curative treatment option for inoperable patients with pretreatment PF as reported in this study. PMID- 22258477 TI - Surveillance of demographic characteristics and health behaviors among adult cancer survivors--Behavioral Risk Factor Surveillance System, United States, 2009. AB - PROBLEM/CONDITION: Approximately 12 million people are living with cancer in the United States. Limited information is available on national and state assessments of health behaviors among cancer survivors. Using data from the Behavioral Risk Factor Surveillance System (BRFSS), this report provides a descriptive state level assessment of demographic characteristics and health behaviors among cancer survivors aged >=18 years. REPORTING PERIOD COVERED: 2009 DESCRIPTION OF SYSTEM: BRFSS is an ongoing, state-based, random-digit-dialed telephone survey of the noninstitutionalized U.S. population aged >=18 years. BRFSS collects information on health risk behaviors and use of preventive health services related to leading causes of death and morbidity. In 2009, BRFSS added questions about previous cancer diagnoses to the core module. The 2009 BRFSS also included an optional cancer survivorship module that assessed cancer treatment history and health insurance coverage for cancer survivors. In 2009, all 50 states, the District of Columbia, Guam, Puerto Rico, and the U.S. Virgin Islands administered the core cancer survivorship questions, and 10 states administered the optional supplemental cancer survivorship module. Five states added questions on mammography and Papanicolaou (Pap) test use, eight states included questions on colorectal screening, and five states included questions on prostate cancer screening. RESULTS: An estimated 7.2% of the U.S. general population aged >=18 years reported having received a previous cancer diagnosis (excluding nonmelanoma skin cancer). A total of 78.8% of cancer survivors were aged >=50 years, and 39.2% had received a diagnosis of cancer >10 years previously. A total of 57.8% reported receiving an influenza vaccination during the previous year, and 48.3% reported ever receiving a pneumococcal vaccination. At the time of the interview, 6.8% of cancer survivors had no health insurance, and 12% had been denied health insurance, life insurance, or both because of their cancer diagnosis. The prevalence of cardiovascular disease was higher among male cancer survivors (23.4%) than female cancer survivors (14.3%), as was the prevalence of diabetes (19.6% and 14.7%, respectively). Overall, approximately 15.1% of cancer survivors were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in any leisure-time physical activity during the past 30 days. Demographic characteristics and health behaviors among cancer survivors varied substantially by state. INTERPRETATION: Health behaviors and preventive health care practices among cancer survivors vary by state and demographic characteristics. A large proportion of cancer survivors have comorbid conditions, currently smoke, do not participate in any leisure-time physical activity, and are obese. In addition, many are not receiving recommended preventive care, including cancer screening and influenza and pneumococcal vaccinations. PUBLIC HEALTH ACTION: Health-care providers and patients should be aware of the importance of preventive care, smoking cessation, regular physical activity, and maintaining a healthy weight for cancer survivors. The findings in this report can help public health practitioners, researchers, and comprehensive cancer control programs evaluate the effectiveness of program activities for cancer survivors, assess the needs of cancer survivors at the state level, and allocate appropriate resources to address those needs. PMID- 22258476 TI - Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer. AB - INTRODUCTION: Estrogen is known to promote proliferation and to activate the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) is a known estrogen responsive gene in breast cancer. We sought to determine whether the VEGF pathway is also regulated by estrogen in lung cancer cells, and whether combining an inhibitor of the ER pathway with a dual vascular endothelial growth factor receptor (VEGFR)/EGFR inhibitor would show enhanced antitumor effects. METHODS: We examined activation of EGFR and expression of VEGF in response to beta-estradiol, and the antitumor activity of the multitargeted VEGFR/EGFR/RET inhibitor, vandetanib, when combined with the antiestrogen fulvestrant both in vitro and in vivo. RESULTS: NSCLC cells expressed VEGFR-3 and EGFR. Vandetanib treatment of NSCLC cells resulted in inhibition of EGFR and VEGFR-3 and inhibition of beta-estradiol-induced P-MAPK activation, demonstrating that vandetanib blocks beta-estradiol-induced EGFR signaling. Treatment with beta-estradiol stimulated VEGFA mRNA and protein (p < 0.0001 over baseline), suggesting estrogenic signaling causes heightened VEGFA pathway activation. This estrogenic induction of VEGFA mRNA seems largely dependent on cross-talk with EGFR. Long-term vandetanib treatment also significantly increased ERbeta protein expression. The combination of vandetanib with fulvestrant maximally inhibited cell growth compared with single agents (p < 0.0001) and decreased tumor xenograft volume by 64%, compared with 51% for vandetanib (p < 0.05) and 23% for fulvestrant (p < 0.005). Antitumor effects of combination therapy were accompanied by a significant increase in apoptotic cells compared with single agents. CONCLUSIONS: Fulvestrant may enhance effects of vandetanib in NSCLC by blocking estrogen-driven activation of the EGFR pathway. PMID- 22258478 TI - Verbal and nonverbal memory impairment in aphasia. AB - Repetition is frequently impaired in aphasia, most strikingly in conduction aphasia. The still not fully answered question is whether this relates to a linguistic deficit or to a general impairment of working memory extending to other modalities as well. To contribute to this problem, we assessed 49 aphasic and 50 non-aphasic stroke patients using an aphasia test plus three memory tests in forward and backward fashion, taxing verbal, numerical, spatial, and facial retention. The results show that in aphasics there is a memory gradient declining gradually from verbal to nonverbal content reflecting aphasia severity and that aphasics generally perform worse than non-aphasics, even if they present with similar cerebral lesions. PMID- 22258480 TI - Improving survival in a large French ALS center cohort. AB - The aim of this work was to determine whether survival changed during 2002-2009 at a French amyotrophic lateral sclerosis (ALS) center. We included all patients with ALS who were seen consecutively at the center from January 2002-May 2009. Participants were followed from date of first visit through death, date of censoring, or December 31, 2009, whichever occurred first. Cox proportional hazard models computed hazard ratios (HR; 95% confidence interval CI) of death, and flexible modeling of continuous predictors (splines) assessed trends in survival. We analyzed a total of 2,037 ALS patients, of whom 1,471 died before the end of follow-up. Median survival was 2.83 years from onset and 1.65 years from first visit. Compared to patients first seen before 2004, the HR of death was 0.97 (95% CI = 0.85-1.11, p = 0.6721) for patients first seen in 2004-2005, 0.96 (95% CI = 0.83-1.10, p = 0.5125) for 2006-2007, and 0.56 (95% CI = 0.46 0.69, p < 0.0001) after 2007, while adjusting for other survival predictors. Spline analysis confirmed that survival remained stable during 2002-2006, then markedly improved. The proportion of patients receiving non-invasive ventilation (NIV) increased from 16 (2004) to 51% (2008). At this large ALS center, survival improved after 2006. Because more aggressive use of NIV was the principal therapeutic adaptation, our data suggest that better survival resulted from improved respiratory care. PMID- 22258479 TI - Fractional anisotropy in the centrum semiovale as a quantitative indicator of cerebral white matter damage in the subacute phase in patients with carbon monoxide poisoning: correlation with the concentration of myelin basic protein in cerebrospinal fluid. AB - Carbon monoxide (CO) poisoning leads to demyelination of cerebral white matter (CWM) fibers, causing chronic neuropsychiatric symptoms. To clarify whether fractional anisotropy (FA) from diffusion tensor imaging in the centrum semiovale can depict demyelination in the CWM during the subacute phase after CO inhalation, we examined correlations between FA in the centrum semiovale and myelin basic protein (MBP) in cerebrospinal fluid. Subjects comprised 26 adult CO poisoned patients <=60 years old. MBP concentration was examined for all patients at 2 weeks after CO inhalation. The mean FA of the centrum semiovale bilaterally at 2 weeks was also examined for all patients and 21 age-matched healthy volunteers as controls. After these examinations, the presence of chronic symptoms was checked at 6 weeks after CO poisoning. Seven patients displayed chronic symptoms, of whom six showed abnormal MBP concentrations. The remaining 19 patients presented no chronic symptoms and no abnormal MBP concentrations, with MBP concentrations undetectable in 16 patients. The MBP concentration differed significantly between patients with and without chronic symptoms. The mean FA was significantly lower in patients displaying chronic symptoms than in either patients without chronic symptoms or controls. After excluding the 16 patients with undetectable MBP concentrations, a significant correlation was identified between MBP concentration and FA in ten patients. The present results suggest that FA in the centrum semiovale offers a quantitative indicator of the extent of demyelination in damaged CWM during the subacute phase in CO-poisoned patients. PMID- 22258481 TI - Progress in cerebrovascular disease research in the last year. AB - Herein, we review the main papers in cerebrovascular diseases published in the Journal of Neurology over the last year. PMID- 22258482 TI - Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment. AB - OBJECTIVES: To compare health-related quality of life (HRQoL) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis using spydergram representations. METHODS: Data from randomised, controlled trials of etanercept in patients with RA, PsA and psoriasis were analysed. HRQoL was assessed by the medical outcomes survey short form 36 (SF-36) physical (PCS) and mental (MCS) component summary and domain scores. Baseline comparisons with age and gender matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure. RESULTS: Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA, but near normative values in patients with psoriasis; MCS scores at baseline were near normal in PsA and psoriasis but low in RA. Treatment with etanercept resulted in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications. Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA; clinically meaningful improvements in SF-6D were observed in all three patient populations following treatment with etanercept. CONCLUSIONS: Patients with RA, PsA and psoriasis demonstrated unique HRQoL profiles at baseline. Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA, PsA and psoriasis. PMID- 22258483 TI - Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. AB - OBJECTIVES: Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. METHODS: Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. RESULTS: Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb-IV). CONCLUSIONS: While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy. PMID- 22258484 TI - Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice. AB - OBJECTIVE: A growing body of evidence indicates that the protein deacetylase, SirT1, affects chondrocyte biology and survival. This report aims to evaluate in vivo attributes of SirT1 in cartilage biology of 129/J murine strains. METHODS: Heterozygous haploinsufficient (SirT1(+/-)) and wild-type (WT; SirT1(+/+)) 129/J mice aged 1 or 9 months were systematically compared for musculoskeletal features, scored for osteoarthritis (OA) severity, and monitored for chondrocyte apoptosis in articular cartilage. Sections of femorotibial joints were stained for type II collagen and aggrecan. Protein extracts from articular chondrocytes were isolated and immunoblotted for SirT1 and active caspase 3. RESULTS: Phenotypic observations show that, at 1 month of age, SirT1(+/-) mice were smaller than WT and showed a significant decrease in full-length SirT1 (FLSirT1; 110 kDa) protein levels. Levels of FLSirT1 were further decreased in both strains at 9 months. Immunoblot assays for 9-month-old strains revealed the presence of the inactive cleaved SirT1 variant (75 SirT1; 75 kDa) in WT mice, which was undetected in age-matched SirT1(+/-) mice. Nine-month-old SirT1(+/-) mice also showed increased OA and increased levels of apoptosis compared with age-matched WT mice. CONCLUSION: The data suggest that the presence of 75 SirT1 may prolong viability of articular chondrocytes in adult (9-month-old) mice. PMID- 22258485 TI - Influence of replacing tuberculin skin test with ex vivo interferon gamma release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. AB - BACKGROUND: The recommendations for detecting latent tuberculosis infection (LTBI) before antitumour necrosis factor (anti-TNF) therapy are based on the tuberculin skin test (TST), which lacks both specificity and sensitivity and can lead to unnecessary treatment with antibiotics. A study was undertaken to investigate the effect of replacing TST with interferon gamma (IFNgamma) release assays (IGRA) in screening for LTBI and deciding to begin prophylactic antituberculosis (TB) antibiotics before anti-TNF therapy in immune-mediated inflammatory diseases. METHODS: In 15 tertiary care hospitals, consecutive patients with rheumatoid arthritis, spondylarthropathies or Crohn's disease were screened for LTBI before anti-TNF therapy with TST, QuantiFERON TB Gold in tube (QTF-Gold IT) and T-SPOT.TB at the same time. The potential diagnosis of LTBI and the effect on the decision to begin antibiotic prophylaxis were assessed. RESULTS: Among 429 patients, 392 had results for the three tests. The results for TST, T-SPOT.TB and QTF Gold IT were positive for 35.2%, 15.1% and 9.9% of patients, respectively (p<0.0001). Antibiotics were required for 177 patients (45.2%) if positive TST results were included in the LTBI definition, 107 patients (27.3%) if TST results were replaced with results from one of the IGRA tests and 84 patients (21.4%) if TST results were replaced with QTF-Gold IT results (p<0.0001). The decision on the use of antibiotic prophylaxis was changed for 113 patients (28.8%, 95% CI 24.4% to 33.6%) if TST results were replaced with QTF-Gold IT results. CONCLUSIONS: Replacing TST with IGRA for determining LTBI allowed the proportion of patients with immune-mediated inflammatory diseases needing prophylactic anti-TB antibiotics before beginning anti-TNF agents to be reduced by half. PMID- 22258486 TI - Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage. AB - OBJECTIVE: To determine serum concentrations and tissue expression of matrix metalloproteinase-12 (MMP-12) and their correlation with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls. RESULTS: Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue. CONCLUSIONS: MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage. PMID- 22258487 TI - Validity and predictive ability of the juvenile arthritis disease activity score based on CRP versus ESR in a Nordic population-based setting. AB - OBJECTIVE: To compare the juvenile arthritis disease activity score (JADAS) based on C reactive protein (CRP) (JADAS-CRP) with JADAS based on erythrocyte sedimentation rate (ESR) (JADAS-ESR) and to validate JADAS in a population-based setting. METHODS: The CRP and ESR values and the corresponding JADAS scores (JADAS10/27/71) were compared in a longitudinal cohort study of 389 children newly diagnosed with juvenile idiopathic arthritis (JIA) in the Nordic JIA study. The construct validity and the discriminative and predictive ability of JADAS were assessed during a median disease course of 8 years by comparing JADAS with other measures of disease activity and outcome. RESULTS: At the first study visit the correlation between JADAS27-CRP and JADAS27-ESR was r=0.99 whereas the correlation between CRP and ESR was r=0.57. Children with higher JADAS scores had an increased risk of concomitant pain, physical disability and use of disease modifying antirheumatic drugs (DMARDs). A higher JADAS score at the first study visit also significantly predicted physical disability, damage and no remission off medication at the final study visit, and also use of DMARDs during the disease course. Sensitivity to change, demonstrated as change in JADAS score compared with the American College of Rheumatology paediatric measures of improvement criteria, mostly showed excellent classification ability. CONCLUSION: The JADAS-CRP and JADAS-ESR correlate closely, show similar test characteristics and are feasible and valid tools for assessing disease activity in JIA. PMID- 22258488 TI - Quantification of circulating endothelial progenitor cells in systemic sclerosis: a direct comparison of protocols. AB - BACKGROUND: It has been proposed that dysfunctional endothelial progenitor cells (EPCs) play a role in pathogenic vasculopathy in systemic sclerosis (SSc). However, there is some debate as to whether the EPC count is reduced in SSc. The European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group recently proposed recommendations for evaluating EPCs. OBJECTIVE: To validate the proposed EUSTAR recommendations by a side-by-side comparison of methods for quantifying EPCs. METHODS: Peripheral blood samples were obtained from 11 patients with SSc and 11 age-matched healthy controls. EPCs were simultaneously quantified by two methods: flow cytometry combined with immunomagnetic CD34+ cell enrichment or rosette-based lineage-negative (Lin-) cell enrichment. EPCs, defined as CD34+CD133+VEGFR2+ cells, were counted with and without fluorosphere calibration. RESULTS: EPC counts measured with fluorosphere calibration correlated well with each other, regardless of the enrichment procedure used. In contrast, EPC counts from protocols that did not use fluorospheres correlated poorly with results from other protocols. CONCLUSIONS: The EUSTAR recommendations are valid when they are combined with fluorosphere calibration. PMID- 22258489 TI - Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sjogren's syndrome treated with rituximab. AB - OBJECTIVE: To evaluate the responsiveness of the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) and EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) in patients with primary Sjogren's syndrome (pSS) treated with rituximab. METHODS: Twenty-eight patients with pSS treated with rituximab (1000 mg) infusions on days 1 and 15 were included in the study. Data were collected prospectively at baseline and 16, 24, 36, 48 and 60 weeks after treatment. Internal responsiveness was assessed using standardised response means (SRM) and effect sizes (ES). SRM and ES <0.5, 0.5-0.8 and >0.8 were interpreted as small, moderate and large, respectively. External responsiveness was assessed using Spearman correlation coefficients. RESULTS: Median (range) ESSPRI and ESSDAI scores at baseline were 6.7 (0.3-9.0) and 8 (2-18), respectively. Both indices improved significantly after treatment. SRM and ES values for ESSPRI and ESSDAI were >=0.8 at week 16 and decreased afterwards, and were larger for ESSDAI than for ESSPRI. SRM and ES values for patient's and physician's global disease activity (GDA) and rheumatoid factor broadly followed the pattern of those of ESSPRI and ESSDAI. SRM and ES for stimulated whole salivary flow were small at all time points. At baseline and for most change scores, moderate to good correlations were found between ESSPRI and patient's GDA and between ESSDAI and physician's GDA. Poor association was found between ESSPRI and ESSDAI. CONCLUSIONS: ESSPRI and ESSDAI are sensitive measures of change in disease activity after therapeutic intervention, which supports the usefulness of these indices for future clinical trials in patients with pSS. The responsiveness of ESSDAI was greater than that of ESSPRI. PMID- 22258490 TI - The risk of comorbidity. PMID- 22258491 TI - Combination of IL-17 and TNFalpha induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells. AB - OBJECTIVE: Cardiovascular events remain the leading cause of death in rheumatoid arthritis (RA). To study the role of cytokines in these observations, the effects of tumour necrosis factor alpha (TNFalpha) and interleukin (IL)-17, a classical and a new key player in RA, were assessed in endothelial cell (EC) dysfunction. METHODS: Primary human EC were treated with IL-17 alone or combined with TNFalpha. mRNA expression was quantified by qRT PCR and Affymetrix microarrays. The role of IL-17 was studied using functional assays of platelet aggregation, EC migration and invasion. RESULTS: IL-17 alone induced 248 pro-inflammatory genes and 9803, when combined with TNFalpha. IL-17 plus TNFalpha induced synergistically chemokine genes such as CCL5, IL-8 and cytokine genes such as IL 6. In contrast, IL-17 decreased genes involved in the regulation of inflammation such as IL-33. IL-17 induced EC migration and invasion in synergy with TNFalpha. Such invasion was inhibited with an antiCXCR4 antibody, indicating the contribution of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis. Supernatants of IL-17-treated EC induced strong platelet aggregation. IL-17 inhibited endothelial CD39/ATPDase expression, an inhibitor of platelet activation. Finally, IL-17 enhanced genes critical for coagulation such as tissue factor and decreased thrombomodulin, leading to a pro-thrombotic state. CONCLUSION: These results indicate that IL-17 specifically when combined with TNFalpha has major pro-coagulant and pro-thrombotic effects on vessels. PMID- 22258492 TI - Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis. AB - OBJECTIVES: The hallmark of systemic sclerosis (SSc) is the accumulation of extracellular matrix proteins by pathologically activated fibroblasts. This study analysed the antifibrotic effects of the selective c-Jun N-terminal kinase (JNK) inhibitor, CC-930, which recently entered first clinical trials as a novel antifibrotic approach. METHODS: Phosphorylated c-Jun was detected by western blot and immunohistochemistry. The model of bleomycin-induced dermal fibrosis and the tight skin 1 (TSK1) mouse model were used to investigate the effects of CC-930 on the prevention of experimental fibrosis. The potential of CC-930 to induce regression of fibrosis was assessed in a modified model of established fibrosis. RESULTS: Transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) activate JNK and stimulate the phosphorylation of its downstream target c-Jun. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen. Inhibition of JNK prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis. CONCLUSIONS: These data identify JNK as a downstream mediator of the pro-fibrotic effects of of TGFbeta and PDGF in SSc fibroblasts. Selective inhibition of JNK by CC-930 exerted potent antifibrotic effects in vitro and in different models in vivo. JNK might thus be a novel molecular target for the treatment of fibrosis in SSc. PMID- 22258493 TI - Early structural changes in cartilage and bone are required for the attachment and invasion of inflamed synovial tissue during destructive inflammatory arthritis. AB - OBJECTIVE: To elucidate the mechanisms involved in cartilage damage in an experimental model of rheumatoid arthritis (RA) by specifically addressing the time course of extracellular matrix degradation and the contribution of cell matrix interactions for initiation and perpetuation of this process. METHODS: The human tumour necrosis factor (TNF) transgenic (hTNFtg) mouse model of RA was used to analyse the time course of pannus attachment to the cartilage and cartilage destruction, respectively, and crossed hTNFtg mice with interleukin (IL)-1(-/-) animals were used to investigate the role of IL-1 on these TNF-induced mechanisms in vivo. In addition, an in vitro attachment assay using synovial fibroblasts (SFs) from hTNFtg mice and freshly isolated articular cartilage was used to determine the role of proteoglycan loss in attachment of SFs and the role of the transmembrane heparan sulfate proteoglycan syndecan-4. RESULTS: In vivo analyses of hTNFtg mice showed that proteoglycan loss induced by IL-1 precedes and constitutes an important prerequisite for these processes as, in hTNFtg mice, IL 1 deficiency protected from the loss of cartilage proteoglycans and almost completely prevented the attachment and subsequent invasion of inflamed synovial tissue into cartilage. In vitro studies confirmed that loss of cartilage proteoglycans is required for attachment of SFs and that syndecan-4 is prominently involved in SF attachment and activation. CONCLUSIONS: The results of this study suggest that the loss of cartilage proteoglycans is an early event in the course of destructive arthritis that facilitates the attachment of the inflamed synovial membrane and also initiates matrix degradation and inflammation through cell-matrix interactions. PMID- 22258495 TI - The trehalose coating effect on the internal protein dynamics. AB - (15)N and (13)C NMR experiments were applied to conduct a comparative study of a cold shock protein (Csp) in two states-lyophilized powder and a protein embedded in a glassy trehalose matrix. Both samples were studied at various levels of rehydration. The experiments used (measuring relaxation rates R(1) and R(1rho), motionally averaged dipolar couplings and solid state exchange method detecting reorientation of the chemical shift anisotropy tensor) allow obtaining abundant information on the protein structural features and internal motions in a range of correlation times from nanoseconds to seconds. The main results are: (a) the trehalose coating makes the protein structure more native in comparison with the dehydrated lyophilized powder, however, trehalose still cannot remove all non native hydrogen bonds which are present in a dehydrated protein; (b) trehalose has an appreciable effect on the internal dynamics: the motion of the backbone N H groups in the nanosecond and microsecond time scales becomes slower while the motional amplitude remains constant; (c) upon adding water to the Csp-trehalose mixture, water molecules accumulate around proteins forming a layer between the protein surface and the trehalose matrix. The protein dynamics become faster, however, not as fast as in the fully hydrated state; (d) the hydration response of dynamics of the NH and CH(CH(2)) groups in a protein is qualitatively different: upon increasing protein hydration, the correlation times of the N-H motions become shorter and the amplitude remains stable, and for CH(CH(2)) groups the motional amplitude increases and the correlation times do not change. This can be explained by a different ability of the NH and CH(CH(2)) groups to form hydrogen bonds. PMID- 22258497 TI - Effect of pH, sulphate concentration and total organic carbon on mercury accumulation in sediments in the Volta Lake at Yeji, Ghana. AB - In this study, pH, total organic carbon, sulphate concentration and mercury concentrations of sediment samples from the Volta Lake at Yeji in the northern part of Ghana were determined. The results indicate that pH ranged from 6.32 to 8.21, total organic carbon ranged from 0.17 to 3.02 g/kg and sulphate concentration from 10.00 to 57.51 mg/kg. Total mercury concentrations ranged from 32.61 to 700 ng/g which is below the International Atomic Energy Agency recommended value of 810 ng/g. Humic substance-bound mercury ranged from 81.15 to 481.31 mg/kg in sediments and its two fractions existed as humic acid-bound mercury > fulvic acid-bound mercury with the ratio of humic substance-bound mercury to fulvic acid-bound mercury as 1.62 on the average. Humic substance bound mercury and the two fractions fulvic acid-bound mercury and humic substance bound mercury in sediments were favorably determined and found to correlate significantly positive with total organic carbon (r = 0.538) and total mercury (r = 0.574). However, there were poor correlations between SO(4) (2-) concentrations and humic substance-bound mercury (r = -0.391) as well as the two fractions; fulvic acid (r = -0.406) and humic acid (r = -0.381). By assuming that methyl mercury is mostly formed in sediments, these significant relations suggest that the efficiency of mercury being methylated from a given inorganic form depends on the amount, and most likely biochemical composition of total organic carbon in the lake sediment but not the SO(4) (2-) concentration. PMID- 22258494 TI - Neuroendoscopic management of posterior third ventricle and pineal region tumors: technique, limitation, and possible complication avoidance. AB - The endoscopic approach has gained an increased popularity in recent years for the biopsy and, in selected cases, the removal of tumors of the posterior third ventricle and pineal region. The authors report their experience on a series of 20 patients discussing also the technical limitations and complication avoidance. This is a prospective study of 20 patients with posterior third ventricle and pineal region tumors surgically managed by endoscopic biopsy and/or excision and simultaneous third ventriculostomy. The removal of the lesion could be achieved in 12 cases whereas in 8, only a biopsy could be performed. A histological diagnosis could be obtained in all cases. No delayed third ventricular stoma failures were recorded in any patient at the latest follow-up (mean follow-up, 39 months). Severe postoperative complications were recorded in 2 out of 12 cases of tumor removal attempt and in zero out of eight cases of biopsy. A delayed (3 weeks) postoperative mortality occurred in a patient harboring a GBM that developed an intratumoral hematoma 48 h postoperatively, one patient was in a vegetative state. Transient postoperative complications included: nausea and vomiting (five cases) and diplopia (two cases). One patient developed a bilateral ophthalmoplegia that recovered within 6 months due to residual tumor hemorrhage. Higher rate of complications was found in the case of vascularized and/or larger lesions. Endoscopic management of posterior third ventricle lesions may represent an effective option. However, though biopsies remain often a safe procedure, tumor excision should be limited to highly selected cases (cystic, poorly vascularized, and/or smaller than 2.5-cm lesions). PMID- 22258498 TI - Percutaneous nephrolithotomy: keeping the bridge for one night. PMID- 22258499 TI - Effects of cumulus cells on vitreous cryopreservation of human mature oocytes and clinical pregnancy outcomes. AB - The purpose of this study was to explore the effects of cumulus cells on vitreous cryopreservation of human mature oocytes and clinical pregnancy outcomes. The study was divided into group A (cumulus cells were removed from the oocytes before freezing) containing 24 participants and 193 oocytes and group B (cumulus cells were retained with the oocytes before freezing) containing 26 participants and 240 oocytes. Based on no significant differences in age, duration of infertility, infertile causes, and number of retrieved oocytes between both groups when oocytes were retrieved from infertile women, we found that the survival rate of post thaw oocytes (88% vs 58%), cleavage rate (80% vs 56%), and high-quality embryo rate (75% vs 59%) were significantly higher in group B than in group A. Under the conditions that there were no significant differences between the 2 groups in the general status of the participants undergoing embryo transfer, the embryo implantation rate (37% vs 15%) and the clinical pregnancy rate (50% vs 17%) were significantly higher in group B than in group A, all with Ps < .05. We conclude that the retention of cumulus cells can improve the developmental competence of vitrified-thawed human mature oocytes and clinical pregnancy outcomes. PMID- 22258500 TI - Gout and organ transplantation. AB - Acute and chronic gout are common complications following organ transplantation. Risk factors include those shared with the general population (eg, diuretic use) and transplant-specific risk factors (eg, cyclosporine). Clinical features of gout are similar to those seen in the general population, although tophi may be more common. A definitive diagnosis requires demonstration of monosodium urate crystals within synovial fluid or tophi. Treatment is often empiric, although a poor response should prompt joint aspiration to exclude septic arthritis. Corticosteroids are commonly used to treat acute gout due to the adverse profile and drug interactions with NSAIDs and colchicine. Sustained reduction of serum urate (<=6 mg/dL) is critical in long-term management. Allopurinol is the most commonly used agent, although vigilant monitoring is required if combined with azathioprine. Other options include febuxostat and benzbromarone. The role of newer agents such as interleukin-1 inhibitors and uricases remains to be determined. General measures should include minimizing diuretic use. PMID- 22258501 TI - Using HIV viral load to guide treatment-for-prevention interventions. AB - PURPOSE OF REVIEW: To provide evidence that HIV-1 RNA load can guide treatment for-prevention interventions to mitigate the HIV epidemic. RECENT FINDINGS: Some HIV-infected individuals maintain increased levels of HIV-1 RNA load after acute infection for an extended period of time, and can disproportionately contribute to the spread of HIV in the community. The recent HIV Prevention Trials Network 052 study has demonstrated 96% efficacy for initiation of early antiretroviral treatment (ART) in HIV-1 serodiscordant couples. SUMMARY: The level of HIV-1 RNA load in plasma is the major biological predictor of virus transmission. HIV infected individuals who maintain increased levels of HIV-1 RNA load, extended high viremics, can transmit virus at higher rates. Combinatorial ART decreases HIV replication, thus reducing rates of virus transmission. Identifying high viremics and placing them on ART seems an attractive strategy that has the potential to achieve both individual benefits by lowering risk for early onset of clinical AIDS and public health benefits by reducing HIV transmission. A key logistical challenge is to screen for high viremics among HIV-positive individuals. Efficacy of the modified treatment-for-prevention approach focused on high viremics is being evaluated in ongoing and upcoming clinical trials. If efficacious, such an approach could be used widely to mitigate and control the HIV epidemic. PMID- 22258502 TI - The role of tripartite motif family members in mediating susceptibility to HIV-1 infection. AB - PURPOSE OF REVIEW: This review highlights new roles of the large family of tripartite motif (TRIM) proteins in antiviral defense. RECENT FINDINGS: Recent research explores the participation of several TRIM family members in regulating the innate immune response. A large number of TRIM genes are upregulated upon treatment by interferon and are directly involved in signaling (TRIM5, 13, 16, 20, 21, 22, 23, 25, 27, 30, 32 and 38). Notably, TRIM5alpha has been identified as a 'pattern recognition receptor' triggering a cascade of signals upon viral recognition, and contributing to the establishment of the antiviral state. SUMMARY: The identification of new roles for TRIM5alpha and other family members contributes to an emerging paradigm of host antiretroviral factors as mediators of the innate immune response and of the antiviral state. This leads both to direct therapeutic applications, such as gene therapy, and to the possibility of immune modulation. PMID- 22258503 TI - Treatment as prevention: translating efficacy trial results to population effectiveness. AB - PURPOSE OF REVIEW: The understanding that antiretroviral treatment prevents HIV transmission through suppression of viral load provides significant new opportunities in HIV prevention. However, knowledge of efficacy is only a first step to having an impact on the spread of HIV at a population level, the ultimate goal of all primary prevention modalities. This review explores what we know about treatment as prevention and how it could be used as a tool, as part of a combination approach, in the global response to HIV. RECENT FINDINGS: Efficacy data show that treatment as prevention works at high levels in trial conditions in stable serodiscordant couples; a finding that can reasonably be generalized to other populations at risk of transmitting the virus. Modelling shows that treatment as prevention should have an impact, but the extent of this depends primarily upon whether optimistic or pessimistic assumptions are made about the programmatic use of antiretrovirals (ARVs). SUMMARY: We describe research questions that need to be addressed in developing optimal programmatic public health treatment strategies including how best to target and implement the use of treatment as prevention, how to balance the needs of treatment for the individual patients' clinical benefit against population level benefits, and how to create programmes that are able to link people to and retain them in care. PMID- 22258504 TI - Ultrasound-guided core-needle biopsy and magnetic resonance imaging in the accurate diagnosis of intramuscular haemangiomas of the head and neck. AB - INTRODUCTION: Intramuscular haemangiomas of the digastric muscle are often misdiagnosed due to their low incidence and non-specific manifestation. Only two out of six previously reported cases were diagnosed correctly before excision. Ultrasound may not reveal their vascularity, and fine-needle aspiration biopsy is unhelpful as it reveals only blood. METHODS: A case of intramuscular haemangioma of the posterior belly of the digastric muscle is described. Previously reported cases are reviewed. Investigations used to diagnose the lesions and reasons for their common failure are discussed. RESULTS: Core-needle biopsy led to the correct histological diagnosis, and magnetic resonance imaging precisely located the lesion within the digastric muscle. CONCLUSION: Core-needle biopsy was safely used in the diagnosis of an intramuscular haemangioma. The combination of core needle biopsy and meticulous review of magnetic resonance imaging enables accurate diagnosis pre-operatively. PMID- 22258505 TI - Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. AB - Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2 beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise. PMID- 22258506 TI - Pathway complexity in supramolecular polymerization. AB - Self-assembly provides an attractive route to functional organic materials, with properties and hence performance depending sensitively on the organization of the molecular building blocks. Molecular organization is a direct consequence of the pathways involved in the supramolecular assembly process, which is more amenable to detailed study when using one-dimensional systems. In the case of protein fibrils, formation and growth have been attributed to complex aggregation pathways that go beyond traditional concepts of homogeneous and secondary nucleation events. The self-assembly of synthetic supramolecular polymers has also been studied and even modulated, but our quantitative understanding of the processes involved remains limited. Here we report time-resolved observations of the formation of supramolecular polymers from pi-conjugated oligomers. Our kinetic experiments show the presence of a kinetically favoured metastable assembly that forms quickly but then transforms into the thermodynamically favoured form. Quantitative insight into the kinetic experiments was obtained from kinetic model calculations, which revealed two parallel and competing pathways leading to assemblies with opposite helicity. These insights prompt us to use a chiral tartaric acid as an auxiliary to change the thermodynamic preference of the assembly process. We find that we can force aggregation completely down the kinetically favoured pathway so that, on removal of the auxiliary, we obtain only metastable assemblies. PMID- 22258507 TI - DNA breaks and chromosome pulverization from errors in mitosis. AB - The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement. PMID- 22258508 TI - Neuron-type-specific signals for reward and punishment in the ventral tegmental area. AB - Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We 'tagged' dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error. PMID- 22258509 TI - Genome-wide structure and organization of eukaryotic pre-initiation complexes. AB - Transcription and regulation of genes originate from transcription pre-initiation complexes (PICs). Their structural and positional organization across eukaryotic genomes is unknown. Here we applied lambda exonuclease to chromatin immunoprecipitates (termed ChIP-exo) to examine the precise location of 6,045 PICs in Saccharomyces. PICs, including RNA polymerase II and protein complexes TFIIA, TFIIB, TFIID (or TBP), TFIIE, TFIIF, TFIIH and TFIIK were positioned within promoters and excluded from coding regions. Exonuclease patterns were in agreement with crystallographic models of the PIC, and were sufficiently precise to identify TATA-like elements at so-called TATA-less promoters. These PICs and their transcription start sites were positionally constrained at TFIID-engaged downstream +1 nucleosomes. At TATA-box-containing promoters, which are depleted of TFIID, a +1 nucleosome was positioned to be in competition with the PIC, which may allow greater latitude in start-site selection. Our genomic localization of messenger RNA and non-coding RNA PICs reveals that two PICs, in inverted orientation, may occupy the flanking borders of nucleosome-free regions. Their unambiguous detection may help distinguish bona fide genes from transcriptional noise. PMID- 22258511 TI - Cognitive function and decline in obesity. AB - Obesity is a significant contemporary health concern that carries wide-ranging implications for society, as well as for individual health and well-being. In particular, the neuropsychological sequelae of obesity carry wide ranging functional implications. While research in this area is growing, our knowledge of obesity-related cognitive dysfunction and brain alterations has not yet been synthesized. The present review integrates the recent literature regarding patterns of obesity-related cognitive dysfunction and brain alterations and also indicates potential mechanisms for these neuropathological changes. The review culminates in a preliminary model of obesity-related cognitive dysfunction and suggestions for future research, including the potential reversibility of these changes with weight-loss. PMID- 22258510 TI - Genetic contributions to stability and change in intelligence from childhood to old age. AB - Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change. PMID- 22258512 TI - Why have we failed to cure Alzheimer's disease? AB - There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer's disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, just like hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, like apoptosis or amyloid-beta accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for "senile dementia of the Alzheimer type", some genetic but most environmental and therefore modifiable. Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age. PMID- 22258513 TI - Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases. AB - Ceramide has been suggested to participate in the neuronal cell death that leads to Alzheimer's disease (AD), but its role is not yet well-understood. We compared the levels of six ceramide subspecies, which differ in the length of their fatty acid moieties, in brains from patients who suffered from AD, other neuropathological disorders, or both. We found elevated levels of Cer16, Cer18, Cer20, and Cer24 in brains from patients with any of the tested neural defects. Moreover, ceramide levels were highest in patients with more than one neuropathologic abnormality. Interestingly, the range of values was higher among brains with neural defects than in controls, suggesting that the regulation of ceramide synthesis is normally under tight control, and that this tight control may be lost during neurodegeneration. These changes, however, did not alter the ratio between the tested ceramide species. To explore the mechanisms underlying this dysregulation, we evaluated the expression of four genes connected to ceramide metabolism: ASMase, NSMase 2, GALC, and UGCG. The patterns of gene expression were complex, but overall, ASMase, NSMase 2, and GALC were upregulated in specimens from patients with neuropathologic abnormalities in comparison with age-matched controls. Such findings suggest these genes as attractive candidates both for diagnostic purposes and for intervening in neurodegenerative processes. PMID- 22258514 TI - Blood clusterin levels, rs9331888 polymorphism, and the risk of Alzheimer's disease. AB - Variants in the clusterin gene have been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels. PMID- 22258515 TI - Hormesis and amyloid-beta protein: physiology or pathology? AB - Hormesis is the concept that low doses of a toxin can have beneficial effects while high doses are harmful. This is also known as the inverted-U shaped dose response curve. Hormesis appears to be a universal law for the function of memory mimetics. Amyloid-beta protein is widely recognized to be a toxic agent responsible for plaque formation in Alzheimer's disease. In high doses it also produces amnesia. In lower, physiological doses, it enhances long term potentiation and memory. Blocking amyloid-beta protein in animals without overproduction of the protein results in amnesia. At low doses, amyloid-beta also increases neurite outgrowth, produces presynaptic enhancement, and may quench oxidative damage. It is postulated that both over- and underproduction of amyloid beta can lead to memory deficits. This is similar to a number of hormonal diseases, e.g., thyroid, where both low and high levels produce disease. PMID- 22258516 TI - Measurement of altered AbetaPP isoform expression in frontal cortex of patients with Alzheimer's disease by absolute quantification real-time PCR. AB - Enzymatic cleavage of amyloid-beta protein precursor (AbetaPP) produces amyloid beta (Abeta) peptides which form the insoluble cortical plaques characteristic of Alzheimer's disease (AD). AbetaPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AbetaPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AbetaPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AbetaPP and all three major isoforms (AbetaPP695, AbetaPP751, and AbetaPP770) in addition to glyceraldehyde-3 dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n = 12) and without AD (n = 10). Both total AbetaPP and AbetaPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p = 0.037 and p = 0.034, respectively). AbetaPP751 and AbetaPP770 transcripts numbers were not significantly different between AD and control (p > 0.15). There was trend for decreased percentage AbetaPP695 (p = 0.051) and increased percentage AbetaPP770 (p = 0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p = 0.005). Decreasing total AbetaPP and AbetaPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AbetaPP isoform transcripts by real-time PCR and confirm previous studies showing altered AbetaPP isoform expression patterns in AD. PMID- 22258517 TI - Copper hypothesis in the missing hereditability of sporadic Alzheimer's disease: ATP7B gene as potential harbor of rare variants. AB - Sporadic Alzheimer's disease (LOAD) is the most common form of dementia and has a high heritability. The genes associated with LOAD explain a small proportion of the genetic contribution to LOAD, leaving several genetic risk factors to be identified. Some authors have suggested a shift from the paradigm "common disease common gene variants", which is currently the basis for genome-wide association studies, to a "common disease-multiple rare gene variants" hypothesis aimed at identifying rarer allele variants with large effect size on LOAD onset, suggesting that they may account for the 'missing' heritability of LOAD. Recent studies have demonstrated the connection between copper imbalance and LOAD. Some studies have pointed out the pivotal role of 'free' copper, the portion of serum copper non-bound to ceruloplasmin. Free copper has been already identified as a biological marker of Wilson's disease (WD), the paradigmatic disease of free copper toxicosis or accumulation. The ATP7B gene controls free copper levels, and its mutations cause WD. The paradigm shift to "common disease-multiple rare variants" may suitably fit the ATP7B gene; the high heterogeneity of the ATP7B gene may have hidden multiple rare variants with large effect sizes for LOAD. Demonstrating that the ATP7B gene harbors rare variants which may account for some of the missing hereditability of LOAD would support previous evidence of copper involvement in LOAD from a new and totally different perspective and would bring almost immediate benefits in the clinical community in terms of early diagnosis, treatment efficacy, LOAD prevention, and cost savings. PMID- 22258518 TI - The Toulouse Gerontopole Research Center: report of activities, 2007-2011. AB - The formation of the first Gerontopole in Toulouse was a response to a mission letter sent by French Ministers of Health on February 2007. The mission of the Toulouse Gerontopole is based around three major axes: 1) To facilitate the access of frail elderly people to innovative therapy and clinical research: the Gerontopole set up the national network for clinical investigation into Alzheimer's disease (AD) funded through the CeNGEPS (National Centre For Management of Trials on Health Products) calls for proposals since July 2008. In addition, the Gerontopole coordinates several national clinical trials with promising drugs with potential effect on the mechanisms and evolution of AD and actively participates in studies on biomarkers; 2) To develop health promotion actions and prevention trials for healthy elderly people, through the Institute of Aging: the Gerontopole has implemented the GuidAge (Phase III trial concerning the efficiency of Ginkgo Biloba on the impact and delay of appearance of an Alzheimer type dementia) and MAPT (Multi-domain Alzheimer Preventive Trial) studies on prevention of AD and cognitive decline. It is curently working on the new generation of preventive trials based on biomarkers; 3) To develop clinical research for dependant elderly people, through the implementation of the REHPA research network including 240 nursing homes in France. In December 2009, additional grants were delivered by the French government to extend the three research axes for two more years, and establish a charter of quality for geriatric care in relation with the administration and relevant agencies. PMID- 22258519 TI - Apparent diffusion coefficient correlation with oesophageal tumour stroma and angiogenesis. AB - OBJECTIVE: Because diffusion-weighted imaging (DWI) can predict the prognosis of patients with oesophageal squamous cell carcinoma (ESCC), we hypothesised that apparent diffusion coefficient (ADC) values might be correlated with the collagen content and tumour angiogenesis. The purpose of this study was to determine the correlation between ADC values of ESCC before treatment and oesophageal tumour stroma and angiogenesis. METHODS: Seventeen patients with ESCC were enrolled. The ADC values were calculated from the DWI score. Seventeen patients who had undergone oesophagectomy were analysed for tumour stroma, vascular endothelial growth factor (VEGF) and CD34. Tissue collagen was stained with azocarmine and aniline blue to quantitatively analyse the extracellular matrix in cancer stroma. Tissues were stained with VEGF and CD34 to analyse the angiogenesis. RESULTS: The ADC values decreased with stromal collagen growth. We found a negative correlation between the tumour ADC and the amount of stromal collagen (r = 0.729, P = 0.001), i.e. the ADC values decreased with growth of VEGF. We also found a negative correlation between the ADC of the tumours and the amount of VEGF (r = 0.538, P = 0.026). CONCLUSION: Our results indicated that the ADC value may be a novel prognostic factor and contribute to the treatment of oesophageal cancer. KEY POINTS: * Magnetic resonance apparent diffusion coefficient values inversely indicate tumour stromal collagen * There is also negative correlation between ADCs and vascular endothelial growth factor * ADC values may contribute to the treatment of oesophageal cancer. PMID- 22258520 TI - Clinical utility gene card for: Werner syndrome. PMID- 22258521 TI - Impact of diagnostic misclassification on estimation of genetic correlations using genome-wide genotypes. AB - Disorders that share genetic risk factors often are placed in closely related diagnostic categories and treated similarly. Until recently, evidence for shared genetic etiology derived from classical research strategies--coaggregation in family and twin studies. Accumulating sufficient numbers of families was often problematic. However, in the era of genome-wide genotyping, we can now directly estimate the degree of sharing of genetic risk factors between disorders. This strategy is practical even for very rare disorders, where it is infeasible to ascertain informative families. Importantly, the estimates of genetic correlations from genome-wide genotypes are derived using such distant relatives that contamination by shared environmental factors seems unlikely. However, any method that seeks to quantify the shared etiology of disorders assumes they can be distinguished diagnostically from one another without error. Here we investigate the impact of misdiagnosis on estimates of genetic correlation both from traditional family data and from genome-wide genotypes of case-control samples from unrelated individuals. Our analyses show similar results for levels of misdiagnosis in both types of data. In both scenarios, genetic variances and heritabilities tend to be slightly underestimated but genetic correlations are overestimated, sometimes substantially so. For example, two genetically distinct but equally heritable disorders each with prevalence 1%, can generate false positive estimates of genetic correlations of >0.2 in the presence of 10% reciprocal misdiagnosis. Strategies for minimizing the effects of misdiagnosis in cross-disorder genetic studies are discussed. PMID- 22258522 TI - Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror image polydactyly. AB - PITX1 is a bicoid-related homeodomain transcription factor implicated in vertebrate hindlimb development. Recently, mutations in PITX1 have been associated with autosomal-dominant clubfoot. In addition, one affected individual showed a polydactyly and right-sided tibial hemimelia. We now report on PITX1 deletions in two fetuses with a high-degree polydactyly, that is, mirror-image polydactyly. Analysis of DNA from additional individuals with isolated lower-limb malformations and higher-degree polydactyly identified a third individual with long-bone deficiency and preaxial polydactyly harboring a heterozygous 35 bp deletion in PITX1. The findings demonstrate that mutations in PITX1 can cause a broad spectrum of isolated lower-limb malformations including clubfoot, deficiency of long bones, and mirror-image polydactyly. PMID- 22258523 TI - Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype. AB - Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases. PMID- 22258524 TI - Questionable pathogenicity of FOXG1 duplication. PMID- 22258525 TI - Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease. AB - Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81+/-26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients. PMID- 22258526 TI - Disease gene identification strategies for exome sequencing. AB - Next generation sequencing can be used to search for Mendelian disease genes in an unbiased manner by sequencing the entire protein-coding sequence, known as the exome, or even the entire human genome. Identifying the pathogenic mutation amongst thousands to millions of genomic variants is a major challenge, and novel variant prioritization strategies are required. The choice of these strategies depends on the availability of well-phenotyped patients and family members, the mode of inheritance, the severity of the disease and its population frequency. In this review, we discuss the current strategies for Mendelian disease gene identification by exome resequencing. We conclude that exome strategies are successful and identify new Mendelian disease genes in approximately 60% of the projects. Improvements in bioinformatics as well as in sequencing technology will likely increase the success rate even further. Exome sequencing is likely to become the most commonly used tool for Mendelian disease gene identification for the coming years. PMID- 22258527 TI - Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes. AB - The microphthalmia-associated transcription factor (MITF) is a basic helix-loop helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci. PMID- 22258528 TI - Discovery of variants unmasked by hemizygous deletions. AB - Array-based genome-wide segmental aneuploidy screening detects both de novo and inherited copy number variations (CNVs). In sporadic patients de novo CNVs are interpreted as potentially pathogenic. However, a deletion, transmitted from a healthy parent, may be pathogenic if it overlaps with a mutated second allele inherited from the other healthy parent. To detect such events, we performed multiplex enrichment and next-generation sequencing of the entire coding sequence of all genes within unique hemizygous deletion regions in 20 patients (1.53 Mb capture footprint). Out of the detected 703 non-synonymous single-nucleotide variants (SNVs), 8 represented variants being unmasked by a hemizygous deletion. Although evaluation of inheritance patterns, Grantham matrix scores, evolutionary conservation and bioinformatic predictions did not consistently indicate pathogenicity of these variants, no definitive conclusions can be drawn without functional validation. However, in one patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis and bilateral hearing loss, we discovered a second smaller deletion, inherited from the other healthy parent, resulting in loss of both alleles of the highly conserved heat shock factor binding protein 1 (HSBP1) gene. Conceivably, inherited deletions may unmask rare pathogenic variants that may exert a phenotypic impact through a recessive mode of gene action. PMID- 22258530 TI - Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy. AB - Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the alpha-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the alpha/beta spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants. PMID- 22258529 TI - Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome. AB - Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder. PMID- 22258531 TI - Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay. AB - Duane retraction syndrome (DRS) is a rare congenital strabismus condition with genetic heterogeneity. DRS associated with intellectual disability or developmental delay is observed in several genetic diseases: syndromes such as Goldenhar or Wildervanck syndrome and chromosomal anomalies such as 12q12 deletion. We report on the case of a patient with DRS, developmental delay and particular facial features (horizontal and flared eyebrows, long and smooth philtrum, thin upper lip, full lower lip and full cheeks). We identified a duplication of the long arm of chromosome 8 (8q12) with SNP-array. This is the third case of a patient with common clinical features and 8q12 duplication described in the literature. The minimal critical region is 1.2 Mb and encompasses four genes: CA8, RAB2, RLBP1L1 and CHD7. To our knowledge, no information is available in the literature regarding pathological effects caused by to overexpression of these genes. However, loss of function of the CHD7 gene leads to CHARGE syndrome, suggesting a possible role of the overexpression of this gene in the phenotype observed in 8q12 duplication patients. We have observed that patients with 8q12 duplication share a common recognizable phenotype characterized by DRS, developmental delay and facial features. Such data combined to the literature strongly suggest that this entity may define a novel syndrome. We hypothesize that CHD7 duplication is responsible for a part of the features observed in 8q12.2 duplication. PMID- 22258532 TI - A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility. AB - Genome-wide association studies for breast cancer have identified over 40 single nucleotide polymorphisms (SNPs), a subset of which remains statistically significant after genome-wide correction. Improved strategies for mining of genome-wide association data have been suggested to address heritable component of genetic risk in breast cancer. In this study, we attempted a two-stage association design using markers from a genome-wide study (stage 1, Affymetrix Human SNP 6.0 array, cases=302, controls=321). We restricted our analysis to DNA repair/modifications/metabolism pathway related gene polymorphisms for their obvious role in carcinogenesis in general and for their known protein-protein interactions vis-a-vis, potential epistatic effects. We selected 22 SNPs based on linkage disequilibrium patterns and high statistical significance. Genotyping assays in an independent replication study of 1178 cases and 1314 controls were attempted using Sequenom iPLEX Gold platform (stage 2). Six SNPs (rs8094493, rs4041245, rs7614, rs13250873, rs1556459 and rs2297381) showed consistent and statistically significant associations with breast cancer risk in both stages, with allelic odds ratios (and P-values) of 0.85 (0.0021), 0.86 (0.0026), 0.86 (0.0041), 1.17 (0.0043), 1.20 (0.0103) and 1.13 (0.0154), respectively, in combined analysis (N=3115). Of these, three polymorphisms were located in methyl CpG-binding domain protein 2 gene regions and were in strong linkage disequilibrium. The remaining three SNPs were in proximity to RAD21 homolog (S. pombe), O-6-methylguanine-DNA methyltransferase and RNA polymerase II-associated protein 1. The identified markers may be relevant to breast cancer susceptibility in populations if these findings are confirmed in independent cohorts. PMID- 22258533 TI - KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations. AB - The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa. PMID- 22258534 TI - A major locus on chromosome 3p22 conferring predisposition to human herpesvirus 8 infection. AB - Infection with human herpesvirus 8 (HHV-8), the etiological agent of Kaposi's sarcoma, has been shown to display strong familial aggregation, in countries in which HHV-8 infection is endemic. We investigated 40 large families (608 subjects aged one to 88 years) living in an isolated area of Cameroon in which HHV-8 is highly endemic. We performed a two-step genetic analysis for HHV-8 infection status (HHV-8+/HHV-8- determined by immunofluorescence) consisting of an initial segregation analysis followed by a model-based genome-wide linkage analysis. Overall HHV-8 seroprevalence was 60%, increasing with age. Segregation analysis provided strong evidence for a recessive major gene conferring predisposition to HHV-8 infection. This gene is predicted to have a major effect during childhood, with almost all homozygous predisposed subjects (~7% of the population) becoming infected by the age of 10. Linkage analysis was carried out on the 15 most informative families, corresponding to 205 genotyped subjects. A single region on chromosome 3p22 was significantly linked to HHV-8 infection (LOD score=3.83, P=2.0 * 10(-5)). This study provides the first evidence that HHV-8 infection in children in endemic areas has a strong genetic basis involving at least one recessive major locus on chromosome 3p22. PMID- 22258536 TI - Hypertensive Cardiovascular and Renal Disease and Target Organ Damage: Lessons from Animal Models. AB - This brief review discusses some aspects of hypertensive damage to the kidneys and cardiovascular system. A comparison of renal and cardiac manifestations of hypertensive disease between results of clinical and experimental studies was made, with a major focus on the possible role of salt and the renin-angiotensin system (RAS) in inducing target organ damage. Thus, some degree of renal impairment is often present in patients with essential hypertension, varying from microalbuminuria to end-stage renal disease, whereas in rats with spontaneous hypertension only slight renal damage is seen in old rats with little evidence of renal failure. Since renal damage in hypertensive rats is induced when they are exposed to increased salt intake, we suggested that salt may also account for kidney injury in hypertensive patients. Similarly, cardiac damage is aggravated in hypertensive human beings and rats when given salt excess. We further presented evidence that the RAS may mediate adverse cardiac and renal effects of excessive salt intake. Finally, we also discussed some aspects of the cardiovascular physiology in the giraffe, the only mammal that in comparison with the human being has extremely high pressure at the level of the heart and kidneys but no target organ damage. PMID- 22258537 TI - Plasma Brain Natriuretic Peptide Levels in Cardiac Function Assessment in Chronic Dialysis Patients. AB - BACKGROUND: Brain natriuretic peptide (BNP) is elevated in patients with end stage renal disease and could reflect left ventricular dysfunction. AIM: To evaluate the plasma levels of BNP in two groups of asymptomatic patients on different dialysis programs and to correlate their variations with echocardiographic parameters. METHODS: Group A consisted of 36 patients on chronic hemodialysis (HD), and group B included 38 patients on continuous ambulatory peritoneal dialysis (CAPD). ECG and echocardiography were performed, and concomitantly plasma BNP levels were determined before and after a regular 4 hour session in HD patients and before performing a dialysate exchange in patients on CAPD. RESULTS: BNP values in group A were found to be higher than in group B (419 +/- 76 vs. 193 +/- 56 pg/ml; p < 0.03). The cutoff point which discriminated both groups was 194 pg/ml (sensitivity: 64% and specificity: 76%; p = 0.001). Significant differences were found with respect to the following echocardiographic data (group A vs. group B): left atrial (LA) size (40 +/- 13 vs. 34 +/- 1 mm), LA volume (59 +/- 16 vs. 41 +/- 32 ml), transmitral flow E/A (1.17 +/- 0.01 vs. 0.9 +/- 0.06), the movement of the mitral valve annulus e/a (tissue Doppler imaging; 1.19 +/- 0.15 vs. 1.05 +/- 0.13) and left ventricular mass index (133 +/- 10 vs. 108 +/- 11). CONCLUSION: Patients on CAPD had lower levels of BNP, and echocardiographic findings indicated decreased volume overload. In asymptomatic patients, marked increases in BNP levels may reflect early stages of pathological processes that precede the development of apparent cardiac manifestations (left ventricular hypertrophy). Only echocardiographic parameters of cardiac dysfunction should be used as diagnostic criteria. PMID- 22258538 TI - Elevated Levels of N-Terminal Pro-Brain Natriuretic Peptide in Patients with Chronic Dyspnea and Moderate Renal Dysfunction: Decreased Clearance or Increased Cardiac Stress. AB - BACKGROUND/AIMS: Serum levels of N-terminal pro-brain natriuretic peptide (NT proBNP) are often increased in patients with impaired renal function. The objective of this study was to investigate whether the increase in NT-proBNP is predominantly due to a reduced renal clearance or an increased cardiac secretion. METHODS: A series of 697 outpatients (age: 57.5 +/- 16.4 years) referred for evaluation of dyspnea were assigned to 4 groups according to their estimated glomerular filtration rate [eGFR (ml/min per 1.73 m2)]: group 1, eGFR <60 (n = 77); group 2, eGFR ?60 to <75 (n = 139); group 3, eGFR ?75 to <90 (n = 191), and group 4, eGFR ?90 (n = 289). The patients were also grouped into 2 categories based on the presence (n = 176) or absence (n = 521) of heart disease. RESULTS: In patients with heart disease, the adjusted values for NT-proBNP were higher in eGFR group 1 than in eGFR groups 2-4 (p <= 0.01). In patients without heart disease, eGFR group 1 membership had no effect on NT-proBNP. CONCLUSION: A reduced renal clearance does not explain increased NT-proBNP levels in patients with moderate renal impairment and dyspnea. Our data suggest that a moderate reduction in renal function places additional stress on the heart in patients with established cardiac disease. PMID- 22258539 TI - Physical Activity in the Prevention of Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease (CVD) and mortality. The increase in CKD in recent decades has paralleled increases in obesity, diabetes, and the metabolic syndrome. Physical inactivity is a modifiable risk factor that may affect the development and course of CKD. It is well established that exercise training improves a number of metabolic factors, including blood pressure and insulin resistance, which would be expected to preserve renal function as well as lower CVD risk. Epidemiological studies have suggested that partaking in vigorous physical activity may protect against kidney disease. However, to date few studies have rigorously measured physical activity levels. Instead, investigators have relied on subjective measures of physical activity and patient recall. This is particularly problematic when attempting to capture low- and very-low-intensity physical activity and in quantifying sedentary behavior. Improvements in vascular endothelial function, insulin sensitivity, adipocytokine profiles, and oxidative stress likely mediate the benefits of physical activity on the kidney. While formal exercise recommendations have been published for diabetes and hypertension, guidelines regarding the optimal type, frequency, intensity and duration of physical activity for preventing CKD have yet to be formalized. PMID- 22258540 TI - Role of Growth Hormone Deficiency and Treatment in Chronic Kidney Disease. AB - Malnutrition and inflammation are strong predictors of mortality in advanced kidney disease, especially in patients on renal replacement therapy. The complex relationship between kidney disease, uremia, and malnutrition significantly contributes to the increased morbidity and mortality in this patient population potentially through a relative deficiency in growth hormone (GH). With an approximate 26 million Americans currently affected by some stage of chronic kidney disease and a predicted 750,000 people to be on dialysis by 2020, there is a need to develop innovative strategies aimed at reducing the high mortality seen in dialysis patients. We will review evidence on one such intervention with infusion of recombinant GH to improve the nutritional and inflammatory state, thereby expecting to improve the mortality and morbidity in this patient population. PMID- 22258541 TI - Long-term impacts of early and surgical menopause. PMID- 22258542 TI - Human immunodeficiency virus and the postmenopausal woman: genital shedding may remain the same. PMID- 22258543 TI - Smoking lowers the age at natural menopause among smokers and raises important questions. PMID- 22258544 TI - Detecting cross-cultural differences in somatization. PMID- 22258545 TI - The effect of acute aromatase inhibition on breast parenchymal enhancement in magnetic resonance imaging: a prospective pilot clinical trial. AB - OBJECTIVE: The breast is highly hormonally sensitive especially to the sex steroid hormone estrogen. Both physiological and iatrogenic steroid hormone modifications could affect how the breast tissue may appear in breast imaging techniques. We hypothesized that estrogen deprivation therapy could reduce breast nonspecific enhancement on magnetic resonance imaging (MRI). METHODS: This study was a prospective pilot phase II clinical trial. The study was approved by Health Canada and the institutional research ethics board, and participants signed informed consent forms. Sixteen healthy postmenopausal women were enrolled, and 14 completed the study. Baseline breast MRI was done followed 1 month later by administration of a high-dose aromatase inhibitor (letrozole 12.5 mg/day) for 3 successive days before a second breast MRI. Background breast parenchymal enhancement was compared between the pretreatment and posttreatment studies. RESULTS: There was a statistically significant reduction of the average background breast enhancement after treatment with aromatase inhibitors compared with baseline MRI. Of particular interest, specific areas of benign breast enhancement were reduced after aromatase inhibitor treatment. No significant adverse effects were recorded using this relatively high dose of the aromatase inhibitors. CONCLUSIONS: This preliminary study provided evidence that aromatase inhibitors could reduce the parenchymal background enhancement of benign breast tissue during MRI and may improve the specificity of the technique. PMID- 22258546 TI - Assessing burrowing, nest construction, and hoarding in mice. AB - Deterioration in the ability to perform "Activities of daily living" (ADL) is an early sign of Alzheimer's disease (AD). Preclinical behavioural screening of possible treatments for AD currently largely focuses on cognitive testing, which frequently demands expensive equipment and lots of experimenter time. However, human episodic memory (the most severely affected aspect of memory in AD) is different to rodent memory, which seems to be largely non-episodic. Therefore the present ways of screening for new AD treatments for AD in rodents are intrinsically unlikely to succeed. A new approach to preclinical screening would be to characterise the ADL of mice. Fortuitously, several such assays have recently been developed at Oxford, and here the three most sensitive and well characterised are presented. Burrowing was first developed in Oxford. It evolved from a need to develop a mouse hoarding paradigm. Most published rodent hoarding paradigms required a distant food source to be linked to the home cage by a connecting passage. This would involve modifying the home cage as well as making a mouse-proof connecting passage and food source. So it was considered whether it would be possible to put the food source inside the cage. It was found that if a container was placed on the floor it was emptied by the next morning., The food pellets were, however, simply deposited in a heap at the container entrance, rather than placed in a discrete place away from the container, as might be expected if the mice were truly hoarding them. Close inspection showed that the mice were performing digging ("burrowing") movements, not carrying the pellets in their mouths to a selected place as they would if truly hoarding them. Food pellets are not an essential substrate for burrowing; mice will empty tubes filled with sand, gravel, even soiled bedding from their own cage. Moreover, they will empty a full tube even if an empty one is placed next to it. Several nesting protocols exist in the literature. The present Oxford one simplifies the procedure and has a well-defined scoring system for nest quality. A hoarding paradigm was later developed in which the mice, rather than hoarding back to the real home cage, were adapted to living in the "home base" of a hoarding apparatus. This home base was connected to a tube made of wire mesh, the distal end of which contained the food source. This arrangement proved to yield good hoarding behaviour, as long as the mice were adapted to living in the "home base" during the day and only allowed to enter the hoarding tube at night. PMID- 22258548 TI - Human gouty arthritis is associated with a distinct serum trace elemental profile. AB - Homeostatic imbalance of essential trace elements is deeply involved in many pathophysiological states, especially in joint disorders such as gout. A total of 64 elements were measured in the serum samples in three regionally independent groups of patients with gouty arthritis (n = 100) and an age-matched healthy control group (n = 40) by inductively coupled plasma-mass spectrometry (ICP-MS). A distinct elemental profile of gouty arthritis encompassing significantly altered Li, Al, Ti, Fe, Cu, Se, Sr, Ta, Hg, Bi, Th, and U was obtained with a sensitivity of 0.97 (95% confidence interval (CI): 0.92-0.99) and a specificity of 0.95 (95% CI: 0.83-0.99) for gout diagnosis. An independent group of 52 subjects (39 gout patients and 13 healthy controls) was further used to validate the elemental signature, yielding a sensitivity of 1.00 (95% CI: 0.91-1.00) and a specificity of 1.00 (95% CI: 0.75-1.00) for gout prediction. It is also noteworthy that we were able to achieve >=95.7% correct classification rate in both discovery and validation groups using only three elemental markers, Li, Al, and U. We also observed a good correlation between Li, Zn, and Cu and the other two risk factors, age and serum urate concentration, in gout patients. Our findings underscore that gouty arthritis possesses a unique elemental expression profile regardless of many other nutritional and environmental factors. PMID- 22258547 TI - Use of hydroxychloroquine in corticodependent and recurrent scleritis. PMID- 22258549 TI - Bioactive composite gradient coatings of nano-hydroxyapatite/polyamide66 fabricated on polyamide66 substrates. AB - Tightly bonding of bioactive coating is the first crucial need for orthopaedic implants. This study describes a novel and convenient technique to prepare bioactive coating with high adhesion on orthopaedic substitutes made of polymeric matrix. Here, a chemical corrosion method has been adopted to fabricate a coating on the surface of injection-moulded polyamide66 (PA66) substrates by corrosive nano-hydroxyapatite/polyamide66 (n-HA/PA66) composite slurry. Scanning electron microscopy observation shows that a porous chemical corrosion region presents between the coating and dense PA66 substrate. Energy-dispersive X-ray spectroscopy analysis indicates that the chemical corrosion region is mainly composed of PA66 matrix, and the coating layer is an n-HA-rich layer. Both the pore size and n-HA composition increase gradually from the polymeric substrate towards the coating surface. Mechanical testing shows the bonding strength can reach 13.7 +/- 0.2 MPa, which is much higher than that fabricated on polymeric matrix by other coating methods. The gradual transition in coating structure and composition benefits for the interface bonding and for the surface bone-bonding bioactivity. Subsequent cell experiments corroborate n-HA-rich coating and a porous structure is benefitting for cell attachment and proliferation. The convenient coating method could be popularized and applied on similar polymer implants to produce a tightly and porous bioactive coating for bone tissue regeneration. PMID- 22258550 TI - Adhesion energy can regulate vesicle fusion and stabilize partially fused states. AB - Release of neurotransmitters from nerve terminals occurs by fusion of synaptic vesicles with the plasma membrane, and this process is highly regulated. Although major molecular components that control docking and fusion of vesicles to the synaptic membrane have been identified, the detailed mechanics of this process is not yet understood. We have developed a mathematical model that predicts how adhesion forces imposed by docking and fusion molecular machinery would affect the fusion process. We have computed the membrane stress that is produced by adhesion-driven vesicle bending and find that it is compressive. Further, our computations of the membrane curvature predict that strong adhesion can create a metastable state with a partially opened pore that would correspond to the 'kiss and run' release mode. Our model predicts that the larger the vesicle size, the more likely the metastable state with a transiently opened pore. These results contribute to understanding the mechanics of the fusion process, including possible clamping of the fusion by increasing molecular adhesion, and a balance between 'kiss and run' and full collapse fusion modes. PMID- 22258552 TI - A passerine spreads its tail to facilitate a rapid recovery of its body posture during hovering. AB - We demonstrate experimentally that a passerine exploits tail spreading to intercept the downward flow induced by its wings to facilitate the recovery of its posture. The periodic spreading of its tail by the White-eye bird exhibits a phase correlation with both wingstroke motion and body oscillation during hovering flight. During a downstroke, a White-eye's body undergoes a remarkable pitch-down motion, with the tail undergoing an upward swing. This pitch-down motion becomes appropriately suppressed at the end of the downstroke; the bird's body posture then recovers gradually to its original status. Employing digital particle-image velocimetry, we show that the strong downward flow induced by downstroking the wings serves as an external jet flow impinging upon the tail, providing a depressing force on the tail to counteract the pitch-down motion of the bird's body. Spreading of the tail enhances a rapid recovery of the body posture because increased forces are experienced. The maximum force experienced by a spread tail is approximately 2.6 times that of a non-spread tail. PMID- 22258551 TI - The effect of changes in condom usage and antiretroviral treatment coverage on human immunodeficiency virus incidence in South Africa: a model-based analysis. AB - This study aims to assess trends in human immunodeficiency virus (HIV) incidence in South Africa, and to assess the extent to which prevention and treatment programmes have reduced HIV incidence. Two models of the South African HIV epidemic, the STI (sexually transmitted infection)-HIV Interaction model and the ASSA2003 AIDS and Demographic model, were adapted. Both models were fitted to age specific HIV prevalence data from antenatal clinic surveys and household surveys, using a Bayesian approach. Both models suggest that HIV incidence in 15-49 year olds declined significantly between the start of 2000 and the start of 2008: by 27 per cent (95% CI: 21-32%) in the STI-HIV model and by 31 per cent (95% CI: 23 39%) in the ASSA2003 model, when expressed as a percentage of incidence rates in 2000. By 2008, the percentage reduction in incidence owing to increased condom use was 37 per cent (95% CI: 34-41%) in the STI-HIV model and 23 per cent (95% CI: 14-34%) in the ASSA2003 model. Both models also estimated a small reduction in incidence owing to antiretroviral treatment by 2008. Increased condom use therefore appears to be the most significant factor explaining the recent South African HIV incidence decline. PMID- 22258553 TI - Fitness-maximizing foragers can use information about patch quality to decide how to search for and within patches: optimal Levy walk searching patterns from optimal foraging theory. AB - Optimal foraging theory shows how fitness-maximizing foragers can use information about patch quality to decide how to search within patches. It is amply supported by empirical studies. Nonetheless, the theory largely ignores the fact that foragers may need to search for patches as well as for the targets within them. Here, using an exact but simple mathematical argument, it is shown how foragers can use information about patch quality to facilitate the execution of Levy walk movement patterns with MU = 2 at inter-patch scales. These movement patterns are advantageous when searching for patches that are not depleted or rejected once visited but instead remain profitable. The analytical results are verified by the results of numerical simulations. The findings bring forth an innovative theoretical synthesis of searching for and within patches and, suggest that foragers' memories may be adaptive under spatially heterogeneous reward schedules. PMID- 22258554 TI - Changes in kinematics and aerodynamics over a range of speeds in Tadarida brasiliensis, the Brazilian free-tailed bat. AB - To date, wake measurements using particle image velocimetry (PIV) of bats in flight have studied only three bat species, all fruit and nectar feeders. In this study, we present the first wake structure analysis for an insectivorous bat. Tadarida brasiliensis, the Brazilian free-tailed bat, is an aerial hunter that annually migrates long distances and also differs strikingly from the previously investigated species morphologically. We compare the aerodynamics of T. brasiliensis with those of other, frugivorous bats and with common swifts, Apus apus, a bird with wing morphology, kinematics and flight ecology similar to that of these bats. The comparison reveals that, for the range of speeds evaluated, the cyclical pattern of aerodynamic forces associated with a wingbeat shows more similarities between T. brasiliensis and A. apus than between T. brasiliensis and other frugivorous bats. PMID- 22258556 TI - Work and non-pathological gambling. AB - Most economists believe that people would value an additional $1,000 in income more if they were poor than if rich, but if so, people should not gamble according to standard expected utility theory. Thus, economists have been challenged to explain the pervasiveness of gambling in human behavior. A recently proposed solution to this theoretical challenge (Nyman 2004; Nyman et al. in Journal of Socio-Economics 37:2492-2504, 2008) suggests that, because having to work for one's income is a fact of life in market economies, many individuals view the winnings from gambling not only as additional income, but as additional income for which one does not need to work. As a result, individuals, and especially those who are disadvantaged in the labor market, attach a utility premium to gambling winnings and gamble because of that. This utility premium would explain the pervasiveness of gambling in society, especially among the economically disadvantaged. This paper reviews the economic approaches to explaining non-pathological gambling, presents an overview of the new theory, and uses data from the National Epidemiological Survey of Alcohol and Related Conditions from 2001 to test it. The results indicate that the respondent's work characteristics explain the decision to gamble in a way that is consistent with theory. PMID- 22258555 TI - Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. AB - A proline-to-serine substitution at position 56 in the gene encoding vesicle associated membrane protein-associated protein B (VAPB; VAPBP56S) causes some dominantly inherited familial forms of motor neuron disease, including amyotrophic lateral sclerosis (ALS) type-8. Here, we show that expression of ALS mutant VAPBP56S but not wild-type VAPB in neurons selectively disrupts anterograde axonal transport of mitochondria. VAPBP56S-induced disruption of mitochondrial transport involved reductions in the frequency, velocity and persistence of anterograde mitochondrial movement. Anterograde axonal transport of mitochondria is mediated by the microtubule-based molecular motor kinesin-1. Attachment of kinesin-1 to mitochondria involves the outer mitochondrial membrane protein mitochondrial Rho GTPase-1 (Miro1) which acts as a sensor for cytosolic calcium levels ([Ca(2+)]c); elevated [Ca(2+)]c disrupts mitochondrial transport via an effect on Miro1. To gain insight into the mechanisms underlying the VAPBP56S effect on mitochondrial transport, we monitored [Ca(2+)]c levels in VAPBP56S-expressing neurons. Expression of VAPBP56S but not VAPB increased resting [Ca(2+)]c and this was associated with a reduction in the amounts of tubulin but not kinesin-1 that were associated with Miro1. Moreover, expression of a Ca(2+) insensitive mutant of Miro1 rescued defective mitochondrial axonal transport and restored the amounts of tubulin associated with the Miro1/kinesin-1 complex to normal in VAPBP56S-expressing cells. Our results suggest that ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca(2+) homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin. PMID- 22258557 TI - A case of monoclonal immunoglobulin G1-lambda deposition associated with membranous feature in a patient with hepatitis C viral infection. AB - A 63-year-old man with hepatitis C virus infection was admitted to our hospital for nephrotic syndrome. Light microscopic analysis of a percutaneous renal biopsy showed thickening of the glomerular capillary walls and spike formation. Immunofluorescence revealed granular deposition of monoclonal immunoglobulin G1 lambda and C3 complement along the glomerular basement membrane. Urinary protein excretion decreased slightly after combined treatment with steroid and an immunosuppressive agent. Monoclonal immunoglobulin deposition disease with membranous feature is rare. Additional reports of such cases are needed to elucidate the mechanisms and optimal therapy for this rare entity. PMID- 22258558 TI - A case of minimal change nephrotic syndrome with immunoglobulin A nephropathy transitioned to focal segmental glomerulosclerosis. AB - A 50-year-old woman with a 1-month history of lower extremity edema and a 5 kg weight increase was admitted to our hospital with suspected nephrotic syndrome in October 1999. Urine protein level was 3.5 g per day, 10-15 erythrocytes in urine per high-power field, and serum albumin level 2.5 g/dl. Furthermore, an accumulation of pleural effusion was confirmed by chest X-ray. The results of a renal biopsy indicated slight mesangial proliferation in the glomeruli by light microscopy, and an immunofluorescence study confirmed the deposition of immunoglobulin (Ig) A and C3 in the mesangial area. Diffuse attenuation of foot processes and dense deposits in the mesangial area were observed by electron microscopy. Treatment with 40 mg/day of prednisolone was effective, and proteinuria was negative 1 month later. Because of this course, we diagnosed minimal change nephrotic syndrome complicated by mild-proliferative IgA nephropathy. In November 2000, there was a relapse of nephrotic syndrome, which was believed to be induced by an influenza vaccination, but response to increased steroid treatment was favorable, and proteinuria disappeared on day 13 of steroid increase. A second relapse in May 2001, showed steroid resistance with renal insufficiency, and an increase in the selectivity index to 0.195. Light microscopy revealed focal sclerotic lesions of the glomeruli, and an immunofluorescence study revealed attenuation of mesangial IgA and C3 deposition. These findings led to the diagnosis that minimal change nephrotic syndrome had transitioned to focal segmental glomerulosclerosis, whereby mesangial IgA deposition was reduced by immunosuppressive treatment. Subsequently, her renal function gradually worsened to the point of end-stage renal failure by 27 months after the second relapse of nephrotic syndrome. PMID- 22258559 TI - Predicting inpatient aggression using the InterRAI risk of harm to others clinical assessment protocol: a tool for risk assessment and care planning. AB - This study examined the ability of a risk assessment algorithm, the Risk of Harm to Others Clinical Assessment Protocol (RHO CAP) to predict inpatient aggression within a mental health and addictions treatment facility in Ontario, Canada. Anonymized patient records were retrospectively reviewed from April 1, 2004 to July 31, 2009 (N = 6,425). Survival analysis using Cox's regression was used to predict time to inpatient aggression using the RHO CAP. Approximately 10% of inpatients were at moderate risk of harm to others, and 2% were considered high risk. The pattern of survival curves revealed that within the first month of admission, approximately 10% of inpatients at high risk of harm to others displayed physical aggression. Patients at high risk were also two times more likely to display physical aggression. Clinical teams can use the RHO CAP to implement preventive safety measures, reduce the incidence of inpatient aggression and improve quality of care. PMID- 22258560 TI - The role of upstream stimulatory factor 1 in the transcriptional regulation of the human TBX21 promoter mediated by the T-1514C polymorphism associated with systemic lupus erythematosus. AB - T-bet is a key regulator for the lineage commitment in CD4+ T helper (Th) 1 cells by activating the hallmark production of interferon-gamma. Previously, two single nucleotide polymorphisms (SNPs) in the TBX21 promoter, T-1993C and T-1514C, have been shown by statistic studies to associate with systemic lupus erythematosus (SLE). The effect of -1993 SNP on the Yin Yang 1 transcription factor-mediated promoter activity has been already indicated. This study aimed to investigate roles of the T-1514C SNP on TBX21 transcription and its functional effect by luciferase reporter, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assay, and flow cytometric analysis of intracellular T bet, IFN-gamma, and IL-4 expression in activated CD4+ T cells. The TBX21 promoter carrying -1514C possessed significantly lower transcriptional activity than that of -1514T and was markedly downregulated by the overexpression of upstream stimulatory factor 1 (USF-1) when compared with the promoter carrying -1514T. EMSA indicated that the transcription factor USF-1 was bound to the -1514C allele probe with the affinity higher than that to the -1514T allele probe. ChIP assay suggested that USF-1 bound around -1514 of TBX21 genomic DNA in vivo in the human T cell line Jurkat with -1514C/T. The individuals carrying -1514C allele were determined to have significantly diminished expression of T-bet and IFN-gamma and increased IL-4 production in CD4+ T cells compared with those of -1514T allele. The findings demonstrate that the T-1514C polymorphism affects TBX21 gene expression and Th1 cytokine production by binding USF-1 to the SNP site. PMID- 22258561 TI - The shortest isoform of dystrophin (Dp40) interacts with a group of presynaptic proteins to form a presumptive novel complex in the mouse brain. AB - Duchenne muscular dystrophy (DMD) causes cognitive impairment in one third of the patients, although the underlying mechanisms remain to be elucidated. Recent studies showed that mutations in the distal part of the dystrophin gene correlate well with the cognitive impairment in DMD patients, which is attributed to Dp71. The study on the expression of the shortest isoform, Dp40, has not been possible due to the lack of an isoform specific antibody. Dp40 has the same promoter as that found in Dp71 and lacks the normal C-terminal end of Dp427. In the present study, we have raised polyclonal antibody against the N-terminal sequence common to short isoforms of dystrophin, including Dp40, and investigated the expression pattern of Dp40 in the mouse brain. Affinity chromatography with this antibody and the consecutive LC-MS/MS analysis on the interacting proteins revealed that Dp40 was abundantly expressed in synaptic vesicles and interacted with a group of presynaptic proteins, including syntaxin1A and SNAP25, which are involved in exocytosis of synaptic vesicles in neurons. We thus suggest that Dp40 may form a novel protein complex and play a crucial role in presynaptic function. Further studies on these aspects of Dp40 function might provide more insight into the molecular mechanisms of cognitive impairment found in patients with DMD. PMID- 22258562 TI - Arthroscopically determined degree of injury after shoulder dislocation relates to recurrence rate. AB - BACKGROUND: The glenohumeral joint is the most mobile articulation in the body and the most commonly dislocated diarthrodial joint with peaks in the incidence of dislocation occurring during the second and sixth decades. Age at the time of the initial dislocation is inversely related to the recurrence rate. Traumatic anterior instability is often associated with intraarticular injuries. The frequency of injuries may increase with dislocation or subluxation episodes. QUESTIONS/PURPOSES: We compared the frequency of lesions associated with traumatic anterior instability in patients with primary and recurrent instability. METHODS: We retrospectively reviewed 96 selected patients with traumatic anterior instability treated arthroscopically between 2005 and 2008. Forty-five had arthroscopy after a first episode of dislocation (Group I) and 51 had two or more episodes of instability (Group II). We compared the frequencies and percentage of intraarticular lesions in both groups. RESULTS: We observed a Bankart lesion in all patients of both groups. The posterior Bankart lesion was observed more frequently in Group II than in Group I: 47% versus 28%. SLAP lesions were observed in 12% in Group I and 24% in Group II. In 10 patients in Group II, there was an associated rotator cuff tear. CONCLUSIONS: Patients with recurrent shoulder dislocation had a higher arthroscopic degree of injury. These patients presented more posterior labral lesions, SLAP tears, and rotator cuff pathology than patients with a first episode of shoulder dislocation. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22258563 TI - Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. AB - In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e., HepG2, HepaRG cells, and fresh primary human hepatocytes) at the gene expression level and analyze their metabolic cytochrome P450 capabilities. The cellular models were exposed to three different CYP450 inducers; beta naphthoflavone (BNF), phenobarbital (PB), and rifampicin (RIF). HepG2 cells responded very weakly to the different inducers at the gene expression level, and this translated generally into low CYP450 activities in the induced cells compared with the control cells. On the contrary, HepaRG cells and the three human donors were inducible after exposure to BNF, PB, and RIF according to gene expression responses and CYP450 activities. Consequently, HepaRG cells could be used in screening as a substitute and/or in complement to primary hepatocytes for CYP induction studies. The second objective was to investigate the predictivity of the different cellular models to detect hepatotoxins (16 hepatotoxic and 5 nonhepatotoxic compounds). Specificity was 100% with the different cellular models tested. Cryopreserved human hepatocytes gave the highest sensitivity, ranging from 31% to 44% (depending on the donor), followed by lower sensitivity (13%) for HepaRG and HepG2 cells (6.3%). Overall, none of the models under study gave desirable sensitivities (80-100%). Consequently, a high metabolic capacity and CYP inducibility in cell lines does not necessarily correlate with a high sensitivity for the detection of hepatotoxic drugs. Further investigations are necessary to compare different cellular models and determine those that are best suited for the detection of hepatotoxic compounds. PMID- 22258565 TI - Effect of do-not-resuscitate orders on the penumbra of care. PMID- 22258564 TI - Bedside prediction rule for infections after pediatric cardiac surgery. AB - PURPOSE: Infections after pediatric cardiac surgery are a common complication, occurring in up to 30% of cases. The purpose of this study was to develop a bedside prediction rule to estimate the risk of a postoperative infection. METHODS: All consecutive pediatric cardiac surgery procedures between April 2006 and May 2009 were retrospectively analyzed. The primary outcome variable was any postoperative infection, as defined by the Center of Disease Control (2008). All variables known to the clinician at the bedside at 48 h post cardiac surgery were included in the primary analysis, and multivariable logistic regression was used to construct a prediction rule. RESULTS: A total of 412 procedures were included, of which 102 (25%) were followed by an infection. Most infections were surgical site infections (26% of all infections) and bloodstream infections (25%). Three variables proved to be most predictive of an infection: age less than 6 months, postoperative pediatric intensive care unit (PICU) stay longer than 48 h, and open sternum for longer than 48 h. Translation into prediction rule points yielded 1, 4, and 1 point for each variable, respectively. Patients with a score of 0 had 6.6% risk of an infection, whereas those with a maximal score of 6 had a risk of 57%. The area under the receiver operating characteristic curve was 0.78 (95% confidence interval 0.72-0.83). CONCLUSIONS: A simple bedside prediction rule designed for use at 48 h post cardiac surgery can discriminate between children at high and low risk for a subsequent infection. PMID- 22258566 TI - Femtosecond to millisecond studies of electron transfer processes in a donor-(pi spacer)-acceptor series of organic dyes for solar cells interacting with titania nanoparticles and ordered nanotube array films. AB - Time-resolved emission and absorption spectroscopy are used to study the photoinduced dynamics of forward and back electron transfer processes taking place between a recently synthesized series of donor-(pi-spacer)-acceptor organic dyes and semiconductor films. Results are obtained for vertically oriented titania nanotube arrays (inner diameters 36 nm and 70 nm), standard titania nanoparticles (25 nm diameter) and, as a reference, alumina nanoparticle (13 nm diameter) films. The studied dyes contain a triphenylamine group as an electron donor, cyanoacrylic acid part as an electron acceptor, and differ by the substituents in a spacer group that causes a shift of its absorption spectra. Despite a red-shift of the dye absorption band resulting in an improved response to the solar spectrum, smaller electron injection rates and smaller extinction coefficients result in reduced dye sensitized solar cell (DSSC) conversion efficiencies. For the most efficient dye, TPC1, electron injection from the hot locally excited state to titania on a time scale of about 100 fs is suggested, while from the relaxed charge transfer state it proceeds in a non-exponential way with time constants from 1 ps to 50 ps. Our results imply that the latter process involves the trap states below the conduction band edge (or the sub-bandgap tail of the acceptor states), localized close to the dye radical cation, and is accompanied by fast electron recombination to the parent dye's ground state. This process should limit the efficiency of DSSCs made using these types of organic dyes. The residual, slower recombination can be described by a stretched exponential decay with a characteristic time of 0.5 MUs and a dispersion parameter of 0.33. Both the electron injection and back electron transfer dynamics are similar in titania nanoparticles and nanotubes. Variations between the two film types are only found in the time resolved emission transients, which are explained in terms of the difference in local electric fields affecting the position of the emission bands. PMID- 22258567 TI - Antarctic Treaty is cold comfort. PMID- 22258568 TI - Face up to fraud. PMID- 22258569 TI - Cap in hand. PMID- 22258570 TI - Break down boundaries in climate research. PMID- 22258581 TI - Pollutants key to climate fix. PMID- 22258582 TI - Database tallies US emissions. PMID- 22258583 TI - Evolution advocate turns to climate. PMID- 22258584 TI - Murders unlikely to slow Iran's nuclear efforts. PMID- 22258585 TI - Russian drug law hinders clinical trials. PMID- 22258586 TI - Gemini's twin telescopes reboot. PMID- 22258587 TI - Finding philanthropy: Like it? Pay for it. PMID- 22258588 TI - Alternative funding: Sponsor my science. PMID- 22258589 TI - Philanthropy: The price of charity. PMID- 22258594 TI - Pharmaceutical industry: Investors unfazed by drug-patent expiry. PMID- 22258595 TI - Overfishing: Call to split fisheries at home and abroad. PMID- 22258596 TI - Leap year: Rare day to highlight rare diseases. PMID- 22258597 TI - Asian medicine: Small species at risk. PMID- 22258598 TI - Paul Mead Doty (1920-2011). PMID- 22258599 TI - Genomics: The path to retinoblastoma. PMID- 22258600 TI - Galaxy formation: Distant dwarfs. PMID- 22258602 TI - Cell cycle: A division duet. PMID- 22258603 TI - Organic chemistry: Stabilizers cause instability. PMID- 22258604 TI - Cancer: Reprogramming clinical outcome. PMID- 22258605 TI - Frontiers in biology. PMID- 22258606 TI - Inflammasomes in health and disease. AB - Inflammasomes are a group of protein complexes built around several proteins, including NLRP3, NLRC4, AIM2 and NLRP6. Recognition of a diverse range of microbial, stress and damage signals by inflammasomes results in direct activation of caspase-1, which subsequently induces secretion of potent pro inflammatory cytokines and a form of cell death called pyroptosis. Inflammasome mediated processes are important during microbial infections and also in regulating both metabolic processes and mucosal immune responses. We review the functions of the different inflammasome complexes and discuss how aberrations in them are implicated in the pathogenesis of human diseases. PMID- 22258607 TI - The DNA damage response and cancer therapy. AB - Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease. PMID- 22258608 TI - The promise of induced pluripotent stem cells in research and therapy. AB - The field of stem-cell biology has been catapulted forward by the startling development of reprogramming technology. The ability to restore pluripotency to somatic cells through the ectopic co-expression of reprogramming factors has created powerful new opportunities for modelling human diseases and offers hope for personalized regenerative cell therapies. While the field is racing ahead, some researchers are pausing to evaluate whether induced pluripotent stem cells are indeed the true equivalents of embryonic stem cells and whether subtle differences between these types of cell might affect their research applications and therapeutic potential. PMID- 22258609 TI - Clonal evolution in cancer. AB - Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control. PMID- 22258610 TI - The contribution of bone to whole-organism physiology. AB - The mouse genetic revolution has shown repeatedly that most organs have more functions than expected. This has led to the realization that, in addition to a molecular and cellular approach, there is a need for a whole-organism study of physiology. The skeleton is an example of how a whole-organism approach to physiology can broaden the functions of a given organ, reveal connections of this organ with others such as the brain, pancreas and gut, and shed new light on the pathogenesis of degenerative diseases affecting multiple organs. PMID- 22258612 TI - Gravitational detection of a low-mass dark satellite galaxy at cosmological distance. AB - The mass function of dwarf satellite galaxies that are observed around Local Group galaxies differs substantially from simulations based on cold dark matter: the simulations predict many more dwarf galaxies than are seen. The Local Group, however, may be anomalous in this regard. A massive dark satellite in an early type lens galaxy at a redshift of 0.222 was recently found using a method based on gravitational lensing, suggesting that the mass fraction contained in substructure could be higher than is predicted from simulations. The lack of very low-mass detections, however, prohibited any constraint on their mass function. Here we report the presence of a (1.9 +/- 0.1) * 10(8) M dark satellite galaxy in the Einstein ring system JVAS B1938+666 (ref. 11) at a redshift of 0.881, where M denotes the solar mass. This satellite galaxy has a mass similar to that of the Sagittarius galaxy, which is a satellite of the Milky Way. We determine the logarithmic slope of the mass function for substructure beyond the local Universe to be 1.1(+0.6)(-0.4), with an average mass fraction of 3.3(+3.6)(-1.8) per cent, by combining data on both of these recently discovered galaxies. Our results are consistent with the predictions from cold dark matter simulations at the 95 per cent confidence level, and therefore agree with the view that galaxies formed hierarchically in a Universe composed of cold dark matter. PMID- 22258611 TI - The Amazon basin in transition. AB - Agricultural expansion and climate variability have become important agents of disturbance in the Amazon basin. Recent studies have demonstrated considerable resilience of Amazonian forests to moderate annual drought, but they also show that interactions between deforestation, fire and drought potentially lead to losses of carbon storage and changes in regional precipitation patterns and river discharge. Although the basin-wide impacts of land use and drought may not yet surpass the magnitude of natural variability of hydrologic and biogeochemical cycles, there are some signs of a transition to a disturbance-dominated regime. These signs include changing energy and water cycles in the southern and eastern portions of the Amazon basin. PMID- 22258614 TI - Kimberlite ascent by assimilation-fuelled buoyancy. AB - Kimberlite magmas have the deepest origin of all terrestrial magmas and are exclusively associated with cratons. During ascent, they travel through about 150 kilometres of cratonic mantle lithosphere and entrain seemingly prohibitive loads (more than 25 per cent by volume) of mantle-derived xenoliths and xenocrysts (including diamond). Kimberlite magmas also reputedly have higher ascent rates than other xenolith-bearing magmas. Exsolution of dissolved volatiles (carbon dioxide and water) is thought to be essential to provide sufficient buoyancy for the rapid ascent of these dense, crystal-rich magmas. The cause and nature of such exsolution, however, remains elusive and is rarely specified. Here we use a series of high-temperature experiments to demonstrate a mechanism for the spontaneous, efficient and continuous production of this volatile phase. This mechanism requires parental melts of kimberlite to originate as carbonatite-like melts. In transit through the mantle lithosphere, these silica-undersaturated melts assimilate mantle minerals, especially orthopyroxene, driving the melt to more silicic compositions, and causing a marked drop in carbon dioxide solubility. The solubility drop manifests itself immediately in a continuous and vigorous exsolution of a fluid phase, thereby reducing magma density, increasing buoyancy, and driving the rapid and accelerating ascent of the increasingly kimberlitic magma. Our model provides an explanation for continuous ascent of magmas laden with high volumes of dense mantle cargo, an explanation for the chemical diversity of kimberlite, and a connection between kimberlites and cratons. PMID- 22258613 TI - Coherent singlet-triplet oscillations in a silicon-based double quantum dot. AB - Silicon is more than the dominant material in the conventional microelectronics industry: it also has potential as a host material for emerging quantum information technologies. Standard fabrication techniques already allow the isolation of single electron spins in silicon transistor-like devices. Although this is also possible in other materials, silicon-based systems have the advantage of interacting more weakly with nuclear spins. Reducing such interactions is important for the control of spin quantum bits because nuclear fluctuations limit quantum phase coherence, as seen in recent experiments in GaAs based quantum dots. Advances in reducing nuclear decoherence effects by means of complex control still result in coherence times much shorter than those seen in experiments on large ensembles of impurity-bound electrons in bulk silicon crystals. Here we report coherent control of electron spins in two coupled quantum dots in an undoped Si/SiGe heterostructure and show that this system has a nuclei-induced dephasing time of 360 nanoseconds, which is an increase by nearly two orders of magnitude over similar measurements in GaAs-based quantum dots. The degree of phase coherence observed, combined with fast, gated electrical initialization, read-out and control, should motivate future development of silicon-based quantum information processors. PMID- 22258616 TI - Are wider surgical margins needed for early oral tongue cancer? AB - BACKGROUND: Traditionally, a 1-cm surgical resection margin is used for early oral tongue tumours. METHODS: All tumour stage one (n = 65) and stage two (n = 13) oral tongue cancers treated between January 1999 and January 2009 were followed for a median of 38 months (minimum 12 months). The sites of close and involved margins were histologically reviewed. RESULTS: Involved and close margins occurred in 14 and 55 per cent of cases, respectively. The number of involved vs clear or close margins was equivalent in tumour stage one (90 vs 82 per cent), node-negative (100 vs 84 per cent) and perineural or lymphovascular invasion (20 vs 21 per cent) cases. Close or involved margins were similarly likely to be posterior (59 per cent) as anterior (41 per cent, p = 0.22), lateral (57 per cent) as medial (43 per cent, p = 0.34), and mucosal (59 per cent) as deep (41 per cent, p = 0.22). Local recurrence occurred in 28 per cent of cases at a median of 12 months, and was more likely in cases with involved (50 per cent) than clear or close margins (25 per cent, p = 0.10). Disease-free survival was worse in involved margins cases (p = 0.002). CONCLUSION: Involved margins are common in early tongue tumours, and are associated with increased local recurrence and worse survival. Close or involved margins occur in all directions and all tumour types. A wider margin may be justified. PMID- 22258618 TI - Introduction. Canines only. PMID- 22258617 TI - ENU mutagenesis in mice identifies candidate genes for hypogonadism. AB - Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low-density genome-wide SNP arrays. Ten of the 15 lines were pursued further using higher-resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism, candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility. PMID- 22258619 TI - Fluorescent dye-doped silica nanoparticles: new tools for bioapplications. AB - The need to decipher various biological events has led to the elucidation of the molecular mechanisms underlying a number of disease processes. Consequently, the detection and simultaneous monitoring of chemical interactions between biological targets has become indispensable in medical diagnosis, targeted therapeutics, and molecular biology. Multiplexed applications employing nanomaterials, which represent the integration of nanotechnology and biology, have changed the bioanalytical outlook and provided various promising tools. Among these nanomaterials, fluorescent dye-doped silica nanoparticles have demonstrated excellent potential for use in advanced bioanalysis to facilitate deeper understanding of biology and medicine at the molecular level. In particular, silica nanoparticles have been applied to diagnostics and therapeutic applications in cancer and gene/drug delivery. This feature article summarizes recent developments in the synthesis, biocompatibility, and bioapplications of fluorescent dye-doped silica nanoparticles. PMID- 22258620 TI - Pten coordinates retinal neurogenesis by regulating Notch signalling. AB - Development of nervous tissue is a coordinated process of neural progenitor cell (NPC) proliferation and neuronal differentiation. Intracellular signalling events that regulate the balance between NPC proliferation and neuronal differentiation, therefore, determine the size and composition of nervous tissues. Here, we demonstrate that negative regulation of phosphoinosite 3-kinase (PI3K)-Akt signalling by phosphatase tensin homologue (Pten) is essential for maintaining NPC population in mouse retina. We found that mouse retinal progenitor cells (RPCs) lacking the Pten gene complete neurogenesis earlier than their normal developmental schedule, resulting in their premature depletion in the mature retina. We further discover that Notch intracellular domain (NICD) fails to form transcription activator complex in Pten-deficient RPCs, and thereby unable to support RPC maintenance. Taken together, our results suggest that Pten plays a pivotal role in retinal neurogenesis by supporting Notch-driven RPC maintenance against neurogenic PI3K-Akt signalling. PMID- 22258621 TI - DNA binding to proteolytically activated TLR9 is sequence-independent and enhanced by DNA curvature. AB - Toll-like receptor 9 (TLR9) recognizes microbial DNA in endolysosomal compartments. The ectodomain of TLR9 must be proteolytically cleaved by endosomal proteases to produce the active receptor capable of inducing an innate immune signal. We show that the cleaved TLR9 ectodomain is a monomer in solution and that DNA ligands with phosphodiester backbones induce TLR9 dimerization in a sequence-independent manner. Ligands with phosphorothioate (PS) backbones induce the formation of large TLR9-DNA aggregates, possibly due to the propensity of PS ligands to self-associate. DNA curvature-inducing proteins including high mobility group box 1 and histones H2A and H2B significantly enhance TLR9 binding, suggesting that TLR9 preferentially recognizes curved DNA backbones. Our work sheds light on the molecular mechanism of TLR9 activation by endogenous protein nucleic acid complexes, which are associated with autoimmune diseases including systemic lupus erythematosus. PMID- 22258622 TI - Cost-effectiveness of a classification-based system for sub-acute and chronic low back pain. AB - PURPOSE: Identifying relevant subgroups in patients with low back pain (LBP) is considered important to guide physical therapy practice and to improve outcomes. The aim of the present study was to assess the cost-effectiveness of a modified version of Delitto's classification-based treatment approach compared with usual physical therapy care in patients with sub-acute and chronic LBP with 1 year follow-up. METHODS: All patients were classified using the modified version of Delitto's classification-based system and then randomly assigned to receive either classification-based treatment or usual physical therapy care. The main clinical outcomes measured were; global perceived effect, intensity of pain, functional disability and quality of life. Costs were measured from a societal perspective. Multiple imputations were used for missing data. Uncertainty surrounding cost differences and incremental cost-effectiveness ratios was estimated using bootstrapping. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated. RESULTS: In total, 156 patients were included. The outcome analyses showed a significantly better outcome on global perceived effect favoring the classification-based approach, and no differences between the groups on pain, disability and quality-adjusted life-years. Mean total societal costs for the classification-based group were 2,287, and for the usual physical therapy care group 2,020. The difference was 266 (95% CI -720 to 1,612) and not statistically significant. Cost effectiveness analyses showed that the classification-based approach was not cost effective in comparison with usual physical therapy care for any clinical outcome measure. CONCLUSION: The classification-based treatment approach as used in this study was not cost-effective in comparison with usual physical therapy care in a population of patients with sub-acute and chronic LBP. PMID- 22258623 TI - In vivo imaging of the mouse spinal cord using two-photon microscopy. AB - In vivo imaging using two-photon microscopy in mice that have been genetically engineered to express fluorescent proteins in specific cell types has significantly broadened our knowledge of physiological and pathological processes in numerous tissues in vivo. In studies of the central nervous system (CNS), there has been a broad application of in vivo imaging in the brain, which has produced a plethora of novel and often unexpected findings about the behavior of cells such as neurons, astrocytes, microglia, under physiological or pathological conditions. However, mostly technical complications have limited the implementation of in vivo imaging in studies of the living mouse spinal cord. In particular, the anatomical proximity of the spinal cord to the lungs and heart generates significant movement artifact that makes imaging the living spinal cord a challenging task. We developed a novel method that overcomes the inherent limitations of spinal cord imaging by stabilizing the spinal column, reducing respiratory-induced movements and thereby facilitating the use of two-photon microscopy to image the mouse spinal cord in vivo. This is achieved by combining a customized spinal stabilization device with a method of deep anesthesia, resulting in a significant reduction of respiratory-induced movements. This video protocol shows how to expose a small area of the living spinal cord that can be maintained under stable physiological conditions over extended periods of time by keeping tissue injury and bleeding to a minimum. Representative raw images acquired in vivo detail in high resolution the close relationship between microglia and the vasculature. A timelapse sequence shows the dynamic behavior of microglial processes in the living mouse spinal cord. Moreover, a continuous scan of the same z-frame demonstrates the outstanding stability that this method can achieve to generate stacks of images and/or timelapse movies that do not require image alignment post-acquisition. Finally, we show how this method can be used to revisit and reimage the same area of the spinal cord at later timepoints, allowing for longitudinal studies of ongoing physiological or pathological processes in vivo. PMID- 22258624 TI - Results and relevance of molecular detection of pathogens by SeptiFast--a retrospective analysis in 75 critically ill children. AB - BACKGROUND: Sepsis is a common cause of death in children. Early detection of bloodstream pathogens is crucial for the appropriate antibio-tic treatment. Blood cultures (BC) are the gold standard test used for detection. Recently, additional molecular detection methods of microbial DNA by multiplex PCR (SeptiFast, SF) have become available. AIM: Our retrospective study was aimed to compare results of BC to those of SF regarding results and therapeutic relevance. METHOD: We identified a total of 110 SF samples in 75 patients with suspected systemic infection by retrospective chart review. Each patient underwent SF and BC testing simultaneously. RESULTS: The initial analysis displayed no statistical significant difference in positive SF results compared to BC (p=0.19): in 26 of 110 samples (24%) microbial DNA was found. 19 BC (17%) showed microbial growth. 14 samples were positive in SF but negative in BC (13%). In patients who were pretreated with antibiotics (n=97) pathogens were identified in 24 samples by SF (25%) but only in 11 samples by BC (11%). Based on the clinical presentation and the spectrum of bacterial isolates 3 BC were considered contaminated. Considering this, SF yielded pathogens significantly more often than BC in the overall study population (p=0.04). SF results were available at least 31 h before BC results. Based on SF result antibiotic therapy was adjusted in 14 patients (13%). CONCLUSION: Molecular detection of pathogens by SF was faster and more frequently positive than BC. We have therefore demonstrated that SF might be superior to BC in testing for bloodstream pathogens. Prospective multicentric studies are required to determine whether this hypothesis can be maintained. PMID- 22258625 TI - 3D morphology of Au and Au@Ag nanobipyramids. AB - The morphologies of Au and Au@Ag nanobipyramids were investigated using electron tomography. The 3D reconstruction reveals that the Au bipyramids have an irregular six-fold twinning structure with highly stepped dominant {151} facets. These short steps/edges stabilized via surface adsorbed CTAB favor the growth of silver on the lateral facets leading to strong blue shifts in longitudinal plasmon surface resonance. PMID- 22258626 TI - Cadmium and lead content in several brands of rice grains (Oryza sativa) in central Iran. AB - The aim of this study was to investigate the cadmium (Cd) and lead (Pb) content of several commercially available brands of rice grains (Oryza sativa) in central Iran. A total of 67 samples of the most widely consumed brands of rice grains were purchased from local bazaar markets in Shahrekord, Iran. The first step, grains of raw rice were digested by acid digestion method and then were analyzed by atomic absorption spectrometer. The results showed that Cd concentration in rice grains ranged from 0.0378 to 0.1225 ppm dry weight and its average concentration was 0.062 +/- 0.019 ppm and Pb content ranged from 0.0405 to 0.1281 ppm dry weight and its average concentration was 0.068 +/- 0.0185 ppm. Cd and Pb concentrations in the sampled rice grains were lower in comparison with their upper limits (0.2 and 0.2 ppm for Cd and Pb, respectively) approved by food sanitary standard. Therefore, it can be concluded that there is no health problems due to the consumption of brands of rice grains, for these two elements. The results indicated that weekly intake of Cd and Pb from rice grains was below the provisional tolerable weekly intakes recommended by WHO/FAO. PMID- 22258627 TI - Effects of progesterone application on antioxidant enzyme activities and K+/Na+ ratio in bean seeds exposed to salt stress. AB - This study aimed to investigate the influence of progesterone, a mammalian sex hormone, on germination of bean (Phaseolus vulgaris L.) seeds exposed to salt stress. The exogenous addition of 10(-6), 10(-8) and 10(-10) M progesterone to the stressing media in which bean seeds were germinated in combination with the salt (100 mM NaCl) stressor induced significant protective changes in the germination and early growth parameters. The mitigating effect of progesterone was evaluated by the measurement of radicle and plumule lengths, activities of antioxidant enzymes superoxide dismutase (SOD), peroxidase (POX) and catalase (CAT). In addition, it is the first study that exhibited changes in K/Na ratio. The obtained results showed that progesterone application stimulated germination and growth of salt-stressed seeds. Similarly, it stimulated significantly SOD, POX and CAT activities compared to both control and salt control. Salt stress significantly increased the lipid peroxidation compared to the control seeds. However, parallel to the increase in antioxidant activity, lipid peroxidation was significantly reduced by progesterone application. The best stimulatory effects on investigated parameters were recorded at 10(-8) M progesterone-applied seeds. On the other hand, salt stress reduced remarkably K/Na ratio by 50% in radicle and by 80% in plumule. However, progesterone application significantly mitigated the reduction in K/Na ratio. These findings clearly demonstrate that progesterone has a positive role in moderate detrimental effects induced by salt. PMID- 22258628 TI - Need and supply gap in occupational health manpower in India. AB - Industrial growth in India has resulted in increased employment opportunities, thereby inflating the size of the workforce engaged in both organized and unorganized sectors. This workforce is exposed to various occupational factors at workplace and hence is susceptible to occupational diseases, which requires trained occupational health manpower. The present study is undertaken to estimate the need and supply gap of occupational health manpower, based on present regulations. The total workforce in the organized sector in India is 26.92 million. There are 254,951 working registered industrial factories in India, with about 11.16 million workers. These factories have employed 6953 factory medical officers (FMOs) and 2308 safety officers (SOs). Hence, for 26.92 million of total workforce engaged in organized sector, we would require a total of 16,728 FMOs and 5619 SOs, thereby estimating the deficit of 58% for FMOs and 59% for SOs based on current ratio of employment. PMID- 22258629 TI - Toxic effects of chromium on tannery workers at Sialkot (Pakistan). AB - Chromium is widely used in the leather industry, and tannery workers are under constant threat of adverse health effects due to its excessive exposure. Our objective was to find out the toxic effects of chromium on tannery workers at Sialkot, Pakistan. A total of 240 males consisting of 120 workers from tanneries at Sialkot and equal number of controls were included. Blood complete counts, high-sensitive C-reactive protein, malondialdehyde and routine biochemical tests were carried out by routine procedures. Chromium levels in blood (BCr) and urine were analyzed using graphite furnace atomic absorption spectrophotometer Perkin Elmer analyst-200. Results revealed that all the workers were male with average age of 33 years and 15 (13%) had skin rashes, 14 (12%) had chronic bronchitis, 10 (8%) had gastritis and 4 (3%) conjunctivitis. The tannery workers had significantly raised median (interquartile range) of BCr 569 (377-726) nmol/L as compared to 318 (245-397) nmol/L in the control (p < 0.001). Sixty-five (54%) workers had BCr levels above the upper limit set by Agency for Toxic Substance and Drug Registry. The urinary chromium excretion was significantly high in workers 131 (46-312) nmol/L as compared to 13 (3-26) nmol/L in controls (p < 0.01). The workers had hematological, hepatic and renal function impairment because of oxidative stress on body systems. It is concluded that about half of the workers had excessive exposure to chromium in the tanneries at Sialkot. They had significantly raised chromium levels in their biological fluids and adverse health effects due to enhanced oxidative stress and inflammatory changes. PMID- 22258630 TI - Unfavourable consequences of chronic cardiac HIF-1alpha stabilization. AB - AIMS: The hypoxia-inducible factor-1 (HIF-1) is the master modulator of hypoxic gene expression. The effects of chronically stabilized cardiac HIF-1alpha and its role in the diseased heart are not precisely known. The aims of this study were as follows: (i) to elucidate consequences of HIF-1alpha stabilization in the heart; (ii) to analyse long-term effects of HIF-1alpha stabilization with ageing and the ability of the HIF-1alpha overexpressing hearts to respond to increased mechanical load; and (iii) to analyse HIF-1alpha protein levels in failing heart samples. METHODS AND RESULTS: In a cardiac-specific HIF-1alpha transgenic mouse model, constitutive expression of HIF-1alpha leads to changes in capillary area and shifts the cardiac metabolism towards glycolysis with a net increase in glucose uptake. Furthermore, Ca(2+) handling is altered, with increased Ca(2)(+) transients and faster intracellular [Ca(2+)] decline. These changes are associated with decreased expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a but elevated phosphorylation of phospholamban. HIF-1alpha transgenic mice subjected to transverse aortic constriction exhibited profound cardiac decompensation. Moreover, cardiomyopathy was also seen in ageing transgenic mice. In parallel, we found an increased stabilization of HIF-1alpha in heart samples of patients with end-stage heart failure. CONCLUSION: Changes induced with transgenic cardiac HIF-1alpha possibly mediate beneficial effects in the short term; however, with increased mechanical load and ageing they become detrimental for cardiac function. Together with the finding of increased HIF 1alpha protein levels in samples from human patients with cardiomyopathy, these data indicate that chronic HIF-1alpha stabilization drives autonomous pathways that add to disease progression. PMID- 22258632 TI - Reduction in IL-33 expression exaggerates ischaemia/reperfusion-induced myocardial injury in mice with diabetes mellitus. AB - AIMS: The underlying mechanism(s) of vulnerability of the diabetic myocardium to ischaemia/reperfusion (I/R)-induced injury is not fully understood. Interleukin 33 (IL-33) has been reported showing the beneficial effect to the myocardium on I/R injury. The aims of this study were to test whether diabetes mellitus (DM) affects myocardial levels of IL-33 and to examine whether reduction in IL-33 is responsible for exaggerated I/R injury in the diabetic myocardium. METHODS AND RESULTS: DM hearts were challenged with I/R in vivo, whereas while isolated cardiomyocytes in vitro were conditioned with high glucose (HG) followed by an anoxia/reoxygenation (A/R) challenge. Myocardial levels of IL-33 were decreased in mice with DM which was associated with increased protein kinase C betaII (PKCbetaII) activation. Exogenous IL-33 prevented the DM-induced PKCbetaII activation and attenuated I/R injuries (myocardial infarction size and apoptosis). HG-conditioned myocytes incurred exaggerated apoptosis when compared with naive myocytes after A/R which was attenuated by IL-33. HG activated PKCbetaII in cardiomyocytes, which was further enhanced by A/R. IL-33 prevented the PKCbetaII activation in myocytes with HG or HG and A/R. Inhibition of PKCbetaII prevented the beneficial effect of IL-33. Finally, IL-33 up-regulated diacylglycerol kinase zeta (DGK-zeta) in cardiomyocytes and reversed the down regulation of myocardial DGK-zeta in mice with DM. CONCLUSION: Our results indicate that decreased levels of IL-33 are responsible for the increased sensitivity of the myocardium to I/R in DM. Reduction in IL-33 results in a chronic activation of PKCbetaII. I/R further enhances PKCbetaII activation in the diabetic myocardium which results in exaggeration of myocardial injury. PMID- 22258631 TI - Microparticles: major transport vehicles for distinct microRNAs in circulation. AB - AIMS: Circulating microRNAs (miRNAs) have attracted major interest as biomarkers for cardiovascular diseases. Since RNases are abundant in circulating blood, there needs to be a mechanism protecting miRNAs from degradation. We hypothesized that microparticles (MP) represent protective transport vehicles for miRNAs and that these are specifically packaged by their maternal cells. METHODS AND RESULTS: Conventional plasma preparations, such as the ones used for biomarker detection, are shown to contain substantial numbers of platelet-, leucocyte-, and endothelial cell-derived MP. To analyse the widest spectrum of miRNAs, Next Generation Sequencing was used to assess miRNA profiles of MP and their corresponding stimulated and non-stimulated cells of origin. THP-1 (monocytic origin) and human umbilical vein endothelial cell (HUVEC) MP were used for representing circulating MP at a high purity. miRNA profiles of MP differed significantly from those of stimulated and non-stimulated maternal THP-1 cells and HUVECs, respectively. Quantitative reverse transcription-polymerase chain reaction of miRNAs which have been associated with cardiovascular diseases also demonstrated significant differences in miRNA profiles between platelets and their MP. Notably, the main fraction of miRNA in plasma was localized in MP. Furthermore, miRNA profiles of MP differed significantly between patients with stable and unstable coronary artery disease. CONCLUSION: Circulating MP represent transport vehicles for large numbers of specific miRNAs, which have been associated with cardiovascular diseases. miRNA profiles of MP are significantly different from their maternal cells, indicating an active mechanism of selective 'packaging' from cells into MP. These findings describe an interesting mechanism for transferring gene-regulatory function from MP-releasing cells to target cells via MP circulating in blood. PMID- 22258633 TI - Opportunities for cost reduction of medical care: part 3. AB - The level of health care spending in the United States and other developed nations is rising at a disturbingly rapid rate. However, in the United States, these increases are not justified by superior performance. Rather, most other wealthy countries' inhabitants live longer and suffer from fewer medical problems than the average American. This paper demonstrates the continued abundance of opportunities for substantially reducing health care costs without decreasing the quality of care. In particular, it emphasizes the need to reduce the practice of defensive medicine and to enlarge the cadre of non-specialist physicians who educate future doctors. Such cost-saving opportunities are not rare phenomena but are widely available and offer the United States opportunities to move toward the markedly lower cost levels that have been achieved in other countries. PMID- 22258634 TI - All-terrain vehicle injury prevention: healthcare providers' knowledge, attitudes, and the anticipatory guidance they provide. AB - All-terrain vehicles (ATVs) continue to be an increasing cause of injuries and deaths in children, especially in rural communities. More children die in the United States each year from ATV-related events than from bicycle crashes. The purpose of this study was to determine the ATV anticipatory guidance practices of primary care providers, as well as their attitudes, knowledge, and the barriers faced in educating families about the risk of ATV use. An electronic survey was administered to primary care providers belonging to state medical societies. More than 60% of respondents (Total N = 218) believed that ATV anticipatory guidance was important to provide to pediatric patients and their families. However, 78% stated they provide ATV safety counseling less than 10% of the time during regular pediatric exams, and only 12% stated they do so greater than 25% of the time. Families rarely ask providers for advice on ATV safety issues; 84% of providers were asked once a year or less. ATV knowledge scores were low (median score 2 of 12); however, those with previous ATV exposure had significantly higher scores. Many respondents affirmed insufficient knowledge (47%) and inadequate resources (63%), but the most commonly identified barrier was that it was not a routine part of their practice. Providers in the study demonstrated limited knowledge, reported multiple barriers, and provided little or no ATV safety counseling. However, they consider ATV anticipatory guidance important for their patients. Armed with increased knowledge and appropriate resources, providers could play a significant role in promoting ATV safety. PMID- 22258635 TI - Female reproductive competition within families in rural Gambia. AB - Many studies show that the extended human family can be helpful in raising offspring, with maternal grandmothers, in particular, improving offspring survival. However, less attention has been given to competition between female kin and co-residents. It has been argued that reproductive conflict between generations explains the evolution of menopause in cooperatively breeding species where females disperse, and that older females are related to the offspring of younger females through their sons, whereas younger, incoming females are unrelated to older females. This means the pattern of help will be asymmetric, so older females lose in reproductive conflict and become 'sterile helpers'. Here, we seek evidence for female reproductive competition using longitudinal demographic data from a rural Gambian population, and examine when women are helping or harming each other's reproductive success. We find that older women benefit and younger women suffer costs of reproductive competition with women in their compound. But the opposite is found for mothers and daughters; if mother and daughter's reproductive spans overlap, the older woman reduces her reproduction if the younger woman (daughter) reproduces, whereas daughters' fertility is unaffected by their mothers' reproduction. Married daughters are not generally co-resident with their mothers, so we find not only competition effects with co-resident females, but also with daughters who have dispersed. Dispersal varies across human societies, but our results suggest reproductive conflict could be influencing reproductive scheduling whatever the dispersal pattern. A cultural norm of late male marriage reduces paternal grandmother/daughter-in-law reproductive overlap almost to zero in this population. We argue that cultural norms surrounding residence and marriage are themselves cultural adaptations to reduce reproductive conflict between generations in human families. PMID- 22258636 TI - Contraction type influences the human ability to use the available torque capacity of skeletal muscle during explosive efforts. AB - The influence of contraction type on the human ability to use the torque capacity of skeletal muscle during explosive efforts has not been documented. Fourteen male participants completed explosive voluntary contractions of the knee extensors in four separate conditions: concentric (CON) and eccentric (ECC); and isometric at two knee angles (101 degrees , ISO101 and 155 degrees , ISO155). In each condition, torque was measured at 25 ms intervals up to 150 ms from torque onset, and then normalized to the maximum voluntary torque (MVT) specific to that joint angle and angular velocity. Explosive voluntary torque after 50 ms in each condition was also expressed as a percentage of torque generated after 50 ms during a supramaximal 300 Hz electrically evoked octet in the same condition. Explosive voluntary torque normalized to MVT was more than 60 per cent larger in CON than any other condition after the initial 25 ms. The percentage of evoked torque expressed after 50 ms of the explosive voluntary contractions was also greatest in CON (ANOVA; p < 0.001), suggesting higher concentric volitional activation. This was confirmed by greater agonist electromyography normalized to M(max) (recorded during the explosive voluntary contractions) in CON. These results provide novel evidence that the ability to use the muscle's torque capacity explosively is influenced by contraction type, with concentric contractions being more conducive to explosive performance due to a more effective neural strategy. PMID- 22258637 TI - Guidance on the use of adalimumab for juvenile idiopathic arthritis in Japan. AB - Adalimumab is a monoclonal antibody produced by DNA recombination technology, and is the first human monoclonal antibody against human tumor necrosis factor (TNF) alpha in the world. Adalimumab binds with high affinity and specificity to soluble TNF-alpha and normalizes its biological action. The clinical development of adalimumab started in Europe. Adalimumab was approved for the treatment of rheumatoid arthritis (RA) in December 2002 in the United States and in September 2003 in the European Union. Since then, adalimumab has been approved for the expanded indications of psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis (Ps), and juvenile idiopathic arthritis (JIA) in the United States and the European Union, and it is now used widely for the treatment of these diseases. In Japan, adalimumab was approved for the treatment of RA in April 2008, and its use was approved for the indications of Ps and PsA in January 2010, and for CD and AS in October 2010. In Japan, children who have been diagnosed and treated according to the "Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007)" (published in this journal in 2007; see reference 1 in the main text), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adherence to the indications and exclusion criteria and should be used, for the time being, only by physicians trained in how to use them. In Japan, adalimumab was approved for the treatment of JIA in July 2011. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidance presented here define the indications, exclusion criteria, usage, and evaluation criteria of adalimumab for the treatment of polyarticular JIA. PMID- 22258638 TI - Indirect measurement of pinch and pull forces at the shaft of laparoscopic graspers. AB - The grasping instruments used in minimally invasive surgery reduce the ability of the surgeon to feel the forces applied on the tissue, thereby complicating the handling of the tissue and increasing the risk of tissue damage. Force sensors implemented in the forceps of the instruments enable accurate measurements of applied forces, but also complicate the design of the instrument. Alternatively, indirect estimations of tissue interaction forces from measurements of the forces applied on the handle are prone to errors due to friction in the linkages. Further, the force transmission from handle to forceps exhibits large nonlinearities, so that extensive calibration procedures are needed. The kinematic analysis of the grasping mechanism and experimental results presented in this paper show that an intermediate solution, force measurements at the shaft and rod of the grasper, enables accurate measurements of the pinch and pull forces on tissue with only a limited number of calibration measurements. We further show that the force propagation from the shaft and rod to the forceps can be approximated by a linear two-dimensional function of the opening angle of the grasper and the force on the rod. PMID- 22258639 TI - Statistical characteristics of finger-tapping data in Huntington's disease. AB - Measuring the rate of finger tapping is a technique commonly used as an indicator of impairment in degenerative neurological conditions, such as Huntington's disease. The information it provides can be greatly enhanced by analysing not simply the overall tapping rate, but also the statistical characteristics of the individual times between each successive response. Recent technological improvements in the recording equipment allow the responses to be analysed extremely quickly, and permit modification of the task in the interest of greater clinical specificity. Here we illustrate its use with some pilot data from a group of manifest HD patients and age-matched controls. Even in this small cohort, differences in the responses are apparent that appear to relate to the severity of the disease as measured by conventional behavioural tests. PMID- 22258641 TI - Expression and characterization of styrene monooxygenases of Rhodococcus sp. ST-5 and ST-10 for synthesizing enantiopure (S)-epoxides. AB - Styrene monooxygenase (StyA, SMOA)- and flavin oxidoreductase (StyB, SMOB)-coding genes of styrene-assimilating bacteria Rhodococcus sp. ST-5 and ST-10 were successfully expressed in Escherichia coli. Determined amino acid sequences of StyAs and StyBs of ST-5 and ST-10 showed more similarity with those of Pseudomonas than with self-sufficient styrene monooxygenase (StyA2B) of Rhodococcus. Recombinant enzymes were purified from E. coli cells as functional proteins, and their properties were characterized in detail. StyBs (flavin oxidoreductase) of strains ST-5 and ST-10 have similar enzymatic properties to those of Pseudomonas, but StyB of strain ST-10 exhibited higher temperature stability than that of strain ST-5. StyAs of strains ST-5 and ST-10 catalyzed the epoxidation of vinyl side-chain of styrene and its derivatives and produced (S) epoxides from styrene derivatives and showed high stereoselectivity. Both StyAs showed higher specific activity on halogenated styrene derivatives than on styrene itself. Additionally, the enzymes could catalyze the epoxidation of short chain 1-alkenes to the corresponding (S)-epoxides. Aromatic compounds including styrene, 3-chlorostyrene, styrene oxide, and benzene exhibited marked inhibition of SMO reaction, although linear 1-alkene showed no inhibition of SMO activity at any concentration. PMID- 22258640 TI - Backwash intensity and frequency impact the microbial community structure and function in a fixed-bed biofilm reactor. AB - Linkages among bioreactor operation and performance and microbial community structure were investigated for a fixed-bed biofilm system designed to remove perchlorate from drinking water. Perchlorate removal was monitored to evaluate reactor performance during and after the frequency and intensity of the backwash procedure were changed, while the microbial community structure was studied using clone libraries and quantitative PCR targeting the 16S rRNA gene. When backwash frequency was increased from once per month to once per day, perchlorate removal initially deteriorated and then recovered, and the relative abundance of perchlorate-reducing bacteria (PRB) initially increased and then decreased. This apparent discrepancy suggested that bacterial populations other than PRB played an indirect role in perchlorate removal, likely by consuming dissolved oxygen, a competing electron acceptor. When backwash intensity was increased, the reactor gradually lost its ability to remove perchlorate, and concurrently the relative abundance of PRB decreased. The results indicated that changes in reactor operation had a profound impact on reactor performance through altering the microbial community structure. Backwashing is an important yet poorly characterized procedure when operating fixed-bed biofilm reactors. Compared to backwash intensity, changes in backwash frequency exerted less disturbance on the microbial community in the current study. If this finding can be confirmed in future work, backwash frequency may serve as the primary parameter when optimizing backwash procedures. PMID- 22258642 TI - Enzyme-based glucose delivery as a high content screening tool in yeast-based whole-cell biocatalysis. AB - The influence of glucose release on growth and biotransformation of yeasts was examined by using the medium EnBase(r) Flo in shake flasks. The medium contains a polysaccharide acting as substrate, which is degraded to glucose by the addition of an enzyme. In the present paper, this medium was adapted for the cultivation of yeasts by increasing the complex components (booster) and the enzyme concentrations to guarantee a higher glucose release rate. Important changes were an increase of the complex component booster to 10-15% and an increased glucose release by increasing the enzyme content to 15 U L(-1). The 20 yeasts investigated in the present work showed an improvement of growth and biomass production when cultivated with the EnBase medium in comparison to yeast extract dextrose (YED) medium. Values of optical densities (OD(600)) of approximately 40 AU (corresponding to over 60 g L(-1) wet cell weight) were achieved for all 20 yeast strains tested. During the following screening of the yeasts in whole-cell biotransformation, an improvement of the conversion for 19 out of the 20 yeasts cultivated with the EnBase Flo medium could be observed. The biomass from the EnBase Flo cultivation showed a higher conversion activity in the reduction of 2 butanone to (R/S)-2-butanol. The enantioselectivity (ee) of 15 yeast strains showed an improvement by using the EnBase medium. The number of yeasts with an ee >97% increased from zero with YED to six with EnBase medium. Thus, the use of a glucose release cultivation strategy in the screening process for transformation approaches provides significant benefits compared to standard batch approaches. PMID- 22258644 TI - Response letter to the article: "scorpion sting envenomation in children: factors affecting the outcome". PMID- 22258643 TI - Production, purification, and characterization of the cecropin from Plutella xylostella, pxCECA1, using an intein-induced self-cleavable system in Escherichia coli. AB - Antimicrobial peptides (AMPs) are widely expressed and play an important role in innate immune defense against infectious agents such as bacteria, viruses, fungi, and parasites. Cecropins are a family of AMPs synthesized in the fat body of insects that have proven effective at killing specific pathogens. In order to fulfill their clinical potential as antimicrobial drugs, a simple, cost-effective method to express AMPs is sorely needed. In this study, we expressed and characterized the cecropin from Plutella xylostella (pxCECA1) using an intein dependent expression system in Escherichia coli. We cloned the pxCECA1 gene from larva by RT-PCR and fused the encoding sequence of mature pxCECA1 with an intein gene and a chitin-binding domain gene (CBD) in pTWIN1 plasmid. The fusion protein CBD-intein-pxCECA1 was expressed in E. coli BL21 (DE3) and separated by flowing cell extracts through a chitin column. Subsequently, self-cleavage of the intein at its C-terminus was induced in a temperature- and pH-dependent manner, resulting in the release of mature pxCECA1. The optimal conditions for self cleavage were determined to be pH 6.0 for 48 h at 4 degrees C, under which 12.3 mg of recombinant pxCECA1 could be recovered from 1 l of E. coli culture. The purified pxCECA1 displayed antimicrobial activity against a broad variety of gram positive and gram-negative bacteria. This preparation was especially effective against Staphylococcus aureus, including methicillin-resistant strains. Catalase release assays demonstrated that pxCECA1 acts as a microbicidal agent. These results show for the first time that the IMPACT-TWIN expression system is an efficient, cost-effective way to produce fully functional AMPs and that the AMP pxCECA1 is a novel microbicidal agent with promising therapeutic applications. PMID- 22258645 TI - Role of interferon gamma release assays in childhood tuberculosis. PMID- 22258646 TI - A Novel endo-1,4-beta-mannanase from Bispora antennata with good adaptation and stability over a broad pH range. AB - An endo-beta-1,4-mannanase encoding gene, man5, was cloned from Bispora antennata CBS 126.38, which was isolated from a beech stump. The cDNA of man5 consists of 1,299 base pairs and encodes a 432-amino-acid protein with a theoretical molecular mass of 46.6 kDa. Deduced MAN5 exhibited the highest amino acid sequence identity of 58% to a beta-mannanase of glycoside hydrolase family 5 from Aspergillus aculeatus. Recombinant MAN5 was expressed in Pichia pastoris and purified to electrophoretic homogeneity. The specific activity of the final preparation towards locust bean gum was 289 U mg(-1). MAN5 showed optimal activity at pH 6.0 and 70 degrees C and had good adaptation and stability over a broad range of pH values. The enzyme showed more than 60% of peak activity at pH 3.0-8.0 and retained more than 80% of activity after incubation at 37 degrees C for 1 h in both acid and alkaline conditions (pH 4.0-11.0). The K (m) and V (max) values were 1.33 mg ml(-1) and 444 MUmol min(-1) mg(-1) and 1.17 mg ml(-1) and 196 MUmol min(-1) mg(-1) for locust bean gum and konjac flour, respectively. Of all tested metal ions and chemical reagents, Co(2+), Ni(2+), and beta mercaptoethanol enhanced the enzyme activity at 1 mM, whereas other chemicals had no effect on or partially inhibited the enzyme activity. MAN5 was highly resistant to acidic and neutral proteases (trypsin, alpha-chymotrypsin, collagenase, subtilisin A, and proteinase K). By virtue of the favorable properties of MAN5, it is possible to apply this enzyme in the paper and food industries. PMID- 22258647 TI - Proteomic analysis of plasma proteins in diabetic rats by 2D electrophoresis and MALDI-TOF-MS. AB - Despite tremendous advances in our understanding of the molecular basis of diabetes mellitus, substantial gaps still remain in our understanding of disease pathogenesis and in the development of effective strategies for early diagnosis and treatment. The proteomic approach has offered many opportunities and challenges in identifying new marker proteins and therapeutic targets, i.e., using 2D-polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionisation-time of flight mass spectrometry. The differential protein expressions were analyzed in alloxan-induced diabetic rats treated with Cynodon dactylon leaf extract. The plant extract was administered for 15 days that resulted in a significant increase in plasma insulin and C-peptide levels. We have also identified four differentially expressed proteins from rat plasma. These four diabetes-associated proteins were broadly classified into three groups as per their function: (1) lipid metabolism-associated protein (Apo A-IV), (2) antioxidant activity-related proteins [preprohaptoglobin and heat shock proteins B8 (HspB8)], and (3) muscle function-related protein (TPM3). Apo A-IV, HspB8, and preprohaptoglobin may play a key role in the recovery of diabetes mellitus and also prevent the diabetes-associated complications such as prevention of oxidative stress due to free radical and free hemoglobin. These results show the value of proteomic approach in identifying the potential markers that may eventually serve as diagnostic markers or therapeutic targets. PMID- 22258648 TI - Synthesis, characterization and antiproliferative activity of 1,2-naphthoquinone and its derivatives. AB - In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized by spectroscopic studies (UV, FT-IR, 1H NMR, 13 C NMR and elemental analysis). These compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G2 for liver sarcoma, MG-63 for osteosarcoma and MCF-7 for human breast cancer). The cells were dosed with these ortho-naphthoquinone derivatives at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay with doxorubicin as positive control. Significant anticancer activities were observed in vitro for some members of the series, and compounds 1,2-naphthoquinone 2-thiosemicarbazone, 1,2-naphthoquinone-2-semicarbazone, 4 amino-1,2-naphthoquinone 2-thiosemicarbazone and 4-amino-1,2-naphthoquinone-2 semicarbazone are active cytotoxic agents against different cancer cell lines with IC50 values in the range of 5.73-17.67 MUM. The obtained data suggested that better anticancer activity was linked with introduction of thiosemicarbazone and semicarbazone moiety in 1,2-naphthoquinone ring system. Outcomes of experimentation also reveal that incorporation of amino group in 1,2 naphthoquinone moiety contributes positively for cytotoxic action of compounds. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC50 values of all these compounds. PMID- 22258649 TI - The molecular anatomy of human Hsp60 and its similarity with that of bacterial orthologs and acetylcholine receptor reveal a potential pathogenetic role of anti chaperonin immunity in myasthenia gravis. AB - Heat-shock protein 60 (Hsp60) is ubiquitous and highly conserved being present in eukaryotes and prokaryotes, including pathogens. This chaperonin, although typically a mitochondrial protein, can also be found in other intracellular sites, extracellularly, and in circulation. Thus, it can signal the immune system and participate in the development of inflammation and immune reactions. Both phenomena can be elicited by human and foreign Hsp60 (e.g., bacterial GroEL), when released into the blood by infectious agents. Consequently, all these Hsp60 proteins become part of a complex autoimmune response characterized by multiple cross reactions because of their structural similarities. In this study, we demonstrate that Hsp60 proteins from humans and two common pathogens, Chlamydia trachomatis and Chlamydia pneumoniae, share various sequence segments of potentially highly immunogenic epitopes with acetylcholine receptor alpha1 subunit (AChRalpha1). The structural data indicate that AChRalpha1 antibodies, implicated in the pathogenesis of myasthenia gravis, could very well be elicited and/or maintained by self- and/or bacterial Hsp60. PMID- 22258650 TI - Knee rotational laxity and proprioceptive function 2 years after partial ACL reconstruction. AB - PURPOSE: The aim of our study was to evaluate knee rotational laxity and proprioceptive function 2 years after partial anterior cruciate ligament (ACL) reconstruction. According to our hypothesis, partial ACL reconstruction could restore knee laxity and function to the intact level. METHODS: We conducted a study in fifteen consecutive patients undergoing partial ACL reconstruction. Fifteen anteromedial bundle tears were identified intraoperatively. Partial ACL reconstructions were performed by the same senior surgeon using a single-incision technique. A bone-patellar tendon-bone graft was used in 13 cases and a double stranded semitendinosus graft in 2 cases of chronic patellar tendonitis. The mean age at surgery was 29 years. The time between ACL tear and surgery averaged 7.8 months (range 2.5-29.5 months). We developed an original device designed to assess knee proprioception (passive and active) and measure weight-bearing rotational laxity in full extension and at 30 degrees , 60 degrees and 90 degrees of knee flexion. All measurements were taken on both the reconstructed and healthy knee. RESULTS: The mean follow-up of the study was 3.4 years (range 2.6-4.4). No statistically significant difference in rotational laxity, active or passive proprioception could be observed between the reconstructed and healthy knee. External rotation was significantly greater than internal rotation in full extension and at 30 degrees of flexion in the reconstructed and the healthy knee (P < 0.05). For each knee, active proprioception was found to be significantly different (higher) than passive proprioception (P < 0.05). CONCLUSION: Our study did not detect any difference in rotational laxity and proprioception between the reconstructed and the healthy knee. Therefore, partial ACL reconstruction appears to restore satisfactory knee laxity and function in case of partial ACL tear. LEVEL OF EVIDENCE: IV. PMID- 22258651 TI - Arthroscopic decompression of suprapatellar cyst: case report. AB - Bursae around the knee reduce friction between moving structures. When involution of suprapatellar septum fails to occur ("complete septum"), then suprapatellar bursa may stay completely separated from the knee joint cavity to form a cystic cavity. In the case of the increased volume, suprapatellar bursitis can cause painful suprapatellar swelling. The aim is to point to the possibility of arthroscopic decompression of suprapatellar cyst. In the case presented, the indication for knee arthroscopy was based on clinical examination, ultrasonography and magnetic resonance studies. The preoperative diagnosis was verified intra-operatively, and intra-articular cyst decompression was performed by arthroscopy. At the final examination 8 months postoperatively, the patient still had no pain, swelling and had full range of motion. This minimally invasive operative procedure resulted in a satisfactory anatomic and functional outcome. In this case report, we present a patient with suprapatellar cyst submitted to arthroscopic cyst decompression. PMID- 22258652 TI - Radiographic parameters associated with lateral patella degeneration in young patients. AB - PURPOSE: Localized articular cartilage degeneration in the patellofemoral joint is a common but yet understudied condition in younger patients. The purpose of this paper was to determine whether there are significant differences in radiographic alignment between those with and without isolated lateral patellofemoral degeneration. METHODS: Subjects with isolated symptomatic lateral patellofemoral degeneration and control subjects with no radiographic degeneration participated in the study. Variables of interest included the Caton Deschamps index, sulcus angle, lateral patellofemoral angle, Dejour classification of trochlear dysplasia, patella linear displacement and the tibial tubercle-trochlear groove distance. RESULTS: We found significant differences between the patellofemoral degeneration group versus control group, respectively, for the Caton-Deschamps index (1.12 +/- 0.1 vs. 1.00 +/- 0.1), lateral patellofemoral angle (10.6 +/- 4.3 vs. 16.6 +/- 5.5) and tibial tubercle trochlear groove distance (16.6 +/- 4.0 vs. 9.0 +/- 4.3). However, we found no difference in the sulcus angle (141.2 +/- 8.2 vs. 137.0 +/- 6.0), patella linear displacement (3.7 +/- 1.9 vs. 4.0 +/- 1.7) or in the Dejour Classification. CONCLUSION: It appears that isolated lateral patellofemoral degeneration is associated with specific radiographic indices. Even though the radiographic measures in patients with degeneration may not be considered pathologic, they are "high normal" and may represent a risk factor for the development of focal chondral degeneration in the lateral trochlea and patella. LEVEL OF EVIDENCE: III. PMID- 22258653 TI - Arthroscopically assisted retrograde drilling for osteochondritis dissecans (OCD) lesions of the knee. AB - PURPOSE: Accurate retrograde drilling for osteochondritis dissecans lesions remains technically challenging. A novel, radiation-free method using an electromagnetic guidance system was developed, and its feasibility and accuracy for retrograde drilling procedures evaluated in an experimental setting. METHODS: Sixteen arthroscopically assisted, electromagnetically guided retrograde drilling procedures were performed in 4 human cadaveric knee joints. Therefore, two artificial cartilage lesions were set consecutively on each condyle. Final drill bit position was documented in two planes using fluoroscopy. Subsequently, drilling accuracy was measured in terms of distance from the final position of the drill bit to the articular cartilage surface (D1), and distance between the tip of the drill bit to the centre of the cartilage lesion on the articular cartilage surface (D2). All procedures were timed using a stopwatch. RESULTS: Successful retrograde drilling was accomplished in all 16 cases. The overall mean time for the retrograde drilling procedures was 361.6 +/- 34.7 s. Mean D1 was 2.2 +/- 0.5 mm; mean D2 was 0.8 +/- 0.7 mm. No complications occurred. CONCLUSIONS: The novel electromagnetic guidance system used in this study showed accurate targeting results, required no radiation, was associated with no complications and demonstrated user-friendliness. LEVEL OF EVIDENCE: II. PMID- 22258654 TI - Relationship between muscle volume and muscle torque of the hamstrings after anterior cruciate ligament lesion. AB - PURPOSE: This study was conducted to identify factors other than morphological muscle strength factors that affect injured and uninjured sides of knee flexors with anterior cruciate ligament (ACL) lesions. METHODS: The study population consisted of 22 patients with ACL lesions. Their hamstring muscle volume was measured on MRI, and muscle torque per muscle volume was calculated as the peak torque of knee flexion divided by hamstring muscle volume. RESULTS: The mean muscle torque per unit volume of hamstrings in patients with ACL rupture was 0.09 +/- 0.02 Nm/cm(3) at 60 degrees /s and 0.08 +/- 0.01 Nm/cm(3) at 180 degrees /s on the injured side, and 0.11 +/- 0.02 Nm/cm(3) at 60 degrees /s and 0.08 +/- 0.01 Nm/cm(3) at 180 degrees /s on the uninjured side. The mean muscle torque per unit volume of hamstrings in control subjects was 0.11 +/- 0.02 Nm/cm(3) at 60 degrees /s and 0.08 +/- 0.03 Nm/cm(3) at 180 degrees /s. One-factor ANOVA analysis found no significant differences between the three groups at either flexion velocity. CONCLUSIONS: Neurological dysfunction does not appear to exist in knee flexor muscles after ACL injury, unlike the quadriceps. Since the mechanism of muscle weakness will differ depending on the muscle, it is important for clinicians to take this discrepancy into consideration. LEVEL OF EVIDENCE: II. PMID- 22258655 TI - Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro. AB - PURPOSE: Nicotine has been reported that it has a dose-dependent effect on matrix mineralization by human bone marrow cells. However, there is no relevant research concerning on chondrogenic differentiation potential of bone marrow stromal stem cells (BMSCs) treated with nicotine in vitro. The aims of the study were to examine the effects of nicotine (0, 10(-7), 10(-6) and 10(-5) M) on the proliferation and chondrogenic differentiation of BMSCs from three healthy donors in vitro. METHODS: BMSCs proliferation was analyzed by CCK8 assay and real-time polymerase chain reaction was used to assay the expression of type II collagen, aggrecan, type I collagen and type X collagen. The proteoglycan content was stained by Alcian blue, and the sulfated glycosaminoglycan (sGAG) content of BMSCs was quantified spectrofluorometrically using dimethylmethylene blue. RESULTS: The cell viability was not significantly impaired until up to a concentration of 10(-5) M nicotine. Nicotine promoted the proliferation and enhanced the expression of type II collagen at the level up to 10(-6) M (P < 0.05). The expression of aggrecan was reduced at the concentration of 10(-5) M nicotine at day 14 (P < 0.05), and there was no significant difference in aggrecan gene expression at 10(-7) and 10(-6) M nicotine levels compared to control group (n.s.). Also the fibroblastic and hypertrophic gene expressions were down-regulated in the chondrogenic medium with 10(-7)-10(-5) M nicotine (P < 0.05). CONCLUSION: It was implied that local application of nicotine at an appropriate concentration may be a promising approach for enhancing chondrogenic differentiation capacity of BMSCs in cell-based cartilage tissue engineering. Also these results indicate that nicotine maybe a potentially useful drug for the treatment of Osteoarthritis. PMID- 22258656 TI - Evaluation of the prevalence, lesion, and depth of osteoarthritic changes in the patella. AB - PURPOSE: The aim of this study was to determine the prevalence, type of lesion, and depth of osteoarthritic (OA) changes in the patella. METHODS: One hundred and forty-six cadaveric knees were included in this study with an median age of 83 years (54-97). Patella OA lesion was classified using Han's method: Type 1, no or minimal lesion; Type 2, medial facet lesion without involvement of the ridge; Type 3, lateral facet lesion without involvement of the ridge; Type 4, lesion involvement of the ridge; Type 5, medial facet lesion with involvement of the ridge, Type 6, lateral facet lesion with involvement of the ridge; and Type 7, Global lesion. The depth of OA evaluation was performed following Outerbridge's classification. RESULTS: OA lesions were observed as follows: (Type 1) 31%, (Type 2) 16%, (Type 3) 3%, (Type 4) 12%, (Type 5) 22%, (Type 6) 2%, and (Type 7) 14%. Outerbridge's classification of over Grade 2 OA depth was observed in 63.7% of subjects. A significant difference of patella OA type in gender was observed. Severe patella OA occurred in female subjects. Greater depth of OA was observed in Types 5 and 7. Most OA occurred in the medial facet of the patella including the ridge. Isolated OA in the lateral facet of the patella was observed in only 2% of all knees. CONCLUSION: There is a risk of patella OA in female subjects. Patella OA occurred mainly on the medial side. Isolated OA in the lateral facet of the patella was rare. 63.7% of subjects had patella OA. LEVEL OF EVIDENCE: Controlled laboratory study, Level III. PMID- 22258657 TI - Arthroscopic, suture anchor repair through a novel medial quadriceptal portal for medial meniscal root tear. AB - Current options for meniscal root repair include repair into trans-osseous bone tunnels, trans-osseous suture passage for surface fixation, and suture anchor fixation. Suture anchor repair techniques have been developed since it eliminates the issue of the suture abrasion, tunnel drilling, and distal fixation inherent to trans-osseous tunnel. We present a description of a new variation in the more vertical suture anchor repair technique for meniscal root tear using a novel medial quadriceptal portal. Level of evidence Therapeutic, Level V. PMID- 22258658 TI - Estimating the prevalence of infertility in Canada. AB - BACKGROUND: Over the past 10 years, there has been a significant increase in the use of assisted reproductive technologies in Canada, however, little is known about the overall prevalence of infertility in the population. The purpose of the present study was to estimate the prevalence of current infertility in Canada according to three definitions of the risk of conception. METHODS: Data from the infertility component of the 2009-2010 Canadian Community Health Survey were analyzed for married and common-law couples with a female partner aged 18-44. The three definitions of the risk of conception were derived sequentially starting with birth control use in the previous 12 months, adding reported sexual intercourse in the previous 12 months, then pregnancy intent. Prevalence and odds ratios of current infertility were estimated by selected characteristics. RESULTS: Estimates of the prevalence of current infertility ranged from 11.5% (95% CI 10.2, 12.9) to 15.7% (95% CI 14.2, 17.4). Each estimate represented an increase in current infertility prevalence in Canada when compared with previous national estimates. Couples with lower parity (0 or 1 child) had significantly higher odds of experiencing current infertility when the female partner was aged 35-44 years versus 18-34 years. Lower odds of experiencing current infertility were observed for multiparous couples regardless of age group of the female partner, when compared with nulliparous couples. CONCLUSIONS: The present study suggests that the prevalence of current infertility has increased since the last time it was measured in Canada, and is associated with the age of the female partner and parity. PMID- 22258659 TI - Anti-Mullerian hormone as a predictor of follicular reserve in ovarian insufficiency: special emphasis on FSH-resistant ovaries. AB - BACKGROUND: Anti-Mullerian hormone (AMH) is secreted by ovarian granulosa cells and its serum levels reflect ovarian follicle reserve. The main objective of this study was to test the use of AMH assay in identifying women with primary amenorrhea (PA) and existing follicles and to study follicle phase dependent AMH secretion. METHODS: Serum levels of AMH were measured in subjects with FSH resistant ovaries (FSHRO, n= 12), primary ovarian insufficiency (POI) with PA (n= 11) or secondary amenorrhea (SA n= 20) of unknown etiology, and controls (n= 23), and in Turner syndrome (TS) [45,X (n= 18), mosaicism (n= 7), structural X chromosome abnormalities (SCA, n= 10)], and healthy controls (n= 34). RESULTS: Serum levels of AMH in women with FSHRO were comparable with those in control women (2.76 +/- 2.37 versus 3.77 +/- 2.36 ng/ml) and significantly higher than in women with PA (0.05 +/- 0.04 ng/ml; P < 0.001) or SA of unknown origin (0.12 +/- 0.20 ng/ml; P < 0.001). TS girls/women with 45,X or SCA had low serum AMH levels (0.13 +/- 0.09 and 0.27 +/- 0.19 ng/ml) compared with their controls (3.34 +/- 2.23 ng/ml) or subjects with mosaicism (2.33 +/- 2.81 ng/ml). AMH expression was detected in granulosa cells of women with FSHRO but not in any of the 45,X fetal ovarian specimens. CONCLUSIONS: A serum AMH assay could be used to identify patients with decreasing ovarian reserves and POI. Moreover, our results support the notion that AMH is secreted mainly by small non-selected follicles, since follicular granulosa cells were AMH-positive and serum AMH levels were normal/low normal in women with FSHRO, who lack follicle development beyond the small antral stage. PMID- 22258660 TI - Assisted reproduction using donated embryos: outcomes from surveillance systems in six countries. AB - BACKGROUND: Embryo donation, though less often performed than other assisted reproductive technology (ART), can represent an attractive option for couples who do not wish to discard their embryos remaining after IVF, and for those who cannot or should not conceive naturally. Clinicians and potential participants could benefit from information comparing outcomes of embryo donation with those of other ARTs, in various countries. METHODS: We analyzed outcome information from ART treatment cycles using 2001-2008 data from national surveillance systems in the USA, Canada, the UK, Australia, New Zealand and Finland. We calculated the live birth rate (LBR) with relative risks, the average number of embryos transferred per cycle and the ratio between them (LBR per embryo transferred). We compared outcomes of embryo donation cycles with those for autologous IVF, frozen embryo transfer (FET) and oocyte donation (OD). RESULTS: LBRs for embryo donation cycles were 14-33%, compared with 16-28% for autologous FET, 22-35% for autologous IVF and 15-52% for OD. In every country except Australia/New Zealand, and in all countries combined, the LBR for embryo donation approximated that for IVF, with no statistically significant differences in Finland and Canada. The average number of embryos transferred per cycle was 1.5-2.8. The LBR per embryo transferred was 11-12% for donor embryo cycles, compared with 8-11% for autologous FET, 12-15% for autologous IVF and 9-21% for OD. CONCLUSIONS: We found that transfer of donated embryos in these countries yields pregnancy outcomes comparable to those of autologous ART procedures. The variation in outcome rates among countries is not entirely explained by the number of embryos transferred. The relatively high success rates and low costs make embryo donation an attractive family building alternative. PMID- 22258661 TI - Tackling burden in ART: an integrated approach for medical staff. AB - Discontinuation is a problem in fertility clinics. Many couples discontinue assisted reproductive technologies (ART) without achieving a live birth for reasons other than poor prognosis or the cost of treatment. Discontinuation has been attributed to the burden of treatment. The causes of burden can be broadly classified according to whether they originate in the patient, clinic or treatment. Interventions to alleviate these burdens include provision of comprehensive educational material, screening to identify highly distressed patients, provision of tailored coping tools and improvements in the clinic environment and medical interventions. Practical interventions to reduce the different causes of burden in ART exist, but further development and evaluation of the efficacy of these interventions requires more precise definition of terms and theory. In this paper, we propose a general integrated approach to cover different perspectives in dealing with burden in ART clinics. We firstly describe the integrated approach and present common sources of burden. We then describe interventions that could help reduce the burden in ART. Our paper is aimed at fertility clinic staff because of their day-to-day involvement with patients. However, this discussion should also be relevant to companies that develop treatments and to psychosocial experts. Reducing the burden of treatment should lead to improved outcomes, namely better quality of life during treatment and lower discontinuation rates. PMID- 22258662 TI - The effect of postponement of first motherhood on permanent involuntary childlessness and total fertility rate in six European countries since the 1970s. AB - BACKGROUND: Postponement of childbearing since the 1970s has led to an increase in permanent involuntarily childlessness. We will address the magnitude of this trend, the effect of IVF/ICSI and the effect on total fertility rate (TFR an often used demographic measure for the level of fertility) in six EU countries. METHODS: Using a fertility micro-simulation model, we estimate the effect of postponement of first motherhood on permanent involuntary childlessness in six representative European countries since 1970/1985: Sweden, Austria, Czech Republic, The Netherlands, West Germany and Spain. To estimate the effect of IVF/ICSI on this trend, we use data on the results of all IVF/ICSI cycles performed in The Netherlands in 2003 and 2004. RESULTS: Permanent involuntary childlessness approximately doubled since 1970s and rose to ~4% in the Czech Republic and to ~7% in Spain with the other countries in between. If all couples entitled to have IVF/ICSI were to be treated, the effect of postponement would almost have been neutralized. However, only a limited proportion of eligible couple are being treated. Without postponement, TFRs would have been between 0.03 and 0.05 higher. CONCLUSIONS: The effect of postponement on permanent involuntary childlessness is considerable. So far IVF/ICSI only had a slight effect on this trend. The impact of postponement on TFRs is small compared with other demographic trends. PMID- 22258663 TI - Vitrification at the pre-antral stage transiently alters inner mitochondrial membrane potential but proteome of in vitro grown and matured mouse oocytes appears unaffected. AB - BACKGROUND: Vitrification is a fast and effective method to cryopreserve ovarian tissue, but it might influence mitochondrial activity and affect gene expression to cause persistent alterations in the proteome of oocytes that grow and mature following cryopreservation. METHODS: In part one of the study, the inner mitochondrial membrane potential (Psi(mit)) of JC-1 stained oocytes from control and CryoTop vitrified pre-antral follicles was analyzed by confocal microscopy at Day 0, or after culture of follicles for 1 or 12 days. In part two, proteins of in vivo grown germinal vesicle (GV) oocytes were subjected to proteome analysis by SDS polyacrylamide gel electrophoresis, tryptic in-gel digestion of gel slices, and one-dimensional-nano-liquid chromatography of peptides on a multi dimensional-nano-liquid chromatography system followed by mass spectrometry (LC MS/MS) and Uniprot Gene Ontology (GO) analysis. In part three, samples containing the protein amount of 40 GV and metaphase II (MII) oocytes, respectively, from control and vitrified pre-antral follicles cultured for 12 or 13 days were subjected to 2D DIGE saturation labeling and separated by isoelectric focusing and SDS gel electrophoresis (2D DIGE), followed by DeCyder(Tm) analysis of spot patterns in three independent biological replicates. Statistical and hierarchical cluster analysis was employed to compare control and vitrified groups. RESULTS: (i) Mitochondrial inner membrane potential differs significantly between control and vitrified GV oocytes at Day 0 and Day 1, but is similar at Day 12 of culture. (ii) LC-MS/MS analysis of SDS gel fractionated protein lysates of 988 mouse GV oocytes revealed identification of 1123 different proteins with a false discovery rate of <1%. GO analysis assigned 811 proteins to the 'biological process' subset. Thirty-five percent of the proteins corresponded to metabolic processes, about 15% to mitochondrion and transport, each, and close to 8% to oxidation reduction processes. (iii) From the 2D-saturation DIGE analysis 1891 matched spots for GV-stage and 1718 for MII oocyte proteins were detected and the related protein abundances in vitrified and control oocytes were quantified. None of the spots was significantly altered in intensity, and hierarchical cluster analysis as well as histograms of p and q values suggest that vitrification at the pre antral stage does not significantly alter the proteome of GV or MII oocytes compared with controls. CONCLUSIONS: Vitrification appears to be associated with a significant transient increase in Psi(mit) in oocyte mitochondria, which disappears when oocyte/cumulus cell apposition is restored upon development to the antral stage. The nano-LC-MS/MS analysis of low numbers of oocytes is useful to obtain information on relevant biological signaling pathways based on protein identifications. For quantitative comparisons, saturation 2D DIGE analysis is superior to LC-MS/MS due to its high sensitivity in cases where the biological material is very limited. Genetic background, age of the female, and/or stimulation protocol appear to influence the proteome pattern. However, the quantitative 2D DIGE approach provides evidence that vitrification does not affect the oocyte proteome after recovery from transient loss of cell-cell interactions, in vitro growth and in vitro maturation under tested conditions. Therefore, transient changes in mitochondrial activity by vitrification do not appear causal to persistent alterations in the mitochondrial or overall oocyte proteome. PMID- 22258664 TI - Solely inhibin B producing ovarian tumour as a cause of secondary amenorrhoea with hot flushes: case report and review of literature. AB - In this report, we describe a case of a solely inhibin B producing fibrothecoma presenting with secondary amenorrhoea and hot flushes. Typical laboratory findings were an elevated LH, elevated inhibin B, low FSH and low estrogen. The World Health Organization classification of amenorrhoea was not applicable since the combination of low estrogen and low FSH suggested a central cause, whereas actually there was an ovarian cause. With staging laparotomy, a bilateral borderline tumour was detected in combination with a fibrothecoma. This report underpins the concept of inhibin B being a selective FSH secretion inhibitor of ovarian origin. Furthermore, a literature review on these topics is included. PMID- 22258665 TI - Intermediates and kinetics for phenol gasification in supercritical water. AB - We processed phenol with supercritical water in a series of experiments, which systematically varied the temperature, water density, reactant concentration, and reaction time. Both the gas and liquid phases were analyzed post-reaction using gas chromatographic techniques, which identified and quantified the reaction intermediates and products, including H(2), CO, CH(4), and CO(2) in the gas phase and twenty different compounds--mainly polycyclic aromatic hydrocarbons--in the liquid phase. Many of these liquid phase compounds were identified for the first time and could pose environmental risks. Higher temperatures promoted gasification and resulted in a product gas rich in H(2) and CH(4) (33% and 29%, respectively, at 700 degrees C), but char yields increased as well. We implicated dibenzofuran and other identified phenolic dimers as precursor molecules for char formation pathways, which can be driven by free radical polymerization at high temperatures. Examination of the trends in conversion as a function of initial water and phenol concentrations revealed competing effects, and these informed the kinetic modeling of phenol disappearance. Two different reaction pathways emerged from the kinetic modeling: one in which rate ? [phenol](1.73)[water](-16.60) and the other in which rate ? [phenol](0.92)[water](1.39). These pathways may correspond to pyrolysis, which dominates when there is abundant phenol and little water, and hydrothermal reactions, which dominate in excess water. This result confirms that supercritical water gasification of phenol does not simply follow first-order kinetics, as previous efforts to model phenol disappearance had assumed. PMID- 22258666 TI - Extensive nodal involvement increases the positivity of blue nodes in the axillary reverse mapping procedure in patients with breast cancer. AB - BACKGROUND: The axillary reverse mapping (ARM) technique has been proposed to prevent arm lymphedema. We conducted this study to assess the feasibility of the technique and the outcomes of patients with neoadjuvant chemotherapy (NAC). METHODS: From July 2009 to May 2010, a prospective study was performed in 36 patients with breast cancer undergoing an ALND. The ARM technique was performed injecting 3 cm(3) of Patent Blue in the ipsilateral arm. Of the 36 patients, 29 patients received NAC previously to the ARM and 7 patients had an ALND and ARM performed as first treatment for positive axillary nodes. RESULTS: The identification rate of blue nodes was 83.3% (30 patients). Sentinel lymph node (SLN) was performed in 15 of 29 (42%) patients in the NAC group. Of these 15, two patients (13%) had a concordance between the blue and the hot node. Blue nodes were positive in 4 (13%) of the 30 patients. CONCLUSIONS: The ARM technique is feasible in patients undergoing NAC. Patients with extensive nodal involvement have increased risk of having positive blue nodes. More studies are needed to assess the subgroup of patients with positive axilla that may have the blue node spared without compromising the oncological treatment. PMID- 22258667 TI - Urolithiasis in infants: evaluation of risk factors. AB - OBJECTIVE: Urolithiasis in infants is not a very rare situation in Turkey, and the incidence has been increasing in recent years. The purpose of this paper was to investigate the clinical characteristics, metabolic and anatomic risk factors for urolithiasis and microlithiasis in infants. METHODS: The cases of 178 infants (63 girls, 115 boys), who were referred to our department between 1999 and 2009 with urolithiasis, were evaluated. RESULTS: The mean age at diagnosis of stone disease was 11.5 months (range, 10 days-24 months). The mean follow-up duration was 33.6 months (1.2-110 months). The major clinical symptoms of our patients were restlessness in 24 children (13.5%) and vomiting in 23 (13%). Thirty-five infants (19.7%) had a urinary tract abnormality; vesico-ureteral reflux was the most common abnormality (12.9%). Hypercalciuria and hyperuricosuria were detected in 46 and 56%, respectively. Stone analysis was performed in 56 infants, and calcium oxalate was determined in 36 patients (64.3%). A family history of urolithiasis, presenting symptoms and underlying metabolic abnormalities were similar for patients with microlithiasis and those with larger stones. However, infants with microlithiasis had higher ratios for history of vitamin D administration and feeding with formula. Surgical treatment was performed in 42 infants and extracorporeal shock wave lithotripsy in 30 infants. CONCLUSION: Our results showed that urolithiasis in infants may present nonspecific symptoms and may even be asymptomatic and that a positive family history for urolithiasis, urologic abnormalities, metabolic disorders, urinary tract infections, vitamin D administration and feeding with formula may increase the occurrence of urolithiasis in infants. PMID- 22258668 TI - Anaerobic thermophilic digestion of sewage sludge with a thickened sludge recycle. AB - The process of anaerobic thermophilic digestion of municipal wastewater sludge with a recycled part of thickened digested sludge, was studied in semi-continuous laboratory digesters. This modified recycling process resulted in increased solids retention time (SRT) with the same hydraulic retention time (HRT) as compared with traditional digestion without recycling. Increased SRT without increasing of HRT resulted in the enhancement of volatile substance reduction by up to 68% in the reactor with the recycling process compared with 34% in a control conventional reactor. Biogas production was intensified from 0.3 L/g of influent volatile solids (VS) in the control reactor up to 0.35 L/g VS. In addition, the recycling process improved the dewatering properties of digested sludge. PMID- 22258669 TI - Integration of seawater and grey water reuse to maximize alternative water resource for coastal areas: the case of the Hong Kong International Airport. AB - Development, population growth and climate change have pressurized water stress in the world. Being an urbanized coastal city, Hong Kong has adopted a dual water supply system since the 1950s for seawater toilet flushing for 80% of its 7 million inhabitants. Despite its success in saving 750,000 m(3)/day of freshwater, the saline sewage (consisting of about 20-30% of seawater) appears to have sacrificed the urban water cycle in terms of wastewater reuse and recycling. Can seawater toilet flushing be applied without affecting the urban water cycle with respect to sustainable water resource management? To address this issue, we examined the entire urban water cycle and developed an innovative water resource management system by integrating freshwater, seawater and reclaimed grey water into a sustainable, low-freshwater demand, low-energy consumption, and low-cost triple water supply (TWS) system. The applicability of this novel system has been demonstrated at the Hong Kong International Airport which reduced 52% of its freshwater demand. PMID- 22258670 TI - Modelling the failure modes in geobag revetments. AB - In recent years, sand filled geotextile bags (geobags) have been used as a means of long-term riverbank revetment stabilization. However, despite their deployment in a significant number of locations, the failure modes of such structures are not well understood. Three interactions influence the geobag performance, i.e. geobag-geobag, geobag-water flow and geobag-water flow-river bank. The aim of the research reported here is to develop a detailed understanding of the failure mechanisms in a geobag revetment using a discrete element model (DEM) validated by laboratory data. The laboratory measured velocity data were used for preparing a mapped velocity field for a coupled DEM simulation of geobag revetment failure. The validated DEM model could identify well the critical bag location in varying water depths. Toe scour, one of the major instability factors in revetments, and its influence on the bottom-most layer of the bags were also reasonably represented in this DEM model. It is envisaged that the use of a DEM model will provide more details on geobag revetment performance in riverbanks. PMID- 22258671 TI - Changes in the drift and the settlement of the freshwater mussel Limnoperna fortunei along a headrace channel. AB - The nuisance species Limnoperna fortunei is a freshwater mussel whose infestations have harmed water intake facilities, such as water supply systems. We investigated the changes in the drift and the settlement of L. fortunei along a headrace channel. The densities of the drift and the settlement both decreased dramatically with the downstream distance from the L. fortunei source (a reservoir). In comparison with larval densities in the reservoir, drift densities decreased by 10 to 25% at 0.5 km downstream from the reservoir, and were less than 2% at sites more than 4.8 km downstream. Although larval densities at midnight (0:00-2:00) were approximately 1.5 times higher than those at noon (12:00-14:00) in a shallow layer (3 m depth) of the reservoir, we found no diurnal variation of drift densities in the headrace channel. Settlement densities at the site nearest the intake gate were much higher than those of the other sites further downstream in the headrace channel. The L. fortunei adult population in the channel could reduce drift individuals by attracting the larva. The attraction probably induces the massive aggregation at the location of the channel immediately below the drift source, resulting in biofouling. PMID- 22258672 TI - Electrogeneration of aluminium to remove silica in water. AB - This paper presents the results of a study on electrogeneration of aluminium, as a coagulant to remove silica in make-up water for cooling towers. Three electrochemical systems were tested, two with aluminium electrodes (one with polarity change and another without it), and a third one with aluminium anodes and cathodes of stainless steel. From the obtained results it was concluded that under the studied conditions, the most advantageous system to produce aluminium and remove silica is the one with both electrodes of aluminium working with direct current. Due to chemical production of aluminium at the cathode, the concentration of aluminium in the water at the outlet of the electrochemical reactor is much higher than the one calculated according to Faraday's law. Under the tested conditions it was possible to remove up to 66% of silica from water containing around 50 mg L(-1). PMID- 22258673 TI - Oligonucleotide-based fluorescence system for sensitive and selective detection of Ag(I) ions in aqueous solution. AB - In this letter, a new homogeneous assay with high sensitivity and selectivity was developed for the detection of silver ions in aqueous media at room temperature by using EvaGreen (EG), polycytosine oligonucleotide C20 and single-walled carbon nanotubes (SWNTs). The fluorescence of EG is weak in the absence or presence of randomly coiled C20 After C20 interacted specifically with Ag(+) ions through C Ag(+)-C bonding, C20 would form a folded structure that preferentially binds to EG. As a result, the fluorescence of the mixture of C20 and EG increased in the presence of Ag(+). As having a higher affinity with ssDNA and organic dye, SWNTs could easily form a complex with EG and C20, which led to fluorescence quenching of the dye. Additionally, they can also effectively reduce background-signal fluorescence of the dye and greatly improve its specificity. Under the optimum conditions, the EG/C20 probe exhibited a high selectivity towards Ag(+) over other metal ions. The detection limit was up to 7.4 nM (0.8 ppb). This method is low cost, label-free, and easy to use. PMID- 22258674 TI - Full-scale experience with the deammonification process to treat high strength sludge water -- a case study. AB - More stringent effluent criteria with regard to nitrogen calls for improved nutrient removal techniques in wastewater treatment plants (WWTPs). Besides optimisation of the liquid treatment train of the plants, attention has increasingly centred on the problem of return flows from sludge treatment. One of the most recent developments aimed at the reduction of this nitrogen load is deammonification which has been used at one of Ruhrverband's plants since 2002 by applying a moving bed system. To gain additional experience in operating this process, another full scale plant was modified in 2007 by integration of deammonification, using a SBR system with suspended biomass based on the DEMON((r)) control scheme. By using seeding sludge from Strass WWTP in Austria, start-up has been achieved within only 1 day. After stable operation for several months, increasing nitrate concentrations were observed in the effluent of the system indicating growing activity of nitrite oxidising bacteria (NOB). Following severe process deterioration, it was decided to re-start the system again but the same behaviour, i.e. increasing levels of nitrate, was observed once again. Several approaches were used to suppress NOB organisms in full-scale without success, e.g. low oxygen levels and high free ammonia concentrations. Finally, the reduction of the aerobic cycle length during intermittent aeration down to 8 min, followed by an anoxic mixing period of only 18 min was successful in inhibiting the activity of NOB organisms, most probably due to their elevated lag phase compared with ammonium oxidising bacteria. Today, nitrogen elimination that has been stabilised at more than 80% at a daily volumetric loading rate of 0.5 kg N/(m3 d). The total costs amount to ?2.3/kg N(eli). PMID- 22258675 TI - Effect of nickel ions on anaerobic methane production from water hyacinth. AB - The effect of different concentrations of nickel ions (Ni(2+), 0, 10, 40 and 80 mg/L) on the anaerobic methane production of water hyacinth were investigated. Under these four concentrations, the methane production in 40 d was 2,275, 2,703, 3,210 and 2,481 mL, respectively. This situation illustrated that the Ni(2+) promoted the growth of hydrogen-producing acetic acid bacteria and methanogenic bacteria, even at high concentrations (i.e. 40-80 mg/L). The highest methane production per unit weight water hyacinth reached 206 mL/gTS with 40 mg/L Ni(2+). Meanwhile, the modified Gompertz and Logistic equations were applied to describe the effect on anaerobic culture of Ni(2+). According to these models, the values of methane production potential (mL) for four concentrations were in the following order: 40 mg/L (3,123.42 +/- 60.08) > 10 mg/L (2,541.16 +/- 46.94) > 80 mg/L (2,432.36 +/- 40.18) > 0 mg/L (2,238.10 +/- 31.90). According to the analysis of the digestate, the residual concentration of Ni(2+) was approximately 1.05-4.9 mg/L, which was relatively low compared with the Ni(2+) concentrations in the raw feedstock. The results would provide academic guidance and technical support for treatment of water hyacinth with an accumulation of heavy metals. PMID- 22258676 TI - Column studies to determine mercury settling in road runoff. AB - A study was performed using a settling column to remove mercury (Hg) from road runoff. The emphasis was placed on the relationship between Hg removal and critical settling velocities, as well as the distribution of total suspended solids (TSS). The impact of rainfall characteristics and temperature on Hg removal was also discussed. Results indicated that Hg removal was significant within the initial 30 min of the settling process. The Hg removal rate increased with the decrease of critical settling velocity, and this trend became gradually significant, which could be used as an important reference for the optimization of sedimentation basin design. Hg removal at different settling times was significantly related to initial distribution of TSS. The impact of rainfall intensity on Hg removal was greater than other parameters of precipitation features, followed by rainfall. In addition, Hg removal was moderately related to temperature. The effect of antecedent dry periods on Hg removal was restricted by rainfall and rainfall intensity. PMID- 22258677 TI - Biosorption of chromium(VI), nickel(II) and Remazol blue by Rhodotorula muciloginosa biomass. AB - The passive removal of commonly used reactive dye and two heavy metals, from aqueous solutions by inexpensive biomaterial, yeast Rhodotorula muciloginosa biomass, termed biosorption, was studied with respect to pH, initial dye concentration and initial metal ion concentration. The biomass exhibited maximum dye and chromium(VI) uptake at pH 5 and pH 6 for nickel(II) in media containing 50 mg/L heavy metal and 50 mg/L remazol blue. It was found that the highest chromium(VI) removal yields measured were 31.3% for 49.0 mg/l initial chromium(VI) concentrations. The nickel(II) removal yield was 32.5% for 22.3 mg/L. Higher R. Blue removal yields were obtained, such as 77.1% for 117.5 mg/L. The maximum dye biosorption yield was investigated in medium with a constant dye (approximately 50 mg/L) and increasing heavy metal concentration. In the medium with 48.8, 103.8 and 151.8 mg/L chromium(VI) and constant dye concentration, the maximum chromium(VI) biosorption was 7.4, 9.3 and 17.1%, whereas the maximum dye biosorption was 61.6, 56.6 and 55.9%. The maximum nickel(II) biosorptions in the medium with dye were 38.1, 22.1 and 8.8% at 23.7, 37.7 and 60.1 mg/L nickel(II) concentrations. In these media, dye biosorptions were 93.9, 86.4 and 93.3%, respectively. PMID- 22258678 TI - Attenuation of an ultrasonic beam by suspended particles and range of acoustic flow meters in sewer networks. AB - Ultrasonic flow meters are commonly used in wastewater management. Under certain circumstances, a reduction in the flow meter range may occur and cause significant error in the flow rate measurement. Attenuation due to suspended particles is one of the phenomena capable of reducing the flow meter range. The present paper examines attenuation resulting from re-suspended pond sediment over a wide range of concentration values. It appears that a formula established for sand suspensions provides a good estimate of ultrasound attenuation for these types of particles as well. Experiments conducted for wastewater under particle concentrations commonly encountered in sewer networks demonstrate that the attenuation by particles only contributes to a negligible extent towards intensity decay, in accordance with theoretical predictions. We also theoretically determine herein the operating conditions under which the range of an ultrasonic flow meter would be significantly reduced due to particle attenuation. PMID- 22258679 TI - Performance of an ultra-compact biofilm reactor treating domestic and synthetic wastewaters. AB - The performance of an ultra-compact biofilm reactor (UCBR) treating domestic wastewater (DWW) collected from a local water reclamation plant; and gradually shifting to a mono-type carbon source synthetic wastewater (SWW) combined with DDW (CWW) and finally SWW; was investigated in this study. The total COD concentrations of influent DWW and CWW/SWW were 413.6 +/- 80.8 mg/L and 454.9 +/- 51.3 mg/L, respectively. The UCBR was able to achieve average total COD removal efficiencies of 70 +/- 10% and 80 +/- 4% for DWW and SWW respectively. The total COD concentrations of the effluent of DWW and CWW/SWW were 122.5 +/- 44.4 mg/L and 89.7 +/- 10.3 mg/L, respectively. These observations suggested that heterotrophs in the UCBR system were able to better assimilate and remove carbon of mono-type SWW compared to diverse carbon sources such as DWW; although the influent soluble COD concentrations of the SWW were higher than those of the DWW. However, the effluent NH(4)(+)-N concentrations for both types of wastewater were rather similar, <3.0 mg/L; although the influent NH(4)(+)-N concentrations of the DWW were 1.5 times those of the SWW. PMID- 22258681 TI - Optimizing the coagulation process in a drinking water treatment plant -- comparison between traditional and statistical experimental design jar tests. AB - In this study of coagulation operation, a comparison was made between the optimum jar test values for pH, coagulant and coagulant aid obtained from traditional methods (an adjusted one-factor-at-a-time (OFAT) method) and with central composite design (the standard design of response surface methodology (RSM)). Alum (coagulant) and polymer (coagulant aid) were used to treat a water source with very low pH and high aluminium concentration at Sri-Gading water treatment plant (WTP) Malaysia. The optimum conditions for these factors were chosen when the final turbidity, pH after coagulation and residual aluminium were within 0-5 NTU, 6.5-7.5 and 0-0.20 mg/l respectively. Traditional and RSM jar tests were conducted to find their respective optimum coagulation conditions. It was observed that the optimum dose for alum obtained through the traditional method was 12 mg/l, while the value for polymer was set constant at 0.020 mg/l. Through RSM optimization, the optimum dose for alum was 7 mg/l and for polymer was 0.004 mg/l. Optimum pH for the coagulation operation obtained through traditional methods and RSM was 7.6. The final turbidity, pH after coagulation and residual aluminium recorded were all within acceptable limits. The RSM method was demonstrated to be an appropriate approach for the optimization and was validated by a further test. PMID- 22258680 TI - Removal of C.I. Reactive Red 2 from aqueous solutions by chitin: an insight into kinetics, equilibrium, and thermodynamics. AB - In this study, C.I. Reactive Red 2 (RR2) was removed from aqueous solutions by chitin. Exactly how the RR2 concentration, chitin dosage, pH, and temperature affected adsorption of RR2 by chitin was then determined. After reaction for 120 min, the amount of 10 and 20 mg/L RR2 absorbed onto chitin was 5.7 and 7.5 mg/g, respectively. The adsorption percentage increased from 56 to 94% when the chitin dosage was increased from 1.5 to 2.5 g/L. Experimental results indicated that the pseudo-second-order model best represents adsorption kinetics. Adsorption of RR2 increased as the temperature increased; however, it decreased with an increased pH. Experimental results further demonstrated that the Freundlich model is superior to the Langmuir model in fitting experimental isotherms. The DeltaH degrees and DeltaS degrees were 16.34 kJ/mol and 152.10 J/mol K, respectively. DeltaH degrees suggested that adsorption of RR2 onto chitin was via physisorption. PMID- 22258682 TI - Photosynthetic bacteria production from food processing wastewater in sequencing batch and membrane photo-bioreactors. AB - Application of photosynthetic process could be highly efficient and surpass anaerobic treatment in releasing less greenhouse gas and odor while the biomass produced can be utilized. The combination of photosynthetic process with membrane separation is possibly effective for water reclamation and biomass production. In this study, cultivation of mixed culture photosynthetic bacteria from food processing wastewater was investigated in a sequencing batch reactor (SBR) and a membrane bioreactor (MBR) supplied with infrared light. Both photo-bioreactors were operated at a hydraulic retention time (HRT) of 10 days. Higher MLSS concentration achieved in the MBR through complete retention of biomass resulted in a slightly improved performance. When the system was operated with MLSS controlled by occasional sludge withdrawal, total biomass production of MBR and SBR photo-bioreactor was almost equal. However, 64.5% of total biomass production was washed out with the effluent in SBR system. Consequently, the higher biomass could be recovered for utilization in MBR. PMID- 22258683 TI - Evaluating the effects of nitrogen loading rate and substrate inhibitions on partial nitrification with FISH analysis. AB - The effects of free ammonia (FA) or free nitrous acid (FNA) on partial nitrification (PN) has been well investigated. Nevertheless, little information was known about the combined effects of nitrogen loading rate (NLR) and substrate inhibition, as well as the impact on the community structure of nitrifiers. In this work, real reject water was treated in a pre-denitrification reactor. PN was achieved by gradually increasing NLR, and it was successfully maintained when average FA and FNA were within 0.8-3.2 mg NH3-N/L and 0.003-0.067 mg HNO2-N/L, respectively. When NLR was reduced, PN was slightly affected due to the FA declination. As FNA inhibition was also eliminated by adding alkalinity into the influent, PN was completely destroyed quickly. FISH results indicated the deterioration of the PN was mainly attributed to the recovery of NOB when inhibition effects were limited. It concluded the increase of NLR benefited the partial nitrification. However, the stability of the nitrite path way was more dependent on selective substrate inhibition effects, especially the FNA inhibition. These findings would be important for further treatment of actual reject water. PMID- 22258684 TI - Full-scale operating experience of deep bed denitrification filter achieving <3 mg/l total nitrogen and <0.18 mg/l total phosphorus. AB - The Arlington County Wastewater Pollution Control Plant (ACWPCP) is located in the southern part of Arlington County, Virginia, USA and discharges to the Potomac River via the Four Mile Run. The ACWPCP was originally constructed in 1937. In 2001, Arlington County, Virginia (USA) committed to expanding their 113,500 m3/d, (300,000 pe) secondary treatment plant to a 151,400 m3/d (400,000 pe) to achieve effluent total nitrogen (TN) to <3 mg/l and total phosphorus (TP) < 0.18 mg/l. Key to this conversion was the implementation of deep bed denitrification filters to simultaneously achieve both low effluent TN and TP concentrations. A challenge with implementing this technology is maintaining a health denitrifying biomass within the denitrification filters while reducing an essential nutrient, phosphorus, to very low concentrations. This paper will review the steps from concept to the first year of operation, including pilot and full-scale operating data and the capital cost for the denitrification filters. PMID- 22258685 TI - System design and treatment efficiency of a surface flow constructed wetland receiving runoff impacted stream water. AB - This study reported the efficiency of a free water surface flow constructed wetland (CW) system that receives runoff impacted stream water from a forested and agricultural watershed. Investigations were conducted to examine the potential effect of hydraulic fluctuations on the CW as a result of storm events and the changes in water quality along the flow path of the CW. Based on the results, the incoming pollutant concentrations were increased during storm events and greater at the near end of the storm than at the initial time of storm. A similar trend was observed to the concentrations exiting the CW due to the wetland being a relatively small percentage of the watershed (<0.1%) that allowed delays in runoff time during storm events. The concentrations of most pollutants were significantly reduced (p < 0.05) except for nitrate (p = 0.5). Overall, this study suggests that the design of the system could feasibly function for the retention of most pollutants during storm events as the actual water quality of the outflow was significantly better by 21-71% than the inflow and the levels of pollutants were reduced to appreciable levels. PMID- 22258686 TI - Simultaneous copper ion removal and hydrogen production from water over a TiO2 nanotube photocatalyst. AB - A one-dimensional (1-D) mesoporous TiO2 nanotube (TiNT) was successfully synthesized via a hydrothermal-calcination process, and employed in simultaneous photocatalytic Cu(2+) removal and H2 production. Under irradiation, Cu(2+) in the wide concentration range of 8-800 ppm, could be reduced rapidly, and the reduction was not severely impacted by co-existing inorganic ions in solution. Simultaneous with Cu(2+) reduction, noticeable H2 was produced over the in-situ fabricated Cu incorporated TiNT (Cu-TiNT) photocatalyst, while H2 evolution rate was controlled by the Cu(2+) reduction process, due to competition of electron capture between protons and Cu(2+). In addition, H2 generation activity of Cu TiNT depended on the initial Cu(2+)/Ti ratio, and could be depressed by co existing ions in solution. Fast Cu(2+) reduction and remarkable H2 evolution confirmed the feasibility of simultaneous Cu(2+) removal and H2 production over a TiNT photocatalyst. PMID- 22258687 TI - Multi-variable sensitivity and identifiability analysis for a complex environmental model in view of integrated water quantity and water quality modeling. AB - Environmental models are often over-parameterized. A sensitivity analysis can identify influential model parameters for, e.g. the parameter estimation process, model development, research prioritization and so on. This paper presents the results of an extensive study of the Latin-Hypercube-One-factor-At-a-Time (LH OAT) procedure applied to the Soil and Water Assessment Tool (SWAT). The LH-OAT is a sensitivity analysis method that can be categorized as a screening method. The results of the sensitivity analyses for all output variables indicate that the SWAT model of the river Kleine Nete is mainly sensitive to flow related parameters. Rarely, water quality parameters get a high priority ranking. It is observed that the number of intervals used for the Latin-Hypercube sampling should be sufficiently high to achieve converged parameter rankings. Additionally, it is noted that the LH-OAT method can enhance the understanding of the model, e.g. on the use of water quality input data. PMID- 22258688 TI - Pedotransfer functions to determine water conducting macroporosity in South African soils. AB - Macropores play an important role in the rapid transport of water, solutes and pollutants through the soil. Transport through these pores (>0.5 mm) is dominated by gravitational forces (i.e. matrix forces have low impact) resulting in flow rates orders of magnitude higher than rates that would be predicted, posing problems for modelling and understanding water and solute transport through soils. This study aimed to quantify the water conducting macroporosity (WCM) in a range of soils in South Africa and to develop three pedotransfer functions (PTFs) able to predict WCM. Saturated (K(s)) and unsaturated (K30) conductivities were measured in situ on 120 soil profiles using double ring and tension infiltrometers methods. Differences between K(s) and K30 in conjunction with Poiseuille's law and the capillary rise equation were used to calculate WCM. The first two multiple regression functions made use of all available soil properties influencing WCM using a 'best model' and 'backward' analysis approach respectively. The third model used only easily observable soil properties to predict the WCM. The functions were validated using a double-cross method. Results are encouraging with R2 values of 0.78, 0.74 and 0.69 for functions 1, 2 and 3 respectively. PMID- 22258689 TI - Comparison of different conditions, substrates and operation modes by dynamic simulation of a full-scale anaerobic SBR plant. AB - Simulation studies for a full-scale anaerobic unit of a wastewater treatment plant (WWTP) were performed using the anaerobic digestion model no. 1 (ADM1). The anaerobic full-scale plant consists of one mesophilic and one thermophilic digester, operated in an anaerobic sequential batch reactor (ASBR) mode, and sludge enrichment reactors (SER) for each digester. The digesters are fed with a mixture of vegetable waste and process wastewater from the food factory. Characteristics such as COD(total), N(total) and NH(4)-N concentrations in the influent and effluent of the digester and SERs were measured and used for input fractionation. Parameters such as level, pH, biogas amount and composition in the digester were measured online and used for calibration. For simulation studies, different temperatures and operation modes with varying chemical oxygen demand (COD) input loads corresponding to feedstocks such as fruits, vegetables and grain were analysed and compared. Higher gas production and digestion efficiency in the thermophilic reactor and in shorter cycles were found and confirmed at full scale. Serial operation mode increased the gas production, but pH inhibition occurred earlier. Feeding only biosolids into digester I and the effluent of digester I together with process water into digester II further improved gas production in serial operation mode. PMID- 22258690 TI - Disruption of Synechocystis PCC 6803 for lipid extraction. AB - In order to extract intracellular lipids from cyanobacterial Synechocystis PCC 6803 for biofuel production, seven cell-disruption methods - autoclaving, bead beating, freeze drying, French press, microwave, pulsed electric fields (PEF), and ultrasound - were tested prior to lipid extraction to make intracellular lipids more accessible by organic solvents. The different methods brought about distinct disruption effects to the cell envelope, plasma membrane, and thylakoid membranes that were related to extraction efficiency. Microwave, PEF, and ultrasound with temperature control had significant enhancement of lipid extraction (9-13% increases). Bead beating, freeze drying, and French press did not provide significant enhancement of lipid extraction. Furthermore, autoclaving, French press, and ultrasound treatments caused significant release of lipid into the medium, which may increase solvent usage and make medium recycling difficult. In order to minimize the cost of cell-disruption and lipid extraction steps, microwave and PEF (with temperature control) might be best suited for large-scale cell disruption among all techniques investigated. PMID- 22258691 TI - Electron beam-based functionalization of polymer membranes. AB - A new electron beam-based approach for the direct functionalization of polyethersulfone, polyvinylidene fluoride, polysulfone as well as polyacrylonitrile membranes in a one-step procedure is presented. Aqueous solutions of functional molecules were immobilized on the membrane surface by electron beam treatment. The resulting membranes show significantly increased flux and water wettability accompanied by decreased protein adsorption. Stability tests demonstrated the permanence of the modification. This new method neither requires any preceding surface functionalization nor the use of catalysts/photoinitiators or other toxic reagents. In addition, it avoids the synthesis of hydrophilic monomers/polymers, thus avoiding additional synthetic and purification steps as well as the use of organic solvents. PMID- 22258692 TI - Rapid start-up of a nitrifying reactor using aerobic granular sludge as seed sludge. AB - In this study, the effectiveness of aerobic granular sludge as seed sludge for rapid start-up of nitrifying processes was investigated using a laboratory-scale continuous stirred-tank reactor (CSTR) fed with completely inorganic wastewater which contained a high concentration of ammonia. Even when a large amount of granular biomass was inoculated in the reactor, and the characteristics of influent wastewater were abruptly changed, excess biomass washout was not observed, and biomass concentration was kept high at the start-up period due to high settling ability of the aerobic granular sludge. As a result, an ammonia removal rate immediately increased and reached more than 1.0 kg N/m(3)/d within 20 days and up to 1.8 kg N/m(3)/d on day 39. Subsequently, high rate nitritation was stably attained during 100 days. However, nitrite accumulation had been observed for 140 days before attaining complete nitrification to nitrate. Fluorescence in situ hybridization analysis revealed the increase in amount of ammonia-oxidizing bacteria which existed in the outer edge of the granular sludge during the start-up period. This microbial ecological change would make it possible to attain high rate ammonia removal. PMID- 22258693 TI - Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice. AB - Interleukin-7 is a critical cytokine for lymphoid development and a direct inhibitor of in vitro osteoclastogenesis in murine bone marrow cultures. To explore the role of IL-7 in bone, we generated transgenic mouse lines bearing the 2.3-kb rat collagen 1alpha1 promoter driving the expression of human IL-7 specifically in osteoblasts. In addition, we crossed these mice with IL-7 deficient mice to determine if the alterations in lymphopoiesis, bone mass, and osteoclast formation observed in the IL-7 knockout (KO) mice could be rescued by osteoblast-specific overexpression of IL-7. Here, we show that mice overexpressing human IL-7 in the osteoblast lineage showed increased trabecular bone volume in vivo by uCT and decreased osteoclast formation in vitro. Furthermore, targeted overexpression of IL-7 in osteoblasts rescued the osteopenic bone phenotype and B-cell development of IL-7 KO mice but did not have an effect on T lymphopoiesis, which occurs in the periphery. The bone phenotypes in IL-7 KO mice and targeted IL-7-overexpressing mouse models were observed only in females. These results likely reflect both direct inhibitory effects of IL-7 on osteoclastogenesis in vivo and sex-specific differences in responses to IL-7. PMID- 22258694 TI - TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. AB - Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1. PMID- 22258696 TI - Bicyclo[4.4.0]decane oxygenated sesquiterpenes from Eryngium maritimum essential oil. AB - Investigation of the essential oil of the aerial parts of Eryngium maritimum L. from Corsica led to the isolation of one known sesquiterpene (1) and three new oxygenated sesquiterpenes with a muurolane or cadinane skeleton (2-4). Structure assignments of 4 betaH -muurol-9-en-15-al (1), 4 betaH -cadin-9-en-15-al (2), 4 betaH -muurol-9-en-15-ol (3) and 4 betaH -cadin-9-en-15-ol (4) were carried out by GC/MS (EI and CI) and comprehensive 1D and 2D NMR spectroscopy. Antibacterial activity of Eryngium maritimum L. oil and column chromatography fractions have been investigated for the first time. The oxygenated fraction, which contains the four sesquiterpenes, was efficient against Listeria monocytogenes and Echerichia coli. PMID- 22258697 TI - Synthesis of bimetallic gold-silver alloy nanoclusters by simple mortar grinding. AB - A macroscale quantity of bimetallic Au-Ag alloy nanoclusters was achieved through sequential reduction by simple mortar grinding. The chitosan biopolymer was used as both a stabilizing and reducing agent. These nanoclusters exhibit excellent catalytic activity toward the reduction of 4-nitrophenol. PMID- 22258698 TI - What is the utility of distal forearm DXA in primary hyperparathyroidism? AB - BACKGROUND: Primary hyperparathyroidism (PHPT) leads to increased bone turnover, low bone mineral density, and increased fracture risk. These effects are, however, preferentially seen in the distal forearm, which is rich in cortical bone. This study aimed to determine how frequently the distal forearm T score was the worst T score and if this T score alone led to higher rate of diagnosis of osteopenia or osteoporosis. MATERIALS AND METHODS: We retrospectively reviewed a prospective database of 300 patients undergoing parathyroidectomy at our institution between November 2000 and January 2009. The bone mineral density of the lumbar spine, total proximal femurs, and distal third of the nondominant radius was measured by dual x-ray absorptiometry. Data on bone density are reported as T scores. RESULTS: The mean T scores were -1.30 +/- 0.2 in the distal forearm, -1.0 +/- 0.1 in the total proximal femurs, and -0.9 +/- 0.1 in the spine. The distal forearm T score was the worst bone mineral density T score in 39% of patients. This T score alone led to an upstaging in diagnosis to osteopenia or osteoporosis in 9.4% of patients. CONCLUSION: In patients with PHPT, the worst T score is commonly found in the distal forearm. This T score can identify additional patients with a diagnosis of osteopenia or osteoporosis. Distal forearm bone mineral density should, therefore, be assessed in all patients who have a diagnosis of PHPT. PMID- 22258699 TI - Ethnic/racial disparities in the fetal growth outcomes of Ecuadorian newborns. AB - Size at birth is an important indicator of future infant morbidity and mortality. Ethnic/racial disparities in birth weight and other fetal growth outcomes are well documented for US and Canadian minority groups but not for those in Latin America. The study compared the growth outcomes of 1,227 full-term Ecuadorian newborns delivered by Afro-descendant and indigenous minority women with those of ethnic majority (mestizo) women. Minority newborns had higher risk for congenital microcephaly but no excess risk for low birth weight or stunted linear growth compared to mestizos. However, minority newborns were significantly heavier at birth, weighing an average of 3-5% more than mestizos. Afro-Ecuadorians newborns also were fatter. The risk profile of Ecuadorian ethnic groups for certain fetal growth outcomes differs from some of those reported for North American minorities. Further studies are needed to investigate the origins of these between-group differences and to develop ethnic specific interventions for adverse growth outcomes. PMID- 22258700 TI - The clinical value of routine whole-body magnetic resonance imaging (MRI) in palliative care. AB - BACKGROUND: Whole-body MRI (WBMRI) has become an accessible method for detecting different types of pathologies both in the skeleton and the viscera, which may explain painful conditions, for example tumors and inflammation. PURPOSE: To assess a possible value of using WBMRI in order to improve palliative care. MATERIAL AND METHODS: Twenty patients (all eligible patients) admitted to the Department for Palliative Care were consecutively included in this study. They underwent a modified WBMRI, with fewer and shorter pulse sequences than in a standard WBMRI, to reduce patient stress. However, the patients' physicians were to exclude patients where little might be obtained and discomfort, distress, and pain could be induced. The treating physicians registered clinical utility directly after receiving the MRI report in a questionnaire. The registration was repeated after ended treatment. RESULTS: Eighty percent had new findings detected, and 40% of the patients had a change in treatment due to the MRI result, mainly changes in analgesics and/or radiation therapy. CONCLUSION: The WBMRI helped the clinicians to improve treatment and a majority of the patients benefited from this. In eight patients the treatment was changed due to the results. The clinical value (utility) was indicated to be high. PMID- 22258701 TI - Tissue organization of fasciated lateral roots of Arabidopsis mutants suggestive of the robust nature of outer layer patterning. AB - In three temperature-sensitive mutants of Arabidopsis, root redifferentiation 1 (rrd1), rrd2, and root initiation defective 4 (rid4), formation of fasciated lateral roots was previously observed under high temperature conditions of 28 degrees C. When lateral roots were induced from explants of very young seedlings of these mutants by culture with exogenously supplied auxin at 28 degrees C, expansion of lateral root primordia leading to lateral root fasciation occurred reproducibly and semi-synchronously with a high frequency. This experimental system allowed us to examine how radial organization of root tissues is altered in association with expansion of primordia. Analysis with various tissue-specific reporter genes indicated that in the fasciated lateral roots, cell files of the stele are increased markedly while the numbers of cortical and epidermal cell layers are not changed. This suggests that radial organization during root primordium development involves a mechanism that makes outer layer patterning more robust than inner layer patterning against unusual enlargement of the morphogenetic field. PMID- 22258702 TI - Origin of Dryopteris shibipedis (Dryopteridaceae), a fern species extinct in the wild. AB - Dryopteris shibipedis was once treated as an extinct species in the Red List (2007) by the Japanese Ministry of the Environment, but 'rediscovered' in the Tsukuba Botanical Garden. To clarify its origin, using 'overlooked' cultivated stocks we analyzed nuclear PgiC intron sequences. As the PgiC genotype of D. shibipedis can be explained by a combination of alleles of D. kinkiensis and those of D. pacifica, the hypothesis of hybrid origin of the species is supported. PMID- 22258705 TI - Presently available biosimilars in hematology-oncology: G-CSF. AB - Biopharmaceuticals were copies of endogenous human proteins developed in the mid 1990s that were characterized by complex three-dimensional, high-molecular weight compounds. What made them unique was that contrary to classical chemotherapeutical drugs, they were manufactured by living cells. One of these biopharmaceuticals was granulocyte-colony stimulating factor (G-CSF). Once their patent expired, generic versions appeared in pharmacies. They are now called biosimilars. There are several biosimilar G-CSFs approved in Europe: Biograstim(r)/Filgrastim ratiopharm/Ratiograstim(r)/Tevagrastim(r) (XM02); Zarzio(r) and Nivestim(r). All these new products are manufactured in facilities with state-of-the-art technology. All products have passed the regulatory requirements for approval, mainly phase I and phase III, with the consequent PD/PK evaluations and studies on efficacy and safety. However, there are still some concerns regarding their long-term evaluation, in particular, the limited experience at the time of approval of these products in terms of efficacy, safety and immunogenicity. For this reason, pharmacovigilance should be rigorous. A lot of work remains to be done in terms of clarification with regard to substituting a biosimilar G-CSF for the innovator product and, finally, information must be provided to physicians, pharmacists and patients to allow for proper decision making. Ultimately, only clinical trials and effective post-marketing pharmacovigilance will provide definitive evidence that a biosimilar is comparable to the originator-reference product in terms of efficacy and safety. PMID- 22258704 TI - The oncogenic RNA-binding protein Musashi1 is regulated by HuR via mRNA translation and stability in glioblastoma cells. AB - Musashi1 (Msi1) is an evolutionarily conserved RNA-binding protein (RBP) that has profound implications in cellular processes such as stem cell maintenance, nervous system development, and tumorigenesis. Msi1 is highly expressed in many cancers, including glioblastoma, whereas in normal tissues, its expression is restricted to stem cells. Unfortunately, the factors that modulate Msi1 expression and trigger high levels in tumors are largely unknown. The Msi1 mRNA has a long 3' untranslated region (UTR) containing several AU- and U-rich sequences. This type of sequence motif is often targeted by HuR, another important RBP known to be highly expressed in tumor tissue such as glioblastoma and to regulate a variety of cancer-related genes. In this report, we show an interaction between HuR and the Msi1 3'-UTR, resulting in a positive regulation of Msi1 expression. We show that HuR increased MSI1 mRNA stability and promoted its translation. We also present evidence that expression of HuR and Msi1 correlate positively in clinical glioblastoma samples. Finally, we show that inhibition of cell proliferation, increased apoptosis, and changes in cell-cycle profile as a result of silencing HuR are partially rescued when Msi1 is ectopically expressed. In summary, our results suggest that HuR is an important regulator of Msi1 in glioblastoma and that this regulation has important biological consequences during gliomagenesis. PMID- 22258706 TI - What do prescribers think of biosimilars? AB - Until recently, prescribers had to deal with generics, considered to be simple molecules that are easy to copy. But as discussed in this paper, the biodisponibility of generics remains a source of uncertainty. And now there are biosimilars, limited for the time being in the cancer setting to granulocyte colony stimulating factors (G-CSFs) and epoetins. Soon there will be biosimilar monoclonal antibodies with anticancer activity. Prescribers will ask, as they did for generics, if such drugs have the same activity as originators, if their safety profile is the same, if quality of the production process is guaranteed. Prescribers will want to know if their patients are indeed receiving the prescribed product, and not another. Finally prescribers will want to check that the lower cost of biosimilars will allow them to adhere to international guidelines. This should benefit patients and the community. PMID- 22258707 TI - Enzyme-linked immunosorbent assays based on Neospora caninum dense granule protein 7 and profilin for estimating the stage of neosporosis. AB - Neospora caninum is an intracellular protozoan parasite that causes bovine and canine neosporosis, characterized by fetal abortion and neonatal mortality and by neuromuscular paralysis, respectively. Although many diagnostic methods to detect parasite-specific antibodies or parasite DNA have been reported, to date no effective serodiagnostic techniques for estimating pathological status have been described. Our study aimed to elucidate the relationship between the parasite specific antibody response, parasite activation, and neurological symptoms caused by N. caninum infection by using a recombinant antigen-based enzyme-linked immunosorbent assay. Among experimentally infected mice, anti-N. caninum profilin (NcPF) antibody was only detected in neurologically symptomatic animals. Parasite numbers within the brains of the symptomatic mice were significantly higher than those in asymptomatic animals. In addition, anti-NcPF and anti-NcGRA7 antibodies were mainly detected at the acute stage in experimentally infected dogs, while anti-NcSAG1 antibody was produced during both acute and chronic stages. Furthermore, among anti-NcSAG1 antibody-positive clinical dogs, the positive rates of anti-NcGRA7 and anti-NcPF antibodies in the neurologically symptomatic dogs were significantly higher than those in the non-neurologically symptomatic animals. Our results suggested that the levels of anti-NcGRA7 and anti-NcPF antibodies reflect parasite activation and neurological symptoms in dogs. In conclusion, antibodies against NcGRA7 and NcPF may have potential as suitable indicators for estimating the pathological status of neosporosis. PMID- 22258708 TI - Persistence of immunogenicity of a monovalent influenza virus A/H1N1 2009 vaccine in healthy volunteers. AB - After WHO declared H1N1 pandemic, global vaccination was carried out immediately after much research. However, the data on long-term immunogenicity were lacking. We aimed to investigate the long-term immunogenicity of different H1N1 vaccine dosage groups 24 weeks after vaccination by a randomized clinical trial. A total of 218 participants were stratified into adult (<=60 years old) and elderly (>60 years old) groups. The adults were randomized in a 1:1:1 ratio. The first group received a single dose of vaccine with 15 MUg hemagglutination antigen (HA). The other two groups received two doses with 15 MUg or 30 MUg HA triweekly. The elderly were randomized 1:1 for two doses of 15 or 30 MUg HA. We evaluated serologic responses at prevaccination and weeks 3, 6, and 24. We also examined possible associated factors of immunogenicity by multivariate logistic regression analyses. At week 24, seroprotection (anti-HA antibody level >= 1:40) remained at 76.8% and 46.2% in the adult and elderly groups, respectively. The adult group had a higher seroprotection rate (odds ratio of 2.98, 95% confidence interval [CI]: 1.21 to 7.36) than the elderly group. There was no statistical difference in seroprotection and seroconversion rates between different adult and elderly dosage groups. Lower immunogenicity in the elderly than in the adults 24 weeks after the vaccination was observed. However, there was no statistically significant difference among different dose groups. Therefore, we suggest only a single vaccination dose of 15 MUg HA for adults and two doses of 15 MUg HA for the elderly in the future. PMID- 22258709 TI - Failure of the smallpox vaccine to develop a skin lesion in vaccinia virus-naive individuals is related to differences in antibody profiles before vaccination, not after. AB - Successful vaccination against smallpox with conventional vaccinia virus is usually determined by the development of a vesicular skin lesion at the site of vaccinia inoculation, called a "take." Although previous vaccination is known to be associated with attenuation of the take, the immunology that underlies a no take in vaccinia-naive individuals is not well understood. We hypothesized that antibody profiling of individuals before and after receiving vaccinia virus would reveal differences between takes and no-takes that may help better explain the phenomenon. Using vaccinia virus proteome microarrays and recombinant protein enzyme-linked immunosorbent assays (ELISAs), we first examined the antibody response in vaccinia-naive individuals that failed to take after receiving different doses of the replication-competent DryVax and Aventis Pasteur (APSV) smallpox vaccines. Most that received diluted vaccine failed to respond, although four no-takes receiving diluted vaccine and four receiving undiluted vaccine mounted an antibody response. Interestingly, their antibody profiles were not significantly different from those of controls that did show a take. However, we did find elevated antibody titers in no-takes prior to receiving DryVax that were significantly different from those of takes. Although the sample size studied was small, we conclude the failure to take in responders correlates with preexisting immunity of unknown etiology that may attenuate the skin reaction in a way similar to previous smallpox vaccination. PMID- 22258710 TI - 18F-Fluorodeoxyglucose positron emission tomography pulmonary imaging in idiopathic pulmonary fibrosis is reproducible: implications for future clinical trials. AB - PURPOSE: Noninvasive markers of disease activity in patients with idiopathic pulmonary fibrosis (IPF) are lacking. We performed this study to investigate the reproducibility of pulmonary (18)F-FDG PET/CT in patients with IPF. METHODS: The study group comprised 13 patients (11 men, 2 women; mean age 71.1 +/- 9.9 years) with IPF recruited for two thoracic (18)F-FDG PET/CT studies performed within 2 weeks of each other. All patients were diagnosed with IPF in consensus at multidisciplinary meetings as a result of typical clinical, high-resolution CT and pulmonary function test features. Three methods for evaluating pulmonary (18)F-FDG uptake were used. The maximal (18)F-FDG pulmonary uptake (SUVmax) in the lungs was determined using manual region-of-interest placement. An (18)F-FDG uptake intensity histogram was automatically constructed from segmented lungs to evaluate the distribution of SUVs. Finally, mean SUV was determined for volumes of-interest in pulmonary regions with interstitial lung changes identified on CT scans. Processing included correction for tissue fraction effects. Bland-Altman analysis was performed and interclass correlation coefficients (ICC) were determined to assess the reproducibility between the first and second PET scans, as well as the level of intraobserver and interobserver agreement. RESULTS: The mean time between the two scans was 6.3 +/- 4.3 days. The interscan ICCs for pulmonary SUVmax analysis and mean SUV corrected for tissue fraction effects were 0.90 and 0.91, respectively. Intensity histograms were different in only 1 of the 13 paired studies. Intraobserver agreement was also excellent (0.80 and 0.85, respectively). Some bias was observed between observers, suggesting that serial studies would benefit from analysis by the same observer. CONCLUSION: This study demonstrated that there is excellent short-term reproducibility in pulmonary (18)F-FDG uptake in patients with IPF. PMID- 22258711 TI - Choline PET/CT compared with bone scintigraphy in the detection of bone metastases in prostate cancer patients. PMID- 22258713 TI - Quantitative volumetric analysis of gliomas with sequential MRI and 11C methionine PET assessment: patterns of integration in therapy planning. AB - PURPOSE: The aim of the study was to evaluate the volumetric integration patterns of standard MRI and (11)C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade. METHODS: We studied 23 patients with suspected or previously treated glioma who underwent preoperative (11)C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by (11)C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately. RESULTS: Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high (11)C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p < 0.001, kappa = 0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5). CONCLUSION: The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas. PMID- 22258715 TI - Irradiation induces homing of donor endothelial progenitor cells in allogeneic hematopoietic stem cell transplantation. AB - Functional abnormalities of the endothelial system may be caused by allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study is to explore the possibility that endothelial progenitor cells (EPCs) can be used in endothelial repair post-HSCT. EPCs were isolated from mouse bone marrow by density centrifugation and differential adherence. Numbers of endothelial cells (ECs) (CD31(+)CD133(-)CD45(-)), EPCs (CD31(+)CD133(+)-CD45(low/-)) and carboxyfluorescein succinimidyl ester (CFSE)-positive cells in peripheral blood, spleen and bone marrow were determined at various time points by flow cytometry. The distribution of labeled EPCs was observed by fluorescence microscopy; morphological alterations of tissues were assessed by light microscopy and transmission electron microscopy. In the irradiated group, the numbers of circulating ECs and EPCs were elevated after pre-conditioning, reaching peaks at days 3 and 5; the counts remained high for about 5 days. In addition, CFSE labeled cells were visualized in tissue and bone marrow. In conclusion, these results suggest the following: (a) the EPCs derived from mouse bone marrow mononuclear cells express phenotypes characteristic of normal EPCs, (b) irradiation during preconditioning damaged the endothelium, which initiated mobilization of EPCs, and (c) injury to the endothelium also caused extrinsic EPCs home to the damaged tissue. PMID- 22258716 TI - Early use of needle-knife fistulotomy is safe in situations where difficult biliary cannulation is expected. AB - BACKGROUND AND AIMS: Difficult cannulation is a well known risk for post-ERCP pancreatitis. This study evaluated the outcomes of needle-knife fistulotomy (NKF) used prior to being faced with difficult biliary cannulation. METHODS: Patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for the purpose of biliary endotherapy between January 2007 and December 2008 were eligible for this study; 218 patients were recruited. Biliary cannulation was performed only by a standard catheter or a pull type papillotome, without wire guided assistance in all patients. If selective cannulation was not achieved within five cannulation attempts, NKF was performed, and the results were compared with the easy cannulation group that succeeded biliary cannulation within five attempts. RESULTS: Needle-knife fistulotomy (NKF) was performed in 72 (33.0%) of the 218 patients. The total success rate of the ERCP was 98.2% (214/218), and for the NKF group the success rate was 94.4% (68/72). The rate of complications in patients with NKF did not increase compared to patients in the easy cannulation group (P > 0.05): 4.2% (3/72) versus 3.4% (5/146) for acute pancreatitis, 6.9% (5/72) versus 6.8% (10/146) for bleeding, and 1.4% (1/72) versus 0% (0/146) for perforation, respectively. CONCLUSIONS: Our results suggest that the use of NKF for biliary cannulation might be safe and effective. Therefore, in experienced hands, early use of NKF might be recommended. PMID- 22258717 TI - Anti-stress effects of transcutaneous electrical nerve stimulation (TENS) on colonic motility in rats. AB - BACKGROUND: Disorders of colonic motility may contribute to symptoms in patients with irritable bowel syndrome (IBS), and stress is widely believed to play a major role in developing IBS. Stress increases corticotropin releasing factor (CRF) of the hypothalamus, resulting in acceleration of colonic transit in rodents. In contrast, hypothalamic oxytocin (OXT) has an anti-stress effect via inhibiting CRF expression and hypothalamic-pituitary-adrenal axis activity. Although transcutaneous electrical nerve stimulation (TENS) and acupuncture have been shown to have anti-stress effects, the mechanism of the beneficial effects remains unknown. AIMS: We tested the hypothesis that TENS upregulates hypothalamic OXT expression resulting in reduced CRF expression and restoration of colonic dysmotility in response to chronic stress. METHODS: Male SD rats received different types of stressors for seven consecutive days (chronic heterotypic stress). TENS was applied to the bilateral hind limbs every other day before stress loading. Another group of rats did not receive TENS treatment. RESULTS: TENS significantly attenuated accelerated colonic transit induced by chronic heterotypic stress, which was antagonized by a central injection of an OXT antagonist. Immunohistochemical study showed that TENS increased OXT expression and decreased CRF expression at the paraventricular nucleus (PVN) following chronic heterotypic stress. CONCLUSIONS: It is suggested that TENS upregulates hypothalamic OXT expression which acts as an anti-stressor agent and mediates restored colonic dysmotility following chronic stress. TENS may be useful to treat gastrointestinal symptoms associated with stress. PMID- 22258718 TI - Anorectal symptoms before and after laparoscopic sacrocolpoperineopexy for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: To evaluate changes in anorectal symptoms before and after pelvic organ prolapse (POP) surgery, using laparoscopic sacrocolpoperineopexy. METHODS: Preoperative and postoperative anorectal symptoms, colorectal-anal distress inventory (CRADI) and colorectal-anal impact questionnaire (CRAIQ) scores were prospectively compared from 90 consecutive women undergoing laparoscopic sacrocolpoperineopexy. RESULTS: After a median follow-up of 30.7 months, laparoscopic surgery significantly worsened CRADI (p = 0.02) with no effect on CRAIQ (p = 0.37) scores. Post-operative and de novo straining (27%) and the need for digital assistance (17%) were the most frequent anorectal symptoms. No correlation was found between laparoscopic surgery and anorectal symptoms after multivariate analysis (OR = 2.45[95% confidence interval 0.99-6.05], p = 0.05). CONCLUSION: Anorectal symptoms are not improved after POP surgery by laparoscopic sacrocolpoperineopexy. PMID- 22258719 TI - Candidates and major determinants for endovascular repair of abdominal aortic aneurysms in Korean patients. AB - The purpose of this study was to determine what proportion of patients with an abdominal aortic aneurysm (AAA) would be eligible for endovascular aneurysm repair (EVAR) and to examine the major determinants for suitability of EVAR with the currently available indications. We retrospectively reviewed 3-D reconstructed computed tomography angiography of 88 patients with an atherosclerotic AAA who underwent open repair or EVAR between October 2003 and October 2010 at the Cardiovascular Center, Seoul National University Bundang Hospital. Of the 88 patients, 71 (80.7%) were treated with open repair and 17 (19.3%) were treated with EVAR. The rate of minor complications, postprocedural intensive care unit stay, and total hospital stay were significantly lower in the EVAR group. When the suitability of EVAR was reevaluated using morphologic criteria, a total of 33 (37.5%) patients were considered eligible for EVAR. Multivariate analysis revealed that proximal neck length, proximal neck angle, and aneurismal sac size were independent determinants for suitability of EVAR. Taking into account the increased clinical experience and the availability of new devices, EVAR would be applicable in about 40% of atherosclerotic AAA cases in this series of Korean patients. Accurate identification of candidates for EVAR by detailed preoperative evaluation, especially for morphologic characteristics, is essential. PMID- 22258720 TI - Introduction: Extracellular matrix and cardiovascular remodeling-using microscopy to delineate mechanisms. PMID- 22258722 TI - Structural remodeling and mechanical function in heart failure. AB - The cardiac extracellular matrix (ECM) is the three-dimensional scaffold that defines the geometry and muscular architecture of the cardiac chambers and transmits forces produced during the cardiac cycle throughout the heart wall. The cardiac ECM is an active system that responds to the stresses to which it is exposed and in the normal heart is adapted to facilitate efficient mechanical function. There are marked differences in the short- and medium-term changes in ventricular geometry and cardiac ECM that occur as a result of volume overload, hypertension, and ischemic cardiomyopathy. Despite this, there is a widespread view that a common remodeling "phenotype" governs the final progression to end stage heart failure in different forms of heart disease. In this review article, we make the case that this interpretation is not consistent with the clinical and experimental data on the topic. We argue that there is a need for new theoretical and experimental models that will enable stresses acting on the ECM and resultant deformations to be estimated more accurately and provide better spatial resolution of local signaling mechanisms that are activated as a result. These developments are necessary to link the effects of structural remodeling with altered cardiac mechanical function. PMID- 22258723 TI - Quantitative mineralogical properties (morphology-chemistry-structure) of pharmaceutical grade kaolinites and recommendations to regulatory agencies. AB - The physical and chemical characteristics of kaolinite (kaolin) may be variable, and minor amounts of other clay minerals, nonclay minerals, and other impurities may affect the properties of kaolinites. Thus specific technical properties of pharmaceutical grade kaolinites become very important because these clays are used in medical applications, e.g., as pharmaceutical excipients, and will be consumed by humans. Seven pharmaceutical grade kaolinite specimens were used in this study: K1004, KA105, 2242-01, K2-500, Acros, Acros-mono, and KX0007-1. In addition, two kaolinites from the Clay Minerals Society Source Clays, KGa-1b and KGa-2, were used for comparison purposes. The Acros-mono and 2242-01 kaolinites contained minor amounts of illite, which was demonstrated both compositionally and structurally by using inductively coupled plasma spectroscopy and powder X ray diffraction. The KX0007-1 kaolinite powder was found to be heavily contaminated with quartz, cristobalite, and alunite. Crystal structure computations also showed excess Si in its tetrahedral site, and the mineral no longer has the typical kaolinite crystal structure. These widely-used industrial standards should be quantitatively characterized morphologically, compositionally, and structurally. Results of the mineralogical characteristics should be clearly labeled on the pharmaceutical grade kaolinites and reported to the relevant regulatory agencies. PMID- 22258724 TI - A transmission electron microscopy study of the effect of interfaces on bubble formation in He-implanted Cu-Nb multilayers. AB - Magnetron sputtered thin films of Cu, Nb, and Cu-Nb multilayers with 2.5 and 5 nm nominal layer thickness were deposited on Si and implanted with 4He+ and 3He+ ions. Secondary ion mass spectroscopy and nuclear reaction analysis, respectively, were used to measure the 4He+ and 3He+ concentration profile with depth inside the films. Cross-sectional transmission electron microscopy was used to characterize the helium bubbles. Analysis of the contrast from helium bubbles in defocused transmission electron microscope images showed a minimum bubble diameter of 1.25 nm. While pure Cu and Nb films showed bubble contrast over the entire range of helium implantation, the multilayers exhibited bubbles only above a critical He concentration that increased almost linearly with decreasing layer thickness. The work shows that large amounts of helium can be trapped at incoherent interfaces in the form of stable, nanometer-size bubbles. PMID- 22258725 TI - Phase contrast synchrotron microtomography: improving noninvasive investigations of fossil embryos in ovo. AB - Fossil embryos are paramount for our understanding of the development of extinct species. However, although thousands of fossil amniote eggs are known, very few embryos in ovo have been described. First reports of fossil embryos were based on broken eggs, where the embryonic remains were already exposed, because destructive methods on complete eggs were avoided. Investigations of complete eggs therefore required nondestructive approaches, such as X-ray microtomography (MUCT). However, due to the general low density contrast between fossilized bones and infilling matrix, only a few specimens have been reported using these techniques. Using propagation phase contrast X-ray synchrotron microtomography (PPC-SR-MUCT), we report here the discovery of three well-preserved embryos in Early Cretaceous eggs from Thailand. By scanning these eggs using different imaging techniques, we show that vastly different interpretations can be made regarding the preservation state and/or the developmental stage of these embryos. PPC-SR-MUCT also revealed differential contrast between bone categories, presumably reflecting the ossification pattern of these embryos. Applying such an approach to large-scale studies of fossil eggs could lead to more discoveries and detailed studies of fossil embryos, providing important developmental and phylogenetic information on extinct and extant amniotes. PMID- 22258726 TI - Improving accuracy and precision of strain analysis by energy-filtered nanobeam electron diffraction. AB - This article deals with uncertainty in the analysis of strain in silicon nanoscale structures and devices using nanobeam electron diffraction (NBED). Specimen and instrument related errors and instabilities and their effects on NBED analysis are addressed using a nanopatterned ultrathin strained silicon layer directly on oxide as a model system. We demonstrate that zero-loss filtering significantly improves the NBED precision by decreasing the diffuse background in the diffraction patterns. To minimize the systematic deviations the acquired data were verified through a reliability test and then calibrated. Furthermore, the effect of strain relaxation by specimen preparation using a FIB is estimated by comparing profiles, which were acquired by analyzing slices of strained structures in a 220-nm-thick region of the sample (invasive preparation) and the entire strained nanostructures, which are embedded in a thicker region of the same sample (noninvasive preparation). Together with the random deviation, the corresponding systematic shift results in a total deviation of ~1 * 10(-3) for NBED analyses, which is employed to estimate the measurement uncertainty in the thinner sample region. In contrast, the strain in the thick sample region is not affected by the preparation; the systematic shift reduces to a minimum, which improves the total deviation by ~50%. PMID- 22258721 TI - The glomerular basement membrane as a model system to study the bioactivity of heparan sulfate glycosaminoglycans. AB - The glomerular basement membrane and its associated cells are critical elements in the renal ultrafiltration process. Traditionally the anionic charge associated with several carbohydrate moieties in the glomerular basement membrane are thought to form a charge selective barrier that restricts the transmembrane flux of anionic proteins across the glomerular basement membrane into the urinary space. The charge selective function, along with the size selective component of the basement membrane, serves to limit the efflux of plasma proteins from the capillary lumen. Heparan sulfate glycosaminoglycans are anionically charged carbohydrate structures attached to proteoglycan core proteins and have a role in establishing the charge selective function of the glomerular basement membrane. Although there are a large number of studies in the literature that support this concept, the results of several recent studies using molecular genetic approaches to minimize the anionic charge of the glomerular basement membrane would suggest that the role of heparan sulfate glycosaminoglycans in the glomerular capillary wall are still not yet entirely resolved, suggesting that this research area still requires new and novel exploration. PMID- 22258727 TI - Examination of a polycrystalline thin-film model to explore the relation between probe size and structural correlation length in fluctuation electron microscopy. AB - We examine simulated electron microdiffraction patterns from models of thin polycrystalline silicon. The models are made by a Voronoi tessellation of random points in a box. The Voronoi domains are randomly selected to contain either a randomly-oriented cubic crystalline grain or a region of continuous random network material. The microdiffraction simulations from coherent probes of different widths are computed at the ideal kinematical limit, ignoring inelastic and multiple scattering. By examining the normalized intensity variance that is obtained in fluctuation electron microscopy experiments, we confirm that intensity fluctuations increase monotonically with the percentage of crystalline grains in the material. However, anomalously high variance is observed for models that have 100% crystalline grains with no imperfections. We confirm that the reduced normalized variance, V(k,R) - 1, that is associated with four-body correlations at scattering vector k, varies inversely with specimen thickness. Further, for probe sizes R larger than the mean grain size, we confirm that the reduced normalized variance obeys the predicted form given by Gibson et al. [Ultramicroscopy, 83, 169-178 (2000)] for the kinematical coherent scattering limit. PMID- 22258728 TI - Implications of surgical intervention in the treatment of neuroblastomas: 20-year experience of a single institution. AB - PURPOSE: The implications of surgical intervention for neuroblastomas were assessed in one institution. METHODS: We analyzed the clinical characteristics and extension of resection in 123 pediatric patients with neuroblastoma diagnosed between 1985 and 2004. RESULTS: The 5-year survival rate of the 82 patients under 12 months of age, 59 of whom were treated with complete resection of the primary tumor, was 97%. The 5-year survival rate of the 41 patients over 12 months of age did not differ significantly according to whether complete (n = 19) or incomplete resection (n = 22) was performed (46 vs. 38%, respectively). No local recurrence was observed in ten patients over 12 months of age with stage 4 disease who underwent complete resection of the primary tumor; however, four of these ten patients died of metastatic recurrence. CONCLUSION: Considering that the majority of infantile neuroblastomas in this study had favorable biology, complete resection might be unnecessary for patients under 12 years of age. For advanced neuroblastomas in patients over 12 months of age, the main treatment for metastasis is systemic chemotherapy, although extirpation of the primary tumor without extensive surgery might prevent local recurrence when combined with radiation therapy. PMID- 22258729 TI - Primary extragastrointestinal stromal tumor arising in the pancreas: report of a case. AB - Primary extragastrointestinal stromal tumors (EGISTs) arising in the pancreas are extremely rare, with only ten cases documented to our knowledge. We report a further case of EGIST of the pancreas. The patient was a 55-year-old man who presented with postprandial abdominal discomfort. Abdominal computed tomography and magnetic resonance imaging showed a lobulated heterogenous enhancing mass, 11 cm in diameter, in the abdominal cavity. No regional lymphadenopathy, ascites, or metastasis was seen radiologically. There was no obvious lesion in the stomach or small intestine. The initial diagnosis was a solid pseudopapillary tumor or serous cystic neoplasm. The patient underwent distal pancreatectomy with splenectomy. Microscopically, the tumor consisted of spindle cells arranged in short fascicles. Mitotic figures were seen in 7/50 high-power fields. Immunohistochemical examination revealed strongly positive staining for CD117. Based on these findings, the final pathologic diagnosis was a primary EGIST of the pancreas. This case consolidates the possibility that this rare tumor can involve the pancreas as a primary site and should be included in the differential diagnosis of cystic lesions in this site. PMID- 22258730 TI - Dipolar-modulated charge-doped trilayer organic semiconductor n-n heterojunction. AB - A novel dipolar-modulated charge-doped trilayer n-n organic heterojunction with a bidirectional tunable energy band discontinuity is constructed. The rectifying mechanism of the trilayer is similar to the rectifying and inverse-rectifying characteristics from n-p and p-n junctions, respectively. Zero-bias optoelectronic behavior and persistent photoconductivity are discovered. These results show that what are viewed as technological hurdles in the development of an organic n-n heterojunction should, in fact, lead to a better approach in organic optoelectronics. PMID- 22258731 TI - Automatic patient table removal in CT images. AB - In many medical imaging applications, it is desirable and important to localize and remove the patient table from CT images. However, existing methods often require user interactions to define the table and sometimes make inaccurate assumptions about the table shape. Due to different patient table designs, shapes, and characteristics, these methods are not robust in identifying and removing the patient table. This paper proposes a new automatic approach which first identifies and locates the patient table in the sagittal planes and then removes it from the axial planes. The method has been tested successfully against different tables in different products from multiple vendors, showing it is both a versatile and robust technique for patient table removal. PMID- 22258732 TI - An open-standards grammar for outline-style radiology report templates. AB - Structured reporting uses consistent ordering of results and standardized terminology to improve the quality and reduce the complexity of radiology reports. We sought to define a generalized approach for radiology reporting that produces flexible outline-style reports, accommodates structured information and named reporting elements, allows reporting terms to be linked to controlled vocabularies, uses existing informatics standards, and allows structured report data to be extracted readily. We applied the Regular Language for XML-Next Generation (RELAX NG) schema language to create templates for 110 reporting templates created as part of the Radiological Society of North America reporting initiative. We evaluated how well this approach addressed the project's goals. The RELAX NG schema language expressed the cardinality and hierarchical relationships of reporting concepts, and allowed reporting elements to be mapped to terms in controlled medical vocabularies, such as RadLex(r), Systematized Nomenclature of Medicine Clinical Terms(r), and Logical Observation Identifiers Names and Codes(r). The approach provided extensibility and accommodated the addition of new features. Overall, the approach has proven to be useful and will form the basis for a supplement to the Digital Imaging and Communication in Medicine Standard. PMID- 22258734 TI - What I look like: college women, body image, and spirituality. AB - Despite public acknowledgment of the importance of spiritual development, little has been written globally on female young adults' personal views of their spiritual values and body image. This article briefly presents the findings of a pilot study that explored female college students' reflections on body image and spirituality. Responses from participants showed that (1) many students are interested in faith and spiritual development; (2) body dissatisfaction affects those women who viewed themselves as spiritual (92%) as well as those who said they were free thinkers (49%). Nevertheless, religion and spiritual values seemed to confer some behavioral protection. Implications for educational programs that will address the spiritual dimension of learning are discussed. PMID- 22258733 TI - An exploratory study of HIV+ adolescents' spirituality: will you pray with me? AB - The aims of the study were (1) to determine whether adolescents find it acceptable to have physicians explore their spiritual beliefs as part of their medical care, (2) to characterize the role of spirituality and religious beliefs in adolescents with and without HIV, and (3) to examine associations between spirituality/religion and quality of life. Adolescents receiving their medical care at an urban Adolescent Health Clinic completed a study-specific questionnaire about spiritual inquiry by their physician, the Brief Multidimensional Measurement of Religiousness/Spirituality, and the Pediatric Quality of Life Inventory 4.0. Chi-squared analysis, Fischer's exact test, and t tests were used to assess associations. A total of 45 participants enrolled: 19 HIV+ (53% vertical transmission) and 26 HIV-; mean age 17.2 years; 80% African American. Four out of 45 (9%) had ever been asked by their doctor about their spiritual/religious beliefs, and only 8 (18%) had ever shared these beliefs with their healthcare provider. Most teens wanted their provider to ask them about their spiritual beliefs during some visits, especially when dealing with death/dying or chronic illness (67%). Those with HIV were more likely to endorse wanting their doctors to pray with them (42% vs. 15%), feeling "God's presence" (Mean = 3.95 vs. 2.83), being "part of a larger force" (Mean = 2.58 vs. 1.69), and feeling "God had abandoned them" (Mean = 1.63 vs. 1.15). There are certain circumstances in which healthcare providers should include a spiritual history with teenage patients. Few differences emerged in the teens studied with and without HIV. PMID- 22258735 TI - Commentary: why do research on spirituality and health, and what do the results mean? AB - I address two related questions in this article. First, why conduct research on religion/spirituality (R/S) and health? Second, what are the dangers of misinterpreting or misapplying the results from such research? If relationships are found, so what? What is the practical value or clinical relevance of such information? Why should investigators spend time and scarce financial resources to explore such connections? What might health care professionals do differently as a result? How would people live their lives differently in light of such information? Questions like these need solid answers for the field to continue to move forward. Related to the "So what?" question is the issue of how results from research in this area are translated into popular understanding and application. After discussing why conducting research on religion and health is important, I identify a recently published research report that focuses on the relationship between R/S and self-control, an article that received considerable media press coverage. I present the results reported by the authors of this study and then examine a column written about the study that appeared in the New York Times. Finally, I explore what the findings mean, how the media portrayed the findings, and problems that might result depending on how people applied those findings. PMID- 22258736 TI - Participation and conflict in the decision-making process for endoscopic resection or surgical gastrectomy for early gastric cancer. AB - BACKGROUND: This study was to evaluate the participation role and conflict of patients during the decision-making process for endoscopic or surgical treatment for early gastric cancer (EGC). METHODS: In this prospective observational study, the sequential survey for patients under consideration for treatment of differentiated EGC was performed at the tertiary referral center. RESULTS: Among the 82 responders, 63.4% preferred endoscopic resection. The total decisional conflict scores were high and significantly different between groups that preferred endoscopic resection or surgical treatment (44.8 vs. 51.6, P = 0.016). Values assigned to the two treatment attributes "preservation of stomach (OR = 0.51)" and "bother in case of incomplete resection (OR = 2.13)" clearly discriminated between patients reaching a final decision of surgical gastrectomy or endoscopic resection. Regarding the participation role, a shared role was more frequent in the group with preference for endoscopic treatment before consultation (42.3% vs. 24.0%, P = 0.045). However, at the time of therapeutic decision, the passive role was most remarkable, both for the endoscopic (53.2%) and surgical (71.4%) groups. CONCLUSION: Despite the high overall decisional conflict, patients with preference for endoscopic treatment tended to be more autonomous. After consultation, all patients exhibited a passive participation role in the decision-making process. PMID- 22258737 TI - Fabrication of chitosan single-component microcapsules with a micrometer-thick and layered wall structure by stepwise core-mediated precipitation. AB - Incubation of CaCO(3) microparticles in chitosan (CS) solution at pH 5.2 and following with ethylenediaminetetraacetic acid disodium salt (EDTA) treatment resulted in CS single-component microcapsules with an ultra-thick wall structure. Repeating the incubation caused stepwise increase of wall thickness and finally resulted in CS microcapsules with a layered structure. This unique method is mediated by precipitation of CS on the CaCO(3) particles as a result of pH increase caused by the partial dissolution of CaCO(3) . The obtained CS capsules are stable at neutral pH. PMID- 22258738 TI - Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis. AB - Previous studies have reported inconsistent findings regarding the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of fracture. We identified relevant studies by searching three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) from their inception to October 20, 2010. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect. We identified 12 studies: seven case-control studies and five cohort studies. A meta-analysis of these 12 observational studies showed that the overall risk of fracture was higher among people using SSRIs (adjusted odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.51-1.90, I(2 ) = 89.9%). Subgroup analysis by adjusted number of key risk factors for osteoporotic fracture showed a greater increased fracture risk in those adjusted for fewer than four variables (adjusted OR = 1.83, 95% CI 1.57-2.13, I(2) = 88.0%) than those adjusted for four or more variables (adjusted OR = 1.38, 95% CI 1.27-1.49, I(2) = 46.1%). The pooled ORs anatomical site of fracture in the hip/femur, spine, and wrist/forearm were 2.06 (95% CI 1.84-2.30, I(2 ) = 62.3%), 1.34 (95% CI 1.13-1.59, I(2 ) = 48.5%), and 1.51 (95% CI 1.26-1.82, I(2 ) = 76.6%), respectively. Subgroup analysis by exposure duration revealed that the strength of the association decreased with a longer window of SSRI administration before the index date. The risk of fracture was greater within 6 weeks before the index date (adjusted OR = 3.83, 95% CI 1.96-7.49, I(2 ) = 41.5%) than 6 weeks or more (adjusted OR = 1.60, 95% CI 0.93-2.76, I(2 ) = 63.1%). Fracture risk associated with SSRI use may have a significant clinical impact. Clinicians should carefully consider bone mineral density screening before prescribing SSRIs and proper management for high-risk populations. PMID- 22258739 TI - Stereocontrolled asymmetric synthesis of syn-E-1,4-diol-2-enes using allyl boronates and its application in the total synthesis of solandelactone F. AB - The solandelactones A-H comprise a novel class of oxygenated fatty acids bearing an eight-membered lactone, trans cyclopropane, and a 2-ene-1,4-diol subunit. The relative stereochemistry of the 1,4-diol subunit is anti in solandelactones A, C, E & G, and syn in solandelactones B, D, F & H. Having prepared one member of the solandelactones bearing anti stereochemistry (solandelactone E), we have targeted the syn series and developed methodology for the synthesis of enantioenriched syn 2-ene-1,4-diols. The methodology comprises asymmetric deprotonation of an alkyl 2,4,6-triisopropylbenzoate using sBuLi/sparteine, followed by addition of the alpha-lithiobenzoate to beta-silyl vinyl boronic acid ethylene glycol ester. The boron-ate complex generated undergoes a 1,2-metallate rearrangement furnishing an intermediate allyl boronic ester which is trapped by an aldehyde in the presence of MgBr(2) to furnish anti-beta-hydroxy E-allylsilanes in good yields, high diastereoselectivity and high enantioselectivity. These sensitive products were oxidized using mCPBA to the corresponding epoxides and subsequently treated with acid to furnish syn-E-2-ene-1,4-diols (~4:1 d.r.). Application of the methodology to appropriately functionalized aldehyde and omega-alkenyl 2,4,6 triisopropylbenzoate coupling partners, led to a short, highly selective route to solandelactone F (bearing a syn-E-2-ene-1,4-diol). PMID- 22258740 TI - Optimization of pressure gauge locations for water distribution systems using entropy theory. AB - It is essential to select the optimal pressure gauge location for effective management and maintenance of water distribution systems. This study proposes an objective and quantified standard for selecting the optimal pressure gauge location by defining the pressure change at other nodes as a result of demand change at a specific node using entropy theory. Two cases are considered in terms of demand change: that in which demand at all nodes shows peak load by using a peak factor and that comprising the demand change of the normal distribution whose average is the base demand. The actual pressure change pattern is determined by using the emitter function of EPANET to reflect the pressure that changes practically at each node. The optimal pressure gauge location is determined by prioritizing the node that processes the largest amount of information it gives to (giving entropy) and receives from (receiving entropy) the whole system according to the entropy standard. The suggested model is applied to one virtual and one real pipe network, and the optimal pressure gauge location combination is calculated by implementing the sensitivity analysis based on the study results. These analysis results support the following two conclusions. Firstly, the installation priority of the pressure gauge in water distribution networks can be determined with a more objective standard through the entropy theory. Secondly, the model can be used as an efficient decision making guide for gauge installation in water distribution systems. PMID- 22258741 TI - Assessment of water quality of some swimming pools: a case study in Alexandria, Egypt. AB - In spite of the importance and popularity of swimming pools in summer, they have been identified as posing some public health risks to users due to either chemical or microbiological contamination. This study was carried out aiming at assessing the quality of water for some Alexandria's swimming pools in order to determine its compliance with the Egyptian standards no. 418/1995. Five swimming pools were selected randomly from different districts. Physical and chemical parameters, as well as biological examination of a total of 30 samples, were carried out using standard analytical methods. Water samples were collected from the studied swimming pools monthly over 6 months and pool water monitoring was carried out during afternoon of the weekends when the pools were most heavily used. The results indicated overall poor compliance with the standards. Compliance of the pool water to the microbial parameters, residual chlorine, pH, and turbidity were 56.7% (17 samples), 20% (6 samples), 46.7% (14 samples), and 46.7% (14 samples), respectively. Statistical analysis showed significant association between water contamination with microbial indicators and physical chemical aspects such as residual chlorine, temperature, turbidity, and load of swimmers. Furthermore, Cryptosporidium oocysts and Giardia lamblia cysts has been found in 10% of samples. It was concluded that there is a need to improve disinfection and cleaning procedures, with consideration given to safety, and size of the pool in relation to bathing load. There is also a need to monitor swimming pool water quality continuously, and to increase bather hygienic practices and awareness of the risks as well as training of governmental inspectors. PMID- 22258742 TI - Ionic liquid-based dispersive liquid-liquid microextraction for the determination of formaldehyde in wastewaters and detergents. AB - Spectrophotometry in combination with ionic liquid-based dispersive liquid-liquid microextraction (DLLME) was applied for the extraction and determination of formaldehyde in real samples. The method is based on the reaction of formaldehyde with methyl acetoacetate in the presence of ammonia. The variation in the absorbance of the reaction product was measured at 375 nm. An appropriate mixture of ethanol (disperser solvent) and ionic liquid, 1-hexyl-3 methylimidazoliumhexafluoro-phosphate [C(6)MIM][PF(6)] (extraction solvent) was rapidly injected into a water sample containing formaldehyde. After extraction, sedimented phase was analyzed by spectrophotometry. Under the optimum conditions, the calibration graph was linear in the range of 0.1-20 ng mL(-1) with the detection limit of 0.02 ng mL(-1) and limit of quantification of 0.08 ng mL(-1) for formaldehyde. The relative standard deviation (RSD%, n = 5) for the extraction and determination of 0.8 ng mL(-1) of formaldehyde in the aqueous samples was 2.5%. The results showed that DLLME is a very simple, rapid, sensitive, and efficient analytical method for the determination of trace amounts of formaldehyde in wastewaters and detergents, and suitable results were obtained. PMID- 22258744 TI - 4th Wurzburg Summer School of Thyroid Cancer Management. PMID- 22258745 TI - "Hevesy Gyorgy" Hungarian Society of Nuclear Medicine. The XVIIth Congress in Budapest, May 25-27, 2011: a technologist's perspective. PMID- 22258746 TI - The role of CCoAOMT1 and COMT1 in Arabidopsis anthers. AB - Arabidopsis caffeoyl coenzyme A dependent O-methyltransferase 1 (CCoAOMT1) and caffeic acid O-methyltransferase 1 (COMT1) display a similar substrate profile although with distinct substrate preferences and are considered the key methyltransferases (OMTs) in the biosynthesis of lignin monomers, coniferyl and sinapoylalcohol. Whereas CCoAOMT1 displays a strong preference for caffeoyl coenzyme A, COMT1 preferentially methylates 5-hydroxyferuloyl CoA derivatives and also performs methylation of flavonols with vicinal aromatic dihydroxy groups, such as quercetin. Based on different knockout lines, phenolic profiling, and immunohistochemistry, we present evidence that both enzymes fulfil distinct, yet different tasks in Arabidopsis anthers. CCoAOMT1 besides its role in vascular tissues can be localized to the tapetum of young stamens, contributing to the biosynthesis of spermidine phenylpropanoid conjugates. COMT1, although present in the same organ, is not localized in the tapetum, but in two directly adjacent cells layers, the endothecium and the epidermal layer of stamens. In vivo localization and phenolic profiling of comt1 plants provide evidence that COMT1 neither contributes to the accumulation of spermidine phenylpropanoid conjugates nor to the flavonol glycoside pattern of pollen grains. PMID- 22258747 TI - Artificial ubiquitylation is sufficient for sorting of a plasma membrane ATPase to the vacuolar lumen of Arabidopsis cells. AB - Sorting of transmembrane proteins into the inner vesicles of multivesicular bodies for subsequent delivery to the vacuole/lysosome can be induced by attachment of a single ubiquitin or K63-linked ubiquitin chains to the cytosolic portion of the cargo in yeast and mammals. In plants, large efforts have been undertaken to elucidate the mechanisms of vacuolar trafficking of soluble proteins. Sorting of transmembrane proteins, by contrast, is still largely unexplored. As a proof of principle, that ubiquitin is involved in vacuolar sorting in plants we show that a translational fusion of a single ubiquitin to the Arabidopsis plasma membrane ATPase PMA-EGFP is sufficient to induce its endocytosis and sorting into the vacuolar lumen. Sorting of the artificial reporter is not dependent on ubiquitin chain formation, but involves ubiquitin's hydrophobic patch and can be inhibited by coexpression of a dominant-negative version of the ESCRT (endosomal sorting complex required for transport) related protein AtSKD1 (SUPPRESSOR OF K+ TRANSPORT GROWTH DEFECT1). Our results suggest that ubiquitin can in principle act as vacuolar sorting signal in plants. PMID- 22258748 TI - Distribution of glucomannans and xylans in poplar xylem and their changes under tension stress. AB - Present work investigated glucomannan (GM) and xylan distribution in poplar xylem cells of normal- (NW), opposite- (OW) and tension wood (TW) with immunolocalization methods. GM labeling was mostly detected in the middle- and inner S(2) (+S(3)) layer of NW and OW fibers, while xylan labeling was observed in the whole secondary cell wall. GM labeling in vessels of NW and OW was much weaker than in fibers and mostly detected in the S(2) layer, whereas slightly stronger xylan labeling than fibers was detected in the whole secondary cell wall of vessels. Ray cells in NW and OW showed no GM labeling, but strong xylan labeling. These results indicate that GMs and xylans are spatially distributed in poplar xylem cells with different concentrations present in different cell types. Surprisingly, TW showed significant decrease of GM labeling in the normal secondary cell wall of gelatinous (G) fibers compared to NW and OW, while xylan labeling was almost identical indicating that the GM and xylan synthetic pathways in fibers have different reaction mechanisms against tension stress. Unlike fibers, no notable changes in GM labeling were detected in vessels of TW, suggesting that GM synthesis in vessels may not be affected by tension stress. GM and xylan was also detected in the G-layer with slightly stronger and much weaker labeling than the normal secondary cell wall of G-fibers. Differences in GM and xylan distribution are also discussed for the same functional cells found in hardwoods and softwoods. PMID- 22258749 TI - The soybean F3'H protein is localized to the tonoplast in the seed coat hilum. AB - We previously isolated a soybean (Glycine max (L.) Merr.) flavonoid 3' hydroxylase (F3'H) gene (sf3'h1) corresponding to the T locus, which controls pubescence and seed coat color, from two near-isogenic lines (NILs), To7B (TT) and To7G (tt). The T allele is also associated with chilling tolerance. Here, Western-blot analysis shows that the sf3'h1 protein was predominantly detected in the hilum and funiculus of the immature seed coat in To7B, whereas sf3'h1 was not detected in To7G. A truncated sf3'h1 protein isolated from To7G was detected only upon enrichment by immunoprecipitation. An analysis using diphenylboric acid 2 aminoethyl ester (DBPA) staining revealed that flavonoids accumulated in the hilum and the funiculus in both To7B and To7G. Further, the scavenging activity of the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical in methanol extracts from the funiculus and hilum of To7B was higher than that of To7G. Moreover, the enzymatic activity of F3'H was detected using microsomal fractions from yeast transformed with sf3'h1 from To7B, but not from To7G. These results indicate that sf3'h1 is involved in flavonoid biosynthesis in the seed coat and affects the antioxidant properties of those tissues. As shown by immunofluorescence microscopy, the sf3'h1 protein was detected primarily around the vacuole in the parenchymatic cells of the hilum in To7B. Further immunoelectron microscopy detected sf3'h1 protein on the membranous structure of the vacuole. Based on these observations, we conclude that F3'H, which is a cytochrome P450 monooxygenase and has been found to be localized to the ER in other plant systems, is localized in the tonoplast in soybean. PMID- 22258750 TI - Utilization of vinasse for the production of polyhydroxybutyrate by Haloarcula marismortui. AB - Vinasse, a recalcitrant waste of the ethanol industry was employed for the production of polyhydroxyalkanoate (PHA) by the extremely halophilic archaeon, Haloarcula marismortui in shake flasks. The PHA was recovered by osmotic lysis of the cells and subsequent purification by sodium hypochlorite and organic solvents. Through UV-vis spectroscopy, differential scanning calorimetry, Fourier transform infrared, and nuclear magnetic resonance spectroscopy, the PHA was found to have characteristics very similar to that of the standard polyhydroxybutyrate (PHB) from Sigma. Inhibitory effect of polyphenols contained in vinasse was assessed by a quick and reliable cup-plate agar-diffusion method. Raw vinasse (10%) was utilized leading to accumulation of 23% PHA (of cell dry weight) and following an efficacious pre-treatment process through adsorption on activated carbon, 100% pre-treated vinasse could be utilized leading to 30% accumulation of PHB by H. marismortui. Maximum specific growth rate, specific production rate, and volumetric productivity attained using 10% raw vinasse were comparable to that obtained using a previously reported nutrient deficient medium (NDM), while the values with 100% pre-treated vinasse were higher than that determined using NDM medium. This is the first report of polyhydroxybutyrate production by a halophilic microorganism utilizing vinasse. PMID- 22258751 TI - An imported case of bloody diarrhea in the Czech Republic caused by a hybrid enteroaggregative hemorrhagic Escherichia coli (EAHEC) O104:H4 strain associated with the large outbreak in Germany, May 2011. AB - A large outbreak caused by a rare Shiga toxin-producing Escherichia coli serotype O104:H4 occurred in Germany in May to July 2011. The National Reference Laboratory for E. coli and Shigella investigated the stool sample from an American tourist with bloody diarrhea who arrived in the Czech Republic from Germany where she consumed salads with raw vegetable a week ago. Using culture of the enriched stool on extended-spectrum beta-lactamase agar, we isolated E. coli strain which belonged to serotype O104:H4 as determined by conventional and molecular serotyping. The strain contained the major virulence characteristics of enterohemorrhagic E. coli (stx (2) encoding Shiga toxin 2) and enteroaggregative E. coli (aggA encoding aggregative adherence fimbriae I). This unique combination of virulence traits demonstrated that this strain belongs to the hybrid enteroaggregative hemorrhagic E. coli clone which caused the German outbreak. Using advanced culture and molecular biological approaches is the prerequisite for identification of new, unusual pathogens. PMID- 22258752 TI - Facile modification of silica substrates provides a platform for direct-writing surface click chemistry. AB - Please click here: a facile two-step functionalization strategy for silicon oxide based substrates generates a stable platform for surface click chemistry via direct writing. The suitability of the obtained substrates is proven by patterning with two different direct-writing techniques and three different molecules. PMID- 22258753 TI - Content-based image-retrieval system in chest computed tomography for a solitary pulmonary nodule: method and preliminary experiments. AB - PURPOSE: The aim of this study was to develop a new diagnostic support system using content-based image-retrieval technology. In this article, we describe the mechanism and preliminary evaluation of this system for use with CT images of solitary pulmonary nodules. MATERIALS AND METHODS: With the approval of the institutional review board of Shizuoka Cancer Center, we built a database that included CT images of 461 solitary pulmonary nodules. With this database, we developed a system that automatically extracts the pulmonary nodule when the nodule area is clicked, retrieves previous cases based on an image analysis of the extracted lesion, and generates reports of the pulmonary nodule semi automatically. We compared the percentage of correct diagnoses with and without the system using 30 solitary pulmonary nodules, which were not included in the database, with one radiologist and two residents. As a per-user evaluation, the number of clicks required to extract the nodule region and the extracted regions was compared, and presented candidate cases were evaluated. As an evaluation of the retrieval results, the presented candidate cases were evaluated by comparing the number of diagnostic matches (benign/malignant) between the queries and four presented cases. Additionally, to evaluate the validity of the retrieval technology, the radiologist selected the most similar cases presented by the system and evaluated the visual similarity on a five-point scale. RESULTS: With this system, the percentage of correct diagnoses for the radiologist improved from 80 to 93%. For the two residents, the diagnostic accuracy improved from 66.7 to 80% and from 76.7 to 90%, respectively. The evaluation of the number of clicks required indicated that for 19 cases with the radiologist and 12 and 11 cases with the two residents, respectively, only one click was required to extract the region. When the extracted regions were compared between the radiologist and the residents, 22 and 19 cases had a Dice's Coefficient of 0.85 or higher, respectively. For the radiologist, the number of cases that matched the diagnosis (benign/malignant) averaged 3.7 +/- 0.5 among 23 malignant cases and 1.7 +/- 1.4 among 7 benign cases, while for the residents, these values were 3.6 +/- 0.5 and 1.1 +/- 0.9, and 3.4 +/- 0.8 and 1.1 +/- 1.3, respectively. With regard to visual evaluations by the radiologist, there were 15 similar cases and 11 somewhat similar cases. CONCLUSION: These results suggest that, despite some differences in the search results among the users, this system has been confirmed that it can improve the accuracy of diagnosis as it displays similar cases at high probability. In addition, with the use of this system, past cases and their reports can be effectively referred to. Therefore, this diagnostic-assistant system has the potential to improve the efficiency of the CT image-reading workflow. PMID- 22258754 TI - Management of pediatric patients with pseudotumor cerebri. AB - INTRODUCTION: The care of patients with pseudotumor cerebri (idiopathic intracranial hypertension) involves ophthalmologists, neurologists and neurosurgeons. Its clinical characteristics in the pediatric population are distinct from those in adult patients. PATIENTS AND METHODS: Fifty-nine patients diagnosed with pseudotumor cerebri were identified from the neurosurgery and neurology databases at Children's Hospital, Birmingham, AL, USA. Clinical data were collected from the ophthalmology, neurology and neurosurgery departments. RESULTS: The average age of patients at diagnosis was 11.4 years (range 3-17). The average opening pressure of lumbar puncture (LP) was 37 cm of water. Most of the patients responded well to therapeutic LPs and medical management. Neurosurgical interventions included intracranial pressure monitoring and shunt insertion in nine patients. In three patients who presented with acute visual decline, two recovered and one remains legally blind. CONCLUSIONS: The care of patients with pseudotumor cerebri requires a multiple-disciplinary approach. Neurosurgical interventions are sometimes needed for diagnostic and treatment purpose. Prompt and accurate communication among specialists is necessary to ensure timely treatment and optimal outcomes. PMID- 22258755 TI - Assessment of the release of rehabilitated vervet monkeys into the Ntendeka Wilderness Area, KwaZulu-Natal, South Africa: a case study. AB - In South Africa, vervet monkeys (Chlorocebus aethiops) are frequently persecuted, resulting in large numbers of injured and/or orphaned animals. Rehabilitation centres aim to care for these monkeys and ultimately return them to the wild whenever possible. However, it is unknown whether rehabilitation is successful in its goal of creating wild-living, independent, self-sustaining troops due to limited published research in this area. This study describes the release and subsequent fate of a troop of rehabilitated vervet monkeys over a 6-month period. A troop of 16 monkeys was released into the Ntendeka Wilderness Area, a protected part of Ngome Forest, by the WATCH (Wild Animal Trauma Centre and Haven) rehabilitation centre in KwaZulu-Natal, South Africa. Monitoring data were evaluated with regard to survival, mortality, suitability of the release site, breeding, condition, troop composition, behaviour, group dynamics, ranging patterns and the effectiveness of monitoring tools. The release was considered to be a partial success in that the troop exhibited behaviour, group dynamics and ranging patterns similar to wild conspecifics. However, the survival rate was low and the troop was judged to be non-self-sustaining. The main problems identified were the limited lifetimes of radio collars, which resulted in missing animals and caused monitoring to be cut short, illegal hunting activities, predation and a small troop size with few adults. The authors recommend improvements that may increase success, such as retaining troops in release enclosures for longer periods, releasing a larger troop with more adults that more closely matches wild troop composition, selecting a release site at least 3 km from the nearest human settlement and the use of GPS collars to allow for a longer monitoring period encompassing all seasonal conditions. Furthermore, all primates for release should be medically screened so as to avoid potential negative impacts on wild populations. PMID- 22258756 TI - Free peritoneal tumor cells detection in gastric and colorectal cancer patients. AB - BACKGROUND: Free peritoneal tumor cells (FPTC) derive from the detachment of primary cancer and may result in peritoneal carcinomatosis. Since peritoneal lavage cytology has low sensitivity in detecting FPTC, our aim was to estimate the clinical relevance of FPTC detected using an approach based on multiple molecular techniques. MATERIALS AND METHODS: Samples of peritoneal lavage were collected from 27 gastric and 48 colorectal cancer patients. FPTC recovery and detection from peritoneal washes was performed by cytological examination and immunomagnetic enrichment for epithelial cells followed by immunofluorescence analysis for epithelial marker EpCAM/CD326 and carcinoembryonic antigen (CEA). CEA and CK20 mRNA levels were quantified using a real-time qRT-PCR system. RESULTS: For gastric carcinoma the FPTC positivity rate acquired by cytology, immunofluorescence and qRT-PCR was 14.8%, 14.8%, and 78% and for colorectal carcinoma was 0%, 17%, and 42%, respectively. qRT-PCR positivity was correlated with a poor cancer-specific survival and time-to-recurrence rates in both gastric and colorectal carcinoma. CONCLUSIONS: Epithelial immunoenrichment and immunofluorescence analysis allows unequivocal identification of the FPTC. The real time qRT-PCR showed higher sensitivity for the detection of CEA and CK20 mRNA levels and confirmed its prognostic value in gastrointestinal cancers. PMID- 22258757 TI - Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta. AB - Pathology in the craniocervical junction is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze the prevalence and natural course of craniocervical junction anomalies in patients with OI during growth. In a one-center retrospective study, we analyzed lateral skull radiographs and midsagittal magnetic resonance images of 76 patients with either type I, III, or IV OI. The material included longitudinal series of 31 patients. In total, 150 patient images taken at ages 0 to 39 years were analyzed and compared with age matched control data. Craniocervical anomalies were observed in 37% of patients and in all OI types studied. Of the three types of anomalies, basilar invagination was seen in 13%, basilar impression in 15%, and platybasia in 29% of the patients. From those with an abnormal finding, 44% displayed more than one type of anomaly. At a group level, we found no evidence of progression of craniocervical junction pathology with age. We provide longitudinal and cross sectional data on craniocervical junction dimensions in growing patients with OI and, based on those, suggest a radiological management strategy for diagnosis of cranial base pathology. A higher risk of having any of the pathological conditions was associated with a lower height Z-score. Careful follow-up of cranial base anomalies particularly in subjects with OI and severe growth failure is warranted. PMID- 22258758 TI - Genetics of age at menarche: a systematic review. AB - BACKGROUND: Menarche is the first menstrual period of a girl at puberty. The timing of menarche is important for health in later life. Age at menarche is a complex trait and has a strong genetic component. This review summarizes the results of the genetic studies of age at menarche conducted to date, highlights existing problems in this area and outlines prospects of future studies on genetic factors for the trait. METHODS: PubMed and Google Scholar were searched until May 2011 using the keywords: 'menarche', 'puberty' and 'age at menarche' in combination with the keywords 'polymorphism', 'candidate gene', 'genome-wide association study' and 'linkage'. RESULTS: Our search yielded 170 papers, 35 of which were selected for further analysis. Several large-scale genome-wide association studies along with a powerful meta-analysis of their aggregated data identified about 50 candidate genes for the trait. Some genes were replicated in different studies of Caucasians (e.g. LIN28B, TMEM38B) or in different ethnicities (e.g. SPOCK, RANK and RANKL). However, despite the large volume of results obtained, there is a huge gap in relevant data on ethnic groups other than Caucasians. CONCLUSIONS: The reviewed studies laid a solid basis for future research on genetics of age at menarche. However, as yet specific genes for this trait have not been identified consistently in all ethnicities and types of studies. We suggest expanding the research to different ethnicities and propose several methodologies to increase the efficiency of studies in this area, including a systems approach, which combines existing high-throughput methods in a single pipeline. PMID- 22258759 TI - Aspirin is not recommended for women undergoing IVF. PMID- 22258760 TI - Item-level discordance in parent and adolescent reports of parenting behavior and its implications for adolescents' mental health and relationships with their parents. AB - The phenomenon of discordance between parents' and children's ratings of the child's mental health symptoms or of parenting behavior until recently has been treated as a problem of reliability. More recent work has sought to identify factors that may influence discordance, yet much remains to be learned about why informants' ratings of developmental phenomena are discordant and the meaning of such discordance. This study examined the extent to which discordance can be treated as a measure of the difference between two equally valid perceptions, and as such an indicator of the quality of the parent-adolescent relationship. One category of concordance and three patterns of discordance were derived from item level differences in ratings of affection, control, and punitiveness provided by a diverse sample (53% female; 46% Hispanic-American, 35% African-American, 15% European-American, 4% another race/ethnicity) of 484 adolescents aged 12-20 years (M = 15.67, SD = 1.72) and their parents. Over and above adolescents' and parents' independent ratings of parenting, the discordance between these ratings was found to predict adolescent reports of anxiety and conduct disorder symptoms, as well as the quality of the parent-adolescent relationship. This was particularly true when adolescents and parents were discordant in their ratings of affection and when adolescents rated their parents higher on affection than did parents themselves. Implications of these findings and future research directions are discussed. PMID- 22258761 TI - Photoinduced electron transfer in covalent ruthenium-anthraquinone dyads: relative importance of driving-force, solvent polarity, and donor-bridge energy gap. AB - Four rigid rod-like molecules comprised of a Ru(bpy)(3)(2+) (bpy = 2,2' bipyridine) photosensitizer, a 9,10-anthraquinone electron acceptor, and a molecular bridge connecting the two redox partners were synthesized and investigated by optical spectroscopic and electrochemical means. An attempt was made to assess the relative importance of driving-force, solvent polarity, and bridge variation on the rates of photoinduced electron transfer in these molecules. Expectedly, introduction of tert-butyl substituents in the bipyridine ligands of the ruthenium complex and a change in solvent from dichloromethane to acetonitrile lead to a significant acceleration of charge transfer rates. In dichloromethane, photoinduced electron transfer is not competitive with the inherent excited-state deactivation processes of the photosensitizer. In acetonitrile, an increase in driving-force by 0.2 eV through attachment of tert butyl substituents to the bpy ancillary ligands causes an increase in electron transfer rates by an order of magnitude. Replacement of a p-xylene bridge by a p dimethoxybenzene spacer entails an acceleration of charge transfer rates by a factor of 3.5. In the dyads from this study, the relative order of importance of individual influences on electron transfer rates is therefore as follows: solvent polarity >= driving-force > donor-bridge energy gap. PMID- 22258762 TI - Water-developable poly(2-oxazoline)-based negative photoresists. AB - Copoly(2-oxazoline)-based photoresists are prepared from pEtOx(80) Bu(=) Ox(20) and pPhOx(80) Dc(=) Ox(20) , respectively, a tetrathiol, and a photosensitive initiator. It is possible to prepare copoly(2-oxazoline)s bearing unsaturated side chains in a microwave reactor on a decagram scale in reaction times of 100 min or shorter. UV irradiation of dried polymer films through a quartz mask induces the thiol-ene reaction in the illuminated areas. Subsequent development of the polymer films in halogen-free solvents reproduces the negative pattern of the mask with a resolution of 2 MUm. The pEtOx(80) Bu(=) Ox(20) -derived photoresists can also be developed in water. PMID- 22258763 TI - A right Royal porphyria fallacy. PMID- 22258764 TI - Troponin T percentiles from a random population sample, emergency room patients and patients with myocardial infarction. AB - BACKGROUND: High-sensitivity cardiac troponin T (cTnT) assays detect small clinically important myocardial infarctions (MI) but also yield higher rates of false-positive results owing to increased concentrations sometimes present in patients without MI. Better understanding is needed of factors influencing the 99th percentile of cTnT concentrations across populations and the frequency of changes in cTnT concentrations >20% often used in combination with increased cTnT concentrations for diagnosis of MI. METHODS: cTnT percentiles were determined by use of the Elecsys(r) hscTnT immunoassay (Modular(r) Analytics E170) in a random population sample, in emergency room (ER) patients, and in patients with non-ST elevation MI (NSTEMI). Changes in cTnT concentrations were determined in hospitalized patients without MI. RESULTS: The 99th cTnT percentile in a random population sample (median age, 65 years) was 24 ng/L. In ER patients <65 years old without obvious conditions that increase cTnT, the 99th cTnT percentile was 12 ng/L with little age dependence, whereas in those >65 years old it was 82 ng/L and highly age dependent. In hospitalized patients without MI the 97.5th percentile for change in the cTnT concentration was 51%-67%. cTnT remained below the 99th percentile (12 ng/L) in 1% of patients with NSTEMI until 8.5 h after symptom onset and 6 h after ER arrival. CONCLUSIONS: Age >65 years was the dominant factor associated with increased cTnT in ER patients. This age association was more prominent in ER patients than in a random population sample. Changes in serial cTnT concentrations >20% were common in hospitalized patients without MI. PMID- 22258765 TI - A functional, new short isoform of death receptor 4 in Ewing's sarcoma cell lines may be involved in TRAIL sensitivity/resistance mechanisms. AB - Ewing's sarcoma (ES) is a high-grade neoplasm arising in bones of children and adolescents. Survival rate decreases from greater than 50% to only 20% after 5 years for patients not responding to treatment or presenting metastases at diagnosis. TRAIL, which has strong antitumoral activity, is a promising therapeutic candidate. To address TRAIL sensitivity, 7 human ES cell lines were used. Cell viability experiments [3'[1-(phenylaminocarbonyl)-3,4-tetrazolium] bis(4-methoxy-6-nitro-)benzene sulfonic acid hydrate (XTT) assay] showed that 4 of the 7 ES cell lines were resistant to TRAIL. Western blotting and flow cytometry analyses revealed that DR5 was uniformly expressed by all ES cell lines, whereas DR4 levels were higher in sensitive cell lines. In TRAIL-sensitive TC-71 cells, knockdown of TNFRSF10A/DR4 by short hairpin RNA (shRNA) was associated with a loss of sensitivity to TRAIL, in spite of DR5 presence. Interestingly, we identified a new transcript variant that results from an alternative splicing and encodes a 310-amino acid protein which corresponds to the 468 aa of DR4 original isoform but truncated of aa 11 to 168 within the extracellular TRAIL-binding domain. According to modeling studies, the contact of this new DR4 isoform (bDR4) with TRAIL seemed largely preserved. The overexpression of bDR4 in a TRAIL-resistant cell line restored TRAIL sensitivity. TRAIL resensitization was also observed after c-FLIP knockdown by shRNA in two TRAIL-resistant cell lines, as shown by XTT assay and caspase-3 assay. The results presented in this study showed that DR4, both as the complete form or as its new short isoform, is involved in TRAIL sensitivity in ES. PMID- 22258766 TI - SPINDLIN1 promotes cancer cell proliferation through activation of WNT/TCF-4 signaling. AB - SPINDLIN1, a new member of the SPIN/SSTY gene family, was first identified as a gene highly expressed in ovarian cancer cells. We have previously shown that it is involved in the process of spindle organization and chromosomal stability and plays a role in the development of cancer. Nevertheless, the mechanisms underlying its oncogenic role are still largely unknown. Here, we first showed that expression of SPINDLIN1 is upregulated in clinical tumors. Ectopic expression of SPINDLIN1 promoted cancer cell proliferation and activated WNT/T cell factor (TCF)-4 signaling. The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function. Collectively, these results suggest that SPINDLIN1, which may be a novel substrate of the Aurora-A kinase, promotes cancer cell growth through WNT/TCF-4 signaling activation. PMID- 22258768 TI - The role of orthopaedic device registries in improving patient outcomes. PMID- 22258767 TI - Triiodothyronine stimulates glucose transport in bone cells. AB - Thyroid hormones increase energy expenditure and bone turnover in vivo. To study whether 3,3',5-triiodo-l-thyronine (T3) stimulates the uptake of glucose in osteoblastic cells, PyMS (a cell line derived from rat bone) cells were kept in serum-free culture medium and treated with T3. We measured [1-14C]-2-deoxy-D: glucose (2DG) uptake and looked for expression of the high-affinity glucose transporters GLUT1 and GLUT3 by northern and western analysis. T3 did not influence the cell number but slightly (1.3-fold) increased the protein content of the cell cultures. 2DG uptake was low in serum-deprived cell cultures and was increased by T3 (up to 2.5-fold at 1 nmol l-1 after 4 days) in a dose- and time dependent manner. Triiodothyronine at 1 nmol l-1 increased GLUT1 and GLUT3 abundance in membranes. Therefore, increased glucose uptake induced by T3 in osteoblasts may be mediated by the known high-affinity glucose transporters GLUT1 and GLUT3. PMID- 22258769 TI - Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme. AB - BACKGROUND: The white blood-cell count and neutrophil differential of the synovial fluid have been reported to have high sensitivity and specificity in the diagnosis of periprosthetic infection following total knee arthroplasty. We hypothesized that neutrophils recruited into an infected joint secrete enzymes that may be used as markers for infection. In this prospective study, we determined the sensitivity and specificity of one of these enzymes, leukocyte esterase, in diagnosing periprosthetic joint infection. METHODS: Between May 2007 and April 2010, synovial fluid was obtained preoperatively from the knees of patients with a possible joint infection and intraoperatively from the knees of patients undergoing revision knee arthroplasty. The aspirate was tested for the presence of leukocyte esterase with use of a simple colorimetric strip test. The color change (graded as negative, trace, +, or ++), which corresponded to the level of the enzyme, was noted after one or two minutes. RESULTS: On the basis of clinical, serological, and operative criteria, thirty of the 108 knees undergoing revision arthroplasty were infected and seventy-eight were uninfected. When only a ++ reading was considered positive, the leukocyte esterase test was 80.6% sensitive (95% confidence interval [CI], 61.9% to 91.9%) and 100% specific (95% CI, 94.5% to 100.0%), with a positive predictive value of 100% (95% CI, 83.4% to 100.0%) and a negative predictive value of 93.3% (95% CI, 85.4% to 97.2%). The leukocyte esterase level correlated strongly with the percentage of polymorphonuclear leukocytes (r = 0.7769) and total white blood-cell count (r = 0.5024) in the aspirate as well as with the erythrocyte sedimentation rate (r = 0.6188) and C-reactive protein level (r = 0.4719) in the serum. CONCLUSIONS: The simple colorimetric strip test that detects the presence of leukocyte esterase in synovial fluid appears to be an extremely valuable addition to the physician's armamentarium for the diagnosis of periprosthetic joint infection. The leukocyte esterase reagent strip has the advantages of providing real-time results, being simple and inexpensive, and having the ability to both rule out and confirm periprosthetic joint infection. However, additional multicenter studies are required to substantiate the results of our preliminary investigation before the reagent strip can be used confidently in the clinic or intraoperative setting. PMID- 22258770 TI - Increasing incidence of shoulder arthroplasty in the United States. AB - BACKGROUND: The number of total shoulder arthroplasties performed in the United States increased slightly between 1990 and 2000. However, the incidence of shoulder arthroplasty in recent years has not been well described. The purpose of the present study was to examine recent trends in shoulder hemiarthroplasty and total shoulder arthroplasty along with the common reasons for these surgical procedures in the United States. METHODS: We modeled the incidence of shoulder arthroplasty from 1993 to 2008 with use of the Nationwide Inpatient Sample. On the basis of hemiarthroplasty and total shoulder arthroplasty cases that were identified with use of surgical procedure codes, we conducted a design-based analysis to calculate national estimates. RESULTS: While the annual number of hemiarthroplasties grew steadily, the number of total shoulder arthroplasties showed a discontinuous jump (p < 0.01) in 2004 and increased with a steeper linear slope (p < 0.01) since then. As a result, more total shoulder arthroplasties than hemiarthroplasties have been performed annually since 2006. Approximately 27,000 total shoulder arthroplasties and 20,000 hemiarthroplasties were performed in 2008. More than two-thirds of total shoulder arthroplasties were performed in adults with an age of sixty-five years or more. Osteoarthritis was the primary diagnosis for 43% of hemiarthroplasties and 77% of total shoulder arthroplasties in 2008, with fracture of the humerus as the next most common primary diagnosis leading to hemiarthroplasty. CONCLUSIONS: The number of shoulder arthroplasties, particularly total shoulder arthroplasties, is growing faster than ever. The use of reverse total arthroplasty, which was approved by the United States Food and Drug Administration in November 2003, may be part of the reason for the greater increase in the number of total shoulder arthroplasties. A long-term follow-up study is warranted to evaluate total shoulder arthroplasty in terms of patient outcomes, safety, and implant longevity. PMID- 22258771 TI - Procedural sedation with propofol for painful orthopaedic manipulation in the emergency department expedites patient management compared with a midazolam/ketamine regimen: a randomized prospective study. AB - BACKGROUND: The use of procedural sedation and analgesia to allow painful orthopaedic manipulations in the emergency department has become a standard practice over the last decade. Both propofol and midazolam/ketamine are attractive sedative regimens for routine use in the emergency department. We hypothesized that sedation with propofol as compared with midazolam/ketamine will save time in the emergency department. The purpose of the present study was to compare the recovery time, the total sedation time, and the adverse events of procedural sedation and analgesia induced with propofol as compared with midazolam/ketamine. METHODS: This prospective randomized study was conducted in the emergency department of a tertiary care, university-affiliated medical center. All sedations and orthopaedic manipulations were performed by trained and approved orthopaedic residents assisted by a registered nurse according to the same protocol. Sedation time and adverse events were recorded in real time. RESULTS: Sixty adults (thirty-five men and twenty-five women) with a mean age (and standard deviation) of 45 +/- 17 years were randomly enrolled in the study, with thirty patients being managed with each regimen. The average recovery time was 7.8 +/- 3.7 minutes following sedation with propofol, compared with 30.7 +/- 10.1 minutes following sedation with midazolam/ketamine (p < 0.001). The average total sedation time was 16.2 +/- 3.8 minutes for the propofol group, compared with 41.6 +/- 10.7 minutes for the midazolam/ketamine group (p < 0.001). The overall rate of respiratory and hemodynamic adverse events was 20% for the propofol group and 10% for the midazolam/ketamine group. CONCLUSIONS: The use of propofol for an orthopaedic procedure requiring sedation in the emergency department expedites patient management and saves time in comparison with the use of midazolam/ketamine. PMID- 22258772 TI - Dynamic ultrasound assessment of the effects of knee and ankle position on Achilles tendon apposition following acute rupture. AB - BACKGROUND: Previous reports have suggested that knee flexion improves tendon edge apposition following acute rupture of the Achilles tendon. The aim of the present study was to determine, with use of ultrasonography, the effects of knee and ankle position on the Achilles tendon gap distance in patients with an acute rupture. METHODS: Twenty-six patients with a unilateral acute complete Achilles tendon rupture that had been confirmed with ultrasonography were recruited within a week after the injury. The mean age at the time of presentation was forty-one years. Ultrasound measurements included the location of the rupture and the gap distance between the superficial tendon edges with the ankle in neutral and the knee extended. The gap distance was sequentially measured with the foot in maximum equinus at the ankle and with 0 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion. RESULTS: The mean distance of the rupture from the calcaneal enthesis was 52 mm (range, 40 to 76 mm). The mean gap distance with the ankle in neutral and the knee extended was 12 mm (95% confidence interval, 10 to 13 mm). This distance decreased to 5 mm (95% confidence interval, 4 to 7 mm) when the foot was placed in maximum ankle equinus with 0 degrees of knee flexion and to 4 mm (95% confidence interval, 3 to 5 mm) with 30 degrees of knee flexion, 3 mm (95% confidence interval, 2 to 4 mm) with 60 degrees of knee flexion, and 2 mm (95% confidence interval, 1 to 2 mm) with 90 degrees of knee flexion. Expressing the reduction in gap distance with each successive position as a percentage of the gap distance with the knee extended and the ankle in neutral revealed a mean reduction of 55.7%, 64.4%, 75.4%, and 84.8% with maximum ankle equinus and 0 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion, respectively. The difference in gap distance between each of these positions was significant (p < 0.05). CONCLUSIONS: Maximum ankle equinus alone significantly reduces the gap distance after acute Achilles tendon rupture. Increasing knee flexion further reduces the gap distance by small increments that, although significant, may not be clinically important. PMID- 22258773 TI - Concomitant traumatic spinal cord and brachial plexus injuries in adult patients. AB - BACKGROUND: Combined injuries to the spinal cord and brachial plexus present challenges in the detection of both injuries as well as to subsequent treatment. The purpose of this study is to describe the epidemiology and clinical factors of concomitant spinal cord injuries in patients with a known brachial plexus injury. METHODS: A retrospective review was performed on all patients who were evaluated for a brachial plexus injury in a tertiary, multidisciplinary brachial plexus clinic from January 2000 to December 2008. Patients with clinical and/or imaging findings for a coexistent spinal cord injury were identified and underwent further analysis. RESULTS: A total of 255 adult patients were evaluated for a traumatic traction injury to the brachial plexus. We identified thirty-one patients with a combined brachial plexus and spinal cord injury, for a prevalence of 12.2%. A preganglionic brachial plexus injury had been sustained in all cases. The combined injury group had a statistically greater likelihood of having a supraclavicular vascular injury (odds ratio [OR] = 22.5; 95% confidence interval [CI] = 1.9, 271.9) and a cervical spine fracture (OR = 3.44; 95% CI = 1.6, 7.5). These patients were also more likely to exhibit a Horner sign (OR = 3.2; 95% CI = 1.5, 7.2) and phrenic nerve dysfunction (OR = 2.5; 95% CI = 1.0, 5.8) compared with the group with only a brachial plexus injury. CONCLUSION: Heightened awareness for a combined spinal cord and brachial plexus injury and the presence of various associated clinical and imaging findings may aid in the early recognition of these relatively uncommon injuries. PMID- 22258774 TI - Osteoinductivity of demineralized bone matrix is independent of donor bisphosphonate use. AB - BACKGROUND: Demineralized bone matrix is commonly used as a bone graft substitute, either alone or to supplement an osteoconductive material, because of its osteoinductive properties. The aging of the population has led to an increase in the number of prospective donors of demineralized bone matrix who have taken bisphosphonates to prevent osteoclast-mediated bone resorption. The aim of this study was to determine whether oral bisphosphonate usage affects the osteoinductivity of demineralized bone matrix from donors. METHODS: Sex-matched and age-matched pairs of samples were provided by four tissue banks (three or four pairs per bank). Demineralized bone matrix donors without bisphosphonate treatment had a mean age (and standard deviation) of 69.1 +/- 2.5 years, and donors with bisphosphonate treatment had a mean age of 68.9 +/- 2.0 years. Each pair included one donor known to have taken bisphosphonates and one who had not taken bisphosphonates. Demineralized bone matrix previously confirmed as osteoinductive was the positive control, and heat-inactivated demineralized bone matrix was the negative control. Demineralized bone matrix incubated with 1 mL of phosphate-buffered saline solution containing 0, 0.002, 2.0, or 2000 ng/mL of alendronate was also tested. Gelatin capsules containing 15 mg of demineralized bone matrix were implanted bilaterally in the gastrocnemius muscle of male nude mice (eight implants per group). The mice were killed thirty-five days after implantation, and hind limbs were recovered and processed for histological analysis. Osteoinductivity was measured with use of a qualitative score and by histomorphometry. RESULTS: Nine of fifteen samples from donors who had had bisphosphonate treatment and ten of fifteen samples from patients who had not had bisphosphonate treatment were osteoinductive. Qualitative mean scores were comparable (1.7 +/- 0.4 for those without bisphosphonates and 1.9 +/- 0.7 for those with bisphosphonates). Osteoinductive demineralized bone matrix samples produced ossicles of comparable size, regardless of bisphosphonate usage. Histomorphometric measurements of the area of new bone formation and residual demineralized bone matrix were also comparable. The addition of alendronate to control demineralized bone matrix did not affect its osteoinductivity. CONCLUSIONS: Demineralized bone matrix samples from donors treated with bisphosphonates and donors not treated with bisphosphonates have the same ability to induce bone formation. However, it is not known if the quality of the new bone is affected, with subsequent consequences affecting bone remodeling. PMID- 22258775 TI - Five-year results of the ASR XL Acetabular System and the ASR Hip Resurfacing System: an analysis from the Australian Orthopaedic Association National Joint Replacement Registry. AB - BACKGROUND: Articular Surface Replacement (ASR) hip prostheses, which have metal on-metal bearing surfaces, were manufactured by DePuy Orthopaedics (Warsaw, Indiana) for use in both conventional total hip arthroplasty and hip resurfacing. Both the ASR XL Acetabular System and the ASR Hip Resurfacing System were recently recalled worldwide by the manufacturer. This report summarizes an analysis by the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) of the outcome of arthroplasties involving the ASR prostheses. METHODS: The first recorded use of the ASR XL Acetabular System in Australia occurred in 2004, and the Registry recorded 4406 procedures involving this system through December 31, 2009. The first recorded use of the ASR Hip Resurfacing System in Australia occurred in 2003, and the Registry recorded 1167 procedures through December 31, 2009. The Kaplan-Meier method and proportional-hazard modeling were used to compare the revision rate of primary total hip arthroplasties involving the ASR XL Acetabular System with that of arthroplasties involving all other conventional prostheses as well as with that of arthroplasties involving all other conventional prostheses with a metal-on-metal articulation. In addition, the revision rate of primary arthroplasties involving the ASR Hip Resurfacing System was compared with that of arthroplasties involving all other hip resurfacing prostheses. Patient demographics, prosthesis characteristics, and information regarding the type of revision and the reason for revision were also compared. RESULTS: Arthroplasties involving both ASR designs had a significantly greater revision rate compared with those involving all other prostheses. The cumulative revision rate of arthroplasties involving the ASR XL Acetabular System at five years postoperatively was 9.3% (95% confidence interval [CI], 7.3% to 11.9%) compared with 3.4% (95% CI, 3.3% to 3.5%) for total hip arthroplasties involving all other conventional prostheses. The cumulative revision rate of arthroplasties involving the ASR Hip Resurfacing System at five years postoperatively was 10.9% (95% CI, 8.7% to 13.6%) compared with 4.0% (95% CI, 3.7% to 4.5%) for arthroplasties involving all other resurfacing prostheses. Arthroplasties involving the ASR XL Acetabular System had a greater rate of revision due to implant loosening and/or osteolysis and due to metal sensitivity compared with total hip arthroplasties involving all other conventional prostheses. Arthroplasties involving the ASR XL Acetabular System also had a significantly greater revision rate compared with total hip arthroplasties involving all other conventional metal-on-metal prostheses. Arthroplasties involving the ASR Hip Resurfacing System had a greater rate of revision due to metal sensitivity compared with total hip arthroplasties involving all other resurfacing prostheses. CONCLUSIONS: ASR prostheses used in conventional hip arthroplasty and in hip resurfacing exhibited a greater revision rate compared with other prostheses in the AOANJRR. These results are consistent with those derived from other registries and from published studies of individual cohorts. PMID- 22258776 TI - Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: identification of "protective" and "risk" factors. AB - BACKGROUND: Multiple hereditary exostoses is an autosomal dominant skeletal disorder characterized by wide variation in clinical phenotype. The aim of this study was to evaluate whether the severity of the disease is linked with a specific genetic background. METHODS: Five hundred and twenty-nine patients with multiple hereditary exostoses from two different European referral centers participated in the study. According to a new clinical classification based on the presence or absence of deformities and functional limitations, the phenotype of the patients was assessed as mild (the absence of both aspects), intermediate, or severe (the concurrent presence of both aspects). An identical molecular screening protocol with denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification was performed in both institutions. RESULTS: In our cohort of patients, variables such as female sex (odds ratio = 1.840; 95% confidence interval, 1.223 to 2.766), fewer than five skeletal sites with exostoses (odds ratio = 7.588; 95% confidence interval, 3.479 to 16.553), EXT2 mutations (odds ratio = 2.652; 95% confidence interval, 1.665 to 4.223), and absence of EXT1/2 mutations (odds ratio = 1.975; 95% confidence interval, 1.051 to 3.713) described patients with a mild phenotype; in contrast, a severe phenotype was associated with male sex (odds ratio = 2.431; 95% confidence interval, 1.544 to 3.826), EXT1 mutations (odds ratio = 6.817; 95% confidence interval, 1.003 to 46.348), and more than twenty affected skeletal sites (odds ratio = 2.413; 95% confidence interval, 1.144 to 5.091). Malignant transformation was observed in 5% of patients, and no evidence of association between chondrosarcoma onset and EXT mutation, sex, severity of disease, or number of lesions was detected. CONCLUSIONS: The identified "protective" and "risk" factors, as well as the proposed classification system, represent helpful tools for clinical management and follow-up of patients with multiple hereditary exostoses; moreover, homogeneous cohorts of patients, useful for studies on the pathogenesis of multiple hereditary exostoses, have been identified. PMID- 22258777 TI - Meta-analyses in joint arthroplasty: a review of quantity, quality, and impact. PMID- 22258778 TI - Femoral fixation in revision total hip arthroplasty. PMID- 22258779 TI - What's new in limb lengthening and deformity correction. PMID- 22258780 TI - Functional outcomes in children with osteonecrosis secondary to treatment of developmental dysplasia of the hip. AB - BACKGROUND: Osteonecrosis of the femoral head is a major potential complication following the treatment of developmental dysplasia of the hip. It remains unclear if the radiographic changes associated with osteonecrosis are clinically relevant. METHODS: In the present cross-sectional study, we determined the relationship between morphological changes on radiographs (classified with use of the Bucholz-Ogden system) and health-related quality of life (assessed with the Health Utilities Index Mark 3 [HUI3]; maximum score, 1), physical function (assessed with the Activities Scale for Kids [ASK]; maximum score, 100), and hip function (assessed with the Children's Hospital Oakland Hip Evaluation Scale [CHOHES]; maximum score, 100). The study group included seventy-two children (mean age, 14 +/- 2.5 years) with a diagnosis of osteonecrosis of the hip secondary to the treatment of developmental dysplasia of the hip. Patient assessments were standardized (intraclass correlation coefficient, >=0.93). Radiographs were graded by three experts according to consensus. Analyses were adjusted for the number of previous surgical procedures on the hip and for the severity of residual hip dysplasia. RESULTS: The median ASK score was 97 (interquartile range, 93 to 100), the median CHOHES score was 86 (interquartile range, 77 to 96), and the median HUI3 score was 1 (interquartile range, 0.9 to 1). The ASK summary scores were nearly equal (median, >90) across all radiographic grades. Adjusted mean scores showed a downward shift with worse radiographic grades. The ASK scores (p = 0.004) and CHOHES scores (p = 0.006) differed across radiographic grades, with Bucholz-Ogden grade-I and II hips demonstrating significantly better scores than grade-III and IV hips. DISCUSSION: Osteonecrosis secondary to the treatment of developmental dysplasia of the hip is a relatively benign condition in children and teenagers. While it was associated with limited hip function, it was not associated with physical disability. However, we speculate that this function will decline with increasing age. With regard to clinical outcome, Bucholz-Ogden grade-I hips are similar to grade-II hips and grade-III hips are similar to grade-IV hips. PMID- 22258782 TI - Revision of ceramic hip replacements for fracture of a ceramic component: AAOS exhibit selection. PMID- 22258781 TI - Risk factors for pulmonary embolism and the effects of fondaparinux after total hip and knee arthroplasty: a retrospective observational study with use of a national database in Japan. AB - BACKGROUND: Clinical evidence demonstrating the effectiveness of pharmacological and mechanical thromboprophylaxis for the prevention of pulmonary embolism is limited because the prevalence of postoperative pulmonary embolism following total hip and knee arthroplasty is very low. Our purposes were to characterize a patient population with in-hospital pulmonary embolism, to identify perioperative risk factors associated with pulmonary embolism, and to analyze the effect of combining fondaparinux with mechanical prophylaxis on the prevalence of pulmonary embolism following total hip and knee arthroplasty. METHODS: We retrospectively identified 27,542 patients who underwent total hip or knee arthroplasty at 793 hospitals, using data from the Diagnosis Procedure Combination database, collected from July 1 to December 31 in 2007 and 2008. We extracted data on patient sex, age, primary diagnoses, and comorbidities that could potentially affect the prevalence of pulmonary embolism. The dates of pharmacological and mechanical thromboprophylaxis were identified for each patient. Logistic regression analysis was performed to analyze the concurrent effects of various factors on the prevalence of postoperative pulmonary embolism. RESULTS: The mean age (and standard deviation) of the patients at the time of arthroplasty was 69.9 +/- 10.3 years, and 23,783 patients (86.4%) were diagnosed as having osteoarthritis. The overall mean duration of anesthesia was 159 +/- 84 minutes. The overall prevalence of postoperative pulmonary embolism was 0.55% (151 of 27,542). Significant risk factors for postoperative pulmonary embolism included age, number of comorbidities, diagnosis of rheumatoid arthritis, type of anesthesia, and duration of anesthesia. Multivariate analysis found that the prevalence of postoperative pulmonary embolism was significantly reduced when fondaparinux was used in combination with mechanical prophylaxis, compared with the use of mechanical prophylaxis alone (0.40% versus 0.66%; odds ratio, 0.60; 95% confidence interval, 0.42 to 0.84; p = 0.003). CONCLUSIONS: These findings could help to identify patients at higher risk of postoperative pulmonary embolism after total hip or knee arthroplasty. Our results demonstrate the effectiveness of fondaparinux in combination with mechanical prophylaxis for the prevention of postoperative pulmonary embolism after total hip or knee arthroplasty. PMID- 22258783 TI - Concealed degloving injury (the Morel-Lavallee lesion) in childhood sports: a case report. PMID- 22258784 TI - Spontaneous osteonecrosis of the knee treated with autologous chondrocyte implantation, autologous bone-grafting, and osteotomy: a report of two cases with follow-up of seven and nine years. PMID- 22258785 TI - The American Orthopaedic Association-Japanese Orthopaedic Association 2010 traveling fellowship. AB - We started this journey excited by the prospects of visiting Japan, a country with a proud and historic past. We ended the fellowship accomplishing those goals, and we left with a great deal of admiration for our orthopaedic colleagues halfway around the world for their excellence in education, clinical care, and research. Their hospitality and attention to the details of our visit were exemplary and a lesson to us as we host visiting fellows in the future. Japan reflects its past, but it also offers a preview into our own nation's future: an aging population, a shrinking workforce, a stagnant economy, nationalized health care, and a mushrooming national debt. Of all of these factors, it is the aging population that we, as orthopaedic surgeons, will be most acutely aware of and involved with. The degenerative disorders that affect elderly patients dominate the landscape of surgical care in Japan. Osteoporosis and osteopenia permeate many aspects of care across orthopaedic subspecialties. The surgeons in Japan are developing innovative and cost-effective means of treating the large volume of older patients within the fiscal constraints of a nationalized health-care system. We learned, and will continue to learn more, from Japan about the management of this growing patient population with its unique pathologies and challenges. With the recent natural disaster and ongoing safety concerns in Japan, the character and will of the people of Japan have been on display. Their courage and resolve combined with order and compassion are a testament to the nation's cultural identity. The seeds of the Traveling Fellowship were planted shortly after Japan's last wide-scale reconstruction, and the ties that have bound the JOA and the AOA together are strengthened through this trying time. We strongly urge our colleagues in the U.S. to help support the people, the physicians, and the health-care system of Japan through its most recent tribulations and offer them the same care and hospitality that we were shown during our fellowship. Japan is an open and friendly nation, and we encourage anyone interested to seek out opportunities to visit or work with our orthopaedic colleagues there. We are grateful to our hosts at each institution as well as to the JOA and AOA organizations for continuing this wonderful tradition. This exchange is now entering its twentieth year. It remains a "trip of a lifetime" for those fortunate enough to be selected. For us, as for many who have participated before us, it will shape our careers in the years to come. PMID- 22258786 TI - Reflection: Paul Randall Harrington (1911-1980). PMID- 22258787 TI - A simple, inexpensive, one-minute tool to help diagnose periprosthetic infection. PMID- 22258788 TI - Concomitant traumatic spinal cord and brachial plexus injuries: do they affect outcome? PMID- 22258790 TI - Printed glycan array: antibodies as probed in undiluted serum and effects of dilution. AB - Using printed glycan array (PGA) we compared the results of antibody profiling in undiluted, moderately (1:15) and highly (1:100) diluted human blood serum. Undiluted serum is suitable for studying blood as a tissue in its native state, whereas to study the serum of newborns or small animals one usually has to dilute the starting material in order to have sufficient volume for PGA experimentation. The PGA used in this study allows for the use of whole serum without modifications to the protocol, and the background is surprisingly low. Antibodies profiles observed in undiluted serum versus 1:15 dilution were similar, with only a limited number of new signals identified in the undiluted serum. However, unexpected irregularities were found when IgG and IgM are measured separately, namely, at a 1:15 dilution more intensive IgG signals for many glycans are observed. We believe that in conditions of moderate dilution IgG and IgM antibodies can compete with each other for antigen and as a result, the higher affinity anti-glycan IgGs give rise to more intense signals. Therefore depending on the purpose, different dilutions of serum will be optimal: in competitive 1:15 conditions the observed IgG/IgM ratio corresponds to their titer, whereas at 1:100 dilution the measured ratio corresponds to real molar concentration of IgG and IgM. PMID- 22258792 TI - Correlation of HLA-A02* genotype and HLA class I antigen down-regulation with the prognosis of epithelial ovarian cancer. AB - BACKGROUND: In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue. MATERIALS AND METHODS: One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and beta(2)-microglobulin (beta(2)-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan-Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression. RESULTS: Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and beta(2)-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation. CONCLUSIONS: HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III-IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products. PMID- 22258793 TI - Diffusion-weighted MRI beyond the central nervous system in children. AB - Diffusion-weighted imaging has recently been incorporated into extra neurological pediatric imaging protocols because of its various clinical advantages. Because diffusion-weighted imaging does not require intravenous contrast media, it can be safely used in patients with reduced renal function. Furthermore, diffusion-weighted imaging can be performed within several minutes by using the echo planar imaging technique. Its clinical advantages include improved tissue characterization, as well as the ability to assess organ functionality, monitor the treatment response after chemotherapy or radiation therapy and predict patient outcomes. The aims of this pictorial essay were to explain the physical principles underlying diffusion-weighted imaging, to outline the interpretation of diffusion-weighted images and apparent diffusion coefficient maps, and to list the extra-neurological applications of diffusion- weighted imaging in children. PMID- 22258791 TI - Synthesis of beta-arabinofuranoside glycolipids, studies of their binding to surfactant protein-A and effect on sliding motilities of M. smegmatis. AB - Surfactant protein A (SP-A), which is a lung innate immune system component, is known to bind glycolipids present at the cell surface of a mycobacterial pathogen. Lipoarabinomannan (LAM), a component of mycobacterial thick, waxy cell wall, is one of the glycolipid ligands for SP-A. In order to assess binding of synthetic glycolipids with SP-A and the glycosidic linkage preferences for the interaction, beta-arabinofuranoside trisaccharide glycolipids constituted with beta-(1->2), beta-(1->3) and beta-(1->2), beta-(1->5) linkages relevant to LAM were synthesized through chemical glycosylations. The efficacies of synthetic glycolipids to interact with SP-A were assessed by using the surface plasmon resonance (SPR) technique, from which association-dissociation rate constants and equilibrium binding constants were derived. The equilibrium binding constants of the interaction of two constitutionally varying beta-arabinofuranoside glycolipids with SP-A were found to be in the millimolar range. A comparison of the results with few alpha-anomeric arabinofuranoside glycolipids showed that glycolipids with beta-anomeric linkages were having relatively lower equilibrium binding constants than those with alpha-anomeric linkages in binding to the protein, whereas oligosaccharides alone, without lipidic chains, exhibited higher equilibrium binding constants. Further, the synthetic compounds inhibited the growth of mycobacteria and affected sliding motilities of the bacteria, although to an extent relatively lesser than that of synthetic compounds constituted with alpha-anomeric linkages. PMID- 22258794 TI - Hepatic steatosis: correlations of body mass index, CT fat measurements, and liver density with biopsy results. AB - PURPOSE: To assess the relationship between body mass index (BMI), subcutaneous and intra-abdominal fat, liver density, and histopathologic hepatic steatosis. MATERIALS AND METHODS: In this retrospective study, 143 patients (male/female, 67/76; mean age, 50 years) underwent a non-targeted transjugular (n = 125) or percutaneous (n = 18) liver biopsy between 2006 and 2010. The biopsy indications included chronic liver parenchymal disease staging (n = 88), elevated enzymes (n = 39), or other reasons (n = 16). The BMI and non-contrast liver computed tomography liver density were recorded for each patient. The thicknesses of the anterior, posterior, and posterolateral subcutaneous fat, along with the intra abdominal fat, were measured. The values were then correlated with histopathologic steatosis. RESULTS: Of the patients, 47/143 (32%), 39/143 (28%), and 57/143 (40%) were normal weight, overweight, and obese, respectively. Steatosis was present in 13/47 (28%) of normal weight, 18/39 (46%) of overweight, and 38/57 (67%) of obese patients. Significant differences in BMI (26.7 kg/m(2) vs. 31.7 kg/ m2 vs. 35.0 kg/m(2), P < 0.001), liver density (52.8 HU vs. 54.4 HU vs. 42.0 HU, P < 0.001), anterior subcutaneous (1.8 cm vs. 2.4 cm vs. 2.9 cm, P < 0.001), posterolateral subcutaneous (2.8 cm vs. 3.2 cm vs. 4.4 cm, P < 0.004), posterior subcutaneous (1.9 cm vs. 2.5 cm vs. 3.4 cm, P < 0.001), and intra abdominal fat thickness (1.1 cm vs. 1.3 cm vs. 1.4 cm, P < 0.013) were identified in patients with different degrees of steatosis (none, minimal to mild, moderate to severe, respectively). BMI (r = 0.37, P < 0.001) and the anterior subcutaneous fat (r = 0.30, P < 0.001) had a moderate correlation with the presence of liver steatosis. A combination of a BMI >= 32.0 kg/ m(2) and an anterior subcutaneous fat thickness >= 2.4 cm had a 40% sensitivity and 90% specificity for the identification of steatosis. CONCLUSION: Increase in the anthropomorphic metrics of obesity is associated with an increased frequency of liver steatosis. PMID- 22258795 TI - Pseudolymphomatous luetic lymphadenitis associated with B cell clonality. PMID- 22258796 TI - Modulation of in vivo GABA-evoked responses by nitric oxide-active compounds in the globus pallidus of rat. AB - Nitric oxide (NO) is a gaseous molecule acting as a messenger in both the peripheral and the central nervous systems. NO affects synaptic activity by modulating neurotransmitter release and/or receptor function. We previously observed that NO-active compounds modify the bioelectric activity of basal ganglia (BG) units. In this study, we applied microiontophoresis to extracellular in vivo recordings to investigate the effect of NO-active compounds on GABA evoked responses in the globus pallidus (GP) of anesthetized rats. The changes induced by NO-active drugs on the GABA-induced inhibition were used as indicators of NO modulation. The response to GABA release was tested on recorded GP neurons before and during the administration of S-nitroso-glutathione (SNOG, a NO donor) and/or Nomega-nitro-L: -arginine methyl ester (L: -NAME), an inhibitor of nitric oxide synthase (NOS); furthermore, SNOG and L: -NAME were tested at different ejection currents in order to highlight the possibility of a current-dependent effect in the nitrergic modulation of GABA transmission. In general, during SNOG ejection the magnitude of GABA-evoked responses was reduced, whereas the administration of L: -NAME produced the opposite effect. The results suggest that NO-active drugs modulate the response of GP neurons to GABA transmission; the effects induced by SNOG and L: -NAME were strictly related to the ejection currents. Then, the modulation of GABAergic transmission by NO could represent a mechanism to finely regulate the GP neurons activity with important consequences on the overall BG function. PMID- 22258797 TI - The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications. AB - Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood-brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines. PMID- 22258798 TI - Dynamic cultural modulation of neural responses to one's own and friend's faces. AB - Long-term cultural experiences influence neural response to one's own and friend's faces. The present study investigated whether an individual's culturally specific pattern of neural activity to faces can be modulated by temporary access to other cultural frameworks using a self-construal priming paradigm. Event related potentials were recorded from British and Chinese adults during judgments of orientations of one's own and friend's faces after they were primed with independent and interdependent self-construals. We found that an early frontal negative activity at 220-340 ms (the anterior N2) differentiated between one's own and friend's faces in both cultural groups. Most remarkably, for British participants, priming an interdependent self-construal reduced the default anterior N2 to their own faces. For Chinese participants, however, priming an independent self-construal suppressed the default anterior N2 to their friend's faces. These findings indicate fast modulations of culturally specific neural responses induced by temporary access to other cultural frameworks. PMID- 22258799 TI - Enhanced amygdala reactivity to emotional faces in adults reporting childhood emotional maltreatment. AB - In the context of chronic childhood emotional maltreatment (CEM; emotional abuse and/or neglect), adequately responding to facial expressions is an important skill. Over time, however, this adaptive response may lead to a persistent vigilance for emotional facial expressions. The amygdala and the medial prefrontal cortex (mPFC) are key regions in face processing. However, the neurobiological correlates of face processing in adults reporting CEM are yet unknown. We examined amygdala and mPFC reactivity to emotional faces (Angry, Fearful, Sad, Happy, Neutral) vs scrambled faces in healthy controls and unmedicated patients with depression and/or anxiety disorders reporting CEM before the age of 16 years (n = 60), and controls and patients who report no childhood abuse (n = 75). We found that CEM was associated with enhanced bilateral amygdala reactivity to emotional faces in general, and independent of psychiatric status. Furthermore, we found no support for differential mPFC functioning, suggesting that amygdala hyper-responsivity to emotional facial perception in adults reporting CEM may be independent from top-down influences of the mPFC. These findings may be key in understanding the increased emotional sensitivity and interpersonal difficulties, that have been reported in individuals with a history of CEM. PMID- 22258800 TI - Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events. AB - Fear learning is a crucial process in the pathogeneses of psychiatric disorders, which highlights the need to identify specific factors contributing to interindividual variation. We hypothesized variation in the serotonin transporter gene (5-HTTLPR) and stressful life events (SLEs) to be associated with neural correlates of fear conditioning in a sample of healthy male adults (n = 47). Subjects were exposed to a differential fear conditioning paradigm after being preselected regarding 5-HTTLPR genotype and SLEs. Individual differences in brain activity as measured by functional magnetic resonance imaging (fMRI), skin conductance responses and preference ratings were assessed. We report significant variation in neural correlates of fear conditioning as a function of 5-HTTLPR genotype. Specifically, the conditioned stimulus (CS(+)) elicited elevated activity within the fear-network (amygdala, insula, thalamus, occipital cortex) in subjects carrying two copies of the 5-HTTLPR S' allele. Moreover, our results revealed preliminary evidence for a significant gene-by-environment interaction, such as homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs demonstrated elevated reactivity to the CS(+) in the occipital cortex and the insula. Our findings contribute to the current debate on 5-HTTLPR x SLEs interaction by investigating crucial alterations on an intermediate phenotype level which may convey an elevated vulnerability for the development of psychopathology. PMID- 22258801 TI - Disgust trait modulates frontal-posterior coupling as a function of disgust domain. AB - Following the two-stage model of disgust, 'core disgust' (e.g. elicited by rotten food) is extended to stimuli that remind us of our animal nature 'AR disgust' (e.g. mutilations, animalistic instincts). There is ample evidence that core and AR represent distinct domains of disgust elicitors. Moreover, people show large differences in their tendency to respond with disgust to potential disgust elicitors (propensity), as well as in their appraisal of experiencing disgust (sensitivity). Thus these traits may be important moderators of people's response patterns. Here, we aimed to find brain mechanisms associated with these distinct disgust domains and traits, as well as the interaction between them. The right ventrolateral occipitotemporal cortex, which preferentially responded to visual AR, was functionally coupled to the middle cingulate cortex (MCC), thalamus and prefrontal cortex (medial, dorsolateral), as a function of disgust domain. Coupling with the anterior part of MCC was modulated by disgust 'propensity', which was strongest during AR. Coupling with anterior insula and ventral premotor cortex was weaker, but relied fully on this domain-trait interaction. Disgust 'sensitivity' modulated left anterior insula activity irrespective of domain, and did not affect functional connectivity. Thus a frontal-posterior network that interacts with disgust 'propensity' dissects AR and core disgust. PMID- 22258802 TI - Application of a pull on a disk method to measure surface tension of liquids. AB - The intrinsic property of liquids is a vital indicator of formulation performance and stability. Therefore, investigation of the interfacial phenomenon of surface tension is a routine procedure in the development of products in a wide variety of areas including foods, pharmaceuticals, cosmetics, and painting technologies. We hypothesize that studies related to the maximum pull on a rod can be extrapolated to disk geometry and applied to measure surface tension using a texture analyzer. A glass disk probe was attached to the arm of a texture analyzer and pulled from the liquid surface. The maximum force of detachment was used to calculate surface tension extrapolating from the theory of maximum pull on a rod. The surface tension of water, ethanol, and a hydroalcoholic solution was measured and compared with literature values to validate this hypothesis. The calculated values of surface tension for the liquids studied were within 5% of the reported values. Probe diameter appears to have an important role on surface tension accuracy compared with literature values. Slight discrepancies can be attributed to temperature control and leveling of liquid surface, although still in accordance with the reported values of surface tension measured using different methods. This study presents a simple, precise, and quick method to determine the surface tension of liquids from the maximum pull on a disk. Further studies are warranted to determine the optimum glass disk probe diameter for better accuracy. PMID- 22258803 TI - Controlled release of modified insulin glargine from novel biodegradable injectable gels. AB - The objective of this study was to investigate the duration of biological effects of modified insulin glargine released from a novel biodegradable injectable gel in type II diabetic Zucker diabetic fatty (ZDF) rats. Modified insulin glargine was purified from the marketed formulation by process of dialysis followed by freeze-drying, and the purity was confirmed by the single peak, corresponding to insulin glargine in the HPLC chromatogram. To determine and to compare the biological activity of purified insulin glargine with marketed formulation, it was suspended in isotonic saline solutions and administered subcutaneously to ZDF rats at a dose of 10 IU/kg of insulin and the blood glucose levels were measured. The blood glucose levels of ZDF rats after a subcutaneous injection of a suspension of purified insulin glargine decreased below 200 mg/dL within 2 h and remained at this level up to 6 h, then steadily raised above 400 mg/dL in 12 h. Insulin glargine particles were loaded into a novel biodegradable injectable gel formulation prepared from a blend of polylactic-co-glycolic acid (PLGA) and biocompatible plasticizers. Approximately 0.1 mL of insulin glargine-loaded gel prepared with PLGA was administered subcutaneously to the ZDF rats, and blood glucose levels were measured. The PLGA gel formulations prepared with insulin glargine particles had duration of action of 10 days following a single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations. PMID- 22258804 TI - Transdermal absorption enhancement of rice bran bioactive compounds entrapped in niosomes. AB - Niosomes composed of Tween 61 and cholesterol at 1:1 molar ratio were entrapped with the mixture of the three semi-purified rice (Oryza sativa L., Family Gramineae) bran bioactive compounds [ferulic acid (F), gamma-oryzanol (O), and phytic acid (P)] at 0.5%, 1.5%, and 1.5%, respectively, by the supercritical CO(2) technique. The transdermal absorption by vertical Franz diffusion cells of the compounds entrapped in niosomes (Nio FOP), the unentrapped compounds (Mixed FOP), the compounds incorporated in gel and cream (Gel FOP and Cream FOP), and the compounds entrapped in niosomes and incorporated in gel and cream (Gel nio and Cream nio) was investigated. At 6 h, F and P from Nio FOP gave lower cumulative amount in viable epidermis and dermis (VED) than from Mixed FOP of 1.1 and 1.6 times, respectively, while O from Nio FOP exhibited higher cumulative amount in VED than from Mixed FOP of 2.4 times. The highest cumulative amount in VED of F, O, and P were from Gel nio, Cream nio, and Mixed FOP at 1.564 +/- 0.052, 15.972 +/- 0.273, and 25.857 +/- 0.025 ng/cm(2), respectively. Niosomes enhanced the transdermal absorption of the hydrophobic compound O, while retarded the hydrophilic compounds F and P indicating the less systemic risk of F and P than O when entrapped in niosomes. Thus, transdermal absorption of F, O, and P appeared to depend on niosomal size, lipophilicity of the bioactive compounds, and types of formulations. These preclinical results can be applied for the design of the clinical study of the developed rice bran niosomal topical products. PMID- 22258806 TI - Novel micro-extraction by packed sorbent procedure for the liquid chromatographic analysis of antiepileptic drugs in human plasma and urine. AB - A method for the simultaneous determination of the antiepileptic drugs, phenobarbital (PHB), phenytoin (PTN), carbamazepine (CBZ), primidone (PRM) and oxcarbazepine (OXC) in human plasma and urine samples by using micro-extraction in a packed syringe as the sample preparation method connected with LC/UV (MEPS/LC/UV) is described. Micro-extraction in a packed syringe (MEPS) is a new miniaturized, solid-phase extraction technique that can be connected online to gas or liquid chromatography without any modifications. In MEPS approximately 1 mg of the solid packing material is inserted into a syringe (100-250 MUL) as a plug. Sample preparation takes place on the packed bed. The bed can be coated to provide selective and suitable sampling conditions. The new method is very promising, easy to use, fully automated, inexpensive and quick. The standard curves were obtained within the concentration range 1-500 ng/mL in both plasma and urine samples. The results showed high correlation coefficients (R(2) >0.988) for all of the analytes within the calibration range. The extraction recovery was found to be between 88.56 and 99.38%. The limit of quantification was found to be between 0.132 and 1.956 ng/mL. The precision (RSD) values of quality control samples (QC) had a maximum deviation of 4.9%. A comparison of the detection limits with similar methods indicates high sensitivity of the present method. The method is applied for the analysis of these drugs in real urine and plasma samples of epileptic patients. PMID- 22258805 TI - Age-related changes in proximal humerus bone health in healthy, white males. AB - The proximal humerus is a common site for osteoporotic fracture. The current study demonstrates the rate of age-related decline in proximal humerus bone health. The data suggest aging is associated with considerable loss of bone mass, structural deterioration and reduced bone strength at the proximal humerus. INTRODUCTION: The proximal humerus is relatively under investigated despite being the fourth most common site for osteoporotic fracture. METHODS: A cross-sectional study was performed to assess age-related changes in dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) properties of the proximal humerus in a cohort of 170 healthy, white males. RESULTS: Regression models estimated considerable age-related loss of DXA measured bone quantity at the proximal humerus, with areal bone mineral density modeled to decline by 29% (95% confidence interval [CI], 17.5-35.0%) in the 50 years between ages 30 and 80 years (p < 0.001). pQCT measures indicated aging was associated with progressive periosteal and endosteal expansion, with the later occurring more rapidly as indicated by age-related declines in cortical bone mass, area and thickness (all p < 0.01). The net result of the density, mass and structural changes was a 26% (95% CI, 13.5-38.0%) decline in pQCT estimated proximal humerus bone strength in the 50 years between ages 30 and 80 years (p < 0.001). CONCLUSION: Aging is associated with considerable declines in proximal humeral bone health which, when coupled with a traumatic event such as a fall, may contribute to osteoporotic fracture at this site. PMID- 22258807 TI - Synthesis and bioanalytical evaluation of morphine-3-O-sulfate and morphine-6-O sulfate in human urine and plasma using LC-MS/MS. AB - The aim of this work was to synthesize morphine-3-O-sulfate and morphine-6-O sulfate for use as reference substances, and to determine the sulfate conjugates as possible heroin and morphine metabolites in plasma and urine by a validated LC MS/MS method. Morphine-6-O-sulfate and morphine-3-O-sulfate were prepared as dihydrates from morphine hydrochloride, in overall yields of 41 and 39% with product purities of >99.5% and >98%, respectively. For bioanalysis, the chromatographic system consisted of a reversed-phase column and gradient elution. The tandem mass spectrometer was operated in the positive electrospray mode using selected reaction monitoring, of transition m/z 366.15 to 286.40. The measuring range was 5-500 ng/mL for morphine-3-O-sulfate and 4.5-454 ng/mL for morphine-6-O sulfate in plasma. In urine, the measuring range was 50-5000 ng/mL for morphine-3 O-sulfate and 45.4-4544 ng/mL for morphine-6-O-sulfate. The intra-assay and total imprecision (coefficient of variation) was below 11% for both analytes in urine and plasma. Quantifiable levels of morphine-3-O-sulfate in authentic urine and plasma samples were found. Only one authentic urine sample contained a detectable level of morphine-6-O-sulfate, while no detectable morphine-6-O-sulfate was found in plasma samples. PMID- 22258808 TI - Determination of hyperoside and isoquercitrin in rat plasma by membrane-protected micro-solid-phase extraction with high-performance liquid chromatography. AB - A novel method, micro-solid-phase extraction based on membrane-protected molecularly imprinted polymer, was developed to extract hyperoside and isoquercitrin in rat plasma. Synthesized hyperoside MIPs were packed in a porous polyether sulfone membrane envelope to perform extraction. The parameters sorbent materials, membrane types, extraction time and desorption conditions were optimized for micro-solid-phase extraction. Under the optimal conditions, correlation coefficients, 0.998 and 0.999, were obtained for hyperoside and isoquercitrin, respectively, with the linear range between 1 and 120 MUg/mL. The absolute extraction recoveries from 84.5 to 89.3% were found. The method detection limits of hyperoside and isoquercitrin were 0.24 and 0.22 MUg/mL, respectively. Compared with traditional methods, solid-phase extraction, liquid liquid extraction and protein precipitation, the developed method was simple, highly efficient for extraction, environmentally friendly, and particularly suitable for complex biological samples. PMID- 22258809 TI - Analysis of cholesterol oxidation products by Fast gas chromatography/mass spectrometry. AB - The aim of the present study was to set-up a Fast gas chromatography/mass spectrometry method for the analysis of cholesterol oxidation products (COPs). A silylated mixture of seven oxysterol standards was injected into a Fast GC/MS system. A capillary GC column (10 m*0.1 mm internal diameter*0.1 MUm film thickness) coated with 95% dimethyl- and 5% diphenyl-polysiloxane, was used. The method gave a fast (total analysis time=3.5 min) and satisfactory resolution (R>1.2) of the COPs standards, with a good repeatability and sensitivity, similar to those of conventional GC/MS; recoveries were tested on mice liver. Fast GC/MS method suitability for COPs analysis in food was also tested on an oxidized sardine fillet, which had been previously saponified and purified by NH(2) solid phase extraction (SPE); a good repeatability and sensitivity was also obtained. The analytical performance of the Fast GC/MS method for the determination of COPs, together with the consequent significant reduction of the analysis time and consumables, demonstrates that Fast GC/MS represents a valid alternative to conventional GC/MS and evinces the great potential of such an analytical technique, which could be applied for both food and biological samples. PMID- 22258810 TI - Band broadening of DNA fragments isolated by polyacrylamide gel electrophoresis in capillary electrophoresis. AB - Polyacrylamide gel electrophoresis (PAGE) is used frequently for isolation and purification of DNA fragments. In the present study, DNA fragments extracted from polyacrylamide gels showed significant band broadening in capillary electrophoresis (CE). A pHY300PLK (a shuttle vector functioning in Escherichia coli and Bacillus subtilis) marker, which contained nine fragments ranging from 80 to 4870 bp, was separated by PAGE, and each fragment was isolated by phenol/chloroform extraction and ethanol precipitation. After extraction from the polyacrylamide gel, the peaks of the isolated DNA fragments exhibited band broadening in CE, where a linear poly(ethylene oxide) was used as a sieving matrix. The theoretical plate numbers of the DNA fragments contained in the pHY300PLK marker were >10(6) for all the fragments before extraction. However, the DNA fragments extracted from the polyacrylamide gel showed decreased theoretical plate numbers (5-20 times smaller). The degradation of the theoretical plate number was significant for middle sizes of the DNA fragments ranging from 489 to 1360 bp, whereas the largest and smallest fragments (80 and 4870 bp) had no obvious influence. The band broadening was attributed to contamination of the DNA fragments by polyacrylamide fibers during the separation and extraction process. PMID- 22258811 TI - Ionic liquid-based single-drop liquid-phase microextraction combined with high performance liquid chromatography for the determination of sulfonamides in environmental water. AB - A simple, rapid and environment-friendly technique of single-drop liquid-phase microextraction has been developed for the determination of sulfonamides in environmental water. Several important parameters including stirring rate, extraction solvent, extraction pH, salinity and extraction time were optimized to maximize the extract efficiency. Extraction solvent 1-octyl-3-methylimidazolium hexafluorophosphate [C(8) MIM][PF(6) ] ionic liquid showed better extraction efficiency than 1-butyl-3-methylimidazolium hexafluorophosphate [C(4) MIM][PF(6) ] and 1-octanol. The optimum experimental conditions were: pH, 4.5; sodium chloride content, 36% w/v; extraction time, 20 min. This method provided low detection limits (0.5-1 ng/mL), good repeatability (the RSD ranging from 4.2 to 9.9%, n=5) and wide linear range (1-1500 ng/mL), with determination coefficients (r(2) ) higher than 0.9989 for all the target compounds. Real sample analysis showed relative recoveries between 63.5 and 115.8% for all the target compounds. PMID- 22258812 TI - Successful hyperbaric oxygen therapy for laryngeal radionecrosis after chemoradiotherapy for mesopharyngeal cancer: case report and literature review. AB - Laryngeal radionecrosis is one of the most troublesome late complications of radiotherapy, because it is frequently resistant to treatment and laryngectomy is required in the worst case. Here, we report a case of laryngeal radionecrosis, successfully treated by use of hyperbaric oxygen (HBO) therapy, in which laryngectomy was avoided. A 67-year-old male received radical chemoradiotherapy (CRT) for mesopharyngeal cancer, which included radiotherapy with a total dose of 71.4 Gy/38 Fr and chemotherapy with CDDP + S-1. He developed dyspnea and throat pain 9 months after completion of CRT. Laryngoscopy revealed vocal cord impairment because of severe laryngeal edema. He was diagnosed as having laryngeal radionecrosis and initially received conservative therapy combined with antibiotics, steroids, and prostaglandins. Because his dyspnea was persistent despite this treatment, HBO therapy was administered 20 times, and resulted in complete remission of the dyspnea. HBO therapy, therefore, is regarded as an effective conservative therapeutic option for laryngeal radionecrosis. PMID- 22258813 TI - A case of cervical multicentric Castleman disease treated with intensity modulated radiation therapy using helical tomotherapy. AB - Castleman disease (CD) is a rare lymphoproliferative disorder. Two clinical entities are described: a unicentric form with disease confined to a single lymph node region and a multicentric form characterized by generalized lymphadenopathy and systemic symptoms. Although surgery is regarded as standard therapy for the unicentric form, no consensus has been reached concerning the standard treatment for multicentric CD. We report here a case of cervical multicentric CD treated with intensity-modulated radiation therapy (IMRT), using helical tomotherapy to minimize xerostomia in comparison with conventional radiotherapy. A 29-year-old woman complained of neck swelling. Computed tomography showed lymphadenopathy in both sides of the neck. The patient was diagnosed with the plasma cell subtype of CD on biopsy. After initial treatment with prednisone, IMRT was planned to avoid normal structures, for example the parotid gland. The cervical lymphadenopathy shrank gradually during IMRT with 44 Gy in 22 fractions. Four years and 3 months after IMRT, regrowth of cervical lymph nodes has not been detected. The parotid function improved dramatically on quantitative salivary scintigraphy between 3 and 12 months after IMRT. Radiotherapy could be an option for multicentric CD, and IMRT is an effective means of minimizing xerostomia in head and neck lesions. PMID- 22258814 TI - Survivin-mediated therapeutic efficacy of gemcitabine through glucose-regulated protein 78 in hepatocellular carcinoma. AB - BACKGROUND: Survivin is an antiapoptotic molecule that is widely expressed in cancers, including hepatocellular carcinoma (HCC). Survivin has become a general therapeutic target for cancers because of its selective overexpression in a majority of tumors. However, little is known regarding the effect of survivin expression in combination with gemcitabine on HCC. METHODS: We generated survivin knockdown cells (survivin-KD) via a short interfering RNA (siRNA) technique. The antiproliferation effects of gemcitabine were determined by MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay, and cell cycle evaluation. RESULTS: According to the MTT assay, we found that survivin-KD cells were more sensitive than parental cells and scrambled control cells to gemcitabine treatment. The apoptotic cell population increased in survivin-KD cells that were treated with gemcitabine in comparison to scrambled control cells, as observed by the cell cycle distribution and TUNEL assays. We found that survivin knockdown resulted in a reduction of glucose-regulated protein 78 (GRP78), which may be responsible for the observed increased survivin-KD cell sensitivity to gemcitabine. CONCLUSIONS: We conclude that survivin knockdown may contribute to a therapeutic effect of gemcitabine through GRP78 on HCC cells. PMID- 22258815 TI - A novel genetically modified oncolytic vaccinia virus in experimental models is effective against a wide range of human cancers. AB - BACKGROUND: Replication-competent oncolytic viruses have shown great promise as a potential cancer treatment. This study aimed to determine whether a novel vaccinia virus, GLV-1h151, with genetic modifications enhancing cancer specificity and enabling virus detection, is effective against a range of human cancers and is safe when administered in preclinical models. METHODS: GLV-1h151 was modified with deletion of thymidine kinase enhancing specificity and insertion of the green fluorescent protein (GFP) gene. The virus was tested in several human cancer cell lines for cytotoxicity including breast, lung, pancreatic, and colorectal. Virus replication was assessed via visualization of GFP expression and bioluminescence, and viral plaque assays. Finally, GLV-1h151 was administered systemically or intratumorally in mice with pancreatic cancer xenografts (PANC-1) to assess virus biodistribution, toxicity, and effect on tumor growth. RESULTS: GLV-1h151 effectively infected, replicated in, and killed several cancer cell types. Detection and visualization of virus replication was successful via fluorescence imaging of GFP expression, which was dose dependent. When administered intravenously or intratumorally in vivo, GLV-1h151 regressed tumor growth (P < 0.001) and displayed a good biosafety profile. GLV-1h151 infection and replication in tumors was successfully visualized via GFP and bioluminescence, with virus presence in tumors confirmed histologically. CONCLUSIONS: GLV-1h151 is effective as an oncolytic agent against a wide range of cancers in cell culture and is effective against pancreatic human xenografts displaying a good biosafety profile and ability to be detected via optical imaging. GLV-1h151 thus adds another potential medium for the killing of cancer and detection of virus in infected tissue. PMID- 22258816 TI - Defined clinical classifications are associated with outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy. AB - BACKGROUND: We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy. METHODS: We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded. RESULTS: Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22). CONCLUSIONS: This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival. PMID- 22258817 TI - Safety and efficacy of carboxymethylcellulose in the treatment of glottic insufficiency. AB - OBJECTIVES/HYPOTHESIS: No studies to date have examined the clinical safety and efficacy of carboxymethylcellulose (CMC) for vocal fold injection. The current study investigates the voice outcomes and complications of CMC injection. STUDY DESIGN: Retrospective review. METHODS: All patients who underwent CMC injection from three independent sites in a 1-year period were reviewed. Voice outcomes in the form of voice handicap index-10 (VHI-10) and complications from injection were recorded. RESULTS: Seventy-eight patients with VHI-10 results from 1 to 8 weeks after CMC injection were evaluated. Thirty-eight patients were treated for vocal fold immobility, and 15 patients underwent treatment for hypomobility, 15 for vocal fold atrophy, seven for scar/sulcus, one for previous laryngeal fracture, one for functional dysphonia, and one for persistent granuloma. In 60 patients with available VHI-10 data, overall improvement in voice was seen. There was a mean decrease in VHI-10 of 7.48 (26.4 to 18.9, P < .05), correlating to a 19.9% decrease. Forty-five patients (75%) showed a decrease in VHI-10, nine (15%) showed an increase, and six (10%) showed no change. Statistically significant differences were seen for patients with immobility (decrease of 8.6, or 31%) and hypomobility (decrease of 10.7, or 37.8%). There were no complications of vocal fold stiffness, inflammatory reaction, or scar in the 78 patients during the total follow-up period. CONCLUSIONS: CMC is a viable, safe, and efficacious material for the temporary treatment of glottic insufficiency in vocal fold immobility and hypomobility, with minimal risk of permanent adverse voice outcomes. PMID- 22258818 TI - Visuospatial bootstrapping: long-term memory representations are necessary for implicit binding of verbal and visuospatial working memory. AB - It has recently been shown that presenting additional visuospatial information alongside to-be-remembered numbers in a digit span task enhances participants' memory for those items. However, the mechanisms behind this visuospatial bootstrapping effect have remained unspecified. In this article, we report evidence that this effect involves an integration of information from verbal and visuospatial temporary memory with long-term-memory (LTM) representations and that the existence of a relevant LTM representation is necessary for bootstrapping to occur. PMID- 22258819 TI - The effect of the first glimpse at a scene on eye movements during search. AB - Previewing scenes briefly makes finding target objects more efficient when viewing is through a gaze-contingent window (windowed viewing). In contrast, showing a preview of a randomly arranged search display does not benefit search efficiency when viewing during search is of the full display. Here, we tested whether a scene preview is beneficial when the scene is fully visible during search. Scene previews, when presented, were 250 ms in duration. During search, the scene was either fully visible or windowed. A preview always provided an advantage, in terms of decreasing the time to initially fixate and respond to targets and in terms of the total number of fixations. In windowed visibility, a preview reduced the distance of fixations from the target position until at least the fourth fixation. In full visibility, previewing reduced the distance of the second fixation but not of later fixations. The gist information derived from the initial glimpse of a scene allowed for placement of the first one or two fixations at information-rich locations, but when nonfoveal information was available, subsequent eye movements were only guided by online information. PMID- 22258820 TI - What's in a word? A parametric study of semantic influences on visual word recognition. AB - To what extent does semantic information play a functional role in visual word recognition? Theories of word recognition vary in the importance assigned to semantic information in visual lexical decision, with past research suggesting that the nature of the foils is a crucial determinant of semantic reliance. Here, we explored the conditions under which semantic variables influence lexical decision. Normal readers performed visual lexical decision tasks in which imageability and semantic priming were manipulated, with nonword foils varying systematically in their orthographic and phonological similarity to the real words. The effects of imageability and semantic priming increased in magnitude as nonword foils became progressively more wordlike. These findings provide a clear illustration of the flexible use of semantic information to support normal visual word recognition. PMID- 22258821 TI - Suggestion does not de-automatize word reading: evidence from the semantically based Stroop task. AB - Recent studies have shown that the suggestion for participants to construe words as meaningless symbols reduces, or even eliminates, standard Stroop interference in highly suggestible individuals (Raz, Fan, & Posner, 2005; Raz, Kirsch, Pollard, & Nitkin-Kaner, 2006). In these studies, the researchers consequently concluded that this suggestion de-automatizes word reading. The aim of the present study was to closely examine this claim. To this end, highly suggestible individuals completed both standard and semantically based Stroop tasks, either with or without a suggestion to construe the words as meaningless symbols (manipulated in both a between-participants [Exp. 1] and a within-participants [Exp. 2] design). By showing that suggestion substantially reduced standard Stroop interference, these two experiments replicated Raz et al.'s (2006) results. However, in both experiments we also found significant semantically based Stroop effects of similar magnitudes in all suggestion conditions. Taken together, these results indicate that the suggestion to construe words as meaningless symbols does not eliminate, or even reduce, semantic activation (assessed by the semantically based Stroop effect) in highly suggestible individuals, and that such an intervention most likely reduces nonsemantic task relevant response competition related to the standard Stroop task. In sum, contrary to Raz et al.'s claim, suggestion does not de-automatize or prevent reading (as shown by a significant amount of semantic processing), but rather seems to influence response competition. These results also add to the growing body of evidence showing that semantic activation in the Stroop task is indeed automatic. PMID- 22258822 TI - Fracture risk in women with breast cancer: a population-based study. AB - A positive association has been reported between greater bone density and higher breast cancer risk, suggesting that these women could be at reduced risk of fracture. To estimate fracture risk among unselected community women with breast cancer and to systematically assess associations with various risk factors including breast cancer treatments, we conducted a population-based historical cohort study of 608 Olmsted County, MN, USA, women with invasive breast cancer first diagnosed in 1990 to 1999 (mean age 61.6 +/- 14.8 years), who were followed for 5776 person-years. Altogether, 568 fractures were observed in 270 women (98 per 1000 person-years). Overall fracture risk was elevated 1.8-fold, but the absolute increase in risk was only 9%, and 56% of the women did not experience a fracture during follow-up. Excluding pathologic fractures (15%) and those found incidentally (24%), to allow for ascertainment bias, the standardized incidence ratio was 1.2 (95% confidence interval [CI] 0.99 to 1.3) for total fracture risk and 0.9 (95% CI 0.7 to 1.2) for osteoporotic fracture risk alone. Various breast cancer treatments were associated with an increased risk of fracture, but those associations were strongest for pathologic fractures, which were relatively more common among the women who were premenopausal when their breast cancer was diagnosed. Moreover, underlying clinical characteristics prompting different treatments may have been partially responsible for the associated fracture outcomes (indication bias). These data thus demonstrate that breast cancer patients in general are not at greatly increased risk of fracture but neither are they protected from fractures despite any determinants that breast cancer and high bone density may have in common. PMID- 22258823 TI - Comparative effects of vivax malaria, fever and diarrhoea on child growth. AB - BACKGROUND: The adverse impact of Plasmodium vivax on child health beyond acute febrile illness is poorly studied. The effect of vivax malaria on child growth was evaluated and compared with diarrhoeal disease and non-specific fever. METHODS: Using data from a 43-month longitudinal cohort of children 0-72 months of age (n = 442) in the Peruvian Amazon, ponderal and linear growth velocities over 2-, 4- and 6-month periods were examined using longitudinal models and related to the incidence of disease during the same period. RESULTS: An episode of vivax malaria led to 138.6 g (95% confidence interval (CI) 81.9-195.4), 108.6 g (62.8-153.2) and 61 g (20.9-101.1) less weight gain over 2-, 4- and 6-month intervals, respectively. These deficits were larger than both diarrhoea (21.9, 17.2 and 13.8 g less weight gain, respectively) and fever (39.0, 30.3 and 25.6 g less weight gain, respectively). An incident episode of vivax also led to 0.070 cm (0.004-0.137) and 0.083 cm (0.015-0.151) less linear growth over 4 and 6 months, respectively, which were also larger than deficits from diarrhoea (0.029 and 0.028 cm, respectively) and fever (not associated with linear growth deficits). Despite the larger effect of P. vivax incident episodes on growth of a particular child, diarrhoeal disease had a larger cumulative impact on growth deficits as diarrhoeal incidence rates in this community are >10-fold higher than vivax malaria. CONCLUSIONS: Disease control measures for vivax malaria and diarrhoeal disease have the potential to improve the growth of children in endemic areas. PMID- 22258824 TI - Transcription profile of DNA damage response genes at G0 lymphocytes exposed to gamma radiation. AB - Ionizing radiation induces a plethora of DNA damages in human cells which may alter the level of mRNA expression. We have analyzed mRNA expression profile of DNA damage response genes involved in G(0)/G(1) check point pathway in whole blood to assess their radio-adaptive response, if any, to gamma radiation. Blood samples were collected from twenty-five random, normal, and healthy male donors with written informed consent and irradiated at doses between 0.1 and 2.0 Gy (0.7 Gy/min). DNA strand breaks were studied using comet assay, whereas DNA double strand breaks were visualized using gammaH2AX as a biomarker. Dose response if any, at transcriptional level was studied for all these dose groups at 1 and 5-h post-irradiation. Adaptive response at transcriptional level was studied at three different priming doses (0.1, 0.3, and 0.6 Gy) separately followed by a challenging dose of 2.0 Gy after 4 h. For both the experiments, total RNA was isolated from PBMCs obtained from irradiated whole blood and reverse transcribed to cDNA. The level of mRNA expression of ATM, ATR, GADD45A, CDKN1A, P53, CDK2, MDM2, and Cyclin E was studied using real-time quantitative PCR. A significant dose-dependant increase in the percentage of DNA damage in tail was observed using comet assay. Similarly, increased number of foci was observed at gammaH2AX with increasing dose. At transcriptional level, a significant dose-dependent up regulation at GADD45A, CDKN1A, and P53 genes up to 1.0 Gy was observed at 5-h post-irradiation (P <= 0.05). Radio-adaptive response at mRNA expression level was observed at CDK2, Cyclin E, and P53, whereas ATM, ATR, GADD45A, MDM2, ATM, and ATR have not shown any radio-adaptive changes in the expression profile. DNA damage response genes involved in G(0)/G(1) checkpoint pathway has important implications in terms of radiosensitivity in vivo and changes in the transcriptional profile might throw some new insights to understand the mechanism of adaptive response. PMID- 22258825 TI - 4G/5G polymorphism modulates PAI-1 circulating levels in obese women. AB - The increase in plasminogen activator inhibitor type 1 (PAI-1) has been described as a risk factor to thrombosis-related diseases. In addition, it has been demonstrated that the variant 4G of polymorphism 4G/5G located in promoter region of PAI-1 gene is associated with higher PAI-1 levels. We investigate the role of this polymorphism on circulating PAI-1 concentration in a population of 57 obese women (23%, 4G/4G; 49%, 4G/5G and 28%, 5G/5G genotypes). Our results demonstrate a genotype-specific modulation on PAI-1 levels in obese women, thus 5G/5G genotype presented significantly lower levels of plasma PAI-1 when compared to 4G/4G group (46 +/- 19 ng/mL vs. 63 +/- 13 ng/mL, respectively). Our findings indicate that obese carriers of 4G/4G genotype may have increased risk to develop thrombotic diseases. PMID- 22258827 TI - Novel source of trifluoromethyl radical as efficient initiator for the polymerization of vinylidene fluoride. AB - A persistent perfluoroalkyl radical (PPFR), perfluoro-3-ethyl-2,4-dimethyl-3 pentyl, is shown to be a good source of *CF(3) radicals and a useful radical capable of initiating the polymerization of vinylidene fluoride (VDF). NMR characterizations of the resulting PVDF homopolymers showed that polymerization of VDF was exclusively initiated by *CF(3) radicals. The addition of *CF(3) radical onto VDF was regioselective leading to CF(3) -CH(2) -CF(2) -PVDF and the CF(3) end-group acted as an efficient label to assess the molecular weights by (19) F NMR spectroscopy. Various [PPFR](0) /[VDF](0) initial molar ratios lead to CF(3) -PVDF-CF(3) of different molecular weights. When that ratio decreased, both the molecular weights and the thermostability of these PVDFs increased, showing less defects of chaining and higher crystallinity. PMID- 22258826 TI - The molecular interaction of a copper chelate with human P-glycoprotein. AB - One of the major reasons for multidrug resistance (MDR) in cancer is the overexpression of P-glycoprotein (P-gp, ABCB1), a drug efflux pump. A novel copper complex, namely, copper (II) N-(2-hydroxyacetophenone) glycinate (CuNG) previously synthesized and characterized by the authors had been tested in this study. In a cell-based assay system with human MDR1 cDNA overexpressed mouse fibroblast NIH MDR1-G185 cell line, we demonstrated that this metal complex can directly interact with this transporter. As CuNG increased cellular accumulation of doxorubicin in P-gp-expressing cells, we presumed that of CuNG may be potential to reverse P-gp-mediated drug resistance probably by lowering the P-gp expression at the protein as well as mRNA level. Interestingly, our studies on UIC2 (a conformation sensitive monoclonal antibody) binding assay indicated the direct interaction of CuNG with P-gp. However, CuNG did not compete for the substrate binding as photoaffinity labeling of P-gp with a substrate analog [(125)I] iodoarylazidoprazosin ([(125)I] IAAP) showed approximately twofold increase in [(125)I] IAAP binding in presence of CuNG. In vitro study showed that CuNG significantly stimulated P-gp-specific ATPase activity in isolated membrane preparations from NIH MDR1-G185 cells. This result further confirmed the CuNG-P gp direct interaction. This study also demonstrated that CuNG has a drug interaction site different from verapamil-, vinblastine- and progesterone-binding sites on P-gp. Taken together, this is the first report of molecular interaction of any Schiff's base metal chelate CuNG with human P-gp. This information may be useful to design more efficacious nontoxic metal-based drugs as MDR-reversing agents. PMID- 22258828 TI - Using evolutionary algorithms for fitting high-dimensional models to neuronal data. AB - In the study of neurosciences, and of complex biological systems in general, there is frequently a need to fit mathematical models with large numbers of parameters to highly complex datasets. Here we consider algorithms of two different classes, gradient following (GF) methods and evolutionary algorithms (EA) and examine their performance in fitting a 9-parameter model of a filter based visual neuron to real data recorded from a sample of 107 neurons in macaque primary visual cortex (V1). Although the GF method converged very rapidly on a solution, it was highly susceptible to the effects of local minima in the error surface and produced relatively poor fits unless the initial estimates of the parameters were already very good. Conversely, although the EA required many more iterations of evaluating the model neuron's response to a series of stimuli, it ultimately found better solutions in nearly all cases and its performance was independent of the starting parameters of the model. Thus, although the fitting process was lengthy in terms of processing time, the relative lack of human intervention in the evolutionary algorithm, and its ability ultimately to generate model fits that could be trusted as being close to optimal, made it far superior in this particular application than the gradient following methods. This is likely to be the case in many further complex systems, as are often found in neuroscience. PMID- 22258829 TI - Surgical approaches to left ventricular reconstruction: a matter of perspective. AB - Surgical reconstruction of physiological shape and size of a postischemically remodeled left ventricle has been advocated to improve ventricular function and improve patient long-term outcome. What initially started as linear aneurysm resection surgery developed over the years into the endoventricular repair techniques (surgical ventricular reconstruction, SVR) that have also been applied in patients with postischemically dilated ventricles and mainly anterior akinesia. SVR improved function as measured by the ejection fraction. Whether it affects survival was finally tested in the largest surgical trial ever conducted, the STICH trial (Surgical Treatment for IsChemic Heart failure). The trial, however, presented rather sobering information with its Hypothesis 2 outcome by demonstrating identical 5-year survival rates between SVR plus bypass grafting (CABG) and CABG alone. SVR also did not improve quality of life. This neutral finding spawned a series of critical responses with respect to trial design and conduct accompanied by appropriate responses by the trial's leadership. At the end of this dispute, it appears that SVR has been accepted as not very useful for most patients and is less and less performed in daily practice. What remains is a series of different perspectives that will be discussed in this review. The conclusion will be that SVR may be of low value for the patient with dilated and massively remodeled ventricles, but the technique bears therapeutic potential for some patients for different reasons so that the surgeon's ability to perform this operation should not get lost. PMID- 22258831 TI - The continuing saga of aging and heart failure. PMID- 22258832 TI - Maxillofacial reconstruction using polyetheretherketone patient-specific implants by "mirroring" computational planning. AB - In the vast majority of cases, precise symmetric reconstruction of maxillofacial defects remains an unsolved problem for craniofacial surgeons. Computer-designed alloplastic implants have contributed considerably to improvement in the accuracy and reliability of facial rehabilitation, rapidly becoming an irreplaceable part of the surgical armamentarium. In recent years, the subsequently developed new generation of computational technologies has allowed planning to be done by preoperative "mirroring" using the healthy side as a template to fabricate an ideal prosthesis for reestablishment of facial symmetry. Two cases of facial defects are reported, one of the midface and another of the lower face reconstructed using a computer-designed polyetheretherketone (PEEK) patient specific implant (PSI) technique based on "mirroring" computational planning. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258830 TI - The paradox of left ventricular assist device unloading and myocardial recovery in end-stage dilated cardiomyopathy: implications for heart failure in the elderly. AB - Dilated cardiomyopathy (DCM) is a common debilitating condition with limited therapeutic options besides heart transplantation or palliation. It is characterized by maladaptive remodeling of cardiomyocytes, extracellular collagen matrix (ECCM) and left ventricular (LV) geometry which contributes to further dysfunction. LV assist devices (LVADs) can reverse adverse remodeling in end stage DCM. However, there is a disconnect between the benefits of prolonged unloading with LVAD at molecular and cellular levels and the low rate of bridge to recovery (BTR). Potential explanations for this paradox include insufficient reverse ECCM remodeling and/or excessive reverse cardiomyocyte remodeling with atrophy. LVAD therapy is associated with decreased collagen turnover and cross linking and increased tissue angiotensin II (AngII), whereas LVAD combined with angiotensin-converting enzyme inhibition results in decreased tissue AngII and collagen cross-linking, normalizes LV end-diastolic pressure volume relationships and is associated with modestly higher rates of BTR. Much remains to be learned about ventricular reverse remodeling after LVAD. This can be facilitated through systematic collection and comparison of recovered and unrecovered myocardium. Importantly, vigilant monitoring for ventricular recovery among LVAD patients is needed, particularly in older patients receiving LVAD for destination therapy. In addition, prospective multicenter trials are needed to clarify the potential benefit of concomitant heart failure therapy with selective beta2 agonism on ventricular recovery. PMID- 22258833 TI - Mammae erraticae: a case report and reappraisal of the related theories. AB - Extra nipples and breast tissue outside the orthotopic location of the mammary glands are called polythelia and polymastia, respectively. Although the theory of mammary ridge remnants can explain extra breast tissue along the milk line, other locations such as the dorsum of the body still need further discussion. This report describes a 28-year-old Caucasian woman with a perfectly formed breast together with a meningocele in the lumbar region. Kyphoscoliosis and growth retardation were accompanying pathologies. As far as the authors can discern, this is the first case in the literature showing a well-formed breast and dysraphism occurring together. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258834 TI - A technique for auricular keloid core excision using a skin biopsy punch. AB - BACKGROUND: Keloids of the auricular region, resulting from ear piercing or external injury, are a common cosmetic problem. Surgical treatment followed by conservative management often is needed. The "hollowing out method for keloids of the auricle" retains the skin over the keloid lesion to minimize tension on the wound. This is considered to be the appropriate surgical treatment method, but skill is required to remove the keloid and retain the skin with a uniform thickness and appropriate form. MATERIAL AND METHODS: Four patients with auricle keloids were included in this study. All the patients were females between the ages of 18 and 29 years (average age, 24.8 years). Keloid core excision using a skin biopsy punch with the patient under local anesthesia was performed for all the patients. RESULTS: Use of a skin biopsy punch resulted in a shorter operating time without causing ear deformity. CONCLUSION: The authors report a technique for keloid core excision using a skin biopsy punch and believe it is a useful method LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258835 TI - Monsplasty for women after massive weight loss. AB - BACKGROUND: Ptosis with excess skin in the pubic area is a very common deformity in patients after massive weight loss. This deformity requires adequate surgical treatment whether combined with abdominoplasty or not. The enlarged pubogenital area may lead to psychosocial distress and impaired quality of life. METHODS: A series of 23 women with a mean age of 39.5 years who previously underwent bariatric surgeries and later presented with pubogenital ptosis underwent monsplasty. The preoperative surgical markings and the surgical technique presented are easily reproducible. In this prospective study, the surgical outcomes were assessed by questionnaires applied to the patients, who scored the following parameters: movement dynamics, aesthetic appearance, sexual performance, improved hygiene, and use of clothing items. RESULTS: Four of the parameters assessed (movement dynamics, aesthetic appearance, hygiene, and use of clothing items) showed clear improvement, with scores ranging from good to very good. A small percentage of the patients (13%) reported fair improvement in sexual performance. CONCLUSION: The findings showed monsplasty to be a simple and reproducible technique with favorable outcomes and low morbidity rates. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258837 TI - Comparison of autogenous cartilage, acellular dermis, and solvent-dehydrated pericardium for the prevention and correction of dorsal nasal irregularities: an experimental study. AB - BACKGROUND: Numerous materials have been used for the correction and prevention of dorsal nasal irregularities. Experimental and clinical studies have been useful but have provided insufficient results for several reasons, including the impossibility of obtaining pathologic specimens from aesthetic patients and imprecise experimental models. In this study, an experimental model for rhinoplasty is used for the comparative evaluation of solvent-dehydrated pericardium, acellular dermal matrix, and autogenous ear cartilage as onlay grafts for the prevention and correction of nasal dorsal irregularities. We used an experimental rabbit rhinoplasty model that has a human nose-like osteocartilaginous junction. Thus, our goal is to get a more realistic idea about the features of these three materials. METHODS: Thirty New Zealand rabbits weighing 2,100-2,550 g were used. The noses of the rabbits were evaluated with computerized tomographic measurements, "pinch" tests were performed for skin properties, and all were photographed before the surgical procedures. They were divided into three groups: Autogenous cartilage grafts were applied after the rhinoplasty operation in group 1, acellular dermal matrixes were used after the rhinoplasty in group 2, and pericardium allografts were used after the rhinoplasty in group 3. The rabbits were followed up for 4 months before they were evaluated by photography, computerized tomography, and "pinch" tests for the skin properties of the nose. Then they were killed for histopathologic evaluation. Adhesion and resorption rates of the onlay grafts were observed and subdermal thickness measurements were made to determine the fate of the grafts as well as their effects on the overlying skin. RESULTS: The major advantages of the allografts used in groups 2 and 3 are the ease of obtaining them without any donor site morbidity, shorter operative procedures, and lower distortion rates due to lack of cartilage memory. The results of this study conform to those of previous reports and demonstrate that the used allografts had no adverse effects such as ulceration or extrusion. The evaluation of the internal nasal valve angles before and after the surgical interventions showed that cartilage grafts created a spreader effect as expected, but acellular dermis and solvent dehydrated pericardium did not. Despite a moderate graft reaction, pericardium or acellular dermis remained intact. None of the materials caused adhesion to the overlying skin. CONCLUSION: The results of this experimental study showed that acellular dermis (AlloDerm(r)) or solvent-dehydrated pericardium (Tutogen) may be used successfully as an "onlay" graft for dorsal nasal problems compared to autogenous cartilage, which is commonly used for this purpose. There has been more cartilage resorption than thought. This should be considered when overcorrection is performed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258836 TI - Comparing breast-reduction techniques: time-to-event analysis and recommendations. AB - BACKGROUND: Breast reduction is a common procedure used to improve physical and aesthetic factors associated with breast hypertrophy. This study investigated how surgical technique alone affects the risk factors for complications and profiled differences between techniques. Complications were assessed by the use of time-to event methods. METHODS: Patient information was extracted from a cohort of 283 patients. Demographic, surgical, and follow-up information was analyzed for patients undergoing surgical procedures using the inferior pedicle Wise pattern (IPWP) and modified Hall-Findlay (MHF) techniques. The patients managed with the IPWP technique were considered control subjects. The failure rates were described using the Kaplan-Meier failure estimator to provide a true estimate of the experienced complication rates. RESULTS: Overall, few differences were noted between the groups except for total tissue removed. The overall failure (complication) rate at 6 months was 18.8%, with 9% of all the patients experiencing a major complication that required operative intervention/revision. As expected, the period with the greatest risk of complication was the first month after surgery. Surgical technique, total tissue removed, and age were nonpredictive of complications. Overall, the IPWP group had significantly more total tissue removed than the MHF group (median difference, 227 g; P=0.002). There was no evidence of a learning curve when an experienced surgeon moved from the one technique to the other. CONCLUSION: At 6 months after surgery, 19% of patients are expected to have experienced a complication. There appears to be few differences in outcomes between the techniques of breast reductions used, and the success or otherwise almost certainly relates to factors independent of surgical technique and includes patient selection, operative skill, and experience. Time to-event analysis provides a precise assessment and description of the complication profile. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258838 TI - The V-Y latissimus dorsi musculocutaneous flap in the reconstruction of large posterior chest wall defects. AB - Posterior chest wall defects are frequently encountered after excision of tumors as a result of trauma or in the setting of wound dehiscence after spine surgery. Various pedicled fasciocutaneous and musculocutaneous flaps have been described for the coverage of these wounds. The advent of perforator flaps has allowed the preservation of muscle function but their bulk is limited. Musculocutaneous flaps remain widely employed. The trapezius and the latissimus dorsi (LD) flaps have been used extensively for upper and middle posterior chest wounds, respectively. Their bulk allows for obliteration of the dead space in deep wounds. The average width of the LD skin paddle is limited to 10-12 cm if closure of the donor site is expected without skin grafting. In 2001 a modification of the skin paddle design was introduced in order to allow large flaps to be raised without requiring grafts or flaps for donor site closure. This V-Y pattern allows coverage of large anterior chest defects after mastectomy. We have modified this flap to allow its use for posterior chest wall defects. We describe the flap design, its indications, and its limitations with three clinical cases. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22258839 TI - Infections at sea past and present. PMID- 22258840 TI - Infection on board ships in the 21st century: overview of IMHA workshop, Singapore 2010. PMID- 22258841 TI - Summary of workshop proceedings: infection on board ship in the 21st century. PMID- 22258842 TI - Influenza and SARS: the impact of viral pandemics on maritime health. AB - Global travel and transport play a critical role in the spread of infections. We see this clearly in the first two pandemics of the 21st century: SARS and influenza H1N1-2009. Although air travel contributed to dissemination in these two pandemics, the travel restrictions, quarantines, and heightened vigilance which resulted had an impact on maritime health. Seasonal, pandemic, and avian influenza have some important differences with regards to exposure risks, infectivity, and severity. Most of the data for maritime influenza outbreaks focus on seasonal influenza on cruise ships, but influenza among crew members occurs due to close working conditions and is potentially preventable with staff vaccination programs. To date, avian influenza has low human-to-human transmission; infection typically requires close contact with poultry, but presents with severe disease and a high fatality rate. Pandemic (swine) influenza was readily transmitted between people, including young adults, and caused severe illness in high-risk groups including pregnant women, children, and those with co morbidities and obesity. In contrast, SARS had lower infectivity compared to influenza, and a longer incubation period. These characteristics slowed its propagation enough that outbreak control measures, such as isolation of infected cases and quarantine of exposed but well persons, were effective in terminating this pandemic. No effective vaccine exists for SARS at this time, whereas countries were able to deploy millions of doses of pandemic influenza vaccine within 7 months after the outbreak was first recognized in Mexico. The lack of a protective vaccine and the higher case fatality rate in SARS will mean that stringent quarantine measures may still be required for outbreak control if SARS ever occurs again. Compliance with international health regulations, and the ability to adapt these to maritime health needs, will be important in the shipping industry. PMID- 22258843 TI - AIDS prophylaxis--achievements due to appropriate strategies. AB - Seafaring as an occupation possesses a special blend of conditions that is strongly influencing the spread of HIV and is making prevention programs difficult to succeed. Actual prevention programs in the shipping industry are not showing success. Social partners are in a unique position to promote prevention efforts, particularly in relation to changing attitudes and behaviours through the provision of information and education, and in addressing socio-economic factors. Together with major international organizations they have created an initiative named "Global Partnership on HIV and Mobile Workers in the Maritime Sector", designed to be a project that is realistic, achievable, and focused on prevention among seafarers whose sustainability will be created through linking organizations with a long-term commitment and integration in the lives of seafarers with intergovernmental organizations. This new global prevention programme aims to address this challenge by making a series of interventions along the route of their migration. The identified problems of HIV prevention in the shipping industry addressed in its design are presented together with its structure and aims. PMID- 22258844 TI - Infectious diseases and medical guides for seafarers. PMID- 22258845 TI - Wound infections on board ship--prevention, pathogens, and treatment. AB - Wounds are common in seafarers and they can easily become infected in the marine environment. Pre-sea tetanus immunization is essential. Without diagnostic facilities and only a limited range of antibiotics onboard, injury prevention and early treatment to reduce the likelihood of infection are important measures. Suturing clean cuts reduces healing time and risk of infection. Fresh, clean cuts, especially on the face or head, can be closed by adhesive tape or sutures, but if infection arises, then one or more sutures should be removed to enable drainage. Most wounds must be considered contaminated and should not be closed, just covered with sterile dressing after cleaning. Antibiotic treatment should be started immediately in seafarers with hand and puncture wounds. The primary treatment for a simple abscess is incision and drainage. Antibiotic treatment is recommended for abscesses if the infection spreads to the surrounding tissue (associated cellulitis), if there is lack of response to incision and drainage alone, or if the abscess is in an area difficult or dangerous to drain (e.g. face, palm, genitalia). Recommended therapy for cellulitis is 5-10 days of dicloxacillin, cephalexin, clindamycin, or erythromycin, but if there is no improvement after 2-3 days, methicillin-resistant Staphylococcus aureus (MRSA) should be suspected. Bites and burn wounds require special attention. Since wound infections can deteriorate rapidly, a telemedicine advice service (TMAS) should be consulted during the early stages, and serial digital photographs of the affected area, transmitted by e-mail to TMAS, are often useful during treatment at sea. PMID- 22258846 TI - Infections onboard ship--analysis of 1290 advice calls to the Radio Medical (RM) doctor in Sweden. Results from 1997, 2002, 2007, and 2009. AB - Results from a descriptive study on Swedish Telemedical Advice Services (TMAS) from 1997, 2002, 2007, and the first six months of 2009 on infectious conditions are presented. These findings concern symptoms, actions taken, number of evacuations, means of communication, and use of digital photos. They show that infectious conditions are a significant contributor to calls to the service and that they can be more frequently treated on board than can other conditions. PMID- 22258847 TI - Pandemic planning in the shipping industry--lessons learnt from the 2009 Influenza Pandemic. AB - The events around the 2009 A/H1N1 Influenza Pandemic highlighted the need for better planning to ensure protection of those on vessels, protection for ports of call, and protection of business assets (business continuity). The variety of stakeholders involved in the management of a pandemic made it difficult to achieve a cohesive plan during the event itself. By considering the actions during the last pandemic, and the literature available for the shipping industry on pandemic planning, a pathway to better preparation is suggested. PMID- 22258848 TI - Psychosocial risk factors for work-related stress in Her Majesty's Coastguard. AB - BACKGROUND: To determine the extent to which work-related stress in Her Majesty's Coastguard (HMCG) could be accounted for by the Effort-Reward Imbalance (ERI) and Job Demand-Control- -Support (JDCS) stress models. MATERIAL AND METHODS: Participants included a total of 282 coastguards. Data on risk factors were collected via questionnaire, within the wider context of the UK HSE Management Standards framework for stress reduction. Analyses included an examination of each model and its association with stress and mental health outcomes, as well as their impact in combination with the range of other risk factors measured. RESULTS: Significant predictors of stress included ERI, organisation change, and exposure to physical agents (noise). Anxiety was predicted by ERI, noise, and bullying, and depression by ERI, bullying, noise, training, and role conflict/ambiguity. CONCLUSIONS: For this occupational group, the main source of high stress, anxiety, and depression was ERI. These results raise implications for the use and interpretation of data when using these models, as well as for HSE Management Standards, which are biased towards JDCS. Results from this and other studies also suggest further research is required into the benefits of a more flexible model or framework, which can examine both established and new combinations of risk factors. PMID- 22258851 TI - Application of ex vivo (1)H NMR metabonomics to the characterization and possible detection of renal cell carcinoma metastases. AB - PURPOSE: Renal cell carcinoma (RCC) is the most prevalent malignancy of the kidney. Its survival rates are very low since most of patients develop metastases beyond the kidney at the time of diagnosis. Early detection is currently by far the most promising approach to reduce RCC mortality. Metabolic alterations have been suggested to have a crucial role in cancer development. Metabonomics can present a holistic picture of the metabolites alterations and provide biomarkers that could revolutionize disease characterization and detection. METHODS: Ex vivo (1)H NMR spectra of tumors and the paired adjacent tissues obtained from living patients with RCC were recorded and analyzed using multivariate statistical techniques combined with quantitative statistical analyses. RESULTS: In the present study, we showed that the metabonomes of RCC, either with or without metastases, differ markedly from those of their adjacent tissues. Besides, the RCC patients with metastases can be distinctly differentiated from those without metastases. Metabolic perturbations arising from malignant transformations were also systematically characterized. Compared to the adjacent tissues, RCC tumors had elevated levels of lactate, glutamate, pyruvate, glutamine, and creatine, but decreased levels of acetate, malate, and amino acids including valine, alanine, and aspartate. CONCLUSIONS: Systemic changes in metabolite concentrations are most likely the result of cells switching to glycolysis to maintain energy homeostasis. The results suggest that metabonomics may also facilitate the discovery of novel cancer biomarkers and allows the stratification of tumors under different pathophysiological conditions, which might be a valuable future tool for RCC detection and possibly other cancers. PMID- 22258852 TI - Serum prolidase activity, oxidative stress, and nitric oxide levels in patients with bladder cancer. AB - OBJECTIVES: Prolidase is a member of the matrix metalloproteinase family. It plays a major role in collagen turnover, matrix remodeling and cell growth. Nitric oxide (NO) regulates many processes such as collagen synthesis and matrix remodeling. Thus, NO may augment angiogenesis, tumor invasion, and metastasis. The aim of this study was to investigate total antioxidant status (TAS), malondialdehyde (MDA) and NO levels in patients with bladder cancer and to determine their relationship with prolidase activity. DESIGN AND METHODS: Thirty five patients with bladder cancer and 32 controls were enrolled. Serum TAS, MDA, prolidase activity and NO levels were determined. RESULTS: Serum prolidase activity, NO levels and MDA levels were significantly higher in bladder cancer than controls (all, P < 0.05), while TAS levels were significantly lower (P < 0.05). CONCLUSIONS: Our results show that increased prolidase seems to be associated with increased NO levels and oxidative stress along with decreased antioxidant levels in bladder cancer. PMID- 22258853 TI - Effectiveness and safety of pemetrexed-based doublet versus pemetrexed alone as second-line treatment for advanced non-small-cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: To compared pemetrexed-based doublet with single-agent pemetrexed as second-line treatment for advanced non-small-cell lung cancer METHODS: We systematically searched for randomized clinical trials that compared pemetrexed based doublet with single-agent pemetrexed in patients with histologically proven non-small-cell lung cancer. The primary end point was overall survival. Secondary end points were progression-free survival, overall response rate and grade 3 or 4 toxicity. Data were extracted from the studies by 2 independent reviewers. The meta-analysis was performed by Stata version 10.0 software (Stata Corporation, College Station, Texas, USA). RESULTS: Five randomized clinical trials (totally 1,186 patients) were eligible. Meta-analysis showed that there was significant improvement in PFS (HR 0.82, 95% CI 0.71-0.95, P = 0.007) and overall response rate (OR 2.39, 95% CI 1.58-3.62, P = 0.000) in pemetrexed-based doublet group, compared with pemetrexed alone, though the pooled HR for overall survival (HR 0.89, 95% CI 0.76-1.04; P = 0.129) showed no significant difference between the two groups. However, there were more incidences of grade 3 or 4 neutropenia (OR 2.3, 95% CI 1.4-3.77, P = 0.001), thrombocytopenia (OR 6.41, 95% CI 2.57-16.0, P = 0.000), and leucopenia (OR 2.45, 95% CI 1.13-5.34, P = 0.024) in pemetrexed based doublet group. With regard to the risk of grade 3 or 4 anemia (OR 0.71, 95% CI 0.17-2.91, P = 0.629) and fatigue (OR 1.47, 95% CI 0.92-2.35, P = 0.104), there was no significant difference between the two groups. CONCLUSION: Pemetrexed-based doublet therapy didn't gain any benefit in survival but significantly improved PFS and better ORR compared with single-agent pemetrexed as second-line therapy for advanced non-small-cell lung cancer. However, more incidences of grade 3 or 4 neutropenia, thrombocytopenia, and leucopenia were observed in pemetrexed-based doublet group. PMID- 22258855 TI - Identification of porcine reproductive and respiratory syndrome virus ORF1a encoded non-structural proteins in virus-infected cells. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) replicase gene consists of two large ORFs, ORF1a and ORF1b, the latter of which is expressed by ribosomal frameshifting. The ORF1a-encoded part of the resulting replicase polyproteins (pp1a and pp1ab) is predicted to be processed proteolytically into ten non-structural proteins (nsps), known as nsp1-8, with both the nsp1 and nsp7 regions being cleaved internally (yielding nsp1alpha and nsp1beta, and nsp7alpha and nsp7beta, respectively). The experimental verification of these predictions depends strongly on the ability to identify individual cleavage products with specific antibodies. In this study, a panel of monoclonal and polyclonal antibodies was generated, which together were able to recognize eight ORF1a encoded PRRSV nsps. Using these reagents, replicase cleavage products were detected in PRRSV-infected MARC-145 cells using a variety of immunoassays. By immunofluorescence microscopy, most nsps could be detected by 6 h post-infection. During the early stages of infection, nsp1beta, nsp2, nsp4, nsp7alpha, nsp7beta and nsp8 co-localized in distinct punctate foci in the perinuclear region of the cell, which were determined to be the site of viral RNA synthesis by in situ labelling. Western blot and immunoprecipitation analysis identified most individual nsps and several long-lived processing intermediates (nsp3-4, nsp5-7, nsp5-8 and nsp3-8). The identification and subcellular localization of PRRSV nsps in virus-infected cells documented here provides a basis for the further structure-function studies. Thus, this PRRSV antibody panel will be an important tool for future studies on the replication and pathogenesis of this major swine pathogen. PMID- 22258854 TI - Infection of honey bees with acute bee paralysis virus does not trigger humoral or cellular immune responses. AB - We have studied the responses of honey bees at different life stages (Apis mellifera) to controlled infection with acute bee paralysis virus and have identified the haemolymph of infected larvae and adult worker bees as the compartment where massive propagation of ABPV occurs. Insects respond with a broad spectrum of induced innate immune reactions to bacterial infections, whereas defence mechanisms based on RNA interference play a major role in antiviral immunity. In this study, we have determined that honey bee larvae and adult workers do not produce a humoral immune reaction upon artificial infection with ABPV, in contrast to control individuals challenged with Escherichia coli. ABPV-infected bees produced neither elevated levels of specific antimicrobial peptides (AMPs), such as hymenoptaecin and defensin, nor any general antimicrobial activity, as revealed by inhibition-zone assays. Additionally, adult bees did not generate melanised nodules upon ABPV infection, an important cellular immune function activated by bacteria and viruses in some insects. Challenge of bees with both ABPV and E. coli showed that innate humoral and cellular immune reactions are induced in mixed infections, albeit at a reduced level. PMID- 22258856 TI - Discovery of drugs that possess activity against feline leukemia virus. AB - Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use. PMID- 22258857 TI - Human cytomegalovirus transcriptome activity differs during replication in human fibroblast, epithelial and astrocyte cell lines. AB - Broad cell tropism contributes to the pathogenesis of human cytomegalovirus (HCMV), but the extent to which cell type influences HCMV gene expression is unclear. A bespoke HCMV DNA microarray was used to monitor the transcriptome activity of the low passage Merlin strain of HCMV at 12, 24, 48 and 72 h post infection, during a single round of replication in human fetal foreskin fibroblast cells (HFFF-2s), human retinal pigmented epithelial cells (RPE-1s) and human astrocytoma cells (U373MGs). In order to correlate transcriptome activity with concurrent biological responses, viral cytopathic effect, growth kinetics and genomic loads were examined in the three cell types. The temporal expression pattern of viral genes was broadly similar in HFFF-2s and RPE-1s, but dramatically different in U373MGs. Of the 165 known HCMV protein-coding genes, 41 and 48 were differentially regulated in RPE-1s and U373MGs, respectively, compared with HFFF-2s, and 22 of these were differentially regulated in both RPE 1s and U373MGs. In RPE-1s, all differentially regulated genes were downregulated, but, in U373MGs, some were down- and others upregulated. Differentially regulated genes were identified among the immediate-early, early, early late and true-late viral gene classes. Grouping of downregulated genes according to function at landmark stages of the replication cycle led to the identification of potential bottleneck stages (genome replication, virion assembly, and virion maturation and release) that may account for cell type-dependent viral growth kinetics. The possibility that cell type-specific differences in expressed cellular factors are responsible for modulation of viral gene expression is discussed. PMID- 22258858 TI - Classical swine fever virus NS5B protein suppresses the inhibitory effect of NS5A on viral translation by binding to NS5A. AB - In order to investigate molecular mechanisms of internal ribosome entry site (IRES)-mediated translation in classical swine fever virus (CSFV), an important pathogen of pigs, the expression level of NS3 was evaluated in the context of genomic RNAs and reporter RNA fragments. All data showed that the NS5A protein has an inhibitory effect on IRES-mediated translation and that NS5B proteins suppress the inhibitory effect of NS5A on viral translation, but CSFV NS5B GDD mutants do not. Furthermore, glutathione S-transferase pull-down assay and immunoprecipitation analysis, associated with deletion and alanine-scanning mutations, were performed. Results showed that NS5B interacts with NS5A and that the region aa 390-414, located in the C-terminal half of NS5A, is important for binding of NS5B to NS5A. Furthermore, amino acids K399, T401, E406 and L413 in the region were found to be essential for NS5A-NS5B interaction, virus rescue and infection. The above-mentioned region and four amino acids were observed to overlap with the site responsible for inhibition of IRES-mediated translation by the NS5A protein. We also found that aa 63-72, aa 637-653 and the GDD motif of NS5B were necessary for the interaction between NS5A and NS5B. These findings suggest that the repression activity of the NS5B protein toward the role of NS5A in translation might be achieved by NS5A-NS5B interaction, for which aa 390-414 of NS5A and aa 63-72, aa 637-653 and the GDD motif of NS5B are indispensable. This is important for understanding the role of NS5A-NS5B interaction in the virus life cycle. PMID- 22258859 TI - A novel family of peptides with potent activity against influenza A viruses. AB - The emergence of drug-resistant strains of influenza virus has catalysed a search for new antiviral agents to supplement or replace existing drugs. Following the success of the human immunodeficiency virus entry blocker Enfuvirtide, there has been a resurgence of interest in peptide-based antivirals. In this paper, we report on the discovery of a novel family of peptides (FluPep, FP) that function as inhibitors of influenza A virus infection. The prototype peptide (FP1, also known as Tkip) interacts with haemagglutinin and inhibits the binding of the virus to cell membranes. Using a plaque-reduction assay, we have demonstrated that a variety of influenza A virus subtypes (including H1N1, H3N2 and H5N1) are inhibited by FluPep and its derivatives at nanomolar concentrations. By truncating FluPep we have identified a minimal sequence of 6 aa that binds to haemagglutinin and inhibits infection. Using a mouse model of intranasal influenza virus infection, we observed potent inhibition of virus infection when peptide is given at the time of virus administration. These data indicate that FluPep is a highly effective anti-influenza agent with the potential to translate to the clinic. PMID- 22258860 TI - Beet necrotic yellow vein virus subgenomic RNA3 is a cleavage product leading to stable non-coding RNA required for long-distance movement. AB - Beet necrotic yellow vein virus (BNYVV) is a multipartite RNA virus. BNYVV RNA3 does not accumulate in non-host transgenic Arabidopsis thaliana plants when expressed using a 35S promoter. However, a 3'-derivative species has been detected in transgenic plants and in transient expression assays conducted in Nicotiana benthamiana and Beta macrocarpa. The 3'-derivative species is similar to the previously reported subgenomic RNA3 produced during virus infection. 5' RACE revealed that the truncated forms had identical 5' ends. The 5' termini carried the coremin motif also present on BNYVV RNA5, beet soil-borne mosaic virus RNA3 and 4, and cucumber mosaic virus group 2 RNAs. This RNA3 species lacks a m(7)Gppp at the 5' end of the cleavage products, whether expressed transiently or virally. Mutagenesis revealed the importance of the coremin sequence for both long-distance movement and stabilization of the cleavage product in vivo and in vitro. The isolation of various RNA3 5'-end products suggests the existence of a cleavage between nt 212 and 1234 and subsequent exonucleolytic degradation, leading to the accumulation of a non-coding RNA. When RNA3 was incubated in wheatgerm extracts, truncated forms appeared rapidly and their appearance was protein- and divalent ion-dependent. PMID- 22258861 TI - Release of filamentous and spherical influenza A virus is not restricted by tetherin. AB - The cellular protein tetherin is thought to act as a 'leash' that anchors many enveloped viruses to the plasma membrane and prevents their release. We found that replication of multiple strains of influenza A virus was generally insensitive to alteration of tetherin levels, as assessed by output titre or scanning electron microscopy of cell-associated virions. This included human, swine, avian and equine isolates, strains that form filamentous or spherical particles and viruses that lack the M2 or NS1 proteins. Levels of cell-surface tetherin were not reduced by influenza infection, but tetherin and the viral haemagglutinin co-localized on the plasma membrane. However, tetherin could not be detected in filamentous virions, suggesting that influenza may possess a mechanism to exclude it from virions. Overall, if influenza does encode a specific antagonist of tetherin, it is not M2 or NS1 and we find no evidence for a role in host range specificity. PMID- 22258862 TI - Global phylogeography and evolution of chelonid fibropapilloma-associated herpesvirus. AB - A global phylogeny for chelonid fibropapilloma-associated herpesvirus (CFPHV), the most likely aetiological agent of fibropapillomatosis (FP) in sea turtles, was inferred, using dated sequences, through Bayesian Markov chain Monte Carlo analysis and used to estimate the virus evolutionary rate independent of the evolution of the host, and to resolve the phylogenetic positions of new haplotypes from Puerto Rico and the Gulf of Guinea. Four phylogeographical groups were identified: eastern Pacific, western Atlantic/eastern Caribbean, mid-west Pacific and Atlantic. The latter comprises the Gulf of Guinea and Puerto Rico, suggesting recent virus gene flow between these two regions. One virus haplotype from Florida remained elusive, representing either an independent lineage sharing a common ancestor with all other identified virus variants or an Atlantic representative of the lineage giving rise to the eastern Pacific group. The virus evolutionary rate ranged from 1.62*10(-4) to 2.22*10(-4) substitutions per site per year, which is much faster than what is expected for a herpesvirus. The mean time for the most recent common ancestor of the modern virus variants was estimated at 192.90-429.71 years ago, which, although more recent than previous estimates, still supports an interpretation that the global FP pandemic is not the result of a recent acquisition of a virulence mutation(s). The phylogeographical pattern obtained seems partially to reflect sea turtle movements, whereas altered environments appear to be implicated in current FP outbreaks and in the modern evolutionary history of CFPHV. PMID- 22258863 TI - Altered receptor specificity and fusion activity of the haemagglutinin contribute to high virulence of a mouse-adapted influenza A virus. AB - The viral haemagglutinin (HA) and the viral polymerase complex determine the replication fitness of a highly virulent variant of influenza A virus strain A/PR/8/34 (designated hvPR8) and its high pathogenicity in mice. We report here that the HA of the hvPR8 differs from the HA of a low virulent strain (lvPR8) by the efficiency of receptor binding and membrane fusion. hvPR8 bound to 2,6-linked as well as 2,3-linked sialic acid-containing receptors, whereas lvPR8 bound exclusively to 2,3-linked sialic acids with high avidity. Remarkably, hvPR8 infected its target cells faster than lvPR8 and tolerated an elevated pH for efficient membrane fusion. In spite of these differences, both viruses targeted type II but not type I pneumocytes in the lung of infected mice. The HA of hvPR8 differs from that of lvPR8 by 16 aa substitutions and one insertion. Mutational analyses revealed that amino acid at HA position 190 (H3 numbering) primarily determined the specificity of receptor binding, while the insertion at position 133 influenced the avidity of receptor binding. Both amino acid positions also strongly influenced viral virulence. Furthermore, leucine at position 78 and glutamine at position 354 were critical determinants of increased fusion activity and virulence of hvPR8. Our data suggest that the HA of hvPR8 enhances virulence by mediating optimal receptor binding and membrane fusion thereby promoting rapid and efficient viral entry into host cells. PMID- 22258864 TI - Pathogenicity of a natural reassortant hantavirus CGRn9415 in newborn rats and newborn mice. AB - To better understand the pathogenicity and infectivity of a natural reassortant CGRn9415 generated from Hantaan virus (HTNV) and Seoul virus (SEOV), CGRn9415, HTNV 76-118 and SEOV L99 were used to infect newborn Kunming (KM) mice and newborn Wistar rats. In KM mice, there was no statistical difference between the death rate with CGRn9415 and that of L99, while 76-118 killed all mice even at low dosage; CGRn9415 killed all infected rats similar to L99 at the dosage of 10(5) f.f.u., while no death occurred in rats infected with 76-118 even as high as 2 * 10(5) f.f.u., suggesting that the reassortant CGRn9415 possesses similar pathogenicity as L99. Furthermore, the reassortant CGRn9415 could establish a persistent infection in both KM mice and Wistar rats more easily than 76-118 or L99. These data suggest that the reassorted hantavirus behaves more like SEOV as far as the pathogenicity is concerned. PMID- 22258865 TI - ORF23 of murine gammaherpesvirus 68 is non-essential for in vitro and in vivo infection. AB - Although ORF23 is conserved among gammaherpesviruses, its role during infection is unknown. Here, we studied the expression of ORF23 of murine gammaherpesvirus 68 (MHV-68) and its role during infection. ORF23 mRNA was detected in infected cells as a late transcript. The ORF23 protein product could be expressed and detected as an N-terminally FLAG-tagged protein by Western blot and indirect immunofluorescence. To investigate the role of ORF23 in the infection cycle of a gammaherpesvirus, we constructed an ORF23 deletion mutant of MHV-68. The analysis of the ORF23 deletion mutant suggested that ORF23 of MHV-68 is neither essential for replication in cell culture nor for lytic or latent infection in vivo. A phenotype of the ORF23 deletion mutant, reflected by a moderate reduction in lytic replication and latency amplification, was only detectable in the face of direct competition to the parental virus. PMID- 22258866 TI - Left bundle branch block, an old-new entity. AB - Left bundle branch block (LBBB) is generally associated with a poorer prognosis in comparison to normal intraventricular conduction, but also in comparison to right bundle branch block which is generally considered to be benign in the absence of an underlying cardiac disorder like congenital heart disease. LBBB may be the first manifestation of a more diffuse myocardial disease. The typical surface ECG feature of LBBB is a prolongation of QRS above 0.11 s in combination with a delay of the intrinsic deflection in leads V5 and V6 of more than 60 ms and no septal q waves in leads I, V5, and V6 due to the abnormal septal activation from right to left. LBBB may induce abnormalities in left ventricular performance due to abnormal asynchronous contraction patterns which can be compensated by biventricular pacing (resynchronization therapy). Asynchronous electrical activation of the ventricles causes regional differences in workload which may lead to asymmetric hypertrophy and left ventricular dilatation, especially due to increased wall mass in late-activated regions, which may aggravate preexisting left ventricular pumping performance or even induce it. Of special interest are patients with LBBB and normal left ventricular dimensions and normal ejection fraction at rest but who may present with an abnormal increase in pulmonary artery pressure during exercise, production of lactate during high-rate pacing, signs of ischemia on myocardial scintigrams (but no coronary artery narrowing), and abnormal ultrastructural findings on myocardial biopsy. For this entity, the term latent cardiomyopathy had been suggested previously. PMID- 22258867 TI - Duodenum-stomach anastomosis: a new technique for exocrine drainage in pancreas transplantation. AB - INTRODUCTION: Poor vascular access due to previous surgery can be a major obstacle in pancreas transplantation for which new exocrine and vascular outflow techniques might be useful. A 34-year-old female with early onset type 1 diabetes who underwent living donor kidney transplantation 20 years ago and a failed pancreas transplantation 2 years ago presented for pancreas retransplantation. METHODS: The inferior vena cava was used in the previous deceased donor pancreas transplantation and both iliac arteries had intense perivascular fibrosis, making arterial anastomosis impossible. The only remaining option for the implant was the infrarenal aorta, with venous drainage to the superior mesenteric vein and exocrine drainage to the gastric antrum. RESULTS: The patient had an uneventful recovery and graft function appeared normal. This report shows that when the recipient's abdominal cavity does not provide clear access for the usual surgical techniques regarding exocrine drainage, the stomach drainage procedure is an option. CONCLUSION: Duodenum-stomach anastomosis might be an alternative to portal enteric drainage because there is easy access for graft biopsies and even for procedures involving the papilla major. PMID- 22258868 TI - Socioeconomic factors impact colon cancer outcomes in diverse patient populations. AB - PURPOSE: Cancer disparities among racial and ethnic groups are major public health concerns. Our objective was to examine the impact of socioeconomic status (SES) on survival of colon cancer patients within major racial and ethnic groups. METHODS: Patients with colon adenocarcinoma from Los Angeles County (LAC) were assessed. SES was utilized as an indicator of healthcare access and categorized by tertiles (high, middle, and low). Patient characteristics were compared and survival analyses were performed. RESULTS: In our heterogeneous LAC cohort, we confirmed survival disparities. Asians had the best survival followed by Hispanics, whites, and blacks. For each stage of disease, Asians and Hispanics had better outcomes than whites and blacks. Then, we evaluated the impact of SES on survival within each racial and ethnic group. We observed significantly longer survival for high SES patients compared to middle and low SES patients for all racial/ethnic groups. CONCLUSIONS: While disparities across racial/ethnic groups are well-documented, our study is the first to identify socioeconomic disparities in survival for patients within the same group. These novel findings demonstrate the complex role of SES on race and ethnicity and identify the need to improve healthcare access even within select populations. PMID- 22258869 TI - Intraoperative detection of disappearing colorectal liver metastases as a predictor of residual disease. AB - PURPOSE: The aim of this study was to evaluate the intraoperative detection rate of residual liver metastases after chemotherapy and to assess the correlation between disappeared liver metastases (DLMs) upon preoperative imaging and complete pathological response. METHODS: Between February 2004 and December 2008 clinicopathological data of 292 consecutive patients who underwent liver resection for colorectal liver metastases were prospectively collected and analyzed in a "per lesion" study. Thirty-three patients with 67 DLMs were included. RESULTS: During laparotomy, we identified 45 out of 67 DLMs (67%). Six DLMs were detected by macroscopic liver examination (9%) and 39 (58%) by intraoperative ultrasound (IOUS). Overall, persistent microscopic residual disease at pathological examination of the resected specimen or recurrence in situ identified during the follow-up were observed in 41 (61.2%) of 67 LMs that had shown a complete response by imaging. At multivariate analysis moderate or severe hepatic steatosis (p = 0.016), subglissonian localization of nodules (p = 0.019) and residual microscopic disease (p = 0.0006) were associated with IOUS detection of residual metastases. Preoperative chemotherapy with more than six cycles (p = 0.022) and intraoperative detection of nodules by IOUS (p = 0.001) were independent predictors of residual disease. CONCLUSIONS: Systematic US exploration of the liver leads to increase the intraoperative detection rate of DLMs. Furthermore, the majority of DLMs identified by IOUS presents residual disease at pathological examination and should be treated. PMID- 22258870 TI - Small and potentially resectable focal pancreatic lesions noted on CT/MRI scans in nonjaundiced patients: likelihood of neoplasia and utility of EUS. AB - BACKGROUND: Management of small and potentially resectable "mass" lesions encountered on CT/MRI scans in patients without obstructive jaundice (ObJ) is rather empirical since there is scant data on likelihood of neoplasm to formulate treatment strategies. We evaluated (1) the prevalence of neoplasm and (2) performance characteristics of EUS-FNA for diagnosing neoplasm in above-mentioned subset of patients. PATIENTS: This is a retrospective analysis of 232 patients (without ObJ) with a focal pancreatic lesion, <= 25 mm and potentially resectable on CT/MRI who underwent EUS-FNA from 2002 to 2009. RESULTS: Seventy-five patients (32.3%, 95% CI 26.6, 38.6) were finally diagnosed to have a neoplasm. Four of 92 (4.3%) lesions <= 15 mm, 13 of 57(22.8%) lesions 16-20 mm, and 35 of 83 (42.1%) lesions 21-25 mm had an adenocarcinoma. Larger lesion size, older patient age, and h/o recent weight loss significantly increased the likelihood of adenocarcinoma. EUS-FNA had 98.2% overall accuracy and 98.1% NPV with no significant differences based on lesion size. CONCLUSIONS: In nonjaundiced patient with a potentially resectable pancreatic lesion <=25 mm in size noted on CT/MRI scanning, EUS-FNA can provide useful adjunctive information to optimize the use of surgery and can potentially obviate the need for "wait and watch approach" with repeat imaging in their clinical management. PMID- 22258871 TI - Cyclooxygenase isoenzyme-2 and vascular endothelial growth factor are associated with poor prognosis in esophageal adenocarcinoma. AB - BACKGROUND: Cyclooxygenase isoenzyme-2 (COX-2) and vascular endothelial growth factor (VEGF) contribute to angiogenesis and are overexpressed in various malignancies. The aim of the study was to evaluate expression, prognostic value and correlation between COX-2 and VEGF expression in esophageal adenocarcinoma (EAC). METHODS: Surgical specimens of 154 patients with EAC were used to construct a tissue micro array (TMA). TMA sections were immunohistochemically stained for COX-2 and VEGF and scored on intensity of staining. RESULTS: Estimated 5-year cancer specific survival was 37%. High COX-2 and VEGF expression was observed in 39 (26.5%) and in 77 (53.8%) tumors, respectively. Both markers were associated with poor cancer specific survival (p = .022 and p = .004, respectively, log rank). No significant correlation was found between VEGF and COX-2 expression (r = 063; p = .455). In multivariate analysis, high COX-2 expression (HR 1.65; 95% CI 1.04-2.61; p = .034) was associated with overall survival. In patients with T3 tumors, COX-2 expression was an independent prognostic factor for cancer specific survival (HR 1.81 95% CI 1.10-2.95; p = .019). CONCLUSIONS: This is the first study that evaluated the prognostic value and correlation of COX-2 and VEGF expression in a large and homogenous population of patients with EAC. No correlation between COX-2 and VEGF expression was found. Both markers were expressed in EAC and were associated with poor prognosis. The findings support the use of COX-2 and VEGF inhibitors in future clinical studies. PMID- 22258872 TI - Giant midoesophageal diverticulum--case report and review of the literature. AB - INTRODUCTION: Midoesophageal diverticula >4cm in size are a medical rarity with a dozen reported cases so far. Usually, midoesophageal diverticula tend to be of small size and asymptomatic. CASE REPORT: We herein present a case of a woman suffering from a midoesophageal diverticulum in a very large dimension--never described in the current literature before--who successfully underwent surgical resection via thoracotomy. DISCUSSION: If symptomatic, common symptoms are dysphagia and regurgitation. The risk of malignant transformation is low. Treatment of midoesophageal diverticula is based on size and symptoms of the patient. Asymptomatic or small diverticula detected during routine endoscopy can be followed-up without further therapy, whereas symptomatic or large diverticula should be treated surgically by resection. Myotomy should be performed if any motility disorder is evident. Open as well as minimal invasive approach by thoracoscopical surgery is both feasible. PMID- 22258873 TI - Serous cystadenoma causing the double duct sign. AB - CASE REPORT: An asymptomatic 70-year-old man was found to have elevated liver function tests on a routine screening evaluation. Abdominal ultrasound revealed a pancreatic head mass. Magnetic resonance cholangiopancreatography confirmed a heterogeneously enhancing pancreatic mass that was suspicious for malignancy due to obstruction of the common bile duct and pancreatic duct. Consequently a pylorus-sparing pancreaticoduodenectomy was performed. Histology revealed a serous cystadenoma with scattered foci of PanIN III. DISCUSSION: Serous cystadenomas are benign tumors without significant malignant potential. Unlike pancreatic adenocarcinomas, these tumors tend to be slow growing, well demarcated, and rarely, as in this case, produce a mass effect. PMID- 22258874 TI - Long-term outcome following surgery for colorectal cancers in octogenarians: a single institution's experience of 204 patients. AB - BACKGROUND: The incidence of colorectal cancer in elderly patients is likely to increase with an aging population. The aims of this study are to review our experience in the surgical management of octogenarians with colorectal cancers and to identify factors that influence the short-term and long-term outcomes. METHODS: A retrospective review of all octogenarians who underwent surgery for colorectal cancer from December 2002 to October 2008 was performed. RESULTS: We identified 204 patients with a median age of 84 years (range, 80-97 years). The majority of patients had an American Society of Anesthesiologists score >=3 (n = 142, 69.6%) and a Charlson Comorbidity Index of <=3 (n = 128, 62.7%). Emergency surgery was performed in 83 (40.7%) patients. Left-sided malignancy was seen in 138 patients (67.6%). Most of the patients had either stage II (n = 75, 36.8%) or III (n = 69, 33.8%) diseases. The 30-day mortality rate was 16.2% (n = 33). After multivariate analysis, the independent variables predicting worse perioperative complications and death were age >85 years old, emergency surgery, and Charlson Comorbidity Index >3. The median follow-up for the 171 remaining patients was 27 months (range, 2-92 months). The 30-day readmission rate was 2.9% (n = 5). Thirty one (21.2%) of 146 patients who survived curative surgery developed recurrent disease. Seventy (34.3%) patients died from various etiologies after their first 30 days postoperatively (60% cancer-specific with median survival of 15 months and 40% noncancer-related with median survival of 14 months). Overall and disease free survivals were adversely affected in patients with advanced malignancy and in those with severe perioperative complications. CONCLUSIONS: Surgery for octogenarians with colorectal cancers is associated with significant morbidity and mortality rates which are associated with advanced age, emergency surgery, and Charlson Comorbidity Index >3. Long-term survival is dependent on the stage of the malignancy and the presence of severe perioperative complications. PMID- 22258875 TI - Sarcoid-reaction mimicking metastatic malignant hepatopancreatobiliary tumors: report of two cases and review of the literature. AB - INTRODUCTION: Sarcoidosis is a multisystem chronic granulomatous disease found predominantly in the lungs and lymph nodes. Its pathologic hallmark is the presence of systemic non-caseating granulomas; however, a variation of this disease known as "sarcoid-like reaction" has been described in patients with underlying cancer. REPORT: Sarcoid-like reactions in patients with hepatopancreatobiliary (HPB) tumors are rare findings, with only 15 cases having been reported in the English language literature. These reactions can be found in local lymph nodes or in distant organs, and when present in patients with cancer, they can mimic metastatic disease on imaging, potentially resulting in incorrect cancer staging and management. DISCUSSION: We describe two cases of patients with HPB tumors who had distant organ disease on cross-sectional imaging suspicious for metastases, which on further workup were found to be sarcoid-like reactions. We also discuss malignancy-induced sarcoid-like reactions and provide a review of the literature of sarcoid-like reactions in the setting of HPB tumors. PMID- 22258876 TI - Enteral nutrition reduces delayed gastric emptying after standard pancreaticoduodenectomy with child reconstruction. AB - BACKGROUND: Delayed gastric emptying (DGE) is a common complication following pancreaticoduodenectomy (PD). Our retrospective study aimed to evaluate the influence of enteral nutrition (EN) on DGE incidence after standard PD with antrectomy and Child reconstruction. METHODS: We retrospectively analyzed 275 consecutive patients who underwent standard PD between January 2000 and September 2009. Patients operated on after January 2005 received EN (EN group, n = 152) until total oral alimentation. Patients operated on prior to 2005 did not receive EN (control group, n = 123) and were orally fed after removing the nasogastric tube. Primary endpoint was the incidence of DGE according to the International Study Group of Pancreatic Surgery criteria. Secondary endpoints were the incidence of any other complications. RESULTS: The incidence of DGE was 26% vs. 38% (p = 0.04) in the EN and control groups, respectively, with 17% vs. 19% for grade B DGE (NS) and 9% vs. 19% for grade C DGE (p = 0.02). The differences in DGE did not significantly decrease the duration of stay (18 +/- 11 vs. 19 +/- 13 days; NS). Postpancreatectomy hemorrhage was significantly reduced in the EN group (8% vs. 20%, p = 0.008), with the incidence of postoperative pancreatic fistula being similar in both groups (15% vs. 12%; NS). Using multivariate analysis, EN (p = 0.047, OR = 0.559 [0.315; 0.994]), operative time (p < 0.001, OR = 1.007 [1.003; 1.010]), and patient age (p = 0.014, OR = 1.031 [1.006; 1.057]) were independent factors affecting the incidence of DGE. CONCLUSIONS: EN reduces DGE and postpancreatectomy hemorrhage after PD. PMID- 22258877 TI - Intraductal papillary mucinous neoplasm (IPMN) with extra-pancreatic mucin: a case series and review of the literature. AB - BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized pancreatic neoplasm characterized by excessive mucin secretion by ductal epithelial cells resulting in a cystic dilation of the pancreatic duct. AIM: The objective of this study was to review Thomas Jefferson University's experience and the literature to determine the significance of extra-pancreatic mucin when associated with an IPMN. RESULTS: A retrospective analysis at our institution revealed only two cases of IPMN associated with extra-pancreatic mucin, which were classic IPMNs with rupture of the pancreatic duct and peritoneal mucin spillage. This specific finding is not previously described, although is assumed as five cases were reported in the literature with IPMN and mucin extension demonstrated by pseudomyxoma peritonei (PMP). We propose IPMN of the pancreas may be grossly compared to a mucocele of the appendix, as both are characterized by excessive secretion of mucin by ductal epithelial cells. A morbid complication of a mucocele is PMP. The presence of extra-pancreatic mucin with an IPMN could present a rare but important marker of the eventual seeding of tumor outside the primary IPMN. This has been documented with cases of iatrogenic spilling of pancreatic mucin, as well as multiple cases of IPMN associated with pseudomyxoma peritonei. CONCLUSIONS: At this time, there is scant reporting and consensus for the treatment of IPMN with extra-pancreatic mucin. PMID- 22258878 TI - Extensive mediastinal lymphadenectomy during minimally invasive esophagectomy: optimal results from a single center. AB - INTRODUCTION: Recent advances in thoracoscopic surgery have made it possible to perform esophagectomy with conventional lymphadenectomy (paraesophageal and subcarinal lymph node dissection) using minimally invasive techniques. However, minimally invasive esophagectomy (MIE) combined with extensive lymphadenectomy along the recurrent laryngeal nerves (RLN) has remained technically challenging for thoracic surgeons. The aim of this study was to examine the safety and efficacy of extensive lymphadenectomy when compared to conventional lymphadenectomy during MIE. METHODS: We retrospectively reviewed data from a cohort of 147 consecutive patients who underwent MIE for esophageal cancer (EC) over a 3-year period at our institution. During thoracoscopic esophagectomy, extensive lymphadenectomy along the RLN was performed on 76 patients from June 2009 to December 2010 (group A), while 71 patients underwent conventional lymphadenectomy from June 2008 to May 2009 (group B) and were enrolled as historical controls. Clinical characteristics including patient demographics, operation features, and the rate and type of complications were recorded for both groups. The number of dissected lymph nodes and the number of patients with nodes positive for cancer on histological examination were determined for both groups. Statistical analysis was used to identify differences between the two groups. RESULTS: All patients underwent thoracoscopic esophagectomy without conversion to open thoracotomy. Patient demographics and operation features were similar between the two groups. Of the 76 patients that underwent extensive lymphadenectomy there were 13 patients (17.11%) who were RLN positive, which resulted in upstaging of TNM in 5 patients (6.58%). The overall incidence of postoperative complications (42.10% versus 39.47%, p = 0.742) and permanent recurrent laryngeal nerve palsy (1.32% versus 0%, p = 0.517) was similar between the two groups. CONCLUSIONS: Extensive mediastinal lymphadenectomy during minimally invasive esophagectomy is a feasible procedure for EC patients. It is technically safe and oncologically adequate in experienced hands, and improves the accuracy of tumor staging. Further study is required to discuss its long-term prognostic value for esophagus cancer patients. PMID- 22258879 TI - Robotic anterior RAMPS in well-selected left-sided pancreatic cancer. PMID- 22258881 TI - Testing the psychopathology of psychosis: evidence for a general psychosis dimension. AB - BACKGROUND: Psychiatric taxonomists have sometimes argued for a unitary psychosis syndrome and sometimes for a pentagonal model, including 5 diagnostic constructs of positive symptoms, negative symptoms, cognitive disorganization, mania, and depression. This continues to be debated in preparation for impending revisions of the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases. We aimed to identify general and specific dimensions underlying psychopathological features of psychosis. METHODS: The samples comprised 309 patients admitted to psychiatric services in the acute phase of their first or second episode of psychosis and 507 patients with enduring psychosis recruited from community mental health teams. Patients' symptoms were assessed on the Positive and Negative Symptom Scale. Analyses compared unitary, pentagonal, and bifactor models of psychosis. RESULTS: In both samples, a bifactor model including 1 general psychosis factor and, independently, 5 specific factors of positive symptoms, negative symptoms, disorganization, mania, and depression gave the best fit. Scores of general and specific symptom dimensions were differentially associated with phase of illness, diagnosis, social functioning, insight, and neurocognitive functioning. CONCLUSIONS: The findings provide strong evidence for a general psychosis dimension in both early and enduring psychosis. Findings further allowed for independent formation of specific symptom dimensions. This may inform the current debate about revised classification systems of psychosis. PMID- 22258880 TI - Meta-analysis of histopathological features of primary colorectal cancers that predict lymph node metastases. AB - BACKGROUND: Treatment decisions for colorectal cancer vary based on lymph node status. While some histopathological features of the primary tumor correlate with lymph node spread, the relative influences of these risk factors are not well quantified. OBJECTIVE: This study aims to systematically review published studies relating histopathological features of primary colorectal cancer to the presence of lymph node metastases and to determine how reliable certain factors might be at predicting nodal metastasis when only the primary lesion is available for study. DATA SOURCES: Inclusive literature search using EMBASE and Ovid MEDLINE databases plus manual reference checks of all articles correlating lymphatic spread with colorectal cancer (any T stage) from 1984 to mid-2008 was performed. STUDY SELECTION: This search generated two levels of screening utilized on 602 citations, yielding 123 articles for full review. Data reported from 76 articles were chosen. MAIN OUTCOME MEASURES: The relative influence of each histopathological feature on the likelihood of lymphatic metastases was determined. Fixed-effects meta-analysis was performed, and results were reported as Mantel-Haenszel odds ratios (OR). RESULTS: Of 42 histopathological features analyzed, only 40.4% were reported in >2 articles. The positive predictive values for the top quartile of most frequently reported risk factors were 25.5-86.4%. Among the commonly reported histopathological findings, lymphatic invasion (OR, 8.62) significantly outperformed tumor depth (T2 vs. T1; OR, 2.62) and overall differentiation (OR, 2.38) in predicting nodal spread. For the rectal cancer subset, risk factors differed from the overall colorectal group in predictive ability; poor differentiation at the invasive front (OR, 6.08) and tumor budding (OR, 5.82) were the most predictive. LIMITATIONS: This literature search is limited by the small number of studies examining only rectal cancers and the potential changes in histological and/or surgical techniques over the study period. CONCLUSIONS: No single histopathological feature of colorectal cancer reliably predicted lymph node metastases. Several risk factors that correlate highly with nodal disease are not routine components of standard pathology reports. Until further research establishes histopathological or molecular patterns for predicting lymph node spread, caution should be exercised when basing treatment decisions solely on these factors. PMID- 22258882 TI - Evidence that psychotic symptoms are prevalent in disorders of anxiety and depression, impacting on illness onset, risk, and severity--implications for diagnosis and ultra-high risk research. AB - BACKGROUND: It is commonly assumed that there are clear lines of demarcation between anxiety and depressive disorders on the one hand and psychosis on the other. Recent evidence, however, suggests that this principle may be in need of updating. METHODS: Depressive and/or anxiety disorders, with no previous history of psychotic disorder, were examined for the presence of psychotic symptoms in a representative community sample of adolescents and young adults (Early Developmental Stages of Psychopathology study; n = 3021). Associations and consequences of psychotic symptomatology in the course of these disorders were examined in terms of demographic distribution, illness severity, onset of service use, and risk factors. RESULTS: Around 27% of those with disorders of anxiety and depression displayed one or more psychotic symptoms, vs 14% in those without these disorders (OR 2.23, 95% CI 1.89-2.66, P < .001). Presence as compared with nonpresence of psychotic symptomatology was associated with younger age (P < .0001), male sex (P < .0058), and poorer illness course (P < .0002). In addition, there was greater persistence of schizotypal (P < .0001) and negative symptoms (P < .0170), more observable illness behavior (P < .0001), greater likelihood of service use (P < .0069), as well as more evidence of familial liability for mental illness (P < .0100), exposure to trauma (P < .0150), recent and more distant life events (P < .0006-.0244), cannabis use (P < .0009), and any drug use (P < .0008). CONCLUSION: Copresence of psychotic symptomatology in disorders of anxiety and depression is common and a functionally and etiologically highly relevant feature, reinforcing the view that psychopathology is represented by a network or overlapping and reciprocally impacting dimensional liabilities. PMID- 22258883 TI - Not at issue. PMID- 22258884 TI - Electrophysiological evidence for ventral stream deficits in schizophrenia patients. AB - Schizophrenic patients suffer from many deficits including visual, attentional, and cognitive ones. Visual deficits are of particular interest because they are at the fore-end of information processing and can provide clear examples of interactions between sensory, perceptual, and higher cognitive functions. Visual deficits in schizophrenic patients are often attributed to impairments in the dorsal (where) rather than the ventral (what) stream of visual processing. We used a visual-masking paradigm in which patients and matched controls discriminated small vernier offsets. We analyzed the evoked electroencephalography (EEG) responses and applied distributed electrical source imaging techniques to estimate activity differences between conditions and groups throughout the brain. Compared with controls, patients showed strongly reduced discrimination accuracy, confirming previous work. The behavioral deficits corresponded to pronounced decreases in the evoked EEG response at around 200 ms after stimulus onset. At this latency, patients showed decreased activity for targets in left parietal cortex (dorsal stream), but the decrease was most pronounced in lateral occipital cortex (in the ventral stream). These deficiencies occurred at latencies that reflect object processing and fine shape discriminations. We relate the reduced ventral stream activity to deficient top down processing of target stimuli and provide a framework for relating the commonly observed dorsal stream deficiencies with the currently observed ventral stream deficiencies. PMID- 22258885 TI - A observational study of the efficacy and safety of capecitabine versus bolus infusional 5-fluorouracil in pre-operative chemoradiotherapy for locally advanced rectal cancer. AB - BACKGROUND AND OBJECTIVES: This study is to evaluate the safety and efficacy of preoperative radiotherapy (RT) combined with bolus infusional 5-fluorouracil (5 FU) or oral capecitabine in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Seventy-four patients were retrospectively analyzed. Twenty-seven patients were treated with 5-FU (350 mg/m(2) i.v. bolus) and leucovorin (20 mg/m(2) i.v. bolus) for 5 days/week during week 1 and 5 of RT. Forty-seven patients were treated with capecitabine (850 mg/m(2), twice daily for 5 days/week). Both groups received the same RT course (45-50.4 Gy/25 fractions, 5 days/week, for 5 weeks). Patients underwent surgery in 6 weeks after completion of the chemoradiotherapy. Data of the observational study were collected. RESULTS: Grade 3 or 4 toxicities occurred in 40.7% (5-FU) and 19.1% (capecitabine) of the patients (P = 0.044). Six patients in the 5-FU group (22.2%) and six patients in the capecitabine group (14%) achieved complete response. Primary tumor (T) downstaging were achieved in 51.9% (5-FU) and 69.8% (capecitabine) of the patients. The pathological ypT0-2 stage was 40.7% (5-FU) and 67.4% (capecitabine) (P = 0.028). CONCLUSIONS: In consideration of the better ypT0-2 downstaging rate, less severe toxicities, and no need for indwelling intravenous device on oral capecitabine regimen, the administration of oral capecitabine with RT may be a more favorable option in the neoadjuvant treatment for LARC. PMID- 22258886 TI - Development of a minimally invasive, injectable, shape memory suture and delivery system. AB - Suturing in space-confined surgical settings encountered during microsurgical procedures can be technically complex and time intensive. This paper presents the development of a new injector and new shape-memory alloy clip that can replace conventional suture. Engineering and surgical assessments of the injector and clips were performed. A prototype of the delivery system was tested in simulated surgical settings and compared to conventional suturing techniques for surgical time and wound strength. In various micro-surgical scenarios, the new injectable system proved to be 5 to 20-times more efficient and to have wound strengths over three-times that of conventional suturing. Further, the wounds closed by the shape-memory alloy clips could be forced to open and then recover to a watertight state, unlike conventional sutures which break upon failure. This new injector and shape-memory alloy clips proved to be quicker, stronger, and technically easier than conventional suturing. Future work is underway to test the injectable delivery system and the shape-memory alloy clips using a real-time, in vivo porcine model. PMID- 22258887 TI - Patterning methods for polymers in cell and tissue engineering. AB - Polymers provide a versatile platform for mimicking various aspects of physiological extracellular matrix properties such as chemical composition, rigidity, and topography for use in cell and tissue engineering applications. In this review, we provide a brief overview of patterning methods of various polymers with a particular focus on biocompatibility and processability. The materials highlighted here are widely used polymers including thermally curable polydimethyl siloxane, ultraviolet-curable polyurethane acrylate and polyethylene glycol, thermo-sensitive poly(N-isopropylacrylamide) and thermoplastic and conductive polymers. We also discuss how micro- and nanofabricated polymeric substrates of tunable elastic modulus can be used to engineer cell and tissue structure and function. Such synergistic effect of topography and rigidity of polymers may be able to contribute to constructing more physiologically relevant microenvironment. PMID- 22258889 TI - Relationships between femoral strength evaluated by nonlinear finite element analysis and BMD, material distribution and geometric morphology. AB - Precise quantification of femur strength and accurate assessment of hip fracture risk would help physicians to identify individuals with high risk and encourage them to take preventive interventions. A major contributing factor of hip fracture is the reduction of hip strength, determined by the bone quality. Bone mineral density (BMD) alone cannot determine bone strength accurately. In this paper, subject-specific quantitative computer tomography (QCT) image-based finite element analyses were conducted to identify the quantitative relationships between femoral strength and BMD, material distribution and geometric morphology. Sixty-six subjects with QCT data of hip region were selected from the MrOS cohorts in Hong Kong. Subject-specific nonlinear finite element models were developed to predict strengths of proximal femurs. The models took non-linear elasto-plasticity and heterogeneity of bone tissues into consideration and derived bone strengths with proper bone failure criteria. From finite element analysis (FEA), relationships between femoral strength and BMD, material distribution, and geometric parameters were determined. Results showed that FEA predicted femoral strength was highly correlated with BMD, material distribution, height, weight, diameters of femoral head (HD), and femoral neck (ND), as well as the moment arm for femoral neck bending-offset (OFF). Through principal components analysis, three independent principal components (PCs) were extracted. PC1 was the component of bone material quality. PC2 included height, weight, HD, and ND. PC3 mainly represented OFF. Multivariate linear regression showed that the PCs were strongly predictive of the FEA-predicted strength. This study provided quantitative information regarding the contributing factors of proximal femur strength and showed that such a biomechanical approach may have clinical potential in noninvasive assessment of hip fracture risk. PMID- 22258888 TI - Two-photon and second harmonic microscopy in clinical and translational cancer research. AB - Application of two-photon microscopy (TPM) to translational and clinical cancer research has burgeoned over the last several years, as several avenues of pre clinical research have come to fruition. In this review, we focus on two forms of TPM-two-photon excitation fluorescence microscopy, and second harmonic generation microscopy-as they have been used for investigating cancer pathology in ex vivo and in vivo human tissue. We begin with discussion of two-photon theory and instrumentation particularly as applicable to cancer research, followed by an overview of some of the relevant cancer research literature in areas that include two-photon imaging of human tissue biopsies, human skin in vivo, and the rapidly developing technology of two-photon microendoscopy. We believe these and other evolving two-photon methodologies will continue to help translate cancer research from the bench to the bedside, and ultimately bring minimally invasive methods for cancer diagnosis and treatment to therapeutic reality. PMID- 22258890 TI - Contemporary review: Impact of primary neopharyngoplasty on acoustic characteristics of alaryngeal tracheoesophageal voice. AB - The physiology of the vibratory mechanism in alaryngeal tracheoesophageal speech depends on several factors. The structure and resulting function of the neoglottis (or neopharynx) varies from patient to patient depending on the individual details of the surgical procedure performed, as well as the patient's anatomy. In general, the vibratory segment is a blending of the pharyngeal constrictor muscles, cricopharyngeus, and upper circular fibers of the esophagus. Limited ability to visualize dynamically these three-dimensional structures during rapid events of voice and speech production impedes complete understanding of the vibratory function of the neopharynx. Acoustic studies have elucidated some general characteristics of the pharyngoesophagus and neoglottic vibratory mechanism in the laryngectomized population. A critical degree of tonicity is necessary for apposition of mucosal surfaces in the production of tracheoesophageal voice. Deficiencies in the vibratory segment can usually be managed with various surgical procedures (neopharyngoplasty), resulting in reduced intraesophageal pressure and corresponding increase in fluent, intelligible, effortless speech. The acoustic measures, when correlated with neopharyngoplasty variables, produce many significant associations. Some of them are paramount and deserve further attention. PMID- 22258891 TI - Extracting semantic representations from word co-occurrence statistics: stop lists, stemming, and SVD. AB - In a previous article, we presented a systematic computational study of the extraction of semantic representations from the word-word co-occurrence statistics of large text corpora. The conclusion was that semantic vectors of pointwise mutual information values from very small co-occurrence windows, together with a cosine distance measure, consistently resulted in the best representations across a range of psychologically relevant semantic tasks. This article extends that study by investigating the use of three further factors- namely, the application of stop-lists, word stemming, and dimensionality reduction using singular value decomposition (SVD)--that have been used to provide improved performance elsewhere. It also introduces an additional semantic task and explores the advantages of using a much larger corpus. This leads to the discovery and analysis of improved SVD-based methods for generating semantic representations (that provide new state-of-the-art performance on a standard TOEFL task) and the identification and discussion of problems and misleading results that can arise without a full systematic study. PMID- 22258892 TI - Role of cell cycle-associated proteins in microglial proliferation in the axotomized rat facial nucleus. AB - We analyzed cell cycle-associated proteins, including cyclins, cyclin-dependent protein kinases (Cdks), and Cdk inhibitors (CdkIs) in the axotomized rat facial nucleus. Immunoblotting revealed that cyclin A and cyclin D are induced 3-5 days after transection. The induced cyclin A was immunohistochemically recognized in microglia. Cdk2 and Cdk4 were also detected in the facial nucleus. The CdkI p21 was elevated 5 days after axotomy. Inhibition experiments in vitro using a cFms (receptor for macrophage-colony stimulating factor, M-CSF) inhibitor indicated that M-CSF-cFms signaling leads to upregulation of the levels of cyclin A, cyclin D, proliferating cell nuclear antigen (PCNA), and cFms in microglia. The role of cyclin A/Cdk2 activity in M-CSF-dependent microglial proliferation was ascertained using the specific inhibitor purvalanol A. Experiments using specific mitogen-activated protein kinase inhibitors suggested that c-Jun N-terminal kinase (JNK) is associated with M-CSF-dependent induction of cyclins and PCNA, whereas p38 is associated with cFms induction. Both JNK and p38 were proved to be phosphorylated by stimulation with M-CSF. Our results indicated that cyclin A, cyclin D, Cdk2, Cdk4, and p21 are involved in microglial proliferation in the transected facial nucleus, and that the M-CSF-dependent upregulations of cyclins/PCNA and cFms in microglia are differentially regulated by JNK and p38. PMID- 22258893 TI - The historical foundations of the research-practice distinction in bioethics. AB - The distinction between clinical research and clinical practice directs how we partition medicine and biomedical science. Reasons for a sharp distinction date historically to the work of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, especially to its analysis of the "boundaries" between research and practice in the Belmont Report (1978). Belmont presents a segregation model of the research-practice distinction, according to which research and practice form conceptually exclusive sets of activities and interventions. This model is still the standard in federal regulations today. However, the Commission's deliberations and conclusions about the boundaries are more complicated, nuanced, and instructive than has generally been appreciated. The National Commission did not conclude that practice needs no oversight comparable to the regulation of research. It debated the matter and inclined to the view that the oversight of practice needed to be upgraded, though the Commission stopped short of proposing new regulations for its oversight, largely for prudential political reasons. PMID- 22258894 TI - Periodic eyelid opening associated with burst-suppression electroencephalography due to hypoxic ischemic injury. AB - BACKGROUND: We report four patients who developed periodic eyelid opening following hypoxic ischemic injury. This manuscript reviews the clinical course of our patients as well as previously published cases and discusses the neuroanatomical basis of eyelid opening. METHODS: Data were collected from the patients' electronic medical record and digital electroencephalography recordings. RESULTS: In all patients, periodic eyelid opening was associated with a burst-suppression pattern on electroencephalography (EEG). Rapid eyelid opening appeared with the onset of bursts, while slow eyelid closure coincided with periods of suppression. Progressive rostrocaudal deterioration in brainstem function ensued, in each case culminating in brain death. CONCLUSIONS: Our experience and prior reports suggest that periodic eyelid opening following cardiac arrest is associated with a burst-suppression pattern on EEG. Since burst suppression is highly (though not invariably) predictive of a poor outcome in this patient population, intensivists should be familiar with this neurological sign. Prospective studies are needed to define the neurophysiology of this phenomena and clarify its clinical significance. PMID- 22258895 TI - Targeting angiogenesis as treatment for obesity. PMID- 22258896 TI - Humanizing the problem of transplant vasculopathy. PMID- 22258897 TI - Endothelial-to-mesenchymal transition and microRNA-21: the game is on again. PMID- 22258898 TI - Intraplaque hemorrhage: an imaging marker for atherosclerotic plaque destabilization? PMID- 22258899 TI - Life after GWAS: functional genomics in vascular biology. PMID- 22258900 TI - Strategies beyond genome-wide association studies for atherosclerosis. AB - Atherosclerotic diseases, including coronary artery disease (CAD) and myocardial infarction (MI), are the leading causes of death in the world. The genetic basis of CAD and MI, which are caused by multiple interacting endogenous and exogenous factors, has gained considerable interest in the last years as genome-wide association studies (GWASs) have identified many new susceptibility loci for CAD and MI, and the underlying genes provide new insights into the genetic architecture of these diseases. Here we summarize the recent findings from GWASs of atherosclerosis and discuss their functional and biological implications. We also discuss the different post-GWAS strategies that are currently used for refining the location of causal variants, understanding their role, and shedding light on molecular mechanisms explaining their association to CAD. We finally discuss potential clinical translations of GWAS findings for individual risk prediction, advanced clinical strategies, and personalized treatments. PMID- 22258901 TI - The use of high-throughput technologies to investigate vascular inflammation and atherosclerosis. AB - The greatest challenge of scientific research is to understand the causes and consequences of disease. In recent years, great efforts have been devoted to unraveling the basic mechanisms of atherosclerosis (the underlying pathology of cardiovascular disease), which remains a major cause of morbidity and mortality worldwide. Because of the complex and multifactorial pathophysiology of cardiovascular disease, different research techniques have increasingly been combined to unravel genetic aspects, molecular pathways, and cellular functions involved in atherogenesis, vascular inflammation, and dyslipidemia to gain a multifaceted picture addressing this complexity. Thanks to the rapid evolution of high-throughput technologies, we are now able to generate large-scale data on the DNA, RNA, and protein levels. With the help of sophisticated computational tools, these data sets are integrated to enhance information extraction and are being increasingly used in a systems biology approach to model biological processes as interconnected and regulated networks. This review exemplifies the use of high throughput technologies-such as genomics, transcriptomics, proteomics, and epigenomics-and systems biology to explore pathomechanisms of vascular inflammation and atherosclerosis. PMID- 22258902 TI - Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. AB - The chromosome 9p21 (Chr9p21) locus was discovered in 2007 by independent genome wide association studies for coronary artery disease. Since then, the locus has been replicated numerous times and can be considered the most robust genetic marker of coronary artery disease today. Subsequent work has shown associations of Chr9p21 with a number of additional cardiovascular disease traits, such as carotid artery plaque, stroke, aneurysms, peripheral artery disease, heart failure, and cardiovascular mortality, suggesting a more general role in vascular pathology. Importantly, Chr9p21 lacks associations with common cardiovascular risk factors, such as lipids and hypertension, indicating that the locus exerts its effect through a completely novel mechanism. One of the challenges is that the core haplotype block at Chr9p21 resides in a region of the genome devoid of protein-coding genes. Recent progress has been made by functional studies focusing on differential expression of antisense noncoding RNA in the INK4 locus (ANRIL), which is transcribed from the Chr9p21 locus, as well as neighboring protein-coding genes at the INK4/ARF locus. The emerging concept suggests that ANRIL might constitute a regulator of epigenetic modification and thus modulate cardiovascular risk. Here, we review the current clinical, mechanistic, and diagnostic implications of the Chr9p21 locus in cardiovascular disease. PMID- 22258903 TI - Beyond genome-wide association studies: the usefulness of mouse genetics in understanding the complex etiology of atherosclerosis. AB - The development of population-based genome-wide association studies has led to the rapid identification of large numbers of genetic variants associated with coronary artery disease (CAD) and related traits. Together with large-scale gene centric studies, at least 35 loci associated with CAD per se have been identified with replication. The majority of these associations are with common single nucleotide polymorphisms exhibiting modest effects on relative risk. The modest nature of the effects, coupled with ethical/practical constraints associated with human sampling, makes it difficult to answer important questions beyond gene/locus localization and allele frequency via human genetic studies. Questions related to gene function, disease-causing mechanism(s), and effective interventions will likely require studies in model organisms. The use of the mouse model for further detailed studies of CAD-associated loci identified by genome-wide association studies is highlighted herein. PMID- 22258904 TI - Use of functional genomics to identify candidate genes underlying human genetic association studies of vascular diseases. AB - Recent genome-wide association studies have identified hundreds of genetic loci as being associated with vascular diseases or traits and their risk factors. Many of the loci uncovered represent novel discoveries with no obvious candidate genes and molecular mechanisms, testifying to the complexity of vascular diseases. To understand the functional consequences of genetic variations and help pinpoint the underlying genes and mechanisms of common complex diseases, functional genomics that integrate genetic variations and intermediate molecular traits such as gene expression has been extensively studied in the past few years. This review summarizes the key concepts of functional genomics, the current state of the field, and its application in vascular diseases. PMID- 22258905 TI - Mechanisms of the inhibition of nuclear factor-kappaB by morphine in neuronal cells. AB - Opioids potently modulate neuronal functions, for example, by regulating the activity of transcription factors. Here, we investigated the effect of morphine on the activity of the transcription factor nuclear factor kappaB (NF-kappaB). Establishing cellular models for our investigations, we demonstrated that NF kappaB mediated the tumor necrosis factor (TNF)-induced transcription of the cannabinoid receptor type 1 gene in primary fetal striatal neurons from rats and the human neuroblastoma cell line SH SY5Y. The activity of NF-kappaB in these models was strongly inhibited by morphine, which was achieved by a marked up regulation of the inhibitor of nuclear factor-kappaB (IkappaB). The opioid induced up-regulation of IkappaB was dependent on the transcription factors NF kappaB itself and activator protein-1 (AP-1). In fact, stimulation of the cells with morphine resulted in a transient activation of NF-kappaB and a strong induction of c-Fos, one of the constituents of AP-1. This resulted in IkappaB levels significantly exceeding the basal, constitutive levels of IkappaB. These data, together with experiments in which AP-1 and IkappaB were down-regulated by decoy oligonucleotides and siRNA, suggest that the morphine-induced activation of AP-1 and the subsequent overexpression of IkappaB are key factors in the inhibition of NF-kappaB by the drug. In contrast, stimulation of primary neurons from rats and SH SY5Y cells with TNF, which is a classic activator of NF-kappaB, resulted in a resynthesis of IkappaB, in which the basal levels of IkappaB were restored only but did not result in an activation of AP-1 and overexpression of IkappaB. PMID- 22258906 TI - The effect of regular colchicine treatment on biomarkers related with vascular injury in newly diagnosed patients with familial Mediterranean fever. AB - We aimed to evaluate some of the vascular biomarkers in newly diagnosed, colchicine naive familial Mediterranean fever (FMF) patients. Our primary aim was to investigate the effect of regular colchicine treatment on these variables. Twenty-four (12 males [M] and 12 females [F], 33.3 +/- 13.4 years) newly diagnosed FMF patients were included in the study. These patients were started on colchicine treatment following the initial assessment and were studied again no earlier than 2 months. Five patients were lost to follow-up, and assessment of the on-treatment patients was performed on the remaining 19 patients (8 M and 11 F, 33.6 +/- 11.8 years). There were 19 healthy subjects (11 M and 8 F, 32.2 +/- 7.2 years) who served as a control group. Cellular adhesion molecules (CAMs; soluble intercellular adhesion molecule-1 [sICAM-1] and soluble CD146 [sCD146]), plasminogen activator inhibitor-1 (PAI-1), fetuin-A and hs-CRP were studied. Examinations were performed on attack-free periods. The levels of hs-CRP, fetuin A, sICAM-1, and PAI-1 were significantly higher in newly diagnosed patients compared to those of controls (P < 0.05). All studied parameters were significantly downregulated after regular colchicine therapy (P < 0.05). Comparison of on-treatment data with controls showed that the levels of the vascular biomarkers, except sCD146, were similar between the groups (P > 0.05). On-treatment sCD146 was found significantly lower than the controls (P < 0.05). In regression analysis, none of the independent variables in the model significantly predicted the vascular biomarkers (P > 0.05). Administration of therapeutic doses of colchicine markedly reduces vascular injury parameters and normalizes the values in FMF. PMID- 22258907 TI - [Use of Q-sort assessment methods for diagnostic purposes and in treatment evaluation?]. AB - OBJECTIVES: Does quantifying psychotherapy research do justice to its subject matter? METHODS: Q-sort techniques are presented for the assessment of personality pathology, mental and interpersonal problems, as well as for quantifying the psychotherapeutic process. RESULTS: In studies on psychotherapy planning we identified mechanisms characteristic of nonresponders which could be efficiently captured with q-sort methods. From these clinically relevant intervention techniques can be derived. In psychoanalytic process research we operationalized relevant microelements in the patient-therapist interaction. CONCLUSIONS: Q-sort methods are efficient and helpful for studying research questions that are clinically relevant but often difficult to grasp as well as for dismantling studies. PMID- 22258908 TI - [Unresolved attachment and remembered childhood trauma in patients undergoing psychosomatic inpatient treatment]. AB - OBJECTIVE: Clinical populations are characterised by a high level of childhood trauma and unresolved attachment status ("U"). Unresolved attachment status indicates the inability to integrate attachment-related dangers. Little is known about the interaction of traumatic childhood experiences and an unresolved attachment status. METHOD: We administered the Adult Attachment Projective Picture System (AAP) to 45 newly admitted psychosomatic inpatients. Childhood trauma (CTQ) and distress were assessed by self-report questionnaires, and cognitive-emotional development was evaluated with the Levels of Emotional Awareness Scale (LEAS).We explored whether unresolved (U) and resolved (R) attachment status differentiated the sample with regard to childhood trauma, distress and cognitive-emotional development. RESULTS: 53 % of the sample was characterized by the attachment status U; physical abuse and neglect as well as emotional neglect were correlated with a diminished ability to integrate trauma indicators in the AAP. A resolved attachment status was related to higher LEAS scores. CONCLUSION: The level of cognitive-emotional development may mediate the actual integration of attachment-related dangers and the interaction between actual attachment-related anxiety and past traumatic experiences. PMID- 22258909 TI - [Better patient orientation through certified cancer centres in oncological care? Patient satisfaction in breast cancer patients in certified breast cancer centres and noncertified hospitals]. AB - OBJECTIVES: We investigated whether patient satisfaction (including its subdimensions) among breast cancer patients depends on the place of the treatment (certified breast cancer centre vs. noncertified clinics). Furthermore, we examined the impact of patient- and disease-related factors on patient satisfaction. METHODS: 652 breast cancer patients (n = 480 from certified breast cancer centres and n = 172 from noncertified clinics) took part in the study after their hospital stay and completed a questionnaire. Data on patient satisfaction (Hamburger Fragebogen zum Krankenhausaufenthalt, HFK), psychological distress (HADS), as well as sociodemographic and disease-related characteristics were collected. RESULTS: Regardless of the place of cancer treatment, breast cancer patients reported a high level of satisfaction. There was only one significant difference between the two patient groups in the subdimension "overall judgement" (breast centre: 1.28 vs. noncertified clinic: 1.19; p = 0.017). In the multivariate analysis, the place of treatment had less explanatory power on patient satisfaction than other factors such as psychological distress. CONCLUSIONS: In this study, there were only few differences in patient satisfaction between the two investigated groups of breast cancer patients. This result is discussed in the context of various moderating factors. PMID- 22258910 TI - [The assessment of therapy success after radical prostatectomy]. AB - OBJECTIVES: Patient satisfaction plays an important role in the outcome quality of treatment for localized prostate carcinoma. This paper identifies factors that impact patients' assessment of therapy success one year after surgery. METHODS: Patient assessment of therapy success was measured with the Hamburger Fragebogen zum Krankenhausaufenthalt (Lecher et al. 2002). Also, several sociodemographic, clinical and quality-of-life factors were tested for their impact on the patient assessment of therapy success. RESULTS: 25 % of patients gave a negative assessment of therapy success. Factors with the strongest impact were urinary incontinence, sexual impotence, younger age and higher risk of recidive. CONCLUSIONS: Especially the prevention of urinary continence and sexual dysfunction may lead to a better assessment of therapy. Moreover, the patients' expectations have a great impact on the assessment of therapy success. PMID- 22258911 TI - [Chief expert opinion in psychodynamic therapy - a contribution on ensuring quality in standardized German psychotherapy. Findings from the MARS-Project]. AB - RESEARCH QUESTION: The study investigates the factors that have a bearing on the development of a chief expert opinion in standardized German psychotherapy (psychodynamic therapies). METHODOLOGY: As part of the MARS project a documentation system was developed to record the sociodemographic, clinical and biographical data of the patients as well as data relating to the therapists and the evaluation of the experts, all of which are contained in the therapist's reports. In a comparison of n = 153 chief expert opinions with n = 291 opinions relating to the control group under the normal process, differences occurred between the two groups with respect to the data on both patients and therapists. Moreover, the system records the frequency with which the individual experts contribute to the initiation of a chief expert opinion over a period of 3 years. RESULTS: Proceedings based on chief expert opinions are initiated with patients who have severe psychopathologies and marginal prognostic prospects. Reservations expressed by the experts refer in particular to the psychodynamics described and the foreseen treatment planning. The qualification and gender of the therapists are certainly an issue for chief expert opinions. The experts themselves contribute with varying degrees to the initiation of an expert opinion. DISCUSSION: While the role of patients and therapists in the realization of a chief expert opinion comes as no surprise and is in fact testimony to the quality assurance function of the process, considerable differences have emerged in the handling and approach adopted by the experts themselves. Calls for a better coordination process on the part of the experts should not go unheeded. PMID- 22258912 TI - [Conception and evaluation of an 1-hour psychoeducational group intervention for patients with chronic pruritus]. AB - OBJECTIVE: This study investigated whether dermatology inpatients with chronic pruritus benefit from an 1-hour psychoeducational group therapy, adapted from educational programmes for patients with atopic dermatitis. Such a symptom specific intervention for patients with chronic pruritus has not been evaluated before. METHOD: 91 of the 315 group participants (28.9 %) and 175 of the 318 patients who had been admitted to the hospital without group therapy (55.0 %) were examined at admission and discharge using standardised questionnaires (Adjustment to Chronic Skin Diseases Questionnaire, Itch-Cognition Questionnaire) and a Visual Analogue Scale for itch intensity (randomized pre-post study). RESULT: Evaluation of the standardised questionnaires and of the change in pruritus intensity indicated no additive benefit of group intervention, both for the whole sample and for subgroups with chronic pruritus. DISCUSSION: The results indicate either that group intervention in this form is not effective or that the dermatological medical treatment of the patients is so efficient that the intervention brings no added benefit. Perhaps an intervention of 1 hour is simply too short. Further conceptual developments of the psychoeducational programme are necessary. PMID- 22258913 TI - [Adverse childhood experiences and their association to personality styles in a nonmelancholic depressive sample]. AB - QUESTIONS: Do some life story patterns exist, which are associated with depression? Can some life story factors be identified, which influence or determine a special kind of personality, predisposing to depression? METHODS: Retrospective, cross sectional study with nonexperimental character, using a number of 60 nonmelancholic depressed patients. First, they were asked to give an interview on their life story. Then, they were asked to fill in questionnaires about personality, parental style of raising, clinical symptoms and personality disorders. RESULTS: Significant correlations could be found between parental style of raising, a family history affected by depression, a dysfunctional household, the family composition, negative school experience and all investigated styles of personality. Further, clusters of personality, clusters of parental style of raising and clusters of specific life story factors could be detected. DISCUSSION: Results show a strong relation between life story factors and personality styles, predisposing to depression and emphasize the importance of considering personality, when exploring special life story factors. Vice versa, actual personality styles can point to different patterns of life story and thus, show the relevance for the diagnostic and therapeutic process. PMID- 22258915 TI - Principal component analysis of cerebellar shape on MRI separates SCA types 2 and 6 into two archetypal modes of degeneration. AB - Although "cerebellar ataxia" is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes. PMID- 22258914 TI - Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. AB - The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits. PMID- 22258916 TI - Symptomatic and palliative care for stroke survivors. AB - Stroke is the leading cause of disability and one of the most common causes of death worldwide. Outside the setting of acute management, secondary prevention and stroke rehabilitation, little has been written to address the ongoing symptomatic and palliative needs of these patients and their families. In this literature review, we look beyond secondary prevention with the aim of providing evidence-informed management guidelines for the myriad and often under-recognized symptomatic and palliative care needs of stroke survivors. Some of the most common and disabling post-stroke symptoms that are reviewed here include central post-stroke pain, hemiplegic shoulder pain, painful spasticity, fatigue, incontinence, post-stroke seizures, sexual dysfunction, sleep-disordered breathing, depression and emotionalism. We review the role of caregivers and explore ways to support them and, lastly, remind the reader to be perceptive to the patient's spiritual needs. The literature is most robust, including controlled trials, for central post-stroke pain and depression. Synthesis and discussion outside these areas are frequently limited to smaller studies, case reports and expert opinion. While some data exists to guide informed decision making, there is an urgent need to document best practice and identify appropriate clinical standards for the full spectrum of symptoms experienced by stroke survivors. We present the current and established data to aid health care providers in symptomatic and palliative management of stroke survivors. PMID- 22258918 TI - The placebo phenomenon: implications for the ethics of shared decision-making. AB - Recent research into the placebo effect has implications for the ethics of shared decision-making (SDM). The older biomedical model views SDM as affecting which therapy is chosen, but not the nature or likelihood of any health outcomes produced by the therapy. Research indicates, however, that both the content and manner in which information is shared with the patient, and the patient's experience of being involved in the decision, can directly alter therapeutic outcomes via placebo responses. An ethical tension is thereby created between SDM aimed strictly and solely at conveying accurate information, and "outcome engineering" in which SDM is adapted toward therapeutic goals. Several practical strategies mitigate this tension and promote respect for autonomous decision making while still utilizing the therapeutic potential of SDM. PMID- 22258920 TI - Investigation of Enterobacteriaceae isolates found to have a raised meropenem MIC by Vitek 2. PMID- 22258919 TI - From the editors' desk: it's the social determinants, stupid. PMID- 22258922 TI - Validation of novel fluorescence assays for the routine screening of drug susceptibilities of Trichomonas vaginalis. AB - OBJECTIVES: To evaluate existing protocols, based on Alamar blue (resazurin), for the routine determination of drug susceptibility in trichomonads, develop new ones and validate these by screening small antiprotozoal libraries. METHODS: The resazurin-based assay was evaluated by determining fluorescence development in Trichomonas media with various cell densities after various intervals and in the presence of metronidazole. Similar investigations were performed with the alternative fluorophores propidium iodide (PI) and resorufin. The optimized protocols were used to screen for new antitrichomonal compounds. RESULTS: Anaerobic cultures of Trichomonas vaginalis rapidly reduced blue resazurin to red, fluorescent resorufin. However, the ascorbic acid in the culture medium produced similar effects, even in the absence of cells, causing high background fluorescence and variability. Moreover, T. vaginalis rapidly metabolized resorufin to the non-fluorescent and colourless metabolite dihydroresorufin, making the fluorescent signal transient. In contrast, resorufin proved to be an excellent viability probe for Trichomonas due to its chemical stability in media and rapid metabolism by the parasite. We also show that staining with PI after cell permeabilization similarly constitutes a reliable measurement of trophozoite numbers. Using the PI and resorufin assays we determined reproducible EC(50) values and identified potent antitrichomonal compounds from a limited screen of phosphodiesterase inhibitors and phosphonium salts. CONCLUSIONS: The resorufin- and PI-based assays are suitable for routine and high-throughput drug screening, whereas resazurin-based assays are not. These assays constitute a major advance in the current protocols as demonstrated by a successful screen for new antitrichomonal lead compounds. PMID- 22258923 TI - SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro. AB - OBJECTIVES: To investigate in vitro interaction between two compounds, SQ109 and PNU-100480, currently in development for the treatment of Mycobacterium tuberculosis (MTB). METHODS: The two-drug interactions between SQ109 and PNU 100480 and its major metabolite PNU-101603 were assessed by chequerboard titration, and the rate of killing and intracellular activity were determined in both J774A.1 mouse macrophages and whole blood culture. RESULTS: In chequerboard titration, interactions between SQ109 and either oxazolidinone were additive. In time-kill studies, SQ109 killed MTB faster than PNU compounds, and its rate of killing was further enhanced by both oxazolidinones. The order of efficacy of single compounds against intracellular MTB was SQ109 > PNU-100480 > PNU-101603. At sub-MIC, combinations of SQ109 + PNU compounds showed improved intracellular activity over individual drugs; at >=MIC, the order of efficacy was SQ109 > SQ109 + PNU-100480 > SQ109 + PNU-101603. In whole blood culture, the combined bactericidal activities of SQ109 and PNU-100480 and its major metabolite against intracellular M. tuberculosis did not differ significantly from the sum of the compounds tested individually. CONCLUSIONS: SQ109 and PNU combinations were additive and improved the rate of MTB killing over individual drugs. These data suggest that the drugs may work together cooperatively to eliminate MTB in vivo. PMID- 22258921 TI - Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor. AB - BACKGROUND: Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs. METHODS: We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load >= 400 copies/mL after previous suppression <400 copies/mL, or failure to achieve <400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008-after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm. RESULTS: Three thousand and fifty-six patients were followed for a median (IQR) of 14 (6-30) months, of whom 811 (27%) experienced virological failure. Of these, resistance test results were available on 291 (36%). One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44%), tipranavir (26, 81%) and darunavir (27, 84%). CONCLUSIONS: This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotype-phenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs. PMID- 22258924 TI - The carbon source influences the efflux pump-mediated antimicrobial resistance in clinically important Gram-negative bacteria. AB - OBJECTIVES: Multidrug efflux pumps are proteins known to play an important role in resistance in bacteria. These proteins are located in the inner membrane (IM), together with many other proteins, including inducible permeases that participate in the uptake of non-phosphotransferase system (PTS) carbohydrates (i.e. carbohydrates uptaken by mechanisms other than the PTS). However, lipid bilayer space in the IM is limited. Therefore, we examined whether the overexpression of unrelated IM proteins is able to interfere with the efflux-mediated resistance mechanism, consequently increasing the susceptibility towards different antimicrobial compounds. METHODS: We cultured bacteria under different conditions that increase the synthesis of unrelated IM proteins, either by using a non-PTS carbohydrate as the sole carbon source or by artificially overexpressing IM proteins, prior to determining the resistance to different antimicrobial compounds by disc diffusion assays. RESULTS: We observed that efflux-pump mediated resistance is affected by the carbon source in all the strains tested, exhibiting increased susceptibility when a non-PTS carbohydrate was used as the sole carbon source. Moreover, when we artificially overexpressed an unrelated IM protein, we also observed decreased efflux-mediated resistance. CONCLUSIONS: These results strongly suggest that overexpression of IM proteins, by using a non PTS carbohydrate as the sole carbon source, or by artificially introducing a high number of copies of an unrelated IM protein, competes with the antibiotic efflux systems, thereby decreasing the efflux-mediated resistance to different antimicrobial compounds. This sort of competition arises because of the limited available space in the bacterial IM, or by an unknown mechanism. PMID- 22258925 TI - Clonal diversity and biofilm-forming ability of methicillin-resistant Staphylococcus pseudintermedius. AB - OBJECTIVES: The aim of this study was to investigate the clonal epidemiology of methicillin-resistant Staphylococcus pseudintermedius (MRSP) isolates from dogs in Norway and to evaluate the antimicrobial resistance patterns and determine the biofilm-forming abilities of the isolates. METHODS: All MRSP index isolates from each MRSP-positive dog detected in Norway until June 2011 were included (n = 23). The MICs of antimicrobial agents were determined by the VetMICTM microdilution method. The genetic relationship between the isolates was investigated by multilocus sequence typing (MLST) and PFGE. The isolates' abilities to form biofilm on polystyrene were studied. RESULTS: The MRSP isolates investigated grouped into 11 different sequence types (STs); MRSP ST106 occurred most frequently. There were a relatively smaller number of isolates belonging to ST71, the largely predominant ST in Europe. Isolates belonging to ST71 had a significantly greater ability to produce biofilm compared with the other isolates, and especially compared with MRSP ST106. CONCLUSIONS: A heterogeneous clonal distribution was observed among MRSP from dogs in Norway. As opposed to previous findings in Europe, MRSP clones other than ST71 have spread in Norway, such as MRSP ST106. The results also show that MRSP ST71 is possibly a good biofilm producer, and this may in turn be a contributing factor to the nosocomial character of MRSP ST71. PMID- 22258926 TI - In vitro activity of tigecycline against multidrug-resistant Gram-negative blood culture isolates from critically ill patients. PMID- 22258927 TI - Genomic analysis uncovers a phenotypically diverse but genetically homogeneous Escherichia coli ST131 clone circulating in unrelated urinary tract infections. AB - OBJECTIVES: To determine variation at the genome level in Escherichia coli ST131 clinical isolates previously shown to be phenotypically diverse. METHODS: The genomes of 10 ST131 isolates extensively characterized in previous studies were sequenced using combinations of Illumina and 454 sequencing technology. Whole genome comparisons and phylogenetic comparisons were then performed across the strain set and with other closely related extraintestinal pathogenic E. coli (ExPEC) strain types. RESULTS: E. coli ST131 is overrepresented in a collection of clinical isolates, and there is large phenotypic variation amongst isolates. In contrast, genome sequencing of a selection of non-related clinical isolates shows almost no genetic variation between ST131 strains, and E. coli ST131 shows evidence of a genetically monomorphic pathogen showing a similar evolutionary trend to hypervirulent Clostridium difficile. CONCLUSIONS: A dominant circulating clone of E. coli ST131 has been identified in unrelated clinical urine samples in the UK. The clone splits into two distinct subgroups on the basis of antimicrobial resistance levels and carriage of extended-spectrum beta-lactamase plasmids. This provides the most comprehensive snapshot to date of the true molecular epidemiology of ST131 clinical isolates. PMID- 22258928 TI - Point prevalence survey of antibiotic use in French hospitals in 2009. AB - OBJECTIVES: To evaluate the feasibility of a point prevalence survey for monitoring antibiotic use in a voluntary sample of French hospitals. METHODS: Demographic and medical data were collected for all inpatients. Additional characteristics regarding antimicrobial treatment, type of infection and microbiological results were collected only for patients receiving antimicrobials. RESULTS: Among 3964 patients in 38 hospitals, 343 (8.7%) received antimicrobial prophylaxis and 1276 (32.2%) antimicrobial therapy. The duration of surgical antimicrobial prophylaxis was >1 day in 41 out of 200 (21%) of the cases. Among patients with antimicrobial therapy, 959 (75.2%) received beta lactams (including 34.8% penicillins with beta-lactam inhibitors, 22.1% third generation cephalosporins and 7.8% carbapenems) and 301 (23.6%) received fluoroquinolones (50% orally). A total of 518 (40.6%) patients were treated with more than one drug and 345 (27.2%) were treated for >7 days. Patients treated for hospital-acquired infections (39.2%) were more likely to receive combinations (47.6% versus 34.4%, P < 0.01), carbapenems (14.4% versus 2.6%, P < 0.01), glycopeptides (14.4% versus 3.7%, P < 0.01) and antifungals (17% versus 5.3%, P < 0.01) for a longer duration (7.8 versus 6 days, P < 0.01). Fifty-six patients (4.4%) were treated for >7 days and did not have any microbiological sample drawn. The time allocated for the survey represented 18.3-25.0 h for 100 patients. CONCLUSIONS: The data provide directions for further interventions, such as better use of diagnostic tools, decreasing the treatment duration and the use of combinations. In addition, the survey shows that, although cumbersome, it is feasible to improve the representativeness of national data in European surveys. PMID- 22258929 TI - Antiviral applications of Toll-like receptor agonists. AB - In the past, antiviral research has focused mainly on viral targets. As the search for effective and differentiated antiviral therapies continues, cellular targets are becoming more common, bringing with them a variety of challenges and concerns. Toll-like receptors (TLRs) provide a unique mechanism to induce an antiviral state in the host. In this review we introduce TLRs as targets for the pharmaceutical industry, including how they signal and thereby induce an antiviral state through the production of type I interferons. We examine how TLRs are being therapeutically targeted and discuss several clinically precedented agents for which efficacy and safety data are available. We describe some of the chemistries that have been applied to both small molecule and large molecule leads to tune agonist potency, and offer a differentiated safety profile through targeting certain compartments such as the gut or the lung, thereby limiting systemic drug exposure and affecting systemic cytokine levels. The application of low-dose agonists of TLRs as vaccine adjuvants or immunoprotective agents is also presented. Some of the challenges presented by this approach are then discussed, including viral evasion strategies and mechanism-linked inflammatory cytokine induction. PMID- 22258930 TI - Asiaticoside induces tumour-necrosis-factor-alpha-mediated nitric oxide production to cure experimental visceral leishmaniasis caused by antimony susceptible and -resistant Leishmania donovani strains. AB - OBJECTIVES: The aim of this study was to investigate and characterize the efficacy of asiaticoside in an experimental model of visceral leishmaniasis caused by antimony-susceptible (AG83) and -resistant (GE1F8R and K39) Leishmania donovani. METHODS: The effect of asiaticoside was evaluated by microscopic counting of intracellular amastigotes in cultured macrophages stained with Giemsa. The antileishmanial effect of the compounds was assessed in infected BALB/c mice by estimation of splenic and liver parasite burdens in Leishman Donovan units. Cytokines were measured by real-time PCR and ELISA. Intracellular tumour necrosis factor-alpha (TNF-alpha) was measured by fluorescence-activated cell sorting. Nitric oxide was measured by the Griess reaction. RESULTS: Besides effectively inhibiting in vitro replication of the parasite within macrophages, asiaticoside treatment resulted in almost complete clearance of the liver and splenic parasite burden when administered at a dose of 5 mg/kg * 10 starting on day +30 of challenge with antimony-susceptible (AG83) and -resistant (GE1F8R and K39) L. donovani. Asiaticoside treatment was associated with a switch in the host from a Th2- to a Th1-type immune response accompanied by the induction of TNF alpha-mediated nitric oxide production, all of which are important elements for macrophage function in antileishmanial defence mechanisms. CONCLUSIONS: These results suggest that oral therapy with asiaticoside shows promising antileishmanial efficacy in animals infected by antimony-susceptible (AG83) and resistant (GE1F8R and K39) L. donovani. PMID- 22258931 TI - In vitro efficacy of fosfomycin-containing regimens against methicillin-resistant Staphylococcus aureus in biofilms. AB - OBJECTIVES: To compare the in vitro antibacterial efficacy of antistaphylococcal antibiotics in combination with fosfomycin or rifampicin, using a biofilm model. METHODS: The antibacterial activities of fusidic acid, linezolid, vancomycin, teicoplanin, rifampicin, minocycline, fosfomycin and tigecycline, individually and in fosfomycin or rifampicin combinations, were measured against planktonic or biofilm-embedded methicillin-resistant Staphylococcus aureus (MRSA) with susceptible and resistant breakpoint concentrations (SBCs and RBCs, respectively), using the MTT-staining method and by counting the number of cfu in the biofilms. RESULTS: Linezolid alone at its SBC, and fosfomycin, linezolid, minocycline and tigecycline at their RBCs, exhibited killing effects on biofilm embedded MRSA (P < 0.0001). Of the eight fosfomycin combinations studied, fosfomycin combined with linezolid, minocycline, vancomycin or teicoplanin at their respective SBCs, exhibited enhanced antibacterial activities (P < 0.0001) when compared with the control group, and outperformed rifampicin combinations (P < 0.01). The killing effects of fosfomycin combinations at their respective RBCs were better than those at their respective SBCs (P < 0.05). Significantly enhanced killing effects were observed with fosfomycin in combination with vancomycin or teicoplanin, compared with vancomycin or teicoplanin alone. For 10 randomly selected MRSA isolates, the results of colony counting in biofilms were comparable with those of the MTT-staining method. CONCLUSIONS: Fosfomycin enhanced the activities of linezolid, minocycline, vancomycin and teicoplanin. These combinatorial treatments were even better than rifampicin combination regimens, and may provide therapeutic advantages in catheter-related or prosthetic joint infections. PMID- 22258932 TI - Naturally occurring hepatitis C virus (HCV) NS3/4A protease inhibitor resistance related mutations in HCV genotype 1-infected subjects in Italy. AB - OBJECTIVES: To assess the prevalence of hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) resistance mutations in HCV genotype 1-infected PI-naive individuals in Italy. PATIENTS AND METHODS: One hundred and twelve patients infected with HCV genotype 1a or 1b (based on Versant HCV Genotype 2.0 or 5'UTR/core sequencing) and never treated with any HCV PI were evaluated. The whole NS3 region was analysed by population sequencing and mutations related to resistance to linear and macrocyclic PIs were recorded. RESULTS: Forty-six HCV monoinfected and 66 HCV/HIV-coinfected subjects were studied. Complete NS3 sequence information was obtained for 109 (97.3%) samples: 67 subtype 1a and 42 subtype 1b. Subtype assignment by NS3 sequencing was concordant in 100.0% and 83.9% of cases with the original 5'UTR sequencing and Versant result, respectively. At least one mutation related to PI resistance was detected in 21 (19.3%) isolates. However, 11 of these had only Q80K, expected to confer resistance to one investigational macrocyclic compound, and were detected only in subtype 1a. Boceprevir and telaprevir resistance-related mutations were detected in 10 (9.2%) isolates and included V36L, T54S and V55A. Only one isolate harboured two mutations (V36L and T54S). There was no association between HCV PI resistance and HIV coinfection or exposure to HIV PIs. CONCLUSIONS: A minority of untreated HCV genotype 1 patients in Italy harbour a virus population carrying HCV PI resistance-related mutations. The clinical implications of this finding warrant further analysis. PMID- 22258933 TI - Sharps exposures among otolaryngology-head and neck surgery residents. AB - OBJECTIVES/HYPOTHESIS: Examine the incidence of sharps exposures among otolaryngology residents, assess characteristics of exposures, and determine rates of reporting these potentially career- and life-impacting exposures. STUDY DESIGN: Cohort study of otolaryngology-head and neck surgery residents. METHODS: Survey was administered online to otolaryngology residents in the spring of 2008, gathering demographic information, characteristics of sharps exposures, and residents' self-reporting of sharps exposures. RESULTS: Among 1,407 otolaryngology residents nationwide, 231 completed the survey. Of these, 168 (72.7%) had at least one sharps exposure during residency, with most due to solid bore needles (51.7%) and occurring in the operating room (67%). Fifty percent of residents reported exposures occurring in postgraduate year (PGY)-3 or PGY-4, whereas exposures occurred at slightly lower rates in the other PGYs. There was no difference in incidence of sharps exposures based on gender (Fisher exact test, P = .2742) or history of sharps exposure during medical school (Fisher exact test, P = .7559). Seventy-four participants had an exposure that they did not report to the hospital, with the most common reason for not reporting being the perceived burden of the hospital testing protocol. CONCLUSIONS: Otolaryngology residents report a high rate of sharps exposures during residency training, with a significant number of these exposures going unreported. Better education may be needed to help decrease these often preventable workplace exposures and to improve compliance with reporting and testing procedures. PMID- 22258934 TI - Formate generated by cellular oxidation of formaldehyde accelerates the glycolytic flux in cultured astrocytes. AB - Formaldehyde is a neurotoxic compound that can be endogenously generated in the brain. Because astrocytes play a key role in metabolism and detoxification processes in brain, we have investigated the capacity of these cells to metabolize formaldehyde using primary astrocyte-rich cultures as a model system. Application of formaldehyde to these cultures resulted in the appearance of formate in cells and in a time-, concentration- and temperature-dependent disappearance of formaldehyde from the medium that was accompanied by a matching extracellular accumulation of formate. This formaldehyde-oxidizing capacity of astrocyte cultures is likely to be catalyzed by alcohol dehydrogenase 3 and aldehyde dehydrogenase 2, because the cells of the cultures contain the mRNAs of these formaldehyde-oxidizing enzymes. In addition, exposure to formaldehyde increased both glucose consumption and lactate production by the cells. Both the strong increase in the cellular formate content and the increase in glycolytic flux were only observed after application of formaldehyde to the cells, but not after treatment with exogenous methanol or formate. The accelerated lactate production was not additive to that obtained for azide, a known inhibitor of complex IV of the respiratory chain, and persisted after removal of formaldehyde after a formaldehyde exposure for 1.5 h. These data demonstrate that cultured astrocytes efficiently oxidize formaldehyde to formate, which subsequently enhances glycolytic flux, most likely by inhibition of mitochondrial respiration. PMID- 22258935 TI - Erythropoietin-coated ZP-microneedle transdermal system: preclinical formulation, stability, and delivery. AB - PURPOSE: To evaluate the feasibility of coating formulated recombinant human erythropoietin alfa (EPO) on a titanium microneedle transdermal delivery system, ZP-EPO, and assess preclinical patch delivery performance. METHODS: Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. EPO liquid formulation was coated onto titanium microneedles by dip coating and drying. Stability of coated EPO was assessed by SEC-HPLC, CZE and potency assay. Preclinical in vivo delivery and pharmacokinetic studies were conducted in rats with EPO-coated microneedle patches and compared to subcutaneous EPO injection. RESULTS: Studies demonstrated successful EPO formulation development and coating on microneedle arrays. ZP-EPO patch was stable at 25 degrees C for at least 3 months with no significant change in % aggregates, isoforms, or potency. Preclinical studies in rats showed the ZP-EPO microneedle patches, coated with 750 IU to 22,000 IU, delivered with high efficiency (75-90%) with a linear dose response. PK profile was similar to subcutaneous injection of commercial EPO. CONCLUSIONS: Results suggest transdermal microneedle patch delivery of EPO is feasible and may offer an efficient, dose-adjustable, patient-friendly alternative to current intravenous or subcutaneous routes of administration. PMID- 22258937 TI - Hypermethylation of SHP-1 promoter in patient with high-risk myelodysplastic syndrome and it predicts poor prognosis. AB - To study the role of SHP-1 methylation in the pathogenesis of myelodysplastic syndromes (MDS), we detect the methylation status of SHP-1 promoter and STAT3 phosphorylation of MDS patients by the methylation-specific PCR and Western blotting, respectively. It is found that the methylation rate of SHP-1 promoter of high-risk MDS patients (69.2%) was higher than that of the low-risk MDS patients (21.4%) (P=0.001). The expression rate of STAT3 phosphorylated protein of high-risk group was higher (66.7%), when compared with that of the low-risk group (18.2%) (P=0.0001). Correlation analysis showed that the methylation status of SHP-1 promoter is positive correlated with the expression of phosphorylated STAT3 in MDS patient (P<0.001, r=0.55). Interestingly, in high-risk group, the Kaplan-Meier analysis showed that the 3-year overall survival rate of high-risk MDS patients with SHP-1 methylation was lower than that of patient without SHP-1 methylation (25% vs. 61%) (P=0.033). In summary, it is indicated that the SHP-1 methylation plays important role in the pathogenesis of MDS via activating the JAK/STAT pathway probably and the methylation of SHP-1 promoter is a useful prognostic factor for high-risk MDS patient, with the characteristic of higher methylation lower survival rate. PMID- 22258938 TI - Implications for Research: Getting the Most out of Cochrane Reviews. PMID- 22258939 TI - Amnioinfusion for potential or suspected umbilical cord compression in labour. AB - BACKGROUND: Amnioinfusion aims to prevent or relieve umbilical cord compression during labour by infusing a solution into the uterine cavity. OBJECTIVES: To assess the effects of amnioinfusion for potential or suspected umbilical cord compression on maternal and perinatal outcome . SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2011). SELECTION CRITERIA: Randomised trials of amnioinfusion compared with no amnioinfusion in women with babies at risk of umbilical cord compression in labour. DATA COLLECTION AND ANALYSIS: The original review had one author only (Justus Hofmeyr (GJH)). For this update, two authors (GJH and T Lawrie) assessed 13 additional trial reports for eligibility and quality. We extracted data and checked for accuracy. MAIN RESULTS: We have included 19 studies, with all but two studies having fewer than 200 participants. Transcervical amnioinfusion for potential or suspected umbilical cord compression was associated with the following reductions: caesarean section overall (13 trials, 1493 participants; average risk ratio (RR) 0.62, 95% confidence interval (CI) 0.46 to 0.83); fetal heart rate (FHR) decelerations (seven trials, 1006 participants; average RR 0.53, 95% CI 0.38 to 0.74); Apgar score less than seven at five minutes (12 trials, 1804 participants; average RR 0.47, 95% CI 0.30 to 0.72); meconium below the vocal cords (three trials, 674 participants, RR 0.53, 95% CI 0.31 to 0.92); postpartum endometritis (six trials, 767 participants; RR 0.45, 95% CI 0.25 to 0.81) and maternal hospital stay greater than three days (four trials, 1051 participants; average RR 0.45, 95% CI 0.25 to 0.78). Transabdominal amnioinfusion showed similar trends, though numbers studied were small.Mean cord umbilical artery pH was higher in the amnioinfusion group (seven trials, 855 participants; average mean difference 0.03, 95% CI 0.00 to 0.06) and there was a trend toward fewer neonates with a low cord arterial pH (less than 7.2 or as defined by trial authors) in the amnioinfusion group (eight trials, 972 participants, average RR 0.58, 95% CI 0.29 to 1.14). AUTHORS' CONCLUSIONS: The use of amnioinfusion for potential or suspected umbilical cord compression may be of considerable benefit to mother and baby by reducing the occurrence of variable FHR decelerations, improving short-term measures of neonatal outcome, reducing maternal postpartum endometritis and lowering the use of caesarean section, although there were methodological limitations to the trials reviewed here. In addition, the trials are too small to address the possibility of rare but serious maternal adverse effects of amnioinfusion. More research is needed to confirm the findings, assess longer-term measures of fetal outcome, and to assess the impact on caesarean section rates when the diagnosis of fetal distress is more stringent. Trials should assess amnioinfusion in specific clinical situations, such as FHR decelerations, oligohydramnios or prelabour rupture of membranes. PMID- 22258940 TI - Interventions for helping to turn term breech babies to head first presentation when using external cephalic version. AB - BACKGROUND: Breech presentation is associated with increased complications. Turning a breech baby to head first presentation using external cephalic version (ECV) attempts to reduce the chances of breech presentation at birth, and reduce the adverse effects of breech vaginal birth or caesarean section. Tocolytic drugs and other methods have been used in an attempt to facilitate ECV. OBJECTIVES: To assess interventions such as tocolysis, fetal acoustic stimulation, regional analgesia, transabdominal amnioinfusion or systemic opioids on ECV for a breech baby at term. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2011) and the reference lists of identified studies. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing the above interventions with no intervention or other methods to facilitate ECV at term. DATA COLLECTION AND ANALYSIS: We assessed eligibility and trial quality. Two review authors independently assessed for inclusion all potential studies identified as a result of the search strategy and independently extracted the data using a designed data extraction form. MAIN RESULTS: We included 25 studies, providing data on 2548 women. We used the random-effects model for pooling data due to clinical heterogeneity in the included studies in the various comparisons. The overall quality of the evidence was reasonable, but a number of assessments had insufficient data to provide an answer with any degree of assurance.Tocolytic drugs, in particular betastimulants, were effective in increasing cephalic presentations in labour (average risk ratio (RR) 1.38, 95% confidence interval (CI) 1.03 to 1.85, eight studies, 993 women) and in reducing the number of caesarean sections (average RR 0.82, 95% CI 0.71 to 0.94, eight studies, 1177 women). No differences were identified in fetal bradycardias (average RR 0.95, 95% CI 0.48 to 1.89, three studies, 467 women) although the review is underpowered for assessing this outcome. We identified no difference in success, cephalic presentation in labour and caesarean sections between nulliparous and multiparous women. There were insufficient data comparing different groups of tocolytic drugs. Sensitivity analyses by study quality agreed with the overall findings.Regional analgesia in combination with a tocolytic was more effective than the tocolytic alone in terms of increasing successful versions (assessed by the rate of failed ECVs, average RR 0.67, 95% CI 0.51 to 0.89, six studies, 550 women) but there was no difference identified in cephalic presentation in labour (average RR 1.63, 95% CI 0.75 to 3.53, three studies, 279 women) nor in caesarean sections (average RR 0.74, 95% CI 0.40 to 1.37, three studies, 279 women) or fetal bradycardia (average RR 1.48, 95% CI 0.62 to 3.57, two studies, 210 women).There were insufficient data on the use of vibroacoustic stimulation, amnioinfusion or systemic opioids. AUTHORS' CONCLUSIONS: Betastimulants, to facilitate ECV, increased cephalic presentation in labour and birth, and reduced the caesarean section rate in both nulliparous and multiparous women, but there were insufficient data on adverse effects. Calcium channel blockers and nitric acid donors had insufficient data to provide good evidence. At present we recommend betamimetics for facilitating ECV.There is scope for further research. The possible benefits of tocolysis to reduce the force required for successful version and the possible risks of maternal cardiovascular side effects, need to be addressed further. Further trials are needed to compare the effectiveness of routine versus selective use of tocolysis, the role of regional analgesia, fetal acoustic stimulation, amnioinfusion and the effect of intravenous or oral hydration prior to ECV.Although randomised trials of nitroglycerine are small, the results are sufficiently negative to discourage further trials. PMID- 22258941 TI - Life skills programmes for chronic mental illnesses. AB - BACKGROUND: Most people with schizophrenia have a cyclical pattern of illness characterised by remission and relapses. The illness can reduce the ability of self-care and functioning and can lead to the illness becoming disabling. Life skills programmes, emphasising the needs associated with independent functioning, are often a part of the rehabilitation process. These programmes have been developed to enhance independent living and quality of life for people with schizophrenia. OBJECTIVES: To review the effects of life skills programmes compared with standard care or other comparable therapies for people with chronic mental health problems. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (June 2010). We supplemented this process with handsearching and scrutiny of references. We inspected references of all included studies for further trials. SELECTION CRITERIA: We included all relevant randomised or quasi-randomised controlled trials for life skills programmes versus other comparable therapies or standard care involving people with serious mental illnesses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random effects model. MAIN RESULTS: We included seven randomised controlled trials with a total of 483 participants. These evaluated life skills programmes versus standard care, or support group. We found no significant difference in life skills performance between people given life skills training and standard care (1 RCT, n = 32, MD -1.10; 95% CI -7.82 to 5.62). Life skills training did not improve or worsen study retention (5 RCTs, n = 345, RR 1.16; 95% CI 0.40 to 3.36). We found no significant difference in PANSS positive, negative or total scores between life skills intervention and standard care. We found quality of life scores to be equivocal between participants given life skills training (1 RCT, n = 32, MD -0.02; 95% CI -0.07 to 0.03) and standard care. Life skills compared with support groups also did not reveal any significant differences in PANSS scores, quality of life, or social performance skills (1 RCT, n = 158, MD 0.90; 95% CI -3.39 to 1.59). AUTHORS' CONCLUSIONS: Currently there is no good evidence to suggest life skills programmes are effective for people with chronic mental illnesses. More robust data are needed from studies that are adequately powered to determine whether life skills training is beneficial for people with chronic mental health problems. PMID- 22258942 TI - WITHDRAWN: Services for helping acute stroke patients avoid hospital admission. AB - BACKGROUND: Stroke patients are usually admitted to hospital for their acute care and rehabilitation. Services to help acute stroke patients avoid admission to hospital ('hospital-at-home') have now been developed. OBJECTIVES: To establish the costs and effects of such services compared with conventional services. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register in March 1999 and supplemented this through discussion with colleagues and trialists. SELECTION CRITERIA: Controlled clinical trials recruiting stroke patients who have not been admitted to hospital and compare (1) services which provided support with an aim of helping prevent admission to hospital with (20 conventional services (which could include hospital admission). DATA COLLECTION AND ANALYSIS: Two independent review authors determined the eligibility and methodological quality of trials. Trialists were then contacted to obtain standardised descriptive and outcome data. MAIN RESULTS: Four trials are included in the review, of which three currently have outcome data available (921 patients; 857 from one controlled trial, 64 from two randomised trials). There were no statistically significant differences between the patient and carer outcomes of the intervention and control groups either within individual trials or in pooled analyses. There was a trend toward greater hospital bed use and increased costs in the intervention groups. AUTHORS' CONCLUSIONS: There is currently no evidence from clinical trials to support a radical shift in the care of acute stroke patients from hospital-based care. PMID- 22258943 TI - Steroids for acute spinal cord injury. AB - BACKGROUND: Acute spinal cord injury is a devastating condition typically affecting young people, mostly males. Steroid treatment in the early hours after the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life. OBJECTIVES: To review randomized trials of steroids for human acute spinal cord injury. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register (searched 02 Aug 2011), The Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library), MEDLINE (Ovid) 1948 to July Week 3 2011, EMBASE (Ovid) 1974 to 2011 week 17, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011, ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011 and PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 Aug 2011) for records added to PubMed in the last 90 days). Files of the National Acute Spinal Cord Injury Study (NASCIS) were reviewed (NASCIS was founded in 1977 and has tracked trials in this area since that date). We also searched the reference lists of relevant studies and previously published reviews. SELECTION CRITERIA: All randomized controlled trials of steroid treatment for acute spinal cord injury in any language. DATA COLLECTION AND ANALYSIS: One review author extracted data from trial reports. Japanese and French studies were found through NASCIS and additional data (e.g. SDs) were obtained from the original study authors. MAIN RESULTS: Eight trials are included in this review, seven used methylprednisolone. Methylprednisolone sodium succinate has been shown to improve neurologic outcome up to one year post-injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial results were replicated in a Japanese trial but not in the one from France. Data was obtained from the latter studies to permit appropriate meta-analysis of all three trials. This indicated significant recovery in motor function after methylprednisolone therapy, when administration commenced within eight hours of injury. A more recent trial indicates that, if methylprednisolone therapy is given for an additional 24 hours (a total of 48 hours), additional improvement in motor neurologic function and functional status are observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries. A modified regimen was found to improve recovery after surgery for lumbar disc disease. The risk of bias was low in the largest methyprednisolne trials. Overall, there was no evidence of significantly increased complications or mortality from the 23 or 48 hour therapy. AUTHORS' CONCLUSIONS: High-dose methylprednisolone steroid therapy is the only pharmacologic therapy shown to have efficacy in a phase three randomized trial when administered within eight hours of injury. One trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours, if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacologic therapy for acute spinal cord injury. PMID- 22258944 TI - WITHDRAWN: Antibiotic prophylaxis regimens and drugs for cesarean section. AB - BACKGROUND: Prophylactic antibiotics for cesarean section have been shown to reduce the incidence of maternal postoperative infectious morbidity. Many different antibiotic regimens have been reported to be effective. OBJECTIVES: The objective of this review was to determine which antibiotic regimen is most effective in reducing the incidence of infectious morbidity in women undergoing cesarean section. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register. The date of the most recent search was October 1998. SELECTION CRITERIA: Randomized trials that included women undergoing cesarean section were included. Trials were required to compare at least two different antibiotic regimens. Trials that compared placebo with a single antibiotic regimen were not included as these are studies which have been analyzed in another Cochrane review. DATA COLLECTION AND ANALYSIS: Data were extracted from each publication independently by the reviewers. Reviewers were not blinded to the authors or sources of the articles. The primary outcome variable was endometritis but data on other infectious complications were collected where provided. MAIN RESULTS: Fifty-one trials published between 1979 and 1994 were included in the review and four were excluded from the review. The following results refer to reductions in the incidence of endometritis. Both ampicillin and first generation cephalosporins have similar efficacy with an odds ratio (OR) of 1.27 (95% confidence interval (CI): 0.84-1.93). In comparing ampicillin with second or third generation cephalosporins the odds ratio was 0.83 (95% CI 0.54-1.26) and in comparing a first generation cephalosporin with a second or third generation agent the odds ratio was 1.21 (95% CI 0.97-1.51). A multiple dose regimen for prophylaxis appears to offer no added benefit over a single dose regimen; OR 0.92 (95% CI 0.70-1.23). Systemic and lavage routes of administration appear to have no difference in effect; OR 1.19 (95% CI 0.81-1.73). There was no significant heterogeneity between the trials contained in the various sub-group analyses, although confidence intervals were sometimes wide. AUTHORS' CONCLUSIONS: Both ampicillin and first generation cephalosporins have similar efficacy in reducing postoperative endometritis. There does not appear to be added benefit in utilizing a more broad spectrum agent or a multiple dose regimen. There is a need for an appropriately designed randomized trial to test the optimal timing of administration (immediately after the cord is clamped versus pre-operative). PMID- 22258945 TI - Surgery for nonarteritic anterior ischemic optic neuropathy. AB - BACKGROUND: Nonarteritic ischemic optic neuropathy (NAION) is characterized by sudden and painless loss of vision in the eye, accompanied by pallid swelling of the optic disc. Its etiology is unknown and no medical therapy has been proven effective in treating this condition. Optic nerve decompression surgery, a proposed treatment for NAION, involves making two or more slits or a window in the tissue surrounding the optic nerve, thereby allowing cerebrospinal fluid to escape, and theoretically reducing the pressure surrounding the optic nerve. OBJECTIVES: The objective of this review was to assess the safety and efficacy of surgery compared with other treatment or no treatment in people with nonarteritic ischemic optic neuropathy. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 11), MEDLINE (January 1950 to November 2011), EMBASE (January 1980 to November 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (http://clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 19 November 2011. SELECTION CRITERIA: All randomized trials of surgical treatment of NAION were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: We obtained full copies of all potentially relevant articles. One author extracted data which was verified by another author. No data synthesis was required. MAIN RESULTS: The one included trial randomized 258 participants and was stopped early for futility. At the time of the 24-month report the follow-up rate was 95.3% for six months and 67.4% for 24 months (174 participants; 89 careful follow up and 85 surgery). There was no evidence of a benefit of surgery on visual acuity. Measurements of visual acuity and visual fields were performed by a technician masked to the treatment received. At six months 32.0% of the surgery group had improved visual acuity by three or more lines compared with 42.6% of the careful follow up group (unadjusted relative risk (RR) 0.75, 95% confidence interval (CI) 0.54 to 1.04). At 24 months 29.4% of the surgery group had improved compared with 31.0% of the careful follow up group (unadjusted RR 0.95, 95% CI 0.60 to 1.49). Participants who underwent surgery had a greater risk of losing three or more lines of vision, although the increased risk was not statistically significant. At six months 18.9% in the surgery group had worsened compared with 14.8% in the careful follow up group (RR 1.28; 95% CI 0.73 to 2.24). At 24 months 20.0% in the surgery group had worsened compared with 21.8% in the careful follow up group (RR 0.92; 95% CI 0.51 to 1.64). Participants who received surgery experienced both intraoperative and postoperative adverse events, including central retinal artery occlusion during surgery and light perception vision at six months (one participant); and immediate loss of light perception following surgery and loss of vision that persisted to the 12-month visit (two participants). In the careful follow-up group, two participants had no light perception at the six-month follow-up visit; one of these had improved to light perception at 12 months. Pain was the most common adverse event in the surgery group (17% in surgery group versus 3% in the careful follow-up group at one week). Diplopia (double-vision) was the next most common complication (8% in the surgery group versus 1% in the careful follow-up group at one week); at three months there was no statistically significant difference in proportion of participants with diplopia between the two groups. AUTHORS' CONCLUSIONS: Results from the single trial indicate no evidence of a beneficial effect of optic nerve decompression surgery for NAION. Future research should focus on increasing our understanding of the etiology and prognosis of NAION. New treatment options should be examined in the context of randomized clinical trials. PMID- 22258946 TI - Conservative management for postprostatectomy urinary incontinence. AB - BACKGROUND: Urinary incontinence is common after both radical prostatectomy and transurethral resection of the prostate (TURP). Conservative management includes pelvic floor muscle training with or without biofeedback, electrical stimulation, extra-corporeal magnetic innervation (ExMI), compression devices (penile clamps), lifestyle changes, or a combination of methods. OBJECTIVES: To assess the effects of conservative management for urinary incontinence after prostatectomy. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 24 August 2011), EMBASE (January 1980 to Week 48 2009), CINAHL (January 1982 to 20 November 2009), the reference lists of relevant articles, handsearched conference proceedings and contacted investigators to locate studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials evaluating conservative interventions for urinary continence in men after prostatectomy. DATA COLLECTION AND ANALYSIS: Two or more review authors assessed the methodological quality of trials and abstracted data. We tried to contact several authors of included studies to obtain extra information. MAIN RESULTS: Thirty seven trials met the inclusion criteria, 33 amongst men after radical prostatectomy, three trials after transurethral resection of the prostate (TURP) and one trial after either operation. The trials included 3399 men, of whom 1937 had an active conservative intervention. There was considerable variation in the interventions, populations and outcome measures. Data were not available for many of the pre-stated outcomes. Men's symptoms improved over time irrespective of management. Adverse effects did not occur or were not reported.There was no evidence from eight trials that pelvic floor muscle training with or without biofeedback was better than control for men who had urinary incontinence after radical prostatectomy (e.g. 57% with urinary incontinence versus 62% in the control group, risk ratio (RR) for incontinence after 12 months 0.85, 95% confidence interval (CI) 0.60 to 1.22) as the confidence intervals were wide, reflecting uncertainty. However, one large multicentre trial of one-to-one therapy showed no difference in any urinary or quality of life outcome measures and had narrower confidence intervals. There was also no evidence of benefit for erectile dysfunction (56% with no erection in the pelvic floor muscle training group versus 55% in the control group after one year, RR 1.01, 95% CI 0.84 to 1.20). Individual small trials provided data to suggest that electrical stimulation, external magnetic innervation or combinations of treatments might be beneficial but the evidence was limited. One large trial demonstrated that there was no benefit for incontinence or erectile dysfunction from a one-to-one pelvic floor muscle training based intervention to men who were incontinent after transurethral resection of the prostate (TURP) (e.g. 65% with urinary incontinence versus 62% in the control group, RR after 12 months 1.05, 95% CI 0.91 to 1.23).In eight trials of conservative treatment of all men after radical prostatectomy aimed at both treatment and prevention, there was an overall benefit from pelvic floor muscle training versus control management in terms of reduction of UI (e.g. 10% with urinary incontinence after one year versus 32% in the control groups, RR for urinary incontinence 0.32, 95% CI 0.20 to 0.51). However, this finding was not supported by other data from pad tests. The findings should be treated with caution, as most trials were of poor to moderate quality and confidence intervals were wide. Men in one trial were more satisfied with one type of external compression device, which had the lowest urine loss, compared to two others or no treatment. The effect of other conservative interventions such as lifestyle changes remains undetermined as no trials involving these interventions were identified. AUTHORS' CONCLUSIONS: The value of the various approaches to conservative management of postprostatectomy incontinence after radical prostatectomy remains uncertain. It seems unlikely that men benefit from one-to-one pelvic floor muscle training therapy after transurethral resection of the prostate (TURP). Long-term incontinence may be managed by external penile clamp, but there are safety problems. PMID- 22258947 TI - WITHDRAWN: Extended versus limited lymph nodes dissection technique for adenocarcinoma of the stomach. AB - BACKGROUND: Surgeons disagree about the merits and risks of radical lymph node clearance during gastrectomy for cancer. OBJECTIVES: To evaluate survival and peri-operative mortality after limited or extended lymph node removal during gastrectomy for cancer. SEARCH METHODS: We searched MEDLINE, EMBASE, CancerLit, LILACS, Central Medical Journal Japanese Database and the Cochrane register, references from relevant articles and conference proceedings. We contacted known workers in the field. For the updated review, the Cochrane Library, M EDLINE , E MBASE and LILACS were searched from 2001 to April 2009. SELECTION CRITERIA: Studies published after 1970 which reported 5 year survival or postoperative mortality rates, and clearly defined the node dissection performed, were considered. We excluded studies which overtly included patients receiving perioperative chemotherapy, and comparisons with clear systematic treatment allocation bias. Randomised controlled trials (RCTs), non-randomised comparisons and observational studies were considered separately. DATA COLLECTION AND ANALYSIS: Three reviewers selected trials for inclusion. Quality assessment and data extraction were performed independently by two reviewers. Results of trials of similar design were pooled. Meta-analysis was performed separately for randomised and non-randomised comparisons. MAIN RESULTS: Two randomised and two non-randomised comparisons of limited (D1) versus extended (D2) node dissection and 11 cohort studies of either D1 or D2 resection were analysed. Meta-analysis of randomised trials did not reveal any survival benefit for extended lymph node dissection (Risk ratio = 0.95 (95% CI 0.83 - 1.09), but showed increased postoperative mortality (RR 2.23, 95% CI 1.45 - 3.45). Pre-specified subgroup analysis suggested a possible benefit in stage T3+ tumours (RR = 0.68, 95% CI 0.42-1.10). Non-randomised comparisons showed no significant survival benefit for extended dissection (RR 0.92, 95% CI 0.83 -1.02), but decreased mortality (RR 0.65, 95% CI 0.45-0.93). Subgroup analysis showed apparent benefit in UICC stage II and IIIa. Observational studies of D2 resection reported much better mortality and survival than those of D1 surgery, but the settings were strikingly different. AUTHORS' CONCLUSIONS: D2 dissection carries increased mortality risks associated with spleen and pancreas resection, and probably with inexperience and low case volumes. Randomised studies show no evidence of overall survival benefit, but possible benefit in T3+ tumours. These results may be confounded by surgical learning curves and poor surgeon compliance. Non-randomised comparisons suggest a possible survival benefit for D2 in intermediate UICC stages. Observational studies show high 5 year survival and low operative mortality after D2 dissection in experienced units, and poor results after D1 dissection in non specialist units. Further studies, with precautions to eliminate learning curve effects, contamination and non-compliance, are needed to evaluate D2 dissection in intermediate stage gastric cancer. PMID- 22258948 TI - Exercise interventions for smoking cessation. AB - BACKGROUND: Taking regular exercise may help people give up smoking by moderating nicotine withdrawal and cravings, and by helping to manage weight gain. OBJECTIVES: To determine whether exercise-based interventions alone, or combined with a smoking cessation programme, are more effective than a smoking cessation intervention alone. SEARCH METHODS: In July 2011, we searched the Cochrane Tobacco Addiction Group Specialized Register for studies including the terms 'exercise' or 'physical activity'. We also searched MEDLINE, EMBASE, PsycINFO, Dissertation Abstracts and CINAHL using the terms 'exercise' or 'physical activity' and 'smoking cessation'. SELECTION CRITERIA: We included randomized trials which compared an exercise programme alone, or an exercise programme as an adjunct to a cessation programme, with a cessation programme, recruiting smokers or recent quitters, and with a follow up of six months or more. DATA COLLECTION AND ANALYSIS: We extracted data on study characteristics and smoking outcomes. Because of differences in studies we summarized the results narratively, making no attempt at meta-analysis. MAIN RESULTS: We identified 15 trials, seven of which had fewer than 25 people in each treatment arm. They varied in the timing and intensity of the smoking cessation and exercise programmes. Three studies showed significantly higher abstinence rates in a physically active group versus a control group at end of treatment. One of these studies also showed a significant benefit for exercise versus control on abstinence at the three-month follow up and a benefit for exercise of borderline significance (p = 0.05) at the 12-month follow up. One study showed significantly higher abstinence rates for the exercise group versus a control group at the three-month follow up but not at the end of treatment or 12-month follow up. The other studies showed no significant effect for exercise on abstinence. AUTHORS' CONCLUSIONS: Only one of the 15 trials offered evidence for exercise aiding smoking cessation at a 12 month follow up. All the other trials were too small to reliably exclude an effect of intervention, or included an exercise intervention which was insufficiently intense to achieve the desired level of exercise. Trials are needed with larger sample sizes, sufficiently intense interventions, equal contact control conditions, and measures of exercise adherence and change in physical activity in both exercise and comparison groups. PMID- 22258949 TI - Neuraminidase inhibitors for preventing and treating influenza in children. AB - BACKGROUND: During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed. OBJECTIVES: To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza in children. SEARCH METHODS: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1) which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January week 2, 2011) and EMBASE (January 2010 to January 2011). SELECTION CRITERIA: Double-blind, randomised controlled trials (RCTs) comparing neuraminidase inhibitors with placebo or other antiviral drugs in children aged up to and including 12 years. We also included safety and tolerability data from other types of studies. DATA COLLECTION AND ANALYSIS: Four review authors selected studies, assessed study quality and extracted data for the current and previous versions of this review. We analysed data separately for oseltamivir versus placebo, zanamivir versus placebo and laninamivir octanoate versus oseltamivir. MAIN RESULTS: Six treatment trials involving 1906 children with clinical influenza and 450 children with influenza diagnosed on rapid near patient influenza testing were included. Of these 2356 children, 1255 had laboratory-confirmed influenza. Three prophylaxis trials involving 863 children exposed to influenza were also included. In children with laboratory-confirmed influenza oseltamivir reduced median duration of illness by 36 hours (26%, P < 0.001). One trial of oseltamivir in children with asthma who had laboratory confirmed influenza showed only a small reduction in illness duration (10.4 hours, 8%), which was not statistically significant (P = 0.542). Laninamivir octanoate 20 mg reduced symptom duration by 2.8 days (60%, P < 0.001) in children with oseltamivir-resistant influenza A/H1N1. Zanamivir reduced median duration of illness by 1.3 days (24%, P < 0.001). Oseltamivir significantly reduced acute otitis media in children aged one to five years with laboratory-confirmed influenza (risk difference (RD) -0.14, 95% confidence interval (CI) -0.24 to 0.04). Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in developing influenza after the introduction of a case into a household (RD -0.08, 95% CI -0.12 to -0.05, P < 0.001). The adverse event profile of zanamivir was no worse than placebo but vomiting was more commonly associated with oseltamivir (number needed to harm = 17, 95% CI 10 to 34). The adverse event profiles of laninamivir octanoate and oseltamivir were similar. AUTHORS' CONCLUSIONS: Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. Oseltamivir reduces the incidence of acute otitis media in children aged one to five years but is associated with a significantly increased risk of vomiting. One study demonstrated that laninamivir octanoate was more effective than oseltamivir in shortening duration of illness in children with oseltamivir resistant influenza A/H1N1. The benefit of oseltamivir and zanamivir in preventing the transmission of influenza in households is modest and based on weak evidence. However, the clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups. PMID- 22258950 TI - Amantadine and rimantadine for influenza A in children and the elderly. AB - BACKGROUND: The effectiveness and safety of amantadine (AMT) and rimantadine (RMT) for preventing and treating influenza A in adults has been systematically reviewed. However, little is known about these treatments in children and the elderly. OBJECTIVES: To systematically review the effectiveness and safety of AMT and RMT in preventing and treating influenza A in children and the elderly. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2) which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1966 to June week 3, 2011) and EMBASE (1980 to June 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing AMT and/or RMT with placebo, control, other antivirals or different doses or schedules of AMT or RMT, or both, or no intervention, in children and the elderly. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and assessed methodological quality. We resolved disagreements by consensus. In all comparisons except for one, we separately analysed the trials in children and the elderly using Review Manager software. MAIN RESULTS: A total of 12 studies involving 2494 participants (1586 children and adolescents and 908 elderly) compared AMT and RMT with placebo, paracetamol (one trial; 69 children) or zanamivir (two trials; 545 seniors). All studies were RCTs but most were still susceptible to bias. Two trials in the elderly had a high risk of bias because of incomplete outcome data. In one of those trials there was also a lack of outcome assessment blinding. Risk of bias was unclear in 10 studies due to unclear random sequence generation and allocation concealment. Only two trials in children were considered to have a low risk of bias.AMT was effective in preventing influenza A in children. A total of 773 participants were included in this outcome (risk ratio (RR) 0.11; 95% confidence interval (CI) 0.04 to 0.30). The assumed risk of influenza in the control group was 10 per 100 and the corresponding risk in the RMT group was one per 100 (95% CI 0 to 3). The quality of the evidence was considered low. For treatment purposes, RMT was beneficial for abating fever on day three of treatment. For this purpose one study was selected with low risk of bias and included 69 children (RR 0.36; 95% CI 0.14 to 0.91). The assumed risk was 38 per 100 and the corresponding risk in the RMT group was 14 per 100, 95% CI 5 to 34. The quality of the evidence was moderate.RMT did not show a prophylactic effect against influenza in the elderly, but the quality of evidence was considered very low. There were 103 participants (RR 0.45; 95% CI 0.14 to 1.41, for an assumed risk of 17 per 100 and a corresponding risk in the RMT group of 7 per 100, 95% CI 2 to 23). We did not identify any AMT trials in the elderly that met our inclusion criteria.There was no evidence of adverse effects of AMT and RMT in children or an adverse effect of RMT in the elderly. We did not identify any AMT trials in the elderly that met our inclusion criteria. AUTHORS' CONCLUSIONS: AMT is effective in preventing influenza A in children but the NNTB is high (NNTB: 12 (95% CI 9 to 17). RMT probably helps the abatement of fever on day three of treatment, but the quality of the evidence is poor. Due to the small number of available studies, we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly. PMID- 22258951 TI - Preoperative blood transfusions for sickle cell disease. AB - BACKGROUND: Sickle cell disease is one of the most common inherited diseases in the world, and can cause haemolytic anaemia, vaso-occlusive crises and dysfunction in virtually any organ system in the body. Surgical procedures are often required. Blood transfusion regimens can be used preoperatively in an attempt to increase transport of oxygen around the body and dilute the sickled red blood cells, thus reducing the risk of vaso-occlusion. OBJECTIVES: To assess the relative risks and benefits of preoperative blood transfusion regimens in people with sickle cell disease undergoing surgery of any type in any setting. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 06 October 2011. SELECTION CRITERIA: All randomised or quasi-randomised controlled studies comparing preoperative blood transfusion regimens to different regimens or no transfusion in people with sickle cell disease undergoing surgery. DATA COLLECTION AND ANALYSIS: Both authors independently assessed the risk of bias of the included studies and extracted data. MAIN RESULTS: The searches identified three studies, of which two, involving a total of 920 participants, were eligible for inclusion in the review. The first study compared an aggressive transfusion regimen (decreasing sickle haemoglobin to less than 30%) to a conservative transfusion regimen (increasing haemoglobin to 10 g/dl) in 604 elective operations in people with sickle cell disease. The conservative regimen was found to be as effective as the aggressive regimen in preventing perioperative complications, and was associated with fewer transfusion-related adverse events. The second study compared a preoperative transfusion group to a group receiving standard care, and did not show an advantage to preoperative transfusion. AUTHORS' CONCLUSIONS: While in general, conservative therapy appears to be as effective as aggressive therapy in preparation for surgery in people with sickle cell disease, further research is needed to examine the optimal regimen for different surgical types, and to address whether preoperative transfusion is needed in all surgical situations. PMID- 22258952 TI - Urodynamic studies for management of urinary incontinence in children and adults. AB - BACKGROUND: Urodynamic tests are used to investigate people who have urinary incontinence or other urinary symptoms in order to make a definitive objective diagnosis. The aim is to help to select the treatment most likely to be successful. The investigations are invasive and time consuming. OBJECTIVES: The objective of this review was to discover if treatment according to a urodynamic based diagnosis, compared to treatment based on history and examination, led to more effective clinical care of urinary incontinence and better clinical outcomes. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and CINAHL, and handsearching of journals and conference proceedings (searched 24 May 2011), and the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing clinical outcomes in groups of people who were and were not investigated using urodynamics, or comparing one type of urodynamics against another. Trials were excluded if they did not report clinical outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Seven small trials involving around 400 people were included but data were only available for 385 women in five trials, of whom 197 received urodynamics. There was some evidence of risk of bias. The four deaths and 12 dropouts in the control arm of one trial were unexplained.There was some evidence that the tests did change clinical decision making. There was evidence from two trials that women treated after urodynamic investigations were more likely to receive drugs (RR 2.09, 95% CI 1.32 to 3.31) but not, in three trials, surgery (RR 1.75, 95% CI 0.39 to 7.75). Women in the urodynamic arms of two trials were more likely to have their management changed but this did not quite reach statistical significance (proportion with no change in management 76% versus 99%, RR 0.79, 95% CI 0.57 to 1.10).However, there was not enough evidence to demonstrate whether or not this resulted in a clinical benefit. For example there was no statistically significant difference in the number of women with urinary incontinence if they received treatment guided by urodynamics (70%) versus those whose treatment was based on history and clinical findings alone (62%) (e.g. RR for number with incontinence after first year 1.23, 95% CI 0.60 to 2.55).No trials reported whether or not there were any adverse effects. AUTHORS' CONCLUSIONS: While urodynamic tests may change clinical decision making, there was not enough evidence to suggest whether this would result in better clinical outcomes. There was no evidence abut their use in men, children or people with neurological diseases. Larger definitive trials are needed, in which people are randomly allocated to management according to urodynamic findings or to standard management based on history and clinical examination. PMID- 22258953 TI - Interventions for impetigo. AB - BACKGROUND: Impetigo is a common, superficial bacterial skin infection, which is most frequently encountered in children. There is no generally agreed standard therapy, and guidelines for treatment differ widely. Treatment options include many different oral and topical antibiotics as well as disinfectants. This is an updated version of the original review published in 2003. OBJECTIVES: To assess the effects of treatments for impetigo, including non-pharmacological interventions and 'waiting for natural resolution'. SEARCH METHODS: We updated our searches of the following databases to July 2010: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 2005), EMBASE (from 2007), and LILACS (from 1982). We also searched online trials registries for ongoing trials, and we handsearched the reference lists of new studies found in the updated search. SELECTION CRITERIA: Randomised controlled trials of treatments for non-bullous, bullous, primary, and secondary impetigo. DATA COLLECTION AND ANALYSIS: Two independent authors undertook all steps in data collection. We performed quality assessments and data collection in two separate stages. MAIN RESULTS: We included 57 trials in the first version of this review. For this update 1 of those trials was excluded and 12 new trials were added. The total number of included trials was, thus, 68, with 5578 participants, reporting on 50 different treatments, including placebo. Most trials were in primary impetigo or did not specify this.For many of the items that were assessed for risk of bias, most studies did not provide enough information. Fifteen studies reported blinding of participants and outcome assessors.Topical antibiotic treatment showed better cure rates than placebo (pooled risk ratio (RR) 2. 24, 95% confidence interval (CI) 1.61 to 3.13) in 6 studies with 575 participants. In 4 studies with 440 participants, there was no clear evidence that either of the most commonly studied topical antibiotics (mupirocin and fusidic acid) was more effective than the other (RR 1.03, 95% CI 0.95 to 1.11).In 10 studies with 581 participants, topical mupirocin was shown to be slightly superior to oral erythromycin (pooled RR 1.07, 95% CI 1.01 to 1.13). There were no significant differences in cure rates from treatment with topical versus other oral antibiotics. There were, however, differences in the outcome from treatment with different oral antibiotics: penicillin was inferior to erythromycin, in 2 studies with 79 participants (pooled RR 1.29, 95% CI 1.07 to 1.56), and cloxacillin, in 2 studies with 166 participants (pooled RR 1.59, 95% CI 1.21 to 2.08).There was a lack of evidence for the benefit of using disinfectant solutions. When 2 studies with 292 participants were pooled, topical antibiotics were significantly better than disinfecting treatments (RR 1.15, 95% CI 1.01 to 1.32).The reported number of side-effects was low, and most of these were mild. Side-effects were more common for oral antibiotic treatment compared to topical treatment. Gastrointestinal effects accounted for most of the difference.Worldwide, bacteria causing impetigo show growing resistance rates for commonly used antibiotics. For a newly developed topical treatment, retapamulin, no resistance has yet been reported. AUTHORS' CONCLUSIONS: There is good evidence that topical mupirocin and topical fusidic acid are equally, or more, effective than oral treatment. Due to the lack of studies in people with extensive impetigo, it is unclear if oral antibiotics are superior to topical antibiotics in this group. Fusidic acid and mupirocin are of similar efficacy. Penicillin was not as effective as most other antibiotics. There is a lack of evidence to support disinfection measures to manage impetigo. PMID- 22258954 TI - Surgical decompression for cerebral oedema in acute ischaemic stroke. AB - BACKGROUND: Large cerebral infarction has a high case fatality. Despite the use of conventional medical treatments such as hyperventilation, mannitol, diuretics, corticosteroids and barbiturates, the outcome of this condition remains poor. Decompressive surgery to relieve intracranial pressure is performed in some cases, although evidence of any clinical benefits has not been available until recently. This is an update of a Cochrane review first published in 2002. OBJECTIVES: To examine the effects of decompressive surgery in patients with massive acute ischaemic stroke complicated with cerebral oedema, and to judge whether decompressive surgery is effective in improving survival or survival free of severe disability. SEARCH METHODS: We searched the Cochrane Stroke Group's Trials Register (last searched October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 7), MEDLINE (1966 to October 2010), EMBASE (1980 to October 2010) and Science Citation Index (October 2010). We also searched the reference lists of all relevant articles. SELECTION CRITERIA: Randomised controlled studies of decompressive surgery plus medical treatment versus medical treatment alone in patients with clinically and radiologically confirmed cerebral infarcts complicated with cerebral oedema. DATA COLLECTION AND ANALYSIS: One author assessed the titles and retrieved the relevant studies. The same author extracted data, with discussion among all authors for clarification. Outcomes were death at the end of follow-up, death or disability defined as the modified Rankin Scale (mRS) > 3 at the end of follow up, death or severe disability defined as mRS > 4 at 12 months and disability defined as mRS 4 or 5 at 12 months. The results are given using the Peto odds ratio (Peto OR) with 95% confidence intervals (CIs). MAIN RESULTS: We included three trials in this review, involving 134 patients who were 60 years of age or younger. The time window for the intervention was 30 hours from stroke onset in two studies and 96 hours in one study. All trials were stopped early. Surgical decompression reduced the risk of death at the end of follow-up (OR 0.19, 95% CI 0.09 to 0.37) and the risk of death or disability defined as mRS > 4 at 12 months (OR 0.26, 95% CI 0.13 to 0.51). Death or disability defined as mRS > 3 at the end of follow-up was no different between the treatment arms (OR 0.56, 95% CI 0.27 to 1.15). AUTHORS' CONCLUSIONS: Surgical decompression lowers the risk of death and death or severe disability defined as mRS > 4 in selected patients 60 years of age or younger with a massive hemispheric infarction and oedema. Optimum criteria for patient selection and for timing of decompressive surgery are yet to be defined. Since survival may be at the expense of substantial disability, surgery should be the treatment of choice only when it can be assumed, based on their preferences, that it is in the best interest of patients. Since all the trials were stopped early, an overestimation of the effect size cannot be excluded. PMID- 22258956 TI - Home visits during pregnancy and after birth for women with an alcohol or drug problem. AB - BACKGROUND: One potential method of improving outcome for pregnant or postpartum women with a drug or alcohol problem is with home visits. OBJECTIVES: To determine the effects of home visits during pregnancy and/or after birth for women with a drug or alcohol problem. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2011), CENTRAL (The Cochrane Library 2011, Issue 4 of 4), MEDLINE (1966 to 30 November 2011), EMBASE (1980 to 30 November 2011), CINAHL (1982 to 30 November 2011) and PsycINFO (1974 to 30 November 2011) supplemented by searches of citations from previous reviews and trials and contact with experts. SELECTION CRITERIA: Studies using random or quasi-random allocation of pregnant or postpartum women with a drug or alcohol problem to home visits. Trials enrolling high-risk women of whom more than 50% were reported to use drugs or alcohol were also eligible. DATA COLLECTION AND ANALYSIS: Review authors performed assessments of trials independently. We performed statistical analyses using fixed-effect and random-effects models where appropriate. MAIN RESULTS: Seven studies (reporting 803 mother-infant pairs) compared home visits mostly after birth with no home visits. Visitors included community health nurses, paediatric nurses, trained counsellors, paraprofessional advocates, midwives and lay African-American women. Several studies had significant methodological limitations. There was no significant difference in continued illicit drug use (three studies, 384 women; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.24), continued alcohol use (three studies, 379 women; RR 1.18, 95% CI 0.96 to 1.46), failure to enrol in a drug treatment program (two studies, 211 women; RR 0.45, 95% CI 0.10 to 1.94), not breastfeeding at six months (two studies, 260 infants; RR 0.95, 95% CI 0.83 to 1.10), incomplete six-month infant vaccination schedule (two studies, 260 infants; RR 1.09, 95% CI 0.91 to 1.32), the Bayley Mental Development Index (three studies, 199 infants; mean difference 2.89, 95% CI -1.17 to 6.95) or Psychomotor Index (MD 3.14, 95% CI -0.03 to 6.32), child behavioural problems (RR 0.46, 95% CI 0.21 to 1.01), infants not in care of biological mother (two studies, 254 infants; RR 0.83, 95% CI 0.50 to 1.39), non-accidental injury and non-voluntary foster care (two studies, 254 infants; RR 0.16, 95% CI 0.02 to 1.23) or infant death (three studies, 288 infants; RR 0.70, 95% CI 0.12 to 4.16). Individual studies reported a significant reduction in involvement with child protective services (RR 0.38, 95% CI 0.20 to 0.74) and failure to use postpartum contraception (RR 0.41, 95% CI 0.20 to 0.82). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the routine use of home visits for pregnant or postpartum women with a drug or alcohol problem. Further large, high-quality trials are needed. PMID- 22258957 TI - Positive end expiratory pressure for preterm infants requiring conventional mechanical ventilation for respiratory distress syndrome or bronchopulmonary dysplasia. AB - BACKGROUND: Conventional mechanical ventilation (CMV) of neonates has been used as a treatment of respiratory failure for over 30 years. While CMV facilitates gas exchange, it may simultaneously damage the lung. Positive end expiratory pressure (PEEP) has received less attention than other ventilation parameters when considering this balance of benefit and possible harm. While an appropriate level of PEEP may exert substantial benefits in ventilation, both inappropriately low or high levels may lead to harm. An appropriate level of PEEP for neonates may also be best achieved by an individualized approach. OBJECTIVES: 1. To compare the effects of different levels of PEEP in preterm newborn infants requiring CMV for respiratory distress syndrome (RDS).2. To compare the effects of different levels of PEEP in preterm infants requiring CMV for bronchopulmonary dysplasia (BPD).3. To compare the effects of different methods for individualizing PEEP to an optimal level in preterm newborn infants requiring CMV for RDS. SEARCH METHODS: The search was performed in accordance with the standard search strategy for the Cochrane Neonatal Review Group. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, EMBASE, study references and experts were utilized for study identification. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials studying preterm infants (less than 37 weeks gestational age) requiring CMV with endotracheal intubation and undergoing randomization to either different PEEP levels (RDS or BPD) or two or more alternative methods for individualizing PEEP levels (RDS only) were included. Cross-over trials were included but we limited the findings to those in the first cross-over period. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed in accordance with the recommendations of the Cochrane Neonatal Review Group. MAIN RESULTS: An initial evaluation identified 10 eligible articles. Ultimately, a single study met our inclusion criteria. The study addressed the effects of different levels of PEEP in preterm newborn infants requiring CMV for RDS. Only short term physiologic measures were reported. All results were limited to a small sample size without statistically significant results. No trials addressing the effect of PEEP in infants with BPD or strategies to individualize the management of PEEP were identified. AUTHORS' CONCLUSIONS: There is insufficient evidence to guide selection of appropriate PEEP levels for RDS or CMV. There is a need for well designed clinical trials evaluating the optimal application of this important and frequently applied intervention. PMID- 22258955 TI - Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. AB - BACKGROUND: Bacterial infections are a major cause of morbidity and mortality in patients who are neutropenic following chemotherapy for malignancy. Trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections but not in reducing mortality rates. Our systematic review from 2006 also showed a reduction in mortality. OBJECTIVES: This updated review aimed to evaluate whether there is still a benefit of reduction in mortality when compared to placebo or no intervention. SEARCH METHODS: We searched the Cochrane Cancer Network Register of Trials (2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2011), MEDLINE (1966 to March 2011), EMBASE (1980 to March 2011), abstracts of conference proceedings and the references of identified studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention, or another antibiotic, to prevent bacterial infections in afebrile neutropenic patients. DATA COLLECTION AND ANALYSIS: Two authors independently appraised the quality of each trial and extracted data from the included trials. Analyses were performed using RevMan 5.1 software. MAIN RESULTS: One-hundred and nine trials (involving 13,579 patients) that were conducted between the years 1973 to 2010 met the inclusion criteria. When compared with placebo or no intervention, antibiotic prophylaxis significantly reduced the risk of death from all causes (46 trials, 5635 participants; risk ratio (RR) 0.66, 95% CI 0.55 to 0.79) and the risk of infection-related death (43 trials, 5777 participants; RR 0.61, 95% CI 0.48 to 0.77). The estimated number needed to treat (NNT) to prevent one death was 34 (all-cause mortality) and 48 (infection-related mortality).Prophylaxis also significantly reduced the occurrence of fever (54 trials, 6658 participants; RR 0.80, 95% CI 0.74 to 0.87), clinically documented infection (48 trials, 5758 participants; RR 0.65, 95% CI 0.56 to 0.76), microbiologically documented infection (53 trials, 6383 participants; RR 0.51, 95% CI 0.42 to 0.62) and other indicators of infection.There were no significant differences between quinolone prophylaxis and TMP-SMZ prophylaxis with regard to death from all causes or infection, however, quinolone prophylaxis was associated with fewer side effects leading to discontinuation (seven trials, 850 participants; RR 0.37, 95% CI 0.16 to 0.87) and less resistance to the drugs thereafter (six trials, 366 participants; RR 0.45, 95% CI 0.27 to 0.74). AUTHORS' CONCLUSIONS: Antibiotic prophylaxis in afebrile neutropenic patients significantly reduced all-cause mortality. In our review, the most significant reduction in mortality was observed in trials assessing prophylaxis with quinolones. The benefits of antibiotic prophylaxis outweighed the harm such as adverse effects and the development of resistance since all-cause mortality was reduced. As most trials in our review were of patients with haematologic cancer, we strongly recommend antibiotic prophylaxis for these patients, preferably with a quinolone. Prophylaxis may also be considered for patients with solid tumours or lymphoma. PMID- 22258958 TI - Interventions for replacing missing teeth: treatment of peri-implantitis. AB - BACKGROUND: One of the key factors for the long-term success of oral implants is the maintenance of healthy tissues around them. Bacterial plaque accumulation induces inflammatory changes in the soft tissues surrounding oral implants and it may lead to their progressive destruction (peri-implantitis) and ultimately to implant failure. Different treatment strategies for peri-implantitis have been suggested, however it is unclear which are the most effective. OBJECTIVES: To identify the most effective interventions for treating peri-implantitis around osseointegrated dental implants. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and EMBASE. Handsearching included several dental journals. We checked the bibliographies of the identified randomised controlled trials (RCTs) and relevant review articles for studies outside the handsearched journals. We wrote to authors of all identified RCTs, to more than 55 dental implant manufacturers and an Internet discussion group to find unpublished or ongoing RCTs. No language restrictions were applied. The last electronic search was conducted on 9 June 2011. SELECTION CRITERIA: All RCTs comparing agents or interventions for treating peri-implantitis around dental implants. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. We contacted the authors for missing information. Results were expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CI). Heterogeneity was to be investigated including both clinical and methodological factors. MAIN RESULTS: Fifteen eligible trials were identified, but six were excluded. The following interventions were compared in the nine included studies: different non-surgical interventions (five trials); adjunctive treatments to non-surgical interventions (one trial); different surgical interventions (two trials); adjunctive treatments to surgical interventions (one trial). Follow-up ranged from 3 months to 4 years. No study was judged to be at low risk of bias.Statistically significant differences were observed in two small single trials judged to be at unclear or high risk of bias. After 4 months, adjunctive local antibiotics to manual debridement in patients who lost at least 50% of the bone around implants showed improved mean probing attachment levels (PAL) of 0.61 mm (95% confidence interval (CI) 0.40 to 0.82) and reduced probing pockets depths (PPD) of 0.59 mm (95% CI 0.39 to 0.79). After 4 years, patients with peri-implant infrabony defects > 3 mm treated with Bio-Oss and resorbable barriers gained 1.4 mm more PAL (95% CI 0.24 to 2.56) and 1.4 mm PPD (95% CI 0.81 to 1.99) than patients treated with a nanocrystalline hydroxyapatite. AUTHORS' CONCLUSIONS: There is no reliable evidence suggesting which could be the most effective interventions for treating peri-implantitis. This is not to say that currently used interventions are not effective.A single small trial at unclear risk of bias showed the use of local antibiotics in addition to manual subgingival debridement was associated with a 0.6 mm additional improvement for PAL and PPD over a 4-month period in patients affected by severe forms of peri-implantitis. Another small single trial at high risk of bias showed that after 4 years, improved PAL and PPD of about 1.4 mm were obtained when using Bio-Oss with resorbable barriers compared to a nanocrystalline hydroxyapatite in peri-implant infrabony defects. There is no evidence from four trials that the more complex and expensive therapies were more beneficial than the control therapies which basically consisted of simple subgingival mechanical debridement. Follow-up longer than 1 year suggested recurrence of peri-implantitis in up to 100% of the treated cases for some of the tested interventions. As this can be a chronic disease, re-treatment may be necessary. Larger well-designed RCTs with follow-up longer than 1 year are needed. PMID- 22258959 TI - Self-monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. AB - BACKGROUND: Self-monitoring of blood glucose (SMBG) has been found to be effective for patients with type 1 diabetes and for patients with type 2 diabetes using insulin. There is much debate on the effectiveness of SMBG as a tool in the self-management for patients with type 2 diabetes who are not using insulin. OBJECTIVES: To assess the effects of SMBG in patients with type 2 diabetes mellitus who are not using insulin. SEARCH METHODS: Multiple electronic bibliographic and ongoing trial databases were searched supplemented with handsearches of references of retrieved articles (date of last search: 07 July 2011). SELECTION CRITERIA: Randomised controlled trials investigating the effects of SMBG compared with usual care, self-monitoring of urine glucose (SMUG) or both in patients with type 2 diabetes who where not using insulin. Studies that used glycosylated haemoglobin A(1c) (HbA(1c)) as primary outcome were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from included studies and evaluated the studies' risk of bias. Data from the studies were compared to decide whether they were sufficiently homogeneous to pool in a meta-analysis. Primary outcomes were HbA(1c), health-related quality of life, well-being and patient satisfaction. Secondary outcomes were fasting plasma glucose level, hypoglycaemic episodes, morbidity, adverse effects and costs. MAIN RESULTS: Twelve randomised controlled trials were included and evaluated outcomes in 3259 randomised patients. Intervention duration ranged from 6 months (26 weeks) to 12 months (52 weeks). Nine trials compared SMBG with usual care without monitoring, one study compared SMBG with SMUG, one study was a three-armed trial comparing SMBG and SMUG with usual care and one study was a three-armed trial comparing less intensive SMBG and more intensive SMBG with a control group. Seven out of 11 studies had a low risk of bias for most indicators. Meta-analysis of studies including patients with a diabetes duration of one year or more showed a statistically significant SMBG induced decrease in HbA(1c) at up to six months follow-up (-0.3; 95% confidence interval (CI) -0.4 to -0.1; 2324 participants, nine trials), yet an overall statistically non-significant SMBG induced decrease was seen at 12 month follow-up (-0.1; 95% CI -0.3 to 0.04; 493 participants, two trials). Qualitative analysis of the effect of SMBG on well-being and quality of life showed no effect on patient satisfaction, general well-being or general health-related quality of life. Two trials reported costs of self-monitoring: One trial compared the costs of self-monitoring of blood glucose with self-monitoring of urine glucose based on nine measurements per week and with the prices in US dollars for self-monitoring in 1990. Authors concluded that total costs in the first year of self-monitoring of blood glucose, with the purchase of a reflectance meter were 12 times more expensive than self-monitoring of urine glucose ($481 or 361 EURO [11/2011 conversion] versus $40 or 30 EURO [11/2011 conversion]). Another trial reported a full economical evaluation of the costs and effects of self-monitoring. At the end of the trial, costs for the intervention were L89 (104 EURO [11/2011 conversion]) for standardized usual care (control group), L181 (212 EURO [11/2011 conversion]) for the less intensive self monitoring group and L173 (203 EURO [11/2011 conversion]) for the more intensive self-monitoring group. Higher losses to follow-up in the more intensive self monitoring group were responsible for the difference in costs, compared to the less intensive self-monitoring group.There were few data on the effects on other outcomes and these effects were not statistically significant. None of the studies reported data on morbidity. AUTHORS' CONCLUSIONS: From this review, we conclude that when diabetes duration is over one year, the overall effect of self monitoring of blood glucose on glycaemic control in patients with type 2 diabetes who are not using insulin is small up to six months after initiation and subsides after 12 months. Furthermore, based on a best-evidence synthesis, there is no evidence that SMBG affects patient satisfaction, general well-being or general health-related quality of life. More research is needed to explore the psychological impact of SMBG and its impact on diabetes specific quality of life and well-being, as well as the impact of SMBG on hypoglycaemia and diabetic complications. PMID- 22258960 TI - Interferon beta for secondary progressive multiple sclerosis. AB - BACKGROUND: Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease. OBJECTIVES: The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis Group's Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information. SELECTION CRITERIA: We included all randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals (CI) for the binary outcomes and Standard Mean Difference with 95% CI for the continuous outcomes. MAIN RESULTS: Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (RR, 95% CI: 0.98, [0.82-1.16]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% CI: 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [0.84-0.97]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN treated patients. AUTHORS' CONCLUSIONS: Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse related disability.Overall, these results show that IFNs' anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS. PMID- 22258961 TI - Pentoxifylline for intermittent claudication. AB - BACKGROUND: Intermittent claudication (IC) is a symptom of peripheral arterial occlusive disease (PAD). It is associated with high morbidity and mortality. Pentoxifylline is one of many drugs used to treat IC. Pentoxifylline decreases blood viscosity, improves erythrocyte flexibility, and increases microcirculatory flow and tissue oxygen concentration.Many studies have evaluated the efficacy of pentoxifylline in treating PAD but the results of these studies are very variable. OBJECTIVES: To determine the efficacy of pentoxifylline in improving the walking capacity (that is pain-free walking distance and the total (absolute, maximum) walking distance) of patients with stable intermittent claudication, Fontaine stage II. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched January 2011) and CENTRAL (2011, Issue 1). In addition, we searched MEDLINE (Week 2 January 2011) and EMBASE (2011 Week 03). ClinicalTrials.gov and Current Controlled Trials were searched for ongoing or unpublished trials. SELECTION CRITERIA: All double blind, randomised controlled trials (RCTs) comparing pentoxifylline to placebo or any other pharmacological intervention in patients with IC Fontaine stage II. DATA COLLECTION AND ANALYSIS: Included studies were assessed separately by two review authors. Data were matched and disagreements resolved by discussion. The quality of the studies was assessed using the Jadad score and the Cochrane risk of bias tool. Results relating to pain-free walking distance (PFWD) and total walking distance (TWD) were collected. Studies were compared based on the duration and dose of pentoxifylline. MAIN RESULTS: Twenty-three studies with 2816 participants were included in this review. There was considerable heterogeneity between the included studies with regards to multiple variables including duration of treatment, dose of pentoxifylline, baseline walking distance and patient characteristics, and therefore pooled analysis was not possible. The quality of the included studies was generally low. There was very large variability in the reported findings between the individual studies. In a total of 17 studies which compared pentoxifylline with placebo, of which 14 reported TWD and 11 reported PFWD, the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and for PFWD the difference ranged from 33.8% to 73.9%. Testing for statistical significance of these results was generally not possible due to the lack of data. There was no statistically significant difference in ankle brachial pressure index (ABI) between the pentoxifylline and placebo groups. Pentoxifylline was generally well tolerated. AUTHORS' CONCLUSIONS: Given the generally poor quality of the published studies and the large degree of heterogeneity in the interventions and the results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline is generally well tolerated. Based on the totality of the available evidence, it is possible that pentoxifylline could have a place in the treatment of IC as a means of improving walking distance and as a complimentary treatment assuming all other essential measures such as lifestyle change, exercise and treatment for secondary prevention have been taken into account. However, the response to pentoxifylline should be assessed on an individual basis. PMID- 22258962 TI - Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery. AB - BACKGROUND: Surgery has been used as part of breast cancer treatment for centuries; however any surgical procedure has the potential risk of infection. Infection rates for surgical treatment of breast cancer are documented at between 3% and 15%, higher than average for a clean surgical procedure. Pre- and perioperative antibiotics have been found to be useful in lowering infection rates in other surgical groups, yet there is no consensus on the use of prophylactic antibiotics for breast cancer surgery. OBJECTIVES: To determine the effects of prophylactic (pre- or perioperative) antibiotics on the incidence of surgical site infection (SSI) after breast cancer surgery. SEARCH METHODS: For this second update we searched the Cochrane Wounds Group Specialised Register (searched 31 August 2011); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3); Ovid MEDLINE (2008 to August Week 3 2011); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 30 August 2011); Ovid EMBASE (1980 to 2011 Week 34); and EBSCO CINAHL (2008 to 25 August 2011). We applied no language or date restrictions. SELECTION CRITERIA: Randomised controlled trials of pre- and perioperative antibiotics for patients undergoing surgery for breast cancer were included. Primary outcomes were rates of surgical site infection (SSI) and adverse reactions. DATA COLLECTION AND ANALYSIS: Two review authors independently examined the title and abstracts of all studies identified by the search strategy, then assessed study quality and extracted data from those that met the inclusion criteria. MAIN RESULTS: A total of nine studies (2260 participants) is included in the review. Eight studies evaluated preoperative antibiotic compared with no antibiotic or placebo. One study evaluated perioperative antibiotic compared with no antibiotic. Pooling of the results demonstrated that prophylactic antibiotics administered preoperatively significantly reduce the incidence of SSI for patients undergoing breast cancer surgery without reconstruction (pooled risk ratio (RR) 0.71, 95% confidence interval (CI) 0.53 to 0.94). Analysis of the single study comparing perioperative antibiotic with no antibiotic found no statistically significant effect of antibiotics on the incidence of SSI (RR 0.11, 95% CI 0.01 to 1.95). No studies presented separate data for patients who underwent reconstructive surgery at the time of removal of the breast tumour. AUTHORS' CONCLUSIONS: Prophylactic antibiotics administered preoperatively reduce the risk of SSI in patients undergoing surgery for breast cancer. Further studies involving patients undergoing immediate breast reconstruction are needed as studies have identified this group as being at higher risk of infection than those who do not undergo immediate breast reconstruction. PMID- 22258963 TI - Which anticholinergic drug for overactive bladder symptoms in adults. AB - BACKGROUND: Around 16% to 45% of adults have overactive bladder symptoms (urgency with frequency and/or urge incontinence - 'overactive bladder syndrome'). Anticholinergic drugs are common treatments. OBJECTIVES: To compare the effects of different anticholinergic drugs for overactive bladder symptoms. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 8 March 2011) and reference lists of relevant articles. SELECTION CRITERIA: Randomised trials in adults with overactive bladder symptoms or detrusor overactivity that compared one anticholinergic drug with another, or two doses of the same drug. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Reviewers' Handbook. MAIN RESULTS: Eighty six trials, 70 parallel and 16 cross-over designs were included (31,249 adults). Most trials were described as double-blind, but were variable in other aspects of quality. Crossover studies did not present data in a way that could be included in the meta-analyses. Twenty nine collected quality of life data (the primary outcome measure) using validated measures, but only fifteen reported useable data.Tolterodine versus oxybutynin: There were no statistically significant differences for quality of life, patient reported cure or improvement, leakage episodes or voids in 24 hours, but fewer withdrawals due to adverse events with tolterodine (Risk Ratio (RR) 0.52, 95% confidence interval (CI) 0.40 to 0.66, data from eight trials), and less risk of dry mouth (RR 0.65, 95% CI 0.60 to 0.71, data from ten trials).Solifenacin versus tolterodine: There were statistically significant differences for quality of life (standardised mean difference (SMD) -0.12, 95% CI -0.23 to -0.01, data from three trials), patient reported cure/improvement (RR 1.25, 95% CI 1.13 to 1.39, data from two trials), leakage episodes in 24 hours (weighted mean difference (WMD) -0.30, 95% CI -0.53 to -0.08, data from four studies) and urgency episodes in 24 hours (WMD -0.43, 95% CI -0.74 to -0.13, data from four trials), all favouring solifenacin. There was no difference in withdrawals due to adverse events and dry mouth, but after sensitivity analysis the dry mouth (RR 0.69, 95% CI 0.51 to 0.94) was statistically significantly lower with solifenacin when compared to Immediate Release (IR) tolterodine.Fesoterodine versus extended release tolterodine: Three trials contributed to the meta analyses. There were statistically significant differences for quality of life (SMD -0.20, 95% CI -0.27 to -0.14), patient reported cure/improvement (RR 1.11, 95% CI 1.06 to 1.16), leakage episodes (WMD 0.19, 95% CI -0.30 to -0.09), frequency (WMD -0.27, 95% CI -0.47 to -0.06) and urgency episodes (WMD -0.44, 95% CI -0.72 to -0.16) in 24 hours, all favouring fesoterodine, but those taking fesoterodine had higher risk of withdrawal due to adverse events (RR 1.45, 95% CI 1.07 to 1.98) and higher risk of dry mouth (RR 1.80, 95% CI 1.58 to 2.05) at 12 weeks.Different doses of tolterodine: The standard recommended starting dose (2 mg twice daily) was compared with two lower (0.5 mg and 1 mg twice daily), and one higher dose (4 mg twice daily). The effects of 1 mg, 2 mg and 4 mg doses were similar for leakage episodes and micturitions in 24 hours, with greater risk of dry mouth with 2 and 4 mg doses at two to 12 weeks.Different doses of solifenacin: The standard recommended starting dose of 5 mg once daily was compared to 10 mg: while frequency and urgency were less (better) with 10 mg compared to 5 mg, there was a higher risk of dry mouth with 10 mg solifenacin at four to 12 weeks.Different doses of fesoterodine:The recommended starting dose of 4mg once daily was compared to 8 and 12 mg. The clinical efficacy (patient reported cure, leakage episodes, micturition per 24 hours) of 8 mg was better than 4 mg fesoterodine but with a higher risk of dry mouth with 8 mg.There was no statistically significant difference between 4 and 12 mg in the efficacy but the dry mouth was significantly higher with 12 mg at eight to 12 weeks.Extended versus immediate release preparations of oxybutynin and/or tolterodine: There were no statistically significant differences for cure/improvement, leakage episodes or micturitions in 24 hours, or withdrawals due to adverse events, but there were few data. Overall, extended release preparations had less risk of dry mouth at two to 12 weeks.One extended release preparation versus another: There was less risk of dry mouth with oral extended release tolterodine than oxybutynin (RR 0.75, 95% CI 0.59 to 0.95), but no difference between transdermal oxybutynin and oral extended release tolterodine although some people withdrew due to skin reaction at the transdermal patch site at 12 weeks. AUTHORS' CONCLUSIONS: Where the prescribing choice is between oral immediate release oxybutynin or tolterodine, tolterodine might be preferred for reduced risk of dry mouth. With tolterodine, 2 mg twice daily is the usual starting dose, but a 1 mg twice daily dose might be equally effective, with less risk of dry mouth. If extended release preparations of oxybutynin or tolterodine are available, these might be preferred to immediate release preparations because there is less risk of dry mouth.Between solifenacin and immediate release tolterodine, solifenacin might be preferred for better efficacy and less risk of dry mouth. Solifenacin 5 mg once daily is the usual starting dose, this could be increased to 10 mg once daily for better efficacy but with increased risk of dry mouth.Between fesoterodine and extended release tolterodine, fesoterodine might be preferred for superior efficacy but has higher risk of withdrawal due to adverse events and higher risk of dry mouth.There is little or no evidence available about quality of life, costs, or long-term outcome in these studies. There were insufficient data from trials of other anticholinergic drugs to draw any conclusions. PMID- 22258964 TI - Single layer versus double layer suture anastomosis of the gastrointestinal tract. AB - BACKGROUND: Gastrointestinal anastomosis (GIA) is an essential step to maintain the continuity of gastrointestinal tract following intestinal resection. GIA is still a source of significant controversy among surgeons due to the use of variety of approaches. Adequate apposition by single layer or double layer anastomosis may affect outcome after GIA OBJECTIVES: The objective of this review is to compare the effectiveness of single layer GIA (SGIA) versus double layer GIA (DGIA) being used in general surgery. The particular question we would attempt to answer will be; is single layer hand made GIA in surgical patients is as effective as double layer? SEARCH METHODS: The CCCG (Colorectal Cancer Cochrane Group) Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2011), MEDLINE (until April 2011) , EMBASE ( The Intelligent Gateway to Biomedical & Pharmacological Information until April 2011), LILACS (The Latin American and Caribbean Health Sciences Library until April 2011 ) and Science Citation Index Expanded (SCI-E until April 2011) using the medical subject headings (MeSH) terms were searched without date, language or age restrictions. SELECTION CRITERIA: Randomised, controlled trials comparing the effectiveness of SGIA versus DGIA DATA COLLECTION AND ANALYSIS: At least two review authors independently scrutinised search results, selected eligible studies and extracted data. MAIN RESULTS: Seven randomised, controlled trials encompassing 842 patients undergoing SGIA versus DGIA were retrieved from the electronic databases. There were 408 patients in the SGIA group and 432 patients in the DGIA group. All included studies were small, with sample sizes ranging from 60 to 172. There was no heterogeneity among the included trials. Therefore, in the fixed effects model, incidence of anastomotic dehiscence, peri-operative complications and mortality was statistically equivalent between two techniques of GIA. Average hospital stay following SGIA and DGIA was also comparable. However, SGIA was superior in terms of shorter operative time. Sensitivity analysis of relatively good quality and poor quality trials supported same conclusion. AUTHORS' CONCLUSIONS: SGIA can be performed quicker as compared to double layer GIA. SGIA is comparable to DGIA in terms of anastomotic leak, peri-operative complications, mortality and hospital stay. SGIA may routinely be used for GIA following bowel resection. However, since this conclusion is derived from smaller number of patients recruited in relatively moderate quality trials, further trials should be aimed to reduce the limitations of this review. PMID- 22258965 TI - High-carbohydrate, high-protein, low-fat versus low-carbohydrate, high-protein, high-fat enteral feeds for burns. AB - BACKGROUND: Severe burn injuries increase patients' metabolic needs. Aggressive high-protein enteral feeding is used in the post-burn period to improve recovery and healing. OBJECTIVES: To examine the evidence for improved clinical outcomes in burn patients treated with high-carbohydrate, high-protein, low-fat enteral feeds (high-carbohydrate enteral feeds) compared with those treated with low carbohydrate, high-protein, high-fat enteral enteral feeds (high-fat enteral feeds). SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register (searched 28 Nov 2011), Cochrane Central Register of Controlled Trials (The Cochrane Library 2011, Issue 4), MEDLINE (Ovid) 1950 to Nov (Week 3) 2011, EMBASE (Ovid), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to Nov 2011), ISI Web of Science: Conference Proceedings Citation Index Science (CPCI-S) (1990 to Nov 2011), PubMed (Searched 28 Nov 2011). Online trials registers and conference proceedings were also searched to April 2010. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) comparing high carbohydrate enteral feeds to high-fat enteral feeds for treatment of patients with 10% or greater total body surface area (TBSA) burns in the immediate post burn period, with data for at least one of the pre-specified outcomes. DATA COLLECTION AND ANALYSIS: Two authors collected and analysed the following data: mortality, incidence of pneumonia and days on ventilator. Meta-analysis could only be performed for the outcomes mortality and incidence of pneumonia. A random effects model was used for all comparisons. MAIN RESULTS: Two RCTs, reporting results from 93 patients, were included in this review. Patients given a high carbohydrate feeding formula had an odds ratio (OR) of 0.12 (95% confidence interval (CI) 0.04 to 0.39) for developing pneumonia compared to patients given a high-fat enteral formula (P value = 0.0004). Patients given a high-carbohydrate formula had an OR of 0.36 (95% CI 0.11 to 1.15) for risk of death compared to patients given a high-fat enteral formula; this difference did not reach statistical significance (P value = 0.08). Risk of bias in these studies was assessed as high and moderate. AUTHORS' CONCLUSIONS: The available evidence suggests that use of high-carbohydrate, high-protein, low-fat enteral feeds in patients with at least 10% TBSA burns might reduce the incidence of pneumonia compared with use of a low-carbohydrate, high-protein, high-fat diet. The available evidence is inconclusive regarding the effect of either enteral feeding regimen on mortality. Note that the available evidence is limited to two small studies judged to be of moderate risk of bias. Further research is needed in this area before strong conclusions can be drawn. PMID- 22258966 TI - Interventions for preventing weight gain after smoking cessation. AB - BACKGROUND: Most people who stop smoking gain weight. There are some interventions that have been designed to reduce weight gain when stopping smoking. Some smoking cessation interventions may also limit weight gain although their effect on weight has not been reviewed. OBJECTIVES: To systematically review the effect of: (1) Interventions targeting post-cessation weight gain on weight change and smoking cessation.(2) Interventions designed to aid smoking cessation that may also plausibly affect weight on post-cessation weight change. SEARCH METHODS: Part 1 - We searched the Cochrane Tobacco Addiction Group's Specialized Register and CENTRAL in September 2011.Part 2 - In addition we searched the included studies in the following "parent" Cochrane reviews: nicotine replacement therapy (NRT), antidepressants, nicotine receptor partial agonists, cannabinoid type 1 receptor antagonists and exercise interventions for smoking cessation published in Issue 9, 2011 of the Cochrane Library. SELECTION CRITERIA: Part 1 - We included trials of interventions that were targeted at post cessation weight gain and had measured weight at any follow up point and/or smoking cessation six or more months after quit day.Part 2 - We included trials that had been included in the selected parent Cochrane reviews if they had reported weight gain at any time point. DATA COLLECTION AND ANALYSIS: We extracted data on baseline characteristics of the study population, intervention, outcome and study quality. Change in weight was expressed as difference in weight change from baseline to follow up between trial arms and was reported in abstinent smokers only. Abstinence from smoking was expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial. Where appropriate, we performed meta-analysis using the inverse variance method for weight and Mantel-Haenszel method for smoking using a fixed-effect model. MAIN RESULTS: Part 1: Some pharmacological interventions tested for limiting post cessation weight gain (PCWG) resulted in a significant reduction in WG at the end of treatment (dexfenfluramine (Mean difference (MD) -2.50 kg, 95% confidence interval (CI) -2.98 to -2.02, 1 study), phenylpropanolamine (MD -0.50 kg, 95% CI 0.80 to -0.20, N=3), naltrexone (MD -0.78 kg, 95% CI -1.52 to -0.05, N=2). There was no evidence that treatment reduced weight at 6 or 12 months (m). No pharmacological intervention significantly affected smoking cessation rates.Weight management education only was associated with no reduction in PCWG at end of treatment (6 or 12m). However these interventions significantly reduced abstinence at 12m (Risk ratio (RR) 0.66, 95% CI 0.48 to 0.90, N=2). Personalised weight management support reduced PCWG at 12m (MD -2.58 kg, 95% CI -5.11 to 0.05, N=2) and was not associated with a significant reduction of abstinence at 12m (RR 0.74, 95% CI 0.39 to 1.43, N=2). A very low calorie diet (VLCD) significantly reduced PCWG at end of treatment (MD -3.70 kg, 95% CI -4.82 to 2.58, N=1), but not significantly so at 12m (MD -1.30 kg, 95% CI -3.49 to 0.89, N=1). The VLCD increased chances of abstinence at 12m (RR 1.73, 95% CI 1.10 to 2.73, N=1). There was no evidence that cognitive behavioural therapy to allay concern about weight gain (CBT) reduced PCWG, but there was some evidence of increased PCWG at 6m (MD 0.74, 95% CI 0.24 to 1.24). It was associated with improved abstinence at 6m (RR 1.83, 95% CI 1.07 to 3.13, N=2) but not at 12m (RR 1.25, 95% CI 0.83 to 1.86, N=2). However, there was significant statistical heterogeneity.Part 2: We found no evidence that exercise interventions significantly reduced PCWG at end of treatment (MD -0.25 kg, 95% CI -0.78 to 0.29, N=4) however a significant reduction was found at 12m (MD -2.07 kg, 95% CI 3.78 to -0.36, N=3).Both bupropion and fluoxetine limited PCWG at the end of treatment (bupropion MD -1.12 kg, 95% CI -1.47 to -0.77, N=7) (fluoxetine MD 0.99 kg, 95% CI -1.36 to -0.61, N=2). There was no evidence that the effect persisted at 6m (bupropion MD -0.58 kg, 95% CI -2.16 to 1.00, N=4), (fluoxetine MD -0.01 kg, 95% CI -1.11 to 1.10, N=2) or 12m (bupropion MD -0.38 kg, 95% CI 2.00 to 1.24, N=4). There were no data on WG at 12m for fluoxetine.Overall, treatment with NRT attenuated PCWG at the end of treatment (MD -0.69 kg, 95% CI 0.88 to -0.51, N=19), with no strong evidence that the effect differed for the different forms of NRT. There was evidence of significant statistical heterogeneity caused by one study which reported a 4.3 kg reduction in PCWG due to NRT. With this study removed, the difference in weight change at end of treatment was -0.45 kg (95% CI -0.66 to -0.27, N=18). There was no evidence of an effect on PCWG at 12m (MD -0.42 kg, 95% CI -0.92 to 0.08, N=15).We found evidence that varenicline significantly reduced PCWG at end of treatment (MD -0.41 kg, 95% CI -0.63 to -0.19, N=11), but this effect was not maintained at 6 or 12m. Three studies compared the effect of bupropion to varenicline. Participants taking bupropion gained significantly less weight at the end of treatment (-0.51 kg (95% CI -0.93 to -0.09 kg), N=3). Direct comparison showed no significant difference in PCWG between varenicline and NRT. AUTHORS' CONCLUSIONS: Although some pharmacotherapies tested to limit PCWG show evidence of short-term success, other problems with them and the lack of data on long-term efficacy limits their use. Weight management education only, is not effective and may reduce abstinence. Personalised weight management support may be effective and not reduce abstinence, but there are too few data to be sure. One study showed a VLCD increased abstinence but did not prevent WG in the longer term. CBT to accept WG did not limit PCWG and may not promote abstinence in the long term. Exercise interventions significantly reduced weight in the long term, but not the short term. More studies are needed to clarify whether this is an effect of treatment or a chance finding. Bupropion, fluoxetine, NRT and varenicline reduce PCWG while using the medication. Although this effect was not maintained one year after stopping smoking, the evidence is insufficient to exclude a modest long-term effect. The data are not sufficient to make strong clinical recommendations for effective programmes to prevent weight gain after cessation. PMID- 22258967 TI - Non-pharmacological interventions for preventing venous insufficiency in a standing worker population. AB - BACKGROUND: Chronic venous insufficiency (CVI) is a common problem, affecting up to 50% of the population in industrialised countries. It is a chronic condition which, if untreated, can progress to serious complications that in turn can interfere with working ability. Standing at work is a known risk factor for CVI, yet the true effect of non-pharmacological preventive strategies remains unknown. OBJECTIVES: To undertake a systematic review of randomised or controlled clinical trials to assess the efficacy of non-pharmacological strategies and devices to prevent CVI in a standing worker population. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases (PVD) Group searched their Specialised Register (last searched April 2011) and CENTRAL (Issue 2, 2011). No date or language restrictions were applied. We also handsearched reference lists of relevant studies. SELECTION CRITERIA: Randomised and non-randomised controlled trials that recruited standing workers to evaluate non-pharmacological devices or strategies used to prevent CVI were eligible for inclusion. Trials had to report an objective measure of clinical features of CVI or complaints associated with this condition in order to be included. DATA COLLECTION AND ANALYSIS: Selection of the trials, quality assessment and data abstraction were completed independently by two review authors. We resolved disagreements by discussion. Only one trial was eligible for inclusion in the review so we did not perform meta-analyses. MAIN RESULTS: The primary outcomes of this review were clinical features of CVI and its associated symptoms. One prospective cross-over trial was included in this review. It measured the effect of no compression followed by two phases with different gradients of compression stockings on symptoms in 19 female flight attendants who were required to stand, almost continuously, for long periods of time. The included study provided some evidence that compression stockings improved symptoms of leg fatigue in standing workers. However, the strength of the evidence in this review is weak as it is based on only one very small trial which was at high risk of bias. The included study did not address any of the secondary outcomes including quality of life or economic impact of the interventions. Nor did the study report the length of time that the population were required to stand at work. Furthermore, no trials were found which measured the effectiveness of other non-pharmacological interventions or strategies aimed at preventing CVI in standing workers. AUTHORS' CONCLUSIONS: Due to the extremely limited number of trials, there is insufficient evidence to draw any conclusions about the effectiveness of non-pharmacological interventions for preventing CVI in standing workers. Further large-scale studies examining all possible non pharmacological interventions and outcomes are required. PMID- 22258968 TI - Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common infectious disease in intensive care units (ICUs). The best diagnostic approach to resolve this condition remains uncertain. OBJECTIVES: To evaluate whether quantitative cultures of respiratory secretions are effective in reducing mortality in immunocompetent patients with VAP, compared with qualitative cultures. We also considered changes in antibiotic use, length of ICU stay and mechanical ventilation. SEARCH METHODS: We searched The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to June Week 4, 2011), EMBASE (1974 to June 2011) and LILACS (1982 to June 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing respiratory samples processed quantitatively or qualitatively, obtained by invasive or non-invasive methods from immunocompetent patients with VAP and which analysed the impact of these methods on antibiotic use and mortality rates. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and trials identified in the search results and assessed studies for suitability, methodology and quality. We analysed data using Review Manager software. We pooled the included studies to yield the risk ratio (RR) for mortality and antibiotic change with 95% confidence intervals (CI). MAIN RESULTS: Of the 4459 references identified from the electronic databases, five RCTs (1367 patients) met the inclusion criteria. Three studies compared invasive methods using quantitative cultures versus non-invasive methods using qualitative cultures, and were used to answer the main objective of this review. The other two studies compared invasive versus non-invasive methods, both using quantitative cultures. We combined all five studies to compare invasive versus non-invasive interventions for diagnosing VAP. The studies that compared quantitative and qualitative cultures (1240 patients) showed no statistically significant differences in mortality rates (RR 0.91; 95% CI 0.75 to 1.11). The analysis of all five RCTs showed there was no evidence of reduction in mortality in the invasive group versus the non-invasive group (RR 0.93; 95% CI 0.78 to 1.11). There were no significant differences between the interventions with respect to the number of days on mechanical ventilation, length of ICU stay or antibiotic change. AUTHORS' CONCLUSIONS: There is no evidence that the use of quantitative cultures of respiratory secretions results in reduced mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change when compared to qualitative cultures in patients with VAP. Similar results were observed when invasive strategies were compared with non-invasive strategies. PMID- 22258969 TI - Tranexamic acid for upper gastrointestinal bleeding. AB - BACKGROUND: Tranexamic acid reduces haemorrhage through its antifibrinolytic effects. In a previous version of the present review, we found that tranexamic acid may reduce mortality. The present review includes updated searches of randomised trials on tranexamic acid versus placebo, cimetidine or lansoprazole. OBJECTIVES: To assess the effects of tranexamic acid for upper gastrointestinal bleeding. SEARCH METHODS: Electronic searches (The Cochrane Library, MEDLINE, EMBASE, Science Citation Index) and manual searches were combined. The last search update was in October 2011. SELECTION CRITERIA: Trials in which patients with upper gastrointestinal bleeding were randomised to receive either tranexamic acid or placebo, or any anti-ulcer drug, were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. All-cause mortality was the primary outcome measure. Random-effects model meta-analyses were performed and results presented as relative risks (RR) with 95% confidence intervals (CI). Subgroup, sensitivity, regression and sequential analyses were performed to analyse sources of intertrial heterogeneity and the robustness of the overall result. MAIN RESULTS: Seven double blind randomised trials on tranexamic acid versus placebo, cimetidine, or lanzoprazole were included. One trial offered endoscopic treatment to all patients that were randomised. Random-effects model meta-analysis found that tranexmic acid reduced mortality compared with placebo (41 of 829 versus 68 of 825 patients; RR: 0.61, 95% CI 0.42 to 0.89). The beneficial effect was not confirmed in subgroup analysis stratified for the quality of bias control, in worst case scenario analyses (in which 21% of the randomised patients were excluded), or in sequential analyses. No significant differences were found between tranexamic acid and placebo on bleeding, surgery, or transfusion requirements. No clear effects of tranexamic acid were identified in trials using endoscopic therapy or in the trials comparing tranexamic acid with cimetidine or lansoprazole. In the tranexamic acid group, five cases of serious thromboembolic events occurred (myocardial infarction, pulmonary embolism, and cerebral infarction). Overall, the number of patients with any thrombotic event was not significantly increased in the tranexamic acid group (RR 1.87, 95% CI 0.60 to 5.85). AUTHORS' CONCLUSIONS: Considering the internal and external validity of the evidence, tranexamic acid cannot be recommended for routine use. Additional trials in which tranexamic acid is used in combination with the currently recommended interventions are required. PMID- 22258970 TI - Pentoxifylline for endometriosis. AB - BACKGROUND: Endometriosis is a chronic, recurring condition that occurs during the reproductive years. It is characterized by endometrial tissue developing outside the uterine cavity. This endometrial tissue development is dependent on oestrogen produced primarily by the ovaries and, therefore, traditional management has focused on ovarian suppression. In this review we considered the role of modulation of the immune system as an alternative approach. This is an update of a Cochrane Review previously published in 2009 (Lu 2009). OBJECTIVES: To assess the effects of pentoxifylline, which has anti-inflammatory effects, in subfertile, premenopausal women for the management of endometriosis. SEARCH METHODS: For the first publication of this review we searched the following databases (from inception to December 2008) for trials: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and PsycINFO. In addition, all reference lists of included trials were searched and experts in the field were contacted in an attempt to locate trials. This search was rerun to 23 November 2011, for this update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing pentoxifylline with placebo or no treatment, medical treatment, or surgery in subfertile, premenopausal women were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial risk of bias, and extracted data using data extraction forms. We contacted study authors for additional information and data. The domains assessed for risk of bias were sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. Peto odds ratios (OR) were used for reporting dichotomous data with 95% confidence intervals (CI), whilst mean differences (MD) were expressed for continuous data. Statistical heterogeneity was assessed using the I(2) statistic. MAIN RESULTS: Four trials involving 334 participants were included. One RCT [n=34] showed pentoxifylline had no significant effect on reduction in pain (MD 1.60, 95% CI -3.32 to 0.12). There was no evidence of an increase in clinical pregnancy events in the pentoxifylline group compared with placebo (three RCTs [n=67] OR 1.54, 95% CI 0.89 to 266). One RCT studied recurrence of endometriosis [n=88] (OR 0.88,95% CI 0.27 to 2.84). No trials reported the effects of pentoxifylline on the odds of live birth rate per woman, improvement of endometriosis-related symptoms, or adverse events. AUTHORS' CONCLUSIONS: This review has been updated in 2011. The results of the original review published in 2009 remain unchanged. There is still not enough evidence to support the use of pentoxifylline in the management of premenopausal women with endometriosis in terms of subfertility and relief of pain outcomes. PMID- 22258971 TI - High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. AB - BACKGROUND: Follicular lymphoma (FL) is the most common indolent and second most common Non-Hodgkin's lymphoma (NHL) in the Western world. Standard treatment usually includes rituximab and chemotherapy. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is an option for patients in advanced stages or for second-line therapy, leading to improved progression-free survival (PFS) rates. However, the impact of HDT and ASCT remains unclear, as there are hints of an increased risk of second cancers. OBJECTIVES: We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing HDT plus ASCT with chemotherapy or immuno-chemotherapy in patients with FL with respect to overall survival (OS), PFS, treatment-related mortality (TRM), adverse events and secondary malignancies. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE as well as conference proceedings from January 1985 to September 2011 for RCTs. Two review authors independently screened search results. SELECTION CRITERIA: Randomised controlled trials comparing chemotherapy or immuno-chemotherapy with HDT followed by ASCT in adults with previously untreated or relapsed FL. DATA COLLECTION AND ANALYSIS: We used hazard ratios (HR) as effect measures used for OS and PFS as well as relative risks for response rates. Two review authors independently extracted data and assessed the quality of trials. MAIN RESULTS: Our search strategies led to 3046 potentially relevant references. Of these, five RCTs involving 1093 patients were included; four trials in previously untreated patients and one trial in relapsed patients. Overall, the quality of the five trials is judged to be moderate. All trials were reported as randomised and judged to be open-label studies, because usually trials evaluating stem cell transplantation are not blinded. Due to the small number of studies in each analysis (four or less), the quantification of heterogeneity was not reliable and not evaluated in further detail. A potential source of bias are uncertainties in the HR calculation. For OS, the HR had to be calculated for three trials from survival curves, for PFS for two trials.We found a statistically significant increased PFS in previously untreated FL patients in the HDT + ASCT arm (HR = 0.42 (95% confidence interval (CI) 0.33 to 0.54; P < 0.00001). However, this effect is not transferred into a statistically significant OS advantage (HR = 0.97; 95% 0.76 to 1.24; P = 0.81). The subgroup of trials adding rituximab to both intervention arms (one trial) confirms these results and the trial had to be stopped early after an interim analysis due to a statistically significant PFS advantage in the HDT + ASCT arm (PFS: HR = 0.36; 95% CI 0.23 to 0.55; OS: HR = 0.88; 95% CI 0.40 to 1.92). In the four trials in previously untreated patients there are no statistically significant differences between HDT + ASCT and the control-arm in terms of TRM (RR = 1.28; 95% CI 0.25 to 6.61; P = 0.77), secondary acute myeloid leukaemia/myelodysplastic syndromes (RR = 2.87; 95% CI 0.7 to 11.75; P = 0.14) or solid cancers (RR = 1.20; 95% CI 0.25 to 5.77; P = 0.82). Adverse events were rarely reported and were observed more frequently in patients undergoing HDT + ASCT (mostly infections and haematological toxicity).For patients with relapsed FL, there is some evidence (one trial, N = 70) that HDT + ASCT is advantageous in terms of PFS and OS (PFS: HR = 0.30; 95% CI 0.15 to 0.61; OS: HR = 0.40; 95% CI 0.18 to 0.89). For this trial, no results were reported for TRM, adverse events or secondary cancers. AUTHORS' CONCLUSIONS: In summary, the currently available evidence suggests a strong PFS benefit for HDT + ASCT compared with chemotherapy or immuno chemotherapy in previously untreated patients with FL. No statistically significant differences in terms of OS, TRM and secondary cancers were detected. These effects are confirmed in a subgroup analysis (one trial) adding rituximab to both treatment arms. Further trials evaluating this approach are needed to determine this effect more precisely in the era of rituximab. Moreover, longer follow-up data are necessary to find out whether the PFS advantage will translate into an OS advantage in previously untreated patients with FL.There is evidence that HDT + ASCT is advantageous in patients with relapsed FL. PMID- 22258972 TI - Excimer laser refractive surgery versus phakic intraocular lenses for the correction of moderate to high myopia. AB - BACKGROUND: Myopia is a condition in which the focusing power (refraction) of the eye is greater than that required for clear distance vision. There are two main types of surgical correction for moderate to high myopia; excimer laser and phakic intraocular lenses (IOLs). Excimer laser refractive surgery for myopia works by removing corneal stroma to lessen the refractive power of the cornea and to bring the image of a viewed object into focus onto the retina rather than in front of it. Phakic IOLs for the treatment of myopia work by diverging light rays so that the image of a viewed object is brought into focus onto the retina rather than in front of the retina. They can be placed either in the anterior chamber of the eye in front of the iris or in the posterior chamber of the eye between the iris and the natural lens. OBJECTIVES: The aim of this review is to compare the effect of excimer laser refractive surgery versus phakic IOLs for the correction of moderate to high myopia. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 11), MEDLINE (January 1950 to November 2011), EMBASE (January 1980 to November 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 28 November 2011. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing excimer laser refractive surgery and phakic IOLs for the correction of myopia greater than 6.0 diopters (D) spherical equivalent. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We performed data analysis. We summarised data for outcomes using odds ratios. We used a fixed-effect model as only three trials were included in the review. MAIN RESULTS: This review included three RCTs with a total of 228 eyes. The range of myopia of included patients was -6.0 D to -20.0 D of myopia with up to 4.0 D of myopic astigmatism. The percentage of eyes with uncorrected visual acuity (UCVA) of 20/20 or better at 12 months postoperative was not significantly different between the two groups. Phakic IOL surgery was safer than excimer laser surgical correction for moderate to high myopia as it results in significantly less loss of best spectacle corrected visual acuity (BSCVA) at 12 months postoperatively. However there is a low risk of developing early cataract with phakic IOLs. Phakic IOL surgery appears to result in better contrast sensitivity than excimer laser correction for moderate to high myopia. Phakic IOL surgery also scored more highly on patient satisfaction/preference questionnaires. AUTHORS' CONCLUSIONS: The results of this review suggest that phakic IOLs are safer than excimer laser surgical correction for moderate to high myopia in the range of -6.0 to -20.0 D and phakic IOLs are preferred by patients. While phakic IOLs might be accepted clinical practice for higher levels of myopia (greater than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism), it may be worth considering phakic IOL treatment over excimer laser correction for more moderate levels of myopia (less than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism). Further RCTs adequately powered for subgroup analysis are necessary to further elucidate the ideal range of myopia for phakic IOLs. PMID- 22258973 TI - Manipulative interventions for reducing pulled elbow in young children. AB - BACKGROUND: Pulled elbow (nursemaid's elbow) is a common injury in young children. It results from a sudden pull on the arm, usually by an adult or taller person, which pulls the radius through the annular ligament, resulting in subluxation (partial dislocation) of the radial head. The child experiences sudden acute pain and loss of function in the affected arm. Pulled elbow is usually treated by manual reduction of the subluxed radial head. Various manoeuvres can be applied. Most textbooks recommend supination of the forearm, as opposed to pronation and other approaches. It is unclear which manoeuvre is most successful. This is an update of a Cochrane review first published in 2009. OBJECTIVES: The objective of this review is to compare the effectiveness and painfulness of the different methods used to manipulate pulled elbow in young children. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, LILACS, PEDro, clinical trial registers and reference lists of articles. Date of last search: July 2011. SELECTION CRITERIA: Any randomised or quasi-randomised controlled clinical trials evaluating manipulative interventions for pulled elbow were included. Our primary outcome was failure at the first attempt, necessitating further treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trials for inclusion and, for the included trials, independently assessed the risk of bias and extracted data. MAIN RESULTS: One trial with 66 children was newly included in this update. Overall, four trials with 379 children, all younger than seven years old, were included. All four trials compared pronation versus supination. One trial was at high risk of selection bias because allocation was not concealed and all four trials were at high risk of detection bias due to the lack of assessor blinding. Pronation resulted in statistically significantly less failure than supination (21/177 versus 47/181, risk ratio 0.45; 95% confidence interval 0.28 to 0.73). Pain perception was reported by two trials but data were unavailable for pooling. Both studies concluded that the pronation technique was less painful than the supination technique. AUTHORS' CONCLUSIONS: There is limited evidence from four small low-quality trials that the pronation method might be more effective and less painful than the supination method for manipulating pulled elbow in young children. We recommend that a high quality randomised trial be performed to strengthen the evidence. PMID- 22258974 TI - Parenteral versus oral iron therapy for adults and children with chronic kidney disease. AB - BACKGROUND: The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. OBJECTIVES: To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD. SEARCH METHODS: In March 2010 we searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE and EMBASE without language restriction. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in which oral and IV routes of iron administration were compared in adults and children with CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and for continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. MAIN RESULTS: Twenty eight studies (2098 participants) were included. Risk of bias attributes were poorly performed and/or reported with low risk of bias reported in 12 (43%) studies for sequence generation, incomplete outcome reporting and selective outcome reporting and in 6 (16%) studies for allocation concealment. No study was blinded for participants, investigators and outcome assessors but all were considered at low risk of bias because the primary outcome of haemoglobin was a laboratory outcome and unlikely to be influenced by lack of blinding. Haemoglobin (22 studies, 1862 patients: MD 0.90 g/dL, 95% CI 0.44 to 1.37); ferritin (24 studies, 1751 patients: MD 243.25 MUg/L, 95% CI 188.74 to 297.75); and transferrin saturation (18 studies, 1457 patients: MD 10.20%, 95% CI 5.56 to 14.83) were significantly increased by IV iron compared with oral iron. There was a significant reduction in erythropoiesis-stimulating agent (ESA) dose in patients receiving dialysis who were treated with IV iron (9 studies, 487 patients: SMD -0.76, 95% CI -1.22 to 0.30). There was a high level of heterogeneity in all analyses. Mortality and cardiovascular morbidity did not differ significantly, but were reported in few studies. Gastrointestinal side effects were more common with oral iron, but hypotensive and allergic reactions were more common with IV iron. AUTHORS' CONCLUSIONS: The included studies provide strong evidence for increased ferritin and transferrin saturation levels, together with a small increase in haemoglobin, in patients with CKD who were treated with IV iron compared with oral iron. From a limited body of evidence, we identified a significant reduction in ESA requirements in patients treated with IV iron, and found no significant difference in mortality. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects. PMID- 22258975 TI - Endoscopic or surgical intervention for painful obstructive chronic pancreatitis. AB - BACKGROUND: Endoscopy and surgery are the treatment modalities of choice in patients with obstructive chronic pancreatitis. Physicians face the decision between endoscopy and surgery for this group of patients, without clear consensus. OBJECTIVES: To assess and compare the effectiveness and complications of surgical and endoscopic interventions in the management of pain for obstructive chronic pancreatitis. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE and the Conference Proceedings Citation Index; and performed a cross-reference search. Two review authors performed the selection of trials independently. SELECTION CRITERIA: All randomised controlled trials (RCTs) investigating endoscopic or surgical interventions for obstructive chronic pancreatitis. All trials were included irrespective of blinding, number of patients randomised and language of the article. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the articles. The methodological quality of included trials was evaluated. Authors were requested additional information in the case of missing data. MAIN RESULTS: We screened 2082 publications and identified three eligible trials. Two trials compared endoscopic intervention to surgical intervention. These included a total of 111 patients, 55 in the endoscopic group and 56 in the surgical group. A higher proportion of patients with pain relief was found in the surgical group compared to the endoscopic group (partial or complete pain relief: RR 1.62, 95% confidence interval (CI) 1.11 to 2.37; complete pain relief: RR 2.45, 95% CI 1.18 to 5.09). Surgical intervention resulted in improved quality of life and improved preservation of exocrine pancreatic function in one trial. The number of patients did not allow for a reliable evaluation of morbidity and mortality between the two treatment modalities. One trial compared surgical intervention to conservative treatment. It included 32 patients: 17 in the surgical group and 15 in the conservative group. The trial showed that surgical intervention resulted in a higher percentage of patients with pain relief and better preservation of pancreatic function. The trial had methodological limitations and the number of patients was relatively small. AUTHORS' CONCLUSIONS: For patients with obstructive chronic pancreatitis and dilated pancreatic duct, this review showed that surgery is superior to endoscopy in terms of pain control. Morbidity and mortality seemed not to differ between the two intervention modalities, but the small trials identified do not provide sufficient power to detect the small differences expected in this outcome.Regarding the comparison of surgical intervention versus conservative treatment, this review has shown that surgical intervention in an early stage of chronic pancreatitis seems to be a promising approach in terms of pain control and pancreatic function. Confirmation of these results is needed in other trials due to the methodological limitations and limited number of patients of the present evidence. PMID- 22258976 TI - Material incentives and enablers in the management of tuberculosis. AB - BACKGROUND: Patient adherence to medications, particularly for conditions requiring prolonged treatment such as tuberculosis, is frequently less than ideal, and can result in poor treatment outcomes. Material incentives (given as cash, vouchers and tokens), have been used to improve adherence. OBJECTIVES: To assess the effects of material incentives in people undergoing diagnostic testing, or receiving prophylactic or curative therapy, for tuberculosis. SEARCH METHODS: We undertook a comprehensive search of the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; Science Citation Index; and reference lists of relevant publications; to 22 June 2011. SELECTION CRITERIA: Randomized controlled trials of material incentives in patients being investigated for tuberculosis, or on treatment for latent or active disease. DATA COLLECTION AND ANALYSIS: At least two authors independently screened and selected studies, extracted data, and assessed the risk of bias. The effects of interventions are compared using risk ratios (RR), and presented with 95% confidence intervals (CI). The quality of the evidence was assessed using GRADE. MAIN RESULTS: We identified 11 eligible studies. Ten were conducted in the USA: in adolescents (one trial), in injection drug or cocaine users (four trials), in homeless adults (three trials), and in prisoners (two trials). One additional trial recruited malnourished men receiving active treatment for tuberculosis in Timor Leste.Material incentives may increase the return rate for reading of tuberculin skin test results compared to normal care (two trials, 1371 participants: RR 2.16, 95% CI 1.41 to 3.29, low quality evidence).Similarly, incentives probably improve clinic re-attendance for initiation or continuation of antituberculosis prophylaxis (three trials, 595 participants: RR 1.58, 95% CI 1.27 to 1.96, moderate quality evidence), and may improve subsequent completion of prophylaxis in some settings (three trials, 869 participants: RR 1.79, 95% CI 0.70 to 4.58, low quality evidence).We currently don't know if incentives can improve long-term adherence and completion of antituberculosis treatment for active disease. Only one trial has assessed this and the incentive, given as a daily hot meal, was not well received by the population due to the inconvenience of attending the clinic at midday (one trial, 265 participants, RR 0.98, 95%CI 0.86 to 1.12, very low quality evidence).Several trials have compared different forms or levels of incentive. These comparisons remain limited to single trials and robust conclusions cannot be made. In summary, cash incentives may be more effective than non-cash incentives (return for test results: one trial, 651 participants: RR 1.13, 95%CI 1.07 to 1.19, low quality evidence, adherence to tuberculosis prophylaxis: one trial, 141 participants: RR 1.26, 95%CI 1.02 to 1.56, low quality evidence) and higher amounts of cash may be more effective than lower amounts (return for test results: one trial, 404 participants: RR 1.08, 95%CI 1.01 to 1.16, low quality evidence).Material incentives may also be more effective than motivational education at improving return for tuberculin skin test results (low quality evidence), but may be no more effective than peer counselling, or structured education at improving continuation or completion of prophylaxis (low quality evidence). AUTHORS' CONCLUSIONS: There is limited evidence to support the use of material incentives to improve return rates for tuberculosis diagnostic test results and adherence to antituberculosis preventive therapy. The data are currently limited to trials among predominantly male drug users, homeless, and prisoner subpopulations in the USA, and therefore the results are not easily generalised to the wider adult population, or to low- and middle-income countries, where the tuberculosis burden is highest.Further high quality studies are needed to assess both the costs and effectiveness of incentives to improve adherence to long-term treatment of tuberculosis. PMID- 22258977 TI - Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants. AB - BACKGROUND: Low birth weight and premature infants are at major risk for exaggerated hyperbilirubinaemia and jaundice that can lead to bilirubin encephalopathy. Phototherapy is the most common treatment for neonatal hyperbilirubinaemia and could be most effective in preventing the sequelae of hyperbilirubinaemia if initiated prophylactically. OBJECTIVES: To evaluate the efficacy and safety of prophylactic phototherapy for preterm (< 37 weeks gestational age) or low birth weight infants (birth weight < 2500 g). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3) on 31 March 2011, MEDLINE (1950 to 31 March 2011), EMBASE (1980 to 31 March 2011) and CINAHL (1982 to 31 March 2011). SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled studies evaluating the effects of prophylactic phototherapy for preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: Two authors independently obtained data from published articles. We performed fixed-effect meta-analysis for the outcomes: rate of exchange transfusion, cerebral palsy or other neurodevelopmental impairment, peak serum bilirubin level and all-cause mortality. MAIN RESULTS: Nine studies of 3449 participants were included. The rate of exchange transfusion was reduced in one study with liberal transfusion criteria (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) but not in the other two more recent studies with stringent criteria (typical RR 0.66; 95% CI 0.19 to 2.28). There was no statistically significant difference in the rate of cerebral palsy (typical RR 0.96; 95% CI 0.50 to 1.85; two studies, 756 participants). However, one large study that reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment with prophylactic phototherapy (RR 0.85; 95% CI 0.74 to 0.99; 1804 participants). The prophylactic phototherapy group had lower peak bilirubin levels (mean difference (MD) -2.73; 95% CI -2.89 to -2.57; six studies, 2319 participants) and had fewer neonates with peak unconjugated serum bilirubin levels > 10 mg/dl (typical RR 0.27; 95% CI 0.22 to 0.33; three studies, 1090 participants) or peak unconjugated serum bilirubin levels > 15 mg/dl (typical RR 0.13; 95% CI 0.07 to 0.23; four studies, 1116 participants). There was no statistically significant difference in the rate of all-cause mortality between the two groups (typical RR 1.08; 95% CI 0.93 to 1.26; four studies, 3044 participants). AUTHORS' CONCLUSIONS: Prophylactic phototherapy helps to maintain a lower serum bilirubin concentration and may have an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment. However, further well-designed studies are needed to determine the efficacy and safety of prophylactic phototherapy on long-term outcomes including neurodevelopmental outcomes. PMID- 22258978 TI - Acetylcholinesterase inhibitors for schizophrenia. AB - BACKGROUND: Antipsychotic medication remains the mainstay of treatment for schizophrenia and has been in use for a long time. As evidenced by ongoing research and partial effectiveness of the antipsychotics on cognitive and negative symptoms, the search is on for drugs that may improve these domains of functioning for someone suffering from schizophrenia. Acetylcholinesterase inhibitors have long been in use for treating cognitive symptoms of dementia. OBJECTIVES: The aim of the review was to evaluate the clinical effects, safety and cost effectiveness of acetylcholinesterase inhibitors for treating people with schizophrenia SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Register (February 2009), and inspected the references of all identified studies for further trials. SELECTION CRITERIA: We included all clinical randomised trials comparing acetylcholinesterase inhibitors with antipsychotics or placebo either alone, or in combination, for schizophrenia and schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat (ITT) basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model. MAIN RESULTS: The acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes.1. Mental state - PANSS negative symptoms average end point score (2 RCTs, n = 31, MD -1.69 95% CI -2.80 to -0.57), PANSS General Psychopathology average end point score (2 RCTs, n = 31, MD -3.86 95% CI -5.40 to -2.32), and improvement in depressive symptoms showed at least by one short-term study as measured by CDSS scale (data skewed).2. Cognitive domains - attention, (1 RCT, n = 73, MD 1.20 95% CI 0.14 to 2.26), visual memory (2 RCTs, n = 48 , MD 1.90 95% CI 0.52 to 3.28), verbal memory and language (3 RCTs, n = 42, MD 3.46 95% CI 0.67 to 6.26) and executive functioning (1 RCT, n = 24, MD 17.10 95% CI 0.70 to 33.50).3. Tolerability - EPSE: AIMS, (1 RCT, n = 35, MD 1.50 95% CI 1.04 to 1.96).No difference was noted between the two arms in other outcomes. The overall rate of participants leaving studies early was low (13.6 %) and showed no clear difference between the two groups. AUTHORS' CONCLUSIONS: The results seem to favour the use of acetylcholinesterase inhibitors in combination with antipsychotics on a few domains of mental state and cognition, but because of the various limitations in the studies as mentioned in the main text, the evidence is weak. This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies. PMID- 22258979 TI - Topical treatments for HIV-related oral ulcers. AB - BACKGROUND: In HIV-infected adults, oral ulcers occur more frequently, last longer and produce more painful symptoms than in immunocompetent people. Oral aphthous ulcers observed during the course of HIV infection may be severe and can result in significant morbidity in these patients. Such manifestations may interfere with oral functions and alter patients' quality of life. OBJECTIVES: To evaluate the efficacy and side effects of topical agents used in the treatment of HIV-related oral aphthous ulcers in adults. SEARCH METHODS: The following electronic databases were searched from the year 1980 to May 2011 for randomised controlled trials involving managements of oral ulcers, apthouses in HIV infected adults: EMBASE, PUBMED, the Cochrane Central Register of Controlled Trials (CENTRAL). SELECTION CRITERIA: Only randomised controlled trials that evaluated the efficacy of any topical agent in treating HIV oral aphthous ulcerations in HIV positive adults were considered. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the potentially eligible studies for inclusion. We did not find any studies that meet our eligibility criteria. Therefore, no analysis was performed. MAIN RESULTS: A total of 233 abstracts were retrieved from the databases searched. None of the identified studies met our inclusion criteria. Ten of the studies identified were reports of systemic rather than topical treatment. Therefore, no studies were included in this review. AUTHORS' CONCLUSIONS: There is a need for well designed studies to evaluate the efficacy and safety of topical agents for the treatment of HIV related oral aphthous ulcers. PMID- 22258980 TI - Continuous glucose monitoring systems for type 1 diabetes mellitus. AB - BACKGROUND: Self-monitoring of blood glucose is essential to optimise glycaemic control in type 1 diabetes mellitus. Continuous glucose monitoring (CGM) systems measure interstitial fluid glucose levels to provide semi-continuous information about glucose levels, which identifies fluctuations that would not have been identified with conventional self-monitoring. Two types of CGM systems can be defined: retrospective systems and real-time systems. Real-time systems continuously provide the actual glucose concentration on a display. Currently, the use of CGM is not common practice and its reimbursement status is a point of debate in many countries. OBJECTIVES: To assess the effects of CGM systems compared to conventional self-monitoring of blood glucose (SMBG) in patients with diabetes mellitus type 1. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE and CINAHL for the identification of studies. Last search date was June 8, 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing retrospective or real-time CGM with conventional self-monitoring of blood glucose levels or with another type of CGM system in patients with type 1 diabetes mellitus. Primary outcomes were glycaemic control, e.g. level of glycosylated haemoglobin A1c (HbA1c) and health-related quality of life. Secondary outcomes were adverse events and complications, CGM derived glycaemic control, death and costs. DATA COLLECTION AND ANALYSIS: Two authors independently selected the studies, assessed the risk of bias and performed data-extraction. Although there was clinical and methodological heterogeneity between studies an exploratory meta-analysis was performed on those outcomes the authors felt could be pooled without losing clinical merit. MAIN RESULTS: The search identified 1366 references. Twenty-two RCTs meeting the inclusion criteria of this review were identified. The results of the meta-analyses (across all age groups) indicate benefit of CGM for patients starting on CGM sensor augmented insulin pump therapy compared to patients using multiple daily injections of insulin (MDI) and standard monitoring blood glucose (SMBG). After six months there was a significant larger decline in HbA1c level for real-time CGM users starting insulin pump therapy compared to patients using MDI and SMBG (mean difference (MD) in change in HbA1c level -0.7%, 95% confidence interval (CI) -0.8% to -0.5%, 2 RCTs, 562 patients, I(2)=84%). The risk of hypoglycaemia was increased for CGM users, but CIs were wide and included unity (4/43 versus 1/35; RR 3.26, 95% CI 0.38 to 27.82 and 21/247 versus 17/248; RR 1.24, 95% CI 0.67 to 2.29). One study reported the occurrence of ketoacidosis from baseline to six months; there was however only one event. Both RCTs were in patients with poorly controlled diabetes.For patients starting with CGM only, the average decline in HbA1c level six months after baseline was also statistically significantly larger for CGM users compared to SMBG users, but much smaller than for patients starting using an insulin pump and CGM at the same time (MD change in HbA1c level -0.2%, 95% CI 0.4% to -0.1%, 6 RCTs, 963 patients, I(2)=55%). On average, there was no significant difference in risk of severe hypoglycaemia or ketoacidosis between CGM and SMBG users. The confidence interval however, was wide and included a decreased as well as an increased risk for CGM users compared to the control group (severe hypoglycaemia: 36/411 versus 33/407; RR 1.02, 95% CI 0.65 to 1.62, 4 RCTs, I(2)=0% and ketoacidosis: 8/411 versus 8/407; RR 0.94, 95% CI 0.36 to 2.40, 4 RCTs, I(2)=0%).Health-related quality of life was reported in five of the 22 studies. In none of these studies a significant difference between CGM and SMBG was found. Diabetes complications, death and costs were not measured.There were no studies in pregnant women with diabetes type 1 and in patients with hypoglycaemia unawareness. AUTHORS' CONCLUSIONS: There is limited evidence for the effectiveness of real-time continuous glucose monitoring (CGM) use in children, adults and patients with poorly controlled diabetes. The largest improvements in glycaemic control were seen for sensor-augmented insulin pump therapy in patients with poorly controlled diabetes who had not used an insulin pump before. The risk of severe hypoglycaemia or ketoacidosis was not significantly increased for CGM users, but as these events occurred infrequent these results have to be interpreted cautiously.There are indications that higher compliance of wearing the CGM device improves glycosylated haemoglobin A1c level (HbA1c) to a larger extent. PMID- 22258981 TI - Continuous passive motion for preventing venous thromboembolism after total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is a common form of orthopedic surgery. Venous thromboembolism (VTE), which consists of deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major and potentially fatal complication after TKA. The incidence of DVT after TKA is 40% to 80% and the incidence of PE is approximately 2%. It is generally agreed that thromboprophylaxis should be used in patients who undergo TKA. Both pharmacological and mechanical methods are used in the prevention of DVT. Pharmacological methods alter the blood coagulation profile and may increase the risk of bleeding complications. When pharmacological methods cannot be used, the mechanical methods become crucial for VTE prophylaxis. Continuous passive motion (CPM) is through an external motorised device which enables a joint to move passively throughout a preset arc of motion. Despite the theoretical effectiveness and widespread use of CPM, there are still differing views on the effectiveness of CPM as prophylaxis against thrombosis after TKA. OBJECTIVES: The aim of this review is to determine the effectiveness of continuous passive motion therapy for preventing thrombosis in patients after total knee arthroplasty (TKA). SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched January 2011), CENTRAL (2011, Issue 1), MEDLINE (1948 to Week 2 January 2011) and EMBASE (1980 to Week 3 January 2011). In addition, the authors searched the reference lists of identified trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the use of CPM with control in preventing DVT or PE after TKA. People aged 18 years and older who have undergone TKA were included in this review. We excluded studies of patients who presented with DVT at baseline. Both the experimental and control groups received similar postoperative care and therapy other than the CPM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the citations retrieved by the search strategies for reports of relevant RCTs. They independently selected trials that satisfied the inclusion criteria, extracted data and undertook quality assessment. Effects were estimated as risk ratios (RRs) or mean differences or standardised mean differences with 95% confidence intervals (CI). Meta-analyses were performed using a fixed-effect model for continuous variables. Where heterogeneity existed (determined by the I(2) statistic), a random-effects model was used. MAIN RESULTS: Ten randomised controlled trials involving 764 participants met the inclusion criteria. Four studies with a total of 361 patients reported the incidence of DVT. In the CPM group (182 patients) 36 developed DVT (20%) compared to 28 (16%) the control group of 179 patients. The meta-analysis result showed no evidence that CPM had any effect on preventing VTE after TKA (RR 1.27, 95% CI 0.87 to 1.86). One trial (150 participants) did not find PE in any of the patients during hospitalisation or in the subsequent three months. None of the trials reported any deaths of the included participants. AUTHORS' CONCLUSIONS: There is not enough evidence from the available RCTs to conclude that CPM reduces VTE after TKA. We cannot assess the effect of CPM on death because no such events occurred amongst the participants of these trials. PMID- 22258982 TI - Intramedullary nailing for tibial shaft fractures in adults. AB - BACKGROUND: Intramedullary nailing is commonly used for treating fractures of the tibial shaft. These fractures are one of the most common long bone fractures in adults. OBJECTIVES: To assess the effects (benefits and harms) of different methods and types of intramedullary nailing for treating tibial shaft fractures in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and reference lists of articles to December 2009. The search was subsequently updated to September 2011 to assess the more recent literature. SELECTION CRITERIA: Randomised and quasi-randomised controlled clinical studies evaluating different methods and types of intramedullary nailing for treating tibial shaft fractures in adults were included. Primary outcomes were health related quality of life, patient-reported function and re-operation for treatment failure or complications. DATA COLLECTION AND ANALYSIS: At least two review authors independently performed study selection, risk of bias assessment, and data collection and extraction. MAIN RESULTS: Nine randomised and two quasi randomised clinical trials, involving a total of 2093 participants with 2123 fractures, were included. The evidence was dominated by one large multicentre trial of 1319 participants. Both quasi-randomised trials were at high risk of selection bias. Otherwise, the trials were generally at low or unclear risk of bias. There were very few data on functional outcomes; and often incomplete data on re-operations. The trials evaluated five different comparisons of interventions: reamed versus unreamed intramedullary nailing (six trials); Ender nail versus interlocking nail (two trials); expandable nail versus interlocking nail (one trial); interlocking nail with one distal screw versus with two distal screws (one trial); and closed nailing via the transtendinous approach versus the paratendinous approach (one trial).No statistically significant differences were found between the reamed and unreamed nailing groups in 'major' re-operations (66/789 versus 72/756; risk ratio (RR) 0.88, 95% confidence interval (CI) 0.64 to 1.21; 5 trials), or in the secondary outcomes of nonunion, pain, deep infection, malunion and compartment syndrome. While inconclusive, the evidence from a subgroup analysis suggests that reamed nailing is more likely to reduce the incidence of major re-operations related to non-union in closed fractures than in open fractures. Implant failure, such as broken screws, occurred less often in the reamed nailing group (35/789 versus 79/756; RR 0.42, 95% CI 0.28 to 0.61).There was insufficient evidence established to determine the effects of interlocking nail with one distal screw versus with two distal screws, interlocking nail versus expandable nail and paratendinous approach versus transtendinous approach for treating tibial shaft fractures in adults.Ender nails when compared with an interlocking nail in two trials resulted in a higher re operation rate (12/110 versus 3/128; RR 4.43, 95% CI 1.37 to 14.32) and more malunions. There were no statistically significant differences between the two devices in the other reported secondary outcomes of nonunion, deep infection, and implant failure.One trial found a lower re-operation rate for an expandable nail when compared with an interlocking nail (1/27 versus 9/26; RR 0.11, 95% CI 0.01 to 0.79). The differences between the two nails in the incidence of deep infection or neurological defects were not statistically significant.The trial comparing one distal screw versus two distal screws found no statistically significant difference in nonunion between the two groups. However, it found significantly more implant failures in the one distal screw group (13/22 versus 1/20; RR 11.82, 95% CI 1.70 to 82.38).One trial found no statistically significant differences in functional outcomes or anterior knee pain at three year follow-up between the transtendinous approach and the paratendinous approach for nail insertion. AUTHORS' CONCLUSIONS: Overall, there is insufficient evidence to draw definitive conclusions on the best type of, or technique for, intramedullary nailing for tibial shaft fractures in adults. 'Moderate' quality evidence suggests that there is no clear difference in the rate of major re operations and complications between reamed and unreamed intramedullary nailing. Reamed intramedullary nailing has, however, a lower incidence of implant failure than unreamed nailing. 'Low' quality evidence suggests that reamed nailing may reduce the incidence of major re-operations related to non-union in closed fractures rather than in open fractures. 'Low' quality evidence suggests that the Ender nail has poorer results in terms of re-operation and malunion than an interlocking nail. PMID- 22258983 TI - Narrow band imaging versus conventional white light colonoscopy for the detection of colorectal polyps. AB - BACKGROUND: It has been suggested that narrow band imaging colonoscopy (NBI) might be better for detection of colorectal polyps than white light colonoscopy (WLC). OBJECTIVES: To compare standard or high definition white light colonoscopy with narrow band imaging colonoscopy for detection of colorectal polyps. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, and EMBASE to August 2011. We scanned bibliographies of relevant publications and wrote to experts for additional trials. SELECTION CRITERIA: Two authors (NA and GB) independently applied the inclusion criteria and extracted the data to all potential studies without blinding. DATA COLLECTION AND ANALYSIS: Authors extracted data independently. Trials with adequate randomisation, allocation concealment, and complete outcome data reporting, as well as without selective outcome reporting or other bias were classified as having a lowest risk of bias. Random-effects and fixed-effect meta-analyses were conducted. MAIN RESULTS: We identified 11 randomised trials comparing WLC with NBI for detection of colorectal polyps. In total eight randomised trials with 3673 participants provided data for our analyses. There was no statistically significant difference between WLC (standard definition and high definition pooled) and NBI for the detection of patients with colorectal polyps (6 trials, n = 2832, RR 0.97, 95% CI 0.91 to 1.04), patients with colorectal adenomas (8 trials, n = 3673, RR 0.94, 95% CI 0.87 to 1.02), or patients with colorectal hyperplastic polyps (2 trials, n = 645, RR 0.87, 95% CI 0.76 to 1.00). Number of patients with at least one colorectal adenoma was not significantly different between WLC and NBI group irrespective of adenoma size (< 5 mm:RR 0.95, 95% CI 0.84 to 1.08, I(2) = 56%; 6 to 9 mm: RR 1.06, 95% CI 0.81 to 1.39, I(2) = 0%; >= 10 mm: RR 1.06, 95% CI 0.77 to 1.45, I(2) = 0%). Number of patients with at least one colorectal polyp, or colorectal adenoma was significantly lower in the standard definition WLC group compared to NBI group in fixed-effect meta-analysis (RR 0.87, 95% CI 0.78 to 0.97, I(2) = 78%; RR 0.87, 95% CI 0.77 to 0.99, I(2) = 0%, respectively), but not significantly different in random-effects meta-analysis (RR 0.86, 95% CI 0.68 to 1.10, I(2) = 78%). There was no statistically significant difference between high definition WLC and NBI in the number of patiens with at least one colorectal polyp or colorectal adenoma (RR 1.10, 95% CI 0.95 to 1.28; RR 0.87, 95% CI 0.77 to 0.99, I(2) = 0%, respectively). AUTHORS' CONCLUSIONS: We could not find convincing evidence that NBI is significantly better than high definition WLC for the detection of patients with colorectal polyps, or colorectal adenomas. We found evidence that NBI might be better than standard definition WLC and equal to high definition WLC for detection the patients with colorectal polyps, or colorectal adenomas. PMID- 22258984 TI - Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children. AB - BACKGROUND: Minimally invasive surgery (MIS) is an accepted surgical technique for the treatment of a variety of benign diseases. Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Diagnostic MIS to obtain biopsy specimens for pathology has been accepted as a technique in paediatric surgical oncology, but there is limited experience with the use of MIS for the resection of malignancies. OBJECTIVES: To ascertain the differences in outcome between the minimally invasive and open approach in the treatment of solid intra thoracic and intra-abdominal neoplasms in children, regarding overall survival, event-free survival, port-site metastases, recurrence rate and surgical morbidity. SEARCH METHODS: We searched the electronic databases of MEDLINE/PubMed (from 1966 to February 2011), EMBASE/Ovid (from 1980 to February 2011) and CENTRAL (The Cochrane Library 2011, Issue 1) with pre-specified terms. In addition, we searched reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing MIS and open surgery for the treatment of solid intra-thoracic or intra abdominal neoplasms in children (aged 0 to 18 years). DATA COLLECTION AND ANALYSIS: Two authors performed the study selection independently. MAIN RESULTS: No studies that met the inclusion criteria of this review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs evaluating MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children could be identified, therefore no definitive conclusions could be made about the effects of MIS in these patients. Based on the currently available evidence we are not able to give recommendations for the use of MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children. More high quality studies (RCTs and/or CCTs) are needed. To accomplish this, centres specialising in MIS in children should collaborate. PMID- 22258985 TI - Interventions for fatigue and weight loss in adults with advanced progressive illness. AB - BACKGROUND: Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress. OBJECTIVES: To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews. METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review. MAIN RESULTS: We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies.Management of fatigue Amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration.Management of weight loss ALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition. AUTHORS' CONCLUSIONS: There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures. PMID- 22258986 TI - Non-drug therapies for lower limb muscle cramps. AB - BACKGROUND: About one in every three adults are affected by lower limb muscle cramps. For some people, these cramps reduce quality of life, quality of sleep and participation in activities of daily living. Many interventions are available for lower limb cramps, but some are controversial, no treatment guidelines exist, and often people experience no benefit from the interventions prescribed. OBJECTIVES: To assess the effects of non-drug, non-invasive treatments for lower limb cramp. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (13 September 2011) using the terms: cramp, spasm, contracture, charley horse and lower limb, lower extremity, foot, calf, leg, thigh, gastrocnemius, hamstring, quadriceps. We also searched CENTRAL (2011, Issue 3), MEDLINE (January 1966 to August 2011) and EMBASE (January 1980 to August 2011) and the reference lists of included studies. There were no language or publication restrictions. SELECTION CRITERIA: All randomised controlled trials of non-drug, non-invasive interventions trialled over at least four weeks for the prevention of lower limb muscle cramps in any group of people. We excluded, for example, surgery, acupuncture and dry-needling, as invasive interventions. We selected only trials that included at least one of the following outcomes: cramp frequency, cramp severity, health-related quality of life, quality of sleep, participation in activities of daily living and adverse outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and cross checked data extraction and analysis. A third author was to arbitrate in the event of disagreement. We asked the authors of five trials for information to assist with screening studies for eligibility and received four responses. MAIN RESULTS: One trial was eligible for inclusion. All participants were age 60 years or over and had received a repeat prescription from their general practitioner of quinine for nighttime cramps in the preceding three months. This review includes data from only those participants who were advised to continue taking quinine. Forty-nine participants were advised to complete lean-to-wall calf muscle stretching held for 10 s three times per day. Forty-eight participants were allocated to a placebo stretching group. After 12 weeks, there was no statistically significant difference in recalled cramp frequency between groups. No "significant" adverse effect was reported. Limitations in the study's design impede interpretation of the results and clinical applicability. AUTHORS' CONCLUSIONS: There is limited evidence on which to base clinical decisions regarding the use of non-drug therapies for the treatment of lower limb muscle cramp. Serious methodological limitations in the existing evidence hinder clinical application. There is an urgent need to carefully evaluate many of the commonly recommended and emerging non-drug therapies in well designed randomised controlled trials. PMID- 22258987 TI - Antibiotic therapy for preventing infections in patients with acute stroke. AB - BACKGROUND: Stroke is the main cause of disability in high income countries and ranks second as a cause of death worldwide. Infections occur frequently after stroke and may adversely affect outcome. Preventive antibiotic therapy in the acute phase of stroke may reduce infections and improve outcome. OBJECTIVES: 1. To assess whether preventive antibiotic therapy in patients with acute stroke reduces the risk of dependency and death at follow-up. 2. To assess whether preventive antibiotic therapy in patients with acute stroke reduces infection rate. SEARCH METHODS: We searched the Cochrane Stroke Group's Trials Register (October 2010); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3); MEDLINE (1950 to October 2010) and EMBASE (1980 to October 2010). In an effort to identify further published, unpublished and ongoing trials we searched trials and research registers, scanned reference lists and contacted authors, colleagues and researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) of preventive antibiotic therapy versus control (placebo or open control) in patients with acute ischaemic or haemorrhagic stroke. DATA COLLECTION AND ANALYSIS: Two authors independently selected articles and performed data extraction; we discussed and resolved discrepancies in a consensus meeting with a third observer. We contacted the study authors to obtain missing data when required. An independent observer assessed methodological quality. We calculated relative risks (RRs) for dichotomous outcomes, assessed heterogeneity amongst included studies and performed subgroup analyses on study quality. MAIN RESULTS: We included five studies involving 506 patients. Study population, study design, type of antibiotic and definition of infection differed considerably. The number of patients who died in the preventive antibiotic group was non-significantly reduced (33/248 (13%) versus 38/258 (15%), RR 0.85, 95% confidence interval (CI) 0.47 to 1.51); the number of dependent patients in the preventive antibiotic therapy group was also non-significantly reduced (97/208 (47%) versus 127/208 (61%), RR 0.67, 95% CI 0.32 to 1.43). Preventive antibiotic therapy did reduce the incidence of infections in patients with acute stroke from 36% to 22% (36/166 (22%) versus 61/169 (36%), RR 0.58, 95% CI 0.43 to 0.79). No major side-effects of preventive antibiotic therapy were reported. AUTHORS' CONCLUSIONS: In this meta-analysis, preventive antibiotic therapy seemed to reduce the risk of infection, but did not reduce the number of dependent or deceased patients. However, the included studies were small and heterogeneous. Large randomised trials are urgently needed. PMID- 22258988 TI - Robotic assisted surgery for gynaecological cancer. AB - BACKGROUND: Robotic surgery is the latest innovation in the field of minimally invasive surgery. Robotic surgical systems have been used to perform surgery for endometrial, cervical cancer and ovarian cancer. There is mounting evidence which demonstrates the feasibility and safety of robotic surgery for gynaecological oncology. OBJECTIVES: To evaluate the evidence for and against robotic assisted surgery in gynaecological cancer. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Review Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (up to July 2010) and citation lists of relevant publications. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing robotic assisted surgery for gynaecological cancer to laparoscopic or open surgical procedures as well as RCTs comparing different types of robotic assistants. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion. No RCTs were identified, therefore data collection and analysis could not be performed. MAIN RESULTS: No studies were found that met the inclusion criteria. Controlled clinical trials (CCTs) are summarised and analysed, but are not discussed in the main body of the review as they present a high risk of bias. AUTHORS' CONCLUSIONS: Well-designed RCTs are required as only low quality evidence from CCTs is available. These studies support the use of robotic assisted surgery for endometrial cancer and cervical cancer, but these findings present a high risk of bias. PMID- 22258989 TI - Vigabatrin versus carbamazepine monotherapy for epilepsy. AB - BACKGROUND: The efficacy and safety of vigabatrin (VGB) as an add-on therapy for refractory epilepsy has been well established. However, this needs to be weighed against the risk of the development of visual field defects. Whether VGB monotherapy is an effective and safe treatment compared with the standard antiepileptic drug carbamazepine (CBZ) monotherapy for epilepsy has not been systematically reviewed. OBJECTIVES: To investigate the efficacy and safety of VGB versus CBZ monotherapy for epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (10 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4 of 4, The Cochrane Library 2011) and MEDLINE (1948 to week 4, September 2011), EMBASE (1974 to January 2011) and the Chinese Biomedical Database (CBM) (1979 to January 2011). We searched trials registers and contacted the manufacturer of VGB and authors of included studies for additional information. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing VGB with CBZ monotherapy for epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The primary outcome was time to treatment withdrawal. The secondary outcomes were time to achieve six- and 12 month remission after randomisation, time to first seizure after randomisation and adverse events. Results were presented as hazard ratio (HR) with 95% confidence intervals (CI) (time to event data) or risk ratio (RR) with 95%CI (adverse events). MAIN RESULTS: Five studies involving a total of 734 participants were eligible for inclusion. We assessed only one study as having good quality while the other four were of poor quality. However, it was difficult to perform a meta-analysis by extracting aggregate data to synthesise the results as originally planned, mainly because not all the studies reported the same outcomes as those chosen for this review. There was no significant difference favouring either VGB or CBZ in terms of time to treatment withdrawal and time to achieve six-month remission after dose stabilisation from randomisation, but results did show a disadvantage for VGB on time to first seizure after randomisation. Compared with CBZ, taking VGB was associated with more occurrences of weight gain and less occurrences of skin rash and drowsiness. There were no differences in visual field defects and visual disturbances. AUTHORS' CONCLUSIONS: There is currently insufficient data to address the risk-benefit balance of using VGB versus CBZ monotherapy for epilepsy. Considering the high prevalence of visual field defects, reported in an existing systematic review of observational studies (Maguire 2010), the prescribing of VGB monotherapy for epilepsy should be used with caution and not considered as a first-line choice. If necessary, a frequent assessment of visual field is needed. Future research should focus on investigating the reasons for visual field defects and exploring the potential prevention strategies. Moreover, future monotherapy studies of epilepsy should report results according to the recommendation of International League Against Epilepsy (ILAE) Commission, and methodological quality should be improved. PMID- 22258990 TI - Surgical versus non-surgical interventions for treating humeral shaft fractures in adults. AB - BACKGROUND: Fractures of the shaft of the humerus account for 1% to 3% of all fractures in adults. The management of these fractures, including surgical intervention, varies widely. OBJECTIVES: To assess and compare the effects of surgical versus non-surgical intervention for non-pathological fractures of the humeral shaft in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, trial registers, and bibliographies of trial reports. The full search was conducted in October 2011. SELECTION CRITERIA: Considered for inclusion were all randomised and quasi-randomised (method of allocating participants to a treatment which is not strictly random; e.g. by date of birth, hospital record number or alternation) controlled trials that compared surgical with non-surgical intervention for humeral shaft fractures in adults. DATA COLLECTION AND ANALYSIS: Two authors independently selected and assessed potential eligible studies for inclusion. MAIN RESULTS: We found six completed studies that appeared to meet our inclusion criteria. After scrutiny, we excluded all six studies: five were retrospective studies and one was a prospective study without randomisation. We identified three potentially eligible ongoing studies, two of which involve randomisation of treatment allocation and one, which we excluded, that does not. AUTHORS' CONCLUSIONS: There is no evidence available from randomised controlled trials to ascertain whether surgical intervention of humeral shaft fractures gives a better or worse outcome than no surgery. Sufficiently powered good quality multi-centre randomised controlled trials comparing surgical versus non-surgical interventions for treating humeral shaft fractures in adults are needed. It is likely that the results from the two ongoing randomised trials on this topic will help inform practice in due course. PMID- 22258991 TI - Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. AB - BACKGROUND: Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. Up to now, no curative treatment has been established for those cases. In the last few years, several publications have reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). OBJECTIVES: To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. SEARCH METHODS: The search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to May 2011), Internet-databases of ongoing trials (www.controlled trials.com; www.clinicaltrials.gov), conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to present) and the American Society of Hematology (ASH, 2009 to present). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to 2010 were handsearched. SELECTION CRITERIA: Genetically randomised controlled trials (RCT) comparing alloSCT plus conditioning therapy regardless of agents with conventional therapy as treatment for advanced CTCL were eligible to be included. DATA COLLECTION AND ANALYSIS: From eligible studies data would have been extracted by two review authors and assessed for quality. Primary outcome measures were overall survival, secondary criteria were time to progression, response rate, treatment-related mortality, adverse events and quality of life. MAIN RESULTS: We found 2077 citations but none were relevant genetically or non genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non randomised, not including CTCL or being review articles. AUTHORS' CONCLUSIONS: We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, no randomised trials addressing this question were identified. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL. PMID- 22258992 TI - Neuromodulators for pain management in rheumatoid arthritis. AB - BACKGROUND: Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. OBJECTIVES: The aim of this review was to determine the efficacy and safety of neuromodulators in pain management in patients with RA. Neuromodulators included in this review were anticonvulsants (gabapentin, pregabalin, phenytoin, sodium valproate, lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, tiagabine and topiramate), ketamine, bupropion, methylphenidate, nefopam, capsaicin and the cannabinoids. SEARCH METHODS: We performed a computer-assisted search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, 4th quarter), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44, 2010) and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 and 2009 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conference abstracts and performed a handsearch of reference lists of articles. SELECTION CRITERIA: We included randomised controlled trials which compared any neuromodulator to another therapy (active or placebo, including non pharmacological therapies) in adult patients with RA that had at least one clinically relevant outcome measure. DATA COLLECTION AND ANALYSIS: Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of a neuromodulator on pain, depression and function as well as their safety. MAIN RESULTS: Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants).The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating.In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI 54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this.One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD 0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%). AUTHORS' CONCLUSIONS: There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved. PMID- 22258993 TI - Muscle relaxants for pain management in rheumatoid arthritis. AB - BACKGROUND: Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. OBJECTIVES: The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). SEARCH METHODS: We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. SELECTION CRITERIA: We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. DATA COLLECTION AND ANALYSIS: Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. MAIN RESULTS: Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). AUTHORS' CONCLUSIONS: Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness. PMID- 22258994 TI - Interventions designed to prevent healthcare bed-related injuries in patients. AB - BACKGROUND: Every patient in residential healthcare has a bed. Falling out of bed is associated with preventable patient harm. Various interventions to prevent injury are available. Bed rails are the most common intervention designed to prevent patients falling out of bed; however, their effectiveness is uncertain and bed rail entrapment can also result in injuries. OBJECTIVES: To assess the effectiveness of interventions designed to prevent patient injuries and falls from their beds. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials 2010, Issue 2 (The Cochrane Library), MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCO), ISOI Web of Science and Web-based trials registers (all to December 2010) as well as reference lists. SELECTION CRITERIA: Randomised controlled trials of interventions designed to prevent patient injuries from their beds which were conducted in hospitals, nursing care facilities or rehabilitation units were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data from the included studies. Authors contacted investigators to obtain missing information. MAIN RESULTS: Two studies met the inclusion criteria, involving a total of 22,106 participants. One study tested low height beds and the other tested bed exit alarms. Both studies used standard care for their control group and both studies were conducted in hospitals. No study investigating bed rails met the inclusion criteria. Due to the clinical heterogeneity of the interventions in the included studies pooling of data and meta-analysis was inappropriate, and so the results of the studies are described.A single cluster randomised trial of low height beds in 18 hospital wards, including 22,036 participants, found no significant reduction in the frequency of patient injuries due to their beds (there were no injuries in either group), patient falls in the bedroom (rate ratio 0.69, 95% CI 0.35 to 1.34), all falls (rate ratio 1.26, 95% CI 0.83 to 1.90) or patient injuries due to all falls (rate ratio 1.35, 95% CI 0.68 to 2.68).One randomised controlled trial of bed exit alarms in one hospital geriatric ward, involving 70 participants, found no significant reduction in the frequency of patient injuries due to their beds (there were no injuries in either group), patient falls out of bed (rate ratio 0.25, 95% CI 0.03 to 2.24), all falls (rate ratio 0.42, 95% CI 0.15 to 1.18) or patient injuries due to all falls (no injuries in either group). AUTHORS' CONCLUSIONS: The effectiveness of interventions designed to prevent patient injuries from their beds (including bed rails, low height beds and bed exit alarms) remains uncertain. The available evidence shows no significant increase or decrease in the rate of injuries with the use of low height beds and bed exit alarms. Limitations of the two included studies include lack of blinding and insufficient power. No randomised controlled trials of bed rails were identified. Future reports should fully describe the standard care received by the control group. PMID- 22258995 TI - Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity. AB - BACKGROUND: Even with optimal disease-modifying treatment and good control of disease activity, persistent pain due to structural damage is common in people with inflammatory arthritis and therefore additional treatment for pain might be required. Because comorbidity is highly prevalent in people with inflammatory arthritis, it is important to consider comorbidities such as gastrointestinal or liver diseases in deciding upon optimal pharmacologic pain therapy. OBJECTIVES: To assess the efficacy and safety of pharmacological pain treatment in patients with inflammatory arthritis who have gastrointestinal or liver comorbidities, or both. SEARCH METHODS: We searched MEDLINE, EMBASE and Cochrane CENTRAL for studies to June 2010. We also searched the 2007-2010 ACR and EULAR abstracts and performed a hand search of reference lists of articles. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials (RCTs or CCTs) were considered for inclusion for assessment of efficacy. For safety we also considered single arm trials, controlled before-after studies, interrupted time series, cohort and case-control studies, and case series of 10 or more consecutive cases. Pain therapy comprised paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, opioid-like drugs (tramadol) and neuromodulators (anti-depressants, anticonvulsants and muscle relaxants). The study population comprised adults (>18 years) with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or other spondyloarthritis who had gastrointestinal and/or hepatic comorbid conditions. Outcomes of interest were pain, adverse effects, function and quality of life. Studies that included a mixed population of inflammatory arthritis and other conditions were included only if results for inflammatory arthritis were reported separately. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias and extracted data. MAIN RESULTS: Out of 2869 articles only one single arm open trial was identified that fulfilled our inclusion criteria. This trial assessed the safety and efficacy of naproxen (dosage not specified) in 58 patients with active rheumatoid arthritis and gastrointestinal comorbidities for up to 52 weeks. Thirteen participants (22%) remained on gold therapy, four participants (10%) remained on hydroxychloroquine, 27 (47%) remained on corticosteroids, 12 (21%) remained on salicylates and all participants continued on antacids and bland diet. The presence of faecal occult blood was reported in 1/58 participants tested between weeks 1 to 26 and 2/32 participants tested between weeks 27 to 52. Over the course of the study, seven participants (12.1%) withdrew due to adverse events but of these, only two participants withdrew due to gastrointestinal side effects (abdominal pain n=1, nausea n=1) and no serious adverse events were reported. Noteable, out of 14 studies excluded due to inclusion of mixed population (osteoarthritis or other rheumatic conditions) or intervention already withdrawn, five trials reported higher risk of developing gastrointestinal events in patients with prior gastrointestinal events when treated with NSAIDs. AUTHORS' CONCLUSIONS: On the basis of the current review, there is scant evidence to guide clinicians about how gastrointestinal or liver comorbidities should influence the choice of pain treatment in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or other spondylarthritis. Based upon additional studies that included a mixed population of participants with a range of rheumatic conditions, NSAIDs should be used cautiously in patients with inflammatory arthritis and a history of gastrointestinaI comorbidity as there is consistent evidence that they may be at increased risk. PMID- 22258996 TI - Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. AB - BACKGROUND: Planning for outbreaks of influenza is a high priority public health issue for national governments. Neuraminidase inhibitors (NIs) are thought to help reduce the symptoms of influenza with several possible mechanisms proposed. NIs have been stockpiled with a view to their widespread use in the event of a pandemic. However, the evidence base for this class of agents remains a source of debate. In a previous review we have documented substantial risks of publication bias of trials of NIs for influenza (60% of patient data from phase III treatment trials of oseltamivir have never been published) and reporting bias in the published trials. Our confidence in the conclusions of previous versions of this review has been subsequently undermined. Since we have become aware of a large number of unpublished trials of NIs in the management of influenza, this review updates and merges existing reviews in this area. OBJECTIVES: To review clinical study reports of placebo-controlled randomised trials, regulatory comments and reviews ('regulatory information') of the effects of the NIs oseltamivir and zanamivir for influenza in all age groups and appraise trial programmes, rather than single studies.Clinical study reports are very detailed, unpublished clinical trial data containing in-depth descriptions of protocol rationale, methods analysis plans, trial results and organisational documents (such as contracts). A series of clinical studies designed and conducted by one sponsor represents a trial programme of a drug indication (for example treatment of influenza). SEARCH METHODS: We searched trial registries, cross-referencing published and unpublished sources and corresponded with manufacturers and regulators. We searched the archives of the US Food and Drug Administration (FDA) and European and Japanese regulators. The evidence in this review reflects searches to obtain relevant information up to 12 April 2011. SELECTION CRITERIA: We included regulatory information based on assessments of randomised controlled trials (RCTs) conducted in people of any age who had either confirmed or suspected influenza, or who had been exposed to influenza in the local community or place of residence. We included information which had been made available by our deadline. DATA COLLECTION AND ANALYSIS: We indexed regulatory information in two purpose-built instruments and reconstructed trials using CONSORT statement based templates. To progress to Stage 2 (full analysis) we sought manufacturer explanations of discrepancies in the data. GlaxoSmithKline (GSK) offered us individual patient data and responded to our queries, but Roche did not provide us with complete clinical study reports. In Stage 2 we intended to analyse trials with validated data (i.e. assuming our validation questions aimed at clarifying omissions and discrepancies were resolved). No studies progressed to Stage 2. We carried out analyses of the effects of oseltamivir on time to first alleviation of symptoms and hospitalisations using the intention-to-treat (ITT) population and tested five hypotheses generated post-protocol publication. MAIN RESULTS: We included and analysed data from 25 studies (15 oseltamivir and 10 zanamivir studies). We could not use data from a further 42 studies due to insufficient information or unresolved discrepancies in their data. The included trials were predominantly conducted in adults during influenza seasons in both hemispheres. A small number of studies were conducted in older people residing in care homes and in people with underlying respiratory diseases. The studies had adequate randomisation and blinding procedures, but imbalances in the analysis populations available (ITT influenza-infected) left many of the studies at risk of attrition bias. All the studies were sponsored by manufacturers of NIs. Time to first alleviation of symptoms in people with influenza-like illness symptoms (i.e. ITT population) was a median of 160 hours (range 125 to 192 hours) in the placebo groups and oseltamivir shortened this by around 21 hours (95% confidence interval (CI) -29.5 to -12.9 hours, P < 0.001; five studies) but there was no evidence of effect on hospitalisations based on seven studies with a median placebo group event rate of 0.84% (range 0% to 11%): odds ratio (OR) 0.95; 95% CI 0.57 to 1.61, P = 0.86). These results are based on the comprehensive ITT population data and are unlikely to be biased. A post-protocol analysis showed that participants randomised to oseltamivir in treatment trials had a reduced odds being diagnosed with influenza (OR 0.83; 95% CI 0.73 to 0.94, P = 0.003; eight studies), probably due to an altered antibody response. Zanamivir trials showed no evidence of this. Due to limitations in the design, conduct and reporting of the trial programme, the data available to us lacked sufficient detail to credibly assess a possible effect of oseltamivir on complications and viral transmission. We postponed analysis of zanamivir evidence because of the offer of individual patient data (IPD) from its manufacturer. The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010. AUTHORS' CONCLUSIONS: We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us. PMID- 22258997 TI - Interventions for pregnant women with hyperglycaemia not meeting gestational diabetes and type 2 diabetes diagnostic criteria. AB - BACKGROUND: Pregnancy hyperglycaemia without meeting gestational diabetes mellitus (GDM) diagnostic criteria affects a significant proportion of pregnant women each year. It is associated with a range of adverse pregnancy outcomes. Although intensive management for women with GDM has been proven beneficial for women and their babies, there is little known about the effects of treating women with hyperglycaemia who do not meet diagnostic criteria for GDM and type 2 diabetes (T2DM). OBJECTIVES: To assess the effects of different types of management strategies for pregnant women with hyperglycaemia not meeting diagnostic criteria for GDM and T2DM (referred as borderline GDM in this review). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2011). SELECTION CRITERIA: Randomised and cluster randomised trials comparing alternative management strategies for women with borderline GDM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed risk of bias of included studies. Data were checked for accuracy. MAIN RESULTS: We included four trials involving 543 women and their babies (but only data from 521 women and their babies is included in our analyses). Three of the four included studies had moderate to high risk of bias and one study was at low to moderate risk of bias. Babies born to women receiving management for borderline GDM (generally dietary counselling and metabolic monitoring) were less likely to be macrosomic (birthweight greater than 4000 g) (three trials, 438 infants, risk ratio (RR) 0.38, 95% confidence interval (CI) 0.19 to 0.74) or large-for-gestational (LGA) age (three trials, 438 infants, RR 0.37, 95% CI 0.20 to 0.66) when compared with those born to women in the routine care group. There were no significant differences in rates of caesarean section (three trials, 509 women, RR 0.93, 95% CI 0.68 to 1.27) and operative vaginal birth (one trial, 83 women, RR 1.37, 95% CI 0.20 to 9.27) between the two groups. AUTHORS' CONCLUSIONS: This review found interventions including providing dietary advice and blood glucose level monitoring for women with pregnancy hyperglycaemia not meeting GDM and T2DM diagnostic criteria helped reduce the number of macrosomic and LGA babies without increasing caesarean section and operative vaginal birth rates. It is important to notice that the results of this review were based on four small randomised trials with moderate to high risk of bias without follow-up outcomes for both women and their babies. PMID- 22258998 TI - Interventions for smoking cessation in Indigenous populations. AB - BACKGROUND: Tobacco use in Indigenous populations (people who have inhabited a country for thousands of years) is often double that of the non-Indigenous population. A disproportionate burden of substance-related morbidity and mortality exists as a result. OBJECTIVES: To evaluate the effectiveness of smoking cessation interventions in Indigenous populations and to summarise these approaches for future cessation programmes and research. SEARCH METHODS: The Cochrane Tobacco Addiction Group Specialised Register of Trials was searched (April 2011), with additional searches of MEDLINE (May 2011). Online clinical trial databases and publication references were also searched for potential studies. SELECTION CRITERIA: We included randomized and non-randomized controlled trials for smoking cessation interventions in Indigenous populations. Interventions could include pharmacotherapies, cognitive and behavioural therapies, alternative therapies, public policy and combination therapies. No attempts were made to re-define Indigenous status for the purpose of including a study in this review. DATA COLLECTION AND ANALYSIS: Data pertaining to methodology, participants, interventions and outcomes were extracted by one reviewer and checked by a second, whilst methodological quality was extracted independently by two reviewers. Studies were assessed by qualitative narrative synthesis and where possible meta-analysis. The review process was examined by an Indigenous (Aboriginal) Australian for applicability, acceptability and content. MAIN RESULTS: Four studies met all of the eligibility criteria for inclusion within the review. Two used combination therapies consisting of a pharmacotherapy combined with cognitive and behavioural therapies, whilst the remaining two used cognitive and behavioural therapy through counselling, one via text message support and the other delivered via clinic doctors trained in smoking cessation techniques. Smoking cessation data were pooled across all studies producing a statistically and clinically significant effect in favour of the intervention (risk ratio 1.43, 95%CI 1.03 to 1.98, p=0.032), however following sensitivity analysis a statistically non-significant but clinically significant effect was observed in favour of the intervention (risk ratio 1.33, 95%CI 0.95 to 1.85, p=NS) . AUTHORS' CONCLUSIONS: A significant health disparity exists, whereby Indigenous populations, a minority, are over-represented in the burden of smoking related morbidity and mortality. This review highlights the paucity of evidence available to evaluate the effectiveness of smoking cessation interventions, despite the known success of these interventions in non-Indigenous populations. Due to this lack of published investigations, the external validity of this review is limited, as is the ability to draw reliable conclusions from the results. The limited but available evidence reported does indicate that smoking cessation interventions specifically targeted at Indigenous populations can produce smoking abstinence. However this evidence base is not strong with a small number of methodologically sound trials investigating these interventions. More rigorous trials are now required to assist in bridging the gap between tobacco related health disparities in Indigenous and non-Indigenous populations. PMID- 22258999 TI - Intracutaneous or subcutaneous sterile water injection compared with blinded controls for pain management in labour. AB - BACKGROUND: Intracutaneous or subcutaneous injection of sterile water is rapidly gaining popularity as a method of pain relief in labour and it is therefore essential that it is properly evaluated. Adequate analgesia in labour is important to women worldwide. Sterile water injection is inexpensive, requires basic equipment, and appears to have few side effects. It is purported to work for labour pain. OBJECTIVES: To determine the efficacy of sterile water injections for relief of pain (both typical contraction pain and intractable back pain) during labour compared to placebo (isotonic saline injections) or non pharmacological interventions, and to identify any relevant effects on mode and timing of delivery, or safety of both mother and baby. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 May 2011), MEDLINE, and EMBASE (January 2010 to 30 May 2011), together with reference lists in retrieved studies and review articles. SELECTION CRITERIA: We included randomised, double blind, controlled studies using intracutaneous or subcutaneous sterile water injections for pain relief during labour. There were no restrictions on birth place, parity, risk, age, weight, gestation, or stage of labour. Potential comparators were placebo (saline) and non-pharmacological interventions (e.g. hypnosis or biofeedback). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials, and extracted data. We resolved any disagreements or uncertainties by discussion with a third review author. Primary outcome measures were at least 50% pain relief, or at least 30%, pain relief, patient global impression of change of at least 'good', mode of delivery, perinatal morbidity and mortality, maternal complications and adverse events. Secondary outcomes were women with any pain relief, use of rescue analgesia, and treatment group average pain relief. We made explicit judgements about potential biases in the studies. MAIN RESULTS: We included seven studies, with 766 participants: four used intracutaneous injections, two subcutaneous, and one both. All reported on low back pain in labour only. Methodological quality was good, but four studies were at high risk of bias due to small size of treatment groups, incomplete outcome data, and performance bias.All studies reported treatment group mean or median scores, finding greater reduction in pain for sterile water. However, failure to demonstrate a normal distribution for pain intensity or relief, and use of different scales, meant meta-analysis was inappropriate. No study reported primary dichotomous efficacy outcomes. One reported the number self-scoring 4/10 cm or more reduction in pain; significantly more had this outcome with sterile water (50% to 60%) than with placebo (20% to 25%).There was no significant difference between sterile water and saline for rates of caesarean section (risk ratio (RR) 0.58, 95% confidence interval (CI) 0.33 to 1.02), instrumental delivery (RR 1.31, 95% CI 0.79 to 2.18), rescue analgesia (RR 0.86, 95% CI 0.44 to 1.69), timing of delivery, or Apgar scores. Two studies reported that more women treated with sterile water would request the same analgesia in future.No study reported on women's satisfaction with pain relief, women's sense of control in labour, women's satisfaction with the childbirth experience, mother/baby interaction, rates of breastfeeding, maternal morbidity, infant long-term outcomes, or cost. No adverse events were reported other than transient pain with injection, which was worse with sterile water. AUTHORS' CONCLUSIONS: The outcomes reported severely limit conclusions for clinical practice. We found little robust evidence that sterile water is effective for low back or any other labour pain. Neither did we find any difference in delivery or other maternal or fetal outcomes. Further large, methodologically rigorous studies are required to determine the efficacy of sterile water to relieve pain in labour. PMID- 22259000 TI - Bezafibrate for primary biliary cirrhosis. AB - BACKGROUND: Treatment of primary biliary cirrhosis is complicated. There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid (UDCA), is effective in the treatment of primary biliary cirrhosis, but no systematic review has summarised the evidence yet. OBJECTIVES: To assess the beneficial and harmful effects of bezafibrate in patients with primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, Clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. The searches in Chinese Bio-medical Literature Database, China Network Knowledge Information, Chinese Science Journal Database, Chinese Medical Citation Index, Wanfang Database, and full text searches were conducted until January 2011. Manufacturers and authors were contacted. SELECTION CRITERIA: All randomised clinical trials comparing bezafibrate at any dose or regimen in patients with primary biliary cirrhosis with placebo or no intervention, or with another drug. Any concomitant interventions were allowed if received equally by all treatment groups in a trial. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological domains were used to assess risk of systematic errors (bias). Trial sequential analysis was used to control for random errors (play of chance). MAIN RESULTS: Six trials with 151 Japanese patients were included. All trials had high risk of bias. Four trials compared bezafibrate plus UDCA with no intervention plus UDCA (referenced as bezafibrate versus no intervention in the remaining text), and two trials compared bezafibrate with UDCA. No patient died and no patient developed liver-related complications in any of the included trials. Bezafibrate was without significant effects on the occurrence of adverse events compared with no intervention (5/32 (16%) versus 0/28 (0%)) (RR 5.40, 95% CI 0.69 to 42.32; 3 trials with 60 patients; I2 = 0%) or with UDCA (2/32 (6%) versus 0/37 (0%)) (RR 6.19, 95% CI 0.31 to 122.05; 2 trials with 69 patients; I2 = 0%). Bezafibrate significantly decreased the activity of serum alkaline phosphatases compared with no intervention (MD -186.04 U/L, 95% CI -249.03 to -123.04; 4 trials with 79 patients; I2 = 34%) and when compared with UDCA (MD -162.90 U/L, 95% CI -199.68 to -126.12; 2 trials with 48 patients; I2 = 0%). These results were supported by trial sequential analyses. Bezafibrate compared with no intervention significantly decreased plasma immunoglobulin M (MD -164.00 mg/dl, 95% CI -259.47 to -68.53; 3 trials with 50 patients; I2 = 46%) and serum bilirubin concentration (MD -0.19 mg/dl, 95% CI -0.38 to -0.00; 2 trials with 34 patients; I2 = 0%). However, the latter two results were not supported by trial sequential analyses. Bezafibrate compared with no intervention had no significant effect on the activity of serum gamma-glutamyltransferase (MD -1.22 U/L, 95% CI -11.97 to 9.52; 4 trials with 79 patients; I2 = 42%) and serum alanine aminotransferase (MD -5.61 U/L, 95% CI -24.50 to 13.27; 2 trials with 35 patients; I2 = 34%). Bezafibrate compared with UDCA had no significant effect on the activity of serum gamma glutamyltransferase (MD 38.44 U/L, 95% CI -180.67 to 257.55; 2 trials with 49 patients; I2 = 89%), serum alanine aminotransferase (MD -2.34 U/L, 95% CI -34.73 to 30.06; 2 trials with 49 patients; I2 = 95%), and plasma immunoglobulin M concentration (MD -20.23 mg/dl, 95% CI -218.71 to 178.25; 2 trials with 41 patients; I2 = 90%) in random-effects model meta-analyses, but bezafibrate significantly decreased the activity of serum gamma-glutamyltransferase (MD 58.18, 95% CI -76.49 to -39.88; 2 trials with 49 patients; I2 = 89%), serum alanine aminotransferase (MD -13.94, 95% CI -18.78 to -9.09; 2 trials with 49 patients; I2 = 95%), and plasma immunoglobulin M concentration (MD -99.90, 95% CI -130.72 to -69.07; 2 trials with 41 patients; I2 = 90%) in fixed-effect model meta-analyses. One patient had bezafibrate withdrawn due to an adverse event compared to no intervention (RD 0.03, 95% CI -0.09 to 0.16; 2 trials with 60 patients; I2 = 0%). AUTHORS' CONCLUSIONS: This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors. PMID- 22259001 TI - External counterpulsation for acute ischaemic stroke. AB - BACKGROUND: External counterpulsation (ECP) may improve cerebral blood flow, and it has been proposed as a potential therapy for patients with ischaemic stroke. OBJECTIVES: To assess the efficacy and safety of ECP for acute ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (June 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011 Issue 2), MEDLINE (1948 to June 2011), EMBASE (1980 to June 2011), CINAHL (1982 to June 2011), AMED (Allied and Complementary Medicine) (1985 to June 2011), China Biological Medicine Database (CBM) (1978 to June 2011), Chinese National Knowledge Infrastructure (CNKI) (1979 to June 2011), Chinese Science and Technique Journals Database (VIP) (1989 to June 2011) and Wanfang Data (1984 to June 2011). We also searched ongoing trials registers, reference lists and relevant conference proceedings and contacted authors and manufacturers of external counterpulsation devices. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which ECP (started within seven days of stroke onset) was compared with sham treatment or no treatment, or ECP plus routine treatment was compared with routine treatment alone, in patients with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data, checked for adverse events data and contacted trialists for missing information. MAIN RESULTS: We included two trials involving 160 patients. Numbers of death or dependent patients at the end of at least three months follow-up were not reported in either of the included trials. The outcome measure used in the included trials was only the number of participants with improvement of neurological impairment after treatment according to the Modified Edinburgh-Scandinavian Stroke Scale (MESSS) or self-making criteria. ECP was associated with a significant increase in the number of participants whose neurological impairment improved (risk ratio (RR) 1.75, 95% confidence interval (CI) 1.37 to 2.23). Only one trial reported no adverse events. AUTHORS' CONCLUSIONS: The methodological quality of the included studies was poor, and reliable conclusions could not be drawn from the present data. High-quality and large-scale RCTs are needed. PMID- 22259002 TI - Intravesical gemcitabine for non-muscle invasive bladder cancer. AB - BACKGROUND: Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well established treatment for preventing or delaying tumour recurrence following tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer. OBJECTIVES: To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer (NMIBC). SEARCH METHODS: A search strategy was developed for MEDLINE to identify randomised trials of intravesical gemcitabine for the treatment of non-muscle invasive bladder cancer. The searches were from 1947 to May 2011. Other databases searched included EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS. Handsearching of meeting proceedings, international guidelines and trial registries was also carried out. SELECTION CRITERIA: The titles and abstracts of the combined electronic and handsearching were manually screened by three authors independently to determine if they met the inclusion criteria for this review. Studies were selected if they were randomised, controlled trials or quasi-randomised clinical trials that included intravesical gemcitabine in at least one arm of a comparative study. DATA COLLECTION AND ANALYSIS: Data extraction was carried out by three reviewers. The information retrieved included the author's details, the study design, the characteristics of the recruited patients, details of the interventions and data relating to the primary, and secondary outcome measures. MAIN RESULTS: Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes. One study compared a single post-operative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% versus 39%, respectively) or recurrence-free survival (HR (hazard ratio) 0.95, 95% CI 0.64 to1.39, P = 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% versus 0.8%). A further trial compared gemcitabine with intravesical mitomycin C and demonstrated that the rates of recurrence (28% versus 39%) and progression (11% versus 18%) were lower with gemcitabine but did not reach statistical significance. The global incidence of adverse events was significantly less with gemcitabine (38.8% versus 72.2%, P = 0.02).Three trials compared gemcitabine with intravesical BCG but a meta-analysis was not possible due to clinical heterogeneity. In untreated patients at intermediate risk of recurrence (primary Ta-T1 no CIS) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P = 0.92) and overall progression equal (P = 1.0). Dysuria (12.5% versus 45%, P < 0.05) and frequency (10% versus 45%, P < 0.001) were significantly less with gemcitabine. In a second trial of high risk patients the recurrence rate was significantly greater with gemcitabine compared to BCG (53.1% and 28.1%, P = 0.04) and the time to recurrence significantly shorter with gemcitabine (25.5 versus 39.4 months, P = 0.042). Finally in a third trial of high risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% versus 87.5%, P = 0.002) and a longer time to recurrence (3.9 versus 3.1 months, P = 0.9) compared to BCG. Progression rates were similar in both groups (33% versus 37.5%, P = 0.12) with no significant differences in grade 2 or 3 toxicities.The final trial was a marker lesion study which reported greater response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared to a single dose (9%). AUTHORS' CONCLUSIONS: A single dose immediately following surgery is ineffective based on one study. Gemcitabine may be more active than mitomycin C with a lower toxicity profile. Compared to intravesical BCG therapy, gemcitabine had similar effects in intermediate risk patients, less effective in high risk patient and superior in BCG refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy. Intravesical gemcitabine is a promising drug that may add to the urologist's options in achieving this goal. PMID- 22259003 TI - Ergonomic positioning or equipment for treating carpal tunnel syndrome. AB - BACKGROUND: Non-surgical treatment, including ergonomic positioning or equipment, are sometimes offered to people experiencing mild to moderate symptoms from carpal tunnel syndrome (CTS). The effectiveness and duration of benefit from ergonomic positioning or equipment interventions for treating CTS are unknown. OBJECTIVES: To assess the effects of ergonomic positioning or equipment compared with no treatment, a placebo or another non-surgical intervention in people with CTS. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 June 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2, in The Cochrane Library), MEDLINE (1966 to June 2011), EMBASE (1980 to June 2011), CINAHL Plus (1937 to June 2011), and AMED (1985 to June 2011). We also reviewed the reference lists of randomised or quasi randomised trials identified from the electronic search. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing ergonomic positioning or equipment with no treatment, placebo or another non-surgical intervention in people with CTS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias of included studies. We calculated risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for the primary and secondary outcomes. We pooled results of clinically and statistically homogeneous trials, where possible, to provide estimates of the effect of ergonomic positioning or equipment. MAIN RESULTS: We included two trials (105 participants) comparing ergonomic versus placebo keyboards. Neither trial assessed the primary outcome (short-term overall improvement) or adverse effects of interventions. In one small trial (25 participants) an ergonomic keyboard significantly reduced pain after 12 weeks (MD -2.40; 95% CI -4.45 to -0.35) but not six weeks (MD -0.20; 95% CI -1.51 to 1.11). In this same study, there was no difference between ergonomic and standard keyboards in hand function at six or 12 weeks or palm-wrist sensory latency at 12 weeks. The second trial (80 participants) reported no significant difference in pain severity after six months when using either of the three ergonomic keyboards versus a standard keyboard. No trials comparing (i) ergonomic positioning or equipment with no treatment, (ii) ergonomic positioning or equipment with another non-surgical treatment, or (iii) different ergonomic positioning or equipment regimes, were found. AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised controlled trials to determine whether ergonomic positioning or equipment is beneficial or harmful for treating carpal tunnel syndrome. PMID- 22259004 TI - Therapeutic ultrasound for carpal tunnel syndrome. AB - BACKGROUND: Therapeutic ultrasound may be offered to people experiencing mild to moderate symptoms of carpal tunnel syndrome (CTS). The effectiveness and duration of benefit of this non-surgical intervention remain unclear. OBJECTIVES: To review the effects of therapeutic ultrasound compared with no treatment, placebo or another non-surgical intervention in people with CTS. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (22 February 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 1), MEDLINE (January 1966 to February 2011), EMBASE (January 1980 to February 2011), CINAHL Plus (January 1937 to February 2011), and AMED (January 1985 to February 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any regimen of therapeutic ultrasound with no treatment, a placebo or another non-surgical intervention in people with CTS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias in the included studies. We calculated risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CIs) for primary and secondary outcomes. We pooled results of clinically homogenous trials in a meta-analysis using a random-effects model, where possible, to provide estimates of the effect. MAIN RESULTS: We included 11 studies randomising 443 patients in the review. Two trials compared therapeutic ultrasound with placebo, two compared one ultrasound regimen with another, two compared ultrasound with another non-surgical intervention, and six compared ultrasound as part of a multi-component intervention with another non-surgical intervention (for example, exercises and splint). The risk of bias was low in some studies and unclear or high in other studies, with only three reporting that the allocation sequence was concealed and six reporting that participants were blinded. Overall, there is insufficient evidence that one therapeutic ultrasound regimen is more efficacious than another. Only two studies reported the primary outcome of interest, short-term overall improvement (any measure in which patients indicate the intensity of their complaints compared with baseline, for example, global rating of improvement, satisfaction with treatment, within three months post-treatment). One low quality trial with 68 participants found that when compared with placebo, therapeutic ultrasound may increase the chance of experiencing short-term overall improvement at the end of seven weeks treatment (RR 2.36; 95% CI 1.40 to 3.98), although losses to follow-up in this study suggest that these data should be interpreted with caution. Another low quality trial with 60 participants found that at three months, post-treatment therapeutic ultrasound plus splint increased the chance of short-term overall improvement (patient satisfaction) when compared with splint alone (RR 3.02; 95% CI 1.36 to 6.72), but decreased the chance of short-term overall improvement when compared with low-level laser therapy plus splint (RR 0.87; 95% CI 0.57 to 1.33), though participants were not blinded to treatment and it was unclear if the random allocation sequence was adequately concealed. Differences between groups receiving different frequencies and intensities of ultrasound, and between ultrasound as part of a multi-component intervention versus other non-surgical interventions, were generally small and not statistically significant for symptoms, function, and neurophysiologic parameters. Only four studies measured adverse effects, none of which identified adverse effects due to therapeutic ultrasound. However, more data on this outcome are required before any firm conclusions on the safety of this intervention can be made. AUTHORS' CONCLUSIONS: There is only poor quality evidence from very limited data to suggest that therapeutic ultrasound may be more effective than placebo for either short- or long-term symptom improvement in people with CTS. There is insufficient evidence to support the greater benefit of one type of therapeutic ultrasound regimen over another or to support the use of therapeutic ultrasound as a treatment with greater efficacy compared to other non-surgical interventions for CTS, such as splinting, exercises, and oral drugs. More methodologically rigorous studies are needed to determine the effectiveness and safety of this intervention for CTS. PMID- 22259005 TI - Improvement in PET myocardial perfusion image quality and quantification with flurpiridaz F 18. AB - Rubidium-82 ((82)Rb), the currently commercially available radiotracer for positron emission tomography (PET) myocardial perfusion imaging (MPI), has led to wide availability of PET-MPI for stress-rest imaging. Compared to SPECT MPI, myocardial perfusion PET images have higher spatial and contrast resolution, are less affected by radiotracer scatter, benefit from more precise attenuation correction, and allow dynamic first pass imaging. In addition, PET imaging allows assessment of myocardial function at peak stress and measurement of absolute myocardial blood flow, thus providing critical data not available with SPECT imaging. Further enhancements of the high quality of PET perfusion images may be realized by technologies under development such as respiratory gating, combined respiratory, and ECG gating to generate "motion-frozen" cardiac images, automated patient motion correction software, and high-definition PET, which reduces distortions introduced by the circular geometry of the scanner. Early studies indicate that the experimental PET radiopharmaceutical flurpiridaz F 18 provides high-quality, high-resolution myocardial perfusion images that may enable improved clinical MPI, and has properties well suited to optimized performance by application of these quantitative analytic technologies. PMID- 22259006 TI - Advantages and disadvantages of PET and SPECT in a busy clinical practice. AB - The continued high utilization of rest-stress single-photon emission computed tomographic (SPECT) myocardial perfusion imaging (MPI) is supported by its known clinical benefits, established reimbursement, and wide availability of cameras and radiopharmaceuticals. However, traditional rest-stress SPECT protocols tend to be lengthy and inefficient, and the prevalence of equivocal studies continues to be a problem. The use of stress-only SPECT protocols in selected patients, and a new generation of ultrafast SPECT cameras have led to improved image quality, reduced dosimetry and shorter, more efficient MPI protocols. The utilization of positron emission tomographic (PET) MPI has been accelerated by the availability of radiopharmaceuticals that can be generated on-site, and by the availability of more PET cameras. Emerging evidence consistently demonstrates that PET provides improved image quality, greater interpretive certainty, higher diagnostic accuracy, lower patient dosimetry, and shorter imaging protocols as compared to SPECT. Importantly, PET imaging allows assessment of left ventricular function at peak-stress, and evaluation of microvascular function through the measurement of absolute myocardial blood flow at rest and at peak-stress. Wider utilization of PET MPI is hindered by a high cost of entry, high on-going costs, and an immature reimbursement structure. PMID- 22259007 TI - Properties of an ideal PET perfusion tracer: new PET tracer cases and data. AB - An ideal positron emission tomography (PET) tracer should be highly extractable by the myocardium and able to provide high-resolution images, should enable quantification of absolute myocardial blood flow (MBF), should be compatible with both pharmacologically induced and exercise-induced stress imaging, and should not require an on-site cyclotron. The PET radionuclides nitrogen-13 ammonia and oxygen-15 water require an on-site cyclotron. Rubidium-82 may be available locally due to the generator source, but greater utilization is limited because of its relatively low myocardial extraction fraction, long positron range, and generator cost. Flurpiridaz F 18, a novel PET tracer in development, has a high extraction fraction, short positron range, and relatively long half-life (as compared to currently available tracers), and may be produced at regional cyclotrons. Results of early clinical trials suggest that both pharmacologically and exercise-induced stress PET imaging protocols can be completed more rapidly and with lower patient radiation exposure than with single-photon emission computerized tomography (SPECT) tracers. As compared to SPECT images in the same patients, flurpiridaz F 18 PET images showed better defect contrast. Flurpiridaz F 18 is a potentially promising tracer for assessment of myocardial perfusion, measurement of absolute MBF, calculation of coronary flow reserves, and assessment of cardiac function at the peak of the stress response. PMID- 22259008 TI - Stress-only imaging in patients with prior SPECT MPI: a simulation study. AB - OBJECTIVES: The aim of this study was to determine if omitting the repeat resting scan in patients who had prior single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) would have an impact on the interpretation of the stress test. BACKGROUND: Current guidelines recommend stress and rest imaging for SPECT MPI studies. Stress-only imaging has also entered the guidelines as a feasible option in low-risk patients but has not been studied in high-risk patients. METHODS: Two independent readers interpreted 47 consecutive MPIs with prior images to determine if the repeat resting scan had an impact on interpretation of the stress test images. In this retrospective analysis, we compared interpretation of stress-only SPECT images using the old rest image for comparison versus conventional rest-stress SPECT imaging. Both readers were blinded to study results. The primary end point of this study was a comparison of summed difference scores (SDS) from stress-only interpretation compared to standard rest-stress interpretation. RESULTS: In this study, 36% (98/272) of patients had previous SPECT MPI. Of these patients, 48% (n = 47) were eligible for stress-only imaging. There was strong agreement between the SDS from the new stress versus old rest image compared with the new stress versus new rest image (r = 0.866, P < .001) with a mean difference in SDS of 0.6 +/- 1.7. In this population, 41 of the 47 studies (87%) could have been performed with a stress only SPECT MPI with comparison with the prior resting study. Starting with the stress-only protocol would have reduced the radiation in this population by 76%. CONCLUSIONS: Very similar data is obtained with stress-only imaging in patients who have a prior resting study. Our study suggests that the stress-only imaging may possibly be expanded to populations who have been studied previously or are at higher risk, reserving the option to add a resting study if the interpretation of the stress-only study is unclear. PMID- 22259009 TI - A randomized, double-blind, placebo-controlled study of the safety and tolerance of regadenoson in subjects with stage 3 or 4 chronic kidney disease. AB - BACKGROUND: The safety and tolerability of regadenoson, a pharmacologic stress agent that is excreted primarily by the kidneys, were examined in subjects with chronic kidney disease (CKD). METHODS: This multicenter, double-blind, randomized, placebo-controlled study involved men and women, >=18 years of age, with stage 3 or 4 [estimated glomerular filtration rate (eGFR) 30-59 mL/minute/1.73 m(2) and 15-29 mL/minute/1.73 m(2), respectively] CKD and known or suspected coronary artery disease. Subjects were randomized 2:1 to receive one 10 second intravenous injection of regadenoson 0.4 mg or placebo. The primary outcome measure was the frequency of serious adverse events over 24-h post-dose. RESULTS: The study included 432 subjects with stage 3 (regadenoson n = 287; placebo n = 145) and 72 with stage 4 (regadenoson n = 47; placebo n = 25) CKD. No serious adverse events or deaths were reported over 24-h post-dose. The overall adverse event incidence was higher with regadenoson than placebo (62.6% vs 21.2%; P < .0001). Of the most common adverse events (>=5%) reported by subjects receiving regadenoson, headache (24.9% vs 7.1%), dyspnea (19.2% vs 0.6%), chest discomfort (14.7% vs 0.6%), nausea (14.7% vs 1.2%), flushing (12.0% vs 1.8%), and dizziness (9.6% vs 0.6%) occurred significantly more often (P < .0001) with regadenoson than placebo. There were no trends for clinically meaningful changes in eGFR from baseline to 24-h post-dose in subjects with stage 3 or 4 CKD. CONCLUSIONS: Regadenoson was not associated with any serious or unexpected adverse events in subjects with stage 3 or 4 CKD. PMID- 22259010 TI - Risk stratification of CAD with SPECT-MPI in women with known estrogen status. AB - OBJECTIVE: To compare exercise tolerance testing (ETT) with gated single photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) risk stratification in women with an intermediate to high CAD pretest risk and known estrogen status (ES). BACKGROUND: SPECT-MPI is an effective test for risk stratifying patients with stable angina. However in women, the current guidelines recommend the exercise tolerance testing (ETT) as first line test. Further, the relationship of stress imaging to ES, an independent risk indicator for CAD, is unknown. METHODS: 2,194 women with an intermediate to high CAD pre-test risk were referred for a clinically indicated ETT with gated SPECT-MPI. Duke treadmill scores (DTS) and summed stress score (SSS) were calculated. SSS were classified as normal (SSS < 3), mildly abnormal (SSS 4-8), or moderate-severely abnormal (SSS > 8). The ES was assessed as premenopausal, postmenopausal on hormone replacement therapy (HRT) as ES+ while postmenopausal not on HRT were ES-. An annualized cardiac event rate of a composite of cardiac death, unstable angina (UA) leading to hospitalization, non-fatal myocardial infarction, or late coronary revascularization was calculated for all the groups. RESULTS: The annualized cardiac event rate was 1.3% PPY, 2.1% PPY, and 3.2% PPY for low, intermediate, and high risk DTS (P = .2). Patients with intermediate DTS and mildly abnormal or moderate-severely abnormal gated SPECT-MPI had a significantly higher cardiac event rates (5.3% PPY and 10.8% PPY, respectively) than those with a normal gated SPECT-MPI (1.2%, PPY, P = .01). This was also demonstrated on further Cox-regression analysis. Risk stratification of SPECT-MPI over DTS was independent of ES. CONCLUSION: Gated SPECT-MPI provides risk stratification beyond standard exercise stress testing for women with suspected coronary artery disease, especially in patients with intermediate DTS and is independent of ES. PMID- 22259011 TI - Towards personalized myocardial viability testing: personal reflections. PMID- 22259013 TI - Generation of a human urinary bladder smooth muscle cell line. AB - We report a cell line (hBSM) established from human urinary bladder wall smooth muscle that maintains most of the phenotypic characteristics of smooth muscle cells. Cells were dissociated from the muscular layer with collagenase (1 mg/ml) and collected and grown in M199 supplemented with 10% fetal calf serum and 1% antibiotic-antimycotic. Primary cultures were grown for 2 d and small colonies were isolated by placing glass rings around the colonies. These colonies were picked up with a fine-tipped Pasteur pipette and subcultured. This procedure was repeated several times until a culture with a uniform stable morphology was obtained. hBSM cells are elongated with tapered ends, and in high density cultures, they form swirls of cells arranged in parallel. These cells have a doubling time of approximately 72 h. Western blotting and immunofluorescence microscopy revealed stable expression of smooth muscle-specific proteins, including myosin isoforms (N-terminal isoforms SM-A/B and C-terminal isoforms SM1/2), SM22, alpha-smooth muscle actin, h-caldesmon, Ca(2+)-dependent myosin light chain kinase, and protein kinase G. These cells contract upon exposure to 10 MUM bethanechol and this contraction is reversible by washing away the drug. Karyotyping showed tetraploidy with a modal chromosome number of 87, with multiple rearrangements. To our knowledge, the hBSM cell line is the first human cell line established from bladder wall smooth muscle that expresses both N- and C-terminal smooth muscle myosin isoforms. This cell line will provide a valuable tool for studying transcriptional regulation of smooth muscle myosin isoforms and effects of drugs on cellular function. PMID- 22259014 TI - iPSC-derived fibroblasts demonstrate augmented production and assembly of extracellular matrix proteins. AB - Reprogramming of somatic cells to induced pluripotent stem cells (iPSC) provides an important cell source to derive patient-specific cells for potential therapeutic applications. However, it is not yet clear whether reprogramming through pluripotency allows the production of differentiated cells with improved functional properties that may be beneficial in regenerative therapies. To address this, we compared the production and assembly of extracellular matrix (ECM) by iPSC-derived fibroblasts to that of the parental, dermal fibroblasts (BJ), from which these iPSC were initially reprogrammed, and to fibroblasts differentiated from human embryonic stem cells (hESC). iPSC- and hESC-derived fibroblasts demonstrated stable expression of surface markers characteristic of stromal fibroblasts during prolonged culture and showed an elevated growth potential when compared to the parental BJ fibroblasts. We found that in the presence of L: -ascorbic acid-2-phosphate, iPSC- and hESC-derived fibroblasts increased their expression of collagen genes, secretion of soluble collagen, and extracellular deposition of type I collagen to a significantly greater degree than that seen in the parental BJ fibroblasts. Under culture conditions that enabled the self-assembly of a 3D stromal tissue, iPSC- and hESC-derived fibroblasts generated a well organized, ECM that was enriched in type III collagen. By characterizing the functional properties of iPSC-derived fibroblasts compared to their parental fibroblasts, we demonstrate that these cells represent a promising, alternative source of fibroblasts to advance future regenerative therapies. PMID- 22259015 TI - Impact of medium volume and oxygen concentration in the incubator on pericellular oxygen concentration and differentiation of murine chondrogenic cell culture. AB - Previous studies have demonstrated that oxygen environment is an important determinate factor of cell phenotypes and differentiation, although factors which affect pericellular oxygen concentration (POC) in murine chondrogenic cell culture remain unidentified. Oxygen concentrations in vivo were measured in rabbit musculoskeletal tissues, which were by far hypoxic compared to 20% O(2) (ranging from 2.29 +/- 1.16 to 4.36 +/- 0.51%). Oxygen concentrations in murine chondrogenic cell (C3H10T1/2) culture medium were monitored in different oxygen concentrations (20% or 5%) in the incubator and in different medium volumes (3,700 or 7,400 MUl) within 25-cm(2) flasks. Chondrogenic differentiation was assessed by glycosaminoglycan production with quantitative evaluation of Alcian blue staining in 12-well culture dishes. Expression of chondrogenic genes, aggrecan, and type II collagen alpha1, was examined by quantitative real-time polymerase chain reaction. Oxygen concentrations in medium decreased accordingly with the depth from medium surface, and POC at Day 6 was 18.99 +/- 0.81% in 3,700 MUl medium (1,480-MUm depth) and 13.26 +/- 0.23% in 7,400-MUl medium (2,960-MUm depth) at 20% O(2) in the incubator, which was 4.96 +/- 0.08% (1,480-MUm depth) and 2.83 +/- 0.42% (2,960-MUm depth) at 5% O(2), respectively. The differences of POC compared by medium volume were statistically significant (p = 0.0003 at 20% and p = 0.001 at 5%). Glycosaminoglycan production and aggrecan gene expression were most promoted when cultured in moderately low POC, 1,000 MUl (2,960-MUm depth) at 20% O(2) and 500 MUl (1,480-MUm depth) at 5% O(2) in 12-well culture dishes. We demonstrate that medium volume and oxygen concentration in the incubator affect not only POC but also chondrogenic differentiation. PMID- 22259016 TI - MiR-134 functions as a regulator of cell proliferation, apoptosis, and migration involving lung septation. AB - MicroRNAs (miRNAs) are 21-25 nt long non-coding RNA that modulate various biological processes, including developmental timing via regulating the expression of their target genes. One critical determinant of normal postnatal lung architecture is septation, and there are many miRNAs involved in the development process. miR-134 is reported as a powerful inducer of pluripotent stem cell differentiation, and we have found that miR-134 is strongly downregulated during mice lung septation (from postnatal Day 2 to postnatal Day 21). Further cell function experiments have revealed that over-expression of miR 134 in A549 and Calu-3 cells can promote cell proliferation and inhibit cell apoptosis and migration abilities in vitro, and the down-expression of miR-134 in cells can act in the opposite way, which indicate that miR-134 is associated with lung septation. This study provides a basis for further investigation of its function in lung development. PMID- 22259017 TI - Simultaneous determination of zolazepam and tiletamine in dog plasma by liquid chromatography coupled to a tandem mass spectrometry. AB - A mixture of tiletamine, a dissociative anesthetic, and zolazepam, a minor tranquilizer, has been widely used as an anesthetic or an immobilizing agent in a variety of animal species. However, interestingly, their pharmacokinetic behaviors have been published only in polar bears and pigs. In this study, we introduce a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for determining the two drugs in dog plasma. After simple protein precipitation with acetonitrile including midazolam (internal standard), the analytes were chromatographed on a reversed-phase column with a mobile phase of 10 m m ammonium acetate aqueous solution and acetonitrile (1:4, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of zolazepam and tiletamine in plasma after a single intramuscular 10 mg dose of each in beagle dogs. PMID- 22259018 TI - Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Oncotype DX. PMID- 22259019 TI - Identification of human UDP-glucuronosyltransferases involved in N-carbamoyl glucuronidation of lorcaserin. AB - Lorcaserin, a selective serotonin 5-HT(2C) receptor agonist, is a weight management agent in clinical development. Lorcaserin N-carbamoyl glucuronidation governs the predominant excretory pathway of lorcaserin in humans. Human UDP glucuronosyltransferases (UGTs) responsible for lorcaserin N-carbamoyl glucuronidation are identified herein. Lorcaserin N-carbamoyl glucuronide formation was characterized by the following approaches: metabolic screening using human tissues (liver, kidney, intestine, and lung) and recombinant enzymes, kinetic analyses, and inhibition studies. Whereas microsomes from all human tissues studied herein were found to be catalytically active for lorcaserin N carbamoyl glucuronidation, liver microsomes were the most efficient. With recombinant UGT enzymes, lorcaserin N-carbamoyl glucuronidation was predominantly catalyzed by three UGT2Bs (UGT2B7, UGT2B15, and UGT2B17), whereas two UGT1As (UGT1A6 and UGT1A9) played a minor role. UGT2B15 was most efficient, with an apparent K(m) value of 51.6 +/- 1.9 MUM and V(max) value of 237.4 +/- 2.8 pmol/mg protein/min. The rank order of catalytic efficiency of human UGT enzymes for lorcaserin N-carbamoyl glucuronidation was UGT2B15 > UGT2B7 > UGT2B17 > UGT1A9 > UGT1A6. Inhibition of lorcaserin N-carbamoyl glucuronidation activities of UGT2B7, UGT2B15, and UGT2B17 in human liver microsomes by mefenamic acid, bisphenol A, and eugenol further substantiated the involvement of these UGT2B isoforms. In conclusion, multiple human UGT enzymes catalyze N-carbamoyl glucuronidation of lorcaserin; therefore, it is unlikely that inhibition of any one of these UGT activities will lead to significant inhibition of the lorcaserin N-carbamoyl glucuronidation pathway. Thus, the potential for drug-drug interaction by concomitant administration of a drug(s) that is metabolized by any of these UGTs is remote. PMID- 22259020 TI - Contributions of individual amino acid residues to the endogenous CLV3 function in shoot apical meristem maintenance in Arabidopsis. AB - As a peptide hormone, CLV3 restricts the stem cell number in shoot apical meristem (SAM) by interacting with CLV1/CLV2/CRN/RPK2 receptor complexes. To elucidate how the function of the CLV3 peptide in SAM maintenance is established at the amino acid (AA) level, alanine substitutions were performed by introducing point mutations to individual residues in the peptide-coding region of CLV3 and its flanking sequences. Constructs carrying such substitutions, expressed under the control of CLV3 regulatory elements, were transformed to the clv3-2 null mutant to evaluate their efficiencies in complementing its defects in SAMs in vivo. These studies showed that aspartate-8, histidine-11, glycine-6, proline-4, arginine-1, and proline-9, arranged in an order of importance, were critical, while threonine-2, valine-3, serine-5, and the previously assigned hydroxylation and arabinosylation residue proline-7 were trivial for the endogenous CLV3 function in SAM maintenance. In contrast, substitutions of flanking residues did not impose much damage on CLV3. Complementation of different alanine-substituted constructs was confirmed by measurements of the sizes of SAMs and the WUS expression levels in transgenic plants. These studies established a complete contribution map of individual residues in the peptide-coding region of CLV3 for its function in SAM, which may help to understand peptide hormones in general. PMID- 22259021 TI - The patatin-containing phospholipase A pPLAIIalpha modulates oxylipin formation and water loss in Arabidopsis thaliana. AB - The patatin-related phospholipase A (pPLA) hydrolyzes membrane glycerolipids to produce monoacyl compounds and free fatty acids. Phospholipids are cleaved by pPLAIIalpha at the sn-1 and sn-2 positions, and galactolipids, including those containing oxophytodienoic acids, can also serve as substrates. Ablation of pPLAIIalpha decreased lysophosphatidylcholine and lysophosphatidylethanolamine levels, but increased free linolenic acid. pPLAIIalpha-deficient plants displayed a higher level of jasmonic acid and methyl jasmonate, as well as the oxylipin biosynthetic intermediates 13-hydroperoxylinolenic acid and 12-oxophytodienoic acid than wild-type (WT) plants. The expression of genes involved in oxylipin production was also higher in the pPLAIIalpha-deficient mutant than in WT plants. The mutant plants lost water more quickly than WT plants. The stomata of WT and mutant plants responded similarly to abscisic acid. In response to desiccation, the mutant and WT leaves produced abscisic acid at the same rate, but, after 4 h of desiccation, the jasmonic acid level was much higher in mutant than WT leaves. These results indicate that pPLAIIalpha negatively regulates oxylipin production and suggest a role in the removal of oxidatively modified fatty acids from membranes. PMID- 22259022 TI - Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE-HPLC technique. AB - Adrenocortical carcinoma (ACC) is a rare malignancy with an incompletely understood pathogenesis and a poor prognosis. The adrenalytic activity of mitotane has made it the most important single drug in the treatment of ACC. Unfortunately, the exact mechanism of mitotane action is still unknown. It is believed that mitotane belongs to the class of drugs that require metabolic transformation by cytochrome P450 for therapeutic action; therefore determination of plasma levels of not only mitotane but also its metabolites would help in carrying out the treatment. The objective of this work was to develop and validate an SPE-HPLC method for simultaneous determination of mitotane and its metabolites in different biological fluids. The sample preparation consisted of a solid-phase extraction on a Discovery DSC(18) cartridge, while analysis of extracts was performed on a Symmetry C(18) column. The usefulness of the proposed method was confirmed by analysis of plasma, red cell and urine samples from patient chronically treated with 1.5 g of mitotane. The patient involved in this study had a high plasma concentration of mitotane and none of the investigated metabolites were found. In order to investigate whether the polymorphism of CYP2C9 and CYP2C19 enzymes could be related to the metabolism of mitotane, RT-PCR analysis was performed. PMID- 22259023 TI - Solution-processable septithiophene monolayer transistor. AB - Septithiophene with endgroups designed to form liquid crystalline phases and allows controlled deposition of an electrically connected monolayer. Field effect mobilies mobilities of charge carriers and spectroscopic properties of the monolayer provide evidence of sustainable transport and delocalization of the excitation through intermolecular interactions within the layer. PMID- 22259024 TI - Thromboembolism is common and influences prognosis in patients with pancreatic cancer, study reports. PMID- 22259025 TI - Use of flux pre-analysis to enable 13C tracer studies in pyruvate kinase deficient Escherichia coli. AB - Pyruvate kinase-deficient Escherichia coli (PB25) is a low by-product-producing yet fast-growing mutant that has been shown to have technological potential. Determining the flux limits through finding the extreme point flux sets was previously reported to identify alternate metabolite trafficking scenarios. Previously, the extreme point flux sets were used to design tracer experiments; however, variation in extracellular measurements was not considered, and reaction reversibility was assumed to be low to moderate. In this study, we examined the utility of limiting the fluxes and predetermining the trafficking scenarios in PB25, including confirmation of quasi-linearity between extreme points to ensure sensitivity is maintained. The effects of variation in extracellular measurements and reaction reversibilities were also examined. Tightened flux limits reduced the nonlinearity between label distribution and fluxes. For low to moderate reversibility, contrast was also preserved. However, for highly reversible phosphoglucoisomerase activity, information from common analytes could lead to a flux solution that is biased towards one extreme point. Based on the PB25 model, some suggestions are provided for how predetermining flux limits and trafficking scenarios could enable flux identification in larger network problems. PMID- 22259026 TI - Nifedipine prevents iron accumulation and reverses iron-overload-induced dopamine neuron degeneration in the substantia nigra of rats. AB - The mechanisms of iron accumulation in substantia nigra (SN) of Parkinson's diseases remain unclear. The objective of this study was to investigate effects of nifedipine on iron-overload-induced iron accumulation and neurodegeneration in SN of rats. By high performance liquid chromatography-electrochemical detection, tyrosine hydroxylase (TH) immunohistochemistry, and iron content array, we first quantified iron content and the number of dopamine neurons in SN of experimental rats treated with iron dextran. We further assessed effects of treatment with nifedipine. Our results showed that nifedipine treatment prevents iron dextran induced dopamine depletion in the striatum. Consistently, we found that nifedipine restores the number of TH-positive neurons reduced by iron dextran overload and prevents increase of iron content in the SN. These results suggested that nifedipine may suppress iron toxicity in dopamine neurons and prevent neurodegeneration. PMID- 22259027 TI - Molecular shuttling of a compact and rigid H-shaped [2]rotaxane. PMID- 22259029 TI - Highly efficient hydrophosphonylation of aldehydes and unactivated ketones catalyzed by methylene-linked pyrrolyl rare earth metal amido complexes. AB - A series of rare earth metal amido complexes bearing methylene-linked pyrrolyl amido ligands were prepared through silylamine elimination reactions and displayed high catalytic activities in hydrophosphonylations of aldehydes and unactivated ketones under solvent-free conditions for liquid substrates. Treatment of [(Me(3)Si)(2)N](3)Ln(MU-Cl)Li(THF)(3) with 2-(2,6 Me(2)C(6)H(3)NHCH(2))C(4)H(3)NH (1, 1 equiv) in toluene afforded the corresponding trivalent rare earth metal amides of formula {(MU eta(5):eta(1)):eta(1)-2-[(2,6-Me(2)C(6)H(3))NCH(2)](C(4)H(3)N)LnN(SiMe(3))(2)}(2) [Ln=Y (2), Nd (3), Sm (4), Dy (5), Yb (6)] in moderate to good yields. All compounds were fully characterized by spectroscopic methods and elemental analyses. The yttrium complex was also characterized by (1)H NMR spectroscopic analyses. The structures of complexes 2, 3, 4, and 6 were determined by single crystal X-ray analyses. Study of the catalytic activities of the complexes showed that these rare earth metal amido complexes were excellent catalysts for hydrophosphonylations of aldehydes and unactivated ketones. The catalyzed reactions between diethyl phosphite and aldehydes in the presence of the rare earth metal amido complexes (0.1 mol%) afforded the products in high yields (up to 99%) at room temperature in short times of 5 to 10 min. Furthermore, the catalytic addition of diethyl phosphite to unactivated ketones also afforded the products in high yields of up to 99% with employment of low loadings (0.1 to 0.5 mol%) of the rare earth metal amido complexes at room temperature in short times of 20 min. The system works well for a wide range of unactivated aliphatic, aromatic or heteroaromatic ketones, especially for substituted benzophenones, giving the corresponding alpha-hydroxy diaryl phosphonates in moderate to high yields. PMID- 22259028 TI - Quantitation of unbound sunitinib and its metabolite N-desethyl sunitinib (SU12662) in human plasma by equilibrium dialysis and liquid chromatography tandem mass spectrometry: application to a pharmacokinetic study. AB - A rapid, selective, and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of unbound sunitinib and its active metabolite N-desethyl sunitinib in plasma. Plasma and post-dialysis buffer samples were extracted using a liquid-liquid extraction procedure with acetonitrile-n-butylchloride (1:4, v/v). Chromatographic separation was achieved on a Waters X-Terra(r) MS RP(18) column with a mobile phase consisting of acetonitrile and water (60:40, v/v) containing formic acid (0.1%, v/v) using an isocratic run, at a flow-rate of 0.2 mL/min. Analytes were detected by electrospray tandem mass spectrometry in the selective reaction monitoring mode. Linear calibration curves were generated over the ranges 0.1-100 and 0.02-5 ng/mL for sunitinib and 0.2-200 and 0.04-10 ng/mL for N-desethyl sunitinib in plasma and in phosphate-buffered solution, respectively. The values for both within-day and between-day precision and accuracy were well within the generally accepted criteria for analytical methods. The analytical range was sufficient to determine the unbound and total concentrations of both analytes. The method was applied for measurement unbound concentrations in addition to total concentrations of sunitinib and its metabolite in plasma of a cancer patient receiving 50 mg daily dose. PMID- 22259030 TI - Can we still learn something from the relationship between fertility and mother's employment? Evidence from developing countries. AB - In this work, I study the impact of fertility on mothers' employment for a sample of developing countries. Using the event of multiple births as an instrumental variable (IV) for fertility, I find that having children has a negative impact on female employment. In addition, three types of heterogeneity are found. First, the magnitude of the impact depends on the birth at which the increase in fertility takes place. Second, the types of jobs affected by a fertility shock (multiple births) are jobs identified with a higher degree of informality, such as self-employment or unpaid jobs. Finally, the heterogeneity analysis reveals that an unexpected change in fertility is stronger at a higher education level of the mother and in urban areas. PMID- 22259031 TI - Educational inequality by race in Brazil, 1982-2007: structural changes and shifts in racial classification. AB - Despite overwhelming improvements in educational levels and opportunity during the past three decades, educational disadvantages associated with race still persist in Brazil. Using the nationally representative Pesquisa Nacional de Amostra por Domicilio (PNAD) data from 1982 and 1987 to 2007, this study investigates educational inequalities between white, pardo (mixed-race), and black Brazilians over the 25-year period. Although the educational advantage of whites persisted during this period, I find that the significance of race as it relates to education changed. By 2007, those identified as blacks and pardos became more similar in their schooling levels, whereas in the past, blacks had greater disadvantages. I test two possible explanations for this shift: structural changes and shifts in racial classification. I find evidence for both. I discuss the findings in light of the recent race-based affirmative action policies being implemented in Brazilian universities. PMID- 22259032 TI - Union instability as an engine of fertility? A microsimulation model for France. AB - Opportunities for conceiving and bearing children are fewer when unions are not formed or are dissolved during the childbearing years. At the same time, union instability produces a pool of persons who may enter new partnerships and have additional children in stepfamilies. The balance between these two opposing forces and their implications for fertility may depend on the timing of union formation and parenthood. In this article, we estimate models of childbearing, union formation, and union dissolution for female respondents to the 1999 French Etude de l'Histoire Familiale. Model parameters are applied in microsimulations of completed family size. We find that a population of women whose first unions dissolve during the childbearing years will end up with smaller families, on average, than a population in which all unions remain intact. Because new partnerships encourage higher parity progressions, repartnering minimizes the fertility gap between populations with and those without union dissolution. Differences between the two populations are much smaller when family formation is postponed-that is, when union formation and dissolution or first birth occurs after age 30, or when couples delay childbearing after union formation. PMID- 22259035 TI - Death receptor 3 is essential for generating optimal protective CD4+ T-cell immunity against Salmonella. AB - The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2- and Th17-cell-mediated inflammatory and autoimmune conditions, yet no role in host defence has been reported. Here, we examined the role of DR3 during infection with Salmonella enterica serovar Typhimurium. Infection resulted in protracted expression of the DR3 ligand TL1A but not the related TNF superfamily proteins OX40L or CD30L. TL1A expression was localized to splenic F4/80(+) macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4(+) -cell expansion. To address the relevance of the TL1A-DR3 interaction, we examined immune responses to S. enterica Typhimurium in mice lacking DR3. Infected DR3(-/-) mice harboured reduced numbers of antigen-experienced and proliferating CD4(+) T cells compared with WT mice. Furthermore, the frequency of IFN-gamma(+) CD4(+) T cells in DR3(-/-) mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3(-/-) mice. This defect was intrinsic to CD4(+) T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3(-/-) CD4(+) T cells compared with WT CD4(+) -cell recipients. These data establish for the first time a role for DR3 in a host defence response. PMID- 22259036 TI - Analysis of alternative splicing of cassette exons at single-cell level using two fluorescent proteins. AB - Alternative splicing plays a major role in increasing proteome complexity and regulating gene expression. Here, we developed a new fluorescent protein-based approach to quantitatively analyze the alternative splicing of a target cassette exon (skipping or inclusion), which results in an open-reading frame shift. A fragment of a gene of interest is cloned between red and green fluorescent protein (RFP and GFP)-encoding sequences in such a way that translation of the normally spliced full-length transcript results in expression of both RFP and GFP. In contrast, alternative exon skipping results in the synthesis of RFP only. Green and red fluorescence intensities can be used to estimate the proportions of normal and alternative transcripts in each cell. The new method was successfully tested for human PIG3 (p53-inducible gene 3) cassette exon 4. Expected pattern of alternative splicing of PIG3 minigene was observed, including previously characterized effects of UV light irradiation and specific mutations. Interestingly, we observed a broad distribution of normal to alternative transcript ratio in individual cells with at least two distinct populations with ~45% and >95% alternative transcript. We believe that this method is useful for fluorescence-based quantitative analysis of alternative splicing of target genes in a variety of biological models. PMID- 22259037 TI - A potent 2'-O-methylated RNA-based microRNA inhibitor with unique secondary structures. AB - MicroRNAs (miRNAs) are involved in various biological processes and human diseases. The development of strong low-molecular weight inhibitors of specific miRNAs is thus expected to be useful in providing tools for basic research or in generating promising new therapeutic drugs. We have previously described the development of 'Tough Decoy (TuD) RNA' molecules, which achieve the long-term suppression of specific miRNA activity in mammalian cells when expressed from a lentivirus vector. In our current study, we describe new synthetic miRNA inhibitors, designated as S-TuD (Synthetic TuD), which are composed of two fully 2'-O-methylated RNA strands. Each of these strands includes a miRNA-binding site. Following the hybridization of paired strands, the resultant S-TuD forms a secondary structure with two stems, which resembles the corresponding TuD RNA molecule. By analyzing the effects of S-TuD against miR-21, miR-200c, miR-16 and miR-106b, we have elucidated the critical design features of S-TuD molecules that will provide optimum inhibitory effects following transfection into human cell lines. We further show that the inhibitory effects of a single transfection of S TuD-miR200c are quite long-lasting (>7 days) and induce partial EMT, the full establishment of which requires 11 days when using a lentivirus vector that expresses TuD-miR200c continuously. PMID- 22259039 TI - Palladium-catalyzed carbonylative dimerization of styrenes to 1,5-diarylpent-1-en 3-ones. PMID- 22259038 TI - Integration of DNA into bacterial chromosomes from plasmids without a counter selection marker. AB - Most bacteria can only be transformed with circular plasmids, so robust DNA integration methods for these rely upon selection of single-crossover clones followed by counter-selection of double-crossover clones. To overcome the limited availability of heterologous counter-selection markers, here we explore novel DNA integration strategies that do not employ them, and instead exploit (i) activation or inactivation of genes leading to a selectable phenotype, and (ii) asymmetrical regions of homology to control the order of recombination events. We focus here on the industrial biofuel-producing bacterium Clostridium acetobutylicum, which previously lacked robust integration tools, but the approach we have developed is broadly applicable. Large sequences can be delivered in a series of steps, as we demonstrate by inserting the chromosome of phage lambda (minus a region apparently unstable in Escherichia coli in our cloning context) into the chromosome of C. acetobutylicum in three steps. This work should open the way to reliable integration of DNA including large synthetic constructs in diverse microorganisms. PMID- 22259041 TI - A formal synthesis of vinigrol. PMID- 22259042 TI - Growth behavior and kinetics of self-assembled silica-carbonate biomorphs. AB - Upon slow crystallization from silica-containing solutions or gels at elevated pH, alkaline-earth carbonates spontaneously self-assemble into remarkable nanocrystalline ultrastructures. These so-called silica biomorphs exhibit curved morphologies beyond crystallographic symmetry and ordered textures reminiscent of the hierarchical design found in many biominerals. The formation of these fascinating materials is thought to be driven by a dynamic coupling of the components' speciations in solution, which causes concerted autocatalytic mineralization of silica-stabilized nanocrystals over hours. In the present work, we have studied the precipitation kinetics of this unique system by determining growth rates of individual aggregates using video microscopy, and correlated the results with time-dependent data on the concentration of metal ions and pH acquired online during crystallization. In this manner, insight to the evolution of chemical conditions during growth was gained. It is shown that crystallization proceeds linearly with time and is essentially reaction controlled, which fits well in the proposed morphogenetic scenario, and thus, indirectly supports it. Measurements of the silica concentration in solution, combined with analyses of crystal aggregates isolated at distinct stages of morphogenesis, further demonstrate that the fraction of silica coprecipitated with carbonate during active growth is rather small. We discuss our findings with respect to the role of silica in the formation of biomorphs, and moreover, prove that the external silica skins that occasionally sheath the aggregates--previously supposed to be involved in the growth mechanism--originate from secondary precipitation after growth is already terminated. PMID- 22259043 TI - Determination of aripiprazole in rat plasma and brain using ultra-performance liquid chromatography/electrospray ionization tandem mass spectrometry. AB - Aripiprazole is an important antipsychotic drug. A simple, sensitive and rapid ultra-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for the simultaneous quantification of this compound in rat plasma and brain homogenate. The analyte was extracted from rat plasma and brain homogenate using a weak cation exchange mixed-mode resin-based solid phase extraction. The compound was separated on an Agilent Eclipse Plus C(18) (2.1 * 50 mm, 1.8 um) column using a mobile phase of (A) 0.1% formic acid aqueous and (B) acetonitrile with gradient elution. The analyte was detected in positive ion mode using multiple reaction monitoring. The method was validated and the specificity, linearity, limit of quantitation (LOQ), precision, accuracy, recoveries and stability were determined. The LOQ was 0.5 ng/mL for aripiprazole in plasma and 1.5 ng/g in brain tissue. The MS response was linear over the concentration range 0.5-100 ng/mL for aripiprazole in plasma and 1.5-300 ng/g in brain tissue. The precision and accuracy for intra-day and inter-day were better than 14%. The relative and absolute recoveries were above 72% and the matrix effects were low. This validated method was successfully used to quantify the rat plasma and brain tissue concentrations of the analyte following chronic treatment with aripiprazole. PMID- 22259045 TI - Femtosecond laser nanosurgery of sub-cellular structures in HeLa cells by employing Third Harmonic Generation imaging modality as diagnostic tool. AB - Femtosecond laser assisted nanosurgery of microscopic biological specimens is a relatively new technique which allows the selective disruption of sub-cellular structures without causing any undesirable damage to the surrounding regions. The targeted structures have to be stained in order to be clearly visualized for the nanosurgery procedure. However, the validation of the final nanosurgery result is difficult, since the targeted structure could be simply photobleached rather than selectively destroyed. This fact comprises a main drawback of this technique. In our study we employed a multimodal system which integrates non-linear imaging modalities with nanosurgery capabilities, for the selective disruption of sub cellular structures in HeLa cancer cells. Third Harmonic Generation (THG) imaging modality was used as a tool for the identification of structures that were subjected to nanosurgery experiments. No staining of the biological samples was required, since THG is an intrinsic property of matter. Furthermore, cells' viability after nanosurgery processing was verified via Two Photon Excitation Fluorescence (TPEF) measurements. PMID- 22259048 TI - Efficacy of hypothalamic stimulation for chronic drug-resistant cluster headache. PMID- 22259049 TI - Vestibular evoked myogenic potentials to sound and vibration: characteristics in vestibular migraine that enable separation from Meniere's disease. AB - OBJECTIVES: It can be difficult to distinguish vestibular migraine (VM) from Meniere's disease (MD) in its early stages. Using vestibular-evoked myogenic potentials (VEMPs), we sought to identify test parameters that would help discriminate between these two vestibular disorders. METHODS: We first recorded ocular and cervical VEMPs (oVEMP/cVEMP) to air-conducted clicks and bone conducted vibration in 30 control participants, 30 participants with clinically definite VM and 30 participants with clinically probable VM. Results were compared with a group of 60 MD patients from a previous study. oVEMPs and cVEMPs were then recorded at octave frequencies of 250 Hz to 2000 Hz in 20 controls and 20 participants each with clinically definite VM and MD. Inter-aural amplitude asymmetry ratios and amplitude frequency ratios were compared between groups. RESULTS: For click, tendon-hammer-tap and minishaker-tap VEMPs, there were no significant differences in reflex amplitudes or symmetry between controls, definite VM and probable VM. Compared with MD patients, participants with VM had significantly fewer reflex abnormalities for click-cVEMP, click-oVEMPs and minitap-cVEMPs. The ratio of cVEMP amplitude generated by tone bursts at a frequency of 0.5 kHz to that generated by 1 kHz was significantly lower for MD affected ears than for VM or controls ears. cVEMP asymmetry ratios for 0.5 kHz tone bursts were significantly higher for MD than VM. CONCLUSIONS: The 0.5/1 kHz frequency ratio, 0.5 kHz asymmetry ratio and caloric test combined, separated MD from VM with a sensitivity of 90.0% and specificity of 70.0%. PMID- 22259050 TI - Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway. AB - Neuroblastomas, an embryonic cancer of the sympathetic nervous system, often occur in young children. Honokiol, a small-molecule polyphenol, has multiple therapeutic effects and pharmacological activities. This study was designed to evaluate whether honokiol could pass through the blood-brain barrier (BBB) and induce death of neuroblastoma cells and its possible mechanisms. Primary cerebral endothelial cells (CECs) prepared from mouse brain capillaries were cultured at a high density for 4 days, and these cells formed compact morphologies and expressed the ZO-1 tight-junction protein. A permeability assay showed that the CEC-constructed barrier obstructed the passing of FITC-dextran. Analyses by high performance liquid chromatography and the UV spectrum revealed that honokiol could traverse the CEC-built junction barrier and the BBB of ICR mice. Exposure of neuroblastoma neuro-2a cells and NB41A3 cells to honokiolinduced cell shrinkage and decreased cell viability. In parallel, honokiol selectively induced DNA fragmentation and cell apoptosis rather than cell necrosis. Sequential treatment of neuro-2a cells with honokiol increased the expression of the proapoptotic Bax protein and its translocation from the cytoplasm to mitochondria. Honokiol successively decreased the mitochondrial membrane potential but increased the release of cytochrome c from mitochondria. Consequently, honokiol induced cascade activation of caspases-9, -3, and -6. In comparison, reducing caspase-6 activity by Z-VEID-FMK, an inhibitor of caspase-6, simultaneously attenuated honokiol-induced DNA fragmentation and cell apoptosis. Taken together, this study showed that honokiol can pass through the BBB and induce apoptotic insults to neuroblastoma cells through a Bax-mitochondrion cytochrome c-caspase protease pathway. Therefore, honokiol may be a potential candidate drug for treating brain tumors. PMID- 22259051 TI - The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)-induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs. PMID- 22259052 TI - Deiodinase 2 expression is increased in dorsocervical fat of patients with HIV associated lipohypertrophy syndrome. AB - CONTEXT: The pathogenesis and function of dorsocervical sc adipose tissue (DSAT) accumulation in HIV-infected patients is not known. Previous investigations using either UCP-1 expression or positron emission tomography have been inconclusive as to whether this depot represents brown adipose tissue (BAT). We investigated DSAT gene expression, including DIO2, a deiodinase that contributes to increased thermogenesis in brown fat, and simultaneously determined [18F]fluorodeoxyglucose ([18F]FDG) uptake in lipodystrophic HIV and healthy control subjects. DESIGN: Thirteen HIV-infected and three non-HIV-infected men were recruited. HIV-infected subjects had evidence of significant lipodystrophy, including fat atrophy of the face, arms, and legs, and/or fat accumulation of the neck and abdomen. Subjects were cooled, followed by [18F]FDG positron emission tomography/computed tomography, fat biopsy of DSAT, and measurement of resting energy expenditure (REE). HIV-infected subjects were characterized as lipohypertrophic and lipoatrophic and compared. RESULTS: Mean standardized uptake value of [18F]FDG and UCP-1 expression were not significantly different in DSAT among the groups. However, lipohypertrophic subjects demonstrated increased expression of DIO2 in DSAT compared with lipoatrophic subjects (P = 0.03). Among HIV-infected patients, DIO2 expression was strongly related to REE (r = 0.78, P = 0.002) and was a predictor of REE in multivariate modeling controlling for age, TSH, and lean body mass (r2 = 0.79, P = 0.008). One control subject demonstrated typical BAT in the supraclavicular area. CONCLUSIONS: Adipose tissue accumulating in the dorsocervical area in HIV lipodystrophy does not appear to be classical BAT. However, DIO2 expression is increased in DSAT among patients with HIV lipodystrophy, particularly those with increased visceral adiposity, and is positively associated with energy expenditure. PMID- 22259054 TI - Ectopic substernal thyroid tissue: a challenging differential diagnosis. PMID- 22259053 TI - Young women with cold-activated brown adipose tissue have higher bone mineral density and lower Pref-1 than women without brown adipose tissue: a study in women with anorexia nervosa, women recovered from anorexia nervosa, and normal weight women. AB - CONTEXT: Anorexia nervosa (AN) is associated with depletion of body fat, loss of bone mineral density (BMD), and impaired thermogenesis. Brown adipose tissue (BAT) is lower in obese individuals and decreases during aging. Recent studies have suggested a link between BAT and bone metabolism. OBJECTIVE: Our objective was to investigate the presence and quantity of BAT in patients with AN, recovered AN (AN-R), and normal-weight controls and to study the relationship between BAT and BMD and body composition and investigate hormonal predictors of BAT. DESIGN AND SETTING: This was a cross-sectional study at a clinical research center. PATIENTS: Patients included 15 women: five with AN (mean age 30 +/- 6.3 yr), five AN-R, and five healthy nonobese controls of comparable age. MAIN OUTCOME MEASURES: Cold-activated BAT was determined by fluorodeoxyglucose positron emission tomography/computed tomography. BMD of total-body, spine, and hip, fat and lean mass was determined by dual-energy x-ray absorptiometry. Single slice magnetic resonance imaging at L4 was done for abdominal fat compartments, and preadipocyte factor-1 (Pref-1), T3, and T4 were measured. RESULTS: Within the AN group, one of five; in the AN-R group, two of five; and in the healthy nonobese control group, four of five subjects were BAT positive. Subjects were divided into groups based on the presence (n = 7) or absence (n = 8) of BAT. Both groups were of comparable age and body mass index. Women with BAT had higher total-body BMD, higher T3, and lower Pref-1 compared with women without BAT. There was a positive correlation between BAT and BMD that remained significant after controlling for disease status and body mass index. CONCLUSION: Young women with AN have low cold-activated BAT, which may be due to impaired BAT thermogenesis. Young women with BAT have higher BMD and lower Pref-1 compared with women without BAT, suggesting that BAT may be involved in the regulation of stem cell differentiation into the bone lineage at the expense of adipogenesis. PMID- 22259055 TI - Clinical utility of functional imaging with 18F-FDOPA in Von Hippel-Lindau syndrome. AB - CONTEXT: Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which patients are at risk of developing multiple tumors in different organs. 6-L 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) is a relatively new metabolic imaging tracer proposed for the use of localizing sites of neuroendocrine tumors. There are limited data on the clinical utility of using 18F-FDOPA PET for identifying neuroendocrine tumors in a high-risk population such as VHL. OBJECTIVE: The aim of this prospective study was to evaluate the clinical utility of 18F-FDOPA PET in patients with VHL-related tumors. DESIGN: Radiological findings were prospectively collected from four imaging modalities: computed tomography, magnetic resonance imaging (MRI), 18F fluorodeoxyglucose PET, and 18F-FDOPA PET. 18F-FDOPA PET findings were compared with those from other imaging modalities, as well as with clinical and laboratory data, and pathology findings if patients underwent an operation. RESULTS: In 52 patients with VHL, 390 lesions were identified by computed tomography (n = 139), MRI (n = 117), 18F-fluorodeoxyglucose PET (n = 94), and 18F-FDOPA PET (n = 40). 18F-FDOPA PET identified 20 pancreatic and 20 extrapancreatic tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4), lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen by conventional imaging studies in 9.6% of patients and 4.4% of lesions. Seven of eight patients who had an 18F-FDOPA PET-positive lesion underwent resection, and pathology showed a neuroendocrine tumor. Four of 10 patients with positive adrenal uptake had elevated catecholamine levels, and six of 10 patients had a discrete mass on axial imaging. CONCLUSIONS: 18F-FDOPA PET is a useful complementary imaging study to detect neuroendocrine tumors in patients with VHL undergoing surveillance, especially in those suspected to have adrenal pheochromocytoma or unusual ectopic locations. PMID- 22259056 TI - Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations. AB - CONTEXT: The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas. OBJECTIVE AND DESIGN: The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings. RESULTS: MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions. CONCLUSION: WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others. PMID- 22259057 TI - Adipose tissue remodeling in children: the link between collagen deposition and age-related adipocyte growth. AB - CONTEXT: Extracellular matrix (ECM) remodeling is essential for adipose tissue growth and expansion in high fat-fed mice, and there is evidence of fibrosis in adipose tissue in human obesity. OBJECTIVE: The aim of the study was to explore the role of ECM remodeling in adipose tissue in healthy, growing children. RESEARCH DESIGN, SETTING, AND PARTICIPANTS: Abdominal sc adipose biopsies were obtained from 65 otherwise healthy children [57 boys; age, 5.3 +/- 3.8 yr (mean +/- sd)] having elective surgery (cross-sectional study). Twenty percent of the participants were classified as overweight/obese based on body mass index (BMI) z score. MAIN OUTCOME MEASURES: We examined collagen (total and pericellular), HAM56+ macrophages, CD206+ M2 phenotype macrophages, and CD3+ T cells measured by immunohistochemistry and ECM gene expression markers. RESULTS: Overweight children had significantly less total collagen compared to normal weight children (median, 3.4 vs. 9.1%; P = 0.001). However, collagen areas were not positive for COL6 and showed little evidence of collagen surrounding adipocytes. Fat cell size was negatively correlated with the percentage of total (r = -0.398; P = 0.003) and pericellular collagen (r = -0.462; P < 0.001) but positively correlated with HAM56+ macrophages (r = 0.541; P < 0.001). The percentage of total collagen was inversely associated with BMI z score (r = -0.345; P = 0.01) and age (r = -0.348; P = 0.005), with older (>11 yr old) children in the top BMI z tertile having less collagen (3.8%) than younger (2-5 yr old) children in the bottom BMI z tertile (12.6%). Adipose tissue in overweight children showed little evidence of crown like structures or T cells. CONCLUSION: In healthy, growing children, increased collagen in adipose tissue is associated with decreased fat cell size and BMI z score and increased M2+ phenotype macrophages, suggesting dynamic interaction between ECM remodeling and immune cells even at an early age. PMID- 22259058 TI - Heart failure is a clinically and densitometrically independent risk factor for osteoporotic fractures: population-based cohort study of 45,509 subjects. AB - OBJECTIVE: The aim of the study was to determine whether heart failure is associated with an increased risk of major osteoporotic fractures that is independent of bone mineral density (BMD). METHODS: We conducted a population based cohort study in Manitoba, Canada, by linking a clinical registry of all adults 50 yr of age and older who underwent initial BMD testing from 1998-2009 with administrative databases. We collected osteoporosis risk factors, comorbidities, medications, and BMD results. Validated algorithms identified recent-onset heart failure before the BMD test and new fractures after. The main outcome was time to major osteoporotic fractures (i.e. clinical vertebrae, distal forearm, humerus, and hip), and multivariable proportional hazards models were used for analyses. RESULTS: The cohort consisted of 45,509 adults; 1,841 (4%) had recent-onset heart failure. Subjects with heart failure were significantly (P < 0.001) older (74 vs. 66 yr) and had more previous fractures (21 vs. 13%) and lower total hip BMD [T-score, -1.3 (sd 1.3) vs. -0.9 (sd 1.2)] than those without. There were 2703 incident fractures over the 5-yr observation. Overall, 10% of heart failure subjects had incident major fractures compared with 5% of those without [unadjusted hazard ratio (HR), 2.45; 95% confidence interval (CI), 2.11-2.85]. Adjustment for osteoporosis risk factors, comorbidities, and medications attenuated but did not eliminate this association (HR, 1.33; 95% CI, 1.11-1.60), nor did further adjustment for total hip BMD (HR, 1.28; 95% CI, 1.06 1.53). CONCLUSIONS: Heart failure is associated with a 30% increase in major fractures that is independent of traditional risk factors and BMD, and it also identifies a high-risk population that may benefit from increased screening and treatment for osteoporosis. PMID- 22259059 TI - Kruppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis. AB - CONTEXT: Endometriosis is characterized by progesterone resistance and associated with infertility. Kruppel-like factor 9 (KLF9) is a progesterone receptor (PGR) interacting protein, and mice null for Klf9 are subfertile. Whether loss of KLF9 expression contributes to progesterone resistance of eutopic endometrium of women with endometriosis is unknown. OBJECTIVE: The aims were to investigate 1) KLF9 expression in eutopic endometrium of women with and without endometriosis, 2) effects of attenuated KLF9 expression on WNT-signaling component expression and on WNT inhibitor Dickkopf-1 promoter activity in human endometrial stromal cells (HESC), and 3) PGR and KLF9 coregulation of the stromal transcriptome network. METHODS: Transcript levels of KLF9, PGR, and WNT signaling components were measured in eutopic endometrium of women with and without endometriosis. Transcript and protein levels of WNT signaling components in HESC transfected with KLF9 and/or PGR small interfering RNA were analyzed by quantitative RT-PCR and Western blot. KLF9 and PGR coregulation of Dickkopf-1 promoter activity was evaluated using human Dickkopf-1-luciferase promoter/reporter constructs and by chromatin immunoprecipitation. KLF9 and PGR signaling networks were analyzed by gene expression array profiling. RESULTS: Eutopic endometrium from women with endometriosis had reduced expression of KLF9 mRNA together with those of PGR-B, WNT4, WNT2, and DKK1. KLF9 and PGR were recruited to the DKK1 promoter and modified each other's transactivity. In HESC, KLF9 and PGR coregulated components of the WNT, cytokine, and IGF gene networks that are implicated in endometriosis and infertility. CONCLUSION: Loss of KLF9 coregulation of endometrial stromal PGR responsive gene networks may underlie progesterone resistance in endometriosis. PMID- 22259060 TI - Diagnostic value of salivary cortisol in the CRH stimulation test in premature infants. AB - CONTEXT: According to a recent nationwide survey in Japan, a significant proportion of very low birth weight infants (VLBWI) develop late-onset circulatory collapse after the first week of life. Small doses of glucocorticoid are very effective in these patients, and relative adrenal insufficiency is suspected to be the main cause of the condition. Although the CRH test is required to evaluate the hypothalamic-pituitary-adrenal axis, obtaining multiple blood samples is invasive. OBJECTIVES: The present study was carried out to validate the consistency of the cortisol profiles of matched serum and saliva samples collected as part of the CRH test from VLBWI. SUBJECTS/METHODS: In 23 VLBWI with a gestational age of less than 29 wk, we performed CRH tests at 2 wk after birth and at term. Their cortisol values were measured at the baseline and 30 min after the administration of a single dose of human CRH (1 MUg/kg) using matched serum and saliva samples. RESULTS: In 26 CRH tests in 19 infants, we were able to measure both serum and salivary cortisol. Significant correlations were detected between the infants' serum and salivary cortisol values (r=0.78; P<0.0001), the increases in these values induced in response to the CRH test (r=0.81; P<0.0001), and their peak serum and salivary cortisol values (r=0.68; P=0.0001). CONCLUSION: This study indicated that using salivary cortisol measurements for the CRH test could be a reliable method for evaluating the hypothalamic-pituitary-adrenal axis in VLBWI with gestational age of less than 29 wk. PMID- 22259061 TI - Dens of axis metastasis from medullary thyroid cancer. PMID- 22259062 TI - Filamin-A is essential for dopamine d2 receptor expression and signaling in tumorous lactotrophs. AB - CONTEXT: Dopamine agonists (DA) are the first choice treatment of prolactinomas. However, a subset of patients is resistant to DA, due to undefined dopamine D2 receptor (D2R) alterations. Recently, D2R was found to associate with filamin-A (FLNA), a widely expressed cytoskeleton protein with scaffolding properties, in melanoma and neuronal cells. OBJECTIVE: The aim of the study was to investigate the role of FLNA in D2R expression and signaling in human tumorous lactotrophs and rat MMQ and GH3 cells. DESIGN: We analyzed FLNA expression in a series of prolactinomas by immunohistochemistry and Western blotting. We performed FLNA silencing or transfection experiments in cultured cells from DA-sensitive or resistant prolactinomas and in MMQ and GH3 cells, followed by analysis of D2R expression and signaling. RESULTS: We demonstrated reduced FLNA and D2R expression in DA-resistant tumors. The crucial role of FLNA on D2R was demonstrated by experiments showing that: 1) FLNA silencing in DA-sensitive prolactinomas resulted in 60% reduction of D2R expression and abrogation of DA induced inhibition of prolactin release and antiproliferative signals, these results being replicated in MMQ cells that endogenously express FLNA and D2R; and 2) FLNA overexpression in DA-resistant prolactinomas restored D2R expression and prolactin responsiveness to DA, whereas this manipulation was ineffective in GH3 cells that express FLNA but not D2R. No alteration in FLNA promoter methylation was detected, ruling out the occurrence of epigenetic FLNA silencing in DA resistant prolactinomas. CONCLUSIONS: These data indicate that FLNA is crucial for D2R expression and signaling in lactotrophs, suggesting that the impaired response to DA may be related to the reduction of FLNA expression in DA-resistant prolactinomas. PMID- 22259063 TI - Ghrelin suppresses secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in women. AB - CONTEXT: Ghrelin has been shown to suppress secretion of LH and, less regularly, of FSH in male and female animals and human males. However, no such evidence exists for human females. OBJECTIVE: The aim was to study the effect of ghrelin on secretion of LH and FSH in women. DESIGN/PARTICIPANTS/INTERVENTION: Nocturnal (2000-0700 h) secretion profiles of LH and FSH were determined in six healthy women (age, 25.5+/-2.9 yr) twice, receiving 50 MUg ghrelin or placebo at 2200, 2300, 2400, and 0100 h in this single-blind, randomized, crossover study. RESULTS: LH secretion after ghrelin injection as assessed by the area under the curve (4.01+/-1.37 mIU/min.ml) was significantly (P=0.031) lower than after placebo injection (5.46+/-1.33 mIU/min.ml). Also, FSH secretion after ghrelin injection (5.54+/-0.64 mIU/min.ml) was significantly (P=0.038) lower than after placebo injection (5.87+/-0.56 mIU/min.ml). LH pulses occurred significantly (P=0.007) less frequently after ghrelin injection (2.3+/-0.5) than after placebo injection (3.8+/-0.9). Accordingly, the interval between first and second LH pulse after treatment was significantly (P=0.002) longer after ghrelin injection (300+/-86 min) than after placebo injection (187+/-60 min). One of the six women exhibited clear FSH pulses, which overall paralleled LH pulses; two FSH and LH pulses occurred after ghrelin injection, but three occurred after placebo in this woman. CONCLUSIONS: This is the first report that ghrelin suppresses the secretion of LH and FSH in women. These findings resemble those in male and female animals and in men. PMID- 22259065 TI - Neurodevelopmental follow-up at five years corrected age of extremely low birth weight infants after postnatal replacement of 17beta-estradiol and progesterone. AB - CONTEXT: Extremely low birth weight (ELBW) infants are prone to impaired neurodevelopment. OBJECTIVE: The aim was to determine long-term neurodevelopmental outcome in ELBW infants after postnatal 17beta-estradiol (E2) and progesterone (P) replacement. DESIGN: At 5-yr corrected age, ELBW infants were assessed for standardized cognitive and neurological outcome after postnatal randomized E2 and P replacement or placebo administration. SETTING: The follow-up examination was performed in a neuropediatric ambulatory care center. PATIENTS: Sixty-one of 71 surviving infants (86%) were available for follow-up. MAIN OUTCOME MEASURES: Cognitive and neurological outcome was evaluated using the Kaufmann Assessment Battery for Children, the Gross Motor Function Classification Scale, and clinical neurological examination. RESULTS: No significant differences were found between the replacement and placebo groups for the Gross Motor Function Classification Scale, presence of paresis, cerebral palsy, spasticity, and ametropia. However, a significant time-response relationship was found with E2 and P replacement. Every day of treatment reduced the risk for cerebral palsy (P=0.03), spasticity (P=0.01), and ametropia (P=0.01). CONCLUSION: Postnatal E2 and P replacement may have potential in improving neurodevelopmental outcome in ELBW infants. Larger trials are needed to test this new hypothesis. PMID- 22259064 TI - Acute sleep deprivation enhances the brain's response to hedonic food stimuli: an fMRI study. AB - CONTEXT: There is growing recognition that a large number of individuals living in Western society are chronically sleep deprived. Sleep deprivation is associated with an increase in food consumption and appetite. However, the brain regions that are most susceptible to sleep deprivation-induced changes when processing food stimuli are unknown. OBJECTIVE: Our objective was to examine brain activation after sleep and sleep deprivation in response to images of food. INTERVENTION: Twelve normal-weight male subjects were examined on two sessions in a counterbalanced fashion: after one night of total sleep deprivation and one night of sleep. On the morning after either total sleep deprivation or sleep, neural activation was measured by functional magnetic resonance imaging in a block design alternating between high- and low-calorie food items. Hunger ratings and morning fasting plasma glucose concentrations were assessed before the scan, as were appetite ratings in response to food images after the scan. MAIN OUTCOME MEASURES: Compared with sleep, total sleep deprivation was associated with an increased activation in the right anterior cingulate cortex in response to food images, independent of calorie content and prescan hunger ratings. Relative to the postsleep condition, in the total sleep deprivation condition, the activation in the anterior cingulate cortex evoked by foods correlated positively with postscan subjective appetite ratings. Self-reported hunger after the nocturnal vigil was enhanced, but importantly, no change in fasting plasma glucose concentration was found. CONCLUSIONS: These results provide evidence that acute sleep loss enhances hedonic stimulus processing in the brain underlying the drive to consume food, independent of plasma glucose levels. These findings highlight a potentially important mechanism contributing to the growing levels of obesity in Western society. PMID- 22259066 TI - Evidence of a combined cytotoxic thyroglobulin and thyroperoxidase epitope specific cellular immunity in Hashimoto's thyroiditis. AB - CONTEXT: Hashimoto's thyroiditis (HT) is a common autoimmune disease leading to thyroid destruction due to lymphocytic infiltration. Only rare data are available regarding the recognition of specific cellular antigens, e.g. of thyroperoxidase (TPO) and thyroglobulin (Tg). OBJECTIVE: The aim of this study was to quantify and characterize TPO- and Tg-epitope-specific CD8-positive T cells of HT patients. DESIGN: Six different human leukocyte antigen (HLA)-A2 restricted, TPO- or Tg-specific tetramers were synthesized and used for measuring CD8-positive T cells in HT patients and controls. RESULTS: The frequency of peripheral TPO- and Tg-specific CD8-positive T cells was significantly higher in HLA-A2-positive HT patients (2.8 +/- 9.5%) compared with HLA-A2-negative HT patients (0.5 +/- 0.7%), HLA-A2-positive nonautoimmune goiter patients (0.2 +/- 0.4%), and HLA-A2-positive healthy controls (0.1 +/- 0.2%). The frequency of Tg-specific T cells (3.0%) was very similar to those of TPO-specific CD8-positive T cells (2.9%). Subgroup analyses revealed a steady increase of the number of epitope-specific CD8 positive T cells from 0.6 +/- 1.0% at initial diagnosis up to 9.4 +/- 18.3% in patients with long-lasting disease. Analyses of the number of thyroid infiltrating cells as well as the cytotoxic capacity revealed a similar picture for TPO- and Tg-specific T cells. CONCLUSION: We here report for the first time that both antigens, TPO and Tg, are recognized by CD8-positive T cells and are involved in the thyroid destruction process leading to clinical disease manifestation. PMID- 22259067 TI - Thyrotropin-releasing hormone controls mitochondrial biology in human epidermis. AB - CONTEXT: Mitochondrial capacity and metabolic potential are under the control of hormones, such as thyroid hormones. The most proximal regulator of the hypothalamic-pituitary-thyroid (HPT) axis, TRH, is the key hypothalamic integrator of energy metabolism via its impact on thyroid hormone secretion. OBJECTIVE: Here, we asked whether TRH directly modulates mitochondrial functions in normal, TRH-receptor-positive human epidermis. METHODS: Organ-cultured human skin was treated with TRH (5-100 ng/ml) for 12-48 h. RESULTS: TRH significantly increased epidermal immunoreactivity for the mitochondria-selective subunit I of respiratory chain complex IV (MTCO1). This resulted from an increased MTCO1 transcription and protein synthesis and a stimulation of mitochondrial biogenesis as demonstrated by transmission electron microscopy and TRH-enhanced mitochondrial DNA synthesis. TRH also significantly stimulated the transcription of several other mitochondrial key genes (TFAM, HSP60, and BMAL1), including the master regulator of mitochondrial biogenesis (PGC-1alpha). TRH significantly enhanced mitochondrial complex I and IV enzyme activity and enhanced the oxygen consumption of human skin samples, which shows that the stimulated mitochondria are fully vital because the main source for cellular oxygen consumption is mitochondrial endoxidation. CONCLUSIONS: These findings identify TRH as a potent, novel neuroendocrine stimulator of mitochondrial activity and biogenesis in human epidermal keratinocytes in situ. Thus, human epidermis offers an excellent model for dissecting neuroendocrine controls of human mitochondrial biology under physiologically relevant conditions and for exploring corresponding clinical applications. PMID- 22259068 TI - Oncologists' confidence in knowledge of fertility issues for young women with cancer. AB - We sought to identify factors associated with greater cancer-related fertility knowledge in a national survey of oncologists. We surveyed 344 oncologists from a sampling pool drawn randomly from the AMA Masterfile. We conducted multiple linear regression to determine the relationship between confidence in knowledge and oncologists' characteristics. Respondents' average age was 48.5, and 75.3% were male. The average confidence in knowledge summary score was 23.8 (SD 6.4, range 8-40). In multivariable regression, confidence was higher among oncologists with more information resources, a sense of responsibility to discuss fertility issues and among gynecologic oncologists vs. other oncology specialties. Physician age, gender, and practice setting were not associated with fertility related knowledge. Oncologists lack confidence in their knowledge of fertility issues in young women with breast cancer. Increasing professional responsibility to discuss fertility and greater information access could improve the depth and breadth of education regarding fertility issues among oncologists and their young patients. PMID- 22259069 TI - Effects and permanency of the training program "communication with cancer patients" on the opinions of students. AB - Learning to develop the doctor-patient relationship is very important in the treatment of patients with cancer. We aim to train our students in the early years of study about this subject with a course on the patient-doctor communication, prepared for third year students. One hundred fifty-four third year students participated in our study during the 2006-2007 academic years. The same questionnaire was given to the students in the 2009-2010 academic year; their sixth year of study. The rate of return for the questionnaire is 88.7%. Based on this study, we have the opinion that the training given in the third year is beneficial; however, the efficacy of the training diminishes with the advancing years, and therefore, the length of this training should be increased in the upper classes and additional hours should be added. PMID- 22259070 TI - The Native Comic Book Project: native youth making comics and healthy decisions. AB - BACKGROUND: American Indians and Alaska Natives have traditionally used stories and drawings to positively influence the well-being of their communities. OBJECTIVES: The objective of this study was to describe the development of a curriculum that trains Native youth leaders to plan, write, and design original comic books to enhance healthy decision making. METHODS: Project staff developed the Native Comic Book Project by adapting Dr. Michael Bitz's Comic Book Project to incorporate Native comic book art, Native storytelling, and decision-making skills. After conducting five train-the-trainer sessions for Native youth, staff were invited by youth participants to implement the full curriculum as a pilot test at one tribal community site in the Pacific Northwest. Implementation was accompanied by surveys and weekly participant observations and was followed by an interactive meeting to assess youth engagement, determine project acceptability, and solicit suggestions for curriculum changes. RESULTS: Six youths aged 12 to 15 (average age = 14) participated in the Native Comic Book Project. Youth participants stated that they liked the project and gained knowledge of the harmful effects of commercial tobacco use but wanted better integration of comic book creation, decision making, and Native storytelling themes. CONCLUSION: Previous health-related comic book projects did not recruit youth as active producers of content. This curriculum shows promise as a culturally appropriate intervention to help Native youth adopt healthy decision-making skills and healthy behaviors by creating their own comic books. PMID- 22259071 TI - Effects of 6 months of endurance training on neutrophil functions to produce reactive oxygen species and mental states in male long-distance runners. AB - To clarify changes of neutrophil functions, mental conditions and relationships among them, 19 male elite long-distance runners participated in this study for 6 months. Examinations, with informed consent, were carried out once a month. According to the results of physical characteristics, it was thought that training intensity was reduced after the main race, Hakone-Ekiden. Neutrophil functions were estimated by indices of reactive oxygen species production, determined by luminol- and lucigenin-dependent chemiluminescence (LmCL and LgCL, respectively) and cytochrome c reduction methods. The peak times (PT) in LmCL and LgCL (LgPT) were most prolonged in January and December, respectively. The peak heights (PH) in LmCL (LmPH) were enhanced in February. Decreased levels of negative categories in the profile of mood state (POMS) questionnaire and the total mood state (TMS) of POMS were observed in February without significance. Correlation analysis using measured values revealed significant negative correlation between LmPH and negative categories in POMS; however, these correlations were possibly a mere appearance, caused by personal differences. After eliminating personal differences, LgPT correlated positively to depression (p< 0.05), anger (p< 0.05), fatigue (p < 0.01) and TMS (p< 0.05). These results suggest that the mean time from the recognition of foreign matter to the maximum production of superoxide from neutrophils is prolonged in the mentally suppressed conditions found under continuous physical training. PMID- 22259072 TI - Synthesis of tetrasubstituted alkenes through a palladium-catalyzed domino carbopalladation/C-H-activation reaction. AB - Helical tetrasubstituted alkenes (7) were obtained in a highly efficient way through a palladium-catalyzed domino-carbopalladation/CH-activation reaction of propargylic alcohols 6 in good to excellent yields. Electron-withdrawing- and electron-donating substituents can be introduced onto the upper and lower aromatic rings. The substrates (6) for the domino process were synthesized by addition of the lithiated alkyne (20) to various aldehydes (19); moreover, the substrates were accessible enantioselectively (in 95% ee) by reduction of the corresponding ketone using the Noyori procedure. PMID- 22259073 TI - Do the psychopathic personality traits of fearless dominance and self-centered impulsivity predict attitudes about and influences on research participation? AB - Little is known about potential participants' views about research, their willingness to participate in research, and the extent to which they might be susceptible to coercive attempts to compel their participation, particularly among populations at risk for exploitation (e.g., offenders). The extent to which individual differences variables, such as personality constructs (e.g., psychopathic traits), might affect participants' attitudes toward research is also essentially unknown. The present study sought to examine the psychopathy constructs of Fearless Dominance (FD) and Self-Centered Impulsivity (SCI) via the Multidimensional Personality Questionnaire-Brief Form (MPQ-BF) to assess the extent to which these traits predict attitudes towards research and susceptibility to coercion within a diverse criminal justice sample (N = 631). SCI was modestly associated with perceptions that illicit pressures regarding research participation were likely to occur, and participants high in these traits appeared somewhat vulnerable to succumbing to coercive influences. In contrast, FD failed to predict the likelihood that illicit pressures regarding research participation would occur as well as the potential that these pressures would have to impact participants' voluntariness and likelihood of participating. Implications for recruiting potential participants for research in correctional settings are discussed. PMID- 22259074 TI - The history of ISOTT. PMID- 22259075 TI - Angioplasticity and cerebrovascular remodeling. PMID- 22259076 TI - Cerebral monitoring using near-infrared time-resolved spectroscopy and postoperative cognitive dysfunction. PMID- 22259077 TI - Comparison of the kinetics of pulmonary oxygen uptake and middle cerebral artery blood flow velocity during cycling exercise. PMID- 22259078 TI - Colored light and brain and muscle oxygenation. PMID- 22259079 TI - Assessment of the myogenic and metabolic mechanism influence in cerebral autoregulation using near-infrared spectroscopy. PMID- 22259080 TI - Frontal cortex activation during electrical muscle stimulation as revealed by functional near-infrared spectroscopy. PMID- 22259081 TI - Cerebral oxygen saturation measurements in red cell transfusion. PMID- 22259082 TI - Influence of stress preconditioning on hippocampal neuronal cell death and neurogenesis in rat cerebral ischemia. PMID- 22259083 TI - Differential effects of delta and epsilon protein kinase C in modulation of postischemic cerebral blood flow. PMID- 22259084 TI - Optical topography to measure variations in regional cerebral oxygenation in an infant supported on veno-arterial extra-corporeal membrane oxygenation. PMID- 22259085 TI - Effects of the autonomic nervous system on functional neuroimaging: analyses based on the vector autoregressive model. PMID- 22259086 TI - Assessment of potential short-term effects of intermittent UMTS electromagnetic fields on blood circulation in an exploratory study, using near-infrared imaging. PMID- 22259087 TI - Optical diagnosis of mental stress: review. PMID- 22259088 TI - Neuroprotective properties of ketone bodies. PMID- 22259089 TI - The confounding effect of systemic physiology on the hemodynamic response in newborns. PMID- 22259090 TI - How to conduct studies with neonates combining near-infrared imaging and electroencephalography. PMID- 22259091 TI - Use of a hybrid optical spectrometer for the measurement of changes in oxidized cytochrome c oxidase concentration and tissue scattering during functional activation. PMID- 22259092 TI - Isolated hypoxic liver perfusion with melfalan in humans and its anesthesiologic aspects. PMID- 22259093 TI - Blood flow and oxygenation status of gastrointestinal tumors. PMID- 22259094 TI - Delayed effects of radiation on mitochondrial DNA in radiation-sensitive organs. PMID- 22259095 TI - Radiation-induced elevation of plasma DNA in mice is associated with genomic background. PMID- 22259096 TI - Could multiple myeloma VEGF modify the systemic microcirculation? PMID- 22259097 TI - Impact of environmental parameters on the activity of the P-glycoprotein. PMID- 22259098 TI - 3-D high-resolution mapping of the heterogeneity in mitochondrial redox state of human breast tumor xenografts. PMID- 22259099 TI - High-resolution simultaneous mapping of mitochondrial redox state and glucose uptake in human breast tumor xenografts. PMID- 22259100 TI - Regulation of oxygen delivery by the reaction of nitrite with RBCs under hypoxic conditions. PMID- 22259101 TI - Clinical applications of tissue oxygen saturation measurements. PMID- 22259102 TI - Oscillations in cardiac output in hypoxia with periodic breathing and constant end-tidal PCO2 at high altitude (5,000 m). PMID- 22259103 TI - The relationship of acute mountain sickness to arterial oxygen saturation at altitudes of 3,324 to 5,176 m. PMID- 22259104 TI - Effects of acute anemia and hyperoxia on oxygen distribution. PMID- 22259105 TI - Monitoring cardiopulmonary function and progression toward shock: oxygen micro sensor for peripheral tissue. PMID- 22259106 TI - Whole body oxygen delivery and consumption during cardiopulmonary bypass surgery. PMID- 22259107 TI - Pharmacologic interventions to improve splanchnic oxygenation during ventilation with positive end-expiratory pressure. PMID- 22259108 TI - Effect of pneumoperitoneum on functional residual capacity. PMID- 22259109 TI - Estimation of molecular hydrogen consumption in the human whole body after the ingestion of hydrogen-rich water. PMID- 22259110 TI - Prenylated acylphloroglucinol derivatives: isoprenomics-based design, syntheses and antioxidative activities. PMID- 22259111 TI - Retrograde perfusion of the hind leg in diabetic patients suffering from arteriosclerosis obliterans: theoretical considerations of oxygen supply and lymphatic flow based on rat models. PMID- 22259112 TI - Triplet imaging of oxygen consumption during the contraction of a single smooth muscle cell (A7r5). PMID- 22259113 TI - Relationship between submaximal handgrip muscle force and NIRS-measured motor cortical activation. PMID- 22259114 TI - Feasibility study of non-invasive oxygenation measurement in a deep blood vessel using acousto-optics and microbubbles. PMID- 22259115 TI - Sensitivity enhancement of NIR fluorescence contrast agent utilizing gold nanoparticles. PMID- 22259116 TI - Development of a model to aid NIRS data interpretation: results from a hypercapnia study in healthy adults. PMID- 22259117 TI - Boron tracedrug: design, synthesis, and pharmacological activity of phenolic BODIPY-containing antioxidants as traceable next-generation drug model. PMID- 22259118 TI - Modelling and filtering of physiological oscillations in near-infrared spectroscopy by time-varying Fourier series. PMID- 22259119 TI - Fourier transform infrared microspectroscopy identifies protein propionylation in histone deacetylase inhibitor treated glioma cells. AB - Histone deacetylase inhibitors (HDIs) have attracted considerable attention as potential drug molecules in tumour biology. In order to optimise chemotherapy, it is important to understand the mechanisms of regulation of histone deacetylase (HDAC) enzymes and modifications brought by various HDIs. In the present study, we have employed Fourier transform infrared microspectroscopy (FT-IRMS) to evaluate modifications in cellular macromolecules subsequent to treatment with various HDIs. In addition to CH(3) (methyl) stretching bands at 2872 and 2960 cm( 1) , which arises due to acetylation, we also found major changes in bands at 2851 and 2922 cm(-1) , which originates from stretching vibrations of CH(2) (methylene) groups, in valproic acid treated cells. We further demonstrate that the changes in CH(2) stretching are concentration-dependent and also induced by several other HDIs. Recently, HDIs have been shown to induce propionylation besides acetylation [1]. Since propionylation involves CH(2) groups, we hypothesized that CH(2) vibrational frequency changes seen in HDI treated cells could arise due to propionylation. As verification, pre-treatment of cells with propionyl CoA synthetase inhibitor resulted in loss of CH(2) vibrational changes in histones, purified from valproic acid treated cells. This was further proved by western blot using propionyl-lysine specific antibody. Thus we demonstrate for the first time that propionylation could be monitored by studying CH(2) stretching using IR spectroscopy and further provide a platform for monitoring HDI induced multiple changes in cells. PMID- 22259120 TI - A novel xeno-free and feeder-cell-free system for human pluripotent stem cell culture. AB - While human induced pluripotent stem cells (hiPSCs) have promising applications in regenerative medicine, most of the hiPSC lines available today are not suitable for clinical applications due to contamination with nonhuman materials, such as sialic acid, and potential pathogens from animal-product-containing cell culture systems. Although several xeno-free cell culture systems have been established recently, their use of human fibroblasts as feeders reduces the clinical potential of hiPSCs due to batch-to-batch variation in the feeders and time-consuming preparation processes. In this study, we have developed a xeno free and feeder-cell-free human embryonic stem cell (hESC)/hiPSC culture system using human plasma and human placenta extracts. The system maintains the self renewing capacity and pluripotency of hESCs for more than 40 passages. Human iPSCs were also derived from human dermal fibroblasts using this culture system by overexpressing three transcription factors-Oct4, Sox2 and Nanog. The culture system developed here is inexpensive and suitable for large scale production. PMID- 22259121 TI - Emerging role of ER quality control in plant cell signal perception. AB - The endoplasmic reticulum quality control (ER-QC) is a conserved mechanism in surveillance of secreted signaling factors during cell-to-cell communication in eukaryotes. Recent data show that the ER-QC plays important roles in diverse cell to-cell signaling processes during immune response, vegetative and reproductive development in plants. Pollen tube guidance is a precisely guided cell-cell communication process between the male and female gametophytes during plant reproduction. Recently, the female signal has been identified as small secreted peptides, but how the pollen tube responds to this signal is still unclear. In this review, we intend to summarize the role of ER-QC in plants and discuss the recent advances regarding our understanding of the mechanism of pollen tube response to the female signals. PMID- 22259123 TI - Zan Ding: founder of medical psychology in China. PMID- 22259122 TI - Evolution of iPSC disease models. PMID- 22259124 TI - High-throughput method for the analysis of venlafaxine in pharmaceutical formulations and biological fluids, using a tris(2,2'-bipyridyl) ruthenium(II) peroxydisulphate chemiluminescence system in a two-chip device. AB - A simple, rapid and sensitive chemiluminescent (CL) method for the assay of venlafaxine (VEN) in pharmaceutical formulations and serum samples by a two-chip device is proposed. The method is based on the reaction of this drug with a tris(2,2'-bipyridyl) ruthenium(II)-peroxydisulphate CL system. The optimum chemical conditions for CL emission were investigated. The calibration graph was linear for the concentration range 0.02-8.0 ug/mL. The detection and quantification limits were found to be 0.006 and 0.018 ug/mL, respectively, while the relative standard deviation (RSD) was <2.0%. The present CL procedure was applied to the determination of VEN in pharmaceutical formulations and serum samples; the recovery levels were in the range 96.5-101.2%. The results suggest that the method is unaffected by the presence of common formulation excipients found in these samples. PMID- 22259125 TI - Examining attitudes about and influences on research participation among forensic psychiatric inpatients. AB - Although a growing body of research has examined various types of coercive practices that may occur among psychiatric patients over the years, almost no attention has been given to coercive influences that may occur specifically in the context of recruitment into research projects. Particularly for those who are institutionalized (e.g., in-patient insanity acquittees), there are significant concerns that their autonomous decision-making to consent or not may be significantly impaired due to the highly restrictive and controlled environment in which they live. This exploratory study sought to examine patients' perceptions of coercive influences by presenting them with hypothetical research vignettes regarding possible recruitment into either a biomedical or social behavioral research project. Among 148 multi-ethnic male and female participants across two facilities, participants reported relatively minimal perceptions that their autonomous decision-making would be impacted or that various potentially coercive factors (e.g., pressures from staff) would impair their free choice to participate (or not) in such research. To the extent that such perceptions of coercion did occur, they were moderately associated with patients' more general personality traits and attitudinal variables, such as alienation and external locus of control. Limitations of this study and their implications for future research are discussed. PMID- 22259126 TI - N-heterocyclic carbene catalyzed reactions of alpha-bromo-alpha,beta-unsaturated aldehydes/alpha,beta-dibromoaldehydes with 1,3-dinucleophilic reagents. AB - Carbenes ring true: N-Heterocyclic carbene (NHC) catalyzed reactions of alpha bromo-alpha,beta-unsaturated aldehydes/alpha,beta-dibromoaldehydes with 1,3 dinucleophilic reagents, such as 1,3-dicarbonyl compounds, beta-enamino ketones, and beta-enamino esters through umpolung processes gave functionalized 3,4 dihydropyranones and 3,4-dihydropyridinones. The availability of the starting materials, lack of external oxidant, and usefulness of the products make this strategy attractive. PMID- 22259127 TI - Mucin methods: genes encoding mucins and their genetic variation with a focus on gel-forming mucins. AB - Mucin genes encode the polypeptide backbone of the mucin glycoproteins which are expressed on all epithelial surfaces and are major constituents of the mucus layer. Mucins are, thus, expressed at the interface between the external and the internal environment of the organism, and represent the first line of defence of our body. These genes often have an extensive region of repetitive exonic sequence which codes for the heavily glycosylated domain, whose roles include bacterial interactions and gel hydration. This region shows, in several of the genes, considerable inter-individual variation in repeat number and sequence. Because of their site of expression and their high variability in this important domain, mucin genes are good candidates for conferring differences in genetic susceptibility to multifactorial epithelial and inflammatory disease. However, progress in characterizing the genes has been considerably slower than the rest of the genome because of their size and the GC-rich content of the large, repetitive variable region. Some of the issues relating to the study of these genes are discussed in this chapter. In addition, methods and approaches that have been used successfully are described. PMID- 22259128 TI - Gel-forming and cell-associated mucins: preparation for structural and functional studies. AB - Secreted and transmembrane mucins are important components of innate defence at the body's mucosal surfaces. The secreted mucins are large, polymeric glycoproteins, which are largely responsible for the gel-like properties of mucus secretions. The cell-tethered mucins, however, are monomeric but are typically composed of two subunits, a larger extracellular subunit which is heavily glycosylated while the smaller more sparsely glycosylated subunit has a short extracellular region, a single-pass transmembrane domain, and a cytoplasmic tail. These two families of mucins represent high-molecular-weight glycoproteins containing serine and threonine-rich domains that are the attachment sites for large numbers of O-glycans. The high-M ( r ) and high sugar content have been exploited for the separation of mucins from the majority of components in mucus secretions. In this chapter, we describe current and well-established methods (caesium chloride density-gradient centrifugation, gel-filtration and anion exchange chromatography, and agarose gel electrophoresis) for the extraction and purification of gel-forming and cell-surface mucins which can subsequently be used for a variety of structural and functional studies. PMID- 22259129 TI - Detecting, visualising, and quantifying mucins. AB - The extreme size, extensive glycosylation, and gel-forming nature of mucins make them a challenge to work with, and methodologies for the detection of mucins must take into consideration these features to ensure that one obtains both accurate and meaningful results. In understanding and appreciating the nature of mucins, this affords the researcher a valuable toolkit which can be used to full advantage in detecting, quantifying, and visualising mucins. The employment of a combinatorial approach to mucin detection, using antibody, chemical, and lectin detection methods, allows important information to be gleaned regarding the size, extent of glycosylation, specific mucin species, and distribution of mucins within a given sample. In this chapter, the researcher is guided through considerations into the structure of mucins and how this both affects the detection of mucins and can be used to full advantage. Techniques including ELISA, dot/slot blotting, and Western blotting, use of lectins and antibodies in mucin detection on membranes as well as immunohistochemistry and immunofluorescence on both tissues and cells grown on TranswellTM inserts are described. Notes along with each section advice the researcher on best practice and describe any associated limitations of a particular technique from which the researcher can further develop a particular protocol. PMID- 22259130 TI - Mass spectrometric analysis of mucin core proteins. AB - Mucins are difficult to handle for their identification and characterization via proteomic applications due to their heavily glycosylated nature (up to 90%), high molecular weight (200 kDa-200 MDa), and size (Rg 10-300 nm). Their core proteins are extremely large and highly substituted with oligosaccharides, which only allow access to a highly restricted portion of their protein. For this reason, conventional 1D or 2D polyacrylamide gel-based proteomic approaches are not effective for identification and characterization of mucin molecules. In this chapter, we present our current protocol employing a modified shotgun proteomic approach to identify these complex glycoproteins. PMID- 22259131 TI - O-glycoprotein biosynthesis: site localization by Edman degradation and site prediction based on random peptide substrates. AB - The characterization of mucin-type O-glycosylation is fraught with extreme difficulty at almost every level of analysis: from difficulties in obtaining glycopeptides suitable for study, their structural heterogeneity, lack of broad acting glycosidase tools capable of simplifying the glycans, and finally the vast complexity of performing analysis on multiply glycosylated glycopeptides. This, along with a lack of known peptide sequence motif(s) for the transferases that initiate mucin-type O-glycosylation, significantly hinders our understanding of mucin-type O-glycosylation at almost every level from their biosynthesis to their biological and biophysical properties. In this chapter, the use of partial chemical deglycosylation coupled with Edman amino acid sequencing is described to quantify sites of O-glycosylation. In addition, the use of oriented random peptide substrates is described for providing the specificities of the polypeptide alpha-N-acetylgalactosaminyltransferases, which can be used to estimate transferase-specific sites of O-glycosylation. PMID- 22259132 TI - Analysis of assembly of secreted mucins. AB - Studies of assembly and secretion of gel-forming mucins are complex. The pulse chase methods for mucins described here include metabolic radiolabeling and labeling in animals with azido-GalNAc. The labeled mucins are analyzed by composite agarose-polyacrylamide gel electrophoresis and autoradiography or by mucus-preserving tissue fixation and Click-iT((r)) chemistry. PMID- 22259133 TI - MUC1 membrane trafficking: protocols for assessing biosynthetic delivery, endocytosis, recycling, and release through exosomes. AB - MUC1 is normally apical in polarized epithelial cells but is aberrantly localized in tumor cells. To better understand the mechanism of this altered localization as well as the normal functions of MUC1, we are focused on characterizing the features of MUC1 that regulate the membrane trafficking of this mucin-like transmembrane protein. Previous studies using heterologous expression of MUC1 in CHO and MDCK cells revealed that trafficking to the cell surface as well as endocytosis and recycling is modulated by glycosylation, palmitoylation, and docking of adaptor protein complexes. Protocols for assessing MUC1 trafficking have utilized membrane-impermeant cell surface biotinylation and subsequent stripping with reducing reagents, such as MESNA. The cumulative data have been used for computer modeling and calculation of rate constants. As MUC1 is released through trafficking to exosomes, we have devised protocols for the affinity isolation of MUC1-containing lipid rafts from nanovesicular subpopulations to perform proteomic mapping of protein constituents in these sorting platforms. Our studies to date have shown that plasma membranous MUC1 traffics via lipid raft associated pathways to exosomes, which are independent of caveolin-1 or dynamin, but dependent on flotillin. PMID- 22259134 TI - Glycomic work-flow for analysis of mucin O-linked oligosaccharides. AB - The high-throughput analysis of the glycosylation of high molecular weight proteins, such as mucins, has been the aim of glycomics initiatives for the last decade. Here, we present a work-flow for the efficient and reproducible analysis of reduced oligosaccharides from a typical mucin sample. This work-flow can be applied to any similar samples of oligosaccharides. We include recently developed bioinformatic procedures for the statistical analysis of sample sets. These procedures can be applied in any laboratory environment, using free programs that are platform independent. The scripts are explained and can be adjusted to suit the individual experiment. Finally, a number of example results are given to highlight the use of the statistical analysis in a biological context. PMID- 22259135 TI - O-glycomics: profiling and structural analysis of mucin-type O-linked glycans. AB - The great variability of O-glycan structures makes their analysis a challenging task, which can be solved by the use of several complementary methods. While chromatographic analysis of the fluorescently labeled oligosaccharides shows the quantitative amount of the different glycans in comparison to a standard, mass spectrometry analysis of permethylated oligosaccharides allows identification of new or uncommon glycan structures. In combination with liquid chromatography, all structures present in one sample can be identified. The linkage of the monosaccharides can be analyzed by GC-MS after further derivatization of the permethylated glycans. PMID- 22259136 TI - O-glycoproteomics: site-specific O-glycoprotein analysis by CID/ETD electrospray ionization tandem mass spectrometry and top-down glycoprotein sequencing by in source decay MALDI mass spectrometry. AB - The sites of mucin-type O-glycosylation are difficult to predict, making structural analysis by mass spectrometry indispensible. This chapter refers to state-of-the-art techniques in the site localization of O-linked glycans and their structural characterization in situ using tandem ESI and MALDI mass spectrometry. Detailed protocols are provided that describe the application of nano-LC-ESI-MS/MS with alternative fragmentation modes (collision-induced dissociation vs. electron-transfer dissociation) for the analysis of O glycopeptides. Moreover, a top-down sequencing approach by MALDI-MS is presented that is based on the in-source decay of intact glycoproteins or large glycopeptides and allows a ladder sequencing of up to 70 amino acid residues from both termini with unequivocal assignment of modified sites. PMID- 22259138 TI - Assessment of mucus thickness and production in situ. AB - The nature of the mucus gel layer covering the gastrointestinal tract makes it difficult to study outside its natural site attached to the mucosa. Here, we describe a technique for intravital microscopy studies of the mucus gel layer from the stomach down to the colon in anesthetized rats and mice. Mucus thickness and accumulation rate in each segment of the gastrointestinal tract is measured with a micropipette technique under observation through a stereomicroscope. In this way, the nature of the mucus gel in vivo is readily studied, and effects of interventions or disease on the mucus can be determined in longitudinal studies or by comparing animals. Using this technique, we have been able to demonstrate that there are two forms of mucus gel adherent to the stomach and colon mucosa: one layer which is removable by suction and an underlying firm adherent gel layer, while in the small intestine, all mucus adhering to the mucosa can easily be removed. PMID- 22259137 TI - Analysing mucin degradation. AB - Turnover of mucins in supramucosal gels is essential for the removal of surface contaminants, and the maintenance of normal mucosal barrier function. In addition to the well-known processes promoting the physical turnover of mucus gels, extracellular mucin degradation also requires the coordinated action of a range of enzyme activities including glycosidases and proteases. These are collectively termed "mucinase". Derangements of mucinase activity lead to downstream barrier defects and mucosal disease. This chapter is focussed on methods that can be used to assess the degradation of whole mucins and isolated mucin glycans. A range of approaches is described using labelled or unlabelled substrates utilised in assays based on 96-well plates, size exclusion chromatography, and NP-HPLC. These are suitable for defining the extent and progress of mucin degradation in different mucosal systems, and identifying abnormalities and critical control points. PMID- 22259139 TI - Preservation of mucus in histological sections, immunostaining of mucins in fixed tissue, and localization of bacteria with FISH. AB - As mucus is highly hydrated, special care has to be taken to preserve this in histological preparations during immunostaining. Here, we describe how to fix tissues in such a way that the mucus is preserved in paraffin-embedded tissue. We also describe how the major macromolecular components in the mucus, the mucins, are immunostained and how bacteria can be localized in preparations with preserved mucus by fluorescent in situ hybridization. PMID- 22259140 TI - Ex vivo measurements of mucus secretion by colon explants. AB - An explant tissue system for the study and recording of mucus secretion has been developed. Human colon biopsies or tissue from experimental animals are mounted in a horizontal perfusion chamber and the mucus accumulated on the apical side is observed and measured. PMID- 22259141 TI - Establishment of respiratory air-liquid interface cultures and their use in studying mucin production, secretion, and function. AB - Primary cultures of human airway bronchial airways represent a valuable tool in understanding the roles of the epithelium, cilia, and the mucus layer in coordinating the clearance of mucus from the airways. The ability to obtain cells from both normal and diseased populations (such as cystic fibrosis and Chronic obstructive pulmonary disease (COPD)) allows researchers to investigate the disease phenotype on these processes. Furthermore, such cultures have provided investigators with a vast source of native airway mucus, devoid of external biological processes that occur in vivo, for biochemical and rheological studies. The primary goal of this chapter is to describe the culturing and use of human airway cultures grown under an in vivo-like air-liquid interface for use in a variety of mucus and mucociliary studies. PMID- 22259142 TI - Studying mucin secretion from human bronchial epithelial cell primary cultures. AB - Mucin secretion is regulated by extracellular signaling molecules emanating from local, neuronal, or endocrine sources. Quantifying the rate of this secretion is important to understanding how the exocytic process is regulated, and also how goblet/mucous cells synthesize and release mucins under control and pathological conditions. Consequently, measuring mucins in a quantitatively accurate manner is the key to many experiments addressing these issues. This paper describes procedures used to determine agonist-induced mucin secretion from goblet cells in human bronchial epithelial (HBE) cell cultures. It begins with primary epithelial cell culture, offers methods for purifying MUC5AC and MUC5B mucins for standards, and describes five different microtiter plate binding assays which use various probes for mucins. A polymeric mucin-specific antibody is used in standard and sandwich ELISA formats for two assays while the others target the extensive glycosylated domains of mucins with lectin, periodate oxidation, and antibody based probes. Comparing the data derived from the different assays applied to the same set of samples of HBE cell cultures indicates a qualitative agreement between baseline and agonist stimulated mucin release; however, the polymeric mucin-specific assays yield substantially lower values than the assays using non specific molecular reporters. These results indicate that the more nonspecific assays are suitable to assess overall secretory responses by goblet cells, but are likely unsuited for specific measurements of polymeric mucins, per se. PMID- 22259143 TI - Assessment of intracellular mucin content in vivo. AB - Airway mucus presents a first line of defense against inhaled materials. It also, however, is a significant pathological contributor to chronic lung diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Thus, gaining a better understanding of the mechanisms of mucus production and secretion is an important goal for improving respiratory health. Mucins, the chief glycoprotein components of airway mucus, are very large polymeric glycoproteins, and measuring their production and secretion in experimental animals presents significant technical challenges. Over the past several years, we have developed assays for accurately quantifying mucin production and secretion using histological and biochemical assays. These methods are described here. PMID- 22259144 TI - Techniques for assessment of interactions of mucins with microbes and parasites in vitro and in vivo. AB - Most mammalian pathogens and parasites infect their hosts via the mucosal surfaces. The first barrier they encounter in all mucosal tissues is a layer of viscous mucus which can be modulated by immune responses to the pathogen or parasite. The major macromolecular constituents of mucus are secreted mucin glycoproteins which give mucus its viscous properties. Underneath the mucus layer, the mucosal epithelial cells have a cell surface glycocalyx that is rich in transmembrane mucin glycoproteins. Both the cell surface and secreted mucins present a vast array of potential binding sites for pathogens and parasites and both forms of mucins are involved in protecting the host from infection. However, many pathogens and parasites have evolved mechanisms to subvert the mucin barrier. Thus, studying mucin interactions with pathogens and parasites is critical to understanding host-pathogen interactions at the mucosal surfaces. In this chapter, we describe methods for studying the interactions between mucins and pathogens and parasites, methods for studying the degradation of mucins by pathogens and parasites, and in vitro and in vivo methods for exploring the functional significance of the mucins in host defence from infection. PMID- 22259145 TI - Assessing mucin expression and function in human ocular surface epithelia in vivo and in vitro. AB - Mucins of the corneal and conjunctival epithelia are necessary for the protection of the ocular surface against desiccation, pathogen access, and injury. Detection and quantification of mucins is important for the understanding of ocular surface diseases that cause impaired vision and, in advanced stages, blindness. Advances in the field of molecular biology have made it possible to study membrane mucins and their associated O-glycans in established cell culture models of human ocular surface epithelia. This chapter discusses procedures to detect and quantify mucin RNA and protein in biological samples, as well as methods to experimentally manipulate the epithelia in culture by shRNA, to understand the function of specific mucins. Example protocols are provided to evaluate the role of ocular surface mucins in mucosal barrier function and bacteria-host interactions. PMID- 22259146 TI - Possible reasons for elevated carbon monoxide levels in self-reported ex-smokers. AB - Expired-air carbon monoxide (CO) is often used to validate self-reported nonsmoking in clinical settings and research studies. It sometimes occurs that a person reports to have quit smoking, whereas the CO measurement classifies him/her as a smoker. This commentary summarizes possible explanations for this discrepancy and briefly discusses what to do when there is reason to believe that the CO measurement is incorrect. PMID- 22259147 TI - Smoking cessation treatment preferences, intentions, and behaviors among a large sample of Colorado gay, lesbian, bisexual, and transgendered smokers. AB - INTRODUCTION: Little is known about preferences, intentions, and behaviors regarding evidence-based cessation treatment for smoking cessation among gay, lesbian, bisexual, and transgendered (GLBT) adults. METHODS: We obtained and analyzed questionnaire responses from GLBT smokers (n= 1,633) surveyed in 129 GLBT-identified Colorado venues and online during 2007. RESULTS: Most respondents (80.4%) smoked daily. Nearly one-third smoked 20 or more cigarettes/day. Fewer than half (47.2%) had attempted quitting in the previous year, and only 8.5% were preparing to quit in the next month. More than one-fourth (28.2%) of quit attempters had used nicotine replacement therapy (NRT), and a similar proportion said they intended to use NRT in their next quit attempt. Lesbians were significantly less likely than gay men to have used or intend to use NRT. One fourth of respondents said they were uncomfortable talking to their doctor about quitting smoking. Four factors (daily smoking, ever having used NRT, a smoke-free home rule, and comfort asking one's doctor for cessation advice) were associated with preparation to quit smoking. CONCLUSIONS: GLBT self-identification was not associated with lower than average acceptance of evidence-based smoking cessation strategies, especially NRT, but a large minority of GLBT smokers were unlikely to seek cessation assistance through clinical encounters. Public health campaigns should focus on supporting motivation to quit and providing nonclinical access to evidence-based treatments. PMID- 22259148 TI - Alcohol and marijuana use in the context of tobacco dependence treatment: impact on outcome and mediation of effect. AB - INTRODUCTION: Alcohol and marijuana are among the most commonly used substances together with tobacco worldwide, but their relationship to smoking cessation is unclear. Although alcohol use decreases the likelihood of abstinence from tobacco, mechanisms of this effect have not been identified. Moreover, a small literature has yielded inconsistent findings regarding the effect of marijuana use on tobacco dependence treatment outcome. The aims of this study were to test increased positive-reinforcement smoking urge as a mediator of the relationship between alcohol and cigarette use and evaluate the impact of marijuana use on abstinence from tobacco. METHODS: Participants were adult cigarette smokers (N = 739) from 3 randomized clinical trials of smoking cessation treatment. Alcohol consumption and marijuana use were assessed at pretreatment and postcessation. Biochemically verified, 7-day point prevalence smoking abstinence was determined at Weeks 12, 24, 36, and 52, as were urges to smoke as measured by the Questionnaire of Smoking Urges. RESULTS: Increased positive-reinforcement urge mediated the effect of postcessation alcohol use on smoking abstinence. Although pretreatment alcohol use was associated with a decreased likelihood of abstinence from tobacco, increased positive-reinforcement urge did not account for this relationship. Marijuana use was not associated with abstinence from tobacco. CONCLUSIONS: Smoking cessation treatments should provide those who drink during a quit attempt techniques designed to mitigate positive-reinforcement urge to smoke. Additional research is needed to determine how pretreatment alcohol consumption exerts its effect on cigarette use. Modifying the use of marijuana might not be critical to the success of tobacco interventions. PMID- 22259149 TI - Primary and dual users of cigars and cigarettes: profiles, tobacco use patterns and relevance to policy. AB - INTRODUCTION: The Family Smoking Prevention and Tobacco Control Act provides an unprecedented opportunity to regulate tobacco in the United States. However, restrictions on little cigars, cigarillos, and large cigars are notably absent from the Act, which may create a favorable environment for increased dual usage of cigars. The purpose of this study is to examine demographic profiles and tobacco use behaviors of dual, as opposed to primary, users of cigarettes and cigars. METHODS: This study used data from a cross-sectional nationally representative survey of 2,649 adult smokers and nonsmokers. Multivariable regression analysis was used to compare the demographic characteristics and tobacco use behaviors of dual users versus cigarette-only smokers. RESULTS: Data indicate that 12.5% of cigarette smokers are dual users of cigars. Dual users are more likely to be male, 18-29 years of age, non-Hispanic Black, of lower educational attainment, and either unemployed or out of the work force. Dual users were less likely than cigarette-only smokers to be daily cigarette smokers (odds ratio [OR] = 0.57, 95% CI: 0.32, 1.02), more likely to have made a recent quit attempt (OR = 2.39, 95% CI: 1.44, 3.97), and more likely to have used at least one other alternative product (OR = 2.26, 95% CI: 1.26, 4.05), including snus, e-cigarettes, dissolvables, and chewing tobacco. CONCLUSIONS: As greater restrictions on cigarettes become implemented in the United States, it will be critical to monitor increased dual use of cigars, in order to inform prevention and treatment strategies and guide more comprehensive policy efforts. PMID- 22259150 TI - Increased pouch sizes and resulting changes in the amounts of nicotine and tobacco-specific N-nitrosamines in single pouches of Camel Snus and Marlboro Snus. AB - INTRODUCTION: Initial analyses of the novel smokeless tobacco products Camel Snus and Marlboro Snus demonstrated that these products contain relatively low amounts of nicotine and the carcinogenic tobacco-specific nitrosamines N' nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as compared with traditional smokeless products. It is unknown whether the modifications in packaging, flavors, and pouch sizes that occurred for both Camel Snus and Marlboro Snus since their first introduction to the market were accompanied by any changes in nicotine or nitrosamine levels. METHODS: We examined the available data on nicotine and NNN and NNK levels in 60 samples of Camel Snus and 87 samples of Marlboro Snus that were analyzed in our laboratory between 2006 and 2010. RESULTS: Due to the increase in pouch size, the amounts of total nicotine, unprotonated nicotine, and the sum of NNN and NNK present in the large Camel Snus pouches released in 2010 are 1.9-fold, 2.4-fold, and 3.3-fold higher, respectively, than in the original smaller pouches that entered the market in 2006. Total and unprotonated nicotine content in the current version of Marlboro Snus pouches are 2.1-fold and 1.9-fold higher, respectively, and the sum of NNN and NNK is 1.5-fold lower than in the original version. CONCLUSIONS: We observed an increase in nicotine content in single portions of Camel Snus and Marlboro Snus, and an increase in tobacco-specific N-nitrosamine content in single portions of Camel Snus, due to the increases in pouch size that occurred between 2006 and 2010. This finding stresses the importance of tobacco product regulation and ingredient disclosures. PMID- 22259151 TI - Design of cellulose dissolving ionic liquids inspired by nature. PMID- 22259152 TI - Arctic ice cover, ice thickness and tipping points. AB - We summarize the latest results on the rapid changes that are occurring to Arctic sea ice thickness and extent, the reasons for them, and the methods being used to monitor the changing ice thickness. Arctic sea ice extent had been shrinking at a relatively modest rate of 3-4% per decade (annually averaged) but after 1996 this speeded up to 10% per decade and in summer 2007 there was a massive collapse of ice extent to a new record minimum of only 4.1 million km(2). Thickness has been falling at a more rapid rate (43% in the 25 years from the early 1970s to late 1990s) with a specially rapid loss of mass from pressure ridges. The summer 2007 event may have arisen from an interaction between the long-term retreat and more rapid thinning rates. We review thickness monitoring techniques that show the greatest promise on different spatial and temporal scales, and for different purposes. We show results from some recent work from submarines, and speculate that the trends towards retreat and thinning will inevitably lead to an eventual loss of all ice in summer, which can be described as a 'tipping point' in that the former situation, of an Arctic covered with mainly multi-year ice, cannot be retrieved. PMID- 22259153 TI - A longitudinal study of the relationship between work engagement and symptoms of anxiety and depression. AB - This longitudinal study examined the dynamic relationship between work engagement (vigour and dedication) and symptoms of anxiety and depression. A sample of 3475 respondents from eight different occupational groups (lawyers, physicians, nurses, teachers, church ministers, bus drivers, people working in advertising and people working in information technology) in Norway supplied data at two points in time with a 2-year time interval. The advantages of longitudinal design were utilized, including testing of reversed causation and controlling for unmeasured third variables. In general, the results showed that the hypothesized normal causal relationship was superior to a reversed causation model. In other words, this study supported the assumption that work engagement is more likely to be the antecedent for symptoms of depression and anxiety than the outcome. In particular, the vigour facet of work engagement provides lower levels of depression and anxiety 2 years later. However, additional analyses modelling unmeasured third variables indicate that unknown third variables may have created some spurious effects on the pattern of the observed relationship. Implications of the findings are discussed in the paper. PMID- 22259154 TI - Building personal and professional resources of resilience and agility in the healthcare workplace. AB - This article describes the rationale, implementation and results of a pilot study evaluating the personal and organizational impact of an educational intervention on the stress of health team members. The compelling imperative for the project was to find a positive and effective way to address the documented stress levels of healthcare workers. Pilot study of oncology staff (n=29) and healthcare leaders (n=15) exploring the impact of a positive coping approach on Personal and Organizational Quality Assessment-Revised (POQA-R) scores at baseline and 7 months using paired t-tests. Personal and organizational indicators of stress decreased in the expected directions in both groups over the time intervals. The majority of POQA-R categories were statistically significantly improved in the oncology staff, and many of the categories were statistically significantly improved in the leadership group. The findings from this project demonstrate that stress and its symptoms are problematic issues for hospital and ambulatory clinic staff as evidenced by baseline measures of distress. Further, a workplace intervention was feasible and effective in promoting positive strategies for coping and enhancing well-being, personally and organizationally. PMID- 22259155 TI - The relation of post-work ruminative thinking with eating behaviour. AB - Inability to unwind about work during leisure time has been associated with a number of negative health outcomes. This study was concerned with a possible behavioural pathway between unwinding and disease and examined the relationship between work-related rumination and food choice. Work-related rumination is arguably a core to understanding the 'unwinding process', and food choice is a well-established indicator of nutritional health. Two hundred and sixty-eight full-time workers from a range of white-collar occupations completed a self report measure of ruminative thinking about work and an eating behaviour questionnaire. Three types of ruminative thinking were identified by factor analysis and labelled affective rumination, problem-solving pondering and detachment. In terms of food choice, high-relative to low-affective ruminators reported eating more unhealthy foods, and low detachers reported eating less cooked meals and more processed foods compared to high detachers. Problem-solving pondering was not associated with food choice, and none of the factors were associated with healthy food choice. It was concluded that failure to unwind from work is not necessarily related to unhealthy food choices. What appears to be the crucial factor is the type of perseverative thinking that people engage in post work. Limitations and future directions are discussed. PMID- 22259156 TI - Women in midlife: stress, health and life satisfaction. AB - Midlife is filled with challenges and unique stressors for women, which necessitate a greater understanding of the factors that influence their life satisfaction. This study examined the relationship of family strains/changes and weight to life satisfaction, as mediated by family coping, physical activity, sleep and health stress. The findings indicated that women in midlife, who experienced more stressful life changes and had higher body mass index scores, slept fewer hours and had greater health stress, which resulted in lower life satisfaction. These results have implications for family health professionals and programmes that deal with family and health problems, including sleep, weight and stress. PMID- 22259157 TI - Test anxiety and cardiovascular responses to daily academic stressors. AB - Routine academic events may cause stress and produce temporary elevations in blood pressure. Students who experience test anxiety may be especially prone to cardiovascular activation in response to academic stress. This study drew on self reported stress and ambulatory blood pressure measurements provided by 99 undergraduate participants (30% men, mean age=21 years) who participated over 4 days. Posture, activity level, recent consumption and the previous same-day reading were considered as covariates in a series of hierarchical linear models. Results indicate elevations in systolic blood pressure at times of acute academic stressors; neither diastolic blood pressure nor heart rate was linked with academic stress. In addition, those participants higher in test anxiety exhibited especially pronounced elevations in systolic blood pressure during times of acute academic stress. This research suggests that everyday academic stressors are linked with temporary increases in blood pressure and that test anxiety may contribute to these elevations. Test anxiety has implications for future academic and job success, and cardiovascular responses to everyday stress may contribute to health problems later in life. PMID- 22259158 TI - Attachment insecurity, responses to critical incident distress, and current emotional symptoms in ambulance workers. AB - Ambulance workers are exposed to critical incidents that may evoke intense distress and can result in long-term impairment. Individuals who can regulate distress may experience briefer post-incident distress and fewer long-term emotional difficulties. Attachment research has contributed to our understanding of individual differences in stress regulation, suggesting that secure attachment is associated with effective support-seeking and coping strategies, and fewer long-term difficulties. We tested the effect of attachment insecurity on emotional distress in ambulance workers, hypothesizing that (1) insecure attachment is associated with symptoms of current distress and (2) prolonged recovery from acute post-critical incident distress, coping strategies and supportive contact mediate this relationship. We measured (1) attachment insecurity, (2) acute distress, coping and social contact following an index critical incident and (3) current symptoms of post-traumatic stress, depression, somatization and burnout and tested the hypothesized associations. Fearful avoidant insecure attachment was associated with all current symptoms, most strongly with depression (R=0.38, p<0.001). Fearful-avoidant attachment insecurity was also associated with maladaptive coping, reduced social support and slower recovery from social withdrawal and physical arousal following the critical incident, but these processes did not mediate the relationship between attachment insecurity and current symptoms. These findings are relevant for optimizing post-incident support for ambulance workers. PMID- 22259159 TI - Post-traumatic stress disorder, anxiety and depression among the elderly: a survey of the hard-hit areas a year after the Wenchuan earthquake. AB - Few studies to date have examined psychological sequelae of natural disasters among the elderly in China. The aim of this study was to investigate the prevalence rates of probable post-traumatic stress disorder (PTSD), anxiety and depression in the elderly survivors a year after the Wenchuan earthquake as well as to analyse related risk factors. The community-based sample of the study consisted of 284 elderly survivors (>=60 years). PTSD was assessed by the PTSD Checklist--Civilian version, and anxiety and depression were assessed by the Hopkins Symptoms Checklist. In total, the estimated prevalence rates of probable PTSD, anxiety and depression were 26.3%, 42.9% and 35.2%, respectively. Nearly a fifth of the elderly participants reported symptoms that meet the criteria for all three of these mental disorders. Results indicated that some factors associated with earthquake-exposure intensity, which included loss of livelihood, bereavement, injury and initial fear during the earthquake, were among the significant risk factors for these mental disorders. Women had a higher risk of suffering from probable anxiety as compared to men. Finally, the significance and limitations of this study were also discussed. PMID- 22259160 TI - Developing a model of source-specific interpersonal conflict in health care. AB - Nurses work in complex social environments, and conflict may arise with fellow coworkers, their supervisor, physicians or the patients and family they care for. Although much research has documented the negative effects of conflict on nurses, no research to date has examined the comparative effect that conflict from all four sources can have on nurses. The purpose of this study is to test a model of workplace conflict where the negative effect of conflict on nurses will be experienced via emotional exhaustion. We test the mediator model by analysing the cross-sectional data collected within one hospital (N1=182) and cross-validating those results in a second hospital (N2=161). The pattern of results was largely consistent across the two samples indicating support for a mediated model of workplace conflict for physician, supervisor and patient. Conflict with other nurses, however, did not have a relationship with either emotional exhaustion or other personal and organizational outcomes. The theoretical and practical implications of the current findings, as well as the limitations and future research directions, are discussed. PMID- 22259161 TI - The effects of conscientiousness on the appraisals of daily stressors. AB - Conscientiousness (C) is positively associated with health and longevity although the mechanisms underlying this relationship are not fully understood. Stress may play a role in explaining the C-longevity relationship. This study investigated whether C predicted the cognitive appraisals of daily stressors/hassles. Participants (N=102) completed measures of C and cognitive appraisal in relation to the most stressful hassle they had experienced in the last 7 days. Correlational analysis revealed that Total C, Order and Industriousness were positively correlated with primary appraisals, and Responsibility was positively correlated with secondary appraisals. The facets of C were then entered into hierarchical regression models, controlling for age and gender. This demonstrated that Order (beta=0.27, p<0.05) and Industriousness (beta=0.28, p<0.05) significantly predicted primary appraisals, accounting for 15.8% of the variance. Responsibility significantly predicted secondary appraisals (beta=0.44, p<0.01), accounting for 16.3% of the variance. These findings indicate that higher Order and Industriousness are related to having a greater stake in daily stressors, whereas higher Responsibility is related to greater confidence in one's ability to deal with daily stressors. These results are the first demonstration that C is related to the appraisals of daily hassles and suggest that C may moderate the experience of stress in daily life. PMID- 22259162 TI - Application of multivariate image analysis in modeling (13) C-NMR chemical shifts of mono substituted pyridines. AB - Multivariate image analysis (MIA) descriptors have been applied to the quantitative structure-property relationship (QSPR) study of (13) C-NMR chemical shifts of 2-mono substituted pyridines. In this method, descriptors are generated from pixels of images and are analyzed with different multivariate methods. Correlation ranking-principal component regression and correlation ranking principal component-artificial neural networks were applied in constructing predictor models. In this article, the role of weight update function in artificial neural networks was investigated too. Obtained results using the correlation ranking-principal component-artificial neural network method showed high performance for predicting of (13) C-NMR chemical shifts of pyridine derivatives. Also, these results indicated that MIA descriptors may be useful to predict (13) C-NMR chemical shifts. Finally, The MIA-QSPR approach coupled to artificial neural networks revealed that the predictive ability of MIA descriptors is comparable or even superior for the pyridine derivatives when compared with the ChemDraw program or gauge included atomic orbital procedure for (13) C chemical shifts calculations. PMID- 22259163 TI - Stability studies of crude plant material of Bacopa monnieri and quantitative determination of bacopaside I and bacoside A by HPLC. AB - INTRODUCTION: Bacopa monnieri (BM) contains several dammarane-type triterpenoid saponins including bacopaside I and bacoside A. These bioactive compounds may be used as chemical markers for the quality control of different BM products used for promoting mental health and intellect. OBJECTIVE: Quantification of bacopaside I and bacoside A in crude plant material of BM stored under the stability study conditions by HPLC. METHODOLOGY: Crude BM samples were stored at long-term (LS; 30 degrees C and 65% RH), accelerated (AS; 40 degrees C and 75% RH) and real-time (RT) study conditions. HPLC of BM extracts was carried out using a LiChroCART Purospher(r) STAR RP-18 endcapped column along with a guard column, Purospher STAR RP 18e 4.0 4.0 mm 5 um using a gradient of acetonitrile (A) and water containing 0.05% (v/v) orthophosphoric acid (B) at a flow rate 1.5 mL/min with UV detection at 205 nm. RESULTS: The linear range of bacopaside I and bacoside A was 0.2 to 1 mg/mL. With the help of a regression equation the coefficient of determination (r2) values for bacopaside I and bacoside A were found to be > 0.999 and > 0.994 respectively. Relative standard deviation (RSD) values were < 4.0 for all the concentrations injected (n = 3). The HPLC study indicated that BM samples kept under LS condition are rich in saponin contents as compared with the samples stored under AS and RT study conditions. CONCLUSION: The study indicated that BM plant material should be used fresh to obtain maximum concentration of active saponins or it should be stored under LS conditions up to 3 months. PMID- 22259164 TI - [Measles: immunity and vaccination status in Greater Frankfurt on the Main]. AB - BACKGROUND AND OBJECTIVE: The elimination of measles is a goal of the WHO which has not been achieved in Europe yet. As measles is a vaccine-preventable disease and can be eliminated by immunization the Standing Committee on Vaccination (STIKO) has updated the recommendation of measles vaccination. The goal of this study was to evaluate the immune status by serological testing and by raising immunisation status. METHODS: Antibody-testing from the routine diagnostic of the Institute of Medical Virology (Frankfurt/Main) for patients, health care workers and medical students was investigated retrospectively. RESULTS: Overall all significant increase in seropositivity was shown from 64.8 to 86.2 %. Nevertheless immunity gaps still exist in population, especially in persons under 19 years of age. In 1999 80.7 % of the 5-9 year age group and 75.3 % of the 10-19 year age group were seropositive. In 2009 the percentage in these age groups has decreased to 68.2 % and 71.1 % respectively. By obtaining the immunity status of 230 travellers at our vaccination centre immunity gaps have been recognised as well. Only 29.6 % were completely immunized (at least two vaccination). 54.4 % have been vaccinated incomplete and in 16.1 % vaccination status was unknown. CONCLUSION: Our results indicated that measles immunization status and seroprevalence are still not sufficient to achieve the elimination of measles. PMID- 22259165 TI - [Sepsis in a woman with severe portosystemic encephalopathy. An uncommon complication of drug therapy]. AB - HISTORY: A 60-year-old woman was referred to our hospital, because she was unarousable. She was known to have an impaired liver function due to long-lasting alkohol abuse. Third-party medical history did not explain the patient's condition. TREATMENT AND COURSE: The history and laboratory findings suggested hepatic coma, therefore treatment with ornithin-aspartat, rifaximin, lactulose and antibiotics was started. Lactate concentration indicated severe hypoxic damage. The clinical examinations and circulatory parameters lead to the diagnosis of sepsis, which was suspected to be caused by spontaneous bacterial peritonitis. Computed tomography of the abomen demonstrated colitis but no other pathologic intestinal finding. Inspite of intensive therapy with antibiotics, fluids and catecholamines the patient died 3 days after admission. Autopsy revealed the cause of sepsis: a tablet, swallowed with its blister package had led to a perforation of the terminal ileum. CONCLUSION: Apart from the most cause of peritonitis in patients with liver cirrhosis - the spontaneous bacterial peritonitis - a secondary cause must also be taken into account as a reason for sepsis. A well prepared history could possibly show the direction for detection of the cause. PMID- 22259166 TI - [53-year-old woman with life-threatening complications after use of ciprofloxacin and posaconazol]. PMID- 22259167 TI - [Carotid sinus massage - who is allowed to do it?]. AB - Although carotid sinus massage (CSM) belongs to the basic knowledge of every physician, there are no universally valid and structured guidance on the nature of the implementation and application. We analyzed the existing guidelines and literature in light of who is allowed to perform CSM. In summary, there are two indications for CSM: As part of diagnostic tools to clarify underlying pathology of syncope CSM should be performed only by an experienced physician with ECG control and after sonographic exclusion of carotid atherosclerosis if no other explanations are reasonable. In case of supraventricular tachycardia CSM may be used by any physician without prior sonography of the carotids to terminate the tachycardia before any pharmacological strategies are performed. PMID- 22259168 TI - [Apixaban: pharmacology and action profile]. AB - Vitamin K antagonists are currently the most frequently used anticoagulants. However, practical limitations of their application, such as variability in dose response, a narrow therapeutic index and numerous drug and dietary interactions, have lead to development of new oral anticoagulants with better efficacy and safety profile. Recent advances included the development of orally active FXa inhibitors rivaroxaban and apixaban. Rivaroxaban received its marketing approval in September 2008. Apixaban has recently been approved for prevention of venous thromboembolism after total hip or knee replacement. This review describes the pharmacological properties of apixaban and discusses the latest findings from clinical trials. PMID- 22259169 TI - [Chronic inflammatory bowel disease or psychogenic eating disorder - Case 1/2012. Interdisciplinary challenges in clinical diagnosis and treatment]. AB - HISTORY AND ADMISSION FINDINGS: A 33-year-old female patient with chronic anorexia nervosa was admitted for inpatient psychosomatic treatment after a recent severe weight loss. In addition, an inflammatory bowel disease had been suspected in the past 4 years. The patient was convinced that the weight loss had purely organic reasons. She reported frequent diarrhea after meals. Also laxative abuse was suspected because of melanosis coli. DIAGNOSIS: An MR Sellink showed no evidence for actual intestinal inflammation. No increased inflammation parameters were found in blood tests. Diarrhea could not be proved by investigation of excrements or a symptom diary. TREATMENT AND COURSE: Treatment consisted of a multimodal approach with focus on cognitive behavioural therapy. Treatment revealed eating disorder specific cognitions, fears and behaviour. A partial acceptance of gastrointestinal symptoms and weight loss as eating disorder symptomatology could be achieved. CONCLUSION: Diagnostics and treatment of chronic anorexia nervosa are complicated by a coincidental (or suspected) organic intestinal disease. Gastrointestinal problems are common in eating disorders. Organic symptoms are often difficult to distinguish from psychosomatic symptoms. Somatic fixation complicates treatment of eating disorders. PMID- 22259171 TI - [Treatment of pseudoaneurysms by thrombin injection]. PMID- 22259170 TI - [Renal side effects of long-term lithium therapy]. AB - Lithium is widely used in the treatment of bipolar disorders. Long-term administration of lithium often leads to side effects concerning the subjects: nephrology, endocrinology and surgery. This review emphasizes nephrotoxicity.Lithium treatment may disturb responsiveness to antidiuretic hormone (ADH), causing a nephrogenic diabetes insipidus. Furthermore long-term lithium therapy may trigger hyperparathyreoidism with hypercalcemia and chronic interstitial nephritis with development of microcysts. Long-term patients have an increased risk to develop impaired renal function. Lithium-induced endstage renal disease is rare. Termination of lithium treatment may decrease the risk of progression.To ensure security of lithium treatment regular controls of urine osmolarity, lithium-, creatinine- , thyroid stimulating hormone- and calcium levels are essential. Patients with decreased renal function should be referred to a specialist early. PMID- 22259172 TI - [Treatment of pseudoaneurysms by thrombin injection]. PMID- 22259174 TI - [Does anthroposophic medicine cause measles outbreaks?]. PMID- 22259176 TI - Comparison of clinical and pathological characteristics of isolated aortitis and Takayasu arteritis with ascending aorta involvement. AB - AIMS: Isolated aortitis (IA) is a newly recognized condition, but its differentiation from Takayasu arteritis (TA) is still a challenge. This study aims to explore the characteristics of IA. METHODS: The clinical and pathological data of 965 cases with excised ascending aortas were obtained by chart and slide review. IA cases were compared with TA cases and examined for CD3, CD4, CD8, CD20, CD68, CD138 and IgG4 of the infiltrates using immunohistochemistry. RESULTS: 24 cases of IA and eight cases of TA were identified. IA cases tended to be older than TA cases (mean 46.3 vs 33.9 years). Both groups had the same male/female ratio (1.0). IA cases tended to have a bigger aortic diameter (mean 59.7 vs 47.6 mm), statistically less intimal thickening (mean 678 vs 1101 MUm), fewer lesions outside the ascending aorta (8% vs 100%), a lower erythrocyte sedimentation rate (mean 14.6 vs 27.0 mm/h) and more active aortitis (75.0% vs 62.5%) than TA cases. The number of CD3+ cells was equal to CD20+ cells in the media but fewer than CD20+ cells in the adventitia of IA cases. Their CD4/CD8+ ratio ranged from 1.0 to 1.8 while the number of CD68+ macrophages varied largely. IgG4+ cells ranged from 0 to 40 (mean 4) cells/HPF and the IgG4+/CD138+ ratio ranged from 0 to 0.36 (mean 0.06) in IA cases. CONCLUSIONS: Cases of IA tend to have more histologically active inflammation except for a relatively normal erythrocyte sedimentation rate, localised lesions and milder intimal fibrosis than cases of TA. IgG4 abnormality may not be the main cause of IA. PMID- 22259177 TI - Mucinous subtype as prognostic factor in colorectal cancer: a systematic review and meta-analysis. AB - BACKGROUND: Mucinous adenocarcinoma (MAC) of the colorectum has been known and studied for many years. The prognostic significance of this histological subtype remains controversial. The authors reviewed the prognostic significance of mucinous differentiation in colorectal cancer. MATERIALS AND METHODS: A systematic web-based search was performed using Web of Knowledge and Medline. Articles published in English, German or French which used the WHO definition of MAC and described cohort studies, case-control studies or cross-sectional studies comparing survival in patients with MAC and adenocarcinoma (AC) not otherwise specified were included. Data on first author, year of publication, country, number of patients included, prevalence of MAC, % stage IV disease, % disease located in the proximal colon, mean age at presentation, % male patients and 5 year overall survival were extracted from individual studies. A fixed-effects meta-analysis model was used for analysis. The primary outcome was survival, expressed as the HR. Differences between categorical outcome parameters were quantified using the RR and corresponding 95% CI. RESULTS: 44 studies and 222 256 patients were included. The RR for proximal disease versus distal disease was 1.55 (95% CI 1.53 to 1.58). Mucinous differentiation was less frequent in male subjects (RR 0.93 (95% CI 0.91 to 0.94)). Interestingly, the prevalence of stage IV disease was similar in MAC and AC (RR 0.99 (95% CI 0.96 to 1.02)). Thirty-five articles were included in the survival analysis. A worse survival in MAC versus AC was demonstrated (HR 1.05 (95% CI 1.02 to 1.08)). Conversely, three out of four studies reported a better survival in MAC with microsatellite instability (MSI). Due to heterogeneity a meta-analysis on the effect of MSI was not possible. CONCLUSION: MAC more often originates from the right colon and is less frequent in male subjects. The authors did not identify a difference in the proportion of stage IV patients at presentation. Mucinous differentiation results in a 2-8% increased hazard of death, which persists after correction for stage. More research is needed to define the interaction between mucinous differentiation, MSI and outcome. PMID- 22259178 TI - Chronic gastric ulceration: a novel manifestation of IgG4-related disease? PMID- 22259179 TI - Quality standards and samples in genetic testing. AB - The most critical performance indicator for medical laboratories is the delivery of accurate test results. In any laboratory, there is always the possibility that random or systematic errors may occur and place human health and welfare at risk. Laboratory quality assurance programmes continue to drive improvements in analytical accuracy. The most rigorously scrutinised data on laboratory errors, which come from transfusion medicine, reveal that the incidence of analytical errors has fallen to levels where most of the residual risk is now found in preanalytical links in the chain from patient to result, particularly activities associated with ordering of tests and sample collection. This insight is important for genetic testing because, like pretransfusion testing of patients with unknown blood groups, a substantial proportion of genotyping results cannot be immediately verified. An increasing number of clinical decisions, associated personal and social choices, and legal outcomes are now influenced by genetic test results in the absence of other confirmatory data. An incorrect test result may lead to unnecessary and irreversible interventions, which may in themselves have associated risks for the patient, inaccurate risk assessment regarding the disease, missed opportunities for disease prevention or even wrongful conviction in a court of law. Unfortunately, there is limited information available about the risk of preanalytical errors associated with, and few published guidelines regarding, sample collection for genetic testing. The growing number and range of important decisions made on the basis of genetic findings warrant a reappraisal of current standards to minimise risks in genetic testing. PMID- 22259180 TI - Stromal keratin expression in phyllodes tumours of the breast: a comparison with other spindle cell breast lesions. AB - AIM: To determine the frequency, pattern and distribution of stromal keratin expression in phyllodes tumours if any, which may impact diagnostic approaches. METHODS: The clinicopathological features of 109 phyllodes tumours comprising 70 (64.2%) benign, 30 (27.5%) borderline and nine (8.3%) malignant grades were evaluated, and the immunohistochemical expression of a keratin panel (MNF116, 34betaE12, CK7, CK14, AE1/3, Cam5.2), p63 and CD34 in their stromal component was assessed. RESULTS: There was focal and patchy cytoplasmic keratin staining in 1 5% of stromal cells in 13 (11.9%), 24 (22%), 31 (28.4%), 2 (1.8%), 9 (8.3%) and 2 (1.8%) cases for MNF116, 34betaE12, CK7, CK14, AE1/3, Cam5.2, respectively. CD34 was expressed in 79 (72.5%) cases. There was no stromal staining for p63. Stromal MNF116, 34betaE12 and Cam5.2 reactivity was significantly associated with phyllodes tumour grade (p=0.027, p=0.034, p=0.009 respectively), while MNF116 stromal staining was observed in tumours with increasing cellularity (p=0.036), necrosis (p=0.015) and cystic change (p=0.048). Contrary to common understanding, these findings confirm that stromal cells in phyllodes tumours can sometimes express keratins, albeit focal and in a patchy distribution. In comparison, fibromatosis and dermatofibrosarcoma were uniformly negative for the same keratin panel, while spindle cell components of eight metaplastic carcinomas expressed at least two or more keratins in a wider distribution of up to 90% of positively stained spindle cells. All eight spindle cell sarcomas were negative for keratins. CONCLUSION: The use of keratins as an adjunctive immunohistochemical diagnostic tool in the differential work-up of spindle cell tumours of the breast has to be interpreted with caution especially on limited core biopsy material. PMID- 22259181 TI - Phosphorylated p120-catenin expression has predictive value for oral cancer progression. AB - AIMS: Recent studies have shown that phosphorylation of p120-catenin (p120) promotes progression and invasion of oral squamous cell carcinoma (OSCC) cells. The objective of the current study was to evaluate the usefulness of phosphorylated p120-catenin (pp120) as a biomarker for predicting clinical behaviour in the carcinogenesis of potentially malignant oral lesions. METHODS: In a retrospective follow-up study, the expression pattern of pp120 protein was determined using immunohistochemistry in samples from 68 patients with potentially malignant oral lesions, including patients with untransformed lesions (n=38) and patients with malignant transformed lesions (n=30). Analysis of corresponding post-malignant lesions (OSCCs) was also performed. RESULTS: There was high expression of pp120 in 35 of 68 (51.5%) of general potentially malignant oral lesions and 23 of 30 (76.7%) of OSCCs compared with expression in normal oral mucosa. Kaplan-Meier analysis revealed that patients with potentially malignant oral lesions expressing high levels of membranous pp120 had a significantly higher incidence of OSCC than those expressing low expressing pp120 (p=0.002; log-rank test). Cox regression analysis revealed that this pp120 expression pattern was significantly associated with a 3.43-fold increase in the risk of malignant progression (p=0.007). In addition, there was a significant correlation between high levels of membranous expression of pp120 in pre malignant lesions and cytoplasmic expression in post-malignant lesions (p=0.028). CONCLUSIONS: The data indicated that a high level of membranous expression of pp120 in potentially malignant oral lesions is an early event during oral carcinogenesis, and that the mislocalisation of expression of pp120 from the cell membrane to the cytoplasm is associated with oral cancer progression. pp120 may serve as a useful marker for the identification of a high risk of potentially malignant oral lesions progressing to OSCC. PMID- 22259182 TI - Expression of Dicer and Drosha in triple-negative breast cancer. AB - AIMS: Dicer and Drosha are components of the miRNA-producing machinery and their altered expression may play a role in cancer progression. The main purpose of this study was a detailed investigation of Dicer and Drosha expression and localisation in triple-negative breast cancers. METHODS: Thirty-one triple negative breast cancers and several breast cancer cell lines were investigated. Expression of Dicer and Drosha was evaluated at the mRNA level by quantitative reverse transcription PCR and at the protein level by immunohistochemistry or western blot. RESULTS: Compared with normal breast tissues, a wide variation of Dicer and Drosha mRNA levels was detected in triple-negative breast cancers. As a group, Drosha mRNA levels in triple-negative breast cancers were significantly higher than those in normal breast tissues. Immunohistochemical data confirmed higher expression of Drosha protein in triple-negative breast cancers. In normal breast tissues Dicer was detectable predominantly in the cytoplasm of basal/myoepithelial cells only. In contrast, in the majority of triple-negative breast cancers, intense Dicer staining was detectable also in the nuclear compartment. Detection of Dicer and Drosha mRNA and protein levels in breast cancer cell lines confirmed the nuclear localisation of Dicer, suggesting, in addition, that the steady-state protein levels could be controlled by post-mRNA regulatory events. CONCLUSIONS: These findings indicate that Dicer and Drosha expression is deregulated in triple-negative breast cancers. PMID- 22259183 TI - Delineation of the infrequent mosaicism of KRAS mutational status in metastatic colorectal adenocarcinomas. AB - This study addresses the extent of the heterogeneity of KRAS status, present in a minority of metastatic colorectal carcinomas (mCRCs), on the basis of a thorough analysis of surgical resection specimens. Eighteen patients with mCRC were included. KRAS mutations (exon 2, codons 12 and 13) were determined using PCR and subsequent direct sequencing. This analysis included primary tumours (n=21), synchronous (n=10) and metachronous (n=18) matched metastases, and pelvic recurrence (n=1). Heterogeneity of KRAS status consisted in KRAS mutated in (i) the primary tumour but not in its synchronous metastasis, (ii) the metastasis but not in the primary tumour, (iii) the pelvic recurrence but not in the primary tumour, (iiii) some metastases and not in others from the same patient. Finally, the KRAS status varied among different areas of the same metastatic focus. This study defines the concept of KRAS mosaicism that affects a minority of mCRCs. PMID- 22259184 TI - When do luminance changes capture attention? AB - In two experiments, we examined the ability of task-irrelevant changes in luminance to capture attention in an irrelevant singleton search. By using uniform increment and decrement arrays, we were able to create changes of the same absolute magnitude, but resulting in a singleton with either higher or lower contrast magnitude, relative to other elements in the search array. A condition where a singleton changed contrast polarity without a concomitant change in the overall contrast magnitude was also included. It was found that only luminance changes resulting in a singleton having increased contrast (or saliency) were effective in capturing attention. In addition, no attentional capture was observed when the irrelevant singleton was characterized by the equivalent amount of static luminance differences, suggesting a unique attentional prioritization of luminance changes that increase singleton saliency. PMID- 22259186 TI - Characterization of 4,5-dihydro-1H-pyrazole derivatives by (13) C NMR spectroscopy. AB - The (13) C NMR resonances of 19 1-acyl-3-(2-nitro-5-substitutedphenyl)-4,5 dihydro-1H-pyrazoles, and 19 1-acyl-3-(2-amino-5-substituted)-4,5-dihydro-1H pyrazoles, were completely assigned using the concerted application of one- and two-dimensional NMR experiments (DEPT, gs-HSQC and gs-HMBC). PMID- 22259185 TI - Additive effects of serotonergic and dopaminergic polymorphisms on trait impulsivity. AB - Twin studies suggest 45% heritability of trait impulsivity. Results from candidate gene studies to date are contradictory; impulsivity phenotypes were measured by different behavioral and questionnaire methods related either to the dopaminergic or to the serotonergic system. Here we report an association study of both dopaminergic (COMT rs4680, DRD4 48 bp VNTR, DRD2/ANKK1 rs1800497) and serotonergic (HTR1A rs6925, HTR1B rs13212041, SLC6A4 5-HTTLPR) gene polymorphisms and trait impulsivity assessed with the Barratt Impulsiveness Scale (BIS-11) in a sample of 687 Caucasian young adults. Results showed lower impulsivity in the presence of the DRD4 7-repeat (P = 0.006) and the HTR1B rs13212041 alleles (P = 0.003). These findings stayed significant after Bonferroni correction. A multivariate analysis using Bayesian networks confirmed independent effects of these two polymorphisms and provided a coherent characterization of the system of dependencies with respect to the impulsivity construct as well as its subscales. These results clearly suggest an additive effect of dopaminergic and serotonergic polymorphisms on trait impulsivity. PMID- 22259187 TI - Optimisation of ultrasound-assisted extraction of puerarin and total isoflavones from Puerariae Lobatae Radix (Pueraria lobata (Wild.) Ohwi) with response surface methodology. AB - INTRODUCTION: Isoflavones, particularly puerarin, are a group of important components from Puerariae Lobatae Radix (PLR) which show diverse pharmacological activities, therefore giving rise to the development of various extraction methods. Ultrasound-assisted extraction (UAE) has been explored for isoflavone extraction from PLR as it provides higher extraction efficiency compared with traditional methods. OBJECTIVE: To optimise the UAE conditions for puerarin and total isoflavone extraction from PLR using response surface methodology (RSM). METHODOLOGY: Samples were prepared by use of ultrasound-assisted extraction, and then subjected to HPLC analysis. Box-Behnken Design (BBD), a widely used form of RSM, was used for the optimisation of the UAE process. RESULTS: The effects of ethanol concentration, extraction time and the solvent-to-material ratio on the yields of puerarin and total isoflavones were investigated. The Box-Behnken experimental results demonstrate that optimal extraction was obtained with an ethanol concentration of 71.35%, an extraction time of 49.08 min and a solvent-to material ratio of 21.72 for puerarin, and an ethanol concentration of 80.00%, an extraction time of 55.00 min and a solvent-to-material ratio of 12.81 for total isoflavones. The yields of puerarin and total isoflavones were 41 +/- 0.63 mg/g and 128 +/- 0.82 mg/g, respectively, under the optimised extraction conditions, which are in agreement with the values predicted by the RSM. CONCLUSION: The RSM allows for optimising the extraction parameters such that maximum extraction of puerarin and total isoflavones was achieved experimentally. PMID- 22259188 TI - Genetic variation in GPX1 is associated with GPX1 activity in a comprehensive analysis of genetic variations in selenoenzyme genes and their activity and oxidative stress in humans. AB - Previous studies suggest some effects of selenium on risk of several chronic diseases, which may be mediated through a small number of selenoenzymes with antioxidant properties. In this cross-sectional analysis of 195 participants from the Seattle Barrett's Esophagus Study who were free of esophageal cancer at the time of blood draw, we examined whether the number of the minor alleles in 26 tagging single nucleotide polymorphisms (SNP) of five selenoenzyme genes [i.e., glutathione peroxidase 1-4 (GPX1-4) and selenoprotein P (SEPP1)] was associated with activity of GPX1 in white blood cells and GPX3 in plasma, and concentrations of SEPP1 and markers of oxidative stress [malondialdehyde (MDA) and protein carbonyl content] in plasma. At the gene level, associations were observed between overall variation in GPX1 and GPX1 activity (P = 0.02) as well as between overall variation in GPX2 and SEPP1 concentrations (P = 0.03). By individual SNP, two variants in GPX1 (rs8179164 and rs1987628) showed a suggestive association with GPX1 activity (P = 0.10 and 0.08, respectively) and two GPX2 variants (rs4902346 and rs2071566) were associated with SEPP1 concentration (P = 0.004 and 0.002, respectively). Furthermore, two SNP in the SEPP1 gene (rs230813 and rs230819) were associated with MDA concentrations (P = 0.03 and 0.02, respectively). Overall, our study supports the hypothesis that common genetic variants in selenoenzymes affect their activity. PMID- 22259189 TI - Disturbed one-carbon metabolism causing adverse reproductive outcomes in mice is associated with altered expression of apolipoprotein AI and inflammatory mediators PPARalpha, interferon-gamma, and interleukin-10. AB - Low dietary choline or deficiency of methylenetetrahydrofolate reductase (Mthfr) leads to hyperhomocysteinemia (Hhcy) and adverse reproductive outcomes. Homocysteine reduces synthesis of ApoAI, the major lipoprotein in HDL cholesterol; ApoAI is regulated by PPARalpha and has antiinflammatory properties. Our aim was to determine whether pregnancy complications due to genetic or nutritional deficiencies in 1-carbon metabolism could relate to dysregulation of ApoAI and inflammatory mediators. We fed pregnant mice, with or without a deficiency of Mthfr, control or choline-deficient (ChDD) diets for 10-12 wk and examined levels of ApoAI, PPARalpha, IFNgamma, and IL-10. ApoAI mRNA was reduced in livers of Mthfr(+/-) mice and ApoAI protein was reduced due to Mthfr deficiency or choline deficiency in liver and plasma. Placental ApoAI protein was also reduced due to Mthfr genotype or choline-deficient diet and in developmentally delayed embryos. Reduced liver PPARalpha expression (mRNA and protein) was observed in ChDD-fed mice and was associated with increased methylation of a CpG dinucleotide in its promoter. Hepatic IFNgamma increased due to genotype, and placental IFNgamma was higher in Mthfr(+/-) ChDD-fed dams compared to Mthfr(+/+) mice fed ChDD or Mthfr(+/-) mice fed CD. IL-10 was reduced in livers of ChDD-fed mice. We propose that a deficiency of dietary choline or Mthfr leads to Hhcy and reduced expression of maternal ApoAI, with reduced ApoAI transfer to embryo. Disturbances in 1-carbon metabolism also reduce maternal PPARalpha expression, possibly through promoter hypermethylation, and increase IFNgamma and decrease IL-10 levels. This disturbance of the T helper (Th1) (IFNgamma):Th2 (IL-10) ratio and the increase in inflammatory mediators may contribute to pregnancy complications. PMID- 22259190 TI - Apo-10'-lycopenoic acid, a lycopene metabolite, increases sirtuin 1 mRNA and protein levels and decreases hepatic fat accumulation in ob/ob mice. AB - Lycopene has been shown to be beneficial in protecting against high-fat diet induced fatty liver. The recent demonstration that lycopene can be converted by carotene 9',10'-oxygenase into a biologically active metabolite, ALA, led us to propose that the function of lycopene can be mediated by ALA. In the present study, male ob/ob mice were fed a liquid high-fat diet (60% energy from fat) with ALA supplementation (ALA group, 240 MUg . kg body weight(-1) . d(-1)) or without ALA supplementation as the control (C group) for 16 wk. Steatosis, SIRT1 expression and activity, genes involved in lipid metabolism, and ALA concentrations in the livers of mice were examined. The results showed that ALA supplementation resulted in a significant accumulation of ALA in the liver and markedly decreased the steatosis in the ALA group without altering body and liver weights compared to the C group. The mRNA and protein levels of hepatic SIRT1 were higher in the ALA group compared to the C group. SIRT1 activity also was higher in the ALA group, as indicated by the lower levels of acetylated forkhead box class O1 protein levels. In addition, the mRNA level of acetyl CoA carboxylase 1 was significantly lower in the ALA group than in the C group. Because SIRT1 plays a key role in lipid homeostasis, the present study suggests that the lycopene metabolite, ALA, protects against the development of steatosis in ob/ob mice by upregulating SIRT1 gene expression and activity. PMID- 22259191 TI - Absorption of iron from ferritin is independent of heme iron and ferrous salts in women and rat intestinal segments. AB - Ferritin iron from food is readily bioavailable to humans and has the potential for treating iron deficiency. Whether ferritin iron absorption is mechanistically different from iron absorption from small iron complexes/salts remains controversial. Here, we studied iron absorption (RBC (59)Fe) from radiolabeled ferritin iron (0.5 mg) in healthy women with or without non-ferritin iron competitors, ferrous sulfate, or hemoglobin. A 9-fold excess of non-ferritin iron competitor had no significant effect on ferritin iron absorption. Larger amounts of iron (50 mg and a 99-fold excess of either competitor) inhibited iron absorption. To measure transport rates of iron that was absorbed inside ferritin, rat intestinal segments ex vivo were perfused with radiolabeled ferritin and compared to perfusion with ferric nitrilotriacetic (Fe-NTA), a well-studied form of chelated iron. Intestinal transport of iron absorbed inside exogenous ferritin was 14.8% of the rate measured for iron absorbed from chelated iron. In the steady state, endogenous enterocyte ferritin contained >90% of the iron absorbed from Fe-NTA or ferritin. We found that ferritin is a slow release source of iron, readily available to humans or animals, based on RBC iron incorporation. Ferritin iron is absorbed by a different mechanism than iron salts/chelates or heme iron. Recognition of a second, nonheme iron absorption process, ferritin endocytosis, emphasizes the need for more mechanistic studies on ferritin iron absorption and highlights the potential of ferritin present in foods such as legumes to contribute to solutions for global iron deficiency. PMID- 22259192 TI - Amino acid supplementation does not alter whole-body phenylalanine kinetics in Arabian geldings. AB - Stable isotope infusion methods have not been extensively used in horses to study protein metabolism. The objectives were to develop infusion and sampling methodologies for [1-(13)C] phenylalanine and apply these methods to determine whether the addition of supplemental amino acids to a control diet affected whole body phenylalanine kinetics in mature horses. Arabian geldings were studied using a 6-h primed (9 MUmol/kg), constant (6 MUmol . kg(-1) . h(-1)) i.v. infusion of L [1-(13)C] phenylalanine, with blood and breath sampled every 30 min, to measure whole-body phenylalanine kinetics in response to receiving the control diet (n = 12) or the control diet supplemented with equimolar amounts of glutamate (+Glu; 55 mg . kg(-1) . d(-1); n = 5), leucine (+Leu; 49 mg . kg(-1) . d(-1); n = 5), lysine (+Lys; 55 mg . kg(-1) . d(-1); n = 5), or phenylalanine (+Phe; 62 mg . kg( 1) . d(-1); n = 6). The plasma concentrations of the supplemented amino acid in horses receiving the +Leu, +Lys, and +Phe diets were 58, 53, and 36% greater, respectively, than for the control treatment (P < 0.05). Isotopic plateau was attained in blood [1-(13)C] phenylalanine and breath (13)CO(2) enrichments by 60 and 270 min, respectively. Phenylalanine flux (+20%) and oxidation (+110%) were greater (P < 0.05) in horses receiving the +Phe treatment than in those fed the control diet. There was no effect of treatment diet on nonoxidative phenylalanine disposal or phenylalanine release from protein breakdown. The developed methods are a valuable way to study protein metabolism and assess dietary amino acid adequacy in horses and will provide a useful tool for studying amino acid requirements in the future. PMID- 22259194 TI - Child mortality as predicted by nutritional status and recent weight velocity in children under two in rural Africa. AB - WHO has released prescriptive child growth standards for, among others, BMI-for age (BMI-FA), mid-upper arm circumference-for-age, and weight velocity. The ability of these indices to predict child mortality remains understudied, although growth velocity prognostic value underlies current growth monitoring programs. The study aims were first to assess, in children under 2, the independent and combined ability of these indices and of stunting to predict all cause mortality within 3 mo, and second, the comparative abilities of weight-for length (WFL) and BMI-FA to predict short-term (<3 mo) mortality. We used anthropometry and survival data from 2402 children aged between 0 and 24 mo in a rural area of the Democratic Republic of Congo with high malnutrition and mortality rates and limited nutritional rehabilitation. Analyses used Cox proportional hazard models and receiver operating characteristic curves. Univariate analysis and age-adjusted analysis showed predictive ability of all indices. Multivariate analysis without age adjustment showed that only very low weight velocity [HR = 3.82 (95%CI = 1.91, 7.63); P < 0.001] was independently predictive. With age adjustment, very low weight velocity [HR = 3.61 (95%CI = 1.80, 7.25); P < 0.001] was again solely retained as an independent predictor. There was no evidence for a difference in predictive ability between WFL and BMI FA. This paper shows the value of attained BMI-FA, a marker of wasting status, and recent weight velocity, a marker of the wasting process, in predicting child death using the WHO child growth standards. WFL and BMI-FA appear equivalent as predictors. PMID- 22259193 TI - Dietary intakes of zinc and heme iron from red meat, but not from other sources, are associated with greater risk of metabolic syndrome and cardiovascular disease. AB - Metabolic syndrome (MetS), Type 2 diabetes (T2D), and cardiovascular disease (CVD) share an inflammatory etiology and are known to be influenced by diet. We investigated associations of hypothesized prooxidative (Fe) and antioxidative (Zn, Mg, beta-carotene, vitamin C, vitamin E) micronutrients with incident MetS, T2D, and CVD in the Multi-Ethnic Study of Atherosclerosis. Participants, 45-84 y at baseline (2000-2002), were followed through 2010. Diet was assessed by FFQ. After adjusting for demographics and behavioral confounders, including BMI, dietary vitamin E intake was inversely associated with incident MetS and CVD [HR for extreme quintiles: MetS = 0.78 (95% CI = 0.62, 0.97), P-trend = 0.01; CVD: HR = 0.69 (95% CI = 0.46, 1.03), P-trend = 0.04]. Intakes of heme iron and Zn from red meat, but not from other sources, were positively associated with risk of MetS [heme iron from red meat: HR = 1.25 (95% CI = 0.99,1.56), P-trend = 0.03; Zn from red meat: HR = 1.29 (95% CI = 1.03,1.61), P-trend = 0.04] and CVD [heme iron from red meat: HR = 1.65 (95% CI = 1.10,2.47), P-trend = 0.01; Zn from red meat: HR = 1.51 (95% CI = 1.02, 2.24), P-trend = 0.01]. Dietary intakes of nonheme iron, Mg, vitamin C, and beta-carotene were not associated with risk of MetS, T2D, or CVD. Data provided little support for the associations between specific micronutrients and MetS, T2D, or CVD. However, nutrients consumed in red meat, or red meat as a whole, may increase risk of MetS and CVD. PMID- 22259195 TI - Maternal smoking during pregnancy and child emotional problems: the relevance of maternal and child 5-HTTLPR genotype. AB - Serotonin is involved in the development of neural circuits modulating emotional behavior. The short allele (s) of a polymorphism (5-HTTLPR) of the serotonin transporter gene is a risk factor for psychopathology in the presence of environmental stressors. Maternal smoking is associated with growth restriction of the human fetal brain and adverse effects of nicotine on the developing serotonin system have been documented. We hypothesized that maternal smoking interacts with both child and mother 5-HTTLPR genotype as a risk factor for later child emotional problems. In a sample of n = 1,529 mother-child dyads, smoking habits were assessed by questionnaires during pregnancy. Child emotional problems were measured by the Child Behavior Checklist at the child's age of 3 years. Maternal smoking during pregnancy significantly increased the risk for emotional problems in children carrying the s-allele; beta = 0.24, P = 0.03 (mother report), and beta = 0.46, P = 0.001 (father-report). In children heterozygous at 5-HTTLPR and exposed to maternal prenatal smoking (n = 79) risk of emotional problems increased with each additional s-allele the mother carried. The associations between 5-HTTLPR and child emotional problems were not moderated by paternal prenatal smoking. These findings imply that the vulnerability for emotional problems in s-allele carriers may already originate in fetal life. PMID- 22259196 TI - Elucidating 'undecipherable' chemical structures using computer-assisted structure elucidation approaches. AB - Structure elucidation using 2D NMR data and application of traditional methods of structure elucidation are known to fail for certain problems. In this work, it is shown that computer-assisted structure elucidation methods are capable of solving such problems. We conclude that it is now impossible to evaluate the capabilities of novel NMR experimental techniques in isolation from expert systems developed for processing fuzzy, incomplete and contradictory information obtained from 2D NMR spectra. PMID- 22259197 TI - Medical treatment of early-onset mild gestational hypertension reduces total peripheral vascular resistance and influences maternal and fetal complications. AB - OBJECTIVE: Complications in early-onset mild gestational hypertension (GH) are better predicted by total peripheral vascular resistance (TPVR) > 1350 dyne than by blood pressure. We therefore aimed to assess the possible reduction of severe complications by lowering TPVR with nitric oxide (NO) donors, oral fluids and standard antihypertensive therapy in women with early-onset mild GH. METHODS: A group of 400 patients with early-onset (20-27 weeks' gestation) mild GH (systolic and diastolic blood pressure < 170/110 mmHg) and TPVR > 1350 dyne were enrolled in a prospective non-randomized trial with sequential allocation: 100 patients were treated with nifedipine (Group A); 100 with nifedipine and NO donors (Group B); 100 with nifedipine and oral fluids (Group C); and 100 with nifedipine, NO donors and oral fluids (Group D). TPVR was checked 1 month after initiation of therapy, and the number of patients with severe maternal and fetal complications was recorded in each group. The relationship between reduction in TPVR and the frequency of severe complications was assessed. RESULTS: Severe complications developed in 51% of patients in Group A, 48% in Group B, 53% in Group C and 35% in Group D, the frequency in Group D being significantly lower than that in the other treatment groups (P < 0.05). A reduction in TPVR of < 15% predicted the occurrence of severe complications with sensitivity 95.2% and specificity 88.3%. In Group D a reduction in TPVR of >= 15% was more probable (odds ratio (OR) = 2.03; 95% CI, 1.15-3.60; P < 0.015) and severe complications were less probable (OR = 0.52; 95% CI, 0.29-0.91; P < 0.023). CONCLUSION: In women with early-onset mild GH, combined treatment with NO donors, oral fluids and nifedipine optimally reduces TPVR and seems to reduce maternal and fetal complications. PMID- 22259198 TI - Is transureteroureterostomy performed during multi-organ resection for non urothelial malignancy safe and effective? AB - BACKGROUND: Multi-organ resection in patients with non-urothelial cancer may include segmental ureteral resection. The resulting ureteral defect can be reconstructed with a transureteroureterostomy (TUU); however, whether TUU is safe and effective in this patient group remains unclear. OBJECTIVES: In the current retrospective analysis, we evaluated renal function before and after complex multi-organ resection that included TUU to determine whether TUU is safe and effective. METHODS: We retrospectively reviewed the charts of patients who underwent TUU between 1995 and 2011. Renal imaging studies performed before and after TUU were used to determine whether hydronephrosis was present in either kidney. Kidney function was assessed by measuring serum creatinine levels and calculating the estimated glomerular filtration rate (eGFR) before and after TUU. RESULTS: Twelve patients underwent TUU during multiorgan resection. Median follow up time was 15 months. Three patients with cancer recurrence involving the TUU developed progressive hydronephrosis. Serum creatinine levels did not increase more than 0.5 mg/dl in any patient. Kidney function as assessed by eGFR was maintained in all patients (until the time of recurrence in the three patients with recurrence affecting the TUU). CONCLUSIONS: TUU during multi-organ resection for non-urothelial malignancy is safe and effective. Long-term renal function is maintained in the majority of patients. PMID- 22259199 TI - Molecular detection of Campylobacter jejuni as a cause of culture-negative spondylodiscitis. AB - Spondylodiscitis caused by Campylobacter species is a rare disease which is most often caused by Campylobacter fetus. We report a case of culture-negative spondylodiscitis and a psoas abscess due to Campylobacter jejuni in a 68-year-old woman, as revealed by 16S rRNA gene and Campylobacter-specific PCRs from biopsied tissue. PMID- 22259200 TI - Adiaspiromycosis causing respiratory failure and a review of human infections due to Emmonsia and Chrysosporium spp. AB - We report a case of a 27-year-old male who presented with respiratory distress that required mechanical ventilation. Transbronchial biopsy revealed adiaspores of the fungus Emmonsia crescens within granulomata, a condition known as adiaspiromycosis. The patient received amphotericin products and corticosteroids, followed by itraconazole, and made a full recovery. Emmonsia crescens is a saprobe with a wide distribution that is primarily a rodent pathogen. The clinical characteristics of the 20 cases of human pulmonary adiaspiromycosis reported since the last comprehensive case review in 1993 are described here, as well as other infections recently reported for the genus Emmonsia. Pulmonary adiaspiromycosis has been reported primarily in persons without underlying host factors and has a mild to severe course. It remains uncertain if the optimal management of severe pulmonary adiaspiromycosis is supportive or if should consist of antifungal treatment, corticosteroids, or a combination of the latter two. The classification of fungi currently in the genus Emmonsia has undergone considerable revision since their original description, including being grouped with the genus Chrysosporium at one time. Molecular genetics has clearly differentiated the genus Emmonsia from the Chrysosporium species. Nevertheless, there has been a persistent confusion in the literature regarding the clinical presentation of infection with fungi of these two genera; to clarify this matter, the reported cases of invasive Chrysosporium infections were reviewed. Invasive Chrysosporium infections typically occur in impaired hosts and can have a fatal course. Based on limited in vitro susceptibility data for Chrysosporium zonatum, amphotericin B is the most active drug, itraconazole susceptibility is strain dependent, and fluconazole and 5-fluorocytosine are not active. PMID- 22259201 TI - Clostridium difficile testing algorithms using glutamate dehydrogenase antigen and C. difficile toxin enzyme immunoassays with C. difficile nucleic acid amplification testing increase diagnostic yield in a tertiary pediatric population. AB - We evaluated the performance of the rapid C. diff Quik Chek Complete's glutamate dehydrogenase antigen (GDH) and toxin A/B (CDT) tests in two algorithmic approaches for a tertiary pediatric population: algorithm 1 entailed initial testing with GDH/CDT followed by loop-mediated isothermal amplification (LAMP), and algorithm 2 entailed GDH/CDT followed by cytotoxicity neutralization assay (CCNA) for adjudication of discrepant GDH-positive/CDT-negative results. A true positive (TP) was defined as positivity by CCNA or positivity by LAMP plus another test (GDH, CDT, or the Premier C. difficile toxin A and B enzyme immunoassay [P-EIA]). A total of 141 specimens from 141 patients yielded 27 TPs and 19% prevalence. Sensitivity, specificity, positive predictive value, and negative predictive value were 56%, 100%, 100%, and 90% for P-EIA and 81%, 100%, 100%, and 96% for both algorithm 1 and algorithm 2. In summary, GDH-based algorithms detected C. difficile infections with superior sensitivity compared to P-EIA. The algorithms allowed immediate reporting of half of all TPs, but LAMP or CCNA was required to confirm the presence or absence of toxigenic C. difficile in GDH-positive/CDT-negative specimens. PMID- 22259202 TI - Evaluation of adding a second marker to overcome Staphylococcus aureus spa typing homoplasies. AB - The utility of sequencing a second highly variable locus in addition to the spa gene (e.g., double-locus sequence typing [DLST]) was investigated to overcome limitations of a Staphylococcus aureus single-locus typing method. Although adding a second locus seemed to increase discriminatory power, it was not sufficient to definitively infer evolutionary relationships within a single multilocus sequence type (ST-5). PMID- 22259203 TI - Three cases of post-cataract surgery endophthalmitis due to Rhizobium (Agrobacterium) radiobacter. AB - We present three unrelated post-cataract surgery endophthalmitis cases caused by Rhizobium radiobacter, hospitalized in three different hospitals. Early diagnosis was obtained in two cases by bacterial DNA detection in vitreous samples. All patients recovered from infection, but pars plana vitrectomy was needed in two patients due to rapid clinical deterioration. PMID- 22259204 TI - Phenotypic, biochemical, and molecular techniques for detection of metallo-beta lactamase NDM in Acinetobacter baumannii. AB - Seven NDM-positive Acinetobacter baumannii isolates of worldwide origin were studied to evaluate the best technique for their identification. Detection of carbapenemase producers based on the measurement of carbapenemase activity by UV spectrophotometry (as for A. baumannii strains producing other types of carbapenemase), or by the modified Hodge test, failed. Inhibition activity using EDTA was a sensitive technique but lacked specificity compared to molecular techniques, which remain the gold standard. PMID- 22259205 TI - Performance assessment of a novel two-step multiple displacement amplification PCR assay for detection of Mycobacterium tuberculosis complex in sputum specimens. AB - A novel two-step multiple displacement amplification-PCR (MDA-PCR) assay for tuberculosis detection in 200 sputum specimens was evaluated. The MDA-PCR assay indicated a significant increase in sensitivity and specificity compared with those of standard PCR alone. PMID- 22259206 TI - Nosocomial clustering of NDM-1-producing Klebsiella pneumoniae sequence type 340 strains in four patients at a South Korean tertiary care hospital. AB - In November 2010, NDM-1-producing Klebsiella pneumoniae (NDMKP) was identified for the first time in South Korea from four patients with no history of traveling abroad who stayed for 21 to 205 days in a tertiary care hospital. All were sequence type (ST) 340 and had nearly identical XbaI pulsed-field gel electrophoresis (PFGE) patterns. The bla(NDM-1)-carrying plasmids were in the IncN group, with sizes ranging from 50 to 200 kb. These findings suggest that NDMKP had already been introduced into South Korea before this clustering was found. PMID- 22259207 TI - Current trends in culture-based and molecular detection of extended-spectrum-beta lactamase-harboring and carbapenem-resistant Enterobacteriaceae. AB - The ever-expanding role of extended-spectrum-beta-lactamase (ESBL)-harboring and carbapenem-resistant Enterobacteriaceae in causing serious infections poses a grave public health threat because these organisms also tend to be multidrug resistant, for which very few (if any) antibiotic options remain available. Rapid detection of such panresistant organisms offers one of the best solutions to improve patient screening and hospital infection control practices as well as curb inappropriate antibiotic use. This review discusses and compares primarily the current state-of-the-art culture-based and molecular methods that are commercially available for detection or screening of ESBL-harboring and carbapenem-resistant Enterobacteriaceae. PMID- 22259208 TI - Subpopulation analysis of heteroresistance to fluoroquinolone in Mycobacterium tuberculosis isolates from Beijing, China. AB - The presence of heteroresistance was represented by 23% of 235 fluoroquinolone (FQ)-resistant Mycobacterium tuberculosis isolates in Beijing, China, from 2008 to 2010. The main mechanism of FQ heteroresistance is due to the segregation of a single M. tuberculosis strain in patients; the majority of isolates with multidrug-resistant tuberculosis contained a mixture of bacterial subpopulations consisting of various mutant types, suggesting that the improper use of FQ is the major cause of FQ resistance. PMID- 22259209 TI - Variation of B1 gene and AF146527 repeat element copy numbers according to Toxoplasma gondii strains assessed using real-time quantitative PCR. AB - Using the multicopy B1 gene and AF146527 element for the amplification of Toxoplasma gondii DNA raises the issue of reliable quantification for clinical diagnosis. We applied relative quantification to reference strains using the single-copy P30 gene as a reference. According to the parasite type, the copy numbers for the B1 gene and AF146527 element were found to be 5 to 12 and 4 to 8 times lower than the previous estimations of 35 and 230 copies, respectively. PMID- 22259210 TI - Identification of optimal epitopes for Plasmodium falciparum rapid diagnostic tests that target histidine-rich proteins 2 and 3. AB - Rapid diagnostic tests (RDTs) represent important tools to diagnose malaria infection. To improve understanding of the variable performance of RDTs that detect the major target in Plasmodium falciparum, namely, histidine-rich protein 2 (HRP2), and to inform the design of better tests, we undertook detailed mapping of the epitopes recognized by eight HRP-specific monoclonal antibodies (MAbs). To investigate the geographic skewing of this polymorphic protein, we analyzed the distribution of these epitopes in parasites from geographically diverse areas. To identify an ideal amino acid motif for a MAb to target in HRP2 and in the related protein HRP3, we used a purpose-designed script to perform bioinformatic analysis of 448 distinct gene sequences from pfhrp2 and from 99 sequences from the closely related gene pfhrp3. The frequency and distribution of these motifs were also compared to the MAb epitopes. Heat stability testing of MAbs immobilized on nitrocellulose membranes was also performed. Results of these experiments enabled the identification of MAbs with the most desirable characteristics for inclusion in RDTs, including copy number and coverage of target epitopes, geographic skewing, heat stability, and match with the most abundant amino acid motifs identified. This study therefore informs the selection of MAbs to include in malaria RDTs as well as in the generation of improved MAbs that should improve the performance of HRP-detecting malaria RDTs. PMID- 22259211 TI - Persistent bloodstream infection with Kocuria rhizophila related to a damaged central catheter. AB - A case of persistent bloodstream infection with Kocuria rhizophila related to a damaged central venous catheter in a 3-year-old girl with Hirschsprung's disease is reported. The strain was identified as K. rhizophila by 16S rRNA gene sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Arbitrarily primed PCR analysis showed a clonal strain. The repeated septic episodes were resolved with the catheter repair. PMID- 22259212 TI - Validation of reverse sequence screening for syphilis. PMID- 22259213 TI - Effects of decontamination, DNA extraction, and amplification procedures on the molecular diagnosis of Mycobacterium ulcerans disease (Buruli ulcer). AB - We compared two DNA extraction methods (a semiautomated method using a Maxwell kit and a modified Boom method) and three amplification procedures (a single-step PCR, a nested PCR, and a real-time quantitative PCR) on 74 surgical tissue specimens from patients with clinically suspected Buruli ulcer. All of these procedures were compared before and after decontamination. We observed that, among the procedures tested, real-time PCR after the modified Boom extraction method or a single-run PCR assay after the Maxwell 16 extraction method, performed on nondecontaminated suspensions, are the best for the molecular diagnosis of Mycobacterium ulcerans disease. PMID- 22259215 TI - Comparison of three assays for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in SurePath Pap samples and the role of pre- and postcytology testing. AB - Chlamydia trachomatis and Neisseria gonorrhoeae are common causes of sexually transmitted infections, and there is interest in screening SurePath liquid-based Pap (L-Pap) samples with Aptima Combo 2 (AC2), Amplicor (AMP), and ProbeTec ET (PT) assays. SurePath L-Pap samples and a cervical swab (CS) were collected from 394 women attending health clinics in Hamilton and Toronto, ON, Canada. L-Pap samples were tested with the three assays prior to being processed for cytology, and the CS sample was tested with AC2. The prevalence of C. trachomatis was 8.9%, and that of N. gonorrhoeae was 1.5%. By using the positives from CS testing, as well as CS negatives corresponding to L-Pap samples that tested positive in 2 of 3 assays, the sensitivities of AC2, AMP, and PT for C. trachomatis in precytology samples were calculated to be 97.1% (34 of 35 positive samples were detected), 91.4% (32 of 35 were detected), and 77.1% (27 of 35 were detected), respectively. Six women were infected with N. gonorrhoeae. After cytology processing, the results of testing the remaining liquid in the L-Pap vial and the cell-enriched fraction for C. trachomatis by AC2 showed positive agreements of 98.9% (kappa [k], 0.93) and 98.7% (k, 0.92), respectively, with the results of testing precytology L-Pap samples. Although all testing showed high specificity, testing for C. trachomatis by AC2 was significantly more sensitive than testing by PT for SurePath samples (P = 0.02). Newer versions of AMP (Cobas 4800) and PT (Q(x) with XTR technology) need published evaluations for detecting C. trachomatis and N. gonorrhoeae in L-Pap samples. C. trachomatis testing can be performed with similar results on pre- and postcytology SurePath samples. PMID- 22259214 TI - Phenotypic screening of carbapenemases and associated beta-lactamases in carbapenem-resistant Enterobacteriaceae. AB - Dissemination of carbapenem resistance among Enterobacteriaceae poses a considerable threat to public health. Carbapenemase gene detection by molecular methods is the gold standard but is available in only a few laboratories. The aim of this study was to test phenotypic methods for the detection of metallo-beta lactamase (MBL)- or Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and associated mechanisms of beta-lactam resistance against a panel of 30 genotypically characterized carbapenem-resistant Enterobacteriaceae : 9 MBL, 7 KPC, 6 OXA-48, and 8 extended-spectrum beta-lactamase (ESBL) or AmpC beta-lactamases associated with decreased permeability. We used carbapenemase inhibitor-impregnated agar to test for carbapenem-resistant strains. Differences in the inhibition zone sizes of the meropenem, imipenem, ertapenem, and doripenem disks were measured between control and inhibitor (EDTA or phenylboronic acid [PBA] with or without cloxacillin)-impregnated Mueller-Hinton agar with a cutoff of 10 mm. All 9 MBL- and 7 KPC-producing Enterobacteriaceae were identified from the differences in zone size in the presence and absence of specific inhibitors, regardless of the carbapenem MICs and including isolates with low-level resistance to carbapenems. We also detected their associated beta-lactam resistance mechanisms (11 ESBL-type and 5 class A beta-lactamase 2b). No differences in zone size were observed for OXA-48-producing strains or other carbapenem resistance mechanisms such as ESBL and decreased permeability. We propose a new strategy to detect carbapenemases (MBL- and KPC-type) and associated mechanisms of beta-lactam resistance (ESBL or class A beta-lactamase 2b) by the use of inhibitor-impregnated agar. A rapid phenotypic detection of resistance mechanisms is important for epidemiological purposes and for limiting the spread of resistant strains by implementing specific infection control measures. PMID- 22259216 TI - Multilocus sequence typing and phylogenetic analysis of Propionibacterium acnes. AB - Propionibacterium acnes is a commensal of human skin but is also implicated in the pathogenesis of acne vulgaris, in biofilm-associated infections of medical devices and endophthalmitis, and in infections of bone and dental root canals. Recent studies associate P. acnes with prostate cancer. As the species includes evolutionary lineages with distinct association with health and disease, there is a need for a high-resolution typing scheme. Recently, two multilocus sequence typing (MLST) schemes were reported, one based on nine and one based on seven housekeeping genes. In the present study, the two schemes were compared with reference to a phylogenetic tree based on 78 P. acnes genomes and their gene contents. Further support for a basically clonal population structure of P. acnes and a scenario of the global spread of epidemic clones of P. acnes was obtained. Compared to the Belfast scheme, the Aarhus MLST scheme (http://pacnes.mlst.net/), which is based on nine genes, offers significantly enhanced resolution and phylogenetic inferences more concordant with analyses based on a comprehensive sampling of the entire genomes, their gene contents, and their putative pathogenic potential. PMID- 22259217 TI - Psychiatric disorders in cancer patients at a university hospital in Japan: descriptive analysis of 765 psychiatric referrals. AB - OBJECTIVE: In cancer patients, adjustment disorders, delirium and depression have been identified as common psychiatric disorders. Although a comparable result was reported in the National Cancer Center in Japan, the nature of patients in that hospital may differ from that in local hospitals. There is a possibility to expand the findings of psycho-oncology by evaluation of the data from a local university hospital and comparison with the National Cancer Center data. METHODS: We retrospectively reviewed the medical records of cancer patients who were referred to the Department of Psycho-Oncology at Saitama Medical University International Medical Center. We identified their characteristics and psychiatric diagnoses and compared these with the National Cancer Center data. RESULTS: During the study period, 765 cancer patients were referred. The numbers of inpatients and outpatients were almost the same. The most common psychiatric diagnosis was adjustment disorders (24%), followed by delirium (16%) and then major depressive disorder (12%). The rank of these three was the same as that at the National Cancer Center. Outpatients constituted more than 80% of the patients with major depressive disorder. The proportion of cancer patients with schizophrenia in this study (4.3%) was higher than that in the National Cancer Center (1.6%). CONCLUSIONS: This study revealed basic information about the consultation data of cancer patients at a local university hospital in Japan. The importance of communication with outpatients was suggested. It seems that cancer treatment for patients with schizophrenia in a local hospital is also important. PMID- 22259218 TI - Does a House Divided Stand? Kinship and the Continuity of Shared Living Arrangements. AB - Shared living arrangements can provide housing, economies of scale, and other instrumental support and may become an important resource in times of economic constraint. But the extent to which such living arrangements experience continuity or rapid change in composition is unclear. Previous research on extended-family households tended to focus on factors that trigger the onset of coresidence, including life course events or changes in health status and related economic needs. Relying on longitudinal data from 9,932 households in the Survey of Income and Program Participation (SIPP), the analyses demonstrate that the distribution of economic resources in the household also influences the continuity of shared living arrangements. The results suggest that multigenerational households of parents and adult children experience greater continuity in composition when one individual or couple has a disproportionate share of the economic resources in the household. Other coresidential households, those shared by other kin or nonkin, experience greater continuity when resources are more evenly distributed. PMID- 22259219 TI - Convergent Synthesis of 2H-Chromenes - a Formal [3+3] Cycloaddition by a One-pot, Three-Step Cascade. AB - In cases in which the palladium-catalyzed coupling of a bromoquinone with a vinyl stannane affords a vinyl quinone that enolizes, the resulting ortho-quinone methide undergoes an oxa-6pi electrocyclization. Enolization is promoted by the presence of a polar additive. The net conversion is a formal [3+3] cycloaddition that gives 2H-chromenes. Because the first two steps of the cascade are catalyzed, the overall conversion is an example of multicatalysis. Yields for the optimized, one-pot protocol are dramatically improved over the conventional stepwise process. PMID- 22259220 TI - Factors influencing bacterial adhesion to contact lenses. AB - The process of any contact lens related keratitis generally starts with the adhesion of opportunistic pathogens to contact lens surface. This article focuses on identifying the factors which have been reported to affect bacterial adhesion to contact lenses. Adhesion to lenses differs between various genera/species/strains of bacteria. Pseudomonas aeruginosa, which is the predominant causative organism, adheres in the highest numbers to both hydrogel and silicone hydrogel lenses in vitro. The adhesion of this strain reaches maximum numbers within 1h in most in vitro studies and a biofilm has generally formed within 24 h of cells adhering to the lens surface. Physical and chemical properties of contact lens material affect bacterial adhesion. The water content of hydroxyethylmethacrylate (HEMA)-based lenses and their iconicity affect the ability of bacteria to adhere. The higher hydrophobicity of silicone hydrogel lenses compared to HEMA-based lenses has been implicated in the higher numbers of bacteria that can adhere to their surfaces. Lens wear has different effects on bacterial adhesion, partly due to differences between wearers, responses of bacterial strains and the ability of certain tear film proteins when bound to a lens surface to kill certain types of bacteria. PMID- 22259221 TI - Effects of a novel DNA methyltransferase inhibitor Zebularine on human lens epithelial cells. AB - PURPOSE: Posterior capsular opacification (PCO) is a common long-term complication of modern cataract surgery. We have shown that Zebularine, an inhibitor of DNA methylation, suppresses transforming growth factor-beta (TGFbeta)-induced lens epithelial cells (LECs)-myofibroblasts transdifferentiation. The purpose of this study is to evaluate the role that Zebularine plays in the inhibition of PCO pathogenesis, including its effect on attachment, migration, and proliferation of LECs in vitro. METHODS: A tetrazolium dye-reduction assay (MTT test) was performed to determine cell proliferation. Cell attachment was assessed by modified MTT test. Migration was determined by the transwell method after incubation of LECs with Zebularine. The effect of Zebularine on DNA-methyltransferase 1 (DNMT1), phospho-p44/42 Map Kinase, and protein kinase B (Akt) were analyzed by western blot. RESULTS: Zebularine was an effective inhibitor of human LEC proliferation, attachment, and migration in vitro. A Zebularine concentration of 100 MUM accounted for the following: inhibition of cell proliferation of 57.2%, reduction in cell attachment to 29.6%, and inhibition of cell migration of 58.9%. All effects were dose dependent. Zebularine treatment resulted in dose-dependent decreases of DNMT1, phosphorylated p44/42 MAP Kinase, and phosphorylated Akt. CONCLUSIONS: Zebularine is capable of inhibiting the crucial cellular events in PCO pathogenesis in vitro. Zebularine acts through the inhibition of DNMT1, and it consequently down regulation of the expression of proliferative and survival genes that relate to pathogenesis of PCO. These findings suggest that Zebularine may become a therapeutic approach for the prevention of PCO. PMID- 22259222 TI - Chlamydia infection status, genotype, and age-related macular degeneration. AB - PURPOSE: To evaluate whether Chlamydia (C.) infections are associated with age related macular degeneration (AMD) and to assess if this association is influenced by the complement factor H (CFH) Y402H or the high temperature requirement A serine peptidase 1 (HTRA1) rs11200638 risk genotypes. METHODS: One hundred ninety-nine AMD patients with early and late forms of the disease and 100 unaffected controls, at least 50 years old were included in the study. Patients in the AMD and control groups were selected based on known CFH Y402H variant genotype status (one third homozygous CC, one third heterozygous CT, and one third wild-type TT). Plasma from all patients and controls was tested for C. pneumoniae, C. trachomatis, and C. psittaci IgG seropositivity using a micro immunofluorescent assay to establish previous infection status. Assays were conducted blind to risk genotypes and the results analyzed using univariate and multivariate (logistic regression) analysis. RESULTS: IgG seropositivity to C. pneumoniae was most prevalent (69.2%, n=207), followed by C. trachomatis (7.4%, n=22) and C. psittaci (3.3%, n=10). No association was found between each of the three Chlamydia species IgG seropositivity and AMD status or severity (early/late). There was also no significant association between Chlamydia species IgG seropositivity and AMD status or severity, in patients carrying at least one CFH Y402H risk allele (C) or HTRA1 rs11200638 risk allele (A), with univariate or logistic regression analysis. CONCLUSIONS: Chlamydia infection status does not appear to be associated with AMD status or severity. The presence of CFH Y402H and HTRA1 rs11200638 risk genotypes does not alter this negative association. PMID- 22259223 TI - Regulation of the human tyrosinase gene in retinal pigment epithelium cells: the significance of transcription factor orthodenticle homeobox 2 and its polymorphic binding site. AB - PURPOSE: Tyrosinase is the rate-limiting enzyme responsible for melanin biosynthesis in the retinal pigment epithelium (RPE) of the eye. Melanin has an important role in retinal development, function, and protection against light induced oxidative stress, and melanin levels are associated with age-related macular degeneration (AMD). Because the levels of and protection afforded by melanin seem to decline with increasing age, proper regulation of the human tyrosinase gene (TYR) in the RPE is an important but insufficiently understood process. Our purpose was to obtain detailed information on regulation of the TYR gene promoter in the human RPE and to specify the role of orthodenticle homeobox 2 (OTX2) and microphthalmia-associated transcription factor (MITF). METHODS: We used luciferase reporter constructs to study regulation of the human TYR gene promoter in cultured human RPE cells. We further studied the role of OTX2 and MITF, their binding sites, and endogenous expression by using mutagenesis, electrophoretic mobility shift assay, yeast two-hybrid assay, RNA interference, and gene expression analyses. RESULTS: In the RPE, OTX2 activated the human TYR gene promoter via direct trans-activation of novel OTX2 binding elements. In addition, we found that indirect activation by OTX2 via more proximal MITF binding sites, even in the absence of OTX2 sites, took place. These results are consistent with the physical interaction observed between OTX2 and MITF. Overexpression or knockdown of OTX2 in RPE cells resulted in corresponding changes in tyrosinase mRNA expression. Finally, we found that a single nucleotide polymorphism (SNP rs4547091) at the most proximal OTX2 binding site is associated with altered nuclear protein binding and a remarkable decrease in TYR promoter activity in RPE cells. This single nucleotide polymorphism (SNP) is more common in the European population in which AMD is also more prevalent. CONCLUSIONS: In the RPE, OTX2 activates the human TYR gene promoter by direct DNA binding and by interaction with MITF. Such synergistic interaction highlights the role of OTX2 as a potential coregulator of numerous MITF target genes in the eye. Genetic differences in OTX2 binding sites affect tyrosinase regulation. Collectively, these findings emphasize the role of OTX2 in regulating the human TYR gene, with implications for inter-individual differences in melanin synthesis, retinal development, and function as well as susceptibility to retinal degeneration associated with aging. PMID- 22259224 TI - Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2, including a type 2 Marfan syndrome familial study. AB - PURPOSE: Transforming growth factor beta receptor II (TGFBR2) gene mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear. METHODS: Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband's relatives, and 100 unrelated Chinese control subjects were isolated and screened for fibrillin-1 (FBN1) and TGFBR2 gene mutations by direct sequencing, and a genotype-phenotype study was performed following a review of the literature on TGFBR2 mutations in the search area. Also, the structure of TGFBR2 protein before and after gene mutation was analyzed. RESULTS: The results identified a novel missense TGFBR2 mutation p.V453E (c.1358T>A) in the proband and two relatives that was located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1 mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type 2 Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%). Losartan treatment can slow-down the progression of aortic lesions. CONCLUSIONS: The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. These findings have implications for genetic testing, diagnosis, and treatment in individuals with transforming growth factor beta (TGF-beta) signaling-related disorders. PMID- 22259225 TI - Matrix metalloproteinase-2 and -9 activities in the human lens epithelial cells and serum of steroid induced posterior subcapsular cataracts. AB - PURPOSE: To evaluate the level of matrix metalloproteinase (MMP)-2 and MMP-9 activities in patients with steroid induced posterior subcapsular cataract (PSC). METHODS: This prospective, observational study comprised of 156 patients having either steroid induced PSC (n=50) or non-steroidal PSC (n=106) were performed to evaluate the level of MMP-2 and MMP-9 activities in the lens epithelial cells (LECs) and the serum. Anterior lens capsules harboring LECs were obtained during phacoemulsification and peripheral blood was collected from patients before administration of anesthesia. Serum was separated by centrifugation at 10,000* g for 15 min at 4 degrees C. The LECs and serum samples were processed to analyze MMP-2 and MMP-9 activities using succinylated gelatin assay. Quantitative real time-PCR (qRT-PCR) was performed to determine the mRNA levels of MMP-2 and MMP-9 in LECs. The mRNA levels were expressed as a ratio, using the delta-delta method for comparing the relative expression results between cases with steroid induced PSC and cases with non-steroidal PSC. MMP-2 and MMP-9 levels were also compared in the two groups using immunolocalization. RESULTS: The level of MMP-2 and MMP-9 activity was found to be high in LECs and serum of cases with steroid induced PSC. Further in all steroid induced cases, a 1.4 fold increase was observed in MMP-2 activity in LECs and a 1.4 fold increase in MMP-9 activity in the serum. Both qRT-PCR and immunolocalization showed increased expression of MMP-2 and MMP 9 activity. CONCLUSIONS: MMP-2 and MMP-9 activity in both LECs and serum was significantly higher in cases with steroid induced PSC. The possible use of MMP-9 as a non-invasive biomarker in ascertaining the presence of steroid induced PSC should be evaluated using a larger sample size. PMID- 22259226 TI - Conduct Problems in Adopted and Non-adopted Adolescents and Adoption Satisfaction as a Protective Factor. AB - The present study compared the level of conduct problems at age 17 in a large, non-clinical sample of adopted participants placed in infancy and children in non adoptive families matched to the adoptive families on demographic characteristics. Higher levels of adolescent and parent adoption satisfaction were associated with lower levels of conduct problems. Gender by adoption status interactions were not significant. However, female adopted participants had higher levels of conduct problems than female non-adopted participants, whereas male adopted and non-adopted participants had similar levels of conduct problems. In the overall sample, differences between adopted and matched control participants on all conduct problem measures were nonsignificant. PMID- 22259227 TI - Linear Discriminant Functions in Connection with the micro-RNA Diagnosis of Colon Cancer. AB - Early detection (localized stage) of colon cancer is associated with a five-year survival rate of 91%. Only 39% of colon cancers, however, are diagnosed at that early stage. Early and accurate diagnosis, therefore, constitutes a critical need and a decisive factor in the clinical treatment of colon cancer and its success. In this study, using supervised linear discriminant analysis, we have developed three diagnostic biomarker models that-based on global micro-RNA expression analysis of colonic tissue collected during surgery-can discriminate with a perfect accuracy between subjects with colon cancer (stages II-IV) and normal healthy subjects. We developed our three diagnostic biomarker models with 57 subjects [40 with colon cancer (stages II-IV) and 17 normal], and we validated them with 39 unknown (new and different) subjects [28 with colon cancer (stages II-IV) and 11 normal]. For all three diagnostic models, both the overall sensitivity and specificity were 100%. The nine most significant micro-RNAs identified, which comprise the input variables to the three linear discriminant functions, are associated with genes that regulate oncogenesis, and they play a paramount role in the development of colon cancer, as evidenced in the tumor tissue itself. This could have a significant impact in the fight against this disease, in that it may lead to the development of an early serum or blood diagnostic test based on the detection of those nine key micro-RNAs. PMID- 22259228 TI - Evaluating translocation gene fusions by SNP array data. AB - Somatic cell genetic alterations are a hallmark of tumor development and progression. Although various technologies have been developed and utilized to identify genetic aberrations, identifying genetic translocations at the chromosomal level is still a challenging task. High density SNP microarrays are useful to measure DNA copy number variation (CNV) across the genome. Utilizing SNP array data of cancer cell lines and patient samples, we evaluated the CNV and copy number breakpoints for several known fusion genes implicated in tumorigenesis. This analysis demonstrated the potential utility of SNP array data for the prediction of genetic aberrations via translocations based on identifying copy number breakpoints within the target genes. Genome-wide analysis was also performed to identify genes harboring copy number breakpoints across 820 cancer cell lines. Candidate oncogenes were identified that are linked to potential translocations in specific cancer cell lines. PMID- 22259229 TI - First experience with BAK-free travoprost 0.004% in topical glaucoma medication. AB - OBJECTIVES: Benzalkonium chloride (BAK)-free travoprost 0.004% (Travatan Z((r)), Alcon Laboratories, Inc, Fort Worth, TX) is a new formulation that was developed with the aim of creating a formulation of travoprost that would maintain the intraocular pressure (IOP)-lowering efficacy and have an improved overall safety profile, particularly improved ocular surface tolerability. METHODS: Thirty newly diagnosed primary open-angle glaucoma (POAG) patients were treated with BAK-free travoprost 0.004%. IOP readings were recorded at baseline before initiating treatment, at 4-6 weeks, and after 12 weeks of starting treatment. In addition, patient demographics, subjective symptoms (ie, burning, foreign-body sensation, itching, and stinging), and objective clinical signs such as conjunctival hyperemia were collected. Subjective symptoms were evaluated using a four-point scale ranging from "no symptoms," "mild symptoms," "moderate symptoms" to "severe symptoms." As for clinical signs, severity of conjunctival hyperemia was evaluated. All other adverse events were collected. RESULTS: BAK-free travoprost 0.004% provided an IOP decrease in all patients, with an overall mean of 28.3 +/- 2.1 mmHg at baseline to a mean of 18.7 +/- 1.6 mmHg at 4-6 weeks, and a mean of 18.4 +/- 1.4 mmHg after 12 weeks. Both subjective symptoms and objective clinical signs were very few after treatment. CONCLUSION: The results demonstrate that BAK free travoprost 0.004% is an effective, well tolerated, and safe medication in POAG patients. PMID- 22259230 TI - Randomized study comparing the efficacy of a self-retaining bicanaliculus intubation stent with Crawford intubation in patients with canalicular obstruction. AB - BACKGROUND: The purpose of this study was to compare the efficacy of self retaining stent (SRS) bicanalicular intubation with bicanalicular silicone (Crawford) intubation in patients with canalicular and punctal obstruction. METHODS: In this prospective, randomized clinical trial, 38 patients with canalicular or punctal obstruction (25 partial, 13 complete) and epiphora were randomized into two groups. Twenty-one patients (14 with partial and seven with complete obstruction) underwent SRS intubation and 17 patients underwent bicanalicular silicon intubation in a randomized fashion. RESULTS: After a mean follow-up of 6 months following tube removal, 16 (76%, 12 partial, four complete) of the 21 eyes in the SRS intubation group and 13 (76%, 10 partial, three complete) in the bicanalicular silicon intubation group had a successful outcome and remained symptom-free. For partial obstructions, the success rate was 85% and 90% for the SRS and bicanalicular silicon intubation groups, respectively. The corresponding values for complete obstruction were 63% and 50% for the SRS and bicanalicular silicon intubation groups, respectively. CONCLUSION: SRS could effectively substitute for a more extensive procedure such as bicanalicular silicon intubation in patients with canalicular obstruction, particularly those with partial obstruction. The newly developed SRS intubation procedure has the advantages of simple, easy implementation and extubation, low cost, and a lower rate of trauma when compared with bicanalicular silicon intubation. PMID- 22259231 TI - Letter to the editor: partial central retinal artery occlusion offers a unique insight into the ischemic penumbra. PMID- 22259232 TI - A new manner of reporting pressure results after glaucoma surgery. AB - PURPOSE: To evaluate to what extent contemporary glaucoma abstracts offer complete information and to suggest a new manner of pressure results reporting. MATERIALS, METHODS, AND RESULTS: Most of the 36 relevant surgical glaucoma abstracts found in one issue of International Glaucoma Review contain insufficient data-supported statements. Such abstracts cannot offer a clear picture of the study essence if economic, linguistic, or political barriers prevent access to the full text. In order to enrich abstract content and to avoid typographic space waste, a formula is suggested to provide, in one single line of symbols and figures, all the necessary data for statistical interpretation at two evolution moments: the first significative control (6 months) and the final one. CONCLUSION: The current manner of results reporting in surgical glaucoma abstracts is subject to too little standardization, allowing insufficiently data supported statements. Abstracts, especially those printed in small-circulation language journals, should be conceived and standardized in such a manner that any abstract review reader is capable of grasping the essence of the study at first glance. The suggested manner of reporting results would bring satisfaction to all areas of the process. Publishers would save typographic space, readers would find all the necessary data for statistical analysis and comparison with other studies, and authors would be convinced that the essence of their work would penetrate in spite of any economic, linguistic, or political barriers. PMID- 22259233 TI - Improving quality of life in patients with end-stage age-related macular degeneration: focus on miniature ocular implants. AB - Low vision devices in the past have been mainly extraocular. There are now four new devices in different stages of development and implementation that are currently available. Three of them, the Implantable Miniature Telescope (IMT, VisionCare Ophthalmic Technologies, Saratoga, CA), Intraocular Lens for Visually Impaired People (IOL-VIP, IOL-VIP System, Soleko, Pontecorvo, Italy), and Lipschitz Mirror Implant (LMI, Optolight Vision Technology, Herzlia, Israel) are implanted into the anterior segment while the Argus II (Second Sight Medical Products, Sylmar, CA) is implanted into the posterior segment. The goal of these devices is to increase the patient quality of life which has been measured by Visual Functioning Questionnaire (VFQ) scales. The IMT is the only device that has been shown to increase the VFQ score by seven points at 6 months compared to baseline. It is the only FDA-approved device in the US while the Argus has been approved in Europe. Each of these prosthetics has potential benefits for patients. PMID- 22259234 TI - Penetrating eye injuries from writing instruments. AB - PURPOSE: To consider the potential for ocular injury from writing implements by presenting four such cases, and to consider the incidence of such eye injuries from analysis of a national trauma database. METHODS: The Home and Leisure Accident Surveillance System was searched for records of eye injuries from writing instruments to provide UK estimates of such injuries. Four patients with ocular penetrating injury from pens or pencils (especially when caused by children), and examined by the authors, are described which illustrate mechanisms of injury. RESULTS: It is estimated that around 748 ocular pen injuries and 892 ocular pencil injuries of undetermined severity occurred annually in the UK during the database surveillance period 2000-2002. No eye injuries from swords, including toy swords and fencing foils, were reported. CONCLUSION: Ocular perforation sometimes occur from writing instruments that are thrown in the community, especially by children. Implications for policy and prevention are discussed. Non-specialists should have a low threshold for referring patients with eye injuries if suspicious of ocular penetration, even where caused by everyday objects, such as writing instruments. PMID- 22259235 TI - Helicobacter pylori infection and primary open-angle glaucoma: is there a connection? AB - Glaucoma, the most common form of which is primary open-angle glaucoma (POAG), is a neurodegenerative disease which is the second most common cause of blindness worldwide. Among the factors that have been implicated in the pathophysiology of this disease is infection with Helicobacter pylori. This alleged association has caused a great deal of scientific discussion during the past decade, as the establishment of such a correlation might lead to therapeutic applications for all glaucoma patients. In this review, we assess all relevant major studies and trials in an effort to elucidate the issue. PMID- 22259236 TI - Long term result of silicone oil versus gas tamponade in the treatment of traumatic macular holes. AB - PURPOSE: To compare the effectiveness of pars plana vitrectomy (PPV) with either silicone oil or gas tamponade for the treatment of traumatic macular holes. METHODS: A retrospective comparative study included 22 patients who were operated on by PPV for repair of traumatic macular holes with either silicone oil tamponade (nine patients) or perfluoropropane (C(3)F(8)) gas tamponade (13 patients). RESULTS: Twenty-two cases were reviewed to assess the anatomical and visual outcomes of surgery with silicone oil tamponade in nine cases (40.9%) vs 14% C(3)F(8) gas tamponade in 13 cases (59.1%). The age of the silicone oil treated patients ranged from 10 to 40 years (mean 27.4 +/- 11.3 years), while that of the gas-treated patients ranged from 19 to 35 years (mean 26.54 +/- 5.68 years). Female patients accounted for 33.3% of the silicone oil group and 30.77% of the gas-treated group. The minimal follow-up time for the silicone oil-treated group was 13 months, with a maximum of 18 months after silicone oil removal. The minimal follow-up time for the gas-treated group was 12 months and the maximum was 24 months. The rate of hole closure after the primary operation with oil tamponade was significantly lower than that with gas tamponade (66.67% vs 92.3%; P = 0.022). With re-operations, the final rate of hole closure was higher in the gas group (100%) than in the silicone oil group (77.8%). The final postoperative decimal visual acuity for the gas group was significantly better than for the oil group (0.433 vs 0.245; P = 0.047). CONCLUSIONS: C(3)F(8) gas was a more effective tamponade than silicone oil in achieving initial closure of traumatic macular holes. Eyes receiving an oil tamponade required significantly more re-operations to achieve hole closure than did eyes undergoing a gas tamponade. Final visual acuity was better for gas-treated eyes than for silicone oil-treated eyes. PMID- 22259237 TI - Treatment patterns and health care resource utilization in a 1-year observational cohort study of outpatients with schizophrenia at risk of nonadherence treated with long-acting injectable antipsychotics. AB - PURPOSE: To describe (1) the clinical profiles and the patterns of use of long acting injectable (LAI) antipsychotics in patients with schizophrenia at risk of nonadherence with oral antipsychotics, and in those who started treatment with LAI antipsychotics, (2) health care resource utilization and associated costs. PATIENTS AND METHODS: A total of 597 outpatients with schizophrenia at risk of nonadherence, according to the psychiatrist's clinical judgment, were recruited at 59 centers in a noninterventional prospective observational study of 1-year follow-up when their treatment was modified. In a post hoc analysis, the profiles of patients starting LAI or continuing with oral antipsychotics were described, and descriptive analyses of treatments, health resource utilization, and direct costs were performed in those who started an LAI antipsychotic. RESULTS: Therapy modifications involved the antipsychotic medications in 84.8% of patients, mostly because of insufficient efficacy of prior regimen. Ninety-two (15.4%) patients started an LAI antipsychotic at recruitment. Of these, only 13 (14.1%) were prescribed with first-generation antipsychotics. During 1 year, 16.3% of patients who started and 14.9% of patients who did not start an LAI antipsychotic at recruitment relapsed, contrasting with the 20.9% who had been hospitalized only within the prior 6 months. After 1 year, 74.3% of patients who started an LAI antipsychotic continued concomitant treatment with oral antipsychotics. The mean (median) total direct health care cost per patient per month during the study year among the patients starting any LAI antipsychotic at baseline was ?1,407 (?897.7). Medication costs (including oral and LAI antipsychotics and concomitant medication) represented almost 44%, whereas nonmedication costs accounted for more than 55% of the mean total direct health care costs. CONCLUSION: LAI antipsychotics were infrequently prescribed in spite of a psychiatrist-perceived risk of nonadherence to oral antipsychotics. Mean medication costs were lower than nonmedication costs. PMID- 22259238 TI - Predictors of continuation with olanzapine during the 1-year naturalistic treatment of patients with schizophrenia in Japan. AB - PURPOSE: Treatment continuation is considered an important measure of antipsychotic effectiveness in schizophrenia, reflecting the medication's efficacy, safety, and tolerability from both patients' and clinicians' perspectives. This study identified characteristics of patients with schizophrenia who continue olanzapine therapy for a 1-year period in Japan. METHODS: In a large (N = 1850), prospective, observational study, Japanese patients with schizophrenia who initiated treatment with olanzapine were followed for 1 year. Baseline characteristics were compared using t-tests and chi-square tests. Stepwise logistic regression was used to identify independent baseline predictors of treatment continuation. RESULTS: Most patients (68.2%) continued with olanzapine therapy for the full 1-year study period, with an average duration of 265.5 +/- 119.4 days. At baseline, patients who continued were significantly more likely to be male, older, and inpatients; have longer illness duration, higher negative and cognitive symptoms, better health-related quality of life, and prior anticholinergic use. Continuers were significantly less likely to engage in social activities, live independently, work for pay, or have prior antidepressant use. Continuers showed significantly greater early (3-month) improvement in global symptom severity. Logistic regression found that continuation was significantly predicted by longer illness duration, lower positive symptoms, higher negative symptoms, and better health-related quality of life. CONCLUSIONS: In this large naturalistic study in Japan, most patients with schizophrenia stayed on olanzapine therapy for the full 1-year study period. Treatment completion with olanzapine was independently predicted by longer illness duration, lower positive symptoms, higher negative symptoms, and better health-related quality of life. PMID- 22259239 TI - Impact of household food insecurity on the nutritional status and the response to therapeutic feeding of people living with human immunodeficiency virus. AB - BACKGROUND: The role of household food security (HFS) in the occurrence of wasting and the response to food-based intervention in people living with human immunodeficiency virus (PLHIV), especially adults, is still controversial and needs investigation. METHODS: Face-to-face interviews to collect data for Coping Strategies Index score and Dietary Diversity Score estimation were conducted during a noncontrolled and nonrandomized study assessing the effectiveness of ready-to-use therapeutic food in the treatment of wasting in adults with HIV. Coping Strategies Index score and Dietary Diversity Score were used to determine HFS, and the participants and tertiles of Coping Strategies Index score were used to categorize HFS. RESULTS: The study showed that most participants were from food insecure households at admission, only 2.7% (5/187) ate food from six different food groups the day before enrolment, and 93% (180/194) were applying forms of coping strategy. Acute malnutrition was rare among <5-year-old children from participants' households, but the average (standard deviation) mid-upper arm circumference of other adults in the same households were 272.7 (42.1) mm, 254.8 (33.8) mm, and 249.8 (31.7) mm for those from the best, middle, and worst tertile of HFS, respectively (P = 0.021). Median weight gain was lower in participants from the worst HFS tertile than in those from the other two tertiles combined during therapeutic feeding phase (0.0 [-2.1 to 2.6] kg versus 1.9 [-1.7 to 6.0] kg; P = 0.052) and after ready-to-use therapeutic food discontinuation (-1.9 [ 5.2 to 4.2] kg versus 1.8 [-1.4 to 4.7] kg; P = 0.098). Being on antiretroviral therapy influenced the response to treatment and nutritional status after discontinuation of ready-to-use therapeutic food supplementation. CONCLUSION: Food insecurity is an important contributing factor to the development of wasting in PLHIV and its impact on therapeutic feeding response outlines the importance of food-based intervention in the management of wasting of PLHIV. PMID- 22259240 TI - The MS Choices Survey: findings of a study assessing physician and patient perspectives on living with and managing multiple sclerosis. AB - BACKGROUND: Treatment of multiple sclerosis (MS) with disease-modifying drugs (DMDs) can reduce relapse frequency and delay disability progression. Although adherence to DMDs is difficult to measure accurately, evidence suggests that poor adherence is common and can compromise treatment success. There are likely to be multiple factors underlying poor adherence. To better understand these factors, the global MS Choices Survey investigated patient and physician perspectives regarding key aspects of MS diagnosis, treatment adherence and persistence, and disease management. METHODS: The survey was conducted in seven countries and involved patients with MS (age 18-60 years; MS diagnosis for >=1 year; current treatment with a DMD) and physicians (neurologist for 3-30 years; treating >=15 patients with MS per average month; >60% of time spent in clinical practice). Separate questionnaires were used for physicians and patients, each containing approximately 30 questions. RESULTS: Questionnaires were completed by 331 patients and 280 physicians. Several differences were observed between the responses of patients and physicians, particularly for questions relating to treatment adherence. Overall, the proportion of patients reporting taking a treatment break (31%) was almost twice that estimated by physicians (on average 17%). The reasons cited for poor adherence also differed between patients and physicians. For example, more physicians cited side effects as the main reason for poor patient adherence (82%), than responding patients (42%). CONCLUSIONS: Physicians may underestimate the scale of poor adherence to DMDs, which could impact on their assessment of treatment efficacy and result in inappropriate treatment escalation. In addition, disparities were identified between patient and physician responses regarding the underlying reasons for poor adherence. Improvements in the dialog between patients and neurologists may increase adherence to DMDs. PMID- 22259241 TI - Twice-daily versus once-daily antiretroviral therapy and coformulation strategies in HIV-infected adults: benefits, risks, or burden? AB - The recent development of once-daily antiretroviral agents and fixed-dose combination formulations has been an important development in antiretroviral regimen simplification. Recent studies indicate that once-daily antiretroviral regimens improve adherence, especially in antiretroviral-naive patients and in difficult-to-treat populations, such as the homeless or marginally housed. However, there are potential risks with the higher peak and lower trough plasma drug concentrations that may result from certain once-daily formulations. Due to the multifactorial and complex nature of adherence behavior, clinicians' efforts to improve patient adherence should not be limited to prescribing once-daily regimens, but should also consider social support, side effect management, and adherence support tools, such as pillbox organizers and other targeted interventions. Additional research will clarify the benefits of once-daily and fixed-dose combination regimens on clinical and virologic outcomes. Comprehensive cost-benefit analysis of regimen simplification could help facilitate evidence based decisions regarding antiretroviral regimen choices. PMID- 22259242 TI - Why are some evidence-based care recommendations in chronic obstructive pulmonary disease better implemented than others? Perspectives of medical practitioners. AB - BACKGROUND: Clinical guidelines for management of patients with chronic obstructive pulmonary disease (COPD) include recommendations based on high levels of evidence, but gaps exist in their implementation. The aim of this study was to examine the perspectives of medical practitioners regarding implementation of six high-evidence recommendations for the management of people with COPD. METHODS: Semi-structured interviews were conducted with medical practitioners involved with care of COPD patients in hospital and general practice. Interviews sought medical practitioners' experience regarding implementation of smoking cessation, influenza vaccination, pulmonary rehabilitation, guideline-based medications, long-term oxygen therapy for hypoxemia and plan and advice for future exacerbations. Interviews were audiotaped, transcribed verbatim and analyzed using content analysis. RESULTS: Nine hospital-based medical practitioners and seven general practitioners participated. Four major categories were identified which impacted on implementation of the target recommendations in the care of patients with COPD: (1) role clarity of the medical practitioner; (2) persuasive communication with the patient; (3) complexity of behavioral change required; (4) awareness and support available at multiple levels. For some recommendations, strength in all four categories provided significant enablers supporting implementation. However, with regard to pulmonary rehabilitation and plans and advice for future exacerbations, all identified categories that presented barriers to implementation. CONCLUSION: This study of medical practitioner perspectives has indicated areas where significant barriers to the implementation of key evidence-based recommendations in COPD management persist. Developing strategies to target the identified categories provides an opportunity to achieve greater implementation of those high-evidence recommendations in the care of people with COPD. PMID- 22259243 TI - Adjusting for COPD severity in database research: developing and validating an algorithm. AB - PURPOSE: When comparing chronic obstructive lung disease (COPD) interventions in database research, it is important to adjust for severity. Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines grade severity according to lung function. Most databases lack data on lung function. Previous database research has approximated COPD severity using demographics and healthcare utilization. This study aims to derive an algorithm for COPD severity using baseline data from a large respiratory trial (UPLIFT). METHODS: Partial proportional odds logit models were developed for probabilities of being in GOLD stages II, III and IV. Concordance between predicted and observed stage was assessed using kappa-statistics. Models were estimated in a random selection of 2/3 of patients and validated in the remainder. The analysis was repeated in a subsample with a balanced distribution across severity stages. Univariate associations of COPD severity with the covariates were tested as well. RESULTS: More severe COPD was associated with being male and younger, having quit smoking, lower BMI, osteoporosis, hospitalizations, using certain medications, and oxygen. After adjusting for these variables, co-morbidities, previous healthcare resource use (eg, emergency room, hospitalizations) and inhaled corticosteroids, xanthines, or mucolytics were no longer independently associated with COPD severity, although they were in univariate tests. The concordance was poor (kappa = 0.151) and only slightly better in the balanced sample (kappa = 0.215). CONCLUSION: COPD severity cannot be reliably predicted from demographics and healthcare use. This limitation should be considered when interpreting findings from database studies, and additional research should explore other methods to account for COPD severity. PMID- 22259244 TI - Nutritional deficits in elderly smokers with respiratory symptoms that do not fulfill the criteria for COPD. AB - BACKGROUND AND OBJECTIVE: Whereas nutrition deficits are recognized as an expression of systemic inflammation in the elderly with diagnosed chronic obstructive pulmonary disease (COPD), if they occur in symptomatic elderly smokers, unfulfilled COPD criteria are not confirmed. METHODS: Respiratory function, anthropometry assessment, and diet intake evaluation of 13 COPD patients (COPD group), ten symptomatic elderly smokers (SYSM group), and 27 healthy volunteers (control group) were compared. All were 70 years old or older. RESULTS: The SYSM group had lower body weight, body mass index, percentage ideal body weight, body fat percentage, arm muscle circumference, tricep skin fold thickness, serum albumin, prealbumin, and transferrin than the control group and were similar to the COPD group (P < 0.05 each and nonsignificant each). Resting energy expenditure was no different among the groups. Intake of energy, vitamins (A, B1, B2, and C), calcium, iron, fiber, and sodium was also lower in the SYSM group than in the control group (P < 0.05 all) and was similar to the COPD group. CONCLUSION: Elderly smokers who are symptomatic but who do not fulfill the COPD diagnostic criteria have nutritional deficits related to insufficient energy intake that are similar to those seen in COPD patients. PMID- 22259245 TI - Sensitivity to environmental irritants and quality of life in COPD. AB - It is a common clinical experience that patients with chronic obstructive pulmonary disease (COPD) complain of airway symptoms provoked by environmental irritants like chemicals and scents, although few studies can confirm such connections. The aim was to study the prevalence of airway symptoms induced by chemicals and scents in a group of patients with newly diagnosed CPOD and to analyze any relation to illness severity and quality of life. Eighty-one patients with COPD were recruited to the study. By mail they were asked to answer three questionnaires regarding symptoms, quality of life, and social and emotional influence of airway symptoms induced by environmental irritants. A majority (62%) of the COPD patients claimed to be hyperreactive to chemicals and scents. As a group they scored higher on a questionnaire measuring social and emotional influences of such environmental irritants compared to healthy control subjects. Further, high scores were more common among patients with a very severe form of COPD and among patients with regular use of beta(2)-stimulants. High scores were also associated with significantly more airway symptoms and, in some aspects, with impaired quality of life. In conclusion, the results of this study show that airway symptoms induced by environmental irritants are common in patients with COPD and that this increased airway sensitivity follows the impairment of lung capacity. The mechanisms behind this remain unclear. PMID- 22259246 TI - A pilot study of the impact of high-frequency chest wall oscillation in chronic obstructive pulmonary disease patients with mucus hypersecretion. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) patients with mucus hypersecretion tend to demonstrate increased frequency of infective exacerbations and a steeper slope of decline in lung function. Enhanced mucociliary clearance with high-frequency chest wall oscillation (HFCWO) devices previously used in cystic fibrosis and bronchiectasis patients may offer the opportunity for community-based, self-managed therapy to improve quality of life and lung function. STUDY DESIGN AND METHODS: A randomized controlled crossover pilot study of HFCWO compared with conventional treatment was conducted in 22 patients with moderate to severe COPD and mucus hypersecretion. Patients spent 4 weeks using an HFCWO (SmartVest((r))) device and 4 weeks in a conventional phase with a 2-week washout. Eleven patients started with HFCWO and changed to conventional treatment, whereas the other eleven patients started conventional treatment and crossed over to HFCWO. RESULTS: The patients were elderly with a mean age of 71 (standard deviation [SD] 10) years and were at the upper end of the normal range of body mass index (25 [SD 4.2] kg/m(2)). The majority of patients had moderate to severe COPD with a mean percentage predicted forced expiratory volume in 1 second of 41 (SD 15.6) and percentage predicted forced vital capacity of 73 (SD 17.7). Baseline sputum production was negatively correlated to lung function and positively to St George's Respiratory Questionnaire. Symptom scores and St George's Respiratory Questionnaire symptom dimension improved significantly (-8, P < 0.05). Sputum production showed a declining trend in the HFCWO phase, although not reaching statistical significance. The HFCWO device was well tolerated with good reported compliance. CONCLUSION: This pilot study demonstrated that patients with advanced COPD and mucus hypersecretion at increased risk of declining lung function tolerated the HFCWO treatment well, leading to improvement in quality of life and reduced symptoms. PMID- 22259247 TI - Expression of the androgen receptor and its correlation with molecular subtypes in 980 chinese breast cancer patients. AB - BACKGROUND: Recent studies have shown that androgen displays an inhibitory effect on breast cancer cell lines that express androgen receptor (AR) but not estrogen receptor (ER) and progesterone receptor (PR). We have previously reported that approximately 1/3 of ER negative high grade invasive ductal carcinomas express AR. Thus, AR can serve as a potential therapeutic target for this group of patients. AIM: Here we investigated AR expression patterns in 980 consecutive breast carcinomas. RESULTS: We found that (1) AR was expressed more frequently (77%) than ER (61%) and PR (60%) in breast carcinomas; (2) AR expression was associated with ER and PR expression (P < 0.0001), small tumor size (P = 0.0324) and lower Ki-67 expression (P = 0.0013); (3) AR expression was found in 65% of ER negative tumors; (4) AR expression was associated with PR and Ki-67 in ER negative tumors, but not in ER positive tumors; (5) AR expression was higher in ER positive subtypes (Luminal A, Luminal B and Luminal HER2 subtypes, 80%-86%) and lower in ER negative subtypes [HER2, triple negative (TN), and TN EFGR positive subtypes; 52%-66%], with over 50% of TN tumors expressing AR. CONCLUSION: More breast carcinomas express AR than ER and PR, including significant numbers of ER negative and TN tumors, for which AR could serve as a potential therapeutic target. PMID- 22259248 TI - Delivery of MicroRNA-10b with Polylysine Nanoparticles for Inhibition of Breast Cancer Cell Wound Healing. AB - Recent studies revealed that micro RNA-10b (mir-10b) is highly expressed in metastatic breast cancer cells and positively regulates breast cancer cell migration and invasion through inhibition of HOXD10 target synthesis. In this study we designed anti-mir-10b molecules and combined them with poly L-lysine (PLL) to test the delivery effectiveness. An RNA molecule sequence exactly matching the mature mir-10b minor antisense showed strong inhibition when mixed with PLL in a wound-healing assay with human breast cell line MDA-MB-231. The resulting PLL-RNA nanoparticles delivered the anti-microRNA molecules into cytoplasm of breast cancer cells in a concentration-dependent manner that displayed sustainable effectiveness. PMID- 22259249 TI - An Enterobacter plasmid as a new genetic background for the transposon Tn1331. AB - BACKGROUND: Genus Enterobacter includes important opportunistic nosocomial pathogens that could infect complex wounds. The presence of antibiotic resistance genes in these microorganisms represents a challenging clinical problem in the treatment of these wounds. In the authors' screening of antibiotic-resistant bacteria from complex wounds, an Enterobacter species was isolated that harbors antibiotic-resistant plasmids conferring resistance to Escherichia coli. The aim of this study was to identify the resistance genes carried by one of these plasmids. METHODS: The plasmids from the Enterobacter isolate were propagated in E. coli and one of the plasmids, designated as pR23, was sequenced by the Sanger method using fluorescent dyeterminator chemistry on a genetic analyzer. The assembled sequence was annotated by search of the GenBank database. RESULTS: Plasmid pR23 is composed of the transposon Tn1331 and a backbone plasmid that is identical to the plasmid pPIGDM1 from Enterobacter agglomerans. The multidrug resistance transposon Tn1331, which confers resistance to aminoglycoside and beta lactam antibiotics, has been previously isolated only from Klebsiella. The Enterobacter plasmid pPIGDM1, which carries a ColE1-like origin of replication and has no apparent selective marker, appears to provide a backbone for propagation of Tn1331 in Enterobacter. The recognition sequence of Tn1331 transposase for insertion into pPIGDM1 is the pentanucleotide TATTA, which occurs only once throughout the length of this plasmid. CONCLUSION: Transposition of Tn1331 into the Enterobacter plasmid pPIGDM1 enables this transposon to propagate in this Enterobacter. Since Tn1331 was previously isolated only from Klebsiella, this report suggests horizontal transfer of this transposon between the two bacterial genera. PMID- 22259250 TI - Resistance to antimicrobial drugs in Ghana. AB - BACKGROUND: Antimicrobial drug resistance is a global issue that affects health, economic, and social development. The problem has been attributed to misuse of antimicrobial agents. PURPOSE: To identify the agents of bacterial infection in Ghana, determine their antibiogram, and the possibility of setting up a surveillance program. PATIENTS AND METHODS: A prospective quantitative study set in various hospitals including two teaching hospitals, seven regional hospitals, and two district hospitals in Ghana. A total of 5099 bacterial isolates from various clinical specimens were collected over a period of 1 year, including data related to the patients. Susceptibility of the isolates was determined by the Kirby-Bauer method. In addition, the minimum inhibitory concentration (MIC) of multidrug-resistant isolates of epidemiological significance was also determined using the E-test. RESULTS: A wide range of bacterial isolates were identified in both teaching and regional hospitals. High percentage of resistance was observed for tetracycline (82%), cotrimoxazole (73%), ampicillin (76%), and chloramphenicol (75%). Multidrug resistance was observed to a combination of ampicillin, tetracycline, chloramphenicol, and cotrimoxazole. On the other hand, a lower percentage of resistance was observed for ceftriaxone (6.3%), ciprofloxacin (11%), and amikacin (9.9%). CONCLUSION: Generally, the prevalence of multidrug resistance was widespread among the various isolates. Some multidrug resistant strains of Staphylococcus aureus, Salmonella typhi, and non-typhoidal Salmonella (NTS) had high MIC to cefuroxime (>256), gentamicin (>256), and ciprofloxacin (>32). PMID- 22259251 TI - A necrotic lung ball caused by co-infection with Candida and Streptococcus pneumoniae. AB - INTRODUCTION: A necrotic lung ball is a rare radiological feature that is sometimes seen in cases of pulmonary aspergillosis. This paper reports a rare occurrence of a necrotic lung ball in a young male caused by Candida and Streptococcus pneumoniae. CASE REPORT: A 28-year-old male with pulmonary candidiasis was found to have a lung ball on computed tomography (CT) of the chest. The patient was treated with beta-lactams and itraconazole and then fluconazole, which improved his condition (as found on a following chest CT scan) and serum beta-D-glucan level. The necrotic lung ball was suspected to have been caused by coinfection with Candida and S. pneumoniae. CONCLUSION: A necrotic lung ball can result from infection by Candida and/or S. pneumoniae, indicating that physicians should be aware that patients may still have a fungal infection of the lungs that could result in a lung ball, even when they do not have either Aspergillus antibodies or antigens. PMID- 22259253 TI - Calciphylaxis presenting in early chronic kidney disease with mixed hyperparathyroidism. AB - Calciphylaxis is a disabling and life-threatening complication that primarily affects patients who are dialysis dependent. Reports have grown in the literature of cases occurring in those who have advanced chronic kidney disease (pre-end stage renal disease) or in the setting of transplantation. There are also a few reports of cases occurring in those without any form of chronic kidney disease but with primary hyperparathyroidism. This disease entity is characterized by calcification, intimal hypertrophy, and thrombosis of small vessels that result in necrotizing, nonhealing ulcers - many of which are life threatening. Although several strategies aimed at treating and preventing this affliction have been reported in the literature, the outcome for most patients with calciphylaxis remains quite poor. We describe a patient with comparatively early stage-3 chronic kidney disease who developed calciphylaxis in the setting of both primary and secondary hyperparathyroidism. Predictably, after subtotal parathyroidectomy, her wounds did not completely heal and her biochemical markers of hyperparathyroidism did not completely normalize until her underlying secondary hyperparathyroidism was treated medically. It was only after initiating cinacalcet that the patient experienced complete wound healing and resolution of her calciphylaxis. It also supports other authors' findings that cinacalcet may be an important adjunct in the treatment of calciphylaxis. PMID- 22259252 TI - Transcriptional characteristics of CD4 T cells in young asthmatic children: RORC and FOXP3 axis. AB - BACKGROUND: Asthma is a chronic inflammatory disorder, hypothetically caused by autoreactive Th2 cells, whereas Th1 and regulatory T cells may confer protection. The development of Th subpopulations is dependent on the expression of lineage specific transcription factors. PURPOSE: This study aimed to assess the balance of CD4(+) T cell populations in asthmatic children. METHODS: Peripheral blood mononuclear cells (PBMC) mRNA expression was assessed in 30 asthmatic children (18 patients with mild asthma and 12 with moderate asthma). Real-time polymerase chain reaction (RT-PCR) quantified TBX21, GATA-3, RORC, FOXP3, and EBI3 mRNA expression. Intracellular cytokine expression of IL-2, IL-4, IL-10, and IFN-gamma in CD4(+) T cells in asthmatic children was measured by flow cytometry. IL-6 and IL-17 cytokines were assessed in serum by enzyme-linked immunosorbent assay (ELISA). RESULTS: A significant increase was found in the percentage of CD4(+) and CD8(+) T cell-producing IL-4, IL-6, and IL-17. A decreased percentage of CD4(+) producing IFN-gamma in asthmatic children was found. Expression of GATA-3 (Th2), retinoid-related orphan receptor C (RORC) (Th17), and EBI3 were increased in asthmatic patients compared to healthy controls. Expression of FOXP3 (Treg) and TBX21 (Th1) were decreased (P < 0.0001 and P < 0.0001) in asthmatic children. Analysis of transcription factor ratios revealed an increase in the RORC/FOXP3 (P = 0.0001), and a significant decrease of TBX21/GATA-3 (P = 0.0001) ratios in patients with asthma. CONCLUSION: Young asthmatics were characterized by increased IL-4 production and low IFN-gamma synthesis. The increased serum IL-17 and IL-6 levels sustained an inflammatory environment in young asthmatics. The results indicate that FOXP3 and RORC mRNA expression could be associated with the sustained inflammatory process, transduced by low immune tolerance by Treg cells. The TBX21/GATA-3 and RORC/FOXP3 ratios dysregulation in asthmatics is consistent with the plasticity existing between Th1, Th17, and Treg cells during inflammation. PMID- 22259254 TI - Fibromatosis of the cecum presenting with acute appendicitis: a case report. AB - Although acute appendicitis is a common clinical condition in general surgical practice, <1% of them are associated with malignancies. Appendiceal carcinoids make up most of those malignancies and acute appendicitis cases associated with benign cecal neoplasias are very uncommon. In this study, a 25-year-old female patient who presented with distinct acute appendicitis symptoms is reported. The patient was operated on via open technique. Exploration revealed an appendix with advanced edema and hyperemia. While the cecum was observed to be normal, a solid mass of 2.5 cm diameter was palpated in the appendiceal base. Following the ileocecal resection, histopathological examination revealed the mass as a fibromatosis. The goals of this report are to remind health care professionals that some very rare etiologies may be involved in acute appendicitis diagnosis and treatment, and to underscore the place of laparoscopic approach and preoperative computed tomography in this disease. PMID- 22259255 TI - Controlling anxiety in physicians and nurses working in intensive care units using emotional intelligence items as an anxiety management tool in Iran. AB - INTRODUCTION: Today, anxiety is one of the most common problems of mankind, to the extent that we could claim that it predisposes human to many physical illnesses, mental disorders, behavioral disturbances, and inappropriate reactions. The intensive care unit is a stressful environment for its staff, especially physicians and nurses. These stresses may have negative effects on the mental health and performance of the nurses and physicians. But the complications caused by this stress can be prevented by training emotional intelligence components. In this study, the impact of training emotional intelligence components on stress and anxiety in nurses and expert physicians is examined. METHODOLOGY: A cross-interventional, pre- to post-, case and control group design was used and inferential study design was implemented. Our study included 150 registered hospitals physicians and nurses, who were widely distributed. In the study, a ten-question demographic questionnaire, a 20-question situational anxiety Berger (overt) questionnaire, and a 133-question Bar-on emotional intelligence questionnaire were used. RESULTS: Research results indicate that average score for the situational anxiety of the case group in nurses was 47.20 before the intervention and it was reduced to 42.00 after the intervention, and in physicians was 40.46 before the intervention and it decreased to 33.66 after implementation of training items of emotional intelligence, which indicates the impact of training of emotional intelligence components on reduction of situational anxiety. The average score of situational anxiety of control group nurses was 46.73 before the intervention and it decreased to 45.70. In physicians, it was 38.33 before the intervention and it increased to 39.40 during post-test. However, t-test did not confirmed a statistically significant difference between the average score of situational anxiety of both case and control groups before the intervention, and there was a statistically significant difference between the average score of both case and control groups after training components of emotional intelligence (P = 0.000). CONCLUSION: Training emotional intelligence components reduces situational anxiety of nurses and physicians working in intensive care units and their emotional intelligence score increased and situational anxiety score was significantly reduced. PMID- 22259256 TI - Opioid rotation with extended-release opioids: where should we begin? AB - Opioid rotation is a common and necessary clinical practice in the management of chronic non-cancer pain to improve therapeutic efficacy with the lowest opioid dose. When dose escalations fail to achieve adequate analgesia or are associated with intolerable side effects, a trial of a new opioid should be considered. Much of the scientific rationale of opioid rotation is based on the wide interindividual variability in sensitivity to opioid analgesics and the novel patient response observed when introducing an opioid-tolerant patient to a new opioid. This article discusses patient indicators for opioid rotation, the conversion process between opioid medications, and additional practical considerations for increasing the effectiveness of opioid therapy during a trial of a new opioid. A Patient vignette that demonstrates a step-wise approach to opioid rotation is also presented. PMID- 22259257 TI - Invasive ductal carcinoma within fibroadenoma and lung metastases. AB - Fibroadenomas are one of the most common benign tumors of the breast. Malignant transformation from fibroadenoma to cancer is rare. We present a case of an invasive ductal carcinoma within an otherwise benign fibroadenoma with lung metastasis in a 69-year-old woman. PMID- 22259258 TI - Current state of glycemic control in critically ill subjects in a general intensive care unit. AB - Critically ill patients are predisposed to stress-induced hyperglycemia. Recent evidence suggests that uncontrolled hyperglycemia is associated with poor outcomes within the population of surgical and medical intensive care units. We retrospectively audited our practice in the management of hyperglycemia in the critically ill, in order to identify reasons and periods of time that deviations in blood glucose control are most likely, and to make recommendations on how to improve this. Our study showed poor compliance with the current recommendations for glycemic control in the critically ill and highlighted the need for a successful protocol for glycemic control in our institution. That should be carefully coordinated with the level of nutritional support and metabolic status of the acutely ill patient. PMID- 22259259 TI - Exploring UK attitudes towards unlicensed medicines use: a questionnaire-based study of members of the general public and physicians. AB - AIMS: To undertake a questionnaire-based study to evaluate attitudes towards the use of unlicensed medicines among prescribing doctors and members of the general public (ie, patients). The study also aimed to explore the factors that influence physicians' prescribing decisions and priorities, and to understand the knowledge of the medicines licensing system among members of the public. METHODS: Novartis Pharmaceuticals UK Ltd funded the online interview of 500 members of the general public and 249 prescribing physicians. Best practice standards were followed for questionnaire-based studies; no specific treatments or conditions were mentioned or discussed. RESULTS: Few of the participating physicians, only 14%, were very familiar with the UK General Medical Council (GMC) guidelines on the use of unlicensed medicines and just 17% felt very comfortable prescribing an unlicensed medication when a licensed alternative was available. Key physician concerns included the lack of safety data (76%), legal implications (76%), and safety monitoring associated with unlicensed medicine use (71%). Patients and physicians agreed that safety and efficacy are the most important prescribing considerations, although 48% of participating physicians were worried that budget pressures may increase pressure to prescribe unlicensed medications on the basis of cost. A high proportion of patients (81%) also indicated some degree of concern, were they to be prescribed an unlicensed medication when a licensed alternative was available specifically because it costs less. CONCLUSIONS: This UK-based questionnaire study suggests pervasive concerns among prescribers over the safety, monitoring, and legal implications of unlicensed prescribing. High levels of concern were expressed among patients and physicians if cost were to become an influential factor when making decisions between licensed and unlicensed medications. PMID- 22259260 TI - Factors predicting coronary sinus rupture following cannula insertion for retrograde cardioplegia. AB - BACKGROUND: Coronary sinus rupture (CSR) is a rare preventable complication of cannula insertion for retrograde cardioplegia. In the hands of an inexperienced surgeon, this complication has the risk of potential mortality and morbidity, and its repair is technically challenging. Techniques for repairing CSR have been reported previously. In this study, we determined predictors of CSR following coronary artery bypass graft (CABG) surgery. METHODS: Over a four-year period, we retrospectively analyzed 1500 patients in whom a retrograde coronary sinus catheter was used to administer cardioplegic solution. CSR occurred in 15 patients. (12 women and 3 men). Variables such as age, weight, body mass index, gender, aortic clamp time, pump time, cardiomegaly, ejection fraction, and number of grafts were determined for each patient. Factors correlated with CSR were analyzed using multiple regression analysis, and odd ratios of significant variables were determined. RESULTS: In multiple regression analysis, factors such as female gender, age, weight, and body mass index showed a significant correlation with CSR, and their odd ratios were 4.2, 1.0, 0.96, and 2.2, respectively. CONCLUSION: In all 15 cases, a retrograde cannula with a self inflatable balloon was used and 12 patients were woman with low body mass index. Forceful insertion due to coronary sinus web, fragility of arteries in thin patients, or a small coronary sinus caused CSR in the hands of an inexperienced surgeon. PMID- 22259263 TI - Alexandr Pavlovich Rasnitsyn, (palaeo)entomologist extraordinaire - a personal appreciation. PMID- 22259261 TI - Radiofrequency catheter ablation in children with supraventricular tachycardias: intermediate term follow up results. AB - THE PURPOSE OF THE STUDY: Radiofrequency (RF) catheter ablation represents an important advance in the management of children with cardiac arrhythmias and has rapidly become the standard and effective line of therapy for supraventricular tachycardias (SVTs) in pediatrics. The purpose of this study was to evaluate the intermediate term follow up results of radiofrequency catheter ablation in treatment of SVT in pediatric age group. METHODS: A total of 60 pediatric patients (mean age = 12.4 +/- 5.3 years, ranged from 3 years to 18 years; male: female = 37:23; mean body weight was 32.02 +/- 12.3 kg, ranged from 14 kg to 60 kg) with clinically documented SVT underwent an electrophysiologic study (EPS) and RF catheter ablation at Children's Hospital Mansoura University, Mansoura, Egypt during the period from January 2008 to December 2009 and they were followed up until October 2011. RESULTS: The arrhythmias included atrioventricular reentrant tachycardia (AVRT; n = 45, 75%), atrioventricular nodal reentrant tachycardia (AVNRT; n = 6, 10%), and atrial tachycardia (AT; n = 9, 15%). The success rate of the RF catheter ablation was 93.3% for AVRT, 66.7% for AVNRT, and 77.8% for AT, respectively. Procedure-related complications were infrequent (7/60, 11.7%), (atrial flutter during RF catheter ablation (4/60, 6.6%); ventricular fibrillation during RF catheter ablation (1/60, 1.6%); transient complete heart block during RF catheter ablation (2/60, 3.3%)). The recurrence rate was 8.3% (5/60) during a follow-up period of 34 +/- 12 months. CONCLUSION: RF catheter ablation is an effective and safe method to manage children with SVT. PMID- 22259262 TI - Achieving symptom control in patients with moderate asthma. AB - Disease severity in asthma can be classified as mild, moderate or severe based upon the frequency of symptoms or the severity of airflow obstruction. This review will focus on the treatment of youths greater than 12 years of age and adults with moderate persistent asthma. Moderate asthmatics may have daily symptoms that cause some limitation with normal daily activities and require use of a rescue inhaled short-acting beta(2)-agonist inhaler or experience nocturnal awakenings secondary to asthma that occur more than once per week. Furthermore, spirometry may reveal airflow obstruction with a reduction in FEV(1) to between 60% and 80% of predicted. Although inhaled corticosteroids (ICS) are the primary controller medication used to modify symptoms in moderate asthmatics, additional controller medications, such as inhaled long-acting beta(2)-agonists (LABA), leukotriene receptor antagonists (LTRA) or theophylline, are often needed to obtain optimal disease control. While the addition of an inhaled LABA to an ICS is very effective at improving disease control in moderate asthma, concerns have arisen over the safety of LABAs, in particular the risk of asthma-related death. Therefore, consideration may be given to initially adding a LTRA, rather than a LABA, to ICS when asthma symptoms are not adequately controlled by ICS alone. Furthermore, individualization of medication regimens, treatment of co-morbid conditions, and patient education are crucial to optimizing compliance with therapy, improving disease control, and reducing the risk of exacerbations. Lastly, the development of new asthma treatments, perhaps based upon personalized medicine, may revolutionize the future treatment of moderate asthma. PMID- 22259264 TI - Scientific contributions of Alexandr P. Rasnitsyn, 1959 to present. PMID- 22259265 TI - New Middle Permian palaeopteran insects from Lodeve Basin in southern France (Ephemeroptera, Diaphanopterodea, Megasecoptera). AB - Three new palaeopteran insects are described from the Middle Permian (Guadalupian) of Salagou Formation in the Lodeve Basin (South of France), viz. the diaphanopterodean Alexrasnitsyniidaefam. n., based on Alexrasnitsynia permianagen. etsp. n., the ParelmoidaePermelmoa magnificagen. etsp. n., and Lodevohymen lapeyrieigen. etsp. n. (in Megasecoptera or Diaphanopterodea, family undetermined). In addition the first record of mayflies attributed to family Syntonopteridae (Ephemeroptera) is reported. These new fossils clearly demonstrate that the present knowledge of the Permian insects remains very incomplete. They also confirm that the Lodeve entomofauna was highly diverse providing links to other Permian localities and also rather unique, with several families still not recorded in other contemporaneous outcrops. PMID- 22259266 TI - Rasnitsynala sigambrorum gen. et sp. n., a small odonatopterid ("Eomeganisoptera", "Erasipteridae") from the early Late Carboniferous of Hagen Vorhalle (Germany). AB - Besides Erasipteroides valentini (Brauckmann in Brauckmann, Koch & Kemper, 1985), Zessinella siope Brauckmann, 1988, and Namurotypus sippeli Brauckmann & Zessin, 1989, Rasnitsynala sigambrorumgen. et sp. n. is the fourth species of the Odonatoptera from the early Late Carboniferous (Early Pennsylvanian: Namurian B, Marsdenian) deposits of the important Hagen-Vorhalle Konservat-Lagerstatte in Germany. With its wing-span of about 55 mm it is unusually small even for the "Eomeganisoptera". Its venation resembles other small "Eomeganisoptera", in particular Zessinella siope. This is why it is here assigned to the probably paraphyletic "Erasipteridae" Carpenter, 1939. PMID- 22259267 TI - The diversity of Odonata and their endophytic ovipositions from the Upper Oligocene Fossillagerstatte of Rott (Rhineland, Germany). AB - A commented list of fossil Odonata from the Oligocene outcrop of Rott is given, together with descriptions of new traces of oviposition in plant tissues, very similar to ichnotaxa already known from the early Eocene Laguna del Hunco floras of Patagonia. The joint presences of odonatan larvae and traces of oviposition demonstrate the autochthony of these insects in the palaeolake of Rott, confirming the existence of a diverse and abundant aquatic entomofauna, a situation strikingly different to that in the contemporaneous Oligocene palaeolake of Cereste (France). PMID- 22259268 TI - The smallest Neoptera (Baryshnyalidae fam. n.) from Hagen-Vorhalle (early Late Carboniferous: Namurian B; Germany). AB - With Baryshnyala occultagen. et sp. n. (Baryshnyalidaefam. n.) we report a new small species from early Late Carboniferous (Pennsylvanian) deposits in Hagen Vorhalle. It differs in its unique venation pattern and small size from all other Neoptera known from this Lagerstatte and other contemporaneous locations worldwide. With an estimated wing length of <10 mm it is by far the smallest species of Neoptera from Hagen-Vorhalle and is less than half as long as Heterologopsis ruhrensis Brauckmann & Koch, 1982 (~25 mm). The specimen shows some relations to the earliest Holometabola and may date back the first appearance of holometaboly to the Namurian B (early Bashkirian: Marsdenian). The new species increases the paleo-biodiversity and span of inter-specific variability within the early Neoptera. It shows that very small and tiny specimens and species can easily be overlooked. PMID- 22259269 TI - Nobloedischia rasnitsyni, a new genus and species of Oedischiidae (Orthoptera) from the Lower Permian Wellington Formation of Oklahoma, USA. AB - Nobloedischia rasnitsynigen. et sp. n. (Oedischiidae) is described from the Lower Permian Wellington Formation of Noble County, Oklahoma. The genus is similar to both Petrelcana (Oedischiidae: Mezenoedischiinae) and Oedischia (Oedischiidae: Oedischiinae) and is left unplaced at the subfamily level. The new species is the twelfth Orthoptera species and the fourth species of Oedischiidae from these deposits. PMID- 22259270 TI - Review of the Permian family Permulidae nomen novum pro Aliculidae Storozhenko, 1997 (Grylloblattida). AB - A new replacement name Permulidaenom. n. is proposed for the Permian family Aliculidae Storozhenko, 1997 (Insecta: Grylloblattida). A review of Permulidae is given. All genera and species are redescribed and illustrated. A key to genera of Permulidae is given. New taxa of Permulidae are described: Permula edemskiisp. n., Sojanopermula rasnitsynisp. n., Kazanalicula reductagen. et sp. n., Mezenalicula connatagen. et sp. n., all from the Soyana locality (Middle Permian, Kazanian Stage; Arkhangelsk Region, Russia), and Mezenalicula conjunctasp. n. from the Isady locality (Upper Permian, Severodvinian Stage; Vologda Region, Russia). New combinations are proposed: Permula minor (Aristov, 2004), comb. n. for Sojanopermula minor Aristov, 2004; Permula tshekardensis (Aristov, 2004), comb. n. for Sojanopermula tshekardensis Aristov, 2004. A new genus Acropermulagen. n. (type species: Permula acra Kukalova, 1964, from the Lower Permian of Czech Republic) is established in the family Ideliidae. Neraphidia Novokshonov & Novokshonova, 1997 is transferred from Aliculidae to the order Eoblattida as a genus of uncertain taxonomic position inside this order. PMID- 22259271 TI - A new, enigmatic family for new genus and species of Polyneoptera from the Upper Permian of Russia. AB - Alexarasniidaefam. n. and Alexarasnia rossicagen. et sp. n. are described from the Upper Permian of European Russia. Systematic position of this enigmatic family within the infraclass Polyneoptera is unclear. PMID- 22259272 TI - New earwigs in mid-Cretaceous amber from Myanmar (Dermaptera, Neodermaptera). AB - Two new earwigs (Dermaptera) recently discovered in mid-Cretaceous (latest Albian) amber from Myanmar are described and figured. Astreptolabis ethirosomatiagen. et sp. n. is represented by a peculiar pygidicranoid female, assigned to a new subfamily, Astreptolabidinaesubfam. n., and differs from other protodermapterans in the structure of the head, pronotum, tegmina, and cercal forceps. Tytthodiplatys mecynocercusgen. et sp. n. is a distinctive form of first instar nymph of the Diplatyidae, the earliest record for this basal earwig family. The taxon can be distinguished from other Early Cretaceous nymphs by the structure of the head, antennae, legs, and most notably its filamentous and annulate cerci. The character affinities of these taxa among Neodermaptera are generally discussed as is the identity of an enigmatic 'earwig-like' species from the Jurassic of China. PMID- 22259273 TI - The oldest psyllipsocid booklice, in Lower Cretaceous amber from Lebanon (Psocodea, Trogiomorpha, Psocathropetae, Psyllipsocidae). AB - Libanopsyllipsocus alexanderasnitsynigen. et sp. n., of Psyllipsocidae is described and figured from the Lower Cretaceous amber of Lebanon. The position of the new taxon is discussed and the fossil is compared to other psyllipsocids. The species represents the earliest record of the family Psyllipsocidae. PMID- 22259274 TI - A new family of aphids (Hemiptera, Sternorrhyncha) from the Lower Cretaceous of Baissa, Transbaikalia. AB - The family Rasnitsynaphididaefam. n. has a unique combination of characters: 9 segmented antennae; rhinaria arranged in many transverse rows, surrounding the antennal segments; segment IX narrower than other segments of flagellum, always without rhinaria; cubitus branches separated; ovipositor present; siphuncular pores absent. The new family comprises the genus Rasnitsynaphisgen. n. with three species, Rasnitsynaphis ennearticulatasp. n., Rasnitsynaphis coniunctasp. n., and Rasnitsynaphis quadratasp. n., all from the Lower Cretaceous of Transbaikalia. PMID- 22259275 TI - A new genus and species of Dictyopharidae (Homoptera) from Rovno and Baltic amber based on nymphs. AB - Alicodoxa rasnitsynigen. et sp. n. (Dictyopharinae: Orthopagini) is described based on a nymph from Rovno amber; it also occurs in Baltic amber. A small additional wax plate dorsal to the large wax plate of abdominal tergites VI-VIII is first reported in this and other genera of Dictyopharidae. A lectotype is designated for Pseudophana reticulata Germar & Berendt, 1856 transferred to Protepiptera (Achilidae): Protepiptera reticulata (Germar & Berendt, 1856), comb. n. PMID- 22259276 TI - New shore bug (Hemiptera, Heteroptera, Saldidae) from the Early Cretaceous of China with phylogenetic analyses. AB - A new genus with a new species of Saldidae, Brevrimatus pulchalifergen. et sp. n., is described and illustrated. The fossil specimen was found from the Early Cretaceous Yixian Formation of Duolun County, Inner Mongolia, China. Phylogenetic analyses within Saldidae were performed, and the results indicate Brevrimatus pulchalifergen. et sp. n. should be assigned to the subfamily Chiloxanthinae. PMID- 22259277 TI - Two new species of Sinosmylites Hong (Neuroptera, Berothidae) from the Middle Jurassic of China, with notes on Mesoberothidae. AB - Two new species of the genus Sinosmylites Hong are described from the Middle Jurassic locality at Daohugou (Inner Mongolia, China): Sinosmylites fumosussp. n. and Sinosmylites rasnitsynisp. n. This is the oldest known occurrence of the family Berothidae. The berothid affinity of this genus is confirmed by examination of the hind wing venation characteristic of the family. The Late Triassic family Mesoberothidae may represent an early group of Berothidae. PMID- 22259278 TI - A new fossil silky lacewing genus (Neuroptera, Psychopsidae) from the Early Cretaceous Yixian Formation of China. AB - A new genus and species, Undulopsychopsis alexigen. et sp. n., is described from the Early CretaceousYixian Formation of western Liaoning Province, China. This genus is probably most closely related to the Asian Cretaceous genus Kagapsychops Fujiyama, 1978. The family affinity of Undulopsychopsisgen. n. is discussed. The genus is preliminarily assigned to Psychopsidae, although it shares some character states with Osmylopsychopidae (e.g., crossveins are very scarce; Rs1 and 1A are multi-branched). PMID- 22259279 TI - A new ground beetle (Carabidae, Protorabinae) from the Lower Cretaceous of Inner Mongolia, China. AB - Cretorabus rasnitsynisp. n., belonging to the extinct subfamily Protorabinae of Carabidae, was described based on a well-preserved specimen from the Lower Cretaceous Yixian Formation of Yangshuwanzi, Inner Mongolia. The diagnostic characters forCretorabus are revised, and the key to species of the genus was presented. The fossil record of Protorabinae was summarized. Sinocarabus Hong, 1982 and Obesofemoria Hong, 1982 cannot be attributed to Protorabinae. PMID- 22259280 TI - A long-living species of the hydrophiloid beetles: Helophorus sibiricus from the early Miocene deposits of Kartashevo (Siberia, Russia). AB - The recent hydrophiloid species Helophorus (Gephelophorus) sibiricus (Motschulsky, 1860) is recorded from the early Miocene deposits of Kartashevo assigned to the Ombinsk Formation. A detailed comparison with recent specimens allowed a confident identification of the fossil specimen, which is therefore the oldest record of a recent species for the Hydrophiloidea. The paleodistribution as well as recent distribution of the species is summarized, and the relevance of the fossil is discussed. In addition, the complex geological settings of the Kartashevo area are briefly summarized. PMID- 22259281 TI - Third contribution on Rovno amber silken fungus beetles: a new Eocene species of Cryptophagus (Coleoptera, Clavicornia, Cryptophagidae). AB - Cryptophagus alexagrestis Lyubarsky & Perkovsky, sp. n. is described based on a fossil inclusion in Late Eocene Rovno amber (Ukraine). The new species is similar to the extant Cryptophagus skalitzkyi Reitter and Cryptophagus dilutus Reitter, differing from the latter by having a very transverse, short and dilated 10th antennal segment, and from the former by the very elongate segments of the flagellum. PMID- 22259282 TI - The earliest Mesopsychidae and revision of the family Mesopanorpodidae (Mecoptera). AB - The family Mesopanorpodidae is revised. Most taxa referred to this family are not related to the type genus Mesopanorpodes Tillyard, 1918. The type species of the latter, Mesopanorpodes wianamattensis,is closely related to Mesopsyche Tillyard, 1917. Therefore Mesopanorpodes is transferred to Mesopsychidae Tillyard, 1917 (= Mesopanorpodidae Tillyard, 1918, syn. n.).The earliest Mesopsychidae are described from the Upper Permian of European Russia (Severodvinian; Isady locality, Vologda Province): Permopsyche issadensisgen. etsp. n. (type species) and Permopsyche rasnitsynisp. n. Two species described under Mesopanorpodes from the Upper Permian of Australia are also included into Permopsyche: Permopsyche belmontensis (Riek, 1953), comb. n., Permopsyche robustus (Riek, 1953) comb. n. The first pre-Triassic Mesopsyche, Mesopsyche incompletasp. n. is described from the uppermost Permian (the town of Vyazniki, Vladimir Province). Bittacopanorpa javorskii Zalessky, 1935 from the uppermost Permian or basal Triassic of Kuznetsk Basin is identified as a hindwing of Mesopsyche: Mesopsyche javorskii (Zalessky, 1935) comb. n. The origin, evolutionary history, and stratigraphic occurrence of Mesopsychidae are discussed. PMID- 22259283 TI - A new long-proboscid genus of Pseudopolycentropodidae (Mecoptera) from the Middle Jurassic of China and its plant-host specializations. AB - We describe a new genus and species of Mecoptera with siphonate mouthparts, Sinopolycentropus rasnitsynigen. et sp. n., assigned to the family Pseudopolycentropodidae Handlirsch, 1925. The specimen was collected from late Middle Jurassic nonmarine strata of the Jiulongshan Formation in Inner Mongolia, northeastern China. The new material provides additional evidence for an early diversification of pseudopolycentropodids that was ongoing during the Middle Jurassic. This diversity also adds to the variety of known pseudopolycentropodids with tubular proboscides that apparently fed on ovulate fluids produced by Mesozoic gymnosperms. PMID- 22259285 TI - New Chironomidae (Diptera) with elongate proboscises from the Late Jurassic of Mongolia. AB - Four new species of Chironomidae with well-developed elongate proboscises are described from a Late Jurassic site Shar Teg in SW Mongolia. These are named Cretaenne rasnicynisp. n., Podonomius blepharissp. n., Podonomius macromastixsp. n., ?Podonomius robustussp. n. PMID- 22259284 TI - Ptychoptera deleta Novak, 1877 from the Early Miocene of the Czech Republic: redescription of the first fossil attributed to Ptychopteridae (Diptera). AB - The first fossil that was described in Ptychopteridae, Ptychoptera deletaNovak, 1877 from the classical Early Miocene locality Mokrina (Krottensee) in western Bohemia is re-examined. The re-description of the holotype including a new line drawing and remarks summarizing the scarce fossil record of this group is provided. PMID- 22259286 TI - Palerasnitsynus gen. n. (Trichoptera, Psychomyiidae) from Burmese amber. AB - Palerasnitsynus ohlhoffigen. et sp. n. is described fromBurmese amber of late Albian (Lower Cretaceous) age. This is the first record of the family Psychomyiidae from Burmese amber, and the earliest fossil record of the family. The genus Palerasnitsynusgen. n. differs from all other known psychomyiid genera by the absence of fork III in the forewings. PMID- 22259287 TI - On the systematic position of Baltimartyria Skalski, 1995 and description of a new species from Baltic amber (Lepidoptera, Micropterigidae). AB - This paper describes a rare case of a male moth in Baltic amber in an excellent position for establishing a species. The moth represents the second species of the genus Baltimartyria Skalski, 1995, described herein as Baltimartyria rasnitsynisp. n. The detection of this new species prompts research on the systematic position of the genus within the family Micropterigidae. The genus was found to provide none of the apomorphic characters that would allow placement in one of the monophyletic lineages within the family. The genus is provisionally assigned to the "southern sabatincoid group", a weakly supported assemblage of Southern Hemisphere genera. The sister genus has still to be determined. Baltimartyria is the first North Hemisphere representative in this group. Some general aspects of historical biogeography relevant for the group are briefly discussed. PMID- 22259288 TI - Head capsule characters in the Hymenoptera and their phylogenetic implications. AB - The head capsule of a taxon sample of three outgroup and 86 ingroup taxa is examined for characters of possible phylogenetic significance within Hymenoptera. 21 morphological characters are illustrated and scored, and their character evolution explored by mapping them onto a phylogeny recently produced from a large morphological data set. Many of the characters are informative and display unambiguous changes. Most of the character support demonstrated is supportive at the superfamily or family level. In contrast, only few characters corroborate deeper nodes in the phylogeny of Hymenoptera. PMID- 22259289 TI - A molecular phylogeny of the Cephinae (Hymenoptera, Cephidae) based on mtDNA COI gene: a test of traditional classification. AB - Cephinae is traditionally divided into three tribes and about 24 genera based on morphology and host utilization. There has been no study testing the monophyly of taxa under a strict phylogenetic criterion. A molecular phylogeny of Cephinae based on a total of 68 sequences of mtDNA COI gene, representing seven genera of Cephinae, is reconstructed to test the traditional limits and relationships of taxa. Monophyly of the traditional tribes is not supported. Monophyly of the genera are largely supported except for Pachycephus. A few host shift events are suggested based on phylogenetic relationships among taxa. These results indicate that a more robust phylogeny is required for a more plausible conclusion. We also report two species of Cephus for the first time from Turkey. PMID- 22259290 TI - Lytopylus Forster (Hymenoptera, Braconidae, Agathidinae) species from Costa Rica, with an emphasis on specimens reared from caterpillars in Area de Conservacion Guanacaste. AB - Twelve species of Costa Rican Lytopylus are treated; these include all species reared from Lepidoptera caterpillars in Area de Conservacion Guanacaste, Costa Rica, over 32 years of caterpillar inventory, as well as two species recorded in the literature as occurring in Costa Rica. Ten new species are described, i.e., Lytopylus bradzlotnicki, Lytopylus colleenhitchcockae, Lytopylus gregburtoni, Lytopylus jessicadimauroae, Lytopylus jessiehillae, Lytopylus mingfangi, Lytopylus rebeccashapleyae, Lytopylus robpringlei, Lytopylus sandraberriosae, Lytopylus vaughntani. The following species are transferred to Lytopylus: Metriosoma flavicalcar Enderlein 1920 to Lytopylus flavicalcarcomb. n.; Bassus macadamiae Briceno and Sharkey 2000 to Lytopylus macadamiaecomb. n.; Metriosoma bicarinatum Enderlein 1920 to Lytopylus bicarinatumcomb. n.; Metriosoma brasiliense Enderlein 1920 to Lytopylus brasiliensecomb. n.; Bassus tayrona Campos 2007 to Lytopylus tayronacomb. n.; Microdus femoratus Cameron 1887 to Lytopylus femoratuscomb. n.; Microdus melanocephalus Cameron 1887 to Lytopylus melanocephaluscomb. n.; Bassus pastranai Blanchard 1952 to Lytopylus pastranaicomb. n.; Agathis nigrobalteata Cameron 1911 to Lytopylus nigrobalteatuscomb. n. Two keys to species of Lytopylus are presented, one interactive and the other static. PMID- 22259291 TI - New and revised maimetshid wasps from Cretaceous ambers (Hymenoptera, Maimetshidae). AB - New material of the wasp family Maimetshidae (Apocrita) is presented from four Cretaceous amber deposits - the Neocomian of Lebanon, the Early Albian of Spain, the latest Albian/earliest Cenomanian of France, and the Campanian of Canada. The new record from Canadian Cretaceous amber extends the temporal and paleogeographical range of the family. New material from France is assignable to Guyotemaimetsha enigmatica Perrichot et al. including the first females for the species, while a series of males and females from Spain are described and figured as Iberomaimetsha Ortega-Blanco, Perrichot & Engel, gen. n., with the two new species Iberomaimetsha rasnitsyni Ortega-Blanco, Perrichot & Engel, sp. n. and Iberomaimetsha nihtmara Ortega-Blanco, Delclos & Engel, sp. n.; a single female from Lebanon is described and figured as Ahiromaimetsha najlae Perrichot, Azar, Nel & Engel, gen. et sp. n., and a single male from Canada is described and figured as Ahstemiam cellula McKellar & Engel, gen. et sp. n. The taxa are compared with other maimetshids, a key to genera and species is given, and brief comments made on the family. PMID- 22259292 TI - A new species of the genus Disogmus Forster (Hymenoptera, Proctotrupoidea, Proctotrupidae) from the Eocene Rovno amber. AB - Disogmus rasnitsyni Kolyada & Perkovsky, sp. n. is described from a fossil inclusion of Late Eocene amber (Ukraine). The new species is most similar to Disogmus basalis (Thomson, 1857), in particular, in the shape of the tyloids and the general shortening of the segments of antennae, but distinctly differs from it and the other species of the genus by having tyloids on flagellar segments 2-4 compared to 3-6 and 4-7 in other species. PMID- 22259293 TI - A new genus of fossil Mymaridae (Hymenoptera) from Cretaceous amber and key to Cretaceous mymarid genera. AB - Myanmymar aresconoidesgen n., sp. n. is described from one female in Burmese amber, dated as about 100 my. It is similar to Arescon on wing features but is unique among Mymaridae in having distinctly segmented palpi. It is the fifth mymarid genus definitely referable to the Cretaceous period. A key to Cretaceous mymarid genera is presented and the features of Myanmymar are compared with the other Cretaceous and extant mymarid genera. PMID- 22259294 TI - Compression fossil Mymaridae (Hymenoptera) from Kishenehn oil shales, with description of two new genera and review of Tertiary amber genera. AB - Compression fossils of three genera and six species of Mymaridae (Hymenoptera: Chalcidoidea) are described from 46 million year old Kishenehn oil shales in Montana, USA. Two new genera are described: Eoeustochus Huber, gen. n., with two included species, Eoeustochus kishenehn Huber (type species) and Eoeustochus borchersi Huber, sp. n., and Eoanaphes, gen. n., with Eoanaphes stethynioides Huber, sp. n. Three new species of Gonatocerus are also described, Gonatocerus greenwalti Huber, sp. n. , Gonatocerus kootenai Huber, sp. n., and Gonatocerus rasnitsyni Huber, sp. n. Previously described amber fossil genera are discussed and five genera in Baltic amber are tentatively recorded as fossils: Anagroidea, Camptoptera, Dorya, Eustochus, and Mimalaptus. PMID- 22259295 TI - Revision of fossil species of Deinodryinus, with description of a new species (Hymenoptera, Dryinidae). AB - Deinodryinus veltenisp. n. is described from middle Eocene Baltic amber. The species differs from other fossil Palaearctic species of Deinodryinus Perkins owing to the shape of the antenna (clavate, with distal part very thickened), the large compound eyes, and the distal part of the stigmal vein much longer than the proximal part. A revision and a key to the fossil Palaearctic species of Deinodryinus Perkins, 1907 is presented. PMID- 22259296 TI - Revision of fossil species of Dryinus belonging to lamellatus group, with description of a new species (Hymenoptera, Dryinidae). AB - Dryinus rasnitsynisp. n. is described from amber collected in the Dominican Republic. A revision and a key to the fossil Neotropical species of Dryinus Latreille, 1804 belonging to the lamellatus species group is presented. PMID- 22259297 TI - A new Late Cretaceous family of Hymenoptera, and phylogeny of the Plumariidae and Chrysidoidea (Aculeata). AB - The taxonomic placement of an enigmatic species of wasp known from two specimens in Late Cretaceous New Jersey amber is investigated through cladistic analyses of 90 morphological characters for 33 terminals ranging across non-Aculeata, non Chrysidoidea, most subfamilies of Chrysidoidea and all genera of Plumariidae (the family to which the fossils were initially assigned), based on use of exemplars. The fossil taxon is apparently basal in Chrysidoidea, most likely sister to Plumariidae, but perhaps sister to the remaining chrysidoids, or even sister to Chrysidoidea as a whole. It is described as representing a new family, Plumalexiidaefam. n., containing a single species, Plumalexius rasnitsynigen. et sp. n. Previous estimates of relationships for the genera of Plumariidae and for the higher taxa of Chrysidoidea are mostly confirmed. The importance of outgroup choice, and additivity and weighting of characters are demonstrated. PMID- 22259298 TI - A comparison of the variation in Indian populations of pigeonpea cyst nematode, Heterodera cajani revealed by morphometric and AFLP analysis. AB - The cyst nematode Heterodera cajani is one of the major endemic diseases of pigeonpea, an important legume for food security and protein nutrition in India. It occurs in several pulse crops grown over a range of Indian agro climatic conditions but the extent of its intraspecific variation is inadequately defined. In view of this, 11 populations of Heterodera cajani were analyzed using morphometrics and the results correlated with those obtained from an AFLP approach using 24 primer pair combinations that amplified a total of 1278 AFLP markers. The cluster solution from this binary data indicated similarities for five populations that differed from those suggested by morphometrics. The differences obtained could not be related to geographic distance between populations. The data suggests that recent and long distance dispersal has occurred whose causes need to be defined to restrict further field introductions. Four AFLP primer pairs clustered the populations similarly to that generated using all 24 primer pairs. This simplified approach may provide a rapid basis for discriminating populations for their future management and help to check further distribution in agricultural trade. It may also have potential to determine differences in populations that relate to host range or virulence to resistance genes. PMID- 22259299 TI - First report of Xiphinema brevicolle Lordello et Costa, 1961 (Nematoda, Longidoridae) in Japan. AB - Mixed populations of Xiphinema americanum-group species were detected from a root zone soil sample of Japanese holly, Ilex crenata, during a survey for plant parasitic nematodes of commercial ornamental plant nurseries in Chiba Prefecture, Japan. From the result of the morphological study, the species were identified as Xiphinema brevicolle and Xiphinema sp. This is the first record of Xiphinema brevicolle in Japan. Morphometrics of Xiphinema brevicolle generally agree with those of the type specimens and the topotype specimens. Xiphinema sp. morphometrically resembles Xiphinema paramonovi except for tail length. The mitochondrial COI region, the nuclear 18S rDNA and the nuclear large subunit rDNA D2/D3 region of the species were sequenced and compared in the molecular study. For the COI region, PCR primers were newly designed to obtain longer sequences, ca. 900 bp, than previously used. Sequence identities of COI, 18S and D2/D3 regions between these two populations were 84.0-84.1%, 99.9% and 98.1-98.2%, respectively. Phylogenetic analyses of maximum likelihood trees were carried out to compare genetic relationships among the group and some suggestions were made on the Xiphinema brevicolle-subgroup. PMID- 22259300 TI - A review of Aleurodaphis (Hemiptera, Aphididae, Hormaphidinae) with the description of one new species and keys to species. AB - The genus Aleurodaphis van der Goot is reviewed. One new species Aleurodaphis sinojackiae Qiao & Jiang, sp. n. on Sinojackia xylocarpa from Jiangsu and Zhejiang, China is described. Aleurodaphis sinisalicis Zhang, 1982 is synonymised with Aleurodaphis blumeae van der Goot, 1917. Keys to species, morphological description and features of the new species, host plants, and distribution are provided. The specimens including types are deposited in British Natural History Museum, London (BMNH), Kogakkan University, Japan and the National Zoological Museum of China, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (NZMC). PMID- 22259301 TI - First record of Neolindus Scheerpeltz from French Guiana (Coleoptera, Staphylinidae, Paederinae), with a key to males. AB - The genus Neolindus Scheerpeltz, 1933, of the tribe Cylindroxystina Bierig, 1943, is recorded from French Guiana for the first time. Two new species, Neolindus irmlerisp. n. and Neolindus hermanisp. n., are described and illustrated. A key to males of Neolindus is provided. PMID- 22259302 TI - The genus Camptochaeta in Nearctic caves, with the description of C. prolixa sp. n. (Diptera, Sciaridae). AB - Camptochaeta prolixasp. n. (Diptera, Sciaridae) is described from caves in Nevada, and three other congeneric species are recorded from caves in Nevada and Arkansas, United States. The new species shows some indication to a subterranean mode of life, including long antenna and legs, and in some specimens, reduction of the eye bridge. PMID- 22259303 TI - Revision of Poliaspis (Hemiptera, Coccoidea, Diaspididae), with descriptions of 8 new species from Australia. AB - Eight new Australian species of Poliaspis are described and illustrated: Poliaspis alluviasp. n., Poliaspis araucariaesp. n., Poliaspis ceraflorasp. n., Poliaspis naambasp. n., Poliaspis nalbosp. n., Poliaspis narungga sp. n., Poliaspis ozothamnaesp. n., and Poliaspis waibenensissp. n. Two described species are transferred into Poliaspis and are redescribed and illustrated: Lineaspis callitris (Laing) originally described by Laing as a species of Poliaspis, is transferred back into Poliaspis as Poliaspis callitris Laing, comb. rev., and Leonardaspis wilga (Leonardi) is transferred to Poliaspis as Poliaspis wilga (Leonardi), comb. n. Descriptions and illustrations are also provided for six of the fourteen previously-named Poliaspis species, including five from Australia: Poliaspis attenuata Brimblecombe, Poliaspis elongata Brimblecombe, Poliaspis exocarpi Maskell, Poliaspis nitens Fuller, and Poliaspis syringae Laing. Both Poliaspis cycadis Comstock and Poliaspis gaultheriae Green become junior synonyms of Poliaspis media Maskell. The species not treated here are Poliaspis intermedia Fuller (the location of the types is unknown and Fuller's description is inadequate), Poliaspis casuarinicola Lindinger (missing types), Poliaspis incisa Takagi and de Faveri (recently, and well described in Takagi and de Faveri 2011), and the six New Zealand species recently revised by Henderson (2011). In addition, Laingaspis lanigera (Laing), the adult female of which has 8 clusters of perivulvar pores - as in Poliaspis species - is redescribed and illustrated. Lectotypes are designated for Laingaspis lanigera, Poliaspis callitris, Poliaspis exocarpi, Poliaspis media, and Poliaspis wilga. A key is provided to the species of Poliaspis, excluding Poliaspis casuarinicola and Poliaspis intermedia butincluding Poliaspis incisa and the New Zealand species: Poliaspis chathamica Henderson, Poliaspis floccosa Henderson, Poliaspis lactea (Maskell), Poliaspis media Maskell, Poliaspis raouliae Henderson and Poliaspis salicornicola Henderson. PMID- 22259304 TI - Six new species of Acomoptera from North America (Diptera, Mycetophilidae). AB - Six new species are described, raising the number of North American Acomoptera species to seven and the genus total to ten, and nearly doubling the number of species within the putative clade containing Acomoptera, Drepanocercus, and Paratinia. These novel species forms have implications for the concept of Acomoptera that in turn, may impact our understanding of its generic relationships and the evolution and composition of Gnoristinae and Sciophilinae. The new species, Acomoptera crispa, Acomoptera digitata, Acomoptera echinosa, Acomoptera forculata, Acomoptera nelsoni,and Acomoptera vockerothi, are compared with the type species of the genus, Acomoptera plexipus (Garrett), whose diagnostic features are imaged and illustrated for the first time. The European species, Acomoptera difficilis (Dziedzicki) is also illustrated and compared. Acomoptera spinistyla (Soli) comb. n. is transferred from Drepanocercus. A key to species is provided. Future work will seek to incorporate this knowledge into a systematic phylogenetic study of relationships between these species and their sister taxa. PMID- 22259305 TI - First record of Acaenitinae (Hymenoptera, Ichneumonidae) from South America with description of a new species and a key to the world species of Arotes Gravenhorst. AB - A new species of Acaenitinae, Arotes ucumari Castillo & Saaksjarvi, sp. n., is described and illustrated representing the first record of the subfamily from South America. The new species was collected from a premontane tropical rain forest in the Peruvian Andes at 1500 m. A key to the world species of Arotes Gravenhorst,1829 is provided. The subspecies Arotes albicinctus moiwanus (Matsumura, 1912)is raised to species rank, Arotes moiwanusstat. n. PMID- 22259306 TI - A survey of East Mediterranean Dasumia (Araneae, Dysderidae) with description of new species. AB - Dasumia gasparoisp. n. isdescribed based on specimens of both sexes. The new species is compared with the similar Dasumia crassipalpis (Simon, 1882), described from Syria; and with Dasumia mariandyna Brignoli, 1979, the only previously known species of the genusrecordedfrom Turkey. Furthermore, we point out that, due to some contradictions to the original description of the genus, Dasumia mariandyna may necessarily belong to another genus. Detailed morphological descriptions, diagnosis and figures of the copulatory organs of the new species are presented. PMID- 22259307 TI - Three species of land leeches from Taiwan, Haemadipsa rjukjuana comb. n., a new record for Haemadipsa picta Moore, and an updated description of Tritetrabdella taiwana (Oka). AB - Three species of land leeches, including a new combination Haemadipsa rjukjuanacomb. n., a new record for Haemadipsa picta Moore, as well as an updated description for Tritetrabdella taiwana (Oka), are reported in this study. Morphological characters and DNA barcode analysis were used to identify these species. In addition, since Haemadipsa rjukjuana had been regarded as a variety of the Japanese land leech Haemadipsa japonica for a century, morphological differences between these two species were also compared. PMID- 22259308 TI - A key to species of the genus Gastroserica Brenske of the China (Coleoptera, Scarabaeidae, Sericini), with the description of two new species and two new records for China. AB - Based on a revision of the material housed in Chinese collections and a key to species of Gastroserica of China is provided. Two new species are described, habitus photographs, and illustrations of the genitalia are given: Gastroserica nigrofasciatasp. n. (from China: Guangxi and Guizhou Prov.), Gastroserica yunnanensissp. n. (from China: Yunnan Prov.). Besides, illustrations of the genitalia of species mentioned in the key are provided. Additional distribution records of the Gastroserica species including an updated distribution map are given. PMID- 22259309 TI - A review of Biston Leach, 1815 (Lepidoptera, Geometridae, Ennominae) from China, with description of one new species. AB - The genus Biston Leach, 1815 is reviewed for China. Seventeen species are recognized, of which Biston mediolatasp. n. is described. Biston pustulata (Warren, 1896) and Biston panterinariaexanthemata (Moore, 1888) are newly recorded for China. The following new synonyms are established: Biston suppressaria suppressaria (Guenee, 1858) (= Biston suppressaria benescripta (Prout, 1915), syn. n. = Biston luculentus Inoue, 1992 syn. n.); Biston falcata (Warren, 1893) (= Amphidasiserilda Oberthur, 1910, syn. n. = Amphidasis clorinda Oberthur, 1910, syn. n. = Biston emarginaria Leech, 1897, syn. n.); Biston panterinaria panterinaria (Bremer & Grey, 1853) (= Biston panterinaria abraxata (Leech, 1889), syn. n. = Biston panterinaria lienpingensis (Wehrli, 1939), syn. n. = B. panterinaria szechuanensis (Wehrli, 1939), syn. n.). Biston falcata satura (Wehrli,1941), comb. n. is proposed. A key to Chinese Biston and diagnoses for Chinese species are provided. Illustrations of external features and genitalia are presented. PMID- 22259310 TI - Acquiring Non-Object Terms: The Case for Time Words. AB - We address the issue of children's understanding of abstract words with two studies on preschoolers' knowledge of the time-duration words minutes, hours, days, and years. The first study examines 4- and 5-year-olds' ability to answer questions about durations of common phenomena with duration terms. The second study examines 4- to 6-year-olds' comprehension of duration terms with a forced choice pointing task. Both show that preschoolers' knowledge of such words is incomplete, but that it adheres to the pattern proposed in previous work with toddlers for abstract words. More specifically, children form lexical domains for such words even before they know their individual meanings, thereby allowing the children to often respond appropriately but not usually correctly to questions about abstract dimensions like time. PMID- 22259311 TI - Redetermination of LaZn(5) based on single crystal X-ray diffraction data. AB - The crystal structure of the already known binary title compound LaZn(5) (lanthanum penta-zinc) (space group P6/mmm, Pearson symbol hP6, CaCu(5) structure type) has been redetermined from single-crystal X-ray diffraction data. In contrast to previous determinations based on X-ray powder data [Nowotny (1942). Z. Metallkd.34, 247-253; de Negri et al. (2008). Inter-metallics, 16, 168-178], where unit-cell parameters and assignment of the structure type were reported, the present study reveals anisotropic displacement parameters for all atoms. The crystal structure consists of three crytallographically distinct atoms. The La atom (Wyckoff site 1a, site symmetry 6/mmm) is surrounded by 18 Zn atoms and two La atoms. The coordination polyhedron around one of the Zn atoms (Wyckoff site 2c, site symmetry -6m2) is an icosa-hedron made up from three La and nine Zn atoms. The other Zn atom (Wyckoff site 3g, site symmetry mmm) is surrounded by four La and eight Zn atoms. Bonding between atoms is explored by means of the TB LMTO-ASA (tight-binding linear muffin-tin orbital atomic spheres approximation) program package. The positive charge density is localized around La atoms, and the negative charge density is around Zn atoms, with weak covalent bonding between the latter. PMID- 22259312 TI - Cs(3)Sm(7)Se(12). AB - The title compound, tricaesium hepta-samarium(III) dodeca-selenide, is setting a new starting point for realization of the channel structure of the Cs(3)M(7)Se(12) series, now with M = Sm, Gd-Er. This Cs(3)Y(7)Se(12)-type arrangement is structurally based on the Z-type sesquiselenides M(2)Se(3) adopting the Sc(2)S(3) structure. Thus, the structural set-up of Cs(3)Sm(7)Se(12) consists of edge- and vertex-connected [SmSe(6)](9-) octa-hedra [d(O)(Sm(3+) - Se(2-)) = 2.931 A], forming a rock-salt-related network [Sm(7)Se(12)](3-) with channels along [001] that are apt to take up monovalent cations (here Cs(+)) with coordination numbers of 7 + 1 for one and of 6 for the second cation. The latter cation has a trigonal-prismatic coordination and shows half-occupancy, resulting in an impossible short distance [2.394 (4) A] between symmetrically coupled Cs(+) cations of the same kind. While one Sm atom occupies Wyckoff position 2b with site symmetry ..2/m, all other 11 crystallographically different atoms (namely 2 * Cs, 3 * Sm and 6 * Se) are located at Wyckoff positions 4g with site symmetry ..m. PMID- 22259313 TI - Silver diaquacobalt(II) catena-borodiphosphate(V) hydrate, (Ag(0.79)Co(0.11))Co(H(2)O)(2)[BP(2)O(8)].0.67H(2)O. AB - The structure of the title compound, (Ag(0.79)Co(0.11))Co(H(2)O)(2)[BP(2)O(8)].0.67H(2)O is isotypic to that of its recently published counterparts AgMg(H(2)O)(2)[BP(2)O(8)].H(2)O and (Ag(0.57)Ni(0.22))Ni(H(2)O)(2)[BP(2)O(8)].0.67H(2)O. It consists of infinite borophos-phate helical ribbons [BP(2)O(8)](3-), built up from alternate BO(4) and PO(4) tetra-hedra arranged around the 6(5) screw axes. The vertex-sharing BO(4) and PO(4) tetra-hedra form a spiral ribbon of four-membred rings in which BO(4) and PO(4) groups alternate. The ribbons are connected through slightly distorted CoO(4)(H(2)O)(2) octa-hedra whose four O atoms belong to the phosphate groups. The resulting three-dimensional framework is characterized by hexa-gonal channels running along [001] in which the remaining water mol-ecules are located. The main difference between the Mg-containing and the title structure lies in the filling ratio of Wyckoff positions 6a and 6b in the tunnels. The refinement of the occupancy rate of the site 6a shows that it is occupied by water at 67%, while the refinement of that of the site 6b shows that this site is partially occupied by 78.4% Ag and 10.8% Co, for a total of 82.2%. The structure is stabilized by O H?O hydrogen bonds between water mol-ecules and O atoms that are part of the helices. PMID- 22259314 TI - An ammonium iron(II) pyrophosphate, (NH(4))(2)[Fe(3)(P(2)O(7))(2)(H(2)O)(2)], with a layered structure. AB - Diammonium diaquabis(phosphato)triferrate(II), (NH(4))(2)[Fe(3)(P(2)O(7))(2)(H(2)O)(2)], was synthesized under solvo-thermal conditions at 463 K. The crystal structure, isotypic to its Mn and Ni analogues, is built from iron pyrophosphate layers parallel to (100), which are linked by ammonium ions sitting in the inter-layer space via O-H?O and N-H?O hydrogen bonds. There are two crystallographic Fe sites in the crystal structure, one at a special position (2a, [Formula: see text]), the other at a general position (4e, 1). The former Fe atom on the inversion centre is coordinated by six O atoms, forming an FeO(6) octa-hedron, while the latter is coordinated by five phosphate O atoms and one water mol-ecule, forming an FeO(5)(H(2)O) octa-hedron. Each FeO(6) octa-hedron shares trans edges with two FeO(5)(H(2)O) octa-hedra, forming a linear trimeric unit. These trimers share the lateral edges of FeO(5)(H(2)O) with other trimers, forming a zigzag chain running along [010]. The zigzag chains are further linked by P(2)O(7) groups into a layered structure parallel to (100). PMID- 22259315 TI - Pyrosmalite-(Fe), Fe(8)Si(6)O(15)(OH,Cl)(10). AB - Pyrosmalite-(Fe), ideally Fe(II) (8)Si(6)O(15)(OH,Cl)(10) [refined composition in this study: Fe(8)Si(6)O(15)(OH(0.814)Cl(0.186))(10).0.45H(2)O, octa-iron(II) hexa silicate deca-(chloride/hydroxide) 0.45-hydrate], is a phyllosilicate mineral and a member of the pyrosmalite series (Fe,Mn)(8)Si(6)O(15)(OH,Cl)(10), which includes pyrosmalite-(Mn), as well as friedelite and mcgillite, two polytypes of pyrosmalite-(Mn). This study presents the first structure determination of pyrosmalite-(Fe) based on single-crystal X-ray diffraction data from a natural sample from Burguillos del Cerro, Badajos, Spain. Pyrosmalite-(Fe) is isotypic with pyrosmalite-(Mn) and its structure is characterized by a stacking of brucite type layers of FeO(6)-octa-hedra alternating with sheets of SiO(4) tetra-hedra along [001]. These sheets consist of 12-, six- and four-membered rings of tetra hedra in a 1:2:3 ratio. In contrast to previous studies on pyrosmalite-(Mn), which all assumed that Cl and one of the four OH-groups occupy the same site, our data on pyrosmalite-(Fe) revealed a split-site structure model with Cl and OH occupying distinct sites. Furthermore, our study appears to suggest the presence of disordered structural water in pyrosmalite-(Fe), consistent with infrared spectroscopic data measured from the same sample. Weak hydrogen bonding between the ordered OH-groups that are part of the brucite-type layers and the terminal silicate O atoms is present. PMID- 22259316 TI - Lotharmeyerite, Ca(Zn,Mn)(2)(AsO(4))(2)(H(2)O,OH)(2). AB - Lotharmeyerite, calcium bis-(zinc/manganese) bis-(arsenate) bis (hydroxide/hydrate), Ca(Zn,Mn(3+))(2)(AsO(4))(2)(H(2)O,OH)(2), is a member of the natrochalcite group of minerals, which are characterized by the general formula AM(2)(XO(4))(2)(H(2)O,OH)(2), where A may be occupied by Pb(2+), Ca(2+), Na(+), and Bi(3+), M by Fe(3+), Mn(3+), Cu(2+), Zn(2+), Co(2+), Ni(2+), Al(3+), and Mg(2+), and X by P(V), As(V), V(V), and S(VI). The minerals in the group display either monoclinic or triclinic symmetry, depending on the ordering of chemical components in the M site. Based on single-crystal X-ray diffraction data of a sample from the type locality, Mapimi, Durango, Mexico, this study presents the first structure determination of lotharmeyerite. Lotharmeyerite is isostructural with natrochalcite and tsumcorite. The structure is composed of rutile-type chains of edge-shared MO(6) octa-hedra (site symmetry [Formula: see text]) extending along [010], which are inter-connected by XO(4) tetra-hedra (site symmetry 2) and hydrogen bonds to form [M(2)(XO(4))(2)(OH,H(2)O)(2)] sheets parallel to (001). These sheets are linked by the larger A cations (site symmetry 2/m), as well as by hydrogen bonds. Bond-valence sums for the M cation, calculated with the parameters for Mn(3+) and Mn(2+) are 2.72 and 2.94 v.u., respectively, consistent with the occupation of the M site by Mn(3+). Two distinct hydrogen bonds are present, one with O?O = 2.610 (4) A and the other O?O = 2.595 (3) A. One of the H-atom positions is disordered over two sites with 50% occupancy, in agreement with observations for other natrochalcite-type minerals, such as natrochalcite and tsumcorite. PMID- 22259317 TI - cis-Bis(2,2'-bipyrimidine-kappaN,N)di-iodidomanganese(II). AB - The asymmetric unit of the title complex, [MnI(2)(C(8)H(6)N(4))(2)], contains one half of a neutral Mn(II) complex, with the entire molecule completed by the application of twofold symmetry. The Mn(II) ion is six-coordinated in a distorted octa-hedral environment defined by four N atoms of the two chelating 2,2' bipyrimidine (bpym) ligands and two I(-) anions in a cis-N(4)I(2) coordination geometry. The dihedral angle between the least-squares planes of the two bpym ligands (r.m.s deviation for all non-H atoms = 0.063 A) is 85.04 (6) degrees . In the crystal, complex mol-ecules are connected by C-H?N and C-H?I hydrogen bonds, forming a three-dimensional network. Mol-ecules are stacked in columns along the a axis. Along the c axis, successive mol-ecules stack in the opposite directions. PMID- 22259318 TI - Tetra-aqua-bis-[4-(4H-1,2,4-triazol-4-yl)benzoato-kappaN]nickel(II) deca-hydrate. AB - In the title compound, [Ni(C(9)H(6)N(3)O(2))(2)(H(2)O)(4)].10H(2)O, the Ni(II) ion lies on a twofold rotation axis and displays a slightly distorted octa-hedral geometry defined by two N atoms from two monodentate 4-(1,2,4-triazol-4 yl)benzoate ligands and four water mol-ecules, two of which also lie on the twofold rotation axis. In the crystal, the complex mol-ecules and uncoordinated water mol-ecules are linked via inter-molecular O-H?N and O-H?O hydrogen bonds, forming a three-dimensional supra-molecular network. pi-pi inter-actions between the benzene rings provide additional stability of the crystal packing [centroid centroid distance = 3.792 (2) A]. PMID- 22259319 TI - Bis[2-(1-imino-eth-yl)phenolato-kappaN,O]nickel(II). AB - There are one and a half independent mol-ecules in the asymmetric unit of the title compound, [Ni(C(8)H(8)NO)(2)], one of which is situated on an inversion center. In both mol-ecules, the Ni(II) ion is coordinated by two O and two N atoms from two Schiff base ligands in an approximate square-planar geometry. Inter-molecular N-H?O hydrogen bonds link three mol-ecules into centrosymmetric trimer. The crystal packing exhibits weak inter-molecular C-H?O hydrogen bonds and voids of 37 A(3). PMID- 22259320 TI - Bis(MU-N-benzyl-N-furfuryldithio-carbamato)-1:2kappaS,S':S';2:1kappaS,S':S'-bis [(N-benzyl-N-furfuryldithio-carbamato-kappaS,S')cadmium]. AB - In the centrosymmetric title compound, [Cd(2)(C(13)H(12)NOS(2))(4)], pairs of dithio-carbamate ligands exhibit different structural functions. Each of the terminal ligands is bidentately coordinated to one Cd(II) atom and forms a planar four-membered CS(2)Cd chelate ring, whereas pairs of the tridentate bridging ligands link two neighbouring Cd(II) atoms, forming extended eight-membered C(2)S(4)Cd(2) tricyclic units whose geometry can be approximated by a chair conformation. The coordination polyhedron of the Cd(II) atoms is a distorted square-pyramid. The five-membered furan ring and the benzene ring are disordered over two sets of sites with an occupancy ratio of 0.62 (8):0.38 (8). PMID- 22259321 TI - trans-Dichloridobis[dicyclo-hex-yl(4-isopropyl-phen-yl)phosphane kappaP]platinum(II) acetone monosolvate. AB - The title compound, [PtCl(2)(C(21)H(33)P)(2)].C(3)H(6)O, crystallizes with an accompanying acetone solvent mol-ecule. The metal atom shows a distorted square planar coordination environment, with a P-Pt-P angle of 172.41 (3) degrees as the most prominent feature. Both isopropyl fragments were treated as disordered over two conformations with occupancy ratios of 0.55 (2):0.45 (2) and 0.58 (2):0.42 (2). The solvent mol-ecule was also disordered over two orientations in a 1:1 ratio. The crystal studied was a non-merohedral twin with a twin component of 32.4%. PMID- 22259322 TI - Aqua-(3-fluoro-benzoato-kappaO)(3-fluoro-benzoato-kappaO,O')(1,10-phenanthroline kappaN,N')cobalt(II). AB - In the title compound, [Co(C(7)H(4)FO(2))(2)(C(12)H(8)N(2))(H(2)O)], the Co(II) ion is coordinated by two O atoms from one 3-fluoro-benzoate (fb) ligand and one O atom from another fb ligand, two N atoms from the 1,10-phenanthroline ligand and a water mol-ecule in a distorted octa-hedral geometry. An intra-molecular O H?O hydrogen bond occurs. Inter-molecular O-H?O hydrogen bonds link pairs of mol ecules into centrosymmetric dimers. Weak inter-molecular C-H?O and C-H?F hydrogen bonds and pi-pi inter-actions between the aromatic rings [shortest centroid centroid distance = 3.4962 (2) A] further stabilize the crystal packing. PMID- 22259323 TI - 2-Bromo-1,3-diisopropyl-4,5-dimethyl-1H-imidazol-3-ium dicyanidoargentate. AB - The title structure, (C(11)H(20)BrN(2))[Ag(CN)(2))], is built up from an approximately C(2v)-symmetric imidazolium cation and a nearly linear dicyanidoargentate anion [N-Ag-N = 176.6 (9) degrees and Ag-C-N = 178.8 (9) and 177.2 (11) degrees ]. These two constituents are linked by a remarkably short inter-action between the Br atom of the imidazolium cation [C-Br = 1.85 (3) A] and one N atom of the cyanidoargentate anion [Br?N = 2.96 (2) A], which is much less than the sum of the van der Waals radii (3.40 A). The crystal studied was twinned by merohedry. PMID- 22259324 TI - Bis(MU-di-2-pyridyl disulfide-kappaN,S:N')di-MU(3)-iodido-di-MU(2)-iodido-tetra copper(I). AB - In the centrosymmetric tetra-nuclear title compound, [Cu(4)I(4)(C(10)H(8)N(2)S(2))(2)], there are two different Cu(I) atoms with tetra hedral coordination geometries. One is chelated by a pyridine N atom and an S donor from one di-2-pyridyl disulfide ligand and coordinated by two I atoms, while the second Cu(I) atom is coordinated by a pyridine-N and three I atoms. Iodine bridges between the Cu(I) atoms form a tetra-nuclear structure. PMID- 22259325 TI - catena-Poly[1-[(2-fluoro-benzyl-idene)amino]-quinolinium [plumbate(II)-tri-MU iodido]]. AB - The title complex, {(C(16)H(12)FN(2))[PbI(3)]}(n), consists of 1-[(2-fluoro benzyl-idene)amino]-quinolinium cations and a polymeric PbI(3) (-) anion formed by face-sharing PbI(6) octa-hedra. These octa-hedra form straight and regular infinite chains along the b axis. In the asymmetric unit, one cation and one anionic [PbI(3)](-) fragment are observed in general positions. Polymeric chains are produced by the glide plane perpendicular to the a axis. PMID- 22259326 TI - Bis(formato-kappaO)bis-[1-(pyridin-2-yl)ethanone oxime-kappaN,N']nickel(II). AB - In the title compound, [Ni(HCOO)(2)(C(7)H(8)N(2)O)(2)], the Ni atom is six coordinated by four N atoms from two oxime ligands and by two O atoms from two formate ions in a distorted octa-hedral geometry, with the oxime-N atoms mutually trans. The mol-ecular conformation is stabilized by intra-molecular O-H?O hydrogen bonds. PMID- 22259327 TI - Chloridobis(dimethyl-glyoximato-kappaN,N')(ethyl pyridine-3-carboxyl-ate kappaN)cobalt(III). AB - In the title compound, [Co(C(4)H(7)N(2)O(2))(2)Cl(C(8)H(9)NO(2))], which was prepared as a model complex of vitamin B(12), the Co(III) atom, which is linked to four N atoms of the pseudo-macrocyclic (dmgH)(2) ligand (dmgH is dimethyl glyoximate) in the equatorial plane and one Cl(-) anion and one N atom of ethyl nicotinate in apical positions, displays an approximately octa-hedral coordination. The Co atom is 0.0187 (8) A out of the mean plane of the four equatorial N atoms. The structure has an O?H?O bridge, which is very common in cobaloxime derivatives, with O?H distances of 1.24 (2) and 1.25 (2) A. PMID- 22259328 TI - Poly[[hexa-aqua-(MU(2)-oxalato-kappaO,O:O,O)bis(MU(3)-pyridine-2,4-dicarboxyl-ato kappaN,O:O:O)dicerium(III)] monohydrate]. AB - In the polymeric title compound, {[Ce(2)(C(7)H(3)NO(4))(2)(C(2)O(4))(H(2)O)(6)].H(2)O}(n), the Ce(3+) cation is nine-coordinated in a distorted CeNO(8) tricapped trigonal-prismatic geometry, formed by three pyridine-2,4-dicarboxyl-ate anions, one oxalate anion and three water mol-ecules. The mid-point of the oxalate anion is located on an inversion center. The oxalate and pyridine-2,4-dicarboxyl-ate anions bridge the Ce(3+) cations, forming a two-dimensional polymeric complex parallel to (010). Inter molecular classical O-H?O hydrogen bonding and weak C-H?O hydrogen bonding are present in the crystal structure and pi-pi stacking [centroid-centroid distance = 3.558 (2) A] is observed between parallel pyridine rings of adjacent mol-ecules. The uncoordinated water mol-ecule shows an occupancy of 0.5. PMID- 22259329 TI - (12,17-Dieth-oxy-carbonyl-11,18-dimethyl-2,3:6,7-dibutano corrphycenato)copper(II)-12,17-dieth-oxy-carbonyl-11,18-dimethyl-2:3,6:7-dibutano corrphycene (3/97). AB - The corrphycene mol-ecule of the title compound, [Cu(C(36)H(36)N(4)O(4))](0.034).0.966C(36)H(38)N(4)O(4), has an essentially planar macrocyclic framwork with a slightly distorted trapezoidal N(4) core; the r.m.s. deviation of the peripheral 20 C atoms and four N atoms is 0.054 (3) A. The surface area within the N(4)-coordinating core (8.358 A(2)) is significantly smaller than that (8.503 A(2)) of the corresponding free-base porphyrin. Two intra-molecular N-H?N hydrogen bonds are observed. Detailed structure analysis clarified that the co-crystallization of the free-base corrphycene together with a quite minor component (ca 3%) of corrphycenato-Cu(II) occurred in the recrystallization process. PMID- 22259330 TI - trans-Tetra-aqua-bis-[bis-(pyridin-3-yl)methanone-kappaN]manganese(II) bis (perchlorate). AB - In the title complex, [Mn(C(11)H(8)N(2)O)(2)(H(2)O)(4)](ClO(4))(2), the Mn(2+) ion is located on an inversion center with the slightly distorted N(2)O(4) octa hedral coordination sphere comprising N-atom donors from two monodentate trans related bis-(pyridin-3-yl)methanone ligands and four water ligands. The two perchlorate anions are linked to the mononuclear complex mol-ecule through water O-H?O hydrogen bonds while inter-complex water O-H?N(pyridine) inter-actions form an infinite chain structure extending along the b axis. The perchlorate anions also function as inter-unit links through water O-H?O hydrogen bonds which, together with water O-H?O(carbon-yl) inter-actions, give a three-dimensional framework structure. PMID- 22259331 TI - Di-MU-oxido-bis-[(2-eth-oxy-6-{[2-(2-hy-droxy-ethyl-amino)-ethyl-imino]-meth yl}phenolato-kappaN,N',O)oxidovanadium(V)]. AB - In the title centrosymmetric dinuclear dioxidovanadium(V) complex, [V(2)(C(13)H(19)N(2)O(3))(2)O(4)], the V(V) ion is coordinated by an N,N',O tridendate 2-eth-oxy-6-{[2-(2-hy-droxy-ethyl-amino)-ethyl-imino]-meth yl}phenolate ligand and three oxide O atoms, forming a distorted cis-VN(2)O(4) octa-hedral geometry. The bridging O atoms show one short and one long bond to their two attached V(V) atoms. The dihedral angle between the benzene ring of the ligand and the V(2)O(2) plane is 75.2 (3) degrees . The deviation of the V(V) ion from the plane defined by the three donor atoms of the tridentate ligand and one bridging oxide O atom is 0.337 (2) A towards the terminal oxide O atom. Two N-H?O hydrogen bonds help to establish the conformation of the dimer. In the crystal, the complex mol-ecules are linked by O-H?O hydrogen bonds, forming [100] chains. PMID- 22259332 TI - Poly[[diaquabis(MU(2)-4,4'-bipyridyl)iron(II)] bis{2-[(3-carboxypyridin-2 yl)disulfanyl]nicotinate}]. AB - In the title compound, {[Fe(C(10)H(8)N(2))(2)(H(2)O)(2)](C(12)H(7)N(2)O(4)S(2))(2)}(n), synthesized by hydro-thermal reaction, the 4,4'-bipyridyl ligands (one with symmetry 2, one with symmetry [Formula: see text]) connect Fe(2+) cations, forming a cationic layer parallel to (001). The coordination of the Fe(2+) cation (site symmetry 2) is octahedral, with four N atoms from four 4,4'-bipyridyl ligands and O atoms from two trans water molecules. Adjacent layers are linked with each other by inter molecular O-H?O hydrogen bonds, forming a three-dimensional supra-molecular structure. Parts of the nicotinic acid derivative are equally disordered over two sets of sites. PMID- 22259333 TI - Aqua-bis-(1,1,1,5,5,5-hexa-fluoro-acetyl-acetonato)[4'-(4-pyrid-yl)-2,2':6',2'' terpyridine]-ytterbium(III) chloride methanol monosolvate monohydrate. AB - The title compound, [Yb(C(5)HF(6)O(2))(2)(C(20)H(14)N(4))(H(2)O)]Cl.CH(3)OH.H(2)O, adopts an eight coordinated geometry around the Yb(III) atom consisting of a 4'-(4-pyrid-yl) 2,2':6',2''-terpyridine (pytpy) ligand, two 1,1,1,5,5,5-hexa-fluoro-acetyl acetonate (hfac) anions and an aqua ligand. In the solid state, the compound forms supra-molecular chains running along the b-axis via inter-molecular hydrogen bonds between the Yb-OH(2) unit and the N-atom donor of the 4-pyridyl pendant of pytpy, with an O?N distance of 2.686 (4) A. A chloride counter-anion and lattice methanol and water solvent mol-ecules occupy a hydro-philic columnar space along the coordination chains. O-H?Cl hydrogen bonds occur. The two water molecules and the four trifluoromethyl groups are disordered over two sets of sites, each with different occupancy ratios. PMID- 22259334 TI - catena-Poly[[(8-amino-quinoline-kappaN,N')cadmium]-di-MU-thio-cyanato kappaN:S;kappaS:N-[(8-amino-quinoline-kappaN,N')cadmium]-di-MU-chlorido]. AB - In the title compound, [CdCl(NCS)(C(9)H(8)N(2))](n), the Cd(II) atom is in a distorted octa-hedral coordination environment defined by two chloride anions, two N atoms from an 8-amino-quinoline ligand, one N atom from one thio-cyanate anion and one S atom from a symmetry-related thio-cyanate anion. Two Cd(II) atoms are bridged by two chloride anions, forming an inversion-related Cd(2)Cl(2) unit; these units are further linked through thio-cyanate anions, leading to a chain structure extending parallel to [010]. Weak pi-pi stacking inter-actions with centroid-centroid distances of 3.430 (4) A and an inter-planar separation of 3.390 (3) A between the pyridine and benzene rings link the chains into a two dimensional network parallel to (10[Formula: see text]). Weak inter-molecular C H?Cl hydrogen-bonding inter-actions help to consolidate the crystal packing. PMID- 22259335 TI - 2,9-Dimethyl-1,10-phenanthrolin-1-ium (6-carb-oxy-4-hy-droxy-pyridine-2-carboxyl ato-kappaO,N,O)(4-hy-droxy-pyridine-2,6-dicarboxyl-ato-kappaO,N,O)zincate(II) 2.35-hydrate: a proton-transfer compound. AB - In the title compound, (C(14)H(13)N(2))[Zn(C(7)H(3)NO(5))(C(7)H(4)NO(5))].2.35H(2)O, the Zn(II) atom is coordinated by two N atoms and four O atoms from the carboxyl-ate groups of the 4 hy-droxy-pyridine-2,6-dicarboxyl-ate and 6-carb-oxy-4-hy-droxy-pyridine-2 carboxyl-ate ligands, forming a distored octa-hedral geometry. In the anion, the two pyridine rings are inclined to one another by 87.75 (13) degrees . Two types of robust O-H?O hydrogen bond synthons, viz. R(2) (2)(16) and R(6) (6)(42), link the anions to form a two-dimensional network parallel to the bc plane. Furthermore, O-H?O, N-H?O, N-H?N and weak C-H?O hydrogen bonds connect the two dimensional networks, forming a three-dimensional structure. In the crystal, there are also C-H?pi and pi-pi inter-actions [centroid-centroid distances of 3.5554 (18) and 3.7681 (18) A], and C=O?pi inter-actions [O?centroid distance = 3.117 (2) A] present. One of the three crystal water molecules shows an occupancy of 0.35. PMID- 22259336 TI - Bis(tetra-phenyl-phospho-nium) bis-[N-(trifluoro-methyl-sulfon-yl)dithio carbimato(2-)-kappaS,S']zincate(II). AB - The title salt, (C(24)H(20)P)(2)[Zn(C(2)F(3)NO(2)S(3))(2)], consists of a complex dianion and two tetra-phenyl-phospho-nium cations. The Zn(II) ion displays a distorted tetra-hedral coordination environment with four S atoms from two S,S' chelated N-(trifluoro-methyl-sulfonyl-)dithio-carbimate anions. In the crystal, besides the ionic inter-action of the oppositely charged ions, inter-molecular C H?O inter-actions between cations and anions are observed. One of the cations inter-acts with an inversion-related equivalent by pi-pi stacking between phenyl rings, with a centroid-centroid distance of 3.932 (4) A. PMID- 22259337 TI - Ethyl 3-ferrocenyl-1-(pyridin-2-ylmeth-yl)-1H-pyrazole-5-carboxyl-ate. AB - The title compound, [Fe(C(5)H(5))(C(17)H(16)N(3)O(2))], crystallizes with an essentially eclipsed conformation of the cyclo-penta-dienyl (Cp) rings. The unsubstituted ring is disordered over two positions with the major component being present 90 (1)% of the time. The substituted Cp ring, the pyrazole ring and three atoms of the eth-oxy-carbonyl group form a conjugated pi-system. These 13 atoms are coplanar within 0.09 A. PMID- 22259338 TI - catena-Poly[[bis-(MU-2-formyl-6-meth-oxy-phenolato 1:2kappaO,O:O,O)copper(II)sodium]-MU-tetra-fluorido-borate-1:1'kappaF:F']. AB - In the title heterodinuclear complex, [CuNa(BF(4))(C(8)H(7)O(3))(2)](n), the Cu(II) ion is four-coordinated by four O atoms of two 2-formyl-6-meth-oxy phenolate ligands, giving rise to a square-planar geometry. The Na(+) ion is six coordinated by four O atoms from the two ligands and two F atoms of two tetra fluoridoborate anions. The tetra-fluoridoborate anion links the Na(+) ions, forming a one-dimensional structure along [001]. Three F atoms of the tetra fluoridoborate anion are disordered over two sets of sites, with an occupancy ratio of 0.790 (11):0.210 (11). PMID- 22259339 TI - Poly[[{MU(3)-dihydrogen [(pyridin-4-yl-methyl-imino)-bis-(methyl-ene)]diphos-phon ato-kappaO:O',N,O'':N'}copper(II)] dihydrate]. AB - In the title polymer, {[Cu(C(8)H(12)N(2)O(6)P(2))].2H(2)O}(n), the geometry of the five-coordinate Cu(II) ion can best be described as slightly distorted square pyramidal formed by one N and two O atoms of an N(CH(2)PO(3)H)(2) group and one N atom from a pyridine ring. The elongated apex of the pyramid is occupied by one O atom from a third diphospho-nate ligand. The inter-connection of Cu(2+) ions by the diphospho-nate ligands results in the formation of a double-chain array along the b axis, in which the two sub-chains are inter-locked by pairs of PO(3) groups. The outside of each sub-chain is decorated by other PO(3) groups. These double chains are further assembled into a three-dimensional supra-molecular architecture via a large number of O-H?O hydrogen bonds between the phospho-nate groups and lattice water mol-ecules. PMID- 22259340 TI - Bis{2-[(pyridin-4-yl-kappaN)sulfan-yl]pyrazine}-silver(I) tetra-fluoridoborate. AB - In the title mononuclear complex, [Ag(C(9)H(7)N(3)S)(2)]BF(4), the Ag(I) ion adopts a virtually linear coordination geometry [N-Ag-N = 178.06 (11) degrees ] with the two ligands bound to the metal atom via the pyridine N atoms. The metal coordinated pyridine rings are almost coplanar, making a dihedral angle of 1.5 (2) degrees , while the two pendent pyrazine rings are arranged on the same side of the N-Ag-N line. Along the a axis, the mononuclear coordination units are stacked with pi-pi inter-actions between the pyridine rings [centroid-centroid distance = 3.569 (4) A], leading to infinite chains. The chains are inter connected through inter-molecular N(pyrazine)?pi(pyrazine) inter-actions forming layers parallel to the ab plane [N?centroid = 3.268 (5) A]. These layers are further stacked along the c-axis direction, furnishing a three-dimensional supra molecular framework with the tetra-fluoridoborate anions embedded within the inter-stices. PMID- 22259341 TI - Bis[MU(3)-N'-oxidopyridine-2-carbox-imidamidato(2-)]bis-[MU(2)-N'-oxido-pyridine 2-carboximidamidato(1-)]tetra-pyridine-tetra-nickel(II) dinitrate. AB - The title compound, [Ni(4)(C(6)H(5)N(3)O)(2)(C(6)H(6)N(3)O)(2)(C(5)H(5)N)(4)](NO(3))(2), is a tetra nuclear nickel complex containing a single-decker cation, located on an inversion center. The two unique Ni(II) cations are N,N',N'',O-chelated by carbox-imid-amid ate(2-) and carboximidamidate(1-) anions, forming a distorted four-coordinate planar structure, while the other two Ni(II) atoms are N,N',O,O'-chelated by the same bridging ligands and two pyridine mol-ecules, affording six-coordinated metals in an octa-hedral geometry. The cation is isostructural with the complex crystallized with perchlorate counter-ions in place of nitrate. PMID- 22259342 TI - Penta-aqua-(5-carb-oxy-pyridine-2-carboxyl-ato-kappaN,O)(pyridine-2,5-dicarboxyl ato-kappaN,O)cerium(III) tetra-hydrate. AB - In the title compound, [Ce(C(7)H(3)NO(4))(C(7)H(4)NO(4))(H(2)O)(5)].4H(2)O, the Ce(3+) ion is nine-coordinated by two O atoms and two N atoms from one single and from one double deprotonated pyridine-2,5-dicarboxyl-ate ligand and five water mol-ecules in a distorted monocapped square-anti-prismatic geometry. In the crystal, extensive O-H?O hydrogen-bonding inter-actions result in a three dimensional supra-molecular architecture. PMID- 22259344 TI - {N-[1-(1H-Benzimidazol-2-yl)ethyl-idene-kappaN]-3-(1H-imidazol-1-yl)propan-1 amine-kappaN}dibromidomercury(II). AB - In the title compound, [HgBr(2)(C(15)H(17)N(5))], the Hg(II) ion is tetra hedrally coordinated by two N atoms of the N-[1-(1H-benzimidazol-2-yl)ethyl-idene kappaN]-3-(1H-imidazol-1-yl)propan-1-amine ligand, and two bromide anions. Inter molecular benzimidazole-imidazole N-H?N hydrogen bonds link the mol-ecules into helical chains along the b-axis direction and C-H?Br hydrogen bonds link these chains into layers parallel to the bc plane. PMID- 22259343 TI - Tetra-kis(MU-4-azido-benzoato-kappaO:O')bis-[(N,N-dimethyl-formamide kappaO)copper(II)]. AB - The binuclear title compound, [Cu(2)(C(7)H(4)N(3)O(2))(4)(C(3)H(7)NO)(2)], is a discrete metal-organic compound having a paddle-wheel-type structure. The Cu?Cu distance is 2.6366 (5) A and an inversion center is located at the mid-point of this bond. The Cu(II) cation is coordinated by four carboxyl-ate O atoms from four 4-azido-benzoate ligands, and one O atom from a dimethyl-formamide mol ecule, forming an overall distorted octahedral geometry when the Cu?Cu bond is also considered. PMID- 22259345 TI - cis-Dichloridobis(di-2-pyridyl-amine-kappaN,N')manganese(II). AB - In the title complex, [MnCl(2)(C(10)H(9)N(3))(2)], the Mn(II) ion is six coordinated in a considerably distorted cis-N(4)Cl(2) octa-hedral environment defined by four N atoms of two chelating di-2-pyridyl-amine (dpa) ligands and two Cl(-) anions. In the crystal, the dpa ligands are not planar, the dihedral angles between the two pyridine rings being 29.3 (2) and 30.9 (2) degrees . The complex mol-ecules are stacked in columns along the c axis and are connected by inter molecular N-H?Cl hydrogen bonds, forming a three-dimensional network. Weak inter- and intra-molecular pi-pi inter-actions are present between the pyridine rings, the shortest centroid-centroid distance being 4.406 (3) A. PMID- 22259346 TI - Diaqua-bis-(4-hy-droxy-5-nitro-pyridine-2-carboxyl-ato-kappaN,O)copper(II). AB - In the title compound, [Cu(C(6)H(3)N(2)O(5))(2)(H(2)O)(2)], the Cu(II) ion, lying on an inversion center, is coordinated by two pyridine N atoms and two carboxyl ate O atoms from symmetry-related two 4-hy-droxy-5-nitro-pyridine-2-carboxyl-ate ligands, and two water mol-ecules, forming a distorted octa-hedral geometry. In the crystal, O-H?O hydrogen bonds link the complex mol-ecules. One of the H atoms of the water mol-ecule is disordered over two sites of equal occupancy. PMID- 22259347 TI - trans-Bis(ethyl-enediamine-kappaN,N')bis-(6-methyl-2,2,4-trioxo-3,4-dihydro 1,2lambda,3-oxathia-zin-3-ido-kappaN)copper(II). AB - In the crystal structure of the title compound, [Cu(C(4)H(4)NO(4)S)(2)(C(2)H(8)N(2))(2)], the Cu(2+) ion resides on a centre of symmetry. The environment of Cu(2+) ion is a distorted octa-hedron. The axial bond lengths between the Cu(II) ion and the N atoms are considerably longer than the equatorial bond distances between the Cu(II) ion and the N atoms of the ethyl enediamine ligand as a consequence of the Jahn-Teller effect. The mol-ecular conformation is stabilized by intra-molecular N-H?O hydrogen bonds. In the crystal, mol-ecules are connected by inter-molecular N-H?O hydrogen bonds into chains running along the a axis. PMID- 22259348 TI - Chlorido{N-[(E)-2-(diphenyl-phosphan-yl)benzyl-idene]-2-(thio-phen-2-yl)ethan amine-kappaP}gold(I). AB - The title compound, [AuCl(C(25)H(22)NPS)], crystallizes with two independent mol ecules in the asymmetric unit in which the thio-phene fragments are disordered over two sets of sites with 0.537 (10):0.463 (10) and 0.701 (9):0.299 (9) occupancy ratios. In both cases, the thio-phene ring is rotated by approximately 180 degrees for the second component. Important geometrical parameters include Au-P = 2.235 (2) and 2.237 (2) A, Au-Cl = 2.286 (2) and 2.292 (2) A, and P-Au-Cl = 177.39 (8) and 172.63 (7) degrees . Weak inter-molecular C-H?Cl inter-actions are observed in the crystal structure. PMID- 22259349 TI - Bis[5-(pyridin-2-yl)pyrazine-2-carbo-nitrile-kappaN,N]silver hexa-fluorido phosphate. AB - In the mononuclear title complex, [Ag(C(10)H(6)N(4))(2)]PF(6), two kappa(2)N,N' chelating 5-(pyridin-2-yl)pyrazine-2-carbonitrile ligands surround the Ag(I) atom, forming a distorted N(4) tetra-hedral coordination geometry. The mononuclear units are inter-connected through pi-pi inter-actions [centroid centroid distances = 3.801 (2) and 3.979 (3) A] and the hexa-fluoridophosphate anions are embedded within the inter-stices. C N?pi inter-actions [N?centroid = 3.519 (2) A] and C-H.?N hydrogen-bonding inter-actions also occur. PMID- 22259350 TI - Bis[1,1'-(1,3-phenyl-enedimethyl-ene)di(1H-imidazol-3-ium)] beta-octa-molybdate. AB - In the title compound, (C(14)H(16)N(4))(2)[Mo(8)O(26)], the beta-octa-molybdate anion is centrosymmetric. N-H?O hydrogen bonds link the diimidazolium cations and the polyoxidoanions into a chain structure along [100]. pi-pi inter-actions between the imidazole rings and between the imidazole and benzene rings [centroid centroid distances = 3.611 (2) and 3.689 (3) A, respectively] connect the chains. PMID- 22259351 TI - Bis(morpholin-4-ium) tetra-chlorido-cobalt(II). AB - The title compound, (C(4)H(10)NO)(2)[CoCl(4)], is an ionic compound consisting of two protonated tetra-hydro-1,4-oxazine (morpholine) cations and a [CoCl(4)](2-) dianion. The Co(II) ion is in a tetra-hedral coordination geometry. The cations exhibit chair-shaped conformations. A three-dimensional supra-molecular architecture is formed through N-H?Cl and C-H?Cl hydrogen bonds between the dianions and the cations. PMID- 22259352 TI - Aqua-bis-(4-fluoro-benzoato-kappaO)bis-(nicotinamide-kappaN)copper(II) nicotinamide hemisolvate trihydrate. AB - The asymmetric unit of the title compound, [Cu(C(7)H(4)FO(2))(2)(C(6)H(6)N(2)O)(2)(H(2)O)].0.5C(6)H(6)N(2)O.3H(2)O, contains two aqua-bis-(4-fluoro-benzoato)bis-(nicotinamide)-copper(II) mol-ecules, one nicotinamide solvent mol-ecule and six water mol-ecules. The Cu(II) ion is coordinated by two O atoms from two 4-fluoro-benzoate ligands, two N atoms from two nicotinamide ligands and one water O atom in a distorted square-pyramidal geometry. In the crystal, O-H?O, O-H?N and N-H?O hydrogen bonds consolidate the crystal packing, which also exhibits pi-pi inter-actions between the aromatic rings [centroid-centroid distances 3.692 (2)-3.794 (2) A]. PMID- 22259353 TI - trans-Bis(acridine-kappaN)dichloridopalladium(II). AB - In the title complex, [PdCl(2)(C(13)H(9)N)(2)], the Pd(II) ion is four coordinated in an essentially square-planar environment by two N atoms from two acridine ligands and two Cl(-) anions. The Pd atom is located on an inversion centre, and thus the asymmetric unit contains one half of the complex and the PdN(2)Cl(2) unit is exactly planar. The dihedral angle between the PdN(2)Cl(2) unit and the acridine ligand is 84.66 (6) degrees . In the crystal, the complex mol-ecules are stacked in columns along the a axis connected by C-H?Cl hydrogen bonds, forming chains along [110]. In the columns, numerous inter-molecular pi-pi inter-actions between the six-membered rings are present, the shortest ring centroid-centroid distance being 3.722 (4) A. PMID- 22259354 TI - catena-Poly[[(diaqua-calcium)-bis-(MU-2-fluorobenzoato) 1':1kappaO:O,O';1:1''kappaO,O':O] 2,2'-bipyridine hemi-solvate]. AB - In the title compound, {[Ca(C(7)H(4)FO(2))(2)(H(2)O)(2)].0.5C(10)H(8)N(2)}(n), the Ca(II) atom is coordinated by eigth O atoms from four 2-fluoro-benzoate ligands and two water mol-ecules, resulting in a distorted CaO(8) square-anti prismatic coordination environment. The 2-fluoro-benzoate ligand bridges two symmetry-related Ca(II) atoms, giving rise to a chain structure extending along [100]. The distances between the Ca atom and its two symmetry-related counterparts are 4.054 (2) and 4.106 (2) A. The polymeric chains are connected by classical O-H?N hydrogen bonds into a layer structure parallel to (010). The layers are connected by non-classical C-H?F hydrogen bonds into a three dimensional supra-molecular structure. O-H?O and C-H?O inter-actions also occur. The uncoordinated 2,2'-bipyridine mol-ecule is located on a centre of symmetry at the mid-point of the bond between the two heterocycles. One of the two benzene rings is disordered over two sites with occupancy factors of 0.60 and 0.40. PMID- 22259355 TI - Bis(tetra-n-butyl-ammonium) bis-(5,6-dicyano-pyrazine-2,3-dithiol-ato kappaS,S')palladium(II). AB - In the title complex, (C(16)H(36)N)(2)[Pd(C(6)N(4)S(2))(2)], the centrosymmetric dianion is planar, with an r.m.s. deviation of 0.034 (8) A. The Pd(II) atom, lying on an inversion center, has a square-planar coordination geometry, with Pd S bond lengths of 2.276 (3) and 2.294 (3) A. PMID- 22259356 TI - Bis(O-ethyl dithio-carbonato-kappaS,S')bis-(pyridine-3-carbonitrile kappaN)nickel(II). AB - The Ni(2+) ion in the title complex, [Ni(C(3)H(5)OS(2))(2)(C(6)H(4)N(2))(2)], is in a strongly distorted octa-hedral coordination environment formed by an N(2)S(4) donor set, with the Ni(2+) ion located on a centre of inversion. In the crystal, weak C-H?S and C-H?N inter-actions are observed. PMID- 22259357 TI - catena-Poly[zinc-tris-(MU-dimethyl-carbamato-kappaO:O')-zinc-MU-(2-phenyl benzimidazolido-kappaN:N']. AB - The crystal structure of the title compound, [Zn(2)(C(13)H(9)N(2))(C(3)H(6)NO(2))(3)](n), displays a long chiral chain. This is composed of zinc-dimer clusters capped by dimethyl-carbamate ligands, which lie on crystallographic twofold rotation axes and are polymerically linked in one dimension by 2-phenyl-benzimidadole (2-PBImi) organic ligands. The two Zn(2+) ions defining the dimetal cluster are crystallographically independent, but display very similar coordination modes and tetra-hedral geometry. As such, each Zn(2+) ion is coordinated on one side by the N-donor imidazole linker, while the other three available coordination sites are fully occupied by the O atoms from the capping dimethyl-carbamates. The chirality of the chain extends along the c axis, generating a rather long 52.470 (11) A cell axis. Inter-estingly, the chiral material crystallizes from completely achiral precursors. A twofold axis and 3(1) screw axis serve to generate the long asymmetric unit. PMID- 22259358 TI - Bis(MU-ferrocene-carboxyl-ato)bis-[aqua--bis(ferrocene-carboxyl-ato)methano-l erbium(III)] methanol disolvate. AB - In the centrosymmetric title coordination compound, [Er(2){Fe(C(5)H(5))(C(6)H(4)O(2))}(6)(CH(3)OH)(2)(H(2)O)(2)].2CH(3)OH, the two Er(III) ions are bridged by two ferrocene-carboxyl-ate anions as asymmetrically bridging ligands, leading to dimeric cores. The Er(III) ion has a distorted dodeca-hedral coordination with six coordinating O atoms derived from the ferrocene-carboxyl-ate ligands and two coordinated O atoms from one water mol ecule and one methanol mol-ecule. The asymmetric unit comprises a half of the complex mol-ecule and a methanol solvent mol-ecule. Intra-molecular O-H?O and C H?O inter-actions occur. In the crystal, mol-ecules are linked by inter-molecular O-H?O hydrogen bonds and C-H?O as well as C-H?pi inter-actions. PMID- 22259359 TI - Aqua-cyanido{6,6'-dimeth-oxy-2,2'-[1,2-phenyl-enebis(nitrilo-methanylyl idene)]diphenolato}cobalt(III) acetonitrile hemisolvate. AB - In the title complex, [Co(C(22)H(18)N(2)O(4))(CN)(H(2)O)].0.5CH(3)CN, the Co(III) cation is N,N',O,O'-chelated by a 6,6'-dimeth-oxy-2,2'-[1,2-phenyl-enebis(nitrilo methanylyl-idene)]diphenolate dianion, and is further coordinated by a cyanide anion and a water mol-ecule in the axial sites, completing a distorted octa hedral coordination geometry. In the crystal, pairs of bifurcated O-H?(O,O) hydrogen bonds link adjacent mol-ecules, forming centrosymmetric dimers. The acetonitrile solvent mol-ecule shows 0.5 occupancy. PMID- 22259360 TI - (N-Ethyl-N-phenyl-dithio-carbamato-kappaS)triphenyl-tin(IV). AB - The title compound, [Sn(C(6)H(5))(3)(C(9)H(10)NS(2))], has two independent mol ecules in the asymmetric unit and each features a tetra-hedrally coordinated Sn(IV) atom as the dithio-carbamate ligand coordinates in a monodentate fashion. As the non-coordinating thione S atom is proximate to the Sn atom [Sn?S(thione) = 3.1477 (6) and 2.9970 (5) A for the independent mol-ecules], distortions from the ideal geometry are evident [the widest angle being 120.48 (5) degrees ]. The most notable feature of the crystal packing is the formation of C-H?pi inter-actions that lead to the formation of supra-molecular layers parallel to ([Formula: see text]2[Formula: see text]). PMID- 22259361 TI - {(1R,2R)-N,N'-Bis[2-(N-methyl-anilino)benzyl-idene]cyclo-hexane-1,2-diamine kappaN,N'}dichloridoiron(II). AB - In the title compound, [FeCl(2)(C(34)H(36)N(4))], the Fe(II) ion is coordinated by two Cl atoms and by two N atoms from a (1R,2R)-N,N'-bis[2-(N-methyl anilino)benzyl-idene]cyclo-hexane-1,2-diamine ligand in a distorted tetra-hedral geometry. The mol-ecule has approximate C(2) point symmetry. The dihedral angles between the phenyl and benzene rings on either side of the ligand are 64.56 (14) and 65.61 (13) degrees . PMID- 22259362 TI - Tris(ethyl-enediamine-kappaN,N')cobalt(III) aqua-tris-(oxalato kappaO,O)indate(III). AB - In the cation of the title compound, [Co(C(2)H(8)N(2))(3)][In(C(2)O(4))(3)(H(2)O)], the Co(III) atom is coordinated by six N atoms from three ethyl-enediamine mol-ecules. The Co(III)-N bond lengths lie in the range 1.956 (4)-1.986 (4) A. In the anion, the In(III) atom is seven coordinated by six O atoms from three oxalate ligands and by a water mol-ecule. The cations and anions are linked by extensive O-H?O and N-H?O hydrogen bonds, forming a supermolecular network. PMID- 22259363 TI - Hexa-kis-(dimethyl sulfoxide-kappaO)nickel(II) bis-(2,2-dicyano-ethene-1,1 dithiol-ato-kappaS,S')nickelate(II). AB - The reaction of NiCl(2).6H(2)O with sodium 2,2-dicyano-ethene-1,1-dithiol-ate [Na(2)(i-mnt)] in dimethyl sulfoxide produces the title complex, [Ni(C(2)H(6)OS)(6)][Ni(C(4)N(2)S(2))(2)]. There is half each of an [Ni(C(2)H(6)OS)(6)](2-) complex anion and an [Ni{(CH(3))(2)SO}(6)](2+) complex cation in the asymmetric unit. The i-mnt ligand coordinates in a bidentate manner to the Ni atom in the anion through the two chelating S atoms in an approximate square-planar geometry. The Ni atom in the complex cation has an octahedral coordination environment with six dimethyl sulfoxide mol-ecules as ligands. PMID- 22259364 TI - cis-Bis(acetonitrile-kappaN)bis-(2,2'-bipyridine-kappaN,N')ruthenium(II) tetra fluoridoborate. AB - In the cation of the title compound, [Ru(CH(3)CN)(2)(C(10)H(8)N(2))(2)](BF(4))(2), the Ru(II) atom is six-coordinated in a distorted octa-hedral geometry by the N atoms of the two 2,2'-bipyridine (bpy) ligands and two cis-arranged acetonitrile mol-ecules. The dihedral angles formed by the pyridine rings of the bpy ligands are 8.86 (12) and 10.12 (14) degrees . In the crystal, the cations and anions are linked by C-H?F hydrogen bonds into a three-dimensional network. PMID- 22259365 TI - Diaqua-bis-(5-methyl-1,2-oxazole-3-car-box-yl-ato-kappaN,O)cobalt(II) dihydrate. AB - In the title compound, [Co(C(5)H(4)NO(3))(2)(H(2)O)(2)].2H(2)O, the coordination polyhedron around the six-coordinate Co(II) ion is formed by two equatorial 5 methyl-isoxazole-3-carboxyl-ate ligands in an N,O(3)-bidentate fashion through the isoxazole N atom and a carboxyl-ate O atom, and by two axial water ligands. The asymmetric unit consists of half of the complex and one water mol-ecule (the full comlex being completed by application of inversion). In the crystal, the water mol-ecules participate in the formation of an intricate three-dimensional network of hydrogen bonds involving the coordinated water mol-ecule and the carboxyl-ate groups. PMID- 22259366 TI - Bis(1,1-dimethyl-guanidinium) tetra-aqua-dimethyl-tin(IV) bis-(sulfate). AB - Single crystals of the title salt, (C(3)H(10)N(3))(2)[Sn(CH(3))(2)(H(2)O)(4)](SO(4))(2), formed concomitantly with the already known [Sn(CH(3))(3)](2)SO(4).2H(2)O. In the title structure, the Sn(IV) atom displays a slightly distorted octa-hedral coordination geometry defined by four O water atoms in the equatorial positions and two methyl groups in the axial positions. In the crystal, various O-H?O and N-H?O hydrogen-bonding inter-actions between the organic cation and the coordinated water mol-ecules as donors and the sulfate O atoms as acceptors result in a three-dimensional structure. The Sn(IV) atom is located on an inversion centre, resulting in half of the complex metal cation being in the asymmetric unit. PMID- 22259367 TI - Bis-(MU-pyridine-2,3-dicarboxyl-ato)bis-[aqua-(3-carb-oxy-pyridine-2-carboxyl ato)indium(III)] tetra-hydrate. AB - In the binuclear centrosymmetric title compound, [In(2)(C(7)H(3)NO(4))(2)(C(7)H(4)NO(4))(2)(H(2)O)(2)].4H(2)O, which contains both pyridine-2,3-dicarboxyl-ate and 3-carb-oxy-pyridine-2-carboxyl-ate ligands, the In(III) atom is six-coordinated in a distorted octa-hedral geometry. One pyridine ligand is N,O-chelated while the other is N,O-chelated and at the same time bridging to the other via the second carboxyl group. In the crystal, an extensive O-H?O hydrogen-bonding network, involving the coordinated and lattice water mol ecules and the carboxyl groups of the ligands, together with C-H?O and pi-pi inter-actions [centroid-centroid distance = 3.793 (1) A], leads to the formation of a three-dimensional structure. PMID- 22259368 TI - Tripotassium (bis-{[bis-(carboxyl-atometh-yl)amino]-meth yl}phosphinato)cuprate(II) dihydrate. AB - In the title compound, K(3)[Cu(C(10)H(12)N(2)O(10)P)].2H(2)O, the Cu(II) ion, one potassium cation and a P atom are situated on a twofold rotation axis. The Cu(II) ion is coordinated by two N and four O atoms from one bis-{[bis-(carboxyl-atometh yl)amino]-meth-yl}phosphinate ligand in a distorted octa-hedral coordination geometry. The two crystallographically independent potassium ions exhibit different coordination environments. The potassium ion in a general position is hepta-coordinated by five carboxyl-ate O atoms, one phosphinate O atom and one water mol-ecule [K-O = 2.718 (3)-3.040 (3) A], and the potassium ion situated on the twofold rotation axis is hexa-coordinated by four carboxyl-ate O atoms and two water mol-ecules [K-O = 2.618 (3)-2.771 (3) A]. The water mol-ecules are also involved in formation of inter-molecular O-H?O hydrogen bonds. PMID- 22259369 TI - Bis[6-(1H-benzimidazol-2-yl-kappaN)pyridine-2-carboxyl-ato-kappaN,O]cobalt(II) dihydrate. AB - In the title compound, [Co(C(13)H(8)N(3)O(2))(2)].2H(2)O, the Co(II) atom has a distorted octa-hedral environment defined by four N atoms and two O atoms from two 6-(1H-benzimidazol-2-yl)pyridine-2-carboxyl-ate ligands. In the crystal, the complex mol-ecules and uncoordinated water mol-ecules are linked via N-H?O and O H?O hydrogen bonds, forming a two-dimensional supra-molecular structure parallel to (010). pi-pi inter-actions are present between the imidazole, pyridine and benzene rings [centroid-centroid distances = 3.528 (2), 3.592 (2), 3.680 (2) and 3.732 (3) A]. PMID- 22259370 TI - catena-Poly[[(diaqua-zinc)-MU-3-carb-oxy-pyrazine-2-carboxyl-ato-kappaN,O;N,O] nitrate]. AB - The crystal structure of the title compound, {[Zn(C(6)H(3)N(2)O(4))(H(2)O)(2)]NO(3)}(n), is built of zigzag cationic chains propagating in [010] with nitrate anions located in the space between the chains. The Zn(II) ion is coordinated by N and O atoms of two symmetry-related ligands in equatorial sites, and by two water O atoms at the axial sites of a distorted octa hedron. One carboxyl-ate group of the ligand remains protonated, serving as a donor in a short intra-molecular O-H?O hydrogen bond. The coordinated water mol ecules are donors and the nitrate O atoms act as acceptors in a network of O-H?O hydrogen bonds. PMID- 22259371 TI - Bis(1,10-phenanthroline-5,6-dione-kappaN,N')silver(I) 2-hy-droxy-3,5-dinitro benzoate. AB - In the cation of the title salt, [Ag(C(12)H(6)N(2)O(2))(2)](C(7)H(3)N(2)O(7)), the Ag(I) atom is coordinated in a distorted tetra-hedral geometry by four N atoms from two 1,10-phenanthroline-5,6-dione ligands, while the 3,5-dinitro salicylate anion has only a short contact [2.847 (6) A] between one of its O atoms and the Ag(I) atom. The dihedral angle between the two 1,10-phenanthroline 5,6-dione ligands is 58.4 (1) degrees . There is an intra-molecular O-H?O hydrogen bond in the 3,5-dinitro-salicylate anion. PMID- 22259372 TI - (2,2'-Bipyridine-4,4'-dicarb-oxy-lic acid-kappaN,N')chlorido(2,2':6',2'' terpyridyl-kappaN,N',N'')ruthenium(II) perchlorate ethanol monosolvate monohydrate. AB - In the title compound, [RuCl(C(15)H(11)N(3))(C(12)H(8)N(2)O(4))]ClO(4).C(2)H(5)OH.H(2)O, the geometry of the ClN(5) coordination set around the Ru(II) atom is close to octa-hedral, but distorted on account of the limited bite angles of the polypyridyl ligands. The complexes are linked by O-H?O hydrogen bonds between the carboxyl groups and the crystal lattice water mol-ecules into chains along [110]. Face-to-face stacking inter-actions are formed between terpyridine ligands, with inter-planar separations of 3.66 (1) and 3.42 (1) A, and between bipyridine-4,4'-dicarb-oxy lic acid ligands, with inter-planar separations of 3.65 (1) and 3.72 (1) A. Three O atoms of the perchlorate ion are each disordered equally over two positions. The hy-droxy group of the ethanol mol-ecule is also disordered over two sites with refined occupancies of 0.794 (9) and 0.206 (9). PMID- 22259373 TI - Di-n-butyl-bis-(N-ethyl-N-phenyl-dithio-carbamato-kappaS)tin(IV). AB - The title compound, [Sn(C(4)H(9))(2)(C(9)H(10)NS(2))(2)], features a tetra hedrally coordinated Sn(IV) atom; the dithio-carbamate ligands coordinate in a monodentate fashion, accompanied by two n-butyl chains. The non-coordinating thione S atoms are each proximate to the Sn(IV) atom [3.0136 (7) and 2.9865 (8) A], giving rise to distortions from the ideal geometry as evident in the wide C Sn-C bond angle of 139.06 (12) degrees . In the crystal, C-H?S inter-actions lead to the formation of a linear supra-molecular chain along the b axis. The chains are aligned into layers by C-H?pi inter-actions, and the layers stack along [001]. One of the ethyl groups is statistically disordered over two sets of sites. PMID- 22259374 TI - N'-(4-Hy-droxy-benzyl-idene)ferrocene-1-carbohydrazide. AB - In the title compound, [Fe(C(5)H(5))(2)(C(13)H(11)N(2)O(2))], the dihedral angle between the benzene ring and the cyclo-penta-diene ring bonded to the carbonyl group is 26.1 (2) degrees . In the crystal, bifurcated O-H?(O,N) and N-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 22259375 TI - Bis[MU-N-(diethyl-amino-kappaN)dimethyl-silylanilido-kappaN:N]bis-[chlorido cobalt(II)]. AB - In the title binuclear Co(II) complex, [Co(2)(C(12)H(21)N(2)Si)(2)Cl(2)], an inversion center is located at the mid-point between the two Co atoms in the dimeric mol-ecule. The bidentate N-silylated anilide ligand coordinates the Co(II) atom in an N,N'-chelating mode and provides the anilide N atom as a bridge to link two Co(II) atoms. The two ends of the N-Si-N chelating unit exhibit different affinities for the metal atom. The Co-N(anilide) bond is 2.031 (6) A and Co-N(amino) bond is 2.214 (6) A. The four-coordinate Co atom presents a distorted tetra-hedral geometry, while the dimeric aggregation exhibits a (CoN)(2) rhombus core with 1.998 (6) A as the shortest sides and shows a ladder structure composed of Co, N and Si atoms. PMID- 22259377 TI - Bis(4-fluoro-benz-yl)bis-(4-phenyl-5-sulfanyl-idene-4,5-dihydro-1,3,4-thio diazole-2-thiol-ato)tin(IV). AB - In the title complex, [Sn(C(7)H(6)F)(2)(C(8)H(5)N(2)S(3))(2)], including the weak Sn-N inter-actions, the Sn(IV) atom is situated in a distorted trans-octa-hedral geometry, and the equatorial plane is defined by two chelating 4-phenyl-5 sulfanyl-idene-4,5-dihydro-1,3,4-thio-diazole-2-thiol-ate ligands. The apical positions are occupied by two C atoms of 4-fluoro-benzyl groups. PMID- 22259376 TI - {4,4'-Dimethyl-2,2'-[(2,2-dimethyl-propane-1,3-di-yl)bis-(nitrilo-methanylyl idene)]diphenolato}nickel(II) monohydrate. AB - In the title compound, [Ni(C(21)H(24)N(2)O(2))].H(2)O, both the complex mol-ecule and the water mol-ecule lie on a twofold rotation axis. The Ni(II) ion is coordinated in a distorted square-planar geometry by the tetra-dentate ligand. The dihedral angle between the two symmetry-related benzene rings is 47.12 (8) degrees . In the crystal, pairs of symmetry-related O-H?O hydrogen bonds form R(2) (2)(6) ring motifs. In addition, there are weak inter-molecular C-H?O hydrogen bonds, and pi-pi stacking inter-actions with a centroid-centroid distance of 3.4760 (8) A. PMID- 22259378 TI - Poly[(2,2'-bipyridine-kappaN,N')(MU(3)-2,4,6-trimethyl-isophthalato kappaO,O:O:O,O)cadmium]. AB - In the crystal structure of the polymeric title complex, [Cd(C(11)H(10)O(4))(C(10)H(8)N(2))](n), the Cd(II) cation is chelated by one 2,2 bipyridine ligand and two carboxyl groups from two trimethyl-isophthalate (TMIPA) anions, and is further coordinated by one carboxyl-ate O atom from a third TMIPA anion, forming a distorted penta-gonal-bipyramidal geometry. Each TMIPA anion bridges three Cd(II) cations, forming polymeric complex sheets parallel to (001). Weak C-H?O hydrogen bonding occurs between adjacent sheets. PMID- 22259379 TI - {N'-[(2-Oxidonaphthalen-1-yl)methyl-idene]benzohydrazidato}(1,10 phenanthroline)copper(II) methanol monosolvate. AB - The title mononuclear complex, [Cu(C(18)H(12)N(2)O(2))(C(12)H(8)N(2))].CH(3)OH, contains one N'-[(2-oxidonaphthalen-1-yl)methyl-idene]benzohydrazidate ligand (L(2-)), a Cu(2+) cation, one 1,10-phenanthroline ligand and a methanol solvent mol-ecule. The Cu(II) ion adopts a CuO(2)N(3) distorted square-pyramidal coordination. An O-H?O hydrogen bond is formed between the methanol solvent mol ecule and the hydrazide O atom of the L(2-) ligand. PMID- 22259380 TI - Bis(MU-trimethyl-silanolato-kappaO:O)bis-{[2-(2H-benzotriazol-2-yl)-4,6-di-tert pentyl-phenolato-kappaN,O]zinc}. AB - The binuclear title complex, [Zn(2)(C(22)H(28)N(3)O)(2)(C(3)H(9)OSi)(2)], has a crystallographic imposed centre of symmetry. The Zn(II) atom is coordinated by three O and one N atom from one 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentyl phenolate ligand and two bridging trimethyl-silanolate anions in a distorted tetra-hedral geometry. The dihedral angle between the benzotriazole ring system and the benzene ring is 19.83 (5) degrees . The tert-pentyl groups are disordered over two orientations with refined site-occupancy ratios of 0.858 (4):0.142 (4) and 0.665 (6):0.335 (6). PMID- 22259381 TI - Bis(MU-pyridinium-2-carboxyl-ato-kappaO:O')bis-[triaqua-(sulfato kappaO)manganese(II)]. AB - The asymmetric unit of the title compound, [Mn(2)(SO(4))(2)(C(6)H(5)NO(2))(2)(H(2)O)(6)], comprises half of a centrosymmetric dimer. The Mn(II) atom is coordinated by two O atoms of the monodentate carboxyl-ate ligand, an O atom of the sulfate anion in axial position and three water mol-ecules in a distorted octa-hedral geometry. In the crystal, mol-ecules are connected through N-H?O and O-H?O hydrogen bonds, forming a three dimensional network. The crystal structure is further stabilized by inter molecular pi-pi inter-actions [centroid-centroid distance = 3.842 (2) A]. PMID- 22259382 TI - cis-Bis(4-methyl-piperazine-1-carbo-dithio-ato-kappaS,S')bis-(pyridine kappaN)cadmium. AB - In the title complex, [Cd(C(6)H(11)N(2)S(2))(2)(C(5)H(5)N)(2)], the Cd(II) ion is hexa-coordinated by two N atoms from two pyridine ligands and by four S atoms from two dithio-carbamate ligands in a distorted octa-hedral geometry. The Cd(II) ion lies on a twofold axis. The piperazine ring is in chair conformation and its least-squares plane makes a dihedral angle of 81.4 (1) degrees with that of the pyridine ring. PMID- 22259383 TI - Tetra-kis(1-allyl-1H-imidazole-kappaN)bis-(thio-cyanato-kappaN)manganese(II). AB - The structure of the title compound, [Mn(NCS)(2)(C(6)H(8)N(2))(4)], consists of isolated mol-ecules of [Mn(NCS)(2)(Aim)(4)] (Aim = 1-allyl-imidazole), which contain a compressed octa-hedral MnN(6) chromophore (site symmetry [Formula: see text]). The NCS(-) anions are trans and four N atoms from the Aim ligands define the equatorial plane. The mean Mn-N(Aim) and Mn-N(NCS) distances are 2.270 and 2.229 A, respectively. Weak C-H?N inter-actions contribute to the crystal packing stability. PMID- 22259384 TI - Tetra-hedral zinc in tetra-kis-(1-methyl-1H-imidazole-kappaN)zinc bis-(tetra fluorido-borate). AB - In the title compound, [Zn(C(4)H(6)N(2))(4)](BF(4))(2), the Zn(II) ion is in a slightly distorted tetra-hedral coordination geometry, with Zn-N distances in the range 1.980 (2)-1.991 (2) A. The tetra-hedral angles are in the range 104.93 (9) 118.81 (9) degrees . PMID- 22259385 TI - catena-Poly[[bis-(acetato-kappaO)aqua-copper(II)]-MU-5-(pyridin-3-yl)pyrimidine kappaN:N]. AB - In the title compound, [Cu(CH(3)CO(2))(2)(C(9)H(7)N(3))(H(2)O)](n), the Cu(II) ion is penta-coordinated in a square-pyramidal geometry. The N atoms of the two chelating symmetry-related 5-(pyridin-3-yl)pyrimidine ligands and the O atoms of the two monodentate acetate anions are nearly coplanar, with a mean deviation from the least-squares plane of 0.157 (2) A and the Cu(II) ion is displaced by 0.050 (3) A from this plane towards the apical water O atom. Bridging through the bis-monodentate 5-(pyridin-3-yl)pyrimidine ligand forms a one-dimensional coordination polymer extending parallel to [010]. In the crystal, O-H?O hydrogen bonds link the mol-ecules into a two-dimensional supra-molecular structure parallel to (100). The crystal studied was an inversion twin with a 0.57 (3):0.43 (3) domain ratio. PMID- 22259386 TI - 5',11'-Dihydro-dispiro-[cyclo-hexane-1,6'-indolo[3,2-b]carbazole-12',1''-cyclo hexa-ne]. AB - The title compound, C(28)H(30)N(2), is a symmetrical 2:2 product from the condensation of indole and cyclo-hexa-none. It is the only reported 5,11-dihydro indolo[3,2-b]carbazole compound in which the spiro atoms are quaternary C atoms. Crystals were grown by vapor diffusion in a three-zone electric furnace. The mol ecule resides on a crystallographic inversion center. The cyclo-hexyl rings are in a slightly distorted chair conformation, whereas the indole units and the spiro-carbons are coplanar within 0.014 A. PMID- 22259387 TI - N-Benzoyl-4-nitro-benzene-sulfonamide monohydrate. AB - In the title compound, C(13)H(10)N(2)O(5)S.H(2)O, the dihedral angle between the sulfonyl and benzoyl benzene rings is 83.4 (1) degrees . In the crystal, the water mol-ecule forms four hydrogen bonds with three different mol-ecules of N benzoyl-4-nitro-benzene-sulfonamide. One of the H atoms of H(2)O forms a bifurcated hydrogen bond with a sulfonyl and the carbonyl O atoms. Mol-ecules are linked into a three-dimensional network by N-H?O and O-H?O hydrogen bonds. PMID- 22259388 TI - 2-Eth-oxy-5-methylbis[1,2,4]triazolo[1,5-a:4',3'-c]quinazoline. AB - The title compound, C(13)H(12)N(6)O, is a functionalized ditriazoloquinazoline with substituted eth-oxy and methyl groups attached at the 2-position of each triazole spacer. The fused-ring system is essentially planar [r.m.s. deviation = 0.016 (2) A]. In the crystal, a weak C-H?N hydrogen bond connects the mol-ecules into a chain along [101]. PMID- 22259389 TI - 3,14-Dimethyl-2,6,13,17-tetra-aza-tricyclo-[16.4.0.0]docosa-ne-(naphthalen-1 yl)methanol (1/2). AB - In the title co-crystal, C(20)H(40)N(4).2C(11)H(10)O, the macrocycle is generated by a crystallographic inversion centre. The N atoms show a pyramidal coordination, and the cyclo-hexane ring that is fused to the 14-membered C(10)N(4) ring exists in a chair conformation, whereas the methyl substituent occupies an axial site. The (naphthalen-1-yl)methanol mol-ecule forms an O-H?N hydrogen bond to a cyclam N atom. The mean-square-plane passing through the 14 membered ring is approximately coplanar with the naphthalene fused-ring [dihedral angle = 6.6 (1) degrees ]. PMID- 22259390 TI - 1-Benzyl-3-methyl-3',5'-diphenyl-spiro-[quinoxaline-2(1H),2'(3'H)-1,3,4-thia diazole]. AB - In the title spiro compound, C(29)H(24)N(4)S, the quinoxaline and thia-diazole ring systems share a common C atom; their mean planes are aligned at 87.0 (1) degrees in one mol-ecule and at 84.1 (1) degrees in the other independent mol ecule. The thia-zole ring possesses two aromatic ring substituents and is roughly coplanar with these rings [the dihedral angles between the thia-diazole and phenyl rings are 10.7 (1) and 11.7 (1) degrees in one mol-ecule, and 16.8 (1) and 17.7 (1) degrees in the other]. The aromatic ring of the benzyl unit of one mol-ecule is disordered over two orientations in a 1:1 ratio. PMID- 22259391 TI - 2-Chloro-N-{3-cyano-1-[2,6-dichloro-4-(trifluoro-meth-yl)phen-yl]-1H-pyrazol-5 yl}acetamide. AB - The title compound, C(13)H(6)Cl(3)F(3)N(4)O, was synthesized by the reaction of 5 amino-1-[2,6-dichloro-4-(trifluoro-meth-yl)phen-yl]-1H-pyrazole-3-carbonitrile and 2-chloro-acetyl chloride. The five-membered pyrazole ring makes a dihedral angle of 71.5 (3) degrees with the benzene ring. The -CF(3) group is disordered by rotation, and the F atoms are split over two sets of sites with occupancies of 0.59 (2) and 0.41 (2). The crystal structure features weak C-H?O and N-H?N inter actions involving the carbonyl and cyano groups as acceptors. PMID- 22259392 TI - N-[3-(4-Fluoro-benz-yl)-2,4-dioxo-1,3-diaza-spiro-[4.5]dec-8-yl]-2-methyl-benzene sulfonamide. AB - In the title compound, C(22)H(24)FN(3)O(4)S, the cyclo-hexane ring adopts a chair conformation and the five-membered ring is essentially planar, with a maximum deviation of 0.040 (2) A. The dihedral angles between the five-membered ring and the tolyl and fluoro-benzene rings are 56.74 (12) and 89.88 (12) degrees , respectively. The two terminal benzene rings make a dihedral angle of 63.53 (12) degrees . The crystal structure displays inter-molecular C-H?O and N-H?O hydrogen bonds. An intra-molecular C-H?O hydrogen bond also occurs. PMID- 22259393 TI - 20,23,26,29,32,35,38,41-Octa-oxa-5,9,13-triaza-penta-cyclo-[15.14.10.1.1.1]tetra tetra-conta-1,3(42),7,9,11(44),15(43),16,18,30-nona-ene-6,12-dione acetone mono solvate. AB - In the crystal structure of the title compound, C(33)H(39)N(3)O(10).C(3)H(6)O, the acetone mol-ecule is encapsulated into the cavity of the cryptand and fixed by two N-H?O and one C-H?O hydrogen bond. C-H?O and C-H?N inter-actions link neighbouring cryptands. The dihedral angles between the pyridine ring and the benzene rings are 86.47 (17) and 85.53 (13) degrees . PMID- 22259394 TI - 2-Amino-5-chloro-pyrimidin-1-ium hydrogen maleate. AB - In the title salt, C(4)H(5)ClN(3) (+).C(4)H(3)O(4) (-), the 2-amino-5-chloro pyrimidinium cation is protonated at one of its pyrimidine N atoms. In the roughly planar (r.m.s. deviation = 0.026 A) hydrogen malate anion, an intra molecular O-H?O hydrogen bond generates an S(7) ring. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are connected via further N-H?O hydrogen bonds and a short C-H?O inter-action, forming layers lying parallel to the bc plane. PMID- 22259395 TI - 2-(Dibromo-meth-yl)benzoic acid. AB - In the crystal structure of the title compound, C(8)H(6)Br(2)O(2), the carboxyl groups are involved in pairs of O-H?O hydrogen bonds, which link the mol-ecules into inversion dimers. PMID- 22259396 TI - 1'-Methyl-4'-(4-methyl-phen-yl)dispiro-[1-benzopyran-3(4H),3'-pyrrolidine-2',3'' indoline]-2,2''-dione. AB - In the title compound, C(27)H(24)N(2)O(3), the pyrroldine ring adopts a twist conformation, while the six-membered pyran-one ring of the coumarin ring system is in a sofa conformation. In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into inversion R(2) (2)(8) dimers. These dimers are further connected via C-H?O hydrogen bonds. PMID- 22259397 TI - (S)-3-Acetyl-3-[(R)-1-(4-bromo-phen-yl)-2-nitro-eth-yl]oxolan-2-one. AB - The title compound, C(14)H(14)BrNO(5), has two chiral C atoms. The quaternary C atom in the oxolanone ring has an S configuration, while the adjacent tertiary C atom has an R configuration. The oxolanone ring adopts an envelope conformation, with the flap C atom lying 0.298 (3) A from the mean plane of the remaining four atoms. In the crystal, mol-ecules are connected into chains along [010] via weak C-H?O hydrogen bonds. PMID- 22259398 TI - 5-Bromo-N-methyl-pyrimidin-2-amine. AB - In the title mol-ecule, C(5)H(6)BrN(3), the pyrimidine ring is essentially planar, with an r.m.s. deviation of 0.007 A. The Br and N atoms substituted to the pyrimidine ring are coplanar with the ring [displacements = 0.032 (1) and 0.009 (5) A, respectively], while the methyl C atom lies 0.100 (15) A from this plane with a dihedral angle between the pyrimidine ring and the methyl-amine group of 4.5 (3) degrees . In the crystal, C-H?N, C-H?Br and N-H?N hydrogen bonds link the mol-ecules into a two-dimensional network in the (011) plane. PMID- 22259399 TI - rac-Diethyl 5-oxo-2-[(2,4,4-trimethyl-pentan-2-yl)amino]-4,5-dihydro-pyrano[3,2 c]chromene-3,4-dicarboxyl-ate. AB - The title compound, C(26)H(33)NO(7), comprises a racemic mixture of asymmetric mol-ecules containing one stereogenic centre. The dihedral angle between the mean planes of the fused pyran ring and the coumarin ring system is 8.12 (14) degrees . The mol-ecular structure features a short N-H?O contact, which generates an S(6) ring motif. The crystal packing are stabilized by C-H?O inter-actions. PMID- 22259400 TI - 3,3-Dimethyl-2-benzofuran-1(3H)-one. AB - In the title compound, C(10)H(10)O(2), all the non-H atoms except the methyl C atoms lie on a crystallographic mirror plane. In the crystal, C-H?O hydrogen bonds link the mol-ecules into zigzag chains running parallel to [100]. Weak pi pi stacking inter-actions between the benzene rings [centroid-centroid distance = 3.9817 (5) A] link the chains in the [010] direction. PMID- 22259401 TI - 4-Meth-oxy-3-nitro-biphen-yl. AB - In the title compound, C(13)H(11)NO(3), the dihedral angle between the two benzene rings is 36.69 (2) degrees and the nitro and methy-oxy groups are oriented at 29.12 (14) and 2.14 (12) degrees with respect to the benzene ring to which they are bonded. PMID- 22259402 TI - Methyl 2-[2-(tert-but-oxy-carbonyl-amino)-1,3-benzothia-zole-6-carboxamido] acetate. AB - In the title compound, C(16)H(19)N(3)O(5)S, the dihedral angle between the benzene ring and the carbonyl-amino group is 18.18 (2) degrees . In the crystal, mol-ecules form centrosymmetric dimers via pairs of N-H?N hydrogen bonds. The dimers are connected via N-H?O hydrogen bonds into a three-dimensional network.. PMID- 22259403 TI - 1-(2-Hy-droxy-3,5-dimeth-oxy-phen-yl)ethanone. AB - In title compound, C(10)H(12)O(4), all of the non-H atoms lie approximately in a plane with the largest deviation being 0.061 (2) A. An intra-molecular O-H?O hydrogen bond generates an S(6) ring motif. No classical inter-molecular hydrogen bonding occurs, with only van der Waals forces stabilizing the crystal structure. PMID- 22259404 TI - 2,3-Dibromo-6-meth-oxy-4-[(phenethyl-amino)-methyl-idene]cyclo-hexa-2,5-dien-1 one methanol monosolvate. AB - In the title compound, C(16)H(15)Br(2)NO(2).CH(4)O, the mean planes of the substituted cyclo-hexa-2,5-dien-1-one and phenyl rings are almost parallel [dihedral angle = 7.84 (4) degrees ]. The crystal packing is stabilized by N-H?O hydrogen bonds generating infinite [101] chains. The methanol solvent mol-ecules are connected with the main species by O-H?O inter-actions. PMID- 22259405 TI - Ethyl 2-diethyl-amino-4-oxo-3,5-diphenyl-4,5-dihydro-3H-pyrrolo-[3,2-d]pyrimidine 7-carboxyl-ate. AB - In the title compound, C(25)H(26)N(4)O(3), the two fused pyrrolo-[3,2 d]pyrimidine rings form a dihedral angle of 3.7 (2) degrees . The two substituent phenyl rings are twisted with respect to the pyrrole and pyrimidine rings, making dihedral angles of 57.2 (2) and 69.0 (2) degrees , respectively. The ethyl and eth-oxy groups are disordered over two positions; the site occupancies are 0.53 (1) and 0.47 (1) for ethyl, and 0.63 (1) and 0.37 (1) for eth-oxy. The crystal packing features C-H?O hydrogen bonds. PMID- 22259406 TI - 1-Benzoyl-3-(2,4,5-trichloro-phen-yl)thio-urea. AB - The benzene and phenyl rings in the title compound, C(14)H(9)Cl(3)N(2)OS, form a dihedral angle of 40.98 (6) degrees . The mol-ecule exists in the thione form with typical thio-urea C-S [1.666 (2) A] and C-O [1.227 (3) A] bond lengths as well as shortened C-N bonds [1.345 (3) and 1.386 (2) A]. An intra-molecular N-H?O hydrogen bond stabilizes the mol-ecular conformation. In the crystal, pairs of N H?S hydrogen bonds link the mol-ecules into centrosymmetric dimers. PMID- 22259407 TI - N-(2,3,4-Trifluoro-phen-yl)pyrrolidine-1-carboxamide. AB - In the title compound, C(11)H(11)F(3)N(2)O, a urea derivative, the best plane through the pyrrole ring makes a dihedral angle of 9.69 (13) degrees with the benzene ring. The amino H atom is shielded, so that it is not involved in any hydrogen-bonding inter-actions. PMID- 22259408 TI - 1-Benzoyl-3-(4-n-butyl-phen-yl)thio-urea. AB - The dihedral angle between the benzoyl and phenyl groups in the title compound, C(18)H(20)N(2)OS, is 30.57 (4) degrees . The crystal packing is characterized by N-H?O hydrogen bonds. In the crysta, pairs of N-H?S hydrogen bonds link the molecules into inversion dimers. PMID- 22259409 TI - 2-(2-Carb-oxy-eth-yl)-1,3-dioxoisoindoline-5,6-dicarb-oxy-lic acid methanol monosolvate. AB - In the title compound, C(13)H(9)NO(8).CH(3)OH, the main mol-ecule possesses three carb-oxy-lic acid groups, which are asymmetrically distributed around the mol ecule core. This results in hydrogen-bonding motifs ranging from a chain to various rings. The combination of the chain motif together with a carb-oxy-lic dimer R(2) (2)(8) ring motif creates a ribbon of mol-ecules propagating along the c-axis direction. A second ribbon results from the combination of the chain motif together with a methanol solvent mol-ecule and carboxyl-containing R(4) (4)(12) ring motif. These two ribbons combine alternately, forming a hydrogen-bonded layer of mol-ecules parallel to (2[Formula: see text]0). PMID- 22259410 TI - (E)-1-{4-[Bis(4-bromo-phen-yl)meth-yl]piperazin-1-yl}-3-(4-eth-oxy-3-meth-oxy phen-yl)prop-2-en-1-one. AB - In the title mol-ecule, C(29)H(30)Br(2)N(2)O(3), the piperazine ring has a chair conformation and the C=C double bond has an E conformation. The dihedral angle between the bromo-benzene rings is 79.1 (3) degrees . In the crystal, mol-ecules are linked through C-H?O and C-H?Br hydrogen bonds. PMID- 22259411 TI - Ethyl 2-{[5-(3-chloro-phen-yl)-1-phenyl-1H-pyrazol-3-yl]-oxy}acetate. AB - The title compound, C(19)H(17)ClN(2)O(3), was synthesized by the reaction of 5-(3 chloro-phen-yl)-1-phenyl-1H-pyrazol-3-ol and ethyl 2-bromo-acetate. In the crystal, the C- and N-linked benzene rings are twisted by 45.15 (3) and 53.55 (3) degrees , respectively, from the plane of the bridging 1H-pyrazole ring. PMID- 22259412 TI - 2-Amino-pyridinium 2-meth-oxy-carbonyl-4,6-dinitro-phenolate. AB - In the title mol-ecular salt, C(5)H(7)N(2) (+).C(8)H(5)N(2)O(7) (-), the 2-amino pyridinium cation is essentially planar, with a maximium deviation of 0.015 (1) A, while the 2-meth-oxy-carbonyl-4,6-dinitro-phenolate anion is slightly twisted away from planarity, with a maximium deviation of 0.187 (1) A. Deprotonation of the hy-droxy O atom was observed. The cation and anion are connected by four bifurcated N-H?(O,O) hydrogen bonds, forming a mol-ecular proton-transfer adduct. The dihedral angle between the pyridinium ring in the cation and the benzene ring in the anion is 3.65 (6) degrees . Every adduct connects to six neighboring adducts by N-H?O and C-H?O hydrogen bonds, yielding extended layers parallel to the bc plane. There is a weak pi-pi inter-action between the benzene rings of two neighboring anions; the inter-planar spacing and the centroid-centroid separation are 3.309 (1) and 3.69 (1) A, respectively. PMID- 22259413 TI - (11aS)-7-Bromo-2,3,5,10,11,11a-hexa-hydro-1H-pyrrolo-[2,1-c][1,4]benzodiazepine 3,11-dione. AB - The title compound, C(12)H(11)BrN(2)O(2), was prepared by an intra-cyclization reaction of (S)-1-(5-bromo-2-nitro-benz-yl)-5-oxopyrrolidine-2-carb-oxy-lic acid methyl ester in the presence of EtOH/Fe. The five-membered pyrrolidinone ring adopts an approximate envelope conformation, while the seven-membered diazepanone ring displays a twisted boat conformation. Inter-molecular classical N-H?O hydrogen bonds and weak C-H?O inter-actions help to stabilize the crystal structure. PMID- 22259415 TI - N,N'-Bis(2,6-diethyl-phen-yl)acenaphthyl-ene-1,2-diimine. AB - The title compound, C(32)H(32)N(2), has crystallographic twofold rotation symmetry, with two C atoms lying on the rotation axis. The dihedral angle between the substituted benzene ring and the naphthalene ring system is 79.8 (1) degrees . The crystal structure is stabilized by C-H?N inter-actions, which form a chain motif along the b-axis direction. PMID- 22259414 TI - (Z)-Ethyl 2-(2,4-dimethyl-benzyl-idene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate. AB - In the title compound, C(25)H(24)N(2)O(3)S, the dihedral angles between the thia zole ring and the phenyl and substituted benzene rings are 84.91 (11) and 11.58 (10) degrees , respectively. The dihydro-pyrimidine ring adopts a flattened boat conformation. The olefinic double bond is in a Z configuration. PMID- 22259416 TI - Ethyl 2-(3,5-dinitro-benzamido)-benzoate. AB - The title mol-ecule, C(16)H(13)N(3)O(7), is slightly twisted, with the dihedral angle between the two benzene ring planes being 17.4 (1) degrees . An intra molecular N-H?O hydrogen bond is observed. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into chains along the b axis. PMID- 22259417 TI - N-(2,3,4-Trifluoro-phen-yl)morpholine-4-carboxamide. AB - In title mol-ecule, C(11)H(11)F(3)N(2)O(2), the central -N-C(=O)-N- unit is essentially planar [maximum deviation = 0.013 (2) A] and forms a dihedral angle of 57.33 (9) degrees with the benzene ring. The morpholine ring is in a chair conformation. In the crystal, mol-ecules are linked into chains along [001] by N H?O hydrogen bonds. PMID- 22259418 TI - 2,4,5-Tris(pyridin-4-yl)-1H-imidazole monohydrate. AB - In the crystal structure of the title compound, C(18)H(13)N(5).H(2)O, adjacent mol-ecules are linked by O-H?N and N-H?O hydrogen bonds, generating a chain propagating along [001]. PMID- 22259419 TI - 1H-1,2,4-Triazol-4-ium (3,4-dichloro-phen-yl)methane-sulfonate. AB - In the title molecular salt, C(2)H(4)N(3) (+).C(7)H(5)Cl(2)O(3)S(-), C-C-S angle [112.25 (18) degrees ] deviates slightly from that expected for ideal sp(3) hybridization geometry. In the crystal, the components are linked by N-H?O and bifurcated N-H?(O,O) hydrogen bonds into chains parallel to [110]. PMID- 22259420 TI - 5,6-Dimethyl-pyrazine-2,3-dicarb-oxy-lic acid. AB - The asymmetric unit of the title compound, C(8)H(8)N(2)O(4), consists of one complete mol-ecule and a second mol-ecule generated by the application of twofold axis. The mean planes of the two carboxyl groups attached to the pyrazine ring at neighboring positions are twisted by 10.8 (1) and 87.9 (1) degrees in the complete molecule and 43.0 (1) degrees in the symmetry-generated molecule. The crystal packing features O-H?N hydrogen bonds, which link the mol-ecules into layers along [101]. PMID- 22259421 TI - Methyl 4-(5-meth-oxy-1H-indol-3-yl)benzoate. AB - In the title compound, C(17)H(15)NO(3), the dihedral angle between the benzene ring and the indole ring system is 22.5 (3) degrees . In the crystal, mol-ecules are linked by N-H?pi and C-H?O inter-actions. PMID- 22259422 TI - 1H-Imidazol-3-ium-4-carboxyl-ate. AB - In the title compound, C(4)H(4)N(2)O(2), both imidazole N atoms are protonated and carboxyl-ate group is deprotonated, resulting in a zwitterion. The mol-ecule is essentially planar, with an r.m.s. deviation of 0.012 (1) A. In the crystal, N H?O hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distance = 3.674 (2) A] between the imidazole rings link the mol-ecules into a three dimensional supra-molecular network. PMID- 22259423 TI - 3'-[Hy-droxy(4-oxo-4H-chromen-3-yl)meth-yl]-2-oxospiro-[indoline-3,2' pyrrolidine]-3'-carbonitrile. AB - In the title compound, C(23)H(19)N(3)O(4), the pyran ring adopts a half-chair conformation, while the pyrrolidine (with a C atom as the flap atom) and the five membered ring in the indoline (with a C atom as the flap atom) ring system adopt slight envelope conformations. The pyrrolidine ring makes dihedral angles of 83.3 (1) and 60.4 (1) degrees with the mean plane through all non-H atoms of the indoline and chromene ring systems, respectively. In the crystal, mol-ecules are connected by two unique N-H?O and O-H?O hydrogen-bonding inter-actions, which form centrosymmetric patterns described by graph-set motifs R(2) (2)(18) and R(2) (2)(14). These two motifs combine to form a hydrogen-bonded chain which propagates in the a-axis direction. The crystal structure is also stablized by C H?O inter-actions and by aromatic pi-pi stacking inter-actions between the pyran and benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.755 (1) A and slippage = 1.371 (2) A]. PMID- 22259424 TI - 3-Amino-5-(piperidin-1-yl)thio-phene-2,4-dicarbonitrile. AB - In the title compound, C(11)H(12)N(4)S, the thio-phene ring is roughly planar, with a maximum deviation of 0.012 (1) A for the S atom, and makes a dihedral angle of 7.89 (8) degrees with the mean plane of the piperidine ring, which is in a chair conformation. The crystal packing is stabilized by pairs of centrosymmetric inter-molecular N-H?N hydrogen bonds, which results in the formation of a step-wise chain parallel to [10[Formula: see text]]. PMID- 22259425 TI - 1-[2-(2,4-Dichloro-benz-yloxy)-2-(furan-2-yl)eth-yl]-1H-benzotriazole. AB - In the title compound, C(19)H(15)Cl(2)N(3)O(2), the benzotriazole ring system is approximately planar [maximum deviation = 0.018 (2) A] and its mean plane is oriented at dihedral angles of 30.70 (5) and 87.38 (4) degrees , respectively, to the furan and benzene rings while the dihedral angle between furan and benzene rings is 74.46 (6) degrees . In the crystal, weak C-H?N hydrogen bonds link the mol-ecules into chains along the b axis. pi-pi stacking inter-actions between the parallel dichloro-benzene rings of adjacent mol-ecules [centroid-centroid distance = 3.6847 (9) A] and weak C-H?pi inter-actions are also observed. PMID- 22259426 TI - 6-Chloro-1-methyl-indoline-2,3-dione. AB - The title mol-ecule, C(9)H(6)ClNO(2), is essentially planar: the maximum deviation from the mean plane of the indoline ring is 0.020 (2) A and the substituents do not deviate by more than 0.053 (2) A from this plane. C-H?O hydrogen bonds help to consolidate the crystal structure. PMID- 22259427 TI - 2-(7-Methyl-1H-indol-3-yl)acetonitrile. AB - In the title compound, C(11)H(10)N(2), the carbonitrile group is twisted away from the indole plane [C(cy)-C(me)-C(ar)-C(ar) = 66.6 (2) degrees ; cy = cyanide, me = methyl-ene and ar = aromatic]. In the crystal, N-H?N hydrogen bonds link the mol-ecules into C(7) chains propagating in the [001] direction. PMID- 22259428 TI - 4,6-Dichloro-2-{[(E)-(3-{[(E)-3,5-dichloro-2-hy-droxy-benzyl-idene]amino}-2,2 dimethyl-prop-yl)imino]-meth-yl}phenol. AB - In the title compound, C(19)H(18)Cl(4)N(2)O(2), a potential tetra-dentate Schiff base ligand, the dihedral angle between the two benzene rings is 48.01 (10) degrees . The configuration about the two C=N bonds is E and two intra-molecular O-H?N hydrogen bonds make S(6) ring motifs. In the crystal, mol-ecules are linked along the b axis via inter-molecular C-H?Cl inter-actions. The crystal structure is further stabilized by an inter-molecular pi-pi inter-action [centroid-centroid distance = 3.5744 (12) A]. PMID- 22259429 TI - 2-(4-Meth-oxy-1H-indol-3-yl)acetonitrile. AB - In the title compound, C(11)H(10)N(2)O, the cyanide group is twisted away from the indole-ring plane [C(cy)-C(me)-C(ar)-C(ar) = 70.7 (2) degrees ; cy = cyanide, me = methyl-ene, ar = aromatic], whereas the meth-oxy C atom is almost coplanar with the ring system [displacement = 0.014 (5) A]. In the crystal, N-H?N hydrogen bonds link the mol-ecules into C(7) chains propagating in [100]. PMID- 22259430 TI - 2-(6-Chloro-1H-indol-3-yl)acetonitrile. AB - In the title compound, C(10)H(7)ClN(2), the carbonitrile group is twisted away from the plane of the indole ring system [C(cy)-C(me)-C(ar)-C(ar) = -44.7 (8) degrees ; cy = cyanide, me = methyl-ene and ar = aromatic]. In the crystal, N-H?N hydrogen bonds link the mol-ecules into C(7) chains propagating in [010]. Aromatic pi-pi stacking inter-actions [minimum centroid-centroid separation = 3.663 (3) A] are also observed. PMID- 22259431 TI - 5-Chloro-1H-indole-3-carb-oxy-lic acid. AB - In the title compound, C(9)H(6)ClNO(2), the carboxyl group is twisted from the indole ring system by 9.00 (8) degrees . In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(8) loops and N-H?O hydrogen bonds link the dimers into (001) sheets. Aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.7185 (12) A degrees ] are also observed. PMID- 22259432 TI - 3-Carb-oxy-methyl-1H-indole-4-carb-oxy-lic acid. AB - In the title compound, C(11)H(9)NO(4), the carboxyl group bonded to the six membered ring lies close to the plane of the 1H-indole ring system [dihedral angle = 13.13 (9) degrees ], whereas the carb-oxy-lic acid group linked to the five-membered ring by a methyl-ene bridge is close to perpendicular [78.85 (9) degrees ]. In the crystal, O-H?O and N-H?O hydrogen bonds link the mol-ecules, generating (110) sheets. PMID- 22259433 TI - 1-[(6-Chloro-pyridin-3-yl)meth-yl]imidazolidin-2-iminium chloride. AB - The title compound, C(9)H(12)ClN(4) (+).Cl(-), is a natural metabolic product of imidacloprid [systematic name: (E)-1-(6-chloro-3-pyridyl-meth-yl)-N-nitro imidazolidin-2-yl-idene-amine] and was obtained by the reduction of the latter using Fe in HCl. The dihedral angle between the pyridine and imidazole rings is 62.09 (12) degrees . The crystal structure is stabilized by N-H?Cl and C-H?Cl inter-actions involving the chloride anion. The pyridine N and the chloride atoms are not involved in inter-molecular inter-actions. PMID- 22259434 TI - 3,3'-(Ethane-1,2-di-yl)bis-(3,4-dihydro-2H-1,3-benzoxazine). AB - The title compound, C(18)H(20)N(2)O(2), was prepared by Mannich-type reaction of phenol, ethane-1,2-diamine and formaldehyde. The heterocyclic rings adopt half chair conformations. The acyclic methyl-ene groups attached to the N atoms are in an axial position. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into dimers. These dimers are further connected via C-H?pi contacts. PMID- 22259435 TI - (2R)-8-Benzyl-2-[(S)-hy-droxy(phen-yl)meth-yl]-8-aza-bicyclo-[3.2.1]octan-3-one. AB - The crystal of the title compound, C(21)H(23)NO(2), was chosen from a conglomerate formed by a racemic mixture. An intra-molecular hydrogen bond is formed between hy-droxy group and heterocyclic N atom of the aza-bicyclo [3.2.1]octan-3-one system. The crystal structure is stabilized by C-H?O inter actions between aliphatic C-H groups and the carbonyl O atom. For the title chiral crystal, the highly redundant and accurate diffraction data set collected with low energy copper radiation gave a Flack parameter of 0.12 (18) for anomalous scattering effects originating from O atoms. PMID- 22259436 TI - 2,2',5,5'-Tetra-chloro-N,N'-diethyl-N,N'-[benzene-1,3-diylbis(methyl ene)]dibenzene-sulfonamide. AB - In the title compound, C(24)H(24)Cl(4)N(2)O(4)S(2), the dihedral angles between the central benzene ring and the pendant rings are 58.09 (10) and 62.59 (10) degrees . The dihedral angle between the pendant rings is 81.64 (9) degrees . Both sulfonamide groups lie to the same side of the central ring but the C-S-N-C torsion angles [73.09 (16) and -117.35 (14)] and S-N-C-C torsion angles [-143.80 (14) and -111.45 (16) degrees ] differ significantly for the two pendant chains. The N atoms are close to planar (bond angle sums = 356.4 and 359.5 degrees ). In the crystal, weak C-H?O and C-H?Cl inter-actions link the mol-ecules. PMID- 22259437 TI - (E)-3,3'-(Diazene-1,2-di-yl)bis-(1-methyl-1,4,5,6-tetra-hydro-pyrrolo-[3,4 c]pyrazol-5-ium) dinitrate dihydrate. AB - The title compound, C(12)H(18)N(8) (2+).2NO(3) (-).2H(2)O, was synthesized unexpectedly from 3-amino-1-methyl-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazol-5 ium chloride and cerium(IV) ammonium nitrate. The cation has a crystallographically imposed centre of symmetry. In the crystal, the ions and water mol-ecules are linked via O-H?N, N-H?O and O-H?O hydrogen bonds into a three-dimensional network. PMID- 22259438 TI - 1-(4-Fluoro-phen-yl)-2-(1H-imidazol-1-yl)ethanol. AB - In the title compound, C(11)H(11)FN(2)O, the dihedral angle between the mean planes of the two rings is 1.30 (4) degrees . In the crystal, O-H?N hydrogen bonds link the mol-ecules into chains along the b axis. PMID- 22259439 TI - 4-(Furan-2-ylmeth-oxy)benzene-1,2-dicarbonitrile. AB - In the title compound, C(13)H(8)N(2)O(2), prepared from furfuryl alcohol and 4 nitro-phthalonitrile in the presence of potassium carbonate in dimethyl formamide, the furan and benzene rings are oriented at a dihedral angle of 53.45 (9) degrees . In the crystal, weak C-H?O and C-H?N hydrogen bonds link the mol ecules into a three-dimensional network. PMID- 22259440 TI - (E)-3-(2,4-Dimeth-oxy-phen-yl)-1-(3,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title chalcone derivative, C(20)H(22)O(6), the dihedral angle between the mean planes of the benzene rings is 15.77 (6) degrees . The H atoms of the central C=C double bond are in a trans configuration. There are a number of C-H?O interactions and a C-H?pi interaction present in the crystal structure. PMID- 22259441 TI - 5-(3-Chloro-phen-ylsulfan-yl)-1-methyl-3-trifluoro-methyl-1H-pyrazole-4 carbaldehyde O-[(2-chloro-1,3-thia-zol-5-yl)meth-yl]oxime. AB - In the title compound, C(16)H(11)Cl(2)F(3)N(4)OS(2), the benzene ring and the thia-zole ring make dihedral angles of 83.2 (3) and 78.3 (3) degrees , respectively, with the pyrazole ring. The crystal packing shows S?N contacts of 3.309 (2) A. PMID- 22259442 TI - Methyl (Z)-2-[(2,4-dioxothia-zolidin-3-yl)meth-yl]-3-(2-methyl-phen-yl)prop-2 enoate. AB - The C=C bond in the title compound, C(15)H(15)NO(4)S, has a Z configuration. The thia-zolidine ring is essentially planar [maximum deviation = 0.008 (1) A for the N atom] and is oriented at a dihedral angle of 59.1 (1) degrees with respect to the benzene ring. In the crystal, pairs of C-H?O hydrogen bonds link centrosymmetrically related mol-ecules into dimers, generating R(2) (2)(18) ring motifs. The crystal packing is further stabilized by C-H?pi and C-O?pi [O?centroid = 3.412 (2) A and C-O?centroid = 115.0 (1) degrees ] inter-actions. PMID- 22259443 TI - 3,3'-Bis(quinolin-8-yl)-1,1'-[4,4'-methyl-enebis(4,1-phenyl-ene)]diurea. AB - The title compound, C(33)H(26)N(6)O(2), contains two 3-(quinolin-8-yl)urea groups linked to a diphenyl-methane. The asymmetric unit contains two mol-ecules, A and B. Each quinoline plane is essentially parallel to the attached urea unit [dihedral angles = 8.97 (18) and 8.81 (19) in molecule A and 18.47 (18) and 4.09 (19) degrees in molecule B]. The two benzene rings are twisted, making dihedral angles of 81.36 (8) degrees in A and 87.20 (9) degrees in B. The molecular structures are stabilized by intramolecular N-H?N hydrogen bonds. In the crystal, each urea O atom is involved in two N-H?O hydrogen bonds, generating two inter penetrating three-dimensional sets of mol-ecules. PMID- 22259444 TI - 1-Hy-droxy-11H-benzo[b]fluoren-11-one. AB - The title compound, C(17)H(10)O(2), is nearly planar, the maximum atomic deviation being 0.053 (2) A. In the mol-ecule, an intra-molecular O-H?O hydrogen bond generates an S(6) ring motif. In the crystal, inversion-related mol-ecules are linked by pairs of weak C-H?O hydrogen bonds, forming dimers. pi-pi stacking is observed in the crystal structure, the closest centroid-centroid distance being 3.7846 (16) A. PMID- 22259445 TI - (E)-N'-[(E)-3-Phenyl-allyl-idene]benzo-hydrazide. AB - In the title mol-ecule, C(16)H(14)N(2)O, the dihedral angle between the two phenyl rings is 23.5 (6) degrees . In the crystal, N-H-O hydrogen bonds link mol ecules into chains running along the a axis. PMID- 22259446 TI - (2-Anilino-4-methyl-thia-zol-5-yl)(4-chloro-phen-yl)methanone. AB - The title compound, C(17)H(13)ClN(2)OS, crystallizes with three independent mol ecules (A, B and C) in the asymmetric unit which differ slightly in their conformations. In mol-ecule A, the thiazole ring makes dihedral angles of 27.44 (14) and 66.05 (6) degrees with the phenyl and chloro-benzene rings. In mol ecule B, the respective angles are 29.09 (10) and 47.63 (9) degrees , while values of 25.67 (11) and 51.01 (7) degrees are observed in mol-ecule C. In the crystal, N-H?N and N-H?O hydrogen bonds generate a three-dimensional network structure. PMID- 22259447 TI - Methyl 6-chloro-nicotinate. AB - The mol-ecule of the title compound, C(7)H(6)ClNO(2), is almost planar, with a dihedral angle of 3.34 (14) degrees between the COOMe group and the aromatic ring. In the crystal, the mol-ecules are arranged into (1[Formula: see text]2) layers by C-H?N hydrogen bonds and there are pi-pi stacking inter-actions between the aromatic rings in adjacent layers [centroid-centroid distance 3.8721 (4) A]. PMID- 22259448 TI - 1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)ethanone. AB - In the title compound, C(21)H(16)F(2)O(2), the central benzene ring is inclined at dihedral angles of 30.91 (8) and 46.88 (7) degrees to the two terminal fluoro substituted rings. The dihedral angle between the two terminal fluoro-subsituted rings is 68.34 (8) degrees . An intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. The crystal structure is stabilized by weak C-H?pi inter actions. PMID- 22259449 TI - (Z)-N-[(Z)-3-(2,4-Dimethyl-phenyl-imino)-butan-2-yl-idene]-2,4-dimethyl-aniline. AB - The asymmetric unit of the title compound, C(20)H(24)N(2), contains one half -mol ecule which exhibits a crystallographically imposed center of symmetry. The benzene rings are inclined to the 1,4-diaza-butadiene mean plane by 78.3 (2) degrees . PMID- 22259450 TI - Methyl 2-(8a-hy-droxy-4a-methyl-8-methyl-enedeca-hydro-naphthalen-2-yl)acrylate. AB - The title compound, C(16)H(24)O(3), was synthesized from ilicic acid which was isolated from the aerial part of Inula Viscosa- (L) Aiton [or Dittrichia Viscosa- (L) Greuter]. The mol-ecule contains two fused six-membered rings both in chair conformations. In the crystal, mol-ecules are linked into chains running parallel to the a axis by O-H?O hydrogen bonds. PMID- 22259451 TI - (E)-4-Chloro-N-[4-(methyl-sulfon-yl)benzyl-idene]aniline. AB - In the crystal structure of the title compound, C(14)H(12)ClNO(2)S, the mol ecules display a trans conformation with respect to the C=N double bond. The dihedral angle between the methyl-sulfonyl benzene and chloro-benzene rings is 59.59 (8) degrees . The crystal packing is stabilized by weak C-H?O inter-actions and by pi-pi stacking inter-actions between inversion-related methyl-sulfonyl benzene rings [centroid-centroid distance = 3.8579 (11) A]. PMID- 22259452 TI - 10alpha-Hy-droxy-4,9-dimethyl-13-(morph-o-lin-4-ylmeth-yl)-3,8,15-trioxatetra cyclo-[10.3.0.0.0]penta-decan-14-one. AB - The title compound, C(19)H(29)NO(6), was synthesized from 9alpha-hy-droxy parthenolide (9alpha-hy-droxy-4,8-dimethyl-12-methyl-ene-3,14-dioxatricyclo [9.3.0.0(2,4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule contains a fused five- and ten-membered ring system. The ten-membered ring adopts an approximate chair-chair conformation, while the five-membered ring is in an envelope conformation, with the C atom closest to the hy-droxy group forming the flap. In the crystal, weak C-H?O hydrogen bonds connect the mol-ecules into layers parallel to (001). An intra-molecular O-H?N hydrogen bond is also present. PMID- 22259453 TI - (4R)-4-Benzyl-3-{(4S)-4-chloro-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]butano-yl} 1,3-oxazolidin-2-one. AB - The title compound, C(19)H(24)ClNO(5), was synthesized and subsequently employed in an Evans alkyl-ation. The purpose was to prove the absolute configuration in the projected synthesis of the side chain of (-)-Lytophilippine A. The oxazolidinone and the isopropylidene acetal rings have twisted conformations. The oxazolidinone and side-chain carbonyl groups are orientated in an anti-periplanar arrangement to minimize van der Waals repulsions. Furthermore, the Cl atom and the acetonide-protected secondary alcohol are also in an anti-periplanar arrangement with a torsion angle of 173.64 (14) degrees . The absolute configuration was determined and agrees with the configuration of the used chiral auxiliary. PMID- 22259454 TI - 1-Hexyl-1,3,6,8-tetra-aza-tricyclo-[4.3.1.1]undecan-1-ium iodide. AB - In the title compound, C(13)H(27)N(4) (+).I(-), the ethyl-ene bridge is distorted from the ideal D(2d) symmetry wherein an N-C-C-N planar bridge, around whose C-C bond the C-N and C-H bonds are exactly eclipsed, is disordered over two sites with equal occupancies. In both disorder components, the hexyl chain adopts an ideal all-trans conformation. In the crystal, adjacent ions are connected by C H?I hydrogen bonds, forming ionic pairs that are further linked into chains along [101] via a second C-H?I inter-action. PMID- 22259455 TI - 2,2'-[Imidazolidine-1,3-diylbis(methyl-ene)]diphenol. AB - In the title mol-ecule, C(17)H(20)N(2)O(2), the imidazolidine ring adopts a twist conformation. The mean plane through the five atoms of the imidazolidine ring makes dihedral angles of 70.18 (4) and 74.14 (4) degrees with the planes of the two aromatic rings. The dihedral angle between the benzene rings is 53.11 (5) degrees . Both phenol -OH groups form intra-molecular hydrogen bonds to the N atoms, with graph-set motif S(6). In the crystal, pairs of O-H?O hydrogen bonds link the mol-ecules into dimers with R(4) (4)(18) ring motifs. The crystal packing is further stabilized by C-H?O and weak C-H?pi inter-actions. PMID- 22259456 TI - Ethyl 4,4''-difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-carboxyl-ate. AB - In the title compound, C(22)H(18)F(2)O(3), the two fluoro-substituted rings form dihedral angles of 25.89 (15) and 55.00 (12) degrees with the central benzene ring. The eth-oxy group in the mol-ecule is disordered over two positions with a site-occupancy ratio of 0.662 (7):0.338 (7). In the crystal, mol-ecules are linked by C-H?O hydrogen bonds into chains along the a axis. The crystal packing is further stabilized by C-H?pi and pi-pi inter-actions, with centroid-centroid distances of 3.8605 (15) A. PMID- 22259457 TI - N-{2-[4-(2-Hy-droxy-eth-yl)piperazin-1-yl]eth-yl}phthalimide. AB - In the title compound, C(16)H(21)N(3)O(3), the piperazine ring adopts a chair conformation, with its N-C bonds in pseudo-equatorial orientations. In the crystal, mol-ecules are linked by O-H?N hydrogen bonds, generating C(5) chains propagating in [101]. Weak aromatic pi-pi stacking inter-actions also occur [centroid-centroid separation = 3.899 (1) A]. PMID- 22259458 TI - (2-Amino-phen-yl)methanol. AB - The crystal strucure of the title compound, C(7)H(9)NO, displays N-H?O hydrogen bonds which link mol-ecules related by translation along the b axis, and O-H?N and further N-H?O hydrogen bonds which link mol-ecules related by the 2(1) screw axis along the c axis. The resulting combination is a hydrogen-bonded layer of mol-ecules parallel to (011). PMID- 22259459 TI - 4-[(E)-(4-Fluoro-benzyl-idene)amino]-benzoic acid. AB - In the title compound, C(14)H(10)FNO(2), the benzene rings make a dihedral angle of 57.50 (13) degrees , and the molecule has an E configuration about the C=N bond. In the crystal, molecules are linked via pairs of O-H?O hydrogen bonds, forming inversion dimers. PMID- 22259460 TI - (S)-4-Phenyl-2-(1,2,3,4-tetra-hydro-isoquinolin-3-yl)-1,3-thia-zole. AB - In the title compound, C(18)H(16)N(2)S, the N-containing ring adopts a half-chair configuration. The crystal packing features C-H?N contacts. There is no pi-pi stacking within the crystal structure. PMID- 22259461 TI - (S)-Methyl 2-benzamido-3-(3,4-dimeth-oxy-phen-yl)propano-ate. AB - The dimethoxypbenzene ring in the title compound, C(19)H(21)NO(5), is gauche to the amide group and anti to the ester group. The chirality was confirmed to be S from two-dimensional NMR spectroscopy. In the crystal, N-H?O and C-H?O hydrogen bonds and several short-contact inter-actions (2.07-3.45 A) create chains parallel to [110]. The phenyl ring is disordered over two orientations in a 0.54 (2):0.46 (2) ratio. PMID- 22259462 TI - 6'-Bromo-1'H-spiro-[cyclo-hexane-1,2'-pyrido[2,3-d]pyrimidin]-4'(3'H)-one. AB - The title compound, C(12)H(14)BrN(3)O, is built up from two fused six-membered rings and one six-membered ring linked through a spiro C atom. The hydro pyrimidine ring has an envelope conformation and the cyclo-hexane ring is in a chair conformation. In the crystal, mol-ecules are linked by N-H?O and N-H?N hydrogen bonds, forming a mol-ecular tape along the b axis. PMID- 22259463 TI - 5-(3,4-Dimeth-oxy-benzyl-idene)-1,3-dimethyl-1,3-diazinane-2,4,6-trione. AB - In the title compound, C(15)H(16)N(2)O(5), the dihedral angle between 1,3 diazinane and benzene rings is only 4.27 (1) degrees . The essentially planar mol ecular structure is characterized by a short intra-molecular C-H?O separation and by an exceptionally large bond angle of 138.25 (14) degrees at the bridging methine C atom. The meth-oxy groups deviate somewhat from the plane of the benzene ring, with C-C-O-C torsion angles of -15.6 (1) and 9.17 (6) degrees . In the crystal, mol-ecules form centrosymmetric dimers via donor-acceptor pi-pi inter-actions, with a centroid-centroid distance of 3.401 (1) A. PMID- 22259464 TI - 1,1-Dimethyl-biguanidium(2+) dinitrate. AB - In the crystal structure of the title compound, C(4)H(13)N(5) (2+).2NO(3) (-), the main inter-molecular inter-actions are the N-H?O hydrogen bonds between the cationic amino groups and the O atoms of the nitrate ions. All amino H atoms and nitrate O atoms are involved in the three-dimensional hydrogen-bond network. There are two graph-set motifs R(2) (2)(8), which include the amino groups connected to the N atoms in the biguanide 3-, 4- and 5-positions, and the O atoms of a nitrate ion. They are extended along the a axis. An O atom of the second nitrate ion is involved in a graph-set motif C(4) that is a part of a helix-like N-H?O?H-N-H?O? chain oriented along the b axis. There are also two weak C-H?O inter-actions in the crystal structure. PMID- 22259465 TI - 6-Ethyl-N-methyl-3-nitro-4-nitro-methyl-4H-chromen-2-amine. AB - In the title compound, C(13)H(15)N(3)O(5), the O and N atoms of the nitro-methyl group and the methyl C atom of the ethyl group are disordered over two sets of sites with refined occupancies of 0.629 (7):0.371 (7) and 0.533 (8):0.467 (8), respectively. The dihydro-pyran ring has an extremely flattened conformation. An intra-molecular N-H?O hydrogen bond occurs. In the crystal, pairs of N-H?O hydrogen bonds link mol-ecules, forming inversion dimers. In addition, weak inter molecular C-H?O hydrogen bonds are also present. PMID- 22259466 TI - 3-[(2-Formyl-thio-phen-3-yl)(hy-droxy)meth-yl]thio-phene-2-carbaldehyde. AB - In the title compound, C(11)H(8)O(3)S(2), the dihedral angle between the mean planes of the two thio-phene rings is 65.10 (10) degrees . Intra-molecular C-H?O inter-actions form S(6) and S(7) ring motifs. In the crystal, chains along the a axis are formed by C-H?O inter-actions. Adjacent chains are connected into a three-dimensional network by C-H?O and O-H?O inter-actions. PMID- 22259467 TI - 4-Isopropyl-amino-3-nitro-benzonitrile. AB - In the title compound, C(10)H(11)N(3)O(2), the nitro group is essentially coplanar with the aromatic ring [dihedral angle = 3.4 (3) degrees ] and forms an intra-molecular N-H?O hydrogen bond with the amine group. In the crystal, weak aromatic C-H?O and C-H?N hydrogen bonds link the mol-ecules. Weak aromatic ring pi-pi inter-actions [minimum ring centroid-centroid separation = 3.9841 (16) A] are also present. PMID- 22259468 TI - (E)-2-[(E)-3-(Hy-droxy-imino)-butan-2-yl-idene]-N-methyl-hydrazinecarbothio amide. AB - In the title compound, C(6)H(12)N(4)OS, an intra-molecular N-H?N hydrogen-bond is present giving rise to an S(5) ring motif. In the crystal, double-stranded chains propagating along [10[Formula: see text]] are formed via pairs of O-H?S and N-H?S hydrogen bonds. The chains are further stabilized by C-H?S interactions. PMID- 22259469 TI - 4-Methyl-anilinium perchlorate 18-crown-6 clathrate. AB - In the title compound, C(7)H(10)N(+).ClO(4) (-).C(12)H(24)O(6), the 4-methyl anilinium cation inter-acts with an 18-crown-6 mol-ecule forming a rotator-stator like structure through bifurcated N-H?(O,O) hydrogen bonds between the ammonium group of the cation and the O atoms of the crown ether mol-ecule. All three components of the structure possess mirror symmetry. The benzene ring is inclined to the mean plane of the crown ether molecule by 86.84 (8) degrees . PMID- 22259470 TI - 2,3-Diamino-pyridinium sorbate-sorbic acid (1/1). AB - In the title mol-ecular salt-adduct, C(5)H(8)N(3) (+).C(6)H(7)O(2) ( ).C(6)H(8)O(2), the 2,3-diamino-pyridinium cation is essentially planar, with a maximum deviation of 0.013 (2) A, and is protanated at its pyridine N atom. The sorbate anion and sorbic acid mol-ecules exist in extended conformations. In the crystal, the protonated N atom and one of the two amino-group H atoms are hydrogen bonded to the sorbate anion through a pair of N-H?O hydrogen bonds, forming an R(1) (2)(6) ring motif. The carboxyl groups of the sorbic acid mol ecules and the carboxyl-ate groups of the sorbate anions are connected via O-H?O hydrogen bonds. Furthermore, the ion pairs and neutral mol-ecules are connected via inter-molecular N-H?O hydrogen bonds, forming sheets lying parallel to (100). PMID- 22259471 TI - 5-Fluoro-1H-indole-3-carb-oxy-lic acid. AB - In the title compound, C(9)H(6)FNO(2), the carboxyl group is twisted slightly away from the indole-ring plane [dihedral angle = 7.39 (10) degrees ]. In the crystal, carboxyl inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(8) loops and N-H?O hydrogen bonds connect the dimers into (10[Formula: see text]) sheets. PMID- 22259472 TI - 6-Chloro-quinolin-2(1H)-one. AB - In the title compound, C(9)H(6)ClNO, the Cl atom deviates by 0.142 (1) A from the quinoline ring mean plane (r.m.s. deviation = 0.013 A). In the crystal, N-H?O hydrogen bonds link the mol-ecules into [010] C(4) chains. Aromatic pi-pi stacking inter-actions [shortest centroid?centroid distance = 3.685 (3) A] are also observed. PMID- 22259473 TI - 2-Chloro-N-(4-chloro-3-iodo-phen-yl)-4-(methyl-sulfon-yl)benzamide. AB - In the title compound, C(14)H(10)Cl(2)INO(3)S, the dihedral angle between the benzene rings is 52.13 (10) degrees . In the crystal, the components are linked by pairs of N-H?O(sulfon-yl) hydrogen bonds into centrosymmetric dimers. PMID- 22259474 TI - Form II of adipic acid-nicotinohydrazide (1/2). AB - The crystal structure of the title co-crystal, 2C(6)H(7)N(3)O.C(6)H(10)O(4), is a second polymorph, designated form II, of the co-crystal formed between the two mol-ecules [Lemmerer et al. (2011 ?). CrystEngComm, 13, 55-59]. The asymmetric unit comprises one mol-ecule of nicotinic acid hydrazide, and one half-mol-ecule of adipic acid (the entire mol-ecule is completed by the application of a centre of inversion). In the crystal, mol-ecules assemble into a three-dimensional network of hydrogen bonds, formed by three N-H?O hydrogen bonds and one O-H?N hydrogen bond. The O-H?N hydrogen bond formed between the carboxyl group and the pyridine ring is supported by a C-H?O hydrogen bond. PMID- 22259475 TI - 6,6'-Di-tert-butyl-4,4'-dimeth-oxy-2,2'-[1,3-diazinane-1,3-diylbis(methyl ene)]diphenol 0.19-hydrate. AB - In the title hexa-hydro-pyrimidine derivative, C(28)H(42)N(2)O(4).0.19H(2)O, the 1,3-diazinane ring has a chair conformation with a diequatorial substitution. The asymmetric unit contains one half-organic mol-ecule and a solvent water mol-ecule with occupany 0.095. The mol-ecule lies on a mirror plane perpendicular to [010] which passes through the C atoms at the 2- and 5-positions of the heterocyclic system. The partially occupied water mol-ecule is also located on this mirror plane. The dihedral angle between the planes of the aromatic rings is 17.71 (3) degrees . Two intra-molecular O-H?N hydrogen bonds with graph-set motif S(6) are present. No remarkable inter-molecular contacts exist in the crystal structure. PMID- 22259476 TI - 2-[((E)-2-{2-[(E)-2-Hy-droxy-benzyl-idene]hydrazinecarbon-yl}hydrazinyl idene)meth-yl]phenol. AB - The mol-ecule of the title compound, C(15)H(14)N(4)O(3), is completed by the application of crystallographic twofold symmetry, with the carbonyl group lying on the rotation axis. The mol-ecule is close to planar: the greatest deviation of a torsion angle from 0 degrees is 7.3 (2) degrees about the bond linking the phenol ring to the rest of the mol-ecule. An intra-molecular O-H?N(imine) hydrogen bond is formed in each half of the mol-ecule. The carbonyl O atom is anti with respect to the amine H atoms and this allows for the formation of N H?O(hydrox-yl) hydrogen bonds in the crystal, which results in supra-molecular layers lying parallel to (100). PMID- 22259477 TI - N-{3-[2-(4-Fluoro-phen-oxy)eth-yl]-2,4-dioxo-1,3-diaza-spiro-[4.5]decan-7-yl}-4 meth-oxy-benzene-sulfonamide. AB - In the title compound, C(23)H(26)FN(3)O(6)S, the two terminal aromatic rings form a dihedral angle of 49.26 (12) degrees . The cyclo-hexane ring adopts a chair conformation and the five-membered ring is essentially planar, with a maximum deviation from planarity of 0.0456 (19) A. The dihedral angles between the five membered ring and the meth-oxy-benzene and fluoro-benzene rings are 33.56 (11) and 81.94 (12) degrees , respectively. The crystal structure displays N-H?O hydrogen bonds as well as weak inter-molecular C-H?O inter-actions. PMID- 22259478 TI - Acridin-10-ium 6-carb-oxy-pyridine-2-carboxyl-ate. AB - The title compound, C(13)H(10)N(+).C(7)H(4)NO(4) (-), consists of a protonated acridinium cation and a 6-carb-oxy-pyridine-2-carboxyl-ate monoanion. The carboxyl-ate group of the anion appears to be delocalized on the basis of the nearly equivalent C-O bond lengths. In the crystal, the anions are connected by strong O-H?O hydrogen bonds, forming chains along the b axis. The acridinium cations are linked to the anionic chains by strong N-H?O hydrogen bonds between the carboxyl-ate group of the anion and the N-H group of the cation. Along the b axis, successive chains stack in opposite directions. Weak inter-molecular C-H?O hydrogen bonds further stabilize the crystal structure. PMID- 22259479 TI - Ethyl 1-(2-hy-droxy-eth-yl)-2-[2-(methyl-sulfan-yl)eth-yl]-1H-benzimidazole-5 carboxyl-ate. AB - In the crystal structure of the title compound, C(15)H(20)N(2)O(3)S, the hy-droxy group is involved in the formation of O-H?N hydrogen bonds, which link two mol ecules into a centrosymmetric dimer. Weak C-H?O hydrogen bonds further link these dimers into chains propagating along the a axis. The crystal packing exhibits pi pi inter-actions between the five- and six-membered rings of neighbouring mol ecules [centroid-centroid distance = 3.819 (2) A] and short inter-molecular S?S contacts of 3.495 (1) A. PMID- 22259480 TI - (E)-1-[2-(Methyl-sulfan-yl)phen-yl]-2-({(E)-2-[2-(methyl-sulfan-yl)phen yl]hydrazinyl-idene}(nitro)-meth-yl)diazene. AB - In the title compound, C(15)H(15)N(5)O(2)S(2), the phenyl rings make dihedral angles of 4.03 (4) and 9.77 (5) degrees with the plane defined by the central N N-C-N-N atoms (r.m.s. deviation = 0.010 A). The C-S-C-C torsion angles of the methyl-sulfanyl groups with their respective phenyl rings are -7.47 (13) and 72.07 (13) degrees . The shortest centroid-centroid distance of 3.707 A occurs between the two pi-systems N-N-C-N-N and the benzene ring in the diazene 1 position. The H atom bound to the N atom is involved in intra-molecular N-H?N and N-H?S contacts, while the nitro O atoms are involved in inter-molecular C-H?O contacts. PMID- 22259481 TI - (E)-N'-(4-Hy-droxy-benzyl-idene)-3-nitro-benzohydrazide. AB - The mol-ecule of the title compound, C(14)H(11)N(3)O(4), assumes an E conformation about the C=N double bond. The benzene rings form a dihedral angle of 3.9 (2) degrees . The crystal structure is stabilized by N-H?O, O-H?N, O-H?O and C-H?O hydrogen bonds, forming layers parallel to (101). In addition, intra layer pi-pi stacking inter-actions [centroid-centroid distance = 3.635 (2) A] are observed. PMID- 22259482 TI - N-(Pyrrolidin-1-ylcarbothio-yl)benzamide. AB - In the title compound, C(12)H(14)N(2)OS, the pyrrolidine ring adopts an envelope conformation with the C atom at the 3-position as the flap and makes a dihedral angle of 65.80 (9) degrees with the benzene ring. In the crystal, N-H?O hydrogen bonds join c-glide related mol-ecules into chains extended along [001] that are further connected into (100) layers via C-H?O inter-actions. PMID- 22259483 TI - 4-Chloro-N-(2,3-dimethyl-phen-yl)benzamide. AB - In the title compound, C(15)H(14)ClNO, the ortho- and meta-methyl substituents in the aniline ring are anti to the N-H bond. The dihedral angle between the benzoyl and aniline benzene rings is 95.0 (1) degrees . N-H?O hydrogen bonds and C-H?pi inter-actions link the mol-ecules in the crystal structure. PMID- 22259484 TI - 2-(4-Chloro-1H-indol-3-yl)acetonitrile. AB - The title compound, C(10)H(7)ClN(2), contains two approximately planar mol ecules, A and B (r.m.s. deviations = 0.039 and 0.064 A, respectively) in the asymmetric unit. In the crystal, N-H?N hydrogen bonds link the mol-ecules into C(7) chains of alternating A and B mol-ecules propagating along the a-axis direction. The crystal used for the data collection was found to be a racemic twin. PMID- 22259485 TI - 2,9,10-Trimeth-oxy-dibenzo[b,d]oxepin-7(6H)-one. AB - The title compound, C(17)H(16)O(5), was prepared through a cyclization reaction of 2-(3',4',5-trimeth-oxy-biphenyl-2-yl-oxy)acetyl chloride. The two benzene rings form a dihedral angle of 34.55 (5) degrees . The crystal structure does not feature any hydrogen bonds. PMID- 22259486 TI - 3-(4-Bromo-phenyl-sulfin-yl)-5-cyclo-hexyl-2-methyl-1-benzofuran. AB - In the title compound, C(21)H(21)BrO(2)S, the cyclohexyl ring adopts a chair conformation. The 4-bromo-phenyl ring makes a dihedral angle of 81.62 (6) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi inter-actions. The crystal structure also exhibits a slipped pi-pi inter-action between the furan rings of neighbouring mol ecules [centroid-centroid distances = 3.540 (3) A, inter-planar distance = 3.481 (3) A and slippage = 0.644 (3) A]. PMID- 22259487 TI - 4-Nitro-isophthalic acid. AB - In the crystal structure of the title compound, C(8)H(5)NO(6), both carboxyl groups are involved in inter-molecular centrosymmetric cyclic O-H?O hydrogen bonding associations, which give a zigzag chain structure extending along (2[Formula: see text]1). Weak pi-pi stacking inter-actions are also present [minimum ring centroid separation = 3.893 (4) A]. PMID- 22259488 TI - 3-[(E)-2-Phenyl-ethen-yl]-1H-indole-6-carbonitrile. AB - In the title compound, C(17)H(12)N(2), the inter-planar angle between the indole mean plane [max.deviation 0.030 (1) A] and the phenyl ring is 24.32 (7) degrees . In the crystal, inter-molecular N-H?N C hydrogen bonds form zigzag chains in the a-axis direction augmented by weak C-H?N C contacts. PMID- 22259489 TI - 3a,11b-Dihy-droxy-3a,11b-dihydro-1H-imidazo[4,5-f][1,10]phenanthroline-2(3H) thione. AB - The title compound, C(13)H(10)N(4)O(2)S, was prepared through a cyclization reaction of 1,10-phenanthroline-5,6-dione and thio-urea. The dihedral angle between the pyridine rings is 8.22 (2) degrees . In the crystal, mol-ecules are connected by N-H?O, O-H?N, N-H?S and O-H?S hydrogen bonds, forming a three dimensional network. PMID- 22259490 TI - N-Methyl-3,5-dinitro-benzamide. AB - The asymmetric unit of the title compound, C(8)H(7)N(3)O(5), contains two independent mol-ecules in which the amide plane is oriented at dihedral angles of 29.82 (2) and 31.17 (2) degrees with respect to the benzene ring. In the crystal, mol-ecules are connected via inter-molecular N-H?O hydrogen bonds, forming chains running along the b axis. PMID- 22259491 TI - 2-Fluoro-N'-[(2-hydroxynaphthalen-1-yl)methylidene]benzohydrazide. AB - In the title mol-ecule, C(18)H(13)FN(2)O(2), the hy-droxy group is involved in an intra-molecular O-H?N hydrogen bond. The naphthyl ring system and the benzene ring form a dihedral angle of 31.0 (2) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into chains propagating in [101]. PMID- 22259492 TI - (E)-N-{(E)-2-[(3,5-Dimethylbiphenyl-4-yl)imino]-acenaphthen-1-yl-idene}-2,6-di methyl-4-phenyl-aniline. AB - The title compound, C(40)H(32)N(2), has crystallographic twofold rotation symmetry, with two C atoms lying on the axis. The dihedral angle between the two benzene rings of the 4-phenyl-2,6-dimethyl-phenyl group is 35.74 (17) degrees . The acenaphthene ring makes an angle of 76.93 (11) degrees with the benzene ring bonded to the N atom and an angle of 41.53 (13) degrees with the other benzene ring. PMID- 22259493 TI - 3,3'-[Biphenyl-4,4'-diylbis(-oxy)]diphthalic acid. AB - In the title mol-ecule, C(28)H(18)O(10), the two central benzene rings form a dihedral angle of 31.0 (1) degrees . In the phthalic acid fragments, the carb-oxy groups in the meta positions are approximately coplanar with the attached benzene rings, being inclined to their planes at 2.7 (1) and 10.3 (1) degrees , while the carb-oxy groups in the ortho positions are twisted from the benzene ring planes by 83.5 (1) and 75.4 (1) degrees . In the crystal, O-H?O hydrogen bonds link the mol-ecules into layers parallel to the bc plane. Weak C-H?O hydrogen bonds and pi pi inter-actions between the aromatic rings [centroid-centroid distance = 3.7674 (3) A] further consolidate the crystal packing. PMID- 22259494 TI - Bis(3-hy-droxy-propanaminium) naphthalene-1,5-disulfonate. AB - In the title molecular salt, 2C(3)H(10)NO(+).C(10)H(6)O(6)S(2) (2-), the cations and anions are associated via N-H?O and O-H?O hydrogen-bonding inter-actions, giving rise to a three-dimensional structure with zigzag rows of cations lying between rows of anions. The asymmetric unit contains one cation and one half anion, which is related to the remainder of the mol-ecule by an inversion center. PMID- 22259495 TI - 2-(2-Nitro-anilino)benzoic acid. AB - In the title compound, C(13)H(10)N(2)O(4), the nitro N atom deviates by 0.031 (2) A from the plane of the benzene ring to which it is attached. The aromatic rings are oriented at a dihedral angle of 50.6 (1) degrees . An intra-molecular N-H?O hydrogen bond occurs. In the crystal, inversion dimers are formed by pairs of O H?O inter-actions. PMID- 22259496 TI - Chlorido{2-[(dimethyl-amino)-meth-yl]phenyl-kappaN,C}tellurium. AB - The crystal structure of the title compound, C(9)H(12)ClNTe, contains isolated mol-ecules with no close Te?Cl inter-molecular contacts and has the same composition as a previously published structure [Engman et al. (2004 ?). Phospho rus Sulfur Silicon Relat. Elem.179, 285-292]. However, in this case, the compound has crystallized in a centrosymmetric space group, unlike the previously published structure which contained enanti-omerically pure chiral mol-ecules. In all other aspects, the metrical parameters are similar. The mol-ecules with a T shaped coordination environment about the Te atom are linked into dimers by C H?Cl inter-actions. PMID- 22259497 TI - Dibromidochlorido{2-[(dimethyl-amino)-meth-yl]phenyl-kappaN,C}tellurium(IV). AB - The title compound, C(9)H(13)Br(2)ClNTe, was synthesized by reacting [2-(dimethyl amino-meth-yl)phen-yl]tellurium(II) chlor-ide with Br(2). As a consequence, the Cl and Br atoms are not well ordered but distributed over the three possible positions such that the overall stiochiometry is two Br atoms and one Cl atom. The scrambling of the Br and Cl atoms indicates a small energy barrier for the exchange process between the apical and equatorial positions. Overall, the Te atom geometry is slightly distorted square pyramidal (tau = 0.052 for the major component). However, there is a weak secondary inter-action between the Te atoms and the disordered Br/Cl atoms of a nearby mol-ecule. The Te-Br and Te-Cl distances in both disorder components fall into two groups; a longer distance for the Br/Cl involved in this secondary inter-action [2.6945 (17) A for Br and 2.601 (9)A for Cl] and shorter bond distances to the remaining halogen atoms, indicating that this inter-action has slightly weakened the Te-X bond, as is the case in the previously reported tribromido structure [Singh et al. (1990). J. Chem. Soc. Dalton Trans. pp. 907-913]. Otherwise, the metrical parameters in the two structures are not significantly different. An intermolecular C-H?Br interaction occurs. PMID- 22259498 TI - Methyl 2-{[2-(4,4,5,5-tetra-methyl-1,3-dioxyl-4,5-dihydro-imidazol-2-yl)phen-yl] oxy}acetate. AB - In the title compound, C(16)H(21)N(2)O(5), the benzene ring is nearly perpendicular to the imidazole ring, making a torsion angle of 88.6 (8) degrees .The crystal structure is stabilized by non-classical C-H?O and C-H?pi inter actions, which build up a three-dimensional network. PMID- 22259499 TI - 2-[3-Hy-droxy-4-(2-hy-droxy-eth-oxy)phen-yl]-4,4,5,5-tetra-methyl-2-imidazoline-1 oxyl 3-oxide. AB - In the title compound, C(15)H(21)N(2)O(5), the imidazoline ring displays a twisted conformation. The mean plane of the imidazoline ring makes a dihedral angle of 22.55 (5) degrees with the benzene ring. In the crystal, O-H?O and C H?O hydrogen bonds link the mol-ecules into a layer parallel to the bc plane. PMID- 22259500 TI - 4-Chloro-1-methyl-indoline-2,3-dione. AB - The title mol-ecule, C(9)H(6)ClNO(2), is essentially planar; the maximum deviation of the indoline ring system is 0.027 (3) A and the substituents do not deviate by more than 0.075 (2) A from this plane. Inter-molecular C-H?O hydrogen bonds consolidate the crystal structure. PMID- 22259501 TI - 2,8-Dimesitylboranyl-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazo-cine. AB - In the title compound, C(51)H(56)B(2)N(2), a substituted Troger's base, the dihedral angle between the two benzene rings constituting the Troger's base framework is 104.42 (6) degrees . The crystal structure is stabilized by C-H?pi and weak C-H?N inter-actions. PMID- 22259502 TI - (E)-4-[(3,5-Dimethyl-phen-yl)imino-meth-yl]-2-meth-oxy-3-nitro-phenol. AB - The mol-ecule of the title compound, C(16)H(16)N(2)O(4), exists in the E configuration with respect to the central C=N double bond. The dihedral angle between the two benzene rings is 2.17 (9) A. In the crystal, mol-ecules are linked via O-H?N hydrogen bonds into chains that propagate along the b-axis direction. There is also pi-pi stacking of inversion-related mol-ecules, with inter-planar spacings of 3.479 (5) A and ring centroid-centroid distances of 3.876 (4) A. PMID- 22259503 TI - N-(2-Chloro-5-methyl-phen-yl)succinamic acid. AB - In the title compound, C(11)H(12)ClNO(3), the conformation of the N-H bond in the amide segment is syn with respect to the ortho-Cl atom. The amide and carboxyl C=O groups are syn to each other. Furthermore, the C=O and O-H bonds of the carboxyl group are in syn positions with respect to each other. The dihedral angle between the benzene ring and the amide group is 47.8 (2) degrees . In the crystal, mol-ecules are connected by pairs of O-H?O hydrogen bonds, forming inversion dimers. The dimers are further linked by N-H?O hydrogen bonds into double chains along the b-axis direction. PMID- 22259504 TI - 4-(2,2-Difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile. AB - In the title compound, C(12)H(6)F(2)N(2)O(2), the 2,2-difluoro-1,3-benzodioxole ring system is approximately planar [maximum deviation = 0.012 (2) A] and its mean plane is twisted with respect to the pyrrole ring, making a dihedral angle of 2.51 (9) degrees . In the crystal, N-H?N hydrogen bonds link the mol-ecules into chains running along the a axis. pi-pi stacking is also observed between parallel benzene rings of adjacent mol-ecules, the centroid-centroid distance being 3.7527 (13) A. PMID- 22259505 TI - Ethane-1,2-diaminium (R)-2-[4-(1-carboxyl-atoeth-oxy)phen-oxy]acetate. AB - In the title compound, C(2)H(10)N(2) (2+).C(11)H(10)O(6) (2-), the two acetate groups of the cation form dihedral angles of 74.2 (4) and 63.9 (5) degrees with the central benzene ring. In the crystal, N-H?O hydrogen bonds link the cations and anions into layers parallel to the ab plane. PMID- 22259506 TI - N-(5-Sulfanyl-idene-4,5-dihydro-1,3,4-thia-diazol-2-yl)acetamide dimethyl sulfoxide disolvate. AB - In the title compound, C(4)H(5)N(3)OS(2).2C(2)H(6)OS, the five-membered heterocyclic ring and the N-(C=O)-C plane of the acetamide group are essentially co-planar, with a dihedral angle of 1.25 (3) degrees . Inter-molecular N-H?O hydrogen bonds between the acetamide compound and the dimethyl sulfoxide mol ecules stabilize the crystal structure. The two dimethyl sulfoxide mol-ecules are each disordered over two positions with occupancy ratios of 0.605 (2):0.395 (2) and 0.8629 (18):0.1371 (18). PMID- 22259507 TI - Methyl-ammonium tetra-fluoridoborate 18-crown-6 clathrate. AB - In the title compound, CH(3)NH(3) (+).BF(4) (-).C(12)H(24)O(6), the methyl ammonium cation makes three N-H?O hydrogen bonds to the 18-crown-6 mol-ecule. The -NH(3) (+) and -CH(3) groups of the cation adopt a staggered conformation. The F atoms of the tetra-fluoridoborate anion are disordered over two sets of sites in a 0.519 (11):0.481 (11) ratio. Weak C-H?F inter-actions occur in the crystal, which possibly correlate with the anion disorder. PMID- 22259508 TI - N-(4,6-Dimeth-oxy-pyrimidin-2-yl)-2-(3-methyl-phen-yl)acetamide. AB - In the title compound, C(15)H(17)N(3)O(3), the dihedral angle between the pyrimidine and benzene rings is 87.0 (7) degrees . In the crystal, mol-ecules are linked into inversion dimers with R(2) (2)(8) graph-set motifs by a pair of N-H?O hydrogen bonds. Weak C-H?O hydrogen bonds and inter-molecular pi-pi inter-actions [centroid-centroid distance = 3.544 (1) A] are also observed. PMID- 22259509 TI - 3-Methyl-anilinium hydrogen phthalate. AB - The asymmetric unit of the title salt, C(7)H(10)N(+).C(8)H(5)O(4) (-), consists of two 3-methyl-phenyl-ammonium cations and two hydrogen phthalate anions. There are strong intra-molecular O-H?O hydrogen bonds in the virtually planar (r.m.s. deviations = 0.054 A) phthalate anions. In the crystal, the cations and anions are connected via an extensive sytem of N-H?O hydrogen bonds into a corrugated layer extended parallel to (001). PMID- 22259510 TI - (E)-Methyl 2-[(2-formyl-6-meth-oxy-phen-oxy)meth-yl]-3-phenyl-acrylate. AB - The title compound, C(19)H(18)O(5), crystallizes with two independent mol-ecules (A and B) in an asymmetric unit in both of which the two aromatic rings are in a bis-ectional orientation as evidenced by the dihedral angle between them [41.7 (1) degrees in mol-ecule A and 35.6 (1) degrees in mol-ecule B]. Both mol ecules adopt an E configuration with respect to the C=C bond. An intra-molecular C-H?O hydrogen-bond occurs in mol-ecule A. The crystal packing features inter molecular C-H?O inter-actions. PMID- 22259511 TI - [2,7-Dimeth-oxy-8-(2,4,6-trimethyl-benzo-yl)naphthalen-1-yl](2,4,6-trimethyl-phen yl)methanone. AB - In the title compound, C(32)H(32)O(4), the dihedral angle between the two benzene rings of the 2,4,6-trimethyl-benzoyl groups is 71.43 (7) degrees . The dihedral angles between the two benzene rings and the naphthalene ring system are 81.58 (5) and 84.92 (6) degrees . An intra-molecular C-H?O inter-action is observed. PMID- 22259513 TI - 3-Cyclo-propyl-1-(4-methyl-phenyl-sulfon-yl)piperidine-3,5-diol. AB - In the title compound, C(15)H(21)NO(4)S, both hy-droxy groups on the piperidine ring are located in axial positions, whereas the tosyl group and the cyclo propane ring are in equatorial positions. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, mol-ecules form inversion dimers via pairs of O-H?O hydrogen bonds, generating cyclic R(4) (4)(8) motifs, as noted previously in related diols. PMID- 22259512 TI - 5-Carb-oxy-1,3-bis-(carb-oxy-meth-yl)-4-imidazolinium-4-carboxyl-ate. AB - The title compound, C(9)H(8)N(2)O(8), was obtained by the reaction of imidazole 4,5-dicarb-oxy-lic acid and 2-chloro-acetic acid. An intra-molecular O-H?O hydrogen bond occurs. The crystal packing is stabilized by intermolecular O-H?O and C-H?O hydrogen bonds, which link mol-ecules into a three-dimensional network. PMID- 22259514 TI - (3S*,4S*,E)-tert-Butyl 3,4-dibromo-5-oxo-cyclo-oct-1-ene-carboxyl-ate. AB - The title compound, C(13)H(18)Br(2)O(3), was prepared by a bromination reaction of (1E,3Z)-methyl 5-oxocyclo-octa-1,3-diene-carboxyl-ate, which was obtained by an ep-oxy-dation reaction of tert-butyl cyclo-oct-1,3-diene-carboxyl-ate. The crystal structure confirms unequivocally the absolute configuration of both chiral centres to be S. In the crystal, C-H?O inter-actions link the mol-ecules into chains running along the c axis. PMID- 22259515 TI - 2-[(Z)-4,7-Dichloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-yl-idene]-3-oxopropane nitrile. AB - In the title compound, C(13)H(10)Cl(2)N(2)O, the ring N atom and its three attached atoms are essentially coplanar with angles adding to 359.8 degrees , indicating conjugation with the 2-formyl-acrylonitrile subunit. The aldehyde group is oriented to place the carbonyl O atom 2.02 (3) A from the N-H hydrogen atom. Intra-molecular N-H?O and C-H?Cl inter-actions occur. The geometry of the exocyclic double bond is Z. In the crystal, weak C-H?N hydrogen bonds link the mol-ecules into chains along [1[Formula: see text]0]. PMID- 22259516 TI - 2-(4-Chloro-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-yl-idene)-2-cyano-acetamide. AB - Reaction of 2-(4-chloro-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-yl-idene)propane dial with hydroxyl-amine gives the title compound, C(14)H(14)ClN(3)O, in which the ring N atom is essentially planar [sum of angles around the ring N atom = 361 degrees ], indicating conjugation with the 2-cyano-acryl-amide unit. The orientation of the acetamide group arises from intra-molecular hydrogen bonding between the indole N-H and carbonyl groups. In the crystal, inversion-related acetamide groups form N-H?O hydrogen-bonded dimers in graph-set R(2) (2)(8) motifs, whilst dimers are also formed by pairs of amine-nitrile N-H?N hydrogen bonds in R(2) (2)(12) motifs. These inter-actions together generate ribbons that propagate along the b-axis direction. PMID- 22259517 TI - Tetra-gonal polymorph of 5,5-dichloro-barbituric acid. AB - The tetra-gonal polymorph of 5,5-dichloro-barbituric acid (m.p. 478 K), C(4)H(2)Cl(2)N(2)O(3), forms an N-H?O hydrogen-bonded tape structure along [001]. Two tapes related by a twofold rotation axis are associated via Cl?O contacts [3.201 (1) A], and four such chain pairs are arranged around a fourfold roto inversion axis. The crystal structures of the monoclinic and ortho-rhom-bic polymorphs have been reported previously [Gelbrich et al. (2011 ?). CrystEngComm, 13, 5502-5509]. PMID- 22259518 TI - 5alpha,6alpha-Ep-oxy-7-norcholestan-3beta-yl acetate. AB - The title cholestan, C(28)H(46)O(3), was prepared by epoxidation of 7-norcholest 5-en-3beta-yl acetate and crystallized by slow evaporation from an ethano-lic solution. All rings are trans fused. The 3beta-acetate and the 17beta-cholestane side chain are in equatorial positions. The mol-ecule is highly twisted due to its B-nor characteristic. A quantum chemical ab-initio Roothaan Hartree-Fock calculation of the equilibrium geometry of the isolated mol-ecule gives values for bond lengths and valency angles in close agreement with the experimental ones. PMID- 22259519 TI - 3-Hy-droxy-4-phenyl-1-(prop-2-en-1-yl)-2,3,4,5-tetra-hydro-1H-1,5-benzodiazepin-2 one. AB - The asymmetric unit of the title compound, C(18)H(18)N(2)O(2), contains three independent mol-ecules. In each, the seven-membered diazepine ring adopts a boat conformation with the hy-droxy-substituted C atom at the prow and fused-ring C atoms at the stern. In the crystal, the mol-ecules are linked by O-H?O and N-H?O hydrogen bonds. The allyl group of one mol-ecule is equally disordered over two positions. PMID- 22259520 TI - Ethyl 2-(2-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7-yl)acetate. AB - The nine-membered fused-ring of the title compound, C(10)H(13)N(5)O(2), is approximately planar [maximum deviation = 0.012 (1) A]; the bond angle at the methylene C atom is 111.33 (10) degrees . In the crystal, the amino group forms hydrogen bonds to the N atoms of the triazole rings of adjacent mol-ecules, generating a ribbon running along the a axis. PMID- 22259521 TI - 2-[(3S)-5-Oxooxolan-3-yl]isoindoline-1,3-dione. AB - The oxolan-2-one ring in the title compound, C(12)H(9)NO(4), has an envelope conformation with the atom linking the two five-membered rings being the flap atom. PMID- 22259522 TI - 5-Bromo-1-(prop-2-en-1-yl)-2,3-dihydro-1H-indole-2,3-dione. AB - In the title compound, C(11)H(8)BrNO(2), the nine-membered fused-ring is nearly planar [maximum deviation = 0.022 (2) A] and the allyl group is arched over the nine-membered fused-ring at a dihedral angle of 89.2 (1) degrees . Weak inter molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 22259523 TI - 3-{2-[(3-{(E)-2-[4-(Dimethyl-amino)-phen-yl]ethen-yl}quinoxalin-2-yl)-oxy]eth-yl} 1,3-oxazolidin-2-one monohydrate. AB - In the title compound, C(23)H(24)N(4)O(3).H(2)O, the 1,3-oxazoline ring is nearly planar [maximum deviation = 0.059 (2) A] and its mean plane is twisted by 30.12 (8) degrees with respect to the quinoxaline fused-ring system; the benzene ring is nearly coplanar with the quinoxaline fused-ring system [dihedral angle = 2.52 (2) degrees ]. The water mol-ecule of crystallization is hydrogen-bond donor to an N atom of the quinoxaline ring system as well as an O atom of the oxazolinone unit, the two hydrogen bonds generating a chain running along the c axis. PMID- 22259524 TI - 4,4'-Bipyridine-dimethyl-glyoxime (1/1). AB - In the title compound, C(10)H(8)N(2).C(4)H(8)N(2)O(2), both the dimethyl-glyoxime and the 4,4'-bipyridine mol-ecules have crystallographic C(i) symmetry. The mol ecules stack along the a-axis direction with a dihedral angle of 20.4 (8) degrees between their planes. In the crystal, the components are linked by O-H?N hydrogen bonds into alternating chains along [120] and [1[Formula: see text]0]. PMID- 22259525 TI - Dicyclo-hex-yl[4-(dimethyl-amino)-phen-yl]phosphine selenide. AB - In the title mol-ecule, C(20)H(32)NPSe, the P atom has a distorted tetra-hedral environment resulting in an effective cone angle of 172 degrees . Weak inter molecular C-H?Se inter-actions are observed. PMID- 22259526 TI - N-(3-Chloro-benzo-yl)-3-nitro-benzene-sulfonamide. AB - In the title compound, C(13)H(9)ClN(2)O(5)S, the dihedral angle between the two benzene rings is 83.5 (1) degrees . In the crystal, mol-ecules are linked via N H?O(S) hydrogen bonds into helical chains running along the b axis. PMID- 22259527 TI - (E)-2,2'-[3-(2-Nitro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-cyclo-hex-2-en 1-one). AB - In the title compound, C(21)H(21)NO(6), each of the cyclo-hexenone rings adopts a half-chair conformation. Each of the pairs of hy-droxy and carbonyl O atoms are oriented to allow for the formation of intra-molecular O-H?O hydrogen bonds, which are typical of xanthene derivatives. PMID- 22259528 TI - 2-Hy-droxy-N,N,N-trimethyl-3-tetra-decyl-oxypropan-1-aminium bromide. AB - In the crystal structure of the title compound, C(20)H(44)NO(2) (+).Br(-), the cation and anion are connected via an O-H?Br hydrogen bond, forming an ionic pair. The cation is disordered over two conformations related by a mirror plane, and the anion is situated on a mirror plane so that the asymmetric unit contains half of the ionic pair. The long alkyl chain in the cation adopts an all-trans conformation. The crystal packing exhibits weak inter-molecular C-H?O inter actions. PMID- 22259530 TI - (1H-Benzimidazol-2-yl)methanaminium perchlorate-18-crown-6-water (1/1/1). AB - The crystal structure of the title compound C(8)H(10)N(3) (+).ClO(4) ( ).C(12)H(24)O(6).H(2)O, consists of an organic (1H-benzimidazol-2 yl)methanaminium cation, an inorganic ClO(4) (-) anion, one 18-crown-6 mol-ecule and one water mol-ecule. In the crystal, the cations and 18-crown-6 mol-ecules are linked by N-H?O hydrogen bonds. The crystal packing is stabilized by inter molecular O-H?O, O-H?N and O-H?Cl hydrogen bonds between anions and the water mol ecules. One 18-crown-6 C atom and a perchlorate O atom are disordered; both have an occupancy factor ratio of 0.60 (2) and 0.40 (2). PMID- 22259529 TI - Ethyl 2-(1,3-benzodioxol-5-yl)-1-[3-(1H-imidazol-1-yl)prop-yl]-1H-benzimidazole-5 carboxyl-ate. AB - In the title compound, C(23)H(22)N(4)O(4), the essentially planar [maximum deviation = 0.022 (1) A] benzimidazole ring system forms dihedral angles of 86.16 (7) and 37.38 (6) degrees , respectively, with the imidazole and benzene rings. The dioxolane ring adopts an envelope conformation with the methyl-ene C atom at the flap. In the crystal, C-H?O and C-H?N inter-actions link the mol-ecules into a ribbon along the a axis. The crystal packing is further stabilized by weak pi pi stacking inter-actions [centroid-centroid distances = 3.5954 (8) and 3.7134 (8) A] and C-H?pi inter-actions. PMID- 22259531 TI - N-(4-Bromo-phen-yl)-3,5-dinitro-benzamide. AB - The title mol-ecule, C(13)H(8)BrN(3)O(5), is slightly twisted, with the dihedral angle between the two benzene rings being 5.9 (1) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into one-dimensional chains running along [101]. Further stabilization of the crystal structure is provided by pi-pi inter actions [shortest centroid-centroid distance = 3.6467 (17) A]. PMID- 22259532 TI - 2-({[4-(1,3-Benzothia-zol-2-yl)phen-yl]amino}methyl)-phenol. AB - In the title compound, C(20)H(16)N(2)OS, the aniline substituent essentially coplanar with the benzothia-zole moiety (with an r.m.s. deviation of all fitted non-H atoms of 0.0612 A). The phenol group is almost perpendic-ular to the benzothia-zolylaniline group, with an inter-planar angle of 88.36 (2) degrees . In the crystal, mol-ecules aggregate as centrosymmetric dimers by pairs of O-H?N hydrogen bonds. C-H?O contacts and N-H?pi(arene) inter-actions also occur. PMID- 22259533 TI - (E)-2-[(2-Formyl-phen-oxy)meth-yl]-3-(4-methyl-phen-yl)prop-2-ene-nitrile. AB - In the title compound, C(18)H(15)NO(2), the dihedral angle between the two benzene rings is 74.8 (1) degrees . The carbonitrile chain is almost linear, the C-C-N angle being 176.2 (2) degrees . In the crystal, pi-pi inter-actions [centroid-centroid distance = 3.842 (1) A] are observed. PMID- 22259534 TI - Trimethyl-ammonium 2,6-dioxo-5-(2,4,6-trinitro-phen-yl)-1,2,3,6-tetra-hydro pyrimidin-4-olate. AB - IN THE TITLE BARBITURATE SALT (TRIVIAL NAME: trimethyl-ammonium 2,4,6-trinitro phenyl-barbiturate), C(3)H(10)N(+).C(10)H(4)N(5)O(9) (-), the asymmetric unit contains two sets of anion-cation moieties. The dihedral angle between the rings in the anions are 44.0 (3) and 45.7 (3) degrees . Adjacent anions are connected into ribbons along [100] through R(2) (2)(8) ring motifs formed by N-H?O hydrogen bonds involving the barbiturate rings. Attached to both sides of these ribbons via N-H?O hydrogen bonds are the trimethyl-ammonium cations. C-H?O hydrogen bonds are also observed. PMID- 22259535 TI - 4-[(Hy-droxy)(4-methyl-phen-yl)methyl-idene]isochroman-1,3-dione. AB - In the title compound, C(17)H(12)O(4), the six-membered heterocyclic ring adopts a distorted screw-boat conformation. The mol-ecular structure exhibits an S(6) ring motif, owing to an intra-molecular O-H?O hydrogen bond. In the crystal, weak C-H?O contacts generate an infinite chain along the c axis. There are also pi-pi stacking inter-actions between neighbouring isochromanedione benzene rings, with a centroid-centroid distance of 3.755 (1) A, and C-O?pi inter-actions with an O?centroid distance of 3.964 (2) A. PMID- 22259536 TI - (2,4,6-Trimethyl-phen-yl)boronic acid-triphenyl-phosphine oxide (1/1). AB - In the crystal structure of the title compound, C(9)H(13)BO(2).C(18)H(15)OP, there are O-H?O hydrogen bonds between the O atom of triphenyl-phosphine oxide and one hy-droxy group of the boronic acid. Boronic acid mol-ecules form inversion-related hydrogen-bonded dimers in an R(2) (2)(8) motif. The structure is consolidated by inter-molecular C-H?O bonds and C-H?pi inter-actions. PMID- 22259537 TI - 4',5-Dihy-droxy-7-meth-oxy-flavanone dihydrate. AB - The title compound, C(16)H(14)O(5).2H(2)O [systematic name: 5-hy-droxy-2-(4-hy droxy-phen-yl)-7-meth-oxy-chroman-4-one dihydrate], is a natural phytoalexin flavone isolated from the native chilean species Heliotropium taltalense and crystallizes with an organic mol-ecule and two water mol-ecules in the asymmetric unit. The 5-hy-droxy group forms a strong intra-molecular hydrogen bond with the carbonyl group, resulting in a six-membered ring. In the crystal, the components are linked by O-H?O hydrogen bonds, forming a three-dimensional network. The 4-hy droxy-phenyl benzene ring is bonded equatorially to the pyrone ring, which adopts a slightly distorted sofa conformation. The title compound is the hydrated form of a previously reported structure [Shoja (1990 ?). Acta Cryst. C46, 1969-1971]. There are only slight variations in the mol-ecular geometry between the two compounds. PMID- 22259538 TI - (5S)-5-Methyl-3-phenyl-2-sulfanyl-idene-1,3-thia-zolidin-4-one. AB - In the title mol-ecule, C(10)H(9)NOS(2), the 2-sulfanyl-idene-thia-zolidin-4-one mean plane and phenyl ring form a dihedral angle of 81.7 (1) degrees . In the crystal, C-H?pi inter-actions link mol-ecules into helical chains in [010]. PMID- 22259539 TI - 2-Bromo-4-(3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl)-6-meth-oxy-phenol. AB - In the title compound, C(18)H(20)BrNO(3), the oxazolidine ring adopts an envelope conformation with the N atom at the flap position. The mean plane of oxazolidine ring makes dihedral angles of 82.96 (13) and 70.97 (12) degrees , respectively, with the phenyl and benzene rings. In the crystal, adjacent mol-ecules are connected via O-H?O and C-H?O hydrogen bonds and C-H?pi inter-actions into a zigzag chain along the b axis. PMID- 22259540 TI - 1-Benzyl-4-chloro-indoline-2,3-dione. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(15)H(10)ClNO(2), which differ in the dihedral angles between the mean planes of the phenyl ring and the 4-chloro-indoline-2,3-dione ring system [59.48 (9) and 79.0 (1) degrees ]. In the crystal, mol-ecules are linked through C-H?O hydrogen bonds, forming polymeric chains in [100]. PMID- 22259541 TI - 9-(7-Fluoro-4-oxo-4H-chromen-3-yl)-3,3,6,6-tetra-methyl-2,3,4,5,6,7,8,9-octa hydro-1H-xanthene-1,8-dione. AB - In the title compound, C(26)H(25)FO(5), the terminal cyclo-hexane rings of the xanthene ring system adopt half-boat conformations. The 4H-chromene ring make a dihedral angle of 87.94 (5) degrees with the xanthene ring system and its carbonyl O atom lies above the xanthene O atom. In the crystal, mol-ecules are linked into ribbons propagating along the a-axis direction by C-H?O hydrogen bonds. Aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.7367 (12) A] also occur. PMID- 22259542 TI - 5,6-Dimethyl-1,2,4-triazin-3-amine. AB - In the crystal structure of the title compound, C(5)H(8)N(4), adjacent mol-ecules are connected through N-H?N hydrogen bonds, resulting in a zigzag chain along [100]. The amino groups and heterocyclic N atoms are involved in further N-H?N hydrogen bonds, forming R(2) (2)(8) motifs. PMID- 22259543 TI - (Z)-Methyl 3-(2,4-dichloro-phen-yl)-3-hy-droxy-acrylate. AB - The mol-ecular structure of the title compound, C(10)H(8)Cl(2)O(3), exists in a cis-enol form, which is stabilized by a strong intra-molecular O-H?O hydrogen bond. In the crystal, C-H?O inter-actions generate zigzag chains along the c axis which are, in turn, linked by further C-H?O inter-actions into sheets parallel to (100). PMID- 22259544 TI - 6,6'-Di-tert-butyl-4,4'-dimethyl-2,2'-[1,2-phenyl-enebis(nitrilo-methanylyl idene)]diphenol. AB - In the title mol-ecule, C(30)H(36)N(2)O(2), the dihedral angles between the central benzene ring and the two benzene rings of the butyl-salicylaldimine groups are 14.3 (2) and 40.6 (2) degrees . There are two strong intra-molecular O H?N hydrogen bonds which form S(6) rings. The crystal studied was a non merohedral twin with refined components of 0.270 (4) and 0.730 (4). PMID- 22259545 TI - Kallolide A acetate pyrazoline. AB - IN THE CRYSTAL STRUCTURE OF KALLOLIDE A ACETATE PYRAZOLINE [SYSTEMATIC NAME: 7 methyl-16-oxo-4,10-bis-(prop-1-en-2-yl)-17,18-dioxa-14,15-diaza-tetra-cyclo [9.4.2.1(6,9).0(1,12)]octa-deca-6,8,14-trien-5-yl acetate], C(23)H(28)N(2)O(5), there is a 12-member-ed carbon macrocyclic structure. In addition, there is a tris-ubstituted furan ring, an approximately planar gamma-lactone ring [maximum deviation of 0.057 (3) A] and a pyraz-oline ring, the latter in an envelope conformation. The pyrazoline and the gamma-lactone rings are fused in a cis configuration. In the crystal, mol-ecules are linked by weak C-H?O inter-actions, forming a two-dimensional network parallel to (001). An intra-molecular C-H?O hydrogen bond is also present. PMID- 22259546 TI - 2',6'-Bis(4-carb-oxy-phen-yl)-4,4'-bipyridin-1-ium nitrate 0.25-hydrate. AB - In the title compound, C(24)H(17)N(2)O(4) (+).NO(3) (-).0.25H(2)O, the central pyridine ring of the 2',6'-bis-(4-carb-oxy-phen-yl)-4,4'-bipyridin-1-ium cation is almost coplanar with one benzene ring [dihedral angle = 1.03 (5) degrees ], while it makes dihedral angles of 9.59 (5) degrees with the other benzene ring and 13.66 (6) degrees with the pyridinium ring. In the crystal, N-H?O and O-H?O hydrogen bonds link the cations and nitrate anions into a sheet in the (302) plane. The crystal structure also exhibits pi-pi inter-actions between the central pyridine ring and the benzene rings of neighboring mol-ecules [centroid centroid distance = 3.6756 (13) A]. PMID- 22259547 TI - trans-(Ethene-1,2-di-yl)bis-(diphenyl-phosphine selenide). AB - In the title mol-ecule, C(26)H(22)P(2)Se(2), both P atoms have distorted tetra hedral environments, resulting in effective cone angles of 177 and 174 degrees . Inversion twinning was detected and refined to a ratio of 0.35:0.65. Weak inter molecular C-H?Se inter-actions are observed. PMID- 22259548 TI - [2-(4-Chloro-phen-yl)-5-phenyl-oxolan-3-yl](cyclo-penten-yl)methanone. AB - In the title compound, C(22)H(21)ClO(2), the oxolane ring adopts a twisted conformation. The dihedral angles between the mean plane of the oxolane ring and the mean planes of the 4-chloro-phenyl, phenyl and cyclo-pentenyl rings are 71.81 (18), 76.9 (18) and 82.08 (18) degrees , respectively. PMID- 22259549 TI - 4-Chloro-N-(3-methyl-benzo-yl)benzene-sulfonamide monohydrate. AB - In the title compound, C(14)H(12)ClNO(3)S.H(2)O, the dihedral angle between the sulfonyl and benzoyl benzene rings is 84.4 (2) degrees . In the crystal, every water mol-ecule forms four hydrogen bonds with three different mol-ecules of 4 chloro-N-(3-methyl-benzo-yl)benzene-sulfonamide. One of the water H atoms forms a bifurcated hydrogen bond with both the sulfonyl and the carbonyl O atoms of the same mol-ecule. Mol-ecules are linked into layers in the ab plane through N-H?O and O-H?O hydrogen bonds. PMID- 22259550 TI - Tris(2-carbamoylguanidinium) hydrogen fluoro-phospho-nate fluoro-phospho-nate monohydrate. AB - The title structure, 3C(2)H(7)N(4)O(+).HFPO(3) (-).FPO(3) (2-).H(2)O, contains three independent 2-carbamoylguanidinium cations, one fluoro-phospho-nate, one hydrogen fluoro-phospho-nate and one water mol-ecule. There are three different layers in the structure that are nearly perpendicular to the c axis. Each layer contains a cation and the layers differ by the respective presence of the water mol-ecule, the hydrogen fluoro-phospho-nate and fluoro-phospho-nate anions. N-H?O hydrogen bonds between the guanylurea mol-ecules that inter-connect the mol ecules within each layer are strong. The layers are inter-connected by strong and weak O-H?O hydrogen bonds between the anions and water mol-ecules, respectively. Inter-estingly, the configuration of the layers is quite similar to that observed in 2-carbamoylguanidinium hydrogen fluoro-phospho-nate [Fabry et al. (2012). Acta Cryst. C68, o76-o83]. There is also present a N-H?F hydrogen bond in the structure which occurs quite rarely. PMID- 22259551 TI - 3-Chloro-N-(2-chloro-phen-yl)benzamide. AB - In the title compound, C(13)H(9)Cl(2)NO, the meta-Cl atom in the benzoyl ring is positioned anti to the C=O bond, while the ortho-Cl atom in the aniline ring is positioned syn to the N-H bond. The two aromatic rings are almost coplanar, making a dihedral angle of 4.73 (5) degrees . The crystal structure is stabilized by N-H?O hydrogen bonds, which link the mol-ecules into chains along the b axis. PMID- 22259552 TI - 1,2-Bis(dibromo-meth-yl)benzene. AB - In the title compound, C(8)H(6)Br(4), intra-molecular C-H?Br hydrogen bonds generate two S(6) rings. The two geminal bromine-atom substituents point to opposite sides of the aromatic ring system. In the crystal, mol-ecules are linked by inter-molecular pi-pi inter-actions with centroid-centroid distances of 3.727 (9) and 3.858 (9) A. PMID- 22259553 TI - Cyclo-linopeptide B methanol tris-olvate. AB - The title compound, C(56)H(83)N(9)O(9)S.3CH(3)OH, is a methanol tris-olvate of the cyclo-linopeptide cyclo(Met(1)-Leu(2)-Ile(3)-Pro(4)-Pro(5)-Phe(6)-Phe(7) Val(8)-Ile(9)) (henceforth referred to as CLP-B), which was isolated from flaxseed oil. All the amino acid residues are in an l-configuration based on the CORN rule. The cyclic nona-peptide exhibits eight trans peptide bonds and one cis peptide bond observed between the two proline residues. The conformation is stabilized by an alpha-turn and two consecutive beta-turns each containing a N H?O hydrogen bond between the carbonyl group O atom of the first residue and the amide group H atom of the fourth (alpha-turn) or the third residue (beta-turns), repectively. In the crystal, the components of the structure are linked by N-H?O and O-H?O hydrogen bonds into chains parallel to the a axis. PMID- 22259555 TI - 2-(4H-1,2,4-Triazol-4-yl)pyrimidine. AB - The title compound, C(6)H(5)N(5), is almost planar, the triazole and pyrimidine rings forming a dihedral angle of 2.9 (13) degrees . PMID- 22259554 TI - 2,5-Bis(1,3-dithiol-2-yl-idene)-1,3-dithiol-ane-4-thione. AB - The asymmetric unit of the title compound, C(9)H(4)S(7), contains two independent mol-ecules, in one of which the central five-membered ring is disordered over two orientations in a 0.924 (3):0.076 (3) ratio. The mol-ecular skeleton is almost planar: the average distance of the atoms from their mean plane is 0.128 (7) A in the ordered mol-ecule, and 0.088 (5) and 0.123 (2) A in the major and minor disorder components, respectively. The ordered and disordered mol-ecules form separate columns by stacking along the b axis. Adjacent columns inter-act via short S?S [3.33 (2), 3.434 (3), 3.444 (2), 3.503 (2), 3.519 (3) and 3.53 (4) A] and S?H [2.814 (2), 2.87 (7), 2.92 (2), 2.9269 (18), 2.93 (2), 2.94 (2), 2.939 (2), 2.967 (2) and 2.974 (1) A] contacts. PMID- 22259556 TI - The desoxazoline asidiacyclamide analogue cyclo(Gly-Thr-D-Val-Thz-Ile-Thr-D-Val Thz) acetonitrile monosolvate. AB - THE TITLE PEPTIDE [SYSTEMATIC NAME: 4-(butan-2-yl)-7,20-bis-(1-hy-droxy-eth-yl) 10,23-bis-(propan-2-yl)-12,25-dithia-3,6,9,16,19,22,27,28-octa-aza-tricyclo [22.2.1.1(11,14)]octa-cosa-1(26),11(28),13,24(27)-tetra-ene-2,5,8,15,18,21-hexone acetonitrile monosolvate], C(32)H(48)N(8)O(8)S(2).CH(3)CN, an analogue of ascidiacyclamide (ASC) [cyclo(-Ile-Oxz-D-Val-Thz-)(2)], lies about a twofold rotation axis, so that the glycine (Gly) and isoleucine (Ile) residues are each disordered over two sites with equal occupancies. The acetonitrile mol-ecule is also located on a twofold axis passing through the C and N atoms. In the peptide, the thia-zole rings are faced to each other with a dihedral angle of 9.63 (15) degrees and intra-molecular N-H?O and O-H?O hydrogen bonds are observed. A bifurcated N-H?(O,O) hydrogen bond links the peptide mol-ecules into a layer parallel to the ab plane. PMID- 22259557 TI - (Z)-3-(4-Chloro-phen-yl)-2-{[N-(2-formyl-phen-yl)-4-methyl-benzene-sulfonamido] meth-yl}prop-2-ene-nitrile. AB - In the title compound, C(24)H(19)ClN(2)O(3)S, the sulfonyl-bound benzene ring forms dihedral angles of 38.1 (2) and 81.2 (1) degrees , respectively, with the formyl benzene and benzene rings. The mol-ecular conformation is stabilized by a weak intra-molecular C-H?O hydrogen bond, which generates an S(5) ring motif. The crystal packing is stabilized by C-H?O hydrogen bonds, which generate C(7) zigzag chains along [010] and R(3) (3)(19) ring motifs along [010]. The crystal packing is further stabilized by C-Cl?pi inter-actions [Cl?centroid = 3.456 (2) A and C Cl?centroid = 173.4 (2) degrees ]. PMID- 22259558 TI - 2-(5-Bromo-3-isopropyl-sulfanyl-1-benzofuran-2-yl)acetic acid. AB - The title compound, C(13)H(13)BrO(3)S, was prepared by alkaline hydrolysis of ethyl 2-(5-bromo-3-isopropyl-sulfanyl-1-benzofuran-2-yl)acetate. In the crystal, the carboxyl groups are involved in inter-molecular O-H?O hydrogen bonds, which link the mol-ecules into dimers. These dimers are further packed into stacks along the c axis by inter-molecular C-H?pi inter-actions, and by slipped pi-pi inter-actions between the furan rings of adjacent mol-ecules [centroid-centroid distance = 3.472 (2) A, inter-planar distance = 3.398 (2) A and slippage = 0.713 (2) A]. PMID- 22259560 TI - Benzene-1,3,5-tricarb-oxy-lic acid-5-(4-pyrid-yl)pyrimidine (1/1). AB - In the pyrimidine mol-ecule of the title compound, C(9)H(7)N(3).C(9)H(6)O(6), the pyridine ring is oriented at 33.26 (11) degrees with respect to the pyrimidine ring. In the benzene-1,3,5-tricarb-oxy-lic acid mol-ecule, the three carb-oxy groups are twisted by 7.92 (9), 8.68 (10) and 17.07 (10) degrees relative to the benzene ring. Classical O-H?N and O-H?O hydrogen bonds and weak C-H?O and C-H?N hydrogen bonds occur in the crystal structure. PMID- 22259559 TI - Ethyl 2-(4-nitro-phen-yl)-1-[3-(2-oxopyrrolidin-1-yl)prop-yl]-1H-benzimidazole-5 carboxyl-ate. AB - In the title compound, C(23)H(24)N(4)O(5), the essentially planar benzimidazole ring system [maximum deviation = 0.008 (2) A] forms a dihedral angle of 39.22 (7) degrees with the attached nitro-benzene ring. The pyrrolidin-2-one ring adopts an envelope conformation with a C atom as the flap. In the crystal, mol-ecules are connected by C-H?O inter-actions, forming sheets propagating in (011). The crystal packing also features weak pi-pi stacking inter-actions [centroid centroid = 3.6746 (12) A]. PMID- 22259561 TI - Tris(hy-droxy-meth-yl)methanaminium trifluoro-acetate. AB - In the crystal structure of the title salt, C(4)H(12)NO(3) (+).C(2)F(3)O(2) (-), N-H?O and O-H?O hydrogen bonds link the ions, forming a complex three-dimensional network. PMID- 22259562 TI - (2E)-1-(5-Bromo-thio-phen-2-yl)-3-(2,3,4-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(16)H(15)BrO(4)S, the thio-phene ring is not coplanar with the benzene ring; the dihedral angle between the two planes is 11.08 (12) degrees . The crystal structure is characterized by C-H?O inter-actions. Weak intra-molecular C-H?O hydrogen bonds also occur. PMID- 22259563 TI - (Z)-3-Chloro-N-[(Z)-3-(3-chloro-2-methyl-phenyl-imino)-butan-2-yl-idene]-2-methyl aniline. AB - In the title compound, C(18)H(18)Cl(2)N(2), the complete molecule is generated by the application of C(2) symmetry. The C=N bond has an E configuration. The dihedral angle between the benzene ring and the 1,4-diaza-butadiene plane is 66.81 (9) degrees . PMID- 22259564 TI - {2-[(3,5-Dimethyl-2H-pyrrol-2-yl-idene-kappaN)(4-nitro-phen-yl)meth-yl]-3,5 dimethyl-1H-pyrrol-1-ido-kappaN}difluoridoboron. AB - In an effort to discover novel and potential boron-dipyrromethene (BODIPY) dyes, the title compound, C(19)H(18)BF(2)N(3)O(2), was prepared from 2,4-dimethyl pyrrole, 4-nitro-benzaldehyde and BF(3).Et(2)O in a one-pot reaction. There are two independent mol-ecules, A and B, in the asymmetric unit in which the dihedral angles between the benzene ring and boron-dipyrromethene mean plane have significantly different values [82.71 (8) degrees for mol-ecule A and 73.16 (8) degrees for mol-ecule B]. Inter-molecular C-H?pi inter-actions help to stabilize the crystal structure. PMID- 22259565 TI - (E)-2-(4-tert-But-ylphen-yl)-2-cyano-1-(3-methyl-1-vinyl-1H-pyrazol-5-yl)vinyl 2,2-dimethyl-propano-ate. AB - In the title compound, C(24)H(29)N(3)O(2), the dihedral angle between the benzene and pyrazole rings is 80.55 (7) degrees . The mol-ecule contains an acrylonitrile moiety and exists in an E conformation. Bioassay tests showed that the title compound exhibited higher acaricidal activity than its Z isomer. PMID- 22259566 TI - 5-Amino-1-(4-nitro-phen-yl)-1H-pyrazole-3-carbonitrile. AB - The title compound, C(10)H(7)N(5)O(2), was synthesized by the reaction of 4-nitro aniline and 2,3-dicyano-propionic acid ethyl ester. In the crystal, N-H?O and C H?O hydrogen bonds link the mol-ecules, forming a three-dimensional network. PMID- 22259567 TI - (5-Meth-oxy-1H-indol-3-yl)acetonitrile. AB - In the title compound, C(11)H(10)N(2)O, the O atom and the C atom of the methyl ene group deviate only slightly [0.029 (3) and 0.055 (3) A, respectively] from the approximately planar ring system (r.m.s. deviation = 0.013 A). In the crystal, N-H?O hydrogen bonds link the mol-ecules into zigzag chains running along the b axis. PMID- 22259568 TI - 2,2'-[2,4-Bis(naphthalen-1-yl)cyclo-butane-1,3-di-yl]bis-(1-methyl-pyridinium) diiodide: thermal-induced [2 + 2] cyclo-addition reaction of a heterostilbene. AB - The asymmetric unit of the title compound, C(36)H(32)N(2) (2+).2I(-), consists of one half-mol-ecule of the cation and one I(-) anion. The cation is located on an inversion centre. The dihedral angle between the pyridinium ring and the naphthalene ring system in the asymmetric unit is 19.01 (14) degrees . In the crystal, the cations and the anions are linked by C-H?I inter-actions into a layer parallel to the bc plane. Intra- and inter-molecular pi-pi inter-actions with centroid-centroid distances of 3.533 (2)-3.807 (2) A are also observed. PMID- 22259569 TI - Dihydro-allocryptopine. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 7,8-dimeth-oxy-11-methyl-17,19-dioxa-11 aza-tetra-cyclo-[12.7.0.0(4,9).0(16,20)]henicosa-1(21),4,6,8,14,16 (20)-hexaen-2 ol], C(21)H(25)NO(5), the benzene rings are inclined at a dihedral angle of 23.16 (5) degrees . One of the meth-oxy C atoms is close to coplanar with its attached ring [deviation = 0.129 (3) A], whereas the other is orientated away from the ring [deviation = -1.124 (2) A]. The 10-membered ring is highly puckered, and the OH and CH(3) substituents project to the same side of the ring. In the crystal, O H?O hydrogen bonds link the mol-ecules into [010] chains and C-H?O and C-H?pi inter-actions consolidate the packing. PMID- 22259570 TI - 1,2-Bis[(1,3-benzodioxol-5-yl)methyl-idene]hydrazine. AB - The complete mol-ecule of the title compound, C(16)H(12)N(2)O(4), is generated by the application of a centre of inversion. The (1,3-benzodioxol-5-yl)methyl-idene fused-ring system is approximately planar (r.m.s. deviation = 0.020 A) and is essentially coplanar with the central hydrazine group [dihedral angle = 5.08 (9) degrees ]. Weak pi-pi inter-molecular inter-actions are observed [centroid centroid distance = 3.8553 (8) A], providing some packing stability. PMID- 22259571 TI - 2-Chloro-1-[4-(2,4-difluoro-benz-yl)piperazin-1-yl]ethanone. AB - In the title mol-ecule, C(13)H(15)ClF(2)N(2)O, the piperazine ring is in a chair conformation with the 2,4-difluoro-benzyl and chloro-acetyl substituents in equatorial positions. PMID- 22259572 TI - N-[2-(4-Bromo-benzo-yl)eth-yl]isopropyl-aminium chloride. AB - The crystal structure of the title compound, C(12)H(17)BrNO(+).Cl(-), is stabilized by N-H?Cl and C-H?O hydrogen bonds, forming a three-dimensional network. The inter-actions framework is completed by C-H?pi contacts between a methyl-ene group and the benzene ring of a symmetry-related mol-ecule. PMID- 22259573 TI - 2-(1H-Benzotriazol-1-yl)-1-(furan-2-yl)ethanol. AB - In the title compound, C(12)H(11)N(3)O(2), the benzotriazole ring system is approximately planar [maximum deviation = 0.008 (1) A] and its mean plane is oriented at a dihedral angle of 24.05 (4) degrees with respect to the furan ring. In the crystal, O-H?N hydrogen bonds link the mol-ecules into chains along the ac diagonal. pi-pi stacking between the furan rings, between the triazole and benzene rings, and between the benzene rings [centroid-centroid distances = 3.724 (1), 3.786 (1) and 3.8623 (9) A] are also observed. PMID- 22259574 TI - 6-[(E)-2-Phenyl-vin-yl]-1H-indole. AB - The title compound, C(16)H(13)N, is essentially planar [maximum deviation from the least-squares plane = 0.081 (3) A], with a dihedral angle of 1.65 (13) degrees between the planes of the indole and benzene rings. In the crystal, there are no significant inter-molecular pi-pi inter-actions [minimum ring centroid-centroid separation = 4.217 (5) A]. PMID- 22259575 TI - (1E,4E)-1-(3-Nitro-phen-yl)-5-phenyl-penta-1,4-dien-3-one. AB - In the title compound, C(17)H(13)NO(3), the dihedral angle between the benzene rings is 31.21 (5) degrees . In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds occur. A C-H?pi inter-action is also indicated. PMID- 22259576 TI - (2E)-2-[(3E)-4-Phenyl-but-3-en-2-yl-idene]hydrazinecarboxamide. AB - In the title compound, C(11)H(13)N(3)O, the phenyl ring is disordered over two sites, with occupancy factors in a 0.520 (17):0.480 (17) ratio. The dihedral angle between the ring planes of the major and minor components of the disordered ring is 12.9 (2) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming R(2) (2)(8) ring motifs. C-H?O, C-H?N and C-H?pi inter actions also occur. PMID- 22259577 TI - Hexyl (E)-3-(3,4-dihy-droxy-phen-yl)acrylate. AB - The title mol-ecule, C(15)H(20)O(4), has an E conformation about its C=C bond and is almost planar (r.m.s. deviation of all non-H atoms = 0.04 A). The crystal structurere features O-H?O and C-H?O hydrogen bonds. PMID- 22259578 TI - 3-Carbamoylquinoxalin-1-ium chloride. AB - The title compound, C(9)H(8)N(3)O(+).Cl(-), was isolated from a liquid culture of streptomyces sp. In the cation, the ring system makes a dihedral angle of 0.2 (2) degrees with the amide group. The protonation creating the cation occurs at ome of the N atoms in the quinoxaline ring system. In the crystal, the ions are linked through N-H?O and N-H?Cl hydrogen bonds, forming a two-dimensional network parallel to (10[Formula: see text]). PMID- 22259579 TI - (3-{[N-(5-Chloro-2-hy-droxy-phen-yl)oxamo-yl]amino}-prop-yl)dimethyl-aza-nium perchlorate. AB - In the title compound, C(13)H(19)ClN(3)O(3) (+).ClO(4) (-), the 3-(di-meth-yl ammonio)-propyl group of the cation is disordered over two sets of sites with occupancies 0.772 (6) and 0.228 (6). The cations are joined by pairs of N-H?O hydrogen bonds into centrosymmetric dimers and these dimers are assembled into chains along the a-axis direction, also through N-H?O hydrogen bonds. The perchlorate anions are linked to the hy-droxy groups of the cations by O-H?O hydrogen bonds. The positively charged ammonium groups and the anions give rise to folded layers parallel to the ab plane. PMID- 22259580 TI - 1,2-Bis(3-phen-oxy-benzyl-idene)hydrazine. AB - Mol-ecules of the title compound, C(26)H(20)N(2)O(2), reside on crystallographic centres of inversion located at the mid-point of the N-N bond. The benzyl-idene ring is essentially coplanar with the central hydrazine group, with an inter planar angle of 4.5 (2) degrees , whereas the phenyl ring is oriented at 34.0 (3) degrees with respect to the mean plane of the central 1,2-dibenzyl idenehydrazine group. In the crystal, C-H?pi(arene)-ring inter-actions link mol ecules about inversion centres. PMID- 22259581 TI - (Z)-1,1-Dicyano-2-(4-fluoro-phen-yl)-3-(1-hexyl-pyridin-1-ium-4-yl)prop-2-en-1 ide. AB - The title compound, C(22)H(22)FN(3), exists as a zwitterion with the negative charge on the dicyano-methanide group and the positive charge on the pyridinium N atom. The mol-ecule adopts a Z conformation about the central C=C bond. The dihedral angle between the pyridinium and benzene rings is 65.65 (5) degrees . Weak C-H?N hydrogen bonding is present in the crystal structure. PMID- 22259582 TI - 3-Benzyl-sulfanyl-1H-1,2,4-triazol-5-amine. AB - In the title mol-ecule, C(9)H(10)N(4)S, the dihedral angle between the benzene and triazole rings is 81.05 (5) degrees . In the crystal, N-H?N hydrogen bonds link the mol-ecules into infinite zigzag chains along [010]. PMID- 22259583 TI - 9-[(E)-2-(4,4,5,5-Tetra-methyl-1,3,2-dioxa-borolan-2-yl)ethen-yl]-9H-carbazole. AB - The title compound, C(20)H(22)BNO(2), is a simple olefinic compound which carries both B and N atoms that are trans to one another. The pi-conjugated system of the compound is considered to be isoelectronic with 1,3-butadiene. There are two independent mol-ecules in the asymmetric unit in which the environments around the boron atoms are essentially planar (r.m.s. deviations of 0.0032 and 0.0021 A for the BO(2)C planes). The dihedral angles of the olefinic planes with the boron planes are 5.70 (11) and 9.74 (9) degrees , respectively, while the dihedral angles of the olefinic planes with the carbazole planes are 19.37 (3) and 10.74 (6) degrees . These dihedral angles are consistent with those in 9 ethenylcarbazole and an ethenylboronic ester derivative. The N-Csp(2), B-Csp(2) and C=C bond lengths suggest that the contribution of the canonical structure can be described as N(+)=C-C=B(-). PMID- 22259584 TI - (E)-2-[(1-Benzyl-piperidin-4-yl)imino-meth-yl]phenol. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(19)H(22)N(2)O. Both mol-ecules have an E conformation about their C=N bonds and both piperdine rings adopt chair conformations with their N atoms adopting pyramidal geometries [bond angle sums = 329.8 (4) and 330.2 (4) degrees ]. Both mol-ecules feature an intra-molecular O-H?N hydrogen bond, which generates an S(6) ring. The dihedral angles between the phenyl and benzene ring planes are 45.97 (18) and 66.0 (2) degrees . Short O-H?O contacts occur in the crystal. PMID- 22259585 TI - 2-{1-[(2-Nitro-benzene-sulfonamido)-meth-yl]cyclo-hexyl}acetic acid. AB - In the title compound, C(15)H(20)N(2)O(6)S, the C-SO(2)-NH-C torsion angle is 64.54 (14) degrees . In the mol-ecule, there is a bifurcated N-H?(O,O) hydrogen bond, forming S(7) rings. In the crystal, inversion dimers are formed via O-H?O hydrogen bonds involving the carboxyl group, so forming R(2) (2)(8) rings. These dimers are further linked via pairs of C-H?O hydrogen bonds, forming a C(6) chain propagating along the c-axis direction. PMID- 22259586 TI - Ethyl 2-(4-hy-droxy-3-meth-oxy-phen-yl)-1-[3-(2-oxopyrrolidin-1-yl)prop-yl]-1H benzimidazole-5-carboxyl-ate monohydrate. AB - In the title compound, C(24)H(27)N(3)O(5).H(2)O, the essentially planar benzimidazole ring system [maximum deviation = 0.020 (1) A] forms dihedral angles of 54.10 (11) and 67.79 (6) degrees , respectively, with the mean plane of pyrrolidin-2-one ring and the benzene ring. The pyrrolidin-2-one ring adopts an envelope conformation with one of the methylene C atoms at the flap. An intra molecular C-H?pi inter-action is observed. In the crystal, O-H?O and O-H?N hydrogen bonds link the two components into a double-tape structure along the a axis. The crystal packing is further stabilized by weak pi-pi stacking [centroid centroid distance = 3.6632 (9) A] and C-H?O inter-actions. PMID- 22259587 TI - 4-(4-Bromo-phen-yl)-1-(2,6-difluoro-benz-yl)-3-(3,4,5-trimeth-oxy-phen-yl)-1H 1,2,4-triazole-5(4H)-thione. AB - In the title compound, C(24)H(20)BrF(2)N(3)O(3)S, the triazole ring (r.m.s. deviation = 0.0107 A) makes dihedral angles of 28.18 (14), 63.76 (14) and 77.01 (18) degrees , respectively, with the trimeth-oxy-, bromo-, and difluoro substituted benzene rings. The C atoms of the meta meth-oxy groups are roughly coplanar with their ring [displacements = -0.289 (4) and 0.083 (7) A], whereas the C atom of the para group is displaced [1.117 (3) A]. In the crystal, inversion dimers linked by two pairs of C-H?O hydrogen bonds occur. The ring motif of the two hydrogen bonds to their symmetry-generated O-atom acceptors is R(2) (2)(8). PMID- 22259588 TI - (E)-3-(2-Nitro-phen-yl)-1-{1-phenyl-sulfonyl-2-[(phenyl-sulfon-yl)meth-yl]-1H indol-3-yl}prop-2-en-1-one. AB - In the title compound, C(30)H(22)N(2)O(7)S(2), the configuration about the propene C=C bond is E. The indole unit is essentially planar, with a maximum deviation of 0.031 (3) A. The dihedral angle between the planes of the phenyl rings of the two phenyl-sulfonyl groups is 80.95 (19) degrees . The central prop 2-ene-1-one group is oriented at a dihedral angle of 44.26 (11) degrees with respect to the nitro-phenyl ring and at 39.24 (8) degrees with respect to the indole unit. The S atoms are in a distorted tetra-hedral configuration. In the crystal, mol-ecules are linked into centrosymmetric dimers via pairs of C-H?O hydrogen bonds with an R(2) (2)(24) graph-set motif. The crystal structure is stabilized by further C-H?O inter-actions. Short intra-molecular C-H?O contacts result in several S(6) rings. PMID- 22259589 TI - Bis(trimethyl-ammonium) naphthalene-1,5-disulfonate. AB - The asymmetric unit of the title compound, 2C(3)H(10)N(+).C(10)H(6)S(2)O(6) (2-), contains a half-anion, which is completed by inversion symmetry, and one cation. The cations and anions are associated via strong N-H?O(sulfonate) hydrogen bonding inter-actions, forming cation-anion-cation groups. Secondary inter actions such as C-H(ammonium)?O(sulf-on-ate) and van der Waals inter-actions link the cations and anions together in a three-dimensional crystal structure, with zigzag rows of cations lying between layers of anions. PMID- 22259590 TI - 3-[(3-Benzoyl-4-hy-droxy-1,1-dioxo-2H-1lambda,2-benzothia-zin-2-yl)meth-yl]benzo nitrile. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(23)H(17)N(2)O(4)S, with significant differences in their conformations, e.g. the benzene rings of the benzothia-zine and benzonitrile units are inclined at 28.19 (10) and 17.89 (7) degrees in the two mol-ecules, with the centroids of the rings separated by 3.975 (2) and 3.637 (2) A, respectively. Moreover, the N-C-C-C torsion angles involving the benzoyl group are 14.3 (5) and 8.2 (5) degrees in the two mol-ecules, showing different degrees of rotation of this group. In both mol-ecules, the heterocyclic thia-zine rings adopt half-chair conformations, with the S and N atoms displaced by 0.427 (6) and 0.365 (6) A, respectively, in one mol-ecule and by 0.356 (6) and 0.432 (6) A, respectively, in the other, on opposite sides of the mean planes formed by the remaining ring atoms. The crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds and further consolidated by intra-molecular O-H?O hydrogen bonds. PMID- 22259591 TI - 2-(3-Benzoyl-4-hy-droxy-1,1-dioxo-2H-1lambda,2-benzothia-zin-2-yl)-1-phenyl ethanone. AB - In the title mol-ecule, C(23)H(17)NO(5)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.383 (3) and 0.473 (3) A, respectively, on opposite sides of the mean plane formed by the ring C atoms. The phenyl rings attached to carbonyl groups lie almost parallel to each other at a dihedral angle 7.43 (9) degrees , the distance between the centroids of the rings being 3.780 (1) A. The C(thia-zine)-C=O and O=C-CH(2) groups make dihedral angles of 37.56 (16) and 1.93 (18) degrees , respectively, with the phenyl groups to which they are attached. The crystal structure features O-H?O and C-H?O hydrogen bonds and further consolidated by C-H?pi inter-actions; an intra-molecular O-H?O hydrogen bond is also present. PMID- 22259592 TI - 2,4-Di-tert-butyl-6-[(R/S)-1-(3,5-di-tert-butyl-2-hy-droxy-phen-yl)eth-yl]phenyl [(1R,4S)-7,7-dimethyl-2-oxobicyclo-[2.2.1]heptan-1-yl]methane-sulfonate. AB - The asymmetric unit of the title compound, C(40)H(60)O(5)S, comprises two diastereomers related, except for the chiral camphor groups, by a pseudo inversion centre. In both diasteromers, the camphor sulfate moiety maintained the absolute configuartion (R,S) of the precursor. However, the absolute configurations at the methine C atoms are of opposite chirality. Both mol-ecules reveal intra-molecular O-H?O hydrogen bonds, whereas van der Waals inter-actions define the crystal packing. PMID- 22259593 TI - 2-(5-Fluoro-2,3-dioxoindolin-1-yl)ethyl 4-methyl-piperazine-1-carbodithio-ate. AB - In the title compound, C(16)H(18)FN(3)O(2)S(2), the methyl-piperazine ring adopts a chair conformation, while the (2,3-dioxoindolin-1-yl)ethyl unit is linked to one of the N atoms of the piperazine ring via the carbodithio-ate group. In the crystal, each mol-ecule is linked to its neighbors within the ([Formula: see text]03) plane through weak C-H(methyl-ene)?O, C-H(ar-yl)?O and C-H(methyl-ene)?S inter-actions. Perpendicular to this plane mol-ecules are connected through inter molecular short N?pi(pyrrole ring) contacts [N?C centroid = 3.232 (2) A], another set of C-H(methyl-ene)?O inter-actions and through short contacts between carbodithio-ate S atoms and the pyrrole rings [C?centroid = 3.695 (3), S?centroid = 3.403 (2) A]. PMID- 22259594 TI - 3-(4-Fluoro-phenyl-sulfon-yl)-5-iodo-2,7-dimethyl-1-benzofuran. AB - In the title compound, C(16)H(12)FIO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 72.31 (6) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, and by an I?I contact [3.7764 (3) A]. The crystal structure also exhibits a weak C I?pi [3.901 (3) A] inter-action and a slipped pi-pi inter-action between the furan and benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.845 (3), inter-planar distance = 3.555 (3) and slippage = 1.465 (3) A]. PMID- 22259595 TI - 6,12,18,24-Tetra-meth-oxy-4,10,16,22-tetra-kis-[(meth-oxy-carbon-yl)meth-oxy] 2,8,14,20-tetra-kis-(2-phenyl-eth-yl)resorcin[4]arene. AB - The title compound, C(76)H(80)O(16), is a macrocyclic structure. This novel resorcin[4]arene derivative has (meth-oxy-carbon-yl)meth-oxy 'head' groups on the upper rim. The compound has a C(2v) 'boat' geometry and there are a range of C H?O contacts in the crystal structure. PMID- 22259596 TI - N-(2-Chloro-4-nitro-phen-yl)maleamic acid monohydrate. AB - The title compound, C(10)H(7)ClN(2)O(5).H(2)O, crystallizes with a half-mol-ecule each of N-(2-chloro-4-nitro-phen-yl)maleamic acid (located on a mirror plane) and water (located on a twofold rotation axis) in the asymmetric unit. The main mol ecule is planar by symmetry and its conformation is stabilized by an intra molecular O-H?O hydrogen bond. In the crystal, N-H?O and O-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 22259597 TI - Evaluation of a short food frequency questionnaire used among Norwegian children. AB - OBJECTIVE: The aim of this study was to evaluate a short food frequency questionnaire (FFQ) against a four-day precoded food diary (PFD) with regard to frequency of food intake among Norwegian 9- and 13-year-olds. SUBJECTS AND DESIGN: A total of 733 9-year-olds and 904 13-year-olds completed first a short FFQ and one to two weeks later a four-day PFD. The short FFQ included questions about 23 food items, including different drinks, fruits, vegetables, bread, fish, pizza, sweets, chocolate and savoury snacks. The PFD covered the whole diet. RESULTS: When comparing mean intake from the PFD with comparable food items in the FFQ, all food items showed that increasing intake measured with the PFD corresponded with increasing intake with the short FFQ. However, participants reported a significantly higher frequency of intake for most foods with the short FFQ compared with PFD, except for soft drinks with sugar and sweets. The median Spearman correlation coefficient between the two methods was 0.36 among the 9 year-olds and 0.32 among the 13-year-olds. Often eaten foods such as fruits and vegetables had higher correlations than seldom eaten foods such as pizza and potato chips. The median correlation coefficients for drinks alone were higher (r=0.47) for both age groups. CONCLUSIONS: Results indicate that the short FFQ was able to identify high and low consumers of food intake and had a moderate capability to rank individuals according to food intake. Drinks, fruits and vegetables had better correlations with the PFD than infrequently eaten food items. PMID- 22259599 TI - Staged Complete Revascularization in ST-Segment Elevation Myocardial Infarction Should Be the Treatment of Choice Compared to Primary Complete Revascularization. PMID- 22259598 TI - N-acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Narrative Review. AB - Contrast-induced nephropathy (CIN) affects in-hospital, short- and long-term morbidity and mortality. It also leads to prolonged hospital stay and increased medical cost. Given the potential clinical severity of CIN, there has been considerable interest in the development of preventative strategies to reduce the risk of contrast-induced renal deterioration in at-risk populations. A number of pharmacologic and mechanical preventive measures have been attempted, but no method other than adequate periprocedural hydration has been conclusively successful. Since its introduction in 2000, N-acetylcysteine (NAC) has been widely investigated, albeit with conflicting findings for its nephroprotection capability in patients receiving contrast media procedures. However, there is still virtually no definitive evidence of effectiveness of NAC. Although the exact mechanism responsible for the protective action of NAC from renal function deterioration remains unclear, the antioxidant and vasodilatory properties of NAC have been suggested as the main mechanisms. This review summarizes the current status of NAC as a potential agent to prevent renal functional deterioration and its limitations. PMID- 22259600 TI - Analysis of potential cost-savings after introduction of drug-eluting balloon angioplasty for in-stent restenosis or small vessel disease. AB - BACKGROUND AND OBJECTIVES: The drug-eluting balloon (DEB) catheter system was developed to treat restenosis. Furthermore, DEB angioplasty has been shown to reduce restenosis risk when compared to drug-eluting stents (DES) in patients with in-stent restenosis (ISR) or small vessel disease (SVD). In addition, DEB angioplasty reduces costs due to fewer revascularizations and reduced clopidogrel treatment length. The objective of this study was to predict the expected cost savings when DEB is substituted for DES in patients with ISR or SVD. SUBJECTS AND METHODS: The subjects included were patients treated by DES at Seoul National University Hospital from January 2006 to June 2009, with clinical data after percutaneous coronary intervention, were. A model was developed to allow the costs of DES and the calculated costs of DEB incurred by patients with ISR or SVD to be compared. The overall cost of DEB was calculated to be 1,256,150 won and the overall cost of DES was 2,102,500 won, and the cost of clopidogrel was 2,168 won. Expected repeat revascularizations within 12 months of DEB were calculated based on information provided by the Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery (PEPCAD) I and II trials. RESULTS: By substituting DEB for DES, total cost (including the cost of initial DEB treatment, the cost of repeat revascularization after DEB treatment, and the cost of clopidogrel treatment) was found to be 34% lower in ISR patients and 48% lower in SVD patients. CONCLUSION: DEB angioplasty will significantly reduce costs as compared to DES in ISR and in SVD patients. PMID- 22259601 TI - The economic burden of inflammatory heart disease in Korea. AB - BACKGROUND AND OBJECTIVES: The incidence of inflammatory heart diseases is not yet as high as those of other cardiovascular diseases; however, inflammatory heart diseases do have relatively high mortality rate. Therefore, update information on the economic burden of inflammatory heart diseases are necessary in order to appropriate policy making on these diseases. MATERIALS AND METHODS: This study used a number of resources to obtain data, national health insurance statistics, the Korean Health Panel, and the causes of death report by the Korean National Statistical Office. The total costs of inflammatory heart diseases were estimated as the sum of direct medical care costs, direct non-medical care and indirect costs. RESULTS: The total direct cost of inflammatory heart disease was higher in Korean men than that of Korean women and cost due to inpatient was higher than that of outpatients cost. The costs to cover premature death were highest among all of the components used to determine the total costs for inflammatory heart disease, representing 66.3% of these costs in Korea. CONCLUSION: Inflammatory heart disease has a relatively high mortality rate, and the costs that are associated with premature deaths consume the greatest proportion of the costs associated with this disease. In spite of some limitations of study, this could be a reliable evidence of economic burden of inflammatory heart disease. PMID- 22259602 TI - Culprit-Lesion-Only Versus Multivessel Revascularization Using Drug-Eluting Stents in Patients With ST-Segment Elevation Myocardial Infarction: A Korean Acute Myocardial Infarction Registry-Based Analysis. AB - BACKGROUND AND OBJECTIVES: In patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease, complete revascularization (CR) for non-culprit lesions is not routinely recommended. The aim of this study was to compare the clinical outcomes of multivessel compared with infarct-related artery (IRA)-only revascularization in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI. SUBJECTS AND METHODS: From the Korean Acute Myocardial Infarction Registry (KAMIR) database, 1,094 STEMI patients with multivessel disease who underwent primary PCI with drug-eluting stents were enrolled in this study. The patients were divided into two groups: culprit-vessel only revascularization (COR, n=827) group; multivessel revascularization, including non-IRA (MVR, n=267) group. The primary endpoint of this study included major adverse cardiac events (MACEs), such as death, myocardial infarction, or target or nontarget lesion revascularization at one year. RESULTS: There was no difference in clinical characteristics between the two groups. During the one year follow-up, 102 (15.2%) patients in the COR group and 32 (14.2%) in the MVR group experienced at least one MACE (p=0.330). There were no differences between the two groups in terms of rates of death, myocardial infarction, or revascularization (2.1% vs. 2.0%, 0.7% vs. 0.8%, and 11.7% vs. 10.1%, respectively; p=0.822, 0.910, and 0.301, respectively). The MACE rate was higher in the incompletely revascularized patients than in the completely revascularized patients (15% vs. 9.5%, p=0.039), and the difference was attributable to a higher rate of nontarget vessel revascularization (8.6% vs. 1.8%, p=0.002). CONCLUSION: Although multivessel angioplasty during primary PCI for STEMI did not reduce the MACE rate compared with culprit-vessel-only PCI, CR was associated with a lower rate of repeat revascularization after multivessel PCI. PMID- 22259603 TI - Eutectic mixture of local anesthesia cream can reduce both the radial pain and sympathetic response during transradial coronary angiography. AB - BACKGROUND AND OBJECTIVES: ADIAL ARTERY SPASM IS ONE OF THE MOST COMMON COMPLICATIONS OF TRANSRADIAL CORONARY ANGIOGRAPHY (TRA): the radial artery is prone to cathecholamine-induced contraction and radial pain during TRA could increase the sympathetic tone. The object of this study was to evaluate whether the eutectic mixture of local anesthesia (EMLA) cream, in addition to lidocaine infiltration, could reduce the sympathetic response by reducing radial pain during TRA. SUBJECTS AND METHODS: Seventy-six patients were randomized 1 : 1 to either EMLA or control groups. Radial pain was measured by the visual analogue scale (VAS) and the verbal rating scale (VRS-4). Sympathetic response, including systolic (SBP) and diastolic blood pressure (DBP), pulse rate (PR), stroke volume (SV) and total peripheral resistance (TPR), was measured by photoplethysmography. RESULTS: RADIAL PAIN MEASURED DURING LIDOCAINE INFILTRATION WAS SIGNIFICANTLY LOWER IN THE EMLA GROUP (VAS: 3.1 vs. 4.0, p=0.04; VRS-4: 2.0 vs. 2.2, p=0.03) and the sympathetic response was significantly blunted in the EMLA group from baseline to lidocaine infiltration (DeltaSBP, mm Hg: 5 vs. 13, p<0.01; DeltaDBP, mm Hg: 2 vs. 7, p=0.03; DeltaPR, beat/min: 2 vs. 8, p<0.01, DeltaSV, mL: 3 vs. 21, p<0.01; DeltaTPR, mm Hg . L/min: 1.0 vs. 5.9, p<0.01). CONCLUSION: In patients undergoing TRA, the EMLA cream, in addition to lidocaine infiltration, effectively reduces the radial pain and thereby the sympathetic response, during lidocaine infiltration. PMID- 22259604 TI - Morning hypertension in treated hypertensives: baseline characteristics and clinical implications. AB - BACKGROUND AND OBJECTIVES: Morning hypertension is closely related to target organ damage and cardiovascular events. Little data is available concerning the baseline characteristics and comprehensive blood pressure analysis of hypertensive patients on treatment with morning hypertension. SUBJECTS AND METHODS: We evaluated 1,087 hypertensive patients who had taken stable anti hypertensive medication at least 6 months. The enrolled patients measured their home blood pressure for 7 days. Baseline characteristics and the laboratory data were analyzed. Morning hypertension was defined as a morning blood pressure >=135/85 mm Hg and systolic or diastolic blood pressure difference between morning and evening exceeding 10 mm Hg. RESULTS: One hundred seventy three patients with morning hypertension showed a preponderance of males, older patients, alcohol consumers, and greater waist circumference and waist-to-hip ratio despite the same body mass index. Impaired fasting glucose and metabolic syndrome were more prevalent in the patients with morning hypertension. The morning hypertensives took more anti-hypertensive drugs and displayed higher blood pressure in the clinic and at home. CONCLUSION: The worse clinical variables and relatively poorly controlled blood pressure of those with morning hypertension supports a potential relationship of morning hypertension with poor cardiovascular outcome. Morning blood pressure should be monitored at home for the optimal treatment of hypertension. PMID- 22259605 TI - Right ventricular outflow tract stenting in a low birth weight infant born with tetralogy of fallot and prostaglandin e1 dependency. AB - Surgical skill and strategy for the correction of tetralogy of Fallot (TOF) have improved and resulted in satisfactory outcomes. However, prematurity and low birth weight continue to remain risk factors for poor outcomes. We present a case of a 2,150 g neonate born with TOF, in whom palliation was achieved with right ventricular outflow tract (RVOT) stenting. Seventy-seven days after the procedure, stenosis of RVOT below the stent was identified. At that time his body weight was 4.9 kg and total corrective surgery was deemed feasible. Eight months following surgical repair, the patient remained well without medical intervention. RVOT stenting may be a viable interim procedure while waiting for a low birth weight neonate born with TOF and prostaglandin E1 dependency to reach optimal weight to undergo corrective surgery. PMID- 22259606 TI - Periprocedural myocardial infarction after retrograde approach for chronic total occlusion of coronary artery: demonstrated by cardiac magnetic resonance imaging. AB - A retrograde approach through the collateral channels was recently proposed as one of the most promising current techniques for percutaneous coronary intervention of chronic total occlusion in coronary arteries (CTO). This report describes the case of a 68-year-old man in whom CTO was successfully crossed with a wire by the retrograde approach using septal collateral, but the patient suffered from a complication with septal myocardial infarction demonstrated by cardiac magnetic resonance imaging. PMID- 22259607 TI - A newly developed pericardial tuberculoma during antituberculous therapy. AB - Tuberculosis generally affects the respiratory tract. In developing nations, the pericardium is the most common location of extrapulmonary tuberculosis; however, tuberculous pericarditis rarely appears as a localized mass or tuberculoma. We present here a case of a 62-year-old woman with pericardial tuberculoma. She had a history of effusive tuberculous pericarditis and drainage. Because she had taken regular medication over a period of six months, the pericardial mass with an adjacent lung nodule newly detected on the chest radiogram was initially suspected of being invasive lung cancer. Prior to pathologic confirmation, precise information from imaging tests, including computed tomography, magnetic resonance imaging, and positron emission tomography-computed tomography are helpful when making decisions regarding which methods should be used for surgical approach and treatment. Through imaging, our case showed typical features of pericardial tuberculoma and a favorable clinical course after two months with a change in antituberculous therapy. PMID- 22259608 TI - Very Late Stent Thrombosis due to Neointimal Rupture After Paclitaxel-Eluting Stent Implantation. AB - We report our experience of very late stent thrombosis (VLST) in a young male patient who underwent implantation of two paclitaxel-eluting stents (PES) six years ago. The patient was compliant with standard dual antiplatelet therapy, but he presented with acute myocardial infarction which was associated with VLST. Intravascular ultrasound showed neointimal rupture with thrombus within the PES implanted in the right coronary artery. The lesion was successfully treated with balloon angioplasty without complications, however he was found to be hyporesponsive to clopidogrel when tested for adenosine diphosphate-induced platelet aggregation. The patient was discharged after uneventful recovery with triple anti-platelet therapy using aspirin, clopidogrel and cilostazol. To the best of our knowledge, a time interval of 2,223 days is the longest reported time interval between PES deployment and VLST occurrence. VLST may indeed occur in clinically stable patients, as multiple factors can influence the pathological mechanisms of VLST. PMID- 22259609 TI - Spontaneous spinal epidural hematomas associated with acute myocardial infarction treatment. AB - Many studies have reported spontaneous spinal epidural hematoma (SSEH). Although most cases are idiopathic, several are associated with thrombolytic therapy or anticoagulants. We report a case of SSEH coincident with acute myocardial infarction (AMI), which caused serious neurological deficits. A 56 year old man presented with chest pain accompanied with back and neck pain, which was regarded as an atypical symptom of AMI. He was treated with nitroglycerin, aspirin, low molecular weight heparin, and clopidogrel. A spinal magnetic resonance image taken after paraplegia developed 3 days after the initial symptoms revealed an epidural hematoma at the cervical and thoracolumbar spine. Despite emergent decompressive surgery, paraplegia has not improved 7 months after surgery. A SSEH should be considered when patients complain of abrupt, strong, and non-traumatic back and neck pain, particularly if they have no spinal pain history. PMID- 22259610 TI - Stent fracture at the proximal shaft of the left main stem. AB - Stent fracture is likely to be caused due to mechanical stress at the hinge point or kinking movement at the point of aneurysm formation with stent malapposition. To our knowledge, this is the first published report of stent fracture at the proximal shaft of the left main stem in a patient with acute myocardial infarction. PMID- 22259611 TI - Catheter ablation of parahisian premature ventricular complex. AB - Catheter ablation is performed in selected patients with a symptomatic premature ventricular complex (PVC) or PVC-induced cardiomyopathy. Ablation of PVC from the His region has a high risk of inducing a complete atrioventricular block. Here we report successful catheter ablation of a parahisian PVC in a 63-year-old man. PMID- 22259612 TI - Biatrial myxoma in a young male patient. PMID- 22259613 TI - Treatment of myasthenia gravis based on its immunopathogenesis. AB - The prognosis of myasthenia gravis (MG) has improved dramatically due to advances in critical-care medicine and symptomatic treatments. Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus. Thymectomy is based on this immunological background. For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies. These immunotherapies can be classified into two groups: rapid induction and long term maintenance. Rapid induction therapy includes intravenous immunoglobulin (IVIg) and plasma exchange (PE). These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the perioperative period. High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIg and PE, commonly only after a delay of several weeks. Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission. However, because of significant side effects, other immunosuppressants (ISs) are frequently added as "steroid-sparing agents". The currently available ISs exert their immunosuppressive effects by three mechanisms: 1) blocking the synthesis of DNA and RNA, 2) inhibiting T-cell activation and 3) depleting the B-cell population. In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness. Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials. It is hoped that well-organized studies and newer experimental trials will lead to improved treatments. PMID- 22259614 TI - Vestibular rehabilitation therapy: review of indications, mechanisms, and key exercises. AB - Vestibular rehabilitation therapy (VRT) is an exercise-based treatment program designed to promote vestibular adaptation and substitution. The goals of VRT are 1) to enhance gaze stability, 2) to enhance postural stability, 3) to improve vertigo, and 4) to improve activities of daily living. VRT facilitates vestibular recovery mechanisms: vestibular adaptation, substitution by the other eye movement systems, substitution by vision, somatosensory cues, other postural strategies, and habituation. The key exercises for VRT are head-eye movements with various body postures and activities, and maintaining balance with a reduced support base with various orientations of the head and trunk, while performing various upper-extremity tasks, repeating the movements provoking vertigo, and exposing patients gradually to various sensory and motor environments. VRT is indicated for any stable but poorly compensated vestibular lesion, regardless of the patient's age, the cause, and symptom duration and intensity. Vestibular suppressants, visual and somatosensory deprivation, immobilization, old age, concurrent central lesions, and long recovery from symptoms, but there is no difference in the final outcome. As long as exercises are performed several times every day, even brief periods of exercise are sufficient to facilitate vestibular recovery. Here the authors review the mechanisms and the key exercises for each of the VRT goals. PMID- 22259615 TI - Predictors of poor outcome in patients with acute cerebral infarction. AB - BACKGROUND AND PURPOSE: Plasma D-dimer levels are elevated during the acute phase of cerebral infarction (CI). We investigated whether the D-dimer level on admission and other clinical characteristics could be used to predict the poor outcome of patients with acute CI. METHODS: The clinical characteristics and plasma D-dimer levels measured within 3 days of onset were compared according to outcome among patients with acute CI. RESULTS: In total, 359 consecutive patients (mean age, 71.8 years) were examined, of which 174 had a poor outcome [score on the modified Rankin scale (mRS) >=3] at 30 days after hospitalization. The mean mRS score was higher and a poor outcome was observed more frequently among women than among men (p<0.001 for each). The proportions of women, cardioembolism, atrial fibrillation, advanced age (>=75 years), prior history of CI or transient ischemic attack, and elevated D-dimer level (>=1.0 ug/mL) were significantly higher among patients with a poor outcome than among those with a good outcome. A multivariate analysis showed that elevated D-dimer level [>=1.0 ug/mL; odds ratio (OR), 2.45; 95% confidence interval (95% CI), 1.52-3.89; p<0.01], advanced age (OR, 1.93; 95% CI, 1.21-3.07; p<0.01), and female gender (OR, 1.75; 95% CI, 1.08 2.83; p=0.02) were independent predictors of a poor outcome. CONCLUSIONS: Certain clinical characteristics (gender and advanced age) and an elevated D-dimer level upon admission can be used to predict the outcome of patients with acute CI at 30 days after hospitalization. PMID- 22259617 TI - Effects of lacunar infarctions on cognitive impairment in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AB - BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. Although previous studies have shown an association between lacunar infarction and cognitive impairment, the relationship between MRI parameters and cognition remains unclear. In this study we investigated the influence of MRI parameters on cognitive impairment in CADASIL. METHODS: We applied a prospective protocol to 40 patients. MRI analysis included the normalized volume of white-matter hyperintensities (nWMHs), number of lacunes, and number of cerebral microbleeds. Cognition was assessed with the aid of psychometric tests [Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognition (ADAS-cog), Trail-Making Test, and Stroop interference (Stroop IF)]. RESULTS: A multivariate regression analysis revealed that the total number of lacunes influenced the performance in the MMSE, ADAS-cog, and Stroop IF, while nWMHs had a strong univariate association with ADAS-cog and Stroop IF scores. However, this association disappeared in the multivariate analysis. CONCLUSIONS: These findings demonstrate that the number of lacunes is the main predictive factor of cognitive impairment in CADASIL. PMID- 22259616 TI - High levels of remnant lipoprotein cholesterol is a risk factor for large artery atherosclerotic stroke. AB - BACKGROUND AND PURPOSE: Remnant lipoproteins (RLPs) are products of partially catabolized chylomicrons and very-low-density lipoprotein, from which some triglycerides have been removed. These particles are smaller and denser than the parent particles and are believed to be strongly atherogenic. We explored the association between RLP cholesterol (RLP-C) and ischemic stroke, including stroke subtypes. METHODS: A cohort of 142 ischemic stroke patients (90 men and 52 women; age, 65.2+/-12.8 years, mean+/-SD) was enrolled; all had acute infarcts confirmed by diffusion-weighted MRI, and had fasting lipograms. A full stroke-related evaluation was conducted on each patient. An outpatient population of 88 subjects without a history of cerebrovascular or cardiovascular disease served as a control group. Serum RLP fractions were isolated using an immunoaffinity gel containing specific antiapolipoprotein (anti-apo)B-100 and anti-apoA-I antibodies. RLP-C values were considered to be high when they were in the highest quartile of all values in the study. RESULTS: High RLP-C values were more common in stroke patients than in control patients (31.0% vs. 14.8%, p=0.01), when 5.6 mg/dL (>75th percentile) was used as the cutoff value. Multivariable analyses indicated that RLP-C was a risk factor for stroke, with an odds ratio of 2.54 (p=0.045). The RLP-C level was higher in the large artery atherosclerosis subgroup (5.7+/-3.9 mg/dL) than in any other stroke subgroup (small vessel occlusion, 4.9+/-5.9 mg/dL; cardioembolism, 1.8+/-2.3 mg/dL; stroke of undetermined etiology, 3.1+/-2.9 mg/dL). CONCLUSIONS: We have found an association between high RLP-C levels and ischemic stroke, and in particular large artery atherosclerotic stroke. PMID- 22259618 TI - Elevated levels of alpha-synuclein oligomer in the cerebrospinal fluid of drug naive patients with Parkinson's disease. AB - BACKGROUND AND PURPOSE: The detection of alpha-synuclein in the body fluids of patients with synucleinopathy has yielded promising but inconclusive results, in part because of conformational changes of alpha-synuclein in response to environmental conditions. The aim of this study was to determine the feasibility of using alpha-synuclein as a biological marker for Parkinson's disease (PD). METHODS: Twenty-three drug-naive patients with PD (age 62.4+/-12.7 years, mean+/ SD; 11 males) and 29 age- and sex-matched neurologic control subjects (age 60.1+/ 16.2 years; 16 males) were recruited. The levels of oligomeric and total alpha synuclein in the cerebrospinal fluid (CSF) and plasma were measured using two simultaneous enzyme-linked immunosorbent assays. RESULTS: The level of alpha synuclein oligomer in the CSF of PD patients was significantly higher in PD patients than in neurological controls, but other findings (plasma alpha synuclein oligomer and total alpha-synuclein in CSF and plasma) did not differ significantly between the two groups. When the control subjects were divided into a symptomatic control group (11 patients who complained of parkinsonian symptoms and were diagnosed with hydrocephalus and drug-induced or vascular parkinsonism) and a neurologic control group (10 normal subjects and 8 patients with diabetic ophthalmoplegia), the level of alpha-synuclein oligomer in the CSF was still significantly higher in PD patients than in both of the control subgroups. CONCLUSIONS: These findings provide further evidence for a pathogenic role of the alpha-synuclein oligomer and suggest that CSF levels of alpha-synuclein oligomer can be a reliable marker for PD. PMID- 22259619 TI - Leukoencephalopathy and akinetic mutism in a married couple: a probable association with oriental medicine. AB - BACKGROUND: Oriental medicines have been associated with severe psychiatric, neurological, and other adverse medical events. These medicines occasionally cause a typical reversible toxic encephalopathy, but most such cases are not recognized because these adverse events are complex and are associated with other systemic signs and symptoms. CASE REPORT: We describe a married couple with rapid progressive cognitive impairment and akinetic mutism after taking the same oriental medicines on the same day. Brain magnetic resonance images of the couple showed typical leukoencephalopathy in the periventricular white matter and basal ganglia regions, bilaterally. CONCLUSIONS: The development of neurobehavioral symptoms and toxic leukoencephalopathy in both patients following the ingestion of oriental medicines is suggestive of a cause-and-effect association, although such a relationship needs to be verified. PMID- 22259620 TI - Pure word deafness in a patient with early-onset Alzheimer's disease: an unusual presentation. AB - BACKGROUND AND PURPOSE: The occurrence of PWD in neurodegenerative disease is very rare, and this is the first report of it being related to early-onset AD. We describe a patient with early-onset Alzheimer's disease (AD) who presented with pure word deafness (PWD). CASE REPORT: The patient had experienced PWD for 2 years, followed by other cognitive deficits suggestive of parietotemporal dysfunction. Brain imaging including (18)FDG-PET and [(11)C] PIB-PET supported the diagnosis of AD. CONCLUSIONS: Our case highlights the clinical variability that characterizes early-onset AD. PMID- 22259621 TI - A patient with genetically confirmed myoclonus-dystonia responded to anticholinergic treatment and improved spontaneously. AB - BACKGROUND: The various medical treatments applied to myoclonus-dystonia patients with a mutation of the epsilon-sarcoglycan gene (SGCE) have not been beneficial in most cases. Most patients experience progressive deterioration or static clinical courses, with only rare cases of spontaneous remission. CASE REPORT: A 19-year-old girl presented with a 14-year history of myoclonus and dystonia that severely affected her left arm, neck, and trunk. Genetic studies showed a mutation in SGCE [deletion in exon 6 (c.771_772delAT, Cys258X)]. Both myoclonus and dystonia responded to anticholinergic treatment for 7 years and improved spontaneously. CONCLUSIONS: The possibility of spontaneous improvement should be kept in mind when considering the therapeutic strategy in myoclonus-dystonia patients, especially when contemplating deep-brain stimulation. PMID- 22259622 TI - Ischemic neuropathy associated with livedoid vasculitis. AB - BACKGROUND: Livedoid vasculitis is a chronic dermatological problem with an unclear etiology. Clinical findings are petechiae with painful ulcers in both lower extremities, which heal to become hyperpigmented and porcelain-white satellite lesions. There are only a few reported cases of livedoid vasculitis presenting in combination with peripheral neuropathy. CASE REPORT: We report the first case of a Korean patient presenting with mononeuritis multiplex combined with livedoid vasculitis, which was confirmed by electrophysiological and pathological studies. CONCLUSIONS: Our report supports the possible vaso occlusive etiology of livedoid vasculitis in multifocal ischemic neuropathy. PMID- 22259623 TI - CXCR4 antagonists in hematologic malignancies: more than just mobilizers? PMID- 22259624 TI - Lymphoma stem cells: A step toward a new therapeutic target. PMID- 22259625 TI - HIV-associated plasmablastic lymphoma diagnosed by fine-needle aspiration cytology. PMID- 22259626 TI - Cryoglobulinemic vasculitis and monoclonal gammopathy in end-stage renal disease. PMID- 22259627 TI - Human diversity of killer cell immunoglobulin-like receptors and disease. AB - Natural Killer (NK) cells are the third population of lymphocyte in the mononuclear cell compartment that triggers first-line of defense against viral infection and tumor transformation. Historically, NK cells were thought of as components of innate immunity based on their intrinsic ability to spontaneously kill target cells independent of HLA antigen restriction. However, it is now clear that NK cells are quite sophisticated and use a highly specific and complex target cell recognition receptor system arbitrated via a multitude of inhibitory and activating receptors. Killer cell immunoglobulin-like receptors (KIR) are the key receptors of human NK cells development and function. To date, fourteen distinct KIRs have been identified: eight are inhibitory types, and six are activating types. The number and type of KIR genes present varies substantially between individuals. Inhibitory KIRs recognize distinct motifs of polymorphic HLA class I molecules. Upon engagement of their specific HLA class I ligands, inhibitory KIR dampen NK cell reactivity. In contrast, activating KIRs are believed to stimulate NK cell reactivity when they sense their ligands (unknown). KIR and HLA gene families map to different human chromosomes (19 and 6, respectively), and their independent segregation produces a wide diversity in the number and type of inherited KIR-HLA combinations, likely contributing to overall immune competency. Consistent with this hypothesis, certain combinations of KIR HLA variants have been correlated with susceptibility to diseases as diverse as autoimmunity, viral infections, and cancer. This review summarizes our emerging understanding of KIR-HLA diversity in human health and disease. PMID- 22259629 TI - Indeterminate lupus anticoagulant results: Prevalence and clinical significance. AB - BACKGROUND: Reports of indeterminate lupus anticoagulant (LAC) results are common; however, no published data on their prevalence or clinical significance are available. We investigated the prevalence and clinical characteristics of patients with indeterminate LAC. METHODS: We retrospectively reviewed the clinical and serologic characteristics of 256 unselected patients with LAC results. RESULTS: Indeterminate results were observed in 32.7% of LAC profiles that were least frequent (25.4%) when activated partial thromboplastin time (aPTT) was normal, most frequent (39.8%) when aPTT was elevated, and were observed in 35% of patients taking warfarin. The final indeterminate LAC cohort included 65 patients with a mean follow-up of 18 months. Malignancy and autoimmune disease were present in 29% and 25% of patients, respectively. The most common thrombotic events were deep vein thrombosis (DVT) (28%), cerebral ischemic stroke (14%) and pulmonary embolism (14%). Patients with indeterminate results were more likely to be men, older, and with a history of DVT, superficial thrombosis, or myocardial infarction than patients with negative tests (N=106). Concurrent warfarin therapy was more prevalent in the indeterminate group, but was not statistically significant. In the multivariate analysis, none of the variables showed statistical significance. During follow-up, 10 of 16 patients with indeterminate results showed change in classification upon retesting. CONCLUSION: Patients with indeterminate LAC results were common, and their clinical characteristics differed from those with negative results. There is a need for a prospective study of the clinical history of patients with indeterminate LAC results. PMID- 22259628 TI - Adenovirus as a new agent for multiple myeloma therapies: Opportunities and restrictions. AB - Multiple myeloma is a malignancy of B-cells that is characterized by the clonal expansion and accumulation of malignant plasma cells in the bone marrow. This disease remains incurable, and a median survival of 3-5 years has been reported with the use of current treatments. Viral-based therapies offer promising alternatives or possible integration with current therapeutic regimens. Among several gene therapy vectors and oncolytic agents, adenovirus has emerged as a promising agent, and it is already being used for the treatment of solid tumors in humans. The main concern with the clinical use of this vector has been its high immunogenicity; adenovirus is often able to induce a strong immune response in the host. Furthermore, new limitations in the efficacy of this therapy, intrinsic to the nature of tumor cells, have been recently observed. For example, our group showed a strong antiviral phenotype in vitro and in vivo in a subset of tumors, shedding new insights that may explain the partial failure of clinical trials based on this promising new therapy. In this review, we describe novel therapeutic approaches that implement viral-based treatments in hematological malignancies and address the novelty as well as the possible limitations of these new therapies, especially in the context of the use of adenoviral vectors for treating multiple myeloma. PMID- 22259630 TI - Differential effects of CXCR4 antagonists on the survival and proliferation of myeloid leukemia cells in vitro. AB - BACKGROUND: Antagonists of CXC chemokine receptor 4 (CXCR4), including AMD3100, induce peripheral mobilization of hematopoietic stem cells and have been approved for clinical use. We explored whether the CXCR4 antagonists affected the survival and proliferation of myeloid leukemia cells in vitro. METHODS: The effects of CXCR4 antagonists AMD3100 and T140 on the survival and proliferation of myeloid leukemia cell lines (U937, HL-60, MO7e, KG1a, and K562) as well as CD34(+) cells obtained from patients with AML and CML were analyzed by flow cytometry by using annexin V and a colorimetric cell proliferation assay. RESULTS: AMD3100, but not T140, stimulated the proliferation of leukemia cells in vitro in a dose-dependent manner for up to 5 days (~2-fold increase at a concentration of 10(-5) M), which was not abrogated by pretreatment of the cells with pertussis toxin, but was attenuated by RNAi knockdown of CXCR7 transcripts. In contrast, AMD3100 induced a marked decrease in the cell numbers after 5-7 days. AMD3100, but not T140, induced phosphorylation of MAPK p44/p42. AMD3100 increased the number and size of leukemia cell colonies and reduced cell apoptosis during the first 5-7 days of incubation, but the phenomena were reversed during the later period of incubation. CONCLUSION: The effects of CXCR4 antagonists on the proliferation of myeloid leukemia cells are not uniform. AMD3100, but not T140, exerts dual effects, initially enhancing and subsequently inhibiting the survival and proliferation of the cells in vitro. PMID- 22259631 TI - Hematological manifestations of human immunodeficiency virus infection and the effect of highly active anti-retroviral therapy on cytopenia. AB - BACKGROUND: The aim of this study is to investigate the hematological manifestations of human immunodeficiency virus (HIV) infection, the risk factors for cytopenia, and the effect of highly active anti-retroviral therapy (HAART) on cytopenia. METHODS: Medical records of patients treated for HIV at the Seoul National University Hospital from January 2005 to March 2010 were retrospectively reviewed. To determine the impact of HIV itself, we excluded HIV patients who had other conditions that could have resulted in hematological manifestations. Multiple logistic regression analyses were performed to identify risk factors for cytopenia. RESULTS: A total of 621 cases were investigated, and after exclusion, data of 472 patients were analyzed. The frequency of cytopenia was anemia, 3.0% (14/472); neutropenia, 10.0% (47/472); thrombocytopenia, 2.4% (12/472); lymphopenia, 25.7% (121/470); isolated cytopenia, 11.2% (53/472); and bicytopenia, 2.1% (10/472). The leading risk factor for cytopenia identified by multivariate logistic regression methods was AIDS status at initial presentation. After HAART, cytopenia was reversed in the majority of patients (thrombocytopenia, 100%; neutropenia, 91.1%; and anemia, 84.6%). CONCLUSION: This study isolated the impact of HIV infection alone on hematologic manifestations and confirmed that these changes were reversible by HAART. Control of the HIV infection will have the main role in the management of hematological manifestations of the virus. PMID- 22259632 TI - Clinical implications of chimerism after allogeneic hematopoietic stem cell transplantation in children with non-malignant diseases. AB - BACKGROUND: The effects of chimerism on outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) are unclear and may differ between diseases. We retrospectively evaluated the association between chimerism and transplant outcomes in children with nonmalignant diseases. METHODS: Chimerism was evaluated using short-tandem repeat polymerase chain reaction (STR-PCR) in 48 patients, with mixed chimerism (MC) defined as greater than 1% recipient cells. RESULTS: The only variable exerting a significant influence on patients' chimerism status was the number of infused CD34+ cells. MC was detected in 23 transplants (9 showing transient MC; 10 with sustained low levels [<=30%] of autologous cells; and 4 with high-level MC [>30%]). The degree of STR-PCR at 28 days after HSCT was significantly higher in patients with high-level MC than those with transient or low-level MC. All patients with transient or low-level MC successfully maintained engraftment and showed a clinical response to HSCT, whereas 2 of the 4 patients with high-level MC experienced graft failure. The incidences of grades II-IV acute and chronic graft-versus-host disease (GVHD) were significantly higher in patients with complete donor chimerism (CC) than MC. We observed no significant survival differences between CC and MC groups. However, the survival rate was lower in patients with high MC than those with low level or transient MC (P=0.03). CONCLUSION: In non-malignant diseases, MC may indicate a tolerant state with a decreased incidence of GVHD. However, high-level MC may signify an increased risk of graft failure and a lower survival rate. PMID- 22259633 TI - Characterization of the cytokine profile of platelet rich plasma (PRP) and PRP induced cell proliferation and migration: Upregulation of matrix metalloproteinase-1 and -9 in HaCaT cells. AB - BACKGROUND: The underlying rationale of platelet rich plasma (PRP) therapy is that an injection of concentrated PRP at the site of injury may promote tissue repair via cytokine release from platelets. The molecular mechanisms of PRP therapy in the skin wound healing process are not well understood at present, and would benefit from clarification. METHODS: PRP was stimulated with angonists for 5 min, and cytokine profile analysis was performed. To investigate the wound healing activity of PRP, cell proliferation and migration analyses were performed in skin cells. The effects of PRP were analyzed on the expression and activity of matrix metalloproteinase (MMP)-1, -2, -9, and the activation of transcription factors. RESULTS: Thrombin was found to be a strong stimulator of PRP activation to release growth factors and chemokines. PRP induced cell proliferation and migration in HUVECs, HaCaT cells, and HDFs, as well as MMP-1and MMP-9 expression in HaCaT cells, but PRP did not have a significant effect on the expression or activity of MMPs in HDFs. The transcription factors, including signal transducer and activator of transcription-3 (STAT-3) were found to be phosphorylated following PRP treatment in HaCaT cells. CONCLUSION: In this study, we have identified the cytokine profile of activated PRP after agonist stimulation. We have shown that PRP plays an active role in promoting the proliferation and migration of skin cells via the regulation of MMPs, and this may be applicable to the future development of PRP therapeutics to enhance skin wound healing. PMID- 22259634 TI - Splenic infarction in a patient with autoimmune hemolytic anemia and protein C deficiency. AB - Splenic infarction is most commonly caused by cardiovascular thromboembolism; however, splenic infarction can also occur in hematologic diseases, including sickle cell disease, hereditary spherocytosis, chronic myeloproliferative disease, leukemia, and lymphoma. Although 10% of splenic infarction is caused by hematologic diseases, it seldom accompanies autoimmune hemolytic anemia (AIHA). We report a case of a 47-year-old woman with iron deficiency anemia who presented with pain in the left upper abdominal quadrant, and was diagnosed with AIHA and splenic infarction. Protein C activity and antigen decreased to 44.0% (60-140%) and 42.0% (65-140%), respectively. Laboratory testing confirmed no clinical cause for protein C deficiency, such as disseminated intravascular coagulation, sepsis, hepatic dysfunction, or acute respiratory distress syndrome. Protein C deficiency with splenic infarction has been reported in patients with viral infection, hereditary spherocytosis, and leukemia. This is a rare case of splenic infarction and transient protein C deficiency in a patient with AIHA. PMID- 22259635 TI - Evans syndrome following long-standing Hashimoto's thyroiditis and successful treatment with rituximab. AB - We report a case of a 51-year-old woman with Evans syndrome (autoimmune hemolytic anemia and primary immune thrombocytopenia) and hypothyroidism. She was previously diagnosed with Hashimoto's thyroiditis in 1994 (age, 35) and autoimmune hemolytic anemia (AIHA) 3 years ago. She was treated with oral prednisolone. After a period, in which the anemia waxed and waned, there was an abrupt development of thrombocytopenia (nadir 15*10(9)/L) that coincided with the tapering off of prednisolone after 3 years of administration. Because her thrombocytopenia was refractory to prednisolone, we administered rituximab (375 mg/m(2) weekly) for 4 weeks. Two weeks after the completion of the rituximab treatment, her platelet count was up to 92*10(9)/L. No intermittent peaking of thyroid stimulating hormone occurred after rituximab treatment was initiated. Evans syndrome and autoimmune thyroiditis might share common pathophysiological mechanisms. This notion supports the use of rituximab in a patient suffering from these disorders. PMID- 22259636 TI - Primary cutaneous B-cell lymphoblastic lymphoma in an elderly man. AB - Precursor B-cell lymphoblastic lymphoma (B-LBL) is an uncommon high-grade neoplasm of immature B cells. It occurs predominantly in childhood with extranodal involvement such as skin and bone. Therefore, primary cutaneous involvement in elderly adults is a very rare manifestation of B-LBL. Here, we report a 78-year-old man with B-LBL presenting as a single cutaneous lesion which was immunohistochemically positive for leukocyte common antigen (LCA), CD79a, paired box 5 (PAX5), B cell lymphoma-2 (bcl-2), and terminal deoxynucleotidyl transferase (TdT) staining, but was without systemic involvement. The patient was treated using cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP), and achieved complete response (CR) at the first response assessment conducted after 3 CHOP cycles. After an additional cycle of CHOP treatment, radiotherapy was administered at a total dose of 3,600 cGy over 4 weeks. At the 21-month follow-up, he had maintained CR. PMID- 22259637 TI - The role of B cells in acute graft-versus-host disease. PMID- 22259638 TI - Understanding left-handedness. AB - BACKGROUND: The human cerebrum is asymmetrical, consisting of two hemispheres with differing functions. Recent epidemiological and neurobiological research has shed new light on the development of the cerebral lateralization of motor processes, including handedness. In this article, we present these findings from a medical perspective. METHOD: We selectively searched the PubMed online database for articles including the terms "handedness," "left handedness," "right handedness," and "cerebral lateralization." Highly ranked and commonly cited articles were included in our analysis. RESULTS: The emergence of handedness has been explained by physiological and pathological models. Handedness arose early in evolution and has probably been constitutive for the development of higher cognitive functions. For instance, handedness may have provided the basis for the development of speech and fine motor skills, both of which have played a critical role in the evolution of mankind. The disadvantages of certain types of handedness are discussed, as some cases seem to be associated with disease. CONCLUSION: The consideration of handedness from the epidemiological, neurobiological, and medical points of view provides insight into cerebral lateralization. PMID- 22259639 TI - Secondary prevention following myocardial infarction--there is still more to be done. PMID- 22259640 TI - Prescription prevalence and continuing medication use for secondary prevention after myocardial infarction: the reality of care revealed by claims data analysis. AB - BACKGROUND: Current guidelines recommend using aspirin, clopidogrel, beta blockers, statins, and angiotensin converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI). Although there is evidence that patients often stop taking these medications prematurely, long-term data reflecting the actual reality of care are lacking. We studied prescription prevalence and treatment persistence of secondary prevention in patients who had an AMI by analyzing relevant claims data from a German sickness fund, the Techniker Krankenkasse (these data are not necessarily representative of the entire German population). METHODS: Insurees who were discharged from the hospital between 2001 and 2006 with AMI as their main discharge diagnosis were classified as users or non-users of each of the types of drug listed above on the basis of the prescriptions that they obtained in the first 90 days after they left the hospital. Treatment persistence was statistically assessed with survival analysis. Switches from one drug class to another were not examined. RESULTS: Of 30,028 AMI patients, 82% were initially prescribed a beta-blocker, 73% a statin, 69% an ACE inhibitor, 66% aspirin (without self-medication), and 61% clopidogrel. Five years after discharge, 10% of the patients for whom aspirin was initially prescribed were still taking it; the corresponding figures for the other drug classes were 17% for statins, 31% for ACE inhibitors, and 36% for beta-blockers. The greatest drop in treatment persistence occurred approximately one year after the AMI. CONCLUSION: Treatment persistence with recommended medication after AMI is still in need of improvement. Patient education should start as soon as possible after infarction, because the greatest drops in medication use appear to occur within one year after AMI. PMID- 22259641 TI - The treatment of elderly patients with acute myeloid leukemia. AB - BACKGROUND: In patients over age 60 with acute myeloid leukemia (AML), cure rates are under 10% despite intensive chemotherapy. These patients often have comorbidities, and their treatment must be chosen with care. For those who are not candidates for intensive chemotherapy, one of the available options for palliative treatment should be chosen on the basis of an individual risk-benefit assessment. METHODS: Selective literature review. RESULTS: An evaluation of the patient's general condition and comorbidities, a geriatric assessment, and specially designed risk scores are useful aids to the choice of an appropriate treatment. Some elderly patients with AML can benefit from intensive chemotherapy despite their age; for highly selected elderly patients, allogeneic stem-cell transplantation is an increasingly feasible option. Hypomethylating agents or low dose cytarabine can be suitable for some patients. Further options include experimental treatment as part of a clinical trial, and supportive care alone. In the special case of acute promyelocytic leukemia, more than half of all patients can be cured with combination chemotherapy including all-trans retinoic acid. CONCLUSION: The prognosis of elderly AML patients remains poor despite recent therapeutic advances. The appropriate treatment for each patient can be chosen on the basis of a risk-benefit assessment. Clinical trials evaluating new treatments are urgently needed. PMID- 22259642 TI - Current methods of visual rehabilitation. AB - BACKGROUND: Despite therapeutic progress, many diseases of the eyes and visual pathways still cause persistent visual deficits that make everyday life more difficult in many ways. Rehabilitation aims to compensate for these limitations by optimizing residual vision. The demand for visual rehabilitation will increase markedly in the near future. METHODS: We summarize the state of the art in visual rehabilitation on the basis of a selective review of the literature, including randomized, controlled trials (RCTs) in the Cochrane and PubMed databases as well as Cochrane reviews. We also pay particular attention to studies illustrating an important principle or a clinically established method. RESULTS: Central visual field defects impair reading. Persons with an absolute central scotoma can regain reading ability by eccentric fixation and text magnification. Many kinds of magnifying visual aids are available. Specific reading training can further improve reading speed. Peripheral field defects impair orientation. Persons with a concentric field defect can be helped by tactile aids, such as a cane, and with orientation and mobility training. Persons with hemianopia can benefit from compensatory saccadic training. CONCLUSION: Suitable rehabilitative measures chosen after the thorough diagnostic evaluation of a visual impairment and analysis of its effects can usually restore reading ability, improve orientation, and thereby enhance the patient's independence and quality of life. As the demand for visual rehabilitation is increasing, steps will need to be taken to make it more widely available. Furthermore, as the scientific basis for visual rehabilitation is currently inadequate in some areas, more research in the field will be needed. PMID- 22259643 TI - Novel Therapeutic Agents in Pediatric Sepsis: Peroxisome Proliferator Receptor gamma (PPAR gamma) Agonists. PMID- 22259644 TI - Microwell perfusion array for high-throughput, long-term imaging of clonal growth. AB - Continuous cell tracking by time-lapse microscopy has led to detailed study of cell differentiation pathways using single cell fate maps. There are a multitude of cell fate outcomes, so hundreds of clonal division histories are required to measure these stochastic branching processes. This study examines the principle of condensing cell imaging information into a relatively small region to maximize live cell imaging throughput. High throughput clonal analysis of non-adherent cells by continuous live cell tracking was possible using a microwell perfusion array with an internal volume of 16 MUl and 600 microwells at the base. This study includes examination of biocompatibility of buffer systems, connecting tubing, cell culture substrates, and media degradation. An intermittent perfusion protocol was selected for long-term time-lapse imaging of KG1a cells in the microwell array; 1500 clones were simultaneously cultured and scanned every 3 min at 100 * magnifications for 6 days. The advantages of perfusion microwell culture are continuous long-term cell tracking, higher cell imaging throughput, and greater control over cell microenvironment. Microwell devices facilitate high throughput analysis of cell lineage development and measurement of the probability distribution for cell life events such as mitosis. PMID- 22259645 TI - Nd:YAG Laser Treatment of Keloids and Hypertrophic Scars. AB - Pathological cutaneous scars such as keloids and hypertrophic scars (HSs) are characterized by a diffuse redness that is caused by the overgrowth of capillary vessels due to chronic inflammation. Our group has been using long-pulsed, 1064 nm Nd:YAG laser in noncontact mode with low fluence and a submillisecond pulse duration to treat keloids and hypertrophic scars since 2006 with satisfactory results. The present study examined the efficacy of this approach in 22 Japanese patients with keloids (n = 16) or hypertrophic scars (n = 6) who were treated every 3 to 4 weeks. Treatment settings were as follows: 5 mm spot size diameter; 14 J/cm(2) energy density; 300 MUs exposure time per pulse; and 10 Hz repetition rate. The responses of the pathological scars to the treatment were assessed by measuring their erythema, hypertrophy, hardness, itching, and pain or tenderness. Moreover, skin samples from 3 volunteer patients were subjected to histological evaluation and 5 patients underwent thermography during therapy. The average total scar assessment score dropped from 9.86 to 6.34. Hematoxylin and eosin staining and Elastica Masson-Goldner staining showed that laser treatment structurally changed the tissue collagen. This influence reached a depth of 0.5 to 1 mm. Electron microscopy revealed plasma protein leakage, proteoglycan particles, and a change in the collagen fiber fascicles. Further analyses revealed that noncontact mode Nd:YAG laser treatment is highly effective for keloids and hypertrophic scars regardless of patient age, the origin and multiplicity of scarring, the location of the scar(s), or the tension on the scar. PMID- 22259646 TI - Hormones and skin: A never ending love story! PMID- 22259648 TI - Scleroderma-like skin changes not involving the hand in a prepubertal male with type I diabetes mellitus: A case report. AB - To our knowledge there have been no reports of scleroderma-like skin changes, not affecting the hand in prepubertal patients with Type I Diabetes Mellitus (T1DM). We report a prepubertal caucasian male with T1DM, and early morpheatype skin changes of the trunk and extremities, not involving the hand. PMID- 22259649 TI - Improvement of venous leg ulcers with androgen replacement therapy in a patient with undiagnosed klinefelter syndrome. AB - Klinefelter syndrome (KS) is the most common genetic form of male hypogonadism. The majority (80-90%) of patients have 47, XXY karyotype while mosaicism is seen in only 10-20% of patients. Leg ulcers may be a presenting symptom of KS with a prevalence of 6-13%. Treatment with testosterone has been reported to improve the ulcers. PMID- 22259647 TI - Antimicrobial implications of vitamin D. AB - Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobial properties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections. PMID- 22259650 TI - Vitamin D deficiency and sun avoidance among university students at Abu Dhabi, United Arab Emirates. AB - This study offers evidence that vitamin D deficiency could be a major public health burden among young Emirati adults, mostly because of sun deprivation in a sun-blessed country. This study included a random sample of 138 females and 70 males tested for serum 25-hydroxyvitamin D [25(OH)D] status. To further evaluate the predictors of vitamin D status in this population, the study examined diet, obesity and sun exposure. In summer, the mean serum 25(OH)D concentration for females was 20.9 +/- 14.9 nmol/L, whereas that for males was 27.3 +/- 15.7 nmol/L. Females scored significantly higher than males on the sun avoidance inventory (SAI), indicating that females avoid sun exposure to a greater extent than males, possibly explaining the lower vitamin D status. A significant negative correlation also existed between SAI and vitamin D status (Pearson's r = -0.33; p < 0.01), but no significant association was evident between vitamin D status and body mass index (Pearson's r = 0.03; p = 0.33) or low dietary intake of vitamin D-fortified foods (Pearson's r = 0.08; p = 0.13). The mean serum 25(OH)D concentration for females tested in winter was 31.3 +/- 12.3 nmol/L while in the summer, it was 20.9 +/- 14.9 nmol/L. This difference was statistically significant, suggesting that seasonal variation plays an important role in vitamin D status in the United Arab Emirates. Fortification of foods and drinks with vitamin D, supplementation and sensible sun exposure are important steps toward minimizing vitamin D deficiency. PMID- 22259651 TI - Low birth weight, bone metabolism and fracture risk. AB - As for other diseases of higher age, low birth weight was expected to be a risk factor for an altered bone metabolism and osteoporosis.ON THE FIRST GLANCE THIS EXPECTATION APPEARS TO BE CONFIRMED BY ANIMAL DATA: rats with intrauterine growth restriction following maternal protein malnutrition show a reduction of bone mineral density going in line with a decrease in serum vitamin D concentrations.HOWEVER, THE SITUATION IS LESS CLEAR IN NEWBORNS WITH LOW BIRTH WEIGHT: Some studies show a relation of birth weight and bone mineral density whereas others don't. The older the former low birth weight patients the fainter the effect seems to be. In fact young adults with idiopathic short stature have a low bone mineral density than the low birth weight group irrespective of whether they have experienced catch-up growth or not. As a consequence low birth weight is can not be identified as a relevant risk factor for hip fractures in menopausal women. Postmenopausal women with low birth weight even show higher vitamin D concentrations than normal birth weight individuals.In conclusion, there is no consistent long term effect of low birth weight on bone mineral density or hip fracture risk later in life. Whether methodological weaknesses in the studies performed so far are causal or whether postnatal factors such as physical activity and nutrition are of higher importance can only be speculated upon at present. PMID- 22259653 TI - A retrospective study of thyroid structural abnormalities in alopecia patients. AB - BACKGROUND: Thyroid dysfunction is classically associated with alopecia. Studies focusing on manual thyroid examinations, with ultrasonography of palpable abnormalities, in alopecia patients are lacking. OBJECTIVE: To examine the clinical utility of manual and sonographic evaluation of the thyroid in alopecia patients. METHODS: A retrospective chart review was performed among patients diagnosed with alopecia. RESULTS: We found that 20.2% (74/367) of manual thyroid exams performed were deemed abnormal and 78.8% (41/52) of patients who had an ultrasound had an abnormal finding. Twenty two of the 74 patients did not obtain the requested ultrasound. Non-scarring alopecia was associated with 36 of 41 patients with abnormal ultrasounds (Telogen effluvium 29.3%, Androgenetic alopecia 27.8%, Alopecia areata 24.4%, and Traction alopecia 9.8%). No one specific structural abnormality was associated with a specific hair loss type. Of note, 78% (32/41) of patients with an abnormal ultrasound exam had normal thyroid function tests and only 9/41 (22%) patients had both. LIMITATIONS: THESE INCLUDE: a retrospective study design, small sample size, use of multiple sites for laboratory and sonographic thyroid evaluation, and a high attrition rate for ultrasound evaluation. CONCLUSIONS: This study revealed that the manual examination of the thyroid in alopecia patients may identify additional thyroid abnormalities not detected with serologic evaluation alone. Further prospective studies are required to evaluate the necessity and significance of manual thyroid palpation and subsequent ultrasound studies in this patient population. PMID- 22259652 TI - Solar UV doses of adult Americans and vitamin D(3) production. AB - BACKGROUND: Sunlight contains UV radiation that affects human health in both detrimental (skin cancers) and beneficial (vitamin D(3)) ways. An evaluation of the vitamin D status of adult Americans (22-40, 41-59, 60+ yr) show many have deficient or insufficient serum levels of 25-hydroxyvitamin D, indicating they are not getting enough from dietary sources or sunlight. Those findings are in conflict with calculated values from the American Academy of Dermatology who insist people make "ample" vitamin D(3) (>=1,000 IU/day) from their "casual," or everyday, outdoor UV exposures even if they use sunscreens with sun protection factor 15. OBJECTIVE: We investigated this situation using the everyday outdoor UV doses of indoor-working adult Americans (~7,000) in the north (45 degrees N) and south (35 degrees N) to calculate how much vitamin D(3) they produce each season with and without vacationing. RESULTS: Only during the summer can skin type II Caucasian adults (21-59 yr) meet their minimum (600 IU/day) vitamin D(3) needs from everyday exposures, but only if they do not wear professional clothes or sunscreens (except beach vacations). METHOD: To do vitamin D(3) calculations properly, we used action spectrum and geometric conversion factors, not previously incorporated into other calculations. CONCLUSIONS: Most adult Americans do not go outside enough to meet their minimum or optimum (>=1,200 IU/day) vitamin D(3) needs all year. The darker skin types (III-VI) and the oldest people (>59 yr) are at the highest risk for not making enough vitamin D(3) during the year from everyday outdoor exposures even with a 2-3 week summer vacation. PMID- 22259654 TI - Idiopathic chronic urticaria and thyroid autoimmunity: Experience of a single center. AB - Urticaria is one of the most frequent dermatosis, being its prevalence in general population estimated about 20%. This prospective case-control study was aimed at determining the prevalence of thyroid autoimmune disorders in a cohort of patients with chronic urticaria (CU), all living within an area with mild-to moderate iodine deficiency. Fifty four consecutive patients affected by CU were recruited and compared to 108 healthy controls. Assessment of the thyroid function included measurement of serum concentrations of TSH, FT3, FT4, anti thyreoglobulin (anti-TG) and anti-peroxidase (anti-TPO) antibodies. Ultrasound scan of the thyroid gland was performed in all subjects using a 7.5 MHz linear transducer. All subjects were followed up for 6 months. The prevalence of thyroid antibodies was significantly higher in our cohort of patients with CU than in controls (22% vs. 6.5 %). Hashimoto's thyroiditis was also more frequent in patients than controls (18.5% vs. 1.8%). These frequencies do not differ from those previously reported by some other authors and confirm the association between CU and thyroid autoimmunity also in the area of iodine deficiency. However, presence of antibodies or thyroiditis does not seem to influence clinical course of CU. These results suggest that screening for thyroid function may be useful in all the patients with CU. PMID- 22259655 TI - Reciprocal responses of fibroblasts and melanocytes to alpha-MSH depending on MC1R polymorphisms. AB - The melanocortin 1-receptor (MC1R) exhibits several variants in form of single nucleotide polymorphisms (SNPs) that are known to differentially regulate melanocyte function. However, whether and how MC1R polymorphisms also affect fibroblast function has not been investigated so far.Therefore we measured intracellular cyclic adenosine monophosphate (cAMP) concentrations and cellular proliferation upon stimulation with alpha-melanocyte stimulating hormone (alpha MSH) in eight different human fibroblast and melanocyte cell lines with wild type and different MC1R SNPs.We found that fibroblasts, as well as melanocytes, show differences in MC1R function depending on the MC1R genotype. MC1R stimulation with alpha-MSH in wild type (MC1R(wt)) melanocytes results in an increase of intracellular cAMP and cellular proliferation. In contrast, MC1R(wt) fibroblasts react with a decrease of intracellular cAMP and proliferation. In MC1R polymorphic fibroblasts (R163Q, R151C and V60L) both effects are significantly alleviated. Similar, but inverse effects could be found in MC1R polymorphic melanocytes (R142H and V92M) with a significantly lower cAMP increase and proliferation rate compared to MC1R(wt) melanocytes.Our results indicate that the MC1R displays reciprocal growth responses in melanocytes and fibroblasts, depending on the MC1R genotype. Thus, the MC1R seems to be not solely important for the skin pigmentary system, but also for the fibroblast function, and might influence different processes of the dermal compartment like wound healing, fibrosis and keloid formation. PMID- 22259656 TI - Eccrine angiomatous hamartoma with sudden enlargement and pain in an adolescent girl after menarche. AB - Eccrine angiomatous hamartoma (EAH) is a rare, benign cutaneous lesion characterized histologically by a proliferation of eccrine glands and vascular structures-generally capillaries-in the middle and deep dermis. Sudden enlargement of EAH lesions with or without pain has been noted during puberty and pregnancy and has been attributed to hormonal stimulation. We herein describe a case of EAH that became symptomatic in an adolescent girl. A 13-year-old girl presented with pain associated with a sudden enlargement of a previously asymptomatic swelling on her right second toe. She had an 8-year history of an asymptomatic swelling on her right second toe, and the symptoms appeared approximately 1 year after menarche. Physical examination revealed swelling of the plantar surface of her right second toe. The overlying surface was erythematous with a small amount of fine scales. The biopsied tissue showed a nodular proliferation of eccrine glands intimately admixed with numerous small vessels in the deep dermis and subcutaneous fat tissue. Mucin deposition was present in the stroma surrounding the proliferating eccrine coils and ducts and in the upper dermis. A diagnosis of EAH was made. We suggest that hormonal changes during puberty may have played a role in the rapid growth and pain in the present case. PMID- 22259658 TI - Use and Limitations of E/e' to Assess Left Ventricular Filling Pressure by Echocardiography. AB - Measurement of left ventricular (LV) filling pressure is useful in decision making and prediction of outcomes in various cardiovascular diseases. Invasive cardiac catheterization has been the gold standard in LV filling pressure measurement, but carries the risk of complications and has a similar predictive value for clinical outcomes compared with non-invasive LV filling pressure estimation by echocardiography. A variety of echocardiographic measurement methods have been suggested to estimate LV filling pressure. The most frequently used method for this purpose is the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), which has become central in the guidelines for diastolic evaluation. This review will discuss the use the E/e' ratio in prediction of LV filling pressure and its potential pitfalls. PMID- 22259659 TI - Metabolic syndrome and myocardial contractile reserve. PMID- 22259660 TI - The Effect of Metabolic Syndrome on Myocardial Contractile Reserve during Exercise in Non-Diabetic Hypertensive Subjects. AB - BACKGROUND: Metabolic syndrome (MS) is associated with increased left ventricular (LV) mass and diastolic dysfunction. This study uses relatively load-independent Doppler tissue echocardiography to examine whether MS is associated with decreased longitudinal contractile reserve during dynamic exercise. METHODS: A total of 112 patients with relatively well-controlled, treated hypertension who complained of exertional dyspnea were enrolled (average age: 56.7 +/- 10.5 years). Fifty-six were non-diabetic patients with MS (Group 1), and 56 were age sex matched hypertensive patients without MS (Group 2). Exercise stress echo was performed using a symptom-limited, multistage, supine bicycle exercise test. Multiple Doppler parameters were obtained at baseline, at each stage of exercise, and during recovery. RESULTS: There was no significant difference between the two groups in terms of age, gender, and hemodynamic variables. E/E', an index of LV filling pressure, was significantly higher in the MS group at rest and during exercise. The longitudinal contractile reserve, the change in S' (longitudinal tissue velocity) from baseline to peak exercise, was significantly lower in the MS group (2.00 +/- 1.65 vs. 2.90 +/- 1.66, p = 0.015). Multiple regression analysis showed independent association of MS with longitudinal contractile reserve when controlled for confounding factors, such as LV mass index, gender, blood pressure, and age (beta = -0.235, p = 0.035). CONCLUSION: Longitudinal contractile reserve was reduced in MS patients compared to others, although both groups demonstrated similar longitudinal contractile function at rest. We present the first demonstration that metabolic syndrome is independently associated with LV systolic dysfunction during exercise in hypertensive patients. PMID- 22259661 TI - Evaluation of the Relationship between Circadian Blood Pressure Variation and Left Atrial Function Using Strain Imaging. AB - BACKGROUND: Non-dippers were reported as showing different left atrial function, compared to dippers, but no study to date investigated the changes in the left atrial function according to the diurnal blood pressure pattern, using tissue Doppler and strain imaging. METHODS: Forty never treated hypertensive patients between 30 and 80 years of age were enrolled in this study. Patients were classified as non-dippers when, during night time, they had a blood pressure decrease of less than 10%. Strain of the left atrium was measured during late systole, and peak strain rates of the left atrium were measured during systole, early and late diastolic periods. RESULTS: The left atrial expansion index, left atrial active emptying volume and left atrial active emptying fraction were all significantly increased in non-dippers. They also had increased values of mean peak left atrial strain (dippers = 21.26 +/- 4.23% vs. non-dippers = 24.91 +/- 5.20%, p = 0.02), strain rate during reservoir (dippers = 1.29 +/- 0.23 s(-1) vs. non-dippers =1.52 +/- 0.27 s(-1), p = 0.01) and contractile period (dippers = 1.38 +/- 0.24 s(-1) vs. non-dippers = -1.68 +/- 0.32 s(-1), p < 0.01). CONCLUSION: Strain and strain rate acquired from color Doppler tissue imaging demonstrate exaggerated reservoir and booster pump function in never-treated, non dipper hypertensive patients. These methods are simple and sensitive for the early detection of subtle changes in the left atrial function. PMID- 22259662 TI - Right ventricular compression observed in echocardiography from pectus excavatum deformity. AB - Pectus excavatum exists as varying anatomic deformities and compression of the right heart by the chest wall can lead to patient symptoms including dyspnea and chest pain with exertion. Echocardiography can be difficult but is critical to the evaluation and diagnosis of this patient population. Modifying standard views such as biplane transthoracic and 3-D transesophageal views may be necessary in some patients due to limitations from the abnormal anatomy of the deformed anterior chest wall. Apical four-chamber views when seen clearly can usually visualize any extrinsic compression to the right ventricle of the heart. PMID- 22259663 TI - Thrombus in Transit within a Patent Foramen Ovale: Gone with the Cough! AB - Pulmonary embolism and concomitant right atrial thrombus entrapped in a patent foramen ovale (PFO) is a rare, unusual finding in echocardiography. The diagnosis of paradoxical embolism is usually presumptive when PFO is detected by echocardiography. We herein reported a case of a 53-year-old patient presenting with pulmonary embolism in which a thrombusin-transit through a PFO was found and disappeared during transesophageal echocardiography. PMID- 22259664 TI - Rapidly Progressive Cardiac Manifestation of Behcet's Disease Involving Conduction System and Aortic Valve. AB - Cardiac conduction system impairment is a rare clinical manifestation of Behcet's disease. We report a patient who showed 1st degree atrioventricular block at first presentation, and showed aggravated finding of 3rd degree atrioventricular block on five months later. His cardiac manifestation finally developed to acute severe aortic regurgitation on six months later from his first cardiac manifestation. We observed this rapid progression during 6 months and successfully improved symptom and disease severity of the patient with treatment targeting Behcet's disease. PMID- 22259665 TI - Surgical removal of endovascular stent after migration to the right ventricle following right subclavian vein deployment for treatment of central venous stenosis. AB - Central venous stenosis or occlusion occurs in 11-50% of hemodialysis patients with prior subclavian vein cannulation and ipsilateral fistula or shunt. Most patients are asymptomatic but some require treatment to reduce the risk of thrombosis and improve inadequate hemodialysis pressure. In these cases, endovascular intervention, including ballooning and stenting, is a feasible strategy for selected patents. We report an unusual case of a 40-year-old man on hemodialysis that underwent endovascular stenting to treat right subclavian vein stenosis and experienced stent migration to the right ventricle, requiring surgical removal. PMID- 22259666 TI - Tricuspid valvular myxoma: unusual case of tricuspid valve myxoma mimicking thrombus after pulmonary artery embolectomy and tricuspid annuloplasty in pulmonary thromboembolism patient. AB - A 55-year-old man with massive pulmonary thromboembolism underwent thrombolysis, pulmonary artery embolectomy and tricuspid annuloplasty. Nine months later, a mobile echogenic intra-cardiac mass was found in the tricuspid valve. Because the patient had undergone annuloplasty, thrombosis was suspected as the most likely diagnosis and thrombolytic therapy was instituted. However, the size of the cardiac mass did not change and after surgical excision the mass was found to be a myxoma. Cardiac valvular tumors are uncommon and when they occur they are usually slow growing fibroelastomas. In this case, the rapid growing cardiac myxoma on the tricuspid valve was found after the occurrence of pulmonary thromboembolism. To our knowledge, this is first reported case of tricuspid valve myxoma in Korea. PMID- 22259667 TI - Incidentally detected situs ambiguous in adults. AB - Situs ambiguous is rare congenital anomaly in adults. In 2 adult patients who admitted for different cardiac problems, situs ambiguous with polysplenia was detected. A 42-year-old male admitted for radio frequent catheter ablation of atrial fibrillation, and he had left-sided inferior vena cava (IVC), hepatic segment of IVC interruption with hemiazygos continuation, multiple spleens and intestinal malrotation. And in a 52-year-old female case who was hospitalized due to infective endocarditis after implanting pacemaker for sick sinus syndrome, multiple spleens, left-sided stomach, bilateral liver with midline gallbladder, and left-sided IVC were found. Those findings were consistent with situs ambiguous with polysplenia, but their features were distinctive. PMID- 22259668 TI - Right coronary cusp prolapse resembling subpulmonic stenosis in an old adult patient with ventricular septal defect. AB - Ventricular septal defect (VSD) can be associated with various complications such as aortic regurgitation (AR). AR in VSD come from a deficiency or hypoplasia of the conal septum which leads to abnormal apposition in diastole and prolapse of the poorly supported noncoronary or right coronary cusp through the VSD into the right ventricle resembling subpulmonic stenosis and subsequently results in distortion of the aortic valve and progressive AR. AR often increases in severity with age and it indicates a worse prognosis. Therefore, appropriate timing of surgical repair in progressive AR in VSD might be important. Until now, many earlier experiences about surgical repair of AR complicating VSD were on adolescents or young adults. We reported a case of AR in 48-year-old male patient with right coronary cusp prolapse complicating the subarterial type of VSD which was properly assessed by echocardiography and was successfully treated with surgical repair. Right coronary cusp or noncoronary cusp prolapse should be suspected in AR complicating VSD through proper echocardiographic assessment and the surgical repair on VSD and distorted aortic valve should be considered in the old patient, as well as the young. PMID- 22259669 TI - Reversible pulmonary hypertension in adolescent with left atrial myxoma. AB - We report a patient of left atrial huge myxoma presenting with severe pulmonary hypertension in adolescents. A patient was a 14-year-old boy presented with sudden onset dyspnea. Transthoracic echocardiographic study revealed the presence of a nodular, 4.34 * 8.11 cm sized, mobile, hyperechoic mass in the left atrium and severe pulmonary hypertension with tricuspid insufficiency. After surgical therapy, tricuspid regurgitation and pulmonary hypertension was decreased and the patient was stabilized and had an uneventful clinical course. PMID- 22259670 TI - Importance of clinical and echocardiographic hemodynamic assessment in chronic pulmonary embolism. AB - We describe a 42-year-old man presenting to the emergency department with cardiogenic shock. He had a prior history of acute pulmonary embolism (PE), and had been on anticoagulation for 2 years. Although computed tomographic pulmonary angiography performed at the emergency department showed no change in the extent of PE and did not support a role of surgical treatment, pulmonary embolectomy was recommended by attending physician based on clinical and echocardiographic hemodynamic findings like unstable vital sign and markedly enlarged right ventricle with severely depressed systolic function. Surgery confirmed the presence of fresh thrombi. After surgery, hemodynamic status was progressively improved, but the patient died due to pneumonia and pulmonary hemorrhage. PMID- 22259671 TI - Cardiac myxoma originating from the anterior mitral valve leaflet. AB - Primary cardiac tumors are rare and myxoma is the most common tumor among them. Cardiac myxoma usually occurs in the left atrium. Myxoma originating from mitral valve is extremely rare. We report a case of mitral valve myxoma. The tumor originated from the anterior mitral valve leaflet. The tumor was completely removed and replacement of the mitral valve was not done. PMID- 22259672 TI - Implementation of a multi-level evaluation strategy: a case study on a program for international medical graduates. AB - Evaluation of educational interventions is often focused on immediate and/or short-term metrics associated with knowledge and/or skills acquisition. We developed an educational intervention to support international medical graduates working in rural Victoria. We wanted an evaluation strategy that included participants' reactions and considered transfer of learning to the workplace and retention of learning. However, with participants in distributed locations and limited program resources, this was likely to prove challenging. Elsewhere, we have reported the outcomes of this evaluation. In this educational development report, we describe our evaluation strategy as a case study, its underpinning theoretical framework, the strategy, and its benefits and challenges. The strategy sought to address issues of program structure, process, and outcomes. We used a modified version of Kirkpatrick's model as a framework to map our evaluation of participants' experiences, acquisition of knowledge and skills, and their application in the workplace. The predominant benefit was that most of the evaluation instruments allowed for personalization of the program. The baseline instruments provided a broad view of participants' expectations, needs, and current perspective on their role. Immediate evaluation instruments allowed ongoing tailoring of the program to meet learning needs. Intermediate evaluations facilitated insight on the transfer of learning. The principal challenge related to the resource intensive nature of the evaluation strategy. A dedicated program administrator was required to manage data collection. Although resource intensive, we recommend baseline, immediate, and intermediate data collection points, with multi-source feedback being especially illuminating. We believe our experiences may be valuable to faculty involved in program evaluations. PMID- 22259673 TI - Evaluation of antioxidant properties of a new compound, pyrogallol-phloroglucinol 6,6'-bieckol isolated from brown algae, Ecklonia cava. AB - In this study, antioxidant and free radical scavenging activities of the natural antioxidative compound, pyrogallol-phloroglucinol-6,6'-bieckol (PPB) isolated from brown algae, Ecklonia cava was assessed in vitro by measuring the radical scavenging activities (DPPH, alkyl, hydroxyl, and superoxide) using electron spin resonance (ESR) spectrometry, intracellular reactive oxygen species (ROS) scavenging activity, and DNA damage assay. According to the results of these experiments, the scavenging activity PPB against difference radicals was in the following order: DPPH, alkyl, hydroxyl, and superoxide radicals (IC(50); 0.90, 2.54, 62.93 and 109.05 uM). The antioxidant activities of PPB were higher than that of the commercial antioxidant, ascorbic acid. Furthermore, PPB effectively inhibited DNA damage induced by H(2)O(2). These results suggest that the natural antioxidative compound, PPB, can be used by the natural food industry. PMID- 22259674 TI - The anti-obesity effect of Lethariella cladonioides in 3T3-L1 cells and obese mice. AB - The aim of this study was to investigate whether a water extract of L. cladonioides (LC) has an anti-obesity effect in 3T3-L1 cells and obese mice. Treatment of differentiated 3T3-L1 adipocytes with LC caused a significant increase in glycerol release and reduced the protein expression of the adipogenic transcription factors, PPARgamma and C/EBPalpha. In an animal model, obese mice were artificially induced by a high fat diet for 10 weeks. Experimental groups were treated with LC (100 mg/kg/day) by gavage for the next 10 weeks. At the end of experiment, the body weight of the LC group mice was reduced by 14.2% compared to the high fat diet (HFD) group. The treatment also decreased liver (31.0%), epididymal (18.0%) and retroperitoneal (19.3%) adipose tissue, and kidney (6.7%) weights, respectively, compared with those of the HFD group. LC prevented diet induced increases in the serum level of TC (22.6%), TG (11.6%), and glucose (35.0%), respectively, compared with the HFD group. However, the HDL-C level was higher in the LC group (26.1%) than the HFD group. The results of this study thus suggest that LC suppressed lipid accumulation and expression of adipogenic transcription factors, and increased the amount of glycerol release. LC also indicated an anti-obese and anti-hyperlipidemic effect. PMID- 22259675 TI - Hog millet (Panicum miliaceum L.)-supplemented diet ameliorates hyperlipidemia and hepatic lipid accumulation in C57BL/6J-ob/ob mice. AB - Dietary intake of whole grains reduces the incidence of chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. In an earlier study, we showed that Panicum miliaceum L. extract (PME) exhibited the highest anti lipogenic activity in 3T3-L1 cells among extracts of nine different cereal grains tested. In this study, we hypothesized that PME in the diet would lead to weight loss and augmentation of hyperlipidemia by regulating fatty acid metabolism. PME was fed to ob/ob mice at 0%, 0.5%, or 1% (w/w) for 4 weeks. After the experimental period, body weight changes, blood serum and lipid profiles, hepatic fatty acid metabolism-related gene expression, and white adipose tissue (WAT) fatty acid composition were determined. We found that the 1% PME diet, but not the 0.5%, effectively decreased body weight, liver weight, and blood triglyceride and total cholesterol levels (P < 0.05) compared to obese ob/ob mice on a normal diet. Hepatic lipogenic-related gene (PPARalpha, L-FABP, FAS, and SCD1) expression decreased, whereas lipolysis-related gene (CPT1) expression increased in animals fed the 1% PME diet (P < 0.05). Long chain fatty acid content and the ratio of C18:1/C18:0 fatty acids decreased significantly in adipose tissue of animals fed the 1% PME diet (P < 0.05). Serum inflammatory mediators also decreased significantly in animals fed the 1% PME diet compared to those of the ob/ob control group (P < 0.05). These results suggest that PME is useful in the chemoprevention or treatment of obesity and obesity-related disorders. PMID- 22259676 TI - Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol. AB - Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612(**)), AST (r = 0.652(*)), CD (r = 0.495(*)), and TRAP (r = -0.486(*)). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress. PMID- 22259677 TI - Association between ESR1 rs1884051 polymorphism and dietary total energy and plant protein intake on obesity in Korean men. AB - ESR1 has been listed in the Human Obesity Gene Map as candidate gene associated with obesity. Thus, in this study, we investigated the effect of the ESR1 rs1884051 polymorphism on obesity-related variables, together with their modulations by dietary intake in Korean men. The obesity-related variables and dietary intake of 3,039 Korean men aged 40-59 years from KoGES database were analyzed. Body weight (P = 0.007), BMI (P = 0.003), waist-hip ratio (= 0.011), fat body mass (P = 0.010), and body fat percentage (P = 0.040) were significantly lower in subjects with the minor T allele of ESR1 rs1884051 than in subjects carrying the C allele. Moreover, the rs1884051 T allele was associated with a decreased risk of obesity prevalence (P = 0.040). Among the subjects whose total energy intake was below the median, carrier of the minor T allele of ESR1 rs1884051 had a lower BMI (P = 0.003) when compared with subjects carrying the C allele. In addition, among subjects whose plant protein intake was above the median, carrier of the minor T allele of ESR1 rs1884051 had a lower BMI (P = 0.044) compared with subjects carrying the C allele. Our findings demonstrate that there is a significant association between the ESR1 rs1884051 variant and obesity-related variables and this association can be potentially modified by dietary energy and plant protein intake. PMID- 22259678 TI - Coconut-derived D-xylose affects postprandial glucose and insulin responses in healthy individuals. AB - Metabolic alterations including postprandial hyperglycemia have been implicated in the development of obesity-related diseases. Xylose is a sucrase inhibitor suggested to suppress the postprandial glucose surge. The objectives of this study were to assess the inhibitory effects of two different concentrations of xylose on postprandial glucose and insulin responses and to evaluate its efficacy in the presence of other macronutrients. Randomized double-blind cross-over studies were conducted to examine the effect of D-xylose on postprandial glucose and insulin response following the oral glucose tolerance test (OGTT). In study 1, the overnight-fasted study subjects (n = 49) consumed a test sucrose solution (50 g sucrose in 130 ml water) containing 0, 5, or 7.5 g D-xylose powder. In study 2, the overnight-fasted study subjects (n = 50) consumed a test meal (50 g sucrose in a 60 g muffin and 200 ml sucrose-containing solution). The control meal provided 64.5 g of carbohydrates, 4.5 g of fat, and 10 g of protein. The xylose meal was identical to the control meal except 5 g of xylose was added to the muffin mix. In study 1, the 5 g xylose-containing solutions exhibited significantly lower area under the glucose curve (AUCg) and area under the insulin curve (AUCi) values for 0-15 min (P < 0.0001, P < 0.0001), 0-30 min (P < 0.0001, P < 0.0001), 0-45 min (P < 0.0001, P < 0.0001), 0-60 min (P < 0.0001, P < 0.0001), 0-90 min (P < 0.0001, P < 0.0001) and 0-120 min (P = 0.0071, P = 0.0016). In study 2, the test meal exhibited significantly lower AUCg and AUCi values for 0-15 min (P < 0.0001, P < 0.0001), 0-30 min (P < 0.0001, P < 0.0001), 0-45 min (P < 0.0001, P = 0.0005), 0-60 min (P = 0.0002, P = 0.0025), and 0-90 min (P = 0.0396, P = 0.0246). In conclusion, xylose showed an acute suppressive effect on the postprandial glucose and insulin surges. PMID- 22259679 TI - The effect of carrot juice, beta-carotene supplementation on lymphocyte DNA damage, erythrocyte antioxidant enzymes and plasma lipid profiles in Korean smoker. AB - High consumption of fruits and vegetables has been suggested to provide some protection to smokers who are exposed to an increased risk of numerous cancers and other degenerative diseases. Carrot is the most important source of dietary beta-carotene. Therefore, the objective of this study was to investigate whether carrot juice supplementation to smokers can protect against lymphocyte DNA damage and to compare the effect of supplementation of capsules containing purified beta carotene or a placebo (simple lactose). The study was conducted in a randomized and placebo-controlled design. After a depletion period of 14 days, 48 smokers were supplemented with either carrot juice (n = 18), purified beta-carotene (n = 16) or placebo (n = 14). Each group was supplemented for 8 weeks with approximately 20.49 mg of beta-carotene/day and 1.2 mg of vitamin C/day, as carrot juice (300 ml/day) or purified beta-carotene (20.49 mg of beta-carotene, 1 capsule/day). Lymphocyte DNA damage was determined using the COMET assay under alkaline conditions and damage was quantified by measuring tail moment (TM), tail length (TL), and% DNA in the tail. Lymphocyte DNA damage was significantly decreased in the carrot juice group in all three measurements. The group that received purified beta-carotene also showed a significant decrease in lymphocyte DNA damage in all three measurements. However, no significant changes in DNA damage was observed for the placebo group except TM (P = 0.016). Erythrocyte antioxidant enzyme was not significantly changed after supplementation. Similarly plasma lipid profiles were not different after carrot juice, beta-carotene and placebo supplementation. These results suggest that while the placebo group failed to show any protective effect, carrot juice containing beta-carotene or purified beta-carotene itself had great antioxidative potential in preventing damage to lymphocyte DNA in smokers. PMID- 22259680 TI - The estimated daily manganese intake of Korean children aged 11-12. AB - The purpose of this study was to estimate the daily manganese (Mn) intake of Korean children. This study was done using a three-day dietary intake survey of 257 Korean children (boys 123; girls 134). The Mn intake values were calculated based on a database that provides the Mn content of the frequently consumed Korean foods, alongside the food composition table provided by the Korean National Rural Living Science Institute. The average age, height, weight and body mass index of our subjects were 11.9 years, 155.4 cm, 48.9 kg and 20.2 kg/m(2) in boys and 11.9 years, 154.1 cm, 43.5 kg and 18.3 kg/m(2) in girls. The average daily energy intakes were 2,249.2 kcal in boys and 2,044.5 kcal in girls. Boys consumed significantly more Mn than girls, based on intake estimates of 4,585.3 ug (117.6% of adequate intake) and 4,029.3 ug (117.1% of adequate intake), respectively (P < 0.001). Boys had a Mn intake of 2,041.1 ug per 1,000 kcal of energy consumption, whereas for girls this was at 1,983.9 ug per 1,000 kcal. Neither group exceeded the tolerable upper intake level for Mn. The major food groups which contributed to Mn intake in our subjects were cereals (50.8%), vegetables (21.0%), seasonings (8.9%), and pulses (7.7%). Notably, boys derived a higher Mn intake through cereals and vegetable than did girls (P < 0.001, P < 0.05). The key food sources of Mn, in descending order, were rice, soybean curd, kimchi, black rice and cereals. We propose that the results of our study may be used as a basis for follow-up studies that examine the Mn intake of children. PMID- 22259681 TI - Portion sizes of foods frequently consumed by the Korean elderly: Data from KNHANES IV-2. AB - The purpose of this study was to define a one-portion size of food frequently consumed by the Koreans aged 65 years or over. From the original 8,631 people who took part in the Forth Korea National Health and Nutrition Examination Survey (KNHANES IV-2) 2008, we analyzed the data on 1,458 persons (16.9%) aged 65 and over, and selected food items consumed based on the intake frequency of 30 or more by all participant. A total of 158 varieties of food items were selected. The portion size of food items was set on the basis of the median amount (50 percentile) in a single intake by a single person. In the cereals category, 13 items were selected, of which the most frequently consumed item was well-polished rice with portion size of 75 g. Among legumes, 7 items were selected, of which the most frequent item was dried black soybean with a portion size of 6 g. Among the 16 groups, the most varied food group (49 items) was vegetables, and among these the most frequently occurring item was garlic (5 g), while among the fruit group, only 11 items were selected, as their intake frequency was low. Fish and shellfish were more frequently consumed by the elderly than meats. The most frequently consumed meat was pork loin, with a portion size of 30 g. In fish and shellfish, the most frequently consumed item was dried and boiled large anchovy with a portion size of 2 g. Portion sizes for food items consumed regularly by the elderly may be conveniently and effectively used in dietary planning and in nutritional education programs, and in assessing the diet intake status of the elderly. PMID- 22259682 TI - Association between adherence to the Korean Food Guidance System and the risk of metabolic abnormalities in Koreans. AB - Consumption of a diet consistent with dietary guidelines is believed to have a beneficial effect on the prevention of chronic diseases and the promotion of general health. This study was conducted to explore the relationship between adherence to the Korean Food Guidance System (KFGS), which was based on the 2010 revised KDRIs, and the risk of metabolic abnormalities. Five hundred and ninety six Korean adults between 30 and 59 years of age were recruited by advertisement to the Bundang Jesaeng General Hospital (BJGH), and those not taking regular medications and without diagnoses of fulminant disease were included. Data were collected on anthropometric measurements, diagnostic parameters for metabolic syndrome (MetS), and 3-day dietary intakes from individuals in the study. The number of servings consumed from each food group was compared to the KFGS recommended servings for each of the 6 food groups. Poor adherence to the recommendations for servings of milk and dairy products (OR: 2.038, 1.128-3.682) was associated with a higher risk of MetS, and poor adherence to the guidelines for fruit consumption (OR: 1.849, 1.027-3.329) was associated with a higher risk for the existence an elevated waist circumference. Conversely, the consumption of meat, fish, eggs, and beans above the recommended number of servings was associated with a lower risk of having an elevated waist circumference (OR: 0.523, 0.288-0.950), and the consumption of vegetables above the recommended number of servings was associated with a reduced risk of having elevated fasting glucose (OR: 0.533, 0.298-0.954). These results suggest that adherence to the KFGS guidelines helps to prevent the development of MetS, but this association needs to be confirmed by prospective studies. PMID- 22259684 TI - An Exploratory study of compliance with dietary recommendations among college students majoring in health-related disciplines: application of the transtheoretical model. AB - Compliance with food group and nutrient recommendations, and self-efficacy, stage of change, perceived barriers and benefits for healthy eating were assessed among a convenience sample of college students majoring in health-related disciplines. Dietary and psychosocial data were collected using three-day food records and scales, respectively. Means (SD), frequencies, and percents were calculated on all data, and logistic regressions were used to determine whether any of the psychosocial correlates predicted the stage of change for healthy eating. Noncompliance with food group recommendations ranged from 53% for the meat/meat alternates group to 93% for the vegetables/juice group, whereas noncompliance with nutrient recommendations ranged from 26% for cholesterol to 99% for potassium. A majority of students (57%) self-classified in the preaction and 40% in the action stages of change for eating healthy. The students' self-efficacy to eat healthy was highest in positive/social situations and lowest when experiencing emotional upset. The most important perceived barrier to healthy eating was that friends/roommates do not like to eat healthy foods, and the most important perceived benefit was that eating healthy foods provides the body with adequate nutrients. The difficult/inconvenient self-efficacy subscale predicted the stage of change for healthy eating. These students would benefit from interactive learning opportunities that teach how to purchase and prepare more whole grain foods, fruits, and vegetables, enhance their self-efficacy for making healthy food choices when experiencing negative emotions, and overcome perceived barriers to healthy eating. PMID- 22259683 TI - Dietary patterns are associated with physical growth among school girls aged 9-11 years. AB - The purpose of this study was to identify dietary patterns among Korean elementary school girls based on the change in body mass index (BMI), body fat, bone mineral density (BMD), and bone mineral content (BMC) during 22 months and to explore the characteristics of dietary patterns identified. Girls aged 9-11 years were recruited and 3-day dietary data were collected four times. Subjects with a diet record of 8 or more days and anthropometric data measured at baseline and 22 months later were included (n = 198). Reduced rank regression was utilized to derive dietary patterns using a change in BMI, body fat, and calcaneus BMD and BMC as response variables. Two dietary patterns were identified: the "Egg and Rice" dietary pattern and "Fruit, Nuts, Milk Beverage, Egg, Grain" (FNMBEG) dietary pattern. Subjects who had high score on the FNMBEG pattern consumed various food groups, including fruits, nuts and seeds, and dairy products, whereas subjects in the "Egg and Rice" dietary pattern group did not. Both dietary patterns showed a positive association with change in BMI and body fat. However, subjects who had a higher score on the "Egg and Rice" dietary pattern had less of a BMC increase, whereas subjects who had a higher score on the FMBEG dietary pattern had more increased BMC over 22 months after adjusting for age, body and bone mass, and Tanner stage at baseline. Our results provide evidence that a well-balanced diet contributes to lean body mass growth among young girls. PMID- 22259685 TI - Prior use of 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibitor, simvastatin fails to improve outcome after experimental intracerebral hemorrhage. AB - OBJECTIVE: Contrary to some clinical belief, there were quite a few studies regarding animal models of intracerebral hemorrhage (ICH) in vivo suggesting that prior use of statins may improve outcome after ICH. This study reports the effect of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, simvastatin given before experimental ICH. METHODS: Fifty-one rats were subjected to collagenase-induced ICH, subdivided in 3 groups according to simvastatin treatment modality, and behavioral tests were done. Hematoma volume, brain water content and hemispheric atrophy were analyzed. Immunohistochemical staining for microglia (OX-42) and endothelial nitric oxide synthase (eNOS) was performed and caspase-3 activity was also measured. RESULTS: Pre-simvastatin therapy decreased inflammatory reaction and perihematomal cell death, but resulted in no significant reduction of brain edema and no eNOS expression in the perihematomal region. Finally, prior use of simvastatin showed less significant improvement of neurological outcome after experimental ICH when compared to post-simvastatin therapy. CONCLUSION: The present study suggests that statins therapy after ICH improves neurological outcome, but prior use of statins before ICH might provide only histological improvement, providing no significant impact on neurological outcome against ICH. PMID- 22259686 TI - The effect of hyaluronate-carboxymethyl cellulose on bone graft substitute healing in a rat spinal fusion model. AB - OBJECTIVE: The aim of this study was to evaluate the impact of sodium hyaluronate sodium carboxymethyl cellulose (HA-CMC), an anti-adhesive material for spinal surgery, on bone fusion by applying it to rat spinal models after lumbar posterolateral fusion. METHODS: Lumbar posterolateral fusion was performed at L4 5 using bone graft substitutes in 30 rats. HA-CMC was injected in 15 rats at a dose of 0.2 cc (HA-CMC group) and a saline solution of 0.2 cc in the other 15 rats (control group). Simple radiographs were taken until postoperative 9 weeks with an interval of one week. At postoperative 4 and 9 weeks, three dimensional computed tomography (3D CT) scanning was performed to observe the process of bone fusion. At 9 weeks, bone fusion was confirmed by gross examination and manual palpation. RESULTS: There were no statistically significant differences in bone fusion between the two groups. 3D CT scanning did not reveal significant differences between the groups. The gross examination and manual palpation after autopsy performed at 9 weeks confirmed bone union in 93.3% of both groups. CONCLUSION: The anti-adhesive material used for spinal surgery did not have adverse effects on spinal fusion in rats. PMID- 22259687 TI - Association of estrogen receptor gene polymorphism in patients with degenerative lumbar spondylolisthesise. AB - OBJECTIVE: The purpose of this study was to investigate the possible association of estrogen receptor alpha (ERalpha) gene polymorphisms in a cohort of degenerative spondylolisthesis (DS) patients. METHODS: Accordingly, the authors examined the association between DS and ERalpha gene polymorphisms in 174 patients diagnosed with DS. The Pvu II and Xba I polymorphisms, bone mineral density at the lumbar spine and femoral neck, and biochemical markers were analyzed and compared in the 174 patients with DS and 214 patients with spinal stenosis (SS). RESULTS: A comparison of genotype frequencies in DS and SS patients revealed a significant difference for the Pvu II polymorphism only (p=0.0452). No significant difference was found between these two groups with respect to the Xba I polymorphism, BMD or biochemical markers. No significant association was found between the Pvu II polymorphism of ERalpha and BMD, vertebral slip or biochemical markers in patients with DS. CONCLUSION: These results suggest that the ERalpha gene polymorphism using Pvu II restriction enzyme influences the prevalence of DS. PMID- 22259688 TI - Comparison of the spinal neuropathic pain induced by intraspinal injection of N methyl-d-aspartate and quisquate in rats. AB - OBJECTIVE: Excitatory amino acids play important roles in the development of secondary pathology following spinal cord injury (SCI). This study was designed to evaluate morphological changes in the dorsal horn of the spinal cord and assess profiles of pain behaviors following intraspinal injection of N-methyl-D aspartate (NMDA) or quisqualate (QUIS) in rats. METHODS: Forty male Sprague Dawley rats were randomized into three groups : a sham, and two experimental groups receiving injections of 125 mM NMDA or QUIS into their spinal dorsal horn. Following injection, hypersensitivity to cold and mechanical stimuli, and excessive grooming behaviors were assessed serially for four weeks. At the end of survival periods, morphological changes in the spinal cord were evaluated. RESULTS: Cold allodynia was developed in both the NMDA and QUIS groups, which was significantly higher in the QUIS group than in the NMDA group. The mechanical threshold for the ipsilateral hind paw in both QUIS and NMDA groups was significantly lower than that in the control group. The number of groomers was significantly higher in the NMDA group than in the QUIS group. The size of the neck region of the spinal dorsal horn, but not the superficial layer, was significantly smaller in the NMDA and QUIS groups than in the control group. CONCLUSION: Intraspinal injection of NMDA or QUIS can be used as an excitotoxic model of SCI for further research on spinal neuropathic pain. PMID- 22259690 TI - Efficacy of decompression and fixation for metastatic spinal cord compression: analysis of factors prognostic for survival and postoperative ambulation. AB - OBJECTIVE: The goals of surgical intervention for metastatic spinal cord compression (MSCC) are prolonging survival and improving quality of life. Non ambulatory paraplegic patients, either at presentation or after treatment, have a much shorter life expectancy than ambulatory patients. We therefore analyzed prognostic factors for survival and postoperative ambulation in patients surgically treated for MSCC. METHODS: We assessed 103 patients with surgically treated MSCC who presented with lower extremity weakness between January 2001 and December 2008. Factors prognostic for overall survival (OS) and postoperative ambulation, including surgical method, age, sex, primary tumor site, metastatic spinal site, surgical levels, Tokuhashi score, and treatment with chemo- or radiation therapy, were analyzed retrospectively. RESULTS: Median OS was significantly longer in the postoperatively ambulatory group [11.0 months; 95% confidence interval (CI), 9.29-12.71 months] than in the non-ambulatory group (5.0 months; 95% CI, 1.80-8.20 months) (p=0.035). When we compared median OS in patients with high (9-11) and low (0-8) Tokuhashi scores, they were significantly longer in the former (15.0 months; 95% CI, 9.29-20.71 months vs. 9.0 months; 95% CI, 7.48-10.52 months; p=0.003). Multivariate logistic regression analysis showed that preoperative ambulation with or without aid [odds ratio (OR) 5.35; 95% CI 1.57-18.17; p=0.007] and hip flexion power greater than grade III (OR 6.23; 95% CI, 1.29-7.35; p=0.038) were prognostic of postoperative ambulation. CONCLUSION: We found that postoperative ambulation and preoperative high Tokuhashi score were significantly associated with longer patient survival. In addition, preoperative hip flexion power greater than grade III was critical for postoperative ambulation. PMID- 22259689 TI - Chemotherapy for malignant gliomas based on histoculture drug response assay : a pilot study. AB - OBJECTIVE: The Histoculture Drug Response Assay (HDRA), which measures chemosensitivity using minced tumor tissue on drug-soaked gelfoam, has been expected to overcome the limitations of in vitro chemosensitivity test in part. We analyzed interim results of HDRA in malignant gliomas to see if the test can deserve further clinical trials. METHODS: Thirty-three patients with malignant gliomas were operated and their tumor samples were examined for the chemosensitivity to 10 chosen drugs by HDRA. The most sensitive chemotherapy regimen among those pre-established was chosen based on the number of sensitive drugs or total inhibition rate (IR) of the regimen. The response was evaluated by 3 month magnetic resonance image. RESULTS: Among 13 patients who underwent total resection of the tumor, 12 showed no evidence of disease and one patient revealed progression. The response rate in 20 patients with residual tumors was 55% (3 complete and 8 partial responses). HDRA sensitivity at the cut-off value of more than one sensitive drug in the applied regimen showed a sensitivity of 100%, specificity of 60% and predictability of 70%. Another cut-off value of >80% of total IR revealed a sensitivity of 100%, specificity of 69%, and predictability of 80%. For 12 newly diagnosed glioblastoma patients, median progression-free survival of the HDRA sensitive group was 21 months, while that of the non sensitive group was 6 months (p=0.07). CONCLUSION: HDRA for malignant glioma was inferred as a feasible method to predict the chemotherapy response. We are encouraged to launch phase 2 clinical trial with chemosensitivity on HDRA. PMID- 22259691 TI - Minimally invasive multi-level posterior lumbar interbody fusion using a percutaneously inserted spinal fixation system : technical tips, surgical outcomes. AB - OBJECTIVE: There are technical limitations of multi-level posterior pedicle screw fixation performed by the percutaneous technique. The purpose of this study was to describe the surgical technique and outcome of minimally invasive multi-level posterior lumbar interbody fusion (PLIF) and to determine its efficacy. METHODS: Forty-two patients who underwent mini-open PLIF using the percutaneous screw fixation system were studied. The mean age of the patients was 59.1 (range, 23 to 78 years). Two levels were involved in 32 cases and three levels in 10 cases. The clinical outcome was assessed using the visual analog scale (VAS) and Low Back Outcome Score (LBOS). Achievement of radiological fusion, intra-operative blood loss, the midline surgical scar and procedure related complications were also analyzed. RESULTS: The mean follow-up period was 25.3 months. The mean LBOS prior to surgery was 34.5, which was improved to 49.1 at the final follow up. The mean pain score (VAS) prior to surgery was 7.5 and it was decreased to 2.9 at the last follow up. The mean estimated blood loss was 238 mL (140-350) for the two level procedures and 387 mL (278-458) for three levels. The midline surgical scar was 6.27 cm for two levels and 8.25 cm for three level procedures. Complications included two cases of asymptomatic medial penetration of the pedicle border. However, there were no signs of neurological deterioration or fusion failure. CONCLUSION: Multi-level, minimally invasive PLIF can be performed effectively using the percutaneous transpedicular screw fixation system. It can be an alternative to the traditional open procedures. PMID- 22259692 TI - Percutaneous radiofrequency thermocoagulation under fluoroscopic image-guidance for idiopathic trigeminal neuralgia. AB - OBJECTIVE: We retrospectively investigated the long-term results of percutaneous radiofrequency thermocoagulation (RFT) using fluoroscopic image-guidance for treatment of trigeminal neuralgia. METHODS: A total of 38 patients diagnosed and treated with RFT as an idiopathic trigeminal neuralgia were investigated. To minimize the risks related to conventional technique based on cutaneous landmarks, and to eliminate the need to frequent reposition of cannula, we adopted a technique of image-guided fluoroscopic cannulation of the foramen ovale. To minimize sensory complication following thermal lesion, our target response was a generation of a lesion with mild to moderate hypalgesia rather than dense hypalgesia. RESULTS: The immediate pain-relief was achieved in all patients underwent RFT. With mean duration of follow-up of 38.2 months (range,12 72), 11 (28.9%) experienced recurrence of pain. The mean timing of recurrence was 26.1 months (range,12-46). A 42.7% recurrence rate was estimated by Kaplan-Meier analysis for the 38 patients at 46 months; 20.2% within 2 years, 29.1% within 3 years. In the long-term, 27 patients (71%) and 6 patients (15.8%) showed Barrow Neurological Institute (BNI) score I and BNI score II responses. 3 (7.9%) patients was assessed as BNI score III, 2 patients (5.3%) showed BNI score IV response. As a complication, troublesome dysesthesia occurred in 3 of 38 patients (7.9%), however, there was no permanent cranial nerve palsy or morbidity. CONCLUSION: These results indicates that RFT under fluoroscopic image-guided cannulation of foramen ovale is a safe, effective, and reliable means of treating trigeminal neuralgia. PMID- 22259693 TI - Ruptured intracranial dermoid cyst associated with rupture of cerebral aneurysm. AB - Many tumors have been reported to coexist with cerebral aneurysm. However, intracranial dermoid cysts associated with cerebral aneurysm are very rare. We report a case in which rupture of a cerebral aneurysm resulted in a ruptured dermoid cyst. We present this interesting case and review current literature about the relationship between tumors and aneurysm formation. PMID- 22259694 TI - De novo aneurysm after treatment of glioblastoma. AB - A rare case of spontaneous subarachnoid hemorrhage from newly developed cerebral aneurysm in glioblastoma patient is presented. A 57-year-old man was presented with headache and memory impairment. On the magnetic resonance image and the magnetic resonance angiography, a large enhancing mass was found at right frontal subcortex and intracranial aneurysm was not found. The mass was removed subtotally and revealed as glioblastoma. He took concurrent PCV chemotherapy and radiation therapy, but the mass recurred one month later after radiotherapy. He was then treated with temozolomide for 7 cycles. Three months after the completion of temozolomide therapy, he suffered from a subarachnoid hemorrhage due to a rupture of a small de novo aneurysm at distal anterior cerebral artery. He underwent an aneurysm clipping and discharged without neurologic complication. PMID- 22259695 TI - An unusual case of post-operative spondylitis caused by mycobacterium intracellulare in an immunosuppressed patient. AB - There are few reported cases of post-operative spondylitis caused by Mycobacterium intracellulare. A 75-year-old female presented to our hospital with low back pain and paraparesis after a fall. The radiologic examination revealed compression fractures of L1, L3 and L4 and an epidural hematoma compressing the spinal cord. The dark-red epidural hematoma was urgently evacuated. Four weeks post-operatively, neurologic deficits recurred with fever. On magnetic resonance image, an epidural abscess and osteomyelitis were detected in the previous operative site. Five weeks post-operatively, revision was performed with multiple biopsies. The specimen were positive for acid-fast bacilli and traditional anti tuberculous medications were started. Because the Polymerase Chain Reaction for non-tuberculous mycobacterium (NTM) was positive, the anti-tuberculous medications were changed to anti-NTM drugs. However, the neurologic deficits did not improve and persistent elevation of erythrocyte sedimentation rate and C reactive protein were noted. Eight weeks after the revision, Mycobacterium intracellulare was detected in the specimen cultures. Despite supportive care with medication, the patient died due to multiple organ failure. PMID- 22259696 TI - Guillain-barre syndrome following spinal fusion for thoracic vertebral fracture. AB - There have been very few reports in the literature of Guillain-Barre syndrome (GBS) after spinal surgery. We present a unique case of GBS following spinal fusion for thoracic vertebral fracture. The aim of this report is to illustrate the importance of early neurological assessment and determining the exact cause of a new neurological deficit that occurs after an operation. PMID- 22259697 TI - Primary spinal dumbbell-shaped mesenchymal chondrosarcoma located intradurally and extradurally. AB - Mesenchymal chondrosarcomas are rare malignant tumors of the bone and soft tissue. Spinal mesenchymal chondrosarcomas are even rarer and, to the best of our knowledge those that are concomitantly located in the intradural and extradural regions, have never been reported. We report a case of a 25-year-old man with back pain and bilateral progressive weakness of the lower extremities. Magnetic resonance imaging revealed a markedly enhanced dumbbell-shaped mass at the T7 level. The lesion was intradurally located at the left side of the spinal cord, and extended extradurally to the extraforminal space through the T7-8 intervertebral foramen. The tumor was completely excised through a posterior approach. Microscopic examination and immunohistochemical studies confirmed mesenchymal chondrosarcoma. Postoperative radiation therapy and chemotherapy were also performed to prevent local recurrence and metastasis. The patient has been symptom-free for two years after surgery. Herein, we reviewed and discussed the clinical characteristics, treatments, and outcomes of primary intraspinal mesenchymal chondrosarcomas in the literature. PMID- 22259698 TI - Cortical laminar necrosis in an infant with severe traumatic brain injury. AB - Cortical laminar necrosis appears as hyperinense lesions with a laminar pattern on T1 weighted magnetic resonance (MR) imaging, without signs of hemorrhage or calcification on T2 weighted MR imaging or computed tomography. It has been reported to be associated with hypoxia, metabolic disturbances, drugs, and infections. We present a 12 month-old male infant who suffered diffuse brain injuries following car accident and showed laminar necrosis of cortex. PMID- 22259699 TI - Dandy-walker malformation associated with neurocutaneous melanosis. AB - Neurocutaneous melanosis associated with Dandy-Walker malformation is a rare dysmorphogenesis that is associated with single or multiple giant pigmented cutaneous nevi and diffuse involvement of the central nervous system. In this article, we present a 2-month-old patient with neurocutaneous melanosis associated with Dandy-Walker malformation. In addition, we reviewed the literature and discussed the pathogenesis based on the preferred hypotheses. PMID- 22259700 TI - Accuracy of five implant impression technique: effect of splinting materials and methods. AB - PURPOSE: The aim of this study was to evaluate the effect of dimensional stability of splinting material on the accuracy of master casts. MATERIALS AND METHODS: A stainless steel metal model with 6 implants embedded was used as a master model. Implant level impressions were made after square impression copings were splinted using 5 different techniques as follows. (1) Splinted with autopolymerizing resin and sectioned, reconnected to compensate polymerization shrinkage before the impression procedure. (2) Splinted with autopolymerizing resin just before impression procedure. (3) Primary impression made with impression plaster and secondary impression were made over with polyether impression material. (4) Splinted with impression plaster. (5) Splinted with VPS bite registration material. From master model, 5 impressions and 5 experimental casts, total 25 casts were made for each of 5 splinting methods. The distortion values of each splinting methods were measured using coordinate measuring machine, capable of recordings in the x-, y-, z-axes. A one-way analysis of variance (ANOVA) at a confidence level of 95% was used to evaluate the data and Tukey's studentized range test was used to determine significant differences between the groups. RESULTS: Group 1 showed best accuracy followed by Group 3 & 4. Group 2 and 5 showed relatively larger distortion value than other groups. No significant difference was found between group 3, 4, 5 in x-axis, group 2, 3, 4 in y-axis and group 1, 3, 4, 5 in z-axis (P<.0001). CONCLUSION: Both Splinting impression copings with autopolymerizing resin following compensation of polymerization shrinkage and splinting method with impression plaster can enhance the accuracy of master cast and impression plaster can be used simple and effective splinting material for implant impression procedure. PMID- 22259701 TI - The effect of thermocycling on the bonding of different restorative materials to access opening through porcelain fused to metal restorations. AB - PURPOSE: Porcelain fused to metal (PFM) crowns provide the best treatment option for teeth that have a large or defective restoration. More than 20% of teeth with PFM crowns or bridges require non-surgical root canal treatment (NSRCT). This may be due to the effect of restorative procedures and the possible leakage of bacteria and or their by-products, which leads to the demise of the tooth pulp. Thus, this study was planned to compare the ability of the restorative materials to seal perforated PFM specimens. MATERIALS AND METHODS: The study evaluates the ability of amalgam, composite or compomer restorative materials to close perforated PFM specimen's in-vitro. Ninety PFM specimens were constructed using Ni-Cr alloys and feldspathic porcelain, and then they were divided into 3 groups: amalgam (A), composite + Exite adhesive bond (B) and compomer + Syntac adhesive bond (C). All the PFM samples were embedded in an acrylic block to provide complete sealing of the hole from the bottom side. After the aging period, each group was further divided into 3 equal subgroups according to the thermocycling period (one week for 70 cycles, one month for 300 cycles and three months for 900 cycles). Each subgroup was put into containers containing dye (Pelikan INK), one maintained at 5C and the other at 55C, each cycle for 30 sec time. The data obtained was analyzed by SPSS, 2006 using one way ANOVA test and student t-test and significant difference level at (P<.01). RESULTS: The depth of dye penetration was measured at the interfaces of PFM and filling materials using Co ordinate Vernier Microscope. The lowest levels of the dye penetration for the three groups, as well as subgroups were during the first week. The values of dye leakage had significantly increased by time intervals in subgroups A and C. CONCLUSION: It was seen that amalgam showed higher leakage than composite while compomer showed the lowest level of leakage. PMID- 22259702 TI - A comparative study on the initial stability of different implants placed above the bone level using resonance frequency analysis. AB - PURPOSE: This study evaluated the initial stability of different implants placed above the bone level in different types of bone. MATERIALS AND METHODS: As described by Lekholm and Zarb, cortical layers of bovine bone specimens were trimmed to a thickness of 2 mm, 1 mm or totally removed to reproduce bone types II, III, and IV respectively. Three Implant system (Branemark System(r) Mk III TiUniteTM, Straumann Standard Implant SLA(r), and Astra Tech MicrothreadTM OsseoSpeedTM) were tested. Control group implants were placed in level with the bone, while test group implants were placed 1, 2, 3, and 4 mm above the bone level. Initial stability was evaluated by resonance frequency analysis. Data was statistically analyzed by one-way analysis of variance in confidence level of 95%. The effective implant length and the Implant Stability Quotient (ISQ) were compared using simple linear regression analysis. RESULTS: In the control group, there was a significant difference in the ISQ values of the 3 implants in bone types III and IV (P<.05). The ISQ values of each implant decreased with increased effective implant length in all types of bone. In type II bone, the decrease in ISQ value per 1-mm increase in effective implant length of the Branemark and Astra implants was less than that of the Straumann implant. In bone types III and IV, this value in the Astra implant was less than that in the other 2 implants. CONCLUSION: The initial stability was much affected by the implant design in bone types III, IV and the implant design such as the short pitch interval was beneficial to the initial stability of implants placed above the bone level. PMID- 22259703 TI - A comparison of marginal fit of glass infiltrated alumina copings fabricated using two different techniques and the effect of firing cycles over them. AB - PURPOSE: This study evaluated marginal fit of glass infiltrated alumina cores fabricated using two techniques and their marginal stability after firing cycles of veneering porcelain. MATERIALS AND METHODS: Fifteen standardized all-ceramic crowns were fabricated on a metal die using each technique: slip cast technique of VITA In-Ceram sprint Alumina (Group A as control) and plastic foil matrix technique of Turkom-Cera fused alumina core system (Group B). Copings were compared between groups and within groups at coping stage and after firing each layer of veneering porcelain. A device was used to standardize seating of copings on the metal die and positioning of the specimens under the microscope after each stage of fabrication. The specimens were not cemented and marginal gap was measured using an image analyzing software (Imagepro Express) on the photographs captured under an optical microscope. Two tailed unpaired 't test' was used to compare marginal gaps in two groups and one way ANOVA was used to analyze marginal distortion within each group at 95% confidence interval. RESULTS: The marginal gap was smaller at the coping stage in group B (60 + 30 um) than group A (81 + 21 um) with statistical significance. After firing of veneering porcelain the difference was insignificant. At the final stage, both groups exhibited lower mean marginal gaps than at the initial coping stage with the difference of 11.75 um for group A and 11.94 um for group B, but it was statistically insignificant due to high value of standard deviation. CONCLUSION: Within the limitations of this study, it was concluded that both techniques produced copings with comparable and acceptable marginal fit and marginal stability on firing veneering porcelain. PMID- 22259704 TI - A retrospective study on related factors affecting the survival rate of dental implants. AB - PURPOSE: The aim of this retrospective study is to analyze the relationship between local factors and survival rate of dental implant which had been installed and restored in Seoul Veterans Hospital dental center for past 10 years. And when the relationship is found out, it could be helpful to predict the prognosis of dental implants. MATERIALS AND METHODS: A retrospective study of patients receiving root-shaped screw-type dental implants placed from January 2000 to December 2009 was conducted. 6385 implants were placed in 3755 patients. The following data were collected from the dental records and radiographs: patient's age, gender, implant type and surface, length, diameter, location of implant placement, bone quality, prosthesis type. The correlations between these data and survival rate were analyzed. Statistical analysis was performed with the use of Kaplan-Meier analysis, Chi-square test and odds ratio. RESULTS: In all, 6385 implants were placed in 3755 patients (3120 male, 635 female; mean age 65 +/ 10.58 years). 108 implants failed and the cumulative survival rate was 96.33%. There were significant differences in age, implant type and surface, length, location and prosthesis type (P<.05). No significant differences were found in relation to the following factors: gender, diameter and bone quality (P>.05). CONCLUSION: Related factors such as age, implant type, length, location and prosthesis type had a significant effect on the implant survival. PMID- 22259705 TI - Polymerization behavior and thermal characteristics of two new composites at five temperatures: refrigeration to preheating. AB - PURPOSE: Heat of composite polymerization (HP) indicates setting efficacy and temperature increase of composite in clinical procedures. The purpose of this in vitro experimental study was to evaluate the effects of 5 temperatures on HP of two new composites. MATERIALS AND METHODS: From each material (Core Max II [CM] and King Dental [KD]), 5 groups of 5 specimens each were prepared and their total HPs (J/gr) were measured and recorded, at one of the constant temperatures 0C, 15C, 23C, 37C and 60C (2 * 5 * 5 specimens) using a differential scanning calorimetry (DSC) analyzer. The data were analyzed using a two-way ANOVA, a Tukey's test, an independent-samples t-test, and a linear regression analysis (alpha=0.05). RESULTS: No polymerization reactions occurred at 0C; then this temperature was excluded from statistical analyses. The mean HP of the remaining 20 KD specimens was 20.5 +/- 14.9 J/gr, while it was 40.7 +/- 12.9 J/gr for CM. The independent-samples t-test showed that there were significant differences between the HP of the two materials at the temperatures 15C (P=.0001), 23C (P=.0163), 37C (P=.0039), and 60C (P=.0106). Linear regression analysis showed statistically significant correlations between environment temperatures and HP of CM (R(2)=0.777). CONCLUSION: Using CM is advantageous over conventional composite because of its better polymerization capacity. However due to its high HP, further studies should assess its temperature increase in vivo. Preheating KD is recommended. Refrigerating composites can negatively affect their polymerization potential. PMID- 22259706 TI - Influence of surface modification techniques on shear bond strength between different zirconia cores and veneering ceramics. AB - PURPOSE: Veneering porcelain might be delaminated from underlying zirconia-based ceramics. The aim of this study was the evaluation of the effect of different surface treatments and type of zirconia (white or colored) on shear bond strength (SBS) of zirconia core and its veneering porcelain. MATERIALS AND METHODS: Eighty zirconia disks (40 white and 40 colored; 10 mm in diameter and 4 mm thick) were treated with three different mechanical surface conditioning methods (Sandblasting with 110 um Al(2)O(3) particle, grinding, sandblasting and liner application). One group had received no treatment. These disks were veneered with 3 mm thick and 5 mm diameter Cercon Ceram Kiss porcelain and SBS test was conducted (cross-head speed = 1 mm/min). Two and one way ANOVA, Tukey's HSD Past hoc, and T-test were selected to analyzed the data (alpha=0.05). RESULTS: In this study, the factor of different types of zirconia ceramics (P=.462) had no significant effect on SBS, but the factors of different surface modification techniques (P=.005) and interaction effect (P=.018) had a significant effect on SBS. Within colored zirconia group, there were no significant differences in mean SBS among the four surface treatment subgroups (P=0.183). Within white zirconia group, "Ground group" exhibited a significantly lower SBS value than "as milled" or control (P=0.001) and liner (P=.05) groups. CONCLUSION: Type of zirconia did not have any effect on bond strength between zirconia core and veneer ceramic. Surface treatment had different effects on the SBS of the different zirconia types and grinding dramatically decreased the SBS of white zirconia-porcelain. PMID- 22259707 TI - A 5-year retrospective clinical study of the Dentium implants. AB - PURPOSE: The aim of this retrospective study was to evaluate cumulative survival rate (CSR) of Implantium implants followed for 5 years and association between risk factors and the CSR. MATERIALS AND METHODS: A total of two hundred forty nine Implantium Implants System (Dentium, Seoul, Korea) placed in ninety-five patients from 2004 to 2009 were investigated with several identified risk factors (sex, systemic disease, smoking, alchohol, reason of tooth loss, length, arch (maxilla or mandible), replace tooth type (incisor, canine, premolar or molar) Kennedy classification, prosthodontic type, prosthodontic design, opposite dentition, abutment type, occlusal material, occlusal unit, splint to tooth, cantilever, other surgery). Clinical examination (mobility, percussion, screw loosening, discomfort, etc.) and radiographic examination data were collected from patient records including all problems during follow-up period according to protocols described earlier. Life table analysis was undertaken to examine the CSR. Cox regression method was conducted to assess the association between potential risk factors and overall CSR. RESULTS: Five of 249 implants were failed. Four of these were lost before loading. The 5-year implant cumulative survival rate was 97.37%. Cox regression analysis demonstrated a significant predictive association between overall CSR and systemic disease, smoking, reason of tooth loss, arch, Kennedy classification and prosthodontic design (P<.05). The screw related complication was rare. Two abutment screw fractures were found. Another complications of prosthetic components were porcelain fracture, resin facing fracture and denture fracture (n=19). CONCLUSION: The 5-year CSR of Implantium implants was 97.37%. Implant survival may be dependent upon systemic disease, smoking reason of tooth loss, arch, Kennedy classification and prosthodontic design (P<.05). The presence of systemic diseases and combination of other surgical procedures may be associated with increased implant failure. PMID- 22259708 TI - Frenectomy for improvement of a problematic conventional maxillary complete denture in an elderly patient: a case report. AB - Maxillary labial and buccal frena are considered as normal anatomic structures in the oral cavity. However, they may exist intraorally as a thick broad fibrous attachment and/or become located near the crest of the residual ridge, thus interfering with proper denture border extension resulting in inferior denture stability, retention and overall patient satisfaction. This case report highlights the importance of clinical examination and treatment planning which may mandate preprosthetic surgery prior to fabrication of a new conventional complete denture. Adequate patient satisfaction with conventional complete dentures can be significantly increased after frenectomy. PMID- 22259709 TI - Analgesic effects of intrathecal curcumin in the rat formalin test. AB - BACKGROUND: Curcumin has been reported to have anti-inflammatory, antioxidant, antiviral, antifungal, antitumor, and antinociceptive activity when administered systemically. We investigated the analgesic efficacy of intrathecal curcumin in a rat model of inflammatory pain. METHODS: Male Sprague Dawley rats were prepared for intrathecal catheterization. Pain was evoked by injection of formalin solution (5%, 50 ul) into the hind paw. Curcumin doses of 62.5, 125, 250, and 500 ug were delivered through an intrathecal catheter to examine the flinching responses. The ED(50) values (half-maximal effective dose) with 95% confidence intervals of curcumin for both phases of the formalin test were calculated from the dose-response lines fitted by least-squares linear regression on a log scale. RESULTS: In rats with intrathecal administration of curcumin, the flinching responses were significantly decreased in both phases. The slope of the regression line was significantly different from zero only in phase 2, and the ED(50) value (95% confidence interval) of curcumin was 511.4 ug (23.5-1126.5). There was no apparent abnormal behavior following the administration of curcumin. CONCLUSIONS: Intrathecal administration of curcumin decreased inflammatory pain in rats, and further investigation to elucidate the precise mechanism of spinal action of curcumin is warranted. PMID- 22259710 TI - Enhancement of Antinociception by Co-administrations of Nefopam, Morphine, and Nimesulide in a Rat Model of Neuropathic Pain. AB - BACKGROUND: Neuropathic pain is a chronic pain due to disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Analgesic drugs combined can reduce pain intensity and side effects. Here, we studied the analgesic effect of nimesulide, nefopam, and morphine with different mechanisms of action alone and in combination with other drugs in chronic constriction injury (CCI) model of neuropathic pain. METHODS: Male Wistar rats (n = 8) weighing 150-200 g were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. Nimesulide (1.25, 2.5, and 5 mg/kg), nefopam (10, 20, and 30 mg/kg), and morphine (1, 3, and 5 mg/kg) were injected 30 minutes before surgery and continued daily to day 14 post-ligation. In the combination strategy, a nonanalgesic dose of drugs was used in combination such as nefopam + morphine, nefopam + nimesulide, and nimesulide + morphine. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were, respectively, used as pain behavioral tests. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post injury. RESULTS: Nefopam (30 mg/kg) and nimesulide (5 mg/kg) blocked mechanical and thermal allodynia; the analgesic effects of morphine (5 mg/kg) lasted for 7 days. Allodynia was completely inhibited in combination with nonanalgesic doses of nefopam (10 mg/kg), nimesulide (1.25 mg/kg), and morphine (3 mg/kg). CONCLUSIONS: It seems that analgesic drugs used in combination, could effectively reduce pain behavior with reduced adverse effects. PMID- 22259711 TI - Radiation safety and education in the applicants of the final test for the expert of pain medicine. AB - BACKGROUND: The C-arm fluoroscope is known as the most important equipment in pain interventions. This study was conducted to investigate the completion rate of education on radiation safety, the knowledge of radiation exposure, the use of radiation protection, and so on. METHODS: Unsigned questionnaires were collected from the 27 pain physicians who applied for the final test to become an expert in pain medicine in 2011. The survey was composed of 12 questions about the position of the hospital, the kind of hospital, the use of C-arm fluoroscopy, radiation safety education, knowledge of annual permissible radiation dose, use of radiation protection, and efforts to reduce radiation exposure. RESULTS: In this study, although most respondents (93%) had used C-arm fluoroscopy, only 33% of the physicians completed radiation safety education. Even though nine (33%) had received education on radiation safety, none of the physicians knew the annual permissible radiation dose. In comparing the radiation safety education group and the no-education group, the rate of wearing radiation-protective glasses or goggles and the use of radiation badges or dosimeters were significantly higher in the education group. However, in the use of other protective equipment, knowledge of radiation safety, and efforts to reduce radiation exposure, there were no statistical differences between the two groups. CONCLUSIONS: The respondents knew very little about radiation safety and had low interest in their radiation exposure. To make the use of fluoroscopy safer, additional education, as well as attention to and knowledge of practices of radiation safety are required for pain physicians. PMID- 22259712 TI - The Correlation between Caudal Epidurogram and Low Back Pain. AB - BACKGROUND: The common causes of lower back pain with or without leg pain includes disk disease and spinal stenosis. A definitive diagnosis is usually made by means of magnetic resonance imaging (MRI), but treatment is often difficult because the MRI findings are not consistent with the symptoms of the patient in many cases. The objective of this study was to observe the correlation between the patterns of epidurography performed in patients having lower back pain with or without leg pain and the position or severity of the pain as subjectively described by the patients. METHODS: The subjects of this study were 69 outpatients with lower back pain with or without leg pain who visited our clinic and complained of predominant pain on one side. We performed caudal epidural block using an image intensifier. A mixture of the therapeutic drug and the contrast agent (10 ml) was injected to observe the contrast flow pattern. The patients who complained of predominant pain on one side were divided into the left side group and the right side group. A judgment of inconsistency was made if the contrast agent flowed to the side of the pain, while a judgment of consistency was made if the contrast agent flowed to the opposite side of the pain. The degree of the drug distribution was evaluated by counting the number of cells to which the contrast agent's flowed for evaluating the correlation between the contrasted cell and the severity of pain (one group <= VAS 7, the other group >= VAS 8) the degree of the contrast agent's contrast was evaluated by dividing and counting an image into 15 cells (the left, right, and middle sections at each level of L4, L5, S1, S2, and S3). RESULTS: Thirty out of the 69 patients who had laterality in pain, that is, those who complained of predominant pain on one side, showed that the laterality of the pain and the contrast agent flow was consistent, while 39 patients showed that the laterality was inconsistent (P: 0.137). The evaluation of the correlation between the pain and the contrast agent flow showed that the mean number of contrasted cells was 9.0 +/- 2.2 for the 46 patients in the group with a VAS of 7 or lower and 6.5 +/- 2.0 for the 23 patients in the group with a VAS of 8 or higher, indicating that the former group showed a significantly greater number of contrasted cells (P < 0.001). CONCLUSIONS: This study, conducted with patients having lower back pain with or without leg pain, showed that the contrast flow pattern of caudal epidurography had a significant correlation with the severity of the pain but not with the laterality of the pain. PMID- 22259713 TI - Efficacy of glycopyrrolate in primary hyperhidrosis patients. AB - BACKGROUND: Primary hyperhidrosis is a disorder of excessive sweating, which shares several features with anxiety disorders and has a negative impact on a patient's quality of life. Oral glycopyrrolate is one of the treatments available. There are a few published studies on the use of glycopyrrolate given orally in the treatment of hyperhidrosis. METHODS: Thies is study was a review of case notes in a series of 36 patients with primary hyperhidrosis. We made a comparison between the Keller's scale score of a pre-glycopyrrolate medication group and the Keller's scale score f a post-glycopyrrolate medication group. The Milanez de Campos score, Short Form_36 (SF-36) score, Beck Depression Inventory (BDI) score, Beck Anxiety Inventory (BAI) score, and autonomic nervous system (ANS) scale score were also compared between the two groups. RESULTS: In the post glycopyrrolate medication group, there were declines in Keller's scale, and Milanez de Campos scale score and BAI score (P < 0.001). In addition, there were increases in SF_36 score in the post-glycopyrrolate medication group (P = 0.03) However, no changes were seen in, BDI score and ANS score in the post glycopyrrolate medication group (P < 0.001). CONCLUSIONS: Glycopyrrolate is an effective initial method of treating primary hyperhidrosis that, reduces anxiety and improve patients' quality of life. PMID- 22259714 TI - Ultrasound-guided Aspiration of the Iatrogenic Pneumothorax Caused by Paravertebral Block -A Case Report-. AB - Thoracic paravertebral block is performed for the treatment of patients with chronic pain, such as complex regional pain syndrome (CRPS) and post-herpetic neuralgia. Thoracic paravertebral block can result in iatrogenic pneumothorax. Because pneumothorax can develop into medical emergencies and needle aspiration or chest tube placement may be needed, early diagnosis is very important. Recently, thoracic ultrasonography has begun to be used to diagnose pneumothorax. In addition, ultrasound-guided aspiration can be an accurate and safe technique for treatment of pneumothorax, as the needle position can be followed in real time. We report a case of iatrogenic pneumothorax following thoracic paravertebral block for the treatment of chronic pain due to CRPS, treated successfully by ultrasound-guided aspiration. PMID- 22259715 TI - A new technique for inferior hypogastric plexus block: a coccygeal transverse approach -a case report-. AB - Chronic pelvic pain is a common problem with variable etiology. The sympathetic nervous system plays an important role in the transmission of visceral pain regardless of its etiology. Sympathetic nerve block is effective and safe for treatment of pelvic visceral pain. One of them, the inferior hypogastric plexus, is not easily assessable to blockade by local anesthetics and neurolytic agents. Inferior hypogastric plexus block is not commonly used in chronic pelvic pain patients due to pre-sacral location. Therefore, inferior hypogastric plexus is not readily blocked using paravertebral or transdiscal approaches. There is only one report of inferior hypogastric plexus block via transsacral approach. This approach has several disadvantages. In this case a favorable outcome was obtained by using coccygeal transverse approach of inferior hypogastric plexus. Thus, we report a patient who was successfully given inferior hypogastric plexus block via coccygeal transverse approach to treat chronic pelvic pain conditions involving the lower pelvic viscera. PMID- 22259716 TI - Unilateral, single needle approach using an epidural catheter for bilateral superior hypogastric plexus block. AB - The superior hypogastric plexus block (SHPB) is used for treating pelvic pain, especially in patients with gynecological malignancies. Various approaches to this procedure have been reported due to the anatomic obstacles of a high iliac crest or large transverse process of the 5(th) lumbar vertebra. Here, we report a new technique of superior hypogastric plexus block using a unilateral single needle approach to block the bilateral superior hypogastric plexus with a Tuohy needle and epidural catheter. We have confidence that this new technique can be another option in performing the SHPB when the conventional bilateral approach is difficult to perform. PMID- 22259717 TI - Catheter obstruction of intrathecal drug administration system -a case report-. AB - Intrathecal drug administration system (ITDAS) can reduce the side effects while increasing the effectiveness of opioids compared to systemic opioid administration. Therefore, the use of ITDAS has increased in the management of cancer pain and chronic intractable pain. Catheter obstruction is a serious complication of ITDAS. Here, we present a case of catheter obstruction by a mass formed at the side hole and in the lumen. A 37-year-old man suffering from failed back surgery syndrome received an ITDAS implantation, and the ITDAS was refilled with morphine every 3 months. When the patient visited the hospital 18 months after ITDAS implantation for a refill, the amount of delivered morphine sulfate was much less than expected. Movement of the pump rotor was examined with fluoroscopy; however, it was normal. CSF aspiration through the catheter access port was impossible. When the intrathecal catheter was removed, we observed that the side hole and lumen of the catheter was plugged. PMID- 22259718 TI - Treatment experience of pulsed radiofrequency under ultrasound guided to the trapezius muscle at myofascial pain syndrome -a case report-. AB - Trigger point injection treatment is an effective and widely applied treatment for myofascial pain syndrome. The trapezius muscle frequently causes myofascial pain in neck area. We herein report a case in which direct pulsed radiofrequency (RF) treatment was applied to the trapezius muscle. We observed that the RF treatment produced continuous pain relief when the effective duration of trigger point injection was temporary in myofascial pain. PMID- 22259719 TI - Clinical experiences of transforaminal balloon decompression for patients with spinal stenosis. AB - Lumbar spinal stenosis is a commonly treated with epidural injections of local anesthetics and corticosteroids, however, these therapies may relieve leg pain for weeks to months but do not influence functional status. Furthermore, the majority of patients report no substantial symptom change over the repeated treatment. Utilizing balloon catheters, we successfully treated with three patients who complained persistent symptoms despite repeated conventional steroid injections. Our results suggest that transforaminal decompression using a balloon catheter may have potential in the nonsurgical treatment of spinal stenosis by modifying the underlying pathophysiology. PMID- 22259720 TI - Pulsed radiofrequency lesioning of the axillary and suprascapular nerve in calcific tendinitis. AB - The patient was a 45-year-female who presented with pain at right shoulder and right upper arm. The patient suffered from right shoulder and arm pain for 3 years and had pain management which was performed using medication and conservative management after she had been diagnosed with calcific tendinitis. However, substantial pain relief was not consistently achieved, and recurrence of pain was reported. Therefore, we performed right axillary nerve and suprascapular nerve block through pulsed radiofrequency. Two months after the procedure, the shoulder pain gradually subsided with the size reduction of the calcified nodule and she needed no more pain management. PMID- 22259721 TI - Applicability of the ISO Reference Terminology Model for Nursing to the Detailed Clinical Models of Perinatal Care Nursing Assessments. AB - OBJECTIVES: The purpose of this study was to examine the applicability of the International Organization for Standardization (ISO) reference terminology model for nursing to describe the terminological value domain content regarding the entities and attributes of the detailed clinical models (DCMs) used for nursing assessments. METHODS: The first author mapped 52 DCM entities and 45 DCM attributes used for perinatal care nursing assessments to semantic domains and their qualifiers to the ISO model. The mapping results of the entity and attribute concepts were classified into four categories: mapped to a semantic domain qualifier, mapped to a semantic domain, mapped to a broader semantic domain concept, and not mapped. The DCM mapping results were classified into three categories: fully mapped, partially mapped, and not mapped. The second author verified the mapping. RESULTS: All of the entities and 53.3% of the attribute concepts of the DCMs were mapped to semantic domains or semantic domain qualifiers of the ISO model, 37.8% of the attributes were mapped to the broader semantic domain concept, and 8.9% of the attributes were not mapped. At the model level, 48.1% of the DCMs were fully mapped to semantic domains or semantic domain qualifiers of the ISO model, and 51.9% of the DCMs were partially mapped. CONCLUSIONS: The findings of this study demonstrate that the ISO reference terminology model for nursing is applicable in representing the DCM structure for perinatal care nursing assessment. However, more qualifiers of the Judgment semantic domain are required in order to clearly and fully represent all of the entities and attributes of the DCMs used for nursing assessment. PMID- 22259722 TI - The development of clinical document standards for semantic interoperability in china. AB - OBJECTIVES: This study is aimed at developing a set of data groups (DGs) to be employed as reusable building blocks for the construction of the eight most common clinical documents used in China's general hospitals in order to achieve their structural and semantic standardization. METHODS: The Diagnostics knowledge framework, the related approaches taken from the Health Level Seven (HL7), the Integrating the Healthcare Enterprise (IHE), and the Healthcare Information Technology Standards Panel (HITSP) and 1,487 original clinical records were considered together to form the DG architecture and data sets. The internal structure, content, and semantics of each DG were then defined by mapping each DG data set to a corresponding Clinical Document Architecture data element and matching each DG data set to the metadata in the Chinese National Health Data Dictionary. By using the DGs as reusable building blocks, standardized structures and semantics regarding the clinical documents for semantic interoperability were able to be constructed. RESULTS: Altogether, 5 header DGs, 48 section DGs, and 17 entry DGs were developed. Several issues regarding the DGs, including their internal structure, identifiers, data set names, definitions, length and format, data types, and value sets, were further defined. Standardized structures and semantics regarding the eight clinical documents were structured by the DGs. CONCLUSIONS: This approach of constructing clinical document standards using DGs is a feasible standard-driven solution useful in preparing documents possessing semantic interoperability among the disparate information systems in China. These standards need to be validated and refined through further study. PMID- 22259723 TI - The Development of a Graphical User Interface Engine for the Convenient Use of the HL7 Version 2.x Interface Engine. AB - OBJECTIVES: The Health Level Seven Interface Engine (HL7 IE), developed by Kyungpook National University, has been employed in health information systems, however users without a background in programming have reported difficulties in using it. Therefore, we developed a graphical user interface (GUI) engine to make the use of the HL7 IE more convenient. METHODS: The GUI engine was directly connected with the HL7 IE to handle the HL7 version 2.x messages. Furthermore, the information exchange rules (called the mapping data), represented by a conceptual graph in the GUI engine, were transformed into program objects that were made available to the HL7 IE; the mapping data were stored as binary files for reuse. The usefulness of the GUI engine was examined through information exchange tests between an HL7 version 2.x message and a health information database system. RESULTS: Users could easily create HL7 version 2.x messages by creating a conceptual graph through the GUI engine without requiring assistance from programmers. In addition, time could be saved when creating new information exchange rules by reusing the stored mapping data. CONCLUSIONS: The GUI engine was not able to incorporate information types (e.g., extensible markup language, XML) other than the HL7 version 2.x messages and the database, because it was designed exclusively for the HL7 IE protocol. However, in future work, by including additional parsers to manage XML-based information such as Continuity of Care Documents (CCD) and Continuity of Care Records (CCR), we plan to ensure that the GUI engine will be more widely accessible for the health field. PMID- 22259724 TI - A multi-classifier based guideline sentence classification system. AB - OBJECTIVES: An efficient clinical process guideline (CPG) modeling service was designed that uses an enhanced intelligent search protocol. The need for a search system arises from the requirement for CPG models to be able to adapt to dynamic patient contexts, allowing them to be updated based on new evidence that arises from medical guidelines and papers. METHODS: A sentence category classifier combined with the AdaBoost.M1 algorithm was used to evaluate the contribution of the CPG to the quality of the search mechanism. Three annotators each tagged 340 sentences hand-chosen from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) clinical guideline. The three annotators then carried out cross-validations of the tagged corpus. A transformation function is also used that extracts a predefined set of structural feature vectors determined by analyzing the sentential instance in terms of the underlying syntactic structures and phrase-level co-occurrences that lie beneath the surface of the lexical generation event. RESULTS: The additional sub filtering using a combination of multi-classifiers was found to be more effective than a single conventional Term Frequency-Inverse Document Frequency (TF-IDF) based search system in pinpointing the page containing or adjacent to the guideline information. CONCLUSIONS: We found that transformation has the advantage of exploiting the structural and underlying features which go unseen by the bag-of-words (BOW) model. We also realized that integrating a sentential classifier with a TF-IDF-based search engine enhances the search process by maximizing the probability of the automatically presented relevant information required in the context generated by the guideline authoring environment. PMID- 22259726 TI - Development of detailed clinical models for nursing assessments and nursing interventions. AB - OBJECTIVES: The aim of this study was to develop and validate Detailed Clinical Models (DCMs) for nursing assessments and interventions. METHODS: First, we identified the nursing assessment and nursing intervention entities. Second, we identified the attributes and the attribute values in order to describe the entities in more detail. The data type and optionality of the attributes were then defined. Third, the entities, attributes and value sets in the DCMs were mapped to the International Classification for Nursing Practice Version 2 concepts. Finally, the DCMs were validated by domain experts and applied to case reports. RESULTS: In total 481 DCMs, 429 DCMs for nursing assessments and 52 DCMs for nursing interventions, were developed and validated. The DCMs developed in this study were found to be sufficiently comprehensive in representing the clinical concepts of nursing assessments and interventions. CONCLUSIONS: The DCMs developed in this study can be used in electronic nursing records. These DCMs can be used to ensure the semantic interoperability of the nursing information documented in electronic nursing records. PMID- 22259725 TI - A Comparison of Intensive Care Unit Mortality Prediction Models through the Use of Data Mining Techniques. AB - OBJECTIVES: The intensive care environment generates a wealth of critical care data suited to developing a well-calibrated prediction tool. This study was done to develop an intensive care unit (ICU) mortality prediction model built on University of Kentucky Hospital (UKH)'s data and to assess whether the performance of various data mining techniques, such as the artificial neural network (ANN), support vector machine (SVM) and decision trees (DT), outperform the conventional logistic regression (LR) statistical model. METHODS: The models were built on ICU data collected regarding 38,474 admissions to the UKH between January 1998 and September 2007. The first 24 hours of the ICU admission data were used, including patient demographics, admission information, physiology data, chronic health items, and outcome information. RESULTS: Only 15 study variables were identified as significant for inclusion in the model development. The DT algorithm slightly outperformed (AUC, 0.892) the other data mining techniques, followed by the ANN (AUC, 0.874), and SVM (AUC, 0.876), compared to that of the APACHE III performance (AUC, 0.871). CONCLUSIONS: With fewer variables needed, the machine learning algorithms that we developed were proven to be as good as the conventional APACHE III prediction. PMID- 22259727 TI - An Analysis of the Correlation between Alopecia and Chief Complaints. AB - OBJECTIVES: In this study, we measured the extent of ten levels of classified symptoms by 300 (male and female) patients visiting the hair loss clinics of "S" hospitals in Gangbuk and Gangnam between January 2009 and June 2011 by analyzing the patients' chief complaints. METHODS: The method of measurement was based on a symptom questionnaire possessing 51 categories. Through the statistical analysis of data mining techniques, decision trees, and logistic regression, we derived a logistic regression model and decision tree model that improved both the response rate and significant hair loss-related characteristics of the questionnaire. RESULTS: The results of this study indicate that dry hair, seborrheic scalps and skin, tobacco and/or coffee addiction, anxiety, nausea, indigestion, and facial flushing correlate to hair loss. CONCLUSIONS: We anticipate that the subjective symptoms of hair loss can provide a foundation for preventing secondary diseases and provide clinical data information during the period of treatment. This can contribute to the improvement of patient satisfaction after customized treatment. PMID- 22259728 TI - U-health service for managing chronic disease: a case study on managing metabolic syndrome in a health center in South Korea. AB - OBJECTIVES: We were to analyze the effect of managing metabolic syndrome using a u-health service in a health center. METHODS: We collected biometric data from 316 subjects living in a county (gun) in South Korea before and after the introduction of uhealth services in 2010. Analysis was done by contingency table using SPSS and latent growth model using AMOS. RESULTS: We found that regional u health services affected instance of metabolic syndrome. Further, biometrics and health behavior improved. After six months of u-health services, the number of subjects with three or more factors for metabolic syndrome decreased by 62.5%; 63.3% of regular drinkers stopped drinking; 83.3% of subjects who rarely exercised began to exercise twice a week or more; and 60.9% of smokers stopped smoking. CONCLUSIONS: U-health services can change health behavior and biometrics to manage metabolic syndrome in rural areas. The usefulness of u-health services is discussed. PMID- 22259729 TI - The development of a korean drug dosing database. AB - OBJECTIVES: This report describes the development process of a drug dosing database for ethical drugs approved by the Korea Food & Drug Administration (KFDA). The goal of this study was to develop a computerized system that supports physicians' prescribing decisions, particularly in regards to medication dosing. METHODS: The advisory committee, comprised of doctors, pharmacists, and nurses from the Seoul National University Bundang Hospital, pharmacists familiar with drug databases, KFDA officials, and software developers from the BIT Computer Co. Ltd. analyzed approved KFDA drug dosing information, defined the fields and properties of the information structure, and designed a management program used to enter dosing information. The management program was developed using a web based system that allows multiple researchers to input drug dosing information in an organized manner. The whole process was improved by adding additional input fields and eliminating the unnecessary existing fields used when the dosing information was entered, resulting in an improved field structure. RESULTS: A total of 16,994 drugs sold in the Korean market in July 2009, excluding the exclusion criteria (e.g., radioactivity drugs, X-ray contrast medium), usage and dosing information were made into a database. CONCLUSIONS: The drug dosing database was successfully developed and the dosing information for new drugs can be continually maintained through the management mode. This database will be used to develop the drug utilization review standards and to provide appropriate dosing information. PMID- 22259730 TI - Potential use of antiproliferative factor as a targeting therapy in painful bladder syndrome/interstitial cystitis. PMID- 22259732 TI - Development and changes with age of detrusor overactivity in spontaneous hypertensive rats as observed by simultaneous registrations of intravesical and intraabdominal pressures. AB - PURPOSE: Overactive bladder is especially common in the elderly, although it is not regarded as a normal part of aging. Thus, we investigated how aging alters the cystometric and detrusor overactivity (DO) parameters and the density of nerve growth factor (NGF) in awake spontaneous hypertensive rats (SHRs) of different ages. METHODS: Three age groups of 12- (n=5), 17- (n=6), and 21- (n=6) week-old SHRs (Oriental Bio Inc.) were used. A catheter was implanted into the bladder to record the intravesical pressure (IVP), and a balloon-fitted catheter was positioned in the abdominal cavity to record the intraabdominal pressure (IAP). Of the IVP elevations above 2 cm H(2)O, DO was defined as a rise in IVP without a simultaneous change in IAP and was counted during the filling phase. We measured the expression of NGF in the bladders by enzyme-linked immunosorbent assay. RESULTS: Both the body and bladder weights significantly increased with age, but the normalized ratio between those was not changed. As for DO, none of the12-week-old rats showed DO, whereas the other groups did. DO increased significantly with age (P=0.0045 by Mantel-Haenszel trend test), although no significant differences were found in DO frequency or pressure between the 17- and 21-week-old age groups. NGF did not show any significant differences among the three groups. CONCLUSIONS: Our results showed that SHRs begin to shows DO after a certain age, such as 12 weeks of age, and that the occurrence of DO has a close relationship with aging. However, NGF, which is known to be increased in the bladder wall of patients with overactive bladder, did not show any relationship with aging in this study. PMID- 22259731 TI - Antiproliferative factor signaling and interstitial cystitis/painful bladder syndrome. AB - A unique glycopeptide, antiproliferative factor (APF), has been suggested as a urinary biomarker and potential mediator of long-term bladder disorder Interstitial Cystitis/Painful Bladder Syndrome. There is no known cause for this disease. Several mechanistic approaches have been employed to address the underlying mechanism whereby APF regulates cellular responses in the bladder epithelium. A summary of recent literature is provided, and is focused on signal transduction pathways and networks that are responsive to APF. PMID- 22259733 TI - Effects of Spinal and Peripheral Injection of alpha1A or alpha1D Adrenoceptor Antagonists on Bladder Activity in Rat Models with or without Bladder Outlet Obstruction. AB - PURPOSE: Antagonists of alpha1-adrenergic receptors (alpha1ARs) relax prostate smooth muscle and relieve voiding and storage symptoms. Recently, increased expression of alpha1ARs with change of its subtype expression has been proved in bladder outlet obstruction (BOO). To search for the evidence of changes in alpha1ARs subtype expression and activity in the peripheral and spinal routes, the effects of spinal and peripheral administration of tamsulosin (an alpha1A/D selective AR), naftopidil (an alpha1A/D-selective AR), and doxazosin (non selective AR) on bladder activity were investigated in a rat model with or without BOO. METHODS: A total of 65 female Sprague-Dawley rats were divided into the BOO surgery group (n=47) and the sham surgery group (n=18). After 6 weeks, cystometry was assessed before and after intrathecal and intra-arterial administrations of tamsulosin, naftopidil, and doxazosin. RESULTS: After intra arterial administrations of all three drugs, bladder capacity (BC) was increased and maximal intravesical pressure (Pmax) was decreased in both BOO and the sham rat models (P<0.05). After intrathecal administration of all three drugs, BC was increased and Pmax was decreased in only the BOO group. The episodes of involuntary contraction in the BOO rat models were decreased by intra-arterial administration (P=0.031). The increase of BC after intrathercal and intra arterial administrations of alpha1ARs was significantly greater in the BOO group than in the sham group (P=0.023, P=0.041). In the BOO group, the increase of BC and decrease in Pmax were greater by intra-arterial administration than by intrathecal administration (P=0.035). There were no significant differences of the degrees of changes in the cystometric parameters among the three different alpha1ARs. CONCLUSIONS: Up-regulations of the alpha1ARs in BOO were observed by the greater increases of BC after alpha1AR antagonist administrations in the BOO group than in the sham group. However, there were no subtype differences of the alpha1ARs in functional parameters of bladder activity. In addition, alpha1ARs also act on the lumbosacral cord which implies that the sensitivity of alpha1ARs is increased in pathologic models such as BOO. Further evaluation including differential expression of alpha1ARs in BOO models are need. PMID- 22259734 TI - The prevalence and therapeutic effect of constipation in pediatric overactive bladder. AB - PURPOSE: Overactive bladder (OAB) is a manifestation of urgency, regardless of urge incontinence, due to involuntary bladder contraction during the storage period. There is a close association between constipation and OAB, but constipation cannot be readily diagnosed. The aims of this study were to evaluate the prevalence of constipation in OAB and the consequent therapeutic effects according to the diagnostic criteria for constipation. METHODS: We collected clinical data from 40 children (mean age, 71+/-22 months) with chief complaints of urgency, frequency, and incontinence. A voiding questionnaire and a 2-day voiding diary were collected, and urinalysis, the Bristol stool scale, and plain abdominal radiography were performed. Constipation was defined as conditions satisfying at least one of the following criteria: Rome III diagnostic criteria, Bristol stool scale types I/II, or a Leech score higher than 8 points as determined by plain radiography. Lower urinary tract symptoms, defecation symptoms, and the bladder volume of patients were examined, and the therapeutic outcomes by constipation diagnostic criteria were evaluated. RESULTS: Of the 40 OAB patients, 25 had constipation. Among them, 6 had reduced functional bladder capacity (24%; P>0.05). Regarding treatment, in patients who satisfied only one diagnostic criterion, the symptoms improved in 76.9%, 76.9%, and 69.6% of patients meeting the Rome III criteria, Bristol stool scale, and Leech score, respectively (P<0.05). Among the 8 patients satisfying all three criteria, 75% responded to treatment (P<0.05). CONCLUSIONS: The prevalence of constipation in OAB is high. Constipated patients recruited by use of the Rome III criteria, Bristol scale, and Leech score alone and together showed similar outcomes on OAB improvement after the treatment of constipation, which implies that each criterion has the same strength and can be applied comprehensively and generally. PMID- 22259735 TI - Clinical factors associated with low valsalva leak point pressure among women with stress urinary incontinence. AB - PURPOSE: The purpose of this study is to determine the predictive factors that are associated with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD) in women. METHODS: Between January 2008 and December 2009, 185 women with urodynamically proven SUI were included in this study and retrospectively reviewed the medical record. Preoperative SUI symptoms were classified by Stamey grade. Valsalva leak point pressure (VLPP) determination series was repeated two times in each subject after finishing one series of VLPP measurement. The patients were classified into three groups according to VLPP; 1) ISD: VLPP<=60 cm H(2)O, 2) equivocal: 6090 cm H(2)O. Chi-square test and multivariate (logistic regression test) analyses were performed to determine the factors associated with ISD. RESULTS: The mean patient age was 54.2 years (range, 44.5 to 68.4 years). Seventy-one women (38.3%) were in the ISD group and 70 (37.8%) in the AI group. The results of univariate and multivariate analyses found that women with ISD had a higher symptom grade than women with AI (P=0.001 and 0.0001, respectively). The number of patients in the ISD and AI group in accordance with the symptom grade were 7 (10%) and 44 (62%) in grade I, 50 (54%) and 23 (25%) in grade II, and 14 (63%) and 3 (14%) in grade III respectively. There was no correlation between VLPP and other clinical factors. CONCLUSIONS: High symptom grade was the only independent clinical factor that predicted the presence of ISD. This should be considered when counseling the patients with SUI. PMID- 22259736 TI - Analysis of prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors from the urology department and other departments. AB - PURPOSE: We analyzed the prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors (PDE5Is) in the urology department as well as in other departments of the general hospital. METHODS: We investigated the frequency of prescription of alpha-blockers and PDE5Is from 3 general hospitals from January 1, 2007 to December 31, 2009. For alpha-blockers, data were collected from patients to whom alpha-blockers were prescribed from among patients recorded as having benign prostatic hyperplasia according to the 5th Korean Standard Classification of Diseases. For PDE5Is, data were collected from patients to whom PDE5Is were prescribed by the urology department and by other departments. Alpha-blockers were classified into tamsulosin, alfuzosin, doxazosin, and terazosin, whereas PDE5Is were classified into sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil. RESULTS: Alpha-blockers were prescribed to 11,436 patients in total over 3 years, and the total frequency of prescriptions was 68,565. Among other departments, the nephrology department had the highest frequency of prescription of 3,225 (4.7%), followed by the cardiology (3,101, 4.5%), neurology (2,576, 3.8%), endocrinology (2,400, 3.5%), pulmonology (1,102, 1.6%), and family medicine (915, 1.3%) departments in order. PDE5Is were prescribed to 2,854 patients in total over 3 years, and the total frequency of prescriptions was 10,558. The prescription frequency from the urology department was 4,900 (46.4%). Among other departments, the endocrinology department showed the highest prescription frequency of 3,488 (33.0%), followed by the neurology (542, 5.1%), cardiology (467, 4.4%), and family medicine (407, 3.9%) departments in order. CONCLUSIONS: A high percentage of prescriptions of alpha-blockers and PDE5Is were from other departments. For more specialized medical care by urologists is required in the treatment of lower urinary tract symptoms and erectile dysfunction. PMID- 22259737 TI - Continence rate and oncological feasibility after total transurethral resection of the prostate as an alternative therapy for the treatment of prostate cancer: a pilot study. AB - PURPOSE: The value of total transurethral resection of prostate cancer (TURPC) as an alternative therapy was first recognized by Hans J. Reuter. Thus, we conducted the study of prospectively collected data to verify total TURPC as an alternative therapy forlocalized prostate cancer. METHODS: From January 2008 to July 2011, 14 patients with a mean age of 76.1 years (range, 66 to 89 years) with clinically localized prostate cancer were treated by prostatic resection by the corresponding author with curative intention. RESULTS: The mean duration of TURPC was 51.7 minutes (range, 30 to 120 minutes) and the mean amount of prostatic tissue resected was 21.2 g (range, 5 to 66 g). An intra- and/or postoperative blood transfusion was necessary in 2 cases. Hyponatremia was found in 7 patients. Six months after TURPC, 3 cases of grade 1 and 1 case of grade 2 incontinence were observed. Three patients in the high-risk group did not achieve a prostate specific antigen (PSA) nadir of <=0.2 ng/mL. PSA recurrence occurred in one case in our series. Newly developed lymph node or distant metastases were not observed during the follow-up period. CONCLUSIONS: According to our results, transurethral resection for prostate cancer can be performed with reasonable oncological results. The PSA nadir levels, and rates of biochemical failure and postoperative complications, including incontinence, were comparable with the published results for other procedures. TURPC is also inexpensive and non-invasive, and requires short hospitalization and a short surgical time without vesicourethral anastomosis. PMID- 22259738 TI - Concomitant laparoendoscopic single-site surgery for vesicolithotomy and finger assisted single-port transvesical enucleation of the prostate. AB - Transurethral resection of the prostate is the most common surgery for benign prostatic hyperplasia. However, it doesn't work best for men with very large prostate and bladder stones. Herein we report our initial experience with concomitant laparoendoscopic single-site surgery and finger-assisted single-port transvesical enucleation of the prostate for the treatment of the condition. PMID- 22259739 TI - Clinical characteristics of ischemic colitis according to the localization. PMID- 22259740 TI - How to treat retrorectal cysts or tumors in adult. PMID- 22259741 TI - Optimal treatment of symptomatic hemorrhoids. AB - Hemorrhoids are the most common anorectal complaint, and approximately 10 to 20 percent of patients with symptomatic hemorrhoids require surgery. Symptoms of hemorrhoids, such as painless rectal bleeding, tissue protrusion and mucous discharge, vary. The traditional therapeutic strategies of medicine include surgical, as well as non-surgical, treatment. To alleviate symptoms caused by hemorrhoids, oral treatments, such as fiber, suppositories and Sitz baths have been applied to patients. Other non-surgical treatments, such as infrared photocoagulation, injection sclerotherapy and rubber band ligation have been used to fixate the hemorrhoid's cushion. If non-surgical treatment has no effect, surgical treatments, such as a hemorrhoidectomy, procedure for prolapsed hemorrhoids, and transanal hemorrhoidal dearterialization are used. PMID- 22259742 TI - Clinical characteristics of ischemic colitis according to location. AB - PURPOSE: The aim of this study was to analyze various clinical characteristics of ischemic colitis according to its location. METHODS: The medical records of 92 cases of gastrointestinal ischemic colitis (IC) diagnosed at Bundang CHA Hospital from 1995 to 2008 were reviewed and analyzed retrospectively. The patients were diagnosed by using colonoscopic biopsies or laparotomy findings. The patients were divided into two groups, right and left, according to the main involvement area of the IC at the embryologic boundary line of the distal transverse colon, and the two groups were compared as to clinical characteristics and co-morbid diseases. RESULTS: Left IC was present in 59 patients (64.1%) and right IC in 33 patients (35.9%). No differences between the two groups in terms of clinical characteristics, cardiovascular disease and diabetes mellitus were observed. However, in 16 cases with renal failure, 10 patient had right IC and 6 patients had left IC, and this difference had statistical significance (P = 0.014). Among the 16, the 11 patients requiring hemodialysis included 8 with right IC (24.2%) and 3 with left IC (5.1%; P = 0.009). Among the 19 cases of severe IC requiring surgical treatment or involving mortality, irrespective of surgery, 11 patients showed right IC and 8 patients showed left IC (P = 0.024). CONCLUSION: Right-side ischemic colitis was significantly associated with renal failure and disease severity, so patients with right-side colon ischemia should be more carefully observed and managed. PMID- 22259743 TI - Single-incision Laparoscopic Surgery for Appendiceal Mucoceles: Safety and Feasibility in a Series of 16 Consecutive Cases. AB - PURPOSE: The aim of this study was to evaluate the technical feasibility, safety, and oncological outcomes of transumbilical single-incision laparoscopic surgery in patients with an uncomplicated appendiceal mucocele. METHODS: A review of a prospectively collected database at the Kyungpook National University Hospital from January 2006 to September 2010 revealed that a series of 16 consecutive patients underwent single-incision laparoscopic surgery (SILS) for an appendiceal mucocele. Data regarding patient demographics, operating time, conversion, surgical morbidity, lateral lymph node status, and mid-term oncologic result were analyzed. RESULTS: The reported series consisted of 7 women (50%) and 9 men with a mean age of 61.6 years (range, 41 to 88 years). The mean operative time was 66.8 minutes (range, 33 to 150 minutes). Perioperative mortality and morbidity were 0% and 6.2%, respectively. Recovery after the procedure was rapid, and the mean hospital stay was 6.8 days (range, 3 to 22 days). Pathology revealed 12 lesions compatible with a mucinous cystadenoma and four others compatible with benign cystic tumors. All surgical margins were clear. In one case, an extra port had to be placed, and another case required conversion from SILS to a standard open laparotomy immediately after identification of the tumor because of a micro perforation with focal mucin collection. With a median follow-up of 28.7 months, no re-admission or tumor recurrence, such as pseudomyxoma peritonei, was noted in 14 patients. CONCLUSION: A single-port laparoscopic mucocelectomy should be safe and feasible and has the advantage of being a minimally invasive approach. Prospective controlled studies comparing SILS and conventional open surgery, with long-term follow-up evaluation, are needed to confirm the author's initial experience. PMID- 22259744 TI - A Clinical Comparison of Laparoscopic versus Open Appendectomy for Complicated Appendicitis. AB - PURPOSE: Although laparoscopic appendectomies (LAs) are performed universally, a controversy still exists whether the LA is an appropriate surgical approach to complicated appendicitis (CA). We retrospectively evaluated the outcomes of laparoscopic versus open appendectomies for CA. METHODS: We retrospectively analyzed 60 consecutive patients who were diagnosed as having CA from July 2009 to January 2011. Outcomes such as operative time, time to soft diet, length of hospital stay, and postoperative complications were analyzed. RESULTS: There were no statistically significant differences in operative time between the LA and the open appendectomy (OA) groups. Return to soft diet was faster in the LA group (2.1 +/- 1.2 vs. 3.5 +/- 1.5 days; P = 0.001). Length of hospital stay was shorter for the LA group (4.4 +/- 2.3 vs. 5.8 +/- 2.9 days; P = 0.045). The overall complication rates showed no statistically significant difference between the two groups. In cases involving a periappendiceal abscess, the LA had a significantly higher incidence of intra-abdominal abscess (IAA) and postoperative ileus (PI; P = 0.028). CONCLUSION: The LA showed good results in terms of the time to soft diet, the length of hospital stay, and surgical site infection (SSI) whereas the overall complication rates were similar for the two groups. However, the LA was associated with significantly higher incidence of IAA and PI for the cases with a periappendiceal abscess. Therefore, when using a LA, the surgeon must take great care to minimize the incidence of IAA and PI if a periappendiceal abscess is present. PMID- 22259745 TI - One Year Follow-up Result of Doppler-guided Hemorrhoidal Artery Ligation and Recto-Anal Repair in 97 Consecutive Patients. AB - PURPOSE: Doppler-guided hemorrhoidal artery ligation and recto-anal repair (DG HAL & RAR) is known for low recurrence, high patient satisfaction, and less postoperative pain. The purpose of this study is to analyze the 1-year follow-up results in patients who underwent a DG-HAL & RAR and to establish the benefits of the procedure. METHODS: Among the hemorrhoid patients who were admitted to our hospital from March 2008 to May 2010 and who underwent a DG-HAL & RAR, 97 patients who were followed up for a year were investigated. Recurrence, complications, admission period, difference in preoperative and postoperative pain, operation time, and time to return to daily activities were investigated. RESULTS: The average admission period was 1.6 +/- 1.1 days. Pain at postoperative day 7 showed no significant difference from preoperative pain (P > 0.05). The operation time was 34.0 +/- 7.3 minutes on average, and return to daily activities was timed at 2.3 +/- 2.0 days postoperatively. At the one year follow up, no serious complications were noted, and preoperative symptoms recurred only in 14 patients (14.4%). CONCLUSION: In most patients with hemorrhoids, excluding those with severe prolapsed hemorrhoids, less pain, no serious complications, and good long-term outcome can be expected from a DG-HAL & RAR. PMID- 22259746 TI - Clinical Study and Review of Articles (Korean) about Retrorectal Developmental Cysts in Adults. AB - PURPOSE: A retrorectal developmental cyst (tailgut cyst, epidermoid cyst, dermoid cyst, teratoma, and duplication) is very rare disease, and the symptoms are not characteristic so that sometimes this disease is still misdiagnosed as a supralevator abscess or a complex anal fistula. We would like to present a clinical approach to this disease. METHODS: We retrospectively examined the charts of 15 patients who were treated for retrorectal cysts from January 2001 to November 2009. RESULTS: All 15 patients were female. The average age was 41 years (range, 21 to 60 years). Fourteen patients (93.3%) were symptomatic, and the most common symptom was anal pain or discomfort. Nine patients (60%) had more than one previous operation (range, 1 to 9 times) for a supralevator abscess, an anal fistula, etc. In 12 patients (80%), the diagnosis could be made by using the medical history and physical examination. Thirteen cysts (80%) were excised completely through the posterior approach. The average diameter of the cysts was 4.8 cm (range, 2 to 10 cm). Pathologic diagnoses were 8 tailgut cysts (53.3%), 5 epidermoid cysts (33.3%) and 2 dermoid cysts (13.3%). The average follow-up period was 18.3 months (range, 1 to 64 months). CONCLUSION: In our experience, high suspicion and physical examination are the most important diagnostic methods. If a female patient has a history of multiple perianal operations, a retrorectal bulging soft mass, a posterior anal dimple, and no conventional creamy foul odorous pus in drainage, the possibility of a retrorectal developmental cyst must be considered. PMID- 22259747 TI - Risk factors of early postoperative small bowel obstruction following a proctectomy for rectal cancer. AB - PURPOSE: Postoperative small bowel obstruction is a common and serious complication following a proctectomy, and early postoperative small bowel obstruction (EPSBO) leads to longer hospital stays, delays chemotherapy in advanced cases, and may be a contributor to mortality. The goal of this study is to identify the risk factors of EPSBO after a proctectomy for rectal cancer, thereby seeking to reduce the incidence of EPSBO. METHODS: Patients (735) who underwent a proctectomy for rectal cancer between March 2005 and February 2010 were entered into this study, and data were collected prospectively. Patients were judged to have EPSBO if, within the first 30 days, they presented symptoms such as nausea, vomiting and abdominal distention lasting for 2 days, and radiologic finding of small bowel obstruction after evidence of return of small bowel motility. The association between EPSBO and patients and surgery-related variables were studied by using univariate and multivariate analyses. RESULTS: EPSBO developed in 47 cases (6.4%) and was the most frequently occurring complication in the early perioperative period following a proctectomy. The frequency of EPSBO according to operative variables shows that EPSBO developed in 3.0% of the patients who underwent laparoscopic surgery (LS) compared with 8.4% of the patients who underwent open surgery (OS) (P = 0.004). OS (odds ratio [OR], 2.5) and a previous laparotomy (OR, 2.3) were independent risk factors for the development of EPSBO after a proctectomy for rectal cancer. CONCLUSION: EPSBO is more likely to occur in patients who undergo OS or who have had a previous laparotomy. LS may be considered as a surgical procedure that can reduce the risk of EPSBO in patients undergoing a proctectomy for rectal cancer. PMID- 22259749 TI - A case of successful colonoscopic treatment of acute appendiceal bleeding by endoclips. AB - Lower gastrointestinal bleeding is a common disease among elderly patients. The common sources of lower gastrointestinal bleeding include vascular disease, Crohn's disease, neoplasm, inflammatory bowel disease, hemorrhoid, and ischemic colitis. However, bleeding from the appendix has been reported very rarely in patients with lower gastrointestinal tract bleeding. In general, after a colonoscopic diagnosis of appendiceal bleeding, a laparoscopic or surgical appendectomy would be recommended. We report a case of successful colonoscopic treatment of appendiceal bleeding without complications by endoclips. This report suggests that colonoscopic clipping is a safe and effective means to treat bleeding from appendiceal lesions. Further study is needed to evaluate procedure related complications and to confirm the procedure's safety and efficacy. PMID- 22259748 TI - Effectiveness of Adjuvant Chemotherapy with 5-FU/Leucovorin and Prognosis in Stage II Colon Cancer. AB - PURPOSE: The aims of this study were to investigate the survival results and the prognostic factors of adjuvant chemotherapy in stage II colon cancer in the sparsity of Korean data. METHODS: From 1993 to 2006, 363 curatively resected pathologic stage II colon cancer patients were enrolled. Six cycles of adjuvant chemotherapy was performed: intravenous bolus 5-fluorouracil (5-FU) 500 mg/m(2) with leucovorin 20 mg/m2 for 2 hours daily for 5 days, followed by a 3-week resting period (n = 308). Fifty-five patients received only curative surgery. A high risk of recurrence was defined as the presence of one or more of the following factors: T4 tumor, lympho-vascular invasion, perineural invasion, perforation, obstruction, retrieved lymph node < 12, and poorly differention. The median follow-up period was 68 months (1 to 205 months). RESULTS: The five-year overall survival (OS) rate was 90.1%, and the five-year disease-free survival (DFS) rate was 84.7%. Among high-risk patients, the OS and the DFS rates of the treatment group were significantly higher than those of the non-treatment group (OS: 90.6% vs. 69.1%, P < 0.0001; DFS: 85.9% vs. 54.1%, P < 0.0001). Among low risk patients, the survival results of the treatment group were also significantly superior (OS: 97.7% vs. 88.2%, P < 0.0001; DFS: 93.0% vs. 80.0%, P = 0.001). In the multivariate analysis, adjuvant chemotherapy was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.41; 95% confidence interval, 0.22 to 0.75; P = 0.004). CONCLUSION: In our population, adjuvant chemotherapy showed superior survival to curative surgery alone and significantly reduced the risk of death. A nationwide multicenter randomized trial is needed. PMID- 22259750 TI - From the bench to the bedside: Genetics of intellectual disability, Gustatopic mapping, Molecular origins of oligodendrogliomas, Back pain and the brain, and more.... PMID- 22259751 TI - Neurosurgery concepts. PMID- 22259752 TI - Development and Implementation of an Academic-Community Partnership to Enhance Care among Homeless Persons. AB - An academic-community partnership between a Health Care for the Homeless (HCH) clinic and a school of pharmacy was created in 2005 to provide medication education and identify medication related problems. The urban community based HCH clinic in the Richmond, VA area provides primary health care to the homeless, uninsured and underinsured. The center also offers eye care, dental care, mental health and psychiatric care, substance abuse services, case management, laundry and shower facilities, and mail services at no charge to those in need. Pharmacist services are provided in the mental health and medical clinics. A satisfaction survey showed that the providers and staff (n = 13) in the clinic were very satisfied with the integration of pharmacist services. The quality and safety of medication use has improved as a result of the academic-community collaborative. Education and research initiatives have also resulted from the collaborative. This manuscript describes the implementation, outcomes and benefits of the partnership for both the HCH clinic and the school of pharmacy. PMID- 22259754 TI - Nonconservative current-induced forces: A physical interpretation. AB - We give a physical interpretation of the recently demonstrated nonconservative nature of interatomic forces in current-carrying nanostructures. We start from the analytical expression for the curl of these forces, and evaluate it for a point defect in a current-carrying system. We obtain a general definition of the capacity of electrical current flow to exert a nonconservative force, and thus do net work around closed paths, by a formal noninvasive test procedure. Second, we show that the gain in atomic kinetic energy over time, generated by nonconservative current-induced forces, is equivalent to the uncompensated stimulated emission of directional phonons. This connection with electron-phonon interactions quantifies explicitly the intuitive notion that nonconservative forces work by angular momentum transfer. PMID- 22259753 TI - Optical properties of fully conjugated cyclo[n]thiophenes - An experimental and theoretical approach. AB - Optical properties of two series of fully conjugated cyclo[n]thiophenes were analyzed experimentally and theoretically. The absorption spectra reveal a shift to higher wavelengths with increasing size of the cycles, which can be successfully described by an excitonic approach based on a Frenkel exciton Hamiltonian. Furthermore, intriguing new bands in the absorption and fluorescence spectra of the smaller macrocycles disclose the dominance of their ring strain. PMID- 22259756 TI - Lifetime analysis of individual-atom contacts and crossover to geometric-shell structures in unstrained silver nanowires. AB - We study the crossover of quantum point contacts from (i) individual-atom contacts to (ii) electronic-shell effects and finally to (iii) geometric-shell effects in electrochemically deposited silver contacts. The method allows the fabrication of mechanically unstrained structures, which is a requirement for determining the individual atomic configuration by means of a detailed lifetime analysis of their conductance. Within the geometric-shell model, the sequence of conductance maxima is explained quantitatively based on the crystal structure data of silver, and the growth mechanism of the nanowires is discussed. PMID- 22259755 TI - Generation and agglomeration behaviour of size-selected sub-nm iron clusters as catalysts for the growth of carbon nanotubes. AB - Mass-selected, ligand-free Fe(N) clusters with N = 10-30 atoms (cluster diameter: 0.6-0.9 nm) were implanted into [Al@SiO(x)] surfaces at a low surface coverage corresponding to a few thousandths up to a few hundredths of a monolayer in order to avoid initial cluster agglomeration. These studies are aimed towards gaining an insight into the lower limit of the size regime of carbon nanotube (CNT) growth by employing size-selected sub-nm iron clusters as catalyst or precatalyst precursors for CNT growth. Agglomeration of sub-nm iron clusters to iron nanoparticles with a median size range between three and six nanometres and the CNT formation hence can be observed at CVD growth temperatures of 750 degrees C. Below 600 degrees C, no CNT growth is observed. PMID- 22259757 TI - Towards quantitative accuracy in first-principles transport calculations: The GW method applied to alkane/gold junctions. AB - The calculation of the electronic conductance of nanoscale junctions from first principles is a long-standing problem in the field of charge transport. Here we demonstrate excellent agreement with experiments for the transport properties of the gold/alkanediamine benchmark system when electron-electron interactions are described by the many-body GW approximation. The conductance follows an exponential length dependence: G(n) = G(c) exp(-betan). The main difference from standard density functional theory (DFT) calculations is a significant reduction of the contact conductance, G(c), due to an improved alignment of the molecular energy levels with the metal Fermi energy. The molecular orbitals involved in the tunneling process comprise states delocalized over the carbon backbone and states localized on the amine end groups. We find that dynamic screening effects renormalize the two types of states in qualitatively different ways when the molecule is inserted in the junction. Consequently, the GW transport results cannot be mimicked by DFT calculations employing a simple scissors operator. PMID- 22259758 TI - Effect of the environment on the electrical conductance of the single benzene-1,4 diamine molecule junction. AB - We investigated the effect of the environment on the electrical conductance of a single benzene-1,4-diamine (BDA) molecule bridging Au electrodes, using the scanning tunneling microscope (STM). The conductance of the single BDA molecule junction decreased upon a change in the environment from tetraglyme, to mesitylene, to water, and finally to N(2) gas, while the spread in the conductance value increased. The order of the conductance values of the single BDA molecule junction was explained by the strength of the interaction between the solvent molecules and the Au electrodes. The order of the spread in the conductance values was explained by the diversity in the coverage of the BDA molecule at metal electrodes and atomic and molecular motion of the single molecule junction. PMID- 22259759 TI - Approaches to nanostructure control and functionalizations of polymer@silica hybrid nanograss generated by biomimetic silica mineralization on a self assembled polyamine layer. AB - We report the rational control of the nanostructure and surface morphology of a polyamine@silica nanoribbon-based hybrid nanograss film, which was generated by performing a biomimetic silica mineralization reaction on a nanostructured linear polyethyleneimine (LPEI) layer preorganized on the inner wall of a glass tube. We found that the film thickness, size and density of the nanoribbons and the aggregation/orientation of the nanoribbons in the film were facile to tune by simple adjustment of the biomimetic silicification conditions and LPEI self assembly on the substrate. Our LPEI-mediated nanograss process allows the facile and programmable generation of a wide range of nanostructures and surface morphologies without the need for complex molecular design or tedious techniques. This ribbon-based nanograss has characteristics of a LPEI@silica hybrid structure, suggesting that LPEI, as a polymeric secondary amine, is available for subsequent chemical reaction. This feature was exploited to functionalize the nanograss film with three representative species, namely porphyrin, Au nanoparticles and titania. Of particular note, the novel silica@titania composite nanograss surface demonstrated the ability to convert its wetting behavior between the extreme states (superhydrophobic-superhydrophilic) by surface hydrophobic treatment and UV irradiation. The anatase titania component in the nanograss film acts as a highly efficient photocatalyst for the decomposition of the low-surface-energy organic components attached to the nanosurface. The ease with which the nanostructure can be controlled and facilely functionalized makes our nanograss potentially important for device-based application in microfluidic, microreactor and biomedical fields. PMID- 22259760 TI - Micro- and mesoporous solids: From science to application. PMID- 22259761 TI - Template-assisted formation of microsized nanocrystalline CeO(2) tubes and their catalytic performance in the carboxylation of methanol. AB - Polymethylmethacrylate (PMMA)/ceria composite fibres were synthesized by using a sequential combination of polymer electrospinning, spray-coating with a sol, and a final calcination step to yield microstructured ceria tubes, which are composed of nanocrystalline ceria particles. The PMMA template is removed from the organic/inorganic hybrid material by radio frequency (rf) plasma etching followed by calcination of the ceramic green-body fibres. Microsized ceria (CeO(2)) tubes, with a diameter of ca. 0.75 um, composed of nanocrystalline agglomerated ceria particles were thus obtained. The 1-D ceramic ceria material was characterized by X-ray diffraction, scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), UV-vis and photoluminescence spectroscopy (PL), as well as thermogravimetric analysis (TGA). Its catalytic performance was studied in the direct carboxylation of methanol with carbon dioxide leading to dimethyl carbonate [(CH(3)O)(2)CO, DMC], which is widely employed as a phosgene and dimethyl sulfate substitute, and as well as a fuel additive. PMID- 22259762 TI - Synthesis and catalytic applications of combined zeolitic/mesoporous materials. AB - In the last decade, research concerning nanoporous siliceous materials has been focused on mesoporous materials with intrinsic zeolitic features. These materials are thought to be superior, because they are able to combine (i) the enhanced diffusion and accessibility for larger molecules and viscous fluids typical of mesoporous materials with (ii) the remarkable stability, catalytic activity and selectivity of zeolites. This review gives an overview of the state of the art concerning combined zeolitic/mesoporous materials. Focus is put on the synthesis and the applications of the combined zeolitic/mesoporous materials. The different synthesis approaches and formation mechanisms leading to these materials are comprehensively discussed and compared. Moreover, Ti-containing nanoporous materials as redox catalysts are discussed to illustrate a potential implementation of combined zeolitic/mesoporous materials. PMID- 22259763 TI - STM study on the self-assembly of oligothiophene-based organic semiconductors. AB - The self-assembly properties of a series of functionalized regioregular oligo(3 alkylthiophenes) were investigated by using scanning tunneling microscopy (STM) at the liquid-solid interface under ambient conditions. The characteristics of the 2-D crystals formed on the (0001) plane of highly ordered pyrolitic graphite (HOPG) strongly depend on the length of the pi-conjugated oligomer backbone, on the functional groups attached to it, and on the alkyl substitution pattern on the individual thiophene units. Theoretical calculations were performed to analyze the geometry and electronic density of the molecular orbitals as well as to analyze the intermolecular interactions, in order to obtain models of the 2-D molecular ordering on the substrate. PMID- 22259764 TI - Enhancement of the critical current density in FeO-coated MgB(2) thin films at high magnetic fields. AB - The effect of depositing FeO nanoparticles with a diameter of 10 nm onto the surface of MgB(2) thin films on the critical current density was studied in comparison with the case of uncoated MgB(2) thin films. We calculated the superconducting critical current densities (J(c)) from the magnetization hysteresis (M-H) curves for both sets of samples and found that the J(c) value of FeO-coated films is higher at all fields and temperatures than the J(c) value for uncoated films, and that it decreases to ~10(5) A/cm(2) at B = 1 T and T = 20 K and remains approximately constant at higher fields up to 7 T. PMID- 22259765 TI - Current-induced dynamics in carbon atomic contacts. AB - BACKGROUND: The effect of electric current on the motion of atoms still poses many questions, and several mechanisms are at play. Recently there has been focus on the importance of the current-induced nonconservative forces (NC) and Berry phase derived forces (BP) with respect to the stability of molecular-scale contacts. Systems based on molecules bridging electrically gated graphene electrodes may offer an interesting test-bed for these effects. RESULTS: We employ a semi-classical Langevin approach in combination with DFT calculations to study the current-induced vibrational dynamics of an atomic carbon chain connecting electrically gated graphene electrodes. This illustrates how the device stability can be predicted solely from the modes obtained from the Langevin equation, including the current-induced forces. We point out that the gate offers control of the current, independent of the bias voltage, which can be used to explore current-induced vibrational instabilities due the NC/BP forces. Furthermore, using tight-binding and the Brenner potential we illustrate how Langevin-type molecular-dynamics calculations including the Joule heating effect for the carbon-chain systems can be performed. Molecular dynamics including current-induced forces enables an energy redistribution mechanism among the modes, mediated by anharmonic interactions, which is found to be vital in the description of the electrical heating. CONCLUSION: We have developed a semiclassical Langevin equation approach that can be used to explore current induced dynamics and instabilities. We find instabilities at experimentally relevant bias and gate voltages for the carbon-chain system. PMID- 22259766 TI - Self-assembly at solid surfaces. PMID- 22259767 TI - Mechanical characterization of carbon nanomembranes from self-assembled monolayers. AB - This paper reports on the mechanical characterization of carbon nanomembranes (CNMs) with a thickness of 1 nm that are fabricated by electron-induced crosslinking of aromatic self-assembled monolayers (SAMs). A novel type of in situ bulge test employing an atomic force microscope (AFM) is utilized to investigate their mechanical properties. A series of biphenyl-based molecules with different types of terminal and/or anchor groups were used to prepare the CNMs, such as 4'-[(3-trimethoxysilyl)propoxy]-[1,1'-biphenyl]-4-carbonitrile (CBPS), 1,1'-biphenyl-4-thiol (BPT) and 4-nitro-1,1'-biphenyl-4-thiol (NBPT). The elastic properties, viscoelastic behaviors and ultimate tensile strength of these biphenyl-based CNMs are investigated and discussed. PMID- 22259768 TI - Direct monitoring of opto-mechanical switching of self-assembled monolayer films containing the azobenzene group. AB - The potential for manipulation and control inherent in molecule-based motors holds great scientific and technological promise. Molecules containing the azobenzene group have been heavily studied in this context. While the effects of the cis-trans isomerization of the azo group in such molecules have been examined macroscopically by a number of techniques, modulations of the elastic modulus upon isomerization in self-assembled films were not yet measured directly. Here, we examine the mechanical response upon optical switching of bis[(1,1'-biphenyl) 4-yl]diazene organized in a self-assembled film on Au islands, using atomic force microscopy. Analysis of higher harmonics by means of a torsional harmonic cantilever allowed real-time extraction of mechanical data. Quantitative analysis of elastic modulus maps obtained simultaneously with topographic images show that the modulus of the cis-form is approximately twice that of the trans-isomer. Quantum mechanical and molecular dynamics studies show good agreement with this experimental result, and indicate that the stiffer response in the cis-form comprises contributions both from the individual molecular bonds and from intermolecular interactions in the film. These results demonstrate the power and insights gained from cutting-edge AFM technologies, and advanced computational methods. PMID- 22259769 TI - Self-assembled monolayers and titanium dioxide: From surface patterning to potential applications. AB - The ability to control the properties of self-assembled monolayers (SAMs) attached to solid surfaces and the rare photocatalytic properties of titanium dioxide provide a rationale for the study of systems comprising both. Such systems can be realized in the form of SAMs grown on TiO(2) or, in a complementary manner, as TiO(2) grown on SAMs. Accordingly, the current status of knowledge regarding SAMs on TiO(2) is described. Photocatalytic phenomena that are of specific relevance to SAMs, such as remote degradation, and cases where SAMs were used to study photocatalytic phenomena, are discussed as well. Mastering of micro-patterning is a key issue en route to a successful assimilation of a variety of titanium dioxide based devices. Accordingly, particular attention is given to the description of a variety of methods and techniques aimed at utilizing the photocatalytic properties of titanium dioxide for patterning. Reports on a variety of applications are discussed. These examples, representing the areas of photovoltaics, microelectronics, microelectromechanics, photocatalysis, corrosion prevention and even biomedicine should be regarded as appetizers paving the way for further studies to be performed. PMID- 22259770 TI - When "small" terms matter: Coupled interference features in the transport properties of cross-conjugated molecules. AB - Quantum interference effects offer opportunities to tune the electronic and thermoelectric response of a quantum-scale device over orders of magnitude. Here we focus on single-molecule devices, in which interference features may be strongly affected by both chemical and electronic modifications to the system. Although not always desirable, such a susceptibility offers insight into the importance of "small" terms, such as through-space coupling and many-body charge charge correlations. Here we investigate the effect of these small terms using different Hamiltonian models with Huckel, gDFTB and many-body theory to calculate the transport through several single-molecule junctions, finding that terms that are generally thought to only slightly perturb the transport instead produce significant qualitative changes in the transport properties. In particular, we show that coupling of multiple interference features in cross-conjugated molecules by through-space coupling will lead to splitting of the features, as can correlation effects. The degeneracy of multiple interference features in cross-conjugated molecules appears to be significantly more sensitive to perturbations than those observed in equivalent cyclic systems and this needs to be considered if such supernodes are required for molecular thermoelectric devices. PMID- 22259772 TI - Multilocus sequence typing for clonality analysis of antimicrobial-resistant Stenotrophomonas maltophilia strains. PMID- 22259773 TI - Managing the pre- and post-analytical phases of the total testing process. AB - For many years, the clinical laboratory's focus on analytical quality has resulted in an error rate of 4-5 sigma, which surpasses most other areas in healthcare. However, greater appreciation of the prevalence of errors in the pre- and post-analytical phases and their potential for patient harm has led to increasing requirements for laboratories to take greater responsibility for activities outside their immediate control. Accreditation bodies such as the Joint Commission International (JCI) and the College of American Pathologists (CAP) now require clear and effective procedures for patient/sample identification and communication of critical results. There are a variety of free on-line resources available to aid in managing the extra-analytical phase and the recent publication of quality indicators and proposed performance levels by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) working group on laboratory errors and patient safety provides particularly useful benchmarking data. Managing the extra-laboratory phase of the total testing cycle is the next challenge for laboratory medicine. By building on its existing quality management expertise, quantitative scientific background and familiarity with information technology, the clinical laboratory is well suited to play a greater role in reducing errors and improving patient safety outside the confines of the laboratory. PMID- 22259774 TI - Effect of iron deficiency anemia on hemoglobin A1c levels. AB - BACKGROUND: Iron deficiency anemia is the most common form of anemia in India. Hemoglobin A1c (HbA1c) is used in diabetic patients as an index of glycemic control reflecting glucose levels of the previous 3 months. Like blood sugar levels, HbA1c levels are also affected by the presence of variant hemoglobins, hemolytic anemias, nutritional anemias, uremia, pregnancy, and acute blood loss. However, reports on the effects of iron deficiency anemia on HbA1c levels are inconsistent. We conducted a study to analyze the effects of iron deficiency anemia on HbA1c levels and to assess whether treatment of iron deficiency anemia affects HbA1c levels. METHODS: Fifty patients confirmed to have iron deficiency anemia were enrolled in this study. HbA1c and absolute HbA1c levels were measured both at baseline and at 2 months after treatment, and these values were compared with those in the control population. RESULTS: The mean baseline HbA1c level in anemic patients (4.6%) was significantly lower than that in the control group (5.5%, P<0.05). A significant increase was observed in the patients' absolute HbA1c levels at 2 months after treatment (0.29 g/dL vs. 0.73 g/dL, P<0.01). There was a significant difference between the baseline values of patients and controls (0.29 g/dL vs. 0.74 g/dL, P<0.01). CONCLUSIONS: In contrast to the observations of previous studies, ours showed that HbA1c levels and absolute HbA1c levels increased with treatment of iron deficiency anemia. This could be attributable to nutritional deficiency and/or certain unknown variables. Further studies are warranted. PMID- 22259775 TI - Diagnostic utility of osteocalcin, undercarboxylated osteocalcin, and alkaline phosphatase for osteoporosis in premenopausal and postmenopausal women. AB - BACKGROUND: We aimed to investigate the diagnostic utility of osteocalcin (OC), undercarboxylated osteocalcin (ucOC), and alkaline phosphatase (ALP) in pre- and postmenopausal women for femoral neck, L1-4, and L2-4 bone mineral density (BMD) values by taking into consideration their age, body mass index (BMI), and menopausal status. METHODS: Premenopausal (N=40) and postmenopausal cases (N=42) were classified as 25-34 or 35-45 yr of age and within the first 5 yr or 5 yr or more after the onset of menopause, respectively. RESULTS: Among the groups, statistical differences were found for age, BMI, OC, ucOC, ALP, femoral neck BMD, L1-4 BMD, and L2-4 BMD. The highest serum OC, ucOC, and ALP levels were observed in cases within the first 5 yr after the onset of menopause, probably due to a more rapid bone turnover rate. The best predictors for the femoral neck osteoporosis were ALP, OC, and calcium (areas under the ROC curve [AUC]=0.882, 0.829, and 0.761, respectively), and those for L1-4 and L2-4 osteoporosis were OC, ALP, and ucOC (AUC=0.949, 0.873, and 0.845; and 0.866, 0.819, and 0.814, respectively). Multiple logistic regression analysis revealed that the most discriminative parameter for osteoporosis was OC. CONCLUSIONS: These results indicate that serum OC levels, with or without ucOC and ALP, may be useful to monitor follow-up changes that currently cannot be assessed with BMD and to diagnose femoral neck, L1-4 spine, and L2-4 spine osteoporosis. PMID- 22259776 TI - Analysis of methylmercury concentration in the blood of Koreans by using cold vapor atomic fluorescence spectrophotometry. AB - BACKGROUND: Methylmercury is an organic form of mercury that is highly toxic to humans. Here, we present and establish a novel method to detect methylmercury concentrations in the blood of Koreans. METHODS: Methylmercury concentration was analyzed with an automated methylmercury analytic system (MERX, Brooks Rand Co., USA) using cold vapor atomic fluorescence spectrophotometry (CVAFS). A variety of biological materials were digested in methanolic potassium hydroxide solution. The analysis method was validated by examination of certified reference material (955c, National Institute of Standard and Technology, USA). We randomly selected 30 Korean adults (age 20 yr or older) to analyze total blood mercury and methylmercury concentrations. RESULTS: The detection limit and methylmercury recovery rate using this method were 0.1 pg/L and, 99.19% (range: 89.33-104.89%), respectively. The mean blood concentration of methylmercury was 4.54+/-2.15 ug/L (N=30). The mean proportion of methylmercury to the total mercury concentration was 78.27% (range: 41.37-98.80%). CONCLUSIONS: This study is the first report to analyze blood methylmercury concentration using CVAFS in Korea. We expect that this method will contribute to the evaluation of mercury exposure and the assessment of the toxicological impact of mercury in future studies. PMID- 22259777 TI - Expression of Sme efflux pumps and multilocus sequence typing in clinical isolates of Stenotrophomonas maltophilia. AB - BACKGROUND: Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen, which causes infections that are often difficult to manage because of the inherent resistance of the pathogen to a variety of antimicrobial agents. In this study, we analyzed the expressions of smeABC and smeDEF and their correlation with antimicrobial susceptibility. We also evaluated the genetic relatedness and epidemiological links among 33 isolates of S. maltophilia. METHODS: In total, 33 S. maltophilia strains were isolated from patients in a tertiary hospital in Daejeon. Minimum inhibitory concentrations (MICs) of 11 antimicrobial agents were determined by using agar dilution method and E-test (BioMerieux, France). Real-time PCR analysis was performed to evaluate the expression of the Sme efflux systems in the S. maltophilia isolates. Additionally, an epidemiological investigation was performed using multilocus sequence typing (MLST) assays. RESULTS: The findings of susceptibility testing showed that the majority of the S. maltophilia isolates were resistant to beta lactams and aminoglycosides. Twenty-one clinical isolates overexpressed smeABC and showed high resistance to ciprofloxacin. Moreover, a high degree of genetic diversity was observed among the S. maltophilia isolates; 3 sequence types (STs) and 23 allelic profiles were observed. CONCLUSIONS: The smeABC efflux pump was associated with multidrug resistance in clinical isolates of S. maltophilia. In particular, smeABC efflux pumps appear to perform an important role in ciprofloxacin resistance of S. maltophilia. The MLST scheme for S. maltophilia represents a discriminatory typing method with stable markers and is appropriate for studying population structures. PMID- 22259778 TI - Evaluation of the Seeplex(r) Meningitis ACE Detection kit for the detection of 12 common bacterial and viral pathogens of acute meningitis. AB - BACKGROUND: Bacterial meningitis is an infectious disease with high rates of mortality and high frequency of severe sequelae. Early identification of causative bacterial and viral pathogens is important for prompt and proper treatment of meningitis and for prevention of life-threatening clinical outcomes. In the present study, we evaluated the value of the Seeplex Meningitis ACE Detection kit (Seegene Inc., Korea), a newly developed multiplex PCR kit employing dual priming oligonucleotide methods, for diagnosing acute meningitis. METHODS: Analytical sensitivity of the kit was studied using reference strains for each pathogen targeted by the kit, while it's analytical specificity was studied using the human genome DNA and 58 clinically well-identified reference strains. For clinical validation experiment, we used 27 control cerebrospinal fluid (CSF) samples and 78 clinical CSF samples collected from patients at the time of diagnosis of acute meningitis. RESULTS: The lower detection limits ranged from 10(1) copies/uL to 5*10(1) copies/uL for the 12 viral and bacterial pathogens targeted. No cross-reaction was observed. In the validation study, high detection rate of 56.4% was obtained. None of the control samples tested positive, i.e., false-positive results were absent. CONCLUSIONS: The Seeplex Meningitis ACE Detection kit showed high sensitivity, specificity, and detection rate for the identification of pathogens in clinical CSF samples. This kit may be useful for rapid identification of important acute meningitis-causing pathogens. PMID- 22259779 TI - Comparison of modified multiple-locus variable-number tandem-repeat fingerprinting with pulsed-field gel electrophoresis for typing clinical isolates of Staphylococcus aureus. AB - BACKGROUND: Multiple-locus variable-number tandem-repeat fingerprinting (MLVF) is based on multiplex PCR, utilizing variable number tandem repeat. Our goal was to compare the performance of MLVF in distinguishing clinical Staphylococcus aureus isolates with that of pulsed-field gel electrophoresis (PFGE), which has traditionally been the gold standard. METHODS: Sixty-three clinically significant S. aureus isolates were tested using both PFGE and MLVF. Multiplex PCR for MLVF was performed using PCR primers for clfA, clfB, sdrCDE, sspA, and spa. PFGE was performed with genomic DNA fragments generated by SmaI endonuclease digestion. Banding patterns of MLVF or PFGE were analyzed using InfoQuestFP software. RESULTS: The hands-on time of our modified method was about 3 h, on average, for each of 18 isolates. PFGE (80% cutoff) or MLVF (75% cutoff) separated all of the 63 isolates into 13 and 12 types, respectively. Three types generated by PFGE were identical to those generated by MLVF. PFGE and MLVF yielded similar Simpson's diversity indices, indicating similar discriminatory power. The overall concordance between PFGE and MLVF was low, as represented by adjusted Rand indices (0.266-0.278). PFGE predicted MLVF type better than MLVF predicted PFGE type, as reflected by Wallace coefficients (PFGE cutoff 80% vs. MLVF cutoff 75%, 0.389 vs. 0.233). Analysis of the relationship between a pair of isolates showed 91.0% concordance between the PFGE (80% cutoff) and MLVF (75% cutoff). CONCLUSIONS: Our simple, low-cost, modified MLVF protocol can effectively discriminate between S. aureus clinical isolates. MLVF can replace PFGE for the hospital infection control of S. aureus. PMID- 22259780 TI - Use of PCR with sequence-specific primers for high-resolution human leukocyte antigen typing of patients with narcolepsy. AB - BACKGROUND: Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles. METHODS: The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT). RESULTS: The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci. CONCLUSIONS: The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy. PMID- 22259781 TI - Application of calculated panel reactive antibody using HLA frequencies in Koreans. AB - BACKGROUND: Introduction of the Luminex panel reactive antibody (PRA)-single antigen (SA) assay has increased the detection rates of unacceptable antigens in sensitized patients; the calculated PRA (CPRA) level represents the percentage of actual organ donors that express 1 or more of these unacceptable antigens. We developed a CPRA calculator based on the HLA frequencies in Koreans to measure sensitization levels in Korean patients. METHODS: To develop the calculator, we obtained the HLA-A, HLA-B, and HLA-DR phenotypes of 1,622 Koreans, and compared these with previously reported frequencies in Koreans. Sera from patients awaiting kidney transplantation were tested for HLA antibodies by Luminex PRA screen, PRA-identification (ID), and PRA-SA assays. The measured %PRA from the PRA-screen (N=55) and PRA-ID (N=71) were compared to the %CPRA for the unacceptable antigens obtained from PRA-SA. RESULTS: Phenotype frequencies used for the CPRA calculator agreed with previously reported data. The concordance rates among the 3 PRA methods for the detection of class I and class II antibodies were 76.1-81.8% (kappa, 0.519-0.636) and 72.7-83.6% (0.463-0.650), respectively. For the detection of broadly sensitized sera (>50% or >80%), the concordance rates were over 80%. In sera with 80-100% CPRA, 91.7% and 94.4% of the samples had concordant results (80-100% PRA) in the PRA-screen and PRA-ID assay, respectively. CONCLUSIONS: Although further clinical studies are required to confirm the benefits of CPRA values, adoption of CPRA analysis based on HLA frequencies in Koreans may be useful for sensitization measurements and organ allocation algorithms. PMID- 22259782 TI - Pre- and post-transfusion testing for hepatitis B virus surface antigen and antibody in blood recipients: a single-institution experience in an area of high endemicity. AB - BACKGROUND: Hepatitis B remains the most common transfusion-transmitted viral infection. We explored the current status of pre-transfusion screening and post transfusion follow-up testing for hepatitis B virus (HBV) surface antigen (HBsAg) and antibodies (anti-HBs) in blood recipients from an area of high HBV endemicity. METHODS: A total of 7,780 blood recipients were transfused with at least 1 unit of blood component at a single university hospital in Korea between January 2006 and December 2009. Their medical records were reviewed, and their demographic and transfusion-related data were analyzed. RESULTS: Pre-transfusion HBsAg and anti-HBs levels were tested in 77.6% (6,037/7,780) of the recipients. The results varied widely according to recipient age. In all, 32.8% (1,982/6,037) of the recipients who were tested had dual negative pre-transfusion results for HBsAg and anti-HBs and, therefore, were at increased risk of HBV transmission. Post-transfusion follow-up testing for HBsAg and/or anti-HBs was performed in 22% (436/1,982) of the increased-risk group. CONCLUSIONS: Our data show that current transfusion-related laboratory testing practice is not sufficient to properly investigate possible post-transfusion infections. Routine laboratory tests, including HBsAg and anti-HBs, should be recommended in transfusion guidelines. PMID- 22259783 TI - Evaluation of a new immunochromatographic assay kit for the rapid detection of norovirus in fecal specimens. AB - Rapid and accurate detection of norovirus is essential for the prevention and control of norovirus outbreaks. This study compared the effectiveness of a new immunochromatographic assay kit (SD BIOLINE Norovirus; Standard Diagnostics, Korea) and real-time reverse transcription-PCR (RT-PCR) for detecting norovirus in fecal specimens. Compared with real-time RT-PCR, the new assay had sensitivity, specificity, positive predictive value, and negative predictive value of 76.5% (52/68), 99.7% (342/343), 98.1% (52/53), and 95.5% (342/358), respectively. The sensitivity of the assay was 81.8% (18/22) for GII.3 and 75.7% (28/37) for GII.4. None of the 38 enteric virus-positive specimens (3 for astrovirus, 5 for enteric adenovirus, and 30 for rotavirus) tested positive in the cross-reactivity test performed by using this assay. The new immunochromatographic assay may be a useful screening tool for the rapid detection of norovirus in sporadic and outbreak cases; however, negative results may require confirmatory assays of greater sensitivity. PMID- 22259784 TI - Characterization of a vancomycin-resistant Enterococcus faecium outbreak caused by 2 genetically different clones at a neonatal intensive care unit. AB - In July 2010, we identified an outbreak of vancomycin-resistant enterococci (VRE) in our 26-bed neonatal intensive care unit. We performed an epidemiological investigation after clinical cultures of 2 neonates were positive for VRE. Identification, susceptibility testing, and molecular characterization were performed. Cultures of 3 surveillance stool samples of inpatients and 5 environmental samples were positive for VRE. All isolates were identified as Enterococcus faecium containing the vanA gene. Two distinct clones were identified by performing pulsed-field gel electrophoresis. The 2 clones exhibited different pulsotypes, but they represented identical Tn1546 types. Two sequence types, ST18 and ST192, were identified among all of the isolates with multilocus sequence typing. Our investigation determined that the outbreak in the neonatal intensive care unit was caused by 2 genetically different clones. The outbreak may have occurred through clonal spread and horizontal transfer of the van gene. PMID- 22259785 TI - Chronic pulmonary disease due to Mycobacterium monacense infection: the first case from Iran. AB - We herein report a case in which the recently characterized species Mycobacterium monacense was isolated from the sputum of an Iranian patient. This case represents the first isolation of M. monacense from Iran. The isolate was identified by conventional and molecular techniques. Our findings show that M. monacense infection is not restricted to developed countries. PMID- 22259786 TI - A case of partial trisomy 20p resulting from meiotic recombination of a maternal pericentric inversion. AB - Here we report the cytogenetic and clinical manifestations observed in a patient with a rec(20)dup(20p)inv(20)(p11.2q13.3)mat. The patient was a full-term newborn girl with asymmetric intrauterine growth restriction and multiple congenital malformations, including a ventricular septal defect, pulmonary atresia, ambiguous genitalia, clinodactyly, and sacral dimpling. To our knowledge, this is the 4th report in the world and the 1st one in Korea of a patient with rec(20)dup(20p). PMID- 22259787 TI - CD5-negative blastoid variant mantle cell lymphoma with complex CCND1/IGH and MYC aberrations. AB - The coexistence of CCND1/IGH and MYC rearrangements in mantle cell lymphoma (MCL) is a rare finding associated with a very poor prognosis. In this study, a patient with blastoid variant (MCL) is reported. The disease was clinically aggressive and refractory to chemotherapy, and the patient only survived for 1 month following diagnosis. Conventional cytogenetic study, FISH, and multicolor FISH (mFISH) demonstrated the involvement of the BCL1/CCND1 locus in a complex translocation, t(3;11)(q25;p15)t(11;14)(q13;q32). In addition, subclonal abnormalities in the 8q24 region, manifested as a t(8;14)(q24;q32)/MYC rearrangement, were identified. To the best of our knowledge, this is the first MCL case in Korea bearing these complex genomic aberrations. PMID- 22259788 TI - The first study on nucleotide-level identification of Hb Koriyama in a patient with severe hemolytic anemia. AB - Hereditary hemolytic anemia comprises a group of disorders in which red blood cells are destroyed faster than they are produced in the bone marrow; various hereditary factors can cause this condition, including production of defective Hb and erythrocyte membrane. Recently, we identified Hb Koriyama, a rare Hb variant that was undetectable in Hb electrophoresis and stability tests, in a patient with severe hemolytic anemia. This is the first study to show the nucleotide level sequence variations in Hb Koriyama. On the basis of our results, we conclude that unstable Hb may not be detectable by conventional Hb electrophoresis or stability tests. Thus, we suggest further genetic workup in cases of unexplained hereditary hemolytic anemia. PMID- 22259789 TI - Osseointegration: promise and platitudes. PMID- 22259790 TI - Denture wearing by individuals among the older segment of European populations. AB - PURPOSE: The aim of this study was to describe differences in denture wearing by individuals among the older segment of different European populations. MATERIALS AND METHODS: Data from the Survey of Health, Ageing, and Retirement in Europe was used to estimate a series of multivariate logistic regression models to analyze differences in self-reported denture wearing by individuals older than 50 years of age from 14 European countries (P < .05). RESULTS: Comparably high population proportions with dentures prevail in Austria, Ireland, Poland, Belgium, The Netherlands, and Germany. Median levels are observed in Czechia and Spain. Relatively low levels of denture wearing are reported from elderly residents in Sweden, Greece, Italy, Denmark, Switzerland, and France. CONCLUSION: There are considerable differences in denture wearing by individuals from the older segment across various European populations. Future research is encouraged to detect the precise causes of such variations in prosthetic care. PMID- 22259791 TI - Prognosis of zirconia ceramic fixed partial dentures: a 7-year prospective study. AB - The aim of this study was to evaluate the time-dependent clinical efficacy of anterior and posterior zirconia fixed partial dentures (FPDs). A convenience sample of 28 patients, each wearing 1 FPD, was recalled annually throughout a 6 year follow-up period (mean: 6.5 years). Four patients did not participate in the study (dropouts), and 24 FPDs were in use during the observation period. The cumulative survival and success rates were 88.9% and 81.8%, respectively. Fixed prostheses with zirconia frameworks may be regarded as acceptable alternatives to metal-ceramic anterior and posterior FPDs. PMID- 22259792 TI - Speech intelligibility enhancement through maxillary dental rehabilitation with telescopic prostheses and complete dentures: a prospective study using automatic, computer-based speech analysis. AB - PURPOSE: A completely edentulous or partially edentulous maxilla involving missing anterior teeth may impact speech production and lead to reduced speech intelligibility. The aim of this study was to prospectively evaluate the effect of a dental prosthetic rehabilitation on speech intelligibility in patients with a toothless or interrupted maxillary arch by means of an automatic, standardized speech recognition system. MATERIALS AND METHODS: The speech intelligibility of 45 patients with complete tooth loss or a loss including missing anterior teeth in the maxilla was evaluated by means of a polyphone-based automatic speech recognition system that assessed the percentage of correctly recognized words (word accuracy). To replace inadequate maxillary removable dentures, 20 patients from the overall sample had been rehabilitated with complete dentures and 25 patients with telescopic prostheses. Speech recordings were made in four recording sessions (with and without existing prostheses and then at 1 week and 6 months after placement of newly fabricated prostheses). RESULTS: Significantly higher speech intelligibility was observed in both patient groups compared to the original results without the dentures inserted. After 6 months of adaptation, both groups had reached a level of speech quality that was comparable to the healthy control group. However, patients receiving new telescopic prostheses showed significantly higher levels of speech intelligibility compared to those receiving new complete dentures. Within 6 months, speech intelligibility did not significantly improve from the level found 1 week after insertion of new prostheses for both groups. CONCLUSION: Patients benefit from the fabrication of new dentures in terms of speech intelligibility, regardless of the type of prosthesis. However, telescopic crown prostheses yield significantly better speech quality compared to complete dentures. PMID- 22259793 TI - Influence of resin cements and aging on the fracture resistance of IPS e.max press posterior crowns. AB - The purpose of this study was to evaluate the effect of different adhesive cements and thermocycling on the fracture resistance of IPS e.max Press posterior single crowns. Thirty-two sound maxillary molars were subjected to standardized preparation and received IPS e.max Press crowns. Another 16 molars were left unprepared to serve as controls (group 1). Panavia F 2.0 and Rely X Unicem luting cements were used to bond the fabricated crowns (n = 16 each) to their respective prepared teeth. Eight specimens from each of the three groups were selected randomly for further thermocycling (5,000 cycles). All specimens were then subjected to fracture resistance testing using anatomical metal attachments fixed to the upper portion of the universal testing machine (1 mm/min). Data were analyzed statistically using two-way analysis of variance and the Student t test (alpha = .05). Natural teeth presented significantly higher (1,043 and 1,279 N) fracture resistance than that of adhesively cemented ceramic crowns (907 to 986 N) before and after thermocyling, respectively (P < .05). Cement type did not significantly affect fracture resistance results (986 N and 974 N for Panavia F 2.0 and Rely X Unicem, respectively; P > .05). Thermocycled specimens showed lower fracture resistance than that of nonthermocycled ones (P < .05). Neither conventional adhesive cement nor self-etching adhesive cement affected the fracture resistance of IPS e.max crowns. Thermocycling decreased the fracture strength of the crowns in both cement groups. Natural teeth fractured at significantly higher loads than the ceramic crowns. PMID- 22259794 TI - Esthetics and psyche-part 1: assessment of the influence of patients' perceptions of body image and body experience on selection of existing natural tooth color. AB - PURPOSE: The aim of this research was to test the hypothesis that patients' attitudes toward their body affect their capacity to accurately select their existing natural tooth color. MATERIALS AND METHODS: Standard validated psychologic assessments were used to determine a person's perception of body image and experience. Oral images were compared with the patients' perceptions of their natural tooth color, which were then compared with the actual tooth color judged by a dental professional. RESULTS: For the vital body dynamic and disliking body experience subscales, women exhibited a significantly more negative attitude toward their bodies than men (P = .000). Patients with a negative attitude toward their body tended to choose a lighter tooth color. The correlation between patients' and the testing physician's choices of color was r = 0.540 for women and r = 0.746 for men. CONCLUSIONS: Unhappiness with body image and experience results in poor perception of a patient's own oral image, which in turn results in a patient perceiving that his or her natural tooth color is lighter than that judged by a dental professional. This has clinical implications when trying to achieve patient satisfaction with dental prostheses. PMID- 22259795 TI - Accuracy of three implant impression techniques with different impression materials and stones. AB - The purpose of this study was to compare the accuracy of casts made using three different impression techniques to obtain an accurate definitive cast for fabrication of multiple-implant prostheses. Twelve experimental groups were formed combining the following conditions: three impression techniques, two impression materials, and two cast materials. The main effects of the three factors were analyzed by three-way analysis of variance using the full factorial general linear model between factors. The results showed that there were no significant differences in mean values for the transferred dimensions between the control and experimental groups. None of the measurements in the horizontal plane of the definitive casts demonstrated significant differences among the impression techniques with different impression and cast materials (P > .01). PMID- 22259796 TI - On osseointegration: the healing adaptation principle in the context of osseosufficiency, osseoseparation, and dental implant failure. AB - The host-implant interface is remarkably enduring given the functional and biologic challenges it faces, and our success in assisting patients to lead better lives because of implant biotechnology is the envy of many other health care practitioners. It is therefore vital that dentists accept that clinically significant marginal bone loss is uncommon and that implant failure is rare. In this paper, important elements regarding why implants experience marginal bone loss, why implants may fail as a result of such bone loss, and how to describe the continuum of bone loss with respect to patient-mediated outcomes are outlined. PMID- 22259797 TI - Resinous denture base fracture resistance: effects of thickness and teeth. AB - PURPOSE: Fracture is a frequent complication of resinous prostheses. The purpose of this study was to evaluate the effect of thickness on flexural strength of a resinous prosthesis containing a prosthetic tooth. MATERIALS AND METHODS: Beam shaped specimens 65-mm long, 12-mm wide, and 1, 2, 3, 4, or 6 mm in thickness were made from high-impact strength polymethyl methacrylate denture base material, each containing a resin-based molar prosthetic tooth at the center of the beam. A group of 3-mm-thick specimens without a prosthetic tooth (n = 7) were also made. Specimens were aged artificially, loaded in three-point flexure, examined fractographically, and analyzed. RESULTS: The 1- and 2-mm-thick beams underwent considerable deformation at low loads. Maximum loads varied considerably from 0.6 kg (1-mm beams) to 38 kg (6-mm beams). The 3-, 4-, and 6-mm beam groups all underwent brittle fracture, with mean relative flexural strengths of approximately 73 MPa. Denture teeth reduced the relative flexural strength of resin beams by 0.7 x. Fracture initiation sites were generally at tiny surface defects, but did not directly involve denture teeth. Denture resin fracture toughness was 3.2 MPa m1/2, and modulus of rupture was 104 MPa. CONCLUSION: Denture teeth substantially decreased the strength of resinous beams. Increased thickness markedly increased the load-bearing capacity of resinous beams containing denture teeth. Beams less than 2 mm in thickness with denture teeth were weakened substantially more than comparable beams of 2 mm or more in thickness. Surface finish was of critical importance. Fracture toughness was calculated fractographically, facilitating future forensic examination of clinically failed resinous prostheses. PMID- 22259798 TI - Dental implants in patients with Ehlers-Danlos syndrome: a case series study. AB - Ehlers-Danlos syndrome (EDS) encompasses six types of hereditary connective tissue disorders, with skin hyperextensibility, joint hypermobility, and connective tissue fragility as the main findings. Oral health is also affected, sometimes including periodontitis and tooth loss. This is the first report on dental implant treatment for patients with hypermobility or classic EDS. Five female patients aged 19 to 68 years who tolerated treatment under local anesthesia and did not require bone augmentation were enrolled in the study and received 16 implants. They were observed for 2 to 12 years. No implants were lost, bone loss was minimal, and all patients were pleased with the treatment outcomes. PMID- 22259799 TI - Effects of different root coping materials for abutment teeth on secondary caries and periodontal conditions: a retrospective study. AB - This study evaluated secondary caries and periodontal conditions associated with metal (MCs) and composite resin copings (RCs) of abutment teeth for overdentures. The rates of secondary caries and periodontal problems in 70 root copings (41 MCs, 29 RCs) in 35 patients were retrospectively investigated for a period of 6.9 years. Statistical analysis was performed using chi-square tests and logistic regression (P < .05). No significant differences in secondary caries or periodontal conditions were detected between MCs and RCs. These results suggest that RCs and MCs can be used as root copings of abutment teeth for overdentures. PMID- 22259800 TI - Design of removable partial dentures: a survey of dental laboratories in Greece. AB - The aim of this study was to compare data on design and fabrication methods of removable partial dentures (RPDs) in two major cities in Greece. A questionnaire was sent to 150 randomly selected dental technicians. The participation rate was 79.3%. The anterior palatal strap, the lingual bar, and the Roach-type clasp arm designs were preferred. Half of the RPDs fabricated were retained using precision attachments. Differences between the two cities were observed in types of major maxillary connectors used, types of attachments and impression materials used, as well as the design of distal-extension RPDs. Postdoctoral education was found to have an impact on RPD fabrication. Despite the differences observed, design and fabrication of RPDs followed commonly used principles. PMID- 22259801 TI - Clinical long-term evaluation and failure characteristics of 1,335 all-ceramic restorations. AB - PURPOSE: The aim of this clinical retrospective study was to evaluate the clinical quality, estimated survival rate, and failure analysis of different all ceramic restorations in a long-term analysis of up to 20 years. MATERIALS AND METHODS: Different all-ceramic restorations (crowns [n = 470], veneers [n = 318], onlays [n = 213], and inlays ]n = 334[) were placed in 302 patients (120 men, 182 women) between 1987 and 2009 at Medical University Innsbruck, Innsbruck, Austria. Clinical examination was performed during patients' regularly scheduled maintenance appointments. Esthetic match, porcelain surface, marginal discoloration, and integrity were evaluated following modified California Dental Association/Ryge criteria. Number of restoration failures and reasons for failure were recorded. The study population included 106 (35.1%) individuals diagnosed with bruxism. The success rate was determined using Kaplan-Meier survival analysis. RESULTS: The mean observation time was 102 +/- 60 months. Ninety-five failures were recorded. The main reason for failure was fracture of the ceramic (33.68%). The estimated survival rate was 97.3% after 5 years, 93.5% at 10 years, and 78.5% at 20 years. Nonvital teeth showed a significantly higher risk of failure (P < .0001). There was a 2.3-times greater risk of failure associated with existing parafunction (bruxism, P = .0045). Cementation using Variolink showed significantly fewer failures than Optec Cement (P = .0217) and Dual Cement (P = .0099). No significant differences were found for type of restoration and distribution in the mouth. CONCLUSION: All-ceramic restorations offer a predictable and successful restoration with an estimated survival probability of 93.5% over 10 years. Significantly increased failure rates are associated with bruxism, nonvital teeth, and specific cementation agents. PMID- 22259802 TI - Clinical performance of porcelain laminate veneers for up to 20 years. AB - PURPOSE: The aim of this clinical retrospective study was to evaluate the clinical quality, success rate, and estimated survival rate of anterior veneers made of silicate glass-ceramic in a long-term analysis of up to 20 years. MATERIALS AND METHODS: Anterior teeth in the maxillae and mandibles of 84 patients (38 men, 46 women) were restored with 318 porcelain veneer restorations between 1987 and 2009 at the Medical University Innsbruck, Innsbruck, Austria. Clinical examination was performed during patients' regularly scheduled maintenance appointments. Esthetic match, porcelain surface, marginal discoloration, and integrity were evaluated following modified California Dental Association/Ryge criteria. Veneer failures and reasons for failure were recorded. The study population included 42 (50.0%) patients diagnosed with bruxism and 23 (27.38%) smokers. The success rate was determined using Kaplan-Meier survival analysis. RESULTS: The mean observation time was 118 +/- 63 months. Twenty-nine failures (absolute: 82.76%, relative: 17.24%) were recorded. The main reason for failure was fracture of the ceramic (44.83%). The estimated survival rate was 94.4% after 5 years, 93.5% at 10 years, and 82.93% at 20 years. Nonvital teeth showed a significantly higher failure risk (P = .0012). There was a 7.7-times greater risk of failure associated with existing parafunction (bruxism, P = .0004). Marginal discoloration was significantly greater in smokers (P ? .01). CONCLUSION: Porcelain laminate veneers offer a predictable and successful restoration with an estimated survival probability of 93.5% over 10 years. Significantly increased failure rates were associated with bruxism and nonvital teeth, and marginal discoloration was worse in patients who smoked. PMID- 22259803 TI - Medically complex patients in the dental clinic. PMID- 22259804 TI - A combined prosthodontic and orthodontic treatment approach in a case of growth inhibition induced by dental implants: a case report. AB - Functional and esthetic results can improve significantly when a combined prosthodontic-orthodontic treatment approach is employed in cases requiring extensive oral rehabilitation. The patient presented in this case report was treated in his late teens with dental implants as a replacement for his maxillary incisors. Ten years later, the entire maxillary anterior segment was in infraocclusion compared to the rest of the dentition and lip line. Since prosthodontic follow-up treatment alone could not achieve an optimal functional and esthetic outcome, the patient was treated orthodontically prior to renewing the restoration. A fixed appliance was used to intrude the mandibular anterior teeth as well as vertically align the infrapositioned maxillary lateral incisors. PMID- 22259805 TI - Root anatomy and canal configuration of the permanent mandibular first molar: clinical implications and recommendations. AB - Root canal anatomy may present clinicians with a complex clinical challenge that requires diagnostic approaches, access modification, and clinical skills to successfully localize, negotiate, disinfect, and seal the root canal system. This article discusses the clinical implications of endodontic therapy on permanent mandibular first molars. The number of roots on the mandibular first molar is directly related to ethnicity. Canal morphology has a significant effect on treatment protocol: Mesial roots present two canals on a regular basis, adopting 2-2 and 2-1 as the most common configurations. A third canal is present in 2.6% of the population. The most common configuration in the distal root is type I (62.7%), followed by type II (14.5%) and type IV (12.4%). Diagnosis and treatment of complex root canal systems often require specialized training that may be beyond the scope of the average general practitioner. Access modifications are required to find extra roots and/or canals. The instrumentation of the third root requires a different access and small, flexible instruments, given the curvature that is usually present buccally in the apical third. The incidence of isthmuses is 55% in the mesial root and 20% in the distal root. This anatomical configuration should be taken into consideration during endodontic treatment as well as during periapical surgery. PMID- 22259806 TI - Considerations for a staged approach in implant dentistry. AB - Full-arch and partial reconstruction is demanding for the clinician and a challenge for the patient. Traditionally, teeth are extracted, and implants are placed; the patient wears a provisional removable prosthesis during implant osseointegration. The patient is left to deal with a difficult transition from a fixed dentition to a removable one, albeit temporarily. This drastic alteration can generate functional, emotional, and esthetic changes for the patient, thereby making a difficult time even more challenging. Reconstructing the dentition through a staged approach has been documented and involves strategic extractions along with the placement of several implants, but leaves select abutment teeth for a fixed provisional prosthesis. This allows for the provisional prosthesis to be tooth-supported during implant integration and later converted to an implant supported prosthesis. In this manner, the patient will benefit from a fixed provisional prosthesis throughout the treatment process. A staged approach is contingent upon a thorough periodontal and prosthetic evaluation and work-up. Success requires proper communication between the periodontist, surgeon, restorative dentist, laboratory, and patient. A team approach is necessary for success. The protocol, advantages, and disadvantages for a staged approach to a full-arch implant-supported reconstruction are discussed. The authors also present a case to show how the staged approach can be used for sextant or quadrant rehabilitation. PMID- 22259807 TI - Vertical root fractures in crowned teeth: a report of 32 cases. AB - OBJECTIVE: To clarify the mode of root fracture in 32 endodontically treated teeth that resulted in vertical root fracture (VRF) despite the provision of a crown for fracture prevention. METHOD AND MATERIALS: The teeth included in the study underwent root canal treatment and were restored with crowns without the use of an intracanal post. All teeth underwent photo documentation. Clinical signs and symptoms as well as the patients' ages were recorded. The diameters of the roots and the root canal fillings were measured on radiographs. Fractured roots were investigated using a scanning electron microscope (SEM). RESULTS: The mean patient age was 60.2 years. The VRFs in the group occurred most frequently in the mesial roots of the mandibular first molars. The fracture was predominantly buccolingual. The mean ratio measured between the diameters of the root canal obturations and the outer root surfaces in the radiographs was 33.2%. SEM evaluation showed that most fractures ran from the inner to the outer root surface, and the cracks predominantly ran apical to coronal. CONCLUSION: Endodontically treated and crowned teeth without root canal posts can develop VRFs. The cracks start at the root canal wall in the apical part of the root and extend toward the outer root surface and coronally. Further investigation is necessary to determine the possible causes and evidence of fracture development. PMID- 22259808 TI - Transmigration of mandibular canines in siblings: a case report. AB - Transmigration is the pre-eruptive intrabony migration of a tooth across the midline. This rare phenomenon, the etiology of which is unknown, is usually seen in canines. Two cases of transmigration in the mandibular canines are reported; one shows the transposition of a mandibular canine and premolar. Familial occurence of this phenomenon and a 5-year follow-up showing a change in the inclination of the impacted tooth are outlined. PMID- 22259809 TI - A study to evaluate the efficacy of toluidine blue and cytology in detecting oral cancer and dysplastic lesions. AB - OBJECTIVE: Recent advances in techniques for detecting oral premalignant lesions and oral squamous cell carcinoma have improved the chances of early diagnosis. Adjuncts for detection of lesions include toluidine blue staining and cytologic examination. The primary objective of this study was to assess the efficacy of 1% toluidine blue (modified Mashberg technique) and cytology in detection of oral premalignant lesions and oral squamous cell carcinoma. METHOD AND MATERIALS: The study included 86 participants suspected of having oral premalignant lesions or oral squamous cell carcinoma. One percent toluidine blue was applied to the lesions, followed by cytology. A biopsy was then performed on the tissue. Histopathologically proven oral premalignant lesions/oral squamous cell carcinoma lesions were analyzed for sensitivity, specificity, postive predictive value, and negative predictive value of both screening techniques. The association of screening techniques and histopathologic diagnosis among the oral premalignant lesions, oral squamous cell carcinoma, and benign groups were analyzed using the Fisher exact test. P < .05 was considered significant. RESULTS: The specificity and sensitivity for oral squamous cell carcinoma and oral premalignant lesions detection of 1% toluidine blue was 81.35% and 66.67%, respectively, while cytology attained 77.97% and 70.37%, respectively. Negative predictive value and positive predictive value were 84.21% and 62.06% for 1% toluidine blue and 85.18% and 59.37% for cytologic examination, respectively. Comparison of 1% toluidine blue and cytology with histopathologic diagnosis shows a significant difference between carcinoma/epithelial dysplasia and no dysplasia and carcinoma/epithelial dysplasia and benign lesions (all, P < .05). CONCLUSION: The results of this study suggest that 1% toluidine blue and cytology have high sensitivity, specificity, and accuracy in detecting oral premalignant lesions and oral squamous cell carcinoma and can be used as an adjunct for early detection of such lesions. PMID- 22259810 TI - Pain perception following first orthodontic archwire placement--thermoelastic vs superelastic alloys: a randomized controlled trial. AB - OBJECTIVES: Orthodontic thermoelastic archwires produce lighter and more biologic forces than superelastic archwires and could therefore offer the possibility of reducing initial orthodontic pain. Nevertheless, evidence concerning this issue is scarce. The aim of this study was to compare pain perception following first archwire placement in patients with thermal heat-activated (HANT) and superelastic (SE) nickel-titanium archwires. METHOD AND MATERIALS: Thirty subjects (11 males, 19 females; range, 11 to 26 years of age) were recruited. Metal brackets were bonded in the maxillary or mandibular arch. Round 0.016-inch HANT or 0.016-inch SE archwires were randomly placed and tied with elastic ligatures. Each patient was invited to score tooth pain for 7 days at different time points (8:00, 12:00, 16:00, 20:00, and 24:00) using the visual analog scale (VAS). RESULTS: In both groups, pain was highest at day 2 and lowest at day 7. Patients with HANT archwires had significantly lower VAS scores (P < .005) at days 2, 3, and 4 than subjects with SE archwires. This was also the case after adjusting for analgesic consumption, sports practicing, overlapping pain of different origin, and the concomitance of stressful events. The frequency of analgesic consumption was higher in the SE than in HANT group at day 3 (P < .05). No differences in pain perception were found between time points, nor was any correlation found between dental crowding and pain. No difference in pain perception was found between the maxillary and mandibular dental arches. CONCLUSION: Initial orthodontic pain is reduced when using HANT orthodontic archwires. PMID- 22259811 TI - Necrotizing periodontal diseases in HIV-infected Brazilian patients: a clinical and microbiologic descriptive study. AB - OBJECTIVE: Nowadays, necrotizing periodontal diseases have a low prevalence; however, a better understanding of the etiopathogenesis of these diseases is necessary for determining more adequate preventive and therapeutic strategies. METHOD AND MATERIALS: From a pool of 1,232 HIV-infected patients, 15 presented with necrotizing periodontal diseases, which were evaluated by full-mouth periodontal clinical measurements. Subgingival biofilm samples were collected from necrotizing lesions of six of these individuals. The presence and levels of 47 bacterial species were determined by checkerboard DNA-DNA hybridization. RESULTS: All 15 patients (10 had severe immunodeficiency) had been infected sexually. Thirteen patients were taking antiretroviral medication (66.7% undergoing highly active antiretroviral therapy). Regarding necrotizing periodontal diseases, necrotizing ulcerative gingivitis (60%) was more prevalent than necrotizing ulcerative periodontitis (40%). The frequency of supragingival biofilm and bleeding on probing ranged from 11.5% to 59.2% and 3.0% to 54.0%, respectively, whereas the mean probing depth and clinical attachment level were between 1.48 and 2.61 mm and 1.30 and 2.62 mm, respectively. Species detected in high prevalence and/or counts in necrotizing lesions included Treponema denticola, Eikenella corrodens, Dialister pneumosintes, Enterococcus faecalis, Streptococcus intermedius, Aggregatibacter actinomycetemcomitans, and Campylobacter rectus. In contrast, Parvimonas micra, Prevotella melaninogenica, Fusobacterium nucleatum, Eubacterium nodatum, and Helicobacter pylori were observed in the lowest mean prevalence and/or counts. CONCLUSION: Necrotizing periodontal disease lesions in HIV-infected patients present a microbiota with high prevalence and/or counts of classical periodontal pathogens, in particular T denticola, as well as species not commonly considered as periodontal pathogens, such as E faecalis and D pneumosintes. In addition, these individuals with necrotizing periodontal disease frequently display severe immunodeficiency and AIDS-defining diseases such as tuberculosis. PMID- 22259812 TI - Effects of different acids and etching times on the bond strength of glass fiber reinforced composite root canal posts to composite core material. AB - OBJECTIVE: To investigate the effects of different acids and etching times on the bond strength of glass fiber-reinforced composite (FRC) posts to composite core material. METHOD AND MATERIALS: Twenty-six FRC posts (FRC Postec Plus) were randomly divided into 13 groups (each n = 2). One group received no surface treatment (control). The posts in the other groups were acid etched with 35% phosphoric acid and 5% and 9.6% hydrofluoric acid gel for four different etching times (30, 60, 120, and 180 seconds). A cylindric polytetrafluoroethylene mold was placed around the treated posts and filled with dual-cure composite core material (MultiCore Flow). All samples were light cured for 60 seconds. After 24 hours of water storage, the specimens were sectioned perpendicularly to the bonded interface under water cooling to obtain 2-mm post-and-core specimens. Eight specimens were made from each group. Push-out tests were performed at a crosshead speed of 0.5 mm/min using a universal testing machine. Data were analyzed by one-way ANOVA followed by the Tukey honestly significant difference test (alpha = .05). RESULTS: The lowest bond strength was observed in the control group (12.51 megapascal [MPa]). No statistical significant difference was observed among group H5-120 (20.31 MPa), group H9-120 (20.55 MPa), or group P-180 (20.57 MPa) (P > .05). These groups demonstrated the highest bond strength values (P < .05). CONCLUSION: For the FRC posts, all acid-etching procedures tested showed significantly increased bond strength when compared with the control group. Acid-etching with 5% hydrofluoric acid and 9.6% hydrofluoric acid for 2 minutes and with 35% phosphoric acid for 3 minutes (groups H5-120, H9-120, and P 180, respectively) demonstrated the highest bond strength values between the FRC post and composite core material. Although the bond strength was increased by prolonged acid etching, the microstructure of the FRC posts might have been damaged. PMID- 22259813 TI - Caries removal in primary teeth--a systematic review. AB - OBJECTIVE: This systematic review addressed what the ideal limit is for removing carious tissue to address a caries lesion. METHOD AND MATERIALS: The Medline, Cochrane, and PubMed databases were searched for abstracts of English-language articles published between 2000 and 2010 as well as randomized clinical trials about the total, partial, and/or nonmechanical removal of carious tissue in primary teeth. The analysis of the abstracts was performed individually by two reviewers. The full text of potentially relevant studies was obtained, analyzed based on criteria for quality assessment of a randomized clinical trial, and placed in an evidence-based table. RESULTS: After reading the abstracts, 151 articles were excluded. Six references met the inclusion criteria and were selected for full reading. After the reviewers consulted with one another, three papers were considered potentially relevant to this review. CONCLUSION: This analysis suggests that minimally invasive procedures for dental tissue are viable choices for stopping caries lesions. Partial or nonmechanical removal of carious tissue favors the arrest of dental caries lesions. PMID- 22259827 TI - Methodist Debakey Heart & Vascular Center update. PMID- 22259829 TI - [13th Annual Congress of the Croatian Rheumatologic Society, 20-23 October, 2011, Cavtat, Croatia]. PMID- 22259828 TI - Museum of TMH Multimodality Imaging Center. PMID- 22259830 TI - Self-Monitoring Blood Glucose Workshop I: Promoting meaningful dialogue and action at the provincial level. PMID- 22259831 TI - Self-Monitoring Blood Glucose Workshop II: Development and dissemination of the DCPNS decision tool for self-monitoring blood glucose in non-insulin-using type 2 diabetes. PMID- 22259832 TI - Improvements in sound attenuation performance with earplugs following checklist based self-practice. AB - The hearing protectors most often used in noisy workplaces are earplugs. The sound attenuation performance of earplugs depends in part on the user's skill and knowledge. This study sought to clarify whether individual training and self practice based on a checklist can improve sound attenuation. Measurements were performed as follows: Ten subjects, including both men and women, were provided with semi-insert earplugs (E-A-R flex 350-1001) and wore them based only on the printed instructions of the product. Sound attenuation was measured from 125 Hz to 8000 Hz, in accordance with JIS T8161-1983. Intervention was provided through 5 minute individual training with oral and written instructions, followed by 10 minute self-practice each day for 7 days. Sound attenuation was then measured once again. The results indicated significantly improved attenuation, ranging from 7.7 dB to 11.7 dB, in all frequencies following training, confirming the effectiveness of the intervention. This is an easy and effective method for training workers in how to wear earplugs most effectively. PMID- 22259833 TI - Status of occupational health and safety in Iran. AB - In recent decades, Iran has had a steadily growing economy with an annual rate of 6% on average. The country's economy is dominantly influenced by oil and natural gas production and related industries like petrochemicals and fertilizers. There are two million job units and sixteen million employees. The occupational health and safety (OHS) system is mainly regulated by two bodies: the Ministry of Health and Medical Education, responsible for occupational health services and legislations; and the Ministry of Labour and Social Affairs, which undertakes the enactment and enforcement of occupational safety legal issues. Inspectorates in each ministry carry out regular health and safety monitoring according to the OHS legislations. The most common occupational health disorders are musculoskeletal problems, respiratory diseases, noise induced hearing loss, and occupational injuries. Because the OHS is a complex system with overlapping responsibilities among the co-responders, its improvement needs well-organized collaboration among Iranian universities, industries, and governmental agencies, and reliable basic data. The present study takes a glance at the situation and activities of the Iranian OHS system. PMID- 22259834 TI - Apocrine carcinoma of the breast. AB - Apocrine carcinoma is a rare variant of breast carcinoma, and accounts for 0.3 to 1.0% of all breast cancers. A 55-year-old Japanese female patient presented with a right breast tumor, which had been detected by mass-screening, and she was admitted to our hospital. The physical examination revealed an elastic hard lump in the upper lateral quadrant of the right breast. The tumor size was approximately 1.0 cm in diameter, and the border was clear. There were no palpable axillary lymph nodes nor supraclavicular nodes. Fine-needle aspiration cytology revealed invasive ductal carcinoma. The patient underwent a partial resection of the right breast (breast conserving therapy) and a right axillary lymphadenectomy. Macroscopically, the resected specimen revealed a white tumor measuring 1.2 x 1.2 x 1.0 cm. The TNM classification was diagnosed as T1cN0M0 stage I. Histopathologically, the tumor revealed a proliferation of atypical epithelial cells with apocrine differentiation, arranged in a papillotubular or cribriform growth pattern with stromal invasion. The tumor cells showed irregular round-shaped nuclei often containing prominent nucleoli, and had particularly abundant eosinophilic granular cytoplasm. In the immunohistochemical analysis, these carcinoma cells were positive for Gross Cystic Disease Fluid Protein 15 and the androgen receptor, whereas they were negative for the estrogen and progesterone receptors. Immunohistochemical staining for Her2 using the HercepTest was found to be negative (score 0). Thus, the pathological diagnosis was apocrine carcinoma. There were no metastases in the axillary lymph nodes. The patient has had no recurrence in 8 years after surgery. PMID- 22259836 TI - Alopecia universalis following two sequential traffic accidents: possible association with increased Th1 and Th17 cells and decreased Th2 cells. AB - A 37-year-old Japanese man presented with alopecia after being involved in a traffic accident. An immunohistochemical study of the biopsy specimen demonstrated that CD8+ T cells infiltrated into hair follicles with satellite cell necrosis of keratinocytes. Four weeks after his initial visit, he again had another traffic accident. Despite the treatment with oral prednisolone and a topical steroid, the alopecia became universalis. Treatment with systemic and topical steroids was continued, and 12 weeks later, white vellus hairs grew over the whole scalp. Intracytoplasmic study revealed that there was a positive correlation between the severity of the alopecia and the increase of interferon gamma producing Th1 cells or interleukin (IL)-17 producing Th17 cells, whereas the number of IL-4 expressing Th2 cells was inversely proportional to the extent of alopecia. The autoimmune hair loss might occur via the activation of T helper 1 (Th1) and Th17 cells. PMID- 22259835 TI - Surgical treatment for a ruptured true posterior communicating artery aneurysm arising on the fetal-type posterior communicating artery--two case reports and review of the literature. AB - Only a small number of aneurysms arising on the posterior communicating artery itself (true Pcom aneurysm) have been reported. We report two cases of ruptured true Pcom aneurysms with some characteristic features of true Pcom aneurysm. A 43 year old man suffering from subarachnoid hemorrhage (SAH) had an aneurysm arising on the fetal-type Pcom artery itself, and underwent surgery for clipping. Most of the aneurysm was buried in the temporal lobe, so retraction of the temporal lobe was mandatory. During the retraction, premature rupture was encountered. After tentative dome clipping and the control of bleeding, complete clipping was achieved. Another patient, a 71 year old woman presenting with consciousness disturbance due to SAH, had an aneurysm on the fetal-type Pcom artery itself, and underwent surgery for clipping. It has been generally considered that hemodynamic factor plays an important role in the formation, the growth, and the rupture of the cerebral aneurysm. This factor is especially significant in true Pcom aneurysm formation and rupture. According to the literature, a combination of fetal type Pcom and formation of the true Pcom aneurysm has been reported in most cases (81.8%). Most of the aneurysm can be buried in the temporal lobe, and the retraction of the temporal lobe during the dissection of the neck would be necessary, which causes premature rupture of the true Pcom aneurysm. In the surgery for a true Pcom aneurysm, we should be aware of possible premature rupture when temporal lobe retraction is necessary. PMID- 22259837 TI - [Nontuberculous mycobacteria in wet areas of a hospital and standard residences]. AB - From 1998 to 2000, UOEH Hospital identified a problem with bronchoscopes which were contaminated with mycobacteria. While conducting research into the problem, we found an extensive amount of nontuberculous mycobacteria (NTM) in wet areas. In this study, we collected a total of 114 samples to screen wet areas such as drains and taps in our hospital and in standard residences. We used the Ziehl Neelsen staining method and specific PCR for mycobacteria. As a result, mycobacteria were detected in 96% (27/28) of hospital samples and 40% (34/86) of standard residential samples. Next, we tried to isolate mycobacteria. Eleven isolates from hospital samples and 24 isolates in standard residential samples were isolated through cultivation. Seventeen isolates of Mycobacterium gordonae were isolated. Four isolates of M avium were isolated exclusively in hospital samples. Three isolates of M. avium were resistant to 8 antimicrobial agents, including antituberculous agents. Two hospital isolates survived in phagocytes. Although 80% ethanol solution was effective in all 13 tested isolates, it was not effective in decontaminating the one drain we tested. After brushing the drain with 80% ethanol solution, mycobacteria were not detected for 3 months. This indicated to us that brushing with 80% ethanol solution was an effective procedure for eradicating mycobacteria. PMID- 22259838 TI - [Relationship between physical configuration of hood and velocity for local exhaust systems]. AB - The hood performance of a local exhaust ventilation system is determined by the capture velocity and the air flow rate. The equation proposed by Dalla Valle has been widely used to speculate this relationship. However, Dalla Valle used different formulae for slot and plain opening (rectangular) hoods, and the calculated values near the boundary between the slot and plain opening by these formulae do not always match each other. In this study, we measured capture velocity of four hoods by changing the distance from the hood face for different aspect ratios. We also tried to develop an empirical formula to express a relationship that could be applied to both types of hoods. As a result, it was found that the relationship between air velocity in front of exterior hoods and air flow rate could be expressed as the sum of two exponential functions with distance. In addition, when the hood aspect ratio was less than 9 the values of the capture velocity calculated by the proposed equation were in good agreement with the experimental ones. PMID- 22259839 TI - [Autophagy in liver diseases]. AB - Two major degradation systems exist in cells: the lysosome and proteasome. In the lysosome system, extracellular materials are degraded via endocytosis. Intracellular materials are degraded by autophagy, a cellular pathway crucial for various intracellular events. It has recently been demonstrated that autophagy is involved in the pathogenesis of various liver diseases. In hepatitis B or hepatitis C virus infection, autophagy is enhanced in hepatocytes. In hepatic steatosis, hepatocyte autophagy is inhibited. The expression of the autophagy protein is disrupted in hepatocellular carcinoma. I summarize recent advances in the study of the involvement of autophagy in various liver diseases. The regulation of autophagy in the liver may be a useful therapeutic strategy for various liver diseases. PMID- 22259840 TI - [Analysis of drug safety information using large-scale adverse drug reactions database]. AB - The worldwide situations of drug safety have changed dramatically. Drugs are used based on the evaluation of safety data collected in clinical practice worldwide. US Food Drug Administration collects spontaneous reports and requires manufacturers to report adverse drug reactions (ADRs) of US marketed drugs occurring worldwide. These worldwide data are available through the Adverse Event Reporting System (AERS) (about 4.1 million reports on about 3,073,340 patients, for 13 years: 1997.4th qr-2010.4th qr.). The current issues are how to analyze and utilize such large-scale safety data. Potential biases should always be kept in mind, because AERS is based on spontaneous reports. However, its huge volumes and exhaustiveness allow for sufficient scientific evaluation with the aid of current IT technology. Therefore, analysis of large-scale ADR database becomes a new research area not only from the medical science but also from the statistical viewpoint. In this report, I introduce some case studies in which we analyzed the AERS data on psychotropics including antipsychotics, antiepileptics, and antidepressants. Antipsychotics caused ADRs specific to each drug, and, in combination therapy, increased the incidences of diabetes mellitus, pancreatitis, and neuroleptic malignant syndrome; antiepileptics caused AEs (adverse events) including serious skin reactions such as Stevens-Johnson syndrome (SJS), congenital anomaly, and closed-angle glaucoma; and antidepressants caused AEs including serotonin syndrome, suicidal events, and congenital anomaly, and AEs occurring at a higher incidence for other indications, drugs often used in the elderly and AEs in combination therapy. We have analyzed ADRs associated with concomitant drug therapies using Bayesian approach. In the analysis we faced difficulties of overdispersion and we have to estimate a number of parameters, given a large number of target drugs as well as ADRs. In addition, ADR reports are not collected from uniform populations, we also have to consider the variations in the target populations. So, we use Bayesian statistics. Bayesian analysis has become feasible with advances in computer technologies and the Markov chain Monte Carlo (MCMC) methods. It allows us to analyze ADRs associated with concomitant drug therapies and estimate the ADR signals for each drug. Therefore, the analysis and evaluation of large-scale ADR database can provide important safety information in clinical practice and the studies on ADR database are the most important issues in ensuring the postmark safety of pharmaceutical products. PMID- 22259841 TI - [Regenerative medicine and characteristics of stem cells]. AB - Recently, regenerative medicine has attracted much attention as a newly developed medical technology capable of treating various previously untreatable diseases. Research in this field has been rapidly and competitively conducted, and a large national budget has been disbursed. In particular, great expectations exist for the establishment of iPS cells as a new method that should contribute to regenerative medicine. A new regulatory framework for controlling this new technology is necessary to ensure the efficacy and safety for all people involved, including patients, physicians, and biologic suppliers. An official meeting for the establishment of such a framework was organized by the MHLW between 2009 and 2010. In this article, the discussions held at the meeting and the conclusions that were made are explained. Furthermore, some interesting molecular features of stem cells for regenerative medicine will be introduced. PMID- 22259842 TI - [Current topics on inactivation of norovirus]. AB - Human norovirus is the most important foodborne virus in Japan. According to the statistics of food poisoning by the Ministry of Health, Labour, and Welfare (MHLW), the number of patients infected with norovirus has accounted for half of all the patients with food poisoning in recent years. One of the most important measures for the control of infectious diseases is establishing of techniques for inactivating pathogens. For the prevention of food poisoning caused by norovirus, MHLW recommends that foods be subjected to heat treatment at 85 degrees C for 1 min or more; moreover, it recommends the use of sodium hypochlorite to inactivate (disinfect) this virus. However, application of these treatments is not always feasible because heat results in denaturation and sodium hypochlorite can be toxic to the human body and can cause discoloration. Therefore, it is necessary to develop and improve the efficacy of disinfectants and physiochemical treatments against the virus. Human norovirus cannot be propagated in cell culture or in a small animal. This matter is the greatest hindrance for testing the stability of this virus in environments or for evaluating the efficacy of disinfectants, heat treatment, pH treatment, ultraviolet or gamma irradiation, high hydrostatic pressure treatment, and other methods for the inactivation of the virus. Hence, some viruses such as human enterovirus, feline calicivirus, or mouse norovirus have been used as surrogates of human norovirus. The data on inactivation and stability of surrogate viruses are exclusively used as the data of human noroviruses. In recent years, some attempts to distinguish between infectious and noninfectious virus particles by genetic methods such as polymerase chain reaction have been made. These methods include pretreatments by RNase for digesting viral RNAs from non-intact or destroyed virus particles, or addition of a reagent such as ethidium monoazide for inhibiting PCR amplification of viral RNAs from them, before RNA extraction. Non-intact virus particles, which may represent virus particles with some damage (s) in the structural protein(s), are not necessarily synonymous with non-infectious virus particles. However, the results of methods using these treatments, compared to the results of traditional methods without these treatments, seem to be more correlated to the amount of the infectious virus particles. Although many disinfectants or physiochemical treatments have been reported, traditional techniques such as removal of virus particles by washing in running water, heat treatment, or disinfection by sodium hypochlorite are still important control measures. Establishment of control measures for human norovirus and successful propagation of the virus in cell culture are strongly desired. PMID- 22259843 TI - [Determination of the particle size and relative light scattering intensity of aggregates of human IgG and humanized monoclonal antibody product induced by various stress using dynamic light scattering]. AB - To evaluate the usefulness of dynamic light scattering for the analysis of aggregates in the manufacturing process of monoclonal antibody and its final product, the particle size and relative light scattering intensity of aggregates of human IgG and humanized monoclonal antibody product induced by various stress such as stirring, increasing temperature, shaking and freeze-thaw were determined using dynamic light scattering. It was found that 1.3% of relative light scattering intensity as the minimum range and the range of particle size from 28.91nm to 3,000 nm of aggregates induced were determined by dynamic light scattering. These findings indicate that dynamic light scattering is useful for the in-process control tests of aggregates during the manufacturing and evaluation tests of aggregates for final products including the formulation and the storage. Some points well taken at the application of dynamic light scattering are discussed from the viewpoint of its merits and demerits. PMID- 22259844 TI - [Detection methods of enterohemorrhagic Escherichia coli O111 in beef: a collaborative study]. AB - To establish a detection method for enterohemorrhagic Escherichia coli (EHEC) O111 in meat, a single-laboratory evaluation and a collaborative study were conducted focusing on comparisons of the efficiencies in combination with enrichment, a direct plating method and a plating method with immunomagnetic separation (IMS-plating method) using various agar media for EHEC O111, loop mediated isothermal amplification (LAMP) assay targeting the Verocytotoxin (VT) gene as a molecular detection method. On a single-laboratory evaluation, enrichment in modified EC at 36 degrees C was inferior to that in modified EC supplemented with novobiocin (NmEC) and mEC at 42 degrees C to isolate EHEC O111 by plating methods. On a collaborative study, there were no significant differences between combinations of enrichment in NmEC at 42 degrees C-LAMP assay and enrichment in mEC at 42 degrees C-LAMP assay. The combinations of enrichment in NmEC at 42 degrees C-direct plating and enrichment in NmEC at 42 degrees C-IMS plating were superior to combinations of enrichment in mEC at 42 degrees C-direct plating and enrichment in mEC at 42 degrees C-IMS-plating (p<0.05). There were no significant differences among the six different agar media by the direct plating and IMS-plating methods. As a result, it was suggested that the following methods are adequate for detection of EHEC O111 in beef: combinations of enrichment in NmEC at 42 degrees C, and direct plating and IMS-plating methods, or LAMP assay as a screening assay to detect VT gene followed by direct plating and IMS-plating methods. PMID- 22259845 TI - Chemical category approach of genotoxicity studies for branched alkylphenols. AB - A chemical category is a group of chemicals whose toxicological properties are expected to be similar or follow a regular pattern as a result of structural similarity. The category approach is beneficial for decreasing in the resource of risk assessment for huge amount of unevaluated existing chemicals, and also in the use of all kinds of animal tests including even in vivo genotoxicity tests from a point of view of the animal welfare. The present paper reports the results of in vivo micronucleus tests of o-sec-butylphenol (CAS:89-72-5) and 2-isopropyl 5-methylphenol (CAS:89-83-8) and discusses genotoxic potential of seven alkylphenols, o-sec-butylphenol, 2-isopropyl-5-methylphenol, p-sec-butylphenol (CAS:99-71-8), 2-tert-butylphenol (CAS:88-18-6), 2, 4-di-tert-butylphenol (CAS:96 76-4), 4-tert-butylphenol (CAS:98-54-4) and 6-tert-butyl-m-cresole (CAS:88-60-8) by the category approach. Based on the negative results of in vivo micronucleus tests, it can be concluded that these category chemicals are not likely clastogenic in vivo. Further in vivo micronucleus assays on untested substances may not be required by using the category approach, but further supporting information such as physicochemical profiles and (Q) SAR predictions may be necessary to strengthen the rationale for the category approach. PMID- 22259846 TI - [Volatile organic compounds (VOCs) emitted from large furniture]. AB - Indoor air pollution by volatile organic compounds (VOCs), which may cause a hazardous influence on human being such as sick building (sick house) syndrome, has become a serious problem. In this study, VOCs emitted from nine pieces of home furniture, three sets of dining tables, three sets of chest of drawers and three sofas, were analyzed as potential sources of indoor air pollution by large chamber test method (JIS A 1911). Based on the emission rates of total VOC (TVOC), the impacts on the indoor TVOC was estimated by the sample model with a volume of 20 m3 and ventilation frequency of 0.5 times/h. The estimated TVOC increment values were exceeded the provisional target value for indoor air (400 microg/m3) in three sets of dining tables, one set of chest of drawer and one sofa. The estimated increment of formaldehyde were exceeded the guideline value (100 microg/m3) in one set of dining table, two sets of chest of drawers and one sofa. These results revealed that VOC emissions from furniture may influence significantly indoor air quality. Also, in this study, to establish the alternative method for large chamber test methods, emission rates from representative three parts of furniture unit were evaluated using the small chamber and emission rate from full-sized furniture was predicted. Emission rates of TVOC and formaldehyde predicted by small chamber test were 3-46% and 6-252% of the data obtained using large chamber test, respectively. PMID- 22259847 TI - [Volatile organic compounds (VOCs) emitted from wood furniture--estimation of emission rate by passive flux sampler]. AB - The aim of this study was to evaluate aldehydes and other volatile organic compounds (VOCs) emission from furniture, which may cause hazardous influence on human being such as sick building/sick house syndrome. In this study, VOCs emitted from six kinds of wood furniture, including three set of dining tables and three beds, were analyzed by large chamber test method (JIS A 1911). Based on the emission rates of total VOCs (TVOC), the impacts on the indoor TVOC was estimated by the simulation model with volume of 20 m3 and ventilation frequency of 0.5 times/h. The estimated increment of formaldehyde were exceeded the guideline value (100 microg/m3) in one set of dining table and one bed. The estimated TVOC increment values were exceeded the provisional target value for indoor air (400 microg/m3) in two sets of dining tables and two beds. These results revealed that VOC emissions from wood furniture may influence significantly indoor air quality. Also, in this study, to establish the alternative method for large chamber test methods, emission rates from representative five areas of furniture unit were evaluated by passive sampling method using flux sampler and emission rate from full-sized furniture was predicted. Emission rates predicted by flux passive sampler were 10-106% (formaldehyde) and 8-141% (TVOC) of the data measured using large chamber test, respectively. PMID- 22259848 TI - [Analysis of volcanic-ash-based insoluble ingredients of facial cleansers]. AB - The substance termed "Shirasu balloons", produced by the heat treatment of volcanic silicates, is in the form of hollow glass microspheres. Recently, this substance has gained popularity as an ingredient of facial cleansers currently available in the market, because it lends a refreshing and smooth feeling after use. However, reports of eye injury after use of a facial cleanser containing a substance made from volcanic ashes are on the rise. We presumed that the shape and size of these volcanic-ash-based ingredients would be the cause of such injuries. Therefore, in this study, we first developed a method for extracting water-insoluble ingredients such as "Shirasu balloons" from the facial cleansers, and then, we examined their shapes and sizes. The insoluble ingredients extracted from the cleansers were mainly those derived from volcanic silicates. A part of the ingredients remained in the form of glass microspheres, but for the most part, the ingredients were present in various forms, such as fragments of broken glass. Some of the fragments were larger than 75 microm in length. Foreign objects having a certain hardness, shape, and size (e.g., size greater than 75 microm) can possibly cause eye injury. We further examined insoluble ingredients of facial scrubs, such as artificial mineral complexes, mud, charcoal, and polymers, except for volcanic-silicate-based ingredients. The amounts of insoluble ingredients extracted from these scrubs were small and did not have a sharp edge. Some scrubs had ingredients with particles larger than 75 microm in size, but their specific gravities were small and their hardness values were much lower than those of glass microspheres of ingredients such as "Shirasu balloons". Because the fragments of glass microspheres can possibly cause eye injury, the facial cleansers containing large insoluble ingredients derived from volcanic ashes should be avoided to use around eyes. PMID- 22259849 TI - [Analytical method for natamycin in wine using high-performance liquid chromatography]. AB - An analytical method was developed for determining amount of natamycin in wine using a C18 minicartridge column and high-performance liquid chromatography (HPLC) with photodiode array (PDA) detection. Natamycin purified from wine was identified in accordance with the retention time and UV spectrum obtained from PDA detection. The limit of quantification of natamycin in wine was estimated as 0.05 microg/ml. Recovery of natamycin in wine was acceptable at 91.0% with low relative standard deviation (2.3%). PMID- 22259850 TI - [Effects of transplacental and trans-breast milk exposure to the organophosphate compound chlorpyrifos on the developing immune system of mice]. AB - Navarro et al (2001) have reported that neonatal exposure of rat to the organophosphate compound chlorpyrifos (CPF) resulted in long-term deficits in T lymphocyte mitogenic response, although the mechanism has been unclear. In this study, pregnant BALB/c mice were exposed to 0, 2.8, 14, 70 ppm CPF via diet from gestational day 10 to postnatal day (PND) 21, and subpopulational changes in T lymphocytes of offspring were analyzed at PND21. The irreversibility of the effects was also investigated at PND77 after ceasing exposure by weaning at PND21. Serum cholinesterase activity was significantly reduced after exposure to CPF at PND21. An increase in the proportion of CD4 positive splenocytes was observed after exposure to CPF, which remained until PND77. We found that regulatory T cells were the only one CD4 positive subset which increased in the spleen of CPF-exposed mice at PND77. PMID- 22259851 TI - [Current movements of four serious adverse events induced by medicinal drugs based on spontaneous reports in Japan]. AB - Spontaneous reports on suspected serious adverse events caused by medicines from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated by the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety features. Although causal relationship between the medicine and the adverse event is not evaluated, and one incidence may be redundantly reported, this information would be useful to roughly grasp the current movements of drug-related serious adverse events, We searched open-source data of the spontaneous reports publicized by Pharmaceutical and Medical Devices Agency for 4 serious adverse events (interstitial lung disease, rhabdomyolysis, anaphylaxis, and Stevens-Johnson syndrome/toxic epidermal necrolysis) from 2004 to 2010 fiscal year (for 2010, from April 1 st to January 31th). Major drug-classes suspected to the adverse events were antineoplastics for interstitial lung disease, hyperlipidemia agents and psychotropics for rhabdomyolysis, antibiotics/chemotherapeutics, antineoplastics and intracorporeal diagnostic agents for anaphylaxis (anaphylactic shock, anaphylactic reactions, anaphylactoid shock and anaphylactoid reactions), and antibiotics/chemotherapeutics, antipyretics and analgesics, anti-inflammatory agents/common cold drugs, and antiepileptics for Stevens-Johnson syndrome/toxic epidermal necrolysis. These results would help understanding of current situations of the 4 drug-related serious adverse events in Japan. PMID- 22259852 TI - [Food-poisoning bacterial contamination on food: a comparison between European countries and Japan]. AB - "Shokuhin no shokuchudokukin osenjittai chosa (The national survey of food poisoning bacterial contamination on food)" has been performed annually in Japan since 1998. This surveillance is thought to be the useful baseline study of bacterial contamination on food in Japan. On the other hand, "The community summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in the European Union" published by the European Food Safety Authority (EFSA) is the annual surveillance report about zoonoses, zoonotic agents and food borne outbreaks in the European Union based on the Directive 2003/99/EC. The results of these annual surveillances in the EU and Japan were summarized for comparing the baseline of bacterial contamination on food between European countries and Japan. PMID- 22259853 TI - [Study of radiation dose rate in air at Setagaya in Tokyo]. AB - The great earthquake occurred at East Japan on March 11, 2011 and the following tsunami induced the accident which environmentally leaked radioactive materials from the nuclear power plant of the Fukushima Daiichi. We measured radiation dose rate in air by the NaI (Tl) scintillation and GM survey meters from March 15 to May 30 at Setagaya in Tokyo. Three measured points were at the 1m height from the ground on asphalt surfaced road, at the 5cm height from ground with weeds, and at the room of a reinforced concrete building. As a result, a transient increase was observed on March 15, a sustained rise was observed on both days of March 21 and 22. The latter was thought to be due to the radioactive rainfall. These measured values were compared with the radiation dose rate in air of the cities in Kanto area, and it was confirmed that the measured values at Setagaya are not so different from that of those cities. PMID- 22259854 TI - [Analysis of the changes of amide A in rabbit heart after death by FTIR spectroscopy]. AB - OBJECTIVE: To explore the relationship of changes of amide A in rabbit heart and the postmortem interval (PMI) by FTIR spectroscopy technique. METHODS: Thirty-two rabbits were sacrificed and the hearts were sampled at 20 degrees C within 48 h postmortem points. All samples were sliced and tested by FTIR spectroscopy technique. The images of amide A were created by FTIR spectroscopic imaging. The positive and negative area ratios of amide A were analyzed using imaging analysis system. RESULTS: The positive and negative area ratios declined regularly with the prolongation of death time in 48 h. There was a significant quadric relationship between the area ratios (y) of amide A (positive and negative area) and PMI(x). The regression equation was y = 0.001x2-0.038x + 0.747(R2 = 0.940). CONCLUSION: The ratios of positive and negative area of amide A showed a strong correlation with PMI and could be used to estimate PMI. PMID- 22259855 TI - [Diatom test in lung tissue of corpses in water and causes of death]. AB - OBJECTIVE: To explore potential application of diatom test of lung tissue in investigation of cause of death in victim found in the water. METHODS: Four hundred and seven cases were collected and analyzed for cause of death and the nature of case. Diatom test was performed in tissues and the amount was quantified. Forty-five rabbits died in the water (antemortem, postmortem and different seasons drowning) were randomly divided into 9 groups and the diatom content in lung tissue were tested with the method of nitric acid. RESULTS: In 407 drowning cases, 372 cases showed a positive result of diatom test. In positive cases, the amount of accidents or suicide were 35 and homicide were 21. Thirty-five cases showed negative result of diatom test and majority were homicide in which bodies were thrown into the water after killing. Some drowning cases were in special circumstances. Animal experiments confirmed that a large amount of diatoms in lung tissue were detected in drowning victim and showed the same type in water. The amount of diatom in lung tissue was usually lower in the summer and winter comparing with spring and autumn. CONCLUSION: The diatom test could be considered as an auxiliary evidence in determination of cause of death in body found in the water. The test results were related with manner of death. The nature of case should be synthetically determined based on autopsy, criminal scene and details of the cases, etc. PMID- 22259856 TI - [Influence of visual attention in visual evoked potential examination]. AB - OBJECTIVE: To explore the influence of visual attention in visual evoked potential (VEP) examination. METHODS: The pattern visual evoked potential (PVEP) and flash visual evoked potential (FVEP) were used to examine 110 normal subjects whose visual acuity or corrected visual acuity is in the range of 4.8-5.2, and age between 20 to 30 years old. In PVEP inspection, subjects were asked to watch with three ways, to stare at the central screen (at the same time count silently the number of alternating of black and white squares to improve the subjects' attention), to stare at the central screen at the same time thinking other things, to look sideways (the left eye stared at the left bottom corner of the screen or the right eye stared at the right one). In FVEP inspection, subjects were checked with eyes open and closed respectively. The latency and amplitude of P100 wave were recorded. The data were statistically analyzed by SPSS 13.0 software. RESULTS In PVEP inspection, the latency and amplitude of P100 wave were statistically different among three watching ways. In FVEP inspection, latency and amplitude of P100 wave were statistically different between eyes open and closed group. CONCLUSION: Although the visual evoked potential test is an objective electrophysiological visual function test, it is susceptible to the influence of various subjective factors such as visual attention. It should arise the attention of forensic experts. PMID- 22259857 TI - [Establishment of universal algorithms for commonly used kinship indices between two individuals]. AB - OBJECTIVE: To establish universal algorithms for commonly used kinship indices between two individuals. METHODS: Based on the formulas of paternity index in duos(PID), full sibling index(FSI), half sibling index (HSI), avuncular index (AI), grandparental index (GI) and first cousin index (CI1st) deduced from ITO method, the common factors, 1 plus reciprocal of the frequency of the allele with identity by state between the two individuals, shared in these formulas were abstracted with induction method, following with reconstruction of these formulas with the common factor and the coefficient of relationship (r). RESULTS: A universal algorithm for PI(D), HSI, AI, GI and CI1st, was developed with the common factor and r value according to the heterozygosity of the two individuals. Meanwhile, a group of two formulas for FSI calculation was also established according to the individuals' heterozygosity. CONCLUSION: The universal algorithms for the 6 types of kinship indices are practical in corresponding kinship determination and the batch arithmetic operation with the universal algorithms can be easily programmed. PMID- 22259858 TI - [Universal algoritihms for paternity index in trios and its extended application]. AB - OBJECTIVE: To introduce an universal algorithm for kinship index between a baby and a random person with biologic mother reference. METHODS: Based on the formulas of paternity index in trios (PIT), common factors shared in these formulas were deduced following reconstructions of these formulas with the common factors. Universal algorithms for other common kinship indices, such as grandparental index (GI), half sibling index (HSI), avuncular index (AI) and first cousin index (CI1st), were investigated according to avuncular index rule and the coefficient of relationship (r). RESULTS: The common factor shared in the formulas for PI(T) calculation was 1 plus reciprocal of the frequency of the allele with identity by state between the alleged father and the detected baby. Two general formulas for PI(T), GI, AI, HSI and CI1st with biologic mother reference were successfully established with the common factor and r value. CONCLUSION: The calculation was simplified with the universal algorithms for common kinship indices between random person and the baby with biologic mother reference and the batch arithmetic operation with the universal algorithms can be easily realized with programming. PMID- 22259859 TI - [Genotyping and linkage disequilibrium analysis of 67 SNP loci on X chromosome]. AB - OBJECTIVE: To screen a panel of SNP loci on X chromosome (X-SNP loci) that is informative in Chinese Han population and evaluate its potential value in forensic identification. METHODS: Sixty-seven candidate X-SNP loci were selected according to the information on dbSNP and HapMap. Genomic DNA extracted from blood samples of 428 unrelated Chinese Han individuals were analyzed through multiplex amplification followed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry, and allele frequencies of the 67 X-SNP loci were calculated. In view of the population data and situation of linkage disequilibrium, X-SNP markers promising in forensic identification were sorted out. RESULTS: Population data of the 67 X-SNP loci were obtained. Except rs12849634, no deviations from Hardy-Weinberg equilibrium could be found. Of the rest 66 X-SNP loci, two loci (rs1229078 and rs1544545) were found to be low informative (minor allele frequency < 0.3). Closely linked alleles were observed at six pairs of X-SNP loci and slightly linked alleles were observed at two pairs of X-SNP loci. Fifty-two X-SNP loci showing independent inheritance and high polymorphisms were finally selected. The markers were promising in forensic identification. CPE in trio and duo cases were 0.999 999 999 96 and 0.999 999 5, respectively. CDP in female and male populations were 0.999 999 999 999 999 999 999 84 and 0.999 999 999 999 999 31, respectively. CONCLUSION: A panel of 52 informative X-SNP loci showing independent inheritance is selected. These markers meet the needs of individual identification and relationship testing in judicially disputed cases. PMID- 22259860 TI - [Application of modified overt aggression scales on risk behavior assessment of patients with mental illness]. AB - OBJECTIVE: To explore the value of Modified Overt Aggression Scales (MOAS) in assessing risk behavior of patients with mental illness. METHODS: Four hundred and ninety patients, who were from three mental health institutions (Refined Control Ward in Ankang Hospital, Mental Health Center of West China Hospital, Relief Ward in De Kang Hospital) belong to public security, health and civil system respectively, were evaluated with MOAS. RESULTS: Three hundred and thirteen patients did not have dangerous behavior, but 177 patients did (99 aggression, 78 violence). The descending order of risk behavior in patients with mental illness were Refined Control Ward in Ankang Hospital, Mental Health Center of West China Hospital, Relief Ward in De Kang Hospital. Physical and total aggression scores were higher in Refined Control Ward in Ankang Hospital than that in other two hospitals (P < 0.05). Autoaggression score in Mental Health Center of West China Hospital was higher than that in other two hospitals (P < 0.05). Physical and total aggression scores in male were higher than that in female (P < 0.05). Autoaggression score in female was higher than that in male (P < 0.05). Score of every single item and total score were higher in violent and aggressive group than that in non dangerous behavior group (P < 0.05). Physical and total aggression scores in violent group were higher than that in aggressive group (P < 0.05). CONCLUSION: The proportion, type and degree of risk behaviors in three mental health institutions are different and the type of risk behavior has gender difference. PMID- 22259861 TI - [Evaluating on recognition impairment after traumatic brain injury with WCST]. AB - OBJECTIVE: To explore the value of Wisconsin Card Sorting Test (WCST) in evaluating the recognition impairment after traumatic brain injury (TB1). METHODS: WCST and Wechsler Adult Intelligence Scale Revised in China (WAIS-RC) were adopted to assess the cognitive function in 186 patients with brain injury (experimental group) and 180 healthy volunteers (control group), respectively. The cognition between the experimental group and the control group was compared. The correlation between WCST and IQ was analyzed. The correlation between age, education level, the severity of TBI and the executive function were also analyzed. RESULTS: (1) The performances of WAIS-RC and WCST in the experimental group were significantly worse than that of the control group. (2) There were significantly negative correlation between the performance of total errors, percentage of preservative errors, percentage of random errors, response number on first category and IQ (P < 0.05). While there were significantly positive correlation between the categories completed, percentage of conceptual level and IQ (P < 0.05). (3) There was significantly negative correlation between percentage of conceptual level and the severity of TBI. While there were significantly positive correlation between percentage of preservative errors, percentage of random errors, response number on first category and the severity of TBI. CONCLUSION: WCST could be an important method in evaluating cognition of patients with brain injury. PMID- 22259862 TI - [Determination of doxepin in whole blood by SPE-LC-MS/MS]. AB - OBJECTIVE: To develop a method of SPE-LC-MS/MS for the determination of doxepin in whole blood. METHODS: After solid phase extraction, the samples were identified by LC-MS/MS. Positive ion electrospray ionization mode and multiple reaction monitoring (MRM) mode was selected. Amitriptyline was used as internal standard. The m/z of doxepin: 280-->107, 280-->235 and 280-->220. The m/z of amitriptyline: 278-->233. The retaining time of doxepin and amitriptyline were 15.15 and 16.94 min, respectively. RESULTS: The calibration curve was linear among the concentration of doxepin range from 0.005 to 1.00 microg/mL. The linear correlation equation was y = 3.2047x + 0.0339, the correlation coefficient was 0.9996. The detection limit of doxepin was 0.001 microg/mL and average recovery rate was 78.0%-82.9%. The relative standard precision for within-day and between day were less than 2.55% and 5.90%, respectively. CONCLUSION: The method is effective, simple, reliable and can be used in the determination of doxepin in whole blood. PMID- 22259863 TI - [Analysis of death cases involved in TASER in the State of Maryland]. AB - OBJECTIVE: To evaluate the features of autopsy cases involved in electronic weapon (TASER) in the State of Maryland, and to discuss the appraisable points. METHODS: Thirteen autopsy cases involving TASER were collected from 2004 to 2011 in the Office of the Chief Medical Examiner, State of Maryland. All the cases include detailed scene investigations, complete autopsy, toxicological analysis and histopathological examination. Statistical analysis were conducted including general information of victim, type of TASER, type of contact, toxicological results, manner and cause of death. RESULTS: Majority of victims were male with an acute onset of agitated and delusional behavior. Drugs were often involved. Deaths were attributed to multiple factors. CONCLUSION: Most of cases involved in TASER resulted from multiple fatal factors. Further researches are needed for the principal mechanism. Thorough scene investigation and complete autopsy examination play crucial role in evaluation of such cases. PMID- 22259864 TI - [Analysis of 57 abdominal penetrating injury cases with exploratory laparotomy]. AB - OBJECTIVE: To explore the characteristics of abdominal penetrating injuries with exploratory laparotomy, as well as to summarize the key points of injury degree, and to supply reasonable reference for the practice and criterion modification in forensic clinical medicine identification. METHODS Fifty-seven cases which were all abdominal penetrating injuries with exploratory laparotomy from July 1990 to February 2011 were retrospectively analyzed including the instrument causing trauma, amount of the hemoperitoneum, the organs of the injury, conclusion of the forensic indentification, and so on. RESULTS: There was some correlation between the organ injury patterns, volume of hemoperitoneum and identification conclusion for the abdominal penetrating injury cases with exploratory laparotomy. CONCLUSION The intra-abdominal injury has important effect for the injury degree of the abdominal penetrating injury cases with exploratory laparotomy and should be considered in the practice and criterion modification of these kinds of cases. PMID- 22259865 TI - [Analysis of 54 mental disability reappraisal cases due to brain damage]. AB - OBJECTIVE: To investigate the different kinds of controversial cases of mental disability after brain damage, to analysis the problems in the first appraisal, and to explore solutions of the problems. METHODS: The reappraisals of mental disorders after traumatic brain damage were collected from 2007-2011 in Shanghai forensic center, and the first appraisal and reappraisal cases were analyzed and compared. RESULTS: The changes of conclusion in reappraisal cases showed the following major reasons: inappropriate appraisal time, not comprehensive and object investigation of mental state of patients in first appraisal, misunderstanding the standards, etc. CONCLUSION: The quality improvement of appraisal should adopt the following measures: regulating the practice, improvement of the professional skills of experts, choosing appropriate appraisal time, improvement of appraisal standards, etc. PMID- 22259866 TI - [Forensic application of investigator Argus X-12 kit in Han population from East China]. AB - OBJECTIVE: To investigate the genetic data of the 12 X-STR included in Investigator Argus X-12 kit and to evaluate the forensic application in Han population from East China. 9: By detecting 309 unrelated individuals with Investigator Argus X-12 kit, allele frequencies, population genetics parameters and the information of linkage disequilibrium of the 12 X-STR were analyzed by statistics and were compared with available data of other Han populations from different regions. RESULTS: No deviations from Hardy-Weinberg equilibrium were detected. Except loci of DXS10103 and DXS10101 linked closely, all other loci were independent while HET exceed 0.5 and PIC all above 0.4. Distributions of allele frequencies of all loci were not significant statistically except for locus of DXS10146 in Han population from Guangdong. CONCLUSION: Loci of Investigator Argus X-12 kit were highly polymorphic in Han population from East China, which is suitable for forensic application in paternity testing and individual identification. PMID- 22259867 TI - [Application of brain natriuretic peptide in evaluation of cardiac function in forensic medicine]. AB - Brain natriuretic peptide (BNP) is a major marker for evaluating cardiac function and has been widely used in clinical practice. Recent researches show that BNP is also useful for identification of sudden cardiac death in forensic pathology. This article reviews the molecular structure and biological characteristics of the BNP and its application as a functional indicate in forensic medicine. It shows that the expression of BNP in cardiac muscles, together with the expression of BNP in blood and pericardium liquid can be used to evaluate the pathological physiology changes and dysfunction degrees of the heart during the cardiac sudden death. PMID- 22259868 TI - [Costicartilage analysis inspection technology in the application of forensic medicine]. AB - The traditional costicartilage analysis inspection is limited to morphological inspection. In recent years, with the development of forensic radiology and molecular genetics, the costicartilage analysis inspection technology has been further enriched and developed. At present, the costicartilage analysis inspection technology have been able to be used in the practice of forensic medicine. This paper reviews the research advances about the costicartilage analysis inspection technology in the identification of human gender, age and so on in order to provide the references for forensic appraisers. PMID- 22259869 TI - [Application of liquid chromatography-high resolution mass spectrometry in toxicological screening]. AB - Due to the diversity of toxicologically relevant substances, the uncertainty of target compounds and the specificity of samples, toxicological screening techniques have always been valued by the forensic toxicologists. Depending on its powerful separation ability, superhigh resolution and accurate mass measurement, combined with the two levels spectrum database matching and abundance ratio of isotope ion, the liquid chromatography-high resolution mass spectrometry (LC-HRMS) analyzers have increasingly advantage in screening and identification of chemical compound. This review focuses on the applications of LC-HRMS in screening and identification of drug-of-abuse, prescription drugs, pesticide and stimulant. The prospect of LC-HRMS in forensic toxicology analysis is also included. PMID- 22259870 TI - U.S. Preventive Services Task Force recommendations highly authoritative. PMID- 22259871 TI - Treating uterine fibroids using MR-guided ultrasound. PMID- 22259873 TI - Physicians who want to work for hospitals. PMID- 22259872 TI - Plans can help manage dually eligible population. PMID- 22259874 TI - Health plans and Medicare step up to eliminate costly variation. PMID- 22259875 TI - A conversation with Lee N. Newcomer, MD, MHA. Payments with purpose. Interview by John Marcille. PMID- 22259876 TI - New hepatitis C regimen stimulates changes in therapy management. PMID- 22259877 TI - Human factors inhibit medication adherence. PMID- 22259878 TI - Copayment coupons undermine formularies. PMID- 22259879 TI - Long-term safety data support use of bronchial thermoplasty. PMID- 22259880 TI - Seven therapeutic categories account for most drug cost increases. PMID- 22259881 TI - Combat drug resistance. PMID- 22259882 TI - Evaluation of two doses of triclabendazole in treatment of patients with combined schistosomiasis and fascioliasis. AB - To determine the safety and efficacy of 2 consecutive doses of triclabendazole (TCBZ) in the treatment of Schistosoma mansoni infection in human cases infected with both S. mansoni and Fasciola sp., we conducted a field survey involving 6314 individuals from 15 villages. The overall prevalence of schistosomiasis alone was 15.8%, of fascioliasis alone 2.2%, and of combined infection 0.7%. Treatment with 2 doses of TCBZ was given to the 49 cases with combined infection. Eight weeks after treatment, the cure rate was 96% for fascioliasis and was 32.7% for schistosomiasis. All schistosomiasis cases cured had a low intensity infection. Liver function tests done before treatment and 8 weeks after substantiate the safety of 2 doses of TCBZ given to those with combined infection. Administration of TCBZ should precede praziquantel in treatment of combined infection, however TCBZ cannot be recommended for infection with S. mansoni alone. PMID- 22259883 TI - Female spouses of injection drug users in Pakistan: a bridge population of the HIV epidemic? AB - An estimated 21% of injection drug users (IDUs) in Pakistan are HIV-positive and data suggest that the spouses of IDUs may be a critical component of the HIV transmission chain. This study interviewed 101 spouses of male IDUs about their sexual practices and drug use. We found that 43% had been sexually active with their partners in the past month but only 4% reported selling sex. Almost a quarter (23%) used drugs and 19% injected drugs, usually a combination of diazepam and pheniramine. Although sex work was infrequent among spouses of IDUs, their risk of contracting HIV and transmitting it to others was high because they received injection drugs, sometimes along with their IDU husbands, from the same health centres that provided therapeutic injections to the rest of the community. IDU spouses may thus serve as a bridge group via therapeutic injections, rather than via sex work. PMID- 22259884 TI - Low rate of placental pathological examination in a tertiary care hospital in Sana'a, Yemen. AB - The aim of this study was to evaluate the rate of submission of placentas for pathological examination and compare the observed and expected numbers of placentas submitted. Records were reviewed for all deliveries occurring at a tertiary care hospital in Sana'a, Yemen, during 2007. Data from pathology department records were compared with data on pathology request forms. The observed and expected numbers of placentas examined were compared. Of 11 472 placentas delivered, 1501 were expected to be pathologically examined, based on College of American Pathologists indications. Only 73 of these (4.9%) had actually been examined. The examination rates for conditions associated with the possible recurrence risks in the subsequent pregnancies were low, below 20%. Only 42% of the pathology request forms gave detailed clinical histories and 0% gave information about Apgar scores. Placental pathological examination was under utilized in this hospital. PMID- 22259885 TI - Relationship between maternal characteristics and neonatal birth size in Egypt. AB - This study in Egypt investigated the influence of selected maternal factors on neonatal birth size. Data were collected after delivery from 782 apparently healthy pregnant women and their neonates. A questionnaire on personal, medical, socioeconomic status, smoking habits and exposure to smoking was completed. Maternal weight and height, food frequency intake during pregnancy and haemoglobin levels were recorded for 594, 234 and 246 of the mothers respectively. Neonatal birth weight, length and head circumferences were measured. A significant positive correlation between maternal anthropometric variables with neonatal birth dimensions was observed and the effect was more evident in girls than boys for BMI and head circumference. Statistically significant negative correlations were found between maternal haemoglobin levels and birth size. Birth size was strongly correlated with maternal consumption of micronutrient-rich food at all stages of gestation. Passive smoking significantly affected birth weight and BMI of girls more than boys. PMID- 22259886 TI - Relationship between birth weight and domestic maternal passive smoking exposure. AB - This study aimed to assess the relationship between birth weight and maternal exposure to passive smoking during pregnancy, and to investigate some other determinants of birth weight. A retrospective cohort study in Baghdad, Iraq was conducted during February to August 2004 on a random sample of 300 non-smoker housewife mothers, interviewed 24 hours after delivery: 150 were not exposed to passive smoking at home and 150 were exposed. The mean birth weight of exposed newborns was significantly lower than non-exposed newborns. In exposed newborns, a significant inverse relationship was noticed between birth weight and the number of cigarettes smoked by household members (r = -0.27). Multiple regression analysis showed that after controlling for all the variables studied, birth weight had a significant inverse correlation with the maternal exposure to passive smoking and a positive correlation with adequate antenatal care. PMID- 22259887 TI - Knowledge and attitude about antismoking legislation in Morocco according to smoking status. AB - Despite tobacco control legislation enacted in Morocco in 1996, the Moroccan population appears to have little interest in or awareness of tobacco control measures. This household survey aimed to assess sectional study was conducted on a random sample of 9195 Moroccans. Only 33.3% knew about the antismoking legislation: 38.7% of smokers versus 32.3% of non-smokers. Among the 3050 people who knew about the law, 60.1% knew about the ban on smoking in public areas and 22.4% knew there was an obligatory health warning on tobacco packaging. The attitude questions showed that 27.2% agreed that the price of tobacco products should increase sharply and 45.0% that antismoking legislation should prohibit tobacco sales to children. These data demonstrate low levels of information among Moroccans concerning current tobacco control legislation. PMID- 22259888 TI - Parental smoking and risk of childhood cancer: hospital-based case-control study in Shiraz. AB - This case-control study in Shiraz aimed to determine the relationship between parental smoking and childhood cancer. A questionnaire was completed by the mothers of 98 children newly diagnosed with cancer before the age of 14 years and 100 age- and sex-matched controls. Maternal smoking (prior to and during pregnancy and after the birth), and the numbers of maternal cigarettes smoked were not associated with an increased risk of childhood cancer. However, maternal exposure to passive smoke during pregnancy increased the risk of cancer childhood (OR = 3.6, 95% CI: 1.3-5.0). Father's smoking prior to (OR = 1.8, 95% CI: 1.4 6.0) and during pregnancy (OR = 3.0, 95% CI 1.4-5.0) was significantly associated with an increased risk of cancer and this increased with heavy smoking. There were no relationship between an enhanced risk of childhood cancer and father's smoking after the child's birth. PMID- 22259889 TI - Smoking among Saudi university students: consumption patterns and risk factors. AB - Tobacco use is increasing among young people, especially in Gulf nations such as Saudi Arabia. The objectives of this study were to estimate the prevalence and behavioural patterns of tobacco use among undergraduate students at King Saud University, Riyadh, Saudi Arabia during the academic year 2008/09 and investigate factors that influenced their tobacco use. A cross-sectional study was done of a representative sample (n = 6793) of the undergraduate student population using a modified version of the global youth tobacco survey questionnaire. The prevalence of smoking was 14.5% among students, 22.2% and 2.2% among fathers and mothers and 43.1% and 14.8% for male and female siblings; 15.0% reported all or most of their friends smoked. The most important independent predictors of smoking were: friends' smoking (some: OR = 6.7 and all: OR = 54.9), sister's smoking (OR = 2.2), mother's smoking (OR = 2.1), single status (OR = 1.7) and age (OR = 1.18). PMID- 22259890 TI - High prevalence of vitamin D deficiency in the sunny Eastern region of Saudi Arabia: a hospital-based study. AB - This study evaluated the vitamin D status of a cohort of healthy young Saudi Arabians in the Eastern region of Saudi Arabia. A sample of 139 blood donors (87 males and 52 females) answered a questionnaire about their clinical history, including intake of vitamin D supplements and calcium-rich foods and exposure to sunshine. Blood samples were taken for routine biochemistry, serum 25 hydroxyvitamin D [25(OH)3] and plasma parathyroid hormone (PTH) levels. Serum 25(OH)D levels did not differ significantly between males and females, although the levels were low [10.1 (SD 4.6) ng/mL and 9.9 (SD 4.5) ng/mL respectively]. When subjects with elevated PTH levels were excluded, serum 25(OH)3 levels were still in the deficiency range. There was a high prevalence of a vitamin D deficiency in this sample of Saudi Arabians despite > 65% of participants having adequate exposure to sunlight and > 90% reporting adequate intake of dairy products. PMID- 22259891 TI - [Of the environmental health knowledge, attitudes and practices in Ramallah and Al-Bireh District Palestine]. AB - We assessed the knowledge, attitudes and practices of some aspects of environmental health among residents of Ramallah and Al-Bireh district, Palestine. We found that few residents had attended sessions of awareness in environmental health but 83.6% were willing to participate in such events to raise public awareness. Most residents (91.2%) were aware of the relationship between water and human health, but only 39.7% reported that they or their families cleaned their water tanks more than once a year. Only 76.3% of the respondents reported that they always washed their hands before eating and only 67.0% reported that they checked the safety of food before eating. Only 33.7% felt reassured when they ate in restaurants. This was due to lack of cleanliness of the restaurants, staff and utensils, and the uncertainty regarding the source of the food. PMID- 22259892 TI - Knowledge about standard precautions among university hospital nurses in the United Arab Emirates. AB - Standard/universal precautions reduce the risk of transmission of bloodborne infections among patients and health care workers. This study was conducted to assess the awareness and knowledge of standard precautions among nurses in a university teaching hospital in Ajman, United Arab Emirates. All nurses working in the hospital were given a structured, self-administered, anonymous questionnaire: 101 nurses participated (range of experience from < 1 to 22 years). Overall 97.0% of respondents were familiar with the concept of standard precautions. Of these 61.2% believed that the blood and body fluids of all patients are potentially infectious irrespective of their diagnostic status, while 27.6% thought only diagnosed patients and 11.2% only suspected cases are potentially infectious. Less than half agreed that standard precautions aimed to protect both health care workers as well as patients (45.9%). The study highlights a need to implement a programme to improve knowledge on standard precautions. PMID- 22259893 TI - Validity and reliability of the Persian (Farsi) version of the Job Content Questionnaire: a study among hospital nurses. AB - Stress is an increasingly important occupational health problem, even in developing countries suc as the Islamic Republic of Iran. The Job Content Questionnaire (JCQ) is a widely used self-administered to measure dimensions of job stress in the workplace. This study describes the preparation of a Persian (Farsi) language version of the questionnaire (P-JCQ). In the first stage, linguistic validation was done by forward and backward translation. In the psychometric evaluation stage, the reliability and validity of the P-JCQ were explored among 107 hospital nurses in Shiraz city. Cronbach alpha coefficients for decision latitude and psychological job demands scales were 0.54 and 0.58 respectively and ranged from 0.64 to 0.85 for other scales. Exploratory factor analysis showed 3 meaningful factors that could explain support, psychological job demands and physical loads and hazard exposure. The P-JCQ has satisfactory linguistic validity and psychometric properties, provided the recommended factor pattern is used. PMID- 22259894 TI - Clinical management guidelines for pandemic (H1N1) 2009 virus infection in the Eastern Mediterranean Region: technical basis and overview. AB - During the spring of 2009, a novel influenza A (H1N1) virus of swine origin caused human infection and acute respiratory illness in Mexico. After initially spreading in North America, the virus spread globally resulting in the first influenza pandemic since 1968. While the majority of illnesses caused by pandemic (H1N1) 2009 were mild and self-limiting, severe complications, including fatalities, were also reported. In view of the increasing number of laboratory confirmed cases and deaths from pandemic (H1N1) 2009 in the Eastern Mediterranean Region of the World Health Organization, the Regional Office convened a consultation meeting of experts involved in the clinical management of patients infected with pandemic (H1N1) 2009 virus. The consultation resulted in developing an interim guidance and algorithm for clinical management of pandemic (H1N1) 2009 virus infection in health-care settings. This paper describes the process, the technical basis and the components of this interim guidance. PMID- 22259895 TI - Smoking and normative influence among Egyptian youth: a review of the literature. AB - Youth aged 15-24 years form 21% of Egypt's population. Tobacco smoking among the young is a health priority in Egypt. This paper reviews the literature on smoking among Egyptian youth, focusing on factors related to social normative influences. The PubMed and PsycInfo databases were searched for articles related to youth, Egypt and smoking; and grey literature from the World Health Organization, Population Council and the Egypt Demographic and Health Survey were also accessed. The PubMed and PsycInfo searches returned 52 and 3 publications respectively, of which 14 were retained. Smoking is more common among male youth and older youth. Peer smoking is consistently associated with youth smoking, but family smoking is not consistently associated. Employment and educational factors appear to be important. The limitations of the review and recommendations for future research are discussed. PMID- 22259896 TI - Adherence to medication among chronic patients in Middle Eastern countries: review of studies. AB - This paper reviewed studies that have investigated adherence to medication among patients with chronic conditions in Middle Eastern countries. A comprehensive literature search yielded 19 relevant studies. These focused on the extent and predictors of nonadherence to medication across different conditions, including hypertension, chronic obstructive pulmonary disease, asthma, diabetes, depression, schizophrenia and epilepsy. Estimated rates of nonadherence to medication ranged from 1.4% to 88%. This review confirms the existence of nonadherence as a problem among patients with chronic diseases and examines our understanding about the reasons and variables affecting patients' adherence to their medication in the Middle Eastern countries. However, the studies employed a wide range of methods, sometimes with limitations. Further work to determine the prevalence and causes of patients' nonadherence to medication in Middle Eastern countries is needed in order to recommend the best interventions to improve adherence. PMID- 22259897 TI - Prevalence of peripheral vascular calcifications in patients on chronic hemodialysis at a tertiary care center in Beirut: a pilot study. AB - BACKGROUND: Vascular calcifications are highly prevalent in patients maintained on chronic hemodialysis. They have been linked to numerous risk factors and have been associated with an increased risk of cardiovascular morbidity and mortality. The purpose of this pilot study is to assess the prevalence of vascular calcifications among dialysis patients in our tertiary care center and to identify the associated risk factors. METHODS: In the current study, we reviewed the charts of 43 patients undergoing hemodialysis at our center. We estimated the prevalence of vascular calcifications among dialysis patients using plain X-ray of the hand as the screening tool. We compared patient's characteristics and tried to identify possible risk factors, with a special emphasis on the subgroup of patients with diabetes. RESULTS: Vascular calcifications were prevalent among half of the patients on hemodialysis. Duration of dialysis (p = 0.02), diabetes (p < 0.001), and hypertension (p = 0.01) were highly associated with vascular calcifications. No association was found between vascular calcifications and age, gender, calcium-based phosphate binders, vitamin D supplementation, smoking, and lipid control. In multivariate analyses, diabetes and duration of dialysis were the only independent predictors of vascular calcifications and diabetics developed vascular calcifications earlier than nondiabetics (31 months vs 69 months). CONCLUSION: Vascular calcifications are moderately prevalent among patients undergoing hemodialysis at our center, and were found to be strongly correlated with diabetes and duration of dialysis. A larger, multicenter, prospective study should be conducted at national level, in order to confirm the findings of this study and to identify further modifiable risk factors, to decrease the incidence of vascular calcifications and the incurring cardiovascular morbidity and mortality in our population. PMID- 22259898 TI - [Chemoradiotherapy in early stage Hodgkin's lymphoma]. AB - OBJECTIVE: To evaluate the response to and toxicities of chemo-radiotherapy (CT RT) in patients with early stage Hodgkin lymphoma treated in our institution. MATERIALS AND METHODS: Retrospective study of 42 patients with early stage Hodgkin lymphoma treated between 2002 and 2007. RESULTS: The age of patients ranges from 11 to 57 with a mean of 30.7 years; the sex-ratio is 0.8 (19 males and 23 females). There are 33 cases of nodular-sclerosing Hodgkin lymphoma, 6 of mixed cellularity, one lymphocyte-rich, one interfollicular and one granulomatous. As for the stages, 31 Hodgkin lymphomas are stage IIA, 6 stage IA, 3 bulky and 2 stage IAe. The ABVD protocol was given to 38 patients, the VBVP to 3 patients and the ABV to one patient. IFRT was used with dose ranging from 19.8 to 39.6 Gy. The acute toxicity of chemotherapy was hematologic only, grade 1 anemia accounting for 11.1% and grade 2 anemia for 14.8%, grade 1 leukopenia for 51.8%, grade 2 leukopenia for 333% and grade 3 leukopenia for 14.8%. Dysphagia, radiodermitis and radiomucositis were seen after radiotherapy, accounting for 16.5%, 4.6% and 9.1% respectively. No long-term toxicity of the combined therapy was found. During the follow-up period, one relapse occurred and no death was reported. CONCLUSION: The overall survival (OS), the disease free survival (DFS) and the toxicities of the combined therapy CT-RT of the patients with early stage Hodgkin lymphoma stage IA and IIA treated in our institution were similar to those seen in the literature. PMID- 22259899 TI - General anaesthesia combined with bilateral paravertebral blockade (T11-T12-L1) vs general anaesthesia for bilateral varicocelectomy. A randomized double-blind clinical trial. AB - INTRODUCTION: Varicocelectomy is a common operation in urology associated with considerable postoperative pain. The aim of this prospective, randomized, double blind study was to investigate whether a combination of general anesthesia and bilateral nerve stimulator guided paravertebral nerve blocks could provide better postoperative pain relief compared to general anesthesia in combination with placebo paravertebral nerve block. METHODS: Sixty patients scheduled for varicocelectomy were randomized prospectively. Thirty patients each in either the active group (general anaesthesia combined with nerve stimulator guided bilateral paravertebral block) or the control group (general anaesthesia combined with normal saline nerve stimulator guided bilateral paravertebral block). Postoperative pain was assessed by visual analogue scale scores at predetermined time intervals. RESULTS: The active group was found to have better postoperative pain-relief (p < 0.005), reduced need for analgesics (p < 0.05), and also a more rapid return to normal activities (p < 0.001) compared to control group. Higher surgeon and patient satisfaction (p < 0.001) were noted in the active group compared to the control group. CONCLUSION: Preoperative paravertebral blockade combined with general anesthesia showed significantly reduced postoperative pain scores and analgesic consumption, earlier return to normal activity and was associated with better patient and surgeon satisfaction during varicocelectomy surgery. PMID- 22259900 TI - Bone mass in a group of Lebanese girls from Beirut and French girls from Orleans. AB - AIM OF THE STUDY: To compare bone mineral content (BMC) and bone mineral density (BMD) in a group of Lebanese girls from Beirut and French girls from Orleans. METHODS: This study included 26 French adolescent girls (153 +/- 0.7 years old) and 24 maturation-matched (15.4 +/- 1.1 years old) Lebanese adolescent girls. BMC, BMD at the whole body (WB) and body composition (lean mass and fat mass) were assessed by dual-energy X-ray absorptiometry (DXA). Calculations of the bone mineral apparent density (BMAD) and the ratio BMC/height were completed for the WB. Weight and height were similar in the two groups. RESULTS: Lean mass was higher in French girls compared to Lebanese girls (p < 0.05). In the whole population, lean mass was a positive determinant of BMC and BMD. French girls displayed higher values of BMC, BMD, BMC/height and BMAD than Lebanese girls (p < 0.05). Finally, BMC and BMD remained higher in French girls in comparison to Lebanese girls even after adjusting for lean mass. CONCLUSION: In this study group, Lebanese girls have lower BMC and BMD in comparison to French girls. PMID- 22259901 TI - The status of pediatric cardiology at a tertiary center in Lebanon. AB - PROBLEM: Cardiac disease, both congenital and acquired, contributes significantly to morbidity and mortality in children. METHODS: This article describes the status of pediatric cardiology at the Children's Heart Center in the American University of Beirut Medical Center. It addresses the available clinical services as well as the research and educational activities that are present at a tertiary center in Lebanon, a developing country with a population of 4 million. RESULTS: Lebanon has witnessed major developments in the field of pediatric cardiology over the past few years. About 650 babies are born with heart disease every year, with more than 425 needing treatment. Nearly all types of interventional catheterization procedures are currently being performed. About 300 open and closed pediatric cardiac surgeries are performed per year in Lebanon. In 2008, the in-hospital surgical mortality rate at our center was 2.6%, reflecting the good level of care in the treatment of children with congenital heart disease (CHD) in Lebanon. Basic research in the field of pediatric cardiology is emerging at our center. Our team has been studying the effect of chronic hypoxemia on the neonatal myocardium in an animal model of chronic hypoxia, as well as the study of molecular basis of CHD. CONCLUSION: Appropriate identification of cardiac disease, its epidemiology, and outcome is of utmost importance in guiding adequate care. Centralization of facilities is important to improve results and level of care. PMID- 22259902 TI - Trends and prevalence of intestinal parasites at a tertiary care center in Lebanon over a decade. AB - Intestinal parasitic infections or infestation are amongst the most prevalent infections worldwide. This study aimed at revealing the changing trends over a decade duration of intestinal parasites identified at a major tertiary care center in Lebanon between 1997-1998 and 2007-2008. The total number of specimens tested were 14,771 for 1997-1998 vs 7477 for 2007-2008. The positive findings for parasites were 2077 (14%) vs 1047 (14%), respectively. The majority of recovered parasites in both study periods belonged to intestinal protozoa (91% and 95%), followed by cestodes (6% and 3%), and nematodes (3% and 2%), while trematodes were negligible in both periods. The highest prevalence occurred among ages 16 to 35 years for 1997-1998, and without age predominance in the second period. The detected parasites from 1686 individuals (11.4%) in the first period vs 904 (12.1%) in the second period encompassed 18 species. The most common "pathogenic" parasite in both periods were: Entamoeba histolytica (14% vs 12%), Giardia lamblia (16% vs 6%), Taenia spp. (6% vs 3%), and Ascaris lumbricoides (2% vs 1%). Generally, these were detected more in males than females, in adults than in children, and during the summer (= 30%) and autumn (= 26%) than winter (= 20%) seasons for both periods. Despite some observable decrease in prevalence among the two study periods, sustainability of substantial intestinal parasites detection continues to exist. The latter is a valuable indicator for a state of collective ill-health, warranting more attention and efforts for public health awareness to improve hygiene and sanitation in order to minimize the prevalence of these parasites in this country. PMID- 22259903 TI - Absence of GJA1 gene mutations in four patients with anomalous left coronary artery from the pulmonary artery (ALCAPA). AB - PROBLEM: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare form of congenital heart disease with no known genetic cause. It is usually diagnosed within the first year of life; it results in myocardial cell death, congestive heart failure and lethality if left untreated. Connexin 43alpha1 is a member of the gap junction family of proteins demonstrated by animal studies to have a role in coronary artery patterning during development. No previous studies have investigated the role of this gene in patients with ALCAPA. METHODS: We forth herein describe the clinical presentation of four patients who presented to the Children's Heart Center at AUBMC and had the final diagnosis of ALCAPA. Screening the GJA1 gene coding for connexin 43alpha1 was undertaken. RESULTS: No mutations were found in the patients or their parents, except for one polymorphism in one of the parents in the 3' untranslated region. All four patients underwent surgical repair with excellent outcome. CONCLUSION: This paper raises the awareness of this rare condition enabling physicians to reach the adequate diagnosis which will allow early surgical intervention and better prognosis. Our patient sample did not exhibit any evidence of association between connexin 43alpha1 and the clinical phenotype. PMID- 22259904 TI - New trends in the management of hepatic Echinococcus granulosus. AB - The liver is the most commonly involved organ in the body by cystic echinococcosis (CE) secondary to infection with Echinococcus granulosus. In this article, the authors discuss the classification, recent advances in magnetic resonance (MR) imaging for the diagnosis of hepatic CE, and approaches for management of hepatic CE using five therapeutic options that include: antihelminthic chemotherapy, surgery, percutaneous treatment, endoscopic approach, and the "watch and wait" approach. PMID- 22259905 TI - Spontaneous lateral abdominal wall hematoma complicating chronic obstructive pulmonary disease exacerbation. AB - Lateral abdominal wall hematoma is a rare and potentially life-threatening condition. We report a case of a spontaneous lateral abdominal wall hematoma that developed in a patient with severe cough caused by chronic obstructive pulmonary disease (COPD) exacerbation. The hematoma resolved with conservative management. PMID- 22259906 TI - Acquired nonmalignant tracheoesophageal fistula. AB - Acquired nonmalignant tracheoesophageal fistula is a rare clinical entity and a difficult problem to diagnose and manage. We report a 59-year-old woman diagnosed with a tracheoesophageal fistula secondary to prolonged intubation. The diagnosis was delayed for a year, hence her mild symptoms; cough and dysphagia mainly to liquids. These symptoms were thought to be side effects of her psychiatric medications especially that she had a buccal and lingual dyskinesia. She later had a trial of conservative treatment that failed and then she underwent surgical resection of the fistula and interposition of a muscle flap. Acquired nonmalignant tracheoesophageal fistula is a preventable disease in intubated patient if some measures are taken, but even with the use of the newer endotracheal tubes (high-volume, low-pressure cuffs) this complication can still occur. The surgical treatment remains the best option. PMID- 22259907 TI - Inflammatory breast cancer with refractory diarrhea: a case report. AB - Excessive amounts of vasoactive intestinal polypeptide (VIP) cause a special clinical syndrome characterized by secretory diarrhea, hypokalemia and dehydration. A careful clinical workup of a 62-year-old female admitted for refractory diarrhea revealed a neglected inflammatory right breast ductal carcinoma with VIP hypersecretion without any localized abdominal tumor. Immunohistochemistry of the breast biopsy showed neuroendocrine characteristics with positive staining for VIP, and Octreotide scan showed hyperfixation to the right breast and axilla. Primary therapy of breast cancer with hormones and chemotherapy achieved transitory regression of diarrhea, VIP level decrease, and tumor border reduction. Bilateral modified radical mastectomy and irradiation of the tumor failed to prevent liver and bone dissemination of the disease. Once more, partial response was obtained by octreotide and salvage chemotherapy; however, the patient died from progressive disease 23 months after initial diagnosis. To our best knowledge, this unusual presentation of a breast carcinoma with related VIPoma syndrome is the first reported case in the literature. PMID- 22259908 TI - Successful treatment of von Zumbusch generalized pustular psoriasis with cyclosporine after eruption post etanercept injection. AB - Von Zumbusch generalized pustular psoriasis (GPP) is the most severe type of psoriasis with possible life-threatening complications. We report the case of a 22-year-old woman who presented with a severe eruption of generalized pustular psoriasis 48 hours after receiving an injection of etanercept (Enbrel). PMID- 22259909 TI - [A case of wandering spleen: a rare cause of acute abdomen]. AB - We present the case of a 17-year-old patient known to have an asymptomatic ectopic spleen, who presented with an acute abdomen. Clinical symptoms and ultrasound led to suspect an acute appendicitis, confirmed later on by pathology. Twenty-four hours after the appendectomy, the patient complained of an abdominal pain of acute onset. Torsion of the pedicle of the ectopic spleen was suspected. Imaging studies supported this diagnosis, and an urgent splenectomy was performed. Did the torsion happen by simple coincidence 24 hours after appendectomy, knowing that the spleen has been asymptomatic for 17 years, or was it precipitated by the surgical intervention? Should we have removed the ectopic spleen during the appendectomy? This is the first report of a case of torsion of a wandering spleen after a laparotomy; a review of the literature is done in order to explain the physiopathology of the disease, and to propose its management. PMID- 22259910 TI - Transduodenal EUS-guided FNA of the right adrenal gland to diagnose lung cancer where percutaneous approach was not possible. AB - Although endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) of the left adrenal gland is safe and accurate compared to the percutaneous approach, there are no reports to our knowledge about EUS-guided FNA of the right adrenal gland performed in Lebanon and the Middle East. We report the case of a 64-year-old male who presented with a swollen right calf and right flank pain and was diagnosed with deep vein thrombosis with a right calf deep venous thrombosis. A computerized tomography of the chest and abdomen revealed a round solid mass of the right adrenal gland, a right upper lobe mass and centrilobular emphysema of both lungs. Percutaneous biopsy of the right adrenal gland was declined as the patient was quoted a high risk of bleeding. EUS-guided FNA of the right adrenal was performed via the transduodenal approach confirming the final diagnosis of metastatic lung cancer. This case shows that the right adrenal gland can be sampled with EUS-FNA via the duodenal approach to diagnose metastatic lung cancer, especially when the percutaneous approach is not feasible. PMID- 22259911 TI - One World, one home, one heart. PMID- 22259912 TI - Tranexamic acid--a recipe for saving lives in traumatic bleeding. PMID- 22259913 TI - Cardiovascular disease and risk factors in patients with type 2 diabetes mellitus in Mashhad, Islamic Republic of Iran. AB - The aim of this study in 2006-08 was to determine the prevalence and risk factors of CVD in an Iranian population of patients with type 2 diabetes mellitus. History and physical examinations were recorded and laboratory tests were performed in 752 patients attending the Mashhad Endocrine and Metabolism Research Center. The prevalence of CVD was 20.1%. CVD was significantly associated with age, duration of diabetes, hypertension, diabetic retinopathy, metabolic syndrome, renal insufficiency, triglycerides, high-density lipoprotein (HDL) cholesterol, uric acid and triglycerides/HDL ratio. Using a logistic regression model, age, metabolic syndrome and HDL cholesterol were significant independent predictors of CVD. The high prevalence of CVD in Iranian patients with type 2 diabetes underscores the importance of better detection and treatment of metabolic risk factors of CVD in these patients. PMID- 22259914 TI - Road traffic injuries in Rawalpindi city, Pakistan. AB - Data on road traffic accident (RTA) injuries and their outcome are scarce in Pakistan. This study assessed patterns of RTA injuries reported in Rawalpindi city using standard surveillance methods. All RTA injury patients presenting to emergency departments of 3 tertiary care facilities from July 2007 to June 2008 were included. RTA injuries (n = 19 828) accounted for 31.7% of all injuries. Among children aged 0-14 years females suffered twice as many RTA injuries as males (21.3% versus 11.4%), whereas this trend reversed for the age group 15-24 years (41.9% versus 21.7%). One-fifth of injuries were either fractures or concussion. Severity and outcome of injuries were worse for the age group 45 years and older. For every road traffic death in Rawalpindi city, 29 more people were hospitalized and 177 more received emergency department care. These results suggest the need for better RTA injury surveillance to identify preventive and control measures for the increasingly high road disease burden in this city. PMID- 22259915 TI - Health disparities between Muslim and non-Muslim countries. AB - We examined differences in health indicators and associated factors across countries according to the proportion of the population who are Muslim. Of 190 UN countries, 48 were classified as Muslim-majority countries (MMC) and 142 as non MMC. Data on 41 potential determinants of health were obtained from 10 different data sources, and 4 primary outcome measures (male and female life expectancy, maternal mortality ratio and infant mortality rate) were analysed. Annual per capita expenditure on health in MMC was one-fifth that of non-MMC. Maternal mortality and infant mortality rates were twice as high in MMC as non-MMC. Adult literacy rate was significantly higher for non-MMC. Four significant predictors explained 52%-72% of the differences in health outcomes between the 2 groups: gross national income, literacy rate, access to clean water and level of corruption. PMID- 22259916 TI - Incidence and causes of sudden death in a university hospital in eastern Saudi Arabia. AB - Sudden death is non-violent, unexpected death occurring less than 24 hours from the onset of symptoms. In this retrospective descriptive study we report the frequency and main causes of sudden deaths in relation to total deaths at a large university hospital in the Eastern region of Saudi Arabia over a 6-year period. The medical files of 1273 consecutive deaths were retrospectively investigated and showed 223 (17.5%) cases of sudden death. Males were 56.0% of cases. The incidence of sudden death was highest in the 2 age extremes (32.2% were infants and 31.4% were elderly). There was a seasonal variation, with the highest incidence (29.6%) during spring followed by summer (25.1%). The most important direct causes of sudden death were cardiovascular diseases in 59.2% of cases, respiratory disease in 24.7%, diabetes mellitus in 23.8%, liver disease in 23.3% and infectious disease in 20.2%. PMID- 22259917 TI - Evaluation of old-age disability and related factors among an Iranian elderly population. AB - Old-age disability has become a public health concern. This study was conducted to evaluate the prevalence of disability and its related factors among the elderly population in Kashan city, Islamic Republic of Iran. A cross-sectional study was conducted on a multistage random sample of 350 elderly people. The World Health Organization Disability Assessment Schedule II was used as the disability measure. Overall, 37.1% had mild ageing disability, 38.6% moderate, 20.0% severe and 4.3% extreme disability. Significant relationships were observed between disability and sex, age, living status, needing help, marital status, urban/rural residence, drug addiction, duration of addiction, employment status, having regular physical activity, level of education, health perception, history of hospitalization in the last year and having multiple diseases. Considering the rapid increase in the aged population in Islamic Republic of Iran, more attention should be paid to the health of elderly people. PMID- 22259918 TI - Health information systems in the Islamic Republic of Iran: a case study in Kerman Province. AB - Health information systems provide information for decision-making at all levels, from planning and management to evaluation of health services. Registration of vital events is the most basic level of any health information system. This case study used in-depth interviews, observations and examination of documents to explore the system of births and deaths registration in Kerman province. The findings were evaluated under 3 headings: data input, data processing and data usage. A range of problems were identified concerning legal requirements, staffing, data checking and publication of data. Different approaches are suggested to strengthen the system, such as introducing regulations to oblige different data sources to provide data and allocating sufficient resources, including human resources, and an improved technology infrastructure. PMID- 22259919 TI - Lipoprotein changes in women taking low-dose combined oral contraceptive pills: a cross-sectional study in Basra, Iraq. AB - We assessed lipid and lipoprotein levels in 100 women taking low-dose COCs and a control group of 100 non-users attending the family planning centre Basra Maternity and Child Hospital, Iraq. Venous blood was collected after 12-14 hours fasting, and serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein (VLDL) levels were measured. Serum TG, HDL-C and VLDL levels were significantly higher and LDL-C levels lower in users than non users but TC levels did not differ between the 2 groups. TG, HDL-C and VLDL levels rose with age and duration of use while LDL-C levels decreased; TC levels did not change. PMID- 22259920 TI - Educational needs assessment for men's participation in perinatal care. AB - To assess men's educational needs to improve their involvement in perinatal care we carried out a descriptive, cross-sectional study on 400 women seeking perinatal care in Shahid Beheshti University of Medical Sciences hospitals and 400 men who were accompanying them. Participants were recruited using a quota sampling method. A questionnaire was used to collect information on demography, men's educational needs and attitude assessment. The mean attitude score was 79.13% (SD 10.5%). More than 95% of participants agreed with perinatal care education for men and the content most required was "Signs of risks during the perinatal period" and "Mothers' nutrition". The majority of participants preferred the face-to-face couples' counselling method, at home as the best place, evening and weekends as the best time and marriage classes as the best time for initiation. Men's education is necessary to promote male involvement in perinatal care. PMID- 22259921 TI - Effect of quinine therapy on plasma glucose and plasma insulin levels in pregnant women infected with Plasmodium falciparum malaria in Gezira state. AB - To determine if quinine has a metabolic effect during treatment of severe or complicated malaria, we studied its effects on plasma glucose and plasma insulin levels in 150 pregnant women with malaria referred to Madani maternity teaching hospital, Gezira state and 50 healthy pregnant controls. Levels were determined at baseline (day 0) before the start of quinine treatment, after 2 days of treatment (2 hours after the 4th dose) and after 7 days of treatment (day 8). There was a statistically significant increase in plasma insulin concentrations during the quinine infusion and fall in plasma glucose concentration (P < 0.001). Quinine administered at the recommended dose and rate can disrupt plasma glucose homeostasis although it is still the drug of choice for severe and complicated malaria in Sudan. PMID- 22259922 TI - Incidence of congenital malformation in 2 major hospitals in Rivers state of Nigeria from 1990 to 2003. AB - Although congenital malformations are believed to be on the rise in the oil production areas of Nigeria, few baseline data are available. This retrospective study documented the incidence of congenital abnormalities in 2 major hospitals in Port Harcourt, an oil-rich city in Rivers state, Nigeria. Delivery and nursery records were reviewed from January 1990 to December 2003. In the first hospital 78 congenital anomalies were recorded out of 19 572 births (4.00/1000), principally affecting the central nervous system (1.84/1000) and skeletal system (1.74/1000). In the second hospital, 47 congenital anomalies were recorded out of 20121 births (2.20/1000), with malformations of the central nervous system (0.80/1000) and skeletal system (1.14/1000) again predominating. More research is needed into long-term trends in congenital malformations and possible associations with environmental pollution in Rivers state. PMID- 22259923 TI - Detection of Trichomonas vaginalis by different methods in women from Dohok province, Iraq. AB - This study compared 4 different diagnostic methods for the detection of Trichomonas vaginatis in vaginal swab specimens from women attending a hospital in Dohuk in Iraq. A total of 425 vaginal swabs were obtained from women complaining of vaginal discharge associated with vaginitis, cervicitis and pelvic inflammatory disease. The results showed that 10 (2.4%) swabs were positive for T. vaginalis by wet smear preparation, 15 (3.5%) by haematoxylin-eosin stained smear, 17 (4.0%) by Papanicolaou stain and 23 (5.4%) using Diamond modified culture. The rate varied significantly by age and was highest in young women aged 20-25 years (7.6%) and lowest in the age group 36-40 years (2.2%). The highest rate of infection with T vaginalis was detected by Diamond modified culture. PMID- 22259924 TI - Impact of intestinal parasites on haematological parameters of sickle-cell anaemia patients in Nigeria. AB - The majority of patients with sickle-cell anaemia live in the underdeveloped nations where endemic parasitic diseases are prevalent and this may exacerbate the severity of steady-state anaemia in infected patients. We studied the impact of intestinal parasites on haematological parameters of sickle-cell anaemia patients aged 18-35 years in Kano, Nigeria. Of 100 patients studied, 27 were found to be infected with intestinal parasites. There were no significant differences between patients with and without parasitic infections with respect to leukocyte and platelet counts. However, patients without parasitic infections had a significantly higher mean haematocrit than patients with parasitic infections [0.27 L/L (SD 0.03) versus 0.23 (SD 0.03) L/L]. Anaemia in sickle-cell anaemia patients may be exacerbated by intestinal parasites, and these patients should have regular stool examinations for detection and treatment of parasitic infections in order to improve their haematocrit and avoid the risk of blood transfusion. PMID- 22259925 TI - Evaluation of an interferon-gamma release assay in young contacts of active tuberculosis cases. AB - In a cross-sectional study in a hospital in Tehran in 2006-08 the QuantiFERON-TB interferon-gamma release assay (QTB) was compared with the tuberculin skin test (TST) in 59 young people (aged < 20 years) with close contact with immunocompetent cases of proven pulmonary tuberculosis. After 1 year follow-up 10 subjects had progressed to tuberculosis disease and received treatment; TSTwas positive in 30% and QTB in 100%. Of the 49 non-progressive subjects, TST was positive in 10.4% and QTB in 16.3%. The agreement between TST and QTB assay in non-progressive subjects was poor (K = 0.43). False positive and false negative rates for TST were 40.0% and 9.3% respectively; positive and predictive values were 60.0% and 90.7%. We suggest adding the interferon assay to the skin test in the decision to perform chest X-ray or to start chemoprophylaxis at least in younger subjects (aged < 20 years). PMID- 22259926 TI - Continuing analysis into the roles, functions, models, and caseloads of case management. PMID- 22259927 TI - ACS launches inspiring quality tour of Chicago. PMID- 22259928 TI - Hospital puts ACS NSQIP to the test and improves patient safety. PMID- 22259929 TI - Is there a role for race in science and medicine. PMID- 22259930 TI - ACS eases the pain of providing palliative care. PMID- 22259931 TI - Accountable care organizations: a primer for surgeons. PMID- 22259932 TI - Governors' Committee on Surgical Infections and Environmental Risks: a update. PMID- 22259933 TI - Geographic distribution of general surgeons: comparisons across time and specialties. PMID- 22259934 TI - Coding hernia and other complex abdominal repairs. PMID- 22259935 TI - Graduated driver licensing: keeping teen drivers safe. PMID- 22259936 TI - Rural surgery symposium and skills course held in Chicago. PMID- 22259937 TI - TJC Center takes on wrong site surgery prevention. PMID- 22259938 TI - Physicians need to find their collective voice. PMID- 22259939 TI - One instrument, many functions. PMID- 22259940 TI - Recognizing the individual patient. PMID- 22259941 TI - State medical liability reform. PMID- 22259942 TI - Centers for Medicare and Medicaid services tighten reimbursements. AB - Hospitals will suffer when the Medicaid Recovery Audit Contractor (RAC) starts on Jan. 1, 2012, if case managers aren't scrutinizing those patients as closely as those who are covered by Medicare. Make sure your documentation is complete to avoid denials and prepare for appeals. Work with your state Medicaid provider to determine how the program will work in your state. Learn the rules for all states in which your patients reside. Be aware that the Medicaid RACs are charged with taking a proactive approach to identify potential fraud. PMID- 22259943 TI - Medicaid RACs--whole new ballgame. PMID- 22259944 TI - Improving transitions cuts HF readmissions. AB - Cooley Dickinson Hospital in Northampton, MA, has cut heart failure readmissions by 50% by collaborating with post-acute providers and improving patient education. Coalition focuses on improved communication as patients transition. Transition coaches work with at-risk patients. Patients use a personal health record to track their progress. PMID- 22259945 TI - Good communication smoothes transitions. PMID- 22259946 TI - The full scope of case manager and social workers roles, functions, models, and caseloads. PMID- 22259947 TI - Heart failure rates cut after initiative. AB - Charleston (WV) Area Medical Center cut readmissions for targeted heart failure patients by 50% in just a few months. A multidisciplinary team designed the program. A subcommittee revised and simplified discharge materials. CMs make follow-up appointments while patients are in hospital. PMID- 22259948 TI - ACO final rule cuts provider burden. AB - The Centers for Medicare and Medicaid Services (CMS) made significant changes in the final rule for creating accountable care organizations (ACOs) to coordinate care across healthcare settings. CMS made changes in how ACOs will share savings based on input from the industry. ACOs are one way the healthcare field is recognizing the value of care coordination. The number of quality measures on which ACOs report has been reduced from 65 to 33. PMID- 22259949 TI - Staff can determine shorter wait times. PMID- 22259951 TI - A case for visual communication. PMID- 22259950 TI - Upward mobility. PMID- 22259952 TI - Putting the right signs in the right places. PMID- 22259953 TI - Take the guesswork out of selecting apparel. PMID- 22259954 TI - Pressure to perform. PMID- 22259955 TI - Two-way learning. PMID- 22259956 TI - Life safety in overdrive. PMID- 22259957 TI - A pitch for safer cultures. PMID- 22259958 TI - Secrets of turnaround training. PMID- 22259959 TI - Pay review body must stand up to Osborne. PMID- 22259960 TI - Chancellor's pay cap overshadows announcement of staffing review. PMID- 22259961 TI - Pay policy and inflation combine to slash nurses' spending power. PMID- 22259962 TI - Business case proves ward managers are best used solely as supervisors. PMID- 22259963 TI - Academics, specialists and leaders chosen as Lords representatives. PMID- 22259964 TI - Hear the clarion call. AB - Nurses are responding to the Care campaign's rallying cry to improve patient care. They identify factors that hamper their work and discuss how these could be resolved. PMID- 22259965 TI - The cost of giving. AB - Rising waiting lists for organs, eggs and sperm have sparked debate about the best way to encourage people to become donors. Some argue that the principle of altruism should be stretched to allow payments. PMID- 22259966 TI - The Nightingale murder. AB - Queen's Nursing Institute director Rosemary Cook has published a book on the unsolved murder of Florence Nightingale Shore, an eminent early 20th century nurse and god-daughter of her famous namesake. Ms Shore's remarkable nursing career provides an insight into the profession during the Victorian/Edwardian era. PMID- 22259967 TI - Strategies to assist prevention of burnout in nursing staff. AB - This article explores strategies that nurses can use to protect themselves from burnout. The literature emphasises the need for organisational reform to prevent burnout. In the absence of organisational change the use of problem-focused strategies and emotion-focused strategies, such as reflection, may offer some protection against burnout. There is evidence that improving nurses' wellbeing results in better patient care. PMID- 22259968 TI - Malnutrition and dehydration after stroke. AB - By identifying malnutrition and dehydration in patients who have had a stroke, nurses can intervene to prevent significant complications developing and so improve patient outcomes. Poor intake of fluid and food may result from difficulties in swallowing, as well as other physical and functional problems that occur as a result of a stroke. The aim of this article is to encourage nurses to identify the frequency and causes of malnutrition and dehydration, to consider the complications this can cause and to be aware of optimum feeding strategies for stroke patients. PMID- 22259969 TI - Mental health problems in childhood and adolescence. AB - The emotional health and wellbeing of children and young people is of fundamental importance. Unmet mental health needs during childhood lead to difficulties in adolescence and problems in adulthood. The need to develop comprehensive prevention, early recognition and timely intervention services is essential. Despite this, many mental health problems go unnoticed or are only treated when advanced. Late intervention can often be associated with severe impairments for children and young people as well as their families. This article aims to improve nurses' understanding of children's emotional wellbeing and mental health, and identifies some of the risk and protective factors that combine to produce positive or negative outcomes. Individual and family-based psychological treatments that are available to support children are summarised. The learning activities offer nurses helpful interpersonal and practical strategies to promote emotional wellbeing and mental health in children. PMID- 22259970 TI - Thyroidectomy. PMID- 22259971 TI - Protecting the vulnerable. PMID- 22259972 TI - I am very proud to be called a Queen's Nurse. PMID- 22259973 TI - Testing times. PMID- 22259974 TI - Canada's approach to functional foods. PMID- 22259975 TI - Administrative drug submissions to be excluded from the PM(NOC) regulations? PMID- 22259976 TI - Supreme Court rules on safe injection site. PMID- 22259977 TI - FOI-ables. Answers to hospital questions about FIPPA. PMID- 22259978 TI - [Reconstruction of oral soft tissue defects with free anterolateral thigh flap]. AB - OBJECTIVE: To assess the clinical features and therapeutic efficacy of anterolateral thigh (ALT) flaps for the intraoral defects reconstruction. METHODS: The clinicopathologic data of 67 cases with oral tumors were obtained from School of Stomatology, Nanjing University Medical Center from Dec. 2008 to Dec. 2010. All the patients underwent the simultaneous tumor resection and intraoral defects reconstruction with free anterolateral thigh flaps. The defects included the tongue, buccal, gingival, mouth floor, and so on. The descending branch of lateral femoral circumflex artery was anastomosed to the external maxillary artery or superior thyroid artery; the vein was anastomosed to the common facial vein or external jugular vein. The flaps were divided into three types: musculocutaneous ALT flap, fasciocutaneous ALT flap and thinned ALT flap. RESULTS: There were 38 male patients and 29 female. The anterolateral thigh flaps included 35 musculocutaneous flaps, 17 fasciocutaneous flaps and 15 thinned flaps. The success rate was 98.5% (66/67). Partial necrosis happened in one case with diabetes, which healed after debridement and dressing. 1 flap was totally necrosis. Double venous anastomosis was performed in 41 flaps, and one venous anastomosis was performed in 26 flaps. 8 patients required operative exploration in the perioperative period including 6 flaps with thrombotic events (5 flaps were complete survival after the salvages, and 1 flap was failure) , 1 flap with hematoma, and 1 flap with twisting of perforator. The follow-up period ranged from 2 to 24 months( mean, 8.7 months). The result was satisfied. The donor sites were closed directly in all patients, and the wounds healed uneventfully. CONCLUSIONS: The free anterolateral thigh flap is an ideal soft tissue flap for the intraoral defects reconstruction with good functional result at recipient area and less morbidity at the donor site. PMID- 22259979 TI - [Segmental monobloc osteotomy and bi-directional distraction for the treatment of Crouzon syndrome in an infant]. AB - OBJECTIVE: To discuss the segmental monobloc osteotomy and bi-directional distraction for the treatment of Crouzon syndrome in an infant. METHODS: A 9 month-old female infant underwent monobloc osteotomy through combined intra- and extra-cranial way. The facial skull was divided into frontal, orbital and maxillary segments. The external distractor was used to move the frontal segment, orbital segment and midface forward. The internal distractor was used to move the maxilla downward. The consolidation lasted for 3 months after distraction. RESULTS: The osteotomy and distraction were successfully completed. The distraction distance reached 18 mm, showing by distractor. The real distraction distance of facial bone was 12 mm, documented by 3-D image. The skull deformity and severe depression of midface improved a lot. The exophthalmos and underbite were corrected. The obstructive sleep apnea also improved markedly. However, the downward movement of maxilla was limited. CONCLUSIONS: Monobloc osteotomy with external distractor, as well as maxillary distraction, could be used for Crouzon syndrome in infant. It is safe and effective method which can be performed in an early age for Crouzon syndrome with obstructive sleep apnea. PMID- 22259980 TI - [Application of distraction osteogenesis in the treatment of severe mandibular micrognathia with severe obstructive sleep apnea and hypopnea syndrome]. AB - OBJECTIVE: To investigate the effect of distraction osteogenesis (DO) in the treatment of severe mandibular micrognathia with severe obstructive sleep apnea and hypopnea syndrome (OSAHS). METHODS: 19 cases of severe mandibular micrognathia with OSAHS were treated by DO. All the patients received PSG and MSCT examination before and after DO to evaluate the therapeutic effect and changes in the upper airway. RESULTS: According to the evaluation standard, 17 cases were cured and 2 cases improved markedly. The sagittal distance and area, transverse distance and area of the upper airway increased markedly after DO. The volume of upper airway increased from (15 572.03 +/- 3 370.11) mm3 to (21 182.69 +/- 4 533.15) mm3.The airway change happened mainly in velopharyngeal region and the lingopharyngeal region, but not in the laryngopharyngeal region. CONCLUSIONS: DO can treat severe mandibular micrognathia patients with OSAHS effectively by enlarging the volume of upper airway,especially in the velopharynx and glossopharyngeum region. The MSCT plays an effective and important role. PMID- 22259981 TI - [The application of the horn shaped fasciocutaneous flap in lower leg]. AB - OBJECTIVE: To explore the application of the horn shaped fasciocutaneous flap for the middle or small defect of low leg. METHODS: Between April 2008 and November 2010,12 cases were covered the defects with horn flap in the leg, in which 4 cases were male, and 8 cases were female, such as squamous cell carcinoma, basal cell carcinoma, angioneoplasm, trauma and so on. Surgical repair of tissue defect size of about 3 cm x 3 cm-5 cm x 5 cm. RESULTS: Twelve cases were treated. Vascular deficiency happened at the distal end of one flap. All the other 11 flaps survived. The appearance and functional results were satisfactory with following up for 6 to 24 months. CONCLUSIONS: The horn shaped fasciocutaneous flap is simple, reliable, easy to perform, has a low complication rate, is cosmetically acceptable PMID- 22259982 TI - [Application of the island flap at the dorsum of the middle phalange with the pedicel of the digital proper artery]. AB - OBJECTIVE: To explore a method for the treatment of the skin defects at the distal phalanges of 2-5th fingers. METHODS: The island flap at the dorsum of the middle phalange was designed with the pedicle of dorsal branches from the digital proper artery. When the flap was used to repair defect at finger pulp, the dorsal branch of the digital proper nerve in the flap was kept to be anastomosed to the digital proper nerve at the recipient finger. From Feb. 2005 to May. 2010, 54 cases with skin defects at the distal phalanges of 61 fingers were treated with the flap, including 35 defects at finger pulp and 26 defects at finger tip. RESULTS: The maximum size of defects and flaps was 2.2 cm x 2.5 cm and 2.4 cm x 2.7 cm, respectively. 61 flaps survived completely. Blister was happened in 3 flaps 2 days after operation, which healed spontaneously without necrosis. 54 cases were followed up for 5 to 22 months (average, 11 months). The flaps had good texture and color match with normal sensation (grade S4). The 2-point discrimination distance was 6-9 mm. The interphalangeal joint had normal movement. CONCLUSIONS: The island flap at the dorsum of the middle phalange is an ideal method for the skin defect at the distal phalange of finger. PMID- 22259983 TI - [Laparoscopy-insisted vaginoplasty with peritoneum in patients with androgen insensitivity syndrome]. AB - OBJECTIVE: To investigate the technique and therapeutic effect of laparoscopy insisted vaginoplasty with peritoneum in patients with androgen insensitivity syndrome. METHODS: From May. in the Fifth People' s Hospital of Shenzhen. The therapeutic effect was retrospectively analyzed. RESULTS: Laparoscopy-insisted vaginoplasty was successfully completely with peritoneum in patients with androgen in 4 cases. Ileumtivity segyndroment was used instead of peritoneum in one case. Open operation was not adopted in any cases. The ectopic testicles were removed during operation in 4 cases. The average operation time and bleeding volume was 60 min and 20 ml, respectively. Rectum, bladder and urethra were not injured in any case. The average vaginal length was 9 cm (range 8-10 cm) 21-28 days after operation. 6 months after operation, the surface of reconstructed vagina was smooth, ruddy and flexible, with satisfactory anatomical and functional results. Normal sexual activity was achieved in 2 cases. CONCLUSIONS: Laparoscopy-insisted vaginoplasty with peritoneum could be used for female patients with androgen insensitivity syndrome. The ectopic testicles should be removed. Estrogen supplement and psychological guide after operation are also important. PMID- 22259984 TI - [Laser treatment of port wine stains]. AB - OBJECTIVE: To assess the efficiency of the PDL in the treatment of PWS in Chinese patients with skin type III-IV. METHODS: 252 patients with PWS at different anatomical sites were retrospectively studied. A flashlamp-pumped pulsed dye laser was used. The differences in therapeutic effect of laser were analyzed in the following ways: (1) by dermatomal distribution of face and neck; (2) by anatomical subdivision of face; (3) by the size of the lesion. The therapeutic effect was graded as 0 < or = poor < 25%, 25% < or = fair < 50%, 50% < or = good < 75%, 75% < or = excellent < or = 100%. RESULTS: It revealed that the lesions at neck had the best response. The dermatome II zone showed the least response to PDL. Among the anatomical subdivision of face, the frontal area had the highest clearance, while the zygoma and cheek had the lowest clearance. Patients with PWS on the extremities respond less favorably with the fair lightening effect. Furthermore, the mean lightening was decreased as the size of PWS was increased. CONCLUSIONS: The response difference of PWS to PDL was not only related to the anatomical region, but also related to the lesion size. It is imperative to give the patients rational treatment suggestion and normal expectation. PMID- 22259985 TI - [The technique of periorbital defects reconstruction with island orbicularis oculi myocutaneous flap in orbital zone]. AB - OBJECTIVE: To investigate the technique of periorbital defects reconstruction with island orbicularis oculi myocutaneous flap in orbital zone. METHODS: The upper or lower eyelid island orbicularis oculi myocutaneous flap,medially based,were used for the defects of the periorbital area, according to the position,shape and size of the defects. The donor site was closed directly. RESULTS: From July 2003 to October 2009, 24 patients were treated in this method, the flaps survived totally. The flap proved to be flexible, safe, relatively simple, and provided good functional and aesthetic results with follow up 6 to 24 months. Complications were minimal. CONCLUSIONS: The upper eyelid or lower eyelid island orbicularis oculi myocutaneous flap, medially based, is a satisfied method in repairing periorbital defects in one stage with good blood supply, excellent color texture matching and inconspicuous donor scar and deformity. PMID- 22259986 TI - [A clinical study of the male anterior hairline]. AB - OBJECTIVE: To measure the male anterior hairline (AH) and provide data for hair transplantation. METHODS: 205 males were randomly involved and divided into different age groups, as the young group( age 18-29), the middle-aged group (age 30-49) and the old group (age 50+). Their AH shape and height were measured. The data was then analyzed. RESULTS: According to the morphological classification of AH, the linear type was most common in the young and middle-aged groups (48.40% and 37.33%), the anterior protrusion type was most common in the old group (34.80%). The mean height of AH was 6.42 cm (5.00-8.50 cm)for the median line, and there was no statistical difference between groups (P > 0.05); the mean ratio of median line AH height to facial length was 0.30 (0.22-0.37), there were significant differences between the old group against the young, or the middle aged group (P < 0.05), and no difference between the young group and the middle aged group (P > 0.05); the mean height of AH was 5.83 cm (3.5-8.0 cm) for the paramedian line, and there was no statistical difference between groups (P > 0.05); the mean height of AH was 8.34 cm (5.5-10.5 cm) for the lateral line, there were significant differences between the young group against the middle aged, or the old group (P < 0.05), and no difference between the middle-aged group and the old group (P > 0.05). CONCLUSIONS: The shape and height of AH were age-associated. The linear type is most common in the young and middle-aged groups, the anterior protrusion type is most common in the old group. The change first occurs on the lateral lines since the age of 30, and the central portion is involved since the age of 50. The older the age gets, the higher the hairline is. PMID- 22259987 TI - [The change of serum vascular endothelial growth factor and matrix metalloproteinases-9 in proliferative hemangioma treated with propranolol]. AB - OBJECTIVE: To study the level of serum vascular endothelial growth factor, matrix metalloproteinases-9 in the proliferative hemangioma before and after propranolol treatment. METHODS: The serum VEGF, MMP-9 was detected with ELISA assay before treatment and after 4 weeks and 8 weeks of propranolol treatment. The relationship between the serum VEGF, MMP-9 and the prognosis was analyzed. RESULTS: The serum VEGF (295.4 +/- 158.1) pg/ml was high before treatment, then decreased after 4 weeks and 8 weeks of treatment (255.7 +/- 130.4) pg/ml, (224.2 +/- 120.6) pg/ml. The serum VEGF was significantly lower after 8 weeks of treatment (P < 0.05). The serum MMP-9 was also decreased after treatment, showing a positive relationship with VEGF. CONCLUSIONS: Propranolol can treat the proliferative hemangioma through decreasing the serum VEGF and MMP-9. PMID- 22259988 TI - [Experimental study on the induced differentiation of human amnion mesenchymal cells into osteoblasts]. AB - OBJECTIVE: To investigate the feasibility of inducing differentiation of the human amniotic mesenchymal cells (hAMCs) into osteoblasts in vitro, so as to provide the seed cells for bone tissue engineering. METHODS: The hAMCs were isolated from abandoned human amnion and cultured in osteogenic media to induce the osteogenic differentiation in vitro. After hAMCs were induced by osteogenic media for 15 days, morphological observation, immunocytochemistry and western blot were used to study the cellular morphology and expression of alkaline phosphatase (ALP), type I collagen, osteopontin and osteocalcin. RESULTS: The primary cultured hAMCs had long spindle shape or irregular shape, which were distributed evenly. The cells were usually suheultured in 5 or 7 days. After subculture, the cells became larger. After cultured by osteogenic media for 15 days, the hAMCs were detected to express ALP, osteocalcin and osteopontin, and secrete type I collagen. CONCLUSIONS: The hAMCs are isolated, cultured and amplified easily in vitro. The induced differentiated cells by osteogenic media have typical osteoblast morphological and functional characteristics, which can be used as seed cells for bone tissue engineering. PMID- 22259989 TI - [Influence of in vivo or vitro microenvironment on the mechanical properties and histological structure of tissue engineered cartilage]. AB - OBJECTIVE: To investigate the influence of in vivo or vitro microenvironment on the mechanical properties and histological structure of tissue engineered cartilage, and to provide the appropriate parameters for cartilage construct in vitro. METHODS: Human fetal articular chondrocytes were cultured and expanded in vitro, the passage 2 chondrocytes were seeded at the density of 6 x 10(7) cells/cm3 to cylindric dimensional scaffolds made by polyglycolic acid (PGA) and polylactic acid (PLA). These constructs were cultured in vitro for 4 weeks. After 4 weeks, part of samples were implanted subcutaneously into nude mice for 6 and 12 weeks, the others continued to be cultured in vitro. All specimens were harvested after 6 and 12 weeks, and evaluated by gross observation, histology, histochemistry, ultrastructure and mechanical test. RESULTS: All specimens in vivo and vitro eventually formed good shape hyaline cartilage. The constructs in vivo group was white color with smooth surface, and had better mechanical properties than those in vitro, by TEM we can observe the thick and striated collagen fibers in regularly arranged collagen fibril which was similar to adult articular cartilage. The constructs in vitro group was yellow color with coarse surface, the appearance and ultrastructure was similar to fetal articular cartilage. Specimens implanted for 12 weeks in vivo had better compressive modulus(38.28 +/- 3.95) MPa and collagen diameter (41.58 +/- 2.78) nm than those cultured in vitro at the same time (4.12 +/- 0.63) MPa, (15.83 +/- 1.70) nm (P < 0. 01). CONCLUSIONS: The structure and function of human tissue engineered cartilage became mature gradually from vitro to vivo, thick and striated collagen fibrils net similar to adult articular cartilage can be formed in constructs of vivo group,increased collagen cross-linking might be the reason that their mechanical properties been greatly improved. PMID- 22259990 TI - [Establishment of new vessels model by implantation of VEGF165 in mouse]. AB - OBJECTIVE: To investigate the feasibility of establishing a murine new vessels model with Lentiviral vector (LVs) mediated human vascular endothelial growth factor-165 (pcDNA3.1/ VEGF165) gene. METHODS: Lentivirus plasmid carrying a human VEGF165 was constructed and was used to transfect mouse's NIH/3T3 cells. The NIH/3T3 cells with high secretion of VEGF were injected into the skeletal muscle of mouse to establish a mouse new vessels model by implantation of vascular endothelium growth factor (VEGF) gene. The external secretion of VEGF was measured with ELISA. Histological examination was carried out after injection. The expression of CD31 was assessed with immunohistochemical method. RESULTS: The lenti-VEGF165-EGFP was correctly constructed and confirmed by restriction endonuclease analysis, polymerase chain reaction and DNA sequencing analysis. Lentivirus plasmid carrying a human VEGF165 was constructed. lenti-VEGF165-EGFP was used to transfect mouse's NIH/ 3T3 cells, and human VEGF165 gene was assessed. NIH/3T3 cells mediated VEGF gene implantation can produce stable and effective mouse new vessels model. The external secretion of VEGF in peripheral blood was measured with ELISA. The legs became swollen in experimental group 14 d after injection. It found the cells expression of CD31 44 d after injection, and histological analysis showed the swollen tissue was composed of small new vessels. CONCLUSIONS: NIH/3T3 cells mediated VEGF gene implantation can produce stable and effective mouse new vessels model. PMID- 22259991 TI - [The effect of RhoA/Rho kinase signal pathway on TGF-beta1-induced phenotypic differentiation of human dermal fibroblasts]. AB - OBJECTIVE: To examine the effect of RhoA/Rho kinase signal pathway on TGF-beta1 induced phenotypic differentiation of human dermal fibroblasts. METHODS: The 4th generation of primary cultured human dermal fibroblasts were stimulated with TGF beta1, (10 ng/ml). The expression of alpha-SMA was detected after treatment with TGF-beta1, for 0, 3, 6, and 24 h. The expression of alpha-SMA was also detected after treatment with different concentration of TGF-beta1 (0, 2, 10, 50 ng/ml). Then the human dermal fibroblasts (4th generation) were stimulated with TGF beta1, (10 ng/ml) after being treated with the RhoA/Rho kinase signaling pathway inhibitor Y-27632 (10 umol/ml). The fibroblasts were treated with nothing as sham control, or with Y-27632 (10 umol/L) only as negative control group, or with TGF beta1 (10 ng/ml) only as positive control group. The expression of alpha-SMA was detected in all the groups. Protein expression was analyzed with ANOVA statistical method. RESULTS: alpha-SMA expression in fibroblasts with 10 ng/ml TGF-beta1 stimulation for 0, 3, 6, 24 h was 1.0, 1.9 0.2, 2.1 +/- 0. 1, 3. 1 +/- 0.1, respectively. Alpha-SMA expression in 24 h group was significantly higher than that in other three groups (n = 4, P < 0.05). alpha-SMA expression in human dermal fibroblasts after stimulation with different concentration of TGF-beta1 (0, 2, 10, 50 ng/ml) was 1.0, 1.4 +/- 0.2, 3.2 + 0.1, 3.1 +/- 0.2, respectively. alpha-SMA expression in 10 ng/ ml group was significantly higher than that in 2 ng/ml group and control group (n = 4, P < 0.05). There was no statistical difference in alpha-SMA expression between 10 ng/ml group and 50 ng/ml group (n = 4, P > 0.05). With both Y-27632 (10 micromol/L) and TGF-beta1 stimulation, the cell phenotype differentiation was inhibited. Alpha-SMA expression in experimental group (1.2 +/- 0.2) was significantly reduced, when compared with that in positive control group (2.9 +/- 0.1) (n = 5, P < 0.05). There was no significant difference (n = 5, P > 0.05) in alpha-SMA expression between control group (1.0) and negative control group (1.1 +/- 0.1). CONCLUSIONS: RhoA/Rho kinase signaling pathway should be involved in TGF-beta1-induced phenotypic differentiation of human dermal fibroblasts. PMID- 22259992 TI - [Effect of electroporation-mediated gene transfect on the expression of cyclins during mandible distraction in rabbit]. AB - OBJECTIVE: To investigate the effect of electroporation-mediated gene transfect on the expression of cyclins during mandible distraction in rabbit. METHODS: Bilateral mandibular osteotomy was performed in 45 New-Zeland rabbits. After a latency of 3 days, the mandibles were elongated using distractors with a rate of 0.8 mm/day for 7 days. After the completion of distraction, the rabbits were randomly divided into 5 groups. 2 microg (0.1 microg/microl) of pIRES-hVEGF165 hBMP2, recombinant plasmid pIRES-hBMP2, recombinant plasmid pIRES-hVEGF165, pIRES and the same volume of normal saline (NS) was injected into the distraction area in each group, respectively. After injection, electroporation was performed in every group. Three animals in each group were sacrificed at 7, 14, and 28 days after completion of distraction, respectively. The lengthened mandibles were harvested and processed for immunohistochemical examinations. The expression of cyclins A, D1 ,E in positive cells were measured by CMIAS-2001A computerized image analyzer. The data were analyzed with the single factor analysis of variance and q test. RESULTS: Cyclins A, D1, E staining was mainly located in inflammatory cells, granulation tissue monocyte, fibroblast, osteoblasts, osteocyte and the connective tissues around the new bone. The expression reached to the peak at 7th day of consolidation, and decreased at 14th day, and weak at 28th day. Image analysis results showed that, at 7th day, the expression absorbance A in group C (0.59 +/- 0.14) was the strongest, compared to group A (0.41 +/- 0.13), B (0.38 +/- 0.14), D (0.34 +/- 0.12) and E (0.31 +/- 0.10), showing a significant difference (P < 0.05, P < 0.01). There was no significance difference between group A and B (P > 0.05), but the difference between group A/B and group D/E (P < 0.05). At 14th and 28th day, there was no significant difference among group A (0.39 +/- 0.11), B (0.34 +/- 0.10) and C (0.33 +/- 0.09) (P > 0.05), but there was significant difference between group A/B/C and group D (0.19 +/- 0.12) or E (0.14 +/- 0.04) (P < 0.05 or P < 0.01). CONCLUSIONS: Electroporation-mediated gene transfection can promote cyclins A, D1, E expression effectively, which may promote cell differentiation and proliferation, stimulate extracellular matrix synthesis and new bone formation in distraction gap. PMID- 22259993 TI - [The content dynamics of glycyrrhizic acid and soluble sugar in glycyrrhizae radix et rhizoma]. AB - OBJECTIVE: To study the content dynamics of glycyrrhizic acid and soluble sugar in Glycyrrhizae Radix et Rhizoma. METHODS: Adopted the PVP root canal and the field experiment, the active ingredient content of glycyrrhizic acid and soluble sugar 2 years old cultivated Glycyrrhiza uralensis in the samples was studied. RESULTS: The content of glycyrrhizic acid was high in the root morphology of the bottom of the vertical distribution; The content of glycyrrhizic acid was decreased in the rhizome from the root to the direction away from the main root; in one year, the content of glycyrrhizic acid was varied with the Glycyrrhiza uralensis developmental stages. The accumulation peak was in early July, the peak of soluble sugar content was the period in mid-July to early August. CONCLUSION: The optimum harvest period is the late September to early October. PMID- 22259994 TI - [Observation on biological characteristics of wild Pseudostellaria heterophylla]. AB - OBJECTIVE: To study the status and regular pattern in growing development of wild Pseudostellaria heterophylla. METHODS: Observed and studied on wild Pseudostellaria heterophylla during growth periods continuously. RESULTS: The growing development of Pseudostellaria heterophylla could be divided into three stages: asexual reproduction stage, coexistence of asexual and sexual reproduction stage. In the first two years of seed germination, there was only asexual reproduction, from which substitute tuberous root and cauline tuberous root were formed; Afterward flowering and fructifying sexual reproduction occurred to the plant that had developed from tuberous root while it continued with asexual reproduction; Only sexual reproduction existed during the last year of the Pseudostellaria heterophylla plant before its death. The Pseudostellaria heterophylla plant above ground grew from early spring to late autumn and over wintered with tuberous root. There were two patterns of asexual reproduction: substitution with tuberous root in spring and expanding of adventitious root on stolon into cauline tuberous root in autumn. All tuberous roots of Pseudostellaria heterophylla were originated from adventitious root; The existence of tuberous root was one year at most; The rapidly expanding period of tuberous root was during February and March. CONCLUSIONS: The results provide a reference for reformative cultivation of Pseudostellaria heterophylla. PMID- 22259995 TI - [The standard operating procedure of the standardization breeding for Poecilobdella manillensis]. AB - OBJECTIVE: To prepare Standard Operating Procedure (SOP) for the artificial breeding technology of Poecilobdella manillensi. METHODS: The environment of producing area and breeding technology, the control of diseases, reserving seeds for breeding, harvesting and processing,the standard of the product quality and supervision for the standardization breeding of Poecilobdella Manillensis was studied. RESULTS: The average yield of vital specimen of Poecilobdella Manillensis was 420.88 kg/mu, the natural hirudin in 1kg of the living specimen of Poecilobdella Manillensis contained 430,000 AT-U, and the quality index and hygienic standard of all products complied with the regulations and standards of the State. CONCLUSION: SOP is applicable for the breeding of Poecilobdella manillensi for Guangxi district. PMID- 22259996 TI - [Cloning and distribution pattern of HMGR gene conserved fragment in Alisma orientale]. AB - OBJECTIVE: To clone and study the distribution pattern of 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMGR) gene conserved fragment in Alisma orientale. METHODS: The HMGR conserved fragment in A. orientale was amplified by RT-PCR strategy with the total RNA of young leaves as the template. HMGR mRNA expression in different organs was detected by real-time quantitative PCR (QRT PCR). RESULTS: The conserved fragment was 458 bp (accession NO. HQ913638). NCBI Blast sequence analysis showed the resulting protein had high homology to HMGR with 86.8% similarity to Artemisia annua, 88.2% to Bupleurum chinense, 88.2% to Eucommia ulmoides, and 85.5% to Salvia miltiorrhiza. The result of QRT-PCR showed that the HMGR gene was expressed in different organs (i. e. leaves, petioles, tubers, and roots) which was higher in leaves relative to other tissues. CONCLUSION: The HMGR gene conserved fragment from A. orientale was cloned and its distribution pattern was detected for the first time. This work provides a foundation for exploring the synthetic pathway and bioengineering of Alisma terpenes. PMID- 22259997 TI - [Establishment of molecular markers linked to sex in Schisandra sphenanthera]. AB - OBJECTIVE: To establish the gender-related RAPD markers in Schisandra sphenanthera. METHODS: The genomic DNA was extracted from the young leaves of male and female Schisandra sphenanthera by modified CTAB method. The gender differences in the genome were studied by RAPD which was optimized by the single factor and orthogonal experiments. RESULTS: 25 microL total volume included Mg2+ of 2.5 mmol/L, dNTPs of 0.08 mmol/L, primer of 0.6 micromol/L, Taq enzyme 1.5 U, DNA template 60 ng, annealing temperature 41.3 degrees C, 35 cycles. In 400 random primers, only a male specific band 541 bp was generated by S353. CONCLUSION: The marker can be used as the basis of gender identification. PMID- 22259998 TI - [Quality standard of stewed rhizoma polygonati with yellow wine]. AB - OBJECTIVE: To improve the quality standard of stewed Rhizoma Polygonati with yellow wine. METHODS: On the basis of Chinese Pharmacopoeia 2010, some items were added, which included assay of reducing sugars, water-soluble extracts, acid insoluble ash content and 5-hydroxymethylfurfural. RESULTS: Reducing sugars was no less than 34.0%, water-soluble extracts no less than 19.0%, acid insoluble ash content no more than 0.2%, 5-hydroxymethylfurfural no more than 0.02%. CONCLUSION: The quality standard of stewed Rhizoma Polygonati with yellow wine is improved on the basis of Chinese Pharmacopoeia. PMID- 22259999 TI - [Study on HPLC fingerprint of Alpinia officinarum]. AB - OBJECTIVE: To establish the chromatography fingerprint of Alpinia officinarum by HPLC. METHODS: An optimum HPLC conditions which were obtained under the assessment of LC-MS were as follows: Shim-pack VP-ODS column (2.0 mm x 250 mm, 5 microm), 0.1% HAc aqueous solution as phase A, 15% Acetonitrile: 40% Methanol: 45% Tetrafuran as phase B, the flow rate was 0.20 mL/min, column temperature was 35 degrees C and UV detector was set at 280 nm. RESULTS: The HPLC fingerprint of Alpinia officinarum was established, the consensus 10 peaks and their relative retention times along with the ranges of relative area were determined. CONCLUSION: The method is reliable and stable and can be used for the quality control and identification of Alpinia officinarum. PMID- 22260000 TI - [Identification of marsdeniae tenacissimae caulis and its adulterants by RAPD]. AB - OBJECTIVE: To identify Marsdeniae Tenacissimae Caulis and its adulterants by RAPD (random amplified polymorphic DNA) and analyze the gene homology of Marsdeniae Tenacissimae Caulis from various habitats. METHODS: General DNA was isolated from Marsdeniae tenacissimae Caulis which were from seven various habitats and its six adulterants by CTAB, the twenty RAPD was used to identify them. RESULTS: Random primer 285 (GGG AAC CCT T) could amplify the gene of Marsdeniae tenacissimae Caulis from various habitats stablely, Marsdeniae tenacissimae Caulis and its adulterants could be identified by primer E01 (CCC AAG GTC C) effectively. CONCLUSION: The method of RAPD can be used to identify Marsdeniae Tenacissimae Caulis and its adulterants, the gene of Marsdeniae tenacissimae Caulis from various habitats have homology. PMID- 22260001 TI - [Study on chemical constituents of the bulbs of Lycoris longituba]. AB - OBJECTIVE: To study the chemical constituents of the Bulbs of Lycoris longituba. METHODS: The chemical constituents were isolated and purified by means of chromatographic techniques and their structures were elucidated by spectroscopic methods. RESULTS: Six compounds were isolated and identified as Crinine (1), Narciclasine (2), Squamigine (3), 11-Hydroxyvittatine (4), Pancracine (5), Lycorine (6). CONCLUSION: Compounds 1 - 6 are isolated from this plant for the first time. PMID- 22260002 TI - [Study on the chemical constituents of Phryma leptostachya]. AB - OBJECTIVE: To study the chemical constituents of Phryma leptostachya. METHODS: The chemical constituents were isolated and purified by silica gel column, recrystallization and Pre-RP-HPLC and their structwes were elucidated by spectroscopic methods. RESULTS: Five compounds were obtained and identified as ursolic acid (1), quercetin (2), isovanillic acid (3), p-hydroxybenzoic acid (4), adenine arabinoside (5). CONCLUSION: Compounds 2 - 5 are isolated from this genus for the first time. PMID- 22260003 TI - [Study on chemical constituents from the root of Hemerocallis citrina]. AB - OBJECTIVE: To study the chemical constituents root of Hemerocallis citrina. METHODS: The chemical constituents were extracted by microwave method and purified by silica gel column. Their structures were elucidated by their physical and chemical properties and spectral methods. RESULTS: 7 compounds were isolated and identified as: chrysophanol(I), 2-methoxy-obtusifolin(II), obtusifolin (III), rhein (IV), aloe-emodin (V), hemerocallone ( VI) and hemerocallin (VII). CONCLUSION: Compounds IV and VI are isolated from this plant for the first time. PMID- 22260004 TI - [Research of correlation between microscopic characteristic constants and chemical components of honeysuckle]. AB - OBJECTIVE: To explore the correlation between microscopic characteristics constant of Honeysuckle and its chemical component. METHODS: Capacity analysis was used to assay the number of pollen grain and non-glandular hair of Honeysuckle powder and the content of chlorogenic acid was determined by HPLC. RESULTS: In Honeysuckle, the microscopic characteristic constants of pollen grain and non-glandular hairs and chlorogenic acid content were significantly correlated. CONCLUSION: Determination of the microscopic characteristics of pollen grain and non-glandular hair constant value can be used as a means of quality control. PMID- 22260005 TI - [Analysis of lipid-soluble components of Amomum villosum fruits by GC/MS]. AB - OBJECTIVE: To analyse the lipid-soluble components of Amomum villosum fruits by GC/MS. METHODS: Lipid-soluble components in pericarps and seeds of A. villosum were extracted by Soxhlet extraction. The Lipid-soluble components were esterified and then analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: Twenty-five and thirteen compounds were identified in pericarps and seeds of A. villosum, respectively, mainly including fatty acids and their esters. CONCLUSION: The results indicate that it is highly potential and significant to exploit its value in foods, medicines and healthy care. PMID- 22260006 TI - [Study on the volatile oil of leaf of red gland Lonicera in guangxi]. AB - OBJECTIVE: To compare volatile oil of Lonicera confusa (red gland Lonicera) fresh leaves with dry leaves and provide evidence for further study of Lonicera confusa leaves. METHODS: GC-MS was used to identify chemical composition in volatile oil in red gland Lonicera leaves. RESULTS: 93 chemical components were separated in fresh leaves in which 39 chemical components were identified; 88 chemical components were separated in dry leaves in which 51 chemical components were identified. The main components of fresh leaves of red gland Lonicera were n Hexadecanoic acid (11.90%), Phytol (11.79) and 9,12,15-Octadecatrienoic acid, methyl ester, (Z, Z, Z)(7.08); The main components of dry leaves of red gland Lonicera were 1,6-Octadien-3-ol, 3,7-dimethyl-(27.62%), Phytol (7.57%) and 2, 6, 10, 14, 18, 22-Tetracosahexaene, 2, 6, 10, 15, 19, 23-hexamethyl-, (all-E) (4.70%). CONCLUSION: There are significant differences between volatile oil between fresh and dry leaves. PMID- 22260007 TI - [Effect of Astragalus and Salvia's effective components and their compatibility on JAK/STAT pathway]. AB - OBJECTIVE: To study the effect of Astragalus and Salvia's effective components and their compatibility on JAK/STAT pathway of rats' renal fibrosis. METHODS: 66 SD rats were randomly divided into 7 groups: normal group,model group,fosinopril group, salvianolic acids group, astragalus saponins group, granules compatibility of Astragalus and Salvia group, components combination of Astragalus and Salvia group. The variation of beta2-microglobulin(beta2-MG), the changes of renal pathology and JAK/STAT pathway were observed. RESULTS: The changes in renal pathology of treatment groups had different degrees of improvement; Astragalus and Salvia could reduce the urinary beta2-MG of unilateral ureteral obstruction (UUO) rat (P < 0.05), which was equal with fosinopril group. The rest of the treatment groups decreased especially fosinopril group while the difference was not significant when compared with the model group. Astragalus and its effective components could reduce the expression of renal tissue JAK, STAT1, STAT3 protein, among which fosinopril group and granules compatibility of Astragalus decreased significantly. Astragalus saponins group was not obvious, and the rest of the treatment group had significantly minor effect. CONCLUSION: Astragalus and Salvia's effective components and their compatibility may protect renal tubular function in unilateral ureteral obstruction, which may interfere with UUO rat kidney with JAK/STAT signaling pathway. PMID- 22260008 TI - [Study on the pharmacokinetics of tashinone II(A) -loaded polylactic acid nanoparticles in rabbit]. AB - OBJECTIVE: To establish a HPLC method for measuring tashinone II(A) concentration in rabbit plasma and study the pharmacokinetics of tashinone II(A) -loaded polylactic acid nanoparticles and tashinone II(A) injection in rabbits. METHODS: A single dose of TS-PLA-NP and TS II(A) injection was administered to 8 healthy rabbits via the ear-edge vein, at the set time withdrew the blood and prepared. The concentrations of tashinone II(A) in plasma were measured by HPLC with gemfibrozil as the internal standard. The pharmacokinetic parameters of TS-PLA-NP and tashinone II(A) injection were calculated by program DAS2.0. RESULTS: The average retention times of gemfibrozil and tashinone II(A) were 10.5 and 14.5 min, respectively. The half-life was prolonged from 2. 573 h of free tashinone II(A) to 4. 117 h and MRT(0-infinity) from 2.585 h to 6.033 h. The max concentration of tashinone II(A) was reduced from 0.21 to 0.134 mg/L. CONCLUSION: The method for the pharmacokinetic research of tshinone II A in rabbit plasma is accuracy, rapid and sensitive. TS-PLA-NP shows significant characteristic of delayed-release. PMID- 22260009 TI - [Study on the pharmacokinetics Oxytropis falcate total flavonoids ointment in rats]. AB - OBJECTIVE: To study the pharmacokinetics of Oxytropis falcate total flavonoids ointment after transdermal administration in rats. METHODS: The content of 2',4' dihydroxychalcone (TFC) in plasma was determined by high performance liquid chromatography. The concentration was determined at various time and the data was processed by 3P97. RESULTS: TFC behaved as a one-compartment and a two compartment model after transdermal administration of total Oxytropis falcate total flavonoids ointment and solution, respectively. And the C(max) of ointment was improved about 3 times compared with that of the solution. CONCLUSION: The results show that the ointment possesses sustained release property and significantly prolong the degradation half life of TFC. The ointment is benefit to improve the analgesic and anti-inflammatory activity after transdermal administration. PMID- 22260010 TI - [Protective effects of Leonurus japonicas on myocardial remodeling induced by isoproterenol in rats]. AB - OBJECTIVE: To investigate the effects of Leonurus japonicas on myocardial remodeling induced by isoproterenol (ISO) in rats. METHODS: The model of rat myocardial remodeling was established by subcutaneous injection of ISO (20,10 and 5 mg/kg for 3 days, subsequently 3 mg/kg for 7 days). Rats were randomly divided into five groups: Control, ISO, ISO + enalapril, ISO + Leonurus 8 g/ kg and ISO + Leonurus 16 g/kg. Recorded the values of LVSP, LVEDP, +/- dp/dt (max), cardiac output ( CO). Weighed the body weight (BW), heart weight (HW) and left ventricular weight (LVW) of rats to calculate the values of HW/BW and LVW/BW. The hydroxyproline contents were investigated by spectrophotometric measurement. The contents of type I collagen and type III collagen and ratio of I/III collagen were assessed by immunohistochemical stain. RESULTS: Leonurus (16 g/kg x day(-1)) could increased the value of LVSP, + dp/dt(max), CO (P < 0.05). Leonurus (8 g/kg) could increased the value of -dp/dt(max), decreased the ratios of HW/BW and LVW/BW (P < 0.05), the contents of hydroxyproline, type I collagen, type III collagen and the ratios of I/III collagen (P < 0.05). CONCLUSIONS: Leonurus at a dosage of 16 g/kg may improve the systolic function; Leonurus at a dosage of 8 g/kg may improve the diastolic function, down-regulate the expression of collagen and normalize the ratio of I/III collagen. PMID- 22260011 TI - [Effect of Cordyceps sinensis sporocarp on learning-memory in mice]. AB - OBJECTIVE: To study the effect of extracts of Cordyceps sinensis sporocarp on learning-memory in scopolamine treated mice and the possible mechanism. METHODS: ICR mice were randomly divided into five groups: sham control, model, piracetam and CSE 0.5, 1 g/kg. Lotomotor activity was assessed. Morris water maze was used to evaluate the memory ability of mice 30 min later after ip scopolamine 1.0 mg/kg BW. Then acitivity of AchE was measured after behavioral test. RESULTS: CSE had no influence on lotomotor activity. However, CSE 0.5, 1 g/kg both shortened escape latency and increased times of come-crossing platform in Morris water maze, meanwhile activity of AchE in the brain was decreased by CSE. CONCLUSION: CSE can significantly improve the learning and memory impairment in mice induced by scopolamine, which may be correlated with the inhibition of activity of AchE. PMID- 22260012 TI - [Preparation conditions optimization of Epimedium polysaccharide liposome]. AB - OBJECTIVE: To optimize the preparation conditions of Epimedium polysaccharide liposome (EPSL). METHODS: EPSL was prepared by membrane distribution-supersound method. In preparation of EPSL test, an orthogonal L9 (3(4)) test was used to optimize the preparation conditions, with four factors of ratio of drug to lipid, ratio of lecithin to cholesterol, ultrasonic time and water bath temperature and two indexes of encapsulation efficiency and drug-loading rate. The encapsulation efficiency of EPSL was determined by protamine method. RESULTS: Optimal preparation condition of EPSL was that ratio of drug to lipid, ratio of lecithin to cholesterol, ultrasonic time and water bath temperature were 1: 30, 4: 1,10 min and 40 degrees C respectively. CONCLUSION: EPSL prepared under Optimal conditions has the property of high encapsulation efficiency and drug-loading rate. PMID- 22260013 TI - [Research for thermal stability of fructose, glucose, 5-hydroxymethyl-2-furfural during the process of refining honey of honeyed pill]. AB - OBJECTIVE: To research the thermal stability of Fructose, Glucose, 5 Hydroxymethyl-2-furfural (5-HMF) during the process of refining honey. METHODS: The refined honey was placed under different temperature and time. High Performance of Liquid Chromatography (HPLC) coupled with Evaporative Light Scattering Detection (ELSD) were used for the determination of fructose and glucose content and HPLC-UV detector was used to detect the content of 5-HMF in refined honey. RESULTS: The contents of fructose and glucose decreased meanwhile the amount of 5-HMF conversion increased with the temperature increasing and the time extension. CONCLUSION: Temperature is the main factor and the content of fructose, glucose and 5-HMF has no significant change below 8 degrees C. Therefore, low-temperature method is recommended for the process of increasing the viscosity of honey. PMID- 22260014 TI - [Study on extraction process of available components of tea]. AB - OBJECTIVE: To investigate the optimum ethanol extraction process conditions for the available components in the tea - Catechines (CT) including Epigallo catechin gallate (EGCG) and Caffeine (CF). METHODS: The content of EGCG, CT and CF, extraction rate, DPPH * Free radical scavenging capacity were chosen as the assessment indexes. With the alcohol ratio (A), solid-liquid ratio (B) and reflux time (C) as investigation factors, the optimum ethanol extraction process of the available components from tea was determined by L9 (3(4)) orthogonal experimental design. RESULTS: It would obtain different extraction conditions to analyze the assessment indexes depending on the different extraction purposes. For the purpose of CT, the contents of EGCG and CT, extraction rate and DPPH * Free radical scavenging capacity were chosen as the assessment indexes, the optimum extraction conditions were selected as follows: the ratio of raw material to 75% alcohol was 1: 12, the reflux time was 30 minutes and extraction times were three; For the purpose of CF, the content of CF and extraction rate were chosen as the assessment indexes, the optimum extraction conditions were selected as follows: the ratio of raw material to 60% alcohol was 1: 12, the reflux time was 30 minutes and extraction times were three; For the purpose of integrated extraction, the contents of CT and CF, extraction rate and DPPH * Free radical scavenging capacity were chosen as the assessment indexes, the optimum extraction conditions were selected as follows: the ratio of raw material to 60% alcohol was 1: 8, the reflux time was 30 minutes and extraction times were three. CONCLUSION: The optimum extraction process in order to attain different purposes can give a reference to the research of a new medicine and industry production. PMID- 22260015 TI - [Effects of bushenhuoxue granules on sleep quality in Parkinson's patients]. AB - OBJECTIVE: To study the effects of Bushenhuoxue Granules on Parkinson's disease sleep scale (PDSS) score in Parkinson's patients. METHODS: 120 patients were enrolled and divided into two groups randomly,the control group were treated with placebo and treatment group with Bushenhuoxue Granules, both group based on Madopar treatment. Double-blinded clinical trial was adopted in treatment period. Follow-up period for 6 months, PDSS was adopted to measure sleep condition of PD patients at baseline time, after 3 months and after 9 months. RESULTS: Bushenhuoxue Granules treatment group showed a higher efficacy than the placebo group in relieving the sleep disorders of Parkinson disease patients,both in treatment and follow-up period (P < 0.01). No adverse effects were found in this trial. CONCLUSIONS: Bushenhuoxue Granules can markedly improve sleep disorders in Parkinson's patients. The effects are stable and obvious along with the process of treatment. PMID- 22260016 TI - [Advances in the study of organic anion transporting polypeptide 1B3]. AB - OATP1B3, a member of SLC superfamily, is specifically expressed on the sinusoidal membrane of hepatocytes and is considered to be important in hepatic drug elimination. The overexpression of OATP1B3 was found recently in tumor tissues such as prostate, colon, and pancreatic tumors. Sequence variations in SLCO1B3 gene, such as SNPs, have been described and a common haplotype consisting of 334T>G and 699G>A SNPs is related to altered transport characteristics of OATP1B3. OATP1B3 is of relevance to drug metabolism through affecting alteration of hepatic concentration of endo- and xenobiotic compounds that interact with nuclear receptors such as PXR and CAR, and thereby directly alter the extent of target gene transcription, including major CYP isoenzymes such as CYP3A4. This review will provide an overview of substrates and inhibitors of OATP1B3 and subsequently to assess the effect of genetic mutation on transport activity. The studies linking OATP1B3 with cancer clinical outcomes are also discussed in this review. PMID- 22260018 TI - [Recent advance in the discovery of allosteric inhibitors binding to the AMP site of fructose-1,6-bisphosphatase]. AB - Fructose-1, 6-bisphosphatase (FBPase), a rate-limiting enzyme involved in the pathway of gluconeogenesis, can catalyze the hydrolysis of fructose-1, 6 bisphosphate to fructose-6-phosphate. Upon inhibiting the activity of FBPase, the production of endogenous glucose can be decreased and the level of blood glucose lowered. Therefore, inhibitors of FBPase are expected to be novel potential therapeutics for the treatment of type II diabetes. Recent research efforts were reviewed in the field of developing allosteric inhibitors interacting with the AMP binding site of FBPase. PMID- 22260017 TI - [Advances in the study of small molecule antagonists of chemokine receptors as anti-asthma agents]. AB - Asthma is a chronic inflammatory respiratory disease accompanied with airway inflammation, airway remodeling and bronchial hyperresponsiveness. Chemokines are important for the recruitment of immune cells to the lung, which play an important role in the formation and development of asthma. Targeting the chemokine receptors to anti-inflammation and anti-asthma is a new strategy and some candidate drugs are discovered recently. This review is focused on the development of chemokine receptor antagonists for anti-asthma, which will promote the compound designations. PMID- 22260019 TI - [Recent developments of drug eluting stent coatings]. AB - Drug eluting stents (DESs) have revolutionized the interventional cardiology over the past decade since the first DES became commercially available in Europe in 2002. Compared to bare metal stents that are deployed to keep the vessel open by mechanical force, DESs have an additional function of reducing restenosis by the action of the drug on the target site. Coatings on the stent surface which ensure the maximum delivery of therapeutic agents to the target site with minimal systematic toxicity, also play an important role in adjusting the drug release profile. Coating material and technology not only affect the surface biocompatibility and the integrity maintenance during the implanting process, but also decide the way of drug delivering and transmitting from the coating. This paper reviews the basic principles of DES coating design, the categories of DES coatings, the commonly used clinical DES coatings and their efficiency in reducing restenosis, and finally provides the future perspectives for DES coatings. PMID- 22260020 TI - [Effect of the chelator BPCBG on the decorporation of uranium in vivo and uranium induced damage of human renal tubular epithelial cells in vitro]. AB - This study is to assess the efficacy of BPCBG on the decorporation of uranium (VI) and protecting human renal proximal tubular epithelial cells (HK-2) against uranium-induced damage. BPCBG at different doses was injected intramuscularly to male SD rats immediately after a single intraperitoneal injection of UO2(CH3COO)2. Twenty-four hours later uranium contents in urine, kidneys and femurs were measured by ICP-MS. After HK-2 cells were exposed to UO2(CH3COO)2 immediately or for 24 h followed by BPCBG treatment at different doses for another 24 or 48 h, the uranium contents in HK-2 cells were measured by ICP-MS, the cell survival was assayed by cell counting kit-8 assay, formation of micronuclei was determined by the cytokinesis-block (CB) micronucleus assay and the production of intracellular reactive oxygen species (ROS) was detected by 2',7'-dichlorofluorescin diacetate (DCFH-DA) oxidation. DTPA-CaNa3 was used as control. It was found that BPCBG at dosages of 60, 120, and 600 micromol kg(-1) resulted in 37%-61% increase in 24 h-urinary uranium excretion, and significantly decreased the amount of uranium retention in kidney and bone to 41%-31% and 86% 42% of uranium-treated group, respectively. After HK-2 cells that had been pre treated with UO2(CH3COO)2 for 24 h were treated with the chelators for another 24 h, 55%-60% of the intracellular uranium was removed by 10-250 micromol L(-1) of BPCBG. Treatment of uranium-treated HK-2 cells with BPCBG significantly enhanced the cell survival, decreased the formation of micronuclei and inhibited the production of intracellular ROS. Although DTPA-CaNa3 markedly reduced the uranium retention in kidney of rats and HK-2 cells, its efficacy of uranium removal from body was significantly lower than that of BPCBG and it could not protect uranium induced cell damage. It can be concluded that BPCBG effectively decorporated the uranium from UO2(CH3COO)2-treated rats and HK-2 cells, which was better than DTPA CaNa3. It could also scavenge the uranium-induced intracellular ROS and protect against the uranium-induced cell damage. BPCBG is worth further investigation. PMID- 22260021 TI - [Effect of lactuside B on the expression of bcl-2 and bax mRNA and their protein in rats' cerebral cortex after cerebral ischemia-reperfusion injury]. AB - This study is to investigate the effect of the major chemical composition in rhizome of Pterocypsela elata, lactuside B, on expression of bcl-2, bax mRNA and their protein in rats' cerebral cortex after cerebral ischemia-reperfusion injury. First, middle cerebral artery ischemia-reperfusion injury model was established, and each group was treated with the corresponding medicines. Animals were separately sacrificed at 24 h and 72 h. The brain infarct volumes were detected by TTC dye, bcl-2 and bax mRNA expression was checked by RT-PCR, and the proteins of bcl-2 and bax were explored by two-step immunohistochemistry in cerebral cortex of rats. Lactuside B can reduce brain infarct volume of cerebral cortex of rats, increase the expression of bcl-2 mRNA and decrease that of bax mRNA. Moreover, the ratio of bcl-2 to bax mRNA is higher in 12.5 and 25 mg kg(-1) dose group, respectively, which is significantly different from that of model group (P < 0.05 or P < 0.01). Generally, either 12.5 or 25 mg kg(-1) dose group is better than positive control medicine nimodipine (P < 0.05 or P < 0.01). In addition, the expression of bcl-2 and bax protein is consistent with their gene expression. Infarct volume and the ratio of bcl-2 to bax mRNA expression are significantly different (P < 0.05 or P < 0.01) between 72 h and 24 h group. The results demonstrated that lactuside B could play a good role in resisting cerebral ischemia by upregulating the expression of bcl-2 mRNA and protein and downregulating that of bax mRNA and protein. PMID- 22260022 TI - [Lidamycin inhibits the proliferation of HERG K+ channel highly expressing cancer cells and shows synergy with anticancer drugs]. AB - This study is to investigate inhibitory effects of lidamycin (LDM) on the proliferation of HERG K+ channel highly expressing cancer cells and its synergy with anticancer drugs. MTT assay was used to examine the inhibitory effects of lidamycin combined with various anticancer drugs on the proliferation of human lung cancer A549 cells, human colon cancer HT-29 cells and herg-stably transfected A549 cells. Using the xenograft model of subcutaneously transplanted HT-29 in nude mice, inhibitory effect was appraised in vivo. The coefficient of drug interaction (CDI) was used to evaluate the synergistic effect of drug combination. LDM significantly inhibited the proliferation ofA549 cells and HT-29 cells with IC50 values of 2.14 and 4.64 ng mL(-1), respectively. The efficacy in HT-29 cells with high HERG potassium expression level is less potent than that in A549 cells with low expression level. In terms of IC50 values, LDM suppressed the growth of herg-stably-transfected A549 cells less potently than pCDNA3.1-stably transfected A549 cells. There existed synergistic effects in the combinations of fluorouracil (5-FU) and LDM, doxorubicin (DOX) and LDM, or hydroxycamptothecine (HCPT) and LDM. CDI values of the combinations of 5-FU and LDM were more than 0.75. CDI values of LDM and DOX were more than 0.70, but some CDI values of LDM and HCPT were less than 0.70. As for the CDI values, synergistic effects of the combination of LDM and HCPT were the most potent of the three groups. There is no relationship between the inhibitory effect of the growth of cancer cells by 5-FU and HERG potassium expression level. HERG expression level negatively correlated with inhibitory effect on the proliferation of cancer cells by DOX. HERG expression levels and chemosensitivity were positively correlated for HCPT. In the model of subcutaneously xenograft transplanted HT-29 in vivo, LDM and/or HCPT effectively inhibited the growth of HT-29 in nude mice, and the optimum CDI of the combination of LDM and HCPT was less than 1. HERG expression level negatively correlates the chemosensitivity of cancer cells to LDM. There exist synergistic effects in vitro and in vivo in the combination of LDM and HCPT, which inhibitory effects of the proliferation of cancer cells positively modulated by HERG potassium expression level. HERG K+ channel may become a target of combined therapy for choosing anticancer drugs. PMID- 22260023 TI - [Construction and immunological analysis of a combined multi-epitope vaccine against EGFR/HER2]. AB - A recombinant plasmid pET28a-HBcAg-delta n was constructed, in which three mimic B-epitopes of HER family were inserted into the truncated HBc vector. The fusion protein expressed was purified and used to immunize BALB/c mice to induce antibody against the epitopes. Three mimic epitope genes were inserted into the sequences of amino acid residues 78 and 79 of HBcAg by overlap PCR. The PCR product was then cloned into pET28a to construct recombinant expression plasmid which was transformed to E. coli BL21 (DE3) and induced by IPTG. After purification, the fused protein designed HBHE was used to immunize BALB/c mice to detect humoral immunoresponse. The recombinant plasmid was successfully constructed by DNA sequencing analysis. A fusion protein with correct molecular mass was expressed and confirmed by SDS-PAGE. High titre antibody was elicited in the mice immunized with HBHE by indirect ELISA and Western blotting. The HBc particle vector containing three B-epitopes of HER family had been successfully prepared, purified and high titre antibody against HBHE was detected. All these data are helpful in further research of the broad-spectrum anti-tumour effect of combine polypeptide epi-position vaccine of EGFR and HER2. PMID- 22260024 TI - [Involvement of p38-p53 signal pathway in resveratrol-induced apoptosis in MCF-7 cells]. AB - This paper is to report the study of resveratrol-induced apoptosis and its mechanisms in MCF-7 cells. MTT assay was performed to assess the cytotoxicity of resveratrol on MCF-7 cells. Hoechst 33258 staining was used to observe cellular morphologic changes in apoptosis. Apoptosis was measured by flow cytometric analysis and the protein expression was examined by Western blotting analysis. The results indicated that resveratrol could inhibit MCF-7 cell growth in a time- and concentration-dependent manner. Remarkable morphologic changes in the cells after 60 micromol L(-1) resveratrol treatment, including cell nuclear shrinkage, DNA condensation and apoptotic bodies, were observed by Hoechst 33258 staining. Resveratrol could induce apoptosis and activate p38 and p53 in a time dependent manner in MCF-7 cells. In addition, the cell growth inhibitory ratio and the apoptotic ratio of resveratrol-treated group decreased markedly by the p38 MAPK inhibitor SB203580 or p53 inhibitor pifithrin-alpha. Further experiments confirmed that resveratrol-induced p53 activation was reduced by SB203580 whereas the activation of p38 was not affected by pifithrin-alpha. In conclusion, resveratrol induced apoptosis in MCF-7 cells could be through activating p38-p53 signal pathway. PMID- 22260025 TI - [Synthesis and biological evaluation of 3-aromatic Shiff base-5-fluoroindol-2-one derivatives]. AB - Based on the structure of 5-fluoroindol-2-one and fragments from thirteen multi target tyrosine kinase inhibitors which have been marketed or in the phase of clinical research, eleven 3-aromatic Shiff base-5-fluoroindol-2-one derivatives were designed and synthesized. Their structures were identified by 1H NMR, MS and elemental analysis. In vitro antitumor bioactivities evaluation was done by MTT method. It was shown that most of synthesized compounds had antitumor activities and compounds 1b, 1g, 1i and 1h were better than or equal to the antitumor activity of positive control. PMID- 22260026 TI - [Design, synthesis and activity of a new type of influenza virus N1 neuraminidase inhibitors]. AB - In this study, the "150-cavity", next to the H5N1 influenza virus neuraminidase activity site, has been used as the target to design and synthesize a structural analogue of chlorogenic acid, N-caffeoyl-GABA, using the flexible docking simulation. The docking study showed that the N-caffeoyl-GABA could be inserted into the "150-cavity" and combined with the Arg156 side chain by hydrogen bond. The best binding free energy of H5N1 NA-N-caffeoyl-GABA complex was -7.70 kcal mol(-1), equivalent that of the NA-oseltamivir. At the same time, using the H5N1 pseudotyping virus-based NA inhibitors screening model, we determined the inhibitory effect of oseltamivir, chlorogenic acid and N-caffeoyl-GABA on the NA. Compared with chlorogenic acid, N-caffeoyl-GABA significantly enhanced the inhibitory effect on NA, but less than oseltamivir. This study showed that the "150-cavity" could possibly be used as a new neuraminidase inhibitors target, and provided a path for the development of new neuraminidase inhibitors. PMID- 22260027 TI - [Sesquiterpenoids from the whole plant of Sarcandra glabra]. AB - To study the sesquiterpenoid constituents in the whole plant of Sarcandra glabra, silical column chromatography, Sephadex LH-20, reverse phase ODS column chromatography and preparative HPLC were used to isolate 70% EtOH extract of Sarcandra glabra. The structures were elucidated based on spectroscopic data (HR ESI-MS, 1H NMR, 13C NMR, HSQC, HMBC and NOESY). Four sesquiterpenoids were obtained and identified as 4alpha-hydroxy-5alphaH-lindan-8 (9)-en-8, 12-olide (1), chloranthalactone E (2), 8beta, 9alpha-dihydroxylindan-(5), 7 (1)-ieb 8alpha, 12-olide (3) and chloranoside A (4), respectively. Compound 1 is a new sesquiterpene lacone. PMID- 22260028 TI - Determination and biosynthesis of multiple salvianolic acids in hairy roots of Salvia miltiorrhiza. AB - Danshen (Salvia miltiorrhiza Bunge) hairy roots were obtained by infecting Danshen leaves with Agrobacterium rhizogenes 9402. Besides rosmarinic acid (RA) and salvianolic acid B (SAB), the hairy root could also produce salvianolic acid K (SAK), salvianolic acid L, ethyl salvianolic acid B (ESAB), methyl salvianolic acid B (MSAB), and a compound with a molecular weight of 538 (compound 538) identified by using LC-MS. Effects of methyl jasmonate (MeJA) and yeast elicitor (YE) on the accumulation of these compounds had been investigated. MeJA increased the accumulation of SAB, RA, SAK, and compound 538 from 4.21%, 2.48%, 0.29%, and 0.01% of dry weight to 7.11%, 3.38%, 0.68%, and 0.04%, respectively. YE stimulated the biosynthesis of RA from 2.83% to 5.71%, but depressed the synthesis of SAB, SAK and compound 538. It was indicated in all the results that these Danshen hairy roots could be used as alternative resources to produce salvianolic acids. Analysis of the content variation of these compounds after elicitation suggested that SAK and compound 538 might be the intermediates in the biosynthesis from RA to SAB in Danshen hairy roots. PMID- 22260029 TI - [Polymorphism of the 5R-5-hydroxytriptolide]. AB - 5R-5-hydroxytriptolide (LLDT-8) is a new drug candidate which is in clinical trial treating rheumatoid arthritis. Polymorph screening of the compound was carried out in this study. Polymorph of LLDT-8 was prepared by evaporative crystallization and antisolvent crystallization methods and was characterized by powder X-ray diffraction (p-XRD), infrared spectrometry (IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TG). It was found that p-XRD patterns, DSC curves, TG curves and IR spectra of the LLDT-8 samples prepared by the above recrystallization methods were all consistent. The 20 of main peaks in the p-XRD patterns appeared at 7.58 degrees, 8.14 degrees, 8.66 degrees, 15.46 degrees, 16.46 degrees, 29.54 degrees, 31.16 degrees and 38.26 degrees, while the infrared absorption peaks appeared at 3 471.3, 2 962.2, 2 887.0, 1 762.6, 1 677.8, 1 432.9, 1 365.4, 1 247.7, 1 080.0, 1 031.7 and 877.5 cm(-1). LLDT-8 was decomposed at 271.2 degrees C based on the determination from DSC and TG. It was showed in single crystal X-ray diffraction study that LLDT-8 crystal was monoclinic with the space group being P2 (1). The cell parameters were found to be: a = 11.460 1 (11), b = 6.320 5 (6), c = 13.028 1 (12), alpha = 90.00, beta = 115.557 (2) and gamma = 90.00. The crystal was a hydrogen-bonded dimmer. The slurry experiments, which were further conducted in solvents with different polarities, confirmed the stability of solid state of LLDT-8 based on the p-XRD determination. The polymorph of LLDT-8 made assurance of its efficacy consistence during its clinical trials. PMID- 22260030 TI - [Metabolic pathway and metabolites of pseudolaric acid B]. AB - The metabolic profile of pseudolaric acid B (PB) was investigated by using in vivo and in vitro tests. Pseudolaric acid C2 (PC2) was identified as the specific metabolite of PB in plasma, urine, bile and feces using HPLC and HPLC-ESI/MS(n) after both oral and intravenous administration to rats, and almost no prototype was detected in all kinds of samples. The metabolic behaviors of PB orally administered in rats treated with antibiotics to eliminate intestinal microflora were identical with those in untreated rats, demonstrating that the metabolism of PB is independent of intestinal microflora. PB was stable in 48 h respective incubation with artificial gastric juice and artificial intestinal juice, suggesting that neither pepsin nor trypsin is in charge of metabolism of PB, and also demonstrating that PB is stable in both pH environments of gastric tract and intestinal tract. In vitro research on metabolism of PB in rat liver microsomes incubation revealed that little PB was metabolized and that the proposed metabolites were the demethoxy and demethoxydecarboxy products of the prototype. The amount of metabolites was extremely low compared with the prototype, indicating that liver microsomes are not responsible for the metabolism of PB either. PB was gradually metabolized into PC2 during 1 h in whole blood incubation in vitro, and the metabolic process showed dynamically dependent manner with incubation time. Once absorbed into blood, PB was quickly metabolized into PC2, accordingly, little prototype was detected in all kinds of samples. The metabolism was attributed to the rapid hydrolysis of C-19 ester bond by plasma esterase. These results clarified the metabolic pathway of PB for the first time, which was of great significance to identify the in vivo active form and interpret acting mechanism of the active compounds of P. kaempferi. PMID- 22260031 TI - [Analysis of metabolites of daphnetin in the intestinal wall of rats by liquid chromatography and quatrupole-time of flight mass spectrometry]. AB - In this study, daphnetin and its major metabolites in the intestinal wall of rats were identified by liquid chromatography and quatrupole-time of flight mass spectrometry. Perfusion fluid of duodenum, jejunum, ileum and colon were collected separately for 2 hours from the rat intestine following perfusion with daphnetin. The metabolites of daphnetin in the perfusion fluid of different intestine segments were analyzed by the liquid chromatography and quatrupole-time of flight mass spectrometry. It is shown that the parent drug daphnetin and four metabolites were found in the perfusion fluid of duodenum, jejunum and ileum. However, no metabolites were found in the colon. Among the four metabolites, two daphnetin sulfates (m/z 257) were first discovered as the phase II metabolites of daphnetin in rats, which revealed a new way of daphnetin metabolism in rats. PMID- 22260032 TI - [Pharmacokinetics of cantide, an antisense oligonucleotide, and its metabolites in rhesus monkeys]. AB - To study the pharmacokinetics of cantide, an antisense oligonucleotide, and its metabolites after iv gtt administration in rhesus monkeys, a dual solid phase extraction pretreatment method coupling with non-gel sieving capillary electrophoresis analysis method was used for determination of cantide and its metabolites in plasma and their pharmacokinetic parameters were calculated. The pharmacokinetic behavior of cantide and its metabolites (M1 and M2) after iv gtt administration (8, 16 and 24 mg kg(-1)) in rhesus monkeys were investigated. After iv gtt administration of cantide to rhesus monkeys, cantide in plasma was eliminated rapidly and the terminal elimination half-life (t1/2) was 57.91-77.97 min, the correlation coefficients (r) to the dose of Cmax AUC(o-inf) and AUC(0-t) of the prototype was 0.9918, 0.9568 and 0.9773, respectively. The metabolites of cantide reached the Cmax following cantide immediately and the Cmax of metabolites were lower than that of the prototype. The CL(S) of cantide and its metabolites (M1 and M2) were 1.60-2.19, 5.92-8.58 and 6.07-8.78 mL min(-1) kg( 1), respectively. So, it is concluded that the Cmax of cantide and its metabolites increased with the dose, which is the same as their AUC(0-inf) and AUC(0-t). The CL(S) of metabolites were higher than that of the prototype. The MRT and t1/2 of metabolites in the high dose group increased obviously. PMID- 22260033 TI - [Identification of the metabolites of Sinisan extract in rat plasma, urine, feces and bile after intragastric administration]. AB - Sinisan is a widely used traditional Chinese medicine (TCM) in treating various diseases; however, the in vivo metabolic profile of its multiple components remains unknown. In this paper, ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was applied to identify the metabolites of Sinisan extract in rat plasma, urine, feces and bile after intragastric administration. Using MS(E) and mass defect filter techniques, 41 metabolites of 10 parent compounds (naringin, naringenin, hesperidin, neohesperidin, liquiritin, liquiritigenin, glycyrrhizic acid, glycyrrhetinic acid, saikosaponin a and saikosaponin d) were detected and tentatively identified. It was shown by our results that these compounds was metabolized to the forms of hydroxylation, glucuronidation, sulfation, glucuronidation with sulfation and glucuronidation with hydroxylation in vivo. PMID- 22260034 TI - Simultaneous determination of five nucleosides and nucleobases of Rehmannia glutinosa Libosch. by high performance liquid chromatography. AB - This study is to establish a method for simultaneously determination of five nucleosides and nucleobases, including hypoxanthine, uridine, adenine, guanosine and adenosine in Rehmannia glutinosa Libosch. which was collected from different regions in China. A Diamonsil C18 column (250 mm x 4.6 mm, 5 microm) was used. Acetonitrile and 0.04 mol L(-1) potassium dihydrogen phosphate solution were adopted as mobile phase with gradient elution. The flow rate was 1 mL min(-1) and column temperature was 30 degrees C. The detection wavelength was at 254 nm. The method had good linearity over the range of 1.0 - 16.0 microg mL(-1) (r2 = 0.999 8), 5.0 - 80.0 microg mL(-1) (r2 = 0.999 8), 1.0 - 16.0 microg mL(-1) (r2 = 0.999 5), 1.25 - 20.0 microg mL(-1) (r2 = 0.999 8) and 1.0 - 16.0 microg mL(-1) (r2 = 0.999 8) for hypoxanthine, uridine, adenine, guanosine and adenosine, respectively. The average recoveries were between 98.8% and 100.7%. The content of hypoxanthine, uridine, adenine, guanosine and adenosine in Rehmannia glutinosa Libosch. from different regions was significantly different. This established method was sensitive and reliable for the quantification of five chemical constituents in Rehmannia glutinosa Libosch. PMID- 22260035 TI - [Compound erythromycin sustained release preparation and its in vitro release]. AB - Using the weight-average molecular weight 50 000 polylactic acid (PLA) as a carrier, and a certain proportion of erythromycin (EM) and prednisone acetate (PNA) to mixed prepare the compound erythromycin sustained release preparation (sustained-release tablets). Using ultraviolet spectrophotometry and high performance liquid chromatography (HPLC) to detect separately the release amount of EM and PNA in vitro medium. The sustained-release tablets release for about 21 days, the average content of EM is 99.7 mg/table, RSD = 0.82%; and the average content of PNA is 10.03 mg/table, RSD = 0.93%. Within 21 days, the cumulative releases of EM and PNA are 86.1% and 78.3%, respectively. The drug release is steady and slow after 5 days, the burst release phenomenon in early stage is more significant. The results showed that the sustained-release tablet preparation method is feasible, the release performance is good and the clinical efficacy is significant. PMID- 22260036 TI - [Supra-molecular assembly and magnetic targeted slow-release effect of "dextran magnetic layered double hydroxide-fluorouracil" drug delivery system]. AB - The drug-loading system of DMF (dextran - magnetic layered double hydroxide - fluorouracil) was synthesized by "co-precipitation intercalated assembly - dextran composite in situ - solvent conversion" technology. The crystal-phase characteristic and slow-release performance of DMF were investigated through X ray diffraction (XRD), infrared spectrum (IR), transmission electron microscopy (TEM), thermogravimetry (TG) and in vitro release experiment. The targeted transshipment and slow-release effect of DMF system were evaluated by in vivo animal experiment. It was showed that the XRD of DMF matched with R-sixtetragonum type layered double hydroxide and Fd-3m cubic type ferrite. IR test demonstrated that the DMF system was a supra-molecular complex consisted of Dextran (DET), magnetic layered double hydroxide (MLDH) and fluorouracil (FU) components. The two-level supra-molecular MLDH-FU presented six-edge lozenge TEM morphology, with layered characteristics. DET on the surface of DMF was capable of protecting the layered structure of MLDH-FU, improving particle dispersion properties, and strengthening the slow-release performance of the drug delivery system. The drug release model of DMF at pH 7.35 of PBS in vitro fit to the zero-order kinetics equation C = 1.1716 x 10(-5) + 4.4626 x 10(-7) t. The drug delivery system DMF could transport drugs principally to in vivo target organs with a local effect, targeted specificity, and excellent circulation transshipment performance. The pharmacokinetic process of DMF presented multi-peak phenomenon with peak attenuation and cyclic growth. The peaks appeared at 0.25, 1, 3, 5 and 9 d separately after dosing intervention. The first peak process of DMF accorded with a pharmacokinetic equation of C(FU) = 14.34 e(-0.530t) + 36.04 e(-0.321t) + 24.18 e(-0.96t), and presented the characteristic of slow absorption and fast elimination. As for subsequent peak processes, half-life increased, bioavailability increased, and plasma clearance decreased. The highest peak value of DMF was 1/37 of original value of FU, and the relative bioavailability was 419% to original FU. PMID- 22260037 TI - [Preparation of two poor water soluble drugs - nanoporous ZnO solid dispersions and the mechanism of drug dissolution improvement]. AB - Nanoporous ZnO was used as a carrier to prepare drug solid dispersion, the mechanism of which to improve the drug dissolution was also studied. Nanoporous ZnO, obtained through chemical deposition method, was used as a carrier to prepare indomethacin and cilostazol solid dispersions by melt-quenching method, separately. The results of scanning electron microscope, surface area analyzer, fourier transform infra-red spectroscopy, differential scanning calorimeter and X ray diffraction showed that drugs were implanted into nanopores of ZnO by physical adsorption effect and highly dispersed into nanopores of ZnO in amorphous form, moreover, these nanopores strongly inhibited amorphous recrystallization in the condition of 45 degrees C and 75% RH. In addition, the results of the dissolution tested in vitro exhibited that the accumulated dissolutions of indomethacin and cilostazol solid dispersions achieved about 90% within 5 min and approximately 80% within 30 min. It was indicated in this study that the mechanism of drug dissolution improvement was associated with the effects of nanoporous ZnO carrier on increasing drug dispersion, controlling drug in nanopores as amorphous form and inhibiting amorphous recrystallization. PMID- 22260039 TI - [Biosynthetic pathway and synthetic strategy of spinosad--a review]. AB - Spinosad is a novel macrolide insecticide produced by Saccharopolyspora spinasa, widely used in agriculture. Here its biosynthetic pathway, and key regulatory nodes were reviewed and analyzed. A synthetic strategy to reprogram spinosad biosynthetic pathway was proposed. PMID- 22260038 TI - [Identification of Daturae flos and its adulterants based on DNA barcoding technique]. AB - To identify the original plant of Daturae Flos from its adulterants by DNA barcoding, the sequences of ITS2, psbA-trnH, matK, rbcL of four species including Datura metel, Darura innoxia, Darura stramonium and Brugmansia arborea were compared and analyzed. The PCR and sequencing success rate of the four regions (ITS2, psbA-trnH, matK, rbcL) was 100%, 90%, 100% and 85%, respectively. Sequences were assembled with CodonCode Aligner. K2P distances were calculated and NJ tree was performed by MEGA 4.1. Thirty SNPs were found among ITS2 sequences, and 33 insert/deletes were found among psbA-trnH intergenic regions. The interspecific K2P distance of ITS2 and psbA-trnH was obviously higher than that of the intraspecific one. As to matK and rbcL, there was no "Barcoding Gap" existing between inter- and intra-specific distances. The NJ trees of the four regions/combinations were built separately. Samples of Brugmansia arborea were clustered into one clade, and the other species of Datura L. formed another clade. The results showed that either ITS2 or psbA-trnH was useful to identify Daturae Flos from its adulterants. PMID- 22260040 TI - [Progress and perspectives of surface layer proteins from Bacillus species--a review]. AB - S-layer proteins are crystalline arrays composed of numerous identical protein or glycoprotein subunits. They comprise the outermost cell envelope component in most archaea and many bacteria. The remarkable properties of S-layer proteins are their capability to self-assemble and specific binding, which give S-layer proteins a wide application potential in nanotechnology and biomimetics. Recently most study in this field was concerned on the S-layer proteins of Bacillus species. This review provided a brief survey of the current state of the study about the genetics, function, properties, pathogenic correlation and application of the S-layer proteins of Bacillus species. The aim of this review was to gain more knowledge about the function of S-layers and lead to the development of new types of surface display system and recombinant vaccines, diagnostic agents and biocompatible surfaces. PMID- 22260041 TI - [Advance in detection methods of microbes on historic stones--a review]. AB - We reviewed the methods for identification of microorganisms on the surface of historic stones, including nucleic acid analysis, cell membrane analysis, secondary metabolites analysis and the traditional culture analysis. After comprehensive comparison of the advantages and disadvantages of each method, we addressed the biological protection of stone artifacts. The establishment of rapid detection of microorganisms on the historic stones is important to prevent corrosion caused by microorganisms and to protect our valuable cultural heritage. PMID- 22260042 TI - [Phylogenetic diversity characteristics of soil bacteria producing nematode attracting volatiles and identification of their active compounds]. AB - OBJECTIVE: This study characterized the phylogenetic diversity of soil bacteria producing nematode-attracting volatiles and their nematode-attracting compounds. Results would enhance our understanding on the interaction between nematodes and soil microorganisms and potentially enhance the biocontrol efficiency when combined the attractants with nemacides. METHODS: Bacteria producing volatiles with functions of nematode-attracting activities were isolated from 187 agricultural soil samples collected in 26 provinces of China with the method of double-Petri dishes. The phylogenetic diversity of these bacteria was characterized by RFLP-16S rRNA gene sequence analysis. The nematode-attracting volatiles of bacteria were detected using the SPME-GC/MS, and volatile compounds with attractive activity were determined by confirming with individual commercial compounds. RESULTS: Among the 3800 bacteria isolated from the 187 soil samples, 196 isolates(5.16% of the total) showed attractive activity (AN)more than 30% to Panagrellus redivivus. Of the 196 isolates, 66 (1.74%) showed AN > or = 70%, 62 isolates (1.63%) showed AN between 50% and 70%, and 68 isolates (1.79%) showed AN less than 50%. Phylogenetic analysis revealed that the 196 bacteria were clustered into 5 groups: Bacilli, Gammaproteobacteria, Alphaproteobacteria, Sphingobacteria and Actinobacteria. But, Bacillus were the dominant, which covered 13 species. And 11 volatiles with nematode-attracting activity were determined, including benzaldehyde, 2-heptanone, benzyl benzoate, ethyl palmitate, (+)-longifolene, benzyl alcohol, p-anisaldehyde, vanatone, ethyl butyrate, isovanilin and d-alaninol. CONCLUSION: Some species of bacteria in agriculture soil can produce volatiles to attract nematodes. PMID- 22260043 TI - [Diversity of cultured actinomycete in the Baltic Sea]. AB - OBJECTIVE: Actinomycetes (actinobacteria) are getting more and more recognized as a natural source for new drug exploration. In order to find new lead compounds, the diversity and selected bioactivities of cultured actinomycetes in the Baltic Sea (Germany) were investigated. METHODS: One hundred sediment samples were collected from south of the Baltic Sea, of which 809 purified cultures of actinomycetes were obtained by using 7 media. The phylogenetic analysis of 280 selected strains based on 16S rRNA gene sequences was carried out. In addition, activities of 21 enzymes, which play a role in metabolic processes, and anti microbial activities were determined. RESULTS: Fifteen genera and eight possible new species of actinobacteria were identified. Members of 3 genera were not isolated from marine habitats before. Of the 280 strains 21% and 20% inhibited the growth of Bacillus subtilis and Staphylococcus lentus, respectively. More than 75% of the strains exhibited 8 types of enzymatic activities, including esterase lipase (C8), catalase and naphthol-AS-BI-phosphohydrolase. CONCLUSION: Baltic Sea provides a rich diversity of actinobacteria regarding the phylogenetic analysis and the biological activities. Research and utilization of marine actinomycetes should be strengthened. PMID- 22260044 TI - [Engineering of Escherichia coli for convenient expression of [FeFe] hydrogenase]. AB - OBJECTIVE: A new method used to heterologously express [FeFe]-hydrogenase in Escherichia coli was investigated in our present study. METHODS: By homologous recombination, three assistant genes (hydE, hydF and hydG) for hydrogenase were integrated into the chromosome of E. coli BW 25113-10, in which all hydrogenase genes were inactivated. A hydrogenase structural gene hydA from Clostridium butyricum was used to test the hydrogenase maturation ability of the recombined E. coli. BW 25113-13. RESULTS: The corrected integration of the three assistant genes was confirmed by PCR, and RT-PCR results indicated that the three accessory genes were transcripted in the recombinant. The active expression of hydA indicated that the constitutively expressed accessory proteins could assist the maturation of the [FeFe]-hydrogenases. CONCLUSIONS: A simplified [FeFe] hydrogenase expression recombinant E. coli BW25113-13 was constructed. It would lay foundations for the functional screening of [FeFe]-hydrogenases and the construction of novel hydrogen producing pathways in E. coli. PMID- 22260045 TI - [Effect of gamma-glutamyl kinase gene knock-out on metabolism in L-arginine producing strain Corynebacterium crenatum 8-193]. AB - OBJECTIVE: In order to optimize precursor supply for L-arginine biosynthesis, we constructed a Corynebacterium crenatum 8-193 mutant with gamma-glutamyl kinase gene (proB) in-frame deletion. The effects of proB knock-out on physiological characteristics of the mutant were investigated. METHODS: The upstream and downstream fragments of proB were cloned from C. crenatum 8-193 chromosome and ligated to integration vector. The mutant C. crenatum 8-193-deltaproB was obtained by homologous recombination. The mutant phenotype can be reversed by complementation with proB gene from the expression vector. The physiological characteristics of the mutant were investigated by measurement of the activities of phosphoenolpyruvate carboxylase (PEPCx) and pyruvate carboxylase (PYC). RESULTS: The proB gene in-frame deletion was screened and confirmed by PCR, gamma glutamyl kinase determination and complementation. The mutant lost the ability of growth on minimal medium without proline addition. The proB knock-out mutant resulted a decrease of cell mass by 9.6% and an increase of L-arginine accumulation by 13.6% compared with that of the parent strain. The analysis of by products of fermentation broth showed that the concentrations of glutamate related and aspartate-related amino acids increased, and the concentrations of alpha-ketoglutaric acid, PEP and succinic acid decreased. The specific activities of PEPCx and PYC increased in 8-193-deltaproB. CONCLUSION: The proB gene knock out of the strain 8-193 blocked branch catabolism of L-glutamate and improved efficiency of the glucose utilization and L-arginine accumulation. PMID- 22260046 TI - [Rapid identification for Paenibacillus mucilaginosus by PCR]. AB - OBJECTIVE: Paenibacillus mucilaginosus is widely used as microbial fertilizers, therefore, rapid identification of this species by Polymerase Chain Reaction (PCR) is necessary for detection and ecological evaluation of microbial fertilizer. METHODS: A species-specific primer pair of P. mucilaginosus, orf06701 F(5'-ATGGAGGAAACATGGGGTGA-3')/orf06701-R (5'-TCAGGAATGAAGGCCCCCTT-3') was designed. Optimization of PCR, specificity and sensitivity determination were followed and the rapid identification was established. RESULTS: A single band with 333 bp was consistently amplified from all the strains of P. mucilaginosus tested and negative results were obtained from all the reference strains, such as other strains of Paenibacillus and Bacillus. The PCR detection limitation was 400 - 1000 cells per assay, indicating the sensitivity of the rapid culture-PCR method. To verify the rapid identification, soil was sampled and cultured. Five of 11 soil isolates were rapidly identified as P. mucilaginosus by the method, and the similarity of 333bp sequences were 100%. CONCLUSION: The methods can be used in the rapid identification of P. mucilaginosus and the results will provide technical supports for the detection and ecological evaluation of microbial fertilizer. PMID- 22260047 TI - [Two optimized transformation protocols for a cellulose-utilizing fungus Chaetomium globosum NK-102]. AB - OBJECTIVE: We developed the transformation methods of the strain Chaetomium globosum NK-102. METHODS: We constructed plasmid pUCATPH-Pgap and compared the transformation efficiency with pUCATPH and pCM768. We established the PEG mediated protoplast transformation and Agrobacterium tumefaciens EHA105 mediated transformation methods. RESULTS: In protoplast approach, approximately 3 -5 transformants/microg DNA could be obtained. The highest efficiency of transformation was obtained by employing pUCATPH-Pgap. A. tumefaciens EHA105 successfully mediated T-DNA insertion into the genome of C. globosum NK-102 and the transformation rate was 3.2 x 10(2) transformants/10(7) spores. The transformants retained stable after generations. Southern blot analyses confirmed that the DNA had integrated into the chromosomal DNA of C. globosum NK-102. CONCLUSION: The transformation systems were good basis for selection of C. globosum mutant strains that effectively utilizing cellulose. PMID- 22260048 TI - [Construction and toxicity the recombinant SpltMNPV expressing the scorpion toxin gene]. AB - OBJECTIVE: To develop a high toxic recombinant Spodoptera litura multicapsid nucleopolyhedroviruse (SpltMNPV) insecticide. METHODS: We constructed a recombinant transfer vector that was characterized by disrupting of ecdysterioid UDP-glucosyltransferase (egt) gene and expressing the mature peptide of the Chinese scorpion, B. martensi Karsch (BmK ITal) gene at the control of ie-1 promoter. The transfer vector and the SpltMNPV II DNA cotransfected the SpLi cells. Recombinant viruses were purified by the end point dilution and fluorescent spot purification. RESULTS: We successfully screened the recombinant SpltMNPV-deltaegt-Pph-egfp-ie-1-BmK ITal of which the egt gene was knocked out and expressed the mature peptide of the BmK ITal gene at the control of ie-1 promoter. Bioassays showed that, compared to the wide-type SpltMNPV, the speed of the recombinant virus killing the S. litura (LT50) increased by 0.7-0.8 days. CONCLUSION: The insecticidal effect of SpltNPV could be increased by inserting the foreign gene, which provided a further opportunity to develop the SpltNPV into commercially viable products to control the S. litura. PMID- 22260049 TI - [Characterization of an acidotolerant, thermophilic Thermoanaerobacter sp. xyl-d with a high xylose conversion]. AB - OBJECTIVE: We screened a thermophilic xylolytic bacterium that produced fuel ethanol from a high-temperature oil reservoir, and provided microbial resources to genetic engineering strains construction and consolidated bioprocessing. METHODS: We adopted Hungate anaerobic technique to isolate strain xyl-d from oil reservoir water sample enriched for two years from Shengli Oilfield in China, and we identified strain xyl-d with morphological, physiological, biochemical and phylogenetic analysis. RESULTS: Strain xyl-d was gram-negative, rod-shaped, spore forming and strictly anaerobic. The growth temperature ranged from 30 degrees C to 85 degrees C (optimum 65 degrees C) and the pH ranged from 3.0 to 10.0 (optimum 7.5) and salt concentration was 0% - 4% (optimum at 2.0%). It converted D-xylose into ethanol, acetate, CO2, trace amount of iso-butanol and propionate. The genomic DNA G + C contents of strain xyl-d was 45.6 mol%. Based on 16S rRNA gene sequence, strain xyl-d was most close to Thermoanaerobacter wiegelii DSM10319(T) and Thermoanaerobacter ethanolicus DSM 2246(T) both with the 99.3% similarity. It produced more ethanol and less acetate at initial pH 8.5 than other pH. Ethanol yield was increased significantly with yeast extract, and ethanol became the main end product. In addition, growth of strain xyl-d was inhibited obviously with ethanol concentration more than 7% (V/V). In the optimum growth conditions, xylose degradation rates reached to 91.37%. CONCLUSION: Strain xyl-d was thermophilic, high xylose conversion rate, acidotolerant anaerobe. It was a potential bacterium that can be used for consolidated bioprocessing. PMID- 22260050 TI - [Purification and characterization of mannanase from an alkaliphilic mannanase producing bacterium HMTS15]. AB - OBJECTIVE: To isolate and identify an alkaliphilic mannanase producing bacterium, purify and characterize mannanase thereof. METHODS: Mannanase-producing alkaliphilic bacterium HMTS15 was isolated by alkaline agar with konjak from water sample of Hamatai Lake in Inner Mongolia, China. The morphological, biochemical and physiological characteristics and 16S rRNA gene were analyzed to identify the taxonomic position of strain HMTS15. Mannanase produced by strain HMTS15 was purified by four steps including (NH4)2SO4 precipitation, cellulose DEAE-sepharose, twice Superdex 200. The enzyme properties including optimal temperature, optimal pH, thermal stability, pH stability, NaCl tolerance, metal ion tolerance, EDTA and SDS tolerance were tested. RESULTS: Strain HMTS15 was Gram-positive rod. Its growth pH ranged from 7.0 to 11.0 and growth temperature ranged from 10 degrees C to 45 degrees C. The G + C content of the DNA was 40 mol%. Phylogenetic analyses based on 16S rRNA gene sequence comparisons indicated that strain HMTS15 was a member of Bacillus. The extracellular mannanase from strain HMTS15 was purified as a single band with molecular weight of about 45 kD on SDS-PAGE. The optimal catalytic activity was showed at 75 degrees C and pH 10. The mananase was stable up to 60 degrees C and retained about 60% residual activity at 65 degrees C for 30 min. The ions Fe2+, Mn2+, Co2+, Zn2+, Ag+, Hg2+ and EDTA inhibited the acitivity of the mannanase. CONCLUSION: Polyphasic taxonomy revealed that strain HTMS15 was a new member of Bacillus agaradhaerens. The alkaline mannanase produced by strain HMTS15 hold the valuable property in stability at high temperature and broad range of pH. PMID- 22260051 TI - Antibacterial effect and cytotoxicity of beta-1,3-1, 4-glucanase from endophytic Bacillus subtilis SWB8. AB - OBJECTIVE: We studied the antibiotic activity and selective cytotoxicity of beta 1,3-1,4-glucanase from endophytic Bacillus subtilis SWB8. METHODS: Based on gel permeation chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry methods, protein fragments of beta-1,3-1,4-glucanase from endophytic Bacillus subtilis strain SWB8 were purified and identified. Then, beta-1,3-1,4-glucanase was used to evaluate the antimicrobial activity against Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis, Escherichia coli, Salmonella typhi, Salmonella paratyphi A, Shigella dysenteriae, Candida albicans and Cryptococcus neoformans and cytotoxicity against human pulmonary adenocarcinoma cells (A549) and human bone marrow mesenchymal stem cells (MSCs) by using the disc diffusion, methyl thiazolyl tetrazolium and flow cytometry methods, respectively. RESULTS: Bacterial beta-1,3-1,4-glucanase showed broad antimicrobial spectrum against all nine bacterial and fungal strains. Furthermore, beta-1,3-1,4-glucanase possessed significant anticancer activity against A549 cells that the IC50 and IC90 values were 11.5 and 20.1 microg/mL, respectively. The percentage of apoptotic A549 cells treated with different concentrations of beta-1,3-1,4-glucanase was significantly increased from 4.43% of the control to 43.1% of 19.2 microg/mL glucanase in a dose dependent manner. In contrast, these changes could not be observed in human bone marrow mesenchymal stem cells. CONCLUSION: Beta-1,3-1,4 glucanase could be a potential source of desirable antimicrobial agent, or anticancer compounds with higher efficiency and lower toxicity. PMID- 22260052 TI - [Isolation and biodiversity of heavy metal tolerant endophytic bacteria from halotolerant plant species located in coastal shoal of Nantong]. AB - OBJECTIVE: We isolated and identified endophytic bacteria from halotolerant plants collected from coastal shoal of Nantong and investigated their heavy-metal tolerance and plant growth promoting potential. METHODS: In total 45 strains were obtained from 4 halotolerant plants and 23 representative isolates were selected to detect their tolerance against NaCl and heavy metals of Cu2+, Pb2+, Cd2+, Zn2+, Hg2+; plant growth promoting index of nitrogen fixation, phosphate solubilization, indoleacetic acid (IAA) production and 1-aminocyclopropane-1 carboxylic acid (ACC) deaminase. RESULTS: Most of the isolates could grow under high consistency of Cu2+ and Pb2+. Of the bacteria 26.1% had the ability of nitrogen fixation, 21.7% of phosphate solubilization, 60.9% of IAA production and 39.1% of ACC deaminase activity. The results of 16S rRNA sequencing show that they belonged to the genera of Bacillus, Halobacillus, Oceanobacillus, Exiguobacterium, Serratia, Brevundimonas, Vibrio and Staphylococcus. Among them, strains KLBMP 2432 and KLBMP 2447 were potential novel species. CONCLUSION: The halotolerant plants located in the area of coastal shoal contain a variety of endophytic bacteria as well as the source of novel taxa. Some of them had the ability of plant growth promoting and high resistance against heavy-metal Cu2+ and Pb2+. PMID- 22260053 TI - [Phylogenetic and degrading genes analysis of a PAH-degrading bacterium TVG9-VII from deep-sea hydrythermal environment]. AB - OBJECTIVE: The aim of this study is to identify a polycyclic aromatic hydrocarbons (PAHs)-degrading bacterium isolated from deep-sea hydrothermal environment, including its taxonomy, characteristics and mechanism involved in PAH degradation. METHODS: The phylogeny was studied by 16S rRNA gene clone, and the degradation rates against different PAHs were determined by GC-MS. Meanwhile, PAH-degrading gene cluster was cloned by the genomic Fosmid library construction; the function of the key degrading-gene expression was examined by RT-PCR and qPCR to observe gene expression in the response to different PAHs. RESULTS: A PAH degrading strain TVG9-VII was isolated from the hydrothermal chimney sample of the Lau basin in Southwest Pacific Ocean. It showed 99.7% similarities with 16S rRNA gene of Novosphingobium indicum strain H25(T). The degradation rates of this strain against phenanthrene, fluoranthene and pyrene were 95.2%, 57.3% and 69.6% in 21 days, respectively. A gene cluster, containing PAHs initial dioxygenase genes pheA1a and pheA1b, was obtained from genomic fosmid library, with the insertion size of 12.522 kb. The gene pheA1a was enhanced by 4.2 folds in mRNA expression in presence of phenanthrene, but expression enhancement was not observed in other tested PAHs including naphthalene, pyrene and fluoranthene. CONCLUSION: Strain TVG9-VII is isolated from deep-sea hydrothermal environment in genus Novosphingobium. It can degrade many kinds of PAHs, especially the high weight-molecular PAHs. PMID- 22260054 TI - [Construction and characterization of Listeria monocytogenes deltaprfA mutant strains]. AB - OBJECTIVE: Listeria monocytogenes (Lm) is an important pathogen that can cause serious listeriosis in humans and animals. The pathogenicity of Lm has a close relationship with the PrfA protein regulating the expression of virulence genes. Therefore, we studied the regulation functions of PrfA and its role on Lm's virulence. METHODS: The prfA genes of LM4, serotype 1/2a, and F4636, serotype 4b, were deleted by homologous recombination technology, and the biological characteristics of the mutants were further studied. RESULTS: The prfA gene deleted strains LM4deltaprfA and F4636deltaprfA and their back mutation strains were successfully constructed. The results show that the hemolysis activity was lost in prfA deleted strains and was recovered in the reverse mutant strains. The prfA deleted strains lost phospholipase activity; their adhesion and invasion ability significantly decreased. Furthermore, their 50% lethal doses (LD50) were 5 logs higher comparing with wild type strains. CONCLUSION: PrfA regulates hly, plcB and inl gene family and affects significantly Lm's virulence. PMID- 22260055 TI - [Quorum-sensing behavior of Lactobacillus paracasei HD1.7]. AB - OBJECTIVE: Paracin 1.7 was a bacteriocin extracted from Lactobacillus paracasei HD1.7. In this study, we investigated quorum-sensing mechanism that regulates the metabolism of Paracin 1.7 in strain HD1.7. METHODS: The antibacterial activity of strain HD1.7 under different growth conditions was analyzed using an agar-well diffusion method, and the cell density was controlled by adjusting nutrient levels in the culture medium. RESULTS: The antibacterial activity of strain HD1.7 depended on cell density. Strain HD1.7 exhibited the antibacterial activity when the cell density reached a threshold (OD600 of 0.8 and cell dried weight of 0.3311 g/L). Addition of different concentrations of a signaling molecule in the supernatant of the fermentation broth affected the antibacterial activity. After removing the signal molecule, the antibacterial activity was significantly decreased. CONCLUSION: Paracin1.7 was the quorum-sensing signaling molecule in the HD1.7 fermentation broth and it could be auto-induced. The antibacterial activity of Paracin1.7 was regulated by the quorum-sensing system in HD1.7. PMID- 22260056 TI - [Mechanism and application of molecular self-assembly in Sup35 prion domain of Saccharomyces cerevisiae]. AB - Sup35 in its native state is a translation termination factor in Saccharomyces cerevisiae. The prion domain of Sup35p can form amyloid-like proteinaceous fibrils in vitro and in vivo. Furthermore, the in-register cross beta-sheet structure of Sup35p amyloid fibrils is similar to those formed in other species. Therefore, studies on mechanism of Sup35p self-assembly can be an appropriate model to study protein misfolding-related diseases and prion biology. Because of its ability to self-assemble into nanowires, the prion domain of Sup35p has been widely used in biotechnology and nanotechnology. PMID- 22260057 TI - [Research progress in fusion expression of antimicrobial peptides]. AB - Antimicrobial peptides (AMPs) are of great significance in the field of food, feed and medicine due to their wide spectrum of antimicrobial activity and new mechanism of action different from conventional antibiotics. AMPs production from natural sources is usually limited, and chemical synthesis is not economically practical, especially for the production of long peptides. Therefore, heterologous expression of AMPs has been widely studied as an alternative, and fusion expression plays an important role in increasing production. The present review mainly focuses on the types and bioactivities of AMPs. In addition, the recent strategies to the most commonly used carrier proteins for fusion expression of AMPs and prospects for future research were also discussed. PMID- 22260058 TI - [Application of microfluidics in cell transfection: a review]. AB - Microfluidics deals with the manipulation of fluidics in the structure with dimensions of micrometers or nanometers. As an emerging field, microfluidics has numerous advantages, such as controllable fluid flow and reduced reagents consumption. Recently, microfluidic has been applied into the area of cell transfection, providing opportunities to investigate cell transfection process on microscale. This review summarizes recent technical development of cell transfection based on microfluidics, including transfeceted microarray, transfecetion established in miniaturization flowing space, microdrops, microinjection and microfluidic electroporation. The factors that affect the transfection efficiency and improvement approaches are also discussed. PMID- 22260059 TI - [Anti-angiogenic activities of Lj-RGD3 toxin protein from Lampetra japonica and its mutation protein Lj-112 without RGD motifs]. AB - Arg-Gly-Asp (RGD)-toxin protein Lj-RGD3 of Lampetra japonica shares homologous with a Histidine-rich glycoprotein (HRG), and both RGD-toxin protein and HRG have antiangiogenic activities with different targets. To study the relationship between the function and the structure of Lj-RGD3, we studied the anti-angiogenic characteristics of both Lj-RGD3 and the mutation named Lj-112 of which three RGD motifs of Lj-RGD3 were deleted. We synthesized the gene of Lj-112, constructed it to the plasmid pET23b, and expressed the recombinant proteins in Escherichia coli BL21. Both recombinant proteins with the C-terminal his-tag were 15 kDa soluble proteins. Then we purified rLj-RGD3 and rLj-112 using the His-Bind affinity chromatography. To examine the effect of both proteins on bFGF-induced proliferation of ECV304 cell, we carried out the 3-(4,5)-dimethylthiahiazo (-z yl)-3,5-di-phenytetrazoliumromide (MTT) assays. For cell migration and invasion assays, we used Transwell containing insert filter and Matrigel to imitate the in vivo environment. To examine whether both proteins were capable of interrupting the angiogenesis in vivo, we used the chick chicken embryonic chorioallantoic membrane (CAM) as an angiogenesis model. We used Integrin-linked kinase1 (ILK1) ELISA method to study functionary mechanisms of rLj-RGD3 and rLj-112. Both rLj RGD3 and rLj-112 inhibited bFGF-induced proliferation of ECV304 cells in a dose dependent manner with IC50 at 0.889 micromol/L and 0.160 micromol/L, respectively. The results of migration and invasion assays revealed that both rLj RGD3 and rLj-112 showed significant inhibition on bFGF induced migration and invasion of ECV304; and rLj-112 was more active than rLj-RGD3. The result of CAM angiogenesis assay demonstrated that both proteins inhibited the angiogenesis in chick CAM, and rLj-112 was more active than rLj-RGD3. ELISA assay of ILK1 showed that both rLj-RGD3 and rLj-112 down-regulated ILK1 expression of ECV304 cell. The fact of rLj-112 was more active than rLj-RGD3 on anti-angiogenesis indicate that rLj-112 was likely with histidine-rich glycoprotein (HRG), and the factor of sequence homologous between rLj-RGD3 and HRG cannot enhance antiangiogenic activities of rLj-RGD3, the signal pathway of anti-angiogenesis of rLj-RGD3 and rLj-112 are differently. PMID- 22260061 TI - [Acetone-butanol fermentation from the mixture of fructose and glucose]. AB - A mixture of fructose and glucose was developed to simulate the hydrolysate of Jerusalem artichoke tubers, the fructose-based feedstock suitable for butanol production. With the initial pH of 5.5 without regulation during mixed-sugar fermentation, as high as 23.26 g/L sugars were remained unconverted, and butanol production of 5.51 g/L were obtained. Compared with either glucose or fructose fermentation, the early termination of mixed-sugar fermentation might be caused by toxic organic acids and the low pH. When the pH of the fermentation system was controlled at higher levels, it was found that sugars utilization was facilitated, but less butanol was produced due to the over-accumulation of organic acids. On the other hand, when the pH was controlled at lower levels, more sugars were remained unconverted, although butanol production was improved. Based on these experimental results, a stage-wise pH regulation strategy, e.g., controlling the pH of the fermentation system at 5.5 untill the OD620 reached 1.0, and then the pH control was removed, was developed, which significantly improved the fermentation performance of the system, with only 2.05 g/L sugars unconverted and 10.48 g/L butanol produced. PMID- 22260060 TI - [Effect of overexpression of nicotinic acid phosphoribosyl transferase on succinic acid production in Escherichia coli NZN111]. AB - Escherichia coli strain NZN111 is a promising candidate for the fermentative production of succinate. However, because lactate dehydrogenase and pyruvate formate lyase were inactivated in NZN111, this strain had an unbalanced NADH/NAD+ ratio and could not use glucose under anaerobic conditions. In this study, a recombinant strain E. coli NZN111/pTrc99a-pncB was constructed to overexpress the nicotinic acid phosphoribosyl transferase gene (pncB). Under anaerobic conditions with the addition of 0.5 mmol/L nicotinic acid and 0.3 mmol/L isopropyl beta-D thiogalactopyranoside (IPTG), the specific nicotinic acid phosphoribosyl transferase (NAPRTase, EC 2.4.2.11) activity in the recombinant strain was 11 fold higher than that in E. coli NZN111, the concentration of NAD(H) was increased by 3.85-fold, especially the concentration of NAD+ was increased by 5.17-fold and NADH/NAD+ was decreased from 0.640 to 0.125. The recombinant strain regained the capability of growth and glucose utilization under anaerobic conditions. PMID- 22260062 TI - [Application of a pH feedback-controlled substrate feeding method in glutamic acid fermentation]. AB - A novel method based on pH value was proposed to simplify the substrate feeding method for glutamic acid fermentation. The linear relationship between the consumption amounts of ammonia (x) and that of glucose (y) was established (y = 7.4744x, R2 = 0.9989) which could be used as the ratio of the amount of ammonia and that of glucose in the feeding broth. Thus the concentration of glucose could be controlled through the adjustment of pH automatically. In the glutamic acid fermentation using the pH feedback-controlled glucose feeding method, the glucose concentration in fermentation broth was maintained between 12 and 21 g/L. Compare with the constant glucose concentration feeding method, the glucose conversion rate and glutamic acid productivity increased by 9.06% and 17.5% respectively, when the pH feedback-controlled glucose feeding method was employed, and fermentation period was shorten above 2 h. PMID- 22260063 TI - [Effects of microbial pretreatment of kenaf stalk by the white-rot fungus Pleurotus sajor-caju on bioconversion of fuel ethanol production]. AB - Kenaf stalk was pretreated by the white-rot fungus Pleurotus sajor-caju incubated in solid-state kenaf stalk cultivation medium. Delignification and subsequent enzymatic saccharification and fermentation of kenaf stalk were investigated in order to evaluate effects of microbial pretreatment on bioconversion of kenaf lignocellulose to fuel ethanol production. The highest delignification rate of 50.20% was obtained after 25-35 days cultivation by P. sajor-caju, which could improve subsequent enzymatic hydrolysis efficiency of kenaf cellulose. And the saccharification rate of pretreated kenaf stalk reached 69.33 to 78.64%, 4.5-5.1 times higher than the control. Simultaneous saccharification and fermentation (SSF) with microbial-pretreatment kenaf stalk as substrate was performed. The highest overall ethanol yield of 68.31% with 18.35 to 18.90 mg/mL was achieved after 72 h of SSF. PMID- 22260064 TI - [Effect of antibody CR6261 V(H) and scFv expression on influenza virus infection]. AB - The emerging CR6261 antibody could neutralize several subtype influenza virus with high affinity, whose VH domain binds to the HA protein conserved domain. Therefore, it has drawn much attention as a potential broad-spectrum therapeutic antibody against influenza virus. In this study, we constructed the eukaryotic expression vectors pCR6261V(H), pCR6261V(H)-GFP and pCR6261scFv and screened the monoclonal cell lines that could stably express CR6261V(H), CR6261V(H)-GFP and CR6261scFv on the cell membrane. After influenza virus infecting the stable cell lines, the titers of viruses were tested by hemagglutination inhibition test. The result shows that the titers of viruses in CR6261scFv and CR6261V(H)-GFP stable expression cell lines decreased and there was no obvious discrimination between the CR6261V(H) expression cell line and the negative control, suggesting that CR6261V(H) and CR6261scFv expressing on the cell membrane could partly inhibit the virus infection. Though the effective inhibition strategy is undergoing, our research will provide new clues for the breeding of anti influenza transgenic animals. PMID- 22260065 TI - [PCR-based sequencing for detection and genotyping of human papillomavirus in 325 cervical cell specimens from Beijing area]. AB - To evaluate PCR-sequencing for clinical detection of human papillomavirus (HPV) genotypes in cervical cell specimens, we applied PCR-sequencing to HPV detection and genotyping by general primer PGMY09/11, which targets the HPV most conserved L1 gene. Samples with multiple infections were subjected to HPV type-specific PCR. Among the 325 cervical samples, 228 were HPV positive, of which 66 showed multiple infections. In all, 27 different HPV genotypes were identified, with HPV 16 being the most prevalent, followed by HPV 58 and 52. The prevalence of high risk HPV infection increased with the severity of cervical lesions (P < 0.05), whereas the proportion of multiple infections declined significantly from LSIL to SCC (P < 0.05). Both rates of overall and high-risk HPV infection were the highest in 21-30 age groups. There was substantial agreement between the HC2 and PCR-sequencing assay for detection of high-risk HPV (kappa = 0.675). PCR sequencing was effective in HPV detection and genotyping, and it could be potentially applied to large scale HPV screening. PMID- 22260066 TI - [Hyperlipidemia in hepatic MED1 deficient mice in response to fasting]. AB - MED1 is a key transcription co-activator subunit of the Mediator complex that is essential for RNA polymerase II-dependent transcription. MED1 functions as a co activator for PPARs and other nuclear receptors and transcription factors, and plays an important role in lipid metabolism. To examine how MED1 might affect plasma lipids, plasma triglyceride, cholesterol levels, and lipoprotein profiles, were measured in MED1(deltaLiv) mice fasted for 24, 48 and 72 hours. Histological changes in liver sections from MED1(deltaLiv) mice after 72 hours of fasting were also examined using H&E staining. There was no fat accumulation in livers of MED1(deltaLiv) mice compared to MED1(fl/fl) and PPARalpha -/- control mice after 72 hours of fasting. Compared with MEDl(fl/fl) mice, plasma triglycerides in MED1(deltaLiv) mice were significantly increased after 24, 48 and 72 hours of fasting, and plasma cholesterol was significantly increased after 48 and 72 hours of fasting. Lipoprotein profiles were similar in fed MED1(fl/fl) and MED1(deltaLiv) mice. However, very low density lipoprotein (VLDL) was significantly increased in MED1(deltaLiv) mice after 24 hours of fasting. We conclude that, hyperlipidemia in MED1(deltaLiv) mice in response to fasting is due to the accumulation of VLDL, which suggests that MED1 plays a pivotal role in the regulation of plasma triglyceride and cholesterol levels. PMID- 22260067 TI - X-ray diffraction analysis of glycoprotein D from herpes simplex virus type 2. AB - Glycoprotein D (gD) of Herpes simplex virus type 2 (HSV-2) is a key factor mediating the entry of HSV-2 into host cells. In order to explain the mechanism underlying the gD-mediated receptor-binding and viral entry, we performed a structural study on HSV-2 gD. The ectodomain of the gD protein encompassing residues 1 to 285 was expressed by baculovirus-infected insect cells as a secreted soluble protein with a C-terminal hexa-his tag. The protein was then purified by affinity and size-exclusion chromatography. The purified protein was successfully crystallized using the hanging-drop vapor-diffusion at 18 degrees C in a condition consisting of 0.1 mol/L Hepes pH 7.2, 5% (V/V) 2-methyl-2,4 pentanediol (MPD) and 10% PEG 10 000. The crystals diffracted to 1.8 angstroms resolution and belonged to space group P21, with unit-cell parameters alpha = 63.6, b = 55.4, c = 65.3 angstroms, beta = 96.3 degrees. PMID- 22260068 TI - [Eukaryotic expression of human IL17-RD-ECD and generation of its monoclonal antibody]. AB - IL-17 Receptor D (IL-17 RD) is a cytokine receptor that mediates IL-17 signaling and plays an important role in responding to the invasion of extracellular pathogens and many inflammatory and autoimmune diseases such as rheumatoid arthritis. In this study we report the generation of a mouse monoclonal antibody against human IL-17 RD. The recombinant human IL-17RD extracellular domain (hIL 17RD-ECD) was produced in the baculovirus expression system and purified from culture medium of sf9 insect cells. The purified protein was used as a T dependent antigen to immune Balb/C mice. B cells from the spleen of immunized mice were fused with murine cell SP2/0. Hybridoma cell lines were screened for the production of the monoclonal antibody against hIL-17-RD-ECD using ELISA. A hybridoma cell line 1F8 was found to have a high production of the antibody, which was further confirmed for the specificity by both western blot and ELISA analyses. The monoclonal antibody obtained from hybridoma 1F8 was characterized to be IgG1+Kappa subclass. This study provided a base for the further therapeutic application of the antibody on the autoimmune disease including rheumatoid arthritis. PMID- 22260069 TI - [Characterization of recombinant single-stranded DNA-binding protein from Escherichia coli and its application in accurate pyrosequencing]. AB - We expressed recombinant single-stranded DNA-binding protein (r-SSBP) from Escherichia coli with the molecular weight of 24-kDa by using genetic engineering strategy, and demonstrated the single-stranded DNA (ssDNA)-binding activity of r SSBP by electrophoretic mobility shift assay (EMSA). To further characterize r SSBP, we studied the effects of r-SSBP on melting temperature (T(m)) of DNA. The results showed that r-SSBP could bind to ssDNA, and lower the T(m) of DNA, especially for single-base mismatched DNA. Therefore, r-SSBP significantly increased the T(m) difference between single-base mismatched DNA and perfect matched DNA. These results are very beneficial for single-nucleotide polymorphism detection. Moreover, we applied r-SSBP in high sensitive pyrosequencing system developed by our group. The results suggest that the r-SSBP decreased non specific signals, corrected the proportion of signal peak height and improved the performance of pyrosequencing. PMID- 22260070 TI - [Expression, purification and interaction of human leukocyte antigen F and cluster of differentiation 8alpha homodimers]. AB - To obtain large quantity of human leukocyte antigen F (HLA-F) and cluster of differentiation 8alpha homodimers (CD8alphaalpha) proteins and to study their relationship, HLA-F and CD8alpha genes with rare codon in Escherichia coli were cloned using an N-terminal synonymous mutation method. High-efficiency expression protein inclusion bodies were acquired. The proteins were refolded using the dilution method and purified with gel-filtration and anion exchange chromatography. The results of gel-filtration and native-PAGE indicate that HLA-F interacts with CD8alphaalpha. This interaction may affect the binding between CD8alphaalpha and other MHC molecules to regulate immune responses. These results provide a basis for further research of HLA-F. PMID- 22260071 TI - [Construction of gold film solid-phase carrier of myoglobin monoclonal antibody based on thiol self-assembly]. AB - In order to immobilize myoglobin (Mb) monoclonal antibody on gold film solid phase carrier, we grew a mixed self-assembled monolayers (SAMs) of acid thiol and mercapto ethanol on gold film. Then we analyzed the property of the sample by atomic force microscopy and X-ray photoelectron spectroscopy. Then, we used 1-(3 dimethyl aminopropyl)-3-ethyl carbodiimide hydrochloride as catalyst to couple SAMs with amino of antibody so that we immobilized antibody on surface of gold film, followed by detecting myoglobin antigen. Results showed that, by optimizing experimental conditions, when we treated gold film by a mixture of mercapto hexadecanoic acid and mercapto undecanol ethanol solution of concentration of 50 mmol/L at temperature of 60 degrees C for 3 hours, and Mb monoclonal antibody of concentration of 40 mg/L for 3 hours, respectively, antibody had high immobilization efficiency and the MbAg was detected to 30 microg/L. The method provided a theoretical and practical basis for using magnetoresistence biosensors to diagnosis myocardial infarction. PMID- 22260072 TI - [Diagnosis and surgical approach of parapharyngeal space neoplasms]. AB - OBJECTIVE: To explore the diagnosis and reasonable surgical approach for parapharyngeal space neoplasms. METHOD: From July 2004 to July 2009, a retrospective review of 45 patients with neoplasms of parapharyngeal space was performed. Fourty-five cases were examined by CT, some of them were examined by MRI or DSA. Several surgical approaches were selected. The transcervical approach was used in 35 cases, the transparotid approach was used in 5 cases, the transmandible approach was used in 2 cases, and the transparotid and temporal approach was used in 3 cases. RESULT: Among 45 patients, 37 cases (82.22%) were benign and 8 cases (17.78%) were malignant. Neurogenic neoplasms and salivary glands neoplasms were the most common tumors. Using CT, MRI or DSA could obtain useful information about the location, size, shape, density and degree of enhancement of the parapharyngeal space neoplasms, acquire their relationship with styloid and carotid, and make preoperative diagnosis. The diagnostic coincidence rate between preoperative diagnosis and pathological diagnosis was 80% (origin of tissue). All benign tumors were completely resected. A lymphangiomas had recurrence after 1 year,and the second operation had no recurrence. In the 45 cases, 8 cases were malignant tumors. Of 2 patients with malignant mixed tumors, 1 survived disease free after a follow-up of 4 years,and another was still alive with disease after a follow-up of 3 years; Of 2 patients with synovial sarcomas, 1 survived disease free for a follow-up of 3 years, the other one survived disease free after a follow-up of 2 years; 1 patient of nasopharyngeal carcinoma with metastasis in the parapharyngeal space had post operative radical radiotherapy and survived disease free after a follow-up of 5 years. One patient with chordoma was still alive with disease after a follow-up of 3 years; 1 patient with poorly differentiated squamous cell carcinoma, died of pulmonary metastasis after a 4 year follow-up; 1 case with follicular dendritic cell sarcoma survived disease free after a follow-up of 2 years. CONCLUSION: CT, MRI and DSA are essential for the diagnosis and differentiation of parapharyngeal space neoplasm. The transcervical approach is a simple, safe and minimal invasive procedure for resecting parapharyngeal space neoplasms. It is the best approach for treatment of parapharyngeal space neoplasms. PMID- 22260073 TI - [Clinical significance of Stat3 and Cyclin D1 expression in laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To examine the expression and clinical significance of the Stat3 and Cyclin D1 in laryngeal squamous cell carcinoma (LSCC). METHOD: The expression of Stat3 and Cyclin D1 in LSCC tissue were detected by the RT-PCR and Western blot method respectively, and then the relationship between Stat3 and Cyclin D1 protein expression level and relevant clinical factors of LSCC was explored. RESULT: Compared to the normal larynx mucosa group, the expression level of Stat3 and Cyclin D1 was significantly higher in LSCC (P < 0.01). The high expression level of Stat3 and Cyclin D1 protein in LSCC was correlated with the clinical stage, tumor differentiation and lymph node metastases (P < 0.01). The expression level of Stat3 was positively correlated with that of Cyclin D1, The correlation coefficient(r) was 0.564 (P < 0.01) for the protein expression and 0.552 (P < 0.01) for the mRNA expression. CONCLUSION: Stat3 signaling pathway may play an important role in the tumorigenesis and progression of LSCC. The expression level of Stat3 and its target gene Cyclin D1 can reflect the malignancy degree of LSCC. PMID- 22260074 TI - [Significance of heparanase, bFGF and VEGF in angiogenesis for nasopharyngeal angiofibroma outspreading]. AB - OBJECTIVE: To observe the expression of HPA, bFGF and VEGF in nasopharyngeal angiofibroma, and then explore its significance of inducing angiogenesis in the tumor's expansibility growth. METHOD: The expression of heparanase, bFGF, VEGF and CD105 were examined in 30 (I - II period 9 cases, III - IV period 21 cases) samples from nasopharyngeal angiofibroma and 20 inferior turbinate tissues by immunohistochemical staining technique. The microvascular density (MVD) were measured by the immunohistostaining of CD105. The MVD was analyzed with the clinical stage. RESULT: The positive rates of the HPA, bFGF and VEGF expression in JNA tissues were significantly higher than that in inferior turbinate group (P < 0.05). The positive rates of HPA, bFGF and VEGF expression in III - IV period were obviously higher than that in I - II period (P < 0.05). The expression of bFGF and VEGF in JNA tissues was respectively positive correlated with the HPA (r = by 0.499, 0.582, P < 0.05); In JNA tissues, the mean MVD in both HPA and bFGF positive group was higher than each one single positive group or both negative express group (P < 0.05). And the mean MVD in both HPA and VEGF positive group was higher than each one single positive group or both negative express group (P < 0.05). CONCLUSION: HPA can induce angiogenesis to promote tumor growth by releasing bFGF and VEGF. Targeting the HPA can be a new direction in JNA adjuvant treatment. PMID- 22260075 TI - [Clinical significances of serum NO and oxLDL in obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To study the correlation between the serum levels of nitrogen oxide (NO) and oxidized low density lipoprotein (oxLDL) in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). METHOD: NO and oxLDL levels were measured in 60 OSAHS patients and 26 healthy subjects. OSAHS patients were divided into mild, moderate and severe groups according to AHI. RESULT: NO levels in the moderate and sever OSAHS groups was significantly lower than that in the control group, but the levels of oxLDL was increased compared with the control group. (P < 0.05). The serum levels of NO was negatively correlated with AHI (P < 0.01) and positively correlated with the lowest SaO2 (P < 0.01), the serum levels of oxLDL was positively correlated with AHI (P < 0.01) and negatively correlated with the lowest SaO2 (P < 0.01), NO levels showed negative correlations with oxLDL levels (P < 0.01). CONCLUSION: The serum level of NO is reduced in response to the increase of AHI and the acceleration of hypoxia, which indicated that there is a correlation between vascular endothelial dysfunction and the severity of hypoxia. The decrease of the level of NO and the increase of the oxLDL can promote the formation of atherosclerosis, which increased the incidence of cardiocerebrovascular disease in patients with OSAHS. PMID- 22260076 TI - [Secondary laryngeal tuberculosis at high altitudes of Tibet]. AB - OBJECTIVE: To improve the diagnostic and therapeutic efficiency for secondary laryngeal tuberculosis through an analysis on the clinical features of patients with this disease. METHOD: A retrospective study was made among 49 cases with laryngeal tuberculosis treated in Tibetan General Hospital of Chinese PLA, and the clinical data were carefully analyzed to summarize the clinical experience of this disease. RESULT: Of 49 patients, 24 cases had 1 year history, 11 cases had 1 to 3 years, 9 cases had 3 to 5 years, 5 cases had 5 years or more. Thirty-eight patients had the history of tuberculosis and 11 had none. Thirty-four patients had taken anti-tuberculosis drugs but none had standard therapy as demanded. All cases had mild general symptoms (mild fever, night sweats, weight loss, et al) and atypical local symptoms (hoarseness, sore throat). Therefore, 42 cases were misdiagnosed as non-specific chronic laryngitis, of which 15 cases got worse after oral administration or inhaling of steroid hormones. Seven persons were misdiagnosed as laryngeal cancer. All patients were confirmed pulmonary tuberculosis by X ray exam or CT scanning. Twelve cases had strong positive PPD tests and 2 cases were detected positive by sputum smear. All patients was treated by standard systematic and local chemical therapy against tuberculosis (inhaling of antituberculosis drugs for 1 to 2 months). All were cured but one died in a road accident, and none had recurrence after 1- to 9- year follow-up. CONCLUSION: All of those the patients with long period hoarseness and sore throat should take chest CT scan or X-ray exam for the highest incidence of pulmonary tuberculosis at high altitudes. CT scanning is the prefer for its high resolution. Pathological biopsy and diagnostic therapy should be taken to make accurate diagnosis. Usually steroid hormones should not be recommended. PMID- 22260078 TI - [Treatment of low-dose erythromycin and sinus displacement on sinusitis in patients with nasopharyngeal carcinoma after radiotherapy]. AB - OBJECTIVE: To study the effect of low-dose erythromycin combined with sinus displacement therapy on treating sinusitis in patients with nasopharyngeal carcinoma after radiotherapy. METHOD: The sinus displacement were used with mixed liquid of metronidazole, protease and dexamethasone, and meantime roxithromycin was orally administered. RESULT: Effective rate was 97.1% in 35 nasopharyngeal carcinoma patients with sinusitis after radiotherapy. CONCLUSION: Low-dose erythromycin combined with sinus displacement therapy is effective to treat sinusitis in patients with nasopharyngeal carcinoma after radiotherapy. Its advantages are safe, effective, and easy to do. PMID- 22260077 TI - [Clinical manifestations of cluster headache accompanied by chronic nasosinusitis]. AB - OBJECTIVE: To master the clinical manifestations of rhinogenic headache and improve the diagnostic ability of chronic rhinosinusitis accompanied by primary headache. METHOD: The clinical manifestations, the diagnostic process, and the treatment of 1 patient with headache were analyzed, and also the related articles were studied. RESULT: Rhinogenic headache and primary headache had different clinical features and different treatment. In clinical work misdiagnosis were easily made if not being carefully analyzed. CONCLUSION: Diagnosis of rhinogenic headache do need strong clinical evidence, but the differential diagnosis of other headache should be made. PMID- 22260079 TI - [Mutation of ING1 gene in laryngeal squamous cell carcinoma and its association with p33ING1b protein expression]. AB - OBJECTIVE: To investigate the ING1 gene mutation status in human laryngeal squamous cell carcinoma(LSCC), and the association of p33(ING1b) protein expression with p53 protein expression. METHOD: DNA of LSCC tissue was extracted, and nucleotide of the second exon was amplified and sequenced to determine the chromosome status. The p23(ING1b) and p53 protein expression were detected by immunohistochemistry and the association between them were analyzed. RESULT: No mutation was detected in ING1 gene, but a single polymorphism from GGG to AGG at codon 170 of ING1 gene was found in 2 of the 25 LSCC tissues. The immunohistochemical analysis showed that 4 had positive p33(ING1b) expression. No association was found between p33(ING1b) expression and LSCC clinical features, or between p53 and clinical features. However, significant difference was found between p33(ING1b) and p53 expression. p33(ING1b) tended to be negative in p53 expression positive tissue. CONCLUSION: ING1 gene mutation appears rare in LSCC. In normal physical condition, p33(ING1b) may play a synergistic effect with p53 protein. PMID- 22260080 TI - [Postoperative changes of immunity in children undergoing adenoidectomy with tonsil ablation or with partial tonsillectomy]. AB - OBJECTIVE: To investigate the changes of humoral and cellular immune responses in children with OSAHS after adenoidectomy with tonsil ablation or partial tonsillectomy by a plasma-mediated radiofrequency-based device. METHOD: Seventy children with OSAHS were enrolled in the study. According to the size of tonsils, they were divided into two groups: the adenoidectomy with tonsil ablation group and the adenoidectomy with partial tonsillectomy group. 4 ml of peripheral venous blood was drawn before and 1 month, 3 months after operation. Serum IgG, IgA, IgM levels and peripheral blood T lymphocyte subsets were measured. RESULT: In the adenoidectomy with tonsil ablation group, the level of CD3+ and CD4+ /CD8+ ration were slightly increased, while the levels of CD4+ and CD8+ were slightly reduced at 1 month after operation as compared to preoperative period. However, in the adenoidectomy with partial tonsillectomy group, the levels of CD8+ at 1 month after operation were slightly increased compared with that in preoperative examination, while the CD3+, CD4+ level and the CD4+/CD8+ ratio were slightly reduced during the same period. In addition, the levels of serum immunoglobulins showed no significant difference between the two groups, and returned to the preoperative levels at 3 months after operation in both groups (P > 0.05). CONCLUSION: The results of the present study indicate that the humoral and cellular immunity is not affected in children with OSAHS who undergo adenoidectomy with tonsil ablation or partial tonsillectomy using plasma-mediated radiofrequency ablation. The patients' immune functions can return to normal levels at 3 months after the surgery. PMID- 22260081 TI - Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. PMID- 22260082 TI - Diffusion in hierarchical mesoporous materials: applicability and generalization of the fast-exchange diffusion model. AB - Transport properties of cyclohexane confined to a silica material with an ordered, bimodal pore structure have been studied by means of pulsed field gradient nuclear magnetic resonance. A particular organization of the well defined pore structure, composed of a collection of spatially ordered, spherical mesopores interconnected via narrow worm-like pores, allowed for a quantitative analysis of the diffusion process in a medium with spatially ordered distribution of the fluid density for a broad range of the gas-liquid equilibria. The measured diffusion data were interpreted in terms of effective diffusivities, which were determined within a microscopic model considering long-range molecular trajectories constructed by assembling the alternating pieces of displacement in the two constituting pore spaces. It has further been found that for the system under study, in particular, and for mesoporous materials with multiple porosities, in general, this generalized model simplifies to the conventional fast-exchange model used in the literature. Thus, not only was justification of the applicability of the fast-exchange model to a diversity of mesoporous materials provided, but the diffusion parameters entering the fast-exchange model were also exactly defined. The equation resulting in this way was found to nicely reproduce the experimentally determined diffusivities, establishing a methodology for targeted fine-tuning of transport properties of fluids in hierarchical materials with multiple porosities. PMID- 22260084 TI - K2M(III)2(M(VI)O4)(PO4)2 (M(III) = Fe, Sc; M(VI) = Mo, W), novel members of the lagbeinite-related family: synthesis, structure, and magnetic properties. AB - The possibility of PO(4)(3-) for MoO(4)(2-) partial substitution in the langbeinite framework has been studied by exploration of the K-Fe(Sc)-Mo(W)-P-O systems using the high-temperature solution method. It was shown that 1/3PO(4)(3 ) for MoO(4)(2-) substitution leads to formation of three novel compounds K(2)Fe(MoO(4))(PO(4))(2), K(2)Sc(MoO(4))(PO(4))(2), and K(2)Sc(WO(4))(PO(4))(2) with slightly increased lattice parameters and significant distortion of the anion tetrahedra without structure changes. In contrast, the antiferromagnetic structure is modified by substitution in the low-temperature region. The structural peculiarities are discussed in light of bond-valence sums calculations. PMID- 22260083 TI - Assessing the effect of patterns of cocaine and alcohol use on the risk of adverse acute cocaine intoxication. AB - INTRODUCTION AND AIMS: Although, in the laboratory, most acute adverse effects of cocaine are dose-dependent and alcohol potentiates some of these effects, there are few observational studies, and scarce awareness that the risk of acute cocaine intoxication (ACI) can increase as the amounts of cocaine and alcohol consumed increase. Our objectives were to assess if the risk of ACI increases with the level cocaine use, both in chronic and binge use; and also to determine whether it increases when a cocaine binge is combined with binge drinking or with regular excessive drinking. DESIGN AND METHODS: Hypotheses were evaluated using logistic regression and case-crossover analyses in a sample of 720 young regular cocaine users who did not regularly use heroin, recruited at drug scenes in 2004 2006. All data on ACI, predictor and confounding variables were obtained through a computer-assisted personal interview. RESULTS: The annual prevalence of ACI was 21%. In the last year 10.3% of the participants reported cocaine binges (>= 0.5 g in 4 h). ACI risk increased considerably in the 4 h following a cocaine binge (odds ratio = 34.6; 95% confidence interval 11.5-170.8). Also, it increased with increases in the average level of cocaine used over a long period and when users regularly drank excessively. Finally, the results suggest that the high risk of ACI associated with cocaine binge may increase even more when combined with binge drinking. DISCUSSION AND CONCLUSIONS: Awareness of the dose-dependent effect of cocaine on ACI risk, as well as the possible synergistic effect of alcohol, ought to be incorporated into preventive and care strategies. PMID- 22260086 TI - Enantioselective acylation of 1,2- and 1,3-diols catalyzed by aminophosphinite derivatives of (1S,2R)-1-amino-2-indanol. AB - A phosphinite derivative that can be easily prepared in two steps from commercially available aminoindanol was found to be an effective catalyst for enantioselective acylation of diols. For the asymmetric desymmetrization of meso 1,2-diols, the corresponding monoester was obtained in up to 95% ee from the reaction in the presence of 5 mol % catalyst. PMID- 22260085 TI - Migrant health in French Guiana: are undocumented immigrants more vulnerable? AB - BACKGROUND: Few data exist on the health status of the immigrant population in French Guiana. The main objective of this article was to identify differences in its health status in relation to that of the native-born population. METHODS: A representative, population-based, cross-sectional survey was conducted in 2009 among 1027 adults living in Cayenne and St-Laurent du Maroni. Health status was assessed in terms of self-perceived health, chronic diseases and functional limitations. The migration variables were immigration status, the duration of residence in French Guiana and the country of birth. Logistic regression models were conducted. RESULTS: Immigrants account for 40.5% and 57.8% of the adult population of Cayenne and St-Laurent du Maroni, respectively. Most of them (60.7% and 77.5%, respectively) had been living in French Guiana for more than 10 years. A large proportion were still undocumented or had a precarious legal status. The undocumented immigrants reported the worst health status (OR = 3.18 [1.21-7.84] for self-perceived health, OR = 2.79 [1.22-6.34] for a chronic disease, and OR = 2.17 [1.00-4.70] for a functional limitation). These differences are partially explained by socioeconomic status and psychosocial factors. The country of birth and the duration of residence also had an impact on health indicators. CONCLUSION: Data on immigrant health are scarce in France, and more generally, immigrant health problems have been largely ignored in public health policies. Immigrant health status is of crucial interest to health policy planners, and it is especially relevant in French Guiana, considering the size of the foreign-born population in that region. PMID- 22260087 TI - Biosynthesis of the iron-guanylylpyridinol cofactor of [Fe]-hydrogenase in methanogenic archaea as elucidated by stable-isotope labeling. AB - [Fe]-hydrogenase catalyzes the reversible hydride transfer from H(2) to methenyltetrahydromethanoptherin, which is an intermediate in methane formation from H(2) and CO(2) in methanogenic archaea. The enzyme harbors a unique active site iron-guanylylpyridinol (FeGP) cofactor, in which a low-spin Fe(II) is coordinated by a pyridinol-N, an acyl group, two carbon monoxide, and the sulfur of the enzyme's cysteine. Here, we studied the biosynthesis of the FeGP cofactor by following the incorporation of (13)C and (2)H from labeled precursors into the cofactor in growing methanogenic archaea and by subsequent NMR, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) and IR analysis of the isolated cofactor and reference compounds. The pyridinol moiety of the cofactor was found to be synthesized from three C-1 of acetate, two C-2 of acetate, two C-1 of pyruvate, one carbon from the methyl group of l-methionine, and one carbon directly from CO(2). The metabolic origin of the two CO-ligands was CO(2) rather than C-1 or C 2 of acetate or pyruvate excluding that the two CO are derived from dehydroglycine as has previously been shown for the CO-ligands in [FeFe] hydrogenases. A formation of CO from CO(2) via direct reduction catalyzed by a nickel-dependent CO dehydrogenase or from formate could also be excluded. When the cells were grown in the presence of (13)CO, the two CO-ligands and the acyl group became (13)C-labeled, indicating either that free CO is an intermediate in their synthesis or that free CO can exchange with these iron-bound ligands. Based on these findings, we propose pathways for how the FeGP cofactor might be synthesized. PMID- 22260088 TI - The use of aortic occlusion balloon catheter without fluoroscopy for life threatening post-partum haemorrhage. AB - This article describes the use of a balloon catheter introduced via the femoral artery into the abdominal aorta without the use of fluoroscopy to stabilize six patients with life-threatening post-partum haemorrhage. The femoral artery was localized blindly or with the use of ultrasound. Immediate control of the bleeding was achieved in all patients, and the procedure was believed to be life saving for some patients. One patient with a narrow and fragile aorta had an aortic rupture necessitating surgical repair, which may have been caused by the balloon. In these six cases, the procedures were carried out by interventional radiologists. However, this procedure can also be performed by anaesthesiologists or surgeons who are trained in vascular access techniques. PMID- 22260089 TI - The influence of muscles activation on the dynamical behaviour of the tympano ossicular system of the middle ear. AB - The human ear is a complex biomechanical system and is divided into three parts: outer, middle and inner ear. The middle ear is formed by ossicles (malleus, incus and stapes), ligaments, muscles and tendons, which transfers sound vibrations from the eardrum to the inner ear, linking with mastoid and Eustachian tube. In this work, a finite element modelling of the tympano-ossicular system of the middle ear was developed. A dynamic study based on a structural response to harmonic vibrations, for a sound pressure level (SPL) of 110, 120 and 130 dB SPL applied in the eardrum, is presented. The connection between the ossicles is made using a contact formulation. The model includes the different ligaments considering its hyperelastic behaviour. The activation of the muscles is based on the constitutive model proposed by previous work. The harmonic responses of displacement and pressure obtained on the stapes footplate, for a frequency range between 100 Hz and 10 kHz, are obtained simulating the muscle activation. The results are compared considering the passive and active states. The results are discussed and they are in accordance with audiological data published with reference to the effects of the middle ear muscles contraction. PMID- 22260090 TI - Evaluation of Capilia TB assay for rapid identification of Mycobacterium tuberculosis complex in BACTEC MGIT 960 and BACTEC 9120 blood cultures. AB - BACKGROUND: Capilia TB is a simple immunochromatographic assay based on the detection of MPB64 antigen specifically secreted by the Mycobacterium tuberculosis complex (MTC). Capilia TB was evaluated for rapid identification of MTC from BACTEC MGIT 960 and BACTEC 9120 systems in Kampala, Uganda. Since most studies have mainly dealt with respiratory samples, the performance of Capilia TB on blood culture samples was also evaluated. METHODS: One thousand samples from pulmonary and disseminated tuberculosis (TB) suspects admitted to the JCRC clinic and the TB wards at Old Mulago hospital in Kampala, Uganda, were cultured in automated BACTEC MGIT 960 and BACTEC 9120 blood culture systems. BACTEC-positive samples were screened for purity by sub-culturing on blood agar plates. Two hundred and fifty three (253) samples with Acid fast bacilli (AFB, 174 BACTEC MGIT 960 and 79 BACTEC 9120 blood cultures) were analyzed for presence of MTC using Capilia TB and in-house PCR assays. RESULTS: The overall Sensitivity, Specificity, Positive and Negative Predictive values, and Kappa statistic for Capilia TB assay for identification of MTC were 98.4%, 97.6%, 97.7%, 98.4% and 0.96, respectively. Initially, the performance of in-house PCR on BACTEC 9120 blood cultures was poor (Sensitivity, Specificity, PPV, NPV and Kappa statistic of 100%, 29.3%,7%, 100% and 0.04, respectively) but improved upon sub-culturing on solid medium (Middlebrook 7H10) to 100%, 95.6%, 98.2%, 100% and 0.98, respectively. In contrast, the Sensitivity and Specificity of Capilia TB assay was 98.4% and 97.9%, respectively, both with BACTEC blood cultures and Middlebrook 7H10 cultured samples, revealing that Capilia was better than in house PCR for identification of MTC in blood cultures. Additionally, Capilia TB was cheaper than in-house PCR for individual samples ($2.03 vs. $12.59, respectively), and was easier to perform with a shorter turnaround time (20 min vs. 480 min, respectively). CONCLUSION: Capilia TB assay is faster and cheaper than in-house PCR for rapid identification of MTC from BACTEC MGIT 960 and BACTEC 9120 culture systems in real-time testing of AFB positive cultures. PMID- 22260091 TI - Web-based environmental simulation: bridging the gap between scientific modeling and decision-making. AB - Data availability in environmental sciences is growing rapidly. Conventional monitoring systems are collecting data at increasing spatial and temporal resolutions; satellites provide a constant stream of global observations, and citizen scientist generate local data with electronic gadgets and cheap devices. There is a need to process this stream of heterogeneous data into useful information, both for science and for decision-making. Advances in networking and computer technologies increasingly enable accessing, combining, processing, and visualizing these data. This Feature reflects upon the role of environmental models in this process. We consider models as the primary tool for data processing, pattern identification, and scenario analysis. As such, they are an essential element of science-based decision-making. The new technologies analyzed here have the potential to turn the typical top-down flow of information from scientists to users into a much more direct, interactive approach. This may accelerate the dissemination of environmental information to a larger community of users. It may also facilitate harvesting feedback, and evaluating simulations and predictions from different perspectives. However, the evolution poses challenges, not only to model development but also to the communication of model results and their assumptions, shortcomings, and errors. PMID- 22260093 TI - Anthropometric profiles of elite older triathletes in the Ironman Brazil compared with those of young Portuguese triathletes and older Brazilians. AB - The objective of this study was to describe the anthropometric profiles of elite older triathletes participating in the 2009 Ironman Brazil and to compare their somatotype, anthropometric and body composition characteristics with those of elite young triathletes and older non-athletes. The sample consisted of 64 males, divided into three groups: (1) older triathletes (n = 17), (2) young triathletes (n = 24), and (3) older non-athletes (n = 23). Somatotype was analysed according to the Carter and Heath ( 1990 ) method. Body mass index, sum of four skinfolds, percentage body fat, body fat mass, and fat-free mass were also estimated. Older non-athletes had higher endomorphy, sum of four skinfolds, fat percentage, and body fat mass than the athletes. Older athletes who participated in the Ironman and elite young triathletes had higher fat-free mass than older non-athletes. Older triathletes and older non-athletes were considered mainly endomorphic mesomorphs and young triathletes mainly ectomorphic mesomorphs. The findings that characterize the anthropometric profile of athletes in this sports modality could be used as a reference. PMID- 22260094 TI - A molecular carrier to transport and deliver cisplatin into endometrial cancer cells. AB - The leader peptide of a recombinant manganese superoxide dismutase (rMnSOD-Lp) acts as a molecular carrier. Clonogenic tests on normal (MRC-5) and endometrial adenocarcinoma cells (HTB-112) were carried out in the presence of rMnSOD-Lp, cisplatin alone (CC) or cisplatin conjugated to the rMnSOD-Lp (rMnSOD-Lp-CC). The platinum delivered into the cells was measured by atomic spectrophotometric absorbance. The treatments on tumor and normal cells were finally evaluated by LM and TM microscopy. Tumor cell death in the case of 0.5 MUM cisplatin on its own was minimal, while in the presence of 0.5 MUM rMnSOD-Lp-CC, no tumor cells survived. Atomic absorbance analysis showed that rMnSOD-Lp-CC delivered approximately four times more cisplatin into HTB-112 cells than the amount delivered using cisplatin alone. By LM observation, the cells treated with rMnSOD Lp-CC showed signs of nuclear and cytoplasmic fragmentation, that is, apoptosis induced by the treatment. The therapeutic effect of rMnSOD-Lp-CC on endometrial cancer cells was significant, while on the normal cells it showed only a minimal toxicity. We believe that rMnSOD-Lp deserves to be considered as a molecular carrier to deliver cisplatin directly into tumor cells, thus transforming its antireplicative activity into a specific and selective antitumor agent. PMID- 22260096 TI - Canine intravascular lymphoma with overt leukemia. AB - A 6-year-old spayed Labrador Retriever Mix dog was evaluated for a 2-week history of progressive generalized weakness and reluctance to stand. Physical examination revealed severe weakness with obtunded mentation, head tilt, bilateral nystagmus, and decreased vision. CBC findings included mild nonregenerative anemia, marked thrombocytopenia, and a few atypical mononuclear cells on the blood film. The cells were 15-30 MUm in diameter and had round to oval to reniform centrally placed nuclei with stippled chromatin, prominent nucleoli, and abundant basophilic cytoplasm with numerous discrete vacuoles and, occasionally, small azurophilic granules. Similar cells were found in bone marrow. On histologic examination of tissues collected at necropsy, neoplastic cells were detected in bone marrow, hepatic sinusoids, cerebral and meningeal vessels, and in capillaries of the heart, renal interstitium, small intestinal submucosa, and muscularis, and alveolar septa. A small discrete mass in the right atrium consisted of similar neoplastic cells, and the spleen was diffusely infiltrated. Tissue distribution was suggestive of intravascular lymphoma. Neoplastic cells in tissue sections were immunoreactive for vimentin, CD18, CD45, and granzyme B and lacked immunoreactivity for cytokeratin. Neoplastic cells on bone marrow aspirate smears and blood films lacked immunoreactivity for CD3, CD79a, CD1c, CD11b, CD11c, CD11d, and E-cadherin. In the absence of immunophenotypic evidence for the neoplastic cells being derived from B-cell, T-cell, or histocytic/dendritic lineages and the lack of clonal antigen receptor gene rearrangement(s), along with positive immunoreactivity for granzyme B, a tumor of NK cells was considered likely. Based on current knowledge, this is the first report of canine intravascular lymphoma, of probable NK cell origin, with peripheral blood involvement. PMID- 22260095 TI - IntegromeDB: an integrated system and biological search engine. AB - BACKGROUND: With the growth of biological data in volume and heterogeneity, web search engines become key tools for researchers. However, general-purpose search engines are not specialized for the search of biological data. DESCRIPTION: Here, we present an approach at developing a biological web search engine based on the Semantic Web technologies and demonstrate its implementation for retrieving gene- and protein-centered knowledge. The engine is available at http://www.integromedb.org. CONCLUSIONS: The IntegromeDB search engine allows scanning data on gene regulation, gene expression, protein-protein interactions, pathways, metagenomics, mutations, diseases, and other gene- and protein-related data that are automatically retrieved from publicly available databases and web pages using biological ontologies. To perfect the resource design and usability, we welcome and encourage community feedback. PMID- 22260097 TI - Relationship between depression and proinflammatory cytokine levels in hemodialysis patients. AB - AIM: To evaluate the presence of the relationship between depression and proinflammatory cytokine levels in hemodialysis (HD) patients. METHODS: The study included 40 HD patients and 20 healthy controls. All participants were evaluated for the presence of depression using the structured clinical interview based on criteria defined by Diagnostic and statistical manual mental disorders (Fourth Edition, Text Revision) Axis I disorders. The severity of depressive symptoms was assessed using the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale. The depressive patients received antidepressants for 8 weeks. Blood samples were taken at baseline and after 8 weeks of antidepressant treatment for interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) levels. RESULTS: A total of 9 (22.5%) of the 40 HD patients had depression. IL-1, IL-6, and TNF-alpha levels were significantly higher in HD patients compared with that in the control group, but were not significantly different between HD patients with and without depression. In the depressive patients, we observed no significant difference in proinflammatory cytokine levels after antidepressant treatment. The psychometric measurements in depressive patients decreased significantly after antidepressant treatment. CONCLUSION: We observed that depression is a common psychiatric disorder and has no significant effect on proinflammatory cytokine levels in HD patients; no important improvement in cytokine levels was observed after antidepressant therapy. PMID- 22260098 TI - A new potassium tetrabromoaurate (III)-luminol chemiluminescence system for the determination of folic acid in milk powder. AB - A new chemiluminescence (CL) system based on the CL-emitting reaction between potassium tetrabromoaurate (III) [Au(III)] and luminol in alkaline medium is described in this paper. On the basis of this study, folic acid (FA) could dramatically enhance CL intensities, and incorporated with flow injection (FI) and solid-phase extraction (SPE), the novel CL system has been applied for the determination of FA in infant formula milk powder. Under optimum conditions, the CL intensities were linearly related to the concentration of FA in the range of 8.0 * 10-8 to 4.0 * 10-5 g/L with a correlation coefficient of 0.999, and the detection limit was 2.0 * 10-8 g/L. The relative standard deviation was 3.5% for 1.0 * 10-6 g/L FA. The optimal conditions for the detection of FA were evaluated, and the interferences from some common inorganic ions and a couple of relevant organic compounds were also investigated. PRACTICAL APPLICATION: The new Au(III) luminol chemiluminescent system is proposed for the determination of FA; it will be an adequate technique for the analysis of low FA concentrations in pharmaceutical preparations and food samples, and it will have potential analytical applications for other substances. PMID- 22260099 TI - Effect of storage conditions on lipid components and color of Mugil cephalus processed roes. AB - The salted and semidried mullet (Mugil cephalus) ovary product (bottarga) is proposed as an important source of the long-chain n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid, and docosahexaenoic acid. In this work, we investigated the extent of lipid oxidation and browning of grated bottarga samples during 7 mo of storage at -20 degrees C, 2 to 3 degrees C in the absence of light, and at room temperature in the presence or absence of light. Modifications of the levels of total choline (as index of phospholipid breakdown), total sugars, and free amino acids such as lysine, methionine, and tryptophan (involved in nonenzymatic browning) were also studied at different storage conditions. Storage of bottarga did not significantly affect the n-3 PUFA and cholesterol levels with respect to the control; nevertheless, a significant hydroperoxide increase was observed during 7 mo in bottarga samples at all the storage conditions, while low malondialdeyde levels were measured. Samples placed at room temperature in the absence and in the presence of light showed over time a marked browning process, lipid breakdown, a sensible decrease in the levels of total sugars, tryptophan, and methionine with respect to control and samples stored at -20 degrees C and 2 to 3 degrees C. The resistance against the oxidation of the isolated bottarga lipids was also assessed in dry state at several temperatures (37, 75, and 140 degrees C). PRACTICAL APPLICATION: We evaluated the change in lipid compounds and color of dried and salted mullet roes under different storage conditions. The obtained results suggest the importance of the low temperatures to preserve the nutritional properties of this fish product during long storage. PMID- 22260100 TI - Total phenols and antioxidant capacity in 10 Moroccan pomegranate varieties. AB - The study focused on characterizing the 10 major Moroccan cultivars to acknowledge the quality and bioactive compounds of the fruits. The following determinations were assessed: pomegranate fruit maturity index, which truly defines juice taste, as well as organic acids and sugar contents, total phenols, and antioxidant activity of pomegranate juice. The cultivar per se (genotype) behaved as the most influencing factor conditioning pomegranate sugar and organic acids profiles, antioxidant activity, and total phenolics. The assessment of pomegranate chemical compositions implies the great potential of Moroccan cultivars for both fresh market and fruit processing. In fact, the "Hamde" sour cv. seems particularly suitable for juice production because of its high phenolics content. Additionally, the presence of bioactive compounds in pomegranate juices may encourage their consumption for potential health benefits. PRACTICAL APPLICATION: The cultivar per se (genotype) behaved as the most influencing factor conditioning pomegranate sugar and organic acids profiles, antioxidant activity, and total phenolics. Given the divergence observed on bioactive compounds concentrations and antioxidant activity among evaluated cultivars, the genotype factor should be considered as the most influencing factor in future breeding programs to enhance the synthesis of beneficial bioactive compounds. PMID- 22260101 TI - The effects of different chilling methods on meat quality and calpain activity of pork muscle longissimus dorsi. AB - The objective of this study was to investigate the effects of conventional chilling (0 to 4 degrees C), rapid chilling (RC, -20 degrees C for 30 min, followed by 0 to 4 degrees C), and short-duration chilling (0 to 4 degrees C for 30 min, followed by 25 degrees C) on meat quality and calpain activity of pork muscle longissimus dorsi (LD). The muscle quality characteristics pH, color, cooking loss, pressing loss and tenderness, and calpain activities were measured 0-, 3-, 12-, and 24-h postmortem. Results show that the RC resulted in a faster temperature decline of the muscle, and prevented the meat pH and Commission Internationale de l'Eclairage L* value from declining during postmortem aging. RC also reduced meat cooking loss and pressing loss compared with the other two chilling methods. However, the chilling methods did not significantly affect meat shear force. During the first 24-h postmortem, there was not a noticeable change in the activity of m-calpain. But MU-calpain activity decreased regardless of chilling method. In the rapidly chilled carcasses, MU-calpain activity remained the same 3- and 12-h postmortem. However, in the short-duration chilled and conventionally chilled carcasses, the activity was visibly reduced. At 24-h postmortem, no clear zones on the gel were observed in all three treatments. PRACTICAL APPLICATION: Conventional and RC methods are commonly used for pork in commercial practice nowadays. Compared with conventional chilling, the effect of RC on quality parameters of pork varies. In recent years, short-duration chilling (SC) is widely used in many Chinese pig slaughtering facilities. However, few researchers have studied the effect of SD on pork quality. Therefore, the present study investigated the effect of different chilling methods on functionalities or quality of chilled pork meat. PMID- 22260102 TI - Optimization of microwave-assisted extraction of anthocyanins from mulberry and identification of anthocyanins in extract using HPLC-ESI-MS. AB - Anthocyanins are naturally occurring compounds that impart color to fruits, vegetables, and plants. This study aims to optimize the microwave-assisted extraction (MAE) conditions of anthocyanins from mulberry (M. atropurpurea Roxb.) using response surface methodology (RSM). A Box-Behnken experiment was employed in this regard. Methanol concentration, microwave power, and extraction time were chosen as independent variables. The optimized conditions of MAE were as follows: 59.6% acidified methanol, 425 W power, 25 (v/w) liquid-to-solid ratio, and 132 s time. Under these conditions, 54.72 mg anthocyanins were obtained from 1.0 g mulberry powder. Furthermore, 8 anthocyanins were identified by high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) in mulberry extract. The results showed that cyanidin-3-glucoside and cyanidin-3 rutinoside are the major anthocyanins in mulberry. In addition, in comparison with conventional extraction, MAE is more rapid and efficient for extracting anthocyanins from mulberry. PMID- 22260103 TI - Volatile compounds formation in alcoholic fermentation from grapes collected at 2 maturation stages: influence of nitrogen compounds and grape variety. AB - The aim of this work was to study the influence of nitrogen compounds on the formation of volatile compounds during the alcoholic fermentation carried out with 4 nonaromatic grape varieties collected at 2 different maturation stages. To do this, Monastrell, Merlot, Syrah, and Petit Verdot grapes were collected 1 wk before harvest and at harvest. Then, the musts were inoculated with the same Saccharomyces cerevisiae yeast strain and were fermented in the same winemaking conditions. Amino acids that showed the highest and the lowest concentration in the must were the same, regardless of the grape variety and maturation stage. Moreover, the consumption of amino acids during the fermentation increased with their concentration in the must. The formation of volatile compounds was not nitrogen composition dependent. However, the concentration of amino acids in the must from grapes collected 1 wk before harvest can be used as a parameter to estimate the concentration of esters in wines from grapes collected at harvest and therefore to have more information to know the grape oenological capacity. Application of principal components analysis (PCA) confirmed the possibility to estimate the concentration of esters in the wines with the concentration of nitrogen compounds in the must. PMID- 22260104 TI - Quality, antioxidative ability, and cell proliferation-enhancing activity of fermented black soybean broths with various supplemental culture medium. AB - The fermented soybean-based foods have played an important role in traditional diets around the world for many centuries, and Bacillus subtilis is typically used in the fermentation of soybean-based foods. The fermentation process may improve not only the flavor but also the nutritional value of food, and substances produced in this fermented broth were affected by many factors including culture medium and the selected soybeans. In this study, we use 3 potential culture mediums in the fermentation of black soybean and the fermented black soybean broths were used for the examination of amino acid composition, total phenolics content, flavonoids and anthocyanins contents, the antioxidant properties, and cytotoxicity. Our results indicated that the fermented black soybean broth, fermentation III, have the most abundant essential amino acid (79.77 mg/g), phenolics (19.33 mg/g), flavonoids (46.01 mg/g), and anthocyanins (1.06 mg/g). Besides, all of the fermented black soybean broths exhibited the significant antioxidative abilities with 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging effect, reducing power and ferrous ion chelating effect. In addition, the fermented black soybean broths demonstrated the cell proliferation enhancing activity in Detroit 551 cells. The cells were augmented up to the maximum value of 183.6% (compared with control) at 10 mg/mL of the fermentation I. Therefore, the different supplemental culture medium fermented black soybean broths may be used as a functional ingredient in the products of nutritional drinks and health foods. PRACTICAL APPLICATION: The present study illustrated the potential of various supplemental culture medium fermented black soybean broths in the application of functional ingredient for nutritional drinks and health foods. PMID- 22260105 TI - Feasibility of using dialysis for determining calcium ion concentration and pH in calcium-fortified soymilk at high temperature. AB - Dialysis was performed to examine some of the properties of the soluble phase of calcium (Ca) fortified soymilk at high temperatures. Dialysates were obtained while heating soymilk at temperatures of 80 and 100 degrees C for 1 h and 121 degrees C for 15 min. It was found that the pH, total Ca, and ionic Ca of dialysates obtained at high temperature were all lower than in their corresponding nonheated Ca-fortified soymilk. Increasing temperature from 80 to 100 degrees C hardly affected Ca ion concentration ([Ca2+]) of dialysate obtained from Ca chloride-fortified soymilk, but it increased [Ca2+] in dialysates of Ca gluconate-fortified soymilk and Ca lactate-fortified soymilk fortified with 5 to 6 mM Ca. Dialysates obtained at 100 degrees C had lower pH than dialysate prepared at 80 degrees C. Higher Ca additions to soymilk caused a significant (P<= 0.05) reduction in pH and an increase in [Ca2+] of these dialysates. When soymilk was dialyzed at 121 degrees C, pH, total Ca, and ionic Ca were further reduced. Freezing point depression (FPD) of dialysates increased as temperature increased but were lower than corresponding soymilk samples. This approach provides a means of estimating pH and ionic Ca in soymilks at high temperatures, in order to better understand their combined role on soymilk coagulation. PMID- 22260106 TI - Provenance of the oil in par-fried French fries after finish frying. AB - Frozen par-fried French fries are finish-fried either by using the same type of oil used for par frying, or a different type. The nutritive quality of the final oil contained in the product depends on the relative amounts and the fatty acid (FA) composition of the oils used for par frying and finish frying. With the aim of understanding the provenance of the oil in the final product, par-fried French fries-either purchased ready or prepared in the laboratory-were finish fried in oils different from the ones used for par frying. The moisture content, oil content, and FA compositions of the par-fried and finish-fried products were experimentally determined, and the relative amounts of each of the oils present in the final product were calculated using the FAs as markers and undertaking a mass balance on each component FA. The results demonstrate that 89% to 93% of the total oil in the final product originates from the finish-frying step. The study also shows that a significant proportion of the oil absorbed during par frying is expelled from the product during finish frying. Further, the expulsion of par frying oil was found to occur in the early stages of the finish-frying step. Experiments involving different combinations of par-frying and finish-frying oils showed that the relative proportions of the 2 oils did not depend on the individual fatty acid profiles. This study concludes that any positive health benefits of using an oil having a favorable FA profile for par frying, can potentially be lost, if the oil used for finish frying has a less favorable composition. PRACTICAL APPLICATION: This paper estimates the relative amounts of oil in French fries that have been fried in 2 stages-a par-frying step and a finish-frying step-which is commonly practiced in food service establishments as well as homes. The 2 key conclusions are: (1) nearly 90% of the oil content of the final product is the one used for finish frying; that is, a processor may use very good oil for par frying but if the oil used for finish frying is inferior, its effect will dominate. (2) The paper also shows that a significant proportion of the oil used by the processor gets expelled during finish frying. PMID- 22260107 TI - Tagatose stability in milk and diet lemonade. AB - The monosaccharide tagatose has been shown to behave physiologically as a prebiotic. To provide its healthful prebiotic effect to consumers, tagatose must not break down during food processing and storage. The objective of this study was to evaluate the storage and thermal stabilities of tagatose in milk and lemonade. Tagatose (0.9% to 1.5%) was added to commercially available shelf stable milk and diet lemonade. Samples were stored at 20, 40, 61, and 81 degrees C. Tagatose loss was monitored chromatographically. Pseudo-first-order rate constants for tagatose degradation were determined along with the reaction's activation energy. No tagatose degradation was observed in lemonade at temperatures equal to or less than 61 degrees C. Degradation occurred faster in milk because of its higher pH in comparison to lemonade and its dairy proteins enabling the Maillard reaction. The activation energy for tagatose degradation in milk was 24.6 kcal/mol. Using this activation energy, it was estimated that less than 0.1% tagatose would be lost during pasteurization and less than 4% would be lost during storage at 25 degrees C for 6 mo. Although tagatose degradation occurs in beverages, the extent of its loss during pasteurization and storage would be very low. Tagatose can be formulated into beverages with minimal concern about its degradation and the subsequent loss of prebiotic activity. PRACTICAL APPLICATION: Tagatose can be incorporated into beverages as a prebiotic to improve the healthful characteristics of the product without significant degradation. PMID- 22260108 TI - Comparative study on the antioxidant capacity and cholinesterase inhibitory activity of Citrus aurantifolia Swingle, C. aurantium L., and C. bergamia Risso and Poit. peel essential oils. AB - The interest in medicinal plant research and in the aroma-therapeutic effects of essential oils in humans has increased in recent years, especially for the treatment of pathologies of relevant social impact such as Alzheimer's disease. The present study was taken up to evaluate the antioxidant capacity and the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity of the peel essential oils from three Citrus species, C. aurantifolia Swingle, C. aurantium L., and C. bergamia Risso & Poit. Essential oils were analyzed by GC and GC-MS and they contain mainly limonene, alpha-pinene, beta-pinene, gamma terpinene, and linalyl acetate. C. aurantifolia oil showed the highest radical scavenging activity on ABTS assay (IC50 value of 19.6 MUg/mL), while C. bergamia exhibited a good antioxidant activity evaluated by the beta-carotene bleaching test (IC50 = 42.6 MUg/mL after 60 min of incubation). C. aurantifolia inhibited more selectively AChE. Obtained data suggest a potential use of Citrus oils as a valuable new flavor with functional properties for food or nutraceutical products with particular relevance to supplements for the elderly. PRACTICAL APPLICATION: The demonstrated antioxidant activity and procholinesterase properties of Citrus essential oils suggested their use as a new potential source of natural antioxidant to added as extra-nutrient for using in food industries as a valuable new flavor with functional properties for food or nutraceutical products with particular relevance to supplements for the elderly. PMID- 22260109 TI - Antioxidant, antimicrobial, 15-LOX, and AGEs inhibitions by pineapple stem waste. AB - Pineapple stem has been extensively used for bromelain extraction; however, almost no attention has been given to the waste obtained during bromelain manufacturing. In this regard, antioxidant, antimicrobial, and inhibitions against 15-lipoxygenase and advanced glycation end product formations by pineapple stem waste (PSW) obtained during bromelain manufacturing process were studied. The PSW had moderate bioactivities in all the performed assays. It also showed a considerable inhibition against fungal growth, probably due to high amounts of the benzoic acid present in the sample. These results indicate that PSW could be utilized as an economic source of preventive or therapeutic agent in disease and in different functional food industries. PRACTICAL APPLICATION: A large amount of wastes are generated during bromelain manufacturing from pineapple stem. So far, these wastes are not utilized and are often considered as a burden while disposing them. However, we found some important phytochemicals with considerable bioactivities in these wastes. We believe that these wastes may have a promising usage as a cheap source of one of the ingredients in functional food based industries. PMID- 22260113 TI - Growth inhibition of foodborne pathogens by Oenococcus oeni. AB - To explore the possibility of using Oenococcus oeni to inhibit foodborne pathogens, and to characterize antimicrobial compounds produced by O. oeni, 24 strains of O. oeni were tested for their ability to inhibit growth of foodborne pathogens, Escherichia coli O157:H7, Salmonella enteritidis, and Listeria monocytogenes by using the spot-on-lawn method. Of the 24 strains, 17 strains were able to inhibit all 3 pathogens in this study. Proteases, catalase, and buffer solutions were used for determining the type of inhibitory compounds produced from 4 selected strains with stronger inhibitory activity. Antimicrobial activity of 2 strains against the pathogens was completely inactivated by buffer solution, and other 2 strains against E. coli O157:H7 were partially removed. The antimicrobial compound was not sensitive to selected proteases and catalase. PRACTICAL APPLICATION: There is little information available about using O. oeni for human pathogens control. The results of this study revealed such discovery and potential applications for pathogen control. PMID- 22260114 TI - Aggregation and hydrophobicity properties of 6 dairy propionibacteria strains isolated from homemade Turkish cheeses. AB - In the present study, 6 dairy Propionibacterium strains were assessed with regard to their hydrophobic characteristics and their autoaggregation and coaggregation abilities since these traits have been shown to be indicative of adherence in other microorganisms. Aggregation assays and bacterial adhesion to hydrocarbons demonstrated significant differences in cell surface properties among the tested propionibacteria strains. Almost all strains appeared relatively hydrophilic, which showed low affinity for p-xylene. Four of the tested strains showed the strong adhesion to ethyl acetate, a basic solvent, in comparison with microbial adhesion to chloroform, an acidic solvent, which demonstrated the particularity of propionibacteria to have an important electron donor and acidic character. Also, these strains simultaneously showed affinity to 3 hydrocarbons, suggesting a high complexity of the cell surface. All propionibacteria strains tested showed autoaggregation and coaggregation ability with the Escherichia coli ATTC 11229, but the results were strain-specific and dependent on incubation conditions. Anaerobic incubation conditions were determined as the best condition for aggregation abilities of propionibacteria strains. A relationship was obtained between aggregation abilities (auto- and coaggregation) and a correlation between adhesion to hydrocarbon (chloroform) and autoaggregation was possible. Our results indicate that the ability to autoaggregation together with cell surface hydrophobicity and coaggregation abilities with E. coli strain can be used for preliminary screening in order to identify potentially probiotic bacteria suitable for human or animal use. PRACTICAL APPLICATION: Autoaggregation, cell surface hydrophobicity, and coaggregation abilities with E. coli of the selected dairy propionibacteria strains could be used as probiotic in foods after in vivo studies. PMID- 22260115 TI - Effects of slightly acidic low concentration electrolyzed water on microbiological, physicochemical, and sensory quality of fresh chicken breast meat. AB - Anticmicrobial effect of slightly acidic low concentration electrolyzed water (SlALcEW) and strong acidic electrolyzed water (StAEW) on fresh chicken breast meat was evaluated in this study. Meat samples each of 10 +/- 0.2 g in weight and 2.5 * 2.5 cm2 in size were experimentally inoculated with Listeria monocytogenes (ATCC 19115) and Salmonella Typhimurium (ATCC 14028) and subjected to dipping treatment (22 +/- 2 degrees C for 10 min) with SlALcEW and StAEW. Shelf-life study was conducted for inoculated and noninoculated meat samples treated with SlALcEW and StAEW at storage temperatures of 5, 15, and 25 degrees C. Dipping treatment with electrolyzed water significantly (P < 0.05) reduced the background and inoculated pathogens compared to untreated controls. The reduction of 1.5 to 2.3 log CFU/g was achieved by SlALcEW and StAEW against background flora, L. monocytogenes and Salmonella Typhimurium. There was no significant difference (P > 0.05) between the SlALcEW and StAEW treatments efficacy. Comparing treated samples to untreated controls showed that SlALcEW and StAEW treatments extended the shelf life of chicken meat at different temperatures with marginal changes of sensory quality. Although SlALcEW and StAEW treatments showed similar antimicrobial effects but SlALcEW was more beneficial in practical application for its semineutral pH and low chlorine content. PRACTICAL APPLICATION: Food safety issues have led to development of new sanitizers to eliminate spoilage and pathogenic organisms in food. This study provides the foundation for further application of slightly acidic low concentration electrolyzed water (SlALcEW) as a sanitizing agent in meat industry. SlALcEW can be produced on site on demand and no chemicals are necessary except NaCl solution. It does not leave any residue in food due to low chlorine concentration and it is safe to handle for its semineutral pH. PMID- 22260116 TI - Impact of storage time and temperature on thermal inactivation of Salmonella Enteritidis PT 30 on oil-roasted almonds. AB - Whole Nonpareil variety almonds were inoculated with Salmonella Enteritidis PT 30 and stored at 4 or 23 degrees C for up to 48 wk. At 1, 12, 24, 37, and 48 wk of storage, almonds were heated by immersion in 121 degrees C oil. After heating for 0.5 to 2.5 min, almonds were drained, transferred to tryptic soy broth, and mixed with a stomacher prior to plating onto tryptic soy and bismuth sulfite agars. Over the 48 wk of storage, Salmonella declined by 0.5 and 2.1 log CFU/g at 4 and 23 degrees C, respectively. The survivor inactivation curves were upwardly concave with rapid initial reductions in the levels of Salmonella. For up to 24 wk of storage, the mean counts of the survivors after treatment were not significantly different. The Weibull model predicted 4- and 5-log reductions of Salmonella in 0.85 +/- 0.16 and 1.8 +/- 0.43 min, respectively, for almonds stored at 4 degrees C, and in 1.6 +/- 0.53 and 3.2 +/- 1.0 min, respectively, for almonds stored at 23 degrees C. Refrigerated storage had little impact on heat resistance of Salmonella that were inoculated on almonds. PRACTICAL APPLICATION: This research provides information of value in performing or evaluating validation studies for thermally processed almonds. The sensitivity of Salmonella to oil roasting is demonstrated during typical commercial almond storage times and temperatures. PMID- 22260117 TI - Survival and growth of foodborne pathogens in minimally processed vegetables at 4 and 15 degrees C. AB - We conducted this study to investigate the survival and growth of pathogens on fresh vegetables stored at 4 and 15 degrees C. Vegetables (romaine lettuce, iceberg lettuce, perilla leaves, and sprouts) were inoculated with 4 pathogens (Salmonella enterica serovar Typhimurium, Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli O157:H7) and stored at 2 different temperatures for different periods of time (3, 6, 9, 12, and 15 d at 4 degrees C and 1, 2, 3, 5, and 7 d at 15 degrees C). Populations of the 4 pathogens tended to increase on all vegetables stored at 15 degrees C for 7 d. Populations of E. coli O157:H7 and S. Typhimurium increased significantly, by approximately 2 log10 CFU/g, on loose and head lettuce stored at 15 degrees C for 1 d. No significant differences were observed in the growth of different pathogens on vegetables stored at 4 degrees C for 15 d. E. coli O157:H7 did not survive on sprouts stored at 15 or 4 degrees C. The survival and growth of food pathogens on fresh vegetables were very different depending on the pathogen type and storage temperature. PRACTICAL APPLICATION: Survivals and growth of pathogens on various vegetables at 4 and 15 degrees C were observed in this study. Survivals and growth of pathogens on vegetables were different depending on the pathogen type and storage temperature. Therefore, vegetables should be stored under refrigerated conditions (below 4 degrees C) prior to consumption. This recommendation may vary depending on the type of vegetable. PMID- 22260118 TI - Use of autochthonous Pediococcus acidilactici and Staphylococcus vitulus starter cultures in the production of "chorizo" in 2 different traditional industries. AB - The present study determined how the different ripening conditions affected the growth and development of 3 autochthonous starter cultures, and the physico chemical and sensory characteristics of chorizo. Each of 3 strains of Pediococcus acidilactici (MC184, MS198, and MS200) and one of Staphylococcus vitulus (RS34) were associated to prepare the starter cultures, P184S34, P198S34, and P200S34. Then, chorizo was prepared following 2 manufacturing procedures. The autochthonous starter cultures were able to compete and colonize the sausages in both ripening procedures. The use of the starter cultures showed evident differences by the texture analysis, with the control batches being generally tougher than the starter culture batches. Also, the highest biogenic amine (BA) levels were found in control batches and the lowest in P200S34 batches. While the use of these starter cultures does not change the sensory characteristics of these traditional fermented sausages, it improves their homogeneity and safety, except for P184S34 batch in which more BAs are detected in industry 2. PRACTICAL APPLICATION: The 3 autochthonous starter cultures selected could be used in traditional industries because they are able to compete well and colonize the dry fermented sausages "chorizo." The use of these starter cultures improves the texture and homogeneity of traditional fermented sausages. Biogenic amines decreased in the starter cultures batches improving the safety. PMID- 22260119 TI - Ultrastructural analysis of buckwheat starch components using atomic force microscopy. AB - Morphological and structural features of buckwheat starch granules and nanocrystals were examined using atomic force microscopy and dynamic light scattering. Partially digested starch granules revealed a clear pattern of growth rings with the central core revealing lamellar structure. Atomic force microscopy and dynamic light scattering experiments revealed that the buckwheat starch granules were polygonal in shape and were in the range of 2 to 19 MUm in diameter. The optimized acid hydrolysis process produced nanocrystals with the shape of spherical structure with lengths ranging from 120 to 200 nm, and the diameter from 4 to 30 nm from aqueous suspensions of buckwheat starch solution. The sorption isotherms on buckwheat starch nanocrystal/glycerol composite exhibited a 3-stage transition of moisture in the blending. The biocompatible nature of buckwheat starch nanocrystals and their structural properties make them a promising green nanocomposite material. PRACTICAL APPLICATION: Buckwheat starches had never been studied on a nanoscale, but we have achieved new understanding of starch granule morphology and concentric growth rings using nanoscale imaging. Since buckwheat is an underutilized crop, we foresee the potential application of buckwheat starch, starch-based nanocrystals, and nanoparticles, to expand markets and encourage producers to expand their buckwheat acreage. The atomic force image analysis suggests that buckwheat starch could be used as a new biopolymer material in food industries. PMID- 22260120 TI - Characterization of ergocalciferol loaded solid lipid nanoparticles. AB - The use of solid lipid nanoparticles (SLNs) is a technique that has been widely used in the pharmaceutical industry for the last 2 decades and has become of increasing interest to food scientists due to its potential for encapsulation and controlled release. Ergocalciferol (vitamin D2) is a bioactive compound whose deficiency may lead to rickets in children and osteomalacia in adults. In this study, ergocalciferol was encapsulated in tripalmitin SLNs stabilized by polysorbate 20 (Tween 20). SLN dispersions (5% w/w) were prepared by hot homogenization technique using a nozzle-type high-pressure homogenizer. Ergocalciferol at 0%, 5%, 10%, 15%, and 20% (w/w of lipid) was dissolved in the molten lipid at 80 degrees C, mixed with a 5% (w/w) aqueous solution of polysorbate 20 and homogenized at 138 MPa at 80 degrees C. Particle size, thermal properties, and microstructure were evaluated by dynamic light scattering (DLS), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM) respectively. As the proportion of ergocalciferol in the SLN increased from 0% to 20%, the Z-average values of the particles gradually decreased (P<= 0.05) from approximately 120 nm to approximately 65 nm. DSC analysis of freeze dried SLN samples showed gradual decrease in enthalpies of fusion and crystallization for stable beta-subcell whereas for SLN dispersions, the enthalpy of fusion of unstable alpha-subcell crystal increased with increased ergocalciferol loading. The TEM images of the ergocalciferol loaded SLN samples showed the presence of spherical as well as rod-shaped nanoparticles. It was also observed that the turbidity of the SLN dispersions reduced noticeably with increased ergocalciferol loading. This finding could be useful in terms of fortification of clear juices with ergocalciferol. PRACTICAL APPLICATION: Solid lipid nanoparticles (SLNs) were used in this study to encapsulate vitamin D2, a vitamin important for bone health. It was found that as the concentration of vitamin D2 increased in the lipid phase of SLN dispersion, the clarity of the dispersion increased. Also, with increased vitamin D2 concentration, the stability of lipid crystal structure was affected in a way that indicates higher capacity of lipid to incorporate the vitamin molecules and hence to protect them better from oxygen and light. This vitamin loaded SLNs may offer alternatives to milk and margarine as a source of vitamin D. PMID- 22260121 TI - Formation risk of toxic and other unwanted compounds in pressure-assisted thermally processed foods. AB - Consumers demand, in addition to excellent eating quality, high standards of microbial and chemical safety in shelf-stable foods. This requires improving conventional processing technologies and developing new alternatives such as pressure-assisted thermal processing (PATP). Studies in PATP foods on the kinetics of chemical reactions at temperatures (approximately 100 to 120 degrees C) inactivating bacterial spores in low-acid foods are severely lacking. This review focuses on a specific chemical safety risk in PATP foods: models predicting if the activation volume value (V(a) ) of a chemical reaction is positive or negative, and indicating if the reaction rate constant will decrease or increase with pressure, respectively, are not available. Therefore, the pressure effect on reactions producing toxic compounds must be determined experimentally. A recent model solution study showed that acrylamide formation, a potential risk in PATP foods, is actually inhibited by pressure (that is, its V(a) value must be positive). This favorable finding was not predictable and still needs to be confirmed in food systems. Similar studies are required for other reactions producing toxic compounds including polycyclic aromatic hydrocarbons, heterocyclic amines, N-nitroso compounds, and hormone like peptides. Studies on PATP inactivation of prions, and screening methods to detect the presence of other toxicity risks of PATP foods, are also reviewed. PMID- 22260122 TI - Food protein-derived bioactive peptides: production, processing, and potential health benefits. AB - Bioactive peptides (BAPs), derived through enzymatic hydrolysis of food proteins, have demonstrated potential for application as health-promoting agents against numerous human health and disease conditions, including cardiovascular disease, inflammation, and cancer. The feasibility of pharmacological application of these peptides depends on absorption and bioavailability in intact forms in target tissues, which in turn depends on structure of the peptides. Therefore, production and processing of peptides based on important structure-function parameters can lead to the production of potent peptides. This article reviews the literature on BAPs with emphasis on strategic production and processing methods as well as antihypertensive, anticancer, anticalmodulin, hypocholesterolemic, and multifunctional properties of the food protein-derived peptides. It is recommended that future research efforts on BAP should be directed toward elucidation of their in vivo molecular mechanisms of action, safety at various doses, and pharmacological activity in maintaining homeostasis during aberrant health conditions in human subjects. PMID- 22260123 TI - Production technologies for reduced alcoholic wines. AB - The production and sale of alcohol-reduced wines, and the lowering of ethanol concentration in wines with alcohol levels greater than acceptable for a specific wine style, poses a number of technical and marketing challenges. Several engineering solutions and wine production strategies that focus upon pre- or postfermentation technologies have been described and patented for production of wines with lower ethanol concentrations than would naturally arise through normal fermentation and wine production techniques. However, consumer perception and acceptance of the sensory quality of wines manufactured by techniques that utilize thermal distillation for alcohol removal is generally unfavorable. This negative perception from consumers has focused attention on nonthermal production processes and the development or selection of specific yeast strains with downregulated or modified gene expression for alcohol production. The information presented in this review will allow winemakers to assess the relative technical merits of each of the technologies described and make decisions regarding implementation of novel winemaking techniques for reducing ethanol concentration in wine. PMID- 22260124 TI - Analytical methods for gelatin differentiation from bovine and porcine origins and food products. AB - Usage of gelatin in food products has been widely debated for several years, which is about the source of gelatin that has been used, religion, and health. As an impact, various analytical methods have been introduced and developed to differentiate gelatin whether it is made from porcine or bovine sources. The analytical methods comprise a diverse range of equipment and techniques including spectroscopy, chemical precipitation, chromatography, and immunochemical. Each technique can differentiate gelatins for certain extent with advantages and limitations. This review is focused on overview of the analytical methods available for differentiation of bovine and porcine gelatin and gelatin in food products so that new method development can be established. PMID- 22260125 TI - On quantifying nonthermal effects on the lethality of pressure-assisted heat preservation processes. AB - Direct experimental identification and quantification of the pressure contribution to a pressure-assisted sterilization process efficacy is difficult. However, dynamic kinetic models of thermal inactivation can be used to assess the lethality of a purely thermal process having the same temperature profile. Thus, a pressure-assisted process' temperature record can be used to generate a corresponding purely thermal survival curve with parameters determined in conventional heating experiments. Comparison of the actual final survival ratio with that calculated for the purely thermal process would reveal whether the hydrostatic pressure had synergistic or antagonistic effect on bacterial spores survival. The effect would be manifested in the number of log cycles subtracted or added to the survival ratio, and in the length of time at the holding temperature needed to produce the final survival ratio of the combined process. A set of combined treatments would reveal how the temperature and pressure profiles affect the pressure's influence on the process' lethality to either vegetative cells or spores. The need to withdraw samples during the thermal and combined processes would be avoided if the thermal survival parameters could be calculated by the "three endpoints method," which does not require the entire survival curve determination. Currently however, this method is limited to thermal inactivation patterns characterized by up to 3 survival parameters, the Weibull-Log logistic (WeLL) model, for example. PMID- 22260126 TI - Mechanisms of objectionable textural changes by microwave reheating of foods: a review. AB - Microwave reheating, compared to a conventional method, is notorious for lack of crust formation and severe toughening of flour and starch-based products. This review discusses how the typical thermal characteristics of microwave heating are involved in affecting the texture as well as the possible role of non-thermal effects. While low surface temperature is the well known mechanism why microwave heating is incapable of crust formation, the most severe toughening problems are caused by internal boiling. Beside moisture loss, the internally generated steam causes 2 main textural effects when it is vented out. The first is the replacing of non-condensable gases (air) in the product voids with a condensable one (steam). When the latter is condensed by cooling, a vacuum may be created in the voids causing their collapse and a formation of a more compact and tougher structure. The second textural effect involves amylose extraction from starch granules and its redistribution to eventually form a rich layer on the walls of the structural foam cells of the baked goods. Relatively fast crystallization of the amylose seems to be the main cause of toughening a short while after microwave heating. This mechanism is relevant mainly to products where starch is an important structural element. Structural disruptions by localize excessive steam pressure at hot-spots are also discussed in this review as well as methods of preventing or alleviating the most objectionable textural changes. The most effective ways of preventing these undesirable changes are by avoiding internal boiling and/or by manipulating the starch content and properties. PMID- 22260127 TI - Effects of cooking temperatures on the physicochemical properties and consumer acceptance of chicken stock. AB - As a base for sauces, soups, and cooking liquids for meats, grains, and vegetables, stocks can be integral to the overall quality of restaurant menu items, however, science-based studies on the effects of cooking methods on the physiochemical and sensory properties of stock are lacking. The effects of starting (22 degrees C, 85 degrees C, and 99 degrees C) and cooking temperatures (85 degrees C and 99 degrees C) of chicken stock on clarity, color, viscosity, protein content, amino acid content, mineral content, and overall liking were measured. Protein content and viscosity were significantly higher for stocks cooked at 99 degrees C, but no effect on amino acid content, color, or clarity was observed. Calcium concentration in stocks cooked at 99 degrees C was significantly (P < 0.0001) lower (9.3 and 10.1 mg/mL, for stocks started at temperatures of 22 and 99 degrees C, respectively) than stock cooked at 85 degrees C (16.6 and 17.5 mg/mL for stocks started at temperatures of 22 and 85 degrees C, respectively). Stocks prepared at 99 degrees C scored higher on overall liking compared to commercial samples and those cooked at 85 degrees C (P= 0.0101). These data can be used by culinary scientists and professionals to develop more efficient techniques in the kitchen, and by product developers to optimize the overall quality and acceptance of stock. PRACTICAL APPLICATION: This work documents the effects of preparation method on the physical and chemical properties, and consumer acceptance of chicken stock. This information can be used by product developers, culinary scientists, and professional chefs to optimize stock-based products. Culinary educators can use this information to provide students with objective evidence-based rationale for the techniques underlying a celebrated culinary tradition. This is also an example of how research can facilitate collaboration between culinary and food science professionals. PMID- 22260128 TI - Sensory acceptance and survival of probiotic bacteria in ice cream produced with different overrun levels. AB - The effect of different overrun levels on the sensory acceptance and survival of probiotic bacteria in ice cream was investigated. Vanilla ice creams supplemented with Lactobacillus acidophilus were processed with overruns of 45%, 60%, and 90%. Viable probiotic bacterial counts and sensory acceptance were assessed. All the ice creams presented a minimum count of 6 log CFU/g at the end of 60 d of frozen storage. However, higher overrun levels negatively influenced cell viability, being reported a decrease of 2 log CFU/g for the 90% overrun treatment. In addition, it was not reported an influence about acceptability with respect to appearance, aroma, and taste of the ice creams (P > 0.05). Overall, the results suggest that lower overrun levels should be adopted during the manufacture of ice cream in order to maintain its probiotic status through the shelf life. PMID- 22260129 TI - Assessment of the long-term stability of retort pouch foods to support extended duration spaceflight. AB - To determine the suitability of retort processed foods to support long-duration spaceflight, a series of 36-mo accelerated shelf life studies were performed on 13 representative retort pouch products. Combined sensory evaluations, physical properties assessments, and nutritional analyses were employed to determine shelf life endpoints for these foods, which were either observed during the analysis or extrapolated via mathematical projection. Data obtained through analysis of these 13 products were later used to estimate the shelf life values of all retort processed spaceflight foods. In general, the major determinants of shelf life appear to be the development of off-flavor and off-color in products over time. These changes were assumed to be the result of Maillard and oxidation reactions, which can be initiated or accelerated as a result of the retort process and product formulation. Meat products and other vegetable entrees are projected to maintain their quality the longest, between 2 and 8 y, without refrigeration. Fruit and dessert products (1.5 to 5 y), dairy products (2.5 to 3.25 y), and starches, vegetable, and soup products (1 to 4 y) follow. Aside from considerable losses in B and C vitamin content, nutritional value of most products was maintained throughout shelf life. Fortification of storage-labile vitamins was proposed as a countermeasure to ensure long-term nutritive value of these products. The use of nonthermal sterilization technologies was also recommended, as a means to improve initial quality of these products and extend their shelf life for use in long-duration missions. Data obtained also emphasize the importance of low temperature storage in maintaining product quality. PRACTICAL APPLICATION: Retort sterilized pouch products are garnering increased commercial acceptance, largely due to their improved convenience and quality over metal canned products. Assessment of the long-term stability of these products with ambient storage can identify potential areas for improvement, and ultimately increase consumer satisfaction with these technologies. PMID- 22260130 TI - Sensory characteristics and consumer acceptance and purchase intention toward fresh-cut potatoes. AB - For a new product to succeed in the market, it must be accepted by consumers. This study investigates consumer opinions on fresh-cut potatoes packaged under vacuum and under a modified atmosphere using home use tests. The data obtained were related to demographic characteristics and patterns of consumption and to purchase intention toward potatoes and other vegetables. The sensory characteristics evaluated by a panel of assessors trained in the sensory evaluation of potato were also considered. The results indicate that although both products were accepted by the consumer, vacuum-packed potatoes received slightly higher ratings and more consumers intended to purchase this product. PRACTICAL APPLICATION: The fresh-cut potato packaged under vacuum is a product with all the sensory characteristics that will be accepted by the consumers. The adaptation to the productive process at the industrial level, it can be performed with enough guarantees that the product will definitely be purchased by the consumers. PMID- 22260132 TI - Effect of flax addition on the flavor profile and acceptability of bagels. AB - Bakery products containing flaxseed, a rich source of alpha linolenic acid (ALA), may provide health benefits. However, the effect of adding flaxseed, especially in the high amounts required for use as the food supplement in clinical trials (23% by weight of the raw ingredients), may affect the flavor characteristics and consumer acceptability. Sensory attributes of bagels containing 30 g of milled flaxseed were evaluated by a 9 member trained panel using a descriptive test and by 89 participants using a consumer test. Grain/flax aroma and flavor were significantly higher for the flax bagels compared to the nonflax bagels. The cinnamon raisin bagel had significantly lower grain/flax aroma and flavor and significantly higher sweet aroma and taste compared to the plain and sunflower sesame types. Older consumers rated the appearance, color, and flavor of the bagels significantly higher than the younger consumers possibly leading to higher compliance in clinical studies for this age group. Bagels with flax showed a significantly lower mean value for flavor acceptability, overall acceptability, and frequency of eating compared to bagels without flax. Appearance, color, and texture acceptability showed no significant differences. The cinnamon raisin bagel had significantly higher flavor acceptance compared to sunflower sesame and plain bagels. In conclusion, for bagels containing 6 g ALA in the form of milled flaxseed, cinnamon raisin appears to be a promising flavoring alternative for ALA fortification for use in clinical trials or as part of the daily diet. PRACTICAL APPLICATION: Consumers are seeking functional foods that contain omega-3 fatty acids. Bagels made with 23% milled flaxseed (approximately 2 times the amount in regular flax baked products) provided 6 g ALA, an amount high enough to test the efficacy of ALA in human subjects without causing gastrointestinal distress. This study showed that flaxseed aroma and flavor were detected in fortified compared to nonfortified bagels but bagels with this high flaxseed amount were still acceptable with the addition of cinnamon raisin flavoring. Commercial bakeries can use these results to formulate healthy, tasty, and convenient products. PMID- 22260131 TI - Varying the temperature of the liquid used for high-pressure processing of prerigor pork: effects on fresh pork quality, myofibrillar protein solubility, and frankfurter textural properties. AB - The objective was to evaluate high-pressure processing (HPP) with varying liquid (water) temperatures on pork quality and textural properties of frankfurters. HPP pressurization liquid temperatures were 15.5 degrees C (HPP Low) and 29.4 degrees C (HPP Med). Analyses were conducted using paired boneless loins and paired boneless hams. Loins were evaluated for pH, purge loss, objective color, subjective color, firmness; and changes in color after a bloom period. Eight independent batches (2 batches each of HPP Low, paired untreated, HPP Med, and paired untreated) of frankfurters were manufactured from the outside portion of the ham and the knuckle. Both HPP treatments resulted in higher (P < 0.05) ultimate pH and less (P < 0.05) purge loss of the loin. Loin tenderness was not different among either HPP treatment temperature groups when compared to untreated controls except HPP Med chops were more tender (P = 0.02) than untreated controls. Salt-soluble protein extractability of inside ham muscles was lower (P < 0.05) for both HPP treatment levels when compared to untreated controls, but was not different between the 2 HPP treatment levels. Textural properties of frankfurters were not different for either HPP treatment group when compared to its respective untreated control for any parameter except springiness. HPP Low frankfurters had lower (P = 0.10) springiness values than untreated controls. Fracturability of HPP Med samples was lower (P = 0.12) than untreated controls. Overall, HPP caused higher ultimate pH and increased water holding capacity, but did not affect tenderness of fresh meat or textural properties of frankfurters. PRACTICAL APPLICATION: HPP can be used on prerigor pork as means to improve fresh pork quality. Loins from HPP-treated pork sides had higher ultimate pH values and less package purge loss. Tenderness values were not affected positively or negatively by HPP treatment. The high pH and water holding capabilities of treated samples have positive implications for further processing applications. Frankfurter textural properties suggest emulsified products can be made with pressurized pork without sacrifice to the textural profile. PMID- 22260133 TI - Development of soy-based bread with acceptable sensory properties. AB - Consumption of soy protein has been associated with benefits related to numerous areas of health. Due to the widespread consumption of bread, one means of contributing to the health of individuals is through the incorporation of soy protein into bread. To this end, soy flour (SF) or soy protein isolates (SPIs) in 20% and 12% substitution levels, respectively, were added to flour during bread manufacture. The developed breads were tested using a consumer panel for acceptability, using a refined white bread as a control. These data were compared to attribute intensity data collected by the trained panel to identify specific flavor and texture characteristics affecting liking. The sensory profile of the 20% SF bread was acceptable and comparable to the control bread, despite a significantly stronger beany flavor. No significant differences in sensory properties of the SF and control breads were detected by the trained panel for many sensory attributes. The SPI bread, however, had a sensory profile that was significantly more firm, dense, sour, beany, bitter, and astringent with a strong aftertaste in comparison to the wheat control bread. Consumer liking scores for the SPI bread was significantly lower than the liking of the control and the SF added bread. PRACTICAL APPLICATION: Many soy-enriched foods, while contributing positively to health, are considered unacceptable by consumers. This is due to negative sensory properties, such as beany, painty, and astringent notes, often perceived by consumers. This study provides information on the level of SF that can be included in bread in an amount that does not detract from consumer acceptability. This level also allows for a Food and Drug Administration (FDA) health claim to be made. PMID- 22260134 TI - Effect of sexual maturation on thermal stability, viscoelastic properties, and texture of female rainbow trout, Oncorhynchus mykiss, fillets. AB - The nutrient and energy demand of sexual maturation in many fish cultivars causes structural change to key contractile proteins and thereby, affects fillet firmness. Thermal denaturation and viscoelastic properties of white muscle from diploid (2N; fertile) and triploid (3N; sterile) female rainbow trout were investigated at 6 age endpoints from July 2008 through spawning in March 2009. Differential scanning calorimetry showed, in March, that the actin denaturation temperature (T(max,actin)) of 2N females was higher than that observed in 3N females (78.17 versus 77.27 degrees C). From 35 to 45 degrees C, viscoelastic measurement revealed that muscle from 2N females and younger fish (July, 16 mo) had greater elasticity (lower tan delta) than muscle from 3N females and older fish (November to March; 20 to 24 mo), respectively. The highest elastic response and the firmest fillets were observed in July. Raw fillets were softer (Allo Kramer shear; P < 0.05) from September to January (288.77 g/g on average) than those collected in July (475.15 g/g) and March (366.79 g/g). Soft fillets became firmer after cooking except for January samples. Greater cook yield and softer fillets were observed in January compared to December. Lipid accumulation in 3N females may lubricate muscle fibers and protect them from losing functionality during the spawning season for animals on a high plane of nutrition. PRACTICAL APPLICATION: The relationship between fish maturation, measured as egg development, and chemical characteristics of fillets from fertile and sterile fish was evaluated. Thermal denaturation and viscoelastic characterization revealed changes in stability and gelling properties of muscle proteins that were related to changes in fillet texture. PMID- 22260135 TI - The effect of crowding stress on bacterial growth and sensory properties of chilled Atlantic salmon fillets. AB - Atlantic salmon were subjected to minimal preslaughter crowding stress (Control), short-term crowding for 20 min (SS-group), or long-term crowding for 24 h (LS group). The fish were filleted prerigor, cut into 270 g pieces, and packaged in modified atmosphere (60% CO2 and 40% N2). Fillet quality analyses were determined during 22 d of storage at 0.3 degrees C. Bacterial growth and unpleasant sensory properties increased earlier in the LS-group. The negative effects of long-term preslaughter stress were more pronounced for raw than cooked samples, and more pronounced for odor than flavor. Sequence analyses of bacterial DNA at the end of storage revealed that 100% of the bacteria were comprised by Photobacterium phosphoreum of the SS- and LS-group, whereas the Control group also contained 21% of Carnobacterium maltaromaticum (lactic acid bacteria, LAB). Counting of LAB, using Man-Rogosa-Sharke agar, similarly showed higher numbers of the Control group after 15 d of storage. A total bacterial count of log 6 CFU/g was observed after 15 d of storage of the LS-group, which was 3 and 7 d earlier compared with the Control and SS-group, respectively. Fillet color, texture, and liquid losses were not negatively affected by preslaughter crowding stress. From the sensory and bacterial analyses, it is concluded that long-term crowding stress accelerates bacterial growth and development of unpleasant sensory properties, hence reduces the shelf life of prerigor modified atmosphere packaged (MAP) salmon. PRACTICAL APPLICATION: Stressful handling of Atlantic salmon before slaughter resulted in faster reduction of fresh taste and smell, faster bacterial growth, and hence shorter shelf life. The deteriorative effects were more pronounced of raw compared to cooked salmon. Therefore, salmon should be handled carefully in connection with slaughter to avoid impaired welfare and fillet quality, in particularly for fish that is consumed raw, such as sushi. PMID- 22260136 TI - Physicochemical properties and sensory analysis of duck meatballs containing duck meat surimi-like material during frozen storage. AB - The physicochemical properties and sensory analysis of duck meatballs containing duck meat surimi-like material during frozen storage were evaluated. Properties of meatballs containing duck surimi-like material prepared by acid solubilization (ACDS), alkaline solubilization (ALDS), and conventional processing (CDS) as well as duck mince (as the control, CON) were compared. ACDS had significantly higher (P < 0.05) moisture and protein content and lower fat content compared with CON. The thiobarbituric acid-reactive substances (TBARS) value of all samples increased as the storage time increased up to week 8 (P < 0.05), but thereafter it decreased in most of the samples. ACDS and ALDS had significantly higher TBARS values (P < 0.05), and these values remained higher than those of the other samples throughout the frozen storage period. Addition of surimi-like material to the meatballs had significant effects (P < 0.05) on springiness, gumminess, and chewiness values of all samples. Ingredients and frozen storage affected most sensory attributes in samples significantly (P<0.05). No significant increase in growth of organisms occurred during 12-wk frozen storage The results indicate that acid-alkaline solubilization methods improve both physicochemical and sensory properties of duck meatballs containing duck surimi-like material. Thus, these techniques should be applicable to product development of duck surimi-like material. PRACTICAL APPLICATION: Surimi-like material from duck meat is an alternative source of meat protein to produce ready-to eat or value-added products. Little is known about duck surimi-like material and physicochemical and sensory properties of such products. Therefore, the results of this study are critical for assessing the possibility of duck meat surimi-like material for human food. PMID- 22260137 TI - Safety evaluation of supercritical carbon dioxide extract of Aloe vera gel. AB - The gel of the Aloe vera plant has been used safely for oral and external applications. Previously, we found phytosterols derived from an extract of Aloe vera gel obtained with an organic solvent to have hypoglycemic and antiobesity effects. While developing of functional foods using Aloe vera gel, we produced an active Aloe vera gel extract (AVGE) using a supercritical carbon dioxide (CO2) extraction procedure. In this study, we tested the safety of AVGE in vitro and in vivo. In an acute oral toxicological test in which AVGE was administered to rats at a dose of 150 mg/kg body weight, there were no deaths or apparent abnormalities at necropsy. In a 90-d toxicity test in which rats were continuously administrered AVGE at 30 or 150 mg/kg, euthanized, and subjected to pathological examinations, no abnormalities attributable to the AVGE were found. AVGE was nonmutagenic in the Ames test and a chromosomal aberration test at concentrations of up to 5000 MUg/plate and 1600 MUg/plate, respectively, and in an in vivo bone marrow micronucleus test at up to 150 mg/kg/d. PRACTICAL APPLICATION: AVGE can be safely used as a functional food material. PMID- 22260138 TI - Antioxidant, antimicrobial, and anticancer activity of 3 Umbilicaria species. AB - The aim of this study is to investigate in vitro antioxidant, antimicrobial, and anticancer activity of the acetone extracts of the lichens Umbilicaria crustulosa, U. cylindrica, and U. polyphylla. Antioxidant activity was evaluated by 5 separate methods: free radical scavenging, superoxide anion radical scavenging, reducing power, determination of total phenolic compounds, and determination of total flavonoid content. Of the lichens tested, U. polyphylla had largest free radical scavenging activity (72.79% inhibition at a concentration of 1 mg/mL), which was similar as standard antioxidants in the same concentration. Moreover, the tested extracts had effective reducing power and superoxide anion radical scavenging. Total content of phenol and flavonoid in extracts was determined as pyrocatechol equivalent, and as rutin equivalent, respectively. The strong relationships between total phenolic and flavonoid contents and the antioxidant effect of tested extracts were observed. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. The most active was extract of U. polyphylla with minimum inhibitory concentration values ranging from 1.56 to 12.5 mg/mL. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method. All extracts were found to be strong anticancer activity toward both cell lines with IC50 values ranging from 28.45 to 97.82 MUg/mL. The present study shows that tested lichen extracts demonstrated a strong antioxidant, antimicrobial, and anticancer effects. That suggests that lichens may be used as possible natural antioxidant, antimicrobial, and anticancer agents. PMID- 22260140 TI - Editorial: Losing a friend and major contributor to JFS; 2011 overview. PMID- 22260147 TI - DNA methyltransferases: mechanistic models derived from kinetic analysis. AB - The sequence-specific transfer of methyl groups from donor S-adenosyl-L methionine (AdoMet) to certain positions of DNA-adenine or -cytosine residues by DNA methyltransferases (MTases) is a major form of epigenetic modification. It is virtually ubiquitous, except for some notable exceptions. Site-specific methylation can be regarded as a means to increase DNA information capacity and is involved in a large spectrum of biological processes. The importance of these functions necessitates a deeper understanding of the enzymatic mechanism(s) of DNA methylation. DNA MTases fall into one of two general classes; viz. amino MTases and [C5-cytosine]-MTases. Amino-MTases, common in prokaryotes and lower eukaryotes, catalyze methylation of the exocyclic amino group of adenine ([N6 adenine]-MTase) or cytosine ([N4-cytosine]-MTase). In contrast, [C5-cytosine] MTases methylate the cyclic carbon-5 atom of cytosine. Characteristics of DNA MTases are highly variable, differing in their affinity to their substrates or reaction products, their kinetic parameters, or other characteristics (order of substrate binding, rate limiting step in the overall reaction). It is not possible to present a unifying account of the published kinetic analyses of DNA methylation because different authors have used different substrate DNAs and/or reaction conditions. Nevertheless, it would be useful to describe those kinetic data and the mechanistic models that have been derived from them. Thus, this review considers in turn studies carried out with the most consistently and extensively investigated [N6-adenine]-, [N4-cytosine]- and [C5-cytosine]-DNA MTases. PMID- 22260148 TI - Evaluation of a cognitive behavioural self-help manual for reducing depression: a randomized controlled trial. AB - The prevalence of depression is increasing in Thailand. We used a randomized controlled trial to examine the effectiveness of a self-help programme in reducing depression in people with depression in Chiang Mai Province in Thailand. Fifty-six individuals diagnosed with moderate depression participated. They were assigned randomly to an intervention (n= 27) or control (n= 29) group. The intervention group were given a self-help manual along with standard care and treatment, while the control group continued to receive standard care and treatment. Both groups were also given a short weekly telephone call. The findings showed statistically significant differences between the groups, and within the intervention group, in their depression levels. Between baseline and post-test, a sharp decrease in depression was evident in the intervention group, whereas the level of depression increased in the control group. Between post-test and follow-up, a decrease was apparent in depression in both groups. However, the intervention group showed a much lower level of depression than the control group. The results support the use of bibliotherapy as an adjunct to mental health nurses' and other professionals' work in caring for people with moderate depression in the community. TRIAL REGISTRATION: http://www.ANZCTR.org.au/ACTRN12611000905965.aspx. PMID- 22260149 TI - Fracture resistance of maxillary complete dentures subjected to long-term water immersion. AB - OBJECTIVE: This study investigated the fracture resistance of maxillary acrylic resin complete dentures subjected to long-term water immersion. MATERIALS AND METHODS: Maxillary acrylic resin complete dentures were fabricated from five denture base resins. Half of the dentures were stored in water for 50 h, and the other half were kept in water for 180 days before testing. Ten specimens were fabricated per group. The flexural load at the proportional limit (FL-PL) of the dentures was tested. RESULTS: A two-way anova revealed a significant difference in FL-PL because of the denture base material variable. There were no significant differences in FL-PL because of the effect of water immersion and the interaction between the effect of water immersion and the denture base material. The FL-PLs of the dentures fabricated with the two conventional heat-processed resins, the pour-type autopolymerizing resin and the microwave energy-processed resin were not significantly different from each other; they were significantly higher than the light-activated resin in regard to their FL-PL. CONCLUSION: The FL-PLs of the maxillary acrylic resin complete dentures did not change after long-tern water immersion, and the FL-PL of the denture fabricated from the light-activated resin was lower than those of the other materials. PMID- 22260150 TI - Oncological outcome in patients treated for rectal carcinoma and followed up for 20 years was associated with local recurrence and a new primary cancer. PMID- 22260151 TI - Analysis of molecular mechanisms and anti-tumoural effects of zoledronic acid in breast cancer cells. AB - Zoledronic acid (ZOL) is the most potent nitrogen-containing bisphosphonate (N BPs) that strongly binds to bone mineral and acts as a powerful inhibitor of bone resorption, already clinically available for the treatment of patients with osteolytic metastases. Recent data also suggest that ZOL, used in breast cancer, may provide more than just supportive care modifying the course of the disease, though the possible molecular mechanism of action is still unclear.As breast cancer is one of the primary tumours with high propensity to metastasize to the bone, we investigated, for the first time, differential gene expression profile on Michigan Cancer Foundation-7 (MCF-7) breast cancer cells treated with low doses of ZOL (10 MUM). Microarrays analysis was used to identify, describe and summarize evidence regarding the molecular basis of actions of ZOL and of their possible direct anti-tumour effects. We validated gene expression results of specific transcripts involved in major cellular process by Real Time and Western Blot analysis and we observed inhibition of proliferation and migration through 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Matrigel assay. We then focused on changes in the cytoskeletal components as fibronectin 1 (FN1), actin, and anti angiogenic compounds as transforming growth factor-beta1 (TGF-beta1) and thrombospondin 1 (THBS1). The up-regulation of these products may have an important role in inhibiting proliferation, invasion and angiogenesis mediated by ZOL. PMID- 22260152 TI - Median nerve neuropathy in the forearm due to recurrence of anterior wrist ganglion that originates from the scaphotrapezial joint: Case Report. AB - BACKGROUND: Median nerve neuropathy caused by compression from a tumor in the forearm is rare. Cases with anterior wrist ganglion have high recurrence rates despite surgical treatment. Here, we report the recurrence of an anterior wrist ganglion that originated from the Scaphotrapezial joint due to incomplete resection and that caused median nerve neuropathy in the distal forearm. CASE PRESENTATION: A 47-year-old right-handed housewife noted the appearance of soft swelling on the volar aspect of her left distal forearm, and local resection surgery was performed twice at another hospital. One year after the last surgery, the swelling reappeared and was associated with numbness and pain in the radial volar aspect of the hand. Magnetic resonance imaging revealed that the multicystic lesion originated from the Scaphotrapezial joint and had expanded beyond the wrist. Exploration of the left median nerve showed that it was compressed by a large ovoid cystic lesion at the distal forearm near the proximal end of the carpal tunnel. We resected the cystic lesion to the Scaphotrapezial joint. Her symptoms disappeared 1 week after surgery, and complications or recurrent symptoms were absent 13 months after surgery. CONCLUSIONS: A typical median nerve compression was caused by incomplete resection of an anterior wrist ganglion, which may have induced widening of the cyst. Cases with anterior wrist ganglion have high recurrence rates and require extra attention in their treatment. PMID- 22260153 TI - A method for the field assessment of rolling resistance properties of manual wheelchairs. AB - This article presents an examination and validation of a method to measure the field deceleration of a manual wheelchair (MWC) and to calculate the rolling resistances properties of the front and rear wheels. This method was based on the measurements of the MWC deceleration for various load settings from a 3D accelerometer. A mechanical model of MWC deceleration was developed which allowed computing the rolling resistance factors of front and rear wheels on a tested surface. Four deceleration sets were conducted on two paths on the same ground to test the repeatability. Two other deceleration sets were conducted using different load settings to compute the rolling resistance parameters (RPs). The theoretical decelerations of three load settings were computed and compared with the measured decelerations. The results showed good repeatability (variations of measures represented 6-11% of the nominal values) and no statistical difference between the path results. The rolling RPs were computed and their confidence intervals were assessed. For the last three sets, no significant difference was found between the theoretical and measured decelerations. This method can determine the specific rolling resistance properties of the wheels of a MWC, and be employed to establish a catalogue of the rolling resistance properties of wheels on various surfaces. PMID- 22260154 TI - Long-term renal outcome of snake bite and acute kidney injury: a single-center experience. AB - BACKGROUND: Snake bite can cause acute kidney injury (AKI) through multiple mechanisms. Many of these patients have severe kidney injury requiring renal replacement therapy. The long-term outcome of survivors of such severe AKI is not known. METHODS: We prospectively followed up 60 patients who developed dialysis requiring severe AKI following snake bite and had survived the hospital stay. RESULTS: A total of 25 (41%) patients showed persistent renal involvement in the form of renal dysfunction, proteinuria, or hypertension at a mean period of follow-up of 45 months. Totally 5% of the patients progressed to end-stage renal disease (ESRD) while 20% had glomerular filtration rate (GFR) <45 mL/min. CONCLUSIONS: Long-term outcome of snake bite and AKI is not benign with a significant percentage of patients continuing to have features of persistent renal damage. PMID- 22260155 TI - Childhood aerobic fitness predicts cognitive performance one year later. AB - Aerobically fit children outperform less fit peers on cognitive control challenges that involve inhibition, cognitive flexibility, and working memory. The aim of this study was to determine whether, compared with less fit children, more fit 9- and 10-year-old pre-adolescents exhibit superior performance on a modified compatible and incompatible flanker task of cognitive control at the initial time of fitness testing and approximately one year later. We found that more fit children demonstrated increased flanker accuracy at both test sessions, coupled with a superior ability to flexibly allocate strategies during task conditions that required different amounts of cognitive control, relative to less fit children. More fit children also gained a speed benefit at follow-up testing. Structural MRI data were also collected to investigate the relationship between basal ganglia volume and task performance. Bilateral putamen volumes of the dorsal striatum and globus pallidus volumes predicted flanker performance at initial and follow-up testing one year later. The present findings suggest that childhood aerobic fitness and basal ganglia volumes relate to cognitive control at the time of fitness testing and may play a role in cognitive performance in the future. We hope that this research will encourage public health and educational changes that will promote a physically active lifestyle in children. PMID- 22260156 TI - Assessing compensation for loss of vacuolar function in Saccharomyces cerevisiae. AB - We analyzed how Saccharomyces cerevisiae cells compensate for the lack of a functional vacuole, an acidic membrane-bound degradative and ion storage compartment. We hypothesized that cells lacking a functional vacuole would compensate for the loss of the functions of the vacuole by altering gene expression and (or) metabolic flux. We used gene expression profiling and Biolog phenotype microarray analysis to determine the compensatory mechanisms of cells lacking vacuolar function. In steady state, vps33 and vps41 cells changed the transcriptional profile of some genes, but no complete pathways were upregulated or downregulated. We treated vps41 cells with calcium to tease out cellular compensation for loss of vacuole function under ionic stress; however, changes in gene expression were not utilized to compensate for loss of vacuole function under stress either, as genes whose transcriptional profiles were changed did not function together in any one cellular process. Phenotype microarray analysis indicated that logarithmically growing vps33 or vps41 cells did not seem to compensate for loss of vacuolar function but instead demonstrated additional pleiotropic phenotypes due to the function of the vacuole. Under rich media conditions, yeast utilize the vacuole to regulate stress, ion response, and peptide degradation. However, loss of the vacuole does not lead to observable compensation mechanisms. PMID- 22260157 TI - Waldenstrom macroglobulinemia with a durable clinical response to epoetin beta. PMID- 22260158 TI - Interfollicular Hodgkin lymphoma in children: an uncommon mimicker of reactive lymphadenopathy. PMID- 22260159 TI - Sequential combination of high dose methotrexate and L-asparaginase followed by allogeneic transplant: a first-line strategy for CD4+/CD56+ hematodermic neoplasm. PMID- 22260160 TI - Toxicities and outcomes among septuagenarians and octogenarians with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone therapy. AB - The diagnosis of non-Hodgkin lymphoma (NHL) is increasingly common among the elderly and it is well recognized that this patient population may benefit from therapy. No guidelines exist for chemotherapy dosing in the elderly population, and a clear assessment of treatment toxicity and benefits has not been previously reported. In this single-institution study, we report the toxicities and treatment outcomes of septuagenarians and octogenarians with large cell lymphoma treated with chemo-immunotherapy with or without radiation, as primary therapy with curative intent. We identified 37 patients over the age of 70 years diagnosed with large cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) and compared their experience with 65 patients aged less than 70 years. Our retrospective analysis suggests that elderly patients are more susceptible to treatment-related toxicity despite more frequent chemotherapy dose reductions and greater utilization of supportive care. While our aged patients experienced greater frequency of hospitalization during R-CHOP treatment, the vast majority were able to receive relative chemotherapy dose-intensity greater than 70% and experienced similar rates of complete remission. PMID- 22260161 TI - Transcription factor CCAAT/enhancer-binding protein alpha and critical circadian clock downstream target gene PER2 are highly deregulated in diffuse large B-cell lymphoma. AB - Disturbances of circadian rhythms and mammalian clock genes have been implicated in the etiologies of many chronic illnesses, including cancer. We show that transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha)-regulated PER2 activation is a potential tumor suppressor pathway in diffuse large B-cell lymphoma (DLBCL), one of the commonest types of mature B-cell lymphoma. Expression analysis of human B-cell lymphoma samples including DLBCL (n = 50), mantle cell (n = 21), follicular (n = 25) and Burkitt (n = 18) lymphoma revealed markedly down-regulated CEBPA and PER2 mRNA levels exclusively in DLBCL samples compared to control lymphatic tissue. We demonstrated direct regulation of the circadian core clock gene PER2 by C/EBPalpha in the pro-B cell line Ba/F3, and forced expression of PER2 resulted in decreased proliferation, G0/G1 cell cycle arrest and increased rates of apoptosis. Interestingly, treatment of human DLBCL cell lines with the histone deacetylase-inhibitor suberoylanilide hydroxamic acid (SAHA) significantly increased the expression of C/EBPalpha and Per2, accompanied by cell growth inhibition; in contrast, siRNA knockdown of CEBPA reduced the anti proliferative effect of SAHA treatment. Our results show for the first time that C/EBPalpha with its associated direct core clock gene target, PER2, are highly deregulated in DLBCL, suggesting an important tumor suppressive pathway in the pathogenesis of this lymphoma entity. PMID- 22260162 TI - Clinical impact of in vitro cellular drug resistance on childhood acute lymphoblastic leukemia in Taiwan. AB - Despite the successful treatment of childhood acute lymphoblastic leukemia (ALL), the resistance to chemotherapy in ALL cells continues to play an important role in treatment failure. In vitro drug resistance determined using an MTT [3(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was carried out in 16 children with newly diagnosed ALL between November 2009 and December 2010. The in vitro therapeutic effects of asparaginase, vincristine, prednisolone, dexamethasone, epirubicin and cytarabine were examined. Although there was no significant association between in vitro drug resistance of leukemic cells and ALL subtypes, ETV6-RUNX1 ALL tended to be more sensitive to asparaginase, vincristine and prednisolone. Leukemic cells from girls were significantly more sensitive to epirubicin compared with boys (p = 0.008). Higher leukocyte count at diagnosis was correlated with in vitro resistance to asparaginase and prednisolone (p = 0.03 and 0.05, respectively). Relapse or death occurred in five patients. The leukemic cells from these five patients demonstrated increased in vitro resistance to asparaginase compared to those from the other 11 patients (p = 0.009). From the present case series, the demonstrated in vitro resistance to chemotherapeutic agents may have a prognostic value in children with ALL before comprehensive minimal residual disease measurement is available. PMID- 22260164 TI - Pioneering studies of histone deacetylase inhibitors in myeloma: signals of activity set the stage for combination therapy trials. PMID- 22260163 TI - Triptolide enhances the sensitivity of multiple myeloma cells to dexamethasone via microRNAs. AB - Recently triptolide (TPL) has been proved to have the capacity to inhibit the proliferation of multiple myeloma (MM) cells as well as leukemic cells in vitro. In the present study, we found a synergistic effect when TPL was added to dexamethasone to induce apoptosis in MM.1S cells. This combination induced a significantly higher proportion of apoptotic cells compared with those treated with each drug separately. TPL down-regulated the expression of miR142 - 5p and miR181a, which have been shown to inhibit glucocorticoid receptor (GR) expression. MicroRNA mimics and inhibitors inhibited or enhanced the synergistic effect between TPL and dexamethasone in inducing apoptosis in MM.1S cells, suggesting an important role of miR142 - 5p and miR181a in GR regulation by TPL. The in vitro proapoptotic effect of TPL associated with dexamethasone reveals a new lead for further clinical investigation into the treatment of patients with MM with TPL. PMID- 22260165 TI - Protein-bound water molecules in primate red- and green-sensitive visual pigments. AB - Protein-bound water molecules play crucial roles in the structure and function of proteins. The functional role of water molecules has been discussed for rhodopsin, the light sensor for twilight vision, on the basis of X-ray crystallography, Fourier transform infrared (FTIR) spectroscopy, and a radiolytic labeling method, but nothing is known about the protein-bound waters in our color visual pigments. Here we apply low-temperature FTIR spectroscopy to monkey red (MR)- and green (MG)-sensitive color pigments at 77 K and successfully identify water vibrations using D(2)O and D(2)(18)O in the whole midinfrared region. The observed water vibrations are 6-8 for MR and MG, indicating that several water molecules are present near the retinal chromophore and change their hydrogen bonds upon retinal photoisomerization. In this sense, color visual pigments possess protein-bound water molecules essentially similar to those of rhodopsin. The absence of strongly hydrogen-bonded water molecules (O-D stretch at <2400 cm( 1)) is common between rhodopsin and color pigments, which greatly contrasts with the case of proton-pumping microbial rhodopsins. On the other hand, two important differences are observed in water signal between rhodopsin and color pigments. First, the water vibrations are identical between the 11-cis and 9-cis forms of rhodopsin, but different vibrational bands are observed at >2550 cm(-1) for both MR and MG. Second, strongly hydrogen-bonded water molecules (2303 cm(-1) for MR and 2308 cm(-1) for MG) are observed for the all-trans form after retinal photoisomerization, which is not the case for rhodopsin. These specific features of MR and MG can be explained by the presence of water molecules in the Cl(-) biding site, which are located near positions C11 and C9 of the retinal chromophore. The averaged frequencies of the observed water O-D stretching vibrations for MR and MG are lower as the lambda(max) is red-shifted, suggesting that water molecules are involved in the color tuning of our vision. PMID- 22260166 TI - Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors. AB - Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complementary chemo-active groups within a single molecular architecture, we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors. These dual-acting agents are derived from suberoylanilide hydroxamic acid (SAHA) and anthracycline daunorubicin, prototypical histone deacetylase (HDAC) and topoisomerase II (Topo II) inhibitors, respectively. We report herein that these agents present the signatures of inhibition of HDAC and Topo II in both cell-free and whole-cell assays. Moreover, these agents potently inhibit the proliferation of representative cancer cell lines. PMID- 22260167 TI - Protective efficacy of a Treponema pallidum Gpd DNA vaccine vectored by chitosan nanoparticles and fused with interleukin-2. AB - In the present study, immunomodulatory responses of a DNA vaccine constructed by fusing Treponema pallidum (Tp) glycerophosphodiester phosphodiesterase (Gpd) to interleukin-2 (IL-2) and using chitosan (CS) nanoparticles as vectors were investigated. New Zealand white rabbits were immunized by intramuscular inoculation of control DNAs, Tp Gpd DNA vaccine, or Gpd-IL-2 fusion DNA vaccine, which were vectored by CS nanoparticles. Levels of the anti-Gpd antibodies and levels of IL-2 and interferon-gamma in rabbits were increased upon inoculation of Gpd-IL-2 fusion DNA vaccine, when compared with the inoculation with Gpd DNA vaccine, with CS vectoring increasing the effects. The Gpd-IL-2 fusion DNA vaccine efficiently enhanced the antigen-specific lymphocyte proliferative response. When the rabbits were challenged intradermally with 10(5) Tp (Nichols) spirochetes, the Gpd-IL-2 fusion DNA vaccine conferred better protection than the Gpd DNA vaccine (P < 0.05), as characterized by lower detectable amounts of dark field positive lesions (17.5%), lower ulcerative lesion scores (15%), and faster recovery. Individuals treated with the Tp Gpd-IL-2 fusion DNA vaccine vectored by CS nanoparticles had the lowest amounts of dark field positive lesions (10%) and ulcerations (5%) observed and the fastest recovery (42 days). These results indicate that the Gpd-IL-2 fusion DNA vaccine vectored by CS nanoparticles can efficiently induce Th1-dominant immune responses, improve protective efficacy against Tp spirochete infection, and effectively attenuate development of syphilitic lesions. PMID- 22260168 TI - Life satisfaction and mortality in elderly people: the Kangwha Cohort Study. AB - BACKGROUND: As well as biomedical risk factors, psychological factors have been reported to be related to mortality rate. The purpose of this study was to examine the relationship between life satisfaction and mortality in elderly people through an 11.8-year follow-up study of a prospective cohort. METHODS: Among 3,600 participants of the Kangwha Cohort Study who survived in 1994, 1,939 respondents of the Life Satisfaction Index (LSI)-A questionnaire were included (men, 821; women, 1118). The mortality risk for the period up to December 2005 was measured using the Cox Proportional Hazard Model. RESULTS: When the relationship between LSI and mortality was evaluated in men, the unsatisfied group with lower LSI scores showed a significantly higher risk of all-cause mortality (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.11-1.83) than the satisfied group with higher LSI scores. In women, the unsatisfied group showed a significantly higher risk of all-cause mortality (HR, 1.51; 95% CI, 1.18 1.92) and cardiovascular mortality (HR, 2.23; 95% CI, 1.30-3.85) than the satisfied group. CONCLUSION: We found that elderly people with a lower LSI score, regardless of gender, were at risk of increased mortality from all causes, and low LSI score was also associated with cardiovascular mortality. PMID- 22260169 TI - Intranasal fentanyl in the treatment of acute pain--a systematic review. AB - Due to its non-invasive mode of administration, intranasal (IN) application of drugs may be a valuable alternative to non-invasive pain management. With characteristics that appear to be ideal for IN application, IN fentanyl may have a place in the out-of-hospital treatment and the paediatric population. The objective of this systematic review was to evaluate the current evidence of IN fentanyl in the treatment of acute pain. Reports of randomized controlled trials (RCTs) of IN fentanyl in treatment of pain were systematically sought using the PubMed database, Embase, Google scholar, Cochrane database, and Cumulative Index to Nursing and Allied Health Literature. Reports were considered for inclusion if they were double-blinded randomized controlled trials (RCTs) of IN fentanyl in the treatment of acute pain. Thirty-two RCTs were identified, and 16 were included in the final analysis. No significant analgesic differences between IN fentanyl and intravenous (IV) fentanyl were demonstrated in treatment of acute and post-operative pain. Significant analgesic effect of IN fentanyl was demonstrated in the treatment of breakthrough pain in cancer patients. In the paediatric population, results demonstrated some analgesic effect of IN fentanyl following myringotomy, no analgesic effect following voiding cystourethrography, and finally, no significant analgesic difference after long bone fractures, in burns patients, and in post-operative pain relief when compared to IV morphine, oral morphine, or IV fentanyl, respectively. Significant analgesic effect of IN fentanyl was demonstrated in the treatment of breakthrough pain in cancer patients. However, the significant deficiencies in trials investigating acute and post-operative pain, and the paediatric population makes firm recommendations impossible. PMID- 22260170 TI - A single Cu(II) catalyst for the three-component coupling of diverse nitrogen sources with aldehydes and alkynes. AB - A single Cu(II) catalyst without the addition of ligand or base couples a diverse range of nitrogen sources with alkynes and aldehydes bearing alkyl, halogenated, silyl, aryl, and heteroaryl groups. The first example of a copper-catalyzed alkynylation involving p-toluenesulfonamide provides high yields of N-Ts protected propargylamines. The superior activity of copper(II) triflate also allows this three-component alkynylation to incorporate a ketone. PMID- 22260171 TI - Macromolecule functionalization of disulfide-bonded polymer hydrogel capsules and cancer cell targeting. AB - We present a generic and versatile method for functionalization of disulfide stabilized PMA hydrogel capsules (HCs) with macromolecules, including a number of specific antibodies to cancer cells. Functionalization was achieved by reversible addition-fragmentation chain transfer (RAFT) polymerization of poly(N-vinyl pyrrolidone) (PVPON), which introduced biorelevant heterotelechelic end groups (thiol and amine) to the polymer chain. The PVPON with heterotelechelic end groups was conjugated to the outermost layer of PMA HCs through the thiol groups and reacted with biotin via the amine groups to generate PMA/PVPON(biotin) HCs. On the basis of the high specific interaction and high affinity between biotin and avidin, and its derivates, such as NeutrAvidin (NAv), we functionalized the PMA HCs with biotinylated antibodies. We demonstrate significantly enhanced cellular binding and internalization of the antibody (Ab)-functionalized capsules compared with control human immunoglobulin (IgG)-functionalized capsules, suggesting these capsules can specifically interact with cells through antibody/antigen recognition. We anticipate that the versatility of the functionalization approach reported in this study will assist in targeted therapeutic delivery applications. PMID- 22260172 TI - Sol-gel route to zirconia-Pt-nanoelectrode arrays 8 nm in radius: their geometrical impact in mass transport. AB - The fabrication of advanced nanoelectrode arrays and their electrochemical characterization are presented. These nanoelectrode arrays are constituted of nanoperforations of 8 nm in radius leading to platinum and protected by an inorganic matrix made of crystalline zirconia. These nanoelectrodes arrays provide a ceramic support with a high thermal and chemical stability. These devices present a well characterized structure with a control of size, shape, and spacing of the nanoelectrodes, allowing studying in depth both the mass transport and the charge transfer properties in the nanometer range. The radial diffusion occurs when the experimental scan rate is superior to a theoretical scan rate estimated from the model proposed by Amatore and colleagues. The coupling between electrochemical analysis and nanoscale structural characterizations successfully demonstrates that the theory defined for microelectrode arrays can be directly transposed for well-defined metal-ceramic nanocomposite nanoelectrodes. PMID- 22260173 TI - Effect of fermentation on the nutrient and antinutrient composition of baobab (adansonia digitata) seeds and rice (oryza sativa) grains. AB - This study is part of an ongoing investigation on the effect of fermentation on chemical and antinutrient compositions of baobab seeds and rice grains. Baobab seeds and rice grains were cleaned and fermented for 24, 48, and 72 h, respectively, by the microflora present in both the seed and the grains. The pH and titratable acidity of the unfermented and fermented samples were determined. The samples were dried and milled into fine flours respectively. Standard assay techniques were used to evaluate the f lours for proximate, mineral, and some antinutrient composition. Fermentation of baobab decreased protein and carbohydrate but increased fat levels. The rice carbohydrate and fat were decreased during fermentation except for the carbohydrate of the 48 and 72 h fermented samples. Protein was only increased in the 24 h fermented rice. Fermentation had varied effects on the mineral concentrations of the baobab seeds and the rice grains. It reduced their antinutrients (phytate and tannins), decreased pH, and increased the titratable acidity of the samples. The biochemical and biological evaluation of the blends of baobab and rice flours as complementary food is in progress in this laboratory. PMID- 22260174 TI - Does fish still matter? Changes in the diet of two brazilian fishing communities. AB - Coastal communities are experiencing rapid changes on their livelihood due to the degradation of coastal areas and growing tourism. We analyze the changes in the diet of two fishing communities from the southeastern Brazilian coast, in regard to their consumption of animal protein. Using multivariate methods, we followed the diet of 32 households through the 24-hour recall method (three days per month, September 1998 to August 1999) in order to compare the niche breadth of the communities, and to verify the relationships between fish consumption and socioeconomic characteristics. The nutritional quality of the diets is analyzed. Even with the partial abandonment of fishing activities, fishing activity still guides fish consumption. Nutritional adequacy is above the recommended levels for protein intake, but is below it for food energy. Non-local industrialized food items influence the increase of the niche breadth. The abandonment of livelihood activities that historically assured Caicara's self-sufficiency are resulting in the food delocalization. PMID- 22260175 TI - Social status and food preference in southern Brazil. AB - The prestige value of food and food behaviors is a topic of inquiry that complements the study of nutritional aspects of food use. In this work, varying social groups in Brazil are examined with regard to their evaluation of the status of available foods, and in turn, the frequencies with which they consume high and low status foods. Ethnographic and structured interviews were used to collect data, with agreement among groups tested by using Cultural Consensus Modeling. It was found that most social groups had a distinct notion of what foods are prestigious, although the high consumption of these same foods did not necessarily follow. PMID- 22260176 TI - World war ii's mobilization of the science of food acceptability: how ration palatability became a military research priority. AB - This article focues on the U. S. Army's solicitation of the science of food acceptability in its development of the World War II combat ration. The story of the Army's eventual inclusion of the science of food acceptability in its combat ration reseach program records the growth of food science generally, and palatable rations specifically, into critical components of the nation's security and subtenance. PMID- 22260177 TI - Silica-rubber microstructure visualised in three dimensions by focused ion beam scanning electron microscopy. AB - A focused ion beam-scanning electron microscope (FIB-SEM) technique for three dimensional reconstruction and representation of material microstructures was applied to a silica-filled synthetic rubber for the first time. Backscattered electron imaging allowed differentiation between rubber matrix, silica filler and zinc oxide (used as an activator for the sulphur vulcanisation reaction). Subsequent image processing allowed three-dimensional isosurface model generation of the particulate structure within the rubber composite and separation of zinc oxide from the silica filler. The potential for development and application of this technique using finite element analysis modelling is also highlighted. PMID- 22260178 TI - LogSpin: a simple, economical and fast method for RNA isolation from infected or healthy plants and other eukaryotic tissues. AB - BACKGROUND: Rapid RNA extraction is commonly performed with commercial kits, which are very expensive and can involve toxic reagents. Most of these kits can be used with healthy plant tissues, but do not produce consistently high-quality RNA from necrotic fungus-infected tissues or fungal mycelium. FINDINGS: We report on the development of a rapid and relatively inexpensive method for total RNA extraction from plants and fungus-infected tissues, as well as from insects and fungi, based on guanidine hydrochloride buffer and common DNA extraction columns originally used for the extraction and purification of plasmids and cosmids. CONCLUSIONS: The proposed method can be used reproducibly for RNA isolation from a variety of plant species. It can also be used with infected plant tissue and fungal mycelia, which are typically recalcitrant to standard nucleic acid extraction procedures. PMID- 22260179 TI - Synthesis, magnetostructural correlation, and catalytic promiscuity of unsymmetric dinuclear copper(II) complexes: models for catechol oxidases and hydrolases. AB - Herein, we report the synthesis and characterization, through elemental analysis, electronic spectroscopy, electrochemistry, potentiometric titration, electron paramagnetic resonance, and magnetochemistry, of two dinuclear copper(II) complexes, using the unsymmetrical ligands N',N',N-tris(2-pyridylmethyl)-N-(2 hydroxy-3,5-di-tert-butylbenzyl)-1,3-propanediamin-2-ol (L1) and N',N'-bis(2 pyridylmethyl)-N,N-(2-hydroxybenzyl)(2-hydroxy-3,5-di-tert-butylbenzyl)-1,3 propanediamin-2-ol (L2). The structures of the complexes [Cu(2)(L1)(MU OAc)](ClO(4))(2).(CH(3))(2)CHOH (1) and [Cu(2)(L2)(MU OAc)](ClO(4)).H(2)O.(CH(3))(2)CHOH (2) were determined by X-ray crystallography. The complex [Cu(2)(L3)(MU-OAc)](2+) [3; L3 = N-(2-hydroxybenzyl)-N',N',N-tris(2 pyridylmethyl)-1,3-propanediamin-2-ol] was included in this study for comparison purposes only (Neves et al. Inorg. Chim. Acta2005, 358, 1807-1822). Magnetic data show that the Cu(II) centers in 1 and 2 are antiferromagnetically coupled and that the difference in the exchange coupling J found for these complexes (J = 4.3 cm(-1) for 1 and J = -40.0 cm(-1) for 2) is a function of the Cu-O-Cu bridging angle. In addition, 1 and 2 were tested as catalysts in the oxidation of the model substrate 3,5-di-tert-butylcatechol and can be considered as functional models for catechol oxidase. Because these complexes possess labile sites in their structures and in solution they have a potential nucleophile constituted by a terminal Cu(II)-bound hydroxo group, their activity toward hydrolysis of the model substrate 2,4-bis(dinitrophenyl)phosphate and DNA was also investigated. Double electrophilic activation of the phosphodiester by monodentate coordination to the Cu(II) center that contains the phenol group with tert-butyl substituents and hydrogen bonding of the protonated phenol with the phosphate O atom are proposed to increase the hydrolase activity (K(ass.) and k(cat.)) of 1 and 2 in comparison with that found for complex 3. In fact, complexes 1 and 2 show both oxidoreductase and hydrolase/nuclease activities and can thus be regarded as man made models for studying catalytic promiscuity. PMID- 22260180 TI - Quality of life in patients with Cushing's disease: a modern approach. PMID- 22260181 TI - Attachment efficiency of nanoparticle aggregation in aqueous dispersions: modeling and experimental validation. AB - To describe the aggregation kinetics of nanoparticles (NPs) in aqueous dispersions, a new equation for predicting the attachment efficiency is presented. The rationale is that at nanoscale, random kinetic motion may supersede the role of interaction energy in governing the aggregation kinetics of NPs, and aggregation could occur exclusively among the fraction of NPs with the minimum kinetic energy that exceeds the interaction energy barrier (E(b)). To justify this rationale, we examined the evolution of particle size distribution (PSD) and frequency distribution during aggregation, and further derived the new equation of attachment efficiency on the basis of the Maxwell-Boltzmann distribution and Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The new equation was evaluated through aggregation experiments with CeO(2) NPs using time-resolved dynamic light scattering (TR-DLS). Our results show that the prediction of the attachment efficiencies agreed remarkably well with experimental data and also correctly described the effects of ionic strength, natural organic matter (NOM), and temperature on attachment efficiency. Furthermore, the new equation was used to describe the attachment efficiencies of different types of engineered NPs selected from the literature and most of the fits showed good agreement with the inverse stability ratios (1/W) and experimentally derived results, although some minor discrepancies were present. Overall, the new equation provides an alternative theoretical approach in addition to 1/W for predicting attachment efficiency. PMID- 22260182 TI - Seroepidemiology of Klebsiella pneumoniae colonizing the intestinal tract of healthy Chinese and overseas Chinese adults in Asian countries. AB - BACKGROUND: Capsular serotypes K1 and K2 of Klebsiella pneumoniae are thought to the major virulence determinants responsible for liver abscess. The intestine is one of the major reservoirs of K. pneumoniae, and epidemiological studies have suggested that the majority of K. pneumoniae infections are preceded by colonization of the gastrointestinal tract. The possibility of fecal-oral transmission in liver abscess has been raised on the basis of molecular typing of isolates. Data on the serotype distribution of K. pneumoniae in stool samples from healthy individuals has not been previously reported. This study investigated the seroepidemiology of K. pneumoniae isolates from the intestinal tract of healthy Chinese in Asian countries. Stool specimens from healthy adult Chinese residents of Taiwan, Japan, Hong Kong, China, Thailand, Malaysia, Singapore, and Vietnam were collected from August 2004 to August 2010 for analysis. RESULTS: Serotypes K1/K2 accounted for 9.8% of all K. pneumoniae isolates from stools in all countries. There was no significant difference in the prevalence of K1/K2 isolates among the countries excluding Thailand and Vietnam. The antimicrobial susceptibility pattern was nearly the same in K. pneumoniae isolates. The result of pulsed-field gel electrophoresis revealed no major clonal cluster of serotype K1 isolates. CONCLUSIONS: The result showed that Chinese ethnicity itself might be a major factor predisposing to intestinal colonization by serotype K1/K2 K. pneumoniae isolates. The prevalent serotype K1/K2 isolates may partially correspond to the prevalence of K. pneumoniae liver abscess in Asian countries. PMID- 22260183 TI - Amniotic membrane-derived cells inhibit proliferation of cancer cell lines by inducing cell cycle arrest. AB - Cells derived from the amniotic foetal membrane of human term placenta have drawn particular attention mainly for their plasticity and immunological properties, which render them interesting for stem-cell research and cell-based therapeutic applications. In particular, we have previously demonstrated that amniotic mesenchymal tissue cells (AMTC) inhibit lymphocyte proliferation in vitro and suppress the generation and maturation of monocyte-derived dendritic cells. Here, we show that AMTC also significantly reduce the proliferation of cancer cell lines of haematopoietic and non-haematopoietic origin, in both cell-cell contact and transwell co-cultures, therefore suggesting the involvement of yet-unknown inhibitory soluble factor(s) in this 'cell growth restraint'. Importantly, we provide evidence that the anti-proliferative effect of AMTC is associated with induction of cell cycle arrest in G0/G1 phase. Gene expression analyses demonstrate that AMTC can down-regulate cancer cells' mRNA expression of genes associated with cell cycle progression, such as cyclins (cyclin D2, cyclin E1, cyclin H) and cyclin-dependent kinase (CDK4, CDK6 and CDK2), whilst they up regulate cell cycle negative regulator such as p15 and p21, consistent with a block in G0/G1 phase with no progression to S phase. Taken together, these findings warrant further studies to investigate the applicability of these cells for controlling cancer cell proliferation in vivo. PMID- 22260185 TI - Relationship of serum and saliva calcium, phosphorus and alkaline phosphatase with dry mouth feeling in menopause. AB - OBJECTIVES: The aim of this study was to compare serum and saliva calcium, phosphorus and alkaline phosphatase of menopausal women with/without dry mouth (DM) feeling. BACKGROUND: The composition of saliva in menopause women with/without DM feeling is different. Some of these differences are in hormones that are related to bone turnover. METHODS: A case-control study was carried out on 60 selected menopausal women aged 45-79 years with or without DM feeling (30 as case, 30 as control), conducted at the Clinic of Oral Medicine, Tehran University of Medical Sciences. The phosphorus concentration was measured by photometrical measurement of the blue colour formed after the addition of ammonium molybdate and stannous chloride; calcium was measured by Arsenazo reaction; and alkaline phosphatase by the pNPP-AMP method. Statistical analysis of Student's t-test was used. RESULTS: The mean serum phosphorus and alkaline phosphatase, stimulated and unstimulated saliva calcium and alkaline phosphatase levels were significantly higher in the menopausal women suffering from DM. There were no significant differences between groups regarding saliva phosphorus and serum calcium concentration. CONCLUSION: Calcium, phosphorus and alkaline phosphatase appear associated with DM feeling in menopause. PMID- 22260186 TI - Use of the Ethicon EndoSurgery anoscope retractor for anorectal procedures other than stapled haemorrhoidectomy. PMID- 22260184 TI - Oxidative and pre-inflammatory stress in wedge resection of pulmonary parenchyma using the radiofrequency ablation technique in a swine model. AB - BACKGROUND: Radiofrequency ablation (RFA) is a thermal energy delivery system used for coagulative cellular destruction of small tumors through percutaneous or intraoperative application of its needle electrode to the target area, and for assisting partial resection of liver and kidney. We tried to evaluate the regional oxidative and pre-inflammatory stress of RFA-assisted wedge lung resection, by measuring the MDA and tumor Necrosis Factor Alpha (TNF-alpha) concentration in the resected lung tissue of a swine model. METHOD: Fourteen white male swines, divided in two groups, the RFA-group and the control group (C group) underwent a small left thoracotomy and wedge lung resection of the lingula. The wedge resection in the RFA-group was performed using the RFA technique whereas in C-group the simple "cut and sew" method was performed. We measured the malondialdehyde (MDA) and TNF-alpha concentration in the resected lung tissue of both groups. RESULTS: In C-group the MDA mean deviation rate was 113 +/- 42.6 whereas in RFA-group the MDA mean deviation rate was significantly higher 353 +/- 184 (p = 0.006). A statistically significant increase in TNF-alpha levels was also observed in the RFA-group (5.25 +/- 1.36) compared to C-group (mean +/- SD = 8.48 +/- 2.82) (p = 0.006). CONCLUSION: Our data indicate that RFA assisted wedge lung resection in a swine model increases regional MDA and TNF-a factors affecting by this oxidative and pre-inflammatory stress of the procedure. Although RFA-assisted liver resection can be well tolerated in humans, the possible use of this method to the lung has to be further investigated in terms of regional and systemic reactions and the feasibility of performing larger lung resections. PMID- 22260187 TI - Mild traumatic brain injury. AB - Traumatic Brain Injury (TBI) is among the most frequent neurological disorders. Of all TBIs 90% are considered mild with an annual incidence of 100-300/100.000. Intracranial complications of Mild Traumatic Brain Injury (MTBI) are infrequent (10%), requiring neurosurgical intervention in a minority of cases (1%), but potentially life-threatening (case fatality rate 0,1%). Hence, a true health management problem exists because of the need to exclude the small chance of a life threatening complication in large numbers of individual patients. The 2002 EFNS guidelines used a best evidence approach based on the literature until 2001 to guide initial management with respect to indications for CT, hospital admission, observation and follow up of MTBI patients. This updated EFNS guideline version for initial management inMTBI proposes a more selectively strategy for CT when major (dangerous mechanism, GCS<15, 2 points deterioration on the GCS, clinical signs of (basal) skull fracture, vomiting, anticoagulation therapy, post traumatic seizure) or minor (age, loss of consciousness, persistent anterograde amnesia, focal deficit, skull contusion, deterioration on the GCS) risk factors are present based on published decision rules with a high level of evidence. In addition clinical decision rules for CT now exist for children as well. Since 2001 recommendations, although with a lower level of evidence, have been published for clinical in hospital observation to prevent and treat other potential threads to the patient including behavioral disturbances (amnesia, confusion and agitation) and infection. PMID- 22260190 TI - A single g factor is not necessary to simulate positive correlations between cognitive tests. AB - In the area of abilities testing, one issue of continued dissent is whether abilities are best conceptualized as manifestations of a single underlying general factor or as reflecting the combination of multiple traits that may be dissociable. The fact that diverse cognitive tests tend to be positively correlated has been taken as evidence for a single general ability or "g" factor. In the present study, simulations of test performance were run to evaluate the hypothesis that multiple independent abilities that affect test performance in a consistent manner will produce a positive manifold. Correlation matrices were simulated from models using either one or eight independent factors. The extent to which these factors operated in a consistent manner across tests (i.e., that a factor that facilitates performance on one test tends to facilitate performance on other tests) was manipulated by varying the mean value of the randomly selected weights. The tendency of both a single factor and eight independent factors to produce positive correlations increased as the randomly selected weights operated in a more consistent fashion. Thus the presence of a positive manifold in the correlations between diverse cognitive tests does not provide differential support for either single factor or multiple factor models of general abilities. PMID- 22260191 TI - The affecting factors and comparison of tuberculin skin test in peritoneal dialysis and hemodialysis patients. AB - Compared with the general population, patients with chronic renal failure have increased tuberculosis (TB) prevalence and mortality rates. In this study, we aimed to investigate tuberculin skin test (TST) positivity rates in hemodialysis (HD) and peritoneal dialysis (PD) patients and the factors influencing TST positivity. Ninety-two HD patients and 44 PD patients who had been on HD and PD treatment for at least 3 months were recruited into the study. TST was administered in all patients. Positivity was defined as an induration diameter >10 mm. At least 5 mm of induration following skin testing together with a chest radiography indicating previous infection was defined as latent TB infection. TST positivity rates, diameter of TST indurations, and serum albumin levels in HD patients were higher than the PD patients. TST induration size was not correlated with any other parameters in both HD and PD groups. TST-positive patients had higher albumin levels and lower leukocyte count than the TST-negative patients. In TST-positive patients, albumin level was correlated with the duration of dialysis but TST induration size was not correlated with the lymphocyte count and albumin level. In our study, TST positivity of patients was found in 30.4% of HD patients, 9% of PD patients, and 23.5% of total patients. It is still recommended to use TST for the screening test of TB. We found a significant relationship between TST and albumin level. It should be remembered that TST response may be lower in PD patients, especially in cases in which TB is suspected. PMID- 22260193 TI - Fast, high-throughput creation of size-tunable micro/nanoparticle clusters via evaporative self-assembly in picoliter-scale droplets of particle suspension. AB - We report a fast, high-throughput method to create size-tunable micro/nanoparticle clusters via evaporative assembly in picoliter-scale droplets of particle suspension. Mediated by gravity force and surface tension force of a contacting surface, picoliter-scale droplets of the suspension are generated from a nanofabricated printing head. Rapid evaporative self-assembly of the particles on a hydrophobic surface leads to fast clustering of micro/nanoparticles and forms particle clusters of tunable sizes and controlled spacing. The evaporating behavior of the droplet is observed in real-time, and the clustering characteristics of the particles are understood based on the physics of evaporative-assembly. With this method, multiplex printing of various particle clusters with accurate positioning and alignment are demonstrated. Also, size unifomity of the cluster arrays is thoroughly analyzed by examining the metallic nanoparticle cluster-arrays based on surface-enhanced Raman spectroscopy (SERS). PMID- 22260194 TI - Constraints on competitive performance of attacker-defender dyads in team sports. AB - Previous research on coordination dynamics of 1 vs. 1 sub-phases in team sports has reported stable emergent patterns of coordination in the displacement trajectories of attackers and defenders. The aim of this study was to use attacker-defender interactions in competitive team match-play to investigate how the locations of the goal and ball constrain the pattern-forming dynamics of attacker-defender dyadic systems. Ten high-level futsal matches were filmed and 13 goal sequences selected for analysis. Displacements of the players and the ball were filmed and digitized from 52 attacker-defender dyadic system interactions. Results showed that, although attackers and defenders exhibited similar angular orientations to the goal, the latter always remained closer to the goal than attackers. Observations revealed that in-phase patterns of coordination emerged from changes to both the distances and angles of attackers and defenders to the goal. Attackers always remained closer to the ball than defenders, while the latter exhibited a lower angle to the ball than attackers. A pattern of in-phase coordination modes emerged between the attackers and defenders' distances and angles to the ball. This study helps us to understand interpersonal interactions in team sports by explaining how attackers and defenders use information about their relative positioning to the goal and the ball to perform successfully. PMID- 22260195 TI - The GLAMA (Girls! Lead! Achieve! Mentor! Activate!) physical activity and peer leadership intervention pilot project: a process evaluation using the RE-AIM framework. AB - BACKGROUND: Implementing new initiatives and physical activity interventions in schools represents a myriad of challenges that if overcome can potentially facilitate a range of behavioural changes. The aim of this paper is to describe the process evaluation of specific design constructs used in the GLAMA (Girls! Lead! Achieve! Mentor! Activate!) peer leadership and physical activity pilot project. Conducted in a state secondary school in Australia, the intervention was designed to provide students with opportunities to develop leadership skills, school and social connectedness in addition to a range of physical activity experiences. METHODS: This process evaluation used the RE-AIM (Reach, Efficacy, Adoption, Implementation and Maintenance) health promotion evaluation framework to assess three design constructs of the intervention: the effectiveness of leadership training and leader preparedness, activity suitability and participation, and the barriers to implementation of the intervention and potential solutions to overcome these barriers. As it was not the specific aim of this pilot, no behavioural change data were collected from students. Data were collected using a mixed methods approach including student questionnaires, teachers and researchers reporting on their own observations and feedback from students. RESULTS: There were three main considerations evident across more than one RE-AIM dimension that need to be addressed to assist with future GLAMA dissemination. Firstly, the development of teacher, school and student participation. This needs to be through a variety of professional development opportunities for teachers, integration of the program within timetabled classes within the school and promoting the program to students as an opportunity to develop a range of skills to apply to future learning and workplace environments. Secondly, the successful translation of leadership training to practice is necessary to ensure that leaders are effectively able to motivate, facilitate and activate their teams. Finally, the need for consistent activity implementation requires sequential, competitive elements, purposeful team selection and clearly defined scoring and time periods for team 'challenges'. CONCLUSIONS: Factors that have the greatest impact on intervention success are those that come from within the school setting including: the structure of the curriculum, pressure to meet curriculum and assessment content, lack of support for new initiatives, multiple programs already running within the school, time allowances for teachers, appropriate training for teachers, and support for students to participate. These barriers need to be considered when developing all secondary school interventions. PMID- 22260196 TI - Automatic tracking of individual migrating cells using low-magnification dark field microscopy. AB - Many fundamental biological processes, such as the search for food, immunological responses and wound healing, depend on cell migration. Video microscopy allows the magnitude and direction of cell migration to be documented. Here, we present a simple and inexpensive method for simultaneous tracking of hundreds of migrating cells over periods of several days. Low-magnification dark-field microscopy was used to visualize individual cells whereas time-lapse video images were acquired by computer for future analysis. We employed an automated tracking algorithm to identify individual cells on each video image allowing migration paths to be tracked using a nearest neighbour algorithm. To test the method, we followed the time-course of migration of 3T3 fibroblasts, endothelial cells and individual amoeba in the absence of any chemical stimulus gradient. All cell types showed a 'random walk' behaviour in which mean squared displacement in position increased linearly with time. We defined a 'migration coefficient' (D(mig)), analogous to a diffusion coefficient, which gave an estimate of cell migration rate. D(mig) depended on cell type and temperature. When amoebas were made to undergo chemotaxis, the cells no longer followed a random walk but instead moved at a near constant velocity (V(av)) towards the chemotactic stimulus. PMID- 22260197 TI - Agonistic autoantibodies to the alpha(1) -adrenergic receptor and the beta(2) adrenergic receptor in Alzheimer's and vascular dementia. AB - Although primary causes of Alzheimer's and vascular dementia are unknown, the importance of preceding vascular lesions is widely accepted. Furthermore, there is strong evidence for the involvement of autoimmune mechanisms. Here, we report the presence of agonistic autoantibodies directed at adrenergic receptors in the circulation of patients with mild to moderate Alzheimer's and vascular dementia. In 59% of these patients, agonistic autoantibodies against the alpha(1) adrenergic receptor and the beta(2) -adrenergic receptor were identified. The majority of positive patients (66%) contained both types of autoantibodies in combination. In a control group of patients with neurological impairments others than Alzheimer's and vascular dementia, only 17% were found to harbour these autoantibodies. The autoantibodies to the alpha(1) -adrenergic receptor interacted preferably with the extracellular loop1 of the receptor. They were further studied in IgG preparations from the column regenerate of a patient who underwent immunoadsorption. The alpha(1) -adrenergic receptor autoantibodies specifically bound to the extracellular loop1 peptide of the receptor with an apparent EC(50) value of 30 nm. They mobilized intracellular calcium in a clonal cell line expressing the human form of the alpha(1) -adrenergic receptor. Our data support the notion that autoimmune mechanisms play a significant role in the pathogenesis of Alzheimer's and vascular dementia. We suggest that agonistic autoantibodies to the alpha(1) -adrenergic and the beta(2) -adrenergic receptor may contribute to vascular lesions and increased plaque formation. PMID- 22260198 TI - Extraction of the antimicrobial peptide cerein 8A by aqueous two-phase systems and aqueous two-phase micellar systems. AB - Cerein 8A is an antimicrobial peptide with potential application against food spoilage and pathogenic bacteria. The partitioning of cerein 8A was investigated in two liquid-liquid extraction systems that are considered promising for bioseparation and purification purposes. Aqueous two-phase systems (ATPSs) were prepared with polyethylene glycol (PEG) and inorganic salts, and the addition of NaCl was investigated in this system. The best results concerning partition coefficients (K (b)) were obtained with PEG + ammonium sulphate, and K (b) value significantly increases when NaCl was added. Cerein 8A was effectively extracted into the micelle-rich phase in a 4% Triton X-114 medium. Recovery yield was higher for ATPS compared to micellar systems. Cerein 8A can be isolated from a crude suspension containing the bioactive molecule by ATPSs. Successful implementation of peptide partitioning represents an important step towards developing a low-cost effective separation method for cerein 8A. PMID- 22260199 TI - Venous flow dynamics during spinal block in normotensive and hypertensive elderly patients: a duplex ultrasonographic study. AB - BACKGROUND: Spinal block induces hyperkinetic change in lower extremity blood flow. We compared the venous flow dynamic responses to spinal block in normotensive and hypertensive elderly patients. METHODS: Following spinal block using 10 mg 0.5% (w/v) bupivacaine, we measured changes in blood pressure, heart rate, and venous flow dynamics of the popliteal vein by duplex ultrasonography in 20 normotensive (NBP group) and 18 hypertensive (HIBP group) patients. RESULTS: Spinal block caused significant decreases in blood pressure in both groups; similar rates of hypotension were observed. At baseline, peak velocity, time averaged maximum velocity, and time-averaged mean velocity were higher in the HIBP than in the NBP group. During spinal block, peak velocity increased in both groups, and the between-group differences were no longer significant. At baseline, volume flow in the two groups was similar and increased by 141.5% in the NBP and 131.7% in the HIBP group during spinal block. CONCLUSIONS: Blood pressure and flow dynamics in the popliteal vein showed similar changes during spinal anaesthesia in elderly patients taking antihypertensive medication and normotensive patients, despite differences in baseline values. PMID- 22260200 TI - Turning on red and near-infrared phosphorescence in octahedral complexes with metalated quinones. AB - We report the synthesis of pi-bonded ruthenium, rhodium, and iridium o benzoquinones [Cp*M(o-C(6)H(4)O(2))](n) [M = Ru (2), n = 1-; Rh (3), n = 0; Ir (4), n = 0] following a novel synthetic procedure. Compounds 2-4 were fully characterized by spectroscopic methods and used as chelating organometallic linkers, "OM-linkers", toward luminophore bricks such as Ru(bpy)(2)(2+), Rh(ppy)(2)(+), and Ir(ppy)(2)(+) (bpy = 2,2'-bipyridine; ppy = 2-phenylpyridine) for the design of a novel family of octahedral bimetallic complexes of the general formula [(L-L)(2)M(OM-linkers)][X](m) (X = counteranion; m = 0, 1, 2) whose luminescent properties depend on the choice of the OM-linker and the luminophore brick. Thus, dinuclear assemblies such as [(bpy)(2)Ru(2)][OTf] (5 OTf), [(bpy)(2)Ru(2)][Delta-TRISPHAT] (5-DeltaT) {TRISPHAT = tris[tetrachlorobenzene-1,2-bis(olato)]phosphate}, [(bpy)(2)Ru(3)][OTf](2) (6 OTf), [(bpy)(2)Ru(4)][OTf](2) (7-OTf), [(bpy)(2)Ru(4)][Delta-TRISPHAT](2) (7 DeltaT), [(ppy)(2)Rh(2)] (8), [(ppy)(2)Rh(3)][OTf] (9-OTf), [(ppy)(2)Rh(4)][OTf] (10-OTf), [(ppy)(2)Rh(4)][Delta-TRISPHAT] (10-DeltaT), [(ppy)(2)Ir(2)] (11), [(ppy)(2)Ir(3)][OTf] (12-OTf), [(ppy)(2)Ir(4)][OTf] (13-OTf), and [(ppy)(2)Ir(4)][Delta-TRISPHAT] (13-DeltaT) were prepared and fully characterized. The X-ray molecular structures of three of them, i.e., 5-OTf, 8, and 11, were determined. The structures displayed a main feature: for instance, the two oxygen centers of the OM-linker [Cp*Ru(o-C(6)H(4)O(2))](-) (2) chelate the octahedral chromophore metal center, whether it be ruthenium, rhodium, or iridium. Further, the carbocycle of the OM-linker 2 adopts a eta(4)-quinone form but with some catecholate contribution due to metal coordination. All of these binuclear assemblies showed a wide absorption window that tailed into the near-IR (NIR) region, in particular in the case of the binuclear ruthenium complex 5-OTf with the anionic OM-linker 2. The latter feature is no doubt related to the effect of the OM-linker, which lights up the luminescence in these homo- and heterobinuclear compounds, while no effect has been observed on the UV-visible and emission properties because of the counteranion, whether it be triflate (OTf) or Delta-TRISPHAT. At low temperature, all of these compounds become luminescent; remarkably, the o-quinonoid linkers [Cp*M(o-C(6)H(4)O(2))](n) (2-4) turn on red and NIR phosphorescence in the binuclear octahedral species 5-7. This trend was even more observable when the ruthenium OM-linker 2 was employed. These assemblies hold promise as NIR luminescent materials, in contrast to those made from organic 1,2-dioxolene ligands that conversely are not emissive. PMID- 22260201 TI - The History, present state, and future prospects of the Asian College of Psychosomatic Medicine (ACPM). AB - The Asian College of Psychosomatic Medicine (ACPM) was founded as the Asian Chapter of the International College of Psychosomatic Medicine (ICPM-AC) in Tokyo on April 12, 1982.The first president was Hitoshi ISHIKAWA (Japan), the vice presidents were Mahalingam MAHADEVAN (Malaysia) and Burton G.BURTON-BRADLEY (Papua- New Guinea), and the general secretary was Sueharu TSUTSUI (Japan).Five years previously, preparation for creation of the ICPM-AC was started at the 4th World Congress of the International College of Psychosomatic Medicine (ICPM) held in Kyoto, Japan, September 5-9, 1977.The First Congress of the ICPM-AC was held by the President Yujiro IKEMI in Tokyo on May 19-20, 1984. The main members in the early stage were Y. IKEMI, H. ISHIKAWA, S. TSUTSUI, Taisaku KATSURA, Tetsuya NAKAGAWA. Hiroyuki SUEMATSU and others from Japan and Hsien RIN (Taiwan), Seock Young KANG (Korea), M. MAHADEVAN. B.G. BURTON-BRADLEY and others from other Asian countries.Thereafter, academic congresses of the ICPM-AC, the 2nd to the 9th, were held approximately every two years, in Japan, India, Malaysia, Taiwan, Korea, and China. The name was changed to the Asian College of Psychosomatic Medicine (ACPM), and the 10th to 14th congresses were held in Taiwan, Okinawa (Japan), Australia, Korea, and China.The current president of the Executive Board of ACPM is Chiharu KUBO, the Director of Kyushu University Hospital.The next academic congress is the 15th ACPM and will be hosted by Tserenkhuugyin LKHAGVASUREN in Ulaanbaatar, Mongolia from August 24-26, 2012.Participating countries have expanded to include Asian-Oceanic countries such as Mongolia, Micronesia, Australia and Sri Lanka.The main themes of the congresses have focused on psychosomatic disorders, culture - bound syndromes, oriental medicine, etc... To date,"Health promotion"by raising the level of mental health based on psychoneuroendocrinoimmunomodulation has been very important. Prevention is also important in the Asia - Oceana area, from the viewpoints of both psychosomatics and culture.Above all, an awareness of existential, authentic health is a sure way to promote healthy longevity and psychosomatic well - being.To pursue happiness and well-being subjectively, objectively, and ecologically will be the most important purposes of ACPM in the future. PMID- 22260202 TI - Benzofurans or isochromenes via the ring-opening cyclization of cyclopropene derivatives with organolithiums. AB - A new and efficient approach to benzocycles from cyclopropene derivatives is described. Deprotection by organolithiums and subsequent ring-opening cyclization of the related 2-cyclopropenyl phenyl or benzyl acetates generated benzofurans and isochromenes in one pot. PMID- 22260203 TI - [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: antagonists of the Wnt pathway that inhibit tankyrases 1 and 2 via novel adenosine pocket binding. AB - The Wnt signaling pathway is critical to the regulation of key cellular processes. When deregulated, it has been shown to play a crucial role in the growth and progression of multiple human cancers. The identification of small molecule modulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggable nodes in this pathway. Several recent publications have identified small molecule inhibitors of the Wnt pathway, and tankyrase (TNKS) inhibition has been demonstrated to antagonize Wnt signaling via axin stabilization. Herein, we report the early hit assessment of a series of compounds previously reported to antagonize Wnt signaling. We report the biophysical, computational characterization, structure-activity relationship, and physicochemical properties of a novel series of [1,2,4]triazol-3 ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole inhibitors of TNKS1 and 2. Furthermore, a cocrystal structure of compound 24 complexed to TNKS1 demonstrates an alternate binding mode for PARP family member proteins that does not involve interactions with the nicotinamide binding pocket. PMID- 22260204 TI - Glucose can promote a glucocorticoid resistance state. AB - It has been shown that ingestion of glucose, amino acids, protein or mixed meals tends to increase serum and salivary cortisol concentrations in healthy adults. Recently, it has been demonstrated that morning glucose ingestion stimulates pulsatile cortisol and adrenocorticotropic hormone (ACTH) secretion, thus elevating their mean concentrations. In light of the above, a question arises: could the frequent food--and specifically glucose--consumption lead to hypercortisolism with possible clinical implications? And can the human body, under normal conditions raise defence mechanisms against the transient hypercortisolism caused by the frequent glucose consumption? Studies have revealed novel mechanisms, which are implicated in the glucocorticoid receptor (GR)-mediated action, providing a kind of glucocorticoid resistance. This glucocorticoid resistance could be mediated through both enhancing acetylation (via, among others, regulation of essential clock genes such as Per) and inhibiting deacetylation of GR (via possible regulation of sirtuin activity). Interestingly, the acetylation/deacetylation processes seem to be regulated by glucose. Thus, glucose apart from causing increased cortisol secretion can, simultaneously, counter-regulate this hypercortisolism, by promoting directly and/or indirectly a glucocorticoid resistance state. Undoubtedly, before extracting conclusions regarding the clinical significance of the increased cortisol secretion following glucose ingestion, we should first thoroughly investigate the 'defence' mechanisms provided by 'nature' to handle this hypercortisolism. PMID- 22260205 TI - Robust non-linear differential equation models of gene expression evolution across Drosophila development. AB - BACKGROUND: This paper lies in the context of modeling the evolution of gene expression away from stationary states, for example in systems subject to external perturbations or during the development of an organism. We base our analysis on experimental data and proceed in a top-down approach, where we start from data on a system's transcriptome, and deduce rules and models from it without a priori knowledge. We focus here on a publicly available DNA microarray time series, representing the transcriptome of Drosophila across evolution from the embryonic to the adult stage. RESULTS: In the first step, genes were clustered on the basis of similarity of their expression profiles, measured by a translation-invariant and scale-invariant distance that proved appropriate for detecting transitions between development stages. Average profiles representing each cluster were computed and their time evolution was analyzed using coupled differential equations. A linear and several non-linear model structures involving a transcription and a degradation term were tested. The parameters were identified in three steps: determination of the strongest connections between genes, optimization of the parameters defining these connections, and elimination of the unnecessary parameters using various reduction schemes. Different solutions were compared on the basis of their abilities to reproduce the data, to keep realistic gene expression levels when extrapolated in time, to show the biologically expected robustness with respect to parameter variations, and to contain as few parameters as possible. CONCLUSIONS: We showed that the linear model did very well in reproducing the data with few parameters, but was not sufficiently robust and yielded unrealistic values upon extrapolation in time. In contrast, the non-linear models all reached the latter two objectives, but some were unable to reproduce the data. A family of non-linear models, constructed from the exponential of linear combinations of expression levels, reached all the objectives. It defined networks with a mean number of connections equal to two, when restricted to the embryonic time series, and equal to five for the full time series. These networks were compared with experimental data about gene transcription factor and protein-protein interactions. The non-uniqueness of the solutions was discussed in the context of plasticity and cluster versus single gene networks. PMID- 22260206 TI - Involvement of cytochrome c CymA in the anaerobic metabolism of RDX by Shewanella oneidensis MR-1. AB - Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a cyclic nitramine explosive commonly used for military applications that is responsible for severe soil and groundwater contamination. In this study, Shewanella oneidensis MR-1 was shown to efficiently degrade RDX anaerobically (3.5 umol.h(-1).(g protein)(-1)) via two initial routes: (1) sequential N-NO(2) reductions to the corresponding nitroso (N NO) derivatives (94% of initial RDX degradation) and (2) denitration followed by ring cleavage. To identify genes involved in the anaerobic metabolism of RDX, a library of ~2500 mutants of MR-1 was constructed by random transposon mutagenesis and screened for mutants with a reduced ability to degrade RDX compared with the wild type. An RDX-defective mutant (C9) was isolated that had the transposon inserted in the c-type cytochrome gene cymA. C9 transformed RDX at ~10% of the wild-type rate, with degradation occurring mostly via early ring cleavage caused by initial denitration leading to the formation of methylenedinitramine, 4-nitro 2,4-diazabutanal, formaldehyde, nitrous oxide, and ammonia. Genetic complementation of mutant C9 restored the wild-type phenotype, providing evidence that electron transport components have a role in the anaerobic reduction of RDX by MR-1. PMID- 22260207 TI - Potato CONSTANS is involved in photoperiodic tuberization in a graft transmissible manner. AB - CONSTANS (CO) is involved in the photoperiodic control of plant developmental processes, including flowering in several species and seasonal growth cessation and bud set in trees. It has been proposed that CO could also affect the day length regulation of tuber induction in Solanum tuberosum (potato), a plant of great agricultural relevance. To address this question, we examined the role of CO in potato. A potato CO-like gene, StCO, was identified and found to be highly similar to a previously reported potato gene of unknown function. Potato plants overexpressing StCO tuberized later than wild-type plants under a weakly inductive photoperiod. StCO silencing promoted tuberization under both repressive and weakly inductive photoperiods, but did not have any effect under strongly inductive short days, demonstrating that StCO represses tuberization in a photoperiod-dependent manner. The effect of StCO on tuber induction was transmitted through grafts. In addition, StCO affected the mRNA levels of StBEL5 a tuberization promoter, the mRNA of which moves long distances in potato plants - and StFT/StSP6A, a protein highly similar to FLOWERING LOCUS T (FT), which is a key component of systemic flowering signals in other species. We also found that StFT/StSP6A transcript levels correlate with the induction of tuber formation in wild-type plants. These results show that StCO plays an important role in photoperiodic tuberization and, together with the recent demonstration that StFT/StSP6A promotes tuberization, indicate that the CO/FT module participates in controlling this process. Moreover, they support the notion that StCO is involved in the expression of long-distance regulatory signals in potato, as CO does in other species. PMID- 22260208 TI - Can arsenic occurrence rates in bedrock aquifers be predicted? AB - A high percentage (31%) of groundwater samples from bedrock aquifers in the greater Augusta area, Maine was found to contain greater than 10 MUg L(-1) of arsenic. Elevated arsenic concentrations are associated with bedrock geology, and more frequently observed in samples with high pH, low dissolved oxygen, and low nitrate. These associations were quantitatively compared by statistical analysis. Stepwise logistic regression models using bedrock geology and/or water chemistry parameters are developed and tested with external data sets to explore the feasibility of predicting groundwater arsenic occurrence rates (the percentages of arsenic concentrations higher than 10 MUg L(-1)) in bedrock aquifers. Despite the under-prediction of high arsenic occurrence rates, models including groundwater geochemistry parameters predict arsenic occurrence rates better than those with bedrock geology only. Such simple models with very few parameters can be applied to obtain a preliminary arsenic risk assessment in bedrock aquifers at local to intermediate scales at other localities with similar geology. PMID- 22260209 TI - Evaluation of the efficacy of two mouthrinses formulated for the relief of xerostomia of diverse origin in adult subjects. AB - OBJECTIVE: To evaluate the efficacy of two new mouthrinses in the reduction of xerostomia-associated symptomatology. BACKGROUND: Xerostomia is a common chronic health condition that affects a great number of adults and significantly deteriorates quality of life, such that treatment is necessary. MATERIALS AND METHODS: Sixty-seven adult subjects of both sexes presenting xerostomia of diverse origin were selected. Mouthrinses were tested using a double-blind, randomized, cross-over clinical trial with an intervining wash out period. RESULTS: The 100% of subjects presented sensation of dry mouth, and 86% stated sensation of thick saliva. Burning tongue sensation, need to drink liquids to swallow and the sensation of swallowing difficulty were recorded in more than 50% of the patients. The most frequent pathologies in the sample were depression, arthritis, and arterial hypertension. Results of the clinical tests showed that mouthrinse 1 relieves sensation of dry mouth, need to drink liquids, and swallowing difficulty. In contrast, mouthrinse 2 relieves only latter two symptoms. Both rinses were more effective in relieving xerostomia-associated symptomatology in patients taking 3 or more medicines simultaneously. CONCLUSION: Both mouthrinses were effective in relieving various xerostomia symptoms, could be distributed at a low cost, thereby improving the quality of life of population affected. PMID- 22260210 TI - Chemical enhancement by nanomaterials under X-ray irradiation. AB - We report here a new phenomenon of dynamic enhancement of chemical reactions by nanomaterials under hard X-ray irradiation. The nanomaterials were gold and platinum nanoparticles, and the chemical reaction employed was the hydroxylation of coumarin carboxylic acid. The reaction yield was enhanced 2000 times over that predicted on the basis of the absorption of X-rays only by the nanoparticles, and the enhancement was found for the first time to depend on the X-ray dose rate. The maximum turnover frequency was measured at 1 * 10(-4) s(-1) Gy(-1). We call this process chemical enhancement, which is defined as the increased yield of a chemical reaction due to the chemical properties of the added materials. The chemical enhancement described here is believed to be ubiquitous and may significantly alter the outcome of chemical reactions under X-ray irradiation with the assistance of nanomaterials. PMID- 22260212 TI - Effects of stimulation site and stimulation parameters on bladder inhibition by electrical nerve stimulation. AB - What's known on the subject? and What does the study add? Electrical stimulation of the dorsal nerve of the penis, the compound pudendal nerve and the S1 sacral nerve have been used clinically to treat the symptoms of overactive bladder, but the relative efficacy of the three locations was unclear and the optimal stimulation parameters across locations had not been determined. In the present paper we quantified the effects of acute electrical stimulation location, frequency and amplitude on isovolumetric reflex bladder contractions and maximum cystometric capacity in anaesthetized male cats. Our results could influence the selection of anatomical targets for clinical neuromodulation and how neuromodulation devices are programmed. OBJECTIVE: To quantify the effects of acute electrical stimulation frequency and amplitude at the dorsal nerve of the penis (DNP), pudendal nerve (PN) and S1 sacral nerve (S1) on isovolumetric reflex bladder contractions and maximum cystometric capacity in anaesthetized male cats. MATERIALS AND METHODS: Experiments were conducted in 14 adult male cats anaesthetized with alpha-chloralose. The effects of stimulation on the pressure - time integral of reflex bladder contractions were evaluated using a randomized block design with the following factors randomized: stimulation intensity (0.8, 1, or 2 * the threshold for evoking a reflex electromyogram response in the external anal sphincter [T]), frequency (2 Hz, 5 Hz, 7.5 Hz, 10 Hz, 15 Hz, 20 Hz, or 33 Hz) and location (PN, S1 or DNP). The effects of stimulation (with parameters that produced maximum inhibition of isovolumetric bladder contractions) on cystometric capacity were evaluated using a randomized block design, with the order of stimulation location randomized and control trials interleaved with stimulation trials. RESULTS: Inhibition of isovolumetric bladder contractions was significantly dependent on stimulation location, frequency, amplitude and the interactions between any two of these variables. Stimulation of the DNP, at 5 Hz, 7.5 Hz or 10 Hz, and at 2T caused greater reductions in normalized bladder contraction area than any other location, frequency or amplitude tested. Stimulation of the PN or S1 at 7.5 Hz or 10 Hz and 2T, or of the DNP at 5 Hz, 7.5 Hz or 10 Hz and 0.8T, 1T or 2T generated maximum inhibition of isovolumetric bladder contractions. Cystometric capacity was significantly larger with stimulation (10 Hz, 1T-2T) than control. There was no significant difference in cystometric capacity based upon stimulation location. CONCLUSIONS: There was no significant difference in the maximum degree to which the respective optimum parameters inhibited bladder contractions or increased cystometric capacity by location. The range of amplitudes and frequencies that caused maximum inhibition was larger for DNP stimulation than for PN or S1 stimulation. These findings have implications on the selection of anatomical target and device programming for clinical neuromodulation for treatment of the symptoms of overactive bladder. PMID- 22260213 TI - Electrochromic properties of a metallo-supramolecular polymer derived from tetra(2-pyridyl-1,4-pyrazine) ligands integrated in thin multilayer films. AB - The electrochromic behavior of iron complexes derived from tetra-2-pyridyl-1,4 pyrazine (TPPZ) and a hexacyanoferrate species in polyelectrolytic multilayer adsorbed films is described for the first time. This complex macromolecule was deposited onto indium-tin oxide (ITO) substrates via self-assembly, and the morphology of the modified electrodes was studied using atomic force microscopy (AFM), which indicated that the hybrid film containing the polyelectrolyte multilayer and the iron complex was highly homogeneous and was approximately 50 nm thick. The modified electrodes exhibited excellent electrochromic behavior with both intense and persistent coloration as well as a chromatic contrast of approximately 70%. In addition, this system achieved high electrochromic efficiency (over 70 cm(2) C(-1) at 630 nm) and a response time that could be measured in milliseconds. The electrode was cycled more than 10(3) times, indicating excellent stability. PMID- 22260211 TI - Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. AB - BACKGROUND: Exposure to ethanol during early development triggers severe neuronal death by activating multiple stress pathways and causes neurological disorders, such as fetal alcohol effects or fetal alcohol syndrome. This study investigated the effect of ethanol on intracellular events that predispose developing neurons for apoptosis via calcium-mediated signaling. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, mitochondrial dysfunction, altered calcium homeostasis and apoptosis-related proteins have been implicated in ethanol neurotoxicity. The present study was designed to evaluate the neuroprotective mechanisms of metformin (Met) and thymoquinone (TQ) during ethanol toxicity in rat prenatal cortical neurons at gestational day (GD) 17.5. RESULTS: We found that Met and TQ, separately and synergistically, increased cell viability after ethanol (100 mM) exposure for 12 hours and attenuated the elevation of cytosolic free calcium [Ca2+]c. Furthermore, Met and TQ maintained normal physiological mitochondrial transmembrane potential (DeltapsiM), which is typically lowered by ethanol exposure. Increased cytosolic free [Ca2+]c and lowered mitochondrial transmembrane potential after ethanol exposure significantly decreased the expression of a key anti-apoptotic protein (Bcl-2), increased expression of Bax, and stimulated the release of cytochrome-c from mitochondria. Met and TQ treatment inhibited the apoptotic cascade by increasing Bcl-2 expression. These compounds also repressed the activation of caspase-9 and caspase-3 and reduced the cleavage of PARP-1. Morphological conformation of cell death was assessed by TUNEL, Fluoro-Jade-B, and PI staining. These staining methods demonstrated more cell death after ethanol treatment, while Met, TQ or Met plus TQ prevented ethanol-induced apoptotic cell death. CONCLUSION: These findings suggested that Met and TQ are strong protective agents against ethanol induced neuronal apoptosis in primary rat cortical neurons. The collective data demonstrated that Met and TQ have the potential to ameliorate ethanol neurotoxicity and revealed a possible protective target mechanism for the damaging effects of ethanol during early brain development. PMID- 22260214 TI - A novel small insertion mutation, C.1030_1031ins (T) in alpha-galactosidase A leads to renal variant fabry disease. AB - Fabry disease is a rare X-linked recessive glycosphingolipid storage disease that is caused by a deficiency of the lysosomal alpha-galactosidase A (GLA) enzyme, encoded by the GLA gene. This deficiency leads to the accumulation of glycosphingolipids throughout the body, which, in turn, causes multisystem diseases associated with renal, cardiovascular, and cerebrovascular complications. Recent molecular studies of GLA have demonstrated the existence of atypical variants in Fabry disease, suggesting significant genotype-phenotype correlations. In this study, we describe a renal variant of Fabry disease caused by a novel small insertion mutation in the GLA gene. PMID- 22260217 TI - Literacy: Exploring working memory systems. AB - Previous research showed an important association between reading and writing skills (literacy) and the phonological loop. However, the effects of literacy on other working memory components remain unclear. In this study, we investigated performance of illiterate subjects and their matched literate controls on verbal and nonverbal working memory tasks. Results revealed that the phonological loop is significantly influenced by literacy, while the visuospatial sketchpad appears to be less affected or not at all. Results also suggest that the central executive might be influenced by literacy, possibly as an expression of cognitive reserve. PMID- 22260218 TI - Concentrated dispersions of equilibrium protein nanoclusters that reversibly dissociate into active monomers. AB - Stabilizing proteins at high concentration is of broad interest in drug delivery, for treatment of cancer and many other diseases. Herein, we create highly concentrated antibody dispersions (up to 260 mg/mL) comprising dense equilibrium nanoclusters of protein (monoclonal antibody 1B7, polyclonal sheep immunoglobulin G, and bovine serum albumin) molecules which, upon dilution in vitro or administration in vivo, remain conformationally stable and biologically active. The extremely concentrated environment within the nanoclusters (~700 mg/mL) provides conformational stability to the protein through a novel self-crowding mechanism, as shown by computer simulation, while the primarily repulsive nanocluster interactions result in colloidally stable, transparent dispersions. The nanoclusters are formed by adding trehalose as a cosolute which strengthens the short-ranged attraction between protein molecules. The protein cluster diameter was reversibly tuned from 50 to 300 nm by balancing short-ranged attraction against long-ranged electrostatic repulsion of weakly charged protein at a pH near the isoelectric point. This behavior is described semiquantitatively with a free energy model which includes the fractal dimension of the clusters. Upon dilution of the dispersion in vitro, the clusters rapidly dissociated into fully active protein monomers as shown with biophysical analysis (SEC, DLS, CD, and SDS-PAGE) and sensitive biological assays. Since the concept of forming nanoclusters by tuning colloid interactions is shown to be general, it is likely applicable to a variety of biological therapeutics, mitigating the need to engineer protein stability through amino acid modification. In vivo subcutaneous injection into mice results in indistinguishable pharmacokinetics versus a standard antibody solution. Stable protein dispersions with low viscosities may potentially enable patient self-administration by subcutaneous injection of antibody therapeutics being discovered and developed. PMID- 22260216 TI - Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers. AB - Pre-clinical studies suggest that the neurokinin-1 (NK1) receptor may modulate the response to opioids, with NK(1) inactivation leading to decreased opioid reinforcement, tolerance and withdrawal. Aprepitant is a selective NK1 antagonist currently marketed for clinical use as an anti-emetic. This 6-week in-patient study used a randomized, double-blind, double-dummy, within-subject, crossover design. Subjects (n = 8; 6 male/2 female) were healthy, adult volunteers who provided subjective and objective evidence of current prescription opioid abuse (without physical dependence) and underwent careful medical and psychiatric screening. Fifteen experimental conditions, consisting of one aprepitant dose (0, 40 and 200 mg, p.o. given as a 2-hour pre-treatment) in combination with one oxycodone dose [placebo, oral (20 and 40 mg/70 kg) and intranasal (15 and 30 mg/70 kg)], were examined. Sessions were conducted at least 48-hour apart and multi-dimensional measures were collected repeatedly throughout the 6-hour session duration. Oxycodone, by both routes of administration, produced significant dose-related effects on the predicted measures (e.g. subjective measures of abuse liability, respiratory depression and miosis). Pre-treatment with aprepitant (200 mg) significantly enhanced ratings of oxycodone subjective effects related to euphoria and liking and doubled the street value estimates for the highest test doses of oxycodone by both routes. Some objective measures (respiratory function, observer-rated opioid agonist effects) were similarly enhanced by pre-treatment with the highest dose of aprepitant. All dose combinations were safely tolerated. These findings are discussed in the context of the potential utility of NK1 antagonists in the treatment of opioid use disorders. PMID- 22260219 TI - Different outcomes of atherosclerotic renal artery stenosis managed with stenting: results from a cohort study. AB - BACKGROUND: To determine whether the type of renal artery stenosis and the rapid decline of renal function may have an impact on renal outcome after stenting. METHODS: Thirty patients with chronic kidney disease stages 3-4 and renal artery stenosis underwent stenting. The mean follow-up was 33 months; the change of estimated glomerular filtration rate was expressed as negative or positive value in mL/mo (DeltaGFR). We identified two types of subgroups, on the basis of stenosis type: 1 (unilateral) N = 13 and 2 (7 bilateral, 2 single kidney, 8 prevalent kidney) N = 17; on the basis of declining DeltaGFR in a pre-stenting period of 10 months: slow progressor (N = 11) and fast progressor (N = 13). RESULTS: Thirty-seven stents were placed successfully. After stenting the median DeltaGFR value was significantly greater in subgroup 2 compared with subgroup 1 (0.02 vs. -0.16; p = 0.02). Being in fast progressor and in subgroup 2 were associated with improved renal function after stenting (8 of 13 patients, p = 0.013; 11 of 17 patients, p = 0.032). In a logistic regression the only significant relationship is between improvement of renal function and rapid decline of pre-stenting GFR (odds ratio 16; p = 0.005). CONCLUSION: The predictable benefit from renal stenting may be most likely in patients presenting with a rapid decline of GFR associated with renal artery stenosis affecting the whole renal mass that is both kidneys or single functioning kidney. PMID- 22260220 TI - Allergen challenge differentially affects the number of circulating monocyte subsets. AB - Peripheral blood monocyte (PBM) subsets play different roles in inflammatory response and tissue remodelling. The aim of this study was to investigate how allergen challenge affects the number of circulating PBMs in Dermatophagoides pteronyssinus (Dp) allergic patients (Dp-APs). Among 34 Dp-APs challenged, in 22 patients significant bronchoconstriction was demonstrated [responders (Rs)], while in 12, only upper respiratory symptoms were seen [non-responders (NRs)]. Twelve healthy, non-atopic subjects were used as controls (HCs). Expression of CD14, CD16 and CCR4 was evaluated by flow cytometry on the whole-blood samples before (T(0) ), 6 h (T(6) ) and 24 h (T(24) ) after the challenge. Plasma concentrations of CCL2, CX3CL1 and CCL17 were evaluated using ELISA. At T(0) , the mean percentage of CD14++ CD16+ PBMs in Rs (35.4%; 95%CI 26.9-43.9%) was significantly greater than in HCs (14.6%; 95%CI 7.3-21.8%; P = 0.006) and in NRs (17.5%; 95%CI 9.6-25.4%; P = 0.001). The baseline number of CD14++ CD16+ PBMs correlated with airway hyper responsiveness (AHR) (r = -0.507; 95%CI -0.834 to 0.432, P < 0.001). At T(24) , the number of CD14++ CD16+ PBMs significantly decreased in Rs but not in NRs and the numbers inversely correlated with plasma CCL17 concentration. Changes in the number of circulating CD14++ CD16+ cells after Dp challenge correlated with AHR (r = 0.706, 95%CI 0.43-0.861; P < 0.001). In all subjects, the greatest expression of CCR4 was found on CD14++ CD16+ PBMs. Expansion of CD14++ CD16+ monocytes in the peripheral blood with subsequent mobilization of those cells after allergen challenge may facilitate the development of AHR in Dp-APs. PMID- 22260222 TI - Essential oil of Myrica esculenta Buch. Ham.: composition, antimicrobial and topical anti-inflammatory activities. AB - Hydrodistilled oil obtained from the stem bark of Myrica esculenta Buch. Ham. ex D. Don (yield 0.3%) was analysed by capillary GC and GC-MS. The volatile oil consisted mainly of n-hexadecanol (25.2%), eudesmol acetate (21.9%), palmitic acid (11.6%), cis-beta-caryophyllene (8.7%), n-pentadecanol (7.7%) and n octadecanol (7.6%). The oil was found to be a potential antimicrobial agent against Bacillus pumilus, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Aspergillus niger and Saccharomyces cerevisiae. The essential oil exhibited significant topical anti inflammatory activity compared to standard drug in Swiss albino mice ear. PMID- 22260221 TI - Regulatory interactions for iron homeostasis in Aspergillus fumigatus inferred by a Systems Biology approach. AB - BACKGROUND: In System Biology, iterations of wet-lab experiments followed by modelling approaches and model-inspired experiments describe a cyclic workflow. This approach is especially useful for the inference of gene regulatory networks based on high-throughput gene expression data. Experiments can verify or falsify the predicted interactions allowing further refinement of the network model. Aspergillus fumigatus is a major human fungal pathogen. One important virulence trait is its ability to gain sufficient amounts of iron during infection process. Even though some regulatory interactions are known, we are still far from a complete understanding of the way iron homeostasis is regulated. RESULTS: In this study, we make use of a reverse engineering strategy to infer a regulatory network controlling iron homeostasis in A. fumigatus. The inference approach utilizes the temporal change in expression data after a change from iron depleted to iron replete conditions. The modelling strategy is based on a set of linear differential equations and offers the possibility to integrate known regulatory interactions as prior knowledge. Moreover, it makes use of important selection criteria, such as sparseness and robustness. By compiling a list of known regulatory interactions for iron homeostasis in A. fumigatus and softly integrating them during network inference, we are able to predict new interactions between transcription factors and target genes. The proposed activation of the gene expression of hapX by the transcriptional regulator SrbA constitutes a so far unknown way of regulating iron homeostasis based on the amount of metabolically available iron. This interaction has been verified by Northern blots in a recent experimental study. In order to improve the reliability of the predicted network, the results of this experimental study have been added to the set of prior knowledge. The final network includes three SrbA target genes. Based on motif searching within the regulatory regions of these genes, we identify potential DNA-binding sites for SrbA. Our wet-lab experiments demonstrate high-affinity binding capacity of SrbA to the promoters of hapX, hemA and srbA. CONCLUSIONS: This study presents an application of the typical Systems Biology circle and is based on cooperation between wet-lab experimentalists and in silico modellers. The results underline that using prior knowledge during network inference helps to predict biologically important interactions. Together with the experimental results, we indicate a novel iron homeostasis regulating system sensing the amount of metabolically available iron and identify the binding site of iron-related SrbA target genes. It will be of high interest to study whether these regulatory interactions are also important for close relatives of A. fumigatus and other pathogenic fungi, such as Candida albicans. PMID- 22260223 TI - Zinc-specific fluorescent response of tris(isoquinolylmethyl)amines (isoTQAs). AB - Isoquinoline-based tetradentate ligands with C(3)-symmetry, tris(1- or 3 isoquinolylmethyl)amine (1- or 3-isoTQA), have been prepared and their zinc induced fluorescence enhancement was investigated. Upon excitation at 324 nm, 1 isoTQA shows very weak fluorescence (phi = ~0.003) in DMF/H(2)O (1/1) solution. In the presence of zinc ion, 1-isoTQA exhibits fluorescence increase (phi = 0.041) at 359 and 470 nm. This fluorescence enhancement at 470 nm is specific for zinc. However, 3-isoTQA exhibited a smaller fluorescence enhancement upon zinc complexation (phi = 0.017, lambda(em) = 360 and 464 nm) compared with 1-isoTQA. Crystal structures of zinc complexes of isoTQAs demonstrate the diminished steric crowding and shorter Zn-N(aromatic) distances compared with isoTQENs (N,N,N',N' tetrakis(isoquinolylmethyl)ethylenediamines) leads to a higher fluorescent response toward zinc relative to cadmium. PMID- 22260224 TI - An improved method for isolation of RNA from bone. AB - BACKGROUND: Bone physiology is increasingly appreciated as an important contributor to metabolic disorders such as type 2 diabetes. However, progress in understanding the role of bone in determining metabolic health is hampered by the well-described difficulty of obtaining high quality RNA from bone for gene expression analysis using the currently available approaches. RESULTS: We developed a simple approach to isolate bone RNA that combines pulverizing the bone and the phenol-guanidinium based RNA extraction in a single step while maintaining near-freezing temperatures. This single step method increases the yield of high quality RNA by eight-fold, with RNA integrity numbers ranging from 6.7 to 9.2. CONCLUSIONS: Our streamlined approach substantially increases the yield of high-quality RNA from bone tissue while facilitating safe and efficient processing of multiple samples using readily available platforms. The RNA obtained from this method is suitable for use in gene expression analysis in real time quantitative PCR, microarray, and next generation sequencing applications. PMID- 22260225 TI - Enhanced partitioning and transport of phenolic micropollutants within polyamide composite membranes. AB - Aromatic phenols represent an important class of endocrine-disrupting and toxic pollutants, many of which (e.g., bisphenol A and substituted phenols) are known to be insufficiently removed by reverse osmosis (RO) and nanofiltration polyamide membranes that are widely used for water purification. In this study, the mechanism of phenol transport across the polyamide layer of RO membranes is studied using model phenolic compounds hydroquinone (HQ) and its oxidized counterpart benzoquinone (BQ). The study employs filtration experiments and two electrochemical techniques, impedance spectroscopy (EIS) and chronoamperometry (CA), to evaluate the permeability of an RO membrane SWC1 to these solutes in the concentration range 0.1-10 mM. In addition, combination of the permeability data with EIS results allows separately estimating the average diffusivity and partitioning of BQ and HQ. All methods produced permeability of the order 10(-7) to 10(-6) m s(-1) that decreased with solute concentration, even though the permeability obtained from filtration was consistently lower. The decrease of permeability with concentration could be related to the nonlinear convex partitioning isotherm, in agreement with earlier measurements by FTIR. The diffusivity of HQ and BQ was estimated to be of the order 10(-15) m(2) s(-1) and partitioning coefficient of the order 10. The high affinity of phenols toward polyamide and their high uptake may change membrane characteristics at high concentration of the solute. EIS results and hydraulic permeability indeed showed that permeability to ions and water significantly decreases with increasing concentration of organic solute. PMID- 22260226 TI - Weight perceptions of parents with children at risk for diabetes. AB - BACKGROUND: The growing epidemic of obesity and diabetes among African American, Latino American, and Native American children in the United States has led to increasing focus on strategies for prevention. However, little is known about the perceptions toward weight, nutrition, and physical activity among these youth. This pilot study explored the perceptions of body weight among overweight and obese children and their parents. RESULTS: Thirty eight children, ages 8-16 years who were enrolled in a diabetes prevention study were surveyed to assess their perception of their weight. Nearly all (84%) of the children were obese. When asked whether they considered themselves to be overweight, African-American children were less likely to report that they were overweight than other children (33% vs. 80% of other children, p = 0.01). The parents of these children (n = 29) were also surveyed to assess their perception of their child's weight. The parents of two-thirds (65%) of the children reported that the child was overweight, while the rest reported their child was underweight or the right weight. African-American parents were less likely to report that their child's weight was unhealthy compared to other parents (46% vs. 77%, p = 0.069). CONCLUSIONS: This study's findings indicate that future intervention efforts should assess children's and parents' awareness of obesity and diabetes risk and these factors should be considered when developing prevention interventions for families with youth at risk for diabetes in underserved communities. PMID- 22260227 TI - A new class of transition metal pincer ligand: tantalum complexes that feature a [CCC] X3-donor array derived from a terphenyl ligand. AB - A new class of [CCC] X(3)-donor pincer ligand for transition metals has been constructed via cyclometalation of a 2,6-di-p-tolylphenyl ([Ar(Tol(2))]) derivative. Specifically, addition of PMe(3) to [Ar(Tol(2))]TaMe(3)Cl induces elimination of methane and formation of the pincer complex, [kappa(3) Ar(Tol'(2))]Ta(PMe(3))(2)MeCl (Tol' = C(6)H(3)Me), which may also be obtained by treatment of Ta(PMe(3))(2)Me(3)Cl(2) with [Ar(Tol(2))]Li. Solutions of [kappa(3) Ar(Tol'(2))]Ta(PMe(3))(2)MeCl undergo ligand redistribution with the formation of [kappa(3)-Ar(Tol'(2))]Ta(PMe(3))(2)Me(2)and [kappa(3) Ar(Tol'(2))]Ta(PMe(3))(2)Cl(2), which may also be synthesized by the reactions of [kappa(3)-Ar(Tol'(2))]Ta(PMe(3))(2)MeCl with MeMgBr and ZnCl(2), respectively. Reduction of [kappa(3)-Ar(Tol'(2))]Ta(PMe(3))(2)Cl(2) with KC(8) in benzene gives the benzene complex [kappa(3)-Ar(Tol'(2))]Ta(PMe(3))(2)(eta(6)-C(6)H(6)) that is better described as a 1,4-cyclohexadienediyl derivative. Deuterium labeling employing Ta(PMe(3))(2)(CD(3))(3)Cl(2) demonstrates that the pincer ligand is created by a pair of Ar-H/Ta-Me sigma-bond metathesis transformations, rather than by a mechanism that involves alpha-H abstraction by a tantalum methyl ligand. PMID- 22260228 TI - Central venous oxygen saturation is a good indicator of altered oxygen balance in isovolemic anemia. AB - BACKGROUND: Red blood cell transfusion is done primarily as a means to improve oxygen delivery (DO2). Current transfusion guidelines are based solely on hemoglobin levels, regardless of actual DO2 need. As central venous oxygen saturation (ScvO2) may reflect imbalances in DO2 and consumption (VO2) the aim of this study was to investigate the value of ScvO2 as an indicator of oxygen balance in isovolemic anemia. METHODS: After splenectomy, anesthetized Vietnamese mini pigs (n = 13, weight range: 18-30 kg) underwent controlled bleeding in five stages (T0-T5). During each stage approximately 10% of the estimated starting total blood volume was removed and immediately replaced with an equal volume of colloid. Hemodynamic measurements and blood gas analysis were then performed. RESULTS: Each stage of bleeding resulted in a significant fall in hemoglobin, T0 : 125 (113-134) to T(5) : 49 (43-55) g/l [T0 : 7.7 (6.9-8.2) to T5 : 3.0 (2.6 3.4) mmol/l]. The O2-extraction (VO2/DO2) increased significantly only from T3 : 35 (21-40) %, P < 0.05. The change of ScvO2 showed a similar pattern and dropped below the physiological threshold of 70% at T4 : 68 (61-76) %. At this point, hemoglobin was below the recommended transfusion trigger value, 59 (53-67) g/l [3.6 (3.3-4.1) mmol/l]. There was a strong significant association between ScvO2< 70%) and VO2/DO2 > 30%): r = -0.71, r2 = 0.50, P < 0.001. CONCLUSION: The results of this study show that ScvO2 reflects changes of VO2/DO2 in isovolemic anemia better than Hb alone, therefore it may be used as an additional indicator of blood transfusion in clinical practice. PMID- 22260229 TI - Copper(I)-catalyzed boryl substitution of unactivated alkyl halides. AB - Borylation of alkyl halides with diboron proceeded in the presence of a copper(I)/Xantphos catalyst and a stoichiometric amount of K(O-t-Bu) base. The boryl substitution proceeded with normal and secondary alkyl chlorides, bromides, and iodides, but alkyl sulfonates did not react. Menthyl halides afforded the corresponding borylation product with excellent diastereoselectivity, whereas (R) 2-bromo-5-phenylpentane gave a racemic product. Reaction with cyclopropylmethyl bromide resulted in ring-opening products, suggesting the reaction involves a radical pathway. PMID- 22260230 TI - Proliferation and differentiation potential of cryopreserved human skin-derived precursors. AB - OBJECTIVES: Skin-derived precursors are recognized to be a potentially autologous and accessible source of neural precursor cells for drug screening or cell-based treatments, in many neurological disorders. Thus, it is necessary to investigate appropriate methods for cryopreservation of such human skin-derived precursors (hSKPs). The aim of this study was to evaluate different cryopreservation techniques for retention of hSKPs to discover an optimized protocol. MATERIALS AND METHODS: We cryopreserved hSKPs treated with 0%, 10%, 20%, 30% and 40% foetal bovine serum (FBS) and three concentrations of dimethylsulphoxide (DMSO) 5%, 10% and 15%, with two different storage periods in liquid nitrogen (2 days: short term storage; and 2 months: long-term storage). Then, we assessed survival and proliferation levels of the cells after freeze-thaw processes, by viability measurement and colony-forming assay. For detecting hSKPs, we used immunocytochemistry and RT-PCR assessments. RESULTS: Our findings indicated that hSKPs cryopreserved in 5% DMSO without FBS, had better survival and proliferation potentials compared to other working formulations. With various concentrations of cryoprotectants over different time periods, hSKPs retained their differentiation potentiality and were able to differentiate into neurons (NFM and betaIotaIotaIota tubulin-positive), glial cells (GFAP-positive) and smooth muscle cells (SMA-positive). CONCLUSIONS: Results revealed that in only 5% DMSO, hSKPs could be cryopreserved for long-term storage with considerable survival and proliferation levels, without losing multipotency. PMID- 22260231 TI - SKY1 and IXR1 interactions, their effects on cisplatin and spermine resistance in Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae has been previously used as a model eukaryotic system to identify genes related to drug resistance. Deletion of the IXR1 gene increases resistance to cisplatin, and deletion of the SKY1 gene increases resistance to cisplatin and spermine. Three S. cerevisiae strains and their derivatives, carrying single Deltaixr1 and Deltasky1 and double Deltaixr1Deltasky1 deletions, were compared in terms of resistance against these compounds. We found that the effects of these deletions are highly dependent on the genetic background of the selected strains. These results are valuable in the selection of yeast strains to be used in genetic screenings of compounds with putative pharmacological interest. PMID- 22260232 TI - Brain insulin resistance accelerates Abeta fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes. AB - Type 2 diabetes mellitus is thought to be a significant risk factor for Alzheimer's disease. Insulin resistance also affects the central nervous system by regulating key processes, such as neuronal survival and longevity, learning and memory. However, the mechanisms underlying these effects remain uncertain. To investigate whether insulin resistance is associated with the assembly of amyloid beta-protein (Abeta) at the cell surface of neurons, we inhibited insulin signalling pathways of primary neurons. The treatments of insulin receptor (IR) knockdown and a phosphatidylinositol 3-kinase inhibitor (LY294002), but not an extracellular signal-regulated kinase inhibitor, induced an increase in GM1 ganglioside (GM1) levels in detergent-resistant membrane microdomains of the neurons. The aged db/db mouse brain exhibited reduction in IR expression and phosphorylation of Akt, which later induced an increase in the high-density GM1 clusters on synaptosomes. Neurons treated with IR knockdown or LY294002, and synaptosomes of the aged db/db mouse brains markedly accelerated an assembly of Abetas. These results suggest that ageing and peripheral insulin resistance induce brain insulin resistance, which accelerates the assembly of Abetas by increasing and clustering of GM1 in detergent-resistant membrane microdomains of neuronal membranes. PMID- 22260233 TI - Standardized diaper care regimen: a prospective, randomized pilot study on skin barrier function and epidermal IL-1alpha in newborns. AB - Adaptation of skin barrier function and interleukin-1alpha (IL-1alpha) content in diapered and nondiapered skin are poorly characterized in newborns receiving standard skin care. In a monocentric, prospective pilot study 44 healthy, full term neonates were randomly assigned to skin care with baby wipes (n = 21) or water-moistened washcloth (n = 23) at each diaper change. Transepidermal water loss (TEWL), skin hydration, skin-pH, IL-1alpha, and epidermal desquamation were measured on days 2, 14, and 28 postpartum. Microbiological colonization was evaluated at baseline and on day 28. Significantly lower TEWL was found on the buttock in the group using baby wipes compared to water. IL-1alpha and skin hydration significantly increased and pH decreased independent of skin care regimen. IL-1alpha was significantly higher in diapered skin compared to nondiapered skin. Although skin care with wipes seems to stabilize TEWL better than using water, the skin condition and microbiological colonization were comparable using both cleansing procedures. Increase of epidermal IL-1alpha may reflect postnatal skin barrier maturation. These data suggest that neither of the two cleansing procedures harms skin barrier maturation within the first four weeks postpartum. Longer observations on larger populations could provide more insight into postnatal skin barrier maturation. PMID- 22260235 TI - Ethanol increases phosphate-mediated mineralization and osteoblastic transformation of vascular smooth muscle cells. AB - Vascular calcification is implicated in the pathogenesis of atherosclerosis, diabetes and chronic kidney disease. Human vascular smooth muscle cells (HSMCs) undergo mineralization in response to elevated levels of inorganic phosphate (Pi) in an active and well-regulated process. This process involves increased activity of alkaline phosphatase and increased expression of core binding factor alpha-1 (CBF-alpha1), a bone-specific transcription factor, with the subsequent induction of osteocalcin. It has been shown that heavy alcohol consumption is associated with greater calcification in coronary arteries. The goal of our study was to examine whether ethanol alters mineralization of HSMCs provoked by high Pi. Exposure of HSMCs to ethanol increased extracellular matrix calcification in a dose responsive manner, providing a significant additional calcium deposition at concentrations of >=60 mmol/l. HSMC calcification was accompanied by further enhancement in alkaline phosphatase activity. Ethanol also provoked a significant increase in the synthesis of osteocalcin. Moreover, in cells challenged with ethanol the expression of CBF-alpha1, a transcription factor involved in the regulation of osteoblastic transformation of HSMCs, was elevated. The observed effects of ethanol were not due to alterations of phosphate uptake by HSMCs. We conclude that ethanol enhances Pi-mediated human vascular smooth muscle calcification and transition of these cells into osteoblast-like cells. PMID- 22260236 TI - The relationship between the level of serum creatinine, modified diet and renal disease formula, Cockcroft-Gault formula, and renal tubulointerstitial lesion. AB - OBJECTIVE: This study investigated the relationship between the levels of serum creatinine (SCr), the estimated glomerular filtration rate (eGFR), and the degree of tubulointerstitial injury. METHODS: A total of 511 patients of Zhongshan hospital in China were hospitalized due to physical abnormalities and diagnosed with kidney disease by renal biopsy. The clinical and pathological data were retrospectively analyzed. The level of SCr was determined in all patients, and the eGFR was calculated with modification of diet in renal disease and Cockcroft Gault formulae, whereas the renal histopathology was quantified according to the Katafuchi semi-quantitative standards. RESULTS: With the aggravation of tubulointerstitial injury, SCr level increased and eGFR decreased gradually. The degree of tubulointerstitial lesion showed a positive correlation with SCr level and negative correlation with Cockcroft-Gault formula and modification of diet in renal disease (r = 0.627, -0.649, -0.626; p < 0.001). When the SCr was in the normal range, above 90% of the patients had various degrees of tubulointerstitial damage and 12.2% of the patients had moderate-to-severe tubulointerstitial lesions. The correlation between SCr level and tubulointerstitial damage became weak. CONCLUSIONS: The morphologic changes of tubulointerstitium are closely linked with renal function, but incompletely parallel. SCr in the abnormal range could be used to diagnose tubulointerstitial injury well. However, when the level of SCr was in the so-called normal range, eGFR by the modification of diet in renal disease or Cockcroft-Gault formula may be preferred to assess renal tubulointerstitial injury. PMID- 22260237 TI - Evolvability of feed-forward loop architecture biases its abundance in transcription networks. AB - BACKGROUND: Transcription networks define the core of the regulatory machinery of cellular life and are largely responsible for information processing and decision making. At the small scale, interaction motifs have been characterized based on their abundance and some seemingly general patterns have been described. In particular, the abundance of different feed-forward loop motifs in gene regulatory networks displays systematic biases towards some particular topologies, which are much more common than others. The causative process of this pattern is still matter of debate. RESULTS: We analyzed the entire motif-function landscape of the feed-forward loop using the formalism developed in a previous work. We evaluated the probabilities to implement possible functions for each motif and found that the kurtosis of these distributions correlate well with the natural abundance pattern. Kurtosis is a standard measure for the peakedness of probability distributions. Furthermore, we examined the functional robustness of the motifs facing mutational pressure in silico and observed that the abundance pattern is biased by the degree of their evolvability. CONCLUSIONS: The natural abundance pattern of the feed-forward loop can be reconstructed concerning its intrinsic plasticity. Intrinsic plasticity is associated to each motif in terms of its capacity of implementing a repertoire of possible functions and it is directly linked to the motif's evolvability. Since evolvability is defined as the potential phenotypic variation of the motif upon mutation, the link plausibly explains the abundance pattern. PMID- 22260238 TI - Development and characterization of BAC-end sequence derived SSRs, and their incorporation into a new higher density genetic map for cultivated peanut (Arachis hypogaea L.). AB - BACKGROUND: Cultivated peanut (Arachis hypogaea L.) is an important crop worldwide, valued for its edible oil and digestible protein. It has a very narrow genetic base that may well derive from a relatively recent single polyploidization event. Accordingly molecular markers have low levels of polymorphism and the number of polymorphic molecular markers available for cultivated peanut is still limiting. RESULTS: Here, we report a large set of BAC end sequences (BES), use them for developing SSR (BES-SSR) markers, and apply them in genetic linkage mapping. The majority of BESs had no detectable homology to known genes (49.5%) followed by sequences with similarity to known genes (44.3%), and miscellaneous sequences (6.2%) such as transposable element, retroelement, and organelle sequences. A total of 1,424 SSRs were identified from 36,435 BESs. Among these identified SSRs, dinucleotide (47.4%) and trinucleotide (37.1%) SSRs were predominant. The new set of 1,152 SSRs as well as about 4,000 published or unpublished SSRs were screened against two parents of a mapping population, generating 385 polymorphic loci. A genetic linkage map was constructed, consisting of 318 loci onto 21 linkage groups and covering a total of 1,674.4 cM, with an average distance of 5.3 cM between adjacent loci. Two markers related to resistance gene homologs (RGH) were mapped to two different groups, thus anchoring 1 RGH-BAC contig and 1 singleton. CONCLUSIONS: The SSRs mined from BESs will be of use in further molecular analysis of the peanut genome, providing a novel set of markers, genetically anchoring BAC clones, and incorporating gene sequences into a linkage map. This will aid in the identification of markers linked to genes of interest and map-based cloning. PMID- 22260239 TI - Risk factors for mortality in stable peritoneal dialysis patients. AB - BACKGROUND: The mortality rates of end-stage renal disease patients have significantly declined over the past decade. However, there are few reports on the risk factors for mortality in stable peritoneal dialysis (PD) patients who survive for a considerable time. PATIENTS AND METHODS: We reviewed the medical records and identified all adult patients who received PD between April 2001 and March 2009 in our institution. The total cohort was 550 patients. Among these patients, 383 patients were enrolled as stable PD patients. RESULTS: The cumulative survival of the stable PD patients was 91.6% at 3 years and 78.7% at 5 years. On univariate analysis, old age (>=65 years of age), hypoalbuminemia (<35 g/L), log C-reactive protein (CRP) (>=0.84), phosphorus (<1.13 mmol/L), statin, icodextrin, and the Davies index were associated with mortality for all PD patients. Old age, hypoalbuminemia, log CRP, phosphorus, the residual renal function (RRF) (<=4 mL/min/1.73 m2) at 24 months, renin-angiotensin system blockade, icodextrin, and the Davies index were associated with mortality for the stable PD patients. Multivariate analysis showed that, among the variables, age, log CRP, phosphorus, initial RRF, and the Davies index were associated with mortality for all PD patients. In stable PD patients, age, log CRP, phosphorus, RRF at 24 months, and the Davies index were associated with mortality. CONCLUSION: Initial high RRF combined with the RRF preservation, maintenance of proper phosphorus, control of inflammation, and proper management of comorbidities may help to improve the survival of PD patients including stable PD patients. PMID- 22260240 TI - Direct and indirect regulatory mechanisms in TH17 cell differentiation and functions. AB - T helper 17 (TH17) cells have well-described roles in autoimmune diseases. The immune modulations of development and function of TH17 have become a key issue. In this review, we summarize the recent findings regarding the direct and indirect signalling regulatory mechanisms of TH17 cells in the general mouse model of autoimmune diseases and other human diseases. PMID- 22260241 TI - Photofabrication of fullerene-shelled quantum dots supramolecular nanoparticles for solar energy harvesting. AB - Quantum dots-based electron donor-acceptor systems play a rising role in the design of renewable and carbon-free energy harvesting technologies. In this article, we discuss the photofabrication of fullerene-shelled quantum dots supramolecular nanoparticles, in which the fullerene shell acts as not only a well-defined electron acceptor but also a robust protecting layer against the photocorrosion of the quantum dot core. We evaluate the ensemble and single molecule electron transfer from the core to the shell in the nanoparticles and the photocurrent response of a photoelectrochemical cell constructed using the nanoparticles. The supramolecular nanoparticle has been prepared by the covalent tethering of a fullerene-thiol monolayer to the quantum dot followed by the photochemical reactions of free fullerene-thiol to the tethered monolayer. The nanoparticles are characterized using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. Correlated single-photon emission and the two-state ON-OFF photoluminescence show that single quantum dots are included in the supramolecular nanoparticles. The fullerene-shells suppress the blinking of single quantum dots by acting as well-defined electron traps, without allowing the transfer of Auger electrons to unknown traps. Electron transfer from the quantum dot-core to the fullerene-shell is apparent from the short ON and OFF durations in the photoluminescence intensity trajectories of single quantum dots, quenching of the photoluminescence intensity and lifetime of quantum dots at the ensemble level, and the characteristic transient absorption band of the anion radical of fullerene. We next construct a photoelectrochemical cell using the supramolecular nanoparticles, and the transferred electron is externally driven in the cell to generate ~400 MUA/cm(2) photocurrent. Electron transfer from the highly stable quantum dots to the protecting fullerene-shells places the supramolecular nanoparticles among the most promising antenna systems for the construction of cost-effective and stable next generation solar energy harvesting systems. PMID- 22260243 TI - Sliding/rolling phobic droplets along a fiber: measurement of interfacial forces. AB - Phobic droplet-fiber systems possess complex geometries, which have made full characterization of such systems difficult. This work has used atomic force microscopy (AFM) to measure droplet-fiber forces for oil droplets on oleophobic fibers over a range of fiber diameters. The work adapted a previous method and a theoretical model developed by the authors for philic droplet-fiber systems. A Bayesian statistical model was also used to account for the influence of surface roughness on the droplet-fiber force. In general, it has been found that the force required to move a liquid droplet along an oleophobic filter fiber will be less than that required to move a droplet along an oleophilic fiber. However, because of the effects of pinning and/or wetting behavior, this difference may be less than would otherwise be expected. Droplets with a greater contact angle (~110 degrees ) were observed to roll along the fiber, whereas droplets with a lesser contact angle (<90 degrees ) would slide. PMID- 22260242 TI - Is increasing complexity of algorithms the price for higher accuracy? virtual comparison of three algorithms for tertiary level management of chronic cough in people living with HIV in a low-income country. AB - BACKGROUND: The algorithmic approach to guidelines has been introduced and promoted on a large scale since the 1970s. This study aims at comparing the performance of three algorithms for the management of chronic cough in patients with HIV infection, and at reassessing the current position of algorithmic guidelines in clinical decision making through an analysis of accuracy, harm and complexity. METHODS: Data were collected at the University Hospital of Kigali (CHUK) in a total of 201 HIV-positive hospitalised patients with chronic cough. We simulated management of each patient following the three algorithms. The first was locally tailored by clinicians from CHUK, the second and third were drawn from publications by Medecins sans Frontieres (MSF) and the World Health Organisation (WHO). Semantic analysis techniques known as Clinical Algorithm Nosology were used to compare them in terms of complexity and similarity. For each of them, we assessed the sensitivity, delay to diagnosis and hypothetical harm of false positives and false negatives. RESULTS: The principal diagnoses were tuberculosis (21%) and pneumocystosis (19%). Sensitivity, representing the proportion of correct diagnoses made by each algorithm, was 95.7%, 88% and 70% for CHUK, MSF and WHO, respectively. Mean time to appropriate management was 1.86 days for CHUK and 3.46 for the MSF algorithm. The CHUK algorithm was the most complex, followed by MSF and WHO. Total harm was by far the highest for the WHO algorithm, followed by MSF and CHUK. CONCLUSIONS: This study confirms our hypothesis that sensitivity and patient safety (i.e. less expected harm) are proportional to the complexity of algorithms, though increased complexity may make them difficult to use in practice. PMID- 22260245 TI - Inhibition of sympathetic neuroeffector transmission in human corpus cavernosum. AB - What's known on the subject? and What does the study add? In the present study the mechanisms regulating EFS-evoked neurogenic contraction in the human corpus cavernosum (HCC) were investigated. Overall, our data adds to current knowledge that the NO-independent heme dependent activation of sGC and the RhoA/Rho-kinase signaling pathways play an important role in the regulation of neurogenic contractile activity in HCC tissue. OBJECTIVE: To investigate the mechanisms of adrenergically mediated smooth muscle contraction in the human corpus cavernosum (HCC) using an organ bath approach. METHODS: Human corpus cavernosum specimens were obtained from patients (aged 59-72 years) with erectile dysfunction (ED), undergoing penile prosthesis implantation surgery. Isolated HCC strips (1 * 1 * 6 mm) were suspended in tissue bath chambers for isometric tension recording. The effects of various drugs on neurogenic contractions evoked by electrical field stimulation (EFS) were investigated. The drugs included nitric oxide (NO) donors, phosphodiesterase 5 (PDE5) inhibitor, Rho kinase (ROCK) inhibitor, NO-independent stimulator, L-type Ca2+ channel blocker and alpha-receptor antagonist. RESULTS: Pre-incubation with the NO donor sodium nitroprusside (SNP; 10(4) M) significantly reduced the initial peak increase in tension evoked by EFS (by 71%, P < 0.05). The PDE5 inhibitor sildenafil (10(-4) M) reduced the increase in tension by 69%, while a combination of sildenafil and ROCK inhibitor, fasudil, inhibited tension by 81%. The EFS-induced contractile response at 80 Hz was decreased by 65% with fasudil and by 70% with isradipine (P < 0.001), while a combination of these drugs decreased the response by 88%. An NO-independent stimulator soluble guanylate cyclase (sGC), BAY 41-8543, significantly reduced the response (by 82%, P < 0.001) Phentolamine, an alpha-receptor antagonist, nearly eliminated the contractile response (98%, P < 0.001). CONCLUSIONS: These data suggest that neurogenic contractions are mediated by an increase in Ca(2+) influx via L-type voltage-gated Ca(2+) channels and that an increase in Ca(2+) sensitivity is mediated by the ROCK pathway and the PDE5 enzyme system as well as by the inhibitory NO/sGC/cGMP pathway. The neurogenic contractile response in HCC is mediated by several intracellular pathways, including adrenergic receptors, Ca(2+) entry, Ca(2+) sensitization and activation of the PDE5 enzyme. The Rho kinase (ROCK) inhibitor fasudil, L-type Ca(2+) channel antagonist isradipine, and PDE5 inhibitor sildenafil, as well as a NO-independent stimulator of sGC, had similar inhibitory effects, suggesting parallel mechanisms in the HCC. PMID- 22260244 TI - Alcohol administration attenuates hypothalamic-pituitary-adrenal (HPA) activity in healthy men at low genetic risk for alcoholism, but not in high-risk subjects. AB - Acute alcohol challenge studies in rodents and naturalistic observations in drinking alcoholics suggest that alcohol stimulates the hypothalamic-pituitary adrenal (HPA) system. The literature on respective studies in healthy volunteers is more inconsistent, suggesting differential alcohol effects depending on dosage, recent drinking history, family history of alcoholism and alcohol-induced side effects. These papers and the putative pharmacologic mechanisms underlying alcohol effects on the HPA system are reviewed here and compared with a new study, in which we investigated how secretion of adrenocorticotrophin (ACTH) and cortisol is affected by ingestion of 0.6 g/kg ethanol in 33 young healthy socially drinking males with a paternal history of alcoholism (PHP) versus 30 family history negative (FHN) males. Alcohol and placebo were administered in a 2 day, double-blind, placebo controlled crossover design with randomized administration sequence. After administration of placebo, ACTH and cortisol decreased steadily over 130 minutes. In FHN subjects, secretion of both hormones was even more attenuated after alcohol, resulting in significantly lower levels compared with placebo. In PHP subjects, no alcohol effect on hormone secretion could be detected. The ratio of cortisol to ACTH secretion, each expressed as area under the secretion curve, was significantly increased by alcohol in FHN and PHP participants. These results argue against HPA stimulation being a mechanism that promotes the transition from moderate to dependent drinking. The fact that alcohol-induced HPA suppression was not detected in PHP males is consistent with the general concept that subjects at high risk for alcoholism exhibit less pronounced alcohol effects. PMID- 22260246 TI - Four polyanionic compounds in the K-Au-Ga system: a case study in exploratory synthesis and of the art of structural analysis. AB - The K-Au-Ga system has been investigated at 350 degrees C for <50 at. % K. The potassium gold gallides K(0.55)Au(2)Ga(2), KAu(3)Ga(2), KAu(2)Ga(4) and the solid solution KAu(x)Ga(3-x) (x = 0-0.33) were synthesized directly from the elements via typical high-temperature reactions, and their crystal structures were determined by single crystal X-ray diffraction: K(0.55)Au(2)Ga(2) (I, I4/mcm, a = 8.860(3) A, c = 4.834(2) A, Z = 4), KAu(3)Ga(2) (II, Cmcm, a = 11.078(2) A, b = 8.486(2) A, c = 5.569(1) A, Z = 4), KAu(2)Ga(4) (III, Immm, a = 4.4070(9) A, b = 7.339(1) A, c = 8.664(2) A, Z = 2), KAu(0.33)Ga(2.67) (IV, I-4m2, a = 6.0900(9) A, c = 15.450(3) A, Z = 6). The first two compounds contain different kinds of tunnels built of puckered six- (II) or eight-membered (I) ordered Au/Ga rings with completely different cation placements: uniaxial in I and III but in novel 2D-zigzag chains in II. III contains only infinite chains of a potassium-centered 20-vertex polyhedron (K@Au(8)Ga(12)) built of ordered 6-8-6 planar Au/Ga rings. The main structural feature of IV is dodecahedral (Au/Ga)(8) clusters. Tight binding electronic structure calculations by linear muffin-tin-orbital methods were performed for idealized models of I, II, and III to gain insights into their structure-bonding relationships. Density of states curves reveal metallic character for all compounds, and the overall crystal orbital Hamilton populations are dominated by polar covalent Au-Ga bonds. The relativistic effects of gold lead to formation of bonds of greater population with most post-transition elements or to itself, and these appear to be responsible for a variety of compounds, as in the K-Au-Ga system. PMID- 22260247 TI - Live Legionella pneumophila induces MUC5AC production by airway epithelial cells independently of intracellular invasion. AB - The airway epithelium is the initial barrier against airborne pathogens, and it plays many roles in host airway defense. Legionella pneumophila is an intracellular pathogen that causes rapidly advancing pneumonia and is sometimes life-threatening. Here, we evaluated the role of the airway epithelial cells in the defense against L. pneumophila by examining mucus production in vitro. The production of MUC5AC, a major mucin protein, was not induced by formalin- or ultraviolet-killed L. pneumophila, but it was induced by live L. pneumophila. Similarly, nuclear factor-kappaB (NF-kappaB) was activated only by live L. pneumophila. Inhibitors of ERK and JNK, but not p38, dose-dependently inhibited the induction of MUC5AC by live L. pneumophila. Inhibition of intracellular invasion by cytochalasin D did not affect MUC5AC production. Taken together, the results suggest that live L. pneumophila induces MUC5AC production via the ERK JNK and NF-kappaB pathways without internalization of bacteria and that the airway epithelium produces mucin as part of the immune response against L. pneumophila. PMID- 22260248 TI - Prevalence and correlates for school truancy among pupils in grades 7-10: results from the 2004 Zambia Global School-based Health Survey. AB - BACKGROUND: There are limited data on the prevalence and associated factors of truancy in southern Africa. Yet truancy should attract the attention of public health professionals, educators and policy makers as it may be associated with adolescent problem behaviours. The objectives of the study were to estimate the prevalence and determine correlates of school truancy among pupils in Zambia. FINDINGS: We used data collected in 2004 in the Zambia Global School-based Health Survey. Logistic regression analysis was conducted to identify factors associated with truancy. A total of 2257 pupils participated in the survey of whom 53.9% were male. Overall 58.8% of the participants (58.1% of males and 58.4% of females) reported being truant in the past 30 days. Factors associated with truancy were having been bullied (AOR = 1.34, 95% CI [1.32, 1.36]), current alcohol use (AOR = 2.19, 95% CI [2.16, 2.23]), perception that other students were kind and helpful (AOR = 1.12, 95% CI [1.10, 1.14]), being male and being from the lowest school grade. Pupils whose parents or guardians checked their homework (AOR = 0.91 95% CI, [0.89, 0.92]) and those who reported parental supervision (AOR = 0.94, 95% CI [0.92-0.95]) were less likely to report being truant. CONCLUSIONS: We found a high prevalence of truancy among pupils in grades 7-10 in Zambia. Interventions aimed to reduce truancy should be designed and implemented with due consideration of the associated factors. PMID- 22260249 TI - High-efficiency removal of NOx using a combined adsorption-discharge plasma catalytic process. AB - A combined adsorption-discharge plasma catalytic process was used for the removal of NO(x) using zeolites as catalysts without external heating. It was found that the types of plasma carrier gases exert great effect on the conversion of adsorbed NO(x). The conversion of adsorbed NO(x) is much lower in N(2) plasma than in Ar plasma, which is attributed to the reverse reaction, NO(x) formation reaction. The momentary increase of oxygen species derived from the decomposition of adsorbed NO(x) is considered to be the main cause as their collisions with nitrogen species can generate NO(x) again. Thus, solid carbon was added to the catalyst to act as a scavenger for active oxygen species to improve the conversion of adsorbed NO(x) in N(2) plasma. A NO(x) removal rate of 97.8% was obtained on 8.5wt.% carbon mixed H-ZSM-5 at an energy efficiency of 0.758 mmol NO(x)/W.h. PMID- 22260250 TI - Ammonia increases paracellular permeability of rat brain endothelial cells by a mechanism encompassing oxidative/nitrosative stress and activation of matrix metalloproteinases. AB - Ammonia is responsible for cerebral edema associated with acute liver failure, but the role of the vasogenic mechanism has been a matter of dispute. Here, we tested the hypothesis that ammonia induces changes in blood-brain barrier (BBB) permeability by a mechanism coupled to oxidative/nitrosative stress (ONS) evoked in the BBB-forming cerebral capillary endothelial cells. Treatment of a rat brain endothelial cell line with ammonia (5 mmol/L, 24 h) caused accumulation of ONS markers: reactive oxygen species, nitric oxide and peroxidation products of phospholipid-bound arachidonic acid, F2-isoprostanes. Concurrently, ammonia increased the activity of extracellular matrix metalloproteinases (MMP-2/MMP-9), increased cell permeability to fluorescein isothiocyanate-dextran (40 kDa), and increased the expression of y+LAT2, a transporter that mediates the uptake to the cells of the nitric oxide precursor, arginine. The increase of cell permeability was ameliorated upon co-treatment with a MMP inhibitor, SB-3CT and with an antioxidant, glutathione diethyl ester, which also reduced F2-isoprostanes. Ammonia-induced ONS was attenuated by cytoprotective agents l-ornithine, phenylbutyrate, and their conjugate l-ornithine phenylbutyrate, an ammonia trapping drug used to treat hyperammonemia. The results support the concept that ONS and ONS-related activation of MMPs in cerebral capillary endothelial cells contribute to the alterations in BBB permeability and to the vasogenic component of cerebral edema associated with acute liver failure. PMID- 22260251 TI - A new lupane triterpene from Tetracera scandens L., xanthine oxidase inhibitor. AB - From the MeOH extract of the stem of Tetracera scandens L., a new nor-lupane triterpene, 28-O-beta-D-glucopyranosyl ester of platanic acid (1), has been isolated together with six known compounds. Their structures were elucidated on the basis of spectroscopic data. Compounds 1-6 displayed significant xanthine oxidase inhibitory activity in a concentration-dependent manner, and compound 4 showed more potent inhibitory activity with an IC(50) value of 1.9 uM than that of a positive control allopurinol (IC(50) 2.5 uM). PMID- 22260253 TI - Fat pad-derived mesenchymal stem cells as a potential source for cell-based adipose tissue repair strategies. AB - BACKGROUND: Mesenchymal stem cells are able to undergo adipogenic differentiation and present a possible alternative cell source for regeneration and replacement of adipose tissue. The human infrapatellar fat pad is a promising source of mesenchymal stem cells with many source advantages over from bone marrow. It is important to determine whether a potential mesenchymal stem-cell exhibits tri lineage differentiation potential and is able to maintain its proliferation potential and cell-surface characterization on expansion in tissue culture. We have previously shown that mesenchymal stem cells derived from the fat pad can undergo chondrogenic and osteogenic differentiation, and we characterized these cells at early passage. In the study described here, proliferation potential and characterization of fat pad-derived mesenchymal stem cells were assessed at higher passages, and cells were allowed to undergo adipogenic differentiation. MATERIALS AND METHODS: Infrapatellar fat pad tissue was obtained from six patients undergoing total knee replacement. Cells isolated were expanded to passage 18 and proliferation rates were measured. Passage 10 and 18 cells were characterized for cell-surface epitopes using a range of markers. Passage 2 cells were allowed to undergo differentiation in adipogenic medium. RESULTS: The cells maintained their population doubling rates up to passage 18. Cells at passage 10 and passage 18 had cell-surface epitope expression similar to other mesenchymal stem cells previously described. By staining it was revealed that they highly expressed CD13, CD29, CD44, CD90 and CD105, and did not express CD34 or CD56, they were also negative for LNGFR and STRO1. 3G5 positive cells were noted in cells from both passages. These fat pad-derived cells had adipogenic differentiation when assessed using gene expression for peroxisome proliferator activated receptor gamma2 and lipoprotein lipase, and oil red O staining. DISCUSSION: These results indicate that the cells maintained their proliferation rate, and continued expressing mesenchymal stem-cell markers and pericyte marker 3G5 at late passages. These results also show that the cells were capable of adipogenic differentiation and thus could be a promising source for regeneration and replacement of adipose tissue in reconstructive surgery. PMID- 22260254 TI - Xenon is not superior to isoflurane on cardiovascular function during experimental acute pulmonary hypertension. AB - BACKGROUND: Acute right ventricular afterload increase is a known perioperative challenge for the anaesthetic regime especially for patients with a compromised right ventricle. The accused negative inotropic action of volatile anaesthetics, with the exception of xenon, might be crucial for the adaptation of the right ventricle. METHODS: Reversible pulmonary hypertension (mean pressure 40 mmHg) was induced by an infusion of the stable thromboxane A(2) analog U46619 in a porcine model (n = 35). The effects of 70 vol% xenon and 0.9 vol% isoflurane on biventricular function were studied by conductance catheter technique. Inflammation and myocardial injury was quantified using serum probes [tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL-6), troponin] and myocardial tissue [B natriuretic peptide (BNP), TNFalpha, activated caspase 3] by enzyme linked immunosorbance assays and reverse-transcription polymerase chain reaction. RESULTS: After wash in of xenon global haemodynamic parameters remained stable whereas isoflurane caused a systemic vasodilation. This led to a significant decrease in mean arterial pressure in the isoflurane group whereas cardiac output remained stable. Both substances did not alter the biventricular contractility nor did they induce changes in preload for both ventricles. Xenon led to an additional increase in right ventricular afterload, whereas isoflurane reduced pulmonary vascular resistance. No effects on systemic inflammatory response and myocardial injury were found, whereas higher apoptosis rate and expression of BNP and IL-6 was determined in the right ventricle. CONCLUSIONS: These results do not support the idea that xenon is more beneficial than isoflurane in right ventricular failure during pulmonary hypertension. Isoflurane did not compromise systolic ventricular function during acute PHT it only led to vasodilation in contrast to xenon. PMID- 22260255 TI - Physiological reactivity to faces via live and video-mediated communication in typical and atypical development. AB - The human face is a powerful elicitor of emotion, which induces autonomic nervous system responses. In this study, we explored physiological arousal and reactivity to affective facial displays shown in person and through video-mediated communication. We compared measures of physiological arousal and reactivity in typically developing individuals and those with the developmental disorders Williams syndrome (WS) and autism spectrum disorder (ASD). Participants attended to facial displays of happy, sad, and neutral expressions via live and video mediated communication. Skin conductance level (SCL) indicated that live faces, but not video-mediated faces, increased arousal, especially for typically developing individuals and those with WS. There was less increase of SCL, and physiological reactivity was comparable for live and video-mediated faces in ASD. In typical development and WS, physiological reactivity was greater for live than for video-mediated communication. Individuals with WS showed lower SCL than typically developing individuals, suggesting possible hypoarousal in this group, even though they showed an increase in arousal for faces. The results are discussed in terms of the use of video-mediated communication with typically and atypically developing individuals and atypicalities of physiological arousal across neurodevelopmental disorder groups. PMID- 22260256 TI - Physiological mechanisms of signal termination in biological systems. AB - Studies on the regulation of cellular activity mainly focus on signal generation, but termination of signalling is an equally important factor, which prevents inappropriate activity. This paper reviews the mechanisms, which can cause termination of signalling, and provides examples that illustrate the importance of these processes. Inactivation of voltage-gated Na(+) channels and the photoactivated rhodopsin molecule is caused by rapid conformational rearrangements. Negative feedback can also contribute to the termination of signalling for various mechanisms, including plasma membrane ion channels or cAMP signal generation. In immune cells, the tyrosine-based inhibitory motif (ITIM) containing molecules are essential negative regulatory components. Desensitization of G-protein-coupled receptors can occur with homologous and heterologous mechanisms, mediated by beta-arrestin molecules and second messenger induced kinases respectively. In NF-kappaB signalling, resynthetized IkappaB and other enzymes form negative feedback loops. GTPase-activating proteins are also dedicated to termination of signalling, because they can switch off the small G proteins by increasing their endogenous GTP hydrolysis. In many systems, signal termination is a result of a combined action of several different mechanisms, which underlines the importance of these processes. PMID- 22260257 TI - Melodinines M-U, cytotoxic alkaloids from Melodinus suaveolens. AB - Nine new alkaloids, melodinines M-U (1-9), and 11 known alkaloids were isolated from Melodinus suaveolens. The new structures were elucidated by extensive NMR and mass spectroscopic analyses and comparison to known compounds. All compounds were evaluated for their cytotoxicity against five human cancer cell lines. Compounds 6, 11, and 16 showed significant cytotoxicity. PMID- 22260259 TI - Cleidocranial dysplasia presenting with retained deciduous teeth in a 15-year-old girl: a case report. AB - INTRODUCTION: Cleidocranial dysplasia is a rare congenital defect of autosomal dominant inheritance caused by mutations in the Cbfa1 gene, also called Runx2, located on the short arm of chromosome 6. It primarily affects bones which undergo intramembranous ossification. This condition is of clinical significance to dentistry due to the involvement of the facial bones, altered eruption patterns and multiple supernumerary teeth. CASE PRESENTATION: Our patient, a 15 year-old Indian girl, presented with the typical features of prolonged retention of deciduous dentition and delayed eruption of permanent teeth, that is, mandibular prognathism along with other skeletal abnormalities like shrugged shoulder and the absence of clavicles. A multidisciplinary approach was followed, comprising orthodontic, surgical and pedodontic teams for management. CONCLUSION: Successful treatment of such a case lies in a holistic approach that takes care of all aspects, including the primary pathology, the deformity itself and even the psychological angle. PMID- 22260258 TI - Nano-regenerative medicine towards clinical outcome of stem cell and tissue engineering in humans. AB - Nanotechnology is a fast growing area of research that aims to create nanomaterials or nanostructures development in stem cell and tissue-based therapies. Concepts and discoveries from the fields of bio nano research provide exciting opportunities of using stem cells for regeneration of tissues and organs. The application of nanotechnology to stem-cell biology would be able to address the challenges of disease therapeutics. This review covers the potential of nanotechnology approaches towards regenerative medicine. Furthermore, it focuses on current aspects of stem- and tissue-cell engineering. The magnetic nanoparticles-based applications in stem-cell research open new frontiers in cell and tissue engineering. PMID- 22260261 TI - Room-temperature giant persistent photoconductivity in SrTiO3/LaAlO3 heterostructures. AB - SrTiO(3)/LaAlO(3) interfaces show an unprecedented photoconductivity effect that is persistent even at room temperature and giant as it gives rise to a conductivity increase of about 5 orders of magnitude at room temperature. The persistent photoconductivity effects play a paramount role in the still controversial intrinsic behavior of the SrTiO(3)/LaAlO(3) interfaces, as even a limited exposure to visible light is able to strongly modify the electrical transport properties of the interface even above room temperature, while only an appropriate thermal treatment in a dark environment can completely suppress the persistent photoconductivity effect unveiling the intrinsic conduction mechanism of the interface. Moreover, our study demonstrates that the origin of the high conductivity, revealed at the STO/LAO interface at room temperature, is purely electronic. PMID- 22260260 TI - Dying at home in Belgium: a descriptive GP interview study. AB - BACKGROUND: While increasing attention is being paid to enabling terminal patients to remain at home until death, limited information is available on the circumstances in which people at home actually die. Therefore this study aims to describe patient characteristics, functional and cognitive status and physical and psychological symptom burden in the last three months of life among Belgian patients dying at home, according to their GPs. METHODS: In 2005, a nationwide and retrospective interview study with GPs took place on people dying at home in Belgium as reported by Sentinel Network of GPs in Belgium. GPs registered all deaths (patients aged 1 year or more) weekly and were interviewed about all patients dying non-suddenly at home, using face-to-face structured interviews. RESULTS: Interviews were obtained on 205 patients (90% response rate). Between the second and third month before death, 55% were fully invalid or limited in self-care. In the last week of life, almost all were fully invalid. Fifty four percent were unconscious at some point during the last week; 46% were fully conscious. Most frequently reported symptoms were lack of energy, lack of appetite and feeling drowsy. Conditions most difficult for GPs to manage were shortness of breath, lack of energy and pain. CONCLUSIONS: Many people dying at home under the care of their GPs in Belgium function relatively well until the last week of life and cognitive status seems to be preserved until the end in many cases. However, symptoms which GPs find difficult to control still manifest in many patients in the final week of life. PMID- 22260262 TI - Beneficial effects of montelukast against cisplatin-induced acute renal damage in rats. AB - OBJECTIVE: In this study, the therapeutic and protective effects of montelukast against cisplatin (CP)-induced acute renal damage were investigated. MATERIALS AND METHODS: Thirty-five female rats were divided into five groups as follows: (1) control, (2) montelukast (10 mg/kg daily for 10 days per-oral (p.o.), (3) CP (single dose 7 mg/kg intraperitoneally (i.p.)), (4) CP + montelukast (10 mg/kg daily for 10 days p.o., after 3 days of the injection of CP), (5) montelukast (10 mg/kg daily for 10 days p.o.) + CP (single dose 7 mg/kg i.p., after the last dose of montelukast). At the end of the experiment, malondialdehyde (MDA), a lipid peroxidation product, myeloperoxidase (MPO), and reduced glutathione (GSH) levels were determined in the renal tissue. Also, blood urea nitrogen (BUN) and creatinine (Cr) levels were assayed from the trunk blood samples. RESULTS: CP treatment caused a significant elevation of MDA, MPO, BUN, and Cr levels when compared with the control group. Also, GSH levels were found to be reduced due to the CP treatment. Montelukast administration after CP injection ameliorated all of these parameters. Our histopathological findings (marked swelling of epithelial cells, tubular dilatation, tubular desquamation, and loss of brush border in the kidney) were consistent with the biochemical results. CONCLUSION: Montelukast treatment after CP injection exerted therapeutic effects against CP induced acute kidney damage. PMID- 22260263 TI - A possible role of different PTPN genes in immune regulation. PMID- 22260264 TI - TiO2 thin films prepared via adsorptive self-assembly for self-cleaning applications. AB - Low-cost controllable solution-based processes for preparation of titanium oxide (TiO(2)) thin films are highly desirable, because of many important applications of this oxide in catalytic decomposition of volatile organic compounds, advanced oxidation processes for wastewater and bactericidal treatments, self-cleaning window glass for green intelligent buildings, dye-sensitized solar cells, solid state semiconductor metal-oxide solar cells, self-cleaning glass for photovoltaic devices, and general heterogeneous photocatalysis for fine chemicals etc. In this work, we develop a solution-based adsorptive self-assembly approach to fabricate anatase TiO(2) thin films on different glass substrates such as simple plane glass and patterned glass at variable compositions (normal soda lime glass or solar-grade borofloat glass). By tuning the number of process cycles (i.e., adsorption-then-heating) of TiO(2) colloidal suspension, we could facilely prepare large-area TiO(2) films at a desired thickness and with uniform crystallite morphology. Moreover, our as-prepared nanostructured TiO(2) thin films on glass substrates do not cause deterioration in optical transmission of glass; instead, they improve optical performance of commercial solar cells over a wide range of incident angles of light. Our as-prepared anatase TiO(2) thin films also display superhydrophilicity and excellent photocatalytic activity for self cleaning application. For example, our investigation of photocatalytic degradation of methyl orange indicates that these thin films are indeed highly effective, in comparison to other commercial TiO(2) thin films under identical testing conditions. PMID- 22260265 TI - Spontaneous emission control of CdSe/ZnS nanoparticle monolayer in polymer nanosheet waveguide assembled on a one-dimensional silver grating surface. AB - We present spontaneous emission control of a core-shell CdSe/ZnS nanoparticle array assembled with polymer ultrathin films consisting of polymer nanosheets on a silver grating substrate, which served as a unique and simple photonic cavity. The grating-coupled waveguide modes enabled 10(3) order luminescence enhancement and one-fourth spectral narrowing. The light emission from a CdSe/ZnS nanoparticle array can be controlled by tuning the film thickness of hybrid polymer nanoassemblies, which provides multiple emission performance with good tuning ability from red to green at low-power continuous wave laser excitation (~MUW). PMID- 22260266 TI - Safety of older generations of gadolinium in mild-to-moderate renal failure. AB - Nephrogenic systemic fibrosis (NSF) is a rare disease that is mostly reported in patients with chronic kidney disease (CKD) who have received gadolinium as a contrast in imaging techniques. The exact pathogenetic role of renal failure or gadolinium is not known. The aim of this study is to show whether mild-to moderate renal failure is a risk for NSF as it is described in severe renal failure. In this cross-sectional study, we enrolled 164 patients with serum creatinine levels >1.5 mg/dL who were in different stages of CKD and had received gadolinium (gadopentetate). The average lag time between the gadolinium administration and the study was 4 months. The most prevalent skin symptom was itching (19%) and the least frequent was induration and papules (<1%). At the follow-up, all skin lesions were relieved. No patients had characteristic lesions of NSF. Twenty-five percent of patients had acute kidney injury at the time of gadolinium exposure. No patients had liver disease and only five were receiving erythropoietin. None of our patients were taking immunosuppressive agents, but all of them suffered from cardiovascular diseases. We conclude that in patients with mild-to-moderate renal failure, it seems that gadolinium is associated with no or very low risk for NSF. We did not find any NSF in patients with severe renal failure. However, because of the rarity of NSF, the low number of such patients in the study, and the high mortality, the use of gadolinium in these patients should be avoided. PMID- 22260267 TI - Effects of repeated treatment with MDMA on working memory and behavioural flexibility in mice. AB - Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces dopaminergic neurotoxicity in mice. However, it is still not clear whether this exposure induces deficits in cognitive processing related to specific subsets of executive functioning. We evaluated the effects of neurotoxic and non-neurotoxic doses of MDMA (0, 3 and 30 mg/kg, twice daily for 4 days) on working memory and attentional set-shifting in mice, and changes in extracellular levels of dopamine (DA) in the striatum. Treatment with MDMA (30 mg/kg) disrupted performance of acquired operant alternation, and this impairment was still apparent 5 days after the last drug administration. Decreased alternation was not related to anhedonia because no differences were observed between groups in the saccharin preference test under similar experimental conditions. Correct responding on delayed alternation was increased 1 day after repeated treatment with MDMA (30 mg/kg), probably because of general behavioural quiescence. Notably, the high dose regimen of MDMA impaired attentional set-shifting related to an increase in total perseveration errors. Finally, basal extracellular levels of DA in the striatum were not modified in mice repeatedly treated with MDMA with respect to controls. However, an acute challenge with MDMA (10 mg/kg) failed to increase DA outflow in mice receiving the highest MDMA dose (30 mg/kg), corroborating a decrease in the functionality of DA transporters. Seven days after this treatment, the effects of MDMA on DA outflow were recovered. These results suggest that repeated neurotoxic doses of MDMA produce lasting impairments in recall of alternation behaviour and reduce cognitive flexibility in mice. PMID- 22260269 TI - Photophysical properties of {[Au(CN)2]-}2 dimers trapped in a supramolecular electron-acceptor organic framework. AB - Dicyanoaurate reacts with the organic acceptor molecule, 1,1'-bis-(2,4 dinitrophenyl)-4,4'-bipyridinium, DNP, to form a supramolecular complex with the general formula {[Au(CN)(2)](2)DNP}.4H(2)O. The complex was characterized by X ray crystallography, and its photophysical properties were investigated in the solid-state. Although the initial (DNP)Cl(2) compound does not show photoluminescence behavior and the dicyanoaurate shows photoluminescence only in the UV range, the resulting supramolecular complex displays two simultaneous, essentially independent, photoluminescence bands in the visible range originating from individual contributions of the DNP unit and the dicyanoaurate dimers. This unusual simultaneous photoluminescence behavior displayed by both the dicyanoaurate donor units and the redox-active 4,4'-bipyridinium acceptor have lifetimes of 0.5 MUs and several hundred MUs, respectively. PMID- 22260268 TI - Effect of n-3 polyunsaturated fatty acid on gene expression of the critical enzymes involved in homocysteine metabolism. AB - BACKGROUND: Previous studies showed that plasma n-3 polyunsaturated fatty acid (PUFA) was negatively associated with plasma homocysteine (Hcy). OBJECTIVE: We investigated the regulatory effect of n-3 PUFA on mRNA expression of the critical genes encoding the enzymes involved in Hcy metabolism. METHODS: HepG2 cells were treated with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha linolenic acid (ALA) respectively for 48 h. The cells were collected and total RNA was isolated. The mRNA expression levels of the genes were determined by using Real Time-PCR. RESULTS: Compared with controls, the mRNA expression levels of 5-methyltetrahydrofolate reductase (MTHFR) were significantly increased in the DHA group (p < 0.05) and ALA group (p < 0.05); Significantly down-regulated mRNA expression of methionine adenosyltransferase (MAT) was observed with the treatments compared with the controls; the level of MAT expression was significant lower in the DHA group than the ALA group (p < 0.05); Cystathionine gamma-lyase (CSE) expression was significantly increased in the DHA (p < 0.05) and EPA groups (p < 0.05) compared with control. No significant changes were shown in mRNA expression levels of S-adenosylhomocysteine hydrolases (SAHH), cystathionine beta-synthase (CBS), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). CONCLUSIONS: Our results suggest that DHA up-regulates CSE and MTHFR mRNA expression and down-regulates MAT mRNA expression involved in Hcy metabolism. PMID- 22260270 TI - Coal fly ash as a source of iron in atmospheric dust. AB - Anthropogenic coal fly ash (FA) aerosol may represent a significant source of bioavailable iron in the open ocean. Few measurements have been made that compare the solubility of atmospheric iron from anthropogenic aerosols and other sources. We report here an investigation of iron dissolution for three FA samples in acidic aqueous solutions and compare the solubilities with that of Arizona test dust (AZTD), a reference material for mineral dust. The effects of pH, simulated cloud processing, and solar radiation on iron solubility have been explored. Similar to previously reported results on mineral dust, iron in aluminosilicate phases provides the predominant component of dissolved iron. Iron solubility of FA is substantially higher than of the crystalline minerals comprising AZTD. Simulated atmospheric processing elevates iron solubility due to significant changes in the morphology of aluminosilicate glass, a dominant material in FA particles. Iron is continuously released into the aqueous solution as FA particles break up into smaller fragments. These results suggest that the assessment of dissolved atmospheric iron deposition fluxes and their effect on the biogeochemistry at the ocean surface should be constrained by the source, environmental pH, iron speciation, and solar radiation. PMID- 22260271 TI - Characteristic morphology of intracellular microcolonies of Legionella oakridgensis OR-10. AB - Legionella oakridgensis occasionally causes pneumonia in humans. We report here the characteristic morphology of intracellular microcolonies of L. oakridgensis OR-10 in infected epithelial cells. By light microscopy after Gimenez staining, the bacteria showed serpentine-like chain, disk-like conglomerate, and granular forms when they grew intracellularly in Vero cells, HeLa cells, and A549 cells. In a time-lapse study, we observed the progressive change from a serpentine-like chain form to a conglomerate form in Vero cells. Transmission electron microscopy showed that L. oakridgensis OR-10 proliferated both inside membrane structures and in the cytoplasm. Such highly serpentine chain growth has not been reported in any intracellular bacteria. Furthermore, these results imply that L. oakridgensis OR-10 may be proliferating inside the endoplasmic reticulum. PMID- 22260272 TI - Durable strategies to deploy plant resistance in agricultural landscapes. AB - The deployment of resistant crops often leads to the emergence of resistance breaking pathogens that suppress the yield benefit provided by the resistance. Here, we theoretically explored how farmers' main leverages (resistant cultivar choice, resistance deployment strategy, landscape planning and cultural practices) can be best combined to achieve resistance durability while minimizing yield losses as a result of plant viruses. Assuming a gene-for-gene type of interaction, virus epidemics are modelled in a landscape composed of a mosaic of resistant and susceptible fields, subjected to seasonality, and a reservoir hosting viruses year-round. The model links the genetic and the epidemiological processes, shaping at nested scales the demogenetic dynamics of viruses. The choice of the resistance gene (characterized by the equilibrium frequency of the resistance-breaking virus at mutation-selection balance in a susceptible plant) is the most influential leverage of action. Our results showed that optimal strategies of resistance deployment range from 'mixture' (where susceptible and resistant cultivars coexist) to 'pure' strategies (with only resistant cultivar) depending on the resistance characteristics and the epidemiological context (epidemic incidence and landscape connectivity). We demonstrate and discuss gaps concerning virus epidemiology across the agro-ecological interface that must be filled to achieve sustainable disease management. PMID- 22260273 TI - Sexual function with localized prostate cancer: active surveillance vs radical therapy. AB - Study Type - Outcomes (cohort sample) Level of Evidence 2b. What's known on the subject? and What does the study add? The study compares the sexual function of men with low-risk prostate cancer who chose active surveillance (expectant management) with similar men who received radiation therapy or radical prostatectomy. The first group appeared to be sexually active more frequently and had less erectile dysfunction. The study was non-randomized. No other studies exist on the effect of active surveillance on sexual function vs other treatment methods. OBJECTIVE: To compare sexual function of men with localized prostate cancer (PCa) on active surveillance (AS) with similar patients who received radical therapy. PATIENTS AND METHODS: Two groups of men with screening-detected localized PCa were compared. The first were men on AS within the prospective protocol-based Prostate Cancer Research International: Active Surveillance study. The second were men participating in the European Randomized Study of Screening for Prostate Cancer study who had received radical prostatectomy (RP) or radiation therapy (RT). * Questionnaires were completed at two different timepoints after diagnosis or treatment (6 and 12-18 months). These contained 10 items on sexual function, the mental and physical component summary from the Short-Form 12-item health survey, the Center for Epidemiologic Studies Depression scale depression measure and the State Trait Anxiety Inventory general anxiety measure. * Sexual function was compared between groups, and determinants were analysed in multivariable analysis, adjusting for baseline differences. RESULTS: A total of 65-68% of men on AS, 35-36% of those who underwent RP, 36-37% of those who underwent RT and 36% of men in the RP and RT groups combined (combined Tx) were sexually active. * A total of 20-30% of men in the AS group, 86-91% of men in the RP group, 56-60% of men in the RT group and 71-76% of men in the combined Tx group were sexually inactive as a result of erectile dysfunction. * A total of 44-51% of men in the AS group, 96% of men in the RP group, 73-76% of men in the RT group and 84-85% of men in the combined Tx group who were sexually active had problems getting or keeping an erection. * In multivariable analysis these differences were significant, except for AS vs RT. CONCLUSIONS: Men with localized PCa on AS were more often sexually active than similar men who received radical therapy, especially RP. If not sexually active, this was less often attributable to erectile dysfunction for those on AS. If sexually active, this was less often associated with problems getting or keeping an erection for those on AS. * The study was non-randomized; the latest advances in RP and RT might impact results. PMID- 22260274 TI - The role of emotional promiscuity in unprotected sex. AB - Sexual promiscuity is a known risk factor for unprotected sex. A related variable, emotional promiscuity, has conceptual relevance but has yet to be studied with respect to unprotected sex. Data from four studies (total N = 908) indicated that both sexual promiscuity and emotional promiscuity were associated with womens' reports of unprotected sex. Independent of those contributions, the interaction between sexual promiscuity and emotional promiscuity was also significant for women: Scoring high on both variables was associated with the highest number of unprotected partners. This synergistic interaction emerged whether the question about number of unprotected partners referred to the past year or lifetime total. The interaction held up even after controlling for other relevant factors (lifetime partners, romantic beliefs, and attachment styles). In sum, among sexually active women, the susceptibility to falling in love puts them at risk for unprotected sex. Our discussion addresses possible mechanisms and why the key interaction only emerged in women. PMID- 22260275 TI - The transmission of Leishmania infantum chagasi by the bite of the Lutzomyia longipalpis to two different vertebrates. AB - BACKGROUND: Sandflies are vectors of Leishmania, the causative agent of leishmaniasis in mammalian hosts, including humans. The protozoan parasite is transmitted by the sandfly bite during salivation that occurs at the moment of blood feeding. The components of vector saliva include anticlotting and vasodilatory factors that facilitate blood flow and immunomodulatory factors that inhibit wound healing and quell the immune response. Not surprisingly, these factors also play important roles in the establishment of Leishmania infection. To date, the majority of knowledge that has been generated regarding the process of Leishmania infection, including L. infantum chagasi transmission has been gathered by using intradermal or subcutaneous inoculation of purified parasites. FINDINGS: This study presents the establishment of a transmission model of Leishmania infantum chagasi by the bite of Lutzomyia longipalpis, the vector of American visceral leishmaniasis. The parasites were successfully transmitted by infected sandfly bites to mice and hamsters, indicating that both animals are good experimental models. The L. infantum chagasi dose that was transmitted in each single bite ranged from 10 to 10, 000 parasites, but 75% of the sandflies transmitted less than 300 parasites. CONCLUSIONS: The strategy for initiating infection by sandfly bite of experimental animals facilitates future investigations into the complex and dynamic mechanisms of visceral leishmaniasis. It is important to elucidate the transmission mechanism of vector bites. This model represents a useful tool to study L. infantum chagasi infection transmitted by the vector. PMID- 22260276 TI - Forest elephant mitochondrial genomes reveal that elephantid diversification in Africa tracked climate transitions. AB - Among elephants, the phylogeographic patterns of mitochondrial (mt) and nuclear markers are often incongruent. One hypothesis attributes this to sex differences in dispersal and in the variance of reproductive success. We tested this hypothesis by examining the coalescent dates of genetic markers within elephantid lineages, predicting that lower dispersal and lower variance in reproductive success among females would have increased mtDNA relative to nuclear coalescent dates. We sequenced the mitochondrial genomes of two forest elephants, aligning them to mitogenomes of African savanna and Asian elephants, and of woolly mammoths, including the most divergent mitogenomes within each lineage. Using fossil calibrations, the divergence between African elephant F and S clade mitochondrial genomes (originating in forest and savanna elephant lineages, respectively) was estimated as 5.5 Ma. We estimated that the (African) ancestor of the mammoth and Asian elephant lineages diverged 6.0 Ma, indicating that four elephantid lineages had differentiated in Africa by the Miocene-Pliocene transition, concurrent with drier climates. The coalescent date for forest elephant mtDNAs was c. 2.4 Ma, suggesting that the decrease in tropical forest cover during the Pleistocene isolated distinct African forest elephant lineages. For all elephantid lineages, the ratio of mtDNA to nuclear coalescent dates was much greater than 0.25. This is consistent with the expectation that sex differences in dispersal and in variance of reproductive success would have increased the effective population size of mtDNA relative to nuclear markers in elephantids, contributing to the persistence of incongruent mtDNA phylogeographic patterns. PMID- 22260279 TI - Integrated bioinformatics analysis of microRNA expression profiles for an in depth understanding of pathogenic mechanisms in non-alcoholic fatty liver disease. PMID- 22260278 TI - Influenza research database: an integrated bioinformatics resource for influenza research and surveillance. AB - BACKGROUND: The recent emergence of the 2009 pandemic influenza A/H1N1 virus has highlighted the value of free and open access to influenza virus genome sequence data integrated with information about other important virus characteristics. DESIGN: The Influenza Research Database (IRD, http://www.fludb.org) is a free, open, publicly-accessible resource funded by the U.S. National Institute of Allergy and Infectious Diseases through the Bioinformatics Resource Centers program. IRD provides a comprehensive, integrated database and analysis resource for influenza sequence, surveillance, and research data, including user-friendly interfaces for data retrieval, visualization and comparative genomics analysis, together with personal log in-protected 'workbench' spaces for saving data sets and analysis results. IRD integrates genomic, proteomic, immune epitope, and surveillance data from a variety of sources, including public databases, computational algorithms, external research groups, and the scientific literature. RESULTS: To demonstrate the utility of the data and analysis tools available in IRD, two scientific use cases are presented. A comparison of hemagglutinin sequence conservation and epitope coverage information revealed highly conserved protein regions that can be recognized by the human adaptive immune system as possible targets for inducing cross-protective immunity. Phylogenetic and geospatial analysis of sequences from wild bird surveillance samples revealed a possible evolutionary connection between influenza virus from Delaware Bay shorebirds and Alberta ducks. CONCLUSIONS: The IRD provides a wealth of integrated data and information about influenza virus to support research of the genetic determinants dictating virus pathogenicity, host range restriction and transmission, and to facilitate development of vaccines, diagnostics, and therapeutics. PMID- 22260280 TI - Finding a role for Th17 cells in hepatitis C pathogenesis. PMID- 22260281 TI - Magnetic nanoparticles for treatment of gastric cancer. PMID- 22260282 TI - Risk of non-melanoma skin cancer with thiopurine use in inflammatory bowel disease. PMID- 22260283 TI - Education and imaging. Gastrointestinal: Cavitating mesenteric lymph node syndrome as manifestation of anaplastic large cell lymphoma. PMID- 22260284 TI - Education and imaging. Gastrointestinal: Acquired double pylorus; long-term endoscopic observation. PMID- 22260285 TI - Education and imaging. Gastrointestinal: Duodenal tumour and cutaneous skin lesions. PMID- 22260286 TI - Education and imaging. Hepatobiliary and Pancreatic: Aberrant hepatic arteries and pancreatic surgery. PMID- 22260287 TI - Education and imaging. Hepatobiliary and Pancreatic: Detection of early hepatocellular carcinoma by enhanced magnetic resonance imaging. PMID- 22260290 TI - Human cardiomyocyte progenitor cells: a short history of nearly everything. AB - The high occurrence of cardiac disease in the Western world has driven clinicians and cardiovascular biologists to look for alternative strategies to treat patients. A challenging approach is the use of stem cells to repair the heart, in itself an inspiring thought. In the past 10 years, stem cells from different sources have been under intense investigation and, as a result, a multitude of studies have been published on the identification, isolation, and characterization, of cardiovascular progenitor cells and repair in different animal models. However, relatively few cardiovascular progenitor populations have been identified in human hearts, including, but not limited to, cardiosphere derived cells, cKit+ human cardiac stem cells , Isl1+ cardiovascular progenitors, and, in our lab, cardiomyocyte progenitor cells (CMPCs). Here, we aim to provide a comprehensive summary of the past findings and present challenges for future therapeutic potential of CMPCs. PMID- 22260291 TI - Effect of organic acids on the growth and lipid accumulation of oleaginous yeast Trichosporon fermentans. AB - BACKGROUND: Microbial lipids have drawn increasing attention in recent years as promising raw materials for biodiesel production, and the use of lignocellulosic hydrolysates as carbon sources seems to be a feasible strategy for cost-effective lipid fermentation with oleaginous microorganisms on a large scale. During the hydrolysis of lignocellulosic materials with dilute acid, however, various kinds of inhibitors, especially large amounts of organic acids, will be produced, which substantially decrease the fermentability of lignocellulosic hydrolysates. To overcome the inhibitory effects of organic acids, it is critical to understand their impact on the growth and lipid accumulation of oleaginous microorganisms. RESULTS: In our present work, we investigated for the first time the effect of ten representative organic acids in lignocellulosic hydrolysates on the growth and lipid accumulation of oleaginous yeast Trichosporon fermentans cells. In contrast to previous reports, we found that the toxicity of the organic acids to the cells was not directly related to their hydrophobicity. It is worth noting that most organic acids tested were less toxic than aldehydes to the cells, and some could even stimulate the growth and lipid accumulation at a low concentration. Unlike aldehydes, most binary combinations of organic acids exerted no synergistic inhibitory effects on lipid production. The presence of organic acids decelerated the consumption of glucose, whereas it influenced the utilization of xylose in a different and complicated way. In addition, all the organic acids tested, except furoic acid, inhibited the malic activity of T. fermentans. Furthermore, the inhibition of organic acids on cell growth was dependent more on inoculum size, temperature and initial pH than on lipid content. CONCLUSIONS: This work provides some meaningful information about the effect of organic acid in lignocellulosic hydrolysates on the lipid production of oleaginous yeast, which is helpful for optimization of biomass hydrolysis processes, detoxified pretreatment of hydrolysates and lipid production using lignocellulosic materials. PMID- 22260292 TI - Melatonin prevents testicular damage in hyperlipidaemic mice. AB - The damaging effect of hyperlipidaemia on testicular structure was determined, and the influence of melatonin was evaluated in testicular damage related to hyperlipidaemia. Hyperlipidaemia was induced in ApoE-knockout C57BL/6J male mice fed with high-fat diet alone (group A), or with high-fat diet and melatonin (group B). Six ApoE wild-type C57BL/6J male mice were fed with normal diet, served as controls. At the end of the experimental period, ultrastructural observations showed dramatically histopathological alterations in testicular tissues of group A. The basement membranes of seminiferous tubules were partially thickened and wavy-like in testes of mice with hyperlipidaemia, and vacuolar degeneration of mitochondria and dilation of endoplasmic reticulum were identified as well as the number of mitochondria and lipid droplets decreased significantly in Leydig cells and Sertoli cells. Electrondense deposits were observed in cytoplasms of germ cells. The testicular histostructure in group B treated with melatonin was similar to that of control. Apoptosis was determined by terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labelling. Apoptotic germ cells were significantly more numerous in group A than in group B and controls. The results suggest that melatonin may be potential to attenuate testicular damage by improving histopathological changes and reducing germ cell apoptosis in hyperlipidaemic mice. PMID- 22260293 TI - Co3O4/ZnO nanocomposites: from plasma synthesis to gas sensing applications. AB - Herein, we describe the design, fabrication and gas sensing tests of p Co(3)O(4)/n-ZnO nanocomposites. Specifically, arrays of (001) oriented ZnO nanoparticles were grown on alumina substrates by plasma enhanced-chemical vapor deposition (PECVD) and used as templates for the subsequent PECVD of Co(3)O(4) nanograins. Structural, morphological and compositional analyses evidenced the successful formation of pure and high-area nanocomposites with a tailored overdispersion of Co(3)O(4) particles on ZnO and an intimate contact between the two oxides. Preliminary functional tests for the detection of flammable/toxic analytes (CH(3)COCH(3), CH(3)CH(2)OH, NO(2)) indicated promising sensing responses and the possibility of discriminating between reducing and oxidizing species as a function of the operating temperature. PMID- 22260294 TI - Amyrisins A-C, O-prenylated flavonoids from Amyris madrensis. AB - Three new O-prenylated flavonoids, amyrisins A-C (1-3), were isolated from the leaves and twigs of Amyris madrensis, along with the known compound polygamain (4). The structures of 1-3 were elucidated on the basis of the analysis of spectroscopic data interpretation. Amyrisins B (2) and C (3) showed moderate cytotoxicity against PC-3 and DU 145 prostate cancer cells with IC(50) values of 17.5 and 23 MUM, respectively, while amyrisin A (1) did not show any cytotoxicity at the highest concentration tested, 50 MUM. Polygamain (4) exhibited potent antiproliferative and microtubule-depolymerizing activities. PMID- 22260295 TI - Dual growth of adolescent smoking and drinking: evidence for an interaction between the mu-opioid receptor (OPRM1) A118G polymorphism and sex. AB - Smoking and alcohol use often co-occur during adolescence, but little is known about the codevelopment of these substances. In the search for etiological factors that help to explain the development of adolescent substance use patterns, studies have revealed substantial heritability for both alcohol use and smoking. In this regard, the u-opioid receptor gene (OPRM1, chromosome 6q24-q25) has been linked to both substances. This study examined the predictive relationships between initial level and growth of smoking and drinking in 311 early adolescents (13-15 years old) over a 4-year period. In addition, the effects of the A118G polymorphism of the OPRM1 gene on the initial values and the development over time of alcohol use and smoking were assessed. Finally, as prevalence and heritability estimates for both alcohol- and smoking-related behaviors differ between males and females, OPRM1 by sex interactions were tested. We found that high initial levels of early adolescent alcohol consumption were related to a stronger increase in smoking levels over time. In contrast, high initial levels of smoking were not related to growth of alcohol use. No main OPRM1 effects were found, but sex-specificity of the gene was found for smoking development. Male A-allele carriers showed a faster development in smoking behavior, whereas in females, the G-allele led to a faster development in smoking. Thus, in addition to high levels of alcohol as a risk factor for the development of smoking behavior, sex-specific effects exist for OPRM1, which may additionally have consequences for the development of adolescent smoking. PMID- 22260296 TI - Applicability of a short/rapid 13C-urea breath test for Helicobacter pylori: retrospective multicenter chart review study. AB - BACKGROUND: Carbon labeled urea breath tests usually entail a two point sampling with a 20 to 30-minute gap. Our aim was to evaluate the duration of time needed for diagnosing Helicobacter pylori by the BreathID(r) System. METHODS: This is a retrospective multicenter chart review study. Test location, date, delta over baseline, and duration of the entire test were recorded. Consecutively 13C urea breath tests results were extracted from the files over a nine year period. RESULTS: Of the 12,791 tests results, 35.1% were positively diagnosed and only 0.1% were inconclusive. A statistically significant difference in prevalence among the countries was found: Germany showing the lowest, 13.3%, and Israel the highest, 44.1%. Significant differences were found in time to diagnosis: a positive diagnosis had the shortest and an inconclusive result had the longest. Overall test duration averaged 15.1 minutes in Germany versus approximately 13 minutes in other countries. Diagnosis was achieved after approximately 9 minutes in Israel, Italy and Switzerland, but after 10 on average in the others. The mean delta over baseline value for a negative diagnosis was 1.03 +/- 0.86, (range, 0.9 - 5), versus 20.2 +/- 18.9, (range, 5.1 - 159.4) for a positive one. CONCLUSIONS: The BreathID(r) System used in diagnosing Helicobacter pylori can safely shorten test duration on average of 10-13 minutes without any loss of sensitivity or specificity and with no test lasting more than 21 minutes. PMID- 22260297 TI - Intravenous lidocaine has no impact on rocuronium-induced neuromuscular block. Randomised study. AB - BACKGROUND: Intravenous lidocaine is increasingly used in surgical patients. As it has neuromuscular blocking effects, we tested the impact of an intravenous lidocaine infusion on the time course of a rocuronium-induced neuromuscular block. METHODS: Fifty-two adults undergoing surgery were randomly allocated to intravenous lidocaine 1.5 mg/kg followed by a continuous infusion of 2 mg/kg/h or physiological saline (control) throughout surgery. Anaesthesia was induced and maintained with a target-controlled propofol infusion and sufentanil. After loss of consciousness, rocuronium 0.6 mg/kg was given. Neuromuscular transmission was measured using train-of-four (TOF)-watch SX (Organon, Swords Co., Dublin, Ireland) acceleromyography. RESULTS: Onset time (to 95% depression of first twitch) was on average 113.9 s (standard deviation 35.3) with lidocaine and 119.5 s (44.9) with saline (P = 0.618). Total recovery time (TOF ratio 0.9) was on average 58.1 min (15.1) with lidocaine and 54.3 min (16.9) with saline (P = 0.394). Clinical duration (until first twitch has recovered to 25%) was on average 33.3 min (7.2) with lidocaine and 30.6 min (8.1) with saline (P = 0.21). Recovery index (time between 25% and 75% recovery of the first twitch) was on average 11.5 min (5.0) with lidocaine and 10.6 min (4.1) with saline (P = 0.458). Recovery time (between 25% recovery of the first twitch and TOF ratio 0.9) was on average 24.8 min (9.3) with lidocaine and 23.2 min (9.2) with saline (P = 0.541). CONCLUSION: A continuous intravenous infusion of lidocaine has no impact on the time course of the neuromuscular blockade induced by a standard intubation dose of rocuronium. PMID- 22260298 TI - Identification of recurring patterns in fractionated atrial electrograms using new transform coefficients. AB - BACKGROUND: Identification of recurrent patterns in complex fractionated atrial electrograms (CFAE) has been used to differentiate paroxysmal from persistent atrial fibrillation (AF). Detection of the atrial CFAE patterns might therefore be assistive in guiding radiofrequency catheter ablation to drivers of the arrhythmia. In this study a technique for robust detection and classification of recurrent CFAE patterns is described. METHOD: CFAE were obtained from the four pulmonary vein ostia, and from the anterior and posterior left atrium, in 10 patients with paroxysmal AF and 10 patients with longstanding persistent AF (216 recordings in total). Sequences 8.4 s in length were analyzed (8,192 sample points, 977 Hz sampling). Among the 216 sequences, two recurrent patterns A and B were substituted for 4 and 5 of the sequences, respectively. To this data, random interference, and random interference + noise were separately added. Basis vectors were constructed using a new transform that is derived from ensemble averaging. Patterns A and B were then detected and classified using a threshold level of Euclidean distance between spectral signatures as constructed with transform coefficients. RESULTS: In the presence of interference, sensitivity to detect and distinguish two patterns A and B was 96.2%, while specificity to exclude nonpatterns was 98.0%. In the presence of interference + noise, sensitivity was 89.1% while specificity was 97.0%. CONCLUSIONS: Transform coefficients computed from ensemble averages can be used to succinctly quantify synchronized patterns present in AF data. The technique is useful to automatically detect recurrent patterns in CFAE that are embedded in interference without user bias. This quantitation can be implemented in real-time to map the AF substrate prior to and during catheter ablation. PMID- 22260299 TI - A short bedside battery for visuoconstructive hemispatial neglect: Sunnybrook Neglect Assessment Procedure (SNAP). AB - Although it is currently not known whether early assessment and treatment of hemispatial neglect improves rehabilitation outcome, identification in the acute phase of post stroke is important for nursing, counseling families, and planning intervention strategies. Previous tests of neglect either fail to detect mild forms of neglect or are too lengthy for use at the bedside. We tested and selected an efficient, small battery of tests to address this gap. Two hundred and twenty-four stroke patients completed the Sunnybrook Neglect Assessment Procedure (SNAP). Normal performance was determined from a population of 100 normal elderly volunteers. The SNAP was shown to be a highly reliable and valid instrument. Factor analysis showed good internal consistency, suggesting that performance on each subtest is positively correlated with the others. The SNAP is a useful and reliable tool to assess neglect at the bedside in acute stroke patients. PMID- 22260300 TI - Epidemiology: clues to the pathogenesis of Burkitt lymphoma. AB - The two major epidemiological clues to the pathogenesis of Burkitt lymphoma (BL) are the geographical association with malaria--BL incidence relates to the malaria transmission rate--and early infection by Epstein-Barr virus (EBV). Both agents cause B cell hyperplasia, which is almost certainly an essential component of lymphomagenesis in BL. The critical event in lymphomagenesis is the creation of a MYC translocation, bringing the MYC gene into juxtaposition with immunoglobulin genes and causing its ectopic expression, thereby driving the proliferation of BL cells. It is highly likely that such translocations are mediated by the activation-induced cytidine deaminase (AID) gene, which is responsible for hypervariable region mutations as well as class switching. Stimulation of the Toll-like receptor 9 by malaria-associated agonists induces AID, providing a mechanism whereby malaria could directly influence BL pathogenesis. EBV-containing cells must reach the memory cell compartment in order to survive throughout the life of the individual, which probably requires traversal of the germinal centre. Normally, cells that do not produce high affinity antibodies do not survive this passage, and are induced to undergo apoptosis. EBV, however, prevents this, and in doing so may also enhance the likelihood of survival of rare translocation-containing cells. PMID- 22260301 TI - Molybdenum(VI) complexes of a 2,2'-biphenyl-bridged bis(amidophenoxide): competition between metal-ligand and metal-amidophenoxide pi bonding. AB - The 2,2'-biphenyl-bridged bis(2-aminophenol) ligand 4,4'-di-tert-butyl-N,N' bis(3,5-di-tert-butyl-2-hydroxyphenyl)-2,2'-diaminobiphenyl ((t)BuClipH(4)) reacts with MoO(2)(acac)(2) to form ((t)BuClipH(2))MoO(2), where the diarylamines remain protonated and bind trans to the terminal oxo groups. This complex readily loses water on treatment with pyridine or 3,5-lutidine to form mono-oxo complexes ((t)BuClip)MoO(L), which exhibit predominantly a cis-beta geometry with an aryloxide trans to the oxo group. Exchange of the pyridine ligands is rapid and takes place by a dissociative mechanism, which occurs with retention of stereochemistry at molybdenum. Oxo-free alkoxide complexes ((t)BuClip)Mo(OR)(2) are formed from ((t)BuClipH(2))MoO(2) and ROH. Treatment of NMo(O(t)Bu)(3) with (t)BuClipH(4) results in complete deprotonation of the bis(aminophenol) and formation of a dimolybdenum complex ((t)BuClip)Mo(MU-N)(MU-NH(2))Mo((t)BuClip) containing both a bridging nitride (Mo-N = 1.848 A, Mo-N-Mo = 109.49 degrees ) and a bridging amide group. The strong pi bonding of this bis(amidophenoxide) ligand allows the molybdenum center to interconvert readily among species forming three, two, one, or zero pi bonds from multiply bonded ligands. PMID- 22260302 TI - Timing of initiation of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. AB - OBJECTIVE: The aim of the study is to summarize the effects of timing of initiation of renal replacement therapy (RRT) on mortality. METHODS: A systematic search for randomized controlled trials (RCTs) and other clinical studies was performed without language restriction in PubMed, Web of Science, and Embase. We estimated pooled relative risk ratios (RRs) and 95% confidence intervals (CIs) using fixed effects model or random effects model as appropriate. Heterogeneity, publication bias, and subgroup analyses were conducted. RESULTS: We analyzed the date extracted from 15 studies (3 RCTs, 2 prospective, and 10 retrospective comparative cohort studies) with a total of 2955 patients. Overall, 51.0% (772/1514) patients died in the "early" RRT group compared with 58.0% (836/1441) in the "late" RRT group. The pooled RR was 0.71 (95% CI: 0.59, 0.86), but the heterogeneity existed (p < 0.00001). Subgroup analysis based on modality did not record heterogeneity across trials. In continuous RRT (CRRT) group (n = 607), patients treated with "early" CRRT suggested a significant decrease in mortality compared with those in "late" CRRT group (27.8% vs. 43.0%) and the RR was 0.69 (95% CI: 0.56, 0.84) without evidence of heterogeneity (I2 = 33%, p = 0.18). In intermittent hemodialysis (IHD) group (n = 115), the RR was 0.26 (95% CI: 0.15, 0.45) without evidence of heterogeneity (I2 = 0%, p = 0.50). In the mixed group, heterogeneity existed. CONCLUSION: "Early" CRRT and "early" IHD both could reduce the mortality of patients with acute kidney injury compared with "late" CRRT or IHD. PMID- 22260303 TI - Exploring how organic matter controls structural transformations in natural aquatic nanocolloidal dispersions. AB - The response of the dispersion nanostructure of surface river bed sediment to the controlled removal and readdition of natural organic matter (NOM), in the absence and presence of background electrolyte, was examined using the technique of small angle neutron scattering (SANS). Partial NOM removal induced aggregation of the mineral particles, but more extensive NOM removal restored colloidal stability. When peat humic acid (PHA) was added to a NOM-deficient sediment concentration related structural transformations were observed: at 255 mg/L PHA aggregation of the nanocolloid was actually enhanced, but at 380 mg/L PHA disaggregation and colloidal stability were promoted. The addition of 2 mM CaCl(2) induced mild aggregation in the native sediment but not in sediments with added PHA, suggesting that the native NOM and the PHA respond differently to changes in ionic strength. A first attempt at using SANS to directly characterize the thickness and coverage of an adsorbed PHA layer in a natural nanocolloid is also presented. The results are discussed in the context of a hierarchical aquatic colloidal nanostructure, and the implications for contemporary studies of the role of dissolved organic carbon (DOC) in sustaining the transport of colloidal iron in upland catchments. PMID- 22260304 TI - Transitioning from a hospital rehabilitation programme to home: exploring the experiences of people with complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is difficult to diagnose and is characterised by burning pain in one or more limbs. Treatment is palliative not curative and focuses on improving function. This requires patients to make long term changes to their behaviour. As with all such regimens, adherence is often poor. This study explored the lived experience of 10 patients who had returned home after completing a two-week in-patient treatment programme. The interviews focused on how they coped with the transition from hospital to home, and on the things that they considered had facilitated or hindered this transition. Battling for control was an overarching theme that connected the four superordinate themes: 'gaining momentum' that facilitated the implementation of treatment advice, 'distance from the pool of expertise' that detailed the barriers to adherence experienced; 'It helped me realise it was not all in my head' that detailed a facilitative process, and the 'nag list' that was a technique patients' used to garner support. This article offers insights into the transition experience. A key outcome is the recognition of the need to better prepare patients for their transition back home. PMID- 22260305 TI - Nec-1 protects against nonapoptotic cell death in cisplatin-induced kidney injury. AB - BACKGROUND/AIMS: Necrostatin-1 (Nec-1) inhibits necroptosis, a nonapoptotic cell death pathway. Acute kidney injury (AKI) is a clinical problem of high incidence and mortality. It involves several mechanisms of cell death. We aim to evaluate the effect of Nec-1 in the toxic kidney injury model by cisplatin. METHODS: We analyzed the effect of Nec-1 in AKI by cisplatin in human proximal tubule cells by flow cytometry. RESULTS: Our results show that Nec-1 has no effect on apoptosis in renal tubular epithelial cells (Nec-1 + Cis group 13.4 +/- 1.7% vs. Cis group 14.6 +/- 1.4%) (p > 0.05). But, in conditions in which apoptosis was blocked by benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk) the use of Nec-1 completely reversed cell viability (Nec-1 + Cis + z-VAD group 72.9 +/- 6.3% vs. Cis group 35.5 +/- 2.2%) (p < 0.05) suggesting that Nec-1 has effect on nonapoptotic cell death (necroptosis). CONCLUSION: Our findings suggest that the combined use of apoptosis and necroptosis inhibitors can provide additional cytoprotection in AKI. Furthermore, this is the first study to demonstrate that Nec-1 inhibits tubular kidney cell death and restores cell viability via a nonapoptotic mechanism. PMID- 22260306 TI - [Microbiological quality of wheat flour consumed in Morocco]. AB - Cereal products (soft and hard wheat) are a basic staple food in the Moroccan diet. A total of 60 samples of two types of wheat flours used for human consumption were collected; 30 samples among this collection were obtained from various households using Moroccan varieties of wheat produced in traditional flour mills. The rest of the samples were purchased from retail wheat flour sources in the Rabat and Sale city markets. Standard plate counts (SPC), total and faecal coliforms, Clostridium, Salmonella spp., Shigella spp., Staphylococcus aureus, Listeria monocytogenes, yeast, lactic acid bacteria, and molds, were carried out to assess the microbiological quality of wheat flour. Microbiological interpretation of the criteria was performed according to standards implemented by the Codex Alimentarius Commission. Most frequent counts, in traditional and industrial wheat flour, were total aerobic mesophilic bacteria with an average 4 * 104 and 2.5 * 104 cfu/g, respectively. The results showed higher coliform and fungi counts in house than in commercial samples. Pathogenic flora as Salmonella spp., Shigella spp., S. aureus, L. monocytogenes, and Clostridium were not detected in all investigated samples. Bacterial strains isolated from both flours belong to the following genera: Enterobacter spp., Serratia spp., Klebsiella spp., Pantoea spp., Leclercia spp., Proteus spp. The most frequent genus of the investigated isolates was Aspergillus (81 %). Microbial counts were lower than the limit laid down in the Codex Alimentarius, attributing to these flours a satisfactory microbiological quality. PMID- 22260307 TI - Anterior suspension combined with posterior reconstruction during robot-assisted laparoscopic prostatectomy improves early return of urinary continence: a prospective randomized multicentre trial. AB - What's known on the subject? and What does the study add? Urinary incontinence is one of the major drawbacks of radical prostatectomy, regardless of the procedure used (i.e. open, laparoscopic or robotic-assisted). Several technical modifications have been described to improve postoperative continence, highlighting the role of puboprostatic ligaments and posterior reconstruction of the rhabdomyosphincter. The results obtained are inconsistent when applied to robotic surgery. The present multicentre randomized study shows that anterior suspension combined with posterior reconstruction is a safe and easy-to-perform technique for improving early continence after robotic-assisted laparoscopic prostatectomy. OBJECTIVE: To assess the impact on urinary continence of anterior retropubic suspension with posterior reconstruction during robot-assisted laparoscopic prostatectomy (RALP). PATIENTS AND METHODS: In total, 72 patients who were due to undergo prostatectomy between July 2009 and July 2010 were prospectively randomized into two groups: group A underwent a standard RALP procedure and group B had anterior suspension and posterior reconstruction during RALP. The primary outcome measure was urinary continence, assessed using the University of California Los Angeles Prostate Cancer Index questionnaire at 15 days, and at 1, 3 and 6 months, after surgery. Other data recorded were operation duration, blood loss, length of hospital stay, duration of bladder catheterization, complications and positive margin rate. RESULTS: The continence rates at 15 days, and at 1, 3 and 6 months, after surgery were 3.6%, 7.1%, 15.4% and 57.9%, respectively, in group A, and 5.9%, 26.5%, 45.2% and 65.4%, respectively, in group B. The continence rates differed statistically between groups at 1 and 3 months (P = 0.047 and P = 0.016, respectively). There was no significant difference between groups regarding complications (P = 0.8) or positive margin rate (P = 0.46). CONCLUSION: Anterior suspension associated with posterior reconstruction during RALP improved the early return of continence, without increasing complications. PMID- 22260308 TI - Sleep research: observing dreams and inducing hypnagogic images. PMID- 22260310 TI - Investigation of amplitude of accommodation among Ghanaian school children. AB - BACKGROUND: Deficient amplitude of accommodation is the most frequently used criteria in an optometric practice in diagnosing whether a patient has accommodative insufficiency. This deficiency is determined based on an age related expected finding calculated using Hofstetter's equation derived from Donder's and Duane's data. The aim of the present study was to investigate the amplitude of accommodation among Ghanaian school children and to compare the findings with age-expected norms predicted by Hofstetter's equation. METHODS: The amplitude of accommodation was measured using the push-up method in a random sample of 435 school children from the Cape Coast Municipality. The mean amplitude of accommodation was compared with the age-expected amplitude of accommodation as predicted by Hofstetter's equation for average amplitude of accommodation. RESULTS: The mean amplitude of accommodation was 16.86 +/- 3.07 D (95% CI = 16.57, 17.15). This is significantly higher than age-expected norms calculated using Hofstetter's equation. The amplitude of accommodation showed the characteristic decline with age. CONCLUSION: From the results, we conclude that the age-expected norms for amplitude of accommodation using Hofstetter's equation might not be accurate for Ghanaian children. PMID- 22260311 TI - Simultaneous histochemical and immunohistochemical staining as a simple tool to identify mast cells within CD117-positive cell populations. PMID- 22260312 TI - Efficient domino approaches to multifunctionalized fused pyrroles and dibenzo[b,e][1,4]diazepin-1-ones. AB - Efficient domino approaches for the synthesis of multifunctionalized tricyclic fused pyrroles and dibenzo[b,e][1,4]diazepin-1-ones have been established. The reaction pathways were controlled by varying enaminones with different substituted patterns to give a series of new fused pyrroles and dibenzo[b,e][1,4]diazepin-1-ones selectively. The complete anti diastereoselectivity was achieved for the first reaction. PMID- 22260313 TI - "Familial" versus "sporadic" intellectual disability: contribution of subtelomeric rearrangements. AB - BACKGROUND: Cryptic subtelomeric rearrangements have been proposed as a significant cause of sporadic intellectual disability (ID) but the role of such aberrations in familial ID has not yet been studied. As positive family history of ID had been proposed as an important and significant predicting factor of subtelomeric rearrangements, it was assumed that the contribution of subtelomeric aberrations in familial ID would be much more than the sporadic ones. Three hundred and twenty two patients from 102 unrelated families with more than two ID patients in the first degree relatives have been investigated. Assessment of subtelomeric rearrangements were carried out using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique. Detected aberrations were then confirmed by Fluorescence in Situ Hybridization (FISH) method. RESULTS: Among the families studied, 27.4% had 4-12, 36.3% had 3 and 36.3% had 2 affected individuals in the first degree relatives. One unbalanced translocation and 4 polymorphic changes were detected. The prevalence of clinically significant subtelomeric rearrangements was 0.98%. CONCLUSION: This is the first investigation of subtelomeric aberrations in a large sample set of familial ID patients. Our results show that the contribution of subtelomeric rearrangements to familial ID is not as much as what had been determined for sporadic ones in the literature. Moreover, this study shows that the positive family history by alone, cannot be the most important and determining indicator of subtelomeric aberrations while it would be a good predicting factor when associated with dysmorphism or congenital malformations. These findings propose that other cryptic chromosomal abnormalities or even single gene disorders may be the main cause of familial ID rather than subtelomeric aberrations. PMID- 22260314 TI - Suppression of cancer stemness p21-regulating mRNA and microRNA signatures in recurrent ovarian cancer patient samples. AB - BACKGROUND: Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease. METHODS: Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples. RESULTS: Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component. CONCLUSION: We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in ovarian disease. Targeting CSCs within ovarian cancer represents a potential therapeutic avenue. PMID- 22260315 TI - Implementation and evaluation of a harm-reduction model for clinical care of substance using pregnant women. AB - BACKGROUND: Methamphetamine (MA) use during pregnancy is associated with many pregnancy complications, including preterm birth, small for gestational age, preeclampsia, and abruption. Hawaii has lead the nation in MA use for many years, yet prior to 2007, did not have a comprehensive plan to care for pregnant substance-using women. In 2006, the Hawaii State Legislature funded a pilot perinatal addiction clinic. The Perinatal Addiction Treatment Clinic of Hawaii was built on a harm-reduction model, encompassing perinatal care, transportation, child-care, social services, family planning, motivational incentives, and addiction medicine. We present the implementation model and results from our first one hundred three infants (103) seen over 3 years of operation of the program. METHODS: Referrals came from community health centers, hospitals, addiction treatment facilities, private physician offices, homeless outreach services and self-referral through word-of-mouth and bus ads. Data to describe sample characteristics and outcome was obtained prospectively and retrospectively from chart abstraction and delivery data. Drug use data was obtained from the women's self-report and random urine toxicology during the pregnancy, as well as urine toxicology at the time of birth on mothers, and urine and meconium toxicology on the infants. Post-partum depression was measured in mothers with the Edinburgh Post-Partum depression scale. Data from Path clinic patients were compared with a representative cohort of women delivering at Kapiolani Medical Center for Women and Children during the same time frame, who were enrolled in another study of pregnancy outcomes. Ethical approval for this study was obtained through the University of Hawaii Committee for Human Studies. RESULTS: Between April 2007 and August 2010, 213 women with a past or present history of addiction were seen, 132 were pregnant and 97 delivered during that time. 103 live-born infants were delivered. There were 3 first-trimester Spontaneous Abortions, two 28-week intrauterine fetal deaths, and two sets of twins and 4 repeat pregnancies. Over 50% of the women had lost custody of previous children due to substance use. The majority of women who delivered used methamphetamine (86%), either in the year before pregnancy or during pregnancy. Other drugs include marijuana (59.8%), cocaine (33%), opiates (9.6%), and alcohol (15.2%). Of the women served, 85% smoked cigarettes upon enrollment. Of the 97 women delivered during this period, all but 4 (96%) had negative urine toxicology at the time of delivery. Of the 103 infants, 13 (12.6%) were born preterm, equal to the state and national average, despite having many risk factors for prematurity, including poverty, poor diet, smoking and polysubstance use. Overwhelmingly, the women are parenting their children, > 90% retained custody at 8 weeks. Long-term follow-up showed that women who maintained custody chose long-acting contraceptive methods; while those who lost custody had a very high (> 50%) repeat pregnancy rate at 9 months post delivery. CONCLUSION: Methamphetamine use during pregnancy doesn't exist is isolation. It is often combined with a multitude of other adverse circumstances, including poverty, interpersonal violence, psychiatric comorbidity, polysubstance use, nutritional deficiencies, inadequate health care and stressful life experiences. A comprehensive harm reduction model of perinatal care, which aims to ameliorate some of these difficulties for substance-using women without mandating abstinence, provides exceptional birth outcomes and can be implemented with limited resources. PMID- 22260316 TI - Molecular analysis of the beta-globin gene cluster haplotypes in a Sudanese population with sickle cell anaemia. AB - INTRODUCTION: Sudan has a multiethnic population with a high frequency of Hb S, but little is known about the beta(S) haplotypes in this population. METHODS: Blood samples from Sudanese Hb SS individuals were taken at two locations. Family history, age, ethnicity and clinical symptoms were recorded for each subject. Hb S was investigated using cellulose acetate electrophoresis (CAE) and cation exchange-high performance liquid chromatography. Dried blood samples from 93 individuals were used for beta(S) haplotype identification based on restriction fragment length polymorphism analysis for seven restriction sites. RESULTS: Haplotypes could be assigned unequivocally to 143 chromosomes. Four of the five typical beta(S) -globin haplotypes were identified. The most frequent was the Cameroon (35.0%), followed by the Benin (29.4%), the Senegal (18.2%) and the Bantu (2.8%). The Indian-Arab haplotype was not observed. Three atypical haplotypes were identified in 17 patients, occurring at a combined frequency of 14.6%. One of these, found at the high frequency of 11.8%, possibly represented a new Sudan haplotype. CONCLUSION: beta(S) Haplotyes were demonstrated successfully from dried blood samples. A new haplotype is apparent in Sudan, in addition to the four African haplotypes. PMID- 22260317 TI - Single-walled aluminosilicate nanotube/poly(vinyl alcohol) nanocomposite membranes. AB - The fabrication, detailed characterization, and molecular transport properties of nanocomposite membranes containing high fractions (up to 40 vol %) of individually-dispersed aluminosilicate single-walled nanotubes (SWNTs) in poly(vinyl alcohol) (PVA), are reported. The microstructure, SWNT dispersion, SWNT dimensions, and intertubular distances within the composite membranes are characterized by scanning and transmission electron microscopy (SEM and TEM), energy-dispersive spectroscopy (EDS), X-ray diffraction (XRD), XRD rocking curve analysis, small-angle X-ray scattering (SAXS), and solid-state NMR. PVA/SWNT nanocomposite membranes prepared from SWNT gels allow uniform dispersion of individual SWNTs in the PVA matrix with a random distribution of orientations. SAXS analysis reveals the length (~500 nm) and outer diameter (~2.2 nm) of the dispersed SWNTs. Electron microscopy indicates good adhesion between the SWNTs and the PVA matrix without the occurrence of defects such as voids and pinholes. The transport properties of the PVA/SWNT membranes are investigated experimentally by ethanol/water mixture pervaporation measurements, computationally by grand canonical Monte Carlo and molecular dynamics, and by a macroscopic transport model for anisotropic permeation through nanotube-polymer composite membranes. The nanocomposite membranes substantially enhance the water throughput with increasing SWNT volume fraction, which leads to a moderate reduction of the water/ethanol selectivity. The model is parameterized purely from molecular simulation data with no fitted parameters, and shows reasonably good agreement with the experimental water permeability data. PMID- 22260318 TI - Galantamine attenuates reinstatement of cue-induced methamphetamine-seeking behavior in mice. AB - Methamphetamine (METH) dependence is becoming a serious socioeconomic health problem worldwide. The enhancement of the cholinergic nervous system is expected to greatly alleviate drug dependence. We investigated the effect of galantamine on the reinstatement of cue-induced METH-seeking behavior using a self administration experiment. Treatment with galantamine (1 mg/kg, p.o.) 30 minutes before exposure to the cues suppressed the reinstatement of METH-seeking behavior. However, galantamine did not affect the cue-induced reinstatement of food-seeking behavior or locomotor activity. These results suggest that galantamine may be a candidate drug for treating relapses of METH-seeking behavior. PMID- 22260321 TI - Metrical oxidation states of 2-amidophenoxide and catecholate ligands: structural signatures of metal-ligand pi bonding in potentially noninnocent ligands. AB - Catecholates and 2-amidophenoxides are prototypical "noninnocent" ligands which can form metal complexes where the ligands are best described as being in the monoanionic (imino)semiquinone or neutral (imino)quinone oxidation state instead of their closed-shell dianionic form. Through a comprehensive analysis of structural data available for compounds with these ligands in unambiguous oxidation states (109 amidophenolates, 259 catecholates), the well-known structural changes in the ligands with oxidation state can be quantified. Using these correlations, an empirical "metrical oxidation state" (MOS) which gives a continuous measure of the apparent oxidation state of the ligand can be determined based on least-squares fitting of its C-C, C-O, and C-N bond lengths to this single parameter (a simple procedure for doing so is provided via a spreadsheet in the Supporting Information). High-valent d(0) metal complexes, particularly those of vanadium(V) and molybdenum(VI), have ligands with unexpectedly positive, and generally nonintegral, MOS values. The structural effects in these complexes are attributed not to electron transfer, but rather to amidophenoxide- or catecholate-to-metal pi bonding, an interpretation supported by the systematic variation of the MOS values as a function of the degree of competition with the other pi-donating groups in the structures. PMID- 22260319 TI - Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of TB disease in a high burden setting. AB - BACKGROUND: Confirming tuberculosis (TB) disease in suspects in resource limited settings is challenging and calls for the development of more suitable diagnostic tools. Different Mycobacterium tuberculosis (M.tb) infection phase-dependent antigens may be differentially recognized in infected and diseased individuals and therefore useful as diagnostic tools for differentiating between M.tb infection states. In this study, we assessed the diagnostic potential of 118 different M.tb infection phase-dependent antigens in TB patients and household contacts (HHCs) in a high-burden setting. METHODS: Antigens were evaluated using the 7-day whole blood culture technique in 23 pulmonary TB patients and in 19 to 21 HHCs (total n = 101), who were recruited from a high-TB incidence community in Cape Town, South Africa. Interferon-gamma (IFN-gamma) levels in culture supernatants were determined by ELISA. RESULTS: Eight classical TB vaccine candidate antigens, 51 DosR regulon encoded antigens, 23 TB reactivation antigens, 5 TB resuscitation promoting factors (rpfs), 6 starvation and 24 other stress response-associated TB antigens were evaluated in the study. The most promising antigens for ascertaining active TB were the rpfs (Rv0867c, Rv2389c, Rv2450c, Rv1009 and Rv1884c), with Areas under the receiver operating characteristics curves (AUCs) between 0.72 and 0.80. A combination of M.tb specific ESAT-6/CFP-10 fusion protein, Rv2624c and Rv0867c accurately predicted 73% of the TB patients and 80% of the non-TB cases after cross validation. CONCLUSIONS: IFN-gamma responses to TB rpfs show promise as TB diagnostic candidates and should be evaluated further for discrimination between M.tb infection states. PMID- 22260322 TI - Predictive environmental risk assessment of chemical mixtures: a conceptual framework. AB - Environmental risks of chemicals are still often assessed substance-by-substance, neglecting mixture effects. This may result in risk underestimations, as the typical exposure is toward multicomponent chemical "cocktails". We use the two well established mixture toxicity concepts (Concentration Addition (CA) and Independent Action (IA)) for providing a tiered outline for environmental hazard and risk assessments of mixtures, focusing on general industrial chemicals and assuming that the "base set" of data (EC50s for algae, crustaceans, fish) is available. As mixture toxicities higher than predicted by CA are rare findings, we suggest applying CA as a precautious first tier, irrespective of the modes/mechanisms of action of the mixture components. In particular, we prove that summing up PEC/PNEC ratios might serve as a justifiable CA-approximation, in order to estimate in a first tier assessment whether there is a potential risk for an exposed ecosystem if only base-set data are available. This makes optimum use of existing single substance assessments as more demanding mixture investigations are requested only if there are first indications of an environmental risk. Finally we suggest to call for mode-of-action driven analyses only if error estimations indicate the possibility for substantial differences between CA- and IA-based assessments. PMID- 22260323 TI - Risk factors and treatment of childhood and adolescent Burkitt lymphoma/leukaemia. AB - Burkitt lymphoma/leukaemia is the most common (40%) form of non-Hodgkin lymphoma that occurs in children and adolescents. The prognosis of advanced (disseminated) Burkitt lymphoma/leukaemia in children and adolescents three decades ago had a 5 year event-free survival (EFS) of <40%, and required combination chemotherapy and radiation therapy over a 1-2 year period. Currently, the prognosis for the same advanced stage has a 5-year EFS of 85-90% with <6 months of chemotherapy only. Radiation therapy has been eliminated for children and adolescents with Burkitt lymphoma/leukaemia except in emergencies, such as superior vena cava syndrome and acute neurological impairment or in patients with relapse/progression. Current risk factors in the prognosis of childhood and adolescent Burkitt lymphoma/leukaemia include: lactate dehydrogenase level >= 2* the upper normal limit at diagnosis, bone marrow and central nervous system involvement, poor response to cyclophosphamide, vincristine and prednisone reduction therapy and poor risk cytogenetics. New and novel therapeutic approaches include monoclonal antibody (anti-CD20) therapy, targeted cellular immune therapy and small molecule inhibitors. Future strategies should include improved staging and risk classification, reduction of cytotoxic chemotherapy, the investigation of targeted therapy, an increased understanding of the underlying biology of Burkitt lymphoma/leukaemia, strategies for prevention and approaches to reduce acute and chronic toxicities. PMID- 22260324 TI - The delayed post-injury administration of soluble fas receptor attenuates post traumatic neural degeneration and enhances functional recovery after traumatic cervical spinal cord injury. AB - Spinal cord injury (SCI) is a devastating condition that currently lacks clinically-relevant and effective neuroprotective therapeutic options. Optimal therapeutic agents for clinical translation should show efficacy in a cervical compression/contusion model using a clinically-relevant post-injury therapeutic time window. To date, few compounds have met that rigorous standard. The objective of this work was to evaluate the efficacy of delayed post-injury administration of soluble Fas receptor (sFasR) via intrathecal catheter following acute cervical SCI in a clinically-relevant contusion/compression model. Female Wistar rats were given a C7-T1 moderately severe clip compression injury, followed by either 8-h or 24-h delayed treatment initiation. Long-term neurobehavioral analysis of motor recovery and neuropathic pain development was undertaken. The extent of oligodendrocyte and neuron survival was assessed in peri-lesional cord sections 8 weeks post-SCI. This was complemented by an evaluation of the level of tissue preservation at and adjacent to the site of injury. In animals treated with sFasR delayed 8 h post-injury, significant behavioral effects were observed, coinciding with enhanced cell survival, peri lesional tissue sparing, and enhanced integrity of descending fiber tracts compared to control treatments. Animals treated with sFasR delayed by 24 h showed more modest improvements in behavioral recovery, and had consistent improvements in cell survival and tissue preservation. This work has shown for the first time that the Fas-mediated apoptotic pathway can be therapeutically targeted in a clinically-relevant time window post-SCI. PMID- 22260325 TI - Generating singlet oxygen bubbles: a new mechanism for gas-liquid oxidations in water. AB - Laser-coupled microphotoreactors were developed to bubble singlet oxygen [(1)O(2) ((1)Delta(g))] into an aqueous solution containing an oxidizable compound. The reactors consisted of custom-modified SMA fiberoptic receptacles loaded with 150 MUm silicon phthalocyanine glass sensitizer particles, where the particles were isolated from direct contact with water by a membrane adhesively bonded to the bottom of each device. A tube fed O(2) gas to the reactor chambers. In the presence of O(2), singlet oxygen was generated by illuminating the sensitizer particles with 669 nm light from an optical fiber coupled to the top of the reactor. The generated (1)O(2) was transported through the membrane by the O(2) stream and formed bubbles in solution. In solution, singlet oxygen reacted with probe compounds (9,10-anthracene dipropionate dianion, trans-2-methyl-2 pentanoate anion, N-benzoyl-D,L-methionine, or N-acetyl-D,L-methionine) to give oxidized products in two stages. The early stage was rapid and showed that (1)O(2) transfer occurred via bubbles mainly in the bulk water solution. The later stage was slow; it arose only from (1)O(2)-probe molecule contact at the gas/liquid interface. A mechanism is proposed that involves (1)O(2) mass transfer and solvation, where smaller bubbles provide better penetration of (1)O(2) into the flowing stream due to higher surface-to-volume contact between the probe molecules and (1)O(2). PMID- 22260326 TI - Comparative analysis of recombinant Human Papillomavirus 8 L1 production in plants by a variety of expression systems and purification methods. AB - Human papillomavirus 8 (HPV-8), one of the high-risk cutaneous papillomaviruses (cHPVs), is associated with epidermodysplasia verruciformis and nonmelanoma skin cancer in immuno-compromised individuals. Currently, no vaccines against cHPVs have been reported; however, recent studies on cross-neutralizing properties of their capsid proteins (CP) have fostered an interest in vaccine production against these viruses. We examined the potential of producing HPV-8 major CP L1 in Nicotiana benthamiana by agroinfiltration of different transient expression vectors: (i) the binary vector pBIN19 with or without silencing suppressor constructs, (ii) the nonreplicating Cowpea mosaic virus-derived expression vector pEAQ-HT and (iii) a replicating Tobacco mosaic virus (TMV)-based vector alone or with signal peptides. Although HPV-8 L1 was successfully expressed using pEAQ-HT and TMV, a 15-fold increase was obtained with pEAQ-HT. In contrast, no L1 protein could be immune detected using pBIN19 irrespective of whether silencing suppressors were coexpressed, although such constructs were required for identifying L1-specific transcripts. A fourfold yield increase in L1 expression was obtained when 22 C-terminal amino acids were deleted (L1DeltaC22), possibly eliminating a nuclear localization signal. Electron microscopy showed that plant made HPV-8 L1 proteins assembled in appropriate virus-like particles (VLPs) of T = 1 or T = 7 symmetry. Ultrathin sections of L1DeltaC22-expressing cells revealed their accumulation in the cytoplasm in the form of VLPs or paracrystalline arrays. These results show for the first time the production and localization of HPV-8 L1 protein in planta and its assembly into VLPs representing promising candidate for potential vaccine production. PMID- 22260328 TI - Antitumor activity and molecular dynamics simulations of paclitaxel-laden triazine dendrimers. AB - The antitumor activities of triazine dendrimers bearing paclitaxel, a well-known mitotic inhibitor, are evaluated in SCID mice bearing human prostate cancer xenografts. To increase the activity of a first generation prodrug 1 that contained twelve paclitaxel molecules tethered via an ester linkage, the new construct described here, prodrug 2, tethers paclitaxel with linkers containing both an ester and disulfide. While PEGylation is necessary for solubility, and may improve biocompatibility and increase plasma half-life, it increases the heterogeneity of the sample with an average of eight to nine PEG chains (2 kDa each) incorporated. The heterogeneous population of PEGylated materials was used without fractionation based on models obtained from molecular dynamics simulations. Three models were examined; hexaPEGylated, nonaPEGylated, and dodecaPEGylated constructs. Intravenous delivery of prodrug 2 was performed by single, double or triple dosing regimes with doses spaced by one week. The doses varied from 50 mg of paclitaxel/kg to 200 mg of paclitaxel/kg. Tumor growth arrest and regression was observed over the 10-week treatment period without mortality for mice treated with the 50 mg of paclitaxel/kg treated three times. PMID- 22260327 TI - EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. AB - Epidermal growth factor (EGF) family peptides are ligands for the EGF receptor (EGFR). Here, we elucidate functional differences among EGFR ligands and mechanisms underlying these distinctions. In 32D/EGFR myeloid and MCF10A breast cells, soluble amphiregulin (AR), transforming growth factor alpha (TGFalpha), neuregulin 2 beta, and epigen stimulate greater EGFR coupling to cell proliferation and DNA synthesis than do EGF, betacellulin, heparin-binding EGF like growth factor, and epiregulin. EGF competitively antagonizes AR, indicating that its functional differences reflect dissimilar intrinsic activity at EGFR. EGF stimulates much greater phosphorylation of EGFR Tyr1045 than does AR. Moreover, the EGFR Y1045F mutation and z-cbl dominant-negative mutant of the c cbl ubiquitin ligase potentiate the effect of EGF but not of AR. Both EGF and AR stimulate phosphorylation of EGFR Tyr992. However, the EGFR Y992F mutation and phospholipase C gamma inhibitor U73122 reduce the effect of AR much more than that of EGF. Expression of TGFalpha in 32D/EGFR cells causes greater EGFR coupling to cell proliferation than does expression of EGF. Moreover, expression of EGF in 32D/EGFR cells causes these cells to be largely refractory to stimulation with soluble EGF. Thus, EGFR ligands are functionally distinct in models of paracrine and autocrine signaling and EGFR coupling to biological responses may be specified by competition among functionally distinct EGFR ligands. PMID- 22260329 TI - Preparation of a single-chain variable fragment and a recombinant antigen-binding fragment against the anti-malarial drugs, artemisinin and artesunate, and their application in an ELISA. AB - Two different recombinant antibodies, a single-chain variable fragment (scFv) and an antigen-binding fragment (Fab), were prepared against artemisinin (AM) and artesunate (AS) and were developed for use in an enzyme-linked immunosorbent assay (ELISA). The recombinant antibodies, which were derived from a single monoclonal antibody against AM and AS (mAb 1C1) prepared by us, were expressed by Escherichia coli cells and their reactivity and specificity were characterized. As a result, to obtain sufficient signal in indirect ELISA, a much greater amount of a first antibody was needed in the use of scFv due to the differences of the secondary antibody and conformational stability. Therefore, we focused on the development of the recombinant Fab antibodies and applied it to indirect competitive ELISA. The specificity of the Fab was similar to that of mAb 1C1 in that it showed specific reactivity toward AM and AS only. The sensitivity of the icELISA (0.16 MUg/mL to 40 MUg/mL for AM and 8.0 ng/mL to 60 ng/mL for AS) was sufficient for analysis of antimalarial drugs, and its utility for quality control of analysis of Artemisia spp. was validated. The Fab expression and refolding systems provided a good yield of high-quality antibodies. The recombinant antibody against AM and AS provides an essential component of an economically attractive immunoassay and will be useful in other immunochemical applications for the analysis and purification of antimalarial drugs. PMID- 22260330 TI - The course of hypercalciuria and related markers of bone metabolism parameters associated with corticosteroid treatment. AB - BACKGROUND AND OBJECTIVE: Prolonged corticosteroid (CS) use induces osteoporosis; the pathogenesis of this condition is multifactorial and includes CS-induced hypercalciuria. We investigated the course of hypercalciuria and related markers of bone metabolism parameters during and after the CS treatment. MATERIALS AND METHODS: We recruited 42 patients who were taking at least 10 mg/day of methylprednisolone or an equivalent dose of CSs for at least 30 days. The 24-h urinary calcium and sodium, a spot urinary calcium/creatinine ratio, and urinary deoxypyridinoline were measured prior to the treatment, at day 7, at days 30-60, and after the cessation of the treatment. Additionally, the serum levels of phosphorus, calcium, alkaline phosphatase (ALP), albumin, creatinine, osteocalcin, and parathyroid hormone (PTH) were analyzed. RESULTS: The 24-h urinary calcium excretion was significantly increased at day 7 (182.2 +/- 158.6 mg/day; p < 0.001) and at days 30-60 (196.9 +/- 167.8 mg/day; p < 0.001) compared with baseline (98.7 +/- 88.1 mg/day) and returned to basal level after the cessation of the CSs (118.9 +/- 90.2 mg/day; p = 0.725). The urinary deoxypyridinoline level was significantly higher at days 30-60 compared with basal level. The serum osteocalcin level was decreased at days 30-60 when compared with day 7. No significant changes were detected in the PTH, phosphorus, creatinine, and ALP levels. CONCLUSIONS: CS treatment induces hypercalciuria just after starting the treatment until the end of it. CS-induced hypercalciuria promptly improved after cessation of the treatment. By days 30-60, the excretion of urinary deoxypyridinoline was accompanied by hypercalciuria. The serum osteocalcin level was decreased at days 30-60 when compared with day 7. PMID- 22260331 TI - Effect of stem cell factor and granulocyte-macrophage colony-stimulating factor induced bone marrow stem cell mobilization on recovery from acute tubular necrosis in rats. AB - BACKGROUND: Acute tubular necrosis (ATN) is the most common reason for acute kidney injury (AKI), and there is still an absence of effective therapies. OBJECTIVE: To assess the value of bone marrow cell mobilization by stem cell factor (SCF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy in rats with gentamicin-induced ATN. METHODS: ATN was induced in male Sprague-Dawley (SD) rats with five daily high-dose intraperitoneal injections of gentamicin. Subcutaneous injections of SCF and GM-CSF were administered simultaneously and these cytokines were observed on days 2, 5, 10, 17, 24, and 31. Peripheral blood and renal tissue CD34+ cell count, mortality rate, blood urea nitrogen (BUN), serum creatinine (SCr), creatinine clearance rate (CCr), and histopathologic lesion scores were determined. Twelve hours after bone marrow ablation (BMA) by lethal X-ray radiation, specific pathogen-free (SPF) ATN rats were given five daily injections of SCF and GM-CSF. BUN, SCr, and histopathologic lesion scores were evaluated on days 2, 5, and 10. RESULTS: Peripheral blood CD34+ cell count increased significantly in ATN rats between 2 and 10 days after SCF and GM-CSF injection. Mortality was reduced from 34.7% in the ATN group to 18.6% in the ATN+CSF. In addition, cytokines administration significantly decreased SCr and BUN. Moreover, cytokines rapidly ameliorated tubular injury. There was no significant effect on ATN rats after BMA. CONCLUSIONS: This study demonstrated that SCF and GM-CSF effectively mobilized bone marrow cells in ATN rats, and cytokines administration partially prevented gentamicin-induced ATN. These results suggest that bone marrow stem cell (BMSC) mobilization may be an effective therapy for ATN. PMID- 22260332 TI - CuO Nanoparticles from the strongly hydrated ionic liquid precursor (ILP) tetrabutylammonium hydroxide: evaluation of the ethanol sensing activity. AB - The sensing potential of CuO nanoparticles synthesized via precipitation from a water/ionic liquid precursor (ILP) mixture was investigated. The particles have a moderate surface area of 66 m(2)/g after synthesis, which decreases upon thermal treatment to below 5 m(2)/g. Transmission electron microscopy confirms crystal growth upon annealing, likely due to sintering effects. The as-synthesized particles can be used for ethanol sensing. The respective sensors show fast response and recovery times of below 10 s and responses greater than 2.3 at 100 ppm of ethanol at 200 degrees C, which is higher than any CuO-based ethanol sensor described so far. PMID- 22260333 TI - Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene. AB - BACKGROUND: The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature. RESULTS: We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15. DISCUSSION: This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement. PMID- 22260334 TI - Ten-week lifestyle changing program reduces several indicators for metabolic syndrome in overweight adults. AB - We aim to investigate the effectiveness of a 10-week lifestyle intervention focusing on physical activity and high fiber intake for reducing indicators for metabolic syndrome in overweight-obese individuals. A prospective study of 50 overweight (OW) adults (22 in the general educational group - G1; 28 in the high fiber nutrition group - G2) was performed. Both groups were offered dietary counseling and supervised exercise. Clinical, anthropometric, dietary and plasma biochemical tests were performed at baseline - time 0 (T0) and after 10 weeks - time 1 (T1). Both groups improved their dietary quality, but only G2 presented higher intake of fruit and vegetables (servings/day), higher plasma beta-carotene levels and a 24% reduction of MetS incidence. Additionally G2 showed greater reductions in body fat (4%), and waist circumference (7%), obesity class III (2%) and obesity class II (14%) rate. Lifestyle intervention, including a high dietary fiber intake, improved healthy eating index and decreased body fat composition and plasma lipid concentrations leading to MetS incidence reduction. PMID- 22260335 TI - Implicit and explicit alcohol cognitions and observed alcohol consumption: three studies in (semi)naturalistic drinking settings. AB - AIMS: Dual-process models imply that alcohol use is related to implicit as well as explicit cognitive processes. Few studies have tested whether both types of processes are related to ad libitum drinking. In a series of three studies, we tested whether both implicit and explicit alcohol-related cognitions predicted the amount of alcohol consumed in an ad libitum (semi)naturalistic drinking situation. DESIGN: Two experimental studies used trained confederates (same-sex peers) who consumed either alcoholic or non-alcoholic beverages, while observing participants' drinking behaviour in a 30-minute session. The third study involved observations of participants' alcohol use during a 45-minute session in which participants spent time with five to seven friends. SETTING: A (semi)naturalistic drinking setting, a laboratory bar. PARTICIPANTS: Participants were undergraduates recruited at Radboud University (study 1: n = 115; study 2: n = 121; study 3: n = 200). MEASUREMENTS: We used coding of drinking behaviour from observations, questionnaire data on positive alcohol expectancies and alcohol use patterns and implicit association tests to assess alcohol associations. FINDINGS: Implicit associations were not related to observed alcohol use, whereas explicit positive expectancies were related positively to observed alcohol use in study 1 and study 2. CONCLUSIONS: Among undergraduate students in (semi)naturalistic drinking settings with peers, implicit alcohol-related cognitions do not predict the amount of alcohol consumed. PMID- 22260336 TI - Antifungal efficacy of soft contact lens disinfecting solutions against Fusarium solani and Candida albicans. AB - PURPOSE: The aim was to evaluate the disinfection properties of six multi-purpose contact lens disinfection solutions (MPDS) available in Iran against Fusarium solani and Candida albicans, based on the International Organization for Standardization (ISO) 14729 guidelines. METHODS: Three lots each of six multi purpose solutions, namely, Renu MultiPlus, Solo Care Aqua, All-Clean soft, Contact All In One Advanced, Hippia, Ginza Multi-Purpose Solution and 0.9% normal saline solution were inoculated with standard strains of Fusarium solani (ATCC 36031) and Candida albicans (ATCC 10231). Surviving fungi were determined by counting colony-forming units on recovery plates at specified times. The mean log reduction in fungal numbers at the manufacturer's minimum recommended disinfection time was determined and compared with the criteria for stand-alone disinfection products for each MPDS against each fungal strain. RESULTS: Renu MultiPlus, Contact All In One Advanced and All-Clean Soft were effective in achieving the mean 1.0 log reduction in fungal numbers, based on ISO 14729 stand alone primary acceptance criteria. Solo Care Aqua failed to achieve the ISO 14729 stand-alone primary acceptance criteria for Candida albicans. The other solutions were not effective against test microorganisms after the specified times. CONCLUSIONS: There were differences in the rates of disinfection efficacy. Generally, Renu MultiPlus, Contact All In One Advanced and All-Clean Soft exceeded the primary acceptance criteria of the ISO 14729 guidelines for stand alone contact lens solutions. PMID- 22260337 TI - Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers. AB - Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 agonist oral Delta9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers and compare these with dronabinol's effects. Participants (4 female; 10 male) smoking marijuana 6.6 (standard deviation = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over seven sessions, the time-dependent subjective, cognitive and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect and/or 'high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol, and effects were more dose-related, suggesting improved bioavailability. Nabilone was well tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence. PMID- 22260338 TI - Posterolateral versus posterior interbody fusion in isthmic spondylolisthesis. AB - Spondylolisthesis is a heterogeneous disorder characterized by subluxation of a vertebral body over another in the sagittal plane. Its most common form is isthmic spondylolisthesis (IS). This study aims to compare clinical outcomes of posterolateral fusion (PLF) with posterior lumbar interbody fusion (PLIF) with posterior instrumentation in the treatment of IS. We performed a randomized prospective study in which 80 patients out of a total of 85 patients with IS were randomly allocated to one of two groups: PLF with posterior instrumentation (group I) or PLIF with posterior instrumentation (group II). Posterior decompression was performed in the patients. The Oswestry low back pain disability (OLBP) scale and Visual Analogue Scale (VAS) were used to evaluate the quality of life (QoL) and pain, respectively. Fisher's exact test was used to evaluate fusion rate and the Mann-Whitney U test was used to compare categorical data. Fusion in group II was significantly better than in group I (p=0.012). Improvement in low back pain was statistically more significant in group I (p=0.001). The incidence of neurogenic claudication was significantly lower in group I than in group II (p=0.004). In group I, there was no significant correlation between slip Meyerding grade and disc space height, radicular pain, and low back pain. There was no significant difference in post-operative complications at 1-year follow-up. Our data showed that PLF with posterior instrumentation provides better clinical outcomes and more improvement in low back pain compared to PLIF with posterior instrumentation despite the low fusion rate. PMID- 22260339 TI - Personality disorders and accentuations in at-risk persons with and without conversion to first-episode psychosis. AB - AIM: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Cluster A personality disorders (PDs), particularly schizotypal PD, are considered a part of the schizophrenia spectrum and a risk factor of psychosis. The role of PDs and personality accentuations (PAs) in predicting conversion to psychosis was studied in patients symptomatically considered at risk, assuming a major role of the schizotypal subtype. METHODS: PDs and PAs, assessed at baseline with a self-report questionnaire, were compared between risk-, gender- and age matched at-risk patients with (n = 50) and without conversion to psychosis (n = 50). RESULTS: Overall, Cluster A-PDs were the least frequent cluster (14%), and schizotypal PD was rare (7%). Yet, PDs in general were frequent (46%), especially Cluster B- (31%) and C-PDs (23%). Groups did not differ in frequencies of PDs, yet converters tended to have a higher expression of schizoid (P = 0.057) and Cluster A-PAs (P = 0.027). In regression analyses, schizoid PA was selected as sole but weak predictor of conversion (OR = 1.685; 95% CIs: 1.134/2.504). CONCLUSIONS: Unexpectedly, schizotypal PD was infrequent and did not predict conversion. Conversion was best predicted by schizoid PA, indicating more severe, persistent social deficits already at baseline in later converters. This corresponds to premorbid social deficits reported for genetic high-risk children and low social functioning in at-risk patients later converting to psychosis. Further, PDs occurred frequently in at-risk patients irrespective of conversion. As psychopathology and personality relate closely to one another, this result highlights that, beyond the current narrow focus on schizotypal PD, personality related factors should be considered more widely in the prevention of psychosis. PMID- 22260340 TI - Criterion validity of a 10-category scale for ranking physical activity in Norwegian women. AB - BACKGROUND: Accurate measurement of physical activity (PA) is critical to establish dose-response relationships with various health outcomes. We compared the self-administered PA questionnaire from the Norwegian Women and Cancer Study (NOWAC) with a criterion method in middle-aged Norwegian women. METHODS: A sample of 177 randomly recruited healthy women attended two clinical visits approximately 4-6 months apart. At each visit, the women completed the NOWAC PA questionnaire (NOPAQ), rating their overall PA level on a 10-category scale (1 being a "very low" and 10 being a "very high" PA level) and performed an 8-minute step-test to estimate aerobic fitness (VO2max). After each visit, the women wore a combined heart rate and movement sensor for 4 consecutive days of free-living. Measures of PA obtained from the combined heart rate and movement sensor, which were used as criterion, included individually calibrated PA energy expenditure (PAEE), acceleration, and hours/day of moderate-to-vigorous intensity PA (MVPA). These were averaged between visits and compared to NOPAQ scores at visit 2. RESULTS: Intra-class correlation coefficients for objective measures from both free-living periods were in the range of 0.65-0.87 (P < 0.001), compared to 0.62 (P < 0.001) for NOPAQ. There was a moderate but significant (P < 0.001) Spearman's rank correlation coefficient in the range of 0.36-0.46 between NOPAQ and objective measures of PA. Linear trends for the association between the NOPAQ rating scale with PAEE, hours/day of MVPA and VO2max (P < 0.001) were also demonstrated. CONCLUSIONS: Self-reported PA level measured on a 10-category scale appears valid to rank PA in a female Norwegian population. PMID- 22260341 TI - Resonantly enhanced multiphoton ionization and zero kinetic energy photoelectron spectroscopy of benzo[g,h,i]perylene. AB - We report zero kinetic energy (ZEKE) photoelectron spectroscopy of benzo[g,h,i]perylene (BghiP) via resonantly enhanced multiphoton ionization (REMPI). Our analysis concentrates on the vibrational modes of both the first electronically excited state and the ground cationic state. Extensive vibronic coupling due to a nearby electronically excited state manifests through strong Franck-Condon (FC) forbidden bands, which are stronger than even the FC allowed bands in the REMPI spectrum. Theoretical calculations using Gaussian are problematic in identifying the electronic configurations of the excited electronic states and predicting the transition energies. However, by setting the keyword for the second excited electronic state, both density functional theory and configuration interaction methods can reproduce the observed spectrum qualitatively. The general agreement significantly helps with the vibrational assignment. The ZEKE spectra demonstrate propensity in preserving the vibrational excitation of the intermediate electronic state. In addition, almost all ZEKE spectra exhibit a similar vibrational distribution, and the distribution can be reproduced by an FC calculation from the vibronic origin of the first excited electronic state to the cationic state using Gaussian 09. These results suggest a remarkable structural stability of BghiP in accommodating the additional charge. All observed vibrational bands of the cation are IR active, establishing the role of ZEKE spectroscopy in mapping out far-infrared bands for astrophysical applications. PMID- 22260343 TI - Intrusion pressure to initiate flow through pores between spheres. AB - In this work, clusters of three or four spheres were used to examine intrusion pressure. Polytetrafluoroethylene (PTFE) or polyamide 66 (PA66) spheres were arranged horizontally to create a single pore. Liquid drops of water or ethylene glycol were gently introduced from above. If the spheres were too large, drops flowed through as soon as they were deposited. If the spheres were too small, liquid was suspended in the neck of the pore and could not pass through; drops became unstable and fell to one side. Alternatively, if spheres of a certain size were chosen, then capillary forces initially prevented drops of lesser stature from breaking though. However, as these drops grew taller, they eventually reached a height where the gravitational force exceeded the capillary force and the liquid flowed through the pore. A simple model for intrusion pressure was derived. Estimates from the model agreed well with experimentally measured values. PMID- 22260342 TI - Distribution of 5-ht(1E) receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study. AB - BACKGROUND AND PURPOSE: The 5-ht(1E) receptor is highly expressed in the human brain and its structure is conserved in humans, suggesting an important physiological role for 5-ht(1E) receptors. However, neither the function nor the distribution of this receptor has been characterized in the mammalian brain. EXPERIMENTAL APPROACH: Rats and mice lack the 5-ht(1E) receptor gene; thus, we used guinea pig brain tissue and immunofluorescent staining techniques to provide the first specific localization of 5-ht(1E) receptors in the mammalian brain. KEY RESULTS: High levels of 5-ht(1E) receptors are detected in olfactory bulb glomeruli as well as the molecular layer of the dentate gyrus (DG). In DG membranes, BRL54443, a 5-ht(1E) /5-HT(1F) agonist, selectively stimulated 5 ht(1E) receptors and potently inhibited forskolin-dependent cAMP production (IC50 = 14 nM). The staining pattern of 5-ht(1E) receptors in brain tissue suggests that this receptor is expressed predominantly in neurons rather than in glia. Additionally, 5-ht(1E) receptors were detected in the adventitial layer of cerebral arteries but not in the microvasculature, venous tissue or other brain arteries. CONCLUSIONS AND IMPLICATIONS: These observations should help to predict clinical effects of 5-ht(1E) -selective drugs. For example, the stimulation of 5 ht(1E) receptors and subsequent inhibition of adenylate cyclase activity in the DG suggests that 5-ht(1E) receptors may mediate regulation of hippocampal activity by 5-HT, making it a possible drug target for the treatment of neuropsychiatric disorders characterized by memory deficits (such as Alzheimer's disease) or as a target for the treatment of temporal lobe epilepsy. PMID- 22260344 TI - Drug resistance mutations and heteroresistance detected using the GenoType MTBDRplus assay and their implication for treatment outcomes in patients from Mumbai, India. AB - BACKGROUND: Only 5% of the estimated global multidrug resistant TB (MDRTB) load is currently detected. Endemic Mumbai with increasing MDR would benefit from the introduction of molecular methods to detect resistance. METHODS: The GenoType MTBDRplus assay was used to determine mutations associated with isoniazid and rifampicin resistance and their correlation with treatment outcomes. It was performed on a convenience sample comprising 88 onset and 67 fifth month isolates for which phenotypic drug susceptibility testing (DST) was determined by the Buddemeyer technique for an earlier study. Simultaneous presence of wild type and mutant bands was referred to as "mixed patterns" (heteroresistance). RESULTS: Phenotypically 41 isolates were sensitive; 11 isoniazid, 2 rifampicin, 2 pyrazinamide and 5 ethambutol monoresistant; 16 polyresistant and 78 MDR. The agreement between both methods was excellent (kappa = 0.72-0.92). Of 22 rifampicin resistant onset isolates, the predominant rpoB mutations were the singular lack of WT8 (n = 8) and mixed D516V patterns (n = 9). Of the 64 rifampicin resistant fifth month isolates, the most frequent mutations were in WT8 (n = 31) with a further 9 showing the S531L mutation. Mixed patterns were seen in 22 (34%) isolates, most frequently for the D516V mutation (n = 21). Of the 22 onset and 35 fifth month katG mutants, 13 and 12 respectively showed the S315T1 mutation with loss of the WT. Mixed patterns involving both S315T1 and S315T2 were seen in 9 and 23 isolates respectively. Seventeen of 23 and 23/35 inhA mutant onset and fifth month isolates showed mixed A16G profiles. Additionally, 10 fifth month isolates lacked WT2. Five onset and 6 fifth month isolates had both katG and inhA mutations. An association was noted between only katG but not only inhA resistance and poor outcome (p = 0.037); and additional resistance to ethambutol (p = 0.0033). More fifth month than onset isolates had mixed profiles for at least 1 gene (p = 0.000001). CONCLUSIONS: The use of the assay to rapidly diagnose MDR could guide simultaneous first- and second-line DST, and reduce the delay in administering appropriate regimens. Furthermore, detection of heteroresistance could prevent inaccurate "cured" treatment outcomes documented through smear microscopy and permit more sensitive detection of neonascent resistance. PMID- 22260345 TI - A mild and efficient direct alpha-amination of beta-dicarbonyl compounds using iodosobenzene and p-toluenesulfonamide catalyzed by perchlorate zinc hexahydrate. AB - A direct alpha-amination of beta-dicarbonyl compounds has been achieved by using iodosobenzene (PhIO) as an oxidant and p-toluenesulfonamide (TsNH(2)) as an aminating reagent in the presence of a catalytic amount of perchlorate zinc hexahydrate. The present amination reaction proceeds quickly at rt (<30 min needed for most tested substrates) to provide the corresponding alpha-N tosylamido beta-dicarbonyl compounds in high to excellent yields. PMID- 22260347 TI - Fluorescence signaling of Zr4+ by hydrogen peroxide assisted selective desulfurization of thioamide. AB - Thioamide derivative with a pyrene fluorophore was smoothly transformed to its corresponding amide by Zr(4+) ions in the presence of hydrogen peroxide. The transformation was evidenced by (1)H NMR spectroscopy and the signaling was completed within 10 min after sample preparation. Interference from Ag(+) and Hg(2+) ions in Zr(4+)-selective fluorescence signaling was readily suppressed with the use of Sn(2+) as a reducing additive. Discrimination of Zr(4+) from closely related hafnium, which is a frequent contaminant in commercial zirconium, was not possible. Prominent Zr(4+)-selective turn-on type fluorescence signaling was possible with a detection limit of 4.6 * 10(-6) M in an aqueous 99% ethanol solution. PMID- 22260348 TI - Assessing and forecasting atmospheric outflow of alpha-HCH from China on intra-, inter-, and decadal time scales. AB - Atmospheric outflow of alpha-HCH from China from 1952 to 2009 was investigated using Chinese Gridded Pesticide Emission and Residue Model (ChnGPERM). The model results show that the outflows via the northeast boundary (NEB, longitude 115-135 degrees E along 55 degrees N and latitude 37-55 degrees N along 135 degrees E) and the mid-south boundary (MSB, longitude 100-120 degrees E along 17 degrees N) of China account for 47% and 35% of the total outflow, respectively. Two climate indices based on the statistical association between the time series of modeled alpha-HCH outflow and atmospheric sea-level pressure were developed to predict the outflow on different time scales. The first index explains 70/83% and 10/46% of the intra-annual variability of the outflow via the NEB and MSB during the periods of 1952-1984 and 1985-2009, respectively. The second index explains 16% and 19% of the interannual and longer time scale variability in the outflow through the NEB during June-August and via the MSB during October-December for 1991-2009, respectively. Results also revealed that climate warming may potentially result in stronger outflow via the NEB than the MSB. The linkage between the outflow with large scale atmospheric circulation patterns and climate warming trend over China was also discussed. PMID- 22260349 TI - Therapeutic efficacy of Hypericum perforatum L. extract for mice infected with an influenza A virus. AB - Hypericum perforatum L., a plant used in Chinese herbal medicine, has been proven effective against many viral diseases. In the present study, the therapeutic efficacy of an extract of H. perforatum (HPE) against influenza A virus (IAV) was investigated in mice. Whether HPE would be a promising agent for influenza treatment was evaluated by measuring the protection rate, mean survival days, lung index, and viral titer, as well as the secretion of IL-6, interleukin 10 (IL-10), tumour necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN gamma) in lung tissue and serum on days 3 and 5 post-infection. The results showed that HPE could reduce the lung index and viral titer of mice infected with IAV, decrease mortality, and prolong the mean survival time. HPE decreased the concentration of IL-6 and TNF-alpha in lung tissue and serum on day 5 post infection. In contrast, HPE enhanced the lung and serum levels of IL-10 and IFN gamma on the days 3 and 5 post-infection. Our study indicates that HPE has significant therapeutic efficacy for mice infected with IAV. The possible reasons for these results were concluded to be pertaining to up-regulating the expression of IL-10 and IFN-gamma, and down-regulating the secretion of IL-6 and TNF-alpha in lung and serum. PMID- 22260350 TI - Immunostaining for mismatch repair (MMR) protein expression in colorectal cancer is better and easier to interpret when performed on diagnostic biopsies. PMID- 22260352 TI - SPIO-enhanced magnetic resonance imaging study of placental perfusion in a rat model of intrauterine growth restriction. AB - OBJECTIVE: To assess placental perfusion with magnetic resonance imaging (MRI) and superparamagnetic iron oxide (SPIO) in a rat model of intrauterine growth restriction (IUGR). DESIGN: Experimental animal study. SETTING: The study complied with US National Institutes of Health recommendations for animal care. POPULATION: Thirty-two rats at day 16 of gestation underwent surgical ligation of the left uterine vessel to induce IUGR. METHODS: Eighteen rats were examined by MRI 3 days later, after bolus injection of ferucarbotran. MAIN OUTCOME MEASURE: Signal intensities were measured in the maternal left ventricle and in the placentas of the two horns. Quantitative microcirculation parameters were calculated and compared between the placentas of the two horns. RESULTS: Fifty four kinetic curves of placental perfusion were obtained in 11 rats. The mean placental blood flow was significantly lower in the ligated horns than in the normal horns (108.1 versus 159.4 ml/minute/100 ml, p = 0.0004). The mean fractional volume of the maternal vascular placental compartment did not differ significantly between the pathological (42.8%) and normal placentas (39.2%). CONCLUSIONS: Placental perfusion, including changes during experimental IUGR, can be measured in rats by using MRI with SPIO. These findings could have implications for human studies of placental microcirculation and for the management of disorders related to placental dysfunction. PMID- 22260353 TI - Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome. AB - Propofol is an anesthetic agent widely used for induction and maintenance of anesthesia, and sedation in children. Although generally considered as reliable and safe, administration of propofol can occasionally induce a potentially fatal complication known as propofol infusion syndrome (PRIS). Mitochondrial dysfunction has been implicated in the pathogenesis of PRIS. We report on an adult patient with Leber hereditary optic neuropathy (LHON) who developed PRIS. He was a carrier of the m.3460G>A mutation, one of the major three pathogenic point mutations associated with LHON. The propositus was blind and underwent propofol sedation after severe head injury. Five days after start of propofol infusion, the patient died. The activity of complex I of the oxidative phosphorylation (OXPHOS) system was severely deficient in skeletal muscle. Our observation indicates that fulminate PRIS can occur in an adult patient with an inborn OXPHOS defect and corroborates the hypothesis that PRIS is caused by inhibition of the OXPHOS system. PMID- 22260354 TI - Sources of uncertainty in type 2 diabetes: explication and implications for health communication theory and clinical practice. AB - According to the American Diabetes Association, nearly 24 million Americans live with type 2 diabetes, and clinical data project that this figure will increase 165% from 2000 to 2050. Thus, there is a pressing need to understand not only the physiological and medical needs, but also the psychological demands associated with the illness. Even though uncertainty has been explicated in various other illness contexts and potentially shapes the experience of type 2 diabetes, very little attention has been paid to the nature of uncertainty in this context. The present study examines the nature of uncertainty through qualitative interviews with 49 individuals diagnosed with type 2 diabetes. Using grounded theory methods, various themes emerged relative to the sources of uncertainty. These themes are discussed in light of their potential extension of health communication theory and application to intervention and educational programs for individuals living with type 2 diabetes. PMID- 22260356 TI - Metacommunity dynamics over 16 years in a pyrogenic shrubland. AB - Metacommunity theory allows predictions about the dynamics of potentially interacting species' assemblages that are linked by dispersal, but strong empirical tests of the theory are rare. We analyzed the metacommunity dynamics of Florida rosemary scrub, a patchily distributed pyrogenic community, to test predictions about turnover rates, community nestedness, and responses to patch size, arrangement, and quality. We collected occurrence data for 45 plant species from 88 rosemary scrub patches in 1989 and 2005 and used growth form, mechanism of regeneration after fire, and degree of habitat specialization to categorize species by life history. We tested whether patch size, fire history, and structural connectivity (a measure of proximity and size of surrounding patches) could be used to predict apparent extinctions and colonizations. In addition, we tested the accuracy of incidence-function models built with the patch survey data from 1989. After fire local extinction rates were higher for herbs than woody plants, higher for species that regenerated only from seed than species able to resprout, and higher for generalist than specialist species. Fewer rosemary specialists and a higher proportion of habitat generalists were extirpated on recently burned patches than on patches not burned between 1989 and 2005. Nestedness was highest for specialists among all life-history groups. Estimated model parameters from 1989 predicted the observed (1989-2005) extinction rates and the number of patches with persistent populations of individual species. These results indicate that species with different life-history strategies within the same metacommunity can have substantially different responses to patch configuration and quality. Real metacommunities may not conform to certain assumptions of simple models, but incidence-function models that consider only patch size, configuration, and quality can have significant predictive accuracy. PMID- 22260357 TI - A recurrent translocation is mediated by homologous recombination between HERV-H elements. AB - BACKGROUND: Chromosome rearrangements are caused by many mutational mechanisms; of these, recurrent rearrangements can be particularly informative for teasing apart DNA sequence-specific factors. Some recurrent translocations are mediated by homologous recombination between large blocks of segmental duplications on different chromosomes. Here we describe a recurrent unbalanced translocation casued by recombination between shorter homologous regions on chromosomes 4 and 18 in two unrelated children with intellectual disability. RESULTS: Array CGH resolved the breakpoints of the 6.97-Megabase (Mb) loss of 18q and the 7.30-Mb gain of 4q. Sequencing across the translocation breakpoints revealed that both translocations occurred between 92%-identical human endogenous retrovirus (HERV) elements in the same orientation on chromosomes 4 and 18. In addition, we find sequence variation in the chromosome 4 HERV that makes one allele more like the chromosome 18 HERV. CONCLUSIONS: Homologous recombination between HERVs on the same chromosome is known to cause chromosome deletions, but this is the first report of interchromosomal HERV-HERV recombination leading to a translocation. It is possible that normal sequence variation in substrates of non-allelic homologous recombination (NAHR) affects the alignment of recombining segments and influences the propensity to chromosome rearrangement. PMID- 22260358 TI - Substrate/Product-targeted NMR monitoring of pyrimidine catabolism and its inhibition by a clinical drug. AB - We report the application of one-dimensional triple-resonance NMR to metabolic analysis and thereon-based evaluation of drug activity. Doubly (13)C/(15)N labeled uracil ([(15)N1,(13)C6]-uracil) was prepared. Its catabolic (degradative) conversion to [(13)C3,(15)N4]-beta-alanine and inhibition thereof by gimeracil, a clinical co-drug used with the antitumor agent 5-fluorouracil, in mouse liver lysates were monitored specifically using one-dimensional triple-resonance ((1)H {(13)C-(15)N}) NMR, but not double-resonance ((1)H-{(13)C}) NMR, in a ratiometric manner. The administration of labeled uracil to a mouse resulted in its non selective distribution in various organs, with efficient catabolism to labeled beta-alanine exclusively in the liver. The co-administration of gimeracil inhibited the catabolic conversion of uracil in the liver. In marked contrast to in vitro results, however, gimeracil had practically no effect on the level of uracil in the liver. The potentiality of triple-resonance NMR in the analysis of in vivo pharmaceutical activity of drugs targeting particular metabolic reactions is discussed. PMID- 22260359 TI - Does alcohol consumption really affect asymmetry perception? A three-armed placebo-controlled experimental study. AB - AIMS: A possible explanation for increased levels of attractiveness of faces when under the influence of alcohol is the reduced ability to perceive bilateral asymmetry. This study tested the degree of preference by alcohol-dosed and non alcohol-dosed participants for symmetrical faces and their ability to detect facial symmetry, while controlling for other explanations. DESIGN: Volunteers were recruited to a random allocation experiment with three conditions: alcoholic drink (alcohol dosed), non-alcoholic drink (placebo) and diluted orange cordial (control). Data on concentration, personality and demographics were collected. Dependent variables were symmetry preference and detection. SETTING: Laboratory, University of Roehampton. PARTICIPANTS: A total of 101 participants, mainly students (41 alcohol-dosed, 40 placebo, 20 control). MEASUREMENTS: Participants provided verbal responses to images of faces which were presented on a computer screen for 5 seconds each; the first task required a preference judgement and the second task consisted of a forced-choice response of whether or not a face was symmetrical. Levels of concentration, weight and level of alcohol dose were measured, and demographics plus additional psychological and health information were collected using a computer-based questionnaire. FINDINGS: In contrast to a previous investigation, there was no difference in symmetry preference between conditions (P = 0.846). In agreement with previous findings, participants who had not drunk alcohol were better at detecting whether a face was symmetrical or asymmetrical (P = 0.043). Measures of concentration did not differ between conditions (P = 0.214-0.438). Gender did not affect ability to detect symmetry in placebo or alcohol-dosed participants (P = 0.984, 0.499); however, alcohol-dosed females were shown to demonstrate greater symmetry preference than alcohol-dosed males (P = 0.004). CONCLUSIONS: People who are alcohol-dosed are subtly less able to perceive vertical, bilateral asymmetry in faces, with gender being a possible moderating factor. PMID- 22260360 TI - Epigallocatechin-3-gallate and penta-O-galloyl-beta-D-glucose inhibit protein phosphatase-1. AB - Protein phosphatase-1 (PP1) and protein phosphatase-2A (PP2A) are responsible for the dephosphorylation of the majority of phosphoserine/threonine residues in cells. In this study, we show that (-)-epigallocatechin-3-gallate (EGCG) and 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), polyphenolic constituents of green tea and tannins, inhibit the activity of the PP1 recombinant delta-isoform of the PP1 catalytic subunit and the native PP1 catalytic subunit (PP1c) with IC(50) values of 0.47-1.35 MUm and 0.26-0.4 MUm, respectively. EGCG and PGG inhibit PP2Ac less potently, with IC(50) values of 15 and 6.6 MUm, respectively. The structure-inhibitory potency relationships of catechin derivatives suggests that the galloyl group may play a major role in phosphatase inhibition. The interaction of EGCG and PGG with PP1c was characterized by NMR and surface plasmon resonance-based binding techniques. Competitive binding assays and molecular modeling suggest that EGCG docks at the hydrophobic groove close to the catalytic center of PP1c, partially overlapping with the binding surface of microcystin-LR or okadaic acid. This hydrophobic interaction is further stabilized by hydrogen bonding via hydroxyl/oxo groups of EGCG to PP1c residues. Comparative docking shows that EGCG binds to PP2Ac in a similar manner, but in a distinct pose. Long-term treatment (24 h) with these compounds and other catechins suppresses the viability of HeLa cells with a relative effectiveness reminiscent of their in vitro PP1c-inhibitory potencies. The above data imply that the phosphatase-inhibitory features of these polyphenols may be implicated in the wide spectrum of their physiological influence. PMID- 22260361 TI - Riluzole treatment reduces motoneuron death induced by axotomy in newborn rats. AB - Nerve injury in neonatal rats leads to considerable motoneuron death. We investigated whether treatment with riluzole (a presynaptic inhibitor of glutamate release) is able to enhance survival of motor units (MUs) in the slow soleus (Sol) and fast extensor digitorum longus (EDL) muscles after sciatic nerve crush in newborn rats. Examination of 3- to 4-month-old rats revealed a beneficial effect of riluzole treatment after injury carried out on the first day after birth. At this time increased MU survival occurred in both the Sol and EDL muscles. In rats with nerve injury carried out on the second day after birth, increased MU survival occurred only in the Sol. We conclude that although riluzole treatment can rescue motoneurons destined to die and improve muscle performance, its beneficial effect is age-dependent, and the difference between the rescue of Sol and EDL MUs may be due to the slower maturation of motoneurons to soleus muscle. These findings have important implications regarding the motoneuron properties required for riluzole's beneficial effect. PMID- 22260362 TI - Effects of phosphonoformic acid and renagel on renal type IIa sodium-dependent phosphate cotransporter mRNA expression in hyperphosphatemia rats. AB - OBJECTIVE: To investigate the effects of phosphonoformic acid (PFA) and sevelamer hydrochloride (Renagel) on renal type IIa sodium-dependent phosphate cotransporter (NaPi-2) mRNA expression in hyperphosphatemia rats. METHODS: Thirty rats were randomly divided into five groups based on the diet for 2 weeks after 5/6 nephrectomy (Nx): Nx + high-phosphate (HP; 1.2% P) diet; Nx + low-phosphate (LP; 0.2% P) diet; HP + PFA (injected with 0.15 g/kg PFA daily); HP + Saline (injected with the same amount of saline daily); and HP + Renagel (2%) group. Another 12 rats were sham operated and divided into Sham + HP and Sham + LP groups. Serum ionized calcium, phosphorus (P), and intact parathyroid hormone (iPTH) were measured on days 2, 7, and 14. Serum 1,25(OH)2D3 was measured on day 14 and NaPi-2 mRNA levels were assayed by RT-PCR. RESULTS: PFA decreased iPTH level but had no effect on NaPi-2 mRNA expression. Renagel decreased serum P and iPTH levels, but upregulated renal NaPi-2 mRNA expression. CONCLUSIONS: Both PFA and Renagel are effective drugs to decrease iPTH level and they might be potential candidates for treatment of clinical secondary hyperparathyroidism. Renagel can also decrease serum P and upregulate renal NaPi-2 mRNA expression. PMID- 22260363 TI - Heart valve disease: investigation by cardiovascular magnetic resonance. AB - Cardiovascular magnetic resonance (CMR) has become a valuable investigative tool in many areas of cardiac medicine. Its value in heart valve disease is less well appreciated however, particularly as echocardiography is a powerful and widely available technique in valve disease. This review highlights the added value that CMR can bring in valve disease, complementing echocardiography in many areas, but it has also become the first-line investigation in some, such as pulmonary valve disease and assessing the right ventricle. CMR has many advantages, including the ability to image in any plane, which allows full visualisation of valves and their inflow/outflow tracts, direct measurement of valve area (particularly for stenotic valves), and characterisation of the associated great vessel anatomy (e.g. the aortic root and arch in aortic valve disease). A particular strength is the ability to quantify flow, which allows accurate measurement of regurgitation, cardiac shunt volumes/ratios and differential flow volumes (e.g. left and right pulmonary arteries). Quantification of ventricular volumes and mass is vital for determining the impact of valve disease on the heart, and CMR is the 'Gold standard' for this. Limitations of the technique include partial volume effects due to image slice thickness, and a low ability to identify small, highly mobile objects (such as vegetations) due to the need to acquire images over several cardiac cycles. The review examines the advantages and disadvantages of each imaging aspect in detail, and considers how CMR can be used optimally for each valve lesion. PMID- 22260365 TI - Studying survival studies in PD versus HD: is there something more to know? AB - Peritoneal dialysis (PD) has been introduced more than 25 years ago as an alternative to hemodialysis for the treatment of end-stage renal disease. However, after the peak of the number of PD patients, which was noted in the mid 1980s, and despite the fact that in some countries there is a tendency for PD first, the number of incident PD patients in Europe and the United States is constantly decreasing. A large number of studies comparing the effect of these two treatment modalities on patients' outcomes have yielded conflicting results, which raise confusing messages to nephrologists. Epidemiologic methods, survival analysis models, and interpretation of results are not always clear and understandable for the average nephrologist. This review will focus on the exploration of possible causes of discrepancy among survival studies and it will try to clarify the basic key points of survival analysis in order to make the results as clear as possible. PMID- 22260364 TI - Influence of ERbeta selective agonism during the neonatal period on the sexual differentiation of the rat hypothalamic-pituitary-gonadal (HPG) axis. AB - BACKGROUND: It is well established that sexual differentiation of the rodent hypothalamic-pituitary-gonadal (HPG) axis is principally orchestrated by estrogen during the perinatal period. Here we sought to better characterize the mechanistic role the beta form of the estrogen receptor (ERbeta) plays in this process. METHODS: To achieve this, we exposed neonatal female rats to three doses (0.5, 1 and 2 mg/kg) of the ERbeta selective agonist diarylpropionitrile (DPN) using estradiol benzoate (EB) as a positive control. Measures included day of vaginal opening, estrous cycle quality, GnRH and Fos co-localization following ovariectomy and hormone priming, circulating luteinizing hormone (LH) levels and quantification of hypothalamic kisspeptin immunoreactivity. A second set of females was then neonatally exposed to DPN, the ERalpha agonist propyl-pyrazole triol (PPT), DPN+PPT, or EB to compare the impact of ERalpha and ERbeta selective agonism on kisspeptin gene expression in pre- and post-pubescent females. RESULTS: All three DPN doses significantly advanced the day of vaginal opening and induced premature anestrus. GnRH and Fos co-labeling, a marker of GnRH activation, following ovariectomy and hormone priming was reduced by approximately half at all doses; the magnitude of which was not as large as with EB or what we have previously observed with the ERalpha agonist PPT. LH levels were also correspondingly lower, compared to control females. No impact of DPN was observed on the density of kisspeptin immunoreactive (-ir) fibers or cell bodies in the arcuate (ARC) nucleus, and kisspeptin-ir was only significantly reduced by the middle (1 mg/kg) DPN dose in the preoptic region. The second experiment revealed that EB, PPT and the combination of DPN+PPT significantly abrogated preoptic Kiss1 expression at both ages but ARC expression was only reduced by EB. CONCLUSION: Our results indicate that selective agonism of ERbeta is not sufficient to completely achieve male-typical HPG organization observed with EB or an ERalpha agonist. PMID- 22260366 TI - Can receipt of a regular postcard reduce suicide-related behaviour in young help seekers? A randomized controlled trial. AB - AIM: Suicide attempt, ideation and deliberate self-harm are common among adolescents. Limited evidence exists regarding interventions that can reduce risk; however, research indicates that maintaining contact with at-risk adults following discharge from services via letter or postcard can reduce risk. The aim of the study was to test a postcard intervention among people aged 15-24 who presented to mental health services but were not accepted, yet were at risk of suicide. METHODS: A randomized controlled trial of 3 years in duration was used. The intervention consisted of 12 postcards sent once a month for 12 months following presentation to the service. Key outcomes of interest were reduced rates of suicide attempt, suicidal ideation and deliberate self-harm, assessed at 12 and 18 months. RESULTS: Participants reported that they liked receiving the postcard and that they used the strategies recommended. However, no significant effect of the postcard intervention was found on suicide risk, although participants in both groups improved on measures of mental health over the course of the study. CONCLUSIONS: There remains a need for further research into youth friendly interventions for young people at risk of suicide. PMID- 22260367 TI - One-step formation of w/o/w multiple emulsions stabilized by single amphiphilic block copolymers. AB - Multiple emulsions are complex polydispersed systems in which both oil-in-water (O/W) and water-in-oil (W/O) emulsion exists simultaneously. They are often prepared accroding to a two-step process and commonly stabilized using a combination of hydrophilic and hydrophobic surfactants. Recently, some reports have shown that multiple emulsions can also be produced through one-step method with simultaneous occurrence of catastrophic and transitional phase inversions. However, these reported multiple emulsions need surfactant blends and are usually described as transitory or temporary systems. Herein, we report a one-step phase inversion process to produce water-in-oil-in-water (W/O/W) multiple emulsions stabilized solely by a synthetic diblock copolymer. Unlike the use of small molecule surfactant combinations, block copolymer stabilized multiple emulsions are remarkably stable and show the ability to separately encapsulate both polar and nonpolar cargos. The importance of the conformation of the copolymer surfactant at the interfaces with regards to the stability of the multiple emulsions using the one-step method is discussed. PMID- 22260368 TI - Direct chemoselective allylation of inert amide carbonyls. AB - Direct allylation of inert amide carbonyls utilizing the Schwartz reagent afforded either substituted tertiary or secondary amines. A preactivation step was successfully avoided, which is generally a requisite to increase the electrophilicity of amides. The reaction exhibited remarkable functional group tolerance and proceeded even in the presence of methyl esters and nitro groups. PMID- 22260369 TI - Glucose challenge test for detecting gestational diabetes mellitus: a systematic review. AB - BACKGROUND: The best strategy to identify women with gestational diabetes mellitus (GDM) is unclear. OBJECTIVES: To perform a systematic review to calculate summary estimates of the sensitivity and specificity of the 50-g glucose challenge test for GDM. SEARCH STRATEGY: Systematic search of MEDLINE, EMBASE and Web of Science. SELECTION CRITERIA: Articles that compared the 50-g glucose challenge test with the oral glucose tolerance test (OGTT, with a 75- or 100-g reference standard) before 32 weeks of gestation. DATA COLLECTION AND ANALYSIS: Summary estimates of sensitivity and specificity, with 95% confidence intervals and summary receiver operating characteristic curves, were calculated using bivariate random-effects models. Two reviewers independently selected articles that compared the 50 g glucose challenge test to the oral glucose tolerance test (OGTT, 75 or 100 gram, reference standard) before 32 weeks of gestation. MAIN RESULTS: Twenty-six studies were included (13,564 women). Studies that included women with risk factors showed a pooled sensitivity of the 50-g glucose challenge test of 0.74 (95% CI 0.62-0.87), a pooled specificity of 0.77 (95% CI 0.66-0.89) (threshold value of 7.8 mmol/l), a derived positive likelihood ratio (LR) of 3.2 (95% CI 2.0-5.2) and a negative LR of 0.34 (95% CI 0.22-0.53). In studies with consecutive recruitment, the pooled sensitivity was 0.74 (95% CI 0.62-0.87) for a specificity of 0.85 (95% CI 0.80-0.91), with a derived positive LR of 4.9 (95% CI 3.5-7.0) and negative LR of 0.31 (95% CI 0.20-0.47). Increasing the threshold for disease (OGTT result) increased the sensitivity of the challenge test, and decreased the specificity. AUTHOR'S CONCLUSIONS: The 50-g glucose challenge test is acceptable to screen for GDM, but cannot replace the OGTT. Further possibilities of combining the 50-g glucose challenge test with other screening strategies should be explored. PMID- 22260370 TI - Wound infiltration with local anesthetics for post-operative pain relief in lumbar spine surgery: a systematic review. AB - BACKGROUND: In this systematic review, we evaluated double-blind, randomized and controlled trials on the effect of wound infiltration with local anesthetics compared with the effect of placebo on post-operative pain after lumbar spine surgery. METHODS: Medline, the Cochrane Library and Google Scholar were searched for appropriate trials. Qualitative analysis of post-operative effectiveness was evaluated by assessment of significant difference (P < 0.05) between study groups regarding pain relief using pain scores, supplemental analgesic consumption and time to first analgesic request as outcome measures. Data on adverse effects were extracted and evaluated. RESULTS: Nine trials including 12 comparisons and 529 patients met the inclusion criteria. Ten comparisons presented data on pain scores. In only three of these 10 comparisons (30%), a reduction in pain score using local anesthetic infiltration was observed averaging between 8 and 40 mm on a 100 mm visual analog scale. In six out of 12 comparisons, the local anesthetic infiltration significantly reduced the supplemental opioid consumption after surgery. Observed reductions in analgesic consumption over the first 24 h averaged between 2.5 mg and approximately 15 mg of morphine. Data on opioid related adverse effects were incomplete and difficult to interpret. CONCLUSION: Interpretation of the results was difficult because of diversity of the studies. However, clinical significance was in general questionable, with only a few trials showing a small or a modest reduction in pain intensity, which was observed mainly immediately after the operation. Similarly, although more frequently observed, only a minor and probably not clinically relevant reduction in opioid consumption was shown. PMID- 22260372 TI - Methylcarbonate and bicarbonate phosphonium salts as catalysts for the nitroaldol (Henry) reaction. AB - Phosphonium ionic liquids exchanged with bicarbonate and methylcarbonate anions (CILs) exhibit catalytic performances comparable to those of sterically hindered (non nucleophilic) organosuperbases such as DBU. At 25-50 degrees C, under solventless conditions, CILs efficiently catalyze the Henry addition of different aldehydes and ketones to nitroalkanes: not only they allow the selective formation of nitroaldols but they unlock a novel high-yielding access to dinitromethyl derivatives of ketones. PMID- 22260373 TI - A sensitive and selective fluorescence sensor for the detection of arsenic(III) in organic media. AB - Arsenic contamination is a leading environmental problem. As such, levels of this toxic metalloid must be constantly monitored by reliable and low-cost methodologies. Because the currently accepted upper limit for arsenic in water is 10 ppb, very sensitive and selective detection strategies must be developed. Herein we describe the synthesis and characterization of a fluorescent chemical probe, namely, ArsenoFluor1, which is the first example of a chemosensor for As(3+) detection in organic solvents at 298 K. AF1 exhibits a 25-fold fluorescence increase in the presence of As(3+) at lambda(em) = 496 nm in THF, which is selective for As(3+) over other biologically relevant ions (such as Na(+), Mg(2+), Fe(2+), and Zn(2+)) and displays a sub-ppb detection limit. PMID- 22260374 TI - Lymphoid tissue inducer cells: innate cells critical for CD4+ T cell memory responses? AB - Lymphoid tissue inducer cells (LTi) are a relatively new arrival on the immunological cellular landscape, having first been characterized properly only 15 years ago. They are members of an emerging family of innate lymphoid cells (ILCs). Elucidation of their function reveals links not only with the ancient innate immune system, but also with adaptive immune responses, in particular the development of lymph nodes and CD4(+) T cell memory immune responses, which on one hand underpin the success of vaccination strategies, and on the other hand drive many human immunologically mediated diseases. This perspective article is not an exhaustive account of the role of LTi in the development of lymphoid tissues, as there have been many excellent reviews published already. Instead, we combine current knowledge of genetic phylogeny and comparative immunology, together with classical mouse genetics, to suggest how LTi might have evolved from a primitive lymphocytic innate cell in the ancestral 500-million-year-old vertebrate immune system into a cell critical for adaptive CD4(+) T cell immune responses in mammals. PMID- 22260375 TI - Validation of interstitial iron and consequences of nonstoichiometry in mackinawite (Fe(1+x)S). AB - A theoretical investigation of the relationship between chemical composition and electronic structure was performed on the nonstoichiometric iron sulfide, mackinawite (Fe(1+x)S), which is isostructural and isoelectronic with the superconducting Fe(1+x)Se and Fe(1+x)(Te(1-y)Se(y)) phases. Even though Fe(1+x)S has not been measured for superconductivity, the effects of stoichiometry on transport properties and electronic structure in all of these iron-excess chalcogenide compounds has been largely overlooked. In mackinawite, the amount of Fe that has been reported ranges from a large excess, Fe(1.15)S, to nearly stoichiometric, Fe(1.00(7))S. Here, we analyze, for the first time, the electronic structure of Fe(1+x)S to justify these nonstoichiometric phases. First principles electronic structure calculations using supercells of Fe(1+x)S yield a wide range of energetically favorable compositions (0 < x < 0.30). The incorporation of interstitial Fe atoms originates from a delicate balance between the Madelung energy and the occupation of Fe-S and Fe-Fe antibonding orbitals. A theoretical assessment of various magnetic structures for "FeS" and Fe(1.06)S indicate that striped magnetic ordering along [110] is the lowest energy structure and the interstitial Fe affects the values of moments in the square planes as a function of distance. Moreover, the formation of the magnetic moment is dependent on the unit cell volume, thus relating it to composition. Finally, changes in the composition cause a modification of the Fermi surface and ultimately the loss of a nested vector. PMID- 22260376 TI - Challenges to interdisciplinary research in ecosystem-based management. AB - Despite its necessity, integration of natural and social sciences to inform conservation efforts has been difficult. We examined the views of 63 scientists and practitioners involved in marine management in Mexico's Gulf of California, the central California coast, and the western Pacific on the challenges associated with integrating social science into research efforts that support ecosystem-based management (EBM) in marine systems. We used a semistructured interview format. Questions focused on how EBM was developed for these sites and how contextual factors affected its development and outcomes. Many of the traditional challenges linked with interdisciplinary research were present in the EBM projects we studied. However, a number of contextual elements affected how mandates to include social science were interpreted and implemented as well as how easily challenges could be addressed. For example, a common challenge is that conservation organizations are often dominated by natural scientists, but for some projects it was easier to address this imbalance than for others. We also found that the management and institutional histories that came before EBM in specific cases were important features of local context. Because challenges differed among cases, we believe resolving challenges to interdisciplinary research should be context specific. PMID- 22260378 TI - Serum T3 level can predict cardiovascular events and all-cause mortality rates in CKD patients with proteinuria. AB - BACKGROUND: Patients with proteinuria frequently show changes in thyroid hormone levels. Serum T3 depression predicts a negative outcome in chronic kidney disease (CKD) patients and may be associated with cardiovascular complications or chronic inflammation. Few studies have explored the relationship between thyroid hormone dysregulation and clinical outcome in patients with proteinuria. METHODS: We reviewed thyroid function test results obtained from 211 patients with 24 h urinary protein excretion greater than 150 mg/day and found a correlation of thyroid hormone level with cardiovascular events and mortality. RESULTS: T3 decreased with age (p = 0.001) and 24 h urine albumin (p = 0.028). Free T4 decreased in accordance with 24 h urine protein and serum creatinine (p = 0.034 and p = 0.033, respectively). In the Kaplan-Meier survival analysis, lower cumulative survival, higher cardiovascular events, and mortality were found in the low T3 group compared with the normal T3 group (p = 0.000, p = 0.013, and p = 0.001, respectively). In Cox regression analysis, we observed that, with low T3, decreased sodium, and old age, the incidence of cardiovascular complications (p = 0.000, p = 0.016, and p = 0.000, respectively), cardiovascular mortality (p = 0.000, p = 0.048, and p = 0.001, respectively), and all-cause mortality (p = 0.000, p = 0.017, and p = 0.000, respectively) increased. CONCLUSION: In CKD patients with proteinuria, low T3 concentration predicted all-cause mortality and cardiovascular event independently of the severity of proteinuria. PMID- 22260380 TI - Spectral analyses of cardiovascular control in rodents with spinal cord injury. AB - The severity of injury to cardiovascular autonomic pathways following clinical spinal cord injury (SCI) can be evaluated with spectral analyses. Whether this technique provides a translatable assessment of cardiovascular autonomic function in rodent SCI is unknown. Beat-to-beat blood pressure and pulse interval were measured in male rats 1 month after complete T3 or T10 SCI, and in uninjured control animals. Univariate autoregressive spectral analyses were performed and the power of the low frequency (LF), high frequency (HF), and very low frequency (VLF) peaks identified. Frequency domain variables were correlated with the severity of orthostatic hypotension (OH) and the severity of hypertension during autonomic dysreflexia (AD). Total heart rate variability (HRV) and blood pressure variability (BPV) were reduced in animals with T3, but not T10, SCI. VLF and LF HRV were reduced and HF HRV was increased in animals with T3 SCI compared to controls; there were no changes in animals with T10 SCI. BPV in the VLF and LF range was reduced in animals with T3 SCI, but not T10 SCI. In all animals with SCI, severity of OH was positively correlated with LF BPV, and negatively correlated with HF BPV. Severity of AD was positively correlated with HF BPV and HF HRV, and negatively correlated with VLF HRV. Spectral analyses can detect alterations in cardiovascular autonomic function in animals with SCI at rest. These parameters underscore the distinct cardiovascular ramifications of high- versus low-thoracic SCI, and correlate with the severity of AD and OH, clinically relevant measures of abnormal blood pressure control. PMID- 22260379 TI - An in silico analysis of dynamic changes in microRNA expression profiles in stepwise development of nasopharyngeal carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA (mRNA) and protein synthesis. Recent studies have shown that some miRNAs are involved in the progression of nasopharyngeal carcinoma (NPC). However, the aberrant miRNAs implicated in different clinical stages of NPC remain unknown and their functions have not been systematically studied. METHODS: In this study, miRNA microarray assay was performed on biopsies from different clinical stages of NPC. TargetScan was used to predict the target genes of the miRNAs. The target gene list was narrowed down by searching the data from the UniGene database to identify the nasopharyngeal specific genes. The data reduction strategy was used to overlay with nasopharyngeal-specifically expressed miRNA target genes and complementary DNA (cDNA) expression data. The selected target genes were analyzed in the Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway. The microRNA-Gene-Network was build based on the interactions of miRNAs and target genes. miRNA promoters were analyzed for the transcription factor (TF) binding sites. UCSC Genome database was used to construct the TF-miRNAs interaction networks. RESULTS: Forty-eight miRNAs with significant change were obtained by Multi-Class Dif. The most enriched GO terms in the predicted target genes of miRNA were cell proliferation, cell migration and cell matrix adhesion. KEGG analysis showed that target genes were significantly involved in adherens junction, cell adhesion molecules, p53 signalling pathway et al. Comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-29a/c, miR-34b, miR-34c-3p, miR-34c-5p, miR 429, miR-203, miR-222, miR-1/206, miR-141, miR-18a/b, miR-544, miR-205 and miR 149 may play important roles on the development of NPC. We proposed an integrative strategy for identifying the miRNA-mRNA regulatory modules and TF miRNA regulatory networks. TF including ETS2, MYB, Sp1, KLF6, NFE2, PCBP1 and TMEM54 exert regulatory functions on the miRNA expression. CONCLUSIONS: This study provides perspective on the microRNA expression during the development of NPC. It revealed the global trends in miRNA interactome in NPC. It concluded that miRNAs might play important regulatory roles through the target genes and transcription factors in the stepwise development of NPC. PMID- 22260381 TI - The Five Eras of Chiropractic & the future of chiropractic as seen through the eyes of a participant observer. AB - Chiropractic has endured a turbulent history, marked by tremendous advances in areas such as education and licensing while marred by interprofessional conflict and a poor public image. The prolonged interprofessional conflict was instrumental in shaping the culture of chiropractic. These obstacles have long since been removed although there are lingering effects from them.This article examines the chiropractic profession's history by dividing it into five Eras and suggests that there are three options available for the future of the profession. One: maintaining the status quo. Two: uniting under an evidence based scientific approach as partners in the health care delivery system that has buried the "one cause, one-cure" sacred cow. The steps required to achieve this outcome are outlined. Three: openly dividing the profession into evidence based practitioners and subluxation based practitioners. Adopting this option would allow each branch of the profession to move forward in the health care delivery system unhindered by the other.It is unclear which option the profession will choose and whether the profession is mature enough to follow option two remains to be seen. What is evident is that the time to act is now. PMID- 22260382 TI - Tonsillectomy delays progression of advanced IgA nephropathy to end-stage kidney disease. AB - AIMS: Several investigators have described the effect of tonsillectomy on urinary abnormalities and long-term renal survival rates in patients with IgA nephropathy (IgAN), especially during the early stage of the disease. However, whether tonsillectomy affects the rate of IgAN progress, even when the disease is in the advanced stage, remains obscure. METHODS: Of 365 patients who were histologically diagnosed with IgAN, 46 eventually reached end-stage kidney disease (ESKD) between 1981 and 2006. The periods from diagnosis to ESKD with renal replacement therapy (RRT) were compared between patients with ESKD who had undergone tonsillectomy (n = 15) as initial therapy for IgAN or not (n = 31). Relationships among risk factors, initial treatment, and rates of progression to ESKD were also examined using multivariate analysis in a retrospective cohort study of the 46 patients. RESULTS: The duration between renal biopsy and initiation of RRT was significantly extended for patients with, than without, tonsillectomy (9.8 +/- 6.0 vs. 5.8 +/- 4.0 years, p = 0.007; unpaired t-test). The RRT-free survival advantage in patients with tonsillectomy was also evident in Kaplan-Meier curves (p = 0.007 by log-rank test). Logistic regression analysis showed that a high serum creatinine value at biopsy and severe histological damage were risk factors affecting rapid progression (within 7 years from diagnosis) to ESKD, whereas tonsillectomy apparently delayed disease progression [odds ratio, 0.09; 95% confidence interval (CI), 0.01-0.75; p = 0.026]. CONCLUSION: Tonsillectomy might delay the rate of progression even when IgAN is relatively advanced, although this study could not confirm whether it prevents progression to ESKD. PMID- 22260384 TI - Diagnostic yield of the cytomegalovirus (CMV) antigenemia assay and clinical features in solid organ transplant recipients and hematopoietic stem cell transplant recipients with CMV pneumonia. AB - Data are limited on the value of non-invasive diagnostic methods, such as the cytomegalovirus (CMV) antigenemia assay, and the clinical features of CMV pneumonia in patients who have undergone solid organ transplant (SOT) compared with those who have had hematopoietic stem cell transplant (HSCT). All adult patients with suspected CMV pneumonia, who had received SOT or HSCT in a tertiary hospital during a 5-year period, were retrospectively enrolled. CMV pneumonia was defined as clinical and radiographic evidence of pneumonia in association with the isolation of CMV in viral cultures of bronchoalveolar lavage or lung tissue specimens, or with the identification of CMV in lung tissue. In total, 36 patients with CMV pneumonia were identified. Of these, 29 (80%) had received SOT and 7 (20%) had received HSCT. The incidence of CMV pneumonia in the patients with SOT (3.0 per 1000 person-years [95% confidence interval {CI} 0.6-8.7]) was lower than in those with HSCT (17.0 per 1000 person-years [95% CI 9.9-27.2], P = 0.003) and CMV-related mortality showed a tendency to have lower mortality in patients with SOT (10% [3/29]) than with HSCT (43% [3/7], P = 0.07). The overall sensitivity of the CMV assay (>= 1/200,000 leukocytes) in patients with CMV pneumonia was 69% (95% CI 52-84%). The CMV antigenemia test is of limited value in diagnosing CMV pneumonia, given the high cost of false-negative diagnoses of CMV pneumonia. PMID- 22260385 TI - Themes of relational uncertainty and interference from partners in depression. AB - This article draws on the relational turbulence model to illuminate the dynamics of depression in romantic relationships using a thematic analysis of online discourse. Three content areas of relational uncertainty were apparent: (a) depression uncertainty (questions about physical harm, source of depression, and understanding), (b) self and partner uncertainty (questions about helplessness and identity), and (c) relationship uncertainty (questions about physical intimacy, relationship satisfaction, and the future of the relationship). Three content areas of interference from partners also emerged: (a) daily routines (disruptions to household tasks; finances, work, and school; children and parenting; and family and social life), (b) personal well-being (disruptions to health and safety as well as treatment), and (c) the relationship (disruptions to sexual activity, emotional intimacy, and openness). Relational uncertainty and interference from partners coincided in people's experiences in seven ways. The article concludes by discussing the conceptual, empirical, and pragmatic implications of the findings. PMID- 22260386 TI - p63, CK7, PAX8 and INI-1: an optimal immunohistochemical panel to distinguish poorly differentiated urothelial cell carcinoma from high-grade tumours of the renal collecting system. AB - AIMS: High-grade, poorly differentiated, infiltrative carcinomas involving the renal sinus region often pose challenging differential diagnostic considerations, specifically differentiation of urothelial carcinoma (UC) from renal cell carcinoma (RCC) subtypes. Accurate classification, especially the distinction of UC from RCC, is critical, as therapeutic approaches differ. METHODS AND RESULTS: Cluster analysis was performed on immunohistochemical data from 18 invasive UCs, six CDCs, two RMCs, 18 type 2 papillary renal cell carcinomas (PRCCs) and 20 high grade clear cell renal cell carcinomas (CRCCs) using a broad panel of traditional and novel immunohistochemical markers. The initial analysis with all antibodies segregates almost all the RCCs (45 of 46, 98%) from all the UCs based on the lack of expression of p63 in all (100%) RCCs, along with predominant strong expression of paired box gene 8 (PAX8) and vimentin, predominant lack of expression of high molecular weight cytokeratin (HMCK) and CK7 and variable expression of RCC, CD10, CA1X and PAX2. All the UCs cluster together with strong, diffuse reactivity for p63, predominant reactivity for CK7 and high molecular weight kininogen (HMWK), and absent to minimal staining with PAX8, RCC antigen, PAX2, alpha-methylacyl-CoA racemase (AMACR), carbonic anhydrase IX (CAIX) and vimentin. After removing antibodies with significant overlap and/or minimal impact, a second analysis with a limited panel including p63, CK7, vimentin, integrase interactor 1 (INI-1) and PAX8 was performed. Again, the majority of UCs cluster into one group and p63 positivity separates all UCs from RCCs. CONCLUSIONS: Lack of INI-1 expression, noted exclusively in RMCs, segregates RMCs into a separate cluster. PAX8 is rarely positive (17%) in UC, is commonly expressed in CDC, RMC, PRCC and CRCC and is superior to PAX2. PMID- 22260387 TI - Sub-10 nm carbon nanotube transistor. AB - Although carbon nanotube (CNT) transistors have been promoted for years as a replacement for silicon technology, there is limited theoretical work and no experimental reports on how nanotubes will perform at sub-10 nm channel lengths. In this manuscript, we demonstrate the first sub-10 nm CNT transistor, which is shown to outperform the best competing silicon devices with more than four times the diameter-normalized current density (2.41 mA/MUm) at a low operating voltage of 0.5 V. The nanotube transistor exhibits an impressively small inverse subthreshold slope of 94 mV/decade-nearly half of the value expected from a previous theoretical study. Numerical simulations show the critical role of the metal-CNT contacts in determining the performance of sub-10 nm channel length transistors, signifying the need for more accurate theoretical modeling of transport between the metal and nanotube. The superior low-voltage performance of the sub-10 nm CNT transistor proves the viability of nanotubes for consideration in future aggressively scaled transistor technologies. PMID- 22260388 TI - Regression of left ventricular mass following conversion from conventional hemodialysis to thrice weekly in-centre nocturnal hemodialysis. AB - BACKGROUND: Increased left ventricular mass (LVM) is associated with adverse outcomes in patients receiving chronic hemodialysis. Among patients receiving conventional hemodialysis (CHD, 3*/week, 4 hrs/session), we evaluated whether dialysis intensification with in-centre nocturnal hemodialysis (INHD, 3*/week, 7 8 hrs/session in the dialysis unit) was associated with regression of LVM. METHODS: We conducted a retrospective cohort study of CHD recipients who converted to INHD and received INHD for at least 6 months. LVM on the first echocardiogram performed at least 6 months post-conversion was compared to LVM pre-conversion. In a secondary analysis, we examined echocardiograms performed at least 12 months after starting INHD. The effect of conversion to INHD on LVM over time was also evaluated using a longitudinal analysis that incorporated all LVM data on patients with 2 or more echocardiograms. RESULTS: Thirty-seven patients were eligible for the primary analysis. Mean age at conversion was 49 +/- 12 yrs and 30% were women. Mean pre-conversion LVM was 219 +/- 66 g and following conversion, LVM declined by 32 +/- 58 g (p = 0.002). Among patients whose follow up echocardiogram occurred at least 12 months following conversion, LVM declined by 40 +/- 56 g (p = 0.0004). The rate of change of LVM decreased significantly from 0.4 g/yr before conversion, to -11.7 g/yr following conversion to INHD (p < 0.0001). CONCLUSION: Conversion to INHD is associated with a significant regression in LVM, which may portend a more favourable cardiovascular outcome. Our preliminary findings support the need for randomized controlled trials to definitively evaluate the cardiovascular effects of INHD. PMID- 22260391 TI - Synthesis of highly transparent ultrananocrystalline diamond films from a low pressure, low-temperature focused microwave plasma jet. AB - This paper describes a new low-temperature process underlying the synthesis of highly transparent ultrananocrystalline diamond [UNCD] films by low-pressure and unheated microwave plasma jet-enhanced chemical vapor deposition with Ar-1%CH4 10%H2 gas chemistry. The unique low-pressure/low-temperature [LPLT] plasma jet enhanced growth even with added H2 and unheated substrates yields UNCD films similar to those prepared by plasma-enhanced growth without addition of H2 and heating procedure. This is due to the focused plasma jet which effectively compensated for the sluggish kinetics associated with LPLT growth. The effects of pressure on UNCD film synthesis from the microwave plasma jet were systematically investigated. The results indicated that the substrate temperature, grain size, surface roughness, and sp3 carbon content in the films decreased with decreasing pressure. The reason is due to the great reduction of Halpha emission to lower the etching of sp2 carbon phase, resulting from the increase of mean free path with decreasing pressure. We have demonstrated that the transition from nanocrystalline (80 nm) to ultrananocrystalline (3 to 5 nm) diamond films grown via microwave Ar-1%CH4-10%H2 plasma jets could be controlled by changing the pressure from 100 to 30 Torr. The 250-nm-thick UNCD film was synthesized on glass substrates (glass transition temperature [Tg] 557 degrees C) using the unique LPLT (30 Torr/460 degrees C) microwave plasma jet, which produced UNCD films with a high sp3 carbon content (95.65%) and offered high optical transmittance (approximately 86% at 700 nm). PMID- 22260390 TI - Antinuclear antibodies testing as a routine screening for systemic lupus erythematosus in patients presenting first-episode psychosis. AB - AIMS: This report discusses the use of antinuclear antibody (ANA) detection as a screening test for neuropsychiatry systemic lupus erythematosus (NPSLE) in patients presenting a first-episode psychosis. METHODS: We reviewed the medical records of 85 patients admitted to an emergency service due to first-episode psychosis, during a 1-year period, for whom ANA detection was performed through an IFI HEp2 cell assay. ANA-positive patients were subsequently evaluated for autoantibodies and neuroimaging exams. RESULTS: Three patients presented as ANA positive in the initial screening and further investigation confirmed NPSLE in two patients. The patients were treated with antipsychotics and cyclophosphamide pulses with satisfactory outcomes. CONCLUSION: Even though ANA detection is not specific, it is a low-cost procedure and could be an important screening test for NPSLE in the early-onset psychosis. PMID- 22260389 TI - Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis. AB - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases that develop as a result of deregulated immune responses causing glial activation and destruction of CNS tissues. Oleanolic acid and erythrodiol are natural triterpenes that display strong anti-inflammatory and immunomodulatory activities. Oleanolic acid beneficially influences the course of established EAE. We now extend our previous observations to erythrodiol and address the efficacy of both compounds to protect against EAE, given under different regimens. EXPERIMENTAL APPROACH: The utility of both triterpenes in disease prevention was evaluated at a clinical and molecular level: in vivo through their prophylactic administration to myelin oligodendrocyte protein-immunized C57BL/6 mice, and in vitro through their addition to stimulated-BV2 microglial cells. KEY RESULTS: These triterpenes protected against EAE by restricting infiltration of inflammatory cells into the CNS and by preventing blood-brain barrier disruption. Triterpene-pretreated EAE-mice exhibited less leptin secretion, and switched cytokine production towards a Th2/regulatory profile, with lower levels of Th1 and Th17 cytokines and higher expression of Th2 cytokines in both serum and spinal cord. Triterpenes also affected the humoral response causing auto-antibody production inhibition. In vitro, triterpenes inhibited ERK and rS6 phosphorylation and reduced the proliferative response, phagocytic properties and synthesis of proinflammatory mediators induced by the addition of inflammatory stimuli to microglia. CONCLUSIONS AND IMPLICATIONS: Both triterpenes restricted the development of the characteristic features of EAE. We envision these natural products as novel helpful tools for intervention in autoimmune and neurodegenerative diseases including MS. PMID- 22260392 TI - Predictors of successful short-term tobacco cessation in UK resident female Bangladeshi tobacco chewers. AB - AIM: To identify predictors of short-term smokeless tobacco cessation in Bangladeshi women resident in the United Kingdom. DESIGN: Prospective cohort study. SETTING: A tobacco cessation service offering culturally tailored smokeless tobacco cessation support. PARTICIPANTS: A total of 419 Bangladeshi women chewing paan with tobacco. MEASUREMENTS: Demographics, tobacco use and dependence and cessation attempt process and outcomes. FINDINGS: Client mean age was 48.92 [95% confidence interval (CI) 47.5, 50.34] years and the mean area social deprivation score was 3.65 (95% CI 3.33, 3.97). Mean daily smokeless tobacco intakes, as paan, was 9.96 (95% CI 9.22, 10.7); 69.8% were recruited from primary care, 78.8% received behavioural support and nicotine replacement therapy (NRT) and the remainder behavioural support alone. Self-reported 4-week continuous abstinence was 58.3%, predicted by NRT use [odds ratio (OR) = 4.93, 95% CI 2.02, 12.00], community recruitment (OR = 1.84, 95% CI 1.01, 3.35) and relatively lower social deprivation (IMD) score (OR = 1.98, 95% CI 1.18, 3.33). CONCLUSION: Bangladeshi women in the UK attending clinics to help cessation of paan with tobacco appear to be more likely to be successful in the short term if they use nicotine replacement therapy, are recruited via the community and have relatively lower levels of social deprivation. PMID- 22260394 TI - Response of midgut epithelial cells to Cry1Aa is toxin-dependent and depends on the interplay between toxic action and the host apoptotic response. AB - Cry1Aa is an insecticidal protein produced by Bacilllus thuringiensis. To elucidate the mechanisms of cell/individual death and healing in the midgut epithelium, Bombyx mori larva were given different concentrations of Cry1Aa, and sections from the midgut were examined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. In the lethal condition, most midgut columnar cells were observed to swell and burst without being stained by TUNEL 4 h after intoxication, and the epithelial layer collapsed by 24 h. In the sublethal to nonlethal conditions, midgut columnar cells did not swell, but their nuclei were intensely stained by TUNEL at 4-24 h after intoxication. These apoptotic cells dropped out of the epithelial layer, and the epithelial layer was finally renewed by newly mature columnar cells within 72 h after intoxication. These results suggest that the reaction, which occurs in the midgut of intoxicated insects, is determined by the interplay between passive toxic action and the active host healing response, in a toxin concentration-dependent manner. To investigate the signal pathways regulating apoptosis and the proliferation of the intoxicated epithelial layer, the expression of several genes was further examined by quantitative real-time PCR. Bm-Apaf1 was the most upregulated gene postintoxication. PMID- 22260396 TI - Molecular simulations of wetting of a rough surface by an oily fluid: effect of topology, chemistry, and droplet size on wetting transition rates. AB - The goal of this work is to study via molecular simulations the wetting kinetics of a rough surface by an oily fluid. We use forward flux sampling to compute the wetting transition rate and elucidate the transition mechanism of a small droplet on a surface of nails. The nails provide the re-entrant geometry necessary to keep the droplet in the nonwetted, composite state. The effects of nail height, droplet size, and surface chemistry are investigated. Because the droplet must touch the bottom surface to transition, increasing the nail height is an effective way to increase the barrier to wetting for both phobic and slightly philic drops, although as the fluid becomes very philic, chemistry dominates and the effect of nail height disappears. Generally, smaller drops transition more easily. Overall, our results suggest that nonwettability could be practically enhanced by promoting the "kinetic" trapping of the system in the nonwetted state. PMID- 22260395 TI - Titanium dioxide nanoparticles in food and personal care products. AB - Titanium dioxide is a common additive in many food, personal care, and other consumer products used by people, which after use can enter the sewage system and, subsequently, enter the environment as treated effluent discharged to surface waters or biosolids applied to agricultural land, incinerated wastes, or landfill solids. This study quantifies the amount of titanium in common food products, derives estimates of human exposure to dietary (nano-) TiO(2), and discusses the impact of the nanoscale fraction of TiO(2) entering the environment. The foods with the highest content of TiO(2) included candies, sweets, and chewing gums. Among personal care products, toothpastes and select sunscreens contained 1% to >10% titanium by weight. While some other cremes contained titanium, despite being colored white, most shampoos, deodorants, and shaving creams contained the lowest levels of titanium (<0.01 MUg/mg). For several high-consumption pharmaceuticals, the titanium content ranged from below the instrument detection limit (0.0001 MUg Ti/mg) to a high of 0.014 MUg Ti/mg. Electron microscopy and stability testing of food-grade TiO(2) (E171) suggests that approximately 36% of the particles are less than 100 nm in at least one dimension and that it readily disperses in water as fairly stable colloids. However, filtration of water solubilized consumer products and personal care products indicated that less than 5% of the titanium was able to pass through 0.45 or 0.7 MUm pores. Two white paints contained 110 MUg Ti/mg while three sealants (i.e., prime coat paint) contained less titanium (25 to 40 MUg Ti/mg). This research showed that, while many white-colored products contained titanium, it was not a prerequisite. Although several of these product classes contained low amounts of titanium, their widespread use and disposal down the drain and eventually to wastewater treatment plants (WWTPs) deserves attention. A Monte Carlo human exposure analysis to TiO(2) through foods identified children as having the highest exposures because TiO(2) content of sweets is higher than other food products and that a typical exposure for a US adult may be on the order of 1 mg Ti per kilogram body weight per day. Thus, because of the millions of tons of titanium-based white pigment used annually, testing should focus on food-grade TiO(2) (E171) rather than that adopted in many environmental health and safety tests (i.e., P25), which is used in much lower amounts in products less likely to enter the environment (e.g., catalyst supports, photocatalytic coatings). PMID- 22260397 TI - Synthesis of 6-substituted 6-nitroperhydro-1,4-diazepines via novel tandem retro Henry and Mannich/Michael reactions. AB - N,N'-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-diazepines. The tandem retro Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved. PMID- 22260398 TI - Reduction of terphenyl Co(II) halide derivatives in the presence of arenes: insertion of Co(I) into a C-F bond. AB - Reduction of [(3,5-(i)Pr(2)-Ar*)Co(MU-Cl)](2) (3,5-(i)Pr(2)-Ar* = -C(6)H-2,6 (C(6)H(2)-2,4,6-(i)Pr(3))(2)-3,5-(i)Pr(2)) with KC(8) in the presence of various arene molecules resulted in the formation of a series of terphenyl stabilized Co(I) half-sandwich complexes (3,5-(i)Pr(2)-Ar*)Co(eta(6)-arene) (arene = toluene (1), benzene (2), C(6)H(5)F (3)). X-ray crystallographic studies revealed that the three compounds adopt similar bonding schemes but that the fluorine substituted derivative 3 shows the strongest cobalt-eta(6)-arene interaction. In contrast, C-F bond cleavage occurred when the analogous reduction was conducted in the presence of C(6)F(6), affording the salt K[(3,5-(i)Pr(2) Ar*)Co(F)(C(6)F(5))] (4), in which there is a three-coordinate cobalt complexed by a fluorine atom, a C(6)F(5) group, and the terphenyl ligand Ar*-3,5-(i)Pr(2). This salt resulted from the formal insertion of a putative 3,5-(i)Pr(2)-Ar*Co species as a neutral or anionic moiety into one of the C-F bonds of C(6)F(6). Reduction of [(3,5-(i)Pr(2)-Ar*)Co(MU-Cl)](2) in the presence of bulkier substituted benzene derivatives such as mesitylene, hexamethylbenzene, tert butylbenzene, or 1,3,5-triisopropylbenzene did not afford characterizable products. PMID- 22260399 TI - Significance of a change between two consecutive measured values. AB - BACKGROUND: The interpretation of a change between two consecutive measured values of a given quantity in the same patient is still controversial and it is not commonly found in clinical laboratory reports. We present here a manageable and affordable approach for all clinical laboratories to help physicians to interpret these differences. METHODS: We selected all pairs of two consecutive measured values of serum albumin concentration and serum thyrotropin concentration, both within the biological reference interval, delivered by our clinical laboratory in a 2-year period (2008-2009). We calculated the relative difference between pairs from which we estimated percentiles 2.5 and 97.5 in order to set an interval defining the significance of a change. We verified these intervals with data from the year 2010. RESULTS: During the 2-year period, we found 122,626 consecutive pairs of serum albumin concentration and 9 374 pairs of serum thyrotropin concentration, with both measured values within our biological reference interval. The intervals defining the significance of a change between two consecutive measured values were: (-14.0 to 17.6)% for the relative differences of albumin concentration, and (-61.4 to 177.8)% for the differences of thyrotropin concentration, which determined 12.7% and 18.4% of significant relative differences, respectively. Similar results were obtained from data for the year 2010. CONCLUSIONS: The interval that defines the significance of a change could easily be estimated with the patients' measured values obtained daily in the laboratory. Our proposal is more appropriate to each specific population than the conventional intra-individual biological variation approach. PMID- 22260400 TI - Verification of endotracheal intubation in obese patients - temporal comparison of ultrasound vs. auscultation and capnography. AB - BACKGROUND: Ultrasound (US) may have an emerging role as an adjunct in verification of endotracheal intubation. Obtaining optimal US images in obese patients is generally regarded more difficult than for other patients. This study compared the time consumption of bilateral lung US with auscultation and capnography for verifying endotracheal intubation in obese patients. METHODS: A prospective, paired and investigator-blinded study performed in the operating theatre. Twenty-four adult patients requiring endotracheal intubation for bariatric surgery were included. During post-intubation bag ventilation, bilateral lung US was performed for detection of lungsliding indicating lung ventilation simultaneous with capnography and auscultation of epigastrium and chest. Primary outcome measure was the time difference to confirmed endotracheal intubation between US and auscultation alone. The secondary outcome measure was time difference between US and auscultation combined with capnography. RESULTS: Both methods verified endotracheal tube placement in all patients. No significant difference was found between US compared with auscultation alone. Median time for verification by auscultation alone was 47.5 s [interquartile (IQR) 40-51 s], with a mean difference of -0.3 s in favor of US (95% confidence interval -3.5-2.9 s) P = 0.87. Comparing US with the combination of auscultation and capnography, there was a significant difference between the two methods. Median time for verification by US was 43 s (IQR 40-51 s) vs. 55 s (IQR 46-65 s), P < 0.0001. CONCLUSION: In obese patients, verification of endotracheal tube placement with US is as fast as auscultation alone and faster than the standard method of auscultation and capnography. PMID- 22260401 TI - Influence of substituents on the through-space shielding of aromatic rings. AB - A series of naphthalene derivatives, bearing a methyl group and a substituted phenyl ring in a 1,8-relationship, have been synthesized. The chemical shifts of the protons of the methyl group, which are pointed toward the shielding zone of the phenyl ring, were monitored as the phenyl substituents were varied. This work indicates that the shielding effect of the phenyl ring is not so severely altered by the substituents as to significantly influence the chemical shift of the methyl group. Nonetheless, within the small changes observed experimentally, there appears to be a tendency for electron-withdrawing X to shift the methyl signal downfield, whereas electron-donating X-groups cause a more upfield shift. Polarization and field effects are discussed as possible causes for this phenomenon. Chemical shifts computed for selected members of the series, using the recently published procedures of Rablen and Bally, are in agreement with the experimentally observed trends. PMID- 22260403 TI - Induction of gut IgA production through T cell-dependent and T cell-independent pathways. AB - The gut immune system protects against mucosal pathogens, maintains a mutualistic relationship with the microbiota, and establishes tolerance against food antigens. This requires a balance between immune effector responses and induction of tolerance. Disturbances of this strictly regulated balance can lead to infections or the development inflammatory diseases and allergies. Production of secretory IgA is a unique effector function at mucosal surfaces, and basal mechanisms regulating IgA production have been the focus of much recent research. These investigations have aimed at understanding how long-term IgA-mediated mucosal immunity can best be achieved by oral or sublingual vaccination, or at analyzing the relationship between IgA production, the composition of the gut microbiota, and protection from allergies and autoimmunity. This research has lead to a better understanding of the IgA system; but at the same time seemingly conflicting data have been generated. Here, we discuss how gut IgA production is controlled, with special focus on how differences between T cell-dependent and T cell-independent IgA production may explain some of these discrepancies. PMID- 22260402 TI - Factors influencing uptake and timing of risk reducing salpingo-oophorectomy in women at risk of familial ovarian cancer: a competing risk time to event analysis. AB - OBJECTIVE: To evaluate factors affecting uptake of risk-reducing salpingo oophorectomy (RRSO) over time in women at high-risk of familial ovarian cancer. DESIGN: Prospective observational cohort. SETTING: Tertiary high-risk familial gynaecological cancer clinic. POPULATION/SAMPLE: New clinic attendees between March 2004 and November 2009, fulfilling the high-risk criteria for the UK Familial Ovarian Cancer Screening Study. METHODS: Risk management options discussed included RRSO and ovarian surveillance. Outcome data were analysed from a bespoke database. The competing risk method was used to model the cumulative incidence function (CIF) of RRSO over time, and the sub-hazard ratio (SHR) was used to assess the strength of the association of variables of interest with RRSO. Gray's test was used to evaluate the difference in CIF between two groups and multivariable competing risk regression analysis was used to model the cumulative probabilities of covariates on the CIF. RESULTS: Of 1133 eligible women, 265 (21.4%) opted for RRSO and 868 (69.9%) chose screening. Women undergoing RRSO were older (49 years, interquartile range 12.2 years) than those preferring screening (43.4 years, interquartile range 11.9 years) (P < 0.0005). The CIF for RRSO at 5 years was 0.55 (95% CI 0.45-0.64) for BRCA1/2 carriers and 0.22 (95% CI 0.19-0.26) for women of unknown mutation status (P < 0.0001); 0.42 (95% CI 0.36-0.47) for postmenopausal women (P < 0.0001); 0.29 (95% CI 0.25-0.33) for parity >=1 (P = 0.009) and 0.47 (95% CI 0.39-0.55) for a personal history of breast cancer (P < 0.0001). Variables of significance from the regression analysis were: a BRCA1/2 mutation (SHR 2.31, 95% CI 1.7-3.14), postmenopausal status (SHR 2.16, 95% CI 1.62-2.87)) and a personal history of breast cancer (SHR 1.5, 95% CI 1.09-2.06). CONCLUSIONS: Decision-making is a complex process and women opt for surgery many years after initial risk assessment. BRCA carriers, postmenopausal women and women who had breast cancer are significantly more likely to opt for preventative surgery. PMID- 22260404 TI - Using density functional theory to interpret the infrared spectra of flexible cyclic phosphazenes. AB - The cyclic phosphazene trimer P(3)N(3)(OCH(2)CF(3))(6)and the related cyclic tetramer P(4)N(4)(OCH(2)CF(3))(8) have been synthesized, isolated and their vapor phase absorption spectra recorded at moderate resolution using an FTIR spectrometer. The interpretation of these spectra is achieved primarily by comparison with the results of high-precision density functional calculations, which enable the principal absorption features to be assigned and conclusions to be drawn regarding the geometries and conformations adopted by both molecules. These in turn allow interesting comparisons to be made with analogous cyclic halo phosphazenes (such as P(3)N(3)Cl(6)) and other related ring compounds. The highly flexible nature of the two cyclic phosphazenes precludes a complete theoretical study of their potential energy hypersurfaces and a novel alternative approach involving the analysis of a carefully selected subset of the possible molecular conformations has been shown to produce satisfactory results. The two cyclic phosphazene oligomers have been proposed as the major low-to-medium temperature pyrolysis products of the parent polyphosphazene (PN(OCH(2)CF(3))(2))(n), and the identification of vibrational absorption features characteristic of each molecule will enable future studies to test the validity of this proposition. PMID- 22260405 TI - Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice. AB - For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zurich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally <= 5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (>= 5 BU) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications. PMID- 22260406 TI - Is there any association between IgA nephropathy, Crohn's disease and Helicobacter pylori infection? AB - A case of IgA nephropathy (IgAN) associated with Crohn's disease (CD) and preceded Helicobacter pylori (Hp) infection is described. Therapy with corticosteroids and azathioprine resulted in clinical improvement. The connection between IgAN and CD is well established, while tonsillar Hp is a potential antigen causative of IgAN. The three entities may reflect a common immunopathogenetic mechanism involving an IgA response to mucosal challenge. PMID- 22260407 TI - The role of disease characteristics in the ethical debate on personal genome testing. AB - BACKGROUND: Companies are currently marketing personal genome tests directly-to consumer that provide genetic susceptibility testing for a range of multifactorial diseases simultaneously. As these tests comprise multiple risk analyses for multiple diseases, they may be difficult to evaluate. Insight into morally relevant differences between diseases will assist researchers, healthcare professionals, policy-makers and other stakeholders in the ethical evaluation of personal genome tests. DISCUSSION: In this paper, we identify and discuss four disease characteristics--severity, actionability, age of onset, and the somatic/psychiatric nature of disease--and show how these lead to specific ethical issues. By way of illustration, we apply this framework to genetic susceptibility testing for three diseases: type 2 diabetes, age-related macular degeneration and clinical depression. For these three diseases, we point out the ethical issues that are relevant to the question whether it is morally justifiable to offer genetic susceptibility testing to adults or to children or minors, and on what conditions. SUMMARY: We conclude that the ethical evaluation of personal genome tests is challenging, for the ethical issues differ with the diseases tested for. An understanding of the ethical significance of disease characteristics will improve the ethical, legal and societal debate on personal genome testing. PMID- 22260408 TI - Social function in children and adolescents after traumatic brain injury: a systematic review 1989-2011. AB - Clinical reports and case studies suggest that traumatic brain injury (TBI) can have significant social consequences, with social dysfunction reported to be the most debilitating problem for child and adolescent survivors. From a social neuroscience perspective, evidence suggests that social skills are not localized to a specific brain region, but are mediated by an integrated neural network. Many components of this network are susceptible to disruption in the context of TBI. In early development, a brain injury can disrupt this neural network while it is in the process of being established, resulting in social dysfunction. In order to clarify the prevalence and nature of social dysfunction after child TBI, studies of social outcomes in children and adolescents after TBI over the last 23 years have been reviewed. Despite casting a wide net initially, only 28 articles met review criteria. These studies were characterized by methodological weaknesses, including variations in definitions of TBI, limited assessment tools, reliance on parent reports, small sample sizes, and absent control groups. Despite these limitations, the weight of evidence confirmed an elevated risk of social impairment in the context of moderate and severe injury. While rarely examined, younger age at insult, pathology to frontal regions and the corpus callosum, and social disadvantage and family dysfunction may also increase the likelihood of social difficulties. More research is needed to obtain an accurate picture of social outcomes post-brain injury. PMID- 22260409 TI - New insights into uric acid effects on the progression and prognosis of chronic kidney disease. AB - Hyperuricemia is particularly common in patients with arterial hypertension, metabolic syndrome, or kidney disease. Its role, however, as a risk factor for both renal and cardiovascular outcomes and in the context of the well-established interrelationship between cardiovascular disease and chronic kidney disease (CKD) is debated. For decades high serum uric acid levels were mainly considered the result of renal dysfunction and not a true mediator of renal disease development and progression. However, recent epidemiological studies suggest an independent association between asymptomatic hyperuricemia and increased risk of arterial hypertension, CKD, cardiovascular events, and mortality. Furthermore, data from experimental models of hyperuricemia have provided robust evidence in this direction. Hyperuricemia causes increased arterial pressure, proteinuria, renal dysfunction, and progressive renal and vascular disease in rats. The main pathophysiological mechanisms of these deleterious effects caused by uric acid are endothelial dysfunction, activation of local renin-angiotensin system, increased oxidative stress, and proinflammatory and proliferative actions. A small number of short-term, single-center clinical studies support the beneficial influence of pharmaceutical reduction of serum uric acid on total cardiovascular risk, as well as on renal disease development and progression. Hyperuricemia is probably related to the incidence of primary hypertension in children and adolescents, as serum uric acid lowering by allopurinol has an antihypertensive action in this group of patients. Finally, it is clear that adequately powered randomized controlled trials are urgently required to elucidate the role of uric acid in cardiovascular events and outcomes, as well as in the development and progression of CKD. PMID- 22260410 TI - Risk factors and clinical outcomes of cytomegalovirus disease occurring more than one year post solid organ transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) disease typically occurs during the first year after solid organ transplantation, after cessation of antiviral prophylaxis. CMV occurring after the first year is uncommon and not well described. METHODS: We conducted a case-control study to identify potential risk factors and a retrospective cohort study to evaluate 1-month mortality in solid organ transplant (SOT) recipients who developed CMV disease after the first year post transplant, or "very late CMV" (VLCMV), compared with those developing CMV within the first year (CMV Y1), adjusting for demographics, donor and recipient CMV serostatus, immunosuppression, rejection, and co-morbidities. RESULTS: We identified 85 SOT recipients with CMV disease at a single transplant center between January 2006 and October 2008: 23 (27%) had VLCMV and 62 (73%) had CMV Y1. Heart transplantation was independently associated with increased risk (adjusted odd ratio [OR] 4.11; 95% confidence interval [CI] 1.34-12.61; P = 0.01) for VLCMV. Patients with VLCMV had increased 1-month mortality (unadjusted OR 5.39; 95% CI 1.06-27.48; P = 0.02). Mortality was uncommonly attributable to CMV. CONCLUSIONS: CMV disease continues to occur after the first year post solid organ transplantation, particularly in heart transplant recipients, and can be associated with poor outcomes. CMV should be suspected in patients with symptoms or laboratory findings consistent with CMV, even if the patients present >1 year post transplant. PMID- 22260411 TI - Using default constraints of the spindle assembly checkpoint to estimate the associated chemical rates. AB - : BACKGROUND: Default activation of the spindle assembly checkpoint provides severe constraints on the underlying biochemical activation rates: on one hand, the cell cannot divide before all chromosomes are aligned, but on the other hand, when they are ready, the separation is quite fast, lasting a few minutes. Our purpose is to use these opposed constraints to estimate the associated chemical rates. RESULTS: To analyze the above constraints, we develop a markovian model to describe the dynamics of Cdc20 molecules. We compute the probability for no APC/C activation before time t, the distribution of Cdc20 at equilibrium and the mean time to complete APC/C activation after all chromosomes are attached. CONCLUSIONS: By studying Cdc20 inhibition and the activation time, we obtain a range for the main chemical reaction rates regulating the spindle assembly checkpoint and transition to anaphase. PMID- 22260414 TI - Oestrogen receptor beta in adenoid cystic carcinoma of salivary glands. AB - AIMS: This study aimed to describe the expression of oestrogen receptor (ER)alpha, ERbeta and aromatase in salivary gland adenoid cystic carcinoma (ACC). METHODS AND RESULTS: ERalpha, ERbeta and aromatase expression was analysed by immunohistochemistry in tissue microarray blocks from 38 cases of ACC and seven normal salivary glands. The intracellular localization and amount of total protein expression were investigated by immunofluorescence and western blotting in an ACC cell line. Western blotting analysis showed overexpression of ERalpha, ERbeta and aromatase in the ACC cell line; however, with immunofluorescence, only ERbeta was shown to be expressed in the nucleus. Immunohistochemistry revealed positive nuclear expression of ERbeta, positive cytoplasmic expression of aromatase and a lack of ERalpha expression as compared with normal salivary glands. CONCLUSIONS: The nuclear expression of ERbeta indicates that oestrogen may be active in ACC and possibly able to mediate E2-targeted gene transcription. This study strongly suggests that ERbeta may be involved in tumour progression, playing a role in tumour development, and thus corroborating the indication for ER antagonists in the clinical control of ACC. This study opens a new perspective on the potential use of anti-oestrogens and aromatase inhibitors as therapeutic agents against ACC. PMID- 22260413 TI - Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up. AB - BACKGROUND: High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential "reverse causality" where undetected disease modifies cholesterol prior to diagnosis. METHODS: We conducted a prospective cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence. We excluded cancers detected within at least 5 years of cholesterol assay. RESULTS: 650 men developed prostate cancer in up to 37 years' follow-up. Baseline plasma cholesterol was positively associated with hazard of high grade (Gleason score>=8) prostate cancer incidence (n = 119). The association was greatest among men in the 2nd highest quintile for cholesterol, 6.1 to < 6.69 mmol/l, Hazard Ratio 2.28, 95% CI 1.27 to 4.10, compared with the baseline of < 5.05 mmol/l. This association remained significant after adjustment for body mass index, smoking and socioeconomic status. CONCLUSIONS: Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but not overall risk of prostate cancer. Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer. PMID- 22260415 TI - Bioengineered nisin derivatives with enhanced activity in complex matrices. AB - Nisin A is the best known and most extensively characterized lantibiotic. As it is ribosomally synthesized, bioengineering-based strategies can be used to generate variants. We have previously demonstrated that bioengineering of the hinge region of nisin A can result in the generation of variants with enhanced anti-microbial activity against Gram-positive pathogens. Here we created a larger bank of hinge variant producers and screened for producers that exhibit enhanced bioactivity as assessed by agar-based assays against a selection of target strains. Further analysis of 12 'lead' variants reveals that in many cases enhanced bioactivity is not attributable to enhanced specific activity but is instead as a consequence of an enhanced ability to diffuse through complex polymers. In the case of two variants, which contain the residues SVA and NAK, respectively, within the hinge region, we demonstrate that this enhanced trait enables the peptides to dramatically outperform nisin A with respect to controlling Listeria monocytogenes in commercially produced chocolate milk that contains carrageenan as a stabilizer. PMID- 22260416 TI - The Netherlands: the struggle between universalism and cost containment. AB - The Dutch home-care system is embedded in a universalistic and comparatively generous long-term care (LTC) scheme that was introduced in the late 1960s. The tension between guaranteeing access to good-quality care and controlling costs has been a key issue since the inception of the LTC scheme. The article addresses the question of how these two distinct objectives have been dealt with in the political debate and by policy-making in the past 20 years. It does so by looking at existing studies, official statistics and policy documents. First, the analysis shows that home care - the development of which results from the de institutionalisation policies pursued since the 1980s - has shifted from being considered a cost-containment measure to representing a battlefield on cost containment. Second, the article argues that the issue of cost containment is a leitmotif in the development of home care that has been accompanied and legitimised over time by distinct normative views. On the one hand, traditional forms of cost containment - namely direct budgetary controls - have been predicated on the need to ensure the financial sustainability of the system and its universalistic features. On the other hand, the discourse and practice of cost containment has, since the early 1990s, also been accompanied by normative views that structurally challenge universalism through the introduction of new ideas about the responsibility for LTC risks, resource allocation and regulation of the system. PMID- 22260417 TI - Wild type, mutant protein unfolding and phase transition detected by single nanopore recording. AB - Understanding protein folding remains a challenge. A difficulty is to investigate experimentally all the conformations in the energy landscape. Only single molecule methods, fluorescence and force spectroscopy, allow observing individual molecules along their folding pathway. Here we observe that single-nanopore recording can be used as a new single molecule method to explore the unfolding transition and to examine the conformational space of native or variant proteins. We show that we can distinguish unfolded states from partially folded ones with the aerolysin pore. The unfolding transition curves of the destabilized variant are shifted toward the lower values of the denaturant agent compared to the wild type protein. The dynamics of the partially unfolded wild type protein follows a first-order transition. The denaturation curve obtained with the aerolysin pore is similar to that obtained with the alpha-hemolysin pore. The nanopore geometry or net charge does not influence the folding transition but changes the dynamics. PMID- 22260419 TI - Enantioselective hydrocyanation of N-protected aldimines. AB - Enantioselective hydrocyanation of N-benzyloxycarbonyl aldimines catalyzed by a Ru[(S)-phgly](2)[(S)-binap]/C(6)H(5)OLi system or a bimetallic complex [Li{Ru[(S) phgly](2)[(S)-binap]}]Cl affords the amino nitriles in 92-99% ee. The reaction is carried out in tert-C(4)H(9)OCH(3) with a substrate-to-catalyst molar ratio in the range of 500-5000 at -20 to 0 degrees C. Primary, secondary, and tertiary alkyl imines as well as the aryl and heteroaryl substrates are smoothly cyanated to produce the desired products in high yield. PMID- 22260420 TI - Platinum-modified adenines: unprecedented protonation behavior revealed by NMR spectroscopy and relativistic density-functional theory calculations. AB - Two novel Pt(IV) complexes of aromatic cytokinins with possible antitumor properties were prepared by reaction of selected aminopurines with K(2)PtCl(6). The structures of both complexes, 9-[6-(benzylamino)purine] pentachloroplatinate (IV) and 9-[6-(furfurylamino)purine] pentachloroplatinate (IV), were characterized in detail by using two-dimensional NMR spectroscopy ((1)H, (13)C, (15)N, and (195)Pt) in solution and CP/MAS NMR techniques in the solid state. We report for the first time the X-ray structure of a nucleobase adenine derivative coordinated to Pt(IV) via the N9 atom. The protonation equilibria for the complexes in solution were characterized by using NMR spectroscopy (isotropic chemical shifts and indirect nuclear spin-spin coupling constants) and the structural conclusions drawn from the NMR analysis are supported by relativistic density-functional theory (DFT) calculations. Because of the presence of the Pt atom, hybrid GGA functionals and scalar-relativistic and spin-orbit corrections were employed for both the DFT calculations of the molecular structure and particularly for the NMR chemical shifts. In particular, the populations of the N7-protonated and neutral forms of the complexes in solution were characterized by correlating the experimental and the DFT-calculated NMR chemical shifts. In contrast to the chemical exchange process involving the N7-H group, the hydrogen atom at N3 was determined to be unexpectedly rigid, probably because of the presence of the stabilizing intramolecular interaction N3-H...Cl. The described methodology combining the NMR spectroscopy and relativistic DFT calculations can be employed for characterizing the tautomeric and protonation equilibria in a large family of transition-metal-modified purine bases. PMID- 22260418 TI - Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients. AB - BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients. PMID- 22260421 TI - Enhancement of diastereoselectivity in photodimerization of alkyl 2-naphthoates with chiral auxiliaries via inclusion within gamma-cyclodextrin cavities. AB - Irradiations of alkyl 2-naphthoates are known to result in four isomeric "cubane like" photodimers: anti(HH)-2, syn(HH)-2, anti(HT)-2, and syn(HT)-2 where the anti(HH)-2, anti(HT)-2, and syn(HT)-2 consist of pairs of diastereomers. Here, chiral auxiliary and chiral microreactor strategies have been combined to achieve high diastereoselectivity in photodimerizations of an enantiomeric pair of 2 naphthoates with (R)- and (S)-1-methoxycarbonylethyl esters as chiral auxiliaries (1R and 1S). Thus, irradiations of their gamma-cyclodextrin (gamma-CD) complexes have been conducted. Fluorescence, IR, and NMR spectra of both enantiomers of 1 demonstrate that their gamma-CD complexes are mainly 2:2 with the molecules of 1 in head-to-head orientations. Irradiation of the complexes in the solid state mainly resulted in anti(HH)-2. The absolute configuration of each diastereomer of anti(HH)-2 has been established for the first time here. The diastereomeric excesses (de's) of anti(HH)-2 from 1R and 1S were 94% and 86%, respectively. These de's are much higher than those found from irradiations in solution (55% for 1R and 1S), where the opposite diastereomeric form is in excess! Calculations of the energies of various conformations of the head-to-head 2:2 inclusion complexes were performed using the PM3 approach. The predicted major diastereomers based on the calculation are consistent with those found experimentally. PMID- 22260422 TI - Physicians' communicative strategies in interacting with Internet-informed patients: results from a qualitative study. AB - This article describes the strategies used by physicians to interact with Internet-informed patients, alongside illustrating the motives underlying such strategies. Semistructured interviews were conducted with a sample of 17 physicians from primary care and medical specialist practices in the Italian part of Switzerland. The sample was diversified in terms of specialty, age, and gender. Data collection and analysis were driven by grounded theory and supported by a computer-assisted qualitative analysis program. A typology of four communicative strategies has been outlined. The adoption of these strategies is shaped by physicians' general attitude toward Internet-informed patients, based on their conception of medical information for lay people through the Internet. However, this general attitude is mediated by doctors' interpretation of the specific communicative context, that is, their appraisal of three aspects: the patient's health literacy, the relevance of the online information to be discussed, and their own communicative efficacy. At the end, the process of interpretation underlying the strategies is discussed to expand on it and to identify implications for practice and research. PMID- 22260423 TI - Reactions of a sulfonamide antimicrobial with model humic constituents: assessing pathways and stability of covalent bonding. AB - The mechanism of covalent bond formation of the model sulfonamide sulfathiazole (STZ) and the stronger nucleophile para-ethoxyaniline was studied in reactions with model humic acid constituents (quinones and other carbonyl compounds) in the absence and presence of laccase. As revealed by high resolution mass spectrometry, the initial bonding of STZ occurred by 1,2- and 1,4-nucleophilic additions of the aromatic amino group to quinones resulting in imine and anilinoquinone formation, respectively. Experiments using the radical scavenger tert-butyl-alcohol provided the same products and similar formation rates as those without scavenger indicating that probably not radical coupling reactions were responsible for the initial covalent bond formation. No addition with nonquinone carbonyl compounds occurred within 76 days except for a slow 1,4 addition to the beta-unsaturated carbonyl 1-penten-3-one. The stability of covalent bonds against desorption and pressurized liquid extraction (PLE) was assessed. The recovery rates showed no systematic differences in STZ extractability between the two product types. This suggests that the strength of bonding is not controlled by the initial type of bond, but by the extent of subsequent incorporation of the reaction product into the formed polymer. This incorporation was monitored for (15)N aniline by (1)H-(15)N HMBC NMR spectroscopy. The initial 1,2- and 1,4-addition bonds were replaced by stronger heterocyclic forms with increasing incubation time. These processes could also hold true for soils, and a slow nonextractable residue formation with time could be related to a slow increase of the amount of covalently bound sulfonamide and the strength of bonding. PMID- 22260424 TI - Training volume and body composition as risk factors for developing jumper's knee among young elite volleyball players. AB - Training volume and body composition have been suggested as risk factors for jumper's knee among athletic youth, but research is lacking. The aim of this 4 year prospective cohort study was to examine the relationship between training and competition load, body composition, and risk for developing jumper's knee. Participants are elite volleyball players, aged 16-18 years. Training and competition load was recorded continuously and body composition semiannually. Jumper's knee was diagnosed on a standardized clinical examination. We recruited 141 healthy students (69 males and 72 females), and 28 developed jumper's knee (22 boys and six girls). In a multivariate analyses, boys had three to four times higher risk compared with girls. Volleyball training had an odds ratio (OR) 1.72 (1.18-2.53) for every extra hour trained, and match exposure was the strongest sports-related predictor for developing jumper's knee with an OR of 3.88 (1.80 8.40) for every extra set played per week. We did not detect any significant differences between the groups in body composition at the time of inclusion or in the change of body composition during the study period. Conclusion, male gender, a high volume of volleyball training and match exposure were risk factors for developing jumper's knee. PMID- 22260425 TI - Toward understanding the influence of ethylbenzene in p-xylene selectivity of the porous titanium amino terephthalate MIL-125(Ti): adsorption equilibrium and separation of xylene isomers. AB - The potential of the porous crystalline titanium dicarboxylate MIL-125(Ti) in powder form was studied for the separation in liquid phase of xylene isomers and ethylbenzene (MIL stands for Materials from Institut Lavoisier). We report here a detailed experimental study consisting of binary and multi-component adsorption equilibrium of xylene isomers in MIL-125(Ti) powder at low (<=0.8 M) and bulk (>=0.8 M) concentrations. A series of multi-component breakthrough experiments was first performed using n-heptane as the eluent at 313 K, and the obtained selectivities were compared, followed by binary breakthrough experiments to determine the adsorption isotherms at 313 K, using n-heptane as the eluent. MIL 125(Ti) is a para-selective material suitable at low concentrations to separate p xylene from the other xylene isomers. Pulse experiments indicate a separation factor of 1.3 for p-xylene over o-xylene and m-xylene, while breakthrough experiments using a diluted ternary mixture lead to selectivity values of 1.5 and 1.6 for p-xylene over m-xylene and o-xylene, respectively. Introduction of ethylbenzene in the mixture results however in a decrease of the selectivity. PMID- 22260426 TI - The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders. AB - This brief review will first consider HIV associated neurocognitive disorder followed by the current understanding of its neuropathogenesis. Against this background the role of the kynurenine pathway will be detailed. Evidence both direct and indirect will be discussed for involvement of the kynurenine pathway at each step in the neuropathogenesis of HIV associated neurocognitive disorder. PMID- 22260427 TI - Early pain after laparoscopic inguinal hernia repair. A qualitative systematic review. AB - BACKGROUND: Early post-operative pain after laparoscopic groin hernia repair may, as in other laparoscopic operations, have its own individual pain pattern and patient-related predictors of early pain. The purpose of this review was to characterise pain within the first post-operative week after transabdominal pre peritoneal repair (TAPP) and total extraperitoneal repair (TEP), and to identify patient-related predictors of early pain. METHODS: A qualitative systematic review was conducted. Pubmed, Embase, CINAHL, and the Cochrane database were searched for studies on early pain (first week) after TAPP or TEP. RESULTS: We included 71 eligible studies with 14,023 patients. Post-operative pain is most severe on day 0 and mainly on a level of 13-58 mm on a visual analogue scale and decreases to low levels on day 3. There seems to be no difference in pain intensity and duration when TEP and TAPP are compared. Deep abdominal pain (i.e. groin pain/visceral pain) dominates over superficial pain (i.e. somatic pain) and shoulder pain (i.e. referred pain) after TAPP. Predictors of early pain are young age and pre-operative high pain response to experimental heat stimulation. Furthermore, evidence supported early pain intensity as a predictive risk factor of chronic pain after laparoscopic groin hernia repair. CONCLUSION: Early pain within the first week after TAPP and TEP is most severe on the first post operative day, and the pain pattern is dominated by deep abdominal pain. Early post-operative pain is most intense in younger patients and can be predicted by pre-operative high pain response to experimental heat stimulation. PMID- 22260428 TI - Prosthetic joint infection in solid organ transplant recipients: a retrospective case-control study. AB - BACKGROUND: The clinical features and outcome of prosthetic joint infection (PJI) among solid organ transplant (SOT) recipients have not been characterized. We performed a retrospective, matched case-control study to examine potential risk factors. METHODS: We reviewed cases of PJI among transplant recipients who were evaluated at the Mayo Clinic between 1989 and 2009. Cases were matched to non infected controls based on transplant type, prosthetic joint type, and order of organ transplantation/joint implantation. RESULTS: Among 367 patients with both a joint prosthesis and an SOT, there were 12 cases of infection in those receiving immunosuppression. These occurred in 8 renal recipients, 3 liver recipients, and 1 heart transplant recipient. Six subjects had hip and 6 had knee arthroplasty infections. The observed time to prosthesis failure ranged from 0.5 to 148 months after implantation. Gram-positive bacteria (staphylococci and streptococci) caused the infection in 8 subjects. Two cases were caused by nontuberculous mycobacteria, whereas the remaining 2 cases were culture-negative in the setting of antimicrobial use. We did not find a statistically significant association between obesity, diabetes mellitus, or antimicrobial prophylaxis (given in the setting of immunosuppression) and development of PJI. A marginal association was seen between surgical site infection and the risk of PJI; however, this did not reach statistical significance. CONCLUSION: In our series, infection was mainly caused by gram-positive bacterial pathogens, similar to the commonly encountered organisms in the immunocompetent host, although opportunistic pathogens were also isolated. PMID- 22260429 TI - Comparison of perinatal outcome after pre-viable preterm prelabour rupture of membranes in two centres with different rates of termination of pregnancy. AB - OBJECTIVE: To assess perinatal outcomes after expectant management in the case of preterm prelabour rupture of membranes (PPROM) before 25 weeks of gestation, according to the rate of termination of pregnancy (TOP). DESIGN: Retrospective comparative cohort study. POPULATION: Singleton pregnancies complicated by PPROM between 15(0/7) and 24(6/7) weeks of gestation, from January 2003 to January 2007. METHODS: Comparison of perinatal outcomes in two French tertiary care referral centres presumed to have different rates of TOP. MAIN OUTCOME MEASURE: Rates of TOP, survival and survival without major morbidity. RESULTS: A total of 113 women experienced PPROM (49 in centre A and 64 in centre B). A lower proportion of patients opted for TOP in centre A (40.8%) than in centre B (56.3%). The baseline characteristics of patients and pregnancies, and gestational age at PPROM, were not different between the two centres. Mean gestational age at delivery (28.1 versus 25.4 weeks of gestation; P < 0.01), mean latency period (45.5 versus 16.1 days; P < 0.01), mean birthweight (1295 versus 929 g; P = 0.04) and survival (46.9 versus 20.3%; P < 0.01) were significantly higher in centre A than in centre B. The percentage of neonates alive without major morbidity was also higher in centre A than in centre B (42.9 versus 20.3%; P = 0.01). CONCLUSIONS: Perinatal outcomes of pregnancies managed expectantly were not better in the centre where the TOP rate was higher. The perinatal risk of pregnancies complicated by pre-viable PPROM remains high. PMID- 22260430 TI - Understanding unintentional childhood home injuries: pilot surveillance data from Karachi, Pakistan. AB - BACKGROUND: Childhood injuries, an important public health issue, globally affects more than 95% of children living in low-and middle-income countries. The objective of this study is to describe the epidemiology of childhood unintentional injuries in Karachi, Pakistan with a specific focus on those occurring within the home environment. METHODS: This was a secondary analysis of a childhood unintentional injury surveillance database setup in the emergency department of the Aga Khan Hospital, Karachi, Pakistan for 3 months. The data was collected by interviewing caretakers of children under 12 years of age presenting with an unintentional injury to the emergency departments of the four major tertiary care hospitals of Karachi, Pakistan. RESULTS: The surveillance included 566 injured children of which 409 (72%) injuries had taken place at/around home. Of 409 children, 66% were males and mostly between 5 and 11 years of age. Injuries commonly occurred during play time (51%). Fall (59%), dog bites (11%) and burns (9%) were the commonest mechanisms of injury. The majority of the children (78%) were directly discharged from the emergency room with predicted short term disability (42%). There were 2 deaths in the emergency department both due to falls. CONCLUSION: Childhood injury surveillance system provides valuable in-depth information on child injuries. The majority of these unintentional childhood injuries occur at home; with falls, dog bites and burns being the most common types of unintentional childhood home injuries. Specific surveillance systems for child injuries can provide new and valuable information for countries like Pakistan. PMID- 22260431 TI - Supramolecular structure characterization of cellulose II nanowhiskers produced by acid hydrolysis of cellulose I substrates. AB - Cellulose II nanowhiskers (CNW-II) were produced by treatment of microcrystalline cellulose with sulfuric acid by both controlling the amount of H(2)SO(4) introduced and the time of addition during the hydrolysis process. The crystalline structure was confirmed by both XRD and (13)C CP-MAS NMR spectroscopy. When observed between crossed polarizers, the cellulose II suspension displayed flow birefringence and was stable for several months. The CNW-II nanowhiskers were significantly smaller than the cellulose I nanowhiskers (CNW-I) and had a rounded shape at the tip. The CNW-II average length and height were estimated by AFM to be 153 +/- 66 and 4.2 +/- 1.5 nm, respectively. An average width of 6.3 +/- 1.7 nm was found by TEM, suggesting a ribbon-shape morphology for these whiskers. The average dimensions of the CNW-II elementary crystallites were estimated from the XRD data, using Scherrer's equation. A tentative cross-sectional geometry consistent with both XRD and NMR data was then proposed and compared with the geometry of the CNW-I nanowhiskers. PMID- 22260432 TI - The growing burden of end-stage renal disease in Egypt. AB - BACKGROUND: End-stage renal disease (ESRD) has significantly increased in developing countries such as Egypt. Diabetes mellitus is still the leading cause of ESRD, while numbers of hypertensive patients among that population have significantly risen. MATERIALS AND METHODS: The data presented in this article were obtained from various nephrology centers in response to the specific questionnaires distributed by the researchers. RESULTS: Hemodialysis is available in most parts of the country. Continuous ambulatory peritoneal dialysis and renal transplantation programs have been performed in few nephrology centers. Costs for dialysis and renal transplantation are still unaffordable for most patients with ESRD. Since the cost burden has significantly increased, nephrology services should be changed from curative medicine to preventive medicine. Currently, the Egyptian Ministry of Health plans to have a detection and prevention program for chronic kidney disease. CONCLUSION: These data give the impression that both incidence and prevalence rates of ESRD in various areas of Egypt are increasing over time, although the rates presented here are far lower than expected. PMID- 22260433 TI - Identification of a small molecule yeast TORC1 inhibitor with a multiplex screen based on flow cytometry. AB - TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high-throughput flow cytometry multiplexed screen using five GFP-tagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded, and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose response analysis to alter GFP expression in one or more clones. To validate the concept of the high-throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in a manner analogous to that of rapamycin. We have shown that CID 3528206 inhibited yeast cell growth and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC(50)'s of 150 nM and 3.9 MUM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors. PMID- 22260434 TI - Size scaling and stiffness of avian primary feathers: implications for the flight of Mesozoic birds. AB - The primary feathers of birds are subject to cyclical forces in flight causing their shafts (rachises) to bend. The amount the feathers deflect during flight is dependent upon the flexural stiffness of the rachises. By quantifying scaling relationships between body mass and feather linear dimensions in a large data set of living birds, we show that both feather length and feather diameter scale much closer to predictions for geometric similarity than they do to elastic similarity. Scaling allometry also indicates that the primary feathers of larger birds are relatively shorter and their rachises relatively narrower, compared to those of smaller birds. Two-point bending tests indicated that larger birds have more flexible feathers than smaller species. Discriminant functional analyses (DFA) showed that body mass, primary feather length and rachis diameter can be used to differentiate between different magnitudes of feather bending stiffness, with primary feather length explaining 63% of variance in rachis stiffness. Adding fossil measurement data to our DFA showed that Archaeopteryx and Confuciusornis do not overlap with extant birds. This strongly suggests that the bending stiffness of their primary feathers was different to extant birds and provides further evidence for distinctive flight styles and likely limited flight ability in Archaeopteryx and Confuciusornis. PMID- 22260435 TI - TGF-beta1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells. AB - BACKGROUND: Metastasis is the main factor responsible for death in breast cancer patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are essential for the metastatic process. We have previously shown a positive correlation between MMPs and their inhibitors expression during breast cancer progression; however, the molecular mechanisms underlying this coordinate regulation remain unknown. In this report, we investigated whether TGF-beta1 could be a common regulator for MMPs, TIMPs and RECK in human breast cancer cell models. METHODS: The mRNA expression levels of TGF-beta isoforms and their receptors were analyzed by qRT-PCR in a panel of five human breast cancer cell lines displaying different degrees of invasiveness and metastatic potential. The highly invasive MDA-MB-231 cell line was treated with different concentrations of recombinant TGF-beta1 and also with pharmacological inhibitors of p38 MAPK and ERK1/2. The migratory and invasive potential of these treated cells were examined in vitro by transwell assays. RESULTS: In general, TGF-beta2, TbetaRI and TbetaRII are over-expressed in more aggressive cells, except for TbetaRI, which was also highly expressed in ZR-75-1 cells. In addition, TGF-beta1-treated MDA-MB 231 cells presented significantly increased mRNA expression of MMP-2, MMP-9, MMP 14, TIMP-2 and RECK. TGF-beta1 also increased TIMP-2, MMP-2 and MMP-9 protein levels but downregulated RECK expression. Furthermore, we analyzed the involvement of p38 MAPK and ERK1/2, representing two well established Smad independent pathways, in the proposed mechanism. Inhibition of p38MAPK blocked TGF-beta1-increased mRNA expression of all MMPs and MMP inhibitors analyzed, and prevented TGF-beta1 upregulation of TIMP-2 and MMP-2 proteins. Moreover, ERK1/2 inhibition increased RECK and prevented the TGF-beta1 induction of pro-MMP-9 and TIMP-2 proteins. TGF-beta1-enhanced migration and invasion capacities were blocked by p38MAPK, ERK1/2 and MMP inhibitors. CONCLUSION: Altogether, our results support that TGF-beta1 modulates the mRNA and protein levels of MMPs (MMP 2 and MMP-9) as much as their inhibitors (TIMP-2 and RECK). Therefore, this cytokine plays a crucial role in breast cancer progression by modulating key elements of ECM homeostasis control. Thus, although the complexity of this signaling network, TGF-beta1 still remains a promising target for breast cancer treatment. PMID- 22260436 TI - Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation. AB - The NF-kappaB/REL-family of transcription factors plays a central role in coordinating the expression of a wide variety of genes controlling immune responses including autoimmunity of the central nervous system (CNS). The inactive form of NF-kappaB consists of a heterodimer which is complexed with its inhibitor, IkappaB. Conditional knockout-mice for IkappaBalpha in myeloid cells (lysMCreIkappaBalpha(fl/fl)) have been generated and are characterized by a constitutive activation of NF-kappaB proteins allowing the study of this transcription factor in myelin-oligodendrocyte-glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE), a well established experimental model for autoimmune demyelination of the CNS.In comparison to controls, lysMCreIkappaBalpha(fl/fl) mice developed a more severe clinical course of EAE. Upon histological analysis on day 15 p.i., there was an over two fold increased infiltration of T-cells and macrophages/microglia. In addition, lysMCreIkappaBalpha(fl/fl) mice displayed an increased expression of the NF kappaB dependent factor inducible nitric oxide synthase in inflamed lesions. These changes in the CNS are associated with increased numbers of CD11b positive splenocytes and a higher expression of Ly6c on monocytes in the periphery. Well in accordance with these changes in the myeloid cell compartment, there was an increased production of the monocyte cytokines interleukin(IL)-12 p70, IL-6 and IL-1beta in splenocytes. In contrast, production of the T-cell associated cytokines interferon gamma (IFN-gamma) and IL-17 was not influenced.In summary, myeloid cell derived NF-kappaB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells. PMID- 22260437 TI - Desiccation induces viable but Non-Culturable cells in Sinorhizobium meliloti 1021. AB - Sinorhizobium meliloti is a microorganism commercially used in the production of e.g. Medicago sativa seed inocula. Many inocula are powder-based and production includes a drying step. Although S. meliloti survives drying well, the quality of the inocula is reduced during this process. In this study we determined survival during desiccation of the commercial strains 102F84 and 102F85 as well as the model strain USDA1021.The survival of S. meliloti 1021 was estimated during nine weeks at 22% relative humidity. We found that after an initial rapid decline of colony forming units, the decline slowed to a steady 10-fold reduction in colony forming units every 22 days. In spite of the reduction in colony forming units, the fraction of the population identified as viable (42-54%) based on the Baclight live/dead stain did not change significantly over time. This change in the ability of viable cells to form colonies shows (i) an underestimation of the survival of rhizobial cells using plating methods, and that (ii) in a part of the population desiccation induces a Viable But Non Culturable (VBNC)-like state, which has not been reported before. Resuscitation attempts did not lead to a higher recovery of colony forming units indicating the VBNC state is stable under the conditions tested. This observation has important consequences for the use of rhizobia. Finding methods to resuscitate this fraction may increase the quality of powder-based seed inocula. PMID- 22260438 TI - Securin predicts aneuploidy and survival in breast cancer. AB - AIMS: Securin is known to participate in maintaining chromosomal integrity during the cell cycle through regulation of metaphase-anaphase transition, DNA damage repair, and apoptosis. The aim of this study was to investigate the role of securin in aneuploidy and prognosis in human breast cancer. METHODS AND RESULTS: The study was based on 603 breast cancer patients with up to 20 years of follow up. DNA content was determined by image cytometry on cell imprints, and securin immunohistochemistry was performed on tissue microarrays of breast cancer tissue. We show, for the first time in human breast cancer, that high-level securin expression predicts abnormal DNA content, with up to 9.8-fold odds for aneuploid DNA content (P = 0.0007). Securin also shows strong independent prognostic value for disease-specific survival, with a significant difference in survival time between patients with low-level and high-level securin expression. CONCLUSIONS: The main result of the present study is the association of aneuploidy and securin expression. According to our results, securin immunohistochemistry is also a potential new prognosticator for treatment decisions concerning breast cancer patients. PMID- 22260440 TI - Hyperkalemia-induced accelerated idioventricular rhythm in a patient with acute renal failure. AB - Electrolyte disorders can alter cardiac ionic currents and depending on the changes can promote proarrhythmic effects. Potassium (K(+)) is the most common intracellular cation related to arrhythmic disorders. Hyperkalemia is mainly seen in the setting of impaired renal function. Severe hyperkalemia may lead to rhythm disorders. Herein, we report a patient with accelerated idioventricular rhythm (AIVR) due to hyperkalemia, which was successfully treated with glucose-insulin (GI) infusion. PMID- 22260441 TI - Para-selective gold-catalyzed direct alkynylation of anilines. AB - A method for the para-selective alkynylation of anilines is reported using AuCl as catalyst and triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) as an electrophilic acetylene equivalent. Para-alkynyl anilines substituted at positions 2 or 3 were obtained in one step from simple anilines under mild conditions (room temperature to 60 degrees C) under air. The methodology could also be extended to the alkynylation of trimethoxybenzenes. PMID- 22260439 TI - Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. AB - Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid alpha-glucosidase (GAA) is present. An adeno associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses. PMID- 22260442 TI - Nonadiabatic decay dynamics of a benzylidene malononitrile. AB - The photoinduced nonadiabatic decay dynamics of 2-[4 (dimethylamino)benzylidene]malononitrile (DMN) in the gas phase is investigated at the semiempirical OM2/MRCI level using surface hopping simulations. A lifetime of 1.2 ps is predicted for the S(1) state, in accordance with experimental observation. The dominant reaction coordinate is found to be the twisting around the C7?C8 double bond accompanied by pronounced pyramidalization at the C8 atom. Motion along this coordinate leads to the lowest-energy conical intersection (CI(01alpha)). Several other S(0)/S(1) conical intersections have also been located by full optimization but play no role in the dynamics. The time-resolved fluorescence spectrum of DMN is simulated by computing emission energies and oscillator strengths along the trajectories. It compares well with the experimental spectrum. The use of different active spaces in the OM2/MRCI calculations yields similar results and thus demonstrates their internal consistency. PMID- 22260443 TI - Development of conserved microsatellite markers of high cross-species utility in bat species (Vespertilionidae, Chiroptera, Mammalia). AB - Comparative ecological and behavioural studies of the widespread and diverse Vespertilionidae, which comprise almost 400 of the 1100 bat species, have been limited by the availability of markers. The potential of new methods for developing conserved microsatellite markers that possess enhanced cross-species utility has recently been illustrated in studies of birds. We have applied these methods to develop enhanced microsatellite markers for vespertilionid bats, in particular for the genus Myotis (103 species). We compared published bat microsatellites with their homologues in the genome sequence of the little brown bat, Myotis lucifugus, to create consensus sequences that were used to design candidate primer sets. Primer sets were then tested for amplification and polymorphism in 22 species of bat from nine of the largest families (including 11 Vespertilionidae). Of 46 loci tested, 33 were polymorphic, on average, in each of seven Myotis species tested, 20 in each of four species in other vespertilionid genera, and two in 11 nonvespertilionid species. PMID- 22260444 TI - Importance of questionnaire context for a physical activity question. AB - Adequate information about physical activity habits is essential for surveillance, implementing, and evaluating public health initiatives in this area. Previous studies have shown that question order and differences in wording result in systematic differences in people's responses to questionnaires; however, this has never been shown for physical activity questions. The aim was to study the influence of different formulations and question order on self report physical activity in a population-based health interview survey. Four samples of each 1000 adults were drawn at random from the National Person Register. A new question about physical activity was included with minor differences in formulations in samples 1-3. Furthermore, the question in sample 2 was included in sample 4 but was placed in the end of the questionnaire. The mean time spent on moderate physical activity varied between the four samples from 57 to 100 min/day. Question order was associated with the reported number of minutes spent on moderate-intensity physical activity and with prevalence of meeting the recommendation, whereas physical inactivity was associated with the differences in formulation of the question. Questionnaire context influences the way people respond to questions about physical activity significantly and should be tested systematically in validation studies of physical activity questionnaires. PMID- 22260446 TI - Attenuation of microglial activation with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in adult mice. AB - Neurogenesis is stimulated following injury to the adult brain and could potentially contribute to tissue repair. However, evidence suggests that microglia activated in response to injury are detrimental to the survival of new neurons, thus limiting the neurogenic response. The aim of this study was to determine the effect of the anti-inflammatory drug minocycline on neurogenesis and functional recovery after a closed head injury model of focal traumatic brain injury (TBI). Beginning 30 min after trauma, minocycline was administered for up to 2 weeks and bromodeoxyuridine was given on days 1-4 to label proliferating cells. Neurological outcome and motor function were evaluated over 6 weeks using the Neurological Severity Score (NSS) and ledged beam task. Microglial activation was assessed in the pericontusional cortex and hippocampus at 1 week post-trauma, using immunohistochemistry to detect F4/80. Following immunolabeling of bromodeoxyuridine, double-cortin, and NeuN, cells undergoing distinct stages of neurogenesis, including proliferation, neuronal differentiation, neuroblast migration, and long-term survival, were quantified at 1 and 6 weeks in the hippocampal dentate gyrus, as well as in the subventricular zone of the lateral ventricles and the pericontusional cortex. Our results show that minocycline successfully reduced microglial activation and promoted early neurological recovery that was sustained over 6 weeks. We also show for the first time in the closed head injury model, that early stages of neurogenesis were stimulated in the hippocampus and subventricular zone; however, no increase in new mature neurons occurred. Contrary to our hypothesis, despite the attenuation of activated microglia, minocycline did not support neurogenesis in the hippocampus, lateral ventricles, or pericontusional cortex, with none of the neurogenic stages being affected by treatment. These data provide evidence that a general suppression of microglial activation is insufficient to enhance neuronal production, suggesting that further work is required to elucidate the relationship between microglia and neurogenesis after TBI. PMID- 22260449 TI - Binding of a truncated form of lecithin:retinol acyltransferase and its N- and C terminal peptides to lipid monolayers. AB - Lecithin:retinol acyltransferase (LRAT) is a 230 amino acid membrane-associated protein which catalyzes the esterification of all-trans-retinol into all-trans retinyl ester. A truncated form of LRAT (tLRAT), which contains the residues required for catalysis but which is lacking the N- and C-terminal hydrophobic segments, was produced to study its membrane binding properties. Measurements of the maximum insertion pressure of tLRAT, which is higher than the estimated lateral pressure of membranes, and the positive synergy factor a argue in favor of a strong binding of tLRAT to phospholipid monolayers. Moreover, the binding, secondary structure and orientation of the peptides corresponding to its N- and C terminal hydrophobic segments of LRAT have been studied by circular dichroism and polarization-modulation infrared reflection absorption spectroscopy in monolayers. The results show that these peptides spontaneously bind to lipid monolayers and adopt an alpha-helical secondary structure. On the basis of these data, a new membrane topology model of LRAT is proposed where its N- and C terminal segments allow to anchor this protein to the lipid bilayer. PMID- 22260451 TI - Brucella infection with pancytopenia after pediatric liver transplantation. AB - Brucellosis is considered the most widespread zoonosis in the world. It has been reported that the prevalence of seropositivity among the Turkish population varies from 3% to 14%. We present a case of brucellosis after pediatric liver transplantation. A 15-year-old boy with the diagnosis of neuro Wilson's disease underwent deceased-donor liver transplantation. The postoperative immunosuppressive protocol consisted of steroids and tacrolimus. Two months after the operation the patient experienced fever to 40 degrees C. The patient complained of poor appetite, headache, and diarrhea. He had had pancytopenia. Despite administration of appropriate antibiotics, antiviral and antifungal agents, fever persisted for > 1 month. Multiple blood, urine, stool, and sputum cultures were negative. Bone marrow aspirate revealed hypocellularity. Liver biopsy was performed, but rejection was not observed on biopsy specimen. Brucella serology was positive and Brucella agglutination titer was 1:320. Bone marrow culture was positive for Brucella but blood culture was negative. The patient was then treated with oral doxycycline and rifampin for 8 weeks. No previous case report about Brucella infection after liver transplantation has appeared in the literature, to our knowledge; our case is presented as the first. Bone marrow hypoplasia is a rare feature of Brucella infection. Our patient with brucellosis and pancytopenia had had hypocellular bone marrow. The clinical and hematologic findings resolved with treatment of the infection. Brucella infection should be suspected in liver transplanted recipients with fever of unknown origin, especially in a recipient who has lived in an endemic area. Brucella also should be considered as a possible diagnosis in patients with pancytopenia. PMID- 22260450 TI - Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. AB - Klotho is a recently discovered anti-aging gene. The purpose of this study was to investigate whether klotho gene transfer attenuates superoxide production and oxidative stress in rat aorta smooth muscle (RASM) cells. RASM cells were transfected with AAV plasmids carrying mouse klotho full-length cDNA (mKL) or LacZ as a control. Klotho gene transfer increased klotho expression in RASM cells. Notably, klotho gene expression decreased Nox2 NADPH oxidase protein expression but did not affect Nox2 mRNA expression, suggesting that the inhibition may occur at the posttranscriptional level. Klotho gene transfer decreased intracellular superoxide production and oxidative stress in RASM cells. Klotho gene expression also significantly attenuated the angiotensin II (AngII) induced superoxide production, oxidative damage, and apoptosis. Interestingly, klotho gene delivery dose dependently increased the intracellular cAMP level and PKA activity in RASM cells. Rp-cAMP, a competitive inhibitor of cAMP, abolished the klotho-induced increase in PKA activity, indicating that klotho activated PKA via cAMP. Notably, inhibition of cAMP-dependent PKA activity by RP-cAMP abolished klotho-induced inhibition of Nox2 protein expression, suggesting an important role of cAMP-dependent PKA in this process. This finding revealed a previously unidentified role of klotho in regulating Nox2 protein expression in RASM cells. Klotho not only downregulated Nox2 protein expression and intracellular superoxide production but also attenuated AngII-induced superoxide production, oxidative damage, and apoptosis. The klotho-induced suppression of Nox2 protein expression may be mediated by the cAMP-PKA pathway. PMID- 22260452 TI - p-Quaterphenyls laterally substituted with a dimesitylboryl group: a promising class of solid-state blue emitters. AB - A new family of p-quaterphenyls 1-6 laterally substituted with a bulky electron accepting dimesitylboryl group has been designed and synthesized. These compounds were characterized by X-ray crystallography, UV-vis and fluorescence spectroscopy, and DFT calculations as well as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and cyclic voltammetry (CV). X-ray single-crystal analysis revealed that the p-quaterphenyl main chain framework exhibits a twisted structure due to the steric effect of the lateral boryl group, and the intermolecular interactions are effectively suppressed in the solid state. Despite the significantly twisted main-chain structure, these molecules still display efficient intramolecular charge-transfer emissions with large Stokes shifts. An intriguing finding is that all these molecules show bright fluorescence with good to excellent quantum yields in the blue region in the solid state. In addition, the two representative p-quaterphenyls 3 and 4 containing both the electron-accepting boryl group and the electron-donating carbazolyl (3) or diphenylamino group (4) possess high thermal stability and good oxidation-reduction reversibility, which together with their excellent solid state fluorescence efficiency make them promising bipolar transporting blue emitters. PMID- 22260453 TI - Synthesis and in vivo lead detoxification evaluation of Poly-alpha,beta-dl aspartyl-l-methionine. AB - To increase the metal selectivity of polyaspartic acid, a so-called green chelant, poly-alpha,beta-dl-aspartyl-l-methionine (PDM) was synthesized as a novel lead chelating agent. The phosphoric acid (80%) catalyzed thermal poly condensation of dl-aspartic acid provided poly succinimide, which was amidated with l-methionine to form PDM (MW: 29161). At the doses of 0.1, 1.0, and 10.0 nmol/kg, either by intraperitoneal injection (i.p.) or oral administration, PDM removed Pb from the spleens, hearts, and kidneys of mice, especially dose dependently decreasing the accumulation of Pb in the brains, livers, and femurs of the mice, and did not interfere with the essential metals, including Cu, Fe, Mn, and Ca. Even at the dose of 0.1 nmol/kg, the i.p. injection of PDM removed Pb from the spleens, hearts, and kidneys of mice and increased the amount of urinary volume and urinary Pb, and the amount of fecal matter and the amount of fecal Pb, resulting in effective removal of Pb from the body of mice given Pb by i.p. injection. Our findings revealed that in aqueous solution PDM formed diverse nanospecies. PMID- 22260456 TI - Importance of the cell membrane on the mechanism of action of cyclotides. AB - Their distinctive structures, diverse range of bioactivities, and potential for pharmaceutical or agricultural applications make cyclotides an intriguing family of cyclic peptides. Together with the physiological role in plant host defense, cyclotides possess antimicrobial, anticancer, and anti-HIV activities. In all of the reported activities, cell membranes seem to be the primary target for cyclotide binding. This article examines recent literature on cyclotide-membrane studies and highlights the hypothesis that the activity of cyclotides is dependent on their affinity for lipid bilayers and enhanced by the presence of specific lipids, i.e., phospholipids containing phosphatidylethanolamine headgroups. There is growing evidence that the lipid composition of target cell membranes dictates the amount of cyclotides bound to the cell and the extent of their activity. After membrane targeting and insertion in the bilayer core, cyclotides induce disruption of membranes by a pore formation mechanism. This proposed mechanism of action is supported by biophysical studies with model membranes and by studies on natural biological membranes of known lipid compositions. PMID- 22260454 TI - High prevalence of multidrug resistance in bacterial uropathogens from Kathmandu, Nepal. AB - BACKGROUND: Urinary Tract Infection (UTI) is one of the most common infectious diseases and people of all age-groups and geographical locations are affected. The impact of disease is even worst in low-resource developing countries due to unaware of the UTIs caused by multidrug-resistant (MDR) pathogens and the possibility of transfer of MDR traits between them. The present study aimed to determine the prevalence of MDR bacterial isolates from UTI patients, the antibiotic resistance pattern and the conjugational transfer of multidrug resistance phenotypes in Escherichia coli (E. coli). RESULTS: Two hundred and nineteen bacterial isolates were recovered from 710 urine samples at Kathmandu Model hospital during the study period. All samples and isolates were investigated by standard laboratory procedures. Among the significant bacterial growth (30.8%, 219 isolates), 41.1% isolates were MDR. The most prevailing organism, E. coli (81.3%, 178 isolates) was 38.2% MDR, whereas second most common organism, Citrobacter spp. (5%, 11 isolates) was found 72.7% MDR. Extended spectrum beta-lactamase (ESBL) production was detected in 55.2% of a subset of MDR E. coli isolates. Among the 29 MDR E. coli isolates, plasmids of size ranging 2-51 kb were obtained with different 15 profiles. The most common plasmid of size 32 kb was detected in all of the plasmid-harbored E. coli strains. The majority of E. coli isolates investigated for the multidrug resistance transfer were able to transfer plasmid-mediated MDR phenotypes along with ESBL pattern with a frequency ranging from 0.3 * 10-7 to 1.5 * 10-7 to an E. coli HB101 recipient strain by conjugation. Most of the donor and recipient strain showed high levels of minimum inhibitory concentration (MIC) values for commonly-used antibiotics. CONCLUSIONS: The high prevalence of multidrug resistance in bacterial uropathogens was observed. Particularly, resistance patterns were alarmingly higher for amoxycillin, co-trimoxazole, flouroquinolones and third-generation cephalosporins, which necessitate the re-evaluation of first and second line therapies for UTI. In addition, conjugational co-transfer of MDR phenotypes with ESBL-positive phenotypes was observed in MDR E. coli. PMID- 22260457 TI - Efficacy of aliskiren in Japanese chronic kidney disease patients with hypertension. AB - BACKGROUND: Aliskiren, a novel direct renin inhibitor, is hypothesized to inhibit the renin-angiotensin- system. This study attempted to provide insight into this mechanism by examining the antihypertensive and renoprotective effects of aliskiren in hypertensive chronic kidney disease (CKD) patients. METHODS: After recruitment, 43 hypertensive CKD patients (mean age, 53.7 years) began treatment of aliskiren. The patients were classified into high (over 30 mL/min/1.73 m(2)) estimated glomerular filtration rate (eGFR) group or low (under 30 mL/min/1.73 m(2)) eGFR group for comparison of measurements of various parameters over the 6 month observation period. RESULTS: Systolic blood pressure/diastolic blood pressure of 150 mg/day group decreased to an average of 126.8 +/- 21.6 mmHg/69.3 +/- 15.1 mmHg (average decrease: -7.4/-8.3 mmHg) over the 6-month observation period, while that of 300 mg/day group significantly decreased to an average of 133.5 +/- 14.0 mmHg/71.5 +/- 11.7 mmHg (average decrease: -21.1/-14.6 mmHg). Urinary protein of all patients decreased slightly and insignificantly to 1.1 +/- 1.7 g/gCr from 1.4 +/- 2.5 g/gCr. The serum creatinine (Cr) level of all patients decreased from 1.81 +/- 1.10 mg/dL to 1.78 +/- 0.82 mg/dL. Although the serum Cr level of the high eGFR group decreased from 1.28 +/- 0.45 mg/dL to 1.27 +/- 0.57 mg/dL, that of the low eGFR group slightly but insignificantly increased from 2.49 +/- 0.64 mg/dL to 2.69 +/- 1.11 mg/dL. CONCLUSION: Administration of aliskiren exerts an antihypertensive effect on hypertensive CKD patients that may lead to a decrease in urinary protein and an improvement in renal functioning. PMID- 22260458 TI - Airway management of recovered pediatric patients with severe head and neck burns: a review. AB - There are approximately 10,000 pediatric burn survivors in the United States each year, many of whom will present for reconstructive surgery after severe burns in the head and neck (1). These recovered burn victims, who are beyond the acute phase of injury, often have significant scarring and contractures in the face, mouth, nares, neck, and chest, which can make airway management challenging and potentially lead to a 'cannot intubate, cannot ventilate' scenario (2). Although numerous cases have been presented in the literature on this topic (3-17), there are no comprehensive review articles on the unique challenges of airway management in the recovered pediatric burn patient with distorted airway anatomy. This article aims to provide a comprehensive review of airway management in such patients, focusing on challenges encountered during mask ventilation and tracheal intubation, as well as the role of surgical release of neck contractures to facilitate tracheal intubation. Lessons learned from all reported cases identified in a thorough literature search are incorporated into this review. PMID- 22260459 TI - Human immunodeficiency virus type 1 envelope proteins traffic toward virion assembly sites via a TBC1D20/Rab1-regulated pathway. AB - BACKGROUND: The cellular activity of many factors and pathways is required to execute the complex replication cycle of the human immunodeficiency virus type 1 (HIV-1). To reveal these cellular components, several extensive RNAi screens have been performed, listing numerous 'HIV-dependency factors'. However, only a small overlap between these lists exists, calling for further evaluation of the relevance of specific factors to HIV-1 replication and for the identification of additional cellular candidates. TBC1D20, the GTPase-activating protein (GAP) of Rab1, regulates endoplasmic reticulum (ER) to Golgi trafficking, was not identified in any of these screens, and its involvement in HIV-1 replication cycle is tested here. FINDINGS: Excessive TBC1D20 activity perturbs the early trafficking of HIV-1 envelope protein through the secretory pathway. Overexpression of TBC1D20 hampered envelope processing and reduced its association with detergent-resistant membranes, entailing a reduction in infectivity of HIV-1 virion like particles (VLPs). CONCLUSIONS: These findings add TBC1D20 to the network of host factors regulating HIV replication cycle. PMID- 22260461 TI - Distribution of aldehyde dehydrogenase 1-positive stem cells in benign mammary tissue from women with and without breast cancer. AB - AIMS: Aldehyde dehydrogenase 1 (ALDH1) in female breast tissue has been linked to stem cells, but little is known about the benign cellular organization in situ. We investigated the distribution of ALDH1-immunoreactive (ALDH1+) cells in histomorphologically benign breast tissue from 28 women with or without breast cancer. METHODS AND RESULTS: ALDH1+ cells were detected in benign tissue of women aged 20-72 years, located most commonly at the luminal and intermediate ductular levels and in the stroma. ALDH1+ cell populations and Ki67+ cell populations were present in separate ductules, both cell types rarely showing epithelial differentiation. ALDH1+ cells were non-reactive to Ki67 and oestrogen receptor. Stromal round/oval ALDH1+ non-leukocyte cells in both age groups expressed contractile protein. There was a lower concentration of luminal and intermediate ductular ALDH1+ cells in postmenopausal women than in premenopausal women, and in cancer patients than in non-cancer patients, and a higher concentration in women receiving exogenous hormones. CONCLUSIONS: This study provides further evidence for the stem cell character of ALDH1+ cells, here in benign breast tissue of cancer and non-cancer patients throughout non-lactating adult life, and contributes evidence of benign stromal ALDH1+ cells. The distribution of ductular ALDH1+ stem cells appears to be influenced by hormonal status. PMID- 22260460 TI - Risk factors associated with fatal pulmonary hemorrhage in locally advanced non small cell lung cancer treated with chemoradiotherapy. AB - BACKGROUND: The purpose of this study was to identify the risk factors associated with fatal pulmonary hemorrhage (PH) in patients with locally advanced non-small cell lung cancer (NSCLC), treated with chemoradiotherapy. METHODS: The medical records of 583 patients with locally advanced NSCLC, who were treated with chemoradiotherapy between July 1992 and December 2009 were reviewed. Fatal PH was defined as PH leading to death within 24 h of its onset. Tumor cavitation size was defined by the cavitation diameter/tumor diameter ratio and was classified as minimum (< 0.25), minor (>= 0.25, but < 0.5), and major (>= 0.5). RESULTS: Of the 583 patients, 2.1% suffered a fatal PH. The numbers of patients with minimum, minor, and major cavitations were 13, 11, and 14, respectively. Among the 38 patients with tumor cavitation, all 3 patients who developed fatal PH had major cavitations. On multivariate analysis, the presence of baseline major cavitation (odds ratio, 17.878), and a squamous cell histology (odds ratio, 5.491) proved to be independent significant risk factors for fatal PH. Interestingly, all patients with fatal PH and baseline major cavitation were found to have tumors with squamous cell histology, and the occurrence of fatal PH in patients having both risk factors was 33.3%. CONCLUSIONS: Patients at high risk of fatal PH could be identified using a combination of independent risk factors. PMID- 22260463 TI - Delivery of AAV2-CYP2J2 protects remnant kidney in the 5/6-nephrectomized rat via inhibition of apoptosis and fibrosis. AB - The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), which are highly abundant in the kidney and considered renoprotective. Accumulating evidence suggests that EETs are important in regulating renal and cardiovascular function. Further, EETs have been confirmed to exert diverse biological activities including potent vasodilation; fibrinolytic properties; and antiinflammatory, antiapoptotic, and mitogenic effects. In the current study, we investigated the effects of overexpression of CYP2J2 via recombinant adeno-associated virus (rAAV) in protection against renal damage in a rat 5/6 nephrectomy (5/6-Nx) model of chronic renal failure. The rAAV-CYP2J2 gene delivery in vivo increased EET generation; attenuated the rise in blood pressure; and reduced the levels of proteinuria, serum creatinine, and blood urea nitrogen. Morphological analysis indicated that rAAV-CYP2J2 gene delivery reduced 5/6 nephrectomy-induced glomerular sclerosis, tubular dilatation, luminal protein cast formation, and tubulointerstitial fibrosis. rAAV-CYP2J2 gene delivery also significantly lowered collagen I and IV deposition, as well as renal cell apoptosis detected by TUNEL staining, caspase-3 activity, and the loss of mitochondrial membrane potential (DeltaPsi(m)). Furthermore, rAAV-CYP2J2 gene delivery regulated the level of protein expression including transforming growth factor (TGF)-beta(1)/SMADs; matrix metalloproteinases (MMPs); mitogen-activated protein kinases (MAPKs); and apoptosis-related proteins Bax, Bcl-2, and Bcl-x(L). Together, these findings demonstrated that rAAV-CYP2J2 gene delivery can protect remnant kidney against renal injury in 5/6-Nx rats by inhibiting apoptosis and fibrosis via regulation of protein expression including TGF-beta(1)/SMADs, MMPs, MAPKs, and apoptosis related proteins. PMID- 22260481 TI - Ab initio structural and vibrational investigation of sulfuric acid monohydrate. AB - We employ ab initio methods to find stable geometries and to calculate potential energy surfaces and vibrational wavenumbers for sulfuric acid monohydrate. Geometry optimizations are carried out with the explicitly correlated coupled cluster approach that includes single, double, and perturbative triple excitations (CCSD(T)-F12a) with a valence double-zeta basis set (VDZ-F12). Four different stable geometries are found, and the two lowest are within 0.41 kJ mol( 1) (or 34 cm(-1)) of each other. Vibrational harmonic wavenumbers are calculated at both the density-fitted local spin component scaled second-order Moller Plesset perturbation theory (DF-SCS-LMP2) with the aug-cc-pV(T+d)Z basis set and the CCSD-F12/VDZ-F12 level. Water O-H stretching vibrations and two highly anharmonic large-amplitude motions connecting the three lowest potential energy minima are considered by limiting the dimensionality of the corresponding potential energy surfaces to small two- or three-dimensional subspaces that contain only strongly coupled vibrational degrees of freedom. In these anharmonic domains, the vibrational problem is solved variationally using potential energy surfaces calculated at the CCSD(T)-F12a/VDZ-F12 level. PMID- 22260483 TI - Water-gated charge doping of graphene induced by mica substrates. AB - We report on the existence of water-gated charge doping of graphene deposited on atomically flat mica substrates. Molecular films of water in units of ~0.4 nm thick bilayers were found to be present in regions of the interface of graphene/mica heterostacks prepared by micromechanical exfoliation of kish graphite. The spectral variation of the G and 2D bands, as visualized by Raman mapping, shows that mica substrates induce strong p-type doping in graphene with hole densities of (9 +/- 2) * 10(12) cm(-2). The ultrathin water films, however, effectively block interfacial charge transfer, rendering graphene significantly less hole-doped. Scanning Kelvin probe microscopy independently confirmed a water gated modulation of the Fermi level by 0.35 eV, which is in agreement with the optically determined hole density. The manipulation of the electronic properties of graphene demonstrated in this study should serve as a useful tool in realizing future graphene applications. PMID- 22260484 TI - Tailoring the synthesis and heating ability of gold nanoprisms for bioapplications. AB - The paper describes a novel and straightforward wet-chemical synthetic route to produce biocompatible single-crystalline gold tabular nanoparticles, herein called nanoprisms (NPRs) due to their characteristic shape. Besides the novelty of the method to produce NPRs with an unprecedented high yield, the synthesis avoids the use of highly toxic cetyltrimethylammonium bromide (CTAB), the most widely used surfactant for the synthesis of gold anisotropic nanoparticles such as nanorods or nanoprisms. The method presented here allows for tuning the edge length of NPRs in the range of 100-170 nm by adjusting the final concentration/molar ratio of gold salt and reducing agent (thiosulfate), while the thickness of NPRs remained constant (9 nm). Thus, the surface plasmon band of NPRs can be set along the near-infrared (NIR) range. The resulting NPRs were derivatized with heterobifunctional polyethylene glycol (PEG) and 4-aminophenyl beta-D-glucopyranoside (glucose) chains to improve their stability and cellular uptake, respectively. The heating properties of colloidal solutions of NPRs upon 1064 nm light illumination were evaluated. As a proof of concept, the biocompatibility and suitability of functional NPRs as photothermal agents were studied in cell cultures. Due to their biocompatibility (avoiding CTAB), ease of production, ease of functionalization, and remarkable heating features, the NPRs discussed herein represent a significant advance in the biocompatibility of nanoparticles and serve as an attractive alternative to those currently in use as plasmonic photothermal agents. PMID- 22260482 TI - Delving into somatic variation in sporadic melanoma. AB - Melanoma, the most aggressive form of skin cancer, has increased in incidence more rapidly than any other cancer. The completion of the human genome project and advancements in genomics technologies has allowed us to investigate genetic alterations of melanoma at a scale and depth that is unprecedented. Here, we survey the history of the different approaches taken to understand the genomics of melanoma - from early candidate genes, to gene families, to genome-wide studies. The new era of whole-exome and whole-genome sequencing has paved the way for an in-depth understanding of melanoma biology, identification of new therapeutic targets, and development of novel personalized therapies for melanoma. PMID- 22260485 TI - Intrinsic predictive factors for ankle sprain in active university students: a prospective study. AB - The ankle is the joint most affected among the sports-related injuries. The current study investigated whether certain intrinsic factors could predict ankle sprains in active students. The 125 participants were submitted to a baseline assessment in a single session were then followed-up for 52 weeks regarding the occurrence of sprain. The baseline assessment were performed in both ankles and included the questionnaire Cumberland ankle instability tool - Portuguese, the foot lift test, dorsiflexion range of motion, Star Excursion Balance Test (SEBT), the side recognition task, body mass index, and history of previous sprain. Two groups were used for analysis: one with those who suffered an ankle sprain and the other with those who did not suffer an ankle sprain. After Cox regression analysis, participants with history of previous sprain were twice as likely to suffer subsequent sprains [hazard ratio (HR) 2.21 and 95% confidence interval (CI) 1.07-4.57] and people with better performance on the SEBT in the postero lateral (PL) direction were less likely to suffer a sprain (HR 0.96 and 95% CI 0.92-0.99). History of previous sprain was the strongest predictive factor and a weak performance on SEBT PL was also considered a predictive factor for ankle sprains. PMID- 22260487 TI - Asymmetric synthesis of cis-7-methoxycalamenene via the intramolecular Buchner reaction of an alpha-diazoketone. AB - The asymmetric synthesis of cis-7-methoxycalamenene 1 has been accomplished using the intramolecular Buchner reaction of alpha-diazoketone 7 as the key step in the synthetic route. Upon reduction of the equilibrating azulenone structure 8, the resulting azulenol 9 rearranges to dihydronaphthalene 10 containing the 6,6 membered bicyclic ring system characteristic of 1, by means of an acid-catalyzed aromatization process. Transformation of 10 to 1 is accomplished through a three step reaction sequence. PMID- 22260486 TI - The pathway of cross-presentation is influenced by the particle size of phagocytosed antigen. AB - Cross-presentation is the presentation by MHC class I of antigenic peptides from exogenous proteins that have been internalized and processed by professional antigen-presenting cells, e.g. dendritic cells. We have investigated the influence of particle size and antigen load on cross-presentation following antigen delivery on microspheres (MS). Cross-presentation from small particles (0.8-MUm) is sensitive to proteasome inhibition and the blockade of endoplasmic reticulum-resident MHC class I complex export, whereas cross-presentation from larger particles (aggregated clumps of 0.8-MUm MS) is resistant to these antagonists. This observation may have been overlooked previously, because of the heterogeneity of particle size and MS uptake in unsorted dendritic cell populations. Larger particles carry more antigen, but we show that antigen load does not influence the cross-presentation pathway used. Whereas early endosome autoantigen 1 (EEA1) could be observed in all phagosomes, we observed endoplasmic reticulum SNARE of molecular weight 24 000 (ERS24) and cathepsin S in association with 3.0-MUm and aggregated 0.8-MUm MS, but not individual 0.8-MUm MS. A potential mechanism underlying our observations may be the activation of beta catenin by disruption of E-cadherin-mediated adhesion. Activated beta-catenin was detected in the cytoplasm of cells after phagocytosis of MS (highest levels for the largest particles). We propose that particle size can direct the use of different pathways for the cross-presentation of an identical antigen. Furthermore, these pathways have differing yields of MHC class I-peptide complexes, which is an important variable in designing vaccination strategies for maximal antigen expression and CD8(+) T-cell priming. PMID- 22260488 TI - Childhood onset diabetes posttransplant in a girl with TCF2 mutation. AB - Heterozygous mutations of TCF2 (transcription factor 2) have been associated with maturity onset diabetes of the young, renal malformations, hyperuricemia, and occasionally internal genital malformations in female. We report a female patient with bilateral renal hypodysplasia and de novo heterozygous TCF2 gene mutation. At the age of 9 yr, she developed transient ketoacidosis immediately posttransplant, temporarily requiring insulin. During glucocorticoid tapering, impaired glucose tolerance persisted and overt insulin-dependent diabetes mellitus developed 1 yr later. Pathogenic factors which might have played a role in the acceleration of diabetes were (i) switch from cyclosporine to tacrolimus, (ii) weight excess, and (iii) cytomegalovirus infection. TCF2 analysis might, therefore, be of interest in patients with congenital abnormalities of the kidney and the urinary tract in order to improve posttransplant management in terms of steroid and tacrolimus exposure. PMID- 22260490 TI - To be or not to be exact. PMID- 22260495 TI - The international chemical biology community synthesizes a new society. PMID- 22260496 TI - Different mechanisms govern the two-phase Brust-Schiffrin dialkylditelluride syntheses of Ag and Au nanoparticles. AB - Here we report the first unambiguous identification of the chemical structures of the precursor species involving metal (Au and Ag) ions and Te-containing ligands in the Brust-Schiffrin syntheses of the respective metal nanoparticles, through which the different reaction pathways involved are delineated. PMID- 22260497 TI - Wild-type amyloid beta 1-40 peptide induces vascular smooth muscle cell death independently from matrix metalloprotease activity. AB - Cerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhages in the elderly, characterized by amyloid-beta (Abeta) peptide accumulating in central nervous system blood vessels. Within the vessel walls, Abeta-peptide deposits [composed mainly of wild-type (WT) Abeta(1-40) peptide in sporadic forms] induce impaired adhesion of vascular smooth muscle cells (VSMCs) to the extracellular matrix (ECM) associated with their degeneration. This process often results in a loss of blood vessel wall integrity and ultimately translates into cerebral ischemia and microhemorrhages, both clinical features of CAA. In this study, we decipher the molecular mechanism of matrix metalloprotease (MMP)-2 activation in WT-Abeta(1-40) -treated VSMC and provide evidence that MMP activity, although playing a critical role in cell detachment disrupting ECM components, is not involved in the WT-Abeta(1-40) -induced degeneration of VSMCs. Indeed, whereas this peptide clearly induced VSMC apoptosis, neither preventing MMP-2 activity nor hampering the expression of membrane type1-MMP, or preventing tissue inhibitors of MMPs-2 (TIMP-2) recruitment (two proteins evidenced here as involved in MMP-2 activation), reduced the number of dead cells. Even the use of broad-range MMP inhibitors (GM6001 and Batimastat) did not affect WT-Abeta(1-40) induced cell apoptosis. Our results, in contrast to those obtained using the Abeta(1-40) Dutch variant suggesting a link between MMP-2 activity, VSMC mortality and degradation of specific matrix components, indicate that the ontogenesis of the Dutch familial and sporadic forms of CAAs is different. ECM degradation and VSMC degeneration would be tightly connected in the Dutch familial form while being two independent processes in sporadic forms of CAA. PMID- 22260499 TI - Assessment of the range of the HIV-1 infectivity enhancing effect of individual human semen specimen and the range of inhibition by EGCG. AB - Recently, it has been shown that human ejaculate enhances human immunodeficiency virus 1 (HIV-1) infectivity. Enhancement of infectivity is conceived to be mediated by amyloid filaments from peptides that are proteolytically released from prostatic acid phosphatase (PAP), termed Semen-derived Enhancer of Virus Infection (SEVI). The aim of this study was to test the range of HIV-1 infectivity enhancing properties of a large number of individual semen samples (n = 47) in a TZM-bl reporter cell HIV infection system. We find that semen overall increased infectivity to 156% of the control experiment without semen, albeit with great inter- and intraindividual variability (range -53%-363%). Using transmission electron microscopy, we provide evidence for SEVI fibrils in fresh human semen for the first time. Moreover, we confirm that the infectivity enhancing property can be inhibited by the major green tea ingredient epigallocatechin-3-gallate (EGCG) at non-toxic concentrations. The median inhibition of infection by treatment with 0.4 mM EGCG was 70.6% (p < 0.0001) in our cohort. Yet, there were substantial variations of inhibition and in a minority of samples, infectivity enhancement was not inhibited by EGCG treatment at all. Thus, topical application of EGCG may be a feasible additional measure to prevent the sexual transmission of HIV. However, the reasons for the variability in the efficacy of the abrogation of semen-mediated enhancement of HIV-1 infectivity and EGCG efficacy have to be elucidated before therapeutic trials can be conducted. PMID- 22260500 TI - Isovolaemic hemodilution with gelatin and hydroxyethylstarch 130/0.42: effects on hemostasis in piglets. AB - OBJECTIVES: Artificial colloids, frequently used to prevent hemorrhagic shock in children, impair blood coagulation. To determine the impact of acute isovolaemic hemodilution with artificial colloids on clot formation, we conducted an experimental study in a pediatric animal model. METHODS: Fifteen piglets underwent hemorrhage by withdrawing 40 ml.kg(-1) of blood volume in steps of 10 ml.kg(-1) each within 1 hour. After each withdrawal, the blood loss was randomly compensated by administering 4% gelatin (GEL) or hydroxylethyl starch 130/0.42 (HES) in a ratio of 1 : 1, or isotonic crystalloid solution (ICS) in a ratio of 1 : 4 for isovolaemic hemodilution. Quality of clot formation and platelet function was measured using Thrombelastometry (ROTEM((r))) and Multiple electrode impedance aggregometry (Multiplate((r))) after 10, 20, and 40 ml.kg(-1) blood replacement. RESULTS: Moderate hemodilution (10-20 ml.kg(-1) blood replacement) caused no significant differences among groups (e.g. INTEM((r))-MCF after 20 ml.kg(-1) blood replacement (ICS vs GEL vs HES, P > 0.05). Profound hemodilution with 40 ml.kg(-1) blood replacement showed a significant difference between ICS and both colloids (P < 0.05), but no significant differences between GEL and HES. CONCLUSIONS: Impairment of clot formation by moderate isovolaemic hemodilution did not significantly differ between ICS, GEL, and HES. Profound hemodilution of more than 50% of the estimated blood volume with GEL and HES caused significant impairment of clot formation in comparison to ICS and has to be considered when using high amounts of these synthetic colloids. PMID- 22260501 TI - Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells. AB - BACKGROUND: Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. RESULTS: Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. CONCLUSION: These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells. PMID- 22260502 TI - Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration resistant prostate cancer. AB - AIMS: Recently, ETS-related gene (ERG) gene rearrangements, phosphatase tensin homologue (PTEN) deletions and serine protease inhibitor Kazal type 1 (SPINK1) overexpression were investigated as potential markers for molecularly subtyping prostate cancer (PCA). However, their incidence and co-association in castration resistant PCA (CRPC) has not been characterized fully. METHODS AND RESULTS: A cohort of 59 CRPC patients was investigated for ERG rearrangements, PTEN deletions and androgen receptor (AR) amplification by fluorescence in-situ hybridization. SPINK1 overexpression was assessed by immunohistochemistry. ERG rearrangements and PTEN deletions were detected in 22 of 53 (41.5%) and 35 of 55 (63.6%) of cases, with 15 of 22 (68.1%) of ERG rearrangements occurring through deletions. SPINK1 overexpression occurred in three of 51 (5.8%) of cases exclusively in non-ERG rearranged and AR amplification was detected in 12 of 49 (24.4%) of cases. Only PTEN deletions showed intrafocal heterogeneity occurring in nine of 35 (25.7%) of cases. PTEN deletions were significantly associated with each of ERG rearrangements occurring by deletions only (P = 0.001), AR amplification (P = 0.002) and SPINK1 overexpression (P = 0.002). None of the SPINK1 overexpressing tumours showed AR amplification (P = 0.005) and all occurred in PTEN deleted foci (P = 0.002). CONCLUSION: Te study supports the heterogeneous nature of CRPC and confirms a significant association between PTEN, ERG, AR and SPINK1. Characterizing combined markers will aid in defining PCA subgroups relevant to prognosis contributing to the design of improved therapeutic approaches for CRPC. PMID- 22260503 TI - Isometric handgrip training lowers blood pressure and increases heart rate complexity in medicated hypertensive patients. AB - Hypertension is characterized by elevated blood pressure (BP) and autonomic dysfunction, both thought to be improved with exercise training. Isometric handgrip (IHG) training may represent a beneficial, time-effective exercise therapy. We investigated the effects of IHG training on BP and traditional and nonlinear measures of heart rate variability (HRV). Pre- and post-measurements of BP and HRV were determined in 23 medicated hypertensive participants (mean +/- SEM, 66 +/- 2 years) following either 8 weeks of IHG training (n = 13) or control (n = 10). IHG exercise consisted of four unilateral 2-min isometric contractions at 30% of maximal voluntary contraction, each separated by 4 min of rest. IHG training was performed 3 days/week for 8 weeks. IHG training decreased systolic BP (125 +/- 3 mmHg to 120 +/- 2 mmHg, P < 0.05) and mean BP (90 +/- 2 mmHg to 87 +/- 2 mmHg, P < 0.05), while sample entropy was increased (1.07 +/- 0.1 to 1.35 +/- 0.1, P < 0.05) and the fractal scaling distance score was decreased (0.34 +/- 0.1 to 0.19 +/- 0.1, P < 0.05). No significant changes were observed in traditional spectral or time-domain measures of HRV or control participants. IHG training improves nonlinear HRV, but not traditional HRV, while reducing systolic and mean BP. These results may highlight the benefits of IHG training for patients with primary hypertension. PMID- 22260505 TI - A content validated questionnaire for assessment of self reported venous blood sampling practices. AB - BACKGROUND: Venous blood sampling is a common procedure in health care. It is strictly regulated by national and international guidelines. Deviations from guidelines due to human mistakes can cause patient harm. Validated questionnaires for health care personnel can be used to assess preventable "near misses"--i.e. potential errors and nonconformities during venous blood sampling practices that could transform into adverse events. However, no validated questionnaire that assesses nonconformities in venous blood sampling has previously been presented. The aim was to test a recently developed questionnaire in self reported venous blood sampling practices for validity and reliability. FINDINGS: We developed a questionnaire to assess deviations from best practices during venous blood sampling. The questionnaire contained questions about patient identification, test request management, test tube labeling, test tube handling, information search procedures and frequencies of error reporting. For content validity, the questionnaire was confirmed by experts on questionnaires and venous blood sampling. For reliability, test-retest statistics were used on the questionnaire answered twice. The final venous blood sampling questionnaire included 19 questions out of which 9 had in total 34 underlying items. It was found to have content validity. The test-retest analysis demonstrated that the items were generally stable. In total, 82% of the items fulfilled the reliability acceptance criteria. CONCLUSIONS: The questionnaire could be used for assessment of "near miss" practices that could jeopardize patient safety and gives several benefits instead of assessing rare adverse events only. The higher frequencies of "near miss" practices allows for quantitative analysis of the effect of corrective interventions and to benchmark preanalytical quality not only at the laboratory/hospital level but also at the health care unit/hospital ward. PMID- 22260504 TI - Differential expression of wound fibrotic factors between facial and trunk dermal fibroblasts. AB - Clinically, wounds on the face tend to heal with less scarring than those on the trunk, but the causes of this difference have not been clarified. Fibroblasts obtained from different parts of the body are known to show different properties. To investigate whether the characteristic properties of facial and trunk wound healing are caused by differences in local fibroblasts, we comparatively analyzed the functional properties of superficial and deep dermal fibroblasts obtained from the facial and trunk skin of seven individuals, with an emphasis on tendency for fibrosis. Proliferation kinetics and mRNA and protein expression of 11 fibrosis-associated factors were investigated. The proliferation kinetics of facial and trunk fibroblasts were identical, but the expression and production levels of profibrotic factors, such as extracellular matrix, transforming growth factor-beta1, and connective tissue growth factor mRNA, were lower in facial fibroblasts when compared with trunk fibroblasts, while the expression of antifibrotic factors, such as collagenase, basic fibroblast growth factor, and hepatocyte growth factor, showed no clear trends. The differences in functional properties of facial and trunk dermal fibroblasts were consistent with the clinical tendencies of healing of facial and trunk wounds. Thus, the differences between facial and trunk scarring are at least partly related to the intrinsic nature of the local dermal fibroblasts. PMID- 22260506 TI - Nanoparticles: a review of particle toxicology following inhalation exposure. AB - It is expected that the rapid expansion of nanotechnology will bring many potential benefits. However, initial investigations have demonstrated that nanomaterials may adversely affect human health and the environment. By increasing the application of nanoparticles, protection of the human respiratory system from exposure to airborne nanoparticles and ultrafine particulates has become an emerging health concern. Available research has demonstrated an association between exposure to ambient airborne particulates and ultrafine particles and various adverse heath effects including increased morbidity and mortality. Nanomaterial structures are more likely to be toxic than the same materials of conventional sized samples and can be inhaled more deeply into the lungs. While the respiratory tract is considered as the primary target organ for inhaled nanoparticles, recent research has demonstrated that extrapulmonary organs are also affected. The very small size distribution and large surface area of nanoparticles available to undergo reactions may play a significant role in nanotoxicity, yet very little is known about their interactions with biological systems. This review explores the possible underlying toxicity mechanisms of nanoparticles following inhalational exposure. Nanoparticles differ from the same conventional material at a larger scale in physical, chemical and biological characteristics; therefore it is critical to recognize the potential risk of nanoparticle exposure using appropriate toxicity test methods. Current advances and limitations of toxicity assessment methods of nanoparticles are discussed highlighting the recent improvements of in vitro screening tools for the safety evaluation of the rapidly expanding area of nanotechnology. PMID- 22260509 TI - NGAL as an early biomarker of kidney disease in Joubert syndrome: three brothers compared. AB - Joubert syndrome (JBTS) is a rare autosomal recessive disorder with an underestimated prevalence due to lack of recognition of clinical signs or failure to diagnose this pathology. JBTS is clinically heterogeneous, and it is characterized by a multiple organ involvement predominantly due to the requirement for Joubert gene function in several tissues. Renal disease affects approximately 30% of patients with JBTS, presenting itself in most cases as nephronophthisis (NPHP), a structural tubulo-interstitial disorder characterized by thickened basal membrane of the tubular epithelium and progressive interstitial fibrosis, associated with cysts at the cortico-medullary junction. We propose three cases concerning three patients with JBTS having different years of illness and degrees of renal impairment, evaluating the parameters of renal function at the time of genetic diagnosis and seen after a follow-up of 7 years. We measured neutrophil gelatinase-associated lipocalin (NGAL), considered as an excellent predictor of kidney injury, to evaluate whether this biomarker might be an early biomarker for JBTS-related kidney disease. NGAL was high in all three cases, but with different levels, indicating a tubular suffering typical of this syndrome, with dissimilar severity in the analyzed subjects. NGAL could represent an early indicator of renal damage useful to start an intensive nephrologic follow-up. PMID- 22260507 TI - Toll-like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR-mediated effects). AB - The Toll-like receptors (TLRs) 3, 7, 8 and 9 stimulate innate immune responses upon recognizing pathogen-derived nucleic acids. TLR3 is located on the cell surface and in cellular endosomes and recognizes double-stranded viral RNA or the synthetic mimic poly rI:rC. Recently, unformulated small interfering RNA (siRNA) has been reported as ligand for surface-expressed murine TLR3. Blockage of TLR3 is achieved by single-stranded DNA. We confirm and expand the observation that poly rI:rC-mediated TLR3 immune activation is blocked in a sequence-, length-, backbone- and CpG-dependent manner. However, human TLR3 is not activated by siRNA, which may be the result of differences in the amino acid composition of the TLR3 loop 1 of mice and humans. Although CD14 was previously described as a co-receptor for murine TLR3 and other nucleic acid-recognizing TLRs, human CD14 acts only as co-receptor to human TLR9, but not TLR3, TLR7 or TLR8. We show that CD14 up-regulates the TLR9 immune response of A, B and C-class oligodeoxynucleotides but down-regulates the phosphoro-diester version of B-class oligodeoxynucleotides. PMID- 22260510 TI - In situ synthesis of thermochemically reduced graphene oxide conducting nanocomposites. AB - Highly conductive reduced graphene oxide (GO) polymer nanocomposites are synthesized by a well-organized in situ thermochemical synthesis technique. The surface functionalization of GO was carried out with aryl diazonium salt including 4-iodoaniline to form phenyl functionalized GO (I-Ph-GO). The thermochemically developed reduced GO (R-I-Ph-GO) has five times higher electrical conductivity (42,000 S/m) than typical reduced GO (R-GO). We also demonstrate a R-I-Ph-GO/polyimide (PI) composites having more than 10(4) times higher conductivity (~1 S/m) compared to a R-GO/PI composites. The electrical resistances of PI composites with R-I-Ph-GO were dramatically dropped under ~3% tensile strain. The R-I-Ph-GO/PI composites with electrically sensitive response caused by mechanical strain are expected to have broad implications for nanoelectromechanical systems. PMID- 22260512 TI - Three-dimensional structure and defects in colloidal photonic crystals revealed by tomographic scanning transmission X-ray microscopy. AB - Self-assembled colloidal crystals have attracted major attention because of their potential as low-cost three-dimensional (3D) photonic crystals. Although a high degree of perfection is crucial for the properties of these materials, little is known about their exact structure and internal defects. In this study, we use tomographic scanning transmission X-ray microscopy (STXM) to access the internal structure of self-assembled colloidal photonic crystals with high spatial resolution in three dimensions for the first time. The positions of individual particles of 236 nm in diameter are identified in three dimensions, and the local crystal structure is revealed. Through image analysis, structural defects, such as vacancies and stacking faults, are identified. Tomographic STXM is shown to be an attractive and complementary imaging tool for photonic materials and other strongly absorbing or scattering materials that cannot be characterized by either transmission or scanning electron microscopy or optical nanoscopy. PMID- 22260513 TI - The effect of nitric-oxide-related supplements on human performance. AB - Nitric oxide (NO) has led a revolution in physiology and pharmacology research during the last two decades. This labile molecule plays an important role in many functions in the body regulating vasodilatation, blood flow, mitochondrial respiration and platelet function. Currently, it is known that NO synthesis occurs via at least two physiological pathways: NO synthase (NOS) dependent and NOS independent. In the former, L-arginine is the main precursor. It is widely recognized that this amino acid is oxidized to NO by the action of the NOS enzymes. Additionally, L-citrulline has been indicated to be a secondary NO donor in the NOS-dependent pathway, since it can be converted to L-arginine. Nitrate and nitrite are the main substrates to produce NO via the NOS-independent pathway. These anions can be reduced in vivo to NO and other bioactive nitrogen oxides. Other molecules, such as the dietary supplement glycine propionyl-L carnitine (GPLC), have also been suggested to increase levels of NO, although the physiological mechanisms remain to be elucidated. The interest in all these molecules has increased in many fields of research. In relation with exercise physiology, it has been suggested that an increase in NO production may enhance oxygen and nutrient delivery to active muscles, thus improving tolerance to physical exercise and recovery mechanisms. Several studies using NO donors have assessed this hypothesis in a healthy, trained population. However, the conclusions from these studies showed several discrepancies. While some reported that dietary supplementation with NO donors induced benefits in exercise performance, others did not find any positive effect. In this regard, training status of the subjects seems to be an important factor linked to the ergogenic effect of NO supplementation. Studies involving untrained or moderately trained healthy subjects showed that NO donors could improve tolerance to aerobic and anaerobic exercise. However, when highly trained subjects were supplemented, no positive effect on performance was indicated. In addition, all this evidence is mainly based on a young male population. Further research in elderly and female subjects is needed to determine whether NO supplements can induce benefit in exercise capacity when the NO metabolism is impaired by age and/or estrogen status. PMID- 22260517 TI - Functional expression of voltage-gated calcium channels in human melanoma. AB - The expression of voltage-gated calcium channels (VGCCs) has not been reported previously in melanoma cells in spite of increasing evidence of a role of VGCCs in tumorigenesis and tumour progression. To address this issue we have performed an extensive RT-PCR analysis of VGCC expression in human melanocytes and a range of melanoma cell lines and biopsies. In addition, we have tested the functional expression of these channels using Ca(2+) imaging techniques and examined their relevance for the viability and proliferation of the melanoma cells. Our results show that control melanocytes and melanoma cells express channel isoforms belonging to the Ca(v) 1 and Ca(v) 2 gene families. Importantly, the expression of low voltage-activated Ca(v) 3 (T-type) channels is restricted to melanoma. We have confirmed the function of T-type channels as mediators of constitutive Ca(2+) influx in melanoma cells. Finally, pharmacological and gene silencing approaches demonstrate a role for T-type channels in melanoma viability and proliferation. These results encourage the analysis of T-type VGCCs as targets for therapeutic intervention in melanoma tumorigenesis and/or tumour progression. PMID- 22260514 TI - A between sex comparison of anterior-posterior knee laxity after anterior cruciate ligament reconstruction with patellar tendon or hamstrings autograft: a systematic review. AB - Anterior-posterior (AP) knee laxity after anterior cruciate ligament (ACL) reconstruction may differ between sexes for different graft types. Females may experience an increase in AP knee laxity following an ACL reconstruction with a hamstrings graft, which is not seen in males with a hamstrings graft or in males or females with a bone-patellar tendon-bone (BTB) graft. The hypothesis of this review is sex differences in AP knee laxity and this will be identified in patients who undergo an ACL reconstruction with a hamstrings graft, while no sex differences will be observed in patients who have an ACL reconstruction with a BTB graft. A systematic search was performed in PubMed, CINAHL and SPORTDiscus. Inclusion criteria were articles published in the English language that studied human subjects who underwent an ACL reconstruction with a BTB or hamstrings autograft, and the presence of a sex comparison on outcome measures including side-to-side difference in AP knee laxity. Methodological quality was assessed using a Modified Coleman Methodology Score. Eleven cohort studies met the inclusion criteria. Six investigated sex differences in both hamstrings and BTB grafts. Three only investigated BTB grafts and two only investigated hamstrings grafts. These studies consistently reported increases in AP knee laxity in females after an ACL reconstruction with a hamstrings graft that was not observed in the other cohorts. This systematic review indicates that female patients have greater AP knee laxity following an ACL reconstruction with a hamstrings autograft compared with males with a similar procedure, and both females and males following an ACL reconstruction with a BTB autograft. These results are derived from lower level evidence, as no randomized control trials have attempted to answer this question. Future studies need to rigorously address this clinical question to confirm the results currently in the literature. PMID- 22260519 TI - A diastereoselective, nucleophile-promoted aldol-lactonization of ketoacids leading to bicyclic-beta-lactones. AB - An improved, tandem acid activation/aldol-lactonization process is described. This more practical protocol shortens reaction times for the construction of bicyclic beta-lactones from ketoacids and implements the use of commercially available reagents p-toluenesulfonyl chloride (p-TsCl) as activator and 4 dimethylaminopyridine (4-DMAP) as nucleophilic promoter (Lewis base). Substrates with beta-substituents, with respect to the carboxylic acid, consistently showed excellent levels of diastereoselectivity during the bis-cyclization event. PMID- 22260518 TI - Poly(alkylene oxide) copolymers for nucleic acid delivery. AB - The advancement of gene-based therapeutics to the clinic is limited by the ability to deliver physiologically relevant doses of nucleic acids to target tissues safely and effectively. Over the last couple of decades, researchers have successfully employed polymer and lipid based nanoassemblies to deliver nucleic acids for the treatment of a variety of diseases. Results of phase I/II clinical studies to evaluate the efficacy and biosafety of these gene delivery vehicles have been encouraging, which has promoted the design of more efficient and biocompatible systems. Research has focused on designing carriers to achieve biocompatibility, stability in the circulatory system, biodistribution to target the disease site, and intracellular delivery, all of which enhance the resulting therapeutic effect. The family of poly(alkylene oxide) (PAO) polymers includes random, block, and branched structures, among which the ABA type triblocks copolymers of ethylene oxide (EO) and propylene oxide (PO) (commercially known as Pluronic) have received the greatest consideration. In this Account, we highlight examples of polycation-PAO conjugates, liposome-PAO formulations, and PAO micelles for nucleic acid delivery. Among the various polymer design considerations, which include molecular weight of polymer, molecular weight of blocks, and length of blocks, the overall hydrophobic-lipophilic balance (HLB) is a critical parameter in defining the behavior of the polymer conjugates for gene delivery. We discuss the effects of varying this parameter in the context of improving gene delivery processes, such as serum stability and association with cell membranes. Other innovative macromolecular modifications discussed in this category include our work to enhance the serum stability and efficiency of lipoplexes using PAO graft copolymers, the development of a PAO gel-based carrier for sustained and stimuli responsive delivery, and the development of biodegradable PAO-based amphiphilic block copolymers. PMID- 22260520 TI - Self-assembled poly(imidazole-palladium): highly active, reusable catalyst at parts per million to parts per billion levels. AB - Metalloenzymes are essential proteins with vital activity that promote high efficiency enzymatic reactions. To ensure catalytic activity, stability, and reusability for safe, nontoxic, sustainable chemistry, and green organic synthesis, it is important to develop metalloenzyme-inspired polymer-supported metal catalysts. Here, we present a highly active, reusable, self-assembled catalyst of poly(imidazole-acrylamide) and palladium species inspired by metalloenzymes and apply our convolution methodology to the preparation of polymeric metal catalysts. Thus, a metalloenzyme-inspired polymeric imidazole Pd catalyst (MEPI-Pd) was readily prepared by the coordinative convolution of (NH(4))(2)PdCl(4) and poly[(N-vinylimidazole)-co-(N-isopropylacrylamide)(5)] in a methanol-water solution at 80 degrees C for 30 min. SEM observation revealed that MEPI-Pd has a globular-aggregated, self-assembled structure. TEM observation and XPS and EDX analyses indicated that PdCl(2) and Pd(0) nanoparticles were uniformly dispersed in MEPI-Pd. MEPI-Pd was utilized for the allylic arylation/alkenylation/vinylation of allylic esters and carbonates with aryl/alkenylboronic acids, vinylboronic acid esters, and tetraaryl borates. Even 0.8-40 mol ppm Pd of MEPI-Pd efficiently promoted allylic arylation/alkenylation/vinylation in alcohol and/or water with a catalytic turnover number (TON) of 20,000-1,250,000. Furthermore, MEPI-Pd efficiently promoted the Suzuki-Miyaura reaction of a variety of inactivated aryl chlorides as well as aryl bromides and iodides in water with a TON of up to 3,570,000. MEPI Pd was reused for the allylic arylation and Suzuki-Miyaura reaction of an aryl chloride without loss of catalytic activity. PMID- 22260521 TI - Upper normal threshold of serum alanine aminotransferase in identifying individuals at risk for chronic liver disease. AB - BACKGROUND/AIMS: Serum alanine aminotransferase (ALT) is an easily available, low cost screening tool for detecting silent chronic liver disease. Recent studies have suggested that the currently accepted healthy ALT thresholds be lowered. METHODS: In this retrospective cross-sectional study, we determined upper thresholds for ALT values in a nationally representative healthy cohort (n = 3337) from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV). Sensitivity and specificity of the currently used ALT threshold (40 IU/L, regardless of gender) was compared against study-derived, gender-specific ALT thresholds for detecting individuals at risk for chronic liver disease in 27 913 health check-up participants. RESULTS: The 95th percentile levels for ALT in healthy weight, metabolically normal, liver disease-free KNHANES participants were 34 IU/L for men and 25 IU/L for women. The prevalence of ALT elevation among health check-up participants was 11.0% in currently used thresholds, and increased to 22.6% with study-derived, gender-specific thresholds. Of the population who were additionally defined to have elevated ALT levels under new ALT threshold, 65.7% were at risk for chronic liver disease. Sensitivity for detecting individuals at risk for chronic liver disease improved from 18 to 33% with new thresholds whereas a trade-off in specificity (from 96 to 88%) was observed. CONCLUSIONS: It is recommendable to lower the current ALT thresholds to better identify individuals at risk for chronic liver disease. PMID- 22260522 TI - Correlation of antidepressive agents and the mortality of end-stage renal disease. AB - AIM: Depression is one of the most common psychological disorders in end-stage renal disease (ESRD) patients and is associated with impaired quality of life and increased mortality and rate of hospitalization. We aimed to examine the contributions of depression and the use of antidepressive agents in the mortality of ESRD patients. METHODS: A retrospective observatory study was conducted using the National Health Insurance Research Database in Taiwan. Patients with newly diagnosed as ESRD during the year 2001 to 2007 were collected. A total of 2312 ESRD patients were identified in the database. Statistical analyses were conducted to examine the contributions of depression and exposure of antidepressive agents in mortality rates of ESRD patients. RESULTS: Diagnosis of depression did not influence mortality rate (mortality rate in patients with depression: 26.5%; mortality rate in patients without depression: 26.2%; P= 1.000). Those who had antidepressive agents exposure had significantly higher mortality rate (mortality rate: 32.3%) than those who did not (mortality rate: 24.5%) (P < 0.001). CONCLUSIONS: Our findings suggest that (i) the mortality rate of ESRD patients was not affected by the diagnosis of depression, and (ii) exposure of antidepressive agents in ESRD patients was associated with a higher mortality rate. The high mortality rate in ESRD patients exposed to antidepressive agents can be a bias by indication. Equally, a true contribution of the antidepressive agents cannot be ruled out and this needs clarification. PMID- 22260524 TI - Minimal Invasive Follicular Thyroid Carcinoma Developed in Dyshormonogenetic Multinodular Goiter Due to Thyroid Peroxidase Gene Mutation. AB - Background: The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has been reported in only one patient harboring mutations in the thyroid peroxidase (TPO) gene. Patient findings: We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of L thyroxine treatment and consequently normal TSH levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland. Summary: Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG. Conclusions: Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma. PMID- 22260523 TI - Induction of cell proliferation and survival genes by estradiol-repressed microRNAs in breast cancer cells. AB - BACKGROUND: In estrogen responsive MCF-7 cells, estradiol (E2) binding to ERalpha leads to transcriptional regulation of genes involved in the control of cell proliferation and survival. MicroRNAs (miRNAs) have emerged as key post transcriptional regulators of gene expression. The aim of this study was to explore whether miRNAs were involved in hormonally regulated expression of estrogen responsive genes. METHODS: Western blot and QPCR were used to determine the expression of estrogen responsive genes and miRNAs respectively. Target gene expression regulated by miRNAs was validated by luciferase reporter assays and transfection of miRNA mimics or inhibitors. Cell proliferation was evaluated by MTS assay. RESULTS: E2 significantly induced bcl-2, cyclin D1 and survivin expression by suppressing the levels of a panel of miRNAs (miR-16, miR-143, miR 203) in MCF-7 cells. MiRNA transfection and luciferase assay confirmed that bcl-2 was regulated by miR-16 and miR-143, cyclinD1 was modulated by miR-16. Importantly, survivin was found to be targeted by miR-16, miR-143, miR-203. The regulatory effect of E2 can be either abrogated by anti-estrogen ICI 182, 780 and raloxifene pretreatment, or impaired by ERalpha siRNA, indicating the regulation is dependent on ERalpha. In order to investigate the functional significance of these miRNAs in estrogen responsive cells, miRNAs mimics were transfected into MCF-7 cells. It revealed that overexpression of these miRNAs significantly inhibited E2-induced cell proliferation. Further study of the expression of the miRNAs indicated that miR-16, miR-143 and miR-203 were highly expressed in triple positive breast cancer tissues, suggesting a potential tumor suppressing effect of these miRNAs in ER positive breast cancer. CONCLUSIONS: These results demonstrate that E2 induces bcl-2, cyclin D1 and survivin by orchestrating the coordinate downregulation of a panel of miRNAs. In turn, the miRNAs manifest growth suppressive effects and control cell proliferation in response to E2. This sheds a new insight into the integral post-transcriptional regulation of cell proliferation and survival genes by miRNAs, a potential therapeutic option for breast cancer. PMID- 22260526 TI - Phylogenetic analysis of strains of Orf virus isolated from two outbreaks of the disease in sheep in Greece. AB - BACKGROUND: Although orf is endemic around the world, there are few descriptions of Orf virus strains and comparisons of these strains. We report the sequence and phylogenetic analysis of the partial B2L gene of Orf virus from two outbreaks of the disease in Greece. The first was an outbreak of genital form of the disease in a flock imported from France, whilst the second was an outbreak of the disease in the udder skin of ewes and around the mouth of lambs in an indigenous flock. RESULTS: Phylogenetic analysis was performed on a part (498 bp) of the B2L gene of 35 Parapoxvirus isolates, including the two Orf virus isolates recovered from each of the two outbreaks in the present study. This analysis revealed that the maximum nucleotide and amino-acid variation amongst Orf virus strains worldwide (n = 33) was 8.1% and 9.6%, respectively. The homology of the nucleotide and amino-acid sequences between the two Greek isolates was 99.0% and 98.8%, respectively. The two Greek isolates clustered only with Orf virus strains. CONCLUSIONS: We suggest that there can be differences between strains based on their geographical origin. However, differences in the origin of strains or in the clinical presentation of the disease may not be associated with their pathogenicity. More work is required to determine if differing clinical presentations are linked to viral strain differences or if other factors, e.g., flock immunity, method of exposure or genetic susceptibility, are more important to determine the clinical presentation of the infection. PMID- 22260527 TI - A case series on lung deposition analysis of inhaled medication using functional imaging based computational fluid dynamics in asthmatic patients: effect of upper airway morphology and comparison with in vivo data. AB - CONTEXT: Asthma affects 20 million Americans resulting in an economic burden of approximately $18 billion in the US alone (Allergies and Asthma Foundation 2000; National Center for Environmental Health (NCEH) 1999). Research studies based on differences in patient-specific airway morphology for asthma and the associated effect on deposition of inhaled aerosols are currently not available in the literature. Therefore, the role of morphological variations such as upper airway (extrathoracic) occlusion is not well documented. OBJECTIVE: Functional imaging based computational fluid dynamics (CFD) of the respiratory airways for five asthmatic subjects is performed in this study using computed tomography (CT) based patient-specific airway models and boundary conditions. METHODS: CT scans for 5 asthma patients were used to reconstruct 3D lung models using segmentation software. An averaged inhalation profile and patient-specific lobar flow distribution were used to perform the simulation. The simulations were used to obtain deposition for BDP/Formoterol(r) HFA pMDI in the patient-specific airway models. RESULTS: The lung deposition obtained using CFD was in excellent agreement with available in vivo data using the same product. Specifically, CFD resulted in 30% lung deposition, whereas in vivo lung deposition was reported to be approximately 31%. CONCLUSION: It was concluded that a combination of patient specific airway models and lobar boundary conditions can be used to obtain accurate lung deposition estimates. Lower lung deposition can be expected for patients with higher extrathoracic resistance. Novel respiratory drug delivery devices need to accommodate population sub-groups based on these morphological and anatomical differences in addition to subject age. PMID- 22260525 TI - Graft rejection - endogenous or allogeneic? AB - The presence and persistence of alloantigen is necessary for graft-specific T cell-mediated immunity. However, specificity comprises only a single facet of an extremely complex process. Evidence is accruing to suggest that immunogenicity could be manipulated by endogenous ligands released during tissue injury. Stress molecules are significantly up-regulated following transplantation and stimulate conserved receptors on a range of leucocytes, including dendritic cells (DCs). The DCs are essential for co-stimulation and the induction of adaptive immunity. Stress signals can act as an adjuvant leading to DC maturation and activation. DCs stimulated by endogens exhibit enhanced alloantigen presentation, co stimulation and production of pro-inflammatory cytokines, such as interleukin 1beta (IL-1beta) and IL-18. Inflammasomes have a major role in IL-1beta/IL-18 production and secretion, and can be stimulated by endogens. Importantly, the polarization toward inflammatory T helper type 17 cells as opposed to regulatory T cells is dependent upon, among other factors, IL-1beta. This highlights an important differentiation pathway that may be influenced by endogenous signals. Minimizing graft damage and stress expression should hypothetically be advantageous, and we feel that this area warrants further research, and may provide novel treatment modalities with potential clinical benefit. PMID- 22260528 TI - Melatonin and vitamin C ameliorate alcohol-induced oxidative stress and eNOS expression in rat kidney. AB - OBJECTIVES: The aim of this study was to investigate the preventive effects of melatonin and vitamin C as antioxidants on renal injury in chronic alcohol consumption. MATERIALS AND METHODS: A total of 24 adult male Wistar rats weighing 200-250 g were used in the study. Rats were divided into four equal groups. Group I (control): rats were not fed on alcohol; Group II: rats were fed on alcohol; Group III: rats were fed on alcohol and 40 mg/kg vitamin C; and Group IV: rats were fed on alcohol and 4 mg/kg melatonin. RESULTS: Light microscopic examination revealed atrophic renal corpuscles, dilatation and congestion of the peritubular vessels, and renal corpuscles with obscure Bowman's space and a few foamy appearing tubules due to alcohol consumption were observed. Expression of endothelial nitric oxide synthase (eNOS) was localized to glomerulus, distal, and collector tubules. eNOS staining decreased in alcohol treatment group and melatonin and vitamin C encore increased expression pattern of eNOS. Alcohol consumption increased malondialdehyde (MDA) level and superoxide dismutase (SOD) and catalase (CAT) activities significantly in the alcohol consumption groups compared with that in the control group, while in melatonin give group just MDA level was decreased statistically significant and SOD and CAT activities were also decreased numerically compared with the alcohol consumption groups. CONCLUSIONS: These results indicated that chronic alcohol consumption caused renal damage by increased lipid peroxidation and melatonin and vitamin C administration produced in some degree protection against alcohol-induced damage. PMID- 22260529 TI - Intradural chordoma of the Meckel's cave: a challenging differential diagnosis. AB - Chordomas are midline tumors that arise from embryonic remnants of the notochord and are considered to be malignant tumors because of their tendency to invade and destroy the involved bone. Cases of intradural chordomas without bone involvement have been rarely described with a predilection for prepontine location. The absence of bony invasion renders the complete excision of these tumors more feasible and is related to their better prognosis in comparison to conventional chordomas. Herein we report the first intradural chordoma arising in the Meckel's cave. The intradural location of the lesion, outside midline structures, in the absence of bone infiltration, made the differential diagnosis versus other meningeal lesions such as chordoid meningioma challenging. The intense and strong immunohistochemical expression of pan-cytokeratins, S100, cytokeratin-19 and of the notochordal marker brachyury allowed differential diagnosis toward other tumors showing chordoid morphology. The expression of brachyury, which had not been previously analyzed in intradural chordoma, definitely links the histogenesis of this neoplasia to the notochord, similar to that of conventional chordoma. We also show that, different from conventional chordoma, intradural chordoma does not express the metallo-proteinases (MMPs) -2 and -9, which may account for its indolent biological behavior. PMID- 22260530 TI - Diversity-oriented synthesis of polycyclic diazinic scaffolds. AB - An efficient and versatile synthesis of a polycyclic diazinic system starting from oxazine has been developed using a two-step Michael/retro Michael and cyclization sequence. The substrates were synthesized with good to high yields giving rapid access to molecular diversity. PMID- 22260531 TI - The impact of Porphyromonas gingivalis lipids on apoptosis of primary human chondrocytes. AB - The role of oral bacterial infections including periodontal disease in the pathogenesis of rheumatoid arthritis (RA) has gained increasing interest. Among the major periodontal pathogens, Porphyromonas gingivalis has been mostly associated with RA pathogenesis. The aim of this study was to analyze the effect of P. gingivalis total lipid (TL) fraction and dihydroceramides, as potent virulence factors, on human primary chondrocytes. Primary chondrocyte cultures were incubated with P. gingivalis phosphoglycerol dihydroceramide (PG DHC) lipids, the TL fraction or phosphoethanolamine dihydroceramide. Cell morphology changes were determined by phase contrast light microscopy. Early and late apoptosis cell analysis was performed by Annexin-V, active caspases, and 7 Aminoactinomycin D staining, and examined by flow cytometry, and cell necrosis was evaluated by lactate dehydrogenase release. Procaspase-3 activation was determined by Western blot analysis. Microscopic analysis showed altered cell morphology and cell shrinkage following incubation with P. gingivalis TLs and PG DHC lipids. Flow cytometry demonstrated an increase of Annexin-V positive and active caspases positive chondrocytes after incubation with TL and PG DHC fractions but not after phosphoethanolamine dihydroceramide (control lipid) treatment or in untreated control cells. Furthermore, Western blot analysis showed an early cleavage of procaspase-3 after 1 hr. Significant lactate dehydrogenase release following incubation with P. gingivalis lipids was demonstrated. The present data demonstrate that P. gingivalis lipids promote apoptosis in primary human chondrocytes, and thereby may contribute to the joint damage seen in the pathogenesis of RA. PMID- 22260532 TI - A small IncQ-type plasmid carrying the quinolone resistance (qnrS2) gene from Aeromonas hydrophila. AB - AIMS: To investigate the qnrS2 gene encoded by a plasmid obtained from Aeromonas hydrophila. METHODS AND RESULTS: To investigate the full-length sequence of the plasmid carrying qnrS2 (plasmid designated pAHH04) from the strain SNUFPC-A10, the full-length coding sequence of the qnrS region was first amplified. The remaining part of the plasmid was read outwards from this region. The plasmid pAHH04 contained the repC, repA, mobA and mobC genes, and its total size was 7191 bp with a G+C content of 60%. CONCLUSIONS: This study describes the full-length sequence of a plasmid carrying the qnrS2 gene from Aer. hydrophila. The plasmid pAHH04 carried plasmid replication and mobilization genes from IncQ-type plasmids. SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated qnrS2 gene encoded by a plasmid from an Aer. hydrophila strain is of significant importance because it emphasizes the problem of antibiotic resistance as well as the ability of the determinants to spread among the different bacterial species that impact human health. PMID- 22260534 TI - Keratin expression in colorectal cancer: freak of nature or significant finding? PMID- 22260536 TI - Mycobacterium tuberculosis Infection of the placenta: a study of the early (innate) inflammatory response in two cases. AB - Infections with Mycobacterium tuberculosis (MTb) are globally prevalent in many countries, yet descriptions of placental pathology in tuberculous patients are scanty. The usual necrotizing granulomatous response associated with tuberculous infections requires an activation of the adaptive immune system. However, before this system is turned on, the 1st encounter with the tubercle bacillus is mediated by the innate immune system. This pathway utilizes innate surface receptors in neutrophils and histiocytes predominantly and does not produce a granulomatous pattern of inflammation. In this report we describe 2 cases of placental involvement with MTb in which an acute abscess-like inflammatory response with Myeloperoxidase and CD68-positive neutrophils and histiocytes causing acute villitis and intervillitis, with abundant acid-fast mycobacteria, were identified. Other cellular markers consistent with adaptive immunity were negative. These nongranulomatous lesions are seen in primary tuberculous infections occurring in a naive woman and, obviously, a naive fetus. These cases with early response inflammation in the placenta are frequently missed precisely because the mother is not known to be infected or has been recently diagnosed and because the symptoms in the newborn may not develop for several weeks, by which time the placenta may have been discarded. This report also shows that the differential diagnosis of acute villitis and intervillitis in the placenta should include tuberculosis aside from the more common bacterial infections such as listeriosis. PMID- 22260537 TI - Tunable diacetylene polymerized shell microbubbles as ultrasound contrast agents. AB - Monodisperse gas microbubbles, encapsulated with a shell of photopolymerizable diacetylene lipids and phospholipids, were produced by microfluidic flow focusing, for use as ultrasound contrast agents. The stability of the polymerized shell microbubbles against both aggregation and gas dissolution under physiological conditions was studied. Polyethylene glycol (PEG) 5000, which was attached to the diacetylene lipids, was predicted by molecular theory to provide more steric hindrance against aggregation than PEG 2000, and this was confirmed experimentally. The polymerized shell microbubbles were found to have higher shell-resistance than nonpolymerizable shell microbubbles and commercially available microbubbles (Vevo MicroMarker). The acoustic stability under 7.5 MHz ultrasound insonation was significantly greater than that for the two comparison microbubbles. The acoustic stability was tunable by varying the amount of diacetylene lipid. Thus, our polymerized shell microbubbles are a promising platform for ultrasound contrast agents. PMID- 22260539 TI - Factors affecting the yield of microRNAs from laser microdissectates of formalin fixed tissue sections. AB - BACKGROUND: Quantification of microRNAs in specific cell populations microdissected from tissues can be used to define their biological roles, and to develop and deploy biomarker assays. In this study, a number of variables were examined for their effect on the yield of microRNAs in samples obtained from formalin-fixed paraffin-embedded tissues by laser microdissection. RESULTS: MicroRNA yield was improved by using cresyl violet instead of hematoxylin-eosin to stain tissue sections in preparation for microdissection, silicon carbide instead of glass fiber as matrix in RNA-binding columns, and overnight digestion of dissected samples with proteinase K. Storage of slides carrying stained tissue sections at room temperature for up to a week before microdissection, and storage of the microdissectates at room temperature for up to a day before RNA extraction did not adversely affect microRNA yield. CONCLUSIONS: These observations should be of value for the efficient isolation of microRNAs from microdissected formalin fixed tissues with a flexible workflow. PMID- 22260540 TI - Improving the electrode performance of Ge through Ge@C core-shell nanoparticles and graphene networks. AB - Germanium is a promising high-capacity anode material for lithium ion batteries, but it usually exhibits poor cycling stability because of its huge volume variation during the lithium uptake and release process. A double protection strategy to improve the electrode performance of Ge through the use of Ge@C core shell nanostructures and reduced graphene oxide (RGO) networks has been developed. The as-synthesized Ge@C/RGO nanocomposite showed excellent cycling performance and rate capability in comparison with Ge@C nanoparticles when used as an anode material for Li ion batteries, which can be attributed to the electronically conductive and elastic RGO networks in addition to the carbon shells and small particle sizes of Ge. The strategy is simple yet very effective, and because of its versatility, it may be extended to other high-capacity electrode materials with large volume variations and low electrical conductivities. PMID- 22260544 TI - Comparative medicine. PMID- 22260545 TI - Hyperoestrogenism and mammary adenosis associated with a metastatic Sertoli cell tumour in a male Pekingese dog. PMID- 22260541 TI - Estimation of the epidemiological burden of human papillomavirus-related cancers and non-malignant diseases in men in Europe: a review. AB - BACKGROUND: The role of human papillomavirus (HPV) in malignant and non-malignant genital diseases in women is well known and the corresponding epidemiological burden has been widely described. However, less is known about the role of HPV in anal, penile and head and neck cancer, and the burden of malignant and non malignant HPV-related diseases in men. The objective of this review is to estimate the epidemiological burden of HPV-related cancers and non-malignant diseases in men in Europe. METHODS: The annual number of new HPV-related cancers in men in Europe was estimated using Eurostat population data and applying cancer incidence rates published by the International Agency for Research on Cancer. The number of cancer cases attributable to HPV, and specifically to HPV16/18, was calculated based on the most relevant prevalence estimates. The annual number of new cases of genital warts was calculated from the most robust European studies; and latest HPV6/11 prevalence estimates were then applied. A literature review was also performed to retrieve exhaustive data on HPV infection at all anatomical sites under study, as well as incidence and prevalence of external genital warts, recurrent respiratory papillomatosis and HPV-related cancer trends in men in Europe. RESULTS: A total of 72, 694 new cancer cases at HPV-related anatomical sites were estimated to occur each year in men in Europe. 17,403 of these cancer cases could be attributable to HPV, with 15,497 of them specifically attributable to HPV16/18. In addition, between 286,682 and 325,722 new cases of genital warts attributable to HPV6/11were estimated to occur annually in men in Europe. CONCLUSIONS: The overall estimated epidemiological burden of HPV-related cancers and non-malignant diseases is high in men in Europe. Approximately 30% of all new cancer cases attributable to HPV16/18 that occur yearly in Europe were estimated to occur in men. As in women, the vast majority of HPV-positive cancer in men is related to HPV16/18, while almost all HPV-related non-malignant diseases are due to HPV6/11. A substantial number of these malignant and non-malignant diseases may potentially be prevented by quadrivalent HPV vaccination. PMID- 22260547 TI - Polyphenolic content and comparative antioxidant capacity of flavoured black teas. AB - The content of selected flavonoids and phenolic acids of 12 commercial flavoured black tea infusions was determined by high-performance liquid chromatography with tandem mass spectrometry in the negative electrospray ionization mode. Assays for the evaluation of their antioxidant capacity were carried out by cupric ion reducing antioxidant capacity, Folin-Ciocalteu assay, cyclic voltammetry and potentiometry. Flavonoids were predominantly present as glycosides in the studied infusions. Only quercetin as a free aglycone was found at trace levels. Notable amount of naringin and hesperidin was determined in teas with citrus aromas or fruits. These compounds were not found in premium black tea. Two principal groups of the studied teas were found using cluster analysis in relation to the values of their antioxidant activities. PMID- 22260548 TI - Rebuilding government credibility in Chinese environmental resident activism. PMID- 22260549 TI - Malignant Wegener's granulomatosis with fibrosing mediastinitis and vena cava superior syndrome. AB - A 47-year-old man was admitted to hospital for migratory joint pain, fatigue, and cough with bloody sputum and proteinuria with increased serum creatinine level. Diagnosis of Wegener's granulomatosis was established. During follow-up, the vena cava superior syndrome developed. The patient died of respiratory failure after 12 years of follow-up. The autopsy revealed rigid, whitish, 12 mm thick tissue, which embedded and compressed the large vessels upwards from their origin in the heart, thus causing vena cava superior syndrome. This tissue was composed of fibrous material without inflammatory cellulization. We consider this fibrous tissue as a manifestation of fibrosing mediastinitis that may or may not share pathogenesis with Wegener's granulomatosis. PMID- 22260550 TI - Structure refinement of protein low resolution models using the GNEIMO constrained dynamics method. AB - The challenge in protein structure prediction using homology modeling is the lack of reliable methods to refine the low resolution homology models. Unconstrained all-atom molecular dynamics (MD) does not serve well for structure refinement due to its limited conformational search. We have developed and tested the constrained MD method, based on the generalized Newton-Euler inverse mass operator (GNEIMO) algorithm for protein structure refinement. In this method, the high-frequency degrees of freedom are replaced with hard holonomic constraints and a protein is modeled as a collection of rigid body clusters connected by flexible torsional hinges. This allows larger integration time steps and enhances the conformational search space. In this work, we have demonstrated the use of torsional GNEIMO method without using any experimental data as constraints, for protein structure refinement starting from low-resolution decoy sets derived from homology methods. In the eight proteins with three decoys for each, we observed an improvement of ~2 A in the rmsd in coordinates to the known experimental structures of these proteins. The GNEIMO trajectories also showed enrichment in the population density of native-like conformations. In addition, we demonstrated structural refinement using a "freeze and thaw" clustering scheme with the GNEIMO framework as a viable tool for enhancing localized conformational search. We have derived a robust protocol based on the GNEIMO replica exchange method for protein structure refinement that can be readily extended to other proteins and possibly applicable for high throughput protein structure refinement. PMID- 22260551 TI - The complement C1qA enhances retinoic acid-inducible gene-I-mediated immune signalling. AB - The cellular innate immune response is essential for recognizing and defending against viral infection. Retinoic acid-inducible gene-I (RIG-I) and virus-induced signaling adaptor (VISA) mediated immune signalling is critically involved in RNA virus-induced innate immune responses. Here we demonstrate that the complement C1qA interacts with different RIG-I pathway components and enhances RIG-I-VISA mediated signalling pathway as well as TBK1-mediated activation of interferon beta (IFN-beta) promoter. Our data show that over-expression of C1qA up-regulates RIG-I-mediated activation of IFN-stimulated responsive element (ISRE) and nuclear factor-kappaB reporters and IFN-beta transcription, but not IFN regulatory factor 3-mediated and inhibitor of kappaB kinase-mediated activation of ISRE and nuclear factor-kappaB promoter. In addition, C1qA can counteract the function of the C1q receptor gC1qR in RIG-I-mediated signalling. Our results reveal the important role of complement C1qA in the innate immune response. PMID- 22260552 TI - 'Out-patient' albumin dialysis for cholestatic patients with intractable pruritus. AB - BACKGROUND: Intractable pruritus is a major problem for some patients with cholestasis. Albumin dialysis has been shown to ameliorate pruritus, but long term outcome data are limited. AIM: To evaluate the safety and efficacy of 'out patient' albumin dialysis using the molecular adsorbent recirculating system (MARS) in the treatment of intractable pruritus in cholestatic patients referred for liver transplantation for symptomatic relief. METHODS: Fifteen patients who failed to respond to standard medical therapy to control pruritus were included. Three MARS (6 h) sessions were performed per admission, and were repeated, if necessary. The intensity and severity of itch was quantified using itch severity and visual analogue scales (ISS and VAS). RESULTS: Molecular adsorbent recirculating system treatment was safe and associated with immediate and complete response in 11 patients; two patients had a partial response and two patients had no response. Thirty-four treatments were performed during a follow up period of 15.7 months (3-46) with patients requiring a mean of two admissions (1-6). The mean VAS and ISS improved significantly (both P < 0.001) with improvement in the patient's perception of their quality of life. The duration of acceptable relief in responders was 3.3 months (range 2-5). No serious adverse events were recorded, but the platelet count and haemoglobin were reduced significantly. CONCLUSION: Molecular adsorbent recirculating system therapy delivered in an 'out-patient' setting is safe and effective with a high degree of patient acceptability. Albumin dialysis can be considered a viable therapeutic option for patients with severe intractable pruritus, in whom, the only other effective treatment option is liver transplantation. PMID- 22260554 TI - Potassium-titanyl-phosphate laser photoselective vaporization for benign prostatic hyperplasia: 5-year follow-up from a district general hospital. AB - BACKGROUND AND PURPOSE: The 80-W potassium-titanyl-phosphate (KTP) laser photoselective vaporization of the prostate (PVP) is a minimally invasive surgical option for patients with symptomatic benign prostatic hyperplasia, although evidence of long-term efficacy is limited. We present the long-term outcomes from a heterogeneous patient population. PATIENTS AND METHODS: We prospectively collected data for all patients who underwent 80-W KTP laser PVP treatment between 2004 and 2005. Evaluation occurred pr-operatively, and then at 3, 6, 12, and 60 months postoperatively. This included International Prostate Symptom Score (IPSS), peak urinary flow rate (Qmax), postvoid residual (PVR) volume, serum prostate-specific antigen measurement, and transrectal ultrasonography-estimated prostate volume. RESULTS: A total of 115 patients were eligible for analysis, with a mean age of 77 years and mean prostate volume of 55.8 cc. Of these, 74% were operated on for lower urinary tract symptoms, 23% for acute urinary retention, and 3% for chronic retention; 30% of patients were American Society of Anesthesiologists score >= 3, and 93% were treated as 23-hour stays. No patients needed blood transfusion, and there were no cases of transurethral resection syndrome. An initial trial-without catheter failed in 11 (9.6%), although 8 of these successfully voided after a further week. At 5-year follow-up, mean Qmax improved from 8.0 +/- 5.0 mL to 13.9 +/- 7.7 mL and mean IPSS improved from 22 +/- 5 to 9 +/- 7. There were no cases of urethral strictures, but there was a 3.3% rate of bladder neck stenosis and an overall re treatment rate of 21% over 5 years. CONCLUSION: We confirm the long-term durability of the 80-W KTP laser PVP with minimal perioperative morbidity. It is therefore a safe option for high-risk patients with medical comorbidities, although its high reoperation rate may limit its use to this specific patient population. PMID- 22260556 TI - Communication: Beyond Boltzmann's H-theorem: demonstration of the relaxation theorem for a non-monotonic approach to equilibrium. AB - Relaxation of a system to equilibrium is as ubiquitous, essential, and as poorly quantified as any phenomena in physics. For over a century, the most precise description of relaxation has been Boltzmann's H-theorem, predicting that a uniform ideal gas will relax monotonically. Recently, the relaxation theorem has shown that the approach to equilibrium can be quantified in terms of the dissipation function first defined in the proof of the Evans-Searles fluctuation theorem. Here, we provide the first demonstration of the relaxation theorem through simulation of a simple fluid system that generates a non-monotonic relaxation to equilibrium. PMID- 22260553 TI - A mixture of anatase and rutile TiO2 nanoparticles induces histamine secretion in mast cells. AB - BACKGROUND: Histamine released from mast cells, through complex interactions involving the binding of IgE to FcepsilonRI receptors and the subsequent intracellular Ca2+ signaling, can mediate many allergic/inflammatory responses. The possibility of titanium dioxide nanoparticles (TiO2 NPs), a nanomaterial pervasively used in nanotechnology and pharmaceutical industries, to directly induce histamine secretion without prior allergen sensitization has remained uncertain. RESULTS: TiO2 NP exposure increased both histamine secretion and cytosolic Ca2+ concentration ([Ca2+]C) in a dose dependent manner in rat RBL-2H3 mast cells. The increase in intracellular Ca2+ levels resulted primarily from an extracellular Ca2+ influx via membrane L-type Ca2+ channels. Unspecific Ca2+ entry via TiO2 NP-instigated membrane disruption was demonstrated with the intracellular leakage of a fluorescent calcein dye. Oxidative stress induced by TiO2 NPs also contributed to cytosolic Ca2+ signaling. The PLC-IP3-IP3 receptor pathways and endoplasmic reticulum (ER) were responsible for the sustained elevation of [Ca2+]C and histamine secretion. CONCLUSION: Our data suggests that systemic circulation of NPs may prompt histamine release at different locales causing abnormal inflammatory diseases. This study provides a novel mechanistic link between environmental TiO2 NP exposure and allergen-independent histamine release that can exacerbate manifestations of multiple allergic responses. PMID- 22260557 TI - Communication: High speed optical investigations of a character of boiling-up onset. AB - In this communication, we discuss the phenomenon of attainable superheat of liquid and the peculiarities of its release by spontaneous boiling-up. We have combined the apparatus for superheating, namely, bubble chamber, with a high speed micro-optical method for detailed monitoring of the initial stage of boiling-up. In experiments on the isothermal pressure drop, it was found that the boiling-up onset of n-hexane is accompanied by characteristic step signal. The signal has proved to be typical of the heterogeneous character of boiling-up onset in a whole range of superheating degrees. The performance of the method for investigation of the refractive index and density for superheated liquids as functions of temperature and pressure has been revealed. The experimental error is estimated to be 0.1%. PMID- 22260558 TI - Electronic structure calculations in arbitrary electrostatic environments. AB - Modeling of electronic structure of molecules in electrostatic environments is of considerable relevance for surface-enhanced spectroscopy and molecular electronics. We have developed and implemented a novel approach to the molecular electronic structure in arbitrary electrostatic environments that is compatible with standard quantum chemical methods and can be applied to medium-sized and large molecules. The scheme denoted CheESE (chemistry in electrostatic environments) is based on the description of molecular electronic structure subject to a boundary condition on the system/environment interface. Thus, it is particularly suited to study molecules on metallic surfaces. The proposed model is capable of describing both electrostatic effects near nanostructured metallic surfaces and image-charge effects. We present an implementation of the CheESE model as a library module and show example applications to neutral and negatively charged molecules. PMID- 22260559 TI - Coarse-grained potential models for structural prediction of carbon dioxide (CO2) in confined environments. AB - In this paper, we propose coarse-grained single-site (CGSS), wall-CO(2), and CO(2)-CO(2) interaction potential models to study the structure of carbon dioxide under confinement. The CGSS potentials are used in an empirical potential based quasi-continuum theory, EQT, to compute the center-of-mass density and potential profiles of CO(2) confined inside different size graphite slit pores. Results obtained from EQT are compared with those obtained from all-atom molecular dynamics (AA-MD) simulations, and are found to be in good agreement with each other. Though these CGSS interaction potentials are primarily developed and parameterized for EQT, they are also used to perform coarse-grained molecular dynamics (CG-MD) simulations. The results obtained from CG-MD simulations are also found to be in reasonable agreement with AA-MD simulation results. PMID- 22260560 TI - An energy decomposition analysis for intermolecular interactions from an absolutely localized molecular orbital reference at the coupled-cluster singles and doubles level. AB - We propose a wave function-based method for the decomposition of intermolecular interaction energies into chemically-intuitive components, isolating both mean field- and explicit correlation-level contributions. We begin by solving the locally-projected self-consistent field for molecular interactions equations for a molecular complex, obtaining an intramolecularly polarized reference of self consistently optimized, absolutely-localized molecular orbitals (ALMOs), determined with the constraint that each fragment MO be composed only of atomic basis functions belonging to its own fragment. As explicit inter-electronic correlation is integral to an accurate description of weak forces underlying intermolecular interaction potentials, namely, coordinated fluctuations in weakly interacting electronic densities, we add dynamical correlation to the ALMO polarized reference at the coupled-cluster singles and doubles level, accounting for explicit dispersion and charge-transfer effects, which map naturally onto the cluster operator. We demonstrate the stability of energy components with basis set extension, follow the hydrogen bond-breaking coordinate in the C(s)-symmetry water dimer, decompose the interaction energies of dispersion-bound rare gas dimers and other van der Waals complexes, and examine charge transfer-dominated donor-acceptor interactions in borane adducts. We compare our results with high level calculations and experiment when possible. PMID- 22260561 TI - Calculation of the surface tension and pressure components from a non-exponential perturbation method of the thermodynamic route. AB - Surface tension is probably the most important interfacial property and a large number of techniques have been devoted to its calculation. Usually, this calculation is carried out using mechanical or thermodynamic definitions. The mechanical route uses an arbitrary choice to affect the contribution of the pairwise force. To overcome this arbitrariness, a thermodynamic route based on the area perturbation (test-area (TA) method) has been developed for the calculation of surface tension. The volume perturbation (VP) method provides an original route to compute the components of the pressure tensor. These two routes are developed from the perturbation theory leading to working expressions using exponential averages of energy. The use of exponential averages makes the calculation strongly dependent on the occurrence of low values of DeltaU. Additionally, the decomposition of the energy to obtain local surface tension is nontrivial. From the explicit derivation of the partition function the exponential average is avoided providing an interesting alternative to TA, VP, and mechanical methods. To make a consistent comparison, we study the profiles of the surface tension along the direction normal to the surface for the different definitions and techniques in the cases of liquid-vapor interfaces of acids gases, binary, and apolar systems. PMID- 22260562 TI - A spin-adapted size-extensive state-specific multi-reference perturbation theory. I. Formal developments. AB - We present in this paper a comprehensive formulation of a spin-adapted size extensive state-specific multi-reference second-order perturbation theory (SA SSMRPT2) as a tool for applications to molecular states of arbitrary complexity and generality. The perturbative theory emerges in the development as a result of a physically appealing quasi-linearization of a rigorously size-extensive state specific multi-reference coupled cluster (SSMRCC) formalism [U. S. Mahapatra, B. Datta, and D. Mukherjee, J. Chem. Phys. 110, 6171 (1999)]. The formulation is intruder-free as long as the state-energy is energetically well-separated from the virtual functions. SA-SSMRPT2 works with a complete active space (CAS), and treats each of the model space functions on the same footing. This thus has the twin advantages of being capable of handling varying degrees of quasi-degeneracy and of ensuring size-extensivity. This strategy is attractive in terms of the applicability to bigger systems. A very desirable property of the parent SSMRCC theory is the explicit maintenance of size-extensivity under a variety of approximations of the working equations. We show how to generate both the Rayleigh-Schrodinger (RS) and the Brillouin-Wigner (BW) versions of SA-SSMRPT2. Unlike the traditional naive formulations, both the RS and the BW variants are manifestly size-extensive and both share the avoidance of intruders in the same manner as the parent SSMRCC. We discuss the various features of the RS as well as the BW version using several partitioning strategies of the hamiltonian. Unlike the other CAS based MRPTs, the SA-SSMRPT2 is intrinsically flexible in the sense that it is constructed in a manner that it can relax the coefficients of the reference function, or keep the coefficients frozen if we so desire. We delineate the issues pertaining to the spin-adaptation of the working equations of the SA SSMRPT2, starting from SSMRCC, which would allow us to incorporate essentially any type open-shell configuration-state functions (CSF) within the CAS. The formalisms presented here will be applied extensively in a companion paper to assess their efficacy. PMID- 22260563 TI - A spin-adapted size-extensive state-specific multi-reference perturbation theory with various partitioning schemes. II. Molecular applications. AB - Following the theoretical development of a spin-adapted state-specific multi reference second-order perturbation theory (SA-SSMRPT2) as expounded in the preceding publication, we discuss here its implementation and the results of its applications to potential energy curves (PECs) of various electronic states of small molecules. In particular, we illustrate its efficacy in states of various spin multiplicities and varying multi-reference character. Both Moller-Plesset (MP) and Epstein-Nesbet (EN) type of partitions have been explored. Also, a straightforward Rayleigh-Schrodinger (RS) and Brillouin-Wigner (BW) version of the SA-SSMRPT2 have been studied. Ground state PECs were computed for singlet states of HF, BH, and H(2)O molecules as well as the doublet state of NH(2) and BeH radicals and compared to corresponding full configuration interaction numbers, which serve as benchmark results. As an extensive application on a production level, the ground state PECs of N(2), a classic example of multiple bond breaking, were calculated using cc-pVXZ (X = 3,4,5) basis and then extrapolated to obtain estimates of the complete basis set limit. Vibrational energy levels were extracted from these N(2) PECs, which compare favorably to the experimental values. In addition, extensive studies were also carried out on PECs of the seven low-lying excited states of the N(2) molecule. Finally, it is shown that the flexibility to relax configuration coefficients in SA-SSMRPT2 helps to provide good descriptions for the avoided crossing between the two lowest (1)Sigma states of the LiF molecule. Our results indicate (1) that more studies are needed to draw firm conclusions about the relative efficacies of the MP and EN results and (2) that the RS version works so well as compared to the BW version that the extra computational expenses needed in the later formalism is not warranted. PMID- 22260564 TI - Theoretical and numerical assessments of spin-flip time-dependent density functional theory. AB - Spin-flip time-dependent density functional theory (SF-TD-DFT) with the full noncollinear hybrid exchange-correlation kernel and its approximate variants are critically assessed, both formally and numerically. As demonstrated by the ethylene torsion and the C(2v) ring-opening of oxirane, SF-TD-DFT is very useful for describing nearly degenerate situations. However, it may occasionally yield unphysical results. This stems from the noncollinear form of the generalized gradient approximation, which becomes numerically instable in the presence of spin-flip excitations from the closed- to vacant-shell orbitals of an open-shell reference. To cure this defect, a simple modification, dubbed as ALDA0, is proposed in the spirit of adiabatic local density approximation (ALDA). It is applicable to all kinds of density functionals and yields stable results without too much loss of accuracy. In particular, the combination of ALDA0 with the Tamm Dancoff approximation is a promising tool for studying global potential energy surfaces. In addition to the kernel problem, SF-TD-DFT is also rather sensitive to the choice of reference states, as demonstrated by the spin multiplet states of closed-shell molecules of H(2)O, CH(2)O, and C(2)H(4). Surprisingly, SF-TD-DFT with pure density functionals may also fail for valance excitations with large orbital overlaps, at variance with the spin-conserving counterpart (SC-TD-DFT). In this case, the inclusion of a large amount of Hartree-Fock exchange is mandatory for quantitative results. Nonetheless, for spatially degenerate cases such as CF, CH, and NH(+), SF-TD-DFT is more advantageous than SC-TD-DFT, unless the latter is also space adapted. These findings are very instructive for future development and applications of TD-DFT. PMID- 22260565 TI - A new general Renner-Teller (including E ? 1) spectroscopic formalism for triatomic molecules. AB - We present a general approach and its implementation for calculating the rovibronic levels and spectra of rigid or floppy Renner-Teller triatomic molecules, which is not limited in the number and quantum numbers (Lambda, S) of electronic states. The case of strong Renner-Teller coupling (E ? 1) is specially studied and it is shown that the proposed implementation provides very accurate and stable results for this complicated problem. Few examples (BF(2), HBF, and CCO) illustrate the performance of the code. PMID- 22260566 TI - Intermolecular torsional motion of a pi-aggregated dimer probed by two dimensional electronic spectroscopy. AB - The energetic splitting of the two exciton states of a molecular dimer depends strongly on the relative orientation of the monomers with respect to each other. The curvature of the corresponding adiabatic potential energy surfaces can lead to torsional motion of the monomers. It has been suggested recently that this torsional motion could provide a possible relaxation mechanism for the upper state which proceeds via a crossing of the two singly excited state potentials. Another, competing, relaxation mechanism is provided by coupling to the environment, leading to direct exciton relaxation. Here we examine theoretically the combined dynamics of torsional motion and excitonic relaxation for a pi aggregated dimer. Using two-dimensional (2D) spectroscopy, it is shown how torsional motion through a crossing of the adiabatic excitonic potential surfaces could be distinguished from direct relaxation. For the calculations a mixed quantum/classical approach is used, where the torsional motion is treated by an Ehrenfest type of equation, while the excitonic dynamics including dephasing and direct relaxation is described by a quantum master equation. PMID- 22260567 TI - Correlation effects of pi electrons on the band structures of conjugated polymers using the self-consistent GW approximation with vertex corrections. AB - Many-body perturbation theory is used to investigate the effect of pi-electron correlations on the quasi-particle band structures of conjugated polymers at the level of the Pariser-Parr-Pople model. The self-consistent GW approximation with vertex corrections to both the self-energy and the polarization in Hedin's equations is employed in order to eliminate self-interaction errors and include the effects of electron-hole attraction in screening processes. The dynamic inverse dielectric function is constructed from the generalized plasmon-pole approximation with the static dressed polarization given by the coupled-perturbed Hartree-Fock equation. The bandgaps of trans-polyacetylene, trans polyphenylenevinylene and poly(para)phenylene are calculated by both the Hartree Fock and GW approximation, and a lowering of bandgaps due to electron correlations is found. We conclude that both dielectric screening and vertex corrections are important for calculating the quasi-particle bandgaps of conjugated polymers. PMID- 22260568 TI - Nonspherical model density matrices for Rung 3.5 density functionals. AB - "Rung 3.5" exchange-correlation functionals for Kohn-Sham density functional theory depend linearly on the nonlocal one-particle density matrix of the noninteracting Kohn-Sham reference system. Rung 3.5 functionals also require a semilocal model for the one-particle density matrix. This work presents new model density matrices for Rung 3.5 functionals. The resulting functionals give reasonable predictions for total energies, molecular thermochemistry and kinetics, odd-electron bonds, and conjugated polymer bandgaps. Global-hybrid-like combinations of semilocal and Rung 3.5 exchange, and empirical density matrix models, also show promise. PMID- 22260569 TI - Phonon-mediated path-interference in electronic energy transfer. AB - We present a formalism to quantify the contribution of path-interference in phonon-mediated electronic energy transfer. The transfer rate between two molecules is computed by considering the quantum mechanical amplitudes associated with pathways connecting the initial and final sites. This includes contributions from classical pathways, but also terms arising from interference of different pathways. We treat the vibrational modes coupled to the molecules as a non Markovian harmonic oscillator bath, and investigate the correction to transfer rates due to the lowest-order interference contribution. We show that depending on the structure of the harmonic bath, the correction due to path-interference may have a dominant vibrational or electronic character, and can make a notable contribution to the transfer rate in the steady state. PMID- 22260570 TI - A new fragment-based approach for calculating electronic excitation energies of large systems. AB - We present a new fragment-based scheme to calculate the excited states of large systems without necessity of a Hartree-Fock (HF) solution of the whole system. This method is based on the implementation of the renormalized excitonic method [M. A. Hajj et al., Phys. Rev. B 72, 224412 (2005)] at ab initio level, which assumes that the excitation of the whole system can be expressed by a linear combination of various local excitations. We decomposed the whole system into several blocks and then constructed the effective Hamiltonians for the intra- and inter-block interactions with block canonical molecular orbitals instead of widely used localized molecular orbitals. Accordingly, we avoided the prerequisite HF solution and the localization procedure of the molecular orbitals in the popular local correlation methods. Test calculations were implemented for hydrogen molecule chains at the full configuration interaction, symmetry adapted cluster/symmetry adapted cluster configuration interaction, HF/configuration interaction singles (CIS) levels and more realistic polyene systems at the HF/CIS level. The calculated vertical excitation energies for lowest excited states are in reasonable accordance with those determined by the calculations of the whole systems with traditional methods, showing that our new fragment-based method can give good estimates for low-lying energy spectra of both weak and moderate interaction systems with economic computational costs. PMID- 22260571 TI - Visualizing the zero order basis of the spectroscopic Hamiltonian. AB - Recent works have shown that a generalization of the spectroscopic effective Hamiltonian can describe spectra in surprising regions, such as isomerization barriers. In this work, we seek to explain why the effective Hamiltonian is successful where there was reason to doubt that it would work at all. All spectroscopic Hamiltonians have an underlying abstract zero-order basis (ZOB) which is the "ideal" basis for a given form and parameterization of the Hamiltonian. Without a physical model there is no way to transform this abstract basis into a coordinate representation. To this end, we present a method of obtaining the coordinate space representation of the abstract ZOB of a spectroscopic effective Hamiltonian. This method works equally well for generalized effective Hamiltonians that encompass above-barrier multiwell behavior, and standard effective Hamiltonians for the vicinity of a single potential minimum. Our approach relies on a set of converged eigenfunctions obtained from a variational calculation on a potential surface. By making a one to-one correspondence between the energy eigenstates of the effective Hamiltonian and those of the coordinate space Hamiltonian, a physical representation of the abstract ZOB is calculated. We find that the ZOB basis naturally adjusts its complexity depending on the underlying nature of phase space, which allows spectroscopic Hamiltonians to succeed for systems sampling multiple stationary points. PMID- 22260572 TI - Cavity ring-down spectroscopy of the oxygen B-band with absolute frequency reference to the optical frequency comb. AB - Absolute positions of several oxygen B-band lines were measured with the Pound Drever-Hall-locked frequency-stabilized cavity ring-down spectrometer. The frequency axis of spectra was linked to the optical frequency comb. Achieved uncertainties of line positions are between 0.9 and 2.9 MHz. Self-pressure shifts coefficients are also reported. PMID- 22260573 TI - Singly and doubly lithium doped silicon clusters: geometrical and electronic structures and ionization energies. AB - The geometric structures of neutral and cationic Si(n)Li(m)(0/+) clusters with n = 2-11 and m = 1, 2 are investigated using combined experimental and computational methods. The adiabatic ionization energy and vertical ionization energy (VIE) of Si(n)Li(m) clusters are determined using quantum chemical methods (B3LYP/6-311+G(d), G3B3, and CCSD(T)/aug-cc-pVxZ with x = D,T), whereas experimental values are derived from threshold photoionization experiments in the 4.68-6.24 eV range. Among the investigated cluster sizes, only Si(6)Li(2), Si(7)Li, Si(10)Li, and Si(11)Li have ionization thresholds below 6.24 eV and could be measured accurately. The ionization threshold and VIE obtained from the experimental photoionization efficiency curves agree well with the computed values. The growth mechanism of the lithium doped silicon clusters follows some simple rules: (1) neutral singly doped Si(n)Li clusters favor the Li atom addition on an edge or a face of the structure of the corresponding Si(n)(-) anion, while the cationic Si(n)Li(+) binds with one Si atom of the bare Si(n) cluster or adds on one of its edges, and (2) for doubly doped Si(n)Li(2)(0/+) clusters, the neutrals have the shape of the Si(n+1) counterparts with an additional Li atom added on an edge or a face of it, while the cations have both Li atoms added on edges or faces of the Si(n)(-) clusters. PMID- 22260574 TI - Accurate calculation of the intensity dependence of the refractive index using polarized basis sets. AB - Using the single and double excitation coupled cluster level of theory (CCSD) and the density functional theory/Becke 3-parameter Lee-Yang and Parr (DFT/B3LYP) methods, we test the performance of the Pol, ZPol, and LPol-n (n = ds, dl, fs, fl) basis sets in the accurate description of the intensity dependence of the refractive index in the Ne atom, and the N(2) and the CO molecules. Additionally, we test the aug-pc-n (n = 1, 2) basis sets of Jensen, and the SVPD, TZVPD, and QZVPD bases by Rappoport and Furche. Tests involve calculations of dynamic polarizabilities and frequency dependent second hyperpolarizabilities. The results are interpreted in terms of the medium constants entering the expressions for optically induced birefringences. In all achiral systems, the performance of the LPol-n sets is very good. Also the aug-pc-2 set yields promising results. Accurate CCSD results available in the literature allow us to select the best basis sets in order to carry out DFT/B3LYP calculations of medium constants in larger molecules. As applications, we show results for (R)-fluoro-oxirane and (R) methyloxirane. PMID- 22260575 TI - Energy landscapes of ion clusters in isotropic quadrupolar and octupolar traps. AB - The energy landscapes of ion clouds confined in isotropic quadrupolar and octupolar traps are characterized for several representative cluster sizes. All clusters exhibit stable multishell structures that belong to separate funnels. Quadrupolar confinement leads to more homogeneous clusters and denser distributions of isomers than octupolar confinement. Statistical analysis of the transition states indicates that the barriers associated with intrashell motion are lower but more asymmetric and more cooperative compared to intershell motion. The relaxation between low-energy funnels with different arrangements of shells mostly exhibits Arrhenius kinetics, with a weak variation of the activation energy at higher temperatures. PMID- 22260576 TI - Experimental and theoretical investigation of the triple differential cross section for electron impact ionization of pyrimidine molecules. AB - Cross-section data for electron impact induced ionization of bio-molecules are important for modelling the deposition of energy within a biological medium and for gaining knowledge of electron driven processes at the molecular level. Triply differential cross sections have been measured for the electron impact ionization of the outer valence 7b(2) and 10a(1) orbitals of pyrimidine, using the (e, 2e) technique. The measurements have been performed with coplanar asymmetric kinematics, at an incident electron energy of 250 eV and ejected electron energy of 20 eV, for scattered electron angles of -5 degrees , -10 degrees , and -15 degrees . The ejected electron angular range encompasses both the binary and recoil peaks in the triple differential cross section. Corresponding theoretical calculations have been performed using the molecular 3-body distorted wave model and are in reasonably good agreement with the present experiment. PMID- 22260577 TI - Electronic structure and bonding of HBeLi, HmgLi, and HCaLi in their bent equilibrium geometries. AB - Compact, yet accurate, non-orthogonal multi-configuration wavefunctions have been computed for HBeLi, HMgLi, and HCaLi in their respective nonlinear equilibrium geometries. They appear to be dominated by just two configurations, "orbitally relaxed" versions of the single-configuration spin-coupled and generalized valence bond (GVB) wavefunctions, respectively, with a smaller contribution from a self-consistent field (SCF)-like configuration. Double excitations out of the main configurations, while required for quantitative accuracy, enter the wavefunction with such small weights that they do not alter the qualitative picture that emerges from the orbital structure of the two main configurations. For comparison, calculations have also been carried out with two orthogonality free configurations as reference, and no GVB-like or SCF-like configuration. Atoms-in-molecules (AIM) topological analyses of the overall electron densities, and considerations of local energetics in the differential neighbourhood of the equilibrium geometries, have been used to provide independent assessments of the nature of bonding in these molecules. Orbital structure and AIM results together suggest the existence of three-centre two-electron M-H-M' bonds through hydrogen in all three molecules. Orbital pictures suggest these bonds are at least partially covalent, while a strict interpretation of values of the electron density Laplacian at AIM bond critical points would imply closed-shell interactions. Also for all three molecules, the orbital structures of the two main configurations suggest the presence of a one-electron two-centre bond between Li and the alkaline-earth atom. This bond may provide at least a partial explanation for the relative shortness of the inter-metallic distances, but is apparently too spread out to show up in AIM analyses of the total electron density. Considerations of local energetics support the more nuanced description of bonding that emerges, for these three molecules, from their orbital structure. PMID- 22260578 TI - Nuclear motion captured by the slow electron velocity imaging technique in the tunnelling predissociation of the S1 methylamine. AB - Predissociation dynamics of methylamines (CH(3)NH(2) and CH(3)ND(2)) on the first electronically excited states are studied using the slow-electron velocity imaging method to unravel the multi-dimensional nature of the N-H(D) chemical bond dissociation reaction which occurs via tunnelling. The nearly free internal rotation around the C-N bond axis is found to be strongly coupled to the reaction pathway, revealing nuclear motions actively involved in the tunnelling process on the S(1) potential energy surfaces. The vibrational state-resolved energy and angular distributions of photoelectron, ejected from the ionization mediated by the metastable intermediate S(1) state provide a unique way for mapping the predissociative potential energy surfaces. PMID- 22260579 TI - Competitive partitioning of rotational energy in gas ensemble equilibration. AB - A wide-ranging computational study of equilibration in binary mixtures of diatomic gases reveals the existence of competition between the constituent species for the orbital angular momentum and energy available on collision with the bath gas. The ensembles consist of a bath gas AB(v;j), and a highly excited minor component CD(v';j'), present in the ratio AB:CD = 10:1. Each ensemble contains 8000 molecules. Rotational temperatures (T(r)) are found to differ widely at equilibration with T(r)(AB)/T(r)(CD) varying from 2.74 to 0.92, indicating unequal partitioning of rotational energy and angular momentum between the two species. Unusually, low values of T(r) are found generally to be associated with diatomics of low reduced mass. To test effects of the equi partition theorem on low T(r) we undertook calculations on HF(6;4) in N(2)(0;10) over the range 100-2000 K. No significant change in T(r)(N2)/T(r)(HF) was found. Two potential sources of rotational inequality are examined in detail. The first is possible asymmetry of -Deltaj and +Deltaj probabilities for molecules in mid- to high j states resulting from the quadratic dependence of rotational energy on j. The second is the efficiency of conversion of orbital angular momentum, generated on collision with bath gas molecules, into molecular rotation. Comparison of these two possible effects with computed T(r)(AB)/T(r)(CD) shows the efficiency factor to be an excellent predictor of partitioning between the two species. Our finding that T(r) values for molecules such as HF and OH are considerably lower than other modal temperatures suggests that the determination of gas ensemble temperatures from Boltzmann fits to rotational distributions of diatomics of low reduced mass may require a degree of caution. PMID- 22260580 TI - Comparison of two-body and three-body decomposition of ethanedial, propanal, propenal, n-butane, 1-butene, and 1,3-butadiene. AB - We investigated two-body (binary) and three-body (triple) dissociations of ethanedial, propanal, propenal, n-butane, 1-butene, and 1,3-butadiene on the ground potential-energy surfaces using quantum-chemical and Rice-Ramsperger Kassel-Marcus calculations; most attention is paid on the triple dissociation mechanisms. The triple dissociation includes elimination of a hydrogen molecule from a combination of two separate terminal hydrogen atoms; meanwhile, the rest part simultaneously decomposes to two stable fragments, e.g., C(2)H(4), C(2)H(2), or CO. Transition structures corresponding to the concerted triple dissociation were identified using the B3LYP/6-311G(d,p) level of theory and total energies were computed using the method CCSD(T)/6-311+G(3df, 2p). The forward barrier height of triple dissociation has a trend of ethanedial < propanal < propenal < n butane < 1-butene < 1,3-butadiene, pertaining to the reaction enthalpy. Ratios of translational energies of three separate fragments could be estimated from the transition structure of triple dissociation. The synchronous concerted dissociation of propanal, propenal, and 1-butene leading to three different types of molecular fragments by breaking nonequivalent chemical bonds is rare. The triple dissociation of propanal, n-butane, 1-butene, and 1,3-butadiene were investigated for the first time. To outline a whole picture of dissociation mechanisms, some significant two-body dissociation channels were investigated for the calculations of product branching ratios. The triple dissociation plays an important role in the three carbonyl compounds, but plays a minor or negligible role in the three hydrocarbons. PMID- 22260581 TI - Spectroscopic observation of jet-cooled 2-fluoro-m-xylyl radical. AB - The jet-cooled 2-fluoro-m-xylyl radical was generated and vibronically excited in a corona excited supersonic expansion from precursor 2-fluoro-m-xylene seeded in a large amount of carrier gas helium. The well-resolved visible vibronic emission spectrum of the jet-cooled 2-fluoro-m-xylyl radical was recorded using a long path monochromator. From the analysis of the spectrum, we determine an accurate electronic energy of the D(1) -> D(0) transition and the frequencies of vibrational modes in the ground electronic state by comparison with those of ab initio calculations and the known spectroscopic data of 2-fluoro-m-xylene for the first time. PMID- 22260582 TI - Rotationally resolved infrared spectroscopy of adamantane. AB - We present the first rotationally resolved spectra of adamantane (C(10)H(16)) applying gas-phase Fourier transform infrared (IR) absorption spectroscopy. High resolution IR spectra are recorded in the 33-4500 cm(-1)range using as source of IR radiation both synchrotron radiation (at the AILES beamline of the SOLEIL synchrotron) as well as a classical globar. Adamantane is a spherical top molecule with tetrahedral symmetry (T(d) point group) and has no permanent dipole moment in its vibronic ground state. Of the 72 fundamental vibrational modes in adamantane, only 11 are IR active. Here we present rotationally resolved spectra for seven of them: nu(30), nu(28), nu(27), nu(26), nu(25), nu(24), and nu(23). The typical rotational structure of spherical tops is observed and analyzed using the STDS software developed in the Dijon group, which provides the first accurate energy levels and rotational constants for seven fundamental modes. Rotational levels with quantum numbers as high as J = 107 have been identified and included in the fit leading to a typical standard deviation of about 10(-3) cm(-1). PMID- 22260583 TI - Dissociation and ionization competing processes for H2+ in intense laser field: which one is larger? AB - Competition between dissociation and ionization of H(2)(+) in intense laser field has been investigated by using an accurate three-dimensional time-dependent wavepacket approach. The disagreement between the experiment and the former one dimensional theory has been resolved. In a comparison of the calculated results with the available experimental data, a good agreement is reached, not only for the relative probabilities between dissociation and ionization but also for the two-peak structures and the peak energy locations for these two processes. PMID- 22260584 TI - Influence of the cluster dimensionality on the binding behavior of CO and O2 on Au13. AB - We present an ab initio density functional theory study of the binding behavior of CO and O(2) molecules to two- and three-dimensional isomers of Au(13) in order to investigate the potential catalytic activity of this cluster towards low temperature CO oxidation. First, we scanned the potential energy surface of Au(13) and studied the effect of spin-orbit coupling on the relative stabilities of the 21 isomers we identified. While spin-orbit coupling increases the stability of the three-dimensional more than the two-dimensional isomers, the ground state structure at 0 K remains planar. Second, we systematically studied the binding of CO and O(2) molecules onto the planar and three-dimensional structures lowest in energy. We find that the isomer dimensionality has little effect on the binding of CO to Au(13). O(2), on the other hand, binds significantly to the three-dimensional isomer only. The simultaneous binding of multiple CO molecules decreases the binding energy per molecule. Still, the CO binding remains stronger than the O(2) binding. We did not find a synergetic effect due to the co-adsorption of both molecular species. On the three dimensional isomer, we find O(2) dissociation to be exothermic with an dissociation barrier of 1.44 eV. PMID- 22260585 TI - Vibrational dynamics of pyrrole via frequency-domain spectroscopy. AB - The N-H stretch overtones of pyrrole, a key constituent of biologic building blocks, were studied by room temperature photoacoustic and jet-cooled action spectroscopies to unravel their intramolecular dynamics. Contrary to "isolated" states excited with two and three N-H stretch quanta, the one with four quanta shows strong accidental resonances with two other states involving three quanta of N-H stretch and one quantum of C-H stretch. The inhomogeneously reduced features in the action spectra provide the means for getting insight into the intramolecular interactions and the factors controlling energy flow within pyrrole. The time dependence of the survival probability of the 4nu(1) N-H stretch, deduced from the vibrational Hamiltonian, shows an initial decay in ~0.3 ps with ensuing quantum beats from the N-H-C-H resonance and their decay with a time constant of about 5 ps as a result of weaker coupling to bath states. PMID- 22260586 TI - Adsorption of small molecules on silver clusters. AB - We report investigations of adsorption of N(2) and O(2) molecules on silver cluster cations. We have first revisited structures of small silver clusters based on first-principles calculations within the framework of density functional theory with hybrid functional. The 2D to 3D transition for the neutral clusters occurs from n = 6 to 7 and for cations, in agreement with experiments, from n = 4 to 5. With the refined structures, adsorption energies of N(2) and O(2) molecules have been calculated. We have identified characteristic drops in the adsorption energies of N(2) that further link our calculations and experiments, and confirm the reported 2D-3D transition for cations. We have found that perturbations caused by physisorbed molecules are small enough that the structures of most Ag clusters remain unchanged, even though physisorption stabilizes the 3D Ag(7)(+) structure slightly more than the 2D counterpart. Results for pure O(2) adsorption indicate that charge transfer from Ag(n)(+) to O(2) occurs when n > 3. Below that size oxygen essentially physisorbes such as nitrogen to the cluster. We interpret the experimentally observed mutually cooperative co-adsorption of oxygen and nitrogen using results from density functional theory with generalized gradient approximations. The key to the enhancement is N(2)-induced increase in charge transfer from Ag(n)(+) cations to O(2). PMID- 22260587 TI - Full configuration interaction calculations of the second hyperpolarizabilities of the H4 model compound: summation-over-states analysis and interplay with diradical characters. AB - The second hyperpolarizability (gamma) of the one-dimensional H(4) model compound has been calculated at the full configuration interaction level to describe its relationships with the diradical characters y(i) [the occupation numbers of the lowest unoccupied natural orbital (LUNO) + i] and the geometry. It is found that the system with intermediate y(0) ( = 0.527) and small y(1) ( = 0.178) exhibits the largest gamma value [enhanced by a factor of 9 compared to that of a nearly closed-shell H(4) analog (y(0) = 0.099, y(1) = 0.029)], where both the outer H-H distances are slightly larger than the inner one. These results provide a molecular design guideline for enhancing and controlling the third-order nonlinear optical properties of singlet multiradical linear molecular systems such as multiradical organic aggregates, supermolecular systems, and extended metal atom chains. PMID- 22260588 TI - Electronic structure of the [MgO3]+ cation. AB - Accurate ab initio calculations are performed to investigate the stable isomers of [MgO(3)](+) and its lowest electronic states at both molecular and asymptotic regions. The calculations are done using large basis sets and configuration interaction methods including the complete active space self-consistent field, the internally contracted multi-reference configuration interaction, the standard coupled cluster (RCCSD(T)) approaches and the newly implemented explicitly correlated coupled cluster method (RCCSD(T)-F12). The presence of three stable forms is predicted: a cyclic global minimum c-MgO(3)(+), which is followed by a quasi-linear isomer, l2-MgO(3)(+). A third isomer of C(s) symmetry (l1-MgO(3)(+)) is also found. Moreover, we computed the one-dimensional cuts of the six dimensional potential energy surfaces of the lowest doublet and quartet electronic states of [MgO(3)](+) along the R(MgO) and R(OO) stretching coordinates covering both the molecular and the asymptotic regions. These curves are used later for discussing the metastability of this cation and to propose plausible mechanisms for the Mg(+) + O(3) atmospherically important ion-molecule reaction and related reactive channels. PMID- 22260589 TI - (PbS)32: a baby crystal. AB - Theoretical calculations based on density functional theory have found (PbS)(32) to be the smallest cubic cluster for which its inner (PbS)(4) core enjoys bulk like coordination. Cubic (PbS)(32) is thus a "baby crystal," i.e., the smallest cluster, exhibiting sixfold coordination, that can be replicated to obtain the bulk crystal. The calculated dimensions of the (PbS)(32) cluster further provide a rubric for understanding the pattern of aggregation when (PbS)(32) clusters are deposited on a suitable surface, i.e., the formation of square and rectangular, crystalline nano-blocks with predictable dimensions. Experiments in which mass selected (PbS)(32) clusters were soft-landed onto a highly ordered pyrolytic graphite surface and the resulting aggregates imaged by scanning tunneling microscopy provide evidence in direct support of the computational results. PMID- 22260590 TI - Transport coefficients and cross sections for electrons in water vapour: comparison of cross section sets using an improved Boltzmann equation solution. AB - This paper revisits the issues surrounding computation of electron transport properties in water vapour as a function of E/n(0) (the ratio of the applied electric field to the water vapour number density) up to 1200 Td. We solve the Boltzmann equation using an improved version of the code of Ness and Robson [Phys. Rev. A 38, 1446 (1988)], facilitating the calculation of transport coefficients to a considerably higher degree of accuracy. This allows a correspondingly more discriminating test of the various electron-water vapour cross section sets proposed by a number of authors, which has become an important issue as such sets are now being applied to study electron driven processes in atmospheric phenomena [P. Thorn, L. Campbell, and M. Brunger, PMC Physics B 2, 1 (2009)] and in modeling charged particle tracks in matter [A. Munoz, F. Blanco, G. Garcia, P. A. Thorn, M. J. Brunger, J. P. Sullivan, and S. J. Buckman, Int. J. Mass Spectrom. 277, 175 (2008)]. PMID- 22260591 TI - Resonant inelastic x-ray scattering of methyl chloride at the chlorine K edge. AB - We present a combined experimental and theoretical study of isolated CH(3)Cl molecules using resonant inelastic x-ray scattering (RIXS). The high-resolution spectra allow extraction of information about nuclear dynamics in the core excited molecule. Polarization-resolved RIXS spectra exhibit linear dichroism in the spin-orbit intensities, a result interpreted as due to chemical environment and singlet-triplet exchange in the molecular core levels. From analysis of the polarization-resolved data, Cl 2p(x, y) and 2p(z) electronic populations can be determined. PMID- 22260592 TI - Quantum dynamics of proton migration in H2O dications: H2+ formation on ultrafast timescales. AB - Irradiation of isolated water molecules by few-cycle pulses of intense infrared laser light can give rise to ultrafast rearrangement resulting in formation of the H(2) (+) ion. Such unimolecular reactions occur on the potential energy surface of the H(2)O(2+) dication that is accessed when peak laser intensities in the 10(15) W cm(-2) range and pulse durations as short as 9-10 fs are used; ion yields of ~1.5% relative to the H(2)O(+) ion are measured. We also study such reactions by means of time-dependent wavepacket dynamics on an ab initio potential energy surface of the dication and show that a proton, generated from O H bond rupture, migrates towards the H-atom, and forms vibrationally excited H(2)(+) in a well-defined spatial zone. PMID- 22260593 TI - A comparison of the decomposition of electronically excited nitro-containing molecules with energetic moieties C-NO2, N-NO2, and O-NO2. AB - Decomposition of electronically excited nitro-containing molecules with different X-NO(2) (X = C, N, O) moieties has been intensively investigated over the past decades; however, their decomposition behavior has not previously been compared and contrasted. Comparison of their unimolecular decomposition behavior is important for the understanding of the reactivity differences among electronically excited nitro-containing molecules with different X-NO(2) (X = C, N, O) bond connections. Nitromethane (NM), dimethylnitramine (DMNA), and isopropylnitrate (IPN) are used as model molecules for C-NO(2), N-NO(2), and O NO(2) active moieties, respectively. Ultraviolet lasers at different wavelengths, such as 226, 236, and 193 nm, have been employed to prepare the excited states of these molecules. The decomposition products are then detected by resonance enhanced two photon ionization (R2PI), laser induced fluorescence (LIF) techniques, or single photon ionization at 10.5 eV. NO molecules are observed to be the major decomposition product from electronically excited NM, DMNA, IPN using R2PI techniques. The NO products from decomposition of electronically excited (226 and 236 nm) NM and IPN display similar rotational (600 K) and vibrational distributions [both (0-0) and (0-1) bands of the NO molecule are observed]. The NO product from DMNA shows rotational (120 K) and vibrational distributions (only (0-0) transition is observed) colder than those of NM and IPN. At the 193 nm excitation, electronically excited NO(2) products are observed from NM and IPN via fluorescence detection, while no electronically excited NO(2) products are observed from DMNA. Additionally, the OH radical is observed as a minor dissociation product from all three compounds. The major decomposition pathway of electronically excited NM and IPN involves fission of the X-NO(2) bond to form electronically excited NO(2) product, which further dissociates to generate NO. The production of NO molecules from electronically excited DMNA is proposed to go through a nitro-nitrite isomerization pathway. Theoretical calculations show that a nitro-nitrite isomerization for DMNA occurs on the S(1) surface following a (S(2)/S(1))(CI) conical intersection (CI), whereas NO(2) elimination occurs on the S(1) surface following the (S(2)/S(1))(CI) conical intersection for NM and IPN. The present work provides insights for the understanding of the initiation of the decomposition of electronically excited X NO(2) energetic systems. The presence of conical intersections along the reaction coordinate plays an important role in the detailed mechanism for the decomposition of these energetic systems. PMID- 22260594 TI - Theoretical study of photodetachment processes of anionic boron clusters. I. Structure. AB - Photo-induced electron detachment spectroscopy of anionic boron clusters, B(4)(-) and B(5)(-), is theoretically investigated by performing electronic structure calculations and nuclear dynamics simulations. While the electronic potential energy surfaces (X(1)A(g), a(3)B(2u), b(3)B(1u), A(1)B(2u), c(3)B(2g), and B(1)B(2g) of neutral B(4) and X(2)B(2), A(2)A(1), B(2)B(2), C(2)A(1), D(2)B(1), and E(2)A(1) of neutral B(5)) and their coupling surfaces are constructed in this paper, the details of the nuclear dynamics on these electronic states are presented in Paper II. Electronic structure calculations are carried out at the complete active space self-consistent field-multi-reference configuration interaction level of theory employing the correlation consistent polarized valance triple zeta basis set. Using the calculated electronic structure data suitable vibronic Hamiltonians are constructed utilizing a diabatic electronic basis and displacement coordinates of the normal vibrational modes. The theoretical results are discussed in relation to those recorded in recent experiments. PMID- 22260595 TI - Theoretical study of photodetachment processes of anionic boron clusters. II. Dynamics. AB - Photodetachment bands of anionic boron clusters, B(n) (n = 4,5) are theoretically examined here. The model Hamiltonians developed through extensive ab initio quantum chemistry calculations in Paper I are employed for the required nuclear dynamics study. While the precise location of vibronic lines and progression of vibrational modes within a given electronic band is derived from time-independent quantum mechanical studies, the broadband spectral envelopes and the nonradiative decay rate of electronic states are calculated by propagating wave packets in a time-dependent quantum mechanical framework. The theoretical results are in good accord with the experiment to a large extent. The discrepancies between the two can be partly attributed to the inadequate energy resolution of the experimental results and also to the neglect of dynamic spin-orbit interactions and computational difficulty related with detachment channels involving multi electron transitions in the theoretical formalism. PMID- 22260596 TI - Low-energy electron scattering with the purine bases of DNA/RNA using the R matrix method. AB - R-matrix calculations on electron collisions with the purine bases found in DNA and RNA (i.e., adenine and guanine) are presented. Resonant anion states of these systems are identified by employing different approximation levels of ab initio theoretical methods, such as the static exchange, the static exchange plus polarization, and the close-coupling methods. The results are compared with other available calculations and experiments. All of these ab initio approximations, which we refer to as a scattering "model," give four shape resonances of (2)A'' (pi) symmetry within the energy range of 10 eV for both molecules. For adenine, the most sophisticated method, the close-coupling model, gives two very narrow (2)A' (sigma) symmetry Feshbach-type resonances at energies above 5 eV. Quantitative results for the total elastic and electronic excitation cross sections are also presented. PMID- 22260597 TI - Molecular dynamics simulation study of the water-mediated interaction between zwitterionic and charged surfaces. AB - We calculated the potential of mean force (PMF) for the interaction between a model zwitterionic bilayer and a model charged bilayer. To understand the role of water, we separated the PMF into two components: one due to direct interaction and the other due to water-mediated interaction. In our calculations, we observed that water-mediated interaction is attractive at larger distances and repulsive at shorter. The calculation of the entropic and enthalpic contributions to the solvent-mediated components of the PMF showed that attraction is entropically dominant, while repulsion is dominated by the enthalpy. PMID- 22260598 TI - Phase separation dynamics in a two-dimensional magnetic mixture. AB - Based on classical density functional theory (DFT), we investigate the demixing phase transition of a two-dimensional, binary Heisenberg fluid mixture. The particles in the mixture are modeled as Gaussian soft spheres, where one component is characterized by an additional classical spin-spin interaction of Heisenberg type. Within the DFT we treat the particle interactions using a mean field approximation. For certain magnetic coupling strengths, we calculate phase diagrams in the density-concentration plane. For sufficiently large coupling strengths and densities, we find a demixing phase transition driven by the ferromagnetic interactions of the magnetic species. We also provide a microscopic description (i.e., density profiles) of the resulting non-magnetic/magnetic fluid fluid interface. Finally, we investigate the phase separation using dynamical density functional theory, considering both nucleation processes and spinodal demixing. PMID- 22260599 TI - High-pressure study of tetramethylsilane by Raman spectroscopy. AB - High-pressure behavior of tetramethylsilane, one of the Group IVa hydrides, was investigated by Raman scattering measurements at pressures up to 142 GPa and room temperature. Our results revealed the phase transitions at 0.6, 9, and 16 GPa from both the mode frequency shifts with pressure and the changes of the full width half maxima of these modes. These transitions were suggested to result from the changes in the inter- and intra-molecular bonding of this material. We also observed two other possible phase transitions at 49-69 GPa and 96 GPa. No indication of metallization in tetramethylsilane was found with stepwise compression to 142 GPa. PMID- 22260600 TI - Spherical momentum distribution of the protons in hexagonal ice from modeling of inelastic neutron scattering data. AB - The spherical momentum distribution of the protons in ice is extracted from a high resolution deep inelastic neutron scattering experiment. Following a recent path integral Car-Parrinello molecular dynamics study, data were successfully interpreted in terms of an anisotropic Gaussian model, with a statistical accuracy comparable to that of the model independent scheme used previously, but providing more detailed information on the three dimensional potential energy surface experienced by the proton. A recently proposed theoretical concept is also employed to directly calculate the mean force from the experimental neutron Compton profile, and to evaluate the accuracy required to unambiguously resolve and extract the effective proton potential from the experimental data. PMID- 22260601 TI - Infrared spectra and ultraviolet-tunable laser induced photochemistry of matrix isolated phenol and phenol-d5. AB - Monomers of phenol and its ring-perdeuterated isotopologue phenol-d(5) were isolated in argon matrices at 15 K. The infrared (IR) spectra of these species were recorded and analyzed. In situ photochemical transformations of phenol and phenol-d(5) were induced by tunable UV laser light. The photoproducts have been characterized by IR spectroscopy supported by theoretical calculations of the infrared spectra. The primary product photogenerated from phenol was shown to be the phenoxyl radical. The analysis of the progress of the observed phototransformations led to identification of 2,5-cyclohexadienone as one of the secondary photoproducts. Spectral indications of other secondary products, such as the Dewar isomer and the open-ring ketene, were also detected. Identification of the photoproducts provided a guide for the interpretation of the mechanisms of the observed photoreactions. PMID- 22260602 TI - Reference molecules for nonlinear optics: a joint experimental and theoretical investigation. AB - Hyper-Rayleigh scattering (HRS) experiments and quantum chemical calculations are combined to investigate the second-order nonlinear optical responses of a series of reference molecules, namely, carbon tetrachloride, chloroform, trichloroacetonitrile, acetonitrile, and dichloromethane. The multipolar decomposition of the first hyperpolarizability tensor through the use of the spherical harmonics formalism is employed to highlight the impact of the symmetry of the molecular scatterers on their nonlinear optical responses. It is demonstrated that HRS is a technique of choice to probe the molecular symmetry of the compounds. Coupled-cluster calculations performed at the coupled-cluster level with singles, doubles, and perturbative triples in combination with highly extended basis sets and including environment effects by using the polarizable continuum model qualitatively reproduce the molecular first hyperpolarizabilities and depolarization ratios of the molecular scatterers. PMID- 22260603 TI - Freezing lines of colloidal Yukawa spheres. I. A Rogers-Young integral equation study. AB - Using the Rogers-Young (RY) integral equation scheme for the static structure factor combined with the one-phase Hansen-Verlet (HV) freezing rule, we study the equilibrium structure and two-parameter freezing lines of colloidal particles with Yukawa-type pair interactions representing charge-stabilized silica spheres suspended in dimethylformamide (DMF). Results are presented for a vast range of concentrations, salinities and effective charges covering particles with masked excluded-volume interactions. The freezing lines were obtained for the low-charge and high-charge solutions of the static structure factor, for various two parameter sets of experimentally accessible system parameters. All RY-HV based freezing lines can be mapped on a universal fluid-solid coexistence line in good agreement with computer simulation predictions. The RY-HV calculations extend the freezing lines obtained in earlier simulations to a broader parameter range. The experimentally observed fluid-bcc-fluid reentrant transition of charged silica spheres in DMF can be explained using the freezing lines obtained in this work. PMID- 22260604 TI - Molecular orientation and lattice ordering of C60 molecules on the polar FeO/Pt(111) surface. AB - C(60) molecules assemble into close packing layer under the domination of the intermolecular interaction when deposited onto Pt(111)-supported FeO layer kept at 400 K. From corresponding high resolution scanning tunneling microscopy (STM) image, a kind of C(60) molecular orientational ordering stabilized by the intermolecular interaction is revealed as C(60)/FeO(111)-(?133 * ?133) R17.5 degrees structure and determined from the commensurability between the C(60) nearest-neighbor distance and the lattice of the underlying oxygen layer. Moreover, due to the inhomogeneously distributed work function of the underlying FeO layer, the C(60) molecular electronic state is periodically modulated resulting in a bright-dim STM contrast. In addition, one coincidence lattice ordering is determined as 8 * 8 superstructure with respect to the C(60) primitive cell, which overlays a 3 * 3 moire cell of the underlying FeO layer. PMID- 22260605 TI - Water monomer interaction with gold nanoclusters from van der Waals density functional theory. AB - We investigate the interaction between water molecules and gold nanoclusters Au(n) through a systematic density functional theory study within both the generalized gradient approximation and the nonlocal van der Waals (vdW) density functional theory. Both planar (n = 6-12) and three-dimensional (3D) clusters (n = 17-20) are studied. We find that applying vdW density functional theory leads to an increase in the Au-Au bond length and a decrease in the cohesive energy for all clusters studied. We classify water adsorption on nanoclusters according to the corner, edge, and surface adsorption geometries. In both corner and edge adsorptions, water molecule approaches the cluster through the O atom. For planar clusters, surface adsorption occurs in a O-up/H-down geometry with water plane oriented nearly perpendicular to the cluster. For 3D clusters, water instead favors a near-flat surface adsorption geometry with the water O atom sitting nearly atop a surface Au atom, in agreement with previous study on bulk surfaces. Including vdW interaction increases the adsorption energy for the weak surface adsorption but reduces the adsorption energy for the strong corner adsorption due to increased water-cluster bond length. By analyzing the adsorption induced charge rearrangement through Bader's charge partitioning and electron density difference and the orbital interaction through the projected density of states, we conclude that the bonding between water and gold nanocluster is determined by an interplay between electrostatic interaction and covalent interaction involving both the water lone-pair and in-plane orbitals and the gold 5d and 6s orbitals. Including vdW interaction does not change qualitatively the physical picture but does change quantitatively the adsorption structure due to the fluxionality of gold nanoclusters. PMID- 22260606 TI - Quantitative evaluation of blinking in surface enhanced resonance Raman scattering and fluorescence by electromagnetic mechanism. AB - We analyze blinking in surface enhanced resonance Raman scattering (SERRS) and surface enhanced fluorescence (SEF) of rhodamine 6G molecules as intensity and spectral instability by electromagnetic (EM) mechanism. We find that irradiation of intense NIR laser pulses induces blinking in SERRS and SEF. Thanks to the finding, we systematically analyze SERRS and SEF from stable to unstable using single Ag nanoparticle (NP) dimers. The analysis reveals two physical insights into blinking as follows. (1) The intensity instability is inversely proportional to the enhancement factors of decay rate of molecules. The estimation using the proportionality suggests that separation of the molecules from Ag NP surfaces is several angstroms. (2) The spectral instability is induced by blueshifts in EM enhancement factors, which have spectral shapes similar to the plasmon resonance. This analysis provides us with a quantitative picture for intensity and spectral instability in SERRS and SEF within the framework of EM mechanism. PMID- 22260607 TI - Different growth regimes on prepatterned surfaces: consistent evidence from simulations and experiments. AB - Molecule deposition on a prepatterned substrate is a recently developed technique to generate desired structures of organic molecules on surfaces via self organization. For the case of prepatterned stripes, the time-resolved process of structure formation is studied via lattice Monte Carlo simulations. By systematic variation of the interaction strength, three distinct growth regimes can be identified: localized growth, bulge formation, and cluster formation. All three growth regimes can be recovered in the experiment when choosing appropriate organic molecules. Some key microscopic observables, reflecting the properties of the structure formation, display a non-monotonous dependence on the interaction strength. PMID- 22260608 TI - Slip length of water on graphene: limitations of non-equilibrium molecular dynamics simulations. AB - Data for the flow rate of water in carbon nanopores is widely scattered, both in experiments and simulations. In this work, we aim at precisely quantifying the characteristic large slip length and flow rate of water flowing in a planar graphene nanochannel. First, we quantify the slip length using the intrinsic interfacial friction coefficient between water and graphene, which is found from equilibrium molecular dynamics (EMD) simulations. We then calculate the flow rate and the slip length from the streaming velocity profiles obtained using non equilibrium molecular dynamics (NEMD) simulations and compare with the predictions from the EMD simulations. The slip length calculated from NEMD simulations is found to be extremely sensitive to the curvature of the velocity profile and it possesses large statistical errors. We therefore pose the question: Can a micrometer range slip length be reliably determined using velocity profiles obtained from NEMD simulations? Our answer is "not practical, if not impossible" based on the analysis given as the results. In the case of high slip systems such as water in carbon nanochannels, the EMD method results are more reliable, accurate, and computationally more efficient compared to the direct NEMD method for predicting the nanofluidic flow rate and hydrodynamic boundary condition. PMID- 22260609 TI - A theoretical investigation on photocatalytic oxidation on the TiO2 surface. AB - The TiO(2) photocatalytic oxidation mechanism was theoretically investigated by using long-range corrected time-dependent density functional theory (LC-TDDFT) with a cluster model of the anatase TiO(2)(001) surface. We found that LC-TDDFT with the cluster model quantitatively reproduces the photoexcitations of the TiO(2) surface by calculating the electronic spectra of a clean TiO(2) surface and one with oxygen defects. We calculated the electronic spectra of a molecularly adsorbed TiO(2) surface for the adsorptions of phenol, methanol, and methane molecules as typical organic molecules. We obtained the surprising result that the main peak of the phenol-adsorbed TiO(2) surface, which overlaps with the main peak of the clean TiO(2) surface, corresponds to charge transfers from the phenol molecule to the TiO(2) surface. This indicates that the TiO(2) photocatalytic oxidation proceeds through direct charge transfer excitation from the substrate molecules to the TiO(2) surface. In contrast, we found slight and no charge transfer for methanol and methane adsorption, respectively, in agreement with the experimental findings for their reactivities. In light of these results, we propose a new mechanism for heterogeneous TiO(2) photocatalytic oxidations. PMID- 22260610 TI - Stretching semiflexible polymer chains: evidence for the importance of excluded volume effects from Monte Carlo simulation. AB - Semiflexible macromolecules in dilute solution under very good solvent conditions are modeled by self-avoiding walks on the simple cubic lattice (d = 3 dimensions) and square lattice (d = 2 dimensions), varying chain stiffness by an energy penalty epsilon(b) for chain bending. In the absence of excluded volume interactions, the persistence length l(p) of the polymers would then simply be l(p) = l(b)(2d - 2)(-1)q(b) (-1) with q(b) = exp(-epsilon(b)/k(B)T), the bond length l(b) being the lattice spacing, and k(B)T is the thermal energy. Using Monte Carlo simulations applying the pruned-enriched Rosenbluth method (PERM), both q(b) and the chain length N are varied over a wide range (0.005 <= q(b) <= 1, N <= 50,000), and also a stretching force f is applied to one chain end (fixing the other end at the origin). In the absence of this force, in d = 2 a single crossover from rod-like behavior (for contour lengths less than l(p)) to swollen coils occurs, invalidating the Kratky-Porod model, while in d = 3 a double crossover occurs, from rods to Gaussian coils (as implied by the Kratky Porod model) and then to coils that are swollen due to the excluded volume interaction. If the stretching force is applied, excluded volume interactions matter for the force versus extension relation irrespective of chain stiffness in d = 2, while theories based on the Kratky-Porod model are found to work in d = 3 for stiff chains in an intermediate regime of chain extensions. While for q(b) ? 1 in this model a persistence length can be estimated from the initial decay of bond-orientational correlations, it is argued that this is not possible for more complex wormlike chains (e.g., bottle-brush polymers). Consequences for the proper interpretation of experiments are briefly discussed. PMID- 22260611 TI - Weak-to-strong confinement transition of semi-flexible macromolecules in slit and in channel. AB - We compare confinement of stiff macromolecule in channel and in slit. Whereas in the channel a distinct and established transition exists, we elucidate here an ongoing controversy reported from previous experiment and simulation on existence of such transition in the slit. Our extensive molecular simulations in both geometries show only a very weak conformational crossover between moderate and strong confinements in slit in the same range of confinements where the distinct transition in channel is observed. In contrast to situation in channels relatively stable hairpin-like structures are not indicated around this weak transition in the slit. Observed difference from the prediction on behavior in blob regime under moderate confinement is explained by a crossover between dimensionalities in the slit and the extent of ideal conformation statistics to which the stiffer chains are prone. The strong confinement regime of stiff chain in slit characterized here has not been interpreted yet and it differs from the respective saturation-like Odijk regime in the channel. PMID- 22260612 TI - Investigation of the interfacial tension of complex coacervates using field theoretic simulations. AB - Complex coacervation, a liquid-liquid phase separation that occurs when two oppositely charged polyelectrolytes are mixed in a solution, has the potential to be exploited for many emerging applications including wet adhesives and drug delivery vehicles. The ultra-low interfacial tension of coacervate systems against water is critical for such applications, and it would be advantageous if molecular models could be used to characterize how various system properties (e.g., salt concentration) affect the interfacial tension. In this article we use field-theoretic simulations to characterize the interfacial tension between a complex coacervate and its supernatant. After demonstrating that our model is free of ultraviolet divergences (calculated properties converge as the collocation grid is refined), we develop two methods for calculating the interfacial tension from field-theoretic simulations. One method relies on the mechanical interpretation of the interfacial tension as the interfacial pressure, and the second method estimates the change in free energy as the area between the two phases is changed. These are the first calculations of the interfacial tension from full field-theoretic simulation of which we are aware, and both the magnitude and scaling behaviors of our calculated interfacial tension agree with recent experiments. PMID- 22260613 TI - A lattice model of the translational dynamics of nonrotating rigid rods. AB - We present a lattice model of oriented, nonrotating, rigid rods in three dimensions with random walk dynamics, computer simulation results for the model, and a theory for the translational diffusion constant of the rods in the perpendicular direction, D(?), in the semidilute regime. The theory is based on the "tube model" of Doi-Edwards (DE) theory for the rotational diffusion constant of rods that can both translate and rotate in continuous space. The theory predicts that D(?) is proportional to (nuL(3))(-2), where nu is the concentration of rods and L is the length of the rods, which is analogous to the Doi-Edwards scaling law for rotational diffusion. The simulations find that, as nuL(3) is increased, the approach to the limit of DE scaling is slow, and the -2 power in the DE scaling law is never quite achieved even at the highest concentration (nuL(3) = 200) simulated. We formulate a quantitative theory for the prefactor in the scaling relationship using only DE ideas, but it predicts a proportionality constant that is much too small. To explain this discrepancy, we modify the DE approach to obtain a more accurate estimate of the average tube radius and take into account effects of perpendicular motion of rods that are not included in the original DE theory. With these changes, the theory predicts values of D(?) that are in much better agreement with the simulations. We propose a new scaling relationship that fits the data very well. This relationship suggests that the DE scaling law is the correct description of the scaling for infinitely thin rods only in the limit of infinite concentration, and that corrections to the DE scaling law because of finite concentration are significant even at concentrations that are well inside the semidilute regime. The implications of these results for the DE theory of rotating rods are discussed. PMID- 22260614 TI - Exploring the dynamics of dimer crossing over a Kramers type potential. AB - We explore the escape rate of a dimer crossing a potential barrier using both analytical and numerical approaches. We find that for small coupling strength k, the barrier hopping can be well approximated by a two step reaction scheme where one monomer hops over the barrier and is then followed by the other. In this regime the escape rate increases with k showing that the cooperativity between monomers enhances the crossing rate. However, in the limit of large coupling strength, applying the method of adiabatic elimination, we find that the escape rate is a decreasing function of k. Thus, we find that the escape rate is a non monotonic function of the spring constant which is peaked at an optimal coupling strength. Furthermore, in the presence of a weak periodic signal, we show that the system response to the periodic signal is pronounced at a particular spring constant showing the dimer can be transported rapidly across the reaction coordinate in a half period. PMID- 22260615 TI - On binding of DNA-bending proteins to DNA minicircles. AB - We present a theoretical study of binding of DNA-bending proteins to circular DNA, using computer simulations of the wormlike chain model of DNA. We find that the binding affinity is affected by the bending elasticity and the conformational entropy of the polymer and that while protein adsorption is identical on open and closed long DNA molecules, there is significant enhancement of binding on DNA minicircles, compared to their linear counterparts. We also find that the ratio of the radii of gyration of open and closed chains depends on protein concentration for short DNA molecules. Experimental tests of our predictions are proposed. PMID- 22260616 TI - Amino acid analogues bind to carbon nanotube via pi-pi interactions: comparison of molecular mechanical and quantum mechanical calculations. AB - Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the pi-pi stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated pi-pi interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in pi-pi interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of pi-pi interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to pi-pi interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the pi-pi interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments. PMID- 22260617 TI - Note: Molecular dynamics studies of high-density amorphous ice: influence of long range Coulomb interactions. PMID- 22260619 TI - Diffuse p63 positivity in prostate cancer: a mimic of prostatic atrophy. PMID- 22260620 TI - Lycorine derivatives against Trichomonas vaginalis. AB - Six lycorine derivatives were prepared, characterized, and evaluated for their in vitro anti-Trichomonas vaginalis activity. Compounds bearing an acetyl (2), lauroyl (3), benzoyl (4 and 5), and p-nitrobenzoyl (6 and 7) groups were synthesized. The best activity was achieved with lycorine esterified at C-2 position with lauroyl group. Preliminary structure-activity relationship points that unprotected OH group at C-1 and C-2 is not necessary to the antiparasitic activity, and none of the derivative was less active than lycorine. The lycorine structural requisites required to kill this amitochondriate cell seem to be different in comparison with the derivatives most active against other parasites and tumor cell lines, both mitochondriated cells. This result is an important contribution with our ongoing studies regarding the mechanism of action of the Amaryllidaceae alkaloids on T. vaginalis cell death opening a new perspective to optimize this innovative pharmacological potential. PMID- 22260621 TI - Proteomic analysis of the ventral disc of Giardia lamblia. AB - BACKGROUND: Giardia lamblia is a multiflagellated protozoan that inhabits the small intestine of vertebrates, causing giardiasis. To colonize the small intestine, the trophozoites form of the parasite remains attached to intestinal epithelial cells by means of cytoskeletal elements that form a structure known as the ventral disc. Previous studies have shown that the ventral disc is made of tubulin and giardins. RESULTS: To obtain further information on the composition of the ventral disc, we developed a new protocol and evaluated the purity of the isolation by transmission electron microscopy. Using 1D- and 2D-PAGE and mass spectrometry, we identified proteins with functions associated with the disc. In addition to finding tubulin and giardin, proteins known to be associated with the ventral disc, we also identified proteins annotated in the Giardia genome, but whose function was previously unknown. CONCLUSIONS: The isolation of the ventral disc shown in this work, compared to previously published protocols, proved to be more efficient. Proteomic analysis showed the presence of several proteins whose further characterization may help in the elucidation of the mechanisms involved in the attachment of the protozoan to epithelial cells. PMID- 22260622 TI - Site selective generation of sol-gel deposits in layered bimetallic macroporous electrode architectures. AB - The elaboration of an original composite bimetallic macroporous electrode containing a site-selective sol-gel deposit is reported. Regular colloidal crystals, obtained by a modified Langmuir-Blodgett approach, are used as templates for the electrogeneration of the desired metals in the form of a well defined layered bimetallic porous electrode. This porous matrix shows a spatially modulated electroactivity which is subsequently used as a strategy for targeted electrogeneration of a sol-gel deposit, exclusively in one predefined part of the porous electrode. PMID- 22260623 TI - Visible light photoredox catalysis: generation and addition of N aryltetrahydroisoquinoline-derived alpha-amino radicals to Michael acceptors. AB - The photoredox-catalyzed coupling of N-aryltetrahydroisoquinoline and Michael acceptors was achieved using Ru(bpy)(3)Cl(2) or [Ir(ppy)(2)(dtb-bpy)]PF(6) in combination with irradiation at 455 nm generated by a blue LED, demonstrating the trapping of visible light generated alpha-amino radicals. While intermolecular reactions lead to products formed by a conjugate addition, in intramolecular variants further dehydrogenation occurs, leading directly to 5,6 dihydroindolo[2,1-a]tetrahydroisoquinolines, which are relevant as potential immunosuppressive agents. PMID- 22260624 TI - FOXP3+ regulatory T cells in children with helicobacter pylori infection. AB - Despite an intensive pro-inflammatory response, the immune system is unable to clear the organism in Helicobacter pylori gastritis. Regulatory T (Treg) cells, which suppress the immune response of antigen-specific T cells, have recently been demonstrated to play a key role in chronic inflammation by immunologic tolerance. The purpose of our study was to investigate the histopathology, FOXP3+CD4+CD25(high)Treg (FOXP3+Treg) cell expression, and immune responses in children with H. pylori infection. Twenty-four H. pylori -positive and 24 H. pylori -negative children who underwent esophagogastroduodenoscopy for dyspeptic symptoms were included. Histopathologic grading according to the updated Sydney classification and immunohistochemical stains for FOXP3, transforming growth factor-beta1 (TGF-beta1), and CD4 were performed. Histopathologic bacterial density score, gastritis activity score, and chronic inflammation score were higher in the H. pylori -positive group than in the negative group (P < 0.01). The number of FOXP3+Treg cells and CD4+T cells and the grade of TGF-beta1 expression were significantly increased in the H. pylori -positive group compared to the negative group (P < 0.01). The number of FOXP3+Treg cells correlated positively with the grade of TGF-beta1 expression regardless of H. pylori status (P < 0.05). The number of FOXP3+Treg cells and the grade of TGF-beta1 expression correlated positively with H. pylori density, gastritis activity score, and chronic inflammation score regardless of H. pylori status (P < 0.01). These findings indicate that FOXP3+Treg cells could play a role in persistent H. pylori infection. PMID- 22260626 TI - Electrochemistry and electrogenerated chemiluminescence of twisted anthracene functionalized bimesitylenes. AB - The electrochemistry, spectroscopy, and electrogenerated chemiluminescence (ECL) of a variety of 2- and 4-fold anthracene-functionalized tetraarylbimesityls, AB1 4, were investigated. AB1-4 compounds contain a bimesityl core with 2- and 4-fold anthracene functionalities, which generate a rigid D(2d)-symmetric structure. Cyclic voltammetry of AB1 and AB2 showed two reversible, closely spaced one electron transfers for both oxidation and reduction, and that of AB3 and AB4 showed four reversible, closely spaced one-electron transfers for oxidation and reduction in a benzene/acetonitrile solution. The multielectron transfer properties of all four compounds were confirmed by chronoamperometric experiments with an ultramicroelectrode and digital simulations. These serve as models to probe how interacting groups on a molecule affect the energies of successive electron transfers. AB1-4 compounds are highly fluorescent in nonaqueous solvents and display blue-green emission. They produce very strong ECL with emission at 480 nm, near that of the photoluminescence spectra that can be assigned to emission by direct formation of the singlet via the S-route. PMID- 22260627 TI - Treating chronically ill people with diabetes mellitus with limited life expectancy: implications for performance measurement. AB - OBJECTIVES: To develop an algorithm to identify individuals with limited life expectancy and examine the effect of limited life expectancy on glycemic control and treatment intensification in individuals with diabetes mellitus. DESIGN: Individuals with diabetes mellitus and coexisting congestive heart failure, chronic obstructive pulmonary disease, dementia, end-stage liver disease, and/or primary or metastatic cancer with limited life expectancy were identified. To validate the algorithm, 5-year mortality was assessed in individuals identified as having limited life expectancy. Rates of meeting performance measures for glycemic control between individuals with and without limited life expectancy were compared. In individuals with uncontrolled glycosylated hemoglobin (HbA(1c) ) levels, the effect of limited life expectancy on treatment intensification within 90 days was examined. SETTING: One hundred ten Department of Veterans Affairs facilities; October 2006 to September 2007. PARTICIPANTS: Eight hundred eighty-eight thousand six hundred twenty-eight individuals with diabetes mellitus. MEASUREMENTS: HbA(1c) ; treatment intensification within 90 days of index HbA(1c) reading. RESULTS: Twenty-nine thousand sixteen (3%) participants had limited life expectancy. Adjusting for age, 5-year mortality was five times as high in participants with limited life expectancy than in those without. Participants with limited life expectancy had poorer glycemic control than those without (glycemic control: 77.1% vs 78.1%; odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.81-0.86) and less-frequent treatment intensification (treatment intensification: 20.9% vs 28.6%; OR = 0.71, 95% CI = 0.67-0.76), even after controlling for patient-level characteristics. CONCLUSION: Participants with limited life expectancy were less likely than those without to have controlled HbA(1c) levels and to receive treatment intensification, suggesting that providers treat these individuals less aggressively. Quality measurement and performance-based reimbursement systems should acknowledge the different needs of this population. PMID- 22260628 TI - The nucleotide, inhibitor, and cation binding sites of P-type II ATPases. AB - P-type ATPases constitute a ubiquitous superfamily of cation transport enzymes, responsible for carrying out actions of paramount importance in biology such as ion transport and expulsion of toxic ions from cells. The harmonized toggling of gates in the extra- and intracellular domains explain the phenomenon of specific cation binding in selective physiological states. A quantitative understanding of the fundamental aspects of ion transport mechanism and regulation of P-type ATPases requires detailed knowledge of thermodynamical, structural, and functional properties. Computational studies have made significant contributions to our understanding of biological ion pumps. Various 3D structures of Ca(2+) ATPase between E1 and E2 transition states have given a impetus to the theorists to work on the Na(+) K(+) - and H(+) K(+) -ATPase to address important questions about their function. The current review delineates the importance of cation, nucleotide, and inhibitor binding domains, with a focus on the therapeutic potential and biological relevance of the three P-type II ATPases. This will give an insight into the ion selectivity and their conduction across the transmembrane helices of P-type II ATPases, which may pave the way to a range of fundamental questions about the mechanism and aid in the efforts of structure- and analog based drug design. PMID- 22260629 TI - The DARE study of relapse prevention in depression: design for a phase 1/2 translational randomised controlled trial involving mindfulness-based cognitive therapy and supported self monitoring. AB - BACKGROUND: Depression is a common condition that typically has a relapsing course. Effective interventions targeting relapse have the potential to dramatically reduce the point prevalence of the condition. Mindfulness-based cognitive therapy (MBCT) is a group-based intervention that has shown efficacy in reducing depressive relapse. While trials of MBCT to date have met the core requirements of phase 1 translational research, there is a need now to move to phase 2 translational research - the application of MBCT within real-world settings with a view to informing policy and clinical practice. The aim of this trial is to examine the clinical impact and health economics of MBCT under real world conditions and where efforts have been made to assess for and prevent resentful demoralization among the control group. Secondary aims of the project involve extending the phase 1 agenda to an examination of the effects of co morbidity and mechanisms of action. METHODS/DESIGN: This study is designed as a prospective, multi-site, single-blind, randomised controlled trial using a group comparison design between involving the intervention, MBCT, and a self-monitoring comparison condition, Depression Relapse Active Monitoring (DRAM). Follow-up is over 2 years. The design of the study indicates recruitment from primary and secondary care of 204 participants who have a history of 3 or more episodes of Major Depression but who are currently well. Measures assessing depressive relapse/recurrence, time to first clinical intervention, treatment expectancy and a range of secondary outcomes and process variables are included. A health economics evaluation will be undertaken to assess the incremental cost of MBCT. DISCUSSION: The results of this trial, including an examination of clinical, functional and health economic outcomes, will be used to assess the role that this treatment approach may have in recommendations for treatment of depression in Australia and elsewhere. If the findings are positive, we expect that this research will consolidate the evidence base to guide the decision to fund MBCT and to seek to promote its availability to those who have experienced at least 3 episodes of depression. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12607000166471. PMID- 22260630 TI - Regulation of human microsomal prostaglandin E synthase-1 by IL-1beta requires a distal enhancer element with a unique role for C/EBPbeta. AB - The studies of PGE2 (prostaglandin E2) biosynthesis have focused primarily on the role of cyclo-oxygenases. Efforts have shifted towards the specific PGE2 terminal synthases, particularly mPGES-1 (microsomal PGE synthase 1), which has emerged as the crucial inducible synthase with roles in pain, cancer and inflammation. mPGES 1 is induced by pro-inflammatory cytokines with studies focusing on the proximal promoter, mediated specifically through Egr-1 (early growth-response factor 1). Numerous studies demonstrate that the mPGES-1 promoter (PTGES) alone cannot account for the level of IL-1beta (interleukin 1beta) induction. We identified two DNase I-hypersensitive sites within the proximal promoter near the Egr-1 element and a novel distal site near -8.6 kb. Functional analysis of the distal site revealed two elements that co-operate with basal promoter expression and a stimulus-dependent enhancer. A specific binding site for C/EBPbeta (CCAAT/enhancer-binding protein beta) in the enhancer was directly responsible for inducible enhancer activity. ChIP (chromatin immunoprecipitation) analysis demonstrated constitutive Egr-1 binding to the promoter and induced RNA polymerase II and C/EBPbeta binding to the promoter and enhancer respectively. Knockout/knockdown studies established a functional role for C/EBPbeta in mPGES-1 gene regulation and the documented interaction between Egr-1 and C/EBPbeta highlights the proximal promoter co-operation with a novel distal enhancer element in regulating inducible mPGES-1 expression. PMID- 22260632 TI - Secondary cutaneous Epstein-Barr virus-associated diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma: a case report and review of literature. AB - Only a few cases of extranodal Epstein-Barr virus (EBV)-associated B-cell lymphomas arising from patients with angioimmunoblastic T-cell lymphoma (AITL) have been described. We report a case of AITL of which secondary cutaneous EBV associated diffuse large B-cell lymphoma (DLBCL) developed after the initial diagnosis of AITL. A 65-year-old Chinese male patient was diagnosed as AITL based on typical histological and immunohistochemical characteristics in biopsy of the enlarged right inguinal lymph nodes. The patient initially received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, prednisone), but his symptoms did not disappear. Nineteen months after initial diagnosis of AITL, the patient was hospitalized again because of multiple plaques and nodules on the skin. The skin biopsy was performed, but this time the tumor was composed of large, polymorphous population of lymphocytes with CD20 and CD79a positive on immunohistochemical staining. The tumor cells were strong positive for EBER by in situ hybridization. The findings of skin biopsy were compatible with EBV-associated DLBCL. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) was then administered, resulting in partial response of the disease with pancytopenia and suppression of cellular immunity. To our knowledge, this is the first case of cutaneous EBV-associated DLBCL originated from AITL in Chinese pepole. We suggest the patients with AITL should perform lymph node and skin biopsies regularly in the course of the disease to detect the progression of secondary lymphomas. PMID- 22260633 TI - Seasonal patterns of predation for gray wolves in the multi-prey system of Yellowstone National Park. AB - 1. For large predators living in seasonal environments, patterns of predation are likely to vary among seasons because of related changes in prey vulnerability. Variation in prey vulnerability underlies the influence of predators on prey populations and the response of predators to seasonal variation in rates of biomass acquisition. Despite its importance, seasonal variation in predation is poorly understood. 2. We assessed seasonal variation in prey composition and kill rate for wolves Canis lupus living on the Northern Range (NR) of Yellowstone National Park. Our assessment was based on data collected over 14 winters (1995 2009) and five spring-summers between 2004 and 2009. 3. The species composition of wolf-killed prey and the age and sex composition of wolf-killed elk Cervus elaphus (the primary prey for NR wolves) varied among seasons. 4. One's understanding of predation depends critically on the metric used to quantify kill rate. For example, kill rate was greatest in summer when quantified as the number of ungulates acquired per wolf per day, and least during summer when kill rate was quantified as the biomass acquired per wolf per day. This finding contradicts previous research that suggests that rates of biomass acquisition for large terrestrial carnivores tend not to vary among seasons. 5. Kill rates were not well correlated among seasons. For example, knowing that early-winter kill rate is higher than average (compared with other early winters) provides little basis for anticipating whether kill rates a few months later during late winter will be higher or lower than average (compared with other late winters). This observation indicates how observing, for example, higher-than-average kill rates throughout any particular season is an unreliable basis for inferring that the year-round average kill rate would be higher than average. 6. Our work shows how a large carnivore living in a seasonal environment displays marked seasonal variation in predation because of changes in prey vulnerability. Patterns of wolf predation were influenced by the nutritional condition of adult elk and the availability of smaller prey (i.e. elk calves, deer). We discuss how these patterns affect our overall understanding of predator and prey population dynamics. PMID- 22260635 TI - Ex vivo comparison of available morcellation devices during holmium laser enucleation of the prostate through objective parameters. AB - BACKGROUND and Purpose: Holmium laser enucleation of the prostate (HoLEP) is a recognized option for surgical management of benign prostatic hyperplasia (BPH). While laser parameters and enucleation techniques have been widely investigated, morcellation techniques remain poorly evaluated in the literature. Our goal was to objectively evaluate the available devices used for morcellation during HoLEP. MATERIAL AND METHODS: An in vitro evaluation of two morcellators (Lumenis and Wolf) and two nephroscopes (Wolf and Storz) was conducted. For morcellators, the following parameters were assessed: Aspiration power (time to aspirate 1 L of water), morcellation power (g of baked chicken meat morcellated in 2 minutes), and visual control of the cutting part of the device (visible or not visible). For nephroscopes, data collected were: Field of vision (measured on a 4 cm distant sight) and irrigation flow (time needed to drain a 3-liter bag of water suspended at 1 m of height). RESULTS: For the Wolf and Lumenis morcellators, aspiration power parameters were 20.4 mL/s and 22.2 mL/s, and morcellating power parameters were 2.5 g and 6 g of tissue per minute, respectively. The cutting part of the Wolf morcellator was permanently under control during the procedure, whereas the distal part of the cutting device was out of vision control with the Lumenis. Evaluation of Storz and Wolf nephroscopes showed that field of vision was larger with the Storz, and irrigation flow was 0.35 and 0.52 L/min, respectively. CONCLUSIONS: The Storz nephroscope has a greater field of vision but less important blood flows. The Lumenis morcellator is faster than the Wolf morcellator. These objective data could set up the basis for a prospective trial comparing the two devices. PMID- 22260636 TI - Evaluation of multiple myeloma patients presenting with renal failure in a university hospital in the year 2010. AB - BACKGROUND: The aim of this cross-sectional study was to evaluate multiple myeloma patients presenting with renal failure in a University hospital. METHODS: The records of all the patients diagnosed with multiple myeloma in the departments of hematology and nephrology at Gazi University Hospital between January 2010 and January 2011 were reviewed retrospectively. Renal failure was defined as a serum creatinine level of >=2 mg/dL. Median age was 63 (range 37-80) years, with 13 male and 17 female patients. RESULTS: Eight (26.7%) of the 30 patients had renal failure and 4 (50%) patients with renal failure required renal replacement therapy with hemodialysis after admission. Renal functions recovered in four (50%) of the eight patients after treatment. In one of the eight patients (12.5%) creatinine levels improved, but did not reach the level defined as reversal of renal failure. The renal functions of the three (37.5%) patients did not improve and they remained on chronic hemodialysis program during which one of them died due to a cerebrovascular accident and one other patient was lost due to follow-up. CONCLUSION: A substantial proportion of myeloma patients referred with renal failure might enjoy a disease-free survival and could be saved from chronic renal replacement therapy with prompt diagnosis and treatment in the era of new generation anti-myeloma agents which provide fast and effective responses. Multiple myeloma should be considered in the differential diagnosis of acute renal failure even in the absence of hyperglobulinemia and hypercalcemia. PMID- 22260637 TI - The sequential organ failure assessment (SOFA) score is prognostically superior to the model for end-stage liver disease (MELD) and MELD variants following paracetamol (acetaminophen) overdose. AB - BACKGROUND: The prognostic value of the model for end-stage liver disease (MELD) and sodium-based MELD variants in predicting survival following paracetamol overdose remains unclear. AIM: To examine the prognostic accuracy of sodium-based MELD variants in paracetamol-induced acute liver injury compared with the sequential organ failure assessment (SOFA) score. METHODS: Retrospective analysis of 138 single time point paracetamol overdoses admitted to a tertiary liver centre. Individual laboratory samples were correlated with the corresponding clinical parameters in relation to time post-overdose, and the daily MELD, MELD Na, MELDNa, MESO, iMELD, UKELD, updated MELD and SOFA scores were calculated. RESULTS: Sixty-six (47.8%) patients developed hepatic encephalopathy, of whom 7 were transplanted and 21 died without liver transplantation. SOFA had a significantly greater area under the receiver operator characteristic for the prediction of spontaneous survival compared with MELD at both 72 (P = 0.024) and 96 (P = 0.017) h post-overdose. None of the sodium-based MELD variants improved the prognostic accuracy of MELD. A SOFA score >6 by 72 h or >7 by 96 h, post overdose predicted death/transplantation with a negative predictive value of 96.9 (95% CI 90.2-99.4) and 98.8 (95% CI 93.6-99.9) respectively. SOFA and MELD had similar accuracy for predicting the development of hepatic encephalopathy (P = 0.493). CONCLUSIONS: The SOFA score is superior to MELD in predicting spontaneous survival following paracetamol-induced acute liver injury. Modification of the MELD score to include serum sodium does not improve prognostic accuracy in this setting. SOFA may have potential as a quantitative triage marker following paracetamol overdose. PMID- 22260638 TI - New anthocyanidin and anthocyanin pigments from blue plumbago. AB - Phytochemical investigations of blue plumbago ( Plumbago auriculata Poir. syn. Plumbago capensis Thunb.) flowers have led to the isolation of six new anthocyanins based on three new anthocyanidins with 5,7-dimethoxylated A-rings. Their structures were identified by 2D nuclear magnetic resonance and high resolution mass spectrometry as the 3-O-beta-galactopyranosides (1,2,4) and 3-O alpha-rhamnopyranosides (3,5,6) of 5,7-dimethyldelphinidin, 5,7 dimethylpetunidin, and 5,7-dimethylmalvidin. Identification of 1-6 implies new structures for the previously reported anthocyanidins pulchellidin, europinidin, and capensinidin to be 5,7-dimethoxy-3,3',4',5'-tetrahydroxyflavylium, 5,7,3' trimethoxy-3,4',5'-trihydroxyflavylium, and 5,7,3',5'-tetramethoxy-3,4' dihydroxyflavylium cations, respectively. The anthocyanins (0.4 mg/g flowers) were accompanied by the dihydroflavonol taxifolin 3'-O-beta-glucopyranoside (1.4 mg/g) and the flavonols 5-methylquercetin 3-O-alpha-rhamnopyranoside (8.8 mg/g) and 5-methylquercetin (0.4 mg/g). The anthocyanins 1-6 are the first reported natural anthocyanins with no free hydroxyl groups in their 5- and 7-positions on their A-rings. They have thus no possibility of forming the tautomeric quinonoidal bases (anhydrobases), which are related to the free hydroxyl groups in the 5- and 7-positions of previously reported anthocyanins. The genes behind the 5,7-dimethoxylated anthocyanins might be useful for making anthocyanins with special properties (colors, etc.). PMID- 22260639 TI - Individual differences on immunostimulatory activity of raw and black garlic extract in human primary immune cells. AB - The immunostimulatory activities of garlic extract using a cell line or animal models have been reported; however, no previous studies have evaluated individual differences in regards to the immunostimulatory activities. The immunostimulatory activities such as cell proliferation, tumor necrosis factor (TNF-alpha) and nitric oxides (NO) production of raw garlic and black garlic extracts on individual primary lymphocytes or macrophages isolated from the blood of 21 volunteers were evaluated. The antioxidant and anticancer effects of raw garlic and black garlic ethanol extract was measured to determine the optimum conditions for extraction. The 70% ethanol black garlic extracts at 70 degrees C for 12 h (70% BGE) showed the strongest antioxidant and anticancer activities. Immunostimulatory activities of garlic extracts extracted under optimal condition on primary immune cells obtained from 21 volunteers were analyzed. Results showed that the cell proliferation, TNF-alpha and NO production of primary immune cells treated with 70% raw garlic extract (70% RGE) were significantly different; however, little difference was observed for the 70% BGE treatment. BGE showed stronger immunostimulatory activities than RGE. These results indicate that the immunostimulatory activities of RGE and BGE can be strongly correlated with the antioxidant and anticancer activities. Determination of immunostimulatory activities of different types of garlic using immune cells isolated from volunteers was dependent on the individual constituents due to changes in the composition of garlic during processing. Individual primary immune cells might be used as important tools to determine individual differences in all food ingredients for the development of personalized immunostimulatory active foods. PMID- 22260641 TI - Charge transfer in model peptides: obtaining Marcus parameters from molecular simulation. AB - Charge transfer within and between biomolecules remains a highly active field of biophysics. Due to the complexities of real systems, model compounds are a useful alternative to study the mechanistic fundamentals of charge transfer. In recent years, such model experiments have been underpinned by molecular simulation methods as well. In this work, we study electron hole transfer in helical model peptides by means of molecular dynamics simulations. A theoretical framework to extract Marcus parameters of charge transfer from simulations is presented. We find that the peptides form stable helical structures with sequence dependent small deviations from ideal PPII helices. We identify direct exposure of charged side chains to solvent as a cause of high reorganization energies, significantly larger than typical for electron transfer in proteins. This, together with small direct couplings, makes long-range superexchange electron transport in this system very slow. In good agreement with experiment, direct transfer between the terminal amino acid side chains can be dicounted in favor of a two-step hopping process if appropriate bridging groups exist. PMID- 22260642 TI - Convalescent plasma levels of TAFI activation peptide predict death and recurrent vascular events in ischemic stroke survivors. PMID- 22260643 TI - Studies toward the synthesis of spirolide C: exploration into the formation of the 23-membered all-carbon macrocyclic framework. AB - The synthesis of two complex subunits en route to spirolide C is described. A key alkyllithium addition to an aldehyde joins the fragments, which are advanced in order to investigate a ring-closing metathesis to form the 23-membered all-carbon macrocyclic framework. PMID- 22260644 TI - Use of a culture medium (McCoy(r)), as a method for evaluating Bos indicus * Bos taurus embryos. AB - The aim of this study was to use culture medium (McCoy(r)) as a test to evaluate the classification of embryos after a primary grading using stereoscopic microscopy to further confirm whether embryos have been correctly scored by stereoscopic microscopy evaluating the level of apoptosis. Forty-six Bos indicus embryos were collected with a non-surgical method and evaluated with stereoscopic microscopy for scoring in three categories (good, fair and poor). Cell proliferation and apoptosis were assessed and compared between the control group (n = 14) at the onset of the experiment and in an experimental group (n = 32) after stored for 4 h in a culture medium. Embryos were processed using TUNEL and BrdU markers to determine the apoptosis and cell proliferation. Seventy-four per cent of good quality embryos developed favourably after the 4 h of culture; 60% of fair embryos maintained their evolution, while 100% of poor quality embryos presented degenerative changes from the beginning. No statistical differences were found between the experimental and the control groups in the count of positive BrdU and apoptotic nuclei. In poor quality embryos, a higher number of apoptotic cells were found relative to good and fair embryos, both in the experimental and control groups (P < 0.05). These results suggest that the culture medium may be used for a short time as a fast, practical and non-invasive alternative to further confirm whether embryos have been correctly scored by stereoscopic microscopy. PMID- 22260646 TI - The loci recommended as universal barcodes for plants on the basis of floristic studies may not work with congeneric species as exemplified by DNA barcoding of Dendrobium species. AB - BACKGROUND: Based on the testing of several loci, predominantly against floristic backgrounds, individual or different combinations of loci have been suggested as possible universal DNA barcodes for plants. The present investigation was undertaken to check the applicability of the recommended locus/loci for congeneric species with Dendrobium species as an illustrative example. RESULTS: Six loci, matK, rbcL, rpoB, rpoC1, trnH-psbA spacer from the chloroplast genome and ITS, from the nuclear genome, were compared for their amplification, sequencing and species discrimination success rates among multiple accessions of 36 Dendrobium species. The trnH-psbA spacer could not be considered for analysis as good quality sequences were not obtained with its forward primer. Among the tested loci, ITS, recommended by some as a possible barcode for plants, provided 100% species identification. Another locus, matK, also recommended as a universal barcode for plants, resolved 80.56% species. ITS remained the best even when sequences of investigated loci of additional Dendrobium species available on the NCBI GenBank (93, 33, 20, 18 and 17 of ITS, matK, rbcL, rpoB and rpoC1, respectively) were also considered for calculating the percent species resolution capabilities. The species discrimination of various combinations of the loci was also compared based on the 36 investigated species and additional 16 for which sequences of all the five loci were available on GenBank. Two-locus combination of matK+rbcL recommended by the Plant Working Group of Consortium for Barcoding of Life (CBOL) could discriminate 86.11% of 36 species. The species discriminating ability of this barcode was reduced to 80.77% when additional sequences available on NCBI were included in the analysis. Among the recommended combinations, the barcode based on three loci - matK, rpoB and rpoC1- resolved maximum number of species. CONCLUSIONS: Any recommended barcode based on the loci tested so far, is not likely to provide 100% species identification across the plant kingdom and thus is not likely to act as a universal barcode. It appears that barcodes, if based on single or limited locus(i), would be taxa specific as is exemplified by the success of ITS among Dendrobium species, though it may not be suitable for other plants because of the problems that are discussed. PMID- 22260647 TI - Prodrugs of acyclovir--a computational approach. AB - Density functional theory calculation results demonstrated that the efficiency of the acid-catalyzed hydrolysis of Kirby's acid amides 1-15 is strongly dependent on the substitution on the C-C double bond and the nature of the amide N-alkyl group. Further, the results established that while in the gas phase the hydrolysis rate-limiting step is the tetrahedral intermediate formation in polar solvents such as water, the rate-limiting step could be either the formation or the collapse of the tetrahedral intermediate depending on the substitution on the C-C double bond and on the amide nitrogen substituent. Based on a linear correlation between the calculated and experimental effective molarities, the study on the systems reported herein could provide a good basis for designing prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log effective molarities values, the predicted t(1/2) (a time needed for 50% of the reactant to be hydrolyzed to products) for acyclovir prodrugs, ProD 1-4, was 29.2 h, 6097 days, 4.6 min, and 8.34 h, respectively. Hence, the rate by which acyclovir prodrug releases acyclovir can be determined according to the structural features of the linker (Kirby's acid amide moiety). PMID- 22260648 TI - Chemical imaging of protein adsorption and crystallization on a wettability gradient surface. AB - The use of self-assembled monolayers is an established method to study the effect of surface properties on proteins and other biological materials. The generation of a monolayer with a gradient of chemical properties allows for the study of multiple surface properties simultaneously in a high throughput manner. Typically, in order to detect the presence of proteins or biological material on a surface, the use of additional dyes or tags is required. Here we present a novel method of studying the effect of gradient surface properties on protein adsorption and crystallization in situ through the use of ATR-FTIR spectroscopic imaging, which removes the need for additional labeling. We describe the successful application of this technique to the measurement of the growth of a gradient monolayer of octyltrichlorosilane across the surface of a silicon ATR element. ATR-FTIR imaging was also used to study the adsorption of lysozyme, as a model protein, onto the modified surface. The sensitivity of measurements obtained with a focal plane array (FPA) detector were improved though the use of pixel averaging which allowed small absorption bands to be detected with minimal effect on the spatial resolution along the gradient. Study of the effect of surface hydrophobicity on both adsorption of lysozyme to the element and lysozyme crystallization revealed that more lysozyme adsorbed to the hydrophobic side of the ATR element and more lysozyme crystals formed in the same region. These findings strongly suggest a correlation exists between surface protein adsorption and protein crystallization. This method could be applied to the study of other proteins and whole cells. PMID- 22260649 TI - Iron-catalyzed intramolecular allylic C-H amination. AB - A highly selective C-H amination reaction under iron catalysis has been developed. This novel system, which employs an inexpensive, nontoxic [Fe(III)Pc] catalyst (typically used as an industrial ink additive), displays a strong preference for allylic C-H amination over aziridination and all other C-H bond types (i.e., allylic > benzylic > ethereal > 3 degrees > 2 degrees ? 1 degrees ). Moreover, in polyolefinic substrates, the site selectivity can be controlled by the electronic and steric character of the allylic C-H bond. Although this reaction is shown to proceed via a stepwise mechanism, the stereoretentive nature of C-H amination for 3 degrees aliphatic C-H bonds suggests a very rapid radical rebound step. PMID- 22260650 TI - Interspecific interactions drive cultural co-evolution and acoustic convergence in syntopic species. AB - 1. Antagonistic interactions have been favourite subjects of studies on species co-evolution, because coexistence among competing species often results in quantifiable character displacement. A common output for competitive interactions is trait divergence, although the opposite phenomenon, convergence, has been proposed to evolve in some instances, for example in the communication behaviour of species that maintain mutually exclusive territories. 2. I use here experimental and observational evidence to study how species interactions drive heterospecific signal convergence and analyse how convergence feeds back to the interaction itself, in the form of aggressive behaviour. I recorded the learned territorial signals of two non-hybridizing larks, Galerida cristata and G. theklae, and used allopatric populations as controls for evaluating acoustic convergence in syntopy. Acoustic variation was analysed with respect to social conditions controlling for other potential agents of natural selection, habitat and climate. 3. Interspecific convergence of Galerida calls peaked in syntopy. Although call acoustic structure was affected by climate and habitat, it matched gradients of density and proximity to congeners even at small local scales. The process of cultural transmission, in which individuals may acquire components of behaviour by copying neighbours, enhances the correlation between call acoustics and the local social milieu. 4. Territories were defended against both species, but playback stimuli of convergent congener calls elicited a stronger aggressive reaction than congener calls from allopatric locations. 5. This study shows that learned behaviours may co-evolve as a consequence of antagonistic interactions, determining reciprocal cultural evolution or cultural co-evolution. As for (biological) co-evolution, the distribution of competing species influences whether a particular area becomes a syntopic environment in which convergence is occurring, or an allopatric environment lacking interactions and reciprocal change. Because of their plastic nature, cultural coadaptations may rapidly shift in response to fluctuating social selection, thus propelling dynamic interactions and fine adjustments to the local environment. PMID- 22260651 TI - Integrating prior knowledge in multiple testing under dependence with applications to detecting differential DNA methylation. AB - DNA methylation has emerged as an important hallmark of epigenetics. Numerous platforms including tiling arrays and next generation sequencing, and experimental protocols are available for profiling DNA methylation. Similar to other tiling array data, DNA methylation data shares the characteristics of inherent correlation structure among nearby probes. However, unlike gene expression or protein DNA binding data, the varying CpG density which gives rise to CpG island, shore and shelf definition provides exogenous information in detecting differential methylation. This article aims to introduce a robust testing and probe ranking procedure based on a nonhomogeneous hidden Markov model that incorporates the above-mentioned features for detecting differential methylation. We revisit the seminal work of Sun and Cai (2009, Journal of the Royal Statistical Society: Series B (Statistical Methodology)71, 393-424) and propose modeling the nonnull using a nonparametric symmetric distribution in two sided hypothesis testing. We show that this model improves probe ranking and is robust to model misspecification based on extensive simulation studies. We further illustrate that our proposed framework achieves good operating characteristics as compared to commonly used methods in real DNA methylation data that aims to detect differential methylation sites. PMID- 22260652 TI - The cost-effectiveness of celecoxib vs diclofenac in the treatment of osteoarthritis in the UK; an update to the NICE model using data from the CONDOR trial. AB - OBJECTIVES: The National Institute for Health and Clinical Excellence (NICE) health economic model for assessing the cost-effectiveness of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus PPI in the treatment of osteoarthritis has been updated using new adverse event (AE) risks from the CONDOR trial. In light of this new information, this study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus PPI compared to diclofenac plus PPI. METHODS: NICE developed a health economic model as part of their 2008 multiple technology assessment of treatments for osteoarthritis. The model was adapted for this study to update the relative risks of adverse events, using data from the CONDOR trial. RESULTS: Using the AE data from the CLASS trial alone, celecoxib plus PPI has an ICER of L9538 per QALY when compared to diclofenac plus PPI. When the AE data from CONDOR alone is used, this ICER decreases to L4773 per QALY. Using the pooled data from both trials, celecoxib plus PPI has an ICER of L9377 per QALY compared to diclofenac plus PPI. DISCUSSION: The results suggest that when new AE risks are used, celecoxib plus PPI remains a cost-effective treatment for OA when compared to diclofenac plus PPI. However, this analysis is limited by the short time horizon, and additional AEs that have not been considered. PMID- 22260653 TI - Synthesis of indium borate and its application in photodegradation of 4 chlorophenol. AB - Indium borate has been prepared by a sol-gel method. The structure, morphology, and photophysics of the resultant photocatalysts have been studied via the techniques of X-ray diffraction (XRD), transmission electron microscopy (TEM), and diffuse reflectance UV-visible light spectroscopy. These photocatalysts have been used to photodegrade 4-chlorophenol. The photocatalytic activity depends on the annealing temperature during preparation. It is found that borates can exhibit a high photodegradation activity under UV-light irradiation, for which the efficiency can be higher than that of as-prepared TiO(2). This is explained according to the results of fluorescence spectra and valence band X-ray photoelectron spectroscopy (XPS). It is confirmed by the results of time-resolved photoluminescence decay spectra; i.e., the lifetime of electrons and holes involved in the radiative process can be longer for the borates than that for TiO(2). This implies that indium borate can be a promising photocatalyst for future applications in treatment of environment contaminants. PMID- 22260654 TI - High resolution clustering of Salmonella enterica serovar Montevideo strains using a next-generation sequencing approach. AB - BACKGROUND: Next-Generation Sequencing (NGS) is increasingly being used as a molecular epidemiologic tool for discerning ancestry and traceback of the most complicated, difficult to resolve bacterial pathogens. Making a linkage between possible food sources and clinical isolates requires distinguishing the suspected pathogen from an environmental background and placing the variation observed into the wider context of variation occurring within a serovar and among other closely related foodborne pathogens. Equally important is the need to validate these high resolution molecular tools for use in molecular epidemiologic traceback. Such efforts include the examination of strain cluster stability as well as the cumulative genetic effects of sub-culturing on these clusters. Numerous isolates of S. Montevideo were shot-gun sequenced including diverse lineage representatives as well as numerous replicate clones to determine how much variability is due to bias, sequencing error, and or the culturing of isolates. All new draft genomes were compared to 34 S. Montevideo isolates previously published during an NGS-based molecular epidemiological case study. RESULTS: Intraserovar lineages of S. Montevideo differ by thousands of SNPs, that are only slightly less than the number of SNPs observed between S. Montevideo and other distinct serovars. Much less variability was discovered within an individual S. Montevideo clade implicated in a recent foodborne outbreak as well as among individual NGS replicates. These findings were similar to previous reports documenting homopolymeric and deletion error rates with the Roche 454 GS Titanium technology. In no case, however, did variability associated with sequencing methods or sample preparations create inconsistencies with our current phylogenetic results or the subsequent molecular epidemiological evidence gleaned from these data. CONCLUSIONS: Implementation of a validated pipeline for NGS data acquisition and analysis provides highly reproducible results that are stable and predictable for molecular epidemiological applications. When draft genomes are collected at 15*-20* coverage and passed through a quality filter as part of a data analysis pipeline, including sub-passaged replicates defined by a few SNPs, they can be accurately placed in a phylogenetic context. This reproducibility applies to all levels within and between serovars of Salmonella suggesting that investigators using these methods can have confidence in their conclusions. PMID- 22260655 TI - Maternal contact differentially modulates central and peripheral oxytocin in rat pups during a brief regime of mother-pup interaction that induces a filial huddling preference. AB - Central oxytocin mediates the acquisition of a filial preference for maternal odour in rat pups, manifested by their huddling preferences. The present study was designed to examine whether maternal care modulates oxytocin concentrations in rat pups and, if so, how different types of maternal contact are associated with the pups' oxytocin concentrations. Pairs of 14-day-old littermates were removed from their home cage for 1 h and then placed with a lactating foster mother for 2 h, or they remained isolated at room temperature. Enzyme immunoassays revealed that maternal care and maternal separation can differentially modulate pups' oxytocin concentrations. Both hypothalamic and serum oxytocin increased during the 1-h separation. Pups placed with a foster mother after the separation maintained the same concentrations in the hypothalamus and serum through the fostering period. By contrast, pups placed with no mother showed a further increase in hypothalamic oxytocin but serum oxytocin decreased. Behavioural analyses revealed that skin-to-skin contact with the mother, but not simple physical contact or maternal licking/grooming, was positively correlated with the pups' hypothalamic oxytocin concentrations. These neuroendocrine data match previous findings showing that skin-to-skin contact with mother facilitates the acquisition of the pups' huddling preference for a maternally-associated odour. Taken together, the present study suggests that maternal skin-to-skin contact stimulates pups' central oxytocin, at the same time as creating the conditions for inducing a preference for maternal odour and establishing a social affiliation in rat pups; the natural schedule of maternal separation and reunion may modulate pups' oxytocin concentrations, providing scaffolding for the acquisition of their filial huddling preference. PMID- 22260656 TI - Novel control of cAMP-regulated transcription in vascular endothelial cells. AB - Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel 'protective' mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease. PMID- 22260657 TI - Epac2: a sulfonylurea receptor? AB - Sulfonylureas are widely used oral drugs in the treatment of diabetes mellitus. They function by the inhibition of ATP-sensitive K+ channels in pancreatic beta cells, which are thus considered the 'classical' sulfonylurea receptor. Next to the ATP-sensitive K+ channels, additional sulfonylurea-interacting proteins were identified, which might contribute to the physiological effects of this drug family. Most recently, Epac2 (exchange protein directly activated by cAMP 2) was added to the list of sulfonylurea receptors. However, this finding caused controversy in the literature. The critical discussion of the present paper comes to the conclusion that sulfonylureas are not able to activate Epac2 directly and are unlikely to bind to Epac2. Increased blood glucose levels after food intake result in the secretion of insulin from pancreatic beta-cells. Glucose levels are detected 'indirectly' by beta-cells: owing to increased glycolysis rates, the ratio of cellular ATP/ADP increases and causes the closure of ATP-sensitive K+ channels. In consequence, cells depolarize and voltage-dependent Ca2+ channels open to cause an increase in the cellular Ca2+ concentration. Finally, Ca2+ induces the fusion of insulin-containing granules with the plasma membrane. Sulfonylureas, such as tolbutamide, glibenclamide or acetohexamide, form a class of orally applicable drugs used in the treatment of non-insulin-dependent diabetes mellitus. PMID- 22260658 TI - cGMP-cAMP interplay in cardiac myocytes: a local affair with far-reaching consequences for heart function. AB - cAMP and cGMP signalling pathways are common targets in the pharmacological treatment of heart failure, and often drugs that modulate the level of these second messengers are simultaneously administered to patients. cGMP can potentially affect cAMP levels by modulating the activity of PDEs (phosphodiesterases), the enzymes that degrade cyclic nucleotides. This biochemical cross-talk provides the means for drugs that increase cGMP to concomitantly affect cAMP signals. Recent studies using FRET (fluorescence resonance energy transfer) reporters and real-time imaging show that, in cardiac myocytes, the interplay between cGMP and cAMP has different outcomes depending on the specific location where the cross-modulation occurs. cGMP can either increase or decrease the cAMP response to catecholamines, based on the cyclase that generates it and on the PDEs associated with each subcellular compartment. cGMP mediated modulation of cAMP signals has functional relevance as it affects protein phosphorylation downstream of protein kinase A and myocyte contractility. The physical separation of positive and negative modulation of cAMP levels by cGMP offers the previously unrecognized possibility to selectively modulate local cAMP signals to improve the efficacy of therapy. PMID- 22260659 TI - Negative co-operativity in the EGF receptor. AB - Scatchard analyses of the binding of EGF (epidermal growth factor) to its receptor (EGFR) yield concave up Scatchard plots, indicative of some type of heterogenity in ligand-binding affinity. This was typically interpreted as being due to the presence of two independent binding sites: one of high affinity representing <=10% of the receptor population, and one of low affinity making up the bulk of the receptors. However, the concept of two independent binding sites is difficult to reconcile with the X-ray structures of the dimerized EGFR that show symmetrical binding of the two ligands. A new approach to the analysis of 125I-EGF-binding data combined with the structure of the singly-occupied Drosophila EGFR have now shown that this heterogeneity is due to the presence of negative co-operativity in the EGFR. Concerns that negative co-operativity precludes ligand-induced dimerization of the EGFR confuse the concepts of linkage and co-operativity. Linkage refers to the effect of ligand on the assembly of dimers, whereas co-operativity refers to the effect of ligand binding to one subunit on ligand binding to the other subunit within a preassembled dimer. Binding of EGF to its receptor is positively linked with dimer assembly, but shows negative co-operativity within the dimer. PMID- 22260660 TI - Neuropilin signalling in angiogenesis. AB - VEGFs (vascular endothelial growth factors) are master regulators of vascular development and of blood and lymphatic vessel function during health and disease in adults. This family of five mammalian ligands acts through three RTKs (receptor tyrosine kinases). In addition, co-receptors such as NRPs (neuropilins) associate with the ligand-receptor signalling complex and modulate the output. Therapeutics to block several of the VEGF signalling components as well as NRP function have been developed with the aim of halting blood vessel formation, angiogenesis, in diseases that involve tissue growth and inflammation, such as cancer. The present review outlines the current understanding of NRPs in relation to blood and lymphatic vessel biology. PMID- 22260661 TI - Regulation of signalling by microRNAs. AB - Stringent regulation of biochemical signalling pathways involves feedback and feedforward loops, which underlie robust cellular responses to external stimuli. Regulation occurs in all horizontal layers of signalling networks, primarily by proteins that mediate internalization of receptor-ligand complexes, dephosphorylation of kinases and their substrates, as well as transcriptional repression. Recent studies have unveiled the role of miRNAs (microRNAs), post transcriptional regulators that control mRNA stability, as key modulators of signal propagation. By acting as genetic switches or fine-tuners, miRNAs can directly and multiply regulate cellular outcomes in response to diverse extracellular signals. Conversely, signalling networks temporally control stability, biogenesis and abundance of miRNAs, by regulating layers of the miRNA biogenesis pathway. In the present mini-review, we use a set of examples to illustrate the extensive interdependence between miRNAs and signalling networks. PMID- 22260663 TI - How phosphoinositide 3-phosphate controls growth downstream of amino acids and autophagy downstream of amino acid withdrawal. AB - The simple phosphoinositide PtdIns3P has been shown to control cell growth downstream of amino acid signalling and autophagy downstream of amino acid withdrawal. These opposing effects depend in part on the existence of distinct complexes of Vps34 (vacuolar protein sorting 34), the kinase responsible for the majority of PtdIns3P synthesis in cells: one complex is activated after amino acid withdrawal to induce autophagy and another regulates mTORC1 (mammalian target of rapamycin complex 1) activation when amino acids are present. However, lipid-dependent signalling almost always exhibits a spatial dimension, related to the site of formation of the lipid signal. In the case of PtdIns3P-regulated autophagy induction, recent data suggest that PtdIns3P accumulates in a membrane compartment dynamically connected to the endoplasmic reticulum that constitutes a platform for the formation of some autophagosomes. For PtdIns3P-regulated mTORC1 activity, a spatial context is not yet known: several possibilities can be envisaged based on the known effects of PtdIns3P on the endocytic system and on recent data suggesting that activation of mTORC1 depends on its localization on lysosomes. PMID- 22260662 TI - Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis. AB - LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy. PMID- 22260664 TI - The essential role of cAMP/Ca2+ signalling in mammalian circadian timekeeping. AB - Approximately daily, or circadian, rhythms are ubiquitous across eukaryotes. They are manifest in the temporal co-ordination of metabolism, physiology and behaviour, thereby allowing organisms to anticipate and synchronize with daily environmental cycles. Although cellular rhythms are self-sustained and cell intrinsic, in mammals, the master regulator of timekeeping is localized within the hypothalamic SCN (suprachiasmatic nucleus). Molecular models for mammalian circadian rhythms have focused largely on transcriptional-translational feedback loops, but recent data have revealed essential contributions by intracellular signalling mechanisms. cAMP and Ca2+ signalling are not only regulated by the cellular clock, but also contribute directly to the timekeeping mechanism, in that appropriate manipulations determine the canonical pacemaker properties of amplitude, phase and period. It is proposed that daily auto-amplification of second messenger activity, through paracrine neuropeptidergic coupling, is necessary and sufficient to account for the increased amplitude, accuracy and robustness of SCN timekeeping. PMID- 22260665 TI - Role of Epac in brain and heart. AB - Epacs (exchange proteins directly activated by cAMP) are guanine-nucleotide exchange factors for the Ras-like small GTPases Rap1 and Rap2. Epacs were discovered in 1998 as new sensors for the second messenger cAMP acting in parallel to PKA (protein kinase A). As cAMP regulates many important physiological functions in brain and heart, the existence of Epacs raises many questions regarding their role in these tissues. The present review focuses on the biological roles and signalling pathways of Epacs in neurons and cardiac myocytes. We discuss the potential involvement of Epacs in the manifestation of cardiac and central diseases such as cardiac hypertrophy and memory disorders. PMID- 22260666 TI - Immediate-early gene activation by the MAPK pathways: what do and don't we know? AB - The study of IE (immediate-early) gene activation mechanisms has provided numerous paradigms for how transcription is controlled in response to extracellular signalling. Many of the findings have been derived from investigating one of the IE genes, FOS, and the models extrapolated to regulatory mechanisms for other IE genes. However, whereas the overall principles of activation appear similar, recent evidence suggests that the underlying mechanistic details may differ depending on cell type, cellular stimulus and IE gene under investigation. In the present paper, we review recent advances in our understanding of IE gene transcription, chiefly focusing on FOS and its activation by ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway signalling. We highlight important fundamental regulatory principles, but also illustrate the gaps in our current knowledge and the potential danger in making assumptions based on extrapolation from disparate studies. PMID- 22260667 TI - Regulation of MEK/ERK pathway output by subcellular localization of B-Raf. AB - The strength and duration of intracellular signalling pathway activation is a key determinant of the biological outcome of cells in response to extracellular cues. This has been particularly elucidated for the Ras/Raf/MEK [mitogen-activated growth factor/ERK (extracellular-signal-regulated kinase) kinase]/ERK signalling pathway with a number of studies in fibroblasts showing that sustained ERK signalling is a requirement for S-phase entry, whereas transient ERK signalling does not have this capability. A major unanswered question, however, is how a cell can sustain ERK activation, particularly when ERK-specific phosphatases are transcriptionally up-regulated by the pathway itself. A major point of ERK regulation is at the level of Raf, and, to sustain ERK activation in the presence of ERK phosphatases, sustained Raf activation is a requirement. Three Raf proteins exist in mammals, and the activity of all three is induced following growth factor stimulation of cells, but only B-Raf activity is maintained at later time points. This observation points to B-Raf as a regulator of sustained ERK activation. In the present review, we consider evidence for a link between B Raf and sustained ERK activation, focusing on a potential role for the subcellular localization of B-Raf in this key physiological event. PMID- 22260668 TI - Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. AB - The Raf/MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal regulated kinase) kinase 1/2]/ERK1/2 signalling pathway is frequently activated in human tumours due to mutations in BRAF or KRAS. B-Raf and MEK1/2 inhibitors are currently undergoing clinical evaluation, but their ultimate success is likely to be limited by acquired drug resistance. We have used colorectal cancer cell lines harbouring mutations in B-Raf or K-Ras to model acquired resistance to the MEK1/2 inhibitor selumetinib (AZD6244). Selumetinib-resistant cells were refractory to other MEK1/2 inhibitors in cell proliferation assays and exhibited a marked increase in MEK1/2 and ERK1/2 activity and cyclin D1 abundance when assessed in the absence of inhibitor. This was driven by a common mechanism in which resistant cells exhibited an intrachromosomal amplification of their respective driving oncogene, B-Raf V600E or K-RasG13D. Despite the increased signal flux from Raf to MEK1/2, resistant cells maintained in drug actually exhibited the same level of ERK1/2 activity as parental cells, indicating that the pathway is remodelled by feedback controls to reinstate the normal level of ERK1/2 signalling that is required and sufficient to maintain proliferation in these cells. These results provide important new insights into how tumour cells adapt to new therapeutics and highlight the importance of homoeostatic control mechanisms in the Raf/MEK1/2/ERK1/2 signalling cascade. PMID- 22260669 TI - Roles of p38 MAPKs in invasion and metastasis. AB - Cells from primary tumours need to go through several steps to become fully metastatic. During this process, cancer cells acquire the ability to invade, migrate across the surrounding tissue, enter into the circulation and colonize distant organs. In the present paper, we review recent progress in understanding how the p38 MAPK (mitogen-activated protein kinase) signalling pathway participates in the different steps of metastasis. Experimental evidence suggests that tumour cells need to modulate p38 MAPK activity levels to successfully metastasize. PMID- 22260670 TI - Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies. AB - JNK (c-Jun N-terminal kinase) is a member of the MAPK (mitogen-activated protein kinase) family that regulates a range of biological processes implicated in tumorigenesis and neurodegenerative disorders. For example, genetic studies have demonstrated that the removal of specific Jnk genes can reduce neuronal death associated with cerebral ischaemia. As such, targeting JNK signalling constitutes an obvious opportunity for therapeutic intervention. However, MAPK inhibitors can display toxic effects. Consequently, dual-specificity MKKs (MAPK kinases) may represent more attractive targets. In particular, evidence that blocking JNK activation by removing MKK4 offers an effective therapy to treat pathological conditions has started to emerge. MKK4 was the first JNK activator identified. The remaining level of JNK activity in cells lacking MKK4 expression led to the discovery of a second activator of JNK, named MKK7. Distinct phenotypic abnormalities associated with the targeted deletion of Mkk4 and Mkk7 in mice have revealed that MKK4 and MKK7 have non-redundant function in vivo. Further insights into the specific functions of the JNK activators in cancer cells and in neurons will be of critical importance to validate MKK4 and MKK7 as promising drug targets. PMID- 22260671 TI - Phosphorylation of basic helix-loop-helix transcription factor Twist in development and disease. AB - The transcription factor Twist plays vital roles during embryonic development through regulating/controlling cell migration. However, postnatally, in normal physiological settings, Twist is either not expressed or inactivated. Increasing evidence shows a strong correlation between Twist reactivation and both cancer progression and malignancy, where the transcriptional activities of Twist support cancer cells to disseminate from primary tumours and subsequently establish a secondary tumour growth in distant organs. However, it is largely unclear how this signalling programme is reactivated or what signalling pathways regulate its activity. The present review discusses recent advances in Twist regulation and activity, with a focus on phosphorylation-dependent Twist activity, potential upstream kinases and the contribution of these factors in transducing biological signals from upstream signalling complexes. The recent advances in these areas have shed new light on how phosphorylation-dependent regulation of the Twist proteins promotes or suppresses Twist activity, leading to differential regulation of Twist transcriptional targets and thereby influencing cell fate. PMID- 22260672 TI - Sphingosine 1-phosphate signalling in cancer. AB - There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1 S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin-proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor-receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression. PMID- 22260673 TI - The glycerophosphoinositols and their cellular functions. AB - Interest in the glycerophosphoinositols has been increasing recently, on the basis of their biological activities. The cellular metabolism of these water soluble bioactive phosphoinositide metabolites has been clarified, with the identification of the specific enzyme involved in their synthesis, PLA2IValpha (phospholipase A2 IValpha), and the definition of their phosphodiesterase-based catabolism, and thus inactivation. The functional roles and mechanisms of action of these compounds have been investigated in different cellular contexts. This has led to their definition in the control of various cell functions, such as cell proliferation in the thyroid and actin cytoskeleton organization in fibroblasts and lymphocytes. Roles for the glycerophosphoinositols in immune and inflammatory responses are also being defined. In addition to these physiological functions, the glycerophosphoinositols have potential anti-metastatic activities that should lead to their pharmacological exploitation. PMID- 22260674 TI - Cellular geography of IP3 receptors, STIM and Orai: a lesson from secretory epithelial cells. AB - Pancreatic acinar cells exhibit a remarkable polarization of Ca2+ release and Ca2+ influx mechanisms. In the present brief review, we discuss the localization of channels responsible for Ca2+ release [mainly IP3 (inositol 1,4,5 trisphosphate) receptors] and proteins responsible for SOCE (store-operated Ca2+ entry). We also place these Ca2+-transporting mechanisms on the map of cellular organelles in pancreatic acinar cells, and discuss the physiological implications of the cellular geography of Ca2+ signalling. Finally, we highlight some unresolved questions stemming from recent observations of co-localization and co immunoprecipitation of IP3 receptors with Orai channels in the apical (secretory) region of pancreatic acinar cells. PMID- 22260675 TI - Morphological and functional aspects of STIM1-dependent assembly and disassembly of store-operated calcium entry complexes. AB - The SOCE (store-operated Ca2+ entry) pathway is a central component of cell signalling that links the Ca2+-filling state of the ER (endoplasmic reticulum) to the activation of Ca2+-permeable channels at the PM (plasma membrane). SOCE channels maintain a high free Ca2+ concentration within the ER lumen required for the proper processing and folding of proteins, and fuel the long-term cellular Ca2+ signals that drive gene expression in immune cells. SOCE is initiated by the oligomerization on the membrane of the ER of STIMs (stromal interaction molecules) whose luminal EF-hand domain switches from globular to an extended conformation as soon as the free Ca2+ concentration within the ER lumen ([Ca2+]ER) decreases below basal levels of ~500 MUM. The conformational changes induced by the unbinding of Ca2+ from the STIM1 luminal domain promote the formation of higher-order STIM1 oligomers that move towards the PM and exposes activating domains in STIM1 cytosolic tail that bind to Ca2+ channels of the Orai family at the PM and induce their activation. Both SOCE and STIM1 oligomerization are reversible events, but whether restoring normal [Ca2+]ER levels is sufficient to initiate the deoligomerization of STIM1 and to control the termination of SOCE is not known. The translocation of STIM1 towards the PM involves the formation of specialized compartments derived from the ER that we have characterized at the ultrastructural level and termed the pre-cortical ER, the cortical ER and the thin cortical ER. Pre-cortical ER structures are thin ER tubules enriched in STIM1 extending along microtubules and located deep inside cells. The cortical ER is located in the cell periphery in very close proximity (8-11 nm) to the plasma membrane. The thin cortical ER consists of thinner sections of the cortical ER enriched in STIM1 and devoid of chaperones that appear to be specialized ER compartments dedicated to Ca2+ signalling. PMID- 22260676 TI - Regulation of store-operated calcium entry during cell division. AB - Store-operate Ca2+ channels gate Ca2+ entry into the cytoplasm in response to the depletion of Ca2+ from endoplasmic reticulum Ca2+ stores. The major molecular components of store-operated Ca2+ entry are STIM (stromal-interacting molecule) 1 (and in some instances STIM2) that serves as the endoplasmic reticulum Ca2+ sensor, and Orai (Orai1, Orai2 and Orai3) which function as pore-forming subunits of the store-operated channel. It has been known for some time that store operated Ca2+ entry is shut down during cell division. Recent work has revealed complex mechanisms regulating the functions and locations of both STIM1 and Orai1 in dividing cells. PMID- 22260677 TI - Mammalian Hippo signalling: a kinase network regulated by protein-protein interactions. AB - The Hippo signal transduction cascade controls cell growth, proliferation and death, all of which are frequently deregulated in tumour cells. Since initial studies in Drosophila melanogaster were instrumental in defining Hippo signalling, the machinery was named after the central Ste20-like kinase Hippo. Moreover, given that loss of Hippo signalling components Hippo, Warts, and Mats resulted in uncontrolled tissue overgrowth, Hippo signalling was defined as a tumour-suppressor cascade. Significantly, all of the core factors of Hippo signalling have mammalian orthologues that functionally compensate for loss of their counterparts in Drosophila. Furthermore, studies in Drosophila and mammalian cell systems showed that Hippo signalling represents a kinase cascade that is tightly regulated by PPIs (protein-protein interactions). Several Hippo signalling molecules contain SARAH (Salvador/RASSF1A/Hippo) domains that mediate specific PPIs, thereby influencing the activities of MST1/2 (mammalian Ste20-like serine/threonine kinase 1/2) kinases, the human Hippo orthologues. Moreover, WW domains are present in several Hippo factors, and these domains also serve as interaction surfaces for regulatory PPIs in Hippo signalling. Finally, the kinase activities of LATS1/2 (large tumour-suppressor kinase 1/2), the human counterparts of Warts, are controlled by binding to hMOB1 (human Mps one binder protein 1), the human Mats. Therefore Hippo signalling is regulated by PPIs on several levels. In the present paper, I review the current understanding of how these regulatory PPIs are regulated and contribute to the functionality of Hippo signalling. PMID- 22260678 TI - Cell migration and invasion in human disease: the Tks adaptor proteins. AB - Cell invasion plays a central role in a wide variety of biological phenomena and is the cause of tumour growth and metastasis. Understanding the biochemical mechanisms that control cell invasion is one of the major goals of our laboratory. Podosomes and invadopodia are specialized cellular structures present in cells with physiological or pathological invasive behaviours. These transient structures are localized at the ventral cell surface, contain an array of different proteins and facilitate cell-substrate adhesion, as well as the local proteolytic activity necessary for extracellular matrix remodelling and subsequent cellular invasion. We have shown previously that the adaptor proteins and Src substrates Tks4 and Tks5 are required for podosome and invadopodia formation, for cancer cell invasion in vitro, and for tumour growth in vivo. We have also defined a role for the Tks-mediated generation of ROS (reactive oxygen species) in both podosome and invadopodia formation, and invasive behaviour. Tks4 and Tks5 are also required for proper embryonic development, probably because of their roles in cell migration. Finally, we recently implicated podosome formation as part of the synthetic phenotype of vascular smooth muscle cells. Inhibitors of podosome and invadopodia formation might have utility in the treatment of vascular diseases and cancer. We have therefore developed a high-content cell based high-throughput screening assay that allows us to identify inhibitors and activators of podosome/invadopodia formation. We have used this assay to screen for small-molecule inhibitors and defined novel regulators of invadopodia formation. In the present paper, I review these recent findings. PMID- 22260679 TI - Multi-pathway network analysis of mammalian epithelial cell responses in inflammatory environments. AB - Inflammation is a key physiological response to infection and injury and, although usually beneficial, it can also be damaging to the host. The liver is a prototypical example in this regard because inflammation helps to resolve liver injury, but it also underlies the aetiology of pathologies such as fibrosis and hepatocellular carcinoma. Liver cells sense their environment, including the inflammatory environment, through the activities of receptor-mediated signal transduction pathways. These pathways are organized in a complex interconnected network, and it is becoming increasingly recognized that cellular adaptations result from the quantitative integration of multi-pathway network activities, rather than isolated pathways causing particular phenotypes. Therefore comprehending liver cell signalling in inflammation requires a scientific approach that is appropriate for studying complex networks. In the present paper, we review our application of systems analyses of liver cell signalling in response to inflammatory environments. Our studies feature broad measurements of cell signalling and phenotypes in response to numerous experimental perturbations reflective of inflammatory environments, the data from which are analysed using Boolean and fuzzy logic models and regression-based methods in order to quantitatively relate the phenotypic responses to cell signalling network states. Our principal biological insight from these studies is that hepatocellular carcinoma cells feature uncoupled inflammatory and growth factor signalling, which may underlie their immune evasion and hyperproliferative properties. PMID- 22260680 TI - Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. AB - In the present paper, we describe multiple levels of cross-talk between the PI3K (phosphoinositide 3-kinase)/Akt and Ras/MAPK (mitogen-activated protein kinase) signalling pathways. Experimental data and computer simulations demonstrate that cross-talk is context-dependent and that both pathways can activate or inhibit each other. Positive influence of the PI3K pathway on the MAPK pathway is most effective at sufficiently low doses of growth factors, whereas negative influence of the MAPK pathway on the PI3K pathway is mostly pronounced at high doses of growth factors. Pathway cross-talk endows a cell with emerging capabilities for processing and decoding signals from multiple receptors activated by different combinations of extracellular cues. PMID- 22260681 TI - From parathyroid hormone to cytosolic Ca2+ signals. AB - PTHR1 (type 1 parathyroid hormone receptors) mediate the effects of PTH (parathyroid hormone) on bone remodelling and plasma Ca2+ homoeostasis. PTH, via PTHR1, can stimulate both AC (adenylate cyclase) and increases in [Ca2+]i (cytosolic free Ca2+ concentration), although the relationship between the two responses differs between cell types. In the present paper, we review briefly the mechanisms that influence coupling of PTHR1 to different intracellular signalling proteins, including the G-proteins that stimulate AC or PLC (phospholipase C). Stimulus intensity, the ability of different PTH analogues to stabilize different receptor conformations ('stimulus trafficking'), and association of PTHR1 with scaffold proteins, notably NHERF1 and NHERF2 (Na+/H+ exchanger regulatory factor 1 and 2), contribute to defining the interactions between signalling proteins and PTHR1. In addition, cAMP itself can, via Epac (exchange protein directly activated by cAMP), PKA (protein kinase A) or by binding directly to IP3Rs [Ins(1,4,5)P3 receptors] regulate [Ca2+]i. Epac leads to activation of PLCepsilon, PKA can phosphorylate and thereby increase the sensitivity of IP3Rs and L-type Ca2+ channels, and cAMP delivered at high concentrations to IP3R2 from AC6 increases the sensitivity of IP3Rs to InsP3. The diversity of these links between PTH and [Ca2+]i highlights the versatility of PTHR1. This versatility allows PTHR1 to evoke different responses when stimulated by each of its physiological ligands, PTH and PTH-related peptide, and it provides scope for development of ligands that selectively harness the anabolic effects of PTH for more effective treatment of osteoporosis. PMID- 22260682 TI - Triggering of Ca2+ signals by NAADP-gated two-pore channels: a role for membrane contact sites? AB - NAADP (nicotinic acid-adenine dinucleotide phosphate) is a potent Ca2+-mobilizing messenger implicated in many Ca2+-dependent cellular processes. It is highly unusual in that it appears to trigger Ca2+ release from acidic organelles such as lysosomes. These signals are often amplified by archetypal Ca2+ channels located in the endoplasmic reticulum. Recent studies have converged on the TPCs (two-pore channels) which localize to the endolysosomal system as the likely primary targets through which NAADP mediates its effects. 'Chatter' between TPCs and endoplasmic reticulum Ca2+ channels is disrupted when TPCs are directed away from the endolysosomal system. This suggests that intracellular Ca2+ release channels may be closely apposed, possibly at specific membrane contact sites between acidic organelles and the endoplasmic reticulum. PMID- 22260683 TI - Mitochondrial organization and Ca2+ uptake. AB - Mitochondria may function as multiple separate organelles or as a single electrically coupled continuum to modulate changes in [Ca2+]c (cytoplasmic Ca2+ concentration) in various cell types. Mitochondria may also be tethered to the internal Ca2+ store or plasma membrane in particular parts of cells to facilitate the organelles modulation of local and global [Ca2+]c increases. Differences in the organization and positioning contributes significantly to the at times apparently contradictory reports on the way mitochondria modulate [Ca2+]c signals. In the present paper, we review the organization of mitochondria and the organelles role in Ca2+ signalling. PMID- 22260684 TI - Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis. AB - mTORC1 (mammalian target of rapamycin complex 1) is controlled by diverse signals (e.g. hormones, growth factors, nutrients and cellular energy status) and regulates a range of processes including anabolic metabolism, cell growth and cell division. We have studied the impact of inhibiting mTOR on protein synthesis in human cells. Partial inhibition of mTORC1 by rapamycin has only a limited impact on protein synthesis, but inhibiting mTOR kinase activity causes much greater inhibition of protein synthesis. Using a pulsed stable-isotope-labelling technique, we show that the rapamycin and mTOR (mammalian target of rapamycin) kinase inhibitors have differential effects on the synthesis of specific proteins. In particular, the synthesis of proteins encoded by mRNAs that have a 5'-terminal pyrimidine tract is strongly inhibited by mTOR kinase inhibitors. Many of these mRNAs encode ribosomal proteins. mTORC1 also promotes the synthesis of rRNA, although the mechanisms involved remain to be clarified. We found that mTORC1 also regulates the processing of the precursors of rRNA. mTORC1 thus co ordinates several steps in ribosome biogenesis. PMID- 22260685 TI - DNA double-strand break repair within heterochromatic regions. AB - DNA DSBs (double-strand breaks) represent a critical lesion for a cell, with misrepair being potentially as harmful as lack of repair. In mammalian cells, DSBs are predominantly repaired by non-homologous end-joining or homologous recombination. The kinetics of repair of DSBs can differ widely, and recent studies have shown that the higher-order chromatin structure can dramatically affect the pathway utilized, the rate of repair and the genetic factors required for repair. Studies of the repair of DSBs arising within heterochromatic DNA regions have provided insight into the constraints that higher-order chromatin structure poses on repair and the processing that is uniquely required for the repair of such DSBs. In the present paper, we provide an overview of our current understanding of the process of heterochromatic DSB repair in mammalian cells and consider the evolutionary conservation of the processes. PMID- 22260686 TI - cAMP measurements with FRET-based sensors in excitable cells. AB - The development of FRET (fluorescence resonance energy transfer)-based sensors for measuring cAMP has opened the door to sophisticated insights into single-cell cAMP dynamics. cAMP can be measured in distinct cell populations and even in distinct microdomains within cells. However, there is still only limited information on cAMP dynamics in excitable cells, particularly as a function of the activity of voltage-gated Ca2+ channels. A major reason for this is the pH shifts that can occur in excitable cells and their effects on fluorescent proteins. PMID- 22260687 TI - Human epidermal growth factor receptor (HER1) aligned on the plasma membrane adopts key features of Drosophila EGFR asymmetry. AB - Current models suggest that ligand-binding heterogeneity in HER1 [human EGFR (epidermal growth factor receptor] arises from negative co-operativity in signalling HER1 dimers, for which the asymmetry of the extracellular region of the Drosophila EGFR has recently provided a structural basis. However, no asymmetry is apparent in the current crystal structure of the isolated extracellular region of HER1. This receptor also differs from the Drosophila EGFR in that negative co-operativity is found only in full-length receptors in cells. Structural insights into HER1 in epithelial cells, derived from FLIM (fluorescence lifetime imaging microscopy) and two-dimensional FRET (Forster resonance energy transfer) combined with Monte Carlo and molecular dynamics simulations, have demonstrated a high-affinity ligand-binding HER1 conformation consistent with the extracellular region aligned flat on the plasma membrane. This conformation shares key features with that of the Drosophila EGFR, suggesting that the structural basis for negative co-operativity is conserved from invertebrates to humans, but that, in HER1, the extracellular region asymmetry requires interactions with the plasma membrane. PMID- 22260688 TI - Investigating extracellular in situ EGFR structure and conformational changes using FRET microscopy. AB - The crystallographic structures of functional fragments of ErbBs have provided excellent insights into the geometry of growth factor binding and receptor dimerization. By placing together receptor fragments to build structural models of entire receptors, we expect to understand how these enzymes are allosterically regulated; however, several predictions from these models are inconsistent with experimental evidence from cells. The opening of this gap underlines the need to investigate intact ErbBs by combining cellular and structural studies into a full picture. PMID- 22260689 TI - The regulatory role of the juxtamembrane region in the activity of the epidermal growth factor receptor. AB - Although the EGFR (epidermal growth factor receptor) was discovered over 30 years ago, its mechanism of activation is still the subject of intense study. There are many published studies on the mechanism of EGFR activation and regulation, including biochemical and biophysical analyses and crystallographic structures of EGFR in different activation states and conformations, mutated at various amino acids or bound to different pharmacological inhibitors. The cumulative biochemical, biophysical and structural data have led to a nearly complete account of the mechanism of activation of EGFR. The role of the JXM (juxtamembrane) domain in EGFR structure and activity has only recently begun to be elucidated through biochemical, biophysical and structural studies. In the present article, I review the studies that have highlighted the role of the JXM domain in EGFR activation. PMID- 22260690 TI - Non-genomic progesterone signalling and its non-canonical receptor. AB - The steroid hormone progesterone regulates many critical aspects of vertebrate physiology. The nuclear receptor for progesterone functions as a ligand-activated transcription factor, directly regulating gene expression. This type of signalling is referred to as the 'genomic' pathway. Nevertheless, progesterone also stimulates rapid physiological effects that are independent of transcription. This pathway, termed 'non-genomic', is mediated by the mPRs (membrane progesterone receptors). These mPRs belong to a larger class of membrane receptors called PAQRs (progestin and adipoQ receptors), which include receptors for adiponectin in vertebrates and osmotin in fungi. mPRs have been shown to activate inhibitory G-proteins, suggesting that they act as GPCRs (G protein-coupled receptors). However, PAQRs do not resemble GPCRs with respect to topology or conserved sequence motifs. Instead, they more closely resemble proteins in the alkaline ceramidase family and they may possess enzymatic activity. In the present paper, we highlight the evidence in support of each model and what is currently known for PAQR signal transduction of this non canonical receptor. PMID- 22260691 TI - Growth and metabolic control of lipid signalling at the Golgi. AB - PtdIns4P is a key regulator of the secretory pathway and plays an essential role in trafficking from the Golgi. Our recent work demonstrated that spatial control of PtdIns4P at the ER (endoplasmic reticulum) and Golgi co-ordinates secretion with cell growth. The central elements of this regulation are specific phosphoinositide 4-kinases and the phosphoinositide phosphatase Sac1. Growth dependent translocation of Sac1 between the ER and Golgi modulates the levels of PtdIns4P and anterograde traffic at the Golgi. In yeast, this mechanism is largely dependent on the availability of glucose, but our recent results in mammalian cells suggest that Sac1 phosphatases play evolutionarily conserved roles in the growth control of secretion. Sac1 lipid phosphatase plays also an essential role in the spatial control of PtdIns4P at the Golgi complex. A restricted pool of PtdIns4P at the TGN (trans-Golgi network) is required for Golgi integrity and for proper lipid and protein sorting. In mammalian cells, the stress-activated MAPK (mitogen-activated protein kinase) p38 appears to play a critical role in transmitting nutrient signals to the phosphoinositide signalling machinery at the ER and Golgi. These results suggest that temporal and spatial integration of metabolic and lipid signalling networks at the Golgi is required for controlling the secretory pathway. PMID- 22260692 TI - PKA phosphorylation of the small heat-shock protein Hsp20 enhances its cardioprotective effects. AB - The small heat-shock protein Hsp20 (heat-shock protein 20), also known as HspB6, has been shown to protect against a number of pathophysiological cardiac processes, including hypertrophy and apoptosis. Following beta-adrenergic stimulation and local increases in cAMP, Hsp20 is phosphorylated on Ser16 by PKA (protein kinase A). This covalent modification is required for many of its cardioprotective effects. Both Hsp20 expression levels and its phosphorylation on Ser16 are increased in ischaemic myocardium. Transgenic mouse models with cardiac specific overexpression of Hsp20 that are subject to ischaemia/reperfusion show smaller myocardial infarcts, and improved recovery of contractile performance during the reperfusion phase, compared with wild-type mice. This has been attributed to Hsp20's ability to protect against cardiomyocyte necrosis and apoptosis. Phosphomimics of Hsp20 (S16D mutants) confer improved protection from beta-agonist-induced apoptosis in the heart, whereas phospho-null mutants (S16A) provide no protection. Naturally occurring mutants of Hsp20 at position 20 (P20L substitution) are associated with markedly reduced Hsp20 phosphorylation at Ser16, and this lack of phosphorylation correlates with abrogation of Hsp20's cardioprotective effects. Therefore phosphorylation of Hsp20 at Ser16 by PKA is vital for the cardioprotective actions of this small heat-shock protein. Selective targeting of signalling elements that can enhance this modification represents an exciting new therapeutic avenue for the prevention and treatment of myocardial remodelling and ischaemic injury. PMID- 22260693 TI - Unbiased identification of substrates for the Epac1-inducible E3 ubiquitin ligase component SOCS-3. AB - The anti-inflammatory effects of the prototypical second messenger cAMP have been extensively documented in multiple cell types. One mechanism by which these effects are achieved is via Epac1 (exchange protein directly activated by cAMP 1) dependent induction of SOCS-3 (suppressor of cytokine signalling 3), which binds and inhibits specific class I cytokine receptors. One important aspect of SOCS-3 functionality is its role as the specificity determinant within an E3 ubiquitin ligase complex which targets cellular substrates for polyubiquitylation and proteasomal degradation. In the present review, we describe key inhibitory processes that serve to reduce cytokine receptor signalling, focusing primarily on SOCS protein function and regulation. We also outline a strategy we have developed to identify novel ubiquitylated substrates for the Epac1-inducible SOCS 3 E3 ubiquitin ligase complex following purification of the ubiquitinome. It is anticipated that identifying substrates for the Epac1-regulated SOCS-3 E3 ubiquitin ligase, and assessment of their functional significance, may pinpoint new sites for therapeutic intervention that would achieve therapeutic efficacy of cAMP-elevating drugs while minimizing the adverse effects usually associated with these agents. PMID- 22260694 TI - cAMP-dependent allostery and dynamics in Epac: an NMR view. AB - Epac (exchange protein directly activated by cAMP) is a critical cAMP receptor, which senses cAMP and couples the cAMP signal to the catalysis of guanine exchange in the Rap substrate. In the present paper, we review the NMR studies that we have undertaken on the CBD (cyclic-nucleotide-binding domain) of Epac1. Our NMR investigations have shown that cAMP controls distal autoinhibitory interactions through long-range modulations in dynamics. Such dynamically mediated allosteric effects contribute not only to the cAMP-dependent activation of Epac, but also to the selectivity of Epac for cAMP in contrast with cGMP. In addition, we have mapped the interaction networks that couple the cAMP-binding site to the sites involved in the autoinhibitory interactions, using a method based on the covariance analysis of NMR chemical shifts. We anticipate that this approach is generally applicable to dissect allosteric networks in signalling domains. PMID- 22260695 TI - ERK phosphorylation and nuclear accumulation: insights from single-cell imaging. AB - Many stimuli mediate activation and nuclear translocation of ERK (extracellular signal-regulated kinase) by phosphorylation on the TEY (Thr-Glu-Tyr) motif. This is necessary to initiate transcriptional programmes controlling cellular responses, but the mechanisms that govern ERK nuclear targeting are unclear. Single-cell imaging approaches have done much to increase our understanding of input-output relationships in the ERK cascade, but few studies have addressed how the range of ERK phosphorylation responses observed in cell populations influences subcellular localization. Using automated microscopy to explore ERK regulation in single adherent cells, we find that nuclear localization responses increase in proportion to stimulus level, but not the level of TEY phosphorylation. This phosphorylation-unattributable nuclear localization response occurs in the presence of tyrosine phosphatase and protein synthesis inhibitors. It is also seen with a catalytically inactive ERK2-GFP (green fluorescent protein) mutant, and with a mutant incapable of binding the DEF (docking site for ERK, F/Y-X-F/Y-P) domains found in many ERK-binding partners. It is, however, reduced by MEK (mitogen-activated protein kinase/ERK kinase) inhibition and by mutations preventing TEY phosphorylation or in the ERK common docking region. We therefore show that TEY phosphorylation of ERK is necessary, but not sufficient, for the full nuclear accumulation response and that this 'phosphorylation-unattributable' component of stimulus-mediated ERK nuclear localization requires association with partner proteins via the common docking motif. PMID- 22260696 TI - The roles of ATF2 (activating transcription factor 2) in tumorigenesis. AB - MAPK (mitogen-activated protein kinase) pathways are among the most frequently deregulated signalling events in cancer. Among the critical targets of MAPK activities are members of the AP-1 (activator protein 1) transcription factor, a dimeric complex consisting of Jun, Fos, Maf and ATF (activating transcription factor) family DNA-binding proteins. Depending on the cellular context, the composition of the dimeric complexes determines the regulation of growth, survival or apoptosis. JNK (c-Jun N-terminal kinase), p38 and a number of Jun and Fos family proteins have been analysed for their involvement in oncogenic transformation and tumour formation. These data are also emerging for the ATF components of the AP-1 factor. The aim of the present review is to provide an overview of the functions of two ATF family proteins, ATF2 and ATF7, in mammalian development and their potential functions in tumour formation. PMID- 22260697 TI - MKP-2: out of the DUSP-bin and back into the limelight. AB - The MKPs (mitogen-activated protein kinase phosphatases) are a family of at least ten DUSPs (dual-specificity phosphatases) which function to terminate the activity of the MAPKs (mitogen-activated protein kinases). Several members have already been demonstrated to have distinct roles in immune function, cancer, fetal development and metabolic disorders. One DUSP of renewed interest is the inducible nuclear phosphatase MKP-2, which dephosphorylates both ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase) in vitro. Recently, the understanding of MKP-2 function has been advanced due to the development of mouse knockout models, which has resulted in the discovery of novel roles for MKP-2 in the regulation of sepsis, infection and cell-cycle progression that are distinct from those of other DUSPs. However, many functions for MKP-2 still await to be characterized. PMID- 22260698 TI - Targeting phosphoinositide 3-kinase delta for allergic asthma. AB - Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kdelta (phosphoinositide 3-kinase delta) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kdelta inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kdelta is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kdelta should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kdelta inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kdelta inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma. PMID- 22260699 TI - Organization of cAMP signalling microdomains for optimal regulation by Ca2+ entry. AB - Cross-talk between cAMP and Ca2+ signalling pathways plays a critical role in cellular homoeostasis. Several AC (adenylate cyclase) isoforms, catalysing the production of cAMP from ATP, display sensitivity to submicromolar changes in intracellular Ca2+ and, as a consequence, are key sites for Ca2+ and cAMP interplay. Interestingly, these Ca2+-regulated ACs are not equally responsive to equivalent Ca2+ rises within the cell, but display a remarkable selectivity for regulation by SOCE (store-operated Ca2+ entry). Over the years, considerable efforts at investigating this phenomenon have provided indirect evidence of an intimate association between Ca2+-sensitive AC isoforms and sites of SOCE. Now, recent identification of the molecular components of SOCE [namely STIM1 (stromal interaction molecule 1) and Orai1], coupled with significant advances in the generation of high-resolution targeted biosensors for Ca2+ and cAMP, have provided the first detailed insight into the organization of the cellular microdomains associated with Ca2+-regulated ACs. In the present review, I summarize the findings that have helped to provide our most definitive understanding of the selective regulation of cAMP signalling by SOCE. PMID- 22260700 TI - ERK5 and its role in tumour development. AB - The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the 'hallmarks of cancer' as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer. PMID- 22260701 TI - The emerging role of PtdIns5P: another signalling phosphoinositide takes its place. AB - Of the seven phosphoinositides, PtdIns5P remains the most enigmatic. However, recent research has begun to elucidate its physiological functions. It is now clear that PtdIns5P is found in several distinct subcellular locations, and the identification of a number of PtdIns5P-binding proteins points to its involvement in a variety of key processes, including signal transduction, membrane trafficking and regulation of gene expression. Although the mechanisms that control its turnover are not yet fully understood, the existence of multiple pathways for PtdIns5P regulation is consistent with this emerging versatility. PMID- 22260702 TI - The regulation of myosin phosphatase in pregnant human myometrium. AB - Myometrial smooth muscle contractility is regulated predominantly through the reversible phosphorylation of MYLs (myosin light chains), catalysed by MYLK (MYL kinase) and MYLP (MYL phosphatase) activities. MYLK is activated by Ca2+ calmodulin, and most uterotonic agonists operate through myometrial receptors that increase [Ca2+]i (intracellular Ca2+ concentration). Moreover, there is substantial evidence for Ca2+-independent inhibition of MYLP in smooth muscle, leading to generation of increased MYL phosphorylation and force for a given [Ca2+]i, a phenomenon known as 'Ca2+-sensitization'. ROCK (Rho-associated kinase) mediated phosphorylation and inhibition of MYLP has been proposed as a mechanism for Ca2+-sensitization in smooth muscle. However, it is unclear to date whether the mechanisms that sensitize the contractile machinery to Ca2+ are important in the myometrium, as they appear to be in vascular and respiratory smooth muscle. In the present paper, we discuss the signalling pathways regulating MYLP activity and the involvement of ROCK in myometrial contractility, and present recent data from our laboratory which support a role for Ca2+-sensitization in human myometrium. PMID- 22260703 TI - The small Rho GTPase Rif and actin cytoskeletal remodelling. AB - The Rif GTPase is a recent addition to small Rho GTPase family; it shares low homology with other members in the family and evolutionarily parallels with the development of vertebrates. Rif has the conserved Rho GTPase domain structures and cycles between a GDP-bound inactive form and a GTP-bound active form. In its active form, Rif signals through multiple downstream effectors. In the present review, our aim is to summarize the current information about the Rif effectors and how Rif remodels actin cytoskeleton in many aspects. PMID- 22260704 TI - Decoding neurohormone pulse frequency by convergent signalling modules. AB - GnRH (gonadotropin-releasing hormone) mediates control of reproduction. It is secreted in pulses and acts via intracellular effectors to activate gene expression. Submaximal GnRH pulse frequency can elicit maximal responses, yielding bell-shaped frequency-response curves characteristic of genuine frequency decoders. GnRH frequency decoding is therapeutically important (pulsatile GnRH can drive ovulation in assisted reproduction, whereas sustained activation can treat breast and prostate cancers), but the mechanisms are unknown. In the present paper, we review recent work in this area, placing emphasis on the regulation of transcription, and showing how mathematical modelling of GnRH effects on two effectors [ERK (extracellular-signal-regulated kinase) and NFAT (nuclear factor of activated T-cells)] reveals the potential for genuine frequency decoding as an emergent feature of the GnRH signalling network, rather than an intrinsic feature of a given protein or pathway within it. PMID- 22260705 TI - IP3R, store-operated Ca2+ entry and neuronal Ca2+ homoeostasis in Drosophila. AB - The IP3R (inositol 1,4,5-trisphosphate receptor) releases Ca2+ from the ER (endoplasmic reticulum) store upon binding to its ligand InsP3, which is thought to be generated by activation of certain membrane-bound G-protein-coupled receptors in Drosophila. Depletion of Ca2+ in the ER store also activates SOCE (store-operated Ca2+ entry) from the extracellular milieu across the plasma membrane, leading to a second rise in cytosolic Ca2+, which is then pumped back into the ER. The role of the IP3R and SOCE in mediating Ca2+ homoeostasis in neurons, their requirement in neuronal function and effect on neuronal physiology and as a consequence behaviour, are reviewed in the present article. PMID- 22260706 TI - Putative roles for phospholipase Ceta enzymes in neuronal Ca2+ signal modulation. AB - The most recently identified PLC (phospholipase C) enzymes belong to the PLCeta family. Their unique Ca2+-sensitivity and their specific appearance in neurons have attracted great attention since their discovery; however, their physiological role(s) in neurons are still yet to be established. PLCeta enzymes are expressed in the neocortex, hippocampus and cerebellum. PLCeta2 is also expressed at high levels in pituitary gland, pineal gland and in the retina. Driven by the specific localization of PLCeta enzymes in different brain areas, in the present paper, we discuss the roles that they may play in neural processes, including differentiation, memory formation, circadian rhythm regulation, neurotransmitter/hormone release and the pathogenesis of neurodegenerative disorders associated with aberrant Ca2+ signalling, such as Alzheimer's disease. PMID- 22260707 TI - Protein kinase D in the hypertrophy pathway. AB - Chronic neurohormonal stimulation can have direct adverse effects on the structure and function of the heart. Heart failure develops and progresses as a result of the deleterious changes. It is well established that phosphorylation of class II HDAC5 (histone deacetylase 5) is an important event in the transcriptional regulation of cardiac gene reprogramming that results in the hypertrophic growth response. To date, experimentation on phosphorylation mediated translocation of HDAC5 has focused on the regulatory properties of PKD (protein kinase D) within intact cells. With regard to the potential role of PKD in myocardium, recent observations raise the possibility that PKD-mediated myocardial regulatory mechanisms may represent promising therapeutic avenues for the treatment of heart failure. The present review summarizes the most recent and important insights into the role of PKD in hypertrophic signalling pathways. PMID- 22260708 TI - Histone H4 histidine phosphorylation: kinases, phosphatases, liver regeneration and cancer. AB - Phosphorylation of histone H4 on one or both of its two histidine residues has been known to occur in liver cells for nearly 40 years and has been associated with proliferation of hepatocytes during regeneration of the liver following mechanical damage. More recently, large increases in histone H4 histidine kinase activity have been found to occur associated with proliferation and differentiation of liver progenitor cells following chemical damage that prevents hepatocyte proliferation. In addition, it has been shown this histone H4 histidine kinase activity is elevated nearly 100-fold in human foetal liver and several hundredfold in hepatocellular carcinoma tissue compared with normal adult liver. In the present paper, we review what is currently known about histone H4 histidine phosphorylation, the kinase(s) responsible and the phosphatases capable of catalysing its dephosphorylation, and briefly summarize the techniques used to detect and measure the histidine phosphorylation of histone H4 and the corresponding kinase activity. PMID- 22260710 TI - Interim-treatment quantitative PET parameters predict progression and death among patients with Hodgkin's disease. AB - PURPOSE: We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients. METHODS: Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS >= 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUV mean), maximum SUV (SUV max) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS). RESULTS: Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUV max from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre treatment values) were associated with OS: MTV int/pre (p < 0.01), SUV mean int/pre (p < 0.05), SUV max int/pre (p = 0.01), and iSUV int/pre (p < 0.01). Absolute value SUV max from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTV int/pre (p = 0.01), SUV max int/pre (p = 0.02) and iSUV int/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01). CONCLUSIONS: Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification. PMID- 22260711 TI - Heteroarylation of azine N-oxides. AB - Azine N-oxides undergo highly regioselective metalation with TMPZnCl.LiCl under mild conditions. A palladium-catalyzed Negishi cross-coupling reaction of the resulting organozinc species with heteroaromatic bromides provides heterobiaryls specifically oxidized at one nitrogen position in up to 95% yield. PMID- 22260712 TI - Proton-coupled intervalence charge transfer: concerted processes. AB - The kinetics of proton-induced intervalence charge transfer (IVCT) may be measured electrochemically by generating one of the members of the IVCT couple in situ and following its conversion by means of the electrochemical signature of the other member of the couple. In the case of the diiron complex taken as an example, the reaction kinetics analysis, including the H/D isotope effect, clearly points to the prevalence of the concerted proton-intervalence charge transfer pathway over the stepwise pathways. A route is thus open toward systematic kinetic studies of proton-induced IVCT aiming at uncovering the main reactivity parameters and the factors that control the occurrence of concerted versus stepwise pathways. PMID- 22260713 TI - Effect of running therapy on depression (EFFORT-D). Design of a randomised controlled trial in adult patients [ISRCTN 1894]. AB - BACKGROUND: The societal and personal burden of depressive illness is considerable. Despite the developments in treatment strategies, the effectiveness of both medication and psychotherapy is not ideal. Physical activity, including exercise, is a relatively cheap and non-harmful lifestyle intervention which lacks the side-effects of medication and does not require the introspective ability necessary for most psychotherapies. Several cohort studies and randomised controlled trials (RCTs) have been performed to establish the effect of physical activity on prevention and remission of depressive illness. However, recent meta analysis's of all RCTs in this area showed conflicting results. The objective of the present article is to describe the design of a RCT examining the effect of exercise on depressive patients. METHODS/DESIGN: The EFFect Of Running Therapy on Depression in adults (EFFORT-D) is a RCT, studying the effectiveness of exercise therapy (running therapy (RT) or Nordic walking (NW)) on depression in adults, in addition to usual care. The study population consists of patients with depressive disorder, Hamilton Rating Scale for Depression (HRSD) >= 14, recruited from specialised mental health care. The experimental group receives the exercise intervention besides treatment as usual, the control group receives treatment as usual. The intervention program is a group-based, 1 h session, two times a week for 6 months and of increasing intensity. The control group only performs low intensive non-aerobic exercises. Measurements are performed at inclusion and at 3,6 and 12 months.Primary outcome measure is reduction in depressive symptoms measured by the HRSD. Cardio-respiratory fitness is measured using a sub maximal cycling test, biometric information is gathered and blood samples are collected for metabolic parameters. Also, co-morbidity with pain, anxiety and personality traits is studied, as well as quality of life and cost-effectiveness. DISCUSSION: Exercise in depression can be used as a standalone or as an add-on intervention. In specialised mental health care, chronic forms of depression, co-morbid anxiety or physical complaints and treatment resistance are common. An add-on strategy therefore seems the best choice. This is the first high quality large trial into the effectiveness of exercise as an add-on treatment for depression in adult patients in specialised mental health care. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1894. PMID- 22260715 TI - High-level tolerance to triclosan may play a role in Pseudomonas aeruginosa antibiotic resistance in immunocompromised hosts: evidence from outbreak investigation. AB - BACKGROUND AND METHODS: Pseudomonas aeruginosa is a major infectious threat to immunocompromised patients. We recently reported a fatal epidemic of multidrug resistant P. aeruginosa in an onchoematology unit, linked to massive contamination of a triclosan-based disinfectant. The aim of this study is to evaluate the antimicrobial activity of triclosan and chlorhexidine digluconate against the epidemic strain of P. aeruginosa, to confirm the hypothesis that the soap dispenser acted as a continuous source of the infection during the outbreak, and to explore the potential role of triclosan in increasing the level of resistance to selected antibiotics.Susceptibility tests and time-kill assays for disinfectans were performed using two commercial formulations containing triclosan and chlorhexidine digluconate, respectively. Antibiotic susceptibility testing was performed by the broth microdilution method. FINDINGS: The P. aeruginosa epidemic strain exhibited an extremely high level of triclosan resistance (apparent MIC = 2,125 mg/L), while it was markedly susceptible to chlorhexidine digluconate (apparent MIC = 12.5 mg/L). Upon gradual adaptation to triclosan, the epidemic strain survived for a long period (> 120 h) in the presence of 3,400 mg/L (equivalent to 1.6 * MIC) of triclosan, concomitantly increasing the resistance to six antibiotics that are typical substrates of drug efflux pumps of the resistance nodulation division family. This effect was reversed by efflux pump inhibitors. CONCLUSIONS: The epidemic P. aeruginosa strain was resistant to triclosan and its previous exposure to triclosan increases antibiotic resistance, likely through active efflux mechanisms. Since P. aeruginosa can become tolerant to elevated triclosan concentrations, the use of triclosan-based disinfectants should be avoided in those healthcare settings hosting patients at high risk for P. aeruginosa infection. PMID- 22260717 TI - Robot-assisted laparoendoscopic single-site pyeloplasty: technique using the da Vinci Si robotic platform. AB - Conventional laparoscopic dismembered pyeloplasty (LP) is an established alternative to open pyeloplasty given equivalent intermediate-term outcomes and decreased morbidity. Laparoendoscopic single-site (LESS) pyeloplasty has the potential to further decrease the morbidity of LP, while yielding superior cosmesis. It is, however, technically very challenging even with the use of an accessory port, largely because of the difficulty of intracorporeal suturing through a single umbilical incision. Application of the da Vinci robotic surgical platform to LESS pyeloplasty (R-LESS) has the potential to overcome these limitations. We describe our technique for R-LESS pyeloplasty using the da Vinci Si robot. We have found that use of the robotic system in conjunction with certain technique modifications helps to reduce the technical difficulty of LESS pyeloplasty and to shorten the physical learning curve associated with the procedure. PMID- 22260716 TI - Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. AB - BACKGROUND: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. OBJECTIVES: To compare different assays for prediction of events during long-term follow-up. METHODS: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. RESULTS: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. CONCLUSIONS: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping. PMID- 22260718 TI - Hyponatremic renal pseudofailure and massive ascites following normal vaginal delivery: a diagnostic and therapeutic challenge. AB - We report the fifth, to our knowledge, published case of spontaneous intraperitoneal bladder rupture after normal, vacuum-assisted in this occasion, vaginal delivery of a 29-year-old female patient. Diagnosis was established not by imaging or intraoperative findings, but, rather, by the examination and comparison of patient's blood, urine, and peritoneal fluid urea and creatinine levels, which, due to the patient's delayed referral and sequent development of uroperitoneum and hyponatremic renal pseudofailure, were abnormal and characteristic of her medical condition. The patient was successfully managed conservatively and was discharged the sixth day after admission. Due to the rare nature of such medical condition and based on the relative literature, we propose a diagnostic and management algorithm for such cases. PMID- 22260719 TI - Transfer of the K+ cation across a water/dichloromethane interface: a steered molecular dynamics study with implications in cation extraction. AB - In this paper we report the characterization of the dichloromethane (DCM)/water interface in terms of density profile, width, and surface structure. The use of steered molecular dynamics (SMD) to study the transfer of the K(+) cation from the organic layer to the water layer is also described. The corresponding free energy is in semiquantitative agreement with published experimental and theoretical results. The transference of the K(+) cation from the water layer toward the DCM layer occurs with concomitant water transport as a water microdroplet that detaches itself from the water layer after ca. 16 A of penetration into the organic layer by breaking the thin water thread that unites both. Complexation of the water microdroplet by a polyethylene-glycol type podand induces the loss of water molecules from the water microdroplet to bulk DCM and, eventually, to the water layer. PMID- 22260720 TI - High-throughput examination of fluorescence resonance energy transfer-detected metal-ion response in mammalian cells. AB - Fluorescence resonance energy transfer (FRET)-based genetically encoded metal-ion sensors are important tools for studying metal-ion dynamics in live cells. We present a time-resolved microfluidic flow cytometer capable of characterizing the FRET-based dynamic response of metal-ion sensors in mammalian cells at a throughput of 15 cells/s with a time window encompassing a few milliseconds to a few seconds after mixing of cells with exogenous ligands. We have used the instrument to examine the cellular heterogeneity of Zn(2+) and Ca(2+) sensor FRET response amplitudes and demonstrated that the cluster maps of the Zn(2+) sensor FRET changes resolve multiple subpopulations. We have also measured the in vivo sensor response kinetics induced by changes in Zn(2+) and Ca(2+) concentrations. We observed an ~30 fold difference between the extracellular and intracellular sensors. PMID- 22260721 TI - Short communication: Drug resistance mutations in the HIV type 1 protease and reverse transcriptase genes in antiretroviral-naive Vietnamese children. AB - Anti-HIV drugs have recently become available for the treatment of children infected with HIV in Vietnam; however, the genetic background of HIV-1 drug resistance in antiretroviral-naive children has yet to be studied. Of the 104 HIV 1 CRF01-AE subtype strains that were previously isolated from antiretroviral naive children from the provinces of southern Vietnam and hospitalized in Children Hospital 1 in Ho Chi Minh City from 2004 to 2005, 79 strains were used for amplification and sequence analyses of the protease and reverse transcriptase (RT) genes. Minor mutations were found in the protease gene, including L10I, I13V, G16E, M36I, D60E, I62V, I64V, L63P, H69K, V82I, and I93L. Of these mutations, M36I and H69K were detected in all of the strains that were studied. However, all of the amino acid changes in the protease gene were considered to be polymorphisms. In the RT gene, three major mutations were detected in six strains: the V75M mutation in one strain, the Y181C mutation in two strains, and the M184I mutation in three strains. The prevalence of primary or transmitted HIV drug resistance to all of the drugs and drug classes that were evaluated in this study was 7.6%. These findings provide a useful background for antiretroviral therapy in Vietnam and contribute reference data for the surveillance of HIV drug resistance around the world. This study suggests that the prevalence of HIVDR in Vietnam may have recently increased. The monitoring of HIV drug resistance in Vietnam is necessary. PMID- 22260722 TI - A bioinformatics search for selective histamine h4 receptor antagonists through structure-based virtual screening strategies. AB - The prevalence of allergic disease is increasing dramatically in the developed world. Studies of allergic diseases have clearly demonstrated that histamine plays an important role in the pathogenesis of the early-phase allergic response. Histamine effects are mediated by H1, H2, H3, and H4 receptors. The presence of the histamine H4 receptors on leukocytes and mast cells suggests that the new histamine receptor H4 plays an important role in the modulation of the immune system. Thus, histamine H4 receptor is an attractive target for anti-allergic therapy. In our present study, we have generated a histamine H4 receptor model using I-TASSER based on human B2-adrenergic G-protein-coupled receptor. Structurally similar compounds of the three known antagonists JNJ777120, thioperamide, and Vuf6002 were retrieved from PubChem, and database was prepared. Virtual screening of those databases was performed, and six compounds with high docking score were identified. Also the binding mode revealed that all the six compounds had interaction with Asp94 of the receptor. Our results serve as a starting point in the development of novel lead compounds in anti-allergic therapy. PMID- 22260723 TI - Structure of the complex monolayer of gemini surfactant and DNA at the air/water interface. AB - The properties of the complex monolayers composed of cationic gemini surfactants, [C(18)H(37)(CH(3))(2)N(+)-(CH(2))(s)-N(+)(CH(3))(2)C(18)H(37)],2Br(-) (18-s-18 with s = 3, 4, 6, 8, 10 and 12), and ds-DNA or ss-DNA at the air/water interface were in situ studied by the surface pressure-area per molecule (pi-A) isotherm measurement and the infrared reflection absorption spectroscopy (IRRAS). The corresponding Langmuir-Blodgett (LB) films were also investigated by the atomic force microscopy (AFM), the Fourier transform infrared spectroscopy (FT-IR), and the circular dichroism spectroscopy (CD). The pi-A isotherms and AFM images reveal that the spacer of gemini surfactant has a significant effect on the surface properties of the complex monolayers. As s <= 6, the gemini/ds-DNA complex monolayers can both laterally and normally aggregate to form fibril structures with heights of 2.0-7.0 nm and widths of from several tens to ~300 nm. As s > 6, they can laterally condense to form the platform structure with about 1.4 nm height. Nevertheless, FT-IR, IRRAS, and CD spectra, as well as AFM images, suggest that DNA retains its double-stranded character when complexed. This is very important and meaningful for gene therapy because it is crucial to maintain the extracellular genes undamaged to obtain a high transfection efficiency. In addition, when s <= 6, the gemini/ds-DNA complex monolayers can experience a transition of DNA molecule from the double-stranded helical structure to a typical psi-phase with a supramolecular chiral order. PMID- 22260725 TI - Commentary: translating quantitative genetics into molecular genetics: decoupling reading disorder and ADHD - reflections on Greven et al. and Rosenberg et al. (2012). PMID- 22260726 TI - Ultrastructural changes in bacterial membranes induced by nano-assemblies beta cyclodextrin chlorhexidine: SEM, AFM, and TEM evaluation. AB - Chemical hosts bind their guests by the same physical mechanisms as biomolecules and often display similarly subtle structure activity relationships. The cyclodextrins have found increasing application as inert, nontoxic carriers of active compounds in drug formulations. The present study was conducted to prepare inclusion complexes of chlorhexidine:beta-cyclodextrin (Cx:beta-cd), and evaluate their interactions with bacterial membrane through: scanning electron microscopy (SEM) and transmission electron microscopy (TEM); and measuring morphology alterations, roughness values, and cell weights by atomic force microscopy (AFM). It was found that the antimicrobial activity was significantly enhanced by cyclodextrin encapsulation. SEM analysis images demonstrated recognizable cell membrane structural changes and ultrastructural membrane swelling. By TEM, cellular alterations such as vacuolization, cellular leakage, and membrane defects were observed; these effects were enhanced at 1:3 and 1:4 Cx:beta-cd. In addition, AFM analysis at these ratios showed substantially more membrane disruption and large aggregates mixing with microorganism remains. In conclusion, nanoaggregates formed by cyclodextrin inclusion compounds create cluster-like structures with the cell membrane, possibly due to a hydrogen rich bonding interaction system with increasing surface roughness and possibly increasing the electrostatic interaction between cationic chlorhexidine with the lipopolysaccharides of Gram negative bacteria. PMID- 22260727 TI - The reliability and validity of the Turkish version of the Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) with pregnant women. AB - This methodological study was planned to translate the Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) into Turkish and to investigate its reliability for both nulliparous and parous women in Turkish population. A total of 660 healthy women with normal pregnancies at gestational ages of between 28 and 40 weeks were recruited. The internal consistency reliability (Cronbach's alpha) was used for determining the reliability of the W-DEQ. Construct validity was also determined utilizing the known-groups method. In this study, independent sample t-tests were used to compare the nulliparous and parous groups differing in known fear status. In order to test the construct of the W-DEQ, Beck Anxiety Inventory, Depression Anxiety and Stress Scale and Brief Measure of Worry Severity scales were chosen as these scales are expected to correlate with the W DEQ. Analysis of the construct validity of the W-DEQ version A using Pearson's correlation coefficients was performed for both nulliparous and parous women separately. All the scales in both groups showed a statistically significant correlation with the W-DEQ. The alpha coefficient (0.89) is well above the 0.70 criterion for internal consistency reliability. Turkish form of Wijma Delivery Expectancy/Experience Questionnaire Version A was fixed as reliable and valid means to measure the level of fear of childbirth among Turkish pregnants. PMID- 22260728 TI - Apo-8'-lycopenal induces expression of HO-1 and NQO-1 via the ERK/p38-Nrf2-ARE pathway in human HepG2 cells. AB - Lycopene and its metabolite apo-10'-lycopenoic acid have been shown to induce phase II detoxifying/antioxidant enzymes through activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-antioxidant response element (ARE) transcription system. However, little is known about whether apo-8'-lyocpenal, one of the main metabolites of lycopene in rat livers, in lycopene-containing food, and in human plasma, has similar effects. This study investigated the effect of apo-8'-lycopenal on Nrf2-ARE system-mediated heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO-1) expression in human HepG2 cells. It was found that apo-8'-lycopenal (1-10 MUM) significantly increased nuclear Nrf2 accumulation, ARE-luciferase activity, Nrf2-ARE binding activity, chymotrypsin like activity, and downstream HO-1 and NQO-1 expression, but decreased cytosolic Kelch-like ECH-associated protein 1 (Keap1) expression. Results also revealed that the ERK/p38-Nrf2 pathway is involved in activation of HO-1 and NQO-1 expression by apo-8'-lycopenal using Nrf2 siRNA and ERK/p38 specific inhibitors. In addition, the activation time of lycopene on nuclear Nrf2 accumulation is slower than that of apo-8'-lycopenal, suggesting that the chemopreventive effects of lycopene may be partially attributed to its metabolites. PMID- 22260729 TI - Proteomic profiles of white sucker (Catostomus commersonii) sampled from within the Thunder Bay Area of Concern reveal up-regulation of proteins associated with tumor formation and exposure to environmental estrogens. AB - White sucker (Catostomus commersonii) sampled from the Thunder Bay Area of Concern were assessed for health using a shotgun approach to compile proteomic profiles. Plasma proteins were sampled from male and female fish from a reference location, an area in recovery within Thunder Bay Harbour, and a site at the mouth of the Kaministiquia River where water and sediment quality has been degraded by industrial activities. The proteins were characterized using reverse-phase liquid chromatography tandem to a quadrupole-time-of-flight (LC-Q-TOF) mass spectrometer and were identified by searching in peptide databases. In total, 1086 unique proteins were identified. The identified proteins were then examined by means of a bioinformatics pathway analysis to gain insight into the biological functions and disease pathways that were represented and to assess whether there were any significant changes in protein expression due to sampling location. Female white sucker exhibited significant (p = 0.00183) site-specific changes in the number of plasma proteins that were related to tumor formation, reproductive system disease, and neurological disease. Male fish plasma had a significantly different (p < 0.0001) number of proteins related to neurological disease and tumor formation. Plasma concentrations of vitellogenin were significantly elevated in females from the Kaministiquia River compared to the Thunder Bay Harbour and reference sites. The protein expression profiles indicate that white sucker health has benefited from the remediation of the Thunder Bay Harbour site, whereas white sucker from the Kaministiquia River site are impacted by ongoing contaminant discharges. PMID- 22260731 TI - New insights into the impact of the intestinal microbiota on health and disease: a symposium report. AB - The present report summarises key insights from a recent symposium focusing on the impact of the intestinal microbiota on health and disease. A more appropriate definition of health was proposed since health maintenance is a dynamic process better assessed in terms of ability to adapt to stress and maintain physiological homeostasis. Biomarkers specifically for health are needed; use of challenge models and subjects with suboptimal health or specific disease risk were advised. The complexity of interactions between external factors, the intestinal epithelium, intestinal microbiota, the immune system and health was exemplified by describing the effects of antibiotics, the Western diet and non-digestible carbohydrates on the microbiota. The association of certain bacteria with different states of health or disease was acknowledged but also that is not always clear whether this is a cause or effect. Recent identification of three robust faecal metagenome clusters may advance this understanding. It was speculated that knowledge of the intestinal microbiota profile may eventually help in the diagnosis of health risks and choice of therapy. It was agreed that beneficial manipulation of the commensal microbiota can improve health outcome. For this purpose, three areas were reviewed. Firstly, research into probiotics as vaccine adjuvants was considered useful for substantiation of immune function claims. Secondly, positive results with certain probiotics and synbiotics for colorectal cancer are emerging, mostly from in vitro and animal studies. Finally, studies in endurance athletes have shown strain-specific probiotic benefit in terms of maintenance of immune function and, for certain strains, reduction of episodes of respiratory and/or gastrointestinal tract infections. PMID- 22260730 TI - Transcriptional ontogeny of the developing liver. AB - BACKGROUND: During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hematopoietic stem cells, the source for a number of blood cells including nucleated erythrocytes. A comprehensive analysis of the transcriptional changes that occur during the early stages of development to adulthood in the liver was carried out. RESULTS: We characterized gene expression changes in the developing mouse liver at gestational days (GD) 11.5, 12.5, 13.5, 14.5, 16.5, and 19 and in the neonate (postnatal day (PND) 7 and 32) compared to that in the adult liver (PND67) using full-genome microarrays. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were under expressed. Comparison of the dataset to a number of previously published microarray datasets revealed 1) a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2) a nucleated erythrocyte signature in the fetus and 3) under expression of most xenobiotic metabolism genes throughout development, with the exception of a number of transporters associated with either hematopoietic cells or cell proliferation in hepatocytes. CONCLUSIONS: Overall, these findings reveal the complexity of gene expression changes during liver development and maturation, and provide a foundation to predict responses to chemical and drug exposure as a function of early life-stages. PMID- 22260732 TI - The influence of road transport on the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in equine erythrocytes. AB - BACKGROUND: Transport of horses may have significant impact on serum biochemical and hematologic analytes and resistance to infection. OBJECTIVE: The aim of our study was to assess the influence of transport stress on selected enzymatic antioxidants in equine blood. METHODS: The study was conducted on a group of 60 horses of different breeds and ranging in age from 4 to 10 years. Venous blood was collected immediately before loading horses onto trailers for 8 hours of transport (I), immediately after unloading them from the trailer (II), and after subsequent stall rest for 24 hours (III). Hemolysates of blood were prepared, and hemoglobin (Hb) concentration and activities of the enzymatic antioxidants glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) were measured. Enzyme activities were expressed as units of activity per gram of hemoglobin. RESULTS: There were significant decreases in activities (mean +/- SD U/g Hb [minimum-maximum]) of GPx between collection times I (36 +/- 14 U/g Hb [9-67 U/g Hb]) and III (30 +/- 11 U/g Hb [12-51 U/g Hb]) and of GR between collection times I (54 +/- 28 U/g Hb [7-117 U/g Hb]) and II (40 +/- 23 U/g Hb [12-145 U/g Hb]). There was no significant difference in activities of GR between collection times I and III (50 +/- 27 U/g Hb [9-116 U/g Hb]). There were no differences detected in GST activity among the 3 collection times. CONCLUSION: Road transport has an impact on activities of the antioxidant enzymes GPx and GR, with recovery of GR activity evident by 24 hours post-transport. Decreased activity of these enzymes may be one mechanism for increased susceptibility to infections that are manifest after shipping; alternatively, decreases may indicate utilization as these enzymes work to neutralize increases in reactive oxygen species. PMID- 22260733 TI - What mothers know, and want to know, about the complications of general anaesthesia. AB - BACKGROUND: Informed consent should be sought when performing anaesthesia on pregnant patients. There is no standard for consent for general anaesthesia on the delivery suite. This study was designed to assess post-partum women's awareness of the complications of general anaesthesia and the level of risk at which they felt these risks should be discussed. METHODS: One hundred and fifty parturients from two London hospitals who had undergone uncomplicated vaginal deliveries were asked on the first post-partum day about their knowledge of the potential complications of general anaesthesia for obstetrics. They were also asked about the level of risk at which they would wish to be informed before consenting to a general anaesthetic procedure. RESULTS: The knowledge of the risks of general anaesthesia among the parturients was poor, with awareness, allergy, nausea and vomiting being known by over 50%. Knowledge of difficult intubation and its consequences, dental damage, malignant hyperpyrexia and suxamethonium apnoea was known by less than 30% of the respondents. The level of risk at which mothers felt they should be informed was variable, with 50% wishing to know all risks up to 1 : 1000, and 19% wishing to know risks of greater than 1 : 1,000,000. All known risks were wished by nearly 30% of those questioned. CONCLUSIONS: Anaesthetists must be flexible when providing information to mothers about general anaesthesia and should provide more information to mothers if they wish it. PMID- 22260734 TI - A total synthesis of millingtonine A. AB - A total synthesis of millingtonine A, a diglycosylated alkaloid, has been accomplished. Millingtonine A possesses a unique racemic tricyclic core structure not known from any other natural or synthetic source until now. The synthesis features a key bond-forming radical Ueno-Stork cyclization to form the heterocyclic core. PMID- 22260735 TI - Lactic acid production in Saccharomyces cerevisiae is modulated by expression of the monocarboxylate transporters Jen1 and Ady2. AB - We aimed to manipulate the metabolism of Saccharomyces cerevisiae to produce lactic acid and search for the potential influence of acid transport across the plasma membrane in this process. Saccharomyces cerevisiae W303-1A is able to use l-lactic acid but its production in our laboratory has not previously been detected. When the l-LDH gene from Lactobacillus casei was expressed in S. cerevisiae W303-1A and in the isogenic mutants jen1?, ady2? and jen1? ady2?, all strains were able to produce lactic acid, but higher titres were achieved in the mutant strains. In strains constitutively expressing both LDH and JEN1 or ADY2, a higher external lactic acid concentration was found when glucose was present in the medium, but when glucose was exhausted, its consumption was more pronounced. These results demonstrate that expression of monocarboxylate permeases influences lactic acid production. Ady2 has been previously characterized as an acetate permease but our results demonstrated its additional role in lactate uptake. Overall, we demonstrate that monocarboxylate transporters Jen1 and Ady2 are modulators of lactic acid production and may well be used to manipulate lactic acid export in yeast cells. PMID- 22260736 TI - Efficacy of a text messaging (SMS) based smoking cessation intervention for adolescents and young adults: study protocol of a cluster randomised controlled trial. AB - BACKGROUND: Particularly in groups of adolescents with lower educational level the smoking prevalence is still high and constitutes a serious public health problem. There is limited evidence of effective smoking cessation interventions in this group. Individualised text messaging (SMS) based interventions are promising to support smoking cessation and could be provided to adolescents irrespective of their motivation to quit. The aim of the current paper is to outline the study protocol of a trial testing the efficacy of an SMS based intervention for smoking cessation in apprentices. METHODS/DESIGN: A two-arm cluster-randomised controlled trial will be conducted to test the efficacy of an SMS intervention for smoking cessation in adolescents and young adults compared to an assessment only control group. A total of 910 daily or occasional (>= 4 cigarettes in the preceding month and >= 1 cigarette in the preceding week) smoking apprentices will be proactively recruited in vocational school classes and, using school class as a randomisation unit, randomly assigned to an intervention group (n = 455) receiving the SMS based intervention or an assessment only control group (n = 455). Individualised text messages taking into account demographic data and the individuals' smoking behaviours will be sent to the participants of the intervention group over a period of 3 months. Participants will receive two text messages promoting smoking cessation per week. Program participants who intend to quit smoking have the opportunity to use a more intensive SMS program to prepare for their quit day and to prevent a subsequent relapse. The primary outcome measure will be the proportion of participants with 7-day point prevalence smoking abstinence assessed at 6-months follow-up. The research assistants conducting the baseline and the follow-up assessments will be blinded regarding group assignment. DISCUSSION: It is expected that the program offers an effective and inexpensive way to promote smoking cessation among adolescents and young adults including those with lower educational level and independent of their motivation to quit. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN19739792. PMID- 22260737 TI - Crimean-congo hemorrhagic fever virus in ticks from imported livestock, Egypt. PMID- 22260739 TI - Solvated crystals based on [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) with the hexagonal structure and their phase transformation. AB - This work focuses on the structural exploration of micro-sized crystals based on a well-known methanofullerene, [6,6]-phenyl-C(61)-butyric acid methyl ester (PCBM). We have succeeded in producing PCBM crystals with the hexagonal symmetry through the liquid-liquid interfacial precipitation (LLIP) method. We found that smaller but more regular PCBM crystals tend to form in the oversaturated PCBM solutions with solvents of lower solubility for PCBM, such as tetrahydrofuran (THF) and 1,4-dioxane. The structure of the produced crystals also shows a dependence on the solvents, which can be attributed to the incorporation of different solvent molecules into PCBM crystals. Under thermal annealing, for the first time, we have observed a crystalline to crystalline phase transformation of these hexagonal PCBM crystals. Along with the phase transformation, the morphology of the crystals has also been transformed from the hexagon to long needles. In addition, the needlelike crystals arrange themselves with a relative angle of 60 degrees to each other, which implies an intrinsic structural correlation between needlelike and hexagonal crystals. PMID- 22260740 TI - Developing a laparoscopic radical prostatectomy service: defining the learning curve. AB - BACKGROUND AND PURPOSE: Laparoscopic radical prostatectomy (LRP) is an established treatment for patients with prostate cancer in selected centers with appropriate expertise. We studied our single-center experience of developing a LRP service and subsequent training of two additional surgeons by the initial surgeon. We assessed the learning curve of the three surgeons with regard to perioperative outcomes and oncologic results. PATIENTS AND METHODS: Three hundred consecutive patients underwent a LRP between January 2005 and April 2011. Patients were divided into three equal groups (1-100 group 1], 101-200 [group 2], and 201-300 [group 3]). Age, American Society of Anesthesiologists score, preoperative comorbidities, and indications for LRP were comparable for all three patient groups. Perioperative and oncologic outcomes were compared across all three groups to assess the impact of the learning curve for LRP. All surgical complications were classified using the Clavien-Dindo system (CDS). RESULTS: The mean age was 61.9 years (range 46-74 y). There was a significant reduction in the mean operative time (P<0.05), mean blood loss (P<0.05), mean duration of hospital stay (P<0.05), and duration of catherization (P<0.05) between the three groups as the series progressed. The two most important factors predictive of positive surgical margins at LRP were the initial prostate-specific antigen level and tumor stage at diagnosis. The overall positive margin rate was 27.7%. For pT(2) tumors, the positive margin rate was 21%, while patients with pT(3) tumors had a positive margin of 44%. For pT(2) tumors, positive margin rates decreased with increasing experience (group 1, 27% vs group 2, 17% vs group 3, 19%). The incidence of major complications--ie, grade CDS score <= III--was 4.6% (14/300). CONCLUSION: LRP is a safe procedure with low morbidity. As surgeons progress through the learning curve, perioperative parameters and oncologic outcomes improve. Using a carefully mentored approach, LRP can be safely introduced as a new procedure without compromising patient outcomes. PMID- 22260741 TI - Evaluation and stability of the Patient Acceptable Symptom State (PASS) over time in patients with ankylosing spondylitis. AB - OBJECTIVES: The Patient Acceptable Symptom State (PASS) is the value beyond which patients consider themselves well. Our aim was to determine the PASS estimate for patients with AS by assessing pain, disease activity and functional impairment and evaluate whether the PASS is stable over time. METHODS: A 4-week prospective study of patients with AS was carried-out. The PASS was estimated at week 2 and 4 for the following patient reported outcomes: global and nocturnal pain measured on a visual analogue scale, disease activity (BASDAI), and functional impairment (BASFI). We used an anchoring method based on patients answering yes or no to, 'is your current condition satisfactory, when you take your general functioning and your current pain into consideration?' The PASS was defined as the 75th percentile of the score for patients who considered their state satisfactory. Pearson's chi square and binary logistic regression were used to analyse the data. RESULTS: A total of 200 patients were recruited of whom 110 (55%) were in PASS. The PASS estimates were 60 mm for global pain, 40 mm for night pain, 4.0 for BASDAI and 4.3 for BASFI. These PASS values were stable over time for all criteria except for pain. Significant contributors to PASS were low functional impairment ([BASFI]; p<0.001), low pain intensity (p=0.02), intensive physical activity (p=0.004) and high educational level (p=0.01). CONCLUSIONS: A high percentage of Moroccan patients with AS (55%) reported being in PASS. PASS threshold for pain was unexpectedly high, possibly suggesting a high level of patients' tolerance to pain. PMID- 22260742 TI - Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis secondary to rheumatoid arthritis. AB - A 58-year-old Japanese woman on hemodialysis (HD) was admitted for intractable rheumatoid arthritis. Even after HD was started due to end-stage renal failure in 2004, her arthropathy worsened. A soluble tumor necrosis factor receptor inhibitor (etanercept at 25 mg twice weekly), tacrolimus (2 mg daily), and prednisolone (10 mg daily) had been administered since 2005, but high disease activity had persisted. She was admitted to our hospital in July 2007. C-reactive protein (CRP) was 6.8 mg/dL, and the DAS-CRP score was calculated to be 8.3. The cardiothoracic ratio (CTR) was 62% on a chest radiograph, but dialysis hypotension was remarkable. Left ventricular mass (LVM) was calculated as 320 g using echocardiography. Endoscopic biopsy of the stomach and duodenum revealed heavy deposition of AA amyloid. Etanercept was discontinued and tocilizumab was started at a dose of 320 mg (8 mg/kg) monthly. Even after predonisolone and tacrolimus were tapered gradually and discontinued because of her good response, CRP and DAS-CRP became 0.0 mg/dL and 1.5, respectively. In September 2011, re evaluation was performed. CTR was reduced to 51% and LVM was decreased to 180 g. Endoscopic biopsy of the stomach and duodenum revealed disappearance of AA amyloid. Although AA amyloidosis of the gastrointestinal tract has already been reported to be improved by tocilizumab, this is the first report on improvement of myocardial hypertrophy as well as dialysis hypotension. PMID- 22260743 TI - Focal therapy will become standard treatment for localized prostate cancer: pro. PMID- 22260745 TI - Locking tunneled hemodialysis catheters with hypertonic saline (26% NaCl) and heparin to prevent catheter-related bloodstream infections and thrombosis: a randomized, prospective trial. AB - OBJECTIVE: Tunneled cuffed dual-lumen catheters (TCCs) are commonly used for vascular access in hemodialysis (HD) patients. Catheter-related bloodstream infection (CRBSI) is the major problem leading to morbidity and mortality. We investigated whether 26% NaCl solution has any favorable effect on the infections and thrombosis caused by HD catheters. METHODS: TCCs were locked with either 26% NaCl and heparin or standard heparin. The primer end point of the study was the CRBSI or thrombosis of the TCC. We compared the antimicrobial activity of the NaCl solutions (6.5%, 13%, 26%) with 0.9% NaCl solution by time-kill kinetic assay. All tests were performed in triplicate by incubation of test fluids with Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. RESULTS: The mean catheter survival was significantly higher in the 26% NaCl and heparin group (129.5 +/- 50.1 catheter days to 103.3 +/- 59.8, p = 0.008). CRBSI rates (10-15.4%) did not differ significantly between the two groups (p = 0.54). The hypertonic 13% NaCl solution had bactericidal effects on E. coli and P. aeruginosa, but had bacteriostatic effect on S. aureus and S. epidermidis. CONCLUSION: In this study we demonstrated that the 13% NaCl solution and more hypertonic NaCl solutions revealed potent in vitro antimicrobial properties against all checked Gram-negative microorganisms. PMID- 22260746 TI - Mechanisms of protein oligomerization: inhibitor of functional amyloids templates alpha-synuclein fibrillation. AB - Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human alpha-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates alpha-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled alpha synuclein show that upon FN075 addition, alpha-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain beta-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for alpha-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry. PMID- 22260747 TI - Exploiting cell surface thiols to enhance cellular uptake. AB - Efficient cellular delivery is one of the key issues that has hampered the therapeutic development of novel synthetic biomolecules such as oligonucleotides, peptides and nanoparticles. The highly specialized cellular plasma membrane specifically internalizes compounds through tightly regulated mechanisms. It is possible to exploit these natural mechanisms of cellular uptake with rationally designed reagents. Here, we discuss how thiol groups (-SH) naturally present on the cell surface (exofacial thiols) can be used to enhance cellular association and internalization of various materials bearing thiol-reactive groups in their structure. We propose that such thiol modifications should be considered in future design of synthetic biomolecules for optimized cellular delivery. PMID- 22260748 TI - Almond allergens: molecular characterization, detection, and clinical relevance. AB - Almond ( Prunus dulcis ) has been widely used in all sorts of food products (bakery, pastry, snacks), mostly due to its pleasant flavor and health benefits. However, it is also classified as a potential allergenic seed known to be responsible for triggering several mild to life-threatening immune reactions in sensitized and allergic individuals. Presently, eight groups of allergenic proteins have been identified and characterized in almond, namely, PR-10 (Pru du 1), TLP (Pru du 2), prolamins (Pru du 2S albumin, Pru du 3), profilins (Pru du 4), 60sRP (Pru du 5), and cupin (Pru du 6, Pru du gamma-conglutin), although only a few of them have been tested for reactivity with almond-allergic sera. To protect sensitized individuals, labeling regulations have been implemented for foods containing potential allergenic ingredients, impelling the development of adequate analytical methods. This work aims to present an updated and critical overview of the molecular characterization and clinical relevance of almond allergens, as well as review the main methodologies used to detect and quantitate food allergens with special emphasis on almond. PMID- 22260749 TI - Discovery of novel variants in genotyping arrays improves genotype retention and reduces ascertainment bias. AB - BACKGROUND: High-density genotyping arrays that measure hybridization of genomic DNA fragments to allele-specific oligonucleotide probes are widely used to genotype single nucleotide polymorphisms (SNPs) in genetic studies, including human genome-wide association studies. Hybridization intensities are converted to genotype calls by clustering algorithms that assign each sample to a genotype class at each SNP. Data for SNP probes that do not conform to the expected pattern of clustering are often discarded, contributing to ascertainment bias and resulting in lost information - as much as 50% in a recent genome-wide association study in dogs. RESULTS: We identified atypical patterns of hybridization intensities that were highly reproducible and demonstrated that these patterns represent genetic variants that were not accounted for in the design of the array platform. We characterized variable intensity oligonucleotide (VINO) probes that display such patterns and are found in all hybridization-based genotyping platforms, including those developed for human, dog, cattle, and mouse. When recognized and properly interpreted, VINOs recovered a substantial fraction of discarded probes and counteracted SNP ascertainment bias. We developed software (MouseDivGeno) that identifies VINOs and improves the accuracy of genotype calling. MouseDivGeno produced highly concordant genotype calls when compared with other methods but it uniquely identified more than 786000 VINOs in 351 mouse samples. We used whole-genome sequence from 14 mouse strains to confirm the presence of novel variants explaining 28000 VINOs in those strains. We also identified VINOs in human HapMap 3 samples, many of which were specific to an African population. Incorporating VINOs in phylogenetic analyses substantially improved the accuracy of a Mus species tree and local haplotype assignment in laboratory mouse strains. CONCLUSION: The problems of ascertainment bias and missing information due to genotyping errors are widely recognized as limiting factors in genetic studies. We have conducted the first formal analysis of the effect of novel variants on genotyping arrays, and we have shown that these variants account for a large portion of miscalled and uncalled genotypes. Genetic studies will benefit from substantial improvements in the accuracy of their results by incorporating VINOs in their analyses. PMID- 22260750 TI - Cardiac transplantation in adults with aortic valve disease with focus on the bicuspid aortic valve. AB - The frequency of congenitally bicuspid aortic valves in patients having cardiac transplantation (CT) is unknown. We reviewed 243 explanted hearts in patients having CT at Baylor University Medical Center, Dallas from June 1997 through November 2011 to determine the frequency of a bicuspid aortic valve in this population. Of the 243 explanted hearts, 7 (2.9%) were found to have a congenitally bicuspid aortic valve: 3 had severe aortic valve stenosis and before CT had had the aortic valve replaced; the other 4 had normally functioning bicuspid valves and underwent CT for cardiomyopathy (ischemic in 1, idiopathic in 2, and hypertrophic in 1). Review of previously published reports of CT and aortic valve disease disclosed that 4 patients had had aortic valve replacement (AVR) from 2 to 8 years before CT, 3 had AVR or aortic valve repair of the donor heart at the time of CT, and 4 had AVR or transcatheter aortic valve implantation from 1 to 14 years after CT. Some of these aortic valve replacements, before, at the time of, or after CT were in patients with congenitally bicuspid aortic valves. In conclusion, congenitally bicuspid aortic valves were found in 7 of 243 explanted hearts in patients having CT at a single medical center in a 14-year period: 4 had functioned normally and 3 were severely stenotic. Previous reports of patients having AVR or repair before, during, and after CT were reviewed. PMID- 22260751 TI - Fenton-driven chemical regeneration of MTBE-spent granular activated carbon--a pilot study. AB - Three columns containing granular activated carbon (GAC) were placed on-line at a ground water pump and treat facility, saturated with methyl tert-butyl ether (MTBE), and regenerated with hydrogen peroxide (H2O2) under different chemical, physical, and operational conditions for 3 adsorption/oxidation cycles. Supplemental iron was immobilized in the GAC (~6 g/kg) through the amendment of a ferrous iron solution. GAC regeneration occurred under ambient thermal conditions (21-27 degrees C), or enhanced thermal conditions (50 degrees C). Semi continuous H2O2 loading resulted in saw tooth-like H2O2 concentrations, whereas continuous H2O2 loading resulted in sustained H2O2 levels and was more time efficient. Significant removal of MTBE was measured in all three columns using $(USD) 0.6 H2O2/lb GAC. Elevated temperature played a significant role in oxidative treatment, given the lower MTBE removal at ambient temperature (62-80%) relative to MTBE removal measured under thermally enhanced (78-95%), and thermally enhanced, acid pre-treated (92-97%) conditions. Greater MTBE removal was attributed to increased intraparticle MTBE desorption and diffusion and higher aqueous MTBE concentrations. No loss in the MTBE sorption capacity of the GAC was measured, and the reaction byproducts, tert-butyl alcohol and acetone were also degraded. PMID- 22260753 TI - Extraction of humic acid by coacervate: investigation of direct and back processes. AB - The two aqueous phases extraction process is widely used in environmental clean up of industrial effluents and fine chemical products for their reuse. This process can be made by cloud point of polyethoxylated alcohols and micellar solubilization phenomenon. It is commonly called "coacervate extraction" and is used, in our case, for humic acid extraction from aqueous solution at 100mg/L. The surfactants used are alcohol polyethoxylate and alkylphenol polyethoxylate. Phase diagrams of binary water/surfactant and pseudo-binary are plotted. The extraction results are expressed by the following responses: percentage of solute extracted, E (%), residual concentrations of solute and surfactant in dilute phase (X(s,w), and X(t,w) respectively) and volume fraction of coacervate at equilibrium (phi). For each parameter, the experimental results are fitted to empirical equations in three dimensions. The aim of this study is to find out the best compromise between E and phiC. The comparison between experimental and calculated values allows models validation. Sodium sulfate, cetyltrimethylammonium bromide (CTAB) addition and pH effect are also studied. Finally, the possibility of recycling the surfactant has been proved. PMID- 22260752 TI - Preparation of molecularly imprinted nanoparticles with superparamagnetic susceptibility through atom transfer radical emulsion polymerization for the selective recognition of tetracycline from aqueous medium. AB - In the work, we reported an effective method for the preparation of molecularly imprinted nanoparticles with superparamagnetic susceptibility through atom transfer radical emulsion polymerization (ATREP), and then as-prepared magnetic molecularly imprinted nanoparticles (MMINs) were evaluated as adsorbents for selective recognition of tetracycline (TC) molecules from aqueous medium. The resulting nanoparticles were characterized by FT-IR, TGA, VSM, SEM and TEM. The results demonstrated MMINs with a narrow diameter distribution were cross-linked with modified Fe3O4 particles, composed of imprinted layer and exhibited good magnetic sensitivity, magnetic and thermal stability. Batch rebinding studies were carried out to determine the specific adsorption equilibrium, kinetics, and selective recognition. The estimated adsorption capacity of MMINs towards TC by the Langmuir isotherm model was 12.10 mgg(-1) at 298 K, which was 6.33 times higher than that of magnetic non-molecularly imprinted nanoparticles (MNINs). The kinetic property of MMINs was well-described by the pseudo-second-order rate equation. The results of selective recognition experiments demonstrated outstanding affinity and selectivity towards TC over competitive antibiotics. The reusability of MMINs showed no obviously deterioration at least five repeated cycles in performance. In addition, the MMINs prepared were successfully applied to the extraction of TC from the spiked pork sample. PMID- 22260754 TI - A new ion selective electrode for cesium (I) based on calix[4]arene-crown-6 compounds. AB - A polyvinylchloride (PVC) based liquid membrane ion selective electrode (ISE) for cesium has been developed. 25,27-Dihydroxycalix[4]arene-crown-6 (L1), 5,11,17,23 tetra-tert-butyl-25,27-dimethoxycalix[4]arene-crown-6 (L2) and 25,27-bis(1 octyloxy)calix[4]arene-crown-6 (L3) were investigated for their use as ionophores. The cation exchange resin DOWEX-50W was used to maintain low activity Cs+ in inner filling solution to improve the performance. The best response for cesium was observed with L3 along with optimized membrane constituents and composition. Excellent Nernstian response (56.6 mV/decade of Cs(I)) over the concentration range 10(-7) to 10(-2)M of Cs(I) was obtained with a fast response time of less than 10s. Detection limit for Cs(I) using the present ISE is 8.48*10(-8) M Cs(I). Separate solution method (SSM) was applied to ascertain the selectivity for Cs(I) over alkali, alkaline earth and transition metal ions. The response of ISE for Cs(I) was fairly constant over the pH range of 4-11. The lifetime of the electrode is 10 months which is the highest life for any membrane based Cs-ISE so far developed. The concentration of cesium ion in two simulated high level active waste streams was determined and results agreed well with those obtained independently employing AAS. PMID- 22260755 TI - The endoscopic course of scattered white spots in the descending duodenum: a prospective study. AB - AIM: Scattered white spots (SWSs) in the descending duodenum are an uncommon finding of upper gastrointestinal system endoscopy (UGSE). Intestinal lymphangiectasia, chronic nonspecific duodenitis and giardiasis are associated with a SWS appearance. The aim of this study was to determine the frequency of SWS during routine endoscopy, as well as to evaluate the effect of treatment on this finding. MATERIALS AND METHODS: Patients undergoing UGSE with a SWS appearance in the descending duodenum were included prospectively. Appearance of SWSs was graded endoscopically based on density, after which patients were divided into two groups; group 1 (treated group) and group 2 (untreated group). Patients with Helicobacter pylori infection were given eradication therapy, whereas a diet was recommended to patients with intestinal lymphangiectasia. Proton pump inhibitors were initiated for patients with H. pylori negative gastritis. All patients were re-evaluated three months after therapy for the presence of any changes in the SWS appearance. RESULTS: SWSs were observed in 97 (3.2%) out of 3010 patients. This appearance was most commonly associated with chronic non-specific duodenitis followed by intestinal lymphangiectasia. While in the untreated group no statistically significant change in SWS appearance was observed, the decrease in endoscopic grade seen in the treated group was statistically significant (p<0.001). CONCLUSION: The prevalence of SWSs during routine UGSE was 3.2%, with this finding being more commonly associated with chronic non-specific duodenitis and intestinal lymphangiectasia. Treatment of the underlying causes, including H. pylori eradication, proton pump inhibitors and diet decreased the density of the SWSs. PMID- 22260756 TI - [Streptococcus salivarius cellulitis and bacteremia in a cirrhotic patient]. PMID- 22260757 TI - Prenatal diagnosis of partial androgen insensitivity syndrome by means of a 4-D ultrasound technique. PMID- 22260758 TI - Small packages. PMID- 22260759 TI - Screening, diagnosis, and management of intrauterine growth restriction. AB - OBJECTIVE: To provide comprehensive background knowledge relevant to the SOGC Maternal-Fetal Medicine Committee-approved guideline entitled "Intrauterine Growth Restriction: Screening, Diagnosis, and Management." METHODS: Publications in English were retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary via MeSH terms (fetal growth restriction and small for gestational age) and any key words (fetal growth, restriction, growth retardation, intrauterine growth restriction [IUGR], low birth weight, small for gestational age). Results were restricted to systematic reviews, randomized controlled trials or controlled clinical trials, and high-quality prospective and retrospective observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. RESULTS: Evidence obtained from at least one properly randomized controlled trial, Cochrane Reviews, and high quality cohort data have been combined to provide clinicians with evidence to optimize their practice for screening, diagnosis, and management of intrauterine growth restriction. CONCLUSION: Considerable advances have been made to improve clinicians' ability to screen, diagnose, and manage pregnancies with suspected IUGR more effectively, including several properly randomized controlled trials. Pregnancies with late-onset IUGR may be managed equally effectively by early delivery or delayed delivery (with increased surveillance) anticipating favourable outcomes. By contrast, many aspects of the management of early-onset IUGR require further clinical trials. PMID- 22260760 TI - Is there an association between fetal scalp electrode application and early-onset neonatal sepsis in term and late preterm pregnancies? A case-control study. AB - OBJECTIVE: Early-onset neonatal sepsis (EONS), defined as neonatal sepsis occurring within the first week after birth, is a major cause of morbidity and mortality. Fetal scalp electrode application, used for fetal heart rate monitoring during labour, could potentially increase the risk of EONS. The objective of this study was to determine whether this practice is associated with a significant risk for EONS in term and late preterm pregnancies. METHODS: This case-control study enrolled subjects from three maternity hospitals in Edmonton. Cases were neonates with EONS who were born at >= 34 weeks between January 1, 2000, and March 1, 2011. Two control subjects were enrolled for each case identified. Control subjects were neonates of similar gestation (>= 34 weeks), born at the same hospital site, who did not develop EONS. Maternal charts were accessed for information about fetal scalp electrode application and potential confounding variables. RESULTS: Forty cases and 80 control subjects were identified. There was no difference in the rate of exposure to fetal scalp electrode in cases (6/40) and control subjects (10/80) (OR 1.24; 95% CI 0.42 to 3.68, P = 0.92). The association between fetal scalp electrode application and EONS remained non-significant despite adjustment for confounders. CONCLUSION: We did not detect an association between the use of fetal scalp electrode and EONS, but our study was powered to detect only a strong association between the exposure of interest and the disease outcome. We cannot rule out a weakly positive association that may still exist. PMID- 22260761 TI - Impact of a mother's weight history on her offspring. AB - OBJECTIVE: To explore the relationship between maternal lifelong body weight history and anthropometric measurements in the offspring. METHODS: We studied a prospective sample of 48 pregnant women with either gestational diabetes mellitus (GDM, n = 21) or normal glucose tolerance (NGT, n = 27). Reported maternal weight at birth, 20 years of age and 30 years of age, and pre-pregnancy and maximal weight outside pregnancy were obtained by questionnaire. BMI was calculated using data from the questionnaire. Maternal anthropometric parameters were measured during pregnancy. Offspring anthropometrics were obtained at birth and eight weeks later. RESULTS: Maternal weight at birth, weight or BMI at 20 years of age and at 30 years of age, and maximal weight or BMI did not differ between groups. In all women, maternal birth weight, BMI at 20 years of age, and maximal BMI correlated with newborn birth weight (rho = 0.39, 0.37, and 0.27, respectively, P <= 0.05), with newborn length (rho = 0.46, 0.32, and 0.30 respectively, P < 0.05), and with infant weight eight weeks later (rho = 0.43, 0.30, and 0.31, respectively, P < 0.05). Reported maternal BMI at 30 years of age correlated with infant weight (rho = 0.31) and cranial circumference (rho = 0.33) at eight weeks of life (P < 0.05). Besides gestational age, maternal weight at screening was the most significant predictor of infant birth weight. CONCLUSION: Several parameters of maternal weight history were related to offspring anthropometric measurements in early life in a sample of women with and without GDM. PMID- 22260762 TI - Do factors that influence pregnancy planning differ by maternal age? A population based survey. AB - OBJECTIVE: The objectives of this analysis were to describe factors that influenced the decision to conceive among first-time mothers in two Canadian urban centres and to determine if these differed according to the age at which a woman became a mother. METHODS: Women who had given birth to their first live born infant between July 2002 and September 2003 in Calgary and Edmonton were randomly selected from regional notice of birth databases. Women were contacted by telephone, and those who agreed to participate completed a 20-minute survey over the telephone. This analysis was conducted using data from participants with a planned pregnancy. RESULTS: The top three factors that influenced childbearing among women planning a pregnancy were similar regardless of age. They were being in a secure relationship (97%), feeling in control of one's life (82%), and feeling prepared to parent (77%). Less than 30% of women reported career goals as being "very important" in their decision. Women under 25 years of age were less likely than women 25 years or older to indicate the following as being "very important" in the timing of starting a family: being in a stable job (32%), owning a home (36%), financial security (42%), educational training (36%), and career goals (9%) (all P < 0.001). CONCLUSION: This information provides a basis for developing strategies to support couples in their efforts to balance the age related biomedical risks of delaying childbearing with a desire for relationship security and other factors that strongly influence childbearing decisions. PMID- 22260763 TI - Surgical outcomes of abdominal versus laparoscopic sacral colpopexy related to body mass index. AB - OBJECTIVE: Obesity can predispose women to pelvic organ prolapse and can also affect the success of prolapse surgery. Sacral colpopexy is a common surgical approach used to treat significant prolapse, and may be performed by laparotomy or laparoscopy. The objective of this study was to determine whether surgical outcomes following abdominal sacral colpopexy (ASC) and laparoscopic sacral colpopexy (LSC) varied according to BMI. METHODS: We conducted a retrospective cohort study of women who had undergone ASC (n = 90) and LSC (n = 150). Preoperative, perioperative, and postoperative information was collected from patient charts and entered into a database according to BMI category (normal weight 18.5 to 24.9 kg/m2, overweight = 25 to 29.9 kg/m2, obese >= 30 kg/m2). Within each BMI group, outcomes were compared between ASC and LSC patients using Student t, Mann-Whitney U, and Fisher exact tests, and analyses of covariance. RESULTS: In normal weight patients, postoperative apical measurements were worse in ASC patients (P = 0.01). In overweight patients, the ASC group had worse posterior measurements (P = 0.05) and fewer mesh/suture erosions (P = 0.03) but more recurrent prolapse symptoms (P = 0.007). In obese patients, the ASC group had better anterior measurements (P = 0.008). There were no differences in any BMI category for prolapse stage, surgical satisfaction, or classification of surgical success or failure (P > 0.05). CONCLUSION: Differences between ASC and LSC were identified when patients were categorized according to BMI. These findings may be useful in counselling patients and planning the appropriate surgical approach for sacral colpopexy based on BMI. PMID- 22260764 TI - Comparison of morbidity associated with laparoscopic myomectomy and hysterectomy for the treatment of uterine leiomyomas. AB - OBJECTIVE: To compare short-term morbidity and quality of life after laparoscopic hysterectomy (LH) and laparoscopic myomectomy (LM) for the treatment of symptomatic uterine leiomyomas. METHOD: We performed a prospective, observational study of women who were eligible for both surgical procedures. After informed consent was obtained, each participant was asked to complete the SF-12v2 Health Survey before surgery and to repeat it seven days and 28 days after surgery. Data on short-term morbidities, such as operative time, blood loss, length of hospital stay, and surgical complications, were collected by an obstetrician gynaecologist. Women who underwent LH were compared by non-parametric statistical analyses with those who underwent LM. RESULTS: Sixty-one women were recruited between January 1 and December 31, 2008, including 40 who underwent LM and 21 LH. Women who underwent LH were older, had higher parity, and were less likely to have infertility than those who chose LM. Median LH operative time of 223 minutes (IQR 214 to 241) was slightly longer than for LM (188 minutes, IQR 154 to 239; P = 0.02). However, we found no difference between the two groups in terms of SF 12v2 fluctuation, blood loss, hospital stay, and short-term complications. CONCLUSION: Laparoscopic myomectomy is a viable alternative to laparoscopic hysterectomy for women with symptomatic leiomyomas who want conservative surgery. The procedures have similar morbidity and impact on quality of life. PMID- 22260765 TI - Uterine perforation by a cystoperitoneal shunt, an unusual cause of recurrent vaginal discharge. AB - BACKGROUND: We describe the first reported case of uterine perforation by a cystoperitoneal shunt. The mechanism of this unusual complication is unclear. CASE: A 17-year-old patient had a cystoperitoneal shunt for a porencephalic cyst. She presented with recurrent watery vaginal discharge. A pelvic ultrasound examination showed that the uterus had been perforated by the distal tip of the shunt. The cystoperitoneal shunt was converted to a ventriculo-atrial shunt, and the vaginal discharge subsequently resolved. CONCLUSION: The appearance of light and clear vaginal discharge in a patient with a cystoperitoneal shunt raises the possibility of uterine perforation. This can be confirmed by ultrasound and analysis of the discharge. Removal of the shunt leads to spontaneous closure of the uterine defect. PMID- 22260767 TI - Perspectives of Canadian oocyte donors and recipients on donor compensation and the establishment of a personal health information registry. AB - We report the views of 33 women who were involved in an altruistic oocyte donation program about provisions under Canada's Assisted Human Reproduction Act 2004 to prohibit donor compensation and to establish a Personal Health Information Registry. The participants had been either donors of oocytes to a recipient known to them (15) or recipients of such donation (18) through services provided by a clinic in a large Canadian city, and they each participated in a semi-structured face-to-face or telephone interview. Among the 15 donor participants, seven were friends of the recipient, six were sisters, one was a niece of the recipient, and one donor donated twice, once to her sister and once to a friend. In eight cases the donor and recipient participated in interviews independently. At the time of interview, 11 of the 25 separate cases had resulted in a live birth and one in an ongoing pregnancy, so that "successful" and "unsuccessful" donations were equally represented among participants. While divergent views were reported among and between donors and recipients on an altruistic model versus a compensated model of donation, most participants largely endorsed the establishment of a personal health information registry. PMID- 22260766 TI - Negative impact of non-evidence-based information received by women taking antidepressants during pregnancy from health care providers and others. AB - OBJECTIVES: The use of antidepressants by women during pregnancy continues to be a controversial subject, with conflicting information regarding the safety of this group of drugs. We sought (1) to determine the impact of information, advice, and comments women received from health care providers, family, and media about use of antidepressants during pregnancy, and (2) to compare experiences regarding the psychosocial impact of women who continued and discontinued antidepressant therapy during pregnancy. METHODS: Women who had taken an antidepressant at some point during pregnancy were interviewed. The responses of women who continued antidepressant therapy throughout pregnancy were compared with those of women who discontinued therapy at some point in the pregnancy. A questionnaire with questions pertaining to information women had received from various individuals regarding the use of an antidepressant while pregnant was administered to both groups. RESULTS: Ninety-four interviews were completed; 78 were with women who continued antidepressant therapy throughout pregnancy, and 16 were with women who discontinued therapy. The small number of women in the discontinuation group was a result of many women declining to participate. More than one half of the women who continued the medication throughout pregnancy had frequently considered discontinuing, despite reassurance that continuation would cause no harm to their baby. Negative information was recalled far more often than reassuring information. CONCLUSION: Information from friends, family, and health care providers can have a negative impact on decision-making regarding pharmacotherapy for depression during pregnancy. Health care providers should be cognizant of this when counselling patients who require antidepressant therapy during pregnancy. PMID- 22260768 TI - Delayed child-bearing. AB - OBJECTIVE: To provide an overview of delayed child-bearing and to describe the implications for women and health care providers. OPTIONS: Delayed child-bearing, which has increased greatly in recent decades, is associated with an increased risk of infertility, pregnancy complications, and adverse pregnancy outcome. This guideline provides information that will optimize the counselling and care of Canadian women with respect to their reproductive choices. OUTCOMES: Maternal age is the most important determinant of fertility, and obstetric and perinatal risks increase with maternal age. Many women are unaware of the success rates or limitations of assisted reproductive technology and of the increased medical risks of delayed child-bearing, including multiple births, preterm delivery, stillbirth, and Caesarean section. This guideline provides a framework to address these issues. EVIDENCE: Studies published between 2000 and August 2010 were retrieved through searches of PubMed and the Cochrane Library using appropriate key words (delayed child-bearing, deferred pregnancy, maternal age, assisted reproductive technology, infertility, and multiple births) and MeSH terms (maternal age, reproductive behaviour, fertility). The Internet was also searched using similar key words, and national and international medical specialty societies were searched for clinical practice guidelines and position statements. Data were extracted based on the aims, sample, authors, year, and results. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS 1. Women who delay child-bearing are at increased risk of infertility. Prospective parents, especially women, should know that their fecundity and fertility begin to decline significantly after 32 years of age. Prospective parents should know that assisted reproductive technologies cannot guarantee a live birth or completely compensate for age-related decline in fertility. (II-2A) 2. A fertility evaluation should be initiated after 6 months of unprotected intercourse without conception in women 35 to 37 years of age, and earlier in women > 37 years of age. (II-2A) 3. Prospective parents should be informed that semen quality and male fertility deteriorate with advancing age and that the risk of genetic disorders in offspring increases. (II-2A) 4. Women >= 35 years of age should be offered screening for fetal aneuploidy and undergo a detailed second trimester ultrasound examination to look for significant fetal birth defects (particularly cardiac defects). (II-1A) 5. Delayed child-bearing is associated with increased obstetrical and perinatal complications. Care providers need to be aware of these complications and adjust obstetrical management protocols to ensure optimal maternal and perinatal outcomes. (II-2A) 6. All adults of reproductive age should be aware of the obstetrical and perinatal risks of advanced maternal age so they can make informed decisions about the timing of child-bearing. (II-2A) 7. Strategies to improve informed decision-making by prospective parents should be designed, implemented, and evaluated. These strategies should provide opportunity for adults to understand the potential medical, social, and economic consequences of child-bearing throughout the reproductive years. (III-B) 8. Barriers to healthy reproduction, including workplace policies, should be reviewed to optimize the likelihood of healthy pregnancies. (III-C). PMID- 22260769 TI - Screening and characterization of a chemical regulator for plant disease resistance. AB - Plants activate systemic acquired resistance (SAR), a form of long-lasting induced defense, to confer protection against a broad spectrum of pathogens. SAR induction is associated with the salicylic acid (SA)-mediated defense signaling networks. For detailed understandings of the SA-mediated signaling of SAR induction, we screened chemical inhibitors that block SA-mediated signaling from a 9600-compound chemical library. As a result, we identified one candidate chemical, 4-phenyl-2-{[3-(tri-fluoromethyl)anilino]methylidene}cyclohexane-1,3 dione (PAMD), that suppresses the expression of pathogenesis-related (PR) gene. PAMD also down-regulates SA-induced gene expression and enhances susceptibility to pathogen. PMID- 22260770 TI - Synthesis and antihormonal properties of novel 11beta-benzoxazole-substituted steroids. AB - Early studies led to the identification of 11beta-aryl-4',5'-dihydrospiro[estra 4,9-diene-17beta,4'-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present study, we replaced the 4'-dimethylaminophenyl group of mifepristone with the benzoxazol group to give 5a-d. We also prepared the 17beta-formamido analogs 6a,b using a new synthetic strategy via the intermediate epoxide 21. These compounds were evaluated for their antagonist hormonal properties using the T47D cell-based alkaline phosphatase assay and the A549 cell based functional assay. Compound 5c showed potent antagonist activity at GR with better selectivity for GR versus PR than mifepristone and is a promising lead for further development. PMID- 22260771 TI - Computational study of bindings of HK20 Fab and D5 Fab to HIV-1 gp41. AB - Antibodies HK20 and D5 have been shown to target HIV-1 gp41, thereby inhibiting membrane fusion that facilitates viral entry. The binding picture is static, based on the X-ray crystal structures of the Fab regions and gp41 mimetic five helix bundle. In this study, we carried out molecular dynamics simulation to provide the dynamic binding picture. Calculated binding free energies are within reasonable range of and follow the trend of the experimental values: -15.28 kcal/mol for HK20 Fab (expt. -11.60 kcal/mol) and -17.90 kcal/mol for D5 Fab (expt. -11.70 kcal/mol). Alanine scanning at protein-protein interface reveals that the highest contributors to binding for HK20 Fab are F54 and I56, both of V(H) region, as well as R30' of V(L) region; whereas for D5 Fab, F54 of V(H) region, as well as W32' and Y94' of V(L) region. HK20 F54 and I56, as well as D5 I52, F54, and T56, bind to the gp41 hydrophobic binding pocket, an important region targeted by many other fusion inhibitors. Hydrogen bonding analysis also identifies high-occupancy hydrogen bonds at the periphery of gp41 hydrophobic pocket. Considering that almost all interface residues are turn residues, further work may be directed to turn mimics. Pre-orientation by the hydrogen bonds to poise this particular turn towards the binding pocket may also be a point worth pursuing. PMID- 22260772 TI - Efficient synthesis and cell-based silencing activity of siRNAS that contain triazole backbone linkages. AB - An efficient synthesis of siRNAs modified at the backbone with a triazole functionality is reported. Through the use of 4,4'-dimethoxytrityl (DMT) phosphoramidite chemistry, triazole backbone dimers were site-specifically incorporated throughout various siRNAs targeting both firefly luciferase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts as representatives of an exogenous and endogenous gene, respectively. Following the successful silencing of the firefly luciferase reporter gene, triazole-modified siRNAs were also found to be capable of silencing GAPDH in a dose-dependent manner. Backbone modifications approaching the 3'-end on the sense strand were tolerated without compromising siRNA potency. This study highlights the compatibility of triazole-modified siRNAs within the RNAi pathway, and the modification's potential to impart favorable properties to siRNAs designed to target other endogenous genes. PMID- 22260773 TI - Stylissamide X, a new proline-rich cyclic octapeptide as an inhibitor of cell migration, from an Indonesian marine sponge of Stylissa sp. AB - A new proline-rich cyclic octapeptide named stylissamide X (1) was isolated from an Indonesian marine sponge of Stylissa sp. as an inhibitor of cell migration from the guidance of wound-healing assay. The chemical structure of stylissamide X (1) was determined on the basis of spectroscopic analysis, and stereostructure of the amino acids were deduced by Marfey's method. Compound 1 showed inhibitory activity against migration of HeLa cells in the ranges of 0.1-10 MUM concentration through both wound-healing assay and chemotaxicell chamber assay, while the cell viability was maintained more than 75% up to 10 MUM concentration of 1. PMID- 22260774 TI - Hybrid liposomes inhibit growth and invasion of human osteosarcoma cells leading to apoptosis. AB - Marked inhibitory effects of hybrid liposomes (HL-n; n=21, 23, 25) composed of 90 mol% l-alpha-dimyristoylphosphatidylcholine (DMPC) and 10 mol% polyoxyethylene(n) dodecyl ethers on the growth of two human osteosarcoma cell lines (MG-63 and U-2 OS) were obtained. Furthermore, fluorescence microscopic and flow cytometric analyses revealed the induction of apoptosis by HL-n in both cells. It is noteworthy that HL-23 could inhibit the invasion and migration of U-2 OS cells on the basis of matrigel invasion assay and scratch wound assay, respectively. PMID- 22260775 TI - Rational construction of eukaryotic OFF-riboswitches that downregulate internal ribosome entry site-mediated translation in response to their ligands. AB - A strategy for rationally constructing a novel type of eukaryotic OFF-riboswitch, which ligand-dependently turns off translation mediated by an internal ribosome entry site (IRES), has been established. The theophylline-dependent IRES-based OFF-riboswitch obtained through the proposed strategy functioned well in wheat germ extract, independently from the downstream gene, indicating that it can regulate any gene. Despite the fact that it has one theophylline aptamer, its switching efficiency was as high as that of a previously reported theophylline dependent OFF-riboswitch that was constructed by inserting three continuous theophylline aptamers into a 5' untranslated region in mRNA to downregulate the normal 5'-terminus-mediated translation. In addition, because the riboswitch part that was optimized in the theophylline-dependent IRES-based OFF-riboswitch, except for the aptamer domain, can be used as-is for other aptamer-ligand pairs, an arbitrary ligand-dependent IRES-based OFF-riboswitch is easy to construct with the corresponding well-minimized aptamer. PMID- 22260776 TI - Primary ureteral giant cell sarcoma in a Pomeranian. AB - An 8-year-old male neutered Pomeranian dog was presented to the Veterinary Teaching Hospital at Oregon State University for surgical treatment of hydronephrosis of the left kidney and a left cranial abdominal mass. A primary ureteral mass was found during exploratory surgery, and the mass was resected and ureteral anastomosis was performed. Cytologic evaluation of the mass revealed 3 distinct cell populations, including a large number of multinucleated giant cells, a moderate number of thin spindle-shaped cells, and cohesive clusters of transitional epithelial cells. The cytologic diagnosis was giant cell sarcoma. The diagnosis was confirmed by histologic examination, and immunohistochemical staining was performed. The spindle-shaped cells and multinucleated giant cells were both immunoreactive for vimentin and spindle-shaped cells for S-100. Tumor cells did not express wide-spectrum cytokeratin, broad-spectrum muscle actin, smooth muscle actin, sarcomeric actin, desmin, BLA36, Mac 387, synaptophysin, neuron-specific enolase, glial fibrillary acid protein, or von Willebrand factor. These findings are most consistent with an anaplastic sarcoma with giant cells. This is the first case report of a primary ureteral giant cell sarcoma in a dog. PMID- 22260778 TI - Trend in eating habits among Lithuanian school-aged children in context of social inequality: three cross-sectional surveys 2002, 2006 and 2010. AB - BACKGROUND: Intermittent monitoring of food intake at the population level is essential for the planning and evaluation of national dietary intervention programs. Social-economic changes in Lithuania have likely affected dietary habits, but only a limited number of temporal studies on food intake trends among young population groups have been published. The aim of this study was to investigate changes in eating habits among Lithuanian school-aged children from 2002 to 2010, and to explore the association of these changes with the respondents' reported socio-economic status (SES). METHODS: We used Lithuanian data from the cross-national Health Behaviour in School-aged Children (HBSC) study collected in 2002, 2006 and 2010. Analyses were conducted on comparable questionnaire-based data from children aged 11, 13 and 15 (total n = 17,189) from a random sample of schools. A food frequency questionnaire was used to investigate frequencies of food consumption. Logistic regression was used to examine the affects of changing social variables on reported diet trends. RESULTS: In Lithuania, school-aged children have low intakes of fruits and vegetables. Only 21.1% of boys and 27.1% of girls reported daily fruit consumption. Similarly, 24.9% of boys and 29.6% of girls disclosed vegetable intake at least once daily. Comparing 2010 to 2002, the proportion of girls who consumed fruits daily increased from 24.2% to 31.0% (p < 0.001) but the proportion of boys who consumed vegetables daily decreased from 29.3% to 23.1% (p < 0.001). In 2006, for both sexes, there were observed increases in regular (at least five days a week) intake of sweets and chocolates, biscuits and pastries, and soft drinks; however, in the next survey (2010) these figures decreased. In addition, between 2006 and 2010, a substantial decrease in regular consumption of chips and fast food was also detected. Fruit and vegetable consumption as well as intake of sweets and chocolates, biscuits and pastries and soft drinks increased with family social-economic status and family material wealth. Trends in consumption of fruits, and other foods, and their association with changing social variables were demonstrated using the ORs estimated by three logistic models, using 2002 as the reference point. Changes in social variables from 2002 to 2010 affected the likelihood of daily consumption of fruits among boys by 22.5% (the corresponding OR decreased from 1.11 to 0.86) and among girls by 34.0% (the corresponding OR decreased from 1.41 to 1.12). Over the study period, changing social variables had little impact on the daily consumption of vegetables and other foods. CONCLUSIONS: Based on the food consumption trends observed in Lithuania, increases in consumption of fruits and vegetables should be promoted, along with a reduction in the intake of less healthy choices, such as soft drinks and high-fat, high-sugar snack foods, by diminishing social inequalities in food consumption. PMID- 22260779 TI - The gender disparity of immunoreactants in lesional skin of lupus erythematosus patients. AB - OBJECTIVES: The immunoreactants detected by direct immunofluorescence (DIF) from the skin of patients with lupus erythematosus (LE) were related to disease subtypes and skin morphology. Male patients presented more frequently with discoid rashes and females with malar rashes. We investigated the differences in immunoreactants in skin lesions between male and female LE patients. METHODS: The DIF records of 186 LE patients were reviewed and analysed. RESULTS: Among 186 patients (133 female and 53 male), 54 had cutaneous LE (CLE) and 132 had systemic LE (SLE). In the CLE group, eight of 33 (24.2%) women were DIF+ versus nine of 21(42.9%) men (p=0.23). In the SLE group, 49 of 100 (49%) women were DIF+ versus 17 of 32 (53.1%) men (p=0.84). The p-value was 0.01 when comparing DIF incidence between female CLE and SLE patients. IgM and complement component 3 (C3) were present in 84.2% and 52.6% of DIF+female patients, respectively, and both were comparable between genders (p>0.05). However, IgG was observed only in eight of 57 female patients, and in 10 of 26 male patients (p=0.02). Among DIF+CLE patients, IgG was detected in none of the eight female versus three of nine male patients. CONCLUSIONS: Detection of immunoreactants in skin had no gender bias in CLE or SLE, but among women, it was probably lower in CLE than SLE. IgM and C3 were the most frequent immunoreactants in skin with no gender disparity, whereas IgG in female patients was lower than in males. PMID- 22260780 TI - Serotyping and antibiotic susceptibility of Streptococcus pneumoniae strains isolated in Algeria from 2001 to 2010. AB - INTRODUCTION: Pneumococcal infections are a major public health problem because of the virulence of this bacterium and its ability to develop resistance. MATERIAL AND METHOD: Two hundred and ninety-four strains of Streptococcus pneumoniae were isolated from sterile (56.8%) and non-sterile samples (43.2%), from January 2001 to July 2010. RESULTS: The interpretation of antibiotic susceptibility testing, according to CLSI criteria (M100-S21 2011), yielded a 25.2% overall resistance to penicillin, with 23.5% of strains isolated from CSF (meningitis), and only 1.7% in other samples. Resistance to cefotaxime was 8.1% (including 4.4% at a high level). The most common serotypes were: 14 (19.5%), 23F (9.7%), 6B (9.3%), 19F (5.4%), and serotype 1 (5%). The percentage of these serotypes isolated from normally sterile sites in children under 5 years of age was 31.25% for 14, 10.4% for 23F, 8.3% for 19F, 6.25% for 6B, and 4.2% for serotype 1. The theoretical vaccinal coverage against invasive infections in children under 2 years of age was 61.5%, 69.2%, and 76.9% for the 7-valent, 10 valent, and 13-valent conjugate vaccines, respectively. Penicillin non susceptible Streptococcus pneumoniae (PNSP) strains accounted for 67.1, 68.6, and 72.8% for each of these three vaccines. CONCLUSION: There was a variation of serotype rates compared to previous studies. The increase in pneumococcal antibiotic resistance is concerning, particularly for the treatment of pneumococcal infections in children and infants. Pneumococcal vaccination is not compulsory yet in Algeria. PMID- 22260781 TI - Plague epidemic in the Kingdom of Naples, 1656-1658. PMID- 22260782 TI - Slow relaxation dynamics of water in hydroxypropyl cellulose-water mixture traces its phase transition pathway: a spectroscopic investigation. AB - In this study, we have explored the slow (of the order of several hundreds of picoseconds) relaxation dynamics of water associated with the hydration shell of a biocompatible polymer, hydroxypropyl cellulose (HPC)-water mixture as a function of HPC concentration using time-resolved fluorescence spectroscopy. The relaxation dynamics slows down with a progressive increase in HPC content indicating restriction of the relaxation pathway of water molecules specially beyond a cellulose concentration of 20% wherein an isotropic to liquid crystalline cholesteric microscopic phase separation sets in. The activation energy calculated from the temperature dependent solvation dynamics studies also shows a similar trend. The nucleophilic activity of water molecules in these mixtures is determined by measuring the reaction kinetics of solvolysis of benzoyl chloride, and the reaction rate exhibits a marked decrease as the phase separation sets in. The observed results are correlated with a transition between the 'bulk' and 'bound' type of water molecules present in the system. PMID- 22260783 TI - Prediction of HLA class I-restricted T-cell epitopes of islet autoantigen combined with binding and dissociation assays. AB - Identification of cognate peptides recognized by human leucocyte antigen (HLA)/T cell receptor (TCR) complex provides insight into the pathogenic process of type 1 diabetes (T1D). We hypothesize that HLA-binding assays alone are inadequate metrics for the affinity of peptides. Zinc transporter-8 (ZnT8) has emerged in recent years as a novel, major, human autoantigen. Therefore, we aim to identify the HLA-A2-restricted ZnT8 epitopes using both binding and dissociation assays. HLA class I peptide affinity algorithms were used to predict candidate ZnT8 peptides that bind to HLA-A2. We analyzed 15 reported epitopes of seven beta-cell candidate autoantigens and eight predicted candidate ZnT8 peptides using binding and dissociation assays. Using IFN-gamma ELISpot assay, we tested peripheral blood mononuclear cells (PBMCs) from recent-onset T1D patients and healthy controls for reactivity to seven reported epitopes and eight candidate ZnT8 peptides directly ex vivo. We found five of seven recently reported epitopes in Chinese T1D patients. Of the eight predicted ZnT8 peptides, ZnT8(153-161) had a strong binding affinity and the lowest dissociation rate to HLA-A*0201. We identified it as a novel HLA-A*0201-restricted T-cell epitope in three of eight T1D patients. We conclude that ZnT8(153-161) is a novel HLA-A*0201-restricted T cell epitope. We did not observe a significant correlation (P = 0.3, R = - 0.5) between cytotoxic T cell (CTL) response and peptide/HLA*0201 complex stability. However, selection of peptides based on affinity and their dissociation rate may be helpful for the identification of candidate CTL epitopes. Thus, we can minimize the number of experiments for the identification of T-cell epitopes from interesting antigens. PMID- 22260785 TI - Is there a common control mechanism for anti-saccades and reading eye movements? Evidence from distributional analyses. AB - In the saccadic literature, the voluntary control of eye movement involves inhibiting automatic saccadic plans. In contrast, the dominant view in reading is that linguistic processes trigger saccade planning. The present study explores the possibility of a common control mechanism, in which cognitively driven responses compete to inhibit automatic, perceptually driven saccade plans. A probabilistic model is developed to account for empirical distributions of saccadic response time in anti-saccade tasks (Studies 1 and 2) and fixation duration in reading and reading-like tasks (Studies 3 and 4). In all cases the distributions can be decomposed into a perceptually based component and a component sensitive to cognitive demands. Parametric similarities among the models strongly suggest a shared cognitive control mechanism between reading and other voluntary saccadic tasks. PMID- 22260784 TI - MicroRNA-24 regulates cardiac fibrosis after myocardial infarction. AB - Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure. Although dysregulation of microRNA (miRNA) is involved in various pathophysiological processes in the heart, the role of miRNA in fibrosis regulation after MI is not clear. Previously we observed the correlation between fibrosis and the miR-24 expression in hypertrophic hearts, herein we assessed how miR-24 regulates fibrosis after MI. Using qRT-PCR, we showed that miR-24 was down-regulated in the MI heart; the change in miR-24 expression was closely related to extracellular matrix (ECM) remodelling. In vivo, miR-24 could improve heart function and attenuate fibrosis in the infarct border zone of the heart two weeks after MI through intramyocardial injection of Lentiviruses. Moreover, in vitro experiments suggested that up-regulation of miR-24 by synthetic miR-24 precursors could reduce fibrosis and also decrease the differentiation and migration of cardiac fibroblasts (CFs). TGF-beta (a pathological mediator of fibrotic disease) increased miR-24 expression, overexpression of miR-24 reduced TGF-beta secretion and Smad2/3 phosphorylation in CFs. By performing microarray analyses and bioinformatics analyses, we found furin to be a potential target for miR-24 in fibrosis (furin is a protease which controls latent TGF-beta activation processing). Finally, we demonstrated that protein and mRNA levels of furin were regulated by miR-24 in CFs. These findings suggest that miR-24 has a critical role in CF function and cardiac fibrosis after MI through a furin-TGF-beta pathway. Thus, miR-24 may be used as a target for treatment of MI and other fibrotic heart diseases. PMID- 22260786 TI - Expression of fetal hemoglobin in adult humans exposed to high altitude hypoxia. AB - In humans, acute erythroid expansion can lead to maturation of red blood cell (RBC) precursors containing fetal hemoglobin (F red cells). This can occur in patients after recovery from bone marrow transplantation, or in individuals affected by sickle cell or thalassemic syndromes. An accelerated erythroid lineage expansion is also a hallmark of the adaptive response to high altitude hypoxia. To explore the possible effect of this environment on F red cell production, we analyzed RBCs from five subjects during and after 17 days spent at high altitude and investigated the expression of fetal hemoglobin by different methodological approaches. By flow cytometry, we found a moderate increase of circulating F red cells during and after the hypoxia exposure, with respect to control cells analyzed before a stay at high altitude. The increased expression of gamma-globin (as the specific subunit contained in F hemoglobin together with alpha-globin) was further confirmed by immunoblotting of young RBC hemolysates and quantitative RT-PCR of transcripts purified from a reticulocyte-enriched RBC fraction. Thus, in healthy adults the exposure to high altitude hypoxia induces maturation of F red cells at a level higher than under normal condition. The effect appears reduced after return to normoxia. PMID- 22260789 TI - Finite element analysis of bone-implant biomechanics: refinement through featuring various osseointegration conditions. AB - A refinement technique is proposed for developing finite element models capable of simulating peri-implant bone conditions for bone types II, III, and IV at various degrees of osseointegration. The refined models feature a transition region between bone (cortical and cancellous) and implant and designate it partially to fully osseointegrated by assigning corresponding fractions of the bulk bone's elastic properties to this region. Bone is assumed to be transversely isotropic. The refined technique is implemented in a case study, in which osseointegrated (25-100%) peri-implant bone, type II, III, or IV with an implant attached, is loaded with a 100 MPa occlusal load. The biomechanics of this peri implant bone was simulated and analysed. Results showed that the less dense bone must support higher stress and strain, especially at the cortical region. Higher degree of osseointegration induced higher stress but lower strain. Both the bone type and the osseointegration condition significantly affected the stress-strain relation. For minimum stress and strain, denser and more osseointegrated peri implant bone is desirable. When bone failure criteria were set, based on the yield strength and strain of the bone, a higher degree of osseointegration was needed for the less dense peri-implant bone to be considered safe. PMID- 22260788 TI - Hemolymph ion regulation and kinetic characteristics of the gill (Na+, K+)-ATPase in the hermit crab Clibanarius vittatus (Decapoda, Anomura) acclimated to high salinity. AB - We examine hemolymph ion regulation and the kinetic properties of a gill microsomal (Na(+), K(+))-ATPase from the intertidal hermit crab, Clibanarius vittatus, acclimated to 450/00 salinity for 10 days. Hemolymph osmolality is hypo regulated (1102.5 +/- 22.1 mOsm kg(-1) H(2)O) at 450/00 but elevated compared to fresh-caught crabs (801.0 +/- 40.1 mOsm kg(-1) H(2)O). Hemolymph [Na(+)] (323.0 +/- 2.5 mmol L(-1)) and [Mg(2+)] (34.6 +/- 1.0 mmol L(-1)) are hypo-regulated while [Ca(2+)] (22.5 +/- 0.7 mmol L(-1)) is hyper-regulated; [K(+)] is hyper regulated in fresh-caught crabs (17.4 +/- 0.5 mmol L(-1)) but hypo-regulated (6.2 +/- 0.7 mmol L(-1)) at 450/00. Protein expression patterns are altered in the 450/00-acclimated crabs, although Western blot analyses reveal just a single immunoreactive band, suggesting a single (Na(+), K(+))-ATPase alpha-subunit isoform, distributed in different density membrane fractions. A high-affinity (Vm=46.5 +/- 3.5 Umg(-1); K(0.5)=7.07 +/- 0.01 MUmol L(-1)) and a low-affinity ATP binding site (Vm=108.1 +/- 2.5 U mg(-1); K(0.5)=0.11 +/- 0.3 mmol L(-1)), both obeying cooperative kinetics, were disclosed. Modulation of (Na(+), K(+)) ATPase activity by Mg(2+), K(+) and NH(4)(+) also exhibits site-site interactions, but modulation by Na(+) shows Michaelis-Menten kinetics. (Na(+), K(+))-ATPase activity is synergistically stimulated up to 45% by NH(4)(+) plus K(+). Enzyme catalytic efficiency for variable [K(+)] and fixed [NH(4)(+)] is 10 fold greater than for variable [NH(4)(+)] and fixed [K(+)]. Ouabain inhibited ~80% of total ATPase activity (K(I)=464.7 +/- 23.2 MUmol L(-1)), suggesting that ATPases other than (Na(+), K(+))-ATPase are present. While (Na(+), K(+))-ATPase activities are similar in fresh-caught (around 142 nmol Pi min(-1)mg(-1)) and 450/00-acclimated crabs (around 154 nmol Pi min(-1)mg(-1)), ATP affinity decreases 110-fold and Na(+) and K(+) affinities increase 2-3-fold in 450/00 acclimated crabs. PMID- 22260790 TI - Pectoralis major flap for head and neck reconstruction in era of free flaps. AB - The aim of this study was to evaluate factors affecting the selection of pectoralis major flap in the era of free tissue reconstruction for post ablative head and neck defects and flap associated complications. The records of patients who underwent various reconstructive procedures between July 2009 and December 2010 were retrospectively analysed. 147 reconstructive procedures including 79 free flaps and 58 pectoralis major flaps were performed. Pectoralis major flap was selected for reconstruction in 21 patients (36%) due to resource constrains, in 12 (20%) patients for associated medical comorbidities, in 11 (19%) undergoing extended/salvage neck dissections, and in 5 patients with vessel depleted neck and free flap failure salvage surgery. None of the flaps was lost, 41% of patients had flap related complications. Most complications were self-limiting and were managed conservatively. Data from this study suggest that pectoralis major flap is a reliable option for head and neck reconstruction and has a major role even in this era of free flaps. The selection of pectoralis major flap over free flap was influenced by patient factors in most cases. Resource constraints remain a major deciding factor in a developing country setting. PMID- 22260787 TI - A transgenic mouse model expressing exclusively human hemoglobin E: indications of a mild oxidative stress. AB - Hemoglobin (Hb) E (beta26 Glu->Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess alpha-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid beta(E)-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of beta(E) globin mRNA, but are essentially non-thalassemic as demonstrated by RBC alpha/beta (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess alpha chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation. PMID- 22260791 TI - Bipaddled submental artery flap. AB - Oral cancer is a major public health problem in India. Most patients present with locally advanced disease requiring complex resection and reconstruction strategies. Costs, operating time and availability of expertise are major issues that influence efficient health delivery, especially in developing countries such as India. Technically simple and widely reproducible techniques may be used successfully where applicable, to overcome these issues. The submental artery flap is a well described and acceptable alternative to the radial artery forearm free flap in oral cavity reconstruction. Researchers have demonstrated its technical ease of performance and reproducibility amongst trainees. Here the authors describe the bipaddled submental artery flap, a modification of the standard flap, which can be used to provide lining as well as skin cover for a full thickness cheek defect. Two skin paddles are fashioned taking advantage of the vascular anatomy of the submental vessels. PMID- 22260792 TI - Age-related changes in the effects of 5-hydroxytryptamine on substantia gelatinosa neurons of the trigeminal subnucleus caudalis. AB - The trigeminal subnucleus caudalis (Vc) is the critical brainstem relay site of orofacial nociceptive processing to higher brain centers. The descending serotonergic pathway from the brainstem exerts inhibitory or facilitatory effects on nociceptive transmission in the spinal dorsal horn and the Vc, and SG neurons of the Vc exhibit hyperpolarization, no response or depolarization in response to 5-hydroxytryptamine (5-HT) application. In this study, we examined age-related changes in the effects of 5-HT on SG neurons of the Vc using immature, peripubertal and adult male mice and gramicidin-perforated patch recordings under the current-clamp mode. In the three age groups, hyperpolarization was the major response in SG neurons exhibiting membrane potential changes in response to 5-HT application. The proportion of the SG neurons responding to 5-HT by hyperpolarization was significantly higher in the immature (20/27) than in the adult mice (10/26; P<0.05). The proportion of SG neurons showing no response to 5 HT was significantly higher in the peripubertal (11/21) and the adult mice (13/26) compared with the immature mice (5/27). The amplitude of 5-HT-induced hyperpolarization significantly decreased with increasing postnatal age (correlation coefficient=-0.43, P<0.05). The mean amplitude of 5-HT-induced hyperpolarization was significantly higher in the immature mice (-9.7+/-1.1 mV, n=20) than in the peripubertal (-5.3+/-1.0 mV, n=10) and the adult mice (-5.4+/ 0.9 mV, n=10; both P<0.05). These results suggest that the descending serotonergic modulatory influence over the orofacial nociceptive processing in the Vc may change during postnatal development and postnatal age of three weeks is a critical period for changes in 5-HT-induced hyperpolarizing effects in mice. PMID- 22260793 TI - NOGO-66 receptor deficient mice show slow acquisition of spatial memory task performance. AB - The Nogo-66 receptor (NgR1) is part of a co-receptor complex on neurons that transmits a signal for inhibition of neurite outgrowth. In addition, NgR1 function has also been related to other disorders such as schizophrenia and Alzheimer's disease. Here, we studied the effect of life-long deletion of NgR1 (ngr(-/-)) in tests for cognition and positive symptoms of schizophrenia. In the water maze, ngr(-/-) mice learned to locate the hidden platform as well as wild type mice, although with slower acquisition. Deletion of NgR1 did not affect amphetamine- or phencyclidine (PCP)-induced hyperactivity, two models of positive symptoms of schizophrenia. Taken together, ngr(-/-) animals show slower acquisition of a spatial learning and memory task. PMID- 22260794 TI - Frontal lobe role in simple arithmetic calculations: an fNIR study. AB - This study aimed to affirm the use of functional near-infrared spectroscopy (fNIR) in examining frontal lobe role during automatic (i.e., requires retrieval from long-term memory) and method-based (i.e., requires calculation) arithmetic processing. Adult university students (math difficulties [MD] and control) performed simple arithmetic calculations while monitored using an fNIR system designed to image regions within the frontal cortices. Addition and subtraction problems presented on a computer screen belonged to one of three categories: triples "under 10" (e.g., 2+3=?, 5-3=?), triples that "break 10" (e.g., 5+8=?, 13 5=?), or triples "including 10" (e.g., 10+7=?, 17-10=?). fNIR recordings indicated significant interactions between type of triple, operation, and group over left frontal lobe, and between type of triple and group over right frontal lobe. Within-group differences among controls were found in the "break 10" triples with higher DeOxyHb level recorded during subtraction processing. Between group differences were found in the "break 10" and "including 10" triples for subtraction with higher levels of DeOxyHb recorded among controls. Results imply that among adults frontal lobe is still involved during simple mathematical processing and fNIR recordings can differentiate its role in adults of varying mathematical ability. PMID- 22260795 TI - A form of synaptically induced metabotropic glutamate receptor-dependent long term depression that does not require postsynaptic calcium. AB - The calcium control hypothesis posits that postsynaptic calcium increases are required to trigger synaptic plasticity, with large increases inducing LTP and small increases inducing LTD. In CA1 of the hippocampus, however, LTD induced by chemical activation of metabotropic glutamate receptors (agonist-LTD) is independent of increases in postsynaptic calcium. Here we tested whether LTD induced by pairing of presynaptic stimulation with postsynaptic depolarization (synaptic-LTD) is similarly calcium-independent. This protocol induced an NMDA dependent LTP when paired at 0mV, which was converted to mGluR-dependent LTD when paired at -20mV. The LTD was not blocked by calcium chelation, blockers of L- or T-type voltage-dependent calcium channels, or hyperpolarization to -70mV. We conclude that synaptically induced mGluR-dependent LTD, like agonist induced mGluR LTD, does not require calcium influx for its induction. PMID- 22260796 TI - Calcineurin is required for TRPV1-induced long-term depression of hippocampal interneurons. AB - Transient receptor potential vanilloid 1 (TRPV1) mediates a novel form of presynaptic long-term depression (LTD) in hippocampal interneurons. To date, while TRPV1 is currently being heavily studied in the PNS for its anti nociceptive and anti-inflammatory properties, much less is known regarding TRPV1 signaling and function in the CNS, including the mechanism mediating hippocampal interneuron LTD. Here we performed whole-cell voltage clamp electrophysiology experiments on CA1 hippocampal interneurons from Sprague-Dawley male rats to identify this signaling mechanism. Because calcineurin is linked to multiple synaptic plasticity types, we investigated whether TRPV1 activates presynaptic calcineurin, which in turn induces LTD. To do so we employed calcineurin inhibitors cyclosporin A or FK-506. To determine the location of the calcineurin involved we either bath applied calcineurin antagonists, blocking calcineurin activity ubiquitously in the slice, presynaptically and postsynaptically, or applied antagonists to the internal solution to block calcineurin postsynaptically. Both calcineurin antagonists applied to the bath blocked TRPV1 dependent LTD, indicating calcineurin involvement in LTD. Because calcineurin antagonist applied to the internal solution did not block TRPV1-LTD, it suggests presynaptic calcineurin is required for LTD. Finally, because high frequency stimulus used to induce LTD could potentially activate receptors besides TRPV1, we confirmed that bath, but not intracellularly applied cyclosporin A, also blocked TRPV1 agonist-induced depression of CA1 interneurons. In conclusion, these data illustrate that presynaptic calcineurin activity is required for both TRPV1-induced LTD and TRPV1 agonist-induced depression. This finding is the first to demonstrate the TRPV1-induced signaling mechanism in CA1 hippocampus. PMID- 22260797 TI - NAD(+) administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia. AB - Nicotinamide adenine dinuleotide (NAD(+)) plays critical roles in multiple biological functions. Previous studies have indicated that NAD(+) treatment decreases oxidative stress-induced death of primary neurons and astrocytes. Intranasal administration of NAD(+) also reduces brain damage in a rat model of transient focal brain ischemia. However, the mechanisms underlying this protective effect remain unknown. In this study, we used a mouse model of brain ischemia to test our hypothesis that NAD(+) decreases ischemic brain damage partially by preventing autophagy. Adult male mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 90min, and NAD(+) was administered intraperitoneally (i.p.) immediately after reperfusion started. We found that administration with 50mg/kg NAD(+) led to significant decreases in infarct size, edema formation, and neurological deficits at 48h after ischemia. NAD(+) administration also significantly decreased brain ischemia-induced autophagy in the cortex and hippocampus. We further found that prevention of autophagy by 3 methyladenine (3-MA), a selective autophagy inhibitor, significantly reduced ischemic brain damage, suggesting an important role of autophagy in the ischemic brain injury in our animal model. Collectively, our findings have suggested that NAD(+) administration decreases ischemic brain damage at least partially by blocking autophagy. This is the first suggested mechanism regarding the protective effects of NAD(+) in cerebral ischemia, which further highlights the promise of NAD(+) for treating brain ischemia. PMID- 22260800 TI - The SHINE clinic: providing dental services for inner-city youth. PMID- 22260799 TI - Evaluation of the long-term effects of gastric inhibitory polypeptide-ovalbumin conjugates on insulin resistance, metabolic dysfunction, energy balance and cognition in high-fat-fed mice. AB - The effects of active immunisation with gastric inhibitory polypeptide (GIP) or (proline3)GIP-ovalbumin conjugates on insulin resistance, metabolic dysfunction, energy expenditure and cognition were examined in high-fat-fed mice. Normal mice were injected (subcutaneously) once every 14 d for 98 d with GIP-ovalbumin conjugates, with transfer to a high-fat diet on day 21. Active immunisation resulted in GIP antibody generation and significantly (P < 0.01 to P < 0.001) reduced circulating non-fasting plasma insulin concentrations compared to high fat control mice from day 70 onwards. The glycaemic responses to intraperitoneal glucose or nutrient ingestion were significantly improved in all treated mice, with corresponding stimulated plasma insulin levels depressed compared to high fat controls. These changes were associated with substantially (P < 0.001) improved glucose-lowering responses to exogenous insulin and decreases of muscle and fat TAG, pancreatic insulin, circulating total and LDL-cholesterol levels (P < 0.01 to P < 0.001). Treatment with GIP-ovalbumin conjugates was not associated with alterations in energy expenditure, indirect calorimetry or aspects of cognitive function. The observed changes were almost identical in GIP and (Pro3)GIP immunised mice and were independent of any effects on food intake or body weight. Further tests established that coupling of GIP peptides to ovalbumin abolished any intrinsic insulin-releasing or glucose-lowering activity. These results suggest that induction of GIP-neutralising antibodies with GIP-ovalbumin conjugates is an effective means of countering the metabolic abnormalities induced by high-fat feeding and does not adversely have an impact on a marker of cognition function or energy expenditure. PMID- 22260801 TI - The effects of antiepileptic drugs on oral health. AB - OBJECTIVE: Long-term use of phenytoin (PHT) causes gingival hyperplasia; however, little is known about the oral side effects of other antiepileptic drugs (AEDs). Through a systematic review of the literature, we explored the effects of AEDs on the oral health of patients with epilepsy. METHODS: We searched PubMed, EMBASE and the Cochrane library between January 1963 and August 2010. The search strategy retrieved 170 abstracts. We included studies that involved original research and had >= 10 patients in our review. We also checked the reference lists of reviews, letters and other manuscripts to find studies that met our selection criteria. RESULTS: Only 15 articles were included in the final analysis. Gingival hyperplasia was very common in patients taking PHT (16%-94% of patients). Alveolar bone loss occurred in patients taking carbamazepine or PHT. Patients taking valproate, carbamazepine or phenobarbital also had gingival hyperplasia. We found no published studies of newer-generation AEDs. CONCLUSION: Although several studies examined the effects of PHT on oral health, none have studied those of the newer generation of AEDs. Studies exploring oral side effects of AEDs are needed. PMID- 22260802 TI - Complicated subgingivally fractured central and lateral incisors: case report. AB - Dental trauma sometimes causes fractures in the maxillary anterior teeth leading to esthetic, functional and phonetic problems. In this report, we describe the treatment of central and lateral incisors simultaneously subgingivally fractured due to dental trauma. Treatment involved flap surgery, reattachment and splinting of the fractured fragments with glass-fibre and composite resin. This reattachment technique, which uses advanced adhesive systems, is an option that offers satisfactory esthetic and functional outcomes. PMID- 22260803 TI - Diagnostic dilemma: the enigma of an oral burning sensation. AB - Burning mouth syndrome is an enigmatic condition that can be difficult to recognize and diagnose. Dental practitioners must be able to distinguish between primary (essential or idiopathic) and secondary burning mouth syndrome. The primary form is characterized by a burning sensation in the oral mucosa and perioral areas, typically with bilateral, symmetric distribution and an absence of relevant clinical and laboratory findings. In the secondary form, the burning sensation is due to clinical abnormalities or a systemic or psychological condition. To date, primary burning mouth syndrome has been considered a diagnosis of exclusion. A case description of a woman with oral burning sensations and the results of a retrospective case analysis are presented to aid practitioners in the understanding, recognition and diagnosis of primary burning mouth syndrome. PMID- 22260804 TI - Management of burning mouth syndrome. AB - Burning mouth syndrome is a challenging condition in terms of both diagnosis and management. These challenges lead to frustration for patients and difficulties for dental practitioners. Unfortunately, delays are common between initial presentation and definitive diagnosis, and also between diagnosis and appropriate management. Furthermore, interventions are often undertaken without a working diagnosis, knowledge of the underlying condition or knowledge of best management strategies for this form of chronic orofacial pain. This article discusses potential reasons for diagnostic delays. It also presents current strategies for managing burning mouth syndrome, to assist the dental practitioner in making prudent therapeutic choices. PMID- 22260805 TI - We generate our own hope. PMID- 22260806 TI - Xylitol for preventing ear infections in children. PMID- 22260807 TI - Dentists leaders in health: thinking outside of the mouth: audiovisual presentation. PMID- 22260808 TI - Passive archwires for intermaxillary fixation in surgical cases: a clinical report. AB - In intraoperative intermaxillary fixation (IMF), bonding a minimally adapted, rectangular, stainless steel, preformed archwire directly to the teeth with a light-cured composite resin can offer many benefits to clinicians and patients. The procedure is easier and less time-consuming than conventional bracket placement, the risk of occlusal interference is reduced and the patient's comfort is increased. With the use of composite resin, the wire fits buccal tooth surfaces accurately, thus creating a completely passive anchor unit. Crimpable hooks can be easily adjusted along the archwire, thus establishing different directions of postoperative elastic traction. Furthermore, this technique eliminates soft tissue injuries and tooth root damage, which are risks associated with the use of miniscrews for IMF. In this clinical report, we describe the case of a 50-year-old man, who required a passive anchor unit to assist IMF before undergoing maxillomandibular advancement to treat severe obstructive sleep apnea syndrome. PMID- 22260809 TI - Do patients with solid organ transplants or breast implants require antibiotic prophylaxis before dental treatment? PMID- 22260810 TI - Prospective associations between intervention components and website engagement in a publicly available physical activity website: the case of 10,000 Steps Australia. AB - BACKGROUND: Effectiveness of and engagement with website-delivered physical activity interventions is moderate at best. Increased exposure to Internet interventions is reported to increase their effectiveness; however, there is a lack of knowledge about which specific intervention elements are able to maintain website engagement. OBJECTIVE: To prospectively study the associations of website engagement and exposure to intervention components for a publicly available physical activity website (10,000 Steps Australia). METHODS: Between June and July 2006 a total of 348 members of 10,000 Steps completed a Web-based survey to collect demographic characteristics. Website engagement was subsequently assessed over a 2-year period and included engagement data on website components; individual challenges, team challenges, and virtual walking buddies; and indicators of website engagement (average steps logged, days logging steps, and active users). RESULTS: On average participants logged steps on 169 (SD 228.25) days. Over a 2-year period this equated to an average of 1.6 logons per week. Binary logistic regression showed that individuals who participated in individual challenges were more likely to achieve an average of 10,000 steps per day (odds ratio [OR] = 2.80, 95% confidence interval [CI] 1.45-5.40), log steps on a higher than average number of days (OR = 6.81, 95% CI 2.87-13.31), and remain an active user (OR = 4.36, 95% CI 2.17-8.71). Additionally, those using virtual walking buddies (OR = 5.83, 95% CI 1.27-26.80) and of older age logged steps on a higher than average number of days. No significant associations were found for team challenges. CONCLUSIONS: Overall engagement with the 10,000 Steps website was high, and the results demonstrate the relative effectiveness of interactive components to enhance website engagement. However, only exposure to the interactive individual challenge feature was positively associated with all website engagement indicators. More research is needed to examine the influence of intervention components on website engagement, as well as the relationship between website engagement and physical activity change. PMID- 22260811 TI - Complement system in psoriatic arthritis: a useful marker in response prediction and monitoring of anti-TNF treatment. AB - OBJECTIVES: Treatment with anti-TNF agents is well established in psoriatic arthritis (PsA). Anti-TNF agents are capable of modulating complement activity in vitro but there are no data on the in vivo effect. Anti-TNF have high costs and potential risks, thus, there is an urgent need for accurate predictors of response. We aimed at studying the usefulness of erythrocyte-sedimentation-rate (ESR), C-reactive protein (CRP), and complement for response prediction and monitoring of anti-TNF treatment in PsA patients. METHODS: Fifty-five patients were included consecutively before starting etanercept or adalimumab. ESR, CRP, plasma complement C3, C4, and C3 and B cleavage fragments were evaluated at baseline and after 22 weeks of anti-TNF treatment. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. Complement was evaluated at baseline in 30 healthy subjects as well. RESULTS: At baseline, C3 and C4 levels were significantly higher than in controls (C3 126.9+/-22 vs. 110+/-25 mg/dl, p=0.000002; C4 31.2+/-9.2 vs. 22.7+/-8.3 mg/dl, p=0.0003). After anti-TNF therapy, C3 and C4 levels were significantly reduced to normalization (p=0.0009 and 0.0005, respectively) and ESR, CRP and DAS28 showed a significant reduction (p=0.002, 0.004 and 0.0001, respectively). Split products of C3 and B were not observed at baseline and after 22 weeks. Higher baseline C3 levels were associated with EULAR non-response (p=0.011). CONCLUSIONS: PsA patients with moderate to severe disease show elevated C3 and C4 levels, reverted by anti-TNF treatment. High C3 may be considered a hallmark of inflammation and C3 revealed the highest predictive value for response to anti-TNF. PMID- 22260812 TI - Leprosy, still present in La Reunion. PMID- 22260813 TI - Occurrence of non-cerebral coenurosis in sheep. AB - This study reports seven rare cases of non-cerebral coenurosis in sheep. The sheep were slaughtered in abattoirs of Abu Dhabi (United Arab Emirates) but originated from India, Iran, Oman and Sudan. The prevalence of infection with non cerebral coenurosis was 0.008%. The locations of the cysts were the triceps brachii muscle, the diaphragm, the infraspinatus muscle of the shoulder, the muscles of the thigh and the abdomen, and the ommentum. The Coenurus cysts were surrounded by a fibrous, semi-opaque membrane, cloudy white in colour. Altogether, 12 cysts were recovered and all contained a single bladderworm. Cysts had a volume of 7.3 +/- 1.30 cm3 (ml), with 7.3 +/- 4.0 clusters of scolices, and an average number of scolices 75.3 +/- 24.4. These features in sheep were similar to those reported for non-cerebral Coenurus cysts in goats. No cysts were found in the brain or spinal cord of any of the infected sheep. No clinical evidence of non-cerebral coenurosis had been recorded during the antemortem veterinary inspection of the infected sheep. PMID- 22260814 TI - Comprehensive conformational studies of five tripeptides and a deduced method for efficient determinations of peptide structures. AB - Thorough searches on the potential energy surfaces of five tripeptides, GGG, GYG, GWG, TGG, and MGG, were performed by considering all possible combinations of the bond rotational degrees of freedom with a semiempirical and ab initio combined computational approach. Structural characteristics of the obtained stable tripeptide conformers were carefully analyzed. Conformers of the five tripeptides were found to be closely connected with conformers of their constituting dipeptides and amino acids. A method for finding all important tripeptide conformers by optimizing a small number of trial structures generated by suitable superposition of the parent amino acid and dipeptide conformers is thus proposed. Applying the method to another five tripeptides, YGG, FGG, WGG, GFA, and GGF, studied before shows that the new approach is both efficient and reliable by providing the most complete ensembles of tripeptide conformers. The method is further generalized for application to larger peptides by introducing the breeding and mutation concepts in a genetic algorithm way. The generalized method is verified to be capable of finding tetrapeptide conformers with secondary structures of strands, helices, and turns, which are highly populated in larger peptides. This show some promise for the proposed method to be applied for the structural determination of larger peptides. PMID- 22260815 TI - Cognitive functions before and 1 year after surgical and endovascular treatment in patients with unruptured intracranial aneurysms. AB - BACKGROUND AND PURPOSE: This prospective study investigated whether surgery or endovascular treatment for unruptured intracranial aneurysms (UIAs) affects cognitive functions. METHODS: Four neuropsychological variables from an Auditory Verbal Learning Test (overall capacity of verbal memory and delayed recall) and a Trail Making Test (psychomotor speed and cognitive flexibility) were investigated before and 1 year after treatment for UIAs in 65 patients < 61 years of age. This cohort consists of 15 men and 50 women aged 15-60 (mean age 44.9) years. RESULTS: Group-rate analysis showed a non-significant increase in post-treatment scores in the four neuropsychological variables. In addition, no significant differences were found between the surgical clipping (SC) and endovascular coiling (EC) group. Event-rate analysis demonstrated that two patients from the EC and one from the SC group developed cognitive impairment after treatment. CONCLUSIONS: Surgical and endovascular repair for UIAs do not impair cognition in patients without postoperative restrictions in lifestyle. PMID- 22260816 TI - Amygdala and hippocampus fail to habituate to faces in individuals with an inhibited temperament. AB - Habituation is a basic form of learning that reflects the adaptive reduction in responses to a stimulus that is neither threatening nor rewarding. Extremely shy, or inhibited individuals, are typically slow to acclimate to new people, a behavioral pattern that may reflect slower habituation to novelty. To test this hypothesis, we used functional magnetic resonance imaging to examine habituation to neutral faces in 39 young adults with either an extreme inhibited or extreme uninhibited temperament. Our investigation focused on two key brain regions involved in response to novelty--the amygdala and the hippocampus. Habituation to neutral faces in the amygdala and hippocampus differed significantly by temperament group. Individuals with an uninhibited temperament demonstrated habituation in both the amygdala and hippocampus, as expected. In contrast, in individuals with an inhibited temperament, the amygdala and hippocampus failed to habituate across repeated presentations of faces. The failure of the amygdala and hippocampus to habituate to faces represents a novel neural substrate mediating the behavioral differences seen in individuals with an inhibited temperament. We propose that this failure to habituate reflects a social learning deficit in individuals with an inhibited temperament and provides a possible mechanism for increased risk for social anxiety. PMID- 22260817 TI - Mutations I117V and I117M and oseltamivir sensitivity of pandemic (H1N1) 2009 viruses. AB - Analysis of mutations I117V and I117M in the neuraminidase of influenza A pandemic (H1N1) 2009 viruses showed that I117V confers a mild reduction in oseltamivir sensitivity and has a synergistic effect of further increasing resistance when combined with H275Y. Contrary to recent reports, the I117M mutation does not alter oseltamivir sensitivity. PMID- 22260819 TI - Vaccinia virus zoonotic infection, Sao Paulo State, Brazil. PMID- 22260818 TI - Effect of oral clodronate on structural damage and bone turnover in rheumatoid arthritis. AB - OBJECTIVES: To study the effect of oral clodronate on structural damage and bone metabolism in rheumatoid arthritis (RA). METHODS: In this 2-year proof-of-concept study, sixty patients with at least moderately active RA were randomised to receive anti-rheumatic therapy alone or together with oral clodronate 1600 mg daily. Radiographs of hands and feet and serum samples for bone biomarkers were studied at baseline and at 24 months. RESULTS: At 24 months, progression of radiographic joint damage was similar in the 2 groups. Clodronate suppressed carboxyterminal cross-linked peptide of type I collagen (p=0.03) and aminoterminal propeptide of type I procollagen (p=0.01). Eight patients (27%) withdrew from clodronate therapy due to adverse drug reactions. CONCLUSIONS: Oral clodronate did not retard the focal bone damage in RA despite its beneficial effect on overall bone metabolism, as judged by the decrease in the reference bone biomarkers. PMID- 22260820 TI - Gallbladder motility disorders estimated by non-invasive methods. AB - BACKGROUND/AIMS: The aim is to compare the radionuclide (DC) and ultrasonographic (US) method in the assessment of gallbladder (GB) motility. METHODOLOGY: The study was performed in 15 controls (C), 10 patients with acute cholecystitis (AC), 20 patients with chronic acalculous cholecystitis (CAC), 26 patients with chronic cholecystitis with calculosis (CCC) as well as in 15 patients with GB dyskinesia (D). GB emptying period (EP), ejection fraction (EF) and ejection rate (ER) were estimated with dynamic cholescintigraphy (DC) and US. RESULTS: The DC and US finding in the patients with AC was typical in all the patients, i.e. GB was not visualized at all on DC, while on US, stone was visible in the cystic duct. There were significant differences (p<0.05) between the EF and ER values obtained between C and the three groups of patients CAC, CCC and D, using both methods. However, there were no significant differences in EF, EP and ER values among CAC, CCC and D (p>0.05). There was also high correlation between the results obtained with both methods in all the groups of patients studied. CONCLUSIONS: The results obtained by both methods are valuable for the assessment of GB motility. Although there are no significant differences and there is a high correlation between the values, radionuclide method is more precise, because it can register motility continuously. PMID- 22260821 TI - Complications of laparoscopic cholecystectomy and its prevention: a review and experience of 400 cases. AB - In the present era laparoscopic cholecystectomy (LC) has become the gold standard treatment of choice for gallstone disease. This technique has made a new revolution in minimal invasive surgery, but also the spectrum of complications has changed. In this paper we shared our personal experience of LC in 400 hundred cases from January 2007 to December 2010, its complications and prevention. According to our experience the complications were liver bed injury (n=32, 8%), spilled gall stones (n=29, 7.25%), port site infection (n=11, 2.75%), vascular injury (n=18, 4.5%), conversion to open surgery (n=16, 4%), biliary leak (n=10, 2.5%), bowel injury (n=3, 0.75%), CBD stricture (n=4, 1%) and umbilical port hernia (n=2, 0.5%). Before the procedure, patient consent and awareness to all possible complications which may occur intra-operatively is very important. A good surgical team and experience in this procedure seems to prevent hazardous complications. PMID- 22260822 TI - The effect of laparoscopic cholecystectomy on the development of alkaline reflux gastritis and intestinal metaplasia. AB - BACKGROUND/AIMS: Laparoscopic cholecystectomy is the gold standard treatment for symptomatic gallstones. The goal of this study was to investigate the effect of cholecystectomy on alkaline reflux, histopathological changes in the gastric mucosa and H. pylori colonization. METHODOLOGY: Eighty five patients who had undergone laparoscopic cholecystectomy were included in this trial (20 males; 65 females; 44.97 +/- 11.22 years). All the patients had an upper gastrointestinal endoscopy before and 6 months after the surgery and biopsies in the antrum and corpus were taken to investigate the mucosal changes and assay for the presence of H. pylori. RESULTS: At 6 months post-surgery, the presence of bile in the fasting gastric fluid and an increase in the endoscopic gastritis findings were detected. While none of the patients had chemical gastritis prior to surgery, 7 patients were diagnosed with this condition after surgery. Intestinal metaplasia was detected in 6 patients prior to surgery and 20 patients after surgery. H. pylori was observed in 64 patients before surgery and 52 patients after surgery. CONCLUSIONS: An increase in duodenogastric reflux, alkaline reflux gastritis and intestinal metaplasia, and a reduction in H. pylori colonization were observed to occur post-cholecystectomy. PMID- 22260823 TI - Rikkunshito improves the symptoms in patients with functional dyspepsia, accompanied by an increase in the level of plasma ghrelin. AB - BACKGROUND/AIMS: Functional dyspepsia (FD) is a common disease but there is no established treatment. Rikkunshito is a traditional Japanese medicine that is widely used for treating upper gastrointestinal symptoms and its effect on ghrelin is of great interest. The aim of this study was to investigate the effect of rikkunshito on upper gastrointestinal symptoms and the levels of acylated ghrelin (AG) in patients with FD. METHODOLOGY: This study was a paralleled, randomized controlled trial. Patients were treated with either rikkunshito (group R) or domperidone (group D) for 4 weeks. The overall change in dyspeptic symptoms was evaluated by the GSRS (Gastrointestinal Symptom Rating Scale) questionnaire score. RESULTS: 27 patients were enrolled. There was a significant improvement in dyspeptic symptoms in both groups, based on the GSRS score. AG levels increased significantly in plasma in group R at 2 weeks after treatment (paired t-test, p<0.05). The improvements of reflux (Pearson's correlation test, r=-0.73, p=0.04) and indigestion (r=-0.76, p=0.03) symptoms in group R showed a good correlation with the increase of AG. CONCLUSIONS: Rikkunshito improves upper gastrointestinal symptoms in patients with FD, accompanied by an increase in the levels of AG. PMID- 22260824 TI - ALTA injection sclerosing therapy:non-excisional treatment of internal hemorrhoids. AB - BACKGROUND/AIMS: Aluminum potassium sulfate and tannic acid (ALTA) is a new sclerosing therapy for internal hemorrhoids. This injection therapy is a four step direct injection sclerosing procedure intended to shrink and harden internal hemorrhoids to eliminate hemorrhoidal prolapse and bleeding. The aim of this study was to assess the short term efficacy of this treatment. METHODOLOGY: The procedure was conducted using a four-step injection process under perianal local anesthesia. The entry point for the four-step injection of ALTA is the submucosa of the superior pole, the submucosa in the central part, the mucous lamina propria in the central part and the submucosa at the inferior pole of hemorrhoid. RESULTS: From January 2009 to March 2010, we performed the ALTA sclerosing therapy on 28 patients (14 men and 14 women; mean age, 64.6 years), including 5 second-degree, 16 third-degree and 7 fourth-degree hemorrhoids. There were 6 postoperative complications (2 cases of low grade fever, 2 anal pains, 1 necrosis at injection site and 1 perianal dermatitis). All symptoms of prolapse or bleeding disappeared after 29 postoperative days. There were 3 recurrent cases (10.7%). CONCLUSIONS: ALTA sclerosing therapy is a useful and less invasive treatment for internal hemorrhoids. PMID- 22260825 TI - The feasibility of laparoscopic splenectomy for ITP patients without preoperative platelet transfusion. AB - BACKGROUND/AIMS: The aim of this study was to investigate the feasibility and safety of laparoscopic splenectomy for idiopathic thrombocytopenic purpura patients without platelet transfusion before surgery. METHODOLOGY: From 2004 to 2010, laparoscopic splenectomy was performed in 30 patients with ITP (idiopathic thrombocytopenic purpura, ITP) in our department and clinical information was recorded. Inclusion criteria is patient with a preoperative platelet count of <20x109/L. All of the 30 patients retrospectively reviewed were divided into 2 groups, according to whether they received platelet transfusion preoperatively or not. Perioperative data were analyzed. RESULTS: The clinical efficacy of treatment was significant (obvious response rates of the two cohorts were 17/19 and 9/10). There was no significant difference in the surgical procedure or postoperative efficacy of laparoscopic splenectomy for ITP patients, regardless of whether there was preoperative platelet transfusion, including operating time, ratio of intraoperative blood transfusion, estimated blood loss, the rate of conversion, postoperative platelet counts, amount of postoperative drainage and postoperative hospital stay. CONCLUSIONS: Laparoscopic splenectomy without platelet transfusion can be a feasible and safe procedure in patients with a platelet count lower than 20x109/L, with a normal prothrombin time and without any preoperative bleeding tendency or severe coagulopathy. PMID- 22260827 TI - Intraoperative observation using a fluorescence imaging instrument during hepatic resection for liver metastasis from colorectal cancer. AB - BACKGROUND/AIMS: We have found that liver metastasis from colorectal cancer (LM CRC) can be easily detected by its fluorescence using a fluorescence imaging instrument (photodynamic eye (PDE)) in patients who have received an intravenous injection of indocyanine green (ICG). Therefore, our aim is to demonstrate the usefulness of PDE observation for hepatic resection in patients with LM-CRC. METHODOLOGY: Between February and October 2009, seven patients who underwent hepatic resection for LM-CRC were enrolled. After previous ICG injection (0.1mg/kg/mL), PDE observation was performed to detect fine invisible residual tumors on the surface of the resected liver. RESULTS: All of the 46 resected LM CRCs that had been pointed out preoperatively were easily detected by their fluorescence using PDE observation. Three of the seven patients underwent additional partial resection because fine invisible residual tumors were detected by their fluorescence using PDE observation. All of these patients who underwent additional resection had no recurrence of LMCRC on the surface of the resected liver after surgery. CONCLUSIONS: PDE observation is useful for detecting fine invisible residual tumors that cannot be revealed under visible light during hepatic resection in patients with LM-CRC and may reduce the incidence of local recurrence on the superficial parenchyma of the liver. PMID- 22260826 TI - The effect of preoperative nutritional supports on patients with gastrointestinal cancer: prospective randomized study. AB - BACKGROUND/AIMS: Malnutrition adversely affects the postoperative outcome of patients with gastrointestinal cancer. Therefore, the malnourished cancer patients are supported by enteral or parenteral nutrition. In this study, we aimed to investigate the effects of preoperative nutritional supports on total antioxidant capacity (TAC) in malnourished patients with gastrointestinal (GI) cancers. METHODOLOGY: Seventy-five malnourished patients with GI cancers and 25 patients with non-cancer surgical problems were included in the study. The dietary of cancer patients were supported with immune-enhancing enteral solution in group II or standard enteral solution in group III and with parenteral solution in group IV. Plasma TAC levels were measured prior and after nutritional support. Data were expressed as mmol Trolox eq./L. RESULTS: The mean TAC levels of groups before treatment were 1.10+/-0.17, 0.92+/-0.19, 0.89+/-0.17 and 0.92+/ 0.18, respectively. It was significantly higher in group I than others. The mean TAC levels of supported groups after treatment were 1.11+/-0.20, 1.08+/-0.21 and 1.09+/-0.27, respectively. Although there was a statistically significant increase in TAC after treatment in group II and III, it was not statistically significant in group IV. CONCLUSIONS: It was concluded that preoperative nutritional support with standard or immune-enhancing enteral solutions significantly increased TAC levels of malnourished patients with GI cancers. PMID- 22260828 TI - Colorectal surgery in patients over 80 years old. AB - BACKGROUND/AIMS: We analyzed colorectal resections in patients over 80 years old, performed for all benign and malign diseases. METHODOLOGY: We collected 300 consecutive colorectal resections between 2002 and 2008. Patients were divided into two groups: group A was composed by patients younger than 80 years old and group B by patients older than 80. Data were evaluated with t-test and chi-square test. RESULTS: We analyzed 180 women and 120 men. The median age was 66 years old (range, 30-90). Most frequent indications were colorectal cancer (46%), diverticulitis (35%) and extra-colic cancers (10%). Group B was composed of 60 patients (20%). Old patients had more concomitant diseases (62% vs. 33%, p<0.005), but complications, mortality and hospital stay were comparable in both groups. Surgical emergency increases morbidity (38% vs. 9%) and mortality (13.45 vs. 0.8%). CONCLUSIONS: Colorectal resections can be performed with good results in elderly patients. A colic disease must be detected before the patient develops a surgical complication because urgent surgery has more complications and deaths compared to elective surgery, especially for older patients. PMID- 22260829 TI - Serum biomarkers of colorectal cancer with AU and NP20 chips including a diagnosis model. AB - BACKGROUND/AIMS: Colorectal cancer, including colon cancer and rectal cancer, is often diagnosed at an intermediate or late stage with poor prognosis. Hence, there is an urgent need for new biomarkers for the early detection of colorectal cancer. Proteomics in combination with other techniques is rapidly being developed as a potential route in tumor diagnosis. METHODOLOGY: A case-control study was performed on serum proteomics of colorectal cancer in the Chinese population using magnetic beads associated with surface enhanced laser desorption/ionization time-of-flight mass spectrometry with gold chips and normal phase 20 chips. By serum protein profiling, peak intensities between colorectal cancer and normal controls were compared, as well as the different clinical stages of colorectal, colon or rectal cancer. RESULTS: Experiments with NP20 and AU chips showed two protein peaks, m/z=13732-4 and m/z=13912-3, which could discriminate colorectal samples from normal controls. Early- and late-stage colorectal cancer could also be easily distinguished, though the distinction between colon cancer and rectal cancer was less clear. CONCLUSIONS: These results suggest that the use of magnetic beads combined with a surface enhanced laser desorption/ionization protein chip is a promising route for the diagnosis of early colorectal cancer. PMID- 22260830 TI - Treatment of high-risk gastric cancer postoperatively using intensity-modulated radiotherapy: a single-institution experience. AB - BACKGROUND/AIMS: The aim of this study was to determine the efficacy and acute toxicity of our early experience with treating postoperatively non-metastatic gastric cancer with intensity-modulated radiotherapy (IMRT). METHODOLOGY: A retrospective review was performed on 47 consecutive patients with gastric cancer and treated with postoperatively adjuvant IMRT at Department of radiation oncology, Zhejiang cancer hospital, China, between January 2007 and August 2009. One patient who did not complete his radiation course was excluded, leaving 46 patients for analyses. The median radiation dose delivered was 4500cGy using 180cGy fractions. Concurrent chemotherapy administered were 5-fluorouracil (n=36), capecitabine (n=9) and none (n=1). RESULTS: The median follow-up time was fifteen months (range 6-28 months). 1-year OS and 2-year OS were 98.0% and 80.0%, assessed by Kaplan-Meier methods. Of the six patients who died, five (83.3%) developed a distant metastases. The overall survival time by tumor size was significantly different (>6cm vs. =6cm, p<0.05). There was no significant survival difference between 5-fluorouracil group and capecitabine group (p=0.80). CONCLUSIONS: The data support the use of IMRT in the adjuvant treatment in high risk gastric cancer postoperatively. Acute toxicity is tolerable. Capecitabine with concurrent IMRT was as effective and tolerable as 5-FU/IMRT. Distant metastasis was the main reason of treatment failure that must be addressed in future trials. PMID- 22260831 TI - S-adenosylmethionine does not reduce ischaemia-reperfusion injury to a marginal liver graft in an in vivo experiment. AB - BACKGROUND/AIMS: There are a limited number of appropriate cadaver liver donors. One possible solution is the use of marginal liver grafts from cadaver donors for liver transplantation. METHODOLOGY: Rats with liver steatosis were divided into four containing seven animals each: I-a: steatotic liver grafts; +S adenosylmethionine; I-b: steatotic liver grafts were transplanted; no S adenosylmethionine; II-a: normal liver grafts, +S-adenosylmethionine; II-b: normal liver grafts. Blood samples were taken at days -1, 3 and 14. RESULTS: ALT values at day 14: 1.75 +/- 1.10ukat/L (in group I-a), 1.91 +/- 1.41ukat/L (in group I-b), 2.13+/-1.85ukat/L (in group II-a) and 2.08 +/- 1.35ukat/L (in group II-b). There were no significant differences between these values. GSH values at day 14 post-transplantation were: 44.90 +/- 8.61uM/mg (in group I-a), 43.82+/ 8.58uM/mg (in group I-b), 41.65 +/- 4.87uM/mg (in group II-a) and 42.71 +/- 4.17uM/mg (in control group II-b). CONCLUSIONS: Our study did not demonstrate the positive effect of S-adenosylmethionine on ischaemia-reperfusion injury during liver transplantation in rats. PMID- 22260832 TI - Lipiodol accumulation and transarterial chemoembolization efficacy for HCC patients. AB - BACKGROUND/AIMS: To elucidate the prognostic factors for hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE). METHODOLOGY: We studied 85 TACE-treated HCC patients, including 117 lesions, who fulfilled the Milan criteria. The area of iodized poppy-seed oil (lipiodol) accumulation on CT immediately after TACE was classified into three groups, by comparing with the area of HCC detected by CT during hepatic arteriography; accumulation surrounding the HCC lesion (group I), accumulation involving the entire area of the HCC lesion (group II), and accumulation that covered a portion of the HCC lesion (group III). RESULTS: Among 85 patients, the 1- and 2-year disease free survival (DFS) rates were 67% and 50% in group I, 49% and 29% in group II and 29% and 15% in group III. DFS rate was higher in group I than in groups II and III (p=0.016 and p<0.001). Difference in DFS by lipiodol accumulation pattern was evident in patients aged 75 or younger. CONCLUSIONS: Lipiodol accumulation pattern as evaluated by CT immediately after TACE may be a powerful indicator of the therapeutic efficacy of TACE in HCC patients. PMID- 22260833 TI - Graft size alone should not affect donors selection and be used to predict the prognosis of recipients after living donor liver transplantation. AB - BACKGROUND/AIMS: Graft size is recognized as one of the most important factors that affect prognosis of the liver recipients. This study determines whether the graft to recipient weight ratio (GRWR) alone can be used to select the liver donor and as an outcome predictor before living donor liver transplantation (LDLT). METHODOLOGY: LDLT patients (202) were divided into three groups according to the GRWR: Group S (n=46, GRWR <0.8); Group M (n=83, GRWR 0.8-1.0); Group L (n=73, GRWR >1.0). Recovery of graft function, incidence of small-for-size syndrome and rate of complications were compared among the three groups. RESULTS: There were no significant differences in the baseline characteristics in both the donors and recipients, nor in the intensive care unit stay hours, re-operation rate, hospital stay after operation, Clavien System score and recovery of graft function after transplantation, among the three groups. The small-for-size syndrome rates were 13%, 7.23% and 11% in Groups S, M and B, and no significant difference was noted among the three groups. CONCLUSIONS: GRWR may not be the only factor affecting recipient prognosis after LDLT. Local graft dysfunction such as impaired venous outflow, severity of disease and portal hyperperfusion in the recipient, and fatty liver in donor may influence the graft and thus the prognosis of transplantation. PMID- 22260834 TI - Risk factors of gene-resistant mutations in different nucleosides. AB - BACKGROUND/AIMS: To explore the risk factors of gene-resistant mutations during nucleotide treatment. METHODOLOGY: A total of 320 patients with CHB were randomly divided into lamivudine (LAM, 107 cases), adefovir (ADV, 106 cases) and entecavir (ETV, 107 cases) groups, and P gene mutations of HBV were regularly detected. Kaplan-Meier and Cox regression analysis were performed. RESULTS: There was no statistical significance in baseline data between the three groups. The gene resistant mutation rates were 20.0%, 0.0% and 0.0% one year later, 37.1%, 3.8% and 0.0% two years later, 42.8%, 9.5% and 0.9% three years later, and 64.7%, 25.7% and 0.9% four years later in LAM, ADV and ETV groups, respectively. In LAM group, rtL180M combined with rtM204V mutations accounted for 32.7% and in ADV group, rtN236T mutation accounted for 12.3%. The gene-resistant mutation rate was the most strong in LAM group. CONCLUSIONS: With an extension of time, gene resistant mutation rates are increased, but it is the highest in LAM group and the lowest in ETV group. Family history, the negative conversion time of HBV DNA and different nucleosides are independent risk factors of gene-resistant mutations. PMID- 22260835 TI - Decrease in size of non-treated lesions after cryoablation for hepatocellular carcinoma. AB - We present the case of one 58-year-old man with advancd hepatocellular carcinoma and hepatitis-B virus-related liver cirrhosis who received hepatic cryoablation. Magnetic resonance imaging (MRI) showed multiple liver tumors and the diameter of the largest tumor was more than 10cm. The patient received 2 percutaneous cryoablations in December 2009 and January 2010. Ten months later, MRI showed that not only the treated areas underwent necrosis but also the non-treated area decreased. The a-fetoprotein (AFP) level and the frequency of circulated regulatory T cell (Treg) before treatment were 13,800ng/mL and 15.6%, respectively. Following the cryoablations they dropped to 436ng/mL and 7.6%, respectively, 10 months later. The patient remains in good condition until now. PMID- 22260836 TI - Morphometrical differences between resectable and non-resectable pancreatic cancer: a fractal analysis. AB - BACKGROUND/AIMS: Pancreatic cancer is a highly aggressive cancer with a rising incidence and poor prognosis despite active surgical treatment. Candidates for surgical resection should be carefully selected. In order to avoid unnecessary laparotomy it is useful to identify reliable factors that may predict resectability. Nuclear morphometry and fractal dimension of pancreatic nuclear features could provide important preoperative information in assessing pancreas resectability. METHODOLOGY: Sixty-one patients diagnosed with pancreatic cancer were enrolled in this retrospective study between 2003 and 2005. Patients were divided into two groups: one resectable cancer group and one with non-resectable pancreatic cancer. Morphometric parameters measured were: nuclear area, length of minor axis and length of major axis. Nuclear shape and chromatin distribution of the pancreatic tumor cells were both estimated using fractal dimension. RESULTS: Morphometric measurements have shown significant differences between the nuclear area of the resectable group and the non-resectable group (61.9 +/- 19.8um vs. 42.2 +/- 15.6um). Fractal dimension of the nuclear outlines and chromatin distribution was found to have a higher value in the non-resectable group (p<0.05). CONCLUSIONS: Objective measurements should be performed to improve risk assessment and therapeutic decisions in pancreatic cancer. Nuclear morphometry of the pancreatic nuclear features can provide important pre-operative information in resectability assessment. The fractal dimension of the nuclear shape and chromatin distribution may be considered a new promising adjunctive tool for conventional pathological analysis. PMID- 22260837 TI - The eradicating Helicobacter pylori infection in duodenal ulcer patients by three short-term triple therapies in China: a multicenter clinical comparative study. AB - BACKGROUND/AIMS: This study aimed to compare the 7d triple therapy with 3d and 5d triple therapies, to observe the effect of eradicating Helicobacter pylori (Hp) on treating duodenal ulcers. METHODOLOGY: One hundred and sixteen patients who were confirmed duodenal ulcer active period and Hp positive were enrolled in the study. All the patients were divided into three groups: 3d group (n=39), 5d group (n=37) and 7d control group (n=40). All three groups were provided triple therapy first: rabeprazole, 10mg + furazolidone, 100mg + clarithromycin 250mg, twice a day for three days, five days and seven days, respectively. Then rabeprazole 10mg was provided once a day. Following the treatment, 13C urea breath test was performed to observe the Hp eradication rate. The symptoms of patients such as epigastralgia, burning pain and acidity were evaluated. RESULTS: The Hp eradication rate was: 3d group 76% (28/37), 5d 89% (31/35) and 7d 91% (32/35). There was no significant difference between 5d and 7d group (p>0.05). But the rate of groups 5d and 7d was significantly higher than group 3d (p<0.05). All the three groups showed an improvement in symptoms such as epigastralgia, burning pain and acidity. CONCLUSIONS: All three therapy schemes could alleviate symptoms of duodenal ulcer patients efficiently. But as far as eradicating Hp concerned, 5d and 7d therapies were better than 3d. PMID- 22260838 TI - Her-2/neu assessment for gastric carcinoma: validation of scoring system. AB - BACKGROUND/AIMS: Gastric cancer is the second leading cause of cancer mortality in the world. Amplification of HER-2/neu oncogene has become an important biomarker for identifying patients who respond to HER-2 targeting therapy. A number of studies have analyzed HER-2/neu overexpression in gastric carcinoma, and the rate of HER2 positivity is variable, ranging from 6% to 35%. METHODOLOGY: In our study HER-2/neu expression was assessed on 73 samples of primary gastric cancer, using immunohistochemistry. For 19 patients preoperative biopsy samples and resected specimens were available. Additionally, internal ring study was performed to estimate intraobserver variability of IHC scoring among pathologists at our department. RESULTS: HER-2/neu overexpression was found in 10 (13.6%) of the tested samples, and it was more common in intestinal (22.5%) than the diffuse type (3.7%). Not one of the 6 analyzed mixed type tumors showed HER-2/neu expression. For the paired samples (preoperative biopsy samples and resected specimens) the concordance rate for HER-2/neu expression was 94.7%. CONCLUSIONS: According to high concordance rate in paired samples we consider it appropriate to evaluate HER2 expression on biopsy specimens, especially in unresectable cases, and to re-evaluate it on resected specimens if available, due to high heterogeneity of a gastric cancer. PMID- 22260839 TI - Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase. AB - AIMS: The aim of this study was to investigate the aldosterone-angiotensin (Ang) II interaction in human coronary microarteries (HCMAs). METHODS AND RESULTS: HCMAs, obtained from 75 heart-beating organ donors, were mounted in myographs and exposed to Ang II, either directly or following a 30-min pre-incubation with aldosterone, 17beta-oestradiol, hydrocortisone, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the extracellular regulated kinase 1/2 (ERK1/2) inhibitor PD98059, the GPR30 antagonist G15, or the epidermal growth factor receptor (EGFR) antagonist AG1478. Ang II constricted HCMAs in a concentration dependent manner. All steroids, at nanomolar levels, potentiated Ang II and G15 prevented this effect. The potentiation disappeared or was reversed into Ang II antagonism at micromolar steroid levels. NO synthase (NOS) inhibition prevented the latter antagonism in the case of 17beta-oestradiol, whereas both aldosterone and 17beta-oestradiol at micro- (but not nano-) molar levels induced endothelial NOS phosphorylation in human umbilical vein endothelial cells. AG1478, but not SB203580 or PD98059, abolished the Ang II-induced contraction in the presence of aldosterone or 17beta-oestradiol, and none of these drugs affected Ang II alone. CONCLUSION: Steroids including aldosterone affect Ang II-induced vasoconstriction in a biphasic manner. Potentiation occurs at nanomolar steroid levels and depends on GPR30 and EGFR transactivation. At micromolar steroid levels, this potentiation either disappears (aldosterone and hydrocortisone) or is reversed into an inhibition (17beta-oestradiol), and this is due to the endothelial NOS activation that occurs at such concentrations. PMID- 22260840 TI - In vitro and in vivo osteogenic potential of bioactive glass-PVA hybrid scaffolds colonized by mesenchymal stem cells. AB - Bioactive glass/polymer composites are promising materials for bone tissue engineering. The present research group has developed porous hybrid scaffolds comprised of 50% polyvinyl alcohol/50% bioactive glass with a 70%SiO(2)-30%CaO composition. Prior studies have also shown the adequate structural and mechanical behavior of these scaffolds. As such, the present study investigates the in vitro and in vivo osteogenic potential of the scaffold, using mesenchymal stem cells (MSC) from the bone marrow of female rats. MTT, alkaline phosphatase activity, collagen secretion and Von Kossa staining were conducted to evaluate the differentiation ability of MSC in an osteogenic medium. The in vitro results indicate an increase in both cell proliferation and osteogenic differentiation when the hybrid material is present. Von Kossa staining showed a progressive increase in mineralization nodules, coupled with time differentiation. For the in vivo evaluation, three groups were studied: (1) group implanted with the hybrid scaffold, (2) group implanted with scaffold colonized by non-differentiated MSC and (3) group implanted with scaffold colonized by differentiated MSC. The scaffolds were subcutaneously implanted on the back of Wistar rats for 1-8 weeks, and histological and histomorphometric analyses were performed. The tissue ingrowth proved to be higher in the groups colonized by MSC in the first week. In the second week, only the hybrid colonized by differentiated MSC presented a larger percentage of connective tissue. In the third, fourth and eighth weeks, all groups presented 70% of the hybrid scaffold filled with tissue. However, only the group with differentiated MSC presented some form of osteoid tissue, indicating that the hybrid scaffold with differentiated MSC does indeed present osteogenic potential. PMID- 22260841 TI - Vitamin D and adverse pregnancy outcomes: beyond bone health and growth. AB - Concerns exist about adequacy of vitamin D in pregnant women relative to both maternal and fetal adverse health outcomes. Further contributing to these concerns is the prevalence of inadequate and deficient vitamin D status in pregnant women, which ranges from 5 to 84% globally. Although maternal vitamin D metabolism changes during pregnancy, the mechanisms underlying these changes and the role of vitamin D during development are not well understood. Observational evidence links low maternal vitamin D status with an increased risk of non-bone health outcome in the mother (pre-eclampsia, gestational diabetes, obstructed labour and infectious disease), the fetus (gestational duration) and the older offspring (developmental programming of type 1 diabetes, inflammatory and atopic disorders and schizophrenia); but the totality of the evidence is contradictory (except for maternal infectious disease and offspring inflammatory and atopic disorders), lacking causality and, thus, inconclusive. In addition, recent evidence links not only low but also high maternal vitamin D status with increased risk of small-for-gestational age and schizophrenia in the offspring. Rigorous and well-designed randomised clinical trials need to determine whether vitamin D has a causal role in non-bone health outcomes in pregnancy. PMID- 22260842 TI - Preferred sensor sites for surface EMG signal decomposition. AB - Technologies for decomposing the electromyographic (EMG) signal into its constituent motor unit action potential trains have become more practical by the advent of a non-invasive methodology using surface EMG (sEMG) sensors placed on the skin above the muscle of interest (De Luca et al 2006 J. Neurophysiol. 96 1646-57 and Nawab et al 2010 Clin. Neurophysiol. 121 1602-15). This advancement has widespread appeal among researchers and clinicians because of the ease of use, reduced risk of infection, and the greater number of motor unit action potential trains obtained compared to needle sensor techniques. In this study we investigated the influence of the sensor site on the number of identified motor unit action potential trains in six lower limb muscles and one upper limb muscle with the intent of locating preferred sensor sites that provided the greatest number of decomposed motor unit action potential trains, or motor unit yield. Sensor sites rendered varying motor unit yields throughout the surface of a muscle. The preferred sites were located between the center and the tendinous areas of the muscle. The motor unit yield was positively correlated with the signal-to-noise ratio of the detected sEMG. The signal-to-noise ratio was inversely related to the thickness of the tissue between the sensor and the muscle fibers. A signal-to-noise ratio of 3 was found to be the minimum required to obtain a reliable motor unit yield. PMID- 22260843 TI - Mumps vaccine effectiveness against orchitis. PMID- 22260844 TI - Serum CA125 elevation is independently associated with serositis in SLE patients. AB - OBJECTIVES: Some studies have reported that serum CA125 level is elevated in SLE patients, and elevated CA125 level may be associated with kidney involvement and disease activity in SLE. However, none of the previous studies controlled confounding variables and the results remained controversial. The present study was aimed to investigate whether elevated serum CA125 level is independently associated with clinical and laboratory features of SLE by excluding various confounders in Chinese patients. METHODS: A total of 156 SLE patients, consisting of 139 women and 17 men, were included in the study. Some clinical and laboratory characteristics of the patients were obtained by medical record review. Serum CA125 levels were measured by electrochemiluminescence immunoassays. RESULTS: Compared with patients with normal CA125, those with elevated CA125 had significantly more serositis (37.5% vs. 1.9%, p<0.001) and lung involvement (37.5% vs. 12%, p=<0.001), higher SLEDAI scores (p<0.007). Furthermore, disease duration was significantly longer in those with elevated CA125. Univariate logistic regression analysis showed that elevated serum CA125 level was closely associated with disease duration (OR, 95%CI:1.005, 1.001-1.010; p=0.014), serositis (OR, 95%CI: 32.258, 6.993-142.857; p<0.001), renal involvement (OR, 95%CI: 2.283, 1.114-4.673; p=0.024), lung involvement (OR, 95%CI: 4.386, 1.927 10.000; p<0.001) and SLEDAI scores (OR, 95%CI: 1.098, 1.027-1.174; p=0.006). After controlling for various confounding variables, serositis and disease duration were the only two clinical variables significantly associated with elevation of serum CA125 level. The best cut-off value for CA125 using the ROC curve was 38 kU/L (sensitivity 85%, specificity 75%) and the area under the ROC curve was 0.777 with 95%CI of 0.685-0.868 (p<0.001). Furthermore, the serum CA125 levels can fall into the normal range again with the improvement of serositis. CONCLUSIONS: Of various clinical and laboratory variables of SLE, only serositis is independently associated with serum CA125 elevation. PMID- 22260845 TI - Physical and chemical control of the phytoplankton of Ahe lagoon, French Polynesia. AB - The environmental characteristics of Ahe deep lagoon (Tuamotu Archipelago, French Polynesia) were studied over 3 years with the aim of explaining the spatial and temporal variability of the natural food available for pearl oysters with a special focus on phytoplankton biomass and global photosynthesis/respiration ratio of the lagoon. Chlorophyll averaged 0.34+/-0.01 MUg L(-1) and our findings did not confirm increased phytoplankton biomass in deep lagoonal waters. Phytoplankton production appears to be limited firstly by nitrogen and respiratory processes overpass photosynthetic processes at least in the north eastern edge of the atoll. Grazing by pearl oysters in culture seems to decrease the POC concentration but not the phytoplankton biomass. Oysters graze mainly on non chlorophyllian particles. PMID- 22260846 TI - Epirubicin: is it like doxorubicin in breast cancer? A clinical review. AB - Anthracyclines are among the most effective chemotherapy treatments available for various types of cancer. The anthracyclines commonly used in treatment of breast cancer are either epirubicin or doxorubicin. Epirubicin is an epimer of doxorubicin with important role in the chemotherapy treatment of both early and metastatic breast cancer. The efficacy of epirubicin is similar to doxorubicin while epirubicin has a different toxicity profile particularly in regard to cardiotoxicity. Epirubicin has been incorporated into most of the anthracycline containing chemotherapy combinations in well-conducted clinical trials involving large numbers of patients. It has also been investigated in studies involving the administration of epirubicin in dose-dense chemotherapy schedules. Short term follow up of dose-dense clinical trials demonstrated safety comparable to that of doxorubicin. This review summarizes published clinical trials investigating epirubicin in the treatment of early and advanced breast cancer. PMID- 22260847 TI - [Community-acquired methicillin resistant Staphylococcus aureus skin and soft tissue infections in Madrid: prevalence study]. AB - INTRODUCTION: Since it was first described in the 1990s, Methicillin-Resistant Staphylococcus aureus infection among people with no contact with a hospital setting or with no traditional risk factors, has spread worldwide and is now an important epidemiological and public health problem. METHODS: The present prospective and observational study was carried out from April to November 2010. All adult patients with community-acquired suppurative skin and soft tissue infection (SSTI) attending the Emergency Department were enrolled. Clinical, microbiological and epidemiological features of the infection were assessed. RESULTS: A total of 59 samples were collected from 59 patients and CA-MRSA was isolated in 13 of them. Prevalence of CA-MRSA in patients with suppurative SSTI seen in the emergency department was 22.03%, and was 33.3% in patients with staphylococcal infection. Is worth noting the greater presence of necrosis detected in CA-MRSA lesions. Only 3 patients required hospital admission. Eleven of the 13 strains were Panton-Valentine leucocidin producers, and 5 were resistant to non-betalactam antibiotics. CA MRSA infection is still more frequent in the immigrant population. CONCLUSION: Data on CA-MRSA prevalence in Spain are sparse. This study aims to emphasise the current importance of this emergent pathogen in our area. About one third of suppurative staphylococcal SSTI presenting in our emergency department are caused by this agent, confirming a rapid spread in our country. Some clinical features, such as the high presence of necrosis, are closely related to CA-MRSA. PMID- 22260848 TI - Hypofraction radiotherapy of liver tumor using cone beam computed tomography guidance combined with active breath control by long breath-holding. AB - BACKGROUND AND PURPOSE: To evaluate the feasibility and validity of cone beam computed tomography (CBCT) and active breath control (ABC) by long breath-holding in hypofraction radiotherapy of liver tumor. METHODS AND MATERIALS: Twenty-four patients received hypofraction radiotherapy of liver tumor with long breath holding at end-inhale; four prescriptions were used: 6 Gy*7 (n=8), 10 Gy*4 (n=7), 5 Gy*9 (n=6), 4 Gy*10 (n=3). For each fraction, all patients received pre correction CBCT scans with ABC, some patients received post-correction and post treatment CBCT. The interfraction and intrafraction liver positioning errors on medial-lateral (ML), cranial-caudal (CC) and anterior-posterior (AP) directions were obtained. The theoretic margin from clinical target volume (CTV) to planning target volume (PTV) was calculated based on post-treatment error. The dosimetric parameters of PTV and normal tissue were compared between ABC and free breathing (FB). RESULTS: The interfraction error in liver positioning showed system errors (Sigma) of 3.18 mm (ML), 6.80 mm (CC) and 3.05 mm (AP); random error (sigma) of 3.03 mm (ML), 6.78 mm (CC) and 3.62 mm (AP). These errors were significantly reduced with CBCT guided online correction. The intrafraction systematic error was 0.72 mm (ML), 2.21 mm (CC), 1.49 mm (AP), and random error was 2.30 mm (ML), 3.58 mm (CC), 2.49 mm (AP). Dosimetric parameters such as PTV, the liver's volume included by 23, 30 Gy isodose curve (V23, V30), mean dose to normal liver (MDTNL) and mean dose to cord were significantly larger for FB (P<0.05). CONCLUSION: Liver radiotherapy with long time breath-holding at end-inhale is an effective method to reduce liver motion, PTV and dose to normal tissue. Interfraction and intrafraction liver positioning errors were substantial. CBCT guided online correction of positioning error is recommended for liver radiotherapy with end inhale ABC. PMID- 22260849 TI - Bone marrow transplantation enhances trafficking of host-derived myelomonocytic cells that rescue intestinal mucosa after whole body radiation. AB - BACKGROUND: Bone marrow (BM)-derived cells were demonstrated within intestines after radiation damage and were reported to be responsible for intestine repair. However, there was a discrepancy between intestine epithelial clonogenic regeneration, and mouse survival after BM transplantation (BMT) and radiation. The contribution of BM to acute intestine repair after radiation needed further investigation. METHODS: Mouse survival, intestine microcolony assay, immunohistochemical studies of both intestine and BM were evaluated in mice after whole body irradiation (WBI) and BMT. Immunoblotting, flowcytometry, and double immunostaining were used to evaluate the amount and the character of stroma cells within intestines of recipient mice after receiving gender-mismatched BMT or BMT from green fluorescence donors. RESULTS: Stromal cell proliferation within the lamina propria correlated with the beneficial effect of BMT to intestine recovery and day-8 survival of mice. Few donor-derived cells were found before the completion of intestine repair. The number of host but not donor-derived myelomonocytic and stromal cells increased dramatically within one week after radiation and BMT. Depletion of myelomonocytic cells of recipient mice abolished the mitigating effect of BMT. CONCLUSIONS: Besides rescuing injured BM from aplasia, BMT triggers trafficking of host CD11b(+) myelomonocytic cells from the host marrow to the radiation-injured intestinal mucosa, enhancing the proliferation of intestinal stroma cells, leading secondarily to epithelial regeneration. PMID- 22260850 TI - High expression of luteinizing hormone receptors messenger RNA by human cumulus granulosa cells is in correlation with decreased fertilization. AB - OBJECTIVE: To elucidate the LH receptor (LHR) expression patterns in human granulosa cells (GCs) from antral to preovulatory stages, and to investigate a correlation to oocyte function. DESIGN: Luteinized preovulatory GCs were obtained from preovulatory follicles aspirated during IVF (>= 17 mm). The GCs from small- (<10 mm) and medium-sized (10-15 mm) follicles were obtained during in vitro maturation (IVM) procedures. Cumulus GCs were obtained during oocyte denudation for intracytoplasmatic sperm injection (ICSI) procedures (IVF). SETTING: Referral center. PATIENT(S): Seventy IVF patients and 20 IVM patients. INTERVENTION(S): GC collection. MAIN OUTCOME MEASURE(S): The LHR expression levels in mural and cumulus GCs of different follicular sizes and their correlation to oocyte outcome. RESULT(S): The LHR expression increased with follicle size and was higher in mural GCs compared with cumulus cells. The LHR expression in cumulus GCs from preovulatory follicles was higher in metaphase II (MII) oocytes than in metaphase I or germinal vesicle oocytes (IVF). Unexpectedly, higher expression of LHR in cumulus GCs of MII oocytes correlated with decreased fertilization rates. CONCLUSION(S): The LHR expression in small follicles obtained in IVM suggests a role for hCG administration during IVM procedures. Overexpression of LHR in cumulus GCs of MII oocytes may signal malfunction of oocytes and low fertilization capacity. PMID- 22260851 TI - Comment on, "Increase of success rate for women undergoing embryo transfer by transcutaneous electrical acupoint stimulation: a prospective randomized placebo controlled study". PMID- 22260853 TI - Thyroid function during controlled ovarian hyperstimulation as part of in vitro fertilization. AB - OBJECTIVE: To determine the exact nature and timing of alterations in thyroid function throughout controlled ovarian hyperstimulation (COH). DESIGN: Prospective cohort study. SETTING: University fertility clinic. PATIENT(S): Fifty seven women undergoing COH as part of planned in vitro fertilization. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Timing and magnitude of change in serum thyroid hormones, including TSH, total and free T(4), E(2), and thyroxine binding globulin (TBG), measured at six time points from before stimulation to 2 weeks after serum pregnancy test. RESULT(S): Geometric mean serum TSH increased during stimulation, peaking 1 week after hCG administration compared with baseline (2.44 vs. 1.42 mIU/L), as did free T(4) (1.52 vs. 1.38 ng/dL) and TBG (32.86 vs. 21.52 MUg/mL). Estradiol levels increased, peaking at hCG administration (1743.21 vs. 71.37 pg/mL). Of 50 women with baseline TSH <= 2.5 mIU/L, 22 (44.0%) had a subsequent rise in TSH to >2.5 during or after COH. The pattern of change over time in TSH concentrations was significantly influenced by baseline hypothyroidism and whether pregnancy was achieved. CONCLUSION(S): COH led to significant elevations in TSH, often above pregnancy appropriate targets. These findings were particularly evident in women with preexisting hypothyroidism and may have important clinical implications for screening and thyroid hormone supplementation. PMID- 22260854 TI - Does colorectal endometriosis alter intestinal functions? A prospective manometric and questionnaire-based study. AB - OBJECTIVE: To objectively evaluate using anorectal manometry whether endometriotic nodules influence intestinal function and to reveal subjective intestinal dysfunctions in patients with rectosigmoid deep infiltrating endometriosis. DESIGN: Prospective study. SETTING: Tertiary care university hospital. PATIENT(S): Patients (n = 25) with a preoperative diagnosis of rectosigmoid endometriosis. INTERVENTION(S): Patients underwent anorectal manometry; after that, they filled a questionnaire about defecatory functions and ranked their pain symptoms. MAIN OUTCOME MEASURE(S): The parameters studied were resting pressure, maximum squeezing pressure, pushing, rectoanal inhibitory reflex, and rectal sensibility. We analyzed the responses to the defecatory function questionnaire and the scored the endometriosis pain symptoms using a Visual Analogue Scale. RESULT(S): No alterations of the rectoanal inhibitory reflex were found. Hypertone of the internal anal sphincter was found in 20 of 25 patients. Almost half of the patients had an increase of the threshold of desire to defecate, and 7 patients had a reduction of the anal sphincter squeeze pressure. According to the responses to the defecatory function questionnaire, incomplete evacuation was the most common symptom. CONCLUSION(S): We did not find marked motility or sensitive dysfunctions at the anorectal manometry, whereas subjectively patients reported some defecatory disorders. We revealed the presence of hypertone of the internal anal sphincter in most of the patients. CLINICAL TRIAL REGISTRATION NUMBER: 74/2010/O/Sper. PMID- 22260855 TI - Oocyte mitochondrial bioenergy potential and oxidative stress: within-/between subject, in vivo versus in vitro maturation, and age-related variations in a sheep model. AB - OBJECTIVE: To analyze within-/between-subject, in vivo versus in vitro maturation (IVM), and age-related variations of mitochondrial (mt) bioenergy potential and oxidative status of metaphase II (MII) oocytes recovered from hormonally stimulated sheep. DESIGN: Prospective study. SETTING: Academic basic research laboratory. SUBJECT(S): Ten adult ewes. INTERVENTION(S): Estrus synchronization, controlled ovarian hyperstimulation (COH), ovariohysterectomy; follicular and oviductal oocyte retrieval; IVM of follicular oocytes. MAIN OUTCOME MEASURE(S): Mean +/- SD, within-subject (CV(w)) and between-subject (CV(b)) variation coefficients of mt activity, intracellular reactive oxygen species (ROS) levels, and mt/ROS colocalization in sheep oocytes from young and aged donors and matured in vivo (in vivo MIIs) or in vitro (IVM MIIs). RESULT(S): Within- and between subject, in vivo versus IVM, and age-related variations of mt activity were observed in MII oocytes from hormonally stimulated donor sheep. ROS levels increased significantly in oocytes from aged donors. Mt-ROS colocalization was consistently higher in in vivo MIIs compared with IVM MIIs. Oviductal energy/antioxidant ability is influenced by COH. CONCLUSION(S): Oocyte energy/oxidative status is affected by within-/between-subject, in vivo versus IVM, and age-related variations. Mt/ROS colocalization is a reliable marker of in vivo MII oocytes. PMID- 22260856 TI - Clostridium difficile infection in older adults: a review and update on its management. AB - BACKGROUND: Clostridium difficile is a main cause of health care-associated infections. The incidence and severity have been increasing. Elderly persons are at an increased risk of morbidity and mortality from C. difficile infection (CDI). Relatively few advances have been made in the treatment of CDI since it was first identified as a cause of antibiotic-associated diarrhea more than 30 years ago. OBJECTIVE: This article reviews CDI and provides an update on its treatment, including recently published clinical practice guidelines and the recently approved drug, fidaxomicin. METHODS: English-language literature was identified through a search of PubMed (1966-October 2011), Iowa Drug Information Service (1966-October 2011), and International Pharmaceutical Abstracts (1970 October 2011). Key search terms included Clostridium difficile, Clostridium infections, pseudomembranous colitis, antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, elderly, geriatric, epidemiology, microbiology, diagnosis, risk factors, treatment, drug therapy, vancomycin, metronidazole, and fidaxomicin. RESULTS: Metronidazole and vancomycin remain the mainstays of CDI treatment. Current guidelines recommend oral metronidazole for initial mild to moderate episodes or first recurrence. Oral vancomycin is recommended for initial severe episodes, or first or second recurrence. Fidaxomicin was approved in 2011 for treatment of CDI, but its place in therapy has yet to be determined. Other antibiotics have been used with variable success. Saccharomyces boulardii is the only probiotic that has shown efficacy in CDI. Fecal transplants have been used successfully in some patients, but randomized studies are needed. Immune therapy with a vaccine and monoclonal antibodies is being studied in clinical trials. CONCLUSIONS: Treatment of CDI is challenging due to the limited number of drugs that have proven to be effective, concerns about antibiotic resistance, and recurring disease. The recent approval of fidaxomicin provides a new alternative. Immune therapy will likely play a greater role in the future. PMID- 22260857 TI - Total dietary fat and fatty acid content modifies plasma phospholipid fatty acids, desaturase activity indices, and urinary prostaglandin E in women. AB - Compared with diets high in fat, low-fat diets are associated with reduced risk of cardiovascular disease. We hypothesized that a low-fat (LF) (20% fat) and an LF high-omega-3 (n-3) fatty acid diet (LFn3) (23% fat with 3% as alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid [DHA]) would enhance n-3 composition of plasma phospholipid fatty acid and reduce urinary prostaglandin E(2) (PGE(2)) relative to a high-fat diet (HF) (40% fat) and that these changes would be associated with alterations in delta5 desaturase (D5D) and delta6 desaturase (D6D) activity. Phospholipid fatty acids and urinary PGE(2) were measured, and D5D and D6D activity indices calculated in a crossover trial in 17 postmenopausal women fed each of 3 test diets (HF, LF, and LFn3) for 8-week feeding periods. Desaturase activity indices were calculated as D5D, 20:4n 6/20:3n-6, and D6D, 20:3n-6/18:2n-6. Plasma phospholipid fatty acid, alpha linolenic acid, eicosapentaenoic acid, docosapentaenoic acid (DPA), DHA, and total n-3 fatty acids increased, whereas linoleic acid and arachidonic acid decreased with consumption of LFn3. The LF resulted in enhanced arachidonic acid and DHA. High fat reduced D6D, whereas both HF and LF increased D5D. Urinary PGE(2) was reduced in response to both the LF and LFn3 diets. Low-fat diets, with or without long-chain n-3 fatty acids, promote positive health effects due in part to favorable alteration of plasma phospholipid fatty acid profiles and modification in desaturase activity indices, suggesting that the type and amount of fat consumed are modifiable risk factors for the prevention of cardiovascular disease. PMID- 22260858 TI - Supplementation of Korean fermented soy paste doenjang reduces visceral fat in overweight subjects with mutant uncoupling protein-1 allele. AB - The purpose of this study was to examine the hypothesis that the antiobesity effect of doenjang, a Korean fermented soy paste is different between the mutant and the wild-type alleles of a polymorphism upstream of the uncoupling protein-1 (UCP-1) gene in overweight subjects. In our randomized, double-blind, placebo controlled trial, a total of 51 subjects with a body mass index of 23 kg/m(2) or greater and a waist-to-hip ratio of 0.90 or greater for men or 0.85 or greater for women were randomly assigned to take 9.9 g/d of either a placebo or doenjang for 12 weeks. The relative frequency of the mutant G allele of the UCP-1 polymorphism was 0.60 in the placebo group and 0.62 in the doenjang group. Supplementation of doenjang had no significant effect on the visceral fat area compared with that of the placebo group, but there was a significantly reduced amount of visceral fat in subjects with the G allele of UCP-1 polymorphism. Doenjang supplementation was found to significantly increase the free fatty acid concentration in subjects with both the A allele and the G allele. There was a significant association between visceral fat and age in study subjects with both the wild-type and mutant alleles of the UCP-1 gene. Doenjang supplementation significantly reduced visceral fat and increased the free fatty acid concentrations in subjects with the G allele of the UCP-1 polymorphism, which suggests that doenjang may be related to increased free fatty acid levels caused by elevated lipolysis in these subjects. PMID- 22260859 TI - Low-dose fish oil supplementation increases serum adiponectin without affecting inflammatory markers in overweight subjects. AB - Obesity is associated with an increased risk of cardiovascular disease, whereas long-chain n-3 polyunsaturated fatty acids (PUFAs) from fish may have cardioprotective and anti-inflammatory effects. This study aimed to investigate the hypothesis that acute and short-term supplementation with a low dose of marine n-3 PUFA exerts an anti-inflammatory effect in overweight subjects. In a double-blind, placebo-controlled trial with 2 parallel groups, 50 overweight subjects were randomized to receive daily supplementation with 2 capsules containing either 2 g of fish oil (1.1 g marine n-3 PUFA) or 2 g of olive oil. Blood samples and adipose tissue biopsies were collected at baseline, after 1 day (acute effect), and after 6 weeks (short-term effect) of supplementation. No significant effects were seen after supplementation for 1 day, but after 6 weeks, subjects receiving fish oil had a significant increase in the n-3 PUFA content of granulocytes and adipose tissue (P < .01). Serum adiponectin levels were increased by 0.55 MUg/mL (95% confidence interval, 0.02-1.08) in the fish oil group compared with the control group (P = .04) after 6 weeks of supplementation. Levels of interleukin 6 were inversely correlated to the marine n-3 PUFA content of granulocytes and adipose tissue at baseline (excluding alpha-linolenic acid). In conclusion, daily supplementation with 1.1 g of marine n-3 PUFA significantly increased serum adiponectin, but the effect was small, and no overall anti inflammatory effect of the supplement could be demonstrated. PMID- 22260860 TI - The association of alcohol consumption with metabolic syndrome and its individual components: the Taichung community health study. AB - Alcohol has both adverse and protective effects on the individual components of metabolic syndrome (MS). We hypothesize that alcohol consumption increases the risk of developing MS and that the consumption of different types of alcoholic beverages has different effects on the development of MS and its individual components. We enrolled 2358 men for this cross-sectional study. The data were collected from self-reported nutrition and lifestyle questionnaires. Individuals who drank at least once per week for 6 consecutive months were classified as current drinkers. Current drinkers were at a higher risk of developing MS, abdominal obesity, and high triglyceride levels, but they were at a lower risk of developing low levels of high-density lipoprotein cholesterol (HDL-C). The increased risk of developing MS, high triglyceride, and high fasting glucose levels was dose dependent, whereas low HDL-C levels demonstrated a reverse relationship. The dose needed to reduce the risk of having low HDL-C levels was ?50 g/d. This dose, however, resulted in an increased risk of developing high fasting glucose and high triglyceride levels. Consuming mixed types of alcohol increased the risk of developing MS and abdominal obesity. Meanwhile, those who drank liquor or wine had a greater risk of developing high triglyceride or high fasting glucose levels, respectively. In conclusion, alcohol consumption dose dependently increased the risk of developing MS and some of its individual components while dose-dependently decreasing the risk of developing low HDL-C levels. The type of alcoholic beverage had different effects on the development of the individual components of MS. PMID- 22260861 TI - Amino acid mixture acutely improves the glucose tolerance of healthy overweight adults. AB - Certain amino acids have been reported to influence carbohydrate metabolism and blood glucose clearance, as well as improve the glucose tolerance in animal models. We hypothesized that an amino acid mixture consisting of isoleucine and 4 additional amino acids would improve the glucose response of healthy overweight men and women to an oral glucose tolerance test (OGTT). Twenty-two overweight healthy subjects completed 2 OGTTs after consuming 2 different test beverages. The amino acid mixture beverage (CHO/AA) consisted of 0.088 g cystine 2HCl, 0.043 g methionine, 0.086 g valine, 12.094 g isoleucine, 0.084 g leucine, and 100 g dextrose. The control beverage (CHO) consisted of 100 g dextrose only. Venous blood samples were drawn 10 minutes before the start of ingesting the drinks and 15, 30, 60, 120, and 180 minutes after the completion of the drinks. During the OGTT, the plasma glucose response for the CHO/AA treatment was significantly lower than that of the CHO treatment (P < .01), as was the plasma glucose area under the curve (CHO/AA 806 +/- 31 mmol/L.3 hours vs CHO 942 +/- 40 mmol/L.3 hours). Differences in plasma glucose between treatments occurred at 30, 60, 120, and 180 minutes after supplement ingestion. Plasma glucagon during the CHO/AA treatment was significantly higher than during the CHO treatment. However, there were no significant differences in plasma insulin or C-peptide responses between treatments. These results suggest that the amino acid mixture lowers the glucose response to an OGTT in healthy overweight subjects in an insulin-independent manner. PMID- 22260862 TI - Mulberry leaf extract increases adiponectin in murine 3T3-L1 adipocytes. AB - We have previously shown that mulberry leaf extract (MA) causes blood glucose levels to decrease in rats with streptozotocin-induced diabetes while enhancing glucose uptake by isolated fat cells. We hypothesized that the antidiabetic activity of MA is mediated via enhancement of adiponectin secretion and adipogenesis, which consequently decreases blood glucose. In the present study, we aimed to elucidate the molecular basis for the observed antidiabetic activity using murine 3T3-L1 preadipocyte cultures. We found that treatment of differentiating 3T3-L1 cells with MA at concentrations of 5, 15, and 45 MUg/mL increased expression of adiponectin messenger RNA from 1.4-fold (control) to 1.5 , 1.95-, and 2.2-fold above basal values, respectively, while causing adiponectin secretion to increase from 70 +/- 7.4 ng/mL to 100 +/- 1.4, 138 +/- 2.0, and 176 +/- 21.4 ng/mL, respectively. Furthermore, we observed an increase in both lipid accumulation and messenger RNA expression of transcription factors, such as CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma; and of the fatty acid-binding protein aP2 in differentiated 3T3 L1 cells pretreated with MA. Our findings indicate that the stimulatory effects of mulberry leaf extract on adipocyte proliferation and differentiation likely occur through up-regulation of adipogenic transcription factors and downstream gene expression. Such effects of mulberry leaf extract on adiponectin secretion and adipocyte activity may account for, at least in part, the antidiabetic effects of consumption of beverages containing mulberry leaves. PMID- 22260863 TI - Bimodal action of miroestrol and deoxymiroestrol, phytoestrogens from Pueraria candollei var. mirifica, on hepatic CYP2B9 and CYP1A2 expressions and antilipid peroxidation in mice. AB - Miroestrol and deoxymiroestrol are phytoestrogens isolated from Pueraria candollei var. mirifica. The influence of miroestrol and dexoymirosestrol on hepatic cytochrome P450 (P450) enzymes and antioxidative activity in brain was examined in C57BL/6 mice compared with that of a synthetic female sex hormone estradiol. We hypothesized that miroestrol and deoxymiroestrol would induce CYP2B9 expression, whereas CYP1A2 expression would be suppressed compared with estradiol. Miroestrol and deoxymiroestrol treatment significantly increased uterus weight and volume. In addition, both of these phytoestrogens induced the expression of CYP2B9 and suppressed the expression of CYP1A2, as expected. Hepatic P450 activities correspondingly showed that both compounds increased benzyloxyresorufin O-dealkylase activity, whereas methoxyresorufin O-dealkylase activity was reduced. These observations suggested that miroestrol and deoxymiroestrol might affect hepatic P450 enzymes, including the CYP2B9 and CYP1A2 P450 isoforms. Assessment of lipid peroxidation demonstrated that miroestrol and deoxymiroestrol markedly decreased levels of malondialdehyde formation in the mouse brain. This is the first report suggesting miroestrol and deoxymiroestrol as potential alternative medicines to estradiol because of their distinctive ability to regulate mouse hepatic P450 expression and their beneficial antioxidative activities. PMID- 22260864 TI - Dyslipidemia is not associated with cardiovascular disease risk in an animal model of mild chronic suboptimal nutrition. AB - Previous studies performed in an experimental model of nutritional growth retardation (NGR) have observed metabolic adaptation. We hypothesized that changes in lipid-lipoprotein profile, glucose, and insulin levels occur, whereas overall body growth is reduced.The aim of this study was to assess serum lipid lipoprotein profile, hepatogram, insulinemia and glycemia, and CVD risk markers in rats fed a suboptimal diet. Weanling male rats were assigned either to control (C) or NGR group. In this 4-week study, C rats were fed ad libitum a standard diet, and NGR rats received 80% of the amount of food consumed by C. Zoometric parameters, body fat content, serum lipid-lipoprotein profile, hepatogram, insulinemia, and glycemia were determined, and the cardiovascular disease (CVD) risk markers homeostasis model assessment-insulin resistance and homeostasis model assessment and beta-cell function were calculated. Suboptimal food intake induced a significant decrease in body weight and length, which were accompanied by a reduction of 50% in body fat mass. Serum lipoproteins were significantly higher in NGR rats, with the exception of high-density lipoprotein cholesterol, which remained unchanged. Nutritional growth retardation rats had decreased triglycerides compared with C rats. No significant differences were detected in liver function parameters. The CVD risk markers homeostasis model assessment (HOMA)-insulin resistance and homeostasis model assessment and beta-cell function were significantly lower in NGR rats. Mild chronic suboptimal nutrition in weanling male rats led to growth retardation and changes in the lipid-lipoprotein profile, glucose, and insulin levels while preserving the integrity of liver function. These data suggest a metabolic adaptation during suboptimal food intake, which ensures substrates flux to tissues that require constant energy-in detriment to body growth. The CVD risk markers suggested that mild chronic food restriction of approximately 20% could provide protection against this degenerative disease. PMID- 22260865 TI - Magnesium absorption from mineral water decreases with increasing quantities of magnesium per serving in rats. AB - It is hypothesized that magnesium (Mg) absorption from mineral water is affected by the concentration of Mg in the water, the consumption pattern, and the volume consumed per serving. The present study examined the effect of serving volume and consumption pattern of artificial mineral water (AMW) and Mg concentration on Mg absorption in rats. Magnesium in AMW was labeled with magnesium-25 as a tracer. Each group consisted of 6 or 7 rats. In experiment 1, the rats received 1 mL of AMW containing 200 mg Mg/L at 4 times, 400 mg Mg/L twice, or 800 mg Mg/L at 1 time. In experiment 2, the rats received 1 mL of AMW containing 200 mg Mg/L or 0.25 mL of AMW containing 800 mg Mg/L at 4 times or 1 mL of AMW containing 800 mg Mg/L at 1 time. The absorption of Mg decreased with increasing Mg concentrations in the same serving volume of AMW with different serving frequencies. When the AMW containing 800 mg Mg/L was portioned into 4 servings, Mg absorption increased to the level of absorption in the group exposed to AMW containing 200 mg Mg/L served at the same frequency. These results suggest that the Mg concentration and the volume of AMW do not affect Mg absorption per se, but Mg absorption from AMW decreases when the amount of Mg in each serving is increased. Thus, frequent consumption is preferable for mineral water rich in Mg when the total consumption of mineral water is the same. PMID- 22260866 TI - Ascorbate and dehydroascorbic acid as biomarkers of oxidative stress: validity of clinical data depends on vacutainer system used. AB - Ascorbate and dehydroascorbic acid are frequently used as biomarkers of oxidative stress, but their lack of stability ex vivo and rapid postsampling interconversion continue to result in erroneous reference values. One problem is the large variety of vacutainer devices used for blood sampling purposes and the basic question of plasma vs serum as matrix. This study acquired blood samples by using 9 different and commonly used vacutainer systems followed by acidic stabilization and analysis by a well-validated method with the purpose of identifying acceptable means of collecting samples for proper ascorbate/dehydroascorbic acid analysis. In comparison, K(3)-EDTA vacutainers were superior in maintaining low ex vivo oxidation of vitamin C. PMID- 22260868 TI - Animal-related motorcycle collisions in North Dakota. AB - OBJECTIVE: To study the epidemiology and mortality of animal-motorcycle collisions. METHODS: A retrospective study of all motorcycle collisions recorded in the North Dakota Department of Transportation Crash Reporting System from January 2007 to December 2009 was conducted. Mortality was designated as the main outcome measure. RESULTS: Seven hundred sixty-six collisions involving 798 motorcycles were included in this study; 48 of these collisions were with animals (6.3% of all motorcycle collisions). Deer were the most common animal involved (81%). Most animal-motorcycle collisions took place during nighttime with clear weather and on straight rural roads. Drivers were older in animal collisions compared with nonanimal collisions (median of 44 vs 30 years old, respectively, P < .0001). Most drivers were males, whereas most passengers were females. Helmets were worn by only 32% of drivers and 12% of passengers. There were 4 (8%; 95% CI, 3%-20%) fatal animal collisions; 9% of the collisions with large animals were fatal compared with 3% of nonanimal collisions (P = .0411). CONCLUSIONS: Animal motorcycle collisions are a small subgroup of all motorcycle collisions, but with a high mortality rate. Efforts should be made to increase helmet usage, mitigate these collisions, and increase awareness of this problem among motorcycle riders. PMID- 22260869 TI - Arsenite-induced apoptosis of human neuroblastoma cells requires p53 but occurs independently of c-Jun. AB - Arsenite treatment of human SH-SY5Y neuroblastoma cells leads to an upregulation of caspase-3/7 activity and to the fragmentation of chromatin that is accompanied by elevated p53 and c-Jun levels. Expression of a truncated mutant of p53, p53DD, which interfered with the oligomerization of p53, suppressed the arsenite-induced upregulation of caspase-3/7 activity and the fragmentation of chromatin, indicating that p53 is required for arsenite-induced cell death. These data were corroborated by knockdown experiments of p53 following expression of a p53 specific short hairpin RNA. Likewise, expression of either p53DD or knockdown of p53 prevented caspase-3/7 activation and chromatin fragmentation induced by nutlin-3, a compound that prevents the interaction between p53 and the E3 ubiquitin ligase MDM2. Transcriptional upregulation of a chromatin-embedded p53 responsive reporter gene in either arsenite or nutlin-3 stimulated neuroblastoma cells revealed that the transcriptional activity of p53 was increased under these conditions. Expression of a c-Jun-specific short hairpin RNA failed to impair arsenite-induced caspase-3/7 activation and fragmentation of chromatin. Likewise, inhibition of c-Jun target gene expression by expression of a dominant-negative mutant of c-Jun did not interfere with arsenite-induced caspase-3/7 activation and chromatin fragmentation. However, this approach successfully reduced caspase 3/7 activity induced as a result of forced expression of a constitutively active mutant of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase (MEKK)-1. Together, these data show that the upregulation of p53 is causally linked with arsenite-induced cell death in neuroblastoma cells, whereas the upregulation of c-Jun is not part of this apoptotic signaling cascade. PMID- 22260870 TI - Dorsal root ganglia isolated from Nf1+/- mice exhibit increased levels of mRNA expression of voltage-dependent sodium channels. AB - We reported previously that sensory neurons isolated from mice with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited greater excitability and increased sodium current densities compared with wildtype mice. This raises the question as to whether the increased current density resulted from post translational modifications or increased expression of sodium channels. Quantitative real-time polymerase chain reaction was used to measure expression levels of the nine different voltage-gated sodium channel alpha subunits and the four associated auxiliary beta subunits in the dorsal root ganglia (DRG) obtained from wildtype and Nf1+/- mice. The Relative Expression Software Tool indicated that Nav1.1, Nav1.3, Nav1.7, and Nav1.8 were significantly elevated in DRG isolated from Nf1+/- mice. Expression of Nav1.2, Nav1.5, Nav1.6, and Nav1.9 were not significantly altered. The gene transcript for Nav1.4 was not detected. There were no significant changes in the relative expression levels of beta subunits. The Nav1.9 subtype was the most abundant with Nav1.7 and Nav1.8 being the next most abundant subtypes, whereas Nav1.3 was relatively less abundant. For the beta subunits, beta1 was by far the most abundant subtype. These results demonstrate that the increased expression levels of Nav1.7, Nav1.8, and perhaps Nav1.1 in the Nf1+/- DRG make the largest contribution to the increased sodium current density and thus give rise to the enhanced excitability. Though the mechanisms by which many people with NF1 experience increased pain have not been elucidated, these abnormal painful states may involve elevated expression of specific sodium channel subtypes in small diameter nociceptive sensory neurons. PMID- 22260872 TI - The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice. AB - Repeated use of methamphetamine (METH) causes dependence in humans, and to date, there are no effective medication treatments for METH addiction. We previously reported that the antibiotic minocycline attenuated behavioral abnormalities (hyperactivity and behavioral sensitization) and dopaminergic neurotoxicity in mice and monkeys, after the administration of METH. In this study, we examined the effect of minocycline on METH-induced rewarding effects in mice using the conditioned place preference (CPP) paradigm. Minocycline (40 mg/kg, IP) significantly attenuated METH (1.0 mg/kg, SC)-induced place preference in mice. In vivo microdialysis experiments using free-moving mice, showed that minocycline (40 mg/kg, IP) significantly attenuated the increased extracellular dopamine (DA) levels within the nucleus accumbens, typically seen after the administration of METH (1.0 mg/kg, SC). These findings suggest that minocycline may block METH induced rewarding effects by down regulating extracellular DA levels in the nucleus accumbens of mice. This would make minocycline a potential therapeutic drug for the treatment of METH induced disorders. PMID- 22260871 TI - Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects. AB - The psychostimulant methylphenidate (MPD) is currently the most prescribed drug therapy for attention deficit hyperactivity disorder (ADHD) and is used by students as a cognitive enhancer. The caudate nucleus (CN) is a structure within the motive circuit where MPD exerts its effects, it is known to contain high levels of dopaminergic cells and directly influence motor activity. The objective of this study was to understand the role of CN in response to acute and chronic administration of MPD. Specific and non-specific bilateral ablations were created in the CN using electrolytic lesion and 6-Hydoxydopamine (6-OHDA). Four groups of rats were used: control (n=4), sham (n=4), CN electrolytic lesion group (n=8) and CN 6-OHDA injected group (n=8). On experimental day one (ED 1) all rats received a saline injection and baseline locomotive activity was recorded. On ED 2 and ED 3 CN sham, electrolytic lesion and/or 6-OHDA injected groups were made followed by four to five days recovery (ED 3-7), followed by six daily 2.5 mg/kg MPD injections (ED 9-14), three days of washout (ED 15-17) and an MPD re-challenge of drug proceeding the washout days (ED 18). Locomotor activity was obtained at ED 1, 8, 9, and 18 using an open field assay. The results show that the CN electrolytic lesion group responded to the acute and chronic MPD administration similar to the control and sham group, while the CN 6-OHDA injected group prevented the acute and the chronic effects of MPD administration. One possible interpretation why nonspecific electroyltic lesioning of the CN failed to prevent acute and chronic effects of MPD administration is due to destruction of both the direct and the indirect CN pathways which act as an inhibitory/excitatory balance, electroylticelectroyltic. The selective dopaminergic lesioning prevented the effects of MPD administration suggesting that dopaminergic pathways in CN play a significant role in the effects of MPD. PMID- 22260873 TI - Assessment of the aversive effects of peripheral mu opioid receptor agonism in Fischer 344 and Lewis rats. AB - The Fischer 344 (F344) and Lewis (LEW) inbred rat strains differ on a host of biochemical, neuroanatomical, immunological and behavioral endpoints. One behavioral difference of interest is their differential reactivity to the aversive effects of morphine as indexed by the conditioned taste aversion preparation (aversions acquired by F344 rats are significantly greater than those acquired by the LEW strain). This differential effect appears to be specific to opioids that work primarily on the mu opioid receptor. Given that morphine works systemically, it is unknown whether these differential effects in F344 and LEW animals are centrally or peripherally mediated. To address this issue, the present study investigated the ability of the peripherally acting mu preferring opioid agonist loperamide to induce differential taste aversions in F344 and LEW animals. Both F344 and LEW animals acquired dose-dependent taste aversions to the loperamide-associated solution with no difference between them. Additionally, control animals initially injected with vehicle during aversion training with loperamide and subsequently conditioned with morphine displayed the typical aversive profile to morphine (F344>LEW). Although the basis for the present data is unknown, their relation to morphine-induced taste aversions and the role of the interaction of stimulus effects of drugs that produce differential abuse liability were discussed. PMID- 22260874 TI - Contents of second peak in the circadian variation of acute myocardial infarction in the Japanese population. AB - BACKGROUND: Circadian variation has been accepted as a factor in acute myocardial infarction (AMI). An increased incidence of cardiac events in the morning has been reported for a long time. Recent reports have indicated that the onset of AMI shows two peaks, which occur in the morning and evening. It has also been demonstrated that circadian pattern of AMI may vary with sex and age. METHODS AND RESULTS: We investigated 522 consecutive patients who underwent primary percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI) between 2000 and 2010. The patients were classified into 3 age groups: younger (<=59 years old), intermediate (60-79 years old), and older (>=80 years old). Clinical data were investigated, including the age and sex, angiographic characteristics, and time of onset of STEMI. There were two peaks in the onset of STEMI throughout the day, which were at 7:00-10:00 and 19:00-21:00 h, among all patients (male and female). Stratified analysis showed that older females formed the main part of the second peak. CONCLUSIONS: There were two peaks in the onset of STEMI in a Japanese population in Tokyo. The second peak was significantly dominated by the older female group. Age and gender influenced the second peak in the circadian variation of AMI in a Japanese population in Tokyo. PMID- 22260875 TI - Distant plant homologues: don't throw out the baby. AB - Plants and metazoans share many similarities in terms of conserved proteins. Antibodies have been used extensively to detect remote homologues, many of which are yet to be identified conclusively. Genome sequencing and the creation of novel sequence or structure comparison programs have assisted greatly in the identification of distant protein homologues. The continuing development of new software algorithms and the combining of bioinformatics with proteomics offer hope that remaining homologues will be soon identified. PMID- 22260876 TI - Development of new structural alerts suitable for chemical category formation for assigning covalent and non-covalent mechanisms relevant to DNA binding. AB - The need to assess the ability of a chemical to act as a mutagen is one of the primary requirements in regulatory toxicology. Several pieces of legislation have led to an increased interest in the use of in silico methods, specifically the formation of chemical categories and read-across for the assessment of toxicological endpoints. One of the key steps in the development of chemical categories for mutagenicity is defining the mechanistic organic chemistry associated with the formation of a covalent bond between DNA and an exogenous chemical. To this end this study has analysed, by use of a large set of mutagenicity data (Ames test), the mechanistic coverage of a recently published set of in silico structural alerts developed for category formation. The results show that the majority of chemicals with a positive result in the Ames test were assigned at least one covalent binding mechanism related to the formation of a DNA adduct. The remaining chemicals with positive data in the Ames assay were subjected to a detailed mechanistic analysis from which 26 new structural alerts relating to covalent binding mechanisms were developed. In addition, structural alerts for radical and non-covalent intercalation mechanisms were also defined. The structural alerts outlined in this study are not intended to predict mutagenicity but rather to identify mechanisms associated with covalent and non covalent DNA binding. This mechanistic profiling information can then be used to form chemical categories suitable for filling data gaps via read-across. A strategy for chemical category formation for mutagenicity is also presented. PMID- 22260877 TI - Multistate outbreak of MDR TB identified by genotype cluster investigation. AB - In 2008, diagnosis and investigation of 2 multidrug-resistant tuberculosis cases with matching genotypes led to identification of an outbreak among foreign-born persons who performed short-term seafood production work in Alaska during 2006. Tuberculosis control programs should consider the possibility of domestic transmission even among foreign-born patients. PMID- 22260878 TI - Genetic characterization of peste des petits ruminants virus, Sierra Leone. PMID- 22260879 TI - Cutaneous polyarteritis nodosa and common variable immunodeficiency: a previously unreported association. PMID- 22260880 TI - Effects of awareness and nociception on heart rate variability during general anaesthesia. AB - During anaesthesia awareness and nociception are serious complications that may further lead to haemodynamic instability. Specific monitoring of depth of hypnosis and depth of analgesia based on heart rate variability (HRV) analysis is eligible to improve patient safety and reduce efforts in post-operative care. Consequently, in this analysis we assess the applicability of HRV parameters during surgical interventions with standardized intravenous propofol-remifentanil anaesthesia. Peri-operative electrocardiograms were recorded from cardiovascular stable patients (ASA Score I/II, N = 32, age: 36.4 +/- 11.23 a, BMI: 25.2 +/- 3.16) scheduled for trauma and dentofacial surgery. HRV time- and frequency domain parameters, measures of complexity and nonlinear dynamics were compared by analysing longitudinally distributed 300 s intervals preceding/following induction of anaesthesia (BL-I1), intubation (I1-I2) and extubation (E1-E2). Mean value (meanNN) and standard deviation (sdNN) of the heart rate are influenced in BL-I1 (p < 0.001), I1-I2 (p < 0.05) and E1-E2 (p < 0.001). The number of forbidden words of symbolic dynamics changes significantly for BL-I1 (p < 0.001) and not for I1-I2 and E1-E2 (p > 0.05). Probability of low-variability POLVAR10 is significantly altered in all comparisons (BL-I1: Delta = 0.032, p < 0.01, I1 I2: Delta = 0.12, p < 0.05, E1-E2: Delta = 0.169, p < 0.01) but especially during nociception. While standard time-domain parameters lacked selectivity, parameters of symbolic dynamics appear to be specifically influenced by changes in depth of hypnosis and nociception, respectively. However, the lack of steady-state ventilation/breathing in this study needs to be considered in future research. To be used for clinical anaesthesia monitoring our results have to be prospectively validated in clinical studies. PMID- 22260881 TI - New species of Myxosporea from frogs and resurrection of the genus Cystodiscus Lutz, 1889 for species with myxospores in gallbladders of amphibians. AB - Two new myxosporean species in the gallbladders of frogs have recently spread across eastern Australia and cause disease. Cystodiscus axonis sp. n. and Cystodiscus australis sp. n. are species of Myxosporea (Myxozoa) identified from a range of Australian frogs and tadpoles including the introduced Cane toad (Rhinella marina). The new species are defined by their distinct genetic lineage, myxospore morphology and ultrastructure of the pre-sporogonic development. Spores of both species are produced in the gallbladder. Spores of C. axonis sp. n. possess distinct filiform polar appendages (FPA). The pre-sporogonic development of C. axonis sp. n. is within myelinated axons in the central nervous system of hosts, as well as bile ducts of tadpoles. Pre-sporogonic and sporogonic development of C. australis sp. n. is confined to tadpole bile ducts and myxospores of C. australis sp. n. are devoid of FPA. The genus Cystodiscus Lutz, 1889 introduced for Cystodiscus immersus Lutz, 1889 is emended to accompany myxosporean parasites affecting amphibians previously classified in the genus Myxidium sensu lato. A synopsis of described species within Cystodiscus is provided. PMID- 22260882 TI - Comparison of technology-based cooperative learning with technology-based individual learning in enhancing fundamental nursing proficiency. AB - BACKGROUND: The aim of nursing education is to prepare students with critical thinking, high interests in profession and high proficiency in patient care. Cooperative learning promotes team work and encourages knowledge building upon discussion. It has been viewed as one of the most powerful learning methods. Technology has been considered an influential tool in teaching and learning. It assists students in gathering more information to solve the problems and master skills better. PURPOSE: The purpose of this study was to compare the effect of technology-based cooperative learning with technology-based individual learning in nursing students' critical thinking in catheterization knowledge gaining, error discovering, skill acquisitions, and overall scores. METHODS: This study used a pretest-posttest experimental design. Ninety-eight students were assigned randomly to one of two groups. Questionnaires and tests were collected at baseline and after completion of intervention. RESULTS: The results of this study showed that there was no significant difference in related catheterization skill performance. However, the remaining variables differed greatly between the two groups. CONCLUSIONS AND APPLICATIONS: This study's findings guide the researchers and instructors to use technology-based cooperative learning more appropriately. Future research should address the design of the course module and the availability of mobile devices to reach student-centered and learn on the move goals. PMID- 22260884 TI - Dietary assessment of adolescents undergoing laparoscopic Roux-en-Y gastric bypass surgery: macro- and micronutrient, fiber, and supplement intake. AB - BACKGROUND: Extremely obese adolescents are increasingly undergoing bariatric procedures, which restrict dietary intake. However, as yet, no data are available describing the change in caloric density or composition of the adolescent bariatric patient's diet pre- and postoperatively. Our objective was to assess the 1-year change in the dietary composition of adolescents undergoing bariatric surgery at a tertiary care children's hospital. METHODS: A total of 27 subjects (67% female, 77% white, age 16.7 +/- 1.4 yr, baseline body mass index 60.1 +/- 14.1 kg/m(2)) were prospectively enrolled into an observational cohort study 1 month before undergoing laparoscopic Roux-en-Y gastric bypass from August 2005 to March 2008. The 3-day dietary intake was recorded at baseline (n = 24) and 2 weeks (n = 16), 3 months (n = 11), and 1 year (n = 9) postoperatively. The dietary record data were verified by structured interview and compared with the Dietary Reference Intake values for ages 14-18 years. RESULTS: By 1 year after surgery, the mean caloric intake, adjusted for body mass index was 1015 +/- 182 kcal/d, a 35% reduction from baseline. The proportion of fat, protein, and carbohydrate intake did not differ from baseline. However, the protein intake was lower than recommended postoperatively. The calcium and fiber intake was also persistently lower than recommended. Calcium and vitamin B(12) supplementation increased the likelihood of meeting the daily minimal recommendations (P <= .02). CONCLUSION: At 1 year after Roux-en-Y gastric bypass, the adolescents' caloric intake remained restricted, with satisfactory macronutrient composition but a lower than desirable intake of calcium, fiber, and protein. PMID- 22260885 TI - Probing cellular traction forces with magnetic nanowires and microfabricated force sensor arrays. AB - In this paper, the use of magnetic nanowires for the study of cellular response to force is demonstrated. High-aspect ratio Ni rods with diameter 300 nm and lengths up to 20 MUm were bound to or internalized by pulmonary artery smooth muscle cells (SMCs) cultured on arrays of flexible micropost force sensors. Forces and torques were applied to the cells by driving the nanowires with AC magnetic fields in the frequency range 0.1-10 Hz, and the changes in cellular contractile forces were recorded with the microposts. These local stimulations yield global force reinforcement of the cells' traction forces, but this contractile reinforcement can be effectively suppressed upon addition of a calcium channel blocker, ruthenium red, suggesting the role of calcium channels in the mechanical response. The responsiveness of the SMCs to actuation depends on the frequency of the applied stimulation. These results show that the combination of magnetic nanoparticles and micropatterned, flexible substrates can provide new approaches to the study of cellular mechanotransduction. PMID- 22260886 TI - Combined endoscopic-interventional radiologic approach for the treatment of bleeding gastric varices in the setting of a large splenorenal shunt. PMID- 22260887 TI - Contrast-enhanced US-guided ERCP for treatment of common bile duct stones in pregnancy. PMID- 22260888 TI - Secreted microRNAs: a new form of intercellular communication. AB - In multicellular organisms, cell-to-cell communication is of particular importance for the proper development and function of the organism as a whole. Intensive studies over the past three years suggesting horizontal transfer of secreted microRNAs (miRNAs) between cells point to a potentially novel role for these molecules in intercellular communication. Using a microvesicle-dependent, or RNA-binding protein-associated, active trafficking system, secreted miRNAs can be delivered into recipient cells where they function as endogenous miRNAs, simultaneously regulating multiple target genes or signaling events. In this Opinion, we summarize recent literature on the biogenesis and uptake of secreted miRNAs, propose a possible working model for how secreted miRNAs might be sorted and transferred between cells and speculate on their biological significance. PMID- 22260889 TI - Exercise and sedentary habits among adolescents with PCOS. AB - STUDY OBJECTIVE: The purpose of this study was the recording of physical activity and sedentary habits of adolescents with polycystic ovarian syndrome (PCOS). METHODS: We performed a structured interview to assess the level of physical activity and sedentary habits of girls with PCOS. We used a group of healthy adolescents as controls. All girls had their age, height, weight, hip and waist circumference measured and their BMI calculated. RESULTS: 81 girls (35 with PCOS and 46 controls) participated in the study. Girls with PCOS engaged in physical activities less than controls. Even when they did, the frequency and intensity of exercise was less. Also, girls with PCOS were less likely to be aware of the positive effects of exercise on their health. Girls in both groups were sedentary in excess of the 4 hours per day limit, which has been linked with obesity. CONCLUSION: Healthy teenagers were involved in a sporting activity more often and more frequently than the PCOS group. Athletic and sedentary habits of adolescents with PCOS may interact with other factors leading to obesity. PMID- 22260890 TI - Effect of antiandrogen treatment on bone density and bone geometry in adolescents with polycystic ovary syndrome. AB - STUDY OBJECTIVES: To determine the impact of antiandrogen treatment on bone density and geometry. DESIGN: Prospective cohort investigation. SETTING: Academic research institute. PARTICIPANTS: 38 (age 14.96 +/- 1.42 yr) subjects with PCOS. INTERVENTIONS: Treated with metformin (n = 17) or metformin and antiandrogen (n = 21). MAIN OUTCOME MEASURE: Bone density and geometry parameters at baseline and after a mean duration of 1.92 +/- 0.88 years using peripheral quantitative computed tomography of the forearm. RESULTS: At baseline, z-scores for trabecular (0.53 +/- 1.02) and cortical BMD (0.79 +/- 1.55) as well as total (0.62 +/- 1.07) and medullary cross sectional area (CSA) (0.79 +/- 1.29) were elevated. Cortical CSA (-0.01 +/- 1.10) and bone strength strain index (SSI) z-scores (-0.01 +/- 1.10) were normal. Muscle CSA z-score (0.12 +/- 1.70) was normal, but grip strength (-1.60 +/- 1.15) was significantly reduced. There were no significant changes within and between the two treatment options in respect to bone density and bone geometry parameters. With antiandrogen treatment, free androgen index (FAI) was significantly lower and grip strength further decreased (P < .001). CONCLUSIONS: No significant changes in bone mineral density and geometry parameters took place in PCOS women irrespective of treatment followed over a time of almost two years. General muscle weakness expressed as low grip strength may influence further bone development in PCOS. PMID- 22260891 TI - A case of vaginoplasty without grafting. AB - BACKGROUND: Many techniques have been used to create a neovagina in patients with vaginal agenesis, and several surgical procedures involve the use of a graft. Grafting techniques are associated with intraoperative and postoperative morbidity and complications, at both the donor and the recipient site. CASE: A 17 year-old patient with Mayer-Rokitansky-Kuster-Hauser syndrome complicated by unilateral pelvic kidney underwent successful vaginoplasty without the use of a graft, followed by insertion of a vaginal stent for 12 weeks. She had a functional, well-healed, and fully epithelialized neovagina by 6.5 months postoperatively. CONCLUSION: Patients undergoing surgical vaginoplasty may benefit from this simple surgical technique, thereby avoiding the morbidity associated with the alternative grafting techniques commonly used in practice. PMID- 22260892 TI - The connection between young women's body esteem and sexual assertiveness. AB - STUDY OBJECTIVE: Healthy sexuality includes having positive feelings about one's body and developing positive romantic relationships. Previous research predicts that women dissatisfied with their bodies may be less likely to enforce their rights of sexual autonomy (i.e., sexual assertiveness). DESIGN: We assessed whether the body esteem of young women was related to their reports of sexual assertiveness. Young women from local colleges (N = 127) completed a questionnaire that included demographics, self reported weight and height, sexual history, along with body esteem and sexual assertiveness. RESULTS: Overall, body esteem was related to sexual assertiveness regarding condom use when controlling for other variables. Women with less body esteem were less likely to insist that their partner use a condom. Individual components of body esteem did not independently predict insistence of condom use. Body esteem was not related to initiation of sex or refusal of unwanted sex. DISCUSSION: The current study found relationships between body esteem and sexual assertiveness regarding STI prevention behaviors. Given these findings, implications for STI prevention programs are discussed. PMID- 22260893 TI - Human papillomavirus vaccine policies among american Indian tribes in Washington State. AB - STUDY OBJECTIVE: American Indians experience high rates of cervical cancer, which is preventable by vaccination against human papillomavirus (HPV). We sought information on funding, barriers, education, and policies regarding HPV vaccination from clinics that serve tribal members in the Pacific Northwest. DESIGN: We surveyed staff either by telephone or by using a mailed survey at 31 tribal and Indian Health Service clinics serving the 29 federally recognized American Indian tribes in Washington State. The survey included 11 items on policies and use of the HPV vaccine. MAIN OUTCOME MEASURES: Primary outcomes were funding options for HPV vaccine administration, barriers to vaccine delivery, potential gaps in education, and determination of tribal or clinic-specific policies. RESULTS: Thirty-one clinics provided information; 28 administered the vaccine. Vaccination was supported by federal, private, and tribal sources. Barriers were reported by 89% of clinics, most commonly patients' lack of knowledge, distrust of the medical system, and lack of funding. Patient and provider information was widely available. Thirteen clinics had either tribal or internal clinic vaccination policies, or both. CONCLUSION: HPV vaccine is available, but complex policies on administration could result in tribal differences in vaccination rates. PMID- 22260894 TI - A preliminary study of apparent diffusion coefficient in chemotherapy-induced liver damage. AB - OBJECTIVES: To investigate changes in the hepatic apparent diffusion coefficient (ADC) in patients undergoing chemotherapy. METHODS: We enrolled 54 patients (25 women; mean age 57.0+/-13.1 years, range 29-89 years) undergoing chemotherapy for tumor and 10 controls (7 women; mean age 55.1+/-17.5 years, range 23-81 years). The patients were tested for serum alanine aminotransferase (ALT) activity (abnormal, normal) and fatty liver. Hepatic ADC values were compared among controls, patients and subgroups. Pearson correlation coefficient was used to assess the correlation between ADC and ALT activity. RESULTS: Hepatic ADC0,850 (*10(-3) mm2/s) was lower for patients than controls (1.14+/-0.18 vs. 1.28+/ 0.12, P=0.02) and was lower for patients with than without fatty liver and controls (1.01+/-0.06 vs. 1.18+/-0.18 and 1.28+/-0.12, respectively, all P<0.01), with no significant difference between patients without fatty liver and controls (P=0.07). ADC0,850 was lower for patients with abnormal ALT than normal ALT activity and controls (0.99+/-0.06 vs. 1.17+/-0.18 and 1.28+/-0.12, respectively, all P<0.05), with a significant difference also being seen between patients with normal ALT activity and controls (P=0.04). Hepatic ADC0,850 was not correlated with ALT activity in patients (r=-0.24, P=0.08). CONCLUSIONS: Although ADC did not correlate with ALT values, it did distinguish patient likely to have chemotherapy-induced liver damage as indicated by abnormal ALT values or fatty liver. These mechanisms need to be disentangled. PMID- 22260895 TI - Clinical utility of three-dimensional contrast-enhanced ultrasound in the differentiation between noninvasive and invasive neoplasms of urinary bladder. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of three dimensional contrast-enhanced ultrasound in differentiating invasive and noninvasive neoplasms of urinary bladder. METHODS: A total of 60 lesions in 60 consecutive patients with bladder tumors received three dimensional ultrasonography, low acoustic power contrast enhanced ultrasonography and low acoustic power three-dimensional contrast-enhanced ultrasound examination. The IU22 ultrasound scanner and a volume transducer were used and the ultrasound contrast agent was SonoVue. The contrast-specific sonographic imaging modes were PI (pulse inversion) and PM (power modulation). The three dimensional ultrasonography, contrast enhanced ultrasonography, and three-dimensional contrast-enhanced ultrasound images were independently reviewed by two readers who were not in the images acquisition. Images were analyzed off-site. A level of confidence in the diagnosis of tumor invasion of the muscle layer was assigned on a 5 degrees scale. Receiver operating characteristic analysis was used to assess overall confidence in the diagnosis of muscle invasion by tumor. Kappa values were used to assess inter-readers agreement. Histologic diagnosis was obtained for all patients. RESULTS: Final pathologic staging revealed 44 noninvasive tumors and 16 invasive tumors. Three-dimensional contrast-enhanced ultrasound depicted all 16 muscle-invasive tumors. The diagnostic performance of three dimensional contrast-enhanced ultrasound was better than those of three dimensional ultrasonography and contrast enhanced ultrasonography. The receiver operating characteristic curves were 0.976 and 0.967 for three-dimensional contrast-enhanced ultrasound, those for three dimensional ultrasonography were 0.881 and 0.869, those for contrast enhanced ultrasonography were 0.927 and 0.929. The kappa values in the three dimensional ultrasonography, contrast enhanced ultrasonography and three-dimensional contrast-enhanced ultrasound for inter-reader agreements were 0.717, 0.794 and 0.914. CONCLUSION: Three dimensional contrast-enhanced ultrasound imaging, with contrast-enhanced spatial visualization is clinical useful for differentiating invasive and noninvasive neoplasms of urinary bladder objectively. PMID- 22260896 TI - Infrapatellar plica of the knee: revisited with MR arthrographies undertaken in the knee flexion position mimicking operative arthroscopic posture. AB - PURPOSE: To describe the appearance of the infrapatellar plica (IPP) on magnetic resonance arthrography (MRA) taken in 70 degrees knee flexion, corresponding to the arthroscopic posture. MATERIALS AND METHODS: Twenty-two patients (23 knee joints) who underwent MRA with 70 degrees knee flexion were enrolled. All patients underwent MRA with 70 degrees knee flexion to simulate operative arthroscopy. The images included fat-suppressed T1-weighted spin echo axial, sagittal, and coronal images. The visualization and morphology of the IPP were retrospectively assessed by two musculoskeletal radiologists. RESULTS: The IPP was demonstrated in 78.3% (n=18/23) and was best visualized on the sagittal section through the intercondylar notch. The IPP manifested as a linear hypointense structure with variable thicknesses. The intercondylar component was delineated clearly, arising from the anterior intercondylar notch in parallel with the ACL and curving gently downward to attach to the infrapatellar fat pad. On the other hand, the Hoffa's fat pad component was not depicted clearly. The morphology of the IPP was either a separate type (60.9%) or a split type (17.4%). CONCLUSION: The IPPs can be visualized with a high rate of detection and various morphologic appearances must be appreciated under the review of a flexed knee MRA. PMID- 22260897 TI - Clinical significance of creative 3D-image fusion across multimodalities [PET+CT+MR] based on characteristic coregistration. AB - OBJECTIVE: To investigate a registration approach for 2-dimension (2D) based on characteristic localization to achieve 3-dimension (3D) fusion from images of PET, CT and MR one by one. METHOD: A cubic oriented scheme of"9-point & 3-plane" for co-registration design was verified to be geometrically practical. After acquisiting DICOM data of PET/CT/MR (directed by radiotracer 18F-FDG etc.), through 3D reconstruction and virtual dissection, human internal feature points were sorted to combine with preselected external feature points for matching process. By following the procedure of feature extraction and image mapping, "picking points to form planes" and "picking planes for segmentation" were executed. Eventually, image fusion was implemented at real-time workstation mimics based on auto-fuse techniques so called "information exchange" and "signal overlay". RESULT: The 2D and 3D images fused across modalities of [CT+MR], [PET+MR], [PET+CT] and [PET+CT+MR] were tested on data of patients suffered from tumors. Complementary 2D/3D images simultaneously presenting metabolic activities and anatomic structures were created with detectable-rate of 70%, 56%, 54% (or 98%) and 44% with no significant difference for each in statistics. CONCLUSION: Currently, based on the condition that there is no complete hybrid detector integrated of triple-module [PET+CT+MR] internationally, this sort of multiple modality fusion is doubtlessly an essential complement for the existing function of single modality imaging. PMID- 22260898 TI - Simultaneous PET/MR imaging in a human brain PET/MR system in 50 patients- current state of image quality. AB - OBJECTIVES: The present work illustrates the current state of image quality and diagnostic accuracy in a new hybrid BrainPET/MR. MATERIALS AND METHODS: 50 patients with intracranial masses, head and upper neck tumors or neurodegenerative diseases were examined with a hybrid BrainPET/MR consisting of a conventional 3T MR system and an MR-compatible PET insert. Directly before PET/MR, all patients underwent a PET/CT examination with either [18F]-FDG, [11C] methionine or [68Ga]-DOTATOC. In addition to anatomical MR scans, functional sequences were performed including diffusion tensor imaging (DTI), arterial spin labeling (ASL) and proton-spectroscopy. Image quality score of MR imaging was evaluated using a 4-point-scale. PET data quality was assessed by evaluating FDG uptake and tumor delineation with [11C]-methionine and [68Ga]-DOTATOC. FDG uptake quantification accuracy was evaluated by means of ROI analysis (right and left frontal and temporo-occipital lobes). The asymmetry indices and ratios between frontal and occipital ROIs were compared. RESULTS: In 45/50 patients, PET/MR examination was successful. Visual analysis revealed a diagnostic image quality of anatomical MR imaging (mean quality score T2 FSE: 1.27+/-0.54; FLAIR: 1.38+/ 0.61). ASL and proton-spectroscopy was possible in all cases. In DTI, dental artifacts lead to one non-diagnostic dataset (mean quality score DTI: 1.32+/ 0.69; ASL: 1.10+/-0.31). PET datasets of PET/MR and PET/CT offered comparable tumor delineation with [11C]-methionine; additional lesions were found in 2/8 [(68)Ga]-DOTATOC-PET in the PET/MR. Mean asymmetry index revealed a high accordance between PET/MR and PET/CT (1.5+/-2.2% vs. 0.9+/-3.6%; mean ratio (frontal/parieto-occipital) 0.93+/-0.08 vs. 0.96+/-0.05), respectively. CONCLUSIONS: The hybrid BrainPET/MR allows for molecular, anatomical and functional imaging with uncompromised MR image quality and a high accordance of PET results between PET/MR and PET/CT. These results justify the application of this technique in further clinical studies and may contribute to the transfer into whole-body PET/MR systems. PMID- 22260899 TI - Neospora caninum: in vivo and in vitro treatment with artemisone. AB - Neosporosis caused by Neospora caninum has global economic, clinical, and epidemiological impacts, mainly in the cattle industry. Currently, there is no useful drug for treatment of neosporosis. This publication is the first to describe the significant benefits that artemisone has on Neospora infections both in vitro and in vivo. Artemisone is a new semi-synthetic 10-alkylamino artemisinin that is superior to other artemisinin derivatives in terms of its significantly higher antimalarial activity, its tolerance in vivo, lack of detectable neurotoxic potential, improved in vivo pharmacokinetics and metabolic stability. Low micromolar concentrations of artemisone inhibited in vitro Neospora development. Prophylactic and post-infection treatment profoundly reduced the number of infected cells and parasites per cell. In the in vivo gerbil model, a non-toxic dose prevented typical cerebral symptoms, in most animals. There were no signs of clinical symptoms and brain PCR was negative. Most treated gerbils produced high specific antibody titer and were protected against a challenge. Overall, artemisone could be considered as a future drug for neosporosis. PMID- 22260900 TI - Ixodid ticks on ruminants, with on-host initiated moulting (apolysis) of Ixodes, Haemaphysalis and Dermacentor larvae. AB - To screen the host-dependent abundance of hard tick (Acari: Ixodidae) developmental stages on ruminants in South Hungary, red and roe deer, as well as goats and sheep were examined in a season, when larvae and nymphs are active. Altogether 2271 ticks were collected. In the relevant period the prevalence of tick-infestation was significantly higher among goats, than among sheep kept in the very same area, most likely in association with the browsing habit of the former. Roe deer and goats were found to be important hosts for Ixodes ricinus and Haemaphysalis concinna larvae, in contrast to the view that this stage does not usually feed on medium-sized mammals. Interestingly, one third of I. ricinus larvae and one larva of H. concinna and of Dermacentor reticulatus collected from goats in the same herd in August have started the moulting process (showed apolysis) on their host, despite being three-host ticks. This is the first survey involving four species of domestic and wild ruminants in Europe to compare the host-preference of ixodid ticks in the same region. PMID- 22260901 TI - Occurrence of Neospora caninum and Toxoplasma gondii infections in ovine and caprine abortions. AB - Neospora caninum and Toxoplasma gondii are closely related cyst-forming apicomplexan parasites identified as important causes of reproductive failure in cattle and small ruminants, respectively. Protozoan abortion in small ruminants is traditionally associated with T. gondii, but the importance of N. caninum remains uncertain. The aim of this study was to investigate the presence of N. caninum and T. gondii infections in abortion cases in small ruminants submitted for diagnosis. For this purpose, 74 ovine and 26 caprine aborted foetuses were recovered from different areas in Spain. Foetal histopathology was used to detect the presence of protozoal-associated lesions in brain. The presence of N. caninum and T. gondii was confirmed by PCR. Protozoal infection was detected in 17 out of 100 (17%) foetuses examined by at least one of the diagnostic techniques used. Lesions suggestive of protozoal infection were observed in 10.8% (8/74) and 15.4% (4/26) of the ovine and caprine abortions respectively. N. caninum and T. gondii infection was detected by PCR in 6.8% (5/74) and 5.4% (4/74) of sheep foetuses, respectively, of which five showed protozoal-associated lesions. N. caninum DNA was detected in 11.5% (3/26) of goat foetuses, of which two showed protozoal associated lesions, whereas T. gondii DNA was detected in one goat foetus with no lesions. The simultaneous presence of N. caninum and T. gondii DNA was detected in one sheep foetus with severe lesions. This study demonstrates that N. caninum plays a significant role in abortion in small ruminants in the studied population. In addition, our results highlight the importance of differentiating between protozoa whenever characteristic lesions are observed. PMID- 22260902 TI - Biomechanical examination of the 'plateau phenomenon' in ActiGraph vertical activity counts. AB - This paper determines if the leveling off ('plateau/inverted-U' phenomenon) of vertical ActiGraph activity counts during running at higher speeds is attributable to the monitor's signal filtering and acceleration detection characteristics. Ten endurance-trained male participants (mean (SD) age = 28.2 (4.7) years) walked at 3, 5 and 7 km h(-1), and ran at 8, 10, 12, 14, 16, 18 and 20 km h(-1) on a force treadmill while wearing an ActiGraph GT3X monitor at the waist. Triaxial accelerations of the body's center of mass (CoM) and frequency content of these accelerations were computed from the force treadmill data. GT3X vertical activity counts demonstrated the expected 'plateau/inverted-U' phenomenon. In contrast, vertical CoM accelerations increased with increasing speed (1.32 +/- 0.26 g at 10 km h(-1) and 1.68 +/- 0.24 g at 20 km h(-1)). The dominant frequency in the CoM acceleration signals increased with running speed (14.8 +/- 3.2 Hz at 10 km h(-1) and 24.8 +/- 3.2 Hz at 20 km h(-1)) and lay beyond the ActiGraph band-pass filter (0.25 to 2.5 Hz) limits. In conclusion, CoM acceleration magnitudes during walking and running lie within the ActiGraph monitor's dynamic acceleration detecting capability. Acceleration signals of higher frequencies that are eliminated by the ActiGraph band-pass filter may be necessary to distinguish among exercise intensity at higher running speeds. PMID- 22260903 TI - Spectroscopic investigation of collagen scaffolds impregnated with AgNPs coated by PEG/TX-100 mixed systems. AB - Silver nanoparticles have received attention as novel antimicrobial agents due to their high surface area to volume ratio and the unique chemical and physical properties. In order to study the effects of capping agents on silver nanoparticles (AgNPs), the nanoparticles were synthesized via chemical reduction method using different concentrations (0.3 mM, 0.6 mM and 0.9 mM) of polyethylene glycol (PEG) and Triton X-100 (TX). Also, AgNPs capped by the combinations of both PEG and TX were synthesized. These coated AgNPs were incorporated into collagen, lyophilized to form scaffolds and characterized by FTIR and FT-Raman spectroscopy. Results on mechanical property of all the scaffolds displayed no significant difference in the percentage elongation at break. However, the maximum percentage of 46.67% was observed with the combinations (0.9 mM PEG+0.9 mM TX). This implies that the combinations of surfactants increase the elasticity, which is useful for biomedical applications, e.g., Heart-valve preparations. PMID- 22260904 TI - Colpodella spp.-like parasite infection in woman, China. AB - The phylum Apicomplexa comprises intracellular protozoa that include many human pathogens. Their nearest relatives are chromerids and colpodellids. We report a case of a Babesia spp.-like relapsing infection caused by a newly described microorganism related to the Apicomplexa. This case is highly suggestive of a previously undescribed type of colpodellid that infects vertebrates. PMID- 22260905 TI - Brain infecting kudoids of Australia's coral reefs, including a description of Kudoa lemniscati n. sp. (Myxosporea: Kudoidae) from Lutjanus lemniscatus (Perciformes: Lutjanidae) off Ningaloo Reef, Western Australia. AB - A survey of the myxosporean fauna of Australian marine fishes revealed the presence of a number of putative species of Kudoidae (Multivalvulida) forming pseudocysts between the outer meningeal layer and the outer surface of the brains of the lutjanids Caesio cuning, Lutjanus carponotatus, Lutjanus ehrenbergii and Lutjanus fulviflamma and the mugilid Liza vaigiensis from Lizard Island on the Great Barrier Reef, Australia and Lutjanus lemniscatus off Ningaloo Reef, Western Australia. Morphometric data combined with Bayesian inference and maximum likelihood analyses of small subunit (SSU) and large subunit (LSU) ribosomal DNA (rDNA) was used for species identification and to explore relationships among these taxa. The brain-infecting taxa examined here formed a well-supported clade to the exclusion of non-brain infecting species in the phylogenetic analyses. The combined diagnostic approach identified an undescribed taxon, Kudoa lemniscati n. sp., from the brain of L. lemniscatus (Perciformes: Lutjanidae) off Ningaloo Reef, Western Australia, which we describe and characterise here. K. lemniscati n. sp. can be distinguished from all other species of Kudoa based on the combination of the distinct tropism for forming pseudocysts in the brain tissue, spores with 7 or 8 equal shell valves and 7 or 8 polar capsules, spore size and the differences in the SSU and LSU rDNA sequence data relative to other kudoids. Kudoa chaetodoni was found in the lutjanids C. cuning and L. carponotatus, expanding the known host range for this species to include chaetodontids and lutjanids. L. ehrenbergii and L. fulviflamma were infected with Kudoa lethrini off Lizard Island, a parasite previously known only from lethrinids. Specimens putatively identified as Kudoa yasunagai from Liza vaigiensis and Lutjanus ehrenbergii were morphologically similar and genetically identical over the SSU rDNA dataset to previously reported specimens, but differed by 4 to 11 nucleotides over the LSU dataset from the remaining isolates examined here. While these data are not definitive, they suggest the presence of a K. yasunagai complex. PMID- 22260906 TI - [Time for implementation of hypolipemiant treatment in patient with dyslipidemia in general medicine: results of the Prysme study]. AB - INTRODUCTION: Despite of specific guidelines regarding the treatment of dyslipidemia, therapeutic management of patients is not optimal. The objectives of this study were to describe the time for implementation of hypolipemiant treatment and to identify the determinants. METHODS: This was an observational, transversal, prospective, multicenter study carried out in France by general practitioners. Adult patients with dyslipidemia diagnosed since<2 years were eligible for this study. Demographic, diagnosis and disease characteristics, and treatment procedures were collected. RESULTS: Three thousand six hundred and twenty-four patients were enrolled by 1226 physicians, and data from 3268 patients meeting the selection criteria were analyzed. Mean age was 57 years old, 64% were male. More than 45% of the patients were overweight, 26% were obese. Only 12% of the patients had no cardiovascular risk factor at the time of dyslipidemia diagnosis. The most frequent cardiovascular risk factors consisted in arterial hypertension (50%), smoking (43%), family antecedents of coronary disease (28%), HDL-cholesterol less than 0.4g/L (20%); 15% of the patients had personal antecedents of cardiovascular disease. Initial management of dyslipidemia included implementation of lifestyle changes for 98% of the patients. More than 90% of the patients were treated with a statin. The median time for implementation of hypolipemiant treatment was 2.9 months. The hypolipemiant treatment was initiated more than 3 months after dyslipidemia diagnosis for 43% of the patients. The main determinant factor of an early implementation of hypolipemiant treatment (<=3 months) was secondary prevention (OR=2.2). The number of cardiovascular risk factors had no significant impact. CONCLUSION: This study highlights the lack of awareness towards the number of cardiovascular risk factors in the management of dyslipidemia, in primary prevention. PMID- 22260907 TI - [A cause of dilated cardiomyopathy in a child: primary carnitine deficiency]. AB - AIM: The aim of this case report was to show the importance to research metabolic etiology, especially a carnitine deficiency in dilated cardiomyopathy of children. CASE REPORT: A three years old Togolese child presented muscular hypotonia, dyspnea. Examination showed left galop murmur and systolic murmur 2/6. Chest X-ray showed cardiomegaly (CTI: 0.66), electrocardiogram, a sinusal rythm, left ventricle hypertrophy and T wave abnormalities. Echocardiogram showed a markedly dilated left ventricle with reduced systolic function (EF: 0.43; reference range 0.55-0.80) and moderate mitral regurgitation. The inflammatory signs where negatives. Magnetic resonance imaging don't show signs of ischemic or myocarditis. The levels of free and total plasmatic carnitine decreased: 3MUmol/L (N: 18-48MUmol/L) and 5MUmol/l (N: 29-70MUmol/L) respectively. Mutation analysis of the gene SLC22A5 confirms the diagnosis of primary systemic carnitine deficiency. Treatment with oral carnitine was started at 200mg/kg per day. Within three weeks of treatment, we observed the decrease of all symptoms and the left ventricular size and function normalized (EF: 0.62). He has now been on oral carnitine for live. CONCLUSION: Primary carnitine deficiency is a cause of dilated cardiomyopathy in child. It must systematically be suspected when a child presents a primitive cardiomyopathy. The treatment with oral carnitine for live is simple, with excellent prognosis. PMID- 22260908 TI - Let's not skew ourselves. PMID- 22260910 TI - Survival after free flap reconstruction in patients with advanced oral squamous cell carcinoma. PMID- 22260909 TI - Dental injuries in pediatric patients with facial fractures are frequent and severe. AB - PURPOSE: This study was carried out to identify the occurrence, type, location, and severity of dental injuries (DIs), as well as predictors for DIs, in pediatric patients with facial fractures. MATERIALS AND METHODS: This study examined the files of patients aged 16 years or less who had sustained facial fractures during a 12-year period. The outcome variable was DI. The explanatory variables included gender, age, trauma mechanism, and type of facial fracture. Data analysis was carried out with the chi(2) test and logistic regression analysis. RESULTS: A total of 200 patients, 119 (59.5%) of whom were boys, met the inclusion criteria. The mean age was 12.6 years. A total of 45 patients (22.5%) had DIs. Crown fracture, the most common type of DI, occurred in 59.9% of all DIs. The most common location of crown fractures was in the premolars (37.4% of all crown fractures). Multiple DIs occurred in 71.1% of those with DIs and severe DI in 66.7%. DIs were significantly associated with motor vehicle collision (MVC) (P = .02) and mandibular fracture (P = .03). CONCLUSIONS: DIs are common in pediatric patients with facial fracture, often being both multiple and severe. In association with pediatric facial fracture, facial surgeons should be especially alert for crown fractures in the lateral parts of the jaws. PMID- 22260911 TI - Iatrogenic displacement of lower third molar roots into the sublingual space: report of 6 cases. AB - PURPOSE: To describe the clinical characteristics of patients who have had sublingual displacement of a mandibular third molar root, to identify potential risk factors, and to provide the clinician with information on how to prevent and treat this complication. PATIENTS AND METHODS: A retrospective analysis was performed of a series of 6 patients who underwent third molar removal with accidental displacement of a root into the sublingual space. All patients were attended at the Department of Oral Surgery, Faculty of Dentistry, University of Barcelona (Spain) from 2000 through 2010. RESULTS: Four patients were men, and the mean age was 38.2 +/- 11.3 years. In 1 case, the fragment was removed immediately after the complication, in the same surgical procedure. In 4 cases (66.7%), the displaced root remained asymptomatic (mean follow-up, 25.5 mo), and only 1 patient presented symptoms (swelling and pain in the sublingual region). A second surgical procedure using an intraoral approach was used to extract the displaced fragment in 2 patients. These 2 cases presented transitory nerve impairment of the lingual and inferior alveolar nerves, respectively. CONCLUSIONS: Accidental displacement of a lower third molar root into the sublingual space is an uncommon complication. When the fragments are small, surgical removal of the displaced roots seems to be unnecessary, because patients usually remain symptom free. When surgery is needed, a considerable incidence of complications should be expected. PMID- 22260912 TI - Bilateral temporomandibular joint dislocation with locked mandibular impaction. AB - Bilateral anterior temporomandibular joint dislocation is very rare, with only 2 reported cases published. In the present report, we describe a healthy 25-year old man from Haida Gwaii, in British Columbia, Canada, who was transferred to our tertiary trauma center with life-threatening complications of a bilateral anterior temporomandibular joint dislocation with locked mandibular impaction. PMID- 22260913 TI - Preoperative evaluation of spatial relationship between inferior alveolar nerve and fibro-osseous lesion by high resolution magnetic resonance neurography on 3.0 T system: a case report. PMID- 22260914 TI - Corticotomy-assisted orthodontic enhancement by bone morphogenetic protein-2 administration. AB - PURPOSE: To determine the possibility of synergistically enhancing orthodontic tooth movement (OTM) and bone formation in vivo by administering bone morphogenetic protein type 2 (BMP-2) on the tension side or in combination with corticotomy on the pressure side. MATERIALS AND METHODS: The sample consisted of 56 Wistar rats that were subjected to experimental OTM for 32 days using a split mouth design. The sample was divided into 4 groups: a control group, a corticotomy group, a BMP-2 group, and a corticotomy plus BMP-2 group. An OTM force of 10 cN was applied to each group. BMP-2 18 MUL was administered locally on the tension side alone or in conjunction with corticotomy and then compared with the controls using fluorescence-based tartrate-resistant acid phosphatase staining for osteoclast counts, histologic bone resorption, and clinical OTM results. RESULTS: Corticotomy surgery increased the OTM rate (P < .05) by more than 20%. The injection of BMP-2 alone on the tension side did not induce significant changes in the degree of OTM compared with the vehicle-treated or control group (P > .05). When BMP-2 was combined with corticotomy on the tension and pressure sides (corticotomy plus BMP-2 group), respectively, nonsignificant OTM rates were observed (P > .05) compared with the controls; however, decreased osteoclast counts, bone resorption, and clinical results were observed in the corticotomy plus BMP-2 group. CONCLUSIONS: In contrast to reports published to date, the present preliminary study suggests that there are limits to OTM acceleration by bone formation on the tension side and agrees with the idea that there is a single continuous periodontal compartment in OTM, rather than a pressure side and a tension side. PMID- 22260915 TI - Pharyngeal airway changes associated with maxillary distraction osteogenesis in adult cleft lip and palate patients. AB - PURPOSE: To investigate 1) the changes in pharyngeal airway sizes associated with maxillary distraction osteogenesis and 2) the correlations between maxillary skeletal variables and the pharyngeal airway in adult patients with cleft lip and palate. PATIENTS AND METHODS: The study was carried out in 14 adult subjects with cleft lip and palate. Predistraction records were taken at a mean age of 22.7 +/- 4.6 years. All patients had placement of a rigid external distraction device (RED I; KLS Martin, Tuttlingen, Germany) after Le Fort I osteotomy. Lateral cephalograms were assessed before surgery and at short-term follow-up (8.0 +/- 6.4 months). The cephalometric skeletal and pharyngeal airway variables were statistically evaluated by use of the Wilcoxon signed-rank test. Spearman rho correlation was performed to check the correlations between maxillary skeletal and pharyngeal variables. RESULTS: The maxillary movement was 8.7 mm (P < .01). The maxillary depth angle (+7.9 degrees ) and effective maxillary length (9.4 mm) increased significantly (P < .01) after distraction, whereas the palatal plane angle remained unchanged. Anterior nasal spine (8.2 mm) and Posterior nasal spine (6.9 mm) moved anteriorly. The overjet increased (9.5 mm) significantly (P < .01). Posterior, superoposterior, and middle airway spaces increased significantly, with mean differences of 7.5 mm, 5.1 mm, and 3.3 mm, respectively. The soft palate moved anteriorly, with the greatest movement at its superior point. Significant positive correlations were observed for the posterior and superoposterior airway spaces and maxillary movement. PNS changes showed the highest correlation with posterior airway changes. CONCLUSIONS: The significant anterior movement of the maxilla resulted in significant increases in posterior, superoposterior, and middle airway spaces. The posterior airway space showed the highest significant positive correlation with the movement of PNS. The posterior and superoposterior airway spaces also showed significant positive correlations with the maxillary skeletal variables. PMID- 22260916 TI - Orthognathic surgery and partial glossectomy in a patient with merosin-deficient congenital muscular dystrophy. PMID- 22260917 TI - Survey of residents who have participated in humanitarian medical missions. AB - PURPOSE: To survey physicians who participated in humanitarian missions as residents to assess the value of this experience on residency training and future career choices. MATERIALS AND METHODS: An anonymous 26-question survey was electronically mailed to 45 individuals identified as having participated in a cleft lip/palate mission during residency. The survey was created and distributed, and the data were collected using the online survey engine Survey Monkey. RESULTS: Thirty-nine individuals (86.7%) completed the survey. Of these, 27 were men (69.2%) and 12 were women (30.8%). Thirty-two (82.1%) were oral and maxillofacial surgeons, 4 (10.3) were plastic and reconstructive surgeons, 1 (2.6%) was an otolaryngologist, and 2 (5.1%) were pediatric dentists. Twenty-five respondents (64.1%) stated that, before their first mission, they had not operated on a primary cleft lip; 21 (53.8%) noted that they had not operated on a primary cleft palate before their first mission. Thirty-six (92.3%) noted that their mission experience improved their ability to repair facial clefts. Thirty seven (94.9%) believed their mission experience improved their overall surgical skill. All respondents (n = 39, 100%) believed their mission experience improved their overall ability to evaluate patients with cleft. Thirty-six (92.3%) believed their experience in humanitarian missions made them more culturally sensitive/competent health care providers. Thirty-eight respondents (97.4%) believed these missions made them more socially aware of the differences in access/availability of health care globally. Thirty-eight (97.4%) believed that participation in a humanitarian mission was a high point of their residency. Thirty-seven (94.9%) planned to participate in humanitarian medical missions during their career after residency. CONCLUSION: All respondents believed that participation in a humanitarian mission during residency was a positive part of their training. In addition, these missions allowed the residents to develop as surgeons and improve their awareness of global health care and cultural competence. Given these important educational aspects, participation in a humanitarian mission should be considered a required part of residency training. PMID- 22260918 TI - Longitudinal observation of mandibular motion pattern in patients with skeletal Class III malocclusion subsequent to orthognathic surgery. AB - PURPOSE: The aims of the present study were to delineate the characteristic patterns of 3-dimensional (3D) mandibular movement in patients with skeletal Class III malocclusion compared with normal individuals and to investigate the longitudinal changes in mandible and condylar motion after orthognathic surgery (OGS). PATIENTS AND METHODS: The subjects in the present prospective study consisted of 2 groups. The OGS group included 24 patients with skeletal Class III who underwent OGS. The control group consisted of 25 patients who underwent orthodontic treatment only. The patient records included demographic data, lateral and posteroanterior cephalometric radiographs before treatment, and serial mandibular motion data. In the OGS group, the mandibular motion data were obtained before OGS (T1), 1 month after OGS (T2), and at least 6 months after OGS (T3). The differences in cephalometric measurements and mandibular movements between the 2 groups were compared. The Pearson correlation test was performed to assess the relationship between the cephalometric measurements and the mandibular movements. Serial changes in mandibular movement in the OGS group were also compared. RESULTS: The skeletal pattern in the OGS group demonstrated retrusive maxilla and a protrusive mandible, with a larger mandibular plane angle. For the incisal range of motion, the OGS group's maximal mouth opening was larger than the control group's by 6.9 mm. In the OGS group, the condylar range of motion in retrusion and the Bennett angle were asymmetric. Skeletal Class III patients tended to have a smaller range of condylar retrusion. At 1 month after OGS, the maximal incisal range of motion decreased from 57.23 to 25.61 mm. Other variables, including laterotrusion, movement velocity, and angle and distance of condylar movement in protrusion, reduced significantly. The Bennett angle demonstrated increased symmetry on both sides. Six months after OGS, the condylar motion in opening demonstrated improvements, but to a lesser extent than at T1. The condylar motion in retrusion recovered totally. The maximum incisal range of motion reduced slightly, but remained similar in value to that of the control group. The variables, including laterotrusion, movement velocity, and angle and distance of condylar movement in protrusion, demonstrated total recovery. The mandibular movement variables at T3 were not significantly different from those of the control group. CONCLUSIONS: Skeletal Class III patients demonstrated a larger maximal mouth opening than did the controls, along with similar laterotrusion, but with a smaller retrusive condylar range of movement. The range of incisor motion and condylar movement did not correlate. The deterioration in mandibular motion after OGS can recover totally within 6 months. At T3, the mandibular movement remained consistent with the amount in normal subjects. PMID- 22260919 TI - Cranioplasty with custom-made implants: analyzing the cases of 10 patients. AB - PURPOSE: The aim of this study was to assess quantitatively whether a symmetric reconstruction of the calvaria could be achieved using 3-dimensional (3D) custom made implants and to examine any complications caused by the cranioplasty. PATIENTS AND METHODS: Custom-made cranial implants were produced using data obtained from computed tomographic scanning of the defect using computer-aided design and rapid prototyping techniques. Polymethylmethacrylate was used as the reconstruction material and the implant was cast from a silicone rubber mold. These implants were used in 10 patients (9 men and 1 woman) who previously received a craniectomy. The symmetry gained after cranioplasty was quantified by volumetric analysis using 3D reconstructed postoperative computed tomographic imaging. Any complications after cranioplasty also were recorded. RESULTS: The average follow-up was 42.5 months (range, 7 to 85 mo). The esthetic appearance of all patients was much improved. When the volume of the reconstructed right calvaria was compared with the left calvaria, the difference was not statistically significant (P > .05). There were 2 cases of complications. One exhibited a transient seroma collection. Another had a wrinkle formation in the forehead. No infectious episodes or signs of plate rejection were encountered. CONCLUSIONS: The custom-made implants for cranioplasty showed a significant improvement in morphology. The implants may be very useful for repairing large and complex-shaped cranial defects. The technique may be useful for the bone reconstruction of other sites. PMID- 22260920 TI - Triheptanoin in acute mouse seizure models. AB - Triheptanoin, the triglyceride of heptanoate, is used to treat certain hereditary metabolic diseases in USA because of its anaplerotic potential. In two chronic mouse seizure models this clear tasteless oil was found to be reproducibly anticonvulsant. Here we investigated the effects of triheptanoin feeding in C3H and CD1 mice using standard acute seizure models. Feeding 30-40% triheptanoin (caloric intake) consistently elevated blood propionyl-carnitines, but inconsistent anticonvulsant effects were observed in the fluorothyl, pentylenetetrazole and 6Hz seizure models. A 2mA consistent increase in the maximal electroshock threshold was found after 3 weeks of 35% triheptanoin feeding (p=0.018). In summary, triheptanoin shows a unique anticonvulsant profile in seizure models, compared to other treatments that are in the clinic. Therefore, despite small and/or inconsistent effects of triheptanoin in acute seizure models, triheptanoin remains of interest as a potential add-on treatment for patients with medically refractory epilepsy. PMID- 22260921 TI - Occipital lobe epilepsy in children: characterization, evaluation and surgical outcomes. AB - INTRODUCTION: Occipital lobe epilepsy (OLE) poses a diagnostic challenge to clinicians. Here, we present our experience in the surgical management of OLE in children using magnetoencephalography (MEG) in the pre-operative evaluation. METHODS: Retrospective chart review was performed from 2000 to 2010 to identify patients with OLE. Patients were analyzed in two categories: isolated OLE (11 patients) and extended OLE (parietooccipital, temporooccipital, and temporoparietooccipital; 30 patients). Survival analysis and multivariate Cox proportional hazards regression were used to identify independent predictors of seizure outcome. RESULTS: Forty-one patients with a mean follow-up of 3.1 years were identified with an overall 68% rate of satisfactory seizure outcome. Patients with extended OLE had younger ages at seizure onset and different seizure semiologies compared with those with isolated OLE. None of the latter underwent insertion of subdural grid electrodes for localization of the epileptogenic zone compared with 77% of the former (p<0.001). On multivariate analysis, the strongest independent predictor of unsatisfactory outcome was MEG dipoles in the occipital lobe contralateral to resection. CONCLUSION: Here, we find similar seizure outcomes for isolated and extended OLE foci despite the use of less invasive strategies for the former. Furthermore, we describe the role of MEG in evaluation, surgical planning and prognostication of children with OLE. PMID- 22260923 TI - Development of a social inclusion index to capture subjective and objective life domains (Phase II): psychometric development study. AB - OBJECTIVES: To produce a robust measure of social inclusion [Social and Community Opportunities Profile (SCOPE)] that is multidimensional and captures multiple life domains; incorporates objective and subjective indicators of inclusion; has sound psychometric properties including responsiveness; facilitates benchmark comparisons with normative general population and mental health samples [including common mental disorder (CMD) and severe mental illness groups]; can be used with people with mental health problems receiving support from mental health services or not; and can be used across a range of community service settings. DESIGN: Phase I: conceptual framework developed from a review of the literature and concept mapping. Phase II: questionnaire developed including UK national population surveys and other normative data. Pre-testing using cognitive appraisal and evaluation then pilot testing in a small convenience sample. Preliminary testing (following modification) in community (n = 252) and mental health service users (MHSUs) samples (n = 43). Data reduction including factor analysis and Mokken scaling for polytomous item response analysis then psychometric evaluation, including internal consistency and discriminant and construct validity. Test-retest reliability assessed in a convenience sample of students (n = 119). Final testing in clinical services including psychometric evaluation and responsiveness testing. SETTING: The community sample was set in participants' households across the UK. The MHSU sample was set in a south Wales resource centre. The student sample was set in a university. PARTICIPANTS: The community sample was randomly selected from the postal address file in five areas in England and Wales. Forty people in this sample were subgrouped as having a CMD based on their responses to the Mental Health Index five items. Two MHSU samples were obtained from existing services. RESULTS: Psychometric testing on the field data from the SCOPE long version demonstrated good internal consistency of all scales (alpha >= 0.7), good construct validity, with SCOPE scales correlating highly with each other sharing between 40% and 61% of variance and a close but lesser association with community participation and social capital. Chi-squared tests on objective items and analysis of variance between groups on SCOPE scales demonstrated good discriminant validity between different mental health groups (and better than the Mokken scaling results). Acceptability was good, with 77% of the service user sample finding the SCOPE domains relevant. The number of items in SCOPE decreased from 121 to 48 following data reduction. Scales in the short version of SCOPE retained reasonable internal consistency (alpha between 0.60 and 0.75). Test-retest reliability demonstrated reliability over time, with strong associations between all items over a 2-week period. Repeating the discriminant validity tests on the short version demonstrates good discriminant validity between the mental health groups. Acceptability improved, with 90% of the sample describing questions as relevant to them. CONCLUSIONS: The main aim of producing an instrument with good psychometric properties for use in research and clinical settings, namely the SCOPE short version, was achieved. Ongoing data collection will enable responsiveness testing in the future. Further research is needed including larger samples of minority and disadvantaged groups, including those with physical illnesses and disabilities, and specific mental health diagnostic groups. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22260922 TI - Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction. AB - Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria. PMID- 22260924 TI - Assessing prion infectivity of human urine in sporadic Creutzfeldt-Jakob disease. AB - Prion diseases are neurodegenerative conditions associated with a misfolded and infectious protein, scrapie prion protein (PrP(Sc)). PrP(Sc) propagate prion diseases within and between species and thus pose risks to public health. Prion infectivity or PrP(Sc) presence has been demonstrated in urine of experimentally infected animals, but there are no recent studies of urine from patients with Creutzfeldt-Jakob disease (CJD). We performed bioassays in transgenic mice expressing human PrP to assess prion infectivity in urine from patients affected by a common subtype of sporadic CJD, sCJDMM1. We tested raw urine and 100-fold concentrated and dialyzed urine and assessed the sensitivity of the bioassay along with the effect of concentration and dialysis on prion infectivity. Intracerebral inoculation of transgenic mice with urine from 3 sCJDMM1 patients failed to demonstrate prion disease transmission, indicating that prion infectivity in urine from sCJDMM1 patients is either not present or is <0.38 infectious units/mL. PMID- 22260925 TI - Prevalence of antibiotic-resistant enterobacteriaceae isolated from chicken and pork meat purchased at the slaughterhouse and at retail in Bavaria, Germany. AB - The purpose of this study was to investigate chicken and pork meat sampled at the slaughterhouse and at retail for differences in the presence of antibiotic resistant Gram-negative bacteria. For this aim, Escherichia coli (n=677), Enterobacter spp. (n=167), Citrobacter spp. (n=83), Serratia spp. (n=116), Klebsiella spp. (n=125), and Salmonella spp. (n=89) were isolated from 500 chicken and 500 pork samples purchased at the slaughterhouse and at retail (in the same amounts) in Germany. Salmonella were present in 17% of the chicken, and in 0.4% of the pork meat samples. There was a clear shift in the spectrum of coliforms from slaughterhouse to retail: Enterobacter, Citrobacter and Klebsiella were the most frequently detected coliforms (other than E. coli) from slaughterhouse samples, whereas the prevalence of Serratia spp. was up to eight times higher in retail samples. The prevalence of E. coli was higher in slaughterhouse samples, whereas the prevalence of other coliforms and Salmonella spp. was higher in retail samples. E. coli strains were often resistant to penicillins, streptomycin, spectinomycin, doxycycline and sulfamethoxazole/trimethoprim. Resistance rates of the other coliforms were generally low. Resistant and multi-resistant isolates were significantly more common in chicken meat. Compared to samples from the slaughterhouse, the prevalence of resistant bacteria tended to be higher in retail samples, probably due to good conditions for resistant bacteria on the matrix meat and/or due to secondary contamination with resistant strains. Therefore, stringent hygiene measures should be observed to reduce the risk of transmission of resistant bacteria from food to humans. PMID- 22260926 TI - Heat resistance of thermoduric enterococci isolated from milk. AB - Enterococci are reported to survive pasteurisation but the extent of their survival is unclear. Sixty-one thermoduric enterococci isolates were selected from laboratory pasteurised milk obtained from silos in six dairy factories. The isolates were screened to determine log(10) reductions incurred after pasteurisation (63 degrees C/30 min) and ranked from highest to lowest log(10) reduction. Two isolates each of Enterococcus faecalis, Enterococcus faecium, Enterococcus durans and Enterococcus hirae, exhibiting the median and the greatest heat resistance, as well as E. faecalis ATCC 19433, were selected for further heat resistance determinations using an immersed coil apparatus. D values were calculated from survival curves plotted from viable counts obtained after heating isolates in Brain Heart Infusion Broth at 63, 69, 72, 75 and 78 degrees C followed by rapid cooling. At 72 degrees C, the temperature employed for High Temperature Short Time (HTST) pasteurisation (72 degrees C/15s), the D values extended from 0.3 min to 5.1 min, depending on the isolate and species. These data were used to calculate z values, which ranged from 5.0 to 9.8 degrees C. The most heat sensitive isolates were E. faecalis (z values 5.0, 5.7 and 7.5 degrees C), while the most heat resistant isolates were E. durans (z values 8.7 and 8.8 degrees C), E. faecium (z value 9.0 degrees C) and E. hirae (z values 8.5 and 9.8 degrees C). The data show that heat resistance in enterococci is highly variable. PMID- 22260927 TI - Comparison of ESBL contamination in organic and conventional retail chicken meat. AB - Contamination of retail chicken meat by Extended Spectrum Beta-Lactamase (ESBL) producing bacteria likely contributes to the increasing incidence of infections with these bacteria in humans. This study aimed to compare the prevalence and load of ESBL positive isolates between organic and conventional retail chicken meat samples, and to compare the distribution of ESBL genes, strain genotypes and co-resistance. In 2010, 98 raw chicken breasts (n=60 conventional; n=38 organic) were collected from 12 local stores in the Netherlands. Prevalence of ESBL producing micro-organisms was 100% on conventional and 84% on organic samples (p<0.001). Median loads of ESBL producing micro-organisms were 80 (range <20 1360) in conventional, and <20 (range 0-260) CFU/25 g in organic samples (p=0.001). The distribution of ESBL genes in conventional samples and organic samples was 42% versus 56%, respectively (N.S.), for CTX-M-1, 20% versus 42% (N.S.) for TEM-52, and 23% versus 3% (p<0.001) for SHV-12. CTX-M-2 (7%), SHV-2 (5%) and TEM-20 (3%) were exclusively found in conventional samples. Co resistance rates of ESBL positive isolates were not different between conventional and organic samples (co-trimoxazole 56%, ciprofloxacin 14%, and tobramycin 2%), except for tetracycline, 73% and 46%, respectively, p<0.001). Six of 14 conventional meat samples harbored 4 MLST types also reported in humans and 5 of 10 organic samples harbored 3 MLST types also reported in humans (2 ST10, 2 ST23, ST354). In conclusion, the majority of organic chicken meat samples were also contaminated with ESBL producing E. coli, and the ESBL genes and strain types were largely the same as in conventional meat samples. PMID- 22260929 TI - Integrating geographical information and augmented reality techniques for mobile escape guidelines on nuclear accident sites. AB - During nuclear accidents, when radioactive materials spread into the environment, the people in the affected areas should evacuate immediately. However, few information systems are available regarding escape guidelines for nuclear accidents. Therefore, this study constructs escape guidelines on mobile phones. This application is called Mobile Escape Guidelines (MEG) and adopts two techniques. One technique is the geographical information that offers multiple representations; the other is the augmented reality that provides semi-realistic information services. When this study tested the mobile escape guidelines, the results showed that this application was capable of identifying the correct locations of users, showing the escape routes, filtering geographical layers, and rapidly generating the relief reports. Users could evacuate from nuclear accident sites easily, even without relief personnel, since using slim devices to access the mobile escape guidelines is convenient. Overall, this study is a useful reference for a nuclear accident emergency response. PMID- 22260928 TI - Gold nanostars: surfactant-free synthesis, 3D modelling, and two-photon photoluminescence imaging. AB - Understanding the control of the optical and plasmonic properties of unique nanosystems--gold nanostars--both experimentally and theoretically permits superior design and fabrication for biomedical applications. Here, we present a new, surfactant-free synthesis method of biocompatible gold nanostars with adjustable geometry such that the plasmon band can be tuned into the near infrared region 'tissue diagnostic window', which is most suitable for in vivo imaging. Theoretical modelling was performed for multiple-branched 3D nanostars and yielded absorption spectra in good agreement with experimental results. The plasmon band shift was attributed to variations in branch aspect ratio, and the plasmon band intensifies with increasing branch number, branch length, and overall star size. Nanostars showed an extremely strong two-photon photoluminescence (TPL) process. The TPL imaging of wheat-germ agglutinin (WGA) functionalized nanostars on BT549 breast cancer cells and of PEGylated nanostars circulating in the vasculature, examined through a dorsal window chamber in vivo in laboratory mouse studies, demonstrated that gold nanostars can serve as an efficient contrast agent for biological imaging applications. PMID- 22260930 TI - Do subthreshold psychotic experiences predict clinical outcomes in unselected non help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results. AB - BACKGROUND: The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. METHOD: A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. RESULTS: Six cohorts were identified with a 3-24-year follow up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose-response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. CONCLUSIONS: Subthreshold self-reported psychotic experiences in epidemiological non-help seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra high risk, for whom much higher transition rates have been indicated. PMID- 22260931 TI - Current developments and challenges in the search for a naturally selected Diels Alderase. AB - Only a very few examples of enzymes known to catalyze pericyclic reactions have been reported, and presently no enzyme has been demonstrated unequivocally to catalyze a Diels-Alder reaction. Nevertheless, research into secondary metabolism has led to the discovery of numerous natural products exhibiting the structural hallmarks of [4+2] cycloadditions, prompting efforts to characterize the responsible enzymatic processes. These efforts have resulted in a growing collection of enzymes believed to catalyze pericyclic [4+2] cycloaddition reactions; however, in each case the complexity of the substrates and catalytic properties of these enzymes poses significant challenges in substantiating these hypotheses. Herein we consider the principles motivating these efforts and the enzymological systems currently under investigation. PMID- 22260933 TI - The diagnostic accuracy of MRI for the detection of partial- and full-thickness rotator cuff tears in adults. AB - This study assessed the diagnostic test accuracy of magnetic resonance imaging (MRI) in the detection of partial- and full-thickness rotator cuff tears in the adult population. A systematic review was conducted of the following electronic databases: Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, AMED, ISI Web of Science, Current Controlled Trials, National Technical Information Service, the National Institute for Health Research Portfolio, the UK National Research Register Archive and WHO International Clinical Trials Registry Platform database and reference lists of articles. All studies assessing the sensitivity and/or specificity of MRI for adult patients with suspected rotator cuff tear where surgical procedures were the reference standard were included in the study. A meta-analysis was performed to calculate pooled sensitivity, specificity, likelihood and diagnostic odds ratio values, and summary receiver operating characteristic plots were constructed. Forty-four studies were included. These included 2751 shoulders in 2710 patients. For partial-thickness rotator cuff tears, the pooled sensitivity and specificity values were 0.80 [95% confidence interval (CI): 0.79-0.84] and 0.95 (95% CI: 0.94-0.97), respectively. For full-thickness tears, the sensitivity and specificity values were 0.91 (95% CI: 0.86-0.94) and 0.97 (95% CI: 0.96-0.98), respectively. While there was no substantial difference in diagnostic test accuracy between MRIs reviewed by general radiologists and those reviewed by musculoskeletal radiologists, higher field-strength (3.0 T) MRI systems provided the greatest diagnostic test accuracy. PMID- 22260932 TI - Delivery catheter cone separation and embolization after Corevalve dislocation by subclavian approach. AB - Corevalve dislocation has been reported to significantly increase the perioperative risk for severe complications and poor outcomes. We describe the case of an 87-year-old man who was referred to our center for transcatheter aortic valve implantation and who experienced an original complication after Corevalve dislocation by subclavian approach. Indeed, during the attempt to retrieve the partially expanded and dislocated valve through the subclavian introducer sheath, we experienced a dislodgment of the valve from the housing sheath that led to a delivery catheter cone separation and systemic embolization. PMID- 22260934 TI - Assessment of MRI issues for the Argus II retinal prosthesis. AB - OBJECTIVE: The objective was to evaluate magnetic resonance imaging (MRI) issues (magnetic field interactions, heating, artifacts and functional alterations) at 1.5 T and 3 T for the Argus II Retinal Prosthesis (Second Sight Medical Products, Sylmar, CA, USA). MATERIALS AND METHODS: Standardized protocols were used to assess magnetic field interactions (translational attraction and torque; 3 T, worst case), MRI-related heating (1.5 and 3 T), artifacts (3 T; worst case) and functional changes (1.5 and 3 T) associated with MRI. RESULTS: The magnetic field interactions were acceptable. MRI-related heating, which was studied at a relatively high, MR system-reported whole body averaged specific absorption rates, will not pose a hazard to the patient under the conditions used for testing. While artifacts were "moderate" in relation to the dimensions of the Argus II Retinal Prosthesis, optimization of MRI parameters can reduce the size of the artifacts. Exposures to MRI conditions at 1.5 and 3 T did not damage or alter the functional aspects of the Argus II Retinal Prosthesis. CONCLUSIONS: In consideration of the test results, a patient with the Argus II Retinal Prosthesis may undergo MRI at 1.5 T or 3 T when specific guidelines and MRI conditions are followed, including those advised by the manufacturer. PMID- 22260935 TI - Depression recognition using resting-state and event-related fMRI signals. AB - PURPOSE: This paper aimed to develop a method for depression detection using blood-oxygen-level-dependent (BOLD) response estimated from event-related signals and resting-state functional magnetic resonance imaging (fMRI) signals together. MATERIALS AND METHODS: Thirteen patients with unipolar depression and matched healthy subjects were recruited. Resting state data of each subject were collected. Thereafter, event-related paradigm was undertaken using sad facial stimuli. The resting-state fMRI signal was deemed as the baseline of each subject's activity. Coefficient marks were designed to sort and select temporal independent components of event-related signals. Thereafter, stimulus-evoked BOLD response components inside event-related signal were extracted and taken as features to discriminate depressive patients from healthy controls. RESULTS: Accuracy rate for depression recognition was 77.27% with P value of .017 for whole-brain analysis and 81.82% with P value of .009 for region-of-interest analysis. The effectiveness and the superiority of the proposed method for disease recognition were demonstrated via the performance comparison with three other typical methods. CONCLUSIONS: The proposed model was effective in depression recognition. PMID- 22260936 TI - Lateral diffusion in equimolar mixtures of natural sphingomyelins with dioleoylphosphatidylcholine. AB - Cellular membranes of mammals are composed of a complex assembly of diverse phospholipids. Sphingomyelin (SM) and phosphatidylcholine (PC) are important lipids of eukaryotic cellular membranes and neuronal tissues, and presumably participate in the formation of membrane domains, known as "rafts," through intermolecular interaction and lateral microphase decomposition. In these two dimensional membrane systems, lateral diffusion of lipids is an essential dynamic factor, which might even be indicative of lipid phase separation process. Here, we used pulsed field gradient nuclear magnetic resonance to study lateral diffusion of lipid components in macroscopically oriented bilayers composed of equimolar mixtures of natural SMs of egg yolk, bovine brain, bovine milk and dipalmitoylphosphatidylcholine (DPPC) with dioleoylphosphatidylcholine (DOPC). In addition, differential scanning calorimetry was used as a complementary technique to characterize the phase state of the lipid bilayers. In fully liquid bilayers, the lateral diffusion coefficients in both DOPC/DPPC and DOPC/SM systems exhibit mean values of the pure bilayers. For DOPC/SM bilayer system, this behavior can be explained by a model where most SM molecules form short-lived lateral domains with preferential SM-SM interactions occurring within them. However, for bilayers in the presence of their low-temperature gel phase, lateral diffusion becomes complicated and cannot simply be understood solely by a simple change in the liquid phase decomposition. PMID- 22260937 TI - Low levels of 25(OH)D and insulin-resistance: 2 unrelated features or a cause effect in PCOS? AB - BACKGROUND & AIMS: Recent investigations have identified low vitamin D status as a hypothetical mechanism of insulin-resistance in Polycystic Ovary Syndrome (PCOS). Instead, some authors supported the hypothesis that low vitamin D levels and insulin-resistance are 2 unrelated features of body size in PCOS. Hence, we aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) with anthropometric, metabolic and hormonal features in PCOS. METHODS: We assessed the association of low 25(OH)D levels with endocrine parameters, insulin-sensitivity evaluated by hyperinsulinemic euglycemic clamp (HEC) and body composition measured by DEXA in 38 women affected by PCOS. RESULTS: Low 25(OH)D (25(OH)D < 50 nmo/L) was detected in 37% of the entire cohort of patients. Body Mass Index (BMI), in particular total fat mass (p < 0.001), resulted to be the most predictor factor of 25(OH)D levels whereas Sex Hormone Binding Globulin (SHBG), Free Androgen Index (FAI), glucose uptake and fat free mass were not. CONCLUSIONS: Our data demonstrated that in PCOS low 25(OH)D levels are significantly determined by the degree of adiposity. PMID- 22260938 TI - Acute psychosocial stress: does the emotional stress response correspond with physiological responses? AB - Most stress experiences are accompanied by physiological and psychological responses. Laboratory stressors such as the Trier Social Stress Test (TSST) induce reliable stress responses, which are mainly assessed for biological parameters such as cortisol. The associations between physiological and psychological responses to the TSST have been rarely investigated and are addressed in this review. Up to August 2011, 358 studies were published in PubMed examining the impact of the TSST (71%) or variations of the protocol. A total of 49 studies were considered based on the following three inclusion criteria: (1) exposure to the standard TSST or slightly modified TSST versions, (2) at least one assessment of subjective emotional stress experience before, during or after the TSST, (3) reported associations between acute physiological and emotional stress measures. Significant correlations between cortisol responses and perceived emotional stress variables were found in approximately 25% of the studies. Our descriptive analysis revealed various essential elements that potentially contribute to this apparent dissociation, reaching from differing assessment approaches and methodological features of the stress protocols to possible mediating factors and interindividual differences in the degree of psychophysiological correspondence. PMID- 22260939 TI - Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study. AB - Diffusion tensor imaging (DTI) can sensitively detect white matter sex differences and the effects of pharmacological treatments. Before cross-sex hormone treatment, the white matter microstructure of several brain bundles in female-to-male transsexuals (FtMs) differs from those in females but not from that in males. The purpose of this study was to investigate whether cross-sex hormone treatment (androgenization) affects the brain white matter microstructure. Using a Siemens 3 T Trio Tim Magneton, DTI was performed twice, before and during cross-sex hormonal treatment with testosterone in 15 FtMs scanned. Fractional anisotropy (FA) was analyzed on white matter of the whole brain, and the latter was spatially analyzed using Tract-Based Spatial Statistics. Before each scan the subjects were assessed for serum testosterone, sex hormone binding globulin level (SHBG), and their free testosterone index. After at least seven months of cross-gender hormonal treatment, FA values increased in the right superior longitudinal fasciculus (SLF) and the right corticospinal tract (CST) in FtMs compared to their pre-treatment values. Hierarchical regression analyses showed that the increments in the FA values in the SLF and CST are predicted by the free testosterone index before hormonal treatment. All these observations suggest that testosterone treatment changes white matter microstructure in FtMs. PMID- 22260940 TI - Ectopic thyroid tissue in the anterior mediastinum with a normally located gland: a case report. AB - Ectopic thyroid tissue occurs in about 7 to 10% of the general population. Localization in the anterior mediastinum is rare: seven cases reported in the literature, most associated with thyroid dysfunction. We report the case of a 77 year-old woman who presented ectopic thyroid tissue in the anterior mediastinum and a normally-located normally-functioning gland. PMID- 22260941 TI - Association of heart rate variability with arrhythmic events in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is associated with an increased risk of sudden cardiac death (SCD). Risk stratification of ARVC/D patients, however, remains an unresolved issue. In this study we investigated whether heart rate variability (HRV) can be helpful in identifying ARVC/D patients with increased risk of arrhythmic events. METHODS AND RESULTS: We studied 30 consecutive patients (17 males; 45.4 +/- 18 years) with ARVC/D, diagnosed according to guideline criteria; 15 patients (50%) had received an implantable cardioverter defibrillator (ICD) for primary SCD prevention. HRV was assessed on 24-h ECG Holter monitoring. The primary endpoint was the occurrence of major arrhythmic events (SCD, sustained ventricular tachycardia (VT), ICD therapy for sustained VT or ventricular fibrillation (VF)). During the follow-up period (19 +/- 7 months), no deaths occurred, but 5 patients (17%) experienced arrhythmic events (4 VTs and 1 VF, all in the ICD group). All HRV parameters were significantly lower in patients with, compared with those without, arrhythmic events. Low-frequency amplitude was the most significant HRV variable associated with arrhythmic events in univariate Cox regression analysis (P=0.017), and was the only significant predictor of arrhythmic events in multivariable regression analysis (hazard ratio 0.88, P=0.047), together with unexplained syncope (hazard ratio 16.1, P=0.039). CONCLUSIONS: Our data show that among ARVC/D patients HRV analysis might be helpful in identifying those with increased risk of major arrhythmic events. PMID- 22260942 TI - Risk stratification of asymptomatic patients with Brugada type or J-wave type ECG. PMID- 22260943 TI - Effects of exposure to nanoparticle-rich diesel exhaust on adrenocortical function in adult male mice. AB - To investigate the effects of nanoparticle-rich diesel exhaust (NR-DE) on adrenocortical function, seven-week-old male mice were divided into four groups and exposed to either whole NR-DE at low (41.73 MUg/m(3), 8.21 * 10(5) particles/cm3), high (152.01 MUg/m3, 1.80 * 10(6) particles/cm3) concentrations, filtered diesel exhaust (F-DE) or clean air for 8 weeks (5 h/day, 5 days/week). After 8 weeks of exposure, the animals were euthanized under pentobarbital anesthesia and the blood samples were collected to detect serum progesterone and corticosterone. In addition, adrenal glands were excised, and adrenal cells were cultured in the absence or presence of rat adrenocorticotropic hormone (ACTH) (10(-15) to 10(-10)M) for 4 h. There were no significant differences in the body weight, absolute and relative adrenal gland weight among the groups. Serum concentration of corticosterone and progesterone was not changed significantly. Administration of ACTH resulted in a dose-dependent increase in corticosterone and progesterone release in mice-exposed to low-concentration NR-DE and clean air. Moreover, corticosterone and progesterone concentrations in adrenal cells increased significantly in mice-exposed to low-concentration NR-DE basal and administrated with ACTH (10(-15) to 10(-11)M for corticosterone; 10(-14) to 10( 11)M for progesterone) compared with the control mice. In contrast, the concentration of corticosterone and progesterone decreased significantly in mice exposed to high-concentration NR-DE or F-DE basal and administrated with ACTH (10(-12) to 10(-10)M for corticosterone; 10(-15) to 10(-10)M for progesterone) compared with the control mice. These results suggest that exposure to NR-DE or F DE may disrupt adrenocortical function in adult male mice. PMID- 22260945 TI - Conduction abnormalities in pediatric patients with restrictive cardiomyopathy. AB - BACKGROUND: Pediatric restrictive cardiomyopathy carries a poor prognosis secondary to a high risk of sudden death previously attributed to ventricular tachyarrhythmias. The extent of conduction abnormalities in this population and their relationship to life-threatening events has not been previously reported. METHODS AND RESULTS: A retrospective study of pediatric patients with restrictive cardiomyopathy diagnosed between April 1994 and May 2011 was performed. Demographic, cardiac, and ECG characteristics and the mechanisms of serious arrhythmic events (death or episode of acute hemodynamic compromise thought to be secondary to arrhythmia) were evaluated. Sixteen patients (1-17 years of age) were reviewed, with 5 sudden cardiac events noted, including 4 deaths. Two deaths were caused by development of acute heart block; another patient with syncope had intermittent heart block and survived as the result of pacing features of an implanted defibrillator system. The median PR interval (222 versus 144 ms; P<0.01) and the QRS duration (111 versus 74; P=0.01) were significantly longer in those who had an acute cardiac event. Older age at presentation was associated with sudden cardiac events (P<0.01). No other functional or echocardiographic variables were associated with a sudden cardiac event. CONCLUSIONS: Pediatric patients with restrictive cardiomyopathy are at risk for acute high-grade heart block, and, in this cohort, bradycardic events represented a significant portion of all arrhythmic events. Aggressive ECG monitoring strategies looking for conduction system disease should be ongoing in all patients with restrictive cardiomyopathy. Implantation of a defibrillator/pacemaker should be considered as prophylactic management. PMID- 22260944 TI - Association of beta-blocker exposure with outcomes in heart failure differs between African American and white patients. AB - BACKGROUND: beta-Blockers (BB) are a mainstay of heart failure (HF) treatment, yet there are inconclusive data regarding their efficacy in African American individuals. METHODS AND RESULTS: We performed a retrospective study of insured patients who received care from a large health system who were hospitalized for HF between January 2000 and June 2008 and had a documented ejection fraction <50%. BB exposure was estimated over 6-month rolling windows, using pharmacy claims data. Proportional hazards regression was used to test the association between BB exposure and all-cause hospitalization or death with adjustment for baseline covariates and other HF medication exposure. We performed analyses stratified by race and overall with a BB exposure*race interaction term. A total of 1094 patients met inclusion criteria (476 white and 618 African American individuals). Median follow-up was 2.1 years. In adjusted models, BB exposure was associated with lower risk of death or hospitalization in both groups, but more so in white individuals (hazard ratio, 0.40; 95% confidence interval, 0.27, 0.60; P<0.001) compared with African American individuals (hazard ratio, 0.67; 95% confidence interval, 0.48, 0.94; P=0.024). A formal test for interaction indicated that the protection association for BB exposure differed by race (P=0.098, beta=0.40). Reanalysis restricted to BBs approved for HF or HF-specific hospitalizations did not substantively alter the findings. CONCLUSIONS: BB appears to be 40-50% less effective in preventing death or hospitalization among African American patients with HF as compared with white individuals. Further study is needed to better understand BB effectiveness in African Americans with HF. PMID- 22260946 TI - Should women receive left ventricular assist device support?: findings from INTERMACS. AB - BACKGROUND: Small studies have reported women to have worse outcomes and more adverse events after implantation of mechanical circulatory support device compared with men. To further evaluate sex differences in outcome, we used the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). METHODS AND RESULTS: There were 401 women (pulsatile devices=78) and 1535 men (pulsatile devices=402) from 89 institutions who were prospectively enrolled into the INTERMACS database for primary implantation of a left ventricular assist device (LVAD) between June 23, 2006, and March 31, 2010. Extensive preimplantation and outcome data were collected on all patients. With a mean follow-up of 7 months, 67 females (17%) died and 250 males (16%) died. There was no statistically significant sex difference in mortality for either pulsatile flow (P=0.82) or continuous-flow (P=0.95) devices in adjusted and unadjusted models. There were also no statistically significant sex differences with time to first infection, bleeding, or device malfunction. However, female sex was associated with an increased hazard of first neurological event (adjusted hazard ratio, 1.44; 95% CI, 1.05-1.96; P=0.020). CONCLUSIONS: There were no significant sex differences in mortality, time to first infection, bleeding, or device malfunction with either pulsatile- or continuous-flow LVADs. However, women had an increased risk of first neurological event. For urgent/emergent mechanical support, the benefit of LVAD support likely outweighs the risk, but it remains less clear for women undergoing elective LVAD implantation. PMID- 22260947 TI - Activation of AMP-activated protein kinase in cerebella of Atm-/- mice is attributable to accumulation of reactive oxygen species. AB - Ataxia telangiectasia (A-T) is an inherited disease, the most prominent feature of which is ataxia caused by degeneration of cerebellar neurons and synapses. The mechanisms underlying A-T neurodegeneration are still unclear, and many factors are likely to be involved. AMP-activated protein kinase (AMPK) is a sensor of energy balance, and research on its function in neural cells has gained momentum in the last decade. The dual roles of AMPK in neuroprotection and neurodegeneration are complex, and they need to be identified and characterized. Using an Atm (ataxia telangiectasia mutated) gene deficient mouse model, we showed here that: (a) upregulation of AMPK phosphorylation and elevation of reactive oxygen species (ROS) coordinately occur in the cerebella of Atm-/- mice; (b) hydrogen peroxide induces AMPK phosphorylation in primary mouse cerebellar astrocytes in an Atm-independent manner; (c) administration of the novel antioxidant monosodium luminol (MSL) to Atm-/- mice attenuates the upregulation of both phosphorylated-AMPK (p-AMPK) and ROS, and corrects the neuromotor deficits in these animals. Together, our results suggest that oxidative activation of AMPK in the cerebellum may contribute to the neurodegeneration in Atm-/- mice, and that ROS and AMPK signaling pathways are promising therapeutic targets for treatment of A-T and other neurodegenerative diseases. PMID- 22260949 TI - High precision tuning of state for memristive devices by adaptable variation tolerant algorithm. AB - Using memristive properties common for titanium dioxide thin film devices, we designed a simple write algorithm to tune device conductance at a specific bias point to 1% relative accuracy (which is roughly equivalent to seven-bit precision) within its dynamic range even in the presence of large variations in switching behavior. The high precision state is nonvolatile and the results are likely to be sustained for nanoscale memristive devices because of the inherent filamentary nature of the resistive switching. The proposed functionality of memristive devices is especially attractive for analog computing with low precision data. As one representative example we demonstrate hybrid circuitry consisting of an integrated circuit summing amplifier and two memristive devices to perform the analog multiply-and-add (dot-product) computation, which is a typical bottleneck operation in information processing. PMID- 22260948 TI - Childhood maltreatment is associated with increased body mass index and increased C-reactive protein levels in first-episode psychosis patients. AB - BACKGROUND: The high incidence of the metabolic syndrome in patients with psychosis is mainly attributed to antipsychotic treatment. However, it is also possible that psychological stress plays a role, inducing a chronic inflammatory process that may predispose to the development of metabolic abnormalities. We investigated the association between childhood maltreatment and inflammatory and metabolic biomarkers in subjects with first-episode psychosis and healthy controls. METHOD: Body mass index (BMI), weight and waist circumference were measured in 95 first-episode psychosis patients and 97 healthy controls. Inflammatory and metabolic markers were measured in a subsample of 28 patients and 45 controls. In all the subjects we collected information on childhood maltreatment and recent stressors. RESULTS: Patients with childhood maltreatment had higher BMI [25.0 (S.E.=0.6) kg/m2] and C-reactive protein (CRP) levels [1.1 (S.E.=0.6) mg/dl] when compared with healthy controls [23.4 (S.E.=0.4) kg/m2, p=0.030 and 0.2 (S.E.=0.1) mg/dl, p=0.009, respectively]. In contrast, patients without childhood maltreatment were not significantly different from healthy controls for either BMI [24.7 (S.E.=0.6) kg/m2, p=0.07] or CRP levels [0.5 (S.E.=0.2) mg/dl, p=0.25]. After controlling for the effect of BMI, the difference in CRP levels across the three groups remained significant (F 2,58=3.6, p=0.035), suggesting that the increase in inflammation was not driven by an increase in adipose tissue. CONCLUSIONS: Childhood maltreatment is associated with higher BMI, and increased CRP levels, in patients with a first episode psychosis. Further studies need to confirm the mechanisms underlying the putative causal relationship between childhood maltreatment and higher BMI, and whether this is indeed mediated by increased inflammation. PMID- 22260951 TI - Nickel release from orthodontic retention wires-the action of mechanical loading and pH. AB - Nickel (Ni) is a potent sensitizer and may induce innate and adaptive immune responses. Ni is an important component of orthodontic appliances (8-50 wt%). Due to chemical and mechanical factors in the oral environment, Ni is released from these appliances. Retention wires are in situ for a long period of time. OBJECTIVES: To quantitatively evaluate the influence of mechanical loading and pH on the nickel release from orthodontic retention wires. METHODS: Five different types of multi-stranded wires (Original Wildcat, Noninium, Lingual retainer, Dentaflex 3-s, Dentaflex 6-s), were submersed for 24 h in either 10 ml of distilled water or lactic acid, both submitted to cyclic loading in a 3-point bending test (0*, 1000*, 10,000*). The solutions were analyzed by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS), and the data was statistically analyzed (ANOVA, p<0.05). RESULTS: Mechanical loading has a strong effect on the Ni release from orthodontic retention wires, especially in distilled water. Acidity has more impact on Ni release when compared to mechanical loading. Manganese-steel "Ni-free" wires released quantifiable amounts of Ni due to trace elements of Ni within the wire. SIGNIFICANCE: All investigated wires release considerable amounts of Ni to which exposure may have biological implications. PMID- 22260950 TI - High prevalence of multidrug-resistant tuberculosis, Swaziland, 2009-2010. AB - In Africa, although emergence of multidrug-resistant (MDR) tuberculosis (TB) represents a serious threat in countries severely affected by the HIV epidemic, most countries lack drug-resistant TB data. This finding was particularly true in the Kingdom of Swaziland, which has the world's highest HIV and TB prevalences. Therefore, we conducted a national survey in 2009-2010 to measure prevalence of drug-resistant TB. Of 988 patients screened, 420 new case-patients and 420 previously treated case-patients met the study criteria. Among culture-positive patients, 15.3% new case-patients and 49.5% previously treated case-patients harbored drug-resistant strains. MDR TB prevalence was 7.7% and 33.8% among new case-patients and previously treated case-patients, respectively. HIV infection and past TB treatment were independently associated with MDR TB. The findings assert the need for wide-scale intervention in resource-limited contexts such as Swaziland, where diagnostic and treatment facilities and health personnel are lacking. PMID- 22260952 TI - Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions. AB - Ventricular wall rupture represents a catastrophic complication of myocardial infarction (MI) in the clinic while research has long been hampered due to absence of suitable animal models. Since late 1990s, the mouse has become a suitable model for human post-infarct cardiac rupture. Here we review the clinical features of post-infarct rupture, factors associated with a higher risk of rupture, and findings from clinical trials on the incidence of post-infarct rupture. The features of the mouse model of post-infarct cardiac rupture are discussed. Research using this model suggests acute ventricular remodeling as the fundamental change leading to rupture, and has defined several key factors that determine the risk of rupture. We then provide a comprehensive review of the progress of experimental research in this field focusing on recent findings from genetically modified mouse models and experimental therapeutic interventions that reveal molecular mechanisms of post-infarct rupture. Genetic and pharmacological interventions targeting key inflammatory mediators, regulatory factors of extracellular matrix collagen and healing process effectively reduced the risk of rupture. These findings convincingly demonstrate that cardiac inflammation, damage to extracellular matrix proteins or blunted fibrotic healing constitute the central mechanisms for the pathogenesis of cardiac rupture and acute ventricular remodeling. Studies using the mouse model have also identified novel molecular mechanisms and therapeutic targets as well as suitable interventional regimens providing useful clues for clinical translation. PMID- 22260953 TI - Genetic variation of GPLD1 associates with serum GPI-PLD levels: a preliminary study. AB - HDL is a heterogeneous mixture of lipoprotein particles varying in composition, size, and function. We and others have described a small (7.0nm), minor (0.1% of total apolipoprotein AI) particle containing apolipoprotein AI, AIV and glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) in humans the function of which is not entirely known. Circulating GPI-PLD levels are regulated by multiple factors including genetics. To determine if genetic variation in GPLD1 affects circulating GPI-PLD levels, we examined the relationship between 32 SNPS upstream, within, and downstream of GPLD1 and circulating GPI-PLD levels in Caucasians (n=77) and African-Americans (n=99). The genotype distribution among races differed at 13 SNPs. Nine SNPS were associated with circulating GPI-PLD levels in Caucasians but not African-Americans. These results suggest that genetic variation of GPLD1 appears to associate with circulating GPI-PLD levels. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). PMID- 22260954 TI - Global survey of anthropogenic neighborhood threats to conservation of grass shrub and forest vegetation. AB - The conservation value of natural vegetation is degraded by proximity to anthropogenic land uses. Previous global assessments focused primarily on the amount of land protected or converted to anthropogenic uses, and on forest vegetation. Comparative assessments of extant vegetation in terms of proximity to anthropogenic land uses are needed to better inform conservation planning. We conducted a novel comparative survey of global forest and grass-shrub vegetation at risk of degradation owing to proximity of anthropogenic land uses. Using a global land cover map, risks were classified according to direct adjacency with anthropogenic land cover (adjacency risk), occurrence in anthropogenic neighborhoods (neighborhood risk), or either (combined risk). The survey results for adjacency risk and combined risk were summarized by ecoregions and biomes. Adjacency risk threatens 22 percent of global grass-shrub and 12 percent of forest vegetation, contributing to combined risk which threatens 31 percent of grass-shrub and 20 percent of forest vegetation. Of 743 ecoregions examined, adjacency risk threatens at least 50 percent of grass-shrub vegetation in 224 ecoregions compared to only 124 ecoregions for forest. The conservation threats posed by proximity to anthropogenic land cover are higher for grass-shrub vegetation than for forest vegetation. PMID- 22260955 TI - Effect of operating parameters on desulphurization of mine tailings by froth flotation. AB - A site-specific study is carried out to assess the suitability of froth flotation for desulphurization of reactive mine tailings at the Musselwhite Mine, Northern Ontario, Canada, to prevent acid mine drainage (AMD). The results from pilot scale flotation tests on an Outokumpu flotation unit are presented, which confirm that froth flotation is effective to reduce sulphide contents of tailings. The factors affecting the treatment effectiveness, such as the froth depth, air flow rate, pulp density and impeller speed are studied. The sulphur recoveries after 0.25, 0.5, 1, 2, 5, and 12 min of flotation time are fitted to a second-order kinetic model. It is found that the second order rate constant, k(2) is negatively correlated with the froth depth and positively correlated with the air flow rate. Based on the data presented in this study; the maximum recovery of total sulphur was achieved when the operational parameters were set to the froth depth of 5 cm, air flow rate 125 L/min, impeller speed 1300 rpm and pulp density 35%. PMID- 22260956 TI - Rabies in captive deer, Pennsylvania, USA, 2007-2010. AB - Since January 2007, a total of 11 rabid deer from 4 deer farms have been identified in 2 neighboring Pennsylvania counties. Vaccination of deer against rabies, decreasing wildlife animal contact with deer, and education of deer farmers may prevent further cases of rabies in captive deer and exposures to humans. PMID- 22260957 TI - A single centre study of coil embolization of intracranial aneurysms comparing bare platinum and PGLA-coated coils. AB - There is no robust consensus on the efficacy of polyglycolic/polylactic acid (PGLA)-coated coils used in the endovascular embolization of intracranial aneurysms. We present a comparative study of bare platinum coils and PGLA-coated Gugliemi Detachable Coils (GDC) in the treatment of intracranial aneurysms at a single centre, using target aneurysm recurrence and angiographic recanalization as the primary endpoints. We included all patients treated between 1998 and 2009 who had undergone at least one angiographic post-procedural follow-up. Patient demographics, clinical presentation, operative notes, and all relevant imaging were collected. Of the 441 aneurysms with follow-up, 290 were treated with at least one PGLA coil and 151 aneurysms were treated exclusively with bare platinum coils. At follow-up, 26.5% of platinum controls demonstrated angiographic recanalization, compared to 31.4% of PGLA-treated aneurysms (p=0.002). PGLA treated aneurysms were more likely to have an angiographic remnant at follow-up (odds ratio [OR]=1.96, 95% confidence interval [CI]=1.26-3.04, p=0.003). The post operative Raymond score was the only predictor of retreatment (OR=1.6, 95% CI=1.08-2.24, p=0.020), and was the second strongest predictor of a complete angiographic result at follow-up (OR=1.67, 95% CI=1.22-2.27, p=0.001). We concluded that PGLA-coated coils demonstrated poorer post-operative and long-term angiographic occlusion in the treatment of intracranial aneurysms, compared to bare platinum coils. PMID- 22260958 TI - Acoustically presented semantic decision-making tasks provide a robust depiction of the temporo-parietal speech areas. AB - Functional MRI (fMRI) is routinely used to depict language areas, for example in the preoperative diagnostic work-up of patients with a brain tumour. The objective of this study was to test whether semantic decision making can activate the temporo-parietal language areas better than phonological generation stimuli. Five fMRI language stimuli were tested in 20 healthy volunteers: (i) word generation to a given letter (WG); (ii) verb generation to a given noun (VG); (iii) generation of groups of words (GW); (iv) detection of a semantic violation in sentences (SV); and (v) detection of pseudowords (PW). The stimuli were presented both visually and acoustically. We used a block design and evaluated the data with SPM5 with predefined regions of interest in the frontal and temporo parietal language areas. A lateralisation index (LI) was also calculated. We found that WG and VG achieved the best results in frontal language areas; VG, SV and PW presented acoustically achieved the best results in the temporo-parietal language areas; and that LI was most reliably calculated in the frontal language areas. An acoustically presented semantic decision making stimulus should be implemented in the preoperative diagnostic work-up to robustly depict the temporo parietal language areas. The stimulus is easy to understand and perform, and it achieves robust results. PMID- 22260959 TI - Intracranial neuroenteric cysts: a concise review including an illustrative patient. AB - Neuroenteric cysts (NC) are rare, benign lesions lined by mucin-secreting cuboidal or columnar epithelium of an intestinal or respiratory type. They are regarded as ectopic endodermal cysts, and tend to be found in the spine rather than an intracranial location. Advances in neuroimaging have led to an increased frequency of diagnosis of NC, especially as an incidental finding, although such cysts may be confused radiologically with other lesions such as epidermoid and arachnoid cysts. We undertook a PubMed search of the literature using the search terms "neuroenteric cyst" and its many pseudonyms, including "endodermal cyst", "enterogenous cyst", "neurenteric cyst", "epithelial cyst", "intestinome", "teratomatous cyst", "gastrocytoma", and also "enterogenic", "foregut", "respiratory", and "bronchogenic cyst". Only reports in English and those containing histopathologically-confirmed NC were considered for this review. In total, 140 patients with intracranial NC were found, including the patient reported in the present review. This review describes the classification, epidemiology, embryology, clinical presentation, radiology, histopathology, and surgical treatment of NC, and includes an illustrative patient. PMID- 22260960 TI - Targeting Stat3 suppresses growth of U251 cell-derived tumours in nude mice. AB - Malignant gliomas are highly invasive tumours associated with high levels of mortality, and the treatment of gliomas remains a major neurosurgical challenge. Stat3, a member of the signal transducer and activator of transcription family, has a critical role in a variety of cancer cells. We have previously shown that downregulation of Stat3 decreases invasiveness and induces apoptosis in U251 human glioma cells in vitro, but to date it has been unclear whether this treatment would be beneficial in vivo. In the present study, we found that downregulation of Stat3 via RNAi suppressed tumour growth in a xenograft mouse model by inducing apoptosis of U251 tumour cells and inhibiting tumour neo angiogenesis. We also found that Stat3 RNAi suppresses the expression of Bcl-2 in vivo to induce apoptosis. These results indicate that Stat3 is a critical factor in the survival of patients with glioma, and that targeting Stat3 may offer a potential therapeutic approach. PMID- 22260961 TI - A ticking clock for the production of sequential actions: where does the problem lie in schizophrenia? AB - Schizophrenia has been associated to a distorted time clock. By subtracting contact duration from Inter Response Interval, we report evidence for preserved internal clock in schizophrenia, with normal spontaneous tapping tempo. Contact durations were however increased in patients suggesting a specific problem in the fast integration of incoming haptic feedback with outgoing motor efferences. This integration deficit would emerge at an early phase, since Ultra High Risk patients also revealed abnormal tapping stability. Tactile screens revealed to be a simple and low cost apparatus that may constitute a suitable measuring kit for the characterisation of sensory motor deficits in clinical settings. PMID- 22260962 TI - Executive function in first-episode schizophrenia: a three-year prospective study of the Hayling Sentence Completion Test. AB - In recent decade, deficits in the mechanism of Supervisory Attentional System (SAS) have become increasingly influential in explaining the nature of dysexecutive syndrome experienced by schizophrenic patients. The SAS model is characterized by having a detailed sub-classification of specific executive function components, among which semantic inhibition has been investigated using the Hayling Sentence Completion Test (HSCT). Several studies thus far have indicated that schizophrenic patients show impairment in HSCT performance. However, HSCT data concerning first-episode patients is still scarce. Besides, as previous HSCT studies were all cross-sectional in nature, they were not able to assess changes in HSCT performance over time. In order to address the paucity of knowledge about the longitudinal trajectories and correlates of semantic inhibition deficits in early schizophrenia, this paper reports a three-year prospective study of HSCT performance in medication-naive, first-episode patients with schizophrenia-spectrum disorders. HSCT performance was assessed in 34 patients at four times over a period of three years, while the 34 healthy controls were assessed once. We found that medication-naive patients demonstrated impairment in the inhibition condition in HSCT as compared to controls, but not in the initiation condition. Such HSCT impairment gradually improved in the three years following the first psychotic episode; however, HSCT performance did not predict improvement in negative or positive symptoms over the three-year period. The present findings suggest that semantic inhibition impairment is a specific deficit in schizophrenia that may require early intervention efforts, with the goal of facilitating more successful verbal communication and thereby better interpersonal functioning. PMID- 22260963 TI - Clozapine administration ameliorates disrupted long-range synchrony in a neurodevelopmental animal model of schizophrenia. AB - The abnormal synchronisation of neural networks may underlie some of the deficits observed in schizophrenia. Abnormal synchronisation can be induced in animal models. We investigated whether acute clozapine treatment might function therapeutically by ameliorating the deficit in theta frequency coherence between the prefrontal cortex and the hippocampus that is induced in rats exposed to maternal immune activation (MIA)--a risk-factor for schizophrenia. Clozapine treatment increased synchrony levels to that of control animals in a dose dependent manner. Clozapine's effect on synchrony may in part be mediated through increases in local synchrony that occurred in prefrontal cortex but not hippocampus. PMID- 22260964 TI - Motivational intervention increases exercise in schizophrenia and co-occurring substance use disorders. PMID- 22260965 TI - Do psychiatric registries include all persons with schizophrenia in the general population? A population-based longitudinal study. AB - BACKGROUND: Psychiatric hospitalization registries are utilized to investigate the incidence and prevalence of schizophrenia for both research and administrative purposes. The assumption behind this is that most individuals with schizophrenia will be hospitalized at least once in their life-time. METHOD: In an epidemiological survey conducted in the 1980s, a population-based sample (n = 4914) of Israel-born individuals then aged 25-34 were screened in the community, and 29 (0.6%) were subsequently diagnosed by psychiatrists using SADS/RDC criteria. Twenty four years later we linked data from the epidemiological survey with the Israeli National Psychiatric Hospitalization Registry. RESULTS: Twenty seven of the 29 individuals (93%) diagnosed with schizophrenia in the survey were identified in the hospitalization registry with the same diagnosis. Fifty-two (1.0%) participants not diagnosed during the survey with schizophrenia were identified in the psychiatric hospitalization registry 24 years later with schizophrenia. The majority of them were diagnosed with other psychiatric disorders in the survey. If all diagnoses of schizophrenia are accepted at face value, the lifetime prevalence rate would be 1.8% for this cohort. CONCLUSION: The overwhelming majority of individuals diagnosed with schizophrenia at ages 25 34 in an epidemiological survey were present in the Psychiatric Hospitalization Registry. However, the assessment of life-time rates of schizophrenia at these ages is problematic because some future cases are asymptomatic, others have premorbid non-psychotic disorders, while in others it is difficult to differentiate between affective disorders and schizophrenia. Availability of psychiatric services and hospitalization policy must be considered when generalizing these findings to other countries. PMID- 22260966 TI - The separate and combined effects of alcohol and nicotine on anticipatory anxiety: a multidimensional analysis. AB - Individuals who smoke cigarettes are significantly more likely to smoke more when they drink alcohol. Indeed, smoking and drinking appear strongly linked, at both between- and within-person levels of analyses. Anecdotal evidence further suggests that alcohol consumption in combination with smoking cigarettes reduces anxiety, yet the mechanisms by which this may occur are not well understood. The current study assessed the separate and combined effects of alcohol and nicotine on self-reported and psychophysiological (startle eyeblink magnitude) indices of anxiety. Results indicated that alcohol provided anxiolytic benefits alone and in combination with nicotine, as evidenced by significant reductions in startle eyeblink magnitude. According to self-reported anxiety, alcohol and nicotine exerted a conjoint effect on diminishing increases in anxiety subsequent to a speech stressor. These data highlight the importance of studying both the separate and combined effects of these two widely used substances, as well as the advantages of employing a multimodal assessment of emotional response. PMID- 22260967 TI - Characterization of polysorbate 80 with liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy: specific determination of oxidation products of thermally oxidized polysorbate 80. AB - The polysorbate species in polysorbate 80 (PS 80) have been characterized with (1)H NMR, LC-UV/MS and MS/MS. The MS was operated with both negative and positive electrospray ionization (ESI). PS 80 was found to contain mono- and di-fatty acid esters of polyoxyethylene (POE) sorbitan, POE isosorbide and of POE. In addition, the same species were also present without fatty acid esters. The polysorbate species were esterified with C12:0, C14:0, C16:1, C16:0, C18:2, C18:1 and C18:0 fatty acids. The main species were polysorbate esters of C18:1. The C18:2 polysorbate species were shown, by (1)H NMR, to have a large component of fatty acids with a conjugated double bond of ZE and/or EZ configuration. The positive ESI mass spectra of the polysorbate species displayed a specific in-source fatty acid fragment for each fatty acid ester. The mass chromatograms of the in-source fatty acid fragments were used to determine the degradation of specific polysorbate species in PS 80. The C18:2 polysorbate species were completely degraded after 8 weeks at 40 degrees C under an atmosphere of air, while the main C18:1 polysorbate species were reduced to ca. 80-86% accompanied by an increase of short-chain POE C18:1 species. Polysorbate species esterified with C18:1-OH, C18:1 keto and C18:0 epoxy acids were found as degradation products of PS 80 stored at 40 degrees C for 8 weeks under air. C18:1-OH, C18:1 keto and C18:0 epoxy acids were believed to be oxidation products of C18:1. With the present conditions, the positive ESI mass spectra of C18:1-OH and C18:0 epoxy polysorbate species displayed identical ions to the C18:2 polysorbate species due to a facile in-source loss of H(2)O from the protonated molecules. The presence of polysorbate esters of C18:1-OH and C18:0 epoxy acids were established using negative ESI MS. The presence of oxidized fatty acids in degraded PS 80 was also confirmed by saponification and extraction followed by negative ESI LC-MS analysis of the free fatty acids. PMID- 22260968 TI - Screening active compounds acting on the epidermal growth factor receptor from Radix scutellariae via cell membrane chromatography online coupled with HPLC/MS. AB - Radix scutellariae is a traditional Chinese medicine (TCM) and has many pharmacological effects, including antiviral, antibacterial, antifungal, antipyretic, hypotensive, anti-inflammatory and anti-anaphylaxis effects. However, few studies have screened the active compounds in this complex product for tumor therapy. In this study, a two-dimensional online method was developed to screen the active compounds from Radix scutellariae acting on the epidermal growth factor receptor. The screening results showed that wogonin from Radix scutellariae was the targeted component which acted on epidermal growth factor receptor specificity. The in vitro inhibitory activity of wogonin on the viability of cells with high epidermal growth factor receptor expression was tested using the MTT assay. In the dosage range of 0.40-50.0 MUM, inhibition of HEK293/EGFR by wogonin was 8.94 +/- 0.2, 20.64 +/- 5.10, 34.16 +/- 5.90 and 69.03 +/- 7.80 at the concentrations of 0.4 * 10(-6), 2 * 10(-6), 10 * 10(-6) and 50 * 10(-6) molL(-1), respectively. These results showed that wogonin inhibited the growth of cells with high epidermal growth factor receptor expression in a dose dependent manner. PMID- 22260969 TI - HPLC method for determination of biologically active epoxy-transformers of treosulfan in human plasma: pharmacokinetic application. AB - Clinical trials demonstrated treosulfan (TREO) as a promising myeloablative agent prior to hematopoietic stem cell transplantation (HSCT). TREO is a specific pro drug from which biologically active mono- (S,S-EBDM) and diepoxybutane (S,S-DEB) derivatives are formed in vitro or in vivo by a non-enzymatic pH and temperature dependent intramolecular nucleophilic substitution. Following extraction of the plasma samples with a mixture of dichloromethane and acetonitrile, S,S-EBDM and S,S-DEB were derivatized with 3-nitrobenzenesulfonic acid (3-NBS) to UV-absorbing esters. Optimal temperature and time of derivatization as well as extraction method and also the effect of pH on TREO stability in plasma were established. Identity of the synthesized derivatives was confirmed by mass spectrometry. The post-derivatization mixture was purified from the excess of unreacted 3-NBS by extraction with water. The derivatization products and 2,2'-dinitrobiphenyl (internal standard) were separated on Nucleosil 100 C18 column using a mobile phase consisted of acetonitrile and water. The developed method was validated and demonstrated adequate accuracy and precision. Limit of quantification for both S,S-EBDM and S,S-DEB amounted to 2.5 MUM. The method was applied in clinical conditions to quantify the levels of TREO activation products in plasma of children undergoing HSCT. The methodology for simultaneous determination of TREO epoxy-transformers in human plasma is described for the first time. PMID- 22260970 TI - A new expanded solubility parameter approach. AB - The partial or Hansen solubility parameters (HSP) are important properties of the various substances and very useful tools for the selection of their solvents or the prediction of their behaviour in numerous applications. Their design and evaluation relies on the basic rule of "similarity matching" for solubility. The present work attempts to enhance the capacity of HSPs by incorporating into their evaluation the other basic rule of solubility, namely, the rule of "complementarity matching". This is done in a simple and straightforward manner by splitting the hydrogen bonding HSP into its acidic or proton donor component and its basic or proton acceptor one. The splitting is based on the third sigma moments of the screening charge distributions or sigma profiles of the quantum mechanics based COSMO-RS theory. The whole development and application does not involve any sophisticated calculations or any strong specific background. The new method has been applied to a variety of solubility data for systems of pharmaceutical interest in order to verify the significant improvement over the classical HSP approach. The application of the new method requires, of course, the knowledge of the HSPs. For this reason, in Appendix A is presented an updated version of a robust and reliable group-contribution method for the calculation of the HSPs. The key features of this combined tool are critically discussed. PMID- 22260971 TI - [Identification of a new causative gene of amyotrophic lateral sclerosis; optineurin]. AB - Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. ALS patients die within 3 to 5 years without respiratory support. Detecting the causing gene is necessary to elucidate ALS. We identified mutations of optineurin (OPTN) in ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Cell transfection experiments showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B. The missense mutation revealed a cytoplasmic distribution different from that of the wild type. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic retention, and Golgi fragmentation was identified in 70% of the anterior horn cells. TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also immunolabelled with anti-OPTN antibodies. Furthermore, optineurin is co-localized with fused in sarcoma (FUS) in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Our findings suggest that OPTN is involved in the great part of pathogenesis of ALS. PMID- 22260972 TI - [Revival of old diagnostic markers in the cerebrospinal fluid for the detection of infectious meningitis]. AB - Bacterial meningitis and tubercular meningitis are still neurological emergencies characterized by severe mortality and morbidity. Recent studies of meta-analysis have shown the usefulness of cerebrospinal fluid (CSF) lactate and CSF adenosine deaminase (ADA) as markers for the detection of bacterial meningitis and tubercular meningitis, respectively. CSF lactate has a high sensitivity and specificity for the diagnosis of bacterial meningitis, but the sensitivity can be reduced by antibiotic pretreatment. CSF-ADA has a moderate sensitivity but a high specificity and is reliable for the diagnosis of tubercular meningitis. These old diagnostic markers can be evaluated in resource-poor settings including small general hospitals and non-specialized hospitals for infectious diseases, and they can contribute to the quick and accurate diagnosis of infectious meningitis. PMID- 22260973 TI - [Case of an elderly patient with community acquired bacterial meningitis due to extended spectrum beta lactamase producing Escherichia coli]. AB - Community acquired bacterial meningitis due to extended spectrum beta lactamase producing Escherichia coli is very rare. We report the case of a 72-year-old woman being treated for longstanding diabetes mellitus. She developed lower back pain accompanied by elevated body temperature, and was transported to the emergency unit in our hospital five days later because of impaired consciousness. An abdominal plane CT showed acute pyelonephritis and a brain MRI showed inflammatory exudate in the posterior horn of her bilateral ventricles. A lumbar puncture was performed, and examination of the cerebrospinal fluid revealed a marked elevation in her cell count (polymorphonuclear leukocytes dominant) that we diagnosed as bacterial meningitis. Initially, she was treated with intravenous meropenem, ceftriaxon, and vancomycin. Extended spectrum beta lactamase-producing Escherichia coli were then detected in her urinary and blood cultures, and the antibiotics were changed to intravenous meropenem, gentamicin, and intrathecal gentamicin. Her clinical symptoms improved, but her inflammatory reaction was prolonged and we detected spondylitis. She was then treated with levofloxacin, and the inflammatory reaction improved. Extended spectrum beta lactamase producing Escherichia coli should be taken into consideration as a cause of community acquired bacterial meningitis. PMID- 22260974 TI - [Case of NMO (neuromyelitis optica) spectum disorder triggered by interferon alpha, which involved extensive pyramidal tract lesion of the brain]. AB - A 65-year-old woman developed left optic neuritis during the course of peg interferon alpha (PEG-IFN-alpha) and ribavirin combination therapy for chronic hepatitis C. Brain T(2)W-MRI disclosed hyperintense lesions in the corpus callosum and white matter. We diagnosed neuromyelitis optica spectrum disorder (NMOSD) on the basis of anti-aquaporin-4 antibody seropositivity. PEG-IFN-alpha was discontinued, and she received steroid pulse therapy (intravenous high dose methylprednisolone). Two weeks later she also developed right optic neuritis. Repetitive steroid pulse therapy improved the left optic neuritis, but the upper half of the visual field of the right eye remained impaired. One month later she presented with mild dysarthria and mild left hemiparesis. Brain MRI disclosed an extensive pyramidal tract lesion from the right corona radiata to the pedunculus cerebri. This cerebral pyramidal tract lesion is associated with NMOSD. Our case corresponds to the past reports of optic neuritis or multiple sclerosis-like disease triggered by IFN-alpha. IFN-alpha may trigger NMOSD via a biological effect characteristic of Type I IFNs, a group that includes IFN-alpha and IFN beta. PMID- 22260975 TI - [Elderly case of moyamoya disease presenting with hemichorea]. AB - A 61-year-old Japanese female was admitted with sudden onset of choreic movements of the right extremities. MRI demonstrated no abnormality suggestive of acute infarcts. Cerebral angiography revealed high-grade stenosis of bilateral middle cerebral arteries at the origin and abnormal vascular network compatible with moyamoya disease. Administration of low-dose haloperidol rapidly resolved the choreic movements. SPECT obtained one month after the clinical onset demonstrated increase of the regional cerebral blood flow (rCBF) in the left basal ganglia. Moyamoya disease presenting chorea as its initial symptom was only infrequently reported in the elderly. In the present case, increased rCBF in the basal ganglia and remarkable effect of a dopamine D2 blocker suggest functional abnormality of the corresponding striatum as an underlying cause of hemichorea. PMID- 22260976 TI - [Overlap case of Fisher syndrome and pharyngeal-cervical-brachial variant of Guillain-Barre syndrome]. AB - A 29-year-old female developed diplopia, nasal voice and gait disturbance after an upper respiratory infection. On admission, she presented with bilateral external ophthalmoplegia, slight bilateral facial nerve palsy, dysarthria, dysphagia, cervical and brachial muscle weakness, ataxia and areflexia. She had serum anti-GT1a, anti-GQ1b and anti-galactocerebroside IgG antibodies. She was diagnosed with an overlap case of Fisher syndrome and pharyngeal-cervical brachial variant of Guillain-Barre syndrome. Intravenous immunoglobulin therapy was effective for the ophthalmoplegia and ataxia, but did not improve the bilateral facial nerve palsy and brachial muscle weakness. The facial nerve palsy clearly worsened despite improvement in other symptoms, and therefore high-dose intravenous methylprednisolone therapy was added. The distinct response to treatment may be caused by different activity, production, clearance and reactivity to intravenous immunoglobulin of the autoantibodies. The present case suggests that treatment response and patterns of recovery differ according to the causative anti-ganglioside antibodies. PMID- 22260977 TI - [Bow hunter's syndrome with spontaneous improvement]. AB - A 74-year-old man complained of near loss of consciousness when he rotated his head to the left side. The symptom was reversed by returning his head to a neutral position. Transcranial Doppler studies with the patient's neck rotated into the left side revealed reduction of flow in his left vertebral artery. Vertebral angiography revealed a hypoplastic right vertebral artery and occlusion of the left vertebral artery at the C6 level on head rotation. We diagnosed him bow hunter's syndrome and treated him conservatively. Six months later, he was symptom-free on head rotation. Transcranial Doppler and vertebral angiography demonstrated the disappearance of the vertebral artery occlusion at the neck rotation. Some patient without any definite cause can be treated conservatively, and surgical interventions for bow hunter's syndrome should be carefully decided. PMID- 22260978 TI - [Case of focal convexal subarachnoid hemorrhage presenting as transient ischemic attack mimic]. AB - An 82-year-old man was suspected to have experienced a transient ischemic attack since he developed transient weakness in the right upper limb twice. On admission, neurologic examination yielded normal findings except for mild cognitive impairment. Brain CT and images showed an unexpected finding of acute focal subarachnoid hemorrhage in the left central sulcus, although MR angiography and venography did not show any abnormality. T(2)(*) weighted images showed superficial siderosis in the bilateral frontal lobes, which indicated the possibility of a recurrent subarachnoid hemorrhage. We propose that focal subarachnoid hemorrhage should be included in the differential diagnosis of transient ischemic attack. PMID- 22260979 TI - [Astrogliopathy as a loss of astroglial protective function against glycoxidative stress under hyperglycemia]. AB - Reactive oxygen species (ROS) derived from mitochondria play an essential role in stroke as well as in neurodegenerative disorders. Although hyperglycemia associated with diabetes mellitus is well known to enhance ROS production in vascular endothelial cells, the effects of either acute or chronic high glucose environments on neurons and glial cells remain unclear. Astroglia play a pivotal role in glucose metabolism. Thus, the astroglial metabolic response to high glucose environments is an interesting subject. In particular, the glutathione/pentose phosphate pathway (PPP) system, which is a major defense mechanism against ROS in the brain, contributes to glucose metabolism and is more active in astroglia. We propose that high glucose environments activate PPP through an increased flux to the hexosamine biosynthetic pathway (HBP). HBP is known to induce endoplasmic reticulum (ER) stress under hyperglycemia, resulting in the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2), a master regulator of phase 2 detoxifying enzymes including glucose-6 phosphate dehydrogenase that regulates PPP activity, as Nrf2 is reported to be a direct substrate of protein kinase RNA (PKR)-like ER kinase (PERK), a transducer of ER stress. Therefore, the phosphorylation of Nrf2 by hyperglycemia-induced ER stress facilitates Nrf2 translocation through PERK, thus activating the PPP. If acute or chronic hyperglycemia induces PPP activation in astroglia to reduce ROS, reducing the glucose concentration may be accompanied by a risk, which may explain the lack of evidence that strict glycemic control during the acute phase of stroke conveys no beneficial effect. PMID- 22260980 TI - Interaction of prazosin with model membranes--a Langmuir monolayer study. AB - In this study, the effect of prazosin on the molecular interactions between cholesterol and 1,2-dipalmitoylphosphatidylcholine (DPPC) within a monolayer at an air-water interface was studied. A mixed cholesterol/DPPC monolayer was employed as a model lipid membrane. From a detailed analysis of surface pressure area isotherms, it was concluded that DPPC and cholesterol were miscible and formed non-ideal monolayers on prazosin solution. The thermodynamic stability of the mixed monolayers was investigated by analyzing the free energy of mixing. It was found that the mixed monolayers were more stable than the single component monolayers. Monolayers spread over a subphase with prazosin were more compressible than those spread on pure water. To quantify the effect of prazosin on the monolayer stability, the Gibbs free energy due to the presence of prazosin in the water subphase was calculated. It was found that prazosin penetrated and destabilized mixed cholesterol/DPPC monolayers. However, a comparison of the drug penetration into the pure DPPC monolayer and the mixed cholesterol/DPPC monolayer showed that the presence of cholesterol in the DPPC monolayer considerably restricted the drug penetration. PMID- 22260981 TI - Calcium imaging of multiple neurons in freely behaving C. elegans. AB - Caenorhabditis elegans is a popular model organism to study how neural circuits and genes regulate behavior. To reliably correlate circuit function with behavior, it is important to record neuronal activity in freely behaving worms. As neural circuits are composed of multiple neurons that cooperate to process information, it is highly desirable to simultaneously record the activity of multiple neurons in the circuitry. However, such a system has not been available in C. elegans. Here, we report the CARIBN II (Calcium Ratiometric Imaging of Behaving Nematodes version II) system. This system provides smoother data collection and more importantly permits simultaneous imaging of calcium transients from multiple neurons in freely behaving worms. Using this system, we imaged the activity of AVA and RIM, two key neurons in the locomotion circuitry that regulate backward movement (reversal) in locomotion behavior. We found that AVA activity increases while RIM activity decreases during the same reversal events in spontaneous locomotion, consistent with the recent report that the AVA and RIM are involved in promoting the initiation of reversals. The CARIBN II system provides a valuable tool for dissecting the neural basis of behavior in C. elegans. PMID- 22260982 TI - Polycrystalline diamond UV-triggered MESFET receivers. AB - Optically triggered UV sensitive receivers were fabricated on polycrystalline diamond as surface channel MESFETs. Opaque gates with asymmetric structure were designed in order to improve charge photogeneration mainly within the gate-drain region. Photogenerated holes contributed to the channel charge by assistance of the local electric field, in such a way improving the current signal at the drain contact. The sensitivity to UV light is demonstrated by using 3 ns wide laser pulses at 193 nm, well over the diamond bandgap. The receiver transient response to such laser pulses shows that the photogeneration process is only limited by the pulse rise time and charge collection at the drain contact completed in a time scale of a few nanoseconds. Such opaque gate three-terminal devices are suitable for application in emerging photonic technologies, for power-management system optical receivers, where copper wires and EM shielding can be replaced by lightweight optical fibers. PMID- 22260983 TI - Delinquent peer affiliation as an etiological moderator of childhood delinquency. AB - BACKGROUND: Prior research has indicated that affiliation with delinquent peers activates genetic influences on delinquency during adolescence. However, because other studies have indicated that the socializing effects of delinquent peers vary dramatically across childhood and adolescence, it is unclear whether delinquent peer affiliation (DPA) also moderates genetic influences on delinquency during childhood. Method The current study sought to evaluate whether and how DPA moderated the etiology of delinquency in a sample of 726 child twins from the Michigan State University Twin Registry (MSUTR). RESULTS: The results robustly supported etiological moderation of childhood delinquency by DPA. However, this effect was observed for shared environmental, rather than genetic, influences. Shared environmental influences on delinquency were found to be several-fold larger in those with higher levels of DPA as compared to those with lower levels. This pattern of results persisted even when controlling for the overlap between delinquency and DPA. CONCLUSIONS: Our findings bolster prior work in suggesting that, during childhood, the association between DPA and delinquency is largely (although not solely) attributable to the effects of socialization as compared to selection. They also suggest that the process of etiological moderation is not specific to genetic influences. Latent environmental influences are also amenable to moderation by measured environmental factors. PMID- 22260984 TI - Conventional vehicle display panels: the drivers' operative images and directions for their redesign. AB - The proliferation of new displays in modern vehicles sets the challenge to revisit the design of the conventional display units, toward more simplified appearance. The present study aims to evaluate the usefulness of the information provided to the drivers by the conventional vehicle display units, in order to trace directions that would lead to a simplification of the future display panels. Based on the concept of operative images, two working hypotheses were formulated: (i) the experienced drivers have developed an operative image reference (OI-R) for the display panel of their own vehicle(s), reflecting the relative importance they attribute to the information emitted by the various displays of the panel, and (ii) the experienced drivers' drawings of the display panel of their own vehicle will be guided by their OI-R for it - providing therefore traces of the content of their OI-R, while the less experienced drivers' drawings will be closer to the actual display panel of their own vehicle. The method of drawing from memory was used to obtain traces of the operative images of both experienced and less experienced non-professional drivers. The obtained 335 drawings were compared to the actual display panels, as to their overall resemblance and to specific features. The results of the data analysis are in accordance to our working hypotheses. Considering the main features of the experienced drivers' OI-R, directions for the simplification of the appearance of conventional display units are proposed. PMID- 22260985 TI - Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery. AB - The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n=8, P<0.001) and less so by rauwolscine, indicating functional alpha1- and alpha2-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n=8, P<0.01) but augmented noradrenaline responses (n=8, P<0.01), suggesting the release of two endothelium dependent factors with opposite effects. In the presence of endothelium, neurogenic and exogenous noradrenaline vasoconstrictions were enhanced by L-NOArg (n=7, P<0.05 and P<0.01 respectively) and ODQ (n=7, both P<0.05); in denuded arteries, nNOS inhibition with N(omega)-propyl-L-arginine increased neurogenic contraction (n=7, P<0.05). Western blotting indicated the presence of neural and endothelial origin NO (n=6, P<0.001). Tetraethylammonium (n=9, P<0.001), iberiotoxin (n=7, P<0.001) and 4-aminopyridine (n=8, P<0.01) enhanced vasoconstrictions revealing a modulatory role of big conductance Ca2+-activated K+ (BK(Ca)) and voltage-dependent K+ (K(v)) channels in noradrenergic responses. Bosentan pretreatment (n=8, P<0.05) suggested endothelin-1 as the inferred contractile neurogenic endothelial-dependent factor. Indomethacin-induced inhibition involved a muscular prostanoid (n=9, P<0.05), functionally and immunologically localized, and derived from cyclooxygenase (COX)-1 and COX-2, as revealed by Western blots (n=5, P=0.1267). Thus, noradrenergic IMA contractions are controlled by contractile prostanoid activation and endothelin-1 release, and offset by BK(Ca) and K(v) channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass. PMID- 22260987 TI - Prevention of serogroup B meningococcal disease. PMID- 22260988 TI - Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. AB - BACKGROUND: Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents. METHODS: We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaiso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713. FINDINGS: Overall, 1631 adolescents (mean age 13.8 [SD 1.9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0.0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified. INTERPRETATION: On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys. FUNDING: Novartis Vaccines and Diagnostics. PMID- 22260989 TI - Accelerating control of pertussis in England and Wales. AB - Results of an accelerated pertussis vaccination schedule for infants introduced in 1990 in England and Wales were examined. Earlier scheduling and sustained high vaccine coverage resulted in fewer reported cases of pertussis among infants, reinforcing the World Health Organization drive for on-time completion of the infant vaccination schedule. As determined by using the screening method, the first dose of vaccine was 61.7% effective in infants <6 months of age, and effectiveness increased with subsequent doses. Three doses of a good whole-cell pertussis vaccine were 83.7% effective in children 10-16 years of age; a preschool booster vaccination further reduced pertussis incidence in children <10 years of age. As in other industrialized countries, surveillance data during 1998 2009 showed that pertussis in England and Wales mainly persists in young infants (i.e., <3 months of age), teenagers, and adults. Future vaccine program changes may be beneficial, but additional detail is required to inform such decisions. PMID- 22260990 TI - Cardioprotective radiotherapy: the circadian way. AB - Radiotherapy (RT) has been established to improve both local control as well as overall survival rates in breast cancer. However, RT especially in left-sided breast cancer also irradiates a portion of the heart. Radiation associated toxicity to the heart assumes significance because of improval in survival of breast cancer patients. A circadian pattern has been reported in the myocardial oxygen demand and myocardial ischaemia with the cardiac tissue being more susceptible to injury between 6 am and noon. Radiation damages blood vessels of all sizes causing an increase in capillary wall permeability and dilatation of vessels leading to the characteristic radiation erythema followed by an inflammatory cell infiltrate. Coronary artery spasm may be the reason behind some cases of sudden death occurring in patients after radiation therapy. Endothelial behaviour also has a circadian variation and vasodilation is significantly attenuated in the morning. Critical coronary artery disease occurs 10-15 years after radiotherapy. Radiation in the morning hours may be one of the associated risk factor. The application of chrono-therapeutics with radiation therapy in carcinoma breast and in other chest wall irradiation, could possibly decrease the radiation associated cardiac toxicity. PMID- 22260991 TI - Relevance, pathogenesis, and testing algorithm for mismatch repair-defective colorectal carcinomas: a report of the association for molecular pathology. AB - Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5 fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response are similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder. PMID- 22260992 TI - Expression and cellular localization of inducible nitric oxide synthase in lipopolysaccharide-treated rat kidneys. AB - Although inducible nitric oxide synthase (iNOS) is known to play significant roles in the kidney, its renal localization has long been controversial. To resolve this issue, the authors identified iNOS-positive cell types in rat kidneys using double immunohistochemistry and confirmed iNOS positivity using enzyme histochemistry with NADPH-diaphorase (NADPH-d) and in situ RT-PCR. Adult male Sprague-Dawley rats were injected intraperitoneally with lipopolysaccharide (LPS) or saline as a control and sacrificed at various time intervals after injection. Quantitative real-time reverse transcriptase polymerase chain reaction showed that iNOS was not expressed in control kidneys but was induced in LPS treated kidneys. iNOS immunostaining was strongest 6 to 18 hr after injection and decreased gradually to control levels by day 7. Double immunohistochemistry and NADPH-d revealed that iNOS expression was induced in the interstitial cells, glomerular parietal epithelial cells, the proximal part of the short-looped descending thin limb, the upper and middle papillary parts of the long-looped descending thin limb, some inner medullary collecting duct cells, and almost all calyceal and papillary epithelial cells. The present study determines the precise localization of iNOS in LPS-treated rat kidneys and provides an important morphological basis for examining the roles of iNOS in sepsis-induced acute kidney injury. PMID- 22260993 TI - Detection of disease-associated prion protein in the optic nerve and the adrenal gland of cattle with bovine spongiform encephalopathy by using highly sensitive immunolabeling procedures. AB - A sensitive immunohistochemical procedure, the tyramide signal amplification (TSA) system, was applied to detect the localization of immunolabeled disease associated prion protein (PrP(Sc)) in cattle affected with bovine spongiform encephalopathy (BSE). In this procedure, immunolabeling could be visualized in the optic nerve and the adrenal medulla. In the optic nerve, the dual immunofluorescent technique showed that the granular PrP(Sc) was occasionally detected in the astrocytes, microglia, and myelin sheath adjacent to the axon. Clustered PrP(Sc) was also scattered in association with microglial cells and astrocytes of the optic nerve. In the adrenal gland, PrP(Sc) immunolabeling was confined within the sympathetic nerve fibers and endings. The results suggest that (1) PrP(Sc) might centrifugally spread within and between glial cells and/or the non-axonal (also known as ad-axonal) region of nerve fibers, rather than the axonal and/or extracellular space pathway in the optic nerve, and (2) the sympathetic innervations might be important for the trafficking of BSE agent in the adrenal glands of cattle. This study also suggests that tyramide-based immunochemical analysis should be performed to detect immunolabeled PrP(Sc) in the extracerebral tissues of BSE-affected cattle. PMID- 22260994 TI - Localization of transforming growth factor beta receptor II interacting protein-1 in bone and teeth: implications in matrix mineralization. AB - Transforming growth factor beta receptor II (TGFbetaR-II) interacting protein 1 (TRIP-1) is a WD-40 protein that binds to the cytoplasmic domain of the TGF-beta type II receptor in a kinase-dependent manner. To investigate the role of TRIP-1 in mineralized tissues, we examined its pattern of expression in cartilage, bone, and teeth and analyzed the relationship between TRIP-1 overexpression and mineralized matrix formation. Results demonstrate that TRIP-1 was predominantly expressed by osteoblasts, odontoblasts, and chondrocytes in these tissues. Interestingly, TRIP-1 was also localized in the extracellular matrix of bone and at the mineralization front in dentin, suggesting that TRIP-1 is secreted by nonclassical secretory mechanisms, as it is devoid of a signal peptide. In vitro nucleation studies demonstrate a role for TRIP-1 in nucleating calcium phosphate polymorphs. Overexpression of TRIP-1 favored osteoblast differentiation of undifferentiated mesenchymal cells with an increase in mineralized matrix formation. These data indicate an unexpected role for TRIP-1 during development of bone, teeth, and cartilage. PMID- 22260995 TI - Expression of long-form N-acetylglucosamine-6-O-sulfotransferase 1 in human high endothelial venules. AB - Two members of the N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) family, GlcNAc6ST-1 and GlcNAc6ST-2, function in the biosynthesis of 6-sulfo sialyl Lewis X-capped glycoproteins expressed on high endothelial venules (HEVs) in secondary lymphoid organs. Thus, both enzymes play a critical role in L-selectin-expressing lymphocyte homing. Human GlcNAc6ST-1 is encoded by a 1593-bp open reading frame exhibiting two 5' in-frame methionine codons spaced 141 bp apart. Both resemble the consensus sequence for translation initiation. Thus, it has been hypothesized that both long and short forms of GlcNAc6ST-1 may be present, although endogenous expression of either form has not been confirmed in humans. Here, the authors developed an antibody recognizing amino acid residues between the first two human GlcNAc6ST-1 methionines. This antibody specifically recognizes the long form of the enzyme, a finding validated by Western blot analysis and immunofluorescence cytochemistry of HeLa cells misexpressing long and/or short forms of human GlcNAc6ST-1. Using this antibody, the authors carried out immunofluorescence histochemistry of human lymph node tissue sections and found endogenous expression of the long form of the enzyme in human tissue, predominantly in the trans-Golgi network of endothelial cells that form HEVs. PMID- 22260997 TI - Chromosomal composition of micronuclei in human leukocytes exposed to mitomycin C. AB - Micronuclei (MN) can be induced by different mutagenic substances. Even though this has been known for decades, it is still not clear which genetic content, especially which chromosomes, these MN are constituted of and if there are any influences on this content by the MN-inducing substance. Also, the interphase position, size, and gene density of a chromosome could influence its involvement in MN formation. To study some of these questions, fluorescence in situ hybridization using centromeric and whole-chromosome painting probes for chromosomes 3, 4, 6, 7, 9, 16, 17, 18, and X was applied in mitomycin C (MMC) induced MN in human leukocytes. The obtained results showed that material from all studied chromosomes was present in MN. Also, there was no correlation between interphase position, size, and gene density of the studied chromosomes and their migration in MN. Interestingly, material derived from chromosomes 9 and 16 was overrepresented in MMC-induced MN. Finally, further studies using substances other than MMC are necessary to clarify if the MN-inducing mutagen has an influence on the chromosomal content of the MN. PMID- 22260996 TI - Decorin-TGFbeta axis in hepatic fibrosis and cirrhosis. AB - Hepatic fibrosis and cirrhosis are worldwide health care problems, especially in regions with a high rate of hepatitis infection. As these diseases affect a major part of the human population, the search for antifibrotic therapies has a high priority in medical research. Transforming growth factor beta1 (TGF-beta1) is one of the most powerful profibrotic cytokines. Thus, blocking TGF-beta1 activity by natural inhibitors represents a valid and logical strategy to combat hepatic fibrosis. One of the natural inhibitors of TGF-beta1 is decorin, a small leucine rich proteoglycan that binds with high affinity to this cytokine and prevents its interaction with pro-fibrotic receptors. Recent evidence has shown that decorin has a protective role in liver fibrogenesis insofar as its genetic ablation in mice leads to enhanced matrix deposition, impaired matrix degradation, and "activation" of hepatic stellate cells, the main producers of fibrotic tissue. Moreover, TGF-beta1 exerts a stronger effect when functional decorin is absent. These data provide robust genetic evidence for a direct role of endogenous decorin in preventing and retarding hepatic fibrosis. Thus, boosting the endogenous production of decorin or systemic delivery of recombinant decorin could represent an additional therapeutic modality against hepatic fibrosis. PMID- 22260998 TI - Absence of the basement membrane component nidogen 2, but not of nidogen 1, results in increased lung metastasis in mice. AB - Nidogen 1 and 2 are ubiquitous basement membrane (BM) components. They show a divergent expression pattern in certain adult tissues with a prominent localization of nidogen 2 in blood vessel BMs. Deletion of either nidogen 1 or 2 in mice had no effect on BM formation, suggesting complementary functions. However, studies in these mice revealed isoform-specific functions with nidogen 1 deficient mice showing neurological abnormalities and wound-healing defects not seen in the absence of nidogen 2. To investigate this further nidogen 1- or 2 deficient mice were intravenously injected with B16 murine melanoma cells, and lung metastasis was analyzed. The authors could show that loss of nidogen 2, but not of nidogen 1, significantly promotes lung metastasis of melanoma cells. Histological and ultrastructural analysis of nidogen 1- and 2-deficient lungs did not reveal differences in morphology and ultrastructure of BMs, including vessel BMs. Furthermore, deposition and distribution of the major BM components were indistinguishable between the two mouse strains. Taken together, these results suggest that absence of nidogen 2 might result in subtle changes of endothelial BMs in the lung, which would allow faster passage of tumor cells through these BMs, leading to a higher metastasis rate and more larger tumors. PMID- 22260999 TI - Biogenesis of multisubunit RNA polymerases. AB - Gene transcription in the nucleus of eukaryotic cells is carried out by three related multisubunit RNA polymerases, Pol I, Pol II and Pol III. Although the structure and function of the polymerases have been studied extensively, little is known about their biogenesis and their transport from the cytoplasm (where the subunits are synthesized) to the nucleus. Recent studies have revealed polymerase assembly intermediates and putative assembly factors, as well as factors required for Pol II nuclear import. In this review, we integrate the available data into a model of Pol II biogenesis that provides a framework for future analysis of the biogenesis of all RNA polymerases. PMID- 22261001 TI - Nurse IOM members' contributions to the Institute of Medicine. AB - BACKGROUND: Nursing is the largest health care profession, and Institute of Medicine (IOM) nurse members have the potential to contribute to health policy through IOM activities. We studied reported activities of IOM nurse members. PURPOSE: To describe activities of IOM nurse members within the IOM. METHOD: An e mail survey was conducted that asked nurse IOM members to assess self-reported IOM activities. Of 57 members, 47 had functioning e-mail addresses, and 33 usable responses were received. The survey consisted of 9 questions dealing with roles and responsibilities undertaken in the previous 5 years. Data analyses were descriptive. DISCUSSION: The data suggest that nurses have made considerable contributions to the IOM and their participation seems to be as high, or higher, than other disciplines. CONCLUSIONS: In an era of health care reform, there is additional opportunity for nurse IOM members to enhance their work in the IOM. PMID- 22261002 TI - Interventions to promote colorectal cancer screening: an integrative review. AB - Behavior change interventions to promote colorectal cancer (CRC) screening have targeted people in community and primary care settings, health care providers, and health systems. Randomized controlled trials provide the strongest evidence of intervention efficacy. The purpose of this integrative review was to evaluate trials of CRC screening interventions published between 1997 and 2007 and to identify knowledge gaps and future directions for research. Thirty-three randomized trials that met inclusion criteria were evaluated using a modified version of the TREND criteria. Significant intervention effects were reported in 6 of 10 trials focused on increasing fecal occult blood testing, 4 of 7 trials focused on sigmoidoscopy or colonoscopy completion, and 9 of 16 trials focused on completion of any screening test. Several effective interventions to promote CRC screening were identified. Future trials need to use theory to guide interventions, examine moderators and mediators, consistently report results, and use comparable outcome measures. PMID- 22261003 TI - Nursing responsibilities and social justice: an analysis in support of disciplinary goals. AB - Social justice is asserted as a responsibility of the nursing profession. However, a reliable conception of social justice that can undergird practice, research, education, and policy endeavors has proved elusive. We discuss this as a problem for the profession and propose Powers and Faden's model of social justice as useful for nursing purposes because of its focus on exploring and rectifying underlying causes of injustice as they lie within the fabric of society. Their model asserts 6 essential dimensions of well-being as universal human needs. These dimensions are interrelated and nonhierarchical. A serious deficiency in any one affects other dimensions and interferes with the ability to experience "a minimally decent life." The model is applied to the problem of child abuse and the effects of its aftermath on well-being as an example of its potential for structuring nursing knowledge development, practice, and policy initiatives. PMID- 22261004 TI - Effects of lidocaine constant rate infusion on sevoflurane requirement, autonomic responses, and postoperative analgesia in dogs undergoing ovariectomy under opioid-based balanced anesthesia. AB - The effects of constant rate infusion (CRI) of lidocaine on sevoflurane (SEVO) requirements, autonomic responses to noxious stimulation, and postoperative pain relief were evaluated in dogs undergoing opioid-based balanced anesthesia. Twenty four dogs scheduled for elective ovariectomy were randomly assigned to one of four groups: BC, receiving buprenorphine without lidocaine; FC, receiving fentanyl without lidocaine; BL, receiving buprenorphine and lidocaine; FL, receiving fentanyl and lidocaine. Dogs were anesthetized with intravenous (IV) diazepam and ketamine and anesthesia maintained with SEVO in oxygen/air. Lidocaine (2mg/kg plus 50 MUg/kg/min) or saline were infused in groups BL/FL and BC/FC, respectively. After initiation of lidocaine or saline CRI IV buprenorphine (0.02 mg/kg) or fentanyl (4 MUg/kg plus 8 MUg/kg/h CRI) were administered IV in BC/BL and FC/FL, respectively. Respiratory and hemodynamic variables, drug plasma concentrations, and end-tidal SEVO concentrations (E'SEVO) were measured. Behaviors and pain scores were subjectively assessed 1 and 2h post-extubation. Lidocaine CRI produced median drug plasma concentrations <0.4 MUg/mL during peak surgical stimulation. Lidocaine produced a 14% decrease in E'SEVO in the BL (P<0.01) but none in the FL group and no change in cardio-pulmonary responses to surgery or postoperative behaviors and pain scores in any group. Thus, depending on the opioid used, supplementing opioid-based balanced anesthesia with lidocaine (50 MUg/kg/min) may not have any or only a minor impact on anesthetic outcome in terms of total anesthetic dose, autonomic responses to visceral nociception, and postoperative analgesia. PMID- 22261005 TI - Different perspectives on communication quality and emotional functioning during routine oncology consultations. AB - OBJECTIVE: To determine quality of communication in routine oncology consultations from patient, physician, and observer perspectives, and to determine agreement of emotional function content in consultations from these three perspectives. METHODS: In total, 69 consultations were included. Perceived quality of communication and whether or not emotional functioning had been discussed was evaluated with patient- and physician-reported questionnaires. Observer perspective was evaluated by content analysis of audio records of the consultations. Agreement between perspectives was analyzed and means compared using linear mixed models. RESULTS: The patients' ratings of communication quality differed significantly from those of both the physician and observer. Observer and physician scores did not differ significantly. Physicians rated emotional functioning as discussed more often than was reported from patient and observer perspectives. CONCLUSION: The patients' view of the quality of communication differed from that of the physician and observer. Whether emotional functioning was discussed or not was also perceived differently by patients, physicians, and observer. PRACTICE IMPLICATIONS: The underpinnings and implications of these results need to be further explored regarding how to move toward a higher degree of shared understanding, where different perspectives are more in alignment, and how to develop more valid methods for evaluating communication. PMID- 22261006 TI - Mapping of B cell epitopes on desmoglein 3 in pemphigus vulgaris patients by the use of overlapping peptides. AB - BACKGROUND: Pemphigus vulgaris (PV) is a severe autoimmune blistering disease associated with autoantibodies to desmoglein 3 (Dsg 3), a transmembrane glycoprotein of the cadherin family. Previous studies mainly focused on the mapping of conformational epitopes of Dsg 3 using recombinant fragments of Dsg 3 and competition ELISA. OBJECTIVE: Here, we performed a mapping of linear B cell epitopes on Dsg 3 in PV patients by the use of overlapping synthetic peptides. METHODS: A set of 254 overlapping synthetic peptides of 14 amino acids length covering the entire Dsg 3 extracellular domain was generated. Sera of patients with active PV (n=10) and healthy volunteers (n=10) were tested for IgG reactivity with the 254 peptides by ELISA. Testing each peptide separately, 7 major antigenic sites were identified. In order to validate these reactivities, 7 corresponding peptides of 13-33 amino acids in length were generated and employed by ELISA. Additional sera of active PV patients (n=17) and healthy volunteers (n=20) were tested and the most reactive peptide was used to specifically purify anti-Dsg 3 antibodies from PV sera (n=3). RESULTS: The major autoantibody reactivity in PV sera was mapped to amino acids 333-356 within the EC3 domain. Purifying patients IgG using the identified peptide, however, failed to induce acantholysis in keratinocyte dissociation assay. CONCLUSION: We conclude that linear epitopes do not play a major pathogenic role in human PV. PMID- 22261007 TI - Identification of the C-terminal tail domain of AHF/trichohyalin as the critical site for modulation of the keratin filamentous meshwork in the keratinocyte. AB - BACKGROUND: AHF/trichohyalin is a large structural protein abundant in the inner root sheath (IRS) of anagenic hair follicles, which has been thought to mediate the keratin filamentous assembly. However, its functional mechanism is largely unknown. OBJECTIVE: This study aimed at the identification of the key domain in AHF for keratin association and the establishment of a plausible mechanism for the modulation of the keratin meshwork. METHODS: Several keratinocyte cell lines were introduced with the full length or several mutants of AHF, together with IRS specific keratin krt31, and the profile of the AHF granules and the cellular behaviors were carefully analyzed. RESULTS: Full length of AHF formed small round granules that clearly bound to and aligned on the exogenous keratin filaments in the keratinocytes, severely affected cellular growth, mobility and shape. Intriguingly, the removal of only 6 amino acids around the C-terminal tail of AHF resulted not only in the complete loss of its keratin adherent ability but also in a dramatic enlargement of the granules. CONCLUSION: We propose a model for cytoskeletal modulation in the IRS of anagenic hair follicles: AHF latches onto the keratin bundles by its C-terminus and rearranges the keratin meshwork by intrinsic cohesive activity for the granule formation. PMID- 22261008 TI - Batch distillation employing cyclic rectification and stripping operations. AB - Several strategies have been proposed to increase the operating efficiency of batch distillation. In this study, conventional batch rectification and inverted batch stripping are used cyclically to promote high product flow rates for a binary fractionation. Process controls are implemented to maintain constant product purity specifications by varying the slope of the operating line. While rectifying, the light component is removed as distillate, concentrating the heavy component in the reboiler. As a result, the distillate rate decreases with time. The column is then changed from rectification to stripping modes, and the heavy component is removed as bottoms product, concentrating the light component in the distillate drum. This causes the bottoms rate to diminish with time, and the column is once again converted back to rectifying mode. Cyclic operation, transitioning from batch rectifying to stripping back to rectifying, continues until all of the initial charge is fractionated or is combined with a new charge. The fractionation of ethanol and 1-propanol using the proposed operating strategy is shown to provide several advantages including energy and time savings when compared to conventional batch or inverted batch distillation alone. PMID- 22261009 TI - Oral transmission of L-type bovine spongiform encephalopathy in primate model. AB - We report transmission of atypical L-type bovine spongiform encephalopathy to mouse lemurs after oral or intracerebral inoculation with infected bovine brain tissue. After neurologic symptoms appeared, transmissibility of the disease by both inoculation routes was confirmed by detection of disease-associated prion protein in samples of brain tissue. PMID- 22261010 TI - Evaluation of salivary cortisol measurements for the diagnosis of subclinical Cushing's syndrome. AB - Late-night salivary cortisol (NSC) has been recognized as a sensitive and easy-to perform screening test for the diagnosis of overt Cushing's syndrome (CS). However, there have been few reports on the diagnostic utility of salivary cortisol (SC) measurement in the diagnosis of subclinical Cushing's syndrome (SCS). Therefore, the present study was designed to evaluate the usefulness of SC measurements at late-night and after overnight 1 mg dexamethasone suppression test (DST) for the diagnosis of SCS in 42 patients with adrenal incidentaloma. We evaluated 16 patients with SCS, 12 with nonfunctioning adenoma (NFA), 8 with primary aldosteronism (PA), and 6 with pheochromocytoma (Pheo). NSC levels in SCS patients (0.238 +/- 0.106 ug/dL) were significantly (P < 0.05) higher than those in NFA patients (0.154 +/- 0.104 ug/dL); the cutoff value (0.11 ug/dL) by ROC analysis gave high sensitivity (100%) with low specificity (50%). Post DST SC levels in SCS patients (0.238 +/- 0.116 ug/dL) were significantly (P = 0.0081) higher than those in NFA patients (0.136 +/- 0.110 ug/dL); the cutoff value (0.12 ug/dL) by ROC analysis gave high sensitivity (93.8%) with somewhat improved specificity (58.3%). Both NSC and post DST SC levels were comparable between NFA, PA, and Pheo patients. In conclusion, our study revealed that measurements of NSC and/or post DST SC among patients with adrenal incidentaloma prove to have high sensitivities, but low specificities for the diagnosis of SCS from NFA, suggesting its possible alternative option before the screening tests for SCS currently employed in Japan. PMID- 22261011 TI - Range of motion of the metacarpophalangeal joint in rheumatoid patients, with and without a flexible joint replacement prosthesis, compared with normal subjects. AB - BACKGROUND: The metacarpophalangeal is commonly affected by rheumatoid arthritis. This may lead to joint replacement with a flexible prosthesis. The aims of this study were to determine the effects of rheumatoid arthritis on joint motion and to determine whether joint replacement needs to restore the full range of motion. METHODS: Three-dimensional motion analysis was used to measure the range of motion of the metacarpophalangeal joint in rheumatoid patients with and without a flexible silicone arthroplasty, when performing pinch and key grips, when making a fist and when spreading the fingers. The results were compared with those from younger and older normal subjects. FINDINGS: There appeared to be a trend for a decrease in range of motion from younger normal to older normal to rheumatoid (no prosthesis) to rheumatoid (with prosthesis) subject groups. However, statistically different (p<0.05) results were only observed for some movements (mostly involved in making a fist), in some fingers and between some subject groups. The only exception to this apparent trend was in flexion/extension when spreading the fingers into abduction. INTERPRETATION: Making a fist is the most sensitive simple measure of range of motion in the metacarpophalangeal joint. Successful replacement of the metacarpophalangeal joint in patients with rheumatoid arthritis need not restore the normal range of motion. PMID- 22261012 TI - Investigation into three dimensional hip anatomy in anterior dislocation after THA. Influence of the position of the hip rotation centre. AB - BACKGROUND: The components position is a major factor under the surgeon's control in determining the risk of dislocation post total hip arthroplasty. The aim of this study was to investigate the proper three-dimensional components position including the centre of rotation in the case of anterior dislocation. METHODS: Among 1764 consecutive patients who underwent total hip arthroplasty using a direct anterior approach, 27 experienced anterior dislocation. The three dimensional hip anatomy was investigated in 12 patients who were paired with 12 patients from the same initial cohort who did not experience dislocation and also with 36 control patients with osteoarthritis. A pelvic Cartesian referential was defined to perform the acetabular analysis. The coordinates were expressed as percentages of the pelvic width, height and depth. The anteversion angles were measured. FINDINGS: The hip centre of rotation was significantly shifted medially and posteriorly in the dislocation group when compared to the non-dislocation group and also to the control group. There was no significant difference in component angular position between the dislocation-group and the non-dislocation group. However, the stem anteversion in the dislocation group was increased in comparison to the mean natural femoral anteversion of the control group. INTERPRETATION: A medial and posterior displacement of the hip rotation centre was found to correlate to anterior dislocation post total hip arthoplasty. These results suggest the importance of an accurate restoration of the centre of rotation, whilst avoiding an excessive acetabular reaming which may induce a medial and a posterior displacement. LEVEL OF EVIDENCE: III comparative non randomised. PMID- 22261013 TI - Gait patterns of asymmetric ankle osteoarthritis patients. AB - BACKGROUND: In early stages, ankle osteoarthritis is often asymmetric with only partially degenerated joint surfaces. There is only limited knowledge on the effect of asymmetric ankle osteoarthritis on the patients' gait patterns. Therefore, the aim of this study was to characterize kinematic and kinetic changes compared to healthy adults. METHODS: Instrumented gait analysis was performed in eight asymmetric ankle osteoarthritis patients and 15 healthy controls. Beside conventional gait analysis methods, principal component analysis was used to analyze temporal progression of the most important variables: hindfoot dorsiflexion angle and vertical ground reaction force. FINDINGS: Asymmetric ankle osteoarthritis patients had a lower hindfoot dorsiflexion and rotation range of motion as well as reduced peak ground reaction forces and peak kinetic values. Principal component analysis revealed that for both the hindfoot dorsiflexion angle and the vertical ground reaction force those principal component vectors affecting the amplitudes had significantly lower principal component scores in patients than in controls. The use of the principal component scores for classification with a linear support vector machine resulted in a high recognition rate of 97.8% for the discrimination between the affected leg and the healthy controls. INTERPRETATION: Patients with asymmetric ankle osteoarthritis suffer from substantial pathological kinematic and kinetic gait changes. Principal component analysis combined with a linear support vector machine could successfully be used to temporally quantify and classify asymmetric ankle osteoarthritis gait patterns. This study therefore helps to understand the pathomechanism of early stage ankle osteoarthritis from a biomechanical view. PMID- 22261015 TI - Valorization of biodiesel derived glycerol as a carbon source to obtain added value metabolites: Focus on polyunsaturated fatty acids. AB - The amount of glycerol derived from the biodiesel industry is exponentially increasing. The valorization of glycerol has acquired attention and resources with an obvious economic and environmental interest. Glycerol has the potential to improve the profitability of biodiesel in a biorefinery scenario. Added-value metabolites obtained from glycerol-based fermentations are the target of multiple research studies, primarily chemicals and biopolymers. Pigments and polyunsaturated fatty acids are exceptional examples as they have market presence as nutraceuticals. Most of the studies reviewed have been based on microalgae cultures. Depending on the strain and the engineering aspects of such cultures the final yield suffers notable variations. This is an emerging field which shows great potential from the perspective of a byproduct usage and the increasing yields (value) obtained from the bioprocess. PMID- 22261014 TI - Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids. AB - Ergot alkaloids produced by the fungus Claviceps parasitizing on cereals, include three major groups: clavine alkaloids, d-lysergic acid and its derivatives and ergopeptines. These alkaloids are important substances for the pharmatech industry, where they are used for production of anti-migraine drugs, uterotonics, prolactin inhibitors, anti-Parkinson agents, etc. Production of ergot alkaloids is based either on traditional field cultivation of ergot-infected rye or on submerged cultures of the fungus in industrial fermentation plants. In 2010, the total production of these alkaloids in the world was about 20,000 kg, of which field cultivation contributed about 50%. This review covers the recent advances in understanding of the genetics and regulation of biosynthesis of ergot alkaloids, focusing on possible applications of the new knowledge to improve the production yield. PMID- 22261016 TI - Phosphospecific flow cytometry for pharmacodynamic drug monitoring: analysis of the JAK-STAT signaling pathway. AB - Cytokines of the IL-2 receptor family act via activation of the JAK-STAT (janus tyrosine kinase-signal transducer and activator of transcription) signaling pathway. These cytokines are pivotal for the development and function of lymphocyte subsets involved in the immune response after organ transplantation including T, B and natural killer cells. The new small drug molecule and JAK1/3 inhibitor, tofacitinib, is currently being tested in phase II and III clinical trials for rheumatoid arthritis, psoriasis and in organ transplantation. This agent specifically targets the JAK-STAT signaling pathway. Here we discuss phosphospecific flow cytometry as a novel tool to monitor the JAK-STAT signaling pathway in kidney transplant patients and speculate that through the use of this pharmacodynamic tool the efficacy of immunosuppressive drugs can be assessed enabling optimization of the immunosuppressive therapy for individual transplant patients. PMID- 22261017 TI - An appeal to medical journal editors: the need for a full description of laboratory methods and specimen handling in clinical study reports. PMID- 22261018 TI - Recovery from medial prefrontal cortex injury during adolescence: implications for age-dependent plasticity. AB - Focal cortical injuries generate various behavioral deficits associated with different morphological changes. The age and the area of the injury determine the nature and extent of recovery represented by the level of performance in various behavioral tasks. Previously, we have shown that motor cortex injury in early (but not late) adolescence leads to behavioral deficits that do not recover spontaneously with time. Considering the fact that the pace of brain maturation differs in different brain areas, we undertook to examine the pattern of spontaneous recovery following medial prefrontal cortex (mPFC) lesion in early or late adolescence. A battery of motor tasks (postural asymmetry, skilled reaching, sunflower seed manipulation, forepaw inhibition in swimming) was used to investigate the pattern of behavioral recovery following mPFC lesions. Golgi-Cox analysis was used to examine dendritic reorganization of the relevant brain areas. The results indicated that rats perform poorly when receiving mPFC injuries in late adolescence in contrast to when they receive the lesion in early adolescence. Almost opposite pattern of recovery following motor cortex and medial prefrontal injuries in early and late adolescence will be discussed as an age-area dependent model for prognosis of brain injury during adolescence. PMID- 22261019 TI - Reduced thyroid hormones with increased hippocampal SNAP-25 and Munc18-1 might involve cognitive impairment during aging. AB - The mechanism underlying the decline of age-related learning and memory remains unclear. Brain-region-specific changes of synaptic proteins and decreased thyroid hormones (THs) have been implied involving this decline. During normal aging, however, the relationships among synaptic proteins, THs and abilities of learning and memory remain to be elucidated. In this study, the age-related spatial learning and memory ability of 41 Kunming mice (KM) (14 mice aged 6 months, 13 mice aged 11 months, 14 mice aged 22 months) was measured with radial six-arm water maze. The levels of SNAP-25 and Munc18-1 in brain regions were semi quantified by Western blotting and the serum THs were detected by radioimmunoassay. Our results showed the old Kunming mice had marked impairment of spatial learning and memory, with decreased serum free triiodothyronine (FT3) and increased SNAP-25 and Munc18-1 in dorsal hippocampus (DH), ventral hippocampus (VH) and frontal lobe (F). The Pearson's correlation test showed the impairment of spatial learning ability positively correlated with SNAP-25 in DH and Munc18-1 in DH and VH. While, the levels of SNAP-25 (DH, VH and F) and Munc18 1 (DH) negatively correlated with the serum FT3 level, and the spatial memory decline marginal negatively correlate with serum THs. These results suggested that increased hippocampal SNAP-25 and Munc18-1 which seemingly result from decreased serum THs might involve the age-related impairment of spatial learning and memory. PMID- 22261020 TI - Juvenile exposure to methamphetamine attenuates behavioral and neurochemical responses to methamphetamine in adult rats. AB - Previous research has shown that children living in clandestine methamphetamine (MA) labs are passively exposed to the drug [1]. The long-term effects of this early exposure on the dopaminergic systems are unknown, but may be important for adult behaviors mediated by dopamine, such as drug addiction. The current study sought to determine if juvenile exposure to low doses of MA would lead to altered responsiveness to the stimulant in adulthood. Young male and female rats (PD20 34) were injected daily with 0 or 2 mg/kg MA or left undisturbed and then tested at PD90. In the open field, adult rats exposed to MA during preadolescence had reduced locomotor activity compared to control non-exposed rats following an acute injection of MA (2 mg/kg). Likewise, methamphetamine-induced dopamine increases in the dorsal striatum were attenuated in male and female rats that had been exposed to MA as juveniles, although there were no changes in basal in vivo or ex vivo dopamine levels. These findings suggest that exposure of juveniles to MA leads to persistent changes in the behavioral and neurochemical responses to stimulants in adulthood. PMID- 22261021 TI - Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6 benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist. AB - For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N'-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3-yl)-1,3-benzoxazolyl group as a novel replacement of the (N'-phenylureido)phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse alpha(4) antibody (R1-2). PMID- 22261022 TI - Chemical-genomic profiling: systematic analysis of the cellular targets of bioactive molecules. AB - Chemical-genomic (CG) profiling of bioactive compounds is a powerful approach for drug target identification and mode of action studies. Within the last decade, research focused largely on the development and application of CG approaches in the model yeast Saccharomyces cerevisiae. The success of these methods has sparked interest in transitioning CG profiling to other biological systems to extend clinical and evolutionary relevance. Additionally, CG profiling has proven to enhance drug-synergy screens for developing combinatorial therapies. Herein, we briefly review CG profiling, focusing on emerging cross-species technologies and novel drug-synergy applications, as well as outlining needs within the field. PMID- 22261023 TI - Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3beta (GSK-3beta) inhibitors for type 2 diabetics. AB - The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3beta inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3beta inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2MUM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice. PMID- 22261024 TI - Construction of an Indonesian herbal constituents database and its use in Random Forest modelling in a search for inhibitors of aldose reductase. AB - Data on phytochemical constituents of plants commonly used in traditional Indonesian medicine have been compiled as a computer database. This database (the Indonesian Herbal constituents database, IHD) currently contains details on ~1,000 compounds found in 33 different plants. For each entry, the IHD gives details of chemical structure, trivial and systematic name, CAS registry number, pharmacology (where known), toxicology (LD(50)), botanical species, the part(s) of the plant(s) where the compounds are found, typical dosage(s) and reference(s). A second database has been also been compiled for plant-derived compounds with known activity against the enzyme, aldose reductase (AR). This database (the aldose reductase inhibitors database, ARID) contains the same details as the IHD, and currently comprises information on 120 different AR inhibitors. Virtual screening of all compounds in the IHD has been performed using Random Forest (RF) modelling, in a search for novel leads active against AR to provide for new forms of symptomatic relief in diabetic patients. For the RF modelling, a set of simple 2D chemical descriptors were employed to classify all compounds in the combined ARID and IHD databases as either active or inactive as AR inhibitors. The resulting RF models (which gave misclassification rates of 21%) were used to identify putative new AR inhibitors in the IHD, with such compounds being identified as those giving RF scores >0.5 (in each of the three different RF models developed). In vitro assays were subsequently performed for four of the compounds obtained as hits in this in silico screening, to determine their inhibitory activity against human recombinant AR. The two compounds having the highest RF scores (prunetin and ononin) were shown to have the highest activities experimentally (giving ~58% and ~52% inhibition at a concentration of 15MUM, respectively), while the compounds with lowest RF scores (vanillic acid and cinnamic acid) showed the lowest activities experimentally (giving ~29% and ~44% inhibition at a concentration of 15MUM, respectively). These simple virtual screening studies were thus helpful in identifying novel inhibitors of AR, but yielded compounds with only very modest (micromolar) potency. PMID- 22261026 TI - Synthetic approaches to the 2010 new drugs. AB - New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010. PMID- 22261027 TI - Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1,3,4-thiadiazole amide derivatives as novel antitubulin agents. AB - A series of cinnamic acyl 1,3,4-thiadiazole amide derivatives (6a-10e) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 10e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and A549 cell lines with IC(50) values of 0.28 and 0.52MUg/mL, respectively. Compound 10e also exhibited significant tubulin polymerization inhibitory activity (IC(50)=1.16MUg/mL). Docking simulation was performed to insert compound 10e into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 10e with potent inhibitory activity in tumor growth may be a potential anticancer agent. PMID- 22261025 TI - Screening for small molecule inhibitors of embryonic pathways: sometimes you gotta crack a few eggs. AB - Extract prepared from Xenopus eggs represents a cell-free system that has been shown to recapitulate a multitude of cellular processes, including cell cycle regulation, DNA replication/repair, and cytoskeletal dynamics. In addition, this system has been used to successfully reconstitute the Wnt pathway. Xenopus egg extract, which can be biochemically manipulated, offers an ideal medium in which small molecule screening can be performed in near native milieu. Thus, the use of Xenopus egg extract for small molecule screening represents an ideal bridge between targeted and phenotypic screening approaches. This review focuses on the use of this system for small molecules modulators of major signal transduction pathways (Notch, Hedgehog, and Wnt) that are critical for the development of the early Xenopus embryo. We describe the properties of Xenopus egg extract and our own high throughput screen for small molecules that modulate the Wnt pathway using this cell-free system. We propose that Xenopus egg extract could similarly be adapted for screening for modulators of the Notch and Hedgehog pathways. PMID- 22261028 TI - Tributyltin exposure results in craniofacial cartilage defects in rockfish (Sebastiscus marmoratus) embryos. AB - Tributyltin (TBT) is a ubiquitous marine environmental contaminant, which has been known to cause axial skeletal deformities in fish embryos. However, the effects of TBT on the craniofacial cartilage development of fishes remain unclear. The present study was designed to investigate the effects of waterborne TBT at environmental levels (0, 0.1, 1, and 10 ng L(-1) as Sn) on craniofacial cartilage development in embryos of the rockfish (Sebastiscus marmoratus). Our study showed that TBT exposure induced craniofacial skeletal deformities, such as reduction of the craniofacial skeleton elements and a shorter lower jaw. The expressions of retinoic acid receptor alpha, sonic hedgehog, and proliferating cell nuclear antigen were depressed and the expressions of vitamin D receptor were increased in the rockfish embryos after TBT exposure. In addition, the activities of Ca(2+)-ATPase were inhibited after TBT exposure. These results suggested that TBT might perturb the proliferation and differentiation of chondrocytes, and disturb calcium homeostasis, thus disorganizing craniofacial skeletal development. PMID- 22261029 TI - Immunology taught by humans. PMID- 22261030 TI - Arteriovenous malformations in five dimensions. PMID- 22261031 TI - Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. AB - Cutaneous T cell lymphoma (CTCL) is a cancer of skin-homing T cells with variants that include leukemic CTCL (L-CTCL), a malignancy of central memory T cells (T(CM)), and mycosis fungoides (MF), a malignancy of skin resident effector memory T cells (T(EM)). We report that low-dose alemtuzumab (alphaCD52) effectively treated patients with refractory L-CTCL but not MF. Alemtuzumab depleted all T cells in blood and depleted both benign and malignant T(CM) from skin, but a diverse population of skin resident T(EM) remained in skin after therapy. T cell depletion with alemtuzumab required the presence of neutrophils, a cell type frequent in blood but rare in normal skin. These data suggest that T(CM) were depleted because they recirculate between the blood and the skin, whereas skin resident T(EM) were spared because they are sessile and non recirculating. After alemtuzumab treatment, skin T cells produced lower amounts of interleukin-4 and higher amounts of interferon-gamma. Moreover, there was a marked lack of infections in alemtuzumab-treated L-CTCL patients despite the complete absence of T cells in the blood, suggesting that skin resident T(EM) can protect the skin from pathogens even in the absence of T cell recruitment from the circulation. Together, these data suggest that alemtuzumab may treat refractory L-CTCL without severely compromising the immune response to infection by depleting circulating T(CM) but sparing the skin resident T(EM) that provide local immune protection of the skin. PMID- 22261032 TI - Notch4 normalization reduces blood vessel size in arteriovenous malformations. AB - Abnormally enlarged blood vessels underlie many life-threatening disorders including arteriovenous (AV) malformations (AVMs). The core defect in AVMs is high-flow AV shunts, which connect arteries directly to veins, "stealing" blood from capillaries. Here, we studied mouse brain AV shunts caused by up-regulation of Notch signaling in endothelial cells (ECs) through transgenic expression of constitutively active Notch4 (Notch4*). Using four-dimensional two-photon imaging through a cranial window, we found that normalizing Notch signaling by repressing Notch4* expression converted large-caliber, high-flow AV shunts to capillary-like vessels. The structural regression of the high-flow AV shunts returned blood to capillaries, thus reversing tissue hypoxia. This regression was initiated by vessel narrowing without the loss of ECs and required restoration of EphB4 receptor expression by venous ECs. Normalization of Notch signaling resulting in regression of high-flow AV shunts, and a return to normal blood flow suggests that targeting the Notch pathway may be useful therapeutically for treating diseases such as AVMs. PMID- 22261034 TI - Assessments of salivary antioxidant activity using electron spin resonance spectroscopy. AB - OBJECTIVE: In recent years, the function of saliva has been focused on evaluation of general status. The relationship between salivary antioxidant activity and periodontal disease progression is unclear. The aim of this study is to assess the relationship between periodontal disease and salivary antioxidant activity towards various reactive oxygen species (ROS) using electron spin resonance (ESR) technique. METHODS: We demonstrated that whole saliva derived rats or human subjects scavenged ROS such as superoxide (O(2)(.-)) and hydroxyl radical (HO(.)) using ESR spectroscopy with spin trapping agent. In addition, we assessed the relationship between antioxidants activity towards ROS and periodontal index with superoxide dismutase (SOD) activity in human subject saliva. RESULTS: Antioxidant activity towards O(2)(.-) was increased by Porphyromonas gingivalis (P. gingivalis) infection in rat, although antioxidant activity towards HO(.) was not changed. In human, a strong correlation (r = 0.88, p < 0.01) recognized between salivary antioxidant activity towards O(2)(.-) and probing pocket depth (PPD). In addition, the intensity of salivary antioxidant activity depended on SOD activity level. SOD activity was also correlated with PPD. CONCLUSIONS: Rat salivary antioxidant activity towards O(2)(.-) was up-regulated by the inflammatory response caused by P. gingivalis infection. Similar response was recognized in human saliva with periodontal index. Additionally, a linear correlation between antioxidant activity towards O(2)(.-) and SOD activity was verified by ESR technique. Therefore, evaluation of the salivary antioxidant activity towards O(2)(.-) might be an effective parameter for the objective assessment of periodontal disease progression. PMID- 22261035 TI - Putting singular and plural morphology in context*. AB - This study explores the development of children's knowledge of linguistic and pragmatic aspects of singular and plural in Italian, for definite articles (Experiment 1) and verbs (Experiment 2). Participants aged three to adult were asked to pick objects from two dishes, each with a different number of items on them (one vs. two), following the morphological information. Results show that children understand that singular forms refer to 'one' at about age four, whereas they understand that plural forms refer to 'more than one' when they are older than six. Moreover, children use singular and plural knowledge in appropriate relation with the referential context only when they are about six. PMID- 22261033 TI - Cigarette smoke induction of osteopontin (SPP1) mediates T(H)17 inflammation in human and experimental emphysema. AB - Smoking-related lung diseases are among the leading causes of death worldwide, underscoring the need to understand their pathogenesis and develop new effective therapies. We have shown that CD1a+ antigen-presenting cells (APCs) from lungs of patients with emphysema can induce autoreactive T helper 1 (T(H)1) and T(H)17 cells. Similarly, the canonical cytokines interferon-gamma (IFN-gamma) and interleukin-17A (IL-17A) are specifically linked to lung destruction in smokers, but how smoke activates APCs to mediate emphysema remains unknown. Here, we show that, in addition to increasing IFN-gamma expression, cigarette smoke increased the expression of IL-17A in both CD4+ and gammadelta T cells from mouse lung. IL 17A deficiency resulted in attenuation of, whereas lack of gammadelta T cells exacerbated, smoke-induced emphysema in mice. Adoptive transfer of lung APCs isolated from mice with emphysema revealed that this cell population was capable of transferring disease even in the absence of active smoke exposure, a process that was dependent on IL-17A expression. Spp1 (the gene for osteopontin) was highly expressed in the pathogenic lung APCs of smoke-exposed mice and was required for the T(H)17 responses and emphysema in vivo, in part through its inhibition of the expression of the transcription factor Irf7. Thus, the Spp1 Irf7 axis is critical for induction of pathological T(H)17 responses, revealing a major mechanism by which smoke activates lung APCs to induce emphysema and identifying a pathway that could be targeted for therapeutic purposes. PMID- 22261036 TI - Expression profiles of seven glutathione S-transferase (GST) genes from Venerupis philippinarum exposed to heavy metals and benzo[a]pyrene. AB - Glutathione S-transferases (GSTs) are phase II enzymes that facilitate the detoxification of xenobiotics, and also play important roles in antioxidant defense. In this study, we reported the cloning and molecular characteristics of seven genes of the GST family (VpGSTS1, VpGSTS2, VpGSTS3, VpGSTO, VpGSTMi, VpGSTM and VpGSTR) from Venerupis philippinarum together with mRNA tissue distribution patterns and temporal expression profiles in response to cadmium, copper and benzo[a]pyrene (B[a]P) exposures. The deduced amino acid sequences of VpGSTs showed high similarities to counterparts of other species that clustered into the same clades in the phylogenetic analysis. At basal levels of tissue expression, most VpGSTs were highly expressed in hepatopancreas compared with other tissues. All VpGSTs showed differential response profiles depending on the concentrations of various toxicants and exposure times. More notably, the expressions of VpGSTS2 and VpGSTS3 transcripts were significantly up-regulated in hepatopancreas from Cu and B[a]P-exposed animals, indicating that these two sigma VpGSTs were highly sensitive to Cu and B[a]P exposure. However, the expressions of VpGSTM and VpGSTR were significantly induced by Cu or B[a]P exposure, respectively. These findings suggested the role of VpGSTS2, VpGSTS3, VpGSTM and VpGSTR in defense against oxidative stress and highlighted their potential as biomarkers to Cu or B[a]P exposure. PMID- 22261037 TI - Tissue-specific accumulation and speciation of selenium in rainbow trout (Oncorhynchus mykiss) exposed to elevated dietary selenomethionine. AB - The toxicity of selenium in fish is influenced by its chemical speciation and the exposure route. In the natural environment, selenium exposure to fish occurs primarily in the form of selenomethionine in diet. Thus, the main objective of this study was to examine the tissue-specific selenium burden and speciation in fish exposed to elevated dietary selenomethionine. Rainbow trout (Oncorhynchus mykiss) were treated with dietary selenomethionine (40 MUg g(-1) dry mass) for 2 weeks, and at the end of the exposure different tissue samples were collected to assess the tissue-specific distribution and speciation of selenium. We used synchrotron-based X-ray absorption near edge spectroscopy (XANES) to determine the selenium speciation profile. Selenomethionine, selenocysteine and selenocystine were found to be the predominant form of selenium in all of the tissues; however their relative proportion varied across different tissues. In general, the organs primarily involved in selenium handling in fish (e.g., liver, kidney) accumulated a higher percentage of selenocystine. We also found that dietary selenomethionine exposure resulted into a marked increase in selenium burden of all major tissues in fish including the brain. Collectively, our findings provide new insights into the tissue-specific distribution and speciation of selenium in fish exposed to selenomethionine via diet. PMID- 22261038 TI - Examining potential risk factors for anxiety in early childhood. AB - Anxiety disorders are amongst the most prevalent psychiatric disorders in children and adolescents, with occurrence emerging early in the developmental trajectory. This study was one of the first to investigate potential risk factors for anxiety (i.e., behavioural inhibition, parental negative affect, parenting stress) in early childhood. Examination of risk factors was achieved through structural equation modelling and based on mothers' and fathers' report of 236 preschool aged children (4-6 years) in Brisbane, Australia. The structural model was found to fit the data well. All direct predictors of early childhood anxiety were significant and behavioural inhibition partially mediated parents' negative affectivity and mother's parenting stress. Results highlight the unique contribution of both parents in the aetiology of early childhood anxiety and assist in informing the development of intervention and prevention programs for young children. PMID- 22261039 TI - Interfacial effects on the optical behavior of Ge:ITO and Ge:ZnO nanocomposite films. AB - Nanophase semiconductors are of interest for their unique, size-tunable solar spectral absorption characteristics as well as their potential to contribute to the improved energy conversion efficiency of photovoltaics (PV). Embedding these nanoparticles within electrically active transparent conductive oxides (TCO) can also provide an opportunity for enhanced, long-range carrier transport. However, differences in the atomic and electronic structure, dielectric behavior, and chemistry between the matrix and semiconductor phases highlight the influence of interfacial effects on the optical absorption properties of the composite. In this work, nanocomposites of Ge:indium tin oxide (Ge:ITO) and Ge:ZnO were fabricated with sequential RF-magnetron sputtering and annealed at temperatures from 310 to 550 degrees C to investigate the impact of matrix identity on this interface and its contribution to nanostructure-mediated optical absorption. Transmission electron microscopy showed a decrease in Ge nanocrystal size relative to the initial semiconductor domain size in both matrices that was correlated with an increase in absorption onset energy after annealing. The effect was particularly pronounced in Ge:ITO composites in which Raman spectroscopy indicated the presence of germanium oxide at the semiconductor-ITO interface. These results support the primary contribution of carrier confinement in the Ge nanophase to the shifts in absorption onset energies observed. PMID- 22261040 TI - Invasive meningococcal capsular group Y disease, England and Wales, 2007-2009. AB - Enhanced national surveillance for invasive meningococcal disease in England and Wales identified an increase in laboratory-confirmed capsular group Y (MenY) disease from 34 cases in 2007 to 44 in 2008 and 65 in 2009. For cases diagnosed in 2009, patient median age at disease onset was 60 years; 39% of patients had underlying medical conditions, and 19% died. MenY isolates causing invasive disease during 2007-2009 belonged mainly to 1 of 4 clonal complexes (cc), cc23 (56% of isolates), cc174 (21%), cc167 (11%), and cc22 (8%). The 2009 increase resulted primarily from sequence type 1655 (cc23) (22 cases in 2009, compared with 4 cases each in 2007 and 2008). cc23 was associated with lpxL1 mutations and meningitis in younger age groups (<25 years); cc174 was associated with nonmeningitis, particularly pneumonia, in older age groups (>65 years). The increase in MenY disease requires careful epidemiologic and molecular monitoring. PMID- 22261041 TI - Hot and crowded: new insights into the dynamics of thermophilic enzymes from multiscale modeling. PMID- 22261042 TI - The layered structure of coronary adventitia under mechanical load. AB - The mechanical loading-deformation relation of elastin and collagen fibril bundles is fundamental to understanding the microstructural properties of tissue. Here, we use multiphoton microscopy to obtain quantitative data of elastin and collagen fiber bundles under in situ loading of coronary adventitia. Simultaneous loading-imaging experiments on unstained fresh coronary adventitia allowed morphometric measurements of collagen and elastin fibril bundles and their individual deformation. Fiber data were analyzed at five different distension loading points (circumferential stretch ratio lambda(theta) = 1.0, 1.2, 1.4, 1.6, and 1.8) at a physiological axial stretch ratio of lambda(axial) = 1.3. Four fiber geometrical parameters were used to quantify the fibers: orientation angle, waviness, width, and area fraction. The results show that elastin and collagen fibers in inner adventitia form concentric densely packed fiber sheets, and the fiber orientation angle, width, and area fraction vary transmurally. The extent of fiber deformation depends on the initial orientation angle at no-distension state (lambda(theta) = 1.0 and lambda(axial) = 1.3). At higher distension loading, the orientation angle and waviness of fibers decrease linearly, but the width of collagen fiber is relatively constant at lambda(theta) = 1.0-1.4 and then decrease linearly for lambda(theta) >= 1.4. A decrease of the relative dispersion (SD/mean) of collagen fiber waviness suggests a heterogeneous mechanical response to loads. This study provides fundamental microstructural data for coronary artery biomechanics and we consider it seminal for structural models. PMID- 22261043 TI - Effective models of periodically driven networks. AB - Circadian rhythms are governed by a highly coupled, complex network of genes. Due to feedback within the network, any modification of the system's state requires coherent changes in several nodes. A model of the underlying network is necessary to compute these modifications. We use an effective modeling approach for this task. Rather than inferred biochemical interactions, our method utilizes microarray data from a group of mutants for its construction. With simulated data, we develop an effective model for a circadian network in a peripheral tissue, subject to driving by the suprachiasmatic nucleus, the mammalian pacemaker. The effective network can predict time-dependent gene expression levels in other mutants. PMID- 22261044 TI - Substrate-dependent control of ERK phosphorylation can lead to oscillations. AB - The extracellular signal-regulated kinase (ERK) controls cellular processes by phosphorylating multiple substrates. The ERK protein can use the same domains to interact with phosphatases, which dephosphorylate and deactivate ERK, and with substrates, which connect ERK to its downstream effects. As a consequence, substrates can compete with phosphatases and control the level of ERK phosphorylation. We propose that this effect can qualitatively change the dynamics of a network that controls ERK activation. On its own, this network can be bistable, but in a larger system, where ERK accelerates the degradation of a substrate competing with a phosphatase, this network can oscillate. Previous studies proposed that oscillatory ERK signaling requires a negative feedback in which active ERK reduces the rate at which it is phosphorylated by upstream kinase. We argue that oscillations can also emerge even when this rate is constant, due to substrate-dependent control of ERK phosphorylation. PMID- 22261045 TI - PDCD5-regulated cell fate decision after ultraviolet-irradiation-induced DNA damage. AB - Programmed cell death 5 (PDCD5) is a human apoptosis-related molecule that is involved in both the cytoplasmic caspase-3 activity pathway (by regulating Bax translocation from cytoplasm to mitochondria) and the nuclear pathway (by interacting with Tip60). In this study, we developed a mathematical model of the PDCD5-regulated switching of the cell response from DNA repair to apoptosis after ultraviolet irradiation-induced DNA damage. We established the model by combining several hypotheses with experimental observations. Our simulations indicate that the ultimate cell response to DNA damage is dependent on a signal threshold mechanism, and the PDCD5 promotion of Bax translocation plays an essential role in PDCD5-regulated cell apoptosis. Furthermore, the model simulations revealed that PDCD5 nuclear translocation can attenuate cell apoptosis, and PDCD5 interactions with Tip60 can accelerate DNA damage-induced apoptosis, but the final cell fate decision is insensitive to the PDCD5-Tip60 interaction. These results are consistent with experimental observations. The effect of recombinant human PDCD5 was also investigated and shown to sensitize cells to DNA damage by promoting caspase-3 activity. PMID- 22261046 TI - Activated STAT1 transcription factors conduct distinct saltatory movements in the cell nucleus. AB - The activation of STAT transcription factors is a critical determinant of their subcellular distribution and their ability to regulate gene expression. Yet, it is not known how activation affects the behavior of individual STAT molecules in the cytoplasm and nucleus. To investigate this issue, we injected fluorescently labeled STAT1 in living HeLa cells and traced them by single-molecule microscopy. We determined that STAT1 moved stochastically in the cytoplasm and nucleus with very short residence times (<0.03 s) before activation. Upon activation, STAT1 mobility in the cytoplasm decreased ~2.5-fold, indicating reduced movement of STAT1/importinalpha/beta complexes to the nucleus. In the nucleus, activated STAT1 displayed a distinct saltatory mobility, with residence times of up to 5 s and intermittent diffusive motion. In this manner, activated STAT1 factors can occupy their putative chromatin target sites within ~2 s. These results provide a better understanding of the timescales on which cellular signaling and regulated gene transcription operate at the single-molecule level. PMID- 22261048 TI - Muller glial cell-provided cellular light guidance through the vital guinea-pig retina. AB - In vertebrate eyes, images are projected onto an inverted retina where light passes all retinal layers on its way to the photoreceptor cells. Light scattering within this tissue should impair vision. We show that radial glial (Muller) cells in the living retina minimize intraretinal light scatter and conserve the diameter of a beam that hits a single Muller cell endfoot. Thus, light arrives at individual photoreceptors with high intensity. This leads to an optimized signal/noise ratio, which increases visual sensitivity and contrast. Moreover, we show that the ratio between Muller cells and cones-responsible for acute vision is roughly 1. This suggests that high spatiotemporal resolution may be achieved by each cone receiving its part of the image via its individual Muller cell-light guide. PMID- 22261047 TI - A three-dimensional simulation model of cardiomyocyte integrating excitation contraction coupling and metabolism. AB - Recent studies have revealed that Ca(2+) not only regulates the contraction of cardiomyocytes, but can also function as a signaling agent to stimulate ATP production by the mitochondria. However, the spatiotemporal resolution of current experimental techniques limits our investigative capacity to understand this phenomenon. Here, we created a detailed three-dimensional (3D) cardiomyocyte model to study the subcellular regulatory mechanisms of myocardial energetics. The 3D cardiomyocyte model was based on the finite-element method, with detailed subcellular structures reproduced, and it included all elementary processes involved in cardiomyocyte electrophysiology, contraction, and ATP metabolism localized to specific loci. The simulation results were found to be reproducible and consistent with experimental data regarding the spatiotemporal pattern of cytosolic, intrasarcoplasmic-reticulum, and mitochondrial changes in Ca(2+); as well as changes in metabolite levels. Detailed analysis suggested that although the observed large cytosolic Ca(2+) gradient facilitated uptake by the mitochondrial Ca(2+) uniporter to produce cyclic changes in mitochondrial Ca(2+) near the Z-line region, the average mitochondrial Ca(2+) changes slowly. We also confirmed the importance of the creatine phosphate shuttle in cardiac energy regulation. In summary, our 3D model provides a powerful tool for the study of cardiac function by overcoming some of the spatiotemporal limitations of current experimental approaches. PMID- 22261049 TI - Measuring traction forces of motile dendritic cells on micropost arrays. AB - Dendritic cells (DCs) migrate from sites of inflammation to secondary lymphoid organs where they initiate the adaptive immune response. Although motility is essential to DC function, the mechanisms by which they migrate are not fully understood. We incorporated micropost array detectors into a microfluidic gradient generator to develop what we consider to be a novel method for probing low magnitude traction forces during directional migration. We found migration of primary murine DCs is driven by short-lived traction stresses at the leading edge or filopodia. The traction forces generated by DCs are smaller in magnitude than found in neutrophils, and of similar magnitude during chemotaxis and chemokinesis, at 18 +/- 1.4 and 16 +/- 1.3 nN/cell, respectively. The characteristic duration of local DC traction forces was 3 min. The maximum principal stress in the cell occurred in the plane perpendicular to the axis of motion, forward of the centroid. We illustrate that the spatiotemporal pattern of traction stresses can be used to predict the direction of future DC motion. Overall, DCs show a mode of migration distinct from both mesenchymal cells and neutrophils, characterized by rapid turnover of traction forces in leading filopodia. PMID- 22261050 TI - In situ mechanical analysis of myofibrillar perturbation and aging on soft, bilayered Drosophila myocardium. AB - Drosophila melanogaster is a genetically malleable organism with a short life span, making it a tractable system in which to study mechanical effects of genetic perturbation and aging on tissues, e.g., impaired heart function. However, Drosophila heart-tube studies can be hampered by its bilayered structure: a ventral muscle layer covers the contractile cardiomyocytes. Here we propose an atomic force microscopy-based analysis that uses a linearized-Hertz method to measure individual mechanical components of soft composite materials. The technique was verified using bilayered polydimethylsiloxane. We further demonstrated its biological utility via its ability to resolve stiffness changes due to RNA interference to reduce myofibrillar content or due to aging in Drosophila myocardial layers. This protocol provides a platform to assess the mechanics of soft biological composite systems and, to our knowledge, for the first time, permits direct measurement of how genetic perturbations, aging, and disease can impact cardiac function in situ. PMID- 22261051 TI - Timescales of IP(3)-evoked Ca(2+) spikes emerge from Ca(2+) puffs only at the cellular level. AB - The behavior of biological systems is determined by the properties of their component molecules, but the interactions are usually too complex to understand fully how molecular behavior generates cellular behavior. Ca(2+) signaling by inositol trisphosphate receptors (IP(3)R) offers an opportunity to understand this relationship because the cellular behavior is defined largely by Ca(2+) mediated interactions between IP(3)R. Ca(2+) released by a cluster of IP(3)R (giving a local Ca(2+) puff) diffuses and ignites the behavior of neighboring clusters (to give repetitive global Ca(2+) spikes). We use total internal reflection fluorescence microscopy of two mammalian cell lines to define the temporal relationships between Ca(2+) puffs (interpuff intervals, IPI) and Ca(2+) spikes (interspike intervals) evoked by flash photolysis of caged IP(3). We find that IPI are much shorter than interspike intervals, that puff activity is stochastic with a recovery time that is much shorter than the refractory period of the cell, and that IPI are not periodic. We conclude that Ca(2+) spikes do not arise from oscillatory dynamics of IP(3)R clusters, but that repetitive Ca(2+) spiking with its longer timescales is an emergent property of the dynamics of the whole cluster array. PMID- 22261052 TI - Modeling ion channels in the gigaseal. AB - The ability to form gigaseals is essential for patch-clamp electrophysiology; however, ion channels located in the seal can produce measureable currents. To explore the expected properties of channels in the seal (i.e., rim channels), we created a mathematical model. The seal was a two-dimensional cable filled with saline and bounded on one side by membrane (with resistance and capacitance) and on the other side by glass (nonconductive and noncapacitive). We included ion depletion/accumulation around the channels. The channels were ohmic with a conductance that increased with the concentration of permeant ions. The aqueous seal thickness was set nominally to 1 nm. Imaging with fluorescent dyes in the pipette showed that the hydrophilic dye Alexa 488 is impermeant, but lipophilic FM1-43 labels the seal. The model showed that to obtain high-resistance seals, the conductivity of the seal media has to be <10% that of the bath. Stimulus voltages decreased with distance down the seal. In agreement with results in the literature, channels in the seal can produce currents similar to those in the pipette-spanning dome. The transition times of currents are slower due to membrane capacitance. If channel densities are uniform, patch currents are dominated by channels in the dome. PMID- 22261053 TI - Modeling the binding of three toxins to the voltage-gated potassium channel (Kv1.3). AB - The conduction properties of the voltage-gated potassium channel Kv1.3 and its modes of interaction with several polypeptide venoms are examined using Brownian dynamics simulations and molecular dynamics calculations. Employing an open-state homology model of Kv1.3, we first determine current-voltage and current concentration curves and ascertain that simulated results accord with experimental measurements. We then investigate, using a molecular docking method and molecular dynamics simulations, the complexes formed between the Kv1.3 channel and several Kv-specific polypeptide toxins that are known to interfere with the conducting mechanisms of several classes of voltage-gated K(+) channels. The depths of potential of mean force encountered by charybdotoxin, alpha-KTx3.7 (also known as OSK1) and ShK are, respectively, -19, -27, and -25 kT. The dissociation constants calculated from the profiles of potential of mean force correspond closely to the experimentally determined values. We pinpoint the residues in the toxins and the channel that are critical for the formation of the stable venom-channel complexes. PMID- 22261054 TI - Single-channel monitoring of reversible L-type Ca(2+) channel Ca(V)alpha(1) Ca(V)beta subunit interaction. AB - Voltage-dependent Ca(2+) channels are heteromultimers of Ca(V)alpha(1) (pore), Ca(V)beta- and Ca(V)alpha(2)delta-subunits. The stoichiometry of this complex, and whether it is dynamically regulated in intact cells, remains controversial. Fortunately, Ca(V)beta-isoforms affect gating differentially, and we chose two extremes (Ca(V)beta(1a) and Ca(V)beta(2b)) regarding single-channel open probability to address this question. HEK293alpha(1C) cells expressing the Ca(V)1.2 subunit were transiently transfected with Ca(V)alpha(2)delta1 alone or with Ca(V)beta(1a), Ca(V)beta(2b), or (2:1 or 1:1 plasmid ratio) combinations. Both Ca(V)beta-subunits increased whole-cell current and shifted the voltage dependence of activation and inactivation to hyperpolarization. Time-dependent inactivation was accelerated by Ca(V)beta(1a)-subunits but not by Ca(V)beta(2b) subunits. Mixtures induced intermediate phenotypes. Single channels sometimes switched between periods of low and high open probability. To validate such slow gating behavior, data were segmented in clusters of statistically similar open probability. With Ca(V)beta(1a)-subunits alone, channels mostly stayed in clusters (or regimes of alike clusters) of low open probability. Increasing Ca(V)beta(2b)-subunits (co-)expressed (1:2, 1:1 ratio or alone) progressively enhanced the frequency and total duration of high open probability clusters and regimes. Our analysis was validated by the inactivation behavior of segmented ensemble averages. Hence, a phenotype consistent with mutually exclusive and dynamically competing binding of different Ca(V)beta-subunits is demonstrated in intact cells. PMID- 22261055 TI - Permeation and block of the Kv1.2 channel examined using brownian and molecular dynamics. AB - Using both Brownian and molecular dynamics, we replicate many of the salient features of Kv1.2, including the current-voltage-concentration profiles and the binding affinity and binding mechanisms of charybdotoxin, a scorpion venom. We also elucidate how structural differences in the inner vestibule can give rise to significant differences in its permeation characteristics. Current-voltage concentration profiles are constructed using Brownian dynamics simulations, based on the crystal structure 2A79. The results are compatible with experimental data, showing similar conductance, rectification, and saturation with current. Unlike KcsA, for example, the inner pore of Kv1.2 is mainly hydrophobic and neutral, and to explore the consequences of this, we investigate the effect of mutating neutral proline residues at the mouth of the inner vestibule to charged aspartate residues. We find an increased conductance, less inward rectification, and quicker saturation of the current-voltage profile. Our simulations use modifications to our Brownian dynamics program that extend the range of channels that can be usefully modeled. Using molecular dynamics, we investigate the binding of the charybdotoxin scorpion venom to the outer vestibule of the channel. A potential of mean force is derived using umbrella sampling, giving a dissociation constant within a factor of ~2 to experimentally derived constants. The residues involved in the toxin binding are in agreement with experimental mutagenesis studies. We thus show that the experimental observations on the voltage-gated channel, including the toxin-channel interaction, can reliably be replicated by using the two widely used computational tools. PMID- 22261056 TI - Rapid assembly of a multimeric membrane protein pore. AB - We have observed the assembly of the staphylococcal pore-forming toxin alpha hemolysin using single-molecule fluorescence imaging. Surprisingly, assembly from the monomer to the complete heptamer is extremely rapid, occurring in <5 ms. No lower order oligomeric intermediates are detected. Monte Carlo simulation of our experiment shows that assembly is diffusion limited, and pore formation is dependent on the stability of intermediate species. There are close similarities between bacterial pore-forming toxins, such as staphylococcal alpha-hemolysin, the anthrax protective antigen, and the cholesterol-dependent cytolysins, and their eukaryotic analogs, such as the complement pore membrane attack complex and perforin domain. The assembly mechanism we have observed for alpha-hemolysin provides a simple model that aids our understanding of these important pore formers. PMID- 22261057 TI - The effect of environment on the recognition and binding of vancomycin to native and resistant forms of lipid II. AB - Molecular dynamics simulations and free energy calculations have been used to examine in detail the mechanism by which a receptor molecule (the glycopeptide antibiotic vancomycin) recognizes and binds to a target molecule (lipid II) embedded within a membrane environment. The simulations show that the direct interaction of vancomycin with lipid II, as opposed to initial binding to the membrane, leads most readily to the formation of a stable complex. The recognition of lipid II by vancomycin occurred via the N-terminal amine group of vancomycin and the C-terminal carboxyl group of lipid II. Despite lying at the membrane-water interface, the interaction of vancomycin with lipid II was found to be essentially identical to that of soluble tripeptide analogs of lipid II (Ac d-Ala-d-Ala; root mean-square deviation 0.11 nm). Free energy calculations also suggest that the relative binding affinity of vancomycin for native, resistant, and synthetic forms of membrane-bound lipid II was unaffected by the membrane environment. The effect of the dimerization of vancomycin on the binding of lipid II, the position of lipid II within a biological membrane, and the effect of the isoamylene tail of lipid II on membrane fluidity have also been examined. PMID- 22261058 TI - Intermembrane docking reactions are regulated by membrane curvature. AB - The polymorphism of eukaryotic cellular membranes is a tightly regulated and well conserved phenotype. Recent data have revealed important regulatory roles of membrane curvature on the spatio-temporal localization of proteins and in membrane fusion. Here we quantified the influence of membrane curvature on the efficiency of intermembrane docking reactions. Using fluorescence microscopy, we monitored the docking of single vesicle-vesicle pairs of different diameter (30 200 nm) and therefore curvature, as mediated by neuronal soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) and streptavidin-biotin. Surprisingly, the intermembrane docking efficiency exhibited an ~30-60 fold enhancement as a function of curvature. In comparison, synaptotagmin and calcium accelerate SNARE-mediated fusion in vitro by a factor of 2-10. To explain this finding, we formulated a biophysical model. On the basis of our findings, we propose that membrane curvature can regulate intermembrane tethering reactions and consequently any downstream process, including the fusion of vesicles and possibly viruses with their target membranes. PMID- 22261059 TI - Water adsorption isotherms of lipids. AB - Hydration of bilayer lipids is a fundamental property of biological membranes. The available database of lipid hydration isotherms is fitted over the entire range of water activities by using a statistical mechanical approach that is an extension of the common Brunauer-Emmett-Teller model, to include differential energies of association for water molecules beyond the first strongly bound layer. Three-parameter fits are obtained that can be used to represent the experimental isotherms to a good degree of accuracy over the complete range of water-binding activities. Fits are also made in terms of the hydration pressure and correlation length of water ordering, by using the polarization theory of lipid hydration. The relationship of the latter approach to measurements of hydration forces between lipid bilayers is discussed. PMID- 22261060 TI - Self-segregation of myelin membrane lipids in model membranes. AB - Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are multilamellar, lipid-rich membranes produced by oligodendrocytes in the central nervous system. To act as an insulator, myelin has to form a stable and firm membrane structure. In this study, we have analyzed the biophysical properties of myelin membranes prepared from wild-type mice and from mouse mutants that are unable to form stable myelin. Using C-Laurdan and fluorescence correlation spectroscopy, we find that lipids are tightly organized and highly ordered in myelin isolated from wild-type mice, but not from shiverer and ceramide synthase 2 null mice. Furthermore, only myelin lipids from wild-type mice laterally segregate into physically distinct lipid phases in giant unilamellar vesicles in a process that requires very long chain glycosphingolipids. Taken together, our findings suggest that oligodendrocytes exploit the potential of lipids to self-segregate to generate a highly ordered membrane for electrical insulation of axons. PMID- 22261061 TI - Solid character of membrane ceramides: a surface rheology study of their mixtures with sphingomyelin. AB - The compression and shear viscoelasticities of egg-ceramide and its mixtures with sphingomyelin were investigated using oscillatory surface rheology performed on Langmuir monolayers. We found high values for the compression and shear moduli for ceramide, compatible with a solid-state membrane, and extremely high surface viscosities when compared to typical fluid lipids. A fluidlike rheological behavior was found for sphingomyelin. Lateral mobilities, measured from particle tracking experiments, were correlated with the monolayer viscosities through the usual hydrodynamic relationships. In conclusion, ceramide increases the solid character of sphingomyelin-based membranes and decreases their fluidity, thus drastically decreasing the lateral mobilities of embedded objects. This mechanical behavior may involve important physiological consequences in biological membranes containing ceramides. PMID- 22261062 TI - EphA2 receptor activation by monomeric Ephrin-A1 on supported membranes. AB - The receptor tyrosine kinase EphA2 interacts with its glycosylphosphatidylinositol (GPI)-linked ephrin-A1 ligand in a juxtacrine configuration. The soluble ephrin-A1 protein, without its GPI membrane linker, fails to activate EphA2. However, preclustered ephrin-A1 protein is active in solution and has been frequently used to trigger the EphA2 receptor. Although this approach has yielded insights into EphA2 signaling, preclustered ligands bypass natural receptor clustering processes and thus mask any role of clustering as a signal regulatory mechanism. Here, we present EphA2-expressing cells with a fusion protein of monomeric ephrin-A1 (mEA1) and enhanced monomeric yellow fluorescent protein that is linked to a supported lipid bilayer via a nickel decahistidine anchor. The mEA1 is homogeneously dispersed, laterally mobile, and monomeric as measured by fluorescence imaging, correlation spectroscopy, and photon counting histogram analysis, respectively. Ephrin-A1 presented in this manner activates EphA2 on the surface of MDA-MB-231 human breast cancer cells, as measured by EphA2 phosphorylation and degradation. Spatial mutation experiments in which nanopatterns on the underlying substrate restrict mEA1 movement in the supported lipid bilayer reveal spatio-mechanical regulation of this signaling pathway, consistent with recently reported observations using a synthetically cross-linked ephrin-A1 dimer. PMID- 22261063 TI - Quasiperiodic distribution of rigor cross-bridges along a reconstituted thin filament in a skeletal myofibril. AB - Electron microscopy has shown that cross-bridges (CBs) are formed at the target zone that is periodically distributed on the thin filament in striated muscle. Here, by manipulating a single bead-tailed actin filament with optical tweezers, we measured the unbinding events of rigor CBs one by one on the surface of the A band in rabbit skeletal myofibrils. We found that the spacings between adjacent CBs were not always the same, and instead were 36, 72, or 108 nm. Tropomyosin and troponin did not affect the CB spacing except for a relative increase in the appearance of longer spacing in the presence of Ca(2+). In addition, in an in vitro assay where myosin molecules were randomly distributed, were obtained the same spacing, i.e., a multiple of 36 nm. These results indicate that the one dimensional distribution of CBs matches with the 36-nm half pitch of a long helical structure of actin filaments. A stereospecific model composed of three actin protomers per target zone was shown to explain the experimental results. Additionally, the unbinding force (i.e., the binding affinity) of CBs for the reconstituted thin filaments was found to be larger and smaller relative to that for actin filaments with and without Ca(2+), respectively. PMID- 22261064 TI - A structural perspective on the dynamics of kinesin motors. AB - Despite significant fluctuation under thermal noise, biological machines in cells perform their tasks with exquisite precision. Using molecular simulation of a coarse-grained model and theoretical arguments, we envisaged how kinesin, a prototype of biological machines, generates force and regulates its dynamics to sustain persistent motor action. A structure-based model, which can be versatile in adapting its structure to external stresses while maintaining its native fold, was employed to account for several features of kinesin dynamics along the biochemical cycle. This analysis complements our current understandings of kinesin dynamics and connections to experiments. We propose a thermodynamic cycle for kinesin that emphasizes the mechanical and regulatory role of the neck linker and clarify issues related to the motor directionality, and the difference between the external stalling force and the internal tension responsible for the head-head coordination. The comparison between the thermodynamic cycle of kinesin and macroscopic heat engines highlights the importance of structural change as the source of work production in biomolecular machines. PMID- 22261065 TI - The loop 5 element structurally and kinetically coordinates dimers of the human kinesin-5, Eg5. AB - Eg5 is a homotetrameric kinesin-5 motor protein that generates outward force on the overlapping, antiparallel microtubules (MTs) of the mitotic spindle. Upon binding an MT, an Eg5 dimer releases one ADP molecule, undergoes a slow (~0.5 s( 1)) isomerization, and finally releases a second ADP, adopting a tightly MT bound, nucleotide-free (APO) conformation. This conformation precedes ATP binding and stepping. Here, we use mutagenesis, steady-state and pre-steady-state kinetics, motility assays, and electron paramagnetic resonance spectroscopy to examine Eg5 monomers and dimers as they bind MTs and initiate stepping. We demonstrate that a critical element of Eg5, loop 5 (L5), accelerates ADP release during the initial MT-binding event. Furthermore, our electron paramagnetic resonance data show that L5 mediates the slow isomerization by preventing Eg5 dimer heads from binding the MT until they release ADP. Finally, we find that Eg5 having a seven-residue deletion within L5 can still hydrolyze ATP and move along MTs, suggesting that L5 is not required to accelerate subsequent steps of the motor along the MT. Taken together, these properties of L5 explain the kinetic effects of L5-directed inhibition on Eg5 activity and may direct further interventions targeting Eg5 activity. PMID- 22261066 TI - Improving protein template recognition by using small-angle x-ray scattering profiles. AB - Small-angle x-ray scattering (SAXS) is able to extract low-resolution protein shape information without requiring a specific crystal formation. However, it has found little use in atomic-level protein structure determination due to the uncertainty of residue-level structural assignment. We developed a new algorithm, SAXSTER, to couple the raw SAXS data with protein-fold-recognition algorithms and thus improve template-based protein-structure predictions. We designed nine different matching scoring functions of template and experimental SAXS profiles. The logarithm of the integrated correlation score showed the best template recognition ability and had the highest correlation with the true template modeling (TM)-score of the target structures. We tested the method in large-scale protein-fold-recognition experiments and achieved significant improvements in prioritizing the best template structures. When SAXSTER was applied to the proteins of asymmetric SAXS profile distributions, the average TM-score of the top-ranking templates increased by 18% after homologous templates were excluded, which corresponds to a p-value < 10(-9) in Student's t-test. These data demonstrate a promising use of SAXS data to facilitate computational protein structure modeling, which is expected to work most efficiently for proteins of irregular global shape and/or multiple-domain protein complexes. PMID- 22261067 TI - Crowding induces differences in the diffusion of thermophilic and mesophilic proteins: a new look at neutron scattering results. AB - The dynamical basis underlying the increased thermal stability of thermophilic proteins remains uncertain. Here, we challenge the new paradigm established by neutron scattering experiments in solution, in which the adaptation of thermophilic proteins to high temperatures lies in the lower sensitivity of their flexibility to temperature changes. By means of a combination of molecular dynamics and Brownian dynamics simulations, we report a reinterpretation of those experiments and show evidence that under crowding conditions, such as in vivo, thermophilic and homolog mesophilic proteins have diffusional properties with different thermal behavior. PMID- 22261068 TI - Nucleation of sickle hemoglobin mixed with hemoglobin A: experimental and theoretical studies of hybrid-forming mixtures. AB - Sickle hemoglobin (HbS) is a point mutation of the two beta subunits in normal Hb (HbA) that leads to nucleated polymerization and accompanying pathology. We measured the rates of homogeneous and heterogeneous nucleation of HbS in the presence of up to 50% HbA under conditions in which hybrid HbAS molecules will also form. The replacement of 50% of HbS by HbA slows polymerization by factors of ~100 in the physiological range, which is substantially less than previously thought. To provide a theoretical description of these data, we extended the double nucleation model for HbS polymerization to conditions in which hybridized mixtures are present. Measurements of homogeneous nucleation and the theory agree only when at least one of the molecules in the nucleus is not a hybrid. We attribute this to the necessary presence in the nucleus of a molecule that utilizes both beta-subunit mutation sites in intermolecular contacts, whereas the remaining molecules engage only one of the mutation sites. Heterogeneous nucleation appears to require an even greater number of nonhybrid molecules, presumably because of the need for the nucleus to attach to the polymer as well as to form internal bonds. These results also provide insights into the pathophysiology of sickle cell disease, including the occasional severe events that strike persons in whom both HbS and HbA are expressed, a condition known as sickle trait. The studies reported here are necessary for understanding physiologically relevant polymerization in the presence of ligands as well as therapeutically relevant copolymerizing inhibitors. PMID- 22261069 TI - Salt effects on the conformational stability of the visual G-protein-coupled receptor rhodopsin. AB - Membrane protein stability is a key parameter with important physiological and practical implications. Inorganic salts affect protein stability, but the mechanisms of their interactions with membrane proteins are not completely understood. We have undertaken the study of a prototypical G-protein-coupled receptor, the alpha-helical membrane protein rhodopsin from vertebrate retina, and explored the effects of inorganic salts on the thermal decay properties of both its inactive and photoactivated states. Under high salt concentrations, rhodopsin significantly increased its activation enthalpy change for thermal bleaching, whereas acid denaturation affected the formation of a denatured loose bundle state for both the active and inactive conformations. This behavior seems to correlate with changes in protonated Schiff-base hydrolysis. However, chromophore regeneration with the 11-cis-retinal chromophore and MetarhodopsinII decay kinetics were slower only in the presence of sodium chloride, suggesting that in this case, the underlying phenomenon may be linked to the activation of rhodopsin and the retinal release processes. Furthermore, the melting temperature, determined by means of circular dichroism and differential scanning calorimetry measurements, was increased in the presence of high salt concentrations. The observed effects on rhodopsin could indicate that salts favor electrostatic interactions in the retinal binding pocket and indirectly favor hydrophobic interactions at the membrane protein receptor core. These effects can be exploited in applications where the stability of membrane proteins in solution is highly desirable. PMID- 22261070 TI - Analyzing the homeostasis of signaling proteins by a combination of Western blot and fluorescence correlation spectroscopy. AB - The determination of intracellular protein concentrations is a prerequisite for understanding protein interaction networks in systems biology. Today, protein quantification is based either on mass spectrometry, which requires large cell numbers and sophisticated measurement protocols, or on quantitative Western blotting, which requires the expression and purification of a recombinant protein as a reference. Here, we present a method that uses a transiently expressed fluorescent fusion protein of the protein-of-interest as an easily accessible reference in small volumes of crude cell lysates. The concentration of the fusion protein is determined by fluorescence correlation spectroscopy, and this concentration is used to calibrate the intensity of bands on a Western blot. We applied this method to address cellular protein homeostasis by determining the concentrations of the plasma membrane-located transmembrane scaffolding protein LAT and soluble signaling proteins in naive T cells and transformed T-cell lymphoma (Jurkat) cells (with the latter having nine times the volume of the former). Strikingly, the protein numbers of soluble proteins scaled with the cell volume, whereas that of the transmembrane protein LAT scaled with the membrane surface. This leads to significantly different stoichiometries of signaling proteins in transformed and naive cells in concentration ranges that may translate directly into differences in complex formation. PMID- 22261071 TI - Crystal structure of a trapped catalytic intermediate suggests that forced atomic proximity drives the catalysis of mIPS. AB - 1-L-myo-inositol-phosphate synthase (mIPS) catalyzes the first step of the unique, de novo pathway of inositol biosynthesis. However, details about the complex mIPS catalytic mechanism, which requires oxidation, enolization, intramolecular aldol cyclization, and reduction, are not fully known. To gain further insight into this mechanism, we determined the crystal structure of the wild-type mIPS from Archaeoglobus fulgidus at 1.7 A, as well as the crystal structures of three active-site mutants. Additionally, we obtained the structure of mIPS with a trapped 5-keto-glucose-6-phosphate intermediate at 2 A resolution by a novel (to our knowledge) process of activating the crystal at high temperature. A comparison of all of the crystal structures of mIPS described in this work suggests a novel type of catalytic mechanism that relies on the forced atomic proximity of functional groups. The lysine cluster is contained in a small volume in the active site, where random motions of these side chains are responsible for the progress of the complex multistep reaction as well as for the low rate of catalysis. The mechanism requires that functional groups of Lys-274, Lys-278, Lys-306, and Lys-367 assume differential roles in the protonation/deprotonation steps that must occur during the mIPS reaction. This mechanism is supported by the complete loss of activity of the enzyme caused by the Leu-257 mutation to Ala that releases the lysine containment. PMID- 22261072 TI - Zn(++) binding disrupts the Asp(23)-Lys(28) salt bridge without altering the hairpin-shaped cross-beta Structure of Abeta(42) amyloid aggregates. AB - Observations like high Zn(2+) concentrations in senile plaques found in the brains of Alzheimer's patients and evidences emphasizing the role of Zn(2+) in amyloid-beta (Abeta)-induced toxicity have triggered wide interest in understanding the nature of Zn(2+)-Abeta interaction. In vivo and in vitro studies have shown that aggregation kinetics, toxicity, and morphology of Abeta aggregates are perturbed in the presence of Zn(2+). Structural studies have revealed that Zn(2+) has a binding site in the N-terminal region of monomeric Abeta, but not much is precisely known about the nature of binding of Zn(2+) with aggregated forms of Abeta or its effect on the molecular structure of these aggregates. Here, we explore this aspect of the Zn(2+)-Abeta interaction using one- and two-dimensional (13)C and (15)N solid-state NMR. We find that Zn(2+) causes major structural changes in the N-terminal and the loop region connecting the two beta-sheets. It breaks the salt bridge between the side chains of Asp(23) and Lys(28) by driving these residues into nonsalt-bridge-forming conformations. However, the cross-beta structure of Abeta(42) aggregates remains unperturbed though the fibrillar morphology changes distinctly. We conclude that the salt bridge is not important for defining the characteristic molecular architecture of Abeta(42) but is significant for determining its fibrillar morphology and toxicity. PMID- 22261073 TI - Active trans-plasma membrane water cycling in yeast is revealed by NMR. AB - Plasma membrane water transport is a crucial cellular phenomenon. Net water movement in response to an osmotic gradient changes cell volume. Steady-state exchange of water molecules, with no net flux or volume change, occurs by passive diffusion through the phospholipid bilayer and passage through membrane proteins. The hypothesis is tested that plasma membrane water exchange also correlates with ATP-driven membrane transport activity in yeast (Saccharomyces cerevisiae). Longitudinal (1)H(2)O NMR relaxation time constant (T(1)) values were measured in yeast suspensions containing extracellular relaxation reagent. Two-site-exchange analysis quantified the reversible exchange kinetics as the mean intracellular water lifetime (tau(i)), where tau(i)(-1) is the pseudo-first-order rate constant for water efflux. To modulate cellular ATP, yeast suspensions were bubbled with 95%O(2)/5%CO(2) (O(2)) or 95%N(2)/5%CO(2) (N(2)). ATP was high during O(2), and tau(i)(-1) was 3.1 s(-1) at 25 degrees C. After changing to N(2), ATP decreased and tau(i)(-1) was 1.8 s(-1). The principal active yeast ion transport protein is the plasma membrane H(+)-ATPase. Studies using the H(+)-ATPase inhibitor ebselen or a yeast genetic strain with reduced H(+)-ATPase found reduced tau(i)(-1), notwithstanding high ATP. Steady-state water exchange correlates with H(+)-ATPase activity. At volume steady state, water is cycling across the plasma membrane in response to metabolic transport activity. PMID- 22261074 TI - Measuring kinetic dissociation/association constants between Lactococcus lactis bacteria and mucins using living cell probes. AB - In this work we focused on quantifying adhesion between Lactococcus lactis, the model for lactic acid bacteria (LAB) and mucins. Interactions between two strains of L. lactis (IBB477 and MG1820 as control) and pig gastric mucin-based coating were measured and compared with the use of atomic force microscopy. Analysis of retraction force-distance curves shed light on the differential contributions of nonspecific and specific forces. An increased proportion of specific adhesive events was obtained for IBB477 (20% vs. 5% for the control). Blocking assays with free pig gastric mucin and its O-glycan moiety showed that oligosaccharides play a major (but not exclusive) role in L. lactis-mucins interactions. Specific interactions were analyzed in terms of kinetic constants. An increase in the loading rate of atomic force microscope tip led to a higher force between interacting biological entities, which was directly linked to the kinetic dissociation constant (K(off)). Enhancing the contact time between the tip and the sample allowed an increase in the interaction probability, which can be related to the kinetic association constant (K(on)). Variations in the loading rate and contact time enabled us to determine K(on) (3.3 * 10(2) M(-1).s(-1)) and K(off) (0.46 s(-1)), and the latter was consistent with values given in the literature for sugar-protein interactions. PMID- 22261075 TI - Quantum dot fluorescence characterizes the nanoscale organization of T cell receptors for antigen. AB - Changes in the clustering of surface receptors modulate cell responses to ligands. Hence, global measures of receptor clustering can be useful for characterizing cell states. Using T cell receptor for antigen as an example, we show that k-space image correlation spectroscopy of quantum dots blinking detects T cell receptor clusters on a scale of tens of nanometers and reports changes in clustering after T cell activation. Our results offer a general approach to the global analysis of lateral organization and receptor clustering in single cells, and can thus be applied when the cell type of interest is rare. PMID- 22261076 TI - Limitations of electronic energy transfer in the determination of lipid nanodomain sizes. AB - Even though superresolution microscopy indicates that size of plasma membrane rafts is <20 nm, those structures have never been observed. Forster resonance energy transfer (FRET) is therefore still the most powerful optical method for characterization of such domains. In this letter we investigate relation between nanodomain affinity of a donor-acceptor (D/A) pair and the detectable nanodomain size/area. We show that probes with high affinity to the liquid-ordered (L(o)) phase are required for detecting domain sizes of a few nanometers, and/or domains that occupy a few percent of the bilayer area. A combination of donors and acceptors that prefer different phases is the more favorable approach. For instance, a D/A pair with the distribution constant of donors K(D) = 5 and acceptors K(A) = 0.01 can resolve a broad spectrum of nanodomain sizes. On the other hand, currently available donors and acceptors that prefer the same phase, either the liquid-disordered (L(d)) or L(o) phase, are not so convenient for determining domain sizes <20 nm. Here the detection limits of FRET experiments employing several commonly used D/A pairs have been investigated. PMID- 22261077 TI - Ketogenic diet in early myoclonic encephalopathy due to non ketotic hyperglycinemia. AB - Non ketotic hyperglycinemia is a rare inborn error of glycine metabolism due to deficient activity of glycine cleavage system, a multienzymatic complex consisting of four protein subunits: the P-protein, the H-protein, the T-protein and the L-protein. The neonatal form of non ketotic hyperglycinemia presents in the first days of life with encephalopathy, seizures, multifocal myoclonus and characteristic "hiccups". Rapid progression may lead to intractable seizures, coma and respiratory failure requiring mechanical ventilation. Clinical trial with scavenges drugs decreasing glycine levels such as sodium benzoate, and with drugs reducing NMDA receptors excitatory properties, such as ketamine and dextromethorphan, have been tried but the outcome is usually poor; antiepileptic therapy, moreover, is unable to control epileptic seizures. Ketogenic diet has been successfully tried for refractory epilepsy in pediatric patients. We report three cases affected by neonatal non ketotic hyperglycinemia and early myoclonic encephalopathy treated with ketogenic diet. In our patients ketogenic diet, in association with standard pharmacological therapy, determined dramatic reduction of seizures and improved quality of life. PMID- 22261078 TI - Auditory-perceptual speech analysis in children with cerebellar tumours: a long term follow-up study. AB - Mutism and Subsequent Dysarthria (MSD) and the Posterior Fossa Syndrome (PFS) have become well-recognized clinical entities which may develop after resection of cerebellar tumours. However, speech characteristics following a period of mutism have not been documented in much detail. This study carried out a perceptual speech analysis in 24 children and adolescents (of whom 12 became mute in the immediate postoperative phase) 1-12.2 years after cerebellar tumour resection. The most prominent speech deficits in this study were distorted vowels, slow rate, voice tremor, and monopitch. Factors influencing long-term speech disturbances are presence or absence of postoperative PFS, the localisation of the surgical lesion and the type of adjuvant treatment. Long-term speech deficits may be present up to 12 years post-surgery. The speech deficits found in children and adolescents with cerebellar lesions following cerebellar tumour surgery do not necessarily resemble adult speech characteristics of ataxic dysarthria. PMID- 22261079 TI - Expression of N-methyl-d-aspartate receptor 1 and its phosphorylated state in basal ganglia of a neonatal piglet hypoxic-ischemic brain injury model: a controlled study of (1)H MRS. AB - Excitatory amino acids (EAAs) and excitotoxicity medicated by receptors of these amino acids play an important role in hypoxic-ischemic brain injury (HIBI), but most studies were ex vivo experiments, the mechanism in vivo is not well understood. We sought to study the expression of N-methyl-d-aspartate receptor 1 (NR1) and phosphorylated N-methyl-d-aspartate receptor 1 (P-NR1) in basal ganglia in a piglet model of HIBI and to investigate the correlation between Glx(Glu/Gln) value measured by magnetic resonance spectroscopy (MRS) and NR1/P-NR1 expression. Multi-voxel (1)H MRS was applied to detect change in Glx in basal ganglia of the newborn piglets in vivo. Automatic amino acid analyzer was applied to accurately quantify the Glu concentration. Immunohistochemical method was used to examine the expression of NR1 and P-NR1. The NR1 receptors in basal ganglia of the newborn piglets were significantly activated after HIBI. P-NR1 expression in the basal ganglia was consistent with the change in brain Glu content, so the activation status of NMDA receptor in the brain could be indirectly reflected by beta-, gamma-Glx/NAA measured by (1)H MRS. PMID- 22261081 TI - The plague of Thebes, a historical epidemic in Sophocles' Oedipus Rex. AB - Sophocles, one of the most noted playwrights of the ancient world, wrote the tragedy Oedipus Rex in the first half of the decade 430-420 bc. A lethal plague is described in this drama. We adopted a critical approach to Oedipus Rex in analyzing the literary description of the disease, unraveling its clinical features, and defining a possible underlying cause. Our goals were to clarify whether the plague described in Oedipus Rex reflects an actual historical event; to compare it with the plague of Athens, which was described by Thucydides as occurring around the same time Sophocles wrote; and to propose a likely causative pathogen. A critical reading of Oedipus Rex and a comparison with Thucydides' history, as well as a systematic review of historical data, strongly suggests that this epidemic was an actual event, possibly caused by Brucella abortus. PMID- 22261080 TI - Clinical outcomes, quality of life, and costs associated with implantation of vagus nerve stimulation therapy in pediatric patients with drug-resistant epilepsy. AB - BACKGROUND: VNS (Vagus Nerve Stimulation Therapy) is approved in the USA to treat refractory epilepsy as adjunctive to antiepileptic drugs (AEDs) in patients >=12 years with complex partial seizures. AIMS: To evaluate clinical outcomes, quality adjusted life years (QALY), and costs associated with VNS in pediatric patients with drug-resistant epilepsy in a real-world setting. METHODS: A retrospective analysis was conducted using Medicaid data (USA). Patients had >=1 neurologist visits with epilepsy diagnosis (ICD-9 345.xx, 780.3x), >=1 procedure claims for VNS implantation, >=1 AEDs, >=6-months of Pre- and Post-VNS continuous enrollment. Pre-VNS period was 6-months and Post-VNS period extended from implantation until device removal, death, Medicaid disenrollment, or study end (up to 3 years). Incidence rate ratios (IRR) and costs ($2010) were estimated. QALYs were estimated using number of seizure-related events. RESULTS: For patients 1-11 years old (N = 238), hospitalizations and emergency room visits were reduced Post-VNS vs. Pre-VNS (adjusted IRR = 0.73 [95% CI: 0.61-0.88] and 0.74 [95% CI: 0.65-0.83], respectively). Average total healthcare costs were lower Post-VNS vs. Pre-VNS ($18,437 vs. $18,839 quarterly [adjusted p = 0.052]). For patients 12-17 years old (N = 207), hospitalizations and status epilepticus events were reduced Post-VNS vs. Pre-VNS (adjusted IRR = 0.43 [95% CI: 0.34-0.54] and 0.25 [95% CI: 0.16-0.39], respectively). Average total healthcare costs were lower Post-VNS vs. Pre-VNS period ($14,546 vs. $19,695 quarterly [adjusted p = 0.002]). Lifetime QALY gain after VNS was 5.96 (patients 1-11 years) and 4.82 years (patients 12-17 years). CONCLUSIONS: VNS in pediatric patients is associated with decreased resource use and epilepsy-related events, cost savings, and QALY gain. PMID- 22261082 TI - Biomechanical comparison of different acetabular plate systems and constructs- the role of an infra-acetabular screw placement and use of locking plates. AB - INTRODUCTION: The aim of this study was the direct comparison of the static fixation strength of two common plate systems: MPS (Matta Pelvic System) and LPPS (Low Profile Plate System). Furthermore the role of a modified screw placement with addressing the infra-acetabular corridor and the use of locking screws were evaluated. MATERIALS AND METHODS: Custom made anterior column fractures in artificial SYNBONE pelves were fixed with different acetabular plates (group I: MPS, group II: LPPS none locking and group III: LPPS locking). Each pelvis was tested twice, with the additionally placed infra-acetabular lag screw [+] first, followed by a repeated measurement without the infra-acetabular screw [-]. Six pelves per group were tested under static loading with six cycles up to 800N, each. The fracture displacement was measured in the weight bearing dome using an ultrasound based Zebris-3D-Motion Analyzer. RESULTS: The MPS-plate had a less fixation strength compared to the LPPS-plate (mean+/-SD of maximum fracture displacement [mm] in group I vs. group II=0.63+/-0.02 vs. 0.37+/-0.02, p<0.05). The locking feature did not increase the fracture fixation strength (mean+/-SD of maximum fracture displacement [mm] in group II vs. group III: 0.37+/-0.02 vs. 0.37+/-0.03; ns). The infra-acetabular screw significantly reduces the maximum fracture displacement in all groups, independent of the plate systems ([Delta%] in group I=50; group II=63 and group III=40; p<0.05 each). CONCLUSION: The LPPS plate performed superior fixation strength for anterior column fractures compared to the MPS-plate. The locking plate modality did not reduce the maximum fracture displacement, whereas the additional infra-acetabular screw placement actually doubles the fracture fixation strength independent of the used plate system. PMID- 22261083 TI - Secondary hyperparathyroidism and mortality in hip fracture patients compared to a control group from general practice. AB - INTRODUCTION: Previously, little attention has been paid as to how disturbances in the parathyroid hormone (PTH)-calcium-vitamin D-axis, such as secondary hyperparathyroidism (SHPT), relate to mortality amongst hip fracture patients. This study aimed to (1) determine if SHPT is associated with mortality in this group of patients, (2) investigate the association between serum (s-) PTH, s total calcium, s-25-hydroxyvitamin D (s-25(OH)D) and mortality and (3) determine the prevalence of SHPT amongst hip fracture patients and a control group. METHOD: The study included 562 hip fracture patients (HF) (age >= 70 years) admitted to a Danish university hospital. The hip fracture patients were prospectively enrolled in a dedicated hip fracture database. Each hip fracture patient was exactly matched according to age and sex with two controls randomly chosen from a control population of 21,778 subjects who had s-PTH, s-total calcium and s-25(OH)D measured at the Copenhagen General Practitioners Laboratory after referral from their general practitioner. The control group (Con) thus consisted of 1124 subjects. RESULTS: General 1-year mortality: Con-female 8.4%, Con-male 15.3%, HF female 24.6%, HF-male 33.3%, p<0.0001 (log rank). SHPT AND RELATED 1-YEAR MORTALITY: Con-no SHPT 8.9%, Con-SHPT 16.8%, HF-no SHPT 22.7%, HF-SHPT 34.9%, p<0.0001 (log rank). The mortality rates were higher for controls with SHPT (OR 2.06, 95% CI: 1.32-3.23), hip fracture patients without SHPT (OR 3.00, 95% CI: 2.14-4.20) and hip fracture patients with SHPT (OR 5.46, 95% CI: 3.32-8.97) compared to the controls without SHPT. PREVALENCE OF SHPT: Con 16%, HF 20%, p=0.09 (Chi-square). CONCLUSIONS: Our study clearly shows that SHPT is significantly associated with mortality in both hip fracture patients and the control group. In the multivariate Cox regression analysis, s-PTH and s-total calcium were both significantly associated with mortality, whereas s-25(OH)D was not associated with mortality in this analysis. Our study furthermore indicates that SHPT is almost equally prevalent amongst the hip fracture patients and the control group. PMID- 22261084 TI - The usefulness of phosphorylated-signal transduction and activators of transcription 3 in detecting prostate cancer from negative biopsies. AB - AIMS: To avoid the misdiagnosis of prostate cancer (PCA), many patients receive repeated biopsies, despite receiving prior negative biopsies for PCA. Signal transduction and activators of transcription 3 (STAT3), a component of the JAK STAT signaling pathway, can be activated by tyrosine phosphorylation as P-STAT3 and involved in the regulation of cellular growth, survival and oncogenesis. We aimed to assess the reliability of detecting PCA from the expression of P-STAT3 in prostate tissue previously designated as a negative biopsy. METHODS: Prostate tissues were obtained from the biopsies of 52 patients with localized PCA as well as from the biopsies of 80 patients free of PCA. Expression of P-STAT3 in these specimens was examined by immunohistochemical staining (IHC) and used to distinguish tissue with PCA from tissue designated as benign during a biopsy procedure. RESULTS: P-STAT3 staining intensities in all samples (initial negative biopsies, cancer positive cores and other negative cores from the same-batch biopsies) of PCA patients was significantly higher than that of benign patients (F = 23.664, P < 0.001). Analysis of the receiver operating characteristics (ROC) curve showed that the area under curve (AUC) for P-STAT3 staining was 0.785. When positive immuno-labeling of P-STAT3 in samples from initial biopsies was used as a marker for PCA, it showed relatively high sensitivity (80.8%) and specificity (76.3%). CONCLUSIONS: IHC of P-STAT3 could be utilized to detect PCA patients with initial negative biopsies. As a result, it can be a potential adjunctive tool for current PCA diagnostic programs. P-STAT3 can predict the onset of PCA up to 40 months earlier than currently used diagnostic approaches. PMID- 22261085 TI - Preoperative chemotherapy does not influence the number of evaluable lymph nodes in resected gastric cancer. AB - BACKGROUND: While it is suggested that more than 15 lymph nodes (LNs) should be evaluated for accurate staging of gastric cancer, LN yield in western countries is generally low. The effect of preoperative chemotherapy on LN yield in gastric cancer is unknown. The aim of the present study is to determine whether preoperative chemotherapy is associated with any difference in the number of LNs obtained from specimens of patients who underwent curative surgery for gastric adenocarcinoma. PATIENTS AND METHODS: In 1205 patients from Memorial Sloan Kettering Cancer Center (MSKCC) and 1220 patients from the Netherlands Cancer Registry (NCR) who underwent a gastrectomy with curative intent for gastric adenocarcinoma without receiving preoperative radiotherapy, LN yield was analyzed, comparing patients who received preoperative chemotherapy and patients who received no preoperative therapy. RESULTS: Of the 2425 patients who underwent a gastrectomy, 14% received preoperative chemotherapy. Median LN yields were 23 at MSKCC and 10 in the NCR. Despite this twofold difference in LN yield between the two populations, with multivariate Poisson regression, chemotherapy was not associated with LN yield of either population. Variables associated with increased LN yield were institution, female sex, lower age, total (versus distal) gastrectomy and increasing T-stage. CONCLUSIONS: In this patient series, treatment at MSKCC, female sex, lower age, total gastrectomy and increasing primary tumor stage were associated with a higher number of evaluated LNs. Preoperative chemotherapy was not associated with a decrease in LN yield. Evaluating more than 15 LNs after gastrectomy is feasible, with or without preoperative chemotherapy. PMID- 22261086 TI - Online usability and patients with long-term conditions: a mixed-methods approach. AB - BACKGROUND: To improve the information position of health care consumers and to facilitate decision-making behavior in health the Dutch ministry of Health commissioned the National Institute for Public Health and the Environment to develop, host and manage a public national health and care portal (www.kiesbeter.nl) on the Internet. The portal is used by over 4 million visitors in 2010. Among them, an increasing amount of patients that use the portal for information and decision making on medical issues, healthy living, health care providers and other topics. OBJECTIVE: First objective is to examine what usability aspects of the portal kiesBeter.nl matter for chronic patients and their informal carers with regard to information seeking, self-management, decision making, on line health information and other variables. Second objective is to make evidence-based practical recommendations for usability improvement. METHODS: An innovative combination of techniques (semi-structured interviews; eHealth Literacy scale; scenario-based study using think-aloud protocol and screen capture software; focus group) is used to study usability and on line information seeking behavior in a non random judgment sample of three groups of patients (N=21) with long-term medical conditions (arthritis, asthma and diabetes). RESULTS: The search strategy mostly used (65%) by the relatively well educated subjects is 'orienteering'. Users with long-term conditions and their carers expect tailored support from a national health portal, to help them navigate, search and find the detailed information they need. They encounter serious problems with these usability issues some of which are disease-specific. Patients indicate a need for personalized information. They report low impact on self-management and decision making. Overall judgment of usability is rated 7 on a Likert type 0-10 scale. Based on the outcomes recommendations could be formulated. These have led to major adaptations to improve usability. LIMITATIONS: A non-representative composition of a small non random judgment sample does not permit generalization to other populations and cognitive bias cannot be quantified. However if mixed methods are applied valid conclusions can be drawn with regard to usability issues. PMID- 22261087 TI - Effects of induction/inhibition of endogenous heme oxygenase-1 on lipid metabolism, endothelial function, and atherosclerosis in rabbits on a high fat diet. AB - The heme oxygenase-1 (HO-1) / carbon monoxide (CO) system has been presumed as a therapeutic target for preventing atherosclerosis. However, the exact mechanism(s) underlying this system remains largely undefined. This study aims to examine the influence of induction/inhibition of HO-1 on atherosclerotic plaque using pharmacological approaches and to elucidate potential mechanisms. Rabbits were randomly assigned to receive a standard diet (control group), high fat diet (HFD), HFD plus HO inducer hemin (HFD + H group), and HFD plus an HO inhibitor, zinc protoporphyrin-9 (ZnPP9, HFD + Z group). Atherosclerotic plaque was evaluated using oil red O staining and histological analyses. Immunohistochemistry, western blotting, and RT-PCR were employed to study the expression of HO-1 and endothelin-1 (ET-1). Levels of CO, nitric oxide (NO), eNOS/iNOS activities, NF-kappaB activity, and TNF-alpha level were determined. No significant differences of serum lipid levels were observed among the HFD, HFD + Z, and HFD + H groups. In rabbits, HFD induced typical atherosclerotic plaque and increased intima/media thickness ratio, which was markedly reduced in the HFD + H group and further aggravated in the HFD + Z group. Furthermore, hemin increased HO-1 expression, CO levels, and eNOS activity, while decreasing iNOS levels, ET-1 expression, NF-kappaB activity, and TNF-alpha level. ZnPP9 caused opposite effects. Induction of the endogenous HO-1/CO system by hemin can prevent atherosclerosis though increasing CO levels, regulating eNOS activity, NF-kappaB activity, TNF-alpha levels, and ET-1 levels in rabbits. Our results add new evidence for the importance of HO-1 in the genesis and development of atherosclerosis and provide several possible mechanisms underlying the anti atherosclerosis effects of HO-1. PMID- 22261088 TI - The calculation of proton and secondary electron stopping powers in liquid water. AB - The stopping power of energetic protons in liquid water has been calculated using a new model based on different theoretical and semi-empirical approaches. In this model, we consider the relativistic corrections along with the electronic and nuclear stopping power. The present work accounts for the different interactions made with electrons and nuclei inside the target. Interactions of the incident particle with the target's electrons dominate in the high energy regime; in the low energy regime, the interactions of the projectile with the target nuclei contribute importantly and are included in the calculation. We also compute the stopping cross sections and the stopping power of secondary electrons ejected from proton and hydrogen ionization impact, and generated by hydrogen electron loss processes. The consideration of secondary electrons' stopping power can contribute to the study of nano-dosimetry. Our results are in good agreement with existing experimental data. This calculation model can be useful for different applications in medical physics and space radiation health, such as hadron therapy for cancer treatment or radiation protection for astronauts. PMID- 22261089 TI - Effects of the particle sizes and concentrations on the X-ray absorption by CuO compounds. AB - This work presents a study on the effects of the particle size, material concentration and radiation energy on the X-ray absorption. CuO nanoparticles and microparticles were incorporated separately into a polymeric resin in concentrations of 5%, 10% and 30% relative to the resin mass. X-ray absorption by these materials was analyzed with a CdTe detector. The X-ray absorption is higher for the nanostructured material compared to the microstructured one for low energy X-ray beams for all CuO concentrations. PMID- 22261090 TI - Excretory/secretory products from in vitro-cultured Echinococcus granulosus protoscoleces. AB - Cystic hydatid disease (CHD) is caused by infection with Echinococcus granulosus metacestodes and affects humans and livestock. Proteins secreted or excreted by protoscoleces, pre-adult worms found in the metacestode, are thought to play fundamental roles in the host-parasite relationship. In this work, we performed an LC-MS/MS proteomic analysis of the excretory-secretory products obtained from the first 48 h of an in vitro culture of the protoscoleces. We identified 32 proteins, including 18 that were never detected previously in metacestode proteomic studies. Among the novel identified excretory-secretory products are antigenic proteins, such as EG19 and P-29 and a calpain protease. We also identified other important protoscolex excretory-secretory products, such as thioredoxin peroxidase and 14-3-3 proteins, which are potentially involved in evasion mechanisms adopted by parasites to establish infection. Several intracellular proteins were found in the excretory-secretory products, revealing a set of identified proteins not previously thought to be exposed at the host parasite interface. Additionally, immunological analyses established the antigenic profiles of the newly identified excretory-secretory products and revealed, for the first time, the in vitro secretion of the B antigen by protoscoleces. Considering that the excretory-secretory products obtained in vitro might reflect the products released and exposed to the host in vivo, our results provide valuable information on parasite survival strategies in adverse host environments and on the molecular mechanisms underpinning CHD immunopathology. PMID- 22261091 TI - Serum levels of leptin, adiponectin and resistin are interrelated and related to total antioxidant capacity, free fatty acids and phospholipids in early neonatal life. AB - OBJECTIVES: The aims of this study were to determine interrelationships between serum leptin, adiponectin and resistin, insulin-like growth factor-1 (IGF-1), total antioxidant capacity (TAC), non-esterified fatty acids (NEFA) and phospholipids concentrations in infants. DESIGN AND METHODS: A cross-sectional study was conducted to assess serum levels of leptin, adiponectin, resistin, IGF 1, TAC, NEFA and phospholipids in 45 breast-fed infants enrolled at 4-30 days after birth. RESULTS: Serum leptin and adiponectin concentrations were positively correlated. Serum resistin concentrations were inversely correlated to serum leptin and adiponectin concentrations. Serum TAC was positively correlated to serum leptin and adiponectin, and inversely to serum resistin concentrations. Serum adiponectin concentrations were positively related to serum NEFA and phospholipid concentrations. Serum resistin concentrations were inversely related to serum NEFA, and phospholipid concentrations. CONCLUSION: These data show that circulatory levels of leptin, adiponectin and resistin are interrelated and they apparently interact with the anti-oxidant system of infants. PMID- 22261092 TI - Long-term (up to 20 years) effects of 50-Hz magnetic field exposure on blood chemistry parameters in healthy men. AB - OBJECTIVES: The potential effects of a chronic exposure to magnetic fields on blood chemistry in humanswere tested. DESIGN: We examined the nocturnal profiles and levels of the following blood parameters: electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphorus), nonprotein nitrogenous compounds (uric acid, urea, creatinine), and glucose, in 15 men (38.0 +/- 0.9 years) exposed chronically and daily for a period of 1-20 years, in the workplace and at home, to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. The weekly geometric mean of individual exposures ranged from 0.1 to 2.6 MUT. The results are compared to those obtained in our control group: 15 unexposed men of similar age (39.4 +/- 1.2 years), with the same synchronization and physical activity that served as controls (individual exposures ranged from 0.004 to 0.092 MUT). Blood samples were taken hourly from 20:00 h to 08:00 h. RESULTS: This work shows that subjects exposed over a long period (up to 20 years) and on a daily basis to magnetic fields experienced significant changes in serum sodium, chloride, phosphorus and glucose where an effect for field-hour interaction was noted for exposures greater than 0.3 MUT. CONCLUSION: Our data suggest that long-term exposure to 50-Hzmagnetic fields (exposure>0.3 MUT) in healthy men could induce some biological modifications of certain blood parameters, though their clinical relevance needs further investigation. PMID- 22261094 TI - Nanopatterning of ultrananocrystalline diamond nanowires. AB - We report the fabrication of horizontally aligned ultrananocrystalline diamond (UNCD) nanowires (NWs) via two different approaches. First, with the top-down approach by using electron beam lithography (EBL) and reactive ion etching (RIE) with a photo resist layer as an etch mask. Using this approach, we demonstrate fabrication of 50 um long UNCD NWs with widths as narrow as 40 nm. We further present an alternative approach to grow UNCD NWs at pre-defined positions through a selective seeding process. No RIE was needed either to etch the NWs or to remove the mask. In this case, we achieved UNCD NWs with lengths of 50 um and smallest width of 90 nm respectively. Characterization of these nanowires by using scanning electron microscopy (SEM) and atomic force microscopy (AFM) shows that the UNCD NWs are well defined and fully released, with no indication of residual stress. Characterization using visible and ultraviolet (UV) Raman spectroscopy indicates that in both fabrication approaches, UNCD NWs maintain their intrinsic diamond structure. PMID- 22261093 TI - The susceptibility of erythrocytes to oxidation during storage of blood: effects of melatonin and propofol. AB - OBJECTIVES: We investigated the effects of melatonin and propofol in lipid peroxidation and antioxidant capacity of erythrocytes in stored bloods. DESIGN AND METHODS: Donated blood was taken into three citrate-phosphate-dextrose containing blood bags. One bag was used as control, the others were added either melatonin or propofol. Erythrocyte lipid peroxidation and antioxidant capacity and their sensitivity to in vitro oxidation were measured on days 0, 7, 14, 21 and 28. RESULTS: In control group, erythrocyte malondialdehyde levels and sensitivity to in vitro oxidation were increased whereas glutathione, glutathione peroxidase and superoxide dismutase levels were decreased. Melatonin prevented malondialdehyde accumulation and preserved glutathione, glutathione peroxidase and superoxide dismutase levels. Propofol preserved glutathione and glutathione peroxidase levels but did not affect catalase and superoxide dismutase activities. CONCLUSIONS: We showed that melatonin in stored blood could prevent lipid peroxidation and increase the resistance of erythrocytes to in vitro oxidation while propofol did not show such effects. PMID- 22261095 TI - Predictors of suboptimal glycaemic control in type 2 diabetes patients: the role of medication adherence and body mass index in the relationship between glycaemia and age. AB - AIMS: To analyse predictors of glycaemic control including medication adherence and body mass index (BMI) in UK general practice patients with sub-optimally controlled type 2 diabetes. METHODS: Baseline demographic, health- and treatment related measures were evaluated as predictors of one year glycaemic control defined separately as HbA(1c)<= 7.5% and a continuous measure of HbA(1c) concentration, using multivariate regression models. Significant predictors were adjusted for objectively assessed medication adherence and BMI. RESULTS: One-year HbA(1c) concentration was associated with baseline HbA(1c) (p<0.001), BMI (p=0.02), and inversely associated with age (p=0.007) and objectively assessed adherence. Adherent patients had one-year (adjusted) HbA(1c) concentration 0.65% (95% CI -1.04, -0.25; p=0.001) lower than nonadherent. Odds ratios (95% CI) of HbA(1c)<= 7.5% for 10-year higher age were 1.63 (1.08, 2.45); for adherent compared to non-adherent patients 1.89 (0.84, 4.25); for patients receiving >5 compared to <= 5 medications 0.32 (0.13, 0.76); and for each 1% increment in baseline HbA(1c) 0.48 (0.31, 0.73). CONCLUSIONS: The lower HbA(1c) achieved from greater adherence to glucose lowering treatment is comparable to that achieved with additional medication. Relationships between older age and better glycaemic control are not explained by better adherence, but may partly relate to lower BMI. PMID- 22261096 TI - Rural diabetes prevalence quintuples over twenty-five years in low- and middle income countries: a systematic review and meta-analysis. AB - AIMS: To verify the assertions that diabetes pandemic may be spreading across rural parts of low- and middle-income countries (LMICs), we performed a systematic review of published studies reporting diabetes prevalence in rural parts of LMICs. METHODS: Electronic databases (EMBASE and MEDLINE) were searched for papers published from 1990 to 2011. Two independent reviewers screened the articles using structured criteria for inclusion and performed full-text reviews. Pooled prevalence of diabetes was estimated using meta-analysis. Potential factors influencing the estimates were identified by meta-regression and used for sensitivity analyses. RESULTS: Rural prevalence of diabetes of LMICs was 5.6% (95% CI=4.6-6.6), and similar between men and women. This estimate remained robust in separate sensitivity analyses accounting for study quality, level of heterogeneity, age, and sex. In a multivariate meta-regression analysis, pooled prevalence varied by study year and region. Diabetes prevalence increased over time, from 1.8% (1.0-2.6) in 1985-1989, 5.0% (3.8-6.3) in 1990-1994, 5.2% (4.1 6.2) in 1995-1999, 6.4% (5.1-7.7) in 2000-2004, and to 8.6% (6.4-10.7) for 2005 2010 (p=0.001 for secular trend). CONCLUSIONS: Prevalence of diabetes in rural parts of LMICs has risen dramatically. As 55% of LMIC populations live in rural areas, this trend has enormous implications for the global burden of diabetes. PMID- 22261097 TI - In vivo circulation, clearance, and biodistribution of polyglycerol grafted functional red blood cells. AB - The in vivo circulation of hyperbranched polyglycerol (HPG) grafted red blood cells (RBCs) was investigated in mice. The number of HPG molecules grafted per RBC was measured using tritium labeled HPGs ((3)H-HPG) of different molecular weights; the values ranged from 1 * 10(5) to 2 * 10(6) molecules per RBC. HPG grafted RBCs were characterized in vitro by measuring the electrophoretic mobility, complement mediated lysis, and osmotic fragility. Our results show that RBCs grafted with 1.5 * 10(5) HPG molecules per RBC having molecular weights 20 and 60 kDa have similar characteristics as that of control RBCs. The in vivo circulation of HPG-grafted RBCs was measured by a tail vain injection of (3)H HPG60K-RBC in mice. The radioactivity of isolated RBCs, whole blood, plasma, different organs, urine and feces was evaluated at different time intervals. The portion of (3)H-HPG60K-RBC that survived the first day in mice (52%) remained in circulation for 50 days. Minimal accumulation radioactivity in organs other than liver and spleen was observed suggesting the normal clearance mechanism of modified RBCs. Animals gained normal weights and no abnormalities observed in necropsy analysis. The stability of the ester-amide linker between the RBC and HPG was evaluated by comparing the clearance rate of (3)H-HPG60K-RBC and PKH-26 lipid fluorescent membrane marker labeled HPG60K-RBCs. HPG modified RBCs combine the many advantages of a dendritic polymer and RBCs, and hold great promise in systemic drug delivery and other applications of functional RBC. PMID- 22261098 TI - An injectable biodegradable temperature-responsive gel with an adjustable persistence window. AB - E-Caprolactone (CL) and 3-benzyloxymethyl-6-methyl-1,4-dioxane-2,5-dion (fLA), with a benzyloxymethyl group at the 3-position of the lactide, were randomly copolymerized. The methoxy polyethylene glycol (MPEG)-b-[poly(E-caprolactone)-ran poly(3-benzyloxymethyl lactide) (PCL-ran-PfLA)] diblock copolymers were designed such that the PfLA content (0-15 mol%) in the PCL segment was varied. The MPEG-b (PCL-ran-PfLA) diblock copolymers were derivatized by introducing a pendant benzyl group (MC(x)L(y)-OBn), hydroxyl group (MC(x)L(y)-OH), or carboxylic acid group (MC(x)L(y)-COOH) at the PfLA segment. The derivatized MPEG-b-(PCL-ran-PfLA) diblock copolymer solutions exhibited sol-to-gel phase transitions upon a temperature increase. The sol-to-gel phase transition depended on both the type of functional pendant group on the PfLA and the PfLA content in the PCL segment. MC(x)L(y)-COOH diblock copolymer solutions formed gels immediately after injection into Fischer rats. The gels gradually degraded over a period of 0-6 weeks after the initial injection, and the rate of degradation increased for higher concentrations of PfLA. Immunohistochemical characterization showed that the in vivo MPEG-b-(PCL-ran-PfLA) diblock copolymer gels provoked only a modest inflammatory response. These results show that the MPEG-b-(PCL-ran-PfLA) diblock copolymer gel described here may serve as a minimally invasive therapeutic, in situ-forming gel system with an adjustable temperature-responsive and in vivo biodegradable window. PMID- 22261099 TI - Chondrogenic differentiation of rat MSCs on porous scaffolds of silk fibroin/chitosan blends. AB - Adult bone marrow derived mesenchymal stem cells are undifferentiated, multipotential cells and have the potential to differentiate into multiple lineages like bone, cartilage or fat. In this study, polyelectrolyte complex silk fibroin/chitosan blended porous scaffolds were fabricated and examined for its ability to support in vitro chondrogenesis of mesenchymal stem cells. Silk fibroin matrices provide suitable substrate for cell attachment and proliferation while chitosan are promising biomaterial for cartilage repair due to it's structurally resemblance with glycosaminoglycans. We compared the formation of cartilaginous tissue in the silk fibroin/chitosan blended scaffolds with rat mesenchymal stem cells and cultured in vitro for 3 weeks. Additionally, pure silk fibroin scaffolds of non-mulberry silkworm, Antheraea mylitta and mulberry silkworm, Bombyx mori were also utilized for comparative studies. The constructs were analyzed for cell attachment, proliferation, differentiation, histological and immunohistochemical evaluations. Silk fibroin/chitosan blended scaffolds supported the cell attachment and proliferation as indicated by SEM observation, Confocal microscopy and metabolic activities. Alcian Blue and Safranin O histochemistry and expression of collagen II indicated the maintenance of chondrogenic phenotype in the constructs after 3 weeks of culture. Glycosaminoglycans and collagen accumulated in all the scaffolds and was highest in silk fibroin/chitosan blended scaffolds and pure silk fibroin scaffolds of A. mylitta. Chondrogenic differentiation of MSCs in the silk fibroin/chitosan and pure silk fibroin scaffolds was evident by real-time PCR analysis for cartilage specific ECM gene markers. The results represent silk fibroin/chitosan blended 3D scaffolds as suitable scaffold for mesenchymal stem cells-based cartilage repair. PMID- 22261100 TI - Systematic evaluation of avidin-biotin interaction by fluorescence spectrophotometry. AB - The avidin-biotin interaction was evaluated systematically by fluorescence spectroscopy under different conditions of temperature, pressure, pH, metal ions, incubation time and initial avidin concentration. The binding constant was calculated according to the modified Stern-Volmer equation, which deduced the existence of static quenching mechanism. The data obtained revealed that avidin biotin interaction exhibited temperature, pH, metal ions, incubation time and initial avidin concentration sensitivity. The binding constants decreased with increase in temperature, while the binding sites were independent of temperature. The values of thermodynamic parameter DeltaH (-149.85 kJ mol(-1)) and DeltaS ( 284.26 J mol(-1) K(-1)) suggested hydrogen bonds and van der Waals played a major role in the reaction. The binding constants between avidin and biotin increased firstly and then decreased gradually with the increase of pH values. Metal ions can also affected the binding constants between avidin and biotin. The association kinetics firstly acquired by the combination of the change in fluorescence per unit time and the modified Stern-Volmer equation indicated that the reaction time required to reach equilibrium was 2200 s, and the average reaction rate for the binding process was very high in the first 180 s. Reaction of the avidin in the first 180 s was more than 40% of the total avidin involved in the whole process. PMID- 22261101 TI - An in situ FTIR step-scan photoacoustic investigation of kerogen and minerals in oil shale. AB - Step-scan photoacoustic infrared spectroscopy experiments were performed on Green River oil shale samples obtained from the Piceance Basin located in Colorado, USA. We have investigated the molecular nature of light and dark colored areas of the oil shale core using FTIR photoacoustic step-scan spectroscopy. This technique provided us with the means to analyze the oil shale in its original in situ form with the kerogen-mineral interactions intact. All vibrational bands characteristic of kerogen were found in the dark and light colored oil shale samples confirming that kerogen is present throughout the depth of the core. Depth profiling experiments indicated that there are changes between layers in the oil shale molecular structure at a length scale of micron. Comparisons of spectra from the light and dark colored oil shale core samples suggest that the light colored regions have high kerogen content, with spectra similar to that from isolated kerogen, whereas, the dark colored areas contain more mineral components which include clay minerals, dolomite, calcite, and pyrite. The mineral components of the oil shale are important in understanding how the kerogen is "trapped" in the oil shale. Comparing in situ kerogen spectra with spectra from isolated kerogen indicate significant band shifts suggesting important nonbonded molecular interactions between the kerogen and minerals. PMID- 22261102 TI - FT-IR, FT-Raman, ab initio, HF and DFT studies, NBO, HOMO-LUMO and electronic structure calculations on 4-chloro-3-nitrotoluene. AB - In this work, the vibrational spectral analysis was carried out by using Raman and infrared spectroscopy in the range 100-4000 cm(-1) and 50-4000 cm(-1), respectively, for 4-chloro-3-nitrotoluene (C7H6NO2Cl) molecule. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on Hartree Fock (HF) and density functional theory (DFT) method and different basis sets combination. The complete vibrational assignments of wavenumbers were made on the basis of potential energy distribution (PED). The scaled B3LYP/6-311++G(d,p) results show the best agreement with the experimental values over the other methods. The calculated HOMO and LUMO energies shows that charge transfer within the molecule. The effects due to the substitutions of methyl group, nitro group and halogen were investigated. The results of the calculations were applied to simulate spectra of the title compound, which show excellent agreement with observed spectra. Besides, frontier molecular orbitals (FMO), molecular electrostatic potential (MEP) and thermodynamic properties were performed. PMID- 22261103 TI - Raman spectroscopy, thermal and optical properties of TeO2-ZnO-Nb2O5-Nd2O3 glasses. AB - The glasses with composition 75TeO2-10ZnO-(15-x)Nb2O5-xNd2O3 (0<=x<=9 mol%) were prepared using melt quenching method and their physical properties such as density (rho), molar volume (VM), average crosslink density (nc-), oxygen packing density (OPD) and number of bonds per unit volume (nb) were determined. Raman spectroscopic studies showed that the glass network consists of TeO4, TeO3+1, TeO3 and NbO6 units as basic structural units. The glass transition temperature (Tg), crystallization onset (To) and thermal stability (DeltaT) were determined from DSC thermograms. The Raman and DSC results were found to be correlated with the physical properties. In the optical absorption spectra six absorption bands were observed with different relative intensities at around 464, 522, 576, 742, 801 and 871 nm which are assigned to the transition of electrons from (ground state) 4I9/2->G11/2; 4I9/2->2K3/2, 2G7/2; 4I9/2->4G5/2, 4G7/2; 4I9/2->4S3/2; 4F7/2->2H9/2, 4F5/2 and 4I9/2->2F3/2 respectively. From optical absorption data the energy band gap (Eopt) and Urbach energy (DeltaE) were calculated. PMID- 22261104 TI - Configuration interaction study of the electronic states and spectroscopic properties of selenium monoxide. AB - The electronic spectrum of the selenium monoxide (SeO) molecule has been studied theoretically by using ab initio based multireference singles and doubles configuration interaction (MRDCI) methodology, which includes relativistic effective core potentials (RECP) and suitable Gaussian basis sets of the atoms. Potential energy curves of several electronic states correlating with the lowest and second dissociation limit are constructed. Spectroscopic parameters, namely Te, re, and omegae of 10 bound Lambda-S states of the molecule within 4.71 eV are estimated and compared with the available data. In addition, binding energies of the ground and some excited states are computed. The changes in the potential energy curves and spectroscopic properties after the inclusion of the spin-orbit coupling are discussed and also compared with the available data. Transition probabilities of some dipole-allowed and spin forbidden transitions are estimated and radiative lifetimes of some excited states are reported. Dipole moments of some low-lying Lambda-S states as a function of bond distance have also been computed. PMID- 22261105 TI - Comparative spectroscopic studies on drug binding characteristics and protein surface hydrophobicity of native and modified forms of bovine serum albumin: possible relevance to change in protein structure/function upon non-enzymatic glycation. AB - The interaction between serum albumin (SA) and drugs has provided an interesting ground for understanding of drug effects, especially in drug distribution and drug-drug interaction on SA, in the case of multi-drug therapy. Determination of the impact of various factors on drug-protein interaction is especially important upon significant binding of drug to albumin. In the present study, the interaction of two drugs (furosemide and indomethacin) with native and modified albumins were investigated by using various spectroscopic methods. Fluorescence data indicated that 1:1 binding of drugs to bovine serum albumin (BSA) is associated with quenching of albumin intrinsic fluorescence. The Job's plot also confirmed that drug binds to BSA via mentioned stoichiometry. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between drug and albumin may change upon protein modification. The theoretical analyses also suggested some conformational changes of interacting side chains in subdomain IIA binding site (at the vicinity of W237), which were in good agreement with experimental data. Decrease of protein surface hydrophobicity (PSH) was also observed upon both albumin modification and drug binding. PMID- 22261106 TI - Photoinduced electron-transfer from imidazole derivative to nano-semiconductors. AB - Bioactive imidazole derivative absorbs in the UV region at 305 nm. The interaction of imidazole derivative with nanoparticulate WO3, Fe2O3, Fe3O4, CuO, ZrO2 and Al2O3 has been studied by UV-visible absorption, FT-IR and fluorescence spectroscopies. The imidazole derivative adsorbs strongly on the surfaces of nanosemiconductor, the apparent binding constants for the association between nanomaterials and imidazole derivative have been determined from the fluorescence quenching. In the case of nanocrystalline insulator, fluorescence quenching through electron transfer from the excited state of the imidazole derivative to alumina is not possible. However, a possible mechanism for the quenching of fluorescence by the insulator is energy transfer, that is, energy transferred from the organic molecule to the alumina lattice. Based on Forster's non radiation energy transfer theory, the distance between the imidazole derivative and nanoparticles (r0~2.00 nm) as well as the critical energy transfer distance (R0~1.70 nm) has been calculated. The interaction between the imidazole derivative and nanosurfaces occurs through static quenching mechanism. The free energy change (DeltaGet) for electron transfer process has been calculated by applying Rehm-Weller equation. PMID- 22261107 TI - Synthesis, spectral studies and solvatochromic analysis of novel imidazole derivatives. AB - Bioactive imidazole derivatives were synthesized and characterized by spectral techniques. The photophysical properties of imidazole derivatives were studied in several solvents. The observed spectral shift is attributed to a loss of planarity in the excited state provided by the non-co-planarity of the aryl rings attached to C(2) and N(1) atoms of the imidazole ring. The observed solvatochromic shifts were analyzed in detail by Kamlet-Taft and Catalan parameters. The interaction between bioactive imidazole derivative and bovine serum albumin (BSA) was also investigated. PMID- 22261108 TI - Molecular structure and vibrational spectra of ibuprofen using density function theory calculations. AB - The molecular geometry and the theoretical harmonic frequencies and infrared intensities of ibuprofen were calculated for all the molecules using five different density functional methods (mPW1PW91, B3PW91, B3LYP, HCTH and LSDA) with five basic sets, including 6-311G, 6-311++G, 6-311+G (d, p), 6-311++G (d, p) and 6-311++G (2d, 2p). The purpose of this research was to compare the performance of different DFT methods at different basis sets in predicting geometry and vibration spectrum of ibuprofen. The optimized geometric band lengths and bond angles obtained by using mPW1PW91 at 6-311++G (d, p) and 6 311++G (2d, 2p) basic sets show the best agreement with the experimental data. Comparison of the observed fundamental vibrational frequencies of ibuprofen with calculated results indicates that the B3PW91/6-311++G (2d, 2p) level is superior to all the remaining levels for predicting all the vibration spectra on average for ibuprofen. PMID- 22261109 TI - Assessing the potential toxic effect of one persistent organic pollutant: non covalent interaction of dicofol with the enzyme trypsin. AB - Because of the widespread concern that persistent organic pollutants (POPs) may be adversely affecting the health of humans, reliable assessing their toxic effects is urgently needed. We selectively study the interaction between dicofol (DCF) and trypsin by steady state and time resolved fluorescence quenching measurements and UV-visible absorption spectroscopy under physiological conditions as well as applying molecular docking method to establish the interaction model. The fluorescence results indicate DCF can spontaneously form a complex with trypsin mainly by hydrogen bond with only one binding site, which had been validated in molecular docking. The conformational change of trypsin was proved by UV-visible absorption and synchronous fluorescence spectroscopy indicating a red shift of carbonyl absorption peak. All the results indicated DCF had potential toxic effects on both the structure and activity of the enzyme trypsin and the effects enhanced with the increasing concentration of DCF. PMID- 22261110 TI - Vibrational and scaled quantum chemical study of O,O-dimethyl S methylcarbamoylmethyl phosphorodithioate, dimethoate. AB - Infrared and Raman spectra of O,O-dimethyl S methylcarbamoylmethylphosphorodithioate, dimethoate, have been recorded. Density functional theory, DFT, with the B3LYP functional was used for the optimization of the ground state geometry and simulation of the infrared and Raman spectra of this molecule. Calculated geometrical parameters fit very well with the experimental ones. Based on the recorded data, the DFT results and a normal coordinate analysis based on a scaled quantum mechanical (SQM) force field approach, a complete vibrational assignment was made for the first time. PMID- 22261111 TI - Excited state electric dipole moment of nile blue and brilliant cresyl blue: a comparative study. AB - A solvatochromic study on the photophysical properties of two cationic oxazine dyes (brilliant cresyl blue and nile blue) was carried out. The electronic absorption and emission spectra of the dyes were recorded in various organic solvents with different polarity. The ground and the excited state dipole moments of the dyes were estimated from solvatochromic shift method. The solvent dependent spectral shifts in absorption and fluorescence spectra were analyzed by the Katritzky and Kamlet-Taft multi-parameter scales. This work is characterized by detailed quantitative studies on the nature and extent of solvent-solute interactions. PMID- 22261112 TI - Synthesis and evaluation of changes induced by solvent and substituent in electronic absorption spectra of some azo disperse dyes. AB - Five azo disperse dyes were prepared by diazotizing 4'-aminoacetophenone and p anisidine and coupling with varies N-alkylated aromatic amines. Characterization of the dyes was carried out by using UV-vis, FTIR and 1H NMR spectroscopic techniques. The electronic absorption spectra of dyes are determined at room temperature in fifteen solvents with different polarities. The solvent dependent maximum absorption band shifts, were investigated using dielectric constant (E), refractive index (n) and Kamlet-Taft polarity parameters (hydrogen bond donating ability (alpha), hydrogen bond accepting ability (beta) and dipolarity/polarizability polarity scale (pi*)). Acceptable agreement was found between the maximum absorption band of dyes and solvent polarity parameters especially with pi*. The effect of substituents of coupler and/or diazo component on the color of dyes was investigated. The effects of acid and base on the visible absorption maxima of the dyes are also reported. PMID- 22261113 TI - Serious invasive Saffold virus infections in children, 2009. AB - The first human virus in the genus Cardiovirus was described in 2007 and named Saffold virus (SAFV). Cardioviruses can cause severe infections of the myocardium and central nervous system in animals, but SAFV has not yet been convincingly associated with disease in humans. To study a possible association between SAFV and infections in the human central nervous system, we designed a real-time PCR for SAFV and tested cerebrospinal fluid (CSF) samples from children <4 years of age. SAFV was detected in 2 children: in the CSF and a fecal sample from 1 child with monosymptomatic ataxia caused by cerebellitis; and in the CSF, blood, and myocardium of another child who died suddenly with no history of illness. Virus from each child was sequenced and shown to be SAFV type 2. These findings demonstrate that SAFV can cause serious invasive infection in children. PMID- 22261114 TI - Evaluation of the potential of Trichoderma viride in the control of fungal pathogens of Roselle (Hibiscus sabdariffa L.) in vitro. AB - The potential of Trichoderma viride as a bio-control agent was evaluated in vitro against Roselle pathogens i.e. Phoma exigua, Fusarium nygamai and Rhizoctonia solani[1] using the dual culture technique. Volatile and non-volatile inhibitors of Trichoderma were also evaluated for this purpose. T. viride[2] was shown to have a marked inhibitory effect on the tested pathogens in vitro. Maximum inhibition occurred against P. exigua, with 71.76% reduction in mycelial radial growth. The three pathogens, P. exigua, F. nygamai and R. solani were also found to be susceptible to the volatile inhibitors produced by T. viride, giving rise to growth inhibition of about 68% in each case. When T. viride non-volatile metabolites were tested against the pathogens, maximum inhibition occurred against R. solani (73.95% mycelial growth inhibition), followed by P. exigua (37.17% inhibition). The inhibitory effect of the non-volatile metabolites on F. nygamai was, however, minimal. PMID- 22261115 TI - Multilocus genotyping of Giardia duodenalis in lambs from Spain reveals a high heterogeneity. AB - Fecal specimens from 120 lambs in Valencia (Spain) were analyzed for Giardia duodenalis by IFA and nested-PCR using the beta giardin (bg), glutamate dehydrogenase (gdh), triose phosphate isomerase (tpi) and small subunit ribosomal RNA (ssurRNA) genes. The highest prevalence was obtained using the ssurRNA gene (89.2%), whereas values from other techniques ranged from 64.1% to 69.2%. Sequences of the ssurRNA showed a high proportion of assemblage A or mixed assemblage A/E samples (55.1% and 25.2%, respectively). When the other 3 loci were analyzed, between 6.5% and 15.4% were found to be assemblage A or A/E, respectively. Nested PCR for the tpi gene was the most variable of the targets employed. Twelve new sequences of gdh and tpi for G. duodenalis from sheep were found. Multilocus genotyping resulted in 63 patterns from the 71 samples sequenced at the four loci. This high variability among isolates possibly reflects the high frequency of mixed infections. PMID- 22261116 TI - A cue-based approach to the acquisition of grammatical gender in Russian. AB - This article discusses the acquisition of gender in Russian, focusing on some exceptional subclasses of nouns that display a mismatch between semantics and morphology. Experimental results from twenty-five Russian-speaking monolinguals (age 2 ; 6-4 ; 0) are presented and, within a cue-based approach to language acquisition, we argue that children rely on certain morphosyntactic micro-cues in the course of acquisition of semantic agreement. A discrepancy is observed in the acquisition of semantic agreement across the different noun classes, and this suggests that children are highly sensitive to fine distinctions in syntax and morphology and use detailed input information to make specific inferences concerning the gender of different noun classes. Furthermore, we argue that acquisition data may provide a more accurate account of how gender assignment proceeds in the mind of a speaker than has been traditionally assumed by gender assignment theories. PMID- 22261117 TI - Myoglobin-associated acute kidney injury in the setting of ciprofloxacin administration. AB - Myoglobin-associated kidney injury typically is seen in severe rhabdomyolysis. Nontraumatic rhabdomyolysis may be triggered by direct drug toxicity, drug-drug interactions, and individual patient myopathic risk factors. We present a case of myoglobin-associated kidney failure in the setting of repeated ciprofloxacin administration in a lung transplant patient. Kidney biopsy was critical to establishing the diagnosis and avoiding future exposure. PMID- 22261118 TI - Rituximab dosing and monitoring strategies in neuromyelitis optica patients: creating strategies for therapeutic success. AB - BACKGROUND: Neuromyelitis optica (NMO) is an autoimmune condition that predominantly causes severe optic neuritis and transverse myelitis. Rituximab therapy has dramatically improved patient care, but standardized dosing regimens and guidelines are lacking. OBJECTIVES: The objective of this study was to define a rituximab dosing strategy for NMO patients that achieves the lowest rate of relapses. METHODS: This was a retrospective chart review of patients treated with various doses of rituximab. RESULTS: Combining data from the NMO and multiple sclerosis (MS) patients, identified that the mean number of days after a 100 mg dose of rituximab until the CD19 population was greater than 2% was 99 days (standard deviation 36, range 43-172). When allowed to rise, the mean number of days after a 1000 mg dose of rituximab until the CD19 population was greater than 2% was 184 (standard deviation 72, range 52-288). The median number of days until a CD19 percentage of 2% was achieved was 133 days in the 100 mg dosing arm and 259 days in the 1000 mg dosing arm. Analysis of the survival curves via both the Mantel-Cox log-rank test and the Wilcoxon test determined that the difference between medial survival for 100 and 1000 mg doses was statistically significant with p-values <0.0001. CONCLUSIONS: Low doses of rituximab have a high rate of early B-cell repopulation. Any NMO patient treated with rituximab should be followed with monthly CD19 counts in order to identify the rare, but clinically significant, early repopulators. PMID- 22261119 TI - Are Mycobacterium avium subsp. paratuberculosis and Epstein-Barr virus triggers of multiple sclerosis in Sardinia? AB - Sardinia acts as an ideal setting for multiple sclerosis (MS) studies because its prevalence of MS is one of the highest worldwide. Several pathogens have been investigated amongst 119 Sardinian MS patients and 117 healthy controls to determine whether they might have a role in triggering MS in genetically predisposed individuals. Mycobacterium avium subsp. paratuberculosis (MAP) and Epstein Barr virus DNA were detected in 27.5% and 17.3%, respectively, of the MS patients. Moreover an extremely high humoral immune response against MAP recombinant protein MAP FprB (homologous to human myelin P0) was observed, whereas no significant results were found against Mycobacterium tuberculosis FprA and Helicobacter pylori HP986 protein. PMID- 22261120 TI - Novel prion protein in BSE-affected cattle, Switzerland. PMID- 22261121 TI - Thermal noise calculation method for precise estimation of the signal-to-noise ratio of ultra-low-field MRI with an atomic magnetometer. AB - In recent years, there has been considerable interest in developing an ultra-low field magnetic resonance imaging (ULF-MRI) system using an optically pumped atomic magnetometer (OPAM). However, a precise estimation of the signal-to-noise ratio (SNR) of ULF-MRI has not been carried out. Conventionally, to calculate the SNR of an MR image, thermal noise, also called Nyquist noise, has been estimated by considering a resistor that is electrically equivalent to a biological conductive sample and is connected in series to a pickup coil. However, this method has major limitations in that the receiver has to be a coil and that it cannot be applied directly to a system using OPAM. In this paper, we propose a method to estimate the thermal noise of an MRI system using OPAM. We calculate the thermal noise from the variance of the magnetic sensor output produced by current-dipole moments that simulate thermally fluctuating current sources in a biological sample. We assume that the random magnitude of the current dipole in each volume element of the biological sample is described by the Maxwell Boltzmann distribution. The sensor output produced by each current-dipole moment is calculated either by an analytical formula or a numerical method based on the boundary element method. We validate the proposed method by comparing our results with those obtained by conventional methods that consider resistors connected in series to a pickup coil using single-layered sphere, multi-layered sphere, and realistic head models. Finally, we apply the proposed method to the ULF-MRI model using OPAM as the receiver with multi-layered sphere and realistic head models and estimate their SNR. PMID- 22261122 TI - Human papillomavirus oncogene mRNA testing for the detection of anal dysplasia in HIV-positive men who have sex with men. AB - BACKGROUND: Anal human papillomavirus (HPV) infection and anal dysplasia are frequent in HIV-positive men who have sex with men (HIV+MSM), and progression of low-grade (LSIL) to high-grade squamous intraepithelial lesions (HSIL) or anal cancer (AC) occurs faster than in HIV-negative individuals. High-risk (HR)-HPV E6/E7 oncogene mRNA testing has a higher specificity and a higher positive predictive value (PPV) than HR-HPV-DNA testing for detecting high-grade cervical lesions. OBJECTIVE: To evaluate the diagnostic accuracy of the NucliSENS-EasyQ HPV1.1 E6/E7-mRNA-assay for the detection of anal dysplasia in HIV+MSM. STUDY DESIGN: 289 intraanal swabs from HIV+MSM participating in a screening program that included anal cytology, high-resolution anoscopy and histology were analyzed. HR-HPV-DNA detection was performed by PCR and hybridization using a bead-based multiplex genotyping assay. E6/E7-mRNA detection of HR-HPV-types 16, 18, 31, 33 and 45 was performed using the NucliSENS-EasyQ assay. RESULTS: 269 swabs had valid results in both test formats (111 normal, 10 ASCUS, 105 LSIL, 42 HSIL, 1 AC). For the detection of LSIL+(LSIL+HSIL+cancer) sensitivity, specificity, negative predictive value (NPV) and PPV were 80.4%, 26.4%, 52.5%, and 57.2% for HR-HPV-DNA testing, respectively, compared to 75.7%, 57.9%, 66.0% and 68.7% for E6/E7-mRNA testing. The respective values for the detection of HSIL/cancer were 95.3%, 26.1%, 96.7%, 19.7% for HR-HPV-DNA and 95.3%, 46.0%, 98.1%, 25.2% for E6/E7-mRNA detection. CONCLUSION: Compared to HR-HPV-DNA detection, E6/E7-mRNA testing has an increased specificity (approximately two fold), similar sensitivity and higher NPV and PPV for the detection of low- and high-grade anal dysplasia in HIV+MSM. PMID- 22261123 TI - Comparison of a commercial Varicella Zoster glycoprotein IgG enzyme immunoassay with a reference time resolved fluorescence immunoassay (VZV TRFIA) for measuring VZV IgG in sera from pregnant women, sera sent for confirmatory testing and pre and post vOka vaccination sera from healthcare workers. AB - BACKGROUND: Recently, a commercial, standardised VZV IgG glycoprotein EIA, Binding Site VaccZymeTMVZV glycoprotein IgG low level EIA (VaccZymeTMEIA) has become available. The VaccZymeTMEIA is more robust and user friendly than the reference VZV time-resolved fluorescence immunoassay (VZV TRFIA). OBJECTIVES: To assess the usefulness of the VaccZymeTMEIA in the diagnostic laboratory by comparing VZV IgG levels generated by both assays on serum panels representing, non-vaccinated, and vOka vaccinated populations. STUDY DESIGN: Sera from non vaccinated individuals were tested; 248 from pregnant women, 117 from various patient groups referred to the Virus Reference Department for confirmatory VZV IgG testing and 102 from healthcare workers enrolled in a study (ROVE) of antibody/IgG response to vOka. From the ROVE study, 282 post vaccination sera were tested; 108 and 101 collected at six weeks post first and second doses of vOka, respectively, and 73 collected at 18 month follow-up. RESULTS: Sensitivities and specificities (equivocals treated as negatives) of the VaccZymeTMEIA for sera from pregnant women were 97.8% (95% CI: [94.6%, 99.4%]) and 96.8% (95% CI: [89.0%, 99.6%]), respectively, and for sera referred for confirmatory testing were 81.2% (95% CI: [71.2%, 88.8%]) and 96.9% (95% CI: [83.8%, 99.9%]), respectively, and for ROVE baseline sera were 54.2% (95% CI: [32.8%, 74.4%]) and 100% (95% CI: [95.4%, 100.0%]), respectively. For the post vOka serum panels sensitivities of the VaccZymeTMEIA ranged from 65.3% (95% CI: [50.4%, 78.3%]) to 80.4% (95% CI: [71.1%, 87.8%]). Specificities were all 100%. Correlation with VZV TRFIA was high and agreement varied between the serum panels tested. CONCLUSIONS: VaccZymeTMEIA is recommended for detecting VZV IgG in sera from non-vaccinated populations; however, caution is advised when measuring post vOka VZV IgG levels. PMID- 22261124 TI - Human papillomavirus subtypes in oral lesions compared to healthy oral mucosa. AB - BACKGROUND: Human papillomaviruses (HPV) are involved in the etiology of cervix cancer, but it is still unclear whether they play a role in related oral lesions. OBJECTIVES: The presence of HPV in oral leukoplakia biopsies (n=50) and oral squamous carcinoma biopsies (n=50) was compared to normal oral mucosa swabs (n=50) for the purpose of indicating a possible etiological role for the virus. STUDY DESIGN: DNA was extracted from tissue biopsies and from mucosa swabs of control samples. Nested PCR was performed with primers targeting conserved sequences within the capsid gene L1. PCR products were sequenced to identify the HPV genotype. RESULT: The results reveal a profile of low-risk HPV genotypes in oral leukoplakia similar to that in healthy controls, while HPV was less frequently observed in oral squamous carcinoma. CONCLUSIONS: HPV does not seem to represent an important causal factor for the development of oral leukoplakia or oral squamous carcinoma. PMID- 22261125 TI - Comparison of the rate and size of HIV-1 viral load blips with Roche COBAS TaqMan HIV-1 versions 1.0 and 2.0 and implications for patient management. AB - BACKGROUND: The Roche COBAS TaqMan HIV-1 version 1.0 (v1.0) real-time PCR test detects more low level viral loads (VL) compared to the previous Roche Amplicor version 1.5 assay. Due to under-quantification issues, the Roche TaqMan HIV-1 version 2.0 (v2.0) was introduced in 2009. Controversy remains on differences at the low VL end, where clinical decisions regarding possible viral escape are based. OBJECTIVES: To compare the rate and size of VL blips with v1.0 and v2.0 in virologically suppressed patients and describe the impact of v2.0 on patient management. STUDY DESIGN: A cohort study of HIV-positive patients on antiretroviral therapy with a VL <50 copies/ml at the beginning and end of the study period (July 2008-February 2010). VL blips were compared during two consecutive 9-month periods, initially measured by v1.0, then v2.0. Genotypic resistance testing and treatment switches were described. RESULTS: 1037 of 2584 patients (73.1% male) with median age 43 years were included. 2465 VL samples were measured on v1.0 and 2206 on v2.0. 108 (10.4%) patients had blips on v1.0 (4.4% of samples) compared to 99 (9.5%) patients (4.5% of samples) on v2.0. Median log VL was 1.89 (78 copies/ml) for v1.0 and 2.06 (116 copies/ml) for v2.0 (p=0.002). Further characterisation of 11 samples detected no resistance and no treatment modifications were identified. CONCLUSIONS: TaqMan v1.0 and v2.0 have similar blip rates, while blips are higher with v2.0. This study supports the strategy to increase the threshold of concern for VL blips on v2.0. PMID- 22261126 TI - A multicenter study of the clinical characteristics of usual-type vulvar intraepithelial neoplasia in China. AB - OBJECTIVE: To investigate clinical characteristics of usual-type vulvar intraepithelial neoplasia (uVIN) in China. METHODS: A retrospective review of the records of 64 patients with uVIN was performed at 3 academic hospitals between 2004 and 2010. Patients were assigned to a younger (<=40 years) or an older (>40 years) group. Clinical characteristics of lesions were described and analyzed. RESULTS: Mean patient age was 40.6 years. There was a high proportion of incidental findings (34%), multifocal lesions (64%), variegated lesions (59%), and multiple neoplastic lesions in the lower genital tract (20%). As patient age increased, so did numbers of patients reporting pain (P<0.05). Longer time between symptom onset and uVIN diagnosis, and more multifocal lesions were noted in the older group (P<0.05). Whereas younger patients often presented with cervical intraepithelial neoplasia and uVIN, older patients often presented with intraepithelial neoplasia at uncommon locations (e.g. vagina, anus, and periurethral region) (P<0.05). No differences between the groups were found regarding gross appearance or anatomic location of uVIN lesions (P>0.05). CONCLUSION: Age-specific differences were noted in location of neoplastic lesions in the lower genital tract and time to diagnosis of uVIN. However, the clinical features of uVIN lesions were heterogeneous and non-age specific. PMID- 22261127 TI - A shortened postpartum magnesium sulfate prophylaxis regime in pre-eclamptic women at low risk of eclampsia. AB - OBJECTIVE: To determine whether magnesium sulfate (MgSO(4)) prophylaxis is needed for up to 24 hours postpartum in all patients with pre-eclampsia. METHODS: In a randomized open clinical trial conducted in a tertiary health center in India between September 2008 and April 2010, 150 women with severe pre-eclampsia who received intrapartum MgSO(4) and delivered at more than 2 weeks gestation were enrolled. After 6hours postpartum, the participants were randomized to continue receiving (control group) or to discontinue (intervention group) MgSO(4), and outcomes were compared. RESULTS: Administration of MgSO(4) had to be reinstituted for 1 woman in the intervention group. Under the current protocol in the institution, all 75 women in the intervention group would have received MgSO(4) for 24 hours postpartum. A significant reduction in time spent by the doctors (P<0.001) and nurses (P<0.001) was seen in the intervention group. The pain score in the intervention group was significantly less (P<0.001), and women in the intervention group were able to look after themselves better (P<0.001). CONCLUSION: For women at low risk for postpartum eclampsia, a shortened (6-hour) MgSO(4) regime was as effective for seizure prophylaxis as the conventional 24 hour regime, with significant benefits in terms of cost and morbidity. PMID- 22261128 TI - Effect of omega-3 fatty acids on intensity of primary dysmenorrhea. AB - OBJECTIVE: To examine whether dietary supplementation with omega-3 fatty acids relieved symptoms of primary dysmenorrhea. METHODS: Women aged 18-22 years with primary dysmenorrhea were enrolled in a double-blind crossover study. Women assigned to group 1 (n=47) received 1 omega-3 capsule daily for 3 months, followed by placebo for 3 months. Women in group 2 (n=48) received placebo for 3 months, followed by omega-3 for 3 months. A washout period was performed in both groups. Participants used 400mg of ibuprofen as a rescue dose if severe menstrual pains were experienced. RESULTS: A marked reduction in pain intensity was observed after 3 months of treatment with omega-3 fatty acids (P<0.05). Women who received omega-3 fatty acids required fewer rescue doses than women who received placebo (P<0.05). The mean numbers of ibuprofen tablets used after 3 months with omega-3 fatty acids were 4.3+/-2.1 (group 1) and 3.2+/-2.5 (group 2); the mean numbers of tablets used after 3 months of placebo were 5.3+/-2.2 (group 1) and 6.0+/-2.6 (group 2) (P=0.001 for both). CONCLUSION: Supplementation with omega-3 fatty acids reduced the symptom intensity of primary dysmenorrhea. Supplementation efficacy was sufficient to decrease the ibuprofen rescue dose. PMID- 22261129 TI - Multiple-dose vaginal misoprostol and single-dose misoprostol plus oxytocin for termination of second-trimester pregnancy. AB - OBJECTIVE: To compare 2 different methods-multiple doses of misoprostol and a combination of misoprostol and oxytocin-for termination of pregnancy in the second trimester. METHODS: Between 2006 and 2008, 120 women undergoing termination of second-trimester pregnancy in 2 hospitals in Kermanshah, Iran, were enrolled in a randomized trial comparing 2 treatments. In each treatment group, an initial vaginal dose of 600 MUg of misoprostol was placed in the posterior fornix. After 6 hours, an intravenous infusion of concentrated oxytocin was given to women in group A, and 400 MUg of vaginal misoprostol was given every 6 hours to women group B, up to a maximum of 4 doses. The outcomes were compared via chi(2) and independent t tests. RESULTS: Within 30 hours, 96.7% of women in group A and 96.7% of women in group B delivered successfully. The average duration between induction and delivery time was 12.3+/-6.0 hours in group A and 12.1+/-6.0 hours in group B (P>0.05). CONCLUSION: The use of misoprostol with oxytocin, and multiple doses of misoprostol gave similar results for termination of pregnancy in the second trimester. PMID- 22261130 TI - Perinatal outcomes associated with subsequent pregnancy among adolescent mothers in Peru. AB - OBJECTIVE: To assess the perinatal outcomes of a subsequent pregnancy among adolescent mothers living in Peru. METHODS: A large hospital-based retrospective cohort study was conducted to evaluate singleton births during a 9-year period (2001-2009). The study population was divided into 3 groups: adolescents aged 15 19 years who had 1 previous parturition (n=2074), nulliparous adolescents (n=20721), and multiparous adults aged 20-29 years (n=23 129). RESULTS: No significant differences were found between multiparous adolescents and the 2 control groups with regard to preterm delivery, perinatal death, and 5-minute Apgar score below 7. Logistic regression analysis showed no significant differences in the rates of cesarean delivery or preterm birth before 34 or 37 weeks. After adjusting for confounding factors, low birth weight (LBW) and small for gestational age (SGA) were more likely to occur during a subsequent pregnancy among adolescent mothers than during the 1st pregnancy among nulliparous adolescents. The odds ratios were 1.38 (95% CI, 1.14-1.67) and 1.27 (95% CI, 1.02 1.56), respectively. CONCLUSION: Multiparous adolescents are more likely to experience LBW or SGA than are nulliparous adolescents. No significant differences in other perinatal outcomes were found among the 3 study groups. PMID- 22261131 TI - Critical care providers' opinion on unsafe abortion in Argentina. AB - OBJECTIVE: To survey the opinion of critical care providers in Argentina about abortion. METHODS: An anonymous questionnaire was distributed to critical care providers attending the 20th National Critical Care Conference in Argentina. RESULTS: 149 of 1800 attendees completed the questionnaire, 69 (46.3%) of whom were members of the Argentine Society of Critical Care (ASCC). 122 (81.9%) supported abortion decriminalization in situations excluded from the current law; 142 (95.3%) in cases of congenital defects; 133 (89.3%) in cases of rape; 115 (77.2%) when women's mental health is at risk; 71 (47.7%) when pregnancy is unintended; and 61 (40.9%) for economic reasons. 126 (84.6%) supported abortion in public and private institutions, and 121 (81.2%) before 12 weeks of pregnancy. Variables independently associated with abortion support among female versus male attendees were abortion to preserve women's mental health (OR 4.47; 95% CI, 1.61 12.42; P=0.004) and abortion before 12 weeks of pregnancy (OR 3.93; 95% CI, 1.29 11.94; P=0.015). Abortion at request was independently associated with ASCC membership (OR 2.63; 95% CI, 1.07-6.45; P=0.034). CONCLUSION: Critical care providers would support abortion in situations excluded from the current abortion law and before 12 weeks of pregnancy, in both public and private hospitals. PMID- 22261132 TI - Recurrent bladder rupture after cauda equina syndrome. PMID- 22261133 TI - Single-incision total laparoscopic hysterectomy with conventional laparoscopy ports. AB - OBJECTIVE: To study the feasibility of performing single-incision total laparoscopic hysterectomy using conventional ports and instruments. METHODS: Patients undergoing laparoscopic surgery at Galaxy Care Laparoscopic Institute, Pune, India, between January 2007 and December 2010 were selected for participation. All procedures were performed using conventional laparoscopic instruments and trocars. Operative data-including operative time (from incision to port closure), blood loss, additional ports used, energy sources used, and intraoperative complications-were recorded. RESULTS: Twenty-three procedures were performed during the study period. All procedures were completed via single incision only. Operative time, blood loss, and hospital stay were comparable with those associated with conventional laparoscopy. CONCLUSION: It is debatable whether laparoscopic surgery via a single incision would threaten the position of the current gold standard of conventional laparoscopic procedures. The present study showed that single-incision laparoscopic surgery using conventional instruments is feasible and effective. PMID- 22261134 TI - Effect of concomitant oophorectomy on the perioperative outcomes of laparoscopic hysterectomy. PMID- 22261135 TI - Epidemiology of, and behavioural risk factors for, sexually transmitted human papillomavirus infection in men and women in Britain. AB - OBJECTIVES: Persistent infection with high-risk sexually transmitted human papillomaviruses (HR-HPVs) can lead to development of cervical and other cancers, while low-risk types (low-risk HPV) may cause genital warts. We explored the epidemiology of different HPV types in men and women and their association with demographic and behavioural variables. METHODS: We analysed data collected for the British National Survey of Sexual Attitudes and Lifestyles, a cross-sectional survey undertaken in 1999-2001. Half of all sexually experienced male and female respondents aged 18-44 years were invited to provide a urine sample. We tested 3123 stored urine samples using an in-house Luminex-based HPV genotyping system. RESULTS: HPV DNA was detected in 29.0% (95% CI 26.7% to 31.3%) of samples from women and 17.4% (95% CI 15.1% to 19.8%) from men. Any of 13 HR-HPV types was detected in 15.9% (95% CI 14.1% to 17.8%) of women and 9.6% (95% CI 8.0% to 11.6%) of men. HPV types 16/18 were found in 5.5% (95% CI 4.5% to 6.8%) of women and 3.0% (95% CI 2.1% to 4.3%) of men; and types 6/11 in 4.7% (95% CI 1.8% to 5.9%) of women and 2.2% (95% CI 1.5% to 3.1%) of men. In multivariate analysis, HR-HPV was associated with new partner numbers, in women with younger age, single status and partner concurrency, and in men with number of partners without using condom(s) and age at first intercourse. CONCLUSIONS: HPV DNA was detectable in urine of a high proportion of the sexually active British population. In both genders, HR-HPV was strongly associated with risky sexual behaviour. The minority of HPV infections were of vaccine types. It is important to monitor HPV prevalence and type distribution following the introduction of vaccination of girls. PMID- 22261136 TI - The efficacy of acromioplasty in the arthroscopic repair of small- to medium sized rotator cuff tears without acromial spur: prospective comparative study. AB - PURPOSE: To assess the role of acromioplasty in the arthroscopic repair of small- to medium-sized rotator cuff tears. METHODS: A prospective randomized trial of 120 patients who had small- to medium-sized rotator cuff tears and various types of acromions without spurs were included. Sixty patients received arthroscopic rotator cuff repair with acromioplasty (group I), and another sixty received the same procedure without acromioplasty (group II). The mean age at surgery was 57.8 +/- 9.3 years in group I and 55.8 +/- 8.0 years in group II. The shape of the acromion was flat in 18 patients, curved in 32, and hooked in 10 in group I, and it was flat in 15 patients, curved in 36, and hooked in 9 in group II. The mean tear size was similar in the two groups (14.6 +/- 5.2 mm in group I and 15.3 +/- 7.0 mm in group II). Pain and satisfaction were estimated and range of motion was measured at a mean of 35 months after surgery. Functional outcomes were assessed with American Shoulder and Elbow Surgeons: Constant; and University of California, Los Angeles scores. Tendon healing was evaluated by magnetic resonance imaging postoperatively. RESULTS: Clinical outcome was significantly improved in both groups after arthroscopic rotator cuff repair (P < .05). There were no significant differences with respect to pain and range of motion between the groups at the final follow-up (1.1 +/- 0.9 v 1.3 +/- 1.4 on visual analog scale). Functional outcomes also showed no significant differences between the 2 groups (American Shoulder and Elbow Surgeons score, 90.7 +/- 13.1 v 87.5 +/- 12.0; Constant score, 85.0 +/- 11.3 v 83.3 +/- 13.0; and University of California, Los Angeles score, 33.4 +/- 3.3 v 32.3 +/- 3.5). Postoperative imaging showed that the retear rate was 17% in group I and 20% in group II (P = .475). CONCLUSIONS: Arthroscopic repair of small- to medium-sized rotator cuff tears provided pain relief and improved functional outcome with or without acromioplasty. Clinical outcomes were not significantly different, and acromioplasty may not be necessary in the operative treatment of patients with small- to medium-sized rotator cuff tears in the absence of acromial spurs. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 22261138 TI - The modified finger-trap suture technique: a biomechanical comparison of a novel suture technique for graft fixation. AB - PURPOSE: The purpose of this study was to compare the tendon graft holding power of the newly devised modified finger-trap (MFT) suture technique with other currently used sutures. METHODS: We used 40 fresh-frozen porcine flexor profundus tendons randomly divided into 4 groups of 10 specimens. The experimental procedure was designed to assess percent elongation of the suture-tendon construct across four different tendon-grasping techniques: MFT suture, Krackow stitch, locking SpeedWhip stitch (Arthrex, Naples, FL), and nonlocking SpeedWhip stitch. The suture configurations of the MFT suture and Krackow stitch were completed with a No. 2 FiberWire suture (Arthrex). The locking SpeedWhip and nonlocking SpeedWhip stitches were completed with a loop of No. 2 FiberWire suture and a FiberLoop needle (Arthrex). Each tendon was pre-tensioned to 100 N for three cycles and then cyclically loaded to 200 N for 200 cycles. Finally, each tendon was loaded to failure. Percent elongation, load to failure, and mode of failure for each suture-tendon construct were measured. RESULTS: During the pre-tension phase, the MFT suture had the smallest percent elongation (P = .021) of the suture-graft construct (13.5% +/- 1.9%) compared with the Krackow (16.9% +/- 1.2%), locking SpeedWhip (17.6% +/- 0.6%), and nonlocking SpeedWhip (33.3% +/ 5.6%) stitches. During cyclic loading, the MFT suture also showed a significantly smaller percent elongation (P = .037) of the suture-graft construct (27.8% +/- 4.9%) than the Krackow (35.8% +/- 5.4%), locking SpeedWhip (33.7% +/- 5.4%), and nonlocking SpeedWhip (43.8% +/- 7.8%) stitches. The load to failure and cross-sectional area were not significantly different across all the suture groups. CONCLUSIONS: The newly devised MFT suture provided better percent elongation and equal load to failure compared with the Krackow and SpeedWhip suture techniques tested in this in vitro biomechanical evaluation. CLINICAL RELEVANCE: The MFT suture is a simple method that is an attractive alternative to the Krackow and SpeedWhip suture techniques for tendon graft fixation in ligament reconstruction. PMID- 22261139 TI - Culture confirmation of Listeria monocytogenes using tmRNA as a diagnostics target. AB - 16s ribosomal RNA (rRNA) is routinely used to identify bacteria in direct detection culture confirmation assays. In some instances rRNA cannot be used as a target to distinguish between phylogenetically closely related bacteria. Here we evaluate an alternative target, transfer messenger RNA (tmRNA), for the culture confirmation of Listeria monocytogenes. PMID- 22261137 TI - Biomechanical outcomes after bioenhanced anterior cruciate ligament repair and anterior cruciate ligament reconstruction are equal in a porcine model. AB - PURPOSE: The objective of this study was to compare the biomechanical outcomes of a new method of anterior cruciate ligament (ACL) treatment, bioenhanced ACL repair, with ACL reconstruction in a large animal model. METHODS: Twenty-four skeletally immature pigs underwent unilateral ACL transection and were randomly allocated to receive bioenhanced ACL repair with a collagen-platelet composite, allograft (bone-patellar tendon-bone) reconstruction, or no further treatment (n = 8 for each group). The structural properties and anteroposterior laxity of the experimental and contralateral ACL-intact knees were measured 15 weeks postoperatively. All dependent variables were normalized to those of the contralateral knee and compared by use of generalized linear mixed models. RESULTS: After 15 weeks, bioenhanced ACL repair and ACL reconstruction produced superior biomechanical outcomes to ACL transection. However, there were no significant differences between bioenhanced ACL repair and ACL reconstruction for maximum load (P = .4745), maximum displacement (P = .4217), or linear stiffness (P = .6327). There were no significant differences between the 2 surgical techniques in anteroposterior laxity at 30 degrees (P = .7947), 60 degrees (P = .6270), or 90 degrees (P = .9008). CONCLUSIONS: Bioenhanced ACL repair produced biomechanical results that were not different from ACL reconstruction in a skeletally immature, large animal model, although the variability associated with both procedures was large. Both procedures produced significantly improved results over ACL transection, showing that both were effective treatments in this model. CLINICAL RELEVANCE: Bioenhanced ACL repair may one day provide an alternative treatment option for ACL injury. PMID- 22261140 TI - Methods used for the detection and subtyping of Listeria monocytogenes. AB - Listeria monocytogenes is an important foodborne pathogen responsible for non invasive and invasive diseases in the elderly, pregnant women, neonates and immunocompromised populations. This bacterium has many similarities with other non-pathogenic Listeria species which makes its detection from food and environmental samples challenging. Subtyping of L. monocytogenes strains can prove to be crucial in epidemiological investigations, source tracking contamination from food processing plants and determining evolutionary relationships between different strains. In recent years there has been a shift towards the use of molecular subtyping. This has led to the development of new subtyping techniques such as multi-locus variable number tandem repeat analysis (MLVA) and multi-locus sequence based typing (MLST). This review focuses on the available methods for Listeria detection including immuno-based techniques and the more recently developed molecular methods and analytical techniques such as matrix-assisted laser desorption/ionisation time-of-flight based mass spectrometry (MALDI-TOF MS). It also includes a comparison and critical analysis of the available phenotypic and genotypic subtyping techniques that have been investigated for L. monocytogenes. PMID- 22261141 TI - Genotyping of Mycoplasma bovis isolates using multiple-locus variable-number tandem-repeat analysis. AB - Mycoplasma bovis has been considered an important cause of mastitis, pneumonia, and arthritis in bovines with a highly detrimental economic impact in the livestock industry. Previous epidemiological studies, using different typing techniques showed that the isolates were usually heterogeneous and results were difficult to compare between different laboratories. Reliable and comparable molecular typing techniques using geographically and temporal distinct isolates have never been used. The objective of this study was to use multiple-locus variable-number tandem-repeat analysis (MLVA) for the differentiation of M. bovis isolates. This typing scheme was developed using the sequenced genome of the M. bovis PG45 type strain. Nine tandem-repeat sequences were selected and the genetic diversity of 37 isolates of wide geographic and temporal origins was analyzed. The results were compared to those obtained with random amplified polymorphic DNA (RAPD) analysis and pulsed-field gel electrophoresis (PFGE) for the same isolates. Cluster concordance between techniques was evaluated using Adjusted Rand and Wallace coefficients, and different cutoff levels of similarity were tested. Acceptable values of >=0.5 for all techniques for the Wallace coefficient were only observed at the most relaxed cutoff level, i.e., 52% for MLVA, 29% for PFGE and 18% for RAPD. The Simpson's index of diversity was 0.91 for MLVA, 0.99 for RAPD analysis and 0.99 for PFGE. This MLVA assay is compatible with simple PCR and agarose gel-based electrophoresis steps as well as with high throughput automated methods. The molecular typing scheme presented in this study provides a fast, reliable, and cost-effective typing method for surveillance of M. bovis epidemiology. PMID- 22261142 TI - A historical perspective on the specific activity of radiopharmaceuticals: what have we learned in the 35 years of the ISRC? AB - Specific activity (SA), defined as the amount of radioactivity per unit mass of a compound, is arguably one of the most important parameters in radiopharmaceutical development, particularly in quality control of carbon-11- and fluorine-18 labeled compounds. This review article will outline the progression of improvements in SA over the last few decades. The International Symposium of Radiopharmaceutical Chemistry abstracts were an excellent source of materials for this review and will be referenced throughout. PMID- 22261143 TI - Bombesin analogues for gastrin-releasing peptide receptor imaging. AB - OBJECTIVES: The present study describes the design and development of a series of new bombesin (BBN) antagonist peptide ligands of the form [(64)Cu-(NO2A-X-D Phe(6)-BBN(6-13)NHEt)], where Cu-64=a positron emitting radiometal; NO2A=1,4,7 triazacyclononane-1,4-diacetic acid; X=6-amino hexanoic acid, 8-amino octanoic acid or 9-Aminononanoic acid; and BBN(6-13)NHEt=Gln-Trp-Ala-Val-Gly-His-Leu-NHEt, an antagonist analogue of bombesin peptide for specific targeting of the gastrin releasing peptide receptor (GRPR). METHODS: [NO2A-X-D-Phe(6)-BBN(6-13)NHEt] conjugates were manually conjugated with NOTA (1,4,7-triazacyclononane-1,4,7 triacetic acid), and the resulting conjugates were labeled with (64)Cu to yield [(64)Cu-(NO2A-X-D-Phe(6)-BBN(6-13)NHEt)]. The metallated and nonmetallated conjugates were purified via reversed-phase high-performance liquid chromatography and characterized by electrospray ionization-mass spectrometry. RESULTS: Competitive displacement binding assays displayed nanomolar binding affinities toward human GRPR for all of the newly formed peptide analogues. Biodistribution studies showed very high uptake and retention of tumor-associated radioactivity in PC-3 (a prostate tumor model known to express the GRPR) tumor bearing rodent models. The radiolabeled conjugates also exhibited rapid urinary excretion and very high tumor to background ratios. Micro-positron emission tomography (PET) molecular imaging investigations showed clear visualization of tumors in female PC-3 tumor-bearing mice 15 h postinjection. CONCLUSION: The biodistribution and molecular imaging study suggests that these conjugates can be considered as potential PET tracer candidates for the diagnosis of GRPR-positive tumors in human patients. PMID- 22261144 TI - Quantification of regional cerebral blood flow in rats using an arteriovenous shunt and micro-PET. AB - INTRODUCTION: Measurement of regional cerebral blood flow (rCBF) in rodents can provide knowledge of pathophysiology of the cerebral circulation, but generally requires blood sampling for analysis during positron emission tomography (PET). We therefore tested the feasibility of using an arteriovenous (AV) shunt in rats for less invasive blood analysis. METHODS: Six anesthetized rats received [15O]H2O and [15O]CO PET scans with their femoral artery and vein connected by an AV shunt, the activity within which was measured with a germanium ortho oxysilicate scintillation detector. The [15O]H2O was intravenously injected either at a faster or slower injection rate, while animals were placed either with their head or heart centered in the gantry. The time-activity curve (TAC) from the AV shunt was compared with that from the cardiac ventricle in PET image. The rCBF values were calculated by a nonlinear least-square method using the dispersion-corrected AV-shunt TAC as an input. RESULTS: The AV-shunt TAC had higher signal-to-noise ratio, but also had delay and dispersion compared with the image-derived TAC. The delay time between the AV-shunt TAC and image-based TAC ranged from 11 to 21 s, while the dispersion was estimated to be ~5 s as a time constant of the dispersion model of exponential function, and both were properly corrected. In a steady-state condition of [15O]CO PET, the blood activity concentration by AV-shunt TAC was also comparable in height with the image-based TAC corrected for partial volume. Whole-brain CBF values measured by [15O]H2O were 0.37+/-0.04 (mean+/-S.D.) ml/g/min, partition coefficient was 0.73+/-0.04 ml/g, and the CBF varied in a linear relationship with partial pressure of carbon dioxide during each scan. CONCLUSIONS: The AV-shunt technique allows less invasive, quantitative and reproducible measurement of rCBF in [15O]H2O PET studies in rats than direct blood sampling and radioassay. PMID- 22261145 TI - Varenicline increases in vivo striatal dopamine D2/3 receptor binding: an ultra high-resolution pinhole [123I]IBZM SPECT study in rats. AB - INTRODUCTION: Ex vivo storage phosphor imaging rat studies reported increased brain dopamine D2/3 receptor (DRD2/3) availability following treatment with varenicline, a nicotinergic drug. However, ex vivo studies can only be performed using cross-sectional designs. Small-animal imaging offers the opportunity to perform serial assessments. We evaluated whether high-resolution pinhole single photon emission computed tomography (SPECT) imaging in rats was able to reproduce previous ex vivo findings. METHODS: Rats were imaged for baseline striatal DRD2/3 availability using ultra-high-resolution pinhole SPECT (U-SPECT-II) and [123I]IBZM as a radiotracer, and randomized to varenicline (n=7; 2 mg/kg) or saline (n=7). Following 2 weeks of treatment, a second scan was acquired. RESULTS: Significantly increased striatal DRD2/3 availability was found following varenicline treatment compared to saline (time*treatment effect): posttreatment difference in binding potential between groups corrected for initial baseline differences was 2.039 (P=.022), indicating a large effect size (d=1.48). CONCLUSIONS: Ultra-high-resolution pinhole SPECT can be used to assess varenicline-induced changes in DRD2/3 availability in small laboratory animals over time. Future small-animal studies should include imaging techniques to enable repeated within-subjects measurements and reduce the amount of animals. PMID- 22261146 TI - In vitro and in vivo evaluation of a 64Cu-labeled NOTA-Bn-SCN-Aoc-bombesin analogue in gastrin-releasing peptide receptor expressing prostate cancer. AB - INTRODUCTION: Bombesin (BN) is an amphibian peptide that binds to the gastrin releasing peptide receptor (GRPR). It has been demonstrated that BN analogues can be radiolabeled for potential diagnosis and treatment of GRPR-expressing malignancies. Previous studies have conjugated various chelators to the eight C terminal amino acids of BN [BN(7-14)] for radiolabeling with 64Cu. Recently, (1,4,7-triazacyclononane-1,4,7-triacetic acid) (NOTA) has been evaluated as the five-coordinate 64Cu complex, with results indicating GRPR-specific tumor uptake. This study aimed to conjugate S-2-(4-isothiocyanatobenzyl)-NOTA (p-SCN-Bn-NOTA) to BN(7-14) such that it could form a six-coordinate complex with 64Cu and to evaluate the resulting peptide. METHODS: p-SCN-NOTA was conjugated to 8 aminooctanoic acid (Aoc)-BN(7-14) in solution to yield NOTA-Bn-SCN-Aoc-BN(7-14). The unlabeled peptide was evaluated in a cell binding assay using PC-3 prostate cancer cells and 125I-Tyr4-BN to determine the IC50 value. The peptide was radiolabeled with 64Cu and evaluated for internalization into PC-3 cells and for tumor uptake in mice bearing PC-3 xenografts using biodistribution and micro positron emission tomography imaging studies. RESULTS: The binding assay demonstrated that NOTA-Bn-SCN-Aoc-BN(7-14) bound with high affinity to GRPR with an IC50 of 1.4 nM. The radiolabeled peptide demonstrated time-dependent internalization into PC-3 cells. In vivo, the peptide demonstrated tumor-specific uptake and imaging that were comparable to those of previously reported 64Cu labeled BN analogues. CONCLUSIONS: These studies demonstrate that 64Cu-NOTA-Bn SCN-Aoc-BN(7-14) binds to GRPR-expressing cells and that it can be used for imaging of GRPR-expressing prostate cancer. PMID- 22261147 TI - Mammary lipid-rich carcinoma with extensive amyloid deposition in a dog. AB - A 6-year-old female Labrador retriever presented with a mass in the right mammary gland, and swollen right inguinal and axillary lymph nodes. Fine needle aspiration biopsy suggested a malignant lipid-producing tumor, such as liposarcoma. Histopathologically, the neoplasms were solid, lobulated nests of atypical epithelial cells with a large amount of extracellular deposits of amyloid in both mammary gland and lymph nodes. The proliferating cells contained large cytoplasmic vacuoles, positive for oil red-O. These cells were immunopositive for cytokeratin (AE1/AE3) and beta-casein and negative for SMA. The amyloid deposits were immunopositive for beta-casein. These findings suggested that the proliferating cells secreted beta-casein forming amyloid deposits. This is the first report of mammary lipid-rich carcinoma with extensive amyloid deposition derived from beta-casein. PMID- 22261148 TI - Analysis of antibody responses by commercial western blot assay in horses with alveolar echinococcosis. AB - Commercial western blot (WB) assay was used to detect serum antibodies specific to Echinococcus multilocularis in 23 horses in which infection was confirmed by postmortem inspection at a slaughterhouse. Livers contained from 1 to >20 nodular lesions; foci diameter ranged from 1 to 25 mm. Antibody tests of serum from all 23 animals were negative for antigen bands at 7, 16, 18, and 26-28 kDa, which show specificity in the serum of human patients. However, sera from two infected horses with the largest nodules (diameter, 25 mm) showed positive response to one of the 22-kDa and 30-kDa antigen bands. It may be possible to diagnose E. multilocularis infection in horses based on the detection of these bands on commercial WB assay. PMID- 22261149 TI - The RNA-binding protein XSeb4R regulates maternal Sox3 at the posttranscriptional level during maternal-zygotic transition in Xenopus. AB - The maternal-zygotic transition (MZT) is an embryonic event that overlaps with and plays key roles in primary germ layer specification in vertebrates. During MZT, maternally supplied mRNAs are degraded while zygotic transcripts are synthesized to either reinforce the already specified cell fate or to trigger new cell identity. Here, we show that forced expression of the RNA-binding protein, XSeb4R, in animal pole blastomeres of Xenopus embryos, inappropriately stabilizes transcripts there, including maternal Sox3. This leads to the impaired ability of the ectodermal progenitors to respond to factors regulating brain patterning and their eventual loss by apoptosis. XSeb4R protein binds specifically to the 3'UTR of Sox3 mRNA. XSeb4R gain-of-function in ectodermal explants reveals increased stability of the maternal Sox3 transcripts, associated with a robust Sox3 protein production. Conversely, whereas XSeb4R depletion abolishes VegT expression, the amount of the maternal Sox3 mRNA is rather increased but without augmentation in the amount of Sox3 protein. Moreover, XSeb4R protein knockdown leads to the modification of the ectoderm-mesoderm boundary, marked by expanded/shifted expression of the mesodermal marker genes such as Xbra and Apod, followed by an expression inhibition of Epi. K., an ectodermal marker. Overall, our data suggest XSeb4R as a novel player in gene expression regulation, acting at the posttranscriptional level during ectoderm specification in Xenopus. PMID- 22261150 TI - Neural crest delamination and migration: from epithelium-to-mesenchyme transition to collective cell migration. AB - After induction and specification in the ectoderm, at the border of the neural plate, the neural crest (NC) population leaves its original territory through a delamination process. Soon afterwards, the NC cells migrate throughout the embryo and colonize a myriad of tissues and organs where they settle and differentiate. The delamination involves a partial or complete epithelium-to-mesenchyme transition (EMT) regulated by a complex network of transcription factors including several proto-oncogenes. Studying the relationship between these genes at the time of emigration, and their individual or collective impact on cell behavior, provides valuable information about their role in EMT in other contexts such as cancer metastasis. During migration, NC cells are exposed to large number of positive and negative regulators that control where they go by generating permissive and restricted areas and by modulating their motility and directionality. In addition, as most NC cells migrate collectively, cell-cell interactions play a crucial role in polarizing the cells and interpreting external cues. Cell cooperation eventually generates an overall polarity to the population, leading to directional collective cell migration. This review will summarize our current knowledge on delamination, EMT and migration of NC cells using key examples from chicken, Xenopus, zebrafish and mouse embryos. Given the similarities between neural crest migration and cancer invasion, these cells may represent a useful model for understanding the mechanisms of metastasis. PMID- 22261151 TI - Computational model for analyzing the evolutionary patterns of the neuraminidase gene of influenza A/H1N1. AB - In this study, we performed computer simulations to evaluate the changes of selection potentials of codons in influenza A/H1N1 from 1999 to 2009. We artificially generated the sequences by using the transition matrices of positively selected codons over time, and their similarities against the database of influenzavirus A genus were determined by BLAST search. This is the first approach to predict the evolutionary direction of influenza A virus (H1N1) by simulating the codon substitutions over time. We observed that the BLAST results showed the high similarities with pandemic influenza A/H1N1 in 2009, suggesting that the classical human-origin influenza A/H1N1 isolated before 2009 might contain some selection potentials of swine-origin viruses. Computer simulations using the time series codon substitution patterns resulted dramatic changes of BLAST results in influenza A/H1N1, providing a possibility of developing a method for predicting the viral evolution in silico. PMID- 22261152 TI - Unexpected result of Hendra virus outbreaks for veterinarians, Queensland, Australia. AB - A qualitative study of equine veterinarians and allied staff from Queensland, Australia, showed that veterinarians are ceasing equine practice because of fears related to Hendra virus. Their decisions were motivated by personal safety and legal liability concerns. PMID- 22261153 TI - [Mastoid bone graft in implantology. A case report]. AB - INTRODUCTION: In implantology, autogenous bone remains currently a useful material to rebuild horizontal and vertical osseous defects. Usually, it is the needed osseous volume that indicates the grafting procedure, intraoral one for small and middle volume and extraoral one for severely atrophied jaws. The originality of this case report is to show an alternative to usual grafting procedure borrowed from ENT surgeons: osseous mastoid graft. TECHNICAL NOTE: A 63 year-old patient with maxillary sinus pathology underwent during same surgical time maxillary sinus curetting and osseous grafting to finalize the dental treatment. DISCUSSION: Mastoid cortical bone is a source of bone usable in oral implantology. Its use has been proved to be reliable in oto-surgery. Mastoid bone harvesting implies the presence of ENT surgeon; it is nevertheless interesting to know this site from a biological point of view and because of its functional and economical aspects. PMID- 22261154 TI - Functional reorganization in the developing lexicon: separable and changing influences of lexical and phonological variables on children's fast-mapping. AB - Neighbourhood Density (ND) and Phonotactic Probability (PP) influence word learning in children. This influence appears to change over development but the separate developmental trajectories of influence of PP and ND on word learning have not previously been mapped. This study examined the cross-sectional developmental trajectories of influence of PP and ND on fast-mapping in thirty eight English-speaking children aged 3 ; 01-5 ; 02, in a task varying PP and ND orthogonally. PP and ND exerted separable influences on fast-mapping. Overall, low ND supported better fast-mapping. The influence of PP changed across the developmental trajectory, 'switching' from a high to a low PP advantage. A potential explanation for this 'switch' is advanced, suggesting that it represents functional reorganization in the developing lexicon, which emerges from changes in the developing lexicon, as phonological knowledge is abstracted from lexical knowledge, over development. PMID- 22261155 TI - Repeatable switching of the bending direction of ZnO nanoneedles by ion beams. AB - We studied the ion beam bending of ZnO nanoneedles to find the dependence of their bending direction on the ion beam energy and to clarify the bending mechanism. Through gallium focused ion beam (FIB) bending, the stems of the nanoneedles were found to be bent to the direction of the ion beam source for ion beam energies of 30 keV whereas they were bent in the opposite direction at ion energies lower than 20 keV. We found for the first time that the bending direction of ZnO nanoneedles could be changed by repeated switching of the ion beam energy between lower and higher energy levels, and that the thin tip parts of the nanoneedles were bent toward to the ion beam source like the higher energy bending mode during the process of lower energy bending below 20 keV. Through high resolution transmission electron microscopy (HRTEM) observations of the microstructure of a nanoneedle, bent by 30 keV higher energy ion beams, based on the atomic scale, we found that more edge dislocations were created in the rear side, deeper than the central plane of the nanoneedle, than the front side and that each edge dislocation added an extra lattice plane in this region. These observations clearly showed that the bent nanoneedles were plastically deformed by the edge dislocations created by the ion beams. PMID- 22261156 TI - Introducing a novel approach of network oriented analysis of ERPs, demonstrated on adult attention deficit hyperactivity disorder. AB - OBJECTIVE: Introducing a network-oriented analysis method (brain network activation [BNA]) of event related potential (ERP) activities and evaluating its value in the identification and severity-grading of adult ADHD patients. METHODS: Spatio-temporal interrelations and synchronicity of multi-sited ERP activity peaks were extracted in a group of 13 ADHD patients and 13 control subjects for the No-go stimulus in a Go/No-go task. Participants were scored by cross validation against the most discriminative ensuing group patterns and scores were correlated to neuropsychological evaluation scores. RESULTS: A distinct frontal central-parietal pattern in the delta frequency range, dominant at the P3 latency, was unraveled in controls, while central activity in the theta and alpha frequency ranges predominated in the ADHD pattern, involving early ERP components (P1-N1-P2-N2). Cross-validation based on this analysis yielded 92% specificity and 84% sensitivity and individual scores correlated well with behavioral assessments. CONCLUSIONS: These results suggest that the ADHD group was more characterized by the process of exerting attention in the early monitoring stages of the No-go signal while the controls were more characterized by the process of inhibiting the response to that signal. SIGNIFICANCE: The BNA method may provide both diagnostic and drug development tools for use in diverse neurological disorders. PMID- 22261157 TI - Apoptotic DC-SIGN+ cells in normal human decidua. AB - BACKGROUND: Normal pregnancy and spontaneous abortion in humans and mice are associated with immune responses. The decidua harbors dendritic cells identifiable in humans by their expression of DC-SIGN. Because dendritic cells are essential for immune response regulation, decidual DC-SIGN+ cells may play a role in normal or pathological pregnancy outcomes. Previous reports suggested that DC interact with NK cells in decidua, although the functional significance of this phenomenon remains unknown. OBJECTIVE: We studied the presence of conjugates of DC-SIGN+ cells with CD56+ NK cells in normal human decidua. METHODS: Conjugates of DC-SIGN+ cells with CD56+ NK cells were studied in leukocyte suspensions of normal human decidua (6-11 weeks) by flow cytometry and confocal microscopy. The presence of apoptotic cells was determined by the TUNEL assay, incubation with annexin V and confocal microscopy in decidual leukocyte suspensions and by the TUNEL assay in decidual sections. RESULTS: We observed conjugates of decidual DC-SIGN+ cells with CD56+ NK cells (40.2+/-26.1% of all the DC-SIGN+ cells by flow cytometry and 52.3+/-10.2% by confocal microscopy). We also found that a proportion of DC-SIGN+ cells were in apoptosis, since they were TUNEL+ (40.2+/-7.2% of all DC-SIGN+ cells in decidual sections) and annexin V+ (34.4+/-15.2% in leukocyte suspensions). And sorted DC-SIGN+ cells had multilobulated nuclei. CONCLUSIONS: The conjugates of decidual DC-SIGN+ cells with CD56+ NK cells strongly suggest that these latter cells induce apoptosis in DC-SIGN+ cells during normal pregnancy. We discuss this possibility in the context of maternal-fetal tolerance. PMID- 22261158 TI - Imaging in the management of ischemic cardiomyopathy: special focus on magnetic resonance. AB - Heart failure of ischemic origin has become increasingly common over the last decade because of the improved survival of patients with acute myocardial infarction. Revascularization with coronary bypass grafting or percutaneous coronary intervention plays a pivotal role in patients with ischemic cardiomyopathy, although these interventions are often associated with relatively high peri-procedural risk. The pathophysiological substrate of ischemic cardiomyopathy is heterogeneous, varying from predominantly hibernating myocardium to irreversible scarring. There is evidence to suggest that patients with hibernating myocardium benefit most from revascularization, whereas medical therapy is associated with an adverse prognosis. Therefore, noninvasive testing is recommended by relevant guidelines to guide optimal management in these patients. However, the role of noninvasive testing has recently been challenged. There are various imaging modalities available that provide information on different aspects of the disease, and therefore, they differ significantly in sensitivity and specificity. In clinical practice, choosing among the different imaging modalities can be difficult. Cardiac magnetic resonance has evolved into a comprehensive modality that can accurately determine the amount of hibernating myocardium as well as the presence and degree of myocardial ischemia and the extent of the scar. This paper reviews the indications, accuracy, and clinical utility of the available imaging techniques, with a special focus on cardiac magnetic resonance in ischemic cardiomyopathy, and provides an outlook on how this field might evolve in the future. PMID- 22261159 TI - Baseline anemia is not a predictor of all-cause mortality in outpatients with advanced heart failure or severe renal dysfunction. Results from the Norwegian Heart Failure Registry. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic impact of anemia in outpatients with chronic heart failure attending specialized heart failure clinics and specifically to investigate its prognostic utility in patients with severe renal dysfunction or advanced heart failure. BACKGROUND: Anemia is an independent prognostic marker in patients with heart failure. The effect of anemia on mortality decreases with increasing creatinine levels. METHODS: Multivariate Cox regression analyses were used to investigate the prognostic effect of anemia in 4,144 patients with heart failure from 21 outpatient heart failure clinics in Norway. Severe renal failure was defined as estimated glomerular filtration rate <=45 ml/min/1.73 m(2) and advanced heart failure as New York Heart Association functional classes IIIb and IV. RESULTS: Baseline anemia was present in 24% and was a strong predictor of all-cause mortality (adjusted hazard ratio [HR]: 1.30, 95% CI: 1.09 to 1.56, p = 0.004). Baseline anemia did not predict mortality in the 752 patients with severe renal dysfunction (adjusted HR: 1.08, 95 % CI: 0.77 to 1.51, p = 0.662) and the 528 patients with advanced heart failure (adjusted HR: 0.87, 95% CI: 0.56 to 1.34, p = 0.542). In the 1,743 patients who attended subsequent visits, sustained anemia independently predicted worse prognosis (adjusted HR: 1.47, 95% CI: 1.10 to 1.94, p = 0.008), whereas transient and new-onset anemia did not. CONCLUSIONS: According to our study, baseline anemia was not an independent predictor of all cause mortality in outpatients with heart failure and accompanied severe renal dysfunction or advanced heart disease. Sustained anemia after optimizing heart failure treatment might imply worse prognosis independently of renal function and New York Heart Association functional class. PMID- 22261161 TI - Coronary computed tomography angiography. The challenge of coronary calcium. PMID- 22261160 TI - Diagnostic accuracy of computed tomography coronary angiography according to pre test probability of coronary artery disease and severity of coronary arterial calcification. The CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) International Multicenter Study. AB - OBJECTIVES: The purpose of this study was to assess the impact of patient population characteristics on accuracy by computed tomography angiography (CTA) to detect obstructive coronary artery disease (CAD). BACKGROUND: The ability of CTA to exclude obstructive CAD in patients of different pre-test probabilities and in presence of coronary calcification remains uncertain. METHODS: For the CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) study, 371 patients underwent CTA and cardiac catheterization for the detection of obstructive CAD, defined as >=50% luminal stenosis by quantitative coronary angiography (QCA). This analysis includes 80 initially excluded patients with a calcium score >=600. Area under the receiver operating characteristic curve (AUC) was used to evaluate CTA diagnostic accuracy compared to QCA in patients according to calcium score and pre-test probability of CAD. RESULTS: Analysis of patient-based quantitative CTA accuracy revealed an AUC of 0.93 (95% confidence interval [CI]: 0.90 to 0.95). The AUC remained 0.93 (95% CI: 0.90 to 0.96) after excluding patients with known CAD but decreased to 0.81 (95% CI: 0.71 to 0.89) in patients with calcium score >=600 (p = 0.077). While AUCs were similar (0.93, 0.92, and 0.93, respectively) for patients with intermediate, high pre-test probability for CAD, and known CAD, negative predictive values were different: 0.90, 0.83, and 0.50, respectively. Negative predictive values decreased from 0.93 to 0.75 for patients with calcium score <100 or >=100, respectively (p = 0.053). CONCLUSIONS: Both pre-test probability for CAD and coronary calcium scoring should be considered before using CTA for excluding obstructive CAD. For that purpose, CTA is less effective in patients with calcium score >=600 and in patients with a high pre-test probability for obstructive CAD. PMID- 22261162 TI - Survival in patients with poorly compressible leg arteries. AB - OBJECTIVES: This study sought to compare survival of patients with poorly compressible arteries (PCA) to those with a normal ankle-brachial index (ABI) and those with peripheral arterial disease (PAD). BACKGROUND: Limited data are available regarding survival in patients with PCA identified in the clinical setting by noninvasive lower extremity arterial evaluation. METHODS: We conducted a historical cohort study of consecutive patients who underwent outpatient, noninvasive lower extremity arterial evaluation at the Mayo Clinic, Rochester, Minnesota, from January 1998 through December 2007, and who were followed for a mean duration of 5.8 +/- 3.1 years. An ABI 1.00 to 1.30 was considered normal, PAD was defined as a resting or post-exercise ABI <=0.90, and PCA defined as an ABI >=1.4 and/or an ankle systolic blood pressure >255 mm Hg. Patients were followed for all-cause mortality through September 30, 2009. RESULTS: Of 16,493 individuals (mean age 67.8 +/- 13.0 years, 59% male); 29% had normal ABI, 54% had PAD, and 17% had PCA. During follow-up (mean duration 5.8 +/- 3.1 years), 4,365 patients (26%) died. The percent alive at the end of the study period was 88%, 70%, and 60% for normal ABI, PAD, and PCA, respectively. After adjustment for age, sex, cardiovascular risk factors, comorbid conditions, and medication use, the hazard ratios (95% confidence intervals) of death associated with PCA were 2.0 (1.8 to 2.2) and 1.3 (1.2 to 1.4) compared with the normal ABI and PAD groups, respectively. CONCLUSIONS: Patients identified by noninvasive vascular testing to have poorly compressible leg arteries have poor survival, worse than those with a normal ABI or those with PAD. PMID- 22261163 TI - Highs and lows in the peripheral vasculature. PMID- 22261164 TI - Transcriptome characterization of estrogen-treated human myocardium identifies myosin regulatory light chain interacting protein as a sex-specific element influencing contractile function. AB - OBJECTIVES: This study investigated the effects of 17beta-estradiol (E2) on gene regulation in human cardiac tissues. We hypothesized that a candidate E2 effect is cardiomyocyte (CM)- and sex-specific, conserved between humans and mice, and that E2 impairs contractile function in male CMs only. BACKGROUND: Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood. METHODS: We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice. RESULTS: We found 36 E2 dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men. CONCLUSIONS: E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease. PMID- 22261165 TI - On male-specific estrogen action: good for the gander? PMID- 22261167 TI - Response to alemtuzumab in FIP1L1/PDGFRA-negative hypereosinophilic myocarditis on serial cardiac magnetic resonance imaging. PMID- 22261169 TI - Selection bias in "Prognostic impact of staged versus 'one-time' multivessel percutaneous intervention in acute myocardial infarction". PMID- 22261166 TI - Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. AB - OBJECTIVES: This study tested whether interleukin (IL)-17A is involved in the pathogenesis of mouse myocardial ischemia/reperfusion (I/R) injury and investigated the mechanisms. BACKGROUND: Inflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown. METHODS: The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro. RESULTS: Interleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that gammadeltaT lymphocytes but not CD4(+) helper T cells were a major source of IL-17A. Anti-IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression. CONCLUSIONS: IL-17A mainly produced by gammadeltaT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration. PMID- 22261170 TI - Is renal function-based contrast dosing of radiographic contrast media in patients undergoing percutaneous coronary intervention sufficient to delineate safe limits of contrast dose? PMID- 22261172 TI - Wolff-Parkinson-White syndrome and concentric left ventricular hypertrophy in a teenager: Danon disease. PMID- 22261173 TI - Deviation from Murray's law is associated with a higher degree of calcification in coronary bifurcations. AB - OBJECTIVE: Murray's law describes the optimal branching anatomy of vascular bifurcations. If Murray's law is obeyed, shear stress is constant over the bifurcation. Associations between Murray's law and intravascular ultrasound (IVUS) assessed plaque composition near coronary bifurcations have not been investigated previously. METHODS: In 253 patients plaque components (fibrous, fibro-fatty, necrotic core, and dense calcium) were identified by IVUS in segments proximal and distal to the bifurcation of a coronary side branch. The ratio of mother to daughter vessels was calculated according to Murray's law (Murray ratio) with a high Murray ratio indicating low shear stress. Analysis of variance was used to detect independent associations of Murray ratio and plaque composition. RESULTS: Patients with a high Murray ratio exhibited a higher relative amount of dense calcium and a lower amount of fibrous and fibro-fatty tissue than those with a low Murray ratio. After adjustment for age, sex, cardiovascular risk factors or concomitant medications, the Murray ratio remained significantly associated with fibrous volume distal (F-ratio 4.90, P=0.028) to the bifurcation, fibro-fatty volume distal (F-ratio 4.76, P=0.030) to the bifurcation, and dense calcium volume proximal (F-ratio 5.93, P=0.016) and distal (F-ratio 5.16, P=0.024) to the bifurcation. CONCLUSION: This study shows that deviation from Murray's law is associated with a high degree of calcification near coronary bifurcations. Individual deviations from Murray's law may explain why some patients are prone to plaque formation near vessel bifurcations. PMID- 22261174 TI - Production of 10-hydroxystearic acid from oleic acid by whole cells of recombinant Escherichia coli containing oleate hydratase from Stenotrophomonas maltophilia. AB - A putative fatty acid hydratase from Stenotrophomonas maltophilia was cloned and expressed in Escherichia coli. The recombinant enzyme showed the highest hydration activity for oleic acid among the fatty acids tested, indicating that the enzyme is an oleate hydratase. The optimal conditions for the production of 10-hydroxystearic acid from oleic acid using whole cells of recombinant E. coli containing the oleate hydratase were pH 6.5, 35 degrees C, 0.05% (w/v) Tween 40, 10 g l(-1) cells, and 50 g l(-1) oleic acid. Under these conditions, whole recombinant cells produced 49 g l(-1) 10-hydroxystearic acid for 4 h, with a conversion yield of 98% (w/w), a volumetric productivity of 12.3 g l(-1) h(-1), and a specific productivity of 1.23 g g-cells(-1) h(-1), which were 18%, 2.5-, and 2.5-fold higher than those of whole wild-type S. maltophilia cells, respectively. This is the first report of 10-hydroxystearic acid production using recombinant cells and the concentration and productivity are the highest reported thus far among cells. PMID- 22261175 TI - Regulation of the malic enzyme gene malE by the transcriptional regulator MalR in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is a Gram-positive nonpathogenic bacterium that is used for the biotechnological production of amino acids. Here, we investigated the transcriptional control of the malE gene encoding malic enzyme (MalE) in C. glutamicum ATCC 13032, which is known to involve the nitrogen regulator AmtR. Gel shift experiments using purified regulators RamA and RamB revealed binding of these regulators to the malE promoter. In DNA-affinity purification experiments a hitherto uncharacterized transcriptional regulator belonging to the MarR family was found to bind to malE promoter DNA and was designated as MalR. C. glutamicum cells overexpressing malR showed reduced MalE activities in LB medium or in minimal media with acetate, glucose, pyruvate or citrate. Deletion of malR positively affected MalE activities during growth in LB medium and minimal media with pyruvate, glucose or the TCA cycle dicarboxylates l-malate, succinate and fumarate. Transcriptional fusion analysis revealed elevated malE promoter activity in the malR deletion mutant during growth in pyruvate minimal medium suggesting that MalR acts as a repressor of malE. Purified MalR bound malE promoter DNA in gel shift experiments. Two MalR binding sites were identified in the malE promoter by mutational analysis. Thus, MalR contributes to the complex transcriptional control of malE which also involves RamA, RamB and AmtR. PMID- 22261176 TI - Hantavirus in bat, Sierra Leone. PMID- 22261177 TI - Microarray-based bioinformatics analysis of osteoblasts on TiO2 nanotube layers. AB - The TiO(2) nanotube layers fabricated by electrochemical anodization have received considerable attention in dentistry and orthopedic medicine due to their increased osseointegration compared with the unanodized titanium. The molecular mechanisms underlying the interactions between nanotubes and osteoblasts is unknown. To examine this, the mRNA expression profile of MG-63 osteoblast-like cells cultured on the TiO(2) nanotubes was explored by DNA microarray. The differentially expressed genes were identified by bioinformatics analysis. Gene ontology (GO) and Go-map network analysis indicated that the TiO(2) nanotubes enhanced osteoblast proliferation and differentiation and decreased osteoblast adhesion and immunization. The expressions of genes were mainly increased in pathways influencing cell proliferation and differentiation (Cell cycle, Terpenoid backbone biosynthesis, and TGF-beta signaling) and were decreased in pathways controlling cell immunization (Cell adhesion molecules (CAMs), Allograft rejection, and Graft-versus-host disease). Signal network analysis generated from differentially expressed genes suggested that CTNNB1 (beta-catenin) was the central gene for increasing osteoblast proliferation and differentiation, and IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma) was the central gene for repressing osteoblast immunization on nanotube layers. These two genes were further confirmed by quantitative PCR. The identified signal pathways and central genes in the study are well correlated with osteoblast phenotype. Furthermore, microarray-based bioinformatics analysis is a powerful tool in efficiently understanding molecular mechanisms underlying the interactions between osteoblasts and the nanotube layers. PMID- 22261178 TI - Aggregation effects of gold nanoparticles for single-base mismatch detection in influenza A (H1N1) DNA sequences using fluorescence and Raman measurements. AB - Aggregation effects of gold nanoparticles (AuNPs) were examined for the discrimination of single point mutations through the hybridization of oligonucleotides (25-50 nM) modified with a fluorescent Texas red dye. The sequences of oligonucleotides were designed to detect the H1N1 virus gene. Single base mismatch detection due to different adsorption propensities of oligonucleotides could be achieved using fluorescence quenching and surface enhanced Raman scattering (SERS) properties of the dye. We observed that the addition of perfectly matched double stranded DNA (pmdsDNA), modified with the Texas red dye in the suspension of citrate-reduced AuNPs could increase fluorescence recovery intensities more substantially than either single-base mismatched double stranded DNA (sbmdsDNA) or single stranded DNA (ssDNA). We also tested DNA hybridization under both aggregation and near non-aggregation conditions for fluorescence measurements. A spectral difference in fluorescence intensity between pmdsDNA and sbmdsDNA appeared to be more discriminating under near non-aggregation than aggregation conditions. On the other hand, the SERS intensities of pmdsDNA and sbmdsDNA decreased more significantly than that of ssDNA under aggregation conditions, whereas we could not observe any SERS intensities under non-aggregation conditions. PMID- 22261180 TI - Tobacco advertising, environmental smoking bans, and smoking in Chinese urban areas. AB - OBJECTIVES: To evaluate whether cigarette smoking in Chinese urban areas was respectively associated with exposure to tobacco advertising and smoking bans in households, workplaces, and public places. METHODS: Participants were 4735 urban residents aged 15 years and older, who were identified through multi-stage quota sampling conducted in six Chinese cities. Data were collected on individual sociodemographics and smoking status, and regional tobacco control measures. The sample was characterized in terms of smoking prevalence, and multilevel logistic models were employed to analyze the association between smoking and tobacco advertising and environmental smoking restrictions, respectively. RESULTS: Smoking prevalence was 30%. Multilevel logistic regression analysis showed that smoking was positively associated with exposure to tobacco advertising, and negatively associated with workplace and household smoking bans. CONCLUSIONS: The association of smoking with both tobacco advertising and environmental smoking bans further justifies implementation of comprehensive smoking interventions and tobacco control programs in China. PMID- 22261179 TI - Common liability to addiction and "gateway hypothesis": theoretical, empirical and evolutionary perspective. AB - BACKGROUND: Two competing concepts address the development of involvement with psychoactive substances: the "gateway hypothesis" (GH) and common liability to addiction (CLA). METHOD: The literature on theoretical foundations and empirical findings related to both concepts is reviewed. RESULTS: The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations. CONCLUSIONS: Whereas the "gateway" hypothesis does not specify mechanistic connections between "stages", and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non drug-specific prevention and early intervention. PMID- 22261181 TI - The H2O2 scavenger ebselen decreases ethanol-induced locomotor stimulation in mice. AB - BACKGROUND: In the brain, the enzyme catalase by reacting with H(2)O(2) forms Compound I (catalase-H(2)O(2) system), which is the main system of central ethanol metabolism to acetaldehyde. Previous research has demonstrated that acetaldehyde derived from central-ethanol metabolism mediates some of the psychopharmacological effects produced by ethanol. Manipulations that modulate central catalase activity or sequester acetaldehyde after ethanol administration modify the stimulant effects induced by ethanol in mice. However, the role of H(2)O(2) in the behavioral effects caused by ethanol has not been clearly addressed. The present study investigated the effects of ebselen, an H(2)O(2) scavenger, on ethanol-induced locomotion. METHODS: Swiss RjOrl mice were pre treated with ebselen (0-50mg/kg) intraperitoneally (IP) prior to administration of ethanol (0-3.75g/kg; IP). In another experiment, animals were pre-treated with ebselen (0 or 25mg/kg; IP) before caffeine (15mg/kg; IP), amphetamine (2mg/kg; IP) or cocaine (10mg/kg; IP) administration. Following these treatments, animals were placed in an open field to measure their locomotor activity. Additionally, we evaluated the effect of ebselen on the H(2)O(2)-mediated inactivation of brain catalase activity by 3-amino-1,2,4-triazole (AT). RESULTS: Ebselen selectively prevented ethanol-induced locomotor stimulation without altering the baseline activity or the locomotor stimulating effects caused by caffeine, amphetamine and cocaine. Ebselen reduced the ability of AT to inhibit brain catalase activity. CONCLUSIONS: Taken together, these data suggest that a decline in H(2)O(2) levels might result in a reduction of the ethanol locomotor-stimulating effects, indicating a possible role for H(2)O(2) in some of the psychopharmacological effects produced by ethanol. PMID- 22261182 TI - Legionella longbeachae and endocarditis. AB - We report a case of infectious endocarditis attributable to Legionella longbeachae. L. longbeachae is usually associated with lung infections. It is commonly found in composted waste wood products. L. longbeachae should be regarded as an agent of infectious endocarditis, notably in the context of gardening involving handling of potting soils. PMID- 22261183 TI - Cheyne-Stokes respiration due to chronic heart failure abates with coronary artery revascularization. AB - A 78-year-old man presented with dyspnea and mild heart failure with Cheyne Stokes respiration (CSR). Workup revealed inferolateral ischemia in the setting of significant triple vessel coronary disease, and nil else to adequately explain his dyspnea and eventual respiratory failure. After he underwent surgical revascularization, his ventricular function improved, leading to resolution of his respiratory failure and, of interest, his CSR. CSR is a central sleep apnea common in heart failure patients and has been associated with increased mortality. Here, we present the first English-literature report of CSR abating with surgical coronary revascularization, and briefly review the literature. PMID- 22261184 TI - Travelling home for treatment and EU patients' rights to care abroad: results of a survey among German students at Maastricht University. AB - Empirical evidence on patient mobility in Europe is lacking despite widespread legal, policy and media attention which the phenomenon attracts. This paper presents quantitative data on the health care seeking behaviour of German students at Maastricht University in the Netherlands. A cross-sectional survey design was applied with a mixed-methods approach including open and closed questions. Questionnaire items were based on a theoretical model of patient mobility and input from focus group discussions with German students living in Maastricht. 235 valid surveys were completed, representing ca. 8% of the target population. Data collection took place in Oct-Dec 2010. Of respondents who received medical care over the last two years, 97% returned to Germany; of these, 76% travelled to their home city for medical treatment. 72% received care only in Germany, i.e. not even once in Maastricht. Distance partly influenced whether students travelled to Germany, returned home or stayed in Maastricht, and the type of care accessed. Key motivations were familiarity with home providers/system, and reimbursement issues. In the context of the new EU Directive on patients' rights, the findings call into question whether Europeans use entitlements to cross-border care and what the real potential of patient mobility is. The results demonstrate the existence and magnitude of return movements as a sub-group of patient mobility. PMID- 22261185 TI - The emergence of grammar in very-low-birth-weight Finnish children at two years of age. AB - It is not well understood how grammar emerges in very-low-birth-weight (VLBW) children. The main aim of the present study was to gain information on the emergence of grammar in this group at 2 ; 0. The Finnish version of the Communicative Development Inventory was used to collect data from VLBW children (N = 156) and full-term controls (N = 146). At a group level, the grammatical skills of the VLBW children were significantly weaker than those of the controls. However, when the effect of lexicon size and premature birth on the emergence of grammar was analyzed in detail, few significant differences were found between the groups. The results suggest that even though grammar emerges more slowly for the VLBW children, it emerges in a manner comparable to that of the controls, when the effect of lexicon size is taken into consideration. PMID- 22261186 TI - Comparison of the Kato-Katz thick smear and McMaster egg counting techniques for monitoring drug efficacy against soil-transmitted helminths in schoolchildren on Pemba Island, Tanzania. AB - The Kato-Katz thick smear technique is widely used to assess prevalence and intensity in soil-transmitted helminth (STH) control programmes, but its usefulness in monitoring anthelminthic drug efficacy needs to be validated and compared with other methods. A promising alternative is the McMaster egg counting technique. In the present study, the efficacy of single-dose albendazole against STH infections in 430 schoolchildren on Pemba Island was assessed using both the Kato-Katz and McMaster techniques. The study revealed comparable drug efficacy results for both methods and confirmed the potency of the McMaster technique as an alternative method for monitoring large-scale deworming programmes. PMID- 22261187 TI - Changing prevalence of human microsporidiosis. AB - The frequency of publications about microsporidiosis, indexed in PubMed, was tracked on a yearly basis from 1980 to 2010. Search terms (individual and paired) of various degrees of restrictiveness were used (ranging from least restrictive: 'microsporidia', to most restrictive: 'microsporidiosis/HIV', 'microsporidiosis/AIDS'). The annual number of publications indexed under each search term(s) increased from the early 1980s until the mid 1990s. In subsequent years, there was a decline in numbers of publications retrievable via search terms emphasising human disease. This decline mirrors the declining prevalence of microsporidian infections in the HIV-infected population since the mid to late 1990s. PMID- 22261188 TI - Isolation, characterization of melanin derived from Ophiocordyceps sinensis, an entomogenous fungus endemic to the Tibetan Plateau. AB - Melanins are pigments of high molecular weight formed by oxidative polymerization of phenolic or indolic compounds. In this present study, a black pigment was isolated from the fermentation broth of Ophiocordyceps sinensis, an entomogenous fungus which is endemic to the Tibetan Plateau by alkaline extraction, acid hydrolysis, and repeated precipitation. It was designed as melanin since the physical and chemical properties including its ultraviolet (UV) and infrared (IR) spectra of the black pigment conformed to the characteristic of melanin and similar to the commercial synthetic melanin. The antioxidant activity of melanin derived from O. sinensis was evaluated. They showed much stronger scavenging abilities on 1,1-diphenyl-2-picrylhydrazyl (DPPH*) and the chelating ability on ferrous ions than that of the water extract from the mycelia of O. sinensis, with IC(50) value 18.51 +/- 0.85 MUg/ml and 2.58 +/- 0.26 MUg/ml, separately. This is the first report of melanin from O. sinensis and will be helpful for the study on the physiology and the artificial cultivation of this fungus, an endangered species. PMID- 22261189 TI - The synergistic effect of nanocrystal integration and process optimization on solar cell efficiency. AB - This paper investigates the roles of semiconducting single-walled carbon nanotubes (SWNTs) and metallic SWNTs in the SWNT/poly(3-hexylthiophene) (P3HT) based photovoltaic conversion system. SWNTs containing different fractions of semiconducting nanotubes were conjugated with P3HT by virtue of pi-pi interaction. The energy transfer and carrier transport mechanisms in the photovoltaic composites were experimentally investigated by optical absorption spectroscopy, photoluminescence spectroscopy and carrier mobility measurements. At low loading of SWNTs, a high percentage of semiconducting nanotubes result in diminished non-radiative decay of exciton and lower carrier mobility, causing higher open circuit voltage and lower photocurrent. At an optimized morphology, SWNT/P3HT/phenyl-C61-butyric acid methyl ester (PCBM) hybrid-based solar cells demonstrated much higher photocurrent than a reference solar cell (P3HT:PCBM) due to the improved carrier mobility. Further thermal annealing of the devices significantly increased the open circuit voltage to 610 mV, resulting in an 80% increase of power conversion efficiency in comparison to the reference solar cell. These results are expected to lay a foundation for the integration of various nanocrystals into solar cells for efficient photovoltaic conversion. PMID- 22261190 TI - CTRP family: linking immunity to metabolism. AB - It is well known that infectious and inflammatory diseases such as sepsis and severe inflammatory response syndrome are accompanied by metabolic alterations such as insulin resistance. Conversely, metabolic diseases such as visceral obesity and type 2 diabetes are characterized by high levels of proinflammatory cytokines. Metabolism and immunity are linked by proteins of dual function. Adiponectin, a member of the C1q/TNF-related protein (CTRP) family, has attracted much interest because of its anti-inflammatory and insulin-sensitizing effects. To date, 15 additional CTRP family members have been identified that might also play a role in metabolism and immunity. This review focuses on the biochemistry and pleiotropic physiological functions of CTRPs as new molecular mediators connecting inflammatory and metabolic diseases. PMID- 22261191 TI - Varicella-zoster virus-specific cell-mediated immunity in subjects with herpes zoster. AB - Though cell-mediated immunity (CMI) against varicella-zoster virus (VZV) is critical for prevention of the onset of herpes zoster (HZ), clinicians currently lack a simplified procedure to monitor CMI. We have recently developed an assay, called the IFN-gamma release assay, and showed that it is a simple and reliable method to determine VZV-specific CMI. In the present study, we applied an IR assay to measure the VZV-specific CMI of patients with HZ. VZV-specific CMI levels were significantly high at the onset of the disease, but were decreased several weeks later. In contrast, CMI VZV-specific antibody titers increased in convalescent phase compared to those in acute phase. Thus, this technology is likely to be very useful in monitoring ongoing VZV-specific immune status. PMID- 22261193 TI - Extracellular matrix proteomics in cardiac ischemia/reperfusion: the search is on. PMID- 22261192 TI - Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. AB - BACKGROUND: An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia. METHODS AND RESULTS: We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation and examined for an association between the sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks. The median sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared with those who did not (47.0 [25th-75th percentile, 15.5-112.2] versus 10.8 [25th-75th percentile, 4.1-28.6]; P<0.0001). Among those presenting at <34 weeks (n=167), the results were more striking (226.6 [25th-75th percentile, 50.4-547.3] versus 4.5 [25th-75th percentile, 2.0-13.5]; P<0.0001), and the risk was markedly elevated when the highest sFlt1/PlGF ratio tertile was compared with the lowest (odds ratio, 47.8; 95% confidence interval, 14.6-156.6). Among participants presenting at <34 weeks, the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (area under the curve, 0.93 for hypertension, proteinuria, and sFlt1/PlGF versus 0.84 for hypertension and proteinuria alone; P=0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt1/PlGF ratio >=85 compared with 15.8% of women with an sFlt1/PlGF ratio <85 (hazard ratio, 15.2; 95% confidence interval, 8.0-28.7). CONCLUSIONS: In women with suspected preeclampsia presenting at <34 weeks, circulating sFlt1/PlGF ratio predicts adverse outcomes occurring within 2 weeks. The accuracy of this test is substantially better than that of current approaches and may be useful in risk stratification and management. Additional studies are warranted to validate these findings. PMID- 22261194 TI - Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury. AB - BACKGROUND: After myocardial ischemia, extracellular matrix (ECM) deposition occurs at the site of the focal injury and at the border region. METHODS AND RESULTS: We have applied a novel proteomic method for the analysis of ECM in cardiovascular tissues to a porcine model of ischemia/reperfusion injury. ECM proteins were sequentially extracted and identified by liquid chromatography tandem mass spectrometry. For the first time, ECM proteins such as cartilage intermediate layer protein 1, matrilin-4, extracellular adipocyte enhancer binding protein 1, collagen alpha-1(XIV), and several members of the small leucine-rich proteoglycan family, including asporin and prolargin, were shown to contribute to cardiac remodeling. A comparison in 2 distinct cardiac regions (the focal injury in the left ventricle and the border region close to the occluded coronary artery) revealed a discordant regulation of protein and mRNA levels; although gene expression for selected ECM proteins was similar in both regions, the corresponding protein levels were much higher in the focal lesion. Further analysis based on >100 ECM proteins delineated a signature of early- and late stage cardiac remodeling with transforming growth factor-beta1 signaling at the center of the interaction network. Finally, novel cardiac ECM proteins identified by proteomics were validated in human left ventricular tissue acquired from ischemic cardiomyopathy patients at cardiac transplantation. CONCLUSION: Our findings reveal a biosignature of early- and late-stage ECM remodeling after myocardial ischemia/reperfusion injury, which may have clinical utility as a prognostic marker and modifiable target for drug discovery. PMID- 22261195 TI - Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. AB - BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the low-density lipoprotein (LDL) receptor. PCSK9 gain of function in humans leads to autosomal dominant hypercholesterolemia, whereas the absence of functional PCSK9 results in ~7-fold lower levels of LDL cholesterol. This suggests that lowering PCSK9 may protect against atherosclerosis. METHODS AND RESULTS: We investigated the role of PCSK9 in atherosclerosis in C57BL/6 wild-type (WT), apolipoprotein E-deficient, and LDL receptor-deficient mouse models. Circulating cholesterol levels, fast protein liquid chromatography profiles, aortic cholesteryl esters (CE), and plaque sizes were determined. Intima-media thicknesses were measured by ultrasound biomicroscopy. First, mice expressing null (knockout [KO]), normal (WT), or high (transgenic [Tg]) levels of PCSK9 were fed a 12-month Western diet. KO mice accumulated 4-fold less aortic CE than WT mice, whereas Tg mice exhibited high CE and severe aortic lesions. Next we generated apolipoprotein E-deficient mice, known to spontaneously develop lesions, that expressed null (KO/e), normal (WT/e), or high (Tg/e) levels of PCSK9. After a 6-month regular diet, KO/e mice showed a 39% reduction compared with WT/e mice in aortic CE accumulation, whereas Tg/e mice showed a 137% increase. Finally, LDL receptor-deficient mice expressing no (KO/L), normal (WT/L), or high (Tg/L) levels of PCSK9 were fed a Western diet for 3 months. KO/L and Tg/L mice exhibited levels of plasma cholesterol and CE accumulation similar to those of WT/L mice, suggesting that PCSK9 modulates atherosclerosis mainly via the LDL receptor. CONCLUSIONS: Altogether, our results show a direct relationship between PCSK9 and atherosclerosis. PCSK9 overexpression is proatherogenic, whereas its absence is protective. PMID- 22261196 TI - Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior. AB - BACKGROUND: The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node. METHODS AND RESULTS: We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs. CONCLUSIONS: This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial compatible spontaneous cardiomyocytes from the patient's own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers. PMID- 22261197 TI - Human biological pacemakers: intrinsic variability and stability. PMID- 22261198 TI - Impact of progression of diastolic dysfunction on mortality in patients with normal ejection fraction. AB - BACKGROUND: Diastolic dysfunction is an independent predictor of mortality in patients with normal left ventricular ejection fraction. There are limited data, however, on whether worsening of diastolic function is associated with worse prognosis. METHODS AND RESULTS: We reviewed clinical records and echocardiograms of consecutive patients who had baseline echocardiograms between January 1, 2005, and December 31, 2009, that showed left ventricular ejection fraction >=55% and who subsequently had a follow-up echocardiogram within 6 to 24 months. Diastolic function was labeled as normal, mild, moderate, or severe dysfunction. All-cause mortality was determined by use of the Social Security Death Index. Kaplan-Meier survival analysis and Cox regression analysis with a proportional hazard model were performed to assess outcomes. A total of 1065 outpatients were identified (mean+/-SD age, 67.9+/-13.9 years; 58% male). Baseline diastolic dysfunction was present in 770 patients (72.3%), with mild being the most prevalent. On follow-up testing (mean+/-SD, 1.1+/-0.4 years), 783 patients (73%) had stable, 168 (16%) had worsening, and 114 (11%) had improved baseline diastolic function. Eighty eight patients (8.3%) had a decrease in left ventricular ejection fraction to <55% and were more likely to have advanced diastolic dysfunction (P=0.002). After a mean+/-SD follow-up (from the second study) of 1.6+/-0.8 years, 142 patients (13%) died. On multivariate analysis, a decrease in left ventricular ejection fraction to <55% and any worsening of diastolic function were independently associated with increased risk of mortality (hazard ratio, 1.78; 95% confidence interval, 1.10-2.85; P=0.02; and hazard ratio, 1.78; 95% confidence interval, 1.21-2.59; P=0.003, respectively). CONCLUSION: In patients with normal baseline left ventricular ejection fraction, worsening of diastolic function is an independent predictor of mortality. PMID- 22261199 TI - Left ventricle diastolic dysfunction and prognosis. PMID- 22261200 TI - Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. AB - BACKGROUND: The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. METHODS AND RESULTS: We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14 1.49). CONCLUSIONS: The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00391872. PMID- 22261201 TI - Emergence of Blastoschizomyces capitatus yeast infections, Central Europe. AB - We report 5 cases of disseminated infection caused by Blastoschizomyces capitatus yeast in central Switzerland. The emergence of this yeast in an area in which it is not known to be endemic should alert clinicians caring for immunocompromised patients outside the Mediterranean region to consider infections caused by unfamiliar fungal pathogens. PMID- 22261202 TI - Diffusion-weighted magnetic resonance imaging for diagnosis of liver fibrosis and inflammation in chronic viral hepatitis: the performance of low or high B values and small or large regions of interest. AB - OBJECTIVE: To investigate the performance of different b values and regions of interest (ROI) for diagnosing liver fibrosis in patients with chronic viral hepatitis by using diffusion-weighted (DW) magnetic resonance imaging (MRI). METHODS: Eleven healthy participants and 33 patients with viral hepatitis B or C were enrolled. The stage of liver fibrosis and the grade of necroinflammation were determined by using a histologic activity index. Single-shot spin-echo echo planar DW-MRI was performed in all participants at b values of 0-500, 0-700, and 0-1000 s/mm(2) by using 2 circular small and large ROIs of 100 and 200 mm(2). To evaluate the performance of different b values for determining cirrhosis, the receiver-operating characteristic curves were depicted, and the areas under the curves were compared. RESULTS: The average values of apparent diffusion coefficients significantly decreased with increasing stage or grade categories at all the 3 b values and for both small and large ROIs. The performance at b = 500 s/mm(2) was significantly better than b = 1000 s/mm(2) for determining cirrhosis or bridging fibrosis. The cut point of 153.4 for apparent diffusion coefficient (*10(-5) mm(2)/s) at b = 500 s/mm(2) could determine cirrhosis or bridging fibrosis with a sensitivity of 96% and specificity of 82%. No difference was found between the average apparent diffusion coefficient values of large or small ROIs. Also, there was no difference in performance of large or small ROIs in the diagnosis of liver fibrosis. CONCLUSIONS: This study provided beneficial data for clinical utilisation of DW-MRI in diagnosing liver fibrosis: b = 500 s/mm(2) is better in performance than b = 1000 s/mm(2), and a small ROI of 100 mm(2) is sufficient for determining cirrhosis or bridging fibrosis. PMID- 22261203 TI - Primary hepatocyte cultures as in vitro tools for toxicity testing: quo vadis? AB - Cultures of primary hepatocytes are versatile tools that can serve many in vitro toxicity testing purposes. However, they cope with dedifferentiation, a process that is already initiated during the hepatocyte isolation procedure and that is manifested as the progressive loss of functionality upon subsequent cultivation. A number of strategies to prevent dedifferentiation have been introduced over the last decades, all which aim at re-establishing the in vivo hepatocyte micro environment in vitro, but that are of merely limited success. Recent mechanistic insight into the mechanisms that underlie hepatocyte dedifferentiation has opened new avenues for the development of novel approaches that target the actual causes of this deteriorative process and thus for the generation of a long-term hepatic in vitro tool. Such experimental system is urgently needed, especially in the light of the stringent European legislative modifications that are currently encountered by the pharmaceutical, chemical and, particularly, the cosmetic industry. PMID- 22261204 TI - Cytotoxic effects of 109 reference compounds on rat H4IIE and human HepG2 hepatocytes. III: Mechanistic assays on oxygen consumption with MitoXpress and NAD(P)H production with Alamar BlueTM. AB - In vitro toxicity screening can reduce the attrition rate of drug candidates in the pharmaceutical industry in the early development process. The focus in this study is to compare the sensitivity for cytotoxicity of a time-resolved fluoro metric oxygen probe with that of a fluoro metric Alamar BlueTM (AB) assay. Both assays measure mitochondrial activity by either oxygen consumption (LUX-A65N-1 (MitoXpress, Luxcel) probe) or NADH/FADH conversion (AB). Both assays were carried out with increasing concentrations of 109 reference compounds using rat H4IIE and human HepG2 hepatocytes at incubation periods of 24, 48 and 72 h. Prior to this study, the influence on medium with either glucose or galactose was studied to analyze the rate of glycolysis and oxygen consumption, which latter process may be impaired in hepatoma cells. Inhibitors of oxygen consumption in combination with a glucose up-take inhibitor showed the largest consumption rate differences in the presence of 5mM of glucose. The choice for the 109 reference compounds was based on the so-called Multicentre Evaluation for In vitro Cytotoxicity (MEIC) and on diverse drug categories. For 59 toxic reference compounds, an evaluation for both assays was carried up to 10(-3)M. Toxicity was demonstrated with MitoXpress for 23 (39%) and 36 (61%) compounds in H4IIE and HepG2 cells, respectively, and with AB for 44 (75%) and 40 (68%) compounds. For 50 more pharmaceutical drugs more physiological concentrations were used up to 3.16*10(-5)M, and only 19 (38%) of these compounds appeared to be toxic in both assays. In conclusion, overall 63 (58%) and 60 (55%) compounds showed toxic effects with the MitoXpress and AB assays on rat H4IIE and human HepG2 hepatocytes, respectively. AB assays were more sensitive with respect to H4IIE cells and MitoXpress assays with respect to HepG2 cells. At all tested time intervals, MitoXpress showed its sensitivity, while AB is more sensitive at 48 and 72 h. With AB more toxic compounds were identified, whereas MitoXpress was more sensitive for a few compounds. A species specific difference was clearly found with digoxin, a human specific potassium channel inhibitor. Thus both assays are valuable identifiers of early toxicity with discrimination in time, compounds and species. PMID- 22261205 TI - Classical swine fever virus NS5A protein interacts with 3'-untranslated region and regulates viral RNA synthesis. AB - To investigate the function of classical swine fever virus (CSFV) NS5A protein, the experiments for viral RNA synthesis and viral replication were performed in the co-presence of NS5A and NS5B. Results showed that small concentrations of NS5A stimulated, large concentrations of NS5A inhibited, viral RNA synthesis and viral replication. Affinity chromatography experiments and UV-crosslinking assays revealed that CSFV NS5A and NS5B bound its cognate 3'UTR and that NS5A had higher affinity than NS5B protein in binding to 3'UTR. 200 ng of NS5A inhibited NS5B 3'UTR complex formation by about 95%. CSFV 3'UTR was found to contain two NS5A binding sites, located in 3'UTRSL-1 (nt 161-231) and 3'UTRSL-2 (nt 90-160), respectively, a NS5B-binding site, also located in 3'UTRSL-1. The 3'UTRSL-1 is the common binding site for NS5A and NS5B. Furthermore, competitive electrophoretic mobility shift assays indicated that binding of CSFV NS5A to 3'UTRSL-1 is more efficiently than to 3'UTRSL-2. These results suggested that the different concentrations of NS5A, the different binding activities of NS5A and NS5B to 3'UTR and binding of NS5A to different regions of 3'UTR might contribute at least partially to modulation of CSFV replication. PMID- 22261207 TI - Active commuting to school among adolescents in Ho Chi Minh City, Vietnam: change and predictors in a longitudinal study, 2004 to 2009. AB - BACKGROUND: Active commuting (walking or cycling) to/from school is an important part of the overall physical activity levels of children but is on the decline in many countries. Data for adolescents on mode of transportation to and from school are limited for low- and middle-income countries, including Vietnam. PURPOSE: This paper aims to describe the changes in the prevalence of active commuting to and from school, and to examine prospectively the predictors of active commuting, among adolescents from Ho Chi Minh City (HCMC). METHODS: The data are from a 5 year cohort study from 2004 of a representative sample of 759 adolescents from 18 schools in HCMC. Data were obtained at five annual assessments using validated questionnaires to capture commuting behaviors, socioeconomic and demographic factors, individual and family characteristics, and physical and social environmental factors. Height and weight were measured by trained staff using standardized guidelines. Generalized linear latent and mixed models with a hierarchic approach were used to analyze the data in 2011. RESULTS: The results show a remarkable decrease in the prevalence of active commuting in adolescents from 27.8% in 2004 to 19.6% in 2009. Male students, from the least-wealthy families, living in suburban areas, close to school, studying at schools in less wealthy districts, were more likely to actively commute. CONCLUSIONS: In the context of an epidemic of childhood and adolescent obesity in urban Vietnam, the decline in active commuting over the 5 years of this study highlights the need for development of urban physical environments favorable for active commuting and education campaigns to promote active commuting in adolescents. PMID- 22261206 TI - Exergaming and older adult cognition: a cluster randomized clinical trial. AB - BACKGROUND: Dementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual reality-enhanced exercise or "exergames" may elicit greater participation. PURPOSE: To test the following hypotheses: (1) stationary cycling with virtual reality tours ("cybercycle") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain improvement; and (3) brain-derived neurotrophic growth factor (BDNF) will increase. DESIGN: Multi-site cluster randomized clinical trial (RCT) of the impact of 3 months of cybercycling versus traditional exercise, on cognitive function in older adults. Data were collected in 2008 2010; analyses were conducted in 2010-2011. SETTING/PARTICIPANTS: 102 older adults from eight retirement communities enrolled; 79 were randomized and 63 completed. INTERVENTIONS: A recumbent stationary ergometer was utilized; virtual reality tours and competitors were enabled on the cybercycle. MAIN OUTCOME MEASURES: Executive function (Color Trails Difference, Stroop C, Digits Backward); clinical status (mild cognitive impairment; MCI); exercise effort/fitness; and plasma BDNF. RESULTS: Intent-to-treat analyses, controlling for age, education, and cluster randomization, revealed a significant group X time interaction for composite executive function (p=0.002). Cybercycling yielded a medium effect over traditional exercise (d=0.50). Cybercyclists had a 23% relative risk reduction in clinical progression to MCI. Exercise effort and fitness were comparable, suggesting another underlying mechanism. A significant group X time interaction for BDNF (p=0.05) indicated enhanced neuroplasticity among cybercyclists. CONCLUSIONS: Cybercycling older adults achieved better cognitive function than traditional exercisers, for the same effort, suggesting that simultaneous cognitive and physical exercise has greater potential for preventing cognitive decline. TRIAL REGISTRATION: This study is registered at Clinicaltrials.gov NCT01167400. PMID- 22261209 TI - Promoting routine stair use: evaluating the impact of a stair prompt across buildings. AB - BACKGROUND: Although studies have demonstrated that stair prompts are associated with increased physical activity, many were conducted in low-rise buildings over a period of weeks and did not differentiate between stair climbing and descent. PURPOSE: This study evaluated the impact of a prompt across different building types, and on stair climbing versus descent over several months. METHODS: In 2008 2009, stair and elevator trips were observed and analyzed at three buildings in New York City before and after the posting of a prompt stating "Burn Calories, Not Electricity" (total observations=18,462). Sites included a three-story health clinic (observations=4987); an eight-story academic building (observations=5151); and a ten-story affordable housing site (observations=8324). Stair and elevator trips up and down were recorded separately at the health clinic to isolate the impact on climbing and descent. Follow-up was conducted at the health clinic and affordable housing site to assess long-term impact. RESULTS: Increased stair use was seen at all sites immediately after posting of the prompt (range=9.2%-34.7% relative increase, p<0.001). Relative increases in stair climbing (20.2% increase, p<0.001) and descent (4.4% increase, p<0.05) were seen at the health clinic. At both sites with long-term follow-up, relative increases were maintained at 9 months after posting compared to baseline: 42.7% (p<0.001) increase in stair use at the affordable housing site and 20.3% (p<0.001) increase in stair climbing at the health clinic. CONCLUSIONS: Findings suggest that the prompt was effective in increasing physical activity in diverse settings, and increases were maintained at 9 months. PMID- 22261208 TI - School and residential neighborhood food environment and diet among California youth. AB - BACKGROUND: Various hypotheses link neighborhood food environments and diet. Greater exposure to fast-food restaurants and convenience stores is thought to encourage overconsumption; supermarkets and large grocery stores are claimed to encourage healthier diets. For youth, empirical evidence for any particular hypothesis remains limited. PURPOSE: This study examines the relationship between school and residential neighborhood food environment and diet among youth in California. METHODS: Data from 8226 children (aged 5-11 years) and 5236 adolescents (aged 12-17 years) from the 2005 and 2007 California Health Interview Survey were analyzed in 2011. The dependent variables are daily servings of fruits, vegetables, juice, milk, soda, high-sugar foods, and fast food, which were regressed on measures of food environments. Food environments were measured by counts and density of businesses, distinguishing fast-food restaurants, convenience stores, small food stores, grocery stores, and large supermarkets within a specific distance (varying from 0.1 to 1.5 miles) from a respondent's home or school. RESULTS: No robust relationship between food environment and consumption is found. A few significant results are sensitive to small modeling changes and more likely to reflect chance than true relationships. CONCLUSIONS: This correlational study has measurement and design limitations. Longitudinal studies that can assess links between environmental, dependent, and intervening food purchase and consumption variables are needed. Reporting a full range of studies, methods, and results is important as a premature focus on correlations may lead policy astray. PMID- 22261210 TI - Self-reported alcohol-impaired driving in the U.S., 2006 and 2008. AB - BACKGROUND: Alcohol-impaired driving caused 10,839 deaths in 2009. Alcohol impaired driving fatalities as a percentage of all motor vehicle fatalities decreased from 1982 to 1999 but have remained stable since. Understanding characteristics of those who engage in this behavior is critical to achieving future reductions. PURPOSE: The purpose of this study is to estimate the number of episodes of self-reported alcohol-impaired driving and to explore the related demographic factors and drinking patterns. METHODS: Data from the 2006 and 2008 Behavioral Risk Factor Surveillance System were used in 2010 to produce annualized estimates of alcohol-impaired driving episodes. Logistic regression modeling was used to explore the effects of drinking patterns, seatbelt use, and sociodemographics. RESULTS: The percentage of the population reporting at least one alcohol-impaired driving episode in the past 30 days was 2.2% for 2006 and 2008 combined. The number of annualized episodes of alcohol-impaired driving was 147 million. Annualized episode rates varied across states from 165 to 1242 episodes per 1000 population. Characteristics associated with alcohol-impaired driving differed by gender. The strongest correlate of alcohol-impaired driving was binge drinking, with those reporting binge drinking at least once per month being five to six times as likely to report alcohol-impaired driving when adjusting for all other variables. CONCLUSIONS: Understanding who is most likely to report alcohol-impaired driving is important in developing interventions to prevent this behavior. Interventions that are known to be effective, such as sobriety checkpoints and installing ignition interlocks on the vehicles of people convicted of alcohol-impaired driving, should be widely implemented. PMID- 22261211 TI - U.S. hookah tobacco smoking establishments advertised on the internet. AB - BACKGROUND: Establishments dedicated to hookah tobacco smoking recently have proliferated and helped introduce hookah use to U.S. communities. PURPOSE: To conduct a comprehensive, qualitative assessment of websites promoting these establishments. METHODS: In June 2009, a systematic search process was initiated to access the universe of websites representing major hookah tobacco smoking establishments. In 2009-2010, codebook development followed an iterative paradigm involving three researchers and resulted in a final codebook consisting of 36 codes within eight categories. After two independent coders had nearly perfect agreement (Cohen's kappa = 0.93) on double-coding the data in the first 20% of sites, the coders divided the remaining sites and coded them independently. A thematic approach to the synthesis of findings and selection of exemplary quotations was used. RESULTS: The search yielded a sample of 144 websites originating from states in all U.S. regions. Among the hookah establishments promoted on the websites, 79% served food and 41% served alcohol. Of the websites, none required age verification, <1% included a tobacco-related warning on the first page, and 4% included a warning on any page. Although mention of the word tobacco was relatively uncommon (appearing on the first page of only 26% sites and on any page of 58% of sites), the promotion of flavorings, pleasure, relaxation, product quality, and cultural and social aspects of hookah smoking was common. CONCLUSIONS: Websites may play a role in enhancing or propagating misinformation related to hookah tobacco smoking. Health education and policy measures may be valuable in countering this misinformation. PMID- 22261215 TI - Physical activity of children attending afterschool programs: research- and practice-based implications. AB - BACKGROUND: Afterschool programs (3PM-6PM; ASPs) are positioned to play a vital role in the improvement of children's daily physical activity. Recent guidelines specify that children should accumulate 4600 steps per day while attending an ASP. The extent to which ASPs currently meet this goal and how many steps per day children naturally accumulate within the ASP setting is unknown. PURPOSE: The purpose of this study was to describe the pedometer-determined physical activity of a large sample of children attending a diverse range of ASPs and evaluate the extent to which ASPs are meeting current physical activity guidelines. METHODS: Children (N=934, 51% girls, average 8.2 years; range 4-14 years) enrolled across 25 ASPs wore Walk4Life MVPa pedometers (number of steps accumulated, time spent active [hours:minutes:seconds]) up to 4 days. Data were collected in fall/spring 2010-2011 and analyzed in summer 2011. RESULTS: On average, children attended ASPs for 125 minutes per day, accumulated 2944 steps per day, and spent approximately 26.6 minutes per day in physical activity. Only 16.5% of the 1819 daily observations met the 4600 steps per day guideline. No differences in steps per day, minutes per day in physical activity, or demographics were observed among children measured a single day versus 2, 3, or 4 days. Based on current practice, children would need to spend approximately 3.4 hours per day at an ASP to reach 4600 steps per day. CONCLUSIONS: Activity levels in ASPs are well below recommendations. Substantial effort is needed to identify strategies ASPs can employ to ensure children are sufficiently active. PMID- 22261212 TI - Assessing the value of team science: a study comparing center- and investigator initiated grants. AB - BACKGROUND: Large cross-disciplinary scientific teams are becoming increasingly prominent in the conduct of research. PURPOSE: This paper reports on a quasi experimental longitudinal study conducted to compare bibliometric indicators of scientific collaboration, productivity, and impact of center-based transdisciplinary team science initiatives and traditional investigator-initiated grants in the same field. METHODS: All grants began between 1994 and 2004 and up to 10 years of publication data were collected for each grant. Publication information was compiled and analyzed during the spring and summer of 2010. RESULTS: Following an initial lag period, the transdisciplinary research center grants had higher overall publication rates than the investigator-initiated R01 (NIH Research Project Grant Program) grants. There were relatively uniform publication rates across the research center grants compared to dramatically dispersed publication rates among the R01 grants. On average, publications produced by the research center grants had greater numbers of coauthors but similar journal impact factors compared with publications produced by the R01 grants. CONCLUSIONS: The lag in productivity among the transdisciplinary center grants was offset by their overall higher publication rates and average number of coauthors per publication, relative to investigator-initiated grants, over the 10 year comparison period. The findings suggest that transdisciplinary center grants create benefits for both scientific productivity and collaboration. PMID- 22261214 TI - A conflict between nutritionally adequate diets and meeting the 2010 dietary guidelines for sodium. AB - BACKGROUND: Compliance with dietary guidelines means incorporating multiple foods and nutrients into everyday diets, to be consumed in smaller or larger amounts. Feasibility studies can help determine whether one nutrient guideline comes into conflict with another. For one half of the U.S. population, the 2010 dietary guidelines for sodium were set at 1500 mg/d. PURPOSE: To test the compatibility of the 1500 mg/day sodium goal with nutrient-adequate diets. METHODS: Analyses, conducted in 2010, used U.S. federal nutrient composition and dietary intake databases to create modeled food patterns for six gender-age groups using linear programming techniques. The food patterns were designed to meet nutritional standards for 27 nutrients as the mean sodium content was progressively reduced from levels observed in the 2001-2002 National Health and Nutrition Examination Survey (NHANES) down to 1500 mg/day. RESULTS: For adults aged <50 years, the 2300 mg/day sodium goal was consistent with nutrient-adequate diets but required large deviations from current eating patterns. The 1500 mg/day goal was not feasible and no mathematical solution was obtained. The lowest-sodium food patterns that were nutrient-adequate and theoretically achievable were very high in fruit juices, nuts, and seeds but were low in grains and meats. CONCLUSIONS: Compliance with the 2010 sodium guidelines will require large deviations from current eating behaviors and/or a profound modification of the U.S. food supply. PMID- 22261213 TI - Prioritization of evidence-based preventive health services during periodic health examinations. AB - BACKGROUND: Delivery of preventive services sometimes falls short of guideline recommendations. PURPOSE: To evaluate the multilevel factors associated with evidence-based preventive service delivery during periodic health examinations (PHEs). METHODS: Primary care physicians were recruited from an integrated delivery system in southeast Michigan. Audio recordings of PHE office visits conducted from 2007 to 2009 were used to ascertain physician recommendation for or delivery of 19 guideline-recommended preventive services. Alternating logistic regression was used to evaluate factors associated with service delivery. Data analyses were completed in 2011. RESULTS: Among 484 PHE visits to 64 general internal medicine and family physicians by insured patients aged 50-80 years, there were 2662 services for which patients were due; 54% were recommended or delivered. Regression analyses indicated that the likelihood of service delivery decreased with patient age and with each concern the patient raised, and it increased with increasing BMI and with each additional minute after the scheduled appointment time the physician first presented. The likelihood was greater with patient-physician gender concordance and less if the physician used the electronic medical record in the exam room or had seen the patient in the past 12 months. CONCLUSIONS: A combination of patient, patient-physician relationship, and visit contextual factors are associated with preventive service delivery. Additional studies are warranted to understand the complex interplay of factors that support and compromise preventive service delivery. PMID- 22261219 TI - Conditional mutual information-based feature selection for congestive heart failure recognition using heart rate variability. AB - Feature selection plays an important role in pattern recognition systems. In this study, we explored the problem of selecting effective heart rate variability (HRV) features for recognizing congestive heart failure (CHF) based on mutual information (MI). The MI-based greedy feature selection approach proposed by Battiti was adopted in the study. The mutual information conditioned by the first selected feature was used as a criterion for feature selection. The uniform distribution assumption was used to reduce the computational load. And, a logarithmic exponent weighting was added to model the relative importance of the MI with respect to the number of the already-selected features. The CHF recognition system contained a feature extractor that generated four categories, totally 50, features from the input HRV sequences. The proposed feature selector, termed UCMIFS, proceeded to select the most effective features for the succeeding support vector machine (SVM) classifier. Prior to feature selection, the 50 features produced a high accuracy of 96.38%, which confirmed the representativeness of the original feature set. The performance of the UCMIFS selector was demonstrated to be superior to the other MI-based feature selectors including MIFS-U, CMIFS, and mRMR. When compared to the other outstanding selectors published in the literature, the proposed UCMIFS outperformed them with as high as 97.59% accuracy in recognizing CHF using only 15 features. The results demonstrated the advantage of using the recruited features in characterizing HRV sequences for CHF recognition. The UCMIFS selector further improved the efficiency of the recognition system with substantially lowered feature dimensions and elevated recognition rate. PMID- 22261216 TI - External validity reporting in behavioral treatment of childhood obesity: a systematic review. AB - CONTEXT: To aid translation of childhood obesity interventions evidence into practice, research studies must report results in a way that better supports pragmatic decision making. The current review evaluated the extent to which information on key external validity dimensions, participants, settings, interventions, outcomes, and maintenance of effects, was included in research studies on behavioral treatments for childhood obesity. EVIDENCE ACQUISITION: Peer-reviewed studies of behavioral childhood obesity treatments published between 1980 and 2008 were identified from (1) electronic searches of social science and medical databases; (2) research reviews of childhood obesity interventions; and (3) reference lists cited in these reviews. Included studies reported on a controlled obesity intervention trial, targeted overweight or obese children aged 2-18 years, included a primary or secondary anthropometric outcome, and targeted change in dietary intake or physical activity behaviors. EVIDENCE SYNTHESIS: 1071 publications were identified and 77 met selection criteria. Studies were coded on established review criteria for external validity elements. All studies lacked full reporting of generalizability elements. Across criteria, the average reporting was 23.9% (range=0%-100%). Infrequently reported were setting-level selection criteria and representativeness, characteristics regarding intervention staff, implementation of the intervention content, costs, and program sustainability. CONCLUSIONS: Enhanced reporting of relevant and pragmatic information in behavioral investigations of childhood obesity interventions is needed to improve the ability to evaluate the applicability of results to practice implementation. Such evidence would improve translation of research to practice, provide additional explanation for variability in intervention outcomes, and provide insights into successful adaptations of interventions to local conditions. PMID- 22261218 TI - Present and future horizons for transdisciplinary research. PMID- 22261217 TI - Assessing the built environment using omnidirectional imagery. AB - Observational audits commonly are used in public health research to collect data on built environment characteristics that affect health-related behaviors and outcomes, including physical activity and weight status. However, implementing in person field audits can be expensive if observations are needed over large or geographically dispersed areas or at multiple points in time. A reliable and more efficient method for observational audits could facilitate extendibility (i.e., expanded geographic and temporal scope) and lead to more standardized assessment that strengthens the ability to compare results across different regions and studies. The purpose of the current study was to evaluate the degree of agreement between field audits and audits derived from interpretation of three types of omnidirectional imagery. Street segments from St. Louis MO and Indianapolis IN were stratified geographically to ensure representation of neighborhoods with different socioeconomic characteristics in both cities. Audits were conducted in 2008 and 2009 using four methods: field audits, and interpretation of archived imagery, new imagery, and Google Street ViewTM imagery. Agreement between field audits and image-based audits was assessed using observed agreement and the prevalence-adjusted bias-adjusted kappa statistic (PABAK). Data analysis was conducted in 2010. When measuring the agreement between field audits and audits from the different sources of imagery, the mean PABAK statistic for all items on the instrument was 0.78 (archived); 0.80 (new); and 0.81 (Street View imagery), indicating substantial to nearly perfect agreement among methods. It was determined that image-based audits represent a reliable method that can be used in place of field audits to measure several key characteristics of the built environment important to public health research. PMID- 22261220 TI - A review of thresholding strategies applied to human chromosome segmentation. AB - Karyotype analysis is a widespread procedure in cytogenetics to assess the presence of genetic defects by the visualization of the structure of chromosomes. The procedure is lengthy and repetitive and an effective automatic analysis would greatly help the cytogeneticist routine work. Still, automatic segmentation and the full disentangling of chromosomes are open issues. The first step in every automatic procedure is the thresholding step, which detect blobs that represent either single chromosomes or clusters of chromosomes. The better the thresholding step, the easier is the subsequent disentanglement of chromosome clusters into single entities. We implemented eleven thresholding methods, i.e. the ones that appear in the literature as the best performers, and compared their performance in segmenting chromosomes and chromosome clusters in cytogenetic Q-band images. The images are affected by the presence of hyper- or hypo-fluorescent regions and by a contrast variability between the stained chromosomes and the background. A thorough analysis of the results highlights that, although every single algorithm shows peculiar strong/weak points, Adaptive Threshold and Region Based Level Set have the overall best performance. In order to provide the scientific community with a public dataset, the data and manual segmentation used in this paper are available for public download at http://bioimlab.dei.unipd.it. PMID- 22261221 TI - Effect of polar interactions on the nonlinear behavior of phenol and aniline in reversed phase liquid chromatography. AB - The effect of the coverage density and the activity of the unreacted silanol groups of the non-endcapped octadecyl bonded phase on the adsorption properties were investigated. The adsorption of two polar low molecular weight compounds with weak acidic (phenol) and with basic (aniline) character was measured. Adsorption data were acquired by frontal analysis from methanol-water and acetonitrile-water solutions to investigate the influence of the type of the organic modifier on the solute retention mechanism and adsorption under non linear conditions. The adsorption behavior of phenol changes from Langmuir type (from aqueous mixture of methanol) to BET type (from aqueous mixture of acetonitrile). The adsorption of aniline becomes BET-type, regardless of the mobile phase composition in the tested range of the surface coverage of octadecyl ligands. The nature of the organic modifier significantly affects the retention mechanism and the shape of the overloaded elution bands of the studied compounds. PMID- 22261222 TI - Determination of pesticides by capillary chromatography and SERS detection using a novel Silver-Quantum dots "sponge" nanocomposite. AB - In this work the at-line capillary-liquid chromatography-(microdispenser)-surface enhanced Raman spectroscopy coupling was investigated and applied to the determination of pesticides. The use of a microdispenser combined with the use of a precise and reproducible surface enhanced Raman spectroscopy (SERS) substrate yielded a chromatographic detection system with excellent analytical properties. The microdispenser was coupled to a moving CaF2 hot (80 degrees C) plate using a flow-through microdispenser interface to collect the microdrops. Ag-QD nanocomposites, which are highly reproducible thanks to their sponge-shaped structure, were used as substrate with which to measure the SERS spectra in each spot of the plate. The limits of detection ranged from 0.2 to 0.5 ng of pesticide injected (chlortoluron, atrazine, diuron and terbuthylazine) and the precision ranged between 10.2 and 12.5%. PMID- 22261223 TI - Use of factorial design for the multivariate optimization of polypropylene membranes for the cleanup of environmental samples using the accelerated membrane assisted cleanup approach. AB - Accelerated membrane-assisted cleanup (AMAC) is a recently developed method to purify extracts from matrix rich samples such as fish tissue and sediments. In this study, we tested the applicability of cast polypropylene (CPP) membranes in AMAC and evaluated the optimized dialysis procedure for the cleanup of extracts of fish tissue. Design of experiments was used to optimize the factors temperature, solvents and static time of dialysis. Main factors influencing dialysis procedure were solvents and temperature as well as the number of cycles. For the CPP membrane the optimal parameters were a temperature of 55 degrees C, a solvent mixture of n-hexane:acetone (90:10, v:v), a static time of dialysis of 6 min and 20 dialysis cycles. Comparing to the LDPE membrane this was a reduction of dialysis time from 160 to 120 min, but a higher solvent use of 150 ml per sample. However, compared to LDPE membranes CPP exhibited a lower retention of fish tissue matrix and thus reduced cleanup efficiency. Compound specific structural descriptors such as the molecular weight, the van der Waals volume and a shape factor were calculated to explain differences in diffusivity of the different model compounds. We concluded that the permeation of the molecules was related to molecular shapes and the availability of free solvent cavities in the membranes. PMID- 22261224 TI - Development and application of high-performance liquid chromatography for the study of two new oxyprenylated anthraquinones produced by Rhamnus species. AB - Rhamnus spp. is known to contain biologically active anthraquinone secondary metabolites but the presence of oxyprenylated ones is not reported. To this aim, a new simple, and accurate analytical method was developed to reveal chemical fingerprint of these analytes in plant extracts. Plant samples were analysed after extraction with n-hexane (first step) and methanol (second step) using a C(18) column with a mobile phase composed of 35% of water:65% of methanol (both with 1% formic acid, v/v) at 0.7 mL min-1 flow rate in gradient elution mode. For quantitative analyses, selective detection was performed at 435 nm. The limit of quantification (LOQ) was 0.5 MUM, with the only exception of 3-geranyloxyemodin for which the LOQ value was 5.0 MUM, and external matrix-matched standard curves showed linearity up to 125 MUM. The within- and between-batch precision (RSD%) values ranged from 0.2% to 12.9% while within- and between-batch trueness (bias%) values ranged from 12.2% to 12.7%. The method was applied to evaluate for the first time the presence and the quantities of oxyprenylated anthraquinones in Rhamnus spp. barks as well as the anthraquinone profile of Rhamnus pumila Turra. The proposed method could be directly applied to the selective quantification of these analytes in natural sources. PMID- 22261225 TI - LC-MS/MS in clinical chemistry. PMID- 22261226 TI - Attentional set-shifting in fragile X syndrome. AB - The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the well-validated intra/extra dimensional set-shifting paradigm (IED) which offers detailed assessment of rule learning, reversal learning, and attentional set-shifting ability within and between stimulus dimensions. A novel scoring method for IED stage errors was employed to interpret set-shifting failure in terms of repetitive decision-making, distraction to irrelevance, and set-maintenance failure. Performance of FXS males was compared to typically developing children matched on mental age, adults matched on chronological age, and individuals with Down syndrome matched on both mental and chronological age. Results revealed that a significant proportion of FXS males already failed prior to the intra-dimensional set-shift stage, whereas all control participants successfully completed the stages up to the crucial extra dimensional set-shift. FXS males showed a specific weakness in reversal learning, which was characterized by repetitive decision-making during the reversal of newly acquired stimulus-response associations in the face of simple stimulus configurations. In contrast, when stimulus configurations became more complex, FXS males displayed increased distraction to irrelevant stimuli. These findings are interpreted in terms of the cognitive demands imposed by the stages of the IED in relation to the alleged neural deficits in FXS. PMID- 22261227 TI - Evidence for mental ability related individual differences in the attentional blink obtained by an analysis of the P300 component. AB - Attentional blink (AB) refers to impaired identification of a target (T2) when this target follows a preceding target (T1) after about 150-450 ms within a stream of rapidly presented stimuli. Previous research on a possible relation between AB and mental ability (MA) turned out to be highly ambiguous. The present study investigated MA-related individual differences in consolidation of T2 in working memory during the AB as indicated by the P300 component of the event related potential. Thirty high (HA) and 30 low MA (LA) female participants performed an AB task while their brain activity was recorded. The AB did not differ between the two groups. HA individuals exhibited a larger P300 amplitude and longer P300 latencies during the AB suggesting higher mental effort. This higher mental effort, however, did not result in better performance presumably because of more competition between target and distractor stimuli in HA than LA individuals. PMID- 22261228 TI - Insights into spared memory capacity in amnestic MCI and Alzheimer's Disease via minimal interference. AB - Impairment on standard tests of delayed recall is often already maximal in the aMCI stage of Alzheimer's Disease. Neuropathological work shows that the neural substrates of memory function continue to deteriorate throughout the progression of the disease, hinting that further changes in memory performance could be tracked by a more sensitive test of delayed recall. Recent work shows that retention in aMCI patients can be raised well above floor when the delay period is devoid of further material - 'Minimal Interference'. This memory enhancement is thought to be the result of improved memory consolidation. Here we used the minimal interference/interference paradigm (word list retention following 10 min of quiet resting vs. picture naming) in a group of 17 AD patients, 25 aMCI patients and 25 controls. We found (1) that retention can be improved significantly by minimal interference in patients with aMCI and patients with mild to moderate AD; (2) that the minimal interference paradigm is sensitive to decline in memory function with disease severity, even when performance on standard tests has reached floor; and (3) that this paradigm can differentiate well (80% sensitivity and 100% specificity) between aMCI patients who progress and do not progress to AD within 2 years. Our findings support the notion that the early memory dysfunction in AD is associated with an increased susceptibility to memory interference and are suggestive of a gradual decline in consolidation capacity with disease progression. PMID- 22261229 TI - A rare cryptic and complex rearrangement leading to MLL-MLLT10 gene fusion masked by del(10)(p12) in a child with acute monoblastic leukemia (AML-M5). PMID- 22261230 TI - The minimal residual disease concept coming of age - now for the direct comparison of methodologies. PMID- 22261231 TI - Outbreak of porcine epidemic diarrhea in suckling piglets, China. PMID- 22261233 TI - Basic fibroblast growth factor enhances the osteogenic differentiation induced by bone morphogenetic protein-6 in vitro and in vivo. AB - Some members of the bone morphogenetic protein subfamily (BMP-2 and -7) are currently used in orthopedic surgery for several applications. Although their use is considered safe at short term, the high doses of growth factors needed make these treatments expensive and their safety uncertain at long term. BMP-6 has been much less studied than BMP-2 and -7, but some authors suggest that this BMP might have a stronger osteogenic activity than the previously mentioned. Having in mind that angiogenesis plays a well-known role during bone formation, the aim of this work was to study the effect of combining BMP-6 with bFGF on both the growth and differentiation of MC3T3-E1 mouse preosteoblasts and rat bone marrow derived mesenchymal stem cells (MSCs), as well as on in vivo osteogenesis. We demonstrate that a low dose of bFGF enhances the osteogenic differentiation of MSCs induced by BMP-6 in vitro. Furthermore, we also demonstrate that bone formation in vivo induced by BMP-6 can be accelerated and enhanced by adding a low dose of bFGF, what might suggest a synergic effect between these growth factors on in vivo osteogenesis. PMID- 22261234 TI - Regulation of CD28 expression on umbilical cord blood and adult peripheral blood CD8+ T cells by interleukin(IL)-15/IL-21. AB - Interleukin (IL)-15 and IL-21, both belonging to common gamma-chain-signaling cytokine family, have an important role to maintain homeostatic proliferation of CD8(+) T cells. CD28, an essential co-stimulatory molecule on T cells, may be a marker of replicative senescence. We investigated the effect of IL-15 and IL-21, alone or in combination, on activation, apoptosis, cytokine production and cytotoxic function of magnetic bead purified umbilical cord blood (UCB) and adult peripheral blood (APB) CD8(+) T cells with regards to their CD28 expression. We established that (1) IL-15-induced CD8(+) T cell proliferation was associated with a preferential expansion of CD28(-) population in UCB, which could be partially counteracted by IL-21; (2) UCB CD8(+) T cells were more readily responsive to IL-15 compared to their adult counterparts in terms of CD69 expression, with the majority of CD69-bearing CD8(+) T cells were CD28(-); (3) IL 21 further promoted interferon-gamma, but not tumor necrosis factor-alpha production from IL-15 treated CD8(+) T cells; (4) IL-21 also synergized with IL 15 to enhance perforin and granzyme B expression of CD8(+) T cells, especially in APB CD8(+)CD28(-) subsets; (5) IL-21 resulted in CD8(+) T cells apoptosis both in APB and UCB cells, mainly in CD8(+)CD28(-) subsets. Taken together, we demonstrate differential IL-15/IL-21 response in UCB CD8(+) T cells with regards to CD28 expression. Our results suggest that combining IL-21 and IL-15 immunotherapy may be better than IL-15 alone to ameliorate graft-versus-host disease while preserving antitumor effect in the post-UCB transplantation period. PMID- 22261232 TI - Temporal regulation of gene expression of the Escherichia coli bacteriophage phiEco32. AB - Escherichia coli phage phiEco32 encodes two proteins that bind to host RNA polymerase (RNAP): gp79, a novel protein, and gp36, a distant homolog of sigma(70) family proteins. Here, we investigated the temporal pattern of phiEco32 and host gene expression during infection. Host transcription shutoff and three distinct bacteriophage temporal gene classes (early, middle, and late) were revealed. A combination of bioinformatic and biochemical approaches allowed identification of phage promoters recognized by a host RNAP holoenzyme containing the sigma(70) factor. These promoters are located upstream of early phage genes. A combination of macroarray data, primer extension, and in vitro transcription analyses allowed identification of six promoters recognized by an RNAP holoenzyme containing gp36. These promoters are characterized by a single-consensus element tAATGTAtA and are located upstream of the middle and late phage genes. Curiously, gp79, an inhibitor of host and early phage transcription by sigma(70) holoenzyme, activated transcription by the gp36 holoenzyme in vitro. PMID- 22261235 TI - Relationship between cytokine levels in serum and gingival crevicular fluid (GCF) in pregnant women. AB - BACKGROUND: Periodontal disease has been linked to systemic diseases/disorders and a low-grade systemic inflammatory status originated from periodontitis has been proposed as a possible explanation for this association. This study evaluates the relationship, early in pregnancy, between gingival crevicular fluid (GCF) and serum levels of a panel of cytokines that have been implicated in PTB and periodontal disease. METHODS: One hundred pregnant women aged 18-35 years old with a gestational age up to 20 weeks were included (mean+/-SD gestational age:16.1+/-3.5 weeks). Four periodontal sites per subject were randomly selected for GCF collection. Serum and GCF levels of IL-1beta, IL-6, IL-8, IL-10, IL-12p70 and TNF-alpha were analyzed using a cytometric bead array. Regression and correlation analyses were used to assess the relationship between serum and GCF cytokine levels. RESULTS: Participants had widespread periodontal inflammation but limited periodontal destruction. Cytokine levels were significantly higher in GCF than serum for all cytokines but IL-10. GCF levels had small but significant effect on serum levels for IL-10 (beta=0.34+/-0.09, p<0.01), IL-12p70 (beta=0.48+/-0.08, p<0.01) and TNF-alpha (beta=0.29+/-0.09, p<0.01). Periodontal probing depth and bleeding on probing were significantly associated with GCF levels for IL-1beta, IL-6 and IL-8; however, they had negligible effect on serum cytokine levels. Correlation between GCF and serum levels was non-significant, except for IL-12p70, which showed a significant but small correlation between the two sources (r=0.32, p=0.001). CONCLUSIONS: GCF cytokine levels were not strongly associated with serum cytokine levels in pregnant women with widespread periodontal inflammation but limited periodontal destruction. PMID- 22261236 TI - Retention of clinical trial participants in a study of nongonococcal urethritis (NGU), a sexually transmitted infection in men. AB - Nongonococcal urethritis (NGU), an inflammation of the urethra not caused by gonorrhea, is the most common urethritis syndrome seen in men in the United States. It is a sexually transmitted infection commonly caused by Chlamydia trachomatis, a pathogen which occurs more frequently in African-American men compared to white men. The purpose of this study was to investigate factors related to retention of study participants in a randomized, double-blinded clinical trial that evaluated four treatment regimens for the treatment of NGU. After the one-week treatment period, follow-up visits were scheduled during days 15-19 and days 35-45. Participants were phoned prior to scheduled appointments to encourage attendance, and contacted after missed appointments to reschedule their clinic visits. Of the 305 male study participants, 298 (98%) were African American, 164 (54%) were 25 years of age or younger, and 80 (31%) had a post secondary school education. The overall retention rate was 75%. Factors associated with study completion were educational level attained and clinical center. Participants with higher levels of education were more likely to complete the study. Clinical centers with the highest retention rates also provided the highest monetary incentives for participation. The retention rate for this study suggests that strategies are needed for improving the proportion of study participants that complete a clinical trial among young men with a sexually transmitted disease. These strategies may include increasing contacts with study participants to remind them of scheduled study visits using text messaging or social media and the use of financial incentives.